PMID- 27756690 TI - Risk of defeats in the central nervous system during deep space missions. AB - Space flight factors (SFF) significantly affect the operating activity of astronauts during deep space missions. Gravitational overloads, hypo-magnetic field and ionizing radiation are the main SFF that perturb the normal activity of the central nervous system (CNS). Acute and chronic CNS risks include alterations in cognitive abilities, reduction of motor functions and behavioural changes. Multiple experimental works have been devoted to the SFF effects on integrative functional activity of the brain; however, the model parameters utilized have not always been ideal and consistent. Even less is known regarding the combined effects of these SFF in a real interplanetary mission, for example to Mars. Our review aims to systemize and analyse the last advancements in astrobiology, with a focus on the combined effects of SFF; as well as to discuss on unification of the parameters for ground-based models of deep space missions. PMID- 27756691 TI - Endocannabinoids and sleep. AB - Sleep is regulated by several brain structures, neurotransmitters and neuromodulators. Endocannabinoids (eCBs) are a group of lipids with modulatory activity in the brain and bind mainly to cannabinoid receptors CB1R and CB2R, thereby modulating several brain functions, (memory, mood, food intake, pain perception). Oleoylethanolamide and palmitoylethanolamide belong to the N acylethanolamides (NAEs) family, another type of active endogenous lipids. They bind to the peroxisome proliferator-activated receptor alpha but not to CB1R, thereby modulating food satiety, inflammation and pain. Both eCBs and NAEs seem to be regulating the sleep-wake cycle. Our objective is to analyze the experimental evidence published in the literature and to discuss if eCBs and NAEs are actually sleep modulators. Studies suggested 1. eCBs and NAEs are under circadian control. 2. NAEs promote wake. 3. eCBs promote non-rapid-eye movement. 4. eCBs also promote rapid-eye-movement sleep by interacting with melanin concentrating hormone neurons in the lateral hypothalamus. 5. The pharmacological blockade of the CB1R reduces sleep while increasing wake. 6. eCBs restore sleep in a model of insomnia in rats. PMID- 27756692 TI - Review of the photo-induced toxicity of environmental contaminants. AB - Solar radiation is a vital component of ecosystem function. However, sunlight can also interact with certain xenobiotic compounds in a phenomenon known as photo induced, photo-enhanced, photo-activated, or photo-toxicity. This phenomenon broadly refers to an interaction between a chemical and sunlight resulting in increased toxicity. Because most aquatic ecosystems receive some amount of sunlight, co-exposure to xenobiotic chemicals and solar radiation is likely to occur in the environment, and photo-induced toxicity may be an important factor impacting aquatic ecosystems. However, photo-induced toxicity is not likely to be relevant in all aquatic systems or exposure scenarios due to variation in important ecological factors as well as physiological adaptations of the species that reside there. Here, we provide an updated review of the state of the science of photo-induced toxicity in aquatic ecosystems. PMID- 27756693 TI - It's all in the type of the task: Dopamine modulates kinematic patterns during competitive vs. cooperative interaction in Parkinson's disease. AB - Increasing evidence suggests that a dysfunctional dopaminergic system affects the ability to socially interact. Since Parkinson's disease (PD) provides a model for assessing dopaminergic dysfunctions in humans, our study was designed to investigate social interactions in PD patients receiving dopamine replacement therapy (Levodopa=l-Dopa) and in neurologically healthy controls. We focused on the kinematics of one action, reaching to grasp a wooden block, which was performed within the context of two basic modes of social cognition, namely cooperation and competition. During the cooperative tasks, two participants were instructed to reach and grasp their respective objects and to cooperate in forming a specific configuration on the working table. During the competitive tasks, two participants were instructed to compete to place their own object at the bottom of a tower to be built on the working table. PD patients' ability to modulate motor patterning depending on the intention motivating the action they were about to perform was evaluated in both "on" (with l-Dopa) and "off" (without l-Dopa) states. Study results revealed that both the healthy controls and the 'on' PD patients had distinct kinematic patterns for cooperative and competitive actions and that these differed from patterns mirroring similar actions performed by those same participants in non social conditions. The kinematic patterns of the healthy controls and the 'on' patients were highly correlated during the cooperative tasks. The 'off' PD patients were, instead, unable to differentiate between isolated and social conditions. These results support the hypothesis that dopaminergic neurotransmission is involved in shaping the mechanisms underlying social interactions. PMID- 27756694 TI - The neural bases of hemispheric specialization. PMID- 27756695 TI - Enhanced working memory performance via transcranial direct current stimulation: The possibility of near and far transfer. AB - Although working memory (WM) training programs consistently result in improvement on the trained task, benefit is typically short-lived and extends only to tasks very similar to the trained task (i.e., near transfer). It is possible that pairing repeated performance of a WM task with brain stimulation encourages plasticity in brain networks involved in WM task performance, thereby improving the training benefit. In the current study, transcranial direct current stimulation (tDCS) was paired with performance of a WM task (n-back). In Experiment 1, participants performed a spatial location-monitoring n-back during stimulation, while Experiment 2 used a verbal identity-monitoring n-back. In each experiment, participants received either active (2.0mA) or sham (0.1mA) stimulation with the anode placed over either the right or the left dorsolateral prefrontal cortex (DLPFC) and the cathode placed extracephalically. In Experiment 1, only participants receiving active stimulation with the anode placed over the right DLPFC showed marginal improvement on the trained spatial n-back, which did not extend to a near transfer (verbal n-back) or far transfer task (a matrix reasoning task designed to measure fluid intelligence). In Experiment 2, both left and right anode placements led to improvement, and right DLPFC stimulation resulted in numerical (though not sham-adjusted) improvement on the near transfer (spatial n-back) and far transfer (fluid intelligence) task. Results suggest that WM training paired with brain stimulation may result in cognitive enhancement that transfers to performance on other tasks, depending on the combination of training task and tDCS parameters used. PMID- 27756696 TI - Preferential coding of eye/hand motor actions in the human ventral occipito temporal cortex. AB - The human ventral occipito-temporal cortex (OTC) contains areas specialized for particular perceptual/semantic categories, such as faces (fusiform face area, FFA) and places (parahippocampal place area, PPA). This organization has been interpreted as reflecting the visual structure of the world, i.e. perceptual similarity and/or eccentricity biases. However, recent functional magnetic resonance imaging (fMRI) studies have shown not only that regions of the OTC are modulated by non-visual, action-related object properties but also by motor planning and execution, although the functional role and specificity of this motor-related activity are still unclear. Here, through a reanalysis of previously published data, we tested whether the selectivity for perceptual/semantic categories in the OTC corresponds to a preference for particular motor actions. The results demonstrate for the first time that face- and place-selective regions of the OTC exhibit preferential BOLD response to the execution of hand pointing and saccadic eye movements, respectively. Moreover, multivariate analyses provide novel evidence for the consistency across neural representations of stimulus category and movement effector in OTC. According to a 'spatial hypothesis', this pattern of results originates from the match between the region eccentricity bias and the typical action space of the motor effectors. Alternatively, the double dissociation may be caused by the different effect produced by hand vs. eye movements on regions coding for body representation. Overall, the present findings offer novel insights on the coupling between visual and motor cortical representations. PMID- 27756697 TI - Controlling joint instability delays the degeneration of articular cartilage in a rat model. AB - OBJECTIVE: Joint instability induced by anterior cruciate ligament (ACL) transection is commonly considered as a predisposing factor for osteoarthritis (OA) of the knee; however, the influence of re-stabilization on the protection of articular cartilage is unclear. The aim of this study was to evaluate the effect of joint re-stabilization on articular cartilage using an instability and re stabilization ACL transection model. DESIGN: To induce different models of joint instability, our laboratory created a controlled abnormal joint movement (CAJM) group and an anterior cruciate ligament transection group (ACL-T). Seventy-five Wistar male rats were randomly assigned to the CAJM (n = 30), ACL-T (n = 30), or no treatment (INTACT) group (n = 15). Cartilage changes were assessed with soft X ray analysis, histological and immunohistochemistry analysis, and real-time polymerase chain reaction (PCR) analysis at 2, 4, and 12 weeks. RESULTS: Joint instability, as indicated by the difference in anterior displacement between the CAJM and ACL-T groups (P < 0.001), and cartilage degeneration, as evaluated according to the Osteoarthritis Research Society International (OARSI) score, were significantly higher in the ACL-T group than the CAJM group at 12 weeks (P < 0.001). Moreover, joint re-stabilization maintained cartilage structure (thickness [P < 0.001], surface roughness [P < 0.001], and glycosaminoglycan stainability [P < 0.001]) and suppressed tumor necrosis factor-alpha (TNF-alpha) and caspase-3 at 4 weeks after surgery. CONCLUSION: Re-stabilization of joint instability may suppress inflammatory cytokines, thereby delaying the progression of OA. Joint instability is a substantial contributor to cartilage degeneration. PMID- 27756699 TI - Individual differences in context-dependent effects reveal common mechanisms underlying the direction aftereffect and direction repulsion. AB - Both spatial and temporal context influence our perception of visual stimuli. For instance, both nearby moving stimuli and recently viewed motion can lead to biases in the perceived direction of a moving stimulus. Due to similarities in the spatial tuning properties of these spatial and temporal context-dependent effects, it is often assumed that they share a functional goal in motion processing and arise from common neural mechanisms. However, the psychophysical evidence concerning this assumption is inconsistent. Here we used an individual differences approach to examine the relationship between different effects of contextual modulation on perception. We reasoned that if measures of contextual modulation share a common underlying mechanism, they should exhibit a strong positive correlation across participants. To test this hypothesis, estimates of the direction aftereffect, direction repulsion, the tilt aftereffect and contrast adaptation were obtained from 54 healthy participants. Our results show pronounced interindividual differences in the effect sizes of all four tasks. Furthermore, there was a strong positive correlation between the estimates of the direction aftereffect and direction repulsion. This correlation was also evident in the threshold elevations that accompanied these repulsive biases in perceived direction. While the effects of contrast adaptation did not correlate with any of the other tasks, there was a weak, but non-significant, correlation between the direction and tilt aftereffects. These results provide evidence for common mechanisms underlying the direction aftereffect and direction repulsion. PMID- 27756698 TI - A study of acute and chronic tissue changes in surgical and traumatically-induced experimental models of knee joint injury using magnetic resonance imaging and micro-computed tomography. AB - OBJECTIVE: The objective of this study was to monitor the progression of joint damage in two animal models of knee joint trauma using two non-invasive, clinically available imaging modalities. METHODS: A 3-T clinical magnet and micro computed tomography (MUCT) was used to document changes immediately following injury (acute) and post-injury (chronic) at time points of 4, 8, or 12 weeks. Joint damage was recorded at dissection and compared to the chronic magnetic resonance imaging (MRI) record. Fifteen Flemish Giant rabbits were subjected to a single tibiofemoral compressive impact (ACLF), and 18 underwent a combination of anterior cruciate ligament (ACL) and meniscal transection (mACLT). RESULTS: All ACLF animals experienced ACL rupture, and 13 also experienced acute meniscal damage. All ACLF and mACLT animals showed meniscal and articular cartilage damages at dissection. Meniscal damage was documented as early as 4 weeks and worsened in 87% of the ACLF animals and 71% of the mACLT animals. Acute cartilage damage also developed further and increased in occurrence with time in both models. A progressive decrease in bone quantity and quality was documented in both models. The MRI data closely aligned with dissection notes suggesting this clinical tool may be a non-invasive method for documenting joint damage in lapine models of knee joint trauma. CONCLUSIONS: The study investigates the acute to chronic progression of meniscal and cartilage damage at various time points, and chronic changes to the underlying bone in two models of posttraumatic osteoarthritis (PTOA), and highlights the dependency of the model on the location, type, and progression of damage over time. PMID- 27756700 TI - Individual differences in sensory eye dominance reflected in the dynamics of binocular rivalry. AB - Normal binocular vision emerges from the combination of neural signals arising within separate monocular pathways. It is natural to wonder whether both eyes contribute equally to the unified cyclopean impression we ordinarily experience. Binocular rivalry, which occurs when the inputs to the two eyes are markedly different, affords a useful means for quantifying the balance of influence exerted by the eyes (called sensory eye dominance, SED) and for relating that degree of balance to other aspects of binocular visual function. However, the precise ways in which binocular rivalry dynamics change when the eyes are unbalanced remain uncharted. Relying on widespread individual variability in the relative predominance of the two eyes as demonstrated in previous studies, we found that an observer's overall tendency to see one eye more than the other was driven both by differences in the relative duration and frequency of instances of that eye's perceptual dominance. Specifically, larger imbalances between the eyes were associated with longer and more frequent periods of exclusive dominance for the stronger eye. Increases in occurrences of dominant eye percepts were mediated in part by a tendency to experience "return transitions" to the predominant eye - that is, observers often experienced sequential exclusive percepts of the dominant eye's image with an intervening mixed percept. Together, these results indicate that the often-observed imbalances between the eyes during binocular rivalry reflect true differences in sensory processing, a finding that has implications for our understanding of the mechanisms underlying binocular vision in general. PMID- 27756701 TI - Tonic accommodation predicts closed-loop accommodation responses. AB - The purpose of this study is to examine the potential relationship between tonic accommodation (TA), near work induced TA-adaptation and the steady state closed loop accommodation response (AR). Forty-two graduate students participated in the study. Various aspects of their accommodation system were objectively measured using an open-field infrared auto-refractor (Grand Seiko WAM-5500). Tonic accommodation was assessed in a completely dark environment. The association between TA and closed-loop AR was assessed using linear regression correlations and t-test comparisons. Initial mean baseline TA was 1.84diopter (D) (SD+/-1.29D) with a wide distribution range (-0.43D to 5.14D). For monocular visual tasks, baseline TA was significantly correlated with the closed-loop AR. The slope of the best fit line indicated that closed-loop AR varied by approximately 0.3D for every 1D change in TA. This ratio was consistent across a variety of viewing distances and different near work tasks, including both static targets and continuous reading. Binocular reading conditions weakened the correlation between baseline TA and AR, although results remained statistically significant. The 10min near reading task with a 3D demand did not reveal significant near work induced TA-adaptation for either monocular or binocular conditions. Consistently, the TA-adaptation did not show any correlation with AR during reading. This study found a strong association between open-loop TA and closed-loop AR across a variety of viewing distances and different near work tasks. Difference between the correlations under monocular and binocular reading condition suggests a potential role for vergence compensation during binocular closed-loop AR. PMID- 27756702 TI - RIFM fragrance ingredient safety assessment, isobornyl propionate, CAS Registry Number 2756-56-1. PMID- 27756703 TI - RIFM fragrance ingredient safety assessment, 1-(3,3-dimethylcyclohexyl)pent-4-en 1-one, CAS Registry Number 56973-87-6. PMID- 27756704 TI - Dietary exposure of the Italian population to inorganic arsenic: The 2012-2014 Total Diet Study. AB - Dietary exposure of the Italian population to inorganic arsenic has been assessed in the national Total Diet Study (TDS) carried out in 2012-2014. Within the TDS, food samples (>3000) were collected to be representative of the whole diet of the population, prepared as consumed, and pooled into 51 food groups, thus modelling the Italian diet. Inorganic arsenic was determined by HPLC-ICP-MS after chemical extraction and quantified in all samples. Occurrence data were combined with national individual consumption data to estimate mean and high level dietary exposure of the general population and of population subgroups according to age and gender, both at the national level and for each of the four main geographical areas of Italy. The intakes assessed are in the lower range of iAs exposure estimates in other European countries carried out without the support of the TDS approach. However, taking the lower limit of the BMDL01 range established by the EFSA as reference point, the margins of exposure are <2 for the mean intake in infants and toddlers and <1 for the 95th percentile intakes in all younger age groups. Our results indicate the goal to check and further reduce the dietary exposure to inorganic arsenic. PMID- 27756705 TI - Risk factors for complications in the implantation of epicardial pacemakers in neonates and infants. AB - BACKGROUND: Complications related to epicardial pacemakers in infants have been reported, though limited data are available on their incidence and associated risk factors. OBJECTIVE: The hypothesis of the study is that younger, smaller patients and larger devices would be associated with complications in neonates and infants. METHODS: This is a retrospective study of all patients at a single center receiving an epicardial pacemaker at <=12 months of age (1996-2015). Patient and device characteristics were obtained. Characteristics of patients with and without complications were compared. RESULTS: There were 86 patients with a median age of 73 days (interquartile range 13-166 days), of whom 12 (14%) had a complication. Eight (9%) needed surgical intervention, of whom 5 (6%) required explantation. Younger age (9 days vs 89 days; P = .01) and lower weight (2.91 kg vs 4.44 kg; P = .004) at implantation were associated with complications. Device characteristics were not statistically different. Patients <=3 kg in weight and/or <5 days of age had an odds ratio of 18.1 (3.6-91.2; P < .001) for developing a complication with a negative predictive value (NPV) of 97%. Regardless of weight, patients aged >21 days were found to be at lower risk with an NPV of 96%; and regardless of age, patients weighing >4 kg had an NPV of 98%. CONCLUSION: Young age and low weight at the time of implantation are risk factors for complications, while device characteristics appear to play a minor role. Reserving pacemaker implantation for patients >3 kg in weight and 5 days of age may predict patients at low risk of developing complications. PMID- 27756706 TI - The Swiss approach for a heartbeat-driven lead- and batteryless pacemaker. PMID- 27756707 TI - Unique cardiomyocyte ultrastructure in atria: Role of T tubules in subcellular Ca2+ signaling and atrial arrhythmogenesis. PMID- 27756708 TI - A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia. AB - BACKGROUND: Ventricular fibrillation may be caused by premature ventricular contractions (PVCs) whose coupling intervals are <300 ms, a characteristic of the short-coupled variant of torsades de pointes (scTdP). OBJECTIVE: The purpose of this study was to analyze the underlying cardiac ryanodine receptor (RyR2) variants in patients with scTdP. METHODS: Seven patients with scTdP (mean age 34 +/- 12 years; 4 men and 3 women) were enrolled in this study. The RyR2 gene was screened by targeted gene sequencing methods; variant minor allele frequency was confirmed in 3 databases; and the pathogenicity was investigated in silico analysis using multiple tools. The activity of wild-type and mutant RyR2 channels was evaluated by monitoring Ca2+ signals of HEK293 cells with a [3H]ryanodine binding assay. RESULTS: The mean coupling interval of PVCs was 282 +/- 13 ms. The 12-lead electrocardiogram had no specific findings except PVCs with an extremely short-coupling interval. Genetic analysis revealed 3 novel RyR2 variants and 1 polymorphism, all located in the cytoplasmic region. p.Ser4938Phe was not detected in 3 databases, and in silico analysis indicated its pathogenicity. In functional analysis, p.Ser4938Phe demonstrated loss of function and impaired RyR2 channel Ca2+ release, while 2 other variants, p.Val1024Ile and p.Ala2673Val, had mild gain-of-function effects but were similar to the polymorphism p.Asn1551Ser. CONCLUSION: We identified an RyR2 variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia. The mechanisms of arrhythmogenesis remain unclear. PMID- 27756709 TI - Gain-of-function mutations in GATA6 lead to atrial fibrillation. AB - BACKGROUND: The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood. OBJECTIVE: We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects. METHODS: We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early onset AF was prominent in the family, we then screened individuals with early onset AF, defined as an age of onset <66 years, for mutations in GATA6. Variants were functionally characterized using reporter assays in a mammalian cell line. RESULTS: Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6. In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 +/- 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P < .0001; P91S: 2.5-fold, P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity. CONCLUSION: Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early onset AF. PMID- 27756710 TI - Is Ureaplasma spp. the leading causative agent of acute chorioamnionitis in women with preterm birth? AB - OBJECTIVES: Aim of this study was to detect microorganisms in fetal membranes and placental tissue in preterm chorioamnionitis by combining fluorescence in situ hybridization (FISH) with broad range PCR. The combination of the two molecular techniques enables identification and localization of the microorganisms within the tissue, confirming their clinical relevance. METHODS: In a prospective cohort study, we compared 31 women with preterm premature rupture of membranes or preterm labour and preterm delivery by caesarean section with a control group of 26 women undergoing elective caesarean section at term. Fetal membranes and placental tissue were analysed by FISH and broad range 16S rRNA-gene PCR and sequencing. RESULTS: For 20 women in the preterm group, caesarean section was performed because of a clinical diagnosis of chorioamnionitis. Microorganisms were detected in the tissues by both molecular techniques in 11 out of 20 women. Among those, Ureaplasma spp. was most abundant, with five cases that remained culture-negative and would have been missed by routine diagnostic procedures. Other infections were caused by Staphylococcus aureus, Streptococcus mitis or Escherichia coli. FISH and PCR were negative for all women without suspected chorioamnionitis and for the control group. CONCLUSIONS: Combination of FISH with broad-range PCR and sequencing permitted unambiguous identification of the causative microorganisms in chorioamnionitis. The high prevalence of Ureaplasma spp. should lead to a re-evaluation of its clinical significance and possible therapeutic consequences. PMID- 27756711 TI - Imipenem heteroresistance in nontypeable Haemophilus influenzae is linked to a combination of altered PBP3, slow drug influx and direct efflux regulation. AB - OBJECTIVE: To investigate the potential roles of PBPs, efflux pumps and slow drug influx for imipenem heteroresistance in nontypeable Haemophilus influenzae (NTHi). METHODS: Fifty-nine NTHi clinical isolates examined in this study were collected at Geneva University Hospitals between 2009 and 2014. Alterations in PBPs were investigated by gene sequencing. To evaluate the affinities of the PBPs to imipenem, steady-state concentration-response experiments were carried out using imipenem in a competition assay with Bocillin-FL. The effect of the carbonyl cyanide m-chlorophenylhydrazone (CCCP) on imipenem susceptibility was assessed using broth dilution and viable cell counting. Using whole-genome sequencing, we explored the potential roles of outer membrane protein P2 (OmpP2), LytM proteins and the dcw gene cluster in imipenem heteroresistance. RESULTS: All 46 imipenem-heteroresistant isolates (IMIhR) harboured amino acid substitutions in the ftsI gene, which encodes PBP3, corresponding to 25 different mutation patterns that varied from the ftsI gene mutation patterns found in imipenem susceptible isolates. Among all PBPs, the highest affinity to imipenem was documented for PBP3 (IC50, 0.004 MUg/mL). Different amino acid substitutions and insertions were noted in OmpP2, suggesting a relationship with imipenem heteroresistance. The IMIhR isolates were affected by CCCP differently and displayed a higher percentage of killing by imipenem in CCCP-treated cells at concentrations ranging between 0.5 and 8 MUg/mL. CONCLUSIONS: The present study provides robust evidence indicating that in combination with the altered PBP3, the slowed drug influx and its enhanced efflux due to the loss of regulation led to the development of imipenem heteroresistance in NTHi. PMID- 27756712 TI - Clinical management of adults and children with multidrug-resistant and extensively drug-resistant tuberculosis. AB - BACKGROUND: Globally there is a burgeoning epidemic of drug monoresistant tuberculosis (TB), multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Almost 20% of all TB strains worldwide are resistant to at least one major TB drug, including isoniazid. In several parts of the world there is an increasing incidence of MDR-TB, and alarmingly, almost a third of MDR-TB cases globally are resistant to either a fluoroquinolone or aminoglycoside. This trend cannot be ignored because drug-resistant TB is associated with greater morbidity compared to drug-susceptible TB, accounts for almost 25% of global TB mortality, is extremely costly to treat, consumes substantial portions of budgets allocated to national TB programmes in TB-endemic countries and is a major threat to healthcare workers, who are already in short supply in resource-poor settings. Even more worrying is the growing epidemic of resistance beyond XDR-TB, including resistance to newer drugs such as bedaquiline and delamanid, as well as the increasing prevalence of programmatically incurable TB in countries like South Africa, Russia, India and China. These developments threaten to reverse the gains already made against TB. SOURCES: Articles related to MDR-TB and XDR-TB found on PubMed in all languages up to September 2016, published reviews, and files of the authors. AIM AND CONTENT: To review the clinical management of adults and children with MDR- and XDR-TB with a particular emphasis on the utility of newer and repurposed drugs such as linezolid, bedaquiline and delamanid, as well as management of MDR- and XDR-TB in special situations such as in HIV-infected persons and in children. IMPLICATIONS: This review informs on the prevention, diagnosis, and clinical management of MDR-TB and XDR-TB. PMID- 27756713 TI - Low and disparate seroprotection after pentavalent childhood vaccination in the Lao People's Democratic Republic: a cross-sectional study. AB - OBJECTIVE: In Lao People's Democratic Republic, the high burden of vaccine preventable diseases is thought to be mainly due to low vaccine coverage. We investigated the seroprotective response against diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HepB-Hib) vaccine in children. METHODS: Serum was collected from 1131 children aged 9 to 50 months and their mothers in a cross-sectional study between December 2013 and July 2014. All children had records of three injections of the DTPw-HepB-Hib vaccine. Serum was analysed for hepatitis B surface antigen (HBsAg), anti-HBsAg (anti-HBs), anti hepatitis B virus core antigen (anti-HBc), anti-diphtheria and anti-tetanus antibodies. Stool samples were collected for detection of parasites. Demographic and nutritional information were also obtained. RESULTS: Protective levels of anti-HBs antibodies were found in 394 (37.9%) of 1039 children; 529 (55.7%) of 950 and 809 (85.2%) of 950 children were seroprotected against diphtheria and tetanus. Time since vaccination, age, home birth and malnutrition only partially explained the poor vaccine responses. Overall, 81 (7.8%) of 1039 children and 445 (40.3%) of 1105 of mothers were anti-HBc positive. Ten (1.0%) of 1039 of the children and 77 (7.0%) of 1105 of the mothers were HBsAg carriers. CONCLUSIONS: After a full documented course of vaccination, seroprotective rates were unusually low and disparate against components of the pentavalent vaccine. These can only partially be explained by the negative predictors identified. Although many children had been infected, only few were chronic carriers of HBsAg. Our study demonstrates an urgent need to monitor the serologic response to vaccination, particularly in resource-poor countries. PMID- 27756714 TI - Multidetector CT appearance of the pelvis after cesarean delivery: normal and abnormal acute findings. AB - Cesarean section (CS) may have several acute complications that can occur in the early postoperative period. The most common acute complications are hematomas and hemorrhage, infection, ovarian vein thrombosis, uterine dehiscence and rupture. Pelvic hematomas usually occur at specific sites and include bladder flap hematoma (between the lower uterine segment and the bladder) and subfascial or rectus sheath hematoma (rectus sheath or prevescical space). Puerperal hemorrhage can be associated with uterine dehiscence or rupture. Pelvic infections include endometritis, abscess, wound infection, and retained product of conception. Radiologists play an important role in the diagnosis and management of postoperative complications as a result of increasing use of multidetector CT in emergency room. The knowledge of normal and abnormal postsurgical anatomy and findings should facilitate the correct diagnosis so that the best management can be chosen for the patient, avoiding unnecessary surgical interventions and additional treatments. In this article we review the surgical cesarean technique and imaging CT technique followed by description of normal and abnormal post-CS CT findings. PMID- 27756715 TI - Lessons Learned From Methodological Validation Research in E-Epidemiology. AB - BACKGROUND: Traditional epidemiological research methods exhibit limitations leading to high logistics, human, and financial burden. The continued development of innovative digital tools has the potential to overcome many of the existing methodological issues. Nonetheless, Web-based studies remain relatively uncommon, partly due to persistent concerns about validity and generalizability. OBJECTIVE: The objective of this viewpoint is to summarize findings from methodological studies carried out in the NutriNet-Sante study, a French Web-based cohort study. METHODS: On the basis of the previous findings from the NutriNet-Sante e-cohort (>150,000 participants are currently included), we synthesized e-epidemiological knowledge on sample representativeness, advantageous recruitment strategies, and data quality. RESULTS: Overall, the reported findings support the usefulness of Web-based studies in overcoming common methodological deficiencies in epidemiological research, in particular with regard to data quality (eg, the concordance for body mass index [BMI] classification was 93%), reduced social desirability bias, and access to a wide range of participant profiles, including the hard-to-reach subgroups such as young (12.30% [15,118/122,912], <25 years) and old people (6.60% [8112/122,912], >=65 years), unemployed or homemaker (12.60% [15,487/122,912]), and low educated (38.50% [47,312/122,912]) people. However, some selection bias remained (78.00% (95,871/122,912) of the participants were women, and 61.50% (75,590/122,912) had postsecondary education), which is an inherent aspect of cohort study inclusion; other specific types of bias may also have occurred. CONCLUSIONS: Given the rapidly growing access to the Internet across social strata, the recruitment of participants with diverse socioeconomic profiles and health risk exposures was highly feasible. Continued efforts concerning the identification of specific biases in e-cohorts and the collection of comprehensive and valid data are still needed. This summary of methodological findings from the NutriNet-Sante cohort may help researchers in the development of the next generation of high-quality Web-based epidemiological studies. PMID- 27756716 TI - Strengthening Interprofessional Requirements Engineering Through Action Sheets: A Pilot Study. AB - BACKGROUND: The importance of information and communication technology for healthcare is steadily growing. Newly developed tools are addressing different user groups: physicians, other health care professionals, social workers, patients, and family members. Since often many different actors with different expertise and perspectives are involved in the development process it can be a challenge to integrate the user-reported requirements of those heterogeneous user groups. Nevertheless, the understanding and consideration of user requirements is the prerequisite of building a feasible technical solution. In the course of the presented project it proved to be difficult to gain clear action steps and priorities for the development process out of the primary requirements compilation. Even if a regular exchange between involved teams took place there was a lack of a common language. OBJECTIVE: The objective of this paper is to show how the already existing requirements catalog was subdivided into specific, prioritized, and coherent working packages and the cooperation of multiple interprofessional teams within one development project was reorganized at the same time. In the case presented, the manner of cooperation was reorganized and a new instrument called an Action Sheet was implemented. This paper introduces the newly developed methodology which was meant to smooth the development of a user centered software product and to restructure interprofessional cooperation. METHODS: There were 10 focus groups in which views of patients with colorectal cancer, physicians, and other health care professionals were collected in order to create a requirements catalog for developing a personal electronic health record. Data were audio- and videotaped, transcribed verbatim, and thematically analyzed. Afterwards, the requirements catalog was reorganized in the form of Action Sheets which supported the interprofessional cooperation referring to the development process of a personal electronic health record for the Rhine-Neckar region. RESULTS: In order to improve the interprofessional cooperation the idea arose to align the requirements arising from the implementation project with the method of software development applied by the technical development team. This was realized by restructuring the original requirements set in a standardized way and under continuous adjustment between both teams. As a result not only the way of displaying the user demands but also of interprofessional cooperation was steered in a new direction. CONCLUSIONS: User demands must be taken into account from the very beginning of the development process, but it is not always obvious how to bring them together with IT knowhow and knowledge of the contextual factors of the health care system. Action Sheets seem to be an effective tool for making the software development process more tangible and convertible for all connected disciplines. Furthermore, the working method turned out to support interprofessional ideas exchange. PMID- 27756717 TI - Moderate exercise cuts type 2 diabetes risk but more is better, review finds. PMID- 27756718 TI - Author's reply to Fisken. PMID- 27756719 TI - Influence of Maternal Gestational Hypertensive Disorders on Microvasculature in School-Age Children: The Generation R Study. AB - Gestational hypertensive disorders may lead to vascular changes in the offspring. We examined the associations of maternal blood pressure development and hypertensive disorders during pregnancy with microvasculature adaptations in the offspring in childhood. This study was performed as part of the Generation R Study in Rotterdam, the Netherlands (2002-2012), among 3,748 pregnant mothers and their children for whom information was available on maternal blood pressure in different periods of pregnancy and gestational hypertensive disorders. Childhood retinal arteriolar and venular calibers were assessed at the age of 6 years. We found that higher maternal systolic and diastolic blood pressures in early pregnancy were associated with childhood retinal arteriolar narrowing (P < 0.05). Higher maternal systolic blood pressure in late pregnancy, but not in middle pregnancy, was associated with childhood narrower retinal venular caliber (standard deviation score per standardized residual increase in systolic blood pressure: -0.05; 95% confidence interval: -0.08, -0.01). Paternal blood pressure was not associated with childhood retinal vessel calibers. Children of mothers with gestational hypertensive disorders tended to have narrower retinal arteriolar caliber (standard deviation score: -0.13, 95% confidence interval: 0.27, 0.01). Our results suggest that higher maternal blood pressure during pregnancy is associated with persistent microvasculature adaptations in their children. Further studies are needed to replicate these observations. PMID- 27756720 TI - Authors' reply to Hawkins. PMID- 27756721 TI - False discovery rates: a new deal. AB - We introduce a new Empirical Bayes approach for large-scale hypothesis testing, including estimating false discovery rates (FDRs), and effect sizes. This approach has two key differences from existing approaches to FDR analysis. First, it assumes that the distribution of the actual (unobserved) effects is unimodal, with a mode at 0. This "unimodal assumption" (UA), although natural in many contexts, is not usually incorporated into standard FDR analysis, and we demonstrate how incorporating it brings many benefits. Specifically, the UA facilitates efficient and robust computation-estimating the unimodal distribution involves solving a simple convex optimization problem-and enables more accurate inferences provided that it holds. Second, the method takes as its input two numbers for each test (an effect size estimate and corresponding standard error), rather than the one number usually used ($p$ value or $z$ score). When available, using two numbers instead of one helps account for variation in measurement precision across tests. It also facilitates estimation of effects, and unlike standard FDR methods, our approach provides interval estimates (credible regions) for each effect in addition to measures of significance. To provide a bridge between interval estimates and significance measures, we introduce the term "local false sign rate" to refer to the probability of getting the sign of an effect wrong and argue that it is a superior measure of significance than the local FDR because it is both more generally applicable and can be more robustly estimated. Our methods are implemented in an R package ashr available from http://github.com/stephens999/ashr. PMID- 27756722 TI - Tight foreskin. PMID- 27756723 TI - Outcomes of Hip Arthroscopy in the Older Adult: A Systematic Review of the Literature. AB - BACKGROUND: The indications for hip preservation surgery have expanded to include treatment of hip pathology in older adults. While several studies have examined the efficacy of hip arthroscopy in the setting of osteoarthritis, there has been no review of outcomes in older adults. PURPOSE: To review the outcomes of hip arthroscopy in older adults and identify factors associated with treatment failures. STUDY DESIGN: Systematic review. METHODS: PubMed, EMBASE, and the Cochrane Library were searched through March 2016 for studies reporting outcomes of primary hip arthroscopy in patients older than 40 years. Inclusion in the review was based on age, patient-reported outcome (PRO) measures, and duration of follow-up. Two authors screened the results and extracted data for use in this review. Standardized mean difference was calculated to estimate effect size for PRO scores within studies. RESULTS: Eight studies with 401 total patients undergoing hip arthroscopy for femoroacetabular impingement (FAI) or labral tears were included in this review. Seven of the 8 studies reported favorable PRO scores and significant postoperative improvement with moderate to large effect size. The included studies demonstrated a trend toward higher effect sizes with an increasing percentage of labral repair compared to isolated labral debridement. The complication rate was comparable to that of previous reports involving younger patients; however, the overall reoperation rate was 20.8%. Conversion to hip arthroplasty ranged from 0% to 30%, with an overall conversion rate of 18.5% at a mean time of 17.5 months following arthroscopy. The most common risk factors for conversion to arthroplasty were low preoperative PRO scores and advanced arthritis. CONCLUSION: Hip arthroscopy appears to be a safe and efficacious treatment for labral tears and FAI in older patients who do not have significant underlying degenerative changes. However, in this population, there is a significant proportion of patients who eventually require hip arthroplasty. Outcomes may be affected by type of treatment (ie, labral debridement vs repair). Additional high-quality studies are needed to understand how these factors affect outcomes. PMID- 27756724 TI - Effect of Swim Training on the Physical Characteristics of Competitive Adolescent Swimmers. AB - BACKGROUND: Subacromial space distance and forward head and shoulder posture are common characteristics resulting from swim training. These alterations can cause abnormal scapular kinematics and positioning, potentially increasing compression of structures in the subacromial space and increasing the risk for the development of swimmer's shoulder. PURPOSE: To evaluate the effect of the swim training season on subacromial space distance and forward head and forward shoulder posture as well as to determine the relationship between these variables. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Included in the study were 43 competitive adolescent swimmers and 29 nonoverhead adolescent athletes (controls) who were not currently experiencing any shoulder, neck, or back pain that limited their participation in sports activity. All participants were evaluated 3 times: once before the start of the swim training season and then at 2 follow-up sessions 6 and 12 weeks after the initial testing session. At each testing session, each participant completed a physical examination that included evaluation of posture and subacromial space distance. RESULTS: Swimmers had significantly greater decreases in subacromial space distance during the training season compared with nonoverhead athletes. Swimmers also demonstrated significantly greater increases in forward shoulder posture compared with nonoverhead athletes. A significant relationship was noted between changes in forward shoulder posture and changes in subacromial space distance from the baseline testing session to the assessment 6 weeks after baseline assessment. As forward shoulder posture increased, subacromial space significantly decreased. CONCLUSION: Because of their training load, swimmers experience a decrease in subacromial space distance and an increase in forward shoulder posture over the course of 12 weeks of training, potentially making these athletes more vulnerable to the development of shoulder pain and injury. PMID- 27756725 TI - Physiology and pathophysiology of potassium homeostasis. AB - Total body potassium content and proper distribution of potassium across the cell membrane is of critical importance for normal cellular function. Potassium homeostasis is maintained by several different methods. In the kidney, total body potassium content is achieved by alterations in renal excretion of potassium in response to variations in intake. Insulin and beta-adrenergic tone play critical roles in maintaining the internal distribution of potassium under normal conditions. Despite homeostatic pathways designed to maintain potassium levels within the normal range, disorders of altered potassium homeostasis are common. The clinical approach to designing effective treatments relies on understanding the pathophysiology and regulatory influences which govern the internal distribution and external balance of potassium. Here we provide an overview of the key regulatory aspects of normal potassium physiology. This review is designed to provide an overview of potassium homeostasis as well as provide references of seminal papers to guide the reader into a more in depth discussion of the importance of potassium balance. This review is designed to be a resource for educators and well-informed clinicians who are teaching trainees about the importance of potassium balance. PMID- 27756726 TI - Winter course in physiology: a successful example of continuing education for secondary school teachers in Brazil. AB - In international surveys, Brazilian students have been consistently ranking low in science. Continuing education for secondary school teachers is certainly a way to change this situation. To update teachers and provide teaching and learning experiences for graduate students, our department organized a "Winter Course in Physiology" where schoolteachers had the opportunity to attend lectures that were offered by graduate students and participate in discussions on teaching and learning strategies and their applicability, considering different schools and student age groups. This work evaluated the ways in which the Winter Course in Physiology improves continuing education for secondary school teachers. Graduate students prepared, presented, and discussed with the audience the concepts, content, and topics of the program, which were previously presented to the organizing committee and a supervising professor. Potential participants were recruited based on their curriculum vitae and a letter of intent. During the course, they completed a questionnaire that graded different aspects of course organization and lectures. The results indicated that the Winter Course was positively evaluated. Most topics received a grade of >=4.0, considering a range of 1.0 (low) to 5.0 (high). In a followup, both the participants and instructors reported positive impacts on their overall knowledge in physiology. Schoolteachers reported improvements in the performance and participation of their students. In conclusion, the results suggested that the Winter Course is a good way to promote continuing education for schoolteachers and promote university outreach. It also provided an important experience for graduate students to develop teaching skills. PMID- 27756727 TI - Isosmotic is not always isotonic: the five-minute version. PMID- 27756728 TI - Differential effects of bisphenol A diglicydyl ether on bone quality and marrow adiposity in ovary-intact and ovariectomized rats. AB - Bisphenol A diglycidyl ether (BADGE), a PPARgamma2 antagonist, has been shown to inhibit marrow adipogenesis and promote bone formation in intact animals. We investigated the impact of BADGE on a new and more clinically relevant physiological model, the ovariectomized (OVX) rat model. Forty female Wistar rats were divided into four treatment groups for 12 wk (n = 10/group): sham+vehicle, sham+BADGE, OVX+vehicle, and OVX+BADGE. Postmortem analyses included MRI, micro CT, serological test, histomorphometry, biomechanical tests, RT-PCR, and Western blot. Overall, OVX induced a sequential marrow fat expansion accompanied by bone deterioration. Compared with OVX controls, BADGE reduced fat fraction of the distal femur by 36.3%, adipocyte density by 33.0%, adipocyte size by 28.6%, adipocyte volume percentage by 57.8%, and adipogenic markers PPARgamma2 and C/EBPalpha by ~50% in OVX rats. Similar results were observed in sham rats vs. vehicle. BADGE could promote bone quality in sham rats; however, BADGE did not significantly improve trabecular microarchitecture, biomechanical strength, and dynamic histomorphometric parameters except for trabecular separation in OVX rats. We concluded that early BADGE treatment at a dose of 30 mg/kg attenuates marrow adiposity in ovary-intact and OVX rats and stimulates bone formation in ovary-intact rats but does not significantly rescue bone quality in OVX rats. PMID- 27756729 TI - Rethinking medical ward quality. PMID- 27756730 TI - Effects of plant intraspecific diversity across three trophic levels: Underlying mechanisms and plant traits. AB - PREMISE OF STUDY: Although there is increasing recognition of the effects of plant intraspecific diversity on consumers, the mechanisms by which such effects cascade-up to higher trophic levels remain elusive. METHODS: We evaluated the effects of plant (lima bean, Phaseolus lunatus) intraspecific diversity on a suite of insect herbivores (leaf-chewers, aphids, and seed-eating beetles) and their third trophic-level associates (parasitoids and aphid-tending ants). We established plots of three plants, classified as monocultures of one population source or polycultures with mixtures of three of the four population sources (N = 16 plots per level of diversity). Within each plot, plants were individually placed in pots and canopy contact was prevented, therefore eliminating diversity effects on consumers arising from changes in plant traits due to plant physical interactions. KEY RESULTS: Plant diversity reduced damage by leaf-chewers as well as aphid abundance, and the latter effect in turn reduced ant abundance. In contrast, plant diversity increased the abundance of seed-eating beetles, but did not influence their associated parasitoids. There were no effects of diversity on seed traits potentially associated with seed predation, suggesting that differences in early season herbivory between monocultures and polycultures (a likely mechanism of diversity effects on plants since plant interactions were prevented) did not drive concomitant changes in plant traits. CONCLUSIONS: This study emphasizes that effects of plant intraspecific diversity on consumers are contingent upon differences in associate responses within and among higher trophic levels and suggests possible mechanisms by which such effects propagate up this food web. PMID- 27756731 TI - Chasing unicorns: Nodulation origins and the paradox of novelty. PMID- 27756732 TI - Understanding the coevolutionary dynamics of mutualism with population genomics. AB - Decades of research on the evolution of mutualism has generated a wealth of possible ways whereby mutually beneficial interactions between species persist in spite of the apparent advantages to individuals that accept the benefits of mutualism without reciprocating - but identifying how any particular empirical system is stabilized against cheating remains challenging. Different hypothesized models of mutualism stability predict different forms of coevolutionary selection, and emerging high-throughput sequencing methods allow examination of the selective histories of mutualism genes and, thereby, the form of selection acting on those genes. Here, I review the evolutionary theory of mutualism stability and identify how differing models make contrasting predictions for the population genomic diversity and geographic differentiation of mutualism-related genes. As an example of the possibilities offered by genomic data, I analyze genes with roles in the symbiosis of Medicago truncatula and nitrogen-fixing rhizobial bacteria, the first classic mutualism in which extensive genomic resources have been developed for both partners. Medicago truncatula symbiosis genes, as a group, differ from the rest of the genome, but they vary in the form of selection indicated by their diversity and differentiation - some show signs of selection expected from roles in sanctioning noncooperative symbionts, while others show evidence of balancing selection expected from coevolution with symbiont signaling factors. I then assess the current state of development for similar resources in other mutualistic interactions and look ahead to identify ways in which modern sequencing technology can best inform our understanding of mutualists and mutualism. PMID- 27756733 TI - Health service finances are at crunch point, says NHS Providers. PMID- 27756734 TI - Same sex twins should give consent for zygosity testing except when medically necessary. PMID- 27756735 TI - Optimal dosing of rivaroxaban is undefined. PMID- 27756736 TI - Ear wax can cause extraordinary pain. PMID- 27756737 TI - Commentary on: Incidence and Risk Factors for Major Surgical Site Infections in Aesthetic Surgery: Analysis of 129,007 Patients. PMID- 27756738 TI - Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysis. AB - OBJECTIVES: The objective of this study was to perform a meta-analysis of all randomised controlled trials (RCTs) comparing surgical and non-surgical management of fractures of the proximal humerus, and to determine whether further analyses based on complexity of fracture, or the type of surgical intervention, produced disparate findings on patient outcomes. METHODS: A systematic review of the literature was performed identifying all RCTs that compared surgical and non surgical management of fractures of the proximal humerus. Meta-analysis of clinical outcomes was performed where possible. Subgroup analysis based on the type of fracture, and a sensitivity analysis based on the type of surgical intervention, were also performed. RESULTS: Seven studies including 528 patients were included. The overall meta-analysis found that there was no difference in clinical outcomes. However, subgroup and sensitivity analyses found improved patient outcomes for more complex fractures managed surgically. Four-part fractures that underwent surgery had improved long-term health utility scores (mean difference, MD 95% CI 0.04 to 0.28; p = 0.007). They were also less likely to result in osteoarthritis, osteonecrosis and non/malunion (OR 7.38, 95% CI 1.97 to 27.60; p = 0.003). Another significant subgroup finding was that secondary surgery was more common for patients that underwent internal fixation compared with conservative management within the studies with predominantly three-part fractures (OR 0.15, 95% CI 0.04 to 0.63; p = 0.009). CONCLUSION: This meta analysis has demonstrated that differences in the type of fracture and surgical treatment result in outcomes that are distinct from those generated from analysis of all types of fracture and surgical treatments grouped together. This has important implications for clinical decision making and should highlight the need for future trials to adopt more specific inclusion criteria.Cite this article: S. Sabharwal, N. K. Patel, D. Griffiths, T. Athanasiou, C. M. Gupte, P. Reilly. Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysisBone Joint Res 2016;5:470-480. DOI: 10.1302/2046-3758.510.2000638. PMID- 27756739 TI - Defining the fracture population in a pragmatic multicentre randomised controlled trial: PROFHER and the Neer classification of proximal humeral fractures. AB - OBJECTIVES: Accurate characterisation of fractures is essential in fracture management trials. However, this is often hampered by poor inter-observer agreement. This article describes the practicalities of defining the fracture population, based on the Neer classification, within a pragmatic multicentre randomised controlled trial in which surgical treatment was compared with non surgical treatment in adults with displaced fractures of the proximal humerus involving the surgical neck. METHODS: The trial manual illustrated the Neer classification of proximal humeral fractures. However, in addition to surgical neck displacement, surgeons assessing patient eligibility reported on whether either or both of the tuberosities were involved. Anonymised electronic versions of baseline radiographs were sought for all 250 trial participants. A protocol, data collection tool and training presentation were developed and tested in a pilot study. These were then used in a formal assessment and classification of the trial fractures by two independent senior orthopaedic shoulder trauma surgeons. RESULTS: Two or more baseline radiographic views were obtained for each participant. The independent raters confirmed that all fractures would have been considered for surgery in contemporaneous practice. A full description of the fracture population based on the Neer classification was obtained. The agreement between the categorisation at baseline (tuberosity involvement) and Neer classification as assessed by the two raters was only fair (kappa 0.29). However, this disparity did not appear to affect trial findings, specifically in terms of influencing the effect of treatment on the primary outcome of the trial. CONCLUSIONS: A key reporting requirement, namely the description of the fracture population, was achieved within the context of a pragmatic multicentre randomised clinical trial. This article provides important guidance for researchers designing similar trials on fracture management.Cite this article: H. H. G. Handoll, S. D. Brealey, L. Jefferson, A. Keding, A. J. Brooksbank, A. J. Johnstone, J. J. Candal-Couto, A. Rangan. Defining the fracture population in a pragmatic multicentre randomised controlled trial: PROFHER and the Neer classification of proximal humeral fractures.Bone Joint Res 2016;5:481-489. DOI: 10.1302/2046-3758.510.BJR-2016-0132.R1. PMID- 27756740 TI - Commentary on: Influence of the Pectoralis Major Muscle Sling in Chest Wall-Based Flap Suspension After Vertical Mammaplasty: Ten-Year Follow-Up. PMID- 27756741 TI - Commentary on: The Modern Polyurethane-Coated Implant in Breast Augmentation: Long-Term Clinical Experience. PMID- 27756742 TI - Commentary on: In Vivo Changes of Breast Perfusion After Augmentation. PMID- 27756743 TI - What is Wrong With Systematic Reviews and Meta-Analyses: If You Want the Right Answer, Ask the Right Question! PMID- 27756744 TI - 2013 ACC/AHA Cholesterol Guideline and Implications for Healthy People 2020 Cardiovascular Disease Prevention Goals. PMID- 27756745 TI - Patients and their families might not recognise frailty. PMID- 27756746 TI - Reduce NHS's reliance on migrants, HEE is told. PMID- 27756747 TI - Targeting BTK through microRNA in chronic lymphocytic leukemia. AB - Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling. PMID- 27756748 TI - Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. AB - Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2-/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2-/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2-/-Trp53+/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. PMID- 27756749 TI - Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies. AB - Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of 3',5' cyclic adenosine monophosphate in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases spleen tyrosine kinase and phosphatidylinositol 3-kinase and inhibits vascular endothelial growth factor A secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets. PMID- 27756751 TI - UK government is urged to end recruitment of "children" into armed forces. PMID- 27756750 TI - The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein. Integrating the results of these interference RNA screens and additional gene expression data, we identified the transcription factor ZEB2 as a novel AML dependency. ZEB2 depletion impaired the proliferation of both human and mouse AML cells and resulted in aberrant differentiation of human AML cells. Mechanistically, we showed that ZEB2 transcriptionally represses genes that regulate myeloid differentiation, including genes involved in cell adhesion and migration. In addition, we found that epigenetic silencing of the miR-200 family microRNAs affects ZEB2 expression. Our results extend the role of ZEB2 beyond regulating epithelial mesenchymal transition (EMT) and establish ZEB2 as a novel regulator of AML proliferation and differentiation. PMID- 27756752 TI - TSC2 Deficiency Unmasks a Novel Necrosis Pathway That Is Suppressed by the RIP1/RIP3/MLKL Signaling Cascade. AB - Tuberous sclerosis complex (TSC) is a genetic multiorgan disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart, and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach. The current study shows that simultaneous inhibition of two major pathways regulating redox homeostasis using l-buthionine sulfoximine (BSO, glutathione synthesis inhibitor) and auranofin (thioredoxin reductase inhibitor) induces oxidative burst, mitochondrial damage, and necrotic cell death in TSC-deficient cells in a highly synergistic and cell context specific manner. Furthermore, blocking RIP1/RIP3/MLKL-dependent signaling using chemical inhibitors necrostatin-1 (Nec-1) and necrosulfonamide (NSA) synergizes with BSO and auranofin in killing TSC-deficient cells. Expression analysis demonstrated that RIP1, RIP3, and MLKL protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitochondrial dysfunction in a glutaminolysis-dependent and autophagy-independent manner. Finally, supplementation with the mitochondrial metabolite alpha-ketoglutarate, whose synthesis is regulated by RIP1/RIP3/MLKL, rescues cells from the sensitizing effect of Nec-1 and NSA. Together, this study identifies a previously unrecognized novel regulated necrotic death pathway that involves mitochondrial homeostasis, is suppressed by the RIP1/RIP3/MLKL signaling in TSC-deficient cells, and could be a promising therapeutic target for TSC-associated tumors. Cancer Res; 76(24); 7130-9. (c)2016 AACR. PMID- 27756754 TI - An adolescent with acute abdominal pain and bowel wall thickening. AB - : : A 15-year-old girl was admitted with acute crampy abdominal pain and repeated vomiting over the preceding 2 hours; no fever, diarrhoea or abdominal trauma was reported. She had started oestrogen-progestin contraception 3 months ago. She had sought medical advice twice in the previous weeks for self-limiting episodes of right hand swelling, without urticaria. On examination, she was unwell and in pain, with severe tenderness in the right lower quadrant, without guarding or rebound tenderness. Bowel sounds were diminished. Blood tests were unremarkable. Two hours after admission, an abdominal ultrasound scanning showed an impressive wall thickening (>1 cm) of the terminal ileum, caecum and ascending colon (figure 1). Abundant free intraperitoneal fluids in the pelvis and in the hepatorenal recess were present.edpract;103/1/22/EDPRACT2016311823F1F1EDPRACT2016311823F1Figure 1Marked caecal wall thickening evidenced at the ultrasound scanning. QUESTIONS: Which of the following is the most likely diagnosis in this patient? Ileocolic intussusceptionGastrointestinal manifestation of Henoch-Schonlein purpuraAbdominal attack of hereditary angioedema (HAE)Acute pancreatitisWhich of the following blood tests may help to confirm the diagnosis? Erythrocyte sedimentation rateC4Serum amylase: 36 IU/LC1-inhibitorHow should this patient be evaluated and treated?Answers are on page ???. PMID- 27756755 TI - Thumb-sucking or nail-biting in childhood led to a reduction in atopic sensitisation but not asthma or hay fever. PMID- 27756756 TI - Homozygous familial hypercholesterolaemia in two sisters misdiagnosed as rheumatoid arthritis. PMID- 27756753 TI - Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype. AB - Over one third of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long-term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives, that is, the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins, and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic), and the humanized mAb to the IL6R receptor tocilizumab (TOC, reduces IL6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high-affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally delivered TOC, TOC+4-HPR, and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents use diverse mechanisms to disrupt tumorigenesis at multiple venues, that is, intracellular, tumor cell-ECM, and tumor microenvironment; beneficial qualities for secondary chemopreventives. Cancer Prev Res; 10(1); 76-88. (c)2016 AACR. PMID- 27756757 TI - Traumatic gallbladder rupture: a patient with multiple risk factors. AB - Isolated gallbladder rupture following blunt thoracoabdominal trauma is rare; gall bladder rupture is seen in <1% of blunt abdominal trauma. This case report describes a significant mechanism of blunt force injury resulting in an isolated gallbladder rupture. Risk factors for traumatic gallbladder rupture are reviewed and the authors propose that a stiff, cirrhotic liver may exacerbate shear forces in the gallbladder fossa and represents an important risk factor for blunt gallbladder injury. Cholecystectomy remains the definitive management for gallbladder trauma. Almost all gallbladder injuries following blunt trauma are associated with other significant intra-abdominal injuries and in the setting of acute trauma, the authors recommend an open procedure to facilitate a detailed exploration of the peritoneal cavity to exclude associated injuries. PMID- 27756758 TI - Serum sickness-like reaction after the treatment of cellulitis with amoxicillin/clavulanate. AB - Serum sickness-like reaction is a rare disease presentation. We describe a case of a man aged 58 years who presented with acute-onset polyarthralgia, intense pruritus of hands and feet, fever to 39.5 degrees C and leucocytosis to 17.2*103/mm3 5 days after completing a 10-day course of amoxicillin/clavulanate for the treatment of finger cellulitis. With history, symptoms, physical examination findings and reported cases in the literature of serum sickness-like reactions to amoxicillin, a clinical diagnosis of serum sickness-like reaction was made. The patient was treated with non-steroidal anti-inflammatories with improvement in symptoms by the time of discharge. PMID- 27756759 TI - Sludge in a giant left atrium. PMID- 27756760 TI - Paediatric neurologist gets short suspension after support from colleagues and parents. PMID- 27756761 TI - Health bodies urge UK government to begin phasing out coal power. PMID- 27756762 TI - GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes. AB - BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes. PMID- 27756763 TI - Humor Appreciation Involves Parametric and Synchronized Activity in the Medial Prefrontal Cortex and Hippocampus. AB - Humor perception is a ubiquitous phenomenon in human societies. In theories of humor perception, three factors, non-seriousness, social context, and incongruity, have been implicated in humor. In another theory, however, elaboration and reinterpretation of contexts are considered to play a role in eliciting humor. Although the neural correlates of humor appreciation have been investigated using neuroimaging methods, only a few studies have conducted such experiments under natural conditions. In the present study, two functional magnetic resonance imaging experiments, using a comedy movie as a stimulus, were conducted to investigate the neural correlates of humor under natural conditions. The subjects' brain activity was measured while watching and enjoying a movie. In experiment 1, a parametric analysis showed that the medial prefrontal cortex (MPFC) and hippocampus/amygdala had a positive relationship with the subjective rating of funniness. In experiment 2, intersubject correlation was analyzed to investigate synchronized activity across all participants. Signal synchronization that paralleled increased funniness ratings was observed in the MPFC and hippocampus. Thus, it appears that both parametric and synchronized activity in the MPFC and hippocampus are important during humor appreciation. The present study has revealed the brain regions that are predominantly involved in humor sensation under natural condition. PMID- 27756765 TI - Doctor in Germany sent to prison for raping and sexually assaulting patients and coworkers. PMID- 27756764 TI - MACF1 Controls Migration and Positioning of Cortical GABAergic Interneurons in Mice. AB - GABAergic interneurons develop in the ganglionic eminence in the ventral telencephalon and tangentially migrate into the cortical plate during development. However, key molecules controlling interneuron migration remain poorly identified. Here, we show that microtubule-actin cross-linking factor 1 (MACF1) regulates GABAergic interneuron migration and positioning in the developing mouse brain. To investigate the role of MACF1 in developing interneurons, we conditionally deleted the MACF1 gene in mouse interneuron progenitors and their progeny using Dlx5/6-Cre-IRES-EGFP and Nkx2.1-Cre drivers. We found that MACF1 deletion results in a marked reduction and defective positioning of interneurons in the mouse cerebral cortex and hippocampus, suggesting abnormal interneuron migration. Indeed, the speed and mode of interneuron migration were abnormal in the MACF1-mutant brain, compared with controls. Additionally, MACF1-deleted interneurons showed a significant reduction in the length of their leading processes and dendrites in the mouse brain. Finally, loss of MACF1 decreased microtubule stability in cortical interneurons. Our findings suggest that MACF1 plays a critical role in cortical interneuron migration and positioning in the developing mouse brain. PMID- 27756766 TI - Involvement of pax2 in ovarian development and recrudescence of catfish: a role in steroidogenesis. AB - PAX2, a member of paired box family, is an essential transcription factor for the organ development in vertebrates including teleosts, yet no evidence has been shown for its involvement in reproduction. To study this, partial- and/or full length cDNA of pax2 was isolated from the ovary of catfish, Clarias batrachus, along with its other Pax family members, pax1 and pax9 Tissue distribution and ontogeny expression analysis indicated the prevalence of pax2 but not pax1 and pax9 in ovary. Varied phase-wise expression during ovarian cycle and elevation of pax2 after human chorionic gonadotropin induction showed probable regulation by gonadotropins. Pax2 could be localized in various stages of oocytes and in follicular layer of vitellogenic and post-vitellogenic oocytes. To assess the functional significance of pax2, transient RNA silencing was performed using primary catfish ovarian follicle culture, in vitro, and in catfish, in vivo, through ovary-targeted injection of PEI-esiRNA. Pax2 siRNA treatment reduced the expression of various transcripts related to ovarian development like signaling molecules such as wnt4 and wnt5, estrogen receptors, several steroidogenic enzymes and transcription factors. These transitions in transcript levels might have been mediated by Pax2 acting upstream of wnt4/5 that may play a role in steroidogenesis and/or ovarian development along with ad4bp/sf-1 or by direct or indirect interaction with steroidogenic enzyme genes, which is evident from the change in the levels of serum estradiol-17beta but not 17alpha,20beta-dihydroxy-4 pregnen-3-one. Taken together, it seems that pax2 has a plausible role during ovarian development and/or recrudescence of catfish either directly or indirectly through Wnt signaling pathway. PMID- 27756767 TI - Ranolazine reduces atrial fibrillatory wave frequency. AB - Aims: Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. Methods and results: Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 +/- 0.74 vs. 5.79 +/- 0.96 Hz, P = 0.04) but not with changes in OI (0.47 +/- 0.11 vs. 0.50 +/- 0.12, P = 0.71) or amplitude (0.47 +/- 0.43 vs. 0.41 +/- 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 +/- 0.78 vs. 6.03 +/- 0.79 Hz, P = 0.04). Conclusion: Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF. PMID- 27756768 TI - Linc-MAF-4 regulates Th1/Th2 differentiation and is associated with the pathogenesis of multiple sclerosis by targeting MAF. AB - In this study, we strove to substantiate the ability of linc-MAF-4 to act as a regulator of pathogenesis during multiple sclerosis (MS). We recruited 34 patients who were diagnosed with MS according to the revised McDonald criteria. Six patients with MS and 5 healthy volunteers contributed peripheral blood mononuclear cells for microarray analysis. Subsequent knockdown and overexpression of linc-MAF-4 in naive CD4+ T cells from the additional 28 patients with MS was performed to track changes in CD4+ T-cell subsets and their function, as well as to confirm results from the prior microarray analysis. Expression of linc-MAF-4 increased significantly in peripheral blood mononuclear cells of patients with MS compared with those of control participants. In addition, linc-MAF-4 regulated encephalitogenic T helper (Th)1-cell differentiation in patients with MS. Transfection of synthetic linc-MAF-4 into naive CD4+ T cells facilitated Th1-cell differentiation and inhibited Th2-cell differentiation by directly inhibiting MAF, which is a Th2-cell transcription factor. Linc-MAF-4 also promoted activation of CD4+ T cells from patients with MS. Expression level of linc-MAF-4 correlated with the annual relapse rate in patients with MS. Our results suggest that linc-MAF-4 is involved in the pathogenesis of MS, specifically via regulation of encephalitogenic T cells. Zhang, F., Liu, G., Wei, C., Gao, C., Hao, J. Linc-MAF-4 regulates Th1/Th2 differentiation and is associated with the pathogenesis of multiple sclerosis by targeting MAF. PMID- 27756769 TI - Microbiome analysis shows enrichment for specific bacteria in separate anatomical regions of the deep-sea carnivorous sponge Chondrocladia grandis. AB - The Cladorhizidae is a unique family of carnivorous marine sponges characterised by either the absence or reduction of the aquiferous system and by the presence of specialised structures to trap and digest mesoplanktonic prey. Previous studies have postulated a key role of host-associated bacteria in enabling carnivory in this family of sponges. In this study, we employed high-throughput Illumina-based sequencing to identify the bacterial community associated with four individuals of the deep-sea sponge Chondrocladia grandis sampled in the Gulf of Maine. By characterising the V6 through V8 region of the 16S rRNA gene, we compared the bacterial community composition and diversity in three distinct anatomical regions with predicted involvement in prey capture (sphere), support (axis) and benthic substrate attachment (root). A high abundance of Tenacibaculum, a known siderophore producing bacterial genus, was present in all anatomical regions and specimens. The abundance of Colwellia and Roseobacter was greater in sphere and axis samples, and bacteria from the hydrocarbon-degrading Robiginitomaculum genus were most abundant in the root. This first description of the bacterial community associated with C. grandis provides novel insights into the contribution of bacteria to the carnivorous lifestyle while laying foundations for future cladorhizid symbiosis studies. PMID- 27756770 TI - Shifts in bacterial community structure during succession in a glacier foreland of the High Arctic. AB - Primary succession after glacier retreat has been widely studied in plant communities, but bacterial succession is still poorly understood. In particular, few studies of microbial succession have been performed in the Arctic. We investigated the shifts in bacterial community structure and soil physicochemical properties along a successional gradient in a 100-year glacier foreland of the High Arctic. Multivariate analyses revealed that time after glacier retreat played a key role in associated bacterial community structure during succession. However, environmental filtering (i.e. pH and soil temperature) also accounted for a different, but substantial, proportion of the bacterial community structure. Using the functional trait-based approach, we found that average rRNA operon (rrn) copy number of bacterial communities is high in earlier successional stages and decreased over time. This suggests that soil bacterial taxa with higher rrn copy number have a selective advantage in early successional stages due to their ability of rapidly responding to nutrient inputs in newly exposed soils after glacier retreat. Taken together, our results demonstrate that both deglaciation time and environmental filters play key roles in structuring bacterial communities and soil bacterial groups with different ecological strategies occur in different stages of succession in this glacier foreland. PMID- 27756771 TI - Outcomes following first-episode psychosis - Why we should intervene early in all ages, not only in youth. AB - OBJECTIVE: To compare baseline demographics and 10-year outcomes of a first episode psychosis patient incidence cohort in order to establish whether current youth-focussed age-based criteria for early intervention services are justified by patient needs. The patients in this cohort were treated prior to the establishment of early intervention services. The study aimed to test the hypothesis that those who develop psychosis at a younger age have worse outcomes than those who develop psychosis at an older age. METHODS: Data on first-episode psychosis patients from the AESOP-10 longitudinal follow-up study were used to compare baseline characteristics, and 10-year clinical, functional and service use outcomes between those patients who would and would not have met age-based criteria for early intervention services, in Australia or in the United Kingdom. RESULTS: In total, 58% men and 71% women with first-episode psychosis were too old to meet current Australian-early intervention age-entry criteria (chi2 = 9.1, p = 0.003), while 21% men and 34% women were too old for UK-early intervention age-entry criteria (chi2 = 11.1, p = 0.001). The 10-year clinical and functional outcomes did not differ significantly between groups by either Australian- or UK early intervention age-entry criteria. Service use was significantly greater among the patients young enough to meet early intervention age-criteria (Australia: incidence rate ratio = 1.35 [1.19, 1.52], p < 0.001; United Kingdom: incidence rate ratio = 1.65 [1.41, 1.93], p < 0.001). CONCLUSION: Current early intervention services are gender- and age-inequitable. Large numbers of patients with first-episode psychosis will not receive early intervention care under current service provision. Illness outcomes at 10-years were no worse in first episode psychosis patients who presented within the age range for whom early intervention has been prioritised, though these patients had greater service use. These data provide a rationale to consider extension of early intervention to all, rather than just to youth. PMID- 27756773 TI - Accessing the Future: a Disability-Themed Anthology of Speculative Fiction. PMID- 27756772 TI - Silencer-of-Death Domain Mediates Acid-Induced Decrease in Cell Apoptosis in Barrett's Associated Esophageal Adenocarcinoma Cells. AB - We have shown that NADPH oxidase (NOX)5-S may mediate the acid-induced decrease in cell apoptosis. However, mechanisms of NOX5-S-dependent decrease in cell apoptosis are not fully understood. In this study, we found that silencer-of death domain (SODD) was significantly increased in esophageal adenocarcinoma (EA) tissues, EA cell lines FLO and OE33, and a dysplastic cell line CP-B. Strong SODD immunostaining was significantly higher in low-grade dysplasia (66.7%), high grade dysplasia (81.2%), and EA (71.2%) than in Barrett's mucosa (10.5%). Acid treatment significantly increased SODD protein and mRNA expression and promoter activity in FLO cells, an increase that was significantly decreased by the knockdown of NOX5-S and nuclear factor kappaB (NF-kappaB)1 p50 with their small interfering RNAs. Similarly, acid-induced increase of SODD mRNA was blocked by knockdown of NOX5-S and p50 in a BE cell line CP-A. Overexpression of NOX5-S significantly increased SODD protein expression in FLO cells. Moreover, overexpression of NOX5-S or p50 significantly increased the SODD promoter activity and decreased the caspase 9 activity or apoptosis. NOX5-S overexpression induced increase in SODD promoter activity was significantly decreased by knockdown of p50. In addition, acid treatment significantly decreased the caspase 9 activity, a decrease that was significantly inhibited by knockdown of SODD. Furthermore, chromatin immunoprecipitation assay showed that NF-kappaB1 p50 bound to SODD genomic DNA containing a NF-kappaB-binding element GGGGACACCCT. This binding element was further confirmed by a gel mobility shift assay. We conclude that acid-induced increase in SODD expression and decrease in cell apoptosis may depend on the activation of NOX5-S and NF-kappaB1 p50 in FLO cells. PMID- 27756774 TI - Differential Patterns of Risk Factors for Early-Onset Breast Cancer by ER Status in African American Women. AB - BACKGROUND: Given the disproportionately high incidence of early-onset breast cancer and aggressive subtypes, such as estrogen receptor (ER)-negative tumors, in African American (AA) women, elucidation of risk factors for early onset of specific subtypes of breast cancer is needed. METHODS: We evaluated associations of reproductive, anthropometric, and other factors with incidence of invasive breast cancer by age at onset (<45, >=45) in 57,708 AA women in the prospective Black Women's Health Study. From 1995 to 2013, we identified 529 invasive breast cancers among women <45 years of age (151 ER-, 219 ER+) and 1,534 among women >=45 years (385 ER-, 804 ER+). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) for associations by age and ER status. RESULTS: Higher parity, older age at first birth, never having breastfed, and abdominal adiposity were associated with increased risk of early-onset ER- breast cancer: HRs were 1.71 for >=3 births versus one birth; 2.29 for first birth after age 25 versus <20 years; 0.61 for ever having breastfed versus never; and 1.64 for highest versus lowest tertile of waist-to-hip ratio. These factors were not associated with ER- cancer in older women or with ER+ cancer regardless of age. CONCLUSIONS: Differences in risk factors by ER subtype were observed for breast cancer diagnosed before the age of 45 years. IMPACT: Etiological heterogeneity by tumor subtype in early-onset breast cancer, in combination with a higher prevalence of the risk factors in AA women, may explain, in part, racial disparities in breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 26(2); 270-7. (c)2016 AACR. PMID- 27756775 TI - Eating Disorders and Breast Cancer. AB - BACKGROUND: Eating disorders such as anorexia nervosa and bulimia nervosa affect overall and reproductive health and may also affect breast cancer risk. We studied the association between self-reported eating disorders and breast cancer risk in a prospective cohort study. METHODS: In 2003-2009, the Sister Study enrolled women ages 35-74 years who had a sister with breast cancer but had never had it themselves. Using data from 47,813 women, we estimated adjusted HRs and 95% confidence intervals (CI) for the association between eating disorders and invasive breast cancer over a median of 5.4 years of follow-up. RESULTS: Three percent (n = 1,569) of participants reported a history of an eating disorder. Compared with women who never had an eating disorder, women who reported eating disorders in the past had reduced breast cancer risk (HR = 0.62; 95% CI, 0.42 0.92). CONCLUSIONS: In this large prospective, observational cohort study, we observed an inverse association between having a history of an eating disorder and invasive breast cancer. IMPACT: Historical eating disorders may be associated with a long-term reduction in breast cancer risk. Cancer Epidemiol Biomarkers Prev; 26(2); 206-11. (c)2016 AACR. PMID- 27756776 TI - Six Serum-Based miRNAs as Potential Diagnostic Biomarkers for Gastric Cancer. AB - BACKGROUND: Circulating miRNAs in serum may serve as promising diagnostic biomarkers for patients with gastric cancer. METHODS: Using qRT-PCR-based Exiqon panel, we identified 58 differentially expressed miRNAs from three gastric cancer pool samples and one normal control (NC) pool in the initial screening phase. Identified miRNAs were further validated in the training (49 gastric cancer vs. 47 NCs) and validation phases (154 gastric cancer vs. 120 NCs) using qRT-PCR. The expression levels of the miRNAs were also determined in tissues, arterial serum, and exosomes. RESULTS: Consequently, six serum miRNAs (miR10b-5p, miR132-3p, miR185-5p, miR195-5p, miR-20a3p, and miR296-5p) were significantly overexpressed in gastric cancer compared with NCs. The areas under the receiver operating characteristic curve of the six-miRNA panel were 0.764 and 0.702 for the training and validation phases, respectively. miR10b-5p and miR296-5p were significantly upregulated in gastric cancer tissues (n = 188). In addition, patients who did not receive adjuvant chemotherapy with high expression of miR10b-5p or miR296-5p in tissues tended to suffer worse overall survival. Furthermore, the expression levels of miR10b-5p, miR195-5p, miR20a-3p, and miR296-5p were significantly elevated in exosomes from gastric cancer serum samples (n = 30). CONCLUSIONS: We identified a six-miRNA panel in serum for the detection of gastric cancer. IMPACT: Our findings provide a novel serum miRNA signature for gastric cancer diagnosis, and will serve as the basis of the application of circulating miRNAs in clinical for the detection of gastric cancer in the future. Cancer Epidemiol Biomarkers Prev; 26(2); 188-96. (c)2016 AACR. PMID- 27756777 TI - HIV Infection and Survival of Lymphoma Patients in the Era of Highly Active Antiretroviral Therapy. AB - Background: Highly active antiretroviral therapy (HAART) has extended the life expectancy of patients with HIV/AIDS to approach that of the general population. However, it remains unclear whether HIV infection affects the survival of patients with lymphoma in the HAART era.Methods: Patients diagnosed with Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, peripheral T cell lymphoma (PTCL), or follicular lymphoma during 2004-2011 were identified from the National Cancer Database. Survival analyses were conducted, where each HIV-infected patient was propensity score matched to a HIV-uninfected patient on the basis of demographic factors, clinical features, and treatment characteristics.Results: Among 179,520 patients, the prevalence of HIV-infection ranged from 1.0% for follicular lymphoma, 3.3% for PTCL, 4.7% for Hodgkin lymphoma, 5.4% for DLBCL, to 29% for Burkitt lymphoma. HIV infection was significantly associated with inferior overall survival for patients with each lymphoma subtype: Hodgkin lymphoma [HR, 1.47; 95% confidence interval (CI), 1.25 1.74], DLBCL (HR, 1.95; 95% CI, 1.80-2.11), Burkitt lymphoma (HR, 1.46; 95% CI, 1.24-1.73), PTCL (HR, 1.43; 95% CI, 1.14-1.79), and follicular lymphoma (HR, 1.44; 95% CI, 1.04-2.00).Conclusions: HIV/AIDS continues to be independently associated with increased risk of death among patients with lymphoma in the HAART era in the United States, and the association varies by lymphoma histologic subtype.Impact: Examination of effective management strategies for patients with HIV/AIDS-associated lymphoma and enrollment of patients in prospective clinical trials are needed to improve patient outcomes. Cancer Epidemiol Biomarkers Prev; 26(3); 303-11. (c)2016 AACR. PMID- 27756778 TI - Setting an Agenda to Address Intimate Partner Violence Among Young Men Who Have Sex With Men: A Conceptual Model and Review. AB - Research investigating intimate partner violence (IPV) among sexual minorities is limited. The research that does exist has found that rates of IPV are similar to or higher than the rates found for heterosexual women, the most commonly studied population in this area. This limited research has resulted in a dearth of prevention/intervention programs targeted for these populations. While some may argue that existing IPV programs can be used for these populations, this review presents an argument for more targeted work with sexual minority populations, using young men who have sex with men (YMSM) as an example. Drawing on the framework of intersectionality, this article argues that the intersectionality of age, sexual identity, and gender combines to create a spectrum of unique factors that require specific attention. This framework allows for the identification of known correlates for IPV as well as factors that may be unique to YMSM or other sexual minority populations. The article presents a conceptual model that suggests new areas of research as well as a foundation for the topics and issues that should be addressed in an intervention. PMID- 27756779 TI - Of Caps and Gaps, Postnatal Hearts, Elusive Facts, and lncs. PMID- 27756780 TI - Wrestling the Giant: New Approaches for Assessing Titin Variant Pathogenicity. PMID- 27756781 TI - Glycerophosphocholine Metabolites and Cardiovascular Disease Risk Factors in Adolescents: A Cohort Study. AB - BACKGROUND: Glycerophosphocholine (GPC) metabolites modulate atherosclerosis and thus risk for cardiovascular disease (CVD). Preclinical CVD may start during adolescence. Here, we used targeted serum lipidomics to identify a new panel of GPCs, and tested whether any of these GPCs are associated, in adolescence, with classical risk factors of CVD, namely excess visceral fat (VF), elevated blood pressure, insulin resistance, and atherogenic dyslipidemia. METHODS: We studied a population-based sample of 990 adolescents (12-18 years, 48% male), as part of the Saguenay Youth Study. Using liquid chromatography-electrospray ionization mass spectrometry, we identified 69 serum GPCs within the 450 to 680 m/z range. We measured VF with MRI. RESULTS: We identified several novel GPCs that were associated with multiple CVD risk factors. Most significantly, PC16:0/2:0 was negatively associated with VF (P=1.4*10-19), blood pressure (P=7.7*10-5), and fasting triacylglycerols (P=9.0*10-5), and PC14:1/0:0 was positively associated with VF (P=3.0*10-7), fasting insulin (P=5.4*10-32), and triacylglycerols (P=1.4*10-29). The Sobel test of mediation revealed that both GPCs mediated their respective relations between VF (as a potential primary exposure) and CVD risk factors (as outcomes, P values<1.3*10-3). Furthermore, a GPC shown recently to predict incident coronary heart disease in older adults, PC18:2/0:0, was associated with several CVD risk factors in adolescents; these associations were less strong than those with the newly identified GPCs. CONCLUSIONS: We identified novel GPCs strongly associated with multiple CVD risk factors in adolescents. These GPCs may be sensitive indicators of obesity-related risk for CVD outcomes in adults, and may improve biological understanding of CVD risk. PMID- 27756782 TI - Potential and Caveats of Lipidomics for Cardiovascular Disease. PMID- 27756783 TI - Plasma Lipidomic Profiles Improve on Traditional Risk Factors for the Prediction of Cardiovascular Events in Type 2 Diabetes Mellitus. AB - BACKGROUND: Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. METHODS: Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization-tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with >=1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. RESULTS: Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678-0.682) to 0.700 (95% CI, 0.698-0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219-0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738-0.742) to 0.760 (95% CI, 0.757-0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317-0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). CONCLUSIONS: The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00145925. PMID- 27756786 TI - A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy. AB - Purpose: Degarelix, a new gonadotropin-releasing hormone (GnRH) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer, possesses some theoretical advantages over luteinizing hormone-releasing hormone (LHRH) analogues in terms of avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. We set out to determine whether preoperative degarelix influenced surrogates of disease control in a randomized phase II study.Experimental Design: Thirty-nine patients were randomly assigned to one of three different neoadjuvant arms: degarelix only, degarelix/bicalutamide, or LHRH agonist/bicalutamide. Treatments were given for 3 months before prostatectomy. Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment. The primary end point was treatment effect on intratumoral dihydrotestosterone levels.Results: Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms (0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g, P < 0.01). No significant differences existed for other intratumoral androgens, such as testosterone and dehydroepiandrosterone. Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis (P = 0.01). Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm (0.55 and 0.65 vs. 3.65, P < 0.01), and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm (82.14 vs. 126.67, P = 0.02).Conclusions: Neoadjuvant degarelix alone, compared with use of LHRH agonist and bicalutamide, is associated with higher levels of intratumoral dihydrotestosterone, despite similar testosterone levels. Further studies that evaluate the mechanisms behind these results are needed. Clin Cancer Res; 23(8); 1974-80. (c)2016 AACR. PMID- 27756784 TI - TGFbetaR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. AB - PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFbetaR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFbeta1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. RESULTS: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFbeta1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFbeta1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. CONCLUSIONS: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. (c)2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615. PMID- 27756785 TI - A Positive Feedback Loop of lncRNA-PVT1 and FOXM1 Facilitates Gastric Cancer Growth and Invasion. AB - Purpose: The long, noncoding RNA (lncRNA) PVT1 is an important epigenetic regulator with a critical role in human tumors. Here, we aimed to investigate the clinical application and the potential molecular mechanisms of PVT1 in gastric cancer tumorigenesis and progression.Experimental Design: The expression level of PVT1 was determined by RT-qPCR analysis in 190 pairs of gastric cancer tissues and adjacent normal gastric mucosa tissues (ANT). The biologic functions of PVT1 were assessed by in vitro and in vivo functional experiments. RNA protein pull down assays and LS/MS mass spectrometry analysis were performed to detect and identify the PVT1- interacting protein FOXM1. Protein-RNA immunoprecipitation assays were conducted to examine the interaction of FOXM1 and PVT1 Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of FOXM1 on the PVT1 promoter.Results: The lncRNA PVT1 was significantly upregulated in gastric cancer tissues compared with ANTs. High expression of PVT1 predicted poor prognosis in patients with gastric cancer. PVT1 enhanced gastric cancer cell proliferation and invasion in vitro and in vivoPVT1 directly bound FOXM1 protein and increased FOXM1 posttranslationally. Moreover, PVT1 is also a FOXM1-responsive lncRNA, and FOXM1 directly binds to the PVT1 promoter to activate its transcription. Finally, PVT1 fulfilled its oncogenic functions in a FOXM1-mediated manner.Conclusions: Our study suggests that PVT1 promotes tumor progression by interacting with FOXM1. PVT1 may be a valuable prognostic predictor for gastric cancer, and the positive feedback loop of PVT1 FOXM1 could be a therapeutic target in pharmacologic strategies. Clin Cancer Res; 23(8); 2071-80. (c)2016 AACR. PMID- 27756787 TI - A Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients. AB - Purpose: The currently used prognostic models for patients with nonmetastatic clear cell renal cell carcinoma (ccRCC) are based on clinicopathologic features and might be improved by adding molecular markers. Epigenetic alterations occur frequently in ccRCC and are promising biomarkers. The aim of this study is to identify prognostic promoter methylation markers for ccRCC.Experimental Design: We integrated data generated by massive parallel sequencing of methyl-binding domain enriched DNA and microarray-based RNA expression profiling of 5-aza-2' deoxycytidine-treated ccRCC cell lines to comprehensively characterize the ccRCC methylome. A selection of the identified methylation markers was evaluated in two independent series of primary ccRCC (n = 150 and n = 185) by methylation-specific PCR. Kaplan-Meier curves and log-rank tests were used to estimate cause-specific survival. HRs and corresponding 95% confidence intervals (CI) were assessed using Cox proportional hazard models. To assess the predictive capacity and fit of models combining several methylation markers, HarrellC statistic and the Akaike Information Criterion were used.Results: We identified four methylation markers, that is, GREM1, NEURL, LAD1, and NEFH, that individually predicted prognosis of patients with ccRCC. The four markers combined were associated with poorer survival in two independent patient series (HR, 3.64; 95% CI, 1.02-13.00 and HR, 7.54; 95% CI, 2.68-21.19). These findings were confirmed in a third series of ccRCC cases from The Cancer Genome Atlas (HR, 3.60; 95% CI, 2.02 6.40).Conclusions: A four-gene promoter methylation marker panel consisting of GREM1, NEURL, LAD1, and NEFH predicts outcome of patients with ccRCC and might be used to improve current prognostic models. Clin Cancer Res; 23(8); 2006-18. (c)2016 AACR. PMID- 27756788 TI - Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. AB - Purpose: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma.Experimental Design: A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose-escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatment-related and serious adverse events (AEs), as well as treatment-related AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs.Results: Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses >=1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines.Conclusions: Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of >=1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents. Clin Cancer Res; 23(8); 1929-36. (c)2016 AACR. PMID- 27756789 TI - Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug-Drug Interaction with Antidepressants. AB - Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug-drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug-drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy. PMID- 27756790 TI - The compartment syndrome: is the intra-compartment pressure a reliable indicator for early diagnosis? AB - Compartment syndrome (CS) occurs when the pressure in an enclosed compartment increases due to tissue swelling or internal bleeding. As the intra-compartmental pressure (ICP) builds up, the blood flow to the tissue or the organ is compromised, resulting in ischemia, necrosis and damage to the nerves and other tissues. At the present there are no established diagnostic procedures, and clinical observations such as pain, paralysis and even compartment pressure monitoring are an unreliable determinant of the presence of the syndrome. Late diagnosis may result in fasciotomy, neurological dysfunctions, amputation and even death. Focusing on the frequently occurring CS of the lower leg, this work is aimed toward introducing a coherent, mechanically motivated analysis of the disease within the framework of poroelasticity. The fascia enclosing the compartment is treated as an inextensible and impermeable layer, and the tissue inside the compartment is represented as a fully saturated poroelastic solid. The model quantitatively predicts the highly non-uniform ICP buildup as a function of both time and location. These findings, which are in good agreement with clinical observations reported in the literature, shed light on the difficulties associated with the identification of the syndrome and may assist in improved diagnostic procedures. PMID- 27756791 TI - Exploring New Endpoints for Patients With Heart Failure With Preserved Ejection Fraction. AB - The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting. PMID- 27756792 TI - A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability. AB - RATIONALE: Angiogenic hypersprouting and leaky vessels are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs of miR302-367 cluster in angiogenesis and tumors has not yet been fully evaluated. OBJECTIVE: To investigate the functions of miR302-367 in developmental angiogenesis and tumor angiogenesis and explore the molecular mechanisms of microRNA for the treatment of pathological neovascularization-related diseases. METHODS AND RESULTS: Here, we show that miR302-367 elevation in endothelial cells reduces retinal sprouting angiogenesis and promotes vascular stability in vivo, ex vivo, and in vitro. Erk1/2 is identified as direct target of miR302-367, and downregulation of Erk1/2 on miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the antiangiogenic and vascular stabilizing effect of miR302-367 in mice. Tumor angiogenesis shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways. CONCLUSIONS: MiR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth. PMID- 27756793 TI - MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin. AB - RATIONALE: Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood. OBJECTIVE: To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms. METHODS AND RESULTS: Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe-/- and Ldlr-/-, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR 181b in angiotensin II-infused Apoe-/- and Ldlr-/- mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3-/- mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis. CONCLUSIONS: Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture. PMID- 27756794 TI - Identifying Important Gaps in Randomized Controlled Trials of Adult Cardiac Arrest Treatments: A Systematic Review of the Published Literature. AB - BACKGROUND: Cardiac arrest is a major public health concern worldwide. The extent and types of randomized controlled trials (RCT)-our most reliable source of clinical evidence-conducted in these high-risk patients over recent years are largely unknown. METHODS AND RESULTS: We performed a systematic review, identifying all RCTs published in PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library from 1995 to 2014 that focused on the acute treatment of nontraumatic cardiac arrest in adults. We then extracted data on the setting of study populations, types and timing of interventions studied, risk of bias, outcomes reported, and how these factors have changed over time. Over this 20 year period, 92 RCTs were published containing 64 309 patients (median, 225.5 per trial). Of these, 81 RCTs (88.0%) involved out-of-hospital cardiac arrest, whereas 4 (4.3%) involved in-hospital cardiac arrest and 7 (7.6%) included both. Eighteen RCTs (19.6%) were performed in the United States, 68 (73.9%) were performed outside the United States, and 6 (6.5%) were performed in both settings. Thirty-eight RCTs (41.3%) evaluated drug therapy, 39 (42.4%) evaluated device therapy, and 15 (16.3%) evaluated protocol improvements. Seventy-four RCTs (80.4%) examined interventions during the cardiac arrest, 15 (16.3%) examined post cardiac arrest treatment, and 3 (3.3%) studied both. Overall, reporting of the risk of bias was limited. The most common outcome reported was return of spontaneous circulation: 86 (93.5%) with only 22 (23.9%) reporting survival beyond 6 months. Fifty-three RCTs (57.6%) reported global ordinal outcomes, whereas 15 (16.3%) reported quality-of-life. RCTs in the past 5 years were more likely to be focused on protocol improvements and postcardiac arrest care. CONCLUSIONS: Important gaps in RCTs of cardiac arrest treatments exist, especially those examining in-hospital cardiac arrest, protocol improvement, postcardiac arrest care, and long-term or quality-of-life outcomes. PMID- 27756795 TI - Socioeconomic Inequalities in Statin Adherence Under Universal Coverage: Does Sex Matter? AB - BACKGROUND: Previous research shows that low socioeconomic position (SEP; especially low income) is associated with statin nonadherence. We investigated the relationship between SEP and statin adherence in a country with universal coverage using group-based trajectory modeling in addition to the proportion of days covered. METHODS AND RESULTS: Using data from Finnish healthcare registers, we identified 116 846 individuals, aged 45 to 75 years, who initiated statin therapy for primary prevention of cardiovascular disease. We measured adherence as proportion of days covered over an 18-month period since initiation and identified different adherence patterns based on monthly adherence with group based trajectory modeling. When adjusted for age, marital status, residential area, clinical characteristics, and copayment, low SEP was associated with statin nonadherence (proportion of days covered <80%) among men (eg, lowest versus highest income quintile: odds ratio, 1.41; 95% confidence interval, 1.32-1.50; basic versus higher-degree education: odds ratio, 1.18; 95% confidence interval, 1.13-1.24; unemployment versus employment: odds ratio, 1.17; 95% confidence interval, 1.10-1.25). Among women, the corresponding associations were different (P<0.001 for sex-by-income quintile, sex-by-education level, and sex-by-labor market status interactions) and mainly nonsignificant. Results based on adherence trajectories showed that men in low SEP were likely to belong to trajectories presenting a fast decline in adherence. CONCLUSIONS: Low SEP was associated with overall and rapidly increasing statin nonadherence among men. Conversely, in women, associations between SEP and nonadherence were weak and inconsistent. Group-based trajectory modeling provided insight into the dynamics of statin adherence and its association with SEP. PMID- 27756796 TI - Few Disparities in Baseline Laboratory Testing After the Diuretic or Digoxin Initiation by Medicare Fee-For-Service Beneficiaries. AB - BACKGROUND: Despite the persistence of significant disparities, few evaluations examine disparities in laboratory testing by race/ethnicity, age, sex, Medicaid eligibility, and number of chronic conditions for Medicare fee-for-service beneficiaries' newly prescribed medications. In Medicare beneficiaries initiating diuretics or digoxin, this study examined disparities in guideline-appropriate baseline laboratory testing and abnormal laboratory values. METHODS AND RESULTS: To evaluate guideline-concordant testing for serum creatinine and serum potassium within 180 days before or 14 days after the index prescription fill date, we constructed retrospective cohorts from 10 states of 99 711 beneficiaries who had heart failure or hypertension initiating diuretic in 2011 and 8683 beneficiaries who had heart failure or atrial fibrillation initiating digoxin. Beneficiaries initiating diuretics were less likely to have testing if they were non-Hispanic Black (relative risk [RR], 0.99; 95% confidence interval [CI], 0.98-0.99) than non-Hispanic White. Beneficiaries initiating diuretics and beneficiaries initiating digoxin were more likely to have testing if they had multiple chronic conditions relative to 0 to 1 conditions. Beneficiaries initiating diuretics with laboratory values were more likely to have an abnormal serum creatinine value at baseline if they were non-Hispanic Black (RR, 2.57; 95% CI, 1.91-3.44), other race (RR, 2.11; 95% CI, 1.08-4.10), or male (RR, 2.75; 95% CI, 2.14-3.52) or an abnormal serum potassium value if they were aged >=76 years (RR, 1.29; 95% CI, 1.09-1.51) or male (RR, 1.17; 95% CI, 1.03-1.33). CONCLUSIONS: Testing rates were consistently high, so there were negligible disparities in guideline-concordant testing of creatinine and potassium after the initiation of digoxin or diuretics by Medicare beneficiaries. PMID- 27756797 TI - Sex Differences in the Epidemiology of New-Onset In-Hospital Post-Coronary Artery Bypass Graft Surgery Atrial Fibrillation: A Large Multicenter Study. AB - BACKGROUND: New-onset atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG) is associated with increased morbidity and poorer long-term survival. Although many studies show differences in outcome in women versus men after CABG, little is known about the sex-specific incidence and characteristics of post-CABG AF. METHODS AND RESULTS: Overall, 11 236 consecutive patients without preoperative AF underwent isolated CABG from 2002 to 2010 at 4 US academic medical centers and 1 high-volume specialty cardiac hospital. Data routinely collected for the Society of Thoracic Surgeons database were augmented with details on new-onset post-CABG AF events detected via continuous in-hospital ECG/telemetry monitoring. Unadjusted incidence of post-CABG AF was 29.5% (3312/11 236) overall, 30.2% (2485/8214) in men, and 27.4% (827/3022) in women. After adjustment for Society of Thoracic Surgeons-recognized risk factors, women had significantly lower risk for post-CABG AF (odds ratio [95% confidence interval]=0.75 [0.64-0.89]), shorter first, longest, and total duration of AF episodes (mean difference [95% confidence interval]=-2.7 [-4.7 to -0.8] hours; 4.1 [-6.9 to -1.2] hours; -2.4 [-2.5 to -2.3] hours, respectively). At 48 hours, AF-free probabilities were 77% for women and 72% for men (P<0.001). Number of episodes (P=0.18), operative mortality (P=0.048), stroke (P=0.126), and discharge in AF (P=0.234) did not differ significantly by sex. CONCLUSIONS: These novel data on sex-specific characteristics of new-onset AF after isolated CABG show that women had lower adjusted risk for post-CABG AF and experienced shorter episodes. Investigation of sex-specific impacts on outcomes is needed to identify optimal strategies for prevention and management to ensure all patients achieve the best possible outcomes. PMID- 27756798 TI - National Cancer Institute-American Society of Clinical Oncology Teams in Cancer Care Project. PMID- 27756799 TI - Transforming Prior Authorization to Decision Support. AB - PURPOSE: To evaluate a computer-based prior authorization system that was designed to include and test two new concepts for physician review: (1) the tool would minimize denials by providing real-time decision support with alternative options if the original request was noncompliant, and (2) the tool would collect sufficient information to create a patient registry. METHODS: A new prior authorization tool incorporating real-time decision support was tested with a large national payer. The tool used the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology as the content for decision making. Physicians were asked to submit the minimal amount of clinical data necessary to reach a treatment-decision node within the National Comprehensive Cancer Network Guidelines. To minimize denials, all available recommended treatments were displayed for physician consideration and immediate authorization was granted for any compliant selection. RESULTS: During a 1-year pilot in a Florida commercial health plan, 4,272 eligible cases were reviewed with only 42 denials. Chemotherapy drug costs for the prior authorization pilot were compared with a similar time period in the previous year for the state of Florida, as well as for the Southeast region and for the nation, which served as controls. The percentage change between the time periods was -9% in Florida, 10% for the national costs, and 11% for the Southeast region costs. The difference between the regional increase and the Florida decrease represented a savings of $5.3 million dollars for the state of Florida in 1 year. CONCLUSION: There is significant opportunity to reduce the costs of therapy while being compliant with nationally accepted guidelines for cancer chemotherapy. PMID- 27756800 TI - Moving Toward Improved Teamwork in Cancer Care: The Role of Psychological Safety in Team Communication. AB - Effective communication is a requirement in the teamwork necessary for improved coordination to deliver patient-centered, value-based cancer care. Communication is particularly important when care providers are geographically distributed or work across organizations. We review organizational and teams research on communication to highlight psychological safety as a key determinant of high quality communication within teams. We first present the concept of psychological safety, findings about its communication effects for teamwork, and factors that affect it. We focus on five factors applicable to cancer care delivery: familiarity, clinical hierarchy-related status differences, geographic dispersion, boundary spanning, and leader behavior. To illustrate how these factors facilitate or hinder psychologically safe communication and teamwork in cancer care, we review the case of a patient as she experiences the treatment planning process for early-stage breast cancer in a community setting. Our analysis is summarized in a key principle: Teamwork in cancer care requires high quality communication, which depends on psychological safety for all team members, clinicians and patients alike. We conclude with a discussion of the implications of psychological safety in clinical care and suggestions for future research. PMID- 27756801 TI - Team Science in Cancer Care: Questions, an Observation, and a Caution. PMID- 27756802 TI - Chasing Certainty: Issues of Evidence and Value in Cancer Care. PMID- 27756803 TI - Association of passive and active smoking with pre-diabetes risk in a predominantly Hispanic population. AB - Smoking is the leading cause of avoidable death and is associated with type 2 diabetes (T2D) risk. Previous studies on the impact of passive smoking have not been applied to a Hispanic-majority population. We investigated the association between active smoking, exposure to environmental tobacco smoke (ETS), and pre diabetes risk in a New Mexico population. We hypothesized that pre-diabetes risk increases with increasing smoking status after adjustment for important covariates. We screened 219 adults from an ongoing study who were categorized according to their smoking status (never smoker, current smoker, previous smoker) and their exposure to ETS (exposed or unexposed). Glucose homeostasis status was assigned using A1c: no diabetes (A1c <5.7%), pre-diabetes (A1c 5.7-6.4%), and T2D (A1c >6.4%). Among 160 patients with complete data, 51.6% had no diabetes and 48.4% had pre-diabetes. The mean age was 44.8+/-13.5 years. The study population was predominantly female (64.4%), and the ethnic composition was 44.4% Hispanic, 39.4% non-Hispanic White (NHW), 10.6% American Indian, 2.5% African-American, and 3.1% other. Using a logistic model with 2-way interactions, all predicted probabilities for being at risk for pre-diabetes were significant at the 0.001 level for smoking status and ETS exposure after adjusting for age, sex, ethnicity, family history of diabetes, alcohol consumption, BMI, and blood pressure. Active or passive smoking is independently associated with pre-diabetes risk. PMID- 27756804 TI - Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial. AB - OBJECTIVE: The Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA). DESIGN: Eligible patients had IVT started within 4.5 hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformite Europeene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90 min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0-2 at day 90. RESULTS: Ten UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13-21). Median stroke onset to IVT start was 120 min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0-1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0-2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021). CONCLUSIONS: The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival. TRIAL REGISTRATION NUMBER: NCT01745692; Results. PMID- 27756805 TI - Widespread structural brain involvement in ALS is not limited to the C9orf72 repeat expansion. AB - BACKGROUND: In patients with a C9orf72 repeat expansion (C9+), a neuroimaging phenotype with widespread structural cerebral changes has been found. We aimed to investigate the specificity of this neuroimaging phenotype in patients with amyotrophic lateral sclerosis (ALS). METHODS: 156 C9- and 14 C9+ patients with ALS underwent high-resolution T1-weighted MRI; a subset (n=126) underwent diffusion-weighted imaging. Cortical thickness, subcortical volumes and white matter integrity were compared between C9+ and C9- patients. Using elastic net logistic regression, a model defining the neuroimaging phenotype of C9+ was determined and applied to C9- patients with ALS. RESULTS: C9+ patients showed cortical thinning outside the precentral gyrus, extending to the bilateral pars opercularis, fusiform, lingual, isthmus-cingulate and superior parietal cortex, and smaller volumes of the right hippocampus and bilateral thalamus, and reduced white matter integrity of the inferior and superior longitudinal fasciculus compared with C9- patients (p<0.05). Among 128 C9- patients, we detected a subgroup of 27 (21%) with a neuroimaging phenotype congruent to C9+ patients, while 101 (79%) C9- patients showed cortical thinning restricted to the primary motor cortex. C9- patients with a 'C9+' neuroimaging phenotype had lower performance on the frontal assessment battery, compared with other C9- patients with ALS (p=0.004). CONCLUSIONS: This study shows that widespread structural brain involvement is not limited to C9+ patients, but also presents in a subgroup of C9- patients with ALS and relates to cognitive deficits. Our neuroimaging findings reveal an intermediate phenotype that may provide insight into the complex relationship between genetic factors and clinical characteristics. PMID- 27756806 TI - Post-transcriptional regulation of photosynthetic genes is a key driver of C4 leaf ontogeny. AB - C4 photosynthesis allows highly efficient carbon fixation that originates from tightly regulated anatomical and biochemical modifications of leaf architecture. Recent studies showed that leaf transcriptome modifications during leaf ontogeny of closely related C3 (Tarenaya hassleriana) and C4 (Gynandropsis gynandra) species within the Cleomaceae family existed but they did not identify any dedicated transcriptional networks or factors specifically driving C4 leaf ontogeny. RNAseq analysis provides a steady-state quantification of whole-cell mRNAs but does not allow any discrimination between transcriptional and post transcriptional processes that may occur simultaneously during leaf ontogeny. Here we use exon-intron split analysis (EISA) to determine the extent to which transcriptional and post-transcriptional processes are involved in the regulation of gene expression between young and expanded leaves in both species. C4-specific changes in post-transcriptional regulation were observed for genes involved in the Calvin-Benson cycle and some photosystem components but not for C4 core-cycle genes. Overall, this study provides an unbiased genome-wide insight into the post transcriptional mechanisms that regulate gene expression through the control of mRNA levels and could be central to the onset of C4 photosynthesis. This mechanism is cytosolic which implies cell-specific modifications of mRNA stability. Understanding this mechanism may be crucial when aiming to transform C3 crops into C4 crops. PMID- 27756807 TI - Starting points in plant-bacteria nitrogen-fixing symbioses: intercellular invasion of the roots. AB - Agricultural practices contribute to climate change by releasing greenhouse gases such as nitrous oxide that are mainly derived from nitrogen fertilizers. Therefore, understanding biological nitrogen fixation in farming systems is beneficial to agriculture and environmental preservation. In this context, a better grasp of nitrogen-fixing systems and nitrogen-fixing bacteria-plant associations will contribute to the optimization of these biological processes. Legumes and actinorhizal plants can engage in a symbiotic interaction with nitrogen-fixing rhizobia or actinomycetes, resulting in the formation of specialized root nodules. The legume-rhizobia interaction is mediated by a complex molecular signal exchange, where recognition of different bacterial determinants activates the nodulation program in the plant. To invade plants roots, bacteria follow different routes, which are determined by the host plant. Entrance via root hairs is probably the best understood. Alternatively, entry via intercellular invasion has been observed in many legumes. Although there are common features shared by intercellular infection mechanisms, differences are observed in the site of root invasion and bacterial spread on the cortex reaching and infecting a susceptible cell to form a nodule. This review focuses on intercellular bacterial invasion of roots observed in the Fabaceae and considers, within an evolutionary context, the different variants, distribution and molecular determinants involved. Intercellular invasion of actinorhizal plants and Parasponia is also discussed. PMID- 27756809 TI - When Less is More. PMID- 27756808 TI - Membranous Nephropathy: Quantifying Remission Duration on Outcome. AB - Although change in proteinuria has been proposed as a surrogate for long-term prognosis in membranous nephropathy (MGN), variability in proteinuria levels and lag between these changes and acceptable end points, such as ESRD, has limited its utility. This cohort study examined the prognostic significance of remission duration in 376 patients with biopsy-proven idiopathic/primary MGN who achieved a remission after a period of nephrotic-range proteinuria. We defined complete remission (CR), partial remission (PR), and relapse as proteinuria <=0.3, 0.4 3.4, and >=3.5 g/d after CR or PR, respectively. The exposure variable was the remission status of patients at fixed landmarks (3, 6, 12, 24, and 36 months) after the date of first remission. The primary outcome was ESRD or 50% reduction in eGFR. We fitted Cox proportional hazards models to examine the association of remission status at each landmark and the primary end point. Persistent remission associated with unadjusted hazard ratios for the primary outcome that ranged by landmark from 0.35 (95% confidence interval, 0.20 to 0.61) to 0.56 (95% confidence interval, 0.31 to 1.04). Separate analyses for PR and CR yielded similar results. After adjustment, maintaining remission associated with significantly reduced risk of the primary outcome at all landmarks. Durable remissions associated with improved renal survival. Although the longer the remission, the greater the improvement, patients with remission durations as short as 3 months had improved renal prognosis compared with patients who relapsed. This study validates and quantifies PR and CR as surrogates for long term outcome in MGN. PMID- 27756810 TI - MiR-375 Mediates CRH Signaling Pathway in Inhibiting E2 Synthesis in Porcine Ovary. AB - The corticotropin-releasing hormone (CRH) signaling system is involved in numbers of stress-related physiological and pathological responses,including its inhibiting effects on estradiol (E2) synthesis and follicular development in the ovary. In addition, there are reports that microRNAs (miRNAs) can control the function of animal reproductive system. The aim of present study was to investigate the functions of miR-375 and the relationship between miR-375 and CRH signaling molecules in the porcine ovary. First, our common PCR results show that miR-375 and the CRH receptor 1 (CRHR1) are expressed in porcine ovary, whereas CRH receptor 2 (CRHR2) is not detected. We further have located the cell types of miR-375 and CRHR1 by in situ hybridization (ISH), and the results show that miR 375 is located only in the granulosa cells, whereas CRHR1 is positive in all of granulosa cells and oocytes, inferring that miR-375 and CRHR1 are co-localized in granulosa cells. Second, we show that overexpression of miR-375 in cultured granulosa cells suppresses the E2 production, while miR-375 knockdown demonstrates the opposite result. Besides, our in vitro results demonstrate that miR-375 mediates the signaling pathway of CRH inhibiting E2 synthesis. Finally, our data show that the action of miR-375 is accomplished by directly binding to the 3'UTR of specificity protein1 (SP1) mRNA to decrease the SP1 protein level. Thus, we conclude that miR-375 is a key factor in regulating E2 synthesis by mediating the CRH signaling pathway. PMID- 27756811 TI - Risk factors for hypoxemia following surgical repair of acute type A aortic dissection. AB - Objectives: To identify the risk factors for hypoxaemia following surgical repair of acute type A aortic dissection. Methods: This was a retrospective study of patients treated between October 2013 and December 2014 at the Department of Cardiovascular Surgery, Anzhen Hospital, China. Univariable and multivariable analyses were performed on the clinical data of 160 patients with acute type A dissection and who underwent ascending aortic and arch replacement under deep hypothermic circulatory arrest. Results: Hypoxaemia occurred in 30% (48/160) of patients (age: 49 +/- 7.9 years; 40 males, 83.3%). The duration of ventilation and the lengths of intensive care unit and hospital stays were significantly longer in patients with hypoxemia (77.9 +/- 56.0 vs 16.5 +/- 11.5 h, P < 0.0001; 6.0 +/- 2.3 vs 2.0 +/- 1.2 days, P = 0.001; 18.1 +/- 6.3 vs 13.5 +/- 4.7 days, P = 0.0012; respectively). The difference in operative mortality was not statistically significant between the hypoxaemia and non-hypoxaemia groups (6.25% vs 3.57%, P = 0.351). The independent risk factors of postoperative hypoxaemia were time from symptom onset to surgery <=72 h [odds ratio, 3.63; 95% confidence interval, 1.31-10.02; P = 0.013], preoperative PaO2/FiO2 <=300 (odds ratio, 15.30; 95% CI, 5.52-42.43; P < 0.001), preoperative white blood cell count >15 000/MUl (odds ratio, 9.79; 95% CI, 2.47-38.87; P = 0.001); and deep hypothermic circulatory arrest time >25 min (odds ratio, 3.26; 95% CI, 1.18-8.99; P = 0.023). Conclusions: Time from symptom onset to surgery <=72 h, preoperative PaO2/FiO2 <=300, white blood cell count >15 000/MUl and deep hypothermic circulatory arrest time >25 min were found to be independently associated with hypoxaemia after surgery for acute type A aortic dissection. PMID- 27756812 TI - The effectiveness of 10 years of interventions to control postoperative bleeding in adult cardiac surgery. AB - Objectives: Postoperative bleeding in cardiac surgery remains an important complication, leading to increased morbidity and mortality. Different interventions are possible to prevent/treat postoperative bleeding. The present study aims to investigate the effectiveness of these interventions in a real world scenario. Methods: This is a retrospective study based on 19 670 consecutive adult cardiac surgery patients operated from 2000 to 2015. During the study period, the following interventions have been applied and tested for effectiveness with a before versus after analysis: thromboelastography (TEG) based diagnosis and treatment in actively bleeding patients; platelet function tests (PFTs); timing of surgery based on PFTs; fresh frozen plasma (FFP)-free strategy using prothrombin complex concentrate and fibrinogen concentrate. Results: TEG-based diagnostic and therapeutic approach resulted in a significant (P = 0.006) reduction of postoperative bleeding and significant (P = 0.001) increase in platelet concentrate transfusion rate. Timing of surgery based on PFTs resulted in a significant reduction of postoperative bleeding (P = 0.001), surgical re-exploration rate (P = 0.002), FFP (P = 0.001) and platelet concentrate (P = 0.016) transfusion rate. FFP-free strategy was associated with a significant decrease in postoperative bleeding (P = 0.005) and FFP transfusions (P = 0.001). The combination of all the interventions was associated with a significant (P = 0.001) reduction in postoperative bleeding, surgical re exploration rate and FFP transfusions, whereas platelet concentrate transfusion rate was significantly (P = 0.001) higher. Conclusions: Despite a continuous increase in the bleeding risk profile, the application of a bundle of interventions is effective in controlling postoperative bleeding and related complications. Platelet transfusions remain unreplaceable in the present scenario. PMID- 27756813 TI - Stenotrophomonas maltophilia outer membrane vesicles elicit a potent inflammatory response in vitro and in vivo. AB - Stenotrophomonas maltophilia has become one of the most prevalent opportunistic pathogens in hospitalized patients. This microorganism secretes outer membrane vesicles (OMVs), but the pathogenesis of S. maltophilia as it relates to OMVs has not been characterized. This study investigated the cytotoxic activity of S. maltophilia OMVs and their ability to induce inflammatory responses both in vitro and in vivo Stenotrophomonas maltophilia ATCC 13637 and two clinical isolates were found to secrete spherical OMVs during in vitro culture. OMVs from S. maltophilia ATCC 13637 were cytotoxic to human lung epithelial A549 cells. Stenotrophomonas maltophilia OMVs stimulated the expression of proinflammatory cytokine and chemokine genes, including interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha and monocyte chemoattractant protein-1, in A549 cells. Early inflammatory responses such as congestion and neutrophilic infiltrations and profound expression of proinflammatory cytokine and chemokine genes were observed in the lungs of mice injected with S. maltophilia OMVs, and were similar to responses elicited by the bacteria. Our data demonstrate that S. maltophilia OMVs are important secretory nanocomplexes that elicit a potent inflammatory response that might contribute to S. maltophilia pathogenesis during infection. PMID- 27756814 TI - Synthetic Yeast as the New Frontier in Evolutionary Developments in Biology. PMID- 27756815 TI - Eating Behaviors and Dietary Changes in Patients With Dementia. AB - BACKGROUND: Eating problems and dietary changes have been reported in patients with dementia. OBJECTIVES: The aim of this article is to explore the generalized problems with nutrition, diet, feeding, and eating reported among patients with dementia. METHODS: Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published before 2016. Search terms used included behavioral and psychological symptoms of dementia, dementia, dietary changes, eating behavior. Publications found through this indexed search were reviewed for further relevant references. RESULTS: Abnormal eating behaviors, eating problems, and dietary changes are present in most people with dementia, especially in the later stages of the condition. CONCLUSION: Individuals with dementia frequently develop serious feeding difficulties and changes in eating and dietary habits. The changes may be secondary to cognitive impairment or apraxia, or the result of insufficient caregiving, or the consequence of metabolic or neurochemical abnormalities occurring as part of the dementing process. PMID- 27756816 TI - The Plant Cell Begins Opt-in Publishing of Peer Review Reports. PMID- 27756817 TI - Adults' Daily Walking for Travel and Leisure: Interaction Between Attitude Toward Walking and the Neighborhood Environment. AB - PURPOSE: Studies on how the interaction of psychological and environmental characteristics influences walking are limited, and the results are inconsistent. Our aim is to examine how the attitude toward walking and neighborhood environments interacts to influence walking. DESIGN: Cross-sectional phone and mail survey. SETTING: Participants randomly sampled from 6 study sites including Los Angeles, Chicago, Baltimore, Minneapolis, Manhattan, and Bronx Counties in New York City, and Forsyth and Davidson Counties in North Carolina. PARTICIPANTS: The final sample consisted of 2621 persons from 2011 to 2012. MEASURES: Total minutes of walking for travel or leisure, attitude toward walking, and perceptions of the neighborhood environments were self-reported. Street Smart (SS) Walk Score (a measure of walkability derived from a variety of geographic data) was obtained for each residential location. ANALYSIS: Linear regression models adjusting for age, gender, race/ethnicity, education, and income. RESULTS: Attitude toward walking was positively associated with walking for both purposes. Walking for travel was significantly associated with SS Walk Score, whereas walking for leisure was not. The SS Walk Score and selected perceived environment characteristics were associated with walking in people with a very positive attitude toward walking but were not associated with walking in people with a less positive attitude. CONCLUSION: Attitudes toward walking and neighborhood environments interact to affect walking behavior. PMID- 27756818 TI - Control of Autophagy in Chlamydomonas Is Mediated through Redox-Dependent Inactivation of the ATG4 Protease. AB - Autophagy is a major catabolic pathway by which eukaryotic cells deliver unnecessary or damaged cytoplasmic material to the vacuole for its degradation and recycling in order to maintain cellular homeostasis. Control of autophagy has been associated with the production of reactive oxygen species in several organisms, including plants and algae, but the precise regulatory molecular mechanisms remain unclear. Here, we show that the ATG4 protease, an essential protein for autophagosome biogenesis, plays a central role for the redox regulation of autophagy in the model green alga Chlamydomonas reinhardtii Our results indicate that the activity of C. reinhardtii ATG4 is regulated by the formation of a single disulfide bond with a low redox potential that can be efficiently reduced by the NADPH/thioredoxin system. Moreover, we found that treatment of C. reinhardtii cells with norflurazon, an inhibitor of carotenoid biosynthesis that generates reactive oxygen species and triggers autophagy in this alga, promotes the oxidation and aggregation of ATG4. We propose that the activity of the ATG4 protease is finely regulated by the intracellular redox state, and it is inhibited under stress conditions to ensure lipidation of ATG8 and thus autophagy progression in C. reinhardtii. PMID- 27756819 TI - Winter Memory throughout the Plant Kingdom: Different Paths to Flowering. PMID- 27756820 TI - Endogenous Bioactive Jasmonate Is Composed of a Set of (+)-7-iso-JA-Amino Acid Conjugates. AB - Jasmonates (JAs) regulate a wide range of plant defense and development processes. The bioactive JA is perceived by its receptor COI1 to trigger the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins and subsequently derepress the JAZ-repressed transcription factors for activation of expression of JA-responsive genes. So far, (+)-7-iso-JA-l-Ile has been the only identified endogenous bioactive JA molecule. Here, we designed coronafacic acid (CFA) conjugates with all the amino acids (CFA-AA) to mimic the JA amino acid conjugates, and revealed that (+)-7-iso-JA-Leu, (+)-7-iso-JA-Val, (+)-7-iso-JA-Met, and (+)-7-iso-JA-Ala are new endogenous bioactive JA molecules. Furthermore, our studies uncover the general characteristics for all the bioactive JA molecules, and provide a new strategy to synthetically generate novel active JA molecules. PMID- 27756821 TI - Dynamic Interplay between Nucleoid Segregation and Genome Integrity in Chlamydomonas Chloroplasts. AB - The chloroplast (cp) genome is organized as nucleoids that are dispersed throughout the cp stroma. Previously, a cp homolog of bacterial recombinase RecA (cpRECA) was shown to be involved in the maintenance of cp genome integrity by repairing damaged chloroplast DNA and by suppressing aberrant recombination between short dispersed repeats in the moss Physcomitrella patens Here, overexpression and knockdown analysis of cpRECA in the green alga Chlamydomonas reinhardtii revealed that cpRECA was involved in cp nucleoid dynamics as well as having a role in maintaining cp genome integrity. Overexpression of cpRECA tagged with yellow fluorescent protein or hemagglutinin resulted in the formation of giant filamentous structures that colocalized exclusively to chloroplast DNA and cpRECA localized to cp nucleoids in a heterogenous manner. Knockdown of cpRECA led to a significant reduction in cp nucleoid number that was accompanied by nucleoid enlargement. This phenotype resembled those of gyrase inhibitor-treated cells and monokaryotic chloroplast mutant cells and suggested that cpRECA was involved in organizing cp nucleoid dynamics. The cp genome also was destabilized by induced recombination between short dispersed repeats in cpRECA-knockdown cells and gyrase inhibitor-treated cells. Taken together, these results suggest that cpRECA and gyrase are both involved in nucleoid dynamics and the maintenance of genome integrity and that the mechanisms underlying these processes may be intimately related in C. reinhardtii cps. PMID- 27756822 TI - Dirigent Protein Mode of Action Revealed by the Crystal Structure of AtDIR6. AB - Dirigent proteins impart stereoselectivity to phenoxy radical coupling reactions in plants and, thus, play an essential role in the biosynthesis of biologically active natural products. This includes the regioselective and enantioselective coupling and subsequent cyclization of two coniferyl alcohol radicals to pinoresinol as the committed step of lignan biosynthesis. The reaction is controlled by dirigent proteins, which, depending on the species and protein, direct the reaction to either (+)- or (-)-pinoresinol. We present the crystal structure of the (-)-pinoresinol forming DIRIGENT PROTEIN6 (AtDIR6) from Arabidopsis (Arabidopsis thaliana) with data to 1.4 A resolution. The structure shows AtDIR6 as an eight-stranded antiparallel beta-barrel that forms a trimer with spatially well-separated cavities for substrate binding. The binding cavities are two lobed, exhibiting two opposing pockets, each lined with a set of hydrophilic and potentially catalytic residues, including essential aspartic acids. These residues are conserved between (+) and (-)-pinoresinol-forming DIRs and required for activity. The structure supports a model in which two substrate radicals bind to each of the DIR monomers. With the aromatic rings fixed in the two pockets, the propionyl side chains face each other for radical-radical coupling, and stereoselectivity is determined by the exact positioning of the side chains. Extensive mutational analysis supports a previously unrecognized function for DIRs in catalyzing the cyclization of the bis-quinone methide reaction intermediate to yield (+)- or (-)-pinoresinol. PMID- 27756823 TI - DEFECTIVE KERNEL1 (DEK1) Regulates Cell Walls in the Leaf Epidermis. AB - The plant epidermis is crucial to survival, regulating interactions with the environment and controlling plant growth. The phytocalpain DEFECTIVE KERNEL1 (DEK1) is a master regulator of epidermal differentiation and maintenance, acting upstream of epidermis-specific transcription factors, and is required for correct cell adhesion. It is currently unclear how changes in DEK1 lead to cellular defects in the epidermis and the pathways through which DEK1 acts. We have combined growth kinematic studies, cell wall analysis, and transcriptional analysis of genes downstream of DEK1 to determine the cause of phenotypic changes observed in DEK1-modulated lines of Arabidopsis (Arabidopsis thaliana). We reveal a novel role for DEK1 in the regulation of leaf epidermal cell wall structure. Lines with altered DEK1 activity have epidermis-specific changes in the thickness and polysaccharide composition of cell walls that likely underlie the loss of adhesion between epidermal cells in plants with reduced levels of DEK1 and changes in leaf shape and size in plants constitutively overexpressing the active CALPAIN domain of DEK1. Calpain-overexpressing plants also have increased levels of cellulose and pectins in epidermal cell walls, and this is correlated with the expression of several cell wall-related genes, linking transcriptional regulation downstream of DEK1 with cellular effects. These findings significantly advance our understanding of the role of the epidermal cell walls in growth regulation and establish a new role for DEK1 in pathways regulating epidermal cell wall deposition and remodeling. PMID- 27756824 TI - MicroRNA-9 inhibits high glucose-induced proliferation, differentiation and collagen accumulation of cardiac fibroblasts by down-regulation of TGFBR2. AB - To investigate the effects of miR-9 on high glucose (HG)-induced cardiac fibrosis in human cardiac fibroblasts (HCFs), and to establish the mechanism underlying these effects. HCFs were transfected with miR-9 inhibitor or mimic, and then treated with normal or HG. Cell viability and proliferation were detected by using the Cell Counting Kit-8 (CCK-8) assay and Brdu-ELISA assay. Cell differentiation and collagen accumulation of HCFs were detected by qRT-PCR and Western blot assays respectively. The mRNA and protein expressions of transforming growth factor-beta receptor type II (TGFBR2) were determined by qRT PCR and Western blotting. Up-regulation of miR-9 dramatically improved HG-induced increases in cell proliferation, differentiation and collagen accumulation of HCFs. Moreover, bioinformatics analysis predicted that the TGFBR2 was a potential target gene of miR-9 Luciferase reporter assay demonstrated that miR-9 could directly target TGFBR2. Inhibition of TGFBR2 had the similar effect as miR-9 overexpression. Down-regulation of TGFBR2 in HCFs transfected with miR-9 inhibitor partially reversed the protective effect of miR-9 overexpression on HG induced cardiac fibrosis in HCFs. Up-regulation of miR-9 ameliorates HG-induced proliferation, differentiation and collagen accumulation of HCFs by down regulation of TGFBR2. These results provide further evidence for protective effect of miR-9 overexpression on HG-induced cardiac fibrosis. PMID- 27756825 TI - The association between dietary vitamin A intake and pancreatic cancer risk: a meta-analysis of 11 studies. AB - Whether dietary vitamin A intake could reduce pancreatic cancer risk is still conflicting. We therefore conducted a meta-analysis to summarize the evidence from epidemiological studies. We searched the databases of PubMed and Web of Knowledge up to July 2016. Random model was used to combine study-specific relative risks (RR) and 95% confidence interval (CI). Publication bias was assessed by Egger regression asymmetry test and Begg's funnel plot. Eleven studies (10 case-control studies and 1 cohort study) involving 2705 pancreatic cancer cases were included in the present study. The RR (95% CI) of pancreatic cancer for highest category of vitamin A intake compared with lowest category was 0.839 (95% CI=0.712-0.988) with low heterogeneity detected (I2=17.8%, Pheterogeneity=0.274). The relationships were also significant for studies designed by case-control [RR=0.808, 95% CI=0.690-0.947], as well as in European population [RR=0.821, 95% CI=0.693-0.972]. No evidence of publication bias was found. This meta-analysis demonstrated that dietary vitamin A intake might inversely associated with the risk of pancreatic cancer. PMID- 27756826 TI - Effect of polymer rigidity on the phase behaviour of polymer adsorption on to planar surface. AB - We study the process of a semiflexible polymer chain adsorption on to planar surface by the dynamic Monte Carlo (DMC) method, based on the 3D off-lattice model. Both the strength of attractive monomer-surface interaction (epsilona) and bending energy (b) have pronounced effect on the adsorption and shape of semiflexible polymer chain. The semiflexible polymer can just fully adsorb on to the surface at certain epsilona, which is defined as critical epsilona The essential features of the semiflexible polymer adsorption on to surface are that (i) the critical epsilona increases with increase in b; (ii) the shape of the fully adsorbed semiflexible polymer chain is film-like toroid, and the toroid becomes more and more perfect with increase in b In addition, the size of toroid and the number of turns of toroid can be controlled by the b and epsilona. PMID- 27756827 TI - Arrival by ambulance explains variation in mortality by time of admission: retrospective study of admissions to hospital following emergency department attendance in England. AB - BACKGROUND: Studies finding higher mortality rates for patients admitted to hospital at weekends rely on routine administrative data to adjust for risk of death, but these data may not adequately capture severity of illness. We examined how rates of patient arrival at accident and emergency (A&E) departments by ambulance-a marker of illness severity-were associated with in-hospital mortality by day and time of attendance. METHODS: Retrospective observational study of 3 027 946 admissions to 140 non-specialist hospital trusts in England between April 2013 and February 2014. Patient admissions were linked with A&E records containing mode of arrival and date and time of attendance. We classified arrival times by day of the week and daytime (07:00 to 18:59) versus night (19:00 to 06:59 the following day). We examined the association with in-hospital mortality within 30 days using multivariate logistic regression. RESULTS: Over the week, 20.9% of daytime arrivals were in the highest risk quintile compared with 18.5% for night arrivals. Daytime arrivals on Sundays contained the highest proportion of patients in the highest risk quintile at 21.6%. Proportions of admitted patients brought in by ambulance were substantially higher at night and higher on Saturday (61.1%) and Sunday (60.1%) daytimes compared with other daytimes in the week (57.0%). Without adjusting for arrival by ambulance, risk-adjusted mortality for patients arriving at night was higher than for daytime attendances on Wednesday (0.16 percentage points). Compared with Wednesday daytime, risk adjusted mortality was also higher on Thursday night (0.15 percentage points) and increased throughout the weekend from Saturday daytime (0.16 percentage points) to Sunday night (0.26 percentage points). After adjusting for arrival by ambulance, the raised mortality only reached statistical significance for patients arriving at A&E on Sunday daytime (0.17 percentage points). CONCLUSION: Using conventional risk-adjustment methods, there appears to be a higher risk of mortality following emergency admission to hospital at nights and at weekends. After accounting for mode of arrival at hospital, this pattern changes substantially, with no increased risk of mortality following admission at night or for any period of the weekend apart from Sunday daytime. This suggests that risk-adjustment based on inpatient administrative data does not adequately account for illness severity and that elevated mortality at weekends and at night reflects a higher proportion of more severely ill patients arriving by ambulance at these times. PMID- 27756830 TI - The use of dynamic external fixation in the treatment of dorsal fracture subluxations and pilon fractures of finger proximal interphalangeal joints. AB - : The aim of this study was to review the outcome of the treatment of finger proximal interphalangeal joint dorsal fracture subluxations and pilon fractures with a modified external fixator. We treated 36 patients (36 fingers). We assessed the ranges of motion and patient satisfaction. At final follow-up, 23 patients had no pain; 11 had pain in the cold; and two also had mild pain. None had moderate or severe pain. The mean range of proximal interphalangeal joint motion was 86 degrees (60 degrees -100 degrees ). The mean total active range of finger motion was 244 degrees (range 200 degrees -265 degrees ). This system is simple, cheap and relatively easily applied. It gives stable fixation that allows early mobilization. LEVEL OF EVIDENCE: IV. PMID- 27756831 TI - Identity constructions and transition to adulthood for young people with mild intellectual disabilities. AB - This article explores the self-constructions of young adults with mild intellectual disabilities in talk about their everyday living and how parents and professionals construct young adults with disabilities in talk about their involvement in transition processes. The analysis is related to an interpretive tradition and conducted based on individual interviews with four young adults with mild intellectual disability, five parents of young adults with mild intellectual disabilities and five professionals in the adult service system. The findings show that the young adults define themselves as actors in their own lives, while the parents recognize young adults with mild intellectual disabilities as both actors with resources and actors in need of assistance. Professionals in the adult service system, however, appear to rely on an identity perspective that might hamper young adults' agency positioning and opportunities to define themselves and influence their future lives. PMID- 27756828 TI - Signatures of Archaic Adaptive Introgression in Present-Day Human Populations. AB - Comparisons of DNA from archaic and modern humans show that these groups interbred, and in some cases received an evolutionary advantage from doing so. This process-adaptive introgression-may lead to a faster rate of adaptation than is predicted from models with mutation and selection alone. Within the last couple of years, a series of studies have identified regions of the genome that are likely examples of adaptive introgression. In many cases, once a region was ascertained as being introgressed, commonly used statistics based on both haplotype as well as allele frequency information were employed to test for positive selection. Introgression by itself, however, changes both the haplotype structure and the distribution of allele frequencies, thus confounding traditional tests for detecting positive selection. Therefore, patterns generated by introgression alone may lead to false inferences of positive selection. Here we explore models involving both introgression and positive selection to investigate the behavior of various statistics under adaptive introgression. In particular, we find that the number and allelic frequencies of sites that are uniquely shared between archaic humans and specific present-day populations are particularly useful for detecting adaptive introgression. We then examine the 1000 Genomes dataset to characterize the landscape of uniquely shared archaic alleles in human populations. Finally, we identify regions that were likely subject to adaptive introgression and discuss some of the most promising candidate genes located in these regions. PMID- 27756832 TI - Slow Down and Enjoy: The Effects of Cycling Cadence on Pleasure. AB - Pleasure plays a key role in exercise behavior. However, the influence of cycling cadence needs to be elucidated. Here, we verified the effects of cycling cadence on affect, perceived exertion (ratings of perceived exertion), and physiological responses. In three sessions, 15 men performed a maximal cycling incremental test followed by two 30-min constant workload (50% of peak power) bouts at 60 and 100 r/min. The pleasure was higher when participants cycled at 60 r/min, whereas ratings of perceived exertion, heart rate, and oxygen uptake were lower ( p < .05). Additionally, the rate of decrease in pleasure and increase in ratings of perceived exertion was less steep at 60 r/min ( p < .01). Cycling at 60 r/min is more pleasant, and the perceived effort and physiological demand are lower than at 100 r/min. PMID- 27756833 TI - The frontal cortex as a network hub controlling mood and cognition: Probing its neurochemical substrates for improved therapy of psychiatric and neurological disorders. AB - The highly-interconnected and neurochemically-rich frontal cortex plays a crucial role in the regulation of mood and cognition, domains disrupted in depression and other central nervous system disorders, and it is an important site of action for their therapeutic control. For improving our understanding of the function and dysfunction of the frontal cortex, and for identifying improved treatments, quantification of extracellular pools of neuromodulators by microdialysis in freely-moving rodents has proven indispensable. This approach has revealed a complex mesh of autoreceptor and heteroceptor interactions amongst monoaminergic pathways, and led from selective 5-HT reuptake inhibitors to novel classes of multi-target drugs for treating depression like the mixed alpha2-adrenoceptor/5 HT reuptake inhibitor, S35966, and the clinically-launched vortioxetine and vilazodone. Moreover, integration of non-monoaminergic actions resulted in the discovery and development of the innovative melatonin receptor agonist/5-HT2C receptor antagonist, Agomelatine. Melatonin levels, like those of corticosterone and the "social hormone", oxytocin, can now be quantified by microdialysis over the full 24 h daily cycle. Further, the introduction of procedures for measuring extracellular histamine and acetylcholine has provided insights into strategies for improving cognition by, for example, blockade of 5-HT6 and/or dopamine D3 receptors. The challenge of concurrently determining extracellular levels of GABA, glutamate, d-serine, glycine, kynurenate and other amino acids, and of clarifying their interactions with monoamines, has also been resolved. This has proven important for characterizing the actions of glycine reuptake inhibitors that indirectly augment transmission at N-methyl-d-aspartate receptors, and of "glutamatergic antidepressants" like ketamine, mGluR5 antagonists and positive modulators of AMPA receptors (including S47445). Most recently, quantification of the neurotoxic proteins Abeta42 and Tau has extended microdialysis studies to the pathogenesis of neurodegenerative disorders, and another frontier currently being broached is microRNAs. The present article discusses the above themes, focusses on recent advances, highlights opportunities for clinical "translation", and suggests avenues for further progress. PMID- 27756834 TI - Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. AB - In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukemia patients. The UK Chronic Lymphocytic Leukaemia Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year "discontinuation free survival" and 1 year overall survival. With a median of 16 months follow up, data on 315 patients demonstrated a 1 year discontinuation-free survival of 73.7% and a 1 year overall survival of 83.8%. Patients with better pre-treatment performance status (0/1 vs. 2+) had superior discontinuation-free survival (77.5% vs. 61.3%; P<0.0001) and overall survival (86.3% vs. 76.0%; P=0.0001). In univariable analysis, overall survival and discontinuation-free survival were not associated with the number of prior lines of therapy or 17p deletion. However, multivariable analysis identified an interaction between prior lines of therapy, age and 17p deletion, suggesting that older patients with 17p deletion did worse when treated with ibrutinib beyond the second line. Overall, 55.6% of patients had no first year dose reductions or treatment breaks of >14 days and had an overall survival rate of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks of >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year overall survival: 91.7%), but patients who had first year treatment breaks of >14 days, particularly permanent cessation of ibrutinib had both reduced 1 year overall survival (68.5%), and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year overall survival; 90%: progression-free survival; 84%), this may partly reflect the inclusion of performance status 2+ patients, and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression. PMID- 27756836 TI - Effects of a multicomponent exercise program in institutionalized elders with Alzheimer's disease. AB - This study examined the effect of a Multicomponent Training (MT) intervention on cognitive function, functional fitness and anthropometric variables in institutionalized patients with Alzheimer's disease (AD). Thirty-seven institutionalized elders (84.05 +/- 5.58 years) clinically diagnosed with AD (mild and moderate stages) were divided into two groups: Experimental Group (EG, n = 19) and Control Group (CG, n = 18). The EG participated in a six-month supervised MT program (aerobic, muscular resistance, flexibility and postural exercises) of 45-55 minutes/session, twice/week. Cognitive function (MMSE), physical fitness (Senior Fitness Test) and anthropometric variables (Body Mass Index and Waist Circumference), were assessed before (M1), after three months (M2) and after six months (M3) of the experimental protocol. A two-way ANOVA, with repeated measures, revealed significant group and time interactions on cognitive function, chair stand, arm curl, 2-min step, 8-foot up-and-go (UG), chair sit-and-reach (CSR) and back scratch tests as well as waist circumference. Accordingly, for those variables a different response in each group was evident over the time, supported by a significantly better EG performance in chair stand, arm curl, 2-min step, UG, CSR and back scratch tests from M1 to M3, and a significant increase in MMSE from M1 to M2. The CG's performance decreased over time (M1 to M3) in chair stand, arm curl, 2-min step, UG, CSR, back scratch and MMSE. Results suggest that MT programs may be an important non-pharmacological strategy to improve physical and cognitive functions in institutionalized AD patients. PMID- 27756835 TI - New insights on hereditary erythrocyte membrane defects. AB - After the first proposed model of the red blood cell membrane skeleton 36 years ago, several additional proteins have been discovered during the intervening years, and their relationship with the pathogenesis of the related disorders have been somewhat defined. The knowledge of erythrocyte membrane structure is important because it represents the model for spectrin-based membrane skeletons in all cells and because defects in its structure underlie multiple hemolytic anemias. This review summarizes the main features of erythrocyte membrane disorders, dividing them into structural and altered permeability defects, focusing particularly on the most recent advances. New proteins involved in alterations of the red blood cell membrane permeability were recently described. The mechanoreceptor PIEZO1 is the largest ion channel identified to date, the fundamental regulator of erythrocyte volume homeostasis. Missense, gain-of function mutations in the PIEZO1 gene have been identified in several families as causative of dehydrated hereditary stomatocytosis or xerocytosis. Similarly, the KCNN4 gene, codifying the so called Gardos channel, has been recently identified as a second causative gene of hereditary xerocytosis. Finally, ABCB6 missense mutations were identified in different pedigrees of familial pseudohyperkalemia. New genomic technologies have improved the quality and reduced the time of diagnosis of these diseases. Moreover, they are essential for the identification of the new causative genes. However, many questions remain to solve, and are currently objects of intensive studies. PMID- 27756837 TI - Malignant Pleural Effusion and ascites Induce Epithelial-Mesenchymal Transition and Cancer Stem-like Cell Properties via the Vascular Endothelial Growth Factor (VEGF)/Phosphatidylinositol 3-Kinase (PI3K)/Akt/Mechanistic Target of Rapamycin (mTOR) Pathway. AB - Malignant pleural effusion (PE) and ascites, common clinical manifestations in advanced cancer patients, are associated with a poor prognosis. However, the biological characteristics of malignant PE and ascites are not clarified. Here we report that malignant PE and ascites can induce a frequent epithelial-mesenchymal transition program and endow tumor cells with stem cell properties with high efficiency, which promotes tumor growth, chemoresistance, and immune evasion. We determine that this epithelial-mesenchymal transition process is mainly dependent on VEGF, one initiator of the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway. From the clinical observation, we define a therapeutic option with VEGF antibody for malignant PE and ascites. Taken together, our findings clarify a novel biological characteristic of malignant PE and ascites in cancer progression and provide a promising and available strategy for cancer patients with recurrent/refractory malignant PE and ascites. PMID- 27756838 TI - Nucleosomes Selectively Inhibit Cas9 Off-target Activity at a Site Located at the Nucleosome Edge. AB - Nucleosomes affect Cas9 binding and activity at on-target sites, but their impact at off-target sites is unknown. To investigate how nucleosomes affect Cas9 cleavage at off-target sites in vitro, we used a single guide RNA (sgRNA) that has been previously shown to efficiently direct Cas9 cleavage at the edge of the strongly positioned 601 nucleosome. Our data indicate that single mismatches between the sgRNA and DNA target have relatively little effect on Cas9 cleavage of naked DNA substrates, but strongly inhibit cleavage of nucleosome substrates, particularly when the mismatch is in the sgRNA "seed" region. These findings indicate that nucleosomes may enhance Cas9 specificity by inhibiting cleavage of off-target sites at the nucleosome edge. PMID- 27756839 TI - Necroptosis-like Neuronal Cell Death Caused by Cellular Cholesterol Accumulation. AB - Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure. DNA microarray analysis revealed that the gene levels for cholesterol transport (LDL receptor and NPC2) as well as cholesterol biosynthesis (mevalonate pathway enzymes) are increased after exposure to 3 mm l-Nor for ~6 h. Concomitant with this observation, the master transcriptional regulator of cholesterol homeostasis, SREBP-2, is activated by l-Nor. The increase in cholesterol uptake as well as biosynthesis is not accompanied by an increase in cholesterol in the plasma membrane, but rather by aberrant accumulation in cytoplasmic compartments. We also found that cell death by l-Nor can be suppressed by nec-1s, an inhibitor of a regulated form of necrosis, necroptosis. Abrogation of SREBP-2 activation by the small molecule inhibitor betulin or by overexpression of dominant-negative SREBP-2 efficiently reduces cell death by l-Nor. The mobilization of cellular cholesterol in the presence of cyclodextrin also suppresses cell death. These results were also observed in primary culture of striatum neurons. Taken together, our results indicate that the excessive uptake as well as synthesis of cholesterol should underlie neuronal cell death by l-Nor exposure, and suggest a possible link between lysosomal cholesterol storage disorders and the regulated form of necrosis in neuronal cells. PMID- 27756840 TI - Fatty Acid Binding to the Allosteric Subunit of Cyclooxygenase-2 Relieves a Tonic Inhibition of the Catalytic Subunit. AB - Prostaglandin endoperoxide H synthase-2 (PGHS-2), also called cyclooxygenase-2 (COX-2), converts arachidonic acid to PGH2 PGHS-2 is a conformational heterodimer composed of allosteric (Eallo) and catalytic (Ecat) subunits. Fatty acids (FAs) bind to Arg-120 of Eallo increasing to different degrees, depending on the FA, the Vmax of its Ecat partner. We report here that movement of helical residues 120-122 and loop residues 123-129 of Eallo underlies the allosteric effects of FAs and allosteric COX-2 inhibitors, including naproxen and flurbiprofen. An S121P substitution in both PGHS-2 monomers yields a variant (S121P/S121P PGHS-2) that has 1.7-1.8 times the Vmax of native PGHS-2 and is relatively insensitive to activation by FAs or inhibition by allosteric inhibitors. The S121P substitution in Eallo is primarily responsible for these effects. In X-ray crystal structures, the Calpha atoms of helical residues 119-122 of S121P/S121P PGHS-2 are displaced from their normal positions. Additionally, the S121P/S121P PGHS-2 variants in which Pro-127 and Ser-541 are replaced by cysteines spontaneously forms Cys-127 to Cys-541 cross-links between monomers. This is unlike the corresponding native PGHS-2 variant and suggests that S121P substitutions also unhinge the loop involving residues 123-129. We conclude the following: (a) the region involving residues 120-129 of unoccupied Eallo tonically inhibits Ecat; (b) binding of an activating FA (e.g. arachidonic, palmitic, or oleic acid) to Eallo or an S121P substitution in Eallo repositions this region to increase Ecat activity; and (c) allosteric COX inhibitors act by preventing FA binding to Eallo and additionally by relocating Eallo residues to inhibit Ecat. PMID- 27756841 TI - Electrogenic Binding of Intracellular Cations Defines a Kinetic Decision Point in the Transport Cycle of the Human Serotonin Transporter. AB - The plasmalemmal monoamine transporters clear the extracellular space from their cognate substrates and sustain cellular monoamine stores even during neuronal activity. In some instances, however, the transporters enter a substrate-exchange mode, which results in release of intracellular substrate. Understanding what determines the switch between these two transport modes demands time-resolved measurements of intracellular (co-)substrate binding and release. Here, we report an electrophysiological investigation of intracellular solute-binding to the human serotonin transporter (SERT) expressed in HEK-293 cells. We measured currents induced by rapid application of serotonin employing varying intracellular (co-)substrate concentrations and interpreted the data using kinetic modeling. Our measurements revealed that the induction of the substrate exchange mode depends on both voltage and intracellular Na+ concentrations because intracellular Na+ release occurs before serotonin release and is highly electrogenic. This voltage dependence was blunted by electrogenic binding of intracellular K+ and, notably, also H+ In addition, our data suggest that Cl- is bound to SERT during the entire catalytic cycle. Our experiments, therefore, document an essential role of electrogenic binding of K+ or of H+ to the inward facing conformation of SERT in (i) cancelling out the electrogenic nature of intracellular Na+ release and (ii) in selecting the forward-transport over the substrate-exchange mode. Finally, the kinetics of intracellular Na+ release and K+ (or H+) binding result in a voltage-independent rate-limiting step where SERT may return to the outward-facing state in a KCl- or HCl-bound form. PMID- 27756842 TI - An Intronic Enhancer Element Regulates Angiotensin II Type 2 Receptor Expression during Satellite Cell Differentiation, and Its Activity Is Suppressed in Congestive Heart Failure. AB - Patients with advanced congestive heart failure (CHF) or chronic kidney disease often have increased angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II, via its type 1 receptor, causes muscle protein breakdown and apoptosis and inhibits satellite cell (SC) proliferation and muscle regeneration, likely contributing to cachexia in CHF and chronic kidney disease. In contrast, Ang II, via its type 2 receptor (AT2R) expression, is robustly induced during SC differentiation, and it potentiates muscle regeneration. To understand the mechanisms regulating AT2R expression and its potential role in muscle regeneration in chronic diseases, we used a mouse model of CHF and found that muscle regeneration was markedly reduced and that this was accompanied by blunted increase of AT2R expression. We performed AT2R promoter reporter analysis during satellite cell differentiation and found that the 70 bp upstream of the AT2R transcription start site contain a core promoter region, and regions upstream of 70 bp to 3 kbp are dispensable for AT2R induction. Instead, AT2R intron 2 acts as a transcriptional enhancer during SC differentiation. Further deletion/mutation analysis revealed that multiple transcription factor binding sites in the +286/+690 region within intron 2 coordinately regulate AT2R transcription. Importantly, +286/+690 enhancer activity was suppressed in CHF mouse skeletal muscle, suggesting that AT2R expression is suppressed in CHF via inhibition of AT2R intronic enhancer activity, leading to lowered muscle regeneration. Thus targeting intron 2 enhancer element could lead to the development of a novel intervention to increase AT2R expression in SCs and potentiate skeletal muscle regenerative capacity in chronic diseases. PMID- 27756843 TI - Mechanism of Sirt1 NAD+-dependent Protein Deacetylase Inhibition by Cysteine S Nitrosation. AB - The sirtuin family of proteins catalyze the NAD+-dependent deacylation of acyl lysine residues. Humans encode seven sirtuins (Sirt1-7), and recent studies have suggested that post-translational modification of Sirt1 by cysteine S-nitrosation correlates with increased acetylation of Sirt1 deacetylase substrates. However, the mechanism of Sirt1 inhibition by S-nitrosation was unknown. Here, we show that Sirt1 is transnitrosated and inhibited by the physiologically relevant nitrosothiol S-nitrosoglutathione. Steady-state kinetic analyses and binding assays were consistent with Sirt1 S-nitrosation inhibiting binding of both the NAD+ and acetyl-lysine substrates. Sirt1 S-nitrosation correlated with Zn2+ release from the conserved sirtuin Zn2+-tetrathiolate and a loss of alpha-helical structure without overall thermal destabilization of the enzyme. Molecular dynamics simulations suggested that Zn2+ loss due to Sirt1 S-nitrosation results in repositioning of the tetrathiolate subdomain away from the rest of the catalytic domain, thereby disrupting the NAD+ and acetyl-lysine-binding sites. Sirt1 S-nitrosation was reversed upon exposure to the thiol-based reducing agents, including physiologically relevant concentrations of the cellular reducing agent glutathione. Reversal of S-nitrosation resulted in full restoration of Sirt1 activity only in the presence of Zn2+, consistent with S nitrosation of the Zn2+-tetrathiolate as the primary source of Sirt1 inhibition upon S-nitrosoglutathione treatment. PMID- 27756844 TI - Electrostatic and Structural Bases of Fe2+ Translocation through Ferritin Channels. AB - Ferritin molecular cages are marvelous 24-mer supramolecular architectures that enable massive iron storage (>2000 iron atoms) within their inner cavity. This cavity is connected to the outer environment by two channels at C3 and C4 symmetry axes of the assembly. Ferritins can also be exploited as carriers for in vivo imaging and therapeutic applications, owing to their capability to effectively protect synthetic non-endogenous agents within the cage cavity and deliver them to targeted tissue cells without stimulating adverse immune responses. Recently, X-ray crystal structures of Fe2+-loaded ferritins provided important information on the pathways followed by iron ions toward the ferritin cavity and the catalytic centers within the protein. However, the specific mechanisms enabling Fe2+ uptake through wild-type and mutant ferritin channels is largely unknown. To shed light on this question, we report extensive molecular dynamics simulations, site-directed mutagenesis, and kinetic measurements that characterize the transport properties and translocation mechanism of Fe2+ through the two ferritin channels, using the wild-type bullfrog Rana catesbeiana H' protein and some of its variants as case studies. We describe the structural features that determine Fe2+ translocation with atomistic detail, and we propose a putative mechanism for Fe2+ transport through the channel at the C3 symmetry axis, which is the only iron-permeable channel in vertebrate ferritins. Our findings have important implications for understanding how ion permeation occurs, and further how it may be controlled via purposely engineered channels for novel biomedical applications based on ferritin. PMID- 27756845 TI - Oxidized Guanine Base Lesions Function in 8-Oxoguanine DNA Glycosylase-1-mediated Epigenetic Regulation of Nuclear Factor kappaB-driven Gene Expression. AB - A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation. Here, we document TNFalpha-induced enrichment of both 8-oxoG and OGG1 in promoters of pro-inflammatory genes, which precedes interaction of NF-kappaB with its DNA-binding motif. OGG1 bound to 8-oxoG upstream from the NF-kappaB motif increased its DNA occupancy by promoting an on rate of both homodimeric and heterodimeric forms of NF-kappaB. OGG1 depletion decreased both NF-kappaB binding and gene expression, whereas Nei-like glycosylase-1 and -2 had a marginal effect. These results are the first to document a novel paradigm wherein the DNA repair protein OGG1 bound to its substrate is coupled to DNA occupancy of NF-kappaB and functions in epigenetic regulation of gene expression. PMID- 27756847 TI - Optimizing Transition to Home Enteral Nutrition for Pediatric Patients. AB - Enteral nutrition is delivered via the gastrointestinal tract when oral intake is not sufficient to maintain nutrition status. There is evidence that long-term home enteral nutrition (HEN) can be advantageous to pediatric patients by improving quality of life and function. Data from pediatric patients receiving either nasogastric tube or gastrostomy tube feeds indicate good outcomes in terms of maintaining and improving nutrition status as evidenced by anthropometric measurements. As the number of pediatric patients requiring HEN increases, development of an effective program to allow smooth transition to the home is necessary. The formation of a multidisciplinary HEN management team can achieve the important task of taking care of children requiring HEN who are technology dependent. Members of a multidisciplinary HEN team can include care coordinators, nurses, physicians, dietitians, and speech therapists. Planning for patient discharge to home should start well before the actual discharge, with timely identification of home caregivers, the family's learning style, and completion of other requirements for safe administration of HEN. Education should be provided in a continuum, starting at the identification of nutrition support while still in the hospital and continuing after discharge to address concerns and long-term complications of HEN. PMID- 27756846 TI - SYVN1, NEDD8, and FBXO2 Proteins Regulate DeltaF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation. AB - We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (DeltaF508/DeltaF508) airway epithelia partially restored DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl- conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of DeltaF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored DeltaF508-CFTR mediated Cl- transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of DeltaF508-CFTR-mediated Cl- conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade DeltaF508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating DeltaF508-CFTR ubiquitination. PMID- 27756848 TI - Parenteral Nutrition Trace Element Product Shortage Considerations. PMID- 27756849 TI - ENFit Enteral Nutrition Connectors. AB - New enteral connectors are now available based on the development of standards using the International Organization of Standardization process to prevent misconnections between systems that should not connect. Enteral devices with the new patient access connectors, called ENFit, are being now introduced for the purpose of improving patient safety. Transitioning to these new connectors poses benefits and challenges for facilities or agencies implementing these new devices. Information from appropriate resources should be sought by clinicians who need to partner with their suppliers and clinical organizations to see how best to meet these challenges. PMID- 27756850 TI - Visualization of Multidimensional Data in Nursing Science. AB - Nursing scientists have long been interested in complex, context-dependent questions addressing individual- and population-level challenges in health and illness. These critical questions require multilevel data (e.g., genetic, physiologic, biologic, behavioral, affective, and social). Advances in data gathering methods have resulted in the collection of large sets of complex, multifaceted, and often non-comparable data. Scientific visualization is a powerful methodological tool for facilitating understanding of these multidimensional data sets. Our purpose is to demonstrate the utility of scientific visualization as a method for identifying associations, patterns, and trends in multidimensional data as exemplified in two studies. We describe a brief history of visual analysis, processes involved in scientific visualization, and opportunities and challenges in the use of visualization methods. Scientific visualization can play a crucial role in helping nurse scientists make sense of the structure and underlying patterns in their data to answer vital questions in the field. PMID- 27756851 TI - Does the Theory of Planned Behavior Predict Dietary Sodium Intake in Patients With Heart Failure? AB - Sodium intake in heart failure (HF) is a crucial but poorly understood phenomenon. Theoretical models promote understanding and provide a context for rational appraisal of complex situations. The purpose of this study was to determine which factors were associated with sodium intake in HF patients using theory of planned behavior (TPB). In this study, patients' ( N = 244) attitudes, subjective norms, and perceived behavioral control (tenets of the TPB) were assessed using the Dietary Sodium Restriction Questionnaire. Sodium intake was estimated objectively by 24-hr urinary sodium excretion (UNa). The average UNa was 3,811 mg. Subjective norms, gender, and New York Heart Association functional class were associated with sodium intake ( p < .001). Thus, it is important for health care providers to clearly express their approval of following low-sodium diet to their HF patients, and include significant others in interventions to help patients develop/maintain a positive subjective norm to decrease sodium intake and reduce HF exacerbations. PMID- 27756852 TI - Framework for Mining and Analysis of Standardized Nursing Care Plan Data. AB - Despite an unprecedented amount of health-related data being amassed from various technological innovations, our ability to process this data and extract hidden knowledge has yet to catch up with this explosive growth. Although nursing care plans can be an effective tool to support the achievement of desired patient outcomes, their online collection, storage, and processing is lagging far behind. As a result, the impact of nursing care is not well understood from qualitative as well as quantitative perspectives. In this article, we first outline a complete life cycle of nursing care data, and present a knowledge discovery and analysis framework for such data sets. We also highlight Big Data issues pertaining to the analysis of nursing care data. Using an exemplar data set, we demonstrate the broad applicability of the proposed framework by showing knowledge discovery results for different outcomes related to patients, nursing staff, and administrators. PMID- 27756854 TI - The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment. AB - OBJECTIVE: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the simulated adult workplace environment. METHOD: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. RESULTS: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 +/- 11.24 vs. 255.6 +/ 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality ( p = .9542). CONCLUSION: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD. PMID- 27756853 TI - Novel Analytic Methods Needed for Real-Time Continuous Core Body Temperature Data. AB - Affordable measurement of core body temperature (Tc) in a continuous, real-time fashion is now possible. With this advance comes a new data analysis paradigm for occupational epidemiology. We characterize issues arising after obtaining Tc data over 188 workdays for 83 participating farmworkers, a population vulnerable to effects of rising temperatures due to climate change. We describe a novel approach to these data using smoothing and functional data analysis. This approach highlights different data aspects compared with describing Tc at a single time point or summaries of the time course into an indicator function (e.g., did Tc ever exceed 38 degrees C, the threshold limit value for occupational heat exposure). Participants working in ferneries had significantly higher Tc at some point during the workday compared with those working in nurseries, despite a shorter workday for fernery participants. Our results typify the challenges and opportunities in analyzing Big Data streams from real-time physiologic monitoring. PMID- 27756855 TI - Inhibin-B secretion and FSH isoform distribution may play an integral part of follicular selection in the natural menstrual cycle. AB - The aim of the present paper is to expand the concept on how follicular selection takes place in the follicular phase of the natural menstrual cycle. It is suggested that inhibin-B exerts a more intimate role in this process than previously understood. Inhibin-B shows a peak in the circulation around cycle day 7, simultaneous with selection of the dominant follicle, whereas levels of estradiol and inhibin-A only start to increase a few days later suggesting that inhibin-B is mainly responsible for downregulating pituitary FSH release. New data now demonstrate that the circulatory peak of inhibin-B is reflected by peak production of inhibin-B, in contrast to inhibin-A, in the selected follicle with a diameter of 10-12 mm, where concentrations are one thousand times higher than in the circulation. This high inhibin-B concentration also exerts paracrine effects, stimulating theca cell androgen production in concert with LH. New data now suggest that in the corresponding granulosa cells androgens upregulate FSH receptor (FSHR) and LH receptor (LHR) mRNA expression, which in turn stimulate CYP19a mRNA expression providing the follicles which most effectively undertake these processes with the best chance of becoming selected. Inhibin-B production is stimulated by FSH and it appears that the acidic isoforms of FSH induce inhibin-B secretion most efficiently thereby, for the first time, placing the changing FSH isoform profile during the follicular phase in a physiological context. Collectively, it appears that inhibin-B is an integral part of follicular selection in the normal menstrual cycle, exerting both endocrine and paracrine effects and facilitating continued growth of the selected follicle. PMID- 27756856 TI - Social Work Contribution to Desistance Among At-Risk Youth. AB - Desistance as a process to forgo delinquent habits is an important target for intervention into youth at risk of delinquency. The intervention through social work services, nevertheless, has not clearly demonstrated its effectiveness. For such a demonstration, the present study examines the contribution of social work services with reference to the voluntaristic theory of action. The theory suggests that promoting the youth's voluntarism underlying desistance, encompassing appreciation, facilitation, observation, and identification concerning desistance is essential. The suggestion leads to the hypothesis that social work services promote the youth's desistance through the promotion of voluntarism for desistance. This hypothesis gets support from this study of 586 at-risk youths in Hong Kong, with data collected from both the youths and their responsible social workers. The support implies the value of social work services for sustaining the youth's desistance. PMID- 27756857 TI - Genetic analysis of rare coding mutations in CELSR1-3 in Chinese Congenital Heart and Neural Tube Defects. AB - The planar cell polarity (PCP) pathway is critical for proper embryonic development of the neural tube and heart. Mutations in these genes have previously been implicated in the pathogenesis of neural tube defects (NTDs), but not in congenital heart defects (CHDs) in humans. We systematically identified the mutation patterns of CELSR1-3 , one family of the core PCP genes, in human cohorts composed of 352 NTD cases, 412 CHD cases, and matched controls. A total of 72 disease-specific rare novel coding mutations were identified, of which 37 were identified in CHD cases, and 36 were identified in NTD patients. Most of these mutations differed between the two cohorts, as only one novel missense mutation in CELSR1 (c.2609G>A p.P870L) was identified in both NTD and CHD patients. Both in vivo and in vitro assays revealed that CELSR1 P870L is a gain of-function mutation. It up-regulates not only the PCP pathway, but also canonical WNT signaling in cells, and also induced both NTDs and CHDs in Zebrafish embryos. As almost equal numbers of mutations were identified in each cohort, our results provided the first evidence that mutations in CELSR genes are as likely to be associated with CHDs as with NTDs, although the specific mutations differ between the two cohorts. Such differences in mutation panels suggested that CELSRs might be regulated differently during the development of these two organ systems. PMID- 27756858 TI - School Administrator Perceptions of Cyberbullying Facilitators and Barriers to Preventive Action: A Qualitative Study. AB - BACKGROUND: Schools are often held responsible for preventing or addressing cyberbullying, yet little is known about school administrator perceptions of cyberbullying and the challenges they face in addressing this public health issue. AIMS: The goal of this study is to examine school administrators' perceptions of the facilitators of cyberbullying and barriers to primary and secondary prevention strategies. METHOD: Public school administrators ( N = 36) participated in in-depth interviews about bullying and discussed their experiences with cyberbullying and their perceptions of cyberbullying facilitators and barriers to prevention. RESULTS: Three main themes arose from the analysis: (1) cyberbullying as a major challenge; (2) facilitators of cyberbullying and barriers to preventive action, including parents and technology; and (3) prevention efforts, including unclear jurisdiction for action, primary versus secondary prevention efforts, and technology attributes that facilitate school response to bullying. DISCUSSION: Although administrators perceive cyberbullying as a major challenge facing their schools, they are often unsure about appropriate primary and secondary prevention efforts. Relationships with parents and police complicate response and prevention as schools attempt to navigate unclear jurisdiction. Additionally, technology presents a challenge to schools because it is seen as an enabler of cyberbullying, a facilitator of prevention, and a necessary part of education efforts. CONCLUSION: Lack of research on prevention strategies, parents' knowledge and attitudes, and confusion about responsibility for addressing cyberbullying are barriers to action. Findings suggest administrators could benefit from additional clarity on which strategies are most effective for primary prevention of cyberbullying, and that prevention strategies should proactively involve parents to promote effective collaboration with schools. PMID- 27756859 TI - A specifically designed aquatic exercise protocol to reduce chronic lower limb edema. AB - Objective Despite the fact that muscle pump activation is known to positively impact chronic lower limb edema, objective measurements of standardized exercises for venous-lymphatic rehab are lacking. The aim of this investigation is to determine the effectiveness of an addressed physical activity exploiting the advantages of an aquatic environment. Material and methods Thirty-two lower limbs of 16 patients affected by bilateral chronic leg swelling were included (12 females, 4 males). All the patients underwent a protocol of five sessions of physical exercises specifically conceived inside a pool. Volumetry, subcutaneous thickness, ankle range of motion and symptomatology were assessed as outcome measures. Results One week after the end of the protocol, the average reduction in lower limb volume was 303.13 +/- 69.72 ml ( p = 0.00002) and 334.38 +/- 62.50 ml ( p = 0.000003) in the right and left legs, respectively. Ankle range of motion and feeling of heaviness significantly improved. Conclusion A specifically designed aquatic protocol is able to positively impact chronic leg swelling offering a first line rehab for this medical condition. PMID- 27756860 TI - Territories of Engagement in the Design of Ecohumanist Healthcare Environments. AB - BACKGROUND: Increasingly, architectural and allied designers, engineers, and healthcare facility administrators are being challenged to demonstrate success in adroitly identifying and contextualizing ever-shifting and expanding spheres of knowledge with respect to the role of energy conservation and carbon neutrality in healthcare treatment environments and their immediate exterior environs. AIM: This calls for making sense of an unprecedented volume of information on building energy usage and interdigitizing complex and at times contradictory goals with the daily requirements of building occupants. Ecohumanist Design Strategies: In response, a multidimensional framework is put forth with the aim of advancing theory and practice in the realm of designers', direct caregivers', and administrators' engagement with ecohumanist design strategies in the creation of ecohumanist healthcare environments. CONCLUSIONS: Ten territories for engagement are presented that both individually and collectively express salient themes and streams of inquiry in theory and practice, within an operative framework placing the patient, the patient's significant others, and the caregiver at the center of the relationship between the built environment and occupant well-being. PMID- 27756861 TI - Organizing the Evidence for Healthcare Design Projects. AB - OBJECTIVE: This methodology column provides project leaders with helpful tools to organize the evidence analysis for healthcare design projects. BACKGROUND: Searching the evidence to support a design change is encouraged both to guide the development of a project and to determine whether the project is performance improvement, evidence-based design change, or novel research. METHODS: A project charter, evidence summary grid, stem and leaf plot, and decision algorithm are presented as tools to guide evidence analysis at the start of a healthcare design project. CONCLUSIONS: Properly searching the evidence and analyzing results sets the stage for project development and may lead to the dissemination or generation of knowledge from which to set design standards. PMID- 27756862 TI - Structural Characterization of a Capillary Microfluidic Chip Using Microreflectance. AB - The structural characterization of capillary microfluidic chips is important for reliable applications. In particular, nondestructive diagnostic tools to assess geometrical dimensions and their correlations with control processes are of much importance, preferably if they are implemented in situ. Several techniques to accomplish this task have been reported; namely, optical coherence tomography (OCT) jointly with confocal fluorescence microscopy (CFM) to investigate internal features of lab-on-a-chip technologies. In this paper, we report on the use of a simple optical technique, based on near-normal incidence microreflectance, which allows mapping internal features of a microfluidic chip in a straightforward way. Our setup is based on a charge-coupled device camera that allows a lateral resolution of ~2.5 um and allows us to measure in the wavelength range of 640-750 nm. The technique takes advantage of the Fabry-Perot interferences features in the reflectance spectra, which are further analyzed by a discrete Fourier transform. In this way, the amplitude of the Fourier coefficients is modulated by the presence of a microfluidic channel. PMID- 27756863 TI - Carbonate and Silicate Abundance Indexing in Coarse-Grained River Sediments Using Diffuse Reflection Infrared Spectroscopy (DRIFTS) and Ion-Beam-Induced Luminescence (IBIL) Spectroscopies. AB - Two different types of spectroscopic methods, namely diffuse reflection infrared spectroscopy (DRIFTS) as a vibrational spectroscopy and ion-beam-induced luminescence (IBIL) as an optical spectroscopy, have been exploited for the analysis of three sand samples collected from the Adige, Bacchiglione, and Brenta rivers (Veneto, Northern Italy) with the aim to set up a procedure for the comparison of the relative abundance of silicates, carbonates, and feldspars. By fitting the spectra, the features corresponding to different geological compounds have been identified and descriptive indexes of their relative amount have been obtained by comparing the peak area ratios. PMID- 27756864 TI - Molar Absorptivity Measurements in Absorbing Solvents: Impact on Solvent Absorptivity Values. AB - Molar absorptivity is a fundamental molecular property that quantifies absorption strength as a function of wavelength. Absolute measurements of molar absorptivity demand accounting for all mechanisms of light attenuation, including reflective losses at interfaces associated with the sample. Ideally, such measurements are performed in nonabsorbing solvents and reflective losses can be determined in a straightforward manner from Fresnel equations or effectively accounted for by path length difference methods. At near-infrared wavelengths, however, many solvents, including water, are absorbing which complicates the quantification of reflective losses. Here, generalized equations are developed for calculating absolute molar absorptivities of neat liquids wherein the dependency of reflective loss on absorption properties of the liquid are considered explicitly. The resulting equations are used to characterize sensitivity of absolute molar absorptivity measurements for solvents to the absorption strength of the solvent as well as the path length of the measurement. Methods are derived from these equations to properly account for reflective losses in general and the effectiveness of these methods is demonstrated for absolute molar absorptivity measurements for water over the combination region (5000-4000 cm-1) of the near infrared spectrum. Results indicate that ignoring solvent absorption effects can incorporate wide ranging systematic errors depending upon experimental conditions. As an example, systematic errors range from 0 to 10% for common conditions used in the measurement of absolute molar absorptivity of water over the combination region of the near-infrared spectrum. PMID- 27756866 TI - How well do farmers know their badgers? Relating farmer knowledge to ecological survey data. AB - Knowledge of badger distribution is important for the management of bovine tuberculosis. At the farm level, typically the only information on badger activity available is from the farmers themselves. This study compares how well farmer perceptions of badger activity match data obtained from ecological surveys. Farmer estimates of numbers of badger setts (burrows) surrounding their farms were generally correlated with field survey results, but tended to be underestimates. Farmers correctly recorded 50 per cent of setts recorded in surveys, with larger setts and active setts more likely to be correctly recorded. Badger visits to farm buildings and yards were also monitored using surveillance cameras. The majority of farmers were aware of badger visits to their farm buildings, but in 22 per cent of cases farmers were not aware of badger visits. At the farm level, knowledge of badger activity will be useful in informing vets and animal health professionals of the potential risks of disease transmission, and hence directing management interventions. However, the tendency to underestimate activity, combined with a lack of detailed knowledge of sett locations, means that farmer estimates of badger activity should be interpreted with caution and in isolation may not be sufficient to inform management interventions. PMID- 27756865 TI - The Effect of VASER Abdominal Liposuction on Metabolic Profile in Overweight Males. AB - The aim of the current study was to examine the liposuction-induced metabolic changes with regard to release of major adipokines and insulin sensitivity in overweight male patients. Seventeen overweight male patients aged 37.15 +/- 9.60 years (6 with diabetes type 2, 11 without comorbidities) and 10 age-matched healthy lean controls were enrolled in the study. Using Vibration Amplification of Sound Energy at Resonance System, ultrasound assisted liposuction was applied onto the deep layers of abdominal subcutaneous adipose tissue. The mean volume supranatant fat was 2208 +/- 562 ml. To eliminate the confounding effects of postsurgical inflammation and to evaluate delayed metabolic effects, fasting blood was collected on the day of liposuction, within 1 to 2 months and more than 6 months after surgery. Serum leptin, soluble receptor for leptin, adiponectin, insulin, and glucose concentrations were tested and insulin sensitivity was calculated using updated model Homeostasis Model Assessment 2. Both treatment groups (diabetic and nondiabetic patients) experienced similar postsurgical weight reduction with concomitant lowering of body mass index value at 1 to 2 months follow-up, which was sustained after 6 months from surgery. Improvement in insulin sensitivity at 1 to 2 months follow-up was observed ( p = .017 and p = .002, for diabetics and nondiabetics, respectively) and this change persisted over the next 4 months. At the same time, no significant changes in adipokines and soluble leptin receptor were found. These data demonstrate that in terms of metabolic consequences, Vibration Amplification of Sound Energy at Resonance abdominal liposuction might have beneficial effects in overweight diabetic and nondiabetic males by improving their insulin sensitivity. PMID- 27756867 TI - Corrigendum. AB - Oliver SM, Coetzee JC, Nilsson LJ, Samuelson KM, Stone RM, Fritz JE, Giveans MR. Early patient satisfaction results on a modern generation fixed-bearing total ankle arthroplasty. Foot Ankle Int. 2016;37(9):938-943. (Original DOI: 10.1177/1071100716648736 ). PMID- 27756868 TI - Effect of Insurance on Rates of Total Ankle Arthroplasty Versus Arthrodesis for Tibiotalar Osteoarthritis. AB - BACKGROUND: Several studies have examined the effect of insurance on the management of various orthopedic conditions. The purpose of our study was to assess the effect of insurance and other demographic factors on the operative management of tibiotalar osteoarthritis. METHODS: The National Inpatient Sample (NIS) database was used to identify patients who underwent a total ankle arthroplasty (TAA) or tibiotalar arthrodesis (TTA) for tibiotalar osteoarthritis. Insurance status was identified for each patient, and the proportions of each insurance type were computed for each operative modality. A multivariate analysis was performed to account for confounding variables to isolate the effect of insurance type on operative treatment. RESULTS: From 2007 to 2012, a total of 10 010 patients (35.6%) were identified who underwent a total ankle replacement (TAR) procedure and 18 094 patients (64.4%%) who underwent TTA for tibiotalar osteoarthritis. Patients receiving a TAR were older (65.8 vs 64.2, P < .001), more likely to be female (54% vs 51%, P < .001), and had fewer comorbidities (4.2 vs 4.5, P < .001) than patients who underwent a TTA. After controlling for baseline differences, patients with Medicare (odds ratio [OR] 3.00, P < .001), and private insurance (OR 3.19, P < .001) were approximately 3 times more likely to undergo TAR than patients with Medicaid. CONCLUSIONS: Patients with tibiotalar osteoarthritis were more likely to receive a TAR procedure if they had Medicare or private insurance compared with patients who had Medicaid. Further research should be done to better understand the drivers of this phenomenon if equitable care is to be achieved. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 27756869 TI - Correction of Hammertoe Deformity With Novel Intramedullary PIP Fusion Device Versus K-Wire Fixation. AB - BACKGROUND: K-wire fixation has been the most common method of fixation for hammertoe deformity. However intramedullary devices are gaining ground in both number of available choices and in procedures performed. This study aimed to compare the outcomes of hammertoe correction performed with K-wire fixation versus a novel intramedullary fusion device (CannuLink). METHODS: A retrospective review of hammertoe correction by a single surgeon was performed from June 2011 to December 2013. Sixty patients (95 toes) underwent K-wire fixation and 39 patients (54 toes) underwent fusion with the CannuLink implant. Average age was 61.7 years and 61.4 years, respectively. Average length of follow-up was 12.9 and 12.3 months, respectively. Patients were evaluated for medical comorbidities, smoking status, inflammatory arthritis, peripheral vascular disease, peripheral neuropathy, pre- and postoperative visual analog pain scale, bony union percentage, revision rate, complications (hardware and surgery-related), and persistent symptoms at last follow-up. There was no significant difference in demographics or comorbidities between the 2 groups ( P > .05). RESULTS: In the K wire group, 16 patients (18 toes) remained symptomatic at last follow-up (27%). Nine toes (9.5%) had recurrent deformity, 3 toes (3%) developed a late infection because of the recurrent deformity, and 1 toe (1%) developed partial numbness. One patient suffered a calf deep vein thrombosis (DVT) and peroneal nerve neuritis, 1 patient developed foot drop, and 3 patients continued to complain of pain. Five toes required revision surgery (5.3%). In the intramedullary group, 3 (7.7%) patients remained symptomatic and all were associated with a complication. One patient developed chronic regional pain syndrome in the foot, a calf DVT, and a nonfatal pulmonary embolus. A second patient developed a painless recurrent deformity. A third patient had wound dehiscence. Nobody had hardware failure or required a second operation. CONCLUSION: The CannuLink intramedullary device for hammertoe correction resulted in fewer complications, only 1 recurrent deformity, and no reoperations compared with K-wire fixation. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 27756870 TI - Early Goal-Directed Therapy in Severe Sepsis and Septic Shock: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. AB - INTRODUCTION: The Surviving Sepsis Campaign guidelines recommend early goal directed therapy (EGDT) for the resuscitation of patients with sepsis; however, the recent evidences quickly evolve and convey conflicting results. We performed a meta-analysis to evaluate the effect of EGDT on mortality in adults with severe sepsis and septic shock. METHODS: We searched electronic databases to identify randomized controlled trials that compared EGDT with usual care or lactate-guided therapy in adults with severe sepsis and septic shock. Predefined primary outcome was all-cause mortality at final follow-up. RESULTS: We included 13 trials enrolling 5268 patients. Compared with usual care, EGDT was associated with decreased mortality (risk ratio [RR]: 0.87, 95% CI: 0.77-0.98; 4664 patients, 8 trials; Grading of Recommendations Assessment, Development, and Evaluation [GRADE] quality of evidence was moderate). Compared with lactate clearance-guided therapy, EGDT was associated with increased mortality (RR: 1.60, 95% CI: 1.24 2.06; 604 patients, 5 trials; GRADE quality of evidence was low). Patients assigned to EGDT received more intravenous fluid, red cell transfusion, vasopressor infusion, and dobutamine use within the first 6 hours than those assigned to usual care (all P values < .00001). CONCLUSION: Adults with severe sepsis and septic shock who received EGDT had a lower mortality than those given usual care, the benefit may mainly be attributed to treatments administered within the first 6 hours. However, the underlying mechanisms by which lactate clearance-guided therapy benefits these patients are yet to be investigated. PMID- 27756871 TI - Letter by Acampa et al Regarding Article, "Underutilization of Ambulatory ECG Monitoring After Stroke and Transient Ischemic Attack: Missed Opportunities for Atrial Fibrillation Detection". PMID- 27756872 TI - Isoscapes: a new dimension in community ecology. PMID- 27756873 TI - Neighborhood-Level Factors Related to Asthma in Children Living in Urban Areas. AB - Asthma disproportionately affects children who are non-White and of low socioeconomic status. One innovative approach to address these health disparities is to investigate the child's neighborhood environment and factors influencing asthma symptoms. The purpose of this integrative review is to critique research investigating the relationships between neighborhood-level factors and asthma morbidity in urban children. Three literature databases were searched using the terms "asthma," "child," "neighborhood," and "urban." The articles included were organized into six themes within the larger domains of prevalence, physical, and social factors. Literature tables provide in-depth analysis of each article and demonstrate a need for strengthening analysis methods. The current research points to the necessity for a multilevel study to analyze neighborhood-level factors that are associated with increased asthma morbidity in urban children. School nurse clinicians, working within children's neighborhoods, are uniquely positioned to assess modifiable neighborhood-level determinants of health in caring for children with asthma. PMID- 27756874 TI - Mechanism of melanoma cells selective apoptosis induced by a photoactive NADPH analogue. AB - Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment.NS1 established an early Endoplasmic Reticulum stress by the early release of calcium mediated by (a) calcium dependent redox-sensitive ion channel(s). These events initiated autophagy and apoptosis in all tested melanoma cells independently of their mutational status. The autophagy promoted by NS1 was incomplete. The autophagic flux was blocked at late stage events, consistent with the accumulation of p62, and a close localization of LC3 with NS1 associated with NS1 inhibition of NOX1 in autophagosomes. This hypothesis of a specific incomplete autophagy and apoptosis driven by NS1 was comforted by the use of siRNAs and pharmacological inhibitors blocking different processes. This study highlights the potential therapeutic interest of NS1 inducing cell death by triggering a selective ER stress and incomplete autophagy in melanoma cells harbouring wt and BRAF mutation. PMID- 27756875 TI - Eriocalyxin B, a natural diterpenoid, inhibited VEGF-induced angiogenesis and diminished angiogenesis-dependent breast tumor growth by suppressing VEGFR-2 signaling. AB - Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid isolated from the plant Isodon eriocalyx var. laxiflora, has emerged as a promising anticancer agent. The effects of EriB on angiogenesis were explored in the present study. Here we demonstrated that the subintestinal vein formation was significantly inhibited by EriB treatment (10, 15 MUM) in zebrafish embryos, which was resulted from the alteration of various angiogenic genes as shown in transcriptome profiling. In human umbilical vein endothelial cells, EriB treatment (50, 100 nM) could significantly block vascular endothelial growth factors (VEGF)-induced cell proliferation, tube formation, cell migration and cell invasion. Furthermore, EriB also caused G1 phase cell cycle arrest which was correlated with the down regulation of the cyclin D1 and CDK4 leading to the inhibition of phosphorylated retinoblastoma protein expression. Investigation of the signal transduction revealed that EriB inhibited VEGF-induced phosphorylation of VEGF receptor-2 via the interaction with the ATP-binding sites according to the molecular docking simulations. The suppression of VEGFR-2 downstream signal transduction cascades was also observed. EriB was showed to inhibit new blood vessel formation in Matrigel plug model and mouse 4T1 breast tumor model. EriB (5 mg/kg/day) treatment was able to decrease tumor vascularization and suppress tumor growth and angiogenesis. Taken together, our findings suggested that EriB is a novel inhibitor of angiogenesis through modulating VEGFR-2 signaling pathway, which could be developed as a promising anti-angiogenic agent for treatment of angiogenesis-related human diseases, such as cancer. PMID- 27756876 TI - Suppression of skin tumorigenesis in CD109-deficient mice. AB - CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation. Immunohistochemical analysis revealed a higher level of TGF-beta protein expression in the dermis of CD109-deficient mice than in that of wild-type mice. Additionally, immunofluorescence analysis showed that Smad2 phosphorylation and Nrf2 expression were enhanced in primary keratinocytes from CD109-deficient mice compared with in those from wild-type mice. Although no significant difference was found in conversion rates from papilloma to carcinoma between wild-type and CD109-deficient mice in the carcinogenesis model, we observed fewer and smaller papillomas in CD109-deficient mice than in wild-type mice. Apoptosis and DNA damage marker levels were significantly reduced in CD109 deficient skin compared with in wild-type skin at 24 h after 7, 12-dimethylbenz (alpha) anthracene treatment. Furthermore, mutation-specific PCR revealed that the mutation frequency of the H-ras gene was less in CD109-deficient skin than in wild-type skin in this model. These results suggest that CD109 deficiency suppresses skin tumorigenesis by enhancing TGF-beta/Smad/Nrf2 pathway activity and decreasing the mutation frequency of the H-ras gene. PMID- 27756877 TI - Marsdenia tenacissimae extraction (MTE) inhibits the proliferation and induces the apoptosis of human acute T cell leukemia cells through inactivating PI3K/AKT/mTOR signaling pathway via PTEN enhancement. AB - Marsdenia tenacissimae extraction (MTE) as a traditional Chinese herb has long been used to treat some diseases such as tumors in China. However, the potential effectiveness of MTE in leukemia has not yet been fully understood, and the related molecular mechanism is still unknown. In the present study, we aimed to evaluate the effects of MTE on the proliferation and apoptosis of Jurkat cells (T ALL lines) and lymphocytes from T-ALL (T-cell acute lymphoblastic leukemia) patients. Firstly, CCK8 assays and flow cytometry assays revealed that MTE dose dependently reduced the proliferation of Jurkat cells by arresting cell cycle at S phase. Secondly, Annexin V-FITC/PI-stained flow cytometry and TUNEL staining assays showed that MTE promoted the apoptosis of Jurkat cells. Mechanistically, MTE enhanced PTEN (phosphatases and tensin homolog) level and inactivated PI3K/AKT/mTOR signaling pathway in Jurkat cells, which mediated the inhibition of cell proliferation by MTE and MTE-induced apoptosis. Finally, MTE significantly inhibited the proliferation and promoted the apoptosis of lymphocytes from T-ALL patients, compared with lymphocytes from healthy peoples. Taken together, these results reveal an unrecognized function of MTE in inhibiting the proliferation and inducing the apoptosis of T-ALL cells, and identify a pathway of PTEN/PI3K/AKT/mTOR for the effects of MTE on leukemia therapy. PMID- 27756878 TI - Plumbagin protects liver against fulminant hepatic failure and chronic liver fibrosis via inhibiting inflammation and collagen production. AB - Plumbagin is a quinonoid constituent extracted from Plumbago genus, and it exhibits diverse pharmacological effects. This study thoroughly investigated the effects of plumbagin on thioacetamide-induced acute and chronic liver injury. Results shown that plumbagin increased survival rate, reduced liver congestion and inflammation, and decreased macrophages and neutrophils in the fulminant hepatic failure model, and remarkably diminished liver fibrosis and inflammation in the chronic liver injury model. Furthermore, plumbagin significantly suppress the HSCs/myofibroblasts activation by reduced expression of markers alpha-SMA and COL-1/3, and reduced macrophage in liver. In the in vitro study, plumbagin induced apoptosis and suppressed the proliferation of LX-2 cells (human HSCs). Plumbagin treatment increased AMPK phosphorylation and attenuated NF-kappaB, STAT3, and Akt/mTOR signals in LX-2 cells, while SMAD2 phosphorylation was not changed. Noticeably, plumbagin promoted AMPK binding to p300 which is a cofactor of SMAD complex, this may further competitively decreases the p300/SMAD complex initiated transcription of COL-1/3 and alpha-SMA. Additionally, plumbagin hampered inflammation related NF-kappaB signal in RAW 264.7 cells. In conclusion, these findings indicate that plumbagin may be a powerful drug candidate to protect the liver from acute and chronic damage by inhibiting inflammation and collagen production. PMID- 27756879 TI - C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA. AB - PURPOSE: Anaphylatoxin C5a is a strong chemoattractant of the complement system that binds the C5a receptor (C5aR). The expression of C5aR is associated with poor prognosis in several cancers. However, the role of C5aR in gastric cancer (GC) is unknown. The aim of this study was to examine the role of C5aR on GC cell motility and invasion. EXPERIMENTAL DESIGN: The mechanism of invasion via C5aR was assessed by analyzing cytoskeletal rearrangement and RhoA activity after C5a treatment. Moreover, we investigated the relationship between C5aR expression and the prognosis of GC patients. RESULTS: Two human GC cell lines (MKN1 and MKN7) had high C5aR expression. An invasion assay revealed that C5a stimulation promoted the invasive ability of MKN1 and MKN7 cells and that this was suppressed by knockdown of C5aR using siRNA or a C5aR-antagonist. Moreover, overexpression of C5aR in GC cells enhanced the conversion of RhoA-guanosine diphosphate (RhoA GDP) to RhoA-guanosine triphosphate (RhoA-GTP) after C5a stimulation and caused morphological changes, including increased expression of stress fibers and filopodia. Examination of tumor specimens from 100 patients with GC revealed that high C5aR expression (35 of 100 samples, 35.0%) was associated with increased invasion depth, vascular invasion and advanced stage. The 5-year overall survival of patients with high or low C5aR expression was 58.2% and 68.5%, respectively (p=0.008). CONCLUSIONS: This study is the first to demonstrate that C5aR promotes GC cell invasion by activating RhoA and is associated with a poor prognosis in GC patients. Therefore, this study provides a biomarker for GC patients who require an advanced therapeutic strategy. PMID- 27756880 TI - LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients. AB - Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC). In lung ADC cells, LYN expression enhanced cell proliferation, migration, and invasion. Dasatinib inhibited LYN activity and decreased cell viability in LYN-positive ADC cell lines and xenografts. Additionally, we identified the SFKs SRC and YES as candidate dasatinib targets in LYN-negative ADC cell lines. Our findings suggest that LYN is a useful prognostic marker and a selective target of dasatinib therapy in the lung ADC subpopulation especially in female non-smokers with lung ADC. PMID- 27756881 TI - Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. AB - Increased collagen expression in tumors is associated with increased risk of metastasis, and triple-negative breast cancer (TNBC) has the highest propensity to develop distant metastases when there is evidence of central fibrosis. Transforming growth factor-beta (TGF-beta) ligands regulated by cancer-associated fibroblasts (CAFs) promote accumulation of fibrosis and cancer progression. In the present study, we have evaluated TNBC tumors with enhanced collagen to determine whether we can reduce metastasis by targeting the CAFs with Pirfenidone (PFD), an anti-fibrotic agent as well as a TGF-beta antagonist. In patient derived xenograft models, TNBC tumors exhibited accumulated collagen and activated TGF-beta signaling, and developed lung metastasis. Next, primary CAFs were established from 4T1 TNBC homograft tumors, TNBC xenograft tumors and tumor specimens of breast cancer patients. CAFs promoted primary tumor growth with more fibrosis and TGF-beta activation and lung metastasis in 4T1 mouse model. We then examined the effects of PFD in vitro and in vivo. We found that PFD had inhibitory effects on cell viability and collagen production of CAFs in 2D culture. Furthermore, CAFs enhanced tumor growth and PFD inhibited the tumor growth induced by CAFs by causing apoptosis in the 3D co-culture assay of 4T1 tumor cells and CAFs. In vivo, PFD alone inhibited tumor fibrosis and TGF-beta signaling but did not inhibit tumor growth and lung metastasis. However, PFD inhibited tumor growth and lung metastasis synergistically in combination with doxorubicin. Thus, PFD has great potential for a novel clinically applicable TNBC therapy that targets tumor-stromal interaction. PMID- 27756882 TI - Evaluation of the anatomical parameters for normal tissue sparing in the prone position radiotherapy with small sized left breasts. AB - Prone position radiotherapy for a small (< 750 cm3) breast is controversial because of the variable benefits for the irradiated heart volume. The objective anatomical parameters related with chest wall shape that can determine the heart dose sparing patients in the prone position.Twenty-one patients underwent CT simulation in supine and prone position. Dose volume parameters were compared and the objective indexes such as the Haller index, anthropometric index, mid-sternum thickness, and central lung distance (CLD) were evaluated the relationship between the shape of the chest wall and irradiated normal tissue volume in prone position.The median breast volume was 440.10 cm3 (range, 151.5-727.41 cm3). There was no difference of breast target volume between supine and prone position (p = 0.178). The Haller index under 2.5 (p = 0.046), an anthropometric index over 0.05 (p = 0.007), and the CLD over 2 (p = 0.023) conferred a greater heart sparing effect in the prone position.In conclusions, the objective anatomical parameters related chest wall shape predict the decrease in irradiated heart volume in the prone position. Therefore, it is possible to screen for patients with a reduced heart volume irradiation among those with small breasts before applying prone position radiotherapy. PMID- 27756883 TI - Bevacizumab and wound-healing complications: a systematic review and meta analysis of randomized controlled trials. AB - A meta-analysis was conducted to estimate the risk of wound-healing complications in patients who treated with neoadjuvant-adjuvant bevacizumab in various oncological indications. We searched PUBMED, EMBASE and the Cochrane Library through June 2016 to identify randomized controlled trials of bevacizumab and wound-healing complications. Seven RCTs studies involving 5,147 participants were included in the analysis. Compared with routine therapy, bevacizumab increased the incidence of wound-healing complications for various cancers. The pooled estimate of odds ratio (OR) was 2.32, and the 95 % confidence intervals (CI) was 1.43 to 3.75. (P < 0.001). Subgroup analyses revealed the similar result in colon carcinoma patients. In conclusion, bevacizumab increases the incidence of wound healing complications for cancers especially for colon neoplasms patients. However, the adverse effect is not appeared in breast cancer, metastatic renal cell carcinoma, non-small-cell lung cancer and gastro-oesophageal adenocarcinoma. Due to the findings relying chiefly on data from single or two studies, hence, further research is required to assess the wound-healing complications risk of bevacizumab in each oncological indication. PMID- 27756885 TI - Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models. AB - Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs. PMID- 27756884 TI - Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma. AB - Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined (p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients (p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect (p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F (p = 0.01; HR= 0.21). The 5 year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5 year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 (p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment. PMID- 27756886 TI - Properdistatin inhibits angiogenesis and improves vascular function in human melanoma xenografts with low thrombospondin-1 expression. AB - In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function. PMID- 27756888 TI - Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate. AB - Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations. Tumors from 10 consecutive patients with known dPC were sequenced on a targeted next-generation DNA sequencing panel. The median age at diagnosis was 59 years (range, 40-73). Four (40%) patients had metastases upon presentation. Archival tissue from formalin fixed paraffin-embedded prostate tissue samples from nine patients and a biopsy of a metastasis from one patient with castration-resistant prostate cancer were available for analysis. Nine of 10 samples had sufficient material for tumor sequencing. Four (40%) patients' tumors had a mismatch repair (MMR) gene alteration (N = 2, MSH2; N = 1, MSH6; and N = 1, MLH1), of which 3 (75%) had evidence of hypermutation. Sections of the primary carcinomas of three additional patients with known MMR gene alterations/hypermutation were histologically evaluated; two of these tumors had dPC. MMR mutations associated with hypermutation were common in our cohort of dPC patients. Since hypermutation may predict for response to immune checkpoint blockade, the presence of dPC may be a rapid means to enrich populations for further screening. Given our small sample size, these findings require replication. PMID- 27756887 TI - Anti-FIRs (PUF60) auto-antibodies are detected in the sera of early-stage colon cancer patients. AB - Anti-PUF60, poly(U)-binding-splicing factor, autoantibodies are reported to be detected in the sera of dermatomyositis and Sjogren's syndrome that occasionally associated with malignancies. PUF60 is identical with far-upstream element binding protein-interacting repressor (FIR) that is a transcriptional repressor of c-myc gene. In colorectal cancers, a splicing variant of FIR that lacks exon2 (FIRDeltaexon2) is overexpressed as a dominant negative form of FIR. In this study, to reveal the presence and the significance of anti-FIRs (FIR/FIRDeltaexon2) antibodies in cancers were explored in the sera of colorectal and other cancer patients. Anti-FIRs antibodies were surely detected in the preoperative sera of 28 colorectal cancer patients (32.2% of positive rates), and the detection rate was significantly higher than that in healthy control sera (Mann-Whitney U test, p < 0.01). The level of anti-FIRs antibodies significantly decreased after the operation (p < 0.01). Anti-FIRs antibodies were detected in the sera of early-stage and/or recurrent colon cancer patients in which anti-p53 antibodies, CEA, and CA19-9 were not detected as well as in the sera of other cancer patients. Furthermore, the area under the curve of receiver operating characteristic for anti-FIRs antibodies was significantly larger (0.85) than that for anti-p53 antibodies or CA19-9. In conclusions, the combination of anti-FIRs antibodies with other clinically available tumor markers further improved the specificity and accuracy of cancer diagnosis. PMID- 27756889 TI - A meta-analysis on the effect of operation modes on the recurrence of papillary thyroid microcarcinoma. AB - Whether total thyroidectomy reduces the recurrence rate in patients with papillary thyroid microcarcinoma (PTMC) is currently controversy. Conclusions of sporadic, inconsistent, and mono-institutional studies need a meta-analysis to evaluate. 525 relevant studies were obtained from initial search on PubMed, 511 studies were excluded by inclusion and exclusion criteria. Eligible data were extracted from each included study. The Odds ratios (ORs) and 95% confidence interval (CI) were used to assess the difference in the recurrence rates between PTMC patients treated with total thyroidectomy and non-total thyroidectomy. OR and 95% CI were calculated using a fixed-effects or a random-effects model. The Q statistic was used to evaluate homogeneity and Begg's test was used to assess publication bias. 14 studies meeting the inclusion criteria were included in this meta-analysis. The over all recurrence rates of pooled patients with total thyroidectomy and non-total thyroidectomy were 2.83% and 2.84% respectively. Primary random-effects model analysis showed, no significant difference of recurrence rates existed between two operation modes (OR = 0.732, 95% CI: 0.444 - 1.208), while, high heterogeneity among studies was found, I-squared index (I2) = 40.2%. After remove one study with high heterogeneity, the OR of the pooled recurrence rates of the total thyroidectomy and the non-total thyroidectomy groups was 0.786 (95% CI: 0.363 - 1.701), further suggesting no significant difference of the recurrence rate exists between two operation modes. Our meta analysis demonstrated postoperative recurrence of PTMC is not reduced by total thyroidectomy, non-total thyroidectomy is also a good choice to treat PTMC patients. PMID- 27756890 TI - Wogonin prevents TLR4-NF-kappaB-medicated neuro-inflammation and improves retinal ganglion cells survival in retina after optic nerve crush. AB - Chronic neuro-inflammation is involved in the death of retinal ganglion cells (RGCs) in glaucoma. The aim of this study is to determine whether wogonin can suppress inflammatory responses and rescue RGCs death after optic nerve crush (ONC), an ideal animal model of glaucoma. Wogonin was administered intraperitoneally 10 min after establishment of ONC model. In this study, wogonin treatment reduced RGCs loss and inhibited RGCs apoptosis demonstrated by the increased Brn3a labeling RGCs at day 14 and the decreased cleaved caspase-3 expression at day 7 after ONC, respectively. In ONC model, number of GFAP positive glial cells and iba1-positive microglial cells were increased, combined of the elevated level of pro-inflammatory cytokines released in retina at day 7. However, most of these responses were inhibited after wogonin treatment. The level of TLR4 expression, NF-kappaB-P65 nucleus location and NF-kappaB-P65 phosphorylation were increased in retina at day 1 after ONC, which was significantly reduced after wogonin treatment. These results demonstrated that wogonin protected RGCs survival and suppressed neuro-inflammation in retina after ONC by inhibiting TLR4-NF-kappaB pathways. We conclude that wogonin could be a possible strategy for the treatment of glaucoma. PMID- 27756891 TI - c-Myc deregulation induces mRNA capping enzyme dependency. AB - c-Myc is a potent driver of many human cancers. Since strategies for directly targeting c-Myc protein have had limited success, upstream regulators and downstream effectors of c-Myc are being investigated as alternatives for therapeutic intervention. c-Myc regulates transcription and formation of the mRNA cap, which is important for transcript maturation and translation. However, the direct mechanism by which c-Myc upregulates mRNA capping is unclear. mRNA cap formation initiates with the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide, catalysed by mRNA capping enzyme (CE/RNGTT). Here we report that c-Myc increases the recruitment of catalytically active CE to RNA polymerase II and to its target genes. c-Myc-induced target gene expression, cell proliferation and cell transformation is highly dependent on CE, but only when c-Myc is deregulated. Cells retaining normal control of c-Myc expression are insensitive to repression of CE. c-Myc expression is also dependent on CE. Therefore, inhibiting CE provides an attractive route for selective therapeutic targeting of cancer cells which have acquired deregulated c Myc. PMID- 27756893 TI - First Left Hepatic Trisectionectomy Including Segment One with New Associated Liver Partition and Portal Vein Ligation with Staged Hepatectomy (ALPPS) Modification: How To Do It? AB - BACKGROUND Associated Liver Partition and Portal vein ligation with Staged hepatectomy (ALPPS) leads to rapid hepatic hypertrophy and decreases incidence of post-hepatectomy liver failure in patients with a marginal future liver remnant. Various procedural ALPPS modifications were previously described. Here, we present the first case of a new ALPPS modification, carrying out a left hepatic trisectionectomy with segment 1. CASE REPORT We present the case of a 36-year-old woman with locally advanced sigmoid adeno-carcinoma and extensive left liver metastases extending to segment V and VIII, who received state-of-the-art systemic conversion chemotherapy. Preoperative CT volumetric scan demonstrated a FLR/TLV (Future Liver Remnant/Total Liver Volume) of 22%. A left hepatic trisectionectomy procedure was conducted using our new ALPPS modification. Sufficient hepatic hypertrophy of FLR was reached with a volume increase of 100%. The period between the 2 stages was 7 days. The patient underwent left trisectionectomy and left colectomy with tumor-free margins. All dissected lymph nodes were tumor-negative. The surgical intra- and postoperative course was uneventful. Medically, the patient acquired an Acinetobacter infection, with severe sepsis and acute renal injury. After 3 dialysis sessions, the renal function recovered completely. Afterwards, the patient recovered slowly, and reintroduction ambulation and oral feeding was prolonged. Later on, the patient received Xeloda 1500 mg twice daily as adjuvant chemotherapy. CONCLUSIONS The new ALPPS modification leads to a sufficient hypertrophy of FRL within 1 week, allowing left hepatic trisectionectomy with tumor-free FRL. Despite the challenging complications, the new ALPPS modification might represent an alternative procedure for use when the classic ALPPS procedure is not applicable. Further studies are required. PMID- 27756894 TI - Altered microRNA-9 Expression Level is Directly Correlated with Pathogenesis of Nonalcoholic Fatty Liver Disease by Targeting Onecut2 and SIRT1. AB - BACKGROUND MicroRNA-9 (miR-9) was detected in nonalcoholic fatty liver disease (NAFLD) patients to understand the role of miR-9 in NAFLD development. MATERIAL AND METHODS Between February 2014 and February 2015, 105 cases of NAFLD were recruited and confirmed by liver biopsy pathology, including patients with mild NAFLD (n=58) and moderate-severe NAFLD (n=47); nonalcoholic steatohepatitis (NASH) (n=53) and non-NASH (n=52); and 50 healthy participants were regarded as the healthy control group. MiR-9 expression was measured by qRT-PCR. For in vitro experiments, L-02 normal liver cells were divided into normal control group (cultured with original culture medium), dimethyl sulfoxide (DMSO) group (cultured with DMSO) and oleic acid group (cultured with oleic acid to induce fatty change), and MTT assay was used to measure the effect of different oleic acid concentrations on cell proliferation. Nile red staining was used to detect intracellular accumulation of lipid droplets. Further, synthetic miR-9 mimic and its control and miR-9 inhibitors and its control were independently transfected into L-02 cells. RESULTS MiR-9 levels in the mild NAFLD group and moderate-severe NAFLD group were significantly higher than in the healthy control group (both P<0.05). Mean fluorescence intensity of lipid droplets increased with the duration of induction, and were dramatically higher in oleate-treated L-02 cells; intracellular triglyceride (TG) content was also higher. miR-9 levels significantly increased following oleate induction. Importantly, miR-9 levels were significantly elevated upon miR-9 mimic transfection. Conversely, miR-9 level was lowered with miR-9 inhibitors transfection. Additionally, Onecut2 and SIRT1 were identified as miR-9 targets. CONCLUSIONS A positive relationship between miR-9 and steatosis was established with our results that miR-9 mimic transfection decreased intracellular lipid content. Finally, we identified 2 miR 9 targets, Onecut2 and SIRT1, which may be crucial players in NAFLD development. PMID- 27756892 TI - Targeting immune checkpoints in malignant glioma. AB - Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the body's anti cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered "immune privileged" and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma. PMID- 27756895 TI - MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density. AB - At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons. MPP2 also colocalises with the synaptic adhesion molecule SynCAM1. We demonstrate that the SynCAM1 C-terminus interacts directly with the MPP2 PDZ domain and that MPP2 does not interact in this manner with other highly abundant postsynaptic transmembrane proteins. Our results highlight a previously unexplored role for MPP2 at postsynaptic sites as a scaffold that links SynCAM1 cell adhesion molecules to core proteins of the postsynaptic density. PMID- 27756896 TI - A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response. AB - Foxp3+ regulatory T cells (Tregs) migrating from the skin to the draining lymph node (dLN) have a strong immunosuppressive effect on the cutaneous immune response. However, the subpopulations responsible for their inhibitory function remain unclear. We investigated single-cell gene expression heterogeneity in Tregs from the dLN of inflamed skin in a contact hypersensitivity model. The immunosuppressive genes Ctla4 and Tgfb1 were expressed in the majority of Tregs. Although Il10-expressing Tregs were rare, unexpectedly, the majority of Il10 expressing Tregs co-expressed Gzmb and displayed Th1-skewing. Single-cell profiling revealed that CD43+ CCR5+ Tregs represented the main subset within the Il10/Gzmb-expressing cell population in the dLN. Moreover, CD43+ CCR5+ CXCR3- Tregs expressed skin-tropic chemokine receptors, were preferentially retained in inflamed skin and downregulated the cutaneous immune response. The identification of a rare Treg subset co-expressing multiple immunosuppressive molecules and having tissue-remaining capacity offers a novel strategy for the control of skin inflammatory responses. PMID- 27756897 TI - Asperosaponin VI promotes bone marrow stromal cell osteogenic differentiation through the PI3K/AKT signaling pathway in an osteoporosis model. AB - Asperosaponin VI (ASA VI), a natural compound isolated from the well-known traditional Chinese herb Radix Dipsaci, has an important role in promoting osteoblast formation. However, its effects on osteoblasts in the context of osteoporosis is unknown. This study aimed to investigate the effects and mechanism of ASA VI action on the proliferation and osteogenic differentiation of bone marrow stromal cells isolated from the ovariectomized rats (OVX rBMSCs). The toxicity of ASA VI and its effects on the proliferation of OVX rBMSCs were measured using a CCK-8 assay. Various osteogenic differentiation markers were also analyzed, such as ALP activity, calcified nodule formation, and the expression of osteogenic genes, i.e., ALP, OCN, COL 1 and RUNX2. The results indicated that ASA VI promoted the proliferation of OVX rBMSCs and enhanced ALP activity and calcified nodule formation. In addition, while ASA VI enhanced the expression of ALP, OCN, Col 1 and RUNX2, treatment with LY294002 reduced all of these osteogenic effects and reduced the p-AKT levels induced by ASA VI. These results suggest that ASA VI promotes the osteogenic differentiation of OVX rBMSCs by acting on the phosphatidylinositol-3 kinase/AKT signaling pathway. PMID- 27756899 TI - A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity. AB - CACNA1I is a candidate schizophrenia risk gene. It encodes the pore-forming human CaV3.3 alpha1 subunit, a subtype of voltage-gated calcium channel that contributes to T-type currents. Recently, two de novo missense variations, T797M and R1346H, of hCaV3.3 were identified in individuals with schizophrenia. Here we show that R1346H, but not T797M, is associated with lower hCaV3.3 protein levels, reduced glycosylation, and lower membrane surface levels of hCaV3.3 when expressed in human cell lines compared to wild-type. Consistent with our biochemical analyses, whole-cell hCaV3.3 currents in cells expressing the R1346H variant were ~50% of those in cells expressing WT hCaV3.3, and neither R1346H nor T797M altered channel biophysical properties. Employing the NEURON simulation environment, we found that reducing hCaV3.3 current densities by 22% or more eliminates rebound bursting in model thalamic reticular nucleus (TRN) neurons. Our analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt CaV3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology. PMID- 27756898 TI - The room temperature crystal structure of a bacterial phytochrome determined by serial femtosecond crystallography. AB - Phytochromes are a family of photoreceptors that control light responses of plants, fungi and bacteria. A sequence of structural changes, which is not yet fully understood, leads to activation of an output domain. Time-resolved serial femtosecond crystallography (SFX) can potentially shine light on these conformational changes. Here we report the room temperature crystal structure of the chromophore-binding domains of the Deinococcus radiodurans phytochrome at 2.1 A resolution. The structure was obtained by serial femtosecond X-ray crystallography from microcrystals at an X-ray free electron laser. We find overall good agreement compared to a crystal structure at 1.35 A resolution derived from conventional crystallography at cryogenic temperatures, which we also report here. The thioether linkage between chromophore and protein is subject to positional ambiguity at the synchrotron, but is fully resolved with SFX. The study paves the way for time-resolved structural investigations of the phytochrome photocycle with time-resolved SFX. PMID- 27756900 TI - Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes. AB - Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type 2 diabetes. Here we used human primary myotubes (HPM) to investigate if rhythmicity of clock- and metabolic gene expression is altered in donors with obesity or type 2 diabetes compared to metabolically healthy donors. HPM were obtained from skeletal muscle biopsies of four groups: type 2 diabetic patients and their BMI- and age-matched obese controls and from lean, healthy and young endurance trained athletes and their age-matched sedentary controls. HPM were differentiated for 7 days before synchronization by serum shock followed by gene expression profiling over the next 72 hours. HPM display robust circadian rhythms in clock genes, but REVERBA displayed dampened rhythmicity in type 2 diabetes. Furthermore, rhythmicity in NAMPT and SIRT1 expression was only observed in HPM from trained athletes. Rhythmicity in expression of key-regulators of carbohydrate and lipid metabolism was modest. We demonstrate that in human skeletal muscle REVERBA/B, NAMPT and SIRT1 circadian rhythms are affected in donors of sedentary life style and poor health status. PMID- 27756901 TI - A novel rabbit model of early osteoarthritis exhibits gradual cartilage degeneration after medial collateral ligament transection outside the joint capsule. AB - Though many surgical animal models have been used to induce osteoarthritis (OA) of the knee joint, they always open the capsule of the joint. Any surgical procedures that incises the capsule may cause inflammation, pain, and possibly altered gait. One common disadvantage of these surgically induced animal models is that they may affect the initial structures and synovial fluid in joint. These animal models may not be suitable for research into synovial fluid changes during early OA. This study aimed to create an animal model of early OA by resecting the medial collateral ligament (MCL) outside of the capsule. At 1, 2, 3, 4, 5 and 6 weeks after surgery, eight knees from each group were harvested. The joint gap was measured on posteroanterior radiographs after MCL-transection (MCLT). Gross examination and histological analysis were performed to evaluate cartilage damage to the medial femoral condyles, and knee joints were scanned using a Micro-CT system. The MCLT group experienced early stage OA from 3 to 6 weeks according to the histological scores. IL-6, MMP-1 and MMP-13 content in the synovial fluid were higher after MCLT than anterior cruciate ligament transection (ACLT) at 1 and 2 weeks. PMID- 27756902 TI - Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection. AB - Interplay between lncRNAs and mRNAs is rapidly emerging as a key epigenetic mechanism in controlling various cell functions. HIV can actively infect and/or can persist latently for years by manipulating host epigenetics; however, its molecular essence remains undiscovered in entirety. Here for the first time, we delineate the influence of HIV on global lncRNAs expression in monocytic cells lines. Our analysis revealed the expression modulation of nearly 1060 such lncRNAs which are associated with differentially expressed mRNAs in active and latent infection. This suggests a greater role of lncRNAs in regulating transcriptional and post-transcriptional gene expression during HIV infection. The differentially expressed mRNAs were involved in several different biological pathways where immunological networks were most enriched. Importantly, we discovered that HIV induces expression reversal of more than 150 lncRNAs between its active and latent infection. Also, hundreds of unique lncRNAs were identified in both infection conditions. The pathology specific "gene-expression reversal" and "on-and-off" switching of lncRNAs and associated mRNAs may lead to establish the relationship between active and HIV infection. PMID- 27756903 TI - Classical trajectories in polar-asymmetric laser fields: Synchronous THz and XUV emission. AB - The interaction of intense near- and mid-infrared laser pulses with rare gases has produced bursts of radiation with spectral content extending into the extreme ultraviolet and soft x-ray region of electromagnetic spectrum. On the other end of the spectrum, laser-driven gas plasmas has been shown to produce coherent sub harmonic optical waveforms, covering from terahertz (THz) to mid- and near infrared frequency spectral band. Both processes can be enhanced via a combination of a driving field and its second harmonic. Despite this striking similarity, only limited experimental and theoretical attempts have been made to address these two regimes simultaneously. Here we present systematic experiments and a unifying picture of these processes, based on our extension of the semi classical three-step model. Further understanding of the generation and coherent control of time-synchronized transients with photon energies from meV to 1 keV can lead to numerous technological advances and to an intriguing possibilities of ultra-broadband investigations into complex condensed matter systems. PMID- 27756904 TI - A novel gene cluster allows preferential utilization of fucosylated milk oligosaccharides in Bifidobacterium longum subsp. longum SC596. AB - The infant intestinal microbiota is often colonized by two subspecies of Bifidobacterium longum: subsp. infantis (B. infantis) and subsp. longum (B. longum). Competitive growth of B. infantis in the neonate intestine has been linked to the utilization of human milk oligosaccharides (HMO). However, little is known how B. longum consumes HMO. In this study, infant-borne B. longum strains exhibited varying HMO growth phenotypes. While all strains efficiently utilized lacto-N-tetraose, certain strains additionally metabolized fucosylated HMO. B. longum SC596 grew vigorously on HMO, and glycoprofiling revealed a preference for consumption of fucosylated HMO. Transcriptomes of SC596 during early-stage growth on HMO were more similar to growth on fucosyllactose, transiting later to a pattern similar to growth on neutral HMO. B. longum SC596 contains a novel gene cluster devoted to the utilization of fucosylated HMO, including genes for import of fucosylated molecules, fucose metabolism and two alpha-fucosidases. This cluster showed a modular induction during early growth on HMO and fucosyllactose. This work clarifies the genomic and physiological variation of infant-borne B. longum to HMO consumption, which resembles B. infantis. The capability to preferentially consume fucosylated HMO suggests a competitive advantage for these unique B. longum strains in the breast-fed infant gut. PMID- 27756905 TI - Chronic stress prior to pregnancy potentiated long-lasting postpartum depressive like behavior, regulated by Akt-mTOR signaling in the hippocampus. AB - Postpartum depression (PPD) affects over 10% of new mothers and adversely impacts the health of offspring. One of the greatest risk factors for PPD is prepregnancy stress but the underlying biological mechanism is unknown. Here we constructed an animal model which recapitulated prepregnancy stress induced PPD and tested the role of Akt-mTOR signaling in the hippocampus. Female virgin Balb/c mice received chronic restraint stress, followed by co-housing with a normal male mouse. We found that the chronic stress led to a transient depressive-like condition that disappeared within two weeks. However, prepregnantly stressed females developed long-term postpartum depressive-like (PPD-like) symptoms as indicated by deficient performance in tests of sucrose preference, forced swim, and novelty suppressed feeding. Chronic stress induced transient decrease in Akt-mTOR signaling and altered expressions of glutamate receptor subunits NR1 and GluR1, in contrast to long-term deficits in Akt-mTOR signaling, GluR1/NR1 ratio, and hippocampal neurogenesis in PPD-like mice. Acute ketamine improved the molecular signaling abnormality, and reversed the behavioral deficits in PPD-like mice in a rapid and persistent manner, in contrast to ineffectiveness by chronic fluoxetine treatment. Taken together, we find that chronic prepregnancy stress potentiates a long-term PPD, in which Akt-mTOR signaling may play a crucial role. PMID- 27756906 TI - Large-roll growth of 25-inch hexagonal BN monolayer film for self-release buffer layer of free-standing GaN wafer. AB - Hexagonal boron nitride (h-BN) is known as promising 2D material with a wide band gap (~6 eV). However, the growth size of h-BN film is strongly limited by the size of reaction chamber. Here, we demonstrate the large-roll synthesis of monolayer and controllable sub-monolayer h-BN film on wound Cu foil by low pressure chemical vapor deposition (LPCVD) method. By winding the Cu foil substrate into mainspring shape supported by a multi-prong quartz fork, the reactor size limit could be overcome by extending the substrate area to a continuous 2D curl of plane inward. An extremely large-size monolayer h-BN film has been achieved over 25 inches in a 1.2" tube. The optical band gap of h-BN monolayer was determined to be 6.0 eV. The h-BN film was uniformly transferred onto 2" GaN or 4" Si wafer surfaces as a release buffer layer. By HVPE method, overgrowth of thick GaN wafer over 200 MUm has been achieved free of residual strain, which could provide high quality homo-epitaxial substrate. PMID- 27756907 TI - Label-free, rapid and quantitative phenotyping of stress response in E. coli via ramanome. AB - Rapid profiling of stress-response at single-cell resolution yet in a label-free, non-disruptive and mechanism-specific manner can lead to many new applications. We propose a single-cell-level biochemical fingerprinting approach named "ramanome", which is the collection of Single-cell Raman Spectra (SCRS) from a number of cells randomly selected from an isogenic population at a given time and condition, to rapidly and quantitatively detect and characterize stress responses of cellular population. SCRS of Escherichia coli cells are sensitive to both exposure time (eight time points) and dosage (six doses) of ethanol, with detection time as early as 5 min and discrimination rate of either factor over 80%. Moreover, the ramanomes upon six chemical compounds from three categories, including antibiotics of ampicillin and kanamycin, alcohols of ethanol and n butanol and heavy metals of Cu2+ and Cr6+, were analyzed and 31 marker Raman bands were revealed which distinguish stress-responses via cytotoxicity mechanism and variation of inter-cellular heterogeneity. Furthermore, specificity, reproducibility and mechanistic basis of ramanome were validated by tracking stress-induced dynamics of metabolites and by contrasting between cells with and without genes that convey stress resistance. Thus ramanome enables rapid prediction and mechanism-based screening of cytotoxicity and stress-response programs at single-cell resolution. PMID- 27756909 TI - Misassembly of non-mutant full-length Disrupted-in-Schizophrenia 1 protein is induced by dopamine in vitro and in vivo. PMID- 27756908 TI - Horizontal Transfer of a Novel Soil Agarase Gene from Marine Bacteria to Soil Bacteria via Human Microbiota. AB - Seaweed is receiving an increasing amount of attention as a "sea vegetable". The microbiota of coastal populations may acquire seaweed associated enzymes through marine food. Several agarases have been found in non-marine environments; however, their origin is unknown. In this study, a hypothetical protein, Aga1, was identified as an agarase from an inland soil agar-degrading bacterium, Paenibacillus sp. SSG-1.Having low similarity to known glycoside hydrolases, Aga1 may be a distant member of the glycoside hydrolase family 86. Aga1 has good pH stability (pH 3-11) and is stable in the presence of various metal ions. Aga1 is an exo-type beta-agarase that produces NA 4 (neoagarotetraose) and NA 6 (neoagarohexaose) as its main products. In addition, Aga1 may be a cell-surface binding protein. The bioinformatic analysis showed aga1 may have been transfered together with its surrounding genes, from marine bacteria to soil bacteria via human microbiota. The use of seaweed as food and the disposal of human faeces or saliva were the most likely reasons for this gene transfer pathway. Notably, the results also indicated that microbes from inland humans may degrade agar and that these microbes may have acquired seaweed associated genes because of increased seaweed in diets. PMID- 27756910 TI - Validation of the mutant selection window hypothesis with fosfomycin against Escherichia coli and Pseudomonas aeruginosa: an in vitro and in vivo comparative study. AB - The purpose of this study was to validate the mutant selection window (MSW) hypothesis in vitro and in vivo with Escherichia coli and Pseudomonas aeruginosa exposed to fosfomycin. Two standard strains of Gram-negative bacteria, those are E. coli ATCC 25922 and P. aeruginosa ATCC 27853, were exposed to fosfomycin at concentrations below MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC in Luria-Bertani broth and in a tissue-cage infection model, respectively. With the in vitro time-kill studies, there were bacterial re growth and emergence of resistance thereafter for both strains at antibiotic concentrations of * 4, * 8 and * 16 MIC. In our animal model, the loss in susceptibility of P. aeruginosa at fosfomycin concentrations fluctuated between the lower and upper boundaries of the MSW. In contrast, the emergence of resistant mutants of E. coli was not observed in vivo, regardless of fosfomycin dosage. Interestingly, the in vitro-isolated resistant mutants of E. coli showed a decreased growth rate compared with the susceptible parental strains, whereas no fitness cost in P. aeruginosa was observed. The emergence of antibiotic resistance is shaped by several factors. MSW theory may not apply to all antimicrobial-pathogen combinations. Before it can be used as a framework for the design of antimicrobial therapy, the existence of the window must be demonstrated not only in vitro but also in vivo. PMID- 27756911 TI - Antiviral effect of theaflavins against caliciviruses. AB - Caliciviruses are contagious pathogens of humans and various animals. They are the most common cause of viral gastroenteritis in humans, and can cause lethal diseases in domestic animals such as cats, rabbits and immunocompromised mice. In this study, we conducted cytopathic effect-based screening of 2080 selected compounds from our in-house library to find antiviral compounds against three culturable caliciviruses: feline calicivirus, murine norovirus (MNV) and porcine sapovirus (PoSaV). We identified active six compounds, of which two compounds, both related to theaflavins, showed broad antiviral activities against all three caliciviruses; three compounds (abamectin, a mixture of avermectin B1a and B1b; avermectin B1a; and (-)-epigallocatechin gallate hydrate) were effective against PoSaV only; and a heterocyclic carboxamide derivative (BFTC) specifically inhibited MNV infectivity in cell cultures. Further studies of the antiviral mechanism and structure-activity relationship of theaflavins suggested the following: (1) theaflavins worked before the viral entry step; (2) the effect of theaflavins was time- and concentration-dependent; and (3) the hydroxyl groups of the benzocycloheptenone ring were probably important for the anti-calicivirus activity of theaflavins. Theaflavins could be used for the calicivirus research, and as potential disinfectants and antiviral reagents to prevent and control calicivirus infections in animals and humans. PMID- 27756912 TI - Microbacterium lacusdiani sp. nov., a phosphate-solubilizing novel actinobacterium isolated from mucilaginous sheath of Microcystis. AB - A novel actinobacterium, designated strain JXJ CY 01T, was isolated from a mucilaginous sheath of Microcystis aeruginosa FACHB-905 collected from Lake Dianchi, south-west China. Taxonomic position of the isolate was determined by polyphasic approaches. Strain JXJ CY 01T shared 16S rRNA sequence similarities of 98.9 and 98.0% with Microbacterium marinilacus YM11-607T and Microbacterium paludicola US15T, and less than 98% with other members of the genus Microbacterium. The DNA-DNA relatedness values between strains JXJ CY 01T and M. marinilacus JCM 16546T and M. paludicola JCM 14308T were 53.5+/-1.4 and 53.8+/ 2.1%, respectively. l-Ornithine was detected in the cell wall, and rhamnose, galactose, glucose, arabinose, fucose and mannose as signature sugars in the whole-cell hydrolysates. Other chemotaxonomic characteristics determined were MK 12 and MK-11 as predominant menaquinones, anteiso-C15:0, iso-C16:0, anteiso-C17:0 and iso-C17:0 as major cellular fatty acids (>10%), and diphosphatidylglycerol, phosphatidylglycerol, an unidentified glycolipid and two unidentified phospholipids as the polar lipids. The DNA G+C content was 70.4 mol%. On the basis of the above taxonomic data, strain JXJ CY 01T is determined to represent a novel species of the genus Microbacterium, for which the name Microbacterium lacusdiani sp. nov. is proposed. The type strain is JXJ CY 01T (= KCTC 29655T=DSM 29188T). The type strain JXJ CY 01T can solubilize both insoluble inorganic (calcium phosphate) and organic phosphate (l-alpha-phosphatidylcholine) and is possibly one of the mechanism for enhancement of growth of M. aeruginosa FACHB 905. PMID- 27756913 TI - Antibiotics in microbial coculture. AB - Today, the frequency of discovery of new antibiotics in microbial culture is significantly decreasing. The evidence from whole-genome surveys suggests that many genes involved in the synthesis of unknown metabolites do exist but are not expressed under conventional cultivation conditions. Therefore, it is urgently necessary to study the conditions that make otherwise silent genes active in microbes. Here we overview the knowledge on the antibiotic production promoted by cocultivation of multiple microbial strains. Accumulating evidence indicates that cocultivation can be an effective way to stimulate the production of substances that are not formed during pure cultivation. Characterization of the promotive factors produced by stimulator strains is expected to give clues to the development of effective cultivation conditions for drug discovery. PMID- 27756914 TI - Discovery of putative capsaicin biosynthetic genes by RNA-Seq and digital gene expression analysis of pepper. AB - The Indian pepper 'Guijiangwang' (Capsicum frutescens L.), one of the world's hottest chili peppers, is rich in capsaicinoids. The accumulation of the alkaloid capsaicin and its analogs in the epidermal cells of the placenta contribute to the pungency of Capsicum fruits. To identify putative genes involved in capsaicin biosynthesis, RNA-Seq was used to analyze the pepper's expression profiles over five developmental stages. Five cDNA libraries were constructed from the total RNA of placental tissue and sequenced using an Illumina HiSeq 2000. More than 19 million clean reads were obtained from each library, and greater than 50% of the reads were assignable to reference genes. Digital gene expression (DGE) profile analysis using Solexa sequencing was performed at five fruit developmental stages and resulted in the identification of 135 genes of known function; their expression patterns were compared to the capsaicin accumulation pattern. Ten genes of known function were identified as most likely to be involved in regulating capsaicin synthesis. Additionally, 20 new candidate genes were identified related to capsaicin synthesis. We use a combination of RNA-Seq and DGE analyses to contribute to the understanding of the biosynthetic regulatory mechanism(s) of secondary metabolites in a nonmodel plant and to identify candidate enzyme-encoding genes. PMID- 27756916 TI - Effective suppression of efficiency droop in GaN-based light-emitting diodes: role of significant reduction of carrier density and built-in field. AB - A critical issue in GaN-based high power light-emitting diodes (LEDs) is how to suppress the efficiency droop problem occurred at high current injection while improving overall quantum efficiency, especially in conventional c-plane InGaN/GaN quantum well (QW), without using complicated bandgap engineering or unconventional materials and structures. Although increasing thickness of each QW may decrease carrier density in QWs, formation of additional strain and defects as well as increased built-in field effect due to enlarged QW thickness are unavoidable. Here, we propose a facile and effective method for not only reducing efficiency droop but also improving quantum efficiency by utilizing c-plane InGaN/GaN QWs having thinner barriers and increased QW number while keeping the same single well thickness and total active layer thickness. As the barrier thickness decreases and the QW number increases, both internal electric field and carrier density within QWs are simultaneously reduced without degradation of material quality. Furthermore, we found overall improved efficiency and reduced efficiency droop, which was attributed to the decrease of the built-in field and to less influence by non-radiative recombination processes at high carrier density. This simple and effective approach can be extended further for high power ultraviolet, green, and red LEDs. PMID- 27756915 TI - A Mitochondrial Genome of Rhyparochromidae (Hemiptera: Heteroptera) and a Comparative Analysis of Related Mitochondrial Genomes. AB - The Rhyparochromidae, the largest family of Lygaeoidea, encompasses more than 1,850 described species, but no mitochondrial genome has been sequenced to date. Here we describe the first mitochondrial genome for Rhyparochromidae: a complete mitochondrial genome of Panaorus albomaculatus (Scott, 1874). This mitochondrial genome is comprised of 16,345 bp, and contains the expected 37 genes and control region. The majority of the control region is made up of a large tandem-repeat region, which has a novel pattern not previously observed in other insects. The tandem-repeats region of P. albomaculatus consists of 53 tandem duplications (including one partial repeat), which is the largest number of tandem repeats among all the known insect mitochondrial genomes. Slipped-strand mispairing during replication is likely to have generated this novel pattern of tandem repeats. Comparative analysis of tRNA gene families in sequenced Pentatomomorpha and Lygaeoidea species shows that the pattern of nucleotide conservation is markedly higher on the J-strand. Phylogenetic reconstruction based on mitochondrial genomes suggests that Rhyparochromidae is not the sister group to all the remaining Lygaeoidea, and supports the monophyly of Lygaeoidea. PMID- 27756917 TI - Gut microbiota: A protective protozoan in mucosal infection. PMID- 27756918 TI - Radiotherapy: Pharmacological quiescence for radiation-induced intestinal injury. PMID- 27756920 TI - The Influence of Interim Deans: More Than Keeping the Ship Afloat and Warming the Captain's Seat. PMID- 27756919 TI - Problems with extracellular recording of electrical activity in gastrointestinal muscle. AB - Motility patterns of the gastrointestinal tract are important for efficient processing of nutrients and waste. Peristalsis and segmentation are based on rhythmic electrical slow waves that generate the phasic contractions fundamental to gastrointestinal motility. Slow waves are generated and propagated actively by interstitial cells of Cajal (ICC), and these events conduct to smooth muscle cells to elicit excitation-contraction coupling. Extracellular electrical recording has been utilized to characterize slow-wave generation and propagation and abnormalities that might be responsible for gastrointestinal motility disorders. Electrode array recording and digital processing are being used to generate data for models of electrical propagation in normal and pathophysiological conditions. Here, we discuss techniques of extracellular recording as applied to gastrointestinal organs and how mechanical artefacts might contaminate these recordings and confound their interpretation. Without rigorous controls for movement, current interpretations of extracellular recordings might ascribe inaccurate behaviours and electrical anomalies to ICC networks and gastrointestinal muscles, bringing into question the findings and validity of models of gastrointestinal electrophysiology developed from these recordings. PMID- 27756921 TI - The Role of Servant Leadership and Transformational Leadership in Academic Pharmacy. AB - A variety of changes are facing leaders in academic pharmacy. Servant and transformational leadership have attributes that provide guidance and inspiration through these changes. Servant leadership focuses on supporting and developing the individuals within an institution, while transformational leadership focuses on inspiring followers to work towards a common goal. This article discusses these leadership styles and how they may both be ideal for leaders in academic pharmacy. PMID- 27756922 TI - An Observational Case Study of Near-peer Teaching in Medical and Pharmacy Experiential Training. AB - Objective. To compare peer teaching in a medical and a pharmacy clinical teaching unit and to provide suggestions for future research in pharmacy near-peer teaching. Methods. This exploratory observational study used principles of ethnographic methodology for data collection and analysis. Observations were collected in a large downtown teaching hospital. An average of 4-6 hours per day were spent observing a team of medical trainees from the Faculty (School) of Medicine in the general internal medicine (unit for two weeks, followed by a team of pharmacy trainees in an ambulatory hemodialysis (HD) unit for two weeks. Data was collected through field notes and informal interviews that were audiotaped and subsequently transcribed. Data was interpreted by the observer and reviewed weekly by two impartial pharmacists. Results. Five major themes emerged: (1) influence of peer teaching hierarchy; (2) educational distance between peer learners and teachers; (3) effect of the clinical teaching unit size on peer learning; (4) trainees' perception of their teaching role in the clinical teaching unit; and (5) influence of daily schedule and workload on peer teaching. As opposed to pharmacy, a hierarchy and pyramidal structure of peer teaching was observed in medical experiential training. There appeared to be no effect of educational distance on near peer teaching; however, perception of teaching role and influence of daily schedule affected near-peer teaching. Conclusion. Through initial comparisons of medical and pharmacy clinical teaching units, this study provides a reflection of elements that may be necessary to successfully implement near-peer teaching in pharmacy experiential training. Future studies in this area should assess learning outcomes and participant satisfaction, preceptor workload, and impact on patient care. PMID- 27756923 TI - An Analysis of Community Pharmacy Shared Faculty Members' Contributions to Teaching, Service, and Scholarship. AB - Objective. To identify community pharmacy shared faculty members across the United States and to describe their roles and responsibilities in terms of teaching, service, and scholarship. Methods. This study was a mixed-methods analysis using surveys and key informant interviews. Results. Twenty-two faculty members completed the survey; nine were interviewed. Their major roles and responsibilities included teaching in community-based and experiential learning courses, precepting students and/or residents, being actively involved in professional organizations, providing patient care while leading innovation, and disseminating findings through scholarship. Conclusion. Community pharmacy shared faculty members contribute to their academic institutions and community pharmacy organizations by educating learners, providing direct patient care, and advancing community practice through innovation and service to the profession. Findings of this study can be used as a guide for academic institutions and community pharmacy organizations interested in partnering to develop a community pharmacy shared faculty position. PMID- 27756924 TI - Variables Affecting Pharmacy Students' Patient Care Interventions during Advanced Pharmacy Practice Experiences. AB - Objective. To identify the temporal effect and factors associated with student pharmacist self-initiation of interventions during acute patient care advanced pharmacy practice experiences (APPE). Methods. During the APPE, student pharmacists at an academic medical center recorded their therapeutic interventions and who initiated the intervention throughout clinical rotations. At the end of the APPE student pharmacists completed a demographic survey. Results. Sixty-two student pharmacists were included. Factors associated with lower rates of self-initiated interventions were infectious diseases and pediatrics APPEs and an intention to pursue a postgraduate residency. Timing of the APPE, previous specialty elective course completion, and previous hospital experience did not result in any significant difference in self-initiated recommendations. Conclusion. Preceptors should not base practice experience expectations for self-initiated interventions on previous student experience or future intentions. Additionally, factors leading to lower rates of self-initiated interventions on infectious diseases or pediatrics APPEs should be explored. PMID- 27756925 TI - Net Income of Pharmacy Faculty Compared to Community and Hospital Pharmacists. AB - Objective. To compare the net cumulative income of community pharmacists, hospital pharmacists, and full-time pharmacy faculty members (residency-trained or with a PhD after obtaining a PharmD) in pharmacy practice, medicinal chemistry, pharmaceutics, pharmacology, and social and administrative sciences. Methods. Markov modeling was conducted to calculate net projected cumulative earnings of career paths by estimating the costs of education, including the costs of obtaining degrees and student loans. Results. The economic model spanned 49 years, from ages 18 to 67 years. Earning a PharmD and pursuing an academic career resulted in projected net cumulative lifetime earnings ranging from approximately $4.7 million to $6.3 million. A pharmacy practice faculty position following public pharmacy school and one year of residency resulted in higher net cumulative income than community pharmacy. Faculty members with postgraduate year 1 (PGY1) training also had higher net income than other faculty and hospital pharmacy career paths, given similar years of prepharmacy education and type of pharmacy school attended. Faculty members with either a PharmD or PhD in the pharmacology discipline may net as much as $5.9 million and outpace all other PhD graduates by at least $75 000 in lifetime earnings. Projected career earnings of postgraduate year 2 (PGY2) trained faculty and PharmD/PhD faculty members were lower than those of community pharmacists. Findings were more variable when comparing pharmacy faculty members and hospital pharmacists. Conclusion. With the exception of PGY1 trained academic pharmacists, faculty projected net cumulative incomes generally lagged behind community pharmacists, likely because of delayed entry into the job market as a result of advanced training/education. However, nonsalary benefits such as greater flexibility and autonomy may enhance the desirability of academic pharmacy as a career path. PMID- 27756926 TI - A 10-year Study of the Academic Progress of Students Identified as Low Performers after Their First Semester of Pharmacy School. AB - Objective. To examine whether pharmacy students characterized as low performers at the conclusion of their first semester remained low performers throughout their academic career. Methods. Bottom quartile performance on first semester grade point average (GPA) was compared to licensing examination success, cumulative grade point average at the end of the didactic education and whether the student graduated on time, using cross tabulation analysis. Relative risk ratios and confidence intervals were calculated. Results. Students in the bottom quartile for GPA at the end of their first semester in pharmacy school were approximately six times more likely not to graduate on time, not to pass the North American Pharmacist Licensure Exam on their first attempt and to remain in the bottom quartile for GPA at the end of their didactic education. Conclusion. This study suggests that pharmacy students who score in the bottom quartile for GPA at the end of their first semester are more likely to underperform academically unless they take corrective action. PMID- 27756927 TI - Relationship between Student Pharmacist Decision Making Preferences and Experiential Learning. AB - Objective. To determine if student pharmacists' preferences towards experiential and rational thinking are associated with performance on advanced pharmacy practice experiences (APPEs) and whether thinking style preference changes following APPEs. Methods. The Rational Experiential Inventory (REI), a validated survey of thinking style, was administered to student pharmacists before starting APPEs and re-administered after completing APPEs. APPE grades were compared to initial REI scores. Results. Rational Experiential Inventory scores remained consistent before and after APPEs. Overall, APPE grades were independent of REI scores. In a regression model, the REI experiential score was a significant negative predictor of hospital APPE grades. Conclusion. These findings suggest that overall APPE performance is independent of decision-making preference, and decision-making style does not change following immersion into APPEs. Instead of targeting teaching strategies towards a specific decision-making style, preceptors may use pedagogical approaches that promote sound clinical decision making skills through critical thinking and reflection. PMID- 27756928 TI - A Randomized Crossover Comparison of Team-based Learning and Lecture Format on Learning Outcomes. AB - Objective. To compare learning outcomes and student confidence between team-based learning (TBL) and lecture. Methods. A crossover study was conducted with 30 students divided into two sections. Each section was taught six therapeutic topics (three TBL and three lecture). There were two assessments of 24 questions each. A survey (Likert scale) assessing student confidence and attitudes was administered at the end. Results. A significantly higher overall examination score was observed for TBL as compared to lecture. Students were more confident in providing therapeutic recommendations following TBL. Higher survey scores favoring TBL were also seen related to critical-thinking skills and therapeutic knowledge. Conclusion. Learning outcomes and student confidence in performing higher-order tasks were significantly higher with TBL. The findings of this novel crossover type design showed that TBL is an effective pedagogy. PMID- 27756929 TI - The Multiple Mini-Interview as an Admission Tool for a PharmD Program Satellite Campus. AB - Objective. To assess the multiple mini-interview (MMI) as an admission tool for a satellite campus. Methods. In 2013, the MMI was implemented as part of a new admissions model at the UNC Eshelman School of Pharmacy. From fall 2013 to spring 2015, 73 candidates were interviewed by 15 raters on the satellite campus in Asheville, North Carolina. A many-facet Rasch measurement (MFRM) with three facets was used to determine the variance in candidate ratings attributable to rater severity, candidate ability, and station difficulty. Candidates were surveyed to explore their perceptions of the MMI. Results. Rasch measures accounted for 48.3% of total variance in candidate scores. Rater severity accounted for 9.1% of the variance, and candidate ability accounted for 36.2% of the variance. Eighty percent of survey respondents (strongly) agreed that interviewers got to know them based on questions they answered.Conclusion. This study suggests that the MMI is a useful and valid tool for candidate selection at a satellite campus. PMID- 27756930 TI - Effects of Using Personal Genotype Data on Student Learning and Attitudes in a Pharmacogenomics Course. AB - Objective. To evaluate the impact of personal genotyping and a novel educational approach on student attitudes, knowledge, and beliefs regarding pharmacogenomics and genomic medicine. Methods. Two online elective courses (pharmacogenomics and genomic medicine) were offered to student pharmacists at the University of Florida using a flipped-classroom, patient-centered teaching approach. In the pharmacogenomics course, students could be genotyped and apply results to patient cases. Results. Thirty-four and 19 student pharmacists completed the pharmacogenomics and genomic medicine courses, respectively, and 100% of eligible students (n=34) underwent genotyping. Student knowledge improved after the courses. Seventy-four percent (n=25) of students reported better understanding of pharmacogenomics based on having undergone genotyping. Conclusions. Completion of a novel pharmacogenomics elective course sequence that incorporated personal genotyping and genomic medicine was associated with increased student pharmacist knowledge and improved clinical confidence with pharmacogenomics. PMID- 27756931 TI - Assessing the Effectiveness of an Evidence-based Practice Pharmacology Course Using the Fresno Test. AB - Objective. To assess the effectiveness of an evidence-based practice (EBP) pharmacology elective course to teach EBP skills using the Fresno Test (FT). Methods. Pharmacy faculty members and medical librarians developed the elective course and offered it to two cohorts of doctor of pharmacy (PharmD) students. A pre/post intervention study design was used. Seven of 12 FT items were chosen to measure specific EBP skills: Ask, Access, Appraise and Apply. Pre/postcomposite and FT item mean scores were compared using Student's t test with p<0.05 set as significant a priori. Results. Composite FT mean scores increased significantly for both cohorts. Mean scores for both cohorts increased significantly in four of the seven FT items but on different FT items. Conclusion. As a profession that commonly uses evidence-based guidelines, developing and integrating an EBP course in the PharmD curriculum is worth considering. PMID- 27756932 TI - Online Self-testing Resources Prepared by Peer Tutors as a Formative Assessment Tool in Pharmacology Courses. AB - Objective. To assess the effectiveness of optional online quizzes written by peer tutors in a pharmacology course for doctor of pharmacy students. Methods. Online quizzes were written by peer tutors for second-year pharmacy students. Quizzes reflected the material taught during lecture and were in a format similar to that of the examinations. Data related to performance on each quiz and each examination were collected throughout the semester. At the end of the semester, students and peer tutors were surveyed to gather information on the utility and success of the quizzes. Results. Students taking online quizzes performed significantly better on examinations than those who did not take quizzes. In addition, students received higher scores on examinations than when practicing with the quizzes. Surveys suggest that students liked the quizzes and felt they increased their confidence and performance on examinations. Conclusion. The quizzes were beneficial to student performance on examinations as well as student perception of performance and confidence going into the examinations. Quizzes were also beneficial learning experiences for peer tutors. PMID- 27756933 TI - Developing an Assessment Process for a Master's of Science Degree in a Pharmaceutical Sciences Program. AB - Objective. To develop a program-level assessment process for a master's of science degree in a pharmaceutical sciences (MSPS) program. Design. Program-level goals were created and mapped to course learning objectives. Embedded assessment tools were created by each course director and used to gather information related to program-level goals. Initial assessment iterations involved a subset of offered courses, and course directors met with the department assessment committee to review the quality of the assessment tools as well as the data collected with them. Insights from these discussions were used to improve the process. When all courses were used for collecting program-level assessment data, a modified system of guided reflection was used to reduce demands on committee members. Assessment. The first two iterations of collecting program-level assessment revealed problems with both the assessment tools and the program goals themselves. Course directors were inconsistent in the Bloom's Taxonomy level at which they assessed student achievement of program goals. Moreover, inappropriate mapping of program goals to course learning objectives were identified. These issues led to unreliable measures of how well students were doing with regard to program-level goals. Peer discussions between course directors and the assessment committee led to modification of program goals as well as improved assessment data collection tools. Conclusion. By starting with a subset of courses and using course-embedded assessment tools, a program-level assessment process was created with little difficulty. Involving all faculty members and avoiding comparisons between courses made obtaining faculty buy-in easier. Peer discussion often resulted in consensus on how to improve assessment tools. PMID- 27756934 TI - AdvoCaring: A Cocurricular Program to Provide Advocacy and Caring to Underserved Populations in Baltimore. AB - Objective. To incorporate direct patient care and service components throughout a 4-year pharmacy program to enable students to apply knowledge learned in the classroom and develop the human and caring dimensions of Fink's Taxonomy of Significant Learning. Design. Groups of 10-12 students and a faculty advisor partnered with a local agency serving an underserved population of the greater Baltimore area to provide seven hours of service per student each semester. Activities were determined based on students' skills and agency needs. Assessment. Over 10 000 hours of care were provided from fall 2009 through spring 2014 for clients at 12 partner agencies. Student feedback was favorable. Conclusion. Cocurricular learning enables students to use their skills to benefit local communities. Through an ongoing partnership, students are able to build on experiences and sustain meaningful care initiatives. PMID- 27756936 TI - Spread, Scale and Sustain: Report of the Executive Vice President to the House of Delegates. PMID- 27756937 TI - Strategic Priorities for AACP: Address of the 2015-2016 President-elect to the AACP House of Delegates. PMID- 27756935 TI - Pharmacy Student Learning During Advanced Pharmacy Practice Experiences in Relation to the CAPE 2013 Outcomes. AB - Outcomes from The Center for Advancement of Pharmacy Education (CAPE) are intended to represent the terminal knowledge, skills, and attitudes pharmacy students should possess and have guided delivery of pharmacy education for more than two decades. Advanced pharmacy practice experiences (APPEs) are the endpoint of pharmacy curricula where demonstration and assessment of terminal learning occurs. This review examines published literature in relation to the most recent CAPE outcomes to determine the extent to which they have been addressed during APPEs since 1996. Details related to the APPE focus, intervention(s)/learning setting(s), and assessments are summarized according to the 15 CAPE outcomes. Further, the assessments are categorized according to the level of learning achieved using an available method. Common CAPE outcomes are highlighted, as well as those for which published reports are lacking for APPEs. The range and quality of assessments are discussed and emphasize the need for continuous improvement of scholarly design and assessment. PMID- 27756938 TI - AACP Special Taskforce on Diversifying Our Investment in Human Capital Interim Update. AB - The 2015-2017 AACP Special Taskforce on Diversifying our Investment in Human Capital was appointed for a two-year term, therefore the interim update from the Taskforce. A full report will be provided in 2017 in the form of a white paper for academic pharmacy on diversifying our investment in human capital. PMID- 27756940 TI - House of Delegates Sessions, July 24-27, Anaheim, California. PMID- 27756939 TI - Roster of Voting Delegates, 2016. PMID- 27756941 TI - Fixed dose drug combinations: Issues and challenges in India. PMID- 27756942 TI - Evaluation of CYP2C19, P2Y12, and ABCB1 polymorphisms and phenotypic response to clopidogrel in healthy Indian adults. AB - INTRODUCTION: CYP2C19 and P2Y12 polymorphisms have been claimed to alter the pharmacodynamic response to clopidogrel. ABCB1 polymorphism has been associated with the efflux of clopidogrel resulting in decreased bioavailability. Due to paucity of data from Indian population, the present study was undertaken to evaluate the association of genetic polymorphisms of CYP2C19, P2Y12, and ABCB1 with inhibition of platelet aggregation (IPA) by clopidogrel. METHODS: Healthy adults (n = 90) of either gender were administered single dose of 300 mg clopidogrel. Baseline, 4 h postdose, and day 7 assessment of platelet aggregation and genotype of CYP2C19, P2Y12, and ABCB1 were carried out using standardized laboratory methods. The difference in the maximum platelet aggregation (MPA) between baseline and 4 h postdose was considered as delta-MPA (DMPA), and percentage change of MPA at 4 h from baseline was considered as IPA. Those with an IPA of <30% were considered as poor responders. Inferential statistics was applied to find out significant difference of these parameters between various groups of genetic polymorphisms. RESULTS: Mean (standard deviation [SD]) of MPA (%) at baseline, 4 h postdose, and day 7 were 78 (5), 56 (16), and 71 (8), respectively. Similarly, mean (SD) of DMPA (%) and IPA (%) were 23 (17) and 29 (21), respectively. A total of 54/90 (60%) cases were found to be poor responders to clopidogrel. A wild genotype (*1/*1) of CYP2C19 was observed in 35 (40.2%), 42 (48.3%) had *1/*2, 2 (2.3%) individuals had *1/*3, and 8 (9.2%) had *2/*2 mutant genotypes. Although statistically not significant (P = 0.09), a trend was observed in having decreased inhibition values (both MPA and IPA) as we proceed from wild genotype (*1/*1) to mutant genotypes in the order of *1/*2, *1/*3, and *2/*2. Similarly, in P2Y12, a wild haplotype (H1/H1) was present in 77 (89.5%) and 9 (10.5%) individuals had H1/H2 type. A statistically significant difference in DMPA and IPA was observed with more IPA by clopidogrel in individuals with H2 haplotype. No association was observed between the carriers and noncarriers of mutant (T) allele of ABCB1. CONCLUSION: A trend of decrease in the IPA with CYP2C19 genotypes and an increase in the same with the H2 haplotype of P2Y12 following clopidogrel in Indian healthy adults were observed. Assessment of genetic polymorphisms of the same may aid in personalizing the therapy with clopidogrel. PMID- 27756944 TI - Drug dispensing practices at pharmacies in Bengaluru: A cross-sectional study. AB - OBJECTIVES: Pharmacists are one of the crucial focal points for health care in the community. They have tremendous outreach to the public as pharmacies are often the first-port-of-call. With the increase of ready-to-use drugs, the main health-related activity of a pharmacist today is to assure the quality of dispensing, a key element to promote rational medicine use. MATERIALS AND METHODS: A cross-sectional study of 200 pharmacies, 100 each in various residential (R) and commercial (C) areas of Bengaluru, was conducted using a prevalidated questionnaire administered to the chief pharmacist or the person-in charge by the investigators. RESULTS: Dispensing without prescription at pharmacies was 45% of the total dispensing encounters and significantly higher (chi2 = 15.2, P < 0.001, df = 1) in pharmacies of residential areas (46.64%) as compared to commercial areas (43.64%). Analgesics were the most commonly dispensed drugs (90%) without prescription. Only 31% insisted on dispensing full course of antibiotics prescribed and 19% checked for completeness of prescription before dispensing. Although 97% of the pharmacies had a refrigerator, 31% of these did not have power back-up. Only about 50% of the pharmacists were aware of Schedule H. CONCLUSION: This study shows a high proportion of dispensing encounters without prescription, a higher rate of older prescription refills, many irregularities in medication counseling and unsatisfactory storage practices. It also revealed that about half of the pharmacists were unaware of Schedule H and majority of them about current regulations. Hence, regulatory enforcement and educational campaigns are a prerequisite to improve dispenser's knowledge and dispensing practices. PMID- 27756943 TI - Platelet-to-lymphocyte ratio but not neutrophil-to-lymphocyte ratio predicts high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndrome. AB - OBJECTIVES: Dual antiplatelet therapy (DAPT), consisting of clopidogrel and aspirin, is the main-stay treatment of acute coronary syndromes (ACS). However, major adverse cardiovascular events may occur even in patients undergoing DAPT, and this has been related to the variable pharmacodynamic efficacy of these drugs, especially clopidogrel. Platelet-to-lymphocyte ratio (PLR) and neutrophil to-lymphocyte ratio (NLR) are novel inflammatory markers for cardiovascular risk stratification, which may reflect an inflammatory state and thus high on treatment platelet reactivity (HPR). METHODS: We investigated the usefulness of PLR and NLR in predicting HPR in clopidogrel-treated patients with ACS. A total of 244 patients were enrolled in this study, and 43 of them were nonresponsive to clopidogrel. RESULTS: Logistic regression analysis indicated that PLR was significantly associated with HPR (P < 0.001). Using a cutoff level of 331, PLR predicted HPR with a sensitivity of 73% and a specificity of 69% (odds ratio: 376.15, 95% confidence interval = 37.813-3741.728 P < 0.001, receiver operating characteristic curve: 0.885). CONCLUSIONS: We suggest that more attention should be paid to the PLR values of these patients on admission to identify individuals who may not benefit from clopidogrel during the course of ACS. PMID- 27756945 TI - Knowledge and perceptions on antibiotic use and resistance among high school students and teachers in New Delhi, India: A qualitative study. AB - OBJECTIVE: To explore the perceptions and knowledge of school teachers and students about antibiotic use, resistance, and suggestions for practical interventions for the rational use of antibiotics. METHODOLOGY: Five focus group discussions (FGDs) with high school students (Class: 9-11) and five with teachers were conducted in two private and three public schools (one teacher and one student FGD per school) in five municipal wards of Delhi. Qualitative data on antibiotic knowledge, resistance, and behaviors with respect to antibiotics use were collected. There were 4-8 persons per teacher FGD and 15-20 persons per student FGD. FGDs were analyzed using "thematic analyses." RESULTS: Students had poor knowledge regarding antibiotics and antibiotic resistance, while only some teachers had a basic understanding. Four broad themes needing attention emerged: definition of antibiotic and antibiotic resistance, antibiotic use behavior, doctor-patient relationship, and interventional strategies suggested to curtail the misuse of antibiotics and to spread awareness. In order to tackle these problems, both groups suggested a multipronged approach including robust public awareness campaigns also involving schools, better doctor-patient relationships, and stronger regulations. CONCLUSIONS: Although students and teachers exhibited poor knowledge about antibiotic use and resistance, they were keen to learn about these issues. School education programs and public education could be used to shape correct perceptions about antibiotic use among all stakeholders including children. This may help in the containment of antibiotic resistance and thus preservation of antibiotics for future generations. PMID- 27756946 TI - Role of antioxidant property of carvedilol in mild to moderate hypertensive patients: A prospective open-label study. AB - OBJECTIVE: Carvedilol is a nonselective third generation beta-blocker that does not display the negative effects of traditional beta-blockers. Regarding the antioxidant, anti-inflammatory and distinct metabolic properties of carvedilol which are similar to that of high-density lipoprotein (HDL) and paraoxonase 1 (PON1), the present study intends to investigate the effects of carvedilol treatment on malondialdehyde (MDA) and soluble lectin-like ox-low-density lipoprotein (LDL) receptor (sLOX-1) as markers of oxidative stress in association to lipid profiles, apolipoproteins (apo), and PON1 activity in hypertensive patients. PATIENTS AND METHODS: This clinical trial study was performed on forty patients with mild to moderate essential hypertension. Subjects were studied before and after 2 months treatment with carvedilol, 25 mg daily. Lipids and lipoproteins were measured using a biochemistry analyzer. PON and arylesterase activity were assayed using paraoxon and phenyl acetate as substrates, respectively. MDA was quantified using a chemical colorimetric assay. ELISA was used to measure sLOX-1. RESULTS: Our results showed that carvedilol treatment decreased systolic and diastolic blood pressure as much as forty and 16 mmHg, respectively (P < 0.001). It also increased HDL, total cholesterol, and serum PON1 activity (P < 0.05), but the levels of triglyceride, LDL, apo A-I, and apo B did not significantly change. There was an inverse correlation between serum PON1 activity and serum MDA. CONCLUSION: This study confirmed the antihypertensive effect of the drug and its beneficial metabolic effects through augmenting HDL and PON1 activity. We propose that the antioxidant effects of carvedilol can be partially attributed to increased PON-1 activity. PMID- 27756947 TI - Prescribing pattern of analgesics in orthopedic in-patient department at tertiary care hospital in Guwahati, Assam, Northeast India. AB - OBJECTIVES: The aim of this study is to evaluate the prescribing pattern of analgesics and analyze the rational use of analgesic in orthopedic in-patient department of tertiary care teaching hospital, Guwahati, Assam. SUBJECTS AND METHODS: An observational and cross-sectional study was carried out for 1 month from April to May 2014. Collected data included age, sex, diagnosis and line of management during the study. The generic name and the average cost of treatment per patient were evaluated using Indian Drug Review, 2014. The prescribed drugs were assessed with respective National Model List of Essential Medicines (NLEM), 2011 and the rationality of prescriptions was determined using the World Health Organization indicators of drug utilization. The patients' details were recorded in a predeigned data collection form and results were analyzed by descriptive statistics. RESULTS: Out of 200 patients, 123 were male and 77 were female. The average number of analgesic per prescription was 1.46. In this study, 55.5% of patients had received single analgesic. Diclofenac was the most commonly prescribed analgesic (43.49%). During hospitalization, majority of the patients have received parenteral preparation. Gastroprotective agents and antimicrobials were frequently prescribed along with analgesics. Out of 292 analgesics prescribed, 183 (62.67%) were from the NLEM, India. Furthermore, 176 (57.19%) analgesics were prescribed by generic name. The average cost of treatment per patient was 2151.72 INR. Utilization of analgesic in terms of defined daily dose/100 bed-days was 104.01. CONCLUSION: The percentages of analgesics prescribing from NLEM and the use of analgesic by generic name were found satisfactory. Regular educational interventions to improve prescribing practices among physicians at different levels may further promote rational prescribing. PMID- 27756948 TI - Comparative evaluation of nephroprotective potential of resveratrol and piperine on nephrotic BALB/c mice. AB - OBJECTIVE: The objective of this study was to evaluate the nephroprotective potential of resveratrol and piperine at same dose on cationic bovine serum albumin (cBSA) induced immune complex glomerulonephritis (ICGN) in BALB/c mice. MATERIALS AND METHODS: Female BALB/c mice were divided into five groups. Group I served as normal control (complete Freund's adjuvant + Saline). Two weeks later, Groups II, III, IV, and V were administered cBSA (13 mg/kg) via the caudal vein 3 times/week every alternative day for 6 weeks to induce ICGN. Simultaneously, from the 3rd week, Groups III, IV were treated with resveratrol and piperine up to 6 weeks. Group V was treated with methylprednisolone considered as a reference standard. RESULTS: There was a significant decrease in albuminuria, serum creatinine, and blood urea nitrogen in Group IV animals when compared with Group III. In addition, Group III and IV have comparable results with cBSA treated animals. Concurrently, same groups showed significantly comparable variance in antioxidant enzymes, phagocytic index, and neutrophil adhesion assay. Group IV found to be more significant in IgG1 reduction than Group III. CONCLUSION: The findings of this study well-demonstrated that piperine has potential immunomodulatory and anti-inflammatory activity than resveratrol; therefore, piperine needs special attention in autoimmunity and inflammation research. PMID- 27756949 TI - B1-kinin receptors modulate Mesobuthus tamulus venom-induced vasosensory reflex responses in anesthetized rats. AB - OBJECTIVE: Intra-arterial injection of Mesobuthus tamulus (BT) venom produces reflex vasosensory responses modulating cardiorespiratory parameters in albino rats. The present study was conducted to understand the role of kinin receptors in modulating vasosensory reflexes evoked by BT venom. MATERIALS AND METHODS: In urethane-anesthetized rats, tracheostomy was performed to keep the airway patent. The femoral artery was cannulated proximally, as well as distally, to record the blood pressure (BP) and to inject the chemicals, respectively. Electrocardiographic and respiratory excursions were recorded to compute the heart rate (HR) and respiratory rate (RR). A group of animals was pretreated with saline/kinin receptor antagonists intra-arterially (B1/B2 receptor antagonists) before the injection of venom. RESULTS: After intra-arterial injection of BT venom (1 mg/kg), there was an immediate increase in RR, which reached to 40% within 30 s, followed by a decrease of 40%. Further, there was sustained increase in RR (50%) up to 60 min. The BP started to increase at 40 s, peaking at 5 min (50%), and remained above the initial level up to 60 min. The bradycardiac response started after 5 min which peaked (50% of initial) at 25 min and remained at that level up to 60 min. In B1 receptor antagonist (des-Arg) pretreated animals, venom-induced cardiovascular responses were attenuated (by 20-25% in mean arterial pressure and HR) significantly but not in B2 receptor antagonist (Hoe-140) pretreated animals. Either of the antagonists failed to alter the RR responses. CONCLUSIONS: BT venom-induced vasosensory reflex responses modulating cardiovascular parameters are mediated via B1-kinin receptors in anesthetized rats. PMID- 27756951 TI - Acidosis reduces the function and expression of alpha1D-adrenoceptor in superior mesenteric artery of Capra hircus. AB - OBJECTIVE: The objective of this study was to characterize the alpha1 adrenoceptor (alpha1-AR) subtypes and evaluate the effect of acidosis on alpha1 AR function and expression in goat superior mesenteric artery (GSMA). MATERIALS AND METHODS: GSMA rings were mounted in a thermostatically controlled (37.0 degrees C +/- 0.5 degrees C) organ bath containing 20 ml of modified Krebs Henseleit solution, maintained at pHo of 7.4, 6.8, 6.0, 5.5, 5.0, and 4.5. Noradrenaline (NA)- and phenylephrine (PE)-induced contractile response was elicited in the absence or presence of endothelium and prazosin at pHo of 7.4, 6.0, and 5.0. The responses were recorded isometrically by an automatic organ bath connected to PowerLab and analyzed using Labchart 7.1.3 software. Expression of alpha1D-AR was compared at physiological and acidic pHo using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: NA- and PE-induced contractile responses were attenuated proportionately with a decrease in extracellular pH (pHo), i.e. 7.4 -> 6.8 -> 6.0 -> 5.5 -> 5.0 -> 4.5. Endothelium denudation increased the contractile response at both normal and acidic pHo. Prazosin (1 nM, 10 nM, and 0.1 MUM) inhibited the NA- and PE-induced contractile response at pHo 7.4 and the blocking effect of prazosin was potentiated at pHo of 6.0 and 5.0. RT-PCR analysis for alpha1D-AR in GSMA showed that the mRNA expression of alpha1D-AR was decreased under acidic pHo as compared to physiological pHo. CONCLUSION: (i) Adrenergic receptor mediates vasoconstriction in GSMA under normal physiological pHo, and alpha1D is the possible subtype involved in this event (ii) acidosis attenuates the vasocontractile response due to reduced function and expression of alpha1D-AR and also increased the release of endothelial-relaxing factors. PMID- 27756950 TI - Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine induced antinociception in rats. AB - OBJECTIVES: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action. METHODS: Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry. RESULTS: Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1-4). Expression of SP was increased in the morphine + fosaprepitant group. CONCLUSIONS: The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals. PMID- 27756952 TI - Evaluation of effects of melatonin and caffeic acid phenethyl ester on acute potassium dichromate toxicity and genotoxicity in rats. AB - OBJECTIVE: The aim of this study is to investigate the possible protective effects of melatonin and caffeic acid phenethyl ester (CAPE) on potassium dichromate (K2 Cr2O7)-induced nephrotoxicity and genotoxicity. METHODS: A total of 40 Wistar albino rats were divided into five groups: control, K2Cr2O7(K2Cr2O715 mg/kg, one dose, i.p.), K2Cr2O7 + melatonin, K2Cr2O7 + CAPE, and K2Cr2O7 + melatonin + CAPE. Urine and blood samples were collected from rats before scarification. One kidney was collected for histopathological studies, and the other was stored at -80 degrees C for further determination of catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione S-transferase (GST), and glutathione reductase (GR) levels with spectrophotometric method. Comet assay was used to evaluate the genotoxicity. RESULTS: We observed a significant amelioration in genotoxicity by melatonin and simultaneous melatonin + CAPE treatment compared to K2Cr2O7 group (p1, p2< 0.05). SOD, CAT, GSH, GST, and MDA levels did not change when compared with controls. When K2Cr2O7 applied group was treated with melatonin and CAPE, neither melatonin nor CAPE made any changes in kidney GSH, GST, SOD, and MDA levels (P > 0.05). We noted that treatment with CAPE and melatonin + CAPE together caused a significant decrease in renal tissue damage, an upregulation in the kidney CAT levels (P < 0.05) and a slight healing at GR levels when compared with the K2Cr2O7 group. CONCLUSION: Our results revealed, CAPE and melatonin may have protective effects on K2Cr2O7 induced nephrotoxicity and cellular damage in rats. PMID- 27756953 TI - Immunomodulatory activity of aqueous extract of Nyctanthes arbor-tristis flowers with particular reference to splenocytes proliferation and cytokines induction. AB - OBJECTIVES: To investigate the immunomodulatory activity of aqueous extract of Nyctanthes arbor-tristis flowers (NAFE) with particular reference to splenocytes proliferation and induction of cytokines. MATERIALS AND METHODS: Antibody titer was determined by tube agglutination and indirect ELISA assay in four groups of mice-control, antigen alone, and NAFE-treated (400 and 800 mg/kg for 21 days) after immunization with Salmonella antigen while cellular immunity was studied in three groups of rats (control and NAFE-treated - 400 and 800 mg/kg) following DNCB application. Splenocytes from untreated and NAFE-treated rats were stimulated using concanavalin-A (Con-A) and optical density (OD) and stimulation index were determined. Splenocytes from control rats were also treated in vitro with NAFE (50-1600 MUg/ml) and Con-A to determine the effect on splenocytes proliferation. Interleukin-2 (IL-2) and IL-6 levels in splenocytes supernatant from control and NAFE-treated rats and following in vitro treatment of splenocytes with NAFE (50-1600 MUg/ml) were determined using ELISA kits. RESULTS: Marked to a significant increase in antibody titer by both the methods in NAFE treated mice and a significant increase in skin thickness in rats after challenge with DNCB, respectively suggested humoral and cell-mediated immunostimulant potential of NAFE. Significant increase in OD and stimulation index following e x vivo and in vitro exposure of splenocytes and sensitization with Con-A and significant elevation in IL-2 and IL-6 levels in splenocytes supernantant was also observed after their ex vivo and in vitro exposure to NAFE. CONCLUSION: Humoral and cell-mediated immunostimulant activity of NAFE seems to be mediated through splenocytes proliferation and increased production of cytokines, especially IL-2 and IL-6. PMID- 27756954 TI - Phytochemicals, antioxidant, and anthelmintic activity of selected traditional wild edible plants of lower Assam. AB - OBJECTIVE: Clerodendrum viscosum, Eryngium foetidum, Lippia javanica, and Murraya koenigii are one among the common wild edible plants in Northeast India which are also used as antidiabetic, stomach-ache relieving drugs, etc., The present study was aimed to reveal the phytochemical, antioxidant, and anthelmintic activity of the plants. MATERIALS AND METHODS: The antioxidant capacity of methanolic extract of plants was studied by 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power, TBARS, and total antioxidant activity (TAA). Total phenolics, flavonoids, Vitamin C, carbohydrate, and protein are also estimated following standard protocols. Anthelmintic activity of the extracts has also been studied in vitro against trematode parasites. RESULTS: The result showed that the methanolic extracts of plants possess a substantial quantity of alkaloids, phenolics, flavonoids, proteins, carbohydrates, and Vitamin C. Phenolics, flavonoids, and Vitamin C contents were found higher in C. viscosum followed by M. koenigii, L. javanica, and E. foetidum. The in vitro antioxidant assays revealed substantial free radical scavenging property in all the plants. TAA increased in the order C. viscosum > M. koenigii > L. javanica > E. foetidum. Similarly, C. viscosum displayed a better antioxidant capacity with IC50 values 29.74 +/- 3.63 MUg and 148.77 +/- 18.38 MUg for DPPH and thiobarbituric acid reactive species, respectively. In addition, the plant extracts also showed good anthelmintic activity against Paramphistomum sp. Time taken for paralysis and death were 0:56 +/- 0:09 h and 1:35 +/- 0:07 h for L. javanica at 50 mg/mL concentration. CONCLUSION: The study therefore suggests the importance of tested plants as a natural source of free radical scavenger and plausible veterinary uses. PMID- 27756955 TI - Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome. AB - AIM: The aim of this study is to investigate whether nitric oxide (NO)-mediated colonic motility was altered in rat irritable bowel syndrome (IBS) model, using different isoforms of NO-synthase (NOS) inhibitors. MATERIALS AND METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intra-colonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8 to 21. Control animals received saline instead of AA. Experiments were performed at the end of 8 weeks. Distal colon tissues were resected and direct effects of different NOS inhibitors; N-omega-nitro-L-arginine methyl ester hydrochloride, (L NAME), ARL-17477 dihydrochloride hydrate (ARL 17477), N-[3-(Aminomethyl) phenyl] methyl]-ethanimidamidedihydrochloride (1400 W), and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) were evaluated concentration-dependently in vitro tissue bath. Besides, morphology of both groups was assessed with hematoxylin and eosin (H and E) staining and the impact of NO antibodies was determined using the immunohistochemical method. RESULTS: The mean pressure values of spontaneous contractions and KCL (80 mmol/L) responses of distal colonic segments were similar in normal and IBS rats. L-NAME and ARL-17477 significantly increased the mean pressure of spontaneous colonic contractions in normal rats versus own base values (P < 0.05), but this increase did not significantly different when compared to IBS rats. In H and E staining, there was no difference with regard to morphology between two groups. Neuronal NOS (nNOS) immunoreactivity was found to be significantly decreased in IBS when compared to control groups (P < 0.05). CONCLUSION: L-NAME and ARL-17477 mediated mean pressure values were found to be slightly decreased in IBS rats. These findings may be related to a decrease in nNOS level in IBS. PMID- 27756956 TI - Evaluation of antioxidant effect of Nerium indicum in anxious rats. AB - AIM: The aim of this study was to analyze the ethyl acetate extract of Nerium indicum (NIE) flower for its antioxidant effect in anxious Sprague-Dawley rats. MATERIALS AND METHODS: Animals were divided into six groups (n = 6) and treated with 200 mg/kg and 400 mg/kg p.o. of NIE for 21 days to assess its preventive and curative effects. Anxiety was induced by isolating animals socially for 21 days. Elevated plus maze (EPM) and light and dark model were used for measuring anxiety in animals. Oxidative stress parameters such as lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in blood and brain tissue homogenate were monitored after 21 days of social isolation in animals. RESULTS: Rats were treated with NIE 200 mg/kg and 400 mg/kg p.o. Both the treatments showed a significant (P < 0.001) increase in the number of open arm entries and time spent in open arm in EPM when compared with the negative control. Results also demonstrated that there was a significant (P < 0.001) increase in the number of lightbox entries and time spent in light box in light and dark model when compared with negative control. There was a significant (P < 0.001) improvement in endogenous anti-oxidants such as SOD, CAT, reduced GSH, and decreased levels of LPO in blood and brain tissue when compared with the negative control. CONCLUSION: The present study suggests the role of NIE in the treatment of anxiety, possibly by modulating the oxidative stress. PMID- 27756957 TI - Effect of hydro-alcoholic extract of Vernonia cinerea Less. against ethylene glycol-induced urolithiasis in rats. AB - OBJECTIVE: Aim of this study is to evaluate antiurolithiatic potential of whole plant hydro-alcoholic (30:70) extract of Vernonia cinerea Less. in accordance to its claims made in ancient literature and also being one of the ingredients of cystone, a marketed formulation widely used in the management of urolithiasis. MATERIALS AND METHODS: To induce urolithiasis, 0.75% v/v ethylene glycol was administered orally for 14 days. The curative dose of 400 mg/kg b.w. and preventive doses of 100, 200, and 400 mg/kg b.w. were administered from 15th to 28th and 1st to 28 days, respectively. Cystone 750 mg/kg b.w. was selected as the reference standard for both curative and preventive doses. On 28th day, urinate of 24 h was collected and subjected for estimation of calcium, oxalate, and phosphates. Serum biochemical and kidney homogenate analysis was done for determination of renal oxalate contents. RESULTS: The diseased Group II showed marked increase (P < 0.001 vs. normal Group I) in levels of urine calcium, oxalate, and phosphate. Serum creatinine, urea, and uric acid levels were also increased. Histopathological studies of kidney sections revealed significant changes. Treatment with hydro-alcoholic extract of V. cinerea showed significant (P < 0.01 vs. calculi-induced Group II) dose-dependent activity. A progressive increase in urine output, body weight, and decline in concentrations of stone forming components such as calcium, oxalates, and phosphates was observed. CONCLUSION: It can be inferred that V. cinerea Less. is effective in ethylene glycol-induced urolithiasis and may have a potential in preventing and curing urolithiasis. PMID- 27756958 TI - Anti-inflammatory activity of fenugreek (Trigonella foenum-graecum Linn) seed petroleum ether extract. AB - OBJECTIVES: The aim of the present work was to study the anti-inflammatory and anti-arthritic activities of petroleum ether extract of fenugreek seeds. MATERIALS AND METHODS: Fenugreek seed powder was extracted in petroleum ether by cold maceration. This fenugreek seed petroleum ether extract (FSPEE) was analyzed by gas-liquid chromatography (GLC) and tested on rats against carrageenan and formaldehyde-induced paw edema, complete Freund's adjuvant (CFA)-induced arthritis and cotton pellet-induced granuloma. Changes in serum glutamic oxaloacetic tansaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT), and alkaline phosphatase (ALP) activities in liver and serum were also studied in cotton pellet-induced arthritic rats. Data were analyzed by Student's t-test. P <0.05 was considered statistically significant. RESULTS: GLC of FSPEE showed oleic (33.61%), linoleic (40.37%), and linolenic (12.51%) acids. With 0.5 mL/kg FSPEE treatment, there was 37% (P < 0.05) and 85% (P < 0.05) reduction in inflammation of the paw in carrageenan and formaldehyde-induced paw edema. In CFA induced arthritis, a biphasic increase in paw volume followed by decrease was seen. There was 42.5% (P < 0.01) reduction in the weight of cotton pellets and significant (P < 0.01) reductions in the elevated SGPT and ALP activities in serum and liver of FSPEE (0.5 mL/kg) treated rats. CONCLUSION: Thus, petroleum ether extract of fenugreek seeds has significant anti-inflammatory and anti arthritic activities which are due to the presence of linolenic and linoleic acids. PMID- 27756959 TI - Methanolic extract of Anthocephalus cadamba induces apoptosis in Ehrlich ascites carcinoma cells in experimental mice. AB - OBJECTIVE: Anthocephalus cadamba (Roxb.) Miq. (Family: Rubiaceae), a folk medicine commonly known as "Kadam" in Bengali, has been used for the treatment of tumor. The methanolic extract of A. cadamba (MEAC) showing antitumor activity on Ehrlich ascites carcinoma (EAC) cells treated mice was already reported. This study was designed to study the apoptosis-inducing property of MEAC and its mechanism in EAC cells in mice. MATERIALS AND METHODS: Apoptogenic morphology was determined by fluorescent DNA-binding double staining method using dyes acridine orange (AO)/ethidium bromide (EB). Comet assay was estimated to check the DNA damage. Flow cytometry (fluorescence-activated cell sorting [FACS]) was used to detect the apoptotic rate quantitatively by double labeling techniques using annexin V FITC/propidium iodide staining. Apoptotic protein expression was done using Western blotting assay method. STATISTICAL ANALYSIS: Results are expressed as mean +/- standard deviation. Statistical analysis was performed using ANOVA followed by Dunnett's post hoc test of GraphPad Prism software. *P < 0.05, **P < 0.01 and ***P < 0.001 were considered statistically significant. RESULTS: Apoptosis-inducing effect of MEAC on EAC cells was confirmed from AO/EB staining and FACS analysis. MEAC treatment showed dose-dependent induction of DNA damage. Apoptosis was induced by increasing the expression of multiple downstream factors such as pro-apoptotic protein p53 and p21 in EAC. Bax was up-regulated and anti apoptotic protein Bcl-2 was down-regulated resulting in decrease of the Bcl-2/Bax ratio by MEAC treatment. CONCLUSION: Experimental results revealed that MEAC induces apoptosis by modulating the expression of some pro-apoptotic and anti apoptotic proteins in EAC and thus exerts its anti-tumor activity. PMID- 27756960 TI - Assessment of anxiolytic effect of nerolidol in mice. AB - AIM AND OBJECTIVES: The present study was to assess the anxiolytic effect of nerolidol in mice. MATERIALS AND METHODS: The anxiolytic activity was examined using the elevated plus maze (EPM) and open field test (OFT), and motor coordination by rotarod test. Thirty Swiss albino mice were divided into five groups of six mice each. Group 1 received vehicle control (normal saline); Group 2 received diazepam (1 mg/kg); Groups 3, 4, and 5 received nerolidol 12.5, 25, and 50 mg/kg, respectively. RESULTS: Nerolidol (12.5, 25, and 50 mg/kg) significantly (P < 0.05) increased the time spent and a number of entries in open arm as compared to vehicle control in EPM test. In OFT, the nerolidol showed a significant (P < 0.05) increase in number of rearings and time spent in center and periphery, suggesting exploratory behavior of animals. Furthermore, nerolidol did not alter the fall down latency in rotarod test. CONCLUSION: Our findings indicated that nerolidol exerts an anxiolytic effect without altering the motor coordination. PMID- 27756961 TI - Melasma: A rare adverse effect of clomipramine. AB - Melasma is a hyperpigmented dermatological condition common in females. Drugs such as steroids, cosmetics, and photosensitizing agents are known to cause melasma. We report here a case of an adult male with obsessive-compulsive disorder, receiving clomipramine, who developed melasma. PMID- 27756962 TI - A clinically suspected case of Anaphylactoid reaction to vitamin K injection in a child - a case report and review of literature. AB - Vitamin K is commonly indicated in pediatric patients with coagulopathies. Its commercial preparations are available in the market since long. Minor complications are very well-known, but life-threatening events are rarely reported in children. We present a case of 8-year-old child who developed life threatening event following intravenous Vitamin K injection. She was survived after cardiopulmonary resuscitation. The reaction was most probably due to anaphylactoid reaction to Vitamin K. PMID- 27756963 TI - Imatinib-induced thyroiditis in Philadelphia chromosome-positive chronic myeloid leukemia. AB - Here, we present a case of chronic myeloid leukemia for which imatinib therapy was initated. Triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone was normal, and thyroid microsomal autoantibodies (TMA) were positive and patient was diagnosed as thyroiditis treated with corticosteroids for 11/2 months which lead to resolution. PMID- 27756964 TI - Phenytoin-induced encephalopathy in a child. AB - Phenytoin is a commonly used antiepileptic medication in the pediatric age group, but it has a narrow therapeutic range. Various adverse effects have been reported commonly. We report a relatively rare case of encephalopathy in a child from overdose of injectable phenytoin due to ignorance of the previous treatment. Scrutiny of medical records and history is of utmost importance while administering such medications. PMID- 27756965 TI - Torsades de pointes induced by concomitant use of chlorpheniramine and propranolol: An unusual presentation with no QT prolongation. AB - Drug-induced torsades de pointes (TdP) is a rare but potentially fatal adverse effect of commonly prescribed medications including cardiac and noncardiac drugs. Importantly, many drugs have been reported to cause the characteristic Brugada syndrome-linked electrocardiography (ECG) abnormalities and/or (fatal) ventricular tachyarrhythmias. Chlorpheniramine and propranolol have the arrhythmogenic effects reported previously. A review of literature revealed a large number of case reports of chlorpheniramine or propranolol use resulting in QTc prolongation, TdP, or both. However, we wish to report the case of a patient who was treated with a combination of chlorpheniramine and propranolol, whose ECG showed no QT prolongation but who suffered from cardiac arrest due to TdP. PMID- 27756966 TI - Bedaquiline versus placebo for management of multidrug-resistant tuberculosis: A systematic review. PMID- 27756967 TI - Author Reply. PMID- 27756968 TI - Irrational fixed dose combinations of psychotropic drugs in India: Cause of concern. PMID- 27756969 TI - Psychobiotics: A paradigm shift in psychopharmacology. PMID- 27756971 TI - Improving transparency in the pharmaceutical industry. PMID- 27756972 TI - Acute sinusitis and sore throat in primary care. AB - Sore throat and acute sinusitis are not straightforward diagnoses. Trying to guess the responsible pathogen may not be the best approach. Being guided by empirical evidence may be more useful. It suggests some, but very few, benefits for antibiotics. This has to be balanced with some, but few, harms from antibiotics, including diarrhoea, rash and thrush. Prescribers should also be aware of the risk of antibiotic resistance for the individual, as well as for the population as a whole. GPs should explain the evidence for the benefits and the harms of antibiotics to patients within a shared decision-making framework. PMID- 27756973 TI - The management of gout. AB - Gout is a common inflammatory arthritis that is increasing in prevalence. It is caused by the deposition of urate crystals. Non-steroidal anti-inflammatory drugs, colchicine and corticosteroids are options for the management of acute gout. They are equally efficacious and comorbidities guide the best choice. Allopurinol is an effective treatment for reducing concentrations of uric acid. Renal function guides the starting dose of allopurinol and the baseline serum uric acid concentration guides the maintenance dose. Febuxostat is another xanthine oxidase inhibitor. It is clinically equivalent to allopurinol. Uricosuric drugs, such as probenecid, increase uric acid excretion. New drugs in this class will soon become available and are likely to have a role in the treatment of patients who do not respond to other drugs. PMID- 27756974 TI - Managing behavioural and psychological symptoms in dementia. AB - Most patients with dementia have some behavioural and psychological symptoms. While aggression and agitation are easily recognised, symptoms such as apathy may be overlooked. Behavioural and psychological symptoms should be managed without drugs whenever possible. Although there is little evidence to support their use, antipsychotic drugs are often prescribed to people with dementia. Before prescribing it is important to exclude other causes of altered behaviour, such as pain or infection. Some symptoms may be artefacts of memory loss rather than psychosis. Patients with dementia who are prescribed antipsychotic drugs have an increased risk of falls, hospitalisation and death. They should be regularly monitored for adverse effects. If the patient's symptoms resolve with drug treatment, reduce the dose after two or three months. Stop the drug if the symptoms do not return. PMID- 27756975 TI - Prescribing psychotropic drugs to adults with an intellectual disability. AB - Mental illness is common in people with intellectual disability. They may also have physical health problems which can affect their mental state. Difficulties in communication can contribute to mental health problems being overlooked. These may present with changes in behaviour. Psychological management is usually preferable to prescribing psychotropic drugs. Behavioural approaches are the most appropriate way to manage challenging behaviour. If a drug is considered, prescribers should complete a thorough diagnostic assessment, exclude physical and environmental contributions to symptoms, and consider medical comorbidities before prescribing. Where possible avoid psychotropics with the highest cardiometabolic burden. Prescribe the minimum effective dose and treatment length, and regularly monitor drug efficacy and adverse effects. There is insufficient evidence to support the use of psychotropics for challenging behaviour. They should be avoided unless the behaviour is severe and non responsive to other treatments. PMID- 27756976 TI - Rituximab in autoimmune diseases. AB - Rituximab is a monoclonal antibody that depletes B cells from the circulation. It was originally used to treat lymphoma but is increasingly used for the treatment of autoimmune diseases. Rituximab was found to be effective in randomised controlled trials for rheumatoid arthritis, granulomatosis with polyangiitis and other antineutrophil cytoplasmic antibody-associated vasculitides. However, evidence of efficacy is very limited for many other autoimmune conditions. Before starting rituximab, it is important to check the patient's baseline immunoglobulins and immunisation status. Patients should also be screened for latent infections and other contraindications. PMID- 27756977 TI - Top 10 drugs. PMID- 27756978 TI - Medicinal mishap: Trimethoprim-induced critical hyperkalaemia. PMID- 27756979 TI - Nivolumab for melanoma, non-small cell lung cancer. PMID- 27756980 TI - Paritaprevir/ritonavir/ombitasvir plus dasabuvir with ribavirin for chronic hepatitis C. PMID- 27756981 TI - Improvization of conventional cytology by centrifuged liquid-based cytology in oral exfoliative cytology specimen. AB - BACKGROUND: Exfoliative cytology is the microscopic examination of shed or desquamated cells from the epithelial surface. Centrifuged liquid-based cytology (CLBC) is a modified technique that was used in the current study. AIMS: To compare the efficacy of CLBC with conventional cytology in apparently normal mucosa after staining with Papanicolaou (PAP) stain. MATERIALS AND METHODS: Fifty cases of apparently normal mucosa from healthy subjects were selected for the study. The first sample was taken and spread on the slide by the conventional technique. The second sample was flushed out in a suspending solution, centrifuged, and the cell pellet obtained was used to make the smear. The stained smears were compared for seven parameters such as adequate cellularity, clear background, uniform distribution, cellular overlapping, cellular elongation, mucus, and inflammatory cells. Chi-square test was used for statistical analysis and P <= 0.05 was considered to be statistically significant. RESULTS: There was a statistically significant difference between CLBC and conventional cytology with parameters such as adequate cellularity (P = 0.001), clear background (P = 0.001), uniform distribution (0.005), cellular overlapping, and cellular elongation (P = 0). The presence of mucus and inflammatory cells was minimal as the samples were collected from healthy subjects. CONCLUSION: CLBC has better efficacy over the conventional method in all the parameters analyzed. PMID- 27756982 TI - Fine-needle aspiration study of cystic papillary thyroid carcinoma: Rare cytological findings. AB - BACKGROUND: Cystic papillary thyroid carcinoma (CPTC) is a variant of papillary carcinoma that has many mimickers in cytological grounds. AIM: To study the cytomorphologic features of CPTC and compare them to those of other cystic thyroid lesions using fine-needle aspiration cytology (FNAC). We also aimed to identify the cytomorphologic features that distinguish CPTC from other cystic thyroid lesions. MATERIALS AND METHODS: Seventy-three cases of CPTC were included in the study. The cytomorphologic features of these cases were analyzed. The FNA smears of other thyroid lesions with cystic changes (300 colloid goiters, 290 adenomatoid nodules, 11 follicular neoplasms, and 9 hurtle cell neoplasm) were also studied. RESULTS: The smears in CPTC revealed isolated follicular cells, small groups of cells with scalloped margins, cell swirls, small clusters with a cartwheel pattern, papillary clusters, intranuclear inclusions, nuclear grooves, sticky colloid, intracellular colloids, psammoma bodies, multinucleated giant cells, and foamy and hemosiderin laden macrophages. Small groups of cells with scalloped borders, cellular swirls, and small clusters with a cartwheel pattern were seen in CPTC, but not in other cystic lesions. Interestingly, mesothelial like cells and hemophagocytic cells were seen in five and three cases of CPTC, respectively, but not in other cystic lesions. CONCLUSION: Mesothelial-like cells and hemophagocytic cells were observed in five and three cases of CPTC, respectively. Similar finding have not been previously reported in the literature. PMID- 27756983 TI - Evaluation of cytomorphometric changes in tobacco users and diagnosed oral squamous cell carcinoma individuals. AB - AIMS: To determine the cellular and nuclear area of keratinocytes in smears obtained from the oral mucosa of tobacco users, those with oral squamous cell carcinoma (OSCC), and from normal healthy persons and resolve if any significant difference exists in these three groups. MATERIALS AND METHODS: The study group comprised 100 subjects 20 controls, (40 OSCC patients-20 from lesional sites and 20 from nonlesional sites, 20 tobacco smokers and 20 tobacco chewers) in the age group of 25-75 years. Oral mucosal smears obtained by using a cytobrush were stained with Papanicolaou (PAP) stain and using 20X objective in trinocular Olympus model BX53 with Jenoptik scientific grade-dedicated microphotographic camera images were taken. With ProgRes version 8.0 image analysis software, 20 cells with defined borders were evaluated from each slide. Finally, one-way analysis of variance (ANOVA) was used to compare the above parameters in the studied groups. STATISTICAL ANALYSIS USED: Minitab and Excel software were used to analyze the data. One-way ANOVA was used to compare the above parameters in the studied groups. RESULTS: The mean value of the cell area for groups I, II, III, IV, and V were 2838 +/- 275.2, 2762.1 +/- 511.4, 2861.9 +/- 512.9, 2643.8 +/ 333.3, and 3064.3 +/- 362.7, respectively, the nuclear area (NA) was 83.88 +/- 9.86, 106.19 +/- 13.45, 95.11 +/- 14.24, 85.55 +/- 21.11, and 80.83 +/- 13.45, respectively, and nuclear-to-cellular (N:C) ratio was 0.0297, 0.03924, 0.0337, 0.03257, and 0.02678, respectively. CONCLUSIONS: Thus, our study elucidates that cytomorphology gauges the effect of tobacco on the oral mucosa and possibly establishes a link between premalignant and malignant transformations even before a lesion is visibly noted. PMID- 27756984 TI - Cytological grading: An alternative to histological grading in oral squamous cell carcinoma. AB - BACKGROUND: Micronuclei (MN) in oral exfoliative cells have been shown to indicate a disparaging change in genetic information of the cell. Recent studies showed correlation between the frequency of MN and severity of this damage. Grading of lesions can be used to determine the austerity of this damage. Aims: The aim of this study is to compare the MN frequency in oral exfoliated cells of normal and oral squamous cell carcinoma (OSCC) individuals and to cytologically grade the frequency of MN in cytological smears and to correlate it with histological grading. The objective is to ascertain whether MN frequency in oral exfoliated cells can be a parameter for grading of OSCC. SETTINGS AND DESIGN: The study group comprises of 40 subjects (20 controls and 20 OSCC patients) in the age group of 45-85 years. MATERIALS AND METHODS: The cytosmear was obtained from each group and stained with Papanicolaou (PAP) stain. Twenty cells from each slide were counted for MN and cytological grade of OSCC was assigned based on the average frequency of MN. Cytological grade was correlated with histological grading and the data were recorded. Student's t-test and Spearman's correlation were used for the analysis of the data. RESULTS: Average frequency of MN was 2.5 times higher in OSCC patients when compared to that in controls and the difference was found to be highly significant. Sixty percent correlation was found between cytological grade and histological grade of OSCC and the difference between them was not significant. CONCLUSIONS: Cytological grading can be used in grading OSCC, and MN insinuates genotoxic damage occurring in the epithelial cells. PMID- 27756985 TI - Bacterial vaginosis in association with spontaneous abortion and recurrent pregnancy losses. AB - CONTEXT: Bacterial vaginosis (BV) is related to the increased risk of miscarriage, preterm labor, and postpartum endometritis. AIMS: The aim of this study was to evaluate the association between BV and the history of spontaneous abortion and recurrent pregnancy losses. We also examined periods of gestation, including the first and second trimester miscarriages. MATERIALS AND METHODS: The study population consisted of 200 fertile women. Sixty one (30.5%) of 200 women had the history of a spontaneous abortion in the last six months (N = 30) and at least three recurrent pregnancy losses (N = 31). BV was diagnosed either by using Papanicolaou staining, Gram staining, or by culturing with BV-associated bacteria, Gardnerella vaginalis. RESULTS: The presence of BV was statistically associated with the history of a spontaneous abortion in the last 6 months (P < 0.05), whereas there was no significant relationship between BV and recurrent pregnancy losses (P > 0.05). These women were also evaluated in view of periods of gestation. Forty-seven (77%) of 61 women had first trimester miscarriage (<=12 weeks) and 14 (23%) of 61 women had second trimester miscarriage (>12 weeks). There was a statistically significant relationship between BV and second trimester miscarriage (P < 0.05). Positive BV findings were not associated with discharge, itching, and pain (P > 0.05). CONCLUSION: BV may contribute to spontaneous abortion and second trimester miscarriage. PMID- 27756986 TI - Comparison of FNAC smears, cytospin smears, and cellblocks of transthoracic guided FNAC of suspected lung tumor: A study of 100 cases. AB - INTRODUCTION: Transthoracic guided fine needle aspiration cytology (FNAC) of clinically suspected lung tumors is an increasingly common procedure in diagnosis. Cytospin Smear and Cellblock preparations of available material are helpful in subtyping and confirming the diagnosis, and they can also be used for further studies, i.e., special stain and immunohistochemistry, etc. AIMS AND OBJECTIVES: This research was undertaken to study the technique of guided transthoracic lung FNAC of clinically suspected lung tumors and the establish role of FNAC smears, cytospin smears, and cellblocks in the detection and typing of neoplastic lung lesions and correlation. MATERIALS AND METHODS: Guided FNAC was taken from 100 cases of clinically suspected lung tumor and FNAC smears, cytospin smears, and cellblocks of aspirated material were studied over a period of 2 years from September 2011 to September 2013. RESULTS: The material adequacies were 80% in FNAC smears, 83% in cytospin smears, and 89% in cellblocks. Additional information supported by cytospin smear and cellblock was 3% and 9%, respectively. Architectural preservation was better in FNAC smears (85%) and cellblocks (73.03%) than that in cytospin smears (31.33%). Morphological preservation was better in FNAC smears (90%) and cellblocks (75.28%) than that in cytospin smears (14.46%). Diagnostic accuracy was increased in the cellblocks and cytospin smears. CONCLUSION: Cytospin smear was helpful when low cellular material was obtained, and the concomitant examination of cellblocks not only confirmed the diagnosis of malignancy but also helped in classifying the obtained material and allowed further study on the same. PMID- 27756987 TI - Cytomorphologic spectrum of lymphocytic thyroiditis and correlation between cytological grading and biochemical parameters. AB - INTRODUCTION: Chronic lymphocytic thyroiditis [Hashimoto thyroiditis (HT)] is a common thyroid lesion diagnosed on fine-needle aspiration cytology (FNAC). Apart from FNAC, various other parameters, such as clinical features, ultrasonographic findings, antithyroid antibody levels, hormone profiles, and radionuclide thyroid scan, are also taken into consideration in making a diagnosis of HT. AIMS: To grade lymphocytic thyroiditis based on the cytomorphology and to correlate the cytological grades with the levels of antithyroid peroxidase antibody (ATPO), antithyroglobulin antibody (ATG), and thyroid stimulating hormone (TSH). MATERIALS AND METHODS: During a period of one and half years, 1,667 cases underwent FNAC of thyroid at our tertiary care center. Of these, 128 cases had cytological evidence of lymphocytic thyroiditis. Out of these, in 60 cases the levels of ATPO, ATG, and TSH were known. The cytological grades of lymphocytic thyroiditis in these cases were correlated with these parameters. RESULTS: Out of the 60 cases, 55 were females. Age ranged from 5 years to 70 years, with majority of patients in third decade. Diffuse enlargement of thyroid was the commonest presentation. However, 14 cases presented with nodular disease. Majority of the patients had grade 1 thyroiditis (27 cases), followed by grade 2 thyroiditis (22 cases). Cytomorphology was diagnostic of thyroiditis in all 60 cases. ATPO was elevated in 57 cases and ATG was elevated in 40 cases. Elevated level of TSH was seen in only 18 cases. In 39 cases, TSH value was normal. There was no correlation between the cytological grades of thyroiditis and the levels of antithyroid antibodies and TSH. CONCLUSION: Lymphocytic infiltration of thyroid follicles is pathognomonic of lymphocytic thyroiditis. Positivity for antithyroid antibodies is strongly associated with HT but no correlation was observed between the grades of thyroiditis and the levels of ATPO, ATG, and TSH. PMID- 27756988 TI - Cytology of plasma cell rich effusion in cases of plasma cell neoplasm. AB - BACKGROUND: Multiple myeloma or plasmacytoma resulting in malignant effusion is rarely described in literature. AIMS: In this paper, we have studied the seven rare cases of plasma cell infiltration in effusion fluid. MATERIALS AND METHODS: We studied six cases of pleural fluid and one case of ascetic fluid. Detailed cytological features, clinical history, bone marrow examinations, serum electrophoresis, and immunofixation data were analyzed. RESULT: There were two cases of plasmacytoma, four cases of multiple myeloma, and one case of plasmablastic lymphoma. On cytology, all the cases showed excess plasma cells along with mesothelial cells and lymphocytes on effusion cytology smear. CONCLUSION: Plasma cell rich effusion in cases of plasma cell tumor is rare. However, on cytology these cases do not pose much problem if relevant history is known. PMID- 27756989 TI - Destaining of Diff-Quik stained cytologic smears is not necessary for the detection of anaplastic lymphoma kinase gene rearrangement in lung adenocarcinoma by fluorescence in situ hybridization. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangement analysis by fluorescence in situ hybridization (FISH) is one of the standard molecular tests for targeted therapy of lung adenocarcinoma. However, insufficient cell block cellularity may impede molecular testing. A recent study showed that Diff-Quik (DQ) stained cytology smear is suitable for ALK by FISH. AIMS: The aim of our study was to observe the impact of destaining intervals on the quality of FISH signals and determine if DQ smears without destaining would allow FISH analysis. MATERIALS AND METHODS: Thirty-five DQ smears from 27 cases of lung adenocarcinoma were analyzed for ALK gene rearrangement by FISH. Twenty three DQ smears were destained for different intervals, including 30 s (13 cases), 1 min (6 cases), or 2 min (4 cases). Twelve DQ smears were not subjected to destaining. For further validation, FISH signals in 8 smears and 6 cell blocks were compared with the paired destained DQ smears. The signal quality was semi-quantified and analyzed with Chi-squared test. RESULTS: Of the total 27 selected cases, three (11%) were positive for ALK gene rearrangement, whereas 24 (89%) were negative. FISH signal was satisfactory in all DQ smears. There was no significant difference in the quality of signal among smears with different destaining intervals (P = 0.55) or between smears with and without destaining (P = 0.41). DQ smears without destaining showed identical FISH results and similar or better signals as compared with paired destained smears and cell blocks in all cases. CONCLUSIONS: Duration of destaining intervals does not impact the quality of FISH signal on DQ smears. Destaining of DQ smears is not necessary for ALK by FISH. PMID- 27756990 TI - Pleural effusion: Role of pleural fluid cytology, adenosine deaminase level, and pleural biopsy in diagnosis. AB - OBJECTIVE: The present study is designed to evaluate the role of pleural fluid analysis in diagnosing pleural diseases and to study the advantages and disadvantages of thoracocentasis and pleural biopsy. MATERIALS AND METHODS: We prospectively included 66 consecutive indoor patients over a duration of 1 year. Pleural fluid was collected and cytological smears were made from the fluid. Plural biopsy was done in the same patient by Cope needle. Adequate pleural biopsy tissue yielding specific diagnosis was obtained in 47 (71.2%) cases. RESULTS: Tuberculosis was the commonest nonneoplastic lesion followed by chronic nonspecific pleuritis comprising 60% and 33.3% of the nonneoplastic cases respectively and tuberculosis was predominantly diagnosed in the younger age group. Majority (70.8%) of malignancy cases were in the age group of >50-70. Adenocarcinoma was found to be the commonest (66.7%) malignant neoplasm in the pleurae followed by small-cell carcinoma (20.8%). CONCLUSION: Pleural biopsy is a useful and minimally invasive procedure. It is more sensitive and specific than pleural fluid smears. PMID- 27756991 TI - Cytodiagnosis of disseminated histoplasmosis in an immunocompetent individual with molluscum contagiosum-like skin lesions and lymphadenopathy. AB - Disseminated histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum (H. capsulatum). The early clinical manifestations are nonspecific, often lead to diagnostic difficulty, and is misdiagnosed as tuberculosis and seen usually in immunosuppressed states. Fine needle aspiration cytology (FNAC) is a simple, safe, and quick technique to establish the initial diagnosis of H. capsulatum, thereby prompting early treatment. The skin involvement is rare in disseminated disease and we describe a case of disseminated histoplasmosis in an immunocompetent patient with unusual molluscum contagiosum like umbilicated skin lesions and FNAC of the cervical lymph node was the only tool for rapid and early confirmatory diagnosis. PMID- 27756992 TI - Iatrogenic calcinosis cutis: A rare cytological diagnosis. AB - Calcinosis cutis is an uncommon condition characterized by the deposition of calcium salts in the subcutaneous tissues of the body. Calcifications can also occur in a variety of other clinical settings and can be subjected to fine-needle aspiration (FNA). Since cutaneous calcific deposits may clinically mimic a tumor, it is feasible to diagnose them by FNA cytology (FNAC). We reported a case of calcinosis cutis by FNA in a 36-year-old male who presented with a solitary subcutaneous nodule in cubital fossa. Smears showed amorphous granular material consistent with calcium and occasional histiocytes. The diagnosis was confirmed when cytosmears were subjected to a special stain such as the von Kossa stain. PMID- 27756993 TI - Urinary balantidiasis: A rare incidental finding in a patient with chronic obstructive pulmonary disease. AB - Balantidiasis is a rare zoonotic disease in humans. Balantidium coli is the causative ciliated protozoan. We present a case of urinary balantidiasis in a patient having chronic obstructive pulmonary disease (COPD) who was on steroids for a long time. He has no symptoms of bowel or urinary involvement. We are reporting this case because of its rarity in human urine and also for future references. PMID- 27756994 TI - Fine-needle aspiration diagnosis of nodular fasciitis: A case report. AB - A 10-year-old boy presented with a swelling of the left mid upper arm of 1 month duration. Fine-needle aspiration (FNA) diagnosis of pseudosarcomatous lesion, suggestive of nodular fasciitis, was made and advised radiological examination. Magnetic resonance imaging (MRI) diagnosis was benign fibroblastic tumor. Excisional biopsy was done and histopathology confirmed the diagnosis of nodular fasciitis. As of now, the child is absolutely alright after 1 year. PMID- 27756995 TI - Cytological diagnosis of deep-seated cellular hemangioma of the parotid gland by using cell button technique. AB - Intraparotid hemangioma of the children is a rare neoplasm, posing diagnostic dilemma to the diagnosticians as well as treating clinicians. A 2-month-old male infant presented with a diffuse swelling in the parotid region since birth that was gradually increasing in size. The ultrasonography (USG) report was suggestive of a right intraparotid mass of uncertain etiology; whereas magnetic resonance imaging (MRI) report inclined toward a mass associated with chronic inflammatory pathology. Fine-needle aspiration cytology (FNAC) suggested two differentials - a vascular neoplasm of the parotid gland and a spindle cell neoplasm with increased vascularity. The lesion was reaspirated and a cell button was constructed from the aspirated material to reach a conclusive diagnosis by histopathological evaluation and immunohistochemistry (IHC) before attempting any intervention to treat the infant. The final diagnosis after histopathological and IHC studies was given as deep cellular intraparotid hemangioma. Subsequently, the patient was treated with single sitting bleomycin sclerotherapy. A simple technique of cell button resulted in sparing of hospitalization and surgical procedure in the infant. PMID- 27756996 TI - Your High-Alert Medication List Is Relatively Useless Without Associated Risk Reduction Strategies. AB - Risk-reduction strategies for high-alert medication lists. PMID- 27756997 TI - Generics Companies Press for REMS Relief: Potential Law Would Clarify When Brand Name Manufacturers Must Supply Drug Samples. AB - Generic companies press for REMS relief with Senate bill. PMID- 27756998 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 27756999 TI - Pharmaceutical Approval Update. AB - Obeticholic acid (Ocaliva) for primary biliary cholangitis; sofosbuvir 400 mg/velpatasvir 100 mg (Epclusa) for chronic hepatitis C virus infection; and daclizumab (Zinbryta) for relapsing multiple sclerosis. PMID- 27757000 TI - Mepolizumab (Nucala) For Severe Eosinophilic Asthma. AB - Mepolizumab (Nucala) for severe eosinophilic asthma. PMID- 27757001 TI - PTSD Treatment for Veterans: What's Working, What's New, and What's Next. AB - More than a decade of war in the Middle East has pushed post-traumatic stress disorder (PTSD) to the forefront of public health concerns. The author defines the disorder and discusses risk factors, treatments, and the barriers to effective care. PMID- 27757002 TI - Therapeutic Interchange of Clevidipine For Sodium Nitroprusside in Cardiac Surgery. AB - BACKGROUND: Generic price inflation has resulted in rising acquisition costs for sodium nitroprusside (SNP), an agent historically described as the drug of choice for the treatment of perioperative hypertension in cardiac surgery. PURPOSE: To describe the implementation and cost avoidance achieved by utilizing clevidipine as an alternative to SNP in cardiac surgery patients at a 520-bed community teaching hospital that performs more than 300 cardiac surgeries each year. METHODS: A multidisciplinary team inclusive of anesthesiologists, intensivists, pharmacists, and surgeons collaborated to develop a therapeutic interchange for SNP in cardiac surgery patients. Consistent with current guidelines for therapeutic interchange, the goal was to encourage a less expensive alternative that was demonstrated to be at least therapeutically equivalent to SNP based on data derived from clinical trials published in peer-reviewed literature. A comprehensive literature review identified clevidipine as an alternative to SNP for perioperative hypertension in cardiac surgery. Nicardipine was considered as well, but was not chosen as a substitute due to lack of strong evidence and comparative data with SNP. RESULTS: Clevidipine was implemented successfully in our cardiac surgery patients and will result in a net cost avoidance of approximately $300,000 in 2016. This is thought to be driven largely by the difference in acquisition cost between clevidipine and SNP. The operating room in our institution no longer keeps SNP stocked in anesthesia trays as a result of the success of our interchange. No requests have been made to return to the SNP standard. CONCLUSION: Through effective communication and multidisciplinary collaboration, our institution was able to develop an evidence-based and effective therapeutic interchange program for SNP. PMID- 27757003 TI - Off-Label Use of Dexmedetomidine for the Treatment of Delirium in the Intensive Care Unit. AB - OBJECTIVE: Evaluate recent clinical studies involving the use of dexmedetomidine (DEX) infusion for the treatment of delirium in the intensive care unit (ICU). METHODS: A literature search was conducted to identify peer-reviewed articles in MEDLINE (1966-June 2016) using the terms sedation, analgesic, dexmedetomidine, delirium, and critically ill adult patients. RESULTS: Two studies in the ICU setting reported the potential benefits of DEX for managing agitation during weaning from mechanical ventilation. One pilot study and a clinical trial reported the use of DEX in the treatment of ICU delirium. CONCLUSION: Further studies are required to evaluate the use of DEX treatment in critically ill patients presenting with delirium. PMID- 27757004 TI - European Society of Cardiology Congress. AB - More than 33,000 cardiologists and allied medical professionals gathered in Rome to share the latest cardiac research. We review key sessions from a wide range of therapeutic areas, including anticoagulation, obesity, and hypercholesterolemia. PMID- 27757006 TI - Long-Term Health Risks in Childhood Cancer Survivors. PMID- 27757005 TI - Novel Treatments Target Type-2 Diabetes. AB - Patients with type-2 diabetes can control their blood glucose levels through diet and exercise, by losing excess weight, and by taking medications, such as first line metformin. We examine several promising drugs in the type-2 diabetes pipeline. PMID- 27757007 TI - Focused ultrasound in ophthalmology. AB - The use of focused ultrasound to obtain diagnostically significant information about the eye goes back to the 1950s. This review describes the historical and technological development of ophthalmic ultrasound and its clinical application and impact. Ultrasound, like light, can be focused, which is crucial for formation of high-resolution, diagnostically useful images. Focused, single element, mechanically scanned transducers are most common in ophthalmology. Specially designed transducers have been used to generate focused, high-intensity ultrasound that through thermal effects has been used to treat glaucoma (via ciliodestruction), tumors, and other pathologies. Linear and annular transducer arrays offer synthetic focusing in which precise timing of the excitation of independently addressable array elements allows formation of a converging wavefront to create a focus at one or more programmable depths. Most recently, linear array-based plane-wave ultrasound, in which the array emits an unfocused wavefront and focusing is performed solely on received data, has been demonstrated for imaging ocular anatomy and blood flow. While the history of ophthalmic ultrasound extends back over half-a-century, new and powerful technologic advances continue to be made, offering the prospect of novel diagnostic capabilities. PMID- 27757008 TI - Predictive images of postoperative levator resection outcome using image processing software. AB - PURPOSE: This study aims to evaluate the efficacy of processed images to predict postoperative appearance following levator resection. METHODS: Analysis involved 109 eyes from 65 patients with blepharoptosis who underwent advancement of levator aponeurosis and Muller's muscle complex (levator resection). Predictive images were prepared from preoperative photographs using the image processing software (Adobe Photoshop(r)). Images of selected eyes were digitally enlarged in an appropriate manner and shown to patients prior to surgery. RESULTS: Approximately 1 month postoperatively, we surveyed our patients using questionnaires. Fifty-six patients (89.2%) were satisfied with their postoperative appearances, and 55 patients (84.8%) positively responded to the usefulness of processed images to predict postoperative appearance. CONCLUSION: Showing processed images that predict postoperative appearance to patients prior to blepharoptosis surgery can be useful for those patients concerned with their postoperative appearance. This approach may serve as a useful tool to simulate blepharoptosis surgery. PMID- 27757009 TI - Corneal endothelial changes after accelerated corneal collagen cross-linking in keratoconus and postLASIK ectasia. AB - PURPOSE: The purpose of this study was to evaluate the effects of accelerated cross-linking (CXL) on corneal endothelium in keratoconus and postlaser-assisted in situ keratomileusis (LASIK) ectasia. DESIGN: This study is a prospective nonrandomized controlled study. SETTING: This study was conducted in Mansoura Ophthalmic Center (Mansoura University) and Al-Mostakbal Ophthalmic Center, Mansoura, Egypt. METHODS: In total, 40 eyes with progressive keratoconus and 10 eyes with postLASIK ectasia were subjected to an accelerated CXL (10 mW/cm2 for 9 minutes). Qualitative and quantitative analyses of the corneal endothelial cells were conducted before CXL and 3, 6, and 12 months after CXL by using a specular microscope (Tomy EM-3000). RESULTS: There was a significant reduction in endothelial cell count particularly at 3 and 6 months postCXL. In addition, the coefficient of variance was also statistically significantly higher at 3 and 6 months postoperatively than the preCXL value. There was a slight change in the percentage of hexagonal cells. CONCLUSION: The use of accelerated CXL (10 mW/cm2 for 9 minutes) has a transient negative impact on endothelial cell density and/or endothelial morphology. PMID- 27757010 TI - Refractive lenticule extraction (ReLEx) through a small incision (SMILE) for correction of myopia and myopic astigmatism: current perspectives. AB - Small-incision lenticule extraction (SMILE) is an alternative to laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) for the correction of myopia and myopic astigmatism. SMILE can be performed for the treatment of myopia <=-12 D and astigmatism <=5 D. The technology is currently only available in the VisuMax femtosecond laser platform. It offers several advantages over LASIK and PRK; however, hyperopia treatment, topography-guided treatment, and cyclotorsion control are not available in the current platform. The working principles, potential advantages, and disadvantages are discussed in this review. PMID- 27757011 TI - Druggability analysis and classification of protein tyrosine phosphatase active sites. AB - Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability. Particularly focusing on PTP1B, we also demonstrated the influence of several factors on the druggability of PTP active site. For instance, the open conformation showed better druggability than the closed conformation, while the tight-bound water molecules appeared to have minimal effect on the PTP1B druggability. Finally, the allosteric site of PTP1B was found to exhibit superior druggability compared to the catalytic pocket. This analysis can prove useful in the discovery of new PTP inhibitors by assisting researchers in predicting hit rates from high throughput or virtual screening and saving unnecessary cost, time, and efforts via prioritizing PTP targets according to their predicted druggability. PMID- 27757012 TI - Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene polypropylene block copolymer for maximized disintegration and dissolution. AB - The objective of this research was to improve the dissolution of simvastatin and to incorporate it in rapid disintegrating tablets (RDTs) with an optimized disintegration and dissolution characteristics. Polyoxyethylene-polypropylene block copolymer (poloxamer 188) was employed as a hydrophilic carrier to prepare simvastatin solid dispersions (SDs). Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffractometry were employed to understand the interaction between the drug and the carrier in the solid state. The results obtained from Fourier transform infrared spectroscopy showed absence of any chemical interaction between the drug and poloxamer. The results of differential scanning calorimetry and X-ray diffractometry confirmed the conversion of simvastatin to distorted crystalline state. The SD of 1:2 w/w drug to carrier ratio showed the highest dissolution; hence, it was incorporated in RDT formulations using a 32 full factorial design and response surface methodology. The initial assessments of RDTs demonstrated an acceptable flow, hardness, and friability to indicate good mechanical strength. The interaction and Pareto charts indicated that percentage of croscarmellose sodium incorporated was the most important factor affecting the disintegration time and dissolution parameter followed by the hardness value and their interaction effect. Compression force showed a superior influence to increase RDT's porosity and to fasten disintegration rather than swelling action by croscarmellose sodium. On the other hand, croscarmellose sodium was most important for the initial simvastatin release. The results suggest the potential use of poloxamer 188-based SD in RDT for the oral delivery of poor water-soluble antihyperlipidemic drug, simvastatin. PMID- 27757013 TI - Spotlight on frovatriptan: a review of its efficacy in the treatment of migraine. AB - Migraine is a common neurovascular disorder, affecting millions of people worldwide. Current guidelines recommend triptans as first-line treatment for moderate-to-severe migraine attacks. Frovatriptan is a second-generation triptan with a longer terminal elimination half-life in blood than other triptans (~26 hours). Three double-blind, randomized crossover preference studies have been recently conducted, assessing efficacy and safety of frovatriptan versus rizatriptan, zolmitriptan, and almotriptan, respectively. Frovatriptan showed favorable tolerability and sustained effect, with a significantly lower rate of relapse over 48 hours versus the other triptans. These findings were confirmed in a series of analyses of patient subsets from the three studies, including patients with menstrually related and oral contraceptive-induced migraine, hypertension, obesity, weekend migraine, as well as patients with migraine with aura. In all patient subsets analyzed, lower headache recurrence rates were observed versus the comparator triptans, indicating a more sustained pain relieving effect on migraine symptoms. A further randomized, double-blind study demonstrated that frovatriptan given in combination with the fast-acting cyclooxygenase inhibitor dexketoprofen provided improved migraine pain-free activity at 2 hours, and gave more sustained pain-free activity at 24 hours, versus frovatriptan alone. These benefits were observed both when the combination was administered early (<1 hour after symptom onset) or late (>1 hour after onset). Different pharmacokinetic, but synergistic, properties between frovatriptan and dexketoprofen may make the combination of these agents particularly effective in migraine treatment, with rapid onset of action and sustained effect over 48 hours. These benefits, together with potential cost effectiveness advantages versus other triptans could drive selection of the most appropriate treatment for acute migraine attacks. PMID- 27757014 TI - Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus. AB - Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane alpha-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds. PMID- 27757015 TI - Stability of apomorphine in solutions containing selected antioxidant agents. AB - Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To identify the optimum antioxidant agent/combination for apomorphine solution, a high performance liquid chromatography assay was used to study the stability of 50 MUg/mL apomorphine HCI in 0.1% L-ascorbic acid (AA), 0.1% sodium metabisulfite (SMB), 0.1% EDTA, and in selected combinations at 25 degrees C, 32 degrees C, and 37 degrees C over a period of 14 days. The stability of apomorphine HCl (10 mg/mL) in 0.1% AA solution and in 0.1% EDTA solution at 25 degrees C and 37 degrees C was also evaluated. Apomorphine HCI solution (50 MUg/mL) in 0.1% AA plus 0.1% SMB solution retained 99.7% (at 25 degrees C) and 95.9% (at 37 degrees C) of the initial concentration, as 0.1% AA plus SMB solution minimized the reactive oxygen content in solution which, in turn, reduced the oxidation rate of apomorphine HCl, and there was no green coloration perceptible. Conversely, apomorphine HCl solution (50 MUg/mL) in 0.1% SMB solution was unstable as only 0.53% (at 25 degrees C) and 0.06% (at 37 degrees C) of the initial concentration was retained after 14 days. All 10 mg/mL apomorphine HCl samples were stable in both studies. The initial concentration of apomorphine HCl solution markedly affected its rate of oxidation and discoloration. The addition of 0.1% AA to a current formulation of apomorphine HCl injection (Apomine(r)), which contains SMB as an antioxidant, was recommended as providing the most stable solution. PMID- 27757016 TI - A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease. AB - Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved NamzaricTM, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified. PMID- 27757018 TI - Depression and anxiety in age-related macular degeneration. PMID- 27757017 TI - Intracerebroventricular urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats. AB - PURPOSE: Urocortin 3 is a key neuromodulator in the regulation of stress, anxiety, food intake, gut motility, and energy homeostasis, while ghrelin elicits feeding behavior and enhances gastric emptying, adiposity, and positive energy balance. However, the interplays between urocortin 3 and ghrelin on food intake and gastric emptying remain uninvestigated. METHODS: We examined the differential effects of central O-n-octanoylated ghrelin, des-Gln14-ghrelin, and urocortin 3 on food intake, as well as on charcoal nonnutrient semiliquid gastric emptying in conscious rats that were chronically implanted with intracerebroventricular (ICV) catheters. The functional importance of corticotropin-releasing factor (CRF) receptor 2 in urocortin 3-induced responses was examined by ICV injection of the selective CRF receptor 2 antagonist, astressin2-B. RESULTS: ICV infusion of urocortin 3 opposed central acyl ghrelin-elicited hyperphagia via CRF receptor 2 in satiated rats. ICV injection of O-n-octanoylated ghrelin and des-Gln14-ghrelin were equally potent in accelerating gastric emptying in fasted rats, whereas ICV administration of urocortin 3 delayed gastric emptying. In addition, ICV infusion of urocortin 3 counteracted central acyl ghrelin-induced gastroprokinetic effects via CRF receptor 2 pathway. CONCLUSION: ICV-infused urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats. Our results clearly showed that enhancing ghrelin and blocking CRF receptor 2 signaling in the brain accelerated gastric emptying, which provided important clues for a new therapeutic avenue in ameliorating anorexia and gastric ileus found in various chronic wasting disorders. PMID- 27757019 TI - Scale up use of family planning services to prevent maternal transmission of HIV among discordant couples: a cross-sectional study within a resource-limited setting. AB - BACKGROUND: Integration of family planning services (FPS) into human immunodeficiency virus (HIV) care for HIV-infected women is an important aspect of the global prevention of mother-to-child transmission (PMTCT) strategy. We assessed the integration of FPS into routine care of HIV-infected mothers by evaluating the uptake and barriers of contraception and PMTCT services. METHODS: We conducted an interventional study using the interrupted time series approach in the health care facilities located in Yaounde, Cameroon. First, structured questionnaires related to family planning use, PMTCT services use, and infection risk of the sexual partner were administered to the first trimester pregnant women who were HIV infected and living with uninfected partners. Second, 2 weeks before the delivery date, the women were interviewed according to the prior counseling interventions received, in order to assess their behavior on FPS, antiretroviral therapy (ART) use, delivery option, and infant nourishment to be adopted. P-values below 0.05 were considered statistically significant in the statistical analyses. RESULTS: Of 94 HIV-infected women, 69% were stable couples. Only 13% of women had attended FPS before conception. Although the vast majority were knowledgeable about modern and traditional contraception methods, only 19% had experienced effective contraceptive methods. However, 66% preferred condom use, 45% having three children still expressed a desire to conceive, while 44% reported abortions, 65% had tried to avoid the current pregnancy, and 12% of women were ART naive. Several predictors such as education, abortion rate, unplanned pregnancies, and partners' decision were associated with the nonuse of effective contraceptive methods. Moreover, barriers including sex inequity, lack of partner support, ART shortages, and lack of HIV viral load monitoring were prevalent among the participants (P=0.001). However FPS use, ART compliance, and safe options to PMTCT significantly increased after the educational counseling interventions (P=0.001). CONCLUSION: Scaling up the FPS by incorporating routine PMTCT services into reproductive health care should contribute to preventing both horizontal and vertical transmission of HIV. PMID- 27757020 TI - Spotlight on empagliflozin/metformin fixed-dose combination for the treatment of type 2 diabetes: a systematic review. AB - The dramatic rise in the prevalence of obesity and diabetes is associated with increased morbidity, mortality, and public health care costs worldwide. The need for new, effective, and long-lasting drugs is urgent. Recent research has focused on the role of the inhibitors of sodium- glucose co-transporter 2 (SGLT-2). Clinical trials have shown that SGLT-2 inhibitors have glycemic efficacy and weight-lowering potential. Dual drug therapy is a recommended therapy for patients with new-onset type 2 diabetes who need significant glycemic control. Fixed-dose combination therapy represents a particularly attractive option as it may reduce pill burden and improve adherence. The combination of metformin and empagliflozin was approved by the US Food and Drug Administration in 2014 and represents a safe and effective means to combat glycemic control and weight gain. The purpose of this systematic review is to summarize the background of the SGLT 2 inhibitors, particularly empagliflozin, and focus on the safety and efficacy of the fixed-dose combination of empagliflozin and metformin. PMID- 27757021 TI - Oncology providers' perspectives on endocrine therapy prescribing and management. AB - PURPOSE: Adjuvant endocrine therapy (ET) can reduce the risk of recurrence among females with hormone receptor-positive breast cancer. Overall, initiation and adherence to ET are suboptimal, though reasons are not well described. The study's objective was to better understand ET decision making, prescribing, and patient management from oncology providers' perspectives. METHODS: Using purposive sampling, we recruited oncology providers who saw five or more breast cancer patients per week (n=20). We conducted 30-45-minute telephone interviews, using a semistructured guide to elicit perspectives on ET use. We used thematic content analysis to systematically identify categories of meaning and double coded transcripts using Atlas.ti. RESULTS: Providers recommend ET to all eligible patients except those with contraindications or other risk factors. Providers base their ET prescribing decisions on the patient's menopausal status, side effects, and comorbidities. ET is typically discussed multiple times: at the onset of breast cancer treatment and in more detail after other treatment completion. Providers felt that the associated recurrence risk reduction is the most compelling argument for patients during ET decision making. While providers rarely perceived noninitiation as a problem, nonadherence was prevalent, often due to unresolvable side effects. CONCLUSION: From the clinicians' perspectives, side effects from ET are the dominant factor in nonadherence. Efforts to improve adherence should focus on strategies to minimize side effects and ensure clinicians and patients are well informed regarding optimal side effect management. This finding has important implications for novel endocrine regimens that offer improved outcomes through longer duration or more intensive therapy. PMID- 27757022 TI - Individual difficulties and resources - a qualitative analysis in patients with advanced lung cancer and their relatives. AB - PURPOSE: Lung cancer is a disease with a high percentage of patients diagnosed in an advanced stage. In a situation of palliative treatment, both patients and their relatives experience diverse types of distress and burden. Little research has been done to identify the individual difficulties and resources for patients with advanced lung cancer and their relatives. Especially, standardized questionnaire-based exploration may not assess the specific distressing issues that pertain to each individual on a personal level. The purpose of this qualitative study is to explore and compare individual difficulties and resources for lung cancer patients and their relatives within the palliative care context. METHODS: Data were collected by qualitative interviews. A total of 18 participants, nine patients diagnosed with advanced lung cancer (International Classification of Diseases, tenth edition, diagnosis C-34, stage IV) starting or receiving palliative treatment and nine relatives, were interviewed. Data were interpreted through qualitative content analysis. RESULTS: We identified four main categories of difficulties: communication and conflicts, home and everyday life, thinking about cancer, and treatment trajectory. In general, difficulties were related to interpersonal relationships as well as to impact of chemotherapy. Family, professional caregivers, and social life were significant resources and offered support to both patients and relatives. CONCLUSION: Results suggest that patient and relative education could reduce difficulties in several areas. Patients seem to struggle with the fear of not having any perspective in therapy. Relatives seem to experience helplessness regarding their partner's deterioration and have to handle their own life and the care work simultaneously. The most important resource for both patients and relatives is their family. In addition, professional lung cancer nurses support relatives in an emotional and organizational way. Intense supportive care for relatives should be standardized. PMID- 27757023 TI - Is it appropriate regarding patient preference to take Myrtol standardized enteric-coated soft capsules after a meal rather than at fasted state? A food drug pharmacokinetic interaction study in healthy Chinese volunteers. AB - BACKGROUND: According to prescribing information for Myrtol standardized enteric coated soft capsules, the medicine should be taken on an empty stomach. Some patients may experience stomach discomfort after oral administration in fasted state and would prefer to take the medicine after a meal. However, there is no literature addressing the effect of meal on absorption of this drug; therefore, it is desirable to explore the feasibility of taking the capsule after a meal from pharmacokinetic perspective. METHODS: A gas chromatography coupled with triple quadruples mass spectrometry assay was established and validated for determining plasma concentrations of eucalyptol, a target component of Myrtol standardized capsules. A self-control clinical study was carried out in healthy male volunteers in fasted and fed states after a single oral dose of 300 mg capsules. Comparison of pharmacokinetic parameters in the two phases and bioequivalence evaluation were performed. RESULTS: The specificity, sensitivity, accuracy, and precision of the assay satisfied the requirements for biopharmaceutical analysis. Pharmacokinetic parameters of eucalyptol (fasted vs fed) were as follows: maximal plasma concentrations (Cmax) (167.60+/-114.69 vs 518.89+/-314.47 ng.mL-1), time of maximum concentration (Tmax) (3.7+/-1.1 vs 4.8+/-0.7 h), elimination half-life (T1/2) (3.2+/-1.4 vs 2.6+/-0.7 h), area under the plasma concentration-time curve (AUC0-t) (584.91+/-369.90 vs 1,271.61+/ 605.82 ng.h.mL-1), and AUC0-infinity (690.36+/-467.26 vs 1,458.02+/-720.21 ng.h.mL-1). There was statistically significant difference in Cmax, AUC0-t, and AUC0-infinity between the two dosing methods (P<0.05). Pharmacokinetic parameters of eucalyptol given in fasted state in Chinese were comparable to those in Germany population. The 90% confidence intervals for the ratio of Cmax (18.4%~64.7%), AUC0-t (28.9%~68.5%), and AUC0-infinity (31.1%~68.4%) values for the test (fasted) and reference (fed) were beyond the Food and Drug Administration's acceptable range of 80%~125%. In addition, significant difference was obtained in Tmax (P<0.05). CONCLUSION: Compared with dosing at fasted state, taking Myrtol standardized capsules after a meal achieves a delayed absorption rate and an increased absorption extent. The two dosing methods were not bioequivalent in this small study and, thus, not interchangeable. Patient preference and pharmacokinetic food-drug interaction issue should be balanced. Further clinical study is necessary to explore the clinical outcome of oral administration of Myrtol standardized capsules after or with meal. PMID- 27757024 TI - Type 2 diabetes: cost-effectiveness of medication adherence and lifestyle interventions. AB - INTRODUCTION: Type 2 diabetes is a major burden for the payer, however, with proper medication adherence, diet and exercise regime, complication occurrence rates, and consequently costs can be altered. AIMS: The aim of this study was to conduct a cost-effectiveness analysis on real patient data and evaluate which medication adherence or lifestyle intervention is less cost demanding for the payer. METHODS: Medline was searched systematically for published type 2 diabetes interventions regarding medication adherence and lifestyle in order to determine their efficacies, that were then used in the cost-effectiveness analysis. For cost-effectiveness analysis-required disease progression simulation, United Kingdom Prospective Diabetes Study Outcomes model 2.0 and Slovenian type 2 diabetes patient cohort were used. The intervention duration was set to 1, 2, 5, and 10 years. Complications and drug costs in euro (EUR) were based on previously published type 2 diabetes costs from the Health Care payer perspective in Slovenia. RESULTS: Literature search proved the following interventions to be effective in type 2 diabetes patients: medication adherence, the Mediterranean diet, aerobic, resistance, and combined exercise. The long-term simulation resulted in no payer net savings. The model predicted following quality-adjusted life-years (QALY) gained and incremental costs for QALY gained (EUR/QALYg) after 10 years of intervention: high-efficacy medication adherence (0.245 QALY; 9,984 EUR/QALYg), combined exercise (0.119 QALY; 46,411 EUR/QALYg), low-efficacy medication adherence (0.075 QALY; 30,967 EUR/QALYg), aerobic exercise (0.069 QALY; 80,798 EUR/QALYg), the Mediterranean diet (0.057 QALY; 27,246 EUR/QALYg), and resistance exercise (0.050 QALY; 111,847 EUR/QALYg). CONCLUSION: The results suggest that medication adherence intervention is, regarding cost-effectiveness, superior to diet and exercise interventions from the payer perspective. However, the latter could also be utilized by patients without additional costs, but medication adherence intervention requires trained personnel because of its complex structure. Interventions should be performed for >2 years to produce noticeable health/cost results. PMID- 27757025 TI - Older adults' attitudes and barriers toward the use of mobile phones. AB - BACKGROUND AND OBJECTIVES: The limitations caused by the process of aging and the prevalence of chronic diseases contribute to reduced performance in physical, psychological, and social areas of life in older people. The use of mobile phones as easily accessible portable tools with a high performance is associated with an increased health literacy, self-care, and independence in older people. The present study was conducted to determine older people's attitudes toward the use of mobile phones and the barriers to their use. MATERIALS AND METHODS: The present descriptive study was conducted on a sample population of 328 individuals older than 60 years presenting to health centers across cities in west Mazandaran, Iran. The data collection tools used included a mobile phone use checklist, a questionnaire on older people's attitude toward the use of mobile phones, and a questionnaire on the barriers to the use of mobile phones. The reliability and validity of these questionnaires were confirmed by the researchers. The data obtained were recorded and then analyzed using SPSS. The level of statistical significance was set at P<=0.05. RESULTS: According to the results, 80% of the older people had regular mobile phones and 20% had smartphones. In 95% of the male and 80% of the female participants, the greatest use of mobile phones pertained to making phone calls. A total of 5% of the male and 2% of the female participants used the Internet in their mobile phones. A total of 44% of the female and 42.80% of the male participants had poor attitudes (score from 0 to 40) toward mobile phone use. As for the different dimensions of the attitude toward mobile phone use, the highest score obtained by the female participants (71.66%) pertained to the psychoemotional dimension and the highest score in the male participants (72.85%) to the instrumental dimension. The results also revealed the lack of knowledge of English as the greatest barrier to mobile phone use in both sexes. There was a significant relationship between sex and the attitude toward mobile phone use in all the three dimensions examined, the sociocultural, psychoemotional, and instrumental. DISCUSSION AND CONCLUSION: The results of the study revealed that the majority of older people have negative attitudes toward the use of mobile phones as a teaching aid, although they used them for performing daily tasks. Promoting this age group's knowledge about the different mobile phone applications available to help them and increasing their ability to learn the use of these applications through the mass media, family members, and peer groups can help improve older people's attitudes toward the use of mobile phones and thus increase their use of these devices. PMID- 27757026 TI - Vitamin E administration may decrease the incidence of pneumonia in elderly males. AB - BACKGROUND: Vitamin E has influenced the immune system in laboratory studies. Dozens of animal experiments have found that vitamin E offered protection against infections caused by viruses and bacteria. Previously, significant heterogeneity was found in the effect of vitamin E supplementation on pneumonia in humans. The aim of this study was to examine how the effect of vitamin E on pneumonia risk depends on age. METHODS: Secondary analysis of the Alpha-Tocopherol, Beta Carotene Cancer Prevention study in Finland, 1985-1993, was performed. Participants were male smokers aged 50-69 years at the baseline who started to smoke at >=21 years (N=7,469). Intervention was 50 mg/d of vitamin E for 5-8 years. The outcome was the incidence of hospital-treated, community-acquired pneumonia by the age at the follow-up. RESULTS: Among 2,216 participants who smoked 5-19 cigarettes per day at baseline and exercised at leisure time, vitamin E supplementation reduced the incidence of pneumonia by 69% (95% confidence interval [CI]: 43%-83%; 57 pneumonia cases). In this subgroup, vitamin E prevented pneumonia in 12.9% of participants by the age of 74 years. Among 5,253 participants who smoked >=20 cigarettes per day at baseline or did not exercise, the incidence of pneumonia was 14% lower in the vitamin E participants (95% CI: 38% to +21%; 139 cases). One-third of the participants quit smoking for a period, of whom 27 got pneumonia. The incidence of pneumonia was 72% (95% CI: 31%-89%) lower in the vitamin E group, and this benefit was also seen among those males who smoked >=20 cigarettes per day at baseline or did not exercise. CONCLUSION: Although the evidence of benefit from vitamin E against pneumonia in elderly males is strong in this analysis, the overall findings about vitamin E have been complex. Further research on vitamin E in nonsmoking elderly males is warranted. PMID- 27757027 TI - Evaluation of body composition in COPD patients using multifrequency bioelectrical impedance analysis. AB - BACKGROUND: Multifrequency bioelectrical impedance analysis (MF-BIA) is a technique that measures body impedance (Z) at different frequencies (5, 10, 50, 100, and 250 kHz). Body composition may be estimated using empirical equations, which include BIA variables or, alternatively, raw BIA data may provide direct information on water distribution and muscle quality. OBJECTIVES: To compare raw MF-BIA data between COPD patients and controls and to study their relationship with respiratory and functional parameters in COPD patients. METHODS: MF-BIA was performed (Human Im-Touch analyzer) in 212 COPD patients and 115 age- and BMI matched controls. Fat-free mass (FFM) and fat mass were estimated from BIA data, and low- to high-frequency (5 kHz/250 kHz) impedance ratio was calculated. Physical fitness, lung function and respiratory muscle strength were also assessed in COPD patients. RESULTS: After adjusting for age, weight, and body mass index, FFM and the 5/250 impedance ratio were lower in COPD patients (P<0.001) and were negatively affected by disease severity. In both male and female patients, the 5/250 impedance ratio was significantly correlated mainly with age (r=-0.316 and r=-0.346, respectively). Patients with a 5/250 impedance ratio below median value had lower handgrip strength (P<0.001), 6-minute walk distance (P<0.005), respiratory muscle strength (P<0.005), forced expiratory volume in 1 second (P<0.05) and vital capacity (P<0.005). Finally, the 5/250 impedance ratio was reduced (P<0.05) in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) III and IV (compared to those with GOLD I and II) or a BODE index between 6 and 10 points (compared to those with BODE index between 1 and 5 points). CONCLUSION: MF-BIA may be a useful tool for assessing body composition and nutritional status in COPD patients. In particular, the impedance ratio could give valuable information on cellular integrity and muscle quality. PMID- 27757028 TI - Characterization of sputum biomarkers for asthma-COPD overlap syndrome. AB - Asthma-COPD overlap syndrome (ACOS) is a commonly encountered chronic airway disease. However, ACOS is still a consensus-based clinical phenotype and the underlying inflammatory mechanisms are inadequately characterized. To clarify the inflammatory mediatypical for ACOS, five biomarkers, namely interleukin (IL)-13, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), chitinase-like protein (YKL-40), and IL-6, were selected. This study hypothesized that sputum biomarkers relevant for airway inflammation in asthma (IL-13), COPD (MPO, NGAL), or in both asthma and COPD (YKL-40, IL-6) could be used to differentiate ACOS from COPD and asthma. The aim of this study was to characterize the inflammatory profile and improve the recognition of ACOS. Induced sputum levels of IL-13, MPO, NGAL, YKL-40, and IL-6 were measured by enzyme-linked immunosorbent assay/Luminex assay in a Finnish discovery cohort (n=90) of nonsmokers, smokers, and patients with asthma, COPD, and ACOS and validated in a Japanese cohort (n=135). The classification accuracy of potential biomarkers was compared with area under the receiver operating characteristic curves. Only sputum NGAL levels could differentiate ACOS from asthma (P<0.001 and P<0.001) and COPD (P<0.05 and P=0.002) in the discovery and replication cohorts, respectively. Sputum NGAL levels were independently correlated with the percentage of pre-bronchodilator forced expiratory volume in 1 second predicted in multivariate analysis in the discovery and replication cohorts (P=0.001 and P=0.002, respectively). In conclusion, sputum biomarkers reflecting both airway inflammation and remodeling of the tissue show potential in differentiation between asthma, COPD, and ACOS. PMID- 27757029 TI - Comparison of the clinical characteristics and treatment outcomes of patients requiring hospital admission to treat eosinophilic and neutrophilic exacerbations of COPD. AB - PURPOSE: We compared the clinical characteristics and treatment outcomes of patients with eosinophilic and neutrophilic COPD exacerbations requiring hospital admission. PATIENTS AND METHODS: This was a retrospective multicenter study performed between January 2010 and December 2014. In all, 1,688 COPD patients admitted via the outpatient clinics or emergency departments of six university hospitals were enrolled. The patients were grouped by complete blood counts: eosinophilic group, >2% peripheral blood eosinophils, and neutrophilic group, >65% peripheral blood neutrophils or >11,000 leukocytes/mL. The patients with radiographic evidence of pneumonia at the time of admission, those with lung cancer, those admitted for treatment of other medical problems, and those who chronically used steroids were excluded. RESULTS: A total of 605 patients hospitalized with COPD exacerbations (177 eosinophilic and 380 neutrophilic) were included. Pulmonary functions, including the forced expiratory volume in 1 second and forced vital capacity, were better in patients with eosinophilic exacerbations. Treatment outcomes, including the rate of admission to the intensive care unit and mortality, were poorer in patients with neutrophilic exacerbations (4.5% vs 12.4%, P=0.004; 1.1% vs 4.5%, P=0.043, respectively). Congestive heart failure (odds ratio [OR] =3.40, 95% confidence interval [CI]: 1.28-9.01) and neutrophilic exacerbation (OR = 2.81, 95% CI: 1.21-6.52) were independent risk factors for intensive care unit admission. CONCLUSION: COPD patients with neutrophilic exacerbations experienced worse clinical outcomes than did those with eosinophilic exacerbations. The peripheral blood eosinophil count may be a useful predictor of clinical progress during hospitalization of COPD patients with acute exacerbations. PMID- 27757030 TI - A nanoporous surface is essential for glomerular podocyte differentiation in three-dimensional culture. AB - Although it is well recognized that cell-matrix interactions are based on both molecular and geometrical characteristics, the relationship between specific cell types and the three-dimensional morphology of the surface to which they are attached is poorly understood. This is particularly true for glomerular podocytes - the gatekeepers of glomerular filtration - which completely enwrap the glomerular basement membrane with their primary and secondary ramifications. Nanotechnologies produce biocompatible materials which offer the possibility to build substrates which differ only by topology in order to mimic the spatial organization of diverse basement membranes. With this in mind, we produced and utilized rough and porous surfaces obtained from silicon to analyze the behavior of two diverse ramified cells: glomerular podocytes and a neuronal cell line used as a control. Proper differentiation and development of ramifications of both cell types was largely influenced by topographical characteristics. Confirming previous data, the neuronal cell line acquired features of maturation on rough nanosurfaces. In contrast, podocytes developed and matured preferentially on nanoporous surfaces provided with grooves, as shown by the organization of the actin cytoskeleton stress fibers and the proper development of vinculin-positive focal adhesions. On the basis of these findings, we suggest that in vitro studies regarding podocyte attachment to the glomerular basement membrane should take into account the geometrical properties of the surface on which the tests are conducted because physiological cellular activity depends on the three dimensional microenvironment. PMID- 27757031 TI - Antidepressant effects of curcumin and HU-211 coencapsulated solid lipid nanoparticles against corticosterone-induced cellular and animal models of major depression. AB - Major depression is a complex neuropsychiatric disorder with few treatment approaches. The use of nontargeted antidepressants induced many side effects with their low efficacy. A more precise targeting strategy is to develop nanotechnology-based drug delivery systems; hence, we employed solid lipid nanoparticles (SLNs) to encapsulate HU-211 and curcumin (Cur). The antidepressant effects of the dual-drug nanoparticles (Cur/SLNs-HU-211) for major depression treatment were investigated in corticosterone-induced cellular and animal models of major depression. Cur/SLNs-HU-211 can effectively protect PC12 cells from corticosterone-induced apoptosis and can release more dopamine, which may be associated with the higher uptake of Cur/SLNs-HU-211 shown by cellular uptake behavior analysis. Additionally, Cur/SLNs-HU-211 significantly reduced the immobility time in forced swim test, enhanced fall latency in rotarod test, and improved the level of dopamine in mice blood. Cur/SLNs-HU-211 can deliver more Cur to the brain and thus produce a significant increase in neurotransmitters level in brain tissue, especially in the hippocampus and striatum. The results of Western blot and immunofluorescence revealed that Cur/SLNs-HU-211 can significantly enhance the expression of CB1, p-MEK1, and p-ERK1/2. Our study suggests that Cur/SLNs-HU-211 may have great potential for major depression treatment. PMID- 27757032 TI - Pluronic-based micelle encapsulation potentiates myricetin-induced cytotoxicity in human glioblastoma cells. AB - As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer. Immunoblotting and quantitative reverse transcriptase polymerase chain reaction techniques were used for determining the expression levels of related molecules in protein and mRNA. The results indicated that myricetin-induced cytotoxicity was highly potentiated by the encapsulation of myricetin. Mitochondrial apoptotic pathway was demonstrated to be involved in myricetin-induced glioblastoma cell death. The epidermal growth factor receptor (EGFR)/PI3K/Akt pathway located in the plasma membrane and cytosol and the RAS-ERK pathway located in mitochondria served as upstream and downstream targets, respectively, in myricetin-induced apoptosis. MiR-21 inhibitors interrupted the expression of EGFR, p-Akt, and K-Ras in the same fashion as myricetin-loaded mixed micelles (MYR-MCs) and miR-21 expression were dose-dependently inhibited by MYR-MCs, indicating the interaction of miR-21 with MYR-MCs. This study provided evidence supportive of further development of MYR-MC formulation for preferentially targeting mitochondria of glioblastoma cells. PMID- 27757033 TI - Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma. AB - Radiotherapy performs an important function in the treatment of cancer, but resistance of tumor cells to radiation still remains a serious concern. More research on more effective radiosensitizers is urgently needed to overcome such resistance and thereby improve the treatment outcome. The goal of this study was to evaluate and compare the radiosensitizing efficacies of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) on glioma at clinically relevant megavoltage energies. Both AuNPs and AgNPs potentiated the in vitro and in vivo antiglioma effects of radiation. AgNPs showed more powerful radiosensitizing ability than AuNPs at the same mass and molar concentrations, leading to a higher rate of apoptotic cell death. Furthermore, the combination of AgNPs with radiation significantly increased the levels of autophagy as compared with AuNPs plus radiation. These findings suggest the potential application of AgNPs as a highly effective nano-radiosensitizer for the treatment of glioma. PMID- 27757034 TI - Prevalence of major depressive disorder among hemodialysis patients compared with healthy people in Japan using the Structured Clinical Interview for DSM-IV. AB - BACKGROUND: We investigated the prevalence of depression in hemodialysis (HD) patients using the Center for Epidemiologic Studies for Depression (CES-D) scale and the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID) and compared the rates with those of community dwelling people in Japan. PATIENTS AND METHODS: A total of 99 patients undergoing HD were recruited. Blood sampling was performed no later than 2 weeks prior to assessment. As a reference group for SCID and CES-D evaluation, 404 age- and sex-matched healthy controls who had participated in the Iwaki Health Promotion Project were included in this study. The SCID and the CES-D scale were administered to all participants to diagnose their depression. Participants who met the criteria of a major depressive episode according to the SCID were classified as SCID depression and the participants whose CES-D score was 16 or higher were classified as CES-D depression. RESULTS: Ninety-nine HD patients completed the evaluation and data collection. There were no significant differences in age, sex, or CES-D scores between HD patients and controls. There were 12 cases of SCID depression in HD patients and four cases in controls. There was a significant difference between HD patients and controls in the prevalence of SCID depression. There were no significant differences between the two groups with regard to demographic or clinical data. There were 19 HD patients and 24 controls who showed CES-D depression. There was no significant difference between HD patients and controls in the prevalence of CES-D depression. There was a significant difference in potassium level between the two groups, but there were no significant differences in any of the other items. CONCLUSION: There were significantly more HD patients showing SCID depression than controls in the present study. In clinical settings, the SCID might be useful in surveying cases of depression detected by screening tools among HD patients. PMID- 27757036 TI - New developments in acne treatment: role of combination adapalene benzoylperoxide. AB - The fixed-dose combination adapalene 0.1%/benzoylperoxide 2.5% (A/BPO) was introduced as an acne vulgaris therapeutic in 2007. It combines anti inflammatory, keratolytic, comedolytic, and antibacterial properties. Thus, it addresses several pathophysiological factors involved in the pathophysiology of acne. This review highlights the rationale for the use of this fixed-dose combination product, its therapeutic efficacy including effects on adherence and quality of life, its use for different forms of acne, and the side-effect profile. In summary, the fixed-dose combination of A/BPO gel can be regarded as a highly effective and safe formulation. It is not associated with antibiotic resistance. It reduces factors that cause nonadherence and has positive effects on the quality of life of affected patients. The tolerance is good. The initial mild irritation potential can be addressed by adequate counseling. A/BPO can be used for all forms of inflammatory acne, including severe forms, as part of a combination with systemic antibiotics. Finally, it can also be used for the long term treatment of chronic acne. Thus, it is a very valuable therapeutic option in daily practice, which is reflected by its strong recommendation in the "European S3-guidelines". PMID- 27757035 TI - Role of berberine in Alzheimer's disease. AB - Berberine, an important protoberberine isoquinoline alkaloid, has several pharmacological activities, including antimicrobial, glucose- and cholesterol lowering, antitumoral, and immunomodulatory properties. Substantial studies suggest that berberine may be beneficial to Alzheimer's disease (AD) by limiting the pathogenesis of extracellular amyloid plaques and intracellular neurofibrillary tangles. Increasing evidence has indicated that berberine exerts a protective role in atherosclerosis related to lipid- and glucose-lowering properties, implicating that berberine has the potential to inhibit these risk factors for AD. This review also attempts to discuss the pharmacological basis through which berberine may retard oxidative stress and neuroinflammation to exhibit its protective role in AD. Accordingly, berberine might be considered a potential therapeutic approach to prevent or delay the process of AD. However, more detailed investigations along with a safety assessment of berberine are warranted to clarify the role of berberine in limiting these risk factors and AD related pathologies. PMID- 27757039 TI - Importance of organizational culture: a model for increased engagement. PMID- 27757037 TI - Pain management in patients with Parkinson's disease: challenges and solutions. AB - This review focuses on the diagnosis and management of Parkinson-related pain which is one of the more frequently reported nonmotor symptoms in Parkinson's disease (PD), which is the second most common neurodegenerative disease after Alzheimer's disease. Pain is ranked high by patients as a troublesome symptom in all stages of the disease. In early-stage PD, pain is rated as the most bothersome symptom. Knowledge of the correct diagnosis of pain origin and possible methods of treatments for pain relief in PD is of great importance. The symptoms have a great negative impact on health-related quality of life. Separating PD-related pain from pain of other origins is an important challenge and can be characterized as "many syndromes under the same umbrella". Among the different forms of PD-related pain, musculoskeletal pain is the most common form, accounting for 40%-90% of reported pain in PD patients. Augmentation by pathophysiological pathways other than those secondary to rigidity, tremor, or any of the other motor manifestations of the disease seems most probable. In PD, the basal ganglia process somatosensory information differently, and increased subjective pain sensitivity with lower electrical and heat-pain thresholds has been reported in PD patients. The mechanism is assumed to be diminished activity of the descending inhibitory control system of the basal ganglia. PD pain, like many of the nonmotor symptoms, remains underdiagnosed and, thus, poorly managed. A systematic collection of patient descriptions of type, quality, and duration of pain is, therefore, of utmost importance. Recent studies have validated new and more specific and dedicated pain scales for PD-related symptoms. Symptomatic treatments based on clinical pain classification include not only pharmacological but also nonpharmacological methods and, to some degree, invasive approaches. In the clinic, pharmacological and nonpharmacological interventions can be effective to varying degrees - as single therapies or in combination - and should be employed, because no therapeutic strategies have been validated to date for managing PD pain. Multimodal approaches should always be considered, dopamine replacement therapies should be adjusted, and analgesics and/or antidepressants should be considered, including the use of different forms of complementary therapies. PMID- 27757038 TI - Lack of ear care knowledge in nursing homes. AB - BACKGROUND: Rising life expectancy means an increase in the number of elderly people with hearing loss in the population. Many elderly people live in nursing homes, with varying care needs. A substantial proportion of these people will need help with their hearing aids and other hearing devices. OBJECTIVE: The objective of the study has been to assess the knowledge, experience, skills, competence, and need for information of staff at nursing homes in relation to residents' hearing loss and hearing aids. MATERIALS AND METHODS: One hundred and ninety-five employees at seven nursing homes participated in the study. The main approach was a descriptive study, using questionnaires. RESULTS: The main findings are that 73% of informants found that many residents need help with their hearing aids. Only one-tenth report that they know enough about the residents' hearing aids. Almost four out of five informants find that the residents become socially isolated as a result of hearing loss. Seventy-eight percent agree to some extent that more residents would benefit from hearing aids. CONCLUSION: Staff at nursing homes have insufficient knowledge about hearing loss and hearing aids. Increased focus on the elderly with hearing impairment in nursing homes is needed. Contact between nursing homes and audiological specialists should be improved to best followup hearing loss and hearing aids. PMID- 27757040 TI - Same-day physical therapy consults in an outpatient neuromuscular disease physician clinic. AB - BACKGROUND: Team-based care has been shown to offer more comprehensive benefits to patients when compared to standard physician-based care alone in clinics for chronic conditions. However, apart from grant-funded multidisciplinary clinics, there are no reports on the usage of same-day physical therapy (PT) consults within a daily outpatient neuromuscular disease (NMD) physician clinic. OBJECTIVE: To determine the impact of same-day PT consults at the University of Utah's outpatient Clinical Neurosciences Center. DESIGN: A qualitative assessment and survey of patient satisfaction. METHODS: An eight question Health Insurance Portability and Accountability Act-compliant patient satisfaction survey using a 5-point Likert scale was administered. Demographic data and Press-Ganey Provider Satisfaction surveys were retrospectively collected from electronic medical records for patients receiving same-day PT encounters in the neuromuscular division over 1 year. RESULTS: Mean (standard deviation) age was 54.22 (19.81) years for 134 patient encounters, median age was 60 years, with 76 male (57%) and 58 female (43%) patients. Mean Likert score for 61 self-reported patient satisfaction surveys for same-day PT consults was 4.87 (97.4%). Press-Ganey Provider Satisfaction scores improved from 89.9% (N=287) for the year prior to 90.8% (N=320) for the corresponding year (P=0.427). A total of 46 (75.4%) patients have either never before received PT care or never before received PT care for their NMD, 67.4% of whom were male. CONCLUSION: Same-day PT consults in an outpatient NMD physician clinic demonstrated excellent patient satisfaction and improved access to specialty care. This model could potentially be implemented in other academic medical centers to improve access to rehabilitation services for patients with NMD. PMID- 27757041 TI - Infliximab enhances the therapeutic effects of 5-fluorouracil resulting in tumor regression in colon cancer. AB - Colon cancer (CC) is among the most common malignant diseases with a dismal survival. Tumor necrosis factor-alpha (TNF-alpha) has been identified as a therapeutic target in various cancers, and anti-TNF-alpha treatment has shown promising effects in different cancer models. However, if TNF-alpha can be targeted in CC, the therapeutic values of anti-TNF-alpha treatment in CC remain unknown. Our study indicated that TNF-alpha is highly expressed in CC cell lines and patient tumor samples. High expression of TNF-alpha is an independent adverse prognosticator of CC. Targeting the TNF-alpha by its antibody infliximab induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity and enhanced apoptosis leading to cell death. The combination of infliximab with 5-fluorouracil showed better responses in vitro and in vivo than 5-fluorouracil alone. In conclusion, this study identified TNF-alpha as a target of CC and anti TNF-alpha treatment synergized with chemotherapy leading to a better outcome in preclinical models. PMID- 27757042 TI - miR-590-5p regulates gastric cancer cell growth and chemosensitivity through RECK and the AKT/ERK pathway. AB - BACKGROUND: The aim of this study was to determine the role of miRNA-590-5p in gastric cancer (GC) progression. METHODS: Quantitative real-time polymerase chain reaction was performed to measure endogenous miR-590-5p levels in GC cells and tissues. Overexpression or knockdown of miR-590-5p in GC cells was performed by transfection with mimics or an inhibitor, respectively. MTT, matrigel transwell, and Western blot assays were used to assess the effects of miR-590-5p on cell proliferation, invasion, chemosensitivity of GC cells, and the AKT pathway, respectively. In silico prediction and luciferase reporter activity were used to identify potential targets of miR-590-5p. A xenograft model was also established to evaluate the function of miR-590-5p in vivo. RESULTS: The expression of miR 590-5p was significantly increased in GC cells and tissues, and upregulated miR 590-5p was associated with increased tumor size, lymph node metastasis, and poor survival. Overexpression of miR-590-5p promoted cell proliferation and invasion and reduced the sensitivity of GC cells to cisplatin and paclitaxel. In contrast, inhibition of miR-590-5p had the opposite effects on GC cells. RECK was identified as a direct target of miR-590-5p. Knockdown of RECK accelerated cell proliferation and motility and decreased the drug sensitivity. Furthermore, reintroduction of RECK inhibited the oncogenic effects of miR-590-5p by suppressing cell proliferation and invasion and increasing drug sensitivity. We found that the AKT/ERK and STAT3 signaling pathways were activated by miR-590-5p overexpression. The chemoresistance of miR-590-5p was also verified by in vivo analysis. CONCLUSION: In summary, we suggest that the miR-590-5p/RECK/AKT axis contributes to GC and may serve as a promising therapeutic target for treatment. PMID- 27757043 TI - Health and economic benefits of physical activity for patients with spinal cord injury. AB - Spinal cord injury (SCI) is a traumatic, life-disrupting event with an annual incidence of 17,000 cases in the US. SCI is characterized by progressive physical deconditioning due to limited mobility and lack of modalities to allow safe physical activity that may partially offset these deleterious physical changes. Approximately, 50% of patients with SCI report no leisure-time physical activity and 15% report leisure-time physical activity below the threshold where meaningful health benefits could be realized. Collectively, about 363,000 patients with SCI, or 65% of the entire spinal cord injured population in the US, engages in insufficient physical activity and represents a target population that could derive considerable health benefits from even modest physical activity levels. Currently, the annual direct costs related to SCI exceed US$45 billion in the US. Rehabilitation protocols and technologies aimed to improve functional mobility have potential to significantly reduce the risk of medical complications and cost associated with SCI. Patients who commence routine physical activity in the first post-injury year and experience typical motor function improvements would realize US$290,000 to US$435,000 in lifetime cost savings, primarily due to fewer hospitalizations and less reliance on assistive care. New assistive technologies that allow patients with SCI to safely engage in routine physical activity are desperately needed. PMID- 27757044 TI - Myocutaneous revascularization following graded ischemia in lean and obese mice. AB - BACKGROUND: Murine models of diabetes and obesity have provided insight into the pathogenesis of impaired epithelialization of excisional skin wounds. However, knowledge of postischemic myocutaneous revascularization in these models is limited. MATERIALS AND METHODS: A myocutaneous flap was created on the dorsum of wild type (C57BL/6), genetically obese and diabetic (ob/ob, db/db), complementary heterozygous (ob+/ob-, db+/db-), and diet-induced obese (DIO) mice (n=48 total; five operative mice per strain and three unoperated mice per strain as controls). Flap perfusion was documented by laser speckle contrast imaging. Local gene expression in control and postoperative flap tissue specimens was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Image analysis of immunochemically stained histologic sections confirmed microvascular density and macrophage presence. RESULTS: Day 10 planimetric analysis revealed mean flap surface area necrosis values of 10.8%, 12.9%, 9.9%, 0.4%, 1.4%, and 23.0% for wild type, db+/db-, ob+/ob-, db/db, ob/ob, and DIO flaps, respectively. Over 10 days, laser speckle imaging documented increased perfusion at all time points with revascularization to supranormal perfusion in db/db and ob/ob flaps. In contrast, wild type, heterozygous, and DIO flaps displayed expected graded ischemia with failure of perfusion to return to baseline values. RT-PCR demonstrated statistically significant differences in angiogenic gene expression between lean and obese mice at baseline (unoperated) and at day 10. CONCLUSION: Unexpected increased baseline skin perfusion and augmented myocutaneous revascularization accompanied by a control proangiogenic transcriptional signature in genetically obese mice compared to DIO and lean mice are reported. In future research, laser speckle imaging has been planned to be utilized in order to correlate spatiotemporal wound reperfusion with changes in cell recruitment and gene expression to better understand the differences in wound microvascular biology in lean and obese states. PMID- 27757046 TI - Ability of procalcitonin to diagnose bacterial infection and bacteria types compared with blood culture findings. AB - Procalcitonin (PCT) and C-reactive protein serve as biomarkers of infection in patients with sepsis/bacteremia. The present study assessed the clinical characteristics of 280 patients with suspected sepsis who were admitted to Tohoku Medical and Pharmaceutical University Hospital between January 2012 and December 2013. Among the patients, 133 and 147 were positive and negative for PCT, respectively. Patients who were PCT positive were older and more frequently male, had reduced levels of platelets and albumin, and increased levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, and C-reactive protein. Patients who were PCT positive had significantly higher blood culture positivity compared with those who were PCT negative, and the sensitivity and specificity of PCT for detecting positive blood cultures were 74.5% and 59.1%, respectively. Escherichia coli was detected in PCT-positive patients, whereas Staphylococcus epidermidis and Staphylococcus lugdunensis were frequently detected in PCT-negative patients. Levels of PCT were higher in the patients infected with gram-negative rods than those with gram-positive cocci. Furthermore, extended-spectrum beta-lactamase (ESBL)-producing bacteria cases showed higher levels of PCT than those of non-ESBL cases. These results suggest that PCT may be a useful biomarker of sepsis, and it might serve as a strong tool to detect patients with severe gram-negative rod bacteremia including ESBL producing bacteria cases early due to its relative high sensitivity. PMID- 27757045 TI - Pharmacogenomics of statins: understanding susceptibility to adverse effects. AB - Statins are a cornerstone of the pharmacologic treatment and prevention of atherosclerotic cardiovascular disease. Atherosclerotic disease is a predominant cause of mortality and morbidity worldwide. Statins are among the most commonly prescribed classes of medications, and their prescribing indications and target patient populations have been significantly expanded in the official guidelines recently published by the American and European expert panels. Adverse effects of statin pharmacotherapy, however, result in significant cost and morbidity and can lead to nonadherence and discontinuation of therapy. Statin-associated muscle symptoms occur in ~10% of patients on statins and constitute the most commonly reported adverse effect associated with statin pharmacotherapy. Substantial clinical and nonclinical research effort has been dedicated to determining whether genetics can provide meaningful insight regarding an individual patient's risk of statin adverse effects. This contemporary review of the relevant clinical research on polymorphisms in several key genes that affect statin pharmacokinetics (eg, transporters and metabolizing enzymes), statin efficacy (eg, drug targets and pathways), and end-organ toxicity (eg, myopathy pathways) highlights several promising pharmacogenomic candidates. However, SLCO1B1 521C is currently the only clinically relevant pharmacogenetic test regarding statin toxicity, and its relevance is limited to simvastatin myopathy. PMID- 27757047 TI - An observation on inappropriate probiotic subgroup classifications in the meta analysis by Lau and Chamberlain. PMID- 27757048 TI - Medical cannabis - the Canadian perspective. AB - Cannabis has been widely used as a medicinal agent in Eastern medicine with earliest evidence in ancient Chinese practice dating back to 2700 BC. Over time, the use of medical cannabis has been increasingly adopted by Western medicine and is thus a rapidly emerging field that all pain physicians need to be aware of. Several randomized controlled trials have shown a significant and dose-dependent relationship between neuropathic pain relief and tetrahydrocannabinol - the principal psychoactive component of cannabis. Despite this, barriers exist to use from both the patient perspective (cost, addiction, social stigma, lack of understanding regarding safe administration) and the physician perspective (credibility, criminality, clinical evidence, patient addiction, and policy from the governing medical colleges). This review addresses these barriers and draws attention to key concerns in the Canadian medical system, providing updated treatment approaches to help clinicians work with their patients in achieving adequate pain control, reduced narcotic medication use, and enhanced quality of life. This review also includes case studies demonstrating the use of medical marijuana by patients with neuropathic low-back pain, neuropathic pain in fibromyalgia, and neuropathic pain in multiple sclerosis. While significant preclinical data have demonstrated the potential therapeutic benefits of cannabis for treating pain in osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer, further studies are needed with randomized controlled trials and larger study populations to identify the specific strains and concentrations that will work best with selected cohorts. PMID- 27757049 TI - Visceral pain triggered by traction on the ileocecal ligament with ileitis. AB - BACKGROUND: Visceral pain is a common symptom of several gastrointestinal disorders. Despite tremendous progress in understanding its basic mechanisms, it remains a significant health challenge for clinicians. The present study quantified the intensity of visceral pain using ileocecal ligament traction on an inflamed ileum in goats. MATERIALS AND METHODS: A total of 36 male goats weighing 20.05+/-2.1 kg were randomly allocated equally into a 2,4,6 trinitrobenzenesulfonic acid (TNBS) group (n=18) and a saline group (n=18). Ileitis was induced via the injection of 30 mg TNBS dissolved in 30% ethanol into the ileal wall through a laparotomy. An equal volume of normal saline was injected into the ileal wall of the saline goats. Behavioral responses to traction (2, 4, and 6 N) on the ileocecal ligament were observed on days 3, 7, and 14. Six goats from each group received a laparotomy and partial intestinal resection for ileal sample collection immediately after behavioral testing on days 3, 7, and 14. Ileal histopathological changes were assessed and concentrations of myeloperoxidase, IL-1beta, IL-6, and TNFalpha investigated using enzyme-linked immunosorbent assay. RESULTS: The TNBS-treated goats exhibited remarkably increased macroscopic scores, mast-cell counts, myeloperoxidase, and TNFalpha concentrations on days 3 and 7 compared to the saline group, and increased microscopic scores and IL-1beta and IL-6 concentrations on days 3-14. The TNBS-treated goats exhibited behavioral changes in response to traction in the same pattern as their microscopic changes and cytokine levels. The traction force correlated positively with pain-behavior responses. CONCLUSION: Traction on the ileocecal ligament of goats with ileitis provoked an apparent, stable, and reproducible ileum-derived pain. The current model may be helpful in evaluating the efficacy of new drugs for the management of visceral pain and in investigating its underlying mechanisms. PMID- 27757051 TI - Prevalence and comorbidity of relapsing polychondritis. PMID- 27757050 TI - New topical treatment of vulvodynia based on the pathogenetic role of cross talk between nociceptors, immunocompetent cells, and epithelial cells. AB - Topical treatments of localized neuropathic pain syndromes in general are mostly neglected, mainly due to the fact that most pain physicians expect that a topical formulation needs to result in a transdermal delivery of the active compounds. On the basis of the practical experience, this study brings forth a new, somewhat neglected element of the vulvodynia pathogenesis: the cross talk between the nerve endings of nociceptors, the adjacent immunocompetent cells, and vaginal epithelial cells. Insight into this cross talk during a pathogenic condition supports the treatment of vulvodynia with topical (compounded) creams. Vulvodynia was successfully treated with an analgesic cream consisting of baclofen 5% together with the autacoid palmitoylethanolamide 1%, an endogenous anti inflammatory compound. In this review, data is presented to substantiate the rationale behind developing and prescribing topical products for localized pain states such as vulvodynia. Most chronic inflammatory disorders are based on a network pathogenesis, and monotherapeutic inroads into the treatment of such disorders are obsolete. PMID- 27757052 TI - Rehabilitation with implant-retained removable dentures and its effects on perioral aesthetics: a prospective cohort study. AB - BACKGROUND: The onset of perioral wrinkles often prompts patients to request treatment. This aesthetic deterioration linked to aging may be associated with tooth and alveolar bone loss in fully edentulous patients. PURPOSE: To evaluate perioral wrinkles before and after maxillary and mandibular rehabilitation with implant-retained dentures in fully edentulous patients. METHODS: In this prospective cohort, single-center, blinded study, patients requiring maxillary and mandibular rehabilitation with implant-retained dentures were enrolled. The patients were photographed in the same position before and after oral rehabilitation. Wrinkles were evaluated in the photographs by blinded observers using validated rating scales. The following parameters were analyzed: upper and lower radial lip lines, marionette lines, upper and lower lip fullness, nasolabial folds, corner of the mouth lines, and the labiomental crease. Statistical analysis was performed using the Wilcoxon signed ranks test for paired data, with P<0.05 considered significant. RESULTS: Upper and lower implant retained dentures were applied in 31 patients (15 males; mean +/- standard deviation age 62.13+/-8.69 years, range 47-77 years). The oral rehabilitation procedures significantly improved (P<0.05) the upper and lower radial lip lines, marionette lines, upper and lower lip fullness, the nasolabial folds, and the corner of the mouth lines. CONCLUSION: Maxillary and mandibular rehabilitation with implant-retained dentures in fully edentulous patients improves perioral aesthetics. Patients requiring oral rehabilitation and desiring perioral aesthetic improvement could benefit from treatment with this type of prosthesis. PMID- 27757053 TI - Posterior capsule rupture with herniation of lens fragment following blunt ocular trauma. AB - Posterior capsule rupture with herniated lens fragment in the vitreous cavity on magnetic resonance imaging has not been reported in India until now; however, it has been reported in other countries. Therefore, this study reports the case of a 15-year-old boy presenting with posttraumatic loss of vision in the right eye due to posterior capsular rupture and herniation of lens material into the vitreous cavity, which was detected by B-scan ultrasonography and magnetic resonance imaging as no ophthalmic examination was possible due to the posttraumatic cataract. The patient was treated by lens aspiration with anterior chamber vitrectomy and placement of posterior chamber intraocular lens, with the patient achieving 6/6 visual acuity postoperatively. This case is unusual due to the rarity of the findings, and it highlights the crucial role of imaging in achieving timely diagnosis and surgery to restore vision in the affected eye. PMID- 27757054 TI - Characteristics of intracellular Ca2+ signals consisting of two successive peaks in hepatocytes during liver regeneration after 70% partial hepatectomy in rats. AB - Two specific signals for regulating liver regeneration were found after 70% partial hepatectomy (PH) in rats. The first finding was a sustained increasing signal of intracellular Ca2+ ([Ca2+]i) in hepatocytes, consisting of two successive peaks with the first narrow peak at 1 hour and the second broad peak increasing by day 3 and then returning to normal by day 4. The second finding was an abnormal peak in the restoring ratio (Rr) curve of liver regeneration after 70% PH at day 4, where the Rr exceeded 100% temporarily, returned to a lower level, and then proceeded to a termination phase of liver regeneration. For 4 days around the two successive [Ca2+]i peaks and abnormal peak, various physiological activities were induced to promote liver regeneration after 70% PH. mRNA expression of genes encoding Ca2+-binding proteins S100A4 and calpain was induced between the two Ca2+ peaks. Hepatocytes underwent synchronous cell proliferation as the liver was restored from 30% to 70% at day 4, and significant expression of VEGF mRNA at around day 4 promoted angiogenesis to remodel the sinusoidal system. Cytochrome P450 activity levels in microsomes and alanine aminotransferase values at 24 hours after CCl4 administration were decreased after 70% PH, which recovered transiently to the control level at day 4, returned to the decreased level, and then slowly recovered by day 10. Thus, these results indicate that day 4 is important during liver regeneration after 70% PH. PMID- 27757055 TI - Reliability and validity of the Italian version of the 14-item Resilience Scale. AB - BACKGROUND: In recent years resilience has gained clinical relevance in sociological, psychological, and medical disciplines, and a lot of scales measuring resilience have been developed and have been utilized in the western countries. The aim of the study was to assess the psychometric properties of the Italian version of the 14-item Resilience Scale (RS-14), by describing its validity and reliability. As agreed with the authors of the original English version of the RS-14, it was translated into Italian. Then the standard procedure for back-translation was followed. METHODS: In total, 150 participants among the nursing and professional education students of the University of Insubria of Varese and health workers of the "ASST dei Sette Laghi-Ospedale di Circolo" of Varese were enrolled. The responses to the questionnaires were collected only from the students and the health workers between the ages of 18 and 65 years who gave their consent to participate in the study from April to September 2015. A subsample of 26 students and health workers was retested on the RS-14, 5 weeks after the first assessment. The questionnaires were handed out to 214 people, and 150 sets of questionnaires (70%) were returned, of which eight were subsequently removed because >60% of the answers were missing. In order to ensure anonymity, every completed questionnaire was identified only via a code. RESULTS: No significant differences were found between the mean values of the resilience scores between women (76.1) and men (76.3), with unpaired t-test = -0.08 and P=0.93. Similarly, no difference between resilience scores were found between mean age group of 18-25 years (75.3) and 26-65 years (78.7), with t-test = 1.6. The overall Cronbach's alpha of the RS-14 is 0.88, P=0.10. The RS-14 is negatively correlated with the Beck Depression Inventory-Primary Care Version and the 12-item General Health Questionnaire and positively correlated with the World Health Organization Quality of Life-Brief Version. The test-retest reliability, assessed on the 26 subjects 5 weeks after the first evaluation, highlighted an intraclass correlation coefficient value equal to 0.65. Factor analysis retains three factors, and it considers the factor loadings >0.40: RS-14-06 ('I am determined') is loaded on all the factors and RS-14-12 ('In an emergency, I am someone people can generally rely on') is not loaded on any factor. CONCLUSION: This study demonstrates that the Italian RS-14 has psychometric properties with a good level of internal consistency (Cronbach's alpha = 0.88), an adequate concurrent validity, verified by relationships with the other scales and as it was expected from literature, and an acceptable test-retest reliability. PMID- 27757056 TI - Epiglottis cross-sectional area and oropharyngeal airway length in male and female obstructive sleep apnea patients. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is a male-predominant condition, characterized by repeated upper-airway collapse with continued diaphragmatic efforts during sleep, and is accompanied by severe physiological consequences. Multiple morphological aspects, including epiglottis cross-sectional area (CSA) and oropharyngeal airway length (OPAL), can contribute to airway collapsibility in the condition. This study focused on the effects of OSA severity, sex, and race on OPA dimensions. MATERIALS AND METHODS: Two high-resolution T1-weighted image series were collected from 40 mild-to-severe OSA subjects (age 46.9+/-9 years, body mass index 30.4+/-5.4 kg/m2, Apnea-Hypopnea Index score 32.8+/-22.5, 28 males) and 54 control subjects (47+/-9 years, 24.7+/-3.8 kg/m2, 32 males) using a 3 T magnetic resonance-imaging scanner. Caucasian, Asian, African American, and "other" subjects constituted the study pool. Both image series were realigned and averaged, and reoriented to a common space. CSA and OPAL were measured, normalized for subject height, and compared between sexes and disease severity levels in OSA and control subjects. RESULTS: Significantly reduced epiglottis CSA appeared only in severe OSA vs controls (P=0.009). OPAL increased significantly with OSA severity vs controls (mild, P=0.027; moderate, P<0.001; severe, P<0.001). OSA males showed increased CSA and greater OPAL than OSA females, which may underlie the increased proportion of affected males with higher apnea-hypopnea index scores. However, no significant differences appeared between CSA and OPAL measures for male and female controls, suggesting that airway morphology may not be the sole contributor for airway collapse. No ethnic or racial differences appeared for CSA or OPAL measures. CONCLUSION: Sex-based reductions in epiglottis CSA and increased OPAL in OSA subjects may enhance airway-collapse vulnerability, more so with greater disease severity, and partially underlie male vs female susceptibility to the sleep disorder. PMID- 27757057 TI - Contraceptive knowledge, sexual behavior, and factors associated with contraceptive use among female undergraduate university students in Kilimanjaro region in Tanzania. AB - BACKGROUND: Previous studies have shown that knowledge of contraceptives, especially among the youth in universities, remains limited, and the rate of premarital sexual activity, unwanted pregnancies, and illegal abortions remains higher among university students. This study aimed to assess contraceptive knowledge, sexual behavior, and factors associated with contraceptive use among female undergraduate university students in Kilimanjaro region in Tanzania. METHODS: A cross-sectional analytical study was conducted from May to June 2015 among undergraduate female students in four universities in Kilimanjaro region. A self-administered questionnaire was given to the participants. Data analysis was performed using Statistical Package for Social Sciences. Descriptive statistics were used to summarize the data. An odds ratio with 95% confidence interval for factors associated with modern contraceptive use was computed using multiple logistic regression models. A P-value of <5% (two-tailed) was considered statistically significant. RESULTS: A total of 401 students were involved in the study. Two-thirds (260, 64.8%) of the participants had had sexual intercourse. The majority (93.8%) of the participants had knowledge of contraception. One hundred and seventy-five (43.6%) sexually active women reported that they used contraceptives in the past, while 162 (40.4%) were current contraceptive users. More than half (54.2%) of the sexually active group started sexual activity between the ages of 20-24 years. The most popular methods of contraception used were condoms, withdrawal, and periodic abstinence. The main sources of information about contraception were friends, television, and health care workers (44.8%, 40.3%, and 39.0%, respectively). CONCLUSION: Most of the participants had knowledge of contraception. However, the rate of contraceptive use was low. The majority of the respondents were sexually active and started sexual activity at >18 years of age. Hence, advocacy for adolescent reproductive health education to promote the use of the available contraceptive services among university students is needed. PMID- 27757058 TI - From basic research to personalized medicine. AB - In the future, precision medicine will enable every clinician to tailor treatment and even prevention strategies to an individual's unique characteristics. In order to reach this goal, we need to collect and analyze many different types of data, from many different sources, including symptoms, genomics, and brain circuitry, as well as family dynamics, environmental exposures, and cultural background. PMID- 27757059 TI - Neuropsychiatric genomics in precision medicine: diagnostics, gene discovery, and translation. AB - Only a few years after its development, next-generation sequencing is rapidly becoming an essential part of clinical care for patients with serious neurological conditions, especially in the diagnosis of early-onset and severe presentations. Beyond this diagnostic role, there has been an explosion in definitive gene discovery in a range of neuropsychiatric diseases. This is providing new pointers to underlying disease biology and is beginning to outline a new framework for genetic stratification of neuropsychiatric disease, with clear relevance to both individual treatment optimization and clinical trial design. Here, we outline these developments and chart the expected impact on the treatment of neurological, neurodevelopmental, and psychiatric disease. PMID- 27757060 TI - Omics approaches to individual variation: modeling networks and the virtual patient. AB - Every human is unique. We differ in our genomes, environment, behavior, disease history, and past and current medical treatment-a complex catalog of differences that often leads to variations in the way each of us responds to a particular therapy. We argue here that true personalization of drug therapies will rely on "virtual patient" models based on a detailed characterization of the individual patient by molecular, imaging, and sensor techniques. The models will be based, wherever possible, on the molecular mechanisms of disease processes and drug action but can also expand to hybrid models including statistics/machine learning/artificial intelligence-based elements trained on available data to address therapeutic areas or therapies for which insufficient information on mechanisms is available. Depending on the disease, its mechanisms, and the therapy, virtual patient models can be implemented at a fairly high level of abstraction, with molecular models representing cells, cell types, or organs relevant to the clinical question, interacting not only with each other but also the environment. In the future, "virtual patient/in-silico self" models may not only become a central element of our health care system, reducing otherwise unavoidable mistakes and unnecessary costs, but also act as "guardian angels" accompanying us through life to protect us against dangers and to help us to deal intelligently with our own health and wellness. PMID- 27757061 TI - Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders. AB - The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders. Postmortem human tissues are available from many biobanks; nevertheless, collections of neuronal human cells from large patient cohorts representing the human diversity remain scarce. Two tools are gaining popularity for personalized medicine research on neuropsychiatric disorders: human induced pluripotent stem cell-derived neurons and human lymphoblastoid cell lines. This review examines and contrasts the advantages and limitations of each tool for personalized medicine research. PMID- 27757062 TI - Individual variation in functional brain connectivity: implications for personalized approaches to psychiatric disease. AB - Functional brain connectivity measured with functional magnetic resonance imaging (fMRI) is a popular technique for investigating neural organization in both healthy subjects and patients with mental illness. Despite a rapidly growing body of literature, however, functional connectivity research has yet to deliver biomarkers that can aid psychiatric diagnosis or prognosis at the single-subject level. One impediment to developing such practical tools has been uncertainty regarding the ratio of intra- to interindividual variability in functional connectivity; in other words, how much variance is state- versus trait-related. Here, we review recent evidence that functional connectivity profiles are both reliable within subjects and unique across subjects, and that features of these profiles relate to behavioral phenotypes. Together, these results suggest the potential to discover reliable correlates of present and future illness and/or response to treatment in the strength of an individual's functional brain connections. Ultimately, this work could help develop personalized approaches to psychiatric illness. PMID- 27757063 TI - An epigenomics approach to individual differences and its translation to neuropsychiatric conditions. AB - This review concerns epigenetic mechanisms and their roles in conferring interindividual differences, especially as related to experientially acquired and genetically driven changes in central nervous system (CNS) function. In addition, the review contains commentary regarding the possible ways in which epigenomic changes may contribute to neuropsychiatric conditions and disorders and ways in which epigenotyping might be cross-correlated with clinical phenotyping in the context of precision medicine. The review begins with a basic description of epigenetic marking in the CNS and how these changes are powerful regulators of gene readout. Means for characterizing the individual epigenotype are briefly described, with a focus on DNA cytosine methylation as a readily measurable, stable epigenetic mark. This background enables a discussion of how "epigenotyping" might be integrated along with genotyping and deep phenotyping as a means of implementing advanced precision medicine. Finally, the commentary addresses two exemplars when considering how epigenotype may correlate with and modulate cognitive and behavioral phenotype: schizophrenia and Rett syndrome. These two disorders provide an interesting compare-and-contrast example regarding possible epigenotypic regulation of behavior: whereas Rett syndrome is clearly established as being caused by disruption of the function of an epigenetic "reader" of the DNA cytosine methylome-methyl-CpG-binding protein 2 (MeCP2)-the case for a role for epigenetic mechanisms in schizophrenia is still quite speculative. PMID- 27757064 TI - Genomic sequencing in clinical practice: applications, challenges, and opportunities. AB - The development of massively parallel sequencing (or next-generation sequencing) has facilitated a rapid implementation of genomic sequencing in clinical medicine. Genomic sequencing (GS) is now an essential tool for evaluating rare disorders, identifying therapeutic targets in neoplasms, and screening for prenatal aneuploidy. Emerging applications, such as GS for preconception carrier screening and predisposition screening in healthy individuals, are being explored in research settings and utilized by members of the public eager to incorporate genomic information into their health management. The rapid pace of adoption has created challenges for all stakeholders in clinical GS, from standardizing variant interpretation approaches in clinical molecular laboratories to ensuring that nongeneticist clinicians are prepared for new types of clinical information. Clinical GS faces a pivotal moment, as the vast potential of new quantities and types of data enable further clinical innovation and complicated implementation questions continue to be resolved. PMID- 27757065 TI - Personalized prescribing: a new medical model for clinical implementation of psychotropic drugs. AB - The use of pharmacogenetic tests was already being proposed in psychiatry in the early 2000s because genetic factors were known to influence drug pharmacokinetics and pharmacodynamics. However, sufficient levels of evidence to justify routine use have been achieved for only a few tests (eg, major histocompatibility complex, class I, B, allele 1502 [HLA-B*1502] for carbamazepine in epilepsy and bipolar disorders); many findings are too preliminary or, when replicated, of low clinical relevance because of a small effect size. Although drug selection and dose adaptation according to cytochrome P450 genotypes are sound, a large number of patients need to be genotyped in order to prevent one case of severe side effect and/or nonresponse. The decrease in cost for genetic analysis shifts the cost: benefit ratio toward increasing use of pharmacogenetic tests. However, they have to be combined with careful clinical evaluations and other tools (eg, therapeutic drug monitoring and phenotyping) to contribute to the general aim of providing the best care for psychiatric patients. PMID- 27757067 TI - Transforming big data into computational models for personalized medicine and health care. AB - Health care systems generate a huge volume of different types of data. Due to the complexity and challenges inherent in studying medical information, it is not yet possible to create a comprehensive model capable of considering all the aspects of health care systems. There are different points of view regarding what the most efficient approaches toward utilization of this data would be. In this paper, we describe the potential role of big data approaches in improving health care systems and review the most common challenges facing the utilization of health care big data. PMID- 27757066 TI - Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. AB - Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing pharmacokinetics and pharmacodynamics may contribute to some of this variability. Research studies have characterized these pharmacogenetic relationships, and some genetic markers are now available as clinical tests. These advances in pharmacogenetics research and test availability have great potential to improve clinical outcomes and quality of life in psychiatric patients. For clinicians considering using pharmacogenetics, it is important to understand the clinical implications and also the limitations of markers included in currently available tests. This review focuses on pharmacokinetic and pharmacodynamic gene variants that are currently available in commercial genetic testing panels. Associations of these variants with clinical efficacy and adverse effects, as well as other clinical implications, in antipsychotic pharmacotherapy are discussed. PMID- 27757068 TI - Nurse staffing and patient outcomes: a longitudinal study on trend and seasonality. AB - BACKGROUND: Time trends and seasonal patterns have been observed in nurse staffing and nursing-sensitive patient outcomes in recent years. It is unknown whether these changes were associated. METHODS: Quarterly unit-level nursing data in 2004-2012 were extracted from the National Database of Nursing Quality Indicators(r) (NDNQI(r)). Units were divided into groups based on patterns of missing data. All variables were aggregated across units within these groups and analyses were conducted at the group level. Patient outcomes included rates of inpatient falls and hospital-acquired pressure ulcers. Staffing variables included total nursing hours per patient days (HPPD) and percent of nursing hours provided by registered nurses (RN skill-mix). Weighted linear mixed models were used to examine the associations between nurse staffing and patient outcomes at trend and seasonal levels. RESULTS: At trend level, both staffing variables were inversely associated with all outcomes (p < 0.001); at seasonal level, total HPPD was inversely associated (higher staffing related to lower event rate) with all outcomes (p < 0.001) while RN skill-mix was positively associated (higher staffing related to higher event rate) with fall rate (p < 0.001) and pressure ulcer rate (p = 0.03). It was found that total HPPD tended to be lower and RN skill-mix tended to be higher in Quarter 1 (January-March) when falls and pressure ulcers were more likely to happen. CONCLUSIONS: By aggregating data across units we were able to detect associations between nurse staffing and patient outcomes at both trend and seasonal levels. More rigorous research is needed to study the underlying mechanism of these associations. PMID- 27757069 TI - What are we paying for? A cost-effectiveness analysis of patented denosumab and generic alendronate for postmenopausal osteoporotic women in Australia. AB - OBJECTIVE: Zoledronic acid and denosumab were funded by the Australian government for the management of osteoporosis at an equivalent price to alendronate. The price of alendronate has declined by around 65 %, but the price of the other two therapies has remained stable. Using data published since the listing, this paper reports current estimates of the value of denosumab compared to alendronate from an Australian health system perspective. METHODS: A cohort-based state transition model was developed that predicted changes in bone mineral density (BMD), and calibrated fracture probabilities as a function of BMD, age and previous fracture to estimate differences in costs and QALYs gained over a 10-year time horizon. RESULTS: The base-case incremental cost per QALY gained for denosumab versus alendronate was $246,749. There is a near zero probability that denosumab is cost effective at a threshold value of $100,000 per QALY gained. If the price of denosumab was reduced by 50 %, the incremental cost per QALY gained falls to $50,068. DISCUSSION: Current Australian legislation precludes price reviews when comparator therapies come off patent. The presented analysis illustrates a review process, incorporating clinical data collected since the original submission to inform a price at which denosumab would provide value for money. PMID- 27757070 TI - The use of a lot quality assurance sampling methodology to assess and manage primary health interventions in conflict-affected West Darfur, Sudan. AB - BACKGROUND: Organizations working in conflict-affected areas have a need to monitor and evaluate their programs, however this is often difficult due to the logistical challenges of conflict areas. Lot quality assurance sampling may be a suitable method of assessing programs in these situations. METHODS: We conducted a secondary data analysis of information collected during Medair's routine program management functions. Medair's service area in West Darfur, Sudan was divided into seven supervisory areas. Using the available population information, a sampling frame was developed and interviews were conducted from randomly selected caretakers of children in each supervisory area every six months over 19 months. A survey instrument with questions related to key indicators for immunizations and maternal, newborn, and child health was used for the interviews. Based on Medair's goals for each indicator, decision rules were calculated for the indicators; these decision rules determined which supervisory areas and indicators performed adequately in each assessment period. Pearson's chi-squared tests, adjusted for the survey design using STATA "svy: tab" commands, were used to detect overall differences in coverage in this analysis. RESULTS: The coverage of tetanus toxoid vaccination among pregnant women increased from 47.2 to 69.7 % (p value = 0.046), and births attended by a skilled health professional increased from 35.7 to 52.7 % (p value = 0.025) from the first to last assessment periods. Measles vaccinations declined from 72.0 to 54.1 % (p value = 0.046). The estimated coverage for the proportion of women receiving a postpartum dose of vitamin A (54.7 to 61.3 %, p value = 0.44); pregnant women receiving a clean delivery kit (54.6 to 47.1 %, p value = 0.49); and pentavalent vaccinations (49.7 to 42.1 %, p value = 0.28) did not significantly change. CONCLUSIONS: Lot quality assurance sampling was a feasible method for Medair staff to evaluate and optimize primary health programs in a conflict-affected area. Medair managers were able to collect, analyze, and disseminate data to staff alongside the routine work of the organization. These results suggest LQAS may be used in other complex humanitarian emergencies in which there are logistical challenges and limited resources. PMID- 27757071 TI - N-glycosylation proteome enrichment analysis in kidney reveals differences between diabetic mouse models. AB - BACKGROUND: Diabetic nephropathy (DN) is a late complication in both type 1 diabetes mellitus (T1DM) and T2DM. Already at an early stage of DN morphological changes occur at the cell surface and in the extracellular matrix where the majority of the proteins carry N-linked glycosylations. These glycosylated proteins are highly important in cell adhesion and cell-matrix processes but not much is known about how they change in DN or whether the distinct etiology of T1DM and T2DM could have an effect on their abundances. METHOD: We enriched for the N-glycosylated kidney proteome in db/db mice dosed with insulin or vehicle, in streptozotocin-induced (STZ) diabetic mice and healthy control mice dosed with vehicle. Glycopeptides were analyzed with label-free shotgun mass spectrometry and differential protein abundances identified in both mouse models were compared using multivariate analyses. RESULTS: The majority of the N-glycosylated proteins were similarly regulated in both mouse models. However, distinct differences between the two mouse models were for example seen for integrin-beta1, a protein expressed mainly in the glomeruli which abundance was increased in the STZ diabetic mice while decreased in the db/db mice and for the sodium/glucose cotransporter-1, mainly expressed in the proximal tubules which abundance was increased in the db/db mice but decreased in the STZ diabetic mice. Insulin had an effect on the level of both glomerular and tubular proteins in the db/db mice. It decreased the abundance of G-protein coupled receptor-116 and of tyrosine protein phosphatase non-receptor type substrate-1 away from the level in the healthy control mice. CONCLUSIONS: Our finding of differences in the N glycosylation protein profiles in the db/db and STZ mouse models suggest that the etiology of DN could give rise to variations in the cell adhesion and cell-matrix composition in T1DM and T2DM. Thus, N-glycosylated protein differences could be a clue to dissimilarities in T1DM and T2DM at later stages of DN. Furthermore, we observed insulin specific regulation of N-glycosylated proteins both in the direction of and away from the abundances in healthy control mice. PMID- 27757072 TI - Influence of Biphasic Stimulation on Olfactory Ensheathing Cells for Neuroprosthetic Devices. AB - The recent success of olfactory ensheathing cell (OEC) assisted regeneration of injured spinal cord has seen a rising interest in the use of these cells in tissue-engineered systems. Previously shown to support neural cell growth through glial scar tissue, OECs have the potential to assist neural network formation in living electrode systems to produce superior neuroprosthetic electrode surfaces. The following study sought to understand the influence of biphasic electrical stimulation (ES), inherent to bionic devices, on cell survival and function, with respect to conventional metallic and developmental conductive hydrogel (CH) coated electrodes. The CH utilized in this study was a biosynthetic hydrogel consisting of methacrylated poly(vinyl-alcohol) (PVA), heparin and gelatin through which poly(3,4-ethylenedioxythiophene) (PEDOT) was electropolymerised. OECs cultured on Pt and CH surfaces were subjected to biphasic ES. Image-based cytometry yielded little significant difference between the viability and cell cycle of OECs cultured on the stimulated and passive samples. The significantly lower voltages measured across the CH electrodes (147 +/- 3 mV) compared to the Pt (317 +/- 5 mV), had shown to influence a higher percentage of viable cells on CH (91-93%) compared to Pt (78-81%). To determine the functionality of these cells following electrical stimulation, OECs co-cultured with PC12 cells were found to support neural cell differentiation (an indirect measure of neurotrophic factor production) following ES. PMID- 27757074 TI - Effects of Duloxetine Treatment on Cognitive Flexibility and BDNF Expression in the mPFC of Adult Male Mice Exposed to Social Stress during Adolescence. AB - Early stress is a significant risk factor for the onset of mood disorders such as depression during adulthood. Impairments in cognitive flexibility mediated by prefrontal cortex (PFC) dysfunction are increasingly recognized as important etiological and pathological factors in the development of depression. Our previous study demonstrated that social defeat stress during early adolescence produced delayed deficits in cognitive flexibility in adult mice. The potential molecular mechanisms underlying these long-term consequences remain unclear. One candidate molecule is brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity. In this study, we initially examined the effects of adolescent social stress on cognitive flexibility and PFC BDNF expression within a week after the last stress exposure and 6 weeks later during adulthood. Adolescent (PND 28) male mice were subjected to stress or control manipulation for 10 days. The attentional set-shifting task (AST) was used to assess cognitive flexibility. Levels of BDNF mRNA and protein in the PFC were examined after behavioral testing. The results demonstrated that previously stressed mice exhibited delayed extra-dimensional set-shifting deficits in AST when tested as adults but not when tested as adolescents. Consistent with the cognitive alterations, adolescent stress induced dynamic alterations in BDNF expression in the medial PFC (mPFC), with a transient increase observed shortly after the stress, followed by a decrease 6 weeks later during adulthood. Next, we further determined the effects of chronic treatment with the antidepressant duloxetine during early adulthood on cognitive and molecular alterations induced by adolescent stress. Compared with the controls, duloxetine treatment reversed the cognitive deficits and increased the BDNF protein expression in the mPFC during adulthood in previously stressed mice. These findings demonstrated that BDNF expression in the mPFC was sensitive to adolescent social stress, which may contribute to the disturbance of the development and later functioning of this brain region. PMID- 27757075 TI - Editorial: The Role of the Plasminogen Activating System in Neurobiology. PMID- 27757073 TI - A Decade of Boon or Burden: What Has the CHIP Ever Done for Cellular Protein Quality Control Mechanism Implicated in Neurodegeneration and Aging? AB - Cells regularly synthesize new proteins to replace old and abnormal proteins for normal cellular functions. Two significant protein quality control pathways inside the cellular milieu are ubiquitin proteasome system (UPS) and autophagy. Autophagy is known for bulk clearance of cytoplasmic aggregated proteins, whereas the specificity of protein degradation by UPS comes from E3 ubiquitin ligases. Few E3 ubiquitin ligases, like C-terminus of Hsc70-interacting protein (CHIP) not only take part in protein quality control pathways, but also plays a key regulatory role in other cellular processes like signaling, development, DNA damage repair, immunity and aging. CHIP targets misfolded proteins for their degradation through proteasome, as well as autophagy; simultaneously, with the help of chaperones, it also regulates folding attempts for misfolded proteins. The broad range of CHIP substrates and their associations with multiple pathologies make it a key molecule to work upon and focus for future therapeutic interventions. E3 ubiquitin ligase CHIP interacts and degrades many protein inclusions formed in neurodegenerative diseases. The presence of CHIP at various nodes of cellular protein-protein interaction network presents this molecule as a potential candidate for further research. In this review, we have explored a wide range of functionality of CHIP inside cells by a detailed presentation of its co chaperone, E3 and E4 enzyme like functions, with central focus on its protein quality control roles in neurodegenerative diseases. We have also raised many unexplored but expected fundamental questions regarding CHIP functions, which generate hopes for its future applications in research, as well as drug discovery. PMID- 27757076 TI - Contextual Interactions in Grating Plaid Configurations Are Explained by Natural Image Statistics and Neural Modeling. AB - Processing natural scenes requires the visual system to integrate local features into global object descriptions. To achieve coherent representations, the human brain uses statistical dependencies to guide weighting of local feature conjunctions. Pairwise interactions among feature detectors in early visual areas may form the early substrate of these local feature bindings. To investigate local interaction structures in visual cortex, we combined psychophysical experiments with computational modeling and natural scene analysis. We first measured contrast thresholds for 2 * 2 grating patch arrangements (plaids), which differed in spatial frequency composition (low, high, or mixed), number of grating patch co-alignments (0, 1, or 2), and inter-patch distances (1 degrees and 2 degrees of visual angle). Contrast thresholds for the different configurations were compared to the prediction of probability summation (PS) among detector families tuned to the four retinal positions. For 1 degrees distance the thresholds for all configurations were larger than predicted by PS, indicating inhibitory interactions. For 2 degrees distance, thresholds were significantly lower compared to PS when the plaids were homogeneous in spatial frequency and orientation, but not when spatial frequencies were mixed or there was at least one misalignment. Next, we constructed a neural population model with horizontal laminar structure, which reproduced the detection thresholds after adaptation of connection weights. Consistent with prior work, contextual interactions were medium-range inhibition and long-range, orientation-specific excitation. However, inclusion of orientation-specific, inhibitory interactions between populations with different spatial frequency preferences were crucial for explaining detection thresholds. Finally, for all plaid configurations we computed their likelihood of occurrence in natural images. The likelihoods turned out to be inversely related to the detection thresholds obtained at larger inter patch distances. However, likelihoods were almost independent of inter-patch distance, implying that natural image statistics could not explain the crowding like results at short distances. This failure of natural image statistics to resolve the patch distance modulation of plaid visibility remains a challenge to the approach. PMID- 27757077 TI - Impact of Life History on Fear Memory and Extinction. AB - Behavioral profiles are strongly shaped by an individual's whole life experience. The accumulation of negative experiences over lifetime is thought to promote anxiety-like behavior in adulthood ("allostatic load hypothesis"). In contrast, the "mismatch hypothesis" of psychiatric disease suggests that high levels of anxiety-like behavior are the result of a discrepancy between early and late environment. The aim of the present study was to investigate how different life histories shape the expression of anxiety-like behavior and modulate fear memory. In addition, we aimed to clarify which of the two hypotheses can better explain the modulation of anxiety and fear. For this purpose, male mice grew up under either adverse or beneficial conditions during early phase of life. In adulthood they were further subdivided in groups that either matched or mismatched the condition experienced before, resulting in four different life histories. The main results were: (i) Early life benefit followed by late life adversity caused decreased levels of anxiety-like behavior. (ii) Accumulation of adversity throughout life history led to impaired fear extinction learning. Late life adversity as compared to late life benefit mainly affected extinction training, while early life adversity as compared to early life benefit interfered with extinction recall. Concerning anxiety-like behavior, the results do neither support the allostatic load nor the mismatch hypothesis, but rather indicate an anxiolytic effect of a mismatched early beneficial and later adverse life history. In contrast, fear memory was strongly affected by the accumulation of adverse experiences over the lifetime, therefore supporting allostatic load hypothesis. In summary, this study highlights that anxiety-like behavior and fear memory are differently affected by specific combinations of adverse or beneficial events experienced throughout life. PMID- 27757079 TI - Difference in Activity in the Supplementary Motor Area Depending on Limb Combination of Hand-Foot Coordinated Movements. AB - Periodic interlimb coordination shows lower performance when the ipsilateral hand and foot (e.g., right hand and right foot) are simultaneously moved than when the contralateral hand and foot (e.g., right hand and left foot) are simultaneously moved. The present study aimed to investigate how brain activity that is related to the dependence of hand-foot coordination on limb combination, using functional magnetic imaging. Twenty-one right-handed subjects performed periodic coordinated movements of the ipsilateral or contralateral hand and foot in the same or opposite direction in the sagittal plane. Kinematic data showed that performance was lower for the ipsilateral hand-foot coordination than for the contralateral one. A comparison of brain activity between the same and opposite directions showed that there was a greater activation of supplementary motor area for ipsilateral hand-foot coordination as compared to that seen during contralateral hand-foot coordination. We speculate that this might reflect a difference in the degree of inhibition of the neural circuit that disrupts opposite directional movements between ipsilateral and contralateral hand-foot coordinated movements. PMID- 27757078 TI - Functional Connectivity Abnormalities of Brain Regions with Structural Deficits in Young Adult Male Smokers. AB - Smoking is one of the most prevalent dependence disorders. Previous studies have detected structural and functional deficits in smokers. However, few studies focused on the changes of resting state functional connectivity (RSFC) of the brain regions with structural deficits in young adult smokers. Twenty-six young adult smokers and 26 well-matched healthy non-smokers participated in our study. Voxel-based morphometry (VBM) and RSFC were employed to investigate the structural and functional changes in young adult smokers. Compared with healthy non-smokers, young smokers showed increased gray matter (GM) volume in the left putamen and decreased GM volume in the left anterior cingulate cortex (ACC). Moreover, GM volume in the left ACC has a negative correlation trend with pack years and GM volume in the left putamen was positively correlated with pack years. The left ACC and putamen with abnormal volumes were chosen as the regions of interest (ROIs) for the RSFC analysis. We found that smokers showed increased RSFC between the left ACC and right amygdala and between the left putamen and right anterior insula. We revealed structural and functional deficits within the frontostriatal circuits in young smokers, which may shed new insights into the neural mechanisms of smoking. PMID- 27757080 TI - Association between APOE Genotype and Change in Physical Function in a Population Based Swedish Cohort of Older Individuals Followed Over Four Years. AB - The association between decline in physical function and age-related conditions, such as reduced cognitive performance and vascular disease, may be explained by genetic influence on shared biological pathways of importance for aging. The apolipoprotein E (APOE) gene is well-known for its association with Alzheimer's disease, but has also been related to other disorders of importance for aging. The aim of this study was to investigate possible associations between APOE allele status and physical function in a population-based longitudinal study of older individuals. In 2005, at the age of 75, 622 individuals underwent neuropsychiatric and physical examinations, including tests of physical function, and APOE-genotyping. Follow-up examinations were performed at age 79. A significantly larger decline in grip strength (p = 0.015) between age 75 and 79 was found when comparing APOE ??4 allele carriers with non-carriers [10.3 (+/ 10.8) kg versus 7.8 (+/-10.1) kg]. No association was seen with decline in gait speed, chair-stand, or balance. The association with grip strength remained after correction for cognitive and educational level, depression, cardiovascular disease, stroke, and BMI. PMID- 27757082 TI - Clinical Relevance of Specific Cognitive Complaints in Determining Mild Cognitive Impairment from Cognitively Normal States in a Study of Healthy Elderly Controls. AB - Introduction: Subjective memory complaints (SMC) in the elderly have been suggested as an early sign of dementia. This study aims at investigating whether specific cognitive complaints are more useful than others to discriminate Mild Cognitive Impairment (MCI) by examining the dimensional structure of the Everyday Memory Questionnaire (EMQ). Materials and Methods: A sample of community-dwelling elderly individuals was recruited (766 controls and 78 MCI). The EMQ was administered to measure self-perception of cognitive complaints. All participants also underwent a comprehensive clinical and neuropsychological battery. Combined exploratory factor analysis (EFA) and Item Response Theory (IRT) were performed to identify the underlying structure of the EMQ. Furthermore, logistic regression analyses were conducted to study whether single cognitive complaints were able to predict MCI. Results: A suitable five-factor solution was found. Each factor focused on a different cognitive domain. Interestingly, just three of them, namely Forgetfulness of Immediate Information (FII), Executive Functions (EF) and Prospective Memory (PM) proved to be effective in distinguishing between cognitively healthy individuals and MCI. Based on these results we propose a shortened EMQ version comprising 10 items (EMQ-10). Discussion: Not all cognitive complaints have the same clinical relevance. Only subjective complaints on specific cognitive domains are able to discriminate MCI. We encourage clinicians to use the EMQ-10 as a useful tool to quantify and monitor the progression of individuals who report cognitive complaints. PMID- 27757081 TI - Triad of Risk for Late Onset Alzheimer's: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex. AB - Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer's, Parkinson's, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer's disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer's disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases. PMID- 27757083 TI - An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse. AB - Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for "CBD botanical drug substance," on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment. PMID- 27757084 TI - Dilated Cardiomyopathy Mutation (R134W) in Mouse Cardiac Troponin T Induces Greater Contractile Deficits against alpha-Myosin Heavy Chain than against beta Myosin Heavy Chain. AB - Many studies have demonstrated that depressed myofilament Ca2+ sensitivity is common to dilated cardiomyopathy (DCM) in humans. However, it remains unclear whether a single determinant-such as myofilament Ca2+ sensitivity-is sufficient to characterize all cases of DCM because the severity of disease varies widely with a given mutation. Because dynamic features dominate in the heart muscle, alterations in dynamic contractile parameters may offer better insight on the molecular mechanisms that underlie disparate effects of DCM mutations on cardiac phenotypes. Dynamic features are dominated by myofilament cooperativity that stem from different sources. One such source is the strong tropomyosin binding region in troponin T (TnT), which is known to modulate crossbridge (XB) recruitment dynamics in a myosin heavy chain (MHC)-dependent manner. Therefore, we hypothesized that the effects of DCM-linked mutations in TnT on contractile dynamics would be differently modulated by alpha- and beta-MHC. After reconstitution with the mouse TnT equivalent (TnTR134W) of the human DCM mutation (R131W), we measured dynamic contractile parameters in detergent-skinned cardiac muscle fiber bundles from normal (alpha-MHC) and transgenic mice (beta-MHC). TnTR134W significantly attenuated the rate constants of tension redevelopment, XB recruitment dynamics, XB distortion dynamics, and the magnitude of length mediated XB recruitment only in alpha-MHC fiber bundles. TnTR134W decreased myofilament Ca2+ sensitivity to a greater extent in alpha-MHC (0.14 pCa units) than in beta-MHC fiber bundles (0.08 pCa units). Thus, our data demonstrate that TnTR134W induces a more severe DCM-like contractile phenotype against alpha-MHC than against beta-MHC background. PMID- 27757085 TI - Dogs Do Not Show Pro-social Preferences towards Humans. AB - Pro-social behaviors are defined as voluntary actions that benefit others. Comparative studies have mostly focused on investigating the presence of pro sociality across species in an intraspecific context. Taken together, results on both primates and non-primate species indicate that reliance on cooperation may be at work in the selection and maintenance of pro-social sentiments. Dogs appear to be the ideal model when investigating a species' propensity for pro-sociality in an interspecific context because it has been suggested that as a consequence of domestication, they evolved an underlying temperament encouraging greater propensity to cooperate with human partners. In a recent study, using a food delivery paradigm, dogs were shown to preferentially express pro-social choices toward familiar compared to unfamiliar conspecifics. Using the same set-up and methods in the current study, we investigated dogs' pro-social preferences toward familiar and unfamiliar human partners. We found that dogs' pro-social tendencies did not extend to humans and the identity of the human partners did not influence the rate of food delivery. Interestingly, dogs tested with their human partners spent more time gazing at humans, and did so for longer after food consumption had ended than dogs tested with conspecific partners in the initial study. To allow comparability between results from dogs tested with a conspecific and a human partner, the latter were asked not to communicate with dogs in any way. However, this lack of communication from the human may have been aversive to dogs, leading them to cease performing the task earlier compared to the dogs paired with familiar conspecifics in the prior study. This is in line with previous findings suggesting that human communication in such contexts highly affects dogs' responses. Consequently, we encourage further studies to examine dogs' pro-social behavior toward humans taking into consideration their potential responses both with and without human communication. PMID- 27757086 TI - Using Event-Related Brain Potentials to Assess Perceptibility: The Case of French Speakers and English [h]. AB - French speaking learners of English encounter persistent difficulty acquiring English [h], thus confusing words like eat and heat in both production and perception. We assess the hypothesis that the acoustic properties of [h] may render detection of this segment in the speech stream insufficiently reliable for second language acquisition. We use the mismatch negativity (MMN) in event related potentials to investigate [h] perception in French speaking learners of English and native English controls, comparing both linguistic and non-linguistic conditions in an unattended oddball paradigm. Unlike native speakers, French learners of English elicit an MMN response only in the non-linguistic condition. Our results provide neurobiological evidence against the hypothesis that French speakers' difficulties with [h] are acoustically based. They instead suggest that the problem is in constructing an appropriate phonological representation for [h] in the interlanguage grammar. PMID- 27757088 TI - Classroom-Based Physical Activity Breaks and Children's Attention: Cognitive Engagement Works! AB - Classroom-based physical activity breaks are postulated to positively impact children's attention during their school day. However, empirical evidence for this claim is scarce and the role of cognitive engagement in enhancing children's attentional performance is unexplored in studies on physical activity breaks. The aim of the present study was therefore to disentangle the separate and/or combined effects of physical exertion and cognitive engagement induced by physical activity breaks on primary school children's attention. In addition, the role of children's affective reactions to acute interventions at school was investigated. Using a 2 * 2 between-subjects experimental design, 92 children between the ages of 11 and 12 years (M = 11.77, SD = 0.41) were randomly assigned to one of four experimental conditions: (1) combo group (physical activity with high cognitive demands), (2) cognition group (sedentary with high cognitive demands), (3) physical group (physical activity with low cognitive demands), and (4) control group (sedentary with low cognitive demands). Attention and affect were measured before and immediately after a 10-min intervention. ANCOVAs revealed that whereas physical exertion had no effect on any measure of children's attentional performance, cognitive engagement was the crucial factor leading to increased focused attention and enhanced processing speed. Mediational analyses showed that changes in positive affect during the interventions mediated the effect between cognitive engagement and focused attention as well as between cognitive engagement and processing speed. These surprising results are discussed in the light of theories predicting both facilitating and deteriorative effects of positive affect on attention. PMID- 27757089 TI - Flexibility of Expressive Timing in Repeated Musical Performances. AB - Performances by soloists in the Western classical tradition are normally highly prepared, yet must sound fresh and spontaneous. How do musicians manage this? We tested the hypothesis that they achieve the necessary spontaneity by varying the musical gestures that express their interpretation of a piece. We examined the tempo arches produced by final slowing at the ends of phrases in performances of J. S. Bach's No. 6 (Prelude) for solo cello (12 performances) and the Italian Concerto (Presto) for solo piano (eight performances). The performances were given by two experienced concert soloists during a short time period (31/2 months for the Prelude, 2 weeks for the Presto) after completing their preparations for public performance. We measured the tempo of each bar or half-bar, and the stability of tempo across performances (difference of the tempo of each bar/half bar from each of the other performances). There were phrase arches for both tempo and stability with slower, less stable tempi at beginnings and ends of phrases and faster, more stable tempi mid-phrase. The effects of practice were complex. Tempo decreased overall with practice, while stability increased in some bars and decreased in others. One effect of practice may be to imbue well-learned, automatic motor sequences with freshness and spontaneity through cognitive control at phrase boundaries where slower tempi and decreased stability provide opportunities for slower cognitive processes to modulate rapid automatic motor sequences. PMID- 27757087 TI - Impact of Cerebral Visual Impairments on Motor Skills: Implications for Developmental Coordination Disorders. AB - Cerebral visual impairment (CVI) has become the primary cause of visual impairment and blindness in children in industrialized countries. Its prevalence has increased sharply, due to increased survival rates of children who sustain severe neurological conditions during the perinatal period. Improved diagnosis has probably contributed to this increase. As in adults, the nature and severity of CVI in children relate to the cause, location and extent of damage to the brain. In the present paper, we define CVI and how this impacts on visual function. We then define developmental coordination disorder (DCD) and discuss the link between CVI and DCD. The neuroanatomical correlates and aetiologies of DCD are also presented in relationship with CVI as well as the consequences of perinatal asphyxia (PA) and preterm birth on the occurrence and nature of DCD and CVI. This paper underlines why there are both clinical and theoretical reasons to disentangle CVI and DCD, and to categorize the features with more precision. In order to offer the most appropriate rehabilitation, we propose a systematic and rapid evaluation of visual function in at-risk children who have survived preterm birth or PA whether or not they have been diagnosed with cerebral palsy or DCD. PMID- 27757090 TI - "Everyone Needs a Friend Sometimes" - Social Predictors of Long-Term Remission In First Episode Psychosis. AB - Background: Predictors of long-term symptomatic remission are crucial to the successful tailoring of treatment in first episode psychosis. There is lack of studies distinguishing the predictive effects of different social factors. This prevents a valid evaluating of their independent effects. Objectives: To test specific social baseline predictors of long-term remission. We hypothesized that first, satisfaction with social relations predicts remission; second, that frequency of social interaction predicts remission; and third, that the effect of friend relationship satisfaction and frequency will be greater than that of family relations satisfaction and frequency. Material and Methods: A sample of first episode psychosis (n = 186) completed baseline measures of social functioning, as well as clinical assessments. We compared groups of remitted and non-remitted individuals using generalized estimating equations analyses. Results: Frequency of social interaction with friends was a significant positive predictor of remission over a two-year period. Neither global perceived social satisfaction nor frequency of family interaction showed significant effects. Conclusions: The study findings are of particular clinical importance since frequency of friendship interaction is a possibly malleable factor. Frequency of interaction could be affected through behavioral modification and therapy already from an early stage in the course, and thus increase remission rates. PMID- 27757091 TI - To Be or Not To Be Humorous? Cross Cultural Perspectives on Humor. AB - Humor seems to manifest differently in Western and Eastern cultures, although little is known about how culture shapes humor perceptions. The authors suggest that Westerners regard humor as a common and positive disposition; the Chinese regard humor as a special disposition particular to humorists, with controversial aspects. In Study 1, Hong Kong participants primed with Western culture evaluate humor more positively than they do when primed with Chinese culture. In Study 2a, Canadians evaluate humor as being more important in comparison with Chinese participants. In Study 2b, Canadians expect ordinary people to possess humor, while Chinese expect specialized comedians to be humorous. The implications and limitations are discussed. PMID- 27757092 TI - Dietary Restraint Partially Mediates the Relationship between Impulsivity and Binge Eating Only in Lean Individuals: The Importance of Accounting for Body Mass in Studies of Restraint. AB - Binge eating is characteristic of eating and weight-related disorders such as binge eating disorder, bulimia nervosa, and obesity. In light of data suggest impulsivity is associated with overeating specifically in restrained eaters, this study sought to elucidate the exact nature of the associations between these variables, hypothesizing that the relationship between impulsivity and binge eating is mediated by restrained eating. We further hypothesized that the role of dietary restraint as a mediator would be moderated by body mass index (BMI). Study participants (n = 506, 50.6% female) were categorized based on self reported BMI as under- and normal-weight (BMI < 25, 65.8%, n = 333) or overweight and obese (BMI >= 25, 34.2%, n = 173) and completed the "restrained eating" subscale of the Dutch Eating Behavior Questionnaire, the "impulse control difficulties" subscale of the Difficulties with Emotion Regulation Scale, and the Binge Eating Scale. Findings provide initial evidence for the hypothesized moderated mediation model, with dietary restraint partially mediating the relationship between impulsivity and binge eating severity only in lean respondents. In respondents with overweight or obesity, impulsivity was significantly correlated with binge eating severity, but not with dietary restraint. Findings inform our conceptualization of dietary restraint as a possible risk factor for binge eating and highlight the importance of accounting for body mass in research on the impact of dietary restraint on eating behaviors. PMID- 27757093 TI - The Neural Correlates Underlying Belief Reasoning for Self and for Others: Evidence from ERPs. AB - Belief reasoning is typical mental state reasoning in theory of mind (ToM). Although previous studies have explored the neural bases of belief reasoning, the neural correlates of belief reasoning for self and for others are rarely addressed. The decoupling mechanism of distinguishing the mental state of others from one's own is essential for ToM processing. To address the electrophysiological bases underlying the decoupling mechanism, the present event related potential study compared the time course of neural activities associated with belief reasoning for self and for others when the belief belonging to self was consistent or inconsistent with others. Results showed that during a 450-600 ms period, belief reasoning for self elicited a larger late positive component (LPC) than for others when beliefs were inconsistent with each other. The LPC divergence is assumed to reflect the categorization of agencies in ToM processes. PMID- 27757095 TI - Testing Differential Holistic Processing Within a Face: No Evidence of Asymmetry from the Complete Composite Task. AB - The composite face task is one of the most popular research paradigms for measuring holistic processing of upright faces. The exact mechanism underlying holistic processing remains elusive and controversial, and some studies have suggested that holistic processing may not be evenly distributed, in that the top half of a face might induce stronger holistic processing than its bottom-half counterpart. In two experiments, we further examined the possibility of asymmetric holistic processing. Prior to Experiment 1, we confirmed that perceptual discriminability was equated between top and bottom face halves; we found no differences in performance between top and bottom face halves when they were presented individually. Then, in Experiment 1, using the composite face task with the complete design to reduce response bias, we failed to obtain evidence that would support the notion of asymmetric holistic processing between top and bottom face halves. To further reduce performance variability and to remove lingering holistic effects observed in the misaligned condition in Experiment 1, we doubled the number of trials and increased misalignment between top and bottom face halves to make misalignment more salient in Experiment 2. Even with these additional manipulations, we were unable to find evidence indicative of asymmetric holistic processing. Taken together, these findings suggest that holistic processing is distributed homogenously within an upright face. PMID- 27757094 TI - "Feature Detection" vs. "Predictive Coding" Models of Plant Behavior. AB - In this article we consider the possibility that plants exhibit anticipatory behavior, a mark of intelligence. If plants are able to anticipate and respond accordingly to varying states of their surroundings, as opposed to merely responding online to environmental contingencies, then such capacity may be in principle testable, and subject to empirical scrutiny. Our main thesis is that adaptive behavior can only take place by way of a mechanism that predicts the environmental sources of sensory stimulation. We propose to test for anticipation in plants experimentally by contrasting two empirical hypotheses: "feature detection" and "predictive coding." We spell out what these contrasting hypotheses consist of by way of illustration from the animal literature, and consider how to transfer the rationale involved to the plant literature. PMID- 27757096 TI - Spatial-Sequential Working Memory in Younger and Older Adults: Age Predicts Backward Recall Performance within Both Age Groups. AB - Working memory is vulnerable to age-related decline, but there is debate regarding the age-sensitivity of different forms of spatial-sequential working memory task, depending on their passive or active nature. The functional architecture of spatial working memory was therefore explored in younger (18-40 years) and older (64-85 years) adults, using passive and active recall tasks. Spatial working memory was assessed using a modified version of the Spatial Span subtest of the Wechsler Memory Scale - Third Edition (WMS-III; Wechsler, 1998). Across both age groups, the effects of interference (control, visual, or spatial), and recall type (forward and backward), were investigated. There was a clear effect of age group, with younger adults demonstrating a larger spatial working memory capacity than the older adults overall. There was also a specific effect of interference, with the spatial interference task (spatial tapping) reliably reducing performance relative to both the control and visual interference (dynamic visual noise) conditions in both age groups and both recall types. This suggests that younger and older adults have similar dependence upon active spatial rehearsal, and that both forward and backward recall require this processing capacity. Linear regression analyses were then carried out within each age group, to assess the predictors of performance in each recall format (forward and backward). Specifically the backward recall task was significantly predicted by age, within both the younger and older adult groups. This finding supports previous literature showing lifespan linear declines in spatial-sequential working memory, and in working memory tasks from other domains, but contrasts with previous evidence that backward spatial span is no more sensitive to aging than forward span. The study suggests that backward spatial span is indeed more processing-intensive than forward span, even when both tasks include a retention period, and that age predicts backward spatial span performance across the adult lifespan, within both younger and older adulthood. PMID- 27757097 TI - Homework Involvement and Academic Achievement of Native and Immigrant Students. AB - Homework is a debated issue in society and its relationship with academic achievement has been deeply studied in the last years. Nowadays, schools are multicultural stages in which students from different cultures and ethnicities work together. In this sense, the present study aims to compare homework involvement and academic achievement in a sample of native and immigrant students, as well as to study immigrant students' relationship between homework involvement and Math achievement. The sample included 1328 students, 10-16 years old from Spanish families (85.6%) or immigrant students or students of immigrant origin (14.4%) from South America, Europe, Africa, and Asia. The study was developed considering three informants: elementary and secondary students, their parents and their teachers. Results showed higher involvement in homework in native students than in immigrant. Between immigrants students, those who are more involved in homework have better academic achievement in Math at secondary grades. There weren't found gender differences on homework involvement, but age differences were reported. Immigrant students are less involved in homework at secondary grades that students in elementary grades. The study highlights the relevance of homework involvement in academic achievement in immigrant students. PMID- 27757098 TI - Peer Victimization and Depressive Symptoms Among Rural-to-Urban Migrant Children in China: The Protective Role of Resilience. AB - Peer victimization can have a profound effect on children's wellbeing and is a known risk factor for depression in childhood. Migrant children experience peer victimization at higher rates than non-migrant peers; however, limited research has examined psychological factors that may serve to reduce depression risk for this group. In particular, no studies have yet investigated whether resilience, including personal characteristics, and a strong social support network, may moderate the relationship between peer victimization and depressive symptoms for migrant children. This study utilized a latent interaction model to examine the effect of resilience on the relationship between peer victimization and depressive symptoms among 721 rural-to-urban migrant children in Beijing, China. Results indicated that peer victimization was positively associated with depressive symptoms. Resilience was found to be a protective factor for depressive symptoms and also mitigated the effects of peer victimization on depressive symptoms. Exploratory analyses suggest that enrollment in private migrant schools may be linked with poorer psychosocial outcomes for Chinese migrant children. Strengthening the internal resilience and social supports for all migrant children may be an effective strategy to lower their risk for depression. Implications for intervention are discussed. PMID- 27757099 TI - Sex Differences in Rhythmic Preferences in the Budgerigar (Melopsittacus undulatus): A Comparative Study with Humans. AB - A variety of parrot species have recently gained attention as members of a small group of non-human animals that are capable of coordinating their movements in time with a rhythmic pulse. This capacity is highly developed in humans, who display unparalleled sensitivity to musical beats and appear to prefer rhythmically organized sounds in their music. Do parrots also exhibit a preference for rhythmic over arrhythmic sounds? Here, we presented humans and budgerigars (Melopsittacus undulatus) - a small parrot species that have been shown to be able to align movements with a beat - with rhythmic and arrhythmic sound patterns in an acoustic place preference paradigm. Both species were allowed to explore an environment for 5 min. We quantified how much time they spent in proximity to rhythmic vs. arrhythmic stimuli. The results show that humans spent more time with rhythmic stimuli, and also preferred rhythmic stimuli when directly asked in a post-test survey. Budgerigars did not show any such overall preferences. However, further examination of the budgerigar results showed an effect of sex, such that male budgerigars spent more time with arrthymic stimuli, and female budgerigars spent more time with rhythmic stimuli. Our results support the idea that rhythmic information is interesting to budgerigars. We suggest that future investigations into the temporal characteristics of naturalistic social behaviors in budgerigars, such as courtship vocalizations and head-bobbing displays, may help explain the sex difference we observed. PMID- 27757100 TI - Pandemic (H1N1) 2009 Influenza Virus Infection in A Survivor Who Has Recovered from Severe H7N9 Virus Infection, China. AB - We firstly report a patient who presented with severe complications after infection with influenza A(H1N1) pdm2009, more than 1 year after recovery from severe H7N9 virus infections. The population of patients who recovered from severe H7N9 infections might be at a higher risk to suffer severe complications after seasonal influenza infections, and they should be included in the high-risk populations recommended to receive seasonal influenza vaccination. PMID- 27757101 TI - Genes Required for the Anti-fungal Activity of a Bacterial Endophyte Isolated from a Corn Landrace Grown Continuously by Subsistence Farmers Since 1000 BC. AB - Endophytes are microbes that inhabit internal plant tissues without causing disease. Some endophytes are known to combat pathogens. The corn (maize) landrace Chapalote has been grown continuously by subsistence farmers in the Americas since 1000 BC, without the use of fungicides, and the crop remains highly valued by farmers, in part for its natural tolerance to pests. We hypothesized that the pathogen tolerance of Chapalote may, in part, be due to assistance from its endophytes. We previously identified a bacterial endophyte from Chapalote seeds, Burkholderia gladioli strain 3A12, for its ability to combat a diversity of crop pathogens, including Sclerotinia homoeocarpa, the most important fungal disease of creeping bentgrass, a relative of maize used here as a model system. Strain 3A12 represents a unique opportunity to understand the anti-fungal activities of an endophyte associated with a crop variety grown by subsistence farmers since ancient times. Here, microscopy combined with Tn5-mutagenesis demonstrates that the anti-fungal mode of action of 3A12 involves flagella-dependent swarming toward its pathogen target, attachment and biofilm-mediated microcolony formation. The mutant screen revealed that YajQ, a receptor for the secondary messenger c-di-GMP, is a critical signaling system that mediates this endophytic mobility-based defense for its host. Microbes from the traditional seeds of farmers may represent a new frontier in elucidating host-microbe mutualistic interactions. PMID- 27757104 TI - Characterization of Linoleate 10-Hydratase of Lactobacillus plantarum and Novel Antifungal Metabolites. AB - Lactobacilli convert linoleic acid to the antifungal compound 10-hydroxy-12 octadecenoic acid (10-HOE) by linoleate 10-hydratase (10-LAH). However, the effect of this conversion on cellular membrane physiology and properties of the cell surface have not been demonstrated. Moreover, Lactobacillus plantarum produces 13-hydroxy-9-octadecenoic acid (13-HOE) in addition to 10-HOE, but the antifungal activity of 13-HOE was unknown. Phylogenetic analyses conducted in this study did not differentiate between 10-LAH and linoleate 13-hydratase (13 LAH). Thus, linoleate hydratases (LAHs) must be characterized through their differences in their activities of linoleate conversion. Four genes encoding putative LAHs from lactobacilli were cloned, heterologous expressed, purified and identified as FAD-dependent 10-LAH. The unsaturated fatty acid substrates stimulated the growth of lactobacilli. We also investigated the role of 10-LAH in ethanol tolerance, membrane fluidity and hydrophobicity of cell surfaces in lactobacilli by disruption of lah. Compared with the L. plantarum lah deficient strain, 10-LAH in wild-type strain did not exert effect on cell survival and membrane fluidity under ethanol stress, but influenced the cell surface hydrophobicity. Moreover, deletion of 10-LAH in L. plantarum facilitated purification of 13-HOE and demonstration of its antifungal activity against Penicillium roqueforti and Aspergillus niger. PMID- 27757102 TI - Adaptation in Bacillus cereus: From Stress to Disease. AB - Bacillus cereus is a food-borne pathogen that causes diarrheal disease in humans. After ingestion, B. cereus experiences in the human gastro-intestinal tract abiotic physical variables encountered in food, such as acidic pH in the stomach and changing oxygen conditions in the human intestine. B. cereus responds to environmental changing conditions (stress) by reversibly adjusting its physiology to maximize resource utilization while maintaining structural and genetic integrity by repairing and minimizing damage to cellular infrastructure. As reviewed in this article, B. cereus adapts to acidic pH and changing oxygen conditions through diverse regulatory mechanisms and then exploits its metabolic flexibility to grow and produce enterotoxins. We then focus on the intricate link between metabolism, redox homeostasis, and enterotoxins, which are recognized as important contributors of food-borne disease. PMID- 27757105 TI - Mycobacteria Clumping Increase Their Capacity to Damage Macrophages. AB - The rough morphotypes of non-tuberculous mycobacteria have been associated with the most severe illnesses in humans. This idea is consistent with the fact that Mycobacterium tuberculosis presents a stable rough morphotype. Unlike smooth morphotypes, the bacilli of rough morphotypes grow close together, leaving no spaces among them and forming large aggregates (clumps). Currently, the initial interaction of macrophages with clumps remains unclear. Thus, we infected J774 macrophages with bacterial suspensions of rough morphotypes of M. abscessus containing clumps and suspensions of smooth morphotypes, primarily containing isolated bacilli. Using confocal laser scanning microscopy and electron microscopy, we observed clumps of at least five rough-morphotype bacilli inside the phagocytic vesicles of macrophages at 3 h post-infection. These clumps grew within the phagocytic vesicles, killing 100% of the macrophages at 72 h post infection, whereas the proliferation of macrophages infected with smooth morphotypes remained unaltered at 96 h post-infection. Thus, macrophages phagocytose large clumps, exceeding the bactericidal capacities of these cells. Furthermore, proinflammatory cytokines and granuloma-like structures were only produced by macrophages infected with rough morphotypes. Thus, the present study provides a foundation for further studies that consider mycobacterial clumps as virulence factors. PMID- 27757103 TI - Diverse Functions of Small RNAs in Different Plant-Pathogen Communications. AB - RNA silencing is a conserved mechanism that utilizes small RNAs (sRNAs) to direct the regulation of gene expression at the transcriptional or post-transcriptional level. Plants utilizing RNA silencing machinery to defend pathogen infection was first identified in plant-virus interaction and later was observed in distinct plant-pathogen interactions. RNA silencing is not only responsible for suppressing RNA accumulation and movement of virus and viroid, but also facilitates plant immune responses against bacterial, oomycete, and fungal infection. Interestingly, even the same plant sRNA can perform different roles when encounters with different pathogens. On the other side, pathogens counteract by generating sRNAs that directly regulate pathogen gene expression to increase virulence or target host genes to facilitate pathogen infection. Here, we summarize the current knowledge of the characterization and biogenesis of host- and pathogen-derived sRNAs, as well as the different RNA silencing machineries that plants utilize to defend against different pathogens. The functions of these sRNAs in defense and counter-defense and their mechanisms for regulation during different plant-pathogen interactions are also discussed. PMID- 27757107 TI - The Animal Model Determines the Results of Aeromonas Virulence Factors. AB - The selection of an experimental animal model is of great importance in the study of bacterial virulence factors. Here, a bath infection of zebrafish larvae is proposed as an alternative model to study the virulence factors of Aeromonas hydrophila. Intraperitoneal infections in mice and trout were compared with bath infections in zebrafish larvae using specific mutants. The great advantage of this model is that bath immersion mimics the natural route of infection, and injury to the tail also provides a natural portal of entry for the bacteria. The implication of T3SS in the virulence of A. hydrophila was analyzed using the AH 1::aopB mutant. This mutant was less virulent than the wild-type strain when inoculated into zebrafish larvae, as described in other vertebrates. However, the zebrafish model exhibited slight differences in mortality kinetics only observed using invertebrate models. Infections using the mutant AH-1DeltavapA lacking the gene coding for the surface S-layer suggested that this protein was not totally necessary to the bacteria once it was inside the host, but it contributed to the inflammatory response. Only when healthy zebrafish larvae were infected did the mutant produce less mortality than the wild-type. Variations between models were evidenced using the AH-1DeltarmlB, which lacks the O-antigen lipopolysaccharide (LPS), and the AH-1DeltawahD, which lacks the O-antigen LPS and part of the LPS outer-core. Both mutants showed decreased mortality in all of the animal models, but the differences between them were only observed in injured zebrafish larvae, suggesting that residues from the LPS outer core must be important for virulence. The greatest differences were observed using the AH-1DeltaFlaB-J (lacking polar flagella and unable to swim) and the AH-1::motX (non-motile but producing flagella). They were as pathogenic as the wild-type strain when injected into mice and trout, but no mortalities were registered in zebrafish larvae. This study demonstrates that zebrafish larvae can be used as a host model to assess the virulence factors of A. hydrophila. This model revealed more differences in pathogenicity than the in vitro models and enabled the detection of slight variations in pathogenesis not observed using intraperitoneal injections of mice or fish. PMID- 27757108 TI - Encapsulation of Cardamom Essential Oil in Chitosan Nano-composites: In-vitro Efficacy on Antibiotic-Resistant Bacterial Pathogens and Cytotoxicity Studies. AB - Natural antimicrobial agents, particularly essential oils present an excellent alternative to current antibiotics due to their potent and broad-spectrum antimicrobial potential, unique mechanisms of action and low tendency to induce resistance. However their potential as a viable therapeutic alternative is greatly compromised due to their hydrophobic and volatile nature. The objective of the current research was to explore the anti-pathogenic potential of essential oils in a bio-based nano-carrier system. Six different essential oils were tested on multidrug-resistant bacterial pathogens. However, cardamom oil was selected for nano-encapsulation because of most potent anti-microbial activity. Cardamom oil loaded chitosan nano-particles were prepared by ionic gelation method with an encapsulation efficiency of more than 90% and size was estimated to be 50-100 nm. The Zeta potential was more than +50 mV that indicate a stable nano-dispersion. Cytotoxicity analysis indicated non haemolytic and non-cytotoxic behaviour on human corneal epithelial cells and HepG2 cell lines. Cardamom oil loaded chitosan nano-particles were found to exhibit excellent anti-microbial potential against extended spectrum beta lactamase producing Escherichia coli and methicillin resistant Staphylococcus aureus. Our results suggested safety and efficacy of cardamom oil loaded chitosan nano-particles for treating multidrug-resistant pathogens hence offer an effective alternative to current antibiotic therapy. PMID- 27757106 TI - Chloroplast in Plant-Virus Interaction. AB - In plants, the chloroplast is the organelle that conducts photosynthesis. It has been known that chloroplast is involved in virus infection of plants for approximate 70 years. Recently, the subject of chloroplast-virus interplay is getting more and more attention. In this article we discuss the different aspects of chloroplast-virus interaction into three sections: the effect of virus infection on the structure and function of chloroplast, the role of chloroplast in virus infection cycle, and the function of chloroplast in host defense against viruses. In particular, we focus on the characterization of chloroplast protein viral protein interactions that underlie the interplay between chloroplast and virus. It can be summarized that chloroplast is a common target of plant viruses for viral pathogenesis or propagation; and conversely, chloroplast and its components also can play active roles in plant defense against viruses. Chloroplast photosynthesis-related genes/proteins (CPRGs/CPRPs) are suggested to play a central role during the complex chloroplast-virus interaction. PMID- 27757109 TI - Infection of Goose with Genotype VIId Newcastle Disease Virus of Goose Origin Elicits Strong Immune Responses at Early Stage. AB - Newcastle disease (ND), caused by virulent strains of Newcastle disease virus (NDV), is a highly contagious disease of birds that is responsible for heavy economic losses for the poultry industry worldwide. However, little is known about host-virus interactions in waterfowl, goose. In this study, we aim to characterize the host immune response in goose, based on the previous reports on the host response to NDV in chickens. Here, we evaluated viral replication and mRNA expression of 27 immune-related genes in 10 tissues of geese challenged with a genotype VIId NDV strain of goose origin (go/CH/LHLJ/1/06). The virus showed early replication, especially in digestive and immune tissues. The expression profiles showed up-regulation of Toll-like receptor (TLR)1-3, 5, 7, and 15, avian beta-defensin (AvBD) 5-7, 10, 12, and 16, cytokines [interleukin (IL)-8, IL-18, IL-1beta, and interferon-gamma], inducible NO synthase (iNOS), and MHC class I in some tissues of geese in response to NDV. In contrast, NDV infection suppressed expression of AvBD1 in cecal tonsil of geese. Moreover, we observed a highly positive correlation between viral replication and host mRNA expressions of TLR1 5 and 7, AvBD4-6, 10, and 12, all the cytokines measured, MHC class I, FAS ligand, and iNOS, mainly at 72 h post-infection. Taken together, these results demonstrated that NDV infection induces strong innate immune responses and intense inflammatory responses at early stage in goose which may associate with the viral pathogenesis. PMID- 27757110 TI - Characterization and Testing the Efficiency of Acinetobacter baumannii Phage vB GEC_Ab-M-G7 as an Antibacterial Agent. AB - Acinetobacter baumannii is a gram-negative, non-motile bacterium that, due to its multidrug resistance, has become a major nosocomial pathogen. The increasing number of multidrug resistant (MDR) strains has renewed interest in phage therapy. The aim of our study was to assess the effectiveness of phage administration in Acinetobacter baumannii wound infections in an animal model to demonstrate phage therapy as non-toxic, safe and alternative antibacterial remedy. Using classical methods for the study of bacteriophage properties, we characterized phage vB-GEC_Ab-M-G7 as a dsDNA myovirus with a 90 kb genome size. Important characteristics of vB-GEC_Ab-M-G7include a short latent period and large burst size, wide host range, resistance to chloroform and thermal and pH stability. In a rat wound model, phage application effectively decreased the number of bacteria isolated from the wounds of successfully treated animals. This study highlights the effectiveness of the phage therapy and provides further insight into treating infections caused by MDR strains using phage administration. PMID- 27757112 TI - Editorial: State-of-the-Art Research on C1q and the Classical Complement Pathway. PMID- 27757111 TI - Fitness Cost of Fluoroquinolone Resistance in Clinical Isolates of Pseudomonas aeruginosa Differs by Type III Secretion Genotype. AB - Fluoroquinolone (FQ) resistance is highly prevalent among clinical strains of Pseudomonas aeruginosa, limiting treatment options. We have reported previously that highly virulent strains containing the exoU gene of the type III secretion system are more likely to be FQ-resistant than strains containing the exoS gene, as well as more likely to acquire resistance-conferring mutations in gyrA/B and parC/E. We hypothesize that FQ-resistance imposes a lower fitness cost on exoU compared to exoS strains, thus allowing for better adaptation to the FQ-rich clinical environment. We created isogenic mutants containing a common FQ resistance conferring point mutation in parC from three exoU to three exoS clinical isolates and tested fitness in vitro using head-to-head competition assays. The mutation differentially affected fitness in the exoU and exoS strains tested. While the addition of the parC mutation dramatically increased fitness in one of the exoU strains leaving the other two unaffected, all three exoS strains displayed a general decrease in fitness. In addition, we found that exoU strains may be able to compensate for the fitness costs associated with the mutation through better regulation of supercoiling compared to the exoS strains. These results may provide a biological explanation for the observed predominance of the virulent exoU genotype in FQ-resistant clinical subpopulations and represent the first investigation into potential differences in fitness costs of FQ-resistance that are linked to the virulence genotype of P. aeruginosa. Understanding the fitness costs of antibiotic resistance and possibilities of compensation for these costs is essential for the rational development of strategies to combat the problem of antibiotic resistance. PMID- 27757113 TI - Minimal Residual Disease Detection and Evolved IGH Clones Analysis in Acute B Lymphoblastic Leukemia Using IGH Deep Sequencing. AB - Acute B lymphoblastic leukemia (B-ALL) is one of the most common types of childhood cancer worldwide and chemotherapy is the main treatment approach. Despite good response rates to chemotherapy regiments, many patients eventually relapse and minimal residual disease (MRD) is the leading risk factor for relapse. The evolution of leukemic clones during disease development and treatment may have clinical significance. In this study, we performed immunoglobulin heavy chain (IGH) repertoire high throughput sequencing (HTS) on the diagnostic and post-treatment samples of 51 pediatric B-ALL patients. We identified leukemic IGH clones in 92.2% of the diagnostic samples and nearly half of the patients were polyclonal. About one-third of the leukemic clones have correct open reading frame in the complementarity determining region 3 (CDR3) of IGH, which demonstrates that the leukemic B cells were in the early developmental stage. We also demonstrated the higher sensitivity of HTS in MRD detection and investigated the clinical value of using peripheral blood in MRD detection and monitoring the clonal IGH evolution. In addition, we found leukemic clones were extensively undergoing continuous clonal IGH evolution by variable gene replacement. Dynamic frequency change and newly emerged evolved IGH clones were identified upon the pressure of chemotherapy. In summary, we confirmed the high sensitivity and universal applicability of HTS in MRD detection. We also reported the ubiquitous evolved IGH clones in B-ALL samples and their response to chemotherapy during treatment. PMID- 27757114 TI - miRNA-124 in Immune System and Immune Disorders. AB - In recent years, miR-124 has emerged as a critical modulator of immunity and inflammation. Here, we summarize studies on the function and mechanism of miR-124 in the immune system and immunity-related diseases. They indicated that miR-124 exerts a crucial role in the development of immune system, regulation of immune responses, and inflammatory disorders. It is evident that miR-124 may serve as an informative diagnostic biomarker and therapeutic target in the future. PMID- 27757115 TI - Association Mapping for Aluminum Tolerance in a Core Collection of Rice Landraces. AB - Trivalent aluminum (Al3+) has drastic effect on the rice production in acidic soils. Elite genes for aluminum (Al) tolerance might exist in rice landraces. Therefore, the purpose of this research is to mine the elite genes within rice landraces. Association mapping for Al tolerance traits [i.e., relative root elongation (RRE)] was performed by using a core collection of 150 accessions of rice landraces (i.e., Ting's rice core collection). Our results showed that the Ting's rice core collection possessed a wide-range of phenotypic variation for Al tolerance, and the index of Al tolerance (RRE) was ranged from 0.22 to 0.89. Moreover, the groups with different origins and compositions of indica and japonica rice showed different degrees of tolerance to varying levels of Al. These rice landraces were further screened with 274 simple sequence repeat markers, and association mapping was performed using a mixed linear model approach. The mapping results showed that a total of 23 significant (P < 0.05) trait-marker associations were detected for Al tolerance. Of these, three associations (13%) were identical to the quantitative trait loci reported previously, and other 20 associations were reported for the first time in this study. The proportion of phenotypic variance (R2) explained by 23 significant associations ranged from 5.03 to 20.03% for Al tolerance. We detected several elite alleles for Al tolerance based on multiple comparisons of allelic effects, which could be used to develop Al tolerant rice cultivars through marker-assisted breeding. PMID- 27757116 TI - Down-Regulation of KORRIGAN-Like Endo-beta-1,4-Glucanase Genes Impacts Carbon Partitioning, Mycorrhizal Colonization and Biomass Production in Populus. AB - A greater understanding of the genetic regulation of plant cell wall remodeling and the impact of modified cell walls on plant performance is important for the development of sustainable biofuel crops. Here, we studied the impact of down regulating KORRIGAN-like cell wall biosynthesis genes, belonging to the endo-beta 1,4-glucanase gene family, on Populus growth, metabolism and the ability to interact with symbiotic microbes. The reductions in cellulose content and lignin syringyl-to-guaiacyl unit ratio, and increase in cellulose crystallinity of cell walls of PdKOR RNAi plants corroborated the functional role of PdKOR in cell wall biosynthesis. Altered metabolism and reduced growth characteristics of RNAi plants revealed new implications on carbon allocation and partitioning. The distinctive metabolome phenotype comprised of a higher phenolic and salicylic acid content, and reduced lignin, shikimic acid and maleic acid content relative to control. Plant sustainability implications of modified cell walls on beneficial plant-microbe interactions were explored via co-culture with an ectomycorrhizal fungus, Laccaria bicolor. A significant increase in the mycorrhization rate was observed in transgenic plants, leading to measurable beneficial growth effects. These findings present new evidence for functional interconnectedness of cellulose biosynthesis pathway, metabolism and mycorrhizal association in plants, and further emphasize the consideration of the sustainability implications of plant trait improvement efforts. PMID- 27757117 TI - Metabolic and Molecular Changes of the Phenylpropanoid Pathway in Tomato (Solanum lycopersicum) Lines Carrying Different Solanum pennellii Wild Chromosomal Regions. AB - Solanum lycopersicum represents an important dietary source of bioactive compounds including the antioxidants flavonoids and phenolic acids. We previously identified two genotypes (IL7-3 and IL12-4) carrying loci from the wild species Solanum pennellii, which increased antioxidants in the fruit. Successively, these lines were crossed and two genotypes carrying both introgressions at the homozygous condition (DHO88 and DHO88-SL) were selected. The amount of total antioxidant compounds was increased in DHOs compared to both ILs and the control genotype M82. In order to understand the genetic mechanisms underlying the positive interaction between the two wild regions pyramided in DHO genotypes, detailed analyses of the metabolites accumulated in the fruit were carried out by colorimetric methods and LC/MS/MS. These analyses evidenced a lower content of flavonoids in DHOs and in ILs, compared to M82. By contrast, in the DHOs the relative content of phenolic acids increased, particularly the fraction of hexoses, thus evidencing a redirection of the phenylpropanoid flux toward the biosynthesis of phenolic acid glycosides in these genotypes. In addition, the line DHO88 exhibited a lower content of free phenolic acids compared to M82. Interestingly, the two DHOs analyzed differ in the size of the wild region on chromosome 12. Genes mapping in the introgression regions were further investigated. Several genes of the phenylpropanoid biosynthetic pathway were identified, such as one 4-coumarate:CoA ligase and two UDP-glycosyltransferases in the region 12-4 and one chalcone isomerase and one UDP-glycosyltransferase in the region 7-3. Transcriptomic analyses demonstrated a different expression of the detected genes in the ILs and in the DHOs compared to M82. These analyses, combined with biochemical analyses, suggested a central role of the 4 coumarate:CoA ligase in redirecting the phenylpropanoid pathways toward the biosynthesis of phenolic acids in the pyramided lines. Moreover, analyses here carried out suggest the presence in the introgression regions of novel regulatory proteins, such as one Myb4 detected on chromosome 7 and one bHLH detected in chromosome 12. Overall our data indicate that structural and regulatory genes identified in this study might have a key role for the manipulation of the phenylpropanoid metabolic pathway in tomato fruit. PMID- 27757119 TI - Comparative Transcriptome Analyses Reveal a Special Glucosinolate Metabolism Mechanism in Brassica alboglabra Sprouts. AB - Brassica sprouts contain abundant phytochemicals, especially glucosinolates (GSs). Various methods have been used to enhance GS content in sprouts. However, the molecular basis of GS metabolism in sprouts remains an open question. Here we employed RNA-seq analysis to compare the transcriptomes of high-GS (JL-08) and low-GS (JL-09) Brassica alboglabra sprouts. Paired-end Illumina RNA-seq reads were generated and mapped to the Brassica oleracea reference genome. The differentially expressed genes were analyzed between JL-08 and JL-09. Among these, 1477 genes were up-regulated and 1239 down-regulated in JL-09 compared with JL-08. Enrichment analysis of these differentially expressed genes showed that the GS biosynthesis had the smallest enrichment factor and the highest Q value of all metabolic pathways in Kyoto Encyclopedia of Genes and Genomes database, indicating the main metabolic difference between JL-08 and JL-09 is the GS biosynthetic pathway. Thirty-seven genes of the sequenced data were annotated as putatively involved in GS biosynthesis, degradation, and regulation, of which 11 were differentially expressed in JL-08 and JL-09. The expression level of GS degradation enzyme myrosinase in high-GS JL-08 was lower compared with low-GS JL 09. Surprisingly, in high-GS JL-08, the expression levels of GS biosynthesis genes were also lower than those in low-GS JL-09. As the GS contents in sprouts are determined by dynamic equilibrium of seed stored GS mobilization, de novo synthesis, degradation, and extra transport, the result of this study leads us to suggest that efforts to increase GS content should focus on either raising GS content in seeds or decreasing myrosinase activity, rather than improving the expression level of GS biosynthesis genes in sprouts. PMID- 27757118 TI - The ALMT Family of Organic Acid Transporters in Plants and Their Involvement in Detoxification and Nutrient Security. AB - About a decade ago, members of a new protein family of anion channels were discovered on the basis of their ability to confer on plants the tolerance toward toxic aluminum ions in the soil. The efflux of Al3+-chelating malate anions through these channels is stimulated by external Al3+ ions. This feature of a few proteins determined the name of the entire protein family as Aluminum-activated Malate Transporters (ALMT). Meanwhile, after several years of research, it is known that the physiological roles of ALMTs go far beyond Al-detoxification. In this review article we summarize the current knowledge on this transporter family and assess their involvement in diverse physiological processes. PMID- 27757120 TI - Proteomic Identification of Differentially Expressed Proteins during Alfalfa (Medicago sativa L.) Flower Development. AB - Flower development, pollination, and fertilization are important stages in the sexual reproduction process of plants; they are also critical steps in the control of seed formation and development. During alfalfa (Medicago sativa L.) seed production, some distinct phenomena such as a low seed setting ratio, serious flower falling, and seed abortion commonly occur. However, the causes of these phenomena are complicated and largely unknown. An understanding of the mechanisms that regulate alfalfa flowering is important in order to increase seed yield. Hence, proteomic technology was used to analyze changes in protein expression during the stages of alfalfa flower development. Flower samples were collected at pre-pollination (S1), pollination (S2), and the post-pollination senescence period (S3). Twenty-four differentially expressed proteins were successfully identified, including 17 down-regulated in pollinated flowers, one up-regulated in pollinated and senesced flowers, and six up-regulated in senesced flowers. The largest proportions of the identified proteins were involved in metabolism, signal transduction, defense response, oxidation reduction, cell death, and programmed cell death (PCD). Their expression profiles demonstrated that energy metabolism, carbohydrate metabolism, and amino acid metabolism provided the nutrient foundation for pollination in alfalfa. Furthermore, there were three proteins involved in multiple metabolic pathways: dual specificity kinase splA-like protein (kinase splALs), carbonic anhydrase, and NADPH: quinone oxidoreductase-like protein. Expression patterns of these proteins indicated that MAPK cascades regulated multiple processes, such as signal transduction, stress response, and cell death. PCD also played an important role in the alfalfa flower developmental process, and regulated both pollination and flower senescence. The current study sheds some light on protein expression profiles during alfalfa flower development and contributes to the understanding of the basic molecular mechanisms during the alfalfa flowering process. These results may offer insight into potential strategies for improving seed yield, quality, and stress tolerance in alfalfa. PMID- 27757121 TI - GOLDEN 2-LIKE Transcription Factors of Plants. AB - Golden2-like (GLK) transcription factors are members of the GARP family of Myb transcription factors with an established relationship to chloroplast development in the plant kingdom. In the last century, Golden2 was proposed as a second golden producing factor and identified as controlling cellular differentiation in maize leaves. Then, GLKs were also found to play roles in disease defense and their function is conserved in regulating chloroplast development. Recently, research on GLKs has rapidly increased and shown that GLKs control chloroplast development in green and non-green tissues. Moreover, links between phytohormones and GLKs were verified. In this mini-review, we summarize the history, conservation, function, potential targets and degradation of GLKs. PMID- 27757122 TI - Distinct Cell Stress Responses Induced by ATP Restriction in Quiescent Human Fibroblasts. AB - Quiescence is the prevailing state of many cell types under homeostatic conditions. Yet, surprisingly little is known about how quiescent cells respond to energetic and metabolic challenges. To better understand compensatory responses of quiescent cells to metabolic stress, we established, in human primary dermal fibroblasts, an experimental 'energy restriction' model. Quiescence was achieved by short-term culture in serum-deprived media and ATP supply restricted using a combination of glucose transport inhibitors and mitochondrial uncouplers. In aggregate, these measures led to markedly reduced intracellular ATP levels while not compromising cell viability over the observation period of 48 h. Analysis of the transcription factor (TF) landscape induced by this treatment revealed alterations in several signal transduction nodes beyond the expected biosynthetic adaptations. These included increased abundance of NF-kappaB regulated TFs and altered TF subsets regulated by Akt and p53. The observed changes in gene regulation and corresponding alterations in key signaling nodes are likely to contribute to cell survival at intracellular ATP concentrations substantially below those achieved by growth factor deprivation alone. This experimental model provides a benchmark for the investigation of cell survival pathways and related molecular targets that are associated with restricted energy supply associated with biological aging and metabolic diseases. PMID- 27757123 TI - Comparative Genomics Analysis of Rice and Pineapple Contributes to Understand the Chromosome Number Reduction and Genomic Changes in Grasses. AB - Rice is one of the most researched model plant, and has a genome structure most resembling that of the grass common ancestor after a grass common tetraploidization ~100 million years ago. There has been a standing controversy whether there had been five or seven basic chromosomes, before the tetraploidization, which were tackled but could not be well solved for the lacking of a sequenced and assembled outgroup plant to have a conservative genome structure. Recently, the availability of pineapple genome, which has not been subjected to the grass-common tetraploidization, provides a precious opportunity to solve the above controversy and to research into genome changes of rice and other grasses. Here, we performed a comparative genomics analysis of pineapple and rice, and found solid evidence that grass-common ancestor had 2n = 2x = 14 basic chromosomes before the tetraploidization and duplicated to 2n = 4x = 28 after the event. Moreover, we proposed that enormous gene missing from duplicated regions in rice should be explained by an allotetraploid produced by prominently divergent parental lines, rather than gene losses after their divergence. This means that genome fractionation might have occurred before the formation of the allotetraploid grass ancestor. PMID- 27757124 TI - Gender-Specific Incidence and Predictors of Cognitive Impairment among Older Koreans: Findings from a 6-Year Prospective Cohort Study. AB - OBJECTIVE: This study investigated gender-specific incidence and predictors of cognitive impairment among community-dwelling older adults in South Korea. METHODS: Using data from the 2006 and 2012 Korean Longitudinal Study of Ageing (KLoSA), 925 females and 834 males aged 65 and over without cognitive impairment at 2006 were analyzed separately. Cognitive impairment was measured based on the Korean version of the Mini-Mental State Exam (K-MMSE) normative score. Generalized Estimating Equations (GEE) was conducted to examine the predictors of cognitive impairment at 6-year follow up. RESULTS: Incidence of cognitive impairment at 2012 was significantly higher for women (30.5%) than men (26.1%). GEE result showed that depression was significantly associated with cognitive impairment for both genders (female: OR=2.26, 95% CI=1.63-3.12; male: OR=3.26, 95% CI=2.19-4.83). Having IADL limitations (OR=1.15, 95% CI=1.03-1.28), high blood pressure (OR=1.72, 95% CI=1.27-2.34), poor hearing (OR=1.94, 95% CI=1.29 2.92), regular exercise (OR=0.67, 95% CI=0.45-0.99), and normal weight (OR=1.39, 95% CI=1.03-1.86) were significant predictors of cognitive impairment only among women. In contrast, age (OR=1.04, 95% CI=1.01-1.07) and ADL limitations (OR=1.48, 95% CI=1.21-1.82) were significant predictors of cognitive impairment at follow up only among men. CONCLUSION: Findings of this study show gender-specific predictors of cognitive impairment among older Koreans. This study can provide information for clinicians and policy makers to develop different intervention strategies considering gender differences in the progress of cognitive impairment. PMID- 27757125 TI - Effects of Psychiatric Symptoms on Attention in North Korean Refugees. AB - OBJECTIVE: We investigated the performance of North Korean refugees on attention tasks, and the relationship between that performance and psychiatric symptoms. METHODS: Sustained and divided attention was assessed using the computerized Comprehensive Attention Test in North Korean refugees and in South Koreans. All participants also completed the Beck Depression Inventory, the Beck Anxiety Inventory, the Impact of Event Scale-Revised and the Dissociative Experiences Scale-II (DES-II). RESULTS: The North Korean refugees showed slower reaction times (RTs) on the visual sustained attention task compared to the South Koreans after controlling for age and sex. North Korean refugees had a greater number of omission errors (OEs) on the divided attention task and a higher standard deviation (SD) of RT. Total DES-II scores of the North Korean refugees were associated with the number of OEs and the SD of RT on the sustained attention task, and with the number of OEs on the divided attention task. CONCLUSION: North Korean refugees showed poorer performance on computerized attention tasks. In addition, attention deficit among North Korean refugees was associated with their dissociative experiences. Our results suggest that refugees may have attention deficits, which may be related to their psychiatric symptoms, particularly dissociation. PMID- 27757126 TI - Social Behavioral Problems and the Health-Related Quality of Life in Children and Adolescents with Epilepsy. AB - OBJECTIVE: The purpose of this study was to investigate the impact of specific behavioral problems on the health-related quality of life (HRQOL) in children and adolescents with epilepsy. METHODS: Children and adolescents with epilepsy (n=92; age range=6-17 years) and their mothers completed questionnaires about behavioral problems, HRQOL, socio-demographics, and epilepsy-related variables. To determine significant predictor variables of the HRQOL, the stepwise regression analyses and partial correlations were performed to adjust for other behavioral problems and covariates. RESULTS: The analyses revealed that an increase in social behavioral problems and delinquent behavior was associated with a decrease in the HRQOL. Lower levels of maternal education and the number of antiepileptic drugs were also associated with a decline in the HRQOL; the HRQOL and social behavioral problems remained significantly correlated after adjusting for maternal education level, number of antiepileptic drugs, and non-social behavioral problems. CONCLUSION: Parents and practitioners should provide intervention if behavioral problems, particularly social behavioral problems, are observed in children or adolescents with epilepsy. PMID- 27757127 TI - Mental-Physical Comorbidity in Korean Adults: Results from a Nationwide General Population Survey in Korea. AB - OBJECTIVE: The aims of this study were to estimate the prevalence of mental physical comorbidity and health-threatening risk factors in subjects with mental disorders, and the risks of mental disorders in those with physical diseases for the last 12 months in the general Korean population. METHODS: Korean Epidemiologic Catchment Area study replication (KECA-R) was conducted for 6,510 adults between August 2006 and April 2007. The Korean version of Composite International Diagnostic Interview 2.1 (K-CIDI) was used in the survey. Prevalence of mental and physical disorders, and risk factors for physical health were calculated, and their associations were evaluated with adjustment for age and sex. RESULTS: Subjects with any mental disorder showed significantly higher prevalence of chronic physical conditions (adjusted odds ratio, AOR=1.5 to 2.8, p<0.001) and medical risk factors including smoking, heavy drinking, overweight, and hypertension (AOR=1.5 to 4.0, p<0.001). Of those with chronic physical conditions, 21.6% had one or more comorbid mental disorder compared with 10.5% of the subjects without chronic physical disorders (AOR=2.6, p<0.001). Contrary to expectations, depressive disorders did not show significant association with hypertension and prevalence of obesity was not influenced by presence of mental disorders. Further studies should assess these findings. CONCLUSION: This is the first identification of significant mental-physical comorbidity in the general Korean population. Clinicians and health care officials should keep in mind of its potential adverse effects on treatment outcome and aggravated disease-related socioeconomic burden. PMID- 27757128 TI - Thalamic Shape and Cognitive Performance in Amnestic Mild Cognitive Impairment. AB - OBJECTIVE: This study aimed to investigate thalamic shape alterations and their relationships with various episodic memory impairments in subjects with amnestic mild cognitive impairment (aMCI). METHODS: We compared volumes and morphological alterations of the thalamus between aMCI subjects and healthy controls. In addition, we investigated the correlation between thalamic deformations and various memory impairments in aMCI subjects using a comprehensive neuropsychological battery. RESULTS: The normalized left thalamic volumes of the aMCI group were significantly smaller than those of the healthy control group (p<0.0001). aMCI subjects exhibited significant thalamic deformations in the left thalamic dorso-medial and antero-medial areas compared with healthy individuals. CERAD-K Word List Memory scores were significantly correlated with the left dorso medial areas in aMCI subjects. There were no significant correlations between verbal fluency, Boston naming test, constructional praxis, Word List Recognition, and Visuospatial Recall scores and thalamic shape in aMCI subjects. Verbal delayed recall scores were also significantly correlated with the left dorso medial areas in the aMCI group. CONCLUSION: Structural alterations in the thalamic deformations in the left dorso-medial and antero-medial areas might be core underlying neurobiological mechanisms of thalamic dysfunction related to Word List Memory and delayed verbal recall in individuals with aMCI. PMID- 27757129 TI - Surface-Based Parameters of Brain Imaging in Male Patients with Alcohol Use Disorder. AB - OBJECTIVE: The structural alteration of brain shown in patients with alcohol use disorder (AUD) can originate from both alcohol effects and genetic or developmental processes. We compared surface-based parameters of patients with AUD with healthy controls to prove the applicability of surface-based morphometry with head size correction and to determine the areas that were sensitive to brain alteration related to AUD. METHODS: Twenty-six abstinent male patients with AUD (alcohol group, mean abstinence=13.2 months) and twenty-eight age-matched healthy participants (control group) were recruited from an inpatient mental hospital and community. All participants underwent a 3T MRI scan. Surface-based parameters were determined by using FreeSurfer. RESULTS: Every surface-based parameter of the alcohol group was lower than the corresponding control group parameter. There were large group differences in the whole brain, grey and white matter volume, and the differences were more prominent after head size correction. Significant group differences were shown in cortical thicknesses in entire brain regions, especially in parietal, temporal and frontal areas. There were no significant group differences in surface areas, but group difference trends in surface areas of the frontal and parietal cortices were shown after head size correction. CONCLUSION: Most of the surface-based parameters in alcohol group were altered because of incomplete recovery from chronic alcohol exposure and possibly genetic or developmental factors underlying the risk of AUD. Surface-based morphometry with controlling for head size is useful in comparing the volumetric parameters and the surface area to a lesser extent in alcohol-related brain alteration. PMID- 27757130 TI - Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism Is a Risk Factor for Attention-Deficit Hyperactivity Disorder in a Turkish Sample. AB - OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that negatively affects different areas of life. We aimed to evaluate the associations between the Val66Met polymorphism of brain derived neurotrophic factor (BDNF) and ADHD and to assess the effect of the BDNF polymorphism on the neurocognitive profile and clinical symptomatology in ADHD. METHODS: Two hundred one ADHD cases and 99 typically developing subjects (TD) between the ages of 8 and 15 years were involved in the study. All subjects were evaluated using a complete neuropsychological battery, Child Behavior Checklist, the Teacher's Report Form (TRF) and the DSM-IV Disruptive Behavior Disorders Rating Scale-teacher and parent forms. RESULTS: The GG genotype was significantly more frequent in the patients with ADHD than in the TD controls, and the GG genotype was also significantly more frequent in the ADHD-combined (ADHD-C) subtype patients than in the TDs. However, there were no significant associations of the BDNF polymorphism with the ADHD subtypes or neurocognitive profiles of the patients. The teacher-assessed hyperactivity and inattention symptom count and the total score were higher, and the appropriately behaving subtest score of the TRF was lower in the GG genotypes than in the GA and AA (i.e., the A-containing) genotypes. CONCLUSION: We found a positive association between the BDNF gene Val66Met polymorphism and ADHD, and this association was observed specifically in the ADHD-C subtype and not the ADHD-predominantly inattentive subtype. Our findings support that the Val66Met polymorphism of BDNF gene might be involved in the pathogenesis of ADHD. Furthermore Val66Met polymorphism of BDNF gene may be more closely associated with hyperactivity rather than inattention. PMID- 27757131 TI - Decreased Plasma BDNF Levels of Patients with Somatization Disorder. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF), one of the most abundant and important neurotrophins, is known to be involved in the development, survival, maintenance, and plasticity of neurons in the nervous system. Some studies have suggested that BDNF may play a role in the pathophysiology of several psychiatric illnesses such as depression and schizophrenia. Similarly, it is likely that the alteration of BDNF may be associated with the neuro-modulation that contributes to the development of somatization disorder. METHODS: The purpose of this study was to determine whether there is an abnormality of plasma BDNF levels in patients with somatization disorder, and to analyze the nature of the alteration after pharmacotherapy using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The plasma BDNF levels of the patients with a somatization disorder were significantly lower compared with those of the control volunteers (83.61+/-89.97 pg/mL vs. 771.36+/-562.14 pg/mL); moreover, the plasma BDNF levels of those patients who received an antidepressant were significantly increased after the treatment (118.13+/-91.45 pg/mL vs. 72.92+/-88.21 pg/mL). CONCLUSION: These results suggest that BDNF may play a role in the pathophysiology of somatization disorder. PMID- 27757132 TI - 7,8-Dihydroxyflavone, a Tropomyosin-Kinase Related Receptor B Agonist, Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), play important roles in treating depression. In this experiment, we examined whether 7,8-dihydroxyflavone, a novel potent TrkB agonist, could reverse the behavioral and biochemical abnormalities induced by the chronic mild stress (CMS) paradigm in rats. METHODS: SD rats were exposed to a battery of stressors for 56 days. 7,8-dihydroxyflavone (5 and 20 mg/kg) were administered intraperitoneally during the last 28 days of the CMS paradigm. Rats were tested in sucrose consumption test (SCT), forced-swimming test (FST) and elevated T-maze (ETM). Serum corticosterone levels and hippocampal BDNF levels of the rats were measured. RESULTS: Four-week CMS on the rats induced their depression-like behavior in SCT. The CMS-reduced sucrose consumption was reversed starting from 7 days after the 7,8-dihydroxyflavone (20 mg/kg) treatment and remained across the subsequent treatment regime. 7,8-dihydroxyflavone, when given at 5 mg/kg for 3 weeks, reduced the immobility time in the FST in the CMS subjected rats. Additionally, the 4-week treatment with 7,8-dihydroxyflavone (20 mg/kg) attenuated the CMS-induced increase in anxiety-like behavior in the ETM. For the CMS-subjected rats, 7,8-dihydroxyflavone treatment dose-dependently reduced their serum corticosterone levels but increased their hippocampal BDNF levels only at 5 mg/kg. CONCLUSION: 7,8-dihydroxyflavone was beneficial for both depression and anxiety-like behaviors, and may exert fast-onset antidepressant effects. This provides a new insight into the pharmacological management of depression. PMID- 27757133 TI - Chemokine and Chemokine Receptor Polymorphisms in Bipolar Disorder. AB - OBJECTIVE: Bipolar disorder (BD) is a debilitating psychiatric disease with unknown etiology. Recent studies have shown inflammation as a potential contributing factor of BD pathogenesis. However, potential associations between chemokine and chemokine receptor polymorphisms and BD have been fundamentally understudied. To identify participation of chemokines in BD pathogenesis, we examined genetic variants of several chemokine and chemokine receptor genes. METHODS: The study population comprised 200 patients with BD and 195 age- and sex matched healthy controls. Genotyping of monocyte chemotactic protein 1 (MCP-1) A2518G, CCR2 V64I, CCR5 Delta32, CCR5 A55029G, stromal cell-derived factor 1 (SDF 1) 3'A, and CXCR4 C138T polymorphisms was performed using polymerase chain reaction and restriction enzyme digestion. RESULTS: We found that CCR5-Delta32 II and CXCR4-C138T C+ genotype frequencies contributed to an increased risk for BD. However, no statistical significance could be obtained with these genotypes after Bonferroni correction. A significant asssociation was only found with MCP-1 GG and G+ genotypes, which were markedly more prevalent in patients with BD and these genotypes seemed to significantly increase the risk for BD even after Bonferroni correction. CONCLUSION: Our findings indicate an association between genetic variants of certain chemokine and chemokine receptor (especially MCP-1) genes and BD. The exact mechanisms by which these variants contribute to BD pathogenesis and their clinical implications need to be further investigated. PMID- 27757134 TI - Circulating Plasma Micro RNAs in Patients with Major Depressive Disorder Treated with Antidepressants: A Pilot Study. AB - OBJECTIVE: Significant progress was made in the understanding etiopathogenic factors related to MDD, including through research on the role of micro RNAs (miRs). We investigated plasma miRs as potential markers for MDD in patients treated with antidepressants. METHODS: At the initiation and at the end of twelve weeks of treatment, blood samples were collected and a structured diagnostic interview and a standardized depression rating scale for the presence and severity of major depression were done. The average decrease in HAMD score was 76.89%. Plasma miR expression profiling was performed by real time PCR. The lists of up-regulated (cut-off=2) and down-regulated miRs were imported into the miRWalk2.0 algorithm and used for target predictions. KEGG database pathways analysis was used to retrieve the pathways significantly targeted by at least two of the miRs. RESULTS: Of the 222 miRs detected in plasma samples of MDD patients, 40 were differentially expressed after treatment. Twenty-three miRs were significantly overexpressed with fold changes between 1.85 and 25.42, and 17 miRs were significantly downregulated with fold changes from 0.28 to 0.68. Pathway analysis revealed a list of 29 pathways for up-regulated miRs, and 20 pathways for down-regulated miRs. Six dysregulated miRs are common to all the top five pathways (Wnt signaling, Cancer, Endocytosis, Axon guidance, MAPK signaling): miR 146a-5p, miR-146b-5p, miR-221-3p, miR-24-3p, miR-26a-5p. CONCLUSION: Overall, our miRWalk analysis of changes in plasma microRNAs after treatment of patients with major depression might open a new avenue for the understanding of Escitalopram mode of action and for its side effects. PMID- 27757135 TI - What Does Depression Mean for Korean American Elderly?: A Qualitative Follow-Up Study. AB - OBJECTIVE: Korean American Elderly (KAE) have high rates of depression but underuse mental health services. The purpose of this study was to assess the meaning of depression and help seeking among KAE residing in the United States who have clinically significant depressive symptoms. METHODS: As a follow up to the Memory and Aging Study of Koreans (MASK; n=1,118), a descriptive epidemiological study which showed that only one in four of KAE with clinically significant depressive symptoms (Patient Health Questionnaire-9>=10) used mental health services, we conducted a qualitative study using semi-structured interviews with participants with clinically significant depressive symptoms regarding the meaning of depression and beliefs about help seeking. Ten participants with clinically significant depressive symptoms were approached and 8 were recruited for semi-structured interviews. RESULTS: KAE did not identify themselves as depressed though experiencing clinically significant depressive symptoms. They associated depression with social discrimination, social isolation, and suicide in the extreme circumstance. They attributed depression to not achieving social and material success in America and strained relationships with their children. Participants attempted to self-manage distress without telling others in their social network. However, KAE were willing to consult with mental health professionals if the services were bilingual, affordable, and confidential. CONCLUSION: KAE with clinically significant depressive symptoms are a vulnerable group with need and desire for linguistically and culturally relevant mental health services who are isolated due to a complex array of psychological and social factors. PMID- 27757136 TI - The Relationship between Personality, Sense of Efficacy, and Stress in Korean Teachers. AB - Several studies have linked teachers' personality characteristics and sense of efficacy to stress. However, investigating the relationship between these three constructs in this context was limited. This study aims to investigate the relationship between personality, sense of efficacy and perceived stress among Korean teachers. A total of 137 teachers working in elementary, middle, and high schools located in Seoul, South Korea were recruited for the study. The participants were administered Temperament and Character Inventory, Teacher's Sense of Efficacy Scale (TSES), and Perceived Stress Scale. The TSES was negatively correlated with harm avoidance and positively correlated with persistence, self-directedness, cooperativeness, and self-transcendence. Perceived stress was positively correlated with harm avoidance and negatively correlated with persistence and self-directedness. The path analysis showed that harm avoidance directly predicted perceived stress (beta=0.37, 95% CI=0.21-0.53, p=0.002), and self-directedness and persistence predicted one's sense of efficacy (beta=0.18, 95% CI=0.01-0.39 and beta=0.31, 95% CI=0.10-0.47), which predicted perceived stress (beta=-0.21, 95% CI=-0.39 to -0.02). The results of the present study indicate that harm avoidance might be associated with stress-proneness, while persistence, self-directedness, and sense of efficacy might act as protective resources against stress in Korean teachers. PMID- 27757137 TI - The Thai Version of the Addenbrooke's Cognitive Examination III. AB - The objective of our study was to assess the accuracy of the Thai version of the Addenbrooke's Cognitive Examination III (ACE-T). We used the ACE-T to assess 107 participants aged 60 or over, divided into the following groups: early dementia, n=30; mild cognitive impairment (MCI), n=29; and normal controls (NC), n=48. The ACE-T exhibited good internal consistency (0.93) and inter-rater reliability (1.0). The optimal cut-off score for the ACE-T to differentiate MCI from NC was 75/76, giving a sensitivity of 0.9 and specificity of 0.86. At the optimal cut off of 61/62, the ACE-T had excellent sensitivity (1.0) and specificity (0.97) to distinguish early dementia from non-dementia. The ACE-T had high diagnosis accuracy in the detection of the MCI and early dementia in the Thai population. PMID- 27757138 TI - Considering Comorbidity in Adolescents with Social Anxiety Disorder. AB - Social anxiety disorder is a highly prevalent psychiatric disorder, with elevated comorbidity rates with other mental health disorders and may cause severe negative consequences. In adolescence, there is a lack of research on how comorbid disorders to social anxiety tends to form particular associations. With a large sample of adolescents with a clinical diagnosis of social anxiety disorder, data have revealed that certain disorders are more frequent and tend to dwell on concrete aggregates. Thus, it may be particularly useful and efficient for mental health providers, pediatricians and school counselors to screen for generalized anxiety disorder and specific phobia when assessing SAD in youth. Overall, findings stress the presence of comorbidity being the rule rather than the exception in adolescents with social anxiety disorder, and the need for further examination of its impact on assessment and differential diagnosis on this psychiatric disorder. PMID- 27757139 TI - Charles Bonnet Syndrome Following Trans-Sphenoidal Adenomectomy without Optic Nerve Atrophy. AB - Charles Bonnet syndrome (CBS) can develop after trans-sphenoidal adenomectomy (TSA); however, the neural mechanisms remain unknown. Sensory deprivation and releasing phenomenon are both hypothetical explanations for this condition; however, there is no definite evidence that strongly supports either supposition. We report the first case of CBS after TSA without optic nerve atrophy. Postoperatively, the patient's vision seemed to be relatively well preserved, apart from the left-side hemianopsia in the right eye. Distinctive visual hallucinations only appeared when his eyes were closed, and these responded to quetiapine in a dose-dependent manner. Dose dependent change in colors and formation of hallucination was reported. Two weeks after quetiapine initiation, the patient's CBS was completely resolved. This unique case suggests that blocking sensory input from the periphery is more critical than neural damage of the bottom-up connection to the visual association cortex. In addition, quetiapine should be considered as a specific treatment for CBS. PMID- 27757140 TI - Bipolar and Related Disorders Induced by Sodium 4-Phenylbutyrate in a Male Adolescent with Bile Salt Export Pump Deficiency Disease. AB - Bile Salt Export Pump (BSEP) Deficiency disease, including Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2), is a rare disease, usually leading within the first ten years to portal hypertension, liver failure, hepatocellular carcinoma. Often liver transplantation is needed. Sodium 4-phenylbutyrate (4-PB) seems to be a potential therapeutic compound for PFIC2. Psychiatric side effects in the adolescent population are little known and little studied since the drug used to treat children and infants. So we described a case of Caucasian boy, suffering from a late onset PFIC2, listed for a liver transplant when he was sixteen and treated with 4-FB (200 mg per kilogram of body weight per day). The drug was discontinued for the onset of bipolar and related disorders. This case illustrates possible psychiatric side effects of the drug. PMID- 27757141 TI - Prevalence of timely breastfeeding initiation and associated factors in Dembecha district, North West Ethiopia: a cross-sectional study. AB - BACKGROUND: Early initiation of breastfeeding is a simple and cost effective intervention to advance the health of mothers and newborn babies. A large number of neonatal deaths could be prevented if infants were breastfed. However, there is poor practice related to breastfeeding initiation within the first one hour of birth, and the factors affecting it are not well understood. This study was conducted to assess the prevalence of timely breastfeeding initiation and associated factors in Dembecha district, North West Ethiopia. METHODS: A cross sectional study design was conducted from August to September 2015. Multistage sampling techniques were used to select a total of 739 mothers who had children under 2 years of age. A pretested structured questionnaire was used to collect data. Descriptive analysis, bivariate and multiple logistic regression analysis were performed. RESULTS: The level of timely initiation of breastfeeding was 73.1 %. The magnitude of prelacteal feeding and colostrum feeding in this study was 11.9 and 76.2 % respectively. Timely initiation of breastfeeding was significantly associated with the presence of four and above antenatal appointments during the last pregnancy (Adjusted Odds Ratio [AOR] 3.1; 95 % Confidence Interval [CI] 1.2, 8.0), access to mass media such as radio or television (AOR 1.54; 95 % CI 1.10, 2.20), and mothers who were attended by traditional birth attendant during their last birth (AOR 0.23; 95 % CI 0.07, 0.75). CONCLUSIONS: The level of timely initiation of breastfeeding was relatively good compared with previous studies in Ethiopia, although more than quarter of mothers didn't start breastfeeding within the first one hour of birth. Timely initiation of breastfeeding was significantly associated with the presence of four and above antenatal care during the last pregnancy, access to mass media (e.g. radio, television), and last child attended by traditional birth attendant. Programs should encourage mothers to use skilled birth attendants at birth, emphasise the importance of feeding colostrum and to initiate breastfeeding within one hour after childbirth. PMID- 27757143 TI - Maternal-fetal Medicine Subspecialists and Obstetric Physicians: A Match Made in Heaven or Too Many Cooks? PMID- 27757142 TI - Study protocol: a cluster randomized controlled trial to assess the effectiveness of a therapeutic educational program in oral health for persons with schizophrenia. AB - BACKGROUND: Schizophrenia is a severe mental disorder that affects 1 % of the world's population, including 600,000 people in France. Persons with schizophrenia (PWS) have excess mortality (their life expectancy is reduced by 20 %) and excess morbidity. In addition, such persons may have a large number of missing or decayed teeth. Dental caries and periodontal measurement indexes are often twice as high as the level found in the general population. Poor oral health can also affect quality of life and oral health is inseparable from general health. The management of oral health problems needs a multidisciplinary approach. According to the World Health Organization, the aim of therapeutic education (TE) is to help patients take care of themselves and to improve empowerment and recovery. In this educational approach, it is important to take into account the patient's personal experience. Though rarely investigated, the personal experience of PWS in oral health quality of life (OHRQoL) must be used to build a therapeutic educational programme in oral health (TEPOH) in a multidisciplinary approach, and the effectiveness of this program must be evaluated. METHODS/DESIGN: We report the protocol of a randomized controlled cluster study. This study will be conducted in twelve hospitals in France. We hypothesized that a decrease of 20 % in the proportion of patients with CPI >= 3 would establish the effectiveness of TEPOH. Therefore, 12 hospitals will be randomly allocated to either TEPOH or no TEPOH. Altogether, they will have to recruit 230 PWS, who will be randomly allocated with a ratio of 1:1 to one of two conditions: control without intervention versus the group benefitting from TEPOH. DISCUSSION: If successful, the study will generate methodologically sound results that provide knowledge on the effectiveness of a TEP in oral health for PWS. The results can be used to promote OHRQoL in a global health approach and develop appropriate strategies to encourage and facilitate financial support for healthcare, the multidisciplinary treatment of dental disorders, and the development of training in oral and mental health for caregivers. Trial registration Clinical Trials Gov NCT02512367. Date registered 19 July, 2015. PMID- 27757144 TI - The Epigenetics of Normal Pregnancy. AB - Epigenetic modifications to chromatin are essential for the specification and maintenance of cell fate, enabling the same genome to programme a variety of cellular outcomes. Epigenetic modulation of gene expression is also a critical mechanism by which cells stabilize their responses to environmental stimuli, including both nutritional cues and hormonal signalling. Unsurprisingly, epigenetics is proving to be vitally important in fetal development, and this review addresses our current understanding of the roles of epigenetic regulation in the prenatal phase. It is striking that while there has been a major interest in the intersection of fetal health with epigenetics, there has been relatively little discussion in the literature on epigenetic changes in the pregnant woman, and we attempt to redress this balance, drawing on the fragmented but intriguing experimental literature in this field. PMID- 27757145 TI - Novel Insulin Delivery Technologies in Women with Pregestational Type 1 Diabetes: A Review of the Literature. AB - Pregnancy in the setting of type 1 diabetes is associated with an increased risk of adverse outcomes for both mother and fetus. Adequate glycaemic control has been shown to result in improved outcomes, but the strict glycaemic targets required in pregnancy are often difficult to achieve. The development of novel technologies for insulin delivery aim to assist in achieving excellent glycaemic control, while attempting to minimize the significant risk of hypoglycaemia that exists in pregnancy. This review will discuss the use of insulin pump therapy, continuous glucose monitoring and closed loop insulin delivery in the setting of pregestational diabetes, highlighting some of the potential advantages of these technologies. Novel insulin delivery devices have been shown to be safe in the setting of pregnancy, but proper randomized controlled trials are still needed to determine if they are superior to traditional insulin delivery mechanisms. PMID- 27757146 TI - Review of Presentation, Diagnosis and Management of Pituitary Tumours in Pregnancy. AB - Although pituitary tumours are relatively uncommon, their association with menstrual irregularity and infertility brings them into the domain of obstetrics and gynaecology. This review addresses the range of pituitary tumours with particular regard to diagnosis, growth and behaviour and management during pregnancy. PMID- 27757148 TI - Diagnosis of a Myeloproliferative Disorder in Late Pregnancy. AB - A 38-year-old primiparous woman presented with pre-eclampsia at 36 weeks gestation with an abnormal full blood count and leukoerythroblastic blood film. JAK2 V617F was negative and splenomegaly was noted on abdominal ultrasound. Delivery was at 37 weeks gestation by emergency caesarean section due to abnormal cardiotocography. Bone marrow aspirate and trephine confirmed a diagnosis of myelofibrosis. The case highlights a rare presentation of primary myelofibrosis in pregnancy, the difficulties in management, and the UK Obstetric Surveillance System who are collecting epidemiological data on uncommon disorders in pregnancy. PMID- 27757147 TI - Maternal Body Mass Index during Pregnancy and Offspring Neurocognitive Development. AB - BACKGROUND: This hypothesis generating study explores second trimester maternal body mass index (BMI) during pregnancy and offspring neurocognitive development. METHODS: Mothers and offspring served as controls in two earlier studies: 101 children at age two years and 118 children at age eight years. RESULTS: Frequency of maternal BMI >=30 kg/m2 increased from 10% in 1987-1990 to 30% in 2004-2006 (P < 0.001); the socioeconomic gradient became more pronounced. At age two, one or more BSID-III (Bayley Scales of Infant Development, 3rd Edition) scores <85 were more frequent with higher maternal BMI (P = 0.029); regression analysis suggested an inverse relationship between language scores and BMI (P = 0.054). Among eight year-olds, one or more WISC-III (Wechsler Intelligence Scale for Children, 3rd edition) scores <85 increased with maternal BMI (P = 0.017); regression analysis showed an inverse relationship between performance subscale IQ score and BMI (P = 0.023). CONCLUSION: Second trimester maternal obesity may be an independent risk factor for some aspects of children's neurocognitive development. Further study is indicated. PMID- 27757149 TI - Spontaneous Clearance of Hepatitis C Virus during Pregnancy. AB - Spontaneous clearance of hepatitis C virus (HCV) is expected to be unlikely in pregnancy due to the relative immunosuppression and increase in viraemia that occurs. We report the first case of spontaneous clearance of hepatitis C virus (HCV) occurring in pregnancy. PMID- 27757150 TI - An Endocrine Cause of Acute Post-partum Hypertension. AB - This is a case of acute peri-partum hypertension secondary to Conn's syndrome. The timing of presentation offers a rare insight into the hormonal physiology of pregnancy and its impact on blood pressure regulation. This case highlights the challenges of diagnosing primary hyperaldosteronism in the peripartum period and the high index of suspicion required by the obstetric physician. PMID- 27757151 TI - Acute Onset Peripartum Cardiomyopathy in a Woman with Severe Pre-eclamptia: A Diagnostic Dilemma. AB - Peripartum cardiomyopathy (PPCM) is a form of dilated cardiomyopathy that can present as acute life-threatening pulmonary oedema in late pregnancy or early puerperium, its diagnosis is mainly by exclusion of other causes. Morbidity is high due to the reduced physiological reserve in pregnancy. PPCM and severe pre eclampsia can co-exist and their clinical presentation may overlap, making the diagnosis more difficult and often delayed, with potentially devastating consequences. Here, we would like to share our experience of such a case and present to the readers how we dealt with the challenge. As obstetricians we often do not resort to transthoracic echocardiography, which in our case prompted the diagnosis timely. Lateral thinking and a heightened suspicion does help. Proper diagnosis is extremely important not only for the immediate appropriate management but also for advising long-term lifestyle modifications to minimize risk and counselling for future pregnancy. PMID- 27757152 TI - Could it be Quetiapine-induced Peripartum Cardiomyopathy? AB - Peri-partum Cardiomyopathy (PPCM) is a rare and life threatening complication of pregnancy. There are only two cases registered with the World Health Organization of cases of cardiomyopathy in patients taking Quetiapine. Here we discuss an interesting case of potential Quetiapine induced cardiomyopathy. PMID- 27757153 TI - A Case of Breathlessness during Pregnancy: The Difficulty in Diagnosing Heart Failure. AB - We present the case of a 33-year-old woman in her second pregnancy who was transferred to our unit following a one-month history of worsening fatigue and a three-day history of worsening symptoms of heart failure. Shortly after presentation she developed ventricular fibrillation and arrested. At an emergency caesarean section a placental abruption was noted and the baby was stillborn, unable to be resuscitated. The patient required a prolonged intensive and coronary care stay. Echocardiographic findings were consistent with dilated cardiomyopathy and as all investigations to ascertain a cause were negative she was diagnosed with peripartum cardiomyopathy. Her case highlights a potential fatal cause of breathlessness during pregnancy and the role of B-type natriuretic peptide to assist in the differential diagnosis of these cases. PMID- 27757154 TI - Article Commentary: Acute Heart Failure: Is it Peripartum Cardiomyopathy or Not? AB - Peripartum cardiomyopathy (PPCM) is a potentially life-threatening disease that occurs in women of childbearing age. PMID- 27757155 TI - Reply To: Caring for Reproductive-aged Women with Spinal Cord Injuries: A Case Report. Obstet Med 2012;5: 133-4. PMID- 27757156 TI - Obstetric medicine: the Neonatologists's perspective. PMID- 27757157 TI - Effects of prenatal stress on pregnancy and human development: mechanisms and pathways. AB - A growing body of research shows that prenatal stress can have significant effects on pregnancy, maternal health and human development across the lifespan. These effects may occur directly through the influence of prenatal stress-related physiological changes on the developing fetus, or indirectly through the effects of prenatal stress on maternal health and pregnancy outcome which, in turn, affect infant health and development. Animal and human studies suggest that activation of the maternal stress response and resulting changes in endocrine and inflammatory activity play a role in the aetiology of these effects. Ongoing research is focusing on clarifying these mechanisms, understanding the role of racial and cultural factors in these effects, and examining the epigenetic and transgenerational influences of prenatal stress. PMID- 27757159 TI - A systematic review on the use of new anticoagulants in pregnancy. AB - New anticoagulants such as direct factor Xa inhibitors and direct thrombin inhibitors have been recently developed, but their experience in pregnancy is limited. This review therefore aims to systematically search for studies on the use of these newer anticoagulants in pregnancy and the puerperal period. Searches were performed on electronic databases MEDLINE (from 1966), EMBASE (from 1974) and the Cochrane Library, until October 2011 using terms of 'pregnancy', 'puerperium', 'breastfeeding' and names of specific anticoagulants. The search yielded 561 citations and 11 studies (10 on fondaparinux, 1 on ximelagatran) were included. Newer anticoagulants (fondaparinux, hirudin and argatroban) on the limited evidence appear not to have adverse pregnancy outcomes, but there is currently no experience of new oral anticoagulants (rivaroxaban, apixaban, betrixaban or dabigatran) use in pregnancy. There is a need for reporting on new oral anticoagulation use in pregnancy to provide more information about the safety and risks to the fetus in utero. PMID- 27757158 TI - Asthma in pregnancy: a review. AB - Asthma is one of the most common medical conditions in women of childbearing age. There are now data to show that asthma is not a benign condition with respect to maternal and fetal health. Despite this there are several problems encountered in the management of such women. There is a tendency to cease or reduce optimal asthma treatments because pregnant women and/or their clinicians may believe they pose a risk to the fetus. There is also a lack of clinician awareness of the complications of asthma in pregnancy. PMID- 27757160 TI - The management of epilepsy in pregnancy at the Whittington Hospital: a retrospective audit 2004-2006 and 2007-2010. AB - BACKGROUND: In the last maternal death enquiries report there were 14 indirect deaths due to epilepsy. METHODS: Retrospective case-note analysis of epileptic women seen antenatally over two separate time periods were examined. Care in the routine antenatal clinic (ANC) was compared with that in the obstetric medicine clinic (OMC). RESULTS: 1st audit, 65 epileptic women seen. In OMC 14% had documented preconception counselling, 58% were on anti-epileptic drugs (AEDs). In ANC 0% had documented preconception counselling, 34% were on AEDs. 2nd audit, 88 epileptic women seen. In OMC 37.5% of women had preconception counselling, 84% were on AEDs. In ANC, 4.2% had preconception counselling, 31% were on AEDs. CONCLUSIONS: Women seen in OMC received care more compliant with Scottish Obstetric Group and Audit Project recommendations. All women with epilepsy should be reviewed in an OMC. PMID- 27757162 TI - A case report of obstetrical management of a pregnancy with hypermobile Ehlers Danlos syndrome and literature review. AB - We present a case report of a successful pregnancy outcome in a woman diagnosed with Ehlers-Danlos syndrome (EDS) hypermobility type or type III. EDS is a group of connective tissue disorders that has a common genotypic defect, but heterogeneous phenotypic presentations. The variation in EDS manifestations can result in moderate to severe effects on life-expectancy for some types. A number of studies and a review of the literature indicate that generally in pregnant women with EDS, maternal and neonatal outcomes are favourable. However, in EDS type IV, pregnancy can be associated with serious maternal complications. Therefore, obstetrical management should be individualized. This paper discusses the obstetric management of a patient with EDS hypermobility type and compares it to other studies in the literature. PMID- 27757161 TI - When conventional treatment fails: the role of intravenous immunoglobulin in recurrent pregnancy loss secondary to antiphospholipid syndrome. AB - Recurrent pregnancy loss (RPL) is a well-recognized complication of antiphospholipid syndrome (APS). First line therapy consists of low dose aspirin and heparin. Despite conventional therapy some women fail to achieve a successful pregnancy outcome. We describe the case of a patient who had two live births following intravenous immunoglobulin therapy despite previous failure with conventional therapy for RPL in the setting of APS. We will summarize the available literature on intravenous immunoglobulin for this indication. PMID- 27757163 TI - Two young women with chronic daily headache and cognitive impairment: why we need to ask about headache in the postpartum period. AB - Headache, which has a variety of causes, is a common and disabling complaint following childbirth. An important aetiology not to be missed is headache from epidural spinal anaesthesia, known as postdural puncture headache (PDPH), which has been reported in upwards of 85% of pregnant women and is a manifestation of intracranial hypotension from leakage of cerebrospinal (CSF) fluid through a dural tear. The common presenting symptom of PDPH is head pain occurring when a patient is in an upright position that resolves with recumbency. Other neurological issues associated with intracranial hypotension can include cranial nerve palsies, encephalopathy and Parkinsonism. We present two cases of persistent PDPH after pregnancy with secondary cognitive impairment. A review of the clinical manifestations, neuroimaging findings and treatment for PDPH will be presented. Better recognition of this disorder by obstetricians, physicians and anaesthetics will help to reduce the considerable morbidity this syndrome can produce in young mothers. PMID- 27757164 TI - Paraparesis secondary to hypokalaemia with hyporeninemic hypoaldosteronism during pregnancy: a diagnostic dilemma. AB - We report the case of a 22-year-old Ethiopian woman, gravida 1, para 0, who presented at 16 weeks gestation with myalgia and paraparesis. PMID- 27757165 TI - A case of severe pyruvate kinase deficiency in a primigravida: successful outcome. AB - Pyruvate kinase deficiency (PKD) is a rare non-spherocytic type of haemolytic anaemia. During pregnancy, women with severe PKD are at increased risk of infection, thrombosis, hypertension, fetal growth restriction and anaemia. Management of such cases requires close collaboration between a haematologist and an obstetrician. We report a case of severe PKD in pregnancy with good maternal and fetal outcome. PMID- 27757166 TI - The use of therapeutic hypothermia in the management of amniotic fluid embolism. AB - BACKGROUND: Amniotic fluid embolism (AFE) is a rare peripartum obstetric emergency where patients seldom survive neurologically intact. The exact pathophysiology is not completely understood and treatment remains mainly supportive. CASE: A 34-year-old African American woman gravida 1, para 0-0-0-0 at 38 weeks and four days induced for chronic hypertension with superimposed preeclampsia experienced an AFE during labour. Supportive treatment included early use of therapeutic hypothermia resulting in a normal neurological outcome. CONCLUSION: This case demonstrates the timely use of therapeutic hypothermia in a patient surviving an AFE and suffering no neurological sequelae. Therapeutic hypothermia should be considered in the supportive treatment of AFE. PMID- 27757168 TI - Response to Adam Morton's Letter 'Reply to: Timothy A C Snow, Cara AWasywich and Fiona M Stewart. A case of breathlessness during pregnancy: the difficulty in diagnosing heart failure'. PMID- 27757167 TI - Reply to: Timothy A C Snow, Cara A Wasywich and Fiona M Stewart. A case of breathlessness during pregnancy: the difficulty in diagnosing heart failure Obstet Med OM.2012.120031; published ahead of print 20 December 2012, doi:10.1258/OM.2012.120031. PMID- 27757171 TI - BESS Winner and Prizes 2016. PMID- 27757169 TI - Proteomic and metabolomic analyses reveal metabolic responses to 3 hydroxypropionic acid synthesized internally in cyanobacterium Synechocystis sp. PCC 6803. AB - BACKGROUND: 3-hydroxypropionic acid (3-HP) is an important platform chemical with a wide range of applications. In our previous study, the biosynthetic pathway of 3-HP was constructed and optimized in cyanobacterium Synechocystis sp. PCC 6803, which led to 3-HP production directly from CO2 at a level of 837.18 mg L-1 (348.8 mg/g dry cell weight). As the production and accumulation of 3-HP in cells affect cellular metabolism, a better understanding of cellular responses to 3-HP synthesized internally in Synechocystis will be important for further increasing 3-HP productivity in cyanobacterial chassis. RESULTS: Using a engineered 3-HP producing SM strain, in this study, the cellular responses to 3-HP internally produced were first determined using a quantitative iTRAQ-LC-MS/MS proteomics approach and a LC-MS-based targeted metabolomics. A total of 2264 unique proteins were identified, which represented about 63 % of all predicted protein in Synechocystis in the proteomic analysis; meanwhile intracellular abundance of 24 key metabolites was determined by a comparative metabolomic analysis of the 3-HP producing strain SM and wild type. Among all identified proteins, 204 proteins were found up-regulated and 123 proteins were found down-regulated, respectively. The proteins related to oxidative phosphorylation, photosynthesis, ribosome, central carbon metabolism, two-component systems and ABC-type transporters were up-regulated, along with the abundance of 14 metabolites related to central metabolism. The results suggested that the supply of ATP and NADPH was increased significantly, and the precursor malonyl-CoA and acetyl-CoA may also be supplemented when 3-HP was produced at a high level in Synechocystis. Confirmation of proteomic and metabolomic results with RT-qPCR and gene overexpression strains of selected genes was also conducted, and the overexpression of three transporter genes putatively involved in cobalt/nickel, manganese and phosphate transporting (i.e., sll0385, sll1598 and sll0679) could lead to an increased 3-HP production in Synechocystis. CONCLUSIONS: The integrative analysis of up-regulated proteome and metabolome data showed that to ensure the high-efficient production of 3-HP and the normal growth of Synechocystis, multiple aspects of cells metabolism including energy, reducing power supply, central carbon metabolism, the stress responses and protein synthesis were enhanced in Synechocystis. The study provides an important basis for further engineering cyanobacteria for high 3-HP production. PMID- 27757170 TI - High cell density production of multimethyl-branched long-chain esters in Escherichia coli and determination of their physicochemical properties. AB - BACKGROUND: Microbial synthesis of oleochemicals derived from native fatty acid (FA) metabolism has presented significant advances in recent years. Even so, native FA biosynthetic pathways often provide a narrow variety of usually linear hydrocarbons, thus yielding end products with limited structural diversity. To overcome this limitation, we took advantage of a polyketide synthase-based system from Mycobacterium tuberculosis and developed an Escherichia coli platform with the capacity to synthesize multimethyl-branched long-chain esters (MBE) with novel chemical structures. RESULTS: With the aim to initiate the characterization of these novel waxy compounds, here, we describe the chassis optimization of the MBE producer E. coli strain for an up-scaled oil production. By carrying out systematic metabolic engineering, we improved the final titer to 138.1 +/- 5.3 mg MBE L-1 in batch cultures. Fed-batch microbial fermentation process was also optimized achieving a maximum yield of 790.2 +/- 6.9 mg MBE L-1 with a volumetric productivity of 15.8 +/- 1.1 mg MBE (L h)-1. Purified MBE oil was subjected to various physicochemical analyses, including differential scanning calorimetry (DSC) and pressurized-differential scanning calorimetry (P-DSC) studies. CONCLUSIONS: The analysis of the pour point, DSC, and P-DSC data obtained showed that bacterial MBE possess improved cold flow properties than several plant oils and some chemically modified derivatives, while exhibiting high oxidation stability at elevated temperatures. These encouraging data indicate that the presence of multiple methyl branches in these novel esters, indeed, conferred favorable properties which are superior to those of linear esters. PMID- 27757172 TI - Trends in the prevalence of self-reported diabetes in Brazilian capital cities and the Federal District, 2006-2014. AB - BACKGROUND: Diabetes is increasing globally, particularly in low and middle income countries, posing a great challenge to health systems. Brazil is currently ranked 4th in the world in terms of the absolute number of persons with diabetes. Our aim was to analyze the trend in self-reported diabetes prevalence between 2006 and 2014 in Brazilian adults. METHODS: We used data from the national telephone survey-VIGITEL. Over 40,000 individuals from probabilistic sample of subjects >=18 years old residing in 26 state capitals and the Federal District were interviewed per year in each location. Estimates were weighted to represent the surveyed population. We analyzed trends with a linear regression model. We adjusted prevalence with a probability predictive margins model, using as reference categories: men, 18-24 years, >=12 years of schooling and lean/normal weight. RESULTS: From 2006 to 2014, the overall prevalence increased from 5.5 to 8.0 %, a net rise of 0.26 %/year (P = 0.001). After adjustment for sex, age, schooling and BMI categories, the trend decreased only slightly to 0.25 %/year. Relatively greater adjusted increases were present in men (0.28 %/year), in those >=65 years (0.52 %/year), with <=8 years of schooling (0.33 %/year) and in those overweight (0.24 %/year). The most consistent upward trends were observed among men (coefficient of determination, R2 = 0.93), those with educational attainment of 0-8 years (R2 = 0.81), those > 65 years (R2 = 0.79) and those who were overweight (R2 = 0.75). There was no significant trend in diabetes prevalence for the obese. As expected, the prevalence of self-reported diabetes was always higher among those with greater age, less schooling, in women, and in those with obesity. Being obese was associated with having more than twice the prevalence of diabetes of those normal/underweight. CONCLUSIONS: Prevalence of self-reported diabetes in Brazilian adults has risen between 2006 and 2014, especially among those 65 years or older, even after taking into account the sociodemographic and nutritional changes during the period. Regardless of possible causes (higher incidence, increased diagnosis or decreased mortality), this increase in prevalence has enormous implications for the health system, representing >300,000 newly diagnosed cases of diabetes yearly requiring health care. PMID- 27757174 TI - Direct Needle Puncture and Embolization of Splenic Artery Pseudoaneurysm in Case of Chronic Atrophic Calcific Pancreatitis. AB - BACKGROUND: Gastro-Intestinal bleeding remains a frequent clinical dilemma and common cause of hospitalization, morbidity and mortality. CASE REPORT: We report a case of pseudo aneurysm of splenic artery developed after an episode of acute on chronic pancreatitis which was treated by direct percutaneous puncture of pseudoaneurysm and embolization by coils. CONCLUSIONS: The aim was to preserve the main splenic artery and avoid the complications of splenic artery embolization like infarcts and abscess. PMID- 27757175 TI - Sonographic Diagnosis in a Rare Aetiology of Neonatal Scrotal Swellings: A Case Report of Congenital Nephrotic Syndrome. AB - BACKGROUND: Common etiologies of scrotal swelling in neonates include hydrocoele, inguinal hernia and testicular torsion; less common is epididymo-orchitis. Congenital nephrotic syndrome (CNS), a rare entity, is known to present as progressive renal failure and its leading presentation with scrotal involvement has not been reported. MATERIAL/METHODS: We report a rare case of CNS with primary clinical presentation as scrotal cellulitis and epididymo-orchitis. In this neonate, scrotal and abdominal ultrasound examination was performed and the laboratory data were obtained. RESULTS: Sonography revealed bilaterally enlarged echogenic kidneys, testis and epididymis with echogenic peritoneal fluid tracking into both scrotal sacs. Laboratory data revealed proteinuria and severe depletion of serum IgG. Culture of the peritoneal fluid showed gram-negative organisms. A final diagnosis of CNS, complicated with peritonitis tracking into the scrotal sacs was arrived at. CONCLUSIONS: CNS may have a rare presentation with distracting symptoms of scrotal cellulitis and epididymo-orchitis, as seen in our patient. However, diligent use of abdomino-scrotal sonography, supported by relevant laboratory data can clinch the accurate diagnosis. PMID- 27757173 TI - Methylome analysis for spina bifida shows SOX18 hypomethylation as a risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development. AB - BACKGROUND: Neural tube defects (NTDs) are severe congenital malformations that arise from failure of neurulation during early embryonic development. The molecular basis underlying most human NTDs still remains largely unknown. Based on the hypothesis that folic acid prevents NTDs by stimulating methylation reactions, DNA methylation changes could play a role in NTDs. We performed a methylome analysis for patients with myelomeningocele (MMC). Using a candidate CpG analysis for HOX genes, a significant association between HOXB7 hypomethylation and MMC was found. METHODS: In the current study, we analyzed leukocyte methylome data of ten patients with MMC and six controls using Illumina Methylation Analyzer and WateRmelon R-packages and performed validation studies using larger MMC and control cohorts with Sequenom EpiTYPER. RESULTS: The methylome analysis showed 75 CpGs in 45 genes that are significantly differentially methylated in MMC patients. CpG-specific methylation differences were next replicated for the top six candidate genes ABAT, CNTNAP1, SLC1A6, SNED1, SOX18, and TEPP but only for the SOX18 locus a significant overall hypomethylation was observed (P value = 0.0003). Chemically induced DNA demethylation in HEK cells resulted in SOX18 hypomethylation and increased expression. Injection of sox18 mRNA in zebrafish resulted in abnormal neural tube formation. Quantification of DNA methylation for the SOX18 locus was also determined for five families where parents had normal methylation values compared to significant lower values for both the MMC as their non-affected child. SOX18 methylation studies were performed for a MMC patient with a paternally inherited chromosomal deletion that includes BMP4. The patient showed extreme SOX18 hypomethylation similar to his healthy mother while his father had normal methylation values. CONCLUSIONS: This is the first genome-wide methylation study in leukocytes for patients with NTDs. We report SOX18 as a novel MMC risk gene but our findings also suggest that SOX18 hypomethylation must interplay with environmental and (epi)genetic factors to cause NTDs. Further studies are needed that combine methylome data with next-generation sequencing approaches to unravel NTD etiology. PMID- 27757176 TI - Ultrasonography of Extravaginal Testicular Torsion in Neonates. AB - BACKGROUND: Extravaginal testicular torsion (ETT), also called prenatal or perinatal, occurs prenatally and is present at birth or appears within the first month of life. It has different etiology than intravaginal torsion, which appears later in life. Testicular torsion must be taken into consideration in differential diagnosis of acute scrotum and should be confirmed or ruled out at first diagnostic step. Ultrasonography is a basic imaging modality, however diagnostic pitfalls are still possible. There is still wide discussion concerning management of ETT, which varies from immediate orchiectomy to conservative treatment resulting in testicle atrophy. MATERIAL/METHODS: In this article we present ultrasonographic spectrum of ETT in neonates, which were diagnosed and treated in our hospital during the last 8 years (2008-2015), in correlation with clinical and intraoperative findings. RESULTS: Thirteen neonates with ETT were enrolled in the study - 11 patients with a single testicle affected and 2 patients with bilateral testicular torsion. Most common signs on clinical examination were: hardened and enlarged testicle and discoloration of the scrotum. Most common ultrasonographic signs were: abnormal size or echostructure of the affected testicle and absence of the blood flow in Doppler ultrasonography. In 3 patients ultrasound elastography was performed, which appeared very useful in testicle structure assessment. CONCLUSIONS: Testicular torsion may concern boys even in the perinatal period. Ultrasonographic picture of acute scrotum in young boys may be confused. Coexistence of the abnormal size or echostructure of the torsed testicle with absence of the blood flow in Doppler ultrasonography appear as very specific but late ultrasonographic sings. Ultrasound elastography may be a very useful tool for visualisation of a very common clinical sign - hardening of the necrotic testicle. PMID- 27757177 TI - Evaluation of the Anti-inflammatory Effects of Atorvastatin on Patients with Rheumatoid Arthritis: A Randomized Clinical Trial. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder with unknown etiology. Atorvastatin is a lipid-lowering agent that affects the inflammatory processes. OBJECTIVE: This study aimed to determine the anti inflammatory effects of atorvastatin on the Disease Activity Index and high density lipoprotein (HDL) concentrations in RA patients. METHODS: This clinical trial was performed on 38 RA patients, who were referred to the Imam Reza and Ghaem Medical Centers of Mashhad, Iran between 2013 and 2014. Patients were divided into two groups: 1) the intervention group, which received 40 mg of atorvastatin, and 2) the control group. Response to treatment and the clinical status of patients were evaluated using the Disease Activity Score (DAS-28) and Visual Analogue Scale (VAS) at weeks zero, four, eight, and twelve, based on the 2010 ACR/EULAR Criteria by two rheumatologists. Disease activity and laboratory parameters, including erythrocyte sedimentation rate (ESR), high-sensitivity C reactive protein (hs-CRP), DAS-ESR, DAS- hs-CRP, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and liver function test (LFT) were measured in both groups. RESULTS: There was a significant difference in the mean number of swollen joints (p<0.011), ESR (p <0.005), DAS-ESR (P<0.043), LDL (0.036), and HDL (0.016) between the two groups. The changes in trend showed no significant difference in the mean number of tender joints (p =0.38), VAS (p =0.715), CRP (p =0.07), DAS-hs-CRP (p=0.431), total cholesterol (p=0.285), or TG (p =0.331) between the two groups. However, the Disease Activity Index decreased by 48.4% in the intervention group, compared to 35.5% in the control group. CONCLUSION: As the results indicated, atorvastatin has a positive effect on the course of RA. In fact, atorvastatin, as an anti-inflammatory agent, could significantly influence inflammation in RA patients. Therefore, adding a lipid-lowering agent to standard medications in RA may be warranted and could decrease disease activity. CLINICAL TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (Website: http://www.irct.ir, Irct ID: IRCT2015122425648N2). FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 27757178 TI - The association between serum 25-hydroxyvitamin D level and recurrent falls in the elderly population: a cohort study. AB - INTRODUCTION: Serum vitamin D concentration is a major contributing factor for increasing the risk of fall and fall-related injuries in older adults. However, when prescribed and supplemented for these populations, the outcomes are controversial, and in several cases no improvement has been reported in reducing the risk of recurrent falls. This study aimed to examine the association between serum vitamin D concentration and recurrent falls in Iranian older adults. METHODS: This cohort study was conducted in the emergency departments of two university hospitals. A cohort of 82 elderly participants aged over 60 and suffered from an unintentional episode of falling was evaluated six months after their first ED visit. A structured, self-administered checklist was developed to obtain the participants' demographic and clinical information. Participants also were asked about any recurrent fall experience during follow-up. RESULTS: The mean (SD) age of the study population was 75 (8). Over half of the participants were male (57.3%). The mean (median) serum 25-hydroxyvitamin D (25 (OH)D) concentration was 38 (34) ng/ml. Mean serum 25(OH)D levels varied slightly between gender groups (p=0.450). An inverse but insignificant association was found between the age of participants and their serum 25(OH)D levels (r=-0.03, p=0.7). A small but insignificant association also was found between the mean serum 25(OH)D level and the number of recurrent falls in elderly patients irrespective of their age, gender, or physical activity groups (OR=1.008, p=0.992). CONCLUSION: In contrast to previous studies, no significant association of serum 25(OH)D concentration was found with recurrent falls in Iranian older adults. PMID- 27757179 TI - Factors influencing the adoption of health information technologies: a systematic review. AB - INTRODUCTION: The successful implementation of health information technologies requires investigating the factors affecting the acceptance and use of them. The aim of this study was to determine the most important factors affecting the adoption of health information technologies by doing a systematic review on the factors affecting the acceptance of health information technology. METHODS: This systematic review was conducted by searching the major databases, such as Google Scholar, Emerald, Science Direct, Web of Science, Pubmed, and Scopus. We used various keywords, such as adoption, use, acceptance of IT in medicine, hospitals, and IT theories in health services, and we also searched on the basis of several important technologies, such as Electronic Health Records (HER), Electronic Patient Records (EPR), Electronic Medical Records (EMR), Computerized Physician Order Entry (CPOE), Hospital Information System (HIS), Picture Archiving and Communication System (PACS), and others in the 2004-2014 period. RESULTS: The technology acceptance model (TAM) is the most important model used to identify the factors influencing the adoption of information technologies in the health system; also, the unified theory of acceptance and use of technology (UTAUT) model has had a lot of applications in recent years in the health system. Ease of use, usefulness, social impact, facilitating conditions, attitudes and behavior of users are effective in the adoption of health information technologies. CONCLUSION: By considering various factors, including ease of use, usefulness, and social impact, the rate of the adoption of health information technology can be increased. PMID- 27757180 TI - Herbal Medicines for the Management of Irritable Bowel Syndrome: A Systematic Review. AB - Irritable Bowel Syndrome (IBS) is a chronic digestive disorder, which is characterized by abdominal pain, bloating, diarrhea and constipation periods. The etiology is unknown. Based on the different mechanisms in the etiology, treatment focuses on controlling symptoms. Due to the longtime of syndrome, inadequacy of current treatments, financial burden for patients and pharmacologic effects, several patients have turned to the use of complementary and alternative medicine (CAM). Complementary and alternative treatments for IBS include hypnosis, acupuncture, cognitive behavior therapy, yoga, and herbal medicine. Herbal medicines can have therapeutic effects and adverse events in IBS. The aim of this study was to evaluate the efficacy of herbal medicines in the control of IBS, and their possible mechanisms of action were reviewed. Herbal medicines are an important part of the health care system in many developing countries It is important for physicians to understand some of the more common forms of CAM, because some herbs have side effects and some have interactions with conventional drugs. However herbal medicines may have therapeutic effects in IBS, and further clinical research is needed to assess its effectiveness and safety. PMID- 27757181 TI - Determination of intra-axial brain tumors cellularity through the analysis of T2 Relaxation time of brain tumors before surgery using MATLAB software. AB - INTRODUCTION: Timely diagnosis of brain tumors could considerably affect the process of patient treatment. To do so, para-clinical methods, particularly MRI, cannot be ignored. MRI has so far answered significant questions regarding tumor characteristics, as well as helping neurosurgeons. In order to detect the tumor cellularity, neuro-surgeons currently have to sample specimens by biopsy and then send them to the pathology unit. The aim of this study is to determine the tumor cellularity in the brain. METHODS: In this cross-sectional study, 32 patients (18 males and 14 females from 18-77 y/o) were admitted to the neurosurgery department of Shohada-E Tajrish Hospital in Tehran, Iran from April 2012 to February 2014. In addition to routine pulse sequences, T2W Multi echo pulse sequences were taken and the images were analyzed using the MATLAB software to determine the brain tumor cellularity, compared with the biopsy. RESULTS: These findings illustrate the need for more T2 relaxation time decreases, the higher classes of tumors will stand out in the designed table. In this study, the results show T2 relaxation time with a 85% diagnostic weight, compared with the biopsy, to determine the brain tumor cellularity (p<0.05). CONCLUSION: Our results indicate that the T2 relaxation time feature is the best method to distinguish and present the degree of intra-axial brain tumors cellularity (85% accuracy compared to biopsy). The use of more data is recommended in order to increase the percent accuracy of this techniques. PMID- 27757182 TI - Reallocation of Shafa Hospital Beds in Kerman Using Goal Programming Model. AB - INTRODUCTION: In order to improve health, hospital sources such as beds and staffing should be properly allocated and used. The aim of this study is reallocation of Shafa hospital beds in Kerman using a goal-programming model. METHODS: This study was an applied cross-sectional study, which used the goal programming model and software WinQSB to optimize bed allocation. By review of the literature and interviews with experts, the constraints in beds allocation were identified, and using the collected data the desired model was designed. RESULTS: Hospital beds were redistributed based on the constraints of the goal programming model and objectives. The results showed that there was a shortage of beds in departments such as burns, GICU, HICU, cardiac surgery, emergency, and orthopedics, and excess of beds in the ear, nose, and throat (ENT), ophthalmology, and neurology departments. CONCLUSION: It is anticipated that the optimal allocation of hospital beds, regarding hospital activity indicators, can lead to greater justice in the provision of services and a better distribution of resources. PMID- 27757183 TI - Investigating Knowledge Management Status among Faculty Members of Kerman University of Medical Sciences based on the Nonaka Model in 2015. AB - INTRODUCTION: Education and research are two major functions of universities, which require proper and systematic exploitation of available knowledge and information. Therefore, it is necessary to investigate the knowledge management status in an education system by considering the function of faculty members in creation and dissemination of knowledge. This study was conducted to investigate the knowledge management status among faculty members of the Kerman University of Medical Sciences based on the Nonaka and Takeuchi models in 2015. METHODS: This was a descriptive-analytical and cross-sectional study. It was conducted on 165 faculty members at the Kerman University of Medical Sciences, who were selected from seven faculties as weighted using a random stratified sampling method. The Nonaka and Takeuchi knowledge management questionnaire consists of 26 questions in four dimensions of socialization, externalization, internalization, and combination. Scoring of questions was conducted using the five-point Likert scale. To analyze data, independent t-test, one-way ANOVA, Pearson correlation coefficients, and the Kruskal-Wallis test were employed. RESULTS: The four dimensions in the Nonaka and Takeuchi model are based on optimal indicators (3.5), dimensions of combination, and externalization with an average of 3.3 were found in higher ranks and internalization and socialization had averages of 3.1 and 3. According to the findings of this study, the average knowledge management among faculty members of the Kerman University of Medical Sciences was estimated to be 3.1, with a bit difference compared to the average. According to the results of t-tests, there was no significant relationship between gender and various dimensions of knowledge management (p>0.05). The findings of Kruskal Wallis showed that there is no significant relationship between variables of age, academic rank, and type of faculty with regard to dimensions of knowledge management (p>0.05). In addition, according to the results of Pearson tests, there is no significant relation between employment history and dimensions of knowledge management (p>0.05). CONCLUSION: Considering the function and importance of knowledge management in education and research organizations including universities, it is recommended to pay comprehensive attention to establishment of knowledge management and knowledge sharing in universities and provide the required background to from research teams and communication networks inside and outside universities. PMID- 27757184 TI - Prevalence of Syphilis among Blood and Stem Cell Donors in Saudi Arabia: An Institutional Experience. AB - INTRODUCTION: Syphilis is one of the known transfusion-transmissible infections and causes 100,000 deaths yearly, with around 90% of these deaths occurring in the developing world. Little data is available regarding the prevalence of syphilis among Saudi blood and stem cell donors. We conducted a survey on the incidence of syphilis among all blood and stem cell donors. METHODS: This study was conducted at the Prince Sultan Military Medical City in Riyadh, Saudi Arabia in the 10 years period data during 2006-2015. Data were analyzed about full history, physical examination, age, sex, weight, profession, marital status, number of the donations, data of last donation, having a relation who received blood transfusion, as well as the screening test results of the donated blood. We determined the seroprevalence of infection and compared by sex and other variable through frequency analysis, Chi square, Fisher, and prevalence ratios. RESULTS: Approximately 240,000 blood donors were screened and studied in the period of study. Most of the blood donors were male (98.3%) and 89% of them were citizens of Saudi Arabia. According to our findings, we estimated that, in the last 10 years, approximately 0.044% of all the blood donors were syphilis positive cases. No cases were detected as positive for syphilis among stem cell donors. Only 60 blood donors tested positive for syphilis. In addition, we studied 202 stem cell transplant donors during the same period, of which 59% were male and none texted positive for syphilis. CONCLUSIONS: A concerted effort between the government, health care providers, regulatory bodies and accreditation agencies have all contributed in eliminating the risk of spreading syphilis among blood donors. PMID- 27757185 TI - Effect of aqueous and ethanolic extracts of Lippia citriodora on candida albicans. AB - INTRODUCTION: Because of resistance and side effects to common antifungal drugs activity, the research on herbal substances with antifungal activity is frequent. Lemon verbena (Lippia citriodora) is a member of Verbenaceae family. The aim of this study was to determine the anti-candida activities of the ethanolic and aqueous extracts of the lemon verbena leaves and compare them with nystatin and fluconazole. METHODS: In this 2015 study, 15 clinical isolates and standard strain of candida albicans PTCC 5027 were used, and the inhibitory effects of the ethanolic and aqueous extracts, Nystatin and Fluconazole, were evaluated using disk and well diffusion methods. Also, the minimal inhibitory concentration (MIC) was determined. Five concentrations of aqueous and ethanolic extracts (156-2500 MUg/ml), Nystatin (8-128 MUg/ml) and Fluconazole (4-64 MUg/ml) were used in disk and well diffusion methods, and nine concentrations of aqueous and ethanolic extracts (19-5000 MUg/ml), Nystatin (0.5-128 MUg/ml), and Fluconazole (0.25-64 MUg/ml) were applied for MIC. Data were analyzed using Tukey's post-hoc and one way ANOVA tests. The significant level was considered p < 0.05 in the current study. RESULTS: In the well and disk diffusion techniques, limited growth inhibition halos were produced around some clinical isolates at different concentrations of ethanolic extract; however, no growth inhibitory halo was observed with any concentrations of the aqueous extract. The MIC values of ethanolic extract, aqueous extract, Nystatin and Fluconazole for clinical isolated and standard strain were 833 +/- 78.5and 625MUg/ml; 4156 +/- 67.4 and 2500 MUg/ml; 10.13 +/- 1.91 and 4 MUg/ml; and 1.97 +/- 0.25 and 1 MUg/ml, respectively. CONCLUSION: The results showed that the ethanolic extract was stronger than the aqueous extract of this plant, which can be used as an alternative for drugs. It is recommended that the ethanolic extract of this plant be investigated in vivo for better evaluation of its efficacy and properties. PMID- 27757186 TI - Comparison of serum Concentration of Se, Pb, Mg, Cu, Zn, between MS patients and healthy controls. AB - INTRODUCTION: Multiple Sclerosis (MS) is defined as one of the inflammatory autoimmune disorders and is common. Its exact etiology is unclear. There are some evidences on the role of environmental factors in susceptible genetics. The aim of this study is to evaluate the possible role of Selenium, Zinc, Copper, Lead and Magnesium metals in Multiple Sclerosis patients. METHODS: In the present analytical cross-sectional study, 56 individuals including 26 patients and 30 healthy controls were enrolled in the evaluation. The serum level of Se, Zn, Cu, Pb were quantified in graphite furnace conditions and flame conditions by utilizing an atomic absorption Perkin Elmer spectrophotometer 3030. The serum levels of Mg were measured by auto analyzer 1500 BT. The mean level of minerals (Zn, Pb, Cu, Mg, Se) in serum samples were compared in both cases and controls. The mean level of minerals (Zn, Pb, Cu, Mg, Se) in serum samples were compared in both cases and controls by using independent-samples t-test for normal distribution and Mann-Whitney U test as a non-parametric test. All statistical analyses were carried out using SPSS 11.0. RESULTS: As well as the Zn, Cu, and Se, there was no significant difference between MS patients and healthy individuals in Pb concentrations (p-value = 0.11, 0.14, 0.32, 0.20 respectively) but the level of Mg was significantly different (p= 0.001). CONCLUSION: All serum concentrations of Zn, Pb, Se, Cu in both groups were in normal ranges and there was no difference in MS patients compared with the healthy group who were matched in genetics. Blood level of Mg was significantly lower in MS patients. But it should be noted that even with the low level of serum magnesium in MS patients, this value is still in the normal range. PMID- 27757187 TI - Diagnostic Value of Electrocardiogram in Predicting Exaggerated Blood Pressure Response to Exercise Stress Testing. AB - INTRODUCTION: It is believed that an exaggerated blood pressure response (EBPR) to exercise stress test is associated with a higher risk of cardiovascular events. It is also assumed that QT dispersion (QT-d), which was originally proposed to measure the spatial dispersion of ventricular recovery times, may have a relationship to cardiovascular events. The objective of this study was to examine the difference of changes in QT-d, Maxi-QT, Mini-QT, and QT-c (corrected QT interval) of the electrocardiogram in two groups of patients with exaggerated blood pressure responses (EBPR group) and normal responses (control group) to exercise testing. Also, the diagnostic value of each of these criteria in the prediction of EBPR was studied. METHODS: This cross-sectional study was conducted from May 2015 to February 2016 on patients suspected of coronary artery disease (CAD) undergoing exercise testing who had been referred to Ghaem and Imam Reza hospitals in Mashhad (Iran). All patients underwent a treadmill exercise test with the 12-lead ECG, which was optically scanned and digitized for analysis of QT-d, QT max, and QT min. Patients were divided into two groups of normal and EBPR to exercise testing. QT changes of ECG were compared between the two groups, and the diagnostic accuracy of QT variables for prediction of EBPR to exercise testing was studied. A multiple linear regression analysis (MLR), Pearson Chi qquare, independent samples t-test, and receiver operating characteristic (ROC) curve were used as statistical methods in IBM SPSS version 19. RESULTS: Sixty patients (55% male) with a mean age of 50.48 +/- 10.89 years were studied in two groups of normal (n=30) and exaggerated blood pressure response (n=30) to exercise testing. Maximum QT and QT dispersion were statistically different in individuals' exaggerated blood pressure response to exercise stress test (p < 0.05). The logistic regression analysis revealed that none of our parameters predicted the EBPR. The ROC curve showed that 50 and 345 milliseconds for QT dispersion and Maxi-QT were the optimal cut-off points for the prediction of EBPR. CONCLUSION: It seems that Maxi-QT and QT-d may be predictors of EBPR during exercise testing. Also, a significant difference in maxi-QT and QT-d was observed between two groups of patients with normal and EBPR during the exercise testing. PMID- 27757188 TI - Detection of Bisphenol A and Nonylphenol in Rat's Blood Serum, Tissue and Impact on Reproductive System. AB - INTRODUCTION: Bisphenol A (BPA) and Nonylphenol (NP) have estrogen-like activity, and some of their adverse biological effects have been demonstrated. This study was designed to determine the association of plasma and tissue concentrations of BPA and NP and changes in the parameters of the reproductive system in rats. METHODS: Male Wistar rats were administered three doses of BPA and NP (5, 25, and 125 MUg/kg) by gavage for 35 consecutive days in 2014-2015, and a 2-ml blood sample was taken from each treated rat. Concentrations of BPA and NP in the blood were determined using the HPLC-fluorescence detection method. The sperm are produced in the epididymis and vas deferens, and they swim up in Ham's F10 solution, and, then, various parameters were evaluated using an invert microscope, and they included the count, motility, and morphology of the sperm. RESULTS: The weight of the testes and prostate in the rats receiving BPA and NP treatment showed significant decreases compared to the control group. Similarly, NP created higher concentration than BPA in the serum (e.g., 5.48 +/- 0.65 vs. 1.36 +/- 0.25, at 125 MUg/kg). Compared to the control group, dose-dependent significant decreases in count and motility in the sperm were observed following the administration of BPA (25 and 125 MUg/kg) and NP (all three doses). Morphologic aspects of the rats' sperm were changed in various doses of BPA and NP. CONCLUSIONS: According to our findings, BPA and NP induced dose-dependent toxic effects on various parameters, i.e., sperm toxicity, weight of the testes, and weight of the prostate gland. PMID- 27757189 TI - Diagnostic value of computerized tomography venography in detecting stenosis and occlusion of subclavian vein and superior vena in chronic renal failure patients. AB - INTRODUCTION: Currently, venography is the standard diagnostic method to examine veins before implementing access, which is invasive in nature. Computerized tomography venography (CTV) can simultaneously indicate deep and superficial venous systems in the upper extremity and their relation to the surrounding anatomical structures; however, its diagnostic value in the detection of central venous disease has yet to be defined. The aim of this study was to determine the diagnostic value of CT venography compared to venography in the diagnosis of stenosis and the occlusion of subclavian veins and the superior vena in renal failure patients. METHODS: This cross-sectional study was conducted from January to September 2015 on patients with chronic renal failure undergoing upper extremity venography at the Radiology Department of Imam Reza Hospital in Mashhad, Iran. We excluded patients with catheters in their jugular and subclavian vein routes, venous hypertension with reverse-function fistula, or sensitivity to contrast agents. Several factors, including age, gender, catheterization record in jugular and subclavian veins, and fistula record in the upper extremity, as well as clinical symptoms consisting of edema, dermatitis, and ulcers in these organs, were recorded in the corresponding form. Then, the patients consecutively underwent indirect venography and CT venography and traces of stenosis (more than 50%) or complete occlusion in the subclavian vein and superior vena were recorded. The data were analyzed using SPSS software by the chi-squared test, and sensitivity, specificity, and positive and negative predictive values were calculated by means of MedCalc Online, version 16.2. RESULTS: The study was conducted on 40 patients (26 males and 14 females) with a mean age of 46.7 +/- 10.4 years. In this study, 58 subclavian veins, as well as 32 superior vena cava, were studied. The results showed that the diagnostic value of CTV in the detection of subclavian stenosis had a sensitivity and a specificity of 88.2 and 97.5%, respectively. Moreover, in the superior vena cava, the greatest CTV diagnostic sensitivity and specificity was related to vein stenosis detection (sensitivity = 88.8%; specificity = 100%). CONCLUSION: It seems that the CTV, based on its high sensitivity, specificity, and predictive value, can be used as an efficient tool in the study of stenosis in subclavian veins and superior vena in patients undergoing venography. PMID- 27757190 TI - The effect of diagnostic amniocentesis and its complications on early spontaneous abortion. AB - INTRODUCTION: The occurrence of early abortion after amniocentesis is a serious problem in the fields of obstetrics and gynecology, and it is always important to discover the factors influencing this phenomenon. The incidence rate has been reported in different studies, even up to about 10%. So far, no studies have been conducted in Iran on the effect of amniocentesis and related complications on early abortion. The aim of this study was to determine the effects of amniocentesis and relevant complications on the incidence of early abortion in pregnant women undergoing amniocentesis. METHODS: This cohort study was conducted between March 2014 and March 2016 on pregnant candidates for amniocentesis referred to the perinatology clinic at Ommol-Banin Hospital, Mashhad, Iran. Amniocentesis was performed for all patients with about 20-30cc in the same manner by a perinatologist. Maternal blood group, causes of amniocentesis, amniotic fluid profile (liquid color), status of inserting the needle through the placenta during amniocentesis, amniotic fluid leakage, and bleeding after amniocentesis were considered as exposure factors, and spontaneous abortion after amniocentesis until the end of the 20th week of pregnancy was taken as a consequence. Data were analyzed using IBM-SPSS version 20 via t-test and chi square. Relative risk (RR) was calculated to determine the causal relationship of exposure with the consequences of spontaneous abortion during the first week after amniocentesis. RESULTS: This study was performed on 1000 pregnant women with mean age of 33.4+/-6.0 years (minimum 16, maximum 48 years). The incidence rate of spontaneous abortion after amniocentesis was obtained 1%. There was no association among causes of amniocentesis, maternal blood group, maternal underlying diseases, history of diseases associated with pregnancy, and spontaneous abortion. Based on the chi-square test, a significant statistical relationship was found between amniotic fluid leakage and spontaneous abortion (RR=15.37, p=0.001). There was also a significant statistical relationship between bleeding after amniocentesis and spontaneous abortion; so that in patients with more bleeding, spontaneous abortion was more prevalent (RR=6.83, P=0.001). CONCLUSION: According to the results, it seems that amniotic fluid leakage and bleeding after amniocentesis should be considered as two serious complications of amniocentesis, which can cause the incidence of spontaneous abortion in pregnant patients undergoing amniocentesis. PMID- 27757192 TI - Multiple bilateral pulmonary nodules masquerading as pulmonary metastasis; a case of nodular sarcoidosis. AB - Sarcoidosis is a multi-system inflammatory disorder of unknown etiology that is manifested by the presence of non-caseating granulomas. Multiple pulmonary nodules are rare presentations of sarcoidosis. We report a case of nodular sarcoidosis in a young male of Middle-East origin who had initially presented with bilateral painful ankle edema. His chest X-ray showed multiple bilateral pulmonary nodules. A high resolution computed tomography scan of the chest demonstrated multiple pulmonary nodular lesions and also mediastinal and hilar lymphadenopathy. Subsequent biopsies revealed non-necrotizing granuloma with multi-nucleated giant cells indicative of sarcoidosis. An appropriate work-up was done to confirm the true nature of the nodules and facilitate treatment. PMID- 27757193 TI - Giant Cell Tumor of Tendon Sheath in the Knee. AB - The giant cell tumor of the tendon sheath (GCTTS) is a benign lesion which arises from the synovium of a joint, bursa or tendon sheath, with 85% of the tumors occurring in the fingers and 12% of the tumors located in large joints such as the knee and ankle. The GCTTS is usually monoarticular, slowly proliferative and rarely locally aggressive. This paper reports three cases of this rare lesion in the knee. Patients presented with painful swelling in the anterior knee, MRI showed localized soft tissue masses which were able to be excised. A follow up of the cases showed no recurrences. This case report emphasizes the importance of considering GCTTS in the differential diagnosis of soft tissue swelling and pain in large joints. PMID- 27757191 TI - Barriers Against Implementing Blunt Abdominal Trauma Guidelines in a Hospital: A Qualitative Study. AB - INTRODUCTION: Clinical practice guidelines are structured recommendations that help physicians and patients to make proper decisions when dealing with a specific clinical condition. Because blunt abdominal trauma causes a various range of mild, single-system, and multisystem injuries, early detection will help to reduce mortality and resulting disability. Emergency treatment should be initiated based on CPGs. This study aimed to determine the variables affecting implementing blunt abdominal trauma CPGs in an Iranian hospital. METHODS: This study was conducted as a qualitative and phenomenology study in the Family Hospital in Tehran (Iran) in 2015. The research population included eight experts and key people in the area of blunt abdominal trauma clinical practice guidelines. Sampling was based on purposive and nonrandom methods. A semistructured interview was done for the data collection. A framework method was applied for the data analysis by using Atlas.ti software. RESULTS: After framework analyzing and various reviewing and deleting and combining the codes from 251 codes obtained, 15 families and five super families were extracted, including technical knowledge barriers, economical barriers, barriers related to deployment and monitoring, political will barriers, and managing barriers. CONCLUSION: Structural reform is needed for eliminating the defects available in the healthcare system. As with most of the codes, subconcepts and concepts are classified into the field of human resources; it seems that the education and knowledge will be more important than other resources such as capital and equipment. PMID- 27757194 TI - Correlation between inner strength and health-promoting behaviors in women with heart failure. AB - INTRODUCTION: Inner strength is a factor for mental health and well-being and, consequently, a dynamic component of holistic healing. Health-promoting behaviors are appropriate activities to improve health status and prevent the progression of the functional defect resulting from heart failure. The present study aimed to determine the correlation between inner strength and health-promoting behaviors in women with heart failure referred to hospitals affiliated with Shahid Beheshti University of Medical Sciences (SBMU) in 2013. METHODS: In this cross-sectional study, 145 women with hearth failure were selected through convenient sampling from the clients referred to hospitals affiliated with SBMU. The data collection tool included a three-section questionnaire of personal characteristics, inner strength, and health-promoting life profile II (HPLP II). The data analysis used descriptive statistical tests and Pearson correlation coefficient through SPSS version 20. RESULTS: A direct significant correlation was found between inner strength and all dimensions of health-promoting behaviors and overall health promoting behaviors (p=0.000) as well as between all dimensions of inner strength (except for the dimension of knowing and searching with physical activity and the dimension of connectedness with personal accountability in healthcare as well as connectedness with physical activity) with health-promoting behaviors (p=0.000 to p=0008). CONCLUSION: To improve the level of health and well-being and reduce the costs of care services in women with health failure, close attention should be paid to developing and empowering their inner strength. PMID- 27757195 TI - Comparison between the efficacy of metronidazole vaginal gel and Berberis vulgaris (Berberis vulgaris) combined with metronidazole gel alone in the treatment of bacterial vaginosis. AB - BACKGROUND: Bacterial vaginosis is one of the most prevalent complications among reproductive-aged women. Antibacterial and antifungal effects of Berberis vulgaris have been demonstrated in vitro and in vivo. OBJECTIVES: This study aimed to compare the therapeutic effects of the vaginal gel of Berberis vulgaris 5% (in metronidazole base) with metronidazole vaginal gel 0.75% on bacterial vaginosis on 80 patients referred to the Hajar Hospital from January 2012 to April 2013. METHODS: This study was a randomized clinical trial research on 80 women affected by bacterial vaginosis, who were randomly divided into two groups of 40 participants. Diagnostic criteria were Amsel's criteria and Gram stain. Berberis vulgaris 5% (in metronidazole gel base) or metronidazole vaginal gel for five-night usage was prescribed to each group, and after two to seven days therapeutic effects and Amsel criteria were assessed. Data analysis was performed by SPSS 16 using Student t-test, chi-square, and ANOVA tests. RESULTS: Findings of the study showed a statistically significant difference with regard to treatment response between the study groups (p<0.001), and the Berberis vulgaris group had a better response than the metronidazole gel group. The patients in groups of Berberis vulgaris in a metronidazole gel base did not experience any relapse, but, in the metronidazole group, 30% of patients experienced relapse during three weeks' follow-up. CONCLUSIONS: Findings of the study showed that adding Berberis vulgaris fruit extract on metronidazole improve the efficacy of bacterial vaginosis therapy. CLINICAL TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT201411102085N13. FUNDING: Shahrekord University of Medical Sciences supported this research. PMID- 27757196 TI - Rh factor is associated with individual radiosensitivity: A cytogenetic study. AB - INTRODUCTION: Radiosensitivity is an inherent trait, associated with a raised reaction to ionizing radiation on the human body. In radiotherapy and radiation protection fields, individualization of the patient's treatment is one of the main topics. With the goal of determining biomarkers capable of anticipating normal tissue side reactions, we studied the association between the Rh factor and radiosensitivity. METHODS: This experimental study was carried out from January to June 2014 among 50 normal responders with A blood group (25Rh+ and 25Rh-) between the ages of 22 and 23 in Babol, Iran. Human peripheral blood samples were taken from subjects and, using CBMN assay, the biological effects of gamma irradiation, including the frequency of micronuclei (MN) and nuclear division index (NDI), were measured. A data analysis was performed using SPSS version 18 to determine the independent and paired samples t-tests. RESULTS: A significant increment occurred in the frequency of MN in group Rh+ (196 +/- 18.23) compared with Rh- (169 +/- 17.11) following irradiation (p<0.001). CONCLUSIONS: The Rh factor might be a predicting marker in an individual's radiosensitivity to ionizing radiations. However, we believe that additional investigations are needed to prove this hypothesis. PMID- 27757197 TI - Predictive ability of C-reactive protein for stroke. PMID- 27757199 TI - A five-year study on the epidemiological approaches to cholera in Iran. AB - BACKGROUND: Cholera is considered a key indicator of social development but still is reported in various cities of Iran. The present study aimed to analyze the available information regarding cholera outbreaks since 2010 in Iran. METHODS: All cases reported to the Center for Disease Control and Prevention of Ministry of Health and Education who had been confirmed as cholera cases by the Health Reference Laboratory, were entered into this study since 2010. A specific spreadsheet was designed to ensure the safe keeping of the patient records. RESULTS: A total of 1522 patients were clinically diagnosed as cholera with laboratory confirmation over the study period. Cholera was detected in 26 Provinces and 115 cities during this period. Mean age of the patients was 35.1+/ 17, both the Inaba and Ogawa strains were isolated. The highest mortality and the morbidity rate was 1.98% in 2013. The most cholera prevalent provinces in order of frequency were Baluchistan, Alborz, Gilan, Golestan and Qom, as well as Tehran. Inaba serotype was the most common cause of mortality and morbidity in 2013. CONCLUSION: These findings indicate significant outbreaks of cholera in some of the provinces of Iran and warrant appropriate treatment and preventive measures. PMID- 27757198 TI - Determinants of pain in patients with symptomatic knee osteoarthritis. AB - BACKGROUND: Several factors are associated with the development or exacerbation of pain in knee osteoarthritis (KOA). In this study, we reviewed this context based on relevant studies. METHODS: Recent published studies which have addressed the relationship between pain and KOA were summarized. RESULTS: Correlates of the clinical, demographic features, laboratory tests and abnormalities on radiographic as well as magnetic resonance imaging (MRI) with the knee pain have been discussed. The results indicated that many factors such as synovitis, synovial effusion, obesity, as well as structural lesions determined by MRI or radiographic examination, serum cytokines, inflammatory markers are determinants of pain in KOA. CONCLUSION: This context requires further investigations for identification of additional factors which initiate pain in asymptomatic KOA. PMID- 27757200 TI - Serum vitamin D in hypertensive patients versus healthy controls is there an association? AB - BACKGROUND: Both vitamin D deficiency and hypertension are prevalent in the general population. Several observations indicate an association between vitamin D deficiency and high blood pressure. The present case-control study aimed to compare serum 25-hydroxyvitamin D (25-OHD) in hypertensive patients versus healthy controls. METHODS: One hundred patients aged 30-60 years with hypertension (HTN) and 100 healthy controls without history of hypertention were compared regarding serum 25-OHD. Blood pressure was measured using standard method and the systolic and diastolic blood pressure more than140 mmHg and 90 mmHg respectively were considered as HTN. Patients and controls with coexistent morbidities, vitamin D supplementation were excluded. The serum levels of 25-OHD, PTH and calcium were measured after obtaining a written informed consent from the patients and taking their blood pressure under standard conditions. In statistical analysis, the two groups were compared using independent t test and chi-square test using SPSS Version 18. RESULTS: The mean age of patients and controls was comparable (53.7+/-6.4 vs 52.3+/-7.54 years, P=0.17). Serum 25-OHD in HTN was significantly higher than controls (P=0.001). CONCLUSION: In the present study, serum 25-OHD level in hypertension was higher than controls. The results contradict with earlier studies indicating an association of HTN with vitamin D deficiency. This issue warrants further investigations in particular the follow-up of serum 25-OHD deficient and sufficient subjects with regard to the development of HTN. PMID- 27757201 TI - The effect of serum vitamin D normalization in preventing recurrences of benign paroxysmal positional vertigo: A case-control study. AB - BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is a condition with recurrent attacks in a significant proportion of patients. The present case- control study was conducted to assess the influence of serum vitamin D normalization on recurrent attacks of vitamin D deficient patients. METHODS: Diagnosis of BPPV was made based on history and clinical examination and exclusion of other conditions. Serum 25-hydroxy vitamin D (25-OHD) was measured using ELISA method and a levels of < 20 ng/ml was considered a deficiency of vitamin D. Inclusion criteria were as follows: history of recurrent attacks and serum 25-OHD<20.ng/ml. While the patients with history of trauma, surgery and chronic systemic diseases were excluded. The patients were classified into two groups: treatment and control, intermittently. Both groups received Epley rehabilitation therapy one session per week for 4 weeks but the treatment group received an additional supplement of 50.000 IU of vitamin D (cholecalciferol) weekly for two months to achieve serum 25-OHD >= 30 ng/ml and the study patients were followed-up for 6 months. RESULTS: Twenty-seven patients were allocated to each group. At baseline, serum 25-OHD was similar (10.7+/-2.3 vs 11.41+/-1.9, P=0.23). At month 2, serum 25-OHD in the treatment group increased significantly to >= 30 ng/ ml, whereas serum 25-OHD in the control group remained unchanged (34.2+/-3.3 vs 10.6 10.6+/-2.2 ng/ml, P=0.001). During the follow-up period, attacks of BPPV in the treatment group decreased significantly compared with the control group (14.8% vs 96.3% OR= 0.18, P=0.001). CONCLUSION: The findings of this study indicate that the normalization of serum vitamin D significantly reduces BPPV recurrences. PMID- 27757202 TI - Evaluation of soluble human leukocyte antigen-G in peripheral blood of pregnant women with gestational diabetes mellitus. AB - BACKGROUND: Research says that diabetes may develop in over 10% of non-diabetic pregnant women. Diabetes which generally occurs late in second trimester and third trimester of pregnancy, it is called gestational diabetes. Overweight or suffering from obesity before pregnancy is type 2 diabetes risk factor. In most cases, diabetic symptoms disappear after delivery. HLA-G has an important role both in mother and fetus tolerance during pregnancy, it may also be effective in the protection of pancreatic islet cells. In this study, concentration of these molecules in pregnant women with gestational diabetes in comparison with normal pregnant women was investigated. METHODS: In this case-control study, we measured serum HLA-G levels in 24 pregnant women with gestational diabetes compared with 30 normal pregnant women using sandwich ELISA. RESULTS: HLA-G levels were significantly low in pregnant women with gestational diabetes in contrast to normal pregnant women (P=0.001). CONCLUSION: In this study, we found that HLA-G levels were reduced in women with gestational diabetes compared with control group. Therefore, it is suggested that measurement of HLA-G in pregnant women can be considered as an indicator in prognosis of gestational diabetes. PMID- 27757203 TI - Expression of estrogen and progesterone receptors in papillary thyroid carcinoma. AB - BACKGROUND: Papillary thyroid carcinoma (PTC), occurs mostly in women and sex hormones may play a role in the pathogenesis and clinical course. The objective of this study was to determine the status and prevalence of estrogen and progesterone receptors in PTC with regard to age, gender, tumor size and lymph node involvement. METHODS: Immunohistochemical stains were performed on 92 tissue blocks of PTC for estrogen receptor (ER) and progesterone receptor (PR) expression in tumor cells. Chi-square test and Mann-Whitney U test were used to determine statistical difference using statistical software SPSS. RESULTS: The mean age of patients was 39.32+/-1.7 years (range 13-80) with 79(85.9%) women and 13 (14.1%) men. Lymph node involvement was seen in 76.1% of patients. The average tumor size was 3.6+/-2.21 cm. The rate of ER and PR expression were 46.75% and 5.6%, respectively. ER expression for females was higher than males (P=0.014), but no relation was found between males and females in PR expression (P=0.7). Also there was no statistical difference between ER and PR expression with respect to age, lymph node involvement and tumor size. CONCLUSION: Our study showed higher ER expression in females than males with PTC. No relation was found between the expression of these receptors and age of presentation, lymph node involvement and tumor size. Further investigation is required to determine the prognostic importance of ER and PR in PTC. PMID- 27757204 TI - The effect of green tea consumption on oxidative stress markers and cognitive function in patients with Alzheimer's disease: A prospective intervention study. AB - BACKGROUND: Alzheimer's disease (AD) is the most prevalent degenerative disorder of the brain among elderly individuals. Many studies indicate that oxidative stress is an important pathogenic factor which involves oxidizing macromolecules such as DNA, lipids, and proteins in AD. Green tea is a rich source of antioxidant compounds that can remove radical oxygen species. The purpose of this study was to investigate the influence of green tea consumption on markers of oxidative stress in AD. METHODS: In this prospective intervention study, 30 patients with severe AD were recruited. The diagnosis of AD was made based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association (NINCDS/ADRDA) criteria. Brain magnetic resonance imaging (MRI) and computed tomography (CT) scan as well as Mini-Mental State Examination (MMSE) were performed for all participants in which four green tea pills were administered daily for 2 months (2 g/day in 2 divided doses). The plasma total antioxidant capacity, 8-hydroxy-2' deoxyguanosine levels (8-OHdG), malondialdehyde (MDA), carbonyl content, and MMSE scores were measured at baseline and at the end of the study period. RESULTS: The levels of MDA, 8-OHdG and carbonyl decreased significantly as compared to baseline values (P=0.002, P=0.001 and P=0.037, respectively). Whereas, the total antioxidant capacity of plasma and MMSE scores significantly increased at end point (P=0.000, P=0.043, respectively). CONCLUSION: The findings indicate that consumption of green tea for two months by with the improvement of antioxidant system exerts beneficial effect on cognitive function. PMID- 27757205 TI - Metabolic syndrome in lupus patients in northeast of Iran, and their lifestyle habits. AB - BACKGROUND: Systemic lupus erythematous is an autoimmune disease associated with atherosclerotic manifestations or metabolic disturbance due to inflammation. The aim of this study was to determine frequency of metabolic syndrome (MetS) in SLE compared to healthy controls. METHODS: In this cross-sectional study, 150 SLE patients and 220 healthy volunteers were enrolled. MetS was diagnosed according to ATPIII criteria. Patients and controls were compared according to prevalence of MetS. In addition, SLE patients with and without MetS were compared according to laboratory parameters. Each patient also fulfilled a checklist about routine daily activities and diet program. Data were analyzed by SPSS-11 software. RESULTS: MetS was significantly lower in SLE than healthy controls (18% vs 29.1%, P=0.015). Disease manifestations, major organ involvement, serum values of complements and anti-DNA antibody and pharmacological therapy did not correlate with MetS occurrence in patients. The mean TG, FBS, systolic and diastolic BP were statistically higher in lupus patients compared to healthy volunteers in contrast to waist circumference. HDL-cholesterol serum values did not show any significant difference between two groups. CONCLUSION: It seems that despite higher values of blood pressure, serum lipids and glucose in lupus patients, the cumulative metabolic components were in a manner to make MetS more prevalent in healthy volunteers. As far as life habits are concerned, lupus patients in general did not exercise enough and did not go on a healthy diet despite of glucocorticoid therapy and hypertension. PMID- 27757206 TI - Efficacy of alum for treatment of recurrent aphthous stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is the most common painful ulcers of oral mucosal which can cause many sufferings. Treatment of RAS often includes administration of corticosteroids, analgesics and regulators of the immune system. However, considering the side effects of these medications, even their topical application must be done with caution. Alum is used in traditional medicine for treatment of oral ulcers without significant side effect. This study sought to assess the effect of topical application of alum on aphthous ulcers. METHODS: This clinical randomized double-blind placebo-controlled study was conducted on 50 females aged 21 to 27 years. Mucosal adhesive patches were prepared in two forms of basic and 7% alum-containing patches. Subjects in two groups of case and control randomly received the mucosal adhesive patches containing alum and the basic patches, respectively three times in five days. Duration of recovery, changes in size of lesion and severity of pain were recorded. Data were entered into SPSS Version 16 and analyzed using t-test. RESULTS: The average period of full recovery was 7.52 days in the case and 12.2 days in the control groups; which was significantly different (p<0.001). Size of wound and severity of pain were significantly lower at one, three and five days posttreatment compared to baseline values before treatment in the case group (p<0.001) and the difference in this regard between the case and control groups was statistically significant. CONCLUSION: Alum can significantly decrease the size of aphthous lesions, severity of pain and expedite the recovery of patients with RAS. PMID- 27757207 TI - Ability of serum C-reactive protein and white blood cell cout in predicting acute schemic stroke. A short -term follow-up study. AB - BACKGROUND: Stroke is one of the leading causes of mortality and long-term morbidity. The aim of the present study was to determine the ability of baseline serum C-reactive protein (CRP) and white blood cell count (WBC) values in predicting the outcome of acute ischemic stroke (AIS). METHODS: This study consisted of patients with first AIS referred to Poursina Hospital, Rasht, Iran. Severity of stroke was determined according to the National Institute of Health (NIH) Stroke Scale at the time of admission. Serum CRP levels and WBC count were measured at the time of admission. All patients were followed-up for 90 days after discharge and the severity of stroke was assessed using modified Rankin Scale. Receiver operating characteristic curve analysis was used for calculating the most appropriate cutoff point of CRP and WBC count for differentiating patients with and without poor outcome at the end of the study period. RESULTS: A total of 53 out of 102 patients (52%) had poor outcome. The most appropriate cutoff value for CRP in differentiating patients with and without poor outcome was 8.5mg/l (sensitivity: 73.1%, specificity: 69.4%) and for WBC the difference did not reach to a significant level. The cutoff points of CRP > 10.5 mg/ml yielded a predictive ability at sensitivity: 75%, specificity: 63.8% whereas predictive ability of WBC for mortality was at a borderline level. CONCLUSION: These findings indicate that high levels of serum CRP in AIS at the time of admission is associated with poor prognosis. However, this study found no ability for WBC in predicting AIS outcome. PMID- 27757208 TI - Comparison of early and late intravenous gamma globulin treatment of Kawasaki disease on fever and cardiovascular complications. AB - BACKGROUND: Cardiac involvement was the major leading cause of death in patients with Kawasaki and IVIG administration reduces cardiac complications. The objective of this study was to determine the frequency of cardiovascular complications and duration of fever with regard to the time of intravenous immunoglobulin (IVIG) administration of patients with Kawasaki disease. METHODS: This follow-up study was done on all patients with Kawasaki disease who were hospitalized at Amirkola Children's Hospital between 2006 and 2011. Diagnosis of Kawasaki was clinical and included fever more than 5 days with 4 of 5 signs containing mucosal changes, scaling and skin rash, bilateral nonexudative conjunctivitis, cervical lymph adenopathy and edema in lower extremities. After diagnosis of Kawasaki, all patients received standard treatment (intravenous immunoglobulins and aspirin) and undergoing cardiac echocardiography in 2 weeks, 2 months and 6 months. Information including age, sex, sign of diseases, laboratory findings, and cardiac complications in echocardiography were recorded. RESULTS: This study was performed on 100 patients (61 boys and 39 girls) with Kawasaki disease. The mean age of children was 2.8+/-2.6 years. Cardiac complication rate was 47% at the onset of the disease and had reached to 7% at the end of the sixth month (P=0.000). Distribution of cardiovascular complications in the second week, the second month and the sixth month after treatment was not significantly different according to the start of time of treatment (p>0.05). Duration of fever in patients who received treatment before 10th day (1.5+/-1.3) did not have significant difference (P=0.78) with patients who received after 10th day (1.6+/-0.9). CONCLUSION: Result shows that most of patients (99%) responded to the treatment with IVIG and ASA and cardiovascular complication ratio decreased. There was not significant relationship between duration of fever and time of IVIG treatment initiation. PMID- 27757209 TI - Splenic cysts: Analysis of 16 cases. AB - BACKGROUND: Splenic cysts are known as rare clinical encounter. Classifying into primary (true) and secondary cysts (pseudocysts), true cysts contain cellular epithelial lining and subdivided into parasitic and non-parasitic cysts. This study aimed to determine the outcome of treatment in patients with splenic cyst. METHODS: All patients with splenic cyst who had been treated in Department of General Surgery of Ghaem and Omid teaching hospitals over a 24-year period were identified. The medical records of these 16 patients were reviewed. RESULTS: The study patients included 11 females (68.75%) and 5 males (31.25%) with average age of 39.8 years. Fifteen cases had true cyst including 11 parasitic cysts (hydatid) and only one pseudocyst. 37.5% of the splenic cysts had coexistent cysts in liver, pelvis, omentum and paracolic regions. Nine patients underwent total splenectomy and 5 cases partial splenectomy and 2 remaining cases received conservative medical treatment. The size of the cysts varied from 6 to 25 centimeter with average size of 14.3 centimeter. All patients with hydatid cysts received albendazole postoperative medical treatment with albendazole for 6 months. All patients recovered after treatment. CONCLUSION: Open splenectomy whether total or partial is effective and safe in patients with splenec cysts with or without hydatidosis. The outcome of treatment is good without recurrences. PMID- 27757210 TI - A man with dilated superficial abdominal veins: A clinical presentation of non Hodgkin lymphoma. AB - BACKGROUND: The clinical presentation of non-Hodgkin lymphoma (NHL) varies tremendously depending upon the type of lymphoma and the areas of involvement. NHL can rarely present as an abdominal mass compressing the inferior vena cava. The clinical presentation due to obstruction of inferior vena cava has often been called the inferior vena cava syndrome (IVCS). It can present acutely or chronically. CASE PRESENTATION: A 35-year-old male presented with 3 months history of fever, anorexia, weight loss and abdominal discomfort. His abdominal examination showed dilated superficial veins with blood flowing rostrally. CECT abdomen revealed multiple enlarged some necrotic, retroperitoneal lymph nodes. The inferior vena cava was noted to be compressed by the lymph nodes. The lymph node biopsy revealed non- Hodgkin lymphoma, precursor B cell. CONCLUSION: An abdominal mass compressing the inferior vena cava is a rare but possible cause for appearance of dilated superficial abdominal veins and should be looked for. PMID- 27757211 TI - An unusual presentation of spinal dural arteriovenous fistula: A case report. AB - BACKGROUND: Spinal dural AVF is the most common type of spinal vascular malformation. However, presenting symptoms differ according to site of spinal involvement. This study described a case of arteriovenous malformation with paraparesis and incontinence. CASE PRESENTATION: Diagnosis of patient was confirmed by clinical and imaging examination using magnetic resonance image and ruling out other possibilities. RESULT: A definitive diagnosis of arterio venous fistula was confirmed by clinical and MRI examination and demonstrated abnormalities compatible with dural arteriovenous fistula. CONCLUSION: Dural arteriovenous fistula should be considered in patients with paresis in both lower extremities. PMID- 27757212 TI - Two cases of clear cell ovarian cancer in young patients. AB - BACKGROUND: Ovarian cancer is the most common cause of cancer death worldwide. Incidence of ovarian cancer is more common in postmenopausal women. Premenopausal onset is rare and the present study described two cases of ovarian clear cell tumors in young women. CASE PRESENTATION: The patients presented with pelvic mass which was confirmed by sonography and laparotomy and final diagnosis was made according to histologic examination. Both patients showed a solid mass with cystic components in adnexal areas and explorative laparotomy demonstrated extension of tumors to abdomen in both patients. The level of CA 125 increased in both patients. For both tumors, immunohistochemical stainings were positive for CK7 and CD15, but CK20 was negative. CONCLUSION: Although ovarian clear cell tumor is usually diagnosed in postmenopausal women but its diagnosis should be suspected in young women with pelvic mass. PMID- 27757213 TI - Human brucellosis. PMID- 27757214 TI - Positive Impact of Eculizumab Therapy on Surgery for Budd-Chiari Syndrome in a Patient with Paroxysmal Nocturnal Hemoglobinuria and a Long-Term History of Thrombosis. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is associated with severe end-organ damage and a high risk of thrombosis. Budd-Chiari syndrome, which develops after thrombotic occlusion of major hepatic blood vessels, is relatively common in PNH and has been associated with increased mortality. We report the case of a 46-year old male with PNH who presented with Budd-Chiari syndrome associated with portal cavernoma, portal hypertension and hypersplenism. In September 2010, the patient suffered gastrointestinal bleeding, hematuria, and elevated plasma lactate dehydrogenase; he started eculizumab therapy with a good response. In October 2012, he developed upper gastrointestinal variceal bleeding and a splenorenal shunt was placed. At the time of writing, the patient remains stable and eculizumab continues to be effective. There is limited data on the use of eculizumab for prevention of hemolysis and its consequences in PNH patients undergoing surgery. Our findings provide evidence for the efficacy and safety of eculizumab in this setting. PMID- 27757215 TI - Brentuximab Vedotin Therapy for Cutaneous Lesions in T-Prolymphocytic Leukemia: A Case Report. AB - We present an 88-year-old male with simultaneous T-cell prolymphocytic leukemia and stable smoldering myeloma with excellent initial response to three months of alemtuzumab. The patient relapsed at twelve months with severe cutaneous disease. Biopsy of a representative plaque demonstrated CD30 positivity in rare malignant lymphocytes. The patient demonstrated no response to reintroduction with a full course of alemtuzumab. He was therefore treated with brentuximab vedotin, resulting in partial remission of skin involvement that persisted for three months. PMID- 27757216 TI - GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. AB - In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death. We report that GBT440, an agent being developed for the treatment of SCD, increases the affinity of oxygen for Hb and inhibits in vitro polymerization of a mixture of HbS and HbA that simulates SCT blood. Moreover, GBT440 prevents sickling of SCT blood under in vitro conditions mimicking strenuous exercise with hypoxia, dehydration and acidosis. Together, our results indicate that GBT440 may have the potential to protect SCT individuals from sickling-related complications during conditions that favor HbS polymerization. PMID- 27757217 TI - Cross-Modal Transfer of the Tilt Aftereffect From Vision to Touch. AB - Visual input powerfully modulates the dynamics of tactile orientation perception. This study investigated the transfer of the tilt aftereffect (TAE) from vision to somatosensation. In a visual tilt adaptation paradigm, participants were exposed to clockwise or anticlockwise visual tilt, followed by three brief tactile two point stimuli delivered on their forehead. In a two-alternative forced choice task, participants had to indicate whether the haptic stimulus was tilted to the right or left. Repeated exposure to oriented visual gratings produced a tactile TAE, such that the subsequent tactile stimuli appeared tilted toward the opposite direction. To assess the origin of this effect, the experiment was repeated with the head tilted. Adaptation to a gravitationally tilted grating but with the head tilted so that the grating was retinally vertical induced a robust tactile aftereffect suggesting that the visuotactile TAE is due to spatiotopic rather than retinotopic adaptation. PMID- 27757218 TI - Speaker-Sex Discrimination for Voiced and Whispered Vowels at Short Durations. AB - Whispered vowels, produced with no vocal fold vibration, lack the periodic temporal fine structure which in voiced vowels underlies the perceptual attribute of pitch (a salient auditory cue to speaker sex). Voiced vowels possess no temporal fine structure at very short durations (below two glottal cycles). The prediction was that speaker-sex discrimination performance for whispered and voiced vowels would be similar for very short durations but, as stimulus duration increases, voiced vowel performance would improve relative to whispered vowel performance as pitch information becomes available. This pattern of results was shown for women's but not for men's voices. A whispered vowel needs to have a duration three times longer than a voiced vowel before listeners can reliably tell whether it's spoken by a man or woman (~30 ms vs. ~10 ms). Listeners were half as sensitive to information about speaker-sex when it is carried by whispered compared with voiced vowels. PMID- 27757219 TI - Matching Faces Against the Clock. AB - This study examined the effect of time pressure on face-matching accuracy. Across two experiments, observers decided whether pairs of faces depict one person or different people. Time pressure was exerted via two additional displays, which were constantly updated to inform observers on whether they were on track to meet or miss a time target. In this paradigm, faces were matched under increasing or decreasing (Experiment 1) and constant time pressure (Experiment 2), which varied from 10 to 2 seconds. In both experiments, time pressure reduced accuracy, but the point at which this declined varied from 8 to 2 seconds. A separate match response bias was found, which developed over the course of the experiments. These results indicate that both time pressure and the repetitive nature of face matching are detrimental to performance. PMID- 27757220 TI - Clinical safety and efficacy of implantation of octacalcium phosphate collagen composites in tooth extraction sockets and cyst holes. AB - It was demonstrated that octacalcium phosphate collagen composite achieved notable bone regeneration in bone defects in preclinical studies. On the basis of the research results, an investigator-initiated exploratory clinical trial was conducted after approval from a local Institutional Review Board. This clinical study was performed as a single-arm non-randomized intervention study. Octacalcium phosphate collagen composite was implanted into a total of 10 cases of alveolar bone defects after tooth extractions and cystectomy. Safety assessment was performed in terms of the clinical course and several consecutive laboratory examinations, and sequential radiographs were used for efficacy assessment. All participants uneventfully completed the clinical trial without major problems in their general condition. Postoperative wound swelling was observed, as also commonly seen in tooth extraction or cystectomy. Although no serious liver dysfunction, renal dysfunction, electrolyte imbalance, or abnormal urinalysis results were recognized, the number of white blood cells and C reactive protein level temporarily increased after the operation. An increase in radiopacity in the octacalcium phosphate collagen composite-implanted site was observed in all cases. Finally, the border between the original bone and the octacalcium phosphate collagen composite-implanted site became indistinguishable. These results suggest that octacalcium phosphate collagen composite could be utilized safely in clinical situations in the future. PMID- 27757221 TI - Conservation and divergence of bHLH genes in the calcisponge Sycon ciliatum. AB - BACKGROUND: Basic Helix-Loop-Helix (bHLH) genes encode a large family of eukaryotic transcription factors, categorized into six high-order groups: pan eukaryotic group B involved in regulation of cell cycle, metabolism, and development; holozoan-specific groups C and F involved in development and maintenance of homeostasis; and metazoan-specific groups A, D and E including well-studied genes, such as Atonal, Twist and Hairy, with diverse developmental roles including control of morphogenesis and specification of neurons. Current scenarios of bHLH evolution in animals are mainly based on the bHLH gene set found in the genome of demosponge Amphimedon queenslandica. In this species, the majority of the 21 identified bHLH genes belong to group B, and the single group A gene is orthologous to several neurogenic bilaterian subfamilies, including atonal and neurogenin. RESULTS: Given recently discovered differences in developmental toolkit components between siliceous and calcareous sponges, we have carried out genome-wide analysis of bHLH genes in Sycon ciliatum, an emerging calcisponge model. We identified 30 bHLH genes in this species, representing 12 individual families, including four group A families not found in Amphimedon, and two larger family groupings. Notably, the families represented in Sycon are only partially overlapping with those represented in Amphimedon. Developmental expression analysis of a subset of the identified genes revealed patterns consistent with deeply conserved roles, such as specification of sensory cells by Atona-related and stem cells by Myc genes. CONCLUSIONS: Our results demonstrate independent gene loss events in demosponges and calcisponges, implying a complex bHLH toolkit in the last common metazoan ancestor. PMID- 27757222 TI - In utero origin of sex-related differences in future cardiovascular disease. AB - BACKGROUND: There are sex differences in the risk of development of cardiovascular disease (CVD). According to the developmental origins of health and disease paradigm (DOHaD), CVD originates in fetal life. This study examines fetal sex differences in cardiovascular development in utero. METHODS: In 1028 pregnant women, we assessed fetal circulation using pulsed wave Doppler examinations between 28 and 34 weeks gestation. To test associations between fetal sex and fetal circulation measurements, linear regression models were used adjusting for fetal size, gestational age, and fetal heart rate. RESULTS: A higher pulsatility index in the ductus venosus was observed in male fetuses compared to female fetuses (difference 0.02, 95 % CI 0.01; 0.05) with a lower E/A ratio of the tricuspid (difference -0.01, 95 % CI -0.03; -0.00) and mitral (difference -0.02, 95 % CI -0.03; -0.01) valves. This was mainly determined by differences in the E wave of the tricuspid and mitral valves (differences -1.02, 95 % CI -1.81; -0.24 and -1.28, 95 % CI -2.11; -0.46, respectively). Also in males, a lower peak systolic velocity was seen in the pulmonary artery (difference -1.33, 95 % CI -2.63; -0.03) with a similar lower trend regarding peak systolic velocity in the ascending aorta. CONCLUSIONS: Male fetuses exhibit an increased preload and reduced afterload conditions compared to females. While it is difficult to relate these measurements to exact cardiac function, our findings strongly suggest that the known differences in cardiovascular performance between the sexes already start in utero. PMID- 27746902 TI - Applying a complex adaptive system's understanding of health to primary care. AB - This paper explores the diagnostic and therapeutic potential of a new concept of health. Investigations into the nature of health have led to a new definition that explains health as a complex adaptive system (CAS) and is based on five components (a-e). Humans like all biological creatures must satisfactorily respond to (a) the demands of life. For this purpose they need (b) a biologically given potential (BGP) and (c) a personally acquired potential (PAP). These properties of individuals are embedded within (d) social and (e) environmental determinants of health. Between these five components of health there are 10 complex interactions that justify viewing health as a CAS. In each patient, the current state of health as a CAS evolved from the past, will move forward to a new future, and has to be analyzed and treated as an autonomous whole. A diagnostic procedure is suggested as follows: together with the patient, the five components and 10 complex interactions are assessed. This may help patients to better understand their situations and to recognize possible next steps that may be useful in order to evolve toward better health by themselves. In this process mutual trust in the patient-physician interaction is critical. The described approach offers new possibilities for helping patients improve their health prospects. PMID- 27757223 TI - Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration. AB - BACKGROUND: The skeletal muscle stem cell niche provides an environment that maintains quiescent satellite cells, required for skeletal muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite cells, supports communication with the niche, providing cell interactions and signals to maintain quiescent satellite cells. RESULTS: Syndecan-3 ablation unexpectedly improves regeneration in repeatedly injured muscle and in dystrophic mice, accompanied by the persistence of sublaminar and interstitial, proliferating myoblasts. Additionally, muscle aging is improved in syndecan-3 null mice. Since syndecan-3 null myofiber-associated satellite cells downregulate Pax7 and migrate away from the niche more readily than wild type cells, syxndecan 3 appears to regulate satellite cell homeostasis and satellite cell homing to the niche. CONCLUSIONS: Manipulating syndecan-3 provides a promising target for development of therapies to enhance muscle regeneration in muscular dystrophies and in aged muscle. PMID- 27746901 TI - Illustrating and homology modeling the proteins of the Zika virus. AB - The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barre syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our model quality criteria for their further use. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening. PMID- 27757228 TI - Telehealth: Acceptability, clinical interventions and quality of life in peritoneal dialysis. AB - INTRODUCTION: Telehealth technologies are being widely adopted across the globe for management of long-term conditions. There are limited data on its use, effectiveness and patient experience in end-stage renal disease. The aim of this pilot project was to explore patient acceptability of technology and evaluate its effect on clinical interventions and quality of life in patients undergoing peritoneal dialysis. METHODS: Peritoneal dialysis patients were provided with computer tablets (PODs). PODs contained a knowledge database with treatment- and symptom-based questionnaires that generated alerts for the clinical team. Alerts were reviewed daily and followed up by a telephone call or clinic visit. Interventions were at the discretion of clinicians. Data were recorded prospectively and quality of life and Quebec User Evaluation of Satisfaction with assistive Technology questionnaires evaluated at the start and end of the programme. RESULTS: In all, 22 patients have participated over 15 months. The mean age was 61.6 years and PODs were utilised for an average of 341.9 days with 59.1% choosing to continue beyond the study period. We received a total of 1195 alerts with an average of 2.6 alerts per day. A total of 36 admissions were avoided and patients supported to self-manage on 154 occasions. Quebec User Evaluation of Satisfaction with assistive Technology scores remained high throughout the programme although no improvement in quality of life was seen. DISCUSSION: Telehealth is useful to monitor patients with renal failure on peritoneal dialysis. It is acceptable across age groups and provides an additional resource for patients to self-manage. Satisfaction scores and retention rates suggest a high level of acceptability. PMID- 27757226 TI - The microbiota and chronic kidney diseases: a double-edged sword. AB - Recent findings regarding the influence of the microbiota in many inflammatory processes have provided a new way to treat diseases. Now, one may hypothesize that the origin of a plethora of diseases is related to the health of the gut microbiota and its delicate, although complex, interface with the epithelial and immune systems. The 'westernization' of diets, for example, is associated with alterations in the gut microbiota. Such alterations have been found to correlate directly with the increased incidence of diabetes and hypertension, the main causes of chronic kidney diseases (CKDs), which, in turn, have a high estimated prevalence. Indeed, data have arisen showing that the progression of kidney diseases is strictly related to the composition of the microbiota. Alterations in the gut microbiota diversity during CKDs do not only have the potential to exacerbate renal injury but may also contribute to the development of associated comorbidities, such as cardiovascular diseases and insulin resistance. In this review, we discuss how dysbiosis through alterations in the gut barrier and the consequent activation of immune system could intensify the progression of CKD and vice versa, how CKDs can modify the gut microbiota diversity and abundance. PMID- 27757229 TI - Risk of cardiovascular events after initiation of long-acting bronchodilators in patients with chronic obstructive lung disease: A population-based study. AB - OBJECTIVES: Long-acting bronchodilators are mainstay treatment for moderate to severe chronic obstructive pulmonary disease. A growing body of evidence indicates an increased risk of cardiovascular events upon initiation of these medications. We hypothesize that this risk is higher in patients with chronic obstructive pulmonary disease who had a preexisting cardiovascular disease regardless of receipt of any cardiovascular medication. METHODS: A retrospective cohort of patients with a diagnosis of chronic obstructive pulmonary disease based on two outpatient visits or one inpatient visit for chronic obstructive pulmonary disease (International Classification of Diseases, 9th Edition, Clinical Modification codes 491.x, 492.x, 496) in any year between 2001 and 2012 from a commercial insurance database. We then selected those initiating long acting bronchodilator treatments between April 2001 and September 2012. Each patient had a 1 year look back period to determine history of cardiovascular disease or cardiovascular disease treatment from the time of first prescription of long-acting beta agonist, long-acting muscarinic antagonist, or long-acting beta agonist combined with inhaled corticosteroids. Patients were followed for 90 days for hospitalizations or emergency department visits for cardiovascular event. The cohort was divided into four groups based on the presence of cardiovascular disease (including ischemic heart disease, hypertension, ischemic stroke, heart failure, tachyarrhythmias and artery disease based on International Classification of Diseases, 9th Edition, Clinical Modification codes) and cardiovascular disease treatment defined as acetylsalicylic acid, beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet, anticoagulants, calcium channel blockers, nitrate, digoxin, diuretics, antiarrhythmics or statins. Odds of emergency department visit or hospitalization in the 90 days after prescription were examined using multivariable logistic regression models. RESULTS: Of 61,651 eligible patients, 36,755 (59.6%) had cardiovascular disease and were on cardiovascular disease treatment (Group 1), 7250 (11.8%) had cardiovascular disease without cardiovascular disease treatment (Group 2), 4715 (7.7%) had no cardiovascular disease but had cardiovascular disease treatment (Group 3) and 12,931 (21%) had no cardiovascular disease and no treatment (Group 4). In these four groups, the unadjusted risk of emergency department visit or hospitalization for cardiovascular disease within 90 days of initiation was 5.45%, 2.95%, 1.55% and 0.96%, respectively. In multivariable analysis, the adjusted odds ratio with 95% confidence interval of emergency department visit/hospitalization for each of the first three groups to those with no cardiovascular disease and no treatment were 3.50 (95% confidence interval, 2.89-4.24), 2.15 (95% confidence interval, 1.71 2.70) and 1.36 (95% confidence interval, 1.01-1.82), respectively. CONCLUSION: The risk of cardiovascular events after initiation of long-acting bronchodilators is highest in patients with baseline cardiovascular disease and on cardiovascular disease medications. Clinicians should be cautious while prescribing these medications in patients with preexisting cardiovascular disease. PMID- 27757227 TI - New insights into therapeutic strategies for gut microbiota modulation in inflammatory diseases. AB - The interaction between the gut microbiota and the host immune system is very important for balancing and resolving inflammation. The human microbiota begins to form during childbirth; the complex interaction between bacteria and host cells becomes critical for the formation of a healthy or a disease-promoting microbiota. C-section delivery, formula feeding, a high-sugar diet, a high-fat diet and excess hygiene negatively affect the health of the microbiota. Considering that the majority of the global population has experienced at least one of these factors that can lead to inflammatory disease, it is important to understand strategies to modulate the gut microbiota. In this review, we will discuss new insights into gut microbiota modulation as potential strategies to prevent and treat inflammatory diseases. Owing to the great advances in tools for microbial analysis, therapeutic strategies such as prebiotic, probiotic and postbiotic treatment and fecal microbiota transplantation have gained popularity. PMID- 27757231 TI - Emergency department crowding in Singapore: Insights from a systems thinking approach. AB - OBJECTIVES: Emergency Department crowding is a serious and international health care problem that seems to be resistant to most well intended but often reductionist policy approaches. In this study, we examine Emergency Department crowding in Singapore from a systems thinking perspective using causal loop diagramming to visualize the systemic structure underlying this complex phenomenon. Furthermore, we evaluate the relative impact of three different policies in reducing Emergency Department crowding in Singapore: introduction of geriatric emergency medicine, expansion of emergency medicine training, and implementation of enhanced primary care. METHODS: The construction of the qualitative causal loop diagram is based on consultations with Emergency Department experts, direct observation, and a thorough literature review. For the purpose of policy analysis, a novel approach, the path analysis, is applied. RESULTS: The path analysis revealed that both the introduction of geriatric emergency medicine and the expansion of emergency medicine training may be associated with undesirable consequences contributing to Emergency Department crowding. In contrast, enhancing primary care was found to be germane in reducing Emergency Department crowding; in addition, it has apparently no negative side effects, considering the boundary of the model created. CONCLUSION: Causal loop diagramming was a powerful tool for eliciting the systemic structure of Emergency Department crowding in Singapore. Additionally, the developed model was valuable in testing different policy options. PMID- 27757232 TI - Isolated large vulvar varicose veins in a non-pregnant woman. AB - Vulvar varicosities are often asymptomatic, and they may be associated with varicose veins of the lower extremity. Also, they may be a part of pelvic congestion syndrome and usually occur during pregnancy. We present a case of a huge isolated and disfiguring vulvar varicosities in a non-pregnant women managed successfully by combination of surgery and sclerotherapy. PMID- 27757233 TI - A rare nasal cavity mass in a child: Accessory middle turbinate. AB - OBJECTIVES: The accessory middle turbinate, a rare anatomical variation of the nasal cavity, have been systematically studied in adults. Presence of accessory middle turbinate and its clinical significance in a child has not been reported. We describe clinical appearance and radiologic features of accessory middle turbinate in a child. METHODS: Retrospective chart review. RESULTS: A 3-year-old boy presented to the otolaryngology clinic for evaluation of recurrent epistaxis. Anterior rhinoscopy revealed moist nasal mucosa without inflammation and bilateral prominent blood vessels on the anterior nasal septum. Nasal endoscopy showed turbinate like protuberances in bilateral middle meatus. CT images documented accessory middle turbinate in the bilateral nasal cavity. CONCLUSION: Otolaryngologists should be cognizant of anatomical variations of middle turbinate to achieve correct diagnosis and avoid potential complications during surgical management. PMID- 27757230 TI - SF-36 total score as a single measure of health-related quality of life: Scoping review. AB - According to the 36-Item Short Form Health Survey questionnaire developers, a global measure of health-related quality of life such as the "SF-36 Total/Global/Overall Score" cannot be generated from the questionnaire. However, studies keep on reporting such measure. This study aimed to evaluate the frequency and to describe some characteristics of articles reporting the SF-36 Total/Global/Overall Score in the scientific literature. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses method was adapted to a scoping review. We performed searches in PubMed, Web of Science, SCOPUS, BVS, and Cochrane Library databases for articles using such scores. We found 172 articles published between 1997 and 2015; 110 (64.0%) of them were published from 2010 onwards; 30.0% appeared in journals with Impact Factor 3.00 or greater. Overall, 129 (75.0%) out of the 172 studies did not specify the method for calculating the "SF-36 Total Score"; 13 studies did not specify their methods but referred to the SF-36 developers' studies or others; and 30 articles used different strategies for calculating such score, the most frequent being arithmetic averaging of the eight SF-36 domains scores. We concluded that the "SF-36 Total/Global/Overall Score" has been increasingly reported in the scientific literature. Researchers should be aware of this procedure and of its possible impacts upon human health. PMID- 27757234 TI - Lymphatic dysfunction after ligation surgery for varicose vein. AB - OBJECTIVE: Although the lymphatic complications such as lymphocele sometimes occur after surgery for varicose veins, the lymphatic function of such patients has not been evaluated. In this case report, we present a case of lymphocele after ligation surgery for varicose vein. We also detected subclinical dysfunction in lower limb using indocyanine green (ICG) lymphography. CASE REPORT: A 76 year- old female underwent ligation surgery for right lower leg varicose vein, and she noticed the squashy lesion in the medial side of the right knee. Three years later, she consulted our clinic and we performed ICG lymphography. We observed dermal backflow around the mass, which indicated lymphatic dysfunction. After injecting additional ICG around the knee, we punctured and drained the clear, yellow fluid from the mass and it was contrasted with ICG during the examination and the involvement of the lymphatic system was proven. PMID- 27757235 TI - Pass the salt: physiological consequences of ecologically relevant hyposmotic exposure in juvenile gummy sharks (Mustelus antarcticus) and school sharks (Galeorhinus galeus). AB - Estuarine habitats are frequently used as nurseries by elasmobranch species for their protection and abundant resources; however, global climate change is increasing the frequency and severity of environmental challenges in these estuaries that may negatively affect elasmobranch physiology. Hyposmotic events are particularly challenging for marine sharks that osmoconform, and species specific tolerances are not well known. Therefore, we sought to determine the effects of an acute (48 h) ecologically relevant hyposmotic event (25.8 ppt) on the physiology of two juvenile shark species, namely the school shark (Galeorhinus galeus), listed by the Australian Environmental Protection and Biodiversity Conservation Act as 'conservation dependent', and the gummy shark (Mustelus antarcticus), from the Pittwater Estuary (Australia). In both species, we observed a decrease in plasma osmolality brought about by selective losses of NaCl, urea and trimethylamine N-oxide, as well as decreases in haemoglobin, haematocrit and routine oxygen consumption. Heat-shock protein levels varied between species during the exposure, but we found no evidence of protein damage in any of the tissues tested. Although both species seemed to be able to cope with this level of osmotic challenge, overall the school sharks exhibited higher gill Na+/K+-ATPase activity and ubiquitin concentrations in routine and experimental conditions, a larger heat-shock protein response and a smaller decrease in routine oxygen consumption during the hyposmotic exposure, suggesting that there are species-specific responses that could potentially affect their ability to withstand longer or more severe changes in salinity. Emerging evidence from acoustic monitoring of sharks has indicated variability in the species found in the Pittwater Estuary during hyposmotic events, and together, our data may help to predict species abundance and distribution in the face of future global climate change. PMID- 27757236 TI - Salinity tolerances of two Australian freshwater turtles, Chelodina expansa and Emydura macquarii (Testudinata: Chelidae). AB - Freshwater biota experience physiological challenges in regions affected by salinization, but often the effects on particular species are poorly understood. Freshwater turtles are of particular concern as they appear to have limited ability to cope with environmental conditions that are hyperosmotic to their body fluids. Here, we determined the physiological responses of two Australian freshwater chelid turtles, Emydura macquarii and Chelodina expansa, exposed to freshwater (00/00) and brackish water (150/00, representing a hyperosmotic environment). Brackish water is common in the Murray-Darling River Basin within the natural range of these species in Australia during periods of drought, yet it is unknown how well these species tolerate saline conditions. We hypothesized that these turtles would be unable to maintain homeostasis in the 150/00 water treatment and would suffer osmotic loss of water, increased ionic concentrations and a decrease in body mass. Results revealed that these turtles had elevated plasma concentrations of sodium, chloride, urea and uric acid in the plasma. Plasma ionic concentrations increased proportionally more in E. macquarii than in C. expansa. Individuals of both species reduced feeding in 150/00 water, indicating that behaviour may provide an additional means for freshwater turtles to limit ion/solute influx when in hyperosmotic environments. This osmoregulatory behaviour may allow for persistence of turtles in regions affected by salinization; however, growth rates and body condition may be affected in the long term. Although we demonstrate that these turtles have mechanisms to survive temporarily in saline waters, it is likely that sustained salinization of waterways will exceed their short- to medium-term capacity to survive increased salt levels, making salinization a potentially key threatening process for these freshwater reptiles. PMID- 27757237 TI - Coping with heat: behavioural and physiological responses of savanna elephants in their natural habitat. AB - Most of southern Africa's elephants inhabit environments where environmental temperatures exceed body temperature, but we do not know how elephants respond to such environments. We evaluated the relationships between apparent thermoregulatory behaviour and environmental, skin and core temperatures for tame savanna elephants (Loxodonta africana) that were free-ranging in the hot parts of the day, in their natural environment. Environmental temperature dictated elephant behaviour within a day, with potential consequences for fine-scale habitat selection, space use and foraging. At black globe temperatures of ~30 degrees C, elephants adjusted their behaviour to reduce environmental heat load and increase heat dissipation (e.g. shade use, wetting behaviour). Resting, walking and feeding were also influenced by environmental temperature. By relying on behavioural and autonomic adjustments, the elephants maintained homeothermy, even at environmental temperatures exceeding 40 degrees C. Elephants clearly have the capacity to deal with extreme heat, at least in environments with adequate resources of forage, water and shade. Future conservation actions should provide for the thermoregulatory, resource and spatial needs of elephants. PMID- 27757238 TI - Costs of locomotion in polar bears: when do the costs outweigh the benefits of chasing down terrestrial prey? AB - Trade-offs between locomotory costs and foraging gains are key elements in determining constraints on predator-prey interactions. One intriguing example involves polar bears pursuing snow geese on land. As climate change forces polar bears to spend more time ashore, they may need to expend more energy to obtain land-based food. Given that polar bears are inefficient at terrestrial locomotion, any extra energy expended to pursue prey could negatively impact survival. However, polar bears have been regularly observed engaging in long pursuits of geese and other land animals, and the energetic worth of such behaviour has been repeatedly questioned. We use data-driven energetic models to examine how energy expenditures vary across polar bear mass and speed. For the first time, we show that polar bears in the 125-235 kg size range can profitably pursue geese, especially at slower speeds. We caution, however, that heat build up may be the ultimate limiting factor in terrestrial chases, especially for larger bears, and this limit would be reached more quickly with warmer environmental temperatures. PMID- 27757239 TI - Employing individual measures of baseline glucocorticoids as population-level conservation biomarkers: considering within-individual variation in a breeding passerine. AB - Labile physiological variables, such as stress hormones [i.e. glucocorticoids (GCs)], allow individuals to react to perturbations in their environment and may therefore reflect the effect of disturbances or positive conservation initiatives in advance of population-level demographic measures. Although the application of GCs as conservation biomarkers has been of extensive interest, few studies have explicitly investigated whether baseline GC concentrations respond to disturbances consistently across individuals. However, confirmation of consistent responses is of paramount importance to assessing the ease of use of GCs in natural systems and to making valid interpretations regarding population-level change (or lack of change) in GC concentrations. We investigated whether free ranging female tree swallows (Tachycineta bicolor) display individually specific changes in baseline glucocorticoid concentrations naturally over the breeding season (from incubation to offspring provisioning) and in response to a manipulation of foraging profitability (representing a decrease in access to food resources). We show that baseline GC concentrations are repeatable within individuals over reproduction in natural conditions. However, in response to a reduction in foraging ability, baseline GC concentrations increase at the population level but are not repeatable within individuals, indicating a high level of within-individual variation. Overall, we suggest that baseline GCs measured on a subset of individuals may not provide a representative indication of responses to environmental change at the population level, and multiple within individual measures may be necessary to determine the fitness correlates of GC concentrations. Further validation should be completed across a variety of taxa and life-history stages. Moving beyond a traditional cross-sectional approach by incorporating repeated-measures methods will be necessary to assess the suitability of baseline GCs as biomarkers of environmental change and population persistence, particularly from a logistical and ease-of-use perspective for conservation managers. PMID- 27757241 TI - What happens when 55% of acute psychiatric beds are closed in six days: an unexpected naturalistic observational study. AB - OBJECTIVE: The sudden closure of 30 out of 54 acute psychiatric beds in Cornwall presented a stressful challenge to staff but also a natural experiment on how a service dealt with this situation. We aimed to evaluate the outcomes of patients needing to leave the closed ward, how bed occupancy rates were affected and the impact on admission rates. DESIGN: A service evaluation of the impact of the ward closure. SETTING: A comprehensive secondary NHS mental health service in Cornwall serving 550,000 population. MAIN OUTCOME MEASURES: The destination of the patients needing to leave the acute unit, the effect of the closure on bed occupancy, admission rates and serious untoward incidents. RESULTS: Of 26 patients needing to be moved from the acute ward, only 10 needed an acute psychiatric bed. None of the seven patients who had been on the ward longer than nine weeks needed an acute unit. Admission rates fell over the subsequent three months. There was no increase in serious incidents due to the closure. CONCLUSIONS: This naturalistic event suggests that many patients on acute units could be cared for elsewhere, especially recovery/rehabilitation care environments, if political and financial urgency is present. Admission rates are responsive to the pressure on beds. PMID- 27757240 TI - Time-dependent postural control adaptations following a neuromuscular warm-up in female handball players: a randomized controlled trial. AB - BACKGROUND: Female handball athletes are at a particular risk of sustaining lower extremity injuries. The study examines time-dependent adaptations of static and dynamic balance as potential injury risk factors to a specific warm-up program focusing on neuromuscular control. METHODS: Fourty one (24.0 +/- 5.9 years) female handball athletes were randomized to an intervention or control group. The intervention group implemented a 15-min specific neuromuscular warm-up program, three times per week for eleven weeks, whereas the control group continued with their regular warm-up. Balance was assessed at five time points. Measures included the star excursion balance test (SEBT), and center of pressure (COP) sway velocity during single-leg standing. RESULTS: No baseline differences existed between groups in demographic data. Adherence to neuromuscular warm-up was 88.7 %. Mean COP sway velocity decreased significantly over time in the intervention group (-14.4 %; p < .001), but not in the control group (-6.2 %; p = 0.056). However, these effects did not differ significantly between groups (p = .098). Mean changes over time in the SEBT score were significantly greater (p = .014) in the intervention group (+5.48) compared to the control group (+3.45). Paired t-tests revealed that the first significant balance improvements were observed after 6 weeks of training. CONCLUSIONS: A neuromuscular warm-up positively influences balance variables associated with an increased risk of lower extremity injuries in female handball athletes. The course of adaptations suggests that a training volume of 15 min, three times weekly over at least six weeks produces measurable changes. TRIAL REGISTRATION: Retrospectively registered on 4th October 2016. Registry: clinicaltrials.gov. Trial number: NCT02925377. PMID- 27757242 TI - No difference found in time to publication by statistical significance of trial results: a methodological review. AB - OBJECTIVE: Time-lag from study completion to publication is a potential source of publication bias in randomised controlled trials. This study sought to update the evidence base by identifying the effect of the statistical significance of research findings on time to publication of trial results. DESIGN: Literature searches were carried out in four general medical journals from June 2013 to June 2014 inclusive (BMJ, JAMA, the Lancet and the New England Journal of Medicine). SETTING: Methodological review of four general medical journals. PARTICIPANTS: Original research articles presenting the primary analyses from phase 2, 3 and 4 parallel-group randomised controlled trials were included. MAIN OUTCOME MEASURES: Time from trial completion to publication. RESULTS: The median time from trial completion to publication was 431 days (n = 208, interquartile range 278-618). A multivariable adjusted Cox model found no statistically significant difference in time to publication for trials reporting positive or negative results (hazard ratio: 0.86, 95% CI 0.64 to 1.16, p = 0.32). CONCLUSION: In contrast to previous studies, this review did not demonstrate the presence of time-lag bias in time to publication. This may be a result of these articles being published in four high impact general medical journals that may be more inclined to publish rapidly, whatever the findings. Further research is needed to explore the presence of time lag bias in lower quality studies and lower impact journals. PMID- 27757243 TI - An unexpected rash with gastroenteritis: erythema multiforme associated with campylobacter infection. AB - We present the first documented case of erythema multiforme following campylobacter gastroenteritis. PMID- 27757245 TI - Prostate cancer metastasis to calcaneus: a solitary lesion at an atypical site, dormant for more than 10 years. AB - In prostate cancer patients, if bone scan demonstrates a solitary lesion in atypical area, this is possibly an indication of metastatic disease. Therefore, biopsy confirmation is required to determine the nature of the abnormality and therefore dictates further staging investigations and treatment options. PMID- 27757244 TI - Magnesium, zinc, arsenic, selenium and platinum urinary excretion from cancer patients of Antofagasta region, Chile: multi-metal approach. AB - OBJECTIVES: To evaluate the short-term 24 h urinary excretion of platinum, arsenic, selenium, magnesium and zinc in patients with lung cancer and with cancer other than lungs treated with cisplatin or/and carboplatin from Antofagasta, Chile. DESIGN: Urine measurements of Pt and Se were made by inductively coupled plasma optical emission spectrometry, As by hydride generation atomic absorption spectrometry and Mg and Zn by means of flame furnace atomic absorption spectrometry. SETTING: All samples were provided by the Oncological Centre of Antofagasta Regional Hospital (Region of Antofagasta, Chile). PARTICIPANTS: Ninety 24-h urine samples from cancer patients after the infusion of Pt-base drugs and 10 24-h urine samples from cancer patients not treated with metal-base drugs. MAIN OUTCOME MEASURES: Concentrations of Pt, Se, As, Zn and Mg coming from 24-h urine samples. RESULTS: Pt excreted was not significantly different between patients with lung and other cancers treated with cisplatin. The excretion of Mg, Zn and Se was greater than As. Then, Pt favours the excretion of essential elements. For lung and other types of cancers treated with drugs without Pt, excretion of Mg, Zn and Se was also greater than that of As, suggesting antagonism Mg-Zn-Se-anti-cancer drug relationship. CONCLUSIONS: The amounts of Mg, Zn and Se excreted were greater than for As either with or without Pt-containing drugs, suggesting antagonist Mg-Zn-Se-anti-cancer drug relationships. The excretion of As, Mg, Zn and Se is induced by Pt. Knowledge obtained can contribute to understanding the arsenic cancer mechanism and the As Mg-Zn-Se-Pt inter-element association for lung cancer and other types of cancer. PMID- 27757246 TI - Hidden varicella outbreak, Luang Prabang Province, the Lao People's Democratic Republic, December 2014 to January 2015. AB - BACKGROUND: In January 2015, the Lao People's Democratic Republic Ministry of Health received a report of 34 cases of fever and rash with one laboratory confirmed measles case in Houitone village, Pakseng District of Luang Prabang Province. Between 21 and 27 January, we conducted a field investigation to determine the etiology, magnitude and severity of this outbreak. METHODS: We conducted active case findings in Houitone and neighbouring villages and collected information on age, location, date of rash onset, symptoms and measles vaccination status. We collected serum samples from cases with rash onset of less than 28 days and tested for measles and rubella IgM using enzyme-linked immunosorbent assay. RESULTS: Between 22 December 2014 and 23 January 2015, 190 fever and rash cases were identified in seven villages in Pakseng District with the majority of the cases in Houitone village. The most affected age group was between 1 and 9 years. The majority of the rashes were vesicular. Of the additional 43 serum samples collected, no samples tested positive for measles or rubella IgM. The clinical manifestation and epidemiology of the disease suggested a varicella outbreak. CONCLUSION: The rapid response to a single laboratory confirmed measles case did not identify a measles outbreak but suggested a varicella outbreak. Low measles vaccination coverage led us to recommend a routine catch-up vaccination campaign. We also recommend collecting information of rash types and photos of rashes in future fever and rash outbreaks to better differentiate potential etiologies. PMID- 27757247 TI - An outbreak investigation of scrub typhus in Western Province, Solomon Islands, 2014. AB - OBJECTIVE: To identify the etiology and risk factors of undifferentiated fever in a cluster of patients in Western Province, Solomon Islands, May 2014. METHODS: An outbreak investigation with a case control study was conducted. A case was defined as an inpatient in one hospital in Western Province, Solomon Islands with high fever (> 38.5 degrees C) and a negative malaria microscopy test admitted between 1 and 31 May 2014. Asymptomatic controls matched with the cases residentially were recruited in a ratio of 1:2. Serum samples from the subjects were tested for rickettsial infections using indirect micro-immunofluorescence assay. RESULTS: Nine cases met the outbreak case definition. All cases were male. An eschar was noted in five cases (55%), and one developed pneumonitis. We did not identify any environmental factors associated with illness. Serum samples of all five follow-up cases (100%) had strong-positive IgG responses to scrub typhus. All but one control (10%) had a moderate response against scrub typhus. Four controls had low levels of antibodies against spotted fever group rickettsia, and only one had a low-level response to typhus group rickettsia. DISCUSSION: This outbreak represents the first laboratory-confirmed outbreak of scrub typhus in the Western Province of Solomon Islands. The results suggest that rickettsial infections are more common than currently recognized as a cause of an acute febrile illness. A revised clinical case definition for rickettsial infections and treatment guidelines were developed and shared with provincial health staff for better surveillance and response to future outbreaks of a similar kind. PMID- 27757248 TI - An outbreak investigation of congenital rubella syndrome in Solomon Islands, 2013. AB - INTRODUCTION: During May 2012, a rubella outbreak was declared in Solomon Islands. A suspected case of congenital rubella syndrome (CRS) was reported from one hospital 11 months later in 2013. This report describes the subsequent CRS investigation, findings and measures implemented. METHODS: Prospective CRS surveillance was conducted at the newborn nursery, paediatric and post-natal wards, and the paediatric cardiology and ophthalmology clinics of the study hospital from April to July 2013. Retrospective case finding by reviewing medical records was also undertaken to identify additional cases born between January and March 2013 for the same wards and clinics. Cases were identified using established World Health Organization case definitions for CRS. RESULTS: A total of 13 CRS cases were identified, including two laboratory-confirmed, four clinically confirmed and seven suspected cases. Five CRS cases were retrospectively identified, including four suspected and one clinically confirmed case. There was no geospatial clustering of residences. The mothers of the cases were aged between 20 and 36 years. Three of the six mothers available for interview recalled an acute illness with rash during the first trimester of pregnancy. DISCUSSION: Additional CRS cases not captured in this investigation are likely. Caring for CRS cases is a challenge in resource-poor settings. Rubella vaccination is safe and effective and can prevent the serious consequences of CRS. Well planned and funded vaccination activities can prevent future CRS cases. PMID- 27757249 TI - Effect of antiviral prophylaxis on influenza outbreaks in aged care facilities in three local health districts in New South Wales, Australia, 2014. AB - BACKGROUND: There was a record number (n = 111) of influenza outbreaks in aged care facilities in New South Wales, Australia during 2014. To determine the impact of antiviral prophylaxis recommendations in practice, influenza outbreak data were compared for facilities in which antiviral prophylaxis and treatment were recommended and for those in which antivirals were recommended for treatment only. METHODS: Routinely collected outbreak data were extracted from the Notifiable Conditions Information Management System for two Local Health Districts where antiviral prophylaxis was routinely recommended and one Local Health District where antivirals were recommended for treatment but not routinely for prophylaxis. Data collected on residents included counts of influenza-like illness, confirmed influenza, hospitalizations and related deaths. Dates of onset, notification, influenza confirmation and antiviral recommendations were also collected for analysis. The Mann-Whitney U test was used to assess the significance of differences between group medians for key parameters. RESULTS: A total of 41 outbreaks (12 in the prophylaxis group and 29 in the treatment-only group) were included in the analysis. There was no significant difference in overall outbreak duration; outbreak duration after notification; or attack, hospitalization or case fatality rates between the two groups. The prophylaxis group had significantly higher cases with influenza-like illness (P = 0.03) and cases recommended antiviral treatment per facility (P = 0.01). DISCUSSION: This study found no significant difference in key outbreak parameters between the two groups. However, further high quality evidence is needed to guide the use of antivirals in responding to influenza outbreaks in aged care facilities. PMID- 27757250 TI - Engaging the international community during the 2015 Middle East respiratory syndrome outbreak in the Republic of Korea. PMID- 27757251 TI - Surveillance and response of hepatitis B virus in Hong Kong Special Administrative Region, 1988-2014. PMID- 27757252 TI - Communicating about the Middle East respiratory syndrome outbreak to the international community and in-country foreigners, Republic of Korea, 2015. PMID- 27757253 TI - Underreporting of influenza outbreaks in aged care facilities in South Western Sydney, Australia, 2014. PMID- 27757254 TI - Using the two-source capture-recapture method to estimate the incidence and case ascertainment of congenital rubella syndrome in Australia, 1993-2013. PMID- 27757255 TI - Vector-control response in a post-flood disaster setting, Honiara, Solomon Islands, 2014. AB - PROBLEM: The close quartering and exposed living conditions in evacuation centres and the potential increase in vector density after flooding in Solomon Islands resulted in an increased risk of exposure for the occupants to vectorborne diseases. CONTEXT: In April 2014, Solomon Islands experienced a flash flooding event that affected many areas and displaced a large number of people. In the capital, Honiara, nearly 10 000 people were housed in emergency evacuation centres at the peak of the post-flood emergency. At the time of the floods, the number of dengue cases was increasing, following a record outbreak in 2013. ACTION: The National Vector Borne Disease Control Programme with the assistance of the World Health Organization implemented an emergency vector-control response plan to provide protection to the at-risk populations in the evacuation centres. The National Surveillance Unit also activated an early warning disease surveillance system to monitor communicable diseases, including dengue and malaria. OUTCOME: Timely and strategic application of the emergency interventions probably prevented an increase in dengue and malaria cases in the affected areas. DISCUSSION: Rapid and appropriate precautionary vector-control measures applied in a post-natural disaster setting can prevent and mitigate vectorborne disease incidences. Collecting vector surveillance data allows better analysis of vector control operations' effectiveness. PMID- 27757256 TI - Preparedness for Zika virus testing in the World Health Organization Western Pacific Region. AB - On 1 February 2016, the World Health Organization (WHO) declared that clusters of microcephaly cases and other neurological disorders occurring in Zika virus (ZIKV)-affected areas constituted a public health emergency of international concern. Increased surveillance of the virus, including the requirement for laboratory confirmation of infection, was recommended. The WHO Regional Office for the Western Pacific therefore initiated a rapid survey among national-level public health laboratories in 19 countries and areas to determine regional capacity for ZIKV detection. The survey indicated that 16/19 (84%) countries had capacity for molecular detection of ZIKV while others facilitated testing through referral. These results suggest that robust laboratory capacity is in place to support ZIKV surveillance in the Western Pacific Region. PMID- 27757257 TI - Perceptions on the risk communication strategy during the 2013 avian influenza A/H7N9 outbreak in humans in China: a focus group study. AB - OBJECTIVE: To identify the general public's perceptions of the overall risk communication strategy carried out by Chinese public health agencies during the first wave of avian influenza A(H7N9) outbreak in humans in 2013. METHODS: Participants were recruited from communities in Beijing, Lanzhou and Hangzhou, China in May and June 2013 by convenience sampling. Demographics and other relevant information were collected using a self-administered questionnaire. Focus group interviews were conducted using a set of nine pre-developed questions and a tested moderator guide. The interviews were audio recorded and were transcribed verbatim. The constant comparative method was used to identify trends and themes. RESULTS: A total of nine focus group interviews, with 94 participants recruited from nine communities, were conducted. Most participants received H7N9 information via television and the Internet. Most the participants appreciated the transparency and timeliness of the information released by the government. They expressed a sense of trust in the recommended public health advice and followed most of them. The participants suggested that the government release more information about clinical treatment outcomes, have more specific health recommendations that are practical to their settings and expand the use of new media channels for risk communication. CONCLUSION: The public perceived the overall risk communication strategy by the Chinese public health agencies as effective, though the moderator had a governmental agency title that might have biased the results. There is a need to expand the use of social media for risk communication in the future. PMID- 27757258 TI - Measles prevention in adolescents: lessons learnt from implementing a high school catch-up vaccination programme in New South Wales, Australia, 2014-2015. AB - INTRODUCTION: In response to a significant increase of measles cases and a high percentage of unvaccinated adolescents in New South Wales, Australia, a measles high school catch-up vaccination programme was implemented between August and December 2014. This study aimed to explore the factors affecting school-based supplementary immunization activities (SIAs) and to inform future SIA and routine school-based vaccination programme implementation and service provision. METHODS: Focus group analysis was conducted among public health unit (PHU) staff responsible for implementing the SIA catch-up programme. Key areas discussed were pre-programme planning, implementation, resources, consent materials, media activity and future directions for school vaccination programme delivery. Sessions were audio recorded, transcribed verbatim and reviewed. Thematic analysis was conducted to identify the major themes. RESULTS: Two independent focus groups with 32 participants were conducted in January 2015. Barriers to the SIA implementation included lead time, consent processes, interagency collaboration, access to the targeted cohort and the impact of introducing a SIA to an already demanding curriculum and school programme immunization schedule. A positive PHU school coordinator rapport and experience of PHU staff facilitated the implementation. Consideration of different approaches for pre-clinic vaccination status checks, student involvement in the vaccination decision, online consent, workforce sharing between health districts and effective programme planning time were identified for improving future SIA implementation. CONCLUSION: Although many barriers to school programme implementation have been identified in this study, with adequate resourcing and lead time, SIAs implemented via a routine school vaccination programme are an appropriate model to target adolescents. PMID- 27757259 TI - Responding to the syphilis outbreak in Japan: piloting a questionnaire to evaluate potential risk factors for incident syphilis infection among men who have sex with men in Tokyo, Japan, 2015. PMID- 27757260 TI - Medicinal plants used by traditional healers from South-West Algeria: An ethnobotanical study. AB - BACKGROUND/AIM: This study aimed to document and analyzes the local knowledge of medicinal plants' use by traditional healers in South-west Algeria. METHODS: The ethnobotanical survey was conducted in two Saharian regions of South-west of Algeria: Adrar and Bechar. In total, 22 local traditional healers were interviewed using semi-structured questionnaire and open questions. Use value (UV), fidelity level (FL), and informant consensus factor (FIC) were used to analyze the obtained data. RESULTS: Our results showed that 83 medicinal plants species belonging to 38 families are used by traditional healers from South-west of Algeria to treat several ailments. Lamiaceae, Asteraceae, Apiaceae, and Fabaceae were the most dominant families with 13, 8, 6, and 4 species, respectively. Leaves were the plant parts mostly used (36%), followed by seeds (18%), aerial parts (17%) and roots (12%). Furthermore, a decoction was the major mode of preparation (49%), and oral administration was the most preferred (80%). Thymus vulgaris L. (UV = 1.045), Zingiber officinale Roscoe (UV = 0.863), Trigonella foenum-graecum L. (UV=0.590), Rosmarinus officinalis L. (UV = 0.545), and Ruta chalepensis L. (UV = 0.5) were the most frequently species used by local healers. A great informant consensus has been demonstrated for kidney (0.727), cancer (0.687), digestive (0.603), and respiratory diseases. CONCLUSION: This study revealed rich ethnomedicinal knowledge in South-west Algeria. The reported species with high UV, FL, and FIC could be of great interest for further pharmacological studies. PMID- 27757261 TI - DNA protective effect of ginseng and the antagonistic effect of Chinese turnip: A supplementation study. AB - AIM: The aim of this clinical study is to provide scientific evidence for supporting traditional Chinese application and usage to the patients. For this purpose, we tested the ability if Panax ginseng extract to lower oxidative damage to nuclear DNA in human lymphocytes by comparing the effect of cooked Chinese turnip on this effect. MATERIALS AND METHODS: Seven healthy subjects (4 males and 3 females from 37 to 60 years) participated two occasions which were at least 2 weeks apart. About 2 mL of fasting blood sample for baseline measurement was taken on arrival. They were requested to ingest the content of 5 ginseng capsules in 200 mL water. The subject remained fasting for 2 h until the second blood sample taken. In the other occasion, the experiment was repeated except a piece of cooked turnip (10 g) was taken with the ginseng extract. The two occasions could be interchanged. Comet assay was performed on two specimens on the same day for the evaluation of lymphocytic DNA damage with or without oxidative stress. RESULTS: For the group with ginseng supplementation, there was a significant decrease in comet score for hydrogen peroxide (H2O2) treatment over the 2-h period while no change in DNA damage for unstressed sample. For the group with ginseng together with turnip supplementation, there was no significant difference in comet score for both H2O2 treatment and phosphate-buffered saline treatment. Ginseng extract could reduce DNA damage mediated by H2O2 effectively, but this protection effect was antagonized by the ingestion of cooked turnip at the same time. CONCLUSION: In the current study, commercial ginseng extract was used for supplementing volunteers. Ginseng extract could protect DNA from oxidative stress in vivo while turnip diminished the protection. PMID- 27757262 TI - Treatment of hemorrhoids with individualized homeopathy: An open observational pilot study. AB - AIM: Controversies and disagreement exist on conventional treatment strategies of hemorrhoids due to relapse, inefficacy, and complications. We intend to evaluate the role of individualized homeopathic treatment in hemorrhoids. MATERIALS AND METHODS: In this prospective, open, observational trial, hemorrhoids patients were treated using five standardized scales measuring complaints severity and anoscopic score. It was conducted at two homeopathic hospitals in India, during from mid-July 2014 to mid-July 2015. Patients were intervened as per individualized homeopathic principles and followed up every month up to 6 months. RESULTS: Total 73 were screened, 52 enrolled, 38 completed, 14 dropped out. Intention to treat population (n: = 52) was analyzed in the end. Statistically significant reductions of mean bleeding (month 3: -21.8, 95% confidence interval [CI]: -30.3, -13.3, P: < 0.00001, d = 0.787; month 6: -25.5, 95% CI -35.4, -15.6, P: < 0.00001, d = 0.775), pain (month 3: -21.3, 95% CI -28.6, -14.0, P: < 0.00001, d = 0.851; month 6: -27.6, 95% CI -35.6, -19.6, P: < 0.00001, d = 1.003), heaviness visual analog scales (VASs) (month 3: -8.1, 95% CI -13.9, -2.3, P: = 0.008, d = 0.609; month 6: -12.1, 95% CI -19.1, -5.1, P: = 0.001, d = 0.693), and anoscopic score (month 3: -0.4, 95% CI -0.6, -0.2, P: < 0.0001, d = 0.760; month 6: -0.5, 95% CI -0.7, -0.3, P: < 0.0001, d = 0.703) were achieved. Itching VASs reduced significantly only after 6 months (-8.1, 95% CI -14.6, -1.6, P: = 0.017, d = 0.586). No significant lowering of discharge VASs was achieved after 3 and 6 months. CONCLUSION: Under classical homeopathic treatment, hemorrhoids patients improved considerably in symptoms severity and anoscopic scores. However, being observational trial, our study cannot provide efficacy data. Controlled studies are required. Trial Reg. CTRI/2015/07/005958. PMID- 27757263 TI - In vitro xanthine oxidase and albumin denaturation inhibition assay of Barringtonia racemosa L. and total phenolic content analysis for potential anti inflammatory use in gouty arthritis. AB - AIM: This study was conducted to evaluate the in vitro anti-inflammatory activities and total phenolic content (TPC) of methanolic extracts of infloresence axes, endosperms, leaves, and pericarps of Barringtonia racemosa L. METHODS: The anti-inflammatory study was conducted by assessing the potential through xanthine oxidase (XO) and albumin denaturation inhibition assays. Meanwhile, the TPC in the extracts were assessed by Folin-Ciocalteu assay. RESULTS: In the XO inhibition assay, the infloresence axes extract was found to exert the highest inhibition capacity at 0.1% (w/v) with 59.54 +/- 0.001% inhibition followed by leaves (58.82 +/- 0.001%), pericarps (57.99 +/- 0.003%), and endosperms (57.20 +/- 0.003%) extracts. Similarly in the albumin denaturation inhibition assay, the infloresence axes extract had shown the greatest inhibition capacity with 70.58 +/- 0.004% inhibition followed by endosperms (66.80 +/- 0.024%), leaves (65.29 +/- 0.006%), and pericarps extracts (43.33 +/- 0.002%). Meanwhile, for TPC analysis, leaves extract was found to have the highest phenolic content (53.94 +/- 0.000 mg gallic acid equivalent [GAE]/g DW) followed by infloresence axes (31.54 +/- 0.001 mg GAE/g DW), endosperms (22.63 +/- 0.001 mg GAE/g DW), and the least was found in pericarps (15.54 +/- 0.001 mg GAE/g DW). CONCLUSION: The results indeed verified the in vitro anti-inflammatory activities of B. racemosa and supported its potential to be used in alleviating gouty arthritis and XO-related diseases. PMID- 27757264 TI - Hematological changes and nitric oxide levels accompanying high-dose artemether lumefantrine administration in male guinea pigs: Effect of unsweetened natural cocoa powder. AB - BACKGROUND: Unsweetened natural cocoa powder (UNCP), prepared after removal of the cocoa butter, is a common beverage in Ghana. It possesses antimalarial prophylactic property and has a beneficial effect on blood components. AIM: The aim of this study was to determine whether regular dietary supplement of UNCP mitigates high-dose (HD) artemether-lumefantrine (A-L)-induced hematological disorders and to determine the effect on nitric oxide (NO) levels. MATERIALS AND METHODS: Adult male guinea pigs (300 g - 350 g) were randomly divided into 5 groups of 6 guinea pigs each. Among the 5 groups, 3 groups were treated with UNCP (300, 900, and 1500 mg/kg body weight) for 14 days. A-L (75 mg/kg) was administered from the 12th to 14th day. One of the remaining 2 groups received distilled water only, i.e., vehicle control group (VCG) while the other received 75 mg/kg A-L only, i.e., negative control group (NCG). Blood samples from all groups were obtained by cardiac puncture (day 15) followed by hematological and NO analysis. RESULTS: A-L reduced white blood cells (WBC) by 31.87%, lymphocyte count by 45.99%, hemoglobin by 11.72%, hematocrit by 18.56%, and platelet count by 33.08% in the NCG. Administration of various doses of UNCP increased WBC and lymphocyte count (P > 0.05) compared to the NCG. UNCP and A-L combination caused an increase in NO levels when compared to the VCG. CONCLUSION: Regular consumption of UNCP by guinea pigs increases plasma NO and restores some hematological disorders induced by a 3-day HD A-L administration. PMID- 27757265 TI - Antibacterial synergy between rosmarinic acid and antibiotics against methicillin resistant Staphylococcus aureus. AB - AIM/BACKGROUND: Medicinal plants have ability to resist microorganisms by synthesizing secondary metabolites such as phenols. Rosmarinic acid (RA) is a phenylpropanoid widely distributed in plants and well known as therapeutic and cosmetic agent. Methicillin-resistant Staphylococcus aureus (MRSA) which is resistant to all kinds of beta-lactams, threatens even most potent antibiotics. To improve the efficiency of antibiotics against multi-drug resistant bacteria and to reduce the antibiotic dose, the antibacterial activity and the synergistic effect of RA with standard antibiotics against S. aureus and MRSA was investigated. MATERIALS AND METHODS: Antibacterial activity of RA against S. aureus and a clinical isolate of MRSA was evaluated by agar well diffusion method. Minimum inhibitory concentration (MIC) of RA was determined by broth dilution method. Synergism of RA with various antibiotics against S. aureus and MRSA was studied by broth checkerboard method and time-kill kinetic assay. Effect of RA on microbial surface components recognizing adhesive matrix molecules (MSCRAMM's) of S. aureus and MRSA was studied using sodium dodecyl sulfate - polyacrylamide gel electrophoresis. RESULTS: MIC of RA was found to be 0.8 and 10 mg/ml against S. aureus and MRSA, respectively. RA was synergistic with vancomycin, ofloxacin, and amoxicillin against S. aureus and only with vancomycin against MRSA. The time-kill analysis revealed that synergistic combinations were a more effective than individual antibiotics. MSCRAMM's protein expression of S. aureus and MRSA was markedly suppressed by RA + vancomycin combination rather than RA alone. CONCLUSION: The synergistic effects of RA with antibiotics were observed against S. aureus and MRSA. RA showed inhibitory effect on the surface proteins MSCRAMM's. Even though RA was shown to exhibit a synergistic effect with antibiotics, the MIC was found to be higher. Thus, further studies on increasing the efficacy of RA can develop it as an adjuvant for antibiotics. PMID- 27757266 TI - Antidiabetic and antioxidant effects of Croton lobatus L. in alloxan-induced diabetic rats. AB - BACKGROUND: Croton lobatus contains a high amount of antioxidant phytochemicals that probably account for its wide use as food and medicine in the traditional communities of West Africa. METHODS: The study evaluated the modulatory role of methanol extract of Croton lobatus leaf on alloxan-induced diabetes and associated cardiovascular complications. Male rats were randomly selected and assigned to one of six groups (A to F) of eight animals each: A (distilled water); B (corn oil); C (Alloxan); D (Alloxan + 100 mg kg-1 Croton lobatus); E: (Alloxan + 200 mg kg-1 C. lobatus); and F (Alloxan + 100 mg kg-1 glibenclamide). RESULTS: Acute toxicity studies revealed no mortality of rats at the administration of different doses of extract up to the 5,000 mg kg-1 dose. Histology of the pancreas showed focal area of necrosis, and fatty infiltration in diabetic untreated rats, but these lesions were absent in pancreas of rats treated with C. lobatus extract. CONCLUSION: Methanol leaf extract of C. lobatus reduced arteriogenic risk factors, improved antioxidant status, restored the observable pathological lesions associated with experimental diabetes in rats, and thus offers a new therapeutic window as herbal therapy for the treatment of diabetes mellitus and associated cardiovascular complications. PMID- 27757267 TI - Evaluation of the synergistic effect of Allium sativum, Eugenia jambolana, Momordica charantia, Ocimum sanctum, and Psidium guajava on hepatic and intestinal drug metabolizing enzymes in rats. AB - AIMS/BACKGROUND: This study was to investigated the synergistic effect of polyherbal formulations (PHF) of Allium sativum L., Eugenia jambolana Lam., Momordica charantia L., Ocimum sanctum Linn., and Psidium guajava L. in the inhibition/induction of hepatic and intestinal cytochrome P450 (CYPs) and Phase II conjugated drug metabolizing enzymes (DMEs). Consumption of these herbal remedy has been extensively documented for diabetes treatment in Ayurveda. METHODOLOGY: PHF of these five herbs was prepared, and different doses were orally administered to Sprague-Dawley rats of different groups except control group. Expression of mRNA and activity of DMEs were examined by real-time polymerase chain reaction and high performance liquid chromatography in isolated liver and intestine microsomes in PHF pretreated rats. RESULTS: The activities of hepatic and intestinal Phase-II enzyme levels increased along with mRNA levels except CYP3A mRNA level. PHF administration increases the activity of hepatic and intestinal UDP-glucuronyltransferase and glutathione S-transferase in response to dose and time; however, the activity of hepatic sulfotransferase increased at higher doses. CONCLUSIONS: CYPs and Phase-II conjugated enzymes levels can be modulated in dose and time dependent manner. Observations suggest that polyherbal formulation might be a possible cause of herb-drug interaction, due to changes in pharmacokinetic of crucial CYPs and Phase-II substrate drug. PMID- 27757268 TI - In vitro antileishmanial and antimalarial activity of selected plants of Nepal. AB - BACKGROUND: Nepal is very rich in biodiversity, and no extensive effort has yet been carried out to screen plants that are used by traditional healers against parasitic diseases. The aim of this study was to evaluate the in vitro antileishmanial and antimalarial activity of crude methanolic or ethanolic extracts of 29 plant species that are currently used by local people of Nepal for treating different ailments. METHODS: Crude extracts of leaves, twigs, aerial parts, and/or roots of the selected plants were evaluated for in vitro inhibitory activity against intracellular amastigotes of Leishmania infantum and against erythrocytic stages of Plasmodium falciparum. To determine the selectivity index (SI), cytotoxicity was assessed on MRC-5 cells in parallel. RESULTS: Three plant species, namely Phragmites vallatoria and Ampelocissus tomentosa, for which no antiprotozoal activity has previously been reported, and Terminalia chebula revealed antiprotozoal activity. The extract of A. tomentosa exhibited moderate activity against L. infantum with an inhibitory concentration 50% (IC50) of 13.2 +/- 4.3 ug/ml and SI >3, while T. chebula exhibited fairly good antiplasmodial activity with IC50 values of 4.5 +/- 2.4 ug/ml and SI values >5. CONCLUSION: In countries like Nepal, where the current health system is unable to combat the burden of endemic parasitic diseases, evaluation of local plants as a potential source of the drug can help in expanding the treatment options. The extent of untapped resources available in these countries provides an opportunity for future bioprospecting. PMID- 27757269 TI - Anthelmintic activity of a standardized extract from the rhizomes of Acorus calamus Linn. (Acoraceae) against experimentally induced cestodiasis in rats. AB - BACKGROUND: The rhizomes of a herb Acorus calamus Linn. (Acoraceae) have been widely used as a traditional medicine to cure intestinal-helminthic infections in India and South Africa. AIM: This study was undertaken to investigate the in vivo anthelmintic activity of a standardized methanolic extract obtained from the rhizomes A. calamus in a rodent model. MATERIALS AND METHODS: A methanolic extract obtained from rhizomes of A. calamus was characterized for active principle using nuclear magnetic resonance 1H NMR, 13C NMR, mass and infrared spectroscopy. The amount of active principle in rhizome isolated active fraction of plant was assayed using high-performance liquid chromatography (HPLC). Later, the standardized rhizome extract of plant and its active principle were tested for in vivo anthelmintic efficacy against experimentally induced Hymenolepis diminuta, a zoonotic cestode, infections in rats. RESULTS: The study revealed that b-asarone is the active principle of plant. The HPLC analysis of local variety of A. calamus revealed that active fraction contains 83.54% (w/w) of b asarone. The in vivo study revealed that treatment of H. diminuta infected rats by a single 800 mg/kg dose of rhizome extract for 5 days results into 62.30% reduction in eggs per gram of feces counts and 83.25% reduction in worm counts of animals. These findings compared well with the efficacy of a reference drug, praziquantel. The active principle b-asarone showed slightly better anthelmintic effects than crude extract. In acute toxicity assay, a single oral 2000 mg/kg dose of extract did not reveal any signs of toxicity or mortality in mice, and the LD50 of the extract was noted to be >2000 mg/kg. CONCLUSION: Taken together, the results of this study indicate that rhizomes of A. calamus bear significant dose-dependent effects against intestinal helminths. Further, the Indian variety of A. calamus contains high b-asarone content. Therefore, there exists a great potential to develop some suitable anthelmintic herbal products from this plant. PMID- 27757270 TI - Inhibitory effect of leaves extracts of Ocimum basilicum and Ocimum gratissimum on two key enzymes involved in obesity and hypertension in vitro. AB - AIM: To evaluate the phenolics composition and inhibitory effect of the leaves extracts of Ocimum basilicum and Ocimum gratissimum on two key enzymes (pancreatic lipase [PL] and angiotensin 1-converting enzyme [ACE]) involved in obesity and hypertension in vitro. MATERIALS AND METHODS: The phenolics (flavonoids and phenolic acids) were quantified using high-performance liquid chromatography coupled with diode array detection. PL and ACE inhibitory effects; DPPH* and ABTS*+ scavenging activities of the extracts were tested using spectrophotometric methods. RESULTS: O. basilicum had the following major phenolics: Rutin, quercetin, and quercitrin (flavonoids); caffeic, chlorogenic, and gallic acids (phenolic acids); while O. gratissimum had the following major phenolics: Rutin, quercitrin, and luteolin (flavonoids); ellagic and chlorogenic acids (phenolic acids). "Extracts of both plants inhibited PL and ACE; scavenged DPPH* in a dose-dependent manner". O. gratissimum extract was more potent in inhibiting PL (IC50: 20.69 ug/mL) and ACE (IC50: 29.44 ug/mL) than O. basilicum (IC50: 52.14 ug/mL and IC50: 64.99 ug/mL, against PL and ACE, respectively). O. gratissimum also scavenged DPPH* and ABTS*+ more than O. basilicum. CONCLUSION: O. basilicum and O. gratissimum leaves could be used as functional foods for the management of obesity and obesity-related hypertension. However, O. gratissimum may be more effective than O. basilicum. PMID- 27757271 TI - Comparative evaluation of anti-obesity effect of Aloe vera and Gymnema sylvestre supplementation in high-fat diet fed C57BL/6J mice. AB - BACKGROUND: The aim of the present study was to investigate, anti-obesity effect of Aloe vera (AV), and Gymnema sylvestre (GS) whole extract powders administration to high-fat diet (HFD) fed C57BL/6J mice for 12 weeks. MATERIALS AND METHODS: At the end of experiment, different parameters such as body weight, feed intake, organ weights, fasting blood glucose, oral glucose tolerance test, plasma lipid levels, and expression analysis of adipocytokines were evaluated. RESULTS: At the end of experimental period, oral administration of both herbs showed a significant (P < 0.05 and P < 0.001) decrease in the plasma glucose and lipid levels in HFD fed mice. In addition, increased in the epididymal fat (E. fat) weight in the HFD group was significantly (P < 0.05) reduced on GS administration alone. Finally, quantitative mRNA expression analysis of adiponectin gene was significantly up-regulated in AV supplementation. Further, no effect was observed with the both herbs on pro-inflammatory cytokines (interleukin 6 and tumor necrosis factor-a) in the E. fat tissue of HFD fed group. CONCLUSIONS: The anti-obesity and other metabolic studies depend on the type of diet, different parts of herbal extractions, and animal models used. Further studies are required in this area to strengthen the anti-obesity effects of herbs with active component, and it can be used a pro-drug instead of whole extract. PMID- 27757272 TI - Effect of orlistat alone or in combination with Garcinia cambogia on visceral adiposity index in obese patients. AB - AIM: The objective of this study was to estimate the effect of orlistat alone and in combination with Garcinia cambogia on visceral adiposity index (VAI) in obese patients. PATIENTS AND METHODS: A total of 99 obese male patients were recruited with aged range between 37 and 46 years. They were randomized into three equal groups, first group treated with orlistat 120 mg/day, second group treated with G. cambogia 166 mg/day, and third group treated with orlistat 120 mg/day plus G. cambogia 166 mg/day. The duration of the treatments was three consecutive months. Body mass index (BMI), VAI, blood pressure, blood glucose, total lipid profile, atherogenic index, and cardiac risk ratio were recorded at baseline and after 3 months. RESULTS: The treatment with G. cambogia leads to reduction in VAI P < 0.05, whereas orlistat has a beneficial effect on cardiometabolic profiles without a reduction in VAI P > 0.05. Combined therapy of G. cambogia plus orlistat showed the more significant effect in reduction of VAI P < 0.05, cardiometabolic profiles and anthropometric measures P < 0.01 compared to pretreatment period. CONCLUSION: Combination of G. cambogia with orlistat lead to more significant effect than orlistat alone in amelioration of cardiometabolic profile and VAI in obese patients. PMID- 27757273 TI - Evaluation of anti-epileptic activity of leaf extracts of Punica granatum on experimental models of epilepsy in mice. AB - OBJECTIVES: This study was aimed to examine the anti-epileptic activity of leaf extracts of Punica granatum in experimental models of epilepsy in Swiss albino mice. MATERIALS AND METHODS: Petroleum ether leaf extract of P. granatum (PLPG), methanolic LPG (MLPG), and aqueous LPG (ALPG) extracts of P. granatum leaves was initially evaluated against 6-Hz-induced seizure model; the potent extract was further evaluated against maximal electroshock (MES) and pentylenetetrazole (PTZ) induced convulsions. Further, the potent extract was evaluated for its influence on Gamma amino butyric acid (GABA) levels in brain, to explore the possible mechanism of action. In addition, the potent extract was subjected to actophotometer test to assess its possible locomotor activity deficit inducing action. RESULTS: In 6-Hz seizure test, the MLPG has alleviated 6-Hz-induced seizures significantly and dose dependently at doses 50, 100, 200, and 400 mg/kg. In contrast, PLPG and ALPG did not show any protection, only high dose of ALPG (400 and 800 mg/kg, p.o.) showed very slight inhibition. Based on these observations, only MLPG was tested in MES and PTZ models. Interestingly, the MLPG (50, 100, 200 and 400 mg/kg) has offered significant and dose-dependent protection against MES (P < 0.01) and PTZ-induced (P < 0.01) seizures in mice. Further, MLPG showed a significant increase in brain GABA levels (P < 0.01) compared to control and showed insignificant change in locomotor activity in all tested doses (100, 200 and 400 mg/kg). Interestingly, higher dose of MLPG (400 mg/kg, p.o.) and Diazepam (5 mg/mg, p.o.) have completely abolished the convulsions in all the anticonvulsant tests. CONCLUSION: These findings suggest that MLPG possesses significant anticonvulsant property, and one of the possible mechanisms behind the anticonvulsant activity of MLPG may be through enhanced GABA levels in the brain. PMID- 27757274 TI - Effects of herbal medicine on human uterine tumor-bearing nude mice. AB - AIM: Uterine leiomyomas are the most common benign uterine neoplasms associated with significant morbidity. Herbal formulas capable of restoring yin-yang balance by dispersing blood stasis may be useful for managing fibroid symptoms. MATERIALS AND METHODS: In this study, the antitumor properties of three herbs viz., Trogopterus xanthipes Milen-Edwards, Paeonia lactiflora Pallas, and Ulmus davidiana Planch were evaluated in nude mice injected intravenously with human malignant myomas. Tumor fragments were xenografted subcutaneously through a flank incision in female mice. The mice entered the study for 8 weeks when their tumors reached the threshold volume (260 mm3). The mice were randomly allocated to receive subcutaneous injections of normal saline (Group 1; negative control), P. lactiflora Pallas (Group 2), U. davidiana Planch (Group 3), T. xanthipes Milen Edwards (Group 4), and intravenous injections of paclitaxel (Group 5; positive control). The weight and tumor volume were measured, followed by histopathology. RESULTS: A few cases of abdominal distention and death were observed in the negative control group. Furthermore, a considerable enlargement of the liver and spleen was observed in the negative control group at autopsy with a gradual increase in body weight during the experiment. The mean tumor volume which increased in negative control mice reduced in mice treated with herbal remedies or paclitaxel from day 14 onwards (P < 0.05). The degree of necrosis and apoptosis induction from herbal treatments was similar to that of paclitaxel. CONCLUSION: Collectively, three herbs viz., T. xanthipes Milen-Edwards, P. lactiflora Pallas, and U. davidiana Planch were able to induce necrosis and apoptosis of uterine leiomyoma cells, proving antitumor properties against uterine fibroids. PMID- 27757275 TI - In vitro and in vivo anthelmintic effects of Caesalpinia bonducella (L.) Roxb. leaf extract on Hymenolepis diminuta (Cestoda) and Syphacia obvelata (Nematoda). AB - BACKGROUND: Leaves of Caesalpinia bonducella (L.) Roxb. have been traditionally used as an herbal remedy to treat the intestinal helminthic infections in traditional medicine of India. AIM: This study was undertaken to evaluate the potential in vitro and in vivo anthelmintic effects of C. bonducella leaf extract against Syphacia obvelata (Nematoda) and Hymenolepis diminuta (Cestoda). MATERIALS AND METHODS: The in vitro anthelmintic activity of the extract was investigated on adult worms of S. obvelata (Nematoda) and H. diminuta (Cestoda) in terms of physical motility and mortality of parasites. The in vivo study was performed in H. diminuta-rat model and S. obvelata-mice model, by monitoring the egg per gram of feces count and worm count of animals following the treatment with different doses of plant extract. RESULTS: The study recorded significant and dose-dependent anthelmintic effects of the extract on both the parasites. In the in vitro study, 30 mg/ml concentration of extract caused mortality of H. diminuta in 2.5 +/- 0.2 h and S. obvelata in 3.57 +/- 0.16 h. In the in vivo study, the extract showed a comparatively better efficacy on S. obvelata, where its 800 mg/kg dose revealed 93% reduction of worm load in mice, as compared to 85% worm load reduction of H. diminuta in rats. CONCLUSIONS: The findings suggest that leaf extract of C. bonducella possesses significant anthelmintic effects and supports its use as an anthelmintic in traditional medicine. This appears to be the first report of in vivo anthelmintic activity of C. bonducella against these parasites. PMID- 27757276 TI - Evaluation of wound healing activity of cow urine ark in diabetic Wistar albino rats. AB - AIM: To evaluate wound healing activity of cow urine ark in diabetic rats. MATERIALS AND METHODS: Streptozotocin-induced diabetic Wistar albino rats were randomly divided into six groups (n = 6). Three groups - diabetic control, active control (glibenclamide), and treatment (cow urine ark) were operated for excision wounds (EWs). Rats in these groups received distilled water 1 ml/day, glibenclamide 0.5 mg/kg body weight/day, and cow urine ark 5.5 ml/kg body weight/day orally till complete healing of the EWs. EWs were evaluated for wound contraction on 3rd, 7th, and 11th day and for reepithelization on 11th day. The other three groups were operated for incision wounds (IW) as well as dead space wounds (DW) in the same animal which received the above agents orally for 11 days. IWs were analyzed for wound breaking strength and DWs were analyzed for dry weight, hydroxyproline content, and histology of granulation tissue. RESULTS: EWs showed significantly increased wound closure in the treatment group as compared to the diabetic as well as active control groups at 3rd (P < 0.001) and 11th (P < 0.05) post-wounding day and to the only diabetic control group at 7th (P < 0.01) post-wounding day. IWs showed significant improvement in wound breaking strength in the treatment as compared to diabetic (P < 0.001) and active control (P < 0.01) groups. DWs showed significant increase in hydroxyproline content of granulation tissue in the treatment as compared to diabetic control (P < 0.001) and active control (P < 0.001) groups. Wound breaking strength and hydroxyproline content also significantly increased in the active control group compared to diabetic control (P < 0.001 and P < 0.05, respectively). Granulation tissue dry weight was significantly increased in treatment and active control groups as compared to diabetic control (P < 0.001). CONCLUSION: Cow urine ark increases granulation tissue formation as well as collagen content. Wound contraction was also significantly improved. The cow urine ark could be potentially effective in promoting healing of diabetic wounds by increasing granulation tissue formation and collagen content, however, further studies are required for its clinical application. PMID- 27757278 TI - Off target effects of statins shape total mortality? PMID- 27757277 TI - Effects of a diet containing Brazilian propolis on lipopolysaccharide-induced increases in plasma plasminogen activator inhibitor-1 levels in mice. AB - BACKGROUND: Brazilian propolis has many biological activities including the ability to help prevent thrombotic diseases, but this particular effect has not been proven. Plasma levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, increase under inflammatory conditions such as infection, obesity and atherosclerosis and such elevated levels predispose individuals to a risk of developing thrombotic diseases. AIM: This study aimed to determine the effects of a diet containing Brazilian propolis on lipopolysaccharide (LPS)-induced increases in plasma PAI-1 levels. MATERIALS AND METHODS: Mice were fed with a diet containing 0.5% (w/w) Brazilian propolis for 8 weeks. Thereafter, the mice were subcutaneously injected with saline containing 0.015 mg/kg of LPS and sacrificed 4 h later. RESULTS: Orally administered Brazilian propolis significantly suppressed the LPS-induced increase in PAI-1 antigen and its activity in mouse plasma. CONCLUSION: This study indicated that Brazilian propolis contains natural products that can decrease thrombotic tendencies in mice. PMID- 27757279 TI - ULTRASONOGRAPHY, AN EFFECTIVE TOOL IN DIAGNOSING PLANTAR FASCIITIS: A SYSTEMATIC REVIEW OF DIAGNOSTIC TRIALS. AB - BACKGROUND: Plantar fasciitis (PF) is the most common cause of heel pain that affects 10% of the general population, whether living an athletic or sedentary lifestyle. The most frequent mechanism of injury is an inflammatory response that is caused by repetitive micro trauma. Many techniques are available to diagnose PF, including the use of ultrasonography (US). PURPOSE: The purpose of this study is to systematically review and appraise previously published articles published between the years 2000 and 2015 that evaluated the effectiveness of using US in the process of diagnosing PF, as compared to alternative diagnostic methods. METHODS: A total of eight databases were searched to systematically review scholarly (peer reviewed) diagnostic and intervention articles pertaining to the ability of US to diagnose PF. RESULTS: Using specific key words the preliminary search yielded 264 articles, 10 of which were deemed relevant for inclusion in the study. Two raters independently scored each article using the 15 point modified QUADAS scale. DISCUSSION: Six studies compared the diagnostic efficacy of US to another diagnostic technique to diagnose PF, and four studies focused on comparing baseline assessment of plantar fascia before subsequent intervention. The most notable US outcomes measured were plantar fascia thickness, enthesopathy, and hypoechogenicity. CONCLUSION: US was found to be accurate and reliable compared to alternative reference standards like MRI in the diagnosis of PF. The general advantages of US (e.g. cost efficient, ease of administration, non-invasive, limited contraindications) make it a superior diagnostic modality in the diagnosis of PF. US should be considered in rehabilitation clinics to effectively diagnose PF and to accurately monitor improvement in the disease process following rehabilitation interventions. LEVEL OF EVIDENCE: 1A. PMID- 27757280 TI - THE EFFECTIVENESS OF DRY NEEDLING AND STRETCHING VS. STRETCHING ALONE ON HAMSTRING FLEXIBILITY IN PATIENTS WITH KNEE PAIN: A RANDOMIZED CONTROLLED TRIAL. AB - BACKGROUND: Recently, dry needling has emerged as a popular treatment for muscular pain and impairments. While there are numerous studies detailing the benefits of dry needling for pain, few studies exist examining the effects on soft tissue mobility. PURPOSE: The purpose of this study was to determine if the addition of hamstring dry needling to a standard stretching program results in greater improvements in hamstring flexibility compared to sham dry needling and stretching in subjects with atraumatic knee pain. Additionally, squat range of motion, knee pain, and the Lower Extremity Functional Scale were compared between the two groups. STUDY DESIGN: Double blinded randomized controlled trial. METHODS: Thirty-nine subjects were randomized to receive either dry needling (n = 20) or sham (n = 19) dry needling in addition to hamstring stretching, to all detected hamstring trigger points on two visits. All dependent variables were measured at baseline, immediately post intervention, and 1, 3, and 7 days after the initial treatment. Each subject also performed hamstring stretching three times daily for one week. RESULTS: Significant improvements in hamstring range of motion and all other dependent variables were observed across time regardless of treatment group. However, the lack of significant time by group interactions indicated the improvements were not different between dry needling and sham dry needling groups. CONCLUSIONS: The results of the current randomized controlled trial suggest that two sessions of dry needling did not improve hamstring range of motion or other knee pain-related impairments more than sham dry needling in a young active population with atraumatic knee pain. LEVEL OF EVIDENCE: Therapy, Level 2. PMID- 27757282 TI - THE ADOLESCENT MEASURE OF CONFIDENCE AND MUSCULOSKELETAL PERFORMANCE (AMCAMP): DEVELOPMENT AND INITIAL VALIDATION. AB - BACKGROUND: Although the relationship of self-efficacy to sports performance is well established, little attention has been paid to self-efficacy in the movements or actions that are required to perform daily activities and prepare the individual to resume sports participation following an injury and associated period of rehabilitation. There are no instruments to measure self-confidence in movement validated in an adolescent population. PURPOSE: The purpose of this paper is to report on the development of the AMCaMP, a self-report measure of confidence in movement and provide some initial evidence to support its use as a measure of confidence in movement. METHODS: The AMCaMP was adapted from OPTIMAL, a self-report instrument that measures confidence in movement, which had been previously designed and validated in an adult population. Data were collected from 1,115 adolescent athletes from 12 outpatient physical therapy clinics in a single healthcare system. RESULTS: Exploratory factor analysis of the 22 items of the AMCaMP using a test sample revealed a three factor structure (trunk, lower body, upper body). Confirmatory factor analysis using a validation sample demonstrated a similar model fit with the data. Reliability of scores on each of three clusters of items identified by factor analysis was assessed with coefficient alpha (range = 0.82 to 0.94), Standard Error of Measurement (1.38 to 2.74), and Minimum Detectable Change (3.83 to 7.6). CONCLUSIONS: AMCaMP has acceptable psychometric properties for use in adolescents (ages 11 to 18) as a patient-centric outcome measure of confidence in movement abilities after rehabilitation. LEVEL OF EVIDENCE: IV. PMID- 27757281 TI - A DELPHI STUDY OF RISK FACTORS FOR ACHILLES TENDINOPATHY- OPINIONS OF WORLD TENDON EXPERTS. AB - BACKGROUND AND PURPOSE: Achilles tendinopathy can be a debilitating chronic condition for both active and inactive individuals. The identification of risk facors is important both in preventing but also treating tendinopathy, many factors have been proposed but there is a lack of primary epidemiological data. The purpose of this study was to develop a statement of expert consensus on risk factors for Achilles tendinopathy in active and sedentary patient populations to inform a primary epidemiological study. STUDY DESIGN: Delphi study. METHODS AND MEASURES: An online Delphi study was completed inviting participation from world tendon experts. The consensus was developed using three rounds of the Delphi technique. The first round developed a complete list of potential risk factors, the second round refined this list but also separated the factors into two population groups - active/athletic and inactive/sedentary. The third round ranked this list in order of perceived importance. RESULTS: Forty-four experts were invited to participate, 16 participated in the first round (response rate 40%) and two dropped out in the second round (resulting in a response rate of 35%). A total of 27 intrinsic and eight extrinsic risk factors were identified during round one. During round two only 12 intrinsic and five extrinsic risk factors were identified as important in active/athletic tendinopathy while 14 intrinsic and three extrinsic factors were identified as important for inactive/sedentary tendinopathy. CONCLUSIONS: Risk factors for Achilles tendinopathy were identified based on expert consensus, and these factors provide a basis for primary epidemiological studies. Plantarflexor strength was identified as the primary modifiable factor in the active/athletic group while systemic factors were identified as important in the inactive/sedentary group, many of the potential factors suggested for either group were non-modifiable. Non modifiable factors include: previous tendinopathy, previous injury, advancing age, sex, steroid exposure, and antibiotic treatment. LEVEL OF EVIDENCE: Level V. PMID- 27757283 TI - DIAGNOSTIC IMAGING IN A DIRECT-ACCESS SPORTS PHYSICAL THERAPY CLINIC: A 2-YEAR RETROSPECTIVE PRACTICE ANALYSIS. AB - BACKGROUND: While advanced diagnostic imaging is a large contributor to the growth in health care costs, direct-access to physical therapy is associated with decreased rates of diagnostic imaging. No study has systematically evaluated with evidence-based criteria the appropriateness of advanced diagnostic imaging, including magnetic resonance imaging (MRI), when ordered by physical therapists. The primary purpose of this study was to describe the appropriateness of magnetic resonance imaging (MRI) or magnetic resonance arthrogram (MRA) exams ordered by physical therapists in a direct-access sports physical therapy clinic. STUDY DESIGN: Retrospective observational study of practice. HYPOTHESIS: Greater than 80% of advanced diagnostic imaging orders would have an American College of Radiology (ACR) Appropriateness Criteria rating of greater than 6, indicating an imaging order that is usually appropriate. METHODS: A 2-year retrospective analysis identified 108 MRI/MRA examination orders from four physical therapists. A board-certified radiologist determined the appropriateness of each order based on ACR appropriateness criteria. The principal investigator and co-investigator radiologist assessed agreement between the clinical diagnosis and MRI/surgical findings. RESULTS: Knee (31%) and shoulder (25%) injuries were the most common. Overall, 55% of injuries were acute. The mean ACR rating was 7.7; scores from six to nine have been considered appropriate orders and higher ratings are better. The percentage of orders complying with ACR appropriateness criteria was 83.2%. Physical therapist's clinical diagnosis was confirmed by MRI/MRA findings in 64.8% of cases and was confirmed by surgical findings in 90% of cases. CONCLUSIONS: Physical therapists providing musculoskeletal primary care in a direct-access sports physical therapy clinic appropriately ordered advanced diagnostic imaging in over 80% of cases. Future research should prospectively compare physical therapist appropriateness and utilization to other groups of providers and explore the effects of physical therapist imaging privileging on outcomes. LEVEL OF EVIDENCE: Diagnosis, Level 3. PMID- 27757284 TI - THE RELATIONSHIP BETWEEN TRUNK ENDURANCE PLANK TESTS AND ATHLETIC PERFORMANCE TESTS IN ADOLESCENT SOCCER PLAYERS. AB - BACKGROUND: Although it is believed that trunk function is important for athletic performance, few researchers have demonstrated a significant relationship between the trunk function and athletic performance. Recently, the prone plank and side plank tests have been used to assess trunk function. PURPOSE: The purpose of this study was to investigate the relationships between trunk endurance plank tests and athletic performance tests, including whether there is a relationship between long distance running and trunk endurance plank tests in adolescent male soccer players. STUDY DESIGN: Cross sectional study design. METHODS: Fifty-five adolescent male soccer players performed prone and side plank tests and seven performance tests: the Cooper test, the Yo-Yo intermittent recovery test, the step 50 agility test, a 30-m sprint test, a vertical countermovement jump, a standing five-step jump, and a rebound jump. The relationships between each individual plank test, the combined score of both plank tests, and performance tests were analyzed using the Pearson correlation coefficient. RESULTS: The combined score of plank tests was highly correlated with the Yo-Yo intermittent recovery test (r = 0.710, p < 0.001), and was moderately correlated with the Cooper test (r = 0.567, p < 0.001). Poor correlation was observed between the prone plank test and step 50 agility test (r = -0.436, p = 0.001) and no significant correlations were observed between plank tests and jump performance tests. CONCLUSIONS: The results suggest that trunk endurance plank tests are positively correlated with the Yo-Yo intermittent recovery test, the Cooper test, and the step 50 agility test. LEVEL OF EVIDENCE: Level 2. PMID- 27757285 TI - THE CLINICAL, FUNCTIONAL AND BIOMECHANICAL PRESENTATION OF PATIENTS WITH SYMPTOMATIC HIP ABDUCTOR TENDON TEARS. AB - BACKGROUND: Hip abductor tendon (HAT) tearing is commonly implicated in greater trochanteric pain syndrome (GTPS), though limited information exists on the disability associated with this condition and specific presentation of these patients. PURPOSE: To describe the clinical, functional and biomechanical presentation of patients with symptomatic HAT tears. Secondary purposes were to investigate the association between these clinical and functional measures, and to compare the pain and disability reported by HAT tear patients to those with end-stage hip osteoarthritis (OA). STUDY DESIGN: Prospective case series. METHODS: One hundred forty-nine consecutive patients with symptomatic HAT tears were evaluated using the Harris (HHS) and Oxford (OHS) Hip Scores, SF-12, an additional series of 10 questions more pertinent to those with lateral hip pain, active hip range of motion (ROM), maximal isometric hip abduction strength, six minute walk capacity and 30-second single limb stance (SLS) test. The presence of a Trendelenburg sign and pelvis-on-femur (POF) angle were determined via 2D video analysis. An age matched comparative sample of patients with end-stage hip OA was recruited for comparison of all patient-reported outcome scores. Independent t tests investigated group and limb differences, while analysis of variance evaluated pain changes during the functional tests. Pearson's correlation coefficients investigated the correlation between clinical measures in the HAT tear group. RESULTS: No differences existed in patient demographics and patient reported outcome scores between HAT tear and hip OA cohorts, apart from significantly worse SF-12 mental subscale scores (p = 0.032) in the HAT tear group. Patients with HAT tears demonstrated significantly lower (p < 0.05) hip abduction strength and active ROM in all planes of motion on their affected limb. Pain significantly increased throughout the 30-second SLS test for the HAT tear group, with 57% of HAT tear patients demonstrating a positive Trendelenburg sign. POF angle during the test was not significantly associated with pain. CONCLUSION: Patients with symptomatic HAT tears demonstrate poor function, and report pain and disability similar to or worse than those with end-stage hip OA. This information better defines and differentiates the presentation of these patients. LEVEL OF EVIDENCE: Level 3 case-controlled study, with matched comparison. PMID- 27757286 TI - HIP AND GLENOHUMERAL PASSIVE RANGE OF MOTION IN COLLEGIATE SOFTBALL PLAYERS. AB - BACKGROUND AND PURPOSE: Range of motion deficits at the hip and glenohumeral joint (GHJ) may contribute to the incidence of injury in softball players. With injury in softball players on the rise, softball related studies in the literature are important. The purpose of this study was to examine hip and GHJ passive range of motion (PROM) patterns in collegiate softball players. HYPOTHESIS: It was hypothesized that the position players would exhibit significantly different PROM patterns than pitchers. Additionally, position players would exhibit significantly different side-to-side differences in PROM for both the hip and GHJ compared to pitchers. STUDY DESIGN: Prospective cohort study. METHODS: Forty-nine collegiate softball players (19.63 +/- 1.15 years; 170.88 +/- 8.08 cm; 72.96 +/- 19.41 kg) participated. Passive hip and GHJ internal (IR) and external rotation (ER) measures were assessed. Glenohumeral PROM was measured with the participants supine with the arm abducted to 90 degrees . The measurements were recorded when the scapula began to move or a firm capsular end-feel was achieved. The hip was positioned in 90 degrees of flexion and passively rotated until a capsular end-feel was achieved. Total PROM was calculated by taking the sum of IR and ER for both the hip and GHJ. RESULTS: No significant side-to-side PROM differences were observed in pitchers, at the GHJ or hip joint. Position players throwing side hip IR was significantly greater than the non-throwing side hip (p = 0.002). The non-throwing side hip had significantly greater ER compared to the throwing side hip (p = 0.002). When examining side-to-side differences at the GHJ, IR was significantly greater in the non-throwing shoulder (p = 0.047). No significant differences in total range of motion of the hip and GHJ were observed. CONCLUSION: In the current study, position players displayed side-to-side differences in hip and GHJ IR PROM while no statistically significant differences were observed in the softball pitchers. The findings of the current study add to the body of literature related to PROM in throwing athletes, additionally these are the first hip IR and ER PROM data presented in softball players. LEVEL OF EVIDENCE: Level 3. PMID- 27757287 TI - ULTRASOUND MEASUREMENTS AND OBJECTIVE FORCES OF GLENOHUMERAL TRANSLATIONS DURING SHOULDER ACCESSORY PASSIVE MOTION TESTING IN HEALTHY INDIVIDUALS. AB - BACKGROUND: Clinical examination of caspuloligamentous structures of the glenohumeral joint has historically been subjective in nature, as demonstrated by limited intra-rater and inter-rater reproducibility. Musculoskeletal diagnostic ultrasound was utilized to develop a clinically objective measurement technique for glenohumeral inferior and posterolateral translation. PURPOSE: The purpose of this study was to measure the accessory passive force required to achieve end range glenohumeral posterolateral and inferior accessory translation, as well as, to quantify the amount of translation of the glenohumeral joint caused by the applied force. STUDY DESIGN: Cross-sectional descriptive correlational study. METHODS: Twenty-five asymptomatic subjects between the ages of 18 and 30 were recruited via convenience sampling. Posterolateral and inferior shoulder accessory passive translation was assessed and measured using a GE LOGIQe ultrasound, while concurrently using a hand held dynamometer to quantify the passive force applied during assessment. Normative values for force and translation were described as means and standard deviations. RESULTS: Mean values for posterolateral translation were 6.5 +/- 4.0 mm on the right shoulder and 6.3 +/- 3.5 mm on the left with an associated mean force of 127.1 +/- 55.6 N and 114.4 +/- 50.7 N, respectively. Mean values for inferior translation were 4.8 +/- 1.7 mm on the right shoulder and 5.4 +/- 1.8 mm on the left with an associated mean force of 84.5 +/- 30.5 N and 76.1 +/- 30.1 N, respectively. There was a significant association between inferior translation and inferior force (r = .51). No significant association was found between posterolateral translation and posterolateral force. Significant differences were found between dominant and non dominant shoulders for posterolateral translation, posterolateral force to produce translation, and inferior translation values. CONCLUSIONS: Force data in the posterolateral and inferior direction is consistent with previously reported data for passive accessory motion testing at the shoulder. The results of this study provide data for glenohumeral translations and actual forces applied. Musculoskeletal diagnostic ultrasound can be a clinically relevant way to objectively measure the translation of the glenohumeral joint for assessing accessory passive motion joint translation while performing mobilizations or passive structure testing. This study provides a basis for comparison for healthy shoulder joints. LEVEL OF EVIDENCE: 2b. PMID- 27757288 TI - CORRECTED ERROR VIDEO VERSUS A PHYSICAL THERAPIST INSTRUCTED HOME EXERCISE PROGRAM: ACCURACY OF PERFORMING THERAPEUTIC SHOULDER EXERCISES. AB - BACKGROUND AND PURPOSE: The accurate performance of physical therapy exercises can be difficult. In this evolving healthcare climate it is important to continually look for better methods to educate patients. The use of handouts, in person demonstration, and video instruction are all potential avenues used to teach proper exercise form. The purpose of this study was to examine if a corrected error video (CEV) would be as effective as a single visit with a physical therapist (PT) to teach healthy subjects how to properly perform four different shoulder rehabilitation exercises. STUDY DESIGN: This was a prospective, single-blinded interventional trial. METHODS: Fifty-eight subjects with no shoulder complaints were recruited from two institutions and randomized into one of two groups: the CEV group (30 subjects) was given a CEV comprised of four shoulder exercises, while the physical therapy group (28 subjects) had one session with a PT as well as a handout of how to complete the exercises. Each subject practiced the exercises for one week and was then videotaped performing them during a return visit. Videos were scored with the shoulder exam assessment tool (SEAT) created by the authors. RESULTS: There was no difference between the groups on total SEAT score (13.66 +/- 0.29 vs 13.46 +/- 0.30 for CEV vs PT, p = 0.64, 95% CI [-0.06, 0.037]). Average scores for individual exercises also showed no significant difference. CONCLUSION/CLINICAL RELEVANCE: These results demonstrate that the inexpensive and accessible CEV is as beneficial as direct instruction in teaching subjects to properly perform shoulder rehabilitation exercises. LEVEL OF EVIDENCE: 1b. PMID- 27757289 TI - SIXTY SECONDS OF FOAM ROLLING DOES NOT AFFECT FUNCTIONAL FLEXIBILITY OR CHANGE MUSCLE TEMPERATURE IN ADOLESCENT ATHLETES. AB - BACKGROUND: Physiotherapists and other practitioners commonly prescribe foam rolling as an intervention, but the mechanistic effects of this intervention are not known. PURPOSE: The aim of this investigation was to establish if a single bout of foam rolling affects flexibility, skeletal muscle contractility and reflected temperature. METHODS: Twelve adolescent male squash players were evaluated on two separate occasions (treatment and control visits) and were tested on both legs for flexibility of the hip flexors and quadriceps, muscle contractility (as measured by tensiomyography) and temperature of the quadriceps (assessed via thermography) at repeated time points pre- and post a 60s rolling intervention (pre-, immediately post, 5, 10, 15, and 30 minutes post). They rolled one leg on the treatment visit and did not perform rolling on the control visit. RESULTS: The main outcome measure was the flexibility of hip flexor and quadriceps at repeated time points up to 30 minutes post intervention. The average foam rolling force was 68% of subject's body weight. This force affected the combination of hip and quadriceps flexibility (p = 0.03; 2.4 degrees total increase with foam rolling) but not each muscle independently (p = 0.05 - 0.98) following a single 60s bout. Muscle contractility is not affected (p = 0.09 - 0.93) and temperature is not increased by foam rolling across time points (p = 0.19). CONCLUSIONS: A single sixty-second bout of rolling applied to the quadriceps induces a small significant change in flexibility that is of little practical relevance, while muscle contractility and temperature remain unchanged. Investigation of larger doses of rolling is merited in athletic populations to justify current practice. LEVEL OF EVIDENCE: 2c. PMID- 27757290 TI - BIPARTITE PATELLA IN 35-YEAR-OLD FITNESS INSTRUCTOR: A CASE REPORT. AB - BACKGROUND AND PURPOSE: The patella plays an important role in knee biomechanics and provides anterior coverage of the knee joint. One to two percent of the population has an anatomical variant of patella called a bipartite patella that usually does not case pain. However, occasionally after injury or overuse during sport it can be a source of anterior knee pain. The purpose of this case report was to present a rare variant of bipartite patella and highlight conservative treatment of this condition. STUDY DESIGN: Case Report. CASE DESCRIPTION: A 35 year-old female patient presented with persistent bilateral non-traumatic anterior knee pain of a six-year duration that was enhanced by strenuous kinds of sport activity. Standard radiographs and MRI revealed the presence of bipartite patella with medial pole cartilage edema bilaterally. Conservative care including physical therapy, extracorporeal shock wave therapy (ESWT), and viscosupplementation was utilized. OUTCOME: After treatment VAS decreased to 0/10 from 5/10 in the left knee and 1/10 from 5/10 in the right knee. The Kujala Scores improved after treatment to 100 and 95 for the left and right knees respectively. The subject returned to full sport activity and work as a fitness instructor without pain and limitations. DISCUSSION: This case describes a rare finding of bilateral medial bipartite patella and the successful use of physical therapy with viscosupplementation in patellar pain caused by bipartite patella. It also supports the use of Extra Corporeal Shock Wave Therapy in bipartite patella pain as a supplement for therapy. LEVEL OF EVIDENCE: 4. PMID- 27757292 TI - A CLINICAL GUIDE TO THE ASSESSMENT AND TREATMENT OF BREATHING PATTERN DISORDERS IN THE PHYSICALLY ACTIVE: PART 1. AB - BACKGROUND: Appropriate assessment and interventions for breathing patterns prior to assessment of the patient's musculoskeletal complaint may be beneficial. Breathing pattern disorders (BPDs) are remediable and influenced by biochemical, biomechanical, psychological, and/or unknown factors. The purpose of this clinical commentary is to demonstrate the integratration of a BPD assessment into a standard clinical musculoskeletal orthopedic examination. CLINICAL ASSESSMENT: The observation of a patient's breathing pattern begins when they enter the clinic, is followed by palpation and orthopedic tests, which allows for proper classification of BPDs. OUTCOMES: Disease-oriented measures guide the assessment and classification of BPD, while patient-oriented measures describe clinically important differences among patient values. CLASSIFICATION: There are many possible variations of classifications of BPD, however, six primary dysfunctions found in the literature have become the foundation of the BPD assessment. DISCUSSION AND CONCLUSION: Restoring proper breathing mechanics and neuromuscular motor control patterns during breathing may result in a decrease in pain, improved patient outcomes, and overall patient well being associated with their primary musculoskeletal complaint. A comprehensive evaluation of breathing patterns, as a part of an orthopedic examination, may guide a clinician in providing effective and appropriate treatments to decrease pain and improve function. LEVEL OF EVIDENCE: 5. PMID- 27757293 TI - PERTINENT DRY NEEDLING CONSIDERATIONS FOR MINIMIZING ADVERSE EFFECTS - PART TWO. AB - BACKGROUND: Dry needling (DN) is an evidence based treatment technique that is accepted and used by physical therapists in the United States. This clinical commentary is the second in a two-part series outlining some of the pertinent anatomy and other issues that are needed for optimal utilization of this treatment modality. Part one was an overview of the thorax with a summary of reported adverse effects (AEs) and the underlying anatomy that could be used to minimize patient risk. As is the case with any intervention, the technique of dry needling has some inherent patient risk. The incidence of AEs with this procedure is typically low, ranging from zero to approximately 10 percent. Knowledge of the underlying anatomy can be a key factor associated with decreasing the likelihood of an AE. PURPOSE/OBJECTIVE: The second part of this clinical commentary goes beyond the thorax, to explore the anatomy associated with dry needling the abdomen, pelvis, and back. In the abdomen, pelvis and back, dry needling can penetrate the peritoneal cavity or adjacent organs, resulting in AEs. A physiological reaction that is an AE secondary to a needle insertion, pain or fear, is an autonomic vasovagal response. Additionally, suggestions for dealing with the fearful patient, the obese patient, universal precautions, and other clinical considerations, are discussed. The purpose of parts one and part two of this clinical commentary is to minimize the risk of a dry needling AE. CONCLUSIONS/IMPLICATIONS: Dry needling is an effective adjunctive treatment procedure that is within the recognized scope of practice of the physical therapist. An evidence-based implementation of the procedure must be based on a thorough understanding of the underlying anatomy and the potential risks, with risks communicated to patients via informed consent. LEVEL OF EVIDENCE: Level 5. PMID- 27757291 TI - MUSCULOSKELETAL SCREENING AND FUNCTIONAL TESTING: CONSIDERATIONS FOR BASKETBALL ATHLETES. AB - BACKGROUND AND PURPOSE: Youth participation in basketball is on the rise, with basketball one of the top five participation sports in Australia. With increased participation there is a need for greater awareness of the importance of the pre participation examination, including musculoskeletal screening and functional performance testing as part of a multidisciplinary approach to reducing the risk for future injuries. As majority of all basketball injuries affect the lower extremities, pre-participation musculoskeletal screening and functional performance testing should assess fundamental movement qualities throughout the kinetic chain with an emphasis on lower extremity force characteristics, specifically eccentric loading tasks. Thus, the purpose of this clinical commentary is to review the existing literature elucidating pre-participation musculoskeletal screening and functional performance tests that can be used as a framework for rehabilitation professionals in assessing basketball athletes' readiness to safely perform the movement demands of their sport. METHODS: Relevant articles published between 2000 and 2016 using the search terms 'musculoskeletal screening', 'functional testing', 'youth athletes', and 'basketball' were identified using MEDLINE. From a basketball-specific perspective, several relevant musculoskeletal assessments were identified, including: the Functional Hop Test Combination, the Landing Error Scoring System, the Tuck Jump Assessment, the Weight-Bearing Lunge Test, and the Star Excursion Balance Test. Each of these assessments creates movement demands that allow for easy identification of inefficient and/or compensatory movement tendencies. A basic understanding of musculoskeletal deficits including bilateral strength and flexibility imbalances, lower crossed syndrome, and dominance-related factors are key components in determination of injury risk. DISCUSSION: Assessment of sport specific movement demands through musculoskeletal screening and functional performance testing is essential for rehabilitation professionals to determine movement competency during performance of fundamental movements related to basketball performance. Youth athletes represent a unique population due to their developing musculoskeletal and neuromuscular systems and should undergo pre participation musculoskeletal screening for identification of movement limitations. Such an approach to musculoskeletal screening and functional performance may assist in identifying injury risk and also be useful at the end of rehabilitation in determining readiness to return to sport models. LEVEL OF EVIDENCE: Level 5. PMID- 27757294 TI - Targeting Akt in cell transfer immunotherapy for cancer. AB - Pharmacologic inhibitors of the serine/threonine kinase Akt, initially aimed at deranged oncogenic pathways in tumors, have recently been shown to act as immunomodulators that markedly enhance the antitumor properties of T cells. Repurposing Akt inhibitors to improve antitumor immunity may be viewed as a manifestation of a larger paradigmatic shift in which hallmark characteristics of cancer (e.g., immune evasion), rather than merely causal features (e.g., somatic mutations) can be exploited for therapeutic benefit. PMID- 27757295 TI - Cancer cell-derived IL-1alpha induces CCL22 and the recruitment of regulatory T cells. AB - In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1alpha). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1alpha as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumor-induced immunosuppression. PMID- 27757296 TI - Inhibition of SIRPalpha in dendritic cells potentiates potent antitumor immunity. AB - Despite their central function in tumor immunity, dendritic cells (DCs) can respond to inhibitory signals and become tolerogenic, curtailing T cell responses in vivo. Here, we provide the evidence for an inhibitory function of signal regulatory protein (SIRP) alpha in DC survival and activation. In tumors from human liver cancer patients, infiltrative DCs expressed elevated levels of SIRPalpha, which is correlated with the induction of immune tolerance within the tumors. Silencing of SIRPalpha resulted in a significant increase in the longevity of antigen-pulsed DCs in the draining lymph nodes. In addition, SIRPalpha controls the activation and output of DCs. Silencing of DC-expressed SIRPalpha induced spontaneous and enhanced production of IL12 and costimulatory molecules, resulting in more potent cytotoxic T lymphocyte responses, including the eradication of previously established solid tumors. SIRPalpha exerted such effects, at least in part, via the association and sequestration of p85 subunit of PI3K. Thus, SIRPalpha is a critical regulator of DC lifespan and activity, and its inhibition might improve the clinical efficacy of DC-based tumor vaccines. PMID- 27757297 TI - Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity. AB - STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here, we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing a Stat1-Y701F mutant. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity as verified by RNA-seq analysis. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo compared to Stat1-/- NK cells in the absence of detectable transcriptional activity. We thus investigated the STAT1 interactome using primary NK cells derived from Stat1ind mice that inducibly express a FLAG-tagged STAT1. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. In line, immunofluorescence studies uncovered the recruitment of STAT1 to the target-cell interphase during NK cell killing. This led us to propose a novel function for STAT1 at the immunological synapse in NK cells regulating tumor surveillance and cytotoxicity. PMID- 27757298 TI - Exosome-driven transfer of tumor-associated Pioneer Translation Products (TA PTPs) for the MHC class I cross-presentation pathway. AB - Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8+ T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation. Furthermore, the presentation of non canonical translation products, produced during a non-conventional translation event, on class I molecules of tumor cells has been reported but how these peptides are generated, presented to pAPCs, and their capacity to stimulate CD8+ T cells is still not known. Here, we report that pioneer translation peptides (PTPs) derived from intron or exon pre-mRNAs can serve as tumor-associated antigens (TA-PTPs) and are delivered from the producing tumor cells to pAPCs via exosomes where they are processed by the cytosolic pathway. Injection of TA-PTPs and tumor-derived exosomes efficiently induce CD8+ T-cell proliferation and prevent tumor growth in mice. Our results show that TA-PTPs represent an efficient source of antigenic peptides for CD8+ T cell activation and that full length proteins are not required for cross-presentation. These findings can have interesting implications for generating tolerance and for designing vectors to generate vaccines. PMID- 27757299 TI - Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma. AB - Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD 1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment. We found that, in addition to the PD-L1 (p = 0.03), expression levels of PD-1 ligand-2 (PD-L2), granzyme A (GZMA) and human leukocyte antigen-A (HLA-A) in the pre-treatment tumors were significantly higher (p = 0.04, p = 0.01 and p = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of CD8, GZMA and perforin 1 (PRF1) expression levels as well as increased ratio of TBX21/GATA3, suggesting dominancy of helper T cell type 1 (Th1) response to type 2 (Th2) response. T cell receptor beta (TCR-beta) repertoire analysis revealed oligoclonal expansion of tumor-infiltrating T lymphocytes (TILs) in the tumor tissues of the responders. Our findings suggest that melanoma harboring high PD-1 ligands (PD-L1 and PD-L2), GZMA and HLA-A expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs. PMID- 27757300 TI - mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma. AB - INTRODUCTION: Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant melanoma (MM). In addition, clinical and immunological effect of the treatment was evaluated. EXPERIMENTAL DESIGN: Twenty-two patients were enrolled and treated with six cycles of cyclophosphamide 50 mg orally bi-daily for a week every second week (day 1-7). During the six cycles patients received at least 5 * 106 autologous DCs administered by intradermal (i.d.) injection in the week without chemotherapy. Patients were evaluated 12 and 27 weeks and every 3rd mo thereafter with CT scans according to RECIST 1.0. Blood samples for immune monitoring were collected at baseline, at the time of 4th and 6th vaccines. Immune monitoring consisted of IFNgamma ELISpot assay, proliferation assay, and flow cytometry for enumeration of immune cell subsets. RESULTS: Toxicity was manageable. Eighteen patients were evaluable after six cycles. Of these, nine patients had progressive disease as best response and nine patients achieved stable disease. In three patients minor tumor regression was observed. By IFNgamma ELISpot and proliferation assay immune responses were seen in 6/17 and 4/17 patients, respectively; however, no correlation with clinical response was found. The percentage of Tregs was unchanged during treatment. CONCLUSION: Treatment with autologous DCs transfected with mRNA in combination with mCy was feasible and safe. Importantly, mCy did not alter the percentage of Tregs in our patient cohort. There was an indication of clinical benefit; however, more knowledge is needed in order for DCs to be exploited as a therapeutic option. PMID- 27757302 TI - Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis. AB - Approximately 30% of patients treated with ipilimumab will develop gastrointestinal toxicity. The immunological drivers that underpin the clinical observations in human tissues are poorly understood. We report here on the immune consequences of ipilimumab treatment in the colorectal mucosa of patients with treatment-related colitis. Using immunohistochemistry, we evaluated the immune infiltrate by CD8+, FoxP3, and granzyme B (GzmB) in colonic biopsies from 20 patients with ipilimumab-related colitis. We assessed 10 cases with normal colon biopsies for comparison. In eight cases (four on steroids only, four on steroids and infliximab), we evaluated two sequential biopsies. We observed that CD8+, FoxP3+, and GzmB T cell counts were significantly higher in patients with ipilimumab-related colitis compared to normal colon (p < 0.0001). Patients who required infliximab for the resolution of their colitis had a significantly higher CD8+/FoxP3 ratio than those treated only with steroids and this correlated with clinical severity. The analysis of repeat samples revealed that resolution of the colitis was associated with a decrease in CD8+ and FoxP3+ cells both in patients treated with steroids and infliximab. Our data suggest that counts of cytotoxic T cells and Tregs in the colonic mucosa from patients with ipilimumab related colitis correlate with clinical findings and may predict severity and guide management. PMID- 27757301 TI - Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma. AB - Glioblastoma (GBM) is a fatal brain cancer for which new treatment options are sorely needed. Platinum-based drugs have been investigated extensively for GBM treatment but few have shown significant efficacy without major central nervous system (CNS) and systemic toxicities. The relative success of platinum drugs for treatment of non-CNS cancers indicates great therapeutic potential when effectively delivered to the tumor region(s). New insights into the broad anticancer effects of platinum drugs, particularly immunomodulatory effects, and innovative delivery strategies that can maximize these multi-modal effects and minimize toxicities may promote the re-purposing of this chemotherapeutic drug class for GBM treatment. PMID- 27757303 TI - Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome. AB - Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen. The adoptive transfer in conjunction with lymphodepleting and myeloablative preconditioning mediated significant tumor regression but caused weight loss in CEA-Tg, but not in wild-type mice. The weight loss was not associated with overt inflammation in the CEA-expressing gastrointestinal tract but was associated with malnutrition, reflected in elevated systemic levels of cytokines linked to anorexia, which could be controlled by the administration of an anti-IL-6 receptor monoclonal antibody without compromising efficacy. The apparent relationship between lymphodepleting and myeloablative preconditioning, efficacy, and off-tumor toxicity of CAR-T cells would necessitate the development of CEA-specific CAR-T cells with improved signaling domains that require less stringent preconditioning for their efficacy. Taken together, these results suggest that CEA-specific CAR-based adoptive T-cell therapy may be effective for patients with CEA+ solid tumors. Distinguishing the fine line between therapeutic efficacy and off-tumor toxicity would involve further modifications of CAR-T cells and preconditioning regimens. PMID- 27757304 TI - Tim-3 promotes tumor-promoting M2 macrophage polarization by binding to STAT1 and suppressing the STAT1-miR-155 signaling axis. AB - T cell Ig mucin-3 (Tim-3), an immune checkpoint inhibitor, shows therapeutic potential. However, the molecular mechanism by which Tim-3 regulates immune responses remains to be determined. In particular, very little is known about how Tim-3 works in innate immune cells. Here, we demonstrated that Tim-3 is involved in the development of tumor-promoting M2 macrophages in colon cancer. Manipulation of the Tim-3 pathway significantly affected the polarization status of intestinal macrophages and the progression of colon cancer. The Tim-3 signaling pathway in macrophages was explored using microarray, co immunoprecipitation, gene mutation, and high-content analysis. For the first time, we demonstrated that Tim-3 polarizes macrophages by directly binding to STAT1 via residue Y256 and Y263 in its intracellular tail and inhibiting the STAT1-miR-155-SOCS1 signaling axis. We also identified a new signaling adaptor of Tim-3 in macrophages, and, by modulating the Tim-3 pathway, demonstrated the feasibility of altering macrophage polarization as a potential tool for treating this kind of disease. PMID- 27757306 TI - Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity. AB - Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killing in vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A*02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia. Leukemia escape was not associated with loss of the antigenic target, downregulation of cell surface HLA, antibody pharmacokinetic or biodistribution issues, or development of leukemia cell intrinsic resistance to ADCC. Interestingly, the rapidity of leukemic growth determined whether leukemia was able to evade cytotoxicity independent of the presence of sufficient effector cells. By engineering leukemia cells with upregulated p27Kip1 and slower cell cycling times, we show that relapse was inversely correlated with growth rates resulting in the eventual inadequacy of effector to target ratio. Moreover, lack of migration of effector cells into lymphomatous pockets of ALL also allowed local escape. Successful leukemia therapy with mAb might therefore be improved in similar situations by combination with measures to reduce burden and slow leukemia cell growth. PMID- 27757305 TI - Mono- and dual-targeting triplebodies activate natural killer cells and have anti tumor activity in vitro and in vivo against chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8+ T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts. A mono-targeting triplebody ULBP2-aCD19-aCD19 successfully triggered NK cell effector functions against CLL cell line MEC1 and primary tumor cells in allogenic and autologous settings. Additionally, a dual targeting triplebody ULBP2-aCD19-aCD33 specific for two distinct tumor-associated antigens was developed to target antigen loss variants, such as mixed lineage leukemia (MLL). Of note, this triplebody exhibited cytotoxic activity against CD19/CD33 double positive cells and retained its binding features even in the absence of one of the tumor antigens. Further, ULBP2-aCD19-aCD19 showed significant in vivo activity in immune-deficient (NSG) mouse model transplanted with CLL cell line as target cells and human immune cells as an effector population providing a proof-of-principle for this therapeutic concept. PMID- 27757307 TI - CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+ T cell lymphoma. AB - Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg) and a CD1b restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy. PMID- 27757309 TI - Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer: Implications for immunotherapy. AB - Purpose: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design: From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-L1 and 2 was evaluated in paired primary and metastatic lesions and correlated with clinicopathologic features. Results: We included 98 patients with non-small cell (NSCLC, n = 65, 66%), small cell histology (SCLC, n = 29, 30%) and four (4%) atypical carcinoids (AC). In total 8/65 (12%) primary PD-L1 positive NSCLC, had discordant matched metastases (14/17, 82%). PD-L1 negative primaries had universally concordant distant metastases. SCLCs were universally PD-L1 negative across primary and metastatic disease. PD-L2 positive NSCLC (n = 11/65, 17%) had high rate of discordant metastases (n = 24/27, 88%) and four cases (6%) had PD-L2 positive metastases with negative primaries. 2/29 SCLC (7%) and 1/4 AC (25%) were PD-L2 positive with discordance in all the sampled metastatic sites (n = 5). We found no correlation between the expression of PD ligands and clinicopathologic features of LC. Conclusions: Intra-tumoral heterogeneity in the expression of PD ligands is common in NSCLC, while PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC. PMID- 27757308 TI - Chemo-immunotherapy mediates durable cure of orthotopic KrasG12D/p53-/- pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related death in the United States, exhibiting a five-year overall survival (OS) of only 7% despite aggressive standard of care. Recent advances in immunotherapy suggest potential application of immune-based treatment approaches to PDAC. To explore this concept further, we treated orthotopically established K-rasG12D/p53 /- PDAC tumors with gemcitabine and a cell-based vaccine previously shown to generate durable cell-mediated (TH1) immunity. Tumor progression was monitored by IVIS. The results indicated that the combination of chemotherapy and dendritic cell (DC) vaccination was effective in eliminating tumor, preventing metastasis and recurrence, and significantly enhancing OS. No animal that received the combination therapy relapsed, while mice that received gemcitabine-only or vaccine-only regimens relapsed and progressed. Analysis of circulating PBMC demonstrated that mice receiving the combination therapy exhibited significantly elevated levels of CD8+IFNgamma+CCR7+NK1.1+ T-cells with significantly reduced levels of exhausted GITR+CD8+ T-cells after the cessation of treatment. Retro orbital tumor re-challenge of surviving animals at six-months post-treatment demonstrated durable antitumor immunity only among mice that had received the combination therapy. CD8+ splenocytes derived from surviving mice that had received the combination therapy were sorted into NK1.1pos and NK1.1neg populations and adoptively transferred into naive recipients. Transfer of only 1,500 CD8+NK1.1pos T-cells was sufficient to mediate tumor rejection whereas transfer of 1,500 CD8+NK1.1neg T-cells imparted only minimal effects. The data suggest that addition of a TH1 DC vaccine regimen as an adjuvant to existing therapies can mediate eradication of tumors and offer durable protection against PDAC. PMID- 27757310 TI - Zfra induction of memory anticancer response via a novel immune cell. AB - When naive mice receive short Zfra peptides via tail vein injections, they develop lifetime resistance to growth of many cancer xenografts, due to activation of a novel spleen memory Hyal-2+ CD3- CD19- Z lymphocyte. In vitro education of spleen cells with Zfra activates Z cell for conferring memory anticancer response in vivo. PMID- 27757311 TI - Targeting myeloid-derived suppressor cells using a novel adenosine monophosphate activated protein kinase (AMPK) activator. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored. This study was designed to investigate whether treatment of MDSC with OSU-53, a PPAR-inactive derivative that stimulates AMPK kinase, can modulate MDSC function. Our results demonstrate that OSU-53 treatment increases the phosphorylation of AMPK, significantly reduces nitric oxide production, inhibits MDSC migration, and reduces the levels of IL-6 in murine MDSC cell line (MSC2 cells). OSU53 treatment mitigated the immune suppressive functions of murine MDSC, promoting T-cell proliferation. Although OSU-53 had a modest effect on tumor growth in mice inoculated with EMT-6 cells, importantly, administration of OSU53 significantly (p < 0.05) reduced the levels of MDSC in the spleens and tumors. Furthermore, mouse MDSC from EMT-6 tumor bearing mice and human MDSC isolated from melanoma patients treated with OSU-53 showed a significant reduction in the expression of immune suppressive genes iNOS and arginase. In summary, these results demonstrate a novel role of AMPK in the regulation of MDSC functions and provide a rationale of combining OSU-53 with immune checkpoint inhibitors to augment their response in cancer patients. PMID- 27757312 TI - Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. AB - The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent "salvage" treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens-Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (p=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain. PMID- 27757314 TI - Human cytomegalovirus-based immunotherapy to treat glioblastoma: Into the future. AB - Glioblastoma multiforme (GBM) is the most aggressive brain tumor and median survival time with current therapies is only 14.6 mo. Although multiple immunotherapeutic strategies are being explored, efficacy remains poor. In order to improve immunotherapy for GBM, we propose to combine currently used endogenous with human cytomegalovirus (HCMV) specific antigens expressed on cancer cells. PMID- 27757315 TI - Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4+ tumor-infiltrating lymphocytes. AB - The beneficial effects of checkpoint blockade in tumor immunotherapy are limited to patients with increased tumor-infiltrating lymphocytes (TILs). Delineation of the regulatory networks that orchestrate the presence of TILs holds great promise for the design of effective immunotherapies. Podoplanin/gp38 (PDPN)-expressing lymph node stromal cells (LNSCs) are present in tumor stroma; however, their effect in the regulation of TILs remains elusive. Herein we demonstrate that intratumor injection of ex-vivo-isolated PDPN+ LNSCs into melanoma-bearing mice induces elimination of TILs and promotes tumor growth. In support, PDPN+ LNSCs exert their function through direct inhibition of CD4+ T cell proliferation in a cell-to-cell contact independent fashion. Mechanistically, we demonstrate that PDPN+ LNSCs mediate T cell growth arrest and induction of apoptosis to activated CD69+CD4+ T cells. Importantly, LTbR-Ig-mediated blockade of PDPN+ LNSCs expansion and function significantly attenuates melanoma tumor growth and enhances the infiltration and proliferation of CD4+ TILs. Overall, our findings decipher a novel role of PDPN-expressing LNSCs in the elimination of CD4+ TILs and propose a new target for tumor immunotherapy. PMID- 27757316 TI - Anti-CD73 immunotherapy: A viable way to reprogram the tumor microenvironment. AB - The ecto-5'-nucleotidase/CD73 enzyme plays a pivotal role in generating an adenosine-enriched immunosuppressed and pro-angiogenic niche supporting cancer development. The targeting of CD73 leads to reorganization of tumor microenvironment, shaping the phenotype of the infiltrating T cells. The development of CD73 monoclonal antibodies offers a promising new avenue for antineoplastic treatment. PMID- 27757317 TI - Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. AB - Natural killer (NK) cells are promising antitumor effector cells, but the generation of sufficient NK cell numbers for adoptive immunotherapy remains challenging. Therefore, we developed a method for highly efficient ex vivo expansion of human NK cells. Ex vivo expansion of NK cells in medium containing IL-2 and irradiated clinical-grade feeder cells (EBV-LCL) induced a 22-fold NK cell expansion after one week that was significantly increased to 53-fold by IL 21. Repeated stimulation with irradiated EBV-LCL and IL-2 and addition of IL-21 at the initiation of the culture allowed sustained NK cell proliferation with 1011-fold NK cell expansion after 6 weeks. Compared to naive NK cells, expanded NK cells upregulated TRAIL, NKG2D, and DNAM-1, had superior cytotoxicity against tumor cell lines in vitro and produced more IFNgamma and TNF-alpha upon PMA/Iono stimulation. Most importantly, adoptive transfer of NK cells expanded using feeder cells, IL-2 and IL-21 led to significant inhibition of tumor growth in a melanoma xenograft mouse model, which was greater than with NK cells activated with IL-2 alone. Intriguingly, adoptively transferred NK cells maintained their enhanced production of IFNgamma and TNF-alpha upon ex vivo restimulation, although they rapidly lost their capacity to degranulate and mediate tumor cytotoxicity after the in vivo transfer. In conclusion, we developed a protocol for ex vivo NK cell expansion that results in outstanding cell yields. The expanded NK cells possess potent antitumor activity in vitro and in vivo and could be utilized at high numbers for adoptive immunotherapy in the clinic. PMID- 27757313 TI - Trial Watch: Immunotherapy plus radiation therapy for oncological indications. AB - Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation. PMID- 27757319 TI - Erratum: Silicone Breast Implant and Automatic Implantable Cardioverter Defibrillator: Can They Coexist? A Case Report: Erratum. AB - [This corrects the article DOI: 10.1097/GOX.0000000000000855.]. PMID- 27757318 TI - Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4+ T cell help. AB - Natural killer (NK) cell infusions can induce remissions in subsets of patients with different types of cancer. The optimal strategies for NK cell activation prior to infusion are still under debate. There is recent evidence that NK cells can acquire long-term functional competence by preactivation with the cytokines IL-12/15/18. The mechanisms supporting the maintenance of long-term NK cell antitumor activity are incompletely under-stood. Here, we show that NK cells preactivated in vitro with IL-12/15/18, but not with IL-15 alone, maintained high antitumor activity even 1 mo after transfer into lymphopenic RAG-2-/-gammac-/- mice. The NK cell intrinsic ability for IFNgamma production coincided with demethylation of the conserved non-coding sequence (CNS) 1 in the Ifng locus, previously shown to enhance transcription of Ifng. In a xenograft melanoma mouse model, human IL-12/15/18-preactivated NK cells rejected tumors more efficiently. In RAG-2-/-gammac-/- mice, co-transfer of CD4+ T cells further improved the long term competence of NK cells for IFNgamma production that was dependent on IL-2. CD4+ T cell activation during homeostatic proliferation required macrophages and further promoted the long-term NK cell antitumor activity. Thus, NK cells can "remember" a previous exposure to cytokines by epigenetic imprinting resulting in a remarkable stability of the IFNgamma-producing phenotype after adoptive transfer. In addition, our results support combination of cytokine-preactivated NK cells with CD4+ T cell activation upon lymphopenic conditioning to achieve long-term NK cell effector function for cancer immunotherapy. PMID- 27757320 TI - Medial Femoral Condyle Free Flap for Nasal Reconstruction: New Technique for Full Thickness Nasal Defects. AB - The nose is a functionally complex organ implicated in breathing, olfaction, and phonation, with a critical role also in the aesthetic appearance of a person. This latter aspect should be carefully considered whenever a total or subtotal rhinectomy is performed for resection of locally advanced nasal cancer. To reconstruct large nasal defects, several techniques were described, including the use of cartilaginous grafts, bony grafts, local flaps, and free flaps. In cases of extensive full-thickness resections, free flaps probably represent the most adequate option. The aim of this report is to present the functional and aesthetical outcomes of a reconstruction of the nose after rhinectomy, using the medial femoral condyle free flap associated with the forehead flap. PMID- 27757321 TI - Effect of Atherosclerosis on the Lateral Circumflex Femoral Artery and Its Descending Branch: Comparative Study to Nonatherosclerotic Risk. AB - : The anterolateral thigh (ALT) flap has been widely used for reconstructions. Nevertheless, the atherosclerotic risk factors that affect the lateral circumflex femoral artery (LCFA) are still inconclusive. The aim was to study the effect of atherosclerosis on the LCFA and descending branch (dLCFA) visualized by computer tomographic angiography (CTA) between nonatherosclerosis and atherosclerosis. METHODS: Retrospective studies of CTA of lower extremity were reviewed. The patients were divided into 2 groups: nonatherosclerotic and atherosclerotic risk factors. The angiographic study of LCFA and dLCFA was analyzed, and atherosclerotic and nonatherosclerotic risk factors were compared. RESULTS: Ninety-seven patients with 194 lower extremities were enrolled. Atherosclerotic risks comprised 76 patients. A total of 14, 16, and 46 patients had 1, 2, and 3 risk factors, respectively. Musculocutaneous perforator was 79.38%. The LCFA originated from deep femoral, common femoral, and superficial femoral artery was 97.42%, 2.06%, and 0.52%, respectively. The dLCFA was classified into 5 types depending on its origin. Diameters of LCFA in nonatherosclerotic and atherosclerotic patients were 4.03 +/- 0.71 and 4.07 +/- 0.97 mm, respectively. No statistical significance was found between both groups in diameters of LCFA. Diameters of dLCFA in nonatherosclerotic patients were 2.28 +/- 0.28 mm and in atherosclerotic patients were 2.11 +/- 0.28 mm. Statistical significance of diameters of dLCFA was found in patients having 3 risk factors and smoker groups (p < 0.05). CONCLUSIONS: LCFA is not atherosclerosis resistant. Stenosis of the LCFA and dLCFA occurred in varying degrees in atherosclerosis-risk patients. Preoperative CTA should be considered to evaluate the patency in multiple risk factors patients. PMID- 27757322 TI - Reconstruction Approach to a Rare Case of Acquired Scrotal Giant Muscular Hamartoma. AB - Acquired scrotal giant muscular hamartoma is an uncommon benign lesion with fewer than 10 documented cases all over the world. It is characterized by a proliferation of dermal smooth muscle bundles of scrotum dartos fascia. The authors report a rare case of acquired scrotal giant muscular hamartoma, which occurred in a 70-year-old severely obese and diabetic man presenting with a progressive scrotal enlargement and swelling in the last year, causing marked reduction in quality of life and cosmetic problems. The patient underwent a wide excision of the hamartomatous lesion, and then, a reductive scrotoplasty and autologous skin grafting of penis were performed. Anatomopathological examination showed an acquired scrotal giant muscular hamartoma arising from muscular fascia of dartos. This surgical technique is a valid, safe, effective, and minimally invasive option to treat this pathology, achieving both excellent functional and aesthetic results, with a marked improvement of the patient's quality of life. PMID- 27757323 TI - Metallic Fixation of Mandibular Segmental Defects: Graft Immobilization and Orofacial Functional Maintenance. AB - : The aim of this study is to investigate the behavior of the healthy mandible under maximum molar bite force to demonstrate the problems associated with the current standard of care procedures for mandibular segmental defect reconstruction (ie, use of Ti-6Al-4V hardware and either a single- or double barrel fibular graft). With current Ti-6Al-4V mandibular reconstruction hardware, there is a significant stiffness mismatch among the hardware, graft, and the remaining host anatomy. How the distribution of mechanical forces through the mandible is altered after a segmental bone loss and reconstruction is incompletely understood. METHODS: We studied a healthy adult mandible for stress, strain, and reaction force distribution during normal mastication. Stress distribution of this model was then used to study problems encountered after mandibular segmental defect reconstructive surgery. We model the use of both single- and double-barrel fibular grafts to repair the loss of the left M1-3 containing segment of the mandible. These simulations were done using 2 sets of plates with different thicknesses. RESULTS: We found that the stiffness mismatching between the fixation hardware and the graft and host bone causes stress shielding of that bone and stress concentrations in the fixation hardware and screws. These effects are expected, especially during the bone healing period. However, long term, this abnormal stress-strain distribution may lead to either the hardware's failure due to stress concentration or graft failure due to bone resorption as a result of stress shielding. We found that the stress-strain distribution is more normal with a double-barrel fibular graft. Additionally, we found that thinner fixation plates can reduce stress shielding. CONCLUSION: The proposed model can be used to evaluate the performance and optimization of the fixation device. PMID- 27757324 TI - The Chang Gung Memorial Hospital Microsurgery Fellowship: A Review of 1 Year of Experience. PMID- 27757325 TI - Anatomical Basis for "Superficial Flow Volumetry" and "Deep Support Volumetry". PMID- 27757326 TI - Injection Lipolysis with a Cocktail of Phosphatidylcholine and Deoxycholate: An Indian Experience. PMID- 27757327 TI - Quality of Life and Aesthetic Plastic Surgery: A Systematic Review and Meta analysis. AB - : Quality of life (QoL) is an important outcome in plastic surgery. However, authors use different scales to address this subject, making it difficult to compare the outcomes. To address this discrepancy, the aim of this study was to perform a systematic review and a random effect meta-analysis. METHODS: The search was made in two electronic databases (LILACS and PUBMED) using Mesh and non-Mesh terms related to aesthetic plastic surgery and QoL. We performed qualitative and quantitative analyses of the gathered data. We calculated a random effect meta-analysis with Der Simonian and Laird as variance estimator to compare pre- and postoperative QoL standardized mean difference. To check if there is difference between aesthetic surgeries, we compared reduction mammoplasty to other aesthetic surgeries. RESULTS: Of 1,715 identified, 20 studies were included in the qualitative analysis and 16 went through quantitative analysis. The random effect of all aesthetic surgeries shows that QoL improved after surgery. Reduction mammoplasty has improved QoL more than other procedures in social functioning and physical functioning domains. CONCLUSIONS: Aesthetic plastic surgery increases QoL. Reduction mammoplasty seems to have better improvement compared with other aesthetic surgeries. PMID- 27757328 TI - Aquacel Surgical Dressing after Thigh Lift: A Case-Control Study. AB - : The postoperative dressing in patients undergoing thigh lift is often difficult, not very resistant to movement, and uncomfortable for the patient, and often exposes surgical site to infection, maceration, or delay in wound healing. METHODS: We included 40 patients in a case-control crossover study with no period effects, who were treated both by Aquacel Surgical and a traditional wound dressing. Surveys with a 10-point scale evaluation were used to assess nontraumatic removal level, ease of application, adhesion, and strength of the 2 treatments. We reported the number of days necessary for wound healing, the number of infection cases, and wound-related complications. Costs of the 2 medications were also considered. Ten days after surgery, patients answered a questionnaire with 6 multiple-choice questions to assess comfort, pain at dressing change, pruritus, strength, and number of dressing changes. RESULTS: Compared with controls, surveys revealed Aquacel Surgical to be less traumatic to remove, easier to apply, and to be more adherent and stronger. Significant acceleration of the wound healing was also evident with Aquacel Surgical compared with the traditional dressing. Nonsignificant differences were reported about the risk of infection and wound-related complications between the 2 treatments. A statistical analysis of costs revealed that Aquacel Surgical is significantly more expensive than the traditional medication. CONCLUSION: We recommend the use of Aquacel Surgical in all the surgery procedures where the risk of wound dehiscence and maceration is high. PMID- 27757329 TI - Mechanical Stimulation Increases Knee Meniscus Gene RNA-level Expression in Adipose-derived Stromal Cells. AB - : Efforts have been made to engineer knee meniscus tissue for injury repair, yet most attempts have been unsuccessful. Creating a cell source that resembles the complex, heterogeneous phenotype of the meniscus cell remains difficult. Stem cell differentiation has been investigated, mainly using bone marrow mesenchymal cells and biochemical means for differentiation, resulting in no solution. Mechanical stimulation has been investigated to an extent with no conclusion. Here, we explore the potential for and effectiveness of mechanical stimulation to induce the meniscal phenotype in adipose-derived stromal cells. METHODS: Human adipose-derived stromal cells were chosen for their fibrogenic nature and conduciveness for chondrogenesis. Biochemical and mechanical stimulation were investigated. Biochemical stimulation included fibrogenic and chondrogenic media. For mechanical stimulation, a custom-built device was used to apply constant, cyclical, uniaxial strain for up to 6 hours. Strain and frequency varied. RESULTS: Under biochemical stimulation, both fibrogenic (collagen I, versican) and chondrogenic (collagen II, Sox9, aggrecan) genes were expressed by cells exposed to either fibrogenic or chondrogenic biochemical factors. Mechanical strain was found to preferentially promote fibrogenesis over chondrogenesis, confirming that tensile strain is an effective fibrogenic cue. Three hours at 10% strain and 1 Hz in chondrogenic media resulted in the highest expression of fibrochondrogenic genes. Although mechanical stimulation did not seem to affect protein level expression, biochemical means did affect protein level presence of collagen fibers. CONCLUSION: Mechanical stimulation can be a useful differentiation tool for mechanoresponsive cell types as long as biochemical factors are also integrated. PMID- 27757330 TI - Three-dimensional Analysis of Normal Facial Morphologies of Asians and Whites: A Novel Method of Quantitative Analysis. AB - : The purpose of this study is to compare 3-dimensional facial averages of Asians (Koreans and Chinese) and Houstonian white faces using a (3-dimensional) surface imaging system. METHODS: Three-dimensional images of Korean adults (Seoul, Korea) with class I malocclusion captured using the 3dMDface. The images of 138 Koreans were processed to generate average male and female facial shells using Rapidform 2006 plus pack 2 software and then superimposed and compared with the average shells of Chinese adults (Xi' An, China) and white adults (Houston, Tex.). RESULTS: The average Korean male and female faces were wider with prominent malar and zygomatic areas when compared with the white faces. The average white male and female faces showed more protrusion in the glabella, nasion, rhinion, and the soft-tissue pogonion than the Korean faces. The average Korean male face was retrusive at masseteric region while having more prominent lips, nasal tip, and supraglabella than the Chinese counterpart. The average Korean female face was narrower than the average Chinese female face, but there was more protrusion in the periorbital, nasal tip, and malar region seen in the Korean female face. CONCLUSIONS: Although the average faces of Chinese and Korean populations in this study showed remarkable similarities, there were distinct differences seen in the facial morphology of the 2 Asian groups. Three-dimensional imaging can be effectively used to establish population facial norms and to quantify the variations seen between different ethnicities. This information may be used in the clinical environment for plastic, oral, and maxillofacial surgery and orthodontics. PMID- 27757331 TI - Fewer Revisions in Abdominal-based Free Flaps than Latissimus Dorsi Breast Reconstruction after Radiation. AB - : The most commonly chosen flaps for delayed breast reconstruction after postmastectomy radiation therapy (PMRT) are abdominal-based free flaps (ABFFs) and pedicled latissimus dorsi (LD) musculocutaneous flaps. The short-and long term advantages and disadvantages of delayed ABFFs versus LD flaps after PMRT remain unclear. We hypothesized that after PMRT, ABFFs would result in fewer postoperative complications and a lower incidence of revision surgery than LD flaps. METHODS: We retrospectively reviewed a prospectively maintained database of consecutive patients who underwent unilateral, delayed breast reconstruction after PMRT using ABFFs or pedicled LD flaps with implants at the MD Anderson Cancer Center between January 1, 2001, and December 31, 2011. We compared outcomes and additional surgeries required between the 2 groups. Univariate and multivariate logistic regression modeling analyzed the relationships between patient and reconstruction characteristics and postoperative outcomes. RESULTS: A total of 139 consecutive patients' breast reconstructions were evaluated: 101 ABFFs (72.7%) versus 38 LDs (27.3%). Average follow-up was similar for ABFF and LD reconstructions. Although ABFF and LD reconstructions experienced similar rates of overall (30.7% vs 23.7%, respectively; P = 0.53), donor-site (8.91% vs 5.13%, respectively; P = 0.48), and flap (20.7% vs 17.9%, respectively; P = 0.37) complications, the LD reconstructions required more additional surgeries (92.1% vs 67.3%; P < 0.001). Furthermore, LDs required more revision surgeries more than 1 year after reconstruction (37.1% vs 14.7%; P = 0.02). CONCLUSION: Although early complication rates were similar for both types of reconstructions, ABFFs seem to have the advantage of providing a more durable result that required fewer revision surgeries in the long term. PMID- 27757333 TI - The Economics of Skin Cancer: An Analysis of Medicare Payment Data. AB - : The incidence and cost of nonmelanoma skin cancers are skyrocketing. Five million cases cost $8.1 billion in 2011. The average cost of treatment per patient increased from $1000 in 2006 to $1600 in 2011. We present a study of the economics and costs of skin cancer management in Medicare patients. METHODS: We studied data released by the Centers for Medicare and Medicaid Services in 2014. Treatment modalities for the management of skin cancer were reviewed, and costs of treatment were quantified for a sample of 880,000 providers. RESULTS: Review of Medicare payment records related to the management of skin cancer yielded data from over 880,000 health care providers who received $77 billion in Medicare payments in 2012. From 1992 to 2009, the rate of Mohs micrographic surgery (MMS) has increased by 700%, and these procedures typically have Medicare payments 120% to 370% more than surgical excision, even when including pathology fees. From 1992 to 2009, MMS increased by 700%, whereas surgical excisions increased by only 20%. In 2009, 1800 providers billed Medicare for MMS; in 2012, that number increased to 3209. On average, 1 in 4 cases of skin cancer is treated with MMS. CONCLUSION: Mohs excision is more expensive than surgical excision in an office setting. Procedures requiring the operating room are much more expensive than office procedures. In an era of high deductible health plans, patients' financial burden is much less with simple excisions of skin cancers done in a clinic when compared with Mohs surgery or operative interventions. PMID- 27757332 TI - The Northwestern Abdominoplasty Scar Model: A Novel Human Model for Scar Research and Therapeutics. AB - There is a growing interest in the development and evaluation of therapeutic agents that improve the cosmetic appearance of scars. Existing nonhuman animal models to study scarring, while valuable, have well-acknowledged limitations, as it is accepted that the biology of human scarring differs significantly from scarring in other species. Moreover, human clinical trials of scarring require large numbers of subjects to achieve statistical power and are plagued by inherent intersubject variability because of the complex nature of wound healing in human beings. As a better alternative, we have developed the Northwestern Abdominoplasty Scar Model-a novel human clinical model that permits analysis of up to 20 cutaneous scars in a single subject and allows for not only visual scar comparison, but also histologic and molecular analyses of factors involved in scarring and wound healing. We have utilized this model in 5 early phase clinical trials designed to test the safety and efficacy of a variety of scar therapeutics without any complications to date. The model not only is applicable to scar therapeutics, but also can be utilized for other applications, such as the testing of implantable biomaterials, injectable products, therapies such as lasers, or even for in vivo study of wound healing processes in humans. PMID- 27757334 TI - Hand Allograft Saved by an Ultrathin Groin Flap. AB - We report a case of a young double-hand allotransplant patient who presented with a full-thickness skin necrosis of the dorsum of the left hand after vascular compromise of the allotransplantation. Considering the lack of viable dorsal tissue overlying the extensor tendons and the need for early hand rehabilitation, an ultrathin pedicled groin flap was used for the coverage. This procedure resulted in salvaging the allotransplantation, and the patient was able to successfully return to work after his surgery. To our knowledge, this is the only case of an upper extremity allotransplant salvaged by a pedicled flap. PMID- 27757336 TI - Erratum: Medical Photography During the Plastic Surgery Team Briefing: Erratum. AB - [This corrects the article DOI: 10.1097/GOX.0000000000001009.]. PMID- 27757335 TI - Changes in the Dermal Structure during Cultured Epidermal Autograft Engraftment Process. AB - : The use of cultured epithelial autografts for the treatment of extensive burn wounds has become popular in recent years. We examined extensive burn wounds in 14 patients by using a combination of autograft and cultured epithelial autografts developed in Japan (JACE). METHODS: We undertook a skin biopsy at 2, 4, and 6 weeks after transplantation with JACE. By using electron microscopy we observed the engraftment process. RESULTS: In transmission electron microscope findings, we recognized the engraftment process of JACE. Keratinocytes matured gradually. Collagen fibers formed thick bundles in the dermis layer. In scanning electron microscope findings, we observed papillary dermis development on the artificial dermis. CONCLUSIONS: After managing wound bed preparation by using artificial dermis, we were able to recognize the good result of grafting JACE on meshed 6:1 split thickness autografts. This is because the auto dermis from autograft extended under the JACE, binding between JACE, and the dermis became strong. PMID- 27757337 TI - Abdominal Closure after TRAM Flap Breast Reconstruction with Transversus Abdominis Muscle Release and Mesh. AB - Breast reconstruction with a pedicled transverse rectus abdominis muscle (TRAM) flap can result in significant abdominal wall donor-site morbidity. Although the pedicled TRAM flap donor area reinforced with mesh results in decreased rates of postoperative abdominal bulging and hernias, the best technique to accomplish that is yet to be elucidated. We present our novel technique of posterior components separation with transversus abdominis muscle release and retromuscular mesh reinforcement for donor-area closure during pedicled TRAM flap breast reconstruction. PMID- 27757338 TI - The Home-made Biostimulating Thread Lift. AB - Supplemental Digital Content is available in the text. PMID- 27757339 TI - Shift toward Mechanical Isolation of Adipose-derived Stromal Vascular Fraction: Review of Upcoming Techniques. AB - : Standard isolation of adipose stromal vascular fraction (SVF) requires the use of collagenase and is considered more than "minimally manipulated" by current good manufacturing practice requirements. Alternatively, nonenzymatic isolation methods have surfaced using physical forces to separate cells from the adipose matrix. The purpose of this study was to review the literature on the use of mechanical isolation protocols and compare the results. The implication for use as a standard procedure in practice is discussed. METHODS: A systematic review of the literature was performed on mechanical isolation of SVF with a search of six terms on PubMed and Medline databases. One thousand sixty-six articles were subject to evaluation by predetermined inclusion and exclusion criteria. RESULTS: Two level 2 evidence articles and 7 in vitro studies were selected. SVF was isolated using automated closed systems or by subjecting the lipoaspirate to centrifugation only or by shaking or vortexing followed by centrifugation. Six articles reported isolation in laboratory settings and three inside the operating room. Stromal vascular cells expressed CD34, and CD44, CD73, CD90, and CD105, and differentiated along adipogenic and osteogenic lineages. When compared with enzymatic methods, mechanical isolation required less time but yielded fewer cells. Both case-control studies reported improved volume retention with cell supplemented fat grafts for breast reconstruction. CONCLUSIONS: Mechanical isolation methods are alternatives to circumvent safety issues posed by enzymatic protocols. However, randomized comparative studies with long-term clinical outcomes using mechanically isolated stromal vascular cells are needed to identify their ideal clinical applications. PMID- 27757340 TI - The Transareolar-Periareolar Approach. AB - The periareolar approach is limited by areolar diameter. Asian women typically have smaller areolae than Western women. Voluminous and form-stable silicone implants demand larger incisions. Zigzag transareolar approaches closely approximate the nipple and improve exposure, but scar appearance remains problematic, and there is a risk of ductal injury and capsular contracture. We prefer a zigzag incision that straddles the areolar border. Between 2013 and 2015, 11 augmentation mammoplasties (20 incisions) were performed through a transareolar-periareolar (TAPA) incision. The TAPA incision resembles 3 inverted V's that traverse the inferior areolar border. Outcomes were evaluated on the basis of photographs, clinical charts, and surveys. Women were 36 years old (range, 25-50). Silicone implants were used in 10 patients and saline in 1 patient. Implants were 270 cm3, placed in subpectoral position in 6 patients and subglandular position in 5. Follow-up was 12.5 months (range, 5-20 mo); there were no hematomas or infections. There was 1 case each of seroma (9.1%) and unilateral capsular contracture (9.1%) after secondary mammoplasty. There was no implant malposition or contour deformity. There were no keloids or hypertrophic scars. Every patient was satisfied. Nipple sensation was maintained or heightened in 100% of patients surveyed. The incisions were 139% longer than 180-degree periareolar scars. TAPA scars were well tolerated in this series of Asian women. We did not observe malposition, infection, or sensory disturbances. Despite its peripheral position on the nipple-areola complex, there are not enough data to determine whether TAPA incisions reduce risks compared with traditional approaches. PMID- 27757341 TI - Avoiding a Systematic Error in Assessing Fat Graft Survival in the Breast with Repeated Magnetic Resonance Imaging. AB - Several techniques for measuring breast volume (BV) are based on examining the breast on magnetic resonance imaging. However, when techniques designed to measure total BV are used to quantify BV changes, for example, after fat grafting, a systematic error is introduced because BV changes lead to contour alterations of the breast. The volume of the altered breast includes not only the injected volume but also tissue previously surrounding the breast. Therefore, the quantitative difference in BV before and after augmentation will differ from the injected volume. Here, we present a new technique to measure BV changes that compensates for this systematic error by defining the boundaries of the breast to immovable osseous pointers. This approach avoids the misinterpretation of tissue included within the expanded boundaries as graft tissue. This new method of analysis may be a reliable tool for assessing BV changes to determine fat graft retention and may be useful for evaluating and comparing available surgical techniques for breast augmentation and reconstruction using fat grafting. PMID- 27757342 TI - Teaching Surgical Procedures with Movies: Tips for High-quality Video Clips. AB - Video must now be considered as a precious tool for learning surgery. However, the medium does present production challenges, and currently, quality movies are not always accessible. We developed a series of 7 surgical videos and made them available on a publicly accessible internet website. Our videos have been viewed by thousands of people worldwide. High-quality educational movies must respect strategic and technical points to be reliable. PMID- 27757343 TI - Reshaping of the Anterior Nasal Spine: An Important Step in Rhinoplasty. AB - : The importance of analysis of the nasal spine should not be underestimated in the correct planning of rhinoplasty. Deformations in position with respect to the midline and/or in size are often present, and their correction to ensure harmony between the spine and the other components of the nasal pyramid constitutes a key step in rhinoplasty that can lead to excellent results. METHODS: The study includes 160 patients who underwent surgical treatment of the anterior nasal spine with or without other techniques of nasal reshaping. Eighty-seven of these patients presented with hyperplasia of the nasal spine, 43 with hypoplasia, and 30 with deviation. A combination of deviation and hyperplasia was present in 15 cases. RESULTS: No patients developed postoperative complications. Five patients who underwent anterior nasal spine reduction reported postoperative numbness in the premaxillary area, but sensitivity was fully regained within 4 months after surgery in these patients. All the patients reported postoperative improvement of nasal airflow. A total of 142 patients considered their postoperative aesthetic result as excellent and 18 as good. CONCLUSION: The simplicity of the surgical procedures performed on the nasal spine and the marked aesthetic improvements thus achieved suggest that greater attention should be paid to this anatomical region. PMID- 27757344 TI - Retroauricular Pleomorphic Adenoma Arising from Heterotopic Salivary Gland Tissue. AB - A 38-year-old woman is described who presented with a slowly growing mass on the posterior aspect of the left ear. Excision and histopathologic evaluation revealed a pleomorphic adenoma (PA) originating from heterotopic salivary gland tissue. Many authors have presented cases of PAs originating from ceruminous glands in the external auditory canal or of so-called chondroid syringoma originating from apocrine and eccrine sweat glands. This is the only case in the recent literature of a PA originating from a heterotopic rest of salivary gland tissue in the retroauricular region. The 3 main sources of PAs, their embryologic derivation, and treatment are described. PMID- 27757345 TI - 3D Printed Models of Cleft Palate Pathology for Surgical Education. AB - : To explore the potential viability and limitations of 3D printed models of children with cleft palate deformity. BACKGROUND: The advantages of 3D printed replicas of normal anatomical specimens have previously been described. The creation of 3D prints displaying patient-specific anatomical pathology for surgical planning and interventions is an emerging field. Here we explored the possibility of taking rare pediatric radiographic data sets to create 3D prints for surgical education. METHODS: Magnetic resonance imaging data of 2 children (8 and 14 months) were segmented, colored, and anonymized, and stereolothographic files were prepared for 3D printing on either multicolor plastic or powder 3D printers and multimaterial 3D printers. RESULTS: Two models were deemed of sufficient quality and anatomical accuracy to print unamended. One data set was further manipulated digitally to artificially extend the length of the cleft. Thus, 3 models were printed: 1 incomplete soft-palate deformity, 1 incomplete anterior palate deformity, and 1 complete cleft palate. All had cleft lip deformity. The single-material 3D prints are of sufficient quality to accurately identify the nature and extent of the deformities. Multimaterial prints were subsequently created, which could be valuable in surgical training. CONCLUSION: Improvements in the quality and resolution of radiographic imaging combined with the advent of multicolor multiproperty printer technology will make it feasible in the near future to print 3D replicas in materials that mimic the mechanical properties and color of live human tissue making them potentially suitable for surgical training. PMID- 27757346 TI - Complications of Lower Body Lift Surgery in Postbariatric Patients. AB - : There is an exponential rise of patients with massive weight loss because of bariatric surgery or lifestyle changes. The result is an increase of patients with folds of redundant skin that may cause physical and psychological problems. The lower body lift is a procedure to correct deformities in the abdomen, mons, flanks, lateral thighs, and buttocks. Complication rates are quite high and could negatively affect the positive outcomes. The purpose of this study is to assess complication rates and to identify predictors of complications to optimize outcomes for patients after lower body lift surgery. METHODS: A retrospective analysis of 100 patients who underwent a lower body lift procedure was performed. The patients were reviewed for complications, demographic data, comorbidities, smoking, highest lifetime body mass index, body mass index before lower body lift surgery, percentage of excess weight loss, and amount of tissue excised. RESULTS: The overall complication rate was 78%. Twenty-two percent of the patients had major complications and 56% had minor complications. There is a linear relationship between body mass index before lower body lift surgery and complications (P = 0.03). The percentage of excess weight loss (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.92-1.00), highest lifetime body mass index (OR 1.08; 95% CI 1.01-1.15), body mass index before lower body lift surgery (OR 1.17; 95% CI 1.02-1.33), and smoking (OR 7.74; CI 0.98-61.16) are significantly associated with the development of complications. CONCLUSIONS: This study emphasizes the importance of a good weight status before surgery and cessation of smoking to minimize the risk of complications. PMID- 27757347 TI - A Unique Case of Allogeneic Fat Grafting Between Brothers. AB - We present a case of a 65-year-old man with cutaneous T-cell lymphoma treated with radiation therapy and an allogeneic hematopoietic stem cell transplant from his human leukocyte antigen-matched brother. Engraftment was successful, but the patient went on to develop painful, radiation-induced ulcers. The ulcers were fat allografted using liposuctioned fat from his brother because of the patient's unique chimeric state. Postprocedure follow-up revealed epithelialization of the ulcer sites and significant improvement in neuropathic pain. Our unique case study supports the use of fat grafting for its restorative purposes and for its ability to alleviate chronic neuropathic pain. Additionally, it appears that our case provides a basis of a general approach to the treatment of radiation-induced ulcers in chimeric patients with lymphoid malignancies. PMID- 27757348 TI - The Plastic Surgery Compass: Navigating the Reconstructive Ladder in the Personalized Health Care Era. AB - The reconstructive ladder and the reconstructive elevator have withstood the test of time as didactic tools for resident education. Over time, many alternative models have been suggested to incorporate the technological advances in plastic surgery, but none of them have focused on the patient. Changes in practice and the trend toward personalized health care demand a 360-degree evaluation and solution of surgical problems incorporating patient-specific characteristics. We, therefore, suggest the concept of the plastic surgery compass to navigate the ladder. PMID- 27757349 TI - Cross-Face Nerve Grafting with Infraorbital Nerve Pathway Protection: Anatomic and Histomorphometric Feasibility Study. AB - Smiling is an important aspect of emotional expression and social interaction, leaving facial palsy patients with impaired social functioning and decreased overall quality of life. Although there are several techniques available for facial reanimation, staged facial reanimation using donor nerve branches from the contralateral, functioning facial nerve connected to a cross-face nerve graft (CFNG) is the only technique that can reliably reproduce an emotionally spontaneous smile. Although CFNGs provide spontaneity, they typically produce less smile excursion than when the subsequent free functioning muscle flap is innervated with the motor nerve to the masseter muscle. This may be explained in part by the larger number of donor motor axons when using the masseter nerve, as studies have shown that only 20% to 50% of facial nerve donor axons successfully cross the nerve graft to innervate their targets. As demonstrated in our animal studies, increasing the number of donor axons that grow into and traverse the CFNG to innervate the free muscle transfer increases muscle movement, and this phenomenon may provide patients with the benefit of improved smile excursion. We have previously shown in animal studies that sensory nerves, when coapted to a nerve graft, improve axonal growth through the nerve graft and improve muscle excursion. Here, we describe the feasibility of and our experience in translating these results clinically by coapting the distal portion of the CFNG to branches of the infraorbital nerve. PMID- 27757350 TI - Body Builder's Nightmare: Black Market Steroid Injection Gone Wrong: a Case Report. AB - In the pursuit of success in sports, some athletes are not deterred by health risks associated with the (mis)use of black market preparations of dubious origin as performance-enhancing agents. Several studies published in the recent years demonstrated that anabolic-androgenic steroids, but also stimulants and growth hormones, are misused by numerous recreational athletes from all over the world. Trenbolone is an anabolic steroid routinely used in the finishing phase of beef production to improve animal performance and feed efficiency. A 35-year-old male patient presented to our plastic surgery clinic after self-intramuscular administration of Trenbolone to the superior gluteal area bilaterally, which led to a full-thickness defect in a cone-like distribution. The wounds underwent surgical debridement and were treated locally with mafenide acetate irrigation and wound dressings. Closure was achieved by secondary intention healing. In this report, we discuss the first documented case of full-thickness skin and subcutaneous tissue necrosis after black market anabolic steroid injection. This illustrates a plastic complication and resolution of a widespread but seldom reported problem. PMID- 27757351 TI - Volar Plating as a Treatment for Distal Radius Fractures. PMID- 27757353 TI - Lipedema: A Relatively Common Disease with Extremely Common Misconceptions. AB - Lipedema, or adiposis dolorosa, is a common adipose tissue disorder that is believed to affect nearly 11% of adult women worldwide. It is characterized most commonly by disproportionate adipocyte hypertrophy of the lower extremities, significant tenderness to palpation, and a failure to respond to extreme weight loss modalities. Women with lipedema report a rapid growth of the lipedema subcutaneous adipose tissue in the setting of stress, surgery, and/or hormonal changes. Women with later stages of lipedema have a classic "column leg" appearance, with masses of nodular fat, easy bruising, and pain. Despite this relatively common disease, there are few physicians who are aware of it. As a result, patients are often misdiagnosed with lifestyle-induced obesity, and/or lymphedema, and subjected to unnecessary medical interventions and fat-shaming. Diagnosis is largely clinical and based on criteria initially established in 1951. Treatment of lipedema is effective and includes lymphatic support, such as complete decongestive therapy, and specialized suction lipectomy to spare injury to lymphatic channels and remove the diseased lipedema fat. With an incidence that may affect nearly 1 in 9 adult women, it is important to generate appropriate awareness, conduct additional research, and identify better diagnostic and treatment modalities for lipedema so these women can obtain the care that they need and deserve. PMID- 27757352 TI - Fu-Chan Wei-Surgeon, Innovator, and Leader of the Legendary Chang Gung Microsurgery Center. AB - Fu-Chan Wei is a world-renowned plastic and reconstructive surgeon. He is clearly one of the most influential and innovative surgeons in the history of plastic surgery. The Taiwanese legend is the innovator of the osteoseptocutaneous fibula flap, which revolutionized the reconstruction of composite bone and soft tissue defects in the jaw and extremities. He has pioneered several perforator flaps, including the free style variety. He has taken toe-to-hand microsurgical transplantation to a whole new level. He is not only recognized for his surgical skills and clinical innovations, but also for his vision, leadership, and teaching. The establishment and development of the famous Microsurgery Center at Chang Gung Memorial Hospital is unparalleled anywhere. The international fellowship program in microsurgery there remains the envy of all microsurgical trainees. Dr. Wei and his colleagues have trained and influenced more than 1,500 surgeons from all over the world. The aim of this video article is to share what we learned by interviewing Fu-Chan Wei at Chang Gung. The story of Fu Chan Wei, his colleagues, and the development of the Microsurgery Center in Taiwan is worth knowing. PMID- 27757354 TI - The Lesser Palatine Nerve Innervates the Levator Veli Palatini Muscle. AB - When the lesser palatine nerve (LPN) is supposed to be a branch of the trigeminal nerve and innervate sensation of the soft palate, whether the LPN contains motor fibers is unclear. In this study, we monitored the electromyogram of the levator veli palatini (LVP) muscle on stimulating the LPN during palatoplasty in 3 patients. The electromyogram of the muscles showed the myogenic potential induced by electrostimulation of the LPN. Taken together with the finding from our previous anatomical study that the motor fibers come from the facial nerve, this result supports the double innervation theory of the LVP, which posits that both the pharyngeal plexus and the facial nerve innervate it. Identifying and preserving the LPN during palatoplasty might improve postoperative speech results. PMID- 27757355 TI - Bilateral Maxillary Reconstruction Using Fibular Flap in Bisphosphonate-related Osteonecrosis. AB - Recent reports have shown successful transfer of vascularized fibular flap in bisphosphonate-induced mandibular osteonecrosis. We present a case of a 50-year old patient who presented with bisphosphonate-related osteonecrosis of bilateral maxilla, which is reconstructed using a fibular flap. PMID- 27757356 TI - A Prognostic Dilemma of Basal Cell Carcinoma with Intravascular Invasion. AB - Basal cell carcinoma is the most common malignancy; however, it very rarely metastasizes. Despite the low mortality caused by this cancer, once it spreads, it has dim prognosis. We report a case of basal cell carcinoma with rare intravascular invasion and review the literature for risk factors and management of metastasis. PMID- 27757357 TI - Reconstruction after Anterior Chest Wall Keloid Resection Using Internal Mammary Artery Perforator Propeller Flaps. AB - : It is difficult to completely resect huge anterior chest wall keloids and then close the wound directly. We report here our retrospective analysis of our case series of patients with such keloids who underwent reconstruction with internal mammary artery perforator (IMAP) pedicled propeller flaps and then received postoperative high-dose-rate superficial brachytherapy. METHODS: All consecutive patients with large/severe keloids on the anterior chest wall who underwent keloid resection followed by reconstruction with IMAP-pedicled propeller flaps and then high-dose-rate superficial brachytherapy in our academic hospital were identified. All cases were followed for >18 months. Donor site position, perforator pedicle, flap size, angle of flap rotation, complications, and recurrence were documented. RESULTS: There were nine men and one woman. The average age was 37.9 years. The average follow-up duration was 28.7 months. The largest flap was 16 * 4 cm. The dominant perforators of the internal mammary artery were located in the sixth (n = 2), seventh (n = 5), eighth (n = 1), and ninth (n = 2) intercostal spaces. Twelve months after surgery, patients reported marked relief from keloid-associated pain and itching, except in two patients who underwent partial keloid resection; their remaining keloids were still troublesome but after conservative therapies, including steroid ointments/plasters, the keloids gradually ameliorated. Eighteen months after surgery, there was no keloid recurrence or new development of keloids on the donor site. CONCLUSIONS: IMAP-pedicled propeller flaps transfer skin tension from the anterior chest wall to the abdomen. Our series suggests that this approach combined with radiation therapy can control keloid recurrence. PMID- 27757358 TI - Maneuvers to Aid Raising and Survival of the Homodigital Island Flap. PMID- 27757359 TI - Augmented Reality and Wearable Technology in Image-guided Navigation and Preoperative Planning. PMID- 27757360 TI - Plastic Surgery Patients Are Malnourished: Utilizing the Canadian Malnutrition Screening Tool. PMID- 27757361 TI - Mesh Sutured Repairs of Abdominal Wall Defects. AB - : A new closure technique is introduced, which uses strips of macroporous polypropylene mesh as a suture for closure of abdominal wall defects due to failures of standard sutures and difficulties with planar meshes. METHODS: Strips of macroporous polypropylene mesh of 2 cm width were passed through the abdominal wall and tied as simple interrupted sutures. The surgical technique and surgical outcomes are presented. RESULTS: One hundred and seven patients underwent a mesh sutured abdominal wall closure. Seventy-six patients had preoperative hernias, and the mean hernia width by CT scan for those with scans was 9.1 cm. Forty-nine surgical fields were clean-contaminated, contaminated, or dirty. Five patients had infections within the first 30 days. Only one knot was removed as an office procedure. Mean follow-up at 234 days revealed 4 recurrent hernias. CONCLUSIONS: Mesh sutured repairs reliably appose tissue under tension using concepts of force distribution and resistance to suture pull-through. The technique reduces the amount of foreign material required in comparison to sheet meshes, and avoids the shortcomings of monofilament sutures. Mesh sutured closures seem to be tolerant of bacterial contamination with low hernia recurrence rates and have replaced our routine use of mesh sheets and bioprosthetic grafts. PMID- 27757362 TI - What Would Women Choose When Given a Choice in Breast Reconstruction? AB - : Reconstruction after mastectomy is an important milestone for many women treated for breast cancer. However, because many surgeons only offer their preferred method of reconstruction, it is not clear which approach women would choose if offered a genuine choice. METHODS: Between 1998 and 2010, the breast reconstruction service at a major Australian teaching hospital was staffed by a single plastic surgeon trained in both prosthetic and autologous breast reconstruction techniques. The choices of all 837 women who underwent reconstruction were compared across time for publicly and privately funded patients using binary logistic regression. RESULTS: Overall, women chose prosthetic over autologous reconstruction at a ratio of 4.7:1. This ratio increasingly favored prosthetic reconstruction over time, though less strongly for private patients who did not face a 3-year waiting list for autologous reconstruction. CONCLUSIONS: Financial constraints affected these women's reconstruction choices. Nevertheless, and in contrast to the situation in the United States, these women clearly favored prosthetic over autologous reconstruction. PMID- 27757363 TI - Single-stage Reconstruction of Elbow Flexion Associated with Massive Soft-Tissue Defect Using the Latissimus Dorsi Muscle Bipolar Rotational Transfer. AB - : In the upper extremity, the latissimus dorsi muscle can be used as an ipsilateral rotational muscle flap for soft-tissue coverage or functional reconstruction of arm and elbow. Patients who have both major soft-tissue loss and functional deficits can be successfully treated with a single-stage functional latissimus dorsi rotational muscle transfer that provides simultaneous soft-tissue coverage and functional reconstruction. METHODS: Our data base was queried for all patients undergoing a rotational latissimus dorsi muscle transfer for simultaneous soft-tissue coverage and functional reconstruction of elbow flexion. Four patients were identified. A chart review documented the mechanism of injury, associated injuries, soft-tissue defect size, number of surgical procedures, length of follow-up, last elbow range of motion, and flexion strength. RESULTS: Four patients with loss of elbow flexion due to traumatic loss of the anterior compartment muscles and the overlying soft tissue underwent simultaneous soft-tissue coverage and elbow flexorplasty using the ipsilateral latissimus dorsi as a bipolar muscle rotational tissue transfer. All flaps survived and had a recovery of Medical Research Council Grade 4/5 elbow flexion strength. No additional procedures were required for elbow flexion. The surgical technique is described and supplemented with surgical technique video and patient outcome. CONCLUSIONS: This patient series augments the data provided in other series supporting the safety and efficacy of this procedure which provides both soft-tissue coverage and functional restoration of elbow flexion as a single stage procedure in the setting of massive traumatic soft-tissue loss of the arm. PMID- 27757364 TI - Microcirculatory Response In Vivo on Local Intraarterial Infusion of Autogenic Adipose-derived Stem Cells or Stromal Vascular Fraction. AB - : Both adipose-derived stem cells (ASCs) and stromal vascular fraction (SVF) have been demonstrated to have regenerative properties with therapeutic potential for numerous diseases through local or topical applications. However, it is unclear whether ASC or SVF can be delivered systemically through an intra-arterial infusion. The purpose of this study was to examine the microcirculatory response in vivo on local intraarterial infusion of autogenic ASCs or SVF in a vascular pedicle isolated rat cremaster microcirculation model. MATERIALS AND METHODS: Fat tissue was surgically harvested from the flanks of male Sprague-Dawley rats (n = 12) and processed for SVF isolation. Some SVF samples were cultured for 24 hours for ASC purification. The autogenic SVF (1 * 105) cells (n = 6) or purified ASC (1 * 105) cells (n = 6) cells were infused into the microcirculation of cremaster muscle at a speed of 0.05 mL/min through the cannulation of femoral artery. As this is a vascular pedicle isolated preparation, the infused SVF or ASC cells went nowhere but the cremaster muscle. The video image of the microcirculation was monitored in real time during infusion. RESULTS: Arteriole diameter was measured as A1 (100-160 um), A2 (40-80 um), and A3/A4 (10-30 um). Capillary perfusion was quantified in 18 capillary fields of each muscle. There was a significant increase in the diameter of terminal arterioles (P = 0.049) and the capillary density (P = 0.02) after ASC intraarterial infusion. However, a significant cell aggregation, embolisms, and arterial obstruction were observed in the microcirculation in every case during SVF infusion. CONCLUSIONS: Intraarterial infusion is an appropriate route for the delivery of autogenic ASCs, but not of SVF. SVF-induced microembolisms were the reason for narrowing or blocking the lumen of terminal arterioles, resulting in no flow in the corresponding capillaries. PMID- 27757365 TI - Comparative Study of a Novel Tool for Follicular Unit Extraction for Individuals with Afro-textured Hair. AB - : Hair transplantation involving patients with tightly curled Afro-textured hair using follicular unit extraction (FUE) employing conventional rotary punches frequently leads to unacceptably high transection rates. These patients are unsuitable candidates for FUE hair transplantation. Transection rates were observed during FUE in a case series of 18 patients with tightly curled Afro textured hair using different punches. METHODS: Three different punches were sequentially used in patients to extract follicular units with several needle gauges until satisfactory transection rates occurred: conventional sharp and dull rotary punches, followed by a 2-pronged curved nonrotary punch. RESULTS: In all instances, the curved nonrotary punch had the best transection rate of <5%. Sharp and dull rotary punches completely failed or had excessive transection rates in 8 patients. The dull rotary punch performed better than the sharp rotary punch in 9 patients in whom it was used with few restrictions compared to 5 patients in whom there were more restrictions. CONCLUSIONS: A curved nonrotary punch configured to accommodate the curliness of tightly curled Afro-textured hair can overcome high transection rates experienced using conventional sharp or dull rotary punches. Limitations of this study include it being a small, retrospective case series, and that the new technique that could require additional training by current FUE hair transplant practitioners. PMID- 27757366 TI - Absorptive capacity, technological innovation, and product life cycle: a system dynamics model. AB - BACKGROUND: While past research has recognized the importance of the dynamic nature of absorptive capacity, there is limited knowledge on how to generate a fair and comprehensive analytical framework. Based on interviews with 24 Chinese firms, this study develops a system-dynamics model that incorporates an important feedback loop among absorptive capacity, technological innovation, and product life cycle (PLC). RESULTS: The simulation results reveal that (1) PLC affects the dynamic process of absorptive capacity; (2) the absorptive capacity of a firm peaks in the growth stage of PLC, and (3) the market demand at different PLC stages is the main driving force in firms' technological innovations. This study also explores a sensitivity simulation using the variables of (1) time spent in founding an external knowledge network, (2) research and development period, and (3) knowledge diversity. The sensitivity simulation results show that the changes of these three variables have a greater impact on absorptive capacity and technological innovation during growth and maturity stages than in the introduction and declining stages of PLC. CONCLUSIONS: We provide suggestions on how firms can adjust management policies to improve their absorptive capacity and technological innovation performance during different PLC stages. PMID- 27757367 TI - The right of women in property sharing in Bangladesh: Can the islamic inheritance system eliminate discrimination? AB - This study seeks to discover the best solution for women's property sharing between Islamic and current social practices in Bangladesh. A qualitative method has been adopted to achieve this goal. It is found that the majority of the women are marginalised from their property in the social practice. On the other hand, in the Islamic solution, the property is fixed for all classes of women and is based on a property sharing system called fara'id that takes into account the roles and responsibilities of man and woman in the society. Men are responsible for providing maintenance to their wives and children. Men in Islamic society should bear expenditure related to marriage. The research concludes that the Islamic solution is fair and ensures just property sharing rights for women. It suggests that the Islamic solution for property sharing should be implemented to empower women in Bangladesh. PMID- 27757368 TI - Antifungal activity of dual combination of hydroxychavicol with commercialized agents against oral Candida species. AB - Candida spp. is the most prevalent species causing systemic fungal infections. The effect of antifungal agents were screened in vitro and their synergism effect were determined between hydroxychavicol (HC) in association with commercialized antifungal drugs-amphotericin B (AMB), and 5-fluorocytosine (5-FC) alone and in combination against five different oral Candida spp. in their planktonic states at different ratio (1:1 v/v; 1:2 v/v and 2:1 v/v). In vitro susceptibilities of Candida spp. to HC and commercialized antifungal agents were investigated by broth microdilution method as described by Clinical and Laboratory Standards Institute M38-A2. The intensity of the interactions was evaluated by visual reading and spectrophotometric method in checkerboard microdiluton assay, and the nature of the interactions was assessed by fractional inhibitory concentration index. The minimum inhibitory concentration (MIC50) of HC, AMB and 5-FC alone against five different planktonic oral Candida spp. ranged from 240 to 120, 8 to 15, and 2 to 8 ug/mL respectively. Positive synergistic effect existed between HC and AMB at 1:1 ratio in all Candida spp. However, there was no synergy effect observed in the majority of Candida spp. for the combination of HC with 5-FC. The data of combination between HC with AMB may be useful in the treatment of systemic infections caused by oral Candida spp. instead of the combination of HC with 5-FC. PMID- 27757369 TI - Human health risks from heavy metals in fish of Buriganga river, Bangladesh. AB - Heavy metals are known to cause deleterious effects on human health through food chain. Human health risks were evaluated from consumption of heavy metal contaminated fish from Buriganga River in Bangladesh. Whole body of five fish species (Puntius ticto, Puntius sophore, Puntius chola, Labeo rohita and Glossogobius giuris) were analyzed which contained various concentrations of Cd, As, Pb, Cr, Ni, Zn, Se, Cu, Mo, Mn, Sb, Ba, V and Ag. Concentrations of Mn, Zn, Se and Pb in all fish species were above the Food Safety Guideline (FSG) by WHO/FAO. Assessment of noncarcinogenic health hazard by target hazard quotient (THQ) indicated no concern from consumption of these fish except for Mn. However, all metals together may affect human health as revealed by hazard index (HI). The target cancer risk (TR) values suggested carcinogenic risk from Ni and As. Taken together it can be concluded that there is potential human health risk in consuming fish from river Buriganga. PMID- 27757370 TI - Erratum to: Effects of dietary supplementation of golden apple snail (Pomacea canaliculata) egg on survival, pigmentation and antioxidant activity of Blood parrot. AB - [This corrects the article DOI: 10.1186/s40064-016-3051-2.]. PMID- 27757371 TI - Sunk costs, psychological symptomology, and help seeking. AB - Individuals often allow prior investments of time, money or effort to influence their current behavior. A tendency to allow previous investments to impact further investment, referred to as the sunk-cost fallacy, may be related to adverse psychological health. Unfortunately, little is known about the relation between the sunk-cost fallacy and psychological symptoms or help seeking. The current study used a relatively novel approach (i.e., Amazon.com's Mechanical Turk crowdsourcing [AMT] service) to examine various aspects of psychological health in internet users (n = 1053) that did and did not commit the sunk-cost fallacy. In this observational study, individuals logged on to AMT, selected the "decision making survey" amongst the array of currently available tasks, and completed the approximately 200-question survey (which included a two-trial sunk cost task, the brief symptom inventory 18, the Binge Eating Scale, portions of the SF-8 health survey, and other questions about treatment utilization). Individuals that committed the fallacy reported a greater number of symptoms related to Binge Eating Disorder and Depression, being bothered more by emotional problems, yet waited longer to seek assistance when feeling ill. The current findings are discussed in relation to promoting help-seeking behavior amongst individuals that commit this logical fallacy. PMID- 27757372 TI - Ovarian mature cystic teratoma with fistula formation into the rectum: a case report. AB - BACKGROUND: While ovarian mature cystic teratomas are benign ovarian germ-cell tumors and the most common type of all ovarian tumors, the formation of fistulas into surrounding organs such as the bladder and the intestinal tract is extremely rare. This report documents a case of ovarian mature cystic teratoma with a rectal fistula, thought to be caused by local inflammation. CASE DESCRIPTION: A pelvic mass was diagnosed as an ovarian mature cystic teratoma of approximately 10 cm in diameter on transvaginal ultrasound and magnetic resonance examinations. Endoscopic examination of the lower gastrointestinal tract to investigate diarrhea revealed an ulcerative lesion with hair in the rectal wall adjacent to the ovarian cyst, and formation of a fistula from the ovarian teratoma into the rectum was suspected. Laparotomy revealed extensive inflammatory adhesions between a left ovarian tumor and the rectum. Left salpingo-oophorectomy and upper anterior resection of the rectum were performed. The final pathological diagnosis was ovarian mature cystic teratoma with no malignant findings, together with severe rectal inflammation and fistula formation with no structural disorders such as diverticulitis of the colon or malignant signs. DISCUSSION: The formation of fistulas and invasion into the neighboring organs are extremely rare complications for ovarian mature cystic teratomas. The invasion of malignant cells into neighboring organs due to malignant transformation of the tumor is reported as the cause of fistula formation into the neighboring organs. A review of 17 cases including the present case revealed that fistula formation due to malignant transformation comprised only 4 cases (23.5 %), with inflammation as the actual cause in the majority of cases (13 cases, 76.5 %). CONCLUSION: Although malignancy is the first consideration when fistula formation is observed between ovarian tumors and surrounding organs, in mature cystic teratoma, local inflammation is more likely than malignant transformation. PMID- 27757373 TI - Population genetic analysis reveals a low level of genetic diversity of 'Candidatus Phytoplasma aurantifolia' causing witches' broom disease in lime. AB - Witches' broom disease of lime (WBDL) is a serious phytoplasma disease of acid lime in Oman, the UAE and Iran. Despite efforts to study it, no systemic study attempted to characterize the relationship among the associated phytoplasma, 'Candidatus Phytoplasma aurantifolia', from the three countries. This study utilized sequences of the 16S rRNA, imp and secA genes to characterize 57 strains collected from Oman (38), the UAE (9) and Iran (10). Phylogenetic analysis based on the 16S rRNA gene showed that the 57 strains shared 98.5-100 % nucleotide similarity to each other and to strains of 'Ca. P. aurantifolia' available in GenBank. The level of genetic diversity was low based on the 16S rRNA (0-0.011), imp (0-0.002) and secA genes (0-0.015). The presence of low level of diversity among phytoplasma strains from Oman, the UAE and Iran can be explained by the movement of infected lime seedlings from one country to another through trading and exchange of infected plants. The study discusses implication of the findings on WBDL spread and management. PMID- 27757374 TI - Taking the chance: Core self-evaluations predict relative gain in job resources following turnover. AB - Core self-evaluations (CSE) might account for relative gains in job resources across time, especially in situations when these individual differences affect behavior that is relevant for development of job resources. This longitudinal study tests CSE as an individual resource that predicts relative gain in job resources and job satisfaction among job beginners who change or stay with their employer. A questionnaire was filled in by 513 adolescents shortly before the end of vocational training and one year later. Our results replicate previous findings suggesting that job satisfaction is affected by CSE directly and indirectly through the perception of job resources. Multi-group structural equation analysis showed that only leavers had a longitudinal indirect effect of CSE on job satisfaction at the end of vocational training via job resources during their first year of employment. Our findings imply that turnover includes opportunities to optimize one's circumstances and that CSE helps to attain resourceful jobs. PMID- 27757375 TI - Magnesium-permeable TRPM6 polymorphisms in patients with meningomyelocele. AB - BACKGROUND: To evaluate whether there is an association between single nucleotide polymorphisms in magnesium-permeable TRPM6 ion channel and development of meningomyelocele (MMC). Therefore, we examined a total of 150 children with MMC, along with age- and gender-matched controls. DNA collected from whole blood was analyzed for the presence of two polymorphisms, rs2274924 (A > G; K1579E; Leu1579Glu) and rs3750425 (G > A; Val1393Ile), in TRPM6. Serum Mg2+ and calcium levels were also examined. RESULTS: A statistically significant difference in the distribution of rs2274924 genotypes (p = 0.049) was observed between the groups. Decreases in the AA genotype, and increases in the AG heterozygous genotype were also detected in the study group. The distribution of polymorphisms in the rs3750425 genotype and alleles was not statistically different between groups. Serum Mg2+ levels were lower in the GG genotype of rs3750425 compared with the GA and AA genotypes (p = 0.003). CONCLUSIONS: A statistically significant difference in rs3750425 genotypes was observed between the patients with MMC and the controls, which corresponded to lower serum Mg2+ concentrations in these patients. Taken together, these results suggest that genetic variations in the Mg2+-permeable TRPM6 ion channel may play a role in the etiopathogenesis of MMC during embryonic development. PMID- 27757376 TI - Bisphosphonates therapy for osteoarthritis: a meta-analysis of randomized controlled trials. AB - High-turnover type bone metabolism derangement has been considered to be one of the major causes of osteoarthritis (OA). Bisphosphonates can attach to hydroxyapatite binding sites on bony surfaces, particularly those which are undergoing active bone resorption. To evaluate the effectiveness of bisphosphonates in OA treatment, literature databases were searched from inception to February 28, 2016 for clinical studies of bisphosphonates for OA treatment. All randomized controlled trials in which bisphosphonates therapy was compared with a placebo or a conventional medication, were selected. 15/1145 studies were eligible for analysis, which included 3566 participants. Bisphosphonates therapy improved pain, stiffness and function significantly in OA assessed by the Western Ontario and McMaster Universities Arthritis Index scale (MD = 4.59; 95 % CI 2.83-6.34; P < 0.00001; MD = 1.43; 95 % CI 0.83-2.23; P = 0.0005; MD = 2.01; 95 % CI 1.27-2.75; P < 0.00001). Bisphosphonates also reduced osteophyte score significantly (MD = -0.51; 95 % CI -0.84 to -0.19; P = 0.002). However, no significant differences were found in subjective improvement, osteoarthritis progression, the number of required acetaminophen treatment or joint replacement. In conclusion, bisphosphonates therapy is effective in relieving pain,stiffness and accelerating functional recovery in OA. Limitations of the studies we analysed included the differences in duration of bisphosphonates use, the doses and types of bisphosphonates and the lack of long term data on OA joint structure modification after bisphosphonates therapy. More targeted studies are required to evaluate on the effectiveness of bisphosphonates for OA treatment. PMID- 27757377 TI - Comparison of absorbed irrigation fluid volumes during retrograde intrarenal surgery and percutaneous nephrolithotomy for the treatment of kidney stones larger than 2 cm. AB - PURPOSE: Irrigation-induced increase in intrarenal pressure is of concern because it may cause infection due to increased pyelovenous and pyelolymphatic absorption. This study is the first to compare prospectively the absorbed fluid volumes during percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) for stones larger than 2 cm. MATERIALS AND METHODS: General anesthesia was applied to all patients. Isotonic solution containing 1 % ethanol was used as irrigation fluid. Venous blood ethanol concentration was first measured with the start of irrigation and thereafter every 15 min until the patients left the recovery room. Absorbed fluid volumes were measured using the blood ethanol concentrations. Duration of irrigation, irrigated fluid volume, stone size and grade of hydronephrosis were also recorded. RESULTS: A total of 60 patients were included the study. Fluid absorption occurred in all patients. Minimum and maximum ranges of fluid absorption were 20-573 mL for RIRS and 13-364 mL for PCNL. The increase in fluid absorbed volume was observed as a result of the given amount of irrigating fluid used in the PCNL group. Also prolongation of operation led to a significant increase in absorption in the PCNL group. Increase in body mass index, stone size, and hydronephrosis did not affect fluid absorption significantly in either of the two operation techniques in correlation analyzes. CONCLUSION: Both RIRS and PCNL are conducted under high pressure and can be accompanied potential complications such as SIRS. The fluid absorption confirmed in our study should be taken into consideration during RIRS and PCNL. PMID- 27757378 TI - Factors affecting dental diseases presenting at the University of Ghana Hospital. AB - Dental diseases are common in man and range from a toothache to cancers of the head and neck. Dental conditions can affect our capacity to function effectively in areas such as smiling, chewing and speaking. The objective of this study was to describe the main types of dental conditions presenting at the University Hospital between January 2006 and December 2011 and to determine factors associated with the top five diagnosed conditions as well as the acute and chronic conditions. A retrospective review of all 5012 clinical records of dental patients visiting the dental unit within the period stated was carried out. A total of 4196 records which passed the inclusion/exclusion criteria were analysed. Most of the patients who presented were adults. The top 5 dental conditions were apical periodontitis (50.4 %), reversible pulpitis (23.3 %), Gingivitis (11.4 %), Periodontitis (6.2 %) and Halitosis/bad breadth (8.8 %). The top 5 conditions constituted over 75 % of the cases seen. About 84 % of the presentation was acute whilst 16 % was chronic. For the entire dataset and also the top five conditions, approximately 53.0 % were males and 47.0 %. Males outnumbered females on all occasions except for halitosis and most patients presented within 1 month of experiencing symptoms of dental disease. Some significant association was found between the presence of multiple chronic conditions and reversible/irreversible pulpitis. The main dental conditions presenting at the University Hospital during the stated period (i.e. between January 2006 and December 2011) were: apical periodontitis (50.4 %), reversible pulpitis (23.3 %), gingivitis (11.4 %), periodontitis (6.2 %) and halitosis/bad breadth (8.8 %). PMID- 27757379 TI - Tourism guide cloud service quality: What actually delights customers? AB - BACKGROUND: The emergence of advanced IT and cloud services has beneficially supported the information-intensive tourism industry, simultaneously caused extreme competitions in attracting customers through building efficient service platforms. On response, numerous nations have implemented cloud platforms to provide value-added sightseeing information and personal intelligent service experiences. Despite these efforts, customers' actual perspectives have yet been sufficiently understood. To bridge the gap, this study attempts to investigate what aspects of tourism cloud services actually delight customers' satisfaction and loyalty. METHODS: 336 valid survey questionnaire answers were analyzed using structural equation modeling method. RESULTS: The results prove positive impacts of function quality, enjoyment, multiple visual aids, and information quality on customers' satisfaction as well as of enjoyment and satisfaction on use loyalty. CONCLUSIONS: The findings hope to provide helpful references of customer use behaviors for enhancing cloud service quality in order to achieve better organizational competitiveness. PMID- 27757380 TI - Concurrent Ramsay Hunt syndrome and disseminated herpes zoster in a patient with relapsed chronic lymphocytic leukemia. AB - Ramsay Hunt Syndrome (RHS) is a rare complication of latent varicella-zoster virus (VZV) infection that can occur in immunocompetent host. It usually involves ipsilateral facial paralysis, ear pain and facial vesicles. Disseminated herpes zoster is another complication of VZV infection typically seen in immunocompromised hosts. We describe a patient with relapsed chronic lymphocytic leukemia (CLL) who presented simultaneously with RHS and disseminated herpes zoster. While other complications have been documented to coexist with RHS, to our knowledge, this is the first reported case in the literature of concurrent RHS with disseminated herpes zoster. PMID- 27757381 TI - Echinacea Supplementation: Does it Really Improve Aerobic Fitness? AB - PURPOSE: Echinacea is an herbal supplement used by endurance athletes for its performance boosting properties. It is thought that Echinacea improves the blood's oxygen carrying capacity by increasing production of erythropoietin (EPO), a glycoprotein that regulates red blood cell formation. Subsequently, these changes would lead to an overall improvement in maximal oxygen uptake (VO2max) and running economy (RE), two markers of aerobic fitness. The purpose of this review is to briefly discuss the physiological variables associated with distance running performance and how these variables are influenced by Echinacea supplementation. METHODS: To determine Echinacea's ergogenic potential, human studies that used Echinacea in conjunction to analyzing the blood's oxygen carrying capacity and/or aerobic fitness were assessed. RESULTS: Taken together, the majority of the published literature does not support the claim that Echinacea is a beneficial ergogenic aid. With the exception of one study, several independent groups have reported Echinacea supplementation does not increase EPO production, blood markers of oxygen transport, VO2max or RE in healthy untrained or trained subjects. CONCLUSION: To date, the published literature does not support the use of Echinacea as an ergogenic aid to improve aerobic fitness in healthy untrained or trained subjects. PMID- 27757382 TI - The effects of exercise training and type of exercise training on changes in bone mineral denstiy in Korean postmenopausal women: a systematic review. AB - PURPOSE: To systematically review the effects of exercise training and the type of exercise training on changes in bone mineral density (BMD) in Korean postmenopausal women. METHODS: Korean studies Information Service System (KISS) and PubMed were searched and 17 randomized control trials were selected. Changes in BMD of lumbar spine (LS), femur neck (FN), Ward's triangle (WT), and trochanter (Tro) were chosen as major outcomes. RESULTS: Exercise training increased BMD of LS, FN, WT, and Tro. According to the type of exercise training, combined exercise training (aerobic + resistance) showed improvements in BMD of LS, FN, WT, and Tro. However, aerobic exercise training alone and resistance exercise training alone showed inconsistent results. CONCLUSION: Exercise training can improve the BMD of LS, FN, WT, and Tro in Korean postmenopausal women. The type of exercise training may be a crucial factor for maintaining or improving bone health of this population. PMID- 27757383 TI - Effects of voluntary exercise on apoptosis and cortisol after chronic restraint stress in mice. AB - PURPOSE: To determine whether voluntary exercise (wheel running) has the potential of relieving stress. METHODS: In this study, restraint stress with or without voluntary wheel running was performed for mice housed in individual cages. A total of 21 ICR male mice were assigned into control (CON), restraint stress with voluntary exercise (RSVE), or restraint stress (RS) without voluntary exercise groups (n = 7 each). RESULTS: No significant difference in body weight increase was found among the three groups, although CON and RS groups had a tendency of having smaller body weight increase compared to the RSVE group. No significant difference in the expression level of liver heat shock protein 70, Bcl-2, or p53 was found among the three groups. However, caspase-3 protein level in RS group was significantly higher than that in the other two groups. Blood cortisol concentration in RS was higher (p < 0.05) than that in RSVE or CON group. It was the lowest (p < 0.05) in the RSVE group. CONCLUSION: Our findings suggest that apoptosis caused by chronic restraint stress might be suppressed by voluntary exercise in mice. PMID- 27757384 TI - Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice. AB - PURPOSE: The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. METHODS: Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST Cr+Ex, n=9). After five weeks' treatment, we investigated using both anti behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). RESULTS: Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. CONCLUSION: The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment. PMID- 27757385 TI - The Effect of Pueraria Lobata/Rehmannia Glutinosa and Exercise on Fatty Acid Transporters Expression in Ovariectomized Rats Skeletal Muscles. AB - PURPOSE: Pueraria lobata/rehmannia glutinosa (PR) and exercise have been receiving a lot of attention from postmenopausal women, as a result of the side effects of estrogen replacement therapy. However, the effects of PR and exercise on fatty acid transporters (FATPs), which play essential role in fatty acid transport, have not been studied. In this study, we evaluated the effects of PR and aerobic exercise on FATP1, FABPpm and FAT/CD36 expression in ovariectomized rat skeletal muscles. METHODS: Sixty rats were randomly divided into 6 groups: (1)HSV; high fat diet (HFD)+sedentary+vehicle, (2)HSP; HFD+sedentary+PR, (3)HSH; HFD+sedentary+17beta-estradiol, (4)HEV; HFD+exercise+vehicle, (5) HEP; HFD+exercise+PR, (6)HEH; HFD+exercise+17beta-estradiol. Exercise consisted of treadmill exercise (1-4th week: 15 m/min for 30 min, 5-8th week: 18 m/min for 40 min, 5 times/week). RESULTS: Exercise does not alter FATP1 and FAT/CD36 gene levels in soleus and plantaris muscles. In contrast, exercise had main effect on up-regulation of FABPpm mRNA expression in both muscles. However, FABPpm level was not increased by exercise combined with treatments, indicative of no additive effects of PR or hormone on FABPpm gene expression. On the other hand, immunohistochemistry result showed that translocation of FATPs proteins to plasma membrane were higher in PR, exercise groups, and exercise combined with PR groups in both muscles. CONCLUSION: These result showed that aerobic exercise and PR may help increase fat-oxidation through the induction of FABPpm, a muscle specific transporter, in OVX rat skeletal muscles. In addition, FABPpm expression is possibly regulated post-transcriptionally in exercise, or pre-translationally in PR. PMID- 27757386 TI - Effects of high-intensity swimming training on the bones of ovariectomized rats. AB - PURPOSE: This study was performed to assess the effects of high-intensity intermittent swimming training(HIT) on bone in ovariectomized rats. METHODS: Six week-old female Sprague-Dawley rats were randomly assigned to either sham operation or bilateral ovariectomy. After surgery, they were divided into the following four groups: 1) sham-operated sedentary (S), 2) sham-operated exercise training (SE), 3) OVX sedentary (O), 4) OVX exercise training (OE) 5) OVX given 17beta-estradiol (OE2) and 6) OVX exercise training and given 17beta-estradiol (OEE). SE, OE and OEE rats were used extremely high-intensity swim exercise. The rats repeated fourteen 20-s swimming bouts with a weight equivalent to 14, 15, and 16% of body weight for the first 5, the next 9, and the last 5 days, respectively. Between exercise bouts, a 10-s pause was allowed. HIT was originally designed as an exercise method; a method that very quickly induces an increase in the maximum oxygen intake (Tabata I et al., 1996). OEE and OE2 rats were subcutaneously injected ethanol with 25MUg/kg body weight 17beta-estradiol 3 times per week. RESULTS: Bone strength, bone mineral density and trabecular bone parameters were measured after a 8-weeks experimental period. Bone strength was significantly higher in the SE, OE, OE2 and OEE group compared with the O group. BV/TV was significant increase in the SE, OE groups compared with the O group. BMD showed no difference in the OE group compared with the O group. CONCLUSION: This study demonstrate some beneficial effects of postmenopausal osteoporosis of high-intensity intermittent swimming training on bone structure and strength. PMID- 27757387 TI - The reliability and validity of gait speed with different walking pace and distances against general health, physical function, and chronic disease in aged adults. AB - PURPOSE: Gait speed is an important objective values associated with several health-related outcomes including functional mobility in aging people. However, walking test methodologies and descriptions are not standardized considering specific aims of research. This study examine the reliability and validity of gait speed measured at various distances and paces in elderly Koreans. METHODS: Fifty-four female participants >=70 years of age were recruited from a local retirement community. Gait speed was assessed at 4, 6 and 10 meters, and at usual and fast-pace walking mode. The short physical performance battery (SPPB) that estimates senior fitness includes three tests of lower-body function. Data concerning for the chronic conditions and self-perceived health of the participants was collected using questionnaires. Concurrent validity of gait speed using the aforementioned test protocols was determined by calculating the Pearson correlation coefficients. RESULTS: Significant positive correlations were evident between skeletal muscle mass and maximal pace walking regardless of distance (r=.301~.308; p<.05), but not with body fat. All gait tests significantly positively correlated with self-rated health (normal pace r=.328~.346, p<.05; maximal pace r=.427~.472, p<.001) and depression (normal pace r=.279~.430, p<.05; maximal pace r=.413~.456, p<.001). CONCLUSION: Walking test at the normal pace appears suitable for estimating physical function and deterioration due to chronic disease. Walking test at a maximum pace might be useful for estimating subjective general health and skeletal muscle mass. PMID- 27757388 TI - Association between daily step counts and physical activity level among Korean elementary schoolchildren. AB - PURPOSE: The purpose of the current study was to investigate steps per day (steps/d) and physical activity level (PAL) in Korean elementary school children having normal weight (normal-weight). We also clarified whether a gender difference exited between steps/d and PAL. METHODS: Children aged 9 to 12 y were recruited from two elementary schools located in different urban districts in Korea. The present study included 33 Korean children, of which 18 were normal weight boys and 15 were normal-weight girls. During the same 1 week study period under free-living conditions the total energy expenditure (TEE) and step counts were estimated using the doubly labeled water (DLW) method and an accelerometer, respectively. We calculated PAL as the TEE/ resting metabolic rate. RESULTS: The range of PAL was 1.25 - 1.93 with a mean value of 1.57. None of the variables of energy expenditure was significantly different by sex. However, steps/d were significantly higher in boys than in girls. When adjusting regression analysis by gender, steps/ d were positively associated with PAL among all subjects (r = 0.56, P < 0.01). Furthermore, steps/d were positively associated with PAL in boys (r = 0.68, P < 0.01), but not in girls (r = 0.27, P = 0.34). CONCLUSION: Our results suggest that locomotive activity may be the main contributor to the individual PAL differences for elementary school boys, while non-locomotive activity may be the main contributor for elementary school girls. PMID- 27757391 TI - Adequate analgesic regimen would be required after minimally invasive colorectal surgery. PMID- 27757389 TI - The Monoclonal Antitoxin Antibodies (Actoxumab-Bezlotoxumab) Treatment Facilitates Normalization of the Gut Microbiota of Mice with Clostridium difficile Infection. AB - Antibiotics have significant and long-lasting impacts on the intestinal microbiota and consequently reduce colonization resistance against Clostridium difficile infection (CDI). Standard therapy using antibiotics is associated with a high rate of disease recurrence, highlighting the need for novel treatment strategies that target toxins, the major virulence factors, rather than the organism itself. Human monoclonal antibodies MK-3415A (actoxumab-bezlotoxumab) to C. difficile toxin A and toxin B, as an emerging non-antibiotic approach, significantly reduced the recurrence of CDI in animal models and human clinical trials. Although the main mechanism of protection is through direct neutralization of the toxins, the impact of MK-3415A on gut microbiota and its restoration has not been examined. Using a CDI murine model, we compared the bacterial diversity of the gut microbiome of mice under different treatments including MK-3415A, vancomycin, or vancomycin combined with MK-3415A, sampled longitudinally. Here, we showed that C. difficile infection resulted in the prevalence of Enterobacter species. Sixty percent of mice in the vehicle group died after 2 days and their microbiome was almost exclusively formed by Enterobacter. MK-3415A treatment resulted in lower Enterobacter levels and restoration of Blautia, Akkermansia, and Lactobacillus which were the core components of the original microbiota. Vancomycin treatment led to significantly lower survival rate than the combo treatment of MK-3415A and vancomycin. Vancomycin treatment decreased bacterial diversity with predominant Enterobacter and Akkermansia, while Staphylococcus expanded after vancomycin treatment was terminated. In contrast, mice treated by vancomycin combined with MK-3415A also experienced decreased bacterial diversity during vancomycin treatment. However, these animals were able to recover their initial Blautia and Lactobacillus proportions, even though episodes of Staphylococcus overgrowth were detected by the end of the experiments. In conclusion, MK-3415A (actoxumab-bezlotoxumab) treatment facilitates normalization of the gut microbiota in CDI mice. It remains to be examined whether or not the prevention of recurrent CDI by the antitoxin antibodies observed in clinical trials occurs through modulation of microbiota. PMID- 27757390 TI - Caustic Ingestion in Children: a Systematic Review and Meta-Analysis. AB - Introduction: Caustic ingestion that occurs accidently is one of the most common problems in children. Methods: This systematic review has been performed by searching the databases including Science Direct, ProQuest, Google Scholar, and PubMed. A strategic search was performed with keywords including caustic, corrosive, ingestion, and children, and was limited to articles in English and Persian. Data were analyzed using Comprehensive Meta-Analysis2 and PASW Statistics 18. Results: We selected 64 articles regarding caustic ingestion with a total sample of 11,345 cases. The data analysis indicated a higher consumption in young boys (age range 2.78 (2.02) years (OR=0.53 with a 95% confidence interval of 0.49-0.57 (P=0.08)). The most common caustic substances were household cleaning agents, particularly bleaches and cleaners. Esophageal cancer and death were reported as well as digestive and respiratory complications. Invasive and expensive techniques are frequently used for diagnosis, treatment and follow up. Conclusion: The results demonstrated that although caustic ingestion is a serious problem among children, it is a preventable and manageable issue. Therefore, appropriate efforts by families, government, factories, health team and media should be made to handle adequately this matter. PMID- 27757392 TI - Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal cancer: 2-year follow-up results at a single institution in Korea. AB - PURPOSE: The purpose of this study was to examine 2-year follow-up results of cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis (PC) of colorectal cancer. METHODS: We performed 54 cases of CRS and IPC in 53 patients with PC of colorectal cancer from December 2011 to December 2013. We collected data prospectively and analyzed the grade of PC, morbidity and mortality, and short-term follow-up (median, 10 months; range, 2-47 months) results. RESULTS: Mean peritoneal cancer index (PCI) was 15 (range, 1 35), and complete cytoreduction was possible in 35 patients (64.8%). Complications occurred in 25 patients (46.3%) and mortality occurred in 4 patients (7.4%). Excluding the 4 mortalities, 17 patients out of 49 patients (31.5%) were alive at the time of the last follow-up and the overall median survival was 10.3 months. Patients with complete cytoreduction had a median survival of 22.6 months, which was significantly longer than the median survival of 3.5 months for patients without complete cytoreduction (P < 0.001). PCI grade, CCR grade, cell type, and postoperative chemotherapy were significant prognostic factors by univariate analysis. Positive independent prognostic factors by multivariate analysis included PCI grade and postoperative chemotherapy. CONCLUSION: CRS and IPC increased the survival of patients with low PCI and postoperative systemic chemotherapy was mandatory. However, this combined therapeutic approach showed high rate of complications and mortality. Therefore, this aggressive treatment should be performed in only selected patients by considering the general condition of the patient and the extent of PC. PMID- 27757393 TI - The prognostic significance and treatment modality for elevated pre- and postoperative serum CEA in colorectal cancer patients. AB - PURPOSE: The purpose of this study was to evaluate the prognostic significance of serum CEA (s-CEA) changes in colorectal cancer (CRC) patients with sustained elevated postoperative s-CEA levels. METHODS: Between January 1999 and December 2008, 9,380 CRC patients underwent surgery. Curative resection was performed in 1,242 CRC patients with high preoperative s-CEA levels (>6 ng/mL). High s-CEA levels were normalized in 924 patients (74.4%) within 2 weeks from surgery, whereas high s-CEA levels were persistent in 318 patients (25.6%). Patients were divided into 2 groups according to their postoperative s-CEA levels: group 1 (37 patients with a 1-year postoperative s-CEA>6 ng/mL) and group 2 (281 patients with a 1-year postoperative s-CEA<=6 ng/mL). RESULTS: A postoperative recurrence was identified in 24 patients (64.9%) in group 1 and 65 patients (23.1%) in group 2 (P < 0.001). A curative resection after recurrence was performed in 22 patients (33.8%) from group 2, but no patients from group 1 (P = 0.001). The 5-year overall survival and time to recurrence were significantly lower in patients with recurrent cancer in group 1 (P < 0.001). CONCLUSION: Patients with persistent elevated postoperative s-CEA levels are at high risk for recurrence and a low survival rate. More intensive surveillance of patients with high postoperative s CEA levels should be mandatory. PMID- 27757394 TI - Palliative resection of a primary tumor in patients with unresectable colorectal cancer: could resection type improve survival? AB - PURPOSE: The aim of this study was to evaluate the impact of extended resection of primary tumor on survival outcome in unresectable colorectal cancer (UCRC). METHODS: A retrospective analysis was conducted for 190 patients undergoing palliative surgery for UCRC between 1998 and 2007 at a single institution. Variables including demographics, histopathological characteristics of tumors, surgical procedures, and course of the disease were examined. RESULTS: Kaplan Meier survival curve indicated a significant increase in survival times in patients undergoing extended resection of the primary tumor (P < 0.001). Multivariate analysis showed that extra-abdominal metastasis (P = 0.03), minimal resection of the primary tumor (P = 0.034), and the absence of multimodality adjuvant therapy (P < 0.001) were significantly associated poor survival outcome. The histological characteristics were significantly associated with survival times. Patients with well to moderate differentiation tumors that were extensively resected had significantly increased survival time (P < 0.001), while those with poor differentiation tumors that were extensively resected did not have increase survival time (P = 0.786). CONCLUSION: Extended resection of primary tumors significantly improved overall survival compared to minimal resection, especially in well to moderately differentiated tumors (survival time: extended resection, 27.8 +/- 2.80 months; minimal resection, 16.5 +/- 2.19 months; P = 0.002). PMID- 27757395 TI - Long-term oncologic outcomes of neoadjuvant concurrent chemoradiotherapy with capecitabine and radical surgery in locally advanced rectal cancer: 10-year experiences at a single institution. AB - PURPOSE: Oral capecitabine has demonstrated to be safe and efficient as neoadjuvant concurrent chemoradiotherapy (NCRT) for locally advanced rectal cancers. The aim of this study was to evaluate the long-term oncologic outcomes of NCRT with capecitabine and radical surgery. METHODS: From January 2000 to June 2010, 238 patients were treated at our center for locally advanced rectal cancers using conventional NCRT with capecitabine and radical surgery. Univariate and multivariate analyses were used to evaluate the factors associated with oncologic outcomes with log rank and Cox regression tests. RESULTS: The incidence of grade >3 capecitabine-related toxicity was found to be 4.6%. A pathologic complete response was observed in 14.7% of patients. The 5-year overall and 5-year disease free survival rate, local and systemic recurrence rate were 82.8%, 75.1%, 4.8%, and 20.3%. Abdominoperineal resection and node-positive disease were independent prognostic factors of 5-year overall survival, 5-year disease-free survival, and systemic recurrence. CONCLUSION: NCRT with capecitabine and radical surgery showed favorable long-term oncologic outcomes with benefits of acceptable toxicity and convenience. We suggest that capecitabine can be one of the favorable therapeutic options for NCRT in rectal cancer. PMID- 27757396 TI - Feasibility of transanal endoscopic total mesorectal excision for rectal cancer: results of a pilot study. AB - PURPOSE: To evaluate the feasibility of transanal total mesorectal excision (TME) in patients with rectal cancer. METHODS: This study enrolled 12 patients with clinically node negative rectal cancer located 4-12 cm from the anal verge who underwent transanal endoscopic TME with the assistance of single port laparoscopic surgery between September 2013 and August 2014. The primary endpoint was TME quality; secondary endpoints included number of harvested lymph nodes and postoperative complications within 30 days (NCT01938027). RESULTS: The 12 patients included 7 males and 5 females, of median age 59 years and median body mass index 24.2 kg/m2. Tumors were located on average 6.7 cm from the anal verge. Four patients (33.3%) received preoperative chemoradiotherapy. Median operating time was 195 minutes and median blood loss was 50 mL. There were no intraoperative complications and no conversions to open surgery. TME was complete or nearly complete in 11 patients (91.7%). Median distal resection and circumferential resection margins were 18.5 mm and 10 mm, respectively. Median number of harvested lymph nodes was 15. Median length of hospital stay was 9 days. There were no postoperative deaths. Six patients experienced minor postoperative complications, including urinary dysfunction in 2, transient ileus in 3, and wound abscess in 1. CONCLUSION: This pilot study showed that high quality TME was possible in most patients without serious complications. Transanal TME for patients with rectal cancer may be feasible and safe, but further investigations are necessary to evaluate its long-term functional and oncologic outcomes and to clarify its indications. PMID- 27757397 TI - Reduced port laparoscopic surgery for colon cancer is safe and feasible in terms of short-term outcomes: comparative study with conventional multiport laparoscopic surgery. AB - PURPOSE: Laparoscopic surgery was previously accepted as an alternative surgical option in treatment for colorectal cancer. Nowadays, single-port laparoscopic surgery (SPLS) is introduced as a method to maximize advantages of minimally invasive surgery. However, SPLS has several limitations compared to conventional multiport laparoscopic surgery (CMLS). To overcome those limitations of SPLS, reduced port laparoscopic surgery (RPLS) was introduced. This study aimed at evaluating the short-term outcomes of RPLS. METHODS: Patients who underwent CMLS and RPLS of colon cancer between August 2011 and December 2013 were included in this study. Short-term clinical and pathological outcome were compared between the 2 groups. RESULTS: Thirty-two patients underwent RPLS and 217 patients underwent CMLS. Shorter operation time, less blood loss, and faster bowel movement were shown in RPLS group in this study. In terms of postoperative pain, numeric rating scale (NRS) of RPLS was lower than that of CMLS. Significant differences were shown in terms of tumor size, harvested lymph node, perineural invasion, and pathological stage. No significant differences were confirmed in terms of other surgical outcomes. CONCLUSION: In this study, RPLS was technically feasible and safe. Especially in terms of postoperative pain, RPLS was comparable to CMLS. RPLS may be a feasible alternative option in selected patients with colon cancer. PMID- 27757398 TI - Analgesic efficacy of ropivacaine wound infusion after laparoscopic colorectal surgery. AB - PURPOSE: Local anesthetic wound infusion has been previously investigated in postoperative pain management. However, a limited number of studies have evaluated its use in laparoscopic colorectal surgery. This study aims to evaluate whether ropivacaine wound infusion is effective for postoperative pain management after laparoscopic surgery in patients with colorectal cancer. METHODS: This prospective study included 184 patients who underwent laparoscopic surgery for colorectal cancer between July 2012 and June 2013. The patients were grouped as the combined group (intravenous patient-controlled analgesia [IV-PCA] plus continuous wound infusion with ropivacaine, n = 92) and the PCA group (IV-PCA only, n = 92). Efficacy and safety were assessed in terms of numeric rating scale (NRS) pain score, opioid consumption, postoperative recovery, and complications. RESULTS: The total quantity of PCA fentanyl was significantly less in the combined group than in the PCA group (P < 0.001). The NRS score of the combined group was not higher than in the PCA group, despite less opioid consumption. There were no differences between groups for postoperative recovery and most complications, including wound complications. However, the rate of nausea and vomiting was significantly lower in the combined group (P = 0.022). CONCLUSION: Ropivacaine wound infusion significantly reduced postoperative opioid requirements and the rate of nausea/vomiting. This study showed clinical efficacy of ropivacaine wound infusion for postoperative pain control in colorectal cancer patients undergoing laparoscopic surgery. PMID- 27757399 TI - Complete tubular duplication of colon in an adult: a rare cause of colovaginal fistula. AB - Alimentary tract duplications are uncommon congenital anomalies that usually present during the first decade of life. Complete duplication of the colon in adults is very rare and difficult to diagnose preoperatively. We report a case of a 40-year-old female with complete tubular duplication which was initially misdiagnosed as a salpingeal abscess due to colovaginal fistula. PMID- 27757400 TI - Single-port plus an additional port robotic complete mesocolic excision and intracorporeal anastomosis using a robotic stapler for right-sided colon cancer. AB - The concept of complete mesocolic excision and central vascular ligation for colonic cancer has been recently introduced. The paper describes a technique of right-sided complete mesocolic excision and intracorporeal anastomosis by using a single-port robotic approach with an additional conventional robotic port. We performed a single-port plus an additional port robotic surgery using the Da Vinci Single-Site platform via the Pfannenstiel incision and the wristed robotic instruments via an additional robotic port in the left lower quadrant. The total operative and docking times were 280 and 25 minutes, respectively. The total number of lymph nodes harvested was 36 and the proximal and distal resection margins were 31 and 50 cm, respectively. Single-port plus an additional port robotic surgery for right-sided complete mesocolic excision and intracorporeal anastomosis appears to be feasible and safe. This system can overcome certain limitations of the previous robotic systems and conventional single-port laparoscopic surgery. PMID- 27757401 TI - Techniques of Proximal Root Reconstruction and Outcomes Following Repair of Acute Type A Aortic Dissection. AB - BACKGROUND: The goal of this study was to compare the early and late outcomes of different techniques of proximal root reconstruction during the repair of acute Type A aortic dissection, including aortic valve (AV) resuspension, aortic valve replacement (AVR), and a root replacement procedure. METHODS: All patients who underwent acute Type A aortic dissection repair between January 2000 and October 2010 at four academic institutions were compiled from each institution's Society of Thoracic Surgeons Database. This included 189 patients who underwent a concomitant aortic valve (AV) procedure; 111, 21, and 57 patients underwent AV resuspension, AVR, and the Bentall procedure, respectively. The median age of patients undergoing a root replacement procedure was significantly younger than the other two groups. Early clinical outcomes and 10-year actuarial survival rates were compared. Trends in outcomes and surgical techniques throughout the duration of the study were also analyzed. RESULTS: The operative mortality rates were 17%, 29%, and 18%, for AV resuspension, AVR, and root replacement, respectively. Operative mortality (p = 0.459) was comparable between groups. Hemorrhage related re-exploration did not differ significantly between groups (p = 0.182); however, root replacement procedures tended to have decreased rates of bleeding when compared to AVR (p = 0.067). The 10-year actuarial survival rates for the AV resuspension, Bentall, and AVR groups were 72%, 56%, and 36%, respectively (log-rank p = 0.035). CONCLUSIONS: The 10-year actuarial survival was significantly lower in those receiving AVR compared to those receiving root replacement procedures or AV resuspension. Operative mortality was comparable between the three groups. PMID- 27757403 TI - Management of Intra-Aortic Balloon Pump Rupture and Entrapment. AB - While the intra-aortic balloon pump (IABP) itself has many useful and life-saving indications, it has a high complication rate, up to 30% in some studies. This report discusses the surgical removal and subsequent vascular repair in a patient with a ruptured and subsequently entrapped IABP and reviews the literature on the presentation and management of this rare but major complication. PMID- 27757404 TI - Anomalous Origin of the Left Vertebral Artery from the Aortic Arch. AB - Anatomic anomalies of the aortic arch have implications for clinical practice if their significance is understood. Our case study involves a cadaveric finding of the left vertebral artery originating directly from the aortic arch. Although this anatomical variation has been documented, the prevalence of this anomaly may be generally underestimated. After noting this anomaly, we analyzed 27 cases and found that four female cadavers had the left vertebral artery originating from the aortic arch rather than the left subclavian artery. With a prevalence rate of 14.8%, it would seem that this anomaly is more significant than previously thought, which could have implications for surgical practice. PMID- 27757402 TI - Biomechanical Rupture Risk Assessment: A Consistent and Objective Decision-Making Tool for Abdominal Aortic Aneurysm Patients. AB - Abdominal aortic aneurysm (AAA) rupture is a local event in the aneurysm wall that naturally demands tools to assess the risk for local wall rupture. Consequently, global parameters like the maximum diameter and its expansion over time can only give very rough risk indications; therefore, they frequently fail to predict individual risk for AAA rupture. In contrast, the Biomechanical Rupture Risk Assessment (BRRA) method investigates the wall's risk for local rupture by quantitatively integrating many known AAA rupture risk factors like female sex, large relative expansion, intraluminal thrombus-related wall weakening, and high blood pressure. The BRRA method is almost 20 years old and has progressed considerably in recent years, it can now potentially enrich the diameter indication for AAA repair. The present paper reviews the current state of the BRRA method by summarizing its key underlying concepts (i.e., geometry modeling, biomechanical simulation, and result interpretation). Specifically, the validity of the underlying model assumptions is critically disused in relation to the intended simulation objective (i.e., a clinical AAA rupture risk assessment). Next, reported clinical BRRA validation studies are summarized, and their clinical relevance is reviewed. The BRRA method is a generic, biomechanics-based approach that provides several interfaces to incorporate information from different research disciplines. As an example, the final section of this review suggests integrating growth aspects to (potentially) further improve BRRA sensitivity and specificity. Despite the fact that no prospective validation studies are reported, a significant and still growing body of validation evidence suggests integrating the BRRA method into the clinical decision-making process (i.e., enriching diameter-based decision-making in AAA patient treatment). PMID- 27757405 TI - Primary Percutaneous Coronary Intervention in Chronic Type A Aortic Dissection. AB - This case illustrates the complexities of performing a primary percutaneous intervention in a patient with chronic Type A aortic aneurysm and dissection with contraindications for surgical management. We also discuss the significant risk that the patient had to overcome to survive an undiagnosed aortic dissection and an acute ST elevation myocardial infarction. PMID- 27757406 TI - Computed Tomography Imaging Artifact Simulating Type A Aortic Dissection. AB - Contrast-enhanced computed tomography (CT) is an effective tool for assessment of thoracic aortic disease in the modern era. Here, we describe a case of Type A aortic dissection incidentally detected by CT in a 63-year old man. Upon more precise imaging with electrocardiography (ECG)-gated CT, the dissection vanished, revealing it to be an aortic motion artifact. This report highlights the importance of motion artifacts mimicking a dissection flap. CT imaging gated with ECG can distinguish a dissection flap from an artifact. PMID- 27757407 TI - Page for the General Public. PMID- 27757408 TI - Functional Outcomes After Double-Row Versus Single-Row Rotator Cuff Repair: A Prospective Randomized Trial. AB - BACKGROUND: The functional benefits of double-row (DR) versus single-row (SR) rotator cuff repair are not clearly established. PURPOSE: To examine the effect of DR versus SR rotator cuff repair on functional outcomes and strength recovery in patients with full-thickness tears. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Forty-nine patients were randomized to DR or SR repairs; 36 patients (13 women, 23 men; mean age, 62 +/- 7 years; 20 SR, 16 DR) were assessed at a mean 2.2 +/- 1.6 years after surgery (range, 1-7 years; tear size: 17 medium, 13 large, 9 massive). The following data were recorded prior to surgery and at follow-up: Penn shoulder score, American Shoulder and Elbow Surgeons (ASES), and Simple Shoulder Test (SST) results; range of motion (ROM) for shoulder flexion, external rotation (ER) at 0 degrees and 90 degrees of abduction, and internal rotation (IR) at 90 degrees of abduction; and shoulder strength (Lafayette manual muscle tester) in empty- and full-can tests, abduction, and ER at 0 degrees of abduction. Treatment (SR vs DR) * time (pre- vs postoperative) mixed-model analysis of variance was used to assess the effect of rotator cuff repair. RESULTS: Rotator cuff repair markedly improved Penn, ASES, and SST scores (P < .001), with similar improvement between SR and DR repairs (treatment * time, P = .38-.10) and excellent scores at follow-up (DR vs SR: Penn, 91 +/- 11 vs 92 +/- 11 [P = .73]; ASES, 87 +/- 12 vs 92 +/- 12 [P = .21]; SST, 11.4 +/- 1.0 vs 11.3 +/- 1.0 [P = .76]). Patients with DR repairs lost ER ROM at 0 degrees of abduction (preoperative to final follow-up, 7 degrees +/ 10 degrees loss [P = .013]). ER ROM did not significantly change with SR repair (5 degrees +/- 14 degrees gain, P = .16; treatment by time, P = .008). This effect was not apparent for ER ROM at 90 degrees of abduction (treatment * time, P = .26). IR ROM improved from preoperative to final follow-up (P < .01; SR, 17 degrees +/- 27 degrees ; DR, 7 degrees +/- 21 degrees ; treatment * time, P = .23). Rotator cuff repair markedly improved strength in empty-can (54%), full-can (66%), abduction (47%), and ER (54%) strength (all P < .001), with no difference between SR and DR repairs (P = .23-.75). All clinical tests with the exception of the lift-off test were normalized at follow-up (P < .05). CONCLUSION: Outcomes were not different between SR or DR repair, with generally excellent outcomes for both groups. Rotator cuff repair and subsequent rehabilitation markedly improved shoulder strength. PMID- 27757409 TI - Predictors of Latent Tuberculosis Infection Treatment After Introduction of a New Regimen: A Retrospective Cohort Study at an Inner City Clinic. AB - Background. Despite the low and decreasing prevalence of tuberculosis (TB) in the United States, there remain certain high-risk groups with high incidence rates. The targeted screening and treatment of latent TB infection (LTBI) among these high-risk groups are needed to achieve TB elimination; however, by most accounts, LTBI treatment completion rates remain low. Methods. We retrospectively studied all patients accepting treatment for LTBI at the Fulton County Health Department TB clinic over 2 years. Medical chart abstraction was performed to collect information on sociodemographics, medical, and LTBI treatment history. Treatment completion was defined as finishing >=88% of the prescribed regimen. Logistic regression analysis was performed to identify predictors of treatment completion. Results. Among 547 adults offered LTBI treatment, 424 (78%) accepted treatment and 298 of 424 (70%) completed treatment. The median age was 42 years, most patients were black (77%), and close to one third did not have stable housing. No significant difference in completion rates was found between the 3 regimens of 9 months isoniazid (65%), 4 months rifampin (71%), and 3 months of weekly rifapentine and isoniazid (79%). In multivariate analysis, having stable housing increased the odds of finishing treatment, whereas tobacco use and an adverse event decreased the odds. Conclusion. Utilizing comprehensive case management, we demonstrated high rates of LTBI treatment completion, including among those receiving a 3-month regimen. Completion rates were higher among persons with stable housing, and this finding highlights the need to develop strategies that will improve adherence among homeless persons. PMID- 27757410 TI - Fusarium Osteomyelitis in a Patient With Pearson Syndrome: Case Report and Review of the Literature. AB - Fusarium species are ubiquitous fungi causing a wide array of infections, including invasive disease in the immunosuppressed. We present a fusarium bone infection in a child with Pearson syndrome and review the literature. Ten cases of fusarium osteomyelitis were reported in the past 40 years, and we review the treatments. PMID- 27757412 TI - Successful Combined Treatment for Atrophic Thyroiditis With Growth Hormone Deficiency. PMID- 27757411 TI - Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents. AB - In chronic human immunodeficiency virus (HIV)-1 infection, long-lived latently infected cells are the major barrier to virus eradication and functional cure. Several therapeutic strategies to perturb, eliminate, and/or control this reservoir are now being pursued in the clinic. These strategies include latency reversal agents (LRAs) designed to reactivate HIV-1 ribonucleic acid transcription and virus production and a variety of immune-modifying drugs designed to reverse latency, block homeostatic proliferation, and replenish the viral reservoir, eliminate virus-producing cells, and/or control HIV replication after cessation of antiretroviral therapy. This review provides a summary of ongoing clinical trials of HIV LRAs and immunomodulatory molecules, and it highlights challenges in the comparison and interpretation of the expected trial results. PMID- 27757413 TI - Endoscopic management of bleeding gastric varices with N-butyl, 2-cyanoacrylate glue injection in children with non-cirrhotic portal hypertension. AB - Background and study aims: In view of the paucity of literature, we carried out this audit to evaluate the safety and efficacy of N- butyl, 2-cynoacrylate glue injection therapy in secondary prophylaxis of gastric varices in children. Patients and methods: Consecutive children (<= 18 years) with non-cirrhotic portal hypertension who presented with bleeding from gastric varices and who had undergone cyanoacrylate glue injection therapy were included. They were evaluated for safety, efficacy and complications. Their long-term outcomes and follow-up were recorded. Results: Over 11 years, 28 children with median age 13 (range, 8 to 18) years (68 % boys), underwent cyanoacrylate glue injection for bleeding gastric varices. In 25 (89 %) cases, extrahepatic portal venous obstruction was the etiology and isolated gastric varices were the source of the bleeding. Primary and secondary gastric variceal bleeding was seen in 11 (39 %) and 17 (61 %) children, respectively. A total 36 sessions with median volume of 2 (range, 1 5) mL of glue injections were required (2 sessions in 8 children). Hemostasis was achieved in all and 57 % had gastric variceal obliteration. Two children had early (< 1 month) rebleeding and 2 children had late rebleeding. One child had gastric ulcer. Over a median follow-up of 24 (8 - 98) months, 14 children underwent surgery (12 porto-systemic shunt), 2 were lost to follow-up, 1 died and there was no recurrence of bleeding in the remaining 11. Conclusions: Cyanoacrylate glue injection is highly effective mode of secondary prophylaxis of bleeding gastric varices in children with non-cirrhotic portal hypertension. Rebleeding occurred in 14 % but treatment-related complications were uncommon. However, a large controlled clinical trial is required to confirm our findings. PMID- 27757414 TI - Metadisorder for designer light in random systems. AB - Disorder plays a critical role in signal transport by controlling the correlation of a system, as demonstrated in various complex networks. In wave physics, disordered potentials suppress wave transport, because of their localized eigenstates, from the interference between multiple scattering paths. Although the variation of localization with tunable disorder has been intensively studied as a bridge between ordered and disordered media, the general trend of disorder enhanced localization has remained unchanged, and the existence of complete delocalization in highly disordered potentials has not been explored. We propose the concept of "metadisorder": randomly coupled optical systems in which eigenstates can be engineered to achieve unusual localization. We demonstrate that one of the eigenstates in a randomly coupled system can always be arbitrarily molded, regardless of the degree of disorder, by adjusting the self energy of each element. Ordered waves with the desired form are then achieved in randomly coupled systems, including plane waves and globally collective resonances. We also devise counterintuitive functionalities in disordered systems, such as "small-world-like" transport from non-Anderson-type localization, phase-conserving disorder, and phase-controlled beam steering. PMID- 27757415 TI - Monolignol ferulate conjugates are naturally incorporated into plant lignins. AB - Angiosperms represent most of the terrestrial plants and are the primary research focus for the conversion of biomass to liquid fuels and coproducts. Lignin limits our access to fibers and represents a large fraction of the chemical energy stored in plant cell walls. Recently, the incorporation of monolignol ferulates into lignin polymers was accomplished via the engineering of an exotic transferase into commercially relevant poplar. We report that various angiosperm species might have convergently evolved to natively produce lignins that incorporate monolignol ferulate conjugates. We show that this activity may be accomplished by a BAHD feruloyl-coenzyme A monolignol transferase, OsFMT1 (AT5), in rice and its orthologs in other monocots. PMID- 27757416 TI - Virus-mediated archaeal hecatomb in the deep seafloor. AB - Viruses are the most abundant biological entities in the world's oceans, and they play a crucial role in global biogeochemical cycles. In deep-sea ecosystems, archaea and bacteria drive major nutrient cycles, and viruses are largely responsible for their mortality, thereby exerting important controls on microbial dynamics. However, the relative impact of viruses on archaea compared to bacteria is unknown, limiting our understanding of the factors controlling the functioning of marine systems at a global scale. We evaluate the selectivity of viral infections by using several independent approaches, including an innovative molecular method based on the quantification of archaeal versus bacterial genes released by viral lysis. We provide evidence that, in all oceanic surface sediments (from 1000- to 10,000-m water depth), the impact of viral infection is higher on archaea than on bacteria. We also found that, within deep-sea benthic archaea, the impact of viruses was mainly directed at members of specific clades of Marine Group I Thaumarchaeota. Although archaea represent, on average, ~12% of the total cell abundance in the top 50 cm of sediment, virus-induced lysis of archaea accounts for up to one-third of the total microbial biomass killed, resulting in the release of ~0.3 to 0.5 gigatons of carbon per year globally. Our results indicate that viral infection represents a key mechanism controlling the turnover of archaea in surface deep-sea sediments. We conclude that interactions between archaea and their viruses might play a profound, previously underestimated role in the functioning of deep-sea ecosystems and in global biogeochemical cycles. PMID- 27757417 TI - Sustained drag reduction in a turbulent flow using a low-temperature Leidenfrost surface. AB - Skin friction drag contributes a major portion of the total drag for small and large water vehicles at high Reynolds number (Re). One emerging approach to reducing drag is to use superhydrophobic surfaces to promote slip boundary conditions. However, the air layer or "plastron" trapped on submerged superhydrophobic surfaces often diminishes quickly under hydrostatic pressure and/or turbulent pressure fluctuations. We use active heating on a superhydrophobic surface to establish a stable vapor layer or "Leidenfrost" state at a relatively low superheat temperature. The continuous film of water vapor lubricates the interface, and the resulting slip boundary condition leads to skin friction drag reduction on the inner rotor of a custom Taylor-Couette apparatus. We find that skin friction can be reduced by 80 to 90% relative to an unheated superhydrophobic surface for Re in the range 26,100 <= Re <= 52,000. We derive a boundary layer and slip theory to describe the hydrodynamics in the system and show that the plastron thickness is h = 44 +/- 11 MUm, in agreement with expectations for a Leidenfrost surface. PMID- 27757419 TI - Determination of functional collective motions in a protein at atomic resolution using coherent neutron scattering. AB - Protein function often depends on global, collective internal motions. However, the simultaneous quantitative experimental determination of the forms, amplitudes, and time scales of these motions has remained elusive. We demonstrate that a complete description of these large-scale dynamic modes can be obtained using coherent neutron-scattering experiments on perdeuterated samples. With this approach, a microscopic relationship between the structure, dynamics, and function in a protein, cytochrome P450cam, is established. The approach developed here should be of general applicability to protein systems. PMID- 27757418 TI - Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia. AB - Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response. PMID- 27757420 TI - In silico discovery of metal-organic frameworks for precombustion CO2 capture using a genetic algorithm. AB - Discovery of new adsorbent materials with a high CO2 working capacity could help reduce CO2 emissions from newly commissioned power plants using precombustion carbon capture. High-throughput computational screening efforts can accelerate the discovery of new adsorbents but sometimes require significant computational resources to explore the large space of possible materials. We report the in silico discovery of high-performing adsorbents for precombustion CO2 capture by applying a genetic algorithm to efficiently search a large database of metal organic frameworks (MOFs) for top candidates. High-performing MOFs identified from the in silico search were synthesized and activated and show a high CO2 working capacity and a high CO2/H2 selectivity. One of the synthesized MOFs shows a higher CO2 working capacity than any MOF reported in the literature under the operating conditions investigated here. PMID- 27757421 TI - Empty forest or empty rivers? A century of commercial hunting in Amazonia. AB - The Amazon basin is the largest and most species-rich tropical forest and river system in the world, playing a pivotal role in global climate regulation and harboring hundreds of traditional and indigenous cultures. It is a matter of intense debate whether the ecosystem is threatened by hunting practices, whereby an "empty forest" loses critical ecological functions. Strikingly, no previous study has examined Amazonian ecosystem resilience through the perspective of the massive 20th century international trade in furs and skins. We present the first historical account of the scale and impacts of this trade and show that whereas aquatic species suffered basin-wide population collapse, terrestrial species did not. We link this differential resilience to the persistence of adequate spatial refuges for terrestrial species, enabling populations to be sustained through source-sink dynamics, contrasting with unremitting hunting pressure on more accessible aquatic habitats. Our findings attest the high vulnerability of aquatic fauna to unregulated hunting, particularly during years of severe drought. We propose that the relative resilience of terrestrial species suggests a marked opportunity for managing, rather than criminalizing, contemporary traditional subsistence hunting in Amazonia, through both the engagement of local people in community-based comanagement programs and science-led conservation governance. PMID- 27757422 TI - Quasi-particle interference of heavy fermions in resonant x-ray scattering. AB - Resonant x-ray scattering (RXS) has recently become an increasingly important tool for the study of ordering phenomena in correlated electron systems. Yet, the interpretation of RXS experiments remains theoretically challenging because of the complexity of the RXS cross section. Central to this debate is the recent proposal that impurity-induced Friedel oscillations, akin to quasi-particle interference signals observed with a scanning tunneling microscope (STM), can lead to scattering peaks in RXS experiments. The possibility that quasi-particle properties can be probed in RXS measurements opens up a new avenue to study the bulk band structure of materials with the orbital and element selectivity provided by RXS. We test these ideas by combining RXS and STM measurements of the heavy fermion compound CeMIn5 (M = Co, Rh). Temperature- and doping-dependent RXS measurements at the Ce-M4 edge show a broad scattering enhancement that correlates with the appearance of heavy f-electron bands in these compounds. The scattering enhancement is consistent with the measured quasi-particle interference signal in the STM measurements, indicating that the quasi-particle interference can be probed through the momentum distribution of RXS signals. Overall, our experiments demonstrate new opportunities for studies of correlated electronic systems using the RXS technique. PMID- 27757423 TI - Superradiance on the millihertz linewidth strontium clock transition. AB - Laser frequency noise contributes a significant limitation to today's best atomic clocks. A proposed solution to this problem is to create a superradiant laser using an optical clock transition as its gain medium. This laser would act as an active atomic clock and would be highly immune to the fluctuations in reference cavity length that limit today's best lasers. We demonstrate and characterize superradiant emission from the millihertz linewidth clock transition in an ensemble of laser-cooled 87Sr atoms trapped within a high-finesse optical cavity. We measure a collective enhancement of the emission rate into the cavity mode by a factor of more than 10,000 compared to independently radiating atoms. We also demonstrate a method for seeding superradiant emission and observe interference between two independent transitions lasing simultaneously. We use this interference to characterize the relative spectral properties of the two lasing subensembles. PMID- 27757424 TI - The fate of carbon dioxide in water-rich fluids under extreme conditions. AB - Investigating the fate of dissolved carbon dioxide under extreme conditions is critical to understanding the deep carbon cycle in Earth, a process that ultimately influences global climate change. We used first-principles molecular dynamics simulations to study carbonates and carbon dioxide dissolved in water at pressures (P) and temperatures (T) approximating the conditions of Earth's upper mantle. Contrary to popular geochemical models assuming that molecular CO2(aq) is the major carbon species present in water under deep Earth conditions, we found that at 11 GPa and 1000 K, carbon exists almost entirely in the forms of solvated carbonate ([Formula: see text]) and bicarbonate ([Formula: see text]) ions and that even carbonic acid [H2CO3(aq)] is more abundant than CO2(aq). Furthermore, our simulations revealed that ion pairing between Na+ and [Formula: see text]/[Formula: see text] is greatly affected by P-T conditions, decreasing with increasing pressure at 800 to 1000 K. Our results suggest that in Earth's upper mantle, water-rich geofluids transport a majority of carbon in the form of rapidly interconverting [Formula: see text] and [Formula: see text] ions, not solvated CO2(aq) molecules. PMID- 27757425 TI - Comparative cranial morphology in living and extinct platypuses: Feeding behavior, electroreception, and loss of teeth. AB - The modern platypus, Ornithorhynchus anatinus, has an eye structure similar to aquatic mammals; however, platypuses also have a "sixth sense" associated with the bill electro- and mechanoreception that they use without opening their eyes underwater. We hypothesize that Ornithorhynchus and the Miocene taxon Obdurodon have different sensory capacities, which may have resulted from differences in foraging behavior. To estimate differences in foraging, sensory systems, and anatomical divergence between these monotremes, we compared their skull morphologies. Results indicate that the bill of Obdurodon is more dorsally deflected than that of Ornithorhynchus, suggesting a pelagic foraging behavior in Obdurodon compared to the bottom-feeding behavior in Ornithorhynchus. The infraorbital foramen of Obdurodon, through which the maxillary nerve passes sensory data from the bill to the brain, is relatively less developed than that of Ornithorhynchus. Whereas bill-focused sensory perception was likely shared among Mesozoic monotremes, the highly developed electrosensory system of Ornithorhynchus may represent an adaptation to foraging in cloudy water. Computed tomography imagery indicates that the enlarged infraorbital canal of Ornithorhynchus restricts the space available for maxillary tooth roots. Hence, loss of functional teeth in Ornithorhynchus may possibly have resulted from a shift in foraging behavior and coordinate elaboration of the electroreceptive sensory system. Well-developed electroreceptivity in monotremes is known at least as far back as the early Cretaceous; however, there are differences in the extent of elaboration of the feature among members of the ornithorhynchid lineage. PMID- 27757427 TI - Advantages and disadvantages of posterolateral approach for percutaneous endoscopic lumbar discectomy. AB - BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) is one of the less invasive treatments for lumbar disc herniation (LDH), and has 3 different operative approaches. This study focused on the posterolateral approach (PLA) and investigated the appropriate operative indication. METHODS: PLA was performed in 29 patients with foraminal and extraforaminal LDH. The height and width of the foramen, LDH type, and positional relationship between LDH and the foramen were radiologically evaluated. Foraminoplasty was also performed in 12 cases including those combined with intra-canal LDH or osseous foraminal stenosis. Pre- and postoperative status was evaluated using Numerical Rating Scale (NRS) scores. RESULTS: Patient mean age was 56.8 years; there was single-level involvement at L3/4 (13 cases) and at L4/5 (13 cases). The mean pre- and postoperative NRS scores were 6.1 and 1.8, respectively. Early recurrence developed in a patient who was found to have local scoliosis at the corresponding vertebral level. CONCLUSIONS: PLA can be safely used to treat foraminal and extraforaminal LDH with foraminal height >=13 mm and foraminal width >=7 mm. The procedure is effective for preserving the facet joint; however, we should carefully consider the indications when local scoliosis and/or instability are present. PMID- 27757428 TI - Can intraoperative neurophysiologic monitoring during cervical spine decompression predict post-operative segmental C5 palsy? AB - BACKGROUND: C5 nerve root palsy is a known complication after cervical laminectomy or laminoplasty, characterized by weakness of the deltoid and bicep brachii muscles. The efficacy of intraoperative monitoring of these muscles is currently unclear. In the current prospective study, intraoperative monitoring through somatosensory (SSEPs), motor (TcMEPs) evoked potentials and real-time electromyography activity (EMG) were analyzed for their ability to detect or prevent deltoid muscle weakness after surgery. METHODS: One hundred consecutive patients undergoing laminectomy/laminoplasty with or without fusion were enrolled. Intraoperative SSEPs, TcMEPs and EMGs from each patient were studied and analyzed. RESULTS: Intraoperative EMG activity of the C5 nerve root was detected in 34 cases, 10 of which demonstrated a sustained and repetitive EMG activity lasting 5 or more minutes. Paresis of the unilateral deltoid muscle developed in 5 patients, all from the group with sustained C5 EMG activity. None of the patients with weakness of deltoid muscle after surgery demonstrated any abnormal change in TcMEP or SSEP. CONCLUSIONS: Real-time EMG recordings were sensitive to C5 nerve root irritation, whilst SSEPs and TcMEPs were not. Sustained EMG activity of the C5 nerve root during surgery is a possible warning sign of irritation or injury to the nerve. PMID- 27757426 TI - TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1. AB - DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery. PMID- 27757429 TI - Surgeon-driven neurophysiologic monitoring in a spinal surgery population. AB - BACKGROUND: This is a prospective observational study examining the use of a surgeon-driven intraoperative neurophysiologic monitoring system. Intraoperative neurophysiologic monitoring is becoming the standard of care for spinal surgeries with potential post-operative neurologic deficits. This standard applies to both adult and pediatric spinal surgery, but a shortage of appropriately trained and certified technologists and physiologists can compromise monitoring capabilities in some centers. A surgeon-driven, intra-operative monitoring system in the absence of a technologist or physiologist was examined for safety and efficacy. METHODS: One hundred thirty-five patients undergoing a variety of spinal procedures were monitored intra-operatively using a surgeon-driven neuro monitoring system over a period of 80 months. Intraoperative monitoring included serial motor evoked potentials via an automated system that provided visual and audible feedback directly to the operative surgeon. Changes in monitoring and any corresponding surgical responses were evaluated and compared with postoperative neurological status. RESULTS: Of the 135 patients studied, intraoperative adjustments based on neuro-monitoring took place in four patients (3.0%): following reduction in spondylolisthesis, during instrumentation and fusion for a large kyphoscoliosis deformity, due to low hemoglobin, and because of traction. In all cases, surgical and/or anaesthetic modification restored MEPs toward baseline values. The accuracy of the neuro-monitoring results was sensitive to narcotics, benzodiazepines and changes in haemoglobin concentrations. No new postoperative deficits were observed in any patients in the cohort. CONCLUSIONS: The authors concluded that surgeon-driven neuro-monitoring was a safe and effective means of intraoperative neuro-monitoring during spinal surgery. It reliably detected intraoperative insults, which could potentially have resulted in postoperative neurologic compromise, and was not associated with any false negative results in this cohort. Utility of surgeon-driven monitoring, using validated algorithms, may provide an option for this added safety measure even in cases where monitoring personnel are unavailable. PMID- 27757430 TI - The importance of loading the periphery of the vertebral endplate. AB - BACKGROUND: Commercial fusion cages typically provide support in the central region of the endplate, failing to utilize the increased compressive strength around the periphery. This study demonstrates the increase in compressive strength that can be achieved if the bony periphery of the endplate is loaded. METHODS: Sixteen cadaveric lumbar vertebrae (L1-L5) were randomly divided into two even groups. A different commercial mass produced implant (MPI) was allocated to each group: (I) a Polyether-ether-ketone (PEEK) anterior lumber inter-body fusion (ALIF) MPI; and (II) a titanium ALIF MPI. Uniaxial compression at a displacement rate of 0.5 mm/sec was applied to all vertebrae during two phases: (I) with the allocated MPI situated in the central region of the endplate; (II) with an aluminum plate, designed to load the bony periphery of the endplate. The failure load and mode of failure was recorded. RESULTS: From phase 1 to phase 2, the failure load increased from 1.1+/-0.4 to 2.9+/-1.4 kN for group 1; and from 1.3+/-1.0 to 3.0+/-1.9 kN for group 2. The increase in strength from phase 1 to phase 2 was statistically significant for each group (group 1: P<0.01, group 2: P<0.05, paired t-test). There was no significant difference between the groups in either phase (P>0.05, t-test). The mode of failure in phase 1 was the implant being forced through the endplate for both groups. In phase 2, the mode of failure was either a fracture of the epiphyseal rim or buckling of the side wall of the vertebral body. CONCLUSIONS: Loading the periphery of the vertebral endplate achieved significant increase in compressive load capacity compared to loading the central region of the endplate. Clinically, this implies that patient specific implants which load the periphery of the vertebral endplate could decrease the incidence of subsidence and improve surgical outcomes. PMID- 27757431 TI - Duchenne muscular dystrophy: the management of scoliosis. AB - This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group. PMID- 27757432 TI - Single-level selective dorsal rhizotomy for spastic cerebral palsy. AB - The management of cerebral palsy (CP) is complex and requires a multidisciplinary approach. Selective dorsal rhizotomy (SDR) is a neurosurgical technique that aims to reduce spasticity in the lower limbs. A minimally invasive approach to SDR involves a single level laminectomy at the conus and utilises intraoperative electromyography (EMG). When combined with physiotherapy, SDR is effective in selected children and has minimal complications. This review discusses the epidemiology of CP and the management using SDR within an integrated multidisciplinary centre. Particular attention is given to the single-level laminectomy technique of SDR and its rationale, and the patient workup, recovery and outcomes of SDR. PMID- 27757433 TI - Pan-spinal infection: a case series and review of the literature. AB - BACKGROUND: Panspinal infection usually presents with fever, back pain, neurological deficit, and in advanced cases multi-organ failure and septic shock. The choice of treatment for panspinal infection is challenging because these patients are usually medically unstable with severe neurological compromise. The objective of this study is to review management and long term outcomes for patients with panspinal infection. METHODS: A retrospective review of patients with panspinal infection treated in our center over a 5-year period [Jan 2010-Dec 2014] and a review of the current published literatures was undertaken. RESULTS: We identified 4 patients with panspinal infection. One case was managed medically due to high perioperative risk, whilst the other three were managed surgically whilst on antibiotic therapy. All 3 cases managed surgically improved neurologically and infection subsided, whereas the patient managed medically did not change neurologically and infection subsided. CONCLUSIONS: Patients with panspinal infection should be treated surgically unless the medical risk of surgery or anaesthesia is prohibitive. PMID- 27757434 TI - Simultaneous anterior vertebral column resection-distraction and posterior rod contouring for restoration of sagittal balance: report of a technique. AB - With an increasingly aging population, adult spinal deformity is becoming more common. This can be associated with increased morbidity. Results from multicentre studies of deformity surgery correction confirm complication rates as high as 40 percent. Most often a bad result is associated with inadequate restoration of the sagittal balance. Posterior vertebral body resection has been described as a method to correct significant deformity, but this is a complicated procedure. It is possible to do this in the thoracic spine where nerve roots can be sacrificed, but it is difficult in the lumbar spine due to the significant role of the lumbar nerve roots. We describe a safer technique for correction of deformity using a three stage process. This appears to be a good technique for revision surgery. PMID- 27757435 TI - Spinal myxopapillary ependymoma with interval drop metastasis presenting as cauda equina syndrome: case report and review of literature. AB - Myxopapillary ependymoma is a benign slow-growing tumour, arising predominantly in the region of the filum terminale. It has been designated histologically as grade I neoplasm according to the 2007 WHO classification. Despite this benign character dissemination and metastasis along the cerebrospinal axis and metastasis to distant sites have occasionally been reported. There have been previously reported cases of drop metastasis from MPE, however in three of these cases the drop metastasis was diagnosed with concurrent primary spinal MPE. There has been only one previously published case of interval drop metastasis in a case of operated spinal MPE in literature. We hereby present the second case of interval drop metastasis in a case of conus MPE, with history of having undergone a subtotal resection and post operative adjuvant radiotherapy prior to second surgery. The patient presented months after the primary surgery with symptoms of cauda equina syndrome attributable to the drop metastasis. PMID- 27757436 TI - Surfer's myelopathy: a rare presentation in a non-surfing setting and review of the literature. AB - BACKGROUND: Surfers myelopathy can be a rapidly devastating disease and little is known surrounding the pathophysiology of the condition. Although the classical pattern of illness has been well reported, it has never been observed in a non surfing setting. METHODS: A 51-year-old demolition worker presented with acute non-traumatic myelopathy. Clinical examination revealed sensory loss to the level of L2. T2-MRI and MRI-DWI revealed a hyperintense signal suggestive of an ischaemic event. A diagnosis of surfer's myelopathy was made and he was commenced on steroid therapy. RESULTS: Following steroid therapy and fluid management the patient was discharged after 6 days with minor anaethesia but significant overall neurological improvement. CONCLUSIONS: Diagnosis of SM requires a thorough history, clinical examination and imaging (MRI, MRI-DWI). The patient should be admitted early and investigated. The use of rehabilitation services may be useful if available. PMID- 27757437 TI - Point of view: posterior cervical lamino-foraminotomy-safe, viable and cost effective non-fusion technique. PMID- 27757438 TI - Who is the surgically resilient individual with traumatic spinal cord injury? PMID- 27757439 TI - Local steroids and dysphagia in anterior cervical discectomy and fusion-does the employment of rhBMP-2 make their use a necessity? PMID- 27757440 TI - Evaluating post-operative pain management at the iliac crest bone graft site: an editorial. PMID- 27757441 TI - Challenging the state of the art. PMID- 27757442 TI - Evidence update-association between CILP and degeneration of the intervertebral disc: a meta-analysis. PMID- 27757443 TI - Journal of Spine Surgery (JSS) is now indexed in PubMed Central. PMID- 27757444 TI - Should dentists get MS and PhD degrees? PMID- 27757445 TI - Systematic review on highly viscous glass-ionomer cement/resin coating restorations (Part I): ?Do they merge Minamata Convention and minimum intervention dentistry? AB - BACKGROUND: With the Minamata Convention the use of mercury will be phased down, and this undoubtedly will have an effect on dental treatment regimens and economic resources. Composite resin restorations are considered viable alternatives to amalgam fillings; however, these will not be covered completely by health insurance systems in many countries. Recently, a high-viscosity glass ionomer cement (hvGIC) processed with a resinous coating (RC) has been introduced, and has been marketed as a restorative material in load-bearing Class I cavities (and in Class II cavities with limited size), thus serving as a possible alternative to amalgam fillings. OBJECTIVE: To evaluate the literature on this treatment approach, and to focus particularly on the clinical performance of the hvGIC/RC combination. SEARCH STRATEGY: The Cochrane Library as well as Ebsco, Embase, PubMed, and Scopus databases were screened. Moreover, relevant abstracts published with dental meetings were reviewed. SELECTION CRITERIA: All available randomized clinical trials focusing on the hvGIC/RC approach (published either as full-texts or abstracts until June 2016) were selected. Moreover, single-group studies using hvGIC/RC were included. DATA COLLECTION AND ANALYSIS: Screening of titles and abstracts, data extraction, and quality assessments of full-texts according to Oxford scoring were performed. RESULTS: Regarding failure rates, minor differences between hvGIC/RC and GIC or composite resins as comparators could be observed in seven clinical studies. The hvGIC/RC combination showed high survival rates (with only few catastrophic failures) of up to 6 years. CONCLUSION: Class I retention rates of hvGIC/RC seem promising, but further high-quality clinical studies are clearly warranted. PMID- 27757446 TI - Ionic liquids as modulators of physicochemical properties and nanostructures of sodium dodecyl sulfate in aqueous solutions and potential application in pesticide microemulsions. AB - Emulsifiers for pesticide microemulsions contain a part of volatile organic compounds (VOCs), and ionic liquids (ILs) are becoming potential substitutes. In order to apply ILs in pesticide microemulsions, the study of interaction between ILs and surfactants is necessary. Therefore, the surface properties and aggregation of anionic surfactant sodium dodecyl sulfate (SDS) in ILs, including N-hexyl-N-methylmorpholinyl bromide ([C6mm][Br]), N-hexyl-N-methylpiperidyl bromide ([C6mp][Br]), N-hexyl-N-methylpyrrolidyl bromide ([C6mpyr][Br]), N-octyl N-methylpyrrolidyl bromide ([C8mpyr][Br]), N-dodecyl-N-methylpyrrolidyl bromide ([C12mpyr][Br]) and N-hexadecyl-N-methylpyrrolidyl bromide ([C16mpyr][Br]), were investigated in terms of surface tension, conductivity, dynamic light scattering (DLS), viscosity, fluorescence, pseudo-ternary phase diagram and 1H NMR measurements. Generally in agreement, the methods afforded the evaluation of various micellar parameters such as critical micelle concentration (CMC), degree of counterion ionization (alpha), the maximum surface excess concentration (Gammamax), the minimum area per surfactant headgroup (Amin) as well as some thermodynamic parameters, including standard free energy of micellization (DeltaG), standard enthalpy of micellization (DeltaH) and standard entropy of micellization (DeltaS). The results indicated a hydrophobic effect as the primary force of a spontaneous, exothermic, entropy driven micellization process. 1H NMR technique was applied to reveal the solubilization site and interaction of ILs in aqueous SDS micellar solutions. Fluorescence, DLS and viscosity measurements revealed considerable micellar morphologies and various phase behaviors. Furthermore, the 10% difenoconazole microemulsion was successfully prepared and showed good stability and spreadability in mixtures which indicated ILs' potential application in pesticide formulation. PMID- 27757447 TI - A review: the trend of progress about pH probes in cell application in recent years. AB - Intracellular pH values are some of the most important factors that govern biological processes and the acid-base homeostasis in cells, body fluids and organs sustains the normal operations of the body. Subcellular organelles including the acidic lysosomes and the alkalescent mitochondria undergo various processes such as intracellular digestion, ATP production and apoptosis. Due to their precise imaging capabilities, fluorescent probes have attracted great attention for the illustration of pH modulated processes. Furthermore, based on the unique acidic extracellular environment of acidic lysosomes, fluorescent probes can specifically be activated in cancer cells or tumors. In this review, recently reported lysosome and mitochondria specific pH imaging probes as well as pH-activatable cancer cell-targetable probes have been discussed. PMID- 27757448 TI - Feature driven classification of Raman spectra for real-time spectral brain tumour diagnosis using sound. AB - Spectroscopic diagnostics have been shown to be an effective tool for the analysis and discrimination of disease states from human tissue. Furthermore, Raman spectroscopic probes are of particular interest as they allow for in vivo spectroscopic diagnostics, for tasks such as the identification of tumour margins during surgery. In this study, we investigate a feature-driven approach to the classification of metastatic brain cancer, glioblastoma (GB) and non-cancer from tissue samples, and we provide a real-time feedback method for endoscopic diagnostics using sound. To do this, we first evaluate the sensitivity and specificity of three classifiers (SVM, KNN and LDA), when trained with both sub band spectral features and principal components taken directly from Raman spectra. We demonstrate that the feature extraction approach provides an increase in classification accuracy of 26.25% for SVM and 25% for KNN. We then discuss the molecular assignment of the most salient sub-bands in the dataset. The most salient sub-band features are mapped to parameters of a frequency modulation (FM) synthesizer in order to generate audio clips from each tissue sample. Based on the properties of the sub-band features, the synthesizer was able to maintain similar sound timbres within the disease classes and provide different timbres between disease classes. This was reinforced via listening tests, in which participants were able to discriminate between classes with mean classification accuracy of 71.1%. Providing intuitive feedback via sound frees the surgeons' visual attention to remain on the patient, allowing for greater control over diagnostic and surgical tools during surgery, and thus promoting clinical translation of spectroscopic diagnostics. PMID- 27757449 TI - Interaction of Rhodamine 6G molecules with graphene: a combined computational experimental study. AB - In this work, the adsorption of Rhodamine 6G molecules on some graphene substrates is investigated using density functional theory. Some simple models, such as those of perfect graphene, defective graphene, *O/*OH modified graphene and B/N doping graphene, are constructed as substrates to simulate graphene oxide and B/N doping graphene sheets. It is demonstrated that the interactions of Rhodamine 6G molecules with graphene materials are strong. In particular, the amine group of Rhodamine 6G molecules can favor the formation of a chemical bond with some graphene substrates characterized by under-coordinated atoms. The chemical interactions would lead to significant changes in the electronic structures of graphene substrates, which have the potential to tune the electronic properties of graphene. In addition, our calculations predict that the epoxy/hydroxyl group attached to the surface of graphene could be removed by Rhodamine 6G molecules, which suggests that the reduction reaction may occur in graphene oxide upon Rhodamine 6G doping. The surface plasmon resonance spectra of R6G adsorbed on some graphene substrates are also characterized, which are well in agreement with some computational results. Therefore, combined with experimental observations, our results provide an insight into the interaction of Rhodamine 6G molecules with graphene materials. PMID- 27757450 TI - Hypoiodite-catalysed oxidative cyclisation of Michael adducts of chalcones with 1,3-dicarbonyl compounds: a facile and versatile approach to substituted furans and cyclopropanes. AB - Through hypoiodite catalysis, oxidative cyclisation of Michael adducts of chalcones with 1,3-dicarbonyl compounds for divergent synthesis of either furans or cyclopropanes is developed. The selective synthesis of major products is achieved depending on the use of different reaction conditions or substrates. PMID- 27757451 TI - Hydrodynamic thermal confinement: creating thermo-chemical microenvironments on surfaces. AB - We present a new, general concept termed Hydrodynamic Thermal Confinement (HTC), and its implementation for the creation of microscale dynamic thermo-chemical microenvironments on biological surfaces. HTC is based on a scanning probe and operates under physiological conditions. The temperature can be regulated between 30 degrees and 80 degrees C with +/-0.2 degrees C precision and temperature ramps of 5 degrees C s-1 over a footprint of ~50 MUm * 80 MUm in a volume of ~50 * 80 * 15 MUm3 (~50 pl). PMID- 27757452 TI - Spatial organization based reciprocal switching of enzyme-free nucleic acid circuits. AB - We report a new nucleic acid sensing strategy through an intelligent design of spatial organization based reciprocal switching of catalytic hairpin assembly (CHA). The so-called SORS-CHA not only turns a well-designed CHA circuit into a relatively universal detector for any targeting sequence, but also guarantees a much enhanced signal resolution and a believability to minimize the misreading induced by unexpected signal drifts. With more trustworthy results, but a simpler sequence design, nucleic acid circuits could become competitive in real-world applications. PMID- 27757453 TI - Combined covalent and noncovalent carboxylation of carbon nanotubes for sensitivity enhancement of clinical immunosensors. AB - We report here for the first time with quantitative details that the combination of pi-pi stacking of pyrenecarboxylic acid with chemically carboxylated multiwalled carbon nanotubes (MWNT-COOH) offers superior sensitivity compared to MWNT-COOH alone for serum insulin measurements and that this combination is broadly applicable for biosensors, drug delivery, and catalytic systems. PMID- 27757454 TI - Transferability of a coarse-grained atactic polystyrene model: the non-bonded potential effect. AB - In this paper, we construct an efficient and simple coarse grained (CG) model for atactic polystyrene (PS) by using a 1 : 1 mapping scheme at 463 K and 1 atm pressure and derive the corresponding bonded and non-bonded potentials in the CG force field (FF) via a direct Boltzmann inversion approach and a combined structure-based and thermodynamic quantities-based CG method, respectively. For computational considerations, the non-bonded interaction between CG particles is described by Lennard-Jones (LJ) type potentials, and both the radial distribution function (RDF) and the bulk density of the atomistic simulations are taken as target properties in the parameterization of the two LJ parameters. To shed light on the choice of LJ forms of CG non-bonded potentials when designing the CG models, a series of CG models with different LJ potentials are constructed and compared in order to understand how the quality of a CG model in reproducing the structure and thermodynamic properties of chemically realistic systems is affected by the choice of non-bonded potentials. We find that with our structural and thermodynamics combined CG method to construct the CG FF at a single thermodynamic state point without any temperature dependent LJ potential correction and/or pressure optimization, the resulting CG models possess good temperature transferability in a wide range of temperatures 300-600 K, where both the target properties and several other static properties (such as thermal expansion coefficient and mean-square radius of gyration) are generally reproduced. Furthermore, the non-bonded LJ potential influences the density response of CG models to the temperature change, i.e., CG models with harder LJ potentials show better temperature transferability than the softer ones. Meanwhile, the derived Tg increases with increasing LJ repulsion strength while thermal expansion coefficients in both melt and glass states are lowered as the LJ potential hardens. With regard to the local conformation and local packing distribution functions, varying non-bonded LJ potential hardness influences only the magnitude of the peak height but does not affect the peak position, in particular the magnitude of the non-bonded potential effect on local distribution functions becomes stronger at lower temperatures. More specifically, this effect on the local chain conformation statistics at the CG level is different for the distribution of bond-lengths, bond angles and dihedrals. As a result, the size of the CG chains is fairly insensitive to the non-bonded LJ potentials within 300 600 K. In short, the CG model with the harder LJ-type non-bonded CG potential is a more realistic representation of excluded volume interactions of the underlying atomistic PS monomer and thus has the potential to generate a higher Tg to match with the atomistic systems. PMID- 27757456 TI - pH-Switchable vitamin B9 gels for stoichiometry-controlled spherical co crystallization. AB - Vitamin B9 gels were found to be pH-switchable by adding triethylamine or acetic acid. Such recyclable gels can be used as novel co-crystallization media, resulting in four stoichiometric vitamin C co-crystals. Under highly supersaturated conditions, uniform microspheres of (VC).(NA) with different particle sizes were obtained through a spherical crystallization process. PMID- 27757455 TI - The Ebola virus protein VP40 hexamer enhances the clustering of PI(4,5)P2 lipids in the plasma membrane. AB - The Ebola virus is a lipid-enveloped virus that obtains its lipid coat from the plasma membrane of the host cell it infects during the budding process. The Ebola virus protein VP40 localizes to the inner leaflet of the plasma membrane and forms the viral matrix, which provides the major structure for the Ebola virus particles. VP40 is initially a dimer that rearranges to a hexameric structure that mediates budding. VP40 hexamers and larger filaments have been shown to be stabilized by PI(4,5)P2 in the plasma membrane inner leaflet. Reduction in the plasma membrane levels of PI(4,5)P2 significantly reduce formation of VP40 oligomers and virus-like particles. We investigated the lipid-protein interactions in VP40 hexamers at the plasma membrane. We quantified lipid-lipid self-clustering by calculating the fractional interaction matrix and found that the VP40 hexamer significantly enhances the PI(4,5)P2 clustering. The radial pair distribution functions suggest a strong interaction between PI(4,5)P2 and the VP40 hexamer. The cationic Lys side chains are found to mediate the PIP2 clustering around the protein, with cholesterol filling the space between the interacting PIP2 molecules. These computational studies support recent experimental data and provide new insights into the mechanisms by which VP40 assembles at the plasma membrane inner leaflet, alters membrane curvature, and forms new virus-like particles. PMID- 27757457 TI - XPS enables visualization of electrode potential screening in an ionic liquid medium with temporal- and lateral-resolution. AB - We present an X-ray photoelectron spectroscopic (XPS) investigation of potential screening across two gold electrodes fabricated on a porous polymer surface which is impregnated with the ionic liquid (IL) N-N-diethyl-N-methyl-N-(2 methoxyethyl)ammonium bis(trifluoromethanesulfonyl)imide [DEME-TFSI]. The IL provides a sheet of conducting layers to the insulating polymer film, and allows monitoring charging and screening dynamics at the polymer + IL/vacuum interface in a laterally resolved fashion across the electrodes. Time-resolved measurements are also implemented by recording F1s peaks of the IL, while imposing 10 mHz square-wave (SQW) pulses across the two electrodes in a source-drain geometry. Variations in the F1s binding energy reflect directly the transient local electrical potential, and allow us to visualize screening of the otherwise built in local voltage drop on and across the metal electrodes in the range of millimeters. Accordingly, the device is partitioned into two oppositely polarized regions, each following polarization of one electrode through the IL medium. On the other extreme, upon imposing relatively fast 1 kHz SQW pulses the charge screening is prevented and the device is brought to assume a simple resistor role. A simple equivalent circuit model also reproduces the observed voltage transients qualitatively. The presented structure and variants of XPS measurements, enabling us to record voltage transients in unexpectedly large lateral distances away from the electrodes, can impact the understanding of various electrochemical concepts. PMID- 27757461 TI - Blip-summed quantum-classical path integral with cumulative quantum memory. AB - The quantum-classical path integral (QCPI) offers a rigorous methodology for simulating quantum mechanical processes in condensed-phase environments treated in full atomistic detail. This paper describes the implementation of QCPI on system-bath models, which are frequently employed in studying the dynamics of reactive processes. The QCPI methodology incorporates all effects associated with stimulated phonon absorption and emission as its crudest limit, thus can (in some regimes) converge faster than influence functional-based path integral methods specifically designed for system-bath Hamiltonians. It is shown that the QCPI phase arising from a harmonic bath can be summed analytically with respect to the discrete bath degrees of freedom and expressed in terms of precomputed influence functional coefficients, avoiding the explicit enumeration of forced oscillator trajectories, whose number grows exponentially with the length of quantum memory. Further, adoption of the blip decomposition (which classifies the system paths based on the time length over which their forward and backward components are not identical) and a cumulative treatment of the QCPI phase between blips allows elimination of the majority of system paths, leading to a dramatic increase in efficiency. The generalization of these acceleration techniques to anharmonic environments is discussed. PMID- 27757464 TI - An accurate multi-channel multi-reference full-dimensional global potential energy surface for the lowest triplet state of H2O2. AB - The lowest triplet state of the H2O2 system features multiple reaction channels, including several relevant to the combustion of H2. To accurately map out the global potential energy surface, ~28 000 geometries were sampled over a large configuration space including all important asymptotes, and electronic energies at these points were calculated at the level of the explicitly correlated version of the multi-reference configuration interaction (MRCI-F12) method. A new multi channel global potential energy surface was constructed by fitting the ab initio data set using a permutation invariant polynomial-neural network method, resulting in a total root mean square fitting error of only 6.7 meV (0.15 kcal mol-1). Various kinetics and dynamical properties of several relevant reactions were calculated on the new MRCI potential energy surface, and compared with the available experimental results. PMID- 27757466 TI - Solvent-induced on/off switching of intramolecular electron transfer in a cyanide bridged trigonal bipyramidal complex. AB - A cyanide-bridged [Co3Fe2] cluster with trigonal bipyramidal geometry shows solvent-driven reversible on/off switching of its thermally induced electron transfer-coupled spin transition (ETCST) behaviour. PMID- 27757465 TI - Proteomic responses to gold(iii)-toxicity in the bacterium Cupriavidus metallidurans CH34. AB - The metal-resistant beta-proteobacterium Cupriavidus metallidurans drives gold (Au) biomineralisation and the (trans)formation of Au nuggets largely via unknown biochemical processes, ultimately leading to the reductive precipitation of mobile, toxic Au(i/iii)-complexes. In this study proteomic responses of C. metallidurans CH34 to mobile, toxic Au(iii)-chloride are investigated. Cells were grown in the presence of 10 and 50 MUM Au(iii)-chloride, 50 MUM Cu(ii)-chloride and without additional metals. Differentially expressed proteins were detected by difference gel electrophoresis and identified by liquid chromatography coupled mass spectrometry. Proteins that were more abundant in the presence of Au(iii) chloride are involved in a range of important cellular functions, e.g., metabolic activities, transcriptional regulation, efflux and metal transport. To identify Au-binding proteins, protein extracts were separated by native 2D gel electrophoresis and Au in protein spots was detected by laser absorption inductively coupled plasma mass spectrometry. A chaperon protein commonly understood to bind copper (Cu), CupC, was identified and shown to bind Au. This indicates that it forms part of a multi-metal detoxification system and suggests that similar/shared detoxification pathways for Au and Cu exist. Overall, this means that C. metallidurans CH34 is able to mollify the toxic effects of cytoplasmic Au(iii) by sequestering this Au-species. This effect may in the future be used to develop CupC-based biosensing capabilities for the in-field detection of Au in exploration samples. PMID- 27757468 TI - Contributors to the emerging investigators issue 2016. PMID- 27757467 TI - Interfacing digital microfluidics with high-field nuclear magnetic resonance spectroscopy. AB - Nuclear magnetic resonance (NMR) spectroscopy is extremely powerful for chemical analysis but it suffers from lower mass sensitivity compared to many other analytical detection methods. NMR microcoils have been developed in response to this limitation, but interfacing these coils with small sample volumes is a challenge. We introduce here the first digital microfluidic system capable of interfacing droplets of analyte with microcoils in a high-field NMR spectrometer. A finite element simulation was performed to assist in determining appropriate system parameters. After optimization, droplets inside the spectrometer could be controlled remotely, permitting the observation of processes such as xylose borate complexation and glucose oxidase catalysis. We propose that the combination of DMF and NMR will be a useful new tool for a wide range of applications in chemical analysis. PMID- 27757469 TI - Recent advances in the textural characterization of hierarchically structured nanoporous materials. AB - This review focuses on important aspects of applying physisorption for the pore structural characterization of hierarchical materials such as mesoporous zeolites. During the last decades major advances in understanding the adsorption and phase behavior of fluids confined in ordered nanoporous materials have been made, which led to major progress in the physisorption characterization methodology (summarized in the 2015 IUPAC report on physisorption characterization). Here we discuss progress and challenges for the physisorption characterization of nanoporous solids exhibiting various levels of porosity from micro- to macropores. While physisorption allows one to assess micro- and mesopores, a widely employed method for textural analysis of macroporous materials is mercury porosimetry and we also review important insights associated with the underlying mechanisms governing mercury intrusion/extrusion experiments. Hence, although the main focus of this review is on physical adsorption, we strongly emphasize the importance of combining advanced physical adsorption with other complementary experimental techniques for obtaining a reliable and comprehensive understanding of the texture of hierarchically structured materials. PMID- 27757470 TI - Iridium(iii) hydrido complexes for the catalytic dehydrogenation of hydrazine borane. AB - The synthesis of 3,5-disubstituted cyclometalated iridium(iii) hydrido complexes of the type [3,5-R2(POCOP)IrHX] (3,5-R2(POCOP) = kappa3-C5HR2-2,6-(OPtBu2)2 with R = t-Bu, COOMe; X = Cl, H) is described. All complexes were investigated in the catalytic dehydrogenation of hydrazine borane and compared with the unsubstituted compounds [(POCOP)IrHX] (X = Cl, H). All catalysts are highly active and recyclable, clearly maintaining hydrogen production activity. The dehydrogenation products were structurally characterised by solid state NMR and FTIR spectroscopy. Experimental observations were complemented by a dispersion corrected DFT study to rationalise the mechanism of hydrazine borane dehydrogenation. PMID- 27757471 TI - Appointment Lead Time Policy Development to Improve Patient Access to Care. AB - BACKGROUND: Patient access to care has been a known and continuing struggle for many health care providers. In spite of appointment lead time policies set by government or clinics, the problem persists. Justification for how lead time policies are determined is lacking. OBJECTIVES: This paper proposed a data-driven approach for how to best set feasible appointment target lead times given a clinic's capacity and appointment requests. METHODS: The proposed approach reallocates patient visits to minimize the deviation between actual appointment lead time and a feasible target lead time. A step-by-step algorithm was presented and demonstrated for return visit (RV) and new patient (NP) types from a Pediatric clinic excluding planned visits such as well-child exam and the same day urgent appointments. The steps are: 1. Obtain appointment requests; 2. Initialize a target lead time; 3. Set up an initial schedule; 4. Check the feasibility based on appointment availability; 5. Adjust schedule backward to fill appointment slots earlier than the target; 6. Adjust schedule forward for appointments not able to be scheduled earlier or on target to the later slots; 7. Trial different target lead times until the difference between earlier and later lead time is minimized. RESULTS: The results indicated a 59% lead time reduction for RVs and a 45% reduction for NPs. The lead time variation was reduced by 75% for both patient types. Additionally, the opportunity for the participating clinic to achieve their organization's goal of a two-week lead time for RVs and a two-day lead time for NPs is discussed by adjusting capacity to increase one slot for NP and reduce one slot for RV. CONCLUSIONS: The proposed approach and study findings may help clinics identify feasible appointment lead times. PMID- 27757472 TI - Evaluation of a Pilot Asthma Care Program for Electronic Communication between School Health and a Healthcare System's Electronic Medical Record. AB - OBJECTIVE: Asthma is a common childhood chronic lung disease affecting greater than 10% of children in the United States. School nurses are in a unique position to close gaps in care. Indeed, effective asthma management is more likely to result when providers, family, and schools work together to optimize the patient's treatment plan. Currently, effective communication between schools and healthcare systems through electronic medical record (EMR) systems remains a challenge. The goal of this feasibility pilot was to link the school-based care team with primary care providers in the healthcare system network via electronic communication through the EMR, on behalf of pediatric asthma patients who had been hospitalized for an asthma exacerbation. The implementation process and the potential impact of the communication with providers on the reoccurrence of asthma exacerbations with the linked patients were evaluated. METHODS: By engaging stakeholders from the school system and the healthcare system, we were able to collaboratively design a communication process and implement a pilot which demonstrated the feasibility of electronic communication between school nurses and primary care providers. Outcomes data was collected from the electronic medical record to examine the frequency of asthma exacerbations among patients with a message from their school nurse. The percent of exacerbations in the 12 months before and after electronic communication was compared using McNemar's test. RESULTS: The pilot system successfully established communication between the school nurse and primary care provider for 33 students who had been hospitalized for asthma and a decrease in hospital admissions was observed with students whose school nurse communicated through the EMR with the primary care provider. CONCLUSIONS: Findings suggest a collaborative model of care that is enhanced through electronic communication via the EMR could positively impact the health of children with asthma or other chronic illnesses. PMID- 27757473 TI - [Typical atypical ECGs and anterior wall infarction : Subtle signs of an acute coronary artery occlucion]. AB - The ECG is a very important diagnostic tool if an acute coronary syndrome is suspected. It should be performed immediately when medical staff contacts the patient. If an ST elevation myocardial infarction (STEMI) is diagnosed, immediate reperfusion of the occluded vessel should be the primary goal. Therefore, even subtle signs of an anterior wall infarction diagnosed by the ECG which lead to suspicion of complete occlusion of a coronary artery should be known and diagnosed by all physicians who may have contact with these types of patients. The ECG variations presented in this article can be used as a sample for medical personnel who are not familiar with these changes and do not routinely interpret ECGs. PMID- 27757474 TI - Minocycline affects human neutrophil respiratory burst and transendothelial migration. AB - OBJECTIVE: This study aimed at investigating the in vitro activity of minocycline and doxycycline on human polymorphonuclear (h-PMN) cell function. METHODS: h-PMNs were isolated from whole venous blood of healthy subjects; PMN oxidative burst was measured by monitoring ROS-induced oxidation of luminol and transendothelial migration was studied by measuring PMN migration through a monolayer of human umbilical vein endothelial cells. Differences between multiple groups were determined by ANOVA followed by Tukey's multiple comparison test; Student's t test for unpaired data for two groups. RESULTS: Minocycline (1-300 uM) concentration dependently and significantly inhibited oxidative burst of h-PMNs stimulated with 100 nM fMLP. Ten micromolar concentrations, which are superimposable to C max following a standard oral dose of minocycline, promoted a 29.8 +/- 4 % inhibition of respiratory burst (P < 0.001; n = 6). Doxycycline inhibited ROS production with a lesser extent and at higher concentrations. 10 100 uM minocycline impaired PMN transendothelial migration, with maximal effect at 100 uM (42.5 +/- 7 %, inhibition, n = 5, P < 0.001). CONCLUSIONS: These results added new insight into anti-inflammatory effects of minocycline exerted on innate immune h-PMN cell function. PMID- 27757475 TI - Synthetic Biology for Cell-Free Biosynthesis: Fundamentals of Designing Novel In Vitro Multi-Enzyme Reaction Networks. AB - Cell-free biosynthesis in the form of in vitro multi-enzyme reaction networks or enzyme cascade reactions emerges as a promising tool to carry out complex catalysis in one-step, one-vessel settings. It combines the advantages of well established in vitro biocatalysis with the power of multi-step in vivo pathways. Such cascades have been successfully applied to the synthesis of fine and bulk chemicals, monomers and complex polymers of chemical importance, and energy molecules from renewable resources as well as electricity. The scale of these initial attempts remains small, suggesting that more robust control of such systems and more efficient optimization are currently major bottlenecks. To this end, the very nature of enzyme cascade reactions as multi-membered systems requires novel approaches for implementation and optimization, some of which can be obtained from in vivo disciplines (such as pathway refactoring and DNA assembly), and some of which can be built on the unique, cell-free properties of cascade reactions (such as easy analytical access to all system intermediates to facilitate modeling). PMID- 27757476 TI - Coupling of In Vitro Bioassays with Planar Chromatography in Effect-Directed Analysis. AB - Modern analytical test methods increasingly detect anthropogenic organic substances and their transformation products in water samples and in the environment. The presence of these compounds might pose a risk to the aquatic environment. To determine a possible (eco)toxicological risk, aquatic samples are tested using various bioassays, including sub-organismic assays such as the luminescent bacteria inhibition test, the acetylcholinesterase inhibition test, and the umu-test. The effect-directed analysis (EDA) combines physicochemical separation methods with biological (in vitro) tests. High-performance thin-layer chromatography (HPTLC) has proved to be particularly well suited for the separation of organic compounds and the subsequent analysis of effects by the application of the biotests directly on the surface of the HPTLC plate. The advantage of using HPTLC in comparison to high-performance liquid chromatography (HPLC) for EDA is that the solvent which is used as a mobile phase during chromatography is completely evaporated after the separation and therefore can no longer influence the applied bioassays.A prioritization during the complex identification process can be achieved when observed effects are associated with the separated zones in HPTLC. This increases the probability of identifying the substance responsible for an adverse effect from the multitude of organic trace substances in environmental samples. Furthermore, by comparing the pattern of biological effects of a separated sample, it is possible to track and assess changes in biological activity over time, over space, or in the course of a process, even without identifying the substance. HPTLC has already been coupled with various bioassays.Because HPTLC is a very flexible system, various detection techniques can be used and combined. In addition to the UV/Vis absorption and fluorescence measurements, TLC can also be coupled with a mass spectrometer (MS) for compound identification. In addition, detection of functional groups by means of derivatization reagents can support this identification. It is also possible to combine derivatization and HPLC-MS.Two case studies are used to illustrate the significance of HPTLC-EDA in investigating water quality: Study on a wastewater treatment plant Possible influence of an artificial turf surface on ground water. PMID- 27757477 TI - [Pancreatic anastomosis in operative treatment of chronic pancreatitis]. AB - Chronic pancreatitis (CP) is an irreversible, inflammatory process, which is characterized by progressive fibrosis of the pancreas and leads to abdominal pain, endocrine and exocrine insufficiency. Surgical therapy is indicated by the absence of pain relief and local complications. The target of the surgical approach is to relieve the pancreatic and bile ducts and resection of the fibrotic and calcified parenchyma. Drainage procedures, such as the Partington Rochelle method, are used in patients with isolated congestion of the pancreatic duct without further organ complications, such as inflammatory processes of the pancreatic head; however, patients with CP often have an inflammatory swelling of the pancreatic head. In this case classical pancreatoduodenectomy (PD) or organ sparing duodenum-preserving pancreatic head resection (DPPHR) with its various techniques (e.g. Beger, Frey, Bern and V-shape) can be applied. Due to similar long-term results PD should be carried out in cases of suspicion or detection of malignancies and DPPHR for treatment of CP. PMID- 27757478 TI - [Festschrift for Hans-Peter Zenner]. PMID- 27757479 TI - [Diagnosis and treatment of parapharyngeal space tumors]. AB - The parapharyngeal space extends from the nasopharynx to the oropharynx. It is bordered medially by the pharyngeal wall and the constrictor pharyngis muscles, and laterally by the mandible. One distinguishes between a pre- and a poststyloid space. Tumors of the parapharyngeal space are rare and represent less than 1 % of all head and neck neoplasms. Benign (70-80 %) as well as malignant (20-30 %) tumors arise from different structures of the parapharyngeal space, mainly from salivary glands and nerve structures. Concerning salivary gland tumors, most are pleomorphic adenomas typically appearing in the prestyloid space, whereas the schwannomas that may also arise are located in the poststyloid space. The main symptom is dysphagia, with the tumor generally presenting as a visible bulking of the pharyngeal wall, in rare cases also as an externally visible cervical mass. Treatment is generally surgical resection, particularly in benign tumors, preferably via transcervical access. If R0 resection of malignancies is possible, this should be performed. In malignant lymphomas and nonresectable tumors, primary chemo-, radio-, or combination therapy should be considered after histologic confirmation. For neurogenic tumors, particularly vagal nerve schwannoma and especially in older patients, a wait-and-scan strategy is most favorable, since postoperative vagal palsy is unavoidable with surgical resection. Treatment planning for parapharyngeal space tumors requires good knowledge of topographic anatomy and careful evaluation of imaging findings. PMID- 27757481 TI - Refugee crisis in Greece: not a one-country job. PMID- 27757480 TI - [Intracochlear drug delivery in combination with cochlear implants : Current aspects]. AB - Local drug application to the inner ear offers a number of advantages over systemic delivery. Local drug therapy currently encompasses extracochlear administration (intratympanic injection); intracochlear administration, particularly for gene and stem cell therapy; as well as various combinations with auditory neurosensory prostheses, either evaluated in preclinical or clinical studies, or off-label. To improve rehabilitation with cochlear implants (CI), one focus is the development of drug-releasing electrode carriers, e. g., to deliver glucocorticosteroids, antiapoptotic substances, or neurotrophines to the inner ear. By protecting neuronal structures from insertion trauma, reducing fibrosis in the inner ear, and by stimulating growth of neuronal structures in the direction of the electrodes, the performance of CIs should be improved. Controlled drug release after extracochlear or intracochlear application in conjunction with a CI can be achieved by, e.g., use of a biocompatible, resorbable controlled-release drug delivery systems. Two case reports are presented. In order to treat worsened speech discrimination and increased impedance, these CI-wearing patients successfully underwent intracochlear placement of a biocompatible, resorbable drug delivery system for controlled release of dexamethasone. The drug levels reached in inner ear fluids after different types of local drug application strategies can be calculated using computer models. The intracochlear drug concentrations calculated in this way were compared for different dexamethasone application strategies. PMID- 27757482 TI - Migration, public health and human rights. PMID- 27757483 TI - [Tracer diagnosis severe injury/polytrauma in key issue paper 2016]. PMID- 27757484 TI - [Secondary plastic and reconstructive measures following deep-dermal burn injuries : Negligent use of bioethanol]. AB - One representative case of burns caused by the negligent use of bioethanol, which was treated at our burns centre is used to illustrate the severity and depth of the burn injuries as well as the complexity of the further long-term course of treatment including complex secondary-reconstructive techniques. PMID- 27757485 TI - [Consensus Document on the Tracer Diagnosis of Severe Head and Brain Trauma]. PMID- 27757486 TI - [Key issues paper 2016: specific recommendations for tracer diagnoses]. PMID- 27757487 TI - [Barrett's esophagus]. AB - Barrett's esophagus is an endoscopically visible metaplasia of the columnar epithelium in the esophagus with histological detection of a specialized intestinal metaplasia. The circumferential and longitudinal extent are described endoscopically using the Prague classification. Barrett's esophagus mostly occurs as the result of gastroesophageal reflux disease. The risk of developing esophageal adenocarcinoma is increased but the absolute risk is low with 0.10 0.15 % per year. According to guideline recommendations, screening for Barrett's esophagus as well as endoscopic and biopsy surveillance should be limited to high risk groups. On detection of intraepithelial neoplasia (IEN) endoscopic therapy is indicated, whereby a second opinion must be obtained from a specialized pathologist for low-grade IEN. The influence of proton pump inhibitors on the progression to carcinoma is controversially discussed and a preventive anti reflux operation is not indicated. PMID- 27757488 TI - Altered glucose profiles and risk for hypoglycaemia during oral glucose tolerance testing in pregnancies after gastric bypass surgery. AB - AIMS/HYPOTHESIS: A history of gastric bypass surgery can influence the results of the OGTT recommended during pregnancy. Therefore, we compared OGTT glucose kinetics and pregnancy outcome between pregnant gastric bypass patients and BMI matched, lean and obese controls. METHODS: Medical records were used to collect data on glucose measurements during the 2 h 75 g OGTT as well as on pregnancy and fetal outcome for 304 women (n = 76 per group, matched for age and date of delivery). RESULTS: Women after bariatric surgery had lower fasting glucose levels compared with lean, obese and BMI-matched controls, and showed altered postprandial glucose kinetics, including a rise at 60 min followed by hypoglycaemia with serum glucose of <3.34 mmol/l (which occurred in 54.8%). Moreover, their risk of pre-eclampsia or gestational hypertension was reduced, with an increased risk of delivering small for gestational age infants. CONCLUSIONS/INTERPRETATION: Alternative strategies to accurately define impaired glucose metabolism in pregnancies after bariatric surgery should be explored. PMID- 27757490 TI - [Multimodal imaging of breast cancer recurrence : Prospective intraindividual comparison of 18F-FDG PET/CT, contrast-enhanced CT, and bone scintigraphy]. PMID- 27757489 TI - Critical periods and growth patterns from fetal life onwards associated with childhood insulin levels. AB - AIMS/HYPOTHESIS: We aimed to identify critical periods and specific longitudinal growth patterns from fetal life onwards associated with childhood insulin and C peptide levels. METHODS: In a prospective population-based cohort study of 4328 children, we repeatedly measured (femur) length and (estimated fetal) weight from the second trimester of fetal life until 6 years of age. BMI was calculated from 6 months onwards. Insulin and C-peptide levels were measured at 6 years of age. RESULTS: Preterm birth and small or large size for gestational age at birth were not associated with childhood insulin levels. Conditional growth modelling showed that, independent of growth in other time intervals, weight growth in each time interval from birth onwards, length growth from 6 months onwards and BMI growth from 12 months onwards were positively associated with childhood insulin levels. The strongest associations were present for weight and BMI growth between 48 and 72 months of age. Repeated measurement analyses showed that, compared with children in the lowest quartile of childhood insulin, those in the highest quartile had a higher length from birth onwards and a higher weight and BMI from 24 months onwards. These differences increased with age. No associations were observed for fetal growth characteristics. Similar results were observed for C peptide levels. CONCLUSIONS/INTERPRETATION: Our results suggest that rapid length, weight and BMI growth from birth onwards, but not during fetal life, is associated with higher insulin levels in childhood. PMID- 27757491 TI - [Tumors of the posterior cranial fossa]. AB - Various types of brain tumor can occur in the region of the posterior fossa. Brain metastases in adults are the most common malignancies at this localization. Ependymomas, medulloblastomas and pilocytic astrocytomas occur mostly in children and only rarely in adults. Other tumors that occur in the posterior fossa are meningiomas, schwannomas, hemangioblastomas, brain stem gliomas and epidermoid tumors. Due to the fact that the various tumors of the posterior fossa have different treatment approaches and prognoses, an accurate and specific diagnosis is mandatory. This review discusses the imaging aspects by computed tomography (CT) and magnetic resonance imaging (MRI) of the most frequent tumors of the posterior fossa. PMID- 27757492 TI - [Two annular, atrophic plaques on the abdomen of a 35-year-old man]. AB - A 35-year-old man presented with two annular, reddish-brown, atrophic skin lesions in the navel and on the right lower abdomen. The lesions had persisted for more than 4 years and had remained unchanged and asymptomatic. Histology revealed annular atrophic lichen planus with a lichenoid lymphocytic infiltration and cystoid bodies. The patient was treated with local corticosteroids without improvement. PMID- 27757493 TI - The epidemiology of post-traumatic stress disorder in Norway: trauma characteristics and pre-existing psychiatric disorders. AB - PURPOSE: The prevalence of PTSD differs by gender. Pre-existing psychiatric disorders and different traumas experienced by men and women may explain this. The aims of this study were to assess (1) incidence and prevalence of exposure to traumatic events and PTSD, (2) the effect of pre-existing psychiatric disorders prior to trauma on the risk for PTSD, and (3) the effect the characteristics of trauma have on the risk for PTSD. All stratified by gender. METHOD: CIDI was used to obtain diagnoses at the interview stage and retrospectively for the general population N = 1634. RESULTS: The incidence for trauma was 466 and 641 per 100,000 PYs for women and men, respectively. The incidence of PTSD was 88 and 31 per 100,000 PYs. Twelve month and lifetime prevalence of PTSD was 1.7 and 4.3 %, respectively, for women, and 1.0 and 1.4 %, respectively, for men. Pre-existing psychiatric disorders were risk factors for PTSD, but only in women. Premeditated traumas were more harmful. CONCLUSION: Gender differences were observed regarding traumatic exposure and in the nature of traumas experienced and incidences of PTSD. Men experienced more traumas and less PTSD. Pre-existing psychiatric disorders were found to be risk factors for subsequent PTSD in women. However, while trauma happens to most, it only rarely leads to PTSD, and the most harmful traumas were premeditated ones. Primary prevention of PTSD is thus feasible, although secondary preventive efforts should be gender-specific. PMID- 27757494 TI - Can the crossover sign be a reliable marker of global retroversion of the acetabulum? AB - OBJECTIVE: Diagnosis of acetabular retroversion based on crossover sign in the anteroposterior radiograph of the hip joint is well described. Accuracy of the crossover sign to identify global retroversion of the acetabulum in comparison to version of the acetabulum in reconstructed three-dimensional computed tomography (3D CT) scan of the hip was the aim of this study. MATERIALS AND METHODS: X-rays of 500 hips were assessed regarding presence of crossover sign and its location in the upper, middle, or lower third of the acetabulum. Mean of anteversion and true retroversion (defined as less than one standard deviation below the mean of acetabular anteversion) of the acetabulum using reconstructed 3D CT scan by mathematical software was determined among 500 hips. The positive and negative crossover signs were compared to the retroversion obtained by CT scan. RESULTS: The average of acetabular anteversion was 12.5 +/- 4.2 degrees. True global retroversion in 3D CT scans was defined as a version below 8.3 degrees. Although positive crossover sign was seen in 193 out of 500 (38 %), only 69 out of 500 (13.8 %) of hips had version below 8.3 (true retroversion) and 124 subjects had an acetabular version above 8.3. The sensitivity and specificity of crossover signs were about 82 and 70 %, respectively. CONCLUSIONS: The crossover sign could pick up hips with less than normal anteversion with acceptable sensitivity but it has no enough specificity for being used as the sole indication for treatment. PMID- 27757495 TI - Evaluation of the cytotoxic properties, gene expression profiles and secondary signalling responses of cultured cells exposed to fumonisin B1, deoxynivalenol and zearalenone mycotoxins. AB - Mycotoxins are toxic secondary metabolites produced by a range of fungi and are common contaminants of agricultural crops. These toxins are chemically diverse and structurally stable, enabling them to enter the food chain which can lead to numerous adverse health effects in animals and humans. Although mycotoxin exposure is associated with the development of several cancers, it has proved challenging to show a direct connection between exposure and oncogenic change. This study investigates the in vitro cytotoxicity, molecular mechanisms and secondary signalling responses associated with the exposure to three major mycotoxins, fumonisin B1 (FB1), deoxynivalenol (Don) and zearalenone (Zea). The cytotoxicity of FB1, Don and Zea were investigated in cultured HepG2 and Caco-2 cells using cell viability assays as well as flow cytometry. FB1 proved to be less cytotoxic than its counterparts, while Don and Zea demonstrated high cytotoxicity through an apoptotic mechanism. Expression profiles of 84 genes involved in mediating communication between tumour cells and the cellular mediators of inflammation as well as the innate immune system were also studied. The expression profiles associated with the different mycotoxins were further explored for functional networks, biological functions, canonical pathways, toxicological association as well as to predict network associations between the differentially expressed genes. RT-qPCR revealed the significant differential expression of 46 genes, including the expression of several genes strongly associated with cancer and aberrant inflammatory signalling, after mycotoxin exposure. Aberrant inflammatory signalling seems to be a credible contributing factor that initiates the malignant change observed in cells exposed to mycotoxins. PMID- 27757496 TI - Getting More Ecologically Relevant Information from Laboratory Tests: Recovery of Lemna minor After Exposure to Herbicides and Their Mixtures. AB - Recovery after exposure to herbicides-atrazine, isoproturon, and trifluralin their binary and ternary mixtures, was studied under laboratory conditions using a slightly adapted standard protocol for Lemna minor. The objectives of the present study were (1) to compare empirical to predicted toxicity of selected herbicide mixtures; (2) to assess L. minor recovery potential after exposure to selected individual herbicides and their mixtures; and (3) to suggest an appropriate recovery potential assessment approach and endpoint in a modified laboratory growth inhibition test. The deviation of empirical from predicted toxicity was highest in binary mixtures of dissimilarly acting herbicides. The concentration addition model slightly underestimated mixture effects, indicating potential synergistic interactions between photosynthetic inhibitors (atrazine and isoproturon) and a cell mitosis inhibitor (trifluralin). Recovery after exposure to the binary mixture of atrazine and isoproturon was fast and concentration-independent: no significant differences between relative growth rates (RGRs) in any of the mixtures (IC10Mix, 25Mix, and 50Mix) versus control level were recorded in the last interval of the recovery phase. The recovery of the plants exposed to binary and ternary mixtures of dissimilarly acting herbicides was strictly concentration-dependent. Only plants exposed to IC10Mix, regardless of the herbicides, recovered RGRs close to control level in the last interval of the recovery phase. The inhibition of the RGRs in the last interval of the recovery phase compared with the control level is a proposed endpoint that could inform on reversibility of the effects and indicate possible mixture effects on plant population recovery potential. PMID- 27757497 TI - Addition of a general surgeon without addition of appropriate support is inadequate to improve outcomes of trauma patients in a rural setting: a cohort study of 1962 consecutive patients. AB - PURPOSE: Trauma care poses many challenges in small hospitals in rural settings. This report was designed to assess the role of a rural general surgeon with trauma patients. METHODS: A cohort study was designed using a retrospective analysis of a cohort at Bozkir Community Hospital that included trauma patients admitted to the emergency department between June 2007 and May 2009. The patients of group 1 were those treated during the first year of the study period, when the hospital staff was only non-specialist physicians. In the second year, a general surgeon was added to the staff, and the patients from this period constituted group 2. RESULTS: The top three leading causes of injuries were falls (46.5 %), piercing/cutting injuries (38.2 %), and assault (6.5 %). The frequency of trauma due to falls was higher in group 1, and assault and piercing/cutting injuries were higher in group 2 (p < 0.001 for each). The percentage of discharged and transferred patients was not significantly different between groups (p = 0.065 and p = 0.082, respectively). Similar mortality rates were also detected (group 1: 0.5 %, group 2: 0.3 %, p = 0.479). CONCLUSIONS: The presence of a solo general surgeon was not found to be adequate for improving the outcome for trauma patients in a rural hospital. PMID- 27757498 TI - [The results of the LAP07 trial should not be misunderstood as the end of chemoradiotherapy in pancreatic cancer]. PMID- 27757499 TI - [Neoadjuvant short-term radiotherapy followed by FOLFOX chemotherapy : No standard treatment for rectal cancer]. PMID- 27757500 TI - [Association of HPV infection, p16 status, and efficacy of radiotherapy with or without cetuximab in advanced oropharyngeal squamous cell carcinoma]. PMID- 27757501 TI - [Radiation response enhanced by inhibition of XPO1 in preclinical rectal cancer models]. PMID- 27757502 TI - Simultaneous integrated protection : A new concept for high-precision radiation therapy. AB - OBJECTIVE: Stereotactic radiotherapy near serial organs at risk (OAR) requires special caution. A novel intensity-modulated radiotherapy (IMRT) prescription concept termed simultaneous integrated protection (SIP) for quantifiable and comparable dose prescription to targets very close to OAR is described. MATERIALS AND METHODS: An intersection volume of a planning risk volume (PRV) with the total planning target volume (PTV) defined the protection volume (PTVSIP). The remainder of the PTV represented the dominant PTV (PTVdom). Planning was performed using IMRT. Dose was prescribed to PTVdom according to ICRU in 3, 5, 8, or 12 fractions. Constraints to OARs were expressed as absolute and as equieffective doses at 2 Gy (EQD2). Dose to the gross risk volume of an OAR was to respect constraints. Violation of constraints to OAR triggered a planning iteration at increased fractionation. Dose to PTVSIP was required to be as high as possible within the constraints to avoid local relapse. RESULTS: SIP was applied in 6 patients with OAR being large airways (n = 2) or bowel (n = 4) in 3, 5, 8, and 12 fractions in 1, 3, 1, and 1 patients, respectively. PTVs were 14.5 84.9 ml and PTVSIP 1.8-3.9 ml (2.9-13.4 % of PTV). Safety of the plans was analyzed from the absolute dose-volume histogram (dose to ml). The steepness of dose fall-off could be determined by comparing the dose constraints to the PRVs with those to the OARs (Wilcoxon test p = 0.001). Constraints were respected for the corresponding OARs. All patients had local control at a median 9 month follow up and toxicity was low. CONCLUSION: SIP results in a median dose of >=100 % to PTV, to achieve high local control and low toxicity. Longer follow-up is required to verify results and a prospective clinical trial is currently testing this new approach in chest and abdomen stereotactic body radiotherapy. PMID- 27757503 TI - Predictors for occlusion of cerebral AVMs following radiation therapy : Radiation dose and prior embolization, but not Spetzler-Martin grade. AB - BACKGROUND: Intracranial arteriovenous malformations (AVMs) may show a harmful development. AVMs are treated by surgery, embolization, or radiation therapy. OBJECTIVE: This study investigated obliteration rates and side effects in patients with AVMs treated by radiation therapy. METHODS: A total of 40 cases treated between 2005 and 2013 were analyzed. Single-dose stereotactic radiosurgery (SRS) was received by 13 patients and 27 received hypofractionated stereotactic radiation therapy (HSRT). In 20 patients, endovascular embolization had been performed prior to irradiation and 24 patients (60 %) had a history of previous intracranial hemorrhage. RESULTS: Treatment resulted in complete obliteration (CO) in 23/40 cases and partial obliteration in 8/40. CO was achieved in 85 % of patients receiving SRS compared to 44 % of those receiving HSRT. In the HSRT group, a first indication of an influence of AVM volume on obliteration rate was found. Equivalent 2 Gy fraction doses (EQD2) >70 Gy showed an obliteration rate of 50 %. Prior embolization was significantly associated with a higher portion of CO (p = 0.032). Median latency period (24.2 vs. 26 months) until CO was similar in both groups (SRS vs. HSRT). The rate of intracranial hemorrhage in patients with no prior bleeding events was 0 %. CONCLUSION: Excellent obliteration rates were achieved by SRS. Consistent with the literature, this data analysis suggests that the results of HSRT are volume dependent. Furthermore, regimens with EQD2 doses >70 Gy appear more likely to achieve obliteration than schemes with lower doses. The findings indicate that radiation therapy does not increase the risk of bleeding. Prior embolization may have a good prognostic impact. PMID- 27757505 TI - Erratum to: Biomechanical comparison of graft structures in anterior cruciate ligament reconstruction. PMID- 27757504 TI - Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24. AB - PURPOSE: This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment. METHODS: We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients. RESULTS: Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05). CONCLUSIONS: The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes. PMID- 27757506 TI - Public health impact and economic evaluation of vitamin D-fortified dairy products for fracture prevention in France. AB - : The recommended intake of vitamin D-fortified dairy products can substantially decrease the burden of osteoporotic fractures and seems an economically beneficial strategy in the general French population aged over 60 years. INTRODUCTION: This study aims to assess the public health and economic impact of vitamin D-fortified dairy products in the general French population aged over 60 years. METHODS: We estimated the lifetime health impacts expressed in number of fractures prevented, life years gained, and quality-adjusted life years (QALY) gained of the recommended intake of dairy products in the general French population over 60 years for 1 year (2015). A validated microsimulation model was used to simulate three age cohorts for both women and men (60-69, 70-79, and >80 years). The incremental cost per QALY gained of vitamin D-fortified dairy products compared to the absence of appropriate intake was estimated in different populations, assuming the cost of two dairy products per day in base case. RESULTS: The total lifetime number of fractures decreased by 64,932 for the recommended intake of dairy products in the general population over 60 years, of which 46,472 and 18,460 occurred in women and men, respectively. In particular, 15,087 and 4413 hip fractures could be prevented in women and men. Vitamin D fortified dairy products also resulted in 32,569 QALYs and 29,169 life years gained. The cost per QALY gained of appropriate dairy intake was estimated at ?58,244 and fall below a threshold of ?30,000 per QALY gained in women over 70 years and in men over 80 years. CONCLUSION: Vitamin D-fortified dairy products have the potential to substantially reduce the burden of osteoporotic fractures in France and seem an economically beneficial strategy, especially in the general population aged above 70 years. PMID- 27757508 TI - Characterization of the biochemical, physiological, and medicinal properties of Streptomyces hygroscopicus ACTMS-9H isolated from the Amazon (Brazil). AB - Actinomycetes are known to produce numerous secondary bioactive metabolites of pharmaceutical interest. The purpose of this study was to isolate, characterize, and investigate the antibacterial, antifungal, and anticancer activities of metabolites produced by Actinobacteria isolated from the rhizosphere of Paullinia cupana. The Actinobacteria was identified as Streptomyces hygroscopicus ACTMS-9H. Based on a bioguided study, the methanolic biomass extract obtained from submerged cultivation had the most potent antibacterial, antifungal, and cytotoxic activities. This extract was partitioned with n-hexane, ethyl acetate, and 2-butanol. Elaiophylin was isolated from the methanolic biomass extract, and its molecular formula was determined (C54H88O18) based on 1H and 13C NMR, IR and MS analyses. The 2-butanol phase was fractionated into four fractions (EB1, EB2A, EB2B, and EB3M). Chemical prospecting indicated the presence of alkaloids, saponins, and reducing sugars in the methanolic extract and 2-butanol phase. The elaiophylin displayed anticancer activity in HEp-2 and HL-60 cells with an IC50 of 1 MUg/mL. The EB1 fraction was selectively toxic to HL-60 cells with IC50 of 9 ng/mL. Bioautography showed that the EB1 fraction contained an alkaloid with antibacterial and antifungal activities (MIC values <=1.9 and <3.9 MUg/mL, respectively). In conclusion, the EB1 fraction and elaiophylin of S. hygroscopicus have potent antimicrobial, antifungal, and anticancer activities. PMID- 27757510 TI - [Our children: The future is fat : Are we losing the battle against the flab?] PMID- 27757509 TI - Changes in the diversity and composition of gut microbiota of weaned piglets after oral administration of Lactobacillus or an antibiotic. AB - The gut microbiota plays important roles in the health and well-being of animals, and high-throughput sequencing facilitates exploration of microbial populations in the animal gut. However, previous studies have focused on fecal samples instead of the gastrointestinal tract. In this study, we compared the microbiota diversity and composition of intestinal contents of weaned piglets treated with Lactobacillus reuteri or chlortetracycline (aureomycin) using high-throughput sequencing. Nine weaned piglets were randomly divided into three groups and supplemented with L. reuteri, chlortetracycline, or saline for 10 days, and then the contents of three intestinal segments (jejunum, colon, and cecum) were obtained and used for sequencing of the V3-V4 hypervariable region of the 16S rRNA gene. The microbiota diversity and composition in the jejunum were different from those in the colon and cecum among the three treatments. In the jejunum, treatment with L. reuteri increased the species richness of the microbiota, as indicated by the ACE and Chao1 indexes, compared with the chlortetracycline group, in which several taxa were eliminated. In the colon and cecum, relative abundances of the phylum Firmicutes and the genus Prevotella were higher in the chlortetracycline group than in the other groups. Distances between clustered samples revealed that the L. reuteri group was closer to the chlortetracycline group than the control group for jejunum samples, while colon and cecum samples of the L. reuteri group were clustered with those of the control group. This study provides fundamental knowledge for future studies such as the development of alternatives to antibiotics. PMID- 27757507 TI - The obesity-related pathology and Th17 cells. AB - Chronic inflammation associated with obesity plays a major role in the development of metabolic diseases, cancer, and autoimmune diseases. Among Th subsets, Th17 cells are involved in the pathogenesis of autoimmune disorders such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Accumulating data suggest that reciprocal interactions between the metabolic systems and immune system play pivotal roles in the pathogenesis of obesity-associated diseases. We herein outline the developing principles in the control of T cell differentiation and function via their cellular metabolism. Also discussed are recent findings that changes in the intracellular metabolism, including fatty acid metabolism, affect the Th17 cell function in obese individuals. Finally, we will also highlight the unique molecular mechanism involved in the activation of retinoid-related orphan receptor-gamma-t (RORgammat) by intracellular metabolism and discuss a new therapeutic approach for treating autoimmune disorders through the inhibition of RORgammat. PMID- 27757511 TI - [Criteria catalogue to systematize conceptual approaches in universal prevention of childhood overweight : Methodological approach and first results]. AB - BACKGROUND: Overweight and obesity are serious health risks for children and adolescents. Hence, various prevention projects have been initiated and implemented. Until now, a systematic overview of interventions in different settings has been lacking. AIM(S)/RESEARCH QUESTION: The aim of the "Prevention of child overweight" project (SkAP-project) is to prepare a systematic overview of the conceptual approaches used in universal prevention of overweight among children and adolescents. First of all, a comprehensive criteria catalogue will be developed based on systematic searches. In the next step the criteria catalogue will be applied to identify and characterize conceptual approaches. DATA AND METHODS: Criteria to describe conceptual approaches as well as determinants of childhood overweight were determined by systematic searches. The searches included relevant data bases and were further expanded by internet and hand search. Three settings (kindergarten, school and communities) and families are addressed by the systematic searches. Additional non-setting specific searches were conducted. RESULTS: A comprehensive criteria catalogue was developed, which allows a detailed analysis of conceptual approaches. This catalogue covers further quality criteria as well as determinants of childhood overweight. DISCUSSION: Currently, the criteria catalogue is being employed. Although the detailed analysis of conceptual approaches can be regarded as advantage of the criteria catalogue, there are also some limitations, such as the lack of necessary information provided in publications. Overall, the application will reveal an overview regarding universal prevention in childhood overweight, which is still lacking, and will support development in this field. PMID- 27757512 TI - [Electronic media in obesity prevention in childhood and adolescence]. AB - BACKGROUND: The increasing prevalence of childhood obesity is - amongst other factors - due to changed leisure time habits with decreased physical activity and increased media consumption. However, electronic media such as tablets and smartphones might also provide a novel intervention approach to prevent obesity in childhood and adolescence. OBJECTIVES: A summary of interventions applying electronic media to prevent childhood obesity is provided to investigate short term effects as well as long term results of these interventions. METHODS: A systematic literature search was performed in PubMed/Web of Science to identify randomized and/or controlled studies that have investigated the efficacy of electronic media for obesity prevention below the age of 18. RESULTS: A total of 909 studies were identified, and 88 studies were included in the analysis. Active video games did increase physical activity compared to inactive games when applied within a peer group. Interventions via telephone had positive effects on certain lifestyle-relevant behaviours. Interventions via mobile were shown to decrease dropout rates by sending regular SMS messages. To date, interventions via smartphones are scarce for adolescents; however, they might improve cardiorespiratory fitness. The results from internet-based interventions showed a trend towards positive effects on lifestyle-relevant behaviors. The combination of different electronic media did not show superior results compared to interventions with only one medium. Interventions via TV, DVD or video-based interventions may increase physical activity when offered as an incentive, however, effects on weight status were not observed. DISCUSSION: Children and adolescents currently grow up in a technology- and media-rich society with computers, tablets, smartphones, etc. used daily. Thus, interventions applying electronic media to prevent childhood obesity are contemporary. Available studies applying electronic media are however heterogeneous in terms of applied medium and duration. Positive effects on body composition were not observed, but only on certain lifestyle-relevant behaviours. In addition, these effects could only be seen in the short term. Follow-up data are currently scarce. PMID- 27757513 TI - Parallel single-cell analysis of active caspase-3/7 in apoptotic and non apoptotic cells. AB - Analysing the chemical content of individual cells has already been proven to reveal unique information on various biological processes. Single-cell analysis provides more accurate and reliable results for biology and medicine than analyses of extracts from cell populations, where a natural heterogeneity is averaged. To meet the requirements in the research of important biologically active molecules, such as caspases, we have developed a miniaturized device for simultaneous analyses of individual cells. A stainless steel body with a carousel holder enables high-sensitivity parallel detections in eight microvials. The holder is mounted in front of a photomultiplier tube with cooled photocathode working in photon counting mode. The detection of active caspase-3/7, central effector caspases in apoptosis, in single cells is based on the bioluminescence chemistry commercially available as Caspase-Glo(r) 3/7 reagent developed by Promega. Individual cells were captured from a culture medium under microscope and transferred by micromanipulator into detection microvial filled with the reagent. As a result of testing, the limits of detection and quantification were determined to be 0.27/0.86 of active caspase-3/7 content in an average apoptotic cell and 0.46/2.92 for non-apoptotic cells. Application potential of this technology in laboratory diagnostics and related medical research is discussed. Graphical abstract Miniaturized device for simultaneous analyses of individual cells. PMID- 27757514 TI - A novel protocol for enzymatic digestion based on covalent binding by protein immobilization. AB - The process of protein digestion is a critical step for successful protein identification in proteomic analysis. Many efforts have been dedicated to enhancing the digestion efficiency for sufficient digestion. Among these approaches, protein complete denaturation with denaturants is a common process for better digestion. However, the removal of denaturants was tedious or would cause protein loss and other problems. In this work, a feasible digestion approach, immobilized protein digestion (IPD), based on covalent binding has been developed. Proteins can be completely denatured and immobilized on the surface of functional materials by covalent binding to form a monolayer. Subsequently, varieties of denaturants or contaminants would be removed thoroughly by washing. To achieve fast immobilization and high digestion efficiency, different functional materials and denaturants were selected. Compared with traditional in solution digestion, the method achieved a prominent increase in identified peptides numbers and sequence coverage of proteins. Data analysis also showed that covalent binding could evidently decrease enzymatic missed cleavage for various protein sequences. Furthermore, possible peptide losses due to covalent binding were also investigated. Also, it has been proved to be efficient for complex biological sample digestion. Graphical abstract Workflow of the IPD method, including protein denaturation, immobilization, digestion, and identification. PMID- 27757515 TI - High-throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC-MS/MS. AB - The methionine cycle is a key pathway contributing to the regulation of human health, with well-established involvement in cardiovascular diseases and cognitive function. Changes in one-carbon cycle metabolites have also been associated with mild cognitive decline, vascular dementia, and Alzheimer's disease. Today, there is no single analytical method to monitor both metabolites and co-factors of the methionine cycle. To address this limitation, we here report for the first time a new method for the simultaneous quantitation of 17 metabolites in the methionine cycle, which are homocysteic acid, taurine, serine, cysteine, glycine, homocysteine, riboflavin, methionine, pyridoxine, cystathionine, pyridoxamine, S-adenosylhomocysteine, S-adenosylmethionine, betaine, choline, dimethylglycine, and 5-methyltetrahydrofolic acid. This multianalyte method, developed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), provides a highly accurate and precise quantitation of these 17 metabolites for both plasma and cerebrospinal fluid metabolite monitoring. The method requires a simple sample preparation, which, combined with a short chromatographic run time, ensures a high sample throughput. This analytical strategy will thus provide a novel metabolomics approach to be employed in large-scale observational and intervention studies. We expect such a robust method to be particularly relevant for broad and deep molecular phenotyping of individuals in relation to their nutritional requirements, health monitoring, and disease risk management. PMID- 27757518 TI - The European Neuroradiology awards in diagnostic and interventional Neuroradiology and the Lucien Appel Prize of the ESNR 2016. PMID- 27757517 TI - Safety and efficacy of antiplatelet response assay and drug adjustment in coil embolization: a propensity score analysis. AB - INTRODUCTION: The purpose of this study was to explore the safety and efficacy of an antiplatelet response assay and drug adjustment to prevent delayed thromboembolic events after stent-assisted coil embolization. METHODS: A total of 370 patients were enrolled in this study between December 2005 and July 2014. Of these, 124 patients were placed into the drug resistance test (DRT) group with drug adjustment according to response to an antiplatelet agent, and 246 patients comprised the control group with a standard antiplatelet regimen. The response to the antiplatelet agent was evaluated with the VerifyNow Rapid Platelet Function Assay. Propensity score matching analysis was performed with one-to-multiple matching. RESULTS: Among 370 patients, delayed thromboembolic events occurred in 28 (7.6 %) patients including 25 (10.2 %) in the control group and three (2.4 %) in the DRT group. Antiplatelet response test (p = 0.012), diabetes mellitus (DM) (p = 0.014), and hypertension (HTN) (p < 0.001) were associated with delayed infarction in multivariate analysis. In propensity score matching analysis, 331 patients were matched (control group (n = 229) vs. DRT group (n = 103)), and antiplatelet response (hazard ratio 0.247, 95 % confidence interval 0.070-0.868, p = 0.029) was correlated with delayed infarction. Conversely, the two groups were not significantly different with regard to total (p = 0.368) or major hemorrhagic complications (p = 0.108). CONCLUSION: Antiplatelet drug adjustment according to the results of an antiplatelet response assay might be associated with a decreased risk of delayed thromboembolic infarction compared with the standard antiplatelet regimen. PMID- 27757516 TI - Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. AB - PURPOSE: To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. METHODS: The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1-2 who received invasive mechanical ventilation. RESULTS: 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO2/FiO2 ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non pulmonary SOFA scores. CONCLUSIONS: Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02010073. PMID- 27757519 TI - Portal supply of segment IV of the liver based on CT-scan. AB - BACKGROUND: The portal vascularization of segment IV (S4) of the liver has not been well described. Knowledge of the portal supply to S4 is of great interest for liver surgery and for interventional radiological procedures. This study aimed to analyse the distribution of portal vein branches supplying S4. METHODS: We retrospectively analysed data from patients operated on for liver tumours between 2007 and 2016. Patients with involvement of S4 branches or the left portal vein, previous liver surgery or poor quality imaging were excluded. Branches originating from the right portal vein and/or from the transverse part of the left portal vein (TPLPV) and/or from the umbilical part of the portal vein (UPLPV) were identified. RESULTS: In 102 patients who underwent a right hepatectomy, S4 was vascularized by 2-8 branches of the left portal vein, with 84.3 % of patients having 3-6 branches. Only eleven patients (10.8 %) had portal branches originating from the TPLPV, with no impact on the number of branches coming from the UPLPV. Three patients (2.9 %) had one branch from the right portal vein. In patients with only two or three branches supplying S4, the branches had a larger diameter and typically arose from a short common trunk which divided further within its first centimetres. CONCLUSIONS: Portal vascularization of S4 varies widely (2-8 branches) between patients and originates predominantly from the junction between the left portal vein and the round ligament. There is no anatomical rationale to divide S4 into S4a and S4b. PMID- 27757520 TI - Letter to the Editor re: Should fat in the radiofrequency ablation zone of hepatocellular adenomas raise suspicion for residual tumour? PMID- 27757523 TI - The 29th international symposium on paediatric surgical research. PMID- 27757522 TI - Post-dilatation after implantation of bioresorbable everolimus- and novolimus eluting scaffolds: an observational optical coherence tomography study of acute mechanical effects. AB - OBJECTIVES: The objective was to investigate the acute mechanical effects of post dilatation on bioresorbable scaffolds (BRS) as determined by optical coherence tomography (OCT). BACKGROUND: Post-dilatation with high-pressure balloons is regarded as a key component of BRS implantation for treatment of coronary artery stenoses. However, the impact of post-dilatation on BRS in vivo has not been thoroughly investigated. METHODS: OCT was performed after the implantation procedure of 51 everolimus-eluting or novolimus-eluting polylactic acid-based BRS with (n = 27) or without non-compliant balloon post-dilatation (n = 24). The number of malapposed struts, strut fractures, edge dissections, residual in scaffold area stenosis, and incomplete scaffold apposition area was analyzed over the complete length of each BRS with a spacing of 1 mm. RESULTS: OCT revealed a significantly lower incomplete scaffold apposition area if post-dilatation was performed (0.16 +/- 0.49 mm2 with post-dilatation vs. 2.65 +/- 2.78 mm2 without post-dilatation, p < 0.001), as well as a significantly lower absolute number of malapposed struts (1 +/- 2 with post-dilatation vs. 13 +/- 13 without post dilatation, p < 0.001). No significant differences regarding residual in-scaffold area stenosis, strut fracture, edge dissection, symmetry index, or eccentricity index were observed in patients with vs. without post-dilatation. CONCLUSION: Post-dilatation of BRS with non-compliant balloons significantly reduces the number of malapposed struts and incomplete scaffold apposition area without inducing higher rates of edge dissection or strut fracture. PMID- 27757521 TI - The first joint ESGAR/ ESPR consensus statement on the technical performance of cross-sectional small bowel and colonic imaging. AB - OBJECTIVES: To develop guidelines describing a standardised approach to patient preparation and acquisition protocols for magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound (US) of the small bowel and colon, with an emphasis on imaging inflammatory bowel disease. METHODS: An expert consensus committee of 13 members from the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and European Society of Paediatric Radiology (ESPR) undertook a six-stage modified Delphi process, including a detailed literature review, to create a series of consensus statements concerning patient preparation, imaging hardware and image acquisition protocols. RESULTS: One hundred and fifty-seven statements were scored for agreement by the panel of which 129 statements (82 %) achieved immediate consensus with a further 19 (12 %) achieving consensus after appropriate modification. Nine (6 %) statements were rejected as consensus could not be reached. CONCLUSIONS: These expert consensus recommendations can be used to help guide cross-sectional radiological practice for imaging the small bowel and colon. KEY POINTS: * Cross-sectional imaging is increasingly used to evaluate the bowel * Image quality is paramount to achieving high diagnostic accuracy * Guidelines concerning patient preparation and image acquisition protocols are provided. PMID- 27757524 TI - Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal alpha-motoneurons in sporadic amyotrophic lateral sclerosis. AB - Two nerve cells types, Betz cells in layer Vb of the primary motor neocortex and alpha-motoneurons of the lower brainstem and spinal cord, become involved at the beginning of the pathological cascade underlying sporadic amyotrophic lateral sclerosis (sALS). In both neuronal types, the cell nuclei forfeit their normal (non-phosphorylated) expression of the 43-kDa transactive response DNA-binding protein (TDP-43). Here, we present initial evidence that in alpha-motoneurons the loss of normal nuclear TDP-43 expression is followed by the formation of phosphorylated TDP-43 aggregates (pTDP-43) within the cytoplasm, whereas in Betz cells, by contrast, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations. We discuss some implications of this phenomenon of nuclear clearing in the absence of cytoplasmic inclusions, namely, abnormal but soluble (and, thus, probably toxic) cytoplasmic TDP-43 could enter the axoplasm of Betz cells, and following its transmission to the corresponding alpha-motoneurons in the lower brainstem and spinal cord, possibly contribute in recipient neurons to the dysregulation of the normal nuclear protein. Because the cellular mechanisms that possibly inhibit the aggregation of TDP-43 in the cytoplasm of involved Betz cells are unknown, insight into such mechanisms could disclose a pathway by which the development of aggregates in this cell population could be accelerated, thereby opening an avenue for a causally based therapy. PMID- 27757525 TI - Characteristic systolic waveform of left ventricular longitudinal strain rate in patients with hypertrophic cardiomyopathy. AB - We analyzed the waveform of systolic strain and strain-rate curves to find a characteristic left ventricular (LV) myocardial contraction pattern in patients with hypertrophic cardiomyopathy (HCM), and evaluated the utility of these parameters for the differentiation of HCM and LV hypertrophy secondary to hypertension (HT). From global strain and strain-rate curves in the longitudinal and circumferential directions, the time from mitral valve closure to the peak strains (T-LS and T-CS, respectively) and the peak systolic strain rates (T-LSSR and T-CSSR, respectively) were measured in 34 patients with HCM, 30 patients with HT, and 25 control subjects. The systolic strain-rate waveform was classified into 3 patterns ("V", "W", and "?" pattern). In the HCM group, T-LS was prolonged, but T-LSSR was shortened; consequently, T-LSSR/T-LS ratio was distinctly lower than in the HT and control groups. The "?" pattern of longitudinal strain-rate waveform was more frequently seen in the HCM group (74 %) than in the control (4 %) and HT (20 %) groups. Similar but less distinct results were obtained in the circumferential direction. To differentiate HCM from HT, the sensitivity and specificity of the T-LSSR/T-LS ratio <0.34 and the "?" shaped longitudinal strain-rate waveform were 85 and 63 %, and 74 and 80 %, respectively. In conclusion, in patients with HCM, a reduced T-LSSR/T-LS ratio and a characteristic "?"-shaped waveform of LV systolic strain rate was seen, especially in the longitudinal direction. The timing and waveform analyses of systolic strain rate may be useful to distinguish between HCM and HT. PMID- 27757526 TI - Clinical outcomes and antibiotic susceptibilities of Staphylococcus aureus endophthalmitis. AB - PURPOSE: To compare the antibiotic susceptibilities and visual acuity (VA) outcomes in endophthalmitis caused by methicillin-resistant (MRSA) versus methicillin-sensitive S. aureus (MSSA). METHODS: The records of 34 cases of S. aureus endophthalmitis at The New York Eye and Ear Infirmary from Jan 1997 to June 2011 were reviewed. Antibiotic susceptibility profiles over time and VA at presentation and at 3, 6, and >=12 months were recorded. S. aureus isolates were grouped based on oxacillin resistance. RESULTS: Of the 34 cases, 15 (44 %) were MRSA and 19 (56 %) MSSA. Median presenting VA was hand motions (logMAR 4.0) in both the MRSA and MSSA groups. There was no statistically significant difference in VA between the MRSA and MSSA groups at 3, 6, or >=12 months. No MRSA isolates were resistant to vancomycin or gentamicin. While over 85 % of MRSA isolates tested for fourth-generation fluoroquinolones were resistant, just 10 % MSSA isolates tested were resistant. There was a trend suggesting an increase in the proportion of MRSA isolates compared to MSSA isolates over the course of the study period. CONCLUSIONS: There was no statistical difference in short- or long term VA outcomes between the MRSA and MSSA groups at any time point. Resistance to fourth-generation fluoroquinolones was present in over 85 % of MRSA isolates, but just 10 % of MSSA isolates. An increasing proportion of MRSA amongst S. aureus isolates was noted over the course of the study period. PMID- 27757527 TI - Self-perception versus professional assessment of functional outcome after ablative surgery in patients with oral cancer. AB - PURPOSE: The extent of functional impairment after ablative surgery in the orofacial region may be directly reflected in a reduction in Quality of Life. This study intended to compare the patients' perception with an objective functional evaluation of the orofacial system in order to bilaterally distinguish direct influence factors. METHODS: A total of 45 patients were included in this study and were asked to complete the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-30) and the Head and Neck 35 Module (H&N 35). Afterward one independent speech therapist evaluated the patients applying the Frenchay Dysarthria Assessment regarding four main categories: mouth opening, tongue motility, swallowing and intelligibility. Comparisons between groups were performed using Whitney-Mann U-Wilcoxon test and calculating Spearman's rho. RESULTS: Overall the professional assessments by the speech therapists revealed significantly higher scores regarding intelligibility, swallowing and mouth opening when compared to the patients' self-perception. Smaller tumor sizes, no bone resection and local reconstruction techniques led to significantly better functional outcomes, when assessed by speech therapists. Swallowing was perceived significantly better by patients in cases of local reconstruction. CONCLUSIONS: From the professionals' point of view differences were perceived in more items compared to the patients' self-assessments, who widely experienced a more severe functional impairment. Physicians should take this into account when discussing adverse therapy effects with the patients. PMID- 27757528 TI - The recommended treatment strategy for locally advanced gastric cancer in elderly patients aged 75 years and older: a Surveillance, Epidemiology, and End Results database analysis. AB - BACKGROUND: As patients aged 75 years and older are often underrepresented in randomized clinical trials, the external validity of clinical trials-based recommendations in older gastric patients was still controversial. The aim of this study is to explore the recommended treatment strategy for locally advanced gastric cancer in elderly patients. METHODS: We designed our study to specifically evaluate the cancer-specific survival (CSS) of four subgroups of patients according to four different treatment modalities: adjuvant radiation (RT), surgery only, RT only and no surgery/no RT by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. RESULTS: The 5-year CSS was 43.8 % in adjuvant RT, 28.5 % in surgery only, 14.9 % in RT only and 1.4 % in no surgery/no RT, which had significant difference in univariate log-rank test (P < 0.001) and multivariate Cox regression (P < 0.001). Moreover, we observed significant survival benefits in adjuvant RT group in all age categories, including age 75-79 years, age 80-84 years and age >=85 years (all P < 0.001). CONCLUSIONS: Surgery and adjuvant RT may be the recommended treatment strategy in elderly patients with locally advanced gastric cancer, especially for patients medically fit for the combined modality therapy. PMID- 27757530 TI - [Uterine pathology]. PMID- 27757529 TI - Efficacy of Yeast' Vacuoles as Antimicrobial Agents to Escherichia coli Bacteremia in Rat. AB - Yeast vacuoles, lysosomes, are cell organelles that have antimicrobial activity against several bacteria in vitro. Lysosomes have a potential application to the treatment of pathogens such as antibiotics in vivo. Therefore, the in vivo efficacy of lysosomes was examined in a rat infection model against pathogenic Escherichia coli with varying susceptibilities to standard antimicrobial agents. Before in vivo testing, the concentration-dependent safety of lysosomes was confirmed by blood test and histopathology of normal rats. The therapeutic efficacy of lysosomes was examined in terms of the survival of E. coli in infected rat blood. The complete blood count and histopathology results were affected by the lysosomes concentration. In addition, the E. coli growth was inhibited by the initial injection of lysosomes. These results support the use of lysosomes as a bacterial inhibitor of an infected rat model. PMID- 27757532 TI - ? PMID- 27757531 TI - [Metastatic mechanisms of uterine malignancies and therapeutic consequences]. AB - Malignancies of the uterus metastasize by direct invasion of neighboring structures, lymphatically or hematogenously. Endometrial and cervical cancers lymphatically spread to the pelvic and para-aortic lymph nodes. For endometrial cancer the depth of myometrial invasion, lymphosvascular space involvement (LVSI) and a microcystic, elongated and fragmented (MELF) glandular invasion pattern are predictors for lymph node metastases. Metastases to the pelvic lymph nodes occur in approximately 10 % of endometrial cancer patients and in 30 % of these cases the para-aortic lymph nodes are also involved. Sentinel lymph node biopsy is possible for clinical stage I endometrial cancer and early stages of cervical cancer but is not yet routine. The presence of LVSI is considered to be the strongest predictor of distant metastases, particularly if assessed by immunohistochemistry with antibodies against factor VIII-related antigen or CD31. Endometrioid and clear cell carcinomas can hematogenously metastasize to the lungs, bones, liver and brain and can rarely be manifested as a solitary metastasis. In contrast, serous carcinomas can show extensive peritoneal spread. To date molecular biomarkers cannot predict the occurrence of distant metastasis. Overexpression of P53, p16 and L1CAM have been identified as negative prognostic factors and are associated with the prognostically unfavorable serous tumor type. The metastatic spread of squamous cell cervical cancer is strongly associated with tumor volume. Microinvasive carcinomas have a very low rate of parametrial and lymph node involvement and do not require radical hysterectomy. In contrast, lymph node metastases occur in up to 50 % of bulky stages IB and II cervical cancers. Distant metastases can occur in the lungs, liver, bones and brain. Molecular biomarkers have not been shown to predict metastatic spread. In well differentiated adenocarcinoma of the cervix the pattern of invasion is strongly predictive for the presence of lymph node metastases, irrespective of tumor size and depth of invasion. PMID- 27757533 TI - The challenge of diagnosing a malignancy metastatic to the ovary: clinicopathological characteristics vary and morphology can be different from that of the corresponding primary tumor. AB - An accurate diagnosis of metastases to the ovary is essential for adequate patient management. The aim of this retrospective study was to characterize clinicopathological features of metastatic malignancies that presented as an ovarian mass and compare them with their corresponding primary tumors. We reviewed clinical files and histological material of 120 patients with metastases to the ovary, diagnosed in our center between 2000 and 2014. Metastases were diagnosed before (18 %), synchronously (33 %), or after (49 %) the primary tumor was identified; 25 % were single, 40 % were unilateral; 47 % were >=13 cm. Most originated from the gastrointestinal tract (73 %), followed by breast (13 %), and female reproductive organs (10 %). Gross features varied with primary tumor site. Metastases from gastrointestinal malignancies were significantly larger and frequently showed necrosis. Metastases to the appendix were cystic (94 %), and almost all metastases to the stomach (96 %) and breast (87 %) were solid. The predominant histological pattern was discordant in 44 % cases, mostly due to cystic changes in ovarian metastases which were observed across several histological types. Other metastases showed a predominant histological pattern which was present only focally in the primary tumor. Metastases showed significantly more edema, necrosis, and hemorrhage, but less lymphovascular invasion and inflammatory infiltrate than the corresponding primary tumors. Metastases to the ovary present highly variable clinicopathological features which frequently differ from those of the corresponding primary tumor. A metastasis should always be considered in the differential diagnosis of an ovarian mass. All clinical, imaging, macroscopic, and histological aspects must be taken into account to establish a correct diagnosis which is essential for adequate treatment. PMID- 27757534 TI - Pancreatic PEComa is a novel member of the family of tuberous sclerosis complex associated tumors: case report and review of the literature. PMID- 27757535 TI - Fabrication, characterization and application of laccase-nylon 6,6/Fe3+ composite nanofibrous membrane for 3,3'-dimethoxybenzidine detoxification. AB - In this study, laccase was immobilized on nylon 6,6/Fe3+ composite (NFC) nanofibrous membrane and used for the detoxification of 3,3'-dimethoxybenzidine (DMOB). The average size and tensile strength of the NFC membrane were found to be 60-80 nm (diameter) and 2.70 MPa, respectively. The FTIR results confirm that the amine (N-H) group of laccase was attached with Fe3+ particles and the carbonyl (C=O) group of NFC membrane via hydrogen bonding. The half-life of the laccase-NFC membrane storage stability was increased from 6 to 11 weeks and the reusability was significantly extended up to 43 cycles against ABTS oxidation. Enhanced electro-oxidation of DMOB by laccase was observed at 0.33 V and the catalytic current was found to be 30 uA. The DMOB-treated mouse fibroblast 3T3-L1 preadipocytes showed maximum (97 %) cell inhibition at 75 uM L-1 within 24 h. The cytotoxicity of DMOB was significantly decreased to 78 % after laccase treatment. This study suggests that laccase-NFC membrane might be a good candidate for emerging pollutant detoxification. PMID- 27757537 TI - Transvaginal specimen removal in minimally invasive surgery: feasibility and possible complications during the incision of the posterior vaginal wall. PMID- 27757536 TI - Cementogenic genes in human periodontal ligament stem cells are downregulated in response to osteogenic stimulation while upregulated by vitamin C treatment. AB - Regeneration of periodontal tissues, particularly cementum, is key to regaining periodontal attachment and health. Human periodontal ligament stem cells (hPDLSCs) have been shown to be a good cell source to regenerate periodontal tissues. However, their subpopulations and the differentiation induction in relation to cementogenic lineages is unclear. Thus, we aim to examine the expression of cementum-associated genes in PDLSC subpopulations and determine the effect of broadly used osteogenic stimulus or vitamin C (VC) on the expression of cementogenic and osteogenic genes in PDLSCs. Our real-time quantitative polymerase chain reaction (qPCR) analysis showed that cementogenic marker cementum attachment protein (CAP) expressed only slightly higher in STRO 1+/CD146+, STRO-1-/CD146+ and STRO-1-/CD146- subpopulations than in the original cell pool, while cementum protein 1 (CEMP1) expression in these subpopulations was not different from the original pool. Notably, under the stimulation with osteogenic differentiation medium, CAP and CEMP1 were downregulated while osteogenic markers bone sialoprotein (BSP) and osteocalcin (OCN) were upregulated. Both CAP and CEMP1 were upregulated by VC treatment. Transplantation of VC-treated PDLSCs into immunocompromised mice resulted in forming significantly more ectopic cementum- and bone-like mineral tissues in vivo. Immunohistochemical analysis of the ectopic growth showed that CAP and CEMP1 were mainly expressed in the mineral tissue and in some cells of the fibrous tissues. We conclude that osteogenic stimulation is not inductive but appears to be inhibitory of cementogenic pathways, whereas VC induces cementogenic lineage commitment by PDLSCs and may be a useful stimulus for cementogenesis in periodontal regeneration. PMID- 27757539 TI - Morphological and ultrastructural characteristics of Myxobolus ridibundae n. sp. (Myxosporea: Bivalvulida) infecting the testicular tissue of the marsh frog Rana ridibunda (Amphibia: Ranidae) in Egypt. AB - Myxozoans are one of the most economically important groups of protozoan parasites causing many serious diseases of their hosts. In the present study, a total of 60 live adult male specimens of the marsh frog Rana ridibunda have been randomly captured during the period of January-December 2015 in different areas at Kafr El-Sheikh Governorate, Egypt and were examined for infection by myxosporidian parasites. A total of 48 (80.0 %) out of 60 frog specimens were found to be infected with Myxobolus species. Parasitic infection was restricted to the testicular tissue of the examined frogs. Macroscopic cysts (plasmodia) which heavily infested different parts of the testes were recovered. Morphological and ultrastructural characteristics of these myxosporidian species were carried out using light and transmission electron microscopy. Plasmodia measured 0.16-0.53 (0.34 +/- 0.01) mm in diameter. Mature spores appeared oval in frontal view, measuring 8.9-11.5 (9.6 +/- 0.1) MUm in length and 7.5-9.1 (8.4 +/- 0.1) MUm in width containing 5-6 turns of polar filaments. Morphometric characterization revealed that the very small size of the present Myxobolus species was the most distinctive feature that separates them from all previously described Myxobolus species. Ultrastructural analysis showed that the plasmodia are surrounded by a plasma membrane with numerous pinocytotic protrusions extending toward the host cell. The generative cells and the different developmental stages are arranged at the periphery of the plasmodia, while immature and mature spores are centrally located. Sporogenesis, capsulogenesis, valvogenesis, and spore maturation of the present parasite are also described. The present species is described as Myxobolus ridibundae and represents a new species. PMID- 27757540 TI - Impact of restless legs syndrome in patients with inflammatory bowel disease on sleep, fatigue, and quality of life. AB - PURPOSE: Inflammatory bowel disease has been associated with neurological symptoms including restless legs syndrome. Here, we investigated the impact of restless legs syndrome in patients with inflammatory bowel disease on sleep, fatigue, mood, cognition, and quality of life. METHODS: Two groups of inflammatory bowel disease patients, with and without restless legs syndrome, were prospectively evaluated for sleep disorders, fatigue, daytime sleepiness, depression, anxiety, and health-related quality of life. Furthermore, global cognitive function, executive function, attention, and concentration were assessed in both groups. Disease activity and duration of inflammatory bowel disease as well as current medication were assessed by interview. Inflammatory bowel disease patients with and without restless legs syndrome were matched for age, education, severity, and duration of their inflammatory bowel disease. RESULTS: Patients with inflammatory bowel disease and clinically relevant restless leg syndrome suffered significantly more frequent from sleep disturbances including sleep latency and duration, more fatigue, and worse health related quality of life as compared to inflammatory bowel disease patients without restless legs syndrome. Affect and cognitive function including cognitive flexibility, attention, and concentration showed no significant differences among groups, indicating to be not related to restless legs syndrome. CONCLUSIONS: Sleep disorders including longer sleep latency, shorter sleep duration, and fatigue are characteristic symptoms of restless legs syndrome in inflammatory bowel disease patients, resulting in worse health-related quality of life. Therefore, clinicians treating patients with inflammatory bowel disease should be alert for restless legs syndrome. PMID- 27757541 TI - Pathologic response grade after long-course neoadjuvant chemoradiation does not influence morbidity in locally advanced mid-low rectal cancer resected by laparoscopy. AB - PURPOSE: Patients with locally advanced rectal cancer and pathologic complete response to neoadjuvant chemoradiation therapy have lower rates of recurrence compared to those who do not. However, the influences of the pathologic response on surgical complications and survival remain unclear. This study aimed to investigate the influence of neoadjuvant therapy for rectal cancer on postoperative morbidity and long-term survival. METHODS: This was a comparative study of consecutive patients who underwent laparoscopic total mesorectal excision for rectal cancer in two European tertiary hospitals between 2004 and 2014. Patients with and without pathologic complete responses were compared in terms of postoperative morbidity, mortality, and survival. RESULTS: Fifty patients with complete response (ypT0N0) were compared with 141 patients who exhibited non-complete response. No group differences were observed in the postoperative mortality or morbidity rates. The median follow-up time was 57 months (range 1-121). Over this period, 11 (5.8 %) patients, all of whom were in the non-complete response group, exhibited local recurrence. The 5-year overall survival and disease-free survival were significantly better in the complete response group, 92.5 vs. 75.3 % (p = 0.004) and 89 vs. 73.4 % (p = 0.002), respectively. CONCLUSIONS: Postoperative complication rate after laparoscopic total mesorectal excision is not associated with the pathologic response grade to neoadjuvant chemoradiation therapy. PMID- 27757542 TI - Incidence of IP and risk of malignant transformation in the Swedish population 1960-2010. AB - The true incidence of inverted papilloma (IP) is not yet known. From hospital based studies, its incidence has been estimated to approximately 0.5/100,000 person years. Earlier hospital case studies have shown that IP can undergo a malignant transformation in 1-53 %. The frequency of its malignant transformation on a population basis is unknown. To our knowledge, no standardised incidence ratio (SIR) has been reported for malignancies among IPs. This study aims to investigate these incidences on a population basis. Using the data from the Swedish Cancer Registry (SCR), we have identified patients with IP and patients with Squamous Cell Carcinoma (SCC) diagnosed between 1960 and 2010 in Sweden. Incidence of IP and incidence of SCC among patients with IP and SIR were analyzed. Eight hundred and fourteen patients with IP were identified. The incidence of IPs reported to the SCR increased from 1960 to 2010. In this cohort, SCC was overrepresented, as compared with the general population. The incidence of IP in the Swedish population seems to have increased. PMID- 27757543 TI - Photosynthetic responses of a dominant C4 grass to an experimental heat wave are mediated by soil moisture. AB - Extreme heat waves and drought are predicted to increase in frequency and magnitude with climate change. These extreme events often co-occur, making it difficult to separate their direct and indirect effects on important ecophysiological and carbon cycling processes such as photosynthesis. Here, we assessed the independent and interactive effects of experimental heat waves and drought on photosynthesis in Andropogon gerardii, a dominant C4 grass in a native mesic grassland. We experimentally imposed a two-week heat wave at four intensity levels under two contrasting soil moisture regimes: a well-watered control and an extreme drought. There were three main findings from this study. First, the soil moisture regimes had large effects on canopy temperature, leading to extremely high temperatures under drought and low temperatures under well-watered conditions. Second, soil moisture mediated the photosynthetic response to heat; heat reduced photosynthesis under the well-watered control, but not under the extreme drought treatment. Third, the effects of heat on photosynthesis appeared to be driven by a direct thermal effect, not indirectly through other environmental or ecophysiological variables. These results suggest that while photosynthesis in this dominant C4 grass is sensitive to heat stress, this sensitivity can be overwhelmed by extreme drought stress. PMID- 27757544 TI - Marine ecosystem resilience during extreme deoxygenation: the Early Jurassic oceanic anoxic event. AB - Global warming during the Early Jurassic, and associated widespread ocean deoxygenation, was comparable in scale with the changes projected for the next century. This study quantifies the impact of severe global environmental change on the biological traits of marine communities that define the ecological roles and functions they deliver. We document centennial-millennial variability in the biological trait composition of Early Jurassic (Toarcian) seafloor communities and examine how this changed during the event using biological traits analysis. Environmental changes preceding the global oceanic anoxic event (OAE) produced an ecological shift leading to stressed benthic palaeocommunities with reduced resilience to the subsequent OAE. Changes in traits and ecological succession coincided with major environmental changes; and were of similar nature and magnitude to those in severely deoxygenated benthic communities today despite the very different timescales. Changes in community composition were linked to local redox conditions whereas changes in populations of opportunists were driven by primary productivity. Throughout most of the OAE substitutions by tolerant taxa conserved the trait composition and hence functioning, but periods of severe deoxygenation caused benthic defaunation that would have resulted in functional collapse. Following the OAE recovery was slow probably because the global nature of the event restricted opportunities for recruitment from outside the basin. Our findings suggest that future systems undergoing deoxygenation may initially show functional resilience, but severe global deoxygenation will impact traits and ecosystem functioning and, by limiting the species pool, will slow recovery rates. PMID- 27757545 TI - Enhancement of the protective efficacy of a ROP18 vaccine against chronic toxoplasmosis by nasal route. AB - Infection with the parasite Toxoplasma gondii causes serious public health problems and is of great economic importance worldwide. No vaccine is currently available, so the design of efficient vaccine strategies is still a topical question. In this study, we evaluated the immunoprophylactic potential of a T. gondii virulence factor, the rhoptry kinase ROP18, in a mouse model of chronic toxoplasmosis: first using a recombinant protein produced in Schneider insect cells adjuvanted with poly I:C emulsified in Montanide SV71 by a parenteral route or adjuvanted with cholera toxin by the nasal route and second using a DNA plasmid encoding ROP18 adjuvanted with GM-CSF +/- IL-12 DNA. If both intranasal and subcutaneous recombinant ROP18 immunizations induced predominantly anti-ROP18 IgG1 antibodies and generated a mixed systemic Th1-/Th2-type cellular immune response characterized by the production of IFN-gamma, IL-2, Il-10 and IL-5, only intranasal vaccination induced a mucosal (IgA) humoral response in intestinal washes associated with a significant brain cyst reduction (50 %) after oral challenge with T. gondii cysts. DNA immunization induced antibodies and redirected the cellular immune response toward a Th1-type response (production of IFN-gamma and IL-2) but did not confer protection. These results suggest that ROP18 could be a component of a subunit vaccine against toxoplasmosis and that strategies designed to enhance mucosal protective immune responses could lead to more encouraging results. PMID- 27757546 TI - Quantitative evaluation of 3D imaging in laparoscopic surgery. AB - PURPOSE: 3D images offer true depth perception, which overcomes one of the disadvantages of laparoscopic surgery. We evaluated differences in the use of 3D and 2D images in laparoscopic surgery based on the recording of traces of forceps. METHODS: Twelve surgeons at our hospital participated in the study. The task consisted of one suture and three ligations, using a training box. The completion time and number of hold errors were noted, and forceps traces were recorded using the Behavior Checker system (Miura Medical). Participants were divided into two groups based on faster and slower completion times with 2D images. RESULTS: The median completion time in seconds (s) was significantly shorter when using 3D images than when using 2D images (51 s, range 34-146 vs. 63 s, range 38-265 s; p = 0.013). The 3D/2D completion time ratio was significantly higher in the faster 2D group (0.93 vs. 0.69, p = 0.030) indicating a greater effect of the 3D images on less experienced participants. CONCLUSIONS: A quantitative evaluation showed that using 3D images enables more efficient use of laparoscopic forceps than 2D images. A system with 3D images is of particular benefit for inexperienced surgeons. PMID- 27757548 TI - Photorhabdus luminescens Toxins TccC3 and TccC5 Affect the Interaction of Actin with Actin-Binding Proteins Essential for Treadmilling. AB - Actin is one of the most abundant cellular proteins and an essential constituent of the actin cytoskeleton, which by its dynamic behavior participates in many cellular activities. The organization of the actin cytoskeleton is regulated by a large number of proteins and represents one of the major targets of bacterial toxins. A number of bacterial effector proteins directly modify actin: Clostridial bacteria produce toxins, which ADP-ribosylate actin at Arg177 leading to inhibition of actin polymerization. The bacterium Photorhabdus luminescens produces several types of protein toxins, including the high molecular weight Tc toxin complex, whose component TccC3 ADP-ribosylates actin at Thr148 promoting polymerization and aggregation of intracellular F-actin leading to inhibition of several cellular functions, such as phagocytosis. Here, we review recent findings about the functional consequences of these actin modifications and for the Thr148 ADP-ribosylated actin the subsequent alterations in the interaction with actin binding proteins . In addition, we describe the effects of ADP-ribosylation of Rho GTPases by the TccC5 component. PMID- 27757547 TI - Risk of metastasis in adenocarcinoma of the esophagus: a multicenter retrospective study in a Japanese population. AB - BACKGROUND: Little is known about the specific risks of metastasis in esophageal adenocarcinoma in relation to invasion depth or other pathologic factors. METHODS: We conducted a multicenter retrospective study in 13 high-volume centers in Japan from January 2000 to October 2014 to elucidate the risk of metastasis of esophageal adenocarcinoma. A total of 458 patients (217 surgically resected and 241 endoscopically resected) with esophageal adenocarcinoma or esophagogastric adenocarcinoma involving the esophagus were included. Metastasis was considered positive if there was histologically confirmed metastasis in the surgical specimen or clinically confirmed metastasis during follow-up. Metastasis was considered negative if no metastasis was identified in resected specimens and during follow-up in patients treated surgically or no metastasis during follow-up for >5 years in patients treated by endoscopic resection. RESULTS: Metastasis was identified in 72 patients. Multivariate analysis confirmed lymphovascular involvement [odds ratio (OR) 6.20; 95 % confidence interval (CI) 3.12-12.32; p < 0.001], a poorly differentiated component (OR 3.69; 95 % CI 1.92-7.10; p < 0.001), and lesion size >30 mm (OR 3.12; 95 % CI 1.63-5.97; p = 0.001) as independent risk factors for metastasis. No metastasis was detected in patients with mucosal cancer without lymphovascular involvement and a poorly differentiated component (0/186 lesions) or in patients with cancer invading the submucosa (1-500 um) without lymphovascular involvement, a poorly differentiated component, and <=30 mm (0/32 lesions). CONCLUSIONS: Mucosal and submucosal cancers (1-500 um invasion) without risk factors have a low incidence of metastasis and may thus be good candidates for endoscopic resection. PMID- 27757549 TI - Adhesion prevention in ventral hernia repair: an experimental study comparing three lightweight porous meshes recommended for intraperitoneal use. AB - BACKGROUND: In ventral hernia repair, when prosthetic material is placed intraperitoneally, it may lead to an inflammatory reaction resulting in adhesions between the mesh and abdominal viscera. Several meshes have been developed to minimize this process. In this experimental study, the ability of different combined meshes to attenuate the adhesion formation was examined. METHODS: Three commercially available lightweight porous combined meshes were placed intraperitoneally to repair an abdominal wall defect in rats: DynaMesh-IPOM (PVDF + PP), TiMesh (titanium-coated filament PP) and C-QUR/FX (omega-3 fatty acid coated filament PP). The DynaMesh-CICAT (PVDF) was implanted in the control group. Adhesion formation was macroscopically evaluated and scored after 7 and 21 days. RESULTS: All animals except two presented intra-abdominal adhesions. None of the meshes examined in the study demonstrated to prevent adhesions. C-QUR/FX reduced adhesion formation at 7 days' follow-up compared with all other meshes but by 21 days this effect was diminished. Between 7 and 21 days adhesion extension significantly decreased for TiMesh. TAS did not show significant modifications between 7 and 21 days' follow-up for each mesh. CONCLUSIONS: The combined porous meshes tested in the present study demonstrated to reduce but not to prevent the adhesion formation, even if with some differences. Combined porous meshes could be chosen instead of simple meshes for retro-rectus preperitoneal prosthetic ventral hernia repair. PMID- 27757550 TI - Efficacy of various side-to-side toothbrushes and impact of brushing parameters on noncontact biofilm removal in an interdental space model. AB - OBJECTIVES: The objective of this study was to evaluate the efficacy of four different side-to-side toothbrushes and the impact of various brushing parameters on noncontact biofilm removal in an adjustable interdental space model. MATERIALS AND METHODS: A three-species biofilm, consisting of Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus sanguinis, was formed in vitro on protein-coated titanium disks using a flow chamber combined with a static biofilm growth model. Subsequently, the biofilm-coated disks were exposed to four different powered toothbrushes (A, B, C, D). The parameters distance (0 and 1 mm), brushing time (2, 4, and 6 s), interdental space width (1, 2, and 3 mm), and toothbrush angulation (45 degrees and 90 degrees ) were tested. The biofilm volumes were determined using volumetric analyses with confocal laser scanning microscope (Zeiss LSM700) images and Imaris version 7.7.2 software. RESULTS: The median percentages of simulated interdental biofilm reduction by the tested toothbrushes ranged from 7 to 64 %. The abilities of the analyzed toothbrushes to reduce the in vitro biofilm differed significantly (p < 0.05). Three of the tested toothbrushes (A, B, C) were able to significantly reduce a simulated interdental biofilm by noncontact brushing (p <= 0.005). The brushing parameters and their combinations tested in the experiments revealed only minor effects on in vitro interdental biofilm reduction (p > 0.05). CONCLUSIONS: A three-species in vitro biofilm could be altered by noncontact brushing with toothbrushes A, B, and C in an artificial interdental space model. CLINICAL RELEVANCE: Certain side to-side toothbrushes demonstrate in vitro a high efficacy in interdental biofilm removal without bristle-to-biofilm contact. PMID- 27757551 TI - FkbN and Tcs7 are pathway-specific regulators of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis L19. AB - FK506 (tacrolimus), which is produced by many Streptomyces strains, is clinically used as an immunosuppressive agent and for treatment of inflammatory skin diseases. Here, we identified that the FK506 biosynthetic gene cluster in an industrial FK506-producing strain Streptomyces tsukubaensis L19 is organized as eight transcription units. Two pathway-specific regulators, FkbN and Tcs7, involved in FK506 biosynthesis from S. tsukubaensis L19 were characterized in vivo and in vitro. FkbN activates the transcription of six transcription units in FK506 biosynthetic gene cluster, and Tcs7 activates the transcription of fkbN. In addition, the DNA-binding specificity of FkbN was determined. Finally, a high FK506-producing strain was constructed by overexpression of both fkbN and tcs7 in S. tsukubaensis L19, which improved FK506 production by 89 % compared to the parental strain. PMID- 27757552 TI - Safety and tolerability of fingolimod in patients with relapsing-remitting multiple sclerosis: results of an open-label clinical trial in Italy. AB - : The safety profile of fingolimod is well established in clinical trials and post-marketing studies. This study aimed to evaluate the safety and tolerability of fingolimod in a cohort of Italian patients with relapsing-remitting multiple sclerosis (RRMS). This is a non-comparative, open-label, multicentre, interventional study conducted in patients with RRMS with no suitable alternative treatment option. Safety and tolerability of fingolimod 0.5 mg were assessed by recording adverse events (AEs) and serious AEs (SAEs). Of the 906 patients enrolled in the study, 91 % of the patients completed the study. AEs and SAEs were reported in 35.4 and 2.9 % of the patients, respectively. Most common AEs reported were headache (4.1 %), influenza (2.1 %), lymphopenia (1.8 %), asthenia (1.8 %) and pyrexia (1.8 %). Increased alanine aminotransferase levels and hypertension were reported as AE in 1.0 and 1.4 % of the patients, respectively. Macular oedema was reported in three patients. These results emphasize the safety of fingolimod in patients representing the real-world clinical practice in the Italian population. Fingolimod was safe and well tolerated in this population, which, compared to those enrolled in pivotal trials in terms of concomitant diseases and used medications, is broader. TRIAL REGISTRATION: EudraCT 2011 000770-60. PMID- 27757553 TI - Fosaprepitant versus droperidol for prevention of PONV in craniotomy: a randomized double-blind study. AB - PURPOSE: Postoperative nausea and vomiting (PONV) is a common complication after craniotomy. Vomiting may be a potentially hazardous complication in neurosurgical patients. We compared the efficacy of fosaprepitant and droperidol for the prevention of PONV, vomiting in particular, after craniotomy. METHODS: Patients scheduled to undergo elective craniotomy were enrolled in the study and randomly divided in a double-blind manner into two groups to receive either 150 mg of fosaprepitant (group F) or 1.25 mg of droperidol (group D). Dexamethasone (9.9 mg) was given to all patients, except those with diabetes mellitus. The incidence of PONV, frequency of vomiting, nausea score, and use of rescue antiemetic during the first 72 h after surgery were assessed at five time intervals (0-2, 2-6, 6 24, 24-48, and 48-72 h). RESULTS: Of the 200 randomized patients eligible for entry into the study, 186 were ultimately included for analysis. There were no significant differences in demographics or intraoperative variables between the two treatment groups. Over the entire 72-h post-craniotomy observation period the overall and cumulative incidence of vomiting was significantly lower in group F patients than in group D patients, while there were no between-group differences in the overall and cumulative incidence of PONV or in complete response (no PONV and no rescue antiemetic). The incidence and frequency of vomiting during each of the five observational periods were significantly lower in group F patients than group D patients, although there were no differences in the nausea score and antiemetic use between the groups. CONCLUSION: Based on the results, fosaprepitant was more effective than droperidol in the prevention of vomiting after craniotomy over the entire 72-h study period. However, there was no difference in the incidence of nausea and antiemetic use. PMID- 27757554 TI - Thromboelastometry guided fibrinogen replacement therapy in cardiac surgery: a retrospective observational study. AB - This retrospective, observational study compared the impact of a point-of-care rotational thromboelastometry (ROTEM(r)) method versus conventional bleeding management in terms of postoperative (24-h) blood loss, intraoperative and postoperative (24-h) transfusion requirement and length of stay in the postoperative intensive care unit (ICU) in patients undergoing cardiac surgery. Forty consecutive patients undergoing cardiac surgery under ROTEM(r)-guided hemostatic management were enrolled; the control population included 40 selected patients undergoing similar interventions without ROTEM(r) monitoring. Significantly more patients in the thromboelastometry group versus the control group received fibrinogen (45 vs 10 %; p < 0.0001), while fewer received a transfusion (40 vs 72.5 %; p < 0.0033). Compared with control group patients, those in the thromboelastometry group had less postoperative bleeding (285 vs 393 mL; p < 0.0001), a shorter time from cardiopulmonary bypass discontinuation to skin suture (79.3 vs 92.6 min; p = 0.0043) and a shorter stay in the ICU (43.7 vs 52.5 h; p = 0.0002). In our preliminary experience, ROTEM(r)-guided bleeding management was superior to conventional management of bleeding in patients undergoing complex cardiac surgery with cardiopulmonary bypass in terms of reduced postoperative blood loss, transfusion requirement, and length of ICU stay. PMID- 27757555 TI - Analysis of fluctuation for pixel-pair distance in co-occurrence matrix applied to ultrasonic images for diagnosis of liver fibrosis. AB - PURPOSE: Chronic liver disease requires careful follow-up during long-term treatment, and development of a quantitative diagnosis method for liver fibrosis based on an ultrasonic imaging system is highly desired. METHODS: Texture analysis using a co-occurrence matrix was applied to both clinical and simulated ultrasonic images of fibrotic livers. A sequence of matrices was generated for pixel-pair distance, r, and texture feature contrast was chosen to examine the response to r in combination with statistical analysis of echo amplitude distribution using a multi-Rayleigh model. RESULTS: The contrast converged with a larger value and fluctuated more significantly in response to r as fibrosis progressed in both the clinical and simulated ultrasonic images. The convergent value rapidly increased at the early stage of fibrosis, and the fluctuation became larger at the advanced stage of fibrosis. Analysis using simulated ultrasonic images with a known fibrous tissue structure theoretically clarified the relationship between contrast behavior and fibrosis progression. CONCLUSION: It was revealed that contrast convergent value and contrast fluctuation provided information on the fibrous tissue structure, and they are expected to be used for quantitative diagnosis of the degree of liver fibrosis. PMID- 27757556 TI - Clinical presentation, progression, and treatment outcomes of moyamoya disease in the elderly. AB - BACKGROUND: Moyamoya disease is a vascular disorder characterized by progressive stenosis of the internal carotid artery. The presentation, progression, treatment options, and post-operative clinical outcomes for elderly (60 and older) Moyamoya patients have never been reported. METHODS: A retrospective analysis of all patients who were diagnosed with Moyamoya disease by the senior authors between 1991 and 2016 was performed. Patients who were 60 years or older at the time of surgery or last follow-up were further evaluated. RESULTS: Seventy patients were diagnosed with probable or definite Moyamoya disease during the study period (1991-2016). Eight patients (11.4 %; six females: two males; median age 63; range, 60-71 years) were found to be 60 years or older at the time of surgery or last follow-up and were included in the study. All patients had a modified Rankin scale (mRS) of either one or two (median 1) pre-operatively. Six patients (75 %) underwent surgical treatment on a total on seven hemispheres. Post-surgery, one patient had an improved mRS score, three had no changes, and two had worsening in their mRS scores. Both patients who did not undergo surgical interventions suffered from intra-parenchymal hemorrhages post-diagnosis. CONCLUSIONS: Moyamoya disease is most commonly seen in young and middle-aged patients. Presentation in the elderly (defined as 60 years and older in this study) is rare, and has never been reported in the literature. In this study, both direct and indirect revascularization procedures demonstrated potential benefit in some of these patients, with stabilization of progressive symptoms. PMID- 27757558 TI - Scoring method of a Situational Judgment Test: influence on internal consistency reliability, adverse impact and correlation with personality? AB - Situational Judgment Tests (SJTs) are increasingly used for medical school selection. Scoring an SJT is more complicated than scoring a knowledge test, because there are no objectively correct answers. The scoring method of an SJT may influence the construct and concurrent validity and the adverse impact with respect to non-traditional students. Previous research has compared only a small number of scoring methods and has not studied the effect of scoring method on internal consistency reliability. This study compared 28 different scoring methods for a rating SJT on internal consistency reliability, adverse impact and correlation with personality. The scoring methods varied on four aspects: the way of controlling for systematic error, and the type of reference group, distance and central tendency statistic. All scoring methods were applied to a previously validated integrity-based SJT, administered to 931 medical school applicants. Internal consistency reliability varied between .33 and .73, which is likely explained by the dependence of coefficient alpha on the total score variance. All scoring methods led to significantly higher scores for the ethnic majority than for the non-Western minorities, with effect sizes ranging from 0.48 to 0.66. Eighteen scoring methods showed a significant small positive correlation with agreeableness. Four scoring methods showed a significant small positive correlation with conscientiousness. The way of controlling for systematic error was the most influential scoring method aspect. These results suggest that the increased use of SJTs for selection into medical school must be accompanied by a thorough examination of the scoring method to be used. PMID- 27757559 TI - 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. AB - The natural history of a patient's cancer is often characterised by genetic diversity and sequential sweeps of clonal dominance. It is therefore not surprising that identifying the most appropriate tumour-associated antigen for targeted intervention is challenging. The 5T4 oncofoetal antigen was identified by searching for surface molecules shared between human trophoblast and cancer cells with the rationale that they may function to allow survival of the foetus as a semi-allograft in the mother or a tumour in its host. The 5T4 protein is expressed by many different cancers but rarely in normal adult tissues. 5T4 molecules are 72 kD, heavily N-glycosylated proteins with several leucine-rich repeats which are often associated with protein-protein interactions. 5T4 expression is associated with the directional movement of cells through epithelial mesenchymal transition, potentiation of CXCL12/CXCR4 chemotaxis and inhibition of canonical Wnt/beta-catenin while favouring non-canonical pathway signalling; all processes which help drive the spread of cancer cells. The selective pattern of 5T4 tumour expression, association with a tumour-initiating phenotype plus a mechanistic involvement with cancer spread have underwritten the clinical development of different immunotherapeutic strategies including a vaccine, a tumour-targeted superantigen and an antibody drug conjugate. In addition, a chimeric antigen receptor T cell approach targeting 5T4 expressing tumour cells is in pre-clinical development. A key challenge will include how best to combine each 5T4 targeted immunotherapy with the most appropriate standard of care treatment (or adjunct therapy) to maximise the recovery of immune control and ultimately eliminate the tumour. PMID- 27757560 TI - Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma. AB - Recombinant interleukin-2 (rIL-2) is associated with objective responses in 15-20 % of patients with metastatic melanoma and renal cell carcinoma. More recently, rIL-2 has also demonstrated improved clinical activity in patients with melanoma. Given the toxicity of high-dose rIL-2 and the availability of many new immunotherapy agents, it has been suggested that lower doses of rIL-2 may be preferred for combination clinical studies. In order to determine the impact of low doses of rIL-2 on anti-tumor immunity and therapeutic effectiveness, we challenged C57BL/6 mice with poorly immunogenic B16-F10 melanoma and treated them with varying doses of rIL-2 (range 103-105 IU). Tumor growth at day 14 was significantly reduced when rIL-2 was administered at 10,000 (P < 0.02) and 100,000 (P < 0.02) IU doses, but tumor growth was significantly increased when mice were treated at 1000 IU rIL-2 (P < 0.02), as compared to placebo treatment. While the proportions of CD8+ and CD4+ T cells in the tumor were similar at all doses tested, the proportion of NK cells was decreased and the proportion of Tregs was increased in tumors exposed to low-dose rIL-2. The ratio of gp100 specific CD8+ to CD4+ regulatory T cells was increased in tumors treated at 10,000 and 100,000 IU of rIL-2 but was decreased at the 1000 IU dose compared to placebo-treated mice. These findings suggest that low-dose rIL-2 may impair host anti-tumor immunity and promote tumor growth. Early-phase adjuvant and combination clinical studies should include patient cohorts with higher doses of rIL-2. PMID- 27757562 TI - A case series of REM sleep behavior disorder in pure autonomic failure. AB - PURPOSE: Data on the prevalence of RBD in patients with PAF are limited, with discrepancies in the literature regarding prevalence. We aimed to provide further data on this association with a series of eight patients with PAF. METHODS: We reviewed the electronic medical records of all patients seen at the Stanford neurology clinics from 2012 to 2016 who were given a provisional diagnosis of PAF (343 patients), and further screened by procedure codes to identify those patients who underwent both attended video-polysomonography and autonomic testing (18 patients), and met strict exclusionary criteria (8 patients). RESULTS: The mean age of our patients was 69 years, and 63 % were women. The mean duration of autonomic symptoms was 11.2 years, and the mean duration of dream enactment was 3.75 years. All patients demonstrated evidence of adrenergic failure on autonomic testing. Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG. CONCLUSIONS: Our series supports the concept that RBD in PAF may be more common than previously reported, and that the presence of RBD suggests brainstem involvement in some cases of PAF. In addition, the timing of RBD symptoms relative to the emergence of autonomic symptoms may be useful to help distinguish these conditions. PMID- 27757561 TI - Effective induction of cytotoxic T cells recognizing an epitope peptide derived from hypoxia-inducible protein 2 (HIG2) in patients with metastatic renal cell carcinoma. AB - PURPOSE: Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. MATERIALS AND METHODS: Nine patients having HLA-A*0201 or HLA A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study. The patients received subcutaneous administration of the peptide as an emulsion form with Montanide ISA-51 VG once a week in a dose-escalation manner (doses of 0.5, 1.0, or 3.0 mg/body, 3 patients for each dose). The primary endpoint was safety, and the secondary endpoints were immunological and clinical responses. RESULTS: Vaccinations with HIG2-9-4 peptide could be well tolerated without any serious systemic adverse events. Peptide-specific cytotoxic T lymphocyte (CTL) responses were detected in eight of the nine patients. Doses of 1.0 or 3.0 mg/body seemed to induce a CTL response better than did a dose of 0.5 mg/body, although the number of patients was too small to draw a firm conclusion. The disease control rate (stable disease for >=4 months) was 77.8 %, and the median progression-free survival time was 10.3 months. CONCLUSIONS: HIG2-9-4 peptide vaccine treatment was tolerable and effectively induced peptide-specific CTLs in RCC patients. This novel peptide vaccine therapy for RCC is promising. PMID- 27757563 TI - Neointimal response to everolimus-eluting bioresorbable scaffolds implanted at bifurcating coronary segments: insights from optical coherence tomography. AB - Heterogeneity of neointimal thickness is observed after drug-eluting stents implantation in bifurcation lesions (BL). We evaluated the vascular response of everolimus-eluting bioresorbable scaffold (BRS) struts deployed at BL using optical coherence tomography (OCT). 50 patients (64 scaffolds) underwent follow up OCT after BRS implantation. Cross-sectional areas of each BL with a side branch more than 1.5 mm were analyzed using OCT every 200 um. All images were divided into three regions according to shear stress: the 1/2 circumference of the vessel opposite to the ostium (OO), the vessel wall adjacent to the ostium (AO) and the side-branch ostium (SO). The %uncovered strut and the averaged neointimal thickness (NIT) were calculated. Overall, there were significant differences in both NIT and %uncovered strut among the three regions (OO, 119.2 +/- 68.5 MUm vs. AO, 94.2 +/- 35.7 MUm vs. SO, 80.5 +/- 41.4 MUm, p = 0.03; OO, 0.4 %vs. AO, 1.4 %vs. SO, 4.8 %, p = 0.02). Scaffolds were divided into two groups: a large-ratio side-branch group (LRSB; n = 32) and a small-ratio side branch group (SRSB; n = 32), based on the median value of the ratio of the diameter of side branch ostium (Ds) to that of the main branch (Dm). In the LRSB alone, there were significant differences in both NIT and %uncovered strut among the three regions (OO, 128.0 +/- 61.1 MUm vs. AO, 97.3 +/- 34.3 MUm vs. SO, 75.9 +/- 39.4 MUm, p < 0.01; OO, 0.3 % vs. AO, 2.3 % vs. SO, 8.7 %, p < 0.01). After BRS implantation in BL, neointimal response was pronounced at the vessel wall opposite to the side branch ostium, especially in those with large side branches. PMID- 27757564 TI - Three-dimensional printing of an aortic model for transcatheter aortic valve implantation: possible clinical applications. PMID- 27757566 TI - Tectal glioma presenting with clinical triad of obesity, amenorrhea and central cord syndrome with radiological pentad of hydrocephalus, empty sella, suprapineal diverticula, Chiari and syrinx. AB - BACKGROUND: Tectal gliomas (TG) are slow-growing tumors and generally present with features of increased intracranial pressure. CASE DESCRIPTION: We describe an unusual case of a young girl who presented with clinical triad of obesity, primary amenorrhea and central cord syndrome. The radiology unveiled a pentad of hydrocephalus, empty sella, suprapineal recess diverticulum, secondary Chiari malformation and cervical syringomyelia, masking a relatively obscure tectal plate glioma. She was subjected to endoscopic third ventriculostomy (ETV). All of her symptoms improved after ETV and the tumor is being followed up. The possible pathogenesis of such a highly atypical clinico-radiological presentation is described. CONCLUSION: This unusual syndromic presentation of tectal glioma without clinical features of increased intracranial pressure is probably due to increased compliance of third ventricular walls, and is relieved with ETV. PMID- 27757565 TI - The impact of lactoferrin with different levels of metal saturation on the intestinal epithelial barrier function and mucosal inflammation. AB - Translocation of bacteria, primarily Gram-negative pathogenic flora, from the intestinal lumen into the circulatory system leads to sepsis. In newborns, and especially very low birth weight infants, sepsis is a major cause of morbidity and mortality. The results of recently conducted clinical trials suggest that lactoferrin, an iron-binding protein that is abundant in mammalian colostrum and milk, may be an effective agent in preventing sepsis in newborns. However, despite numerous basic studies on lactoferrin, very little is known about how metal saturation of this protein affects a host's health. Therefore, the main objective of this study was to elucidate how iron-depleted, iron-saturated, and manganese-saturated forms of lactoferrin regulate intestinal barrier function via interactions with epithelial cells and macrophages. For these studies, a human intestinal epithelial cell line, Caco-2, was used. In this model, none of the tested lactoferrin forms induced higher levels of apoptosis or necrosis. There was also no change in the production of tight junction proteins regardless of lactoferrin metal saturation status. None of the tested forms induced a pro inflammatory response in Caco-2 cells or in macrophages either. However, the various lactoferrin forms did effectively inhibit the pro-inflammatory response in macrophages that were activated with lipopolysaccharide with the most potent effect observed for apolactoferrin. Lactoferrin that was not bound to its cognate receptor was able to bind and neutralize lipopolysaccharide. Lactoferrin was also able to neutralize microbial-derived antigens, thereby potentially reducing their pro-inflammatory effect. Therefore, we hypothesize that lactoferrin supplementation is a relevant strategy for preventing sepsis. PMID- 27757567 TI - Traumatic atlanto-occipital dislocation in children-a case-based update on clinical characteristics, management and outcome. AB - BACKGROUND: Atlanto-occipital dislocation (AOD) is a rare but severe sequela of high energy trauma. Children are at increased risk, due to their immature spine and biomechanical characteristics. LITERATURE REVIEW: The prevailing mechanism of injury is motor vehicle collision as passenger. AOD commonly presents with cardiorespiratory arrest, spinal cord injury or cranial nerve deficits. Concomitant injuries, such as traumatic brain injury, are frequently encountered. Diagnosis is made on CT and MRI imaging. Posterior internal fixation is the recommended treatment. Thirty-four percent of patients die, 41 % survive with deficits and 25 % have a complete neurological recovery. Initial symptoms, GCS score and degree of spinal cord injury appear to be predictors of outcome. ILLUSTRATIVE CASE: We report the case of a 9-year-old boy, who presented in extremis with cardiac arrest after a motor vehicle collision. Upon successful resuscitation, diagnostic imaging showed AOD and a Chiari I malformation. An occiput-C2 posterior instrumented fusion was performed. The patient subsequently received intensive rehabilitation and recovered to independent ambulation, with a persistent, asymptomatic Chiari I malformation. CONCLUSION: This case highlights the potential for positive outcome in paediatric AOD, despite the presence of strong predictors of poor or fatal outcome at presentation. PMID- 27757568 TI - Bone mineral density and vitamin D status in children with epilepsy, cerebral palsy, and cerebral palsy with epilepsy. AB - PURPOSE: We aimed to evaluate the relationship between bone mineral density (BMD) disorders and possible risk factors in patients with epilepsy only (EO), cerebral palsy only (CPO), and cerebral palsy-epilepsy (CP + E). METHODS: A total of 122 patients [EO (n = 54), CPO (n = 30), CP + E (n = 38)] and 30 healthy children were evaluated. BMD was only measured in patient groups, not in control subjects. BMD of lumbar vertebrae was determined by dual energy X-ray absorptiometry (DXA). An abnormal BMD was defined as low or low normal BMD. RESULTS: Low BMD rate in EO, CPO, and CP + E group was 3.7, 50, and 39.5 %, respectively. Abnormal BMD values were significantly related to inadequate dietary Ca intake (p = 0.017), severe intellectual disability (p < 0.001), and immobility (p = 0.018). In multivariate regression analysis, the risk of abnormal BMD was higher (3.9-fold) in patients not able to walk independently than the others (p = 0.029). However, serum Ca-Vitamin D levels, insufficient exposure to sunlight, low BMI, and use of AED were not correlated with abnormal BMD. CONCLUSION: Abnormal BMD is a common problem in patients with CP and CP + E. Abnormal BMD was related to the severity of CP, but not to vitamin D levels or AED treatment. PMID- 27757569 TI - Multifocal atypical teratoid/rhabdoid tumor: a rare entity. PMID- 27757570 TI - MR imaging of brain pilocytic astrocytoma: beyond the stereotype of benign astrocytoma. AB - BACKGROUND: Pilocytic astrocytoma (PA) is the most common pediatric brain glioma and is considered the prototype of benign circumscribed astrocytoma. Despite its low malignancy, the CT and MRI features of brain PA may resemble those of much more aggressive brain tumors. Misdiagnosis of PA is particularly easy when it demonstrates MR morphological and non-morphological findings that are inconsistent with its non-aggressive nature and that overlap with the features of more aggressive brain tumors. METHOD: Basing on the evidence that the variation in the histological, genetic, and metabolic "fingerprint" for brain PA is dependent on tumor location, and the hypothesis that tumor location is related to the broad spectrum of morphological and non-morphological MR imaging findings, the authors discuss the MR imaging appearance of brain PA using a location-based approach to underline the typical and less typical imaging features and the main differential diagnosis of brain PA. A brief summary of the main pathological and clinical features, the natural history, and the treatment of brain PA is also provided. RESULT: A combination of morphological and non-morphological MR imaging features and a site-based approach to differential diagnosis are required for a pre-operative diagnosis. The new "cutting-edge" MR imaging sequences have the potential to impact the ease and confidence of pediatric brain tumor interpretation and offer a more efficient diagnostic work-up. CONCLUSIONS: Although the typical imaging features of brain pilocytic astrocytoma make radiological diagnosis relatively easy, an atypical and more aggressive appearance can lead to misdiagnosis. Knowing the broad spectrum of imaging characteristics on conventional and advanced MR imaging is important for accurate pre-operative radiological diagnosis and correctly interpreting changes during follow-up. PMID- 27757571 TI - 3-T intraoperative MRI (iMRI) for pediatric epilepsy surgery. AB - PURPOSE: Three-tesla intraoperative MRI (iMRI) is a promising tool that could help confirm complete resections and disconnections in pediatric epilepsy surgery, leading to improved outcomes. However, a large proportion of epileptogenic pathologies in children are poorly defined on imaging, which brings into question the utility of iMRI for these cases. Our aim was to compare postoperative seizure outcomes between iMRI- and non-iMRI-based epilepsy surgeries. METHODS: We performed a comparative retrospective analysis of non-iMRI versus iMRI-based epilepsy surgeries with 2-year follow-up. Patients were stratified into well-defined cases (WDCs), poorly defined cases (PDCs), and diffuse hemispheric cases (DHCs). Primary outcomes were rates of complete seizure freedom and surgical complications. Secondary outcomes included good (Engel class I/II) seizure outcome, extent of resection/disconnection, and operative duration. Regression models were used to adjust for confounding. RESULTS: Thirty-nine iMRI based and 39 non-iMRI-based surgeries were included. The distributions of age, sex, and lesion class in each era were similar, but the distributions of individual pathologies varied. Seizure freedom and complication rates at 2-year follow-up were not different between the groups, but Engel class I/II outcome was more common in the iMRI group. Extent of resection/disconnection and length of surgery were similar in both groups. PDCs had the worst outcomes, which were unchanged by the use of iMRI. CONCLUSION: Three-tesla iMRI-based epilepsy surgery may have the potential to improve patient outcomes. However, we conclude that iMRI, in its current state of use at our institute, does not improve outcomes for children undergoing epilepsy surgery. Given that its use appears safe, further research on this technology is warranted, particularly for the most challenging PDCs. PMID- 27757572 TI - On-road measurements of pollutant concentration profiles inside Yangkou tunnel, Qingdao, China. AB - To obtain physical properties of pollutant concentrations encountered by vehicle commuters during travelling Yangkou tunnel (7.76 km) of Qingdao City, particle concentration measurements are accompanied by the measurements of gaseous species (CO and CO2). The field campaigns are on-road conducted from April 26 to September 23, 2014. Results demonstrate that the mean particle number concentrations observed within the tunnel at the normal traffic volume are 1.15 * 105 and 1.24 * 105 particles cm-3 for the southbound and northbound trip, respectively. Furthermore, the significance level of traffic volume to particle number concentration is analyzed by multivariate regression model. And a high correlation between pollutant concentrations and traffic intensity has been demonstrated. Consequently, the fuel-based emission factors of pollutants inside the tunnel are calculated and the personal exposures are derived. In addition, the profile of particle number concentration exhibits distinct dilution features between the exit of northbound bore and the exit of southbound bore. The explanation is attributed to the different long uphill trip within the tunnel. Results in this study offer meaningful understanding to explore the nature of pollutants within long tunnels. PMID- 27757573 TI - Correlation of lithium levels between drinking water obtained from different sources and scalp hair samples of adult male subjects. AB - There is some evidence that natural levels of lithium (Li) in drinking water may have a protective effect on neurological health. In present study, we evaluate the Li levels in drinking water of different origin and bottled mineral water. To evaluate the association between lithium levels in drinking water with human health, the scalp hair samples of male subjects (25-45 years) consumed drinking water obtained from ground water (GW), municipal treated water (MTW) and bottled mineral water (BMW) from rural and urban areas of Sindh, Pakistan were selected. The water samples were pre-concentrated five to tenfold at 60 degrees C using temperature-controlled electric hot plate. While scalp hair samples were oxidized by acid in a microwave oven, prior to determined by flame atomic absorption spectrometry. The Li content in different types of drinking water, GW, MTW and BMW was found in the range of 5.12-22.6, 4.2-16.7 and 0.0-16.3 ug/L, respectively. It was observed that Li concentration in the scalp hair samples of adult males consuming ground water was found to be higher, ranged as 292-393 MUg/kg, than those who are drinking municipal treated and bottle mineral water (212-268 and 145-208 MUg/kg), respectively. PMID- 27757574 TI - A comparison of carcass decomposition and associated insect succession onto burnt and unburnt pig carcasses. AB - The rate of decomposition and insect succession onto decomposing pig carcasses were investigated following burning of carcasses. Ten pig carcasses (40-45 kg) were exposed to insect activity during autumn (March-April) in Western Australia. Five replicates were burnt to a degree described by the Crow-Glassman Scale (CGS) level #2, while five carcasses were left unburnt as controls. Burning carcasses greatly accelerated decomposition in contrast to unburnt carcasses. Physical modifications following burning such as skin discolouration, splitting of abdominal tissue and leathery consolidation of skin eliminated evidence of bloat and altered microambient temperatures associated with carcasses throughout decomposition. Insect species identified on carcasses were consistent between treatment groups; however, a statistically significant difference in insect succession onto remains was evident between treatments (PERMANOVA F (1, 224) = 14.23, p < 0.01) during an 8-day period that corresponds with the wet stage of decomposition. Differences were noted in the arrival time of late colonisers (Coleoptera) and the development of colonising insects between treatment groups. Differences in the duration of decomposition stages and insect assemblages indicate that burning has an effect on both rate of decomposition and insect succession. The findings presented here provide baseline data for entomological casework involving burnt remains criminal investigations. PMID- 27757575 TI - New models for age estimation and assessment of their accuracy using developing mandibular third molar teeth in a Thai population. AB - Age estimation using developing third molar teeth is considered an important and accurate technique for both clinical and forensic practices. The aims of this study were to establish population-specific reference data, to develop age prediction models using mandibular third molar development, to test the accuracy of the resulting models, and to find the probability of persons being at the age thresholds of legal relevance in a Thai population. A total of 1867 digital panoramic radiographs of Thai individuals aged between 8 and 23 years was selected to assess dental age. The mandibular third molar development was divided into nine stages. The stages were evaluated and each stage was transformed into a development score. Quadratic regression was employed to develop age prediction models. Our results show that males reached mandibular third molar root formation stages earlier than females. The models revealed a high correlation coefficient for both left and right mandibular third molar teeth in both sexes (R = 0.945 and 0.944 in males, R = 0.922 and 0.923 in females, respectively). Furthermore, the accuracy of the resulting models was tested in randomly selected 374 cases and showed low error values between the predicted dental age and the chronological age for both left and right mandibular third molar teeth in both sexes (-0.13 and -0.17 years in males, 0.01 and 0.03 years in females, respectively). In Thai samples, when the mandibular third molar teeth reached stage H, the probability of the person being over 18 years was 100 % in both sexes. PMID- 27757576 TI - Immunohistochemical detection of intrathrombotic fibrocytes and its application to thrombus age estimation in murine deep vein thrombosis model. AB - Deep vein thrombi are dissolved after fibrosis process along with an increase of thrombus age. Fibrocytes are circulating bone marrow-derived cells with mesenchymal features that potentially have a unique and critical function in fibrosis. In this study, a double-color immunofluorescence analysis was carried out by using anti-CD45 and anti-collagen type I antibodies to examine the time dependent appearance of fibrocytes in the murine model of stasis-induced deep vein thrombosis. The thrombus ages were 1, 3, 5, 7, 10, 14, and 21 days. In a thrombus age of less than 5 days, CD45+ and collagen type I+ fibrocytes were never detected. The intrathrombotic fibrocytes were initially observed in thrombi aged 7 days, and their number increased with advances in thrombus age. In a quantitative morphometrical analysis, the average number of intrathrombotic fibrocytes was highest in 14-day-old thrombi, and all of the five samples aged 14 days had the fibrocyte number of more than 25, and in three out of them, the number of intrathrombotic fibrocytes was over 30. On the contrary, in all of thrombus samples with the postligation intervals of 10 and 21 days, the number of intrathrombotic fibrocytes was less than 25. These observations imply that thrombi containing fibrocytes are at least 7 days old and that a fibrocyte number exceeding 30 would indicate the thrombus age of approximately 14 days. Our observations indicate that the detection of fibrocytes could be useful for thrombus age determination. PMID- 27757577 TI - Automated determination of bone age from hand X-rays at the end of puberty and its applicability for age estimation. AB - The BoneXpert method for automated determination of bone age from hand X-rays was introduced in 2009, covering the Greulich-Pyle bone age ranges up to 17 years for boys and 15 years for girls. This paper presents an extension of the method up to bone age 19 years for boys and 18 years for girls. The extension was developed based on images from the First Zurich Longitudinal Study of 231 healthy children born in 1954-1956 and followed with annual X-rays of both hands until adulthood. The method was validated on two cross-sectional studies of healthy children from Rotterdam and Los Angeles. We found root mean square deviations from manual rating of 0.69 and 0.45 years in these two studies for boys in the bone age range 17-19 years. For girls, the deviations were 0.75 and 0.59 years, respectively, in the bone age range 15-18 years. It is shown how the automated bone age method can be applied to infer the age probability distribution for healthy Caucasian European males. Considering a population with age 15.0-21.0 years, the method can be used to decide whether the subject is above 18 years with a false positive rate (children classified as adults) of 10 % (95% confidence interval = 7-13%) and a false negative rate of 30 % (adults classified as children). To apply this method in other ethnicities will require a study of the average of "bone age - age" at the end of puberty, i.e. how much this population is shifted relative to the Greulich-Pyle standard. PMID- 27757578 TI - Paternity calculations in a di-spermy case. AB - In a criminal paternity case, which involved analysis of the product of conception, a rare circumstance was observed. The product of conception was triploidy, apparently due to an egg fertilized by two sperm. Since there is little guidance on how to calculate the probability of the DNA evidence given some basic hypotheses, the formulae were derived and are presented herein. These approaches could provide guidance for similar situations if they arise. PMID- 27757579 TI - Age-related changes in the craniofacial region in a modern Greek population sample of known age and sex. AB - The aim of this paper is to investigate ageing changes in craniofacial region in both sexes and evaluate whether these shape changes are substantial to achieve age discrimination of samples used in anthropological analyses. The study sample consisted of 157 crania of known sex and age (81 males and 76 females) belonging to individuals who lived in Greece during the twentieth century. The sample was divided in three age groups: young adults (YA, 18-39 years old), middle adults (MA, 40-59 years old) and old adults (OA, >60 years old). The three-dimensional coordinates of 31 ecto-cranial landmarks were digitized using a Microscribe 3DX contact digitizer, and landmark configurations were analyzed using the generalized least-squares Procrustes method. The results indicate that both males and females show significant difference among the age groups; however, shape differences can not be used for age group discrimination due to a large range on the accuracy of age group classification. The morphometric changes related to age were different between sexes. PMID- 27757580 TI - Secular change of sexually dimorphic cranial variables in Euro-Americans and Germans. AB - Crania are a reliable source for sex estimation in Euro-Americans, Europeans, and most other populations. Besides morphological assessments, the application of Fordisc(r) has become a useful tool within the last two decades, creating discriminant functions from morphometric data. Unfortunately, until now, white populations are mostly represented by measurements of American individuals. Therefore, classification rates are lower for European skulls than for Euro Americans. The aim of this study was to show differences in sexual dimorphism between German and Euro-American crania. Furthermore, their secular change from the nineteenth to the twentieth century has been investigated. Analyses have been performed on glabella subtense (GLS), mastoid height (MDH), and bizygomatic breadth (ZYB). Fordisc(r) 3.1 was used to study sexual dimorphism and secular change, whereas SAS(r) was used to perform a two-level ANOVA to test for variation in sex dimorphism. Euro-Americans show greater dimorphism than Germans in all three measurements tested. This larger difference is even increasing from the late nineteenth through the late twentieth century in terms of GLS and MDH, while it stays almost the same in the present Europeans. These results explain the unsatisfying classification rates of German and other European crania on Fordisc(r). Data collection for European Fordisc(r) samples is in progress and should improve the current situation. PMID- 27757581 TI - Secretagogue-dependent and -independent transport of zinc hydration forms in rat parietal cells. AB - Prolonged exposure to gastric acid is a leading cause of gastroesophageal reflux disease (GERD) and esophagitis. With the ever increasing number of patients showing insensitivity to proton-pump-inhibitor (PPI) therapy with recurrence of symptoms over time, alternative treatment options remain an important issue. Previous studies from our laboratory have shown that a zinc sulfate salt can inhibit HCl generation at the cellular level of the parietal cell. In this paper, we examine the difference between two hydration forms of ZnSO4 (monohydrate H2O and heptahydrate 7H2O) in their entry characteristics into the parietal cell under several physiological conditions associated with acid secretion. Using the Zn sensitive fluorochrome Newport Green, we examined the rate of Zn entry in Deltafluorescent units/second (DeltaFU/second), at two different concentrations for both hydration states on both fasted and non-fasted animals. In a separate series of studies, we examined the effects of secretagogues on the entry rates and transport mechanisms. Exposure of the secretagogue carbachol transformed the resting parietal cell to an activated state and represents a stimulated condition through the neuronal pathway. The hormonal activation of the parietal cell was achieved by using histamine. Non-fasted conditions were considered to be a state between hormonal and neuronal activation. To demonstrate that ZnSO4 enters the parietal cell through the NKCC1 co-transporter, the inhibitor bumetanide was applied during secretagogue-stimulated acid secretion. Both salts, monohydrate and heptahydrate ZnSO4, show a concentration-dependent cell entry under all conditions studied. During stimulated acid secretion, induced through either the neuronal or the hormonal pathway, heptahydrate ZnSO4 enters the parietal cell significantly faster than monohydrate ZnSO4, whereas monohydrate ZnSO4 exhibits faster entry during resting conditions in fasted animals. At 30 MUM following stimulation with histamine, heptahydrate ZnSO4 enters the cell faster than monohydrate ZnSO4 (DeltaFU/second 30 MUM ZnSO4*7H2O + histamine = 1.782, DeltaFU/second 30 MUM ZnSO4*H2O+histamine = 1.038, respectively). Three hundred micromolar, heptahydrate ZnSO4 shows a faster entry into the cells (DeltaFU/second ZnSO4*7H2O300MUM + carbachol = 4.02407) compared to monohydrate ZnSO4 (DeltaFU/second ZnSO4*H2O300MUM + carbachol = 3.225) following exposure to carbachol. The mechanism of entry of both salts was found to be predominantly via the basolateral NKCC1 transporter with the rate of zinc entry decreasing to minimal values (DeltaFU/second = 0.275) after application of bumetanide during stimulated conditions. PMID- 27757583 TI - Ciclopirox enhances pancreatic islet health by modulating the unfolded protein response in diabetes. AB - Pancreatic dysfunction during diabetes is linked to the induction of endoplasmic reticulum (ER) stress on pancreatic beta (beta) cells. Our laboratory recently discovered that p21 protects from diabetes by modifying the outcome of ER stress response. In the present study, we explored the antidiabetic activity of ciclopirox (CPX), an iron chelator and recently described activator of p21 expression. The effects of CPX in beta cell survival and function were assessed in cultured islets in vitro as well as in diabetic mice in vivo. The consequences of CPX in high glucose-induced insulin release and reactive oxygen species (ROS) production were also evaluated. Islet survival assays confirmed the significance of p21 in the regulation of glucotoxicity and suggested that CPX counteracts glucotoxicity in a manner that depends on p21. In vivo, administration of CPX in wild-type (WT) diabetic mice restored glucose homeostasis. In WT-cultured islets, CPX suppressed the expression of ER stress markers BiP, GRP94, and CHOP and reduced the levels of ROS during culture at high glucose. This reduction of ER stress may be associated with the ability of CPX to inhibit insulin release. Iron citrate stimulated insulin release, which was inhibited by CPX that functions as an iron chelator. It is conceivable that inhibition of insulin production constrains ER stress in islets promoting their survival and thus protecting from diabetes in vivo. This unfolded protein response (UPR)-antagonizing activity of CPX suggests application for the management not only of diabetes but also of other conditions related to ER stress. PMID- 27757582 TI - Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction. AB - Cardiac arrhythmias are associated with raised intracellular [Ca2+] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca2+-dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca2+-dependent phosphatase, calcineurin. Intracellular [Ca2+] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2.Raised [Ca2+]i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca2+]i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca2+-independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca2+]i. PP2A had no role. Conduction velocity was reduced by raised [Ca2+]i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca2+] are regulated by calcineurin-dependent Cx43 S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1. PMID- 27757585 TI - Vomiting in an infant with congenital nephrotic syndrome: Questions. AB - BACKGROUND: Most patients with congenital nephrotic syndrome (CNS) exhibit a failure to thrive. A previous study reported that five of 41 (12 %) infants with CNS had hypertrophic pyloric stenosis (HPS) requiring surgery. The reason for this is undetermined, and there are few reports regarding the relationship between these conditions or their clinical course. CASE DIAGNOSIS/TREATMENT: We present the case of a 4-month-old girl with CNS. She did not show typical manifestations of HPS, but thickened mucosal and submucosal layers and hypertrophy of the pyloric muscle were detected by repeated ultrasound examinations prior to the diagnosis of HPS. Pyloroplasty was performed to improve her poor weight gain and led to ideal growth. CONCLUSIONS: Our case indicates that obstruction of the gastric outlet may be strongly associated with poor weight gain in patients with CNS. We should suspect involvement with HPS even if typical symptoms are lacking, and an aggressive intervention may improve poor growth. Thickened edematous mucosal and submucosal layers at the pyloric antrum have the potential to cause the high frequency of HPS in CNS. PMID- 27757584 TI - Proteinuria in Dent disease: a review of the literature. AB - BACKGROUND: Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review. DESIGN: PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein-creatinine ratio > Albustix) was used for NP classification. RESULTS: Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRLmutation. TPE was not significantly different between both forms (p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP (p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria. CONCLUSION: More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies. PMID- 27757586 TI - Vomiting in infant with congenital nephrotic syndrome: Answers. PMID- 27757587 TI - Poor outcomes for children on the wait list at low-volume kidney transplant centers in the United States. AB - BACKGROUND: Low case volume has been associated with worse survival outcomes in solid organ transplantation. Our aim was to analyze wait-list outcomes in conjunction with posttransplant outcomes. METHODS: We studied a cohort of 11,488 candidates waitlisted in the Organ Procurement and Transplantation Network (OPTN) for pediatric kidney transplant between 2002 and 2014, including both deceased- and living-donor transplants; 8757 (76 %) candidates received a transplant. Candidates were divided into four groups according to the average volume of yearly transplants performed in the listing center over a 12-year period: more than ten, six to nine, three to five, and fewer than three. We used multivariate Cox regression analysis to identify independent risk factors for wait list and posttransplant mortality. RESULTS: Twenty-seven percent of candidates were listed at low-volume centers in which fewer than three transplants were performed annually. These candidates had a limited transplant rate; only 49 % received a transplant versus 88 % in high-volume centers (more than ten transplants annually) (p < 0.001). Being listed at a low-volume center showed a fourfold increased risk for death while on the wait list [hazard ratio (HR) 4.0 in multivariate Cox regression and 6.1 in multivariate competing risk regression]. It was not a significant risk factor for posttransplant death in multivariate Cox regression. CONCLUSIONS: Pediatric transplant candidates are listed at low-volume transplant centers are transplanted less frequently and have a much greater risk of dying while on the wait list. Further studies are needed to elucidate the reasons behind the significant outcome differences. PMID- 27757588 TI - A contemporary approach to the prevention of peritoneal dialysis-related peritonitis in children: the role of improvement science. AB - Peritonitis is a leading cause of hospitalizations, morbidity, and modality change in pediatric chronic peritoneal dialysis (CPD) patients. Despite guidelines published by the International Society for Peritoneal Dialysis aimed at reducing the risk of peritonitis, registry data have revealed significant variability in peritonitis rates among centers caring for children on CPD, which suggests variability in practice. Improvement science methods have been used to reduce a variety of healthcare-associated infections and are also being applied successfully to decrease rates of peritonitis in children. A successful quality improvement program with the goal of decreasing peritonitis will not only include primary drivers directly linked to the outcome of peritonitis, but will also direct attention to secondary drivers that are important for the achievement of primary drivers, such as health literacy and patient and family engagement strategies. In this review, we describe a comprehensive improvement science model for the reduction of peritonitis in pediatric patients on CPD. PMID- 27757589 TI - TRP channels: potential drug target for neuropathic pain. AB - Neuropathic pain is a debilitating disease which affects central as well as peripheral nervous system. Transient receptor potential (TRP) channels are ligand gated ion channels that detect physical and chemical stimuli and promote painful sensations via nociceptor activation. TRP channels have physiological role in the mechanisms controlling several physiological responses like temperature and mechanical sensations, response to painful stimuli, taste, and pheromones. TRP channel family involves six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1) which are expressed in pain sensing neurons and primary afferent nociceptors. They function as transducers for mechanical, chemical, and thermal stimuli into inward currents, an essential first step for provoking pain sensations. TRP ion channels activated by temperature (thermo TRPs) are important molecular players in acute, inflammatory, and chronic pain states. Different degree of heat activates four TRP channels (TRPV1-4), while cold temperature ranging from affable to painful activate two indistinctly related thermo TRP channels (TRPM8 and TRPA1). Targeting primary afferent nociceptive neurons containing TRP channels that play pivotal role in revealing physical stimuli may be an effective target for the development of successful pharmacotherapeutics for clinical pain syndromes. In this review, we highlighted the potential role of various TRP channels in different types of neuropathic pain. We also discussed the pharmacological activity of naturally and synthetically originated TRP channel modulators for pharmacotherapeutics of nociception and neuropathic pain. PMID- 27757590 TI - Niflumic acid, a TRPV1 channel modulator, ameliorates stavudine-induced neuropathic pain. AB - TRP channels have been discovered as a specialized group of somatosensory neurons involved in the detection of noxious stimuli. Desensitization of TRPV1 located on dorsal root and trigeminal ganglia exhibits analgesic effect and makes it potential therapeutic target for treatment of neuropathic pain. With this background, the present study was aimed to investigate the protective effect of niflumic acid, a TRPV1 modulator, on stavudine (STV)-induced neuropathic pain in rats. Stavudine (50 mg/kg) was administered intravenously via tail vein in rats to induce neuropathic pain. Various behavioral tests were performed to access neuropathic pain (hyperalgesia and allodynia) on 7th, 14th, 21st, and 28th days. Electrophysiology (motor nerve conduction velocity; MNCV) and biochemical estimations were conducted after 28th day. Niflumic acid (10, 15, and 20 mg/kg) was administered intraperitoneally and evaluated against behavioral, electrophysiological (MNCV), and biochemical alterations in stavudine-treated rats. Pregabalin (30 mg/kg) was taken as reference standard and administered intraperitoneally. Four weeks after stavudine injection, rats developed behavioral, electrophysiological (MNCV), and biochemical (oxidative, nitrosative stress, and inflammatory cytokines, TRPV1) alterations. Niflumic acid restored core and associated symptoms of peripheral neuropathy by suppressing oxidative nitrosative stress, inflammatory cytokines (TNF-alpha, IL-1beta) and TRPV1 level in stavudine-induced neuropathic pain in rats. Pharmacological efficacy of niflumic acid (20 mg/kg) was equivalent to pregabalin (30 mg/kg). In conclusion, niflumic acid attenuates STV-induced behavioral, electrophysiological and biochemical alterations by manipulating TRP channel activity in two manners: (1) direct antagonistic action against TRPV1 channels and (2) indirect inhibition of TRP channels by blocking oxidative and inflammatory surge. Therefore, NA can be developed as a potential pharmacotherapeutic adjunct for antiretroviral drug induced neuropathy. PMID- 27757591 TI - Acute effects of caffeine-containing energy drinks on physical performance: a systematic review and meta-analysis. AB - PURPOSE: Caffeine-containing energy drinks (EDs) are currently used as ergogenic aids to improve physical performance in a wide variety of sport disciplines. However, the outcomes of previous investigations on this topic are inconclusive due to methodological differences, especially, in the dosage of the active ingredients and the test used to assess performance. METHODS: We performed a systematic review and meta-analysis of published studies to evaluate the effects of acute ED intake on physical performance. The search for references was conducted in the databases PubMed, ISI Web of Knowledge and SPORTDiscus until December 2015. RESULTS: Thirty-four studies published between 1998 and 2015 were included in the analysis. Using a random-effects model, effect sizes (ES) were calculated as the standardized mean difference. Overall, ED ingestion improved physical performance in muscle strength and endurance (ES = 0.49; p < 0.001), endurance exercise tests (ES = 0.53; p < 0.001), jumping (ES = 0.29; p = 0.01) and sport-specific actions (ES = 0.51; p < 0.001), but not in sprinting (ES = 0.14; p = 0.06). The meta-regression demonstrated a significant association between taurine dosage (mg) and performance (slope = 0.0001; p = 0.04), but not between caffeine dosage (mg) and performance (slope = 0.0009; p = 0.21). CONCLUSION: ED ingestion improved performance in muscle strength and endurance, endurance exercise tests, jumping and sport-specific actions. However, the improvement in performance was associated with taurine dosage. PMID- 27757592 TI - Improvement in glucose tolerance and insulin sensitivity by probiotic strains of Indian gut origin in high-fat diet-fed C57BL/6J mice. AB - PURPOSE: Diabetes and obesity are characterized by glucose intolerance, fat deposition, inflammation, and dyslipidemia. Recent reports postulated that distinct gut microbiota alterations were observed in obese/diabetic subjects and modulating gut microbiota beneficially through specific probiotics could be a potential therapeutic option for type 2 diabetes/obesity. Therefore, we attempted to study the efficacy of probiotics of Indian gut origin (Lactobacillus plantarum MTCC5690 and Lactobacillus fermentum MTCC5689) along with a positive control, Lactobacillus rhamnosus (LGG) on glucose/lipid homeostasis in high-fat-diet induced diabetic animal model. METHODS: C57BL/6J male mice were divided into seven groups (n = 6 per group) comprising feeding on: (1) Normal Pellet Diet (NPD), (2) High-Fat Diet (HFD), (3) HFD with LGG, (4) HFD with MTCC5690, (5) HFD with MTCC5689, (6) HFD with metformin, and 7) HFD with vildagliptin for a period of 6 months. Biochemical markers, glucose tolerance, insulin resistance, and GLP 1 and LPS levels were assessed by standard protocols. Gut integrity was measured by intestinal permeability test. Transcriptional levels of tight junction proteins (TJPs) were probed in small intestinal tissues while inflammatory signals and other pathway specific genes were profiled in liver, visceral adipose tissue, and skeletal muscle. RESULTS: Mice fed with HFD became insulin resistant, glucose intolerant, hyperglycemic, and dyslipidemic. Diabetic mice were characterized to exhibit decreased levels of GLP-1, increased gut permeability, increased circulatory levels of LPS, decrease in the gene expression patterns of intestinal tight junction markers (occludin and ZO-1), and increased proinflammatory gene markers (TNFalpha and IL6) in visceral fat along with decreased mRNA expression of FIAF and adiponectin. Diabetic mice also exhibited increased mRNA expression of ER stress markers in skeletal muscle. In addition, liver from HFD-fed diabetic mice showed increased gene expressions of proinflammation, lipogenesis, and gluconeogenesis. Probiotic interventions (most prominently the MTCC5689) resisted insulin resistance and development of diabetes in mice under HFD feeding and beneficially modulated all the biochemical and molecular alterations in a mechanistic way in several tissues. The metabolic benefits offered by the probiotics were also more or less similar to that of standard drugs such as metformin and vildagliptin. CONCLUSION: Native probiotic strains MTCC 5690 and MTCC 5689 appear to have potential against insulin resistance and type 2 diabetes with mechanistic, multiple tissue-specific mode of actions. PMID- 27757593 TI - Differences in food intake and genetic variability in taste receptors between Czech pregnant women with and without gestational diabetes mellitus. AB - PURPOSE: Gestational diabetes mellitus (GDM) represents the most frequent metabolic disorder in pregnancy. Since dietary intake plays an important role in obesity and type 2 diabetes development, it is likely to be for the susceptibility to GDM too. Food preferences, driving partly the diet composition, are changing during pregnancy. Taste and genetic variability in taste receptors is an important factor in determining food preferences. Aims of our study were (1) to characterize dietary habits of pregnant women and to find possible differences in food preferences between healthy pregnant women and those with GDM and (2) to ascertain possible association of several single nucleotide polymorphisms (SNPs) in taste receptor (TR) genes with GDM. METHODS: A total of 363 pregnant women (293 with GDM and 70 with physiologic pregnancy) were included in the study. Dietary pattern spanning the period of approx. 6 months preceding the time of GDM screening was assessed using a semi-quantitative food frequency questionnaire. A total of five SNPs in TR genes were selected for genotyping based on their functionality or previous associations. RESULTS: Women with GDM exhibited significantly more frequent meat consumption (esp. poultry, pork and smoked meat), dairy products and sweet beverages consumption. The legumes consumption was found to be inversely correlated with fasting glycaemia (P = 0.007, Spearman). CC genotype in TAS2R9 gene (SNP rs3741845) was significantly associated with GDM (P = 0.0087, Chi-square test). CONCLUSIONS: Our study showed differences in dietary intake of selected food items between healthy pregnant women and those with GDM and genetic association of bitter taste receptor allele with GDM. PMID- 27757594 TI - Iron bioavailability from supplemented formula milk: effect of lactoferrin addition. AB - PURPOSE: In this work, the absorption and/or bioavailability of iron from two chemical species, 57Fe-Lf (apo-lactoferrin) complex and 57FeSO4 at low and high dose, and in Lf excess were investigated in lactating wistar rats. METHODS: The methodology used is based on the use of stable isotopes in combination with the approach "isotope pattern deconvolution" and ICP-MS for detection. This approach provides quantitative information about exogenous (57Fe) and endogenous iron (natFe) distribution in fluids and tissues in the iron-supplemented rat groups. RESULTS: The observed results with supplemented rats were compared with those found in rats receiving maternal feeding. Interestingly, differences were found between groups in iron for transport and storage compartments, but not in the functional one, depending upon the dose of iron administered and the chemical species. CONCLUSION: Considering the results obtained, supplementation with iron salts in excess of Lf appears to be the best way of iron supplementation of formula milk. PMID- 27757596 TI - Outcome Evaluation of a Policy-Mandated Lifestyle and Environmental Modification Program in a National Job Training Center. AB - Excess weight gain is common when adolescents become young adults, but there are no obesity prevention or weight management interventions that have been tested for emerging adults who follow non-traditional post-secondary paths, such as enrolling in job training programs. We evaluated Healthy Eating & Active Lifestyles (HEALs), a policy-mandated lifestyle education/environmental modification program, at a job training center for low-income 16-24 year olds. We examined average change in body mass index (BMI) z-score from baseline to 6 months for emerging adults (aged 16-24 years) in pre-HEALs implementation (n = 125) and post-HEALs implementation (n = 126) cohorts living at the job training center, by baseline weight status. In both cohorts, average BMI z-score significantly increased from baseline to 6 months for students with BMI < 25. Average BMI z-score significantly decreased for the overweight (BMI 25 to <30; 0.11, p = .03) and obese (BMI >= 30; -0.11, p = .001) students only within the post-HEALs cohort; changes within the pre-HEALs cohort and between cohorts were not significant. HEALs may promote positive weight-related trends for overweight/obese students, but prevention efforts for non-overweight/obese students need to be improved. PMID- 27757595 TI - Effect of soy on metabolic syndrome and cardiovascular risk factors: a randomized controlled trial. AB - BACKGROUND: Cardiovascular diseases are currently the commonest cause of death worldwide. Different strategies for their primary prevention have been planned, taking into account the main known risk factors, which include an atherogenic lipid profile and visceral fat excess. METHODS: The study was designed as a randomized, parallel, single-center study with a nutritional intervention duration of 12 weeks. Whole soy foods corresponding to 30 g/day soy protein were given in substitution of animal foods containing the same protein amount. RESULTS: Soy nutritional intervention resulted in a reduction in the number of MetS features in 13/26 subjects. Moreover, in the soy group we observed a significant improvement of median percentage changes for body weight (-1.5 %) and BMI (-1.5 %), as well as for atherogenic lipid markers, namely TC (-4.85 %), LDL C (-5.25 %), non-HDL-C (-7.14 %) and apoB (-14.8 %). Since the majority of the studied variables were strongly correlated, three factors were identified which explained the majority (52 %) of the total variance in the whole data set. Among them, factor 1, which loaded lipid and adipose variables, explained the 22 % of total variance, showing a statistically significant difference between treatment arms (p = 0.002). CONCLUSIONS: The inclusion of whole soy foods (corresponding to 30 g/day protein) in a lipid-lowering diet significantly improved a relevant set of biomarkers associated with cardiovascular risk. PMID- 27757610 TI - Green stink bug Nezara viridula detects differences in amplitude between courtship song vibrations at stem and petiolus. AB - Green stink bug Nezara viridula courtship songs are transmitted through plants as substrate vibrations. The amplitude of the vibrations is different at different distances from the source of vibration and at different locations on the plant. Amplitudes of the local vibration were measured on stem and petioli of the bean plant (Phaseolus vulgaris) with a Laser-Doppler vibrometer. Differences of the amplitudes of vibration between adjacent points around the nodes were large enough to release differential nerve activities of vibration receptor cells of different legs. There was no correlation between the signal amplitude and the distance from the singing bug, however; the differences in amplitudes of vibrations between the stem and the adjacent petioli of leaves potentially permitted direction finding in the green stink bug males. PMID- 27757597 TI - Understanding Women's Awareness and Access to Preconception Health Care in a Rural Population: A Cross Sectional Study. AB - Despite evidence of the benefits of preconception health care (PCHC), little is known about awareness and access to PCHC for rural, reproductive-aged women. This study aimed to assess the prevalence of PCHC conversations between rural reproductive-age women and health care providers, PCHC interventions received in the past year, and ascertain predictors of PCHC conversations and interventions. Women (n = 868; 18-45 years) completed a questionnaire including reproductive history, health care services utilization, and interest in PCHC. The prevalence of health care providers' PCHC conversations was 53.9 %, and the mean number of interventions reported was 2.6 +/- 2.7 (+/-SD). Significant predictors of PCHC conversation based on adjusted odds ratios from logistic regression were race (Native American 76 % greater than White), health care provider type (non physician 63 % greater than physician), visits to a health care provider (3+ times 32 % greater than 1-2 times), and pregnancy planning (considering in next 1 5 years 51 % greater than no plans). Significant predictors of PCHC interventions received in the past 12 months based on adjusted risk ratios from negative binomial regression were race (Native American 22 % greater than White), PCHC conversation with a health care provider (yes 52 % lower than no), reporting PCHC as beneficial (yes 32 % greater than don't know), and visits to a health care provider in the past year (3+ times 90 % greater than 1-2 times). Increasing conversations about PCHC between health care providers and their reproductive aged patients can improve awareness and increase their likelihood of receiving all of the recommended interventions. PMID- 27757678 TI - Announcements for issue 11, 2016. PMID- 27757679 TI - Answer to the Letter to the Editor of HM Wang et al. concerning "A prospective randomized controlled study comparing the pain relief in patients with osteoporotic vertebral compression fractures with the use of vertebroplasty or facet blocking" by Wang B, Guo H, Yuan L et al. Eur Spine J (2016): doi:10.1007/s00586-016-4425-4. PMID- 27757680 TI - Evaluation of a new approach to compute intervertebral disc height measurements from lateral radiographic views of the spine. AB - PURPOSE: Current standard methods to quantify disc height, namely distortion compensated Roentgen analysis (DCRA), have been mostly utilized in the lumbar and cervical spine and have strict exclusion criteria. Specifically, discs adjacent to a vertebral fracture are excluded from measurement, thus limiting the use of DCRA in studies that include older populations with a high prevalence of vertebral fractures. Thus, we developed and tested a modified DCRA algorithm that does not depend on vertebral shape. METHODS: Participants included 1186 men and women from the Framingham Heart Study Offspring and Third Generation Multidetector CT Study. Lateral CT scout images were used to place 6 morphometry points around each vertebra at 13 vertebral levels in each participant. Disc heights were calculated utilizing these morphometry points using DCRA methodology and our modified version of DCRA, which requires information from fewer morphometry points than the standard DCRA. RESULTS: Modified DCRA and standard DCRA measures of disc height are highly correlated, with concordance correlation coefficients above 0.999. Both measures demonstrate good inter- and intra operator reproducibility. 13.9 % of available disc heights were not evaluable or excluded using the standard DCRA algorithm, while only 3.3 % of disc heights were not evaluable using our modified DCRA algorithm. CONCLUSIONS: Using our modified DCRA algorithm, it is not necessary to exclude vertebrae with fracture or other deformity from disc height measurements as in the standard DCRA. Modified DCRA also yields identical measurements to the standard DCRA. Thus, the use of modified DCRA for quantitative assessment of disc height will lead to less missing data without any loss of accuracy, making it a preferred alternative to the current standard methodology. PMID- 27757681 TI - A unique procedure of joined transoral and retropharyngeal high cervical approach (JTRC) without mandibulectomy for treating upper cervical neoplasm involving both C2 and C3. AB - PURPOSE: To investigate a unique procedure of joined transoral and retropharyngeal high cervical approach (JTRC) without mandibulectomy for treating upper cervical neoplasm involving both C2 and C3. METHOD: A 23-year-old male patient had neoplasma involving C2 and C3 that caused pathologic fracture of C2 and bony destruction of C3. The neoplasm excision and cervical spine reconstruction were performed through JTRC approach without splitting up the mandible. In this approach, there were two surgery windows that could be applied in turns by closing or opening the mouth to gain an ideal exposure. By rotating the mandible, we could gain maximized exposure for either surgery windows. In addition, there was an overlay zone between transoral approach and high cervical retropharyngeal approach that could eliminate the blind area behind the mandible. RESULTS: All the procedures were successfully performed; the surgical incisions healed without infection. By operating alternatively between the two surgery windows, we have successfully performed neoplasm excision and cervical spine reconstruction involving both C2 and C3. Pathologic results showed metastatic renal cell cancer to the resected cervical tumor and confirmed the patient's diagnosis of tuberous sclerosis (Bourneville disease). A 3-month postoperative cervical spine radiography and CT scan demonstrated a favorable placement of the bone implant as well as a favorable instrumentation. CONCLUSION: The JTRC approach could provide good surgical exposure for treating disorders involving both upper and lower cervical spine without splitting up the mandible. PMID- 27757683 TI - Letter to the Editor concerning "Surgical treatment of sacral chordoma: survival and prognostic factors" by C. Ruosi et al. (Eur Spine J; 2015; 24(Suppl 7):S912 S917. PMID- 27757682 TI - Percutaneous versus traditional and paraspinal posterior open approaches for treatment of thoracolumbar fractures without neurologic deficit: a meta-analysis. AB - PURPOSE: This study evaluated differences in outcome variables between percutaneous, traditional, and paraspinal posterior open approaches for traumatic thoracolumbar fractures without neurologic deficit. METHODS: A systematic review of PubMed, Cochrane, and Embase was performed. In this meta-analysis, we conducted online searches of PubMed, Cochrane, Embase using the search terms "thoracolumbar fractures", "lumbar fractures", ''percutaneous'', "minimally invasive", ''open", "traditional", "posterior", "conventional", "pedicle screw", "sextant", and "clinical trial". The analysis was performed on individual patient data from all the studies that met the selection criteria. Clinical outcomes were expressed as risk difference for dichotomous outcomes and mean difference for continuous outcomes with 95 % confidence interval. Heterogeneity was assessed using the chi 2 test and I 2 statistics. RESULTS: There were 4 randomized controlled trials and 14 observational articles included in this analysis. Percutaneous approach was associated with better ODI score, less Cobb angle correction, less Cobb angle correction loss, less postoperative VBA correction, and lower infection rate compared with open approach. Percutaneous approach was also associated with shorter operative duration, longer intraoperative fluoroscopy, less postoperative VAS, and postoperative VBH% in comparison with traditional open approach. No significant difference was found in Cobb angle correction, postoperative VBA, VBA correction loss, Postoperative VBH%, VBH correction loss, and pedicle screw misplacement between percutaneous approach and open approach. There was no significant difference in operative duration, intraoperative fluoroscopy, postoperative VAS, and postoperative VBH% between percutaneous approach and paraspianl approach. CONCLUSIONS: The functional and the radiological outcome of percutaneous approach would be better than open approach in the long term. Although trans-muscular spatium approach belonged to open fixation methods, it was strictly defined as less invasive approach, which provided less injury to the paraspinal muscles and better reposition effect. PMID- 27757684 TI - Letter to the Editor concerning "Anterior corpectomy versus posterior laminoplasty for multilevel cervical myelopathy: a systematic review and meta analysis" (by X. Liu et al. (2014) Eur Spine J 23(2):362-72). PMID- 27757685 TI - Characterization of a recombinant Newcastle disease virus expressing the glycoprotein of bovine ephemeral fever virus. AB - Bovine ephemeral fever (BEF) is caused by the arthropod-borne bovine ephemeral fever virus (BEFV), which is a member of the family Rhabdoviridae and the genus Ephemerovirus. BEFV causes an acute febrile infection in cattle and water buffalo. In this study, a recombinant Newcastle disease virus (NDV) expressing the glycoprotein (G) of BEFV (rL-BEFV-G) was constructed, and its biological characteristics in vitro and in vivo, pathogenicity, and immune response in mice and cattle were evaluated. BEFV G enabled NDV to spread from cell to cell. rL BEFV-G remained nonvirulent in poultry and mice compared with vector LaSota virus. rL-BEFV-G triggered a high titer of neutralizing antibodies against BEFV in mice and cattle. These results suggest that rL-BEFV-G might be a suitable candidate vaccine against BEF. PMID- 27757687 TI - 44. Jahrestagung der Osterreichischen Diabetes Gesellschaft. "Chancen und Risiken fur Menschen mit Diabetes". PMID- 27757686 TI - TAX1BP1 downregulation by EBV-miR-BART15-3p enhances chemosensitivity of gastric cancer cells to 5-FU. AB - MicroRNAs (miRNAs) are a class of noncoding RNA molecules approximately 19 to 25 nucleotides in length that downregulate the expression of target genes at the post-transcriptional level by binding to the 3'-untranslated region (3'-UTR). Epstein-Barr virus (EBV) generates at least 44 miRNAs, but the functions of most of these miRNAs have not yet been identified. Previously, we reported BRUCE as a target of miR-BART15-3p, a miRNA produced by EBV, but our data suggested that there might be other apoptosis-associated target genes of miR-BART15-3p. Thus, in this study, we searched for new target genes of miR-BART15-3p using in silico analyses. We found a possible seed match site in the 3'-UTR of Tax1-binding protein 1 (TAX1BP1). The luciferase activity of a reporter vector including the 3'-UTR of TAX1BP1 was decreased by miR-BART15-3p. MiR-BART15-3p downregulated the expression of TAX1BP1 mRNA and protein in AGS cells, while an inhibitor against miR-BART15-3p upregulated the expression of TAX1BP1 mRNA and protein in AGS-EBV cells. Mir-BART15-3p modulated NF-kappaB activity in gastric cancer cell lines. Moreover, miR-BART15-3p strongly promoted chemosensitivity to 5-fluorouracil (5 FU). Our results suggest that miR-BART15-3p targets the anti-apoptotic TAX1BP1 gene in cancer cells, causing increased apoptosis and chemosensitivity to 5-FU. PMID- 27757688 TI - Drought stress memory in the photosynthetic mechanisms of an invasive CAM species, Aptenia cordifolia. AB - Plants are known for their high capacity to acclimatise to fluctuating environmental conditions. A wide range of environmental conditions can lead to suboptimal physiological efficiency. However, recent studies have shown that plants can withstand repeated periods of stress. To find out how they do it, we studied photosynthetic adjustments to repeated water stress in Aptenia cordifolia: a facultative, invasive CAM species. Plants were subjected to three cycles of water deficit, and photosynthetic parameters and chloroplast antioxidants were quantified to gain an understanding of the mechanisms by which they cope with repeated stress periods. Significant modification of the photosystems' antenna and reaction centres was observed in plants subjected to previous water stress cycles, and this led to higher PSII efficiency than in plants challenged with drought for the first time. These findings underline the biological significance of stress memory and show how plants can adjust their photosynthetic apparatus to fluctuating environmental conditions and thus optimise photosynthesis and photoprotection under drought conditions. PMID- 27757691 TI - The Effect of Substituent Position on Excited State Intramolecular Proton Transfer in Benzoxazinone Derivatives: Experiment and DFT Calculation. AB - The preparation and the photophysical behaviour of two benzoxazinone derivatives isomers 2-(1-hydroxynaphthalen-2-yl)-4H-benzo[e][1, 3]oxazin-4-one(1) and 2-(3 hydroxynaphthalen-2-yl)-4H-benzo[e][1, 3]oxazin-4-one(2) designed for displaying were reported. The effect of substituent position and solvent effect on the excited state intramolecular proton transfer (ESIPT) dynamics and the spectroscopic properties were investigated using a combined theoretical (i.e., time-dependent density function theory (DFT)) and experimental (i.e., steady state absorption and emission spectra and time-resolved fluorescence spectra) study. The results showed that compound 1 would facilitate ESIPT process and favored the keto tautomer emission, while compound 2 suppressed the ESIPT process and favored the enol emission. PMID- 27757689 TI - Correlates of Childhood vs. Adolescence Internalizing Symptomatology from Infancy to Young Adulthood. AB - In light of its associations with child and adolescent health and well-being, there remains a need to better understand the etiological underpinnings and developmental course of internalizing symptomatology in children and adolescents. This study leveraged intensive longitudinal data (N = 959; 49.6 % females) to test the hypothesis that internalizing symptoms in childhood may be driven more strongly by family experiences whereas internalizing symptoms in adolescence may derive more uniquely from familial loading for affective disorders (i.e., maternal depression). We evaluated the relative contributions of (a) family experiences (b) maternal depression, and (c) peer influences in testing this hypothesis. The results indicated that family predictors were more strongly correlated with childhood (relative to adolescent) internalizing symptoms. In contrast to previous findings, maternal depression also exhibited stronger associations with childhood internalizing symptoms. Although often overlooked in theories concerning potential differential origins of childhood vs. adolescent internalizing symptomatology, peer experiences explained unique variation in both childhood and adolescent internalizing problems. PMID- 27757692 TI - Novel Thiazole Based Styryl Dyes with Benzimidazole Unit - Synthesis, Photophysical and TD-DFT Studies. AB - Three new Y-shaped styryl dyes were designed and synthesized from thiazole carbaldehyde with different active methylene compounds as acceptor moieties. All the dyes were characterized by IR, 1HNMR, MS/LCMS/HRMS. Spectroscopic properties and non-linear optical properties styryl derivatives were analyzed and the effect of change in solvent polarity on their absorption and emissive properties has been investigated. The dye with (1-phenylethylidene) propanedinitrile unit shows red shift absorption/emission profile among all the dyes. Density Functional Theory and Time Dependent-Density Functional Theory computations have been used for comparative study with the experimental data and also to understand the structural, molecular, electronic and photophysical parameters of the styryl dyes. The computational method was also employed to investigate the nonlinear optical properties of the styryl dyes in different organic solvent. The unsubstituted benzimidazolyl thiazole styryl dyes possess good non-linear optical properties. PMID- 27757693 TI - Hospitalization Rates for Acute Myocardial Infarction Among Asian-American Subgroups: Have We Been Underestimating the Problem? AB - Concerns about the quality of race/ethnicity data collected by hospitals have limited our understanding of healthcare disparities affecting ethnic minorities in the United States. Using data from the New Jersey State Inpatient Databases and the American Community Survey, we calculated age-adjusted AMI hospitalization rates for Asian-American subgroups before (2005-2006) and after (2008-2009) New Jersey hospitals implemented standardized practices to collect more accurate granular race/ethnicity data from patients. Rates were reported per 100,000 persons for Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese subgroups. AMI hospitalization rates increased for all subgroups except Vietnamese following implementation of the New Jersey program; increases were statistically significant for Asian Indian, Chinese, and Korean subgroups. Rates of hospitalization for AMI increased significantly for multiple Asian-American subgroups following implementation of the New Jersey program. National population health metrics for Asian-American subgroups may be prone to significant underestimation without widespread utilization of similar practices. PMID- 27757694 TI - Sensitivity and Specificity in Three Measures of Depression Among Mexican American Women. AB - This paper examined the prevalence of depressive symptomotology among women of Mexican ancestry (N = 205), over the age of 18, of diverse incomes and nativity. We examined differences in rates of diagnosis by Spanish/English preference and the sensitivity and specificity of three common measures: the Patient Health Questionnaire (PHQ9), the Kessler Psychological Distress Scale (K-10), and depression questions from the Composite International Diagnostic Interview, Short Form (MDD CIDI-SF); PHQ9 was used as the "gold standard" measure. Results indicated 18-32 % of participants met criteria for depression with higher rates found among Spanish preference participants. The K-10 had significantly higher sensitivity (0.81) but lower specificity (0.79) than the MDD CIDI-SF items (0.57 and 0.89, respectively). This study suggests that the K-10 and MDD CIDI-SF measures are complementary to each other for screening of depressive symptomatology. Implications for cultural and linguistic assessment of depression are further discussed. PMID- 27757695 TI - Biochemical characterization of a halophilic, alkalithermophilic protease from Alkalibacillus sp. NM-Da2. AB - An extracellular, halophilic, alkalithermophilic serine protease from the halo alkaliphilic Alkalibacillus sp. NM-Da2 was purified to homogeneity by ethanol precipitation and anion-exchange chromatography. The purified protease was a monomeric enzyme with an approximate molecular mass of 35 kDa and exhibited maximal activity at 2.7 M NaCl, pH55 degrees C 9 and 56 degrees C. The protease showed great temperature stability, retaining greater than 80 % of initial activity after 2 h incubation at 55 degrees C. The protease was also extremely pH tolerant, retaining 80 % of initial activity at pH55 degrees C 10.5 after 30 min incubation. Protease hydrolyzed complex substrates, displaying activity on yeast extract, tryptone, casein, gelatin and peptone. Protease activity was inhibited at casein concentrations greater than 1.2 mg/mL. The enzyme was stable and active in 40 % (v/v) solutions of isopropanol, ethanol and benzene and was stable in the presence of the polysorbate surfactant Tween 80. Activity was stimulated with the oxidizing agent hydrogen peroxide. Inhibition with phenyl methylsulfonylfluoride indicates it is a serine protease. Synthetic saline wastewater treated with the protease showed 50 % protein removal after 5 h. Being halophilic, alkaliphilic and thermophilic, in addition to being resistant to organic solvents, this protease has potential for various applications in biotechnological and pharmaceutical industries. PMID- 27757696 TI - Establishment of gene transfer and gene silencing methods in a desiccation tolerant cell line, Pv11. AB - Larvae of the African midge Polypedilum vanderplanki show extreme desiccation tolerance, known as anhydrobiosis. Recently, the cultured cell line Pv11 was derived from this species; Pv11 cells can be preserved in the dry state for over 6 months and retain their proliferation potential. Here, we attempted to expand the use of Pv11 cells as a model to investigate the mechanisms underlying anhydrobiosis in P. vanderplanki. A newly developed vector comprising a constitutive promoter for the PvGapdh gene allowed the expression of exogenous proteins in Pv11 cells. Using this vector, a stable Pv11 cell line expressing green fluorescence protein (GFP) was established and retained desiccation tolerance. Gene silencing with GFP-specific siRNAs significantly suppressed GFP expression to approximately 7.5-34.6% of that in the non-siRNA-transfected GFP stable line. Establishment of these functional assays will enable Pv11 cells to be utilized as an effective tool to investigate the molecular mechanisms underlying anhydrobiosis. PMID- 27757697 TI - Novel stand-alone RAM domain protein-mediated catalytic control of anthranilate phosphoribosyltransferase in tryptophan biosynthesis in Thermus thermophilus. AB - Regulation of amino acid metabolism (RAM) domains are widely distributed among prokaryotes. In most cases, a RAM domain fuses with a DNA-binding domain to act as a transcriptional regulator. The extremely thermophilic bacterium, Thermus thermophilus, only carries a single gene encoding a RAM domain-containing protein on its genome. This protein is a stand-alone RAM domain protein (SraA) lacking a DNA-binding domain. Therefore, we hypothesized that SraA, which senses amino acids through its RAM domain, may interact with other proteins to modify its functions. In the present study, we identified anthranilate phosphoribosyltransferase (AnPRT), the second enzyme in the tryptophan biosynthetic pathway, as a partner protein that interacted with SraA in T. thermophilus. In the presence of tryptophan, SraA was assembled to a decamer and exhibited the ability to form a stable hetero-complex with AnPRT. An enzyme assay revealed that AnPRT was only inhibited by tryptophan in the presence of SraA. This result suggests a novel feedback control mechanism for tryptophan biosynthesis through an inter-RAM domain interaction in bacteria. PMID- 27757698 TI - Contribution of garment fit and style to thermal comfort at the lower body. AB - The heat and mass transfer between the human body and the environment is not only affected by the properties of the fabric, but also by the size of the air gap thickness and the magnitude of the contact area between the body and garment. In this clothing-human-environment system, there is also an interaction between the clothing and the physiological response of the wearer. Therefore, the aim of this study was to evaluate the distribution of the air gap thickness and the contact area for the male lower body in relation to the garment fit and style using a three-dimensional (3D) body scanning method with a manikin. Moreover, their relation with the physiological response of the lower body was analysed using the physiological modelling. The presented study showed that the change in the air gap thickness and the contact area due to garment fit was greater for legs than the pelvis area due to regional differences of the body. Furthermore, the garment style did not have any effect on the core temperature or total water loss of the lower body, whereas the effect of garment fit on the core temperature and total water loss of lower body was observed only for 40 degrees C of ambient temperature. The skin temperatures were higher for especially loose garments at thigh than the tight garments. Consequently, the results of this study indicated that the comfort level of the human body for a given purpose can be adjusted by selection of fabric type and the design of ease allowances in the garment depending on the body region. PMID- 27757699 TI - Changing epidemiology of Helicobacter pylori in Japan. AB - Helicobacter pylori (H. Pylori) is known as the most important cause of gastric cancer. The prevalence of H. pylori infection varies widely by geographic area, age, and socioeconomic status. In Japan, H. pylori infection has been highly correlated with the incidence rate of gastric cancer, and a reduction in H. pylori infection is therefore crucial for decreasing the incidence of gastric cancer, especially at the population level. Infection occurs during childhood, commonly before 5 years of age. In Japan, where gastric cancer has ranked as the most common cancer by incidence and mortality for the last several decades, the prevalence of H. pylori infection has dramatically declined by birth cohort effect, mainly due to improvements in the general hygiene environment in childhood. Older generations born before around 1950 show a high prevalence of around 80-90 %, decreasing with age to reach around 10 % or less in those born around the 1990s, and less than 2 % for children born after the year 2000. This change will have generational effects on gastric cancer prevention strategies, both primary and secondary. The risk-stratified approach to gastric cancer prevention should be considered in Japan and other countries which have similarly experienced rapid economic development. PMID- 27757700 TI - Agonistic character displacement in social cognition of advertisement signals. AB - Interspecific aggression between sibling species may enhance discrimination of competitors when recognition errors are costly, but proximate mechanisms mediating increased discriminative ability are unclear. We studied behavioral and neural mechanisms underlying responses to conspecific and heterospecific vocalizations in Alston's singing mouse (Scotinomys teguina), a species in which males sing to repel rivals. We performed playback experiments using males in allopatry and sympatry with a dominant heterospecific (Scotinomys xerampelinus) and examined song-evoked induction of egr-1 in the auditory system to examine how neural tuning modulates species-specific responses. Heterospecific songs elicited stronger neural responses in sympatry than in allopatry, despite eliciting less singing in sympatry. Our results refute the traditional neuroethological concept of a matched filter and instead suggest expansion of sensory sensitivity to mediate competitor recognition in sympatry. PMID- 27757701 TI - Young patients and those with a low eGFR benefitted more from denosumab therapy in femoral neck bone mineral density. AB - This study investigated the effect of different severities of CKD on femoral neck bone mineral density (BMD) in patients treated with denosumab. This study was a retrospective case review of CKD patients treated with denosumab. Baseline age, sex, and body mass index (BMI) were recorded for all patients. All comorbidities such as diabetes, hypertension, liver, and estimated glomerular filtration rate (eGFR) serum collagen type 1 cross-linked C-telopeptide (CTX) were also recorded. All subjects underwent dual energy X-ray absorptiometry assay of the femoral neck to determine the BMD. Changes in femoral neck BMD between baseline and 1 year after denosumab administration were recorded. A total 108 patients with CKD who had received denosumab therapy were enrolled. The mean age was 71.04 +/- 9.64 years, and 96 patients (88.9 %) were women. Baseline eGFR correlated negatively with changes in the BMD of femoral neck (Rho =40.6, P < 0.01). The lower the eGFR, the more was the improvement in BMD in the femoral neck after denosumab therapy. When changes in femoral neck BMD were assessed as outcome measures using linear regression, young patients (P = 0.001) and those with a low eGFR benefitted more from denosumab therapy (P = 0.029). Denosumab therapy is effective in cases of low eGFR and young age. Aggressive medical attention is needed in these patients. PMID- 27757702 TI - Increasing dissolved-oxygen disrupts iron homeostasis in production cultures of Escherichia coli. AB - The damaging effect of high oxygen concentration on growth of Escherichia coli is well established. Over-oxygenation increases the intracellular concentration of reactive oxygen species (ROS), causing the destruction of the [4Fe-4S] cluster of dehydratases and limiting the biosynthesis of both branched-chain amino acids and nicotinamide adenine dinucleotide. A key enzyme that reduces the damaging effect of superoxide is superoxide dismutase (SOD). Its transcriptional regulation is controlled by global transcription regulators that respond to changes in oxygen and iron concentrations and pH. Production of biological compounds from E. coli is currently achieved using cultures grown to high cell densities which require oxygen-enriched air supply. It is, therefore, important to study the effect of over-oxygenation on E. coli metabolism and the bacterial protecting mechanism. The effect of over-oxygenation on the superoxide dismutase regulation system was evaluated in cultures grown in a bioreactor by increasing the oxygen concentration from 30 to 300 % air saturation. Following the change in the dissolved oxygen (DO), the expression of sodC, the periplasmic CuZn-containing SOD, and sodA, the cytosolic Mn-containing SOD, was higher in all the tested strains, while the expression of the sodB, the cytosolic Fe-containing SOD, was lower. The down-regulation of the sodB was found to be related to the activation of the small RNA RyhB. It was revealed that iron homeostasis, in particular ferric iron, was involved in the RyhB activation and in sodB regulation but not in sodA. Supplementation of amino acids to the culture medium reduced the intracellular ROS accumulation and reduced the activation of both SodA and SodC following the increase in the oxygen concentration. The study provides evidence that at conditions of over-oxygenation, sodA and sodC are strongly regulated by the amount of ROS, in particular superoxide; and sodB is regulated by iron availability through the small RNA RyhB. In addition, information on the impact of NADH, presence of amino acids and type of iron on SOD regulation, and consequently, on the ROS concentration is provided. PMID- 27757703 TI - Staphylococcus epidermidis DeltaSortase A strain elicits protective immunity against Staphylococcus aureus infection. AB - Staphylococcus aureus and Staphylococcus epidermidis are two of the most significant opportunistic human pathogens, causing medical implant and nosocomial infections worldwide. These bacteria contain surface proteins that play crucial roles in multiple biological processes. It has become apparent that they have evolved a number of unique mechanisms by which they can immobilise proteins on their surface. Notably, a conserved cell membrane-anchored enzyme, sortase A (SrtA), can catalyse the covalent attachment of precursor bacterial cell wall attached proteins to peptidoglycan. Considering its indispensable role in anchoring substrates to the cell wall and its effects on virulence, SrtA has attracted great attention. In this study, a 549-bp gene was cloned from a pathogenic S. epidermidis strain, YC-1, which shared high identity with srtA from other Staphylococcus spp. A mutant strain, YC-1DeltasrtA, was then constructed by allelic exchange mutagenesis. The direct survival rate assay suggested that YC 1DeltasrtA had a lower survival capacity in healthy mice blood compare with the wild-type strain, indicating that the deletion of srtA affects the virulence and infectious capacity of S. epidermidis YC-1. YC-1DeltasrtA was then administered via intraperitoneal injection and it provided a relative percent survival value of 72.7 % in mice against S. aureus TC-1 challenge. These findings demonstrate the possbility that YC-1DeltasrtA might be used as a live attenuated vaccine to produce cross-protection against S. aureus. PMID- 27757704 TI - Betulin inhibits cariogenic properties of Streptococcus mutans by targeting vicRK and gtf genes. AB - Streptococcus mutans, a multivirulent pathogen is considered the primary etiological agent in dental caries. Development of antibiotic resistance in the pathogen has created a need for novel antagonistic agents which can control the virulence of the organism and reduce resistance development. The present study demonstrates the in vitro anti-virulence potential of betulin (lup-20(29)-ene 3beta,28-diol), an abundantly available plant triterpenoid against S. mutans UA159. Betulin exhibited significant dose dependent antibiofilm activity without affecting bacterial viability. At 240 ug/ml (biofilm inhibitory concentration), betulin inhibited biofilm formation and adherence to smooth glass surfaces by 93 and 71 % respectively. It reduced water insoluble glucan synthesis by 89 %, in conjunction with down regulation of gtfBC genes. Microscopic analysis confirmed the disruption in biofilm architecture and decreased exopolysaccharide production. Acidogenicity and aciduricity, key virulence factors responsible for carious lesions, were also notably affected. The induced auto-aggregation of cells upon treatment could be due to the down regulation of vicK. Results of gene expression analysis demonstrated significant down-regulation of virulence genes upon betulin treatment. Furthermore, the nontoxic effect of betulin on peripheral blood mononuclear cells even after 72 h treatment makes it a strong candidate for assessing its suitability to be used as a therapeutic agent. PMID- 27757705 TI - Complex Dynamical Behaviour in an Epidemic Model with Control. AB - We analyse the dynamical behaviour of a simple, widely used model that integrates epidemiological dynamics with disease control and economic constraint on the control resources. We consider both the deterministic model and its stochastic counterpart. Despite its simplicity, the model exhibits mathematically rich dynamics, including multiple stable fixed points and stable limit cycles arising from global bifurcations. We show that the existence of the limit cycles in the deterministic model has important consequences in modelling the range of potential effects the control can have. The stochastic effects further interact with the deterministic dynamical structure by facilitating transitions between different attractors of the system. The interaction is important for the predictive power of the model and in using the model to optimize allocation when resources for control are limited. We conclude that when studying models with constrained control, special care should be given to the dynamical behaviour of the system and its interplay with stochastic effects. PMID- 27757706 TI - Quality of life trajectories after diagnosis of gynecologic cancer: a theoretically based approach. AB - PURPOSE: The course of quality of life after diagnosis of gynecologic cancer is not well understood. We aimed to identify subgroups of gynecologic cancer patients with distinct trajectories of quality of life outcomes in the 18-month period after diagnosis. We also aimed to determine whether these subgroups could be distinguished by predictors derived from Social-Cognitive Processing Theory. METHODS: Gynecologic cancer patients randomized to usual care as part of a psychological intervention trial (NCT01951807) reported on depressed mood, quality of life, and physical impairment soon after diagnosis and at five additional assessments ending 18 months after baseline. Clinical, demographic, and psychosocial predictors were assessed at baseline, and additional clinical factors were assessed between 6 and 18 months after baseline. RESULTS: A two group growth mixture model provided the best and most interpretable fit to the data for all three outcomes. One class revealed subclinical and improving scores for mood, quality of life, and physical function across 18 months. A second class represented approximately 12 % of patients with persisting depression, diminished quality of life, and greater physical disability. Membership of this high-risk subgroup was associated with holding back concerns, more intrusive thoughts, and use of pain medications at the baseline assessment (ps < .05). CONCLUSIONS: Trajectories of quality of life outcomes were identified in the 18-month period after diagnosis of gynecologic cancer. Potentially modifiable psychosocial risk factors were identified that can have implications for preventing quality of life disruptions and treating impaired quality of life in future research. PMID- 27757707 TI - Platelet-Activating Factor Quantification Using Reversed Phase Liquid Chromatography and Selected Reaction Monitoring in Negative Ion Mode. AB - Platelet-activating factor (PAF) is a potent biologically active phospholipid that mediates human physiological and pathophysiologic responses. PAF levels increase transiently and are typically assessed by techniques with limitations related to expense, sensitivity, pre-analysis derivatization and interference with isobaric molecules. This study elucidates a facile, accurate liquid chromatography-mass spectrometry analytical method for PAF. In negative ion mode using electrospray ionization, collisionally-activated dissociation analysis showed a unique product ion for acetate adducts of PAF molecular species representing the loss of methyl acetate from the polar head group and loss of a part of the acetate group from the sn-2 position. This product ion was exploited for selected reaction monitoring of PAF molecular species following separation by reversed-phase liquid chromatography. Standard calibration responses were determined, and this method was able to detect as low as 100 fmol of PAF. Finally, PAF molecular species were quantified in human neutrophils and monocytes. PMID- 27757708 TI - Feasibility of photodynamic therapy for secondary hyperparathyroidism in chronic renal failure rats. AB - BACKGROUND: Feasibility of photodynamic therapy (PDT) for secondary hyperparathyroidism (SHPT) was examined in a rat model of SHPT. METHODS: A photosensitizer, 5-aminolevulinic acid (5-ALA), was injected intraperitoneally, and the parathyroid glands were irradiated either after surgical exposure with 385-nm light or transdermally with 630-nm light from a light-emitting diode (LED) lamp. RESULTS: PDT with high 5-ALA and irradiation doses caused severe hypoparathyroidism in SHPT rats within two days. Low-dose invasive PDT reduced intact parathyroid hormone (iPTH) levels in all rats from 748.9 +/- 462.6 pg/mL at baseline to 138.7 +/- 117.5 pg/mL at week 6, followed by a further decrease to 80.5 +/- 54.0 pg/mL at week 9 in 60 % of rats or an increase to 970.0 +/- 215.6 pg/mL at week 9 in 40 % of rats. Low-dose noninvasive PDT reduced iPTH levels from 1612.5 +/- 607.8 pg/mL at baseline to 591.9 +/- 480.1 pg/mL at week 4 in all rats. Thereafter, iPTH levels remained low in 43 % of rats and were 233.7 +/- 51.6 pg/mL at week 9, whereas 57 % showed an increase, reaching 3305.9 +/- 107.3 pg/mL at week 9. Control SHPT rats had iPTH levels of 2487.8 +/- 350.9 and 2974.6 +/- 372.1 pg/mL at week 4 and 9, respectively. The parathyroid glands of the rats with low iPTH levels were atrophied and had few parathyroid cells surrounded by fibrotic materials and no recognizable blood vessels. Those of the rats with high iPTH levels showed well-preserved gland structure, clusters of parathyroid cells, and blood vessels. CONCLUSION: These results demonstrate that 5-ALA-mediated PDT for SHPT is feasible. PMID- 27757709 TI - Idiopathic pre-capillary pulmonary hypertension in patients with end-stage kidney disease: effect of endothelin receptor antagonists. AB - BACKGROUND: We examined the prevalence, prognosis, and effect of endothelin receptor antagonists on survival in end-stage kidney disease patients with idiopathic pre-capillary pulmonary hypertension. METHODS: We investigated 1988 end-stage kidney disease patients in Toujinkai Hospital from January 1, 2001 to December 31, 2014. Pulmonary hypertension was screened by symptoms (dyspnea, hypotension, or near syncope) and echocardiography, and diagnosed by computed tomography with enhancement, pulmonary flow scintigraphy, and right heart catheterization. RESULTS: Fifteen patients (67 +/- 11 years; 12 women and 3 men) were diagnosed as idiopathic pre-capillary pulmonary hypertension; mean pulmonary arterial pressure, pulmonary vascular resistance, or pulmonary artery wedge pressure were 55 +/- 11 mmHg, 7.5 +/- 2.9 Woods units, or 12 +/- 2 mmHg, respectively. Of the 15 patients, 14 received hemodialysis, and 1 was in a pre dialysis stage. Patients were followed through December 31, 2015, and 11 died of heart failure; their mean survival time was 26.4 +/- 21.0 months. Endothelin receptor antagonists were used for 11 patients, and mean survival times were 57.3 +/- 12.1 months in patients with endothelin receptor antagonists and 7.5 +/- 2.1 months in those without. In the Kaplan-Meier analysis, heart failure death-free survival rates were higher in patients with endothelin receptor antagonists than in those without (P < 0.001); 100 versus 25 % at one year and 71 versus 0 % at 3 years. CONCLUSION: The prognosis of idiopathic pre-capillary pulmonary hypertension seems to be poor in end-stage kidney disease patients. Administration of endothelin receptor antagonists might improve the survival by inhibiting heart failure death. Registration of clinical trials This study was registered to the ClinicalTrials.gov ( https://clinicaltrials.gov/ ): protocol identifier, NCT02743091. PMID- 27757710 TI - The role of natural indigo dye in alleviation of genotoxicity of sodium dithionite as a reducing agent. AB - Indigo blue is a natural dye used for thousands of years by civilizations to dye fabric blue and it is naturally obtained from Isatis tinctoria. I. tinctoria is not only used for extraction of indigo blue color but also used medicinally in Traditional Chinese Medicine because of its active compounds. Sodium dithionite (Na2S2O4) is used in dye bath for indigo blue extraction, but this reducing agent and its derivatives are major pollutants of textile industry and subsequently have hazardous influences on public health. Herein, the present study was designed to obtain the high yield of natural indigo dye but with low possible toxic effect. In this context, genotoxic effects of particular combinations of natural dye solutions obtained from Isatis tinctoria subsp. tomentolla with Na2S2O4 as reducing agent were investigated. Dye solutions were obtained using two different pH levels (pH 9 and 11) and three different concentrations of Na2S2O4 (2.5, 5 and 10 mg/ml). In addition to the dye solutions and reducing agent, aqueous extracts of I. tinctoria were assessed for their genotoxicity on human lymphocytes. For in vitro testing of genotoxicity, chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and mitotic indexes (MI) assays were used. Accordingly, Na2S2O4 caused significant increases in CA and SCE as well decrease in MI but the genotoxic effects of sodium dithionite were reduced with natural indigo dye. As a result, aqueous extracts of Isatis leaves removed the toxic effects of sodium dithionite and showed anti-genotoxic effect. For the optimal and desired quality but with less toxic effects of natural dye, 2.5 mg/ml (for wool yarn) and 5 mg/ml (for cotton yarn) of Na2S2O4 doses were found to be the best doses for reduction in the dye bath at Ph 9. PMID- 27757711 TI - Isolation and characterization of putative mesenchymal stem cells from mammalian gut. AB - Here, we provide a protocol for reliable isolation and subculture of putative mesenchymal stem cells from mice colons. This method provides a good approach to cultivate and characterize putative colonic mesenchymal stem cells (cMSCs). A high purity of cMSCs can be obtained according to this protocol. The whole isolation processes of cMSCs take about 2 h with two important digestion steps involved. Only with common culture medium, maturation of cMSCs in culture proceeds approximately 2 weeks to allow relevant researches to be conducted. This protocol sheds light on better cultivation of MSCs in vitro from post-natal colon tissues. These putative cMSCs share common phenotypic property with those in vivo reported, and contain potential lineage differentiation capacity. The successful culture of cMSCs in vitro provides an ideal model for study of MSCs biology in the intestine. PMID- 27757712 TI - RNA interference mediated downregulation of human telomerase reverse transcriptase (hTERT) in LN18 cells. AB - Human telomerase reverse transcriptase (hTERT) gene is a biomarker for the targeted therapy in various cancers. Presence of increased telomerase activity is a common feature of all cancers including glioblastoma. Both RNA and catalytic subunits of hTERT are the target sites for blocking its activity. The current study focuses on the expression of hTERT in glioblastoma and its regulation using two different novel siRNAs (small interfering RNA). Our patient data demonstrated increased expression of hTERT, which could be correlated with carcinogenesis in glioma. In vitro studies in siRNA transfected LN18 cells confirmed significant cell death (p < 0.05) as evidenced by MTT and trypan blue exclusion assay. These results were further supported by flow cytometry data, which showed significant increase in early and late apoptosis. The hTERT mRNA expression was effectively downregulated by 45 and 39 % with siRNA1 and siRNA2, respectively. These results were further confirmed by immunoblotting analysis (p < 0.05). Our results suggest that both the siRNAs effectively down regulated the expression of hTERT at mRNA and protein levels, thereby decreasing cell viability and proliferation rate. Hence siRNA mediated downregulation of hTERT could be a potential therapeutic avenue in glioblastoma. PMID- 27757713 TI - Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells. AB - Engraftment outcomes are strongly correlated with the numbers of hematopoietic stem and progenitor cells (HSPC) infused. Expansion of umbilical cord blood (CB) HSPC has gained much interest lately since infusion of expanded HSPC can accelerate engraftment and improve clinical outcomes. Many novel protocols based on different expansion strategies of HSPC and their downstream derivatives are under development. Herein, we describe the production and properties of serum free medium (SFM) conditioned with mesenchymal stromal cells derived-osteoblasts (OCM) for the expansion of umbilical CB cells and progenitors. After optimization of the conditioning length, we show that OCM increased the production of human CB total nucleated cells and CD34+ cells by 1.8-fold and 1.5-fold over standard SFM, respectively. Production of immature CD34+ subpopulations enriched in hematopoietic stem cells was also improved with a shorter conditioning period. Moreover, we show that the growth modulatory activities of OCM on progenitor expansion are regulated by both soluble factors and non-soluble cellular elements. Finally, the growth and differentiation modulatory activities of OCM were fully retained after high dose-ionizing irradiation and highly stable when OCM is stored frozen. In summary, our results suggest that OCM efficiently mimics some of the natural regulatory activities of osteoblasts on HSPC and highlight the marked expansion potentials of SFM conditioned with osteoblasts. PMID- 27757714 TI - False Dichotomies and Health Policy Research Designs: Randomized Trials Are Not Always the Answer. AB - Some medical scientists argue that only data from randomized controlled trials (RCTs) are trustworthy. They claim data from natural experiments and administrative data sets are always spurious and cannot be used to evaluate health policies and other population-wide phenomena in the real world. While many acknowledge biases caused by poor study designs, in this article we argue that several valid designs using administrative data can produce strong findings, particularly the interrupted time series (ITS) design. Many policy studies neither permit nor require an RCT for cause-and-effect inference. Framing our arguments using Campbell and Stanley's classic research design monograph, we show that several "quasi-experimental" designs, especially interrupted time series (ITS), can estimate valid effects (or non-effects) of health interventions and policies as diverse as public insurance coverage, speed limits, hospital safety programs, drug abuse regulation and withdrawal of drugs from the market. We further note the recent rapid uptake of ITS and argue for expanded training in quasi-experimental designs in medical and graduate schools and in post-doctoral curricula. PMID- 27757715 TI - Patient State Recognition System for Healthcare Using Speech and Facial Expressions. AB - Smart, interactive healthcare is necessary in the modern age. Several issues, such as accurate diagnosis, low-cost modeling, low-complexity design, seamless transmission, and sufficient storage, should be addressed while developing a complete healthcare framework. In this paper, we propose a patient state recognition system for the healthcare framework. We design the system in such a way that it provides good recognition accuracy, provides low-cost modeling, and is scalable. The system takes two main types of input, video and audio, which are captured in a multi-sensory environment. Speech and video input are processed separately during feature extraction and modeling; these two input modalities are merged at score level, where the scores are obtained from the models of different patients' states. For the experiments, 100 people were recruited to mimic a patient's states of normal, pain, and tensed. The experimental results show that the proposed system can achieve an average 98.2 % recognition accuracy. PMID- 27757716 TI - SIMEDIS: a Discrete-Event Simulation Model for Testing Responses to Mass Casualty Incidents. AB - It is recognized that the study of the disaster medical response (DMR) is a relatively new field. To date, there is no evidence-based literature that clearly defines the best medical response principles, concepts, structures and processes in a disaster setting. Much of what is known about the DMR results from descriptive studies and expert opinion. No experimental studies regarding the effects of DMR interventions on the health outcomes of disaster survivors have been carried out. Traditional analytic methods cannot fully capture the flow of disaster victims through a complex disaster medical response system (DMRS). Computer modelling and simulation enable to study and test operational assumptions in a virtual but controlled experimental environment. The SIMEDIS (Simulation for the assessment and optimization of medical disaster management) simulation model consists of 3 interacting components: the victim creation model, the victim monitoring model where the health state of each victim is monitored and adapted to the evolving clinical conditions of the victims, and the medical response model, where the victims interact with the environment and the resources at the disposal of the healthcare responders. Since the main aim of the DMR is to minimize as much as possible the mortality and morbidity of the survivors, we designed a victim-centred model in which the casualties pass through the different components and processes of a DMRS. The specificity of the SIMEDIS simulation model is the fact that the victim entities evolve in parallel through both the victim monitoring model and the medical response model. The interaction between both models is ensured through a time or medical intervention trigger. At each service point, a triage is performed together with a decision on the disposition of the victims regarding treatment and/or evacuation based on a priority code assigned to the victim and on the availability of resources at the service point. The aim of the case study is to implement the SIMEDIS model to the DMRS of an international airport and to test the medical response plan to an airplane crash simulation at the airport. In order to identify good response options, the model then was used to study the effect of a number of interventional factors on the performance of the DMRS. Our study reflects the potential of SIMEDIS to model complex systems, to test different aspects of DMR, and to be used as a tool in experimental research that might make a substantial contribution to provide the evidence base for the effectiveness and efficiency of disaster medical management. PMID- 27757717 TI - Investigation of breast cancer sub-populations in black and white women in South Africa. AB - PURPOSE: Bimodal age distributions at diagnosis have been widely observed among US and European female breast cancer populations. To determine whether bimodal breast cancer distributions are also present in a sub-Saharan African population, we investigated female breast cancer in South Africa. METHODS: Using the South African National Cancer Registry data, we examined age-at-diagnosis frequency distributions (density plots) for breast cancer overall and by their receptor (oestrogen, progesterone and HER2) determinants among black and white women diagnosed during 2009-2011 in the public healthcare sector. For comparison, we also analysed corresponding 2010-2011 US SEER data. We investigated density plots using flexible mixture models, allowing early/late-onset membership to depend on receptor status. RESULTS: We included 8857 women from South Africa, 7176 (81 %) with known oestrogen receptor status, and 95064 US women. Bimodality was present in all races, with an early-onset mode between ages 40-50 years and a late-onset mode among ages 60-70 years. The early-onset mode was younger in South African black women (age 38), compared to other groups (45-54 years). CONCLUSIONS: Consistent patterns of bimodality and of its receptor determinants were present across breast cancer patient populations in South Africa and the US. Although the clinical spectrum of breast cancer is well acknowledged as heterogeneous, universal early- and late-onset age distributions at diagnosis suggest that breast cancer etiology consists of a mixture two main types. PMID- 27757718 TI - Outcomes of patients with inflammatory breast cancer treated by breast-conserving surgery. AB - PURPOSE: Inflammatory breast cancer (IBC) is rare and associated with a poor prognosis. Following neoadjuvant chemotherapy or endocrine therapy, the multidisciplinary team selected a small number of patients for breast conservation therapy (BCT). The aim of this study was to determine the outcome of IBC patients treated with BCT in Edinburgh. METHODS: Between January 1999 and December 2013, thirty-five women with IBC were treated by BCT. The median follow up was 80 months. RESULTS: The 5-year actuarial survival for the 35 patients was 70.3 %. Median survival for 20 neoadjuvant chemotherapy patients was 12.9 years (95 % CI 7.6, 18.1), and for 14 patient neoadjuvant endocrine therapy patients, it was 11.8 years (95 % CI 1.1, 22.6) (p = 0.34). Five patients developed locoregional recurrence (LRR) between 11 and 72 months after BCT (median 37 months). Three had breast only recurrence, one patient had both breast and axillary recurrence, and one developed axillary recurrence. The 5-year LR-free survival was 87.5 % (95 % CI 76.0, 99.0). In 4 of the 5 patients with LRR, systemic metastases were diagnosed within 6 months and survival post-LRR in these 4 patients was short. CONCLUSION: IBC is not an absolute contraindication to BCT. LRR in patients after BCT appears part of widespread recurrent disease rather than inadequate local treatment. Multicentre data should be collected to confirm that women with IBC who have a good response to systemic therapy may be offered BCT in the knowledge that in a larger series our observations are confirmed. PMID- 27757719 TI - Characterization of a novel germline PALB2 duplication in a hereditary breast and ovarian cancer family. AB - PURPOSE: Mutations in PALB2 have been associated with a predisposition to breast and pancreatic cancers. This study aims to characterize a novel PALB2 exon 13 duplication in a hereditary breast and ovarian cancer family. METHODS: The PALB2 exon 13 duplication in this family was evaluated using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACTTM) and confirmed by multiplex ligation-dependent probe amplification (MLPA). The duplication breakpoints were determined by long-range PCR and DNA sequencing. The effects of this mutation on mRNA splicing were characterized using RT-PCR, cloning, and DNA sequencing. RESULTS: The 5' and 3' breakpoints were mapped to intron 12 and downstream of 3'UTR. The tandem duplication is mediated by Alu elements in these regions. This duplication disrupts normal mRNA splicing and presumably leads to a frameshift and premature protein truncation. This duplication segregates with ovarian and breast cancer in multiple members in this family. CONCLUSIONS: Our results indicate that the PALB2 exon 13 duplication is a pathogenic variant. The presence of the PALB2 duplication in the proband affected with high-grade serous ovarian cancer suggests that PALB2 might be associated with a predisposition to ovarian cancer. PMID- 27757720 TI - Evaluation of matrix metalloproteinase type IV-collagenases in serum of patients with tumors of the central nervous system. AB - The basement membrane collagen IV-degrading matrix metalloproteinases -2 and -9 (MMPs) are most often linked to the malignant phenotype of tumor cells by playing a critical role in invasion, metastasis, angiogenesis, and vasculogenesis. We verified the activity of these two MMPs in the sera of patients affected by brain tumors (20 gliomas, 28 meningiomas and 20 metastasis) by zymography. The sera of 25 healthy volunteers with no concomitant illnesses were used for controls. Zymography showed four dominant gelatinolytic bands of 240, 130, 92 (MMP-9) and 72 (MMP-2) kDa. No statistically significant variations of MMP-2 proteolytic activity between patients and healthy individuals were observed. On the contrary, MMP-9 (both monomeric and multimeric forms) lytic activities were significantly higher in tumors specimens compared to healthy controls (p < 0.001). Moreover, MMP-9 immunohistochemistry revealed: (1) a strong reactivity in neoplastic vessels of high-grade gliomas showing an inverse correlation with serum multimeric gelatinolytic activity; (2) a cytoplasmatic reactivity in meningiomas with a significantly increase in atypical meningioma compared with low-grade ones (p = 0.036); (3) a positive correlation between MMP-9 and Ki-67 (Sperman Rho coefficient r = 0.418 and p = 0.034). Our results suggest that serum and tissue MMP-9 might provide clinicians additional objective information in intracranial neoplasms. Finally, it should be possible to use MMP-9 as a target for new forms of therapy. Nevertheless, due to the small number of patients included in the study, the conclusion may not be transferable to the general population and therefore further evaluations are needed. PMID- 27757722 TI - Mechanisms of post-radiation injury: cerebral microinfarction not a significant factor. AB - Post-radiation leukoencephalopathy is characterized by cognitive impairment and white matter alternations on imaging. Cerebral small vessel disease (SVD) is one of several suggested etiologies. Cerebral microinfarction (CMI) is a recently described marker of SVD. We sought to examine the rate of CMI as a biomarker of ongoing ischemia among patients who underwent brain radiotherapy (RT). 110 patients treated with RT for primary or metastatic brain tumors were enrolled. A total of 685 brain MRI tests performed 1-108 months post-radiation were examined. The annual incidence of CMI was calculated. Only 2 definite CMI were found (2/685, 0.3 %). The calculated annual incidence of CMI was 0.11. This incidence is similar to the normal population, and lower than the reported incidence in patients with intracerebral hemorrhage or cognitive impairment. CMI incidence in patients treated with brain RT is similar to the general population. This finding suggests that post-radiation leukoencephalopathy and cognitive impairment are not due to active SVD solely but rather secondary to other causes such as inflammation, metabolic or direct cell damage. PMID- 27757721 TI - Outcome of patients affected by newly diagnosed glioblastoma undergoing surgery assisted by 5-aminolevulinic acid guided resection followed by BCNU wafers implantation: a 3-year follow-up. AB - The purpose of the study was to evaluate the clinical outcome of the association of BCNU wafers implantation and 5-aminolevulinic acid (5-ALA) fluorescence in the treatment of patients with newly diagnosed glioblastoma (ndGBM). Clinical and surgical data from patients who underwent 5-ALA surgery followed by BCNU wafers implantation were retrospectively evaluated (20 patients, Group I) and compared with data of patients undergoing surgery with BCNU wafers alone (42 patients, Group II) and 5-ALA alone (59 patients, Group III). Patients undergoing 5-ALA assisted resection followed by BCNU wafers implantation (Group I) resulted long survivors (>3 years) in 15 % of cases and showed a median PFS and MS of 11 and 22 months, respectively. Patients treated with BCNU wafers presented a significantly higher survival when tumor was removed with the assistance of 5-ALA (22 months with vs 18 months without 5-ALA, p < 0.0001); these data could be partially explained by the significantly higher CRET achieved in patients operated with 5 ALA assistance (80 % with vs 47 %% without 5-ALA). Moreover, patients of Group I showed a significant increased survival compared with Group III (5-ALA without BCNU) (22 months with vs 21 months without BCNU wafers, p = 0.0025) even with a comparable CRET (80 % vs 76 %, respectively). The occurrence of adverse events related to wafers did not significantly increase with 5-ALA (20 % with and 19 % without 5-ALA) and did not impact in survival outcome. In conclusion, our experience shows that on selected ndGBM patients 5-ALA technology and BCNU wafers implantation show a synergic action on patients' outcome without increasing adverse events occurrence. PMID- 27757724 TI - Can Adiponectin Help us to Target Diastolic Dysfunction? AB - Adiponectin is the most abundant adipokine and exhibits anti-inflammatory, antiatherogenic and antidiabetic properties. Unlike other adipokines, it inversely correlates with body weight and obesity-linked cardiovascular complications. Diastolic dysfunction is the main mechanism responsible for approximately half of all heart failure cases, the so-called heart failure with preserved ejection fraction (HFpEF), but therapeutic strategies specifically directed towards these patients are still lacking. In the last years, a link between adiponectin and diastolic dysfunction has been suggested. There are several mechanisms through which adiponectin may prevent most of the pathophysiologic mechanisms underlying diastolic dysfunction and HFpEF, including the prevention of myocardial hypertrophy, cardiac fibrosis, nitrative and oxidative stress, atherosclerosis and inflammation, while promoting angiogenesis. Thus, understanding the mechanisms underlying adiponectin-mediated improvement of diastolic function has become an exciting field of research, making adiponectin a promising therapeutic target. In this review, we explore the relevance of adiponectin signaling for the prevention of diastolic dysfunction and identify prospective therapeutic targets aiming at the treatment of this clinical condition. PMID- 27757723 TI - Identification of two distinct mesenchymal stromal cell populations in human malignant glioma. AB - Gene profiling has revealed that malignant gliomas can be divided into four distinct molecular subtypes, where tumors with a mesenchymal gene expression are correlated with short survival. The present investigation was undertaken to clarify whether human malignant gliomas contain endogenous mesenchymal stromal cells (MSC), fulfilling consensus criteria defined by The International Society for Cellular Therapy, recruited from the host. We found that MSC-like cells can be isolated from primary human malignant gliomas. Two distinct MSC-like cell populations, differing in their expression of the CD90 surface marker, were discovered after cell sorting. RNA sequencing revealed further genetic differences between these two cell populations and MSC-like cells lacking CD90 produced higher amounts of VEGF and PGE2 compared to cells with the true MSC phenotype, implying that the CD90- MSC-like cells most probably are more active in tumor vascularization and immunosuppression than their CD90+ counterpart. The results highlight the CD90- subpopulation as an important tumor component, however, its functional effects in glioma remains to be resolved. Using the protocols presented here, it will be possible to isolate, characterize and analyze brain tumor-derived MSC-like cells in more detail and to further test their functions in vitro and in in vivo xenograft models of glioma. PMID- 27757725 TI - Adenosine A2A and A2B Receptor Substantially Attenuate Ischemia/Reperfusion Injury in Septic rat Hearts. AB - INTRODUCTION: Mechanical and morphological ischemia and reperfusion (I/R) injury is reduced in septic hearts. The mechanism behind this "cardioprotection" is less well understood. As adenosine receptors play a major role for cardioprotection in non-septic hearts, we investigated the influence of adenosine receptors in a model of I/R in septic hearts. METHODS: SHAM operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats (n = 60). After 24 h of incubation, hearts were isolated and randomly assigned to a group with or without adenosine receptor (Ador) antagonists (SCH 58261 and MRS 1706) administered before reperfusion. Ischemia and reperfusion lasted for 40 min each. Cardiac function of the heart was determined by measuring left ventricular pressure (LVP). RESULTS: Before I/R, CLP hearts showed a significant mechanical left ventricular impairment (CLP: 63 +/- 5 mmHg vs. SHAM: 104 +/- 6 mmHg. After I/R, left ventricular function was significantly reduced in SHAM (24 +/- 32 mmHg), but not in CLP hearts (65 +/- 13 mmHg). mRNA expression for the AdorA2a and AdorA2b was significantly increased in CLP, but not in SHAM hearts. LVP of CLP hearts deteriorated when AdorA2a and AdorA2b were blocked. CONCLUSIONS: The morphological and functional I/R injury in septic animals is less pronounced compared to non-septic animals. By a combined blockade of AdorA2a and AdorA2b this "cardioprotective" effect is nearly abolished in septic hearts. This is the first study showing, that AdorA2a and AdorA2b may play an important role for a reduced functional I/R injury in the septic heart. PMID- 27757726 TI - Risk and Benefits of Triple Therapy in Patients Undergoing Coronary Stent Implantation Requiring Oral Anticoagulation: A Meta-Analysis of 16 Studies. AB - BACKGROUND: Patients with coronary artery disease who undergo stent implantation and have concomitant indication for long-term oral anticoagulation represent a considerable proportion of the overall population. To date there is still no consensus about the optimal antithrombotic strategy to choose in this kind of patients, due to the difficult balance between an increased risk of bleeding and thromboembolic complications. Therefore, the aim of this study was to perform a meta-analysis to evaluate the risk and benefits of triple antithrombotic therapy versus dual antithrombotic therapy in patients undergoing coronary stent implantation, requiring long-term oral anticoagulation. METHODS: We performed formal searches of PubMed, EMBASE, Cochrane central register of controlled trials and major international scientific session abstracts from January 1990 to September 2015 regarding the use of triple antithrombotic therapy (TT) versus dual therapy (DT) in patients undergoing percutaneous coronary stent implantation that required chronic oral anticoagulation. Data regarding study design, inclusion/exclusion criteria, number of patients, and selected endpoints was extracted by 2 investigators. Disagreements were resolved by consensus. RESULTS: Sixteen trials with a total of 21716 patients undergoing coronary stent implantation with indication to long term oral anticoagulation, were finally included. A total of 6950 received TT, whereas 14766 received DT alone. The follow-up period ranged from 180 to 730 days. Data regarding mortality were available in 21658 patients (99.7 %). All cause mortality was observed in 10.4 % patients in TT versus 16.3 % in DT (OR [95 % CI] =0.73 [0.66-0.80], p <0.001; p het <0.001). In addition, TT was associated with a reduced incidence of MI (6.4 versus 9.8 %, OR [95 % CI] = 0.74 [0.65-0.84], p < 0.001; phet < 0.001) and ischemic stroke (1.8 versus 3.9 %, OR [95 % CI] = 0.55 [0.45-0.68], p < 0.001; p het = 0.07). As expected, TT was associated with a significant increase in major bleeding events (10.8 versus 8.5 %, OR [95 % CI] = 1.38 [1.25-1.53], p < 0.001; p het = 0.02). By meta regression analysis we found that benefits in mortality with TT were inversely related with the risk of bleedings (beta [95 % CI] = 2.25 (1.55; 2.95), p < 0.00001). The benefits with TT regarding overall mortality, recurrent MI and ischemic stroke were also confirmed in a pre-specified analysis versus DAPT or oral anticoagulation in association with a single antiplatelet agent. CONCLUSION: This meta-analysis showed that among patients undergoing coronary stent implantation, requiring chronic OAC, the use of a TT is associated with a significant reduction in overall mortality, recurrent MI and ischemic stroke. As expected, we found a higher incidence of bleedings in patients treated with triple therapy. The benefits in mortality were lost in patients at high-risk for bleedings. PMID- 27757727 TI - Analysis of the effectiveness of Sodium Hypochlorite decontamination of cadaveric human tissues at retrieval. AB - Bacterial contamination of tissues retrieved from cadaveric donors is a common feature worldwide, and every tissue bank, albeit using different methods, conducts decontamination to guarantee safe tissues suitable for clinical use. The effectiveness of the methods used to eradicate pathogens differs. In order to reduce the tissue bioburden at retrieval, we have introduced a new method involving rinsing tissues in a sodium hypochlorite solution. To test its effectiveness we analyzed two comparable groups of tissues: Group A: 1881 tissues, all rinsed with isotonic saline solution after retrieval, and Group B: 1968 tissues immersed in an isotonic saline solution containing sodium hypochlorite (final concentration 0.1 %) for different lengths of time and subsequently rinsed with isotonic saline. The rinsing solution of each tissue was then sampled for microbiological cultures in both groups. The resultant overall contamination rate was 40.5 % for Group A and 6.7 % for Group B, with an 82.8 % difference in the reduction of contamination between the two groups. This was especially the case for commensal skin bacteria in musculoskeletal tissue, which accounted for over half the overall contamination. Our data highlighted that decontamination with sodium hypochlorite was helpful in reducing the bacterial bioburden in tissues retrieved from cadaveric donors. PMID- 27757728 TI - Reduced rates of non-union with modified periacetabular osteotomy using peracetic acid sterilized cancellous allografts. AB - The objective of the present study was to analyze the clinical and radiological results of periacetabular osteotomies (PAO) using Kirschner wire fixation and an allogeneic cancellous bone graft. This retrospective cohort study included 73 patients (85 PAOs). The allografts were processed from distal femur of cadaveric donors, defatted, sterilized with a peracetic-acid ethanol solution and freeze dried. The clinical outcome, as measured by the Harris Hip Scores (HHS), the complication rate and the acetabular correction, as measured by radiological parameters, were compared. The postoperative femoral head coverage and HSS were significantly improved. Major complications occurred in five cases (6 %), but in no case did we observe a non-union or a graft-associated adverse effect. Fixation of the acetabular fragment with Kirschner wires in combination with an allogeneic cancellous bone graft is a safe method, with a low complication rate, no loss of correction and can prevent the occurrence of non-union with a high degree of probability. PMID- 27757729 TI - Core curriculum illustration: blunt trauma to the bowel. AB - This is the 22nd installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at http://www.aseronline.org/curriculum/toc.htm . PMID- 27757730 TI - Genetics of Interactive Behavior in Silver Foxes (Vulpes vulpes). AB - Individuals involved in a social interaction exhibit different behavioral traits that, in combination, form the individual's behavioral responses. Selectively bred strains of silver foxes (Vulpes vulpes) demonstrate markedly different behaviors in their response to humans. To identify the genetic basis of these behavioral differences we constructed a large F2 population including 537 individuals by cross-breeding tame and aggressive fox strains. 98 fox behavioral traits were recorded during social interaction with a human experimenter in a standard four-step test. Patterns of fox behaviors during the test were evaluated using principal component (PC) analysis. Genetic mapping identified eight unique significant and suggestive QTL. Mapping results for the PC phenotypes from different test steps showed little overlap suggesting that different QTL are involved in regulation of behaviors exhibited in different behavioral contexts. Many individual behavioral traits mapped to the same genomic regions as PC phenotypes. This provides additional information about specific behaviors regulated by these loci. Further, three pairs of epistatic loci were also identified for PC phenotypes suggesting more complex genetic architecture of the behavioral differences between the two strains than what has previously been observed. PMID- 27757731 TI - The new system of health accounts in Ireland: what does it all mean? AB - BACKGROUND: The Central Statistics Office released new figures on Ireland's health spending in December 2015, based on the System of Health Accounts (SHA2011). These figures differ from previous figures, by virtue of an expanded definition of what constitutes health care. The new figures also provide more detail on health expenditure than the previous figures allowed. AIMS: This article examines the new figures, drawing out findings of note and discussing the implications of these for the Irish health care system. It also compares Ireland with international health systems, highlighting where Ireland is unusual or comparable to international norms. FINDINGS: Healthcare spending in Ireland as a percentage of GDP is higher than in many other countries, having increased during the economic downturn, although this was due more to the contraction in GDP than an increase in spending. While the majority of healthcare expenditure in Ireland comes from the Government, the share of private expenditure on healthcare in Ireland has increased, with implications for equity in the system. Over half of the expenditure is on curative and rehabilitative services, broadly in line with other countries. The proportion of spending going to long-term care facilities is relatively high by international standards. CONCLUSION: Suggestions that Ireland is over-spending on health need to be tempered by cognisance that the Irish health system is under-resourced in a number of areas (particularly the number of doctors and the number of hospital beds) and has not fully recovered from cutbacks in the late 1980s and early 1990s. PMID- 27757732 TI - The More or the Better? How Sex Contributes to Life Satisfaction. AB - Much cross-sectional research documented associations between sexuality and life satisfaction, but very little longitudinal research on the topic has considered whether changes in sexuality and life satisfaction unfold together over time. Using data from 5582 individuals in partnerships surveyed across 5786 intimate relationships (providing 18,712 observations for analysis) during five waves of the German Family Panel (pairfam), this study examined whether intraindividual changes in sexual frequency and satisfaction were associated with corresponding intraindividual changes in life satisfaction. Fixed effects regression modeling results showed that individuals reported a greater increase (decrease) in life satisfaction when they also experienced a more substantial increase (decrease) in sexual frequency and satisfaction. This finding was consistent for men and women. This study contributes to the literature by documenting that naturally occurring increases in sexual frequency and satisfaction over time predicted corresponding increases in life satisfaction. PMID- 27757733 TI - Comparison of two mineralcorticosteroids receptor antagonists for the treatment of central serous chorioretinopathy. AB - PURPOSE: To evaluate the effect of oral spironolactone and eplerenone, two specific antagonists of the mineralocorticoid receptor, in central serous chorioretinopathy (CSCR). METHODS: In this prospective, placebo-controlled trial, sixty patients with persistent CSCR were assigned to three treatment group. Twenty patients in Group 1 were treated with 25 mg of spironolactone (Aldactone; Pfizer) for 1 week, then increased to 50 mg for the following 3 weeks, then shifted to eplerenone 50 mg for 1 month. Twenty patients in Group 2 were treated with 25 mg of eplerenone (Inspra; Pfizer) for 1 week, then increased to 50 mg for the following 3 weeks, and then shifted to spironolactone 50 mg for 1 month. Twenty patients in Group 3 were treated with 1 placebo control tablet for 1 week, then increased to two tablets for the following 3 weeks, and then shifted to spironolactone 50 mg for 1 month. At the end of the second month, all the treatments were stopped, and the patients were followed for two additional months. Primary outcome measure was a change in BCVA at 1, 2, and 4 months. Secondary outcome was a change of >20 % in the size of SRF recorded with OCT at 1, 2, and 4 months of treatment. RESULTS: In terms of BCVA, treatment in Group 1 was effective from the first month (spironolactone, p value 0.01), and in Group 2 effective from the second month (shift to spironolactone, p value 0.004). Since the p value after the first month was 0.2 in Group 2, even with a larger sample, it would be difficult to see an efficacy of an eplerenone treatment after 1 month. As for the SRF, both in Group 1 and Group 2, both treatments were found to be equally effective after 1 month of administration (p values 0.004). At 4 months, only in Group 3, there was no statistical improvement of BCVA and SRF (p values 0.09 and 0.5). CONCLUSIONS: Spironolactone is statistically superior to eplerenone in improving BCVA of patients with CSCR, while both drugs can be considered equally effective in promoting the reabsorption of SRF. PMID- 27757734 TI - Adiponectin exerts cardioprotection against ischemia/reperfusion injury partially via calreticulin mediated anti-apoptotic and anti-oxidative actions. AB - The underlying mechanisms of cardioprotection of adiponectin (APN) against ischemia/reperfusion (I/R) injury remain largely unknown. The present study aimed to investigate whether calreticulin (CRT) mediated APN's cardioprotection against I/R injury. We inhibited mice cardiac CRT expression via intra-myocardial injection of CRT SiRNA, performed transient LAD ligation, measured the cardiac function, apoptosis and oxidative stress to identify CRT's effects on cardioprotective actions of APN against I/R injury in vivo. LDH release and expression of CRT were measured in neonatal cardiomyocytes (NCM) subjected to simulated I/R (SI/R) and APN. CRT specific SiRNA was also utilized in vitro. CRT inhibition partially blunted cardioprotection of APN against I/R injury (evidenced by left ventricular ejection fraction and myocardial infarct size). It also blunted APN's function against I/R induced apoptosis and oxidative stress (evidenced by TUNEL positive staining and reactive oxygen species production). In addition, SI/R increased LDH release, and administration of APN attenuated SI/R induced cell death significantly. However, neither SI/R nor APN altered CRT expression in NCM. Inhibition of CRT expression blunted cardioprotective action of APN against SI/R induced apoptotic events (evidenced by TUNEL positive staining, LDH release and Caspase 3 activity). Furthermore, CRT inhibition significantly blunted APN's anti-oxidative action (evidenced by gp91phox expression and superoxide generation). However, CRT inhibition did not attenuate AMPK phosphorylation by APN administration in NCM. Therefore, these novel findings strongly indicate that APN exerts cardioprotective effects against I/R injury partially via CRT mediated anti-apoptotic and anti-oxidative actions. PMID- 27757736 TI - Brief Report: Reduced Optimism Bias in Self-Referential Belief Updating in High Functioning Autism. AB - Previous research has demonstrated irrational asymmetry in belief updating: people tend to take into account good news and neglect bad news. Contradicting formal learning principles, belief updates were on average larger after better than-expected information than after worse-than-expected information. In the present study, typically developing subjects demonstrated this optimism bias in self-referential judgments. In contrast, adults with high-functioning autism spectrum disorder (ASD) were significantly less biased when updating self referential beliefs (each group n = 21, matched for age, gender and IQ). These findings indicate a weaker influence of self-enhancing motives on prospective judgments in ASD. Reduced susceptibility to emotional and motivational biases in reasoning in ASD could elucidate impairments of social cognition, but may also confer important cognitive benefits. PMID- 27757735 TI - Amsacrine-induced apoptosis of human leukemia U937 cells is mediated by the inhibition of AKT- and ERK-induced stabilization of MCL1. AB - Previous studies have attributed the anticancer activity of amsacrine to its inhibitory effect on topoisomerase II. However, 9-aminoacridine derivatives, which have the same structural scaffold as amsacrine, induce cancer cell apoptosis by altering the expression of BCL2 family proteins. Therefore, in the present study, we assessed whether BCL2 family proteins mediated the cytotoxic effects of amsacrine on human leukemia U937 cells. Amsacrine-induced apoptosis of U937 cells was characterized by caspase-9 and caspase-3 activation, increased intracellular Ca2+ concentration, mitochondrial depolarization, and MCL1 down regulation. Amsacrine induced MCL1 down-regulation by decreasing its stability. Further, amsacrine-treated U937 cells showed AKT degradation and Ca2+-mediated ERK inactivation. Blockade of ERK-mediated phosphorylation of MCL1 inhibited the effect of Pin1 on the stabilization of MCL1, and AKT degradation promoted GSK3beta-mediated degradation of MCL1. Restoration of ERK phosphorylation and AKT expression abrogated amsacrine-induced MCL1 down-regulation. Moreover, MCL1 over expression inhibited amsacrine-induced depolarization of mitochondria membrane and increased the viability of amsacrine-treated cells. Taken together, our data indicate that amsacrine abolishes ERK- and Pin1-mediated stabilization of MCL1 and promotes GSK3beta-mediated degradation of MCL1, leading to activate mitochondria-mediated apoptosis pathway in U937 cells. PMID- 27757738 TI - Overview and Preliminary Evidence for a Social Skills and Self-Care Curriculum for Adolescent Females with Autism: The Girls Night Out Model. AB - A majority of social skills research in autism spectrum disorder (ASD) and interventions target school age males and no published studies target adolescent females with ASD or related disabilities. Females with ASD are at risk for internalizing symptoms, and experience greater challenges in socialization and communication as social demands become increasingly complex in adolescence. This paper provides a thorough description of a social skills and self-care program designed to address the specific needs of adolescent females with ASD. The approach is peer mediated and occurs within natural or community settings to facilitate generalization. Findings from program evaluation data collected across 4 years illustrate significant improvements in perceived social competence, self perception, and quality of life and suggests the approach is feasible and social valid. PMID- 27757737 TI - Parent-Endorsed Sex Differences in Toddlers with and Without ASD: Utilizing the M CHAT. AB - Sex differences in typical development can provide context for understanding ASD. Baron-Cohen (Trends Cogn Sci 6(6):248-254, 2002) suggested ASD could be considered an extreme expression of normal male, compared to female, phenotypic profiles. In this paper, sex-specific M-CHAT scores from N = 53,728 18-month-old toddlers, including n = 185 (32 females) with ASD, were examined. Results suggest a nuanced view of the "extreme male brain theory of autism". At an item level, almost every male versus female disadvantage in the broader population was consistent with M-CHAT vulnerabilities in ASD. However, controlling for total M CHAT failures, this male disadvantage was more equivocal and many classically ASD associated features were found more common in non-ASD. Within ASD, females showed relative strengths in joint attention, but impairments in imitation. PMID- 27757739 TI - Cerebral hemodynamics in sepsis assessed by transcranial Doppler: a systematic review and meta-analysis. AB - Cerebral microcirculation is gradually compromised during sepsis, with significant reductions in the function of capillaries and blood perfusion in small vessels. Transcranial Doppler ultrasound (TCD) has been used to assess cerebral circulation in a typical clinical setting. This study was to systematically review TCD studies, assess their methodological quality, and identify trends that can be associated with the temporal evolution of sepsis and its clinical outcome. A meta-analysis of systematic reviews was conducted according to the PRISMA statement. Articles were searched from 1982 until the conclusion of this review in December 2015. Twelve prospective and observational studies were selected. Evaluations of cerebral blood flow, cerebral autoregulation, and carbon dioxide (CO2) vasoreactivity were summarized. A temporal pattern of the evolution of the illness was found. In early sepsis, the median blood flow velocity (Vm) and pulsatility index (PI) increased, and the cerebral autoregulation (CA) remained unchanged. In contrast, Vm normalization, PI reduction and CA impairment were found in later sepsis (patients with severe sepsis or septic shock). Cerebral haemodynamic is impaired in sepsis. Modifications in cerebral blood flow may be consequence to the endothelial dysfunction of the microvasculature induced by the release of inflammatory mediators. A better understanding of cerebral hemodynamics may improve the clinical management of patients with sepsis and, consequently, improve clinical outcomes. PMID- 27757740 TI - Design and alpha-testing of an electronic rounding tool (CERTAINp) to improve process of care in pediatric intensive care unit. AB - Increasing process complexity in the pediatric intensive care unit (PICU) can lead to information overload resulting in missing pertinent information and potential errors during morning rounds. An efficient model using a novel electronic rounding tool was designed as part of a broader critical care decision support system-checklist for early recognition and treatment of acute illness and injury in pediatrics (CERTAINp). We aimed to evaluate its impact on improving the process of care during rounding. Prospective pre- and post-interventional data included: team performance baseline assessment, patient safety discussion, guideline adherence, rounding time, and a survey of Residents' and Nurses' perception using a Likert scale. Attending physicians were blinded to the components of the assessment. A total of 113 pre-intervention and 114 post intervention roundings were recorded by direct observation. Pre-intervention (108) and post-intervention staff surveys (80) were obtained. Adherence to standard of care guidelines improved to >97 % in all data points, with maximum increase seen in discussions of ulcer prophylaxis, bowel protocol, DVT prophylaxis, skin care, glucose control and head of bed elevation (2-28 % pre-vs. 100 % for all post-intervention, p < 0.01). Significant improvement was noticed in spontaneous breathing trials, sedation breaks and need for devices (45-57 % pre- vs. 100 % for all post-intervention, p < 0.01). Rounding time (mean +/- SD) increased by 2 min/patient (8.0 +/- 5.8 min pre-intervention vs. 9.9 +/- 5.7 min post-intervention, p = 0.002). Staff reported improved perception of all aspects of rounding. Utilization of the CERTAINp rounding tool led to perfect compliance to the discussion of best practice guidelines; had minimal impact on rounding time and improved PICU staff satisfaction. PMID- 27757741 TI - Methylation Status of the RIZ1 Gene Promoter in Human Glioma Tissues and Cell Lines. AB - Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1), a strong tumor suppressor, is silenced in many human cancers. Our previous studies showed that RIZ1 expression was negatively correlated with the grade of glioma and was a key predictor of patient survival. Therefore, RIZ1 could be a potential tumor suppressor during glioma pathogenesis, although the mechanism underlying RIZ1 gene inactivation in gliomas is unknown. We investigated the methylation status of the RIZ1 promoter in human glioma tissues and four glioblastoma (GBM) cell lines, and verified the effect of the methyltransferase inhibitor 5-aza-2 deoxycytidine (5-aza-CdR) on RIZ1 transcription and cell proliferation. Methylation-specific PCR (MSP) was performed to determine RIZ1 promoter methylation in human glioma specimens. The correlation between RIZ1 hypermethylation in tumors and clinicopathological features also was analyzed. 5 Aza-CdR treatment was used to reactivate gene expression silenced by hypermethylation in the U87 glioblastoma cell line, and real-time PCR was then used to measure RIZ1 expression. The ability of 5-aza-CdR to inhibit the proliferation of glioma cell lines whose RIZ1 promoters were hypermethylated was measured by bromodeoxyuridine (BrdU) incorporation. Among 51 human glioma specimens, RIZ1 promoter methylation was detected in 23 cases. Clinicopathological evaluation suggested that RIZ1 hypermethylation was negatively associated with tumor grade and patient age (P < 0.05). Hypermethylation of the RIZ1 promoter was detected in the U87 and U251 cell lines. RIZ1 mRNA expression in U87 cells was upregulated after treatment with 5 aza-Cdr, which correlated with inhibition of cell proliferation in a time- and concentration-dependent manner. Promoter hypermethylation may play an important role in the epigenetic silencing of RIZ1 expression in human glioma tissues and GBM cell lines. PMID- 27757742 TI - Recursive Model Identification for the Evaluation of Baroreflex Sensitivity. AB - A method for the recursive identification of physiological models of the cardiovascular baroreflex is proposed and applied to the time-varying analysis of vagal and sympathetic activities. The proposed method was evaluated with data from five newborn lambs, which were acquired during injection of vasodilator and vasoconstrictors and the results show a close match between experimental and simulated signals. The model-based estimation of vagal and sympathetic contributions were consistent with physiological knowledge and the obtained estimators of vagal and sympathetic activities were compared to traditional markers associated with baroreflex sensitivity. High correlations were observed between traditional markers and model-based indices. PMID- 27757743 TI - In situ toxicity and ecological risk assessment of agro-pesticide runoff in the Madre de Dios River in Costa Rica. AB - The River Madre de Dios (RMD) and its lagoon is a biodiversity rich watershed formed by a system of streams, rivers, channels, and a coastal lagoon communicating with the Caribbean Sea. This basin sustains a large area of agricultural activity (mostly banana, rice, and pineapple) with intensive use of pesticides, continually detected in water samples. We investigated in situ the toxicological effects caused by pesticide runoff from agriculture and the relation of pesticide concentrations with different biological organization levels: early responses in fish biomarkers (sub-organismal), acute toxicity to Daphnia magna (organismal), and aquatic macroinvertebrate community structure. The evaluation was carried out between October 2011 and November 2012 at five sites along the RMD influenced by agricultural discharges and a reference site in a stream outside the RMD that receives less pesticides. Acute toxicity to D. magna was observed only once in a sample from the RMD (Cano Azul); the index of biomarker responses in fish exposed in situ was higher than controls at the same site and at the RMD-Freeman. However, only macroinvertebrates were statistically related to the presence of pesticides, combined with both physical-chemical parameters and habitat degradation. All three groups of variables determined the distribution of macroinvertebrate taxa through the study sites. PMID- 27757744 TI - A comparative study for the stabilisation of heavy metal contaminated sediment by limestone, MnO2 and natural zeolite. AB - Three amendments including limestone, MnO2 and natural zeolite were assessed for their stabilisation effects on Zn, Cu, Pb and Cd in sediment of east Dongting Lake, mid-south China. The metals were first subject to pollution status and potential ecological risk assessment to identify the current and potential hazards to ecology. Speciation of the metals in the sediment treated with amendments was then carried out by BCR sequential extraction procedure in order to evaluate metal contents and their potential mobility. The total concentrations of Zn, Cu, Pb and Cd in the east Dongting Lake were all above the means of national stream sediment and soil guidelines. The sediments were currently unpolluted to moderately pollute with Zn, Cu and Pb and strongly polluted with Cd. Zinc, Cu and Pb posed low risks to the lake ecosystem, and Cd had the highest potential risk that caused the overall risk of the sediment to be high or very high. Limestone stabilised Cu and Zn effectively, yet mobilisation of Cd and Pb by such amendment was also observed. MnO2 effectively reduced the extractable Cd and Pb. The effect of natural zeolite on metal stabilisation in the sediment was least notable. Limestone and MnO2 showed higher metal stabilisation efficiencies than zeolite. However, a single amendment is unable to achieve the goal of stabilisation for all metals. A combination use of the advantageous amendments or a search of a stronger stabiliser should be the interest of our future study. PMID- 27757745 TI - Recovery and reuse of sludge from active and passive treatment of mine drainage impacted waters: a review. AB - The treatment of mine drainage-impacted waters generates considerable amounts of sludge, which raises several concerns, such as storage and disposal, stability, and potential social and environmental impacts. To alleviate the storage and management costs, as well as to give the mine sludge a second life, recovery and reuse have recently become interesting options. In this review, different recovery and reuse options of sludge originating from active and passive treatment of mine drainage are identified and thoroughly discussed, based on available laboratory and field studies. The most valuable products presently recovered from the mine sludge are the iron oxy-hydroxides (ochre). Other by products include metals, elemental sulfur, and calcium carbonate. Mine sludge reuse includes the removal of contaminants, such as As, P, dye, and rare earth elements. Mine sludge can also be reused as stabilizer for contaminated soil, as fertilizer in agriculture/horticulture, as substitute material in construction, as cover over tailings for acid mine drainage prevention and control, as material to sequester carbon dioxide, and in cement and pigment industries. The review also stresses out some of the current challenges and research needs. Finally, in order to move forward, studies are needed to better estimate the contribution of sludge recovery/reuse to the overall costs of mine water treatment. PMID- 27757746 TI - Toxic effect of commercial detergents on organisms from different trophic levels. AB - The toxic effects of four powder detergents: two laundry detergents (A and B), one household detergent (C), one dishwashing detergent (D), and the surfactant alkylbenzene sulfonate (LAS) were analyzed in this study on organisms from different trophic levels (microalgae, cladocerans, ostracods, amphipods, macrophytes, and fish). LC50 and EC50 values obtained in the toxicity bioassays varied between 0.019 and 116.9 mg L-1. The sensitivity of the organisms to the detergents was (from most sensitive to least sensitive) Ostracods > microalgae > amphipods > cladocerans > fishes > macrophytes. The toxicity of the commercial products (from most toxic to least toxic) was LAS > D (dishwashing detergent) > A (laundry detergent) > B (laundry detergent) > C (household detergent). When comparing the sensitivity of organisms that inhabit temperate zones (T = 18 degrees C) to those that are found in tropical zones (T > 25 degrees C), it was clear that the species that inhabit the tropics are more sensitive to detergents. PMID- 27757747 TI - Day-night variability of water-soluble ions in PM10 samples collected at a traffic site in southeastern Spain. AB - The present work reports diurnal and nocturnal concentrations of water-soluble ions associated to PM10 samples collected during the warm and cold seasons in the urban center of Elche (Southeastern Spain). Statistical differences between daytime and nighttime levels of PM10 were only observed during winter. The lower concentrations during the night were most likely the result of a reduction in traffic-induced road dust resuspension, since nocturnal concentrations of calcium also exhibited a significant decrease compared to daytime levels. During the warm season, nitrate was the only component that showed a statistically significant increase from day to night. The lower nocturnal temperatures that prevent the thermal decomposition of ammonium nitrate and the formation of nitric acid favored by the higher relative humidity at night are the most probable reasons for this variation. The close relationship between nitrate formation and relative humidity during nighttime was supported by the results of the correlation analysis. The reaction of sulfuric and nitric acids with CaCO3 occurred to a greater extent during daytime in summer. PMID- 27757748 TI - Upgrading the hydrolytic potential of immobilized bacterial pretreatment to boost biogas production. AB - In this study, surfactant dioctyl sodium sulphosuccinate (DOSS)-mediated immobilized bacterial pretreatment of waste activated sludge (WAS) was experimentally proved to be an efficient and economically feasible process for enhancing the biodegradability of WAS. The maximal floc disruption with negligible cell cleavage was achieved at surfactant dosage of 0.009 g/g SS. Results of the outcome of bacterial pretreatment of sludge biomass revealed that chemical oxygen demand (COD) solubilization for deflocculated (EPS removed bacterially pretreated) sludge was 20 %, which was higher than that of flocculated (14 %) or control (5 %). The pretreatment was swift in deflocculated sludge with a rate constant of about 0.064 h-1. Biochemical methane potential (BMP) assay resulted in significant methane yield at 0.24 gCOD/gCOD for deflocculated sludge. Economic assessment of the proposed method showed a net profit of about 57.39 USD/ton of sludge. PMID- 27757750 TI - Geochemical source, deposition, and environmental risk assessment of cadmium in surface and core sediments from the Bohai Sea, China. AB - Geochemical sources, spatio-temporal distribution, and associated environmental risk of Cd in the Bohai Sea were investigated using data from 405 surface sediment samples and two sediment cores. Local point Cd sources, TOC content, and currents are the main controlling factors of Cd distribution. The contribution of Cd from river discharge surpasses that from atmospheric deposition. Sediment quality guidelines, enrichment factors, and chemical fraction analysis were used to assess metal toxicity in the collected sediments. Results show that Bohai Sea sediments have a moderate Cd enrichment level. This enrichment poses a high risk due to the relatively high mobility and bioavailability of Cd despite measured levels below sediment-quality guidelines at most stations. Vertical profiles of Cd concentrations, Al-normalized enrichment factors, and excess burial fluxes combined with 210Pb dating reveal the history of Cd pollution in the Bohai Sea over the last century. Data show Cd unvaried before the 1800s, a slight increase from the 1800s to the late 1950s, a decrease from the late 1960s to the 1970s, and an increase from the 1980s to 2001, including a relatively high value in 1998. Historic variation in Cd is closely associated with both natural and anthropogenic activities. PMID- 27757749 TI - Effects of alkaloid extracts of mesquite pod on the products of in vitro rumen fermentation. AB - The objective of this study was to evaluate the effects of alkaloid extracts of Prosopis juliflora (Sw.) D.C. pods obtained by two extraction methods as compared with sodium monensin on the gas production kinetic, mitigation of methane, and rumen fermentation products using wheat bran or Tifton 85 hay as substrates, by the semi-automatic in vitro gas production technique. A completely randomized design was adopted, and two natural additives were tested made from mesquite pod (alkaloid extract I and alkaloid extract II) at three levels (3.9, 7.9, and 12 MUg), sodium monensin 5 MUM (positive control), and no inclusion of additives (negative control). The volume of gases produced by the degradation of the fibrous fraction of wheat bran was influenced by the concentration of the extract I added to the medium, and the amounts of 7.9 and 12 MUg were equal to monensin at the lowest value. The degradation rate of the fibrous carbohydrates with additive extract I at 12 MUg was lower in relation to monensin. When Tifton 85 hay was utilized, alkaloid extract I provided a shorter colonization time as compared with monensin at the added amounts of 7.9 and 12 MUg and higher production of gases from the fibrous fraction but without interfering with the total volume of gases produced during 96 h of fermentation of carbohydrates. In the periods of 12 and 24 h of incubation, utilizing alkaloid extract I, the mean values of methane production with wheat bran and Tifton 85 hay were lower than monensin (p < 0.05) when the respective amounts of 7.9 and 12 MUg were added. Alkaloid extract I has similar potential to sodium in reducing production of total gases, methane, and the acetate/propionate ratio. PMID- 27757751 TI - Technoeconomic perspectives on sustainable CO2 capture and utilization. PMID- 27757752 TI - Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo assisted oxidation processes. AB - Cytostatics are part of the forefront research topics due to their high prescription, high toxicity, and the lack of effective solutions to stop their entrance and spread in the environment. Among them, 5-Fluorouracil (5-Fu) has received particular attention because is one of the most prescribed active substances in chemotherapy worldwide. The degradation of 5-Fu by advanced oxidation processes (AOPs) is a poorly addressed topic, and this work brings valuable inputs concerning this matter. Herein, the efficacy of Fenton's process in the degradation of 5-Fu is explored for the first time; the study of the main variables and its successful application to the treatment of real wastewaters is demonstrated. Moreover, hydrogen peroxide-based and photo-assisted techniques (direct photolysis, photodegradation with H2O2 and photo-Fenton) are also investigated for purposes of comparison. Under the best operation conditions obtained (T = 30 degrees C, [Fe2+]0 = 0.5 mM; [H2O2]0 = 240 mM and pH = 3 for [5 Fu]0 = 0.38 mM), 5-Fu was completely eliminated after 2 h of Fenton's reaction and about 50 % of mineralization was reached after 8 h. The best performance was obtained by the photo-Fenton process, with 5-Fu mineralization level as high as 67 %, using an iron dose within the legal limits required for direct water discharge. Toxicity (towards Vibrio fischeri) of the effluents that resulted from the application of the above-mentioned AOPs was also evaluated; it was found that the degradation products generated from the photo-assisted processes are less toxic than the parent compound, putting into evidence the relevance of such technologies for degradation of cytostatics like 5-Fu. PMID- 27757753 TI - A modeling approach to direct interspecies electron transfer process in anaerobic transformation of ethanol to methane. AB - Recent studies have shown that direct interspecies electron transfer (DIET) plays an important part in contributing to methane production from anaerobic digestion. However, so far anaerobic digestion models that have been proposed only consider two pathways for methane production, namely, acetoclastic methanogenesis and hydrogenotrophic methanogenesis, via indirect interspecies hydrogen transfer, which lacks an effective way for incorporating DIET into this paradigm. In this work, a new mathematical model is specifically developed to describe DIET process in anaerobic digestion through introducing extracellular electron transfer as a new pathway for methane production, taking anaerobic transformation of ethanol to methane as an example. The developed model was able to successfully predict experimental data on methane dynamics under different experimental conditions, supporting the validity of the developed model. Modeling predictions clearly demonstrated that DIET plays an important role in contributing to overall methane production (up to 33 %) and conductive material (i.e., carbon cloth) addition would significantly promote DIET through increasing ethanol conversion rate and methane production rate. The model developed in this work will potentially enhance our current understanding on syntrophic metabolism via DIET. PMID- 27757754 TI - Postpartum Health and Wellness: A Call for Quality Woman-Centered Care. AB - Introduction The first 3 months after giving birth can be a challenging time for many women. The Postpartum Health and Wellness special issue explores this period, one that is often overlooked and under-researched. Methods This issue is designed to bring greater focus to the need for woman-centered care during the postpartum period. Articles in this issue focus on four key areas: (1) the postpartum visit and access to care, (2) the content of postpartum care and postpartum health concerns, (3) interconception care including contraception, and (4) policy, systems, and measurement. Results The submissions highlight deficits in the provision of comprehensive care and services during a critical period in women's lives. The research highlighted in this issue supports the recommendation that Maternal and Child Health leaders collaborate to create woman-centered postpartum services that are part of a coordinated system of care. Conclusion In order to achieve optimal health care in the postpartum period it is becoming more apparent that increased flexibility of services, cross-training of providers, a "no wrong door" approach, new insurance and work-place policy strategies, improved communication, and effective coordinated support within a system that values all women and families is required. PMID- 27757755 TI - Viruses That Exploit Actin-Based Motility for Their Replication and Spread. AB - The actin cytoskeleton is a crucial part of the eukaryotic cell. Viruses depend on host cells for their replication, and, as a result, many have developed ways of manipulating the actin network to promote their spread. This chapter reviews the various ways in which viruses utilize the actin cytoskeleton at discrete steps in their life cycle, from entry into the host cell, replication, and assembly of new progeny to virus release. Various actin inhibitors that function in different ways to affect proper actin dynamics can be used to parse the role of actin at these steps. PMID- 27757756 TI - Free Fatty Acid Receptors and Cancer: From Nutrition to Pharmacology. AB - The effects of fatty acids on cancer cells have been studied for decades. The roles of dietary long-chain n-3 polyunsaturated fatty acids, and of microbiome generated short-chain butyric acid, have been of particular interest over the years. However, the roles of free fatty acid receptors (FFARs) in mediating effects of fatty acids in tumor cells have only recently been examined. In reviewing the literature, the data obtained to date indicate that the long-chain FFARs (FFA1 and FFA4) play different roles than the short-chain FFARs (FFA2 and FFA3). Moreover, FFA1 and FFA4 can in some cases mediate opposing actions in the same cell type. Another conclusion is that different types of cancer cells respond differently to FFAR activation. Currently, the best-studied models are prostate, breast, and colon cancer. FFA1 and FFA4 agonists can inhibit proliferation and migration of prostate and breast cancer cells, but enhance growth of colon cancer cells. In contrast, FFA2 activation can in some cases inhibit proliferation of colon cancer cells. Although the available data are sometimes contradictory, there are several examples in which FFAR agonists inhibit proliferation of cancer cells. This is a unique response to GPCR activation that will benefit from a mechanistic explanation as the field progresses. The development of more selective FFAR agonists and antagonists, combined with gene knockout approaches, will be important for unraveling FFAR mediated inhibitory effects. These inhibitory actions, mediated by druggable GPCRs, hold promise for cancer prevention and/or therapy. PMID- 27757757 TI - Mammalian Actins: Isoform-Specific Functions and Diseases. AB - Actin is the central building block of the actin cytoskeleton, a highly regulated filamentous network enabling dynamic processes of cells and simultaneously providing structure. Mammals have six actin isoforms that are very conserved and thus share common functions. Tissue-specific expression in part underlies their differential roles, but actin isoforms also coexist in various cell types and tissues, suggesting specific functions and preferential interaction partners. Gene deletion models, antibody-based staining patterns, gene silencing effects, and the occurrence of isoform-specific mutations in certain diseases have provided clues for specificity on the subcellular level and its consequences on the organism level. Yet, the differential actin isoform functions are still far from understood in detail. Biochemical studies on the different isoforms in pure form are just emerging, and investigations in cells have to deal with a complex and regulated system, including compensatory actin isoform expression. PMID- 27757758 TI - Ligands at the Free Fatty Acid Receptors 2/3 (GPR43/GPR41). AB - A large number of reviews and commentaries have highlighted the potential role of the short-chain fatty acid receptors GPR41 (FFA3) and, particularly, GPR43 (FFA2) as an interface between the intestinal microbiota and metabolic and inflammatory disorders. However, short-chain fatty acids have very modest potency and display limited selectivity between these two receptors, and studies on receptor knockout mice have resulted in non-uniform conclusions; therefore, selective and high potency/high-affinity synthetic ligands are required to further explore the contribution of these receptors to health and disease. Currently no useful orthosteric ligands of FFA3 have been reported and although a number of orthosteric FFA2 agonists and antagonists have been described, a lack of affinity of different chemotypes of FFA2 antagonists at the mouse and rat orthologs of this receptor has hindered progress. Selective allosteric regulators of both FFA2 and FFA3 have provided tools to address a number of basic questions in both in vitro and ex vivo preparations, but at least some of the positive modulators appear to be biased and able to regulate only a subset of the functional capabilities of the short-chain fatty acids. Significant further progress is required to provide improved tool compounds to better assess potential translational opportunities of these receptors for short-chain fatty acids. PMID- 27757759 TI - Molecular Control of Actin Dynamics In Vivo: Insights from Drosophila. AB - The actin cytoskeleton provides mechanical support for cells and generates forces to drive cell shape changes and cell migration in morphogenesis. Molecular understanding of actin dynamics requires a genetically traceable model system that allows interdisciplinary experimental approaches to elucidate the regulatory network of cytoskeletal proteins in vivo. Here, we will discuss some examples of how advances in Drosophila genetics and high-resolution imaging techniques contribute to the discovery of new actin functions, signaling pathways, and mechanisms of actin regulation in vivo. PMID- 27757760 TI - FFA2 and FFA3 in Metabolic Regulation. AB - The short-chain fatty acid receptors FFA2 (GPR43) and FFA3 (GPR41) are activated by acetate, propionate, and butyrate. These ligands are produced by bacteria in the gut. In addition, the body itself can in particular produce acetate, and acetate plasma levels have been shown to be increased, e.g., in diabetic patients or during periods of starvation. FFA2 and FFA3 are both expressed by enteroendocrine cells and pancreatic beta-cells. In addition, FFA2 is found on immune cells and adipocytes, whereas FFA3 is expressed by some peripheral neurons. It has therefore been speculated that short-chain fatty acid receptors are involved in the regulation of various body functions under different nutritional and metabolic conditions. Here we summarize recent data on the role of FFA2 and FFA3 in the regulation of metabolic, immunological, and neuronal functions and discuss the potential pharmacological relevance of this receptor system. PMID- 27757761 TI - Myosins: Domain Organisation, Motor Properties, Physiological Roles and Cellular Functions. AB - Myosins are cytoskeletal motor proteins that use energy derived from ATP hydrolysis to generate force and movement along actin filaments. Humans express 38 myosin genes belonging to 12 classes that participate in a diverse range of crucial activities, including muscle contraction, intracellular trafficking, cell division, motility, actin cytoskeletal organisation and cell signalling. Myosin malfunction has been implicated a variety of disorders including deafness, hypertrophic cardiomyopathy, Usher syndrome, Griscelli syndrome and cancer. In this chapter, we will first discuss the key structural and kinetic features that are conserved across the myosin family. Thereafter, we summarise for each member in turn its unique functional and structural adaptations, cellular roles and associated pathologies. Finally, we address the broad therapeutic potential for pharmacological interventions that target myosin family members. PMID- 27757762 TI - Ligands at Free Fatty Acid Receptor 1 (GPR40). AB - FFA1 is a G protein-coupled receptor activated by medium- to long-chain fatty acids. FFA1 plays important roles in various physiological processes such as insulin secretion and energy metabolism. FFA1 expressed on pancreatic beta-cells and intestine contributes to insulin and incretin secretion, respectively. These physiological functions of FFA1 are interesting as an attractive drug target for type II diabetes and metabolic disorders. A number of synthetic FFA1 ligands have been developed and they have contributed to our current understanding of the physiological and pathophysiological functions of FFA1 both in in vitro and in vivo studies. In addition, these synthetic ligands also provided information on the structure-activity relationships of FFA1 ligands. Further, FFA1 protein crystallized with one of the high affinity agonist leads provided useful insights for the development of more effective ligands. Among FFA1 ligands, several compounds have been further investigated in the clinical trials. Thus, FFA1 ligands have great potential as drug candidates. In this section, recent progress about FFA1 ligands and the possibility of their clinical use are described. PMID- 27757763 TI - Using Biosensors to Study Free Fatty Acid Receptor Pharmacology and Function. AB - The free fatty acid (FFA) family of G protein coupled receptors (GPCRs) has generated significant interest for exploiting its members as potential drug targets. However, unravelling the complex pharmacology of this family of receptors has proven challenging. In recent years the use of biosensor technologies capable of assessing biological functions in living cells, and in real time, has greatly enhanced our ability to study GPCR pharmacology and function. These include genetically encoded sensors that change the intensity or wavelength of light emitted from a bioluminescent or fluorescent protein in response to a stimulus, as well as non-genetically encoded sensors able to measure more global cellular changes, such as mass redistribution within a cell. This chapter will examine how these sensors can be used to study GPCRs, and in particular how they are helping uncover the pharmacology of the FFA family of receptors. PMID- 27757764 TI - Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. AB - Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge-pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small-molecule modulators at the FFA receptors. PMID- 27757765 TI - Signalling Pathways Controlling Cellular Actin Organization. AB - The actin cytoskeleton is essential for morphogenesis and virtually all types of cell shape changes. Reorganization is per definition driven by continuous disassembly and re-assembly of actin filaments, controlled by major, ubiquitously operating machines. These are specifically employed by the cell to tune its activities in accordance with respective environmental conditions or to satisfy specific needs.Here we sketch some fundamental signalling pathways established to contribute to the reorganization of specific actin structures at the plasma membrane. Rho-family GTPases are at the core of these pathways, and dissection of their precise contributions to actin reorganization in different cell types and tissues will thus continue to improve our understanding of these important signalling nodes. Furthermore, we will draw your attention to the emerging theme of actin reorganization on intracellular membranes, its functional relation to Rho-GTPase signalling, and its relevance for the exciting phenomenon autophagy. PMID- 27757766 TI - Telomere length is regulated by FGF-2 in human embryonic stem cells and affects the life span of its differentiated progenies. AB - The ability of human embryonic stem cells (hESCs) to proliferate indefinitely is attributed to its high telomerase activity and associated long telomere. However, factors regulating telomere length in hESCs remain largely uncharacterized. The aims of this study were, to identify factors which modulate telomere length of hESCs, and to determine if the telomere length of hESCs influences cellular senescence of its differentiated progeny cells. Telomerase reverse transcriptase (TERT) gene expression, telomerase activity and telomere length of hESCs cultured in different culture systems were compared. Genetically identical hESCs of different telomere lengths were differentiated into fibroblasts simultaneously, and the population doubling and cellular senescence levels were determined. We found that telomere lengths were significantly different in different culture systems and Fibroblast growth factor-2 (FGF-2) upregulated TERT expression, telomerase activity and telomere length via Wnt/beta-catenin signaling pathway in hESCs in a significant manner. We also provide evidence that fibroblast differentiated from hESCs with longer telomere exhibited significant more population doublings and longer life span than those derived from hESCs with shorter telomeres. Thus, FGF-2 levels in hESCs culture systems can be manipulated to generate cells with longer telomere which would be advantageous in the applications of hESCs in regenerative medicine. PMID- 27757767 TI - A New SEYHAN's Approach in Case of Heterogeneity of Regression Slopes in ANCOVA. AB - In this study, when the assumptions of linearity and homogeneity of regression slopes of conventional ANCOVA are not met, a new approach named as SEYHAN has been suggested to use conventional ANCOVA instead of robust or nonlinear ANCOVA. The proposed SEYHAN's approach involves transformation of continuous covariate into categorical structure when the relationship between covariate and dependent variable is nonlinear and the regression slopes are not homogenous. A simulated data set was used to explain SEYHAN's approach. In this approach, we performed conventional ANCOVA in each subgroup which is constituted according to knot values and analysis of variance with two-factor model after MARS method was used for categorization of covariate. The first model is a simpler model than the second model that includes interaction term. Since the model with interaction effect has more subjects, the power of test also increases and the existing significant difference is revealed better. We can say that linearity and homogeneity of regression slopes are not problem for data analysis by conventional linear ANCOVA model by helping this approach. It can be used fast and efficiently for the presence of one or more covariates. PMID- 27757768 TI - Erratum to: Military and veteran health behavior research and practice: challenges and opportunities. PMID- 27757769 TI - Choose (and use) your tools wisely: "Validated" measures and advanced analyses can provide invalid evidence for/against a theory. PMID- 27757770 TI - Protective effect of sesquiterpene lactone parthenolide on LPS-induced acute lung injury. AB - Acute lung injury (ALI) is a respiratory failure disease and the major source of mortality in the critically ill patients. The main pathological changes involved in ALI include the excessive recruitment and activation of neutrophils by increased pro-inflammatory mediators. However, any specific therapy for ALI has not been developed. The objective of this study was to investigate protective effects of parthenolide, a sesquiterpene lactone produced in feverfew, on LPS induced lung injury. In the present study, parthenolide treatment reduced infiltration of inflammatory cells, airway permeability and production of pro inflammatory cytokines in LPS-induced ALI mouse model. Further, LPS-stimulated phosphorylation of NF-kappaB, the key regulatory transcription factor in ALI, was inhibited by parthenolide treatment in lung epithelial BEAS-2B cells and alveolar macrophage MH-S cells. These results suggest that parthenolide may provide a beneficial therapeutic strategy for ALI. PMID- 27757771 TI - The Influence of Mineral Matrices on the Thermal Behavior of Glycine. AB - On the Hadean-Early Archean Earth, the first islands must have provided hot and dry environments for abiotically formed organic molecules. The heat sources, mainly volcanism and meteorite impacts, were also available on Mars during the Noachian period. In recent work simulating this scenario, we have shown that neat glycine forms a black, sparingly water-soluble polymer ("thermomelanoid") when dry-heated at 200 degrees C under pure nitrogen. The present study explores whether relevant minerals and mineral mixtures can change this thermal behavior. Most experiments were conducted at 200 or 250 degrees C for 2 or 7 days. The mineral matrices used were phyllosilicates (Ca-montmorillonites SAz-1 and STx-1, Na-montmorillonite SAz-1-Na, nontronite NAu-1, kaolinite KGa-1), salts (NaCl, NaCl-KCl, CaCl2, artificial sea salt, gypsum, magnesite), picritic basalt, and three Martian regolith simulants (P-MRS, S-MRS, JSC Mars-1A). The main analytical method employed was high-performance liquid chromatography (HPLC). Glycine intercalated in SAz-1 and SAz-1-Na was well protected against thermomelanoid formation and sublimation at 200 degrees C: after 2 days, 95 and 79 %, respectively, had either survived unaltered or been transformed into the cyclic dipeptide (DKP) and linear peptides up to Gly6. The glycine survival rate followed the order SAz-1 > SAz-1-Na > STx-1 ~ NAu-1 > KGa-1. Very good protection was also provided by artificial sea salt (84 % unaltered glycine after 200 degrees C for 7 days). P-MRS promoted the condensation up to Gly6, consistent with its high phyllosilicate content. The remaining matrices were less effective in preserving glycine as such or as peptides. PMID- 27757773 TI - Cultural Adaptation and Implementation of Family Evidence-Based Interventions with Diverse Populations. AB - Family evidence-based interventions (FEBIs) are effective in creating lasting improvements and preventing children's behavioral health problems, even in genetically at-risk children. Most FEBIs, however, were designed for English speaking families. Consequently, providers have difficulty engaging non-English speaking populations in their own country or in other countries where the content, language, and recruitment methods of the FEBIs do not reflect their culture. The practical solution has been to culturally adapt existing FEBIs. Research suggests this can increase family engagement by about 40 %. This article covers background, theory, and research on FEBIs and the need to engage more diverse families. Steps for culturally adapting FEBIs with fidelity are presented based on our own and local implementers' experiences in 36 countries with the Strengthening Families Program. These steps, also previously recommended by a United Nations Office on Drugs and Crime panel of experts in family skills interventions, include: (1) creating a cultural advisory group, (2) assessing specific needs of cultural subgroups, (3) language translation, (4) hiring implementers from the culture, (5) developing culturally adapted training systems, (6) making cultural adaptations cautiously during repeated delivery, (7) continuous implementation quality and outcome evaluation to assure effectiveness in comparison with the original FEBI, (8) developing local and international dissemination partnerships, and (9) securing funding support for sustainability. Future efficacy trials should compare existing FEBIs to culturally adapted versions to determine comparative cost effectiveness. PMID- 27757772 TI - Skeletal changes after restoration of the euparathyroid state in patients with hypoparathyroidism and primary hyperparathyroidism. AB - Restoration of the euparathyroid state is associated with improvement of bone dynamics both in hypoparathyroidism and primary hyperparathyroidism. To date, no study has directly compared these two groups following correction of parathyroid hormone excess or deficiency. The study was designed to investigate changes in bone mineral density and trabecular bone score with restoration of the euparathyroid state by parathyroidectomy in primary hyperparathyroidism or recombinant parathyroid hormone [rhPTH(1-84)] replacement in hypoparathyroidism. This was a 2-year prospective intervention study in which we evaluated areal bone mineral density by DXA and trabecular bone score in 52 hypoparathyroid patients on rhPTH(1-84) replacement and 27 patients with primary hyperparathyroidism who underwent parathyroidectomy. We evaluated changes in areal bone mineral density by DXA and trabecular bone score at baseline, 6, 12, 18, and 24 months. After parathyroidectomy, areal bone mineral density increased from baseline at the lumbar spine and total hip at 6 months and at the femoral neck at 12 months, while there were no changes at the distal 1/3 radius. Treatment with rhPTH(1-84) was associated with significant increases in lumbar spine and decreases in distal 1/3 radius areal bone mineral density by 18 months in hypoparathyroid patients. At this time point, hypoparathyroid subjects demonstrated a significant increase in trabecular bone score from baseline, while there were no significant changes in trabecular bone score following parathyroidectomy. Bone mineral density increases both with administration of parathyroid hormone in a state of parathyroid hormone deficiency or removal of parathyroid hormone in a state of parathyroid hormone excess. However, only hypoparathyroid patients on rhPTH(1-84) appeared to have improvements in micro-architectural pattern as assessed by trabecular bone score. PMID- 27757774 TI - Testing the psychometric properties of Kidscreen-27 with Irish children of low socio-economic status. AB - BACKGROUND: Kidscreen-27 was developed as part of a cross-cultural European Union funded project to standardise the measurement of children's health-related quality of life. Yet, research has reported mixed evidence for the hypothesised 5 factor model, and no confirmatory factor analysis (CFA) has been conducted on the instrument with children of low socio-economic status (SES) across Ireland (Northern and Republic). METHOD: The data for this study were collected as part of a clustered randomised controlled trial. A total of 663 (347 male, 315 female) 8-9-year-old children (M = 8.74, SD = .50) of low SES took part. A 5- and modified 7-factor CFA models were specified using the maximum likelihood estimation. A nested Chi-square difference test was conducted to compare the fit of the models. Internal consistency and floor and ceiling effects were also examined. RESULTS: CFA found that the hypothesised 5-factor model was an unacceptable fit. However, the modified 7-factor model was supported. A nested Chi-square difference test confirmed that the fit of the 7-factor model was significantly better than that of the 5-factor model. Internal consistency was unacceptable for just one scale. Ceiling effects were present in all but one of the factors. CONCLUSIONS: Future research should apply the 7-factor model with children of low socio-economic status. Such efforts would help monitor the health status of the population. PMID- 27757775 TI - Health-related quality of life associated with systemic corticosteroids. AB - BACKGROUND: Systemic corticosteroids (SCS) are commonly used but are associated with adverse effects. Given their prevalent use, the potential impact of SCS use on health-related quality of life (HRQoL) is important to characterize. OBJECTIVE: To assess the HRQoL of patients taking SCS. METHODS: The 2000-2003 Medical Expenditure Panel Survey was used to examine EQ-5D and SF-6D scores associated with SCS use in adults. The study sample was restricted to those with a condition for which SCS are prescribed. SCS use was categorized into three levels: none; 1-3; and >=4 prescriptions per year. HRQoL scores were regressed on SCS use (1-3 or >=4 annual prescriptions) controlling for age, gender, race, ethnicity, education, income category, geographic region, number of ER visits, number of outpatient visits, total number of chronic conditions (for which SCS are not used) and conditions for which SCS are clinically indicated. RESULTS: There were 54,856 individuals with no SCS exposure, 2245 with 1-3 and 624 with >=4 annual SCS prescriptions. In adjusted analyses, use of >=4 annual SCS prescriptions appeared to be associated with significantly lower EQ-5D (US), EQ 5D (UK), SF-6D and EQ-5D VAS scores compared to no exposure: -0.032, -0.047, 0.036, and -7.58. CONCLUSION: While SCS are efficacious and widely used for numerous conditions, results suggest that their use may be associated with a substantial deleterious impact on HRQoL. This potential negative effect should be considered in balance with the cost and efficacy of comparable treatments. PMID- 27757776 TI - Erratum to: Association of sugary beverages with survival among patients with cancers of the upper aerodigestive tract. PMID- 27757777 TI - Incidence and time trends of childhood lymphomas: findings from 14 Southern and Eastern European cancer registries and the Surveillance, Epidemiology and End Results, USA. AB - PURPOSE: To describe epidemiologic patterns of childhood (0-14 years) lymphomas in the Southern and Eastern European (SEE) region in comparison with the Surveillance, Epidemiology and End Results (SEER), USA, and explore tentative discrepancies. METHODS: Childhood lymphomas were retrieved from 14 SEE registries (n = 4,702) and SEER (n = 4,416), diagnosed during 1990-2014; incidence rates were estimated and time trends were evaluated. RESULTS: Overall age-adjusted incidence rate was higher in SEE (16.9/106) compared to SEER (13.6/106), because of a higher incidence of Hodgkin (HL, 7.5/106 vs. 5.1/106) and Burkitt lymphoma (BL, 3.1 vs. 2.3/106), whereas the incidence of non-Hodgkin lymphoma (NHL) was overall identical (5.9/106 vs. 5.8/106), albeit variable among SEE. Incidence increased with age, except for BL which peaked at 4 years; HL in SEE also showed an early male-specific peak at 4 years. The male preponderance was more pronounced for BL and attenuated with increasing age for HL. Increasing trends were noted in SEER for total lymphomas and NHL, and was marginal for HL, as contrasted to the decreasing HL and NHL trends generally observed in SEE registries, with the exception of increasing HL incidence in Portugal; of note, BL incidence trend followed a male-specific increasing trend in SEE. CONCLUSIONS: Registry-based data reveal variable patterns and time trends of childhood lymphomas in SEE and SEER during the last decades, possibly reflecting diverse levels of socioeconomic development of the populations in the respective areas; optimization of registration process may allow further exploration of molecular characteristics of disease subtypes. PMID- 27757779 TI - Socioeconomic impact of alcohol in patients with alcoholic liver disease in eastern India. AB - AIM: The aim of this study is to estimate the socioeconomic impact of alcohol use on patients with alcoholic liver disease (ALD) and their families. METHODS: The demographic and socioeconomic data were collected from hospitalized ALD patients and attendants using a self designed non validated questionnaire and analyzed. RESULTS: Study subjects included 100 consecutive ALD patients (all males). Sixty percent were between 30 and 50 years. Most were married (96 %), literate (63 %), either businessmen (37 %) or employed (30 %) and belonged to middle socioeconomic class. Ninety percent started alcohol use before age 30 years and half during teenage. Mean alcohol intake was 190 mL/day (mean duration 23 years); 60 % consumed alcohol daily. Concomitant tobacco abuse was noted in 79 %. Average expenditure on alcohol was Rs 3800/month. Average hospitalizations for ALD related problems was 2.6 times/year with average expenditure of INR 30,000 (~440 US$) during each hospitalization. For treatment expenses, 86 % of patients borrowed money from friends/relatives, 36 % used saving deposits, and 4 % sold personal belongings. Eleven percent lost their job, and 7 % sold immovable property. In 43 % of cases, children were deprived of education. Besides, 52 % had disturbed social and family life, 34 % abused their spouse, 20 % suffered accidents, and 37 % indulged in physical violence. CONCLUSION: Majority of ALD patients and their families had disturbed social and family life and incurred severe financial loss arising of alcohol use. PMID- 27757778 TI - Paracoccidioides brasiliensis-associated dermatitis and lymphadenitis in a dog. AB - Paracoccidioidomycosis (PCM) is an endemic disease of humans from Latin America that is caused by Paracoccidioides brasiliensis and P. lutzii, with most cases of PCM in domestic animals being associated with P. brasiliensis. This study presents the clinical, cytological, mycological, serological, and molecular findings associated with P. brasiliensis in a dog from Southern Brazil. Fine needle biopsies were collected from the skin and several lymph nodes of a 5-year old female Labrador dog that had enlargement of most superficial lymph nodes. Cytology of the skin and lymph nodes revealed pyogranulomatous dermatitis and lymphadenitis associated with fine-necked, budding fungal structures consistent with the Paracoccidioides genus of organisms; mycological culture derived from the lymph node aspirate demonstrated similar budding structures. Serological assays using exoantigens obtained from the fungal culture demonstrated that the fungal organisms derived from the lymph node were antigenically similar to P. brasiliensis by immunodiffusion and Western blot. A PCR assay, using the fungal culture as input, amplified a partial segment of the internal transcribed spacer 1 and 2 regions of P. brasiliensis; direct sequencing and phylogenetic analyses confirmed the PCR product as P. brasiliensis. The combined cytological, mycological, serological, and molecular findings confirmed a diagnosis of fungal dermatitis and lymphadenitis due to P. brasiliensis in this dog. This case represents the third description of clinical PCM in dogs and the first confirmation of mycotic dermatitis associated with P. brasiliensis in this species. The participation of dogs in the possible dissemination of PCM is reviewed, and it is proposed that dogs are probable accidental hosts in the epidemiological cycle associated with P. brasiliensis. PMID- 27757780 TI - Comparison of osteoconductivity and absorbability of beta-tricalcium phosphate and hydroxyapatite in clinical scenario of opening wedge high tibial osteotomy. AB - The purpose of this study was to compare the osteoconductivity, and absorbability of hydroxyapatite or beta-tricalcium phosphate in clinical scenario of opening wedge high tibial osteotomy Total 41 knees of 40 patients with follow up period of more than 1 year were enrolled. These patients were divided into two groups, Group I (22 knees, 21 patients) used hydroxyapatite and Group II (19 knees, 19 patients) used beta-tricalcium phosphate as a substitute in the opening gap. According to proven method, the osteoconductivity was assessed radiographically by the extent of new bone formation at osteotomy space and absorbability was evaluated by measuring the area occupied by substitute at immediate postoperative, postoperative 6 months and 1 year. Regarding preoperative demographic data, no significant differences were found between two groups. No statistically significant differences were found between two groups regarding lower limb alignment (mechanical femorotibial angle, weight-bearing line%) and posterior tibial slope at postoperative and final follow up radiographs. Concerning the osteoconductivity, there were no significant differences between two groups in any zone. However, the absorption rate was significantly greater in the Group II than in Group I at 6 months (Group I: 13.7 +/- 6.8, group II: 35.3 +/- 15.8, P = 0.001) and 1 year (Group I: 24.2 +/- 6.3, Group II: 49.6 +/- 14.3, P < 0.0001). The complications related to bone substitutes were not observed. Both hydroxyapatite and beta-tricalcium phosphate showed satisfactory gap healing without complications and can be successfully used as alternative healing materials in opening wedge high tibial osteotomy. Our study showed that beta tricalcium phosphate has superior absorbability than hydroxyapatite. But osteoconductivity showed no significant difference. PMID- 27757781 TI - Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors. AB - Brain metastases (BM) is one of the most crucial distant metastases in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. There is no consensus about which EGFR tyrosine kinase inhibitor (TKI) is most effective against BM in such patients. Here, we compared prognoses of patients with EGFR-TKI naive EGFR-positive BM treated with erlotinib or gefitinib after BM diagnosis. Of 269 patients with NSCLC treated with EGFR TKIs at a single institution, we reviewed medical records of 205 patients with documented EGFR mutations. Eleven patients were administered erlotinib, and 52 patients were administered gefitinib as the first-line EGFR-TKI treatment after diagnosis. We used propensity score matching to balance patient backgrounds between groups, and the log-rank test to compare survival curves. Patients with BM at the induction of chemotherapy had a poorer prognosis than those without BM [median overall survival (OS) 18.5 vs. 28.0 months]. Meanwhile, there was no significant difference in OS between those with or without BM at the initiation of EGFR-TKI treatment (20.3 vs. 23.8 months). Median OS of patients treated with erlotinib was not significantly longer than that of patients treated with gefitinib (25.0 vs. 18.1 months). The presence of BM at the initiation of EGFR TKI treatment had no apparent effect on survival. Erlotinib was deemed more effective than gefitinib in preventing intracranial lesions and prolonging survival; however, prospective studies are needed to confirm these results. PMID- 27757782 TI - Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis. AB - Ovarian cancer is the first leading cause of mortality in gynecological malignancies. To identify key genes and microRNAs in ovarian cancer, mRNA microarray dataset GSE36668, GSE18520, GSE14407 and microRNA dataset GSE47841 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using GEO2R. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. Protein-protein interaction (PPI) network was established by STRING and visualized by Cytoscape. Following, overall survival (OS) analysis of hub genes was performed by the Kaplan-Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Moreover, miRecords was applied to predict the targets of the DEMs. A total of 345 DEGs were obtained, which were mainly enriched in the terms related to cell cycle, mitosis, and ovulation cycle process. A PPI network was constructed, consisting of 141 nodes and 296 edges. Sixteen genes had high degrees in the network. High expression of four genes of the 16 genes was associated with worse OS of patients with ovarian cancer, including CCNB1, CENPF, KIF11, and ZWINT. A significant module was detected from the PPI network. The enriched functions and pathways included cell cycle, nuclear division, and oocyte meiosis. Additionally, a total of 36 DEMs were identified. The expression of KIF11 was negatively correlated with that of has-miR-424 and has-miR-381, and it was also the potential target of two microRNAs. In conclusion, these results identified key genes, which could provide potential targets for ovarian cancer diagnosis and treatment. PMID- 27757783 TI - Overexpression of autotaxin is associated with human renal cell carcinoma and bladder carcinoma and their progression. AB - Autotaxin (ATX) as an important tumor cell motility-stimulating factor is upregulated in many different types of cancer. ATX, a member of the ectonucleotide pyrophosphatase and phosphodiesterase family of enzymes, possesses lysophospholipase D activity which hydrolyzes lysophosphatidylcholine to generate the potent tumor growth factor and mitogen lysophosphatidic acid (LPA). LPA acts on specific G-protein-coupled receptors, thereby regulating cell growth, migration, and survival. This study aimed to investigate the differences in gene expression pattern of ATX between cancerous and adjacent normal tissue of human renal cell carcinoma (RCC) and bladder carcinoma (BC) and find the correlation between ATX expression and clinicopathological features of both of these carcinomas. Both the RCC and BC tissues and with the adjacent normal tissues were collected. Immunohistochemistry and Western blotting analysis were used to detect the extent of ATX expression in all of these samples. Immunohistochemistry and Western blot analysis revealed that expression of ATX protein in carcinoma tissues is significantly higher than that in the adjacent normal tissues. Immunohistochemistry analysis showed that ATX is localized in cytoplasm. Western blotting analysis showed that ATX protein is expressed in both RCC and BC, and the expression levels were 69.5 and 48.0 %, respectively, higher in RCC and BC carcinoma tissue samples than in the adjacent normal tissues, which is consistent with the results of immunohistochemistry study. Thus, this study provided the evidence that ATX is highly expressed in both RCC and BC. Further research can be done to identify the diagnosis and treatment significance of both these carcinomas. PMID- 27757784 TI - Permitting patients to pay for participation in clinical trials: the advent of the P4 trial. AB - In this article we explore the ethical issues raised by permitting patients to pay for participation (P4) in clinical trials, and discuss whether there are any categorical objections to this practice. We address key considerations concerning payment for participation in trials, including patient autonomy, risk/benefit and justice, taking account of two previous critiques of the ethics of P4. We conclude that such trials could be ethical under certain strict conditions, but only if other potential sources of funding have first been explored or are unavailable. PMID- 27757785 TI - 2',3'-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents. AB - Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2',3'-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABAA and 5-HT3 receptors, whose membrane currents were unaffected by the tested compounds. PMID- 27757787 TI - Identification of risk factors for inappropriate and suboptimal initiation of direct oral anticoagulants. AB - Direct Oral Anticoagulants (DOACs) require specific dosing and monitoring to ensure safe and appropriate use. The purpose of this evaluation was to identify patient- and process-related factors that correlate with increased risk of inappropriate prescribing of DOACs. A retrospective chart review was conducted in three outpatient clinics within an academic medical center to identify patients started on DOAC therapy and evaluate the appropriateness of DOAC initiation. Data collected included patient demographics, DOAC medication initiated, dose, indication, baseline laboratory values, concomitant medications, type and specialty of prescriber, and initiation setting. Appropriateness of initial dose was assessed and data were analyzed in order to identify factors correlating with inappropriate use. One-hundred sixty-seven patients initiated on a DOAC were identified. Most patients were prescribed anticoagulation for atrial fibrillation (74.9 %) and most commonly prescribed rivaroxaban (62.9 %). An inappropriate dose was prescribed in 24 (14.4 %) patients. Female patients and patients over 75 years were more likely to be prescribed an inappropriate initial dose. Baseline evaluation of blood counts and organ function were often not performed: hemoglobin values had not been drawn within the month prior to initiation in 28.7 % of patients, serum creatinine in 22.8 %, alanine transaminase in 52.1 %, and total bilirubin in 64.1 %. Lack of baseline labs was more pronounced in patients initiated on a DOAC in the outpatient setting. Dosing and baseline lab collection for DOAC initiation were suboptimal in all settings analyzed. Targeted interventions are needed to ensure the safe and appropriate use of DOAC therapy. PMID- 27757786 TI - MRI can be used to assess advanced T-stage colon carcinoma as well as rectal carcinoma. AB - PURPOSE: To evaluate the feasibility of assessing advanced T-stage (T3-T4) colorectal carcinomas by correlating MRI with histopathological findings. MATERIALS AND METHODS: The study population comprised 31 patients with 32 lesions (22 colon and 10 rectal carcinomas). The relationship between the tumor and bowel layers on T2- and contrast-enhanced T1-weighted images (T2WI, CE-T1WI), bowel wall deformity, and the linear architecture of subserosal fat on T2WI scans was independently assessed by two radiologists. Diagnostic ability and interobserver agreement were evaluated using Fisher's exact test and kappa statistics, respectively. RESULTS: The sensitivity/specificity for disrupting the outer layer on T2WI scans for the differentiation between Tis-T2 and T3-T4 colorectal carcinoma was 100/75 % (p < 0.05) for both observers; on CE-T1WI, it was 88.0/50 % (p = 0.13) for one and 96.0/50 % (p = 0.11) for the other. The sensitivity/specificity for recognizing the reticulated linear architecture to distinguish T3 from T4 colon carcinoma was 83.3/84.6 % (p < 0.05) for one reader and 100/92.3 % (p < 0.05) for the other reader. CONCLUSION: Disruption of the outer low-intensity layer on T2WI scans was the most important finding for the diagnosis of T3-T4 colorectal carcinoma. The reticulated linear architecture of the fat tissue was suggestive of T4 colon carcinoma. PMID- 27757788 TI - Calprotectin Pegylation Enhanced Its Physical and Structural Properties. AB - Calprotectin is member of the S-100 protein family with a wide plethora of intra and extracellular functions. Anticancer activities, antimicrobial effects and being a qualified disease marker are among the compelling features of this protein to be used as a pharmaceutical agent. However, there are several impediments to applications of protein pharmaceuticals including: proteolytic degradation, short circulating half-life, low solubility and immunogenicity. Pegylation is a common bioconjugation polymer capable of overcoming these drawbacks. Recombinant expression and purification of calprotectin along with its pegylation would result in enhanced pharmaco-dynamic and pharmacokinetic properties. Our florescence spectroscopy and far Ultraviolet-optical density results indicate that pegylation altered the physical and structural properties of the calprotectin to become in a more stable and functionally active state. Due to enhanced pharmacodynamic and pharmacokinetic properties of the calprotectin via pegylation, this study would pave the way for better in vitro and in vivo validations of calprotectin applications in medical practice. PMID- 27757789 TI - mHealth Technologies to Influence Physical Activity and Sedentary Behaviors: Behavior Change Techniques, Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: mHealth programs offer potential for practical and cost-effective delivery of interventions capable of reaching many individuals. PURPOSE: To (1) compare the effectiveness of mHealth interventions to promote physical activity (PA) and reduce sedentary behavior (SB) in free-living young people and adults with a comparator exposed to usual care/minimal intervention; (2) determine whether, and to what extent, such interventions affect PA and SB levels and (3) use the taxonomy of behavior change techniques (BCTs) to describe intervention characteristics. METHODS: A systematic review and meta-analysis following PRISMA guidelines was undertaken to identify randomized controlled trials (RCTs) comparing mHealth interventions with usual or minimal care among individuals free from conditions that could limit PA. Total PA, moderate-to-vigorous intensity physical activity (MVPA), walking and SB outcomes were extracted. Intervention content was independently coded following the 93-item taxonomy of BCTs. RESULTS: Twenty-one RCTs (1701 participants-700 with objectively measured PA) met eligibility criteria. SB decreased more following mHealth interventions than after usual care (standardised mean difference (SMD) -0.26, 95 % confidence interval (CI) -0.53 to -0.00). Summary effects across studies were small to moderate and non-significant for total PA (SMD 0.14, 95 % CI -0.12 to 0.41); MVPA (SMD 0.37, 95 % CI -0.03 to 0.77); and walking (SMD 0.14, 95 % CI -0.01 to 0.29). BCTs were employed more frequently in intervention (mean = 6.9, range 2 to 12) than in comparator conditions (mean = 3.1, range 0 to 10). Of all BCTs, only 31 were employed in intervention conditions. CONCLUSIONS: Current mHealth interventions have small effects on PA/SB. Technological advancements will enable more comprehensive, interactive and responsive intervention delivery. Future mHealth PA studies should ensure that all the active ingredients of the intervention are reported in sufficient detail. PMID- 27757790 TI - Hospital length-of-stay and costs among pulmonary embolism patients treated with rivaroxaban versus parenteral bridging to warfarin. AB - We sought to compare length-of-stay (LOS), total hospital costs, and readmissions among pulmonary embolism (PE) patients treated with rivaroxaban versus parenterally bridged warfarin. We identified adult PE (primary diagnostic code = 415.1x) patients in the Premier Database (11/2012-9/2015), and included those with >=1 PE diagnostic test on days 0-2. Rivaroxaban users (allowing <=2 days of prior parenteral therapy) were 1:1 propensity score matched to patients parenterally bridged to warfarin. LOS, total costs, and readmission for venous thromboembolism (VTE) or major bleeding within the same or subsequent 2 months were compared between cohorts. Separate analyses were performed in low-risk PE patients. Rivaroxaban use was associated with a 1.4-day [95 % confidence interval (CI) -1.47 to -1.28] shorter LOS, and $2322 (95 % CI -$2499 to -$2146) reduction in costs compared to parenterally bridged warfarin (p < 0.001 for both). There was no difference in readmission for VTE (1.5 versus 1.7 %) or major bleeding (0.3 versus 0.2 %) between the rivaroxaban and parenterally bridged warfarin cohorts (p >= 0.27 for both). Results were similar in low-risk patients (0.2-1.0 day and $251-$1751 reductions in LOS and costs, respectively, p <= 0.01 for all). In patients with PE, rivaroxaban was associated with reduced LOS and costs, without increased risk of readmission versus parenterally bridged warfarin. Similar results were observed in low-risk PE patients. PMID- 27757791 TI - Treatment of the osmotic demyelination syndrome: the earlier the better? PMID- 27757792 TI - Synthesis and purification of galacto-oligosaccharides: state of the art. AB - Lactose-derived non-digestible oligosaccharides are prominent components of functional foods. Among them, galacto-oligosaccharides (GOS) outstand for being prebiotics whose health-promoting effects are supported on strong scientific evidences, having unique properties as substitutes of human milk oligosaccharides in formulas for newborns and infants. GOS are currently produced enzymatically in a kinetically-controlled reaction of lactose transgalactosylation catalyzed by beta-galactosidases from different microbial strains. The enzymatic synthesis of GOS, although being an established technology, still offers many technological challenges and opportunities for further development that has to be considered within the framework of functional foods which is the most rapidly expanding market within the food sector. This paper presents the current technological status of GOS production, its main achievements and challenges. Most of the problems yet to be solved refer to the rather low GOS yields attainable that rarely exceed 40 %, corresponding to lactose conversions around 60 %. This means that the product or reaction (raw GOS) contains significant amounts of residual lactose and monosaccharides (glucose and galactose). Efforts to increase such yields have been for the most part unsuccessful, even though improvements by genetic and protein engineering strategies are to be expected in the near future. Low yields impose a burden on downstream processing to obtain a GOS product of the required purity. Different strategies for raw GOS purification are reviewed and their technological significance is appraised. PMID- 27757793 TI - Changes in fatty acid composition of Stenotrophomonas maltophilia KB2 during co metabolic degradation of monochlorophenols. AB - The changes in the cellular fatty acid composition of Stenotrophomonas maltophilia KB2 during co-metabolic degradation of monochlorophenols in the presence of phenol as well as its adaptive mechanisms to these compounds were studied. It was found that bacteria were capable of degrading 4-chlorophenol (4 CP) completely in the presence of phenol, while 2-chlorophenol (2-CP) and 3 chlorophenol (3-CP) they degraded partially. The analysis of the fatty acid profiles indicated that adaptive mechanisms of bacteria depended on earlier exposure to phenol, which isomer they degraded, and on incubation time. In bacteria unexposed to phenol the permeability and structure of their membranes could be modified through the increase of hydroxylated and cyclopropane fatty acids, and straight-chain and hydroxylated fatty acids under 2-CP, 3-CP and 4-CP exposure, respectively. In the exposed cells, regardless of the isomer they degraded, the most important changes were connected with the increase of the contribution of branched fatty acid on day 4 and the content of hydroxylated fatty acids on day 7. The changes, particularly in the proportion of branched fatty acids, could be a good indicator for assessing the progress of the degradation of monochlorophenols by S. maltophilia KB2. In comparison, in phenol degrading cells the increase of cyclopropane and straight-chain fatty acid content was established. These findings indicated the degradative potential of the tested strain towards the co-metabolic degradation of persistent chlorophenols, and extended the current knowledge about the adaptive mechanisms of these bacteria to such chemicals. PMID- 27757794 TI - Production of anti-streptococcal liamocins from agricultural biomass by Aureobasidium pullulans. AB - Liamocins are unique heavier-than-water "oils" produced by certain strains of the fungus Aureobasidium pullulans. Liamocins have antibacterial activity with specificity for Streptococcus sp. Previous studies reported that liamocin yields were highest from strains of A. pullulans belonging to phylogenetic clades 8, 9, and 11, cultured on medium containing sucrose. In this study, 27 strains from these clades were examined for the first time for production of liamocins from agricultural biomass substrates. Liamocin yields were highest from strains in phylogenetic clade 11, and yields were higher from cultures grown on sucrose than from those grown on pretreated wheat straw. However, when supplementary enzymes (cellulase, beta-glucosidase, and xylanase) were added, liamocin production on pretreated wheat straw was equivalent to that on sucrose. Liamocins produced from wheat straw were free of the melanin contamination common in sucrose-grown cultures. Furthermore, MALDI-TOF MS analysis showed that liamocins produced from wheat straw were under-acetylated, resulting in higher proportions of the mannitol A1 and B1 species of liamocin, the latter of which has the highest biological activity against Streptococcus sp. PMID- 27757795 TI - Yellow fever and Hajj: with all eyes on Zika, a familiar flavivirus remains a threat. AB - Hajj is among the world's largest mass gatherings, drawing between 2 and 3.5 million Muslims from 183 nations annually to perform pilgrimage in Mecca, Saudi Arabia. Infectious disease outbreaks can be imported both into the Hajj population and exported internationally by returning pilgrims. The domestic Saudi population can also be at risk of outbreaks traveling amid this mass migration. With yellow fever reported for the first time in China following the infection of expatriate Chinese workers in Angola and a full blown outbreak underway in wider West Africa, the prospect of yellow fever outbreaks in Asia threatens to impact Saudi Arabia, both during and beyond the Hajj season. With global focus trained on Zika, the rising threat of yellow fever cannot be overlooked. Strategies to mitigate risk to Saudi Arabia and the global population are thereby suggested. PMID- 27757796 TI - Analysis of 100 consecutive cases of resectable pancreatic neuroendocrine neoplasms: clinicopathological characteristics and long-term outcomes. AB - The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) has increased rapidly in recent years. However, the clinicopathological characteristics of pNENs are poorly understood. Medical records of patients who underwent surgery and were confirmed as pNENs by pathological examination from January 2003 to February 2015 in Qilu Hospital were reviewed retrospectively. A total of 100 patients, 36 males and 64 females, were included with a mean operation age of 46.26 + 13.41 years. Among the 100 cases, 76 had insulinomas and 24 had non functional pNENs. Tumor size ranged from 0.5 cm to 9 cm, and the mean size was 2.20 + 1.40 cm. The percentages of TNM stages I, II, III, and IV tumors were 89.0%, 8.0%, 0.0%, and 3.0%, respectively. Based on the WHO classification, pNENs were classified into three grades: G1, G2, and G3. G1, G2, and G3 tumors were confirmed in 72.9%, 23.7%, and 3.4% patients, respectively. The positive rates of CgA and Syn immunohistochemical staining were 94.5% (69/73) and 100% (74/74), respectively. Compared with insulinoma, non-functional pNENs have larger tumor sizes, more advanced TNM staging, a higher Ki-67 index, and a higher rate of liver metastasis (P < 0.05). In conclusion, pNENs are heterogeneous tumors with varying clinical manifestations, diverse tumor biological characteristics, and different prognoses. Non-functional pNENs present a more aggressive behavioral model and have poorer prognosis than functional pNENs. PMID- 27757797 TI - Light chains removal by extracorporeal techniques in acute kidney injury due to multiple myeloma: a position statement of the Onconephrology Work Group of the Italian Society of Nephrology. AB - Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)kappaB inflammatory pathways. Current mainstays of CN treatment are early removal of precipitating factors such as nephrotoxic drugs, acidosis and dehydration, together with rapid reduction of sFLC levels. Introduction of the proteasome inhibitor bortezomib has significantly improved the response rates in multiple myeloma due to its ability to rapidly reduce sFLC levels and has been referred to as "renoprotective" therapy. As an adjunct to chemotherapy, several new extracorporeal techniques have raised interest as a further means to reduce sFLC concentrations in the treatment of CN. Whether addition of extracorporeal therapies to renoprotective therapy can result in better renal recovery is still a matter of debate and there are currently no guidelines in this field. In this positon paper, we offer an overview of the available data and the authors' perspectives on extracorporeal treatments in CN. PMID- 27757798 TI - Amplicon-Based RNA Interference Targeting V2 Gene of Cotton Leaf Curl Kokhran Virus-Burewala Strain Can Provide Resistance in Transgenic Cotton Plants. AB - The conserved coat or V2 gene of begomoviruses is responsible for viral movement in the plant cells. RNAi technology was used to silence V2 gene for resistance against these viruses in transgenic plants. The transformation of the RNAi-based gene construct targeting V2 gene of CLCuKoV-Bur, cloned under 35S promoter, was done in two elite cotton varieties MNH-786 and VH-289 using shoot apex cut method of gene transformation. The transformation efficiency was found to be 3.75 and 2.88 % in MNH-786 and VH-289, respectively. Confirmation of successful transformation was done through PCR in T 0, T 1, and T 2 generations using gene specific primers. Transgenic cotton plants were categorized on the basis of the virus disease index in T 1 generation. Copy number and transgene location were observed using FISH and karyotyping in T 2 generation which confirmed random integration of V2 RNAi amplicon at chromosome 6 and 16. Real-time quantitative PCR analyses of promising transgenic lines showed low virus titer compared to wild-type control plants upon challenging them with viruliferous whiteflies in a contained environment. From the results, it was concluded that amplicon V2 RNAi construct was able to limit virus replication and can be used to control CLCuV in the field. PMID- 27757799 TI - Fathers' Imprisonment and Mothers' Multiple-Partner Fertility. AB - We consider the intersection between two striking U.S. trends: dramatic increases in the imprisonment of fathers and increases in the proportion of mothers who have children with more than one partner (multiple-partner fertility, or MPF). Using matched longitudinal administrative data that provide unusually comprehensive and accurate information about the occurrence and timing of imprisonment, fertility, and MPF for the population of the state of Wisconsin, we consider the relationship between paternal imprisonment and MPF among unwed mothers. Employing discrete-time event history analysis with multinomial logistic regression, we model the occurrence and timing of the mother's second birth, distinguishing between a birth with the same father and a birth with a different father, and distinguishing between current imprisonment and a history of imprisonment. We find that current imprisonment is associated with an increased likelihood of MPF and a decreased likelihood of fertility with the same father (compared with no additional birth) and that a history of imprisonment is associated with increased MPF in some models but not in our preferred model. To control for unobserved heterogeneity among mothers and assess the evidence of a causal effect of fathers' imprisonment, we also employ the case-time-control method, a fixed-effects method for the analysis of nonrepeated events. Results suggest that fathers' current imprisonment may increase mothers' MPF. Policy implications are discussed. PMID- 27757800 TI - Ready, Willing, and Able? Impediments to the Onset of Marital Fertility Decline in the United States. AB - This study relies on IPUMS samples of the 1850, 1860, 1870, and 1880 censuses, aggregate census data, and the timing of state laws criminalizing abortion to construct regional estimates of marital fertility in the United States and estimate correlates of marital fertility. The results show a significant lag between the onset of marital fertility decline in the nation's northeastern census divisions and its onset in western and southern census divisions. Empirical models indicate the presence of cultural, economic, and legal impediments to the diffusion of marital fertility control and illustrate the need for more inclusive models of fertility decline. PMID- 27757801 TI - Significance of surgical management for cystic prolactinoma. AB - PURPOSE: It is generally accepted that dopamine agonists (DA) represent the first line treatment for most patients with prolactinoma, and patients become candidates for surgical intervention when DA is contraindicated. Surgical indication for cystic prolactinoma remains controversial. This study was performed to investigate the significance of surgery for cystic prolactinoma. METHODS: A total of 28 patients that underwent transsphenoidal resection of prolactinoma between February 2004 and May 2016 were reviewed. Five consecutive patients with cystic prolactinoma were included in this study. Our surgical strategy for cystic prolactinoma was categorized as follows: first, when the purpose of surgical resection was normalization of the prolactin level, aggressive resection was performed; second, when volume reduction was essential to relieve the visual symptoms and headache, internal decompression was performed followed by DA therapy. The clinical outcomes were analyzed accordingly. RESULTS: All cystic prolactinoma were resected via the transsphenoidal approach without any complications, and all symptoms including visual impairment and hypogonadal activity were finally relieved combined with medication. CONCLUSIONS: Surgery for cystic prolactinoma could be a better option. Transsphenoidal surgery is relatively safe to remove the cystic prolactinoma, additionally it can normalize the prolactine level and achieve adequate and rapid decompression of optic chiasm. The risk of transsphenoidal surgery is highly dependent on the skill of the surgeon and treatment decision for cystic prolactinoma needs to be individualized for each patient. PMID- 27757802 TI - Erratum to: Osteochondritis Dissecans Lesions in Family Members: Does a Positive Family History Impact Phenotypic Potency? PMID- 27757803 TI - Low- and high-dose radioiodine therapy for low-/intermediate-risk differentiated thyroid cancer: a preliminary clinical trial. AB - OBJECTIVES: To compare the ablation results, therapeutic responses and adverse reactions between a low dose (1.1 GBq) or high dose (3.7 GBq) of 131I in low /intermediate-risk differentiated thyroid cancer (DTC) patients. The factors influencing the ablation result and therapeutic response were also analyzed. METHODS: The researchers used a random number table to randomly assign the enrolled patients to the low-dose group or high-dose group at a 1:1 ratio, and assessment of ablation result, therapeutic response, and adverse reactions evaluated 6 +/- 3 months after therapy. RESULTS: A total of 140 patients were enrolled in the study through October 2014-June 2015. Until February 2016, 132 patients completed the trial. 99 patients were re-examined under thyroid stimulating hormone (TSH) stimulation 3-9 months after 131I therapy. For the low dose and high-dose groups, the success rates of ablation were 52.7 % (29/55) and 59.1 % (26/44), respectively. The ablation results did not differ significantly between the two groups (P = 0.548). One hundred and thirty two patients were re examined 2-9 months after 131I therapy. The low-dose group had an excellent response rate of ~80 % (53/66), an indeterminate response rate of ~20 % (13/66), and no cases with a biochemical incomplete response. The high-dose group had an excellent response rate of ~85 % (56/66), an indeterminate response rate of ~11 % (7/66), and a biochemical incomplete response rate of ~4 % (3/66). No significant differences in the therapeutic response were observed between the two groups (P = 0.087). Patients in stage N1b had a significantly lower success rate of ablation than those in stage N0 (P = 0.000). The success rate of ablation increased significantly with lower thyroglobulin (Tg) levels (P = 0.000). A pre-treatment Tg level was significantly associated with a higher excellent response rate (P = 0.002). Pre-treatment-stimulated Tg of 0.47 and 3.09 MUg/L were identified as cut off values for predicting the ablation result and therapeutic response, respectively. The incidences of adverse reactions were 18 % (12/66) and 39 % (26/66) in the low-dose and high-dose groups, respectively, and this difference between the two groups was significant (P = 0.007). CONCLUSIONS: The result of thyroid remnant ablation and the response to therapy did not differ significantly between the two groups. The low-dose group had a lower incidence of adverse reactions than the high-dose group. N1b and pre-treatment-stimulated Tg were factors influencing the ablation result, whereas pre-treatment-stimulated Tg was a factor influencing the therapeutic response. Pre-treatment-stimulated Tg of 0.47 and 3.09 MUg/L were identified as cut-off values for predicting the ablation result and therapeutic response, respectively. The study protocol was approved by the Clinical Trials and Biomedical Ethics Committee of our hospital and registered on the Chinese Clinical Trial Registry under the registration number ChiCTR-IOR-15006139. PMID- 27757804 TI - Erratum to: Synthesis of Cholesterol-Conjugated Magnetic Nanoparticles for Purification of Human Paraoxonase 1. PMID- 27757805 TI - Using Flow Cytometry to Evaluate the Stress Physiological Response of the Yeast Saccharomyces carlsbergensis ATCC 6269 to the Presence of 5-Hydroxymethylfurfural During Ethanol Fermentations. AB - Lignocellulosic materials have been considered low-cost effective substrates for bioethanol production. However, lignocellulosic pretreatment releases toxic compounds such as 5-hydroxymethylfurfural (HMF) that is known to inhibit the yeast growth and ethanol production. In this work, flow cytometry was used to monitor the physiological response of the yeast Saccharomyces carlsbergensis ATCC 6269 in the presence of different initial HMF concentrations within the range of 0-15 g/L, in terms of cell membrane integrity, potential, and intracellular lipids. It was observed that the HMF presence affected more significantly the yeast growth than the ethanol production. At 15 g/L HMF, the yeast growth and fermentation ability were completely inhibited. The cell membrane integrity and potential decreased as the initial HMF concentration increased. At the end of the fermentation process with 10 g/L HMF, the yeast culture contained 45 % of cells with depolarized plasma membrane, 52 % of cells with permeabilized plasma membrane, and 53 % of cells with increasing reactive oxygen species (ROS) levels. Using the Nile Red stain, it was observed that intracellular polar lipids were more affected by the initial HMF concentration than the neutral lipids, probably due to the extensive membrane damage. PMID- 27757806 TI - Effects of Low Moisture Anhydrous Ammonia (LMAA) Pretreatment at Controlled Ammoniation Temperatures on Enzymatic Hydrolysis of Corn Stover. AB - Corn stover was treated using low-moisture anhydrous ammonia (LMAA) at controlled ammoniation temperature. Moisturized corn stover (50 % moisture) was contacted with anhydrous ammonia (0.1 g NH3/g-biomass) in a batch reactor at various temperatures (ambient to 150 degrees C). After ammoniation at elevated and controlled temperature, ammoniated corn stover was pretreated at various temperatures (60-150 degrees C) for 72-144 h. Change in composition was marginal at low pretreatment temperature but was relatively severe with pretreatment at high temperature (130-150 degrees C). The latter resulted in low enzymatic digestibility. It was also observed that extreme levels (either high or low) of residual ammonia affected enzymatic digestibility, while residual ammonia improved by 1.0-1.5 %. The LMAA method enhanced enzymatic digestibility compared to untreated corn stover (29.8 %). The highest glucan and xylan digestibility (84.1 and 73.6 %, respectively) was obtained under the optimal LMAA conditions (i.e., ammoniation at 70 degrees C for 20 min, followed by pretreatment at 90 degrees C for 48 h). PMID- 27757807 TI - Funding global emergency medicine research-from seed grants to NIH support. AB - BACKGROUND: Funding for global health has grown significantly over the past two decades. Numerous funding opportunities for international development and research work exist; however, they can be difficult to navigate. The 2013 Academic Emergency Medicine consensus conference on global health and emergency care identified the need to strengthen global emergency care research funding, solidify existing funding streams, and expand funding sources. RESULTS: This piece focuses on the various federal funding opportunities available to support emergency physicians conducting international research from seed funding to large institutional grants. In particular, we focus on the application and review processes for the Fulbright and Fogarty programs, National Institutes of Health (NIH) Career development awards, and the Medical Education Partnership Initiative (MEPI), including tips and pathways through each application process. CONCLUSIONS: Lastly, the paper provides an index that may be used as a guide in determining whether the amount of funding provided by a grant is worth the effort in applying. PMID- 27757808 TI - From Goethe's plant archetype via Haeckel's biogenetic law to plant evo-devo 2016. AB - In 1790, the German poet Johann W. v. Goethe (1749-1832) proposed the concept of a hypothetical sessile organism known as the 'Plant Archetype,' which was subsequently reconstructed and depicted by 19th-century botanists, such as Franz Unger (1800-1870) and Julius Sachs (1832-1897), and can be considered one of the first expressions of Evo-Devo thinking. Here, we present the history of this concept in the context of Ernst Haeckel's (1834-1919) biogenetic law espoused in his Generelle Morphologie der Organismen of 1866. We show that Haeckel's idea of biological recapitulation may help to explain why various phenomena, such as the ontogenetic transformations in the stellar anatomy of lycopods and ferns, the transition from primary to secondary anatomy of seed plants, the presence of unfused juvenile cone scale segments in the Japanese cedar (Cryptomeria japonica), and the transition of C3- to C4-photosynthesis in the ontogeny of maize (Zea mays), appear to support his theories. In addition, we outline the current status of plant evolutionary developmental biology (Evo-Devo), which can be traced back to Haeckel's (1866) biogenetic law, with a focus on the model plant thale cress (Arabidopsis thaliana). PMID- 27757809 TI - A novel cadaveric study of the morphometry of the serratus anterior muscle: one part, two parts, three parts, four? AB - The serratus anterior is portrayed as a homogeneous muscle in textbooks and during functional activities and rehabilitation exercises. It is unclear whether the serratus anterior is composed of subdivisions with distinctive morphology and functions. The purpose of this study was to determine whether the serratus anterior could be subdivided into different structural parts on the basis of its segmental architectural parameters. Eight formalin-embalmed serratus anterior muscles were dissected and the attachments of each fascicle documented. Orientation and size of each fascicle were measured and the physiological cross sectional area (PCSA) calculated. Three subdivisions of the serratus anterior were identified. A new finding was the discovery of two distinctive fascicles attached to the superior and inferior aspects of rib 2. The rib 2 inferior fascicle had the largest PCSA (mean 1.6 cm2) and attached, with the rib 3 fascicle, along the medial border of the scapula to form the middle division. The rib 2 superior and rib 1 fascicles attached to the superior angle of the scapula (upper division). Fascicles from ribs 4-8/9 attached to the inferior angle of the scapula (lower division). Mean fascicle angle relative to a vertical midline reference and PCSA for each division were 29 degrees and 1.3 cm2 (upper), 90 degrees and 2.2 cm2 (middle) and 59 degrees and 3.0 cm2 (lower). This novel study demonstrated the presence of morphologically distinct serratus anterior subdivisions. The results of this study will inform the development of optimal techniques for the assessment, treatment and rehabilitation of this architecturally complex muscle in shoulder and neck pain. PMID- 27757810 TI - Paraplegia related to solitary lesion of the cervicomedullary junction. PMID- 27757812 TI - Call for manuscripts: Digital technologies and cancer survivorship. PMID- 27757811 TI - Catastrophic presentation of a patient with combined NMOSD and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a case report. PMID- 27757813 TI - Reasons for and Against Use of Non-absorbable, Synthetic Mesh During Pelvic Organ Prolapse Repair, According to the Prolapsed Compartment. AB - Awareness and reporting of mesh-related complications of pelvic organ prolapse repairs have increased in recent years. As a result, deciding whether to use a mesh or not has become a difficult task for urogynecologists. Our aim was to summarize reasons for and against the use of mesh in prolapse repair based on a review of relevant literature. Scopus and PubMed databases were searched for papers reporting on the efficacy and safety of native tissue versus non absorbable, synthetic mesh prolapse repairs. Randomized controlled trials, systematic reviews, and meta-analyses were included. Evidence is presented for each vaginal compartment separately. In the anterior compartment, mesh repairs seem to offer clearly superior efficacy and durability of results compared to native tissue repairs, but with an equally clear increase in complication rates. In the isolated posterior compartment prolapse, high-quality evidence is sparse. As far as the apical compartment is concerned, sacrocolpopexy is the most efficacious, yet the most invasive procedure. Data on the comparison of transvaginal mesh versus native tissue repairs of the apical compartment are somewhat ambiguous. Given the inevitable coexistence of advantages and disadvantages of mesh use in each of the prolapsed vaginal compartments, an individualized treatment decision, based on weighing risks against benefits for each patient, seems to be the most rational approach. PMID- 27757814 TI - Points to Consider in the Foundation of Multidisciplinary Units for Psoriatic Arthritis: A Delphi Study and a Systematic Review of the Literature. AB - INTRODUCTION: In numerous clinical practice guidelines, emphasis is placed on the need for coordinated care of psoriatic arthritis (PsA) between rheumatologists and the objective was to develop experience-based points to consider facilitating the implementation of multidisciplinary units (Dermatology/Rheumatology) for the management of patients with PsA. METHODS: A scientific committee of rheumatology and dermatology experts in the management of PsA, and with experience in joint care, discussed the critical aspects of multidisciplinary PsA Units. The discussion became the basis for a Delphi survey in two rounds submitted to a panel of 24 specialists in rheumatology and dermatology not involved in PsA units. The statements and practices that reached a consensus were summarized and further elaborated. RESULTS: After two Delphi rounds, agreement was reached for 49 of the 50 proposed statements. These included a justification of the units, objectives, and utilities, as well as operational aspects of the units, such as the minimal and ideal premises, referral criteria, and necessary resources. The statements were compiled in 11 points to consider. CONCLUSIONS: This consensus offers some points to consider, including premises and recommendations, for the development of specialized Units in the management of PsA based on expert opinion. We trust these guidelines may facilitate their implementation in the future. FUNDING: Pfizer. PMID- 27757815 TI - NUT Midline Carcinoma of the Nasal Cavity. AB - Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare, aggressive, poorly differentiated form of squamous cell carcinoma caused by a chromosomal rearrangement of the NUT gene on chromosome 15. These tumors have a predilection for midline and paramidline structures of the upper aerodigestive tract and mediastinum and can affect patients across a broad age range, including children. In the current example, a 53 year old male presented with a mass originating in the left nasal cavity. The clinical, radiographic, and morphologic features of NMC are discussed. PMID- 27757817 TI - Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline. AB - OPINION STATEMENT: Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder that is characterized by episodic nausea and vomiting. Initially thought to only affect children, CVS in adults was often misdiagnosed with significant delays in therapy. Over the last decade, there has been a considerable increase in recognition of CVS in adults but there continues to be a lack of knowledge about management of this disorder. This paper seeks to provide best practices in the treatment of CVS and also highlight some novel therapies that have the potential in better treating this disorder in the future. Due to the absence of randomized control trials, we provide recommendations based on review of the available literature and expert consensus on the therapy of CVS. This paper will discuss prophylactic and abortive therapy and general measures used to treat an episode of CVS and also discuss pathophysiology as it pertains to novel therapy. Recent recognition of the association of chronic marijuana use with cyclic vomiting has led to the possibility of a new diagnosis called "Cannabinoid Hyperemesis Syndrome," which is indistinguishable from CVS. The treatment for this purported condition is abstinence from marijuana despite scant evidence that marijuana use is causative. Hence, this review will also discuss emerging data on the role for the endocannabinoid system in CVS and therapeutic agents targeting the endocannabinoid system, which offer the potential of transforming the care of these patients. PMID- 27757816 TI - Blood Biomarkers as Outcome Measures in Inflammatory Neurologic Diseases. AB - Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal bands and immunoglobulin index, serum anti aquaporin 4 antibodies, and serum anti-John Cunningham virus antibodies. Thus, there is a significant unmet need for biomarkers to assess prognosis, response to therapy, or potential treatment complications. Here we describe emerging biomarkers that are in development, focusing on those from peripheral blood. There are several limitations in the process of discovery and validation of a good biomarker, such as the pathophysiological complexity of MS and the technical difficulties in globally standardizing methods for sampling, processing, and conserving biological specimens. In spite of these limitations, ongoing international collaborations allow the exploration of many interesting molecules and markers to validate diagnostic, prognostic, and therapeutic-response biomarkers. PMID- 27757819 TI - Brain network connectivity in women exposed to intimate partner violence: a graph theory analysis study. AB - Evidence suggests that women who suffer from intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) have structural and functional alterations in specific brain regions. Yet, little is known about how brain connectivity may be altered in individuals with IPV, but without PTSD. Women exposed to IPV (n = 18) and healthy controls (n = 18) underwent structural brain imaging using a Siemens 3T MRI. Global and regional brain network connectivity measures were determined, using graph theory analyses. Structural covariance networks were created using volumetric and cortical thickness data after controlling for intracranial volume, age and alcohol use. Nonparametric permutation tests were used to investigate group differences. Findings revealed altered connectivity on a global and regional level in the IPV group of regions involved in cognitive emotional control, with principal involvement of the caudal anterior cingulate, the middle temporal gyrus, left amygdala and ventral diencephalon that includes the thalamus. To our knowledge, this is the first evidence showing different brain network connectivity in global and regional networks in women exposed to IPV, and without PTSD. Altered cognitive-emotional control in IPV may underlie adaptive neural mechanisms in environments characterized by potentially dangerous cues. PMID- 27757818 TI - Can Clinical Evaluation Predict Return to Sport after Acute Hamstring Injuries? A Systematic Review. AB - BACKGROUND: The current literature on the value of clinical evaluation for predicting time to return to sport (RTS) after acute hamstring injuries has not been systematically summarised. OBJECTIVES: The aim of this study was to systematically review the literature on the prognostic value of clinical findings (patient history and physical examination) for time to RTS after acute hamstring injuries in athletes. DATA SOURCES: The databases PubMed, EMBASE, SPORTDiscus and Cochrane Library were searched between October 2014 and August 2015. STUDY ELIGIBILITY CRITERIA: Studies evaluating patient history and/or physical assessment findings as possible predictors for time to RTS (described in days or weeks) following acute hamstring injuries in athletes were eligible for inclusion. DATA ANALYSIS: Two authors independently screened the search results and assessed risk of bias using the modified Quality in Prognosis Studies (QUIPS) tool for quality appraisal of prognosis studies. We used a best-evidence synthesis to determine the level of evidence. RESULTS: Sixteen studies were included, of which one study had a low risk of bias and 15 had a high risk of bias. Moderate evidence for an association with time to RTS was found for three clinical findings (visual analogue scale; pain at time of injury, self-predicted time to RTS and clinician predicted time to RTS). There was limited evidence for an association with time to RTS for seven clinical findings (muscle pain during everyday activities, popping sound at injury, forced to stop within 5 min, visual bruising at the site of injury, width (cm) of tenderness to palpation, pain on trunk flexion and pain on active knee flexion initially after injury). The remaining clinical findings revealed either conflicting evidence or limited evidence for an association with time to RTS. CONCLUSION: There is at present no strong evidence that any clinical finding at baseline provides a valuable prognosis for time to RTS after an acute hamstring injury. There is moderate evidence that visual analogue scale pain at time of injury and predictions for time to RTS by the patient and the clinician are associated with time to RTS. The methodological quality of the current literature is characterised by a substantial risk of bias and reporting of RTS definitions and criteria for RTS were inconsistent. We provide recommendations that can guide the design of future studies. PMID- 27757820 TI - Increased brain connectivity and activation after cognitive rehabilitation in Parkinson's disease: a randomized controlled trial. AB - Cognitive rehabilitation programs have demonstrated efficacy in improving cognitive functions in Parkinson's disease (PD), but little is known about cerebral changes associated with an integrative cognitive rehabilitation in PD. To assess structural and functional cerebral changes in PD patients, after attending a three-month integrative cognitive rehabilitation program (REHACOP). Forty-four PD patients were randomly divided into REHACOP group (cognitive rehabilitation) and a control group (occupational therapy). T1-weighted, diffusion weighted and functional magnetic resonance images (fMRI) during resting state and during a memory paradigm (with learning and recognition tasks) were acquired at pre-treatment and post-treatment. Cerebral changes were assessed with repeated measures ANOVA 2 * 2 for group x time interaction. During resting-state fMRI, the REHACOP group showed significantly increased brain connectivity between the left inferior temporal lobe and the bilateral dorsolateral prefrontal cortex compared to the control group. Moreover, during the recognition fMRI task, the REHACOP group showed significantly increased brain activation in the left middle temporal area compared to the control group. During the learning fMRI task, the REHACOP group showed increased brain activation in the left inferior frontal lobe at post-treatment compared to pre-treatment. No significant structural changes were found between pre- and post-treatment. Finally, the REHACOP group showed significant and positive correlations between the brain connectivity and activation and the cognitive performance at post-treatment. This randomized controlled trial suggests that an integrative cognitive rehabilitation program can produce significant functional cerebral changes in PD patients and adds evidence to the efficacy of cognitive rehabilitation programs in the therapeutic approach for PD. PMID- 27757821 TI - Distinct effects of late adulthood cognitive and physical activities on gray matter volume. AB - Engagement in cognitive activity (CA) and physical activity (PA) during the lifespan may counteract brain atrophy later in life. Here, we investigated engagement in CA and PA during late adulthood in association with gray matter volume (GM) in normal older adults, with special focus on the hippocampus. Forty five cognitively normal older individuals (mean age: 72) underwent T1-weighted MRI and self-reported CA and PA assessment. Whole brain voxel-wise multiple regression models were carried out to assess the relationships between CA, PA and GM volume adjusted by age and sex. Further adjustment for years of education and risk factors were performed. Voxel-wise analyses were projected on 3D hippocampal surface views. Cognitive activity and PA demonstrated independent regional associations with GM after adjustment for confounders. Cognitive activity was related to greater GM in extended brain areas including frontal, temporal and parietal cortices, while PA was associated with increased GM in the prefrontal, insular and motor cortices. Regression maps projected on the hippocampal surface showed a common association of PA and CA within the anterior part of the hippocampus, although the effect of CA was more subtle and also extended to the posterior part. Engagement in PA and CA in late adulthood were independently related to regional GM volume, notably in aging and AD vulnerable areas. These results support the idea that both PA and CA- based interventions may be suitable to promote brain health in late adulthood. The potential synergistic effects of PA and CA need to be addressed in future studies including larger samples. PMID- 27757822 TI - Monitoring Conformational Landscape of Ovine Prion Protein Monomer Using Ion Mobility Coupled to Mass Spectrometry. AB - Prion protein is involved in deadly neurodegenerative diseases. Its pathogenicity is linked to its structural conversion (alpha-helix to beta-strand transition). However, recent studies suggest that prion protein can follow a plurality of conversion pathways, which hints towards different conformers that might coexist in solution. To gain insights on the plasticity of the ovine prion protein (PrP) monomer, wild type (A136, R154, Q171), mutants and deletions of ARQ were studied by traveling wave ion mobility experiments coupled to mass spectrometry. In order to perform the analysis of a large body of data sets, we designed and evaluated the performance of a processing pipeline based on Driftscope peak detection and a homemade script for automated peak assignment, annotation, and quantification on specific multiply charged protein data. Using this approach, we showed that in the gas phase, PrPs are represented by at least three conformer families differing in both charge state distribution and collisional cross-section, in agreement with the work of Hilton et al. (2010). We also showed that this plasticity is borne both by the N- and C-terminal domains. Effect of protein concentration, pH and temperature were also assessed, showing that (1) pH does not affect conformer distributions, (2) protein concentration modifies the conformational landscape of one mutant (I208M) only, and (3) heating leads to other unfolded species and to a modification of the conformer intensity ratios. Graphical Abstract ?. PMID- 27757823 TI - Use of Interrupted Helium Flow in the Analysis of Vapor Samples with Flowing Atmospheric-Pressure Afterglow-Mass Spectrometry. AB - The flowing atmospheric-pressure afterglow (FAPA) source was used for the mass spectrometric analysis of vapor samples introduced between the source and mass spectrometer inlet. Through interrupted operation of the plasma-supporting helium flow, helium consumption is greatly reduced and dynamic gas behavior occurs that was characterized by schlieren imaging. Moreover, mass spectra acquired immediately after the onset of helium flow exhibit a signal spike before declining and ultimately reaching a steady level. This initial signal appears to be due to greater interaction of sample vapor with the afterglow of the source when helium flow resumes. In part, the initial spike in signal can be attributed to a pooling of analyte vapor in the absence of helium flow from the source. Time resolved schlieren imaging of the helium flow during on and off cycles provided insight into gas-flow patterns between the FAPA source and the MS inlet that were correlated with mass-spectral data. Graphical Abstract ?. PMID- 27757824 TI - Survey of neuroanesthesia fellowships in Canada. PMID- 27757825 TI - Erratum to: Application of Radiation Chemistry to Some Selected Technological Issues Related to the Development of Nuclear Energy. PMID- 27757826 TI - Teledildonics and New Ways of "Being in Touch": A Phenomenological Analysis of the Use of Haptic Devices for Intimate Relations. AB - The aim of this paper is to analyse teledildonics from a phenomenological perspective in order to show the possible effects they will have on ourselves and on our society. The new way of using digital technologies is to merge digital activities with our everyday praxes, and there are already devices which enable subjects to be digitally connected in every moment of their lives. Even the most intimate ones are becoming mediated by devices such as teledildonics which digitally provide a tactual stimulation allowing users to have sexual intercourse through them. The efforts made in order to provide such an intertwinement of our everyday lives and digital technologies are evident, but the effects produced by them are not clear at all. This paper will analyse these technologies from a phenomenological perspective in order to understand their effects on the constitution of the subjects and on our society at the intimate level. PMID- 27757827 TI - The impact of urban areas on the water quality gradient along a lowland river. AB - The effects of five towns on river water pollution were examined along the Lyna River (southern watershed of the Baltic Sea, northern Poland). The relationships among the spatially derived indicators of urbanization, environmental variables, and physico-chemical and microbiological data (heterotrophic plate count at 22 and 37 degrees C, and fecal coli) obtained from longitudinal river profiling have been examined with the use of multivariate analyses such as principal component analysis with factor analysis (PCA/FA) and hierarchical cluster analysis (HCA). We recognized the river channel as an environmental path that links serial urban areas into an "urban river continuum." An overall increasing trend in nutrients and indicator bacteria from suburban headwaters to urbanized sections of the river was detected despite a significant decrease in those between the towns. We concluded that the role of a multicity is equally as important as a single urban area in predicting the impacts of man-made pollutants on river water quality. PMID- 27757828 TI - Unraveling uncertainties of water table slope assessment with DGPS in lowland floodplain wetlands. AB - In our study, we analyzed the combined standard uncertainty of water table slope assessment done using differential global positioning system (DGPS)-based measurements of water table elevation and distances between measurement locations. We compared and discussed uncertainties in water table slope assessments done in various hypothetical environments of lowland floodplains (water table slopes typically ranged from 1.25 . 10-4 to 1 . 10-3). Our analyses referred to elevation measurements done with the static GPS and DGPS real-time kinematic (RTK) approaches, which are currently among the most frequently used elevation measurement techniques worldwide. Calculations of the combined standard uncertainty of water table slope allowed us to conclude that the DGPS-RTK approach used in water table slope assessment can result in assessment errors as high as 50 % at short (<200 m) distances. Acceptable water table slope measurement errors (lower than 5 %) occur at distances longer than 11,320 m in the case of DGPS-RTK measurements, while, in the case of static GPS measurements, acceptable measurement errors at the same level occur at distances as low as 1350 m. Errors in water table slope assessment as high as 50 % occur at distances of 1130 m and 140 m for DGPS-RTK and static GPS measurements, respectively. We conclude that, although the DGPS-RTK methodology-due to its ease of use and time saving capabilities is very often applied to water level measurements in lowland riparian wetlands, the application of the DGPS-RTK methodology for water table slope assessment at distances shorter than a few couples of meters results in very low accuracy (errors greater than 50 %) and should not be used for calculating local slopes in low slope areas such as lowland riparian zones. PMID- 27757830 TI - Off-label use of 7Fr GuideLiner in the bifurcation coronary intervention protecting 2 side branches. AB - We report a case of percutaneous coronary intervention in a bifurcation lesion involving left circumflex (LCx) artery and 2 major posterolateral (PL) arteries. The target LCx had diffuse long and severely calcified lesion with the acute takeoff angle from the left main. Despite adequate lesion preparation with rotational atherectomy and balloon angioplasty, the stent was not deliverable, even with deep intubation of 7Fr-guiding catheter. Conventional use of guiding extension catheter (GEC) would have required removal of a wire from at least one PL because of the device interference in the GEC. However, successful stenting was achieved without removal of wires from both PL with 7Fr GuideLiner. We have also demonstrated this mechanism on ex vivo bench testing. PMID- 27757829 TI - Effect of Probiotic Soy Milk on Serum Levels of Adiponectin, Inflammatory Mediators, Lipid Profile, and Fasting Blood Glucose Among Patients with Type II Diabetes Mellitus. AB - Probiotic therapies are going to be an effective alternative therapeutic strategy in the treatment and management of diabetes. The mechanism behind the essential effects of probiotic therapies in diabetic patients was not fully understood. The objective of this study was to evaluate the effects of probiotic soy milk containing Lactobacillus planetarum A7 on inflammation, lipid profile, fasting blood glucose, and serum adiponectin among patients with type 2 diabetes mellitus. Forty patients with type 2 diabetes, at the age of 35-68 years old, were assigned to two groups in this randomized, double-blind, controlled clinical trial. The patients in the intervention group consumed 200 ml/day of probiotic soy milk containing L. planetarum A7 and those in control group consumed 200 ml/day of pure soy milk for 8 weeks. Serum TNF-alpha, C reactive protein, adiponectin, lipid profile, and fasting blood glucose were determined before and after intervention. In intervention group, serum adiponectin in pre- and post treatment did not show any significant changes (2.52 +/- 0.74 vs 2.84 +/- 0.61, P = 0.658), as well as changes in serum TNF-alpha and C reactive protein (172.44 +/ 5.7 vs 172.83 +/- 7.6, P = 0.278, 4.2 +/- 1.4 vs 4.5 +/- 1.9, P = 0.765, respectively). Low-density cholesterol and high-density cholesterol changed significantly (P = 0.023, P = 0.017, respectively), but fasting blood glucose did not show any significant changes. The results of this study showed that consumption of probiotic soy milk and soy milk has no effect on serum adiponectin and inflammation, but it can change lipid profile among type 2 diabetic patients. PMID- 27757831 TI - Healthcare and complicity in Australian immigration detention. AB - Australian immigration detention has received persistent criticism since its introduction almost 25 years ago. With the recent introduction of offshore processing, these criticisms have intensified. Riots, violence, self-harm, abuse and devastating mental health outcomes are all now well documented, along with a number of deaths. Clinicians have played a central role working in these environments, faced with the overarching issue of delivering healthcare while facilitating an abusive and harmful system. Since the re-introduction of offshore processing a number of authors have begun to discuss the possibility of a boycott. While taking such action may lead to change, further discussion is needed, not only in relation to the impact of a boycott, but whether it is possible for clinicians to engage with this system in more productive, ethical ways. This article utilises a framework proposed by Lepora and Goodin (On complicity and compromise, Oxford University Press, Oxford, 2013) that provides a structured approach to examine complicity and seeks to explore how clinicians have engaged with Australian immigration detention and ultimately whether they should continue to do so. PMID- 27757832 TI - Pixantrone: A Review in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma. AB - Pixantrone (Pixuvri(r)) is an aza-anthracenedione with a novel mode of action that is conditionally approved in the EU for use as monotherapy in adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma (NHL). In the randomized, open-label, multinational, phase 3 PIX301 trial in patients with multiply relapsed or refractory aggressive NHL, the complete response (CR) plus unconfirmed CR (uCR) rate at the end of treatment (primary endpoint) was significantly higher with intravenous pixantrone monotherapy than with a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine). Post hoc analysis also demonstrated a significantly higher CR/uCR rate in the subgroup of patients with centrally confirmed aggressive B-cell NHL who were receiving pixantrone versus a comparator agent as third- or fourth-line therapy. Pixantrone was generally well tolerated in PIX301, with a manageable adverse event profile. In conclusion, pixantrone is a useful option in patients with multiply relapsed or refractory aggressive B-cell NHL. Further results examining the use of pixantrone in combination with rituximab in patients previously treated with rituximab-containing regimens are awaited with interest. PMID- 27757833 TI - Microtubule Destabilization Paves the Way to Parkinson's Disease. AB - Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of specification and polarization of various cell types, including neurons. Although microtubules could have a role in the death of many cells and tissues, the microtubule-based degenerative mechanisms have been poorly investigated; nevertheless, during the last two decades, many clues have been accumulated suggesting the importance of the microtubule system during neurodegeneration. Thus, the aim of this review is to analyse how the changes of the microtubule cytoskeleton, in terms of organization and dynamics, as well as the failure of the microtubule-dependent neuronal processes, as axonal transport, may play a pivotal role in the chain of events leading to Parkinson's disease. Last but not least, since disease-modifying or neuroprotective strategies are a clinical priority in Parkinson's disease, we will also present the hints about the concrete possibility of a microtubule-targeted therapy, which would have the potentiality to block the running degenerative events and to prompt the regeneration of the lost tissues. PMID- 27757834 TI - Transcriptome Profile Changes in Mice with MPTP-Induced Early Stages of Parkinson's Disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Despite progress in the study of the molecular, genetic, and pathogenic mechanisms of PD, it is unclear which processes trigger the development of the pathology associated with PD. Models of the presymptomatic and early symptomatic stages of PD induced by MPTP have been used to analyze changes in transcriptome profile in brain tissues, to identify specific patterns and mechanisms underlying neurodegeneration in PD. The whole-transcriptome analysis in the brain tissues of the mice with MPTP-induced PD showed that striatum is involved in the pathogenesis in the earliest stages and the processes associated with vesicular transport may be altered. The expression profiles of the genes studied in the substantia nigra and peripheral blood confirm that lymphocytes from peripheral blood may reflect processes occurring in the brain. These data suggest that messenger RNA (mRNA) levels in peripheral blood may provide potential biomarkers of the neurodegeneration occurring in PD. The changes in expression at the mRNA and protein levels suggest that Snca may be involved in neurodegeneration and Drd2 may participate in the development of the compensatory mechanisms in the early stages of PD pathogenesis. Our data suggest that the brain cortex may be involved in the pathological processes in the early stages of PD, including the presymptomatic stage. PMID- 27757835 TI - Effect of Some Growth Factors on Tissue Transglutaminase Overexpression Induced by beta-Amyloid in Olfactory Ensheathing Cells. AB - Herein, we assessed in a particular glial cell type, called olfactory ensheathing cells (OECs), the effect of some growth factors (GFs) on tissue transglutaminase (TG2) overexpression induced by amyloid-beta (Abeta) with native full-length peptide 1-42 or by fragments, 25-35 or 35-25, as control. Previously, we demonstrated that TG2 overexpression induced by some stressors was down-regulated by GFs exposure in OECs. To monitor cell viability, an MTT test was used, while TG2 expression was examined using immunocytochemical and Western blot analysis. We also considered the involvement of the TG2-mediated apoptotic pathway. Vimentin expression was evaluated as well. Reactive oxygen species and reduced glutathione levels were utilized to test the oxidative intracellular status. Lactate dehydrogenase released into the medium, as a marker of necrotic cell death, was evaluated. We found that in OECs exposed to Abeta(1-42) or Abeta(25 35) for 24 h, TG2 expression increased, and we observed that the protein appeared prevalently localized in the cytosol. The pre-treatment with GFs, basic fibroblast growth factor (bFGF) or glial-derived neurotrophic factor (GDNF), down regulated the TG2 level, which was prevalently limited to the nuclear compartment. Vimentin expression and caspase cleavage showed a significant enhancement in Abeta(1-42) and Abeta(25-35) exposed cells. The pre-treatment with bFGF or GDNF was able to restore the levels of the proteins to control values, and the intracellular oxidative status modified by the exposure to Abeta(1-42) or Abeta(25-35). Our data suggest that both bFGF or GDNF could be an innovative mechanism to contrast TG2 expression, which plays a key role in Alzheimer's disease. PMID- 27757836 TI - Lipoprotein Lipase as a Prognostic Marker in Chronic Lymphocytic Leukemia. AB - The marked clinical heterogeneity of CLL makes early prognosis assessment important. Lipoprotein lipase (LPL) has been shown to confer adverse prognosis in CLL, recent data indicating it might also contribute to CLL cell survival and metabolism. We determined LPL mRNA expression in unselected peripheral blood of 84 CLL patients by RT PCR. Results were correlated with other prognostic markers and outcome. 30/84 (40 %) of cases were LPL positive based on the cutoff established by ROC analysis. In LPL positive patients significantly shorter median survival (136 vs 258 months, p < 0.0001) and time to first treatment intervals (36 vs 144 months, p < 0.002) were documented. LPL values correlated with male gender, higher stages, more treatment requirement, CD38 positivity and unmutated IgVH genes. Among cases with 13q deletion, LPL positivity identified a subcohort with poor outcome (median survival 108 months vs NR, p < 0.0001). In multivariate analysis, cytogenetic aberrations and LPL had significant impact on survival. Our results confirm that LPL is a strong predictor of outcome in CLL, able to improve prognostic accuracy in good risk cytogenetic subgroups. The relationship between its prognostic and functional role in CLL needs to be explored further. PMID- 27757837 TI - E2/ERbeta Inhibits PPARalpha to Regulate Cell-Proliferation and Enhance Apoptosis in Hep3B-Hepatocellular Carcinoma. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a member of the nuclear receptor superfamily involved in hepatocarcinogenesis in rodents. In previous studies on liver tumor tissues, PPARalpha mRNA expression was found to be significantly higher and overexpression of ERalpha inhibited the PPARalpha expression, cell-proliferation and also induced apoptosis in Hep3B cell. However, the role of ERbeta is not known yet. Therefore, the aim of this study is to define the role of ERbeta on PPARalpha in Hep3B cells. The effect of PPARalpha signaling cascade were monitored by inducing Hep3B cells by fenofibrate. Further the cells were transfected with pCMV-ERbeta and the consequences of ERbeta overexpression on the PPARalpha induced changes such as enhanced cell proliferation and suppressed apoptosis were determined using western blot analysis and TUNEL assay. The EMSA was used to identify whether ERbeta modulates PPARalpha expression by binding to PPARalpha promoter region to repress PPARalpha promoter activity. In addition, the direct interaction between ERbeta and PPARalpha proteins was verified by co-immunoprecipitation assay. Our results show that the overexpressed ERbeta not only attenuated the effects of fenofibrate to induce the levels of apoptosis protein such as Cyt.c, Caspase 9 and Caspase 3 but also inhibited the levels of survival protein such Bcl-xL, p-Bad, cyclin A and cyclin E. All these effects of E2/ERbeta resulted in the enhancement of mitochondria dependent apoptotic pathway and the attenuation of cell proliferation. Moreover, the overexpressed ERbeta reduced the mRNA and protein levels of PPARalpha and its downstream Acyl-CoA oxidase (ACO). EMSA results show that ERbeta directly binds to PPRE and inhibit PPARalpha gene expression and according to immunoprecipitation assay ERbeta also binds strongly with PPARalpha. The E2/ERbeta further inhibited the fenofibrate-induced nuclear translocation of PPARalpha. Taken together, ERbeta might directly downregulate PPARalpha gene expression and inhibit the nuclear translocation to suppress the proliferation and induce the apoptosis of Hep3B cells. PMID- 27757838 TI - Fucosyltransferase-4 and Oligosaccharide Lewis Y Antigen as potentially Correlative Biomarkers of Helicobacter pylori CagA Associated Gastric Cancer. AB - H. pylori cytotoxin associated antigen A (CagA) plays a significant role in the progression of gastric cancer but their effect on fucosylation to develop gastric cancer is unknown. Fucosyltransferase IV (FUT4) is the key enzyme for synthesis of LewisY (LeY) carried by glycoproteins and glycolipids on the cell membrane. Herein, we compare the expression of CagA, p-EGFR, FUT4 and LeY in gastritis (n = 128, 176), gastric ulcer (n = 174, 213), and gastric cancer (n = 323, 261) tissue and serum samples, respectively by IHC and ELISA. Moreover, we investigated the potential correlation of CagA with FUT4 and LeY overexpression through EGFR activation. IHC and ELISA results showed higher positive cases of H. pylori CagA (83, 86 %), p-EGFR (81, 72 %), FUT4 (91, 97 %) and LeY (93, 92 %) in gastric cancer, compared to gastritis and gastric ulcer, H. pylori CagA (58, 67 & 59, 73 %), p-EGFR (52, 63 & 35, 47 %), FUT4 (68, 78 & 67, 82 %) and LeY (62,76 & 65, 85 %), respectively. We found a significant high expression (H-Value) of CagA (1.79, 1.66), p-EGFR (1.53, 1.58), FUT4 (2.14, 1.66) and LeY (1.69, 1.61) in gastric cancer tissues and serum, respectively as compared to chronic gastritis and gastric ulcers, CagA (0.64,1.14), p-EGFR (0.856, 0.678), FUT4 (0.949,1.197) and LeY (0.68,1.008) (P < 0.0001), respectively. Furthermore, H. pylori CagA showed significant correlation with p-EGFR (R-0.62, -0.74), FUT4 (R-0.81, -0.76) and LeY (R-0.82, -0.70) in gastric tissues and serum (P < 0.0001). H. pylori CagA plays key role in the development of gastric cancer with overexpression of FUT4/LeY, serve as potentially correlative biomarkers of H. pylori CagA associated gastric cancer. PMID- 27757839 TI - Modification of the 2012 CKD-EPI equations for the elderly Chinese. AB - BACKGROUND: Our previous studies demonstrated that 2012 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were inaccurate enough for estimating glomerular filtration rate in elderly Chinese. Thus, this study was constructed to modify these equations. METHODS: A total of 839 subjects (aged >=60 years) from four hospitals in China between October 2009 and December 2014 were included. A random sample of 674 (80.3 %) subjects was used as a training sample set, and the remaining 165 (19.7 %) subjects as the verification set. The equations were modified using the hill-climbing algorithm. RESULTS: Compared with the original CKD-EPI equations, the accuracy assessment indexes (bias, precision, accuracy and misclassification) were obviously improved after modification. Bland Altman analysis also demonstrated that this modification attempt gained success to some extent. CONCLUSIONS: The modified 2012 CKD-EPI equations could be more accurate than the original equations for elderly Chinese individuals. PMID- 27757840 TI - The Key Role of Pain Catastrophizing in the Disability of Patients with Acute Back Pain. AB - PURPOSE: This study investigated the role of anxiety sensitivity, resilience, pain catastrophizing, depression, pain fear-avoidance beliefs, and pain intensity in patients with acute back pain-related disability. METHOD: Two hundred and thirty-two patients with acute back pain completed questionnaires on anxiety sensitivity, resilience, pain catastrophizing, fear-avoidance beliefs, depression, pain intensity, and disability. RESULTS: A structural equation modelling analysis revealed that anxiety sensitivity was associated with pain catastrophizing, and resilience was associated with lower levels of depression. Pain catastrophizing was positively associated with fear-avoidance beliefs and pain intensity. Depression was associated with fear-avoidance beliefs, but was not associated with pain intensity. Finally, catastrophizing, fear-avoidance beliefs, and pain intensity were positively and significantly associated with acute back pain-related disability. CONCLUSION: Although fear-avoidance beliefs and pain intensity were associated with disability, the results showed that pain catastrophizing was a central variable in the pain experience and had significant direct associations with disability when pain was acute. Anxiety sensitivity appeared to be an important antecedent of catastrophizing, whereas the influence of resilience on the acute back pain experience was limited to its relationship with depression. PMID- 27757841 TI - Classifying Fibromyalgia Syndrome as a Mental Disorder?-An Ambulatory Assessment Study. AB - PURPOSE: Fibromyalgia syndrome (FMS) is associated with psychological distress. The recent revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) raises the question of whether FMS is classifiable as "somatic symptom disorder" (SSD) and consequently as a mental disorder. To address this, the present ambulatory assessment study focuses on the everyday life occurrence of SSD symptoms in FMS and their predictive value concerning severity indicators of widespread pain. METHOD: Ambulatory data were assessed six times daily on 14 consecutive days via iPod. Twenty-eight women suffering from FMS indicated symptoms associated with SSD (somatic illness beliefs, health anxiety, time/energy devoted to pain, or health concerns) and momentary pain levels. Questionnaires regarding potential covariates (such as somatization, depression, health status) were completed at two additional sessions in the research laboratory. RESULTS: On average, SSD symptoms occurred three to four times daily and were mild to moderate in severity. Furthermore, these symptoms were both concurrently and prospectively associated with momentary pain intensity and subjective impairment by pain. Twenty percent of the variance in pain intensity and 28 % of the variance in subjective impairment were explained by momentary variables (SSD symptoms and intake of pain medication). Eighty-two percent of persons with FMS fulfilled the psychological SSD criterion when considering everyday occurring symptoms with at least mild severity. CONCLUSION: FMS might be diagnosed as a mental disorder according to DSM-5 in many cases. SSD symptoms proved to have predictive value for FMS severity and may thus have clinical relevance for diagnostic, prognostic, and intervention purposes. PMID- 27757842 TI - Translating Dental Flossing Intentions into Behavior: a Longitudinal Investigation of the Mediating Effect of Planning and Self-Efficacy on Young Adults. AB - PURPOSE: Although poor oral hygiene practices can have serious health consequences, a large number of adults brush or floss their teeth less than the recommended time or not at all. This study examined the mediating effect of two key self-regulatory processes, self-efficacy and planning, as the mechanisms that translate dental flossing intentions into behavior. METHOD: Participants (N = 629) comprised young adults attending a major university in Queensland, Australia. A longitudinal design guided by sound theory was adopted to investigate the sequential mediation chain for the effect of dental flossing intentions (time 1) on behavior (time 3) via self-efficacy and planning (time 2). RESULTS: A latent variable structural equation model with standardized parameter estimates revealed the model was a good fit to the data. Controlling for baseline flossing, the effect of intentions on behavior was mediated via self-efficacy and planning, with 64 % of the flossing variance accounted for by this set of predictors. Controlling for age and sex did not change the results. CONCLUSION: The results extend previous research to further elucidate the mechanisms that help to translate oral hygiene intentions into behavior and make a significant contribution to the cumulative empirical evidence about self-regulatory components in health behavior change. PMID- 27757843 TI - Illness Perceptions and Outcomes in Patients with Inflammatory Bowel Disease: Is Coping a Mediator? AB - PURPOSE: Patients with inflammatory bowel disease (IBD) often experience severe impairment in different life domains. Psychological factors, such as illness perceptions and coping, may play a role in the adjustment to IBD as indicated by mental and physical health, activity, and work impairment. The present study aimed at examining the assumption of the Common Sense Model (CSM) that coping mediates the relationship between illness perceptions and adjustment in patients with IBD. METHOD: In a cross-sectional design, 211 IBD patients (73 % Crohn's disease, 40 % male, mean age 42.9 +/- 12.9 years) attending an outpatient clinic completed questionnaires assessing illness perceptions (IPQ-R), coping (CORS), mental and physical health (SF-36), as well as activity and work impairment (WPAI). Multiple mediation analyses were applied that allow estimating the total and direct effects of all illness perception dimensions and the indirect effects through all coping strategies on the illness outcomes simultaneously. RESULTS: The analyses yielded significant direct effects of perceptions regarding the cyclical course, the chronic course, the severity of the consequences, the comprehensibility, and the emotional impact of IBD on study outcomes. Additionally, significant indirect effects were found for the perceptions regarding the severity of the consequences, the possibility of personal control, and the comprehensibility of IBD on mental and physical health as well as activity impairment through the use of one specific coping strategy, i.e., reduction of activity. CONCLUSION: The results provide evidence for the assumptions of the CSM and suggest the importance of addressing illness perceptions and activity stimulation in quality health care for IBD patients. PMID- 27757844 TI - Computer-Based Interventions for Problematic Alcohol Use: a Review of Systematic Reviews. AB - PURPOSE: The aim of this review is to provide an overview of knowledge and knowledge gaps in the field of computer-based alcohol interventions by (1) collating evidence on the effectiveness of computer-based alcohol interventions in different populations and (2) exploring the impact of four specified moderators of effectiveness: therapeutic orientation, length of intervention, guidance and trial engagement. METHODS: A review of systematic reviews of randomized trials reporting on effectiveness of computer-based alcohol interventions published between 2005 and 2015. RESULTS: Fourteen reviews met the inclusion criteria. Across the included reviews, it was generally reported that computer-based alcohol interventions were effective in reducing alcohol consumption, with mostly small effect sizes. There were indications that longer, multisession interventions are more effective than shorter or single session interventions. Evidence on the association between therapeutic orientation of an intervention, guidance or trial engagement and reductions in alcohol consumption is limited, as the number of reviews addressing these themes is low. None of the included reviews addressed the association between therapeutic orientation, length of intervention or guidance and trial engagement. CONCLUSIONS: This review of systematic reviews highlights the mostly positive evidence supporting computer based alcohol interventions as well as reveals a number of knowledge gaps that could guide future research in this field. PMID- 27757845 TI - Omic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is an epidemic metabolic condition driven by an underlying lipid homeostasis disorder. The lipid droplet (LD), the main organelle involved in neutral lipid storage and hydrolysis, is a potential target for NAFLD therapeutic treatment. In this review, we summarize recent progress elucidating the connections between LD-associated proteins and NAFLD found by genome-wide association studies (GWAS), genomic and proteomic studies. Finally, we discuss a possible mechanism by which the protein 17beta hydroxysteroid dehydrogenase 13 (17beta-HSD13) may promote the development of NAFLD. PMID- 27757847 TI - Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy. AB - Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 (FUNDC1) was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with microtubule-associated protein light chain 3 beta (LC3B) through its LC3 interaction region (LIR). Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDC1 LIR peptide phosphorylated at Ser17 (pS17), demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS17. Alternatively, phosphorylated Tyr18 (pY18) and Ser13 (pS13) in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry (ITC) assays. Therefore, our structural and biochemical results reveal a working model for the specific recognition of FUNDC1 by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy. PMID- 27757846 TI - Evolution from genetics to phenotype: reinterpretation of NSCLC plasticity, heterogeneity, and drug resistance. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities. PMID- 27757848 TI - Management of non-traumatic avascular necrosis of the femoral head-a comparative analysis of the outcome of multiple small diameter drilling and core decompression with fibular grafting. AB - BACKGROUND: The purpose of this study was to compare the clinical and radiological outcomes of multiple small diameter drilling and core decompression with fibular strut grafting in the management of non-traumatic avascular necrosis (AVN) of the femoral head. MATERIALS AND METHODS: Outcomes of patients with AVN treated by multiple small diameter drilling (group 1) were compared retrospectively with patients treated by core decompression and fibular grafting (group 2). Harris hip score (HHS) was used to assess the clinical status pre- and postoperatively. Modified Ficat and Arlet classification was used to assess the radiological stage pre- and postoperatively. RESULTS: Forty-six patients (68 hips) were included in this study. Group 1 consisted of 33 hips, and group 2 consisted of 35 hips. In stages I and IIB, there was no statistically significant difference in the final HHS between the two groups. However, in stages IIA and III, hips in group 2 had a better final HHS (P < 0.05). In terms of radiographic progression, there was no statistical difference between hips in stages I, IIA and stage IIB. However, in stage III, hips belonging to group 2 had better results (P < 0.05). Kaplan-Meier survivorship analysis showed better outcome in group 2 in stage III (P < 0.05). CONCLUSIONS: Hips with AVN in the precollapse stage can be salvaged by core decompression with or without fibular grafting. Multiple small diameter drilling is relatively simple and carries less morbidity and hence preferred in stages I and II. However, in stage III disease, core decompression with fibular strut grafting gives better results. PMID- 27757849 TI - Psychometric properties and validation of a four-item version of the Strauss Carpenter scale in bipolar disorder. AB - BACKGROUND: Bipolar disorder is a chronic illness that impairs functioning and affects the quality of life of patients. The onset of this illness usually occurs at an early age, and the risk of relapse remains high for decades. Thus, due to the great clinical relevance of identifying long-term predictors of functioning in bipolar disorder, Strauss and Carpenter developed a scale composed of items known to have prognostic value. METHODS: To determine the clinical usefulness of the four-item Strauss-Carpenter scale in bipolar disorder, a 1-year prospective follow-up study was carried out. The internal consistency, convergent and discriminant validity, and test-retest reliability of the scale were assessed. We also compared the Strauss-Carpenter scale with the reference scales Global Assessment Functioning (GAF), Clinical Global Impression for Bipolar Disorder, the Modified Version (CGI-BIP-M) and the Sheehan Disability Scale (Sheehan). Additionally, a cut-off point for remission was established. RESULTS: The total sample was composed of 98 patients with a diagnosis of bipolar disorder. The four item version of the Strauss-Carpenter scale showed to have appropriate psychometric properties, comparable to those of reference scales. The best cut off point for remission was 14. CONCLUSIONS: The four-item version of the Strauss Carpenter scale has suitable validity and reliability for the assessment of functioning in patients with bipolar disorder. PMID- 27757850 TI - Overexpression of cannabinoid receptor 1 promotes renal cell carcinoma progression. AB - Renal cell carcinoma (RCC) is a common urologic tumor with a poor prognosis. Cannabinoid receptor 1 (CB1), which is a G protein-coupled receptor, has recently been reported to participate in the genesis and development of various cancers. However, the exact role of CB1 in RCC is unknown. The aim of this study was to determine the role of CB1 in RCC cell lines and RCC prognosis, thus underlying its potential as a therapeutic target. Immunohistochemistry and western blots were performed to investigate the expression of CB1 in RCC tissues and to determine its clinicopathological significance in RCC patients. Additionally, we explored CB1 expression in RCC cell lines and evaluated the effect of AM251, a CB1 inverse agonist, and in vitro siRNA knockdown of CB1 on the cellular proliferation, migration, and apoptosis of RCC cell lines. CB1 was overexpressed in cancerous tissues compared with adjacent normal tissues. Furthermore, CB1 expression levels were an independent risk factor for overall survival for RCC patients. AM251 significantly decreased tumor cell proliferation and induced cell apoptosis by upregulating the expression of the pro-apoptotic protein Bax and decreasing the expression of the anti-apoptotic proteins survivin and Bcl-2. Migration of the RCC cell lines was also significantly inhibited after treatment with AM251 compared with untreated control groups. In addition, knockdown of CB1 expression significantly decreased cell proliferation and invasion and significantly increased apoptosis of RCC cells. CB1 expression is functionally associated to cellular proliferation, apoptosis, and invasion ability of RCC. Our data suggest that CB1 might be a potential target for RCC clinical therapy. PMID- 27757851 TI - Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo. AB - Temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM) as it can effectively inhibit the growth of GBM for some months; however, this cancer type is still incurable. The existence of glioma stem cells (GSCs) is thought to be responsible for the invariable recurrence of GBM after treatment, but GSCs are insensitive to TMZ. Our recent research showed that demethoxycurcumin (DMC), a component of curcumin, was superior to TMZ in its ability to inhibit proliferation and induce apoptosis of GSCs in vitro. In addition, the combined treatment of TMZ + DMC induced more obvious anti-GSC effects. However, in this study, no obvious synergistic anti-GSC effects of TMZ + DMC were found in vivo, while DMC was still superior to TMZ with respect to growth inhibition of GSCs in vivo. Furthermore, immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that such inhibitory effects were mainly related to the inhibition of cell proliferation rather than to apoptosis. However, a high concentration of DMC (50 mg/kg) alone or combined with TMZ could also induce approximately 10 % of the cells to undergo apoptosis according to a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Finally, an investigation of the underlying mechanism revealed that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) 3 signaling pathway played an important role in the anti-GSC effects. When the JAK inhibitor AG490 was applied, the anti-GSC effects of DMC were enhanced. Taken together, the present work reveals that DMC is superior to TMZ with respect to its anti-GSC effects in vivo, which are mediated through the inhibition of the activation of the JAK/STAT3 pathway; however, DMC demonstrated no synergistic effects with TMZ. PMID- 27757852 TI - ? PMID- 27757853 TI - ? PMID- 27757854 TI - ? PMID- 27757855 TI - ? PMID- 27757856 TI - ? PMID- 27757857 TI - ? PMID- 27757858 TI - ? PMID- 27757859 TI - ? PMID- 27757860 TI - ? PMID- 27757861 TI - [Bariatric surgery - who is suitable?] PMID- 27757862 TI - [Verrucae vulgares - clinical overview]. PMID- 27757863 TI - ? PMID- 27757864 TI - [Exocrine pancreatic insufficiency, pancreatic cancer and mesenteric artery stenosis: A rare combination of different diseases leading to an increasing frequency of diarrhea]. PMID- 27757865 TI - ? PMID- 27757866 TI - [Elder abuse and neglect - occurs more often than you may think]. PMID- 27757867 TI - [Cooperation in the nursing home: How to become a teamplayer?] PMID- 27757868 TI - ? PMID- 27757869 TI - ? PMID- 27757870 TI - ? PMID- 27757871 TI - ? PMID- 27757872 TI - ? PMID- 27757874 TI - ? PMID- 27757873 TI - ? PMID- 27757875 TI - ? PMID- 27757876 TI - ? PMID- 27757877 TI - ? PMID- 27757878 TI - ? PMID- 27757879 TI - ? PMID- 27757880 TI - ? PMID- 27757881 TI - ? PMID- 27757882 TI - ? PMID- 27757883 TI - ? PMID- 27757884 TI - ? PMID- 27757885 TI - ? PMID- 27757886 TI - ? PMID- 27757888 TI - ? PMID- 27757887 TI - ? PMID- 27757889 TI - ? PMID- 27757891 TI - ? PMID- 27757892 TI - ? PMID- 27757890 TI - ? PMID- 27757893 TI - ? PMID- 27757894 TI - ? PMID- 27757895 TI - ? PMID- 27757896 TI - ? PMID- 27757897 TI - ? PMID- 27757898 TI - ? PMID- 27757899 TI - ? PMID- 27757900 TI - ? PMID- 27757901 TI - ? PMID- 27757902 TI - ? PMID- 27757903 TI - ? PMID- 27757904 TI - ? PMID- 27757905 TI - ? PMID- 27757906 TI - ? PMID- 27757907 TI - ? PMID- 27757908 TI - ? PMID- 27757909 TI - ? PMID- 27757910 TI - ? PMID- 27757912 TI - ? PMID- 27757913 TI - [Globus sensation: etiology and diagnostics]. PMID- 27757914 TI - Risks of Routinely Clamping External Ventricular Drains for Intrahospital Transport in Neurocritically Ill Cerebrovascular Patients. AB - BACKGROUND: Current guidelines recommend routine clamping of external ventricular drains (EVD) for intrahospital transport (IHT). The aim of this project was to describe intracranial hemodynamic complications associated with routine EVD clamping for IHT in neurocritically ill cerebrovascular patients. METHODS: We conducted a retrospective review of cerebrovascular adult patients with indwelling EVD admitted to the neurocritical care unit (NICU) during the months of September to December 2015 at a tertiary care center. All IHTs from the NICU of the included patients were examined. Main outcomes were incidence and risk factors for an alteration in intracranial pressure (ICP) and cerebral perfusion pressure after IHT. RESULTS: Nineteen cerebrovascular patients underwent 178 IHTs (79.8 % diagnostic and 20.2 % therapeutic) with clamped EVD. Twenty-one IHTs (11.8 %) were associated with post-IHT ICP >= 20 mmHg, and 33 IHTs (18.5 %) were associated with escalation of ICP category. Forty IHTs (26.7 %) in patients with open EVD status in the NICU prior to IHT were associated with IHT complications, whereas no IHT complications occurred in IHTs with clamped EVD status in the NICU. Risk factors for post-IHT ICP >= 20 mmHg were IHT for therapeutic procedures (adjusted relative risk [aRR] 5.82; 95 % CI, 1.76-19.19), pre-IHT ICP 15-19 mmHg (aRR 3.40; 95 % CI, 1.08-10.76), pre-IHT ICP >= 20 mmHg (aRR 12.94; 95 % CI, 4.08-41.01), and each 1 mL of hourly cerebrospinal fluid (CSF) drained prior to IHT (aRR 1.11; 95 % CI, 1.01-1.23). CONCLUSIONS: Routine clamping of EVD for IHT in cerebrovascular patients is associated with post-IHT ICP complications. Pre-IHT ICP >= 15 mmHg, increasing hourly CSF output, and IHT for therapeutic procedures are risk factors. PMID- 27757915 TI - The Impact of Red Blood Cell Transfusion on Cerebral Tissue Oxygen Saturation in Severe Traumatic Brain Injury. AB - BACKGROUND: There are a range of opinions on the benefits and thresholds for the transfusion of red blood cells in critically ill patients with traumatic brain injury (TBI) and an urgent need to understand the neurophysiologic effects. The aim of this study was to examine the influence of red blood cell transfusions on cerebral tissue oxygenation (SctO2) in critically ill TBI patients. METHODS: This prospective observational study enrolled consecutive TBI patients with anemia requiring transfusion. Cerebral tissue oxygen saturation (SctO2) was measured noninvasively with bilateral frontal scalp probes using near-infrared spectroscopy (NIRS) technology. Data were collected at baseline and for 24 h after transfusion. The primary outcome was the applicability of a four-wavelength near-infrared spectrometer to monitor SctO2 changes during a transfusion. Secondary outcomes included the correlation of SctO2 with other relevant physiological variables, the dependence of SctO2 on baseline hemoglobin and transfusion, and the effect of red blood cell transfusion on fractional tissue oxygen extraction. RESULTS: We enrolled 24 patients with severe TBI, of which five patients (21 %) were excluded due to poor SctO2 signal quality from large subdural hematomas and bifrontal decompressive craniectomies. Twenty transfusions were monitored in 19 patients. The mean pre- and post-transfusion hemoglobin concentrations were significantly different [74 g/L (SD 8 g/L) and 84 g/L (SD 9 g/L), respectively; p value <0.0001]. Post-transfusion SctO2 was not significantly greater than pre-transfusion SctO2 [left-side pre-transfusion 69 % (SD 7) vs. post-transfusion 70 % (SD 10); p = 0.68, and right-side pre transfusion 69 % (SD 5) vs. post-transfusion 71 % (SD 7); p = 0.11]. In a multivariable mixed linear analysis, mean arterial pressure was the only variable significantly associated with a change in SctO2. CONCLUSIONS: The bifrontal method of recording changes in NIRS signal was not able to detect a measurable impact on SctO2 in this sample of patients receiving red blood cell transfusion therapy in a narrow but conventionally relevant, range of anemia. PMID- 27757916 TI - How a teaching rotation in medical school affects graduates' subsequent careers. AB - INTRODUCTION: Teaching opportunities and teacher courses for medical students are increasingly offered by medical schools but little has been investigated about their long-term effect. The aim of our study was to investigate the long-term career effect of an intensive elective teaching experience for final year medical students. METHODS: We approached UMC Utrecht medical graduates who had taken a final year, 6-week full time student teaching rotation (STR) elective, 6 to 9 years after graduation, with an online survey to ask about their educational activities and obtained teaching certificates, their current roles related to education, and their appreciation of the rotation, even if this was a long time ago. In addition, we surveyed control groups of students who had not taken the STR, divided into those who had expressed interest in the STR but had not been placed and those who had not expressed such interest. RESULTS: We received responses from 50 STR graduates and 88 non-STR graduates (11 with interest and 77 without interest in the STR). STR graduates were more educationally active, had obtained more university teaching certificates and were more enthusiastic teachers. However, we could not exclude confounding, caused by a general interest in education even before the STR. CONCLUSIONS: Our findings indicate a high appreciation of the student teaching rotation and a likely but not proven long term association between STR participation and building an educational career. PMID- 27757918 TI - A Cost-Utility Analysis of Prostate Cancer Screening in Australia. AB - BACKGROUND AND OBJECTIVES: The Goteborg randomised population-based prostate cancer screening trial demonstrated that prostate-specific antigen (PSA)-based screening reduces prostate cancer deaths compared with an age-matched control group. Utilising the prostate cancer detection rates from this study, we investigated the clinical and cost effectiveness of a similar PSA-based screening strategy for an Australian population of men aged 50-69 years. METHODS: A decision model that incorporated Markov processes was developed from a health system perspective. The base-case scenario compared a population-based screening programme with current opportunistic screening practices. Costs, utility values, treatment patterns and background mortality rates were derived from Australian data. All costs were adjusted to reflect July 2015 Australian dollars (A$). An alternative scenario compared systematic with opportunistic screening but with optimisation of active surveillance (AS) uptake in both groups. A discount rate of 5 % for costs and benefits was utilised. Univariate and probabilistic sensitivity analyses were performed to assess the effect of variable uncertainty on model outcomes. RESULTS: Our model very closely replicated the number of deaths from both prostate cancer and background mortality in the Goteborg study. The incremental cost per quality-adjusted life-year (QALY) for PSA screening was A$147,528. However, for years of life gained (LYGs), PSA-based screening (A$45,890/LYG) appeared more favourable. Our alternative scenario with optimised AS improved cost utility to A$45,881/QALY, with screening becoming cost effective at a 92 % AS uptake rate. Both modelled scenarios were most sensitive to the utility of patients before and after intervention, and the discount rate used. CONCLUSION: PSA-based screening is not cost effective compared with Australia's assumed willingness-to-pay threshold of A$50,000/QALY. It appears more cost effective if LYGs are used as the relevant outcome, and is more cost effective than the established Australian breast cancer screening programme on this basis. Optimised utilisation of AS increases the cost effectiveness of prostate cancer screening dramatically. PMID- 27757919 TI - Comparing Biologic Cost Per Treated Patient Across Indications Among Adult US Managed Care Patients: A Retrospective Cohort Study. AB - BACKGROUND: The relative cost of biologics in the treatment of autoimmune disorders, including rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis, is a key consideration for managed care payers. OBJECTIVES: Our objective was to estimate biologic costs and treatment patterns in US managed care patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, and/or ankylosing spondylitis. METHODS: This retrospective study used administrative claims data from the HealthCore Integrated Research Database (HIRDSM) for adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, and/or ankylosing spondylitis who received abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, or ustekinumab between 1 July 2009 and 31 January 2013. Biologic costs (based on drug utilization) and treatment patterns (discontinued, restarted after a >45-day gap, switched to another biologic, or persisted without switching or stopping) were analyzed for the first year post-index. RESULTS: Most of the 24,460 patients received etanercept (48 %), adalimumab (29 %), or infliximab (12 %) as the index biologic. On the index date, 44 % were new to biologic therapy and 56 % were continuing biologic therapy. Biologic cost per treated patient for 1 year was as follows: etanercept $US24,859, adalimumab $US26,537, and infliximab $US26,468. Treatment patterns across indications for etanercept, adalimumab, and infliximab were as follows: persistent (52, 49, 67 %), restarted (23, 21, 12 %), switched (12, 13, 11 %), and discontinued (14, 18, 10 %). CONCLUSIONS: These findings from a large health benefits organization in the USA are similar to those of several previous cost analyses assessing different populations, which demonstrates the external validity of the results from the previous studies, both over time and across large populations. PMID- 27757917 TI - Magnetic Resonance Imaging of Ferumoxytol-Labeled Human Mesenchymal Stem Cells in the Mouse Brain. AB - The success of stem cell therapy is highly dependent on accurate delivery of stem cells to the target site of interest. Possible ways to track the distribution of MSCs in vivo include the use of reporter genes or nanoparticles. The U.S. Food and Drug Administration (FDA) has approved ferumoxytol (Feraheme(r) [USA], Rienso(r) [UK]) as a treatment for iron deficiency anemia. Ferumoxytol is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) that has recently been used to track the fate of transplanted cells using magnetic resonance imaging (MRI). The major objectives of this study were to demonstrate the feasibility of labeling hUCB-MSCs with ferumoxytol and to observe, through MRI, the engraftment of ferumoxytol-labeled human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) delivered via stereotactic injection into the hippocampi of a transgenic mouse model of familial Alzheimer's disease (5XFAD). Ferumoxytol had no toxic effects on the viability or stemness of hUCB-MSCs when assessed in vitro. Through MRI, hypointense signals were discernible at the site where ferumoxytol-labeled human MSCs were injected. Iron-positive areas were also observed in the engrafted hippocampi. The results from this study support the use of nanoparticle labeling to monitor transplanted MSCs in real time as a follow-up for AD stem cell therapy in the clinical field. PMID- 27757920 TI - Current Scenario of Pediatric Rickettsial Diseases. PMID- 27757921 TI - Enhancement of Bioavailability of Non-nucleoside Reverse Transciptase Inhibitor Using Nanosponges. AB - Efavirenz is a non-nucleoside reverse transcriptase inhibitor which is chronically prescribed for HIV patients. However, it exhibits solubility-limited bioavailability. Aim of this work was to enhance the solubility and dissolution of the Biopharmaceutical Classification System (BCS) class II drug efavirenz, using beta-cyclodextrin-based nanosponges. Nanosponges have high drug loading capacity and are effective for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonates in different ratios to prepare nanosponges. The nanosponges were loaded with efavirenz by solvent evaporation method and the nanosponge with higher drug loading capacity was selected for further studies. Binary and ternary complexes with EFA, NS, and PVP K30 were prepared and characterized by phase solubility, solution state interaction, saturation solubility, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and field emission scanning electron microscopy was performed. Results obtained from spectral characterization confirmed inclusion complexation. Stability constant for ternary complex was found to be 1997 lit/mole, which indicates stable complex formation. The saturation solubility was found to be 17-fold higher with ternary complex in distilled water and about 4-fold in simulated gastric fluid. In vitro dissolution was improved 3 folds with ternary complex. Ternary nanosponge complexes were found to have 2-fold increase in oral bioavailability of efavirenz as compared to plain drug. PMID- 27757922 TI - Potential of Non-aqueous Microemulsions to Improve the Delivery of Lipophilic Drugs to the Skin. AB - In this study, non-aqueous microemulsions were developed because of the challenges associated with finding pharmaceutically acceptable solvents for topical delivery of drugs sparingly soluble in water. The formulation irritation potential and ability to modulate the penetration of lipophilic compounds (progesterone, alpha-tocopherol, and lycopene) of interest for topical treatment/prevention of skin disorders were evaluated and compared to solutions and aqueous microemulsions of similar composition. The microemulsions (ME) were developed with BRIJ, vitamin E-TPGS, and ethanol as surfactant-co-surfactant blend and tributyrin, isopropyl myristate, and oleic acid as oil phase. As polar phase, propylene glycol (MEPG) or water (MEW) was used (26% w/w). The microemulsions were isotropic and based on viscosity and conductivity assessment, bicontinuous. Compared to drug solutions in lipophilic vehicles, MEPG improved drug delivery into viable skin layers by 2.5-38-fold; the magnitude of penetration enhancement mediated by MEPG into viable skin increased with drug lipophilicity, even though the absolute amount of drug delivered decreased. Delivery of progesterone and tocopherol, but not lycopene (the most lipophilic compound), increased up to 2.5-fold with MEW, and higher amounts of these two drugs were released from MEW (2-2.5-fold). Both microemulsions were considered safe for topical application, but MEPG-mediated decrease in the viability of reconstructed epidermis was more pronounced, suggesting its higher potential for irritation. We conclude that MEPG is a safe and suitable nanocarrier to deliver a variety of lipophilic drugs into viable skin layers, but the use of MEW might be more advantageous for drugs in the lower range of lipophilicity. PMID- 27757923 TI - Preparation and Characterization of the Sulfobutylether-beta-Cyclodextrin Inclusion Complex of Amiodarone Hydrochloride with Enhanced Oral Bioavailability in Fasted State. AB - Amiodarone hydrochloride (AMD) is used in the treatment of a wide range of cardiac tachyarrhythmias, including both ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT). The objectives of this study were to improve the solubility and bioavailability in fasted state and to reduce the food effect of AMD by producing its inclusion complex with sulfobutylether-beta-cyclodextrin (SBE-beta-CD). The complex was prepared through a saturated water solution combined with the freeze-drying method and then characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and differential scanning calorimetry. The solubilities of AMD and its complex were 0.35 and 68.62 mg/mL, respectively, and the value of the inclusion complex was significantly improved by 196-fold compared with the solubility of free AMD. The dissolution of the AMD-SBE-beta-CD inclusion complex in four different dissolution media was larger than that of the commercial product. The cumulative dissolution was more than 85% in water, pH 4.5 NaAc-HAC buffer, and pH 1.2 HCl aqueous solution. Moreover, the pharmacokinetic study found that the C max, AUC(0-t), and AUC(0-infinity) of the AMI-SBE-beta-CD inclusion complex had no significant difference in fasted and fed state, which indicated that the absorption of the AMI-SBE-beta-CD inclusion complex in fasted state was increased and not affected by food. PMID- 27757924 TI - Beyond decision! Motor contribution to speed-accuracy trade-off in decision making. AB - Both in real life and experimental settings, increasing response speed typically leads to more error-prone actions. Processes underlying such a "speed-accuracy trade-off" (SAT) are usually assumed to be purely decisional: cautiousness would be determined only by the amount of sensory evidence required to select a response. The present data challenges this largely accepted view, by directly showing that motor processes are speeded up under time pressure. In a choice reaction time task where emphasis was put either on response speed or accuracy, motor processes were investigated through the analysis of muscular activity related to response execution. When response speed was emphasized, the time between electromyographic onset and behavioral response (motor time) was also speeded up (contributing to more than 20 % of the total effect on global reaction time). This speeded execution (likely due to a more efficient motor command) may also explain why participants are less able to interrupt incorrect response execution once started (Burle et al., Psychonomic Bulletin & Review, 21(4), 1003 1010, 2014), leading to more overt errors. Pointing to a speed-accuracy exchange within motor processes themselves, the present results call for a re-evaluation of widely accepted assumptions about SAT, and more generally, decision-making processes. They are discussed in the context of recent extensions of the drift diffusion model framework, questioning the strict separation between decisional and motor processes. PMID- 27757925 TI - Lactam Triterpenoids from the Bark of Toona sinensis. AB - Three new limonoid-type triterpenoids, namely toonasins A-C (1-3) with a rare lactam E ring, along with six known compounds (4-9) were isolated from the barks of Toona sinensis. The structures of new compounds were elucidated by interpretation of spectroscopic data, and the relative configuration of compound 1 was further characterized by X-ray crystallographic analyses. The isolated compounds were evaluated for their cytotoxic activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480), and compounds 3 and 5 showed weak cytotoxicities. PMID- 27757926 TI - Acetylcholinesterase and Cytotoxic Activity of Chemical Constituents of Clutia lanceolata Leaves and its Molecular Docking Study. AB - Phytochemical investigations of the ethanolic extract of leaves of Clutia lanceolata (Family: Euphorbiaceae) resulted in the isolation of four compounds viz. 3,4-dihydroxy-2-methylbenzoic acid (1), 2,2'-dihydroxy-1,1'-binaphthyl (2), 1,3,8-trihydroxy-6-methylanthracene-9,10-dione (3) and 5-hydroxy-1,7-bis(4 hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (4). Although all the isolated compounds were known but this was the first report from this plant source. Their structures were established on the basis of chemical and physical evidences viz. elemental analysis, FT-IR, 1H-NMR, 13C-NMR and mass spectral analysis. Structure of compound 2 and 4 was further authenticated by single-crystal X-ray analysis and density functional theory calculations. The isolated compounds (1-4) were screened for AChE enzyme inhibition assay in which compound 3 and 4 were found to be more potent AChE inhibitor. Molecular docking study of potent AChE inhibitor was performed to find the probable binding mode of the compounds into the active site of receptor. Moreover, the isolated compounds were also screened for in vivo cytotoxicity by brine shrimp lethality assay. PMID- 27757927 TI - Assessing Residents' Confidence in the Context of Pharmacotherapy Competence. AB - OBJECTIVE: We aimed to determine whether residents' confidence initiating medications increased with the number of times they prescribed individual medications and to quantify the relationship between prescription frequency and gains in confidence. METHODS: From July 2011 to June 2014, PGY-3 residents completed a survey of confidence levels at their psychopharmacology clinic orientation and then again 12 months later. The Emory Healthcare electronic medical record was used to identify all medications prescribed by each resident during their 12-month rotation and the frequency of these prescriptions. RESULTS: Confidence in initiating treatment with all medicines/medication classes increased over the 12-month period. For three of the medication classes for which residents indicated they were least confident at orientation, the number of prescriptions written during the year was significantly associated with an increase in confidence. CONCLUSIONS: Measuring resident confidence is a relevant and achievable outcome and provides data for educators regarding the amount of experience needed to increase confidence. PMID- 27757928 TI - Comment on "A Qualitative Analysis of Medical students? Reflection on Attending an Alcoholics Anonymous Meeting: Insights for Future Addiction Curricula". PMID- 27757929 TI - A national survey of Canadian ophthalmologists to determine awareness of published guidelines for the management of uveitis. AB - BACKGROUND: The objectives of this study are to assess Canadian ophthalmologists' awareness of established uveitis treatment guidelines and clinical management of uveitis and to assess the frequency of government applications for immunomodulatory therapy (IMT) and identify primary prescribers. A 25-item questionnaire was sent to 759 practicing Canadian ophthalmologists. Six questions assessed demographics including the year of residency completion, training by uveitis specialists during residency, and fellowship training. Five questions assessed application of guidelines to clinical scenarios, and 12 questions assessed referral patterns and success of obtaining coverage for IMT. RESULTS: Of 144 respondents, 12 (8.3 %) were uveitis specialists; 45.1 % of respondents had uveitis training during residency by a uveitis specialist. Sixty-one percent reported awareness of management guidelines. Recent graduates (2001-2012) referred patients to uveitis specialists (55.3 %) less frequently than earlier graduates. Recent graduates also managed uveitis patients more frequently with corticosteroid injections (15.6 %) than those who graduated before 1980 (9.75 %). The majority (93.6 %) of respondents submitted less than six IMT funding applications for provincial drug coverage yearly, and 5.5 % reported prescribing IMT themselves, rather than referring to other specialists. CONCLUSIONS: Although greater than half of respondents reported awareness of uveitis treatment guidelines, Canadian ophthalmologists' awareness of uveitis treatment guidelines and application of the guidelines to patient care could be improved. Few applications are made for IMT, and the majority of applications are sent by non ophthalmologists. This suggests the need for further education of ophthalmologist about uveitis treatment guidelines and for more ophthalmologists trained to manage uveitis with IMT. PMID- 27757931 TI - Internet addiction, sleep and health-related life quality among obese individuals: a comparison study of the growing problems in adolescent health. AB - BACKGROUND: The rapid rise in the global prevalence of obesity suggests that environmental factors may be responsible. The increased use of technology is associated with increased rates of obesity due to declines in physical activity and significant sedentary life style. Internet addiction is also a growing health issue associated with diminished physical activity and poor sleep quality as well as various health problems. The purpose of this study was to determine associations between Internet addiction and adolescent obesity-related problems. DESIGN AND METHODS: In this case-control study, 71 adolescents with obesity were recruited from the outpatient clinic at Tepecik Teaching Hospital and Katip Celebi University Hospital, Department of Pediatric Endocrinology in Izmir, Turkey. The control group consisted of 64 non-obese adolescents that were matched with patients in the study group by age and gender. All subjects completed socio demographic forms, an Internet addiction scale, the Pediatric Quality of Life Inventory, the Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. RESULTS: Adolescents with obesity were significantly more likely to have Internet addiction (p = 0.002), lower quality of life (p < 0.001), and higher daytime sleepiness (p = 0.008). Moreover, binary regression analysis showed that Internet addiction and less physical activity were associated with increased odds of obesity. CONCLUSION: The results indicated a significant association between Internet addiction and obesity. Health practitioners should take possible Internet addiction, online activities, and physical activities into consideration in follow-up of obese adolescents. In addition to pharmacologic therapies and dietary interventions, providing behavioral therapy targeting healthy Internet use may be promising to reduce the effects of obesity in adolescence. PMID- 27757932 TI - Comparison of the image-derived radioactivity and blood-sample radioactivity for estimating the clinical indicators of the efficacy of boron neutron capture therapy (BNCT): 4-borono-2-18F-fluoro-phenylalanine (FBPA) PET study. AB - BACKGROUND: In boron neutron capture therapy (BNCT), positron emission tomography (PET) with 4-borono-2-18F-fluoro-phenylalanine (FBPA) is the only method to estimate an accumulation of 10B to target tumor and surrounding normal tissue after administering 10B carrier of L-paraboronophenylalanine and to search the indication of BNCT for individual patient. Absolute concentration of 10B in tumor has been estimated by multiplying 10B concentration in blood during BNCT by tumor to blood radioactivity (T/B) ratio derived from FBPA PET. However, the method to measure blood radioactivity either by blood sampling or image data has not been standardized. We compared image-derived blood radioactivity of FBPA with blood sampling data and studied appropriate timing and location for measuring image derived blood counts. METHODS: We obtained 7 repeated whole-body PET scans in five healthy subjects. Arterialized venous blood samples were obtained from the antecubital vein, heated in a heating blanket. Time-activity curves (TACs) of image-derived blood radioactivity were obtained using volumes of interest (VOIs) over ascending aorta, aortic arch, pulmonary artery, left and right ventricles, inferior vena cava, and abdominal aorta. Image-derived blood radioactivity was compared with those measured by blood sampling data in each location. RESULTS: Both the TACs of blood sampling radioactivity in each subject, and the TACs of image-derived blood radioactivity showed a peak within 5 min after the tracer injection, and promptly decreased soon thereafter. Linear relationship was found between blood sampling radioactivity and image-derived blood radioactivity in all the VOIs at any timing of data sampling (p < 0.001). Image-derived radioactivity measured in the left and right ventricles 30 min after injection showed high correlation with blood radioactivity. Image-derived blood radioactivity was lower than blood sampling radioactivity data by 20 %. Reduction of blood radioactivity of FBPA in left ventricle after 30 min of FBPA injection was minimal. CONCLUSION: We conclude that the image-derived T/B ratio can be reliably used by setting the VOI on the left ventricle at 30 min after FBPA administration and correcting for underestimation due to partial volume effect and reduction of FBPA blood radioactivity. PMID- 27757933 TI - Treating Hypertension to Prevent Cognitive Decline and Dementia: Re-Opening the Debate. AB - Hypertension and dementia are two of the most prevalent and damaging diseases associated with aging. Chronic hypertension, particularly during mid-life, is a strong risk factor for late-life cognitive decline and impairment. Hypertension is also the number one risk factor for stroke and a major contributor to the pathogenesis of vascular dementia and Alzheimer's disease. Despite the vast epidemiologic and mechanistic evidence linking hypertension to cognitive impairment, and the positive effects of blood pressure lowering on reducing the risk of post-stroke dementia, uncertainty remains about the benefit of antihypertensive medication on other forms of dementia. This chapter reviews the link between hypertension and cognition, and discusses the evidence for and against the use of antihypertensive medication for dementia prevention. PMID- 27757934 TI - Blood Pressure Self-Measurement. AB - Blood pressure self-measurement has been used extensively as part of several clinical processes including in the home monitoring setting for mitigating white coat effect and gaining more detailed insights into the blood pressure variability of patients over time. Self-measurement of BP is also being used as part of telemonitoring and telemedicine processes, as well as in the waiting rooms and self-measurement rooms of general practice clinics, specialized hospital department's outpatient clinics, and in other types of care facilitates and institutions.The aim of this review is to provide an overview of where, when, and how blood pressure self-measurement is being used, which official clinical guidelines and procedures are available for its implementation, as well as the opportunities and challenges that are related to its use. PMID- 27757935 TI - Impact of Salt Intake on the Pathogenesis and Treatment of Hypertension. AB - Excessive dietary salt (sodium chloride) intake is associated with an increased risk for hypertension, which in turn is especially a major risk factor for stroke and other cardiovascular pathologies, but also kidney diseases. Besides, high salt intake or preference for salty food is discussed to be positive associated with stomach cancer, and according to recent studies probably also obesity risk. On the other hand a reduction of dietary salt intake leads to a considerable reduction in blood pressure, especially in hypertensive patients but to a lesser extent also in normotensives as several meta-analyses of interventional studies have shown. Various mechanisms for salt-dependent hypertension have been put forward including volume expansion, modified renal functions and disorders in sodium balance, impaired reaction of the renin-angiotensin-aldosterone-system and the associated receptors, central stimulation of the activity of the sympathetic nervous system, and possibly also inflammatory processes.Not every person reacts to changes in dietary salt intake with alterations in blood pressure, dividing people in salt sensitive and insensitive groups. It is estimated that about 50-60 % of hypertensives are salt sensitive. In addition to genetic polymorphisms, salt sensitivity is increased in aging, in black people, and in persons with metabolic syndrome or obesity. However, although mechanisms of salt-dependent hypertensive effects are increasingly known, more research on measurement, storage and kinetics of sodium, on physiological properties, and genetic determinants of salt sensitivity are necessary to harden the basis for salt reduction recommendations.Currently estimated dietary intake of salt is about 9-12 g per day in most countries of the world. These amounts are significantly above the WHO recommended level of less than 5 g salt per day. According to recent research results a moderate reduction of daily salt intake from current intakes to 5-6 g can reduce morbidity rates. Potential risks of salt reduction, like suboptimal iodine supply, are limited and manageable. Concomitant to salt reduction, potassium intake by higher intake of fruits and vegetables should be optimised, since several studies have provided evidence that potassium rich diets or interventions with potassium can lower blood pressure, especially in hypertensives.In addition to dietary assessment the gold standard for measuring salt intake is the analysis of sodium excretion in the 24 h urine. Spot urine samples are appropriate alternatives for monitoring sodium intake. A weakness of dietary evaluations is that the salt content of many foods is not precisely known and information in nutrient databases are limited. A certain limitation of the urine assessment is that dietary sources contributing to salt intake cannot be identified.Salt reduction strategies include nutritional education, improving environmental conditions (by product reformulation and optimization of communal catering) up to mandatory nutrition labeling and regulated nutrition/health claims, as well as legislated changes in the form of taxation.Regarding dietary interventions for the reduction of blood pressure the Dietary Approaches to Stop Hypertension (DASH) diet can be recommended. In addition, body weight should be normalized in overweight and obese people (BMI less than 25 kg/m2), salt intake should not exceed 5 g/day according to WHO recommendations (<2 g sodium/day), no more than 1.5 g sodium/d in blacks, middle- and older-aged persons, and individuals with hypertension, diabetes, or chronic kidney disease, intake of potassium (~4.7 g/day) should be increased and alcohol consumption limited. In addition, regular physical activity (endurance, dynamic resistance, and isometric resistance training) is very important. PMID- 27757936 TI - The Concept of Biofilm-Related Implant Malfunction and "Low-Grade Infection". AB - Biofilms have a tremendous impact on industrial machines working in moist environments, while in biological systems their effect is further complicated by the host's response.Implant-related infections are a complex process, starting with bacterial adhesion and biofilm formation, followed by the variable interaction between host, implant, microorganisms and their by-products. Depending on the balance of these factors, different clinical presentations are observed, which may eventually, at times, shift from one into the other.-"Implant malfunction" displays only mild clinical signs/symptoms - light pain and/or slight soft tissue contracture or functional impairment - with negative infection/inflammatory markers; it requires prolonged cultures, antibiofilm and eventually genomic investigations for pathogen detection;-"Low-grade infection" features recurrent or persistent pain and/or soft tissue contracture with various functional impairment and mixed positive/negative markers of infection/inflammation; pathogen identification requires prolonged cultures and antibiofilm techniques;-"High-grade infection" displays classical signs/symptoms of infection/inflammation with positive tests; pathogen identification is often possible with traditional microbiological techniques, but is better achieved with prolonged cultures and antibiofilm processing.Understanding biofilms-related clinical presentations is crucial for physicians, to implement the best diagnostic and therapeutic measures, and for regulatory bodies, to define the evaluation process of technologies aimed at reducing implants' malfunctions and infections, like anti-adhesive and antibiofilm coatings, that should be regulated as (part of) medical devices, requiring a suitable post-marketing surveillance.Only an effective antibiofilm-targeted approach from all players will hopefully allow the medical community to mitigate the current unacceptable social and economical burden of implant-related infections and malfunctions. PMID- 27757937 TI - Algorithm to Diagnose Delayed and Late PJI: Role of Joint Aspiration. AB - Total Joint Arthroplasty (TJA) continues to gain acceptance as the standard of care for the treatment of severe degenerative joint disease, and is considered one of the most successful surgical interventions in the history of medicine. A devastating complication after TJA is infection. Periprosthetic joint infection (PJI), represents one of the major causes of failure and remains a significant challenge facing orthopaedics today. PJI usually requires additional surgery including revision of the implants, fusion or amputations causing tremendous patient suffering but also a heavy health economics burden. PJI is at the origin of around 20-25 % of total knee arthroplasty (Bozic et al. 2010; de Gorter et al. 2015; Sundberg et al. 2015) and 12-15 % of total hip arthroplasty (Bozic et al. 2009; Garellick et al. 2014; de Gorter et al. 2015) failures. PMID- 27757938 TI - Adherence to Treatment in Hypertension. AB - The lack of adherence to treatment in hypertension affects approximately 30 % of patients. The elderly, those with several co-morbidities, social isolation, low incomes or depressive symptoms are the most vulnerable to this problem. There is no ideal method to quantify the adherence to the treatment. Indirect methods are recommended in clinical practice. Any intervention strategy should not blame the patient and try a collaborative approach. It is recommended to involve the patient in decision-making. The clinical interview style must be patient-centered including motivational techniques. The improvement strategies that showed greater effectiveness in the compliance of hypertension treatment were: treatment simplification, appointment reminders systems, blood pressure self-monitoring, organizational improvements and nurse and pharmacists care. The combination of different interventions are recommended against isolated interventions. PMID- 27757939 TI - Comparison of Thymic Stromal Lymphopoietin Concentration in Various Human Biospecimens from Asthma and COPD Patients Measured with Two Different ELISA Kits. AB - Thymic stromal lymphopoietin (TSLP) seems a promising asthma biomarker. In earlier studies, mainly the serum concentration of TSLP was investigated. The aim of the present study was to compare the TSLP concentration measured by two different ELISA kits in the serum, induced sputum, and exhaled breath condensate in asthma, COPD, and control subjects. The study included 24 asthmatics, 36 patients with COPD, and 12 controls. TSLP concentration was measured with the use of R&D and EIAab commercial ELISA kits. The results obtained with the EIAab kit were 3 to even 45-fold higher than those measured with the R&D kit. Significant differences between the investigated groups were found only for the TSLP concentration in induced sputum. When the R&D kit was used, the highest TSLP levels in induced sputum were found in asthmatics, while the EIAab kit showed the highest TSLP levels in controls. The distribution of results in the Bland-Altman plot was typical for a proportional constant error. TSP concentration in induced sputum might be a more reliable asthma biomarker than serum TSLP. We conclude that TSLP level is highly dependent on the ELISA kit used for the measurement. Thus, judgement on TSLP results obtained with different assays might be confusing and lead to wrong conclusions. PMID- 27757940 TI - Spin Orbit Coupling Gap and Indirect Gap in Strain-Tuned Topological Insulator Antimonene. AB - Recently, searching large-bulk band gap topological insulator (TI) is under intensive study. Through k.P theory and first-principles calculations analysis on antimonene, we find that alpha-phase antimonene can be tuned to a 2D TI under an in-plane anisotropic strain and the magnitude of direct bulk band gap (SOC gap) depends on the strength of spin-orbit coupling (SOC) which is strain-dependent. As the band inversion of this TI accompanies with an indirect band gap, the TI bulk band gap is the indirect band gap, not the SOC gap. SOC gap can be enhanced by increasing strain, whereas the indirect band gap can be closed by increasing strain, such that large bulk band gap are forbidden. With the k.P theory analysis on antimonene, we know how to avoid such an indirect band gap. In case of indirect band gap avoided, the SOC gap could become the bulk band gap of a TI which can be enhanced by strain. Thus our theoretical analysis can help searching large bulk band gap TI. PMID- 27757941 TI - Composition Analysis of III-Nitrides at the Nanometer Scale: Comparison of Energy Dispersive X-ray Spectroscopy and Atom Probe Tomography. AB - The enhancement of the performance of advanced nitride-based optoelectronic devices requires the fine tuning of their composition, which has to be determined with a high accuracy and at the nanometer scale. For that purpose, we have evaluated and compared energy dispersive X-ray spectroscopy (EDX) in a scanning transmission electron microscope (STEM) and atom probe tomography (APT) in terms of composition analysis of AlGaN/GaN multilayers. Both techniques give comparable results with a composition accuracy better than 0.6 % even for layers as thin as 3 nm. In case of EDX, we show the relevance of correcting the X-ray absorption by simultaneous determination of the mass thickness and chemical composition at each point of the analysis. Limitations of both techniques are discussed when applied to specimens with different geometries or compositions. PMID- 27757942 TI - The Applications of Gold Nanoparticle-Initialed Chemiluminescence in Biomedical Detection. AB - Chemiluminescence technique as a novel detection method has gained much attention in recent years owning to the merits of high sensitivity, wider linear ranges, and low background signal. Similarly, nanotechnology especially for gold nanoparticles has emerged as detection tools due to their unique physical and chemical properties. Recently, it has become increasingly popular to couple gold nanoparticles with chemiluminescence technique in biological agents' detection. In this review, we describe the superiority of both chemiluminescence and gold nanoparticles and conclude the different applications of gold nanoparticle initialed chemiluminescence in biomedical detection. PMID- 27757943 TI - Enhanced Emission of Quantum System in Si-Ge Nanolayer Structure. AB - It is very interesting that the enhanced peaks near 1150 and 1550 nm are observed in the photoluminescence (PL) spectra in the quantum system of Si-Ge nanolayer structure, which have the emission characteristics of a three-level system with quantum dots (QDs) pumping and emission of quasi-direct-gap band, in our experiment. In the preparing process of Si-Ge nanolayer structure by using a pulsed laser deposition method, it is discovered that the nanocrystals of Si and Ge grow in the (100) and (111) directions after annealing or electron beam irradiation. The enhanced PL peaks with multi-longitudinal-mode are measured at room temperature in the super-lattice of Si-Ge nanolayer quantum system on SOI. PMID- 27757944 TI - Enhancing Performance of CdS Quantum Dot-Sensitized Solar Cells by Two Dimensional g-C3N4 Modified TiO2 Nanorods. AB - In present work, two-dimensional g-C3N4 was used to modify TiO2 nanorod array photoanodes for CdS quantum dot-sensitized solar cells (QDSSCs), and the improved cell performances were reported. Single crystal TiO2 nanorods are prepared by hydrothermal method on transparent conductive glass and spin-coated with g-C3N4. CdS quantum dots were deposited on the g-C3N4 modified TiO2 photoanodes via successive ionic layer adsorption and reaction method. Compared with pure TiO2 nanorod array photoanodes, the g-C3N4 modified photoanodes showed an obvious improvement in cell performances, and a champion efficiency of 2.31 % with open circuit voltage of 0.66 V, short circuit current density of 7.13 mA/cm2, and fill factor (FF) of 0.49 was achieved, giving 23 % enhancement in cell efficiency. The improved performances were due to the matching conduction bands and valence bands of g-C3N4 and TiO2, which greatly enhanced the separation and transfer of the photogenerated electrons and holes and effectively suppressed interfacial recombination. Present work provides a new direction for improving performance of QDSSCs. PMID- 27757945 TI - WO3 Nanoparticles or Nanorods Incorporating Cs2CO3/PCBM Buffer Bilayer as Carriers Transporting Materials for Perovskite Solar Cells. AB - In this work, we demonstrate a novel carrier transporting combination made of tungsten trioxide (WO3) nanomaterials and Cs2CO3/PCBM buffer bilayer for the fabrication of perovskite solar cells (PSCs). Two different types of WO3, including nanoparticles and nanorods, were prepared by sol-gel process and hydrothermal method, respectively. Cs2CO3/PCBM buffer bilayer was inserted between WO3 and perovskite layers to improve charge transfer efficiency and formation of pinhole-free perovskite layer. Besides, the leakage current of the devices containing Cs2CO3/PCBM buffer bilayer was significantly suppressed. The optimized device based on WO3 nanoparticles and Cs2CO3/PCBM bilayer showed an open-circuit voltage of 0.84 V, a short-circuit current density of 20.40 mA/cm2, a fill factor of 0.61, and a power conversion efficiency of 10.49 %, which were significantly higher than those of PSCs without Cs2CO3/PCBM buffer bilayer. The results revealed that the combination of WO3 nanomaterials and Cs2CO3/PCBM bilayer provides an effective solution for improving performances of PSCs. PMID- 27757946 TI - Facile Synthesis of Monodisperse Gold Nanocrystals Using Virola oleifera. AB - The development of new routes and strategies for nanotechnology applications that only employ green synthesis has inspired investigators to devise natural systems. Among these systems, the synthesis of gold nanoparticles using plant extracts has been actively developed as an alternative, efficient, cost-effective, and environmentally safe method for producing nanoparticles, and this approach is also suitable for large-scale synthesis. This study reports reproducible and completely natural gold nanocrystals that were synthesized using Virola oleifera extract. V. oleifera resin is rich in epicatechin, ferulic acid, gallic acid, and flavonoids (i.e., quercetin and eriodictyol). These gold nanoparticles play three roles. First, these nanoparticles exhibit remarkable stability based on their zeta potential. Second, these nanoparticles are functionalized with flavonoids, and third, an efficient, economical, and environmentally friendly mechanism can be employed to produce green nanoparticles with organic compounds on the surface. Our model is capable of reducing the resin of V. oleifera, which creates stability and opens a new avenue for biological applications. This method does not require painstaking conditions or hazardous agents and is a rapid, efficient, and green approach for the fabrication of monodisperse gold nanoparticles. Graphical Abstract The Virola oleifera reduction method for the synthesis of gold nanoparticles (AuNP's). PMID- 27757947 TI - Magnetic and Magnetoresistive Properties of 3D Interconnected NiCo Nanowire Networks. AB - Track-etched polymer membranes with crossed nanochannels have been revealed to be most suitable as templates to produce large surface area and mechanically stable 3D interconnected nanowire (NW) networks by electrodeposition. Geometrically controlled NW superstructures made of NiCo ferromagnetic alloys exhibit appealing magnetoresistive properties. The combination of exact alloy compositions with the spatial arrangement of NWs in the 3D network is decisive to obtain specific magnetic and magneto-transport behavior. A proposed simple model based on topological aspects of the 3D NW networks is used to accurately determine the anisotropic magnetoresistance ratios. Despite of their complex topology, the microstructure of Co-rich NiCo NW networks display mixed fcc-hcp phases with the c-axis of the hcp phase oriented perpendicular to their axis. These interconnected NW networks have high potential as reliable and stable magnetic field sensors. PMID- 27757949 TI - "Rendezvous technique" for intraluminal vacuum therapy of anastomotic leakage of the jejunum. AB - BACKGROUND: Anastomotic leakage (AL) is one of the most common and serious complications following visceral surgery. In recent years, endoluminal vacuum therapy has dramatically changed therapeutic options for AL, but its use has been limited to areas easily accessible by endoscope. CASE PRESENTATION: We describe the first use of endoluminal vacuum therapy in the small intestine employing a combined surgical and endoscopic "rendezvous technique" in which the surgeon assists the endoscopic placement of an endoluminal vacuum therapy sponge in the jejunum by means of a pullback string. This technique led to a completely closed AL after 27 days and 7 changes of the endosponge. CONCLUSION: The combined surgical and endoscopic rendezvous technique can be useful in cases of otherwise difficult endosponge placement. PMID- 27757948 TI - Rice Chloroplast Genome Variation Architecture and Phylogenetic Dissection in Diverse Oryza Species Assessed by Whole-Genome Resequencing. AB - BACKGROUND: Chloroplast genome variations have been detected, despite its overall conserved structure, which has been valuable for plant population genetics and evolutionary studies. Here, we described chloroplast variation architecture of 383 rice accessions from diverse regions and different ecotypes, in order to mine the rice chloroplast genome variation architecture and phylogenetic. RESULTS: A total of 3677 variations across the chloroplast genome were identified with an average density of 27.33 per kb, in which wild rice showing a higher variation density than cultivated groups. Chloroplast genome nucleotide diversity investigation indicated a high degree of diversity in wild rice than in cultivated rice. Genetic distance estimation revealed that African rice showed a low level of breeding and connectivity with the Asian rice, suggesting the big distinction of them. Population structure and principal component analysis revealed the existence of clear clustering of African and Asian rice, as well as the indica and japonica in Asian cultivated rice. Phylogenetic analysis based on maximum likelihood and Bayesian inference methods and the population splits test suggested and supported the independent origins of indica and japonica within Asian cultivated rice. In addition, the African cultivated rice was thought to be domesticated differently from Asian cultivated rice. CONCLUSIONS: The chloroplast genome variation architecture in Asian and African rice are different, as well as within Asian or African rice. Wild rice and cultivated rice also have distinct nucleotide diversity or genetic distance. In chloroplast level, the independent origins of indica and japonica within Asian cultivated rice were suggested and the African cultivated rice was thought to be domesticated differently from Asian cultivated rice. These results will provide more candidate evidence for the further rice chloroplast genomic and evolution studies. PMID- 27757950 TI - Sarcoid reaction in the spleen after sigmoid colon cancer resection: a case report. AB - BACKGROUND: A sarcoid reaction is a phenomenon characterized by histologically proven granulomatous lesions without evidence of sarcoidosis. This pathology is a benign tumor itself, but several reports have described sarcoid reactions accompanying malignant tumors. Sarcoid reactions occur in various cancers, such as skin, lung, ovary, stomach, and breast cancers. However, only a few published reports have described sarcoid reactions in patients with colorectal cancer. CASE PRESENTATION: A 76-year-old woman underwent laparoscopic sigmoidectomy for sigmoid colon cancer. The postoperative follow-up computed tomography and 18 fluorodeoxyglucose positron emission tomography-computed tomography findings were suspicious for splenic metastasis of the sigmoid colon cancer. The patient then underwent laparoscopic splenectomy. Histopathological examination of the resected lymph nodes and spleen showed a non-caseating epithelioid cell granuloma. The patient was diagnosed with a sarcoid reaction. CONCLUSIONS: To our knowledge, this is the first report of a sarcoid reaction in the spleen and regional lymph nodes after colon cancer resection. The effect of a sarcoid reaction on the prognosis in patients with colorectal cancer has not been fully determined because of the small number of such cases. Further analyses involving a larger number of cases are necessary to evaluate the relationship between sarcoid reactions and prognosis in patients with colorectal cancer. We herein present an extremely rare case of a sarcoid reaction in the spleen and regional lymph nodes. PMID- 27757951 TI - Efficacy and tolerability of anti-epileptic drugs-an internet study. AB - OBJECTIVE: To ascertain efficacy and tolerability of carbamazepine (CBZ), sodium valproate (VPA), lamotrigine (LTG) and levetiracetam (LEV) using the UKAED register (www.ukaed.info). METHODS: Patients on CBZ (n=91), VPA (n=61), LTG (n=105), LEV (n=72) and healthy control subjects (CTR) on no medication (n=51) were extracted. All patients had anonymously provided information on seizure type and frequency and completed the Liverpool Adverse Event Profile (LAEP). RESULTS: The number of seizure-free patients in the last 4 weeks was overall CBZ/VPA/LTG/LEV=60%/79%/67%/67%, for generalized epilepsy was CBZ/VPA/LTG/LEV=67%/89%/65%/94%, and for localization-related epilepsy was CBZ/VPA/LTG/LEV=59%/71%/67%/57%. Mean LAEP scores were CBZ/VPA/LTG/LEV/CTR=42.21/39.66/39.86/43.01/29.69. The mean LAEP was significantly higher in patients reporting depression and in patients with active epilepsy than in patients without depression and remission. Central nervous system (CNS) adverse effects including memory problems, difficulty concentrating, depression, unsteadiness, restlessness, feelings of anger, shaky hands and dizziness were significantly more frequent in CBZ, VPA, LTG and LEV than in CTR. The feeling of anger was significantly more frequent in LEV, and depression was significantly more frequent in CBZ compared to the other drugs. CONCLUSION: In this Internet-based register of self-reported efficacy and tolerability, CBZ, VPA, LTG and LEV were similar. Self-reported CNS adverse effects were significantly more frequent than in controls. In addition, anger was associated with LEV and depression with CBZ. Confounding factors were depression and uncontrolled epilepsy. PMID- 27757952 TI - Evolutionary innovation and diversification of carotenoid-based pigmentation in finches. AB - The ornaments used by animals to mediate social interactions are diverse, and by reconstructing their evolutionary pathways we can gain new insights into the mechanisms underlying ornamental innovation and variability. Here, we examine variation in plumage carotenoids among the true finches (Aves: Fringillidae) using biochemical and comparative phylogenetic analyses to reconstruct the evolutionary history of carotenoid states and evaluate competing models of carotenoid evolution. Our comparative analyses reveal that the most likely ancestor of finches used dietary carotenoids as yellow plumage colorants, and that the ability to metabolically modify dietary carotenoids into more complex pigments arose secondarily once finches began to use modified carotenoids to create red plumage. Following the evolutionary "innovation" that enabled modified red carotenoid pigments to be deposited as plumage colorants, many finch species subsequently modified carotenoid biochemical pathways to create yellow plumage. However, no reversions to dietary carotenoids were observed. The finding that ornaments and their underlying mechanisms may be operating under different selection regimes-where ornamental trait colors undergo frequent reversions (e.g., between red and yellow plumage) while carotenoid metabolization mechanisms are more conserved-supports a growing empirical framework suggesting different evolutionary patterns for ornaments and the mechanistic innovations that facilitate their diversification. PMID- 27757955 TI - RANZCOG 2016 Annual Scientific Meeting, 16-19 October 2016, Crown Perth, Western Australia. PMID- 27757953 TI - Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances. AB - Non-alcoholic fatty liver disease (NAFLD) is a continuous spectrum of diseases characterized by excessive lipid accumulation in hepatocytes. NAFLD progresses from simple liver steatosis to non-alcoholic steatohepatitis and, in more severe cases, to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Because of its growing worldwide prevalence, various animal models that mirror both the histopathology and the pathophysiology of each stage of human NAFLD have been developed. The selection of appropriate animal models continues to be one of the key questions faced in this field. This review presents a critical analysis of the histopathology and pathogenesis of NAFLD, the most frequently used and recently developed animal models for each stage of NAFLD and NAFLD-induced HCC, the main mechanisms involved in the experimental pathogenesis of NAFLD in different animal models, and a brief summary of recent therapeutic targets found by the use of animal models. Integrating the data from human disease with those from animal studies indicates that, although current animal models provide critical guidance in understanding specific stages of NAFLD pathogenesis and progression, further research is necessary to develop more accurate models that better mimic the disease spectrum, in order to provide both increased mechanistic understanding and identification/testing of novel therapeutic approaches. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 27757954 TI - Colder environments did not select for a faster metabolism during experimental evolution of Drosophila melanogaster. AB - The effect of temperature on the evolution of metabolism has been the subject of debate for a century; however, no consistent patterns have emerged from comparisons of metabolic rate within and among species living at different temperatures. We used experimental evolution to determine how metabolism evolves in populations of Drosophila melanogaster exposed to one of three selective treatments: a constant 16 degrees C, a constant 25 degrees C, or temporal fluctuations between 16 and 25 degrees C. We tested August Krogh's controversial hypothesis that colder environments select for a faster metabolism. Given that colder environments also experience greater seasonality, we also tested the hypothesis that temporal variation in temperature may be the factor that selects for a faster metabolism. We measured the metabolic rate of flies from each selective treatment at 16, 20.5, and 25 degrees C. Although metabolism was faster at higher temperatures, flies from the selective treatments had similar metabolic rates at each measurement temperature. Based on variation among genotypes within populations, heritable variation in metabolism was likely sufficient for adaptation to occur. We conclude that colder or seasonal environments do not necessarily select for a faster metabolism. Rather, other factors besides temperature likely contribute to patterns of metabolic rate over thermal clines in nature. PMID- 27757956 TI - The right to health is a fundamental human right but better health is a shared responsibility. PMID- 27757957 TI - The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery. AB - Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27757958 TI - Dichloroacetate induces regulatory T-cell differentiation and suppresses Th17 cell differentiation by pyruvate dehydrogenase kinase-independent mechanism. AB - OBJECTIVES: Recently, there has been a growing interest in the mechanism of action of dichloroacetate (DCA) for T-cell differentiation; however, this mechanism has not been elucidated in detail. Therefore, this study aimed to investigate the mechanism of action of DCA for Treg and Th17 differentiation with pyruvate dehydrogenase kinase (PDHK) inhibitor (AZD7545) and PDHK knockdown. METHODS: Inhibitory activity of DCA and AZD7545 against recombinant PDHK and intracellular PDH phosphorylation was measured. The effects of DCA and AZD7545 on T-cell differentiation were assessed by analysing Foxp3+ T-cell populations for Treg differentiation and IL-17A production for Th17 differentiation. For reactive oxygen species (ROS) production, DCFDA was used as an indicator. KEY FINDINGS: Dichloroacetate and AZD7545 inhibited PDHK activity of recombinant PDHK and intracellular PDH phosphorylation. DCA was capable of inducing Treg differentiation and suppressing Th17 differentiation. The effects of DCA were independent of PDHK because neither AZD7545 nor knockdown of PDHK1 or PDHK3 affected T-cell differentiation. DCA was determined to be capable of inducing ROS production, and the effects of DCA on T-cell differentiation were shown to be dependent on ROS production. CONCLUSIONS: Dichloroacetate possesses Treg induction and Th17 suppression, which is independent of PDHK and dependent on ROS production. PMID- 27757959 TI - Seasonal detours by soaring migrants shaped by wind regimes along the East Atlantic Flyway. AB - Avian migrants often make substantial detours between their seasonal destinations. It is likely some species do this to make the most of predictable wind regimes along their respective flyways. We test this hypothesis by studying orientation behaviour of a long-distance soaring migrant in relation to prevailing winds along the East Atlantic Flyway. We tracked 62 migratory journeys of 12 adult European Honey Buzzards Pernis apivorus with GPS loggers. Hourly fixes were annotated with local wind vectors from a global atmospheric model to determine orientation behaviours with respect to the buzzards' seasonal goal destinations. This enabled us to determine hot spots where buzzards overdrifted and overcompensated for side winds. We then determined whether winds along the buzzards' detours differed from winds prevailing elsewhere in the flyway. Honey Buzzards cross western Africa using different routes in autumn and spring. In autumn, they overcompensated for westward winds to circumvent the Atlas Mountains on the eastern side and then overdrifted with south-westward winds while crossing the Sahara. In spring, however, they frequently overcompensated for eastward winds to initiate a westward detour at the start of their journey. They later overdrifted with side winds north-westward over the Sahel and north-eastward over the Sahara, avoiding adverse winds over the central Sahara. We conclude that Honey Buzzards make seasonal detours to utilize more supportive winds further en route and thereby expend less energy while crossing the desert. Lifelong tracking studies will be helpful to elucidate how honey buzzards and other migrants learn complex routes to exploit atmospheric circulation patterns from local to synoptic scales. PMID- 27757960 TI - Strong nonlinear selection against fluctuating asymmetry in wild populations of a marine fish. AB - Theoretical links between fluctuating asymmetry (FA) and fitness have led many to use FA as a proxy for average fitness. However, studies examining whether asymmetry actually correlates with individual fitness in wild populations are relatively rare and often use simple measures of association (e.g., correlation coefficients). Consequently, the pattern of selection on asymmetry in the wild is seldom clear. We examined selection on FA of pectoral fin morphology in two wild populations of a marine fish (the kelp perch; Brachyistius frenatus). As expected, variance in signed FA in each initial sample was significantly greater than that found in the surviving population, indicating selection against FA. Our estimate of the fitness surface confirmed perfect symmetry as the phenotypic optimum and indicated strong, nonlinear selection against asymmetry. No difference in the form of selection was detected between populations. However, the level of FA in the initial samples varied among populations, leading to an overall difference in the level of selective mortality. Our results suggest that selection on asymmetry in wild populations may be strongly nonlinear, and indicate that the demographic costs of asymmetry may play a substantial role in the dynamics of populations. PMID- 27757961 TI - Renal mucous production in Australian freshwater plotosid and ariid catfishes. AB - This study reports the presence of large mucous cells lining the large renal collecting ducts and opisthonephric ducts of the Australian freshwater catfishes Tandanus tandanus and Tandanus tropicanus. Histologic examination of the renal tissue from four other species of Australian freshwater catfishes suggests that this feature is unique to the two species of Tandanus studied. The potential functions of renal mucous secretion in T. tandanus and T. tropicanus are discussed. PMID- 27757962 TI - For love or money? Australian attitudes to financially compensated (commercial) surrogacy. AB - BACKGROUND: Australian law allows for altruistic surrogacy but prohibits compensation of surrogates beyond their expenses, or the use of professional surrogacy agencies. These restrictions limit local access to surrogacy, driving Australians overseas where they can access commercial surrogacy. AIM: To assess the Australian public's views regarding the use of gestational surrogacy under various social and medical scenarios, together with their level of support for financial compensation of surrogates and the use of professional surrogacy agencies. MATERIALS AND METHODS: Online survey of 500 Australians of reproductive age (18-49 years) regarding views on surrogacy and acceptable levels of compensation, conducted during January 2016. RESULTS: The majority of respondents supported access to surrogacy for couples, irrespective of a couple's marital status or sexuality, with only 9% believing that surrogacy was unjustified under any circumstances. Of those who held a view on compensated surrogacy, over half (58%) believed the current ban was unjustified, with close to two-thirds (62%) also believing that Australians should be allowed to access commercial surrogacy overseas. In relation to compensation, most believed that payment should be determined by negotiation between the surrogate and commissioning parents, while also supporting additional payments for 'hardship' pregnancies. Half of the surveyed cohort supported the legalisation of professional surrogacy agencies, with only 17% being totally opposed. CONCLUSIONS: The majority of Australians support surrogacy, compensation for surrogates and professional surrogacy agencies. Therefore, the existing legal restrictions should be replaced with professional guidelines that protect the surrogate and commissioning parents, while also improving Australians' access to surrogacy. PMID- 27757963 TI - Monitoring of Lawsone, p-phenylenediamine and heavy metals in commercial temporary black henna tattoos sold in Turkey. AB - BACKGROUND: Henna has a very low allergic potential, and severe allergenic contact dermatitis is mainly caused by p-phenylenediamine (PPD), which is added to temporary black 'henna tattoos', and potentially also by some heavy metals. OBJECTIVE: To determine the presence of, and quantify, Lawsone, PPD and heavy metal contaminants (cobalt, nickel, lead, and chromium) in commercial temporary black henna tattoo mixtures (n = 25) sold in Turkey. METHODS: Lawsone and PPD concentrations were analysed with high-performance liquid chromatography, and heavy metal quantification was performed with inductively coupled plasma mass spectrometry. RESULTS: PPD was found in all 25 black henna tattoo samples purchased from tattoo shops; levels varied between 3.37% and 51.6%. Lawsone was detected (0.002-88.2%) in 21 of the 25 temporary black henna tattoo samples analysed. Heavy metal contaminant levels were 0.44-3.11 ppm for Co, 1.13-2.20 ppm for Ni, 1.59-17.7 ppm for Pb, and 35.0-76.9 ppm for Cr. CONCLUSIONS: Our results suggest that commercial temporary black henna mixtures containing PPD levels up to 51.6% pose a risk of contact sensitization and severe allergic contact dermatitis among users. It is important to identify both the additives and metallic contaminants of black henna tattoo products; the significance of metal contaminants has still to be assessed. PMID- 27757964 TI - Role of C16, angiopoietin-1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a chronic neurological disorder that affects the central nervous system (CNS), and results in CNS inflammation and damage to myelin. In this study, we examined the possible synergistic effects of C16, angiopoietin-1 (Ang-1) and regeneration gene protein 2 (Reg-2) in alleviating inflammation in an acute experimental autoimmune encephalomyelitis (EAE) model. We employed multiple histological, morphological and iconographic assays to examine the effect of those drugs on disease onset, clinical scores and behavioral deficits. Our results demonstrated that triple combination therapy was more efficient than the monotherapy in EAE treatment. The triple therapy significantly delayed the onset of motor symptoms, reduced disease severity, attenuated inflammatory cell infiltration and suppressed the secretion of proinflammatory cytokines. Additionally, treatment increased anti-inflammatory cytokines expression, inhibited reactive astrocytes proliferation, reduced demyelination and axonal loss, and finally reduced the neural death. Specifically, Reg-2 administration rescued oligodendrocytes and neuronal axons mainly by direct neurotrophic effects, while C16+Ang-1 (C+A) mainly improved the inflammatory milieu. In conclusion, our study suggests a possible synergistic effect through targeting a variety of pathways in relieving the clinical symptoms of inflammation in acute EAE model. Therefore, using molecules that target different molecular pathways can be beneficial for exploring novel therapeutic approaches for MS treatment. PMID- 27757965 TI - Intrapopulation genomics in a model mutualist: Population structure and candidate symbiosis genes under selection in Medicago truncatula. AB - Bottom-up evolutionary approaches, including geographically explicit population genomic analyses, have the power to reveal the mechanistic basis of adaptation. Here, we conduct a population genomic analysis in the model legume, Medicago truncatula, to characterize population genetic structure and identify symbiosis related genes showing evidence of spatially variable selection. Using RAD-seq, we generated over 26,000 SNPs from 191 accessions from within three regions of the native range in Europe. Results from STRUCTURE analysis identify five distinct genetic clusters with divisions that separate east and west regions in the Mediterranean basin. Much of the genetic variation is maintained within sampling sites, and there is evidence for isolation by distance. Extensive linkage disequilibrium was identified, particularly within populations. We conducted genetic outlier analysis with FST -based genome scans and a Bayesian modeling approach (PCAdapt). There were 70 core outlier loci shared between these distinct methods with one clear candidate symbiosis related gene, DMI1. This work sets that stage for functional experiments to determine the important phenotypes that selection has acted upon and complementary efforts in rhizobium populations. PMID- 27757966 TI - P-gp activity and inhibition in the different regions of human intestine ex vivo. AB - Although intestinal P-glycoprotein (P-gp) has been extensively studied in vitro and in animals, its activity and the consequences of P-gp inhibition for drug disposition and toxicity in humans are still difficult to accurately extrapolate from these studies. Moreover, existing in vitro models do not take into consideration that the intestine is heterogeneous with respect to P-gp expression. Recently, we reported rat precision-cut intestinal slices (PCIS) as a physiological ex vivo model to study the regional gradient of P-gp activity and inhibition. Here we extended the application of PCIS to the human intestine. For this purpose rhodamine 123 (R123) accumulation in the presence or absence of the P-gp inhibitors verapamil, cyclosporine A, quinidine, ketoconazole, PSC833 and CP100356 was measured in PCIS of human duodenum, jejunum, ileum and colon. R123 accumulation in the presence of the P-gp inhibitors appeared to be most enhanced in the ileum compared to the other regions. Moreover, the regional differences in accumulation are in line with published differences in abundance of P-gp. The rank order of the potency of the P-gp inhibitors, reflected by their IC50 , was comparable to that in rat PCIS. However, the increase in accumulation of the P-gp substrate R123 by the inhibitors was larger in human ileum PCIS than in rat PCIS, indicating species difference in P-gp abundance. These data show that human PCIS are an appropriate ex vivo model to study the activity of intestinal P-gp and predict the inhibitory effect of drugs and of transporter-mediated drug-drug interactions in the human intestine. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27757967 TI - Diet-induced non-alcoholic fatty liver disease affects expression of major cytochrome P450 genes in a mouse model. AB - OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is associated with impaired liver function, and resveratrol could suppress NAFLD progression. This study examined the effects of NAFLD on the expression of major cytochrome P450 (CYP) subtypes in the liver and whether the expression could be attenuated by resveratrol. METHODS: C57BL/6 mice (male, 10 weeks of age) were fed a high-fat and high-sucrose (HFHS) diet to induce NAFLD. Major Cyp subtype mRNA expression in the liver was measured by real-time RT-PCR. KEY FINDINGS: Body and liver weights at 4 and 12 weeks were significantly higher in mice fed the HFHS diet compared with control. The HFHS diet significantly increased the accumulation of cholesterol and triglycerides at 12 weeks. Under this condition, the HFHS diet increased the expression of Cyp1a2 and decreased that of Cyp3a11 at 1 week and thereafter. On the other hand, Cyp1a1, 2b10 and 2c29 mRNA expression levels in the liver were significantly increased at 12 weeks only. Resveratrol (0.05% (w/w) in diet) slightly suppressed lipid accumulation in the liver, but failed to recover impaired Cyp gene expression levels in NAFLD. CONCLUSIONS: Drug metabolism may be impaired in NAFLD, and each Cyp subtype is regulated in a different manner. PMID- 27757968 TI - Fibroblast growth factors and pulmonary fibrosis: it's more complex than it sounds. AB - Lung fibrosis results from the cumulative effect of dysfunctional wound repair involving multiple cell types, including fibroblasts, epithelial cells, and macrophages responding to an array of soluble and matrix-mediated stimuli. Recent studies have shown that a tyrosine kinase inhibitor that targets FGF, VEGF, and PDGF receptors can slow the rate of decline in pulmonary function in patients with idiopathic pulmonary fibrosis. However, each of these growth factor families is comprised of multiple ligands and receptors with pleiotropic activities on different cell types such that their broad inhibition might have both pro fibrotic and anti-fibrotic effects, limiting the potential therapeutic efficacy. Continued investigation and delineation of specific roles of individual proteins and receptors on different cell types hold promise for targeting specific pathways with precision and optimizing the potential efficacy of future approaches to lung fibrosis therapy. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27757969 TI - Relationships between parenting practices and perceptions of child behaviour among Korean immigrant mothers and fathers. AB - This study examined parenting styles and culturally-specific parenting practices of Korean immigrant mothers (N = 128) and fathers (N = 79) of children (ages 6 10) in New Zealand and the parenting predictors of child behaviour. Participants completed questionnaires on parenting styles and practices, and parental perceptions of child behaviour. Both parents indicated a high degree of devotion (Mo jeong) and involvement in care and education of their child with fathers were more likely than mothers to utilise shaming/love withdrawal and modesty encouragement. Results of regression analyses showed that there were some differences between mothers and fathers in the parenting predictors of child internalising and externalising behaviour problems and prosocial behaviour. Across the whole sample, there were contrasting relationships for authoritative parenting styles, devoted/involved parenting and modesty encouragement/shaming/non-reasoning parenting practices with child behaviour problems. Results indicated a blend of Western and Korean parenting practices were being utilised after settling in New Zealand. PMID- 27757970 TI - A frailty model for recurrent events during alternating restraint and non restraint time periods. AB - We consider recurrent events of the same type that occur during alternating restraint and non-restraint time periods. This research is motivated by a study on juvenile recidivism, where the probationers were followed for re-offenses during alternating placement periods and free-time periods. During the placement periods, the probationers were under a restricted environment with direct supervision of the probation officers. During the free-time periods, the probationers were released to home and not under direct supervision. Although re offenses can occur during both types of time periods, the intensities of the re offenses are very different. Thus, these two types of time periods should be modeled differently. The same data structure also arises in many biomedical settings, as exemplified by tumor metastases during chemotherapy and chemo-free periods. In this paper, we propose a joint modeling framework that explicitly accounts for the different types of time periods, as well as the within-subject dependence during the same type and between different types of time periods. The estimation procedure is implemented in SAS and is easily accessible to practical investigators. We evaluate the proposed method through simulation studies under several realistic scenarios and demonstrate the feasibility of the proposed method by applying it to the juvenile recidivism dataset. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27757972 TI - A rare cause of mucositis. PMID- 27757971 TI - Effects of pair bonding on dopamine D1 receptors in monogamous male titi monkeys (Callicebus cupreus). AB - Pair bonding leads to increases in dopamine D1 receptor (D1R) binding in the nucleus accumbens of monogamous prairie voles. In the current study, we hypothesized that there is similar up-regulation of D1R in a monogamous primate, the titi monkey (Callicebus cupreus). Receptor binding of the D1R antagonist [11 C]-SCH23390 was measured in male titi monkeys using PET scans before and after pairing with a female. We found that within-subject analyses of pairing show significant increases in D1R binding in the lateral septum, but not the nucleus accumbens, caudate, putamen, or ventral pallidum. The lateral septum is involved in a number of processes that may contribute to social behavior, including motivation, affect, reward, and reinforcement. This region also plays a role in pair bonding and paternal behavior in voles. Our observations of changes in D1R in the lateral septum, but not the nucleus accumbens, suggest that there may be broadly similar dopaminergic mechanisms underlying pair bonding across mammalian species, but that the specific changes to neural circuitry differ. This study is the first research to demonstrate neuroplasticity of the dopamine system following pair bonding in a non-human primate; however, substantial variability in the response to pairing suggests the utility of further research on the topic. PMID- 27757973 TI - Comparison of open-access vancomycin dosing websites. AB - WHAT IS KNOWN AND OBJECTIVE: There are many methods for dosing vancomycin. The purpose of this commentary was to compare open-access vancomycin dosing websites with Vancomycin-Calculator.com and describe how body weight can affect their pharmacokinetic (PK) calculations. COMMENT: A vancomycin dosing website, Vancomycin-Calculator.com, was developed to improve the dosing practice at our health system. Nine other vancomycin dosing calculators were identified, including three open-access websites. Each website uses a different dosing method. Most of the websites calculated similar doses for patients with normal body weight. Vancomycin-Calculator.com was the only website to calculate practical doses for obese patients, and it calculated higher daily doses for underweight patients compared to other websites. WHAT IS NEW AND CONCLUSION: Vancomycin-Calculator.com is an open-access vancomycin dosing website that was developed using the Bauer PK method. Compared with three other websites, PK calculations resulted in significant differences for underweight and obese patients. PMID- 27757974 TI - Estimation of acidity constants, ionic mobilities and charges of antimicrobial peptides by capillary electrophoresis. AB - Capillary electrophoresis (CE) was employed for the determination of thermodynamic acidity constants (pKa ) and actual ionic mobilities of polycationic antimicrobial peptides (AMPs). The effective electrophoretic mobilities of AMPs were measured by CE in a series of the background electrolytes within a wide pH range (2.00-12.25), at constant ionic strength (25 mM) and ambient temperature, using polybrene coated fused silica capillaries to suppress sorption of cationic AMPs to the capillary wall. Eventually, Haarhoff-Van der Linde peak fitting function was used for the determination of correct migration times of some AMPs peaks that were distorted by electromigration dispersion. The measured effective mobilities were corrected to 25 degrees C. Mixed acidity constants, pKa,i mix , and actual ionic mobilities, mi , of AMPs were determined by the nonlinear regression analysis of pH dependence of their effective mobilities. The pKa,i mix values were recalculated to thermodynamic pKa s using the Debye-Huckel theory. Thermodynamic pKa of imidazolium group of histidine residues was found to be in the range 3.72-4.98, pKa of alpha-NH3+ group was in the range 6.14-6.93, and pKa of epsilon-NH3+ group of lysine spanned the interval 7.26-9.84, depending on the particular amino acid sequence of the AMPs. Actual ionic mobilities of AMPs with positive charges from one to six elementary units achieved values (9.8 - 36.5) * 10-9 m2 V-1 s-1 . PMID- 27757975 TI - Reply. PMID- 27757976 TI - Solution Focused Brief Therapy: A Systematic Review and Meta-Summary of Process Research. AB - This article presents a systematic review of the process research on solution focused brief therapy (SFBT). We searched published and unpublished studies in English across five databases, five major journals, two book chapters, and four websites to locate studies that investigate why and how SFBT works. Thirty-three studies that used various research methods were located and included for further analysis using a meta-summary approach. The findings supported the significance of the co-construction process within SFBT and the effects of specific types of SFBT techniques. The most empirical support was found for the strength-oriented techniques in comparison to the other techniques and for the co-construction of meaning. Current studies require replications with larger samples and experimental designs that study SFBT process in relationship to outcomes. PMID- 27757977 TI - Contact balanitis to tromantadine. PMID- 27757978 TI - Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field. AB - The effects of electronic polarization in biomolecular interactions will differ depending on the local dielectric constant of the environment, such as in solvent, DNA, proteins, and membranes. Here the performance of the AMOEBA polarizable force field is evaluated under nonaqueous conditions by calculating the solvation free energies of small molecules in four common organic solvents. Results are compared with experimental data and equivalent simulations performed with the GAFF pairwise-additive force field. Although AMOEBA results give mean errors close to "chemical accuracy," GAFF performs surprisingly well, with statistically significantly more accurate results than AMOEBA in some solvents. However, for both models, free energies calculated in chloroform show worst agreement to experiment and individual solutes are consistently poor performers, suggesting non-potential-specific errors also contribute to inaccuracy. Scope for the improvement of both potentials remains limited by the lack of high quality experimental data across multiple solvents, particularly those of high dielectric constant. (c) 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 27757979 TI - A case of erythema multiforme drug eruption associated with erythrodermic psoriasis induced by sofosbuvir and daclatasvir. AB - WHAT IS KNOWN AND THE OBJECTIVE: Sofosbuvir (SOF) and daclatasvir (DCV) have revolutionized the treatment of hepatitis C virus and now represent the preferred therapy for this disease. Limited data are available on the dermatological side effects resulting from co-administration of SOF and DCV. CASE DESCRIPTION: We report a case of an erythema multiforme drug eruption associated with erythrodermic psoriasis induced by SOF and DCV. After ceasing treatment, the skin condition significantly improved. WHAT IS NEW AND CONCLUSION: We should pay attention to adverse skin reactions resulting from SOF and DCV, especially if the patient has a pre-existing dermatosis. PMID- 27757980 TI - Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints. AB - We discuss group-sequential designs in superiority clinical trials with multiple co-primary endpoints, that is, when trials are designed to evaluate if the test intervention is superior to the control on all primary endpoints. We consider several decision-making frameworks for evaluating efficacy or futility, based on boundaries using group-sequential methodology. We incorporate the correlations among the endpoints into the calculations for futility boundaries and sample sizes as a function of other design parameters, including mean differences, the number of analyses, and efficacy boundaries. We investigate the operating characteristics of the proposed decision-making frameworks in terms of efficacy/futility boundaries, power, the Type I error rate, and sample sizes, while varying the number of analyses, the correlations among the endpoints, and the mean differences. We provide an example to illustrate the methods and discuss practical considerations when designing efficient group-sequential designs in clinical trials with co-primary endpoints. PMID- 27757982 TI - Erythropoietin for Neuroprotection in preterm infants. PMID- 27757983 TI - Poly(ADP-ribose) polymerase 1 deficiency increases nitric oxide production and attenuates aortic atherogenesis through downregulation of arginase II. AB - Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12 weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity. PMID- 27757984 TI - The (Un)reliability of Alibi Corroborators: Failure to Recognize Faces of Briefly Encountered Strangers Puts Innocent Suspects at Risk. AB - Some innocent suspects rely on the memory of strangers to corroborate their alibis. However, no research has examined whether such potential alibi corroborators can accurately recognize an innocent suspect with whom they previously interacted. We developed a novel alibi corroboration paradigm in which undergraduate students (representing innocent suspects who would later provide an alibi) interacted with naive university employees (representing potential alibi corroborators). Each student briefly interacted with a different naive university employee (n = 60), and were also each yoked to a different employee with whom they did not interact (n = 60). Employees were presented 24 hours later with either a single photograph of the student or a six-person array containing a photograph of the student and were asked if they recognized anyone. The majority of employees failed to make a correct recognition of the student. False recognitions, however, were rare. Students exhibited overconfidence that they would be recognized. Findings imply that innocent suspects who rely on strangers to corroborate their alibis may be at risk. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27757981 TI - Recent advances in mass spectrometric analysis of glycoproteins. AB - Glycosylation is one of the most common posttranslational modifications of proteins that plays essential roles in various biological processes, including protein folding, host-pathogen interaction, immune response, and inflammation and aberrant protein glycosylation is a well-known event in various disease states including cancer. As a result, it is critical to develop rapid and sensitive methods for the analysis of abnormal glycoproteins associated with diseases. Mass spectrometry (MS) in conjunction with different separation methods, such as capillary electrophoresis (CE), ion mobility (IM), and high performance liquid chromatography (HPLC) has become a popular tool for glycoprotein analysis, providing highly informative fragments for structural identification of glycoproteins. This review provides an overview of the developments and accomplishments in the field of glycomics and glycoproteomics reported between 2014 and 2016. PMID- 27757985 TI - The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas. AB - AIMS: To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma. METHODS AND RESULTS: Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H IIP group), and the other included tumours unrelated to honeycomb lesions (the NH IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4alpha (HNF-4alpha). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups. CONCLUSIONS: Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features. PMID- 27757986 TI - Acceptability of mHealth Technology for Self-Monitoring Eating and Activity among Rural Men. AB - OBJECTIVE: To examine rural men's use and perceptions of mobile and wireless devices to self-monitor eating and physical activity (mHealth). DESIGN AND SAMPLE: Men in this 3-week pilot study used FitBit One(r) to log daily food intake and monitor activity. A companion application (app) allowed activity monitoring of fellow participants. Health-related text messages were received 1-3 times daily. A purposive sample of 12 rural men (ages 40-67) was recruited by community leaders. MEASURES: (1) baseline heart rate, blood pressure, and BMI, (2) FitBit One(r) usage, (3) investigator-generated surveys on acceptability of mHealth, and (4) focus group on experience with mHealth. RESULTS: Men were overweight (n = 3) or obese (n = 9) and 9 of 12 were hypertensive. Nine of twelve wore FitBit One(r) all 21 days. Eleven of 12 men logged food, with 9 of 12 doing this at least 15 of 21 days. Self-monitoring and daily text messaging increased awareness of energy intake and output. Companion app's food log needed targeting for rural foods. Rotating seasons (occupational, religious, recreational) and weak cellular signals created contextual barriers to self-monitoring eating and activity. CONCLUSIONS: FitBit One(r) and text messaging were perceived as useful among the rural men, while the companion apps require adaptation to reflect dietary norms. PMID- 27757987 TI - Does the treatment of amblyopia normalise subfoveal choroidal thickness in amblyopic children? AB - PURPOSE: Recent studies have found a choroidal thickening in amblyopic eyes and suggested that there might be a relationship between the choroid and amblyopia. The present study aimed to evaluate the effect of a six-month treatment of amblyopia on choroidal thickness in anisometropic hyperopic amblyopic children. METHODS: Thirty-two anisometropic hyperopic children with unilateral amblyopia were included in this prospective study. Subfoveal choroidal thickness was measured as the distance between the retinal pigment epithelium and the chorioscleral edge, by using spectral domain enhanced depth imaging optical coherence tomography. The treatment of amblyopia was performed based on the full correction of the refractive error with eyeglasses, a refractive adaptation phase and occlusion by patching the fellow eye. RESULTS: The mean visual acuity of the amblyopic eyes significantly increased from 0.35 +/- 0.3 to 0.16 +/- 0.2 logMAR after the treatment (p < 0.001). The mean initial choroidal thickness was significantly higher in the amblyopic eyes than in the fellow eyes (p = 0.019). There were no significant differences between the pre- and post-treatment mean choroidal thickness in the amblyopic eyes (p = 0.428) and in the fellow eyes (p = 0.343). The mean choroidal thickness was still higher in the amblyopic eyes than in the fellow eyes after the treatment (p = 0.006). CONCLUSIONS: Although a six month treatment of amblyopia increased the visual acuity of the anisometropic hyperopic amblyopic eyes, it could not significantly change choroidal thickness. Our results were in accordance with the conventional explanation, which suggests visual cortex and lateral geniculate nucleus abnormalities in the pathophysiology of amblyopia. PMID- 27757988 TI - Canine epididymal spermatozoa: A hidden treasure with great potential. AB - The hidden treasure represented by epididymal spermatozoa has great potential in the current reproductive technologies in dogs. In case of azoospermia or when a donor male accidentally dies or undergoes orchiectomy, the retrieval of epididymal spermatozoa opens new possibilities to generate progeny. Spermatozoa can be collected by different techniques from ex vivo or in vivo testicles and can be cryopreserved for a future use. Freeze tolerance of canine epididymal spermatozoa seems lower than that of ejaculated spermatozoa; however, puppies were born after artificial insemination with frozen epididymal semen, other than with fresh and chilled. Even though several aspects need to be further investigated, advances have been recently made in the use of epididymal spermatozoa in assisted reproduction in dogs. PMID- 27757990 TI - Freeze-dried spermatozoa: A future tool? AB - Cryopreservation has been routinely used to preserve sperm of human and different animal species. However, frozen sperm storage for a long time brings many inconveniences because of liquid nitrogen. Many attempts have been made to overcome the disadvantages of the current cryopreservation method. Freeze-drying has been proposed as alternative method for sperm preservation to achieve the ability to store sperm doses indefinitely at ambient temperature or in ordinary refrigerators. At present, it has been reported successfully sperm freeze-drying on many animal species including canine and feline. It is well known that during freeze-drying process, sperm DNA could be damaged, but if suitable protection is provided, the sperm nucleus could preserve the ability to activate the oocyte and embryos could be generated by intracytoplasmic sperm injection (ICSI). Many factors influence the freeze-drying efficacy, so current researches have been conducted to find strategies to control these factors to maintain the sperm DNA integrity. This review describes the latest method of sperm freeze-drying for practical application in preserving and transporting genetic resources. In addition, the approaches to improve the efficiency of the technique were studied. We demonstrated that the DNA integrity of freeze-dried dog sperm is affected by the composition of the freeze-drying solution as well as the temperature and period of storage. Further studies are necessary to refine freeze-drying protocol in order to protect the DNA and maintain the sperm functionality and obtain offspring from freeze-dried sperm. PMID- 27757989 TI - Identification of a conserved and acute neurodegeneration-specific microglial transcriptome in the zebrafish. AB - Microglia are brain resident macrophages important for brain development, connectivity, homeostasis and disease. However, it is still largely unclear how microglia functions and their identity are regulated at the molecular level. Although recent transcriptomic studies have identified genes specifically expressed in microglia, the function of most of these genes in microglia is still unknown. Here, we performed RNA sequencing on microglia acutely isolated from healthy and neurodegenerative zebrafish brains. We found that a large fraction of the mouse microglial signature is conserved in the zebrafish, corroborating the use of zebrafish to help understand microglial genetics in mammals in addition to studying basic microglia biology. Second, our transcriptome analysis of microglia following neuronal ablation suggested primarily a proliferative response of microglia, which we confirmed by immunohistochemistry and in vivo imaging. Together with the recent improvements in genome editing technology in zebrafish, these data offer opportunities to facilitate functional genetic research on microglia in vivo in the healthy as well as in the diseased brain. GLIA 2016;65:138-149. PMID- 27757992 TI - Editorial Comment to Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome. PMID- 27757991 TI - Cannabinoids prevent the amyloid beta-induced activation of astroglial hemichannels: A neuroprotective mechanism. AB - The mechanisms involved in Alzheimer's disease are not completely understood and how astrocytes and their gliotransmission contribute to this neurodegenerative disease remains to be fully elucidated. Previous studies have shown that amyloid beta peptide (Abeta) induces neuronal death by a mechanism that involves the excitotoxic release of ATP and glutamate associated to astroglial hemichannel opening. We have demonstrated that synthetic and endogenous cannabinoids (CBs) reduce the opening of astrocyte Cx43 hemichannels evoked by activated microglia or inflammatory mediators. Nevertheless, whether CBs could prevent the astroglial hemichannel-dependent death of neurons evoked by Abeta is unknown. Astrocytes as well as acute hippocampal slices were treated with the active fragment of Abeta alone or in combination with the following CBs: WIN, 2-AG, or methanandamide (Meth). Hemichannel activity was monitored by single channel recordings and by time-lapse ethidium uptake while neuronal death was assessed by Fluoro-Jade C staining. We report that CBs fully prevented the hemichannel activity and inflammatory profile evoked by Abeta in astrocytes. Moreover, CBs fully abolished the Abeta-induced release of excitotoxic glutamate and ATP associated to astrocyte Cx43 hemichannel activity, as well as neuronal damage in hippocampal slices exposed to Abeta. Consequently, this work opens novel avenues for alternative treatments that target astrocytes to maintain neuronal function and survival during AD. GLIA 2016 GLIA 2017;65:122-137. PMID- 27757993 TI - Central corneal thickness and its relationship to ocular parameters in young adult myopic eyes. AB - BACKGROUND: An investigation was carried out to find the distribution of central corneal thickness (CCT) and the association between CCT and ocular factors in a cohort of myopic Chinese adults who underwent laser refractive surgery. METHODS: Medical records of 1,190 subjects (754 males) aged from 18 to 44 years (21.5 +/- 3.5 years for males and 24.9 +/- 5.5 years for females) undergoing myopic refractive surgery were filtered and analysed. Each parameter was stratified by gender and eye, respectively. Multi-linear and linear regressions were used to analyse the effect of intraocular pressure (IOP), period of contact lens wearing, gender, age, refractive error, mean corneal curvature (K) and ocular high-order aberration at 5.0-mm zone on CCT. RESULTS: The mean CCT was 539.2 +/- 37.8 um in the whole study population. Males had greater CCT than females (p < 0.001), while females had greater K than males (p < 0.001). There was no difference in IOP, ocular cylinder or higher-order aberrations between genders. No interocular difference was identified either in IOP or K. Multi-linear regression model revealed that only gender, IOP and K were correlated with CCT (standardised coefficients of right eye are -0.101, p = 0.001 for gender, 0.231, p < 0.001 for IOP and -0.080, p = 0.009 for K; standardised coefficients of left eye are 0.090, p = 0.002 for gender, 0.310, p < 0.001 for IOP and -0.076, p = 0.015 for K). CONCLUSIONS: In a population of myopic candidates for laser refractive surgery, only gender, IOP and K were correlated with CCT. PMID- 27757994 TI - The Impact of Phase Retention on the Structural and Optoelectronic Properties of Metal Halide Perovskites. AB - The extent to which the soft structural properties of metal halide perovskites affect their optoelectronic properties is unclear. X-ray diffraction and micro photoluminescence measurements are used to show that there is a coexistence of both tetragonal and orthorhombic phases through the low-temperature phase transition, and that cycling through this transition can lead to structural changes and enhanced optoelectronic properties. PMID- 27757995 TI - Measuring Residual Renal Function in Hemodialysis Patients without Urine Collection. AB - Many patients on hemodialysis retain significant residual renal function (RRF) but currently measurement of RRF in routine clinical practice can only be achieved using inter-dialytic urine collections to measure urea and creatinine clearances. Urine collections are difficult and inconvenient for patients and staff, and therefore RRF is not universally measured. Methods to assess RRF without reliance on urine collections are needed since RRF provides useful clinical and prognostic information and also permits the application of incremental hemodialysis techniques. Significant efforts have been made to explore the use of serum based biomarkers such as cystatin C, beta-trace protein and beta2 -microglobulin to estimate RRF. This article reviews blood-based biomarkers and novel methods using exogenous filtration markers which show potential in estimating RRF in hemodialysis patients without the need for urine collection. PMID- 27757996 TI - Why social values cannot be changed for the sake of conservation. AB - The hope for creating widespread change in social values has endured among conservation professionals since early calls by Aldo Leopold for a "land ethic." However, there has been little serious attention in conservation to the fields of investigation that address values, how they are formed, and how they change. We introduce a social-ecological systems conceptual approach in which values are seen not only as motivational goals people hold but also as ideas that are deeply embedded in society's material culture, collective behaviors, traditions, and institutions. Values define and bind groups, organizations, and societies; serve an adaptive role; and are typically stable across generations. When abrupt value changes occur, they are in response to substantial alterations in the social ecological context. Such changes build on prior value structures and do not result in complete replacement. Given this understanding of values, we conclude that deliberate efforts to orchestrate value shifts for conservation are unlikely to be effective. Instead, there is an urgent need for research on values with a multilevel and dynamic view that can inform innovative conservation strategies for working within existing value structures. New directions facilitated by a systems approach will enhance understanding of the role values play in shaping conservation challenges and improve management of the human component of conservation. PMID- 27757997 TI - Determination of the normal reference interval for anti-Mullerian hormone (AMH) in bitches and use of AMH as a potential predictor of litter size. AB - Anti-Mullerian hormone (AMH) is a reliable endocrine marker of ovarian reserve in many species with extensive literature in both humans and cattle. However, there are no known hormonal predictors of ovarian reserve and potential reproductive performance in the bitch. A prospective cohort study was performed involving 155 intact bitches of various ages (range 1.2-7.6 years) and breeds that were presented for routine breeding management over a one-year period. All bitches were artificially inseminated with frozen or fresh semen using the transcervical insemination (TCI) technique. AMH concentrations were measured using a commercially available canine AMH ELISA (Ansh Labs(r) , Texas, USA), which we validated prior to performing the study. The reference interval (RI) for AMH for all bitches in the study, regardless of body weight, was 2.9-21.1 ng/ml. There was a significant effect of bitch size and age on AMH concentrations. The RI for giant breeds was significantly (p < .01) lower (1.75-15.6 ng/ml) than small-sized (5.6-24.2 ng/ml), medium-sized (4.3-23.7 ng/ml) and large-sized (4.3-21.0 ng/ml) bitches. The mean AMH concentration in bitches less than 4 years of age was 12.4 ng/ml, whereas the mean AMH concentration in bitches older than 4 years of age was 10.5 ng/ml (p < .05). For each additional year of age above 1 year of age, AMH concentrations fell by 0.5 ng/ml. There was no effect of AMH concentration on the whelping rate. Smaller breeds had smaller litters (and higher AMH concentrations), but within each breed size category, bitches with higher AMH concentrations had significantly larger litter sizes (p < .01). For each 1 ng/ml increase in AMH, litter size increased by 0.3 pups/litter. In conclusion, we determined a normal reference interval for AMH in bitches based on body weight using a canine-specific assay. In agreement with findings in humans and other species, we found that there is a decline in AMH concentrations with advancing age in bitches. Finally, the significant positive correlation between AMH concentrations and litter size indicates that AMH may be a useful management tool for the selection of bitches in breeding programmes. PMID- 27757998 TI - Presence of sucrose in the vitrification solution and exposure for longer periods of time improve post-warming follicle integrity in cat ovarian tissues. AB - Ovarian tissue cryopreservation followed by tissue culture is a promising approach to preserving the fertility of biomedical models and endangered species. The objective of this study was to investigate the impact of exposure time to vitrification solution and presence of sucrose using different exposure temperatures and base media on intra-ovarian follicle integrity. Peripubertal ovarian cortical pieces were obtained by isolating the cortex and dissecting it into 1 * 1 * 0.2 mm3 pieces. The cortical pieces were then exposed to equilibration solution and then vitrification solutions (VS) in one of the conditions mentioned above, plunged directly into liquid nitrogen and stored for >=24 hr in liquid nitrogen. After thawing, the cortical pieces were cultured in vitro for 0, 1 or 7 days to determine the follicle integrity (through histological assessment) and the ability of the tissue to recover from cryoinjury. Fresh controls maintained a constant level of normal morphology (>60% of the total follicles) throughout the culture period. Cortical pieces exposed to VS with sucrose for 10 min had the highest percentage of normal follicles (approximately 20% after 7 days of culture) throughout the culture period. Other conditions using different base medium, lower exposure temperatures or different thawing methods did not improve the follicle integrity. This protocol provides a solid foundation on which to optimize ovarian tissue cryopreservation in the domestic cat and to investigate the molecular effects of vitrification. PMID- 27757999 TI - Tumor size and Fuhrman grade further enhance the prognostic impact of perinephric fat invasion and renal vein extension in T3a staging of renal cell carcinoma. AB - OBJECTIVE: To evaluate the prognostic values of perinephric fat invasion and renal vein invasion in pT3a renal cell carcinoma, as stand-alone factors and in combination with tumor size and Fuhrman grade. METHODS: Survival data of pT1 and pT2 renal cell carcinomas were analyzed alongside pT3a tumors of similar size bands (pT1 vs pT3a <7 cm, pT2 vs pT3a >7 cm). Patients with adjuvant therapy, positive surgical margins, metastasis or pT3b-pT4 tumors were excluded. RESULTS: No significant baseline demographic differences existed between the groups. Patients with renal vein invasion had larger tumors (median, 7.2 +/- 3.0 cm vs 5.5 +/- 3.6 cm, P = 0.039), and were more symptomatic (90.0% vs 61.7%, P = 0.028) compared with patients with perinephric fat invasion alone. Patients with perinephric fat invasion alone appeared to have better disease-free survival compared with those with renal vein invasion (P = 0.009). Having both perinephric fat invasion and renal vein invasion did not result in a poorer disease-free survival. pT3a (perinephric fat invasion) tumors <4 cm and 4-7 cm have significantly worse disease-free survival compared with pT1a and pT1b tumors (P < 0.001). Similarly, pT3a (perinephric fat invasion) tumors measuring >=7 show a trend of poorer disease-free survival compared with pT2a and pT2b tumors (P = 0.267). Disease-free survival correlated with Fuhrman grading for patients with perinephric fat invasion (P = 0.008). In multivariate analysis, the survival curve of pT3a perinephric fat invasion group closely approximates that of pT2 group, whereas survival of the renal vein invasion group was significantly worse than the pT2 and perinephric fat invasion groups (P = 0.001). CONCLUSION: pT3a tumors with perinephric fat invasion appear to have better prognosis than those with renal vein invasion. Further stratification of pT3a renal cell carcinomas with regard to tumor size and Fuhrman grade further enhances the prognostic value in this group. PMID- 27758000 TI - Cell autonomous and noncell-autonomous role of NF-kappaB p50 in astrocyte mediated fate specification of adult neural progenitor cells. AB - In previous work, we demonstrated that NF-kappaB p50 acts as crucial regulator of adult hippocampal neural progenitor cells (ahNPC). Indeed, NF-kappaB p50 knockout (KO) mice are characterized by remarkably reduced hippocampal neurogenesis. As a follow up to that work, herein we show that when cultured in vitro, ahNPC from wild type (WT) and p50KO mice are not significantly different in their neurogenic potential. This observation prompted us to investigate cell-autonomous and noncell-autonomous consequences of p50 absence on neuronal fate specification of ahNPC. In particular, we focused our attention on astrocytes, known to provide soluble proneurogenic signals, and investigated the influence of WT and p50KO astrocyte conditioned media (ACM) on WT and p50KO ahNPC differentiation. Interestingly, while WT ACM promoted both neuronal and astroglial differentiations, p50KO ACM only supported astroglial differentiation of WT ahNPC. By using a LC-MS/MS approach, we identified some proteins, which are significantly upregulated in p50KO compared with WT astrocytes. Among them, lipocalin-2 (LCN-2) was recognized as a novel astroglial-derived signal regulating neuronal fate specification of ahNPC. Interestingly, LCN-2 proneurogenic effect was greatly reduced in p50KO NPC, where LCN-2 receptor gene expression appeared downregulated. In addition to that, we demonstrated p50KO NPC unresponsiveness to both neuronal and astroglial fate specification signals from WT and p50KO ACM, and we identified a reduced expression of alpha2delta1, a thrombospondin-1 receptor, as another phenotypic change occurring in ahNPC in the absence of p50. Altogether, our data suggest that dysregulated NPC-astrocyte communication may contribute to a reduced hippocampal neurogenesis in p50KO mice in vivo. GLIA 2016 GLIA 2017;65:169-181. PMID- 27758002 TI - Spontaneous Electroless Galvanic Cell Deposition of 3D Hierarchical and Interlaced S-M-S Heterostructures. AB - One-pot electroless galvanic cell deposition of a 3D hierarchical semiconductor metal-semiconductor interlaced nanoarray is demonstrated. The fabricated 3D photoanode deviates from the typical planar geometry, and aims to optimize the effective surface area for light harvesting and long-range charge transfer collection pathways. PMID- 27758001 TI - Fabrication of RNA 3D Nanoprisms for Loading and Protection of Small RNAs and Model Drugs. AB - Constructing containers with defined shape and size to load and protect therapeutics and subsequently control their release in the human body has long been a dream. The fabrication of 3D RNA prisms, characterized by atomic force microscopy, cryo-electron microscopy, dynamic light scattering, and polyacrylamide gel electrophoresis, is reported for the loading and protection of small molecules, proteins, small RNA molecules, and their controlled release. PMID- 27758003 TI - Evaluation of follicular growth and tissue viability in vitrified/warmed domestic dog ovaries after in vitro culture. AB - Cryopreservation of gametes is an important tool to preserve fertility, but for most species, including domestic dogs, data regarding ovarian tissue cryopreservation are limited. We aimed to evaluate the follicular and tissue viability and follicular growth after in vitro culture of domestic dog ovarian cortical slices cryopreserved by vitrification. Ovarian cortex was obtained from ten pairs of ovaries from domestic dogs using two methods (A and B), one for each ovary from the same bitch. At least four slices for each method were obtained from each ovary, one was processed for histology and the other three were vitrified. When the vitrified slices were warmed, one slice from each method was processed for histology and the remaining two slices were cultured in vitro for 7 days, after which they were processed for histological evaluation. Density of follicles in fresh samples was similar for both methods. For Method A, density of secondary follicles decreased, while the density of primordial follicles was maintained throughout the process. For Method B, density of primary follicles decreased after 7 days of incubation, but density of secondary follicles increased, confirming follicular growth in Method B. Overall, there were no differences between Methods A and B in follicular integrity after incubation. Fresh samples showed better arterial, venous and follicle preservation, followed by vitrified-warmed samples, but no differences were observed between methods. In conclusion, the methodology used to isolate the ovarian cortex may affect tissue and follicle viability as well as follicular development during in vitro culture. PMID- 27758004 TI - Diagnostic possibilities from a serum sample-Clinical value of new methods within small animal reproduction, with focus on anti-Mullerian hormone. AB - During the last decade, analysis of anti-Mullerian hormone (AMH), highly conserved between mammalian species, has contributed to new information in reproductive endocrinology, due to clinically available diagnostic assays. AMH is produced solely in the gonads, in the Sertoli cells of testes and granulosa cells of the ovary, and thus offers possibilities to diagnose physiologic and pathologic conditions involving these organs. This article reviews indications for AMH analysis in cats and dogs, including diagnosing the presence of gonads, and granulosa or Sertoli cell tumours. Diagnostic challenges are addressed. One specific organ, the prostate, is commonly affected by pathologic changes in older dogs. A commercial assay for analysing canine prostatic specific esterase (CPSE) enables analysis of CPSE in clinical practice, of potential value in the workup of benign prostatic hyperplasia in male dogs. This is described in this review, as is a new method for analysis of steroids: liquid chromatography-tandem mass spectrometry LC-MS/MS. Steroids have since long been analysed in studies on reproduction, and LC-MS/MS has the advantage of allowing analysis of panels of multiple steroids from small sample volumes. Altogether, these available methods may give new insights into small animal reproduction and are valuable tools for the practicing veterinarian. PMID- 27758005 TI - Intensive point-of-care ultrasound training with long-term follow-up in a cohort of Rwandan physicians. AB - OBJECTIVE: We delivered a point-of-care ultrasound training programme in a resource-limited setting in Rwanda, and sought to determine participants' knowledge and skill retention. We also measured trainees' assessment of the usefulness of ultrasound in clinical practice. METHODS: This was a prospective cohort study of 17 Rwandan physicians participating in a point-of-care ultrasound training programme. The follow-up period was 1 year. Participants completed a 10 day ultrasound course, with follow-up training delivered over the subsequent 12 months. Trainee knowledge acquisition and skill retention were assessed via observed structured clinical examinations (OSCEs) administered at six points during the study, and an image-based assessment completed at three points. RESULTS: Trainees reported minimal structured ultrasound education and little confidence using point-of-care ultrasound before the training. Mean scores on the image-based assessment increased from 36.9% (95% CI 32-41.8%) before the initial 10-day training to 74.3% afterwards (95% CI 69.4-79.2; P < 0.001). The mean score on the initial OSCE after the introductory course was 81.7% (95% CI 78-85.4%). The mean OSCE performance at each subsequent evaluation was at least 75%, and the mean OSCE score at the 58-week follow up was 84.9% (95% CI 80.9-88.9%). CONCLUSIONS: Physicians providing acute care in a resource-limited setting demonstrated sustained improvement in their ultrasound knowledge and skill 1 year after completing a clinical ultrasound training programme. They also reported improvements in their ability to provide patient care and in job satisfaction. PMID- 27758006 TI - Mitigation of sperm tail abnormalities using demembranation approach in the clouded leopard (Neofelis nebulosa). AB - Clouded leopards (Neofelis nebulosa) produced high proportion of abnormal spermatozoa (mainly tail defects) that can limit sperm movement and conception. The study aimed to better identify the origin of those defects using a demembranation approach. Ejaculates (1-2 ejaculations/male; n = 9) were allocated to simple washing (control; resulting in 11.7% +/- 1.9% coiled tails) and processed through colloid centrifugation to reduce the number of sperm with tail defects (treatment, resulting in 5.9% +/- 0.9% coiled tails). Aliquots of semen were incubated in hypo-osmotic solution (HOS, 60 mOsm fructose solution) containing 5 mM dithiothreitol (DTT) (a reducing agent) to prevent oxidation of sperm membrane. Thereafter, 20% Triton X-100 (TX) (a detergent) was added to the HOS/DTT-treated samples. After HOS/DTT incubation, the control samples and sperm selected samples presented 73.4% +/- 3.1% and 73.9% +/- 2.5% swollen sperm (bent and coiled) indicating membrane intact, respectively. Most of the coiled tail in the raw ejaculates could not be opened by TX indicating that the cause of coiled sperm tails may be from testicular origin. The proportion of sperm with tightly coiled tail tended to be lower in the sperm-selected group than control group (18.8% +/- 3.8% and 26.5% +/- 3.4%; p = .1), whereas the sperm opened up by TX tended to be higher in the sperm-selected group (53.6% +/- 10.4% and 21.1% +/- 7.9%; p = .06). The results indicated TX was able to uncoil half of the tightly coiled sperm in the semen undergone preparation. In conclusion, the coiled sperm in the clouded leopard semen were likely not a defect of sperm volume regulation during post-ejaculate (osmotic swelling) but pre-ejaculate origin. Semen preparation demonstrated its ability to lessen the primary sperm defects and selected spermatozoa that were prone to be mitigated after demembranation. PMID- 27758008 TI - Solution and Solid-State Studies on the Halide Binding Affinity of Perfluorophenyl-Armed Uranyl-Salophen Receptors Enhanced by Anion-pi Interactions. AB - The enhancement of the binding between halide anions and a Lewis acidic uranyl salophen receptor has been achieved by the introduction of pendant electron deficient arene units into the receptor skeleton. The association and the occurrence of the elusive anion-pi interaction with halide anions (as tetrabutylammonium salts) have been demonstrated in solution and in the solid state, providing unambiguous evidence on the interplay of the concerted interactions responsible for the anion binding. PMID- 27758007 TI - Impact of haemoconcentration during acute heart failure therapy on mortality and its relationship with worsening renal function. AB - AIMS: Treatment goals in acute heart failure (AHF) are poorly defined. We aimed to characterize further the impact of in-hospital haemoconcentration and worsening renal function (WRF) on short- and long-term mortality. METHODS AND RESULTS: Haematocrit, haemoglobin, total protein, serum creatinine, and albumin levels were measured serially in 1019 prospectively enrolled AHF patients. Haemoconcentration was defined as an increase in at least three of four of the haemoconcentration-defining parameters above admission values at any time during the hospitalization. Patients were divided into early (Day 1-4) and late haemoconcentration (>Day 4). Ninety-day mortality was the primary endpoint. Haemoconcentration occurred in 392 (38.5%) patients, with a similar incidence of the early (44.6%) and late (55.4%) phenotype. Signs of decongestion (reduction in BNP blood concentrations, P = 0.003; weight loss, P = 0.002) were significantly more pronounced in haemoconcentration patients. WRF was more common in haemoconcentration patients (P = 0.04). After adjustment for established risk factors for AHF mortality, including WRF and HF therapy at discharge, haemoconcentration was significantly associated with a reduction in 90-day mortality [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.95, P = 0.01]. The beneficial effect of haemoconcentration seemed to be exclusive for late haemoconcentration (late vs. early: adjusted HR 0.41, 95% CI 0.19-0.90, P = 0.03) and persisted in patients with or without WRF. CONCLUSIONS: Haemoconcentration represents an inexpensive and easily assessable pathophysiological signal of adequate decongestion in AHF and is associated with lower mortality. WRF in the setting of haemoconcentration does not appear to offset the benefits of haemoconcentration. PMID- 27758009 TI - Competent Route to Unsymmetric Dimer Architectures: Total Syntheses of (-) Lycodine and (-)-Complanadines A and B, and Evaluation of Their Neurite Outgrowth Activities. AB - Valuable synthetic routes to the Lycopodium alkaloid lycodine (1) and its unsymmetric dimers, complanadines A (4) and B (5), have been developed. Regioselective construction of the bicyclo[3.3.1]nonane core structure of lycodine was achieved by a remote functionality-controlled Diels-Alder reaction and subsequent intramolecular Mizoroki-Heck reaction. A key coupling reaction of the lycodine units, pyridine N-oxide (66) and aryl bromide (65), through C-H arylation at the C1 position of 66 provided the unsymmetric dimer structure at a late stage of the synthesis. This strategy greatly simplified the construction of the dimeric architecture and functionalization. Complanadines A (4) and B (5) were synthesized by adjusting the oxidation level of the bipyridine mono-N-oxide (67). The diverse utility of this common intermediate (67) suggests a possible biosynthetic pathway of complanadines in Nature. Both enantiomers of lycodine (1) and complanadines A (4) and B (5) were prepared in sufficient quantities for biological evaluation. The effect on neuron differentiation of PC-12 cells upon treatment with culture medium, in which human astrocytoma cells had been cultured in the presence of 1, 4, or 5 was evaluated. PMID- 27758010 TI - Morningness-eveningness and daytime functioning in university students: the mediating role of sleep characteristics. AB - The aim of this study was to explore the mediating role of sleep characteristics in the relationship between morningness-eveningness and three different aspects of daytime functioning: daytime sleepiness, depressive mood and substance use in university students. A multiple mediator model was proposed with sleep debt, poor sleep quality and bedtime delay at weekends as parallel mediators in these relationships. We analysed the data of 1052 university students aged 18-25 years who completed a modified version of the School Sleep Habits Survey, which included questions on sleep and the Composite Scale of Morningness, Sleepiness Scale, Depressive Mood Scale and Substance Use Scale. Students with more pronounced eveningness reported greater daytime sleepiness, greater depressive mood and more frequent substance use, as well as greater sleep debt, poorer sleep quality and greater bedtime delay at weekends. Mediation analyses indicated that morningness-eveningness affected daytime sleepiness and substance use both directly and indirectly through all proposed sleep-related mediators. However, the effect of morningness-eveningness on depressive mood was entirely indirect and was accounted for more by poor sleep than by sleep debt or bedtime irregularity. In conclusion, there are multiple possible mechanisms through which morningness-eveningness affects daytime functioning in university students, and sleep characteristics are a significant mechanism. Sleep debt, poor sleep quality and bedtime irregularity can, to a significant extent, explain the feeling of daytime sleepiness and greater substance use in students with eveningness preferences. However, more depressed mood in the evening-orientated students is primarily a consequence of their poor sleep quality. PMID- 27758011 TI - Effects of increasing amount of dietary Prosopis laevigata pods on performance, meat quality and fatty acid profile in growing lambs. AB - A study with finishing lambs assessed the effect of dietary inclusion of Prosopis laevigata pods (PLPs) on performance, carcass characteristics, meat traits and fatty acid profile of subcutaneous fat. Twenty-one Rambouillet lambs (27.0 +/- 3.0 kg BW) were assigned to one of three experimental diets with 0, 150 and 300 g PLP/kg DM. Evaluation of growth performance lasted 49 days. The experimental design was completely randomized and analysed with a mixed model. Lambs fed diets with 0, 150 and 300 g PLP had similar growth performance. Lambs fed diets with 300 g PLP/kg DM had better (p < 0.05) carcass yield and classification, less (p < 0.05) fat deposition and lower lightness (L*) value (p < 0.05) in meat than lambs fed diets with 0 and 150 g PLP/kg DM. Saturated fatty acids (palmitic and stearic) decreased (p < 0.05) and unsaturated fatty acids (oleic and linoleic) increased (p < 0.05) in subcutaneous fat of lambs fed diets with 150 and 300 g pods as compared with lambs not fed PLP. Prosopis laevigata pods are a safe feedstuff that can replace a third of conventional ingredients and reduce feed costs in growing lambs. Addition of PLP reduced (p < 0.05) total feed cost by 21%. PMID- 27758012 TI - Total Synthesis of (-)-Salvinorin A. AB - Salvinorin A (1) is natural hallucinogen that binds the human kappa-opioid receptor. A total synthesis has been developed that parlays the stereochemistry of l-(+)-tartaric acid into that of (-)-1 via an unprecedented allylic dithiane intramolecular Diels-Alder reaction to obtain the trans-decalin scaffold. Tsuji allylation set the C9 quaternary center and a late-stage stereoselective chiral ligand-assisted addition of a 3-titanium furan upon a C12 aldehyde/C17 methyl ester established the furanyl lactone moiety. The tartrate diol was finally converted into the C1,C2 keto-acetate. PMID- 27758013 TI - Effect of soy lecithin on total cholesterol content, fatty acid composition and carcass characteristics in the Longissimus dorsi of Hanwoo steers (Korean native cattle). AB - This study aims to investigate the effect of soy lecithin on the total cholesterol content, the fatty acid composition and carcass characteristics in the Longissimus dorsi in Hanwoo steers. Hanwoo steers (24 head) were fed two diets: Control (CON) (concentrate + alcohol-fermented feed (AFF)) and soy lecithin treatment (CON + soy lecithin at 0.5% of the AFF). Soy lecithin treatment increased average daily gain, serum concentrations of triglyceride, total cholesterol and high-density lipoprotein-cholesterol in the blood. A lower cholesterol concentration was found in the Longissimus dorsi for the soy lecithin diet compared to the CON diet. With respect to the marbling score and quality grade of Longissimus dorsi, soy lecithin supplementation significantly increased the C20:5n3, C22:4 and polyunsaturated fatty acids contents compared to the CON diet. Soy lecithin supplementation would alter the total cholesterol content, polyunsaturated fatty acid profile and meat quality of Longissimus dorsi. PMID- 27758014 TI - Opsins have evolved under the permanent heterozygote model: insights from phylotranscriptomics of Odonata. AB - Gene duplication plays a central role in adaptation to novel environments by providing new genetic material for functional divergence and evolution of biological complexity. Several evolutionary models have been proposed for gene duplication to explain how new gene copies are preserved by natural selection, but these models have rarely been tested using empirical data. Opsin proteins, when combined with a chromophore, form a photopigment that is responsible for the absorption of light, the first step in the phototransduction cascade. Adaptive gene duplications have occurred many times within the animal opsins' gene family, leading to novel wavelength sensitivities. Consequently, opsins are an attractive choice for the study of gene duplication evolutionary models. Odonata (dragonflies and damselflies) have the largest opsin repertoire of any insect currently known. Additionally, there is tremendous variation in opsin copy number between species, particularly in the long-wavelength-sensitive (LWS) class. Using comprehensive phylotranscriptomic and statistical approaches, we tested various evolutionary models of gene duplication. Our results suggest that both the blue sensitive (BS) and LWS opsin classes were subjected to strong positive selection that greatly weakens after multiple duplication events, a pattern that is consistent with the permanent heterozygote model. Due to the immense interspecific variation and duplicability potential of opsin genes among odonates, they represent a unique model system to test hypotheses regarding opsin gene duplication and diversification at the molecular level. PMID- 27758015 TI - Concise Review: Signaling Control of Early Fate Decisions Around the Human Pluripotent Stem Cell State. AB - Human embryonic stem cells (hESCs) present a fascinating and powerful system for generating specialized cell types of the human body. Culture and directed differentiation of these cells however requires an understanding of the pluripotent ground state and of how cell lineage decisions in this system are made. In this review, we highlight both these aspects in light of recent findings and technical progress. Hence, advances in culturing the human preimplantation embryo beyond the implantation barrier and in analyzing it at the single-cell level shed new light on the hESC tissue of origin. We argue that these findings have important implications for our view of hESC identity and we critically discuss recent efforts in converting these cells to a more primitive state. With an emphasis on the roles played by major signaling pathways, we furthermore attempt to infer key principles underlying cell fate control in hESCs from recently published work. This integrated model combines defined signaling pathway manipulation with the regulation of core hESC genes, to aid in controlling cell lineage allocation in a rational manner. Stem Cells 2017;35:277-283. PMID- 27758016 TI - Diffusion kurtosis imaging for differentiating between the benign and malignant sinonasal lesions. AB - PURPOSE: The study aimed to evaluate diffusion kurtosis imaging (DKI) in the differentiation between benign and malignant sinonasal lesions, and to compare the diagnostic performance of DKI with diffusion weighted imaging (DWI). MATERIALS AND METHODS: Eight-one patients with solid sinonasal lesions confirmed by surgery and pathology (46 malignant and 35 benign) underwent conventional MRI, DWI, and DKI. DKI was performed employing a 13 extended b-value ranging from 0 to 2500 s/mm2 . Apparent diffusion coefficient (ADC) from DWI, kurtosis (K), and diffusion coefficient (D) from DKI were measured and compared between two groups. RESULTS: ADC and D values were significantly lower in the malignant sinonasal lesions than in the benign sinonasal lesions (1.11 +/- 0.41 versus 1.58 +/- 0.50 * 10-3 mm2 /s and 1.45 +/- 0.36 versus 2.03 +/- 0.49 * 10-3 mm2 /s, respectively, both P < 0001). K value was significantly higher in the malignant lesions than in the benign lesions (0.91 +/- 0.23 versus 0.57 +/- 0.24, P < 0001). The receiver operating characteristic curve analyses yielded a cutoff ADC value of 1.27 * 10-3 mm2 /s for differentiating between benign and malignant lesions, with a sensitivity of 69.6%, a specificity of 77.1% and an accuracy of 74.0%; a cutoff D value of 1.75 * 10-3 mm2 /s, with a sensitivity of 82.6%, a specificity of 77.1% and an accuracy of 80.2%; a cutoff K value of 0.63 with a sensitivity of 95.7%, a specificity of 77.1% and an accuracy of 87.7%. The area under the curve of K value was significantly larger than that of ADC value (0.875 versus 0.762; P < 0.05). CONCLUSION: K value of DKI demonstrates significantly higher accuracy compared with ADC value for the differentiation between benign and malignant sinonasal lesions. DKI may be a noninvasive method to evaluate the sinonasal lesions. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;45:1446-1454. PMID- 27758017 TI - Reply: "Function of Cryopreserved Mesenchymal Stromal Cells With and Without Interferon-gamma Prelicensing Is Context Dependent". AB - Freshly thawed mesenchymal stromal cells (MSCs) transiently display altered cell physiology and a recent report by Chinnadurai et al. [Stem Cells 2016;34:2429 2442] demonstrated that thawed allogeneic MSCs are also susceptible to T-cell mediated lysis in vitro and that this effect can be mitigated by activating MSCs with IFN-gamma prior to freeze and thaw. In the letter to the editor by Ankrum et al., "Function of Cryopreserved MSCs with and without IFN-gamma pre-licensing is Context Dependent," the author provide data that IFN-gamma pretreatment of human MSCs before cryobanking fails to enhance their potency post thaw in a mouse model of retinal disease. Considering that the experimental set up involves the use of human MSCs in mice with normal immune systems, we propose that IFN-gamma MSC activation enhances the immune incompatibility of xenogenic human cells in a manner which may confound the predictive value for human translational use. Stem Cells 2017;35:1440-1441. PMID- 27758018 TI - Serum ferritin and risk for new-onset heart failure and cardiovascular events in the community. AB - AIMS: Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population. METHODS AND RESULTS: In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron regulatory hormone hepcidin were measured. Mean age was 53.1 +/- 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex. CONCLUSIONS: Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community. PMID- 27758019 TI - Contextual risk: a study of fish out of water. PMID- 27758020 TI - Effect of Forsythia suspensa extract and chito-oligosaccharide alone or in combination on performance, intestinal barrier function, antioxidant capacity and immune characteristics of weaned piglets. AB - We investigated the effects of Forsythia suspensa extract (FSE) and chito oligosaccharide (COS), alone or together, on performance and health status of weaned piglets. The treatments included a basal diet and three diets with 160 mg/kg COS, 100 mg/kg FSE, or 100 mg/kg FSE and 160 mg/kg COS. Supplementation with COS or FSE alone improved (P < 0.01) average daily gain and feed conversion ratio compared with the basal diet in the first 2 weeks. On day 14, COS or FSE supplementation separately produced stronger (P < 0.01) serum total antioxidant capacity and glutathione peroxidase activities and lower serum endotoxin (P < 0.05) and malondialdehyde (P < 0.01) concentrations, generated higher (P < 0.01) serum complement 4 concentration, peripheral blood lymphocyte proliferation and serum-specific ovalbumin antibody level than the basal diet. No differences in oxidative injury and immunity indices were detected on day 28. The combined FSE and COS produced similar results compared with FSE or COS when given alone. These data indicate FSE or COS can increase performance by modulating intestinal permeability, antioxidant status and immune function in younger pigs. There appears to be similar advantage in feeding the additives in combination over those obtained from feeding them separately. PMID- 27758021 TI - Effect of ginseng polysaccharides on the immunity and growth of piglets by dietary supplementation during late pregnancy and lactating sows. AB - There are many reports that dietary supplementation with plant polysaccharides in pigs might promote their growth, but little is known about the maternal effect of ginseng polysaccharides (GPS) on piglets' growth by dietary supplementation to pregnant and lactating sows. In the current study, the effects of dietary supplementation with GPS on the immunity of sows and growth of their piglets were investigated. Results showed no significant difference among the four groups in the total number of piglets, live piglets, weak piglets and birth weight of piglets, indicating the GPS-treatment has no adverse effect on reproduction. Furthermore, the weaning weight of the GPS-treated groups was higher than that of control group (P < 0.05); among them, the addition of 200 mg/kg dose has the best effect. Interestingly, GPS increased the total immunoglobulin G concentration in milk and serum of sows (P < 0.05). The concentrations of interleukin (IL)-2, IL 6, tumor necrosis factor (TNF)-alpha, and interferon-gamma in milk and serum of sows were also increased in the experimental groups relative to the control (P < 0.05). Meanwhile, maternal supplementation of GPS significantly increased IL-2 and TNF-alpha concentration in the piglets' serum of the experimental groups relative to control (P < 0.05). GPS (200 mg/kg) significantly increased the glutathione peroxidase activity in milk and serum (P < 0.05), while the concentrations of malondialdehyde were significantly reduced (P < 0.05). The present results indicated that GPS supplementation during late pregnancy and lactation improved immunity-related bio-molecular levels in sow serum and milk, which may be further beneficial to piglet health and growth through biological transmission effects. PMID- 27758024 TI - Robotic-assisted minimally invasive surgery of the spine (RAMISS): a proof-of concept study using carbon dioxide insufflation for multilevel posterior vertebral exposure via a sub-paraspinal muscle working space. AB - BACKGROUND: Open posterior spinal procedures involve extensive soft tissue disruption, increased hospital length of stay, and disfiguring scars. Our aim was to demonstrate the feasibility of using robotic-assistance for minimally invasive exposure of the posterolateral spine with and without carbon dioxide (CO2 ) insufflation. METHODS: Sheep specimens underwent minimally invasive subperiosteal dissection of the spine during three trials. The da Vinci S Surgical system was used for access with and without working space support via CO2 insufflation. RESULTS: Without insufflation, a sub-paraspinal muscle tunnel measuring 16 cm was developed between two 5 cm incisions. With insufflation, the one-sided tunnel length was 12.5 cm but without the soft tissue trauma and obstructed visualization experienced without CO2 . CONCLUSIONS: The use of robot-assistance for minimally invasive access to the posterior spine appears to be feasible. The use of CO2 insufflation greatly improved our ability to visualize and access the posterior vertebral elements. PMID- 27758025 TI - Generation of Large-Scale DNA Hydrogels with Excellent Blood and Cell Compatibility. AB - Hemocompatibility and cytocompatibility of biomaterials codetermine the success of tissue engineering applications. DNA, the natural component of our cells, is an auspicious biomaterial for the generation of designable scaffolds with tailorable characteristics. In this study, a combination of rolling circle amplification and multiprimed chain amplification is used to generate hydrogels at centimeter scale consisting solely of DNA. Using an in vitro rotation model and fresh human blood, the reaction of the hemostatic system on DNA hydrogels is analyzed. The measurements of hemolysis, platelets activation, and the activation of the complement, coagulation, and neutrophils using enzyme-linked immunosorbent assays demonstrate excellent hemocompatibility. In addition, the cytocompatibility of the DNA hydrogels is tested by indirect contact (agar diffusion tests) and material extract experiments with L929 murine fibroblasts according to the ISO 10993-5 specifications and no negative impact on the cell viability is detected. These results indicate the promising potential of DNA hydrogels as biomaterials for versatile applications in the field of regenerative medicine. PMID- 27758023 TI - Clinical outcomes in youth beyond the first year of type 1 diabetes: Results of the Pediatric Diabetes Consortium (PDC) type 1 diabetes new onset (NeOn) study. AB - OBJECTIVE: Current data are limited on the course of type 1 diabetes (T1D) in children and adolescents through the first few years of diabetes. The Pediatric Diabetes Consortium T1D new onset (NeOn) Study was undertaken to prospectively assess natural history and clinical outcomes in children treated at 7 US diabetes centers from the time of diagnosis. This paper describes clinical outcomes in the T1D NeOn cohort during the first 3 years postdiagnosis. RESULTS: A total of 1048 participants (mean age 9.2 years, 49% female, 65% non-Hispanic White) were enrolled between July 2009 and April 2011. Mean glycated hemoglobin (HbA1c) (+/ SD) was 7.2% (55 mmol/mol) at 3 months, followed by a progressive rise to 8.4% (68 mmol/mol) at 36 months postdiagnosis, with only 30% of participants achieving target HbA1c<7.5% (58 mmol/mol). The percentage of participants in partial remission estimated by insulin dose adjusted HbA1c [HbA1c % + (4*insulin dose unit/kg/24 h)] <=9 sharply declined from 23% at 12 months to 7% at 36 months. The percentage of participants developing diabetic ketoacidosis (DKA) was 1% in the first year after diagnosis, increasing to 6% in years 2 and 3. CONCLUSIONS: These results demonstrate the gradual decline in glycemic control due to waning residual endogenous insulin secretion with increasing duration of T1D in children and adolescents. These data indicate the need to translate recent advances in automated insulin delivery, new insulin analogs, and adjunctive pharmacologic agents into novel treatment strategies to maintain optimal glycemic control even early in the course of T1D. PMID- 27758027 TI - Belowground carbon flux links biogeochemical cycles and resource-use efficiency at the global scale. AB - Nutrient limitation is pervasive in the terrestrial biosphere, although the relationship between global carbon (C) nitrogen (N) and phosphorus (P) cycles remains uncertain. Using meta-analysis we show that gross primary production (GPP) partitioning belowground is inversely related to soil-available N : P, increasing with latitude from tropical to boreal forests. N-use efficiency is highest in boreal forests, and P-use efficiency in tropical forests. High C partitioning belowground in boreal forests reflects a 13-fold greater C cost of N acquisition compared to the tropics. By contrast, the C cost of P acquisition varies only 2-fold among biomes. This analysis suggests a new hypothesis that the primary limitation on productivity in forested ecosystems transitions from belowground resources at high latitudes to aboveground resources at low latitudes as C-intensive root- and mycorrhizal-mediated nutrient capture is progressively replaced by rapidly cycling, enzyme-derived nutrient fluxes when temperatures approach the thermal optimum for biogeochemical transformations. PMID- 27758029 TI - Intraepidermal Merkel cell carcinoma with pagetoid Bowen's disease. PMID- 27758026 TI - Hydrogen peroxide-mediated conversion of coproheme to heme b by HemQ-lessons from the first crystal structure and kinetic studies. AB - : Heme biosynthesis in Gram-positive bacteria follows a recently described coproporphyrin-dependent pathway with HemQ catalyzing the decarboxylation of coproheme to heme b. Here we present the first crystal structure of a HemQ (homopentameric coproheme-HemQ from Listeria monocytogenes) at 1.69 A resolution and the conversion of coproheme to heme b followed by UV-vis and resonance Raman spectroscopy as well as mass spectrometry. The ferric five-coordinated coproheme iron of HemQ is weakly bound by a neutral proximal histidine H174. In the crystal structure of the resting state, the distal Q187 (conserved in Firmicutes HemQ) is H-bonded with propionate p2 and the hydrophobic distal cavity lacks solvent water molecules. Two H2 O2 molecules are shown to be necessary for decarboxylation of the propionates p2 and p4, thereby forming the corresponding vinyl groups of heme b. The overall reaction is relatively slow (kcat /KM = 1.8 * 102 m-1 .s-1 at pH 7.0) and occurs in a stepwise manner with a three-propionate intermediate. We present the noncovalent interactions between coproheme and the protein and propose a two-step reaction mechanism. Furthermore, the structure of coproheme HemQ is compared to that of the phylogenetically related heme b-containing chlorite dismutases. DATABASE: Structural data are available in the PDB under the accession number 5LOQ. PMID- 27758030 TI - Simultaneous Adjustment of Size and Helical Sense of Chiral Nanospheres and Nanotubes Derived from an Axially Racemic Poly(phenylacetylene). AB - Nanospheres and nanotubes with full control of their size and helical sense are obtained in chloroform from the axially racemic chiral poly(phenylacetylene) poly (R)-1 using either Ag+ as both chiral inducer and cross-linking agent or Na+ as chiral inducer and Ag+ as cross-linking agent. The size is tuned by the polymer/ion ratio while the helical sense is modulated by the polymer/cosolvent (i.e., MeCN) ratio. In this way, the helicity and the size of the nanoparticles can be easily interconverted by very simple experimental changes. PMID- 27758031 TI - Characterization of in vitro effects of microcystin-LR on intestinal epithelial cells. AB - The intestinal epithelium is a single-cell layer that provides an important barrier against natural toxins. Microcystin-LR (MC-LR), a cyclic heptapeptide, is one of the best known toxins able to alter the functions of intestine. This study evaluated the toxic effects and the possible mechanisms of MC-LR on barrier function of the intestinal epithelial cells. Intestinal epithelial cells (IEC-6) were exposed to 0, 6.25, 12.5, 25 and 50 MUM MC-LR. Cell viability significantly decreased, while the ratio of apoptotic cells increased after exposure to 12.5MUM and higer concentration of MC-LR. As expected, the integrity of a polarized IEC-6 monolayer was affected by MC-LR exposure, as demonstrated by a decrease in the transepithelial electrical resistance (TEER) values, becoming most pronounced at 50MUM, 24 h. No effects were detected on the protein expression levels of the tight junction protein claudin at 50MUM. However, the expression of occludin and zonula occludens-1 (ZO-1) declined. Furthermore, MC-LR can immigrate into IEC-6 cells. The activity of protein phosphatases 2A (PP2A) decreased from the concentration of 12.5 MUM, showing a dose-dependent decline. These results provide new information that strengthens the concept that the intestinal epithelium is important targets for toxic effects of water contaminants like MC LR. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1539-1547, 2017. PMID- 27758032 TI - Temporal analysis of thyroid cancer management in a Melbourne tertiary centre. AB - BACKGROUND: The American Thyroid Association (ATA) management guidelines for thyroid cancer were revised in 2009. The aim of this study was to determine if management of thyroid cancer in our institution has changed in accordance with the introduction of the revised ATA guidelines (ATA2009 ), and to compare the characteristics and management of thyroid cancer in a Melbourne endocrine surgery unit over a 7-year period. METHODS: All patients treated by the Monash University Endocrine Surgery Unit for thyroid cancer between 2007 and 2013 were divided into two groups - the pre-ATA2009 group (2007-2010) and the post-ATA2009 group (2011 2013). Comparisons were made of the demographics, cytology, pathology, surgical outcome and adjuvant therapy using t-test and chi-squared tests. RESULTS: There were 333 patients in the pre-ATA2009 group and 342 patients in the post-ATA2009 group. Fewer non-diagnostic fine-needle aspiration cytology results were identified in the post-ATA2009 group (4% versus 0.9%; P = 0.01), while the rates of other fine-needle aspiration cytology categories were similar. There was a reduction in the use of radioactive iodine ablation in the post-ATA2009 group, both in the proportion of patients being treated (66% versus 48%; P < 0.001) and the dosages used (mean 96 mCi versus 80 mCi; P < 0.01), despite similar tumour size in both groups. CONCLUSION: The key changes in practice thought to be attributable to the 2009 revised ATA guidelines were the reduction in the use and dosage of radioactive iodine in the management of differentiated thyroid cancer. PMID- 27758033 TI - Quality of life in climacteric Turkish women with urinary incontinence. AB - Urinary incontinence (UI) is a common health problem and negatively affects the quality of life of women who are afflicted. The aim of the study is to explore the prevalence and risk factors of UI among climacteric Turkish women and to examine the effects of UI on their quality of life. This cross-sectional study was conducted with 258 women aged 40-64 years who visited the outpatient clinic in Ankara, Turkey, between 15 June 2012 and 15 January 2013. The data were collected using the International Consultation on Incontinence Questionnaire Short Form and the Incontinence Quality of Life Questionnaire. This paper reveals that the overall prevalence of UI was 45.3%. Stress UI, mixed UI, and urge UI were reported by 54.7%, 22.2%, and 10.3% of the subjects, respectively. The proportion of women suffering from UI who seek medical treatment was low despite mild or moderate negative effect impacts on their quality of life. Increasing women's awareness of UI and protective measures is essential, and standard UI assessment should be added to all patient examinations. PMID- 27758034 TI - Antimicrobial activity of immobilized lactoferrin and lactoferricin. AB - Lactoferrin and lactoferricin were immobilized on glass surfaces via two linkers, 4-azidobenzoic acid (ABA) or 4-fluoro-3-nitrophenyl azide (FNA). The resulting surfaces were characterized by X-ray photoelectron spectroscopy (XPS) and contact angle measurements. The antimicrobial activity of the surfaces was determined using Pseudomonas aeruginosa and Staphylococcus aureus strains by fluorescence microscopy. Lactoferrin and lactoferricin immobilization was confirmed by XPS showing significant increases (p < 0.05) in nitrogen on the glass surface. The immobilization of both proteins slightly increased the overall hydrophobicity of the glass. Both lactoferrin and lactoferricin immobilized on glass significantly (p < 0.05) reduced the numbers of viable bacterial cells adherent to the glass. For P. aeruginosa, the immobilized proteins consistently increased the percentage of dead cells compared to the total cells adherent to the glass surfaces (p < 0.03). Lactoferrin and lactoferricin were successfully immobilized on glass surfaces and showed promising antimicrobial activity against pathogenic bacteria. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2612-2617, 2017. PMID- 27758035 TI - Body size phenology in a regional bee fauna: a temporal extension of Bergmann's rule. AB - Bergmann's rule originally described a positive relationship between body size and latitude in warm-blooded animals. Larger animals, with a smaller surface/volume ratio, are better enabled to conserve heat in cooler climates (thermoregulatory hypothesis). Studies on endothermic vertebrates have provided support for Bergmann's rule, whereas studies on ectotherms have yielded conflicting results. If the thermoregulatory hypothesis is correct, negative relationships between body size and temperature should occur in temporal in addition to geographical gradients. To explore this possibility, we analysed seasonal activity patterns in a bee fauna comprising 245 species. In agreement with our hypothesis of a different relationship for large (endothermic) and small (ectothermic) species, we found that species larger than 27.81 mg (dry weight) followed Bergmann's rule, whereas species below this threshold did not. Our results represent a temporal extension of Bergmann's rule and indicate that body size and thermal physiology play an important role in structuring community phenology. PMID- 27758036 TI - Potentially preventable deaths in the Victorian Audit of Surgical Mortality. AB - BACKGROUND: The Victorian Audit of Surgical Mortality (VASM) seeks to peer-review all deaths associated with surgical care. This study aimed to examine the mortalities that were determined by the assessor to be potentially preventable, and identify the clinical factors associated with these cases. The assessment of preventability of death and its relationship to management issues at different stages of the admission episode, as opposed to whether the management issue(s) alone were preventable have not been reported previously. METHODS: Mortality data from the VASM audit since 2007 that completed the peer-review process were retrospectively analysed. Mortalities identified as being preventable were assessed to determine any treatment errors. RESULTS: A total of 6155 deaths were assessed. Of these, 14.6% (896/6155) were considered to be potentially preventable. Where a second-line assessment was requested (1113/6155, 17.5% cases), 48.3% of these deaths were considered potentially preventable. Elective patient deaths were more likely to be potentially preventable (P < 0.001), especially in public patients. Lack of timely involvement of senior staff, inappropriate treatment delay and failure of problem recognition were factors most frequently associated with potentially preventable mortality. CONCLUSION: Overall assessment of the preventability of death is unique to VASM. This allows an additional level of analysis to be applied to the circumstances surrounding each mortality and correlation of preventability of death with clinical management issues provides important feedback to surgeons and health-care providers to further improve the safety and quality of care. PMID- 27758037 TI - Mothers' understanding of the term 'exclusive breastfeeding': a systematic review. AB - There is a lack of knowledge and understanding of the term exclusive breastfeeding (EBF) among health professionals. The purpose of this review was to examine the best available literature on mothers' understanding of the term EBF. A systematic search of eight electronic databases (Medline, Embase, CINAHL, CDSR, CENTRAL, Cab Abstracts, Scopus and African Index Medicus) was conducted (Protocol registration in PROSPERO: CRD42015019402). All study designs were eligible for inclusion. Studies were included if they: (1) involved mothers aged 18 years or older; (2) assessed mothers' knowledge/understanding/awareness of the term 'EBF'; (3) used the 1991 WHO definition of EBF and (4) were published between 1988 and 2015. Two reviewers retrieved articles, assessed study quality and performed data extraction. Of the 1700 articles identified, 21 articles met the inclusion criteria. Quantitative findings were pooled to calculate a proportion rate of 70.9% of mothers who could correctly define EBF, although the range varied between 3.1 and 100%. Qualitative findings revealed three themes: (1) EBF was understood by mothers as not mixing two milks; (2) the term 'exclusive' in EBF was incorrectly understood as not giving breast milk and (3) mothers believing that water can be given while exclusively breastfeeding. Research investigating aspects of self-reported EBF may consequently be unreliable. A standardised tool to assess mothers' knowledge of EBF could provide more accurate data. Public health campaigns should emphasise EBF to target mothers, while addressing the education of health professionals to ensure that they do not provide conflicting advice. PMID- 27758038 TI - Acid-Cleavable Unimolecular Micelles from Amphiphilic Star Copolymers for Triggered Release of Anticancer Drugs. AB - In this contribution, amphiphilic star copolymers (H40-star-PCL-a-PEG) with an H40 hyperbranched polyester core and poly(epsilon-caprolactone)-a-poly(ethylene glycol) copolymer arms linked with acetal groups are synthesized using ring opening polymerization and a copper (I)-catalyzed alkyne-azide cycloaddition click reaction. The acid-cleavable acetal groups between the hydrophilic and hydrophobic segments of the arms endow the amphiphilic star copolymers with pH responsiveness. In aqueous solution, unimolecular micelles can be formed with good stability and a unique acid degradability, as is desirable for anticancer drug carriers. For the model drug of doxorubicin, the in vitro release behavior, intracellular release, and inhibition of proliferation of HeLa cells show that the acid-cleavable unimolecular micelles with anticancer activity can be dissociated in an acidic environment and efficiently internalized by HeLa cells. Due to the acid-cleavable and biodegradable nature, unimolecular micelles from amphiphilic star copolymers are promising for applications in intracellular drug delivery for cancer chemotherapy. PMID- 27758041 TI - Chemically Integrated Inorganic-Graphene Two-Dimensional Hybrid Materials for Flexible Energy Storage Devices. AB - State-of-the-art energy storage devices are capable of delivering reasonably high energy density (lithium ion batteries) or high power density (supercapacitors). There is an increasing need for these power sources with not only superior electrochemical performance, but also exceptional flexibility. Graphene has come on to the scene and advancements are being made in integration of various electrochemically active compounds onto graphene or its derivatives so as to utilize their flexibility. Many innovative synthesis techniques have led to novel graphene-based hybrid two-dimensional nanostructures. Here, the chemically integrated inorganic-graphene hybrid two-dimensional materials and their applications for energy storage devices are examined. First, the synthesis and characterization of different kinds of inorganic-graphene hybrid nanostructures are summarized, and then the most relevant applications of inorganic-graphene hybrid materials in flexible energy storage devices are reviewed. The general design rules of using graphene-based hybrid 2D materials for energy storage devices and their current limitations and future potential to advance energy storage technologies are also discussed. PMID- 27758042 TI - Mammalian autophagy and the plasma membrane. AB - Autophagy (literally 'self-eating') is an evolutionarily conserved degradation process where cytoplasmic components are engulfed by vesicles called autophagosomes, which are then delivered to lysosomes, where their contents are degraded. Under stress conditions, such as starvation or oxidative stress, autophagy is upregulated in order to degrade macromolecules and restore the nutrient balance. The source of membranes that participate in the initial formation of phagophores is still incompletely understood and many intracellular structures have been shown to act as lipid donors, including the endoplasmic reticulum, Golgi, nucleus, mitochondria and the plasma membrane. Here, we focus on the contributions of the plasma membrane to autophagosome biogenesis governed by ATG16L1 and ATG9A trafficking, and summarize the physiological and pathological implications of this macroautophagy route, from development and stem cell fate to neurodegeneration and cancer. PMID- 27758043 TI - Dispersive liquid-liquid microextraction combined with acetonitrile stacking through capillary electrophoresis for the determination of three selective serotonin reuptake inhibitor drugs in body fluids. AB - Dispersive liquid-liquid microextraction was combined with acetonitrile stacking in capillary electrophoresis for the identification of three selective serotonin reuptake inhibitors (citalopram, fluoxetine, and fluvoxamine) in human fluids such as urine and plasma. Parameters that affect the extraction and stacking efficiency, such as the type and volume of the extraction and disperser solvent, extraction time, salt addition for dispersive liquid-liquid microextraction, and sample matrices, pH, and concentration of the separation buffer for stacking, were investigated and optimized. Under optimum conditions, the enrichment factors were in the range of 1195-1441. Limits of detection ranged from 1.4 to 1.7 nM for the target analytes. Calibration graphs displayed satisfied linearity with R2 greater than or equal to 0.9978, and relative standard deviations of the peak area analysis were in the range of 2.9-5.0% (n = 3). The recoveries of all tricyclic antidepressant drugs from urine and plasma were in the range of 77-117 and 79-106%, respectively. The findings of this study show that dispersive liquid liquid microextraction acetonitrile-stacking capillary electrophoresis is a rapid and convenient method for identifying tricyclic antidepressant drugs in urine and plasma. PMID- 27758046 TI - Hepcidin as a potential biomarker for blood doping. AB - The concentration of hepcidin, a key regulator of iron metabolism, is suppressed during periods of increased erythropoietic activity. The present study obtained blood samples from 109 elite athletes and examined the correlations between hepcidin and markers of erythropoiesis and iron metabolism (i.e., haemoglobin, erythropoietin (EPO), ferritin, erythroferrone (ERFE), and iron concentration). Furthermore, an administration study was undertaken to examine the effect of recombinant human EPO (rhEPO) delta (DynepoTM) on hepcidin concentrations in healthy male volunteers. The effects on hepcidin were then compared with those on reticulocyte percentage (Ret%) and ferritin concentration. There was a significant positive correlation between hepcidin and ferritin, iron, and haemoglobin levels in athletes, whereas hepcidin showed an inverse correlation with ERFE. Administration of rhEPO delta reduced hepcidin levels, suggesting that monitoring hepcidin may increase the sensitivity of the Athlete Biological Passport (ABP) for detecting rhEPO abuse. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27758045 TI - PA-MSHA inhibits the growth of doxorubicin-resistant MCF-7/ADR human breast cancer cells by downregulating Nrf2/p62. AB - Acquired resistance to doxorubicin in breast cancer is a serious therapeutic problem. In this study, we investigated whether Pseudomonas aeruginosa mannose sensitive hemagglutinin (PA-MSHA) could inhibit the growth of doxorubicin resistant breast cancer cells. We found that the expressions of Nrf2 and p62 in breast cancer were higher than that in the corresponding adjacent normal tissues and benign breast epithelial cell. The expressions of Nrf2 and p62 in breast cancer doxorubicin-resistant cells MCF-7/ADR were higher than that in doxorubicin sensitive cells MCF-7. Silencing of Nrf2 or p62 rendered breast cancer cells more susceptible to doxorubicin. We further demonstrated that PA-MSHA inhibited growth and induced apoptosis of MCF-7/ADR cells but not MCF-7 cells. Subcutaneous administration of PA-MSHA greatly inhibited the growth of xenograft tumors from MCF-7/ADR cells in nude mice. In addition, PA-MSHA could downregulate Nrf2 and p62 in vitro and in vivo. These results suggested that activation of Nrf2 and p62 was associated with doxorubicin resistance in breast cancer. PA-MSHA could inhibit the growth of doxorubicin-resistant MCF-7/ADR cells and its potential mechanism might be due to the suppression of Nrf2/p62. It indicated the possibility of using PA-MSHA in doxorubicin-resistant breast cancer. PMID- 27758047 TI - Control of the DNA-Binding and Antiproliferative Properties of Hydroxybenzo[b]quinolizinium Derivatives with pH and Light. AB - The interactions of 8-hydroxybenzo[b]quinolizinium and 9 hydroxybenzo[b]quinolizinium with DNA are investigated in detail. Specifically, spectrophotometric and spectrofluorimetric titrations, thermal DNA-denaturation experiments as well as CD- and LD-spectroscopic analysis show that a pH shift by just one or two orders of magnitude has a significant impact on the interactions of the acidic ligands with the nucleic acid. Both ligands bind with high affinity to DNA at pH 6 (Kb ~105 m-1 ). At pH 7 or 8, however, the binding interactions are much weaker because of the formation of the corresponding charge-neutral conjugate bases, the affinity to DNA of which is reduced because of the resulting lack of a positive charge. Notably, the variation of DNA affinity occurs in a range that corresponds to the fluctuations of pH values under physiological conditions, so that these ligands may be employed to target DNA in tissue with particular pH values, especially, cancer cells. The antiproliferative activity of the title compounds under different conditions is also investigated. In the absence of irradiation, both compounds show only a modest cytotoxicity toward cancer cells. However, upon irradiation, even at low UV-A doses, a significant reduction of cell viability of tumor cell lines is induced by the ligands. PMID- 27758044 TI - Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy. AB - Because of its impact on multiple biological pathways, heparanase has emerged as a major regulator of cancer, inflammation and other disease processes. Heparanase accomplishes this by degrading heparan sulfate which regulates the abundance and location of heparin-binding growth factors thereby influencing multiple signaling pathways that control gene expression, syndecan shedding and cell behavior. In addition, heparanase can act via nonenzymatic mechanisms that directly activate signaling at the cell surface. Clinical trials testing heparanase inhibitors as anticancer therapeutics are showing early signs of efficacy in patients further emphasizing the biological importance of this enzyme. This review focuses on recent developments in the field of heparanase regulation of cancer and inflammation, including the impact of heparanase on exosomes and autophagy, and novel mechanisms whereby heparanase regulates tumor metastasis, angiogenesis and chemoresistance. In addition, the ongoing development of heparanase inhibitors and their potential for treating cancer and inflammation are discussed. PMID- 27758048 TI - Urinary steroid profile in females - the impact of menstrual cycle and emergency contraceptives. AB - Today's doping tests involving longitudinal monitoring of steroid profiles are difficult in women. Women have more complex hormonal fluctuations than men and commonly take drugs such as hormonal contraceptives that are shown to affect biomarkers used in these doping tests. In this study, we followed six women's urinary steroid profile during one menstrual cycle, including both glucuronides and sulfate conjugated fractions. Additionally, we studied what happens to the steroidal module of the Athlete Biological Passport (ABP) after administration of an emergency contraceptive (levonorgestrel, NorLevo(r)). The study shows that there are large individual variations in all metabolites included in the ABP and that the administration of emergency contraceptives may lead to suspicious steroid profile findings in the ABP. Urinary epitestosterone concentration increased during the menstrual cycle, leading to a decrease in the testosterone/epitestosterone ratio. The ratios followed in the ABP varied widely throughout the menstrual cycle, the coefficient of variation (CV) ranging from 4 to 99%. There was a 3-fold decrease in epitestosterone 24 h post administration of the emergency contraceptive pill and androsterone, etiocholanolone, and 5beta- androstan-3alpha,17beta-diol concentrations decreased about 2-fold. When analyzed with the ABP software, one of the six women had an atypical profile after taking the emergency contraceptive. Furthermore, we could not find any alterations in excretion routes (i.e., if the metabolites are excreted as glucuronide or sulfate conjugates) during the menstrual cycle or after administration of emergency contraceptive, indicating no direct effect on phase II enzymes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27758050 TI - Too Depleted to Try? Testing the Process Model of Ego Depletion in the Context of Unhealthy Snack Consumption. AB - BACKGROUND: The process model proposes that the ego depletion effect is due to (a) an increase in motivation toward indulgence, and (b) a decrease in motivation to control behaviour following an initial act of self-control. In contrast, the reflective-impulsive model predicts that ego depletion results in behaviour that is more consistent with desires, and less consistent with motivations, rather than influencing the strength of desires and motivations. The current study sought to test these alternative accounts of the relationships between ego depletion, motivation, desire, and self-control. METHODS: One hundred and fifty six undergraduate women were randomised to complete a depleting e-crossing task or a non-depleting task, followed by a lab-based measure of snack intake, and self-report measures of motivation and desire strength. RESULTS AND CONCLUSIONS: In partial support of the process model, ego depletion was related to higher intake, but only indirectly via the influence of lowered motivation. Motivation was more strongly predictive of intake for those in the non-depletion condition, providing partial support for the reflective-impulsive model. Ego depletion did not affect desire, nor did depletion moderate the effect of desire on intake, indicating that desire may be an appropriate target for reducing unhealthy behaviour across situations where self-control resources vary. PMID- 27758049 TI - Quantitative Identification of Compound-Dependent On-Modules and Differential Allosteric Modules From Homologous Ischemic Networks. AB - Module-based methods have made much progress in deconstructing biological networks. However, it is a great challenge to quantitatively compare the topological structural variations of modules (allosteric modules [AMs]) under different situations. A total of 23, 42, and 15 coexpression modules were identified in baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) in a global anti-ischemic mice network, respectively. Then, we integrated the methods of module-based consensus ratio (MCR) and modified Zsummary module statistic to validate 12 BA, 22 JA, and 8 UA on-modules based on comparing with vehicle. The MCRs for pairwise comparisons were 1.55% (BA vs. JA), 1.45% (BA vs. UA), and 1.27% (JA vs. UA), respectively. Five conserved allosteric modules (CAMs) and 17 unique allosteric modules (UAMs) were identified among these groups. In conclusion, module-centric analysis may provide us a unique approach to understand multiple pharmacological mechanisms associated with differential phenotypes in the era of modular pharmacology. PMID- 27758051 TI - Quantitative phase-filtered wavelength-modulated differential photoacoustic radar tumor hypoxia imaging toward early cancer detection. AB - Overcoming the limitations of conventional linear spectroscopy used in multispectral photoacoustic imaging, wherein a linear relationship is assumed between the absorbed optical energy and the absorption spectra of the chromophore at a specific location, is crucial for obtaining accurate spatially-resolved quantitative functional information by exploiting known chromophore-specific spectral characteristics. This study introduces a non-invasive phase-filtered differential photoacoustic technique, wavelength-modulated differential photoacoustic radar (WM-DPAR) imaging that addresses this issue by eliminating the effect of the unknown wavelength-dependent fluence. It employs two laser wavelengths modulated out-of-phase to significantly suppress background absorption while amplifying the difference between the two photoacoustic signals. This facilitates pre-malignant tumor identification and hypoxia monitoring, as minute changes in total hemoglobin concentration and hemoglobin oxygenation are detectable. The system can be tuned for specific applications such as cancer screening and SO2 quantification by regulating the amplitude ratio and phase shift of the signal. The WM-DPAR imaging of a head and neck carcinoma tumor grown in the thigh of a nude rat demonstrates the functional PA imaging of small animals in vivo. The PA appearance of the tumor in relation to tumor vascularity is investigated by immunohistochemistry. Phase-filtered WM-DPAR imaging is also illustrated, maximizing quantitative SO2 imaging fidelity of tissues. Oxygenation levels within a tumor grown in the thigh of a nude rat using the two-wavelength phase-filtered differential PAR method. PMID- 27758053 TI - Complexation Enhancement Drives Water-to-Oil Ion Transport: A Simulation Study. AB - We address the structures and energetics of ion solvation in aqueous and organic solutions to understand liquid-liquid ion transport. Atomistic molecular dynamics (MD) simulations with polarizable force field are performed to study the coordination transformations driving lanthanide (LnIII ) and nitrate ion transport between aqueous and an alkylamide-oil solution. An enhancement of the coordination behavior in the organic phase is achieved in contrast with the aqueous solution. In particular, the coordination number of Ce3+ increases from 8.9 in the aqueous to 9.9 in the organic solutions (from 8 in the aqueous to 8.8 in the organic systems for Yb3+ ). Moreover, the local coordination environment changes dramatically. Potential of mean force calculations show that the LnIII ligand coordination interaction strengths follow the order of LnIII nitrate>LnIII -water>LnIII -DMDBTDMA. They increase 2-fold in the lipophilic environment in comparison to the aqueous phase, and we attribute this to the shedding of the outer solvation shell. Our findings highlight the importance of outer sphere interactions on the competitive solvation energetics that cause ions to migrate between immiscible phases; an essential ingredient for advancing important applications such as rare earth metal separations. Some open questions in simulating the coordination behavior of heavy metals are also addressed. PMID- 27758054 TI - Devoted fathers or selfish lovers? Conflict between mating effort and parental care in a harem-defending arachnid. AB - When there is a temporal trade-off between mating effort and parental care, theoretical models predict that intense sexual selection on males leads to reduced paternal care. Thus, high-quality males should invest more in mating effort because they have higher chances of acquiring mates, whereas low-quality males should bias their investment towards parental care. Once paternal care has evolved, offspring value should also influence males' decisions to invest in offspring attendance. Here, we performed a manipulation under field conditions to investigate the factors that influence male allocation in either mating effort or parental care. We predicted that facultative paternal care in the harem-holding harvestman Serracutisoma proximum would be negatively influenced by male attractiveness and positively influenced by offspring value. We found that attractive males were less likely to engage in egg attendance and that the higher the perceived paternity, the higher the caring frequency. Finally, egg mortality was not related to caring frequency by males, but predation pressure was much lower than that recorded in previous studies with the same population. Thus, the benefits of facultative male care may be conditional to temporal variation in the intensity of egg predation. In conclusion, males adjust their investment in either territory defence or egg attendance according to their recent mating history and perceived paternity. Our findings suggest that exclusive paternal care can evolve from facultative paternal care only if the trade-off between mating effort and parental care is circumvented. PMID- 27758055 TI - Examining the relationship between multiple primary cancers and psychological distress: A review of current literature. AB - OBJECTIVE: The incidence of multiple primary cancers (MPCs) is increasing, but little is known about psychological distress in this population. The purpose of this study is to review and synthesize the literature regarding what is known about psychological distress in adults who have experienced MPC diagnoses. METHODS: All potentially eligible studies identified in PubMed and CINAHL were reviewed by 2 independent evaluators, and each relevant article was assessed for methodological quality. Data were extracted, organized, and recorded using a coding log, PRISMA flow diagram, and a standardized table of evidence. Effect size (ES) values were calculated using Cohen's d. RESULTS: Five of the 562 potentially relevant articles were selected for final analysis. MPC survivors, when compared with single cancer survivors, had lower global quality of life (d = 0.32-0.37), poorer emotional role function and stress (d = 0.08-0.20), greater and more frequent distress (d = 0.11-0.37), and greater subclinical anxiety (d = 0.15). Depressive symptoms were variable (d = 0.01-0.22), and no differences between MPC and single cancer groups were identified for sleep and suicidal ideation. CONCLUSION: There is a substantial lack of evidence focused on psychological distress among the growing MPC survivor population. ES noted in the 5 studies reflect small but potentially significant increases in psychological distress in survivors of MPC compared with survivors of a single cancer. Clinicians should be aware of this at-risk population when screening for distress in cancer survivors. Suggestions for future research are provided. PMID- 27758057 TI - Swallowing function, skeletal muscle mass and sarcopenia in older adults requiring long-term care. PMID- 27758056 TI - Function of Cryopreserved Mesenchymal Stromal Cells With and Without Interferon gamma Prelicensing is Context Dependent. AB - : Tailoring MSCs to fit the disease. Fresh, cryopreserved and, prelicensed cryopreserved MSC are all being explored to treat numerous diseases, but all are not suitable to treat all conditions. injury. "*" denotes preferred therapeutic strategy when both fresh MSC and cryo-MSC have shown utility in treating the disease but one is more efficacious or logistically suitable. ABBREVIATIONS: CLI, critical limb ischemia; GvHD. graft versus host disease; I/R, ischemia reperfusion (I/R); OI, osteogenesis imperfecta. PMID- 27758058 TI - Cholinesterase inhibitors and dramatic emotional therapy for dementia patients. PMID- 27758059 TI - Subjective memory complaints and depression as clinical symptoms of disseminated nocardiosis by Nocardia abscessus. PMID- 27758060 TI - Bullous pemphigoid and percutaneous endoscopic gastrostomy. PMID- 27758061 TI - Quetiapine-induced absence seizures in a dementia patient. PMID- 27758062 TI - Non-bacterial thrombotic endocarditis in a Trousseau syndrome patient with stomach cancer: A case report. PMID- 27758063 TI - Course of serum autoantibodies in patients after acute angle-closure glaucoma attack. AB - BACKGROUND: The aim of our investigation was to analyze the autoantibody reactivities of patients after acute angle-closure glaucoma (AACG) by means of a protein microarray approach to identify intraocular pressure(IOP)-dependent antibodies. METHODS: Collected sera from different study time points (AACG n = 6, 0, 2, 4 and 12 weeks) and control group (CTRL n = 11, 0 and 12 weeks) were analyzed. Protein-microarrays were incubated with sera, and occurring immunoreactivities were visualized with fluorescence labeled secondary antibodies. To detect changes, spot intensities were digitized and compared with statistical techniques. RESULTS: Three autoantibodies with significant level alteration in the time course of the survey could be identified. Immunoreactivities to heat shock 27-kDa protein (HSP27), tubulin-tyrosine ligase like protein 12 (TTLL12), and neuron-specific enolase (NSE) show an increasing linear trend from week 0 up to week 12 with a positive correlation coefficient (P <= 0.05, r >= 0.4). In the CTRL- group, no significant alterations could be detected in corresponding autoantibody-level. Analysis of variance revealed significant changes of antibody-level between certain time points (anti-HSP27 antibody [week 0 vs. 2], anti-TTLL12 antibody [week 0 vs. 12], and anti-NSE antibody [week 4 vs. 12] [P <= 0.05, respectively]) in AACG group. CONCLUSIONS: With this autoantibodies profiling approach, we were able to detect autoimmune reactivities in sera of patients without former indication for glaucomatous damage after rise of IOP due to AACG attack. After further validation in subsequent studies, this autoantibodies could give further insights into the pathogenesis of glaucoma and could possibly help to understand the effect of IOP on glaucomatous optic neuropathy. PMID- 27758064 TI - Acute effects of aerobic exercise intensity on arterial stiffness after glucose ingestion in young men. AB - Arterial stiffness increases after glucose ingestion. Acute low- and moderate intensity aerobic exercise decreases arterial stiffness. However, the acute effects of 30 min of cycling at low- and moderate-intensity [25% (LE trial) and 65% (ME trial) peak oxygen uptake, respectively] on arterial stiffness at 30, 60 and 120 min of a postexercise glucose ingestion. Ten healthy young men (age, 22.4 +/- 0.5 years) performed LE and ME trials on separate days in a randomized controlled crossover fashion. Carotid-femoral (aortic) pulse wave velocity (PWV), femoral-ankle (leg) PWV, carotid augmentation index (AIx) and carotid blood pressure (BP) (applanation tonometry), brachial and ankle BP (oscillometric device), heart rate (HR) (electrocardiography), blood glucose (UV-hexokinase method) and blood insulin (CLEIA method) levels were measured at before (baseline) and at 30, 60 and 120 min after the 75-g OGTT. Leg PWV, ankle pulse pressure and BG levels significantly increased from baseline after the 75-g OGTT in the LE trial (P<0.05), but not in the ME trial. Insulin levels and HR significantly increased from baseline after the 75-g OGTT in both trials (P<0.05). Aortic PWV, carotid AIx, brachial BP and carotid BP did not change from baseline after the 75-g OGTT in both trials. The present findings indicate that aerobic exercise at moderate intensity before glucose ingestion suppresses increases leg arterial stiffness after glucose ingestion. PMID- 27758065 TI - Blood cultures and bacteraemia in an Australian emergency department: Evaluating a predictive rule to guide collection and their clinical impact. AB - OBJECTIVE: The objective of the present study is to determine whether a predictive rule could safely reduce the number of negative blood cultures collected in an Australian ED and to assess the clinical impact of positive results from blood cultures taken in the ED. METHODS: All positive blood cultures taken in the ED at a single facility were retrospectively identified for the calendar year 2012. Clinically significant bacteraemia episodes were assessed against a predictive rule using major and minor clinical and laboratory criteria gathered from medical records and pathology databases, and compared with a randomly generated sample of ED patient episode with negative blood cultures. The ED and final diagnoses and blood culture impact on clinical management were also collected. RESULTS: The predictive rule has a high sensitivity (98.8%) and modest specificity (48.7%), and if applied stringently would have prevented almost half of all blood cultures in our ED but missed two positives. Blood cultures altered the clinical management of 94.3% bacteraemic patients, representing 3.4% of all ED patients with blood cultures performed. High discordance (54%) between ED diagnosis and discharge diagnosis of bacteraemic patients was noted. CONCLUSIONS: Bacteraemia detected in the ED alters subsequent patient management. The predictive rule can be safely applied in the ED to determine need for blood culture collection. Blood cultures should not be omitted in the ED based entirely on preliminary diagnosis given the high discordance seen between ED and discharge diagnosis. PMID- 27758066 TI - The colour of paternity: extra-pair paternity in the wild Gouldian finch does not appear to be driven by genetic incompatibility between morphs. AB - In socially monogamous species, individuals can use extra-pair paternity and offspring sex allocation as adaptive strategies to ameliorate costs of genetic incompatibility with their partner. Previous studies on domesticated Gouldian finches (Erythrura gouldiae) demonstrated a genetic incompatibility between head colour morphs, the effects of which are more severe in female offspring. Domesticated females use differential sex allocation, and extra-pair paternity with males of compatible head colour, to reduce fitness costs associated with incompatibility in mixed-morph pairings. However, laboratory studies are an oversimplification of the complex ecological factors experienced in the wild and may only reflect the biology of a domesticated species. This study aimed to examine the patterns of parentage and sex ratio bias with respect to colour pairing combinations in a wild population of the Gouldian finch. We utilized a novel PCR assay that allowed us to genotype the morph of offspring before the morph phenotype develops and to explore bias in morph paternity and selection at the nest. Contrary to previous findings in the laboratory, we found no effect of pairing combinations on patterns of extra-pair paternity, offspring sex ratio or selection on morphs in nestlings. In the wild, the effect of morph incompatibility is likely much smaller, or absent, than was observed in the domesticated birds. Furthermore, the previously studied domesticated population is genetically differentiated from the wild population, consistent with the effects of domestication. It is possible that the domestication process fostered the emergence (or enhancement) of incompatibility between colour morphs previously demonstrated in the laboratory. PMID- 27758068 TI - Corrigendum: Ac-LPFFD-Th: A Trehalose-Conjugated Peptidomimetic as a Strong Suppressor of Amyloid-beta Oligomer Formation and Cytotoxicity. PMID- 27758069 TI - The NobelGuide(r) All-on-4(r) Treatment Concept for Rehabilitation of Edentulous Jaws: A Retrospective Report on the 7-Years Clinical and 5-Years Radiographic Outcomes. AB - BACKGROUND: There is a necessity of studies documenting the long-term outcome of full-arch flapless rehabilitations. PURPOSE: To evaluate the 7 years implant and prosthesis survival rate and 5-years marginal bone loss of full-arch fixed prosthetic rehabilitations supported by implants in immediate function with the All-on-4(r) treatment concept using a computer guided surgical protocol (NobelGuide(r) , Nobel Biocare). MATERIALS AND METHODS: This retrospective clinical study included 111 edentulous patients (n = 53 bruxers; n = 21 smokers; n = 59 systemically compromised), rehabilitated between February 2005 and November 2010 with 532 implants with the All-on-4(r) treatment concept using NobelGuide(r) . Outcome measures were implant and prosthesis survival, marginal bone loss at 5-years and the incidence of mechanical and biological complications. Survival was calculated using life-table analysis. Inferential analysis was performed to compare the difference in marginal bone loss between axial and tilted implants. RESULTS: Sixteen patients were lost to follow-up. The implant cumulative survival rate was 94.5% at 7 years. Prosthetic survival was 97.8% (n = 3 prosthetic failures). The average (standard deviation) marginal bone loss at 5 years was 1.3 mm (1.06 mm) overall, 1.27 mm (1.02 mm) for tilted implants and 1.34 mm (1.1 mm) for axial implants (p < .001). Ninety-one patients experienced complications in the provisional prostheses (n = 47 patients who were bruxers; n = 25 patients with implant-supported rehabilitation as opposing dentition) ranging from prosthetic fracture (n = 66 patients) to abutment or prosthetic screw loosening (n = 74 patients). Thirty-three patients experienced complications in the definitive prostheses (all exclusive to patients who were bruxers or had implant-supported rehabilitations as opposing dentition) ranging from acrylic-resin prosthetic/crown fracture (n = 23 patients) to abutment or prosthetic screw loosening (n = 10 patients). Twenty-five patients (22%) registered peri-implant pathology. CONCLUSIONS: Within the limitations of this study, it is possible to conclude that this treatment modality for completely edentulous jaws is possible with high long-term survival outcomes. Bruxing and smoking habits had a negative impact on implant failure, mechanical, and biological complications. PMID- 27758071 TI - Abstracts from the Nordic Congress of Ophthalmology, 8-12 June 2016, Aarhus, Denmark. PMID- 27758072 TI - Vitreous: Not just through it. PMID- 27758073 TI - Femtosecond lasers in cataract surgery. PMID- 27758070 TI - HIV-1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion. AB - To characterize mitochondrial/apoptotic parameters in chronically human immunodeficiency virus (HIV-1)-infected promonocytic and lymphoid cells which could be further used as therapeutic targets to test pro-mitochondrial or anti apoptotic strategies as in vitro cell platforms to deal with HIV-infection. Mitochondrial/apoptotic parameters of U1 promonocytic and ACH2 lymphoid cell lines were compared to those of their uninfected U937 and CEM counterparts. Mitochondrial DNA (mtDNA) was quantified by rt-PCR while mitochondrial complex IV (CIV) function was measured by spectrophotometry. Mitochondrial-nuclear encoded subunits II-IV of cytochrome-c-oxidase (COXII-COXIV), respectively, as well as mitochondrial apoptotic events [voltage-dependent-anion-channel-1(VDAC-1)-content and caspase-9 levels] were quantified by western blot, with mitochondrial mass being assessed by spectrophotometry (citrate synthase) and flow cytometry (mitotracker green assay). Mitochondrial membrane potential (JC1-assay) and advanced apoptotic/necrotic events (AnexinV/propidium iodide) were measured by flow cytometry. Significant mtDNA depletion spanning 57.67% (P < 0.01) was found in the U1 promonocytic cells further reflected by a significant 77.43% decrease of mitochondrial CIV activity (P < 0.01). These changes were not significant for the ACH2 lymphoid cell line. COXII and COXIV subunits as well as VDAC-1 and caspase-9 content were sharply decreased in both chronic HIV-1-infected promonocytic and lymphoid cell lines (<0.005 in most cases). In addition, U1 and ACH2 cells showed a trend (moderate in case of ACH2), albeit not significant, to lower levels of depolarized mitochondrial membranes. The present in vitro lymphoid and especially promonocytic HIV model show marked mitochondrial lesion but apoptotic resistance phenotype that has been only partially demonstrated in patients. This model may provide a platform for the characterization of HIV chronicity, to test novel therapeutic options or to study HIV reservoirs. PMID- 27758074 TI - Microinvasive glaucoma surgery: a new era in therapy. PMID- 27758075 TI - Continuing Professional Development. PMID- 27758077 TI - Good relations with technology: Empirical ethics and aesthetics in care. AB - This article is a written version of the lecture for the IPONS conference in Stockholm. The article starts from the claim that there is no such thing as technology, only different variations of technologies. These technologies, plural, all have their specific workings that we can only learn about by studying these empirically, by analysing the relations between people and their technologies. These relations are always unpredictable, as it is not given beforehand what values the participants pursue. Studying and understanding the workings of healthcare technology is a crucial task for nursing studies, as nurses are often key actors in making these devices work. The article hands the reader some tools to engage in the study of technologies in practice, using an empirical ethics approach. PMID- 27758076 TI - Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma. AB - Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression-free-survival (PFS) is unknown. We aimed to characterize TKI-associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy-four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib- and sorafenib-treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1-7). Median PFS in sunitinib-treated patients was 11 m (95% CI: 6-19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11-25] vs. 4 m [95% CI: 3-8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib-related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding. PMID- 27758078 TI - Skin property can predict the development of skin tears among elderly patients: a prospective cohort study. AB - The aim of this study was to identify skin properties that may be used to predict the development of a skin tear (ST) among elderly patients. A prospective cohort study was conducted among elderly patients aged 65 and older (N = 149) at a long term medical facility in Japan over an 8-month period. Skin properties at baseline were measured on the forearm using a 20-MHz ultrasound scanner, which measured the thickness of the dermis layer and low-echogenic pixels, and skin blotting method, which evaluated the levels of collagen type IV, matrix metalloproteinase-2 and tumour necrosis factor-alpha. Adjusted hazard ratios (HRs) for the main confounders were obtained using the Cox proportional hazard model. A total of 52 STs were recorded among the 21 patients, resulting in an incidence rate of 1.13/1000 person-days. The predictor of STs was dermis thickness (HR = 0.52; 95% confidence interval = 0.33-0.81; P-value = 0.004). The cut-off point for dermis thickness was 0.80 mm (area under the curve = 0.77; 95% confidence interval = 0.66-0.88; P-value = 0.006). Our results suggest that measuring the dermis thickness at baseline is an easy and accurate way to identify a high-risk patient. PMID- 27758079 TI - Not sweet enough: Hypoglycaemia in children. PMID- 27758081 TI - WEO Newsletter. PMID- 27758082 TI - Tribute to Our Reviewers. PMID- 27758080 TI - Prognostic and staging implications of mandibular canal invasion in lower gingival squamous cell carcinoma. AB - A multi-institutional study was undertaken to determine whether mandibular canal (MC) invasion and mandibular medullary bone invasion are independent factors in lower gingival squamous cell carcinoma (SCC). A total of 345 patients with lower gingival SCC were retrospectively reviewed. Mandibular bone invasion was categorized into three types; no bone invasion; invasion through cortical bone (medullary); and MC invasion. The overall survival rate and factors affecting local, regional, and distant failures were assessed by Cox proportional hazards regression analysis and Kaplan-Meier estimates. Bone invasion was present in 201 (58%) patients, of whom 107 (31%) had medullary invasion and 94 (27%) had MC invasion. Using the International Union Against Cancer (UICC) staging system and American Joint Committee on Cancer (AJCC) system, 171 (50%) patients were classified as T4a. When the bone invasion criteria were excluded from the UICC/AJCC system definition, 152 T4a tumors were downstaged and reclassified to T1 in 12 (3%), to T2 in 98 (28%), and to T3 in 42 (12%). In Cox multivariate analysis, MC invasion was an independent predictor of overall survival but medullary bone invasion was not. Medullary bone invasion was an independent variable for distant control. The current T staging system has restricted prognostic utility. The authors recommend a modified T staging system, whereby tumors with MC invasion instead of medullary bone invasion are classified as T4a, and tumors are first classified as T1 to T3 based on size and then upstaged by one T classification in the presence of medullary invasion. PMID- 27758084 TI - Editorial. PMID- 27758086 TI - Looking back on the history of the International Federation of Dental Hygienists. PMID- 27758089 TI - Quality evaluation of moluodan concentrated pill using high-performance liquid chromatography fingerprinting coupled with chemometrics. AB - In this study, a fast and effective high-performance liquid chromatography method was developed to obtain a fingerprint chromatogram and quantitative analysis simultaneously of four indexes including gallic acid, chlorogenic acid, albiflorin and paeoniflorin of the traditional Chinese medicine Moluodan Concentrated Pill. The method was performed by using a Waters X-bridge C18 reversed phase column on an Agilent 1200S high-performance liquid chromatography system coupled with diode array detection. The mobile phase of the high performance liquid chromatography method was composed of 20 mmol/L phosphate solution and acetonitrile with a 1 mL/min eluent velocity, under a detection temperature of 30 degrees C and a UV detection wavelength of 254 nm. After the methodology validation, 16 batches of Moluodan Concentrated Pill were analyzed by this high-performance liquid chromatography method and both qualitative and quantitative evaluation results were achieved by similarity analysis, principal component analysis and hierarchical cluster analysis. The results of these three chemometrics were in good agreement and all indicated that batch 10 and batch 16 showed significant differences with the other 14 batches. This suggested that the developed high-performance liquid chromatography method could be applied in the quality evaluation of Moluodan Concentrated Pill. PMID- 27758088 TI - The CHRNA5/CHRNA3/CHRNB4 Nicotinic Receptor Regulome: Genomic Architecture, Regulatory Variants, and Clinical Associations. AB - Functionally related genes often cluster into a genome region under coordinated regulation, forming a local regulome. To understand regulation of the CHRNA5/CHRNA3/CHRNB4 nicotinic receptor gene cluster, we integrate large-scale RNA expression data (brain and peripheral) from GTEx (Genotype Tissue Expression), clinical associations (GRASP), and linkage disequilibrium data (1000 Genomes) to find candidate SNPs representing independent regulatory variants. CHRNA3, CHRNA5, CHRNB4 mRNAs, and a well-expressed CHRNA5 antisense RNA (RP11 650L12.2) are co-expressed in many human tissues, suggesting common regulatory elements. The CHRNA5 enhancer haplotype tagged by rs880395 not only increases CHRNA5 mRNA expression in all tissues, but also enhances RP11-650L12.2 and CHRNA3 expression, suggesting DNA looping to multiple promoters. However, in nucleus accumbens and putamen, but not other brain regions, CHRNA3 expression associates uniquely with a haplotype tagged by rs1948 (located in the CHRNB4 3'UTR). Haplotype/diplotype analysis of rs880395 and rs1948 plus rs16969968 (a nonsynonymous CHRNA5 risk variant) in GWAS (COGEND, UW-TTURC, SAGE) yields a nicotine dependence risk profile only partially captured by rs16969968 alone. An example of local gene clusters, this nicotinic regulome is controlled by complex genetic variation, with broad implications for interpreting GWAS. PMID- 27758090 TI - The rise and future of glyphosate and glyphosate-resistant crops. AB - Glyphosate and glyphosate-resistant crops had a revolutionary impact on weed management practices, but the epidemic of glyphosate-resistant (GR) weeds is rapidly decreasing the value of these technologies. In areas that fully adopted glyphosate and GR crops, GR weeds evolved and glyphosate and glyphosate traits now must be combined with other technologies. The chemical company solution is to combine glyphosate with other chemicals, and the seed company solution is to combine glyphosate resistance with other traits. Unfortunately, companies have not discovered a new commercial herbicide mode-of-action for over 30 years and have already developed or are developing traits for all existing herbicide types with high utility. Glyphosate mixtures and glyphosate trait combinations will be the mainstays of weed management for many growers, but are not going to be enough to keep up with the capacity of weeds to evolve resistance. Glufosinate, auxin, HPPD-inhibiting and other herbicide traits, even when combined with glyphosate resistance, are incremental and temporary solutions. Herbicide and seed businesses are not going to be able to support what critics call the chemical and transgenic treadmills for much longer. The long time without the discovery of a new herbicide mode-of-action and the epidemic of resistant weeds is forcing many growers to spend much more to manage weeds and creating a worst of times, best of times predicament for the crop protection and seed industry. (c) 2016 Society of Chemical Industry. PMID- 27758091 TI - Global programme to eliminate lymphatic filariasis: progress report, 2015. PMID- 27758092 TI - Summary of global update on preventive chemotherapy implementation in 2015. PMID- 27758093 TI - Real-time monitoring of vaccination campaign performance using mobile phones - Nepal, 2016. PMID- 27758094 TI - Recommended composition of influenza virus vaccines for use in the 2017 southern hemisphere influenza season. PMID- 27758095 TI - Band Gap Tuning and Defect Tolerance of Atomically Thin Two-Dimensional Organic Inorganic Halide Perovskites. AB - Organic-inorganic halide perovskites have proven highly successful for photovoltaics but suffer from low stability, which deteriorates their performance over time. Recent experiments have demonstrated that low dimensional phases of the hybrid perovskites may exhibit improved stability. Here we report first principles calculations for isolated monolayers of the organometallic halide perovskites (C4H9NH3)2MX2Y2, where M = Pb, Ge, Sn and X,Y = Cl, Br, I. The band gaps computed using the GLLB-SC functional are found to be in excellent agreement with experimental photoluminescence data for the already synthesized perovskites. Finally, we study the effect of different defects on the band structure. We find that the most common defects only introduce shallow or no states in the band gap, indicating that these atomically thin 2D perovskites are likely to be defect tolerant. PMID- 27758096 TI - (Pc)Eu(Pc)Eu[trans-T(COOCH3)2PP]/GO Hybrid Film-Based Nonenzymatic H2O2 Electrochemical Sensor with Excellent Performance. AB - A facile approach was developed for preparing the multilayer hybrid films of mixed (phthalocyaninato) (porphyrinato) europium(III) triple-decker compound (Pc)Eu(Pc)Eu[trans-T(COOCH3)2PP] (1) and graphene oxide (GO) using the solution processing QLS method. The combination of the nature of relatively high conductivity and great surface area for GO with the electroactive and semiconductive triple-decker compound in ITO electrode renders the hybrid film excellent sensing property for H2O2, due to the optimized triple-decker molecular packing in the uniform-sized nanoparticles (ca. 70 nm) formed on the GO surface. The amperometric responses are linearly proportional to the concentration of H2O2 in the range of 0.05-1800 MUM with a fast response time of 0.03 s MUM-1, a low detection limit of 0.017 MUM, and good sensitivity of 7.4 MUA mM-1. The present work represents the best result of tetrapyrrole-based nonenzymatic electrochemical sensor for H2O2. Nevertheless, the triple-decker/GO/ITO also shows excellent stability, reproducibility, and selectivity, indicating the great potential of electroactive tetrapyrrole rare earth sandwich compounds in combination with GO in the field of nonenzymatic electrochemical sensors. PMID- 27758097 TI - Uranium Isotopic Fractionation Induced by U(VI) Adsorption onto Common Aquifer Minerals. AB - Uranium groundwater contamination due to U mining and processing affects numerous sites globally. Bioreduction of soluble, mobile U(VI) to U(IV)-bearing solids is potentially a very effective remediation strategy. Uranium isotopes (238U/235U) have been utilized to track the progress of microbial reduction, with laboratory and field studies finding a ~10/00 isotopic fractionation, with the U(IV) product enriched in 238U. However, the isotopic fractionation produced by adsorption may complicate the use of 238U/235U to trace microbial reduction. A previous study found that adsorption of U(VI) onto Mn oxides produced a -0.20/00 fractionation with the adsorbed U(VI) depleted in 238U. In this study, adsorption to quartz, goethite, birnessite, illite, and aquifer sediments induced an average isotopic fractionation of -0.150/00 with the adsorbed U(VI) isotopically lighter than coexisting aqueous U(VI). In bicarbonate-bearing matrices, the fractionation depended little on the nature of the sorbent, with only birnessite producing an atypically large fractionation. In the case of solutions with ionic strengths much lower than those of typical groundwater, less isotopic fractionation was produced than U(VI) solutions with greater ionic strength. Studies using U isotope data to assess U(VI) reduction must consider adsorption as a lesser, but significant isotope fractionation process. PMID- 27758099 TI - Near-Infrared Organic Dye-Based Nanoagent for the Photothermal Therapy of Cancer. AB - Given their easy structural modification and good biocompatibility advantages, near-infrared (NIR) organic dyes with a large molar extinction coefficient, while a superlow fluorescence quantum yield shows considerable potential application in photothermal therapy (PTT). Herein, a new NIR-absorbing asymmetric cyanine dye, namely, RC, is designed and synthesized via the hybrid of rhodamine and hemicyanine derivatives. RC-BSA nanoparticles (NPs) are fabricated by using the bovine serum albumin (BSA) matrix. The NPs exhibit a strong NIR absorption peak at ~868 nm and 28.7% photothermal conversion efficiency. Based on these features, RC-BSA NPs exhibit excellent performance in ablating tumor under a 915 nm laser radiation through a PTT mechanism. These NPs show no obvious toxicity to the treated mice. Thus, RC-BSA NPs can used as a new NIR laser-triggered PTT agent in cancer treatment. PMID- 27758098 TI - Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth. AB - Altered tumor microenvironment (TME) arising from a bidirectional crosstalk between the pancreatic cancer cells (PCCs) and the pancreatic stellate cells (PSCs) is implicated in the dismal prognosis in pancreatic ductal adenocarcinoma (PDAC), yet effective strategies to disrupt the crosstalk is lacking. Here, we demonstrate that gold nanoparticles (AuNPs) inhibit proliferation and migration of both PCCs and PSCs by disrupting the bidirectional communication via alteration of the cell secretome. Analyzing the key proteins identified from a functional network of AuNP-altered secretome in PCCs and PSCs, we demonstrate that AuNPs impair secretions of major hub node proteins in both cell types and transform activated PSCs toward a lipid-rich quiescent phenotype. By reducing activation of PSCs, AuNPs inhibit matrix deposition, enhance angiogenesis, and inhibit tumor growth in an orthotopic co-implantation model in vivo. Auto- and heteroregulations of secretory growth factors/cytokines are disrupted by AuNPs resulting in reprogramming of the TME. By utilizing a kinase dead mutant of IRE1 alpha, we demonstrate that AuNPs alter the cellular secretome through the ER stress-regulated IRE1-dependent decay pathway (RIDD) and identify endostatin and matrix metalloproteinase 9 as putative RIDD targets. Thus, AuNPs could potentially be utilized as a tool to effectively interrogate bidirectional communications in the tumor microenvironment, reprogram it, and inhibit tumor growth by its therapeutic function. PMID- 27758100 TI - Hierarchical Self-Organization of Perylene Bisimides into Supramolecular Spheres and Periodic Arrays Thereof. AB - Perylene bisimide derivatives (PBIs) are known to form only columnar or lamellar assemblies. There is no known example of a PBI self-assembling into a supramolecular sphere. Therefore, periodic and quasiperiodic arrays generated from spherical assemblies produced from PBIs are also not known. Here, a PBI functionalized at its imide groups with a second generation self-assembling dendron is reported to self-assemble into supramolecular spheres. These spheres self-organize in a body-centered cubic (BCC) periodic array, rarely encountered for self-assembling dendrons but often encountered in block copolymers. These supramolecular spheres also assemble into a columnar hexagonal array in which the supramolecular columns are unexpectedly and unprecedentedly made from spheres. At lower temperature, two additional columnar hexagonal phases consisting of symmetric and asymmetric tetrameric crowns of PBI are observed. Structural and retrostructural analysis via X-ray diffraction (XRD), molecular modeling, molecular simulation, and solid state NMR suggests that inversion of the symmetric tetrameric crowns at high temperature mediates their transformation into supramolecular spheres. The tetrameric crowns of PBIs are able to form an isotropic sphere in the cubic phase due to rapid molecular motion at high temperature, unobservable by XRD but demonstrated by solid state NMR studies. This mechanism of hierarchical self-organization of PBI into supramolecular spheres is most probably general and can be applied to other related planar molecules to generate new functions. PMID- 27758101 TI - Observing Extremely Weak Protein-Protein Interactions with Conventional Single Molecule Fluorescence Microscopy. AB - Extremely weak protein-protein interactions (PPIs), signified by micromolar or even millimolar dissociation constants, are one of the keys to understanding the rapid responses of cellular systems. Although single-molecule methods are particularly useful in determining kinetics of biological processes, their application is largely limited to rather strong interactions because of the diffraction-limited observation volume. In this study, we report a single molecule method that allows the characterization of PPIs using a prey concentration 4 orders of magnitude lower than the dissociation constant. Instead of increasing the concentration of diffusing molecules, which is inevitably limited by the optical diffraction limit, we employed an increased density of surface bait protein. The low occupancy of the surface baits permitted determination of the kinetics with single-molecule resolution. We used this approach to study a PPI network consisting of Ras and its downstream proteins including full-length Rafs and catalytic subunits of phosphoinositide 3-kinase. PMID- 27758102 TI - Gold-Nanoparticle-Immobilized Desalting Columns for Highly Efficient and Specific Removal of Radioactive Iodine in Aqueous Media. AB - There has been worldwide attention on the efficient removal of radioactive iodine, because it is commonly released in nuclear plant accidents. Increasing concerns on environmental problems due to the radioactive iodine are leading us to develop stable and sustainable technology for remediation of radioelement contaminants. In this work, we report a highly efficient chromatographic method for specific and rapid capture of radioactive iodine. The gold nanoparticles immobilized dextran gel columns showed excellent removal capabilities of radioactive iodine in various conditions. These results suggested that our platform technology can be a promising method for the desalination of radioactive iodines in water. PMID- 27758103 TI - Effect of Traditional and Extrusion Nixtamalization on Carotenoid Retention in Tortillas Made from Provitamin A Biofortified Maize (Zea mays L.). AB - Provitamin A (proVA) enhanced maize was developed to help alleviate vitamin A deficiency in maize-consuming populations. Nixtamalization (lime-cooking process) is the most commonly used maize-preparation method in Mexico and Central America. In this study, the effect of traditional nixtamalization (TN) and nixtamalized extrusion (NE) on proVA retention was evaluated. Kernel conversion to TN dough led to high proVA apparent retention (>100%), while kernel conversion to NE flour led to lower retention (85%). However, TN tortilla proVA carotenoid concentration was similar to the kernels' original concentration and slightly higher in NE tortillas. Genotypic variation has a strong effect on proVA retention in TN dough and NE flour, but no such variation in proVA retention was observed in tortillas. Tortillas prepared with proVA-enhanced maize, using either TN or NE, are a good source of proVA carotenoids. Also, dough made using TN and proVA-enhanced maize is a high proVA-content ingredient for other food products. PMID- 27758104 TI - Exploring the Effects of the Pb2+ Substitution in MAPbI3 on the Photovoltaic Performance of the Hybrid Perovskite Solar Cells. AB - Here we report a systematic study of the Pb2+ substitution in the hybrid iodoplumbate MAPbI3 with a series of elements affecting optoelectronic, structural, and morphological properties of the system. It has been shown that even partial replacement of lead with Cd2+, Zn2+, Fe2+, Ni2+, Co2+, In3+, Bi3+, Sn4+, and Ti4+ results in a significant deterioration of the photovoltaic characteristics. On the contrary, Hg-containing hybrid MAPb1-xHgxI3 salts demonstrated a considerably improved solar cell performance at optimal mercury loading. This result opens up additional dimension in the compositional engineering of the complex lead halides for designing novel photoactive materials with advanced optoelectronic and photovoltaic properties. PMID- 27758105 TI - Bright Perovskite Nanocrystal Films for Efficient Light-Emitting Devices. AB - The high photoluminescence efficiency, high color purity, and easy tunable bandgap make inorganic perovskite nanocrystals very attractive in luminescent display applications. Here, we report a color-saturated, red light-emitting diode (LED) using an inverted organic/inorganic hybrid structure and perovskite nanocrystals. We demonstrated that through a simple post treatment to the perovskite nanocrystals with polyethylenimine, the surface defects of the perovskite nanocrystals could be well passivated, leading to great enhancements on their absolute photoluminescence quantum yield and photoluminescence lifetime. Through using a well-passivated perovskite nanocrystal film and optimizing the charge balance, we achieved an electroluminescence LED with a current efficiency of 3.4 cd A-1, corresponding to an external quantum efficiency (EQE) of 6.3%, which is the highest value reported among perovskite NC LEDs so far. PMID- 27758106 TI - Sensitivity Modulation of Upconverting Thermometry through Engineering Phonon Energy of a Matrix. AB - Investigation of the unclear influential factors to thermal sensing capability is the only way to achieve highly sensitive thermometry, which is greatly needed to meet the growing demand for potential sensing applications. Here, the effect from the phonon energy of a matrix on the sensitivity of upconversion (UC) microthermometers is elaborately discussed using a controllable method. Uniform truncated octahedral YF3:Er3+/Yb3+ microcrystals were prepared by a hydrothermal approach, and phase transformation from YF3 to YOF and Y2O3 with nearly unchanged morphology and size was successfully realized by controlling the annealing temperature. The phonon energies of blank matrixes were determined by FT-IR spectra and Raman scattering. Upon 980 nm excitation, phonon energy-dependent UC emitting color was finely tuned from green to yellow for three samples, and the mechanisms were proposed. Thermal sensing behaviors based on the TCLs (2H11/2/4S3/2) were evaluated, and the sensitivities gradually grew with the increase in the matrix's phonon energy. According to chemical bond theory and first-principle calculations, the most intrinsic factors associated with thermometric ability were qualitatively demonstrated through analyzing the inner relation between the phonon energy and bond covalency. The exciting results provide guiding insights into employing appropriate host materials with desired thermometric ability while offering the possibility of highly accurate measurement of temperature. PMID- 27758108 TI - Temperature Dependent Border Trap Response Produced by a Defective Interfacial Oxide Layer in Al2O3/InGaAs Gate Stacks. AB - Intentional oxidation of an As2-decapped (100) In0.57Ga0.43As substrate by additional H2O dosing during initial Al2O3 gate dielectric atomic layer deposition (ALD) increases the interface trap density (Dit), lowers the band edge photoluminescence (PL) intensity, and generates Ga-oxide detected by X-ray photoelectron spectroscopy (XPS). Aberration-corrected high resolution transmission electron microscopy (TEM) reveals formation of an amorphous interfacial layer which is distinct from the Al2O3 dielectric and which is not present without the additional H2O dosing. Observation of a temperature dependent border trap response, associated with the frequency dispersion of the accumulation capacitance and conductance of metal-oxide-semiconductor (MOS) structures, is found to be correlated with the presence of this defective interfacial layer. MOS capacitors prepared with additional H2O dosing show a notable decrease (~20%) of accumulation dispersion over 5 kHz to 500 kHz when the measurement temperature decreases from room temperature to 77 K, while capacitors prepared with an abrupt Al2O3/InGaAs interface display little change (<2%) with temperature. Similar temperature-dependent border trap response is also observed when the (100) InGaAs surface is treated with a previously reported HCl(aq) wet cleaning procedure prior to Al2O3 ALD. These results point out the sensitivity of the temperature dependence of the border trap response in metal oxide/III-V MOS gate stacks to the presence of processing-induced interface oxide layers, which alter the dynamics of carrier trapping at defects that are not located at the semiconductor interface. PMID- 27758107 TI - Untargeted Metabolomics Analysis of ABCC6-Deficient Mice Discloses an Altered Metabolic Liver Profile. AB - Loss-of-function mutations in the transmembrane ABCC6 transport protein cause pseudoxanthoma elasticum (PXE), an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. Untargeted metabolomics using liquid chromatography-mass spectrometry was employed to inspect liver cytosolic extracts from mice with targeted disruption of the Abcc6 gene. Absence of the ABCC6 protein induced an altered profile of metabolites in the liver causing accumulation of compounds as more features were upregulated than downregulated in ABCC6-deficient mice. However, no differences of the identified metabolites in liver could be detected in plasma, whereas urine reflected some of the changes. Of note, N-acetylated amino acids and pantothenic acid (vitamin B5), which is involved in acetylation reactions, were accumulated in the liver. None of the identified metabolites seems to explain mineralization in extrahepatic tissues, but the present study now shows that abrogated ABCC6 function does cause alterations in the metabolic profile of the liver in accordance with PXE being a metabolic disease originating from liver disturbance. Further studies of these changes and the further identification of yet unknown metabolites may help to clarify the liver-related pathomechanism of PXE. PMID- 27758109 TI - Domino Ring-Opening Cyclization of Activated Aziridines with Indoles: Synthesis of Chiral Hexahydropyrroloindoles. AB - A highly enantioselective synthetic route to hexahydropyrrolo[2,3-b]indoles via Lewis acid-catalyzed SN2-type ring opening of activated aziridines with indoles having substitutions at 3- and other positions followed by cyclization in a domino fashion has been developed. Hexahydropyrrolo[2,3-b]indoles have been detosylated in the same pot to afford the corresponding products with free NH group in excellent yields (up to 95%) and enantioselectivity (up to >99%). PMID- 27758110 TI - Space, the final frontier: outdoor access for people living with dementia. PMID- 27758111 TI - A Novel Device to Prevent Stone Fragment Migration During Percutaneous Lithotripsy: Results from an In Vitro Kidney Model. AB - PURPOSE: We developed a polyethylene sack (the PercSac) that fits over the shaft of a rigid nephroscope and is deployed into the collecting system to capture a stone and contain fragments during percutaneous nephrolithotomy (PCNL). We previously reported our results using the PercSac in a percutaneous cystolithopaxy model. In this study, we compare the efficiency of stone fragmentation with and without the PercSac in an anatomically correct in vitro PCNL model. MATERIALS AND METHODS: The PCNL model consisted of a human collecting system model created on a 3D printer. Ten BegoStones made in spherical molds of 2.0 cm diameter, matched for weight, were fragmented in the model using a 24F rigid nephroscope and an ultrasonic lithotripter, including five with and five without the PercSac. The total times for stone fragmentation and complete stone clearance, gross assessment of the stone-free status, and need for flexible nephroscopy to achieve a stone-free state were recorded. RESULTS: The median time for stone fragmentation was significantly shorter in the PercSac group compared with the control group (217 seconds [IQR = 169-255] vs 340 seconds [IQR = 310 356], [p = 0.028]). Likewise, the total time for complete stone clearance from the kidney was significantly shorter for the PercSac group (293 seconds [IQR = 244-347] vs 376 seconds [IQR = 375-480], [p = 0.047]). In one trial with the PercSac, residual dust remained in the kidney, while in all five trials without the PercSac small residual fragments remained. All trials without the PercSac required flexible nephroscopy with basket extraction to become stone free, while none of the trials with the PercSac required flexible nephroscopy for stone clearance. CONCLUSIONS: Ultrasonic lithotripsy using the novel PercSac stone entrapment device is more efficient and efficacious than traditional ultrasonic lithotripsy in an in vitro PCNL model. The advantage may be even more pronounced during clinical PCNL where residual fragments migrate into difficult-to-access calices. Further in vivo testing is underway. PMID- 27758112 TI - Promyelocytic Leukemia Protein, a Protein at the Crossroad of Oxidative Stress and Metabolism. AB - SIGNIFICANCE: Cellular metabolic activity impacts the production of reactive oxygen species (ROS), both positively through mitochondrial oxidative processes and negatively by promoting the production of reducing agents (including NADPH and reduced glutathione). A defined metabolic state in cancer cells is critical for cell growth and long-term self-renewal, and such state is intrinsically associated with redox balance. Promyelocytic leukemia protein (PML) regulates several biological processes, at least in part, through its ability to control the assembly of PML nuclear bodies (PML NBs). Recent Advances: PML is oxidation prone, and oxidative stress promotes NB biogenesis. These nuclear subdomains recruit many nuclear proteins and regulate their SUMOylation and other post translational modifications. Some of these cargos-such as p53, SIRT1, AKT, and mammalian target of rapamycin (mTOR)-are key regulators of cell fate. PML was also recently shown to regulate oxidation. CRITICAL ISSUES: While it was long considered primarily as a tumor suppressor protein, PML-regulated metabolic switch uncovered that this protein could promote survival and/or stemness of some normal or cancer cells. In this study, we review the recent findings on this multifunctional protein. FUTURE DIRECTIONS: Studying PML scaffolding functions as well as its fine role in the activation of p53 or fatty acid oxidation will bring new insights in how PML could bridge oxidative stress, senescence, cell death, and metabolism. Antioxid. Redox Signal. 26, 432-444. PMID- 27758113 TI - HIV-2 Surveillance with Next-Generation Sequencing Reveals Mutations in a Cytotoxic Lymphocyte-Restricted Epitope Involved in Long-Term Nonprogression. AB - HIV-2 exhibits a natural history of infection distinct from HIV-1. Primarily found in West Africa and in only 10%-20% of HIV infections in this region, patients with HIV-2 typically exhibit a slower progression to AIDS, lower viral loads, and decreased rates of transmission. Here, we used next-generation sequencing to determine the sequence and phylogenetic classification of nine HIV 2 genomes. We identified a patient with a series of mutations in an invariant cytotoxic lymphocyte (CTL)-restricted gag epitope required for retroviral structure and replication and implicated in long-term nonprogression to AIDS. The presence of wild-type sequence argues these mutations are involved in immune escape, whereas its reversion to a sequence seen only in the sooty mangabey reservoir suggests an alternate means of controlling infection. Surveillance and molecular characterization of circulating strains are essential for continued development of monitoring tools and may provide greater insight into the reduced pathogenicity of HIV-2. PMID- 27758114 TI - Short Communication: Impact of Viral Load Use on Treatment Switch in Perinatally HIV-Infected Children in Asia. AB - We sought to assess the impact of routine HIV viral load (VL) monitoring on the incidence of switching from a first- to a second-line antiretroviral therapy (ART) regimen, and to describe factors associated with switch. Data from a regional cohort of 16 clinical programs in six Asian countries were analyzed. Second-line switch was defined as a change from a non-nucleoside reverse transcriptase inhibitor (NNRTI) to a protease inhibitor (PI) or vice versa, and >=1 of the following: (1) reported treatment failure by local criteria, (2) switch of >=1 additional drug, or (3) a preceding HIV VL >=1,000 copies/ml. Routine VL was having >=1 test after >=24 weeks of ART and >=1 time/year thereafter. Factors associated with time to switch were evaluated with death and loss to follow-up as competing risks. A total of 2,398 children were included in this analysis. At ART initiation, the median (interquartile range) age was 6.0 (3.3-8.9) years, more than half had WHO stage 3 or 4, the median CD4 was 189 (47 456) cells/mm3, 93% were on NNRTI-based first-line ART, and 34% had routine VL monitoring. Treatment switch occurred in 17.6% of patients, at a median of 35 (22 49) months. After adjusting for country, sex, first ART regimen, and CD4% at ART initiation, children with routine VL monitoring were 1.46 (95% confidence interval 1.11-1.93) times more likely to be switched (p = .007). Scale-up of VL testing will lead to earlier identification of treatment failure, and it can help guide earlier switches to prevent resistance. PMID- 27758115 TI - Dynamical Signatures of Structural Connectivity Damage to a Model of the Brain Posed at Criticality. AB - Synchronization of brain activity fluctuations is believed to represent communication between spatially distant neural processes. These interareal functional interactions develop in the background of a complex network of axonal connections linking cortical and subcortical neurons, termed the human "structural connectome." Theoretical considerations and experimental evidence support the view that the human brain can be modeled as a system operating at a critical point between ordered (subcritical) and disordered (supercritical) phases. Here, we explore the hypothesis that pathologies resulting from brain injury of different etiologies are related to this model of a critical brain. For this purpose, we investigate how damage to the integrity of the structural connectome impacts on the signatures of critical dynamics. Adopting a hybrid modeling approach combining an empirical weighted network of human structural connections with a conceptual model of critical dynamics, we show that lesions located at highly transited connections progressively displace the model toward the subcritical regime. The topological properties of the nodes and links are of less importance when considered independently of their weight in the network. We observe that damage to midline hubs such as the middle and posterior cingulate cortex is most crucial for the disruption of criticality in the model. However, a similar effect can be achieved by targeting less transited nodes and links whose connection weights add up to an equivalent amount. This implies that brain pathology does not necessarily arise due to insult targeted at well-connected areas and that intersubject variability could obscure lesions located at nonhub regions. Finally, we discuss the predictions of our model in the context of clinical studies of traumatic brain injury and neurodegenerative disorders. PMID- 27758116 TI - Short Communication: Potential Risk of Replication-Competent Virus in HIV-1 Env Pseudotyped Virus Preparations. AB - Env-pseudotyped viruses are valuable reagents for studies of HIV-1 neutralizing antibodies. It is often assumed that all pseudovirus particles are capable of only a single round of infection, making them a safe alternative to work with live HIV-1. In this study, we show that some Env-pseudotyped virus preparations give rise to low levels of replication-competent virus. These levels did not compromise results in the TZM-bl neutralization assay; however, their presence highlights a need to adhere to the same level of biosafety when working with Env pseudotyped viruses that are required for work with replication competent HIV-1. PMID- 27758117 TI - A Proposed Framework for the Implementation of Early Infant Diagnosis Point-of Care. AB - Early diagnosis of HIV infection in infants and children remains a challenge in resource-limited settings, with approximately half of all HIV-exposed infants receiving virological testing for HIV by the recommended age of 2 months in 2015. To reduce morbidity and mortality among HIV-infected children and close the treatment gap for HIV-infected children, there is an urgent need to evaluate existing programmatic and laboratory practices for early infant diagnosis and introduce strategies to improve identification of HIV-exposed infants and ensure access to systematic, early HIV testing, with early linkage to treatment for HIV infected infants. This article describes progress made in follow-up of HIV exposed infants since 2006, including remaining unmet laboratory and programmatic needs, and recommends strategies for improvement, especially those related to the implementation of point-of-care technology for early infant diagnosis. PMID- 27758119 TI - A Usability Comparison of Laser Suction Handpieces for Percutaneous Nephrolithotomy. AB - INTRODUCTION: The holmium laser has revolutionized the practice of minimally invasive endoscopy for kidney stones. Recently, a novel, rigid handpiece for use in percutaneous nephrolithotomy (PCNL) that couples the holmium laser with suction has been developed. To date, limited data exist regarding the usability and ergonomics of such treatment systems. We thus sought to compare surgeon-rated usability with three different suction laser handpieces in a porcine model. MATERIALS AND METHODS: We performed bilateral reverse PCNL on four female domestic farm pigs. After induction of general anesthesia, percutaneous access was obtained into each kidney by using biplanar fluoroscopy and 8 mm stones (plaster of Paris) were inserted into the calix or renal pelvis for treatment. Four surgeons tested the LASER Suction Tube (Karl Storz(r), Germany), LithAssistTM (Cook(r) Medical), and Suction Handpiece (HP) (Lumenis(r), Israel) by using a combination of fragmentation (5 Joules/20 Hertz) and dusting (0.8 Joules/80 Hertz) settings on the Lumenis pulse 120 H laser. The primary outcome assessed was the ease of use of the three devices as measured by a surgeon questionnaire. RESULTS: A total of 15 stones were treated in 8 renal units. The mean time required for stone fragmentation was 8 min. The mean handling and suction efficiency scores were similar between devices. The Suction HP offered the best laser fiber visibility during lithotripsy. CONCLUSION: Suction laser handpieces offer an option to treat renal stones via PCNL, with limited differences noted in most surgeon ratings between devices. PMID- 27758118 TI - Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells. AB - AIMS: Microglial cells are brain-resident macrophages engaged in surveillance and maintained in a constant state of relative inactivity. However, their involvement in autoimmune diseases indicates that in pathological conditions microglia gain an inflammatory phenotype. The mechanisms underlying this change in the microglial phenotype are still unclear. Since metabolism is an important modulator of immune cell function, we focused our attention on glutamine synthetase (GS), a modulator of the response to lipopolysaccharide (LPS) activation in other cell types, which is expressed by microglia. RESULTS: GS inhibition enhances release of inflammatory mediators of LPS-activated microglia in vitro, leading to perturbation of the redox balance and decreased viability of cocultured neurons. GS inhibition also decreases insulin-mediated glucose uptake in microglia. In vivo, microglia-specific GS ablation enhances expression of inflammatory markers upon LPS treatment. In the spinal cords from experimental autoimmune encephalomyelitis (EAE), GS expression levels and glutamine/glutamate ratios are reduced. INNOVATION: Recently, metabolism has been highlighted as mediator of immune cell function through the discovery of mechanisms that (behind these metabolic changes) modulate the inflammatory response. The present study shows for the first time a metabolic mechanism mediating microglial response to a proinflammatory stimulus, pointing to GS activity as a master modulator of immune cell function and thus unraveling a potential therapeutic target. CONCLUSIONS: Our study highlights a new role of GS in modulating immune response in microglia, providing insights into the pathogenic mechanisms associated with inflammation and new strategies of therapeutic intervention. Antioxid. Redox Signal. 26, 351 363. PMID- 27758120 TI - Bench-Top Feasibility Testing of a Novel Percutaneous Renal Access Technique: The Laser Direct Alignment Radiation Reduction Technique (DARRT). AB - INTRODUCTION: Traditional techniques for obtaining percutaneous renal access utilize continuous fluoroscopy. In an attempt to minimize radiation exposure, we describe a novel laser direct alignment radiation reduction technique (DARRT) for percutaneous access and test it in a bench-top model. METHODS: In this randomized controlled bench-top study, 20 medical personnel obtained renal accesses using both the conventional bullseye technique and the laser DARRT. The primary endpoint was total fluoroscopy time. Secondary endpoints included insertion time, puncture attempts, course corrections, and subjective procedural difficulty. In the laser DARRT, fluoroscopy was used with the C-arm positioned with the laser beam at a 30 degrees angle. The access needle and hub were aligned with the laser beam. Effective caliceal puncture was confirmed with fluoroscopy and direct vision. The Paired samples Wilcoxon signed rank test was used for statistical analysis with significance at p < 0.05. RESULTS: A total of 120 needle placements were recorded. Fluoroscopy time for needle access using the laser DARRT was significantly lower than the bullseye technique in all groups as follows: attendings (7.09 vs 18.51 seconds; p < 0.001), residents (6.55 vs 13.93 seconds; p = 0.001), and medical students (6.69 vs 20.22 seconds; p < 0.001). Students rated the laser DARRT easier to use (2.56 vs 4.89; p < 0.001). No difference was seen in total access time, puncture attempts, or course corrections between techniques. CONCLUSION: The laser DARRT reduced fluoroscopy time by 63%, compared with the conventional bullseye technique. The least experienced users found the laser DARRT significantly easier to learn. This novel technique is promising and merits additional testing in animal and human models. PMID- 27758121 TI - Kidney injury molecule-1 in kidney disease. AB - Kidney injury molecule-1(KIM-1) is a type I membrane protein, comprising an extracellular portion and a cytoplasmic portion, which is expressed at very low levels in the normal kidney. The extracellular portion can cleave and rapidly enter tubule lumens after kidney injury, and can then be detected in the urine. It has been confirmed that the urine KIM-1 level is closely related to tissue KIM 1 level and correlated with kidney tissue damage. Not only is KIM-1 proven to be an early biomarker of acute kidney injury but it also has a potential role in predicting long-term renal outcome. This review summarizes the relationships between KIM-1 and kidney injury, especially in chronic kidney disease. PMID- 27758122 TI - Uremic toxins: some thoughts on acrolein and spermine. AB - Chronic kidney disease (CKD) is characterized by the progressive reduction of glomerular filtration rate and subsequent retention of organic waste compounds called uremic toxins. While patients with CKD are at a higher risk of premature death due to cardiovascular complications, this increased risk cannot be completely explained by classical cardiovascular risk factors such as hypertension, diabetes mellitus, and obesity. Instead, recent research suggests that uremic toxins may play a key role in explaining this marked increase in cardiovascular mortality in patients with CKD. While spermine, a tetra-amine, has previously been hypothesized to act as an uremic toxin, the following review presents a summary of recent literature that casts doubt on this assertion. Instead, acrolein, an oxidative product of spermine and the triamine spermidine, is likely responsible for the toxic effects previously attributed to spermine. PMID- 27758123 TI - Role of lifestyle modifications for patients with laryngeal granuloma caused by gastro-esophageal reflux: comparison between conservative treatment and the surgical approach. AB - CONCLUSIONS: It is considered that a regimen combining pharmacologic management and lifestyle modifications is the most effective treatment for laryngeal granulomas caused by GER. OBJECTIVES: This study compared the results of the combination therapy and surgery to determine the best treatment of laryngeal granuloma caused by gastro-esophageal reflux in 51 patients. METHODS: Prospective study. RESULTS: In the conservative treatment group, the CR rate was 89.7% and recurrence rate was 2.6%, while the lesions remained in patients (7.7%). This study compared the CR and recurrence rates between conservative treatment and surgery for granuloma. The results showed that the laryngeal granuloma recurrence rate was significantly lower with the conservative treatment regimen compared with surgery (p = .0016). PMID- 27758124 TI - A genetic variant within SLC30A6 has a protective role in the severity of rheumatoid arthritis. PMID- 27758125 TI - The novel primers for mammal species identification-based mitochondrial cytochrome b sequence: implication for reserved wild animals in Thailand and endangered mammal species in Southeast Asia. AB - We presented the powerful techniques for species identification using the short amplicon of mitochondrial cytochrome b gene sequence. Two faecal samples and one single hair sample of the Asian tapir were tested using the new cytochrome b primers. The results showed a high sequence similarity with the mainland Asian tapir group. The comparative sequence analysis of the reserved wild mammals in Thailand and the other endangered mammal species from Southeast Asia comprehensibly verified the potential of our novel primers. The forward and reverse primers were 94.2 and 93.2%, respectively, by the average value of the sequence identity among 77 species sequences, and the overall mean distance was 35.9%. This development technique could provide rapid, simple, and reliable tools for species confirmation. Especially, it could recognize the problematic biological specimens contained less DNA material from illegal products and assist with wildlife crime investigation of threatened species and related forensic casework. PMID- 27758126 TI - The effect of vestibular rehabilitation on sleep disturbance in patients with chronic dizziness. AB - CONCLUSIONS: Improvement in sleep, emotional distress, and health-related quality of-life (QoL) accompanied the improvement in dizziness symptoms after vestibular rehabilitation. Persistent sleep disturbance could prevent improvements in self perceived handicap due to chronic dizziness and anxiety. OBJECTIVE: The present study investigated prospectively the effects of intervention for dizziness (vestibular rehabilitation) on sleep disturbance, and the relationship between improvements in dizziness symptoms and improvements in sleep disturbance after the intervention. METHODS: The participants of this study were 127 chronic dizziness inpatients with comorbid sleep disturbance (Pittsburgh sleep quality index [PSQI-J] global score >=6). Participants completed the Dizziness Handicap Inventory (DHI, three sub-scales: Physical, Emotional, and Functional), PSQI-J, Hospital Anxiety and Depression Scale (HADS), and SF-8 (health-related QoL), and underwent gravity center fluctuation measurement before (time 1) and 1 month after (time 2) an in-hospital rehabilitation program. RESULTS: All measured variables were significantly improved at time 2, compared to time 1. At time 2, 80.31% of patients still reported sleep disturbance. Analysis of covariance showed that chronic dizziness patients with sleep disturbance at time 2 had significantly higher DHI total, DHI-physical, and HADS-anxiety scores at time 2 than patients without sleep disturbance at time 2, after adjusting for these scores at time 1. PMID- 27758127 TI - Joint distraction for thumb carpometacarpal osteoarthritis: a feasibility study with 1-year follow-up. AB - OBJECTIVE: The purpose of this pilot study was to evaluate the feasibility of joint distraction of the first carpometacarpal (CMC1) joint in patients with CMC1 osteoarthritis (OA). METHODS: An external joint distractor was placed over the CMC1 joint by K-wire fixation in the trapezium and the metacarpal. The joint was distracted 3 mm during surgery. The device was then kept in place for 8 weeks. Disabilities of the Arm, Shoulder, and Hand (DASH) score, Michigan Hand Outcome Questionnaire (MHQ), Visual Analogue Scale (VAS), and grip strength were recorded preoperatively and at set postoperative intervals. RESULTS: Five female patients with an average age of 53 years (range = 41-61) were included. One year postoperatively, average DASH, MHQ, and VAS scores improved compared to preoperative values; DASH 53 to 27, MHQ 48 to 76, and VAS pain 48 to 14. There were no technical problems associated with the device. One patient had a local pin site infection treated successfully with oral antibiotics. CONCLUSIONS: This study concludes that joint distraction of the osteoarthritic CMC1 joint is technically feasible. In this small, prospective pilot study the majority of the results were favourable during short-term follow-up. PMID- 27758128 TI - Fractionated exposure to low doses of ionizing radiation results in accumulation of DNA damage in mouse spleen tissue and activation of apoptosis in a p53/Atm independent manner. AB - PURPOSE: While the effects of high doses of ionizing radiation (IR) are relatively well characterized, the molecular mechanisms underlying cellular responses to prolonged exposure to low doses of radiation remain largely under investigated. MATERIALS AND METHODS: Here, we addressed the DNA damage and apoptotic response in the spleen tissue of C57BL/6 male mice after fractionated exposure to X-rays within the 0.1-0.5 Gy dose range. RESULTS: The response to initial exposure to 0.1 Gy of IR was characterized by increased DNA damage and elevated levels of apoptosis. Subsequent exposures (cumulative doses of 0.2 and 0.3 Gy) resulted in adaptive response-like changes, represented as increased proliferation and apoptotic response. Cumulative doses of 0.4 and 0.5 Gy were characterized by accumulation of DNA damage and reactivation of apoptosis and apoptosis-related proteins. Additionally, spleen cells with irreversible damage caused by radiation can undergo apoptosis via activation of p38, which does not necessarily involve the Atm/p53 pathway. CONCLUSIONS: Fractionated exposure to low doses of X-rays resulted in accumulation of DNA damage in the murine spleen and induction of apoptotic response in p53/Atm-independent manner. Further studies are needed to understand the outcomes and molecular mechanisms underlying cellular responses and early induction of p38 in response to prolonged exposure to IR. PMID- 27758129 TI - Medical student attitudes toward kidney physiology and nephrology: a qualitative study. AB - Interest in nephrology among trainees is waning in the USA. Early perceptions and attitudes to subject matter can be linked to the quality of pre-clinical curricula. We wanted to explore these attitudes in the setting of modern curriculum redesign. We utilized Q methodology to understand first-year medical student attitudes after an innovative kidney physiology curriculum redesign that focuses on blending multiple learning methods. First-year medical students were invited to take a Q sort survey at the conclusion of a kidney physiology course. Students prioritized statements related to their understanding of kidney physiology, learning preferences, preferred course characteristics, perceived clinical relevance of kidney physiology, and interest in nephrology as a career. Factor analysis was performed to identify different student viewpoints. At the conclusion of our modified course, all students (n = 108) were invited to take the survey and 44 (41%) Q sorts were returned. Two dominant viewpoints were defined according to interest in nephrology. The Potentials are students who understand kidney physiology, perceive kidney physiology as clinically relevant, attend class sessions, utilize videos, and are willing to shadow a nephrologist. The Uninterested are students who are less satisfied with their kidney physiology knowledge, prefer to study alone with a textbook, avoid lectures, and are not interested in learning about nephrology. In an updated renal physiology course, students that use multiple learning methods also have favorable attitudes toward learning kidney physiology. Thus, modern curriculum changes that accommodate a variety of learning styles may promote positive attitudes toward nephrology. PMID- 27758130 TI - Community-based study on elderly CKD subjects and the associated risk factors. AB - OBJECTIVE: To investigate the prevalence and risk factors for chronic kidney disease (CKD) among community elderly population in Shanghai, China, in order to provide early diagnosis and treatment of CKD, and improve the quality of life for elderly people. METHODS: In all, 24,886 residents (>=65 years old) were selected from community population in Changning District of Shanghai, China in 2014. They were interviewed and tested for reduced renal function estimated GFR by CKD-EPI equation. The associations among demographic characteristics, healthy characteristics (e.g., cardiovascular disease and hypertension), and indicators of kidney damage were examined. RESULTS: Approximately, 16.4% of the participants were CKD. The average of them was 74.9 +/- 7.0 years old. Females had a significantly higher prevalence of CKD than males (17.6% vs. 14.9%). CKD patients were present in higher prevalence of female, hyperuricemia (29.6% vs. 18.7%), hypertension (45.1% vs. 40.3%), and cardiovascular disease (23.2% vs. 18.7%) than that of non-CKD population. CKD patients were present in lower prevalence of drinking than that of non-CKD population. The prevalence of CKD in female is 2.002 times than that of male. The prevalence of CKD increased 1.048 times with the age of each increase in 1 year old. The risk factors for CKD are age, female, hyperuricemia, cardiovascular disease, hypertension, hypercholesterolemia, and smoking. CONCLUSIONS: The prevalence of CKD is high in the elderly population than that of adult CKD in Shanghai. The most risk factors for elderly CKD patients are similar to the adult population. But hypercholesterolemia as a risk fact of elderly CKD is different from adult CKD. PMID- 27758131 TI - Assessment of Nutritional Status of Iodine Through Urinary Iodine Screening Among Local Children and Adolescents After the Fukushima Daiichi Nuclear Power Plant Accident. AB - BACKGROUND: Iodine deficiency is an important modifier of the risk of thyroid cancer following irradiation. However, little information is available on the prevalence of iodine deficiency in Fukushima and its surroundings after the Fukushima Daiichi nuclear power plant accident that occurred in March 2011. METHODS: In order to assess urinary iodine concentrations (UIC) and the prevalence of iodine deficiency and to elucidate any associations between demographic characteristics and UIC levels among children and adolescents aged <=18 years at the time of the accident in Fukushima Prefecture and its surroundings, the data on voluntary UIC testing conducted by Hirata Central Hospital, Fukushima, were evaluated. RESULTS: A total of 4410 children and adolescents with a median age of 10 years at examination underwent UIC testing between October 2012 and October 2015. Calculated for all the participants, the median UIC level was 204 MUg/L (range 25-21,100 MUg/L). There were 133 (3.0%), 732 (16.6%), and 1472 (33.4%) participants with UIC levels of <50, <100, or >=300 MUg/L, respectively. Based on the World Health Organization criteria for nutritional iodine status, no participants were severely iodine deficient (<20 MUg/L), but 16.6% of the population were mildly (50-100 MUg/L) or moderately (20 50 MUg/L) iodine deficient. While no significant difference in UIC was noted between those who did and did not increase dietary iodine intake after the accident (p = 0.93), there were significant differences by year (p < 0.01), school level (p < 0.001), and residential area at the time of the accident (p < 0.001). CONCLUSIONS: This study demonstrates that the children and adolescents examined had a sufficient amount of iodine during the period 1.5-4.5 years after the nuclear accident. In addition to the differences in the scale and the countermeasures undertaken between the Fukushima and Chernobyl accidents, differences in dietary iodine intake might have played an additional role in resulting in the reportedly different radiation doses to the thyroid between the two nuclear accidents. PMID- 27758132 TI - A Novel Thyroid Hormone Receptor Beta Gene Mutation (G251V) in a Thai Patient with Resistance to Thyroid Hormone Coexisting with Pituitary Incidentaloma. AB - A patient is reported with resistance to thyroid hormone beta caused by a novel THRB gene mutation and coexisting pituitary microadenoma. A 41-year-old Thai woman presented with elevated serum thyroid hormone levels and non-suppressed thyrotropin (TSH). Magnetic resonance imaging showed a 4 mm * 2 mm pituitary adenoma. Five of her relatives had similar thyroid tests abnormalities, but a sister had Graves' disease. Thyroperoxidase and thyroglobulin antibodies were positive in all affected family members, except for the proband's 4.5-year-old niece. Lack of thyrotoxic symptoms and TSH suppression by triiodothyronine indicated incidentaloma rather than a TSH-secreting pituitary adenoma. Genetic analysis revealed a THRB gene mutation (c.1037G>T), resulting in p.G251V. PMID- 27758134 TI - Quantification of Confocal Images Using LabVIEW for Tissue Engineering Applications. AB - Quantifying confocal images to enable location of specific proteins of interest in three-dimensional (3D) is important for many tissue engineering (TE) applications. Quantification of protein localization is essential for evaluation of specific scaffold constructs for cell growth and differentiation for application in TE and tissue regeneration strategies. Although obtaining information regarding protein expression levels is important, the location of proteins within cells grown on scaffolds is often the key to evaluating scaffold efficacy. Functional epithelial cell monolayers must be organized with apicobasal polarity with proteins specifically localized to the apical or basolateral regions of cells in many organs. In this work, a customized program was developed using the LabVIEW platform to quantify protein positions in Z-stacks of confocal images of epithelial cell monolayers. The program's functionality is demonstrated through salivary gland TE, since functional salivary epithelial cells must correctly orient many proteins on the apical and basolateral membranes. Bio LabVIEW Image Matrix Evaluation (Bio-LIME) takes 3D information collected from confocal Z-stack images and processes the fluorescence at each pixel to determine cell heights, nuclei heights, nuclei widths, protein localization, and cell count. As a demonstration of its utility, Bio-LIME was used to quantify the 3D location of the Zonula occludens-1 protein contained within tight junctions and its change in 3D position in response to chemical modification of the scaffold with laminin. Additionally, Bio-LIME was used to demonstrate that there is no advantage of sub-100 nm poly lactic-co-glycolic acid nanofibers over 250 nm fibers for epithelial apicobasal polarization. Bio-LIME will be broadly applicable for quantification of proteins in 3D that are grown in many different contexts. PMID- 27758133 TI - Combinations of Osmolytes, Including Monosaccharides, Disaccharides, and Sugar Alcohols Act in Concert During Cryopreservation to Improve Mesenchymal Stromal Cell Survival. AB - There is demand for non-dimethyl sulfoxide (DMSO) cryoprotective agents that maintain cell viability without causing poor postthaw function or systemic toxicity. The focus of this investigation involves expanding our understanding of multicomponent osmolyte solutions and their ability to preserve cell viability during freezing. Controlled cooling rate freezing, Raman microscopy, and differential scanning calorimetry (DSC) were utilized to evaluate the differences in recovery and ice crystal formation behavior for solutions containing multiple cryoprotectants, including sugars, sugar alcohols, and small molecule additives. Postthaw recovery of mesenchymal stem cells (MSCs) in solutions containing multiple osmolytes have been shown to be comparable or better than that of MSCs frozen in 10% DMSO at 1 degrees C/min when the solution composition is optimized. Maximum postthaw recovery was observed in these multiple osmolyte solutions with incubation times of up to 2 h before freezing. Raman images demonstrate large ice crystal formation in cryopreserved cells incubated for shorter periods of time (~30 min), suggesting that longer permeation times are needed for these solutions. Recovery was dependent upon the concentration of each component in solution, and was not strongly correlated with osmolarity. It is noteworthy that the postthaw recovery varied significantly with the composition of solutions containing the same three components and this variation exhibited an inverted U shape behavior, indicating that there may be a "sweet spot" for different combinations of osmolytes. Raman images of freezing behavior in different solution compositions were consistent with the observed postthaw recovery. Phase change behavior (solidification patterns and glass-forming tendency) did not differ for solutions with similar osmolarity, but differences in postthaw recovery suggest that biological, not physical, methods of protection are at play. Lastly, molecular substitution of glucose (a monosaccharide) for sucrose (a disaccharide) resulted in a significant drop in recovery. Taken together, the information from these studies increases our understanding of non-DMSO multicomponent cryoprotective solutions and the manner by which they enhance postthaw recovery. PMID- 27758136 TI - Competency Education of Primary Care Physicians in Management of Thyroid Disorders: Implementation Experiences from a Pan India Certificate Course. PMID- 27758135 TI - Development and Validation of Noninvasive Magnetic Resonance Relaxometry for the In Vivo Assessment of Tissue-Engineered Graft Oxygenation. AB - Techniques to monitor the oxygen partial pressure (pO2) within implanted tissue engineered grafts (TEGs) are critically necessary for TEG development, but current methods are invasive and inaccurate. In this study, we developed an accurate and noninvasive technique to monitor TEG pO2 utilizing proton (1H) or fluorine (19F) magnetic resonance spectroscopy (MRS) relaxometry. The value of the spin-lattice relaxation rate constant (R1) of some biocompatible compounds is sensitive to dissolved oxygen (and temperature), while insensitive to other external factors. Through this physical mechanism, MRS can measure the pO2 of implanted TEGs. We evaluated six potential MRS pO2 probes and measured their oxygen and temperature sensitivities and their intrinsic R1 values at 16.4 T. Acellular TEGs were constructed by emulsifying porcine plasma with perfluoro-15 crown-5-ether, injecting the emulsion into a macroencapsulation device, and cross linking the plasma with a thrombin solution. A multiparametric calibration equation containing R1, pO2, and temperature was empirically generated from MRS data and validated with fiber optic (FO) probes in vitro. TEGs were then implanted in a dorsal subcutaneous pocket in a murine model and evaluated with MRS up to 29 days postimplantation. R1 measurements from the TEGs were converted to pO2 values using the established calibration equation and these in vivo pO2 measurements were simultaneously validated with FO probes. Additionally, MRS was used to detect increased pO2 within implanted TEGs that received supplemental oxygen delivery. Finally, based on a comparison of our MRS data with previously reported data, ultra-high-field (16.4 T) is shown to have an advantage for measuring hypoxia with 19F MRS. Results from this study show MRS relaxometry to be a precise, accurate, and noninvasive technique to monitor TEG pO2 in vitro and in vivo. PMID- 27758137 TI - Phosphate adsorption to iron sludge from waterworks, ochre precipitation basins and commercial ferrihydrite at ambient freshwater phosphate concentrations. AB - Measures such as storm water ponds, constructed wetlands and buffer strips along streams are used to reduce diffuse phosphorus (P) loading to surface waters. These systems often retain particulate P well, whereas the retention of dissolved P is less efficient and might require addition of P adsorbents. In this study, we screened waterwork ochre sludge (WWS) originating from groundwater treatment and ochre sludge from ochre precipitation basins along streams for their applicability as P adsorbents at ambient P concentrations. We compared with a commercial ferric hydroxide (CFH 12TM) for which adsorption properties is well described. The adsorption capacity of 9 products was measured over 24 h at different P concentrations (5-2000 ug L-1), a range that covers Danish drainage water and stormwater. WWS desorbed phosphate at concentrations below 50-200 ug P L-1 and should only be considered for use in systems with a constantly high load of dissolved P. High affinity combined with little or no desorption characterized the commercial product and the ochre sludge from the precipitation basins, rendering these useful for treating drainage water and storm water. The study underlines that waste products may act as potentially effective P adsorbers at environmentally relevant P levels. PMID- 27758138 TI - Identification of Specific Long Non-Coding RNA Expression: Profile and Analysis of Association with Clinicopathologic Characteristics and BRAF Mutation in Papillary Thyroid Cancer. AB - BACKGROUND: In recent years, long non-coding RNAs (lncRNAs) have been shown to play a critical regulatory role in cancer biology. However, the contribution of lncRNAs to papillary thyroid cancer (PTC) remains largely unknown. METHODS: RNA sequencing and quantitative reverse transcription polymerase chain reaction were used to detect and verify changes to the transcriptome profile in 12 PTC tissues compared to paired normal adjacent tissues. The statistical correlation between differentially expressed lncRNAs and clinicopathologic characteristics was analyzed, and potential lncRNA functions were predicted by examining annotations for the co-expressed mRNAs. Furthermore, the specific subgroup patterns of the PTC transcriptome remodeled by BRAF mutations were also analyzed. RESULTS: A total of 188 lncRNAs and 505 mRNAs were differentially expressed in 50% or more of the PTC tissues (fold change >2; p < 0.05) as assessed by RNA-sequencing compared with paired normal adjacent tissues. Forty-seven lncRNAs and 39 mRNAs were verified in 31 pairs of PTC specimens using quantitative reverse transcription polymerase chain reaction, and the results were consistent with the RNA sequencing data. The lncRNAs NONHSAT076747 and NONHSAT122730 were associated with lymph node metastasis, and NONHSAG051968 expression was negatively correlated with tumor size. A co-expression network between differentially expressed lncRNAs and protein-coding RNAs was constructed and analyzed, and functional analysis suggested that the differentially expressed genes mainly participate in ECM-receptor interactions and the focal adhesion pathway. Furthermore, a specific PTC transcriptome subtype pattern stratified by BRAF mutation was also uncovered. The p53 signaling pathway was the most highly enriched pathway among the BRAF mutation-related genes. CONCLUSIONS: This study reveals specific changes to the lncRNA profile associated with PTC, and provides new insight into its pathogenesis. The PTC-associated lncRNAs NONHSAG051968, NONHSAT076747, and NONHSAT122730 might be potential diagnostic and therapeutic targets for PTC patients, and lncRNAs with subtype-specific expression stratified by BRAF mutation might be significant in individual molecular subtypes. PMID- 27758139 TI - Bilateral psoas abscess caused by Janibacter terrae, an unusual condition and organism resulting in laboratory and management conundrums. AB - Psoas abscess is commonly regarded as an unusual cause for back pains and usually associated with significant risk factors or co-morbidities. We describe the clinical presentation and findings of a young male Caucasian with bilateral psoas abscesses caused by an unusual organism, Janibacter terrae (an environmental organism) not previously described in literature and the challenges faced in managing this infection. There are very few case reports of this organism causing opportunistic infections, all reported bacteraemia mainly in patients with significant co-morbidities. This case highlights the importance of psoas abscess as a differential diagnosis in patients presenting with back pain and the potential for this organism to cause abscesses in healthy individuals which was difficult to identify using conventional laboratory methods. Management of this infection was challenging and there is limited experience with antimicrobial treatment for this organism. PMID- 27758140 TI - Association of lipoprotein subfractions with endothelial function and arterial stiffness in acute ischemic stroke. AB - Hypercholesterolemia represents a risk factor for the development of atherosclerosis. Lipoprotein research has recently been focused on the phenomenon of atherogenic and non-atherogenic lipoproteins. The aim of this study was to explore the association of lipoprotein subfractions with a measure for endothelial function (represented by reactive hyperemia index [RHI]) and arterial stiffness (represented by augmentation index [AI]) in patients with acute ischemic stroke. We enrolled 51 patients with acute ischemic stroke. Blood samples were obtained within 24 h after the stroke onset in a fasting condition. Electrophoresis method on polyacrylamide gel was used for the analysis of plasma lipoproteins. RHI and AI was measured by peripheral arterial tonometry (EndoPAT2000 device). We failed to find any significant correlation between RHI and baseline characteristics of the population. Significant correlation was found between AI and age, hypertension, low density lipoprotein cholesterol (LDL) 1, LDL 3-7, score for anti-atherogenic risk and atherogenic profile. Age (beta = .362, p = .006) and LDL1 (beta = -0.283, p = .031) were the only independent variables significantly associated with AI in regression analysis. Significantly higher AI was found in an atherogenic lipoprotein profile compared to a non atherogenic profile population (median 25% vs. median 11.5%, p = .043). In conclusion, our results suggest significant inverse correlation between levels of LDL 1 subfraction and measures of AI in patients with acute ischemic stroke. Significantly higher values of AI were observed in the population with an atherogenic lipoprotein profile. PMID- 27758141 TI - First episode of acute low back pain - an exploratory cluster analysis approach for early detection of unfavorable recovery. AB - PURPOSE: To identify recovery patterns in patients with a first episode of acute low back pain (LBP) and to define risk factors for unfavorable outcome. METHODS: One hundred and eight patients (55 male, 53 female; mean age = 40.8, SD 14.2 years) rated pain (NRS) and disability [Oswestry Disability Index (ODI)] before the first treatment and 1 week, 1, 3, 6, and 12 months later. Hierarchical cluster analysis identified recovery patterns based on NRS data. Clusters were compared for age, NRS and ODI at baseline, pain reduction in the first week, gender, radicular signs and traumatic onset using one-way ANOVA (post hoc Bonferroni) and chi2 tests. RESULTS: The cluster analysis revealed four clusters: moderate baseline pain/fast recovery; high baseline pain/fast recovery; high baseline pain/persistent mild pain; high baseline pain/persistent high pain. These clusters differed in baseline NRS [F(3,104) = 39.61, p < 0.001], baseline ODI [F(3,104) = 12.17, p < 0.001], pain reduction in the first week [F(3,104) = 11.51, p < 0.001] and in radicular signs [chi2(3) = 9.20, p = 0.027]. CONCLUSIONS: These results suggest that an initial and regularly repeated assessment of pain intensity and functional disability is important. Initial pain intensity does not seem to be a prognostic factor per se, as it did not negatively affect recovery provided that it decreased early in treatment. Implications for Rehabilitation Prediction of outcome is particularly important in patients with a first episode of acute LBP as one third did not completely recover. Pain intensity and functional disability should be initially assessed and regularly repeated in the first phase of treatment. High initial pain intensity and disability combined with small pain reduction during the first week might predict unfavorable outcome and require adequate treatment. PMID- 27758142 TI - Evaluation of the PROPEL(r) mini sinus implant for the treatment of frontal sinus disease. AB - INTRODUCTION: Propel and Propel Mini sinus implants are mometasone furoate-coated bioabsorbable stents used as an adjunct in the management of chronic rhinosinusitis after endoscopic sinus surgery. The original sinus implant was deployed in the ethmoid sinuses to provide medialization of the middle turbinate, decrease scarring and mucosal adhesions, limit polyp regrowth, and reduce mucosal inflammation. A structurally smaller version of the Propel, the Propel Mini, was developed and now has been approved for endoscopic placement in the frontal sinuses. Areas covered: This evaluation will focus on the technical details of the Propel mini, previous studies documenting Propel's success in the ethmoid sinuses, and the safety and efficacy of the Propel mini implants in frontal sinus surgery. Expert opinion: Devices such as the Propel and Propel Mini stents are the beginning of a trend towards medication-coated bioabsorbable implants that can be used for sinonasal disease to minimize complications or possible side effects of surgical treatment by an increase of topical drug delivery locally. PMID- 27758143 TI - Pharmacogenomics of genes involved in antifolate drug response and toxicity in osteosarcoma. AB - INTRODUCTION: Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities. Here, we summarize the pharmacogenomic information reported so far for genes involved in antifolate metabolism and transport and in MTX-related toxicity in HGOS patients. Expert opinion: Identification and validation of genetic biomarkers that significantly impact clinical antifolate treatment response and related toxicity may provide the basis for a future treatment modulation based on the pharmacogenetic and pharmacogenomic features of HGOS patients. PMID- 27758144 TI - Genetically Engineered Macrophages: A Potential Platform for Cancer Immunotherapy. AB - In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. A novel genetically engineered macrophage-based platform has been developed with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive antitumor immune responses. A newly described lentiviral expression system was validated for the generation of transduced monocytes and monocyte-derived macrophages, and transgene expression was shown to be stable over the course of weeks to months, both in vitro and in a mouse xenograft model of GBM. Furthermore, the genetically engineered macrophages (GEMs) neither caused morbidity in animals nor contributed to accelerated tumor growth. The versatility of GEMs is also highlighted by showing that they can be engineered to secrete proteins that either reduce immune suppression, such as the soluble transforming growth factor beta receptor II, or promote immune cell activation, by expressing interleukin 21. There is also the potential to prevent GEM-mediated immune suppression by using the CRISPR system to knock out genes responsible for dysfunction of cytotoxic cells, including interleukin 10 and programmed death-ligand 1. Together, these results suggest that GEMs are an ideal cell type for transforming the tumor microenvironment and enhancing antitumor immunity. Importantly, it is anticipated that these findings will have broad applicability to other types of tumors with microenvironments that currently preclude successful immunotherapeutic approaches. PMID- 27758145 TI - Defining predictive factors of severity and indications for extracorporeal toxin removal in lithium poisoning: not an easy objective! PMID- 27758146 TI - Targeting mitochondrial dysfunction in the treatment of heart failure. AB - INTRODUCTION: Heart failure (HF) has reached epidemic proportions worldwide. Despite the availability of drugs that reduce mortality and afford good symptom relief, HF continues to exact a considerable clinical and economic burden. Current HF therapies elicit benefit by reducing cardiac workload by lowering heart rate and loading conditions, thereby reducing myocardial energy demands. Areas covered: Recent recognition that the failing heart is 'energy deprived' and its primary energy source, the mitochondria, is dysfunctional, has focused attention on mitochondria as a worthy therapeutic target. In HF, mitochondrial dysfunction leads to reduced adenosine triphosphate (ATP) synthesis and excessive formation of damaging reactive oxygen species (ROS), a combination the failing heart can ill afford. Expert commentary: Correcting mitochondrial dysfunction can help forge a new therapeutic approach based on readily available energy that can meet increasing cardiac demands. This paradigm shift, once implemented successfully, is likely to elicit better overall cardiac function, better quality of life, and improved survival for patients with HF. PMID- 27758147 TI - Same-Day Discharge for Patients Undergoing Robot-Assisted Laparoscopic Radical Prostatectomy Is Safe and Feasible: Results of a Pilot Study. AB - INTRODUCTION: With healthcare reform, cost and patient satisfaction will directly affect hospital reimbursement. We present data on same-day discharge (SDD) for patients who underwent robot-assisted laparoscopic radical prostatectomy (RALP). METHODS: Patient data were gathered in an IRB-approved database. In April 2015, the surgeon (S.J.) began SDD. The SDD protocol for RALP includes multimodal anesthesia/analgesia and extended recovery. Interim analysis revealed that government insurance (CMS) refused hospital reimbursement for SDD. As of that time, only patients with commercial insurance were offered SDD. The demographic and peri-operative data were compared between the two cohorts (Group 1, SDD; Group 2, Admitted patients) by using Mann-Whitney U, chi-squared, or fisher exact tests, where appropriate. RESULTS: During the study period, 21 patients had undergone RALP. Eleven of 21 patients were offered SDS, and nine (81.8%) were discharged. Both those who elected to stay were successfully discharged on the next day. Patient age, body mass index (BMI), prostate-specific antigen, operative time, estimated blood loss (EBL), prostate weight, distance from home to hospital, margin status, marital status, and household income were not statistically significantly different between the two groups. The same is true between patients who underwent RALP both before and after initiation of the SDD protocol with the exception of EBL (greater in the SDD group). There have been no reported complications or readmissions for any of the patients in Group 1. CONCLUSION: Our novel pilot study reveals that SDS is safe and feasible. We are currently conducting a further evaluation of patient satisfaction. Future research is needed to verify these conclusions. PMID- 27758148 TI - Ceftazidime-avibactam for the treatment of complicated intra-abdominal infections. AB - INTRODUCTION: The treatment of complicated intra-abdominal infections (cIAI) is increasingly challenging due to increased resistance of Gram-negative organisms. These multidrug resistant organisms lead to an increase in morbidity and mortality. This has led to renewed interest in use of older beta-lactam antibiotics in combination with newer beta-lactamase inhibitors. Ceftazidime avibactam is one of the newest such combination antibiotics, which has been released for treatment of complicated intra-abdominal infections in combination with metronidazole. Areas covered: In this drug evaluation manuscript cIAI along with the chemistry, pharmacodynamics, pharmacokinetics, metabolism and clinical study results of ceftazidime-avibactam are reviewed. Expert opinion: The role of ceftazidime-avibactam in combination with metronidazole in the treatment of cIAI is still to be defined. Patients with cIAI known to be infected with Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae would be clear candidates for treatment with this agent, as would patients infected with more common types of extended-spectrum beta-lactamase producing Gram-negative pathogens if a carbapenem alternative were desired. At present, it is difficult to establish a clear group of patients with cIAI for whom initial empiric therapy with this agent would be warranted. PMID- 27758149 TI - The Burn Model Systems outcome measures: a content analysis using the International Classification of Functioning, Disability, and Health. AB - BACKGROUND: The National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) Burn Injury Model Systems (BMS) is a nationwide database that uses patient-reported outcome measures to collect data. Though the outcome measures demonstrate good psychometric properties, the question remains whether or not these measures collect data that encompass the entire experience of burn patients over time. METHODS: Each meaningful concept included in the BMS assessments was linked to the International Classification of Functioning, Disability and Health (ICF) in order to classify and describe the content of each measure. The linking was completed by two experienced coders. The perspective of each assessment was also determined. RESULTS: The body function component was most frequently addressed overall followed by the activities and participation component. The component body structures and environmental factors are not extensively covered in the BMS assessments. ICF chapter and category distribution varied greatly between assessments. The assessments were of the health status perspective. CONCLUSION: This study suggests a need to revisit the item composition of the BMS assessments to more evenly distribute ICF topics and subtopics that are pertinent to burn injury which will ensure a broader but more precise understanding of burn injury recovery. Implications for Rehabilitation A better understanding of the data collected through the Burn Model Systems (BMS) project may contribute to improve data collection tools and ultimately lead to clinical practice innovations and improvements. Clinicians interested in using BMS data for research purposes can better understand what topics are included and excluded in the collection and what perspectives are addressed. This study highlights the need for burn clinicians around the world to lend their expertise to the WHO for the development of a much needed burn injury International Classification of Functioning, Disability and Health Core Set. PMID- 27758150 TI - Access to publicly funded outpatient physiotherapy services in Quebec: waiting lists and management strategies. AB - PURPOSE: Problems with access to outpatient physiotherapy services have been reported in publicly funded healthcare systems worldwide. A few studies have reported management strategies aimed at reducing extensive waiting lists, but their association with waiting times is not fully understood. The purpose of this study was to document access to public outpatient physiotherapy services for persons with musculoskeletal disorders in hospitals and explore organizational factors associated with waiting time. METHODS: We surveyed outpatient physiotherapy services in publicly funded hospitals in the province of Quebec (Canada). RESULTS: A total of 97 sites responded (99%) to the survey. The median waiting time was more than six months for 41% of outpatient physiotherapy services. The waiting time management strategies most frequently used were attendance and cancelation policies (99.0%) and referral prioritization (95.9%). Based on multivariate analyses, the use of a prioritization process with an initial evaluation and intervention was associated with shorter waiting times (p = 0.008). CONCLUSIONS: Our findings provide evidence that a large number of persons wait a long time for publicly funded physiotherapy services in Quebec. Based on our results, implementation of a prioritization process with an initial evaluation and intervention could help improve timely access to outpatient physiotherapy services. Implications for Rehabilitation Access to publicly funded outpatient physiotherapy services is limited by long waiting times in a great proportion of Quebec's hospitals. The use of a specific prioritization process that combines an evaluation and an intervention could possibly help improve timely access to services. Policy-makers, managers, and other stakeholders should work together to address the issue of limited access to publicly funded outpatient physiotherapy services. PMID- 27758151 TI - A Study of Occupational Radiation Dosimetry During Fluoroscopically Guided Simulated Urological Surgery in the Lithotomy Position. AB - OBJECTIVE: To quantify through environmental audit the radiation dose that urologists receive during surgery in the lithotomy position, and to quantify the dose reduction achieved by altering exposure techniques and personal protective equipment use. MATERIALS AND METHODS: Simulated surgery in the lithotomy position using an anthropomorphic phantom as a patient and a SimMan(r) mannequin as the surgeon. Pulsed fluoroscopy, focus-to-skin distance (FSD), collimation, and addition of a lead shield at the table end were individually and collectively introduced after a control study. Scattered X-ray dose rates to the simulated surgeon's eye, thyroid, trunk, external genitalia, and leg were measured with each of the technique adjustments. The absorbed dose in air at the phantom skin was measured throughout. Results were compared to discover surgeon dose rates with technique alteration. RESULTS: Increasing FSD leads to a rise in surgeon eye dose, and table end lead protection increases the patient skin dose. Use of all the dose-reduction techniques together reduces the dose to the patient, and a surgeon's trunk dose is decreased by 95%, external genitalia dose by 99%, and leg dose by 97%. Sitting to perform fluoroscopically guided surgery in the lithotomy position increases surgeon dose by a median value of 17%, with the external genitalia dose increased by 78% compared with the standing position. CONCLUSIONS: This study describes effective methods of dose reduction that are easy to instigate. The resulting reduction in radiation dose during urology procedures meets the requirements of international guidelines and legislation. This change in practice improves patient care and reduces risk to urologists from occupational exposure to radiation. By combining all of the dose-reduction techniques, urologists should never reach the threshold for deterministic radiation effects to their eyes during their career, and they will have a significantly lower chance of stochastic risks such as cancer. PMID- 27758152 TI - Fitting prelingually deafened adult cochlear implant users based on electrode discrimination performance. AB - OBJECTIVE: This study investigated the hypotheses that (1) prelingually deafened CI users do not have perfect electrode discrimination ability and (2) the deactivation of non-discriminable electrodes can improve auditory performance. DESIGN: Electrode discrimination difference limens were determined for all electrodes of the array. The subjects' basic map was subsequently compared to an experimental map, which contained only discriminable electrodes, with respect to speech understanding in quiet and in noise, listening effort, spectral ripple discrimination and subjective appreciation. STUDY SAMPLE: Subjects were six prelingually deafened, late implanted adults using the Nucleus cochlear implant. RESULTS: Electrode discrimination difference limens across all subjects and electrodes ranged from 0.5 to 7.125, with significantly larger limens for basal electrodes. No significant differences were found between the basic map and the experimental map on auditory tests. Subjective appreciation was found to be significantly poorer for the experimental map. CONCLUSIONS: Prelingually deafened CI users were unable to discriminate between all adjacent electrodes. There was no difference in auditory performance between the basic and experimental map. Potential factors contributing to the absence of improvement with the experimental map include the reduced number of maxima, incomplete adaptation to the new frequency allocation, and the mainly basal location of deactivated electrodes. PMID- 27758154 TI - Reducing sedentary behaviour after stroke: perspectives of ambulatory individuals with stroke. AB - PURPOSE: Understanding the determinants of sedentary behaviour (sitting or lying with low energy expenditure) in stroke survivors can enhance the development of successful behaviour change strategies. This qualitative study explored the perceptions of stroke survivors about sedentary behaviour and ways in which it can be changed. METHODS: An interpretative qualitative inquiry was used with thematic analysis of interview data. Interviews were conducted using a semi structured guide with 13 stroke survivors. Interview transcripts were analysed using thematic analysis. Self-reported sedentary time was assessed during interviews. RESULTS: Four main themes emerged from the data: meaning of sedentary behaviour, reasons for sedentary behaviour, barriers and facilitators to reducing sedentary behaviour, and strategies to sit less and move more. Only 6 participants knew about sedentary behaviour, and 2 were aware of the associated health risks. Participants encountered barriers in their daily lives that affect engagement in activity including motor impairments, fatigue, cognitive problems, and lack of motivation. Using wearable technologies and action planning to reduce sedentary behaviour hold promise as behaviour change strategies. CONCLUSIONS: There is limited awareness of health risks of sedentary behaviour among stroke survivors. Strategies involving self-monitoring and movement throughout the day are potential ways to reduce sedentary behaviour. Implications for Rehabilitation Reducing sedentary behaviour in ambulatory stroke survivors is dependent on a number of modifiable determinants. Planning regular interruptions in sedentary time, such as standing or walking frequently throughout waking hours, during television commercial breaks or while using the phone are some potential strategies for reducing sedentary behaviour in stroke survivors. Availability of social and professional support and self-monitoring using wearable technologies that provide real-time feedback might result in increased motivation to sit less and move more. Using alarms and devices that provide cues to action by reminding participants to sit less and move more were perceived as important. PMID- 27758153 TI - Development and evaluation of a mixed gender, multi-talker matrix sentence test in Australian English. AB - OBJECTIVE: To develop, in Australian English, the first mixed-gender, multi talker matrix sentence test. DESIGN: Speech material consisted of a 50-word base matrix whose elements can be combined to form sentences of identical syntax but unpredictable content. Ten voices (five female and five male) were recorded for editing and preliminary level equalization. Elements were presented as single talker sentences-in-noise during two perceptual tests: an optimization phase that provided the basis for further level correction, and an evaluation phase that perceptually validated those changes. STUDY SAMPLE: Ten listeners participated in the optimization phase; these and an additional 32 naive listeners completed the evaluation test. All were fluent in English and all but one had lived in Australia for >2 years. RESULTS: Optimization reduced the standard deviation (SD) and speech reception threshold (SRT) range across all speech material (grand mean SRT = -10.6 dB signal-to-noise ratio, median = -10.8, SD =1.4, range =13.7, slope =19.3%/dB), yielding data consistent with cross-validated matrix tests in other languages. Intelligibility differences between experienced and naive listeners were minimal. CONCLUSIONS: The Australian matrix corpus provides a robust set of test materials suitable for both clinical assessment and research into the dynamics of active listening in multi-talker environments. PMID- 27758155 TI - An Investigation of Topics and Trends of Tracheal Replacement Studies Using Co Occurrence Analysis. AB - This study evaluated tracheal regeneration studies using scientometric and co occurrence analysis to identify the most important topics and assess their trends over time. To provide the adequate search options, PubMed, Scopus, and Web of Science (WOS) were used to cover various categories such as keywords, countries, organizations, and authors. Search results were obtained by employing Bibexcel. Co-occurrence analysis was applied to evaluate the publications. Finally, scientific maps, author's network, and country contributions were depicted using VOSviewer and NetDraw. Furthermore, the first 25 countries and 130 of the most productive authors were determined. Regarding the trend analysis, 10 co occurrence terms out of highly frequent words were examined at 5-year intervals. Our findings indicated that the field of trachea regeneration has tested different approaches over the time. In total, 65 countries have contributed to scientific progress both in experimental and clinical fields. Special keywords such as tissue engineering and different types of stem cells have been increasingly used since 1995. Studies have addressed topics such as angiogenesis, decellularization methods, extracellular matrix, and mechanical properties since 2011. These findings will offer evidence-based information about the current status and trends of tracheal replacement research topics over time, as well as countries' contributions. PMID- 27758156 TI - Endochondral Priming: A Developmental Engineering Strategy for Bone Tissue Regeneration. AB - Tissue engineering and regenerative medicine have significant potential to treat bone pathologies by exploiting the capacity for bone progenitors to grow and produce tissue constituents under specific biochemical and physical conditions. However, conventional tissue engineering approaches, which combine stem cells with biomaterial scaffolds, are limited as the constructs often degrade, due to a lack of vascularization, and lack the mechanical integrity to fulfill load bearing functions, and as such are not yet widely used for clinical treatment of large bone defects. Recent studies have proposed that in vitro tissue engineering approaches should strive to simulate in vivo bone developmental processes and, thereby, imitate natural factors governing cell differentiation and matrix production, following the paradigm recently defined as "developmental engineering." Although developmental engineering strategies have been recently developed that mimic specific aspects of the endochondral ossification bone formation process, these findings are not widely understood. Moreover, a critical comparison of these approaches to standard biomaterial-based bone tissue engineering has not yet been undertaken. For that reason, this article presents noteworthy experimental findings from researchers focusing on developing an endochondral-based developmental engineering strategy for bone tissue regeneration. These studies have established that in vitro approaches, which mimic certain aspects of the endochondral ossification process, namely the formation of the cartilage template and the vascularization of the cartilage template, can promote mineralization and vascularization to a certain extent both in vitro and in vivo. Finally, this article outlines specific experimental challenges that must be overcome to further exploit the biology of endochondral ossification and provide a tissue engineering construct for clinical treatment of large bone/nonunion defects and obviate the need for bone tissue graft. PMID- 27758157 TI - Clinical significance of different carnitine levels for improving the prognosis of patients undergoing hemodialysis. AB - OBJECTIVE: To investigate plasma-free carnitine (Fc), acylcarnitine (Ac), and total carnitine (Tc) levels in patients undergoing hemodialysis (HD), and to explore their clinical significance. METHODS: A total of 20 subjects were in the normal control group and 133 patients undergoing HD were divided into medicated (received carnitine treatment) and non-medicated groups. The medicated group was further divided into three subgroups according to Fc level: Fc = 80-199, 200-299, and >= 300 MUmol/L. We used non-derivative tandem mass spectrometry to determine carnitine levels, and clinical symptoms such as weakness, hypotension, and muscle cramps were recorded during dialysis. RESULTS: Fc and Tc levels were significantly lower in the non-medicated group than in the control group, whereas Fc, Ac, and Tc levels were higher in the medicated than non-medicated group (p< .05). The medicated group had fewer symptoms during dialysis than the non medicated group such as weakness, hypotension, and muscle cramps (p< .05). An additional comparison showed that the incidence rates of hypotension and muscle cramps in the Fc < 80-199 MUmol/L group were significantly lower than those in the Fc >= 300 MUmol/L medicated and non-medicated groups. CONCLUSIONS: Patients undergoing HD have low carnitine levels. l-Carnitine can effectively increase Fc concentration and improve clinical symptoms; however, only the proper Fc range can reduce complications caused by dialysis. Thus, this range needs to be determined. PMID- 27758158 TI - Concussion-like symptom reporting in non-concussed adolescent athletes. AB - OBJECTIVE: The primary goals of this study were (1) to report rates of concussion like symptoms in healthy adolescent student athletes assessed using the Sport Concussion Assessment Tool, 3rd edition (SCAT3) at baseline, (2) to examine rates of psychiatric diagnoses in this population, and (3) to evaluate effects of baseline symptoms on SCAT3 cognitive and balance performance. METHODS: 349 adolescent student athletes (245 male) were administered the SCAT3 during pre participation physical examinations. We described the prevalence rate of student athletes meeting criteria for International Classification of Diseases, 10th revision, post-concussional syndrome (ICD-10 PCS) diagnosis at baseline, and evaluated associations between symptom reporting and demographic/medical history factors using chi-square tests. Rates of self-reported psychiatric diagnosis were compared to general population estimates with one-sample binomial tests. We also compared SCAT3 cognitive and balance performance between adolescents with and without baseline ICD-10 PCS symptoms. RESULTS: Overall, 20.3% of participants met ICD-10 PCS criteria at baseline. Rates were similar across sexes and age groups. We found no statistical association with medical history factors. The proportion of student athletes reporting a history of psychiatric diagnosis (5.2%) was significantly lower than general population estimates (14.0%; p < .001), and this effect was consistent across sexes and age groups. SCAT3 cognitive and balance performance did not differ based on baseline symptom reporting. CONCLUSIONS: Healthy adolescent student athletes frequently report concussion-like symptoms at baseline. Clinicians should factor pre-injury symptomatology and medical history into concussion management when determining symptom etiology throughout the course of recovery. PMID- 27758160 TI - The visual number world: A dynamic approach to study the mathematical mind. AB - In the domain of language research, the simultaneous presentation of a visual scene and its auditory description (i.e., the visual world paradigm) has been used to reveal the timing of mental mechanisms. Here we apply this rationale to the domain of numerical cognition in order to explore the differences between fast and slow arithmetic performance, and to further study the role of spatial numerical associations during mental arithmetic. We presented 30 healthy adults simultaneously with visual displays containing four numbers and with auditory addition and subtraction problems. Analysis of eye movements revealed that participants look spontaneously at the numbers they currently process (operands, solution). Faster performance was characterized by shorter latencies prior to fixating the relevant numbers and fewer revisits to the first operand while computing the solution. These signatures of superior task performance were more pronounced for addition and visual numbers arranged in ascending order, and for subtraction and numbers arranged in descending order (compared to the opposite pairings). Our results show that the "visual number world"-paradigm provides on line access to the mind during mental arithmetic, is able to capture variability in arithmetic performance, and is sensitive to visual layout manipulations that are otherwise not reflected in response time measurements. PMID- 27758159 TI - Comparison of Human Hematopoietic Reconstitution in Different Strains of Immunodeficient Mice. AB - Immunodeficient mice play a critical role in hematology research as in vivo models of hematopoiesis and immunology. Multiple strains have been developed, but hematopoietic stem cell engraftment and immune reconstitution have not been methodically compared among them. Four mouse strains were transplanted with human fetal bone marrow or adult peripheral blood CD34+ cells: NSG, NSG-3GS, hSCF-Tg NSG, and hSIRPalpha-DKO. Hematopoietic engraftment in the bone marrow, blood, spleen, and liver was evaluated by flow cytometry 12 weeks after transplant. The highest levels of human engraftment were observed in the liver, spleen, and bone marrow, whereas peripheral blood cell chimerism was notably less. The highest levels of tissue engraftment were in hSCF-Tg-NSG mice, but NSG mice exhibited the highest blood leukocyte engraftment. hSCF-Tg-NSG mice also exhibited the highest levels of CD133+CD34++ stem cells. hSIRPalpha-DKO engrafted poorly and exhibited poor breeding. Myelopoiesis was greatest in NSG-3GS mice, followed by hSCF-Tg-NSG and NSG mice, whereas B cell engraftment exhibited the opposite pattern. Engraftment of CD3+ T cells, CD3+CD161+ T cells, and CD3-CD56+ NK cells was greatest in NSG-3GS mice. Mast cell engraftment was highest in hSCF-Tg-NSG mice, but was also elevated in spleen and livers of NSG-3GS mice. Basophils were most abundant in NSG-3GS mice. Overall, hSCF-Tg-NSG mice are the best recipient mice for studies requiring high levels of human hematopoiesis, stem cell engraftment, and an intermediate level of myelopoiesis, whereas NSG and NSG-3GS mice offer select advantages in the engraftment of certain blood cell lineages. PMID- 27758161 TI - Temporal precision and the capacity of auditory-verbal short-term memory. AB - The capacity of serially ordered auditory-verbal short-term memory (AVSTM) is sensitive to the timing of the material to be stored, and both temporal processing and AVSTM capacity are implicated in the development of language. We developed a novel "rehearsal-probe" task to investigate the relationship between temporal precision and the capacity to remember serial order. Participants listened to a sub-span sequence of spoken digits and silently rehearsed the items and their timing during an unfilled retention interval. After an unpredictable delay, a tone prompted report of the item being rehearsed at that moment. An initial experiment showed cyclic distributions of item responses over time, with peaks preserving serial order and broad, overlapping tails. The spread of the response distributions increased with additional memory load and correlated negatively with participants' auditory digit spans. A second study replicated the negative correlation and demonstrated its specificity to AVSTM by controlling for differences in visuo-spatial STM and nonverbal IQ. The results are consistent with the idea that a common resource underpins both the temporal precision and capacity of AVSTM. The rehearsal-probe task may provide a valuable tool for investigating links between temporal processing and AVSTM capacity in the context of speech and language abilities. PMID- 27758162 TI - Rationale and Design of the Registry for Stones of the Kidney and Ureter (ReSKU): A Prospective Observational Registry to Study the Natural History of Urolithiasis Patients. AB - OBJECTIVES: Registry-based clinical research in nephrolithiasis is critical to advancing quality in urinary stone disease management and ultimately reducing stone recurrence. A need exists to develop Health Insurance Portability and Accountability Act (HIPAA)-compliant registries that comprise integrated electronic health record (EHR) data using prospectively defined variables. An EHR based standardized patient database-the Registry for Stones of the Kidney and Ureter (ReSKUTM)-was developed, and herein we describe our implementation outcomes. MATERIALS AND METHODS: Interviews with academic and community endourologists in the United States, Canada, China, and Japan identified demographic, intraoperative, and perioperative variables to populate our registry. Variables were incorporated into a HIPAA-compliant Research Electronic Data Capture database linked to text prompts and registration data within the Epic EHR platform. Specific data collection instruments supporting New patient, Surgery, Postoperative, and Follow-up clinical encounters were created within Epic to facilitate automated data extraction into ReSKU. RESULTS: The number of variables within each instrument includes the following: New patient-60, Surgery 80, Postoperative-64, and Follow-up-64. With manual data entry, the mean times to complete each of the clinic-based instruments were (minutes) as follows: New patient-12.06 +/- 2.30, Postoperative-7.18 +/- 1.02, and Follow-up-8.10 +/- 0.58. These times were significantly reduced with the use of ReSKU structured clinic note templates to the following: New patient-4.09 +/- 1.73, Postoperative-1.41 +/ 0.41, and Follow-up-0.79 +/- 0.38. With automated data extraction from Epic, manual entry is obviated. CONCLUSIONS: ReSKU is a longitudinal prospective nephrolithiasis registry that integrates EHR data, lowering the barriers to performing high quality clinical research and quality outcome assessments in urinary stone disease. PMID- 27758163 TI - Embedded performance validity tests within the Hopkins Verbal Learning Test - Revised and the Brief Visuospatial Memory Test - Revised. AB - OBJECTIVE: Various research studies and neuropsychology practice organizations have reiterated the importance of developing embedded performance validity tests (PVTs) to detect potentially invalid neurocognitive test data. This study investigated whether measures within the Hopkins Verbal Learning Test - Revised (HVLT-R) and the Brief Visuospatial Memory Test - Revised (BVMT-R) could accurately classify individuals who fail two or more PVTs during routine clinical assessment. METHOD: The present sample of 109 United States military veterans (Mean age = 52.4, SD = 13.3), all consisted of clinically referred patients and received a battery of neuropsychological tests. Based on performance validity findings, veterans were assigned to valid (n = 86) or invalid (n = 23) groups. Of the 109 patients in the overall sample, 77 were administered the HLVT-R and 75 were administered the BVMT-R, which were examined for classification accuracy. RESULTS: The HVLT-R Recognition Discrimination Index and the BVMT-R Retention Percentage showed good to adequate discrimination with an area under the curve of .78 and .70, respectively. The HVLT-R Recognition Discrimination Index showed sensitivity of .53 with specificity of .93. The BVMT-R Retention Percentage demonstrated sensitivity of .31 with specificity of .92. CONCLUSIONS: When used in conjunction with other PVTs, these new embedded PVTs may be effective in the detection of invalid test data, although they are not intended for use in patients with dementia. PMID- 27758164 TI - Curcumin counteracts cisplatin-induced nephrotoxicity by preventing renal tubular cell apoptosis. AB - Curcumin has several biological functions particularly antioxidant and anti inflammatory. The aims of this study are determination of the protective effects of curcumin on cisplatin-induced renal tubular cell apoptosis and related pathways in kidney. Eighteen male Wistar albino rats were randomly divided into three groups (n = 6): the control, cisplatin (CP), and cisplatin + curcumin (CP + CUR). Acute renal damage was induced by single dose of cisplatin (7.5 mg/kg) injected by intraperitoneally (i.p). The animals of curcumin-treated group were received daily 200 mg/kg curcumin per os (po), starting from 2 days before the injection of cisplatin to the day of sacrifice. Forty-eight hours after cisplatin injection, samples of cardiac blood and kidneys were harvested from the animals. In this study, the major finding is that curcumin treatment ameliorates the following conditions associated with cisplatin-induced nephrotoxicity: (1) the development of kidney injury (histopathology), (2) inflammatory responses [myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), IL-6, IL-10 levels], (3) the degree of lipid peroxidation [malondialdehyde (MDA) level], (4) renal tubular cell apoptosis (active caspase 3) and expression of related proteins [p53, Fas, and Fas ligand (Fas-L)] by immunohistochemistry, (5) renal dysfunction (serum urea and creatinine). In a conclusion, this study suggests that curcumin has antiapoptotic effect against cisplatin nephrotoxicity, in addition to anti-inflammatory and antioxidant properties. PMID- 27758680 TI - Complement C4A and C4B Gene Copy Number Study in Alzheimer's Disease Patients. AB - BACKGROUND/OBJECTIVES: Increasing evidence suggests the importance of neuroinflammation in the pathogenesis of Alzheimer's disease (AD), which is a complex neurodegenerative disorder. Complement activation occurs in the brain of patients with AD and seems to contribute to an important local inflammatory state. Increased expression of the fourth serum complement component 4 (C4) has been observed in AD patients in many studies. This protein has two isoforms, encoded by two genes: C4A and C4B localized to the HLA class III region. These genes exhibit copy number variations (CNVs) and this different gene copy number can influence C4 protein levels. We focalized our attention on these two genes, determining the distribution of CNVs in AD patients, compared with healthy controls, in order to analyse their possible involvement in AD pathogenesis. METHODS: We investigated 191 AD patients and 300 healthy controls. The C4A and C4B copy numbers were assessed by quantitative PCR (qPCR). RESULTS: The results obtained showed a statistically significant increase in the number of copies for both C4A and C4B in AD patients, compared with healthy controls (p<0,001). CONCLUSION: The presence of high C4A and C4B copy numbers in AD patients could explain the increased C4 protein expression observed in AD patients, thus highlighting a possible role for C4A and C4B CNVs in the risk of developing AD. PMID- 27758681 TI - Deep Brain Stimulation for Alzheimer's Disease. AB - High-frequency deep brain stimulation (DBS) was introduced in the late 1980s for the treatment of movement disorders. This reversible, adjustable, and non ablative therapy has been used to treat more than 100,000 people worldwide. The surgical procedure used to implant the DBS system, as well as the effects of chronic electrical stimulation, have been shown to be safe and effective through many clinical trials. Given the ability to therapeutically modulate the motor circuits of the brain in this manner, clinicians have considered using DBS for other neurodegenerative and neuropsychiatric disorders involving non-motor circuits, including appetite, mood, and cognition. This article highlights several recent studies exploring the feasibility of using DBS to modulate memory, specifically in the context of memory disorders such as Alzheimer disease. PMID- 27758683 TI - Nanocrystal Based Drug Delivery System: Conventional and Current Scenario. AB - BACKGROUND: Most of the chemical substances which emerge out as potential drug candidates (Active Pharmaceutical Ingredients) are either weak acids or weak bases. The poor aqueous solubility of these drug substances is a common concern. Several R&D centers are focused on developing suitable, economic, simpler and more feasible solubility enhancement techniques for increasing the solubility and thereby bioavailability of such drug substances. Nanocrystals are one of the preferred approaches for solubility enhancement in the last few decades. METHODS: Nanocrystal as a solubility enhancement approach is widely explored and discussed by many researchers. Despite being the most simple and feasible technique, nanocrystal formulation has its own limitations. The present review enlightens some novel technologies which can overcome disadvantages of conventionally well established bottom-up and top-down techniques used for nanocrystal formulation. Results/Applications: The present review summarizes and also highlights the correlation between some novel findings like reduction in the melting point of drug and nanocrystal formulation. The review also includes a special section emphasizing on the patents granted in the field of nanocrystals. The review includes more than ten patents focusing on several aspects of nanocrystal formulations as manufacturing methods, formulation components and conventional and novel applications of nanocrystals in new and hybrid forms. Aspects related to advantages of nanocrystals over other formulation approaches, targeting (Active and Passive) through nanocrystal formulations and issues related to nanotoxicity are also reviewed and discussed in the present article. CONCLUSION: The findings, research outcomes and patents related to nanocrystal formulations, reported in the present review confirm the potential of the stated system as a drug delivery tool. The review emphasizes on the urge for further exploration required in the area of nanocrystal system for enhancing its efficiency as a drug delivery and a diagnostic tool. PMID- 27758684 TI - Elucidation of the Chromatographic Enantiomer Elution Order Through Computational Studies. AB - During the last twenty years, the interest towards the development of chiral compound has exponentially been increased. Indeed, the set-up of suitable asymmetric enantioselective synthesis protocols is currently one of the focuses of many pharmaceutical research projects. In this scenario, chiral HPLC separations have gained great importance as well, both for analytical- and preparative-scale applications, the latter devoted to the quantitative isolation of enantiopure compounds. Molecular modelling and quantum chemistry methods can be fruitfully applied to solve chirality related problems especially when enantiomerically pure reference standards are missing. In this framework, with the aim to explain the molecular basis of the enantioselective retention, we performed computational studies to rationalize the enantiomer elution order with both low- and high-molecular weight chiral selectors. Semi-empirical and quantum mechanical computational procedures were successfully applied in the domains of chiral ligand-exchange and chiral ion-exchange chromatography, as well as in studies dealing with the use of polysaccharide-based enantioresolving materials. PMID- 27758685 TI - Congenital Abnormalities: Consequence of Maternal Zika Virus Infection: A Narrative Review. AB - BACKGROUND: Zika virus (ZIKV) is a deadly flavivirus that has spread from Africa to Asia and European countries. The virus is associated with other viruses in the same genus or family, transmitted by the same mosquito species with known history of fatality. A sudden increase in the rate of infection from ZIKV has made it a global health concern, which necessitates close symptom monitoring, enhancing treatment options, and vaccine production. OBJECTIVES: This paper reviewed current reports on birth defects associated with ZIKV, mode of transmission, body fluids containing the virus, diagnosis, possible preventive measures or treatments, and vaccine development. METHODS: Google scholar was used as the major search engine for research and review articles, up to July, 2016. Search terms such as "ZIKV", "ZIKV infection", "ZIKV serotypes", "treatment of ZIKV infection", "co-infection with zika virus", "flavivirus", "microcephaly and zika", "birth defects and Zika", as well as "ZIKV vaccine" were used. RESULTS: ZIKV has been detected in several body fluids such as saliva, semen, blood, and amniotic fluid. This reveals the possibility of sexual and mother to child transmission. The ability of the virus to cross the placental barrier and the blood brain barrier (BBB) has been associated with birth defects such as microcephaly, ocular defects, and Guillian Barre syndrome (GBS). Preventive measures can reduce the spread and risk of the infection. Available treatments only target symptoms while vaccines are still under development. CONCLUSION: Birth defects are associated with ZIKV infection in pregnant women; hence the need for development of standard treatments, employment of strict preventive measures and development of effective vaccines. PMID- 27758687 TI - Differentiation of Glioblastoma and Lymphoma Using Feature Extraction and Support Vector Machine. AB - Differentiation of glioblastoma multiformes (GBMs) and lymphomas using multi sequence magnetic resonance imaging (MRI) is an important task that is valuable for treatment planning. However, this task is a challenge because GBMs and lymphomas may have a similar appearance in MRI images. This similarity may lead to misclassification and could affect the treatment results. In this paper, we propose a semi-automatic method based on multi-sequence MRI to differentiate these two types of brain tumors. Our method consists of three steps: 1) the key slice is selected from 3D MRIs and region of interests (ROIs) are drawn around the tumor region; 2) different features are extracted based on prior clinical knowledge and validated using a t-test; and 3) features that are helpful for classification are used to build an original feature vector and a support vector machine is applied to perform classification. In total, 58 GBM cases and 37 lymphoma cases are used to validate our method. A leave-one-out crossvalidation strategy is adopted in our experiments. The global accuracy of our method was determined as 96.84%, which indicates that our method is effective for the differentiation of GBM and lymphoma and can be applied in clinical diagnosis. PMID- 27758686 TI - Antimicrobial AApeptides. AB - Antibiotic resistance is one of the biggest public concerns in the 21st century. Host-defense peptides (HDPs) can potentially mitigate the problem through bacterial membrane disruption; however, they suffer from moderate activity and low stability. We recently developed a new class of peptidomimetics termed "AApeptides". This class of peptidomimetics can mimic the mechanism of action of HDPs, and effectively arrest the growth of multidrug resistant Gram-positive and Gram-negative bacteria. As they are built on unnatural backbone, they are resistant to proteolytic degradation. In this review, we summarize the development of this class of antimicrobial peptidomimetics, and discuss the future perspective on how they can move forward on combating antibiotic resistance. PMID- 27758688 TI - Generation of Bispecific Antibodies by Fc Heterodimerization and their Application. AB - Bispecific antibodies with binding specificities for two different antigens have prompted a lot of interest into their development and application. Currently, more than ten bispecific antibodies have been clinically validated for the treatment of various diseases, including cancers and inflammatory diseases. Intensive studies in antibody engineering drive the generation of different bispecific antibody formats that differ in size and shape. However, the most prominent formats, such as IgG-single-chain (sc) Fv or dual-variable domain (DVD) IgG, deviating from the natural IgG structure, may lead to manufacturing difficulties or increase the potential risk of immunogenicity. Thus, the recent efforts focus on the development of bispecific antibodies by Fc heterodimerization that maintain the native structure of the antibody IgG molecule. This review summarizes the various techniques and methods to generate bispecific antibody molecules with Fc heterodimerization, and discusses perspectives of their application. PMID- 27758689 TI - Mechanisms of Anorexia Cancer Cachexia Syndrome and Potential Benefits of Traditional Medicine and Natural Herbs. AB - Anorexia cancer cachexia syndrome is prevalent in advanced cancer patients, which is featured by anorexia, decreased dietary intake, body weight loss (skeletal muscle mass loss), and is unable to be reversed by routine nutritional support therapy. Up to now, the main mechanisms involved in cancer cachexia include excessive systemic inflammation, which is represented by increased plasma levels of IL-1, IL-6, TNF-alpha, tumor-induced factors, such as PIF and LMF. These factors eventually act on orexigenic and anorexigenicneurons located in the hypothalamus or protein and lipid metabolism of peripheral tissues, which lead to anorexia, decreased dietary intake, enhanced basic metabolism rate and hypercatabolism. The treatment modality includes early nutritional intervention, physical activity and drug treatment. However, studies about drugs used to treat cachexia are always controversial or merely effective in stimulating appetite and increasing body weight, though not lean body mass. The main target of pharmaceutical treatment is to improve appetite, decrease systemic inflammation and promote anabolic metabolism. Nevertheless, the treatment effectiveness of chemical drugs are not reaching consensus by existing cachexia guidelines. Complementary and alternative medicine (CAM) is recently known as a promising treatment to improve cachaxia status and quality of life of cancer patients. Traditional Chinese medicine (TCM) and natural herbal medicines have been used in the treatment of cancer for thousands of years worldwide, particularly in China. More and more research show that traditional Hanfang (Chinese medicines) and some natural herbs with less side reactions, have the effects of antagonizing pro inflammatory cytokines, enhancing immune system, inhibiting protein catabolism, boosting the appetite and body weight, which maybe a promising treatment strategy and development tendency for anorexia cancer cachexia syndrome. PMID- 27758690 TI - Synthesis, Characterization and Antimicrobial Evaluation of Lipid Based Norfloxacin Prodrug. AB - BACKGROUND: Fluoroquinolones, the synthetic antibacterial agents are being successfully utilized against bacterial infections, since the time immemorial. Despite of enormous useful features, these drugs are associated with some limitations also. Large number of efforts has been made by various scientists to improve pharmacokinetic properties of these drugs and hence, to overcome the limitations associated with them. OBJECTIVES: The aim of this paper is to introduce a novel scheme for synthesis of prodrug with improved pharmacokinetic properties i.e., lipophilicity and consequently, modified bioavailability of norfloxacin. METHODS: Fatty acid hydrazide of selected fatty acid was synthesized followed by preparation of 5-formyl salicylamide. N-Mannich base of norfloxacin was synthesized by reacting norfloxacin with 5-formyl salicylamide. The prodrug was obtained by covalently coupling this N-Mannich base of norfloxacin with fatty acid hydrazide. The synthesized lipid based prodrug was evaluated for partition coefficient by shake flask method and screened for antimicrobial activity against selected strains. Drug content determination and in vitro dissolution studies utilizing HPLC were also carried out. RESULTS: The synthesized prodrug was found to exhibit improved partition coefficient (1.15) when compared with parent drug, norfloxacin (0.46). The results of antimicrobial evaluation indicate promising antibacterial and antifungal activity. CONCLUSION: The synthesized prodrug proved to be a good antimicrobial substance due to improved lipophilicity and would be expected to be used as a suitable candidate for exploration of possible utilities in treatment of bacterial infections in forthcoming time. PMID- 27758691 TI - Quality by Design Based Fabrication of Iron Oxide Induced Mucoadhesive Microspheres for Enhanced Bioavalibility of Cinnarizine. AB - BACKGROUND: The study was aimed to enhance the mucoadhesive potential of Eudragit RS 100 and RL 100 using iron oxide. METHODS: Microspheres of Eudragit RS/RL100, containing cinnarizine, were prepared by emulsification solvent evaporation technique employing 32 full factorial design. Eudragit RS or RL (X1) and iron oxide (X2) concentrations were the independent variables. Particle size, entrapment efficiency, mucoadhesion, zeta potential and t90% were the response variables. Microspheres when characterized by FTIR-ATR and DSC confirm entrapment of drug. RESULTS: SEM analysis of microspheres exhibits roughness/micropores responsible for drug release. Particle size of Eudragit RS and Eudragit RL microspheres was found to increase from 275.60+/-2.68 to 438.72+/-22.73 nm and 283.14+/-1.95 to 475.55+/-29.66 nm. Incorporation of iron oxide increases zeta potential from 0.88+/-0.18 to 10.74+/-1.78 mV and 1.12+/-0.11 to 14.44+/-2.44 mV for Eudragit RS and RL microspheres, respectively. Highest mucoadhesion and zeta potential were obtained when 4.5% w/v of X1 and 20% w/v of X2 were used in the formulation of microspheres. CONCLUSION: The r2 values were significantly higher (P < 0.01) for the Langmuir equation as compared to Freundlich equation, indicating the involvement of electrostatic forces in the specific adsorption of mucin on to Eudragit microspheres. In vivo study indicates 2.5 to 3 times increased bioavailabity of cinnarizine through mucoadhesive microspheres. PMID- 27758692 TI - Pharmaceutical Cocrystal: An Antique and Multifaceted Approach. AB - BACKGROUND: Pharmaceutical cocrystal is an emerging approach to tailor physicochemical and mechanical properties of drug substances. Cocrystals are composed of API and pharmaceutically acceptable coformer. It is used to address the solubility, dissolution, mechanical properties and stability of drugs. METHODS: This review discusses introduction to cocrystal, preparation, and characterization, what USFDA says on cocrystal and role of Hansen solubility parameter to predict cocrystal. The effect of cocrystal on drug properties, dependence of cocrystal solubility on pH, concept of drug-drug cocrystal, and aerosil 200 as novel cocrystal former and impact of cocrystal on drug pharmacokinetic has also been presented in this review along with highly selected examples of cocrystals. Finally, how cocrystal offers an opportunity for patents is also delineated. RESULTS: Pharmaceutical cocrystals have ability to tailor physichochemical and mechanical properties of drug substances. It also provides opportunity for patentable invention. Therapeutic efficacy of drugs may be improved via drug-drug cocrystal. CONCLUSION: The pharmaceutical cocrystals are not fully explored and have potential for future development. Successful drug delivery can be achieved through cocrystallization. Pharmaceutical industry will be beneficial through successful cocrystallization of drug substances. PMID- 27758693 TI - Assessment of Poly (vinyl alcohol) Coated Flutamide Nanoparticulates and their Efficacy on Prostate Cancer Cells. AB - BACKGROUND: Flutamide (FLT) is a non steroidal antiandrogenic drug used to treat prostate cancer. Its poor aqueous solubility and toxicity are the major hindrance for oral drug delivery. The aims of this study are to introduce nanoformulation of flutamide to increase its aqueous solubility thereby improves the therapeutic efficacy of the chemodrug. METHODS: Poly (vinyl alcohol) (PVA) coated flutamide nanoparticles (PVA FLT NPs) were formulated by nanoprecipitation method and characterized by DLS, TEM, FTIR, Drug release profile and biological assays. RESULTS: The PVA FLT nanoparticles were about 300nm size and spherical in shape. The PVA coated flutamide nanoparticles were monodispersed and polycrystalline. The FTIR spectra confirmed the encapsulation of flutamide in PVA FLT NPs. The encapsulation efficiency and loading efficiency was found to be about 78% and 15% respectively. The in vitro drug release of nanoparticles was calculated and it showed a sustained release up to 120 hrs at pH 7.4. The in vitro cytotoxicity, colony forming ability and blood compatibility were also investigated. The in vitro cytotoxicity study indicated the dose dependent cytotoxicity of PVA FLT NPs. In vitro clonogenic assay revealed that the PVA FLT NPs treated PC3 cells had less colony forming ability than the untreated PC3 cells. In vitro hemolysis assay and blood aggregation studies confirmed the hemocompatibility of the prepared PVA FLT NPs. CONCLUSION: We reported PVA coated FLT NPs were prepared by nanoprecipitation were more aqueous soluble than FLT, which increased its therapeutic efficacy for prostate cancer cells. PMID- 27758695 TI - What's Old is New Again - A Review of the Current Evidence of Colchicine in Cardiovascular Medicine. AB - Colchicine is a well-established drug approved by the Food and Drug Administration (FDA) for the prevention and treatment of gout. It possesses unique anti-inflammatory properties. Interests in the usage of colchicine in cardiovascular medicine have been rekindled recently with several large trials been carried out to investigate its efficacy in treatment of various cardiac conditions including pericarditis, postpericardiotomy syndrome, atrial fibrillation and coronary artery disease. In this review, the basic pharmacological properties of colchicine will be discussed, and the evidences of its benefits for different applications in cardiovascular medicine will be reviewed. PMID- 27758694 TI - Endoplasmic Reticulum Stress in Arterial Smooth Muscle Cells: A Novel Regulator of Vascular Disease. AB - Cardiovascular disease continues to be the leading cause of death in industrialised societies. The idea that the arterial smooth muscle cell (ASMC) plays a key role in regulating many vascular pathologies has been gaining importance, as has the realisation that not enough is known about the pathological cellular mechanisms regulating ASMC function in vascular remodelling. In the past decade endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been recognised as a stress response underlying many physiological and pathological processes in various vascular cell types. Here we summarise what is known about how ER stress signalling regulates phenotypic switching, trans/dedifferentiation and apoptosis of ASMCs and contributes to atherosclerosis, hypertension, aneurysms and vascular calcification. PMID- 27758697 TI - Editorial (Thematic Issue: Pathogenetic Mechanisms of CLL - A Target in Therapy). PMID- 27758696 TI - Immune-Inflammatory Activation in Acute Coronary Syndromes: A Look into the Heart of Unstable Coronary Plaque. AB - In the last twenty years, our comprehension of the molecular mechanisms involved in the formation, progression and complication of atherosclerotic plaque has advanced significantly and the main role of inflammation and immunity in this phenomenon is now largely accepted. Accumulating evidence highlight the crucial role of different inflammatory and immune cells, such as monocytes and T lymphocytes, in the pathophysiology of atherosclerotic lesion, particularly in contributing to its complications, such as rupture or ulceration. According to the new terminology, "vulnerable plaque" identifies an inflamed atherosclerotic lesion that is particularly prone to rupture. Once disrupted, prothrombotic material is exposed to the flowing blood, thus activating coagulation cascade and platelet aggregation, ultimately leading to acute thrombus formation within the coronary vessel. To date this is the key event underlying the clinical manifestations of acute coronary syndromes (ACS). The degree of vessel occlusion (complete vs. incomplete) and the time of blood flow cessation will define the severity of clinical picture. This phenomenon seems to be the final effect of a complex interaction between different local and systemic factors, involving the degree of inflammation, type of cells infiltration and the rheological characteristics of blood flow at the site of plaque rupture, thrombogenic substrates within the atherosclerotic lesion and different soluble mediators, already present or acutely released in the circulating blood. This article will review currently available data on the pathophysiology of ACS, emphasizing the immunological and inflammatory aspects of vulnerable plaque. We may postulate that intraplaque antigens and local microenvironment will define the immune inflammatory response and cells phenotype, thus determining the severity of clinical manifestations. PMID- 27758698 TI - Basic Approaches in Therapy of Multiple Sclerosis (MS) and Related Diseases: Current Achievement and Prospective. AB - INTRODUCTION: This overview is aimed at reevaluating fundamental approaches of current MS therapies with focus being placed on their targeted underlying immune, molecular and cellular mechanisms. Currently used therapies are discussed in regard to their mechanisms of action, clinical accomplishments and unwanted side effects and complications. Special emphasis is given to the current first generation Disease Modifying Therapies (DMT) and their actions at immune mechanisms of disease. Effects of DMT on CD4+Th1 cells and their associated cytokines and signaling pathways are discussed in more detail. CONCLUSION: Attention is paid to emerging role of a CD4 T cell chemotactic cytokine, IL-16 in regulation of relapsing MS and its model, experimental autoimmune encephalomyelitis (EAE). Immune mechanisms mediated by IL-16 are critically evaluated in the context of mechanisms of DMT and its potential as prospective MS therapy. In relation to clinical assessment of therapy, existing and prospective molecular biomarkers are highlighted and discussed where applicable. PMID- 27758699 TI - Design, Synthesis and Molecular Docking Studies of New Potential Piperazine Derivatives as Cognition Enhancers. AB - BACKGROUND: In 2016, the statistical reports stated that Alzheimer is not just memory loss but it kills and has become the 6th leading cause of death. The number of dementia patients is increasing rapidly and expected to rise to 131.5 million by 2050. Still there is not a drug candidate that can cure the cognitive deficits completely. OBJECTIVE: Series of novel piperazine derivatives have been designed, synthesized and evaluated for cognition enhancing activity. METHODS: The synthesized compounds were screened for their in vitro AChE inhibition and reversal of scopolamine induced memory deficit in a passive avoidance stepdown animal model in mice. Enzyme kinetics and molecular docking studies were carried out to elucidate the mechanism of AChE inhibition. RESULTS: All the compounds exhibited excellent IC50 values with potential dual binding site inhibition activity. The IC50 values and inhibition constants of the most promising compounds 1d and 3c were found to be 2.23 MUM, 1.05 MUM, 14.38 MUM and 6.93 MUM respectively. They potentially reversed the scopolamine induced memory deficit at a dose of 1.0 mg/kg i.p. in mice. Furthermore, 1d and 3c showed high CNS penetration and brain AChE inhibition in ex vivo experiments. Additionally, significant free radical scavenging activity was determined taking trolox as the standard. CONCLUSION: Compounds 1d and 3c were emerged as promising of the series and further can be investigated for the future pursuit as drug candidates. PMID- 27758700 TI - Unravelling the Power of Omics for the Infertile Aging Male. AB - The aging phenomenon is intrinsically responsible for diseases and lifestyle associated conditions afflicting the aging male. In particular, male infertility seems to result from deleterious lifestyle choices. However, the aging effect at the individual gene/protein level is poorly discussed and valuable information is certainly missing. We have thus used an omics approach to identify differentially expressed proteins and genes from spermatozoa and seminal plasma samples across several conditions affecting adult male fertility. Our search resulted in 400 differentially expressed proteins in seminal plasma and 409 differentially expressed proteins in spermatozoa as well as, almost 6,000 differentially expressed spermatozoa mRNAs. We have functionally analyzed these proteins and genes to understand and discuss how biological processes and signaling pathways associated with aging might affect male fertility. Sperm and seminal fluid proteins from infertile males display significant alterations in i) processes previously implicated in the aging phenomena, such as mitochondrial dysfunction, DNA instability, oxidative stress, protein misfolding and intracellular mistrafficking, and ii) processes specifically involved in reproductive phenomena, such as sperm-egg recognition/acrosome reaction, embryo and morula development, blastocyst implantation and DNA methylation involved in embryo development. These proteins display a widespread distribution and seem to be significantly influenced by deleteriously lifestyle choices. Conventional assays to assess male fertility are inadequate to comprehensively reveal the broad spectrum of alterations at the transcriptional and translational levels afflicting the infertile aging male. In turn, proteomics and transcriptomics are suitable options for addressing these key issues that may explain many poorly understood fertility-associated phenomena resulting from the aging process. PMID- 27758701 TI - Targeting Obesity for the Prevention of Chronic Cardiovascular Disease Through Gut Microbiota-Herb Interactions: An Opportunity for Traditional Herbs. AB - Cardiovascular disease still remains the primary cause of death worldwide and obesity is becoming recognized as one of the most critical contributing risk factors. The increased prevalence of obesity casts a cloud over the global health and the whole societies and will still be burdened in the future. Therefore, prevention and therapy of obesity is a beneficial strategy for the prevention of chronic cardiovascular disease. Numerous studies have demonstrated that gut microbiota takes part in human health and disease including obesity. Traditional herbs hold great potential to improve people's health and wellness, particularly in the area of chronic inflammatory diseases although the mechanisms of action remain poorly understood. Emerging explorations of gut microbiotaherb interactions provide a potential to revolutionize the way we view herbal therapeutics. This review summarizes the experimental studies performed on animals and humans regarding the gut microbiota-herb interactions targeting obesity. This review also discusses the opportunity of herbs with potent activities but low oral bioavailability conundrum for prevention and therapy for obesity and related cardiovascular disease. PMID- 27758702 TI - Cellular and Molecular Mechanisms of Diuretic Plants: An Overview. AB - Heart failure, hypertension, cirrhosis and nephritic syndrome are among conditions that alter volume and composition of body fluids and are modulated by diuretics. Natural products are important source of diuretics and have been considered remarkable alternative with greater effectiveness and fewer side effects. However, many of these plants used in traditional medicine must be scientifically assessed about their efficacy and toxicity. Despite the large number of published articles claiming that plants or plant-derived components may act as diuretic agents, few studies have addressed the mechanism of action of medicinal plants. Thus, the aim of this review was to provide an overview of the current knowledge about the major cellular and molecular mechanisms of diuretic plants and/or their main compounds. Many well-established mechanisms (water channels, renal carriers, nitric oxide-cGMP and prostaglandin-cAMP pathways, renin-angiotensin and kinin-kallikrein systems, carbonic anhydrase, and osmotic effects), along with other newly identified targets, are connected to the diuretic activity of many natural products. However, the central path responsible for the activity of these agents remains unclear. Further studies may help clarifying the central role of each of these pathways in the pleiotropic response of these agents. PMID- 27758703 TI - The Ever Changing Face of Antibiotic Resistance: Prevailing Problems and Preventive Measures. AB - BACKGROUND: Antibiotic resistance is a global problem that presents significant risk to human health. Driven by selective pressure of antimicrobial agents, spontaneous mutation, recombination and horizontal gene transfer events, inappropriate antibiotic prescribing and use outside healthcare settings has increased their impact on healthcare system. Increasing risk for human health lead us to study resistance development mechanisms, associated factors that increase dissemination of resistance genes along with information of imperative measures necessary to curtail the growing menace. METHODS: In this article, we emphasized on the state of knowledge regarding imprudent use of antibiotics that act as promoters of resistance development. For this, literature based search for articles and entries related to antimicrobial resistance was done. With ample of data available, selected was performed for the epidemiological and clinical based study to curtail the facts present in these data sets so as to get accurate and important information. RESULTS: Resistance mediated by different determinants such as TEM, SHV, OXA and CTX-M, methods of mobilization that increase spread across species and as such failure to available treatment regimens was studied. Addition to detection methods, information of the inhibitors and natural substance useful in mitigating the effect of multidrug resistance was included to strategies the policies and plans for restricting their spread. CONCLUSION: As intervention to this growing problem, modified use of antimicrobial agents, employment of different formulations of herbs along with public health interventions in restricting antibiotic use, are believed to be of great help in restricting their dissemination and as such spread to non-pathogenic bacterial isolates. PMID- 27758704 TI - Plant-derived Compounds as Potential Source of Novel Anti-Biofilm Agents Against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is the most common Gram-negative bacterium associated with nosocomial and life-threatening chronic infections in cystic fibrosis patients. This pathogen is wellknown for its ability to attach to surfaces of indwelling medical devices to form biofilms, which consist of a regular array of extracellular polymers. Tenaciously bound to the surface of devices and inherently resilient to antibiotic treatment, P. aeruginosa poses a serious threat in clinical medicine and contributes to the persistence of chronic infections. Studies on microbial biofilms in the past decade involved mainly the understanding of environment signals, genetic elements and molecular mechanisms in biofilm formation, tolerance and dispersal. The knowledge obtained from the studies of these mechanisms is crucial in the establishment of strategies to eradicate or to prevent biofilm formation. Currently, biofilm infections are usually treated with combinations of antibiotics and surgical removal, in addition to frequent replacement of the infected device. More recently, specific natural sources have been identified as antibiofilm agents against this pathogen. This review will highlight the recent progress made by plant-derived compounds against P. aeruginosa biofilm infections in both in vitro or in vivo models. PMID- 27758705 TI - The Future of Diabetes Management by Healthy Probiotic Microorganisms. AB - BACKGROUND: Diabetes mellitus, a condition of multifactorial origin, is related to the intestinal microbiota by numerous molecular mechanisms. Controlling the vast increase in the prevalence of diabetes needs a natural and safe solution. Probiotics, known as live microorganisms that exert health benefits to the host, have anti-diabetic property. OBJECTIVE: This review will highlight the current evidences in probiotic effectiveness and future prospects for exploring probiotic therapy in the prevention and control of diabetes. METHODS: We searched Pub Med and Science Direct by using "Probiotics" and "Diabetes" for searching the studies aiming the application of probiotics and the beneficial effects of probiotics in diabetes prevention and control. RESULTS: It has been shown that probiotics can increase insulin sensitivity and reduce autoimmune responses by modulating intestinal microbiota and decreasing the inflammatory reactions and oxidative stress. Recent evidences show that probiotics influences the host through modulating intestinal permeability and mucosal immune response, manipulating eating behaviors by appetite-regulating hormones and controlling gut endocannabinoid (eCB) system that is believed to be associated with inflammation and diabetes. Moreover, modulating the intestinal microbiota by probiotics controls host metabolism by affecting energy extraction from food and by biochemically converting molecules derived from the host or from gut microbes themselves. CONCLUSION: Experimental and clinical evidences support the hypothesis that the modulation of the gut microbiota by probiotics could be effective in prevention and management of diabetes. PMID- 27758706 TI - Self Monitoring of Blood Glucose Among Patients with Type 2 Diabetes Mellitus in Eastern Nigeria: Need for Multi-strategic Interventions. AB - BACKGROUND: Self Monitoring of Blood Glucose (SMBG) is a useful adjunct to lifestyle modification and medications for optimal management of type 2 Diabetes Mellitus (DM). This study was aimed at evaluating the practice, cost and associations of SMBG in subjects with type 2 DM in Enugu, Nigeria. METHODS: In a cross-sectional survey conducted at the diabetes clinic in three hospitals, 366 type 2 diabetic subjects aged 18-65 years were consecutively interviewed. Socio demographic and clinical information were documented and glycated hemoglobin was performed for all the participants. RESULTS: A total of 318 subjects with mean age of 49.0 +/- 9.4 years completed the study. 304 subjects (95.6%) reported that they were aware of SMBG and 60.7% practiced SMBG at frequencies ranging from >= 1/day (7.9%), >= 1/week (26.1%) or < 1/week (26.7%). 39.3% of the respondents did not perform any SMBG. Lack of finance was the predominant reason for not performing any SMBG. The median monthly cost of performing SMBG excluding the cost of meters was N2,000 (USD 6.7) per patient, amounting to annual societal cost of N37.8 billion (USD 126 million). Significant associates of performing any SMBG were longer DM duration, previous participation in diabetes education, insulin treatment and infrequent hospitalization. CONCLUSION: Despite high awareness, SMBG practice is grossly inadequate and is associated with a huge economic burden that may be unsustainable in a resource-poor country like Nigeria. Measures aimed at reducing the cost of glucometers and strips, and improving diabetes education are recommended. PMID- 27758709 TI - SAMHD1 Polymorphisms were Significantly Correlated with HIV/SIV Virus Load in PBMC from Chinese Rhesus Macaques and Cynomolgus Macaques. AB - BACKGROUND: Sterile alpha motif and histidine aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is one of the novel restriction factors that potently supresses HIV-1 infection in myeloid cells at an early stage in the viral replication cycle. SAMHD1 activity is blocked by the action of viral accessory protein x (Vpx), which targets and recruits SAMHD1 for proteasomal degradation, in the SIVsm/HIV-2 lineage. METHODS: The impact of SAMHD1 polymorphisms on viral replication in Chinese-origin rhesus macaques (CR) and cynomolgus macaques of Vietnamese origin (CM) have not been reported until now. Therefore, we aimed to explore the polymorphisms, as well as the impact of polymorphisms, on HIV- 2 and SIV infections among CR and CM. RESULTS: We found two variants, T168C and T320C, located in the SAM domain of CR SAMHD1, which were significantly correlated with the HIV-2ROD/SIVmac239 virus load, suggesting that T168C and T320C probably affected HIV-2ROD and anti-SIVmac239 replication in CR, respectively. Conversely, T320C possibly affected CM SAMHD1-mediated HIV-2ROD restriction. However, none of the variants were correlated with CM SAMHD1 mediated SIVmac239 restriction. CONCLUSION: Based on these results, we concluded that SAMHD1 polymorphisms did not affect SIVmac239 replication in CM, but perhaps altered HIV-2ROD infection; however, different sites of the SAM domain of SAMHD1 were responsible for restricting the replication of different viruses in CR. PMID- 27758710 TI - Developing and Evaluating In Vitro Effect of Poly(Ethylene Glycol) Conjugated Curcumin on Human Cancer Cell Lines. AB - BACKGROUND: Curcumin has been shown to possess strong cytotoxic effect against various cancer cell lines. However, curcumin has not applied as a drug for treatment of cancer yet due to low solubility in water and low bioavailability. The aims of this study were to prepare a new polyethylene glycol (PEG) conjugated curcumin and to evaluate its antitumor activity in vitro. METHODS: PEG-CUR was prepared by the reaction between curcumin and PEG. PEG-CUR which was characterized by SEM, TEM, FTIR, DSC and 1H NMR analysis. The physicochemical parameters of PEG-CUR such as zeta potential, size distribution, solubility and percentage of curcumin were also investigated. RESULTS: Our results showed that the percentage of curcumin in PEG-CUR was 13.26 +/- 1.25 %. PEG-CUR has nanosize values of 96.3 nm and the zeta potential values of - 48.4 mV. The PEG-CUR showed significantly increasing curcumin's solubility in water and another medium such as in 0,1 N HCl, phosphate buffer pH 4.5 and pH 6.8 solution and n-octanol. Our data also have shown cytotoxicity effect of PEG-CUR was much greater than curcumin-free in two different HepG2 and HCT116 cancer cell lines. CONCLUSION: It could be concluded from our results that the PEG-CUR may be a potential candidate for cancer treatment. Further studies are needed to evaluate the antitumor efficacy of PEG-CUR in vivo. PMID- 27758707 TI - New Psychoactive Substances 3-Methoxyphencyclidine (3-MeO-PCP) and 3 Methoxyrolicyclidine (3-MeO-PCPy): Metabolic Fate Elucidated with Rat Urine and Human Liver Preparations and their Detectability in Urine by GC-MS, "LC-(High Resolution)-MSn" and "LC-(High Resolution)-MS/MS". AB - BACKGROUND: 3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3 MeOPCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS). METHODS: For metabolism studies, rat urine samples were treated by solid phase extraction or simple precipitation with or without previous enzymatic conjugate cleavage. After analyses via LC-HR-MSn, the phase I and II metabolites were identified. RESULTS: Both drugs showed multiple aliphatic hydroxylations at the cyclohexyl ring and the heterocyclic ring, single aromatic hydroxylation, carboxylation after ring opening, O-demethylation, and glucuronidation. The transferability from rat to human was investigated by pHLM incubations, where Odemethylation and hydroxylation were observed. The involvement of the individual CYP enzymes in the initial metabolic steps was investigated after single CYP incubations. For 3-MeO PCP, CYP 2B6 was responsible for aliphatic hydroxylations and CYP 2C19 and CYP 2D6 for O-demethylation. For 3-MeO-PCPy, aliphatic hydroxylation was again catalyzed by CYP 2B6 and O-demethylation by CYP 2C9 and CYP 2D6 Conclusions: As only polymorphically expressed enzymes were involved, pharmacogenomic variations might occur, but clinical data are needed to confirm the relevance. The detectability studies showed that the authors' SUSAs were suitable for monitoring the intake of both drugs using the identified metabolites. PMID- 27758711 TI - Loss of Eyebrows and Eyelashes During Concomitant Treatment with Sitagliptin and Metformin. AB - : The fixed dose combination of sitagliptin 50 mg and metformin 850 mg (Janumet (r)), is indicated for the treatment of type 2 diabetes mellitus in addition to diet and exercise to improve glycemic control in patients treated with metformin alone. METHODS: We report a 69-year-old man with type 2 diabetes that developed sudden loss of eyebrows and eyelashes about 4 months after the beginning of Janumet(r). Clinical and laboratory findings excluded the presence of systemic or skin diseases able to induce these manifestations, while the Naranjo probability scale documented a possible association between the drug and the adverse drug reaction. PMID- 27758713 TI - Computational Modelling of Magnetic Nanoparticle Properties and In Vivo Responses. AB - Nanoparticles are finding many applications in medicine and other fields like photonics. Magnetic nanoparticles have additional advantages in medicine over non magnetic hard nanoparticles, as their magnetic properties make them ideal for hyperthermic applications in therapy and for sensitive diagnostic imaging applications. I review the literature on computational models of the magnetic properties of nanoparticles specifically. Such models have the potential to accelerate the design of magnetic nanoparticles for medical applications. Much of the current literature relates to the modelling of magnetic nanoparticles for inducing hyperthermia in aberrant cells, with significant bodies of work aimed at simulating and predicting properties for medical imaging and targeted delivery of drugs and gene therapies. PMID- 27758712 TI - STIP Regulates ERK1/2 Signaling Pathway Involved in Interaction with PP1gamma in Lymphoblastic Leukemia. AB - BACKGROUND: Sip1/Tuftelin Interacting Protein (STIP) is highly conserved from Caenorhabditis elegans to Homo sapiens and has essential biological functions. However, its function in leukemia remains unknown. METHODS: Clinic samples and cell model were used in this article to investigate the expression of STIP in lymphoblastic leukemia. The functional research of STIP was performed in ARH-77 by siRNA transfection, immunofluorescence, cell count, cell cycle analysis, qRT PCR, sub-cellular fractionation assays, immunoprecipitation and western blotting. RESULTS: Here, we found that STIP is more highly expressed in both clinical lymphoblastic leukemia samples and cultured leukemia cells than in normal samples. Knockdown of STIP in B lymphoblastic leukemia ARH-77 cells leads to S phase arrest, lower cell proliferation rates, and suppressed AKT and ERK1/2 signaling pathways. Interestingly, when protein phosphatase was inhibited by Calyculin A, STIP knockdown did not result in the dephosphorylation of p-ERK1/2, suggesting the dependence of STIP on protein phosphatase in the regulation of ERK1/2. Among those protein phosphatase inhibited by Calyculin A, PP1gamma was found to interact with STIP proven by immunofluorescence and immunoprecipitation assays. The binding of STIP with PP1gamma may decrease the phosphatase activity of PP1gamma, resulting in hyper-activated ERK1/2 signaling. CONCLUSION: In summary, the high expression and activation effect on the ERK1/2 signaling of STIP in lymphoblastic leukemia suggest that STIP would be a potential therapy target or diagnosis marker for leukemia. PMID- 27758714 TI - Gender Differences in Cancer-associated Venous Thromboembolism. AB - Venous thromboembolism (VTE) is a commonly diagnosed multifactorial condition with significant morbidity and mortality, occurring in up to 20% of cancer patients. Indeed, patients with cancer are in a higher pro-thrombotic state due to alterations in their haemostatic- coagulative system, stasis and blood flow slowdown, endothelial dysfunction, vascular inflammation and platelet activation. Moreover, several cancer-dependent factors can sum up to trigger a first episode of VTE or to cause its recurrence in the course of anticoagulant treatment. Such a pro-thrombotic condition is further worsened by additional favoring risks such as immobilization, infection, surgery, or insertion of a central venous catheter, and anti-cancer therapy. Furthermore, in the secondary prevention setting, the anticoagulant therapy is accompanied by a high incidence of bleeding complications. Given the above, understanding and identifying the factors associated with the incidence and clinical outcome of VTE in cancer patients might be of great value in the prevention and management of VTEattributable complications, including death. Differences associated to gender on cancerrelated VTEs are not yet fully defined; many of the studies that addressed the question have been biased by erroneous/non homogeneous inclusion criteria. In the present review, we analyzed the potential differences in VTEs occurrence in cancer patients, by reporting the most significant findings in the recent literature. The identification of a differential clinical approach according to patient sex, might prompt the design of personalized treatment options tailored and optimized according to algorithms for oncological VTE prevention. PMID- 27758715 TI - Efficacy, safety and immunogenicity of biosimilars in inflammatory bowel diseases: A systematic review. AB - BACKGROUND: Anti-tumor necrosis factor (anti-TNF) monoclonal antibodies have revolutionized the treatment of inflammatory bowel diseases (IBD). However, because of their complexity, their production is expensive contributing to their high price. As the patent protection of these therapies has expired in several countries, biosimilars have been developed to reduce the healthcare costs. The aim of this article is to review the literature on the safety, efficacy and immunogenicity of biosimilars in IBD. METHODS: A PubMed literature search was performed using the following terms until May 2016: 'biosimilars', 'CT-P13', 'infliximab', 'Crohn's disease', 'ulcerative colitis', 'inflammatory bowel diseases', 'efficacy', 'safety', 'immunogenicity'. Additionally, abstracts from international meetings were also reviewed. RESULTS: A total of eleven studies in IBD patients provided real-world evidence on the efficacy, safety and immunogenicity profile of biosimilars in IBD patients. Based on available evidence, CT-P13 is efficacious and well tolerated in IBD patients in a real-life setting. The vast majority of studies only included IBD patients who had never received biological therapies. Information regarding the interchangeability between CT-P13 and its originator is currently being investigated in the NOR SWITCH trial. Otherwise, the immunogenicity profile of CT-P13 seems to be similar to the originator. CONCLUSION: The infliximab biosimilar seems to be efficacious, safe and with a similar immunogenicity profile as the originator in IBD. Large prospective post-marketing studies are needed to assess the long-term safety profile of CT-P13. The use of infliximab biosimilars may lead to major healthcare cost savings. PMID- 27758716 TI - Fructose 1,6-Bisphosphate: A Summary of Its Cytoprotective Mechanism. AB - In clinical and experimental settings, a great deal of effort is being made to protect cells and tissues against harmful conditions and to facilitate metabolic recovery following these insults. Much of the recent attention has focused on the protective role of a natural form of sugar, fructose 1,6-bisphosphate (F16bP). F16bP is a high-energy glycolytic intermediate that has been shown to exert a protective action in different cell types and tissues (including the brain, kidney, intestine, liver and heart) against various harmful conditions. For example, there is much evidence that it prevents neuronal damage due to hypoxia and ischemia. Furthermore, the cytoprotective effects of F16bP have been documented in lesions caused by chemicals or cold storage, in a decrease in mortality during sepsis shock and even in the prevention of bone loss in experimental osteoporosis. Intriguingly, protection in such a variety of targets and animal models suggests that the mechanisms induced by F16bP are complex and involve different pathways. In this review we will discuss the most recent theories concerning the molecular model of action of F16bP inside cells. These include its incorporation as an energy substrate, the mechanism for the improvement of ATP availability, and for preservation of organelle membrane stability and functionality. In addition we will present new evidences regarding the capacity of F16bP to decrease oxidative stress by limiting free radical production and improving antioxidant systems, including the role of nitric oxide in the protective mechanism induced by F16bP. Finally we will review the proposed mechanisms for explaining its anti-inflammatory, immunomodulatory and neuroprotective properties. PMID- 27758718 TI - Current and Future Drug Treatments for Glioblastomas. AB - Glioblastomas are the most aggressive of all gliomas and have the worst prognosis, with 5-year survival rates of less than 10%. Temozolomide (TMZ) is a DNA-methylating agent. Now that TMZ is available, the standard treatment is maximal safe resection, followed by treatment with radiation and TMZ. TMZ has also been used for maintenance therapy. Recently, bevacizumab, which is a monoclonal antibody to vascular endothelial growth factor, has been used for the initial treatment of glioblastomas and for the treatment of recurrent glioblastomas. A 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafer can also be placed on the surface of the cavity after near-complete tumor resection. These are currently the three drugs that are most often used to treat glioblastomas. In the near future, other therapeutic options such as immunotherapy may be used to treat glioblastomas. PMID- 27758717 TI - Pharmacological Activation of Protein Phosphatase 2 A (PP2A): A Novel Strategy to Fight Against Human Malignancies? AB - BACKGROUND: The serine-threonine protein phosphatase 2A (PP2A) regulates multiple cell signaling cascades and its inactivation by viral oncoproteins, mutation of specific structural subunits or upregulation of the cellular endogenous inhibitors may contribute to malignant transformation by regulating specific phosphorylation events. Pharmacological modulation of PP2A activity is becoming an attractive strategy for cancer treatment. Some compounds targeting PP2A are able to induce PP2A reactivation and subsequent cell death in several types of cancer. METHODS: We undertook a search of bibliographic databases for peer reviewed articles focusing on the main item of the review. We selected articles published in indexed journals. The quality of retrieved papers was appraised using the standard bibliometric indicators. RESULTS: One hundred and fourteen papers were included in the review. Twenty-seven papers gave an overview of structure and physiological role of PP2A. Twenty-five papers outlined the role of PP2A in tumor suppression. Forty papers analyzed the mechanism involved in PP2A reactivation by synthetic compounds, and twenty-two papers outlined the capability of natural compounds of restoring PP2A activity and how this could be beneficial. CONCLUSION: Findings analyzed in this review underline the central role of PP2A as a regulator of cell growth and survival, hence its function as tumor suppressor. The discovery that some compounds, either synthetic or natural, are capable of reactivating PP2A opens up new perspectives for future strategies to fully exploit therapeutic potential in human cancer. Thus, this review could also be of particular interest to pharmaceutical or biotechnology companies for drug design and targeted delivery. PMID- 27758719 TI - Nanocellulose and its Composites for Biomedical Applications. AB - Cellulose is a natural linear biopolymer, which is constituted of an assembly of cellulose nanofibrils in a hierarchical order. Nanocelluloses in particular show great promise as a cost-effective advanced material for biomedical applications because of their biocompatibility, biodegradability, and low cytotoxicity. Moreover, with their chemical functionality they can be easily modified to yield useful products. While nature uses the hierarchical nanostructure of cellulose as the load-bearing constituent in plants, a significant amount of research has been directed toward the fabrication of advanced cellulosic materials with various nanostructures and functional properties. Such nanocelluloses are widely applied in medical implants, tissue engineering, drug delivery, wound healing, diagnostics, and other medical applications with real examples in this field. There are also emerging fields being developed to use nanocelluloses and their composites in more novel ways in biomedical applications such as 3D printing and magnetically responsive materials. In this mini-review, recent advances in the design and fabrication of nanocellulose-based materials and composites are presented with a special emphasis on their suitability for material requirements for biomedical applications as well as the new directions and challenges that the materials might face in the future. PMID- 27758720 TI - [Autoimmune encephalitis due to mantle cell lymphoma]. AB - BACKGROUND: Autoimmune encephalitis is a rare condition characterized by subacute development of cognitive and psychiatric symptoms. A paraneoplastic syndrome involves autoimmune encephalitis caused by classic antibodies. Although this condition is often associated with cancer, no malignancy has yet been found in 70 90% of patients at the time of diagnosis. CASE DESCRIPTION: We saw a 58-year-old male patient with fatigue, diarrhoea and weight loss. He was also experiencing hyperekplexia, personality changes and an instable gait. PET-CT revealed generalised lymphadenopathy. Histopathological analysis of a lymph node showed mantle cell lymphoma. Further investigation of the fluid revealed anti-DPPX IgG antibodies. We treated the patient's mantle cell lymphoma with R-CHOP; he achieved complete remission and his neurological symptoms resolved almost completely. CONCLUSION: The presence of anti-DPPX IgG antibodies is rare. Although it has not been proven that these antibodies are related to malignancies, this is the third of 30 known cases in which anti-DPPX IgG antibodies and a lymphatic malignancy were found. PMID- 27758721 TI - [Ascites, pleural effusion and a benign ovarian tumour; the triad of Meigs' syndrome]. AB - BACKGROUND: Classical Meigs' syndrome consists of the triad of an ovarian fibroma, ascites and pleural effusion. A characteristic of the syndrome is that the excess fluid is resorbed after surgical resection of the tumour. CASE DESCRIPTION: A 49-year-old woman was admitted to accident and emergency department in a neglected, cachectic and hypothermic condition. A CT scan revealed an ovarian tumour, ascites and a right-sided pleural effusion. The level of the tumour marker CA-125 was also greatly elevated. Our initial working diagnosis was, therefore, 'high-grade ovarian carcinoma', but on repeated testing no malignant cells were found in the aspirated fluid. We suspected Meigs' syndrome. We first ensured that her general and nutritional condition improved; then she underwent a bilateral adnexectomy. A fibrothecoma was found in each ovary. The ascites and pleural effusion resolved following surgery and the patient recovered well. CONCLUSION: The clinical picture of Meigs' syndrome can resemble that of high-grade ovarian carcinoma. This syndrome should be included in the differential diagnosis in patients with an ovarian tumour, ascites and, possibly, pleural effusion. PMID- 27758722 TI - [IC triage in patients with an acutely worsening condition; challenges, considerations and decisions]. AB - Acute intensive care (IC) triage involves a challenging decision-making process. Physicians are required to make life or death decisions about an unfamiliar patient within a short time frame. An 84-year-old female was admitted to the stroke unit following an extensive cerebral infarction. The intensive care unit (ICU) physician was consulted because of a suspected severe abdominal sepsis even though ICU treatment had never previously been discussed. A 77-year-old female with a previous history of myocardial infarction and severe COPD developed acute respiratory failure on the ward, and was admitted to the ICU for support by a mechanical ventilator. The family felt this was an inappropriate course of treatment, considering her former poor quality of life. When physicians are confronted with sudden deterioration of the patient's clinical condition without advanced care planning a limited-time IC treatment trial is often initiated, possibly leading to inappropriate ICU admissions. ICU treatment options should preferably be discussed beforehand; preliminary background information regarding the patient's wishes is essential for adequate decision-making. PMID- 27758723 TI - [New developments in the treatment of pancreatic cancer]. AB - - The incidence of pancreatic cancer is increasing due to the ageing population among other things, while 5-year survival has improved in the past two decades from 3 to 7%.- In case of biliary obstruction due to pancreatic cancer, biliary drainage before surgery or ablative therapy using a covered metal stent instead of plastic reduces the rate of complications.- In patients with metastasized pancreatic cancer a combination of folinic acid, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) results in improved survival. Approximately 20% of patients with locally, unresectable pancreatic cancer can undergo surgical resection following treatment with FOLFIRINOX.- The effectiveness of radiofrequency ablation, irreversible electroporation and stereotactic radiotherapy for locally, unresectable pancreatic cancer is currently investigated in multicenter trials.- The effectiveness of neo-adjuvant chemoradiation and minimal invasive surgery in patients with resectable pancreatic cancer is currently investigated in randomized multicenter trials. PMID- 27758724 TI - [Recognizing signs of sexual abuse]. AB - Sexual abuse is very common. In the Netherlands 42% of women and 13% of men aged over 25 years have experienced unacceptable sexual behaviour. Most victims do not seek professional help nor do they report the abuse to the police, and most of the victims who do seek medical help do not mention the abuse. Doctors often do not recognize the signs of sexual abuse. Most victims of rape have symptoms that may develop into posttraumatic stress disorder (PTSD) if they persist for more than 4 weeks, such as sleep problems or panic attacks. Victims of sexual abuse also more often develop a psychiatric disorder or medically unexplained symptoms (MUS). Doctors should ask about sexual abuse in cases of MUS or unexplained mental problems. The complications of abuse can be treated with eye movement desensitization and reprocessing (EMDR) or cognitive processing therapy (CPT). PMID- 27758725 TI - [Dysphagia in children]. AB - In this case report we discuss two children with dysphagia. Both presented with difficulties in swallowing and oesophageal impaction of solid food. The first case involves a 16-year-old boy who suffered from dysphagia for many years. After a long diagnostic journey, during which a psychogenic cause was suspected, he was diagnosed with oesophageal achalasia. After a balloon dilatation of the lower oesophageal sphincter his complaints persisted and the treatment procedure was repeated. The second case involves a 15-year-old girl, who presented with a food impaction in the distal oesophagus. After biopsies, she was diagnosed with eosinophilic esophagitis. After short-term acid suppression and treatment with budesonide her symptoms were in remission. The lesson is that there are many causes of dysphagia, including anatomical, functional and psychogenic disorders. In children with dysphagia it is important to rule out somatic disorders before consideration of psychogenic disorders, and to be aware of 'red flag' symptoms such as weight loss. PMID- 27758726 TI - Policies, guideline implementation and practice change - how can the process be understood? AB - Politics and policy: It is important to understand why, in the translational continuum from pilot research and randomised controlled efficacy trials to roll out programmes and routine effectiveness studies, some service innovations are taken up by health service purchasers and providers, while others are not. Why do some innovative interventions or models of care get to the stage of implementation, while others fail to be funded? PMID- 27758727 TI - Differences in Neisseria gonorrhoeae population structure and antimicrobial resistance pattern between men who have sex with men and heterosexuals. AB - This study compared the antimicrobial susceptibility and genotypes of strains of Neisseria gonorrhoeae isolated from men who have sex with men (MSM) and from heterosexuals. One hundred and eleven strains were characterized from 107 patients, comprising 57 strains from 54 heterosexuals and 54 strains from 53 MSM. Antimicrobial resistance rates were higher in strains from heterosexual patients, with resistance to cefixime (P = 0.0159) and ciprofloxacin (P = 0.002) being significantly higher. Typing by N. gonorrhoeae multi-antigen sequence typing (NG MAST) showed that the most prevalent sequence types (ST) and genogroups (G) respectively were ST2400, ST2992, and ST5793, and G1407, G2992, and G2400. A statistically significant association was observed for MSM and genogroups G2400 (P = 0.0005) and G2992 (P = 0.0488), and G1407 with heterosexuals (P = 0.0002). We conclude that in our region distinct populations of gonococci are circulating among subjects with different sexual practices, with their corresponding transmission patterns. Furthermore, the high prevalence of genotype G2400 in MSM, has not to our knowledge been previously described. PMID- 27758728 TI - Treatment of depression in nursing home residents without significant cognitive impairment: a systematic review. AB - BACKGROUND: Depression in nursing facilities is widespread and has been historically under-recognized and inadequately treated. Many interventions have targeted depression among residents with dementia in these settings. Less is known about depression treatment in residents without dementia who may be more likely to return to community living. Our study aimed to systematically evaluate randomized control trials (RCTs) in nursing facilities that targeted depression within samples largely comprised of residents without dementia. METHODS: The following databases were evaluated with searches covering January 1991 to December 2015 (PubMed, PsycINFO) and March 2016 (CINAHL). We also examined national and international clinical trial registries including ClinicalTrials.gov. RCTs were included if they were published in English, evaluated depression or depressive symptoms as primary or secondary outcomes, and included a sample with a mean age of 65 years and over for which most had no or only mild cognitive impairment. RESULTS: A total of 32 RCTs met our criteria including those testing psychotherapeutic interventions (n=13), psychosocial and recreation interventions (n=9), and pharmacologic or other biologic interventions (n=10). Seven psychotherapeutic, six psychosocial and recreation, and four pharmacologic or other biologic interventions demonstrated a treatment benefit. CONCLUSIONS: Many studies had small samples, were of poor methodological quality, and did not select for depressed residents. There is limited evidence suggesting that cognitive behavioral therapies, reminiscence, interventions to reduce social isolation, and exercise-based interventions have some promise for decreasing depression in cognitively intact nursing home residents; little can be concluded from the pharmacologic or other biologic RCTs. PMID- 27758729 TI - Evaluating a social problem solving intervention for juvenile detainees: Depressive outcomes and moderators of effectiveness. AB - This study reports findings from the administration of a social problem-solving training (SPST) intervention to juvenile detainees in the Connecticut Youth Detainee Program. SPST is a cognitive behavioral intervention that teaches children and youth how to more effectively cope with interpersonal stress and conflict. In the current study, we tested whether SPST could decrease depressive symptoms in a sample of detained adolescent offenders. The study used a randomized-control design with detention staff administering the intervention. The results showed that SPST, as a main effect, was not more effective in reducing depressive symptoms than treatment as usual. However, the effectiveness of SPST was moderated by fluid intelligence. Juvenile detainees with high intelligence scores were most likely to benefit from SPST compared to treatment as usual. It was surprising that, for those with lower intelligence scores, SPST increased depressive symptoms relative to treatment as usual. These results help fill a critical need for intervention effectiveness data on juvenile detainees and indicate that SPST may not be useful for reducing outcomes such as depression. PMID- 27758730 TI - Risk and protective factors for comorbid internalizing and externalizing problems among economically disadvantaged African American youth. AB - Comorbidity of internalizing and externalizing problems and its risk and protective factors have not been well incorporated into developmental research, especially among racial minority youth from high-poverty neighborhoods. The present study identified a latent comorbid factor as well as specific factors underlying internalizing and externalizing problems among 592 African American adolescents living in economically disadvantaged neighborhoods (291 male; M age = 15.9 years, SD = 1.43 years). Stressful life events and racial discrimination were associated with higher comorbid problems, whereas stressful life events and exposure to violence were associated with higher specific externalizing problems. Collective efficacy was associated with both lower specific externalizing problems and lower comorbid problems. Moreover, high collective efficacy buffered the risk effects of stressful life events and racial discrimination on comorbid problems. Our results demonstrated the advantages of latent variable modeling to understanding comorbidity by articulating impacts of risk factors on comorbid and specific components underlying internalizing and externalizing problems. They also highlighted the protective effect of collective efficacy in mitigating risks for these problems. These findings broadly call for more studies on comorbidities in developmental psychopathology among youth from diverse sociocultural backgrounds. PMID- 27758732 TI - [Misnaming things adds to the world's misfortune]. PMID- 27758731 TI - Dynamic modelling of strategies for the control of acute haemorrhagic conjunctivitis outbreaks in schools in Changsha, China (2004-2015). AB - Outbreaks of acute haemorrhagic conjunctivitis (AHC) - a rapidly progressing and highly contagious infection - often occur in schools during summer and autumn. We used dynamic modelling to evaluate the efficacy of interventions to control AHC outbreaks in schools. A susceptible-infected-recovered (SIR) model was built to simulate AHC outbreaks in Chinese schools, with isolation or school closure added into the model. We used outbreak data from the period 2004-2015 in our models to estimate the effective reproduction number and assess the efficacy of interventions. The median effective reproduction number (uncontrolled) of AHC outbreaks was 7.00 (range 1.77-25.87). The median effective reproduction number (controlled) of AHC outbreaks was 0.16 (range 0.00-2.28). Intervention efficacy is affected by the timing of isolation; earlier isolation is associated with a lower morbidity peak and smaller total attack rate (TAR). School closures were not effective; TARs were almost 100% and did not change even when different school closure durations were adopted. Isolation and school closure as a combined intervention strategy was used to simulate outbreak control, but the efficacy was the same as isolation alone. An isolation programme could be an effective primary intervention during AHC outbreaks in schools. However, school closure is not recommended. PMID- 27758733 TI - [Cell biology applications for a type III secretion-based protein delivery tool]. PMID- 27758734 TI - [Cell-autonomous defects in satellite cells impair muscle regeneration in Duchenne muscular dystrophy]. PMID- 27758735 TI - [HIV-1 is stored by follicular dendritic cells in lymph nodes even under antiviral treatments]. PMID- 27758736 TI - [New genes protect old minds]. PMID- 27758737 TI - [A new restriction factor against HBV infection: the SMC5/6 complex]. PMID- 27758738 TI - [A murine model for an ignored chronic infection: hepatitis E !] PMID- 27758739 TI - [Cell cycle regulators CDK4 and E2F1 control glucose and lipid homeostasis]. PMID- 27758740 TI - [The defence system MIMIVIRE in mimivirus illustrates Red Queen hypothesis]. PMID- 27758741 TI - [Astrocyte control of neuronal synchrony: mind the GAP!] PMID- 27758742 TI - [The brain uses different frequency channels to communicate]. PMID- 27758743 TI - [The diffusional barrier, a new window for exclusion]. PMID- 27758744 TI - [Cell response to adenovirus 5: going beyond the conventional DNA damage response]. PMID- 27758745 TI - [NADPH oxidase: double agent during inflammation?] PMID- 27758746 TI - [In search of new substrates of ADAM10]. PMID- 27758747 TI - [Liver regeneration : two pieces of the puzzle connected]. PMID- 27758748 TI - [Metabolism and cell cycle, two interconnected processes in bacteria]. AB - To increase chances for a cell to survive in its natural environment, metabolism and cell cycle necessarily have to be interconnected. Indeed, cells need, on the one hand, to check their metabolic status before initiating a cell cycle step often energy-consuming, and, on the other hand, to complete some cell cycle steps before modifying their metabolism. Because bacteria do not differ from the rules, an increasing number of examples of connection between metabolism and cell cycle emerged these last years. Identifying metabolic enzymes as messengers coordinating metabolism and cell cycle allows the addition of another dimension to metabolic maps. Likewise, the very high conservation of these metabolic maps, from bacteria to human, allows inspiring research on tumor cells that are known to have an unrestrained cell cycle and a voracious appetite. PMID- 27758749 TI - [An intimate look at the viral replication cycle through ribosome profiling]. AB - Next Generation Sequencing (NGS) techniques have revolutionized most biomedical research fields over the past decade by allowing a broader vision on biological processes that occur at the molecular level. Among these, ribosome profiling or footprinting is a powerful tool to study mRNA translation in a transcriptome-wide manner. Ribosome profiling has been used to study the impact of translational control of gene expression under many different cellular conditions including viral infections. Indeed, translation is a critical step during the viral replication cycle in which the infected cell is embezzled to produce viral proteins. Ribosome profiling tools can provide new insights on viral translation by monitoring ribosome binding to viral and cellular RNAs with a high definition during the time course of an infection. Here, we describe the potential uses of ribosome profiling for the understanding of viral translational control and the impact of viral infection on host gene expression. We also discuss the main limitations and biases related to the technique that need to be taken into account for its use. PMID- 27758750 TI - [Towards new targets in the treatment of hypertension?] AB - Blood pressure is a major determinant of cardiovascular risk. Blood pressure target to reach with antihypertensive therapy, and the population to whom it should apply, remain debatted. Blood pressure goals established by scientific societies may be revised after the publication of the US multicenter SPRINT study results (Systolic Blood Pressure Intervention Trial) obtained in 2015. Analysis of the generalizability of the SPRINT results shows that they may not be directly applied to the french population which is at lower risk than the US population and would have major medical and economic implications. PMID- 27758751 TI - [Parasites and cancer: is there a causal link?] AB - Over 20 % of cancers have infectious origins, including well-known examples of microbes such as viruses (HPV, EBV) and bacteria (H. pylori). The contribution of intracellular eukaryotic parasites to cancer etiology is largely unexplored. Epidemiological and clinical reports indicate that eukaryotic protozoan, such as intracellular apicomplexan that cause diseases of medical or economic importance, can be linked to various cancers: Theileria and Cryptosporidium induce host cell transformation while Plasmodium was linked epidemiologically to the "African lymphoma belt" over fifty years ago. These intracellular eukaryotic parasites hijack cellular pathways to manipulate the host cell epigenome, cellular machinery, signaling pathways and epigenetic programs and marks, such as methylation and acetylation, for their own benefit. In doing so, they tinker with the same pathways as those deregulated during cancer onset. Here we discuss how epidemiological evidence linking eukaryotic intracellular parasites to cancer onset are further strengthened by recent mechanistic studies in three apicomplexan parasites. PMID- 27758752 TI - [Pragmatics in autism spectrum disorder: recent developments]. AB - Autism spectrum disorder (ASD) is characterized by primary pragmatic difficulties, out of step with verbal and non-verbal developmental level. This selective survey paper addresses three recent domains of research on pragmatic functions in autism. First, we provide an up-to-date discussion of how lack of sensitivity to social cues impacts early acquisition of words. Second, we review recent findings on the comprehension of non-literal language, pointing to a more refined clinical reality. Third, we describe recent developments in the study of conversation skills in autism. PMID- 27758753 TI - [A history of the clinical research in cardiology]. AB - On January 21 1968, nearly an half-century ago, a small Parisian group of cardiologists presented a directional Doppler prototype making possible the detection of forward and backward flows in the arteries. This princeps report, rapidly followed by the Directional Doppler recording of intracardiac flows, has upset the traditional approach to cardiovascular pathophysiology and launched a new examination method that will spread upon the whole word. Single CNRS researcher among this group of clinical cardiologists, Dr Colette Veyrat recalls this early period.... PMID- 27758754 TI - [Causal relationships between health and work: an economist's viewpoint]. AB - The economists interest in the relationships between health and work by studying three relations: the negative effect of the poor health on the position on the labor market, the positive influence of work on health but also the role of hard working conditions and employment on health status. If the international literature is plentiful, the French literature is more recent. In France, the effects of health events are more penalizing on the professional career when they onset in second part of career inviting in the implementation of a premature prevention in companies. The studies also underline fragile populations such as the anxious men. PMID- 27758755 TI - [The herbal pharmaceutical industry in India - Drug reformulation and the market (edited by Jean-Paul Gaudilliere and Laurent Pordie)]. PMID- 27758756 TI - [Synthesizing a human genome?] AB - The recently proposed " HGP-write " project aims to synthetize a full human genome and to introduce it into cells. This ambitious endeavour is fraught with financial and technical uncertainties and, if successful, would make " synthetic humans " a definite possibility even though this is not part of its announced goals. Accordingly, it has not been received with enthusiasm. PMID- 27758757 TI - [Mitotic reprogramming of sperm injected into haploid parthenogenotes embryos]. PMID- 27758758 TI - Effects of Rupatadine on Platelet- Activating Factor-Induced Human Mast Cell Degranulation Compared With Desloratadine and Levocetirizine (The MASPAF Study). AB - BACKGROUND AND OBJECTIVE: Platelet-activating factor (PAF) is a lipid mediator involved in the pathophysiology of several allergic diseases, for example, in the amplification of mast cell (MC) activation in anaphylaxis. Rupatadine is an antihistamine with a demonstrated anti-PAF effect, although its capacity to inhibit PAF-induced MC degranulation has not been fully evaluated. Objectives: To compare the ability of rupatadine to inhibit PAF-induced MC degranulation with that of desloratadine and levocetirizine and to confirm the dual anti-H1 and anti PAF activity of rupatadine. METHODS: The human MC line LAD2 and primary MCs (human lung tissue MCs [hLMCs]) were used. MC mediator release was evaluated using the b-hexosaminidase and histamine release assay. The effects of rupatadine (H1 antagonist + PAF receptor antagonist), desloratadine, and levocetirizine (H1 antagonists) on LAD2 and hLMCs were compared. The PAF receptor antagonists WEB2086, BN52021, and CV6209 were also tested. PAF receptor protein expression was evaluated in both LAD2 and hLMCs. RESULTS: CV6209 and rupatadine inhibited PAF-induced MC degranulation in both LAD2 and hLMCs. In LAD2, rupatadine (5 and 10 uM) and levocetirizine (5 uM), but not desloratadine, inhibited PAF-induced b hexosaminidase release. Rupatadine (1-10 uM), levocetirizine (1-10 uM), and desloratadine (10 uM) inhibited PAF-induced histamine release. Rupatadine at 10 uM had an inhibitory effect on hLMC degranulation, but levocetirizine and desloratadine did not. CONCLUSIONS: This study shows that rupatadine and, to a lesser extent, levocetirizine, but not desloratadine, inhibit PAF-induced degranulation in both LAD2 and hLMCs. These findings support the dual antihistamine and anti-PAF effect of rupatadine in allergic disorders. PMID- 27758759 TI - Nasal Ketorolac Challenge Using Acoustic Rhinometry in Patients With Aspirin Exacerbated Respiratory Disease. AB - BACKGROUND AND OBJECTIVE: Safer and less time-consuming alternatives to single blind placebo-controlled oral challenge (SBPCOC) have been sought for the diagnosis of aspirin-exacerbated respiratory disease (AERD). Nasal challenges with various nonsteroidal anti-inflammatory drugs and assessment methods have been developed. Objective: Our objective was to evaluate the utility and safety of nasal ketorolac challenge (NKC) using acoustic rhinometry in patients with suspected AERD. METHODS: The study population comprised 36 patients with suspected AERD. NKC was performed with placebo (saline) and 13 mg of ketorolac sprayed as aerosol into both nostrils. A positive challenge result was defined as an increase of >=30% in nasal symptoms (recorded using a visual analog scale) and a 30% drop in the sum of the volumes of both nasal cavities at 2-8 cm. Patients with a negative NKC result underwent SBPCOC with aspirin (cumulative dose of 750 mg). RESULTS: A naso-ocular reaction during NKC was detected in 21 patients. Four patients also developed mild asthma exacerbations (although only 1 experienced a decrease in FEV1 >15%). No other significant adverse events occurred. The remaining 15 patients with a negative NKC result had a negative response during aspirin SBPCOC. CONCLUSIONS: NKC assessed using acoustic rhinometry is a reliable method for the study of patients with AERD. We suggest that NKC assessed with acoustic rhinometry was useful and safe for selection of candidates for safe oral aspirin challenge. PMID- 27758760 TI - Primary cutaneous cryptococcosis successfully managed by surgical debridement and liposomal amphotericin B/flucytosine therapy. PMID- 27758761 TI - Eruptive disseminated Spitz nevi. AB - BACKGROUND: The solitary form of Spitz nevus is a common clinical entity in children, typically occurring on the face and extremities. However, less frequent variants of Spitz nevi, such as agminated forms and eruptive disseminated Spitz nevi (EDSN), have been described. The agminated form is characterised by localised clusters or segmental distribution of Spitz nevi on the face, back, or extremities. First described as "eruptive juvenile melanomata", EDSN is the rarest clinical variant, consisting of a widespread eruption of Spitz nevi, most frequently involving the trunk, buttocks, and proximal limbs, and usually occurs in the second to third decade of life. OBJECTIVES: To describe a case of EDSN and review the literature. MATERIALS & METHODS: Twenty-seven cases of EDSN, including a 12-year-old female patient with EDSN presented here, were reviewed. RESULTS: EDSN generally exhibits an abrupt, eruptive onset (developing over few months), followed by a slow progressive course of new lesions that continue to appear over a long period, resulting in hundreds of papules and nodules. In all reported cases, the EDSN lesions involved the trunk, often affecting the legs and arms, and sometimes the scalp. A number of possible precipitating factors were reported. CONCLUSION: A periodic self-examination, total body photography, a dermoscopic 3-6-month follow-up during the eruptive phase (extending to 9-12 months during the stable phase), and prompt surgical excision of lesions that may be malignant is recommended, however, to date, no malignant transformation of EDSN has been reported. PMID- 27758762 TI - Biomarkers of neuroendocrine tumors. AB - Neuroendocrine tumors (NET) are rare heterogenous tumors which prevalence is increasing. Their features vary by anatomical location, functionality and hormonal production. Their management needs a multidisciplinary approach. Functional tumors develop characteristic clinical syndromes in contrast to non functional tumors that are diagnosed fortuitously or at advanced stage. NET can secrete many specific and general biomarkers. CgA is the most sensitive general marker. Its value should be interpreted along with the renal function and the gastrin level. Some new biomarkers such as NTproBNP, proGRP and NET gene transcripts have been identified. The latter are not yet routine in clinical practice. We present In this review biological biomarkers involved in NET with a focus on the assays and their use in clinical practice. PMID- 27758763 TI - Diagnosis of nail psoriasis: evaluation of nail-derived microRNAs as potential novel biomarkers. AB - BACKGROUND: MicroRNA levels in sera or hair may potentially be useful biomarkers for various diseases. The diagnosis of nail diseases is sometimes difficult, and nail psoriasis without skin lesions is indistinguishable from nail changes caused by other diseases. OBJECTIVES: We evaluated nail microRNA levels as biomarkers for the diagnosis of psoriasis patients. MATERIALS & METHODS: MicroRNA levels were examined in psoriasis patients with (11 patients) and without (six patients) nail changes. Normal control nails were collected from 17 healthy subjects. Eight patients with other diseases who also had nail changes were also included as disease controls. RESULTS: Microarray, real-time PCR, and in situ hybridisation indicated that the expression levels of nail miR-4454 were decreased in psoriasis patients with nail changes, compared to those patients with other diseases involving nail change, or healthy subjects. The miR-4454 levels in nails showed a significant inverse correlation with the Nail Psoriasis Severity Index (NAPSI) score, suggesting that nail miR-4454 levels reflect nail condition. CONCLUSION: The levels of microRNAs in nails may be suitable biomarkers for diagnosis or evaluation of disease activity of psoriasis. PMID- 27758764 TI - Why is population information crucial for taxonomy? A case study involving a hybrid swarm and related varieties. AB - Hybridization has become a focal topic in evolutionary biology, and many taxonomists are aware that the process occurs more frequently than previously assumed. Nonetheless many species and varieties are still described without explicitly considering the possibility of hybridization, especially in countries that have relatively short scientific histories, but which often possess the highest species diversities. Furthermore, new taxa are often described based only on herbarium specimens, not taking into account information from wild populations, significantly decreasing the potential to detect morphologies arising from hybridization at this crucial descriptive stage. We used morphological data from a hybrid swarm involving two Rhododendron species to showcase possible character combinations in intermediates. Certain characters used to distinguish taxa were more variable within the same individual than between species, emphasizing the importance of population information for an adequate choice of characters. Most described varieties of the two species fell within the spectrum of hybrid morphology, suggesting that these taxa would be unlikely to have merited formal description if contemporary standards had been employed. In all investigated cases the hybrid nature of described varieties seems to have been detectable with adequate morphological data alone, if populations had been assessed. A post hoc assessment of taxa is often complicated, especially if certain types of information are not provided. To avoid accumulation of such invalid taxa, careful scrutiny should be employed for new descriptions. Hybrids (not hybrid species) described as taxa obscure valuable information about natural processes and impact negatively on further research that depends on taxonomic data. PMID- 27758766 TI - Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/beta-Catenin Canonical Signaling. AB - OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/beta-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation. Endothelial cell (EC) deletion of fzd7 (fzd7ECKO) delayed retinal plexus formation because of an impairment in tip cell phenotype and a decrease in stalk cell proliferation. Dvl (dishevelled) proteins are a main component of Wnt signaling and play a functionally redundant role. We found that Dvl3 depletion in dvl1-/- mice mimicked the fzd7ECKO vascular phenotype and demonstrated that Fzd7 acted via beta-catenin activation by showing that LiCl treatment rescued impairment in tip and stalk cell phenotypes induced in fzd7 mutants. Deletion of fzd7 or Dvl1/3 induced a strong decrease in Wnt canonical genes and Notch partners' expression. Genetic and pharmacological rescue strategies demonstrated that Fzd7 acted via beta-catenin activation, upstream of Notch signaling to control Dll4 and Jagged1 EC expression. CONCLUSIONS: Fzd7 expressed by EC drives postnatal angiogenesis via activation of Dvl/beta-catenin signaling and can control the integrative interaction of Wnt and Notch signaling during postnatal angiogenesis. PMID- 27758765 TI - AMP-Activated Protein Kinase and Sirtuin 1 Coregulation of Cortactin Contributes to Endothelial Function. AB - OBJECTIVE: Cortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly in response to pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined the hypothesis that AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress. APPROACH AND RESULTS: Analysis of the ability of AMPK to phosphorylate recombinant cortactin and oligopeptides whose sequences matched AMPK consensus sequences in cortactin pointed to Thr-401 as the site of AMPK phosphorylation. Mass spectrometry confirmed Thr-401 as the site of AMPK phosphorylation. Immunoblot analysis with AMPK siRNA and SIRT1 siRNA in human umbilical vein ECs and EC-specific AMPKalpha2 knockout mice showed that AMPK phosphorylation of cortactin primes SIRT1 deacetylation in response to shear stress. Immunoblot analyses with cortactin siRNA in human umbilical vein ECs, phospho-deficient T401A and phospho-mimetic T401D mutant, or aceto-deficient (9K/R) and aceto mimetic (9K/Q) showed that cortactin regulates endothelial nitric oxide synthase activity. Confocal imaging and sucrose-density gradient analyses revealed that the phosphorylated/deacetylated cortactin translocates to the EC periphery facilitating endothelial nitric oxide synthase translocation from lipid to nonlipid raft domains. Knockdown of cortactin in vitro or genetic reduction of cortactin expression in vivo in mice substantially decreased the endothelial nitric oxide synthase-derived NO bioavailability. In vivo, atherosclerotic lesions increase in ApoE-/-/cortactin+/- mice, when compared with ApoE-/ /cortactin+/+ littermates. CONCLUSIONS: AMPK phosphorylation of cortactin followed by SIRT1 deacetylation modulates the interaction of cortactin and cortical-actin in response to shear stress. Functionally, this AMPK/SIRT1 coregulated cortactin-F-actin dynamics is required for endothelial nitric oxide synthase subcellular translocation/activation and is atheroprotective. PMID- 27758767 TI - 2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C. AB - APC (activated protein C), derived from the plasma protease zymogen, is antithrombotic and anti-inflammatory. In preclinical injury models, recombinant APC provides neuroprotection for multiple injuries, including ischemic stroke. APC acts directly on brain endothelial cells and neurons by initiating cell signaling that requires multiple receptors. Two or more major APC receptors mediate APC's neuroprotective cell signaling. When bound to endothelial cell protein C receptor, APC can cleave protease-activated receptor 1, causing biased cytoprotective signaling that reduces ischemia-induced injury. Pharmacological APC alleviates bleeding induced by tissue-type plasminogen activator in murine ischemic stroke studies. Remarkably, APC's signaling promotes neurogenesis. The signaling-selective recombinant variant of APC, 3K3A-APC, was engineered to lack most of the APC's anticoagulant activity but retain APC's cell signaling actions. Recombinant 3K3A-APC is in ongoing National Institutes of Health (NIH)-funded clinical trials for ischemic stroke. PMID- 27758768 TI - Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets. AB - OBJECTIVE: Although initially seemingly paradoxical because of the lack of nucleus, platelets possess many transcription factors that regulate their function through DNA-independent mechanisms. These include the farnesoid X receptor (FXR), a member of the superfamily of ligand-activated transcription factors, that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6alpha-ethyl chenodeoxycholic acid, modulate platelet activation nongenomically. APPROACH AND RESULTS: FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization, secretion, fibrinogen binding, and aggregation. Exposure to FXR ligands also reduced integrin alphaIIbbeta3 outside in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR. CONCLUSIONS: This study provides support for the ability of FXR ligands to modulate platelet activation. The atheroprotective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for the prevention of atherothrombotic disease. PMID- 27758769 TI - ABCA1 (ATP-Binding Cassette Transporter A1) Mediates ApoA-I (Apolipoprotein A-I) and ApoA-I Mimetic Peptide Mobilization of Extracellular Cholesterol Microdomains Deposited by Macrophages. AB - OBJECTIVE: We examined the function of ABCA1 (ATP-binding cassette transporter A1) in ApoA-I (apolipoprotein A-I) mobilization of cholesterol microdomains deposited into the extracellular matrix by cholesterol-enriched macrophages. We have also determined whether an ApoA-I mimetic peptide without and with complexing to sphingomyelin can mobilize macrophage-deposited cholesterol microdomains. APPROACH AND RESULTS: Extracellular cholesterol microdomains deposited by cholesterol-enriched macrophages were detected with a monoclonal antibody, 58B1. ApoA-I and an ApoA-I mimetic peptide 5A mobilized cholesterol microdomains deposited by ABCA1+/+ macrophages but not by ABCA1-/- macrophages. In contrast, ApoA-I mimetic peptide 5A complexed with sphingomyelin could mobilize cholesterol microdomains deposited by ABCA1-/- macrophages. CONCLUSIONS: Our findings show that a unique pool of extracellular cholesterol microdomains deposited by macrophages can be mobilized by both ApoA-I and an ApoA-I mimetic peptide but that mobilization depends on macrophage ABCA1. It is known that ABCA1 complexes ApoA-I and ApoA-I mimetic peptide with phospholipid, a cholesterol solubilizing agent, explaining the requirement for ABCA1 in extracellular cholesterol microdomain mobilization. Importantly, ApoA-I mimetic peptide already complexed with phospholipid can mobilize macrophage-deposited extracellular cholesterol microdomains even in the absence of ABCA1. PMID- 27758770 TI - Small GTPase ARF6 Regulates Endocytic Pathway Leading to Degradation of ATP Binding Cassette Transporter A1. AB - OBJECTIVE: ABCA1 (ATP-binding cassette transporter A1) is the principal protein responsible for cellular cholesterol efflux. Abundance and functionality of ABCA1 is regulated both transcriptionally and post-translationally, with endocytosis of ABCA1 being an important element of post-translational regulation. Functional ABCA1 resides on the plasma membrane but can be internalized and either degraded or recycled back to the plasma membrane. The interaction between the degradative and recycling pathways determines the abundance of ABCA1 and may contribute to the efflux of intracellular cholesterol. APPROACH AND RESULTS: Here, we show that the principal pathway responsible for the internalization of ABCA1 leading to its degradation in macrophages is ARF6-dependent endocytic pathway. This pathway was predominant in the regulation of ABCA1 abundance and efflux of plasma membrane cholesterol. Conversely, the efflux of intracellular cholesterol was predominantly controlled by ARF6-independent pathways, and inhibition of ARF6 shifted ABCA1 into recycling endosomes enhancing efflux of intracellular cholesterol. CONCLUSIONS: We conclude that ARF6-dependent pathway is the predominant route responsible for the ABCA1 internalization and degradation, whereas ARF6-independent endocytic pathways may contribute to ABCA1 recycling and efflux of intracellular cholesterol. PMID- 27758773 TI - Emergency Department MRI Scanning of Patients with Multiple Sclerosis: Worthwhile or Wasteful? AB - BACKGROUND AND PURPOSE: The increasing use of the emergency department MR imaging scanner at our institution raises questions about its added value to certain patient groups. We hypothesized that the use of emergency department MR imaging for identifying active demyelination in MS patients presenting with new neurologic symptoms would be of low yield. MATERIALS AND METHODS: Electronic medical records were reviewed for patients with MS who had emergency department MR imaging scans for a suspected MS exacerbation between March 1, 2014, and March 1, 2016. Details surrounding patient disposition, imaging, diagnosis, and management were determined. RESULTS: Of 115 patients in our study, 48 (41.7%) were ultimately diagnosed with an MS exacerbation. Nearly all patients with MS exacerbations (87.5%, 42/48) had active demyelination on their emergency department MR imaging, identified on 30.6% (33/108) of brain MRIs and 20.4% (19/93) of spinal MRIs. The presence of active demyelination at MRI was significantly associated with the ultimate diagnosis of an MS exacerbation (P < .001). MR imaging activity isolated to the spinal cord (ie, not found on concurrent brain MR imaging) was present in only 9 of 93 (9.7%) cases. Pseudoexacerbations accounted for 18 of the alternative diagnoses. CONCLUSIONS: Emergency department MR imaging is a worthwhile endeavor from a diagnostic standpoint for MS exacerbations despite not being part of the diagnostic criteria. This finding has corresponding downstream impact on management decisions to admit and/or administer intravenous steroids. However, we raise the question of whether clinicians over-rely on emergency department imaging for making exacerbation diagnoses. Additionally, spinal MR imaging is of questionable value as an addition to brain MR imaging due to a low yield of isolated spinal disease. PMID- 27758772 TI - Effect of Systemic Therapies on Outcomes following Vertebroplasty among Patients with Multiple Myeloma. AB - BACKGROUND AND PURPOSE: The role of vertebroplasty in patients with myeloma remains relatively undefined. Accordingly, we sought to better define the efficacy of vertebroplasty for myeloma-associated fractures and determine the effect of procedure timing relative to the initiation of systemic therapy on outcomes and complication rates. MATERIALS AND METHODS: Clinical, laboratory, and medication data were retrieved for 172 patients with multiple myeloma treated with vertebroplasty since October 2000. Quantitative outcome data (Roland-Morris Disability Questionnaire [scale, 0-24] and the Numeric Rating Scale [0-10] for pain at rest and with activity) were collected immediately pre- and postoperatively and at 1 week, 1 month, 6 months, and 1 year following vertebroplasty. Patients with >=50% improvement on the Numeric Rating Scale and >=40% improvement on the Roland-Morris Disability Questionnaire were classified as "responders." Peri- and postoperative complications were also collected. RESULTS: Significant median improvement in the Roland-Morris Disability and rest and activity Numeric Rating Scale scores (15, 2, and 6 points, respectively; P < .0001) persisted at 1 year without significant change from the immediate postoperative scores (P > .36). Patients on systemic therapy at the time of vertebroplasty were more likely to achieve "responder status," compared with patients not on systemic therapy, for the Numeric Rating Scale pain at rest score (P < .01) and the Roland-Morris Disability Questionnaire score (P < .003), with no difference in complication rates (chi2 = 0.17, P = .68). CONCLUSIONS: Vertebroplasty is an effective therapy for patients with myeloma with symptomatic compression fractures. Favorable outcomes are more likely to be achieved when spinal augmentation is performed after systemic therapy is initiated. Complication rates were not affected by the timing of systemic therapy. PMID- 27758771 TI - TLR9 activation suppresses inflammation in response to Helicobacter pylori infection. AB - Helicobacter pylori (H. pylori) induces chronic gastritis in humans, and infection can persist for decades. One H. pylori strain-specific constituent that augments disease risk is the cag pathogenicity island. The cag island encodes a type IV secretion system (T4SS) that translocates DNA into host cells. Toll-like receptor 9 (TLR9) is an innate immune receptor that detects hypo-methylated CpG DNA motifs. In this study, we sought to define the role of the H. pylori cag T4SS on TLR9-mediated responses in vivo. H. pylori strain PMSS1 or its cagE- mutant, which fails to assemble a T4SS, were used to infect wild-type or Tlr9-/- C57BL/6 mice. PMSS1-infected Tlr9-/- mice developed significantly higher levels of inflammation, despite similar levels of colonization density, compared with PMSS1 infected wild-type mice. These changes were cag dependent, as both mouse genotypes infected with the cagE- mutant only developed minimal inflammation. Tlr9-/- genotypes did not alter the microbial phenotypes of in vivo-adapted H. pylori strains; therefore, we examined host immunological responses. There were no differences in levels of TH1 or TH2 cytokines in infected mice when stratified by host genotype. However, gastric mucosal levels of IL-17 were significantly increased in infected Tlr9-/- mice compared with infected wild-type mice, and H. pylori infection of IL-17A-/- mice concordantly led to significantly decreased levels of gastritis. Thus loss of Tlr9 selectively augments the intensity of IL 17-driven immune responses to H. pylori in a cag T4SS-dependent manner. These results suggest that H. pylori utilizes the cag T4SS to manipulate the intensity of the host immune response. PMID- 27758774 TI - Body Temperature Modulates Infarction Growth following Endovascular Reperfusion. AB - BACKGROUND AND PURPOSE: The neuronal substrate is highly sensitive to temperature elevation; however, its impact on the fate of the ischemic penumbra has not been established. We analyzed interactions between temperature and penumbral expansion among successfully reperfused patients with acute ischemic stroke, hypothesizing infarction growth and worse outcomes among patients with fever who achieve full reperfusion. MATERIALS AND METHODS: Data from 129 successfully reperfused (modified TICI 2b/3) patients (mean age, 65 +/- 15 years) presenting within 12 hours of onset were examined from a prospectively collected acute ischemic stroke registry. CT perfusion was analyzed to produce infarct core, hypoperfusion, and penumbral mismatch volumes. Final DWI infarction volumes were measured, and relative infarction growth was computed. Systemic temperatures were recorded throughout hospitalization. Correlational and logistic regression analyses assessed the associations between fever (>37.5 degrees C) and both relative infarction growth and favorable clinical outcome (90-day mRS of <=2), corrected for NIHSS score, reperfusion times, and age. An optimized model for outcome prediction was computed by using the Akaike Information Criterion. RESULTS: The median presentation NIHSS score was 18 (interquartile range, 14-22). Median (interquartile range) CTP-derived volumes were: core = 9.6 mL (1.5-25.3 mL); hypoperfusion = 133 mL (84.2-204 mL); and final infarct volume = 9.6 mL (8.3-45.2 mL). Highly significant correlations were observed between temperature of >37.5 degrees C and relative infarction growth (Kendall tau correlation coefficient = 0.24, P = .002). Odds ratios for favorable clinical outcome suggested a trend toward significance for fever in predicting a 90-day mRS of <=2 (OR = 0.31, P = .05). The optimized predictive model for favorable outcomes included age, NIHSS score, procedure time to reperfusion, and fever. Likelihood ratios confirmed the superiority of fever inclusion (P < .05). Baseline temperature, range, and maximum temperature did not meet statistical significance. CONCLUSIONS: These findings suggest that imaging and clinical outcomes may be affected by systemic temperature elevations, promoting infarction growth despite reperfusion. PMID- 27758775 TI - Acute Ischemic Stroke Infarct Topology: Association with Lesion Volume and Severity of Symptoms at Admission and Discharge. AB - BACKGROUND AND PURPOSE: Acute stroke presentation and outcome depend on both ischemic infarct volume and location. We aimed to determine the association between acute ischemic infarct topology and lesion volume and stroke severity at presentation and discharge. MATERIALS AND METHODS: Patients with acute ischemic stroke who underwent MR imaging within 24 hours of symptom onset or last seen well were included. Infarcts were segmented and coregistered on the Montreal Neurological Institute-152 brain map. Voxel-based analyses were performed to determine the distribution of infarct lesions associated with larger volumes, higher NIHSS scores at admission and discharge, and greater NIHSS/volume ratios. RESULTS: A total of 238 patients were included. Ischemic infarcts involving the bilateral lentiform nuclei, insular ribbons, middle corona radiata, and right precentral gyrus were associated with larger infarct volumes (average, 76.7 +/- 125.6 mL versus 16.4 +/- 24.0 mL, P < .001) and higher admission NIHSS scores. Meanwhile, brain stem and thalami infarctions were associated with higher admission NIHSS/volume ratios. The discharge NIHSS scores were available in 218 patients, in whom voxel-based analysis demonstrated that ischemic infarcts of the bilateral posterior insular ribbons, middle corona radiata, and right precentral gyrus were associated with more severe symptoms at discharge, whereas ischemic lesions of the brain stem, bilateral thalami, and, to a lesser extent, the middle corona radiata were associated with higher ratios of discharge NIHSS score/infarct volume. CONCLUSIONS: Acute ischemic infarcts of the insulae, lentiform nuclei, and middle corona radiata tend to have larger volumes, more severe presentations, and worse outcomes, whereas brain stem and thalamic infarcts have greater symptom severity relative to smaller lesion volumes. PMID- 27758776 TI - The Effects of Acetazolamide on the Evaluation of Cerebral Hemodynamics and Functional Connectivity Using Blood Oxygen Level-Dependent MR Imaging in Patients with Chronic Steno-Occlusive Disease of the Anterior Circulation. AB - BACKGROUND AND PURPOSE: Measuring cerebrovascular reactivity with the use of vasodilatory stimuli, such as acetazolamide, is useful for chronic cerebrovascular steno-occlusive disease. The purpose of this study was to evaluate the effects of acetazolamide on the assessment of hemodynamic impairment and functional connectivity by using noninvasive resting-state blood oxygen level dependent MR imaging. MATERIALS AND METHODS: A 20-minute resting-state blood oxygen level-dependent MR imaging scan was acquired with infusion of acetazolamide starting at 5 minutes after scan initiation. A recently developed temporal-shift analysis technique was applied on blood oxygen level-dependent MR imaging data before and after acetazolamide infusion to identify regions with hemodynamic impairment, and the results were compared by using contrast agent based DSC perfusion imaging as the reference standard. Functional connectivity was compared with and without correction on the signal by using information from temporal-shift analysis, before and after acetazolamide infusion. RESULTS: Visually, temporal-shift analysis of blood oxygen level-dependent MR imaging data identified regions with compromised hemodynamics as defined by DSC, though performance deteriorated in patients with bilateral disease. The Dice similarity coefficient between temporal-shift and DSC maps was higher before (0.487 +/- 0.150 by using the superior sagittal sinus signal as a reference for temporal shift analysis) compared with after acetazolamide administration (0.384 +/- 0.107) (P = .006, repeated-measures ANOVA). Functional connectivity analysis with temporal-shift correction identified brain network nodes that were otherwise missed. The accuracy of functional connectivity assessment decreased after acetazolamide administration (P = .015 for default mode network, repeated measures ANOVA). CONCLUSIONS: Temporal-shift analysis of blood oxygen level dependent MR imaging can identify brain regions with hemodynamic compromise in relation to DSC among patients with chronic cerebrovascular disease. The use of acetazolamide reduces the accuracy of temporal-shift analysis and network connectivity evaluation. PMID- 27758777 TI - Five minutes with . . . Kate Lovett. PMID- 27758778 TI - Young men conceived by ICSI have lower sperm quality, finds study. PMID- 27758779 TI - David Oliver: Hospitals are not the enemy. PMID- 27758780 TI - Therapeutic hypothermia has no benefit for in-hospital cardiac arrest, study finds. PMID- 27758781 TI - A plain radiograph in back pain. PMID- 27758782 TI - CCG axes funding for homeopathy. PMID- 27758783 TI - NHS unveils service to help GPs with burnout. PMID- 27758785 TI - A girl with left wrist deformity. PMID- 27758784 TI - Doctors who prescribe antibiotics online face GMC investigation. PMID- 27758786 TI - GP leader attacks CCGs for L30m underspend. PMID- 27758788 TI - Most CCGs in England are failing to meet standards on cancer care. PMID- 27758789 TI - Questions hang over European patent for hepatitis C drug after ruling. PMID- 27758790 TI - NICE recommends new triple therapy option for type 2 diabetes. PMID- 27758791 TI - Diabetes prescribing rises by a third over five years. PMID- 27758792 TI - Beyond open data: realising the health benefits of sharing data. PMID- 27758793 TI - Refugee crisis presents a humanitarian paradox. PMID- 27758794 TI - Severe human monocytic ehrlichiosis presenting with altered mental status and seizures. AB - A previously healthy 66-year-old woman living in the Mid-Atlantic USA presented to the hospital with lethargy, ataxia and slurred speech. 2 weeks prior she had removed a tick from her right groin. She reported malaise, fevers, diarrhoea, cough and a rash. Physical examination revealed a maculopapular rash on her chest, and lung auscultation revealed bi-basilar rales. Laboratory tests were remarkable for hyponatraemia, leucopenia and thrombocytopenia. Chest X-ray demonstrated bilateral pleural effusions with pulmonary oedema. She was treated with ceftriaxone and azithromycin for possible community-acquired pneumonia but declining mental status necessitated intensive care unit transfer. Vancomycin and doxycycline were added. Her course was complicated by seizures requiring antiepileptic therapy. Peripheral blood smear demonstrated morulae in monocytes. Serum Ehrlichia chaffeensis DNA was positive confirming the diagnosis of human monocytic ehrlichiosis. She recovered without residual neurological deficits after 10 days of doxycycline therapy. PMID- 27758795 TI - Ascites: it is not all alcohol-a case of constrictive pericarditis. PMID- 27758796 TI - Severe hypercalcaemia in a child secondary to use of alternative therapies. AB - We describe a case of a 4-year-old boy who presented with acute vomiting, weight loss, loss of appetite, polyuria and polydipsia. Initial investigations revealed a very elevated corrected calcium level which peaked at 4.46 mmol/L. He had a prior diagnosis of autism and his mother had consulted an alternative therapist who had recommended many supplements, including calcium and vitamin D. He required treatment with hyperhydration, calcitonin, furosemide and several doses of pamindronate before his calcium level returned to the normal range 2 weeks later. PMID- 27758797 TI - US traffic deaths show sharp increase. PMID- 27758798 TI - CONSORT extension for reporting N-of-1 trials (CENT) 2015 Statement. PMID- 27758799 TI - Oldest people are most likely to experience care abuse, shows report. PMID- 27758801 TI - Eating oats reduces three markers of cardiovascular risk, finds study. PMID- 27758800 TI - Commentary: data sharing in South East Asia. PMID- 27758802 TI - In individuals at intermediate risk for cardiovascular disease, treatment with rosuvastatin but not candesartan plus hydrochlorothiazide lowers cardiovascular disease event rates. PMID- 27758803 TI - US blood testing company cuts workforce by 40. PMID- 27758805 TI - Diagnosis and Therapy in The Anticipatory Corpse: A Second Opinion. AB - In The Anticipatory Corpse, Jeffrey Bishop claims that modern medicine has lost formal and final causality as the dead body has become epistemologically normative, and that a singular focus on efficient and material causality has thoroughly distorted modern medical practice. Bishop implies that the renewal of medicine will require its housing in alternate social spaces. This essay critiques both Bishop's diagnosis and therapy by arguing, first, that alternate social imaginaries, though perhaps marginalized, are already present within the practice of medicine. And second, the essay argues that alternate social imaginaries in medicine can be reclaimed not through separatist communities but in the re-narration of conceptually underdetermined practices. Given Bishop's invitation for theology to engage medicine, this essay then draws from theologian Dietrich Bonhoeffer for the kind of diagnosis and therapy currently needed, concluding with a contemporary example of how an alternate social imaginary is being instantiated in modern medicine. PMID- 27758804 TI - Tramadol metabolism to O-desmethyl tramadol (M1) and N-desmethyl tramadol (M2) by dog liver microsomes: Species comparison and identification of responsible canine cytochrome P-450s (CYPs). AB - Tramadol is widely used to manage mild to moderately painful conditions in dogs. However, this use is controversial since clinical efficacy studies in dogs showed conflicting results, while pharmacokinetic studies demonstrated relatively low circulating concentrations of O-desmethyltramadol (M1). Analgesia has been attributed to the opioid effects of M1, while tramadol and the other major metabolite (N-desmethyltramadol, M2) are considered inactive at opioid receptors. The aims of this study were to determine whether cytochrome P450 (CYP) dependent M1 formation by dog liver microsomes is slower compared with cat and human liver microsomes; and identify the CYPs responsible for M1 and M2 formation in canine liver. Since tramadol is used as a racemic mixture of (+)- and (-)-stereoisomers, both (+)-tramadol and (-)- tramadol were evaluated as substrates. M1 formation from tramadol by liver microsomes from dogs was slower than from cats (3.9-fold), but faster than humans (7-fold). However, M2 formation by liver microsomes from dogs was faster than from cats (4.8-fold) and humans (19-fold). Recombinant canine CYP activities indicated that M1 was formed by CYP2D15, while M2 was largely formed by CYP2B11 and CYP3A12. This was confirmed by dog liver microsomes studies that showed selective inhibition of M1 formation by quinidine and M2 formation by chloramphenicol and CYP2B11 antiserum, and induction of M2 formation by phenobarbital. Findings were similar for both (+)-tramadol and (-)-tramadol. In conclusion, low circulating M1 concentrations in dogs is explained in part by low M1 formation and high M2 formation, which are mediated by CYP2D15 and CYP2B11/CYP3A12, respectively. PMID- 27758806 TI - Beyond The Anticipatory Corpse-Future Perspectives for Bioethics. AB - This essay explores the two main objectives of Bishop's book, which he analyzes in the context of the care for the dying: (1) the medical metaphysics underlying medical science and (2) biopolitics as governance of the human body. This essay discusses Bishop's claims in view of newer developments in medicine, especially the turn to the construction of life, and confronts the concept of the patient's sovereignty with an alternative model of vulnerable agency. In order to overcome the impasses of contemporary bioethics, the essay argues that practical reason requires a two-fold ethics: first, it must develop a new hermeneutics of illness and disease, and second, in order to protect the individuals in the process of dying, moral claims concerning death must be based on the concept of human rights. PMID- 27758808 TI - Inter-kingdom prediction certainty evaluation of protein subcellular localization tools: microbial pathogenesis approach for deciphering host microbe interaction. AB - Microbial pathogenesis involves several aspects of host-pathogen interactions, including microbial proteins targeting host subcellular compartments and subsequent effects on host physiology. Such studies are supported by experimental data, but recent detection of bacterial proteins localization through computational eukaryotic subcellular protein targeting prediction tools has also come into practice. We evaluated inter-kingdom prediction certainty of these tools. The bacterial proteins experimentally known to target host subcellular compartments were predicted with eukaryotic subcellular targeting prediction tools, and prediction certainty was assessed. The results indicate that these tools alone are not sufficient for inter-kingdom protein targeting prediction. The correct prediction of pathogen's protein subcellular targeting depends on several factors, including presence of localization signal, transmembrane domain and molecular weight, etc., in addition to approach for subcellular targeting prediction. The detection of protein targeting in endomembrane system is comparatively difficult, as the proteins in this location are channelized to different compartments. In addition, the high specificity of training data set also creates low inter-kingdom prediction accuracy. Current data can help to suggest strategy for correct prediction of bacterial protein's subcellular localization in host cell. PMID- 27758809 TI - Dying With a Left Ventricular Assist Device as Destination Therapy. AB - BACKGROUND: Despite the ability of left ventricular assist device as destination therapy (DT-LVAD) to prolong survival for many patients with advanced heart failure, little is known about the eventual end-of-life care that patients with DT-LVAD receive. METHODS AND RESULTS: All patients undergoing DT-LVAD at the Mayo Clinic in Rochester, Minnesota, from January 1, 2007, to September 30, 2014, who subsequently died before July 1, 2015, were included. Information about end-of life care was obtained from documentation in the electronic medical record. Of 89 patients who died with a DT-LVAD, the median (25th-75th percentile) time from left ventricular assist device implantation to death was 14 (4-31) months. The most common causes of death were multiorgan failure (26%), hemorrhagic stroke (24%), and progressive heart failure (21%). Nearly half (46%) of the patients saw palliative care within 1 month before death; however, only 13 (15%) patients enrolled in hospice a median 11 (range 1-315) days before death. Most patients (78%) died in the hospital, of which 88% died in the intensive care unit. In total, 49 patients had their left ventricular assist device deactivated before death, with all but 3 undergoing deactivation in the hospital. Most patients died within an hour of left ventricular assist device deactivation and all within 26 hours. CONCLUSIONS: In contrast to the general heart failure population, most patients with DT-LVAD die in the hospital and few use hospice. Further work is needed to understand these differences and to determine whether patients with DT LVAD are receiving optimal end-of-life care. PMID- 27758810 TI - Impact of Socioeconomic Status on Patients Supported With a Left Ventricular Assist Device: An Analysis of the UNOS Database (United Network for Organ Sharing). AB - BACKGROUND: Low socioeconomic status (SES) is a known risk factor for heart failure, mortality among those with heart failure, and poor post heart transplant (HT) outcomes. This study sought to determine whether SES is associated with decreased waitlist survival while on left ventricular assist device (LVADs) support and after HT. METHODS AND RESULTS: A total of 3361 adult patients bridged to primary HT with an LVAD between May 2004 and April 2014 were identified in the UNOS database (United Network for Organ Sharing). SES was measured using the Agency for Healthcare Research and Quality SES index using data from the 2014 American Community Survey. In the study cohort, SES did not have an association with the combined end point of death or delisting on LVAD support (P=0.30). In a cause-specific unadjusted model, those in the top (hazard ratio, 1.55; 95% confidence interval, 1.14-2.11; P=0.005) and second greatest SES quartile (hazard ratio 1.50; 95% confidence interval, 1.10-2.04; P=0.01) had an increased risk of death on device support compared with the lowest SES quartile. Adjusting for clinical risk factors mitigated the increased risk. There was no association between SES and complications. Post-HT survival, both crude and adjusted, was decreased for patients in the lowest quartile of SES index compared with all other SES quartiles. CONCLUSIONS: Freedom from waitlist death or delisting was not affected by SES. Patients with a higher SES had an increased unadjusted risk of waitlist mortality during LVAD support, which was mitigated by adjusting for increased comorbid conditions. Low SES was associated with worse post-HT outcomes. Further study is needed to confirm and understand a differential effect of SES on post-transplant outcomes that was not seen during LVAD support before HT. PMID- 27758812 TI - Palliative Care Throughout the Journey of Life With a Left Ventricular Assist Device. PMID- 27758811 TI - Left Atrial Remodeling and Atrioventricular Coupling in a Canine Model of Early Heart Failure With Preserved Ejection Fraction. AB - BACKGROUND: Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. METHODS AND RESULTS: Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13-24]% versus 12 [10-14]%, P=0.008; end-systolic pressure-volume relationship slope 2.4 [1.9-3.2]mm Hg/mL HFpEF versus 1.5 [1.2-2.2]mm Hg/mL controls, P=0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [betaLA] 0.16 [0.11-0.18]mm Hg/mL versus 0.06 [0.04-0.10]mm Hg/mL controls; P=0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with betaLA. LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with betaLA. CONCLUSIONS: In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling. PMID- 27758813 TI - Tuberculous meningitis in an immunocompetent male complicated by hydrocephalus. AB - A 39-year-old man, born in India but resident in the UK for 10 years, was travelling in America when he became feverish with an altered mentation. He reported a 10-day history of fever, photophobia, headache and fatigue. His medical history included hypothyroidism and migraine. He was a non-smoker, did not consume alcohol and denied a history of drug use. He was transferred to the emergency department. Laboratory investigations confirmed hyponatraemia (sodium 128 mmol/L). A chest radiograph confirmed no focal consolidation. Further investigation with a CT brain was unremarkable. A lumbar puncture was suggestive of viral meningitis, with a raised white cell count, lymphocytosis, high protein and low glucose. His PCR was negative for enterovirus and herpes simplex virus. Further investigation with a CT thorax, abdomen and pelvis demonstrated bilateral upper-lobe infiltrations. A bronchoalveolar lavage was negative for acid alcohol fast bacilli (AAFB). A diagnosis of tuberculous meningitis was rendered following a repeat lumbar puncture. Gram stain revealed AAFB and PCR was also positive. He started antitubercular treatment and corticosteroids. A repeat CT brain demonstrated ventriculomegaly, suggestive of hydrocephalus and an MRI head revealed likely communicating hydrocephalus with basilar enhancement. He was repatriated to the UK. Eleven days post transfer, he became acutely confused and required external ventricular drain insertion. After surgical management of his hydrocephalus, there was no further neurological deterioration. He remains committed to his neurorehabilitation. PMID- 27758814 TI - Unusual case of globe perforation: the brittle cornea without systemic manifestations. AB - Brittle cornea syndrome is a rare generalised connective tissue disorder with ocular features like keratoglobus or keratoconus, severe corneal thinning and a high risk of perforation. Various authors in different case reports and case series have brought out the fact that brittle cornea is a disorder with characteristic systemic manifestations such as deafness, joint hypermobility, hyperelasticity of skin, kyphoscoliosis and dental abnormalities alongwith ophthalmic features. We report a case of globe perforation following trivial trauma, in an individual with brittle cornea without any extraocular manifestations, posing a challenge in the diagnosis and dilemma in surgical repair of cornea, restoration of globe integrity and visual rehabilitation. The absence of systemic manifestations decreased the index of suspicion and led to a surprise in the theatre-a point this case emphasised. PMID- 27758815 TI - Congenitally missing primary and permanent maxillary lateral incisors. AB - Congenitally missing tooth/teeth are a common developmental abnormality. It is defined as the developmental absence of tooth/teeth excluding the third molars. It is more commonly seen in permanent dentition but rarely in primary dentition. This paper reports a rare case of non-syndromic bilaterally missing primary and permanent lateral incisors in the maxillary region. PMID- 27758816 TI - Treatment of orbital solitary fibrous tumour with gamma knife radiosurgery and systematic review of literature. AB - Solitary fibrous tumours (SFTs) are relatively rare tumours that were originally thought to arise from the pleura but have thereafter been demonstrated as occurring anywhere in the body. These tumours are generally considered benign but have frequently been noted for recurrence and local invasion. Furthermore, their indolence is controversial due to increasing evidence implicating the existence of a spectrum that includes hemangiopericytoma (HPC). Stereotactic radiosurgery (SRS) has been well characterised in the treatment of benign, malignant and vascular conditions, and it appears to be a reasonable option as adjuvant or recurrent treatment for intracranial SFTs. We present in this case the first complete description of an SFT of the orbit treated by SRS as well as a systematic review of available English literature for intracranial SFTs treated by SRS. We report effective local tumour control in our case and conclude that SRS is a reasonable treatment option for recurrent SFT. PMID- 27758817 TI - Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome. AB - Bing Neel syndrome is a rare disease manifestation of Waldenstrom's macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenstrom's macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation. PMID- 27758818 TI - Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDSFlow working group. AB - Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117+ erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84 94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86-97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage. PMID- 27758819 TI - The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells. AB - The development of inhibitory antibodies to therapeutic factor VIII is the major complication of replacement therapy in patients with hemophilia A. The first step in the initiation of the anti-factor VIII immune response is factor VIII interaction with receptor(s) on antigen-presenting cells, followed by endocytosis and presentation to naive CD4+ T cells. Recent studies indicate a role for the C1 domain in factor VIII uptake. We investigated whether charged residues in the C2 domain participate in immunogenic factor VIII uptake. Co-incubation of factor VIII with BO2C11, a monoclonal C2-specific immunoglobulin G, reduced factor VIII endocytosis by dendritic cells and presentation to CD4+ T cells, and diminished factor VIII immunogenicity in factor VIII-deficient mice. The mutation of basic residues within the BO2C11 epitope of C2 replicated reduced in vitro immunogenic uptake, but failed to prevent factor VIII immunogenicity in mice. BO2C11 prevents factor VIII binding to von Willebrand factor, thus potentially biasing factor VIII immunogenicity by perturbing its half-life. Interestingly, a factor VIIIY1680C mutant, that does not bind von Willebrand factor, demonstrated unaltered endocytosis by dendritic cells as well as immunogenicity in factor VIII deficient mice. Co-incubation of factor VIIIY1680C with BO2C11, however, resulted in decreased factor VIII immunogenicity in vivo In addition, a previously described triple C1 mutant showed decreased uptake in vitro, and reduced immunogenicity in vivo, but only in the absence of endogenous von Willebrand factor. Taken together, the results indicate that residues in the C1 and/or C2 domains of factor VIII are implicated in immunogenic factor VIII uptake, at least in vitro Conversely, in vivo, the binding to endogenous von Willebrand factor masks the reducing effect of mutations in the C domains on factor VIII immunogenicity. PMID- 27758820 TI - ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil platelet interactions in sickle cell disease. AB - Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50-500 nM ARQ 092 significantly blocks alphaMbeta2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-alpha. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease. PMID- 27758821 TI - Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus host disease prophylaxis in haploidentical transplant. AB - Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia. PMID- 27758822 TI - Mediastinal gray zone lymphoma: clinico-pathological characteristics and outcomes of 99 patients from the Lymphoma Study Association. AB - Mediastinal gray zone lymphoma, B-cell lymphomas with intermediate features between classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, have not been well described in the literature. We report the clinical characteristics and outcomes of a large retrospective series of 99 cases centrally reviewed by a panel of hematopathologists, with a consensus established for the diagnosis. Cases were defined as classical Hodgkin lymphoma-like morphology (64.6%) with primary mediastinal B-cell lymphoma immunophenotype, primary mediastinal B-cell lymphoma-like morphology (30.3%) with classical Hodgkin lymphoma or composite (5.1%) (synchronous occurrence of classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma). The median age was 32 years (13-83 years); 55% were women. Thirteen of 81 evaluable cases (16%) were Epstein-Barr virus-positive. Twenty-eight percent of patients presented primary refractory disease (progression under first-line treatment or relapse within one year). The 3-year event-free and overall survival rates were 63% and 80%, respectively. Patients treated with a standard regimen (RCHOP/ABVD) had worse event-free survival (P=0.003) and overall survival (P=0.02) than those treated with a dose-intensive chemotherapy (high-dose RCHOP/escalated BEACOPP). Rituximab added to chemotherapy was not associated with better event-free survival (P=0.55) or overall survival (P=0.88). Radiotherapy for patients in complete remission had no impact on event free survival. In multivariate prognostic analysis, ECOG-PS and anemia were the strongest factors associated with a shorter event-free survival and overall survival, respectively. In conclusion, this report describes the largest series of mediastinal gray zone lymphoma. Our data suggest that a dose-intensive treatment might improve the outcome of this rare and aggressive disease. PMID- 27758823 TI - Myelodysplastic syndrome can propagate from the multipotent progenitor compartment. PMID- 27758824 TI - CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T acute lymphoblastic leukemic cells. PMID- 27758825 TI - Absence of CALR mutations in JAK2-negative polycythemia. PMID- 27758826 TI - Misidentification of Bupropion Glucuronide Metabolites and Re-evaluation of Metabolite Pharmacokinetics. PMID- 27758827 TI - Correction to "Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo". PMID- 27758828 TI - Night Shift Work and Breast Cancer Incidence: Three Prospective Studies and Meta analysis of Published Studies. AB - BACKGROUND: It has been proposed that night shift work could increase breast cancer incidence. A 2007 World Health Organization review concluded, mainly from animal evidence, that shift work involving circadian disruption is probably carcinogenic to humans. We therefore aimed to generate prospective epidemiological evidence on night shift work and breast cancer incidence. METHODS: Overall, 522 246 Million Women Study, 22 559 EPIC-Oxford, and 251 045 UK Biobank participants answered questions on shift work and were followed for incident cancer. Cox regression yielded multivariable-adjusted breast cancer incidence rate ratios (RRs) and 95% confidence intervals (CIs) for night shift work vs no night shift work, and likelihood ratio tests for interaction were used to assess heterogeneity. Our meta-analyses combined these and relative risks from the seven previously published prospective studies (1.4 million women in total), using inverse-variance weighted averages of the study-specific log RRs. RESULTS: In the Million Women Study, EPIC-Oxford, and UK Biobank, respectively, 673, 28, and 67 women who reported night shift work developed breast cancer, and the RRs for any vs no night shift work were 1.00 (95% CI = 0.92 to 1.08), 1.07 (95% CI = 0.71 to 1.62), and 0.78 (95% CI = 0.61 to 1.00). In the Million Women Study, the RR for 20 or more years of night shift work was 1.00 (95% CI = 0.81 to 1.23), with no statistically significant heterogeneity by sleep patterns or breast cancer risk factors. Our meta-analysis of all 10 prospective studies included 4660 breast cancers in women reporting night shift work; compared with other women, the combined relative risks were 0.99 (95% CI = 0.95 to 1.03) for any night shift work, 1.01 (95% CI = 0.93 to 1.10) for 20 or more years of night shift work, and 1.00 (95% CI = 0.87 to 1.14) for 30 or more years. CONCLUSIONS: The totality of the prospective evidence shows that night shift work, including long-term shift work, has little or no effect on breast cancer incidence. PMID- 27758829 TI - Not an 'iron pipeline', but many capillaries: regulating passive transactions in Los Angeles' secondary, illegal gun market. AB - OBJECTIVES: California has strict firearm-related laws and is exceptional in its regulation of firearms retailers. Though evidence suggests that these laws can reduce illegal access to guns, high levels of gun violence persist in Los Angeles (LA), California. This research seeks to describe the sources of guns accessed by active offenders in LA, California and reports offenders' motivations for obtaining guns. SETTING: Los Angeles County Jail (LACJ) system (four facilities). METHODS: Random sampling from a screened pool of eligible participants was used to conduct qualitative semistructured interviews with 140 incarcerated gun offenders in one of four (LACJ) facilities. Researchers collected data on firearm acquisition, experiences related to gun violence, and other topics, using a validated survey instrument. Grounded theory guided the collection and analysis of data. RESULTS: Respondents reported possession of 77 specific guns (79.2% handguns) collectively. Social networks facilitate access to illegal guns; the majority of interviewees acquired their illegal guns through a social connection (85.7%) versus an outside broker/unregulated retailer (8.5%). Most guns were obtained through illegal purchase (n=51) or gift (n=15). A quarter of gun purchasers report engaging in a passive transaction, or one initiated by another party. Passive gun buyers were motivated by concerns for personal safety and/or economic opportunity. CONCLUSIONS: In LA's illegal gun market, where existing social relationships facilitate access to guns across a diffuse network, individuals, influenced by both fear and economic opportunity, have frequent opportunities to illegally possess firearms through passive transactions. Gun policies should better target and minimise these transactions. PMID- 27758830 TI - The scientific agreement on firearm issues. AB - INTRODUCTION: No one has systematically collected the views of firearm researchers to determine if and where agreement exists on the scientific evidence about firearms and firearm violence. METHODS: We send a short monthly on-line survey to firearm researchers. Each survey asks respondents their level of agreement with a statement about firearms, their rating of the quality of the scientific evidence on the specific issue, their familiarity with that literature and their area of expertise. Survey participants are first-authors of a firearms article published in a peer-reviewed journal since 2011. For the first 15 surveys, on average, surveys were sent to 322 researchers, and 109 researchers responded (34% response rate). RESULTS: Among respondents, approximately 46% were public health researchers and 32% were sociologists/criminologists. Agreement exists among firearm researchers that more guns and weaker gun laws cause serious public health problems, that the costs of gun availability are typically greater than the benefits and that stronger gun laws may improve public safety and health. 84% of researchers agreed, and only 8% disagreed with the statement 'in the United States, having a gun in the home increases the risk of suicide'. For only three statements did most respondents rate the quality of the scientific evidence as strong or very strong. Overall, there was a higher level of agreement among public health/medicine researchers than among researchers in the other disciplines. DISCUSSION: Surveys of researchers can provide useful information about agreement on specific issues and about the quality of the scientific evidence. PMID- 27758831 TI - Integrating Perspectives on Animal Venom Diversity: An Introduction to the Symposium. PMID- 27758832 TI - Trump and Clinton clash over Obamacare in second presidential debate. PMID- 27758834 TI - A Wellness Program for Men With Spinal Cord Injury: Participation and Meaning. AB - Little is known about how participating in a wellness program influences the well being of individuals with spinal cord injury (SCI). The purpose of this study is to explore how men with SCI describe their experiences and meaning of participating in a wellness center program, how they perceived these experiences as influencing their well-being, and how these experiences relate to co occupations and occupational spin-off concepts. Investigators employed a descriptive qualitative design. Four adult males with an SCI participated in the study. Data collection methods included individual semi-structured interviews and observations. Participation in a wellness program positively influenced the physical, mental, and social well-being of participants. Findings expand our understanding of the value of social environment, social participation, co occupations, and occupational spin-off. It is essential that occupational therapists promote occupational justice by advocating for clients so they can participate in wellness occupations in the community. PMID- 27758835 TI - Relationship between childhood adversity and bipolar affective disorder: systematic review and meta-analysis. AB - BACKGROUND: The relationship between childhood adversity and bipolar affective disorder remains unclear. AIMS: To understand the size and significance of this effect through a statistical synthesis of reported research. METHOD: Search terms relating to childhood adversity and bipolar disorder were entered into Medline, EMBASE, PsycINFO and Web of Science. Eligible studies included a sample diagnosed with bipolar disorder, a comparison sample and a quantitative measure of childhood adversity. RESULTS: In 19 eligible studies childhood adversity was 2.63 times (95% CI 2.00-3.47) more likely to have occurred in bipolar disorder compared with non-clinical controls. The effect of emotional abuse was particularly robust (OR = 4.04, 95% CI 3.12-5.22), but rates of adversity were similar to those in psychiatric controls. CONCLUSIONS: Childhood adversity is associated with bipolar disorder, which has implications for the treatment of this clinical group. Further prospective research could clarify temporal causality and explanatory mechanisms. PMID- 27758836 TI - Adaptive working memory strategy training in early Alzheimer's disease: randomised controlled trial. AB - BACKGROUND: Interventions that improve cognitive function in Alzheimer's disease are urgently required. AIMS: To assess whether a novel cognitive training paradigm based on 'chunking' improves working memory and general cognitive function, and is associated with reorganisation of functional activity in prefrontal and parietal cortices (trial registration: ISRCTN43007027). METHOD: Thirty patients with mild Alzheimer's disease were randomly allocated to receive 18 sessions of 30 min of either adaptive chunking training or an active control intervention over approximately 8 weeks. Pre- and post-intervention functional magnetic resonance imaging (fMRI) scans were also conducted. RESULTS: Adaptive chunking training led to significant improvements in verbal working memory and untrained clinical measures of general cognitive function. Further, fMRI revealed a bilateral reduction in task-related lateral prefrontal and parietal cortex activation in the training group compared with controls. CONCLUSIONS: Chunking based cognitive training is a simple and potentially scalable intervention to improve cognitive function in early Alzheimer's disease. PMID- 27758837 TI - Mediation analysis of severity of needs, service performance and outcomes for patients with mental disorders. AB - BACKGROUND: Needs and service performance assessment are key components in improving recovery among individuals with mental disorders. AIMS: To test the role of service performance as a mediating factor between severity of patients' needs and outcomes. METHOD: A total of 339 adults with mental disorders were interviewed. A mediation analysis between severity of needs, service performance (adequacy of help, continuity of care and recovery orientation of services) and outcomes (personal recovery and quality of life) was carried out using structural equation modelling. RESULTS: The structural equation model provided a good fit with the data. An increase in needs was associated with lower service performance and worse outcomes, whereas higher service performance was associated with better outcomes. Service performance partially mediated the effect of patient needs on outcomes. CONCLUSIONS: Poorer service performance has a negative impact on outcomes for patients with the highest needs. Ensuring more efficient services for patients with high needs may help improve their recovery and quality of life. PMID- 27758839 TI - Physical Inactivity From Adolescence to Young Adulthood: The Relevance of Various Dimensions of Inequality in a Swedish Longitudinal Sample. AB - As physical inactivity may track from adolescence to adulthood, it is important to identify social determinants of physical inactivity in early life. However, most studies have measured socioeconomic position as one dimension. We examine whether multiple dimensions of socioeconomic position, in addition to other dimensions of inequality (i.e., gender, immigrant background), associate with physical inactivity at two time points in youth. Longitudinal data were drawn from the Swedish Level of Living Survey ( N = 765) and analysed by gender stratified logistic regression. Among girls, low parental social class (odds ratio [OR] = 2.63, 95% confidence interval [CI; 1.28, 5.42]) and income (OR = 2.28, 95% [CI 1.12, 4.65]) were associated with physical inactivity, while immigrant background (OR = 2.33, 95% CI [1.03, 5.23]) and a low level of parental education (OR = 3.38, 95% CI [1.15, 9.95]) predicted physical inactivity among women. Among boys, low parental income (OR = 3.27, 95% CI [1.39, 7.69]) was associated with physical inactivity, whereas immigrant background (OR = 2.29, 95% CI [1.04, 5.03]) predicted physical inactivity among men. Our results suggest that physical inactivity is socially patterned, but different dimensions of social stratification should not be considered interchangeable as they may operate independently, through intersection with gender, and at different time points in youth in increasing the risk of physical inactivity. PMID- 27758838 TI - Neuroinflammatory and morphological changes in late-life depression: the NIMROD study. AB - We studied neuroinflammation in individuals with late-life depression, as a risk factor for dementia, using [11C]PK11195 positron emission tomography (PET). Five older participants with major depression and 13 controls underwent PET and multimodal 3T magnetic resonance imaging (MRI), with blood taken to measure C reactive protein (CRP). We found significantly higher CRP levels in those with late-life depression and raised [11C]PK11195 binding compared with controls in brain regions associated with depression, including subgenual anterior cingulate cortex, and significant hippocampal subfield atrophy in cornu ammonis 1 and subiculum. Our findings suggest neuroinflammation requires further investigation in late-life depression, both as a possible aetiological factor and a potential therapeutic target. PMID- 27758840 TI - Cancer Worry Among Urban Dominican Women: A Qualitative Study. AB - BACKGROUND: Two thirds of respondents of a recent survey, primarily self identified urban immigrant Dominican females, indicated that cancer was the health problem they worried about the most. PURPOSE: The purpose of this qualitative study was to gain a greater understanding of the cancer worry experienced by Dominican women. DESIGN: Giorgi's descriptive existential phenomenological framework and methodology guided the study. SETTING: Washington Heights/Inwood community, New York City, New York. PARTICIPANTS: Thirty-eight urban Dominican immigrant women were included in the study. METHOD: Data were gathered using focus group interviews. All interviews were digitally recorded, transcribed verbatim from Spanish to English. The transcripts were analyzed using Giorgi's existential phenomenological data analysis process. FINDINGS: Four essences unfolded: Cancer as Destiny, Faith, Influential Relationships, and Knowledge Acquisition. CONCLUSION: New knowledge was generated on the contextual factors that influence cancer worry among a major Hispanic subgroup. Implications for nursing research and practice are described. PMID- 27758841 TI - Hepatoprotective potential of glyceryl trinitrate against chemically induced oxidative stress and hepatic injury in rats. AB - Glyceryl trinitrate (GTN) has been used widely as a potent vasodilator to treat heart conditions, such as angina pectoris and chronic heart failure. This study aims to elucidate the effect of exogenous nitric oxide (NO) administration, using GTN, on carbon tetrachloride (CCl4)-induced oxidative stress and liver injury in rats. The results obtained demonstrated that NO generated by the administration of GTN affords protection against CCl4-induced oxidative stress and liver injury. Administration of CCl4 resulted in a significant ( p < 0.001) increase in lipid peroxidation and tissue damage markers (aspartate and alanine transaminase and lactate dehydrogenase) release in serum. Parallel to these changes, CCl4 also caused downregulation of antioxidant enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST), and several fold induction in gamma-glutamyl transpeptidase (GGT) activity. Subsequent administration of GTN resulted in significant ( p < 0.001) recovery of GSH-metabolizing enzymes in a dose-dependent manner. Further, administration of NO inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), exacerbated CCl4-induced oxidative tissue injury. Overall, the study suggests that GTN might suppress oxidant-induced tissue injury and hepatotoxicity in rats. PMID- 27758842 TI - Folic acid-conjugated polyethylene glycol-coated magnetic nanoparticles for doxorubicin delivery in cancer chemotherapy: Preparation, characterization and cytotoxicity on HeLa cell line. AB - Conventional chemotherapy is the most valid method to cope with cancer; however, it has serious drawbacks such as decrease in production of blood cells or inflammation of the lining of the digestive tract. These side effects occur since generally the drugs used in chemotherapy are distributed evenly within the body of the patient and cannot distinguish the cancer cells from the healthy ones. In this study, folic acid (FA)-conjugated, polyethylene-coated magnetic nanoparticles (FA-MNPs), and doxorubicin (Dox)-loaded formulation (Dox-FA-MNPs) were prepared. The cytotoxicity of these nanoparticles on HeLa and Dox-resistant HeLa cells was investigated. Magnetic nanoparticles (MNPs), polyethylene glycol (PEG)-coated MNPs (PEG-MNPs), and FA-MNPs were successfully synthesized and characterized by several methods. Dox loading of FA-MNPs and release profile of Dox from the nanoparticles were studied. Cytotoxic effects of FA-MNPs and Dox-FA MNPs on HeLa cells were analyzed. MNPs, PEG-MNPs, and FA-MNPs all had small sizes and supermagnetic behavior. High amounts of Dox could be loded onto the nanoparticles (290 MUgmL-1). In 24 h, 15.7% of Dox was released from the Dox-FA MNPs. The release was increased in acidic conditions (pH 4.1). Internalization studies showed that FA-MNPs and Dox-FA-MNPs were taken up efficiently by HeLa cells. The investigation of cytotoxicity of the particles indicated that 38-500 MUgmL-1 Dox-FA-MNPs significantly decreased the proliferation of HeLa cells compared to FA-MNPs. Due to their size, magnetic properties, internalization, drug release, and cytotoxicity characteristics, the MNPs prepared in this study may have potential application as a drug delivery system in cancer chemotherapy. PMID- 27758843 TI - Pharmacokinetic modeling of carisoprodol and meprobamate disposition in adults. AB - Carisoprodol is a widely prescribed muscle relaxant and is also a drug known to be a subject to abuse. Despite the fact that carisoprodol has been available for prescription since 1959, a number of gaps in our knowledge of the toxicokinetics of this common drug exist. For example, the volume of distribution (Vd) for carisoprodol in humans has not been reported. A two-compartment pharmacokinetic model describing carisoprodol metabolism and that of the primary metabolite, meprobamate, was developed to better understand the pharmacokinetics of this drug. The model accounts for first pass metabolism of carisoprodol and was able to replicate the data from several previously reported data sets. Based on an analysis of four different data sets, the Vd for carisoprodol ranged from 0.93 to 1.3 L/kg, while that for meprobamate ranged from 1.4 to 1.6 L/kg. The model was also used to estimate the probable dose of this drug in an individual where questions concerning the drug's role in her death had been posed. The model may, therefore, have significant utility for estimating doses of carisoprodol in medicolegal cases. PMID- 27758844 TI - Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia. AB - INTRODUCTION: In healthy carriers of the T allele of the transcription factor 7 like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). MATERIAL AND METHODS: This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. RESULTS: Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. DISCUSSION: Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele. PMID- 27758845 TI - Bromocriptine and insulin sensitivity in lean and obese subjects. AB - Bromocriptine is a glucose-lowering drug, which was shown to be effective in obese subjects with insulin resistance. It is usually administered in the morning. The exact working mechanism of bromocriptine still has to be elucidated. Therefore, in this open-label randomized prospective cross-over mechanistic study, we assessed whether the timing of bromocriptine administration (morning vs evening) results in different effects and whether these effects differ between lean and obese subjects. We studied the effect of bromocriptine on insulin sensitivity in 8 lean and 8 overweight subjects using an oral glucose tolerance test. The subjects used bromocriptine in randomized cross-over order for 2 weeks in the morning and 2 weeks in the evening. We found that in lean subjects, bromocriptine administration in the evening resulted in a significantly higher post-prandial insulin sensitivity as compared with the pre-exposure visit (glucose area under the curve (AUC) 742 mmol/L * 120 min (695-818) vs 641 (504 750), P = 0.036, AUC for insulin did not change, P = 0.575). In obese subjects, both morning and evening administration of bromocriptine resulted in a significantly higher insulin sensitivity: morning administration in obese: insulin AUC (55,900 mmol/L * 120 min (43,236-96,831) vs 36,448 (25,213-57,711), P = 0.012) and glucose AUC P = 0.069; evening administration in obese: glucose AUC (735 mmol/L * 120 min (614-988) vs 644 (568-829), P = 0.017) and insulin AUC, P = 0.208. In conclusion, bromocriptine increases insulin sensitivity in both lean and obese subjects. In lean subjects, this effect only occurred when bromocriptine was administrated in the evening, whereas in the obese, insulin sensitivity increased independent of the timing of bromocriptine administration. PMID- 27758849 TI - Sensory Input and Motor Responses After Brain Death Diagnosis. PMID- 27758848 TI - Wound healing of critical limb ischemia with tissue loss in patients on hemodialysis. AB - We assessed wound healing in patients on hemodialysis (HD) with critical limb ischemia (CLI). This study enrolled 267 patients (including 120 patients on HD and 147 patients not on HD) who underwent endovascular therapy (EVT) for CLI. The primary endpoint was wound-healing rate at two years. Secondary endpoints were time to wound healing, wound recurrence rate, and limb salvage at two years. The percentage of male and young patients was higher in the HD patients ( p < 0.01). A lower patency of the pedal arch after EVT was observed frequently in HD patients ( p < 0.01). The wound-healing rate was significantly lower in HD patients (79.5% vs. 92.4%, p < 0.001). Time to wound healing was significantly longer in HD patients (median 132 days vs. 82 days, p = 0.005). Wound recurrence was observed more frequently in HD patients (25.0% vs. 10.2%, p = 0.007). Limb salvage (72.8% vs. 86.4%, p = 0.002) was significantly lower in HD patients. In a cox proportional hazard model, HD was an independent predictor of wound healing (risk ratio (RR), 0.46; 95% confidence interval (CI), 0.33-0.62; p < 0.001) and wound recurrence (RR, 1.58; 95% CI, 1.11-2.22; p = 0.01). HD was independently associated with lower and delayed wound healing, and wound recurrence. PMID- 27758850 TI - Duplication cyst of ileum presenting as acute intestinal obstruction in an adult. AB - Duplication cysts occur because of congenital aberration during gut development. They are commonly diagnosed during infancy and rarely during adulthood. We present an adult male who presented to surgical emergency with acute intestinal obstruction. Intraoperatively, this patient was found to have a non-communicating duplication cyst of ileum causing proximal obstruction. The involved segment of the small bowel was resected and a divided loop ileostomy was created. PMID- 27758851 TI - Multimodality approach in the diagnosis and management of bilateral giant juvenile breast fibroadenoma. AB - Juvenile giant fibroadenoma is a very rare breast disease affecting young girls of premenarche and adolescent ages. It is a benign fibroepithelial tumour characterised by stromal and epithelial proliferation that causes rapidly growing breast mass. Bilateral symmetrical involvement is extremely rare. In this article, we describe this entity in a girl aged 13 years who presented with bilateral gigantically enlarged breasts. Ultrasonography and MRI showed large, multilobulated masses involving both breasts entirely. Endovascular embolisation of bilateral internal mammary arteries and lateral thoracic arteries supplying the masses was performed prior to surgery to reduce their vascularity. The patient subsequently underwent excision of bilateral breast masses and reduction mammoplasty. Histopathologically, bilateral breast masses were confirmed to be juvenile fibroadenomas. PMID- 27758847 TI - Central Metabolic Responses to Ozone and Herbivory Affect Photosynthesis and Stomatal Closure. AB - Plants have evolved adaptive mechanisms that allow them to tolerate a continuous range of abiotic and biotic stressors. Tropospheric ozone (O3), a global anthropogenic pollutant, directly affects living organisms and ecosystems, including plant-herbivore interactions. In this study, we investigate the stress responses of Brassica nigra (wild black mustard) exposed consecutively to O3 and the specialist herbivore Pieris brassicae Transcriptomics and metabolomics data were evaluated using multivariate, correlation, and network analyses for the O3 and herbivory responses. O3 stress symptoms resembled those of senescence and phosphate starvation, while a sequential shift from O3 to herbivory induced characteristic plant defense responses, including a decrease in central metabolism, induction of the jasmonic acid/ethylene pathways, and emission of volatiles. Omics network and pathway analyses predicted a link between glycerol and central energy metabolism that influences the osmotic stress response and stomatal closure. Further physiological measurements confirmed that while O3 stress inhibited photosynthesis and carbon assimilation, sequential herbivory counteracted the initial responses induced by O3, resulting in a phenotype similar to that observed after herbivory alone. This study clarifies the consequences of multiple stress interactions on a plant metabolic system and also illustrates how omics data can be integrated to generate new hypotheses in ecology and plant physiology. PMID- 27758853 TI - A Novel Fucose-binding Lectin from Photorhabdus luminescens (PLL) with an Unusual Heptabladed beta-Propeller Tetrameric Structure. AB - Photorhabdus luminescens is known for its symbiosis with the entomopathogenic nematode Heterorhabditis bacteriophora and its pathogenicity toward insect larvae. A hypothetical protein from P. luminescens was identified, purified from the native source, and characterized as an l-fucose-binding lectin, named P. luminescens lectin (PLL). Glycan array and biochemical characterization data revealed PLL to be specific toward l-fucose and the disaccharide glycan 3,6-O-Me2 Glcbeta1-4(2,3-O-Me2)Rhaalpha-O-(p-C6H4)-OCH2CH2NH2 PLL was discovered to be a homotetramer with an intersubunit disulfide bridge. The crystal structures of native and recombinant PLL revealed a seven-bladed beta-propeller fold creating seven putative fucose-binding sites per monomer. The crystal structure of the recombinant PLL.l-fucose complex confirmed that at least three sites were fucose binding. Moreover, the crystal structures indicated that some of the other sites are masked either by the tetrameric nature of the lectin or by incorporation of the C terminus of the lectin into one of these sites. PLL exhibited an ability to bind to insect hemocytes and the cuticular surface of a nematode, H. bacteriophora. PMID- 27758854 TI - The C-terminal Domains of Apoptotic BH3-only Proteins Mediate Their Insertion into Distinct Biological Membranes. AB - Changes in the equilibrium of pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family in the mitochondrial outer membrane (MOM) induce structural changes that commit cells to apoptosis. Bcl-2 homology-3 (BH3) only proteins participate in this process by either activating pro-apoptotic effectors or inhibiting anti-apoptotic components and by promoting MOM permeabilization. The association of BH3-only proteins with MOMs is necessary for the activation and amplification of death signals; however, the nature of this association remains controversial, as these proteins lack a canonical transmembrane sequence. Here we used an in vitro expression system to study the insertion capacity of hydrophobic C-terminal regions of the BH3-only proteins Bik, Bim, Noxa, Bmf, and Puma into microsomal membranes. An Escherichia coli complementation assay was used to validate the results in a cellular context, and peptide insertions were modeled using molecular dynamics simulations. We also found that some of the C-terminal domains were sufficient to direct green fluorescent protein fusion proteins to specific membranes in human cells, but the domains did not activate apoptosis. Thus, the hydrophobic regions in the C termini of BH3-only members associated in distinct ways with various biological membranes, suggesting that a detailed investigation of the entire process of apoptosis should include studying the membranes as a setting for protein-protein and protein-membrane interactions. PMID- 27758855 TI - Core Binding Factor beta Protects HIV, Type 1 Accessory Protein Viral Infectivity Factor from MDM2-mediated Degradation. AB - HIV, type 1 overcomes host restriction factor apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins by organizing an E3 ubiquitin ligase complex together with viral infectivity factor (Vif) and a host transcription cofactor core binding factor beta (CBFbeta). CBFbeta is essential for Vif to counteract APOBEC3 by enabling the recruitment of cullin 5 to the complex and increasing the steady-state level of Vif protein; however, the mechanisms by which CBFbeta up-regulates Vif protein remains unclear. Because we have reported previously that mouse double minute 2 homolog (MDM2) is an E3 ligase for Vif, we hypothesized that CBFbeta might protect Vif from MDM2-mediated degradation. Co-immunoprecipitation analyses showed that Vif mutants that do not bind to CBFbeta preferentially interact with MDM2 and that overexpression of CBFbeta disrupts the interaction between MDM2 and Vif. Knockdown of CBFbeta reduced the steady-state level of Vif in MDM2-proficient cells but not in MDM2 null cells. Cycloheximide chase analyses revealed that Vif E88A/W89A, which does not interact with CBFbeta, degraded faster than wild-type Vif in MDM2-proficient cells but not in MDM2-null cells, suggesting that Vif stabilization by CBFbeta is mainly caused by impairing MDM2-mediated degradation. We identified Vif R93E as a Vif variant that does not bind to MDM2, and the virus with this substitution mutation was more resistant to APOBEC3G than the parental virus. Combinatory substitution of Vif residues required for CBFbeta binding and MDM2 binding showed full recovery of Vif steady-state levels, supporting our hypothesis. Our data provide new insights into the mechanism of Vif augmentation by CBFbeta. PMID- 27758856 TI - Novel Antibody for the Treatment of Transthyretin Amyloidosis. AB - Familial amyloidotic polyneuropathy (FAP) is a systemic amyloidosis mainly caused by amyloidogenic transthyretin (ATTR). This incurable disease causes death ~10 years after onset. Although it has been widely accepted that conformational change of the monomeric form of transthyretin (TTR) is very important for amyloid formation and deposition in the organs, no effective therapy targeting this step is available. In this study, we generated a mouse monoclonal antibody, T24, that recognized the cryptic epitope of conformationally changed TTR. T24 inhibited TTR accumulation in FAP model rats, which expressed human ATTR V30M in various tissues and exhibited non-fibrillar deposits of ATTR in the gastrointestinal tracts. Additionally, humanized T24 (RT24) inhibited TTR fibrillation and promoted macrophage phagocytosis of aggregated TTR. This antibody did not recognize normal serum TTR functioning properly in the blood. These results demonstrate that RT24 would be an effective novel therapeutic antibody for FAP. PMID- 27758857 TI - Structure of the Shroom-Rho Kinase Complex Reveals a Binding Interface with Monomeric Shroom That Regulates Cell Morphology and Stimulates Kinase Activity. AB - Shroom-mediated remodeling of the actomyosin cytoskeleton is a critical driver of cellular shape and tissue morphology that underlies the development of many tissues including the neural tube, eye, intestines, and vasculature. Shroom uses a conserved SD2 domain to direct the subcellular localization of Rho-associated kinase (Rock), which in turn drives changes in the cytoskeleton and cellular morphology through its ability to phosphorylate and activate non-muscle myosin II. Here, we present the structure of the human Shroom-Rock binding module, revealing an unexpected stoichiometry for Shroom in which two Shroom SD2 domains bind independent surfaces on Rock. Mutation of interfacial residues impaired Shroom-Rock binding in vitro and resulted in altered remodeling of the cytoskeleton and loss of Shroom-mediated changes in cellular morphology. Additionally, we provide the first direct evidence that Shroom can function as a Rock activator. These data provide molecular insight into the Shroom-Rock interface and demonstrate that Shroom directly participates in regulating cytoskeletal dynamics, adding to its known role in Rock localization. PMID- 27758858 TI - Enhancer of Zeste Homolog 2 Inhibition Stimulates Bone Formation and Mitigates Bone Loss Caused by Ovariectomy in Skeletally Mature Mice. AB - Perturbations in skeletal development and bone degeneration may result in reduced bone mass and quality, leading to greater fracture risk. Bone loss is mitigated by bone protective therapies, but there is a clinical need for new bone-anabolic agents. Previous work has demonstrated that Ezh2 (enhancer of zeste homolog 2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated whether inhibition of Ezh2 can be leveraged for bone stimulatory applications. Pharmacologic inhibition and siRNA knockdown of Ezh2 enhanced osteogenic commitment of MC3T3 preosteoblasts. Next generation RNA sequencing of mRNAs and real time quantitative PCR profiling established that Ezh2 inactivation promotes expression of bone-related gene regulators and extracellular matrix proteins. Mechanistically, enhanced gene expression was linked to decreased H3K27 trimethylation (H3K27me3) near transcriptional start sites in genome-wide sequencing of chromatin immunoprecipitations assays. Administration of an Ezh2 inhibitor modestly increases bone density parameters of adult mice. Furthermore, Ezh2 inhibition also alleviated bone loss in an estrogen-deficient mammalian model for osteoporosis. Ezh2 inhibition enhanced expression of Wnt10b and Pth1r and increased the BMP-dependent phosphorylation of Smad1/5. Thus, these data suggest that inhibition of Ezh2 promotes paracrine signaling in osteoblasts and has bone anabolic and osteoprotective potential in adults. PMID- 27758859 TI - Cloning of Glycerophosphocholine Acyltransferase (GPCAT) from Fungi and Plants: A NOVEL ENZYME IN PHOSPHATIDYLCHOLINE SYNTHESIS. AB - Glycero-3-phosphocholine (GPC), the product of the complete deacylation of phosphatidylcholine (PC), was long thought to not be a substrate for reacylation. However, it was recently shown that cell-free extracts from yeast and plants could acylate GPC with acyl groups from acyl-CoA. By screening enzyme activities of extracts derived from a yeast knock-out collection, we were able to identify and clone the yeast gene (GPC1) encoding the enzyme, named glycerophosphocholine acyltransferase (GPCAT). By homology search, we also identified and cloned GPCAT genes from three plant species. All enzymes utilize acyl-CoA to acylate GPC, forming lyso-PC, and they show broad acyl specificities in both yeast and plants. In addition to acyl-CoA, GPCAT efficiently utilizes LPC and lysophosphatidylethanolamine as acyl donors in the acylation of GPC. GPCAT homologues were found in the major eukaryotic organism groups but not in prokaryotes or chordates. The enzyme forms its own protein family and does not contain any of the acyl binding or lipase motifs that are present in other studied acyltransferases and transacylases. In vivo labeling studies confirm a role for Gpc1p in PC biosynthesis in yeast. It is postulated that GPCATs contribute to the maintenance of PC homeostasis and also have specific functions in acyl editing of PC (e.g. in transferring acyl groups modified at the sn-2 position of PC to the sn-1 position of this molecule in plant cells). PMID- 27758860 TI - A New Splice Variant of Large Conductance Ca2+-activated K+ (BK) Channel alpha Subunit Alters Human Chondrocyte Function. AB - Large conductance Ca2+-activated K+ (BK) channels play essential roles in both excitable and non-excitable cells. For example, in chondrocytes, agonist-induced Ca2+ release from intracellular store activates BK channels, and this hyperpolarizes these cells, augments Ca2+ entry, and forms a positive feed-back mechanism for Ca2+ signaling and stimulation-secretion coupling. In the present study, functional roles of a newly identified splice variant in the BK channel alpha subunit (BKalphaDeltae2) were examined in a human chondrocyte cell line, OUMS-27, and in a HEK293 expression system. Although BKalphaDeltae2 lacks exon2, which codes the intracellular S0-S1 linker (Glu-127-Leu-180), significant expression was detected in several tissues from humans and mice. Molecular image analyses revealed that BKalphaDeltae2 channels are not expressed on plasma membrane but can traffic to the plasma membrane after forming hetero-tetramer units with wild-type BKalpha (BKalphaWT). Single-channel current analyses demonstrated that BKalpha hetero-tetramers containing one, two, or three BKalphaDeltae2 subunits are functional. These hetero-tetramers have a smaller single channel conductance and exhibit lower trafficking efficiency than BKalphaWT homo-tetramers in a stoichiometry-dependent manner. Site-directed mutagenesis of residues in exon2 identified Helix2 and the linker to S1 (Trp-158 Leu-180, particularly Arg-178) as an essential segment for channel function including voltage dependence and trafficking. BKalphaDeltae2 knockdown in OUMS-27 chondrocytes increased BK current density and augmented the responsiveness to histamine assayed as cyclooxygenase-2 gene expression. These findings provide significant new evidence that BKalphaDeltae2 can modulate cellular responses to physiological stimuli in human chondrocyte and contribute under pathophysiological conditions, such as osteoarthritis. PMID- 27758861 TI - Hydrogen Bonding to the Substrate Is Not Required for Rieske Iron-Sulfur Protein Docking to the Quinol Oxidation Site of Complex III. AB - Complex III or the cytochrome (cyt) bc1 complex constitutes an integral part of the respiratory chain of most aerobic organisms and of the photosynthetic apparatus of anoxygenic purple bacteria. The function of cyt bc1 is to couple the reaction of electron transfer from ubiquinol to cytochrome c to proton pumping across the membrane. Mechanistically, the electron transfer reaction requires docking of its Rieske iron-sulfur protein (ISP) subunit to the quinol oxidation site (QP) of the complex. Formation of an H-bond between the ISP and the bound substrate was proposed to mediate the docking. Here we show that the binding of oxazolidinedione-type inhibitors famoxadone, jg144, and fenamidone induces docking of the ISP to the QP site in the absence of the H-bond formation both in mitochondrial and bacterial cyt bc1 complexes, demonstrating that ISP docking is independent of the proposed direct ISP-inhibitor interaction. The binding of oxazolidinedione-type inhibitors to cyt bc1 of different species reveals a toxophore that appears to interact optimally with residues in the QP site. The effect of modifications or additions to the toxophore on the binding to cyt bc1 from different species could not be predicted from structure-based sequence alignments, as demonstrated by the altered binding mode of famoxadone to bacterial cyt bc1. PMID- 27758862 TI - Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE. AB - Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr28, leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated T28E phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared with wild-type unphosphorylated Cytc Introduction of T28E phosphomimetic Cytc into Cytc knock-out cells shows that intact cell respiration, mitochondrial membrane potential (DeltaPsim), and ROS levels are reduced compared with wild type. As we show by high resolution crystallography of wild-type and T28E Cytc in combination with molecular dynamics simulations, Thr28 is located at a central position near the heme crevice, the most flexible epitope of the protein apart from the N and C termini. Finally, in silico prediction and our experimental data suggest that AMP kinase, which phosphorylates Cytc on Thr28 in vitro and colocalizes with Cytc to the mitochondrial intermembrane space in the kidney, is the most likely candidate to phosphorylate Thr28 in vivo We conclude that Cytc phosphorylation is mediated in a tissue-specific manner and leads to regulation of electron transport chain flux via "controlled respiration," preventing DeltaPsim hyperpolarization, a known cause of ROS and trigger of apoptosis. PMID- 27758863 TI - Mesenchymal Stromal Cell-derived Extracellular Vesicles Promote Myeloid-biased Multipotent Hematopoietic Progenitor Expansion via Toll-Like Receptor Engagement. AB - Mesenchymal stromal cells (MSCs) present in the bone marrow microenvironment secrete cytokines and angiogenic factors that support the maintenance and regenerative expansion of hematopoietic stem and progenitor cells (HSPCs). Here, we tested the hypothesis that extracellular vesicles (EVs) released by MSCs contribute to the paracrine crosstalk that shapes hematopoietic function. We systematically characterized EV release by murine stromal cells and demonstrate that MSC-derived EVs prompt a loss of HSPC quiescence with concomitant expansion of murine myeloid progenitors. Our studies reveal that HSPC expansion by MSC EVs is mediated via the MyD88 adapter protein and is partially blocked by treatment with a TLR4 inhibitor. Imaging of fluorescence protein-tagged MSC EVs corroborated their cellular co-localization with TLR4 and endosomal Rab5 compartments in HSPCs. The dissection of downstream responses to TLR4 activation reveals that the mechanism by which MSC EVs impact HSPCs involves canonical NF kappaB signaling and downstream activation of Hif-1alpha and CCL2 target genes. Our aggregate data identify a previously unknown role for MSC-derived EVs in the regulation of hematopoiesis through innate immune mechanisms and illustrate the expansive cell-cell crosstalk in the bone marrow microenvironment. PMID- 27758864 TI - Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma. AB - Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient receptor potential vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes would manifest as differences in lung cell responses to these agonists and perhaps correlate with changes in asthma symptom control. The TRPV1-I315M and -T469I variants were more responsive to capsaicin and coal fly ash. The I585V variant was less responsive to coal fly ash particles due to reduced translation of protein and an apparent role for Ile-585 in activation by particles. In HEK-293 cells, I585V had an inhibitory effect on wild-type TRPV1 expression, activation, and internalization/agonist-induced desensitization. In normal human bronchial epithelial cells, IL-8 secretion in response to coal fly ash treatment was reduced for cells heterozygous for TRPV1-I585V. Finally, both the I315M and I585V variants were associated with worse asthma symptom control with the effects of I315M manifesting in mild asthma and those of the I585V variant manifesting in severe, steroid-insensitive individuals. This effect may be due in part to increased transient receptor potential ankyrin-1 (TRPA1) expression by lung epithelial cells expressing the TRPV1-I585V variant. These findings suggest that specific molecular interactions control TRPV1 activation by particles, differential activation, and desensitization of TRPV1 by particles and/or other agonists, and cellular changes in the expression of TRPA1 as a result of I585V expression could contribute to variations in asthma symptom control. PMID- 27758865 TI - An Unbiased Mass Spectrometry Approach Identifies Glypican-3 as an Interactor of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Low Density Lipoprotein Receptor (LDLR) in Hepatocellular Carcinoma Cells. AB - The mechanism of LDL receptor (LDLR) degradation mediated by the proprotein convertase subtilisin/kexin type 9 (PCSK9) has been extensively studied; however, many steps within this process remain unclear and still require characterization. Recent studies have shown that PCSK9 lacking its Cys/His-rich domain can still promote LDLR internalization, but the complex does not reach the lysosome suggesting the presence of an additional interaction partner(s). In this study we carried out an unbiased screening approach to identify PCSK9-interacting proteins in the HepG2 cells' secretome using co-immunoprecipitation combined with mass spectrometry analyses. Several interacting proteins were identified, including glypican-3 (GPC3), phospholipid transfer protein, matrilin-3, tissue factor pathway inhibitor, fibrinogen-like 1, and plasminogen activator inhibitor-1. We then validated these interactions by co-immunoprecipitation and Western blotting. Furthermore, functional validation was examined by silencing each candidate protein in HepG2 cells using short hairpin RNAs to determine their effect on LDL uptake and LDLR levels. Only GPC3 and phospholipid transfer protein silencing in HepG2 cells significantly increased LDL uptake in these cells and displayed higher total LDLR protein levels compared with control cells. Moreover, our study provides the first evidence that GPC3 can modulate the PCSK9 extracellular activity as a competitive binding partner to the LDLR in HepG2 cells. PMID- 27758866 TI - Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis. AB - The acquisition of beige adipocyte features by white fat cells corresponds to protection against obesity-induced metabolic diseases in humans and animal models of type 2 diabetes. In adipose tissue, expression of the E2 small ubiquitin-like modifier ligase ubiquitin carrier protein 9 (Ubc9) is positively correlated with markers of insulin resistance and corresponds with impaired browning of human white adipocytes. However, the molecular regulation of Ubc9 expression in adipocytes and other cells remains unclear. In this study, we demonstrate that the mRNA and protein expression of Ubc9 are regulated by the microRNA miRNA-30a (miR-30a) in human subcutaneous adipocytes. Ubc9 and miR-30a exhibit inverse expression in adipose tissue, with miR-30a robustly elevated in brown fat. Depletion of Ubc9 by siRNA or enforced expression of a miR-30a mimic augments mitochondrial volume and respiration in human white adipocytes, reflecting features of brown fat cells. Furthermore, Ubc9 depletion induces a brown fat gene program in human subcutaneous adipocytes. Induction of the beige-selective gene program corresponds to stabilization of the PR domain-containing 16 (PRDM16) protein, an obligate transcriptional regulator of the brown/beige fat metabolic program in white adipocytes that interacts with Ubc9. Taken together, our data demonstrate a previously unappreciated molecular axis that controls browning of human white adipocytes. PMID- 27758867 TI - The Type B Flagellin of Hypervirulent Clostridium difficile Is Modified with Novel Sulfonated Peptidylamido-glycans. AB - Glycosylation of flagellins is a well recognized property of many bacterial species. In this study, we describe the structural characterization of novel flagellar glycans from a number of hypervirulent strains of C. difficile We used mass spectrometry (nano-LC-MS and MS/MS analysis) to identify a number of putative glycopeptides that carried a variety of glycoform substitutions, each of which was linked through an initial N-acetylhexosamine residue to Ser or Thr. Detailed analysis of a LLDGSSTEIR glycopeptide released by tryptic digestion, which carried two variant structures, revealed that the glycopeptide contained, in addition to carbohydrate moieties, a novel structural entity. A variety of electrospray-MS strategies using Q-TOF technology were used to define this entity, including positive and negative ion collisionally activated decomposition MS/MS, which produced unique fragmentation patterns, and high resolution accurate mass measurement to allow derivation of atomic compositions, leading to the suggestion of a taurine-containing peptidylamido-glycan structure. Finally, NMR analysis of flagellin glycopeptides provided complementary information. The glycan portion of the modification was assigned as alpha-Fuc3N-(1->3)-alpha-Rha (1->2)-alpha-Rha3OMe-(1->3)-beta-GlcNAc-(1->)Ser, and the novel capping moiety was shown to be comprised of taurine, alanine, and glycine. This is the first report of a novel O-linked sulfonated peptidylamido-glycan moiety decorating a flagellin protein. PMID- 27758868 TI - Immunomodulatory and Anti-inflammatory Activity in Vitro and in Vivo of a Novel Antimicrobial Candidate. AB - The synthetic antimicrobial peptide SET-M33 has strong activity against bacterial infections caused by Gram-negative bacteria. It is currently in preclinical development as a new drug to treat lung infections caused by Gram-negative bacteria. Here we report its strong anti-inflammatory activity in terms of reduced expression of a number of cytokines, enzymes, and signal transduction factors involved in inflammation triggered by LPS from Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli Sixteen cytokines and other major agents involved in inflammation were analyzed in macrophages and bronchial cells after stimulation with LPS and incubation with SET-M33. The bronchial cells were obtained from a cystic fibrosis patient. A number of these proteins showed up to 100% reduction in expression as measured by RT-PCR, Western blotting, or Luminex technology. LPS neutralization was also demonstrated in vivo by challenging bronchoalveolar lavage of SET-M33-treated mice with LPS, which led to a sharp reduction in TNF-alpha with respect to non-SET-M33-treated animals. We also describe a strong activity of SET-M33 in stimulating cell migration of keratinocytes in wound healing experiments in vitro, demonstrating a powerful immunomodulatory action generally characteristic of molecules taking part in innate immunity. PMID- 27758869 TI - Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling. AB - Cancer stem cells (CSCs) represent a small subpopulation of self-renewing oncogenic cells. As in many other stem cells, metabolic reprogramming has been implicated to be a key characteristic of CSCs. However, little is known about how the metabolic features of cancer cells are controlled to orchestrate their CSC like properties. We recently demonstrated that hyaluronan (HA) overproduction allowed plastic cancer cells to revert to stem cell states. Here, we adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells. These integrated approaches disclosed an acceleration of metabolic flux in the hexosamine biosynthetic pathway (HBP). A metabolic shift toward glycolysis was also evident by quantitative targeted metabolomics, which was validated by the expression profiles of key glycolytic enzymes. Forced expression of glutamine:fructose-6 phosphate amidotransferase 1 (GFAT1), an HBP rate-limiting enzyme, resembled the results of HA overproduction with regard to HIF-1alpha accumulation and glycolytic program, whereas GFAT1 inhibition significantly decreased HIF-1alpha protein level in HA-overproducing cancer cells. Moreover, inhibition of the HBP HIF-1 axis abrogated HA-driven glycolytic enhancement and reduced the CSC-like subpopulation. Taken together, our results provide compelling evidence that HA production regulates the metabolic and CSC-like properties of breast cancer cells via HBP-coupled HIF-1 signaling. PMID- 27758870 TI - Serine/Threonine Protein Phosphatase PstP of Mycobacterium tuberculosis Is Necessary for Accurate Cell Division and Survival of Pathogen. AB - Protein phosphatases play vital roles in phosphorylation-mediated cellular signaling. Although there are 11 serine/threonine protein kinases in Mycobacterium tuberculosis, only one serine/threonine phosphatase, PstP, has been identified. Although PstP has been biochemically characterized and multiple in vitro substrates have been identified, its physiological role has not yet been elucidated. In this study, we have investigated the impact of PstP on cell growth and survival of the pathogen in the host. Overexpression of PstP led to elongated cells and partially compromised survival. We find that depletion of PstP is detrimental to cell survival, eventually leading to cell death. PstP depletion results in elongated multiseptate cells, suggesting a role for PstP in regulating cell division events. Complementation experiments performed with PstP deletion mutants revealed marginally compromised survival, suggesting that all of the domains, including the extracellular domain, are necessary for complete rescue. On the other hand, the catalytic activity of PstP is absolutely essential for the in vitro growth. Mice infection experiments establish a definitive role for PstP in pathogen survival within the host. Depletion of PstP from established infections causes pathogen clearance, indicating that the continued presence of PstP is necessary for pathogen survival. Taken together, our data suggest an important role for PstP in establishing and maintaining infection, possibly via the modulation of cell division events. PMID- 27758871 TI - Novel Molecular Interactions of Acylcarnitines and Fatty Acids with Myoglobin. AB - Previous research has indicated that long-chain fatty acids can bind myoglobin (Mb) in an oxygen-dependent manner. This suggests that oxy-Mb may play an important role in fuel delivery in Mb-rich muscle fibers (e.g. type I fibers and cardiomyocytes), and raises the possibility that Mb also serves as an acylcarnitine-binding protein. We report for the first time the putative interaction and affinity characteristics for different chain lengths of both fatty acids and acylcarnitines with oxy-Mb using molecular dynamic simulations and isothermal titration calorimetry experiments. We found that short- to medium chain fatty acids or acylcarnitines (ranging from C2:0 to C10:0) fail to achieve a stable conformation with oxy-Mb. Furthermore, our results indicate that C12:0 is the minimum chain length essential for stable binding of either fatty acids or acylcarnitines with oxy-Mb. Importantly, the empirical lipid binding studies were consistent with structural modeling. These results reveal that: (i) the lipid binding affinity for oxy-Mb increases as the chain length increases (i.e. C12:0 to C18:1), (ii) the binding affinities of acylcarnitines are higher when compared with their respective fatty acid counterparts, and (iii) both fatty acids and acylcarnitines bind to oxy-Mb in 1:1 stoichiometry. Taken together, our results support a model in which oxy-Mb is a novel regulator of long-chain acylcarnitine and fatty acid pools in Mb-rich tissues. This has important implications for physiological fuel management during exercise, and relevance to pathophysiological conditions (e.g. fatty acid oxidation disorders and cardiac ischemia) where long-chain acylcarnitine accumulation is evident. PMID- 27758872 TI - Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli. AB - Alveolar macrophages are lung-resident sentinel cells that develop perinatally and protect against pulmonary infection. Molecular mechanisms controlling alveolar macrophage generation have not been fully defined. Here, we show that the actin-bundling protein L-plastin (LPL) is required for the perinatal development of alveolar macrophages. Mice expressing a conditional allele of LPL (CD11c.Crepos-LPLfl/fl) exhibited significant reductions in alveolar macrophages and failed to effectively clear pulmonary pneumococcal infection, showing that immunodeficiency results from reduced alveolar macrophage numbers. We next identified the phase of alveolar macrophage development requiring LPL. In mice, fetal monocytes arrive in the lungs during a late fetal stage, maturing to alveolar macrophages through a prealveolar macrophage intermediate. LPL was required for the transition from prealveolar macrophages to mature alveolar macrophages. The transition from prealveolar macrophage to alveolar macrophage requires the upregulation of the transcription factor peroxisome proliferator activated receptor-gamma (PPAR-gamma), which is induced by exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite abundant lung GM-CSF and intact GM-CSF receptor signaling, PPAR-gamma was not sufficiently upregulated in developing alveolar macrophages in LPL-/- pups, suggesting that precursor cells were not correctly localized to the alveoli, where GM-CSF is produced. We found that LPL supports 2 actin-based processes essential for correct localization of alveolar macrophage precursors: (1) transmigration into the alveoli, and (2) engraftment in the alveoli. We thus identify a molecular pathway governing neonatal alveolar macrophage development and show that genetic disruption of alveolar macrophage development results in immunodeficiency. PMID- 27758875 TI - Process optimization for high-pressure processing of black tiger shrimp ( Penaeus monodon) using response surface methodology. AB - This study aims to investigate the effect of high-pressure processing on the quality of black tiger shrimp using response surface methodology. A central composite rotatable design was applied to evaluate the effects of three processing parameters, namely pressure (300-600 MPa), temperature (30-50 C), and time (0-15 min), on the inactivation rate of Staphylococcus aureus and physical properties (color and texture) of shrimp and to optimize the process conditions to achieve maximum bacterial inactivation with minimal changes in quality attributes. The results revealed that the processing conditions significantly affected the studied responses and the experimental data have been adequately fitted into a second-order polynomial model with multiple regression coefficients (R2) of 0.92, 0.92, and 0.94 for the inactivation rate of S. aureus, hardness, and color changes, respectively. The optimized conditions targeting minimum six log cycle reductions of S. aureus with moderate changes in quality attributes were obtained as: pressure, 361 MPa; time, 12 min and temperature, 46 C. The adequacy of the model equation for predicting the optimum response values was verified effectively by the validation data. PMID- 27758873 TI - Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells. AB - One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graft-versus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease. PMID- 27758874 TI - Replication of associations between genetic polymorphisms and chronic graft versus-host disease. AB - Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs. PMID- 27758876 TI - Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells. AB - : Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMC) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell-cell communications is exosomes, 30-100 nm membrane vesicles of endocytic origin, through the cell-cell transfer of proteins, mRNAs, or microRNAs. Therefore, the goal was to mechanistically characterize how EOC-derived exosomes modulate metastasis. Exosomes from ovarian cancer cells were fluorescently labeled and cocultured with HPMCs which internalized the exosomes. Upon exosome uptake, HPMCs underwent a change in cellular morphology to a mesenchymal, spindle phenotype. CD44, a cell surface glycoprotein, was found to be enriched in the cancer cell derived exosomes, transferred, and internalized to HPMCs, leading to high levels of CD44 in HPMCs. This increased CD44 expression in HPMCs promoted cancer invasion by inducing the HPMCs to secrete MMP9 and by cleaning the mesothelial barrier for improved cancer cell invasion. When CD44 expression was knocked down in cancer cells, exosomes had fewer effects on HPMCs. The inhibition of exosome release from cancer cells blocked CD44 internalization in HPMCs and suppressed ovarian cancer invasion. In ovarian cancer omental metastasis, positive CD44 expression was observed in those mesothelial cells that directly interacted with cancer cells, whereas CD44 expression was negative in the mesothelial cells remote from the invading edge. This study indicates that ovarian cancer-derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion. IMPLICATIONS: Mechanistic insight from the current study suggests that therapeutic targeting of exosomes may be beneficial in treating ovarian cancer. Mol Cancer Res; 15(1); 78 92. (c)2016 AACR. PMID- 27758878 TI - Correlation of angiotensin I-converting enzyme gene insertion/deletion polymorphism with rheumatic heart disease: a meta-analysis. AB - Rheumatic heart disease (RHD) is a serious cardiovascular disorder worldwide. Several articles have reported the effect of angiotensin I-converting enzyme gene insertion/deletion (ACE I/D) polymorphism in RHD risk. However, the results still remain inconsistent. The objective of the present study was to assess more precise estimations of the relationship between ACE I/D variant and RHD susceptibility. Relevant case-control studies published between January 2000 and 2016 were searched in the electronic databases. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the strength of the effect. A total of nine articles were retrieved, including 1333 RHD patients and 1212 healthy controls. Overall, our result did not detect a significant association between ACE I/D polymorphism and RHD risk under each genetic model (P > 0.05). Subgroup analysis by ethnicity showed no positive relationship in Asians as well (P > 0.05). With respect to the severity of RHD, our result found that the frequency differences between mitral valve lesion (MVL), combined valve lesion (CVL) and healthy controls were not significantly different. Furthermore, no significant association was found between female, male RHD patients and the controls regarding to the ACE I/D polymorphism. In conclusion, our result indicated that ACE I/D polymorphism might not be a risk factor for RHD progression based on the existing research results. Additional well-designed studies with larger samples are still needed to confirm these findings. PMID- 27758880 TI - Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity. AB - Cell differentiation within stem cell lineages can check proliferative potential, but nodal pathways that can limit tumor growth are obscure. Here, we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM-p21Cip1-cyclin A2 signaling, encouraging cell proliferation as well as barrier properties. In contrast, SOX9 bound the SLUG promoter to induce SLUG-mediated cell invasion with a spindle-like phenotype. Pharmacologic inhibition of HDAC elevated a SOX9-positive cell population from SOX2-positive cells, whereas ectopic expression of SOX2 inhibited SOX9 with increased H3K9me2 levels on the SOX9 promoter. In clinical specimens, the expression of SOX2 and SOX9 correlated negatively and positively with lung tumor grade, respectively. Our findings identify SOX2 and SOX9 as nodal epigenetic regulators in determining cancer cell plasticity and metastatic progression. Cancer Res; 76(23); 7036-48. (c)2016 AACR. PMID- 27758879 TI - Transcription Factor ZBP-89 Drives a Feedforward Loop of beta-Catenin Expression in Colorectal Cancer. AB - In colorectal cancer, APC-mediated induction of unregulated cell growth involves posttranslational mechanisms that prevent proteasomal degradation of proto oncogene beta-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10% of colorectal tumors also exhibit increased CTNNB1 mRNA. Here, we show in colorectal cancer that increased expression of ZNF148, the gene coding for transcription factor ZBP-89, correlated with reduced patient survival. Tissue arrays showed that ZBP-89 protein was overexpressed in the early stages of colorectal cancer. Conditional deletion of Zfp148 in a mouse model of Apc mediated intestinal polyps demonstrated that ZBP-89 was required for polyp formation due to induction of Ctnnb1 gene expression. Chromatin immunoprecipitation (ChIP) and EMSA identified a ZBP-89-binding site in the proximal promoter of CTNNB1 Reciprocally, siRNA-mediated reduction of CTNNB1 expression also decreased ZBP-89 protein. ChIP identified TCF DNA binding sites in the ZNF148 promoter through which Wnt signaling regulates ZNF148 gene expression. Suppression of either ZNF148 or CTNNB1 reduced colony formation in WNT-dependent, but not WNT-independent cell lines. Therefore, the increase in intracellular beta-catenin protein initiated by APC mutations is sustained by ZBP 89-mediated feedforward induction of CTNNB1 mRNA. Cancer Res; 76(23); 6877-87. (c)2016 AACR. PMID- 27758881 TI - Hybrid Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Modulating Tumor Hypoxia. AB - Hypoxia in the tumor microenvironment (TME) mediates resistance to radiotherapy and contributes to poor prognosis in patients receiving radiotherapy. Here we report the design of clinically suitable formulations of hybrid manganese dioxide (MnO2) nanoparticles (MDNP) using biocompatible materials to reoxygenate the TME by reacting with endogenous H2O2 MDNP containing hydrophilic terpolymer-protein MnO2 or hydrophobic polymer-lipid-MnO2 provided different oxygen generation rates in the TME relevant to different clinical settings. In highly hypoxic murine or human xenograft breast tumor models, we found that administering either MDNP formulation before radiotherapy modulated tumor hypoxia and increased radiotherapy efficacy, acting to reduce tumor growth, VEGF expression, and vascular density. MDNP treatment also increased apoptosis and DNA double strand breaks, increasing median host survival 3- to 5-fold. Notably, in the murine model, approximately 40% of tumor-bearing mice were tumor-free after a single treatment with MDNPs plus radiotherapy at a 2.5-fold lower dose than required to achieve the same curative treatment without MDNPs. Overall, our findings offer a preclinical proof of concept for the use of MDNP formulations as effective radiotherapy adjuvants. Cancer Res; 76(22); 6643-56. (c)2016 AACR. PMID- 27758882 TI - Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process. AB - Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680-9. (c)2016 AACR. PMID- 27758883 TI - Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation. AB - The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway, which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). Although TGFbeta and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understood how Gli1 functional activity is regulated. Here, we report the identification of Gli1 as a substrate for the protein arginine N-methyltransferase PRMT1 in PDAC. We found that PRMT1 methylates Gli1 at R597, promoting its transcriptional activity by enhancing the binding of Gli1 to its target gene promoters. Interruption of Gli1 methylation attenuates oncogenic functions of Gli1 and sensitizes PDAC cells to gemcitabine treatment. In human PDAC specimens, the levels of both total Gli1 and methylated Gli1 were correlated positively with PRMT1 protein levels. Notably, PRMT1 regulated Gli1 independently of the canonical Hh pathway as well as the TGFbeta/Kras-mediated noncanonical Hh pathway, thereby signifying a novel regulatory mechanism for Gli1 transcriptional activity. Taken together, our results identified a new posttranslational modification of Gli1 that underlies its pivotal oncogenic functions in PDAC. Cancer Res; 76(23); 7049-58. (c)2016 AACR. PMID- 27758884 TI - mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer. AB - mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer. Cancer Res; 76(23); 6911-23. (c)2016 AACR. PMID- 27758886 TI - Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors. AB - Approximately 80% of breast cancers overexpress the kinase breast tumor kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast cancer cell proliferation in vitro and in vivo Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast cancer. Cancer Res; 77(1); 175 86. (c)2016 AACR. PMID- 27758885 TI - Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c JUN to Bypass PUMILIO Posttranscriptional Regulation. AB - Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3' untranslated region (3' UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3' UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype-specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. Cancer Res; 76(24); 7231-41. (c)2016 AACR. PMID- 27758887 TI - Tie2 Expression on Macrophages Is Required for Blood Vessel Reconstruction and Tumor Relapse after Chemotherapy. AB - Tumor relapse after chemotherapy is a major hurdle for successful cancer therapy. Chemotherapeutic drugs select for resistant tumor cells and reshape tumor microenvironment, including the blood supply system. Using animal models, we observed on macrophages in tumor tissue a close correlation between upregulated Tie2 expression and tumor relapse upon chemotherapy. Conditional deletion of Tie2 expression in macrophages significantly prohibited blood supply and regrowth of tumors. Tie2+ macrophages were derived from tumor-infiltrating Tie2-CD11b+ cells and hypoxia-induced Tie2 expression on these cells. Mechanistically, expression of Tie2 prevented macrophages from apoptosis in stress conditions via the AKT dependent signaling pathway. Together, these results demonstrate that Tie2 expression by macrophages is necessary and sufficient to promote the reconstruction of blood vessels after chemotherapy, shedding new light on developing novel strategies to inhibit tumor relapse. Cancer Res; 76(23); 6828 38. (c)2016 AACR. PMID- 27758888 TI - Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy. AB - Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ~40% or ~63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERalpha-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-alpha (ERalpha) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERalpha binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERalpha. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERalpha expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERalpha levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERalpha. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. Cancer Res; 76(23); 7012-23. (c)2016 AACR. PMID- 27758889 TI - TRPA1 Mediates Aromatase Inhibitor-Evoked Pain by the Aromatase Substrate Androstenedione. AB - Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024-35. (c)2016 AACR. PMID- 27758890 TI - Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth. AB - Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy. Cancer Res; 76(23); 6924-36. (c)2016 AACR. PMID- 27758891 TI - Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations. AB - Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite graph-based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, that is, the candidate members of the pathway that regulate the transcriptomic module. Computational evaluations indicated that our methods-identified pathways were perturbed by SGA. In particular, our analyses revealed that SGA affecting TP53, PTK2, YWHAZ, and MED1 perturbed a set of signals that promote cell proliferation, anchor-free colony formation, and epithelial-mesenchymal transition (EMT). These proteins formed a signaling complex that mediates these oncogenic processes in a coordinated fashion. Disruption of this signaling complex by knocking down PTK2, YWHAZ, or MED1 attenuated and reversed oncogenic phenotypes caused by mutant p53 in a synthetic lethal manner. This signal-oriented framework for searching pathways and therapeutic targets is applicable to all cancer types, thus potentially impacting precision medicine in cancer. Cancer Res; 76(23); 6785-94. (c)2016 AACR. PMID- 27758892 TI - E2A-PBX1 Remodels Oncogenic Signaling Networks in B-cell Precursor Acute Lymphoid Leukemia. AB - There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5%-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of the key oncogenic effector enzyme PLCgamma2. Depletion of PLCgamma2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. Mechanistically, E2A-PBX1 bound promoter regulatory regions and activated the transcription of its key target genes ZAP70, SYK, and LCK, which encode kinases upstream of PLCgamma2. Depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCgamma2 (pPLCgamma2). Pairwise silencing of ZAP70, SYK, or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy with inhibitors of these kinases. Accordingly, inhibitors such as the SRC family kinase (SFK) inhibitor dasatinib reduced pPLCgamma2 and inhibited proliferation of human and mouse preBCR+/E2A-PBX1+ leukemias in vitro and in vivo Furthermore, combining small-molecule inhibition of SYK, LCK, and SFK showed synergistic interactions and preclinical efficacy in the same setting. Our results show how the oncogenic fusion protein E2A-PBX1 perturbs signaling pathways upstream of PLCgamma2 and renders leukemias amenable to targeted therapeutic inhibition. Cancer Res; 76(23); 6937-49. (c)2016 AACR. PMID- 27758893 TI - Genome-Wide Mapping of Uncapped and Cleaved Transcripts Reveals a Role for the Nuclear mRNA Cap-Binding Complex in Cotranslational RNA Decay in Arabidopsis. AB - RNA turnover is necessary for controlling proper mRNA levels posttranscriptionally. In general, RNA degradation is via exoribonucleases that degrade RNA either from the 5' end to the 3' end, such as XRN4, or in the opposite direction by the multisubunit exosome complex. Here, we use genome-wide mapping of uncapped and cleaved transcripts to reveal the global landscape of cotranslational mRNA decay in the Arabidopsis thaliana transcriptome. We found that this process leaves a clear three nucleotide periodicity in open reading frames. This pattern of cotranslational degradation is especially evident near the ends of open reading frames, where we observe accumulation of cleavage events focused 16 to 17 nucleotides upstream of the stop codon because of ribosomal pausing during translation termination. Following treatment of Arabidopsis plants with the translation inhibitor cycloheximide, cleavage events accumulate 13 to 14 nucleotides upstream of the start codon where initiating ribosomes have been stalled with these sequences in their P site. Further analysis in xrn4 mutant plants indicates that cotranslational RNA decay is XRN4 dependent. Additionally, studies in plants lacking CAP BINDING PROTEIN80/ABA HYPERSENSITIVE1, the largest subunit of the nuclear mRNA cap binding complex, reveal a role for this protein in cotranslational decay. In total, our results demonstrate the global prevalence and features of cotranslational RNA decay in a plant transcriptome. PMID- 27758894 TI - Characterization of a Pipecolic Acid Biosynthesis Pathway Required for Systemic Acquired Resistance. AB - Systemic acquired resistance (SAR) is an immune response induced in the distal parts of plants following defense activation in local tissue. Pipecolic acid (Pip) accumulation orchestrates SAR and local resistance responses. Here, we report the identification and characterization of SAR-DEFICIENT4 (SARD4), which encodes a critical enzyme for Pip biosynthesis in Arabidopsis thaliana Loss of function of SARD4 leads to reduced Pip levels and accumulation of a Pip precursor, Delta1-piperideine-2-carboxylic acid (P2C). In Escherichia coli, expression of the aminotransferase ALD1 leads to production of P2C and addition of SARD4 results in Pip production, suggesting that a Pip biosynthesis pathway can be reconstituted in bacteria by coexpression of ALD1 and SARD4. In vitro experiments showed that ALD1 can use l-lysine as a substrate to produce P2C and P2C is converted to Pip by SARD4. Analysis of sard4 mutant plants showed that SARD4 is required for SAR as well as enhanced pathogen resistance conditioned by overexpression of the SAR regulator FLAVIN-DEPENDENT MONOOXYGENASE1. Compared with the wild type, pathogen-induced Pip accumulation is only modestly reduced in the local tissue of sard4 mutant plants, but it is below detection in distal leaves, suggesting that Pip is synthesized in systemic tissue by SARD4-mediated reduction of P2C and biosynthesis of Pip in systemic tissue contributes to SAR establishment. PMID- 27758897 TI - Adaptation of the Domestic Violence Myth Acceptance Scale to Portuguese and Tests of Its Convergent, Divergent, and Predictive Validities. AB - The Domestic Violence Myth Acceptance Scale was adapted to Portuguese (PDVMAS). The PDVMAS displayed reasonable fit indices (Study 1); was positively correlated with right-wing authoritarianism, social dominance orientation, belief in a just world (Study 2), and ambivalent sexism (Study 3); and negatively correlated with empathetic tendencies (Study 4). PDVMAS significantly predicted victim blame and aggressor exoneration in scenarios of coercion (Study 5) and physical assault (Study 6). Victims and non-victims of domestic violence equally endorsed domestic violence myths. Globally, the PDVMAS is a reliable instrument, and domestic violence myths are pervasive and alter the perception of intimate partner violence. PMID- 27758896 TI - Surgeon-Authored Virtual Laparoscopic Adrenalectomy Module Is Judged Effective and Preferred Over Traditional Teaching Tools. AB - OBJECTIVE: The study assesses user acceptance and effectiveness of a surgeon authored virtual reality (VR) training module authored by surgeons using the Toolkit for Illustration of Procedures in Surgery (TIPS). METHODS: Laparoscopic adrenalectomy was selected to test the TIPS framework on an unusual and complex procedure. No commercial simulation module exists to teach this procedure. A specialist surgeon authored the module, including force-feedback interactive simulation, and designed a quiz to test knowledge of the key procedural steps. Five practicing surgeons, with 15 to 24 years of experience, peer reviewed and tested the module. In all, 14 residents and 9 fellows trained with the module and answered the quiz, preuse and postuse. Participants received an overview during Surgical Grand Rounds session and a 20-minute one-on-one tutorial followed by 30 minutes of instruction in addition to a force-feedback interactive simulation session. Additionally, in answering questionnaires, the trainees reflected on their learning experience and their experience with the TIPS framework. RESULTS: Correct quiz response rates on procedural steps improved significantly postuse over preuse. In the questionnaire, 96% of the respondents stated that the TIPS module prepares them well or very well for the adrenalectomy, and 87% indicated that the module successfully teaches the steps of the procedure. All participants indicated that they preferred the module compared to training using purely physical props, one-on-one teaching, medical atlases, and video recordings. CONCLUSIONS: Improved quiz scores and endorsement by the participants of the TIPS adrenalectomy module establish the viability of surgeons authoring VR training. PMID- 27758895 TI - Epidermal Phytochrome B Inhibits Hypocotyl Negative Gravitropism Non-Cell Autonomously. AB - Seedling hypocotyls display negative gravitropism in the dark but agravitropism in the light. The Arabidopsis thaliana pif quadruple mutant (pifQ), which lacks four PHYTOCHROME-INTERACTING FACTORS (PIFs), is agravitropic in the dark. Endodermis-specific expression of PIF1 rescues gravitropism in pifQ mutant seedlings. Since phytochromes induce light responses by inhibiting PIFs and the COP1-SPA ubiquitin E3 ligase complex in the nucleus, we asked whether phyB can cell autonomously inhibit hypocotyl negative gravitropism in the endodermis. We found that while epidermis-specific expression of PHYB rescues hypocotyl negative gravitropism and all other phyB mutant phenotypes, endodermis-specific expression of PHYB does not. Epidermal phyB induces the phosphorylation and degradation of endodermal PIFs in response to red light. This induces a global gene expression pattern similar to that induced by red light treatment of seedlings expressing PHYB under the control of its own endogenous promoter. Our results imply that epidermal phyB generates an unidentified mobile signal that travels to the endodermis where it promotes PIF degradation and inhibits hypocotyl negative gravitropism. PMID- 27758902 TI - Defra seeks views on the delivery of pet travel legislation. PMID- 27758900 TI - Diagnosed and living with fibromuscular dysplasia: A qualitative inquiry. AB - Fibromuscular dysplasia (FMD) is a vascular disorder about which little has been known until recently. Patients with FMD may suffer from hypertension, aneurysms, or strokes, as well as symptoms associated with local artery damage. As a result of advances in vascular medicine and growing outcomes registries, we now have a better understanding of the FMD disease process and epidemiology. Nevertheless, the consequences of FMD on patients' day-to-day experiences and mental health status are not well understood. The purpose of this study was to begin to identify and characterize the experiences of living with FMD from the perspective of the patient using qualitative inquiry. Interviews with 19 FMD patients (18 female, 1 male) were conducted, audio-recorded, transcribed verbatim, and content analyzed. Individuals with FMD reported a complex array of psychological, physical, emotional, social, and health care concerns, which may be underdiagnosed. Findings suggest new opportunities for enhancing patient care. PMID- 27758909 TI - EU survey suggests a lack of awareness of the benefits of veterinary medicines. PMID- 27758913 TI - Rabies control: going beyond human and animal health services. PMID- 27758914 TI - Questioning the evidence while keeping an open mind. AB - What was billed as 'the largest gathering of veterinary orthopaedic experts and practitioners in the world' took place last month in London, when the European Society of Veterinary Orthopaedics and Traumatology held its 18th congress. Organised as a joint meeting with the British Veterinary Orthopaedic Association, the congress programme featured multiple streams of lectures and presentations, as well as specific streams for students and new graduates and veterinary nurses. Suzanne Jarvis reports on some of the proceedings. PMID- 27758917 TI - Small animal disease surveillance: pruritus, and coagulase-positive staphylococci. AB - Presentation for pruritus comprised 6.5 per cent, 3.6 per cent and 2.0 per cent of canine, feline and rabbit consultations, respectively, between January 2014 and June 2016Topical antimicrobials were the most commonly prescribed pruritus treatments for dogs (33.6 per cent of consultations); for cats, it was systemic glucocorticoids (53.5 per cent)In surveillance of coagulase-positive staphylococci, 16 per cent of 176 coagulase-positive staphylococci isolated from canine diagnostic samples were sensitive to all tested antibacterial classes; multidrug resistance (resistance to three or more antibacterial classes) was found in 6.8 per cent. PMID- 27758918 TI - Tracing disease emergence: canine babesiosis in the UK. PMID- 27758919 TI - Expansion of the range of the West Nile virus vector in Essex. PMID- 27758920 TI - Role of glutamine in oral rehydration of calves. PMID- 27758921 TI - Wildlife rescue and rehabilitation guidelines. PMID- 27758927 TI - Really mixed practice - a career in conservation medicine. AB - James Chatterton is veterinary services manager at Auckland Zoo. Part of his role involves providing veterinary care for the kakapo, one of the most endangered birds in New Zealand. He regularly provides onsite help on two protected islands off the South Island of New Zealand as part of his role as veterinary coordinator to the Kakapo Recovery Group. PMID- 27758928 TI - Towards more accurate assessment of preterm systemic blood flow. PMID- 27758930 TI - Definition and monitoring of neonatal hypoglycaemia: a nationwide survey of NHS England Neonatal Units. PMID- 27758929 TI - Determinants of developmental outcomes in a very preterm Canadian cohort. AB - OBJECTIVES: Identify determinants of neurodevelopmental outcome in preterm children. METHODS: Prospective national cohort study of children born between 2009 and 2011 at <29 weeks gestational age, admitted to one of 28 Canadian neonatal intensive care units and assessed at a Canadian Neonatal Follow-up Network site at 21 months corrected age for cerebral palsy (CP), visual, hearing and developmental status using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Stepwise regression analyses evaluated the effect of (1) prenatal and neonatal characteristics, (2) admission severity of illness, (3) major neonatal morbidities, (4) neonatal neuroimaging abnormalities, and (5) site on neurodevelopmental impairment (NDI) (Bayley-III score < 85, any CP, visual or hearing impairment), significant neurodevelopmental impairment (sNDI) (Bayley-III < 70, severe CP, blind or hearing aided and sNDI or death. RESULTS: Of the 3700 admissions without severe congenital anomalies, 84% survived to discharge and of the 2340 admissions, 46% (IQR site variation 38% 51%) had a NDI, 17% (11%-23%) had a sNDI, 6.4% (3.1%-8.6%) had CP, 2.6% (2.5% 13.3%) had hearing aids or cochlear implants and 1.6% (0%-3.1%) had a bilateral visual impairment. Bayley-III composite scores of <70 for cognitive, language and motor domains were 3.3%, 10.9% and 6.7%, respectively. Gestational age, sex, outborn, illness severity, bronchopulmonary dysplasia, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity, abnormal neuroimaging and site were significantly associated with NDI or sNDI. Site variation ORs for NDI, sNDI and sNDI/death ranged from 0.3-4.3, 0.04-3.5 and 0.12-1.96, respectively. CONCLUSION: Most preterm survivors are free of sNDI. The risk factors, including site, associated with neurodevelopmental status suggest opportunities for improving outcomes. PMID- 27758932 TI - Relationship Between Sexual Abuse in Childhood and the Occurrence of Mental Illness in Adulthood: A Matched Case-Control Study in Nigeria. AB - This study aimed to examine the relationship between exposure to childhood sexual abuse (CSA) and the occurrence of mental illness in adulthood in Nigeria. An age- and gender-matched case-control study was conducted in the University of Port Harcourt Teaching Hospital, Nigeria, from January to March 2014. Cases were defined as individuals aged 18 to 60 years diagnosed with mental illness while controls were aged 18 to 60 years who did not have mental illness. The study had 304 subjects comprised of 152 case-control pairs. This case-control study showed a statistically significant association between exposure to CSA and occurrence of mental illness in adulthood (pair-matched odds ratio = 3.25, 95% CI = [1.70, 6.21]). The association between CSA and mental illness was still significant (adjusted odds ratio = 3.11, 95% CI = [1.67, 5.82]) after controlling for family functionality. A robust CSA prevention and treatment strategy that considers the victim and the perpetrator in Nigeria is hereby advocated. This could be achieved by the collaborative efforts of the government of Nigeria and non-governmental organizations. PMID- 27758931 TI - Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation. AB - Renal transporter-mediated drug-drug interactions (DDIs) are of significant clinical concern, as they can adversely impact drug disposition, efficacy, and toxicity. Emerging evidence suggests that human renal organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) exhibit substrate-dependent inhibition, but their impact on renal drug secretion and intracellular accumulation is unknown. Using metformin and atenolol as the probe substrates, we found that the classic inhibitors (e.g., cimetidine) of renal organic cation secretion were approximately 10-fold more potent for hOCT2 when atenolol was used, suggesting that atenolol is a more sensitive in vitro substrate for hOCT2 than metformin. In contrast, inhibition of hMATE1/2-K was influenced much less by the choice of substrate. Cimetidine is a much more potent inhibitor for hMATE1/2-K when metformin is the substrate but acts as an equally potent inhibitor of hOCT2 and hMATE1/2-K when atenolol is the substrate. Using hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cells, we evaluated the impact of substrate-dependent inhibition on hOCT2/hMATE1-mediated transepithelial flux and intracellular drug accumulation. At clinically relevant concentrations, cimetidine dose dependently inhibited basal-to-apical flux of atenolol and metformin but impacted their intracellular accumulation differently, indicating that substrate-dependent inhibition may shift the major substrate-inhibitor interaction site between apical and basolateral transporters. Cimetidine is effective only when applied to the basal compartment. Our findings revealed the complex and dynamic nature of substrate-dependent inhibition of renal organic cation drug transporters and highlighted the importance of considering substrate dependent inhibition in predicting transporter-mediated renal drug interaction, accumulation, and toxicity. PMID- 27758933 TI - mPGES-1 deletion affects platelet functions in mice. AB - Microsomal prostaglandin E2 synthase-1 (mPGES-1) constitutes an essential player of inflammation and is involved in the pathogenesis of rheumatoid arthritis (RA). Platelets participate in the regulation of inflammatory processes by the release of pro-inflammatory mediators and platelet-derived microparticles (PMPs). However, the role of the inducible mPGES-1/PGE2 pathway on platelet functions has not been investigated. Here we report a significant impact of mPGES-1 on platelet functions during inflammation. Wild-type (WT) and mPGES-1-/- (KO) mice were stimulated with lipopolysaccharide (LPS) for 24 hours. Platelet counts and activation were assessed by flow cytometry analyzing CD62P - CD154 expression, PMPs number, platelet-leukocyte aggregates and platelet aggregation. The accumulation of platelets and fibrinogen in the liver was analyzed by immunofluorescent staining. In native platelets from WT and mPGES-1 KO mice, there were no differences among the investigated functions. After LPS treatment, the number of platelets were significantly decreased in WT mice, but not in KO. Platelet activation, platelet-leukocyte aggregates, and PMP numbers were all significantly lower in KO mice compared to WT after LPS-treatment. In addition, KO mice displayed a significant reduction in platelet aggregation ex vivo In the liver of LPS-stimulated WT and KO mice, there were no differences in platelet accumulation, although, the percentage of total vessel area in the KO liver was significantly lower compared to WT. Our results demonstrate that systemic inhibition of mPGES-1 prevents platelet activation, which should have important implications regarding the cardiovascular safety of mPGES-1 inhibitors. PMID- 27758934 TI - Occupational Exposure to Antineoplastic Agents. AB - Approximately 8 million health care workers are unnecessarily exposed to highly toxic drugs used to treat cancer; antineoplastic drugs can contribute to negative health effects for these workers. The drugs have been detected in the urine of workers and on the floors and counters of worksites. Safety precautions that could reduce the risk of exposure are underutilized. This cross-sectional study of 163 oncology health care workers used a survey to measure workplace and individual factors, and environmental sampling to measure surface contamination. The study objective was to identify potential exposures to antineoplastic drugs and factors influencing safety behavior. Personal protective equipment (PPE) use was lower than recommended; unit of employment was significantly associated with PPE use. Chemical residue from antineoplastic drugs was found, revealing potential exposures. Workplace safety must be a higher organizational priority. The contamination of common work areas where PPE use is not expected was of utmost concern. PMID- 27758936 TI - Methylmercury Exposure in Women of Childbearing Age and Children. AB - As frontline clinicians, occupational and environmental health nurses play an important role in educating workers and the public about the dangers and toxic effects of environmental contaminants. One of these contaminants is methylmercury, which enters the body through the consumption of contaminated fish and seafood. Methylmercury affects the central nervous system where it may cause psychiatric disturbances, ataxia, neuropathy, and visual and hearing loss. Because their central nervous systems are rapidly developing, the most vulnerable subgroups are infants in utero, babies, and young children. Pregnant women and nursing mothers can directly expose their infants because methylmercury passes through the placenta to the infant and is also present in breast milk. The purpose of this article is to provide an overview for occupational and environmental health nurses and other health care practitioners about the causes and consequences of methylmercury exposure in women of childbearing age and children so that they can better educate workers about this environmental contaminant. PMID- 27758935 TI - The American Association of Occupational Health Nurses' Respiratory Protection Education Program and Resources Webkit for Occupational Health Professionals. AB - Organizations are required to adhere to the Occupational Safety and Health Administration's (OSHA) Respiratory Protection Standard (29 CFR 1910.134) if they have workers that wear a respirator on the job. They must also have an employee "suitably trained" to administer their program. The National Institute for Occupational Safety and Health and its National Personal Protective Technology Laboratory have worked to champion the occupational health nurse in this role by collaborating with the American Association of Occupational Health Nurses to develop free, online respiratory protection training and resources (RPP Webkit). This article describes the development, content, and success of this training. To date, 724 participants have completed the training, 32.6% of whom lead their organization's respiratory protection program, 15.3% who indicated they will lead a program in the near future, and 52% who did not lead a program, but indicated that the training was relevant to their work. The majority "strongly agreed" the training was applicable to their work and it enhanced their professional expertise. PMID- 27758937 TI - Using Pedometers to Increase the Non-Workday Steps of Hospital Nursing and Support Staff: A Pilot Study. AB - Nursing is a physically active profession; however, nurses and nursing support staff may limit their physical activity (PA) on non-workdays. The purpose of this pilot study was to examine the effects of a 12-week pedometer-based PA intervention on daily steps of hospital nursing and support staff from two departments, emergency (ED) and oncology (ONC). The 12-week minimal-contact, self managed intervention was designed to increase total and non-workday PA. Twenty participants with an average age of 47.6 +/- 7.1 years completed the intervention. Significant differences were found between total daily steps at baseline (8,446) and at 12 weeks (10,655; p = .014), and between workday steps at baseline (10,398) and at 12 weeks (13,056; p = 0.005). Oncology unit participants significantly increased their non-workday steps from baseline (5,850) to 12 weeks (9,829; p = .003). As part of a comprehensive intervention, pedometers can promote total and non-workday PA of nursing and support staff. PMID- 27758938 TI - Occupational Stress: A Comprehensive Review of the Top 50 Annual and Lifetime Cited Articles. AB - This study determined the impact and influence of published articles on the field of occupational stress. A transdisciplinary approach was used to identify the 50 work-related stress articles with the most lifetime citations and the 50 work related stress articles with the highest annual citation rates. Studies were categorized based on their primary focus: (a) etiology, (b) predictor of outcome for which occupational stress is the outcome or predictor of outcome for which occupational stress is an independent variable, (c) management/intervention, (d) theory/model/framework, or (e) methodologies. The majority of studies with the highest number of lifetime citations as well as the highest annual citation rates used stress as a predictor or outcome of another factor. The proportion of studies that were categorized by etiology, intervention/management, theory/model/framework, or methodologies was relatively low for both lifetime and annual citations. PMID- 27758939 TI - Socioeconomic Status and the Quality of Acute Stroke Care: The China National Stroke Registry. AB - BACKGROUND AND PURPOSE: The association of socioeconomic status (SES) with quality of stroke care is not well understood, and few studies have examined the association with different indicators of SES simultaneously. We assessed the impacts of low levels of education, occupation, and income on the quality of stroke care. METHODS: We examined data from the China National Stroke Registry recording consecutive stroke patients between September 2007 and August 2008. Baseline low SES was measured using educational level <6 years, occupation as manual workers or no job, and average family income per capita at <=Y1000 per month. Compliance with 11 performances was summarized in a composite score defined as the proportion of all needed care given. Poor quality of care was defined as having a composite score of 0.71 or less. RESULTS: Among 12 270 patients with ischemic stroke, 38.6% had <6 educational years, 37.6% had manual workers/no job, and 34.7% had income <=Y1000 per month. There was an increased chance of receiving poor quality of care in patients with low education (adjusted odds ratio 1.15, 95% confidence interval 1.03-1.28), low occupation (adjusted odds ratio 1.16, 95% confidence interval 1.01-1.32), and low income (adjusted odds ratio 1.18, 95% confidence interval 1.06-1.30), respectively. People with low SES had poor performances on some aspects of care quality. Combined effects existed among these SES indicators; those with low SES from all 3 indicators had the poorest quality of care. CONCLUSIONS: There was a social gradient in the quality of stroke care. Continuous efforts of socioeconomic improvement will increase the quality of acute stroke care. PMID- 27758940 TI - ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68+/ 21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770. PMID- 27758942 TI - Cost-Effectiveness of Endovascular Stroke Therapy: A Patient Subgroup Analysis From a US Healthcare Perspective. AB - BACKGROUND AND PURPOSE: Endovascular therapy in addition to standard care (EVT+SC) has been demonstrated to be more effective than SC in acute ischemic large vessel occlusion stroke. Our aim was to determine the cost-effectiveness of EVT+SC depending on patients' initial National Institutes of Health Stroke Scale (NIHSS) score, time from symptom onset, Alberta Stroke Program Early CT Score (ASPECTS), and occlusion location. METHODS: A decision model based on Markov simulations estimated lifetime costs and quality-adjusted life years (QALYs) associated with both strategies applied in a US setting. Model input parameters were obtained from the literature, including recently pooled outcome data of 5 randomized controlled trials (ESCAPE [Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke], EXTEND-IA [Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial], MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], REVASCAT [Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset], and SWIFT PRIME [Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment]). Probabilistic sensitivity analysis was performed to estimate uncertainty of the model results. Net monetary benefits, incremental costs, incremental effectiveness, and incremental cost-effectiveness ratios were derived from the probabilistic sensitivity analysis. The willingness-to-pay was set to $50 000/QALY. RESULTS: Overall, EVT+SC was cost-effective compared with SC (incremental cost: $4938, incremental effectiveness: 1.59 QALYs, and incremental cost-effectiveness ratio: $3110/QALY) in 100% of simulations. In all patient subgroups, EVT+SC led to gained QALYs (range: 0.47-2.12), and mean incremental cost-effectiveness ratios were considered cost-effective. However, subgroups with ASPECTS <=5 or with M2 occlusions showed considerably higher incremental cost-effectiveness ratios ($14 273/QALY and $28 812/QALY, respectively) and only reached suboptimal acceptability in the probabilistic sensitivity analysis (75.5% and 59.4%, respectively). All other subgroups had acceptability rates of 90% to 100%. CONCLUSIONS: EVT+SC is cost-effective in most subgroups. In patients with ASPECTS <=5 or with M2 occlusions, cost-effectiveness remains uncertain based on current data. PMID- 27758941 TI - Substantial Progress Yet Significant Opportunity for Improvement in Stroke Care in China. AB - BACKGROUND AND PURPOSE: Stroke is a leading cause of death in China. Yet the adherence to guideline-recommended ischemic stroke performance metrics in the past decade has been previously shown to be suboptimal. Since then, several nationwide stroke quality management initiatives have been conducted in China. We sought to determine whether adherence had improved since then. METHODS: Data were obtained from the 2 phases of China National Stroke Registries, which included 131 hospitals (12 173 patients with acute ischemic stroke) in China National Stroke Registries phase 1 from 2007 to 2008 versus 219 hospitals (19 604 patients) in China National Stroke Registries phase 2 from 2012 to 2013. Multiple regression models were developed to evaluate the difference in adherence to performance measure between the 2 study periods. RESULTS: The overall quality of care has improved over time, as reflected by the higher composite score of 0.76 in 2012 to 2013 versus 0.63 in 2007 to 2008. Nine of 13 individual performance metrics improved. However, there were no significant improvements in the rates of intravenous thrombolytic therapy and anticoagulation for atrial fibrillation. After multivariate analysis, there remained a significant 1.17-fold (95% confidence interval, 1.14-1.21) increase in the odds of delivering evidence-based performance metrics in the more recent time periods versus older data. The performance metrics with the most significantly increased odds included stroke education, dysphagia screening, smoking cessation, and antithrombotics at discharge. CONCLUSIONS: Adherence to stroke performance metrics has increased over time, but significant opportunities remain for further improvement. Continuous stroke quality improvement program should be developed as a national priority in China. PMID- 27758943 TI - Renal Function and the Risk of Stroke and Bleeding in Patients With Atrial Fibrillation: An Observational Cohort Study. AB - BACKGROUND AND PURPOSE: We sought to determine the risk of stroke/thromboembolism and bleeding associated with reduced renal function in patients with atrial fibrillation and the risk of stroke and bleeding associated with warfarin treatment in specific estimated glomerular filtration rate (eGFR) groups. METHODS: We conducted a register-based cohort study and included patients discharged with nonvalvular atrial fibrillation from 1997 to 2011 with available eGFR. RESULTS: A total of 17 349 patients were identified with eGFR available at baseline. All levels of lower eGFR were associated with higher risk of stroke/thromboembolism and bleeding. Use of warfarin was associated with higher bleeding risk in all eGFR groups; hazard ratios 1.23 (95% confidence interval [CI], 0.97-1.56), 1.26 (95% CI, 1.14-1.40), 1.18 (95% CI, 1.07-1.31), 1.11 (95% CI, 0.87-1.42), 2.01 (95% CI, 1.14-3.54) in patients with eGFR >=90, 60 to 89, 30 to 59, 15 to 29, and <15 mL/min per 1.73 m2, respectively. Use of warfarin was associated with lower risk of stroke/thromboembolism in patients with eGFR >=15 mL/min per 1.73 m2; hazard ratios 0.57 (95% CI, 0.43-0.76), 0.57 (95% CI, 0.51 0.64), 0.48 (95% CI, 0.44-0.54), 0.60 (95% CI, 0.45-0.80) in patients with eGFR >=90, 60 to 89, 30 to 59, and 15 to 29 mL/min per 1.73 m2, respectively. Use of warfarin was not associated with lower risk of stroke/thromboembolism in patients with eGFR<15 mL/min per 1.73 m2; hazard ratio 1.18 (95% CI, 0.58-2.40). CONCLUSIONS: In patients with atrial fibrillation, the risk of stroke and bleeding was associated with levels of renal function. Warfarin treatment was associated with higher risk of bleeding in all eGFR groups and lower risk of stroke in patients with eGFR>=15 mL/min per 1.73 m2. PMID- 27758946 TI - Letter by de Boysson and Pagnoux Regarding Article, "Diagnostic Yield and Safety of Brain Biopsy for Suspected Primary Central Nervous System Angiitis". PMID- 27758944 TI - Combination of Thrombolysis and Statins in Acute Stroke Is Safe: Results of the STARS Randomized Trial (Stroke Treatment With Acute Reperfusion and Simvastatin). AB - BACKGROUND AND PURPOSE: The STARS trial (Stroke Treatment With Acute Reperfusion and Simvastatin) was conducted to demonstrate the efficacy and safety of simvastatin treatment in acute stroke. METHODS: STARS07 was a multicentre, phase IV, prospective, randomized, double-blind, placebo-controlled trial. Patients with Acute ischemic stroke recruited within 12 hours from symptom onset were randomized to oral simvastatin 40 mg or placebo, once daily for 90 days. Primary outcome was proportion of independent patients (modified Rankin Scale score of <=2) at 90 days. Safety end points were hemorrhagic transformation, hemorrhagic events, death, infections, and serious adverse events. RESULTS: From April 2009 to March 2014, 104 patients were included. Fifty-five patients received intravenous tissue-type plasminogen activator. No differences were found between treatment arms regarding the primary outcome (adjusted odds ratio, 0.99 [0.35 2.78]; P=0.98). Concerning safety, no significant differences were found in the rate of hemorrhagic transformation of any type, nor symptomatic hemorrhagic transformation. There were no differences in other predefined safety outcomes. In post hoc analyses, for patients receiving tissue-type plasminogen activator, a favorable effect for simvastatin treatment was noted with higher proportion of patients experiencing major neurological recovery (adjusted odds ratio, 4.14 [1.18-14.4]; P=0.02). CONCLUSIONS: Simvastatin plus tissue-type plasminogen activator combination seems safe in acute stroke, with low rates of bleeding complications. Because of the low recruitment, the STARS trial was underpowered to detect differences in simvastatin efficacy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01073007. PMID- 27758945 TI - Uric Acid Therapy Prevents Early Ischemic Stroke Progression: A Tertiary Analysis of the URICO-ICTUS Trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke). AB - BACKGROUND AND PURPOSE: Identification of neuroprotective therapies in acute ischemic stroke is imperative. We report a predefined analysis of the URICO-ICTUS trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke) assessing the efficacy of uric acid (UA) compared with placebo to prevent early ischemic worsening (EIW) and the relevance of collateral circulation. METHODS: URICO-ICTUS was a double-blind, placebo-controlled, phase 2b trial where a total of 411 patients treated with alteplase within 4.5 hours of stroke onset were randomized (1:1) to receive UA 1000 mg (n=211) or placebo (n=200) before the end of alteplase infusion. EIW defined an increment >=4 points in the National Institutes of Health Stroke Scale score within 72 hours of treatment in the absence of hemorrhage or recurrent stroke. Logistic regression models assessed the interaction between therapy and the collateral circulation in 112 patients who had a pretreatment computed tomographic angiography. RESULTS: EIW occurred in 2 of 149 (1%) patients with good outcome and 23 of 262 (9%) patients with poor outcome (chi2; P=0.002). EIW occurred in 7 of 204 (3%) patients treated with UA and in 18 of 200 (9%) patients treated with placebo (chi2; P=0.01). There was a significant interaction between the efficacy of UA to prevent EIW and collaterals (P=0.029), with lower incidence in patients with good collaterals treated with UA compared with placebo (2% versus 15%, respectively; P=0.048). CONCLUSIONS: UA therapy may prevent EIW after acute stroke in thrombolysed patients. Optimal access of UA to its molecular targets through appropriate collaterals may modify the magnitude of the neuroprotective effect. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00860366. PMID- 27758947 TI - Prehospital Scales to Identify Patients With Large Vessel Occlusion: It Is Time for Action. PMID- 27758948 TI - Letter by Yang et al Regarding Article, "Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults". PMID- 27758949 TI - Response by Gutierrez et al to Letter Regarding Article, "Hemoglobin Concentration and Risk of Incident Stroke in Community-Living Adults". PMID- 27758950 TI - Electrochemotherapy as a single or adjuvant treatment to surgery of cutaneous sarcoid tumours in horses: a 31-case retrospective study. AB - The aim of our study was to evaluate the efficacy of electrochemotherapy (ECT) with cisplatin as a single or adjuvant treatment for sarcoids in equids. Different treatment options with different success rates were proposed. Thirty one horses and one donkey with different clinical type, size and location of tumours were treated with ECT as a single treatment (18 animals with 52 tumour nodules) or as adjuvant treatment with marginal surgical excision (14 animals with 18 tumour nodules). In animals treated only with ECT with cisplatin, complete response was obtained in 48/52 (92.3 per cent) nodules and partial response in the other 4 nodules (7.7 per cent). In most cases, one to three sessions, only in two cases four and in one case five sessions, every 4 weeks were needed to obtain the measurable response. During the observation time, only in one case was the recurrence noted 60 months after treatment. Complete response in all 18 tumour nodules treated with surgery and adjuvant ECT was obtained and only one recurrence was noted after 14 months during the observation time. The results of this study show that ECT with cisplatin is an effective, safe, and simple local treatment of sarcoids in equids. According to the tumour size and location, single or combined treatment should be performed. PMID- 27758951 TI - The Journal Broadens Publishing Opportunities for Authors. PMID- 27758952 TI - The Association of Sleep Disturbances With Quality of Life in Heart Failure Patient-Caregiver Dyads. AB - Sleep disturbance is common in patients with heart failure and their family caregivers. The purpose of this study was to determine whether sleep disturbances of patients and their spousal caregivers predicted their own and their partners' quality of life (QoL) in 78 heart failure patient-spousal caregiver dyads. Sleep disturbance was assessed using a composite score of four common sleep complaints. QoL was assessed by the physical and mental well-being subscales of the Short Form 12 Health Survey. The multilevel dyadic actor-partner interdependence model analysis was used to determine the association between sleep disturbance and QoL. Each individual's sleep disturbance predicted their own poor physical and mental well-being while spousal caregivers' sleep disturbance predicted their partners' mental well-being. Results indicated that patients' mental well-being is sensitive to their spouses' sleep disturbance. Interventions targeting improving sleep and QoL may have to include both patients and spousal caregivers. PMID- 27758953 TI - Absorption and distribution of estradiol from male seminal emissions during mating. AB - Estradiol-17beta (E2) plays critical roles in female maturation, sexual receptivity, ovulation and fertility. In many mammals, contact with males can similarly affect these female parameters, whereas male excretions contain significant quantities of E2 We administered radiolabeled estradiol ([3H]E2) to male mice in doses representing a small fraction of their endogenous E2 These males were paired with sexually receptive females, and radioactivity was traced into the females' systems. In Experiment 1, males were given [3H]E2 at 24 and 1 h before mating. Male-to-female [3H]E2 transfer intensified with increasing numbers of intromissions and spiked in the uterus after insemination. In Experiment 2, sexually experienced young males received [3H]E2 at 72 and 24 h before mating, and all mated to ejaculation. The copulatory plug deposited in the female reproductive tract contained substantial levels of radioactivity. The uteri, other tissues and blood serum of females displayed radioactivity indicative of E2 transfer. In Experiment 3, radioactivity was observed 3 and 18 h after insemination in the females' uteri and other tissues, including parts of the brain. In Experiment 4, we observed substantial levels of radioactivity in semen as well as the copulatory plugs retrieved from the females after mating. Transferred E2 could directly affect abundant estrogen receptors in the female reproductive tract without potential metabolism by the liver. Sexually transferred E2 may facilitate uterine preparation for blastocyst implantation. These data converge with several lines of evidence indicating that male-sourced E2 can transfer to proximate females in bioactive form, contributing to various mammalian pheromonal effects. PMID- 27758955 TI - The impact of adjusted work conditions and disease-modifying drugs on work ability in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a neurological disorder that causes significantly reduced ability to work, and the Expanded Disability Status Scale (EDSS) is one of the main predictors for reduced work ability. OBJECTIVES: To investigate how work requirements, flexible work conditions and disease-modifying drugs (DMDs) influence the work ability in relation to different EDSS grades in two MS populations. METHODS: Work ability was studied in two MS populations: one in the southern and one in the northern part of Sweden, both demographically similar. In the latter population, more active work-promoting interventions have been practised and second-generation DMDs have been widely used from the onset of disease for several years. RESULTS: The proportion of MS patients who participated in the workforce or studied was significantly higher in the northern compared with the southern population ( p < 0.001). The employees in the northern population had significantly lower requirements, greater adapted work conditions and were able to work more hours per week. Higher EDSS was associated with lower reduction in number of worked hours per week in the northern population ( p = 0.042). CONCLUSION: Our data indicated that treatment strategy and adjusted work conditions have impact on work ability in MS. PMID- 27758954 TI - Influence of female sex and fertile age on neuromyelitis optica spectrum disorders. AB - BACKGROUND: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. OBJECTIVE: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). METHODS: Female-to male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. RESULTS: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ?40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years. CONCLUSION: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD. PMID- 27758956 TI - Using appreciative inquiry to implement person-centred dementia care in hospital wards. AB - The quality of care of persons with dementia in hospitals is not optimal and can be challenging. Moreover, staff may find difficulty in translating what they have learned during training into practice. This paper report the development and evaluation of a set of workshops using an appreciative inquiry approach to implement person-centred dementia care in two hospital wards. Staff worked collaboratively to develop a ward vision and to implement a number of action plans. Using appreciative inquiry approach, staff attitudes towards persons with dementia improved, inter-professional collaboration was enhanced and small changes in staff practices were noted. Dementia care in hospitals can be enhanced by empowering staff to take small but concrete actions after they engage in appreciative inquiry workshops, during which they are listened to and appreciated for what they can contribute. PMID- 27758957 TI - An occupational perspective of the lived experience of familial dementia caregivers: A thematic review of qualitative literature. AB - Dementia caregiving is thought to have a negative impact on health and wellbeing. This critical review of qualitative literature explored the lived experience of familial dementia caregivers from an occupational therapy perspective. The method was informed by systematic review and qualitative research methodologies and was structured within the occupational dimensions framework of doing-being-becoming belonging. A comprehensive search of major databases was undertaken which identified 484 studies on the topic; 14 met the inclusion criteria and were included in the review. Ten themes emerged within the doing-being-becoming belonging framework from the analysis of the studies. The occupational participation of caregivers is conveyed within the 'doing' domain. Ways in which caregiving impacts upon opportunities for self-nurture are presented within the 'being' domain. The 'becoming' domain elucidates ways in which caregivers redefine themselves, their values and their priorities through their caregiving role. The 'belonging' domain depicts ways in which caregivers' connections with their care recipient and others are shaped over time. Practice implications for health and social care practitioners who work with familial dementia caregivers are presented in light of the findings. PMID- 27758958 TI - Improving access to a multi-component intervention for caregivers and people with dementia. AB - Due to the increasing social and economic costs of dementia, there are urgent calls to develop accessible and sustainable care for people with dementia and their caregivers. Multi-component non-pharmacological interventions (NPIs) appear effective in improving or maintaining daily functioning and well-being, but are typically labour-intensive for health care professionals, thus hindering access. The current study aimed to explore the feasibility and acceptability of a novel approach to widen access to NPI by involving caregivers to present part of the intervention and with staff from local support organizations instructed to train the caregivers. Trainers and caregivers were shown to comply with training instructions and the direct intervention costs were low. Feedback from trainers and caregivers was positive and well-being ratings from people with dementia and caregivers remained stable over time and caregivers' sense of competence improved. The findings suggest that involving caregivers and trained non professionals to provide the intervention is feasible and acceptable and could be a cost-effective solution to improve access to care. PMID- 27758959 TI - The Cognitive Daisy - A novel method for recognising the cognitive status of older adults in residential care: Innovative practice. AB - The Cognitive Daisy is an innovative assessment system created to provide healthcare staff with an instant snapshot of the cognitive status of older adults in residential care. The Cognitive Daisy comprises a flower head consisting of 15 colour coded petals depicting information about: visual-spatial perception, comprehension, communication, memory and attention. This study confirmed the practicality of the Cognitive Daisy protocol for assessing cognition in a sample of 33 older adults living in residential care and endorsed the use of the Cognitive Daisy as a tool for recognising the cognitive status of care home residents. PMID- 27758960 TI - Progression of mild cognitive impairment to dementia in German specialist practices. AB - The goal of this study was to estimate the rate of the progression of mild cognitive impairment to dementia and identify the potential risk factors in German specialist practices from 2005 to 2015. This study included 4633 patients aged 40 years and over from 203 neuropsychiatric practices, who were initially diagnosed with mild cognitive impairment between 2005 and 2013. The primary outcome was diagnosis of all-cause dementia recorded in the database until the end of the five-year follow-up period. Cox regression models were used to examine mild cognitive impairment progression to dementia when adjusted for confounders (age, sex, and health-insurance type). The mean age was 68.9 years and 46.6% were men. After the five-year follow-up period, 38.1% of women and 30.4% of men had been diagnosed with dementia (p < 0.001). The share of subjects with dementia increased with age, rising from 6.6% in the age group of <= 60 years to 64.7% in the age group of > 80 years (p < 0.001). Men were at a lower risk of being diagnosed with dementia than women (hazard ratio = 0.86). Patients in the age groups 61-70, 71-80, and > 80 years also had a higher risk of developing this psychiatric disorder, with hazard ratios ranging from 3.50 to 11.71. Finally, mild cognitive impairment was less likely to progress to dementia in people with private health-insurance coverage than in people with public health-insurance coverage (hazard ratio = 0.69). Around one in three patients developed dementia in the five years following mild cognitive impairment diagnosis. Sex, age, and type of health insurance were associated with this risk. PMID- 27758961 TI - Editorial. PMID- 27758962 TI - Young onset dementia: Negotiating future workplace roles and identities. PMID- 27758963 TI - Effect of Biomechanical Constraints on Neural Control of Head Stability in Children With Moderate to Severe Cerebral Palsy. AB - BACKGROUND: External support has been viewed as an important biomechanical constraint for children with deficits in postural control. Nonlinear analysis of head stability may be helpful to confirm benefits of interaction between external trunk support and level of trunk control. OBJECTIVE: The purpose of this study was to compare the effect of biomechanical constraints (trunk support) on neural control of head stability during development of trunk control. DESIGN: This was a quasi-experimental repeated-measures study. METHODS: Data from 15 children (4-16 years of age) with moderate (Gross Motor Function Classification System [GMFCS] IV; n=8 [4 boys, 4 girls]) or severe (GMFCS V; n=7 [4 boys, 3 girls]) cerebral palsy (CP) were compared with previous longitudinal data from infants with typical development (TD) (3-9 months of age). Kinematic data were used to document head sway with external support at 4 levels (axillae, midrib, waist, and hip). Complexity, predictability, and active degrees of freedom for both anterior posterior and medial-lateral directions were assessed. RESULTS: Irrespective of level of support, CP groups had lower complexity, increased predictability, and greater degrees of freedom. The effect of support differed based on the child's segmental level of control. The GMFCS V and youngest TD groups demonstrated better head control, with increased complexity and decreased predictability, with higher levels of support. The GMFCS IV group had the opposite effect, showing decreased predictability and increased complexity and degrees of freedom with lower levels of support. LIMITATIONS: Infants with typical development and children with CP were compared based on similar segmental levels of trunk control; however, it is acknowledged that the groups differed for age, cognitive level, and motor experience. CONCLUSIONS: The effect of external support varied depending on the child's level of control and diagnostic status. Children with GMFCS V and young infants with TD had better outcomes with external support, but external support was not enough to completely correct for the influence of CP. Children with GMFCS IV performed worse, with increased predictability and decreased complexity, when support was at the axillae or midribs, suggesting that too much support can interfere with postural sway quality. PMID- 27758967 TI - Intravenous Immune Globulin Stewardship Program at a Tertiary Academic Medical Center. AB - BACKGROUND: In October 2010, a pharmacist-driven stewardship program was implemented at the Brigham and Women's Hospital to ensure continued adherence to the prescribing guideline, focusing on indications for intravenous immune globulin (IVIG) use and dosing per ideal body weight. OBJECTIVE: The primary objective was to describe an IVIG stewardship program at a tertiary academic medical center. METHODS: This was a prospective, observational study from January 2013 through December 2014. All patients ordered to receive IVIG during the defined study period were included. The intervention assessed describes a pharmacist-driven IVIG stewardship program for medication approval. The primary end point was guideline compliance based on indication, dose, dosing weight, and frequency. Secondary end points included the number of patients receiving IVIG, indications, orders discontinued as a result of guideline nonadherence, and total amount dispensed. RESULTS: A total of 418 patients were identified during the study time frame. The top indications were: hypogammaglobulinemia in bone marrow transplantation and hematological malignancy (50.7%), acute solid organ rejection (11.8%), and immune thrombocytopenia with bleeding (10.1%). In all, 12 patients (2.9%) received IVIG for an indication nonadherent with the IVIG prescribing guideline; 9 patients (2.2%) and 2 patients (0.5%), respectively, received a different dose or frequency per the prescribed indication; and 12 orders (2.9%) for indications nonadherent to the guideline were discontinued. A total of 26 033 g of IVIG were dispensed during the study period. CONCLUSIONS: An IVIG stewardship program, including an institution-specific prescribing guideline and a pharmacist-driven stewardship program, may ensure guideline compliance for appropriateness of indication and dose at an academic medical center. PMID- 27758968 TI - Novel Use of Ranolazine as an Antiarrhythmic Agent in Atrial Fibrillation. AB - OBJECTIVE: To review the limitations of current antiarrhythmic drugs in atrial fibrillation (AF) and discuss the rationale and clinical trials supporting the use of ranolazine in AF. DATA SOURCES: MEDLINE was searched from 1980 to September 2016 using the terms ranolazine, atrial fibrillation, coronary artery bypass grafting, and valve surgery. STUDY SELECTION AND DATA EXTRACTION: English language studies and reviews assessing antiarrhythmic drugs, including ranolazine, were incorporated. DATA SYNTHESIS: The use of ranolazine monotherapy has been evaluated in 2 clinical trials. In the RAFFAELLO trial, higher doses of ranolazine showed a trend toward lower AF recurrence versus placebo ( P = 0.053), but further evidence is needed to support its use as a sole therapeutic agent. Ranolazine has shown utility in a limited number of studies as an adjunctive agent, which is critical for those in whom standard therapy is inadequate or the adverse event profile precludes optimized standard therapy. In the HARMONY trial, ranolazine 750 mg and dronedarone 225 mg twice daily reduced the AF burden by 59.1% from baseline ( P = 0.008 vs placebo). In a trial by Koskinas and colleagues, patients receiving ranolazine 1500 mg once and intravenous amiodarone had a higher conversion rate than those receiving amiodarone alone ( P = 0.024). There are also promising studies for the prevention and treatment of post cardiothoracic surgery AF, which require further investigation. CONCLUSIONS: Ranolazine's pharmacological properties and available evidence suggest potential for its use in AF. PMID- 27758969 TI - Extracorporeal membrane oxygenation support for life-threatening acute severe status asthmaticus. AB - INTRODUCTION: Status asthmaticus is a life-threatening condition characterized by progressive respiratory failure due to asthma that is unresponsive to standard therapeutic measures. We used extracorporeal membrane oxygenation (ECMO) to treat patients with near-fatal status asthamticus who did not respond to aggressive medical therapies and mechanical ventilation under controlled permissive hypercapnia. MATERIALS AND METHODS: Between January 2011 and October 2015, we treated 16 adult patients with status asthmaticus (8 women, 8 men, mean age: 50.5+/-10.6years) with veno-venous ECMO (13 patients) or veno-arterial (3 patients). Patients failed to respond to conventional therapies despite receiving the most aggressive therapies, including maximal medical treatments, mechanical ventilation under controlled permissive hypercapnia and general anesthetics. RESULTS: Mean time spent on ECMO was 300+/-11.8 hours (range 36-384 hours). PaO2, PaCO2 and pH showed significant improvement promptly after ECMO initiation p=0.014, 0.001 and <0.001, respectively, and such values remained significantly improved after ECMO, p=0.004 and 0.001 and <0.001, respectively. The mean time of ventilation after decannulation until extubation was 175+/-145.66 hours and the median time to intensive care unit discharge after decannulation was 234+/-110.30 hours. All 16 patients survived without neurological sequelae. CONCLUSIONS: ECMO could provide adjunctive pulmonary support for intubated asthmatic patients who remain severely acidotic and hypercarbic despite aggressive conventional therapy. ECMO should be considered as an early treatment in patients with status asthmaticus whose gas exchange cannot be satisfactorily maintained by conventional therapy for providing adequate gas change and preventing lung injury from the ventilation. PMID- 27758970 TI - Wide discrepancies in activated clotting times measured by two devices were detected for a patient with lupus anticoagulant in a cardiac surgery. AB - INTRODUCTION: For a patient with lupus anticoagulant (LA), activated coagulation time (ACT) was measured with two different types of devices (HEMOCHRON(r) 801 and HEMOCHRON(r) Jr). CASE REPORT: ACTs during heparinization measured with the HEMOCHRON(r) 801 were over the range of measurement, while those with the HEMOCHRON(r) Jr. reflected an almost normal response to heparin. DISCUSSION: The phospholipid contained in an activating agent of the HEMOCHRON(r) Jr was suggested to have counteracted the effect of LA. CONCLUSION: It was indicated that the coagulation status for LA-positive patients might be better assessed by ACT measured with phospholipid in an activating agent, although careful interpretation is required. PMID- 27758972 TI - Implication of alcohol consumption on aggregate wellbeing. AB - AIMS: The effects of drinking alcohol extend beyond the individuals concerned to the wider community. While there is recognition of such a global implication, currently no study has quantified the impact of alcohol consumption on aggregate wellbeing. This study aims to address this gap and attempts to investigate the impact of various levels of alcohol consumption on aggregate happiness. METHODS: The study was carried out on a random selection of participants ( n = 1,817) drawn from the 3Di consumer panel, comprising over 170,000 New Zealanders aged 18 and above. Using a subjective happiness scale (SHS) in conjunction with the Alcohol Use Disorders Identification Test (AUDIT), investigation was carried out to find whether drinking behaviour affected aggregate happiness. RESULTS: SHS and AUDIT scores were negatively correlated and the strength of the correlation increased with the intensity of problematic drinking. Regression analysis showed that the beta coefficient was positive for the low-risk (.074) and negative for the high-risk (-.081) category, suggesting approaches to intervene with the growing problem of alcohol consumption in modern societies. CONCLUSION: Measurements of happiness can explain the global implication of alcohol in wellbeing terms. The findings of this study indicated that low-risk drinkers affected aggregate happiness positively, whereas high-risk drinkers affected aggregate happiness negatively. While the latter observation is not new, the former raises the need to promote moderation in drinking alcohol for the common good of everyone. PMID- 27758971 TI - Physical Strength as a Cue to Dominance: A Data-Driven Approach. AB - We investigate both similarities and differences between dominance and strength judgments using a data-driven approach. First, we created statistical face shape models of judgments of both dominance and physical strength. The resulting faces representing dominance and strength were highly similar, and participants were at chance in discriminating faces generated by the two models. Second, although the models are highly correlated, it is possible to create a model that captures their differences. This model generates faces that vary from dominant-yet physically weak to nondominant-yet-physically strong. Participants were able to identify the difference in strength between the physically strong-yet-nondominant faces and the physically weak-yet-dominant faces. However, this was not the case for identifying dominance. These results suggest that representations of social dominance and physical strength are highly similar, and that strength is used as a cue for dominance more than dominance is used as a cue for strength. PMID- 27758973 TI - Evolution of Chagas' disease in Brazil. Epidemiological perspective and challenges for the future: a critical review. AB - AIMS: This article aimed to provide a critical review of the evolution of Chagas' disease (ChD) in Brazil, its magnitude, historical development and management, and challenges for the future. METHODS: A literature search was performed using PubMed, SciELO and Google Scholar and throughout collected articles' references. Narrative analysis was structured around five main themes identified: vector transmission, control programme, transfusion, oral and congenital transmission. RESULTS: In Brazil, the Chagas' Disease Control Programme was fully implemented in the 1980s, when it reached practically all the endemic areas, and in 1991, the Southern Cone Initiative was created, aiming to control the disease transmission through eliminating the Triatoma infestans and controlling blood banks. As a result, the prevalence of chagasic donors in blood banks reduced from 4.4% in the 1980s to 0.2% in 2005. In 2006, Pan American Health Organization (PAHO) certified the interruption of transmission of ChD through this vector in Brazil. However, there are still challenges, such as the domiciliation of new vector species, the need for medical care of the infected individuals, the prevention of alternative mechanisms of transmission, the loss of political concern regarding the disease and the weakening of the control programme. CONCLUSION: Despite the progress towards control, there are still many challenges ahead to maintain and expand such control and minimise the risk of re-emergence. PMID- 27758974 TI - Reduced haze of transparent conductive films by smaller diameter silver nanowires. AB - Silver nanowires (Ag NWs) have received considerable attention for flexible transparent conductive films (TCFs) since they provide a relatively low sheet resistance at a high transmittance. However, the diffuse light scattering, haze, has been regarded as a hurdle to achieve clarity of films. Here we revisit the Mie scattering theory to calculate the extinction and scattering coefficients of Ag NWs which were employed to estimate haze of TCFs. The theory predicted a decrease in haze with a decrease in Ag NW diameter which was supported by experimental investigations carried out using Ag NWs with 5 different diameters (17.6, 19.9, 22.5, 24.3, and 29.6 nm). Overall, excellent properties of TCFs (haze = 0.21%-1.8%, transmittance = 95.33%-98.45%, sheet resistance = 20.87-81.76 Omega sq-1) were obtained. Ag NWs with a diameter of 17.6 nm provided minimum haze values at equivalent sheet resistances (e.g., haze = 0.21%, transmittance = 98.45%, sheet resistance = 77.36 Omega sq-1) compared with ones with lager diameters and the controls in literatures. This work investigated the interdependence between haze and NW diameter and might provide a design guide for flexible Ag NW TCFs. PMID- 27758976 TI - Electronic confinement in graphene quantum rings due to substrate-induced mass radial kink. AB - We investigate localized states of a quantum ring confinement in monolayer graphene defined by a circular mass-related potential, which can be induced e.g. by interaction with a substrate that breaks the sublattice symmetry, where a circular line defect provides a change in the sign of the induced mass term along the radial direction. Electronic properties are calculated analytically within the Dirac-Weyl approximation in the presence of an external magnetic field. Analytical results are also compared with those obtained by the tight-binding approach. Regardless of its sign, a mass term [Formula: see text] is expected to open a gap for low-energy electrons in Dirac cones in graphene. Both approaches confirm the existence of confined states with energies inside the gap, even when the width of the kink modelling the mass sign transition is infinitely thin. We observe that such energy levels are inversely proportional to the defect line ring radius and independent on the mass kink height. An external magnetic field is demonstrated to lift the valley degeneracy in this system and easily tune the valley index of the ground state in this system, which can be polarized on either K or [Formula: see text] valleys of the Brillouin zone, depending on the magnetic field intensity. Geometrical changes in the defect line shape are considered by assuming an elliptic line with different eccentricities. Our results suggest that any defect line that is closed in a loop, with any geometry, would produce the same qualitative results as the circular ones, as a manifestation of the topologically protected nature of the ring-like states investigated here. PMID- 27758975 TI - Synergistic effects of water addition and step heating on the formation of solution-processed zinc tin oxide thin films: towards high-mobility polycrystalline transistors. AB - Thin-film transistors (TFTs) with high mobility and good uniformity are attractive for next-generation flat panel displays. In this work, solution processed polycrystalline zinc tin oxide (ZTO) thin film with well-ordered microstructure is prepared, thanks to the synergistic effect of water addition and step heating. The step heating treatment other than direct annealing induces crystallization, while adequate water added to precursor solution further facilitates alloying and densification process. The optimal polycrystalline ZTO film is free of hierarchical sublayers, and featured with an increased amount of ternary phases, as well as a decreased fraction of oxygen vacancies and hydroxides. TFT devices based on such an active layer exhibit a remarkable field effect mobility of 52.5 cm2 V-1 s-1, a current on/off ratio of 2 * 105, a threshold voltage of 2.32 V, and a subthreshold swing of 0.36 V dec-1. Our work offers a facile method towards high-performance solution-processed polycrystalline metal oxide TFTs. PMID- 27758977 TI - Self-assembly of gold nanorods coated with phospholipids: a coarse-grained molecular dynamics study. AB - The self-assembly of phospholipid-coated gold nanorods (GNRs) was investigated by coarse-grained molecular dynamics simulations. We predict that in addition to the formation of deformed vesicles encapsulating GNRs with diverse orientations, the lipid-coated GNRs can form a semi-ring attached to an excess vesicle phase, a branch with excess vesicle phase, a ring phase, a branch phase, a stack phase, and a vortex phase. The morphologies of the lipid-GNR complexes depend on the lipid/GNR molar ratio and the interaction strength between the nanorod surface and the lipid head groups. At given lipid-nanorod interactions, removing the lipid induces a phase transition from an isolated ring or branch phase to an aggregated vortex or stack phase and vice versa. As the lipid-coated GNRs transit from an isolated phase to an aggregated phase, the structure of the lipid at the nanorod surface converts from a bilayer state to a non-bilayer state. PMID- 27758978 TI - Theory of spin glasses-commentary. PMID- 27758979 TI - Ultrafast cooling by covalently bonded graphene-carbon nanotube hybrid immersed in water. AB - The increasing power density and the decreasing dimensions of transistors present severe thermal challenges to the design of modern microprocessors. Furthermore, new technologies such as three-dimensional chip-stack architectures require novel cooling solutions for their thermal management. Here, we demonstrate, through transient heat-dissipation simulations, that a covalently bonded graphene-carbon nanotube (G-CNT) hybrid immersed in water is a promising solution for the ultrafast cooling of such high-temperature and high heat-flux surfaces. The G-CNT hybrid offers a unique platform to integrate the superior axial heat transfer capability of individual CNTs via their parallel arrangement. The immersion of the G-CNT in water enables an additional heat dissipation path via the solid liquid interaction, allowing for the sustainable cooling of the hot surface under a constant power input of up to 10 000 W cm-2. PMID- 27758980 TI - Methodologies in the modeling of combined chemo-radiation treatments. AB - The variety of treatment options for cancer patients has increased significantly in recent years. Not only do we combine radiation with surgery and chemotherapy, new therapeutic approaches such as immunotherapy and targeted therapies are starting to play a bigger role. Physics has made significant contributions to radiation therapy treatment planning and delivery. In particular, treatment plan optimization using inverse planning techniques has improved dose conformity considerably. Furthermore, medical physics is often the driving force behind tumor control and normal tissue complication modeling. While treatment optimization and outcome modeling does focus mainly on the effects of radiation, treatment modalities such as chemotherapy are treated independently or are even neglected entirely. This review summarizes the published efforts to model combined modality treatments combining radiation and chemotherapy. These models will play an increasing role in optimizing cancer therapy not only from a radiation and drug dosage standpoint, but also in terms of spatial and temporal optimization of treatment schedules. PMID- 27758981 TI - Systematic study of room-temperature ferromagnetism and the optical response of Zn1-x TM x S/Se (TM = Mn, Fe, Co, Ni) ferromagnets: first-principle approach. AB - The structural, magnetic and optical characteristics of Zn1-x TM x S/Se (TM = Mn, Fe, Co, Ni and x = 6.25%) have been investigated through the full-potential linearized augmented plane wave method within the framework of density functional theory. The optimized structures have been used to calculate the ferromagnetic and the antiferromagnetic ground-state energies. The stability of the ferromagnetic phase has been confirmed from the formation and the cohesive energies. The Heisenberg model is used to elucidate the Curie temperature (T c) of these alloys. From the band structures and density of states plots, it has been observed that TM-doped ZnS/Se alloys appear to be semiconductors and exhibit ferromagnetism. In addition, the observed ferromagnetism has also been explained in terms of direct exchange energy Delta x (d), exchange splitting energy Delta x (pd), crystal-field energy (E crys), exchange constants (N 0 alpha and N 0 beta) and magnetic moments that shows potential spintronic applications. The optical behaviors of these alloys have been explained in terms of real and imaginary parts of the dielectric constant epsilon(omega), refractive index n(omega), extinction coefficient K(omega), reflectivity R(omega) and absorption coefficient sigma(omega), in the energy range 0-25 eV. The calculated static limits of the band gaps and real part of the dielectric constants satisfy the Penn model. The critical limits of the imaginary part of the dielectric constants and absorption coefficients indicate that these alloys can be operated in the visible and the ultraviolet region of the electromagnetic spectrum; therefore, make them important for optoelectronic applications. PMID- 27758982 TI - A new embedded-atom method approach based on the pth moment approximation. AB - Large scale atomistic simulations with suitable interatomic potentials are widely employed by scientists or engineers of different areas. The quick generation of high-quality interatomic potentials is urgently needed. This largely relies on the developments of potential construction methods and algorithms in this area. Quantities of interatomic potential models have been proposed and parameterized with various methods, such as the analytic method, the force-matching approach and multi-object optimization method, in order to make the potentials more transferable. Without apparently lowering the precision for describing the target system, potentials of fewer fitting parameters (FPs) are somewhat more physically reasonable. Thus, studying methods to reduce the FP number is helpful in understanding the underlying physics of simulated systems and improving the precision of potential models. In this work, we propose an embedded-atom method (EAM) potential model consisting of a new manybody term based on the pth moment approximation to the tight binding theory and the general transformation invariance of EAM potentials, and an energy modification term represented by pairwise interactions. The pairwise interactions are evaluated by an analytic numerical scheme without the need to know their functional forms a priori. By constructing three potentials of aluminum and comparing them with a commonly used EAM potential model, several wonderful results are obtained. First, without losing the precision of potentials, our potential of aluminum has fewer potential parameters and a smaller cutoff distance when compared with some constantly-used potentials of aluminum. This is because several physical quantities, usually serving as target quantities to match in other potentials, seem to be uniquely dependent on quantities contained in our basic reference database within the new potential model. Second, a key empirical parameter in the embedding term of the commonly used EAM model is found to be related to the effective order of moments of local density of states. This may provide a way to improve the precision of EAM potentials further through more precise approximations to tight binding theory. In addition, some critical details about construction procedures are discussed. PMID- 27758983 TI - Conjunctival Biopsy as a First Choice to Confirm a Diagnosis of Sarcoidosis. AB - BACKGROUND: Sarcoidosis is a granulomatous systemic disease of unknown aetiology. The diagnosis needs histological confirmation of the presence of non-caseating granulomata. One option is a conjunctival biopsy. The aims of this study were to evaluate conjunctival biopsy for the diagnosis of sarcoidosis with respect to its sensitivity and to assess its cost effectiveness by comparison with other histopathological diagnostic procedures. METHODS: Patients were identified from the database of the Interstitial Lung Disease Clinic (ILDC) of the Chest Department of Ege University Hospital from May 2008 to June 2014. The patients who had biopsy procedures performed for the definitive diagnosis of sarcoidosis were assessed. Their diagnostic procedures and the cost of procedures were recorded. The cost per positive result for each procedure was calculated. Results: In total, 280 patients were followed up with a diagnosis of sarcoidosis, of whom 174 had histological confirmation; these constitute the study population. There were 127 females and 47 males with a median age of 46 years (range 14-78 years). Forty three patients had conjunctival biopsy and we could establish a diagnosis in 54% of these by means of conjunctival biopsy. Moreover, we showed that this biopsy can provide positive result for sarcoidosis patients who lack abnormal eye findings. Additionally, it is cost effective approach and without complications. CONCLUSION: This study re-asserts the value of conjunctival biopsy, which was described in the past but is not commonly used nowadays. In the presence of suggestive clinic and radiologic findings, we recommend conjunctival biopsy as the first choice for the histopathological confirmation of sarcoidosis. PMID- 27758984 TI - Clinical features of Sarcoidosis in Oman: A report from the Middle East region. AB - BACKGROUND: Though clinical features of sarcoidosis follow a similar pattern, some heterogeneity is seen in different ethnic and racial groups. OBJECTIVES: To describe for the first time the clinical characteristics of sarcoidosis patients in the Sultanate of Oman. METHODS: The data on all cases of sarcoidosis followed up in the two tertiary hospitals in Oman were retrieved retrospectively. RESULTS: Of the 92 patients, for representing the ethnic data only Omani patients (n=83) were included. The mean age was 52.90+/-12.35 years. Majority were females (72.3%, n=60). Cough (n=44, 53.0%), dyspnea (n=39, 47%), arthralgia (n=26, 31.3%) and fatigue (30.1%) were the major symptoms. Arthralgia was reported by 41.7% of the females and 4.3% of the males (p= 0.001). Uveitis was present in 16 (19.3%), erythema nodosum in 8 (9.6%) and hypercalcemia in 13 (15.7%). The radiological stage at presentation was stage 0, 18.7%; I, 28%; II, 17.3%; III, 24% and IV, 12%. Majority (61.4%) of the patients had tissue diagnosis; intra-thoracic site 70.6%. Pulmonary function showed abnormal diffusion in 75%. Sixty eight received treatment, 81.9% took prednisolone. Based on radiograph good outcome (Resolving) was noted in 20.9%, intermediate (Stable) in 73.1% and poor (Progressive) in 6%. Lung function wise, resolving, stable and progressive disease was seen in 31.4%, 40.0% and 28.6% respectively. CONCLUSION: The clinical picture of the patients with sarcoidosis from Oman was similar to that reported from the rest of the world. Region wise, our patients were older and arthralgia and hypercalcemia were more common. The management of sarcoidosis needs a more organized approach in the country with clear guidelines on monitoring and treatment. PMID- 27758985 TI - Role of Pulmonary Evaluation in Diagnosis of Neurosarcoidosis. AB - BACKGROUND: Neurosarcoidosis is a serious extra pulmonary manifestation of sarcoidosis. Its presentation ranges from peripheral or cranial neuropathy to central nervous system dysfunction. It can mimic stroke or multiple sclerosis. Due to the variation in clinical presentation, diagnosis is difficult and often delayed. OBJECTIVE: Determine the proportion of patients with neurosarcoidosis who have positive findings on chest CT, lung biopsy or lymph node biopsy. METHODS: Retrospective study at the Sarcoidosis and Interstitial Lung Disease Center at Wayne State University-Detroit Medical Center in Detroit, MI. Medical records of 424 patients were reviewed and 69 patients with neurosarcoidosis identified. RESULTS: We found that most patients diagnosed with neurosarcoidosis had normal PFT values except for reduction in DLCO. However, we also found that 71% of the patients had abnormal findings on chest CT consistent with sarcoidosis. Additionally, 57% of the patients had non-caseating granuloma on hilar lymph node biopsy. CONCLUSION: Patients with neurosarcoidosis may not have any pulmonary symptoms. However, they are most likely to have abnormal chest CT, hilar lymphadenopathy and reduction in DLCO. These data suggest that pulmonary evaluation is warranted in patients who are suspected to have neurosarcoidosis. PMID- 27758986 TI - The Value of Biomarkers as Predictors of Outcome in Patients with Rheumatoid Arthritis-Associated Usual Interstitial Pneumonia. AB - BACKGROUND: Because of the highly variable clinical course of rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP), the prediction of patient prognosis is important. OBJECTIVE: The aim of this study was to investigate the role of blood biomarkers as prognostic predictors in the patients with RA-UIP. METHODS: The blood levels of biomarkers (Krebs von den Lungen-6 [KL 6], surfactant protein-A [SP-A], matrix metalloproteinase-7 [MMP-7], interleukin 6 [IL-6], and interleukin-32 [IL-32]) were retrospectively compared with the clinical courses of 62 patients with RA-UIP. RESULTS: The median follow-up period was 33.4 months. RA-UIP progressed in 15 patients (45.2%) during one year of follow-up. We found that KL-6 and IL-6 were significant predictors of short-term (1 year) prognosis. Multivariate logistic regression analysis showed that the odds ratio (OR) for KL-6 was 1.001 (95% confidence interval [CI]: 1.000-1.003, p = 0.077) and that the OR for IL-6 was 1.040 (95% CI: 1.002-1.080, p = 0.039) for short-term disease progression. The addition of KL-6 and IL-6 to the clinical parameters (concordance index [C-index]: 0.958, p = 0.053) predicted short-term disease progression better than the clinical parameter alone (C-index: 0.853). In addition, patients with high levels of KL-6 (>=933 U/mL) had shorter survival than those with low levels of KL-6 (<933 U/mL) (median survival: 51 vs. 96 months, p = 0.019). CONCLUSIONS: The results of this retrospective study suggested that KL-6 and IL-6 could be used as predictors of short-term disease progression. In addition, high levels of KL-6 could be used as a predictor of mortality. Additional studies involving a larger patient cohort are warranted. PMID- 27758987 TI - Prognostic significance of surfactant protein A, surfactant protein D, Clara cell protein 16, S100 protein, trefoil factor 3, and prostatic secretory protein 94 in idiopathic pulmonary fibrosis, sarcoidosis, and chronic pulmonary obstructive disease. AB - BACKGROUND: Identification of serum and bronchoalveolar lavage fluid (BALF) biomarkers may facilitate diagnosis and prognostication in various lung disorders. OBJECTIVE: Serum and BALF levels of surfactant protein A (SP-A), surfactant protein D (SP-D), Clara cell protein 16 (CC16), S100 protein, trefoil factor 3 (TFF3), and prostatic secretory protein 94 (PSP94) were evaluated in 94 consecutive patients (idiopathic pulmonary fibrosis (IPF; n=18), sarcoidosis (n=25), chronic obstructive pulmonary disease (COPD; n=51)), and in 155 healthy controls. METHODS: Biomarkers were measured at diagnosis and compared with disease characteristics. Both uniparametric and multiparametric analyses were used. RESULTS: Seven significant correlations were found: 1) BALF PSP94 level correlated with prognosis of sarcoidosis (P=0.035); 2) BALF SP-D level with pulmonary functions in IPF (P=0.032); 3) BALF SP-D and TFF3 with IPF mortality (P=0.049 and 0.017, respectively); 4) serum TFF3 level with COPD mortality (P=0.006,); 5) serum SP-A with pulmonary functions impairment in IPF (P=0.011); 6) serum SP-D level was associated with HRCT interstitial score in IPF (P=0.0346); and 7) serum SP-A was associated with staging of COPD according to spirometry (P<0.001). Moreover, our analysis showed that some biomarker levels differed significantly among the diseases: 1) BALF SP-D level differed between sarcoidosis and IPF; 2) serum SP-A level differed among IPF, sarcoidosis, COPD and was also different from healthy controls; 3) serum S100A6, S100A11 levels differed among IPF, sarcoidosis, COPD from healthy controls 4) serum SP-D, CC16, TFF-3 levels distinguished IPF patients from healthy controls; and 5) serum CC16, TFF3, PSP94 distinguished COPD patients from healthy controls. Our study shows that some of selected biomarkers should have prognostic value in the analysed lung disorders. On the other hand, these biomarkers do not appear to be unequivocally suitable for differential diagnosis of these disorders. PMID- 27758988 TI - Lung transplantation for high-risk patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Survival for patients with idiopathic pulmonary fibrosis (IPF) and high lung allocation score (LAS) values may be significantly reduced in comparison to those with lower LAS values. OBJECTIVES: To evaluate outcomes for high-risk IPF patients as defined by LAS values >=46 (N=42) versus recipients with LAS values <46 (N=89). METHODS: We retrospectively reviewed records of 131 consecutive patients with IPF who received lung transplants at our institution between 1999 and 2013. RESULTS: The mean LAS was significantly higher (59.5, interquartile range 43.9-75.9 vs. 39.3, interquartile range 37.7-44.3; p<0.01) for the high-risk cohort. The higher LAS cohort had significantly lower percent predicted forced vital capacity (FVC) versus recipients with LAS <46 (41.3+/ 14.1% vs. 53.2+/-16.2%; p<0.01) and required more supplemental oxygen (7+/-5 vs. 4+/-2 L/min, p<0.01) prior to transplant versus recipients with LAS <46. Although the incidence of early post-LTX pulmonary complications was increased for the higher LAS group versus recipients with LAS <46, 30-day mortality and actuarial survival did not differ between the two cohorts. CONCLUSIONS: Although lung transplantation in patients with IPF and high LAS values is associated with increased risk of early post-transplant complications, long-term post-transplant survival for our high-LAS cohort was equivalent to that for the lower LAS recipients. PMID- 27758989 TI - Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis: a retrospective analysis. AB - BACKGROUND AND OBJECTIVE: There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long-term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. METHODS: A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. RESULTS: AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). CONCLUSION: Our results indicate the potential beneficial efficacy of macrolide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF. PMID- 27758990 TI - Clinical significance of the "galaxy sign" in patients with pulmonary sarcoidosis in a Japanese single-center cohort. AB - BACKGROUND: The galaxy sign is an irregularly marginated pulmonary nodule formed by a confluence of multiple small nodules, and it is a diagnostic radiological finding for pulmonary sarcoidosis. However, the clinical significance of the galaxy sign for sarcoidosis has been poorly investigated. OBJECTIVE: This study aimed to investigate the clinical significance and detailed radiological features of the galaxy sign in patients with pulmonary sarcoidosis. METHODS: We retrospectively reviewed 87 patients with biopsy-proven sarcoidosis and 108 patients with pulmonary tuberculosis. Galaxy sign incidence was assessed on thoracic high-resolution computed tomography (HRCT) images from each group. Correlations of galaxy sign with clinical characteristics and disease outcomes were evaluated for patients with sarcoidosis. RESULTS: HRCT findings were available for 65 of 87 patients with pulmonary sarcoidosis and all 108 patients with pulmonary tuberculosis. Galaxy sign incidence was significantly higher in patients with pulmonary sarcoidosis (n=15, 23.1%) than in those with pulmonary tuberculosis (n=2, 1.9%, p<0.001). Among the 65 patients with pulmonary sarcoidosis, those with galaxy signs (n=15) were significantly younger (median: 32 years, interquartile range [IQR] 28-38 years) than those without (n=50) (median: 62 years, IQR 37.7-73 years). The CD4/CD8 ratio in bronchoalveolar lavage fluid (BALF) was also significantly lower in the former group (median: 2.6, IQR 2.0-3.9 vs. median 5.8, IQR 3.7-8.6, p<0.001). CONCLUSION: Galaxy signs are associated with younger age and low BALF CD4/CD8 ratio but not disease severity. PMID- 27758991 TI - GSTT1 and GSTM1 gene polymorphisims in sarcoidosis. AB - INTRODUCTION: Sarcoidosis is a granulomatous disease of unknown cause, which affects all systems, especially the lungs and the lymphatic system. Genetic and environmental factors are held accountable for the etiology. Based on the general opinion, sarcoidosis develops after exposure to a specific environmental agent by genetically susceptible individuals. The present study aimed to evaluate the disease susceptibility of the GSTT1 and GSTM1 gene polymorphisms in the patients with sarcoidosis. METHOD: The present study included 78 patients; 38 patients with histopathologically verified sarcoidosis and 40 control subjects. Multiplex PCR method was used to determine the GSTT1 and GSTM1 gene polymorphisms. The genotype was determined based on the bands formed in the agarose gel electrophoresis. The statistical analysis was done using the chi-square test. RESULTS: The positive/negative genotype rates were 79%/21% and 53%/47%, respectively in the case group for the GSTT1 and GSTM1 gene polymorphisms, whereas the positive/negative genotype rates were 77%/23% and 55%/45% in the control group. There was no statistically significant difference in the positive and negative genotypes compared with the case group and the control group for the GSTT1 and GSTM1 gene polymorphisms (p > 0.05). DISCUSSION: The results from the present study suggest that there is not any association with the control group for the disease susceptibility of the GSTT1 and GSTM1 gene polymorphisms in patients with sarcoidosis, and this result should be supported by large-scale studies because of the limited number of cases in the present study. PMID- 27758992 TI - Role of Xpert MTB/RIF in differentiating tuberculosis from sarcoidosis in patients with mediastinal lymphadenopathy undergoing EBUS-TBNA: a study of 147 patients. AB - BACKGROUND: In patients with intrathoracic lymphadenopathy, differentiating tuberculosis from sarcoidosis is often difficult. We hypothesized that Xpert MTB/RIF assay, a semi-automated hemi-nested PCR would help in this regard. OBJECTIVE: To evaluate the performance of Xpert MTB/RIF in the differential diagnosis of tuberculosis and sarcoidosis. METHODS: This was a retrospective analysis of patients with intrathoracic lymphadenopathy who underwent endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA), and were diagnosed as either tuberculosis or sarcoidosis. The results of Xpert MTB/RIF assay, tuberculin skin test and endosonographic characteristics (heterogeneous echotexture and coagulation necrosis sign) of the lymph nodes were compared between the two groups. RESULTS: During the study period, 465 EBUS procedures were performed and a diagnosis of sarcoidosis (n=94) or tuberculosis (n=53) was made in 147 patients. Xpert MTB/RIF was positive in 26 (49.1%) and two (2.1%) patients with tuberculosis and sarcoidosis, respectively. The sensitivity, specificity, positive and negative predictive values of Xpert MTB/RIF in the diagnosis of tuberculosis were 49.1 %, 97.9%, 92.9% and 77.3%, respectively. The presence of any of the four features namely positive Xpert MTB/RIF, positive tuberculin skin test, heterogeneous echotexture of the lymph nodes, or the presence of endosonographic coagulation necrosis sign yielded a sensitivity and negative predictive value of 83.0% and 88.0%, respectively in the diagnosis of tuberculosis versus sarcoidosis. CONCLUSIONS: Xpert MTB/RIF has good specificity and positive predictive value in the diagnosis of tuberculosis, and is a useful investigation in separating tuberculosis from sarcoidosis. PMID- 27758993 TI - The predictors of mortality in IPF - Does emphysema change the prognosis? AB - BACKGROUND: Combined idiopathic pulmonary fibrosis (IPF) and emphysema (CPFE) has been reported to be more common in male smokers. A number of studies comparing CPFE patients with fibrosis-only patients have reported a similar prognosis while others have reported a significantly shorter survival. OBJECTIVES: In present study, we aimed to compare baseline characteristics of patients with IPF according to emphysema presence. We asssessed the prognostic value of emphysema along with each other parameter. METHODS: We retrospectively reviewed the clinical, baseline radiological, laboratory and physiological parameters of 92 patients who were diagnosed with IPF. The patients were divided into two groups: those without emphysema (Group 1) and with emphysema (Group 2). All-cause mortality was recorded, and the impact of the variables on survival was evaluated. RESULTS: Emphysema was recorded in 23 patients, all of whom were male. While ever-smoker rate was higher in Group 2 laboratory and physiologic parameters were similar. Radiologically, the presence of honeycombing, ground glass opacity, the extension and symmetry of involvement did not differ between the Groups. The median survival time was 29+/-4 months. Patients in Group 1 and 2 had a median survival of 34 and 9 months, respectively. In univariate analysis; radiological presence of emphysema and honeycombing, male gender, lower baseline levels of albumin and oxygen saturation, forced vital capacity and carbon monoxide diffusing capacity were detected as predictors of mortality. CONCLUSION: In present study, IPF with emphysema was more common in male smokers. When emphysema accompanies IPF, life expectancy is remarkably worse, but not independently so. PMID- 27758994 TI - Causes of death in patients with chronic sarcoidosis. AB - INTRODUCTION: Sarcoidosis is a multi-system, granulomatous disorder of unknown etiology that is associated with a variable prognosis and sometimes results in death. There are conflicting reports regarding the causes of death in patients with sarcoidosis. METHODS: Forty-four consecutive patients with sarcoidosis who underwent an autopsy (35 patients) or died at Mayo Clinic (Rochester, MN, USA) over a 20-yr period, from January 1, 1994 to December 31, 2013 were analyzed. RESULTS: The median age at death was 63 years (range, 33-94 years) and there were 22 (50%) women. Sarcoidosis had not been clinically diagnosed in 16 (36%) patients before death. Fifteen deaths (34%) were related to sarcoidosis and included seven deaths (16%) from cardiac sarcoidosis and four deaths (9%) from progressive pulmonary sarcoidosis. Other sarcoidosis-related causes of death included advanced hepatic sarcoidosis (5%) and opportunistic infections (5%) related to immunosuppressive therapy for treating sarcoidosis. Among seven patients dying from cardiac sarcoidosis, three had been diagnosed with sarcoidosis during life and cardiac involvement was known in two of them. Six of seven deaths from cardiac sarcoidosis occurred in the autopsied cohort while all four deaths from pulmonary sarcoidosis occurred in those not autopsied. CONCLUSIONS: In the majority of patients dying with sarcoidosis the cause of death is unrelated to sarcoidosis. Cardiac involvement is the most common cause of sarcoidosis-related deaths in patients subjected to postmortem examination and was usually undiagnosed during life. The cause distribution of death in patients with sarcoidosis differed depending on whether autopsy was performed. PMID- 27758995 TI - Pulmonary stenting for the treatment of sarcoid induced pulmonary vascular stenosis. AB - BACKGROUND: The best treatment of patients with external pulmonary vascular compression due to advanced sarcoidosis is unknown. OBJECTIVES: To report a single-center experience of percutaneous treatment for pulmonary vascular stenosis caused by external compression due to advanced sarcoidosis. METHODS: We report a case series of 5 patients with biopsy confirmed advanced sarcoidosis, seen at our academic institution with worsening dyspnea despite increase of immunosuppressive therapy. All patients were evaluated by a multidisciplinary team (cardiology, pulmonary and radiology) using a multi-modality approach, including chest-computed tomography angiography, ventilation/perfusion scintigraphy, pulmonary function test, 6-minute walk test and heart catheterization. RESULTS: Three out of five patients underwent pulmonary artery or vein angioplasty and stenting resulting in symptomatic improvement: Patient 1 had persistent symptomatic improvement measured by subjective and objective methods at 30 months; patient 2 required re-intervention due to recurrent pulmonary vein stenosis at 6-months followed by persistent improvement; and patient 3, had a procedure complicated with in-stent thrombosis requiring thrombolysis and anticoagulation with improvement. The remaining two patients were medically treated because underlying thromboembolic disease (patient 4) and diffuse pulmonary vein stenosis not amenable to percutaneous intervention (patient 5). CONCLUSIONS: Pulmonary vascular stenosis from external compression can be a rare but unrecognized caused of worsening symptoms in advanced sarcoidosis. Pulmonary vascular angioplasty and stenting can provide clinical benefit in select patients. PMID- 27758996 TI - Crohn's disease-associated interstitial lung disease mimicking sarcoidosis: a case report and review of the literature. AB - Respiratory involvement in Crohn's disease (CD) is a rare manifestation known to involve the large and small airways, lung parenchyma, and pleura. The clinical presentation is nonspecific, and diagnostic tests can mimic other pulmonary diseases, posing a diagnostic challenge and delay in treatment. We report a case of a 60-year-old female with a history of CD and psoriatic arthritis who presented with dyspnea, fever, and cough with abnormal radiological findings. Diagnostic testing revealed an elevated CD4:CD8 ratio in the bronchoalveolar lavage fluid, and cryoprobe lung biopsy results showed non-necrotizing granulomatous inflammation. We describe here the second reported case of pulmonary involvement mimicking sarcoidosis in Crohn's disease and a review of the literature on the approaches to making a diagnosis of CD-associated interstitial lung disease. PMID- 27758997 TI - Spontaneous resolution of a tumor like pulmonary sarcoidosis. AB - We report a case of thoracic sarcoidosis in a 72-year-old female, snuff taker, who presented with multinodular pulmonary lesions on chest x-ray. Clinical and biological findings were poor. Thoracic imaging showed soft tissue density nodules with irregular borders. The diagnosis of 'cannon ball' metastases was suspected. A thorough investigation strategy could not prove malignancy. A complete radiologic clearing was obtained spontaneously within three months. A rereading of pathology slides performed afterwards showed multinucleated giant cells on hemorrhagic background with a lymphocytic alveolitis. The diagnosis of pseudotumoral sarcoidosis was made. The clinical course was favorable with a 6years follow-up. PMID- 27758998 TI - Subacute sarcoid myositis with ocular muscle involvement; a case report and review of the literature. AB - Sarcoidosis is a chronic granulomatous disease that can affect multiple organs. The lungs, eyes, and skin are known to be highly affected organs in sarcoidosis. There have been reports based on random muscle biopsy that 32-80% of systemic sarcoidosis comprises noncaseating granulomas; however, muscle involvement in sarcoidosis is generally asymptomatic and has an unknown frequency. We describe a case of acute to subacute sarcoid myositis of the skeletal and extraocular muscles. Typical ophthalmic involvement (manifested by infiltration of the ocular adnexa, intraocular inflammation, or infiltration of the retrobulbar visual pathways) and extraocular sarcoid myositis (as with the present case) is infrequently reported. It is important to keep in mind the rare yet perhaps underestimated entity of sarcoid myositis, and to utilize muscle biopsy and imaging tests for appropriate diagnosis and management of patients with sarcoidosis. PMID- 27758999 TI - Isolated extraocular orbital mass: a rare presentation of sarcoidosis. AB - We report a case of orbital sarcoidosis in a 66 year old male who presented with one month history of right eye swelling and intermittent diplopia. MRI revealed an enhancing infiltrative soft tissue mass in the inferior aspect of the right orbit and biopsy of the mass demonstrated non-necrotizing granulomas. Chest CT scan was normal and PET scan showed no other organ involvement. He was treated with tapering doses of prednisone over six months. Although relapse occurred while tapering prednisone to 20 mg per day, he responded well to the addition of azathioprine with complete resolution of visual difficulties and orbital the mass on repeat MRI. Sarcoidosis, presenting as an isolated orbital mass is rare, can be successfully treated and should be included in differential diagnosis. PMID- 27759000 TI - Transcriptional blood signatures of sarcoidosis, sarcoid-like reactions and tubercolosis and their diagnostic implications. AB - N/A. PMID- 27759002 TI - Cranioplasty in neurosurgery: is there a way to reduce complications? AB - BACKGROUND: Cranioplasty is a surgical procedure that has still a high rate of complications, although it is commonly considered an easy and routine operation. In the literature, cranioplasty complications may rise up to 41% of cases, and the most frequently reported are infections, autologous bone flap resorption, and hematomas. Although possible, poor cosmetic results are rarely mentioned. METHODS: We retrospectively analyzed the cases of 313 patients who underwent 377 surgical procedures for cranioplasty and reoperations for complications between 2008 and 2014. In other 2 patients we performed a new surgical procedure for the prosthesis fracture. Pediatric patients ( aging from 5 to 17 years ) have been included in this series in order to compare the complication rate between adult and pediatric populations. The clinical-radiological follow-up of these 313 patients lasted between 1 and 6 years. RESULTS: Overall complications for cranioplasty were seen in 38 ( 12.14% ) out of the 313 patients. However, complications requiring surgical therapy were seen in 28 patients who underwent 64 new surgical procedures. Adult male patients represented the majority of the group with cranioplasty complications. In the pediatric group we have not observed any complication requiring more than a clinical observation. Infections and autologous bone resorption were the most frequent complications reported in this series; however, we observed a poor cosmetic result as a concomitant but separate complication in more than 26% of our 313 patients. CONCLUSIONS: In this paper we present an overview of all the possible complications of cranioplasty reported in the literature, comparing them with those observed in our series. We also discuss critically the most evident causes of complications, suggesting, when possible, solutions to avoid or limit them. PMID- 27759001 TI - No Association Between SNP56 in PDE4D Gene and Susceptibility to Ischemic Stroke: A Meta-Analysis of 15 Studies. AB - BACKGROUND Recent studies demonstrated that polymorphisms in the PDE4D gene were associated with several processes involved in the occurrence of ischemic stroke (IS). The association between specific PDE4D single-nucleotide polymorphism 56 (SNP56) and IS risk was initially identified via genome-wide association studies (GWAS), although the GWAS in different populations produced inconclusive results. Thus, we performed a meta-analysis to better explain the association between PDE4D SNP56 and IS risk. MATERIAL AND METHODS A literature search was conducted using PubMed, Embase, and Web of Science up to June 1, 2015. A fixed-effects or random-effects model was used to calculate the pooled odds ratios (ORs) based on the results from the heterogeneity tests. RESULTS Finally, we performed a meta analysis of 15 studies, involving 8731 IS patients and 10,756 controls. The results showed nonsignificant association between PDE4D SNP56 and IS risk (T vs. A: OR=1.01, 95%CI=0.88-1.15, P=0.90). Similarly, in the subgroup analysis by ethnicity, no significant association was observed in Asian (T vs. A: OR=1.08, 95%CI=0.80-1.44, P=0.62) or European (T vs. A: OR=0.96, 95%CI=0.86-1.08, P=0.54) population. Moreover, funnel plots and Egger regression testing showed no evidence of publication bias. CONCLUSIONS In summary, current evidence suggested that PDE4D SNP56 might not be associated with an increased susceptibility to IS. However, this conclusion needs further validation by well-designed studies with large sample sizes. PMID- 27759004 TI - Spontaneous decays of magneto-elastic excitations in non-collinear antiferromagnet (Y,Lu)MnO3. AB - Magnons and phonons are fundamental quasiparticles in a solid and can be coupled together to form a hybrid quasi-particle. However, detailed experimental studies on the underlying Hamiltonian of this particle are rare for actual materials. Moreover, the anharmonicity of such magnetoelastic excitations remains largely unexplored, although it is essential for a proper understanding of their diverse thermodynamic behaviour and intrinsic zero-temperature decay. Here we show that in non-collinear antiferromagnets, a strong magnon-phonon coupling can significantly enhance the anharmonicity, resulting in the creation of magnetoelastic excitations and their spontaneous decay. By measuring the spin waves over the full Brillouin zone and carrying out anharmonic spin wave calculations using a Hamiltonian with an explicit magnon-phonon coupling, we have identified a hybrid magnetoelastic mode in (Y,Lu)MnO3 and quantified its decay rate and the exchange-striction coupling term required to produce it. PMID- 27759003 TI - Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function. AB - Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development. N-docosahexaenoylethanolamine (synaptamide), an endogenous metabolite of DHA, potently promotes neurogenesis, neuritogenesis and synaptogenesis; however, the underlying molecular mechanism is not known. Here, we demonstrate orphan G-protein coupled receptor 110 (GPR110, ADGRF1) as the synaptamide receptor, mediating synaptamide-induced bioactivity in a cAMP dependent manner. Mass spectrometry-based proteomic characterization and cellular fluorescence tracing with chemical analogues of synaptamide reveal specific binding of GPR110 to synaptamide, which triggers cAMP production with low nM potency. Disruption of this binding or GPR110 gene knockout abolishes while GPR110 overexpression enhances synaptamide-induced bioactivity. GPR110 is highly expressed in fetal brains but rapidly decreases after birth. GPR110 knockout mice show significant deficits in object recognition and spatial memory. GPR110 deorphanized as a functional synaptamide receptor provides a novel target for neurodevelopmental control and new insight into mechanisms by which DHA promotes brain development and function. PMID- 27759005 TI - Heme biomolecule as redox mediator and oxygen shuttle for efficient charging of lithium-oxygen batteries. AB - One of the greatest challenges with lithium-oxygen batteries involves identifying catalysts that facilitate the growth and evolution of cathode species on an oxygen electrode. Heterogeneous solid catalysts cannot adequately address the problematic overpotentials when the surfaces become passivated. However, there exists a class of biomolecules which have been designed by nature to guide complex solution-based oxygen chemistries. Here, we show that the heme molecule, a common porphyrin cofactor in blood, can function as a soluble redox catalyst and oxygen shuttle for efficient oxygen evolution in non-aqueous Li-O2 batteries. The heme's oxygen binding capability facilitates battery recharge by accepting and releasing dissociated oxygen species while benefiting charge transfer with the cathode. We reveal the chemical change of heme redox molecules where synergy exists with the electrolyte species. This study brings focus to the rational design of solution-based catalysts and suggests a sustainable cross-link between biomolecules and advanced energy storage. PMID- 27759006 TI - Precise localization of metal nanoparticles in dendrimer nanosnakes or inner periphery and consequences in catalysis. AB - Understanding the relationship between the location of nanoparticles (NPs) in an organic matrix and their catalytic performances is essential for catalyst design. Here we show that catalytic activities of Au, Ag and CuNPs stabilized by dendrimers using coordination to intradendritic triazoles, galvanic replacement or stabilization outside dendrimers strongly depends on their location. AgNPs are found at the inner click dendrimer periphery, whereas CuNPs and AuNPs are encapsulated in click dendrimer nanosnakes. AuNPs and AgNPs formed by galvanic replacement are larger than precursors and only partly encapsulated. AuNPs are all the better 4-nitrophenol reduction catalysts as they are less sterically inhibited by the dendrimer interior, whereas on the contrary CuNPs are all the better alkyne azide cycloaddition catalysts as they are better protected from aerobic oxidation inside dendrimers. This work highlights the role of the location in macromolecules on the catalytic efficiency of metal nanoparticles and rationalizes optimization in catalyst engineering. PMID- 27759008 TI - Corrigendum: Propagation phasor approach for holographic image reconstruction. PMID- 27759007 TI - SIKs control osteocyte responses to parathyroid hormone. AB - Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH. PMID- 27759011 TI - Corrigendum: An extended patch-dynamic framework for food chains in fragmented landscapes. PMID- 27759009 TI - ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy. AB - The outbreak of the Zika Virus (ZIKV) and its association with fetal abnormalities have raised worldwide concern. However, the cellular tropism and the mechanisms of ZIKV transmission to the fetus during early pregnancy are still largely unknown. Therefore, we ex vivo modeled the ZIKV transmission at the maternal-fetal interface using organ culture from first trimester pregnancy samples. Here, we provide evidence that ZIKV strain circulating in Brazil infects and damages tissue architecture of the maternal decidua basalis, the fetal placenta and umbilical cord. We also show that ZIKV replicates differentially in a wide range of maternal and fetal cells, including decidual fibroblasts and macrophages, trophoblasts, Hofbauer cells as well as umbilical cord mesenchymal stem cells. The striking cellular tropism of ZIKV and its cytopathic-induced tissue injury during the first trimester of pregnancy could provide an explanation for the irreversible congenital damages. PMID- 27759010 TI - Bacterial abundance and diversity in pond water supplied with different feeds. AB - The abundance and diversity of bacteria in two types of ponds were investigated by quantitative PCR and Illumina MiSeq sequencing. The results revealed that the abundance of bacterial 16S rRNA genes in D ponds (with grass carp fed sudan grass) was significantly lower than that in E ponds (with grass carp fed commercial feed). The microbial communities were dominated by Proteobacteria, Cyanobacteria, Bacteroidetes, and Actinobacteria in both E and D ponds, while the abundance of some genera was significantly different between the two types of ponds. Specifically, some potential pathogens such as Acinetobacter and Aeromonas were found to be significantly decreased, while some probiotics such as Comamonadaceae unclassified and Bacillales unclassified were significantly increased in D ponds. In addition, water quality of D ponds was better than that of E ponds. Temperature, dissolved oxygen and nutrients had significant influence on bacterial communities. The differences in bacterial community compositions between the two types of ponds could be partially explained by the different water conditions. PMID- 27759012 TI - Corrigendum: Exactly solvable spin chain models corresponding to BDI class of topological superconductors. PMID- 27759013 TI - Corrigendum: Real-Time Control of a Neuroprosthetic Hand by Magnetoencephalographic Signals from Paralysed Patients. PMID- 27759014 TI - Wax: A benign hydrogen-storage material that rapidly releases H2-rich gases through microwave-assisted catalytic decomposition. AB - Hydrogen is often described as the fuel of the future, especially for application in hydrogen powered fuel-cell vehicles (HFCV's). However, its widespread implementation in this role has been thwarted by the lack of a lightweight, safe, on-board hydrogen storage material. Here we show that benign, readily-available hydrocarbon wax is capable of rapidly releasing large amounts of hydrogen through microwave-assisted catalytic decomposition. This discovery offers a new material and system for safe and efficient hydrogen storage and could facilitate its application in a HFCV. Importantly, hydrogen storage materials made of wax can be manufactured through completely sustainable processes utilizing biomass or other renewable feedstocks. PMID- 27759016 TI - Ocean feedback to pulses of the Madden-Julian Oscillation in the equatorial Indian Ocean. AB - Dynamical understanding of the Madden-Julian Oscillation (MJO) has been elusive, and predictive capabilities therefore limited. New measurements of the ocean's response to the intense surface winds and cooling by two successive MJO pulses, separated by several weeks, show persistent ocean currents and subsurface mixing after pulse passage, thereby reducing ocean heat energy available for later pulses by an amount significantly greater than via atmospheric surface cooling alone. This suggests that thermal mixing in the upper ocean from a particular pulse might affect the amplitude of the following pulse. Here we test this hypothesis by comparing 18 pulse pairs, each separated by <55 days, measured over a 33-year period. We find a significant tendency for weak (strong) pulses, associated with low (high) cooling rates, to be followed by stronger (weaker) pulses. We therefore propose that the ocean introduces a memory effect into the MJO, whereby each event is governed in part by the previous event. PMID- 27759015 TI - A network property necessary for concentration robustness. AB - Maintenance of functionality of complex cellular networks and entire organisms exposed to environmental perturbations often depends on concentration robustness of the underlying components. Yet, the reasons and consequences of concentration robustness in large-scale cellular networks remain largely unknown. Here, we derive a necessary condition for concentration robustness based only on the structure of networks endowed with mass action kinetics. The structural condition can be used to design targeted experiments to study concentration robustness. We show that metabolites satisfying the necessary condition are present in metabolic networks from diverse species, suggesting prevalence of this property across kingdoms of life. We also demonstrate that our predictions about concentration robustness of energy-related metabolites are in line with experimental evidence from Escherichia coli. The necessary condition is applicable to mass action biological systems of arbitrary size, and will enable understanding the implications of concentration robustness in genetic engineering strategies and medical applications. PMID- 27759018 TI - Corrigendum: Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ. PMID- 27759017 TI - Cdk7 mediates RPB1-driven mRNA synthesis in Toxoplasma gondii. AB - Cyclin-dependent kinase 7 in conjunction with CyclinH and Mat1 activates cell cycle CDKs and is a part of the general transcription factor TFIIH. Role of Cdk7 is well characterized in model eukaryotes however its relevance in protozoan parasites has not been investigated. This important regulator of key processes warrants closer examination particularly in this parasite given its unique cell cycle progression and flexible mode of replication. We report functional characterization of TgCdk7 and its partners TgCyclinH and TgMat1. Recombinant Cdk7 displays kinase activity upon binding its cyclin partner and this activity is further enhanced in presence of Mat1. The activated kinase phosphorylates C terminal domain of TgRPB1 suggesting its role in parasite transcription. Therefore, the function of Cdk7 in CTD phosphorylation and RPB1 mediated transcription was investigated using Cdk7 inhibitor. Unphosphorylated CTD binds promoter DNA while phosphorylation by Cdk7 triggers its dissociation from DNA with implications for transcription initiation. Inhibition of Cdk7 in the parasite led to strong reduction in Serine 5 phosphorylation of TgRPB1-CTD at the promoters of constitutively expressed actin1 and sag1 genes with concomitant reduction of both nascent RNA synthesis and 5'-capped transcripts. Therefore, we provide compelling evidence for crucial role of TgCdk7 kinase activity in mRNA synthesis. PMID- 27759019 TI - Robust ultra-low-friction state of graphene via moire superlattice confinement. AB - Two-dimensional (2D) materials possess outstanding lubrication property with their thicknesses down to a few atomic layers, but they are easily susceptible to sliding induced degradation or ubiquitous chemical modification. Maintaining the superior lubricating performance of 2D materials in a harsh working environment is highly desirable yet grandly challenging. Here we show that by proper alignment of graphene on a Ge(111) substrate, friction of graphene could be well preserved at an ultra-low level even after fluorination or oxidation. This behaviour is experimentally found to be closely related to the suppression of molecular-level deformation of graphene within the moire superlattice structure. Atomistic simulations reveal that the formation of an interconnected meshwork with enhanced interfacial charge density imposes a strong anchoring effect on graphene even under chemical modification. Modulating molecular-level deformation by interfacial confinements may offer a unique strategy for tuning the mechanical or even chemical properties of 2D materials. PMID- 27759020 TI - Coherent perfect absorption in one-sided reflectionless media. AB - In optical experiments one-sided reflectionless (ORL) and coherent perfect absorption (CPA) are unusual scattering properties yet fascinating for their fundamental aspects and for their practical interest. Although these two concepts have so far remained separated from each other, we prove that the two phenomena are indeed strictly connected. We show that a CPA-ORL connection exists between pairs of points lying along lines close to each other in the 3D space-parameters of a realistic lossy atomic photonic crystal. The connection is expected to be a generic feature of wave scattering in non-Hermitian optical media encompassing, as a particular case, wave scattering in parity-time (PT) symmetric media. PMID- 27759021 TI - Protection against maternal infection-associated fetal growth restriction: proof of-concept with a microbial-derived immunomodulator. AB - Infection-associated inflammatory stress during pregnancy is the most common cause of fetal growth restriction and/or miscarriage. Treatment strategies for protection of at-risk mothers are limited to a narrow range of vaccines, which do not cover the bulk of the common pathogens most frequently encountered. Using mouse models, we demonstrate that oral treatment during pregnancy with a microbial-derived immunomodulator (OM85), currently used clinically for attenuation of infection-associated airway inflammatory symptoms in infants adults, markedly reduces risk for fetal loss/growth restriction resulting from maternal challenge with bacterial lipopolysaccharide or influenza. Focusing on LPS exposure, we demonstrate that the key molecular indices of maternal inflammatory stress, notably high levels of RANTES, MIP-1alpha, CCL2, KC, and G CSF (granulocyte colony-stimulating factor) in gestational tissues/serum, are abrogated by OM85 pretreatment. Systems-level analyses conducted in parallel using RNASeq revealed that OM85 pretreatment selectively tunes LPS-induced activation in maternal gestational tissues for attenuated expression of TNF, IL1, and IFNG-driven proinflammatory networks, without constraining Type1-IFN associated networks central to first-line antimicrobial defense. This study suggests that broad-spectrum protection-of-pregnancy against infection-associated inflammatory stress, without compromising capacity for efficient pathogen eradication, represents an achievable therapeutic goal. PMID- 27759022 TI - A critical role for IRF5 in regulating allergic airway inflammation. AB - Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the expression of proinflammatory cytokine and responses to infection, but its role in regulating pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral vector-driven overexpression, and adoptive transfer approaches to interrogate the role of IRF5 in pulmonary immunity and during challenge with the aeroallergen, house dust mite. Global IRF5 deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5 was also essential for effective responses to inhaled allergen, controlling airway hyperresponsiveness, mucus secretion, and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the wild-type pulmonary milieu was sufficient to drive airway hyperreactivity, at baseline or following antigen challenge. These data identify IRF5-expressing macrophages as a key component of the immune defense of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and, thus, the treatment of lung disorders. PMID- 27759025 TI - Corrigendum: The NAC transcription factor ANAC046 is a positive regulator of chlorophyll degradation and senescence in Arabidopsis leaves. PMID- 27759024 TI - Stacking sequence and interlayer coupling in few-layer graphene revealed by in situ imaging. AB - In the transition from graphene to graphite, the addition of each individual graphene layer modifies the electronic structure and produces a different material with unique properties. Controlled growth of few-layer graphene is therefore of fundamental interest and will provide access to materials with engineered electronic structure. Here we combine isothermal growth and etching experiments with in situ scanning electron microscopy to reveal the stacking sequence and interlayer coupling strength in few-layer graphene. The observed layer-dependent etching rates reveal the relative strength of the graphene graphene and graphene-substrate interaction and the resulting mode of adlayer growth. Scanning tunnelling microscopy and density functional theory calculations confirm a strong coupling between graphene edge atoms and platinum. Simulated etching confirms that etching can be viewed as reversed growth. This work demonstrates that real-time imaging under controlled atmosphere is a powerful method for designing synthesis protocols for sp2 carbon nanostructures in between graphene and graphite. PMID- 27759023 TI - MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates. AB - Studies on mucosal-associated invariant T cells (MAITs) in nonhuman primates (NHP), a physiologically relevant model of human immunity, are handicapped due to a lack of macaque MAIT-specific reagents. Here we show that while MR1 ligand contact residues are conserved between human and multiple NHP species, three T cell receptor contact-residue mutations in NHP MR1 diminish binding of human MR1 tetramers to macaque MAITs. Construction of naturally loaded macaque MR1 tetramers facilitated identification and characterization of macaque MR1-binding ligands and MAITs, both of which mirrored their human counterparts. Using the macaque MR1 tetramer we show that NHP MAITs activated in vivo in response to both Bacillus Calmette-Guerin vaccination and Mycobacterium tuberculosis infection. These results demonstrate that NHP and human MR1 and MAITs function analogously, and establish a preclinical animal model to test MAIT-targeted vaccines and therapeutics for human infectious and autoimmune disease. PMID- 27759026 TI - Corrigendum: Broken selection rule in the quantum Rabi model. PMID- 27759027 TI - Radiofrequency-electromagnetic field exposures in kindergarten children. AB - The aim of this study was to assess environmental and personal radiofrequency electromagnetic field (RF-EMF) exposures in kindergarten children. Ten children and 20 kindergartens in Melbourne, Australia participated in personal and environmental exposure measurements, respectively. Order statistics of RF-EMF exposures were computed for 16 frequency bands between 88 MHz and 5.8 GHz. Of the 16 bands, the three highest sources of environmental RF-EMF exposures were: Global System for Mobile Communications (GSM) 900 MHz downlink (82 mV/m); Universal Mobile Telecommunications System (UMTS) 2100MHz downlink (51 mV/m); and GSM 900 MHz uplink (45 mV/m). Similarly, the three highest personal exposure sources were: GSM 900 MHz downlink (50 mV/m); UMTS 2100 MHz downlink, GSM 900 MHz uplink and GSM 1800 MHz downlink (20 mV/m); and Frequency Modulation radio, Wi-Fi 2.4 GHz and Digital Video Broadcasting-Terrestrial (10 mV/m). The median environmental exposures were: 179 mV/m (total all bands), 123 mV/m (total mobile phone base station downlinks), 46 mV/m (total mobile phone base station uplinks), and 16 mV/m (Wi-Fi 2.4 GHz). Similarly, the median personal exposures were: 81 mV/m (total all bands), 62 mV/m (total mobile phone base station downlinks), 21 mV/m (total mobile phone base station uplinks), and 9 mV/m (Wi-Fi 2.4 GHz). The measurements showed that environmental RF-EMF exposure levels exceeded the personal RF-EMF exposure levels at kindergartens. PMID- 27759028 TI - BRCA1/2 germline testing in non-mucinous epithelial ovarian carcinoma: changing international practice and implications for service provision. PMID- 27759029 TI - A cross-ethnic survey of CFB and SLC44A4, Indian ulcerative colitis GWAS hits, underscores their potential role in disease susceptibility. AB - The first ever genome-wide association study (GWAS) of ulcerative colitis in genetically distinct north Indian population identified two novel genes namely CFB and SLC44A4. Considering their biological relevance, we investigated allelic/genetic heterogeneity in these genes among ulcerative colitis cohorts of north Indian, Japanese and Dutch origin using high-density ImmunoChip case control genotype data. Comparative linkage disequilibrium profiling and test of association were performed. Of the 28 CFB SNPs, similar strength of association was observed for rs4151657 (novel ulcerative colitis GWAS SNP) in north Indians (P=1.73 * 10-10) and Japanese (P=2.02 * 10-12) but not in the Dutch. Further, a three-marker haplotype was shared between north Indians and Japanese (P<10-8), but a different five-marker haplotype was associated (P=2.07 * 10-6) in the Dutch. Of the 22 SLC44A4 SNPs, rs2736428 (novel ulcerative colitis GWAS SNP) was found significantly associated in north Indians (P=4.94 * 10-10) and Japanese (P=3.37 * 10-9), but not among the Dutch. These results suggest (i) apparent allelic heterogeneity in CFB and genetic heterogeneity in SLC44A4 across different ethnic groups; (ii) shared ulcerative colitis genetic etiological factors among Asians; and finally (iii) re-exploration of GWAS findings together with high-density genotyping/sequencing and trans-ethnic fine mapping approaches may help identify shared and population-specific risk variants and enable to explain missing disease heritability. PMID- 27759030 TI - Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype. AB - The ubiquitin-proteasome pathway is involved in the pathogenesis of several neurogenetic diseases. We describe a Mauritanian patient harboring a homozygous deletion restricted to two contiguous genes HERC2 and OCA2 and presenting with severe developmental abnormalities. The deletion causes the complete loss of HERC2 protein function, an E3-ubiquitin ligase. HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation. We showed that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient's fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair. Our data describe for the first time the phenotypic consequences, both at the clinical and cellular levels, of a complete loss of HERC2 function in a patient. They strongly suggest that profound ubiquitin ligase - associated dysfunction is responsible for the severe phenotype in this patient, and that dysfunction of this pathway may be involved in other patients with similar neurodevelopmental diseases. PMID- 27759031 TI - Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease. AB - Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals. PNPT1 encodes the polynucleotide phosphorylase (PNPase) protein, which is involved in the transport of small RNAs into the mitochondria. These RNAs are involved in the mitochondrial translation machinery, responsible for the synthesis of mitochondrially encoded subunits of the oxidative phosphorylation (OXPHOS) complexes. Both PNPT1 variants are within highly conserved regions and predicted to be damaging. These variants resulted in quaternary defects in the PNPase protein and a clear reduction in protein and mRNA expression of PNPT1 in patient fibroblasts compared with control cells. Protein analysis of the OXPHOS complexes showed a significant reduction in complex I (CI), complex III (CIII) and complex IV (CIV). Enzyme activity of CI and CIV was clearly reduced in patient fibroblasts compared with controls along with a 33% reduction in total mitochondrial protein synthesis. In vitro rescue experiments, using exogenous expression of wild-type PNPT1 in patient fibroblasts, ameliorated the deficiencies in the OXPHOS complex protein expression, supporting the likely pathogenicity of these variants and the importance of WES in efficiently identifying rare genetic disease genes. PMID- 27759032 TI - A genotypic ascertainment approach to refute the association of MYO1A variants with non-syndromic deafness. AB - Variants in the unconventional myosin gene, MYO1A, have been reported to cause non-syndromic sensorineural hearing loss with a pattern of autosomal dominant inheritance. Others have challenged this association. We used a genotypic ascertainment study design to test the association of MYO1A variants with hearing loss. We evaluated MYO1A variants from a cohort of 951 individuals with exome sequencing who were not ascertained for hearing loss. Five individuals had one of two variants claimed to be associated with sensorineural hearing loss in a prior study and 33 individuals had one of 13 predicted deleterious variants. We obtained audiology evaluations for 12 individuals with these variants of interest. The hearing acuity of the participants was compared with age- and sex matched controls and published age- and sex-specific reference ranges from a large population of otologically screened adults. None of the participants had bilateral sensorineural hearing loss of moderate or greater severity. These data do not support a causal relationship of variants in MYO1A to sensorineural hearing loss. We suggest that the genotypic ascertainment method is useful to objectively evaluate gene-phenotype associations. PMID- 27759033 TI - The growth of the central region by acquisition of counterrotating gas in star forming galaxies. AB - Galaxies grow through both internal and external processes. In about 10% of nearby red galaxies with little star formation, gas and stars are counter rotating, demonstrating the importance of external gas acquisition in these galaxies. However, systematic studies of such phenomena in blue, star-forming galaxies are rare, leaving uncertain the role of external gas acquisition in driving evolution of blue galaxies. Here, based on new measurements with integral field spectroscopy of a large representative galaxy sample, we find an appreciable fraction of counter-rotators among blue galaxies (9 out of 489 galaxies). The central regions of blue counter-rotators show younger stellar populations and more intense, ongoing star formation than their outer parts, indicating ongoing growth of the central regions. The result offers observational evidence that the acquisition of external gas in blue galaxies is possible; the interaction with pre-existing gas funnels the gas into nuclear regions (<1 kpc) to form new stars. PMID- 27759034 TI - CDK4 regulates cancer stemness and is a novel therapeutic target for triple negative breast cancer. AB - Triple negative breast cancers exhibit very aggressive features and poor patient outcomes. These tumors are enriched in cancer stem cells and exhibit resistance to most treatments and chemotherapy. In this study, we found the cyclin-dependent kinase (CDK4) to act as a cancer stem cell regulator and novel prognostic marker in triple negative breast cancers. We found CDK4 to be highly expressed in these tumors and its expression to correlate with poor overall and relapse free survival outcomes, high tumor grade and poor prognostic features of triple negative breast cancer patients. Moreover, we found that blocking CDK4 expression or kinase activity, using a pharmacological inhibitor prevented breast cancer stem cell self-renewal. Interestingly, suppression of CDK4 expression or kinase activity reversed the basal-B TNBC mesenchymal phenotype to an epithelial- and luminal-like phenotype which correlates with better clinical prognosis. Finally, blocking CDK4 activity efficiently eliminated both normal and chemotherapy resistant cancer cells in triple negative breast cancers, highlighting CDK4 as a promising novel therapeutic target for these aggressive breast tumors. PMID- 27759035 TI - mdRNA-Seq analysis of marine microbial communities from the northern Red Sea. AB - Metatranscriptomic differential RNA-Seq (mdRNA-Seq) identifies the suite of active transcriptional start sites at single-nucleotide resolution through enrichment of primary transcript 5' ends. Here we analyzed the microbial community at 45 m depth at Station A in the northern Gulf of Aqaba, Red Sea, during 500 m deep mixing in February 2012 using mdRNA-Seq and a parallel classical RNA-Seq approach. We identified promoters active in situ for five different pico-planktonic genera (the SAR11 clade of Alphaproteobacteria, Synechococcus of Cyanobacteria, Euryarchaeota, Thaumarchaeota, and Micromonas as an example for picoeukaryotic algae), showing the applicability of this approach to highly diverse microbial communities. 16S rDNA quantification revealed that 24% of the analyzed community were group II marine Euryarchaeota in which we identified a highly abundant non-coding RNA, Tan1, and detected very high expression of genes encoding intrinsically disordered proteins, as well as enzymes for the synthesis of specific B vitamins, extracellular peptidases, carbohydrate-active enzymes, and transport systems. These results highlight previously unknown functions of Euryarchaeota with community-wide relevance. The complementation of metatranscriptomic studies with mdRNA-Seq provides substantial additional information regarding transcriptional start sites, promoter activities, and the identification of non-coding RNAs. PMID- 27759036 TI - High-Efficiency Transduction of Primary Human Hematopoietic Stem/Progenitor Cells by AAV6 Vectors: Strategies for Overcoming Donor-Variation and Implications in Genome Editing. AB - We have reported that of the 10 commonly used AAV serotype vectors, AAV6 is the most efficient in transducing primary human hematopoietic stem/progenitor cells (HSPCs). However, the transduction efficiency of the wild-type (WT) AAV6 vector varies greatly in HSPCs from different donors. Here we report two distinct strategies to further increase the transduction efficiency in HSPCs from donors that are transduced less efficiently with the WT AAV6 vectors. The first strategy involved modifications of the viral capsid proteins where specific surface exposed tyrosine (Y) and threonine (T) residues were mutagenized to generate a triple-mutant (Y705 + Y731F + T492V) AAV6 vector. The second strategy involved the use of ex vivo transduction at high cell density. The combined use of these strategies resulted in transduction efficiency exceeding ~90% in HSPCs at significantly reduced vector doses. Our studies have significant implications in the optimal use of capsid-optimized AAV6 vectors in genome editing in HSPCs. PMID- 27759038 TI - The stability and catalytic activity of W13@Pt42 core-shell structure. AB - This paper reports a study of the electronic properties, structural stability and catalytic activity of the W13@Pt42 core-shell structure using the First principles calculations. The degree of corrosion of W13@Pt42 core-shell structure is simulated in acid solutions and through molecular absorption. The absorption energy of OH for this structure is lower than that for Pt55, which inhibits the poison effect of O containing intermediate. Furthermore we present the optimal path of oxygen reduction reaction catalyzed by W13@Pt42. Corresponding to the process of O molecular decomposition, the rate-limiting step of oxygen reduction reaction catalyzed by W13@Pt42 is 0.386 eV, which is lower than that for Pt55 of 0.5 eV. In addition by alloying with W, the core-shell structure reduces the consumption of Pt and enhances the catalytic efficiency, so W13@Pt42 has a promising perspective of industrial application. PMID- 27759037 TI - TGF-beta induces p53/Smads complex formation in the PAI-1 promoter to activate transcription. AB - Transforming growth factor beta (TGF-beta) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-beta is still unknown, and it is unclear whether inhibition of TGF-beta signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-beta signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1) transcription. p53 forms a complex with Smad2/3 in the PAI-1 promoter to recruit histone acetyltransferase CREB-binding protein (CBP) and enhance histone H3 acetylation, resulting in transcriptional activation of the PAI-1 gene. Importantly, p53 is required for TGF-beta-induced cytostasis and PAI-1 is involved in the cytostatic activity of TGF-beta in several cell lines. Our results suggest that p53 enhances TGF-beta-induced cytostatic effects by activating PAI-1 transcription, and the functional switching of TGF-beta is partially caused by p53 mutation or p53 inactivation during cancer progression. It is expected that these findings will contribute to optimization of TGF-beta targeting therapies for cancer. PMID- 27759040 TI - Effects of patch contrast and arrangement on benefits of clonal integration in a rhizomatous clonal plant. AB - The availabilities of light and soil water resources usually spatially co-vary in natural habitats, and the spatial pattern of such co-variation may affect the benefits of physiological integration between connected ramets of clonal plants. In a greenhouse experiment, we grew connected or disconnected ramet pairs [consisting of a proximal (relatively old) and a distal (relative young) ramet] of a rhizomatous herb Iris japonica in four heterogeneous environments differing in patch arrangement (reciprocal vs. parallel patchiness of light and soil water) and patch contrast (high vs. low contrast of light and water). Biomass of the proximal part, distal part and clonal fragment of I. japonica were all significantly greater in the intact than in the severed treatment, in the parallel than in the reciprocal patchiness treatment and in the high than in the low contrast treatment, but the effect of severing the connection between ramet pairs did not depend on patch arrangement or contrast. Severing the connection decreased number of ramets of the distal part and the clonal fragment in the parallel patchiness arrangement, but not in the reciprocal patchiness arrangement. Therefore, the spatial arrangement of resource patches can alter the effects of clonal integration on asexual reproduction in I. japonica. PMID- 27759039 TI - LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL). AB - Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, manifests as an over-accumulation of hepatic fat. We have recently shown that mice with genetic knockout of a long non-coding RNA (lncRNA) steroid receptor RNA activator (SRA) (SRAKO) are resistant to high fat diet-induced obesity with a phenotype that includes improved glucose tolerance and attenuated hepatic steatosis. The underlying mechanism was investigated in the present study. We found that hepatic levels of SRA and adipose triglyceride lipase (ATGL), a major hepatic triacylglycerol (TAG) hydrolase, were inversely regulated by fasting in mice, and the expression of liver ATGL was induced by SRAKO under normal and high fat diet (HFD) feeding. Loss of SRA in primary hepatocytes or a hepatocyte cell line upregulates, but forced expression of SRA inhibits ATGL expression and free fatty acids (FFA) beta-oxidation. SRA inhibits ATGL promoter activity, primarily by inhibiting the otherwise-inductive effects of the transcription factor, forkhead box protein O1 (FoxO1). Our data reveal a novel function of SRA in promoting hepatic steatosis through repression of ATGL expression. PMID- 27759041 TI - Cytoplasmic proliferating cell nuclear antigen connects glycolysis and cell survival in acute myeloid leukemia. AB - Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S). By interacting with nicotinamide phosphoribosyltransferase (NAMPT), a protein involved in NAD biosynthesis, PCNA coordinates glycolysis and survival, especially in HL-60R cells. These cells showed a dramatic increase in intracellular NAD+ concentration as well as glycolysis including increased expression and activity of hexokinase 1 and increased lactate production. Furthermore, this functional activity of cytoplasmic PCNA was also demonstrated in patients with acute myeloid leukemia (AML). Our data uncover a novel pathway of nuclear export of PCNA that drives cell survival by increasing metabolism flux. PMID- 27759043 TI - Structural insights into bacterial flagellar hooks similarities and specificities. AB - Across bacteria, the protein that makes the flagellar hook, FlgE, has a high variability in amino acid residue composition and sequence length. We hereby present the structure of two fragments of FlgE protein from Campylobacter jejuni and from Caulobacter crescentus, which were obtained by X-ray crystallography, and a high-resolution model of the hook from Caulobacter. By comparing these new structures of FlgE proteins, we show that bacterial hook can be divided in two distinct parts. The first part comprises domains that are found in all FlgE proteins and that will make the basic structure of the hook that is common to all flagellated bacteria. The second part, hyper-variable both in size and structure, will be bacteria dependent. To have a better understanding of the C. jejuni hook, we show that a special strain of Salmonella enterica, which was designed to encode a gene of flgE that has the extra domains found in FlgE from C. jejuni, is fully motile. It seems that no matter the size of the hook protein, the hook will always have a structure made of 11 protofilaments. PMID- 27759042 TI - Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1. AB - The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly up regulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is mis-regulated. PMID- 27759044 TI - Lipopolysaccharide-induced hemolysis: Evidence for direct membrane interactions. AB - While hemolysis in patients with sepsis is associated with increased mortality its mechanisms are unknown and Toll-like receptor (TLR)-4 mediated effects, complement-mediated hemolysis, or direct cell membrane effects are all conceivable mechanisms. In this study, we tested the hypotheses that toxic lipopolysaccharide (LPS) as well as non-toxic RS-LPS evokes hemolysis (1) by direct membrane effects, and (2) independent of the complement system and TLR-4 activation. We found, that incubation with LPS resulted in a marked time and concentration dependent increase of free hemoglobin concentration and LDH activity in whole blood and washed red cells. Red cell integrity was diminished as shown by decreased osmotic resistance, formation of schistocytes and rolls, and a decrease in red cell membrane stiffness. Non-toxic RS-LPS inhibited the LPS evoked increase in TNF-alpha concentration demonstrating its TLR-4 antagonism, but augmented LPS-induced increase in supernatant hemoglobin concentration and membrane disturbances. Removal of plasma components in washed red cell assays failed to attenuate hemolysis. In summary, this study demonstrates direct physicochemical interactions of LPS with red cell membranes resulting in hemolysis under in vitro conditions. It might thus be hypothesized, that not all effects of LPS are mediated by TLR and may explain LPS toxicity in cells missing TLR. PMID- 27759045 TI - Transient Induced Molecular Electronic Spectroscopy (TIMES) for study of protein ligand interactions. AB - We present a method, Transient Induced Molecular Electronic Spectroscopy (TIMES), to detect protein-ligand interactions without any protein engineering or chemical modification. We developed a physics model for the TIMES signal and mathematically formulated the problem to attain physical insight of protein ligand interactions without any disturbances by molecular probes, fluorescent labels, or immobilization of molecules. To demonstrate the functionality of this method, we have used the TIMES signals to find the dissociation constants for the affinity of reactions, the shear-stress dependent adsorption time of molecules on surface, and other interesting features of protein-ligand interaction in native conditions. As a unique tool, TIMES offers a simple and effective method to investigate fundamental protein chemistry and drug discoveries. PMID- 27759046 TI - Independent Long Fingers are not Essential for a Grasping Hand. AB - The human hand is a complex integrated system with motor and sensory components that provides individuals with high functionality and elegant behaviour. In direct connection with the brain, the hand is capable of performing countless actions ranging from fine digit manipulation to the handling of heavy objects. However the question of which movements mostly contribute to the manipulation skills of the hand, and thus should be included in prosthetic hands, is yet to be answered. Building from our previous work, and assuming that a hand with independent long fingers allowed performance comparable to a hand with coupled fingers, here we explored the actual contribution of independent fingers while performing activities of daily living using custom built orthoses. Our findings show that, when an opposable thumb is present, independent long fingers provide a measureable advantage in performing activities of daily living only when precision grasps are involved. In addition, the results suggest that the remarkable grasping skills of the human hand rely more on the independent abduction/adduction of the fingers than on their independent flexion/extension. These findings are of interest to the designers of artificial hands, including biomimetic prostheses and exoskeletons. PMID- 27759047 TI - Coherent quantum transport features in carbon superlattice structures. AB - Whilst resonant transmission is well understood and can be fully harnessed for crystalline superlattices, a complete picture has not yet emerged for disordered superlattices. It has proven difficult to tune resonant transmission in disordered diamond-like carbon (DLC) superlattices as conventional models are not equipped to incorporate significant structural disorder. In this work, we present concurrent experimental and theoretical analysis which addresses resonant transmission in DLC superlattices. Devices were fabricated by growing alternate layers of DLC with different percentages of sp3 hybridized carbon.Coherent quantum transport effects were demonstrated in these structurally disordered DLC superlattices through distinct current modulation with negative differential resistance (NDR) in the current-voltage (I-V) measurements. A model was developed using tight-binding calculations assuming a random variation of the hopping integral to simulate structural (bond-length) disorder. Calculations of the I-V characteristics compliment the interpretation of the measurements and illustrate that while DLC superlattice structures are unlike their classical counterparts, the near-field structural order will help with the confinement of quantised states. The present model provides an empirical guide for tailoring the properties of future devices, giving rise to much hope that carbon electronics operating at high frequencies over large areas can now be developed. PMID- 27759048 TI - Molecular etiology and genotype-phenotype correlation of Chinese Han deaf patients with type I and type II Waardenburg Syndrome. AB - Waardenburg syndrome (WS) characterized by sensorineural hearing loss and pigmentary abnormalities is genetically heterogeneous and phenotypically variable. This study investigated the molecular etiology and genotype-phenotype correlation of WS in 36 Chinese Han deaf probands and 16 additional family members that were clinically diagnosed with WS type I (WS1, n = 8) and type II (WS2, n = 42). Mutation screening of six WS-associated genes detected PAX3 mutations in 6 (86%) of the 7 WS1 probands. Among the 29 WS2 probands, 13 (45%) and 10 (34%) were identified with SOX10 and MITF mutations, respectively. Nineteen of the 26 detected mutations were novel. In WS2 probands whose parental DNA samples were available, de novo mutations were frequently seen for SOX10 mutations (7/8) but not for MITF mutations (0/5, P = 0.005). Excessive freckle, a common feature of WS2 in Chinese Hans, was frequent in WS2 probands with MITF mutations (7/10) but not in those with SOX10 mutations (0/13, P = 4.9 * 10-4). Our results showed that mutations in SOX10 and MITF are two major causes for deafness associated with WS2. These two subtypes of WS2 can be distinguished by the high de novo rate of the SOX10 mutations and the excessive freckle phenotype exclusively associated with the MITF mutations. PMID- 27759050 TI - Effect of the phenoxy groups on PDIB and its derivatives. AB - The anisotropic hole and electron mobilities in N,N'-3,4,9,10-perylenediimide-1,7 phenoxy (PDIB-2OPh) and N,N'-3,4,9,10-perylenediimide (PDIB) were theoretically predicted using the Marcus-Hush theory. The substituent effect of phenoxy on their mobility rates, absorption spectra, electron affinities, and ionization potentials was explored. By comparing the simulated hole mobility in PDIB and PDIB-2OPh, it is found that the phenoxy rings act as spacers between adjacent stacking columns in the phenoxy-substituted derivatives. The increasement of the number of benzene oxygen groups leads to the absorption spectra red-shift of these molecular systems. This coincides with their change tendency of the adiabatic ionization potentials, vertical ionization potentials. However, the calculated adiabatic electron affinities and vertical electron affinities of N,N' butyl-3,4,9,10-perylenediimide-1,6,7,12-phenoxy (PDIB-4OPh) are larger than those of PDIB;OPh. The steric effect in PDIB-4OPh is expected to cause space reversal and thus to changes in the properties of the molecule. PMID- 27759049 TI - Regional-specific effect of fluoxetine on rapidly dividing progenitors along the dorsoventral axis of the hippocampus. AB - Hippocampus-dependent cognitive and emotional function appears to be regionally dissociated along the dorsoventral (DV) axis of the hippocampus. Recent observations that adult hippocampal neurogenesis plays a critical role in both cognition and emotion raised an interesting question whether adult neurogenesis within specific subregions of the hippocampus contributes to these distinct functions. We examined the regional-specific and cell type-specific effects of fluoxetine, which requires adult hippocampal neurogenesis to function as an antidepressant, on the proliferation of hippocampal neural stem cells (NSCs). Fluoxetine specifically increased proliferation of NSCs located in the ventral region of the hippocampus while the mitotic index of NSCs in the dorsal portion of the hippocampus remained unaltered. Moreover, within the ventral hippocampus, type II NSC and neuroblast populations specifically responded to fluoxetine, showing increased proliferation; however, proliferation of type I NSCs was unchanged in response to fluoxetine. Activation or inhibition of serotonin receptor 1A (5-HTR1A) recapitulated or abolished the effect of fluoxetine on proliferation of type II NSCs and neuroblast populations in the ventral hippocampus. Our study showed that the effect of fluoxetine on proliferation is dependent upon the type and the position of the NSCs along the DV axis of the hippocampus. PMID- 27759051 TI - Gas Protection of Two-Dimensional Nanomaterials from High-Energy Impacts. AB - Two-dimensional (2D) materials can be produced using ball milling with the help of liquid surfactants or solid exfoliation agents, as ball milling of bulk precursor materials usually produces nanosized particles because of high-energy impacts. Post-milling treatment is thus needed to purify the nanosheets. We show here that nanosheets of graphene, BN, and MoS2 can be produced by ball milling of their bulk crystals in the presence of ammonia or a hydrocarbon ethylene gas and the obtained nanosheets remain flat and maintain their single-crystalline structure with low defects density even after a long period of time; post-milling treatment is not needed. This study does not just demonstrate production of nanosheets using ball milling, but reveals surprising indestructible behaviour of 2D nanomaterials in ammonia or hydrocarbon gas under the high-energy impacts; in other milling atmospheres such as air, nitrogen or argon the same milling treatment produces nanosized particles. A systematic study reveals chemisorption of ammonia and hydrocarbon gases and chemical reactions occurring at defect sites, which heal the defects by saturating the dangling bonds. Density functional theory was used to understand the mechanism of mechanochemical reactions. Ball milling in ammonia or hydrocarbon is promising for mass production of pure nanosheets. PMID- 27759052 TI - Nanostructured Boron Nitride With High Water Dispersibility For Boron Neutron Capture Therapy. AB - Highly water dispersible boron based compounds are innovative and advanced materials which can be used in Boron Neutron Capture Therapy for cancer treatment (BNCT). Present study deals with the synthesis of highly water dispersible nanostructured Boron Nitride (BN). Unique and relatively low temperature synthesis route is the soul of present study. The morphological examinations (Scanning/transmission electron microscopy) of synthesized nanostructures showed that they are in transient phase from two dimensional hexagonal sheets to nanotubes. It is also supported by dual energy band gap of these materials calculated from UV- visible spectrum of the material. The theoretically calculated band gap also supports the same (calculated by virtual nano lab Software). X-ray diffraction (XRD) analysis shows that the synthesized material has deformed structure which is further supported by Raman spectroscopy. The structural aspect of high water disperse ability of BN is also studied. The ultra high disperse ability which is a result of structural deformation make these nanostructures very useful in BNCT. Cytotoxicity studies on various cell lines (Hela(cervical cancer), human embryonic kidney (HEK-293) and human breast adenocarcinoma (MCF-7)) show that the synthesized nanostructures can be used for BNCT. PMID- 27759053 TI - Distinct Differences on Neointima Formation in Immunodeficient and Humanized Mice after Carotid or Femoral Arterial Injury. AB - Percutaneous coronary intervention is widely adopted to treat patients with coronary artery disease. However, restenosis remains an unsolved clinical problem after vascular interventions. The role of the systemic and local immune response in the development of restenosis is not fully understood. Hence, the aim of the current study was to investigate the role of the human immune system on subsequent neointima formation elicited by vascular injury in a humanized mouse model. Immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl(NSG) mice were reconstituted with human (h)PBMCs immediately after both carotid wire and femoral cuff injury were induced in order to identify how differences in the severity of injury influenced endothelial regeneration, neointima formation, and homing of human inflammatory and progenitor cells. In contrast to non-reconstituted mice, hPBMC reconstitution reduced neointima formation after femoral cuff injury whereas hPBMCs promoted neointima formation after carotid wire injury 4 weeks after induction of injury. Neointimal endothelium and smooth muscle cells in the injured arteries were of mouse origin. Our results indicate that the immune system may differentially respond to arterial injury depending on the severity of injury, which may also be influenced by the intrinsic properties of the arteries themselves, resulting in either minimal or aggravated neointima formation. PMID- 27759054 TI - Functionalized Stress Component onto Bio-template as a Pathway of Cytocompatibility. AB - This in-vitro study introduces residual stress as a third dimension of cell stimulus to modulate the interaction between cells and bio-template, without the addition of either chemical or physical stimuli onto the bio-template surface. Ultrashort Pulsed Laser (USPL) irradiation of silicon-based bio-template causes recrystallization of silicon, which mismatches the original crystal orientation of the virgin silicon. Consequently, subsurface Induced Residual Stress (IRS) is generated. The IRS components demonstrated a strong cytocompatibility, whereas the peripheral of IRS, which is the interface between the IRS component and the virgin silicon surface, a significant directional cell alignment was observed. Fibroblast cells shown to be more sensitive to the stress component than Hela cancer cells. It revealed that cytocompatibility in terms of cell migration and directional cell alignment is directly proportional to the level of the IRS component. Higher stress level results in more cell alignment and border migration width. There is a stress threshold below which the stress component completely loses the functionality. These results pointed to a functionalized bio template with tunable cytocompatibility. This study may lead to a new tool for the designing and engineering of bio-template. PMID- 27759055 TI - Disentangling the stochastic behavior of complex time series. AB - Complex systems involving a large number of degrees of freedom, generally exhibit non-stationary dynamics, which can result in either continuous or discontinuous sample paths of the corresponding time series. The latter sample paths may be caused by discontinuous events - or jumps - with some distributed amplitudes, and disentangling effects caused by such jumps from effects caused by normal diffusion processes is a main problem for a detailed understanding of stochastic dynamics of complex systems. Here we introduce a non-parametric method to address this general problem. By means of a stochastic dynamical jump-diffusion modelling, we separate deterministic drift terms from different stochastic behaviors, namely diffusive and jumpy ones, and show that all of the unknown functions and coefficients of this modelling can be derived directly from measured time series. We demonstrate appli- cability of our method to empirical observations by a data-driven inference of the deterministic drift term and of the diffusive and jumpy behavior in brain dynamics from ten epilepsy patients. Particularly these different stochastic behaviors provide extra information that can be regarded valuable for diagnostic purposes. PMID- 27759056 TI - Visual attention spreads broadly but selects information locally. AB - Visual attention spreads over a range around the focus as the spotlight metaphor describes. Spatial spread of attentional enhancement and local selection/inhibition are crucial factors determining the profile of the spatial attention. Enhancement and ignorance/suppression are opposite effects of attention, and appeared to be mutually exclusive. Yet, no unified view of the factors has been provided despite their necessity for understanding the functions of spatial attention. This report provides electroencephalographic and behavioral evidence for the attentional spread at an early stage and selection/inhibition at a later stage of visual processing. Steady state visual evoked potential showed broad spatial tuning whereas the P3 component of the event related potential showed local selection or inhibition of the adjacent areas. Based on these results, we propose a two-stage model of spatial attention with broad spread at an early stage and local selection at a later stage. PMID- 27759057 TI - Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability. AB - Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound's potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability. PMID- 27759058 TI - Microwave platform as a valuable tool for characterization of nanophotonic devices. AB - The rich potential of the microwave experiments for characterization and optimization of optical devices is discussed. While the control of the light fields together with their spatial mapping at the nanoscale is still laborious and not always clear, the microwave setup allows to measure both amplitude and phase of initially determined magnetic and electric field components without significant perturbation of the near-field. As an example, the electromagnetic properties of an add-drop filter, which became a well-known workhorse of the photonics, is experimentally studied with the aid of transmission spectroscopy measurements in optical and microwave ranges and through direct mapping of the near fields at microwave frequencies. We demonstrate that the microwave experiments provide a unique platform for the comprehensive studies of electromagnetic properties of micro- and nanophotonic devices, and allow to obtain data which are hardly acquirable by conventional optical methods. PMID- 27759059 TI - Evidence for discrete solar and lunar orientation mechanisms in the beach amphipod, Talitrus saltator Montagu (Crustacea, Amphipoda). AB - Animals that use astronomical cues to orientate must make continuous adjustment to account for temporal changes in azimuth caused by Earth's rotation. For example, the Monarch butterfly possesses a time-compensated sun compass dependent upon a circadian clock in the antennae. The amphipod Talitrus saltator possesses both a sun compass and a moon compass. We reasoned that the time-compensated compass mechanism that enables solar orientation of T. saltator is located in the antennae, as is the case for Monarch butterflies. We examined activity rhythms and orientation of sandhoppers with antennae surgically removed, or unilaterally occluded with black paint. Removing or painting the antennae did not affect daily activity rhythms or competence to orientate using the sun. However, when tested at night these animals were unable to orientate correctly to the moon. We subsequently measured circadian gene expression in the antennae and brain of T. saltator and show the clock genes period and cryptochrome 2 are rhythmically expressed in both tissues, reminiscent of other arthropods known to possess antennal clocks. Together, our behavioural and molecular data suggest that, T. saltator has anatomically discrete lunar and solar orientation apparatus; a sun compass, likely located in the brain and a moon compass in the antennae. PMID- 27759060 TI - Choline and betaine consumption lowers cancer risk: a meta-analysis of epidemiologic studies. AB - A number of human and animal in vitro or in vivo studies have investigated the relationship between dietary choline and betaine and cancer risk, suggesting that choline and betaine consumption may be protective for cancer. There are also a few epidemiologic studies exploring this relationship, however, with inconsistent conclusions. The PubMed and Embase were searched, from their inception to March 2016, to identify relevant studies and we brought 11 articles into this meta analysis eventually. The pooled relative risks (RRs) of cancer for the highest versus the lowest range were 0.82 (95% CI, 0.70 to 0.97) for choline consumption only, 0.86 (95%CI, 0.76 to 0.97) for betaine consumption only and 0.60 (95%CI, 0.40 to 0.90) for choline plus betaine consumption, respectively. Significant protective effect of dietary choline and betaine for cancer was observed when stratified by study design, location, cancer type, publication year, sex and quality score of study. An increment of 100 mg/day of choline plus betaine intake helped reduce cancer incidence by 11% (0.89, 95% CI, 0.87 to 0.92) through a dose response analysis. To conclude, choline and betaine consumption lowers cancer incidence in this meta-analysis, but further studies are warranted to verify the results. PMID- 27759062 TI - Software-defined microwave photonic filter with high reconfigurable resolution. AB - Microwave photonic filters (MPFs) are of great interest in radio frequency systems since they provide prominent flexibility on microwave signal processing. Although filter reconfigurability and tunability have been demonstrated repeatedly, it is still difficult to control the filter shape with very high precision. Thus the MPF application is basically limited to signal selection. Here we present a polarization-insensitive single-passband arbitrary-shaped MPF with ~GHz bandwidth based on stimulated Brillouin scattering (SBS) in optical fibre. For the first time the filter shape, bandwidth and central frequency can all be precisely defined by software with ~MHz resolution. The unprecedented multi-dimensional filter flexibility offers new possibilities to process microwave signals directly in optical domain with high precision thus enhancing the MPF functionality. Nanosecond pulse shaping by implementing precisely defined filters is demonstrated to prove the filter superiority and practicability. PMID- 27759061 TI - Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography. AB - High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 MUm scale, no change was observed in the intracortical structure. At 1 MUm scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR microCT imaging. PMID- 27759063 TI - Comparison of high-resolution peripheral quantitative computerized tomography with dual-energy X-ray absorptiometry for measuring bone mineral density. AB - BACKGROUND/OBJECTIVES: The objective of this study was to compare the measurement of areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) with the measurement of volumetric bone mineral density (vBMD) by high-resolution peripheral computerized tomography (HR-pQCT) in subjects with a wide range of body mass indices (BMI). SUBJECTS/METHODS: We scanned the arms and legs of 49 premenopausal women, aged 21-45 years, with BMI from 18.5 to 46.5, by HR-pQCT and found that there was a nonsignificant change in vBMD associated with increased BMI, whereas aBMD (DXA) was associated with a positive significant increase. HR pQCT scans a slice at the extremity of the tibia and radius, whereas DXA scans the entire leg and arm. RESULTS: The correlation coefficients (r) of BMD (DXA) of the legs with BMI were 0.552, P<0.001, with %fat it was 0.378, P<0.01 and with W it was 0.633, P<0.001. The r of BMD (DXA) of the arms with BMI was 0.804, P<0.001, with %fat it was 0.599, P<0.001 and with W it was 0.831, P<0.001, whereas the r of the average bone density (D100) of legs and arms measured by HR pQCT with BMI, W and %fat were not significant. CONCLUSIONS: Although HR-pQCT and DXA scan different parts of the bone, the high r of BMD with BMI and low r of bone density measured by HR-pQCT with BMI suggest that BMD measured by DXA is artifactually increased in the presence of obesity. PMID- 27759064 TI - Dietary patterns and mortality from cardiovascular disease: Isfahan Cohort Study. AB - BACKGROUND/OBJECTIVES: Evidence about the relation between dietary patterns and cardiovascular disease (CVD) is scarce in Middle Eastern countries. This study was performed to examine the association between major dietary patterns and CVD mortality in Iranian adults. SUBJECTS/METHODS: This population-based prospective cohort study was conducted among 4834 randomly selected participants aged ?35 years from urban and rural areas of central Iran (2001-2009) (the Isfahan Cohort Study). Dietary intakes were assessed using a food frequency questionnaire, and major dietary patterns were identified by means of exploratory factor analysis. Subjects or their next of kin were interviewed biannually looking for possible occurrence of events. Cardiovascular mortality was defined as fatal myocardial infarction, fatal stroke and sudden cardiac death. RESULTS: During the median follow-up of 9.0 years and 50 282 person-years, we found a total of 118 CVD mortalities. Four major dietary patterns were identified: 'Western', 'Mediterranean', 'Animal fat' and 'Fast food'. Adherence to the Mediterranean dietary pattern was protectively associated with CVD mortality, such that those in the highest quartile were 46% (hazard ratio (HR): 0.54; 95% confidence interval (CI): 0.32-0.91; P-value for trend=0.03) less likely to have incident CVD mortality than those in the lowest quartile. Further adjustment for potential confounders strengthened this association (HR: 0.42; 95% CI: 0.19-0.96; P-value for trend=0.02). We found no significant association between adherence to the Western, animal fat and fast food dietary patterns and CVD mortality. CONCLUSIONS: Adherence to a Mediterranean dietary pattern was associated with reduced risk for cardiovascular mortality even in a developing country setting. PMID- 27759066 TI - Lower thigh muscle mass is associated with all-cause and cardiovascular mortality in elderly hemodialysis patients. AB - BACKGROUND/OBJECTIVES: Higher body mass index appears protective in hemodialysis patients, although it remains to be determined which component of muscle or fat mass is primarily associated with this survival advantage. SUBJECTS/METHODS: Eighty-one hemodialysis patients in our institution were prospectively followed from July 2011 to August 2015. Muscle and fat mass were evaluated by measuring the cross-sectional areas of the thigh and abdomen using computed tomography. The relationship between muscle and fat mass, and all-cause and cardiovascular mortality was studied using the Kaplan-Meier analyses and multivariate Cox proportional hazard models. RESULTS: During more than 4 years of follow-up, 26 patients (32%) died. In the Kaplan-Meier curve analyses, lower thigh muscle mass was significantly associated with all-cause and cardiovascular mortality (log rank test, P<0.01 and P<0.001, respectively), but there was no such association with thigh fat, abdominal muscle and fat mass levels. In multivariate Cox proportional hazard models, each 0.1 cm2/kg increase in the thigh muscle area adjusted by dry weight was associated with an estimated 22% lower risk of all cause mortality (95% confidence interval (95% CI), 0.64-0.95, P<0.05) and a 30% lower risk of cardiovascular mortality (95% CI, 0.54-0.90, P<0.01). CONCLUSIONS: Lower thigh muscle mass is significantly associated with all-cause and cardiovascular mortality in hemodialysis patients. Our findings indicate the importance of focusing on the muscle mass of lower extremities to predict the clinical outcomes of hemodialysis patients. PMID- 27759065 TI - Effect of phytase on zinc absorption from a millet-based porridge fed to young Burkinabe children. AB - BACKGROUND/OBJECTIVES: Fortifying cereal staples with zinc is a strategy for increasing zinc intake in young children in developing countries. However, phytic acid (PA) naturally present in cereals strongly decreases zinc absorption. A stable-isotope zinc absorption study was conducted in young children to investigate the ability of the PA-degrading enzyme phytase to improve zinc absorption, when added to a cereal porridge immediately before consumption. SUBJECTS/METHODS: Fractional absorption of zinc (FAZ) was estimated in 35 young healthy Burkinabe children using the double-isotopic tracer ratio method with 67Zn as oral tracer and 70Zn as intravenous tracer, in a crossover design. The test meals were: (a) a millet-based porridge containing 1.4 mg total zinc (native plus 1 mg added as ZnSO4) with a PA:Zn molar ratio of 7.7; (b) the same porridge with the enzyme phytase (20.5 phytase units (FTU)) added immediately before consumption. The exchangeable zinc pool (EZP) was determined as a potential measure of long-term zinc intake in 20 of the 35 children and compared with FAZ. RESULTS: Mean FAZ increased from 9.5+/-3.4 to 16.0+/-5.1% (P<0.0001), when phytase was added to the meal. The mean EZP was 3.6+/-0.5 mg/kg. There was no correlation between the EZP and FAZ values for either of the two test meals. CONCLUSIONS: Adding phytase immediately prior to consumption of a zinc-fortified cereal-based complementary food can improve zinc absorption in young children. PMID- 27759067 TI - Impact of weight loss-associated changes in detailed body composition as assessed by whole-body MRI on plasma insulin levels and homeostatis model assessment index. AB - BACKGROUND/OBJECTIVES: We assessed the effect of weight loss-associated changes in detailed body composition on plasma insulin levels and homeostatic model assessment (HOMA) index to calculate the magnitude of reduction in different adipose tissue depots required to improve insulin sensitivity. SUBJECTS/METHODS: A total of 50 subjects aged 20-69 years were studied. The participants were compiled from low-calorie diet interventions and bariatric surgery and differed in their baseline body mass index (BMI; range 21.6-54.4 kg/m2) and degree of weight losses (range -3.3 to -56.9 kg). Detailed body composition and liver fat were measured using whole-body magnetic resonance imaging (MRI). Insulin resistance was assessed by HOMA. RESULTS: Mean body weight decreased by -16.0+/ 13.6 kg. Significant changes were observed in total adipose tissue (TATMRI, range -0.5 to -36.0 kg), total subcutaneous adipose tissue (SATMRI), visceral adipose tissue (VATMRI), skeletal muscle, liver fat, plasma insulin levels and HOMA. Decreases in insulin and HOMA were correlated with reductions in TATMRI, SATMRI, VATMRI (just with HOMA) and liver fat. Losses of 2.9 and 6.5 kg body weight, 2.0 and 5.0 kg TATMRI as well as 1.6 and 6% liver fat were required to decrease plasma insulin levels by 1 MUU/ml and HOMAadjusted for baseline HOMA by 1 point. Multiple regression analysis showed that baseline liver fat and changes in liver fat explained 49.7% and 55.1% of the variance in weight loss-associated changes in plasma insulin and HOMA, respectively. CONCLUSIONS: Decreases of adipose tissues and liver fat are the major determinants of reduction in plasma insulin levels and improvement in HOMA index. PMID- 27759068 TI - Plasma 25-hydroxy vitamin D and subsequent prostate cancer risk in a nested Case Control study in Japan: The JPHC study. AB - BACKGROUND/OBJECTIVES: Although vitamin D has been experimentally reported to inhibit tumorigenesis, cell growth and prostate cancer invasion, epidemiologic data regarding prostate cancer risk are inconsistent, and some studies have suggested positive but nonsignificant associations. Further, the impact of vitamin D on prostate cancer between Western and Japanese populations may differ due to different plasma vitamin D levels. SUBJECTS/METHODS: We performed a nested case-control study within the Japan Public Health Center-based Prospective (JPHC) Study in 14,203 men (40-69 years) who answered a self-administered questionnaire at baseline (1990-1994) and gave blood samples, and were followed until 2005. We identified 201 prostate cancers which are newly diagnosed during follow-up (mean 12.8 years). We selected two matched controls for each case from the cohort. We used a conditional logistic regression model to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer with respect to levels of 25-hydroxy vitamin D (25(OH)D) in plasma. RESULTS: We did not observe statistically significant association between 25(OH)D level and total prostate cancer (multivariate OR=1.13 (95%CI=0.66-1.94, Ptrend=0.94) for the highest versus lowest tertile) However, 25(OH) levels were slightly positively associated with advanced cancer. The results remained substantially unchanged after stratification by intake of fish or calcium intake. CONCLUSIONS: 25(OH)D level showed no association with overall prostate cancer among Japanese men in this large cohort. PMID- 27759069 TI - Excessive gain in body mass index-for-age Z-score and associated factors: a cohort study in female adolescents. AB - OBJECTIVE: To evaluate the occurrence of excessive gain in body mass index-for age Z-score (BMI/AZ) and its associated factors in adolescent girls. METHODOLOGY: This is a cohort study conducted between 2007 and 2012 with 382 girls between 10 and 18 years of age attending public schools in Recife, Pernambuco, Brazil. Excessive gain in BMI/AZ (EGBMI/AZ) at follow-up was considered if the adolescent had a BMI/AZ >0.63 between follow-up and baseline. RESULTS: In 2007, 33.5% of girls were overweight, and at the end of the study this prevalence was 26.2%, with no statistically significant differences. Of the 382 girls evaluated in the cohort, 33% showed EGBMI/AZ. In 2007, 95% of these girls were normal weight or underweight, and in 2012, 60% were classified as overweight. After adjusting for possible confounding factors, three variables remained independently associated with EGBMI/AZ: underweight, normal weight and maternal overweight. CONCLUSIONS: Both underweight and normal weight were associated with EGBMI/AZ, and this could be due to a physiological protection for the occurrence of menarche. In fact, maternal overweight has considerable influence on adolescents' nutritional status because of exposure to an obesogenic environment. PMID- 27759070 TI - Fruit and vegetable intake and cardiovascular risk factors in people with newly diagnosed type 2 diabetes. AB - BACKGROUND/OBJECTIVES: The cardiovascular benefit of increasing fruit and vegetable (F&V) intake following diagnosis of diabetes remains unknown. We aimed to describe how quantity and variety of F&V intake, and plasma vitamin C, change after diagnosis of type 2 diabetes and examine whether these changes are associated with improvements in cardiovascular risk factors. SUBJECTS/METHODS: A total of 401 individuals with screen-detected diabetes from the ADDITION Cambridge study were followed up over 5 years. F&V intake was assessed by food frequency questionnaire and plasma vitamin C at baseline, at 1 year and at 5 years. Linear mixed models were used to estimate associations of changes in quantity and variety of F&V intake, and plasma vitamin C, with cardiovascular risk factors and a clustered cardiometabolic risk score (CCMR), where a higher score indicates higher risk. RESULTS: F&V intake increased in year 1 but decreased by year 5, whereas variety remained unchanged. Plasma vitamin C increased at 1 year and at 5 years. Each s.d. increase (250g between baseline and 1 year and 270g between 1 and 5 years) in F&V intake was associated with lower waist circumference (-0.92 (95% CI: -1.57, -0.27) cm), HbA1c (-0.11 (-0.20, 0.03) %) and CCMR (-0.04 (-0.08, -0.01)) at 1 year and higher high-density lipoprotein (HDL)-cholesterol (0.04 (0.01, 0.06) mmol/l) at 5 years. Increased plasma vitamin C (per s.d., 22.5 MUmol/l) was associated with higher HDL cholesterol (0.04 (0.01, 0.06) mmol/l) and lower CCMR (-0.07 (-0.12, -0.03)) between 1 and 5 years. CONCLUSIONS: Increases in F&V quantity following diagnosis of diabetes are associated with lower cardiovascular risk factors. Health promotion interventions might highlight the importance of increasing, and maintaining increases in, F&V intake for improved cardiometabolic health in patients with diabetes. PMID- 27759071 TI - UCP2 expression is associated with weight loss after hypocaloric diet intervention. AB - BACKGROUND/OBJECTIVES: Although energy restriction contributes to weight loss, it may also reduce energy expenditure, limiting the success of weight loss in the long term. Studies have described how genetics contributes to the development of obesity, and uncoupling proteins 1 and 2 (UCP1 and UCP2) and beta-3-adrenoceptor (ADRB3) have been implicated in the metabolic pathways that culminate in this condition. This study aimed to evaluate how the UCP1, UCP2 and ADRB3 genes influence weight loss in severely obese women submitted to hypocaloric dietary intervention. SUBJECTS/METHODS: This longitudinal study included 21 women divided into two groups: Group 1 (Dietary intervention (G1)) consisted of 11 individuals with severe obesity (body mass index (BMI) ?40 kg/m2), selected for dietary intervention and Group 2 (Control (G2)) consisted of 10 normal-weight women (BMI between 18.5 and 24.9 kg/m2). Evaluation included weight (kg), height (m), waist circumference (cm), body composition, resting metabolic rate (RMR, kcal) and abdominal subcutaneous adipose tissue collection. The dietary intervention required that G1 patients remained hospitalized in the university hospital for 6 weeks receiving a hypocaloric diet (1200 kcal per day). The statistical analyses included t-test for paired samples, Spearman correlation and multivariate linear regressions, with the level of significance set at P<0.05. RESULTS: Weight (155.0+/-31.4-146.5+/-27.8 kg), BMI (58.5+/-10.5-55.3+/-9.2 kg/m2), fat-free mass (65.4+/-8.6-63.1+/-7.1 kg), fat mass (89.5+/-23.0-83.4+/-21.0 kg) and RMR (2511.6+/-386.1-2324.0+/-416.4 kcal per day) decreased significantly after dietary intervention. Multiple regression analyses showed that UCP2 expression contributed to weight loss after dietary intervention (P=0.05). CONCLUSIONS: UCP2 expression is associated with weight loss after hypocaloric diet intervention. PMID- 27759072 TI - Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort. AB - BACKGROUND/OBJECTIVES: Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. SUBJECTS/METHODS: The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. RESULTS: Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers (?15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction <0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction <0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction <0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. CONCLUSIONS: In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future. PMID- 27759073 TI - Food groups associated with measured net acid excretion in community-dwelling older adults. AB - BACKGROUND/OBJECTIVES: Acid-producing diets have been associated with adverse health conditions. Dietary acid load can be estimated from dietary intake data, but the available methods require a full dietary assessment. We sought to identify a simpler means to estimate 24-h urinary net acid excretion (NAE), a robust measure of net endogenous acid production, using self-reported intakes of fruits, vegetables (acid-neutralizing foods), grain and/or protein (acid producing foods) acquired by two different methods in community-dwelling older adults. Identifying food groups associated with NAE by using a method not requiring a full diet assessment could have a broad clinical application. SUBJECTS/METHODS: Fruit, vegetable, protein and grain servings/day were estimated with a widely used food frequency questionnaire (study A, n=162, 63+/-8 years). Differences in their intakes across NAE categories (<5, ?5 to <15, ?15 to <50, ?50 milliequivalents (mEq)/day) were analyzed using analysis of variance. The findings were verified in a second study, which estimated dietary intakes, using a more detailed record-assisted 24-h recall (study B, n=232, 67+/-6 years). RESULTS: Fruit intake was significantly associated with NAE in both studies. In study A, fruit intake was 9% lower with each categorical NAE increase (unstandardized beta=-0.21, P=0.01) and 7% lower with each categorical NAE increase in study B (unstandardized beta=-0.18; P=0.02). Grain intake was positively associated with NAE in study B only (unstandardized beta=+0.14; P=0.01). Vegetable and protein intake were not associated with NAE in either study. CONCLUSIONS: The inverse association between fruit intake and NAE suggests low self-reported fruit intake may be an indicator of acid-producing diets in older adults. PMID- 27759075 TI - Applying an extended theory of planned behaviour to predict breakfast consumption in adolescents. AB - BACKGROUND/OBJECTIVES: Breakfast skipping increases during adolescence and is associated with lower levels of physical activity and weight gain. Theory-based interventions promoting breakfast consumption in adolescents report mixed findings, potentially because of limited research identifying which determinants to target. This study aimed to: (i) utilise the Theory of Planned Behaviour (TPB) to identify the relative contribution of attitudes (affective, cognitive and behavioural) to predict intention to eat breakfast and breakfast consumption in adolescents and (ii) determine whether demographic factors moderate the relationship between TPB variables, intention and behaviour. SUBJECTS/METHODS: Questionnaires were completed by 434 students (mean 14+/-0.9 years) measuring breakfast consumption (0-2, 3-6 or 7 days), physical activity levels and TPB measures. Data were analysed by breakfast frequency and demographics using hierarchical and multinomial regression analyses. RESULTS: Breakfast was consumed everyday by 57% of students, with boys more likely to eat a regular breakfast, report higher activity levels and report more positive attitudes towards breakfast than girls (P<0.001). The TPB predicted 58% of the variation in intentions. Overall, the model was predictive of breakfast behaviours (P<0.001), but the relative contribution of TPB constructs varied depending on breakfast frequency. Interactions between gender and intentions were significant when comparing 0-2- and 3-6-day breakfast eaters only highlighting a stronger intention-behaviour relationship for girls. CONCLUSIONS: Findings confirm that the TPB is a successful model for predicting breakfast intentions and behaviours in adolescents. The potential for a direct effect of attitudes on behaviours should be considered in the implementation and design of breakfast interventions. PMID- 27759074 TI - Acute effects of a single dose of tocotrienols on insulinemic and inflammatory responses in metabolic syndrome subjects after a high-fat challenge. AB - BACKGROUND/OBJECTIVES: Evidence shows that tocotrienols potentially reverse various chronic disease progressions caused by the metabolic syndrome. We aimed to investigate the acute effects of a single-dose supplementation of gamma and delta tocotrienols (gammadelta-T3, 1:4 ratio) compared with those in placebo on the insulinemic, anti-inflammatory and anti-thrombogenic responses in metabolic syndrome subjects. SUBJECTS/METHODS: Thirty metabolic syndrome subjects (15 men and 15 women) were recruited to a randomized, double-blinded and crossover study. The subjects were administered a single dose of 200 mg or 400 mg gammadelta-T3 emulsions or placebo incorporated into a glass of strawberry-flavored milkshake, consumed together with a high-fat muffin. Blood samples were collected at 0, 5, 15, 30, 60, 90, 120, 180, 240, 300 and 360 min after meal intake. RESULTS: Plasma vitamin E levels reflected the absorption of gammadelta-T3 after treatments. Postprandial changes in serum C-peptide, serum insulin, plasma glucose, triacylglycerol, non-esterified fatty acid and adiponectin did not differ between treatments, with women displaying delayed increase in the aforementioned markers. No significant difference between treatments was observed for plasma cytokines (interleukin-1 beta, interleukin-6 and tumor necrosis factor alpha) and thrombogenic markers (plasminogen activator inhibitor type 1 and D-dimer). CONCLUSIONS: Supplementation of a single dose of gammadelta-T3 did not change the insulinemic, anti-inflammatory and anti-thrombogenic responses in metabolic syndrome subjects. PMID- 27759076 TI - Identification of reference genes for circulating microRNA analysis in colorectal cancer. AB - Quantitative real-time PCR (qPCR) is the most frequently used method for measuring expression levels of microRNAs (miRNAs), which is based on normalization to endogenous references. Although circulating miRNAs have been regarded as potential non-invasive biomarker of disease, no study has been performed so far on reference miRNAs for normalization in colorectal cancer. In this study we tried to identify optimal reference miRNAs for qPCR analysis across colorectal cancer patients and healthy individuals. 485 blood-derived miRNAs were profiled in serum sample pools of both colorectal cancer and healthy control. Seven candidate miRNAs chosen from profiling results as well as three previous reported reference miRNAs were validated using qPCR in 30 colorectal cancer patients and 30 healthy individuals, and thereafter analyzed by statistical algorithms BestKeeper, geNorm and NormFinder. Taken together, hsa-miR-93-5p, hsa miR-25-3p and hsa-miR-106b-5p were recommended as a set of suitable reference genes. More interestingly, the three miRNAs validated from 485 miRNAs are derived from a single primary transcript, indicting the cluster may be highly conserved in colorectal cancer. However, all three miRNAs differed significantly between healthy individuals and non-small cell lung cancer or breast cancer patients and could not be used as reference genes in the two types of cancer. PMID- 27759077 TI - Down-regulation of beta-arrestin2 promotes tumour invasion and indicates poor prognosis of hepatocellular carcinoma. AB - beta-arrestins, including beta-arrestin1 and beta-arrestin2, are multifunctional adaptor proteins. beta-arrestins have recently been found to play new roles in regulating intracellular signalling networks associated with malignant cell functions. Altered beta-arrestin expression has been reported in many cancers, but its role in hepatocellular carcinoma (HCC) is not clear. We therefore examined the roles of beta-arrestins in HCC using an animal model of progressive HCC, HCC patient samples and HCC cell lines with stepwise metastatic potential. We demonstrated that beta-arrestin2 level, but not beta-arrestin1 level, decreased in conjunction with liver tumourigenesis in a mouse diethylnitrosamine induced liver tumour model. Furthermore, beta-arrestin2 expression was reduced in HCC tissues compared with noncancerous tissues in HCC patients. beta-arrestin2 down-regulation in HCC was significantly associated with poor patient prognoses and aggressive pathologic features. In addition, our in vitro study showed that beta-arrestin2 overexpression significantly reduced cell migration and invasion in cultured HCC cells. Furthermore, beta-arrestin2 overexpression up-regulated E cadherin expression and inhibited vimentin expression and Akt activation. These results suggest that beta-arrestin2 down-regulation increases HCC cell migration and invasion ability. Low beta-arrestin2 expression may be indicative of a poor prognosis or early cancer recurrence in patients who have undergone surgery for HCC. PMID- 27759078 TI - Genotype-specific interactions between parasitic arthropods. AB - Despite the ubiquity of coinfection, we know little of the effects of intra specific genetic variability on coinfection by distinct parasite species. Here we test the hypothesis that parasite multiplication depends on the combination of parasite genotypes that coinfect the host (that is Genotype.parasite * Genotype.parasite interaction). To that aim, we infected tomato leaves with the ecto-parasitic mites Tetranychus urticae and Tetranychus evansi. We tested all possible combinations between four T. urticae and two T. evansi populations sampled on different hosts or localities. There was no universal (that is genotype-independent) effect of coinfection on mite multiplication; in many cases the two species had no effect on each other. However, several combinations of T. evansi and T. urticae populations led to elevated T. evansi numbers. Similarly, T. urticae reproduction largely depended on the interaction between T. urticae and T. evansi populations. This evidence for genotype-by-genotype interaction between coinfecting parasites indicates that the effect of coinfection on parasite epidemiology and evolution may vary in space according to the genetic composition of local parasite populations; it further suggests the possibility of coevolution between parasites species that share the same hosts. PMID- 27759080 TI - Improved performance of a barrier-discharge plasma jet biased by a direct-current voltage. AB - One of the challenges that plasma research encounters is how to generate a large scale plasma plume at atmospheric pressure. Through utilizing a third electrode biased by a direct-current voltage, a longer plasma plume is generated by a plasma jet in dielectric barrier discharge configurations. Results indicate that the plume length increases until it reaches the third electrode with increasing the bias voltage. By fast photography, it is found that the plume consists of two types of streamers under the influence of the bias voltage, which develops from a guided streamer to a branching one with leaving the tube opening. The transition from the guided streamer to the branching one can be attributed to the electric field and the air/argon fraction. PMID- 27759079 TI - From next-generation resequencing reads to a high-quality variant data set. AB - Sequencing has revolutionized biology by permitting the analysis of genomic variation at an unprecedented resolution. High-throughput sequencing is fast and inexpensive, making it accessible for a wide range of research topics. However, the produced data contain subtle but complex types of errors, biases and uncertainties that impose several statistical and computational challenges to the reliable detection of variants. To tap the full potential of high-throughput sequencing, a thorough understanding of the data produced as well as the available methodologies is required. Here, I review several commonly used methods for generating and processing next-generation resequencing data, discuss the influence of errors and biases together with their resulting implications for downstream analyses and provide general guidelines and recommendations for producing high-quality single-nucleotide polymorphism data sets from raw reads by highlighting several sophisticated reference-based methods representing the current state of the art. PMID- 27759081 TI - Wall Teichoic Acids Are Involved in the Medium-Induced Loss of Function of the Autolysin CD11 against Clostridium difficile. AB - Bacterial lysins are potent antibacterial enzymes with potential applications in the treatment of bacterial infections. Some lysins lose activity in the growth media of target bacteria, and the underlying mechanism remains unclear. Here we use CD11, an autolysin of Clostridium difficile, as a model lysin to demonstrate that the inability of this enzyme to kill C. difficile in growth medium is not associated with inhibition of the enzyme activity by medium, or the modification of the cell wall peptidoglycan. Rather, wall teichoic acids (WTAs) appear to prevent the enzyme from binding to the cells and cleaving the cell wall peptidoglycan. By partially blocking the biosynthetic pathway of WTAs with tunicamycin, cell binding improved and the lytic efficacy of CD11 was significantly enhanced. This is the first report of the mechanism of lysin inactivation in growth medium, and provides insights into understanding the behavior of lysins in complex environments, including the gastrointestinal tract. PMID- 27759082 TI - Jak/Stat signaling regulates the proliferation and neurogenic potential of Muller glia-derived progenitor cells in the avian retina. AB - Muller glia are capable of de-differentiating and proliferating to become Muller glia-derived progenitor cells (MGPCs) with the ability to regenerate retinal neurons. One of the cell-signaling pathways that drives the reprogramming of Muller glia into MGPCs in the zebrafish retina is the Jak/Stat-pathway. However, nothing is known about the influence of Jak/Stat-signaling during the formation of MGPCs in the retinas of warm-blooded vertebrates. Accordingly, we examined whether Jak/Stat-signaling influences the formation of MGPCs and differentiation of progeny in the avian retina. We found that Jak/Stat-signaling is activated in Muller glia in response to NMDA-induced retinal damage or by CNTF or FGF2 in the absence of retinal damage. Inhibition of gp130, Jak2, or Stat3 suppressed the formation of proliferating MGPCs in NMDA-damaged and FGF2-treated retinas. Additionally, CNTF combined with FGF2 enhanced the formation of proliferating MGPCs in the absence of retinal damage. In contrast to the zebrafish model, where activation of gp130/Jak/Stat is sufficient to drive neural regeneration from MGPCs, signaling through gp130 inhibits the neurogenic potential of MGPCs and promotes glial differentiation. We conclude that gp130/Jak/Stat-signaling plays an important role in the network of pathways that drives the formation of proliferating MGPCs; however, this pathway inhibits the neural differentiation of the progeny. PMID- 27759083 TI - Impact of sialic acids on the molecular dynamic of bi-antennary and tri-antennary glycans. AB - Sialic acids (SA) are monosaccharides that can be located at the terminal position of glycan chains on a wide range of proteins. The post-translational modifications, such as N-glycan chains, are fundamental to protein functions. Indeed, the hydrolysis of SA by specific enzymes such as neuraminidases can lead to drastic modifications of protein behavior. However, the relationship between desialylation of N-glycan chains and possible alterations of receptor function remains unexplored. Thus, the aim of the present study is to establish the impact of SA removal from N-glycan chains on their conformational behavior. We therefore undertook an in silico investigation using molecular dynamics to predict the structure of an isolated glycan chain. We performed, for the first time, 3 independent 500 ns simulations on bi-antennary and tri-antennary glycan chains displaying or lacking SA. We show that desialylation alters both the preferential conformation and the flexibility of the glycan chain. This study suggests that the behavior of glycan chains induced by presence or absence of SA may explain the changes in the protein function. PMID- 27759085 TI - Realizing the measure-device-independent quantum-key-distribution with passive heralded-single photon sources. AB - In this paper, we put forward a new approach towards realizing measurement-device independent quantum key distribution with passive heralded single-photon sources. In this approach, both Alice and Bob prepare the parametric down-conversion source, where the heralding photons are labeled according to different types of clicks from the local detectors, and the heralded ones can correspondingly be marked with different tags at the receiver's side. Then one can obtain four sets of data through using only one-intensity of pump light by observing different kinds of clicks of local detectors. By employing the newest formulae to do parameter estimation, we could achieve very precise prediction for the two-single photon pulse contribution. Furthermore, by carrying out corresponding numerical simulations, we compare the new method with other practical schemes of measurement-device-independent quantum key distribution. We demonstrate that our new proposed passive scheme can exhibit remarkable improvement over the conventional three-intensity decoy-state measurement-device-independent quantum key distribution with either heralded single-photon sources or weak coherent sources. Besides, it does not need intensity modulation and can thus diminish source-error defects existing in several other active decoy-state methods. Therefore, if taking intensity modulating errors into account, our new method will show even more brilliant performance. PMID- 27759084 TI - Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. AB - Vildagliptin is a potent, orally active inhibitor of dipeptidyl peptidase-4 (DPP 4) for the treatment of type 2 diabetes mellitus. It has been reported that vildagliptin can cause hepatic dysfunction in patients. However, the molecular mechanism of vildagliptin-induced liver dysfunction has not been elucidated. In this study, we employed an expression microarray to determine hepatic genes that were highly regulated by vildagliptin in mice. We found that pro-inflammatory S100 calcium-binding protein (S100) a8 and S100a9 were induced more than 5-fold by vildagliptin in the mouse liver. We further examined the effects of vildagliptin and its major metabolite M20.7 on the mRNA expression levels of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. In HepG2 cells, vildagliptin, M20.7, and sitagliptin - another DPP-4 inhibitor - induced S100A9 mRNA. In HL-60 cells, in contrast, S100A8 and S100A9 mRNAs were significantly induced by vildagliptin and M20.7, but not by sitagliptin. The release of S100A8/A9 complex in the cell culturing medium was observed in the HL 60 cells treated with vildagliptin and M20.7. Therefore, the parental vildagliptin- and M20.7-induced release of S100A8/A9 complex from immune cells, such as neutrophils, might be a contributing factor of vildagliptin-associated liver dysfunction in humans. PMID- 27759086 TI - Directionally selective retinal ganglion cells suppress luminance responses during natural viewing. AB - The ON-OFF directionally selective cells of the retina respond preferentially to movement in a preferred direction, but under laboratory conditions they are also sensitive to changes in the luminance of the stationary stimulus. If the response of these neurons contains information about both direction and luminance downstream neurons are faced with the challenge of extracting the motion component, a computation that may be difficult under certain viewing conditions. Here, we show that during natural viewing the response to luminance is suppressed, leaving a relatively pure motion signal that gets transmitted to the brain. PMID- 27759088 TI - Multiscale limited penetrable horizontal visibility graph for analyzing nonlinear time series. AB - Visibility graph has established itself as a powerful tool for analyzing time series. We in this paper develop a novel multiscale limited penetrable horizontal visibility graph (MLPHVG). We use nonlinear time series from two typical complex systems, i.e., EEG signals and two-phase flow signals, to demonstrate the effectiveness of our method. Combining MLPHVG and support vector machine, we detect epileptic seizures from the EEG signals recorded from healthy subjects and epilepsy patients and the classification accuracy is 100%. In addition, we derive MLPHVGs from oil-water two-phase flow signals and find that the average clustering coefficient at different scales allows faithfully identifying and characterizing three typical oil-water flow patterns. These findings render our MLPHVG method particularly useful for analyzing nonlinear time series from the perspective of multiscale network analysis. PMID- 27759087 TI - Artificial light at night affects body mass but not oxidative status in free living nestling songbirds: an experimental study. AB - Artificial light at night (ALAN), termed light pollution, is an increasingly important anthropogenic environmental pressure on wildlife. Exposure to unnatural lighting environments may have profound effects on animal physiology, particularly during early life. Here, we experimentally investigated for the first time the impact of ALAN on body mass and oxidative status during development, using nestlings of a free-living songbird, the great tit (Parus major), an important model species. Body mass and blood oxidative status were determined at baseline (=13 days after hatching) and again after a two night exposure to ALAN. Because it is very difficult to generalise the oxidative status from one or two measures we relied on a multi-biomarker approach. We determined multiple metrics of both antioxidant defences and oxidative damage: molecular antioxidants GSH, GSSG; antioxidant enzymes GPX, SOD, CAT; total non-enzymatic antioxidant capacity and damage markers protein carbonyls and TBARS. Light exposed nestlings showed no increase in body mass, in contrast to unexposed individuals. None of the metrics of oxidative status were affected. Nonetheless, our study provides experimental field evidence that ALAN may negatively affect free-living nestlings' development and hence may have adverse consequences lasting throughout adulthood. PMID- 27759089 TI - The ubiquitin conjugating enzyme, TaU4 regulates wheat defence against the phytopathogen Zymoseptoria tritici. AB - Mycosphaerella graminicola (Zymoseptoria tritici commonly known as Septoria), the causal agent of Septoria Leaf Blotch (STB), is considered one of the major threats to European wheat production. Previous studies have shown the importance of ubiquitination in plant defence against a multitude of pathogens. However the ubiquitination machinery in wheat is under studied, particularly E2 enzymes that have the ability to control the ubiquitination and thereby the fate of many different target proteins. In this study we identify an E2 enzyme, Triticum aestivum Ubiquitin conjugating enzyme 4 (TaU4) that functions in wheat defence against Septoria. We demonstrate TaU4 to be a bona fide E2 enzyme through an E2 charging assay. TaU4 localises in both the cytoplasm and nucleus, therefore potentially interacting with E3 ligases and substrate proteins in multiple compartments. Virus Induced Gene Silencing of TaU4 in wheat leaves resulted in delayed development of disease symptoms, reduced Septoria growth and reproduction. We conclude that TaU4 is a novel negative regulator of defence against Septoria. PMID- 27759090 TI - Comparative risk assessment of tobacco smoke constituents using the margin of exposure approach: the neglected contribution of nicotine. AB - Nicotine was not included in previous efforts to identify the most important toxicants of tobacco smoke. A health risk assessment of nicotine for smokers of cigarettes was conducted using the margin of exposure (MOE) approach and results were compared to literature MOEs of various other tobacco toxicants. The MOE is defined as ratio between toxicological threshold (benchmark dose) and estimated human intake. Dose-response modelling of human and animal data was used to derive the benchmark dose. The MOE was calculated using probabilistic Monte Carlo simulations for daily cigarette smokers. Benchmark dose values ranged from 0.004 mg/kg bodyweight for symptoms of intoxication in children to 3 mg/kg bodyweight for mortality in animals; MOEs ranged from below 1 up to 7.6 indicating a considerable consumer risk. The dimension of the MOEs is similar to those of other tobacco toxicants with high concerns relating to adverse health effects such as acrolein or formaldehyde. Owing to the lack of toxicological data in particular relating to cancer, long term animal testing studies for nicotine are urgently necessary. There is immediate need of action concerning the risk of nicotine also with regard to electronic cigarettes and smokeless tobacco. PMID- 27759091 TI - Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization. AB - Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent TPA was established to study the prophylactic effect of DADS. As a result, we observed that DADS dose-dependently attenuated skin tumor incidence and multiplicity in the model mice, which was related to the up regulation of a bunch of antioxidant enzymes activities and the nuclear accumulation of Nrf2. Furthermore, we developed skin carcinogenesis in Nrf2 knockout mice which could reverse the activity of DADS. Finally, we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2, which was critical for impairing the Keap1-mediated degradation of Nrf2. Based on the results, we concluded that DADS was a promising cancer chemoprevention agent and suggested a garlic-rich diet might be beneficial to reduce the cancer risk in our daily life. PMID- 27759092 TI - Activation of heat shock response to treat obese subjects with type 2 diabetes: a prospective, frequency-escalating, randomized, open-label, triple-arm trial. AB - Activation of heat shock response (HSR) improves accumulated visceral adiposity and metabolic abnormalities in type 2 diabetes. To identify the optimal intervention strategy of the activation of the HSR provided by mild electrical stimulation (MES) with heat shock (HS) in type 2 diabetes. This study was a prospective, frequency-escalating, randomized, open-label, triple-arm trial in Japan. A total of 60 obese type 2 diabetes patients were randomized into three groups receiving two, four, or seven treatments per week for 12 weeks. No adverse events were identified. MES + HS treatment (when all three groups were combined), significantly improved visceral adiposity, glycemic control, insulin resistance, systemic inflammation, renal function, hepatic steatosis and lipid profile compared to baseline. The reduction in HbA1c was significantly greater among those treated four times per week (-0.36%) or seven times per week (-0.65%) than among those treated two times per week (-0.10%). The relative HbA1c levels in seven times per week group was significantly decreased when adjusted by two times per week group (-0.55%. p = 0.001). This research provides the positive impact of MES + HS to treat obese patients with type 2 diabetes mellitus. PMID- 27759093 TI - Live-cell imaging of ER-PM contact architecture by a novel TIRFM approach reveals extension of junctions in response to store-operated Ca2+-entry. AB - Nanometer-spaced appositions between endoplasmic reticulum and plasma membrane (ER-PM junctions) stabilized by membrane-joining protein complexes are critically involved in cellular Ca2+-handling and lipid trafficking. ER-PM junctional architecture and plasticity associated with inter-membrane communication are as yet barely understood. Here, we introduce a method to precisely characterize ER PM junction morphology and dynamics with high temporal resolution and minimal disturbance of junctional intermembrane communication. We show that expression of soluble cytosolic fluorophores in combination with TIRFM enables to delineate ER and PM distance in the range of 10-150 nm. Live-cell imaging of sub-plasmalemmal structures in RBL-2H3 mast cells by this method, designated as fluorescence density mapping (FDM), revealed profound dynamics of ER-PM contact sites in response to store-depletion. We report the existence of a Ca2+-dependent process that expands the junctional ER to enlarge its contact surface with the PM, thereby promoting and stabilizing STIM1-Orai1 competent ER-PM junctions. PMID- 27759094 TI - Effectiveness evaluation of organized screening for esophageal cancer: a case control study in Linzhou city, China. AB - In China, esophageal cancer has remained a large burden, and endoscopic screening is expected to reduce esophageal cancer mortality. Therefore, a population-based case-control study was conducted to evaluate the effect of screening. Cases were defined as individuals who had died of esophageal cancer, and controls were residents from the same area (three per case) who had not died of esophageal cancer, matched by gender and birth year. The exposure status (whether cases and controls had ever attended the screening or not) was acquired by inspecting the well documented screening records. A conditional logistic regression model was used to estimate the odds ratios (OR) and their 95% confidence intervals (95% CI). There were 253 cases and 759 controls. The reduction in risk of esophageal cancer mortality in individuals who had ever attended screening was 47% (OR: 0.53, 95% CI: 0.37-0.77). Compared with never-screened subjects, the ORs for screened subjects within 36 and 48 months before the reference date were 0.59(0.39-0.89) and 0.59(0.40-0.87); the ORs for 50-59 year old subjects were 0.48(0.28-0.85). The results suggest a 47% reduction in esophageal cancer mortality risk due to endoscopic screening, which may have significant implications for esophageal cancer screening in China, especially in rural areas. PMID- 27759095 TI - Biologically responsive carrier-mediated anti-angiogenesis shRNA delivery for tumor treatment. AB - Small interfering RNA (siRNA) has increased the hope for highly-efficient treatment of gene-related diseases. However, the stable and efficient delivery of therapeutic nucleic acids is a prerequisite for the successful clinical translation of RNA interfering therapy. To achieve this, we condensed the low molecular weight polyethyleneimine (PEI, Mw < 2000) with 2,6 pyridinedicarboxaldehyde (PDA) to synthesize a biologically responsive and degradable cationic polymer (abbreviated to PDAPEI) which was utilized as a gene vector for the delivery of a VEGF-A shRNA expression plasmid DNA (pDNA). The resulting electrostatic interaction between PDAPEI and pDNA led to the self assembly of nanoscale polyplexes with suitable particle size and stable zeta potential. The PDAPEI/pDNA polyplexes demonstrated an outstanding gene transfection and silencing efficiency at 30 w/w ratio, as well as negligible cytotoxicity. Also, the designed polymer showed no stimulation to the innate immune system. Moreover, compared with PEI 25 KDa, the polyplexes accomplished comparatively better anti-angiogenesis efficacy, which resulted in the inhibition of tumor growth in subcutaneous tumor mice models. In conclusion, PDAPEI has great potential to be a gene delivery vector for cancer therapy. PMID- 27759096 TI - Core Amino Acid Residues in the Morphology-Regulating Protein, Mms6, for Intracellular Magnetite Biomineralization. AB - Living organisms produce finely tuned biomineral architectures with the aid of biomineral-associated proteins. The functional amino acid residues in these proteins have been previously identified using in vitro and in silico experimentation in different biomineralization systems. However, the investigation in living organisms is limited owing to the difficulty in establishing appropriate genetic techniques. Mms6 protein, isolated from the surface of magnetite crystals synthesized in magnetotactic bacteria, was shown to play a key role in the regulation of crystal morphology. In this study, we have demonstrated a defect in the specific region or substituted acidic amino acid residues in the Mms6 protein for observing their effect on magnetite biomineralization in vivo. Analysis of the gene deletion mutants and transformants of Magnetospirillum magneticum AMB-1 expressing partially truncated Mms6 protein revealed that deletions in the N-terminal or C-terminal regions disrupted proper protein localization to the magnetite surface, resulting in a change in the crystal morphology. Moreover, single amino acid substitutions at Asp123, Glu124, or Glu125 in the C-terminal region of Mms6 clearly indicated that these amino acid residues had a direct impact on magnetite crystal morphology. Thus, these consecutive acidic amino acid residues were found to be core residues regulating magnetite crystal morphology. PMID- 27759097 TI - Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid. AB - The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD+. The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD+ and the product all-trans retinoic acid (REA). The tetrameric ALDH1A3 folds into a three domain-based architecture highly conserved along the ALDHs family. The structural analysis revealed two different and coupled conformations for NAD+ and REA that we propose to represent two snapshots along the catalytic cycle. Indeed, the isoprenic moiety of REA points either toward the active site cysteine, or moves away adopting the product release conformation. Although ALDH1A3 shares high sequence identity with other members of the ALDH1A family, our structural analysis revealed few peculiar residues in the 1A3 isozyme active site. Our data provide information into the ALDH1As catalytic process and can be used for the structure-based design of selective inhibitors of potential medical interest. PMID- 27759099 TI - Study on spin and optical polarization in a coupled InGaN/GaN quantum well and quantum dots structure. AB - The spin and optical polarization based on a coupled InGaN/GaN quantum well (QW) and quantum dots (QDs) structure is investigated. In this structure, spin electrons can be temporarily stored in QW, and spin injection from the QW into QDs via spin-conserved tunneling is enabled. Spin relaxation can be suppressed owing to the small energy difference between the initial state in the QW and the final states in the QDs. Photoluminescence (PL) and time-resolved photoluminescence (TRPL) measurements are carried out on optical spin-injection and -detection. Owing to the coupled structure, spin-conserved tunneling mechanism plays a significant role in preventing spin relaxation process. As a result, a higher circular polarization degree (CPD) (~49.1%) is achieved compared with conventional single layer of QDs structure. Moreover, spin relaxation time is also extended to about 2.43 ns due to the weaker state-filling effect. This coupled structure is believed an appropriate candidate for realization of spin polarized light source. PMID- 27759098 TI - Spatial Dependence of DNA Damage in Bacteria due to Low-Temperature Plasma Application as Assessed at the Single Cell Level. AB - Low temperature plasmas (LTPs) generate a cocktail of reactive nitrogen and oxygen species (RNOS) with bactericidal activity. The RNOS however are spatially unevenly distributed in the plasma. Here we test the hypothesis that this distribution will affect the mechanisms underpinning plasma bactericidal activity focussing on the level of DNA damage in situ. For the first time, a quantitative, single cell approach was applied to assess the level of DNA damage in bacteria as a function of the radial distance from the centre of the plasma jet. Salmonella enterica on a solid, dry surface was treated with two types of LTP: an atmospheric-pressure dielectric barrier discharge plasma jet (charged and neutral species) and a radio-frequency atmospheric-pressure plasma jet (neutral species). In both cases, there was an inverse correlation between the degree of DNA damage and the radial distance from the centre of the plasma, with the highest DNA damage occurring directly under the plasma. This trend was also observed with Staphylococcus aureus. LTP-generated UV radiation was eliminated as a contributing factor. Thus valuable mechanistic information can be obtained from assays on biological material, which can inform the development of LTP as a complementary or alternative therapy for (topical) bacterial infections. PMID- 27759101 TI - Genome-wide profiling of the human papillomavirus DNA integration in cervical intraepithelial neoplasia and normal cervical epithelium by HPV capture technology. AB - HPV integration plays an important role in cervical carcinogenesis. HPV genotypes and the exact integration sites were investigated using HPV capture technology combined with next generation sequencing in 166 women. Three, one and six integration sites were verified in 7 HPV-positive 'normal cervical epithelium', 6 HPV-positive CIN2 and 15 HPV-positive CIN 3 samples, respectively. Of the 10 integrations, one and nine were involved with HPV33 and HPV16, respectively. Our study accurately evaluated HPV integration level in CINs and normal cervical tissues using high-throughput viral integration detection method providing basic evidence for HPV integration-driven cervical carcinogenesis. PMID- 27759100 TI - The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons. AB - SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses. Accordingly, we find that spinal cord glycine levels are significantly reduced in Slc7a10-null mice and spontaneous glycinergic postsynaptic currents in motor neurons show substantially diminished amplitudes, demonstrating an essential role for SLC7A10 in glycinergic inhibitory function in the central nervous system. These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively. PMID- 27759102 TI - Communities as cliques. AB - High-diversity species assemblages are very common in nature, and yet the factors allowing for the maintenance of biodiversity remain obscure. The competitive exclusion principle and May's complexity-diversity puzzle both suggest that a community can support only a small number of species, turning the spotlight on the dynamics of local patches or islands, where stable and uninvadable (SU) subsets of species play a crucial role. Here we map the question of the number of different possible SUs a community can support to the geometric problem of finding maximal cliques of the corresponding graph. This enables us to solve for the number of SUs as a function of the species richness in the regional pool, N, showing that the growth of this number is subexponential in N, contrary to long standing wisdom. To understand the dynamics under noise we examine the relaxation time to an SU. Symmetric systems relax rapidly, whereas in asymmetric systems the relaxation time grows much faster with N, suggesting an excitable dynamics under noise. PMID- 27759103 TI - Caudal migration and proliferation of renal progenitors regulates early nephron segment size in zebrafish. AB - The nephron is the functional unit of the kidney and is divided into distinct proximal and distal segments. The factors determining nephron segment size are not fully understood. In zebrafish, the embryonic kidney has long been thought to differentiate in situ into two proximal tubule segments and two distal tubule segments (distal early; DE, and distal late; DL) with little involvement of cell movement. Here, we overturn this notion by performing lineage-labelling experiments that reveal extensive caudal movement of the proximal and DE segments and a concomitant compaction of the DL segment as it fuses with the cloaca. Laser mediated severing of the tubule, such that the DE and DL are disconnected or that the DL and cloaca do not fuse, results in a reduction in tubule cell proliferation and significantly shortens the DE segment while the caudal movement of the DL is unaffected. These results suggest that the DL mechanically pulls the more proximal segments, thereby driving both their caudal extension and their proliferation. Together, these data provide new insights into early nephron morphogenesis and demonstrate the importance of cell movement and proliferation in determining initial nephron segment size. PMID- 27759104 TI - Single and Transient Ca2+ Peaks in Podocytes do not induce Changes in Glomerular Filtration and Perfusion. AB - Chronic alterations in calcium (Ca2+) signalling in podocytes have been shown to cause proteinuria and progressive glomerular diseases. However, it is unclear whether short Ca2+ peaks influence glomerular biology and cause podocyte injury. Here we generated a DREADD (Designer Receptor Exclusively Activated by a Designer Drug) knock-in mouse line to manipulate intracellular Ca2+ levels. By mating to a podocyte-specific Cre driver we are able to investigate the impact of Ca2+ peaks on podocyte biology in living animals. Activation of the engineered G-protein coupled receptor with the synthetic compound clozapine-N-oxide (CNO) evoked a short and transient Ca2+ peak in podocytes immediately after CNO administration in vivo. Interestingly, this Ca2+ peak did neither affect glomerular perfusion nor filtration in the animals. Moreover, no obvious alterations in the glomerular morphology could be observed. Taken together, these in vivo findings suggest that chronic alterations and calcium overload rather than an induction of transient Ca2+ peaks contribute to podocyte disease. PMID- 27759105 TI - Nondestructive, real-time determination and visualization of cellulose, hemicellulose and lignin by luminescent oligothiophenes. AB - Enabling technologies for efficient use of the bio-based feedstock are crucial to the replacement of oil-based products. We investigated the feasibility of luminescent conjugated oligothiophenes (LCOs) for non-destructive, rapid detection and quality assessment of lignocellulosic components in complex biomass matrices. A cationic pentameric oligothiophene denoted p-HTEA (pentamer hydrogen thiophene ethyl amine) showed unique binding affinities to cellulose, lignin, hemicelluloses, and cellulose nanofibrils in crystal, liquid and paper form. We exploited this finding using spectrofluorometric methods and fluorescence confocal laser scanning microscopy, for sensitive, simultaneous determination of the structural and compositional complexities of native lignocellulosic biomass. With exceptional photostability, p-HTEA is also demonstrated as a dynamic sensor for real-time monitoring of enzymatic cellulose degradation in cellulolysis. These results demonstrate the use of p-HTEA as a non-destructive tool for the determination of cellulose, hemicellulose and lignin in complex biomass matrices, thereby aiding in the optimization of biomass-converting technologies. PMID- 27759106 TI - Increased human occupation and agricultural development accelerates the population contraction of an estuarine delphinid. AB - Over the past few thousand years, human development and population expansion in southern China have led to local extirpation and population contraction of many terrestrial animals. At what extent this early human-induced environmental change has also affected coastal marine species remains poorly known. We investigated the demographic history of the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Delta (PRD); an obligatory inshore species known for its susceptibility to anthropogenic impacts in one of China's most developed coastal regions. Although the deltaic evolution of PRD has been influenced by climate since the Holocene, ~74% reduction of the dolphin's effective population size occurred within the last 2000 years, consistent with ~61% habitat contraction during this period. This considerable and recent population contraction may have been due to land use practices and deforestation in the upper/middle Pearl River region, all leading to increasing sedimentation rate in the estuarine area. As anthropogenic impacts within the drainage of Pearl River affected a vast area, coastal dolphins and large terrestrial mammals in southern China may share a similar demographic history, whilst the demographic and biogeographic history of the PRD humpback dolphins may be symptomatic of similar processes that this species may have undergone elsewhere in the region. PMID- 27759107 TI - Charge Distribution Dependent Spectral Analysis of the Oxidized Diferrocenyl Oligothienylene-Vinylene Molecular Wires. AB - The vibrational spectra have been investigated for revealing the comprehensive structure of diferrocenyl-oligothienylene-vinylene complex, stimulated by the excellent experimental reports [group of Casado J. Am. Chem. Soc. 2012, 134, 12, 5675]. The IR and Raman spectra were simulated. It is found that the change of charge distribution and bond length are associated with the variation in the frequencies of specific vibration in infrared spectra for the neutral and radical oxidation states. The theoretical simulation of charge difference density indicate that charge transfer mechanism for neutral and dication states are significant different. The results can offer hints for the rational design of novel and interesting oligomer semiconductor. PMID- 27759108 TI - An artificial photosynthesis anode electrode composed of a nanoparticulate photocatalyst film in a visible light responsive GaN-ZnO solid solution system. AB - The artificial photosynthesis technology known as the Honda-Fujishima effect, which produces oxygen and hydrogen or organic energy from sunlight, water, and carbon dioxide, is an effective energy and environmental technology. The key component for the higher efficiency of this reaction system is the anode electrode, generally composed of a photocatalyst formed on a glass substrate from electrically conductive fluorine-doped tin oxide (FTO). To obtain a highly efficient electrode, a dense film composed of a nanoparticulate visible light responsive photocatalyst that usually has a complicated multi-element composition needs to be deposited and adhered onto the FTO. In this study, we discovered a method for controlling the electronic structure of a film by controlling the aerosol-type nanoparticle deposition (NPD) condition and thereby forming films of materials with a band gap smaller than that of the prepared raw material powder, and we succeeded in extracting a higher current from the anode electrode. As a result, we confirmed that a current approximately 100 times larger than those produced by conventional processes could be obtained using the same material. This effect can be expected not only from the materials discussed (GaN-ZnO) in this paper but also from any photocatalyst, particularly materials of solid solution compositions. PMID- 27759109 TI - Effect of solidification rate on microstructure evolution in dual phase microalloyed steel. AB - In steels the dependence of ambient temperature microstructure and mechanical properties on solidification rate is not well reported. In this work we investigate the microstructure and hardness evolution for a low C low Mn NbTi microalloyed steel solidified in the cooling rate range of 1-50 Cs-1. The maximum strength was obtained at the intermediate solidification rate of 30 Cs-1. This result has been correlated to the microstructure variation with solidification rate. PMID- 27759112 TI - Plant functional trait diversity regulates the nonlinear response of productivity to regional climate change in Tibetan alpine grasslands. AB - The biodiversity-productivity relationship is still under debate for alpine grasslands on the Tibetan Plateau. We know little about direct and indirect effects of biotic and abiotic drivers on this relationship, especially in regard to plant functional trait diversity. Here, we examine how aboveground net primary productivity (ANPP) and precipitation use efficiency (PUE) respond to climate, soil and community structure across alpine grasslands on the Northern Tibetan Plateau. We found that both ANPP and PUE showed nonlinear patterns along water availability and site altitude variation, which together accounted for 80.3% and 68.8% of variation in ANPP and PUE, respectively, by optimal generalized additive models. Functional trait divergence (FTD) and community weighted mean (CWM) of plant functional traits were as important as plant species diversity (PSD) for explaining the nonlinear productivity-climate relationship. These findings were confirmed by results from principal component analyses and structural equation models. We also found that FTD was negatively correlated with PSD across different alpine grasslands. Our results implicate: first, the combinatorial influences of temperature and precipitation gradients are important for predicting alpine grassland dynamics; second, the convergence and divergence of plant functional traits may have the potential to elucidate the effect of plant diversity on ecosystem functionality. PMID- 27759111 TI - Network Meta-Analysis of the Efficacy of Acupuncture, Alpha-blockers and Antibiotics on Chronic Prostatitis/Chronic Pelvic Pain Syndrome. AB - Alpha-blockers and antibiotics are most commonly used to treat chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in clinical practice. Currently, increasing evidence also suggests acupuncture as an effective strategy. This network meta-analysis intended to assess the comparative efficacy and safety of acupuncture, alpha-blockers and antibiotics for CP/CPPS. Twelve trials involving 1203 participants were included. Based on decreases in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score, a network meta-analysis indicated that electro-acupuncture (standard mean difference [SMD]: 4.29; 95% credible interval [CrI], 1.96-6.65), acupuncture (SMD: 3.69; 95% CrI, 0.27-7.17), alpha-blockers (SMD: 1.85; 95% CrI, 1.07-2.64), antibiotics (SMD: 2.66; 95% CrI, 1.57-3.76), and dual therapy (SMD: 3.20; 95% CrI, 1.95-4.42) are superior to placebo in decreasing this score. Additionally, electro-acupuncture (SMD: 2.44; 95% CrI, 0.08-4.83) and dual therapy (SMD: 1.35; 95% CrI, 0.07-2.62) were more effective than alpha-blockers in decreasing the total NIH-CPSI total score. Other network meta-analyses did not show significant differences between interventions other placebo. The incidence of adverse events of acupuncture was relatively rare (5.4%) compared with placebo (17.1%), alpha blockers (24.9%), antibiotics (31%) and dual therapy (48.6%). Overall, rank tests and safety analyses indicate that electro-acupuncture/acupuncture may be recommended for the treatment of CP/CPPS. PMID- 27759110 TI - Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA) binds human erythrocytes independent of Duffy antigen status. AB - Plasmodium vivax, a major agent of malaria in both temperate and tropical climates, has been thought to be unable to infect humans lacking the Duffy (Fy) blood group antigen because this receptor is critical for erythrocyte invasion. Recent surveys in various endemic regions, however, have reported P. vivax infections in Duffy-negative individuals, suggesting that the parasite may utilize alternative receptor-ligand pairs to complete the erythrocyte invasion. Here, we identified and characterized a novel parasite ligand, Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA), that bound human erythrocytes regardless of Duffy antigen status. PvGAMA was localized at the microneme in the mature schizont-stage parasites. The antibodies against PvGAMA fragments inhibited PvGAMA binding to erythrocytes in a dose-dependent manner. The erythrocyte-specific binding activities of PvGAMA were significantly reduced by chymotrypsin treatment. Thus, PvGAMA may be an adhesion molecule for the invasion of Duffy-positive and -negative human erythrocytes. PMID- 27759113 TI - Historical dimensions of population structure in a continuously distributed marine species: The case of the endemic Chilean dolphin. AB - The complementarity of historical and contemporary processes contributes to understanding the genetic structure of continuously distributed marine species with high dispersal capabilities. Cephalorhynchus eutropia, has a continuous coastal distribution with strong genetic differentiation identified by nuclear DNA markers. We explored the historical dimension of this genetic differentiation between northern and southern populations to evaluate phylogeographic structure. Additionally, we conducted mtDNA and microsatellite analyses to detect past and recent demographic changes. The southern population was characterized by lower genetic diversity with a signal of population expansion, likely associated with ice retreat and habitat extension after the Last Glacial Maximum (LGM). In contrast, structure within the northern population was more consistent with stable historical population size. Approximate Bayesian Computation analyses suggested that during the LGM, C. eutropia persisted in the northern area; while the south was colonized by dispersal ~11,000 years ago followed by population expansion. This study shows that Chilean dolphin population structure is consistent with predictions from the Expansion-Contraction biogeographic model, with a poleward post-glacial shift revealed in current genetic structure. The results also confirm the validity of the population units previously identified, demonstrating their historical origin and highlighting the utility of integrating genetic markers with different temporal scale resolutions. PMID- 27759114 TI - A combined method for correlative 3D imaging of biological samples from macro to nano scale. AB - Correlative analysis requires examination of a specimen from macro to nano scale as well as applicability of analytical methods ranging from morphological to molecular. Accomplishing this with one and the same sample is laborious at best, due to deformation and biodegradation during measurements or intermediary preparation steps. Furthermore, data alignment using differing imaging techniques turns out to be a complex task, which considerably complicates the interconnection of results. We present correlative imaging of the accessory rat lung lobe by combining a modified Scanning Laser Optical Tomography (SLOT) setup with a specially developed sample preparation method (CRISTAL). CRISTAL is a resin-based embedding method that optically clears the specimen while allowing sectioning and preventing degradation. We applied and correlated SLOT with Multi Photon Microscopy, histological and immunofluorescence analysis as well as Transmission Electron Microscopy, all in the same sample. Thus, combining CRISTAL with SLOT enables the correlative utilization of a vast variety of imaging techniques. PMID- 27759115 TI - Kinetics of ventilation-induced changes in diaphragmatic metabolism by bilateral phrenic pacing in a piglet model. AB - Perioperative necessity of deep sedation is inevitably associated with diaphragmatic inactivation. This study investigated 1) the feasibility of a new phrenic nerve stimulation method allowing early diaphragmatic activation even in deep sedation and, 2) metabolic changes within the diaphragm during mechanical ventilation compared to artificial activity. 12 piglets were separated into 2 groups. One group was mechanically ventilated for 12 hrs (CMV) and in the second group both phrenic nerves were stimulated via pacer wires inserted near the phrenic nerves to mimic spontaneous breathing (STIM). Lactate, pyruvate and glucose levels were measured continuously using microdialysis. Oxygen delivery and blood gases were measured during both conditions. Diaphragmatic stimulation generated sufficient tidal volumes in all STIM animals. Diaphragm lactate release increased in CMV transiently whereas in STIM lactate dropped during this same time point (2.6 vs. 0.9 mmol L-1 after 5:20 hrs; p < 0.001). CMV increased diaphragmatic pyruvate (40 vs. 146 MUmol L-1 after 5:20 hrs between CMV and STIM; p < 0.0001), but not the lactate/pyruvate ratio. Diaphragmatic stimulation via regular electrodes is feasible to generate sufficient ventilation, even in deep sedation. Mechanical ventilation alters the metabolic state of the diaphragm, which might be one pathophysiologic origin of ventilator-induced diaphragmatic dysfunction. Occurrence of hypoxia was unlikely. PMID- 27759116 TI - Stability and its mechanism in Ag/CoOx/Ag interface-type resistive switching device. AB - Stability is an important issue for the application of resistive switching (RS) devices. In this work, the endurance and retention properties of Ag/CoOx/Ag interface-type RS device were investigated. This device exhibits rectifying I-V curve, multilevel storage states and retention decay behavior, which are all related to the Schottky barrier at the interface. The device can switch for thousands of cycles without endurance failure and shows narrow resistance distributions with relatively low fluctuation. However, both the high and low resistance states spontaneously decay to an intermediate resistance state during the retention test. This retention decay phenomenon is due to the short lifetime tau (tau = 0.5 s) of the metastable pinning effect caused by the interface states. The data analysis indicated that the pinning effect is dependent on the depth and density of the interface state energy levels, which determine the retention stability and the switching ratio, respectively. This suggests that an appropriate interface structure can improve the stability of the interface-type RS device. PMID- 27759117 TI - Octopamine controls starvation resistance, life span and metabolic traits in Drosophila. AB - The monoamines octopamine (OA) and tyramine (TA) modulate numerous behaviours and physiological processes in invertebrates. Nevertheless, it is not clear whether these invertebrate counterparts of norepinephrine are important regulators of metabolic and life history traits. We show that flies (Drosophila melanogaster) lacking OA are more resistant to starvation, while their overall life span is substantially reduced compared with control flies. In addition, these animals have increased body fat deposits, reduced physical activity and a reduced metabolic resting rate. Increasing the release of OA from internal stores induced the opposite effects. Flies devoid of both OA and TA had normal body fat and metabolic rates, suggesting that OA and TA act antagonistically. Moreover, OA deficient flies show increased insulin release rates. We inferred that the OA mediated control of insulin release accounts for a substantial proportion of the alterations observed in these flies. Apparently, OA levels control the balance between thrifty and expenditure metabolic modes. Thus, changes in OA levels in response to external and internal signals orchestrate behaviour and metabolic processes to meet physiological needs. Moreover, chronic deregulation of the corresponding signalling systems in humans may be associated with metabolic disorders, such as obesity or diabetes. PMID- 27759120 TI - Redox interactions of Au(iii) with carboxylated dithiafulvenes and tetrathiafulvalene analogues in polar organic media. AB - The redox interactions between HAuCl4 and a series of pi-conjugated organic donors, namely carboxylated dithiafulvenes and tetrathiafulvalene vinylogues, were investigated. Interestingly, the dithiafulvene derivative with two carboxylic groups showed the ability to directly induce the formation of Au(0) nanoparticles in dipolar aprotic solvents such as DMF and DMSO. PMID- 27759118 TI - Factor XIII-A transglutaminase deficient mice show signs of metabolically healthy obesity on high fat diet. AB - F13A1 gene, which encodes for Factor XIII-A blood clotting factor and a transglutaminase enzyme, was recently identified as a potential causative gene for obesity in humans. In our previous in vitro work, we showed that FXIII-A regulates preadipocyte differentiation and modulates insulin signaling via promoting plasma fibronectin assembly into the extracellular matrix. To understand the role of FXIII-A in whole body energy metabolism, here we have characterized the metabolic phenotype of F13a1-/- mice. F13a1-/- and F13a1+/+ type mice were fed chow or obesogenic, high fat diet for 20 weeks. Weight gain, total fat mass and fat pad mass, glucose handling, insulin sensitivity, energy expenditure and, morphological and biochemical analysis of adipose tissue was performed. We show that mice lacking FXIII-A gain weight on obesogenic diet, similarly as wild type mice, but exhibit a number of features of metabolically healthy obesity such as protection from developing diet-induced insulin resistance and hyperinsulinemia. Mice also show normal fasting glucose levels, larger adipocytes, decreased extracellular matrix accumulation and inflammation of adipose tissue, as well as decreased circulating triglycerides. This study reveals that FXIII-A transglutaminase can regulate whole body insulin sensitivity and may have a role in the development of diet-induced metabolic disturbances. PMID- 27759119 TI - Enzymatic diversity of the Clostridium thermocellum cellulosome is crucial for the degradation of crystalline cellulose and plant biomass. AB - The cellulosome is a supramolecular multienzyme complex comprised of a wide variety of polysaccharide-degrading enzymes and scaffold proteins. The cellulosomal enzymes that bind to the scaffold proteins synergistically degrade crystalline cellulose. Here, we report in vitro reconstitution of the Clostridium thermocellum cellulosome from 40 cellulosomal components and the full-length scaffoldin protein that binds to nine enzyme molecules. These components were each synthesized using a wheat germ cell-free protein synthesis system and purified. Cellulosome complexes were reconstituted from 3, 12, 30, and 40 components based on their contents in the native cellulosome. The activity of the enzyme-saturated complex indicated that greater enzymatic variety generated more synergy for the degradation of crystalline cellulose and delignified rice straw. Surprisingly, a less complete enzyme complex displaying fewer than nine enzyme molecules was more efficient for the degradation of delignified rice straw than the enzyme-saturated complex, despite the fact that the enzyme-saturated complex exhibited maximum synergy for the degradation of crystalline cellulose. These results suggest that greater enzymatic diversity of the cellulosome is crucial for the degradation of crystalline cellulose and plant biomass, and that efficient degradation of different substrates by the cellulosome requires not only a different enzymatic composition, but also different cellulosome structures. PMID- 27759121 TI - Robust and accurate prediction of protein self-interactions from amino acids sequence using evolutionary information. AB - Self-interacting proteins (SIPs) play an essential role in cellular functions and the evolution of protein interaction networks (PINs). Due to the limitations of experimental self-interaction proteins detection technology, it is a very important task to develop a robust and accurate computational approach for SIPs prediction. In this study, we propose a novel computational method for predicting SIPs from protein amino acids sequence. Firstly, a novel feature representation scheme based on Local Binary Pattern (LBP) is developed, in which the evolutionary information, in the form of multiple sequence alignments, is taken into account. Then, by employing the Relevance Vector Machine (RVM) classifier, the performance of our proposed method is evaluated on yeast and human datasets using a five-fold cross-validation test. The experimental results show that the proposed method can achieve high accuracies of 94.82% and 97.28% on yeast and human datasets, respectively. For further assessing the performance of our method, we compared it with the state-of-the-art Support Vector Machine (SVM) classifier, and other existing methods, on the same datasets. Comparison results demonstrate that the proposed method is very promising and could provide a cost effective alternative for predicting SIPs. In addition, to facilitate extensive studies for future proteomics research, a web server is freely available for academic use at . PMID- 27759122 TI - Formation of lamellar micelle-like oligomers and membrane disruption revealed by the study of short peptide hIAPP18-27. AB - Prefibrillar amyloid aggregates of proteins are known as cytotoxic species and a common pathogenic factor for many degenerative diseases. The mechanism underlying the formation and cytotoxicity of prefibrillar aggregates is believed to be independent of the actual nature of the amyloid protein. In this study, we monitored the formation of the peptide oligomers and examined the disruptive effects of the oligomers on liposomes using the human islet amyloid polypeptide fragment hIAPP18-27 as a model peptide. We observed various morphologies of oligomers formed at different aggregation stages that precede the formation of mature amyloid fibrils. These oligomer species were sufficiently stable to maintain their structures and properties under acidic conditions. We presented the first evidence that an oligomer species with a lamellar crystalline structure and a size of about 20-60 nm in length, 8 nm in width and 1.5 nm in thickness was the most disruptive to the membrane containing the anionic component and toxic to the INS-1 cells. Our results showed that short peptides, in light of their slower fibrillation, could be used as a model system in the study of the toxic mechanism of misfolding oligomers of amyloid peptides. PMID- 27759123 TI - The catalytic effect of TiO2 nanosheets on extracellular electron transfer of Shewanella loihica PV-4. AB - Electron transfer kinetics of Shewanella loihica PV-4 at the up-growing TiO2 nanosheet (TiO2-NS) modified carbon paper (CP) electrode was investigated. The effect of TiO2-NSs, which speeds up the interfacial electron transfer of outer membrane c-type cytochromes (OMCs), was revealed for the first time. TiO2-NSs with a polar surface modified hydrophobic CP into super-hydrophilic TiO2-NS/CP. The favorable interaction between PV-4 and TiO2-NSs not only enhanced microbial adhesion, but also altered the redox nature of OMCs. The mid-point potential of OMCs at TiO2-NS/CP was shifted to a more negative potential, indicating a higher thermodynamic driving force for the protein to release electrons. Moreover, electron transfer from OMCs to TiO2-NSs was also benefited from the positive shift of flat-band potential Vfb owing to reduced pH at the electrode/microorganism interface, as well as good electrical conductivity of TiO2-NSs. As a result, the electron transfer rate constant ket of OMCs at the TiO2-NS/CP anode was about three times faster than that at the CP anode. The accelerated electron transfer kinetics as well as 15% increase of biomass together accounted for a 97% increase of the maximum output power density in the MFC. The result expanded our knowledge about the role of a designed TiO2 nanostructure in microbial electron transfer that can be applied in other bio electrochemical systems. PMID- 27759124 TI - An unusual deprotonation trend in 2-(2'-hydroxyphenyl)pyridoimidazoles. AB - The anion sensitivity and the deprotonation nature of the nitrogenous analogues of 2-(2'-hydroxyphenyl)benzimidazole (HPBI) are investigated in a polar aprotic medium. It is observed that the substitution of pyridyl nitrogen enhances the anion sensitivity. However, despite the enhanced sensitivity of the nitrogenous analogues the deprotonation of these molecules in the presence of strong anions is less favored as compared to HPBI. This anomalous trend observed for the nitrogenous analogs is discussed and explained using theoretical calculations and experimental findings. It is also found that the sensitivity towards anions and the formation of anions also depend on the position of the pyridyl nitrogen. PMID- 27759125 TI - Dynamics of self-propelled filaments pushing a load. AB - Worm-like filaments, which are propelled by a tangential homogeneous force along their contour, are studied as they push loads of different shapes and sizes. The resulting dynamics is investigated using Langevin dynamics simulations. The effects of size and shape of the load, propulsion strength, and thermal noise are systematically explored. The propulsive force and hydrodynamic friction of the load cause a compression in the filament that results in a buckling instability and versatile motion. Distinct regimes of elongated filaments, curved filaments, beating filaments, and filaments with alternating beating and circular motion are identified, and a phase diagram depending on the propulsion strength and the size of the load is constructed. Characteristic features of the different phases, such as beating frequencies and rotational velocities, are demonstrated to have a power-law dependence on the propulsive force. PMID- 27759126 TI - Short protecting-group-free synthesis of 5-acetylsulfanyl-histidines in water: novel precursors of 5-sulfanyl-histidine and its analogues. AB - The discovery of a non-enzymatic oxidative introduction of sulfur to the 5 position of histidine is reported, by activation with bromine or NBS followed by reaction with thioacetic acid forming novel 5-acetylsulfanyl-histidine. Complementing the previously developed regioselective oxidative S-introduction to the 2-position of histidine by reaction with cysteine, this surprising finding provides straightforward access in multi-gram quantities to naturally occurring 5 sulfanyl-histidine and its N-methylated analogues, including a hitherto unknown regioisomer of l-ergothioneine. PMID- 27759127 TI - Evolutionary design of interfacial phase change van der Waals heterostructures. AB - We use an evolutionary algorithm to explore the design space of hexagonal Ge2Sb2Te5; a van der Waals layered two dimensional crystal heterostructure. The Ge2Sb2Te5 structure is more complicated than previously thought. Predominant features include layers of Ge3Sb2Te6 and Ge1Sb2Te4 two dimensional crystals that interact through Te-Te van der Waals bonds. Interestingly, (Ge/Sb)-Te-(Ge/Sb)-Te alternation is a common feature for the most stable structures of each generation's evolution. This emergent rule provides an important structural motif that must be included in the design of high performance Sb2Te3-GeTe van der Waals heterostructure superlattices with interfacial atomic switching capability. The structures predicted by the algorithm agree well with experimental measurements on highly oriented, and single crystal Ge2Sb2Te5 samples. By analysing the evolutionary algorithm optimised structures, we show that diffusive atomic switching is probable by Ge atoms undergoing a transition at the van der Waals interface from layers of Ge3Sb2Te6 to Ge1Sb2Te4 thus producing two blocks of Ge2Sb2Te5. Evolutionary methods present an efficient approach to explore the enormous multi-dimensional design parameter space of van der Waals bonded heterostructure superlattices. PMID- 27759129 TI - Chemoselective reduction of quinols as an alternative to Sonogashira coupling: synthesis of polysubstituted benzofurans. AB - An efficient synthetic approach to polysubstituted benzofurans is described, using 2-methoxyquinone as a benzofuran backbone. Nucleophilic addition of terminal alkynes to 2-methoxy-1,4-benzoquinone afforded the corresponding quinols containing an alkyne unit, which were converted to phenols via mild Zn-mediated reduction. After proper protection of the free phenolic OH, 5-endo-dig iodocyclization allowed facile access to a number of 3-iodobenzofurans. In addition, it was demonstrated for the first time that o-methoxyarylalkynes underwent intramolecular hydroalkoxylation under the influence of AgOTf furnishing the corresponding benzofurans. PMID- 27759128 TI - Dynamics of the conformational transitions during the dimerization of an intrinsically disordered peptide: a case study on the human islet amyloid polypeptide fragment. AB - Amyloid deposits of human islet amyloid polypeptide (hIAPP) are identified in 95% of type II diabetes patients. The oligomers during the early stage of hIAPP aggregation are believed to be more cytotoxic than the mature fibrils. However, the structural details during the initial stage of hIAPP aggregation are still under debate experimentally. To understand its initial nucleation mechanism, we investigate the thermodynamics and kinetics of hIAPP(11-25) dimerization, which is the first manifestation of the interplay between intra- and inter-molecular interactions, via the construction of Markov state models from extensive molecular dynamics simulations. We identified a largely populated metastable dimer state with the antiparallel cross-beta structure, although tangled coil states are also observed. The dimerization process consists of two stages kinetically: the initial collision of separate monomers followed by structural rearrangements. During the collapsing stage, hydrophobic interactions are the main driving force, although electrostatic interactions also play a role. In the subsequent structural rearrangement step, there exist heterogeneous pathways from the initial collapsed complexes to the antiparallel cross-beta structure, with the transition time-scales around hundreds of microseconds. Our replica-exchange molecular dynamics simulations demonstrate that this antiparallel cross-beta state is negligible in the dimer ensemble of the fibril-free S20P mutant, indicating that it is an on-pathway intermediate for hIAPP(11-25) fibrillation. These results, together with those from our previous study of the monomer, prompt us to propose a generalized model with the combination of the induced-fit and conformational-selection mechanisms for this dimerization process. These findings shed light on the understanding of hIAPP(11-25) aggregation mechanisms. PMID- 27759130 TI - Geminal difunctionalization of alpha-diazo arylmethylphosphonates: synthesis of fluorinated phosphonates. AB - A general approach towards diverse fluorinated phosphonates via geminal difunctionalization reactions of alpha-diazo arylmethylphosphonates is described. The diazo functionality (RR'C[double bond, length as m-dash]N2) is successfully converted to RR'CF2, RR'CHF, RR'CFBr or RR'CFNR''2 groups by employing different fluorination reagents. A variety of fluorinated organophosphorus compounds were readily accessed in good to excellent yields from a common type of precursor. PMID- 27759131 TI - Pyranonaphthoquinones - isolation, biology and synthesis: an update. AB - Covering: 2008 to 2015. A review on the isolation, biological activity and synthesis of pyranonaphthoquinone natural products from 2008-2015 is providedThis review discusses the isolation, biological activity and synthesis of pyranonaphthoquinone natural products, covering the years 2008-2015. The pyranonaphthoquinones are a group of metabolites sharing a common naphtho[2,3 c]pyran-5,10-dione ring system that have been isolated from a wide range of microorganisms, plants and insects. In addition to their synthetically challenging molecular structures, pyranonaphthoquinones exhibit a wide array of biological activity, including anti-bacterial, anti-fungal and anti-cancer properties. The therapeutic potential of these compounds has led to a dynamic interplay between total synthesis and biological evaluation. PMID- 27759132 TI - Interface phonon modes in the [AlN/GaN]20 and [Al0.35Ga0.65N/Al0.55Ga0.45N]20 2D multi-quantum well structures. AB - The observation of interface (IF) phonon modes in the recorded Raman spectra of c plane oriented [AlN/GaN]20 and [Al0.35Ga0.65N/Al0.55Ga0.45N]20 multi-quantum well (MQW) structures grown via plasma assisted molecular beam epitaxy is reported. The nominal shift in the IF phonon mode of E1 symmetry for [Al0.35Ga0.65N/Al0.55Ga0.45N]20 compared to that of the [AlN/GaN]20 MQW structure is understood on the basis of change in dielectric constants (epsilonm) of the surrounding medium. The presence of buffer layers in [Al0.35Ga0.65N/Al0.55Ga0.45N]20 MQW over a sapphire substrate is also understood by characterizing the IF phonon mode of A1 symmetry. The observed IF phonon modes in the spectra are attributed to the relaxation of Raman selection rules away from the Brillouin zone centre because of the breakdown of the translational symmetry of surface potential due to the presence of the periodic interfaces and surface modulations in the superlattice structures of MQWs. The corresponding required edge lengths (L) of 2D plates, for the observation of the breakdown of the surface potential, are computed from the simulated dispersion relation curve of IF modes. The integral multiples of uniformly distributed platelets, originated due to the horizontal uneven irregularities on the surface of superlattices, are matched with the calculated L values. PMID- 27759133 TI - Tuneable 2D self-assembly of plasmonic nanoparticles at liquid|liquid interfaces. AB - Understanding the structure and assembly of nanoparticles at liquid|liquid interfaces is paramount to their integration into devices for sensing, catalysis, electronics and optics. However, many difficulties arise when attempting to resolve the structure of such interfacial assemblies. In this article we use a combination of X-ray diffraction and optical reflectance to determine the structural arrangement and plasmon coupling between 12.8 nm diameter gold nanoparticles assembled at a water|1,2-dichloroethane interface. The liquid|liquid interface provides a molecularly flat and defect-correcting platform for nanoparticles to self-assemble. The amount of nanoparticles assembling at the interface can be controlled via the concentration of electrolyte within either the aqueous or organic phase. At higher electrolyte concentration more nanoparticles can settle at the liquid|liquid interface resulting in a decrease in nanoparticle spacing as observed from X-ray diffraction experiments. The plasmonic coupling between the nanoparticles as they come closer together is observed by a red-shift in the optical reflectance spectra. The optical reflectance and the X-ray diffraction data are combined to introduce a new 'plasmon ruler'. This allows extraction of structural information from simple optical spectroscopy techniques, with important implications for understanding the structure of self-assembled nanoparticle films at liquid interfaces. PMID- 27759134 TI - Convective heat transfer in a measurement cell for scanning electrochemical microscopy. AB - Electrochemical experiments, especially those performed with scanning electrochemical microscopy (SECM), are often carried out without taking special care to thermostat the solution; it is usually assumed that its temperature is homogeneous and equal to the ambient. The present study aims to test this assumption via numerical simulations of the heat transfer in a particular system the typical measurement cell for SECM. It is assumed that the temperature of the solution is initially homogeneous but different from that of its surroundings; convective heat transfer in the solution and the surrounding air is taken into account within the framework of the Boussinesq approximation. The hereby presented theoretical treatment indicates that an initial temperature difference of the order of 1 K dissipates with a characteristic time scale of ~1000 s; the thermal equilibration is accompanied by convective flows with a maximum velocity of ~10-4 m s-1; furthermore, the temporal evolution of the temperature profile is influenced by the sign of the initial difference. These results suggest that, unless the temperature of the solution is rigorously controlled, convection may significantly compromise the interpretation of data from SECM and other electrochemical techniques, which is usually done on the basis of diffusion-only models. PMID- 27759135 TI - Transition metal-free N-arylation of secondary amides through iodonium salts as aryne precursors. AB - By using a diaryliodonium salt as a benzyne precursor, a transition metal-free approach for N-arylation of secondary amides is developed. This novel benzyne precursor, which can be prepared easily by a one step process from an aryl iodide, shows different reactivities with previous benzyne precursors in the N arylation reaction. Mechanistic studies confirm the involvement of benzyne species (generated in situ from the diaryliodonium salts) as key intermediates. PMID- 27759136 TI - Quantitative and regiocontrolled cross-photocycloaddition of the anticancer drug 5-fluorouracil achieved in a cocrystal. AB - We describe a [2+2] cross-photocycloaddition of the anticancer drug 5 fluorouracil in the solid state that proceeds regioselectively and in quantitative yield. The photocycloaddition occurs in a cocrystal with trans-2,2' bis(pyridyl)ethylene. PMID- 27759137 TI - Dynamic nitroxyl formation in the ammonia oxidation on platinum via Eley-Rideal reactions. AB - For over 90 years, nitroxyl (HNO) has been postulated to be an important reaction intermediate in the catalytic oxidation of ammonia to NO and its by-products (N2, N2O), but never proven to form or exist on catalytic surfaces. Here we show evidence from reactive ion beam experiments that HNO can form directly on the surface of polycrystalline Pt exposed to NH3via Eley-Rideal abstraction reactions of adsorbed NH by energetic O+ and O2+ projectiles. The dynamic formation of HNO in a single collision followed up by prompt rebound from the surface prevents subsequent reactive interactions with other surface adsorbates and enables its detection. In addition to HNO, NO and OH are also detected as direct products in what constitutes the concurrent abstraction of three surface adsorbates, namely NH, N, and H, by O+ projectiles with entirely predictable kinematics. While its relation to thermal catalysis may be tenuous, dynamic HNO formation could be important on grain surfaces of interstellar or cometary matter under astrophysical conditions. PMID- 27759138 TI - Volume and structural relaxation in compressed sodium borate glass. AB - The structure and properties of glass can be modified through compression near the glass transition temperature (Tg), and such modified structure and properties can be maintained at ambient temperature and pressure. However, once the compressed glass undergoes annealing near Tg at ambient pressure, the modified structure and properties will relax. The challenging question is how the property relaxation is correlated with both the local and the medium-range structural relaxation. In this paper, we answer this question by studying the volume (density) and structural relaxation of a sodium borate glass that has first been pressure-quenched from its Tg at 1 GPa, and then annealed at ambient pressure under different temperature-time conditions. Using 11B MAS NMR and Raman spectroscopy, we find that the pressure-induced densification of the glass is accompanied by a conversion of six-membered rings into non-ring trigonal boron (BIII) units, i.e. a structural change in medium-range order, and an increase in the fraction of tetrahedral boron (BIV), i.e. a structural change in short-range order. These pressure-induced structural conversions are reversible during ambient pressure annealing near Tg, but exhibit a dependence on the annealing temperature, e.g. the ring/non-ring BIII ratio stabilizes at different values depending on the applied annealing temperature. We find that conversions between structural units cannot account for the pressure-induced densification, and instead we suggest the packing of structural units as the main densification mechanism. PMID- 27759139 TI - Investigating the coverage dependent behaviour of CO on Gd/Pt(111). AB - Gd modified Pt(111) single crystals have been prepared in an ultra high vacuum (UHV). By vacuum deposition of ~200 A Gd on a sample heated to 800 degrees C, a Pt5Gd alloy terminated by a single atomic layer of Pt was formed. Subsequently the surfaces were characterized using low energy electron diffraction (LEED), showing that a highly ordered crystal structure had appeared. To study the molecular dynamics on this surface a detailed study of the CO adsorption on the surface was conducted using temperature programmed desorption (TPD) of CO. The TPD spectra show a desorption peak shifted down in temperature compared to those of pure Pt(111). The shape of the desorption peak and the desorption temperature were shown to be strongly dependent on the CO coverage of the surface. A systematic investigation of CO desorption temperature as a function of coverage was consequently performed. A simple simulation of the TPD spectra was carried out, based on adsorption energies from density functional theory (DFT). This simulation reproduces the shift and the narrowing of the desorption spectrum from the experiments and the DFT calculations suggest that the sharp TPD feature arises from cooperative adsorbate interactions, caused by subtle reconstructions occurring at coverages above 1/3 ML CO, whereas the overall temperature shift relative to pure Pt(111) comes from weaker CO binding due to the contraction of the Gd/Pt(111) surface. PMID- 27759140 TI - Using tobacco mosaic virus to probe enhanced surface diffusion of molecular glasses. AB - Recent studies have shown that diffusion on the surface of organic glasses can be many orders of magnitude faster than bulk diffusion. Developing new probes that can readily measure surface diffusion can help study the effect of parameters such as chemical structure, intermolecular interaction, molecules' shape and size on the enhanced surface diffusion. In this study, we develop a novel probe that significantly simplifies these types of studies. Tobacco mosaic virus (TMV) is used as probe particle to measure surface diffusion coefficient of molecular glass N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine (TPD). The evolution of the meniscus formed around TMV is probed as a function of time at various temperatures. TMV has a well-defined, mono-dispersed, cylindrical shape, with a large aspect-ratio (average diameter of 16.6 nm, length of 300 nm). As such, the shape of the meniscus around the center of TMV is semi-two dimensional, which compared to using a nanosphere as probe, increases the driving force for meniscus formation and simplifies the analysis of surface diffusion. We show that under these conditions, after a short transient time the shape of the meniscus is self similar, allowing accurate determination of the surface diffusion coefficient. Measurements at various temperatures are then performed to investigate the temperature dependence of the surface diffusion coefficient. It is found that surface diffusion is greatly enhanced in TPD and has a lower activation barrier compared to the bulk counterpart. These observations are consistent with previous studies of surface diffusion on molecular glasses, demonstrating the accuracy of this method. PMID- 27759141 TI - Anion-directed supramolecular chemistry modulating the magnetic properties of nanoscopic Mn coordination clusters: from polynuclear high-spin complexes to SMMs. AB - We report a supramolecular approach to mixed-valent Mn coordination clusters that demonstrates how halide ions can be applied to influence the assembly of distinct tetranuclear building units to produce a number of related Mn coordination clusters with dense core structures that derive from a cuboctahedral arrangement of Mn ions. In all compounds the alignment of the Jahn-Teller axes of the MnIII centers coincides with the positions of the stabilizing chloride ligands. Thus, the relative chloride concentrations in the reaction mixtures allow us to modify the symmetry and magnetic anisotropy of this basic core structures resulting in isotropic polynuclear high-spin complexes at high Cl- concentrations and Single Molecule Magnets at lower relative Cl- concentrations. PMID- 27759142 TI - A visible-light-induced chemoselective radical/oxidative addition domino process to access alpha-chloro and alpha-alkoxy aryl ketones. AB - A visible-light-induced radical-triggered chemoselective domino process to access alpha,alpha-di-functionalized ketones under mild conditions has been developed. This protocol provides a direct approach to synthesize alpha-chloro or alpha alkoxy aryl ketones based on the electronic properties of the substrates. The reaction can tolerate a variety of functional groups to afford the corresponding products in moderate to good yields. PMID- 27759143 TI - Li intercalation mechanisms in CaTi5O11, a bronze-B derived compound. AB - A first-principles study was performed to elucidate the electrochemical properties of CaTi5O11, a recently discovered compound that is a crystallographic variant of TiO2(B) and that shows promise as an anode material for Li-ion batteries. The crystal structure of CaTi5O11 was further refined and two symmetrically distinct interstitial sites that can accommodate Li at positive voltage were identified. A statistical mechanics study relying on density functional theory (DFT) calculations predicted that interstitial Li in CaTi5O11 forms a solid solution with Li insertion resulting in a sloping voltage profile. Li diffusion within CaTi5O11 was found to be highly anisotropic with low barrier diffusion pathways forming one-dimensional channels parallel to the c axis. PMID- 27759145 TI - Embedding flexible fibers into responsive gels to create composites with controllable dexterity. AB - Using computational modeling, we design a composite that encompasses a thermo responsive gel and photo-responsive fibers that extend from the surface of the gel. By simulating the effect of light and heat on the sample, we isolate scenarios where cooperative interactions within the system allow the gel to actuate the "finger-like" motion of the embedded fibers. To achieve this distinctive behavior, we consider a gel formed from poly(N-isopropylacrylamide) (PNIPAAm), which shrinks when heated above the lower critical solution temperature (LCST). The fibers are functionalized with spirobenzopyran (SP) chromophores that extend a finite region into the polymer network. The application of heat causes the entire gel to shrink, while the application of light causes the regions around the functionalized fibers to collapse. With the fibers arranged in a square or circular pattern in the center of the gel, heating the non-illuminated samples drives the fibers to move apart as they bend outward (away from the center). With the application of light, the tips of fibers come together as the fibers bend inward. In this configuration, the fibers could act as grippers that bind objects in the presence of light. With the illumination turned off, the grippers could controllably release the objects. By placing the fibers closer to the edge of the sample, the combination of heat and light could be harnessed to bind and release larger objects. We also show that by illuminating the fibers separately, we can manipulate the motion of the individual finger-like objects, and thus, potentially expand the utility of the system. Overall, our findings provide guidelines for controllably reconfiguring the shape of soft materials and thus, tailoring the material to display different functionalities in different environments. PMID- 27759149 TI - Cell-free extracts in Development and Cancer Research for over 40 years. AB - Analysis of cell-free extracts has allowed us to understand many of the fundamental processes of cell physiology and pathology, including those involved in embryo development and cancer. This methodology is being continuously modified and improved. Papers selected for this Special Issue will show readers the plethora of systems and applications of this methodology. PMID- 27759150 TI - MPF, starfish oocyte and cell-free extract in the background - an interview with Takeo Kishimoto. AB - Professor Takeo Kishimoto's research has an enormous impact on the cell cycle field. Although his favorite model has always been a starfish oocyte, he has used many other model organisms in his research. Cell-free extracts have been wildly used in his laboratory as a very useful tool to answer cell cycle research questions. Recently, professor Kishimoto discovered the identity of the M-phase promoting factor (MPF) that was thought for years to be cyclin-dependent kinase 1 (CDK1). However, Takeo Kishimoto found that MPF consists in fact of two kinases: CDK1 and Greatwall kinase. While CDK1 phosphorylates mitotic substrates, Greatwall kinase allows these substrates to persist in their phosphorylated state because it regulates phosphatase PP2A, which dephosphorylates the majority of CDK1 substrates. When I started to interview Prof. Kishimoto, I was mostly interested in his experiences with cell-free extracts. However, as you will see below we almost immediately turned to the problem of the identity of MPF. This is fully understandable because the identity of MPF seems to be a major interest in Takeo's scientific career. I hope readers will enjoy this interview and will be able to learn about many aspects of scientific research, which do not usually appear in regular research papers. PMID- 27759151 TI - Xenopus cell-free extracts and their contribution to the study of DNA replication and other complex biological processes. AB - Here we discuss the important contributions that cell-free extracts have made to the study of complex biological processes. We provide a brief history of how cell free extracts of frog eggs were developed to avoid many of the problems that can arise from the dilution and mixing of cellular components that typically occur when cell-free extracts are prepared. We briefly describe how Xenopus egg extracts have been fundamental to the study of many important cellular processes including DNA replication, cell cycle progression, nuclear protein import, nuclear assembly and chromosome organisation. We describe how, in particular, Xenopus egg extracts have made a major contributions to the study of DNA replication, by permitting the direct manipulation of proteins in a system that is extraordinarily faithful to the way that DNA replication occurs in the living embryo. Finally we consider how results obtained using Xenopus egg extracts are being translated to produce diagnostic reagents for cancer screening and diagnosis. PMID- 27759152 TI - Studying essential DNA metabolism proteins in Xenopus egg extract. AB - The correct duplication of genetic information is essential to maintain genome stability, which is lost in cancer cells. Replication fork integrity is ensured by a number of DNA metabolism proteins that assist replication of chromatin regions difficult to replicate due to their intrinsic DNA sequence composition, coordinate repair of DNA molecules resulting from aberrant replication events or protect replication forks in the presence of lesions impairing their progression. Some DNA metabolism genes involved in DNA repair are essential in higher eukaryotes even in unchallenged conditions, suggesting the existence of biological processes requiring these specialized functions in organisms with complex genomes. The impact on cell survival of null mutants of many DNA metabolism genes has precluded complete in depth analysis of their function. Cell free extracts represent a fundamental tool to overcome survival issues. The Xenopus laevis egg cell free extract is an ideal system to study replication associated functions of essential genes. We are taking advantage of this system together with innovative imaging and proteomic based experimental approaches to characterize the molecular function of essential DNA metabolism proteins. Using this approach we have uncovered the role of some essential homologous recombination and fork protection proteins in chromosomal DNA replication and we have characterized some of the factors required for faithful replication of specific vertebrate genomic regions. This approach will be instrumental to study the molecular mechanisms underlying the function of a number of essential DNA metabolism proteins involved in the maintenance of genome stability in complex genomes. PMID- 27759153 TI - The master Greatwall kinase, a critical regulator of mitosis and meiosis. AB - Entry into mitosis requires the coordinated activation of various protein kinases and phosphatases that together activate sequential signaling pathways allowing entry, progression and exit of mitosis. The limiting step is thought to be the activation of the mitotic Cdk1-cyclin B kinase. However, this model has recently evolved with new data showing that in addition to the Cdk1-cyclin B complex, Greatwall (Gwl) kinase is also required to enter into and maintain mitosis. This new concept proposes that entry into mitosis is now based on the combined activation of both kinases Cdk1-cyclin B and Gwl, the former promoting massive phosphorylation of mitotic substrates and the latter inhibiting PP2A-B55 phosphatase responsible for dephosphorylation of these substrates. Activated Gwl phosphorylates both Arpp19 and ENSA, which associate and inhibit PP2A-B55. This pathway seems relatively well conserved from yeast to humans, although some differences appear based on models or techniques used. While Gwl is activated by phosphorylation, its inactivation requires dephosphorylation of critical residues. Several phosphatases such as PP1, PP2A-B55 and FCP1 are required to control the dephosphorylation and inactivation of Gwl and a properly regulated mitotic exit. Gwl has also been reported to be involved in cancer processes and DNA damage recovery. These new findings support the idea that the Gwl-Arpp19/ENSA PP2A-B55 pathway is essential to achieve an efficient division of cells and to maintain genomic stability. PMID- 27759154 TI - Aurora-A: an expedition to the pole of the spindle in Xenopus egg extracts. AB - The aim of this short review is to describe the contribution of Xenopus laevis egg extracts to the discovery and understanding of the regulation and function of the serine/threonine kinase Aurora-A. The power of these extracts to recapitulate cell cycle events makes them a precious tool to decipher complex biological processes at the molecular level, including the mechanisms that affect Aurora-A (post-translational modifications) and mechanisms in which Aurora-A plays a crucial role (bipolar spindle assembly). We focus on the results obtained in cell free extracts, but we also give an updated overview of Aurora A functions found in other systems. PMID- 27759155 TI - Chaperone-mediated chromatin assembly and transcriptional regulation in Xenopus laevis. AB - Chromatin is the complex of DNA and histone proteins that is the physiological form of the eukaryotic genome. Chromatin is generally repressive for transcription, especially so during early metazoan development when maternal factors are explicitly in control of new zygotic gene expression. In the important model organism Xenopus laevis, maturing oocytes are transcriptionally active with reduced rates of chromatin assembly, while laid eggs and fertilized embryos have robust rates of chromatin assembly and are transcriptionally repressed. As the DNA-to-cytoplasmic ratio decreases approaching the mid-blastula transition (MBT) and the onset of zygotic genome activation (ZGA), the chromatin assembly process changes with the concomitant reduction in maternal chromatin components. Chromatin assembly is mediated in part by histone chaperones that store maternal histones and release them into new zygotic chromatin. Here, we review literature on chromatin and transcription in frog embryos and cell-free extracts and highlight key insights demonstrating the roles of maternal and zygotic histone deposition and their relationship with transcriptional regulation. We explore the central historical and recent literature on the use of Xenopus embryos and the key contributions provided by experiments in cell-free oocyte and egg extracts for the interplay between histone chaperones, chromatin assembly, and transcriptional regulation. Ongoing and future studies in Xenopus cell free extracts will likely contribute essential new insights into the interplay between chromatin assembly and transcriptional regulation. PMID- 27759157 TI - Flexibility vs. robustness in cell cycle regulation of timing of M-phase entry in Xenopus laevis embryo cell-free extract. AB - During the cell cycle, cyclin dependent kinase 1 (CDK1) and protein phosphatase 2A (PP2A) play major roles in the regulation of mitosis. CDK1 phosphorylates a series of substrates triggering M-phase entry. Most of these substrates are dephosphorylated by PP2A. To allow phosphorylation of CDK1 substrates, PP2A is progressively inactivated upon M-phase entry. We have shown previously that the interplay between these two activities determines the timing of M-phase entry. Slight diminution of CDK1 activity by the RO3306 inhibitor delays M-phase entry in a dose-dependent manner in Xenopus embryo cell-free extract, while reduction of PP2A activity by OA inhibitor accelerates this process also in a dose dependent manner. However, when a mixture of RO3306 and OA is added to the extract, an intermediate timing of M-phase entry is observed. Here we use a mathematical model to describe and understand this interplay. Simulations showing acceleration and delay in M-phase entry match previously described experimental data. CDC25 phosphatase is a major activator of CDK1 and acts through CDK1 Tyr15 and Thr14 dephosphorylation. Addition of CDC25 activity to our mathematical model was also consistent with our experimental results. To verify whether our assumption that the dynamics of CDC25 activation used in this model are the same in all experimental variants, we analyzed the dynamics of CDC25 phosphorylation, which reflect its activation. We confirm that these dynamics are indeed very similar in control extracts and when RO3306 and OA are present separately. However, when RO3306 and OA are added simultaneously to the extract, activation of CDC25 is slightly delayed. Integration of this parameter allowed us to improve our model. Furthermore, the pattern of CDK1 dephosphorylation on Tyr15 showed that the real dynamics of CDK1 activation are very similar in all experimental variants. The model presented here accurately describes, in mathematical terms, how the interplay between CDK1, PP2A and CDC25 controls the flexible timing of M phase entry. PMID- 27759156 TI - Use of Xenopus cell-free extracts to study size regulation of subcellular structures. AB - Striking size variations are prominent throughout biology, at the organismal, cellular, and subcellular levels. Important fundamental questions concern organelle size regulation and how organelle size is regulated relative to cell size, also known as scaling. Uncovering mechanisms of organelle size regulation will inform the functional significance of size as well as the implications of misregulated size, for instance in the case of nuclear enlargement in cancer. Xenopus egg and embryo extracts are powerful cell-free systems that have been utilized extensively for mechanistic and functional studies of various organelles and subcellular structures. The open biochemical nature of the extract permits facile manipulation of its composition, and in recent years extract approaches have illuminated mechanisms of organelle size regulation. This review largely focuses on in vitro Xenopus studies that have identified regulators of nuclear and spindle size. We also discuss potential relationships between size scaling of the nucleus and spindle, size regulation of other subcellular structures, and extract experiments that have clarified developmental timing mechanisms. We conclude by offering some future prospects, notably the integration of Xenopus extract with microfluidic technology. PMID- 27759159 TI - Volumetric-modulated arc stereotactic radiotherapy for canine adrenocortical tumours with vascular invasion. AB - OBJECTIVES: To evaluate the feasibility and efficacy of hypofractionated stereotactic volumetric-modulated arc radiotherapy in treating canine adrenal tumours with vascular invasion. METHODS: A single-arm clinical study was performed. The dogs underwent total body computed tomography, brain and abdomen magnetic resonance imaging and endocrine assay. Adrenal masses were classified as cortisol-secreting adrenal tumour or non-secreting adrenal tumour. Radiotherapy treatments were delivered by hypofractionated stereotactic volumetric-modulated arc radiotherapy via a linear accelerator. The overall survival was estimated by the Kaplan-Meier method. The overall response and radio-toxicity effects were determined. RESULTS: Nine dogs were enrolled. Three dogs were affected by cortisol-secreting adrenal tumours and the remaining dogs had non-secreting adrenal tumours. The prescribed doses ranged from 30 to 45 Gy in three or five consecutive daily fractions. The median overall survival time was 1030 days, and the overall mean reduction of the diameter and volume were ~32 and 30% respectively. The endocrine profile normalised in two dogs with cortisol secreting adrenal tumours. Radio-toxicities were mild and self-limiting. Seven deaths were recorded during the follow-up period and two dogs were censored. CLINICAL SIGNIFICANCE: Hypofractionated stereotactic volumetric-modulated arc radiotherapy should be considered as a feasible and effective therapeutic option for adrenal tumours with vascular invasion. PMID- 27759158 TI - Chromatin assembly and transcriptional cross-talk in Xenopus laevis oocyte and egg extracts. AB - Chromatin, primarily a complex of DNA and histone proteins, is the physiological form of the genome. Chromatin is generally repressive for transcription and other information transactions that occur on DNA. A wealth of post-translational modifications on canonical histones and histone variants encode regulatory information to recruit or repel effector proteins on chromatin, promoting and further repressing transcription and thereby form the basis of epigenetic information. During metazoan oogenesis, large quantities of histone proteins are synthesized and stored in preparation for the rapid early cell cycles of development and to elicit maternal control of chromatin assembly pathways. Oocyte and egg cell-free extracts of the frog Xenopus laevis are a compelling model system for the study of chromatin assembly and transcription, precisely because they exist in an extreme state primed for rapid chromatin assembly or for transcriptional activity. We show that chromatin assembly rates are slower in the X. laevis oocyte than in egg extracts, while conversely, only oocyte extracts transcribe template plasmids. We demonstrate that rapid chromatin assembly in egg extracts represses RNA Polymerase II dependent transcription, while pre-binding of TATA-Binding Protein (TBP) to a template plasmid promotes transcription. Our experimental evidence presented here supports a model in which chromatin assembly and transcription are in competition and that the onset of zygotic genomic activation may be in part due to stable transcriptional complex assembly. PMID- 27759162 TI - Increased endogenous antigen presentation in the periphery enhances susceptibility to inflammation-induced gastric autoimmunity in mice. AB - How the immune system maintains peripheral tolerance under inflammatory conditions is poorly understood. Here we assessed the fate of gastritogenic T cells following inflammatory activation in vivo. Self-reactive T cells (A23 T cells) specific for the gastric H+ /K+ ATPase alpha subunit (HKalpha) were transferred into immunosufficient recipient mice and immunised at a site distant to the stomach with adjuvant containing the cognate HKalpha peptide antigen. Activation of A23 T cells by immunisation did not impact on either immune tolerance or protection from gastric autoimmunity in wild-type BALB/c mice. However, increased presentation of endogenously derived HKalpha epitopes by dendritic cells (DCs) in the gastric lymph node of IE-H+ /K+ beta transgenic mice (IEbeta) reduces A23 T-cell tolerance to gastric antigens after inflammatory activation, with subsequent development of gastritis. While HKalpha-specific A23 T cells from immunised wild-type mice were poorly responsive to in vitro antigen specific activation, A23 T cells from immunised IEbeta transgenic mice were readily re-activated, indicating loss of T-cell anergy. These findings show that DCs of gastric lymph nodes can maintain tolerance of pathogenic T cells following inflammatory stimulation and that the density of endogenous antigen presented to self-reactive T cells is critical in the balance between tolerance and autoimmunity. PMID- 27759161 TI - Phospholipase Cgamma1 is required for pre-TCR signal transduction and pre-T cell development. AB - Pre-T cell receptor (TCR) signaling is required for pre-T cell survival, proliferation, and differentiation from the CD4 and CD8 double negative (DN) to the double positive (DP) stage. However, the pre-TCR signal transduction pathway is not fully understood and the signaling molecules involved have not been completely identified. Phospholipase Cgamma (PLCgamma) 1 is an important signaling molecule that generates two second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, that are important to mediate PKC activation and intracellular Ca2+ flux in many signaling pathways. Previously, we have shown that PLCgamma1 is important for TCR-mediated signaling, development and T-cell activation, but the role of PLCgamma1 in pre-TCR signal transduction and pre-T cell development is not known. In this study, we demonstrated that PLCgamma1 expression level in pre-T cells was comparable to that in mature T cells. Deletion of PLCgamma1 prior to the pre-TCR signaling stage partially blocked the DN3 to DN4 transition and reduced thymic cellularity. We also demonstrated that deletion of PLCgamma1 impaired pre-T cell proliferation without affecting cell survival. Further study showed that deficiency of PLCgamma1 impaired pre-TCR mediated Ca2+ flux and Erk activation. Thus our studies demonstrate that PLCgamma1 is important for pre-TCR mediated signal transduction and pre-T cell development. PMID- 27759163 TI - Generation of a transgenic medaka (Oryzias latipes) strain for visualization of nuclear dynamics in early developmental stages. AB - In this study, we verified nuclear transport activity of an artificial nuclear localization signal (aNLS) in medaka fish (Oryzias latipes). We generated a transgenic medaka strain expresses the aNLS tagged enhanced green fluorescent protein (EGFP) driven by a medaka beta-actin promoter. The aNLS-EGFP was accumulated in the nuclei of somatic tissues and yolk nuclei of oocytes, but undetectable in the spermatozoa. The fluorescent signal was observed from immediately after fertilization by a maternal contribution. Furthermore, male and female pronuclei were visualized in fertilized eggs, and nuclear dynamics of pronuclear fusion and subsequent cleavage were captured by time-lapse imaging. In contrast, SV40NLS exhibited no activity of nuclear transport in early embryos. In conclusion, the aNLS possesses a strong nuclear localization activity and is a useful probe for fluorescent observation of the pronuclei and nuclei in early developmental stage of medaka. PMID- 27759160 TI - Snapshot: implications for melatonin in endoplasmic reticulum homeostasis. AB - The endoplasmic reticulum (ER) is an important intracellular membranous organelle. Previous studies have demonstrated that the ER is responsible for protein folding and trafficking, lipid synthesis and the maintenance of calcium homeostasis. Interestingly, the morphology and structure of the ER were recently found to be important. Melatonin is a hormone that anticipates the daily onset of darkness in mammals, and it is well known that melatonin acts as an antioxidant by scavenging free radicals and increasing the activity of antioxidant enzymes in the body. Notably, the existing evidence demonstrates that melatonin is involved in ER homeostasis, particularly in the morphology of the ER, indicating a potential protective role of melatonin. This review discusses the existing knowledge regarding the implications for the involvement of melatonin in ER homeostasis. PMID- 27759164 TI - Retention strategies for health disparities preventive trials: findings from the Early Childhood Caries Collaborating Centers. AB - OBJECTIVES: To identify successful strategies for retention of participants in multiyear, community-based randomized controlled trials (RCTs) aiming to reduce early childhood caries in health disparities populations from diverse racial/ethnic backgrounds and across diverse geographic settings. METHODS: Four RCTs conducted by the Early Childhood Caries Collaborating Centers (EC4), an initiative of the National Institute of Dental and Craniofacial Research, systematically collected information on the success of various strategies implemented to promote participant retention in each RCT. The observational findings from this case series of four RCTs were tabulated and the strategies rated by study staff. RESULTS: Participant retention at 12 months of follow-up ranged from 52.8 percent to 91.7 percent, and at 24 months ranged from 53.6 percent to 85.9, across the four RCTs. For the three RCTs that had a 36-month follow-up, retention ranged from 53.6 percent to 85.1 percent. Effectiveness of different participant retention strategies varied widely across the RCTs. CONCLUSIONS: Findings from this case series study may help to guide the design of future RCTs to maximize retention of study participants and yield needed data on effective interventions to reduce oral health disparities. PMID- 27759165 TI - Mosquitoes of field and forest: the scale of habitat segregation in a diverse mosquito assemblage. AB - Knowledge of the distribution of arthropod vectors across a landscape is important in determining the risk for vector-borne disease. This has been well explored for ticks, but not for mosquitoes, despite their importance in the transmission of a variety of pathogens. This study examined the importance of habitat, habitat edges, and the scale at which mosquito abundance and diversity vary in a rural landscape by trapping along transects from grassland areas into forest patches. Significant patterns of vector diversity and distinct mosquito assemblages across habitats were found. The scale of individual species' responses to habitat edges was often dramatic, with several species rarely straying even 10 m from the edge. The present results suggest blood-seeking mosquito species are faithful to certain habitats, which has consequences for patterns of vector diversity and risk for pathogen transmission. This implies that analysts of risk for pathogen transmission and foci of control, and developers of land management strategies should assess habitat at a finer scale than previously considered. PMID- 27759166 TI - REFLECTIVE PRACTICE IN ORGANIZATIONAL LEARNING, CULTURAL SELF-UNDERSTANDING, AND COMMUNITY SELF-STRENGTHENING. AB - The infant mental health field can amplify its effects when it extends its purview beyond the dyad to the larger contexts in which infants and adult caregivers interact and develop over time. Within health, mental health, education, and other human service organizations, the quality of relationships is a critical variable in the individual-level outcomes that such organizations seek. The goals of this work and the means for accomplishing them are highly dependent on human qualities and interactions that are shaped by organizational processes. In communities, too, processes that shape relationships also strongly influence child-, family-, and community-level outcomes. The Touchpoints approach to reflective practice can guide relational processes among professionals, parents, and infants in organizations and communities that influence these outcomes. PMID- 27759167 TI - RELEASE, REFRAME, REFOCUS, AND RESPOND: A PRACTITIONER TRANSFORMATION PROCESS IN A REFLECTIVE CONSULTATION PROGRAM. AB - This article presents findings from a qualitative research study exploring the experiences of early intervention practitioners in a reflective consultation program. Fifteen licensed early childhood special education teachers and speech, occupational, and physical therapists as well as a psychologist from an urban school district participated in interviews discussing their work stressors and involvement with monthly reflective consultation groups. They described a loosely temporal, iterative process which transformed how they thought and felt about both themselves as practitioners and the children and families with whom they worked. These practitioners also shared ways that their participation in reflective consultation changed some of their intervention strategies with young children and families. Analysis of themes from their descriptions led to the creation of a change process model defined as release, reframe, refocus, and respond. These findings contribute the practitioners' voices and experiences in a structured way to a growing body of evidence about the efficacy of reflective supervision and consultation. PMID- 27759168 TI - Another face of demodicosis. PMID- 27759169 TI - CREATING A "NEST" OF EMOTIONAL SAFETY: REFLECTIVE SUPERVISION IN A CHILD-PARENT PSYCHOTHERAPY CASE. AB - Reflective supervision is considered a key practice component for any infant mental health provider to work effectively with young children and their families. This article will provide a brief history and discussion of reflective supervision followed by a case study demonstrating the importance of reflective supervision in the context of child-parent psychotherapy (CPP; A.F. Lieberman, C. Ghosh Ippen, & P. Van Horn, ; A.F. Lieberman & P. Van Horn, , 2008). Given that CPP leverages the caregiver-child relationship as the mechanism for change in young children who have been impacted by stressors and traumas, primary objectives of CPP include assisting caregivers as they understand the meaning of their child's distress and improving the caregiver-child relationship to make it a safe and supportive space in which the child can heal. As this case will demonstrate, when a clinician is emotionally triggered by a family's negative intergenerational patterns of relating, reflective supervision supports a parallel process in which the psychotherapist feels understood and contained by the supervisor so that she or he is able to support the caregiver's efforts to understand and contain the child. PMID- 27759170 TI - Erythrocytapheresis for chronic transfusion therapy in sickle cell disease: survey of current practices and review of the literature. AB - BACKGROUND: Chronic red blood cell (RBC) transfusion therapy (CTT) is an integral component of the management of severe sickle cell disease (SCD) and can prevent complications, such as stroke. RBC units can be administered via simple transfusion or exchange transfusion, and erythrocytapheresis (automated RBC exchange transfusion [aRBX]), is increasingly used for CTT. Comparisons of simple and aRBX transfusions are limited, and the current scope of aRBX use is not known. STUDY DESIGN AND METHODS: We administered a survey to define current transfusion practices for CTT and performed a review of the erythrocytapheresis literature. The survey was disseminated to 62 SCD centers, and 31 institutions responded. RESULTS: Collectively, 1274 of 12,644 patients (10.1%) received CCT, including 929 of 9324 children (10.0%) and 345 of 3320 adults (10.4%). The most common indication for CTT in children was a risk of stroke (86.8%), defined by abnormal transcranial Doppler, previous stroke, or abnormal brain imaging; whereas the most common indications in adults were previous stroke (37.5%) and recurrent/severe pain (29.0%). Simple transfusion was the most common method for children (480 of 919 children; 52.2%) followed by aRBX (344 of 919 children; 37.4%); whereas, in adults, aRBX was more common (180 of 345 adults; 52.2%) than simple transfusion (102 of 345 adults; 29.6%). A smaller percentage of patients received transfusion via manual exchange (7.2% of children and 16.5% of adults) or a combination of methods. CONCLUSIONS: The current literature review was conducted to summarize reported methods, outcomes, and adverse effects with aRBX. Comparisons between chronic simple and aRBX transfusions were included when possible, and areas warranting further study are highlighted. PMID- 27759171 TI - Chemotherapeutic effect of Zerumbone on melanoma cells through mitochondria mediated pathways. AB - BACKGROUND: Zerumbone (ZER) is a phytochemical that appears to regulate cell proliferation and apoptosis. It has been reported to have an anti-tumour effect in various malignant cells; however, the effect and the mechanism of ZER on melanoma cells needs to be clarified. AIM: To explore whether ZER has an effect on human melanoma cells and to identify the mechanisms involved. METHODS: We determined the chemotherapeutic action of ZER on the human malignant melanoma (MM) A375 cell line by CCK-8 immunohistochemistry, Hoechst 33342 staining and flow cytometry analysis. We also investigated the signalling pathways by which ZER induces apoptosis in A375 cells, using western blotting, reverse transcription PCR and caspase-3 activity analysis. RESULTS: ZER induced significant cytotoxic action in A375 cells. Hoechst 33342 staining and flow cytometry apoptosis analysis further demonstrated that ZER induced apoptosis in A375 cells. Treatment with ZER downregulated Bcl-2 gene and protein levels, upregulated Bax and Cytochrome c gene and protein levels, and activated Caspase 3. CONCLUSIONS: ZER might have a chemotherapeutic effect on human melanoma cells through mitochondria-mediated pathways. PMID- 27759173 TI - Thiomaltol-Based Organometallic Complexes with 1-Methylimidazole as Leaving Group: Synthesis, Stability, and Biological Behavior. AB - Thiomaltol, a potential S,O-coordinating molecule, has been utilized for the complexation of four different organometallic fragments, yielding the desired RuII , OsII , RhIII , and IrIII complexes having a "piano-stool" configuration. In addition to the synthesis of these compounds with a chlorido leaving group, the analogous 1-methylimidazole derivatives have been prepared, giving rise to thiomaltol-based organometallics with enhanced stability under physiological conditions. The organometallic compounds have been characterized by NMR spectroscopy, elemental analysis, and X-ray diffraction analysis. Their behavior in aqueous solution and their interactions with certain amino acids have been studied by ESI mass spectrometry. Their pH-dependent stability has been investigated by 1 H NMR in aqueous solution, and their cytotoxicity against three different cancer cell lines has been investigated. Furthermore, their capacity as topoisomerase IIalpha inhibitors as well as their effect on the cell cycle distribution and reactive oxygen species (ROS) generation have been elucidated. PMID- 27759172 TI - Adverse events associated with interactions with dietary and herbal supplements among inpatients. AB - AIMS: Dietary and herbal supplements (DHS) are commonly used among inpatients and may cause interactions with drugs or other DHS. This study explored whether adverse events were actually associated with such interactions and examined specific characteristics among inpatient DHS users prone to such adverse events. METHODS: This was a cross-sectional study of 947 patients hospitalized in 12 departments of a tertiary academic medical centre in Haifa, Israel. It evaluated the rate of DHS use among inpatients, the potential for interactions, and actual adverse events during hospitalization associated with DHS use. It also assessed whether DHS consumption was documented in patients' medical files. Statistical analysis was used to delineate DHS users at risk for adverse events associated with interactions with conventional drugs or other DHS. RESULTS: In 17 (3.7%) of the 458 DHS users, an adverse event may have been caused by DHS-drug-DHS interactions. According to the Drug Interaction Probability Scale, 14 interactions 'probably' caused the adverse events, and 11 'possibly' caused them. Interactions occurred more frequently in older patients (P = 0.025, 95% CI: 2.26 19.7), patients born outside Israel (P = 0.025, 95% CI: 0.03-0.42), those with ophthalmologic (P = 0.032, 95% CI: 0.02-0.37) or gastrointestinal (P = 0.008, 95% CI: 0.05-0.46) comorbidities, and those using higher numbers of DHS (P < 0.0001, 95% CI: 0.52-2.48) or drugs (P = 0.027, 95% CI: 0.23-3.77). CONCLUSIONS: Approximately one in 55 hospitalizations in this study may have been caused by adverse events associated with DHS-drug-DHS interactions. To minimize the actual occurrence of adverse events, medical staff education regarding DHS should be improved. PMID- 27759174 TI - Estimated combined cardiac output and laser therapy for twin-twin transfusion syndrome. AB - INTRODUCTION: Twin-twin transfusion syndrome (TTTS) is the major cause for fetal demise in monochorionic diamniotic pregnancies. Estimated combined cardiac output (CCO) has not been studied in this setting. The primary aims of this study were to compare CCO in twin donor and recipient fetuses and assess differences in CCO before and after laser coagulation therapy. A secondary aim was to evaluate the relationship of CCO with perinatal mortality, defined as intrauterine or neonatal mortality (<=30 days of age) in fetuses that underwent laser coagulation therapy. METHODS: We performed a retrospective review of fetuses with TTTS who received echocardiograms prior to laser therapy. Prelaser echocardiograms were performed in 66 fetuses, of which 45 (21 donor and 24 recipient) survived to the postlaser echocardiogram. RESULTS: Donor CCO increased from a mean of 487+/-137 mL/min/kg prelaser to 592+/-128 mL/min/kg postlaser (P=.025). There was no significant change in mean recipient CCO from prelaser 551+/-165 mL/min/kg to postlaser 575+/ 112 mL/min/kg (P=.564). In recipient fetuses, higher prelaser CCO correlated with increasing Quintero stage (P=.010) and perinatal mortality (P=.003). Thirty-day postnatal outcome data were available for 38 fetuses, of whom 34 (89%) survived. Amongst survivors, 25 (74%) experienced an increase in CCO, while 9 (26%) experienced a decrease in CCO (P=.010). Donor fetuses had higher CCO after laser therapy. CONCLUSIONS: Higher prelaser CCO in recipient fetuses may indicate more advanced disease. Fetuses who exhibit a decrease in CCO after therapy laser may be at higher risk for perinatal mortality. PMID- 27759175 TI - Rabies virus-mediated oligodendrocyte labeling reveals a single oligodendrocyte myelinates axons from distinct brain regions. AB - Oligodendrocytes myelinate neuronal axons during development and increase conduction velocity of neuronal impulses in the central nervous system. Neuronal axons extend from multiple brain regions and pass through the white matter; however, whether oligodendrocytes ensheath a particular set of axons or do so randomly within the mammalian brain remains unclear. We developed a novel method to visualize individual oligodendrocytes and axon derived from a particular brain region in mouse white matter using a combinational injection of attenuated rabies virus and adeno-associated virus. Using this method, we found that some populations of oligodendrocytes in the corpus callosum predominantly ensheathed axons derived from motor cortex or sensory cortex, while others ensheathed axons from both brain regions, suggesting heterogeneity in preference of myelination toward a particular subtype of neurons. Moreover, our newly established method is a versatile tool for analyzing precise morphology of each oligodendrocyte in animal models for demyelinating disorders and addressing the role of oligodendrocyte in higher brain functions. GLIA 2016. GLIA 2017;65:93-105. PMID- 27759177 TI - Stereodivergent Aminocatalytic Synthesis of Z- and E-Trisubstituted Double Bonds from Alkynals. AB - A highly diastereoselective synthesis of trisubstituted Z- or E-enals, which are important intermediates in organic synthesis, as well as being present in natural products, is described using different alkynals and nucleophiles as starting materials. Diastereocontrol is mainly governed by the appropriate catalyst. Therefore, those reactions controlled by steric effects, such as the Jorgensen Hayashi's catalyst, give access to E isomers, and those catalysts that facilitate hydrogen bonding, such as tetrazol-pyrrolidine Ley's catalyst, allow the synthesis of Z isomers. A stereochemical model based on DFT calculations is proposed. PMID- 27759178 TI - Spotlights on our sister journals: Chem. Eur. J. 44/2016. PMID- 27759176 TI - Acaricidal activity of Metarhizium anisopliae isolated from paddocks in the Mexican tropics against two populations of the cattle tick Rhipicephalus microplus. AB - The acaricidal effects of 55 strains of Metarhizium anisopliae (Metschnikoff) Sorokin, 1883 (Hypocreales: Clavicipitaceae) isolated from paddocks of cattle farms were evaluated in two Rhipicephalus microplus (Canestrini 1887) (Ixodida: Ixodidae) populations, of which one was multi-resistant and one was susceptible to chemical acaricides. Percentage mortality and reproductive efficiency indices in R. microplus were evaluated by adult immersion tests at a dose of 1 * 108 conidia/mL for each fungal strain. Some strains were selected to calculate lethal concentrations to kill 50% (LC50 ) and 99% (LC99 ) of engorged ticks. Strains MaV22, MaV26 and MaV55 induced 100% mortality in R. microplus on day 14. Strains MaV05, MaV09 and MaV22 caused mortality of >90% from day 12 onward in both tick populations. The most effective acaricidal fungal strain, MaV55, inhibited egg laying by 54.86 and 55.86% in acaricide-resistant and -susceptible R. microplus populations, respectively. None of the fungal strains had statistically significant effects on larval hatching. In conclusion, nine strains of M. anisopliae demonstrated high acaricidal effects against R. microplus and reduced its egg laying. No differences in acaricidal effects were observed between the two populations of ticks tested. PMID- 27759180 TI - Beating Heart Validation of Safety and Efficacy of a Percutaneous Pericardiotomy Tool. AB - INTRODUCTION: Epicardial procedures frequently require pericardial manipulation. We aimed to develop a nonsurgical percutaneous pericardial modification tool that may (1) facilitate epicardial-based procedures by enabling adhesiolysis or (2) attenuate the myocardial constraining effect of the pericardium. METHODS: Three novel devices were developed to enable pericardiotomy, all of which can be deployed in over-the-wire fashion following percutaneous epicardial access. The grasper permits us to seize the pericardial membrane providing leverage for incision. The scissors enables anterograde cutting maneuvers. The reverse-slitter allows retrograde incisions; in addition, this device has a deflectable tip that increases the potential cutting area. We optimized these tools for safety by including electrodes to test for phrenic nerve stimulation as well as myocardial stimulation to determine directionality of the cutting devices. The base of the scissors and reverse-slitter are also blunt ensuring that the cutting element is always away from the myocardium. RESULTS: Following 5 nonbeating heart bench test experiments for prototype development, 11 animal (9 canine, 2 swine) studies were performed. Of these 2 were proof-of-concept open chest studies; the remaining 9 were entirely closed-chest, percutaneous procedures allowing for remodification of the prototypes. The tools successfully permitted incision of the pericardium in all studies. Hemodynamic measurements were assessed postincision and showed no compromise of systolic function. No coronary artery or phrenic nerve damage was seen in any study. CONCLUSION: Percutaneous pericardiotomy is feasible and appears to be safe. It may provide leverage in epicardial-based procedures and offer treatment options in disease processes characterized by pericardial restraint. PMID- 27759181 TI - Experiences of caring for a sibling with schizophrenia in a Chinese context: A neglected issue. AB - Adult clients with schizophrenia are primarily cared for by their ageing parents. When the parents become ill or die, siblings are considered to be responsible for taking over the caregiving role. However, little is known about caregiving for a sibling with schizophrenia, and no studies have explored this phenomenon in an Asian context. The aim of the present descriptive, qualitative study was to understand the experiences of being the primary caregiver of a sibling with schizophrenia. Data were collected from 10 siblings of currently-hospitalized patients diagnosed with schizophrenia using semistructured, in-depth interviews. Recorded interviews were transcribed and analysed by qualitative content analysis. This analysis identified four themes: (i) stepping forward to become caregiver; (ii) challenges of caregiving; (iii) need for support; and (iv) worries about future care. Our findings suggest that mental health-care professionals should involve all family members, including siblings, in the care plan for the person with schizophrenia, and provide appropriate psychoeducation for all family members to reduce not only the tension and stress of current caregiving, but also anxieties about future care. PMID- 27759182 TI - Whole-Body Imaging Procedures in Resistant Hypertension: Evaluating for Secondary Causes or to Define End-Organ Damages? PMID- 27759183 TI - New endovascular technique for thrombus in the non-stenting zone-the Grab a Clot and Hold ON "(GACHON) technique": Case report. AB - It is difficult to treat a thrombotic embolism in the common femoral artery or popliteal artery (POP A), i.e., the non-stenting zone. We report a new technique for the treatment of thrombotic embolism in the non-stenting zone using a self expandable nitinol stent. Case 1 had an external iliac artery (EIA) occlusion that occurred over several months. A self-expandable nitinol stent was placed in the right EIA lesion via a retrograde approach using a distal 9-Fr balloon protection guide catheter in the right femoral artery. A thrombotic embolism occurred at the balloon protection site. It was too big to be removed using an aspiration catheter; therefore, we attempted removal with a self-expandable stent. Using a crossover approach, we delivered a nitinol self-expandable stent to the distal site of the thrombus, opened the tip of the stent, and pulled it up to the proximal site. Finally, we "grabbed a clot," moved it to the stenting zone, and "held on" the vessel wall without occurrence of a distal embolism. We named this the "GACHON technique." Case 2 underwent endovascular therapy for an acute thrombotic embolism in POP A after thoracic endovascular aortic repair for dissection. This thrombus was too big to aspirate, and we successfully treated it using the "GACHON technique." The "GACHON technique" may be considered as a choice of treatment for a thrombotic embolism in the non-stenting zone. (c) 2016 Wiley Periodicals, Inc. PMID- 27759184 TI - The value of independent specialty designation for interventional cardiology. AB - Interventional cardiology has finally completed, after 26 years of advocacy, a professional hat trick: independent board certification, membership as a unique specialty in the American Medical Association House of Delegates (AMA HOD), and recognition by the Centers for Medicaid and Medicare Services (CMS) as a separate medical specialty. This article points out how these distinctions for interventional cardiology and its professional society, the Society for Cardiovascular Angiography and Interventions (SCAI), have led to clear and definite benefits for interventional cardiologists and their patients. We focus on the least understood of these three-recognition by CMS and its implications for reimbursement and quality assessment for interventional cardiologists. (c) 2016 Wiley Periodicals, Inc. PMID- 27759185 TI - Some Considerations About Primary Aldosteronism and Its Follow-Up. PMID- 27759186 TI - Comprehensive First-Line Magnetic Resonance Imaging in Hypertension: Experience From a Single-Center Tertiary Referral Clinic. AB - European guidelines recommend that patients with hypertension be assessed for asymptomatic organ damage and secondary causes. The authors propose that a single magnetic resonance imaging (MRI) scan can provide comprehensive first-line imaging of patients assessed via a specialist hypertension clinic. A total of 200 patients (56% male, aged 51+/-15 years, office BP 168+/-30/96+/-16 mm Hg) underwent MRI of the heart, kidneys, renal arteries, adrenals and aorta. Comparisons were made with other imaging modalities where available. A total of 61% had left ventricular hypertrophy (LVH), 14% had reduced ejection fraction, and 15 patients had myocardial infarcts. Echocardiography overdiagnosed LVH in 15% of patients and missed LVH in 14%. Secondary causes were identified in 14.5% of patients: 12 adrenal masses, 10 renal artery stenoses, seven thyroid abnormalities, one aortic coarctation, one enlarged pituitary gland, one polycystic kidney disease, and one renal coloboma syndrome. This comprehensive MRI protocol is an effective method of screening for asymptomatic organ damage and secondary causes of hypertension. PMID- 27759188 TI - Resuscitation orders in acute hospitals: A point prevalence study. AB - OBJECTIVE: To determine the prevalence of resuscitation orders and Advance Care Plans, and the relationship with Medical Emergency Team (MET) calls. METHODS: A point prevalence review of patient records at five Victorian hospital services. RESULTS: One thousand nine hundred and thirty-four patient records were reviewed, and 230 resuscitation orders and 15 Advance Care Plans found. Significantly, more resuscitation orders were found at public hospitals. Patients admitted to private hospitals were older, with shorter admissions. A further 24 orders were written following MET calls for 97 patients. Only 16% of patients aged 80+ years had a resuscitation order written within 24 hours of admission. CONCLUSION: Fewer resuscitation orders were written at admission for older adults than might be expected if goals of care and resuscitation outcome are considered. MET continue to have a prominent role in end-of-life care. Consideration and documentation about treatment plans are needed early in an admission to avoid burdensome and futile resuscitation events. PMID- 27759187 TI - Proportion of Patients With Hypertension Resolution Following Adrenalectomy for Primary Aldosteronism: A Systematic Review and Meta-Analysis. AB - Unilateral primary aldosteronism (PA) is often treated with adrenalectomy, but hypertension resolution rates are variable. A valid estimate of the postoperative normotension rate is necessary to inform the utility of PA testing and treatment. The authors searched MEDLINE In-Process & Other Non-Indexed Citations, Embase, and Cochrane Central Register of Controlled Trials. Prospective adult cohort studies with surgically treated PA that reported resolution of hypertension without the aid of medications were included. Among 2620 abstracts identified by the search, 25 studies in the systematic review with data on 1685 patients were investigated. The pooled proportion of normotension following adrenalectomy was 52% (95% confidence interval, 0.44-0.60). Meta-regression demonstrated a significant negative association between length of follow-up and proportion of normotension, with normotension dropping by 6.7% per year of follow-up (coefficient -0.006; 95% confidence interval, -0.01 to 0.002). Overall, approximately half of the patients experienced hypertension resolution, although this outcome may not be durable in all patients. PMID- 27759190 TI - Conservation Genetics: Techniques and Fundamentals. AB - Conservation genetics utilizes the tools and concepts of genetics and applies them to problems in conservation biology. For example, molecular genetic techniques, such as protein electrophoresis, and analysis of mitochondrial DNA and highly variable nuclear genes (including DNA fingerprinting), have been important in documenting the extent and pattern of genetic variation in endangered species. We review these techniques and their advantages and disadvantages, and give examples of their application to endangered species. For captive animal populations, pedigree analysis has become the basic approach to evaluate breeding priority of particular individuals. Several pedigree analysis techniques are commonly used, but peeling and gene dropping give the most information. We compared these techniques and illustrate their value with applications to the Guam Rail, Przewalski's horse, and other endangered captive animals. The rationale for much conservation genetic interpretation is base in evolutionary genetics. We discuss the avoidance of inbreeding depression and the maintenance of genetic variation-both primary conservation genetic goals-from this perspective. In addition, we suggest aspects of these factors that deserve greater attention in their overall application to conservation planning. Finally, we briefly mention three evolutionary topics-the relationship of heterozygosity and fitness, population bottlenecks, and outbreeding depression-that have implications for conservation genetics. Although simple interpretation in these areas is appealing, we feel that because they are only generally understood and often quite controversial, their application to endangered-species management should be carefully evaluated and monitored. PMID- 27759189 TI - Prescribing patterns of psychotropic medications and clinical features in patients with major depressive disorder with and without comorbid dysthymia in China. AB - INTRODUCTION: Little has been reported about the demographic and clinical features of major depressive disorder (MDD) with comorbid dysthymia in Chinese patients. This study examined the frequency of comorbid dysthymia in Chinese MDD patients together with the demographic and clinical correlates and prescribing patterns of psychotropic drugs. METHODS: Consecutively collected sample of 1178 patients with MDD were examined in 13 major psychiatric hospitals in China. Patients' demographic and clinical characteristics and psychotropic drugs prescriptions were recorded using a standardized protocol and data collection procedure. The diagnosis of dysthymia was established using the Mini International Neuropsychiatric Interview. Medications ascertained included antidepressants, antipsychotics, benzodiazepines, and mood stabilizers. RESULTS: One hundred and three (8.7%) patients fulfilled criteria for dysthymia. In multiple logistic regression analyses, compared to non-dysthymia counterparts, MDD patients with dysthymia had more depressive episodes with atypical features including increased appetite, sleep, and weight gain, more frequent lifetime depressive episodes, and less likelihood of family history of psychiatric disorders. There was no significant difference in the pattern of psychotropic prescription between the 2 groups. CONCLUSIONS: There are important differences in the demographic and clinical features of comorbid dysthymia in Chinese MDD patients compared with previous reports. The clinical profile found in this study has implications for treatment decisions. PMID- 27759191 TI - The Challenges of Conservation Biology. PMID- 27759192 TI - Aggregating Fine-Scale Ecological Knowledge to Model Coarser-Scale Attributes of Ecosystems. AB - As regional and global scales become more important to ecologists, methods must be developed for the application of existing fine-scale knowledge to predict coarser-scale ecosystem properties. This generally involves some form of model in which fine-scale components are aggregated. This aggregation is necessary to avoid the cumulative error associated with the estimation of a large number of parameters. However, aggregation can itself produce errors that arise because of the variation among the aggregated components. The statistical expectation operator can be used as a rigorous method for translating fine-scale relationships to coarser scales without aggregation errors. Unfortunately this method is too cumbersome to be applied in most cases, and alternative methods must be used. These alternative methods are typically partial corrections for the variation in only a few of the fine-scale attributes. Therefore, for these methods to be effective, the attributes that are the most severe sources of error must be identified a priori. We present a procedure for making these identifications based on a Monte Carlo sampling of the fine-scale attributes. We then present four methods of translating fine-scale knowledge so it can be applied at coarser scales: (1) partial transformations using the expectation operator, (2) moment expansions, (3) partitioning, and (4) calibration. These methods should make it possible to apply the vast store of fine-scale ecological knowledge to model coarser-scale attributes of ecosystems. PMID- 27759193 TI - The Effects of Bush Clearance on African Ungulates in a Semi-Arid Nature Reserve. AB - Bush encroachment has contributed to the diminishing availability of open grassland areas and possibly caused the decline of the local wildebeest and zebra populations in a semi-arid nature reserve in South Africa. Bush was subsequently cleared to convert dense woodland to parkland savanna. Based on an ecological gradient of habitat utilization previously described for African ungulates, it was assumed that wildebeest and zebra would favor cleared areas, whereas impala and kudu would prefer naturally dense woodland vegetation. Measurements of forage production showed that dry matter yield of grasses was greater in cleared areas. Proportion similarity indices and confidence intervals, representing the monthly occurrence of ungulates in different habitats, suggested that wildebeest and zebra were selecting for cleared areas, whereas impala and kudu occurred randomly in cleared and natural habitats. Results suggested that moderate modifications of woodland savanna habitats by means of bush clearance could be advantageous to ungulates that are common in grassland habitats, while not being detrimental to resident dwellers of dense woodland. Managers, however, should consider carefully the application of bush clearance. The response of ungulates was weak, and therefore clearance might not be justified if done for the purpose of propagating grazers. PMID- 27759194 TI - Implications of Climate Change for Production and Decomposition in Grasslands and Coniferous Forests. AB - A geographical information system, together with a climate-driven, global, regionalized, carbon-budget model, was used to investigate climatic limitations of grassland and coniferous forest vegetation units. The climatic limitations of the fluxes net primary productivity and litter decay were considered for present climatic conditions and for scenario conditions assuming a 3.5 degrees C temperature rise or a 10% precipitation increase, respectively. The two fluxes behave differently in respect to climatic limitations. Global grassland and coniferous forest areas are quite similar in size, but grasslands have the higher productivity while coniferous forests dominate in phytomass. Therefore, grasslands are more important for the seasonal carbon cycle. Coniferous forests have the stronger potential to influence the long-term carbon balance. The assumed climate change will strongly affect the climatic limitations of both vegetation types. PMID- 27759195 TI - Environmental Variation and the Persistence of Small Populations. AB - Understanding the factors that determine the continued survival of small populations is a central problem in conservation biology. The Acorn Woodpecker (Melanerpes formicivorus) naturally occurs in small, isolated populations throughout much of the American Southwest. In spite of this distributional pattern, the species is neither rare nor endangered. Thus it appears to have successfully "solved" the problems to the problems of habitat fragmentation. We used data from a 10-yr field study and simulation models to examine the effects of environmental stochasticity on population survival times. All simulated woodpecker populations went extinct within 49 yr, and the median survival time was only 16 yr. However, when immigration was allowed, persistence times greatly increased; with an immigrant rate of only five individuals per year, most populations lasted >1000 yr. The results of this and other analyses suggest that this population persists only because it is part of a larger "metapopulation," and because it is regularly rescued from extinction by immigration from other, independently varying, populations. This finding has important implications for the development of management strategies designed to preserve small populations that are faced with fragmented distributional patterns and high levels of environmental variation. PMID- 27759196 TI - Competition for Resources Between Understory Vegetation and Overstory Pinus Ponderosa in Northeastern Oregon. AB - The objective of this research was to determine which environmental resources, light, water, and/or nutrients, control understory plant production in a Pinus ponderosa forest in northeastern Oregon. A split-plot experimental design, with three 5.0-ha blocks, four treatments, and 44 plots, was established in the summer of 1985. Twenty plots (4 X 4 m) were trenched (root-reduction treatment) degrees 1 m in depth, and 24 non-trenched plots (root-control treatment) were used to assess the effects of root competition of overstory trees on understory plants. Trees were commercially thinned (canopy-reduction treatment) in half of each block (2.5 ha) during the winter and early spring of 1986, from a density of 345 to 148 trees/ha to increase light levels to the understory. Thinning significantly increased photosynthetically active radiation, decreased midday relative humidity, and increased midday air temperatures. Xylem potential of the dominant graminoid (Carex geyeri), soil water potential, mineralizable nitrogen, and pH were increased within the root-reduction vs. the root-control treatments. Micro- and macronutrients in C. geyeri and Symphoricarpos albus, the dominant shrub, were influenced in both treatments. Increasing light did not increase understory biomass production. Reducing root competition for soil water and nutrients increased understory aboveground biomass by 53 and 94% in 1986 and 1987, respectively. This research demonstrated that belowground resources were the primary controlling factors of understory production in P. ponderosa forests in northeastern Oregon. PMID- 27759197 TI - Integrating Scientific Methods with Habitat Conservation Planning: Reserve Design for Northern Spotted Owls. AB - To meet the requirements of Congressional legislation mandating the production of a "scientifically credible" conservation strategy for the threatened Northern Spotted Owl (Strix occidentalis caurina), the Interagency Spotted Owl Scientific Committee employed scientific methods to design a habitat reserve system. Information on the current and historical distributions of the owl and its habitats was reviewed in light of economic, political, and legal constraints; results were used to develop a preliminary reserve system of habitat "polygons." A map representing these polygons and their attendant properties served as a set of hypotheses that were tested. Statistical analyses of empirical data, predictions from ecological theory, predictions from population dynamics models, and inferences drawn from studies of related species were used to test properties of the preliminary map, including the number and sizes of habitat conservation areas (HCAs), their distribution, configuration, and spacing, and the nature of the landscape matrix between HCAs. Conclusions that failed to confirm specific map properties were used to refine the reserve system, a process that continued iteratively until all relevant data had been examined and all map properties had been tested. This conservation planning process has proven to be credible, repeatable, and scientifically defendable, and should serve as a model for wildlife management, endangered species recovery, and national forest planning. PMID- 27759198 TI - A Probabilistic Model to Study Spatial Variations of Primary Productivity in River Impoundments. AB - A stochastic approach to model the spatial variability of primary productivity in a river impoundment is presented in which data from LANDSAT-TM images of reference data from the field were used as basic inputs to the model. Primary productivity is predicted here by a set of variables (chlorophyll, temperature, and turbidity) combined by means of multivated probabilistic model wherein probability distribution functions were assigned to each variable. Linear regression analysis was used to relate the field reference data to the image data used as input to the model. The model was applied using maps of the variables obtained from the digital imagery. The results was a map of primary productivity probabilities converted to absolute values utilizing the cumulative function for field measurements of primary productivity. The field data were collected over degrees 1.5 yr at 16-d intervals at 12 sample sites. The overall r2 between the model results using field-measured variables and the measured primary productivity carbon values was 0.85 with an RMS (root mean square) error of 16 mg degrees m-3 degrees h-1 , where the carbon values ranged from 4 to 300 mg. m-3. h-1 . To test the methodology for the generation of primary productivity maps from LANDSAT imagery, two maps of primary productivity for Kentucky Lake were generated from data collected in August and December 1988. The model output was, in turn, compared to primary production carbon measurements from the reservoir. The r2 s were 0.89 and 0.76 with RMS errors in these carbon values of 10 and 18 mg degrees m-3 degrees h-1 . No specific assumptions about Kentucky Lake were required for this approach, so the methodology is applicable to other lakes or reservoirs in similar trophic states. PMID- 27759199 TI - Assessing the Indicator Properties of Species Assemblages for Natural Areas Monitoring. AB - The diversity of organisms and complexity of ecosystems prevent through inventory and monitoring of protected areas, yet sound databases are needed to manage ecosystems for long-term persistence. One strategy is therefore to focus monitoring on indicator organisms, but guidelines are lacking for selecting appropriate species or groups. This paper presents a simple protocol based on ordination techniques for establishing the indicator properties of a group of organisms and for selecting an indicator species subset for more intensive monitoring. Use of ordination allows inclusion of many more taxa than have been traditionally used for natural areas monitoring, and need not rely on detailed knowledge of species biology. As an example, I studied the indicator properties of a butterfly taxocene in a rain forest in Madagascar. Butterflies have been suggested as particularly good environmental indicators due to their sensitivity to micro-climate and light level changes, and their interactions as larvae and adults with different sets of host plants. The indicator properties of butterfly assemblages were evaluated in this study with respect to a known pattern of environmental heterogeneity along topographic/moisture and disturbance gradients. Butterfly assemblages were found to be excellent indicators of heterogeneity due to the topographic/moisture gradient, limited indicators of heterogeneity due to anthropogenic disturbance, and poor indicators of plant diversity. The protocol defined in this study is widely applicable to other groups of organisms, spatial scales, and environmental gradients. By examining the environmental correlates of the distribution of species assemblages, this protocol can assess the indicator properties of target species groups. PMID- 27759200 TI - The Performance and Legacy of NAPAP. AB - This paper reviews the performance of the National Acid Precipitation Assessment Program during its initial 10 yr. Special emphasis is given to contributions to science, to public decision-making, and to lessons for future environmental and ecological research. PMID- 27759201 TI - Orchestrating Environmental Research and Assessment. AB - When pressing national environmental problems must be solved, and serve as the justification for large infusions of public funds, mechanisms must be found to assure that the requisite research and assessment are performed. Large, managed programs seem to offer a way to direct energies in the needed directions, but individual creativity and intellectual curiosity must also be fostered through investigator-initiated studies. Research results cannot be achieved to meet imposed deadlines, and assessment in the face of uncertainty must be given due attention. This paper introduces five subsequent papers, four of which present perspectives on the National Acid Precipitation Assessment Program, as a model for coordinated research and assessment programs, and one that presents plans for a national and international research effort on biodiversity. PMID- 27759202 TI - Population Dynamics in Complex Landscapes: A Case Study. AB - The abundance and distribution of natural populations can be strongly influenced by the types and arrangement of habitat patches within a landscape. The impact of landscape changes on population dynamics is difficult to study using conventional population models and field techniques. Spatially explicit simulation models provide a powerful method for modelling landscape and population changes at large spatial scales and may prove useful as a management tool for mobile animal populations. As an example of this approach, we present a model designed to elucidate the effects of landscape-level variation in habitat dispersion on the size and extinction probability of avian populations in a region managed for timber production. In the model, habitat suitability and availability within the landscape change annually as a function of timber harvest and management strategies. The model incorporates life history characteristics of Bachman's Sparrow (Aimophila aestivalis), a species of management concern in the southeastern United States, and the landscape characteristics of the Savannah River Site, South Carolina, an area managed for timber production where the sparrow is relatively common. Life history characteristics used in the model include dispersal, survivorship, and reproductive success information reported for Bachman's Sparrow at this site or elsewhere in its range. Results of the simulations suggest that variation in demographic variables affects population size more than variation in dispersal ability. Changes in adult and juvenile survivorship have especially large impacts on the probability of population extinction. The presence of habitat types that serve as permanent sources of dispersers increases the total population size in the landscape, and lowers the probability of extinction. Results of models such as BACHMAP can suggest modifications to current management plans that would increase the probability of population persistence for species of special concern in managed landscapes. PMID- 27759203 TI - Lessons from NAPAP. AB - NAPAP was an institutional innovation of great benefit in bringing the United States to a decision on acid precipitation control. The nation's return from the $600 000 000 investment in NAPAP will be greater still if the lessons learned in the course of its existence are put to proper use in the future. This essay concentrates on the lessons learned about the interface between science and public policy as experienced in NAPAP. PMID- 27759204 TI - Avian Repellency of Coniferyl and Cinnamyl Derivatives. AB - Phenylpropanoids, a class of common phenolic compounds in plants, may potentially be useful as pest repellents. We investigated the relationship between the chemical structure of coniferyl benzoate and its repellency to birds by comparing coniferyl benzoate to two analogous natural esters, corresponding alcohols, and benzoic acid. The absolute and relative feeding repellency of these compounds were assessed in choice (two-cup) and no-choice (one-cup) tests using European Starlings (Sturnus vulgaris). In addition, benzoin Siam (= gum benzoin Siam) was compared to coniferyl benzoate to ascertain if phenolics that naturally occur with coniferyl benzoate in benzoin Siam enhance its repellency. Two-cup tests suggested that coniferyl alcohol was the most repellent compound followed by 3,4 dimethoxycinnamyl alcohol, 3,4-dimethoxycinnamyl benzoate, cinnamyl alcohol, cinnamyl benzoate, coniferyl benzoate, and benzoic acid. The repellency of most alcohols relative to their corresponding ester reversed in the one-cup tests. One cup tests suggested that 3,4-dimethoxycinnamyl benzoate was the most repellent substance followed by cinnamyl benzoate, benzoin Siam, 3,4 dimethoxycinnamylalcohol, cinnamyl alcohol, coniferyl alcohol, coniferyl benzoate, and benzoic acid. Three conclusions on structure-activity relationships were inferred from these data. First, benzoate esters are more repellent than their corresponding alcohols.Second, repellency is increased by electron-donating groups. Third, acidic functions decrease repellency. We suggest that one function of naturally occurring coniferyl and cinnamyl derivatives may be chemical defense. Genetically engineering agricultural crops to produce analogs of coniferyl alcohol, as an inherent defense against pests and pathogens, may be possible. PMID- 27759205 TI - The Iubs-Scope-Unesco Program of Research in Biodiversity. AB - A planning workshop was called by IUBS (the International Union of Biological Sciences) at the Harvard Forest to develop an international research program in biodiversity, including the inventorying and monitoring of the world's biological diversity. Workshop participants were asked to develop research hypotheses that answer aspects of the question "What is the importance of biodiversity for the proper functioning of biological systems, from populations to ecosystems?" The hypotheses developed dealt with the changes that might be expected in biodiversity as a result of anthropogenic activity and also the complementary issue of how changes in biodiversity will affect the functioning of biological systems. Habitat fragmentation, loss and addition of species, changes in the functional and structural attributes of ecosystems, and the ability of depauperate ecosystems to respond to climatic and other changes, were addressed. Two issues emerged from the workshop as needing serious investigation. The first is the degree to which each species of plants and animals is unique. Many species are similar in appearance; many more perform similar ecological functions (primary producers, herbivores, decomposers, etc.). However, no two species are alike in their genetic structure or in all functional features. A very fundamental question for managers and decision-makers is the degree to which a species can substitute for another in an ecosystem, that is, how much is ecosystem function impaired when a species is lost or gained? Since human activities are resulting in both losses and introductions, a careful and precise answer to this question is essential. The second issue concerns habitat fragmentation. Human activity is creating an unprecedented fragmentation of natural habitats and ecosystems all over the world. Habitat fragmentation disrupts gene flow and propagule dispersal, but can result in increased speciation and differentiation of populations. Much more information is needed before it will be possible to predict the effects of habitat fragmentation. Without this information precise management of natural and artificial ecosystems is not possible. It is one of the issues tagged by the workshop as of crucial importance for future research. The workshop pointed out once more the serious problem that the decline in taxonomic activity is creating. There is a serious shortage of trained systematists all over the world, but particularly in tropical countries where most of the world's diversity is located. A strong recommendation from the workshop is that support for training and research in systematics be increased, that systematic collections be upgraded and supported, and that more employment opportunities for systematists be created. PMID- 27759206 TI - A View of NAPAP from North of the Border. AB - Despite widespread political interference with programs and confusion of science and policy, the NAPAP program has produced a number of sound, if not outstanding, publications documenting the effects of acidic deposition. NAPAP's outstanding strengths in aquatic science are in paleoecology and spatial surveys of chemistry. NAPAP has severe shortcomings in documentation of temporal trends, in deducing biological responses to acidification by organisms other than fish, in considering the effects of nitrogen deposition, and in considering results from countries other than the USA. Summaries of the NAPAP program in 1987 and 1990 underrepresent the extent of damage caused by acidification, as documented elsewhere in NAPAP's publications and by the peer-reviewed literature at large. Overall, it represents a mediocre return for a large amount of investment, and is a poor model for future large, multidisciplinary science projects. PMID- 27759207 TI - Forest Response Research in NAPAP: Potentially Successful Linkage of Policy and Science. AB - The Forest Response Program (FRP), a major component of the National Acid Precipitation Assessment Program (NAPAP), was established only after NAPAP had been underway for five years. Thus, it benefitted from a more sophisticated understanding of the essential policy questions that the research on forests would be required to answer, in comparison to the earlier aquatic studies. The "gradient studies" of the Eastern Hardwoods Research Cooperative were planned as 5-yr projects to determine whether there was any epidemiological pattern in forest responses corresponding to measures of pollutant dose (acidic deposition or oxidants). The NAPAP "Assessment" was written after only 3 yr of the research, and its findings differ in important ways from the 5-yr findings of the gradient studies. The FRP had the potential to be a model study of how applied research can be designed to solve major resource policy questions, but it is perceived to have failed for reasons of multiple non-congruences between planning and reporting. Potential still exists for a positive outcome. PMID- 27759208 TI - Soil Chemistry in a Loblolly/Longleaf Pine Forest with Interval Burning. AB - We examined the 30-yr cumulative effects of prescribed fires at intervals of 1, 2, 3, and 4 yr in a loblolly and longleaf pine forest in the Coastal Plain of South Carolina. The fine fraction of the forest floor (Oe + Oa horizons) contained much more carbon and nitrogen per unit area in the control plots (1.7 and 0.05 kg/m2 , respectively) than in the 1-yr burn interval plots (0.4 and 0.007 kg/m2 , respectively). Mineral soils (0-0.2 m depth) were highly variable in chemistry, and showed only slight differences across the burning treatments for nitrogen and sulfur. No trends were apparent for phosphorus in the forest floor or mineral soil; differences in acidity and extractable cations were also slight. The nutrient content of foliage was generally low, with no differences across burning intervals. Our results are consistent with earlier studies that showed the biogeochemical effects of repeated surface fires in southern pine forests are generally limited to the forest floor, with the possible exception of overall reductions in nitrogen cycling. PMID- 27759209 TI - The Effect of Leaf-Mining by Liriomyza Trifolii on Seed Set in Greenhouse Marigolds. AB - The effect of foliage feeding by the serpentine leafminer, Liriomyza trifolii (Burgess), on seed production and germination by male-sterile marigolds (Tagetes erecta L.) was examined over two cropping seasons in commercial production greenhouses. Five components of T. erecta relative fitness (the number of flowers, ovules, and germinations per plant, seed mass, and plant height) were compared in plants grown under four different control strategies representing three different intensities of L. trifolii herbivory: no control (high herbivory), biological or chemical control (intermediate herbivory), and insect free (low herbivory). In both years of the study, significant between-treatment differences in number of viable seeds per plant were detected but no significant differences were found in the other four relative fitness measures. The number of viable seeds was highest with high herbivory (no-control treatments) and lowest with comparatively low herbivory (chemical and insect-free treatments). L. trifolii damage may reduce photosynthate availability, which may slow seed development and increase the length of time in which ovule physiological and morphological conditions are suitable for successful fertilization. Because all plants within each year received an equal number of pollinations occurring at the same time relative to plant growth, ovules within plants in the high-damage treatments may have had a greater probability of being fertilized, resulting in an increase in production of viable seeds. PMID- 27759210 TI - Tests of Spatial and Temporal Interaction Among Animals. AB - I report a method for analyzing interaction between two animals around a common object or resource (simple association) or within a shared area (spatial-temporal interaction in home range overlap). The pair's association is reduced to binomial events forming a 2 x 2 classification; each is either present or not in the shared area. For the most common home range overlap description, observed frequencies of presence and absence for each animal are compared to expected frequencies based on two null hypotheses of spatially independent home range use by each animal relative to the other, and one null hypothesis of temporally independent home range use by the two animals. The procedure uses any statistically derived, two-dimensional home range representation that allows spatial overlap to be delineated for each animal pair. The temporal order of simultaneous pairs of locations for the two animals can then be evaluated for a pattern of use regarding the area of overlap (shared area). The window of "simultaneity" is dictated by the animal's primary sensory mode and mobility. An overall chi-squared test with three degrees of freedom is partitioned into spatial "main effects" and temporal "interaction," analogous to analysis of variance. The two main effects are each animal's purely spatial attraction to or avoidance of the shared area. When interaction effects are significant, it is possible to interpret temporal attraction to or avoidance of the shared area. This temporal response is in terms of the pair's simultaneous vs. solitary occupation of the shared area relative to overall home range use. Experimental design and assumptions are discussed because degree of adherence affects the validity of inferences and influences interpretation. Detailed examples of analysis and interpretation from North American badgers (Taxidea taxus) and from mule deer (Odocoileus hemionus) interacting with domestic cattle (Bos taurus) illustrate the range of complexity inherent to even this simple form of interaction analysis. PMID- 27759211 TI - Experimental Policies for Water Management in the Everglades. AB - Marshland drainage and water regulation have greatly altered the Florida Everglades. One of the most visible ecological impacts has been a drastic decline in nesting populations of wading birds, and several specific hypotheses have been advanced to explain the decline. Recent efforts at ecological restoration have concentrated on reestablishing more natural seasonal hydropatterns in freshwater marsh areas now used extensively by the wading birds. However, nesting colonies were originally concentrated along the estuarine mangrove edge of the system rather than around upstream marshes. Hydrological simulation models have been used to reconstruct what hydrological conditions might have been like in the natural system, and these simulations indicate that freshwater pools near and flows to the estuary have been drastically reduced, especially late in the annual spring drying season. An experimental program of increased water releases to the estuary could be used to test whether estuarine restoration is a necessary condition for recovery of wading bird populations. This program would require a substantial commitment to deliver runoff from the Everglades Agricultural Area into the marshes, and to minimize water diversions for flood control and well field recharge. PMID- 27759213 TI - Early report on brain arousal regulation in manic vs depressive episodes in bipolar disorder. AB - OBJECTIVES: The arousal regulation model of affective disorders attributes an important role in the pathophysiology of affective disorders to dysregulation of brain arousal regulation. According to this model, sensation avoidance and withdrawal in depression and sensation seeking and hyperactivity in mania can be explained as auto-regulatory attempts to counteract a tonically high (depression) or unstable (mania) arousal. The aim of this study was to compare brain arousal regulation between manic and depressive bipolar patients and healthy controls. We hypothesized that currently depressed patients with bipolar disorder show hyperstable arousal regulation, while currently manic patients show unstable arousal regulation. METHODS: Twenty-eight patients with bipolar disorder received a 15-min resting electroencephalogram (EEG) during a depressive episode and 19 patients received the same during a manic/hypomanic episode. Twenty-eight healthy control subjects were matched for age and sex. The Vigilance Algorithm Leipzig (VIGALL), which classifies 1-s EEG segments as one of seven EEG-vigilance substages, was used to measure brain arousal regulation. RESULTS: Manic patients showed more unstable EEG-vigilance regulation as compared to the control sample (P = .004) and to patients with a depressive episode (P <= .001). Depressive patients had significantly higher mean vigilance levels (P = .045) than controls. CONCLUSIONS: A clear difference was found in the regulation of brain arousal of manic patients vs depressive patients and controls. These data suggest that brain arousal might depend on the current mood state, which would support the arousal regulation model of affective disorders. PMID- 27759214 TI - Neuroprogression and episode recurrence in bipolar I disorder: A study of gray matter volume changes in first-episode mania and association with clinical outcome. AB - OBJECTIVES: Bipolar I disorder (BD-I) is associated with gray matter volume (GMV) alterations in neural regions important for emotional regulation. Reductions found in patients with multiple episodes are not seen at illness onset, suggesting that changes occur with illness progression, although no prospective studies to date have examined this. In the present study, we assessed GMV at baseline and one year following a first manic episode, examining the impact of episode recurrence on the trajectory of change. METHODS: A total of 41 recently remitted first manic episode patients with BD-I and 25 healthy subjects (HS) underwent 3T magnetic resonance imaging at baseline and one year later. Using voxel-based morphometry, we compared GMV change between HS, patients who experienced a recurrence of a mood episode (BDrecurr ), and patients in sustained remission (BDwell ). RESULTS: The GMV change from baseline to one year did not differ significantly between HS and the full BD-I group or BDwell and HS. However, the BDrecurr group had greater GMV loss than HS in left frontal and bilateral temporal regions, and BDwell patients involving bilateral frontal, temporal and left parietal regions. CONCLUSIONS: GMV change early in the course of BD-I is associated with clinical outcome, such that neuroprogression found in patients who experience a recurrence of a mood episode is not seen in those with sustained remission. These findings have important implications for the treatment of BD-I as they suggest that prevention of recurrence might minimize neuroprogression of the disease, possibly requiring a multipronged early intervention approach to achieve this goal. PMID- 27759212 TI - Replication of genome-wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort. AB - OBJECTIVES: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. METHODS: A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations. RESULTS: Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P<=.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5' nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. CONCLUSIONS: These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD. PMID- 27759215 TI - Maximization of Aboveground Grassland Production: The Role of Defoliation Frequency, Intensity, and History. AB - Production of tallgrass prairie vegetation was measured on experimental plots in which defoliation intensity and frequency were manipulated by mowing and using movable exclosures on areas chronically grazed by cattle. Defoliation history largely controlled whether or not defoliated plants overcompensated (exhibited enhanced production compared to undefoliated controls) for tissue removal. Plants on chronically grazed sites only compensated for foliage removed by grazers. Production on plots mowed prior to the year of measurement was similar to that on chronically grazed sites, while previously unmowed plots exhibited substantial aboveground overcompensation. Aboveground production was maximized by the most frequent mowing treatment and by intermediate mowing heights. Nitrogen and phosphorus concentrations and amounts in aboveground tissues were increased by mowing and grazing. Current mowing regime was more important than mowing history in determining nitrogen concentrations except very early in the growing season. Effects of grazing and mowing on belowground biomass were inconsistent, but frequent mowing appeared to limit accumulation of belowground N reserves and biomass. In North American grasslands, overcompensation is a nonequilibrium plant response to grazing. Photosynthate that would be stored as reserves and used for root growth and flower and seed production instead is used to replace lost leaf area, thereby resulting in higher foliage productivity. However, under chronic grazing or mowing, vegetation is prevented from maintaining high nutrient and water uptake capacity (large root biomass) and accumulating reserves that allow overcompensation responses. PMID- 27759216 TI - Copper Dynamics and the Mechanism of Ecosystem Level Recovery in a Standardized Aquatic Microcosm. AB - The Standardized Aquatic Microcosm (SAM) was used to assess the effects and behavior of copper at the ecosystem level. The concentration of algal cells and Daphnia magna, pH, dissolved organic carbon (DOC), and dissolved and ionic copper concentration were measured for 489 d and used to explain the recovery sequence of a community of organisms. The results indicate that a resistant algal species was crucial for initiating the recovery sequence in these microcosms and that the timing of D. magna blooms was variable but highly correlated with decreasing ionic copper. In order to explain copper toxicity and the success of the recovery phase, a stepwise analysis of the functional role of the resistant algal species Oocystis pusilla, and the tolerance of D. magna was undertaken. These process studies determined that O. pusilla was a suitable food for D. magna, and that this algal species could also act as a major ligand for copper, although sorption was probably important only for a limited time during the bloom. These studies also concluded that copper bioavailability controlled toxicity because it was shown that D. magna from the microcosms exhibited no resistance to copper toxicity, even though the dissolved copper concentration was 5 times the LC50 value (concentration lethal to 50% of the population). DOC and pH, which were controlled by algal metabolism, were probably important for decreasing ionic copper, which allowed the recovery sequence to begin. Additional studies showed that the microcosm-derived DOC was able to complex copper at low pH and that DOC was highly correlated with reduced concentrations of ionic copper. PMID- 27759217 TI - Prospects for Weed Control Through Crop Interference. AB - Crop interference with weed growth is a fundamental method of nonchemical weed control. Crop interference, entailing weed suppression, should be distinguished from crop tolerance of weeds, i.e., relatively small yield loss due to the presence of weeds. Tolerance is less desirable than interference in that it may lead to increases in weed seed populations that can cause future yield losses. Ideally, interference should occur as early as possible in growth to prevent resource consumption by weeds. A path analysis of crop-weed interference is presented. The model can be used to estimate the relative magnitude of early vs. later crop interference with weed growth, and to identify crop traits that contribute to the interference with weed growth. Such analysis can identify crop varieties that show strong early interference with weed growth, and traits associated with strong early interference. For illustrative purposes, the model is applied to characterize differences among soybean varieties in interference with common cocklebur. Weed control by crop interference could be enhanced by crop breeding and management. However, several benefits and costs of interference should be evaluated before undertaking such approaches. First, the degree to which crop interference can substitute for other forms of weed control must be determined. Second, yield costs associated with interference should be measured; these may occur in crop varieties that interfere strongly with weeds, particularly when water, temperature, and mineral nutrients are limiting. A more mechanistic understanding of crop interference is needed so that interference can be enhanced through crop breeding and management while minimizing yield costs. PMID- 27759218 TI - Making Ecological Information Practical for Resource Managers. AB - There has been a tendency for ecologists to present results from ecological studies and then be critical of resource managers because the best available scientific information was not incorporated into decisions about natural resources. This unfortunate situation must be remedied by ecologists, who should explicitly consider the ways in which results can be applied to management issues. Ecologists and resource managers should collaborate to establish the topical framework in which concepts such as growth compensation/overcompensation should be considered. Finally, under presettlement conditions, the tallgrass prairie probably produced overcompensation under lightly to moderately grazed conditions. PMID- 27759219 TI - Canopy Architecture of Natural and Planted Cordgrass Marshes: Selecting Habitat Evaluation Criteria. AB - In order to set standards for restoration or mitigation "success" of salt marsh habitat designed for an endangered southern California bird, I explored the bird's nesting requirements, compared constructed habitats that lack the bird with natural habitats that support it, and selected habitat assessment criteria that best distinguish suitable and unsuitable nesting habitats. Selected attributes of canopy architecture are recommended for assessing the suitability of intertidal cordgrass (Spartina foliosa) marshes for the endangered Light footed Clapper Rail (Rallus longirostris levipes) of southern California. Nests are built at degrees 145 cm above Mean Lower Low Water (MLLW = 0 tidal datum), with nest rims at degrees 165-170 cm MLLW; however, extreme high water is 232 cm MLLW during the March-July nesting season, and tidal inundation is a major cause of nest failure. Cordgrass that is >60 cm tall appears necessary for birds to weave a canopy that allows the nest to float upward, but not away, as the tide rises. Cordgrass height distributions and density data describe attributes of canopy architecture that assess Clapper Rail habitat value better than previously used measures (i.e., cover, biomass, mean height, maximum height). Height histograms differ for planted marshes (which do not support Clapper Rails) and natural marshes. The constructed marshes have few plants over 60 cm, while most stems in natural marshes exceed 60 cm. In natural marshes, cordgrass heights increase with freshwater flooding and nitrogen enrichment. Reference data from natural marshes that are used by Clapper Rails indicate that the standard for "suitable habitat" should be a density of at least 100 stems/m2 with at least 90 stems/m2 >60 cm, of which at least 30 stems/m2 are >90 cm in height. High interannual and spatial variability indicates the need for several (e.g., 20) years of data for assessment purposes and a large data base for reference wetlands. PMID- 27759220 TI - Plant and Soil Responses to Chronic Nitrogen Additions at the Harvard Forest, Massachusetts. AB - Data are presented on changes in plant and soil processes in two forest types (red pine plantation and oak-maple forest) at the Harvard Forest, Petersham, Massachusetts, in response to 3 yr of chronic N fertilization. The hardwood stand exhibited greater N limitation on biological function than the pine stand prior to fertilization as evidenced by a lower net N mineralization rate, nearly undetectable rates of net nitrification, and very low foliar N content. N additions were made in six equal applications throughout the growing season, and consisted of 5 and 15 g degrees m-2 degrees yr-1 of N as ammonium nitrate. The pine stand showed larger changes than the hardwood stand for extractable N, foliar N, nitrification, and N leaching loss. Retention of added N was essentially 100% for all but the high application pine plot from which significant N leaching occurred in the 3rd yr of application. From 75 to 92% of N added to fertilized plots was retained in the soil, with larger fractions retained in the hardwood stand than the pine stand for all treatments. As hypothesized, the stands are exhibiting highly nonlinear patterns of nitrogen output in response to continuous nitrogen inputs. The implications of this nonlinearity for regional eutrophication of surface waters and atmospheric deposition control policy are discussed. PMID- 27759221 TI - Spatial and Temporal Variation in Competitive Effects on Soil Moisture and Pine Response. AB - The effects of different plant life-forms, including a bunch grass species, Andropogon virginicus L. (broomsedge), and a sprouting deciduous tree species, Liquidambar styraciflua L. (sweetgum), on soil moisture and competitive responses of a transplanted coniferous tree seedling, Pinus taeda L. (loblolly pine), were investigated. Addition of the bunch grass and/or hardwood sprouts either had no effect or increased soil moisture in the surface soil (0-14 cm) depending on the time, while addition of sweetgum and/or broomsedge (greatest density alone) decreased soil moisture in deeper portions of the solum during the summer months. Soil moisture available to pine seedlings at various points in time was assessed by measuring predawn xylem pressure potential. Temporal variation in predawn xylem pressure potential was accounted for through a water stress integral approach. More than half of the variation in pine size after one growing season could be accounted for by the water stress integral. PMID- 27759222 TI - Herbivory and Its Consequences. AB - We argue that herbivores often induce nonlinear or biphasic growth and development in plants. Collectively these individual responses translate into a system-level optimization curve wherein at low levels of herbivory overall community responses show increases in production potential, whereas extreme herbivory causes extreme reduction in productivity. The transition between these two states defines a point of optimal herbivory in respect to C and N processes.We present four case examples from the literature demonstrating such nonlinear responses, suggesting a widespread existence for this herbivore-plant phenomenon. The nonlinear responses appear to demonstrate temporal and spatial scale dependencies. PMID- 27759223 TI - Grazing and Plant Performance. AB - Grazing is more than just defoliation of plants. The impact of herbivory affects ecosystem structure and function, both above and below ground. Ultimately, effects of herbivory are expressed to varying degrees at many levels of the ecosystem. Herbivory has been shown to affect plant physiology, morphology, and genetics. Plants have evolved many ways to avoid or tolerate herbivory. Whether plant overcompensate, equally compensate, or undercompensate to herbivory depends on pre- and post-harvest conditions of the plants and their environment. To be important to the manager, the magnitude of compensation must be greater than the inherent "noise" in the system. Natural resources managers use scientific information about herbivory to reduce ambiguity in decision-making in an environment of uncertainty. If an ecological response like compensation is to have practical application for the manager, the meaningful effects must occur on time and spatial scales that the manager can respond to with available resources. PMID- 27759224 TI - Compensating Growth of Grazed Plants and Its Relevance to the Use of Rangelands. AB - There are several well-known mechanisms by which grazing can reduce the subsequent growth rate of plants, and several other well-documented mechanisms by which grazing can enhance plant growth rate. The net effect of single or repeated grazing events on the cumulative growth of plants may thus be zero, negative, or positive, depending on availability of leaf area, meristems, stored nutrients, and soil resources, and on the frequency and intensity of defoliation. Plants are preadapted to compensate, up to a certain point, for losses due to grazing, by virtue of their modular structure and development. Reports of "overcompensation" to grazing, as one extreme of a wide range of responses observed in natural grasslands, need not be treated with special skepticism; neither are they a solid base for a general theory of evolved grass-grazer mutualism. The question of compensatory growth is of relevance to management of Western rangelands for livestock production, but of relatively little relevance to conservation goals. No region-wide answers can be expected. Any drastic change in grazing intensity in either direction requires evaluation by community-specific and long-term research. PMID- 27759225 TI - Application of Herbivore Optimization Theory to Rangelands of the Western United States. AB - Ecological research can be misinterpreted by the popular press and misapplied in land management. One example of this concerns the controversial concepts of overcompensation by grazed plants and herbivore optimization of plant productivity (or, as popularly phrased, the idea that plants benefit from being grazed). Although available evidence indicates that whole-plant overcompensation and optimization of productivity rarely occur and may have little or no evolutionary or applied significance, these concepts have been accepted by some popular writers and land managers, and are being used to justify heavy livestock grazing on western North American rangelands. There may be many reasons for this acceptance of unsubstantiated hypotheses, including uncritical reading and overly broad extrapolations by writers and managers, as well as failure by scientists to clearly and accurately communicate results and conclusions. PMID- 27759226 TI - Management of Weed Seed Banks with Microorganisms. AB - Successful weed management in agroecosystems centers on manipulating the weed seed bank in soil, the source of annual weed infestations. Despite advances in aboveground weed control and decreases in the production of new seed, weed infestations continue to be generated from a small portion of the seed bank that persists as a result of dormancy and resistance to decay. Depletion of the persistent seeds using soil-applied chemicals to stimulate germination has received much attention while the search for microorganisms selective for seed decay has been largely overlooked. This paper provides an overview of the effects of microorganisms on weed seed viability relative to seed bank depletion, and how this information can be applied to weed management. Limited studies indicate that microorganisms associated with weed seeds can contribute to seed bank depletion through attraction to seeds by chemotaxis, rapid colonization of the spermosphere and production of enzymes and/or phytotoxins to kill seeds prior to germination. It is recognized, however, that the best opportunity for success will be through integration of selected microorganisms or microbial products with other approaches including germination stimulation, application of low rates of herbicides, manipulation of the soil environment (e.g., solarization), and biological control agents for effectively eliminating dormant, persistent seeds from soil. To achieve success, more in-depth research on microbial factors affecting weed seed banks is required. PMID- 27759227 TI - A Model of the Effects of Tillage on Emergence of Weed Seedlings. AB - A simple model is developed in which the density of weed seedlings emerging in a field is related to (1) the ability of seedlings to emerge from various depths in the soil, (2) the survival of seeds at different depths, and (3) the depth of seed burial in no tillage, rotary tillage, and plow tillage. Other tillage regimes are considered by analogy. Literature is reviewed to determine biologically reasonable functions describing seedling emergence, seed survival, and distribution of seeds with depth, and parameters of these equations are estimated from data in the literature. Problems related to the mathematical description of these phenomena are discussed, and it is noted that some commonly held beliefs regarding survival of seeds in the soil are mutually incompatible. Although many studies have investigated the persistence of seeds as a function of depth in the soil, few have distinguished death from the production of seedlings. The model indicates that in the first year following input of seeds to the soil, no tillage will have more seedlings than tillage, but in later years no tillage will likely have fewer seedlings unless innate or induced dormancy is high or seed survival near the soil surface is unusually good. If seed return is allowed, no tillage or minimum tillage will have more seedlings perennially. Recovery of good weed control following a year with substantial seed input may be easiest if the soil is plowed deeply to bury the seeds, and then shallow or no tillage is used in subsequent years to avoid returning seeds to the surface. Much of the literature on the effects of tillage on weed density is difficult to interpret because little indication is given of the vertical distribution of seeds in the soil at the beginning of the experiment. PMID- 27759228 TI - Grazing Optimization: A Plea for a Balanced Perspective. AB - Compensatory plant growth may be a significant ecological process that minimizes the reduction of primary production in direct proportion to the severity of defoliation in some species and systems given the appropriate combination of environmental variables. However, the potential benefits of compensatory growth should not obscure the well-established ecological processes governing the sustainability of grazed systems in the face of large scale environmental degradation and a rapidly expanding human population. The sustainability of grazed systems is a more fundamental issue than grazing optimization. PMID- 27759229 TI - Herbivore Optimization and Overcompensation: Does Native Herbivory on Western Rangelands Support These Theories? AB - Recent articles in Ecological Applications and a response by Painter and Belsky (this issue) illustrate the controversy over theories of plant response to grazing, such as herbivore optimization and overcompensation. Observations of elk grazing in Yellowstone National Park and mixed cattle and elk grazing in the Southwest are presented as case studies to test these theories. Heavy grazing by elk in Yellowstone caused some areas to be dominated by exotic grasses, while shrubby species were heavily browsed. High-elevation rangeland conditions deteriorated in the Southwest where elk and cattle both grazed. Theories of herbivore optimization and overcompensation do not appear to be supported by the response of western rangelands to grazing by native herbivores. PMID- 27759230 TI - Grasses and Grazers, Science and Management. AB - The evidence that pure ecological science has influenced grazing management practices employed in livestock husbandry on the North American Great Plains is tenuous at best. Those practices arose from critical technological innovations in the 19th century that modified the essential properties of grazing ecosystems when applied to livestock husbandry. Ecological research has identified many significant differences as well as similarities between natural and human-defined grazing systems, and how husbandry can lead to overgrazing. There is considerable evidence that moderate grazing can increase primary productivity and unequivocal evidence that some plants benefit from the presence of grazing animals. PMID- 27759231 TI - Weed Management: A Need to Develop Ecological Approaches. PMID- 27759232 TI - Quantifying Dispersal of Southern Pine Beetles with Mark-Recapture Experiments and a Diffusion Model. AB - Pest management decisions should take into consideration quantitative information on dispersal of insect pests, but such information is often lacking. The goal of this study was to measure intraforest dispersal in the southern pine beetle (SPB). We developed an analytical formula for interpreting data from mark recapture studies of insect dispersal. The formula is obtained by postulating a simple model of diffusion with disappearance (e.g., as a result of death) for the spread of marked insects from the release point. Parameters of the model (assumed to be invariant in space) are estimated by fitting the curve to the cumulative number of recaptured insects as a function of the distance from release. We also derived an expression for the distribution of dispersal distances in terms of the fitted parameters. The proposed methodology was applied to a mark-recapture study of SPB dispersal Statistical analysis of recaptures-with-distance curves obtained in 11 replicate releases indicated that the proposed formula provided an accurate description of the data. There were no systematic departures from the functional relationship prescribed by the formula, and the model consistently outperformed another commonly used formula for fitting data on dispersal distances, the exponential curve. We explored the effect of spatial heterogeneity in the host distribution on SPB movement by regressing the deviation from the recapture rate predicted by the model in each trap on the pine basal area around the trap. This correlation was significantly greater than zero, indicating that beetles tended to aggregate in localities where pines were dense. This result suggests that a diffusion model with spatially varying parameters may provide a more accurate description of the redistribution process in the SPB. Quantitative results on SPB intraforest dispersal were summarized by calculatingradii of circles enclosing a given proportion of SPB dispersal distances. For example, we estimated that one half of released beetles dispersed >0.69 km. This result has important implications for evaluating the area-wide consequences of current or novel control tactics that rely on disrupting SPB movements, e.g., cut-and-leave and treatments with anti-congregation pheromone. PMID- 27759233 TI - Further Considerations on the Debate Over Herbivore Optimization Theory. AB - Criticism of the basis and use of the herbivore optimization theory is discussed. It is argued here that evidence from theory and agricultural practice support the view that compensation and overcompensation of total primary production can occur in plant populations and communities subjected to grazing. However, whether this will occur depends on specific circumstances. Modeling and carefully designed field studies should be used to determine the responses of rangeland systems under a variety of environmental conditions and grazing intensities. PMID- 27759234 TI - Crop Rotation and Intercropping Strategies for Weed Management. AB - Results of a literature survey indicate that weed population density and biomass production may be markedly reduced using crop rotation (temporal diversification) and intercropping (spatial diversification) strategies. Crop rotation resulted in emerged weed densities in test crops that were lower in 21 cases, higher in 1 case, and equivalent in 5 cases in comparison to monoculture systems. In 12 cases where weed seed density was reported, seed density in crop rotation was lower in 9 cases and equivalent in 3 cases when compared to monocultures of the component crops. In intercropping systems where a main crop was intersown with a "smother" crop species, weed biomass in the intercrop was lower in 47 cases and higher in 4 cases than in the main crop grown alone (as a sole crop); a variable response was observed in 3 cases. When intercrops were composed of two or more main crops, weed biomass in the intercrop was lower than in all of the component sole crops in 12 cases, intermediate between component sole crops in 10 cases, and higher than all sole crops in 2 cases. It is unclear why crop rotation studies have focused on weed density, whereas intercropping studies have focused on weed biomass. The success of rotation systems for weed suppression appears to be based on the use of crop sequences that create varying patterns of resource competition, allelopathic interference, soil disturbance, and mechanical damage to provide an unstable and frequently inhospitable environment that prevents the proliferation of a particular weed species. The relative importance and most effective combinations of these weed control tactics have not been adequately assessed. In addition, the weed-suppressive effects of other related factors, such as manipulation of soil fertility dynamics in rotation sequences, need to be examined. Intercrops may demonstrate weed control advantages over sole crops in two ways. First, greater crop yield and less weed growth may be achieved if intercrops are more effective than sole crops in usurping resources from weeds or suppressing weed growth through allelopathy. Alternatively, intercrops may provide yield advantages without suppressing weed growth below levels observed in component sole crops if intercrops use resources that are not exploitable by weeds or convert resources to harvestable material more efficiently than sole crops. Because of the difficulty of monitoring the use of multiple resources by intercrop/weed mixtures throughout the growing season, identification of specific mechanisms of weed suppression and yield enhancement in intercrop systems has so far proven elusive. Significant advances in the design and improvement of weed suppressive crop rotation and intercropping systems are most likely to occur if three important areas of research are addressed. First, there must be continued attention to the study of weed population dynamics and crop-weed interference in crop rotation and intercropping systems. More information is needed concerning the effects of diversification of cropping systems on weed seed longevity, weed seedling emergence, weed seed production and dormancy, agents of weed mortality, differential resource consumption by crops and weeds, and allelopathic interactions. Second, there needs to be systematic manipulation of specific components of rotation and intercropping systems to isolate and improve those elements (e.g., interrow cultivation, choice of crop genotype) or combinations of elements that may be especially important for weed control. Finally, the weed related impacts of combining crop rotation and intercropping strategies should be assessed through careful study of extant, complex farming systems and the design and testing of new integrated approaches. Many aspects of crop rotation and intercropping are compatible with current farming practices and could become more accessible to farmers if government policies are restructured to reflect the true environmental costs of agricultural production. PMID- 27759235 TI - Application of Weed Seedbank Ecology to Low-Input Crop Management. AB - Pesticide use in the United States is concentrated in the Corn Belt, mainly in the form of herbicides on corn (Zea mays) and soybean (Glycine max). If this chemical load to the environment is to be reduced, without appreciably affecting crop yields, an intimate understanding of weed ecology is necessary. For annual weeds in the U.S. Corn Belt, critical ecological information includes seedbank density, seed dormancy, seedling emergence, and environmental variables that regulate these factors. For three weeds (Setaria spp., Amaranthus retroflexus, and Chenopodium album) in Minnesota, this information is summarized and its application to weed management is illustrated. If weed seedbank densities (0-10 cm depth) are <100 seeds/m2 prior to spring tillage operations, subsequent seedling populations are too low (<40 seedlings/m2 ) to require control. Seedbanks ranging from 100-1000 seeds/m2 produce seedling populations (<400 seedlings/m2 ) that can be controlled mechanically. In contrast, pre-tillage seedbanks >1000 seeds/m2 typically result in such high seedling populations that nonchemical control measures alone cannot prevent large crop yield losses. About one-half of all arable fields harbor seedbanks with densities >1000 seeds/m2 . The proportion of buried seeds giving rise to seedlings is controlled by seed dormancy, which in turn is governed partially by April temperatures (in Minnesota), whereas the timing of subsequent seedling emergence is determined by soil temperature and soil water. EMERG models simulate daily percentages of emerging weed seedlings for April through June, when most Corn Belt crops are sown. If seedbeds of fields with potential seedling densities of 100 seedlings/m2 are prepared and sown when simulated emergence exceeds degrees 80% for C. album, 85% for A. retroflexus, and 99% for Setaria spp., then mechanical weed control sufficiently reduces weed populations and crop yield losses are negligible. Accordingly, mechanical weed control may be substituted economically for chemical control, but only when accompanied by adequate understanding of the ecology of pertinent weed species. PMID- 27759236 TI - Application of Herbivore Optimization Theory to Rangelands of the Western United States. AB - The central assumption for management of range condition-that plant response to selective grazing drives changes in plant community structure-is only weakly supported by evidence from semi-arid rangelands. Most of the vegetation changes attributed to selective grazing can instead be explained through proper interpretation of grazing intensity. Specialized livestock grazing systems, which assume that selective seasonal grazing controls ecosystem function, work poorly on semi-arid rangelands when compared to simpler grazing methods based on managing grazing intensity. Compensatory growth has been well linked to ecosystem processes in highly productive and intensively managed pastures, but not on semi arid rangelands. PMID- 27759237 TI - A Reassessment of Areal Variability of Throughfall Deposition Measurements. AB - Throughfall deposition in a low-elevation red spruce-balsam fir stand in east central Maine was measured for 10 chemical constituents over four sampling seasons to evaluate areal variability of throughfall deposition measurements. Forty collectors within one stand were sampled weekly and combined to provide 40 monthly samples. Areal variation in measurements of throughfall deposition differed greatly among chemical constituents and from month to month. Sulfate showed the least areal variability of the chemical constituents; K+ showed the most. Water volume measurements consistently showed less areal variability than any of the chemical constituents. Mean SO42- deposition calculated from 15 collectors was within 20% of the mean value calculated from 40 collectors (with 90% confidence) in 22 out of 23 sampling months; mean K+ deposition calculated from 28 collectors was within 20% of the mean of the 40 collectors (with 90% confidence) in 21 out of 23 mo. Chemical deposition showed less areal variability when calculated on a seasonal basis than when calculated on a monthly basis. Mean seasonal SO42- deposition calculated from 15 collectors was within 12.1% of the mean 40 collectors (90% confidence); mean K+ deposition calculated from 28 collectors was within 21% of the mean of 40 collectors (90% confidence) for the same three seasons. Contrary to the conclusions of previous studies, excessively large numbers of collectors are not needed to obtain the accuracy and precision adequate for most forest deposition studies. This is significant in light of the growing dependence on throughfall measurements for estimating atmospheric deposition. PMID- 27759238 TI - The Lowland-to-Upland Transition--Modelling Plant Responses to Environmental Change. AB - A published correlative model has predicted that the distributional limits of plants and vegetation zones on mountains will increase in altitude with global warming. I test this hypothesis using results from published experimental studies. Investigations and models of the responses of leaf growth to temperature are in accord with the prediction. However, the individualistic responses of species to CO2 enrichment indicate that the prediction is unlikely to be true for all species: growth is stimulated by CO2 enrichment for some species but not for others. Wind speed generally increases with altitude on mountains, and plants from high altitude tend to be more wind resistant than species from the lowland. Therefore it is expected that, particularly on wind-swept mountains, global warming will not necessarily be followed by the spread of lowland species into the uplands. PMID- 27759239 TI - Controlling Forest Damage by Dispersive Beaver Populations: Centralized Optimal Management Strategy. AB - The beaver (Castor canadensis) population in the United States has caused severe damage to valuable timberland through dam-building and flooding of bottomland forest. Traditionally, beavers have provided a source of livelihood to a small group of people. However, recent low pelt prices have failed to stimulate adequate trapping pressure, and thus have resulted in increased beaver populations and damage losses. The low trapping pressure has left the burden of nuisance control on property owners. Since beaver populations are mobile, beaver extermination in controlled parcels results in beaver immigration from neighboring less controlled parcels. Beaver migration from less controlled to controlled parcels imposes an external cost (negative diffusion externality) on the owners of controlled parcels because they must incur the future cost of trapping immigrating beavers. Unless all land owners agree to control the beaver population simultaneously, the diffusion externality can decrease the incentive of individual landowners to control nuisance beavers, thereby driving a wedge between social and private needs for such control. This study attempts to develop a bioeconomic model that incorporates dispersive population dynamics of beavers into the design of a cost-minimizing trapping strategy. Attention is focused on the situation where all landowners in a given habitat share a common interest in controlling beaver damages, and thus collectively agree to place the area-wide control decision in the hands of a public agency on a cost-sharing basis. The public manager is assumed to minimize the present value of combined timber damage and trapping costs over a finite period of time, subject to spatiotemporal dynamics of beaver population. These dynamics are summarized by a parabolic diffusive Volterra-Lotka partial differential equation, and the population control problem is cast in the framework of a distributed-parameter-control model. The cost-minimizing area-wide trapping model accounts for net migration at each location and time, and characterizes the beaver-control strategy that leaves sufficient beavers to strike an optimal balance between timber damage and trapping costs. The marginality condition governing this trade-off requires that avoided timber damage (measured as the imputed nuisance value, or "shadow price," of the beaver stock in the area) be balanced by trapping cost. The optimality system for this problem is solved numerically. The validity of the theoretical model is empirically examined using the bioeconomic data collected for the Wildlife Management Regions of the New York State Department of Environmental Conservation. Empirical simulation generates discrete values for optimal beaver densities and trapping rates across all individual operational units over time. The optimal trapping program causes the initially uneven population distribution to eventually smooth out across the habitat. The sensitivity analysis alternates trapping-cost and timber-damage parameters between high and low values. Increased trapping costs decrease the level of trapping in the initial years of the optimal program, thereby leaving more beavers in the habitat. This triggers more intensive trapping during the later years of the program, requires more beavers to be trapped over the entire time horizon, and results in a higher overall program cost. Alternatively, increased timber-damage potential calls for increased trapping in the initial years of the program. Fewer beavers are maintained in the habitat and less trapping is required in the later years. Perhaps surprisingly, this results in a smaller number of beavers trapped over the entire time horizon. PMID- 27759240 TI - A Spatial Model of Atmospheric Deposition for the Northeastern U.S. AB - Spatial patterns of atmospheric deposition across the northeastern United States were evaluated and summarized in a simple model as a function of elevation and geographic position within the region. For wet deposition, 3-11 yr of annual concentration data for the major ions in precipitation were obtained from the National Atmospheric Deposition Program/National Trend Network (NADP/NTN) for 26 sites within the region. Concentration trends were evaluated by regression of annual mean concentrations against latitude and longitude. For nitrate, sulfate, and ammonium concentrations, a more than twofold linear decrease occurs from western New York and Pennsylvania to eastern Maine. These trends were combined with regional and elevational trends of precipitation amount, obtained from 30-yr records of annual precipitation at >300 weather stations, to provide long-term patterns of wet deposition. Regional trends of dry deposition of N and S compounds were determined using 2-3 yr of particle and gas concentration data collected by the National Dry Deposition Network (NDDN) and several other sources, in combination with estimates of deposition velocities. Contrary to wet deposition trends, the dominant air concentration trends were steep decreases from south to north, creating regional decreases in total deposition (wet + dry) from the southwest to the northeast. This contrast between wet and dry deposition trends suggests that within the northeast the two deposition forms are received in different proportions from different source areas, wet deposited materials primarily from areas to the west and dry deposited materials primarily from urban areas along the southern edge of the region. The equations generated describing spatial patterns of wet and dry deposition within the region were entered into a geographic information system (GIS) containing a digital elevation model (DEM) in order to develop spatially explicit predictions of atmospheric deposition for the region. PMID- 27759241 TI - Transient Ecotone Response to Climatic Change: Some Conceptual and Modelling Approaches. AB - Accurate prediction of the ecological impacts of climatic change is a pressing challenge to the science of ecology. The current state of the art for broad-scale estimates of change in biomes and ecotones between biomes is limited to equilibrium estimates of ecological change under some future equilibrium climate. Uncertainties in these estimates abound, ranging from uncertainties in future climate scenarios to uncertainties in our ecological models and finally to uncertainties in modelling the feedbacks between the climate and the biosphere. Ecologists and policymakers need to go beyond equilibrium estimates of biosphere change to transient responses of the biosphere as the climate changes. Ecotones between biomes have been suggested as sensitive areas of change that could be effectively modelled and monitored for future change. Ecotones are also important in influencing local and regional biodiversity patterns and ecological flows. The ecological processes that could affect change at ecotones and within biomes are discussed; they include internal ecosystem processes, such as competition, and external abiotic processes, most notably drought and related disturbances. Drought followed by infestations and fire appears to be the most likely process that could mediate ecological change under a rapidly changing climate. The impacts would be apparent all across biomes, not just at ecotones. However, specific predictions about the dynamics of ecotones can be made qualitatively, based on a theory of patch scaling and diversity in relation to abiotic stressors. Under current conditions, the size of homogeneous patches is expected to be small at ecotones, but to enlarge with distance from the ecotone. Directional climatic change should promote a coalescence of patches on one side of the ecotone and increased fragmentation on the other side. Ecotones should begin to blur as viewed from a satellite only to re-form at some later date in a new location. This view is in contrast to the notion that ecotones would retain sharp distinction and simply move across the landscape. These changes are presented as hypotheses based on theory and should be testable in a mechanistic modeling framework that is only now being developed. PMID- 27759242 TI - A Model of the Responses of Ecotones to Climate Change. AB - It has been suggested that global climatic change may be detected by monitoring the positions of ecotones. I built a model of the dynamics of ecotones similar to those found in altitudinal or latitudinal treelines, where a slow tendency for the ecotone to advance is counterbalanced by disturbances such as fire or landslides. The model showed that the response of such ecotones to a wide range of simulated climate changes was slow and that the ecotone front was dissected. It would appear that such ecotones would not make suitable sites for monitoring climate change. PMID- 27759243 TI - Ecotones at Local to Regional Scales from Around the World. PMID- 27759244 TI - Fish Assemblage Recovery Along a Riverine Disturbance Gradient. AB - Artificial fluctuations in streamflow have been documented to alter the composition and structure of stream communities. This study tests the hypothesis that a spatial recovery gradient in fish assemblage structure exists downstream of a hydroelectric dam, and that recovery can be identified by the presence and abundance of species largely restricted to flowing-water habitats (fluvial specialists). A longitudinal gradient of change in a shoreline fish assemblage was quantified in a 66-km reach of a mid-sized, species-rich river (Tallapoosa River, Alabama) with daily flow fluctuations from hydropower generation. The shoreline fish assemblage in a nearby and similar river (Cahaba River, Alabama) was quantified as a regional reference for the occurrence of fish assemblage gradients. Fish were collected with prepositioned area electrofishers in 240 randomly located sampling sites, and physical habitat was quantified. Using distributional and habitat use information, fish species were categorized as fluvial specialists or macrohabitat generalists (species that occur in a wide variety of aquatic systems). Sampled habitats were similar between rivers and along each study reach. The longitudinal pattern of species occurrence and fish abundance was consistent in the free-flowing river. A longitudinal gradient of increasing abundance and richness of only fluvial specialist species existed downstream of the hydroelectric dam. No similar spatial gradient existed for macrohabitat generalists in either river. Although a fish community recovery gradient was identified, a recovery endpoint was not evident because assemblage change was gradual and possibly incomplete. The preservation and management of riverine fish faunas will partly depend on incorporating spatial recovery into decisions about permitting and siting of anthropogenic changes like hydroelectric dams. PMID- 27759245 TI - Rarity in Neotropical Bats: Correlations with Phylogeny, Diet, and Body Mass. AB - Bats are an important component of tropical faunas, both in terms of number of species and total biomass. Very little information, however, is available on the status and conservation of this diverse group. To contribute to the solution of this problem, rarity among Neotropical bats was analyzed using a set of 150 species. Rarity was quantified by local abundance and area of distributional range and by a combined index of rarity created by compounding these two variables. Nested analyses of variance showed local abundance to be more variable among genera than at any other taxonomic level, and area of distribution to be more variable among species. No significant correlation with body mass was found for local abundance or for area of distribution. Similarly, no correlation was found between distribution and abundance. Local abundance, but not area of distribution, varied significantly among taxonomic and trophic categories. At the local level, bats of the family Molossidae tend to be less abundant than other species. Bats that feed on plant parts or products (fruit, nectar, and pollen) are more abundant than insectivores and carnivores. The distribution of species among Rabinowitz' categories of rarity varied among taxonomic and trophic groups. The classification of rarity and the combined index of rarity introduced here can be used as guidelines for the identification of vulnerable species. PMID- 27759246 TI - Analyzing Historic Ecotonal Shifts. AB - Complex chains of mutual causation in human-environment relations may be analyzed by tracing past human interaction with the environment at the global, regional, and local scales. Historical analogues can be effectively employed to model the range of potential climate anywhere in the world. Their advantages include the use of actual regional airmass, hydrology, pedology, topography, and species distributional data, in addition to archaeology, documents, and ethnography. Of mediating importance are regions and landscapes, which manifest past and present human-environment relations and focus practical contemporary questions. The shifting position of ecotones is a convenient temporal and spatial marker of inclusive ecosystemic change. Ongoing research in Burgundy (France) is offered as an example. PMID- 27759247 TI - Material Fluxes Across Wetland Ecotones in Northern Landscapes. AB - The spatial and temporal distribution of sediment, nutrients, and cations in a 2 ha wetland near Shawano, Wisconsin (USA) was used to evaluate the effect of wetland ecotones on water- and windborne fluxes at ecosystem and landscape scales. Within the wetland ecosystem the ecotones studied were beach ridges deposited by post-glacial White Clay Lake, and stream levees deposited by a second-order stream flowing through the wetland. Snow, soil, and surface water data collected from a 52-point sampling grid were geostatistically analyzed to derive contour plots of within-wetland concentrations. Wind-blown snow form the frozen lake surface accumulated in the wetland behind a low beach ridge to a depth of >65 cm, nearly 7 times the depth at wind-protected areas of the wetland. As a result of this snow accumulation, areas to the lee of the beach ridge annually received 10% more water and 1.5% more inorganic N from direct precipitation than did other areas of the watershed. The use of geostatistical plots to analyze wetland surface waters revealed that: (1) within-wetland spatial variability was high on every sampling date except early snowmelt; (2) on a given sampling date, concentration patterns differed for different elements, sometimes substantially; (3) with the exception of NO3 -N, the spatial patterns for a given material changed considerably over time; and (4) many of these spatial patterns were interpretable on the basis of observed water flow patterns and wetland ecology. In general, there was a decrease in the concentrations of inorganic solids and most ions, and an increase in Ca++ and chemical oxygen demand with distance from the stream. Overbank fluxes contributed P to the wetland during spring and fall floods, but diluted ambient P concentrations during snowmelt events. During snow-free periods there was a sharp gradient in NO3 -N concentrations from a streamside value of degrees 5 mg/L to <0.4 mg/L in wetland areas >45 m from the stream. Measurement of the concentration gradient perpendicular to the stream indicated NO3 -N disappearance rates of 6.6 g/100 m of distance during the spring flood. Soil concentrations of mineral matter and P were highest in areas of the wetland closest to the stream; soil concentrations of ammonium and nitrate were spatially disaggregated, and related to levee elevation. At the watershed scale the wetland retained and/or denitrified 15.2% of the total solids, 13.7% of the N, and 14.2% of the P fluxes from the watershed, thus benefitting the water quality of White Clay Lake. PMID- 27759248 TI - Peat Accretion and N, P, and Organic C Accumulation in Nutrient-Enriched and Unenriched Everglades Peatlands. AB - Recent (1964-1989) rates of peat accretion and nitrogen (N), phosphorus (P), and organic carbon (C) accumulation were measured in Everglades soils to characterize the effects of altered hydroperiod and nutrient regimes on the nutrient storage capacity of the Everglades ecosystem. Peat accretion was related to hydroperiod and phosphorus loading. Accretion rates were highest in areas of extended hydroperiod (2.8-3.2 mm/yr) and/or phosphorus enrichment (4.0 mm/yr) and lowest in areas of reduced hydroperiod (1.6-2.0 mm/yr). Rates of accumulation of nitrogen were 3.8-ll.6 g degrees m-2 degrees yr-1 (X = 8.2 g degrees m-2 degrees yr-1 ) and those of organic C were 54-161 g degrees m-2 degrees yr-1 (X = 104 g degrees m-2 degrees yr-1 ). Accumulation rates of N and organic C were primarily a function of peat accretion rates. Phosphorus accumulation was controlled by both peat accretion and increased soil P content. Soil P concentrations (1248 @m/g) in an area receiving N and P enriched agricultural runoff were 2-3 times higher than P levels at unenriched locations (432-764 mg/g). As a result, rates of P accumulation at this site (0.46 g degrees m-2 degrees yr-1 ) were 2-8 times greater compared to unenriched Everglades soils (0.06-0.23 g. m- 2@ ?yr-1 ). Inputs of P (0.53 g. m-2. yr-1 ) and N (15.5 g. m-2 degrees yr-1 ) to the nutrient-enriched area of Water Conservation Area (WCA) 2A (via rainfall and surface flow) were nine and twelve times higher than inputs to the unenriched part of WCA 2A. As a result, the efficiency of P removal was lower at the enriched site (87%) than at the unenriched location (100%). Nitrogen removal efficiencies also were lower in the enriched area (75%) as compared to the unenriched area, where N accumulation in peat was 290-450% of the input. The difference in N storage efficiencies between the two sites may reflect differences in N fixation and denitrification in nutrient-enriched and unenriched Everglades peatlands. Our findings suggest that nutrient-enriched agricultural drainage has contributed to increased rates of peat accretion and phosphorus accumulation in areas of the northern Everglades that have been receiving agricultural drainage for the past 25-30 yr. The affected area has functioned effectively as a phosphorus sink, primarily due to increased organic P storage. However, the effects of nutrient loading, especially P, on the long-term stability of the Everglades ecosystem and on the long-term P storage potential of Everglades peats are poorly understood and are currently under investigation. PMID- 27759250 TI - Effects of Habitat Enrichment on Patterns of Diet Selection. AB - Foraging theory predicts that animals should feed more selectively in response to an increased abundance of high-quality foods. We tested these predictions by examining changes in patterns of diet selection by white-tailed deer (Odocoileus virginianus) and Angora goats (Capri hircus) in response to habitat enrichment. When a high-quality supplement was provided ad libitum, both species responded by increasing foraging effort and by feeding more selectively on natural forages. Supplemented animals consumed a greater proportion of plants containing high concentrations of crude protein (CP) and digestible energy (DE), which resulted in an increase in average diet quality. Responses of individual deer and goats varied and appeared to be related to differences in habitat heterogeneity between trial enclosures. Our results suggest that supplementation may be disruptive to normal behavioral processes affecting the distribution of free-ranging herbivores on the landscape. These processes may be important in reducing the probability of excessive utilization of palatable forage species, and to the competitive relationships between range plants. PMID- 27759249 TI - Can We Extrapolate the California Model of Grassland-Shrubland Ecotone? AB - In California, a number of studies on the interaction between shrubs (Baccharis pilularis) and herbaceous species in annual grasslands have led to the proposal of a conceptual functional model for the dynamics of ecotones between species patches. In our study Chile we used a similar shrub (Baccharis linearis) and annual grassland species to test the robustness of the hypothesis that ecotones between similar landscape elements under similar climate constraints also have similar dynamics. The herbaceous and shrubby ecotone vegetation was described using cover measurements along the same transects in aerial photographs of 1955, 1962, and 1980, and in the field in 1987. The herbaceous species were then determined and quantified by their mass on both sides of the ecotone. Colonization capacity of B. linearis was estimated by describing its establishment on perturbed sites and estimating its seed dispersion. Field and laboratory experiments evaluated the effect of herbaceous species on shrubs at seedling stages. We found similarities between the Chilean and California dynamics in the strong inhibition posed by the annual herbaceous strata to shrub colonization. In Chile this inhibition results in little or no shrub invasion for at least three decades. We also found, just as in California, a reduction of the herbaceous biomass under the shrub canoies, once these get established. However, in Chile, grassland species under the canopy of Baccharis shrubs have a higher biomass and relatively higher species diversity than in California. This difference is related to the fact that herbivores and especially leporids, which in Chile are introduced, play completely different roles in the two regions. In California, herbivores, including leporids, tend to be restricted to areas under the shrub canopies and consequently remove most of the grasses under the shrubs, whereas in Chile leporids are not restricted to shrub patches and the total herbivore effect on forbs under and around shrub patches is much smaller. Consequently, in Chile there is no facilitation of shrub invasion due to herbaceous plant removal by herbivores, and the ecotone is less mobile than in California. The 30-yr stability of the ecotone between Baccharis and grassland shown by our data seems to support this proposition. Our results also suggest that the most abundant species of annual grass in California (Bromus mollis), highly influential in the inhibition of Baccharis colonization, does not behave in a comparable way to its Chilelean congener Bromus berterianus, mainly because it germinates and emerges later in the season than Baccharis linearis. In the Chilean case, herbs such as Erodium cicutarian and Trifolium species seem to be more influential on shrub seedling survival. We conclude that in spite of the strong climatic, physiognomic, and taxonomic similarities between the two areas, ecotones in analogous patches are only partially similar. Consequently, eventually management extrapolations between these regions should be done with extreme care. More generally, our study suggests that extrapolation of management decisions between similar regions, even as similar as chaparral-matorral ecosystems, should be postponed until shown that analogous elements really play sufficiently similar roles in the different areas. PMID- 27759251 TI - Ecotone Hierarchies. AB - Ecological phenomena are evident over a broad spectrum of space and time scales. Ecotones, being defined as zones of transition between adjacent ecological systems, also must occur over an equally broad spectrum of space and time scales. Scale-dependent constraints influence ecological phenomena and resulting zones of transition; however, in traditional ecotone studies little treatment has been given to these influences. This paper addresses aspects of the ecotone concept that relate to the strength of interactions between adjacent systems for a hierarchy of ecotones in a biome transition area in central New Mexico on the Sevilleta National Wildlife Refuge. Zones of transition occur at plant, population, patch, landscape, and biome levels in the hierarchy suggested here. Constraints differ across this hierarchy, primarily because of the different scales at which these constraints exert their influences. The basic strategy to understand these cross-scale influences must be to perform studies at different scales, and a hierarchical approach identifies those scales. This also is important for identifying the appropriate technologies that focus at the scales where transition zones between ecological systems/phenomena are expressed. A broad array of technologies are available for integrating the pattern-process relationships that occur across the many scales in ecological systems. PMID- 27759252 TI - River Margins and Environmental Change. AB - The paper discusses how variability of river margins interacts with riparian function at the landscape level, in order to develop inferences about the future of this interaction with respect to potential effects of a global climatic change. A riparian approach to the ecology of river landscapes should be useful in that it offers an opportunity to improve our understanding and management of the effects of environmental change at the ecosystem level. PMID- 27759253 TI - An Approach for Managing Vertebrate Diversity Across Multiple-Use Landscapes. AB - Land managers face the difficult challenge of maintaining biodiversity on lands also used for commodity production. We present an approach for managing the habitats of terrestrial vertebrates at the landscape scale on multiple-use lands. The approach is based on the hypothesis that animal community response to landscape change is a function of species life histories and local patterns of landscape change. Key steps are: (1) set clear objectives; (2) associate target species with specific habitat configurations; (3) assess the potential sensitivity of species by mapping habitat suitability and examining species life histories; (4) evaluate alternative management prescriptions using simulation models; and (5) implement preferred or experimental strategies and monitor the responses of habitats and species. The approach was demonstrated for a watershed in western Oregon. Management objectives were to maximize habitat diversity for early- and late-successional bird species and to produce saw timber at levels compatible with the habitat goals. Habitat associations of 51 bird species were described by four variables that encompass three spatial scales. An analysis of species sensitivity to landscape change revealed several species that may merit special attention. The landscape model LSPA and the gap model ZELIG.PNW were used to simulate four disturbance/management scenarios over a 140-yr period: natural fire, wood production, multiple use, and no action. The results indicated that 65% more saw timber would be produced under the wood production run than the multiple-use run, but the former would maintain habitats for many fewer bird species than the latter. The multiple-use scenario was selected as the preferred alternative. We suggest carrying out management experiments and rigorous monitoring during the implementation phase. While this approach has various limitations, it is an incremental step towards the effective management of species diversity on multiple-use lands. PMID- 27759254 TI - Air-Pollution-Mediated Changes in Alpine Ecosystems and Ecotones. AB - Soil biological parameters (e.g., Collembola), soil types, soil chemical parameters (pH, humus substances), and plant communities were studied in different ecosystems and ecotones in alpine, subalpine, and spruce forest zones in the Tatra National Park, Slovak Republic. The preliminary, selected data, based on a long-term research program, showed a high sensitivity of some alpine ecotones and ecosystems to long-distance transported acid deposits. The changes in different ecosystem parameters since 1977 were more extensive in alpine grasslands on limestone than on granite. The greatest soil pH decrease was in the plant communities Festucetum versicoloris (-1.5 pH), Geranio-Alchemilletum crinitae (-1.32 pH), and Saxifragetum perdurantis (-1.25 pH), which are restricted to places with snow accumulation and water runoff gullies. In these ecosystems the greatest changes occurred in the leaching of humus substances. Some formerly less abundant and rare soil animals restricted to acid bedrock became dominant in some ecosystems on limestone as well as on granite; other formerly dominant species disappeared from the entire study area (e.g., Folsomia alpina). The aerial extent of some ecosystems changed substantially since 1977, and their surrounding ecotones moved into the space formerly occupied by one of the adjacent ecosystems. These changes are detectable by remote-sensing methods. In Central European mountains, strongly affected by global and regional industrial air pollution (e.g., Krusne Hory, Krkonose, Beskydy), spruce forests started to die back from higher to lower mountain elevations. The effects of air pollution on alpine and subalpine vegetation were not studied there. Strong alterations in alpine ecosystems and ecotones were detected by the author during long-term studies in the High Tatra Mountains, and I suggest that subalpine and mountain forest belts will be affected here in the near future as they were in the more polluted Central European mountains. The ecosystems and ecotones in higher alpine zones are likely to be affected earlier than the ecosystems at lower altitudes. Detection of ecosystem alteration in the alpine zone may be used for prediction of acidification processes and global change in ecosystems at lower altitudes. The consequences of global climate change are predictable by monitoring changes in the extent of some ecosystems located in discrete mountain geomorphological units (e.g., karstic sinkholes, water runoff gullies, wind shadows, ridges exposed to wind, etc.) and ecotones among them because of their dependence on duration of snow cover, water supply, wind and frost exposure, and other abiotic and biotic factors. PMID- 27759255 TI - Impacts of a Severe Drought on Grassland Birds in Western North Dakota. AB - We studied the effect of a severe drought on the population dynamics and community structure of grassland birds in western North Dakota. During the spring and summer of 1988 the northern Great Plains suffered one of the warmest, driest periods in its recorded history. We compared the changes in bird populations and nesting productivity over a 3-yr period before, during, and after the drought. Total grassland bird density declined 61% (P < .05) between June 1987 and June 1988. Densities of six of eight common species declined significantly during the drought. Populations of all but two species recovered in 1989 and total bird density in June 1989 did not differ significantly from June 1987. Species richness and species diversity both declined significantly during the drought and recovered to predrought levels in 1989. Species richness declined more on fair condition than on good condition range during the drought. Vesper Sparrow (Pooecetes gramineus) hatching success, number of young fledged per successful nest, and nesting success were significantly lower in 1988 than either 1987 or 1989. Clutch size did not differ among the three years. The decline in nesting success in 1988 was primarily due to nest abandonment during incubation. Nesting of Vesper Sparrows, Horned Larks (Eremophila alpestris), and Western Meadowlarks (Sturnella neglecta) ended abruptly in mid-June 1988 during a period of extremely hot weather. In 1987 and 1989, nesting continued into July. Despite substantial reductions in bird density and productivity during the drought, many species recovered to predrought levels 1 yr following the drought. This suggests that year-to-year fluctuations in densities of some of these species may not be tightly linked to short-term changes in local productivity. However, sequential years of low productivity may have more substantial effects on these short-lived species. Thus, if drought conditions in North American grasslands become more frequent, as some climate models predict, there could be related changes in the avifauna of the region. PMID- 27759256 TI - Contaminant Transport through Agroecosystems: Assessing Relative Importance of Environmental, Physiological, and Management Factors. AB - Agroecosystems can become contaminated by atmospherically released radionuclides. The subsequent concentrations of radionuclides in foods are dependent on numerous environmental, physiological, and management factors. We compared four approaches for estimating the relative importance of several of these factors in determining concentrations of 131 I and 137 Cs in milk. A series of sensitivity analyses with Monte Carlo and full-factorial sampling designs was conducted on the PATHWAY model, which simulates radionuclide transport through an agroecosystem. Sensitivity of time-integrated concentrations in milk was estimated as a function of the time of year that fallout was deposited and as a function of time following a spring deposition. The dominant parameters affecting time-integrated concentrations of 131 I in milk were the initial fraction of radionuclides deposited on vegetation, timing and amount of pasture consumption, and the production rate of milk. For time-integrated concentrations of the longer-lived 137 Cs in milk, resuspension was a dominant parameter and pasture use was less important. The sampling designs were compared by ranking the parameters to which the model output is sensitive. The three sampling designs based on parameter variances produced sets of ranks that were similar to each other but differed from the ranking produced by the sampling design based on parameter magnitude. The results indicate which data are most crucial for real-time calculations following an accident and how subsequent dose from ingestion can be most effectively reduced, provide insight into model behavior, and help prioritize future research. This paper demonstrates the importance of variance-based sensitivity analysis. PMID- 27759257 TI - Watershed Ecosystem Analysis as a Basis for Multiple-Use Management of Eastern Forests. AB - There is ever-increasing competition for the many uses and natural resources of forests in the eastern United States. Multiple-use management has long been a stated goal for these forests, but application has been problematic and seldom satisfactory to all users. There is a need to incorporate more science into management decisions for Eastern forests, and thereby convincingly demonstrate to forest managers and the public why certain combinations of uses may or may not be compatible. One proven approach for doing this is to use watershed ecosystem analysis. Small watersheds, usually <100 ha in area, serve as a convenient ecosystem for studying how forests function in terms of cycling energy, nutrients, and water. Results of these studies allow assessments of forest health and productivity, and evaluations of impacts of both natural and human-related disturbances. This paper provides illustrations of how watershed ecosystem analysis can be used to study the effects of current harvesting practices, acidic deposition, and past land use. The paper also shows how recommendations for land use are derived from watershed ecosystem analysis, and how they are put into practice. PMID- 27759258 TI - New Forestry Principles from Ecosystem Analysis of Pacific Northwest Forests. AB - Forest management practices on Federal lands in the Pacific Northwest of the United States have been the center of intense controversy. Conflicting value systems, new information, and new perspectives have fueled the debate over the balance between timber production and preservation of natural ecosystems. In this paper we consider examples from three aspects of forest management: (1) management of forest stands, (2) management of the patchwork of forest stands at the landscape scale, and (3) management of streams and riparian networks. In each of these cases we examine: management practices and perspectives of the recent past, findings from ecosystem research that are leading to change in those practices, resulting changes in management practices, and future research directions. We also suggest a path for future change, including systems for managing in the face of uncertainty. Results of research in natural and managed forest and stream ecosystems have been pivotal in reassessment and redesign of management practices to provide a broader range of management options for society to consider. Results of studies of natural disturbance processes and their effects are used as reference points for management systems intending to sustain biological diversity and ecosystem productivity. Stand management practices, for example, are being modified to retain some live trees and greater amounts of dead woody debris, both standing and down, in areas that would instead be clear-cut under intensive plantation forestry practices. The motivations for these modified practices are to sustain biological diversity, including key wildlife species, and to maintain soil productivity. Models of alternative forest-cutting patterns at a landscape scale are being used to examine their effects on ecosystem structure and function. One result of this analysis has been to shift from the previous system of dispersing cutting units to a system involving greater aggregation of units using designs to provide for species preferring forest interior habitat as well as species favoring edge and early seral habitats. As a result of ecosystem research, the management of stream and riparian networks can now be based on understanding of forest-stream interactions and designed within a drainage-basin context. Overall, emphasis in research and management seems to be in early stages of shifting from featured species-e.g., Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) and Northern Spotted Owl (Strix occidentalis caurina) to ecosystems, and from the scale of forest stands to landscapes and the entire region. In addition to the contributions of ecosystem research to redesign of management techniques, ecosystem scientists also have roles in the social processes for determining the future course of management of natural resources. An important medium for scientist participation is establishment of adaptive management programs, in which management activities are conducted as experiments to test hypotheses and to develop information needed for future natural resource management. PMID- 27759259 TI - A Metapopulation Model of the Peregrine Falcon in California: Viability and Management Strategies. AB - We modeled the Peregrine Falcon (Falco peregrinus anatum) population in California to determine its viability under different management strategies by modifying Lefkovitch stage class matrix models to include the introduction of captive-reared birds and the dynamics of two subpopulations linked by migration. The model projections using published parameter values indicated that the population would not sustain itself without supplemental introductions. Sensitivity analysis suggested that enhancing adult survivorship is more effective than enhancing fledging success to achieve a viable population. The model with connected subpopulations predicted fewer pairs than did nonspatial models and indicated that concentrating management efforts on the healthier, high density population in northern California, rather than on the poorly performing population in central and southern California, would yield the largest overall population sizes. Fits of the model to yearly population data from 1980-1989 accurately predicted the size of the southern subpopulation, but slightly underestimated the size of the northern subpopulation, by six pairs. The model fit well when we excluded birds on newly discovered sites that possibly were active in previous years. Increasing northern adult survivorship to predict northern population sizes adequately led to a viable population exhibiting a source-sink relationship between subpopulations. Our results provide insight into the critical data to collect and the most successful strategies to execute in a management program, and give further indication of the importance of spatial structure to the dynamics of populations. PMID- 27759260 TI - Integrating Ecological Concepts with Natural Resource Management of Southern Forests. AB - Natural resource management must integrate commercial development and use of forest resources with the maintenance of ecological values. The "New Perspectives" program of the U.S. Forest Service is responding to increased public environmental awareness and legislative mandates in placing a greater emphasis on ecosystem sustainability and non-traditional utilization of national forestlands. The forest of the southern United States is a complexity of associations developed along topographic and environmental gradients and shaped by natural disturbances and anthropogenic perturbations. It is highly fragmented as a result of past clearing for agriculture and timber harvesting and patterns of land ownership. Southern forests, in contrast to those in other regions, are mostly privately owned. This fragmentation is being maintained by current urbanization and industrialization as the population of the south increases. Our purpose is to identify ecological themes and concepts compatible with the stewardship philosophy of the Forest Service's New Perspectives that can be applied to the management of sustainable southern forest resources. Of special concern are the maintenance of biological diversity, watershed and water quality protection, and the assessment of regional land-use effects on the integrity of forest ecosystems and on continued forest productivity. Ecological principles must be integrated with natural resource management on landscape and regional scales to achieve sustainability of the southern forest ecosystem. PMID- 27759262 TI - Ecosystem Perspectives of Multiple-Use Management. PMID- 27759261 TI - Gradient Analysis of Ecological Change in Time and Space: Implications for Forest Management. AB - Gradient analysis is a powerful technique to analyze for, and detect change in, the dynamics, structure, and function of ecosystems. Boundaries between zones or communities occur at distinctive locations along environmental gradients and are expected to be especially sensitive to environmental change. Gradient analysis can be performed at a range of scales, and allows integration and extrapolation of change across scales from those associated with communities to those of biomes. This review outlines the properties of gradients in space and time and uses an example of forests in the Rocky Mountain Physiographic Province to demonstrate constraints, the complex mosaics associated with distributional limits, transfers across boundaries, the role of disturbance, and threshold dynamics. A climate-change scenario is developed to hypothesize future changes in boundary movements, community mosaics, and ecosystem properties along elevational and latitudinal gradients in the Rocky Mountain Province. Mechanistic explanations of ecological phenomena that are necessary for management require information on: (1) the physical environmental constraints operating on the ecosystem; (2) the biota that operate within those constraints; and (3) the interactions among the biota and between the biota and environment. The relative importance of these three elements differs between environments and along environmental gradients. Biota and their interactions may account for much of the variance in system structure and function in mesic environments, while abiotic factors may limit biotic activity in less-favorable (arid) habitats. Plot studies that are analyzed as points along broader scale environmental gradients can provide quantitative information on the major driving variables, and broad-scale analyses of environmental factors along the gradient generate the information for extrapolating between sites and across scales. Modeling that includes such spatial gradients provides the foundation for local to regional management programs. PMID- 27759263 TI - New Perspectives for Sustainable Natural Resources Management. PMID- 27759264 TI - Potential Carbon Losses From Peat Profiles: Effects of Temperature, Drought Cycles, and Fire. AB - Global warming and the resultant increase in evapotranspiration might lead to lowered water tables in peatlands and an increase in fire frequency. The objective of this study was to investigate some of the potential effects of these changes on peat decomposition. Dry mass losses and emissions of CO2 and CH4 from peat samples taken from three depth layers (0-10, 10-20, and 30-40 cm) of a black spruce peatland were measured in the laboratory at 8 degrees , 16 degrees , and 24 degrees C under two moisture treatments. Effects of deep peat fire on decomposition were also simulated by burning the upper layer (0-10 cm) of peat and adding the ash to peat samples from the 10-20 cm layer. CH4 release averaged <1% of total carbon loss in flooded samples. Release of CO2 was 4-9 times greater from the 0-10 cm layer than from the 30-40 cm layer. After 120 d, the 30-40 cm layer had lost <1% of its original dry mass in all treatments. Higher temperatures strongly promoted decomposition of samples exposed to drying cycles but had little effect on decomposition of continuously flooded samples. Ash addition had variable effects on CO2 emissions but may have promoted CH4 production. It is suggested that in certain situations, global warming may not cause appreciable increases in carbon loss from peat deposits. The results indicate that some deeper peats are resistant to decay even when exposed to warm, aerobic conditions. However, further experimental work is needed to predict the long-term response of peat deposits to changes in water levels in different peatland types. PMID- 27759265 TI - Evaluating Models for Spruce Budworm-Forest Management: Comparing Output with Regional Field Data. AB - The evaluation of models used in the management of populations can be complicated by the number of component parts and by the large temporal and spatial scales often required. This is particularly true of models developed for the analysis of management policy in forest pest situations. In this study, two large-scale spruce budworm-forest simulation models were evaluated by comparing their output with data collected annually by the Maine Forest Service survey at 1000 sites from 1975 to 1980. In practice, model evaluation typically involves a comparison of observations, independent of those used to construct the model, with overall model output. We did this, and in addition, separate tests were performed on major components of each large-scale budworm model. These components represent Maine's forest protection policy, the budworm-forest dynamics, and pest control efficacy. Both models produced output that was in some way inconsistent with the Maine survey data. Inconsistencies were most prevalent at low budworm densities, especially after pesticide spraying, when model output predicts budworm populations increase more slowly than the survey data suggest. These inconsistencies pointed to inaccuracies in the models' representation of Maine's forest protection policy, of budworm population growth at low densities, and of the effectiveness of spraying (especially at low budworm densities). Problems translating the results of studies of nonlinear population dynamics from small experimental plots to the larger spatial scale used in the models are implicated. Our results suggest that the optimal threshold density of budworm for insecticide application is probably higher than the upper threshold of 20 egg masses/m2 inferred from the models. PMID- 27759266 TI - Ecological Risks of Transgenic Plants: Effects of Spatial Dispersion on Gene Flow. AB - The spread of advantageous transgenic genes from crop plants into wild and weedy relatives is a potential ecological problem. The available theory indicates that the spread of a gene, over space and time, will depend in part on the relative selective advantage of that gene, and in part on gene flow, or the probability distribution of gene movement from source to target plants within a single generation. Risk assessment will require knowledge of both. This paper describes an empirical investigation of the effect of spatial dispersion on gene flow in Brassica campestris, utilizing a system of wild genotypes for target plants, and agronomic genotypes with a marker gene for source plants. I have found that gene flow can be reliably modeled with an exponential probability density function, and that the mean of that distribution can vary with the spatial dispersion of plants. Two-dimensional arrays of plants had lower mean gene dispersal distance than did one-dimensional arrays. In contrast, the degree of clumping and the size of patches of plants in my experiments had no effect on gene flow. However, I found an increase in mean gene dispersal distance with increased distance between clumps of plants, or between individual plants in one year. These results imply that large isolation distances accompanied by a rare long-distance pollination event will ultimately increase the risk of gene spread. PMID- 27759267 TI - Estrogen-Based Aversion to Eggs Among Free-Ranging Raccoons. AB - Nightly video records of uniquely marked free-ranging raccoons (Procyon lotor) established the events leading to and resulting from estrogen-induced conditioned taste aversion (CTA) to eggs. Observations of animals voluntarily consuming eggs indicated that: (1) some raccoons in the population were more active egg predators than were others and so were the most likely to be treated; (2) a few eggs injected with 30 mg of estrogen were less effective in inducing egg avoidance than were larger numbers of eggs treated with only 10 mg of estrogen; (3) CTA to eggs became well established even though raccoons had become familiar with eggs at the feeding site; (4) treated males tended to abandon egg consumption abruptly, but females tended to sample eggs for a short time before they, too, avoided them at a distance; (5) CTA was not location specific, persisted when surrounding scent cues changed, and failed to extinguish among treated raccoons that were present while untreated individuals consumed untreated eggs freely during the lengthy post-test period; and (6) treated females that avoid eggs may deny their offspring the opportunity to become familiar with egg prey. Observations of egg consumption in the second year of study provided evidence of a prolonged CTA effect in treated animals. Our results enable us to more fully describe a potential non-lethal technology for controlling predation on the eggs of waterfowl or endangered and threatened species. PMID- 27759268 TI - Multi-Level Interactions Arising from Herbivory: A Simulation Analysis of Deciduous Forests Utilizing Foret. AB - We examined potential effects of herbivory on temperate forest ecosystems using FORET, a forest succession simulation model with the capacity for treating various hierarchical levels for long time periods. Two species of trees were chosen for evaluating herbivory effects: white oak (Quercus alba), a relatively slow-growing shade-tolerant species, and tulip poplar (Liriodendron tulipifera), a fast-growing shade-intolerant species. Both are dominants in the Southeastern U.S. forest system selected as a basis for this study. The study focused on four hierarchical levels, covering individual, phenotypic, interspecific, and community interactions. Simulations of herbivory were arrived at by stochastically varying annual incidence that herbivores were present on each simulation plot over a 500-yr period, and by modifying the proportion of energy allocated to either tree growth, or to its defense from herbivore attack. Two hypothetical tree phenotypes were considered, one that allocated specified amounts of energy to herbivore defense mechanisms at all times, and the other that made the allocation only when herbivores were present according to the stochastic determination made for a specific study period. Thus, one phenotype was fixed in its life history strategy; the other was given a facultative strategy where it switched its growth and defense tactics as a function of variation in herbivore presence. The results of the simulations suggest how deciduous forests may respond to long-term variations in the intensity of herbivore stress on two dominant tree species, and show the importance of hierarchical relationships within the community. White oak tended to show a greater sensitivity to interspecific interactions; tulip poplar showed a higher sensitivity to intraspecific interactions. Changes in growth rates associated with the switching strategies (an ultimate factor) were more important in answering variations in productivity than was impact imparted by annual changes in incidence of herbivore presence (a proximate factor) for these two species, although there were important differences in several statistical interactions. While our results suggest that herbivore stress can explain a larger degree of the variation in long-term community dynamics, ecological interactions between herbivore and climate effects must be more closely linked in such long-term studies. PMID- 27759269 TI - Vegetation Responses to Edge Environments in Old-Growth Douglas-Fir Forests. AB - Forest edges created by dispersed-patch clear-cutting have become a conspicuous landscape feature in western North America, but the effects of edge on forest structure and function are still poorly understood. In this paper we describe responses of stocking density, growth, mortality, and regeneration for three conifer species from the clear-cut edge into the interior of old-growth forest patches adjacent to 10-15 yr old clearcuts in southern Washington and central Oregon. The significance of edge effects for each variable was tested through a single-factor (distance) analysis of variance (F test). Relationships between these variables and depth-of-edge influence (i.e., edge width) on old-growth forest were characterized by nonlinear regression models. Near the edge (forest clearcut boundary line), the old-growth forest has (1) reduced stocking density, as measured by canopy cover, number of stems per hectare, and basal area; (2) increased growth rates of dominant Douglas-fir (Pseudotsuga menziesii) and western hemlock (Tsuga heterophylla), as calculated by an index of relative growth rate; (3) elevated rates of tree mortality, as measured by standing dead and down trees (snags and logs); and (4) greater numbers of Douglas-fir and western hemlock seedlings (@<100 cm tall) and saplings (101-200 cm) but fewer of Pacific silver fir (Abies amabilis). The depth-of-edge influence, when calculated as the point along the clearcut-forest gradient at which a given variable has returned to a condition representing 2/3 of the interior forest environment, ranged from 16 to 137 m for variables related to distance from the edge. The amount of a square forest patch affected by edge decreased as patch size increased and varied greatly with the depth-of-edge influence. With increasing concerns about organisms and processes that require interior forest habitat, determining the area of residual forest influenced by adjacent clearcut is critical to current and future resource management. Responses of additional biological variables must be explored and information on edge phenomena should be extended to the scale of landscapes. PMID- 27759270 TI - Long-Term Forage Production of North American Shortgrass Steppe. AB - We evaluated the relationship between annual forage production and annual and seasonal precipitation and temperature at a shortgrass steppe site in north central Colorado using a long-term data set (52 yr). We also constructed a relationship between forage production and aboveground net primary production (ANPP). Precipitation fluctuated randomly, but temperature had clear warming and cooling trends including a 17-yr warming trend from 1974 to 1990. Forage production was significantly related to both annual and seasonal precipitation but not temperature. Precipitation events between 15 and 30 mm accounted for most of the variability in production because they accounted for most of the variability in precipitation and because they wetted the soil layers that have the largest effect on production. Forage production amplified variability in annual precipitation. Production showed time lags of several years in responding to increases in precipitation. Change in vegetation structure has a characteristic response time, which contrains production responses in wet years. Constraint caused by vegetation structure is the reason why regional ANPP precipitation models have a steeper slope than long-term models and point out a weakness of exchanging space for time in predicting production patterns. PMID- 27759271 TI - Autecology of the Endangered Plant Howellia Aquatilis; Implications for Management and Reserve Design. AB - Howellia aquatilis is an annual aquatic plant of ephemeral ponds. It is considered extirpated or endangered throughout its range in the United States Pacific Northwest. I studied populations in the Swan Valley of Montana to determine life history traits and ecological attributed in order to influence planning decisions on lands managed for multiple use. Germination trials demonstrated that seeds of H. aquatilis require an aerobic environment and cool temperatures to germinate. Germination was highest with daily alternating temperatures and total darkness, and was unaffected by different light regime and aeration retreatment conditions of 50- and 100-d durations. Natural seed banks were largest immediately following seed dispersal and pond drawdown, but were reduced 82-90% by the following spring. Seeds remaining in the seed bank showed reduced germinability and vigor. Aquarium experiments indicate that growth of H. aquatilis is best in the peat substrate in which it occurs naturally, and is reduced by 45% in a more fine-textured organic soil and by 85% in a mineral soil. Multiple regression analyses of 12 environmental variables from 23 H. aquatilis ponds and comparisons between ponds with and without H. aquatilis suggest that pond depth, amount of dissolved solids in pond water, depth and composition of pond substrate, and degree of human-caused disturbance have significant effects on the abundance of H. aquatilis in the Swan Valley. Taken together, these results suggest that Howellia aquatilis is rare because it can persist in only a small subset of wetlands-freshwater ephemeral ponds with a shallow, coarse textured organic surface horizon. Thus, H. aquatilis will be sensitive to disturbances that alter pond water quality or substrate composition. Lack of a persistent seed bank makes H. aquatilis prone to large fluctuations in population size due to environmental fluctuations. Both habitat specificity and large variations in population size are often associated with a high risk of extinction. Howellia aquatilis can only persist during periods of climatic fluctuation as a metapopulation in an area that contains large numbers of appropriate ponds of various depths. Consequently, long-term protection of this rare species will require habitat protection in large wetland complexes throughout its range. PMID- 27759272 TI - Power of Sign Surveys to Monitor Population Trends. AB - The urgent need for an effective monitoring scheme for grizzly bear (Ursus arctos) populations led us to investigate the effort required to detect changes in populations of low-density dispersed animals, using sign (mainly scats and tracks) they leave on trails. We surveyed trails in Glacier National Park for bear tracks and scats during five consecutive years. Using these data, we modeled the occurrence of bear sign on trails, then estimated the power of various sampling schemes. Specifically, we explored the power of bear sign surveys to detect a 20% decline in sign occurrence. Realistic sampling schemes appear feasible if the density of sign is high enough, and we provide guidelines for designs with adequate replication to monitor long-term trends of dispersed populations using sign occurrences on trails. PMID- 27759273 TI - Effect of the Focal Taxon on the Selection of Nature Reserves. AB - Among the numerous site-ranking or reserve selection approaches is to select reserves based on the current distribution of a suite of species. This approach only requires distribution data for the species in the "focal taxon." To what extent is the proposed reserve network dependent on the species included in the focal taxon? Can a suite of species act as an umbrella or indicator for other species whose distribution was not directly considered? A simple reserve selection algorithm was applied to species lists from sites where multiple taxa were sampled. The algorithm selected sites so that each species in the focal taxon was represented in at least one reserve. The species lists were complied for birds, mammals, reptiles, and plants on islands in the Gulf of California, and for birds, mammals, and plants in canyons in San Diego County, California. Within both data sets, there were significant rank correlations (P < .01) between the number of species in different taxa per potential reserve. Yet the number of proposed reserves that satisfied the selection algorithm differed strongly between taxa. For example, 2 of 25 canyons were in the San Diego bird reserve network, but 10 of 25 canyons were in the native plant reserve network. The area of the proposed reserves selected by the algorithm ranged from a minimum of 3.2% of the total area for San Diego bird reserves to a maximum of 98.3% of the total area for the Gulf of California plant reserves. The bird reserves included only 45-78% of the species in the other taxa. Conversely, the plant reserve network would contain 88-100% of the vertebrate species. Thus, plants were better indicators than birds for reserve establishment. Plant occurrences were less ordered than bird occurrences, and there were 10 or 20 times more plant species than bird species. The better umbrella taxon was more speciose or had less pattern to species occurrences. Rather than a literal application of plants as reserve indicators, a better approach would be to collect some preliminary distribution data for a number of taxa in the potential reserve network and use these preliminary data to define the focal taxon (or taxa). PMID- 27759274 TI - Lotic Ecosystem Response to a Chlorine Disturbance. AB - The influence of repeated chlorine additions on the resistance and resilience of laboratory stream ecosystems was investigated. Prior to the disturbance, four treatments were imposed on eight laboratory streams in a 2 x 2 factorial design, resulting in two replicate streams per treatment. Treatments included two circulation regimes (once-through or 98% recirculated) and two levels of grazer density (1000 individuals/m2 or 0 individuals/m2 , using the snail Elimia clavaeformis). Resistance of periphyton biomass to an initial set of chlorine additions was greater in once-through than recirculated streams. Periphyton resistance following a second set of chlorine additions was greater in streams without snails compared to those with snails. This appeared to be a biomass mediated response; the greater biomass levels in no-snail streams provided a larger buffer to the oxidizing action of chlorine. Resilience of most structural parameters and area-specific carbon-fixation rates was not influenced to a significant degree either by flow regime or snail density. Resilience of chlorophyll-specific carbon fixation and exoproteolytic activity (an index of microbial activity) was greater in recirculated streams compared to once-through streams, but only when snails were present. Over the entire experimental period (15 wk), most structural parameters and area-specific carbon fixation rates were significantly greater in (1) streams without snails compared to those with them and (2) streams with once-through circulation compared to those that were recirculated, but only for those streams with snails. Our chlorine additions appeared to have relatively little influence on snails, and snail growth over the experiment was significantly greater in once-through compared to recirculated streams. These data are consistent with other findings that total residual chlorine concentrations of <1.0 mg/L can significantly affect periphyton structure and function. However, nutrient cycling rates appeared to be little affected by the chlorine perturbation, which allowed recirculated systems to recover faster than predicted. The findings from this study suggest the periphyton mat physiognomy and integrity strongly influence system resistance (due to buffering capacity) and resilience (because of nutrient cycling). PMID- 27759275 TI - Long-Term Response of an Arctic Sedge to Climate Change: A Simulation Study. AB - It appears that polar regions of the Earth will bear the brunt of global temperature increases. Because of the ecological importance of the sedge Eriophorum vaginatum in the arctic and the large amount of data available on its growth and physiology, we chose this species as a test case to model the potential long-term response of arctic plants to global climate change. Our simulation model utilizes a mechanistic framework and includes the effects of light, temperature, season length, nitrogen availability, and CO2 concentration on E. vaginatum growth dynamics. The model was parameterized based on a series of published studies of the growth responses of E. vaginatum to nutrients and validated using (1) field studies on the growth responses of E. vaginatum to temperature and shading, and (2) the effects of elevated CO2 and temperature on E. vaginatum photosynthesis. The effect of a 50-yr period of climate change on peak biomass (overwintering biomass plus seasonal production) in E. vaginatum was explored. We use climate change here to refer to linear increases over a 50-yr period in temperature (from 8 degrees to 13 degrees C), season length (from 100 to 120 d), and atmospheric CO2 (from 340 to 680 @mL/L). Similarly, a wide range of nitrogen availabilities (from 9 to 18 g degrees m -2 degrees yr-1 ) was also examined because of its importance in productivity. The model predicts that a simultaneous increase in the direct effects of temperature, season length, and CO2 , with no change in nitrogen availability, will result in a slight decrease in peak biomass. A simulated long-term doubling of nitrogen availability results in an degrees 70% increase in peak biomass, whereas with concurrent changes in climate and nitrogen availability, the model predicts a slight decline in peak biomass compared to increases in nitrogen alone. In essence, the model predicts that climate change will have substantial effects on E. vaginatum only indirectly through changes in nitrogen availability. Simulated peak biomass responds linearly up to a doubling of current nitrogen availabilities. Therefore, at low to-moderate increases in nitrogen availability, the predicted response of E. vaginatum to climate change is linearly (and almost exclusively) dependent on our ability to predict the effects of climate change on nitrogen cycling. At nitrogen availabilities >2x current availabilities, the relationship flattens out very rapidly because the plant becomes limited by carbon uptake. Thus, if nitrogen availabilities more than double in the future, E. vaginatum may shift from being a nutrient-limited to a carbon-limited system and, consequently, increased season length and elevated CO2 concentrations may play an important role in controlling E. vaginatum productivity. PMID- 27759276 TI - Soil Microbial Community Response to Silvicultural Intervention in Coniferous Plantation Ecosystems. AB - Five years after planting and initial treatment, we examined the response of a microbial community to three intensive silvicultural practices: soil surface modification (scarification), fertilization, and control of competing vegetation by herbicide. We correlated microbial response with changes in environmental conditions following treatment, including soil temperature and moisture, total and available nutrients in soil, and light intensity in the tree canopy. The microbial biomass C (2.1-5.3 mg/g in the F/H horizon and 0.14-0.62 mg/g in the surface mineral soil) as determined by the fumigation-extraction method was reduced by vegetation control and fertilization. The ratio of microbial to total organic carbon (Cmic /Corg ) was also reduced by vegetation control, and tended to increase in the new organic horizon developed during the 5 yr after soil surface scarification. Microbial biomass N (0.15-0.40 mg/g in the F/H horizon and 0.014 to 0.057 mg/g in the mineral soil) was not affected by the treatments. The microbial community structure (relative volumes of bacteria and fungi) was evaluated on glass slides placed in the litter bags of pine and aspen litter. The treatment effects on the relative volumes of microorganisms on slides were similar to effects noted for microbial biomass C in the soil. Five years of vegetation succession resulted in conservative N cycling and N limitation of the plant community in control plots. In response to silvicultural treatments this state may either remain relatively unchanged after fertilization, the N limitation may be increased (scarification), or apparent C limitation induced (vegetation control). Reducing the nutrient pool by scarification caused an apparent nutrient limitation, and the microbial community tended to widen the C/N ratio. Increasing the nutrient pool by fertilization or vegetation control tended to narrow the C/N ratio of microbial biomass. PMID- 27759277 TI - Response of Woody Plant Communities in Power-Line Corridors to Frequent Anthropogenic Disturbance. AB - Ecological theory predicts that diversity should decline as disturbance frequency increases beyond an intermediate level. However, few data exist on the responses of deciduous forests to high-frequency disturbance. We compared regenerating woody plant communities in northern Kentucky power-line corridors to adjacent second-growth forests to determine if high-frequency disturbance (5-6 yr mechanical or manual cutting cycle) modifies forest development. Black locust (Robinia pseudoacacia) and white ash (Fraxinus americana) dominated corridor communities. Still, many species present in adjacent forests persisted in corridors, with the result that 15 of 20 corridor samples were classified by TWINSPAN close to samples taken from adjacent forests. Of the most important tree species found in the study sites, sugar maple (Acer saccharum) was least favored by high-frequency cutting. In general, high-frequency cutting did not totally inhibit regeneration of a single species, diversity showed a small but nonsignificant increase, and several early-successional, shade-intolerant species established anew. When forests are repeatedly cut before stems reach the stem exclusion stage, individualistic patterns of sprouting and carbon allocation will likely determine dominance. White ash and black locust will assume greater importance in fragmented forests as disturbance frequencies increase. PMID- 27759278 TI - Water Uptake in Woody Riparian Phreatophytes of the Southwestern United States: A Stable Isotope Study. AB - Alluvial forest associations are often dominated by woody phreatophytes, plants that are tightly linked to aquifers for water uptake. Anthropogenic hydrological alterations (e.g., water impoundment or diversion) are of clear importance to riparian ecosystem function. Because decreased frequency of flooding and depression of water tables may, in effect, sever riparian plants from their natural water sources, research was undertaken to determine water uptake patterns for the dominant native and introduced woody taxa of riparian plant communities of the southwestern United States. At floodplain study sites along the Bill Williams and lower Colorado Rivers (Arizona, USA), naturally occurring D and 18 O were used to distinguish among potential water sources. Isotopic ratios from potential uptake locations were compared to water extracted from the dominant woody taxa of the study area (Populus fremontii, Salix gooddingii, and Tamarix ramosissima) to elucidate patterns of water absorption. Isotopic composition of water obtained from sapwood cores did not differ significantly from heartwood or branch water, suggesting that heartwood water exchange, stem capacitance, and phloem sap mixing may be inconsequential in actively transpiring Salix and Populus. There was evidence for close hydrologic linkage of river, ground, and soil water during the early part of the growing season. Surface soils exhibited D enrichment due to cumulative exposure to evaporation as the growing season progressed. Isotopic ratios of water extracted from Populus and Salix did not exhibit isotopic enrichment and were not significantly different from groundwater or saturated soil water sources, indicating a phreatophytic uptake pattern. Associations of isotopic ratios with water relations parameters indicated high levels of canopy evaporation and possible use of moisture from unsaturated alluvial soils in addition to groundwater in Tamarix. PMID- 27759280 TI - Scientific Goals Require Literal Empirical Assumptions. PMID- 27759279 TI - Stochastic Simulation for Characterizing Ecological Spatial Patterns and Appraising Risk. AB - The theory and a case study are presented for a class of techniques known as stochastic simulation. Stochastic simulations can characterize the certainty of estimates of spatially and/or temporally correlated ecological variables. Rather than merely providing a unique estimate, a conditional probability distribution is built for the unsampled location. This distribution provides the researcher with any summary statistic or confidence limit desired. Moreover, the techniques are flexible enough to incorporate expected economic losses into the analysis. A simple analogy of a jigsaw puzzle is used first to introduce key concepts. Then, the mathematical highlights of two leading stochastic simulation procedures are presented. Finally, one simulation method, known as sequential Gaussian conditional simulation, is used to generate multiple, equally probable images of adult corn rootworm densities over a large (225 x 150 km) area in northwestern Iowa during the summer of 1989. The results show the simulated density of rootworms to be influenced strongly by the choice of summary statistic and density threshold. Economic risk is appraised from the point of view of the farmer by incorporating the expected economic losses due to the use of a soil insecticide. Since the cost to the farmer of not using an insecticide when in fact it is needed is over three times greater than the cost of using one when it is not needed, the area identified as potentially requiring treatment is much larger than when a summary statistic like the mean or median is used. Stochastic simulation allows the environmental researcher, policy-maker, or manager the opportunity to characterize uncertainty and economic or other losses, and to determine areas requiring treatment and additional samples. PMID- 27759281 TI - Science and Sustainable Use. PMID- 27759282 TI - Developing Ecological Research That is Relevant for Achieving Sustainability. PMID- 27759283 TI - Estimating Asymptotic Attributes of Forest Stands Based on Bio-Mathematical Rationales. AB - An approach for estimating asymptotic forest stand yield, basal area, and tree density (number of stems per unit of area) is proposed. Available forest stand growth data are used to establish the reciprocal equation of Competition-Density (C-D) effect and develop equations relating the coefficients of C-D effect to stand top height. Asymptotic stand yield, basal area, and tree density are derived based on bio-mathematical rationales and expressed as functions of asymptotic top height. Asymptotic top height can be obtained for different site qualities and/or habitat types by evaluating a height growth model in the limit as age approaches infinity. Estimated asymptotes can be utilized to parameterize sigmoid-shaped growth functions (e.g., Richards growth model) for developing forest growth and yield models. PMID- 27759284 TI - Extreme Anthropogenic Loads and the Northern Ecosystem Condition. AB - In the extreme North, the polar region of Siberian Russia, the largest mining and processing enterprises for metallic and nonmetallic ores, coal, oil, and gas are situated. The extremely vulnerable boreal and polar ecosystems of the North are responding adversely to the impact of these activities, and are in danger of collapse because of them. The mechanisms of such impacts, their formation, continuous extension, and merger have been studied. The deforested and destroyed areas of former forest-tundra and taiga ecosystems resemble the Arctic zones of a much harsher environment more than the typical Arctic zones where they occur. PMID- 27759285 TI - Incomplete Data Sets in Community Ecology and Biogeography: A Cautionary Tale. AB - Many basic and applied studies in ecology, biogeography, and conservation biology rely on data on the distribution of species and the composition of communities that are compiled from the literature or from unpublished sources. Most of these data sets are incomplete, and some contain serious biases. We examine two such data sets. New records of fishes in Australian desert springs, which corrected sampling biases in the original study, revealed different patterns of species distribution and community structure. New records of mammals on Great Basin mountaintops did not materially alter the results and interpretations of earlier studies. In order to avoid serious errors of fact, interpretation, and application, there is no substitute for first-hand field experience with the organisms and habitats. PMID- 27759286 TI - Biomass Production in a Tallgrass Prairie Ecosystem Exposed to Ambient and Elevated CO"2. AB - Responses to elevated CO"2 have not been measured for natural grassland ecosystems. Global carbon budgets will likely be affected by changes in biomass production and allocation in the major terrestrial ecosystems. Whether ecosystems sequester or release excess carbon to the atmosphere will partly determine the extent and rate that atmospheric CO"2 concentration rises. Elevated CO"2 also may change plant community species composition and water status. We determined above- and belowground biomass production, plant community species composition, and measured and modeled water status of a tallgrass prairie ecosystem in Kansas exposed to ambient and twice-ambient CO"2 concentrations in open-top chambers during the entire growing season from 1989 through 1991. Dominant species were Andropogon gerardii, A. scoparius, and Sorghastrum nutans (C"4 metabolism) and Poa pratensis (C"3). Aboveground biomass and leaf area were estimated by periodic sampling throughout the growing season in 1989 and 1990. In 1991, peak biomass and leaf area were estimated by an early August harvest. Relative root production among treatments was estimated using root ingrowth bags which remained in place throughout the growing season. Latent heat flux was simulated with and without water stress. Botanical composition was estimated annually. Compared to ambient CO"2 levels, elevated CO"2 increased production of C"4 grass species, but not of C"3 grass species. composition of C"4 grasses did not change, but Poa pratensis (C"3) declined, and C"3 forbs increased in the stand with elevated CO"2 compared to ambient. Open-top chambers appeared to reduce latent heat flux and increase water-use efficiency similar to the elevated CO"2 treatment when water stress was not severe, but under severe water stress, the chamber effect on water-use efficiency was limited. In natural ecosystems with periodic moisture stress, increased water-use efficiency under elevated CO"2 apparently would have a greater impact on productivity irrespective of photosynthetic pathway. PMID- 27759287 TI - Achieving Sustainable Development That is Mindful of Human Imperfection. PMID- 27759288 TI - Investing in Research for Sustainability. PMID- 27759289 TI - Long-Term Response of Nutrient-Limited Forests to CO"2 Enrichment; Equilibrium Behavior of Plant-Soil Models. AB - Established process-based models of forest biomass production in relation to atmospheric CO"2 concentration (McMurtrie 1991) and soil carbon/nutrient dynamics (Parton et al. 1987) are integrated to derive the @'Generic Decomposition and Yield@' model (G'DAY). The model is used to describe how photosynthesis and nutritional factors interact to determine the productivity of forests growing under nitrogen-limited conditions. A simulated instantaneous doubling of atmospheric CO"2 concentration leads to a growth response that is initially large (27% above productivity at current CO"2) but declines to <10% elevation within 5 yr. The decline occurs because increases in photosynthetic carbon gain at elevated CO"2 are not matched by increases in nutrient supply. Lower foliar N concentrations at elevated CO"2 have two countervailing effects on forest production: decreased rates of N cycling between vegetation and soils (with negative consequences for productivity), and reduced rates of N loss through gaseous emission, fire, and leaching. Theoretical analysis reveals that there is an enduring response to CO"2 enrichment, but that the magnitude of the long-term equilibrium response is extremely sensitive to the assumed rate of gaseous emission resulting from mineralization of nitrogen. Theory developed to analyze G'DAY is applicable to other published production-decomposition models describing the partitioning of soil carbon among compartments with widely differing decay time constants. PMID- 27759290 TI - Science and the Pursuit of a Sustainable World. PMID- 27759291 TI - Direct and Indirect Competition Between Spider Mites Feeding on Grapes. AB - Agents for biological control of arthropod pests have generally come from the trophic level above the pest (predators, parasites, diseases) rather than from the same trophic level (competitors). The rationale behind this approach is twofold. First, interspecific competition among herbivorous arthropods is thought to be weak; populations are kept at low levels through the action of natural enemies. Second, the potential benefits of an herbivorous biological control agent must be weighed against the damage it causes to the host plant through its feeding. In the field we have been successful at using less economically important Willamette mites to control economically important Pacific mites. In greenhouse and field experiments reported here, we examined both direct and indirect mechanisms (via the host plant or a shared predator) to explain this negative interaction. In our first greenhouse experiment we injured leaves on single canes of young Zinfandel grapevines with Willamette mites at four density levels, removed theses mites and then measured consequences of this past injury on Pacific mites placed on newly produced leaves. Pacific mite populations were reduced significantly by previous Willamette mite injury, suggesting a systemic induced response. In our second greenhouse experiment we measured the relative importance of interspecific interactions between concurrent populations of Willamette and Pacific mites, direct predation by a phytoseiid predator, and interactions between predation and competition (apparent competition). Predators and prey were confined to single canes and, at this small scale, direct predation was of overriding importance while interspecific competition and apparent competition were not significant in determining Pacific mite populations. We examined the relative importance of an early season release of Willamette mites, predaceous mites, or both in a large field experiment conducted in a commercial Zinfandel vineyard. Pacific mite populations were most strongly reduced by the early release of Willamette mites and by midseason abundance of predaceous mites. Our ANOVA results did not detect a significant interaction between the early season release of Williamette mites and predaceous mites. The presence of Willamette mites did not make releases of predators more effective at controlling Pacific mites. Grape yield and berry sugar concentration were unaffected by either Willamette mite or predaceous mite treatments in the year of the mite releases nor in the following season. Path analysis showed that Willamette mite density was never strongly negatively correlated with Pacific mite density in the subsequent time period (2-wk intervals between sampling dates), despite the strong negative effect that the early-season release of Willamette mites had on Pacific mite densities later in the season. This suggests that Willamette mites affected Pacific mites indirectly. PMID- 27759292 TI - Production in Natural and Restored Seagrasses: A Case Study of a Macrobenthic Polychaete. AB - Restoration of seagrass beds has been suggested as a method to correct declining vegetation cover in shallow waters. Secondary production of the polychaete Kinbergonuphis simoni was used to evaluate faunal equivalency of newly restored (2-yr-old) seagrass beds to beds that are mature (at least 17 yr old) in an embayment in Tampa Bay, Florida. Information on density of polychaetes, size structure, reproductive characteristics, and production (growth increment summation method) was collected from May 1989 to February 1991 from individuals within monthly sediment cores from both planted and natural seagrass beds. Additionally, total macroinfauna were sampled every 3 mo at the same sites. Deposit-feeding polychaetes were the dominant macroinfaunal taxa in all seagrass beds examined. Three polychaete species, including Kinbergonuphis simoni, displayed significantly enhanced abundances in planted compared to natural seagrass beds. Population abundance and size class distribution of Kinbergonuphis within planted sites displayed more rapid and consistent population increases after populations disappeared in winter 1989 than that recorded for natural sites. Production values of planted areas over 22 mo were an order of magnitude higher than that recorded in natural areas. Higher production values resulted principally from rapid recovery of populations in planted areas in contrast to natural beds, which did not display such resiliency. Biomass allocation to reproduction did not vary among individuals from natural and planted beds, but more total individuals were participating in reproductive events in planted areas. Results of this study suggest that in addition to abundance of some frequently encountered deposit-feeders, functional characteristics of a common polychaete from seagrass beds vary with age of bed. Moreover, the link between faunal functional equivalency and vegetational cover remains obscure. PMID- 27759294 TI - Sustainability and Ecological Research. PMID- 27759293 TI - Measuring Heterotroph-Induced Source-Sink Relationships in Panicum Coloratum with ^1^1C Technology. AB - We report a synthesis from three series of experiments on source-sink relationships in Panicum coloratum L., a C"4 tropical grass obtained from the Serengeti grasslands of Africa. Studies on ^1^1C real-time analyses of P. coloratum to determine aboveground effects of grasshopper grazing and belowground effects of mycorrhizal inoculation and nematode feeding provided the database. A series of multi- and univariate statistical investigations of all available experimental data described responses of leaves, stems, and roots to these biological stresses. From a principal components analysis we have shown differences in distribution of C source-sink locations along three principal component axes, which accounted for 84% of the experimental variance. The first and second components (62% of variance) described C allocation to leaf, stem, and root sinks. The third component (22% of variance) showed a metabolic dichotomy between leaf starch sinks and labile carbon pools throughout the plant. We use the three principal components from a ^1^1C three-compartment model describing leaf, stem, and root C source and sink variables to present patterns, or fingerprints, of responses to the experiments. Time of day, treatment class, number of days since transplanting, and ecotype controlled a large amount of the overall variation in plant C fixation and reallocation. A comparison of ^1^2C leaf carbon exchange rates (CER) measured with an infrared gas analyzer and ^1^1C rates showed a high positive correlation. Slopes for grasshopper grazing, mycorrhizal inoculation experiments, and nematode feeding showed almost identical results; however, differences in the intercept developed as a function of ecotype. We noted a significantly lower intercept in morning studies, but no differences in the slope for morning compared to afternoon studies. CER and all ^1^1C variables for grasshopper and nematode experiments showed a lower coefficient of ^1^1C variables and higher for CER. We conclude that ^1^1C experiments provide the base for developing laboratory, field, modeling studies to incorporate aggregations of real-time C transfers within plants responding to biological stresses, including those of heterotrophs. PMID- 27759295 TI - Environmental Sustainability: Magic, Science, and Religion in Natural Resource Management. PMID- 27759296 TI - Assessing Ecological Impact Assessment: Lessons from Mono Lake, California. AB - Because of its high salinity and alkalinity, Mono Lake, in eastern California (USA), is a relatively simple ecosystem. It has become the focus of an environmental controversy over the effects of 50 yr of diversions of water from tributary streams to supply water to Los Angeles. Diversions lowered the lake level, increased the salinity, changed the availability of aquatic habitats, and altered the configuration of the shoreline and of islands that support breeding colonies of gulls. We consider (1) how two independent panels of experts synthesized scientific information on the lake ecosystem to assess the environmental consequences of these changes, and (2) how the findings of these groups influenced policy decisions and how well subsequent changes in the lake matched expectations. Despite differences in composition and approach, the two panels reached generally similar conclusions. These conclusions have been a major component of legal activities and the development of management plans for the lake and basin ecosystem. Both panels concluded that, because of the simplicity of the lake ecosystem, ecological consequences of changes in lake level and salinity associated with continuing diversions were likely to be unusually clear cut. At certain lake levels these changes would be expected to alter algal and invertebrate populations and the populations of aquatic birds that feed upon them or to disrupt breeding activities in gull colonies. Projections about when critical lake levels might be reached, however, have not been met. This is largely because stream flows into the lake have been altered from recent historic patterns by the cessation of water diversions due to governmental and legal actions (prompted in part by the panels' findings) and by a prolonged drought. These events illustrate the difficulty of projecting a timetable for environmental changes, even in simple and well-studied ecosystems. PMID- 27759297 TI - Environmental Decision Making: Multidimensional Dilemmas. PMID- 27759298 TI - Lessons on Preventing Overexploitation? PMID- 27759299 TI - Foraging Ecology of Bison and Cattle on a Mixed Prairie: Implications for Natural Area Management. AB - There exists considerable uncertainty whether differences between bison () and cattle (Bos taurus) should be exploited in natural area stewardship. Because foraging ecology may prescribe the fundamental relevance of either herbivore, we describe the foraging of bison and cattle on a northern mixed prairie natural area and discuss management implications. As generalist foragers, bison and cattle exhibited seasonal differences in selection for or against C"3 graminoids, C"4 grasses, forbs, and browse. Forty-eight hour in vitro dry matter digestibilities of C"3 graminoids and C"4 grasses were greater by bison than cattle, but equal digestive efficiencies were exhibited for forbs and browse. Dietary in vitro dry matter digestibility and crude protein differed little between herbivores. Cattle allocated more time to grazing than bison did during summer. Our study suggests that the relationship between feeding-time investment and forage patchiness is important in determining differences in diet choice between bison and cattle. In contrast to cattle, it appears that bison balance nutrient and time demands during the rut by consuming almost exclusively graminoids. Apparently, bison and cattle may achieve similar dietary quality through different foraging behavior. We suggest that specific scale-dependent programmatic conditions exist where either herbivore may be the most appropriate for natural area management. PMID- 27759300 TI - Effects of Vegetation Disturbances on Insect Biological Control of Tansy Ragwort, Senecio Jacobaea. AB - Our study had two major objectives: (1) to clarify the roles of buried seed and different types of localized disturbance in activating outbreaks of a pasture weed (tansy ragwort, Senecio jacobaea), and (2) to measure the effectiveness of two natural enemies (the cinnabar moth Tyria jacobaeae and a ragwort flea beetle, Longitarsus jacobaeae) in inhibiting weed population increase and spread. We conducted a 5-yr field experiment on the coast of Oregon using a randomized-block design with four blocks x three levels of disturbance (background vegetation was Tilled, Clipped, Unaltered) x two levels of cinnabar moth (Exposed, Protected) x two levels of flea beetle (Exposed, Protected) = 48 plots (each plot was 0.25 m^2). Disturbance consistently increased ragwort abundance (measured as density of juveniles, adults, and their offspring; cover; and biomass); the effect was generally greater in Tilled compared to Clipped disturbance treatments. We also found striking differences in the contribution of each natural enemy to ragwort control. The flea beetle quickly reduced ragwort survival, and this led to a strong and rapid reduction in ragwort abundance. The cinnabar moth reduced ragwort fecundity, but this did not translate into reductions in ragwort cover (measured in 1986 and 1987) or biomass (measured annually from 1986 through 1990). These results establish that (1) ragwort populations were limited more by availability of microsites for germination and establishment than by availability of seed, (2) the ragwort flea beetle was the key factor regulating ragwort abundance, and (3) reduction in ragwort fecundity by the cinnabar moth had little effect on the dynamics of ragwort populations on local scales of space and time. These findings underscore the value of field experiments for investigating the dynamics of biological control systems, the manner in which they are regulated, and their response to perturbation. They further establish how colonization and invasion by ragwort depend on attributes of the disturbance and of natural enemy regimes. PMID- 27759301 TI - The Limits of Applied Ecological Research. PMID- 27759302 TI - Orchestrating Environmental Research and Assessment for Remediation. PMID- 27759303 TI - Can Fertilization of Soil Select Less Mutualistic Mycorrhizae? AB - It has been noted previously that nutrient-stressed plants generally release more soluble carbohydrate in root exudates and consequently support more mycorrhizae than plants supplied with ample nutrients. Fertilization may select strains of vesicular-arbuscular mycorrhizal (VAM) fungi that are inferior mutualists if the same characteristics that make a VAM fungus successful in roots with a lowered carbohydrate content also reduce the benefits that the fungus provides a host plant. This two-phase study experimentally tests the hypothesis that fertilizing low-nutrient soil selects VAM fungi that are inferior mutualists. The first phase examines the effects of chemical fertilizers on the species composition of VAM fungal communities in long-term field plots. The second phase measures the effects of VAM fungal assemblages from fertilized and unfertilized plots on big bluestem grass grown in a greenhouse. The field results indicate that 8 yr of fertilization altered the species composition of VAM fungal communities. Relative abundance of Gigaspora gigantea, Gigaspora margarita, Scutellispora calospora, and Glomus occultum decreased while Glomus intraradix increased in response to fertilization. Results from the greenhouse experiment show that big bluestem colonized with VAM fungi from fertilized soil were smaller after 1 mo and produced fewer inflorescences at 3 mo than big bluestem colonized with VAM fungi from unfertilized soil. Fungal structures within big bluestem roots suggest that VAM fungi from fertilized soil exerted a higher net carbon cost on their host than VAM fungi from unfertilized soil. VAM fungi from fertilized soil produced fewer hyphae and arbuscules (and consequently provided their host with less inorganic nutrients from the soil) and produced as many vesicles (and thus provisioned their own storage structures at the same level) as fungi from unfertilized soil. These results support the hypothesis that fertilization selects VAM fungi that are inferior mutualists. PMID- 27759304 TI - Uncertainty, Knowledge, and Resource Management. PMID- 27759305 TI - Scientific Research and Sustainable Development. PMID- 27759306 TI - Uncertainty, Resource Exploitation, and Conservation: Lessons from History. PMID- 27759307 TI - Sustainability Needs More than Better Science. PMID- 27759308 TI - Science and the Management of Natural Resources. PMID- 27759309 TI - The Ecological Basis of Sustainability. PMID- 27759310 TI - Influence of Diversionary Food on Red Squirrel Populations and Damage to Crop Trees in Young Lodgepole Pine Forest. AB - This study was designed to test the hypothesis that large-scale provision of diversionary food (sunflower seeds) would reduce red squirrel (Tamiasciurus hudsonicus) feeding damage to lodgepole pine (Pinus contorta) crop trees. Study areas with managed lodgepole pine stands were located near Vernon and Quesnel in south-central British Columbia, Canada. Large-scale applications of sunflower seeds were conducted on a manual basis in 1989, and by manual and aerial means in 1990, and an operational level by aerial means in 1991. Feeding damage to crop trees was assessed in control and treatment blocks. Populations of the red squirrel, northwestern chipmunk (Eutamias amoenus), and Columbian ground squirrel (Spermophilus columbianus) were sampled intensively by live-trapping on control and treatment blocks in 1990. Manual application of seed (clumped distribution) significantly reduced damage in the treatment block (11.3% of trees damaged) compared with the control (57.5% of trees damaged). Aerial application of seed (uniform distribution) also significantly reduced damage in replicated treatment vs. control blocks. Provision of diversionary food resulted in a temporary increase in the overall number of red squirrels caught on the treatment areas followed by a return to control levels within 6 wk. This increase was primarily the result of an increased number of transients in the trapped sample. The population density of resident (transients excluded) red squirrels did not increase when diversionary food was added. Similarly, we could not detect differences in reproduction, body masses, or survival of squirrels between control and food-supplemented areas. Northwestern chipmunks and Columbian ground squirrels also showed a temporary increase in density when food was added. Application of sunflower seed on an operational basis significantly reduced damage by squirrels in replicated study areas covering three different forest ecological zones. Provision of diversionary food is an effective strategy to protect intensively managed stands of lodgepole pine from red squirrel feeding damage. PMID- 27759311 TI - Greed, Scale Mismatch, and Learning. PMID- 27759312 TI - Detecting the Ecological Effects of Environmental Impacts: A Case Study of Kelp Forest Invertebrates. AB - Detecting the environmental impacts of human activities on natural communities is a central problem in applied ecology. It is a difficult problem because one must separate human perturbations from the considerable natural temporal variability displayed by most populations. In addition, most human perturbations are generally unique and thus unreplicated. This raises the problem of deciding whether observed local effects are due to human intervention or to the natural differences in temporal patterns that often occur among different sites. These problems can be successfully addressed with the Before-After/Control-Impact (BACI) sampling design, in which Impact and Control sites are sampled contemporaneously and repeatedly in periods Before and After the human perturbation of interest. In the present case, we use this design to examine the ecological effects of the cooling water discharge from a coastal nuclear power plant in southern California. The results suggest some general lessons about the process of impact assessments that are applicable in many ecological contexts. In systems where plants and animals are long-lived and recruit sporadically, the rates of change in density are often so low that sampling more than a few times per year will introduce serial correlations in the data. As a result, for studies of few years duration, few samples will be taken. A small sample size means that the tests of the assumptions underlying the statistical analyses, e.g., independence and additivity, will have low power. This injects uncertainty into the conclusions. Small sample size also means that the power to detect any but very large effects will be low. In our study, sampling periods of 2- yr both Before and After the impact were not long enough to detect a halving or doubling of populations at the impact site. We concluded that there were significant environmental impacts because: (1) the effect size was generally very large ( degrees -75%); (2) there was a consistent pattern among species; (3) there were two Impact sites, and effects were larger at the site nearest the discharge; (4) the observed effects accorded with physical changes that could be linked with the source of impact; and (5) a number of alternative mechanisms, unrelated to the source of impact, were examined and rejected. Relative to control populations, there were statistically significant reductions in density of snails, sea urchins, and sea stars, all of which occurred primarily on rocky substrates. All of the reductions were larger at the Impact station about 0.4 km from the discharge than at a second Impact station 1.4 km away. The most plausible mechanisms for the declines seem to be linked to the turbidity plume created by the power plant and the resultant increase in suspended inorganic and organic materials (+46% at the Impact site nearest the discharge). Any associated flux of fine particles on rocks would have deleterious effects on many of the hard benthos. Populations of two filter-feeding species, a gorgonian coral and a sponge, showed relative increases in density. Although the increase in populations of filter feeders could be related to the ingestion, killing, and discharge of tons of plankton by the cooling system, an alternative natural mechanism was also considered reasonable. Monitoring studies or relatively long lived organisms will often have low power to detect ecologically significant changes in density. The present study of kelpforest organisms extended over nearly 6 yr, yet the resulting statistical tests generally had power of <30% to detect a doubling or halving in density at a significance level of .05. In such a community it would be a mistake to conclude that there were no significant ecological effects based on conventional hypothesis tests. Unless there is a willingness to accept the fact that changes in natural populations on the order of 50% will often go undetected, the standards and types of evidence used to demonstrate environmental impacts must be changed. PMID- 27759313 TI - Effects of High-Seas Driftnet Fisheries on the Northern Right Whale Dolphin Lissodelphis Borealis. AB - The United Nations (U.N.) resolutions concerning high-seas driftnets called for moratoria by July 1992, unless appropriate conservation measures could be enacted. The analyses presented here show that the population of northern right whale dolphin has been affected by driftnets and that no apparent conservation measures are available. A number of points emerge: (1) Simple "worst-case" estimates of depletion highlight the importance of accurate estimates of population abundance. Current abundance is 24-73% of the abundance in 1978, depending upon which estimate of current population is assumed. The enormous variability associated with the estimates of current population size will create difficulties for "statistically sound analysis" of management plans, as called for by the U.N. resolutions. In addition, depletion caused by high-seas driftnet fisheries could even be greater than the worst-case estimate reported at a scientific review in June 1991 (Anonymous 1991). (2) The catches of driftnets are highly aggregated. Reporting a kill rate of a fraction of an animal per unit of effort assumes that driftnets "cull" the population of animals and masks the more important effect of large, simultaneous kills of large fractions of pods, families, or other reproductive units. In addition, aggregated catches may lead to underestimates of the necessary level of observer effort. However, the operational characteristics of high-seas driftnet fisheries make impossible any management or conservation plan in which highly aggregated catches do not occur. (3) Any "statistically sound analysis" must include discussion of statistical power. To date, this has not been done. The importance of statistical power is that it places the burden of proof upon the fishing nations that wish to claim either no effect or a successful management plan. In summary, this study of northern right whale dolphin illustrates the following broad points concerning resource protection and conservation: abundance estimates (or trends in abundance) are key to advising on the problem, the statistical characterization of the data must take into account the observed patterns, and statistical power needs to be evaluated to clarify results. PMID- 27759314 TI - Reversing the Fragmentation Perspective: Effects of Clearcut Size on Bird Species Richness in Maine. AB - The effects of clearcut size on bird species richness in a forest-dominated landscape were examined. Forty-five clearcuts, ranging in size from 2 to 112 ha and in age from 3 to 10 yr post-cut were selected as study sites in eastern Maine. At least 10% of each clearcut was censused using 1-16 fixed-radius (50-m) circular plots in May and June of 1989 and 1990. Species richness increased with clearcut size but the number of species present per plot did not differ significantly over the size range of cuts. There was some evidence of increased richness in clearcuts up to 20 ha. Of the 15 most common clearcut species in both years, 10 (1989) and 12 (1990) increased in abundance between 2 and 20 ha, beyond which no preference for clearcut size was found. Additionally bird species locations throughout clearcuts were largely independent of distance from the forest edge. PMID- 27759315 TI - Comparing Spatial Pattern in Unaltered Old-Growth and Disturbed Forest Landscapes. AB - We used geographic information systems (GIS) to analyze the structure of a second growth forest landscape (9600 ha) that contains scattered old-growth patches. We compared this landscape to a nearby, unaltered old-growth landscape on comparable landforms and soils to assess the effects of human activity on forest spatial pattern. Our objective is to determine if characteristic landscape structural patterns distinguish the primary old-growth forest landscape from the disturbed landscape. Characteristic patterns of old-growth landscape structure would be useful in enhancing and restoring old-growth ecosystem functioning in managed landscapes. Our natural old-growth landscape is still dominated by the original forest cover of eastern hemlock (Tsuga canadensis), sugar maple (Acer saccharum), and yellow birch (Betula allegheniensis). The disturbed landscape has only scattered, remnant patches of old-growth ecosystems among a greater number of early successional hardwood and conifer forest types. Human disturbances can either increase or decrease landscape heterogeneity depending on the parameter and spatial scale examined. In this study, we found that a number of important structural features of the intact old-growth landscape do not occur in the disturbed landscape. The disturbed landscape has significantly more small forest patches and fewer large, matrix patches than the intact landscape. Forest patches in the fragmented landscape are significantly simpler in shape (lower fractal dimension, D) than in the intact old-growth landscape. Change in fractal dimension with patch size, a relationship that may be characteristic of differing processes of patch formation at different scales, is present within the intact landscape but has been obscured by human activity in the disturbed landscape. Important ecosystem juxtapositions of the old-growth landscape, such as hemlock with lowland conifers, have been lost in the disturbed landscape. In addition, significant landscape heterogeneity in this glaciated region is produced by landforms alone, without natural or human disturbances. The features that distinguish disturbed and old-growth forest landscape structure that we have described need to be examined elsewhere to determine if such features are characteristic of other landscapes and regions. Such forest landscape structural differences that exist more broadly could form the basis of landscape principles to be applied both to the restoration of old-growth forest landscapes and the modification of general forest management for enhancing biodiversity. These principles may be particularly useful for constructing integrated landscapes managed for both commodity production and biodiversity protection. PMID- 27759316 TI - Getting Ahead of the Extinction Curve. AB - I propose four steps to markedly reduce the rate of species loss in the United States: (1) Enact new legislation or an executive order requiring Bureau of Land Management (BLM) and the U.S. Fish and Wildlife Service to maintain viable populations of all native vertebrates on BLM lands and national wildlife refuges; (2) preserve representative examples of all of the natural communities occurring on each national forest, BLM district, or national wildlife refuge; (3) develop a national initiative to protect freshwater biodiversity; and (4) reauthorize and strengthen the Endangered Species Act. PMID- 27759317 TI - Contrasting the Tolerance of Wild and Domesticated Tomatoes to Herbivory: Agroecological Implications. AB - Application of plant life-history theory to strategies for breeding crop plants for sustainable agriculture remains relatively unexplored. We determined the relative tolerance of wild and domesticated tomatoes to simulated herbivory and evaluated plant characteristics that may contribute to tolerance. Wild and domesticated tomatoes were subjected to different levels of defoliation ranging from 0 to 70%. Single defoliation events at lower levels (15-30%) did not significantly affect total fruit mass produced in either wild or domesticated tomatoes. Increased defoliation resulted in significant reductions in total fruit mass per plant and mean mass per fruit. Reduction in fruit output by the cultivar was degrees 3 times greater than the wild tomato for the first 8 wk of fruit production, whereas the loss in seasonal fruit production by the cultivar was 1.7 times greater than the wild tomato. We concluded that domestication of tomatoes may have decreased their relative tolerance to herbivory. Possible mechanisms for decreased tolerance include differences in leaf area index, light capture curves, and the relative allocation pattern to vegetative growth vs. reproductive structures. Optimization of potential life-history trade-offs between tolerance to herbivory and maximum fruiting abilities are proposed for cultivars of sustainable agriculture. PMID- 27759318 TI - Preserving Biodiversity: Species, Ecosystems, or Landscapes? AB - Efforts to preserve biological diversity must focus increasingly at the ecosystem level because of the immense number of species, the majority of which are currently unknown. An ecosystem approach is also the only way to conserve processes and habitats (such as forest canopies, belowground habitats, and hyporheic zones) that, with their constituent species, are poorly known. Continued concern with species is essential, however. Landscape-level issues also need much greater attention. Designing an appropriate system of habitat reserves is one landscape-level concern. Understanding and appropriately manipulating the landscape matrix is at least equal in importance to reserves issues, however, since the matrix itself is important in maintaining diversity, influences the effectiveness of reserves, and controls landscape connectivity. PMID- 27759319 TI - Toward an Experimental Basis for Protecting Forest Wildlife. AB - Social and economic debates over allocation of old-growth forests have spawned conservation strategies that are aimed at protecting sensitive wildlife species while allowing limited timber harvesting. We are interested in improving the scientific underpinnings for such conservation strategies, because doing so might both minimize costs of resource development and provide more reliable protection. Here, we discuss potential consequences from inductive inferencing systems used to develop technical support for protecting wildlife in temperate forests. For examples, we refer to recent conservation strategies for Northern Spotted Owls (Strix occidentalis caurina) and Red-cockaded Woodpeckers (Picoides borealis). Soft inferencing systems could result in conservation strategies that fail to meet intended goals, thereby exacerbating forestry-wildlife debates. Greater emphasis should be placed on hypothetico-deductive inferencing processes that vigorously employ adaptive management principles. Such processes simultaneously test alternative landscape patterns and forestry options as rigorous management experiments, and thus could incrementally predicate forest policy upon an experimental basis. PMID- 27759320 TI - Endangered at What Level? AB - The functioning of the Endangered Species Act has been less effective than expected because remedial action is not triggered until populations are in serious trouble and because of the inadequacies of a species-by-species approach. These problems have stimulated interest in expanding the Act to protect endangered habitats, communities, and ecosystems. Such a development requires the existence of a generally agreed-upon classification system for these larger ecological units. No such classification system exists, and developing one will be difficult and politically contentious. PMID- 27759321 TI - Invasion Resistance to Introduced Species by a Native Assemblage of California Stream Fishes. AB - Assemblages of native stream fishes in California show a remarkable ability to resist invasion by introduced fishes as long as the streams are relatively undisturbed by human activity. Previous studies had indicated a high degree of spatial (microhabitat) segregation among the native fishes, which was confirmed by a principal components analysis of microhabitat use data from Deer Creek, a tributary of the Sacramento River. A null modelling study using the same data set was performed to see if competition was a major force structuring the assemblage, because theoretical studies had indicated that a competitively structured assemblage should be most able to resist invasions. The null models indicated that competition was not the major structuring force, so it is likely the assemblages are structured through a combination of morphological specialization (reflecting evolutionary history), predation, and some competition. The assemblages resist invasion through both environmental and biotic factors. Predation seems to be an especially important biotic factor. PMID- 27759322 TI - A Spatial Simulation Model of Hydrology and Vegetation Dynamics in Semi-Permanent Prairie Wetlands. AB - The objective of this study was to construct a spatial simulation model of the vegetation dynamics in semi-permanent prairie wetlands. A hydrologic submodel estimated water levels based on precipitation, runoff, and potential evapotranspiration. A vegetation submodel calculated the amount and distribution of emergent cover and open water using a geographic information system. The response of vegetation to water-level changes was based on seed bank composition, seedling recruitment and establishment, and plant survivorship. The model was developed and tested using data from the Cottonwood Lake study site in North Dakota. Data from semi-permanent wetland P1 were used to calibrate the model. Data from a second wetland, P4, were used to evaluate model performance. Simulation results were compared with actual water data from 1797 through 1989. Test results showed that differences between calculated and observed water levels were within 10 cm 75% of the time. Open water over the past decade ranged from 0 to 7% in wetland P4 and from 0 to 8% in submodel simulations. Several model parameters including evapotranspiration and timing of seedling germination could be improved with more complex techniques or relatively minor adjustments. Despite these differences the model adequately represented vegetation dynamics of prairie wetlands and can be used to examine wetland response to natural or human-induced climate change. PMID- 27759323 TI - Sampling to Detect Rare Species. AB - Often a sampling program has the objective of detecting the presence of one or more species. One night wish to obtain a species list for the habitat, or to detect the presence of a rare and possibly endangered species. How can the sampling effort necessary for the detection of a rare species can be determined? The Poisson and the negative binomial are two possible spatial distributions that could be assumed. The Poisson assumption leads to the simple relationship n = (1/m)log @b, where n is the number of quadrats needed to detect the presence of a species having density m, with a chance @b (the Type 2 error probability) that the species will not be collected in any of the n quadrats. Even if the animals are not randomly distributed the Poisson distribution will be adequate if the mean density is very low (i.e., the species is rare, which we arbitrarily define as a true mean density of <0.1 individuals per sample unit), and the spatial distribution is not highly aggregated. Otherwise a more complicated relationship based on the negative binomial distribution would have to be used. Published sampling distributions of 37 unionid mollusc species over river miles (distance measured along the path of the river; 1 mile = 1.609347 km) in two southern Appalachian rivers were evaluated to determine the appropriateness of the simple Poisson-based formula for estimation of necessary sample size to detect species presence. For each of 273 species x river mile combinations we estimated the mean, the variance, and the negative binomial parameter k, and then estimated "necessary n" from both the Poisson- and the negative-binomial-based formulae. We defined "Poisson adequacy" to be the proportion that the Poisson estimate is of the negative binomial estimate of necessary sample size, and stated the requirement that it be >0.95. Only 8 of the 273 cases represented rare species that failed this requirement. Thus we conclude that a Poisson-based estimate of necessary sample size will generally be adequate and appropriate. PMID- 27759324 TI - Modeling the Dynamics of Snags. AB - Many wildlife species required standing dead trees (i.e., snags) as part of their habitat. Therefore, the ability to predict future density, distribution, and condition of snags can assist resource managers in making land-use decisions. Here we present methods for modeling the dynamics of snags using data from a 10 yr study on the rates of decay, falling, and recruitment of snags on burned and unburned plots in the Sierra Nevada, California. Snags (all species) in advanced stages of decay usually fell within 5 yr, and snags created by fire decayed rapidly and fell quicker (within 10 yr) than those on unburned plots. Pine (Pinus spp.) snags decayed more rapidly than fir (Abies spp.). Although there was an overall net increase in snag density on unburned plots, most of this increase was in the smaller (>13-38 cm diameter at breast height [dbh]) size classes; there was a net decrease in the larger (>38 cm dbh) snags preferred by many birds for nesting and feeding. Overall, snags remained standing the longest that were larger in diameter, shorter in height, less decayed, fir rather than pine, and lacking tops. A Leslie matrix model of snag dynamics predicted changes in snag decay and density only when adjusted for the specific environmental factors(s) causing initial tree mortality. Many snags are created by episodic events, such as fire, disease, drought, and insects. Models of snag dynamics must include the species and condition of trees becoming snags, as well as the factor(s) causing the tree to die. Forest managers must consider this episodic creation of snags when developing snag-management guidelines, and when planning tree-salvage programs based on short-term inventories. PMID- 27759325 TI - Breeding Success of Hatchery and Wild Coho Salmon (Oncorhynchus Kisutch) in Competition. AB - The divergence of hatchery fish in traits important for reproductive success has raised concerns about their ability to rehabilitate wild populations, and the threat that their inevitable straying poses to biological diversity through introgression. We therefore undertook a study of the breeding competition and success of sea-ranched hatchery fish placed in direct competition with wild fish. Experiments using wild and hatchery coho salmo (Oncorhynchus kisutch) were conducted within a controlled stream channel, allowing selective manipulation of breeding competition and density. Hatchery fish, particularly males, were competitively inferior to wild fish, being less aggressive and more submissive. As a consequence, hatchery males were denied access to ovipositing females; they partook in fewer spawnings, held more distal positions in spawning hierarchies, and attained only an estimated 62% of the breeding success of wild males. By contrast, competition did not appear to inhibit hatchery females as overtly as males. Hatchery and wild females exhibited similar levels of aggressive behavior, however hatchery females did suffer greater delays in the onset of breeding, failed to spawn larger proportions of their eggs, and lost more eggs to nest destruction by other females. They averaged an estimated 82% of the breeding success of wild females. There was thus a sex bias in the breeding disadvantage of hatchery fish, with males suffering more than females. Furthermore, the breeding disadvantage was density dependent with the relative success of hatchery to wild fish declining with increasing density. These results imply that hatchery fish have restricted abilities to rehabilitate wild populations, and may pose ecological and genetic threats to the conservation of wild populations. PMID- 27759326 TI - Seedling Response of Four Birch Species to Simulated Nitrogen Deposition: Ammonium vs. Nitrate. AB - Chronic nitrogen deposition has the potential to alter seedling shade tolerance and growth in the temperate forests of northeastern United States, by affecting both the form and the quantity of available nitrogen. Simulated deposition treatments were applied to seedlings of four birch species that co-occur at Harvard Forest (Betula lenta, B. alleghaniensis, B. populifolia, and B. papyrifera). Seedlings were individually potted in forest soil, and grown under light treatments representative of forest understory and treefall gap light levels. In a split-plot design, N was applied at 25 and 50 kg degrees ha-1 degrees yr-1 , as either nitrate, ammonium nitrate, or ammonium, within each light environment. While B. populifolia and B. papyrifera, and B. lenta all showed increased biomass allocation to leaves with increased N, only B. lenta showed a significant growth response to the type of N added, and this response was conditional on rate of N application and light environment. At low light, nitrate-fed B. lenta grew best, and also at low rate of supply, nitrate treatments out-performed ammonium treatments. Greater growth under these conditions is probably the result of higher biomass allocation to leaves, and greater specific leaf area, which increased the leaf area ratio, and improved the capacity for carbon gain. Under N deposition regimes that increase soil nitrate availability, the differences in response of B. lenta and B. alleghaniensis to nitrate at low light may potentially lead to changes in the species composition of the seedling communities in the understory. When a treefall occurs, a different species mix of seedlings will be released, with potential consequences for sapling and tree species mix. PMID- 27759327 TI - Sucrose Repellency to European Starlings: Will High-Sucrose Cultivars Deter Bird Damage to Fruit? AB - European Starlings (Sturnus vulgaris) are often pests in commercial fruit crops in North America and Europe. Because starlings slack the digestive enzyme sucrase and cannot digest sucrose, they may develop an aversion to high-sucrose fruits. In water-tube drinking trials, we tested captive starlings with aqueous solutions of 15% (mass/volume) mixed sugars to identify the level of sucrose required to develop a conditioned feeding aversion when digestible sugars are present. In one tube tests, starlings decreased intake of 11.25 and 15% sucrose solutions relative to their pretest intake of a 15% glucose-fructose mixture. In two-tube tests with sucrose solutions paired against a digestible glucose-fructose solution, starlings decreased preferences for the sucrose solutions as sucrose concentrations increased. These data suggest that the presence of digestible nutrients mitigates the effect of sucrose in sucrase-deficient birds and that a fruit cultivar would require @> 11.25% sucrose to repel starlings. PMID- 27759328 TI - The Role of Riparian Corridors in Maintaining Regional Biodiversity. AB - Riparian corridors possess an unusually diverse array of species and environmental processes. This "ecological" diversity is related to variable flood regimes, geomorphic channel processes, altitudinal climate shifts, and upland influences on the fluvial corridor. This dynamic environment results in a variety of life history strategies, and a diversity of biogeochemical cycles and rates, as organisms adapt to disturbance regimes over broad spatio-temporal scales. These facts suggest that effective riparian management could ameliorate many ecological issues related to land use and environmental quality. We contend that riparian corridors should play an essential role in water and landscape planning, in the restoration of aquatic systems, and in catalyzing institutional and societal cooperation for these efforts. PMID- 27759329 TI - Interaction Between Sensory and Postingestional Repellents in Starlings: Methyl Anthranilate and Sucrose. AB - Ingestion of concentrated sucrose solutions causes sickness in sucrase-deficient birds. As a result, some suggest that sucrose may represent an environmentally safe avian repellent. In the present experiments, we compared the repellency of sucrose to that of methyl anthranilate (MA), a known avian repellent. We also tested mixtures of sucrose and MA to investigate whether repellency could be enhanced, relative to sucrose or MA presented alone. The results showed that the MA was strongly avoided in both drinking and feeding trials. Conversely, only high sucrose concentrations were avoided, and only in drinking trials. No combination of MA and sucrose was as effective as MA alone. We conclude that sucrose is not sufficiently aversive to serve as an avian repellent in the field. PMID- 27759330 TI - Vegetation-Hydrology Models: Implications for Management of Prosopis Velutina (Velvet Mesquite) Riparian Ecosystems. AB - Prosopis velutina (velvet mesquite) forests are one of many types of aridland riparian ecosystems that are threatened by groundwater pumping and other types of water development. Empirical models developed using both hydrological and vegetational data sets have potential uses in the management of these threatened ecosystems. To this end, we developed models for Prosopis velutina stands across a xeric-to-mesic moisture gradient. The models expressed canopy height, basal area, leaf area index, vegetation volume, and leaflet area as functions of plant water potential, and they expressed plant water potential and riparian stand structure as functions of water table depth. These data indicated that stand structure was strongly related to water availability. Management applications of the models include the ability (1) to identify minimum water-table depths for riparian stand maintenance and (2) to detect stressful hydrological conditions, via water potential measurements, before the onset of structural degradation. PMID- 27759331 TI - Spotlights on our sister journals: ChemPhysChem 20/2016. PMID- 27759332 TI - Quick, easy, cheap, effective, rugged, and safe sample preparation approach for pesticide residue analysis using traditional detectors in chromatography: A review. AB - In pesticide residue analysis, relatively low-sensitivity traditional detectors, such as UV, diode array, electron-capture, flame photometric, and nitrogen phosphorus detectors, have been used following classical sample preparation (liquid-liquid extraction and open glass column cleanup); however, the extraction method is laborious, time-consuming, and requires large volumes of toxic organic solvents. A quick, easy, cheap, effective, rugged, and safe method was introduced in 2003 and coupled with selective and sensitive mass detectors to overcome the aforementioned drawbacks. Compared to traditional detectors, mass spectrometers are still far more expensive and not available in most modestly equipped laboratories, owing to maintenance and cost-related issues. Even available, traditional detectors are still being used for analysis of residues in agricultural commodities. It is widely known that the quick, easy, cheap, effective, rugged, and safe method is incompatible with conventional detectors owing to matrix complexity and low sensitivity. Therefore, modifications using column/cartridge-based solid-phase extraction instead of dispersive solid-phase extraction for cleanup have been applied in most cases to compensate and enable the adaptation of the extraction method to conventional detectors. In gas chromatography, the matrix enhancement effect of some analytes has been observed, which lowers the limit of detection and, therefore, enables gas chromatography to be compatible with the quick, easy, cheap, effective, rugged, and safe extraction method. For liquid chromatography with a UV detector, a combination of column/cartridge-based solid-phase extraction and dispersive solid-phase extraction was found to reduce the matrix interference and increase the sensitivity. A suitable double-layer column/cartridge-based solid-phase extraction might be the perfect solution, instead of a time-consuming combination of column/cartridge-based solid-phase extraction and dispersive solid-phase extraction. Therefore, replacing dispersive solid-phase extraction with column/cartridge-based solid-phase extraction in the cleanup step can make the quick, easy, cheap, effective, rugged, and safe extraction method compatible with traditional detectors for more sensitive, effective, and green analysis. PMID- 27759334 TI - On-line approaches for the determination of residues and contaminants in complex samples. AB - The determination of residues and contaminants in complex matrices such as in the case of food, environmental, and biological samples requires a combination of several steps to succeed in the aimed goal. At least three independent steps are integrated to provide the best available situation to deal with such matrices: (1) a sample preparation technique is employed to isolate the target compounds from the rest of the matrix; (2) a chromatographic (second) step further "purifies" the isolated compounds from the co-extracted matrix interferences; (3) a spectroscopy-based device acts as chromatographic detector (ideally containing a tandem high-resolution mass analyzer) for the qualitative and quantitative analysis. These techniques can be operated in different modes including the off line and the on-line modes. The present report focus the on-line coupling techniques aiming the determination of analytes present in complex matrices. The fundamentals of these approaches as well as the most common set ups are presented and discussed, as well as a review on the recent applications of these two approaches to the fields of bioanalytical, environmental, and food analysis are critically discussed. PMID- 27759333 TI - A Trifunctional, Modular Biomaterial Coating: Nonadhesive to Bacteria, Chlorhexidine-Releasing and Tissue-Integrating. AB - Various potential anti-infection strategies can be thought of for biomaterial implants and devices. Permanent, tissue-integrated implants such as artificial joint prostheses require a different anti-infection strategy than, for instance, removable urinary catheters. The different requirements set to biomaterials implants and devices in different clinical applications call for tailor-made strategies. Here, a modular coating-concept for biomaterials is reported, which in its full, trifunctional form comprises nonadhesiveness to bacteria and antimicrobial release, combined with enhanced tissue integration characteristics. Nonadhesiveness to proteins and bacteria is accomplished by a hydrophilic brush coating (Vitrostealth). The antimicrobial release module is constituted by a chlorhexidine releasing poly(ethylene glycol) diacrylamide based-coating that continues to release its antimicrobial content also when underneath the nonadhesive top-coating. The third module, enhancing tissue integration, is realized by the incorporation of the penta-peptide Glycine-Arginine-Glycine Aspartic acid-Serine (GRGDS) within the nonadhesive top-coating. Modules function in concert or independently of each other. Specifically, tissue integration by the GRGDS-module does not affect the nonadhesiveness of the Vitrostealth-module toward bovine serum albumin and Staphylococcus aureus, while the antimicrobial release module does not affect tissue-integration by the GRGDS-module. Uniquely, using this modular system, tailor-made anti-infection strategies can thus readily be made for biomaterials in different clinical applications. PMID- 27759336 TI - Hypertension Control in India: Are we there Yet? OR Uncontrolled and Resistant Hypertension: The Indian Perspective. PMID- 27759335 TI - Simple and Rapid Bioink Jet Printing for Multiscale Cell Adhesion Islands. AB - A simple and rapid process for multiscale printing of bioinks with dot widths ranging from hundreds of microns down to 0.5 MUm is presented. The process makes use of spontaneous surface charges generated pyroelectrically that are able to draw little daughter droplets directly from the free meniscus of a mother drop through jetting ("p-jet"), thus avoiding time-consuming and expensive fabrication of microstructured nozzles. Multiscale can be easily achieved by modulating the parameters of the p-jet process. Here, it is shown that the p-jet allows us to print well-defined adhesion islands where NIH-3T3 fibroblasts are constrained to live into cluster configurations ranging from 20 down to single cell level. The proposed fabrication approach can be useful for high-throughput studies on cell adhesion, cytoskeleton organization, and stem cell differentiation. PMID- 27759337 TI - Management Practices in Indian Patients with Uncontrolled Hypertension. AB - INTRODUCTION: Hypertension (HTN), being a major risk factor for cardiovascular diseases (CVDs), is an important issue of medical and public health. High blood pressure (BP) is ranked as the third most important risk factor for attributable burden of disease in south Asia (2010). Hypertension (HTN) exerts a substantial public health burden on cardiovascular health status and healthcare systems in India. Uncontrolled hypertension among adults with hypertension is associated with increased mortality. An inadequate data is available in India on uncontrolled hypertension. OBJECTIVES: The present study was planned to evaluate the patient profile, co-morbidities, management in uncontrolled hypertensive patients and also to determine the number of patients with resistant hypertension across India. METHODS: A total of 4725 uncontrolled hypertensive patients who were on anti-hypertensive medications were evaluated in this cross-sectional and observational study. The observed patterns were recorded with respect to the prevalence of uncontrolled hypertension and evaluate the socio-demographic, medical history, anthropometric variables and treatment preferences in Indian patients with uncontrolled hypertension. RESULTS: Majority of the patients with uncontrolled hypertension were males (71.4%) and aged 46-65 years. Most of the study population were pre-obese (males: 35.7%; females: 27.4%). Higher proportion of patients with uncontrolled hypertension were residents of Maharashtra (25.6%) and Gujarat (11.6%). Antihypertensive monotherapy was used by 45.4% and 54.6% patients used combination therapy (>= 2 categories of anti-hypertensive medications). Angiotensin receptor blockers (ARBs) were the most preferred agent as monotherapy (70.6%) and also the most common component of dual and triple combination anti-hypertensive agent. 19.5% (922/4725) patients had resistant hypertension and 80% of the patients were aged 46-65 years. Higher proportion of patients were males (67.2%; 620/922) and higher proportion of patients were to residents of Andhra Pradesh (21.4% patients) and Maharashtra (19.3% patients). All 922 resistant hypertensive patients were on >= 3 anti-hypertensive medications and received ARB + CCB + Diuretics as the most preferred anti hypertensive combination therapy. Diabetes and dyslipidaemia were the major comorbidities reported in patients with uncontrolled and resistant hypertension. Lipid lowering agents followed by oral hypoglycaemic agents and antiplatelet medications were the common concomitant medications used. Various factor responsible for not achieving the desired blood pressure goals may be the physician's lack of awareness about recent hypertensive treatment guidelines that might contribute to patient's poor adherence due to not explaining adequately the benefit and risks of a medication, not giving consideration to the patient's life style, the cost of medication, and inadequate dose titration. CONCLUSIONS: Uncontrolled hypertension is a major problem in India. It is prudent to focus on multiple risk factors while treating hypertension. A combination therapy with multiple blood pressure lowering drugs are important and concerns should be identified while selecting the appropriate dosage of combinations of anti hypertensive therapy and adherence to the therapy. The preferred choices for mono, dual combination and triple combination anti-hypertensive regimens are ARBs; ARB + CCB; ARB + CCB + Diuretics, respectively. In this study, most of the patients were on monotherapy; however a rationale combination therapy or dose adjustment is required for the effective management of hypertension. The protective measures to be taken to control hypertension includes reduction of physicians inertia, diet and physical activity, regular patient follow-up with BP measurements and counselling, and the improvement in patient adherence. PMID- 27759338 TI - Serum Homocysteine, Vitamin B12 and Folic Acid Levels in Patients with Metabolic Syndrome. AB - OBJECTIVE: To study alterations in and factors affecting blood levels of homocysteine and its related vitamins (B12 and folic acid) in patients with metabolic syndrome. Methods: In this case-control study, conducted in a referral hospital in north India, blood levels of vitamin B12, folic acid and homocysteine were compared and also correlated with anthropometric parameters, blood sugar, lipids (total, LDL and HDL cholesterol) and hematological variables. METHODS: Seventy five subjects (50 patients and 25 controls; mean age 48.6+/-11.5 years; 57% males) were studied. As compared to controls, patients with metabolic syndrome had higher blood levels of homocysteine (16.77+/-6.6 vs 6.48+/-0.87 units; P<0.0001), lower levels of B12 (183.7+/-37 vs 346.4+/-74.4 units; P<0.0001) and lower levels of folic acid (3.25+/-1.9 vs 5.31+/-0.75 units; P<0.0001). All 3 levels were abnormal in 64% patients and none of controls (P<0.0001). Blood levels of homocysteine, folic acid and vitamin B12 correlated with weight, waist circumference, body mass index, fasting blood sugar and lipid levels. These levels also correlated with hematological parameters (hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration). CONCLUSIONS: Indian patients with metabolic syndrome have a strong association with elevated blood levels of homocysteine and reduced levels of vitamin B12 and folic acid. Further studies are needed to test the hypotheses that these metabolites have a greater role in Asians and there may be a greater beneficial role of folic acid supplementation. PMID- 27759339 TI - Vitamin D: A Critical Micronutrient for Vascular Health in Type 2 Diabetes Mellitus. AB - OBJECTIVE: Vitamin D deficiency may be responsible for endothelial dysfunction which in turn affects the onset and progression of vascular disease including coronary artery disease and its risk factor, directly or indirectly through various mechanisms. This study was undertaken to find out association between vitamin D and endothelial dilatation of brachial artery, which may help to suggest possible underlying mechanisms and may be of clinical importance in planning preventive and therapeutic strategies. MATERIAL AND METHODS: 50 cases of type 2 diabetes mellitus aged 40-60 years were taken. 50 cases without type 2 diabetes mellitus matched for confounding factors were taken as controls. Venous blood samples were collected for the investigations including vitamin D levels. Then Participants were subjected to ultrasound examination for measurement of flow mediated dilatation (FMD) and endothelial independent dilatation after ingestion of glyceryl tri-nitrate (GTN). Unpaired student T test and correlation coefficient analysis were used to find out association between different variables. RESULTS: The mean values of FMD were 18.85 +/- 5.39% and 10.29 +/- 4.91% in controls and cases respectively (p<0.001). The dilatation after GTN was observed to be 26.16 +/- 4.25% and 18.74 +/- 5.72% in controls and cases respectively (p<0.001). The mean levels of vitamin D among controls and cases were 25.41 +/- 12.18 and 14.52 +/- 8.28 ng/ml respectively. The correlation between endothelial dependent dilatation (FMD), endothelial independent dilatation (after GTN) and vitamin D was found to be more positive in cases (r=0.870, r=0.798) than controls (r=0.079, r=0.158). CONCLUSIONS: Vitamin D deficiency state is higher among cases of type 2 DM. Endothelial dependent dilatation (FMD) was found to be lower among the patients of type 2 DM. The study gives us an insight to identify the diabetics with vitamin D deficiency which may be at higher risk of vascular complications including coronary artery disease. PMID- 27759340 TI - The Role of Smoking as a Modifiable Risk Factor in Diabetic Nephropathy. AB - OBJECTIVE: To study the relation of smoking and abnormal renal function in type 2 diabetes mellitus by estimating urine protein- creatinine ratio, blood urea, serum creatinine, glomerular filtration rate and serum lipid profile in selected subjects. METHODS: Diabetic patients who attended the Diabetic Clinic, Medical College, Kozhikode were enrolled in the study. The study duration was 6 months, from July 2008 to December 2008. It was conducted in four groups of 40 subjects: diabetic smokers, diabetic non-smokers, non-diabetic smokers and non-diabetic non smokers. The parameters assayed were: Blood urea, Serum creatinine, Fasting Blood Glucose and Serum Lipid Profile. The parameters assayed in the different groups were compared. Logistic regression analysis was done to study the effect of smoking on renal function. RESULTS: The mean difference of Urine protein- creatinine ratio between diabetic smokers and non-diabetic smokers is statistically significant (0.46+/-0.21 vs 0.24+/-0.14, p<0.001). The mean differences of Blood Urea between all the groups are statistically significant. The mean difference of Serum Creatinine of diabetic smokers with non-diabetic smokers is statistically significant (1.2+/-0.5 vs 0.96+/-0.2, p<0.05). The mean differences of Total Cholesterol, Triglycerides, HDL, LDL and VLDL between all the study groups is statistically significant. In the regression analysis, it was found that 12.9% of the alteration of renal function can be explained by smoking alone. (R2 = 0.129). CONCLUSIONS: Smoking is an independent risk factor for progression of diabetic nephropathy. 24.8% of deterioration of renal function can be explained by smoking, obesity, hypertension and dyslipidemia and 12.9% of the alteration of renal function by smoking alone. PMID- 27759341 TI - Cardiac Manifestation in Dengue Fever. AB - AIM AND OBJECTIVE: To study the cardiac manifestations of the dengue fever. METHODS: This one year descriptive study was undertaken at KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum under the Department of Medicine. A total of 120 patients with either dengue IgM or IgM and IgG were studied. The assessment of cardiac manifestations was done based on electrocardiogram, 2D echocardiography and cardiac enzymes. RESULTS: Of the 120 patients, 85 (70.83%) were males and the male to female ratio was 2.4:1. The mean age of the patients was 33.02 +/- 12.71 years. The commonest clinical presentation was myalgia (97.5%) followed by fever (92.5%). On clinical examination 33.33% of the patients had petecheia and only 9 patients having active bleeding manifestation at the time of presentation. A raised CK-MB and Troponin I was observed in 33.3% and 26.7% patients ECG findings revealed normal rhythm among 95% with 15.8% of them having an abnormal heart rate. Rhythm disturbance was noted in 5% of the patients with AV block being the most common (66.67%). Cardiac manifestation in the form of myocarditis was observed in 37.50% of the patients with a positive correlation with the severity of the dengue fever defined as by W.H.O. criteria. CONCLUSIONS: Patients with dengue fever are at high risk of developing myocarditis and rhythm disturbance and therefore require a close cardiac monitoring. PMID- 27759342 TI - A Study of Outbreak of Swine Flu (H1N1) in North - West Zone of Rajasthan (Current Status - 2015). AB - BACKROUND: The outbreak of H1N1 virus had previously reported in India during 2009 flu pandemic. In 2015, the outbreak became widespread throughout India. The states of Gujarat and Rajasthan are severely elected. We studied an outbreak of H1N1 Virus in north-west zone of Rajasthan 2015. OBJECTIVE: To demonstrate the current epidemiological scenario of swine flu (H1N1) in north-west zone of Rajasthan with different demographic factors. METHODS: We screened total 6390 patients. Out of them 1405 samples of suspected cases collected from different parts of north-west Rajasthan and analyzed by RT-PCR at Sardar Patel Medical College, Bikaner. RESULTS: A total of 1405 samples examined during three and half months period, out of which 181 cases found positive for H1N1. Out of them 85 (46.97%) males and 96 (53.03%) females (M:F=1:1.13). Most patients (116) were in age group 21-50 years which was 64.09% of total positive cases (Mean age=37.09 +/ 16.07years). The mean time of onset of symptoms to hospitalization was 5.12 +/- 3.38 days. Only 11.05% patients presented within 48 hours whereas 64.09% presented between 3-5 days of onset of symptoms. 109 (60.22%) patients were from rural areas, whereas 72 (39.77%) belonged to urban areas. Total 13 (7.18%) deaths occurred among positive cases. 69.23% deaths were recorded in the age group of 25 to 50 years. The mean age of death being 44.69 years. Females had significant higher mortality (9 females out of 13 deaths). 76.92% died within 3 days of hospitalization, despite of starting Oseltamivir in a dose of 150 mg/bd on the day of admission. 84.61% of the patients who died had one or more risk factors. Bilateral pneumonia was observed in all the 13 patients and MODS in 2 patients. CONCLUSIONS: With the above observation of swine flu trend it is likely that incidence is more in young to middle age group, majority of them having no risk factors, should form the target of future studies. However fatality is highest in patients with co-morbid condition or predisposing risk factors need to vaccinate this group should form a basis on which future directions and interventions have to be built up to reduce the morbidity and mortality. Females have slightly increased susceptibility for infection M:F=1:1.13). but mortality is much higher in this sex group. More patients belong to rural areas reflecting the need of creating public awareness especially in rural areas at primary health centre level and where illiteracy is common and crowded urban areas to present early at screening centres, so future outbreak can be prevent. The in-hospital mortality of 7.18% despite of starting Oseltamivir has raised concern about identifying the so called "Rapid Progressors" [76.92% died within 3 days of hospitalization]. Despite of all mortality is less in north-west zone as compared to rest of Rajasthan. PMID- 27759343 TI - Early Repolarisation Changes in ECG: Are they Benign or Malignant? AB - Till recently, ST segment elevation in the absence of conduction abnormalities or chest pain occurring particularly in young bradycardia individuals has been considered a normal variant called early repolarisation (ER). However, recent studies suggest a more worrisome picture as patients with history of idiopathic ventricular fibrillation showed increased prevalence of ER in ECG. ER is an ECG pattern characterised by elevation of the QRS-ST junction (J point) >= 2 mv from baseline in the inferior (II, III, aVF) or lateral (I, aVL, V4-V6) leads manifested as QRS slurring or notching. The ER pattern describes the patient with appropriate ECG findings in the absence of symptomatic arrhythmias. The Early Repolarisation Syndrome (ERPS) applies to the patient with both appropriate ECG findings and symptomatic arrhythmias. The current experimental data support the concept that J-point elevation is a marker of increased transmural heterogeneity of ventricular .repolarisation, which increases the vulnerability to ventricular tachyarrhythmias. Male gender, history of syncope or sudden cardiac death (SCD) in family, ER in inferior leads or global ER pattern, terminal notching of QRS complex, J wave amplitude of more than 0.2 mv, horizontal or downward direction of ST segment elevation signify higher risk features for SCD in ER patients. Patients with ER pattern on ECG should have complete cardiac evaluation. The management options for ERPS include anti arrhythmic drugs, implantable cardioverter-defibrillator (ICD) and radiofrequency ablation. There is a need for the physicians to be aware of this entity, hitherto considered as variant of normal ECG pattern especially in young adults and understand its implications, identify high risk subsets and manage with appropriate strategy. PMID- 27759345 TI - Measures of Central Tendency and Dispersion. PMID- 27759344 TI - Expanded Dengue. AB - The World Health Organization (WHO) has coined the term expanded dengue to describe cases which do not fall into either dengue shock syndrome or dengue hemorrhagic fever. This has incorporated several atypical findings of dengue. Dengue virus has not been enlisted as a common etiological agent in several conditions like encephalitis, Guillain Barre syndrome. Moreover it is a great mimic of co-existing epidemics like Malaria, Chikungunya and Zika virus disease, which are also mosquito-borne diseases. The atypical manifestations noted in dengue can be mutisystemic and multifacetal. In clinical practice, the occurrence of atypical presentation should prompt us to investigate for dengue. Knowledge of expanded dengue helps to clinch the diagnosis of dengue early, especially during ongoing epidemics, avoiding further battery of investigations. Dengue has proved to be the epidemic with the ability to recur and has a diverse array of presentation as seen in large series from India, Srilanka, Indonesia and Taiwan. WHO has given the case definition of dengue fever in their comprehensive guidelines. Accordingly, a probable case is defined as acute febrile illness with two or more of any findings viz. headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, leucopenia and supportive serology. There have been cases of patients admitted with fever, altered mentation with or without neck stiffness and pyramidal tract signs. Some had seizures or status epilepticus as presentation. When they were tested for serology, dengue was positive. After ruling out other causes, dengue remained the only culprit. We have come across varied presentations of dengue fever in clinical practice and the present article throws light on atypical manifestations of dengue. PMID- 27759346 TI - Cerebral Venous Thrombosis Following Varicella Infection. PMID- 27759347 TI - Hemophilia Pseudotumor. PMID- 27759348 TI - Mesenteric Vasculitis in a Case of Systemic Lupus Erythematosus. AB - We present a case of mesentric vasculitis with systemic lupus erythematosus who relapsed after high dose steroids but achieved subsequent remission after starting pulse cyclophosphamide therapy. 38 years old female who had earlier polyserositis and cerebral venous thrombosis was admitted with provisional diagnosis of SLE and developed acute abdominal pain during hospital stay. She was diagnosed as mesenteric vasculitis and initially responded to pulse methylprednisolone. However, she had relapse which subsequently responded to pulse cyclophosphamide and steroids. During the ward course she also developed acute thyroiditis and was diagnosed to have class IV lupus nephritis on renal biopsy. PMID- 27759349 TI - Cerebral Sinus Venous Thrombosis as a Rare Complication of Primary Varicella Zoster Virus Infection. AB - We present the case of a 23 year old with acute onset left hemiparesis and meningeal irritation, associated with recent history of chickenpox 15 days prior. Varicella-IgG and IgM was positive in the CSF and blood along with reduced serum/CSF ratios of VZV immunoglobulins. MRV showed thrombosis (CVT) of superior sagittal, transverse, right sigmoid sinuses with haemorrhagic infarct in right frontoparietal region. Patient responded well to intravenous heparin, Acyclovir and oral anticoagulant therapy. PMID- 27759350 TI - Pernicious Anaemia with Gastric Carcinoids. AB - We report the case of a 42 year male with history of chronic anaemia who was found to have pernicious anaemia with beta thalassemia trait and had on esophago gastric-duodenoscopy, gastric carcinoids with gastric atrophy. Pernicious anaemia and gastric carcinoids occurring simultaneously in a single individual is rare. Our case emphasises the need for esophago-gastric-duodenoscopy in cases of pernicious anaemia. PMID- 27759351 TI - Progressive Disseminated Histoplasmosis with Coomb's Positive Hemolytic Anemia in an Immunocompetent Host. AB - Progressive Disseminated Histoplasmosis (PDH) is mainly described in immuno compromised individuals and rare in immuno-competent subjects. Here we report a case of progressive disseminated histoplasmosis with Comb's positive hemolytic anemia, which is infrequently reported from a country like India where histoplasmosis is not an endemic mycosis. PMID- 27759352 TI - Kyrle's Disease: A Rare Skin Manifestation of Diabetes Mellitus. AB - Kyrle's disease is a rare skin disorder which is characterized by hyperkeratotic papules and nodules with a central keratotic plug mostly located in lower limbs. Exact etiology of Kyrle's disease is unknown, but its association has been reported sparsely with renal disorders, uremic patients on dialysis, diabetes mellitus, liver disease and paraneoplastic syndromes, tuberculosis and some fungal diseases. We report Kyrle's disease in a middle aged female suffering from diabetes mellitus with diabetic nephropathy on hemodialysis. PMID- 27759353 TI - Amitraz Poisoning Treated Successfully with Atropine. AB - Very few cases have been reported with Amitraz as a suicidal agent from India. Here we present such a case treated successfully with atropine sulphate. PMID- 27759354 TI - Hypothyroidism Presenting as Multiple Body Cavity Effusions. AB - Primary hypothyroidism is a common clinical condition in which serous effusions are rare. Isolated cases have been reported in literature about presence of ascites, pleural effusion, pericardial effusion or combination of any two. But combination of all three is extremely rare. We hereby report a case of multiple body cavity effusions (ascites, pleural and pericardial effusions) and tissue edema (pedal and facial) in a hypothyroid male. He responded well to thyroid hormone replacement therapy. PMID- 27759355 TI - Spondyloepihyseal Dysplasia Congenita. AB - We describe a case of Spondyloepiphyseal Dysplasia Congenita (SEDc) who presented to our rheumatology clinic with complaints of painful swelling of bilateral elbow, knee, distal and proximal interphalangeal joints (DIP and PIP) of hands and small joints of foot. Patient also complained of restriction during extension of bilateral wrist joint and lateral rotation of neck on both sides. He was also unable to walk without support. PMID- 27759356 TI - Tricuspid Valve Endocarditis. AB - We report a case of isolated native tricuspid valve infective endocarditis caused by Coagulase Negative Staphylococcus in a non-IV drug abuser without structural heart disease. Early diagnosis and prompt initiation of appropriate treatment saved the patient without surgical intervention. The recent trend of Coagulase Negative Staphylococci (CoNS) causing native valve endocarditis (NVE) is reviewed with literature. PMID- 27759357 TI - Pheochromocytoma Presenting with Acute Abdomen. AB - Pheochromocytoma, a neuroendocrine tumor of the adrenal medulla, arising from chromaffin cells, usually presents with the clinical triad of paroxysmal headache, profuse sweating and palpitations, associated with labile hypertension. Here, we present the case of an adult male with an unusual manifestation of pheochromocytoma in the form of acute pain abdomen with nausea and abdominal guarding, mimicking acute peritonitis. He had fluctuating blood pressure recordings. On subsequent investigation, a mass lesion in the left suprarenal area on an abdominal CT scan and a 24-hour urinary metanephrine assay confirmed the diagnosis of pheochromocytoma. PMID- 27759358 TI - Symptomatic Primary Selective IgM Immunodeficiency - B Lymphoid Cell Defect in Adult Man with Secondary HLH Syndrome. AB - Selective immunoglobulin M deficiency(sIgMD) is a rare form of dysgammaglobulinaemia characterized by an isolated low level of serum immunoglobulin M (IgM). It was an incidence of less than 0.03% in the general population and 1% in hospitalized patients. sIgMD may occur as a primary or secondary condition. sIgMD is much more common than primary .Hemophagocytic lymphohistiocytosis (HLH) is also a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes and can be primary or secondary, characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations. We report an adult case of primary sIgMD with absent B lymphoid cells and secondary HLH syndrome who presented with recurrent infections, fever and pancytopenia. PMID- 27759359 TI - Statin-Induced Rhabdomyolysis. AB - Rhabdomyolysis is syndrome characterized by muscle necrosis which causes the release of myoglobin into the bloodstream. The manifestations of this syndrome range from asymptomatic elevation of muscle enzymes to life-threatening cases associated with extremely high enzyme levels, electrolyte imbalance and acute renal failure. Symptoms of rhabdomyolysis include dark urine, muscle weakness and fatigue. Statins are the most commonly used drugs for prevention and management of dyslipidemia. We present an interesting case report on statin induced rhabdomyolysis with renal failure. PMID- 27759360 TI - A Relook of Cefuroxime in Community Infections: An Option Still Beneficial. AB - In community and family practice, infections are a common OPD presentation. In the management of common bacterial infections seen in community especially RTI, UTI, SSTI; cefuroxime a second generation cephalosporin with a broad spectrum of activity can be used for empirical treatment. To know current place of cefuroxime in the management of infections, physicians, surgeons, microbiologist, chest physician, gynecologist and pediatrician came together to discuss and debate their experience with cefuroxime and its place in today's world. Cefuroxime is a drug which balances efficacy with safety. Several international bodies and guidelines including the US FDA and The British Thoracic Society, the World Society of Emergency Surgery (WSES) have recommended cefuroxime for the management of community acquired pneumonia and skin and soft tissue infection respectively. Cefuroxime has been recommended in the 2015 list of the US FDA list of drugs which can be used safely during pregnancy. Cefuroxime can become a useful empiric choice antibiotic for the Indian physicians treating urinary tract infections, respiratory tract infections and skin and soft tissue infections in their outpatient departments. PMID- 27759361 TI - Pioneers in Movement Disorders. PMID- 27759362 TI - Yawning: Behavior and Physiology. PMID- 27759363 TI - Drug Interaction between Acenocoumarol and Linezolid: Report of a Case. PMID- 27759364 TI - Fe2O3/Reduced Graphene Oxide/Fe3O4 Composite in Situ Grown on Fe Foil for High Performance Supercapacitors. AB - A Fe2O3/reduced graphene oxide (RGO)/Fe3O4 nanocomposite in situ grown on Fe foil was synthesized via a simple one-step hydrothermal growth process, where the iron foil served as support, reductant of graphene oxide, Fe source of Fe3O4, and also the current collector of the electrode. When it directly acted as the electrode of a supercapacitor, as-synthesized Fe2O3/RGO/Fe3O4@Fe exhibited excellent electrochemical performance with a high capability of 337.5 mF/cm2 at 20 mA/cm2 and a superior cyclability with 2.3% capacity loss from the 600th to the 2000th cycle. PMID- 27759365 TI - Iron Complex Facilitated Copper Redox Cycling for Nitric Oxide Generation as Nontoxic Nitrifying Biofilm Inhibitor. AB - In this study, we developed poly(vinyl chloride) (PVC)-solvent casted mixed metal copper and iron complexes capable of catalytic generation of the antibiofilm nitric oxide (NO) from endogenous nitrite. In the absence of additional reducing agent, we demonstrated that the presence of iron complex facilitates a redox cycling, converting the copper(II) complex to active copper(I) species, which catalyzes the generation of NO from nitrite. Assessed by protein assay and surface coverage analyses, the presence of the mixed metal complexes in systems containing water industry-relevant nitrite-producing nitrifying biofilms was shown to result in a "nontoxic mode" of biofilm suppression, while confining the bacterial growth to the free-floating planktonic phase. Addition of an NO scavenger into the mixed metal system eliminated the antibiofilm effects, therefore validating first, the capability of the mixed metal complexes to catalytically generate NO from the endogenously produced nitrite and second, the antibiofilm effects of the generated NO. The work highlights the development of self-sustained antibiofilm materials that features potential for industrial applications. The novel NO-generating antibiofilm technology diverts from the unfavorable requirement of adding a reducing agent and importantly, the less tendency for development of bacterial resistance. PMID- 27759366 TI - Supramolecular Self-Assemblies with Nanoscale RGD Clusters Promote Cell Growth and Intracellular Drug Delivery. AB - In this work, we reported the generation of a novel supramolecular hydrogelator from a peptide derivative which consisted of a structural motif (e.g., Fc-FF) for supramolecular self-assembly and a functional moiety (e.g., RGD) for integrin binding. Following self-assembly in water at neutral pH, this molecule first tended to form metastable spherical aggregates, which subsequently underwent a morphological transformation to form high-aspect-ratio nanostructures over 2 h when aged at room temperature. More importantly, because of the presence of nanoscale RGD clusters on the surface of nanostructures, the self-assembled nanomaterials (e.g., nanoparticles and nanofibers) can be potentially used as a biomimetic matrix for cell culture and as a vector for cell-targeting drug delivery via multivalent RGD-integrin interactions. PMID- 27759367 TI - Hybrid Energy Cell with Hierarchical Nano/Micro-Architectured Polymer Film to Harvest Mechanical, Solar, and Wind Energies Individually/Simultaneously. AB - We report the creation of hybrid energy cells based on hierarchical nano/micro architectured polydimethylsiloxane (HNMA-PDMS) films with multifunctionality to simultaneously harvest mechanical, solar, and wind energies. These films consist of nano/micro dual-scale architectures (i.e., nanonipples on inverted micropyramidal arrays) on the PDMS surface. The HNMA-PDMS is replicable by facile and cost-effective soft imprint lithography using a nanoporous anodic alumina oxide film formed on the micropyramidal-structured silicon substrate. The HNMA PDMS film plays multifunctional roles as a triboelectric layer in nanogenerators and an antireflection layer for dye-sensitized solar cells (DSSCs), as well as a self-cleaning surface. This film is employed in triboelectric nanogenerator (TENG) devices, fabricated by laminating it on indium-tin oxide-coated polyethylene terephthalate (ITO/PET) as a bottom electrode. The large effective contact area that emerged from the densely packed hierarchical nano/micro architectures of the PDMS film leads to the enhancement of TENG device performance. Moreover, the HNMA-PDMS/ITO/PET, with a high transmittance of >90%, also results in highly transparent TENG devices. By placing the HNMA PDMS/ITO/PET, where the ITO/PET is coated with zinc oxide nanowires, as the top glass substrate of DSSCs, the device is able to add the functionality of TENG devices, thus creating a hybrid energy cell. The hybrid energy cell can successfully convert mechanical, solar, and wind energies into electricity, simultaneously or independently. To specify the device performance, the effects of external pushing frequency and load resistance on the output of TENG devices are also analyzed, including the photovoltaic performance of the hybrid energy cells. PMID- 27759368 TI - Ultrafast Lithium Storage Using Antimony-Doped Tin Oxide Nanoparticles Sandwiched between Carbon Nanofibers and a Carbon Skin. AB - Metal oxides as anode materials for Li-ion batteries (LIBs) are of significant interest to many potential technologies because of their high theoretical capacity value, low price, and environmentally friendly features. In spite of these considerable benefits and ongoing progress in the field, momentous challenges exist, related with structural disintegration due to volume expansion of electrode materials. This leads to rapid capacity decline and must be resolved in order to progress for realistic utilization of LIBs with ultrafast cycling stability. This article proposes a novel architecture of Sb-doped SnO2 nanoparticles sandwiched between carbon nanofiber and carbon skin (CNF/ATO/C) using electrospinning and hydrothermal methods. The CNF/ATO/C exhibits superb electrochemical behavior such as high specific capacity and outstanding cycling stability (705 mA h g-1 after 100 cycles), outstanding high-rate performance (411 mA h g-1 at 2000 mA g-1), and ultrafast cycling stability (347 mA h g-1 at 2000 mA g-1 after 100 cycles), which is high compared to any reported value using SnO2 based anode materials. Thus, this unique architecture furnishes profitable effects, including electroactive sites, structural stability, and electrical conductivity, which can potentially be realizes for ultrafast LIBs. PMID- 27759370 TI - Reducing Capacities and Distribution of Redox-Active Functional Groups in Low Molecular Weight Fractions of Humic Acids. AB - Humic substances (HS) are redox-active organic compounds with a broad spectrum of molecular sizes and reducing capacities, that is, number of electrons donated or accepted. However, it is unknown which role the distribution of redox-active functional groups in different molecule sizes plays for HS redox reactions in varying pore sizes microenvironments. We used dialysis experiments to separate bulk humic acids (HA) into low molecular weight fractions (LMWF) and retentate, for example, the remaining HA in the dialysis bag. LMWF accounted for only 2% of the total organic carbon content of the HA. However, their reducing capacities per gram of carbon were up to 33 times greater than either those of the bulk HA or the retentate. For a structural/mechanistic understanding of the high reducing capacity of the LMWF, we used fluorescence spectroscopy. We found that the LWMF showed significant fluorescence intensities for quinone-like functional groups, as indicated by the quinoid pi-pi* transition, that are probably responsible for the high reducing capacities. Therefore, the small-sized HS fraction can play a major role for redox transformation of metals or pollutants trapped in soil micropores (<2.5 nm diameter). PMID- 27759371 TI - Palladium-Catalyzed Regio- and Enantioselective Synthesis of Allylic Amines Featuring Tetrasubstituted Tertiary Carbons. AB - The first asymmetric synthesis of alpha,alpha-disubstituted allylic N-arylamines based on a palladium-catalyzed allylic amination has been developed. The protocol uses highly modular vinyl cyclic carbonates and unactivated aromatic amine nucleophiles as substrates. The catalytic process features minimal waste production, ample scope in reaction partners, high asymmetric induction up to 97% ee, and operational simplicity. PMID- 27759369 TI - Pyrazinamide Resistance Is Caused by Two Distinct Mechanisms: Prevention of Coenzyme A Depletion and Loss of Virulence Factor Synthesis. AB - Pyrazinamide (PZA) is a critical component of first- and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM). Probing for cross resistance to two structural analogs of POA, nicotinic acid and benzoic acid, showed that the analogs share the PDIM- but not the CoA-related mechanism of action with POA. We demonstrated that POA depletes CoA in wild-type bacteria, which is prevented by mutations in panD. Sequencing 10 POA-resistant Mycobacterium tuberculosis H37Rv isolates confirmed the presence of at least 2 distinct mechanisms of resistance to the drug. The emergence of resistance through the loss of a virulence factor in vitro may explain the lack of clear molecular patterns in PZA resistant clinical isolates, other than mutations in the prodrug-converting enzyme. The apparent interference of POA with virulence pathways may contribute to the drug's excellent in vivo efficacy compared to its modest in vitro potency. PMID- 27759372 TI - para-Selective Alkylation of Benzamides and Aromatic Ketones by Cooperative Nickel/Aluminum Catalysis. AB - We report a method that ensures the selective alkylation of benzamides and aromatic ketones at the para-position via cooperative nickel/aluminum catalysis. Using a bulky catalyst/cocatalyst system allows reactions between benzamides and alkenes to afford the corresponding para-alkylated products. The origin of the high para-selectivity has also been investigated by density functional theory calculations. PMID- 27759373 TI - Stabilization and Improvement of a Promising Influenza Antiviral: Making a PAIN PAINless. AB - The viral envelope protein hemagglutinin (HA) plays a critical role in influenza entry and thus is an attractive target for novel therapeutics. The small molecule tert-butylhydroquinone (TBHQ) has previously been shown to bind to HA and inhibit HA-mediated entry with low micromolar potency. However, enthusiasm for the use of TBHQ has diminished due to the compound's antioxidant properties. In this work we show that the antioxidant properties of TBHQ are not responsible for the inhibition of HA-mediated entry. In addition, we have performed a structure activity relationship (SAR) analysis of TBHQ derivatives. We find that the most promising compound, 3-tert-butyl-4-methoxyphenol, exhibits enhanced potency (IC50 = 0.6 MUM), decreased toxicity (CC50 = 340 MUM), and increased stability (t1/2 > 48 h). Finally, we have characterized the binding properties of 3-tert-butyl-4 methoxyphenol using NMR and molecular dynamics to guide future efforts for chemical optimization. PMID- 27759375 TI - Overexpression of the Global Regulator LaeA in Chaetomium globosum Leads to the Biosynthesis of Chaetoglobosin Z. AB - Overexpression of laeA in Chaetomium globosum CBS148.51 up-regulated expression of the chaetoglobosin gene cluster and resulted in the isolation of a new cytochalasan, chaetoglobosin Z (1), together with six known analogues, chaetoglobosins A (2), B (3), D (4), E (5), O (6), and V (7). RT-PCR analysis confirmed that the key genes in the chaetoglobosin gene cluster were significantly up-regulated. The structure of the new compound chaetoglobosin Z (1) was elucidated using NMR data. The relative and absolute configurations were determined by NOESY and electronic circular dichroism combined with quantum chemical calculations adopting time-dependent density functional theory methods, respectively. These compounds displayed strong biological effects against the HepG 2 cell line compared with the positive control. The results further supported that LaeA is a global regulator that could up-regulate and/or activate cryptic gene clusters to produce new secondary metabolites. PMID- 27759376 TI - Multifunctional and Regenerable Antibacterial Surfaces Fabricated by a Universal Strategy. AB - Development of a versatile strategy for antibacterial surfaces is of great scientific interest and practical significance. However, few methods can be used to fabricate antibacterial surfaces on substrates of different chemistries and structures. In addition, traditional antibacterial surfaces may suffer problems related to the attached dead bacteria. Herein, antibacterial surfaces with multifunctionality and regenerability are fabricated by a universal strategy. Various substrates are first deposited with multilayered films containing guest moieties, which can be further used to incorporate biocidal host molecules, beta cyclodextrin (beta-CD) derivatives modified with quaternary ammonium salt groups (CD-QAS). The resulting surfaces exhibit strong biocidal activity to kill more than 95% of attached pathogenic bacteria. Notably, almost all the dead bacteria can be easily removed from the surfaces by simple immersion in sodium dodecyl sulfate, and the regenerated surfaces can be treated with new CD-QAS for continued use. Moreover, when another functional beta-CD derivative molecule is co-incorporated together with CD-QAS, the surfaces exhibit both functions simultaneously, and neither specific biofunction and antibacterial activity is compromised by the presence of the other. These results thus present a promising way to fabricate multifunctional and regenerable antibacterial surfaces on diverse materials and devices in the biomedical fields. PMID- 27759377 TI - Fighting Cancer with Corroles. AB - Corroles are exceptionally promising platforms for the development of agents for simultaneous cancer-targeting imaging and therapy. Depending on the element chelated by the corrole, these theranostic agents may be tuned primarily for diagnostic or therapeutic function. Versatile synthetic methodologies allow for the preparation of amphipolar derivatives, which form stable noncovalent conjugates with targeting biomolecules. These conjugates can be engineered for imaging and targeting as well as therapeutic function within one theranostic assembly. In this review, we begin with a brief outline of corrole chemistry that has been uniquely useful in designing corrole-based anticancer agents. Then we turn attention to the early literature regarding corrole anticancer activity, which commenced one year after the first scalable synthesis was reported (1999 2000). In 2001, a major advance was made with the introduction of negatively charged corroles, as these molecules, being amphipolar, form stable conjugates with many proteins. More recently, both cellular uptake and intracellular trafficking of metallocorroles have been documented in experimental investigations employing advanced optical spectroscopic as well as magnetic resonance imaging techniques. Key results from work on both cellular and animal models are reviewed, with emphasis on those that have shed new light on the mechanisms associated with anticancer activity. In closing, we predict a very bright future for corrole anticancer research, as it is experiencing exponential growth, taking full advantage of recently developed imaging and therapeutic modalities. PMID- 27759378 TI - Synthesis of GdAlO3:Mn4+,Ge4+@Au Core-Shell Nanoprobes with Plasmon-Enhanced Near Infrared Persistent Luminescence for in Vivo Trimodality Bioimaging. AB - The rise of multimodal nanoprobes has promoted the development of new methods to explore multiple molecular targets simultaneously or to combine various bioimaging tools in one assay to more clearly delineate localization and expression of biomarkers. Persistent luminescence nanophosphors (PLNPs) have been qualified as a promising contrast agent for in vivo imaging. The easy surface modification and proper nanostructure design strategy would favor the fabrication of PLNP-based multifunctional nanoprobes for biological application. In this paper, we have proposed novel multifunctional core-shell nanomaterials, applying the Mn4+ and Ge4+ co-doped gadolinium aluminate (GdAlO3:Mn4+,Ge4+) PLNPs as the near-infrared persistent luminescence emission center and introducing the gold nanoshell coated on the PLNPs to enhance the luminescence efficiency via plasmon resonance. Our developed core-shell nanoprobes have demonstrated the excellent features of ultrabrightness, superlong afterglow, good monodispersity, low toxicity, and excellent biocompatibility. The well-characterized nanoprobes have been utilized for trimodality in vivo imaging, with near-infrared persistent luminescence for optical imaging, Gd element for magnetic resonance imaging, and Au element for computed tomography imaging. PMID- 27759380 TI - Ab Initio Thermodynamic and Thermophysical Properties of Sodium Metasilicate, Na2SiO3, and Their Electron-Density and Electron-Pair-Density Counterparts. AB - Thermodynamic and thermophysical properties of Na2SiO3 in the Cmc21 structural state are computed ab initio using the hybrid B3LYP density functional method. The static properties at the athermal limit are first evaluated through a symmetry-preserving relaxation procedure. The thermodynamic properties that depend on vibrational frequencies, viz., heat capacities, thermal expansion, thermal derivative of the bulk modulus, thermal correction to internal energy, enthalpy, and Gibbs free energy, are then computed in the framework of quasi harmonic approximation. Acoustic branches are computed by solving the Christoffel determinant and are assumed to follow sine wave dispersion when traveling within the Brillouin zone. The procedure generates several thermo-physical properties of interest in materials science and geophysics (transverse and longitudinal wave velocities, shear modulus, Young modulus, Poisson ratio) all consistent with experimentally determined properties. A representative cluster is then abstracted from the cell and a detailed electron localization/delocalization analysis is performed on it, in the ground state geometry, and on deformed states imposed by two peculiar mixed asymmetric stretching/bending modes affecting the silicate chain that, according to literature data, have anomalous mode Gruneisen parameters. A Bader analysis reveals an intriguing feature associated with these deformations: an increase in the covalence of the Si-O bond that strengthens the linkage opposing the weakening induced by thermal stress. Finally, on the same cluster, the Ramsey contributions to the JNM coupling are evaluated by the gauge independent atomic orbital method. The calculated isotropic chemical shifts of both 23Na and 29Si are again in substantial agreement with observations. PMID- 27759379 TI - Balancing the Interactions of Mg2+ in Aqueous Solution and with Nucleic Acid Moieties For a Polarizable Force Field Based on the Classical Drude Oscillator Model. AB - Mg2+ ions are important in biological systems, particularly in stabilizing compact RNA folds. Mg2+ is strongly polarizing, and representing its interactions in heterogeneous environments is a challenge for empirical force field development. To date, the most commonly used force fields in molecular dynamics simulations utilize a pairwise-additive approximation for electrostatic interactions, which cannot account for the significant polarization response in systems containing Mg2+. In the present work, we refine the interactions of Mg2+ with water, Cl- ions, and nucleic acid moieties using a polarizable force field based on the classical Drude oscillator model. By targeting gas-phase quantum mechanical interaction energies and geometries of hydrated complexes, as well as condensed-phase osmotic pressure calculations, we present a model for Mg2+ that yields quantitative agreement with experimental measurements of water dissociation free energy and osmotic pressure across a broad range of concentrations. Notable is the direct modeling of steric repulsion between the water Drude oscillators and Mg2+ to treat the Pauli exclusion effects associated with overlap of the electron clouds of water molecules in the first hydration shell around Mg2+. Combined with the refined interactions with nucleic acid moieties, the present model represents a significant advancement in simulating nucleic acid systems containing Mg2+. PMID- 27759381 TI - Modifications of Structure and Intermolecular Potential of a Canonical Glassformer: Dynamics Changing with Dipole-Dipole Interaction. AB - By systematic modifications of the canonical propylene carbonate, a family of van der Waals glass-formers with similar chemical structures is generated for dielectric studies of the dynamics of the structural alpha-relaxation with the purpose of critically testing the correlation of dynamic properties with the dipole-dipole interaction contribution to the intermolecular potential. With the dielectric strengths at Tg varying over a vast range from 4.2 to 182, the modified propylene carbonates provide strong support of the correlation by themselves and in conjunction with 88 van der Waals glassformers previously considered ( Phys. Rev. Lett. 2016 , 116 , 025702 ). PMID- 27759382 TI - Identifying and Tackling Emergent Vulnerability in Drug-Resistant Mycobacteria. AB - The global mechanisms and associated molecular alterations that occur in drug resistant mycobacteria are poorly understood. To address this, we obtain genomics data and then construct a genome-scale response network in isoniazid-resistant Mycobacterium smegmatis and apply a network-mining algorithm. Through this, we decipher global alterations in an unbiased manner and identify emergent vulnerabilities in resistant bacilli, of which redox response was prominent. Using phenotypic profiling, we find that resistant bacilli exhibit collateral sensitivity to several compounds that block antioxidant responses. We find that nanogram/milliliter concentrations of ebselen, vancomycin, and phenylarsine oxide, in combination with isoniazid, are highly effective against Mycobacterium tuberculosis H37Rv and three clinical drug-resistant strains. Dynamic measurements of cytoplasmic redox potential revealed a surprisingly diminished capacity of clinical drug-resistant strains to counteract oxidative stress, providing a mechanistic basis for efficient and synergistic mycobactericidal activity of the drug combinations. Ebselen and vancomycin appear to be promising repurposable drugs. PMID- 27759383 TI - Differences and Similarities between Lanthanum and Rare-Earth Iodate Anhydrous Polymorphs: Structures, Thermal Behaviors, and Luminescent Properties. AB - The Ln(IO3)3(HIO3)y (y = 1 or 1.33) compounds are isostructural with the La(IO3)3(HIO3)y phases, but thermal studies reveal different behaviors. On the one hand, the partial thermal decompositions of these lanthanide compounds lead to the Ln(IO3)3 formulation, with a room temperature structure different from the beta-La(IO3)3 obtained from La(IO3)3(HIO3)y. On the other hand, the partial thermal decompositions of the La1-xLnx(IO3)3(HIO3)y compounds prepared with lanthanides ions (Ce, Pr, Nd, Sm, Eu, Gd, and Yb) lead to acentric beta-La1 xLnx(IO3)3. As for beta-La(IO3)3, reversible structural transitions from beta-La1 xLnx(IO3)3 to centrosymmetric gamma-La1-xLnx(IO3)3 are observed. Differential scanning calorimetry analyses of La1-xLnx(IO3)3 solid solutions show that the transition temperatures vary with the lanthanide concentration in the solid solution. A transition is observed only up to a certain fraction of lanthanide ion substitution; this substitution limit decreases with the cationic radius of the lanthanide ion. Finally, the beta-La1-xNdx(IO3)3 and beta-La1-xYbx(IO3)3 phases are investigated by luminescence spectroscopy. PMID- 27759384 TI - Zoanthamine-Type Alkaloids from the Zoanthid Zoanthus kuroshio Collected in Taiwan and Their Effects on Inflammation. AB - Zoanthus kuroshio is a colorful zoanthid with a fluorescent pink oral disc and brown tentacles, which dominates certain parts of the Taiwanese and Japanese coasts. This sea anemone is a rich source of biologically active alkaloids. In the current investigation, two novel halogenated zoanthamines [5alpha iodozoanthenamine (1) and 11beta-chloro-11-deoxykuroshine A (2)], along with four new zoanthamines [18-epi-kuroshine A (3), 7alpha-hydroxykuroshine E (4), 5alpha methoxykuroshine E (5), and 18-epi-kuroshine E (6)], and six known compounds were isolated from Z. kuroshio. Compounds 1 and 2 are the first examples of halogenated zoanthamine-type alkaloids isolated from nature. Compounds 3 and 6 are the first zoanthamine stereoisomers with a cis-junction of the A/B rings. All isolated compounds were evaluated for their anti-inflammatory activities by measuring their effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP. PMID- 27759385 TI - Correction to "An Evolved Orthogonal Enzyme/Cofactor Pair". PMID- 27759386 TI - Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due to Trapping of the Product. AB - The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanKII with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm. The cocrystal structures showed that all of the PanAms are phosphorylated by SaPanKII but remain bound at the active site; this occurs primarily through interactions with Tyr240' and Thr172'. Kinetic analysis showed a strong correlation between kcat (slow PanAm turnover) and IC50 (inhibition of pantothenate phosphorylation) values, suggesting that SaPanKII inhibition occurs via a delay in product release. In-depth analysis of the PanAm-bound structures showed that the capacity for accepting a hydrogen bond from the amide of Thr172' was a stronger determinant for PanAm potency than the capacity to pi-stack with Tyr240'. The two new PanAms, N-Pip-PanAm and MeO-N5-PanAm, effectively combine both hydrogen bonding and hydrophobic interactions, resulting in the most potent SaPanKII inhibition described to date. Taken together, our results are consistent with an inhibition mechanism wherein PanAms act as SaPanKII substrates that remain bound upon phosphorylation. The phospho-PanAm-SaPanKII interactions described herein may help future antistaphylococcal drug development. PMID- 27759387 TI - A Hexacyclic, Iboga-Derived Monoterpenoid Indole with a Contracted Tetrahydroazepine C-Ring and Incorporation of an Isoxazolidine Moiety, a Seco Corynanthean, an Aspidosperma-Aspidosperma Bisindole with Anticancer Properties, and the Absolute Configuration of the Pyridopyrimidine Indole Alkaloid, Vernavosine. AB - Examination of the EtOH extract of the Malayan Tabernaemontana corymbosa resulted in the isolation of three new alkaloids, viz., cononuridine (1), an unusual hexacyclic, iboga-derived, monoterpenoid indole characterized by contraction of the tetrahydroazepine C-ring and incorporation of an additional isoxazolidine ring, taberisidine (2), a seco-corynanthean alkaloid, and conofolidine (3), an Aspidosperma-Aspidosperma bisindole that showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, and HCT 116 cells. The structures and absolute configurations of 1 and 3 and the absolute configuration of the novel pyridopyrimidine indole alkaloid vernavosine (4) were confirmed by X-ray diffraction analysis. A reasonable biosynthesis route to cononuridine starting from an iboga precursor is presented. PMID- 27759388 TI - How To Make a Glycopeptide: A Synthetic Biology Approach To Expand Antibiotic Chemical Diversity. AB - Modification of natural product backbones is a proven strategy for the development of clinically useful antibiotics. Such modifications have traditionally been achieved through medicinal chemistry strategies or via in vitro enzymatic activities. In an orthogonal approach, engineering of biosynthetic pathways using synthetic biology techniques can generate chemical diversity. Here we report the use of a minimal teicoplanin class glycopeptide antibiotic (GPA) scaffold expressed in a production-optimized Streptomyces coelicolor strain to expand GPA chemical diversity. Thirteen scaffold-modifying enzymes from 7 GPA biosynthetic gene clusters in different combinations were introduced into S. coelicolor, enabling us to explore the criteria for in-cell GPA modification. These include identifying specific isozymes that tolerate the unnatural GPA scaffold and modifications that prevent or allow further elaboration by other enzymes. Overall, 15 molecules were detected, 9 of which have not been reported previously. Some of these compounds showed activity against GPA-resistant bacteria. This system allows us to observe the complex interplay between substrates and both non-native and native tailoring enzymes in a cell-based system and establishes rules for GPA synthetic biology and subsequent expansion of GPA chemical diversity. PMID- 27759390 TI - Mimicking Photosynthesis with Electrode-Supported Lipid Nanoassemblies. AB - The grand scale, ultimate efficiency, and sustainability of natural photosynthesis have inspired generations of researchers in biomimetic light energy utilization. As an essential and ubiquitous component in all photosynthetic machinery, lipids and their assemblies have long been recognized as powerful molecular scaffolds in building artificial photosynthetic systems. Model lipid bilayers, such as black lipid membranes and liposomes (vesicles), have been extensively used to host natural as well as synthetic photo- and redox active species, thereby enabling key photosynthetic processes, such as energy transfer and photoinduced electron transfer, to be examined in well-defined, natural-like membrane settings. Despite their long history, these lipid models remain highly relevant and still enjoy wide practice today. In this Account, we share with the reader our recent effort of introducing electrode-supported lipid nanoassemblies as new lipid models into photosynthesis biomimicking. This line of research builds off several solid-supported lipid bilayer architectures established relatively recently by workers in membrane biophysics and reveals important new features that match and sometimes exceed what earlier lipid models are capable of offering. Here, our eight-year exploration unfolds in three sections: (1) New photosynthetic mimics based on solid-supported lipid bilayers. This systematic effort has brought three solid-supported bilayers into artificial photosynthesis research: lipid bilayers supported on indium tin oxide electrodes, hybrid bilayers, and tethered lipid bilayers formed on gold. Quantitative on electrode deposition of various photo- and redox-active agents, including fullerene, Ru(bpy)32+, and porphyrin, is realized via liposomal hosts. Vectorial electron transfer across single lipid-bilayer leaflets is achieved between electron donor/acceptor directionally organized therein, taking advantage of multiple incorporation sites offered by these bilayers as well as their sequential formation on electrodes. Supported on electrodes, these bilayers uniformly afford reliable photocurrent generation and modular system design. (2) Gold-supported hybrid bilayers as a powerful model platform for probing biomembrane-associated photoelectrochemical processes. These hybrid nanostructures consist of one alkanethiol (or substituted alkanethiol) and one lipid monolayer, whose chemical identity and makeup can be separately controlled and modified. Such precise molecular organization and flexible formation, in turn, enable a series of physicochemical parameters key to photosynthetic processes to be explicitly examined and cross-compared. A few such examples, based on donor/acceptor distance and loading, interfacial dipole, and redox level, are included here to illustrate the usefulness and versatility of this system. (3) Mimicking photosynthesis with supercomplexed lipid nanoassemblies. This research effort was motivated to address the low light absorption suffered by single-bilayer based photosynthetic mimics and has yielded a new lipid-based approach to mimicking Nature's way of organizing multiple photosynthetic subunits. Rhodamine and fullerene assembled within these lipid supercomplexes display robust electronic communication. The remarkable possibility of using lipid matrix to further improve photoconversion efficiency is revealed by cholesterol, whose addition triggers exciton formation that promotes faster energy and electron transfer in these lipid nanoassemblies. PMID- 27759389 TI - Disruption of de Novo Adenosine Triphosphate (ATP) Biosynthesis Abolishes Virulence in Cryptococcus neoformans. AB - Opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. To address the current paucity of antifungal therapeutic agents, further research into fungal-specific drug targets is required. Adenylosuccinate synthetase (AdSS) is a crucial enzyme in the adeosine triphosphate (ATP) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. We have investigated the potential of this enzyme as an antifungal drug target, finding that loss of function results in adenine auxotrophy in C. neoformans, as well as complete loss of virulence in a murine model. Cryptococcal AdSS was expressed and purified in Escherichia coli and the enzyme's crystal structure determined, the first example of a structure of this enzyme from fungi. Together with enzyme kinetic studies, this structural information enabled comparison of the fungal enzyme with the human orthologue and revealed species specific differences potentially exploitable via rational drug design. These results validate AdSS as a promising antifungal drug target and lay a foundation for future in silico and in vitro screens for novel antifungal compounds. PMID- 27759391 TI - Structure Determination and Time-Resolved Raman Spectroscopy of Yttrium Ion Exchange into Microporous Titanosilicate ETS-4. AB - The ion exchange of yttrium, one of the five most critical rare-earth elements as outlined by the U.S. Department of Energy, into ETS-4 is a dynamic, multistep ion exchange process. The ion exchange process was followed using in situ time resolved Raman spectroscopy, and the crystal structures of the pre-exchange and post-exchange forms were determined by single-crystal X-ray diffraction. In situ Raman spectroscopy is an ideal tool for this type of study, as it measures the spectral changes that are a result of molecular geometry changes at fast time intervals, even where symmetry and unit volume changes are minimally detected by X-ray diffraction. By tracking the stepwise changes in the peak positions and intensities in the spectra, where we focused primarily on the strong spectral features corresponding to titania quantum wires and three-membered-ring bending and breathing modes, we constructed molecular models to explain the changes in the Raman spectrum during ion exchange. The multistep ion exchange process started with rapid absorption of Y into the Na2 site, causing titania quantum wires to kink. After this initial uptake, the exchange process slowed, likely caused by hydration coordination changes within the channels. Next, Y exchange accelerated again, during which time the Y site moved closer to the framework O2 . Crystal structures of the maximal Y exchanged ETS-4 material were determined and confirmed the splitting of the Y site. Inductively coupled plasma optical emission spectroscopy was also used to quantify the extent of Y exchange and to measure if there were indications of titania leaching from the framework. PMID- 27759392 TI - Unravelling the Mechanism of Basic Aqueous Methanol Dehydrogenation Catalyzed by Ru-PNP Pincer Complexes. AB - Ruthenium PNP complex 1a (RuH(CO)Cl(HN(C2H4Pi-Pr2)2)) represents a state-of-the art catalyst for low-temperature (<100 degrees C) aqueous methanol dehydrogenation to H2 and CO2. Herein, we describe an investigation that combines experiment, spectroscopy, and theory to provide a mechanistic rationale for this process. During catalysis, the presence of two anionic resting states was revealed, Ru-dihydride (3-) and Ru-monohydride (4-) that are deprotonated at nitrogen in the pincer ligand backbone. DFT calculations showed that O- and CH- coordination modes of methoxide to ruthenium compete, and form complexes 4- and 3 , respectively. Not only does the reaction rate increase with increasing KOH, but the ratio of 3-/4- increases, demonstrating that the "inner-sphere" C-H cleavage, via C-H coordination of methoxide to Ru, is promoted by base. Protonation of 3- liberates H2 gas and formaldehyde, the latter of which is rapidly consumed by KOH to give the corresponding gem-diolate and provides the overall driving force for the reaction. Full MeOH reforming is achieved through the corresponding steps that start from the gem-diolate and formate. Theoretical studies into the mechanism of the catalyst Me-1a (N-methylated 1a) revealed that C-H coordination to Ru sets-up C-H cleavage and hydride delivery; a process that is also promoted by base, as observed experimentally. However, in this case, Ru-dihydride Me-3 is much more stable to protonation and can even be observed under neutral conditions. The greater stability of Me-3 rationalizes the lower rates of Me-1a compared to 1a, and also explains why the reaction rate then drops with increasing KOH concentration. PMID- 27759393 TI - The Use of Pyranoside-into-Furanoside Rearrangement and Controlled O(5) -> O(6) Benzoyl Migration as the Basis of a Synthetic Strategy To Assemble (1->5)- and (1 >6)-Linked Galactofuranosyl Chains. AB - A new pyranoside-into-furanoside (PIF) rearrangement of selectively protected galactopyranosides, followed by controlled O(5) -> O(6) benzoate migration, gives either 5-OH or 6-OH products. It has been applied for the synthesis of four oligosaccharides related to the galactomannan from Aspergillus fumigatus. The assembly of target oligosaccharides containing both (1->5) and (1->6) linkages between galactofuranosyl residues was performed by applying terminal mannoside and digalactofuranoside blocks, forming a versatile approach toward fungal and bacterial carbohydrate antigens containing both 5-O- and 6-O-substituted galactofuranoside residues. PMID- 27759394 TI - Synergistic Coassembly of Two Structurally Different Molecular Gelators. AB - Coassembly of molecules can produce materials with improved properties and functionalities. To this end, achieving a molecular level understanding of the interactions governing the coassembly is essential. In this work, two molecular gelators with significantly different structures and main intermolecular forces for assembly were coassembled. The elastic moduli of the hybrid gels are more than 1 order of magnitude higher than those of the gels formed by the individual gelators, showing an obvious synergistic effect. The interactions between the gelators were investigated with confocal microscopy and both one-dimensional and two-dimensional nuclear magnetic resonance. It was found that the two gelators coassemble to form fibers due to the nonspecific van der Waals interactions between their alkyl chains and the specific interactions between their functional groups. Switching from one gelator-dominated fiber network to the other gelator dominated fiber network was achieved at a critical molar ratio of the gelators. The two gelators serve as additives of each other to tune the nucleation and growth of the fiber networks. The observations of this work are significant to the development of materials with improved properties by coassembly of different molecules. PMID- 27759395 TI - Through-Linker Intramolecular Singlet Fission: General Mechanism and Designing Small Chromophores. AB - We perform quantum chemistry calculations and quantum dynamics simulations to investigate the covalent linker's through-bond effects in intramolecular singlet fission. A model molecule with two diazadiborine chromophore units and the para phenylene linker is proposed. A general, step-by-step picture for the conversion from the single- to the multiexcitonic state through the linker is presented. On the basis of the picture, we discuss the triplet-pair delocalization into the linker and design two more chromophores with higher fission efficiency. All three designed chromophores have promising picosecond fission time scales and make good candidates for azaborine synthesis. PMID- 27759396 TI - Probing Silica-Biomolecule Interactions by Solid-State NMR and Molecular Dynamics Simulations. AB - Understanding the molecular interactions between inorganic phases such as silica and organic material is fundamental for chromatographic applications, for tailoring silica-enzyme interactions, and for elucidating the mechanisms of biomineralization. The formation, structure, and properties of the organic/inorganic interface is crucial in this context. Here, we investigate the interaction of selectively 13C-labeled choline with 29Si-labeled monosilicic acid/silica at the molecular level. Silica/choline nanocomposites were analyzed by solid-state NMR spectroscopy in combination with extended molecular dynamics (MD) simulations to understand the silica/organic interface. Cross-polarization magic angle spinning (CP MAS)-based NMR experiments like 1H-13C CP-REDOR (rotational-echo double resonance), 1H-13C HETCOR (heteronuclear correlation), and 1H-29Si-1H double CP are employed to determine spatial parameters. The measurement of 29Si-13C internuclear distances for selectively 13C-labeled choline provides an experimental parameter that allows the direct verification of MD simulations. Atomistic modeling using classical MD methodologies is performed using the INTERFACE force field. The modeling results are in excellent agreement with the experimental data and reveal the relevant molecular conformations as well as the nature and interplay of the interactions between the choline cation and the silica surface. Electrostatic interactions and hydrogen bonding are both important and depend strongly on the hydration level as well as the charge state of the silica surface. PMID- 27759397 TI - Synthesis of a Water-Soluble Carboxylatobiphen[4]arene and Its Selective Complexation toward Acetylcholine. AB - The first water-soluble biphen[4]arene containing eight carboxylato moieties (carboxylatobiphen[4]arene, CBP4) has been synthesized. Selective molecular recognition of acetylcholine (ACh) against choline (Ch) and betaine (Bt) and pH responsive host-guest complexation in aqueous media are described. PMID- 27759398 TI - Vapor-Phase Carbenylation of Hard and Soft Material Interfaces. AB - This study describes the formation of functional organic monolayers on hard and soft interfaces via a vapor-phase carbene insertion into Si-H and C-H bonds. We demonstrate that functional diazirine molecules can be used to form monomolecular coatings on silicon, silicon nitride, and urethane-acrylate polymers under mild vacuum conditions and exposure to UV light. We investigate the molecular coverage and the long-term stability of the resulting monolayers in air, isopropanol, and water. Our results suggest that vapor-phase carbenylation can be used as a complementary technology to the traditional self-assembly, permitting functionalization of various passivated substrates with stable and functional molecular coatings under mild and scalable conditions. PMID- 27759400 TI - General Model of Hindered Diffusion. AB - The diffusion of a particle from bulk solution is slowed as it moves close to an adsorbing surface. A general model is reported that is easily applied by theoreticians and experimentalists. Specifically, it is shown here that in general and regardless of the space size, the magnitude of the effect of hindered diffusion on the flux is a property of the diffusion layer thickness. We explain and approximate the effect. Predictions of concentration profiles show that a "hindered diffusion layer" is formed near the adsorbing surface within the diffusion layer, observed even when the particle radius is just a 0.1% of the diffusion layer thickness. In particular, we focus on modern electrochemistry processes involving with impact of particles with either ultrasmall electrodes or particles in convective systems. The concept of the "hindered diffusion layer" is generally important for example in recent biophysical models of particles diffusion to small targets. PMID- 27759399 TI - Metal-Free Direct Amidation of Naphthoquinones Using Hydroxamic Acids as an Amide Source: Application in the Synthesis of an HDAC6 Inhibitor. AB - A novel synthetic approach to amidoquinones by the reaction of naphthoquinones with hydroxamic acids under basic conditions was developed. The reaction is mild and operationally simple, and it affords high yields of amidoquinones. With this new method, a novel, very strong HDAC6 inhibitor, which showed high toxicity to AML cells, was successfully synthesized. PMID- 27759401 TI - Cavity-Enhanced and Ultrafast Superconducting Single-Photon Detectors. AB - Ultrafast single-photon detectors with high efficiency are of utmost importance for many applications in the context of integrated quantum photonic circuits. Detectors based on superconductor nanowires attached to optical waveguides are particularly appealing for this purpose. However, their speed is limited because the required high absorption efficiency necessitates long nanowires deposited on top of the waveguide. This enhances the kinetic inductance and makes the detectors slow. Here, we solve this problem by aligning the nanowire, contrary to usual choice, perpendicular to the waveguide to realize devices with a length below 1 MUm. By integrating the nanowire into a photonic crystal cavity, we recover high absorption efficiency, thus enhancing the detection efficiency by more than an order of magnitude. Our cavity enhanced superconducting nanowire detectors are fully embedded in silicon nanophotonic circuits and efficiently detect single photons at telecom wavelengths. The detectors possess subnanosecond decay (~120 ps) and recovery times (~510 ps) and thus show potential for GHz count rates at low timing jitter (~32 ps). The small absorption volume allows efficient threshold multiphoton detection. PMID- 27759402 TI - Photon Upconversion and Molecular Solar Energy Storage by Maximizing the Potential of Molecular Self-Assembly. AB - The self-assembly of functional molecules into ordered molecular assemblies and the fulfillment of potentials unique to their nanotomesoscopic structures have been one of the central challenges in chemistry. This Feature Article provides an overview of recent progress in the field of molecular self-assembly with the focus on the triplet-triplet annihilation-based photon upconversion (TTA-UC) and supramolecular storage of photon energy. On the basis of the integration of molecular self-assembly and photon energy harvesting, triplet energy migration based TTA-UC has been achieved in varied molecular systems. Interestingly, some molecular self-assemblies dispersed in solution or organogels revealed oxygen barrier properties, which allowed TTA-UC even under aerated conditions. The elements of molecular self-assembly were also introduced to the field of molecular solar thermal fuel, where reversible photoliquefaction of ionic crystals to ionic liquids was found to double the molecular storage capacity with the simultaneous pursuit of switching ionic conductivity. A future prospect in terms of innovating molecular self-assembly toward molecular systems chemistry is also discussed. PMID- 27759403 TI - Pit and fissure sealants or fluoride varnishes? AB - Despite the general advances in dental care, dental caries is still a global health problem affecting many children. Occlusal surfaces of first permanent molars are the most susceptible sites in the developing permanent dentition. Dentists should use sealants or fluoride varnish - as well as other means - to limit the onset of tooth decay. Application of sealants is a recommended procedure to prevent or control caries. Sealing occlusal surfaces of newly erupted permanent molars in children and teenagers delays caries onset up to 48 months compared with unsealed teeth. However longer follow-ups shows a reduction of the preventive effect [Tikhonova et al., 2015]. A review of 2013 pointed out how sealants are effective in high risk children, however information about the benefits of sealing in other conditions is still scant [Ahovuo-Saloranta et al., 2013]. Fluoride varnishes are frequently used to prevent early childhood caries and reduce caries increment in very young children [Weintraub et al., 2006] and in the most vulnerable populations, where the prevalence of caries is higher and specialist visits are occasional [Chu et al., 2010]. Many studies have reported the effectiveness of different types and forms of fluoride agents in preventing dental caries among children and adolescents [Divaris et al., 2013]. A review clarifies that professional application of a 5% sodium fluoride varnish leads to remineralisation of early enamel caries in children. Solutions of 38% silver diamine fluoride are effective in arresting active dentine caries [Gao et al., 2016]. The last systematic review [Ahovuo-Saloranta et al., 2016], comparing pit and fissure sealants with fluoride varnishes explains that the pooled estimate slightly favours resin sealants over fluoride varnishes at two years. At four and nine years, the only comparative study (with high drop-out rates) found more caries on fluoride-varnished occlusal surfaces than on resin-sealed surfaces. There is evidence suggesting the superiority of resin-based fissure sealants over fluoride varnishes for prevention of occlusal caries in permanent molars, however it is not relevant. Eventually, Ahovuo-Saloranta et al. state that current data do not allow to draw definitive conclusions on whether to apply sealants or fluoride varnishes on occlusal surfaces of permanent molars [2016]. We will publish your opinion and experiences related to this topic in the next EJPD issue: join the discussion and write a letter to the editor! PMID- 27759404 TI - An experimental in vivo procedure for the standardised assessment of sealants retention over time. AB - AIM: The elaboration of an experimental system to obtain reproducible and comparable photographs of the occlusal surface to monitor sealants retention. MATERIALS AND METHODS: An intraoral camera connected to a computer was used to obtain photos of the occlusal surfaces. A specific software was utilized to perform measurements on archived pictures. An experimental two-part system, consisting of a dental arch support and a camera support, connected to each other through holes and pins, was made to obtain a standardised and reproducible placement of the camera in the mouth. In the first part, to test the degree of reliability of the procedure and the percentage of image distortion, 120 first molars were sealed and for each molar ten photographs were taken, using the intraoral camera connected with the dental arch support, the camera support and the dedicated software. In the second part, 165 first molars were sealed and photographed, as above described, immediately after sealing (T0), 6 months (T1) and 1 year later (T2). With the software, the sealed areas were measured. The comparison of the selected sealed areas between T0 and T1, T0 and T2, T1 and T2 determined the percentage of sealant loss. RESULTS: In the first part, the experimental procedure showed a reliability of 96.85%. In the second part, the difference in the rate of lost sealant between T0-T1 and T1-T2 was statistically significant (p <0.001). STATISTICS: ANOVA analysis was made. CONCLUSIONS: Photographs, obtained through the experimental two-part system, allowing a reproducible positioning of the intraoral camera in oral cavity, could represent a standardised and useful method to monitor sealants retention over time. PMID- 27759405 TI - Association between clinical and salivary microbial parameters during orthodontic treatment with removable appliances with or without use of fluoride mouth rinse. AB - AIM: To evaluate the correlation between clinical and salivary microbial parameters during treatment with removable orthodontic appliances with or without use of fluoride mouth rinse. MATERIALS AND METHODS: A group of 48 patients completed this randomized, controlled, parallel-group, clinical pilot study. 24 patients of the test group (TG) rinsed after tooth brushing with a fluoride mouth rinse (100 ppm AmF/150 ppm NaF) while 21 patients of the control group (CG) did not. Clinical parameters [Approximal Plaque Index (API), Papillary Bleeding Index (PBI)] as well as levels of salivary mutans streptococci (MS) and lactobacilli (LB) were assessed at baseline and after 3, 6, 9 and 12 months. Compliance was documented by participants. Appliance wear-times were estimated retrospectively by the patients. All participants received the same brushing instructions and were supplied with the same toothbrush/toothpaste. RESULTS: A significant correlation of API values with MS levels (p=0.0003) or with LB levels (p=0.001) was observed. Furthermore, appliance wear-times were significantly associated with API values (p=0.02). The changes of MS or LB levels between beginning and end of the study did not differ significantly between study groups. The changes of the API scores showed slightly different median values (-3.5 in the TG vs. 0 in the CG), the difference, however, was not significant. CONCLUSIONS: The results emphasise the need for a careful monitoring of the oral hygiene status in patients with removable orthodontic appliances. Larger controlled clinical trials are necessary to investigate treatment options such as use of supplementary fluoride mouth rinse. PMID- 27759406 TI - Salivary microbiota and caries occurrence in Mutans Streptococci-positive school children. AB - AIM: To compare the composition of the salivary microbiota in caries-affected vs. caries-free mutans streptococci (MS)- positive children with mixed dentition. MATERIALS AND METHODS: Twenty eight healthy, 11-12-year-old schoolchildren with high MS counts (>10?5 CFU/mL) were included in this study. The children were screened with the Dentocult SM Strip Mutans test (Orion Diagnostica, Espoo, Finland) and examined using the International Caries Detection and Assessment System (ICDAS). The microbial composition of the saliva was assessed using the Human Oral Microbe Identification Microarray (HOMIM). Microbial differences between caries-affected (n=18) and caries-free children (n=10) were compared by Mann-Whitney analysis. RESULTS: The microbiota of the caries-affected vs. caries free children was rather similar. Abiotrophia defectiva and Actinomyces meyeri/A. odontolyticus were significantly higher in caries-affected than in caries-free children (p=0.006, 0.046, respectively). Shuttleworthia satelles was significantly higher in caries-free compared to caries-affected children (p=0.031). A. defectiva and A. meyeri/A. odontolyticus correlated positively with caries severity measured by ICDAS Caries Index (p = 0.494, 0.454, 0.400 respectively) while S. satelles was negatively correlated with caries severity (p= -0.489). CONCLUSIONS: Salivary A. defectiva and A. meyeri/A. odontolyticus and are associated with caries occurrence in MS-positive children with mixed dentition. PMID- 27759407 TI - Is pit and fissure sealing of buccal surfaces useful in reducing incidence of caries of first permanent molars? AB - AIM: The aim of the study was to establish whether caries prevalence on the buccal surfaces of first lower permanent molars (FLPMs) can be compared to those on the occlusal surfaces in order to justify the utility of extending pit and fissure sealing also to the extra-occlusal surfaces. MATERIALS AND METHODS: Design: an observational study was carried out in the children population (n=779) aged <=14 years (mean age 7.68, SD 3.53) that presented at the Paediatric Dentistry Department of the University of Perugia. In the study were included 460 patients, and absolute frequency (number) of FLMP occlusal and buccal caries, together with their ratio and their difference in percentage, were recorded and analysed. Moreover, FLMP buccal caries variation related to age, sex and parent's nationality were calculated. RESULTS: Among the 460 children included (243 males) aged 5-14 years, 103 erupted FLPMs were analysed. Of their decayed surfaces (n=115), the occlusal surfaces were 62 (53.9%) and the buccal surfaces 53 (46.1%); the absolute frequency ratio was 1.17 and the percentage difference was 7.8%. The female gender was significantly related to buccal caries of FLPMs [OR = 2.66 (95% CI; 1.27-5.59; p=0.0096)] as was the age ranging between 10-14 years [OR = 2.73 (95% CI; 1.36-5.50; p =0.004)]. The parents nationality was not significantly related to buccal caries [Odds Ratio =1.47 (95% CI; 0.70-3.06; p = 09040)]. CONCLUSIONS: The similar caries susceptibility of buccal and occlusal surfaces of FLPMs stimulates further comparative studies about the usefulness of extending pit and fissure sealing to the buccal surfaces in addition to the occlusal prophylactic intervention, particularly with regard to the female sex and during the early eruption stages of these teeth. PMID- 27759408 TI - Dental erosion: Prevalence and severity among 16-year-old adolescents in Troms, Norway. AB - AIM: To study the prevalence, distribution and severity of dental erosion among 16-year-old adolescents in the Troms region of Norway. MATERIALS AND METHODS: Study design: The participants were recruited through the Tromso-study ("Fit Futures"), and 392 16-year-olds were examined for dental erosion using clinical intraoral photographs. Three calibrated clinicians used the Visual Erosion Dental Examination (VEDE) system to register and grade the dental erosive wear. RESULTS: More than one third (38%) of the participants showed dental erosion on at least one tooth surface, 18% were limited to the enamel, while 20% of the adolescents showed erosive wear extending into the dentine. The occlusal surfaces of the lower first molars, and the palatal surfaces of the maxillary incisors were the most often and most severely affected. Of the participants showing dental erosion, 93% exhibited "cuppings" on the molars, with 48% limited to the enamel and 52% extending into the dentine. The highest prevalence of "cuppings" (73%) was found on the first lower molars, especially the mesiobuccal cusp of the teeth. The prevalence and severity of dental erosion was found to be higher in male than in female participants (p < 0.0001). CONCLUSION: The results from this study indicate a high prevalence and severity of dental erosion among adolescents in Troms and stress the importance of information, early and effective diagnostics and implementation of prevention strategies. PMID- 27759409 TI - Clinical performance of aesthetic restorative materials in primary teeth according to the FDI criteria. AB - AIM: The purpose of this study is to evaluate the clinical performance of three different restorative materials in primary teeth according to the FDI criteria. MATERIALS AND METHODS: Resin-modified glass ionomer cement, compomer and composite resin restorations (n=93) were made in 31 patients. The restorations were clinically evaluated at baseline, 6th, 12th and 18th month with the FDI criteria. RESULTS: The cumulative survival rate after 18 months was found to be 90.3% for resin modified glass ionomer cement restorations, 100% for compomer restorations and 80.6% for composite resin restorations. Statistically significant increase in surface roughness, colour mismatch, anatomic form loss and marginal deterioration were detected in resin- modified glass ionomer group (p<0.05). The most frequent reason for restoration failure in composite resin group was restoration fractures. CONCLUSIONS: The resin-modified glass ionomer restorations necessitates close follow-up because of the risk of increase in surface roughness, changes in colour and loss in anatomic form and marginal adaptation. The clinical performance of compomer restorations is superior to resin-modified glass ionomer and composite resin restorations in primary teeth. PMID- 27759410 TI - Clarifying the mechanism of effect of the Bionator for treatment of maxillary protrusion: A percentile growth study. AB - AIM: The reported effects of Bionator treatment in patients with mandibular retrognathism are conflicting. This study evaluated the changes in craniofacial morphology resulting from treatment with a Bionator, based on measurement percentiles previously reported, to clarify the mechanism of the effect of this commonly used functional device. MATERIALS AND METHODS: Study Design: Retrospective. SETTING: A private orthodontic clinic. PARTICIPANTS: Forty-two children (mean age, 10.13 years) requiring treatment with a Bionator for Class II malocclusion (mandibular retrognathism). Children were randomly assigned to a Bionator group with or without an expansion screw. Measurements on lateral cephalometric radiographs were taken before and upon completion of Bionator treatment. All parameters measured were characterised according to the measurement percentiles previously reported. Each parameter was compared before and after treatment for all patients and for each treatment group using Wilcoxon's test. RESULTS: No significant differences in cranial length or mandibular body length were seen in any of the 3 groups, but anterior cranial base length and maxillary length were significantly decreased while mandibular ramus height and mandibular length were significantly increased after treatment in the Bionator with expansion screw group and in the all-patient group. CONCLUSIONS: The findings suggest that treatment with a Bionator with expansion screw during the growth and development stage results in increased mandible length and ramus height and inhibits the growth of the maxilla and anterior cranial base bone. PMID- 27759411 TI - Tongue-tie assessment: clinical aspects and a new diode laser technique for its management. AB - : BACKGROUND Often breastfeeding problems experienced by mothers and their babies may be attributed to the abnormal attachment of the infant's tongue (ankyloglossia) and/or maxillary lip-tie. Proper breastfeeding depends upon an infant's ability to correctly latch onto its mother's breast. If born with oral soft tissue abnormalities such as tongue-tie or lip-tie, it may be almost impossible for the infant to breastfeed. During the oral evaluation of an infant presenting with breastfeeding problems, one factor that is often overlooked and undiagnosed - and thus untreated - is the attachment of the upper lip to the maxillary gingival tissue. CASE REPORT: The case is reported of tongue-tie and breastfeeding difficulties, treated with a novel technique: the diode laser (980 nm). PMID- 27759412 TI - Marginal fit of indirect composite inlays using a new system for manual fabrication. AB - AIM: This in vitro study compares a new system for manual chair side fabrication of indirect composite restorations, which uses silicone models after alginate impressions, to CAD/CAM-technology and laboratory manual production techniques. MATRIALS AND METHODS: and study design Each 10 composite inlays were fabricated using different types of production techniques: CAD/CAM- technology (A), the new inlay system (B), plaster model after alginate impression (C) or silicone impression (D). The inlays were adapted into a metal tooth and silicone replicas of the cement gaps were made and measured. Statistical analysis was performed using ANOVA and Tukey's test. Results and Statistics In group A the biggest marginal gaps (174.9MUm +/- 106.2MUm) were found. In group B the gaps were significantly smaller (119.5 MUm +/- 90.6 MUm) than in group A (p=0.035). Between groups C (64.6 MUm +/- 68.0MUm) and D (58.2 MUm +/- 61.7 MUm) no significant differences could be found (p=0.998), but the gaps were significantly smaller compared with group B. Conclusion Chairside manufacturing of composite inlays resulted in better marginal precision than CAD/CAM technology. In comparison to build restorations in a laboratory, the new system is a timesaving and inexpensive alternative. Nevertheless, production of indirect composite restorations in the dental laboratory showed the highest precision. PMID- 27759413 TI - Comparative evaluation of microleakage of a carbomer/fluoroapatite-enhanced glass ionomer cement on primary teeth restorations. AB - AIM: Carbomer cement represents a novel glass-ionomer which gradually mineralises into fluoroapatite. Purpose of this study was to evaluate microleakage around restorations in deciduous teeth made with composite resin, conventional glass ionomer cement, resin-modified glass-ionomer cement and carbomer/fluoroapatite enhanced glass-ionomer cement. MATERIALS AND METHODS: A group of 40 primary upper canines, primary upper and lower molars was divided into 4 groups (n=10). Class I cavities were prepared by diamond cylindrical bur at high speed and were restored with a composite resin (Group 1), with a glass- ionomer cement (Group 2), with a resin-modified glass-ionomer cement (Group 3) and with a carbomer/fluoroapatite enhanced glass- ionomer cement (Group 4). Hard tissue's bonding involved, in the case of composite resin a total etch bonding procedure, and in glass ionomers the use of their respective primers. Restorations were finished and polished. A 24 hour water storage was followed by thermocycling (1500 cycles, 5 degrees C - 36 degrees C - 55 degrees C - 36 degrees C with a dwell time of 15 seconds) and dye penetration test with immersion in 5% methylene blue for 24 hours. In order to assess the degree of microleakage longitudinal cuts were produced by means of a microtome at 0.5 mm and at 1 mm from the restoration margin, and photographs were taken with a stereomicroscope at 100X. Microleakage was classified according to the number of surfaces and the depth at which dye penetration was observed. Data were analysed with ANOVA and post-hoc analysis was performed with Bonferonni test (p<0.05). RESULTS: Statistical analysis exhibited no significant statistical difference between Group 2 and Group 3 (p>0.05). Statistical difference was exhibited between Group 3 and Group 4 (p<0.01), with Group 4 exhibiting lower microleakage values. Group 1 exhibited the lowest mean microleakage values and statistical difference in comparison with all groups (p<0.001). Group 4 exhibited the lowest microleakage values among the cements. CONCLUSION: Superior marginal integrity is achieved in restored primary teeth when composite resin is used. If the clinical case suggests the use of a glass-ionomer cement, carbomer/fluoroapatite-enhanced glass-ionomer cement is prefered in terms of microleakage. PMID- 27759414 TI - Aesthetic rehabilitation in a young patient using a minimally invasive approach. A multidisciplinary case report. AB - BACKGROUND: Optimal integration and long-term stability of oral rehabilitations require correct diagnostic approach, appropriate pre-prosthetic treatments and accurate therapeutic protocols. Technology provides devices to optimise therapeutic results, according to biologic constraints and aesthetic parameters. CASE REPORT: The present report describes a multidisciplinary management in a young patient affected by lateral incisor agenesis, including pre-prosthetic orthodontic treatment and restorative and implant-supported prosthetic rehabilitation. Minimally invasive clinical procedures with veneer restorations and flapless implant placement, followed by immediate prosthesis delivery, are carried out. Tridimensional diagnostic data and dedicated software were used for treatment planning, allowing to achieve optimal results. PMID- 27759415 TI - Which maternal personality traits affect child behaviour during dental treatment. AB - AIM: Maternal personality traits affect child dental behaviour and have a potential link with dental treatment methods. This study aims to evaluate which maternal personality traits affect child dental behaviour. MATERIALS AND METHODS: Research was carried out upon 60 children aged between 3-12 years, who had been admitted to our clinic for tooth extraction. All children were evaluated by means of the Frankl Behavior Scale (FBS): degrees I and II represent negative behaviours, while III and IV positive behaviour. Thirty children with FBS degree III and IV were assigned to Group I and 30 children with FBS degree I and II were assigned to Group II. Children in Group I underwent tooth extraction with local anaesthesia. Children in Group II underwent tooth extraction under deep sedation. During the first visit, the mothers were tested with the Minnesota Multiphasic Personality Inventory to evaluate personality traits. All mothers in Group I and half the mothers in Group II filled a complete and valid test. RESULTS: Group I and II mothers were compared according to the test results: scores of the Minnesota Multiphasic Personality Inventory (MMPI) test were significantly higher in Group II (p<0.05). CONCLUSION: We hypotetise that character features of mothers of children with negative dental behaviour and positive dental behaviour are different and affect child dental behaviour. PMID- 27759416 TI - Dentin caries progression and the role of metalloproteinases: an update. AB - AIM: This review aims to summarise our understanding of the destructive role of acid environment and metalloproteinases in dentin caries progression using a review process. METHOD: The acids resulting from consumption of sugars by acidogenic and aciduric bacteria can cause demineralisation of the tooth surface, but are not able to cause caries-like lesions. The appearance of such lesions requires the activation of enzymatic proteolysis in an acidic environment for degradation of the dentin organic matrix, leading to cavity formation. Bacterial collagenases have long been considered responsible for organic matrix destruction; host cell-derived matrix metalloproteinases (MMPs) have recently been considered to be involved in the dentinal matrix destruction of carious lesions. DISCUSSION AND CONCLUSION: MMPs are initially synthesised as inactive zymogens to be activated in acid environment of dentinal fluid during the carious process, resulting in destruction of the collagenous matrix. The role of acid environment on enamel and dentin demineralisation and the role of salivary and dentinal MMPs in dentin progression of caries has encouraged general dentists to include the monitoring of oral environment not only by control of bacterial oral flora in caries treatment protocol, but mainly by inhibition of dentinal and salivary MMPs through the use of toothpaste and/or mouthwash containing specific active agents. PMID- 27759417 TI - Oral manifestations of gastrointestinal diseases in children. Part 3: Ulcerative colitis and gastro-oesophageal reflux disease. AB - BACKGROUND: Alterations of the oral cavity are common in children: 22% of children aged less than 4 years and 44% of those aged more than 12 develop dental erosion, 9-95% of children in Europe and in North America develop gingivitis, with adolescents showing a prevalence of more than 60% [Italian Ministry of Health, Guidelines 2013]. Alterations within the oral cavity can be the first sign of systemic diseases and may thus allow for an early diagnosis and treatment. In particular, being the oral cavity a part of the gastrointestinal system, oral alterations can be an expression of a gastrointestinal disease. Pyostomatitis vegetans can be a sign of ulcerative colitis. Dental erosion with enamel loss in facial, occlusal, and lingual surfaces, and an increased risk of dental caries have been reported in children and adolescents with gastro oesophageal reflux with varying prevalence. A prompt recognition of systemic diseases through a careful examination of the oral cavity could allow proper investigations and management in a timely fashion. PMID- 27759418 TI - Nasopharyngeal carcinoma (NPC)-issues in the inclusion of cervical nodal region in radiation treatment volume-author's reply. PMID- 27759419 TI - A call to increase physical activity across the globe in the 21st century. PMID- 27759421 TI - Takotsubo cardiomyopathy following recurrent doses of albuterol due to asthma attack: a very rare case report. AB - To present an unusual case in order to clarify one of the most important differential diagnoses of ST-elevation myocardial infarction in a postmenopausal woman. A 72-year-old woman with asthma attack and retrosternal chest pain was presented to our emergency unit. She had used albuterol spray ten-times before admission due to accentuated dyspnea. Initial ECG revealed ST-segment elevation in leads V1-V6, I and aVL. Emergent coronary angiography indicated normal coronary arteries, and left ventriculography showed significant akinesia of apical segments. This unusual case emphasizes the fact that emergency physicians and cardiologists should be familiar with Takotsubo cardiomyopathy following overuse of beta2-agonist due to asthma attack that can mimic ST-elevation myocardial infarction. PMID- 27759420 TI - Nasopharyngeal carcinoma (NPC)-issues in the inclusion of cervical nodal region in radiation treatment volume. PMID- 27759422 TI - Building trust in real-world evidence and comparative effectiveness research: the need for transparency. PMID- 27759423 TI - High-resolution myocardial T1 mapping using single-shot inversion recovery fast low-angle shot MRI with radial undersampling and iterative reconstruction. AB - OBJECTIVE: To develop a novel method for rapid myocardial T1 mapping at high spatial resolution. METHODS: The proposed strategy represents a single-shot inversion recovery experiment triggered to early diastole during a brief breath hold. The measurement combines an adiabatic inversion pulse with a real-time readout by highly undersampled radial FLASH, iterative image reconstruction and T1 fitting with automatic deletion of systolic frames. The method was implemented on a 3-T MRI system using a graphics processing unit-equipped bypass computer for online application. Validations employed a T1 reference phantom including analyses at simulated heart rates from 40 to 100 beats per minute. In vivo applications involved myocardial T1 mapping in short-axis views of healthy young volunteers. RESULTS: At 1-mm in-plane resolution and 6-mm section thickness, the inversion recovery measurement could be shortened to 3 s without compromising T1 quantitation. Phantom studies demonstrated T1 accuracy and high precision for values ranging from 300 to 1500 ms and up to a heart rate of 100 beats per minute. Similar results were obtained in vivo yielding septal T1 values of 1246 +/- 24 ms (base), 1256 +/- 33 ms (mid-ventricular) and 1288 +/- 30 ms (apex), respectively (mean +/- standard deviation, n = 6). CONCLUSION: Diastolic myocardial T1 mapping with use of single-shot inversion recovery FLASH offers high spatial resolution, T1 accuracy and precision, and practical robustness and speed. Advances in knowledge: The proposed method will be beneficial for clinical applications relying on native and post-contrast T1 quantitation. PMID- 27759424 TI - Infant Diet-Related Changes in Syllable Processing Between 4 and 5 Months: Implications for Developing Native Language Sensitivity. AB - Since maturational processes triggering increased attunement to native language features in early infancy are sensitive to dietary factors, infant-diet related differences in brain processing of native-language speech stimuli might indicate variations in the onset of this tuning process. We measured cortical responses (ERPs) to syllables in 4 and 5 month old infants fed breast milk, milk formula, or soy formula and found syllable discrimination (P350) and syntactic-related functions (P600) but not syllable perception (P170) varied by diet, but not gender or background measures. The results suggest breastfed and formula-fed infants differ in onset of this critical period in speech perception. PMID- 27759426 TI - Interaction-Based Feature Selection for Uncovering Cancer Driver Genes Through Copy Number-Driven Expression Level. AB - Driver gene selection is crucial to understand the heterogeneous system of cancer. To identity cancer driver genes, various statistical strategies have been proposed, especially the L1-type regularization methods have drawn a large amount of attention. However, the statistical approaches have been developed purely from algorithmic and statistical point, and the existing studies have applied the statistical approaches to genomic data analysis without consideration of biological knowledge. We consider a statistical strategy incorporating biological knowledge to identify cancer driver gene. The alterations of copy number have been considered to driver cancer pathogenesis processes, and the region of strong interaction of copy number alterations and expression levels was known as a tumor related symptom. We incorporate the influence of copy number alterations on expression levels to cancer driver gene-selection processes. To quantify the dependence of copy number alterations on expression levels, we consider [Formula: see text] and [Formula: see text] effects of copy number alterations on expression levels of genes, and incorporate the symptom of tumor pathogenesis to gene-selection procedures. We then proposed an interaction-based feature selection strategy based on the adaptive L1-type regularization and random lasso procedures. The proposed method imposes a large amount of penalty on genes corresponding to a low dependency of the two features, thus the coefficients of the genes are estimated to be small or exactly 0. It implies that the proposed method can provide biologically relevant results in cancer driver gene selection. Monte Carlo simulations and analysis of the Cancer Genome Atlas (TCGA) data show that the proposed strategy is effective for high-dimensional genomic data analysis. Furthermore, the proposed method provides reliable and biologically relevant results for cancer driver gene selection in TCGA data analysis. PMID- 27759425 TI - Investigating the ability of Pseudomonas fluorescens UW4 to reduce cadmium stress in Lactuca sativa via an intervention in the ethylene biosynthetic pathway. AB - A typical plant response to any biotic or abiotic stress, including cadmium (Cd), involves increased ethylene synthesis, which causes senescence of the affected plant part. Stressed plants can experience reduced ethylene and improved growth if they are inoculated with bacteria that have the enzyme ACC deaminase, which metabolizes the ethylene precursor ACC (1-aminocyclopropane-1-carboxylate). We investigated whether one such bacterium, Pseudomonas fluorescens UW4, reduces the production of ethylene and improves the growth of lettuce (Lactuca sativa) sown in Cd-contaminated potting material (PRO-MIX(r) BX). Plants were inoculated with the wild-type P. fluorescens UW4 or a mutant strain that cannot produce ACC deaminase. Cadmium-treated plants contained up to 50 times more Cd than did control plants. In noninoculated plants, Cd induced a 5-fold increase in ethylene concentration. The wild-type bacterium prevented Cd-induced reductions in root biomass but there was no relationship between Cd treatment and ethylene production in inoculated plants. In contrast, when the concentration of ethylene was plotted against the extent of bacterial colonization of the roots, increased colonization with wild-type P. fluorescens UW4 was associated with 20% less ethylene production. Ours is the first study to show that the protective effect of this bacterium is proportional to the quantity of bacteria on the root surface. PMID- 27759427 TI - Surgical exclusion of a saccular aneurysm within a patent ductus arteriosus in an adult patient with Ortner's syndrome. AB - In adult the patent ductus arteriosus is a rare condition associated sometimes with lethal complications. We describe the case of a 44-year-old woman with a history of systemic lupus erythematosus admitted to our hospital with hoarseness and severe dyspnea. Clinical imaging examinations indicated a saccular aneurysm within a persistent ductus arteriosus with signs of impending rupture. Patient was not considered suitable for transcatheter closure and therefore she underwent open aortic repair. The procedure was uneventful and any significant complications occurred during postoperative course. PMID- 27759428 TI - Comparison of digital tomosynthesis and chest radiography for the detection of pulmonary nodules: systematic review and meta-analysis. AB - OBJECTIVE: To compare the diagnostic accuracy of digital tomosynthesis (DTS) with that of chest radiography for the detection of pulmonary nodules by meta analysis. METHODS: A systematic literature search was performed to identify relevant original studies from 1 January 1 1976 to 31 August 31 2016. The quality of included studies was assessed by quality assessment of diagnostic accuracy studies-2. Per-patient data were used to calculate the sensitivity and specificity and per-lesion data were used to calculate the detection rate. Summary receiver-operating characteristic curves were drawn for pulmonary nodule detection. RESULTS: 16 studies met the inclusion criteria. 1017 patients on a per patient basis and 2159 lesions on a per-lesion basis from 16 eligible studies were evaluated. The pooled patient-based sensitivity of DTS was 0.85 [95% confidence interval (CI) 0.83-0.88] and the specificity was 0.95 (0.93-0.96). The pooled sensitivity and specificity of chest radiography were 0.47 (0.44-0.51) and 0.37 (0.34-0.40), respectively. The per-lesion detection rate was 2.90 (95% CI 2.63-3.19). CONCLUSION: DTS has higher diagnostic accuracy than chest radiography for detection of pulmonary nodules. Chest radiography has low sensitivity but similar specificity, comparable with that of DTS. Advances in knowledge: DTS has higher diagnostic accuracy than chest radiography for the detection of pulmonary nodules. PMID- 27759429 TI - Gene Expression Profiles of HIV/AIDS Patients with Qi-Yin Deficiency and Dampness Heat Retention. AB - OBJECTIVES: Traditional Chinese Medicine (TCM) applied in the clinic as a complementary and alternative therapy has helped improve immunity and reduce side effects and symptomatic treatment in patients with HIV/AIDS. However, the mechanisms of TCM syndromes are not clear. Transcriptomics enables the study of such TCM syndromes. DESIGN: This study compared the messenger RNA (mRNA) expressions of healthy persons and patients with HIV/AIDS who had two common TCM syndromes, qi-yin deficiency and dampness-heat retention, to find the difference in HIV/AIDS with TCM syndromes. RESULTS: Comparison with healthy persons identified 113 mRNAs-41 enhanced and 72 decreased-in the qi-yin deficiency group. Additionally, 76 mRNAs were found in the dampness-heat retention group: 14 increased and 62 decreased. Functional genetic analysis of the mRNAs indicated that two TCM syndromes were correlated with cell apoptosis, immunoinflammatory responses, and lymphocyte activation. Differentially expressed mRNAs in the qi yin deficiency group were obviously associated with cellular activity, communication, protein localization, cellular ion homeostasis, and regulation of cell motion, whereas mRNAs in the dampness-heat retention group were associated with sequence-specific DNA binding, cellular response to stress, and hemopoietic or lymphoid organ development. CONCLUSIONS: These results suggest that the formation of different TCM syndromes in patients with HIV/AIDS were founded on biological transcriptomics, which reveal mechanisms of the formation of these syndromes in HIV/AIDS. Differentially expressed mRNAs in two TCM syndrome groups tended to normalize after TCM intervention, which indicates that TCM might remit symptoms by changing genetic expression. PMID- 27759430 TI - Evaluation of gastric blood supply in diabetic patients with gastroparesis by contrast-enhanced ultrasound. AB - OBJECTIVE: Improvement in regional blood flow has been shown to ameliorate diabetic gastroparesis. We compared the gastric blood supply in patients with diabetes with gastroparesis with that in healthy subjects, by using contrast enhanced ultrasound (CEUS). METHODS: 30 healthy subjects and 40 patients with diabetic gastroparesis were enrolled. The CEUS parameters of greater curvatures of the antrum (GCOA) and lesser curvatures of the antrum (LCOA), including peak intensity (PI) and the area under the curve (AUC), were compared between the two groups. RESULTS: Intraclass correlation coefficient (ICC) for PI in healthy subjects measured on CEUS were 0.831-0.857 and 0.803-0.823, respectively. Intra ICC and inter-ICC values for AUC were 0.805-0.823 and 0.813-0.815, respectively. In both groups, no significant difference was observed in PI and AUC values of GCOA and LCOA (p > 0.05). The PI and AUC of GCOA and LCOA in the diabetes group were less than those in the normal group (p < 0.05). CONCLUSION: CEUS can assess stomach wall vascularity with a high reproducibility. Microcirculation in the antrum of patients with diabetic gastroparesis is poorer than that of normal group, which is consistent with the mechanisms of diabetic neuropathy. CEUS can be used for evaluation of microvascular perfusion in patients with stomach wall disease. Advances in knowledge: This was the first study to use CEUS for assessment of blood supply of the gastric wall and to compare microvascular perfusion between healthy individuals and patients with diabetes with gastroparesis. PMID- 27759431 TI - Human Breast Milk Drops Promote Corneal Epithelial Wound Healing. AB - PURPOSE: To investigate the effects of human breast milk on corneal epithelial wound healing. METHODS: The effects of human breast milk on epithelial healing is compared with autologous serum and artificial tears on 24 female Bal-b/C mice. A central corneal epithelial defect was created using a 2 mm trephine. Four groups were formed. By a random pick-up, topical human breast milk 4 * 1 was given to Group 1, topical mouse autologous serum 4 * 1 was applied to Group 2, and preservative-free artificial tears 4 * 1 was applied to Group 3.Group 4 was evaluated as control. Biomicroscopical examination was performed on days 1, 2, and 3. Mice were sacrificed on the third day. Histopathological and electron microscopic examinations were performed as well. RESULTS: The fastest and best healing group was Group 1, followed by Group 2. Re-epithelization was not complete even at the end of the second day in groups 3 and 4. CONCLUSIONS: The rich content of human breast milk may be an alternative to epithelial healers and artificial tears. PMID- 27759432 TI - Unmet need for specialised rehabilitation following neurosurgery: can we maximise the potential cost-benefits? AB - OBJECTIVE: To identify the needs for specialised rehabilitation provision in a cohort of neurosurgical patients; to determine if these were met, and to estimate the potential cost implications and cost-benefits of meeting any unmet rehabilitation needs. METHODS: A prospective study of in-patient admissions to a regional neurosurgical ward. Assessment of needs for specialised rehabilitation (Category A or B needs) was made with the Patient Categorisation Tool. The number of patients who were referred and admitted for specialised rehabilitation was calculated. Data from the unit's submission to the UK Rehabilitation Outcomes Collaborative (UKROC) national clinical database 2012-2015 were used to estimate the potential mean lifetime savings generated through reduction in the costs of on-going care in the community. RESULTS: Of 223 neurosurgical in-patients over 3 months, 156 (70%) had Category A or B needs. Out of the 105 patients who were eligible for admission to the local specialised rehabilitation service, only 20 (19%) were referred and just 11 (10%) were actually admitted. The mean transfer time was 70.2 (range 28-127) days, compared with the national standard of 42 days. In the 3-year sample, mean savings in the cost of on-going care were L568 per week. Assuming a 10-year reduction in life expectancy, the approximate net lifetime saving for post-neurosurgical patients was estimated as at least L600K per patient. We calculated that provision of additional bed capacity in the specialist rehabilitation unit could generate net savings of L3.6M/bed-year. CONCLUSION: This preliminary single-centre study identified a considerable gap in provision of specialised rehabilitation for neurosurgical patients, which must be addressed if patients are to fulfil their potential for recovery. A 5-fold increase in bed capacity would cost L9.3m/year, but could lead to potential net savings of L24m/year. Our findings now require confirmation on a wider scale through prospective multi-centre studies. PMID- 27759434 TI - Drug-induced eruptive melanocytic nevi. AB - INTRODUCTION: The sudden eruption of melanocytic nevi has been associated with a number of conditions, such as bullous skin diseases, immunodeficiency and immunosuppression. The exact mechanisms leading to the development of eruptive melanocytic nevi are unknown. Areas covered: The aim of this article is to review the literature concerning eruptive melanocytic nevi following the administration of immunosuppressive drugs and other medications. Expert opinion: The literature regarding the development of eruptive nevi in association with pharmacological therapies includes a relatively low number of reports. Prevalence of this phenomenon is likely to be underestimated, thus reporting should be encouraged in order to better define the actual significance and related clinical implications. The development of multiple melanocytic nevi during immunosuppressive treatments highlights the importance of immune system integrity in the regulation of nevi growth. The observation of eruptive nevi as an unexpected effect of targeted therapies for specific types of cancer, including melanoma, provided intriguing hints to understand the mechanisms underlying this paradoxical event. The synergistic role of additional triggers in the occurrence of drug-induced eruptive nevi has not been explored and may be an interesting area of research. PMID- 27759433 TI - Emergency physician accuracy in interpreting electrocardiograms with potential ST segment elevation myocardial infarction: Is it enough? AB - BACKGROUND: Electrocardiogram (ECG) interpretation is widely performed by emergency physicians. We aimed to determine the accuracy of interpretation of potential ST-segment elevation myocardial infarction (STEMI) ECGs by emergency physicians. METHODS: Thirty-six ECGs resulted in putative STEMI diagnoses were selected. Participants were asked to focus on whether or not the ECG in question met the diagnostic criteria for an acutely blocked coronary artery causing a STEMI. Based on the coronary angiogram, a binary outcome of accurate versus inaccurate ECG interpretation was defined. We computed the overall sensitivity, specificity, accuracy and 95% confidence intervals (95%CIs) for ECG interpretation. Data on participant training level, working experience and place were collected. RESULTS: 135 participants interpreted 4603 ECGs. Overall sensitivity to identify 'true' STEMI ECGs was 64.5% (95%CI: 62.8-66.3); specificity in determining 'false' ECGs was 78% (95%CI: 76-80.1). Overall accuracy was modest (69.1, 95%CI: 67.8-70.4). Higher accuracy in ECG interpretation was observed for attending physicians, participants working in tertiary care hospitals and those more experienced. CONCLUSION: The accuracy of interpretation of potential STEMI ECGs was modest among emergency physicians. The study supports the notion that ECG interpretation for establishing a STEMI diagnosis lacks the necessary sensitivity and specificity to be considered a reliable 'stand-alone' diagnostic test. PMID- 27759435 TI - Working Memory in Children With Neurocognitive Effects From Sickle Cell Disease: Contributions of the Central Executive and Processing Speed. AB - Children with sickle cell disease (SCD) are at risk for working memory deficits due to multiple disease processes. We assessed working memory abilities and related functions in 32 school-age children with SCD and 85 matched comparison children using Baddeley's working memory model as a framework. Children with SCD performed worse than controls for working memory, central executive function, and processing/rehearsal speed. Central executive function was found to mediate the relationship between SCD status and working memory, but processing speed did not. Cognitive remediation strategies that focus on central executive processes may be important for remediating working memory deficits in SCD. PMID- 27759436 TI - Primary plasma cell leukemia 2.0: advances in biology and clinical management. AB - INTRODUCTION: Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma. The introduction of novel agents and modern technologies has recently partially changed the clinical and biological scenario of this malignancy, allowing limited, but not negligible, progresses. Areas covered: We will discuss: the complex landscape of genetic alterations in PPCL, derived from conventional and high-throughput technologies; the best available treatments for PPCL; the possible future therapeutic perspectives. Expert commentary: PPCL requires an immediate and intensive multi-phase treatment with short therapy-free intervals, which should include novel agents and autologous stem cell transplantation in eligible patients. Allogeneic transplantation should be considered in selected cases. In older and/or frailer individuals, personalized approaches should be applied. Integrated treatments with next generation proteasome inhibitors/IMIDs and monoclonal antibodies are currently planned or under investigation. The identification of novel genomic biomarkers may be potentially helpful for risk stratification and future personalized therapies. PMID- 27759437 TI - The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer. AB - INTRODUCTION: The effectiveness of conventional cancer chemotherapy is hampered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer. Areas covered: This review focuses on the recent advances in the functionalization of nanocarriers with specific ligands, including antibodies, transferrin, folate, and peptides to overcome MDR cancer. The limitations of effective ligand-functionalized nanoparticles as well as therapeutic successes in ligand targeting are covered in the review. Expert opinion: Targeting MDR tumors with ligand-functionalized nanoparticles is a promising approach to improve the treatment of cancer. With this approach, higher drug concentrations at targeted sites would be achieved with lower dosage frequencies and reduced side effects in comparison to existing formulations of chemotherapeutic drugs. However, potential toxicities and immunological responses to ligands should be carefully reviewed for viable options in for future MDR cancer treatment. PMID- 27759438 TI - Can we prevent venous thrombosis with statins: an epidemiologic review into mechanism and clinical utility. AB - INTRODUCTION: Statins may be causally associated with a decreased risk of venous thrombosis. If so, this could be a substantive breakthrough since statins do not increase the risk of bleeding and could therefore be used as a safer antithrombotic drug. However, scepticism exists on the observed reduction of venous thrombosis by statins, as it may have been confounded by healthy user effects or other biases. Areas covered: The main focus of this review will be the biases that may have arisen in clinical studies that investigated the relationship between statin use and risk of venous thrombosis. We also discuss the suggested causal association from a pathophysiological perspective. Furthermore, we integrate the knowledge from clinical and pathophysiological studies into a proposal for new study designs that are needed to sufficiently answer the question whether we can, and should, prevent recurrent venous thrombosis with statins. Expert commentary: A drug to prevent recurrent venous thrombosis in patients at risk of bleeding that does not induce bleeding and in which the number needed to treat for the prevention of venous thrombosis is sufficiently high, is a remedy that we should continue to look for, and for which statin therapy might be a suitable candidate. PMID- 27759439 TI - Drug-induced steatohepatitis. AB - INTRODUCTION: Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH). Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved. The translational hurdles of these models are discussed, with the example of an organotypic liver system designed to address them. Finally, we describe the clinical assessment and management of DISH. Expert Opinion: The complexity of the interconnected mechanistic pathways underlying DISH makes it important that preclinical evaluation of drugs is done in a physiologically and metabolically relevant context. Advanced organotypic tissue models, coupled with translational functional biomarkers and next generational pan-omic measurements, may offer the best shot at gathering mechanistic knowledge and potential of a drug causing steatohepatitis. Ultimately this information could also help predict, detect or guide the development of specific treatments for DISH, which is an unmet need as of today. PMID- 27759440 TI - Treating adults with acute lymphocytic leukemia: new pharmacotherapy options. AB - INTRODUCTION: Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free survival. After relapse, the outcome of salvage chemotherapy is very disappointing with less than 10% of long survival. Novel agents are therefore desperately required to improve response rates and survival, but also the quality of life of patients. Areas covered: The following review is a comprehensive summary of various novel options reported over the past few years in the therapeutic area of adult ALL. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches. In a near future, the incorporation of monoclonal antibodies and T-cell directed approaches including blinatumomab and chimeric antigen receptor T cells may increase the cure rates and may reduce the need for intensive therapy. PMID- 27759441 TI - Validation of a multiplexing technique to determine the intrathecal, polyspecific antiviral immune response in multiple sclerosis. AB - BACKGROUND: Beside the determination of oligoclonal bands (OCBs) as a diagnostic biomarker in multiple sclerosis (MS), the presence of an intrathecal production of antibodies against the neurotropic viruses measles (M), rubella (R) and Varicella-Zoster (Z), the so called MRZ reaction (MRZR) is an even more specific diagnostic biomarker in MS. METHODS: We compared and validated the determination of the MRZR in 97 cerebrospinal fluid (CSF) and serum sample pairs of a bead based multiplexing technique and a classical enzyme-linked immunosorbent assay (ELISA). RESULTS: Conformity of 94% (M), 94% (R), 94% (Z), 96% (H) and 97% for the interpretation of the MRZR was obtained. CONCLUSION: Based on our findings of high conformity between the multiplex technique and classical ELISA, as well as the time and cost savings multiplexing allows, we conclude that the multiplexing technique is applicable as a diagnostic tool for the determination of the MRZR. PMID- 27759443 TI - Epidemiology of critical states during pregnancy after assisted reproductive technologies. AB - AIM: The aim of this research was to have a thorough study of predictors of critical states during pregnancy after assisted reproductive technologies. MATERIALS AND METHODS: A retrospective study of 303 patients with "near-miss," out of which 37 are pregnancy cases after ART (the main group) and 265 are spontaneous pregnancy cases (the control group). RESULTS: Pregnancy after ART constituted 12.3% of all critical states. In the main group (10.8%), severe ovarian hyperstimulation prevailed over all possible reasons for critical states within the period of up to 22 weeks of gestation, whereas bleeding predominated in the control group (57.1%). When pregnancy terms exceeded 22 weeks, the leading reason for "near-miss" in the main group was preeclampsia (59.5%) with underlying thrombophilia (29.7%) and gestation pancreatic diabetes (32.4%); bleeding was the main factor in the control group (36.6%). CONCLUSION: Women after assisted reproductive technologies constitute a high-risk group for critical obstetric states not only in the nearest time period but also long after ART. PMID- 27759442 TI - Evidence Base Update for Psychosocial Treatments for Children and Adolescents Exposed to Traumatic Events. AB - Child and adolescent trauma exposure is prevalent, with trauma exposure-related symptoms, including posttraumatic stress, depressive, and anxiety symptoms often causing substantial impairment. This article updates the evidence base on psychosocial treatments for child and adolescent trauma exposure completed for this journal by Silverman et al. (2008). For this review, we focus on 37 studies conducted during the seven years since the last review. Treatments are grouped by overall treatment family (e.g., cognitive behavioral therapy), treatment modality (e.g., individual vs. group), and treatment participants (e.g., child only vs. child and parent). All studies were evaluated for methodological rigor according to Journal of Clinical Child & Adolescent Psychology evidence-based treatment evaluation criteria (Southam-Gerow & Prinstein, 2014), with cumulative designations for level of support for each treatment family. Individual CBT with parent involvement, individual CBT, and group CBT were deemed well-established; group CBT with parent involvement and eye movement desensitization and reprocessing (EMDR) were deemed probably efficacious; individual integrated therapy for complex trauma and group mind-body skills were deemed possibly efficacious; individual client-centered play therapy, individual mind-body skills, and individual psychoanalysis were deemed experimental; and group creative expressive + CBT was deemed questionable efficacy. Advances in the evidence base, with comparisons to the state of the science at the time of the Silverman et al. (2008) review, are discussed. Finally, we present dissemination and implementation challenges and areas for future research. PMID- 27759445 TI - Local immunity status in patients with miscarriages and herpetic infection. AB - A study of the endometrium of women with herpetic infection has shown that early miscarriages (under 12 weeks) occurs as activation of cytotoxic natural killer (NK) cells with CD16 + phenotype and a pronounced suppression level of CD56 + cells endometrial type, and late miscarriages (13-22 weeks of gestation) occurs as cell deficit, followed by reduction of all CD8 + cytotoxic lymphocytes, and of CD56 + and CD16 + NK cells. PMID- 27759444 TI - Treatment strategies for pelvic pain associated with adenomyosis. AB - OBJECTIVE: To observe the effects of levonorgestrel-releasing intrauterine system (LNG-IUS) in treatment of chronic pelvic pain associated with adenomyosis (AM) and in prevention of its recurrence. METHODS: A prospective continuing study including 180 patients with chronic pelvic pain associated with AM who received insertion of LNG-IUS who were divided into three groups depending on the pain severity. The visual analog scale (VAS) was used for pain assessment before and during the treatment and transvaginal ultrasonic measurement of the uterine size, while various side effects, were observed and recorded. RESULTS: After placement of LNG-IUS, scores of pain and ratio of severe pelvic pain decreased significantly compared with baselines (p < 0.01), the scores of VAS were 9.0 +/- 0.8, 6.5 +/- 2.8, 4.3 +/- 1.8, 3.3 +/- 2.2, 2.2 +/- 2.1, 2.2 +/- 1.8, 1.4 +/- 1.6 and 1.3 +/- 1.3 at 0, 3, 6 and 12 months, respectively. During 12 months after placement of LNG-IUS, scores of pain had improved significantly compared with preceding period (p < 0.01). We found no universal dependent factors predicting improvement of pain, which was neither relevant with simultaneous changes of menstruation patterns nor with adverse effects (p > 0.005). CONCLUSION: The obtained results allowed to confirm the possibility of using LNG-IUS in the treatment of pelvic pain syndrome associated with AM, particularly with mild and moderately severe pelvic pain syndrome. This is a cost effective, reversible and long-term treatment for women with pelvic pain associated with AM, which reduces the need for surgical interventions. PMID- 27759446 TI - Ectopic pregnancy following in vitro fertilization: meta-analysis and single center experience during 6 years. AB - BACKGROUND: Ectopic pregnancy (EP) has been reported to occur in 1.4-5.4% of all clinical pregnancies resulting from in vitro fertilization (IVF) and embryo transfer (ET). Data on factors associated with abnormal embryo implantation following assisted conception are limited. MATERIALS AND METHODS: A systematic review and meta-analysis was performed to determine whether there is an association between the day (cleavage-stage, D3, versus blastocyst, D5) or the type (fresh versus frozen/thawed) of ET and EP rate. Risk factors for EP were evaluated in a retrospective study of 1194 women, who achieved pregnancy at our IVF unit between 2010 and 2016. RESULTS: Sixteen papers were considered for the meta-analysis. EP rate did not differ between D3 and D5 fresh ET groups (RR = 0.99, 95%CI: 0.76-1.30) and was higher after fresh versus frozen ET (RR = 1.56, 95%CI: 1.25-1.95). At our clinic, 21 (1.76%) pregnancies were documented as ectopic. The risk of EP was associated with tubal pathology (OR = 3.37, 95%CI: 1.39-8.2), previous appendectomy and past chlamydial infection. CONCLUSIONS: Present meta-analysis suggests that EP rate is similar following fresh blastocyst and cleavage ETs, but is significantly reduced after frozen compared with fresh ET. Our own findings demonstrate that tubal pathology has the major impact on EP occurrence following assisted conception. PMID- 27759447 TI - Comparison of the results of preimplantation genetic screening obtained by a-CGH and NGS methods from the same embryos. AB - Chromosomal aneuploidies are known for being the main cause of abnormal development of embryos with normal morphology, their implantation failure and early reproductive losses in IVF treatments. Preimplantation genetic screening (PGS) allows selecting embryos with normal chromosomal content and increases IVF treatment efficiency due to higher implantation rates and less frequent early pregnancy losses. New technologies used for PGS allow making genome-wide analysis of the presence of all chromosomes in embryos. This article presents our study of evaluation of two techniques used for PGS: previously developed and used in our laboratory a-CGH assay based on Agilent technology and newly tested semi conductive NGS technique (Torrent technology). PMID- 27759449 TI - The molecular and genetic aspects of adolescent girls anomalous uterine bleeding: the role of endothelial dysfunction syndrome. AB - The objective of the study is to assess NOS3 and ESR1 gene polymorphism in adolescent girls born with low birth weight (LBW) and suffered by anomalous uterine bleeding (AUB). A total 95 adolescent girls were studied including 32 born with LBW and AUB; 36 girls with normal birth weight and AUB; and 27 healthy girls. Single allele gene polymorphism NOS3 786T > C, 894G > T, ESR1 351A > G and 397T > C was studied. The existence of polymorphous allele S gene NOS3 786T > S (for homozygote OR = 2.03; 95% CI: 1.12-3.68; p = 0.04; for heterozygote OR = 1.68; 95% CI: 1.09-2.60; p = 0.046) and genotype Pvull-CC ESR1 (OR = 4.58; 95% CI: 0.97-21.68; p = 0.04) was detected in LBW girls with AUB. It was suggested that intrauterine programming of endothelial dysfunction syndrome could play a significant role in the development of AUB in adolescent girls born with LBW. PMID- 27759448 TI - Toward optimal set of single nucleotide polymorphism investigation before IVF. AB - BACKGROUND: At present, the patient preparation for IVF needs to undergo a series of planned tests, including the genotyping of single nucleotide polymorphism (SNP) alleles of some genes. In former USSR countries, such investigation was not included in overwhelming majority of health insurance programs and paid by patient. In common, there are prerequisites to the study of more than 50 polymorphisms. An important faced task is to determine the optimal panel for SNP genotyping in terms of price/number of SNP. MATERIALS AND METHODS: During 2009 2015 in the University Hospital of St. Petersburg State University, blood samples were analyzed from 550 women with different reproductive system disorders preparing for IVF and 46 healthy women in control group. In total, 28 SNP were analyzed in the genes of thrombophilia factors, folic acid cycle, detoxification system, and the renin-angiotensin system. The method used was real-time PCR. RESULTS: A significant increase in the frequency of pathological alleles of some polymorphisms in patients with habitual failure of IVF was shown, compared with the control group. As a result, two options defined panels for optimal typing SNP before IVF were composed. Standard panel includes 8 SNP, 5 in thromborhilic factors, and 3 in folic acid cycle genes. They are 20210 G > A of FII gene, R506Q G > A of FV gene (mutation Leiden), -675 5G > 4G of PAI-I gene, L33P T > C of ITGB3 gene, -455 G > A of FGB gene, 667 C > T of MTHFR gene, 2756 A > G of MTR gene, and 66 A > G of MTRR gene. Extended panel of 15 SNP also includes 807 C > T of ITGA2 gene, T154M C > T of GP1BA gene, second polymorphism 1298 A > C in MTHFR gene, polymorphisms of the renin-angiotensin gene AGT M235T T > C and -1166 A > C of AGTR1 gene, polymorphisms I105V A > G and A114V C > T of detoxification system gene GSTP. CONCLUSION: The results of SNP genotyping can be adjusted for treatment tactics and IVF, and also medical support getting pregnant. The success rate of IVF is increased as the result, especially in the group with the usual failure of IVF. PMID- 27759450 TI - Reproductive dysfunctions in viral hepatitis. AB - The viral hepatitis abnormalities in the female reproductive system are due to hepatic and extrahepatic damage. On the background of HBV- and HCV-infections, menstrual disorders prevail in the structure of reproductive system pathology; disorders of reproductive function in the form of pregnancy loss and infertility are detected in each second case. Depression of T-cell immunity in the immune status is observed in the patients with intact reproductive function. When miscarriage was in past medical history then divergent changes subpopulations of lymphocytes are found. When patients have infertility, signify depression of T cell immunity is observed with a decrease in total T-cells, T-helper cells and active lymphocytes. PMID- 27759451 TI - Proangiogenic features in chronic pelvic pain caused by adenomyosis. AB - AIM: The study of peculiarities of expression of vascular endothelial growth factor (VEGF) in the tissues of the endometrium and myometrium in patients with adenomyosis, associated with chronic pelvic pain syndrome. MATERIALS AND METHODS: Uterus macro-preparations obtained after hysterectomy in 60 patients with pelvic pain on a background of diffuse adenomyosis II-III degree were used for morphological examination, and macro-preparations received from 30 women with adenomyosis without pain syndrome. The diagnosis of adenomyosis was confirmed by sonography and magnetic resonance imaging. The expression of VEGF in tissues of the endometrium and myometrium was determined using the immune-histochemical method. The significance of differences of the compared parameters was determined using the criterion of Wilcoxon and Mann-Whitney. The differences were considered statistically significant when p < 0.05. RESULTS: It was found that a higher expression of VEGF is characteristic for patients with pelvic pain associated with adenomyosis, compared to women with adenomyosis and abnormal uterine bleeding, both in epithelial cells of ectopic endometrium (14.7 +/- 1.6% against 10.7 +/- 1.6%, p < 0.01), and in smooth myocytes of the myometrium (12.6 +/- 1.4% against 9.6 +/- 1.2%, p < 0.01) and in the stromal cells of the myometrium (10.1 +/- 1.9% versus 7.4 +/- 1.8%, p < 0.01). CONCLUSIONS: An increased expression of VEGF in the tissues of the uterus is one of the most important pathogenetic mechanisms of algogenesis with adenomyosis, associated syndrome of chronic pelvic pain, compared to the silent form of the disease. PMID- 27759452 TI - Predicting of successful implantation at IVF cycles. AB - Many of the uterine infertility factors are associated with chronic endometritis. Its prevalence reaches 92.6%. Quality of endometrial transformation during the "implantation window" is the basis of successful fertility. In our retrospective comparative study of 101 in vitro fertilization (IVF) cycles, the efficacy of transvaginal Doppler ultrasound (TVDUS) in predicting successful implantation was evaluated. Inclusion criteria were as follows: age younger than 41 years and good quality of embryos. Exclusion criteria were as follows: 41 and older age, poor quality of embryos and uterine cavity lesions. The 1st group included 38 cases with the presence of endometrial blood flow (EBF). The 2nd group included 63 cases with the absence of EBF. TVDUS was performed before embryo transfer (ET). Significant differences of EBF were connected with age and duration of infertility. In women of less than 31 years old, EBF was detected in 47.4% cases versus 26.3% women of older age. EBF was not detected in 74.6% of the cases of duration of infertility for 5 years and more. Pregnancy rate was significantly higher in the 1st group (63.1% versus 39.7%) and when endometrial thickness was 8 11 mm (52.1% versus 30.0%). We offer routine evaluation of endometrial thickness and EBF with TVDUS as a very helpful approach for predicting the implantation in IVF cycles. PMID- 27759453 TI - Innovative approach in assessing the role of neurogenesis, angiogenesis, and lymphangiogenesis in the pathogenesis of external genital endometriosis. AB - Endometriosis is a chronic, progressive, relapsing estrogen-dependent disorder characterized by the growth of tissue structure and function similar to the endometrium outside the normal mucosa of the uterine cavity localization. Endometriosis is found in 10-15% of women in reproductive age and it is one of the main causes of pelvic pain syndrome and infertility. Mechanisms of the development of endometriosis and related pathological pain impulses are still poorly understood and therapeutic approaches do not always have a sufficient effect; in this connection, the study of the pathogenesis of endometriosis and endometriosis-associated pain currently is perspective. Identification of significant factors of angiogenesis, lymphangiogenesis, and neurogenesis in the external genital endometriosis will promote the development of non-invasive early diagnosis and pathogenetic therapy. PMID- 27759454 TI - Perinatal outcome in pregnancies complicated with gestational diabetes mellitus and very preterm birth: case-control study. AB - Preterm birth is defined as all births before 37 completed weeks of gestation. Preterm birth can be further sub-divided based on gestational age: extremely preterm (<28 weeks), very preterm (28 to <32 weeks) and moderate preterm (32 to <37 weeks). Retrospective observational case-control study review (1 year i.e., 2015) is to assess pregnancy outcome among women with gestational diabetes mellitus (GDM) delivering very preterm (28 + 0/7 to 31 + 6/7 weeks of gestation). The study group included all women diagnosed with GDM and were compared to a control group of women delivering at the same gestational age period but without GDM. In all, 30 women were included in the study, of whom 15 were diagnosed with GDM and 15 were not. All women had a cesarean delivery. Neonates of mothers with GDM had higher ponderal index. Birth weight had the positive associations with blood glucose of newborn (r = 0.37, p = 0.047) and term of births (r = 0.52, p = 0.003). Birth weight had the negative associations with maternal systolic pressure (r = -0.7, p < 0.05), pre-eclampsia (r = -0.6, p < 0.05) and maternal pre-pregnancy body mass index (r = -0.5, p < 0.05). There were no differences in mortality or other parameters for neonatal morbidity, including bronchopulmonary dysplasia, prematurity retinopathy, neonatal anemia. According to our data, very preterm delivery occurring in women with GDM does not confer an increased risk for neonatal complications. PMID- 27759455 TI - Study of polymorphic variants of the TNF gene in pregnant women with mycoplasma infection in the Kazakh population. AB - A molecular genetic study of DNA in 98 pregnant women with mycoplasma infection and 100 healthy pregnant women was carried out. The results of the study revealed that the presence of the homozygous mutant genotype AA increases the risk of pro inflammatory processes in the body by 6.7 times, and the carriage of GA genotypic variants increases the risk of its occurrence by 2.6 times. PMID- 27759456 TI - Morphological characteristics of endometrium in patients of reproductive age with viral hepatitis type C. AB - AIM: The purpose of the study was to investigate the morphological features of endometrium in patients with viral hepatitis type C. MATERIALS AND METHODS: A morphological survey was conducted involving endometrium sections stained with hematoxylin and eosin and Van Gieson's picrofuchsin collected from 140 women of reproductive age, among them 70 patients were diagnosed with chronic hepatitis type C (CHC) infection with minimal (40 patients) and moderate activity (30 patients), and 70 women suffered from endometrial proliferative diseases without viral hepatitis (comparison group). In addition, 36 women with CHC and 36 women without CHC underwent immune histochemical test (IHC) of paraffin sections aimed at investigating the expression level of estrogen (ERalpha) and progesterone (PR) receptors and proliferation marker Ki-67. Endometrial biopsy samples were collected on the 10th to 14th day and the 15th to 18th day of the menstrual cycle. RESULTS: Focal changes of endometrium in the form of uneven entering of the endometrium into the next phase of the menstrual cycle with the dominating proliferative phase were found in chronic hepatitis C patients. The number of patients having proliferative activity in the endometrium combined with inflammation increased as viral hepatitis became more active. Immune histochemical test showed the prevalence of the expression levels of ERalpha and PR receptors in the endometrial stroma. Increased expression of Ki-67 was observed mainly in the glandular epithelium and accrued together with the increment in the CHC activity. CONCLUSION: Endometrial pathology in patients of reproductive age with chronic hepatitis type C is characterized primarily by proliferative forms with the increasing mismatch between the nature of structural changes and mucous phase of the menstrual cycle prompting suggestions that direct effect of hepatitis C virus on endometrium is possible. PMID- 27759457 TI - Risk factors vary early preterm birth and perinatal complications after assisted reproductive technology. AB - We conducted a study of markers of endothelial dysfunction and angiogenesis regulation, as well as the identification of the main lymphocyte populations, activated CD3 + CD95+-cells and cytokine-producing CD4 + IFN-gamma+-, CD4 + IL-4+ -lymphocytes in the 1st trimester of gestation in women with ART-induced pregnancy and spontaneous pregnancy. We used the same indicators to assess the immune status of ELBW infants at birth and at the post-conceptual age of 38-40 weeks. It was determined that the risk factors of very early preterm delivery are: threatened miscarriage, chronic placental insufficiency, endothelial dysfunction, increased spontaneous production of intracellular cytokines. Adverse perinatal outcomes in ELBW infants from ART-induced pregnancy are associated with lower anthropometric measures, low Apgar scores high level of inflammatory infections (pneumonia), grade II intraventricular hemorrhage, movement disorders in the form of lower paraparesis. Immune status of those infants is characterized by the increase in the number of CD8+- and CD3-CD16 + CD56+ -lymphocytes, the expression level of Fas-receptor by T-cells, and the increased production of intracellular and serum IFNgamma against the decrease in the number of CD4+ cells, which indicates enhancing of cytotoxic effector potential and proinflammatory orientation of cell responses. PMID- 27759458 TI - Treatment of climacteric symptoms with an ammonium succinate-based dietary supplement: a randomized, double-blind, placebo-controlled trial. AB - Peri- and postmenopausal women commonly suffer from climacteric symptoms. We evaluated the effectiveness and safety of dietary supplement Amberen to relieve vasomotor and psychosomatic symptoms during the course of a 3-month, randomized, double-blind, placebo-controlled study. General clinical assessment, evaluation using the Greene climacteric test and Spielberger-Hanin test, determination of plasma levels of gonadotropins, estradiol, leptin and apolipoproteins were used to evaluate 42-60-year-old women with vasomotor and psychosomatic menopausal symptoms. One hundred and twenty-five women were enrolled in the study and randomized between two groups. Based on the Greene test results, there was a statistically significant improvement (r < 0.05) in 13 out of 21 menopausal symptoms in women who took Amberen. During the course and by the end of the study, patients showed statistically significant changes in the levels of estradiol, gonadotropins and leptin, and decreases in body weight and waist circumference. Spielberger-Hanin test showed that Amberen stabilizes patients' psychological state with a statistically significant decrease in anxiety, increased stress resistance and improved adaptability. Comparative analysis of the vital signs measurements, blood tests and urinalysis did not show any negative effects of Amberen on the patients. Our findings indicate that Amberen can be considered a method of choice to relief mild/moderate climacteric symptoms. PMID- 27759459 TI - Immunohistochemical criteria for endometrial receptivity in I/II stage endometriosis IVF-treated patients. AB - : Abstracts Background: Implantation failure of in vitro fertilization (IVF) cycles is recognized as one of key problems in contemporary reproductive medicine. Implantation itself is a multifactorial process and one can hardly expect to find a single criterion for the endometrium receptivity. Endometrium biopsy still remains the most applicable technique to diagnose abnormalities causing decrease or complete loss of endometrial receptivity. MATERIALS AND METHODS: We have studied 95 endometrial biopsy samples from 45 patient with I/II stage endometriosis and 40 controls from October 2014 to December 2015. Immunohistochemical analysis of key biological molecules participating in implant window formation (LIF, ER, PR, integrin, TGF-beta1 and VEGF) was done to assess their predicting value for endometrial receptivity troubles. RESULTS: The discriminant analysis demonstrated that highest information capacity was characteristic for LIF expression percent area, integrin alphaVbeta3 both percent area and optic density in endometrial stroma and glands and finally TGFbeta1 and VEGF-A percent area expression in endometrial stroma. The model test done on a checking group showed 89.1% correct discrimination. Cross-checking in a teaching group showed a bit lower but still high correct answer percentage (88.8%). A decision-making classification tree was worked out. CONCLUSION: The produced model is sufficient for predicting IVF treatment failure and allows producing reasonable treatment tactics as well as encourages IVF treatment effectiveness improvement in patients with endometriosis. PMID- 27759460 TI - Occult form of premature ovarian insufficiency. AB - Premature ovarian insufficiency (POI) is a life-changing diagnosis, with profound physical and psychological consequences. Despite the description of different genetic, immune and iatrogenic factors of POI, the etiology of most cases of this disease are unexplained, and optimal management strategies are still unclear. Recent data showed that POI may have a long period of oligomenorrhea before the fully developed form (complete ovarian failure stage), with the occurrence of amenorrhea and climacteric symptoms. The main problem in the recognition of early stages of POI is the lack of proper diagnostic criteria. Patients with an undiagnosed occult form of POI may present with menstrual irregularities, unexplained infertility or repeated IVF failures. We evaluated 23 patients with unexplained oligomenorrhea and/or infertility. After a proper evaluation of these patients, a low ovarian reserve was identified, and an occult form of POI was diagnosed. PMID- 27759461 TI - Embryoscopic diagnostics of endometrial defects in missed abortion after IVF. AB - High incidence of missed abortion induces to search for its causes. Apart from genetic and anatomic uterine factors, the state of the decidual endometrium and implantation zone of chorionic structures of the gestational sac are of particular interest. Direct visualization of the intact decidual endometrium is possible with embryoscopy, however, there is lack of presented data of normal and pathological signs of the endometrium during pregnancy. This paper describes the changes of the endometrium in missed abortion obtained by hysteroscopy in 160 women with nonprogressive pregnancy after ART protocols. High incidence of vascular disorders is determined, namely perivascular hemorrhage (70%), thrombosis of small-caliber endometrial vessels (36.9%), necrosis of the decidual endometrium and areas of the endometrium ejection beyond the implantation zone as a source of vaginal bleeding (10%). In addition, a high incidence of capsular decidual membrane defects are detected, namely, dystrophy, thinning and necrosis (60.6%). PMID- 27759462 TI - Peripheral and Intestinal T-regulatory Cells are Upregulated in Children with Inflammatory Bowel Disease at Onset of Disease. AB - BACKGROUND/AIMS: To determine the proportion of T-regulatory cells (CD4+CD25highFOXP3+ cells) in peripheral blood and the number of FOXP3+ cells in intestinal mucosa of children with inflammatory bowel disease (IBD), and to verify whether these parameters correlate with the activity of the disease. MATERIAL AND METHODS: 24 patients newly diagnosed for IBD were included in the study: ulcerative colitis (UC; n = 13) and Crohn's disease (CD; n = 11). Seventeen healthy controls (HC) and 16 patients with irritable bowel syndrome (IBS) served as a control group for peripheral and intestinal Tregs assessment, respectively. The disease activity was assessed by Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI). Quantification of regulatory T cells of CD4+CD25highFOXP3+ phenotype in peripheral blood was based on three-color flow cytometry. Mucosal Tregs represented by FOXP3+ cells were evaluated using immunohistochemistry. RESULTS: Median proportion of CD4+CD25highFOXP3+ cells among CD4+ T cells in peripheral blood (5.1%, range 1.7-84% vs. 4.3%, range 2-8.1%, p = 0.023) and median number of intestinal FOXP3+ cells (115.33 per high-power field, hpf, range 39.33-375.67 vs. 10.16 per hpf, range 5-30, p = 0.0001) were significantly higher in children with IBD than in the controls. The proportion of circulating Tregs and the number of intestinal FOXP3+ cells did not correlate with clinical activity of the disease, as well as with endoscopic and histopathologic scoring. No significant correlation was found between the percentage of peripheral CD4+CD25highFOXP3+ cells and the number of intestinal FOXP3+cells. CONCLUSIONS: Children with IBD likely do not present with a quantitative deficiency of circulating and intestinal Tregs at the moment of diagnosis. PMID- 27759463 TI - Sustained response with ixekizumab treatment of moderate-to-severe psoriasis with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, UNCOVER-3). AB - BACKGROUND: Scalp is a frequently affected and difficult-to-treat area in psoriasis patients. OBJECTIVE: We assessed the efficacy of ixekizumab in the treatment of patients with scalp psoriasis over 60 weeks using the Psoriasis Scalp Severity Index (PSSI). METHODS: In three Phase 3, multicenter, double blind, placebo-controlled trials, patients with moderate-to-severe psoriasis in UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224) and UNCOVER-3 (N = 1346) were randomized to subcutaneous 80 mg ixekizumab every two weeks (Q2W) or every four weeks (Q4W) after a 160 mg starting dose, or placebo through Week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg bi-weekly etanercept through Week 12. Patients entering the open-label long-term extension (LTE) (UNCOVER-3) received ixekizumab Q4W; UNCOVER-1 and UNCOVER-2 included a blinded maintenance period in which static physician global assessment (sPGA) 0/1 responders were re-randomized to placebo, ixekizumab Q4W, or 80 mg ixekizumab every 12 weeks (Q12W) through Week 60. RESULTS: In patients with moderate-to severe psoriasis with baseline scalp involvement, PSSI 90 and 100 were achieved at Week 12 in higher percentages of patients treated with ixekizumab Q2W (81.7% and 74.6%) or ixekizumab Q4W (75.6% and 68.9%) compared with patients treated with placebo (7.6% and 6.7%; p < .001 each ixekizumab arm versus placebo) or etanercept (55.5% and 48.1%; p < .001 each ixekizumab arm versus etanercept). These outcomes were maintained through Week 60 of the maintenance (UNCOVER-1 and UNCOVER-2) and LTE (UNCOVER-3) period in patients who continued on ixekizumab Q4W. CONCLUSION: Ixekizumab was efficacious in treating scalp psoriasis in patients with moderate-to-severe psoriasis, with most patients achieving complete or near-complete resolution of scalp psoriasis and maintaining this response over 60 weeks. PMID- 27759464 TI - Unexpected diversity of sandflies (Diptera: Psychodidae) in tourist caves in Northern Thailand. AB - Certain species of Phlebotomine sandflies (Diptera: Psychodidae) are vectors of the protozoa which causes leishmaniasis. Sandflies are found breeding in enclosed places like caves. Thailand is a popular tourist destination, including for ecotourism activities like caving, which increases the risk of contact between tourists and sandflies. Surveillance of sandflies is important for monitoring this risk but identification of species based on morphology is challenged by phenotypic plasticity and cryptic diversity. DNA barcodes have been used for the identification of sandflies in Thailand. We collected sandflies using CDC light trap from four tourist caves in Northern Thailand. Female sandflies were provisionally sorted into 13 morphospecies and 19 unidentified specimens. DNA was extracted from the thorax and legs of sandflies and the DNA barcode region of cytochrome c oxidase I mtDNA amplified and sequenced. The specimens were sorted into 22 molecular operational taxonomic units (MOTU) based on the 145 DNA barcodes, which is significantly more than the morphospecies. Several of the taxa thought to be present in multiple caves, based on morphospecies sorting, split into cave-specific MOTU which likely represent cryptic species. Several MOTU reported in an earlier study from Wihan Cave, Thailand, were also found in these caves. This supports the use of DNA barcodes to investigate species diversity of sandflies and their useful role in surveillance of sandflies in Thailand. PMID- 27759466 TI - TREG Cells in Cancer: Beyond Classical Immunological Control. AB - A prerequisite for tumor evolution toward a malignant state is the establishment of cell intrinsic and extrinsic mechanisms of immune suppression (Hanahan and Weinberg, 2000, 2011; Schreiber, Old, and Smyth, 2011). Widespread recruitment of Foxp3+ regulatory T cells (TREG) is a prevailing means to dampen antitumor immunity. Advances in the characterization of TREG cell heterogeneity and physiological function of tissue resident TREG cells unfold new possibilities for nontraditional tumor-promoting functions of intratumoral TREG cells. This review will focus on the nonclassical function of TREG cells and their implicancies for cancer biology and treatment. PMID- 27759465 TI - Thromboembolic and major bleeding events in relation to perioperative bridging of vitamin K antagonists in 649 fast-track total hip and knee arthroplasties. AB - Background - The benefit of preoperative bridging in surgical patients with continuous anticoagulant therapy is debatable, and drawing of meaningful conclusions may have been limited by mixed procedures with different thromboembolic and bleeding risks in most published studies. Patients and methods - This was an observational cohort treatment study in consecutive primary unilateral total hip and knee arthroplasty patients between January 2010 and November 2013 in 8 Danish fast-track departments. Data were collected prospectively on preoperative comorbidity and anticoagulants in patients with preoperative vitamin K antagonist (VKA) treatment. We performed 30-day follow-up on in-hospital complications and re-admissions through the Danish National Patient Registry and patient records. Results - Of 13,375 procedures, 649 (4.7%) were in VKA patients with a mean age of 73 (SD 9) years and a median length of stay of 3 days (IQR: 2-4). Preoperative bridging was used in 430 (67%), while 215 (33%) were paused. Of 4 arterial thromboembolic events (ATEs) (0.6%), 2 were in paused patients and 2 were in bridged patients (p = 0.6). Of 3 venous thromboembolic events (VTEs) (0.5%), 2 were in paused patients and 1 was in a bridged patient (p = 0.3). Of 8 major bleedings (MBs) (1.2%), 1 was in a paused patient and 7 were in bridged patients (p = 0.3), 5 of whom received therapeutic bridging. Similar results were found in a propensity-matched cohort. Interpretation - In contrast to recent studies in mixed surgical procedures, no statistically significant differences in ATE, VTE, or MB were found between preoperative bridging and pausation of VKA patients. However, the higher number of thromboembolic events in paused patients and the higher number of major bleedings in bridged patients warrant more extensive investigation. PMID- 27759467 TI - DNA barcoding of the fishes of the genus Alburnoides (Actinopterygii, Cyprinidae) from Caucasus. AB - Spirlins of the genus Alburnoides are widespread fishes, which taxonomy has been rapidly developing in recent years. Mitochondrial cytochrome c oxidase subunit I (COI) was used as DNA barcode marker to create a reference dataset of Caucasian Alburnoides and to test its barcoding efficiency. All four previously known Caucasian species of Alburnoides were confirmed as valid species with high genetic distances to sister species as well confirmed as Caucasian endemics. Alburnoides samiii, previously known from Sefidroud basin (Iran), was discovered in Transcaucasia. The accuracy of species identification of Ponto-Caspian Alburnoides by DNA barcodes was 100%. In addition, one potentially new species within A. gmelini was revealed. Despite the limited ability of COI to infer phylogenetic relationships, study provided evidence that Ponto-Caspian lineage of Alburnoides includes significantly larger number of species from Caspian Sea basin and inland basins of Central Asia. PMID- 27759469 TI - A comperative study for short-term surgical outcomes of midurethral sling procedures in obese and non-obese women with stress urinary incontinence. AB - There is little data comparing the surgical outcomes of tension-free vaginal tape (TVT) and transobturator tape (TOT) procedures in obese women. Therefore, we aimed to compare the surgical outcomes of TOT and TVT procedures among obese women with a diagnosis of stress urinary incontinence (SUI). One hundred and eighty-nine women who underwent TVT or TOT procedures due to pure SUI were included. Women in whom the body mass index (BMI) was >=30 kg/m2 were considered as obese, while <30 kg/m2 were non-obese. And women with BMI >=35 kg/m2 was defined as morbidly obese. At sixth month postoperative follow-up, neither the comparison of TVT and TOT results in obese women nor the comparison of TVT or TOT results between obese and non-obese women showed any significant differences in terms of objective and subjective cure rates, quality of life improvements, or intra/postoperative complications. TVT and TOT procedures also have similar effectiveness among morbidly obese women. We have concluded that TVT and TOT operations seem to be equally effective and safe surgical treatment procedures for female SUI regardless of BMI. PMID- 27759468 TI - Heart failure after conventional metal-on-metal hip replacements. AB - Background and purpose - It is unclear whether metal particles and ions produced by mechanical wear and corrosion of hip prostheses with metal-on-metal (MoM) bearings have systemic adverse effects on health. We compared the risk of heart failure in patients with conventional MoM total hip arthroplasty (THA) and in those with metal-on-polyethylene (MoP) THA. Patients and methods - We conducted a retrospective cohort study using data from the Australian Government Department of Veterans' Affairs health claims database on patients who received conventional THA for osteoarthritis between 2004 and 2012. The MoM THAs were classified into groups: Articular Surface Replacement (ASR) XL Acetabular System, other large head (LH) (> 32 mm) MoM, and small-head (SH) (<= 32 mm) MoM. The primary outcome was hospitalization for heart failure after THA. Results - 4,019 patients with no history of heart failure were included (56% women). Men with an ASR XL THA had a higher rate of hospitalization for heart failure than men with MoP THA (hazard ratio (HR) = 3.2, 95% CI: 1.6-6.5). No statistically significant difference in the rate of heart failure was found with the other LH MoM or SH MoM compared to MoP in men. There was no statistically significant difference in heart failure rate between exposure groups in women. Interpretation - An association between ASR XL and hospitalization for heart failure was found in men. While causality between ASR XL and heart failure could not be established in this study, it highlights an urgent need for further studies to investigate the possibility of systemic effects associated with MoM THA. PMID- 27759470 TI - The influence of low calcium dialysate on left ventricular diastolic function in peritoneal dialysis patients. AB - Left ventricular (LV) diastolic function was found to be a significant predictor of cardiovascular events and general mortality in dialysis. Studies have indicated that dialysate calcium concentrations were significantly associated with cardiac function. However, the relationship between low calcium dialysate and LV diastolic function has not been clear. The aim of this study was to investigate the influence of low calcium dialysate on cardiac function in peritoneal dialysis (PD) patients. A total of 60 PD patients were enrolled in this study, with a calcium content of the PD solution of 1.25 mmol/L in 30 patients (low-calcium group) and 1.75 mmol/L in 30 patients (standard-calcium group). Standard M-mode and two-dimensional ultrasound measurements were applied to detect the cardiac function. After 12-month follow-up, we found no significant difference in blood pressure, calcium, phosphorus, parathyroid hormone (PTH), etc., between the two groups. Residual renal function (RRF), which is associated with LV cardiac function, was significantly decreased in the standard-calcium group compared with the low-calcium group (5.64 +/- 3.23 vs. 9.38 +/- 3.17, p = .001). Compared with the low-calcium group, Emax (peak early diastolic velocity) and Amax (peak late diastolic velocity) were significantly decreased (p < .05), whereas myocardial performance index (MPI) was obviously increased in standard calcium group (9.69 +/- 2.71 vs. 7.75 +/- 0.93, p < .05). In conclusion, our data suggest that low calcium dialysate treatment is significantly associated with better LV diastolic function. PMID- 27759471 TI - Can Doctors Be Divided Into Groups Based on Their Attitudes to Addressing Alcohol Issues in Their Patients? Analyses From a Survey of Portuguese General Practitioners. AB - BACKGROUND: The effectiveness of interventions to increase general practitioners' management of alcohol problems is affected by their attitudes toward at-risk drinkers. Tailoring training programs to general practitioners' attitudes may be useful in increasing alcohol screening and brief advice. OBJECTIVES: to determine whether general practitioners could be divided into distinct groups based on their attitudes toward at-risk drinkers. Another aim of this study was to develop and validate a model for classifying general practitioners into distinct groups. METHODS: A total of 234 general practitioners answered the questionnaire. Physicians' attitudes toward patients with hazardous or harmful alcohol use were measured with the Short Alcohol and Alcohol Problems Perception Questionnaire. Cluster analysis was performed to identify distinct general practitioner groups based on their attitudes toward at-risk drinkers. Logistic regression analysis was used to develop a model for predicting group membership. RESULTS: Cluster analysis identified two distinct groups of general practitioners, one with more positive attitudes (adequacy = 10.8 +/- 1.6, legitimacy = 11.8 +/- 1.7, motivation = 9.8 +/- 1.7, satisfaction = 8.1 +/- 1.9, and self-esteem = 9.7 +/- 2.1), the other with more negative attitudes (adequacy = 8.9 +/- 1.8, legitimacy = 11.0 +/- 1.8, motivation = 7.8 +/- 1.6, satisfaction = 5.7 +/- 2.0, and self esteem = 6.8 +/- 1.7). The predictors in the final model were self-esteem, motivation, and adequacy. The model predicted general practitioner groups on the training set with 90.4% accuracy (area under receiver operating characteristic [ROC] curve = 0.96), and maintained its predictive performance when applied to the test set (accuracy 93.6%, area under ROC curve = 0.97). CONCLUSIONS: General practitioners could be divided into distinct groups based on their attitudes toward at-risk drinkers. These findings may prove useful in designing alcohol specific training programs for general practitioners. PMID- 27759472 TI - Behavioral Risk Profiles of Homeschooled Adolescents in the United States: A Nationally Representative Examination of Substance Use Related Outcomes. AB - BACKGROUND: The homeschool population continues to grow in size and now accounts for 3.4% of all students in the United States. OBJECTIVE: Given the heterogeneous nature of the population, this study examines the relationship between different types of homeschoolers and a number of substance use related outcomes. METHODS: To conduct this study, we used pooled data (2002-2013) from the National Survey on Drug Use and Health (NSDUH). Respondents aged 12-17 who reported they had been homeschooled at any time during the previous 12 months were classified as homeschoolers (N = 1,321). Latent profile analysis (LPA) was conducted to identify latent subgroups of homeschoolers and multinomial regression was executed to assess the relationship between the subgroups and perceived substance use risk, availability, and past 12-month use. RESULTS: The LPA yielded four subgroups, which were summarized as (1) highly religious and engaged, (2) limited parental monitoring, (3) high parental warmth and support, and (4) secular permissive. Of these, the highly religious and engaged subgroup was the least likely to report using substances. CONCLUSION: The results underscore the variation that exists among homeschoolers and the importance of examining the relationship between different types of homeschoolers and outcomes of interest. PMID- 27759473 TI - Social Capital, Perceived Economic Affluence, and Smoking During Adolescence: A Cross-Sectional Study. AB - BACKGROUND: Smoking is among the health risk behaviors taken up by many adolescents with lifelong consequences and associations with multiple health risk behaviors. Smoking and smoking initiation in adolescence involves an interaction between micro-, meso-, and macro systems, including neighborhoods and the greater community. OBJECTIVES: To examine the associations of individual social and economic capital with self-reported health, life satisfaction, and smoking behavior in adolescents. METHODS: Using a multistage random sampling of junior high school students (16-18 years old) in Crete, Greece, 703 adolescents (90.2% 16 years old; 55.6% girls, participation rate 84.2%) completed an anonymous questionnaire based on HBSC study and the Youth Social Capital Scale (YSCS) during April-June 2008. Multiple logistic regression models were performed adjusted for potential confounders. RESULTS: Adolescents with high participation in their neighborhoods and communities (higher structural social capital) displayed lower odds for daily smoking; those feeling unsafe (lower cognitive social capital) were at greater odds of daily smoking. Adolescents with less friends and acquaintances had lower odds of having tried tobacco products. Smoking was not related to any economic capital variables (perceived affluence, paternal and maternal employment status). Adolescents with low/medium versus high total social capital were at higher odds for low life satisfaction and fair/bad versus excellent self-rated health. Conclusions/Importance: Social capital theory may provide a better understanding in identifying the social context that is protective or harmful to adolescents' smoking. Public health organizations at all levels need to incorporate social capital theory in their interventions. PMID- 27759474 TI - Poor 10-year survivorship of hip resurfacing arthroplasty. AB - Background and purpose - In a previous registry report, short-term implant survival of hip resurfacing arthroplasty (HRA) in Finland was found to be comparable to that of total hip arthroplasty (THA). Since then, it has become evident that adverse reactions to metal debris (ARMDs) may also be associated with HRA, not only with large-diameter head metal-on-metal THA. The aim of the study was to assess medium- to long-term survivorship of HRA based on the Finnish Arthroplasty Register (FAR). Patients and methods - 5,068 HRAs performed during the period 2001-2013 in Finland were included. Kaplan-Meier survival analysis was used to calculate survival probabilities and their 95% confidence intervals (CIs). Cox multiple regression, with adjustment for age, sex, diagnosis, femoral head size, and hospital volume was used to analyze implant survival of HRA devices with revision for any reason as endpoint. The reference group consisted of 6,485 uncemented Vision/Bimetric and ABG II THAs performed in Finland over the same time period. Results - The 8-year survival, with any revision as an endpoint, was 93% (CI: 92-94) for Birmingham Hip Resurfacing (BHR), 86% (CI: 78 94) for Corin, 91% (CI: 89-94) for ReCap, 92% (CI: 89-96) for Durom, and was 72% (CI: 69-76) for the Articular Surface Replacement (ASR). The 10-year survival, with any revision as an endpoint, for reference THAs was 92% (CI: 91-92) and for all HRAs it was 86% (CI: 84-87%). Female HRA patients had about twice the revision risk of male patients. ASR had an inferior outcome: the revision risk was 4-fold higher than for BHR, the reference implant. Interpretation - The 10 year implant survival of HRAs is 86% in Finland. According to new recommendations from NICE (The National Institute for Health and Care Excellence), an HRA/THA should have a revision rate of 5% or less at 10 years. None of the HRAs studied achieved this goal. PMID- 27759476 TI - Tumor-associated Glycans and Tregs in Immunogenicity of an Autologous Cell-based Vaccine. AB - Development of cancer vaccines targeting tumor-associated antigens (TAAs) is an alternative approach to chemotherapy with sustained anti-tumor effects. The success of active immunotherapy has been hampered by tumor-induced immune suppressors. Regulatory T cells (Tregs) are a population of immune suppressors with a proven role in regulating anti-tumor immune responses. Removing or subduing Tregs activity leads to more robust anti-tumor immune responses. Here, we used a cell-based vaccination strategy in the 4T1 murine mammary model to examine whether bulk removal of certain TAAs, using their glycan profile, can affect the immunogenicity of the vaccine. We employed affinity columns of several lectins that are reactive with breast cancer cell lines to deplete lectin reactive TAAs, while enriching for other antigens. Wheat germ agglutinin (WGA), concanavalin A (Con A), Vicia villosa (VVA), and Griffonia simplicifolia lectin-I (GS-I) were used to fraction crude tumor secreted antigens (TSA). Fractions were tested for their ability to stimulate Tregs and their anti-tumor efficacy. We observed that crude TSA activated Tregs and activation of CD4+CD25+ cells led to an inhibitory function on CD4+CD25- effector cells. Immunization of mice with GS I- and VVA-depleted fractions significantly delayed tumor establishment and inhibited lung metastases. Depletion of WGA-reactive glycoconjugates led to activation of Tregs, larger tumors and more distant metastases. The data indicate that TAAs can be enriched using their glycan expression pattern to weaken immune suppression and improve anti-tumor response. Therefore, the efficacy of autologous cancer cell vaccination can be improved through enrichment for certain TAAs using carbohydrate specificity. PMID- 27759475 TI - Cessation Strategies Young Adult Smokers Use After Participating in a Facebook Intervention. AB - BACKGROUND: Young adults underutilize current evidence-based smoking cessation strategies; yet social media are widely used and accepted among this population. A better understanding of whether and how young adults try to quit smoking in the context of a social media smoking cessation intervention could inform future intervention improvements. OBJECTIVES: We examined frequency, strategies used, and predictors of self-initiated 24-hour quit attempts among young adults participating in a Facebook intervention. METHODS: A total of 79 young adult smokers (mean age = 20.8; 20.3% female) were recruited on Facebook for a feasibility trial. Participants joined motivationally tailored private Facebook groups and received daily posts over 12 weeks. Assessments were completed at baseline, 3-, 6-, and 12-month follow-up. RESULTS: In 12 months, 52 participants (65.5%) completed 215 quit attempts (mean = 4.1; median = 4; range 1-14); 75.4% of attempts were undertaken with the Facebook intervention alone, 17.7% used an electronic cigarette (e-cigarette), 7.4% used nicotine replacement therapy (NRT), and 3.7% used additional professional advice. Non-daily smokers, those who smoked fewer cigarettes, and those in an advanced stage of change at baseline were more likely to make a quit attempt. E-cigarette use to aide a quit attempt during the study period was associated with reporting a past year quit attempt at baseline. No baseline characteristics predicted NRT use. CONCLUSIONS: After participating in a Facebook smoking cessation intervention, young adults predominantly tried to quit without additional assistance. E-cigarettes are used more frequently as cessation aid than NRT. The use of evidence-based smoking cessation strategies should be improved in this population. PMID- 27759478 TI - Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature. AB - ZAP-70 deficiency is a rare autosomal recessive form of combined immunodeficiency (CID) characterized by selective absence of circulating CD8 T cells with low, normal, or increased CD4 T cells in peripheral blood. Up to now, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID. We present a 3-year-old boy with a history of recurrent bacterial infections and autoimmunity. Initial laboratory findings showed a normal total lymphocyte count, but low levels of CD8 and CD4 T cells and an abnormal lymphocyte proliferation response. Immunoglobulin levels were normal, but the specific antibody response was impaired. Whole exome sequencing revealed a mutation within the kinase domain of ZAP-70. ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial infections, in spite of having palpable lymph nodes, a notable thymus shadow, and a normal total lymphocyte count. PMID- 27759479 TI - MDMB-CHMICA: Availability, Patterns of Use, and Toxicity Associated With This Novel Psychoactive Substance. AB - BACKGROUND: MDMB-CHMICA (methyl 2-[[1-(cyclohexylmethyl)indole-3-carbonyl]amino] 3,3-dimethylbutanoate) is a synthetic cannabinoid receptor agonist that has been detected in several recreational drug products in Europe since August 2014. OBJECTIVES: This article aims to describe the prevalence of use, availability, and desired and adverse effects of MDMB-CHMICA. METHODS: Data were collated from published scientific literature, and systematic searches were conducted of publically available Internet sources (the "gray literature"), including websites offering to sell MDMB-CHMICA and Internet discussion forums featuring user reports. RESULTS: There are two case reports of fatalities in the published literature and one series of analytically confirmed cases of intoxication with MDMB-CHMICA. Seventy-eight websites offered to sell MDMB-CHMICA and a range of quantities were available with discounts for purchase of larger quantities (from 0.25 g at $27.95/g to 100 kg at $1.28/g). We identified 36 reports from MDMB CHMICA users on Internet discussion forums dated October 2014 onwards. The most common positive effect reported by users was euphoria (11; 30.6%) and almost all reports (33; 91.7%) described one or more adverse effects, most commonly palpitations (11; 30.6%), vomiting (9; 25.0%), loss of consciousness (6; 16.7%), visual hallucinations (6; 16.7%), chest pain (5; 13.9%), and anxiety (5; 13.9%). CONCLUSIONS: This systematic review of qualitative and scientific data relating to MDMB-CHMICA shows that it is widely available from Internet-based suppliers. Users describe a spectrum of effects that are consistent with other synthetic cannabinoids, but there was a high prevalence of adverse effects, and both users and suppliers warn of its high potency. PMID- 27759480 TI - Sexual Orientation Disparities in the Use of Emerging Drugs. AB - BACKGROUND: Prescription drug, e-cigarette, smokeless tobacco, and synthetic marijuana use has risen dramatically in the United States over the past decade. OBJECTIVES: This paper investigates the use of risky substances among adolescents, and examines disparities between sexual minority (i.e., mostly heterosexual and lesbian, gay, bisexual; LGB) and heterosexual adolescents in use of novel and emerging substances. Given the public health risk and the imminence of these substances in the media, emerging drug use was examined in a county wide sample of adolescents in a Southern state. METHODS: A probability sample of middle and high school students (N = 3012; ages 11-18) using random cluster methods was obtained in a mid-sized school district in the Southeastern United States. RESULTS: LGB adolescents reported higher past-30 day and lifetime use of cigarettes (AORs =2.77, 2.90, respectively), smokeless tobacco (lifetime only: AOR = 1.88), e-cigarettes (lifetime only; AOR = 1.92), alcohol (AORs = 1.7, 2.20), marijuana (AORs = 3.02, 3.06), synesthetic marijuana (AORs = 3.77, 2.48), and prescription drugs (AORs = 3.82, 2.55). Adolescents who self-identified as "mostly heterosexual" reported higher lifetime cigarette use, and past 30-day use of e-cigarettes and prescription drugs as compared with heterosexual adolescents. CONCLUSIONS: Our results are notable given the dearth of data documenting use of increasingly emerging or "trendy" substances such as prescription drugs. More research is needed to understand the underlying cause of these disparities, and efforts should be targeted toward this population to reduce negative outcomes from misuse. PMID- 27759481 TI - Synthesis and antiviral evaluation of fluorinated acyclo-nucleosides and their phosphoramidates. AB - A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3 tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed. PMID- 27759482 TI - Dermatologic uses of omalizumabtitle. AB - PURPOSE: Omalizumab is a recombinant humanized monoclonal antibody that inhibits the binding of immunoglobulin E (IgE) to the high-affinity IgE receptor (FceRI) on the surface of mast cells and basophils. Omalizumab has been approved for use in asthma, and new reports show promise in a variety of dermatologic diseases. Herein, we review the literature on omalizumab in dermatology and discuss the safety, efficacy and mechanisms of action for this emerging therapy. MATERIALS AND METHODS: PubMED, MEDLINE and Embase databases were searched for the period 1 January 1990 to 1 September 2016. Articles sourced were graded according to the Oxford Center for Evidence-Based Medicine Levels of Evidence Grades of Recommendation criteria. RESULTS: A total of 99 articles met our inclusion criteria. They included reports on the use of omalizumab in chronic spontaneous urticaria, atopic dermatitis, mastocytosis, hyper-IgE syndrome, bullous pemphigoid, Netherton syndrome, urticarial vasculitis, Churg-Strauss syndrome and toxic epidermal necrolysis. CONCLUSIONS: Omalizumab is effective in a variety of recalcitrant immune-mediated and autoimmune skin disorders. It is a safe and effective treatment for use in chronic idiopathic urticaria (Grade of recommendation: A). Randomized clinical trials with long-term follow-ups are warranted to firmly establish the role of omalizumab in the treatment of dermatologic disease. PMID- 27759477 TI - Equilibrative nucleoside transporters-A review. AB - Equilibrative nucleoside transporters (ENTs) are polytopic integral membrane proteins that mediate the transport of nucleosides, nucleobases, and therapeutic analogs. The best-characterized ENTs are the human transporters hENT1 and hENT2. However, non-mammalian eukaryotic ENTs have also been studied (e.g., yeast, parasitic protozoa). ENTs are major pharmaceutical targets responsible for modulating the efficacy of more than 30 approved drugs. However, the molecular mechanisms and chemical determinants of ENT-mediated substrate recognition, binding, inhibition, and transport are poorly understood. This review highlights findings on the characterization of ENTs by surveying studies on genetics, permeant and inhibitor interactions, mutagenesis, and structural models of ENT function. PMID- 27759483 TI - Opinions Toward Physical Activity, Sedentary Behavior, and Interventions to Stimulate Active Living During Early Retirement: A Qualitative Study in Recently Retired Adults. AB - This study aimed to obtain qualitative information about physical activity (PA) and sedentary behaviors (SB)and their determinants, and about recently retired adults' needs regarding PA interventions. Four focus group interviews were organized. The most commonly reported PA types were walking, cycling, swimming and fitness. The most commonly reported SB were reading, TV viewing, and computer use. Car use was limited. Most adults agreed their habits had changed during retirement. The most striking PA determinant was the feeling of being a 'forgotten group' and therefore having too few tailored PA initiatives available. Furthermore, participants were not aware of the negative health effects of SB and not motivated to decrease their SB. Concerning new PA interventions, very diverse ideas were put forward, reflecting the diversity of the target group. It seems that a dynamic intervention in which participants can choose which PA type they want to increase is preferable for recently retired adults. PMID- 27759484 TI - Religious Involvement, Financial Strain, and Poly-Drug Use: Exploring the Moderating Role of Meaning in Life. AB - BACKGROUND: Research indicates that greater involvement in religion is associated with lower rates of substance use and misuse. However, religion is a complex construct that can be assessed in many ways. The purpose of this study is to explore a dimension of religion that has not been evaluated in previous research on poly-drug use: a religious sense of meaning in life. OBJECTIVES: It is hypothesized that a religious sense of meaning in life will offset (i.e., moderate) the effects of chronic financial strain on poly-drug use. In order to instill greater confidence in the findings, the moderating role of a religious sense of meaning in life is compared and contrasted with a general sense of meaning in life. METHODS: The data are provided by a recent nationwide survey of adults of all ages in the United States (N = 2,622). The relationships among the core study constructs are evaluated with ordinary least squares multiple regression. RESULTS: The results indicate that a greater religious sense of meaning in life buffers the effects of financial strain on poly-drug use. In contrast, a general sense of meaning in life does not appear to perform a similar stress-buffering function. Conclusions/Importance: The findings from this study are important because they provide greater insight into the potentially important ways in which involvement in religion may be associated with poly-drug use. PMID- 27759485 TI - Synthesis and biological activity of the novel indanedione anticoagulant rodenticides containing fluorine. AB - Here, 3 fluorinated intermediates of drug were synthesized: (M1), (M2), (M3). Three new anticoagulant rodenticides were designed which were based on 4 hydroxycoumarin or 1,3-indandione, added acute toxicity groups containing fluorine. The structures of synthesized compounds were analyzed and proved by FT IR spectroscopy and 1H nuclear magnetic resonance (1H-NMR). The compounds were also evaluated for their anticoagulant and acute biologic activity. In addition, both the acute orally toxicity and the feeding indexes of R1 and R2 were tested. The result of the experiment proved that the new synthesis of 1, 3 - indan diketone for maternal new anticoagulant rodenticide can replace the current 4 - hydroxyl coumarin as the mother of the second generation anticoagulant rodenticide and 1, 3 - indan diketone for maternal new anticoagulant rodenticides will have a good development prospect. PMID- 27759487 TI - Crosstalk between pluripotency factors and higher-order chromatin organization. AB - Pluripotent cells are characterized by a globally open and accessible chromatin organization that is thought to contribute to cellular plasticity and developmental decision-making. We recently identified the pluripotency factor Nanog as a key regulator of this form of chromatin architecture in mouse embryonic stem cells. In particular, we demonstrated that the transcription factors Nanog and Sall1 co-dependently mediate the epigenetic state of pericentromeric heterochromatin to reinforce a more open and accessible organization in pluripotent cells. Here, we summarize our main findings and place the work into a broader context. We explore how heterochromatin domains could be targets of transcriptional networks in pluripotent cells and are coordinated with cell state. We propose this integration may be to balance the requirement for a dynamic and plastic chromatin organization in pluripotent cells, together with priming for a more restrictive nuclear compartmentalization that is triggered rapidly upon lineage commitment. PMID- 27759489 TI - Bio-inspired artemether-loaded human serum albumin nanoparticles for effective control of malaria-infected erythrocytes. AB - AIM: The intra-erythrocytic development of the malarial parasite is dependent on active uptake of nutrients, including human serum albumin (HSA), into parasitized red blood cells (pRBCs). We have designed HSA-based nanoparticles as a potential drug-delivery option for antimalarials. METHODS: Artemether-loaded nanoparticles (AANs) were designed and antimalarial activity evaluated in vitro/in vivo using Plasmodium falciparum/Plasmodium berghei species, respectively. RESULTS: Selective internalization of AAN into Plasmodium-infected RBCs in preference to healthy erythrocytes was observed using confocal imaging. In vitro studies showed 50% dose reduction for AAN as compared with drug-only controls to achieve IC50 levels of inhibition. The nanoparticles exhibited twofold higher peak drug concentrations in RBCs with antimalarial activity at 50% of therapeutic doses in P. bergei infected mice. CONCLUSION: Novel HSA-based nanoparticles offer safe and effective approach for selective targeting of antimalarial drugs. PMID- 27759488 TI - Contextual Factors Related to Alcohol Abuse Among Intimate Partner Violence Offenders. AB - BACKGROUND: The association between alcohol consumption and intimate partner violence (IPV) has been reiterated in numerous studies. Some authors have found higher levels of risk factors in intimate partner violence offenders (IPVOs) with alcohol problems than in IPVOs without such problems. OBJECTIVE: The aim of this study is to analyze the relationship of contextual variables with harmful alcohol use in a sample of IPVOs. METHOD: This cross-sectional research analyzes data from 231 IPVOs. In addition to demographic data, information was collected on alcohol use, ethnicity, accumulation of stressful life events and perceived social support and rejection. The sample was divided into hazardous and nonhazardous alcohol users, according to the AUDIT test scale. RESULTS: No differences were found between groups on demographic variables. The results of a hierarchical logistic regression analysis supplemented with ROC curves revealed that Latin American immigrants as opposed to Spanish nationality, accumulating stressful life events, and perceiving low social support significantly increased the likelihood of alcohol abuse, with adequate predictive power. CONCLUSION: Contextual variables such as ethnicity, accumulation of stressful life events, and lack of social support may explain harmful alcohol consumption. These variables should be taken into account in batterer intervention programs in order to reduce one of the most relevant risk factors of IPV: alcohol abuse. PMID- 27759486 TI - Preparation of the femoral bone cavity in cementless stems: broaching versus compaction. AB - Background and purpose - Short-term experimental studies have confirmed that there is superior fixation of cementless implants inserted with compaction compared to broaching of the cancellous bone. Patients and methods - 1-stage, bilateral primary THA was performed in 28 patients between May 2001 and September 2007. The patients were randomized to femoral bone preparation with broaching on 1 side and compaction on the other side. 8 patients declined to attend the postoperative follow-up, leaving 20 patients (13 male) with a mean age of 58 (36 70) years for evaluation. The patients were followed with radiostereometric analysis (RSA) at baseline, at 6 and 12 weeks, and at 1, 2, and 5 years, and measurements of periprosthetic bone mineral density (BMD) at baseline and at 1, 2, and 5 years. The subjective part of the Harris hip score (HHS) and details of complications throughout the observation period were obtained at a mean interval of 6.3 (3.0-9.5) years after surgery. Results - Femoral stems in the compaction group had a higher degree of medio-lateral migration (0.21 mm, 95% CI: 0.03-0.40) than femoral stems in the broaching group at 5 years (p = 0.02). No other significant differences in translations or rotations were found between the 2 surgical techniques at 2 years (p > 0.4) and 5 years (p > 0.7) postoperatively. There were no individual stems with continuous migration. Periprosthetic BMD in the 7 Gruen zones was similar at 2 years and at 5 years. Intraoperative femoral fractures occurred in 2 of 20 compacted hips, but there were none in the 20 broached hips. The HHS and dislocations were similar in the 2 groups at 6.3 (3.0 9.5) years after surgery. Interpretation - Bone compaction as a surgical technique with the Bi-Metric stem did not show the superior outcomes expected compared to conventional broaching. Furthermore, 2 periprosthetic fractures occurred using the compaction technique, so we cannot recommend compaction for insertion of the cementless Bi-Metric stem. PMID- 27759490 TI - Ontogeny of Tumor-associated CD4+CD25+Foxp3+ T-regulatory Cells. AB - The critical contribution of CD4+CD25+Foxp3+ T-regulatory cells (Treg) to immune suppression in the tumor microenvironment is well-established. Whereas the mechanisms that drive the generation and accumulation of Treg in tumors have been an active area of study, the information on their origin and population dynamics remains limited. In this review, we discuss the ontogeny of tumor-associated Treg in light of the recently identified lineage markers. PMID- 27759491 TI - DNA-binding study of anticancer drug cytarabine by spectroscopic and molecular docking techniques. AB - The interaction of anticancer drug cytarabine with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multispectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove-binding mode, while the binding constant of UV-vis and the number of binding sites were 4.0 +/- 0.2 * 104 L mol-1 and 1.39, respectively. The fluorimetric studies showed that the reaction between the drugs with CT-DNA is exothermic. Circular dichroism spectroscopy was employed to measure the conformational change of DNA in the presence of cytarabine. Furthermore, the drug induces detectable changes in its viscosity for DNA interaction. The molecular modeling results illustrated that cytarabine strongly binds to groove of DNA by relative binding energy of docked structure -20.61 KJ mol-1. This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the interaction of small molecular pollutants and drugs with biomacromolecules for clarifying the molecular mechanism of toxicity or side effect in vivo. PMID- 27759492 TI - Employing rubusoside to improve the solubility and permeability of antitumor compound betulonic acid. AB - AIM: To examine if rubusoside (RUB) can overcome insolubility of betulonic acid (BEA), it can be accurately evaluated for its intrinsic activity against cancer in cell culture and in tumor animal models. MATERIALS & METHODS: By processing RUB and BEA together using a solvent evaporation method, a joint nanoparticulate structure is formed, designated as BEA-NP. RESULTS: BEA-NP was found over three times more permeable than that solubilized by DMSO in Caco-2 cell monocultures. In an in vivo efficacy study, the tumor growth in the S180 berry mice orally dosed with BEA-NP at 75 mg/kg was inhibited by 50%. CONCLUSION: RUB was effective in solubilizing BEA, maintaining its cytotoxicity, enhancing its permeability and reducing tumor growth when orally administered. PMID- 27759493 TI - Experimental and computational studies on the effects of valganciclovir as an antiviral drug on calf thymus DNA. AB - DNA-binding properties of an antiviral drug, valganciclovir (valcyte) was studied by using emission, absorption, circular dichroism, viscosity, differential pulse voltammetry, fluorescence techniques, and computational studies. The drug bound to calf thymus DNA (ct-DNA) in a groove-binding mode. The calculated binding constant of UV-vis, Ka, is comparable to groove-binding drugs. Competitive fluorimetric studies with Hoechst 33258 showed that valcyte could displace the DNA-bound Hoechst 33258. The drug could not displace intercalated methylene blue from DNA double helix. Furthermore, the induced detectable changes in the CD spectrum of ct-DNA as well as changes in its viscosity confirm the groove-binding mode. In addition, an integrated molecular docking was employed to further investigate the binding interactions between valcyte and calf thymus DNA. PMID- 27759494 TI - Effects of induced placental and fetal growth restriction, size at birth and early neonatal growth on behavioural and brain structural lateralization in sheep. AB - Poor perinatal growth in humans results in asymmetrical grey matter loss in fetuses and infants and increased functional and behavioural asymmetry, but specific contributions of pre- and postnatal growth are unclear. We therefore compared strength and direction of lateralization in obstacle avoidance and maze exit preference tasks in offspring of placentally restricted (PR: 10M, 13F) and control (CON: 23M, 17F) sheep pregnancies at 18 and 40 weeks of age, and examined gross brain structure of the prefrontal cortex at 52 weeks of age (PR: 14M, 18F; CON: 23M, 25F). PR did not affect lateralization direction, but 40-week-old PR females had greater lateralization strength than CON (P = .021). Behavioural lateralization measures were not correlated with perinatal growth. PR did not alter brain morphology. In males, cross-sectional areas of the prefrontal cortex and left hemisphere correlated positively with skull width at birth, and white matter area correlated positively with neonatal growth rate of the skull (all P < .05). These studies reinforce the need to include progeny of both sexes in future studies of neurodevelopmental programming, and suggest that restricting in utero growth has relatively mild effects on gross brain structural or behavioural lateralization in sheep. PMID- 27759496 TI - Does empathy predict altruism in the wild? AB - Why do people act altruistically? One theory is that empathy is a driver of morality. Experimental studies of this are often confined to laboratory settings, which often lack ecological validity. In the present study we investigated whether empathy traits predict if people will act altruistically in a real-world setting, "in the wild". We staged a situation in public that was designed to elicit helping, and subsequently measured empathic traits in those who either stopped to help or walked past and did not help. Results show that a higher number of empathic traits are a significant and positive predictor for altruistic behavior in a real-life situation. This supports the theory that the act of doing good is correlated with empathy. PMID- 27759497 TI - Drug-loaded liposome-capped mesoporous core-shell magnetic nanoparticles for cellular toxicity study. AB - Liposome-capped core-shell mesoporous silica-coated superparamagnetic iron oxide nanoparticles called 'magnetic protocells' were prepared as novel nanocomposites and used for loading anticancer drug doxorubicin (DOX) for cellular toxicity study. Cytotoxicity of the magnetic protocells with or without DOX was tested in vitro on commercial MCF7 and U87 cell lines under alternating magnetic field. MCF7 cell line treated with the DOX-loaded nanoparticles under alternating magnetic field exhibited nearly 20% lower survival rate after 24 h compared with cells treated with free DOX and similarly, it was around 24% when applied to U87. The results indicate that the magnetic protocells could be useful for future cancer treatment in vivo by the combination of targeted drug delivery and magnetic hyperthermia. PMID- 27759498 TI - Efficacy of Pulsed 405-nm Light-Emitting Diodes for Antimicrobial Photodynamic Inactivation: Effects of Intensity, Frequency, and Duty Cycle. AB - OBJECTIVE: This study investigates possible advantages in pulsed over continuous 405-nm light-emitting diode (LED) light for bacterial inactivation and energy efficiency. BACKGROUND: Alternative nonantibiotic methods of disinfection and infection control have become of significant interest. Recent studies have demonstrated the application of systems using 405-nm LEDs for continuous disinfection of the clinical environment, and also for potential treatment of contaminated wounds. METHODS: Liquid suspensions of 103 colony-forming units/mL populations of Staphylococcus aureus were subject to pulsed 405-nm light of different frequencies, duty cycles, and intensities and for different lengths of time. RESULTS: Pulsed exposures with the same average irradiance of 16 mW/cm2 and varying duty cycle (25%, 50%, 75%) showed very similar performance compared with continuous exposures, with 95-98% reduction of S. aureus achieved for all duty cycles. The pulsing frequency was varied in intervals from 100 Hz to 10 kHz and appeared to have little effect on antimicrobial efficacy. However, when comparing pulsed with continuous exposure, an improvement in inactivation per unit optical energy was achieved, with results showing an increase of approximately 83% in optical efficiency. CONCLUSIONS: These results suggest that under pulsed conditions, a lower energy consumption and lower perceived brightness could be achieved, thus potentially providing improved operating conditions for medical/infection control applications without compromising antimicrobial efficacy. PMID- 27759500 TI - A recent trend of drug-nanoparticles in suspension for the application in drug delivery. AB - Persistent development in nanomedicine has enabled successful nanosizing of most drug samples which, in turn, imparts remarkable properties to the drugs such as enhanced solubility and bioavailability for the applications in drug delivery. In this context, several review articles are available in scientific domain covering inorganic nanoparticles such as Au, Ag, SPIONs, Qdots, carbon nanotubes and graphene; however, this review covers the development of drug nanoparticles together with their possibilities and limitation from fabrication (bottom up vs top down) to application in drug delivery during the last 5 years. In addition, some distinguished studies and novel drug particles are presented in order to contribute significantly toward the understanding of drug nanocrystals and its use in drug delivery. PMID- 27759499 TI - Mental health differences between men and women caregivers, BRFSS 2009. AB - This study uses data from the 2009 Behavioral Risk Factors Surveillance System (BRFSS) to examine differences between male and female caregivers by demographics, health-related quality of life (HRQOL), and the effect of social support on HRQOL. Roughly two-thirds of caregivers were women, and demographic characteristics differed among men and women caregivers. Women caregivers reported significantly more mentally and physically unhealthy days than men, but there were no differences between men and women in general health or life satisfaction. Men were significantly more likely to report that they rarely or never received social support. Despite this, the effect of social support on HRQOL was stronger in men than in women. Implications of these findings for caregiver support programs are discussed. PMID- 27759495 TI - Blood-borne biomarkers and bioindicators for linking exposure to health effects in environmental health science. AB - Environmental health science aims to link environmental pollution sources to adverse health outcomes to develop effective exposure intervention strategies that reduce long-term disease risks. Over the past few decades, the public health community recognized that health risk is driven by interaction between the human genome and external environment. Now that the human genetic code has been sequenced, establishing this "G * E" (gene-environment) interaction requires a similar effort to decode the human exposome, which is the accumulation of an individual's environmental exposures and metabolic responses throughout the person's lifetime. The exposome is composed of endogenous and exogenous chemicals, many of which are measurable as biomarkers in blood, breath, and urine. Exposure to pollutants is assessed by analyzing biofluids for the pollutant itself or its metabolic products. New methods are being developed to use a subset of biomarkers, termed bioindicators, to demonstrate biological changes indicative of future adverse health effects. Typically, environmental biomarkers are assessed using noninvasive (excreted) media, such as breath and urine. Blood is often avoided for biomonitoring due to practical reasons such as medical personnel, infectious waste, or clinical setting, despite the fact that blood represents the central compartment that interacts with every living cell and is the most relevant biofluid for certain applications and analyses. The aims of this study were to (1) review the current use of blood samples in environmental health research, (2) briefly contrast blood with other biological media, and (3) propose additional applications for blood analysis in human exposure research. PMID- 27759501 TI - Decomposition in a non-concatenated morphological structure involves more than just the roots: Evidence from fast priming. AB - Complex words in Hebrew are composed of two non-concatenated morphemes: a consonantal root embedded in a nominal or verbal word-pattern morpho-phonological unit made up of vowels or vowels and consonants. Research on written-word recognition has revealed a robust effect of the roots and the verbal-patterns, but not of the nominal-patterns, on word recognition. These findings suggest that the Hebrew lexicon is organized and accessed via roots. We explored the hypothesis that the absence of a nominal-pattern effect reflects methodological limitations of the experimental paradigms used in previous studies. Specifically, the potential facilitative effect induced by a shared nominal-pattern was counteracted by an interference effect induced by the competition between the roots of two words derived from different roots but with the same nominal pattern. In the current study, a fast-priming paradigm for sentence reading and a "delayed-letters" procedure were used to isolate the initial effect of nominal patterns on lexical access. The results, based on eye-fixation latency, demonstrated a facilitatory effect induced by nominal-pattern primes relative to orthographic control primes when presented for 33 or 42 ms. The results are discussed in relation to the role of the word-pattern as an organizing principle of the Hebrew lexicon, together with the roots. PMID- 27759503 TI - Peri-Implant Mucositis and Peri-Implantitis: A Current Understanding of Their Diagnosis, Clinical Implications, and a Report of Treatment Using a Combined Therapy Approach. PMID- 27759502 TI - An ovine model of spinal cord injury. AB - OBJECTIVE: To develop a large animal model of spinal cord injury (SCI), for use in translational studies of spinal cord stimulation (SCS) in the treatment of spasticity. We seek to establish thresholds for the SCS parameters associated with reduction of post-SCI spasticity in the pelvic limbs, with implications for patients. STUDY DESIGN: The weight-drop method was used to create a moderate SCI in adult sheep, leading to mild spasticity in the pelvic limbs. Electrodes for electromyography (EMG) and an epidural spinal cord stimulator were then implanted. Behavioral and electrophysiological data were taken during treadmill ambulation in six animals, and in one animal with and without SCS at 0.1, 0.3, 0.5, and 0.9 V. SETTING: All surgical procedures were carried out at the University of Iowa. The gait measurements were made at Iowa State University. MATERIAL AND METHODS: Nine adult female sheep were used in these institutionally approved protocols. Six of them were trained in treadmill ambulation prior to SCI surgeries, and underwent gait analysis pre- and post-SCI. Stretch reflex and H reflex measurements were also made in conscious animals. RESULTS: Gait analysis revealed repeatable quantitative differences in 20% of the key kinematic parameters of the sheep, pre- and post-SCI. Hock joint angular velocity increased toward the normal pre-injury baseline in the animal with SCS at 0.9 V. CONCLUSION: The ovine model is workable as a large animal surrogate suitable for translational studies of novel SCS therapies aimed at relieving spasticity in patients with SCI. PMID- 27759504 TI - Sexual Pain Disorders in Spanish Women Drug Users. AB - BACKGROUND: The impact of pain in sexuality, couple relationships and the quality of life is very well known. OBJECTIVES: The relationship between substance abuse and the presence of sexual pain disorder is assessed, together with anxiety and sexual attitudes . METHOD: Two samples were selected. One sample for women with a history of substance abuse (n = 129), and another one of women nonconsumers (n = 129). The Golombok Rust Inventory of Sexual Satisfaction (GRISS), the Sexual Opinion Survey (SOS) and the State Trait Anxiety Inventory (STAI) questionnaires were used. RESULTS: The results indicate that women consumers obtained a higher mean scores in sexual pain disorder (4.88 > 2.89, that is 65.12%), plus higher mean scores on state anxiety (23.82 > 14.56) and trait anxiety (30.93 > 16.95), and lower average figure in erotophilia (84.93 < 95.81). It was also verified that the period of abstinence does not improve sexual response. CONCLUSIONS: Substance consumption affects sexual response in women negatively. Sexual response does not improve with abstinence period. PMID- 27759505 TI - Cone Beam Computerized Tomography Analysis of the Posterior and Anterior Mandibular Lingual Concavity for Dental Implant Patients. AB - This study was conducted to evaluate variations in and the prevalence of the lingual concavity. Images were taken between January 1, 2011, and August 31, 2015, from a total of 104 patient charts randomly selected from a private practice. These images were acquired from a single cone beam computerized tomography (CBCT) machine. The CBCTs were reviewed in cross-sectional images in both the left and right anterior incisor and posterior molar regions. These scans were classified into 1 of 3 categories-parallel, concave, or convex-based on the measurements of the level of concavity degree as well as the mandibular morphology observed. Lingual concavity characteristics including depth, angulation, and vertical location were also measured. Most of the posterior mandibular CBCT scans were classified as concave. Although there was no significant difference detected for race or gender, statistical significance was noted with regard to age, with an increase in prevalence observed at age 63 years and older. Of the 3 different morphological classifications used, the vast majority were identified as concave in the posterior mandibular regions and parallel in the anterior mandibular region. There was a significant decrease in concavity VL/height (bone loss) associated with age, which was most commonly seen in edentulous areas. PMID- 27759506 TI - Practice question. AB - This is an interesting and important question of national concern. Responses to the consultation on the Chief Nursing Officer's Review of Mental Health Nursing ( Department of Health 2006 ) and the Royal College of Psychiatrists' ( 2009 ) report noted that people with mental health problems often receive less than adequate care for their physical health. Physical health problems, particularly chronic health problems such as obesity, diabetes and smoking-related illnesses, are more common in people with long-term mental illness. PMID- 27759507 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 27759508 TI - Doing a Literature Review in Health and Social Care Helen Aveyard Doing a Literature Review in Health and Social Care OUP: McGraw-Hill Education L163;17.99 184pp 9780335238859 0335238858 [Formula: see text]. AB - WRITTEN IN simple and easy to understand language, this book provides practical and useful guidance for health and social care students. each chapter is well organised and summarised. The book is well illustrated with real-life scenarios and examples encountered by students. It can help students devise their research question and develop a clear literature search strategy. It also provides detailed information about various critical appraisal tools that can be used to approach different types of studies. PMID- 27759510 TI - Education. AB - The Lindsay Leg Club Foundation has launched an educational programme for staff in UK leg clubs, combining an online learning zone and new competency document. It features presentations aimed at understanding leg ulcers and their management. PMID- 27759511 TI - Diary. AB - Our roundup of what's on. PMID- 27759513 TI - Treatment of chronic obstructive pulmonary disease. AB - 'Obstruction' in chronic obstructive pulmonary disease (COPD) involves the diameters of the peripheral airways becoming progressively smaller so that it becomes difficult, and eventually impossible, to breathe. As the patient's lung function deteriorates he or she may experience exacerbations of the condition with increasing frequency, with sudden and frightening worsening of symptoms. There is no cure for COPD. PMID- 27759514 TI - Essential support while mourning the living. AB - WHEN YOU feel a sense of relief on learning your wife has dementia, you realise this disease is pretty out of the ordinary. We all forget a name. It happens to us all. PMID- 27759515 TI - A practical guide to the spiritual care of the dying person Various Incorporated Catholic Truth Society A practical guide to the spiritual care of the dying person L2.50 44pp 9781860826665 [Formula: see text]. AB - THIS SHORT guide to spiritual care offers clear and concise support on an area that can be difficult for any healthcare professional. PMID- 27759516 TI - Album puts foreign staff in the picture. AB - NURSES AND carers from overseas are being given a glimpse into the past of residents at their care home to help them understand their lives and needs better. PMID- 27759517 TI - Revised dementia strategy renews impetus for change. AB - ALISTAIR BURNS, national clinical director for dementia for England at the Department of Health (DH), tells the story of a female patient. Living in a care home, she customarily became agitated around teatime. There was no apparent reason for this but every day, like clockwork, she would become upset and difficult to calm down. PMID- 27759518 TI - Improving the palatability of oral nutritional supplements. AB - One in three adults admitted to hospital has malnutrition and this rate is even higher in the over-65 age group. Malnutrition in older people contributes to serious illness, functional loss and altered self-perception of health. Oral nutritional supplements are often prescribed but wastage is high because many people dislike the taste, finding them too sweet. PMID- 27759519 TI - NMC should have vetting powers, claims charity. AB - THE NURSING and Midwifery Council (NMC) should be given enhanced powers to ensure that nurses who have been removed from its register cannot work in other areas of health and social care, according to an anti-abuse charity. PMID- 27759520 TI - Forum focus. AB - WELCOME TO the first of a regular RCN older people's forum column. PMID- 27759521 TI - Report on poverty identifies challenges prevalent in old age. AB - HEALTH INEQUALITIES, poor diet and exercise and understaffed care homes are identified as major issues affecting older people in a landmark UK report. PMID- 27759523 TI - Fresh guidelines for falls prevention issued. AB - NEW GUIDANCE for preventing falls in older people recommends that all interventions include exercise and that medications should be cut back. PMID- 27759524 TI - The power of three. AB - My passion for care of older people nursing stems from training and working as a mental health nurse in the 1980s. I was shocked by the institutionalisation, inherent abuse and lack of rights for older people and this has influenced everything I have done. PMID- 27759522 TI - Communicating life views and end of life preferences. AB - The promotion of advance directives has received increasing attention but just documenting treatment decisions does nothing to convey the patient's underlying values or stimulate relevant discussion. Discussion is often delayed until a health crisis occurs, by which time people may be too sick to interpret their treatment options. Previous studies have shown that older people seldom have the chance to share views about death and dying because family members and healthcare professionals want to protect them from raising these sensitive issues. PMID- 27759525 TI - Memory room helps to soothe residents. AB - A 1950s 'time warp' room has been created at one care home to give its residents with Alzheimer's a trip down memory lane. PMID- 27759527 TI - Volunteers with mild dementia sought to trial monitoring system. AB - RESEARCHERS ARE looking for people with mild dementia to take part in a trial of a web-based home-monitoring system. PMID- 27759526 TI - Surgery complications linked to Parkinson's disease. AB - People with Parkinson's disease who undergo surgery have increased rates of mortality. Missing dopamine medication during a period of perioperative starvation can result in life-threatening complications. Some people can tolerate a missed tablet without any major effects, while others become immobile or can experience neuroleptic malignant-like syndrome which is associated with fever, confusion and even death. PMID- 27759528 TI - Dignified care. AB - Do not forget the person: this is the central message of a new dignity campaign by the British Geriatrics Society (BGS), aimed at reminding all those working with older people of the basic principles of dignified care. PMID- 27759529 TI - Review. AB - Really old, like forty five National Theatre, London Running until: April 20 Playwright: Tamsin Oglesby Tickets: 020 7452 3000. PMID- 27759530 TI - Relative values. AB - THE ANNUAL state of social care report was a publication I looked forward to reading each year because it provided comprehensive information on how services were doing, and allowed the reader to make comparisons year-on-year, standard-by standard. PMID- 27759531 TI - Not weather beaten. AB - On behalf of the Registered Nursing Home Association, we should like to express our sincere thanks to nursing home staff throughout the UK for maintaining vital services to patients during the extremely difficult weather conditions that have prevailed over recent weeks. PMID- 27759532 TI - Job satisfaction research. AB - I am a psychology student investigating how nurses and care assistants are affected by the challenging behaviour of older people in non-NHS nursing homes and daycare facilities in the UK. This research is for my final-year dissertation. PMID- 27759534 TI - Can't get the staff. AB - After reading the letter from Janette S Auckland in the February edition (Nursing Older People. 22, 1, 8), I was compelled to respond. PMID- 27759533 TI - Leave stigma behind. AB - Care services minister Phil Hope launched the 'living well' campaign in March to increase awareness of dementia and show how people with the condition can still lead active and fulfilled lives. One in three people surveyed by the government said that they feel uncomfortable around people with dementia. PMID- 27759535 TI - People with dementia campaign to be better understood by public. AB - ONE IN three people are uncomfortable around people with dementia, a survey has found. PMID- 27759537 TI - Flair for business will be expected of nurse consultants in future. AB - THE NURSE consultants of the future will be entrepreneurs involved in the commissioning of health services, a government adviser has predicted. PMID- 27759536 TI - Practice question. AB - The publication of the National Dementia Strategy in 2009 was an important step towards providing health and social care services that are fit for the 21st century (Department of Health ( DH)2009 ). It focuses on three key areas: improved awareness, earlier diagnosis and intervention and higher quality of care. PMID- 27759538 TI - Make respect a reality. AB - As older people's commissioner, one of my functions is to encourage best practice in treatment in Wales. Many older people, and those who provide services for them, share with me examples of excellent services, but they also tell me about instances that have shocked me. PMID- 27759539 TI - Admiral service launched in yorkshire. AB - Three Admiral nurses are supporting the carers of patients with dementia in Yorkshire after the service expanded into the county for the first time. PMID- 27759540 TI - Type 2 Diabetes: Exercise Plans to Improve Your Life Type 2 Diabetes: Exercise Plans to Improve Your Life Paula Coates and Thuvia Flannery A&C Black L6.99 128pp 9780713687200 0713687207 [Formula: see text]. AB - THIS LOW-BUDGET, handy-sized book has been written primarily for patients with type 2 diabetes to motivate them to self-manage their condition. However, it is an equally valuable reference for healthcare professionals. The three colour coded sections offer appropriate levels of information for readers, with interesting illustrations and highlighted boxes to emphasise the details worthy of attention. The dietary advice and gentle physical exercises supported by photographs would be useful for health professionals to adapt for patients for individualised fitness programmes according to their specific needs. PMID- 27759543 TI - Decision-making, personhood and dementia Decision-making, personhood and dementia Deborah O'Connor and Barbara Purves (Eds) Jessica Kingsley L18.99 224pp 9781843105855 1843105853 [Formula: see text]. AB - BASED ON papers from the Centre for Research on Personhood in Dementia workshop, this book is divided into three sections. It aims to move beyond a focus on notions of capability and competence to explore the importance of personhood and the underlying complexities of decision making for people with dementia. PMID- 27759544 TI - Heat-related mortality. AB - It is known that death rates rise during hot spells. Major physiologic mechanisms for heat loss are convection by transferring heat from the skin to the air and evaporation produced by sweat. An inability to increase cardiac output because of cardiovascular disease, drugs or water depletion or to increase sweating because of drugs with anticholinergic properties can considerably impair heat tolerance. If exposed to heat, looking for a cooler place is an important coping strategy but this is impossible for those who are immobile or have a psychiatric disorder. PMID- 27759545 TI - Advance directives. AB - Advance care directives are statements either made orally or in writing by mentally competent adults stating how they wish to be treated should they, at some stage in the future, lose mental capacity. In practice, however, advance care planning is rarely used; end-of-life decisions are made by physicians or family. PMID- 27759546 TI - Reducing winter deaths. AB - Morbidity and mortality rates in the UK rise in cold weather, especially for the over 65s. Highest levels of excess winter mortality tend to be in countries where average winter temperatures are relatively mild. Countries with severe winters have better insulation and indoor heating and the inhabitants use more appropriate outdoor clothing. PMID- 27759547 TI - Donkey work. AB - Rosie the donkey gave care home residents a treat by allowing them to stroke her at an event to mark a national day of dignity. PMID- 27759548 TI - Specialist nurses can improve rheumatoid arthritis care, say MPs. AB - TREATMENT OF patients with rheumatoid arthritis (RA) can be enhanced by specialist nurses, according to a group of MPs. PMID- 27759550 TI - Risk of prosecution higher for those who assist a suicide. AB - NURSES COULD be prosecuted if they help patients take their own lives, guidance from the Crown Prosecution Service (CPS) confirms. Nurses who assist a suicide are specifically highlighted in the guidance. They are named in the section that highlights any scenarios where there is a higher likelihood of prosecution. PMID- 27759549 TI - Staff treated delirium as bad behaviour, says report. AB - OLDER PEOPLE'S nurses have called for all NHS trusts to introduce acute confusion training for staff following revelations that nurses at a beleaguered trust neglected patients with the condition. PMID- 27759551 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 27759553 TI - Diary. AB - Our roundup of what's on. PMID- 27759552 TI - A measured response. AB - In this issue of Nursing Older People we take a look at several hot topics that have implications for the care of older people. In the current climate of financial constraint, and publication of negative reports such as the independent inquiry into care provided by Mid Staffordshire NHS Foundation Trust (see below and page 5 ), it is vital that nurses demonstrate the outcomes and value of what they do and ensure that measures of this are appropriately identified. The development of nursing metrics is therefore a process that older people's nurses need to become involved in. On page 11 Peter Griffiths offers some insightful thoughts and caveats on this process. PMID- 27759554 TI - Posttransplant Outcomes of Patients With Autosomal Dominant Polycystic Kidney Disease Versus Other Recipients: A 10-Year Report From South of Iran. AB - OBJECTIVES: Autosomal dominant polycystic kidney disease is the most common hereditary disorder resulting in end-stage renal disease that can affect other organs besides kidneys. Extrarenal involvement may increase mortality and morbidity. Approximately 50% of patients with this disorder require renal transplant. Posttransplant complications have been reported to be equal in these patients versus other recipients. We conducted this study to determine and compare characteristics and outcomes of transplanted patients with this disease versus other recipients at the only transplant center in southern Iran. MATERIALS AND METHODS: Detailed data of patients with autosomal dominant polycystic kidney disease were collected from medical records from the Shiraz Organ Transplantation Center. We also gathered data on a matched control group of transplant recipients who had end-stage renal disease due to other reasons, including other congenital kidney diseases and type 2 diabetes mellitus. Medical records of patients before and after transplant were reviewed. Statistical analyses were performed with SPSS software version 19 (Chicago, IL, USA). RESULTS: We collected data from 2002 to 2012 on 101 patients with autosomal dominant polycystic kidney disease and 100 control patients, including 74 female (36.8%) and 127 male patients (63.2%). Average duration of pretransplant dialysis was 14.9 +/- 10.3 months in study patients and 12.8 +/- 8.1 months in control patients. Rejection rate was statistically greater in recipients with this disease (30 patients; 68%) versus controls (14 patients; 32%) (P = .010). CONCLUSIONS: Short- and long-term survival rates of patients with autosomal dominant polycystic kidney disease were not statistically different from control patients. However, graft survival was significantly lower. In short- and long-term follow-up of autosomal dominant polycystic kidney disease patients, hemoglobin and hematocrit levels were slightly higher than those of the control group. Autosomal dominant polycystic kidney disease is not a risk factor for posttransplant diabetes mellitus. PMID- 27759555 TI - Effect of Copper Staining in Wilson Disease: A Liver Explant Study. AB - OBJECTIVES: Wilson disease is a rare genetic disease with clinical and histopathologic differential diagnostic challenges. In this study, we evaluated the histopathologic findings of explanted livers in Wilson disease, with special emphasis on copper histochemistry. MATERIALS AND METHODS: Our study group was recruited by reviewing archived histopathology reports and the liver transplant clinic patient records retrospectively for patients who had liver transplant for Wilson disease between January 2010 and June 2015, at Turgut Ozal Medical Center. Archival slides were reevaluated. When needed, relevant clinical and laboratory data were obtained from patient medical records. RESULTS: During the selected period, there were 33 patients fitting the study criteria (22 male, 11 female, mean age of 22 +/- 11 y). All patients had mild to moderate septal inflammation. We found that 29 patients (88%) showed glycogenated hepatocyte nuclei and 27 patients (79%) showed nuclear pleomorphism. Other histopathologic findings were cholestasis (48%) and macrovesicular steatosis (39%). There was no special finding in hilar regions except for 2 patients who had recanalized portal vein thrombosis. In terms of copper histochemistry, 2 copper stains, Timm silver sulfide and rhodanine, were performed in all cases, with orcein staining only done for 25 of the cases. Positivity rates for these copper stains were 85%, 82%, and 36%. Periodic acid-Schiff-diastase- and periodic acid-Schiff-positive granules were detected in 7 of 33 patients (21%). Iron deposition was seen in 12 patients (focal and/or minimal in 11, more than focal in 1). There was no dysplasia or malignancy in any of the patients. CONCLUSIONS: On routine hematoxylin and eosin-stained slides, detection of glycogenated hepatocyte nuclei and the finding of the nuclear pleomorphism should alert the pathologist for the possibility of Wilson disease, especially with cryptogenic liver disease. Timm stain is a more convenient histochemical stain in revealing copper deposition in liver. PMID- 27759556 TI - Ex Vivo Lung Perfusion: Establishment and Operationalization in Iran. AB - OBJECTIVES: Although the number of lung transplants is limited because of general shortage of organ donors, ex vivo lung perfusion is a novel method with 2 main benefits, including better evaluation of lung potential and recovery of injured lungs. The main aim of this study was to establish and operationalize ex vivo lung perfusion as the first experience in Iran. MATERIALS AND METHODS: This was a prospective operational research study on 5 cases, including 1 pig from Vienna Medical University and 4 patients from Masih Daneshvari Hospital. All organ donations from brain dead donors were evaluated according to lung transplant or ex vivo lung perfusion criteria from May 2013 to July 2015 in Tehran, Iran. If a donor did not have any sign of severe chest trauma or pneumonia but had poor oxygenation due to possible atelectasis or neurogenic pulmonary edema, their lungs were included for ex vivo lung perfusion. RESULTS: A successful trend in the difference between the pulmonary arterial Po2 and the left atrial Po2 was observed, as well as an increasing pattern in other functional parameters, including dynamic lung compliance and a decreasing trend in pulmonary vascular resistance. CONCLUSIONS: These initial trials indicate that ex vivo lung perfusion can lead to remarkable progress in lung transplant in Iran. They also provide several important pieces of guidance for successful ex vivo lung perfusion, including the necessity of following standard lung retrieval procedures and monitoring temperature and pressure precisely. The development of novel methods can provide opportunities for further research studies on lungs of deceased donors and lead to undiscovered findings. By keeping this science up to date in Iran and developing such new and creative methods, we can reveal effective strategies to promote the quality of donor lungs to support patients on transplant wait lists. PMID- 27759557 TI - Association of BK Virus Infection with CXCL11 Gene Expression and Protein Levels in Kidney Transplant Patients. AB - OBJECTIVES: It has been hypothesized that BK polyomavirus infection leads to nephropathy in kidney transplant patients via various plausible mechanisms, such as stimulation of chemokines. The CXCL11 gene may also play a role in BK polyomavirus-associated nephropathy. Our aim was to compare expression levels of CXCL11 in BK polyomavirus-infected versus noninfected kidney transplant patients with nephropathy and healthy controls. MATERIALS AND METHODS: We performed a cross-sectional study of 58 kidney transplant patients with the risk of BK polyomavirus infection; these patients were subgrouped as BK polyomavirus infected (23 patients) and noninfected (35 patients). We also enrolled 30 healthy patients as controls in this study. The BK polyomavirus genome load was evaluated using a quantitative real-time polymerase chain reaction protocol in kidney transplant patients. We analyzed CXCL11 gene expression and protein levels using in-house SYBR green real-time polymerase chain reaction and enzyme-linked immunosorbent assay protocols. RESULTS: The expression level of the CXCL11 gene was increased 22.37 +/- 23.1-fold in BK polyomavirus-infected kidney recipients and 12 +/- 24-fold in noninfected patients versus that shown in controls. CONCLUSION: From these results, we concluded that BK polyomavirus infection can induce CXCL11 gene expression in kidney transplant patients compared with that shown in patients without BK infection and healthy patients. However, further studies are needed to determine the accurate counteraction between BK polyomavirus infection and CXCL11 in kidney transplant patients. PMID- 27759558 TI - A Novel Technique of Subclavian Artery Cannulation for Venoarterial Extracorporeal Membrane Oxygenation. AB - OBJECTIVES: The common femoral artery is the standard site for immediate vascular access when initiating adult venoarterial extracorporeal membrane oxygenation. However, this approach is fraught with problems such as femoral artery occlusion, distal limb ischemia, reperfusion injury resulting in compartment syndrome, retroperitoneal hemorrhage, thrombosis, embolization, and most importantly, pulmonary edema. Here, we show our preference of using the subclavian artery with a side graft as a different cannulation technique for outflow of extracorporeal membrane oxygenation, which can avoid complications associated with different access techniques. MATERIALS AND METHODS: Between September 2013 and December 2014, our group established venoarterial extracorporeal membrane oxygenation via subclavian artery-percutaneous femoral vein cannulation in 11 patients (81.1% men). Mean age was 33 +/- 11.1 years (range, 16-55 y). RESULTS: For this technique, the subclavian artery was slung by retrotapes (Retract-o-Tape; Quest Medical Inc. Allen, TX, USA) proximally and distally before arteriotomy. An 8-mm polyethylene terephthalate (Dacron) graft was then sutured in "end-to-side" fashion. The proximal retrotape was removed, and the distal retrotape was passed through a snare. This maneuver allowed us to manage distal flow of subclavian artery by tightening this tape, thus avoiding complications associated with right arm hyperperfusion. After venoarterial extracorporeal membrane oxygenation was established, central venous pressure and lactate levels decreased, and improvements in arterial blood-gas parameters were maintained. CONCLUSIONS: Our protocol for venoarterial extracorporeal membrane oxygenation cannulation uses the subclavian artery for arterial access and provides a safe and perhaps improved means for providing venoarterial extracorporeal membrane oxygenation support. PMID- 27759559 TI - Donor Age Still Matters in Liver Transplant: Results From the United Network for Organ Sharing-Scientific Registry of Transplant Recipients Database. AB - OBJECTIVES: Individuals older than 60 years represent a large proportion of the organs available for orthotopic liver transplant. However, the use of organs from older donors remains controversial. We hypothesized that the use of older donors would not affect patient and graft survival due to significant improvements in donor-recipient management. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using the United Network for Organ Sharing database from February 2002 through December 2012, including non-HCV-infected adults (18 and older) who underwent primary orthotopic liver transplant. We compared patient and graft survival between 4 cohorts based on donor's age (< 60, 60-69, 70-79, and 80+ years) using the Kaplan-Meier estimator. Cox proportional hazards models were constructed to adjust for recipient and donor characteristics to estimate the risk associated with organs from older donors. RESULTS: We identified 35 788 liver transplant recipients. Unadjusted analyses indicated that both patient and graft survival were similar among recipients of donors older than 60 years but significantly inferior compared with those recipients who received a liver from a donor younger than 60 years. Multivariate regression revealed that all 3 categories of donor age > 60 years old were significantly associated with worse patient and graft survival. Model for End-Stage Liver Disease score was not an effective modifier of the association between donor age and survival. CONCLUSIONS: The use of liver grafts from elderly donors has a negative impact on both patient and graft survival. Recipient's Model for End-Stage Liver Disease score did not change survival based on donor age. PMID- 27759560 TI - Strongyloides. PMID- 27759561 TI - Correction: A model for regulation by SynGAP-alpha1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density. PMID- 27759562 TI - TP53 exon-6 truncating mutations produce separation of function isoforms with pro tumorigenic functions. AB - TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations. PMID- 27759564 TI - Correction: Spontaneous mutations and the origin and maintenance of quantitative genetic variation. PMID- 27759563 TI - Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP mediated tumor growth and metastasis. AB - Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment. PMID- 27759566 TI - Reproducibility and variability of very low dose hepatic perfusion CT in metastatic liver disease. AB - PURPOSE: We aimed to determine the intra- and interobserver agreement on the software analysis of very low dose hepatic perfusion CT (pCT). METHODS: A total of 53 pCT examinations were obtained from 21 patients (16 men, 5 women; mean age, 60.4 years) with proven liver metastasis from various primary cancers. The pCT examinations were analyzed by two readers independently and perfusion parameters were noted for whole liver, whole metastasis, metastasis wall, and normal-looking liver (liver tissue without metastasis) in regions of interest (ROIs). Readers repeated the analysis after an interval of one month. Intra- and interobserver agreements were assessed with intraclass correlation coefficients (ICC) and Bland Altman statistics. RESULTS: The mean ICCs of all ROIs between readers were 0.91, 0.93, 0.86, 0.45, 0.53, and 0.66 for blood flow (BF), blood volume (BV), permeability, arterial liver perfusion (ALP), portal venous perfusion (PVP) and hepatic perfusion index (HPI), respectively. The mean ICCs of all ROIs between readings were 0.86, 0.91, 0.81, 0.53, 0.56, and 0.71 for BF, BV, permeability, ALP, PVP, and HPI, respectively. There was greater agreement on the parameters measured for the whole metastasis than on the parameters measured for the metastasis wall. The effective dose of all perfusion CT studies was 2.9 mSv. CONCLUSION: There is greater intra- and interobserver agreement for BF and BV than for permeability, ALP, PVP, and HPI at very low dose hepatic pCT. Permeability, ALP, PVP, and HPI parameters cannot be used in clinical practice for hepatic pCT with an effective dose of 2.9 mSv. PMID- 27759567 TI - Smartphone and Internet Preferences of Parents: Information Needs and Desired Involvement in Infant Care and Pain Management in the NICU. AB - BACKGROUND: Despite an abundance of research that identifies the benefits for both parent and child when parents are actively involved in their infant's care, challenges related to the best methods to engage families persist. PURPOSE: To conduct a feasibility study that aims to understand the preferences of smartphone and Internet use by parents of infants admitted to the neonatal intensive care unit (NICU) related to information seeking and active participation in infant care, with a focus on pain management interventions. METHODS: A paper-based survey was distributed to 90 parents in a tertiary-level NICU from September to November 2013. RESULTS: Response rate was 80% (72 of the 90). Ninety-seven percent accessed the Internet daily, 87% using their smartphone, and ranked it as an important source of NICU information (81%), more than books (56%) and brochures (33%). Participants reported a desire to have more information on how they could provide general comfort (96%), as well as greater participation in comforting their baby during painful procedures (94%). IMPLICATIONS FOR PRACTICE: Parents in the NICU want more information and greater involvement in their infant's care and pain management and place a higher value on the Internet compared with traditional resources. IMPLICATIONS FOR RESEARCH: Researchers and clinicians should work together to determine the quality of online resources to better support and evaluate parent use of the Internet as a health information resource. Future studies should examine parental preference regarding the optimal balance between online sources and face-to-face interactions. PMID- 27759568 TI - Survey of Neonatal Intensive Care Unit Nurse Attitudes Toward Therapeutic Hypothermia Treatment. AB - BACKGROUND: The traumatic experiences of parents of babies treated with therapeutic hypothermia (TH) have been described. No research has assessed neonatal intensive care unit (NICU) nurse experience in providing care to hypothermic babies and emotional support to their parents. PURPOSE: To assess NICU nurse attitudes to the provision of TH with respect to perceptions about baby pain/sedation, need for nurse and parent education, decision making about initiation of TH, and barriers to best care. METHODS: A survey was electronically sent to 219 nurses at 2 affiliated academic level III NICUs: 1 rural and 1 urban location. There were 17 questions where responses were selected from a preset list and 7 opportunities for nurses to provide free text responses. FINDINGS: The response rate was 38% (N = 83). Overwhelming similarities between the urban and rural institutions were found with NICU nurses expressing understanding of the indications for initiating TH, agreement that TH improves long-term outcomes and that the benefits of TH outweigh the risks. Nurses at the urban institution more frequently expressed concerns surrounding inadequate treatment of baby pain/sedation, and nurses at both institutions strongly emphasized the need for more nurse and parent education about TH and improved timeliness of decision making for initiation of TH. IMPLICATIONS FOR PRACTICE: NICU nurses specifically want to learn more about outcomes of babies after treatment with TH and feel that parents need more education about TH. IMPLICATIONS FOR RESEARCH: Research is urgently needed to better understand the implications of TH treatment for parent baby bonding. PMID- 27759569 TI - Aortic knob calcification and cardioankle vascular index in asymptomatic hypertensive patients. AB - BACKGROUND: Patients with hypertension are predisposed to atherosclerosis of large vessels and are at increased risk of target organ damage and related clinical sequelae. Cardioankle vascular index (CAVI) is a novel parameter of arterial stiffness and a surrogate marker of subclinical atherosclerosis. The aim of the present study was to investigate the relation between aortic knob calcification (AKC) and CAVI in asymptomatic hypertensive patients. METHODS AND RESULTS: Sixty patients with AKC and age-matched sex-matched 60 control individuals without AKC were enrolled. Patients with known or having symptoms of atherosclerotic vascular diseases were excluded. AKC was assessed on chest radiography. CAVI was measured using the VaSera - 1000 CAVI instrument. AKC patients had higher CAVI values compared with those without AKC (11.8+/-3.9 vs. 8.2+/-2.1, P<0.001). Patients with subclinical atherosclerosis (CAVI>=9) had higher percent of AKC compared with those who had no atherosclerosis (CAVI<9) (72 vs. 34%, P<0.001). CONCLUSION: The presence of AKC on chest radiography may provide important predictive information of arterial stiffness and subclinical atherosclerosis in asymptomatic hypertensive patients. PMID- 27759565 TI - Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats. AB - Brain and spinal injury reduce mobility and often impair sensorimotor processing in the spinal cord leading to spasticity. Here, we establish that complete transection of corticospinal pathways in the pyramids impairs locomotion and leads to increased spasms and excessive mono- and polysynaptic low threshold spinal reflexes in rats. Treatment of affected forelimb muscles with an adeno associated viral vector (AAV) encoding human Neurotrophin-3 at a clinically feasible time-point after injury reduced spasticity. Neurotrophin-3 normalized the short latency Hoffmann reflex to a treated hand muscle as well as low threshold polysynaptic spinal reflexes involving afferents from other treated muscles. Neurotrophin-3 also enhanced locomotor recovery. Furthermore, the balance of inhibitory and excitatory boutons in the spinal cord and the level of an ion co-transporter in motor neuron membranes required for normal reflexes were normalized. Our findings pave the way for Neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms. PMID- 27759570 TI - Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression. AB - Ketamine is the prototype of a new generation of antidepressant drugs, which is reported in clinical studies to be effective in treatment-resistant patients, with an effect that appears within hours and lasts for a few days. Chronic mild stress (CMS) is a well-established and widely used animal model of depression, in which anhedonia, anxiogenesis and cognitive dysfunction can be observed reliably. Studies using acute or brief ketamine treatment following withdrawal from CMS have replicated the clinical finding of a rapid onset of antidepressant action. However, there have been no CMS studies of chronic daily ketamine treatment or continued stress following ketamine treatment, which would have greater translational potential in relation to the long-term maintenance of antidepressant effects. Wistar rats were drug treated following an initial 2 weeks of CMS exposure, which continued alongside daily drug treatment. A first experiment tested a range of chronic (5 weeks) ketamine doses (5-30 mg/kg); a second compared the effects of subacute (3-5 days) and chronic (5 weeks) treatment. CMS-induced anhedonic, anxiogenic and dyscognitive effects, as measured, respectively, by decreased sucrose intake, avoidance of open arms in the elevated plus maze and loss of discrimination in the novel object recognition test. A sustained antidepressant-like effect of ketamine in the sucrose intake test was observed in both experiments, with an onset at around 1 week, faster than imipramine, and an optimum dose of 10 mg/kg. Anxiogenic and dyscognitive effects of CMS, in the elevated plus maze and novel object recognition test, respectively, were fully reversed by both subacute and chronic ketamine treatment. Daily treatment with ketamine in the CMS model causes sustained long term antidepressant, anxiolytic and procognitive effects. The demonstration of a procognitive effect of ketamine may have particular translational value. PMID- 27759571 TI - Workplace chemical and toxin exposures reported to a Poisons Information Centre: a diverse range causing variable morbidity. AB - OBJECTIVE: The aim of this study is to determine the period prevalence, nature and causes of workplace chemical and toxin exposures reported to the Victorian Poisons Information Centre (VPIC). PATIENTS AND METHODS: All cases classified as 'workplace: acute' when entered into the VPIC database (June 2005-December 2013) were analysed. Data were collected on patient sex, the nature of the chemical or toxin, route of exposure and season. RESULTS: Overall, 4928 cases were extracted. Exposures to men (71.5% of calls) differed from women (P<0.001), with most exposures relating to industry/trade substances (23.7%) and cleaners/bleaches/detergents (36.9%), respectively. Ocular (33.2%), inhalational (27.7%) and dermal (22.1%) exposures were most common. Exposures were most common in Spring and most seasonal variation was found for veterinary/animal, agricultural/plant and household categories (P<0.05). In all, 3445 (69.9%) cases had symptoms related to their exposure at the time of the call. However, the proportion of symptomatic cases within the major substance categories differed significantly (P<0.001). Chemicals associated with the most symptoms were cleaners/bleaches/detergents, industrial/trade substances and acids. CONCLUSION: Mild-moderately important workplace exposures are common. Significant variations exist between the sexes and seasons. Poisons Information Centres may play a role in ongoing surveillance of chemical and toxin exposures and a minimum exposure dataset is recommended. PMID- 27759572 TI - De-novo 'pure' partial trisomy (6)(p22.3->pter): a case report and review of the literature. AB - Partial trisomy of the short arm of chromosome 6 is a rare and clinically distinct syndrome. The breakpoints have been found to be variable ranging from bands 6p11 to 6p25. This study reports partial trisomy for 6p22.3->pter in a 2 year-old boy referred with a complaint of developmental delay and facial dysmorphism. Conventional cytogenetic analysis showed the presence of an abnormal chromosome 5 resulting from an unbalanced translocation in the proband. Array comparative genomic hybridization revealed trisomy of distal 6p which was confirmed by fluorescence in situ hybridization using subtelomeric probes for chromosomes 5 and 6. A comparison of the phenotypic features in similar cases of trisomy for different segments of 6p will facilitate an accurate karyotype phenotype correlation and, subsequently, in the identification of the candidate genes through molecular characterization of the potential genes mapped to these loci. PMID- 27759573 TI - Antitumor activity of recombinant RGD-IFN-alpha2a-core fusion protein in vitro. AB - Interferon (IFN) regulates immune responses and antitumor activity. Arginine glycine-aspartic acid (RGD) peptides can specifically bind to integrin alphavbeta3, a transmembrane receptor that is highly expressed on the surface of various cancer cells. In this study, we expressed recombinant RGD-IFN-alpha2a core fusion proteins and assessed their antitumor activity in vitro. Two RGD-IFN alpha2a-core fusion proteins and a negative control protein were expressed in vitro. These two RGD-IFN-alpha2a-core fusion proteins could bind the tumor cell surface specifically and did not bind to normal cells. RGD-IFN-alpha2a-core fusion protein treatment of tumor cells significantly reduced cell viability and induced apoptosis in a dose-dependent manner. At the 'mRNA' level, both proteins could upregulate CASP3 expression. These data indicate that both laboratory engineered RGD-IFN-alpha2a-core fusion proteins could bind the surface of tumor cells and induce apoptosis in vitro. Further studies will investigate the in-vivo antitumor activities of the RGD-IFN-alpha2a-core fusion proteins. PMID- 27759574 TI - Treatment of hepatocellular carcinoma using transarterial chemoembolization: a real-life, single-centre study from Southern Brazil. AB - OBJECTIVE: The main aim of this study was to evaluate the real-life survival rates of patients with intermediate-stage hepatocellular carcinoma treated with transarterial chemoembolization. METHODS: A retrospective cohort study involving 95 patients was conducted and the studied variables were analysed according to survival. Treatment response was determined using the Modified Response Evaluation Criteria in Solid Tumors assessment. The Kaplan-Meier method and Cox regression were used to analyse survival. RESULTS: Most (72.6%) patients were male, with a mean age of 64.8+/-9.7 years and mean Model for End-Stage Liver Disease score of 10.4+/-3.0. The median alpha-fetoprotein (AFP) level was 29.3 ng/ml. Complications were observed in 31.6% of the patients. A target response assessment revealed that 35.8% of patients exhibited complete response, 22.1% a partial response, 27.4% stable disease and 14.7% progressive disease. According to overall response rates, 63.2% exhibited progressive disease. Mean survival time was 32 months. The 1-, 2-, 3- and 5-year survival rates were 80, 59, 44 and 29%, respectively. In the multivariate model adjusted for overall response rates, only AFP level more than or equal to 100 ng/ml (hazard ratio=2.35, 95% confidence interval: 1.06-5.18, P=0.035) was associated with death. CONCLUSION: Transarterial chemoembolization is an effective therapy; however, AFP levels more than or equal to 100 ng/ml are associated with poorer prognosis. PMID- 27759576 TI - Paraneoplastic Optic Neuropathy Associated With Purkinje Cell Antibody-2 in a Patient With Small Cell Lung Cancer. AB - Paraneoplastic optic neuropathy (PON) is a rare cause of vision loss usually associated with small cell lung cancer. Patients with this condition usually test positive for anti-collapsin response mediating protein-5 (CRMP-5). We describe a case of a 57-year-old woman with bilateral vision loss with the characteristic features of CRMP-5 PON including bilateral optic disc edema and vitreous cells. However, she was negative for anti-CRMP-5 including a negative Western blot on two occasions, but positive for Purkinje Cell Antibody (PCA)-2. Although paraneoplastic antibodies are more predictive of an underlying cancer than a specific syndrome, previously PON has not been associated with PCA-2. Based on this observation, we recommend that the workup should include PCA-2 antibodies in patients who present with bilateral optic neuropathy and vitreous cells. PMID- 27759577 TI - A case report of bullous pemphigoid associated with a melanoma and review of the literature. AB - The association of bullous pemphigoid with melanoma remains controversial and poorly understood. Recent studies report the presence of the bullous pemphigoid antigen, BP180, in melanoma cells, yet not normal melanocytes, suggesting an underlying mechanism for cases of melanoma-associated bullous pemphigoid. We report on an 88-year-old woman who showed a temporal relationship between the development of bullous pemphigoid and melanoma. The patient did not receive programmed death ligand 1 inhibitor therapy and improved rapidly following complete excision of her melanoma, with clobetasol, doxycycline, and niacinamide. We review the literature on the relationship between bullous pemphigoid and melanoma, and propose a mechanism underlying a melanoma-associated bullous pemphigoid. PMID- 27759575 TI - Changes in Urinary Biomarkers Over 10 Years Is Associated With Viral Suppression in a Prospective Cohort of Women Living With HIV. AB - BACKGROUND: Urine biomarkers have helped identify persons at risk for progressing to kidney disease in the setting of HIV infection. We explored factors associated with changes in 3 urine biomarkers over 10 years among women living with HIV. METHODS: Prospective cohort of 294 HIV-infected women from the multicenter Women's Interagency HIV Study. Predictors included HIV viral and immunological parameters, comorbid conditions, and health-related behaviors. Outcomes were patterns of changes of urine interleukin-18 (IL-18), albumin-to-creatinine ratio (ACR), and alpha-1-microglobulin (alpha1m) over 10 years. We used quantile regression to examine patterns of change in each urine biomarker during follow-up and multivariable analysis of variance regression to identify predictors of biomarker changes. RESULTS: Over 10 years, the median concentrations of IL-18 declined from 120 to 64 pg/mL, alpha1m rose from 0.7 to 1.5 ng/mL, and ACR remained stable (9-8 mg/g). In multivariate analyses, the strongest predictors of increases in IL-18 were higher baseline body mass index, increase in waist circumference, higher follow-up HIV viral load, lower follow-up CD4 cell count, hepatitis C virus (HCV) coinfection, and higher follow-up high density lipoprotein cholesterol. Predictors of increasing concentration of alpha1m were lower CD4 cell counts, higher diastolic blood pressure, HCV coinfection, and smoking. Finally, determinants of ACR increases during follow-up were higher follow-up diastolic blood pressure, HCV coinfection, higher follow-up HIV viral load, and triglyceride concentration. CONCLUSIONS: Over 10 years, HIV disease status had different associations with each urine biomarker under study. Overall, the associations with changes in each biomarker support research into their use for longitudinal monitoring of kidney health. PMID- 27759578 TI - Tumor-free osteosclerotic lesions in patients treated for metastatic melanoma using BRAF inhibitors. AB - BRAF inhibitors (vemurafenib and dabrafenib) are commonly prescribed in BRAF mutant metastatic melanoma and allow improvement of the overall survival and progression-free survival. They are, however, accompanied by many adverse effects which mainly affect the skin. We observed on computed tomographic scans in three different patients after 3 months of treatment, the onset of osteosclerotic lesions. In parallel, the computed tomographic scans showed a significant reduction in all of the previously identified metastases in all patients. The occurrence of such bone modifications under treatment was reported previously in others cancers, such as inoperable non-small-cell lung cancers under epidermal growth factor receptor inhibitors, as the 'osteoblastic bone flare phenomenon'. However, it had never been reported in melanoma patients treated with targeted therapies, and the results of two performed bone biopsies are reported here. This phenomenon is generally believed to indicate a better response under treatment, whereas in our study, the patients experienced, after a short partial response, a severe cerebral relapse leading to death. Finally, although its physiopathological mechanisms are poorly understood, the occurrence of tumor-free osteosclerotic lesions in patients under BRAF inhibitors should not be misinterpreted as a progression of the disease. PMID- 27759579 TI - Oral magnesium supplementation improves endothelial function and attenuates subclinical atherosclerosis in thiazide-treated hypertensive women. AB - BACKGROUND: Epidemiological studies demonstrate an inverse association between serum magnesium and incidence of cardiovascular disease. Diuretics commonly cause hypomagneseamia. METHOD: We evaluated effects of magnesium supplementation on blood pressure (BP) and vascular function in thiazide-treated hypertensive women in a randomized, double-blind, clinical trial. Hypertensive women (40-65 years) on hydrochlorothiazide and mean 24-h BP at least 130/80 mmHg were divided into placebo and supplementation (magnesium chelate 600 mg/day) groups. Patients were evaluated for nutritional and biochemical parameters, office and ambulatory blood pressure monitoring, brachial flow-mediated dilatation (FMD), peripheral arterial tonometry, assessment of carotid intima-media thickness, central hemodynamic parameters and pulse wave velocity at inclusion and after 6-month follow-up. RESULTS: The magnesium group had a significant reduction in SBP (144 +/- 17 vs. 134 +/- 14 mmHg, P = 0.036) and DBP (88 +/- 9 vs. 81 +/- 8 mmHg, P = 0.005) at 6 months, without effect on plasma glucose, lipids, or arterial stiffness parameters. The placebo group showed a significant increase in carotid intima media thickness (0.78 +/- 0.13 vs. 0.89 +/- 0.14 mm, P = 0.033) without change in the magnesium group (0.79 +/- 0.16 vs. 0.79 +/- 0.19 mm, P = 0.716) after 6 months. The magnesium group demonstrated a significant increase in variation of FMD vs. the placebo group (+3.7 +/- 2.1 vs. 2.4 +/- 1.2%, P = 0.015). There was a significant correlation between the intracellular magnesium variation and FMD (r = 0.44, P = 0.011). CONCLUSION: Magnesium supplementation was associated with better BP control, improved endothelial function and amelioration of subclinical atherosclerosis in these thiazide-treated hypertensive women. PMID- 27759580 TI - Diagnostic and Therapeutic Challenges. PMID- 27759581 TI - OUTCOMES OF AN INTRAVITREAL INJECTION CLINIC. AB - PURPOSE: To examine the safety outcomes of an intravitreal injection-only clinic where patients needing long-term anti-vascular endothelial growth factor therapy are treated with injections at a predetermined interval for a set number of injections without an accompanying clinic visit. METHODS: This is a retrospective chart review of all patients with exudative macular degeneration treated in an intravitreal injection clinic over a 4-year period. Data on the outcome measures of interest were gathered from electronic medical records. RESULTS: There were 556 patients who received 4,386 injections in the injection-only clinic in a total of 1,524 injection cycles. One hundred six cycles were interrupted. The most common causes for interruption were decreased vision in the injected eye (32), decreased vision in the fellow eye (23), flashing lights (6), pain (5), and irritation in the noninjected eye (2). Of patients who had interruption of the cycle, 32 had a new diagnosis (6 corneal abrasions, 6 exudative age-related macular degeneration in fellow eye). There were six instances of conversion to exudative age-related macular degeneration found in the other eye at a routine follow-up visit following the injection clinic. CONCLUSION: An injection-only clinic may provide a reasonable approach to streamline retina practices to ensure that patients receive timely injections. PMID- 27759582 TI - MICROVASCULAR FLOW ABNORMALITIES ASSOCIATED WITH RETINAL VASCULITIS: A Potential of Mechanism of Retinal Injury. AB - PURPOSE: To investigate the structural optical coherence tomography and related microvascular flow characteristics in eyes with retinal vasculitis. METHODS: Regions involved with perivascular infiltration in eyes with retinal vasculitis, but no evidence of large vessel occlusion were evaluated with optical coherence tomography (OCT), OCT angiography, and fluorescein angiography. RESULTS: Ten eyes of 5 patients with a variety of etiologies of retinal vasculitis were evaluated. These patients did not have either cotton wool spots or deeper placoid areas of retinal ischemia. Around large vessels there was perivascular infiltration with leakage and staining seen during fluorescein angiography. Structural OCT showed slight thickening with loss of visualization of normal retinal laminations. OCT angiography showed a lack of flow signal in capillary sized vessels in the same areas. Treatment resulted in a rapid thinning of the affected areas, with the inner and middle layers of the retina becoming thinner than surrounding uninvolved areas. OCT angiography did not show a return of capillary perfusion in these regions. The thickness change in the structural OCT as shown by a heat map had a pattern mimicking the original perivascular infiltration around large retinal vessels. CONCLUSION: Capillary level perfusion abnormalities can develop in regions adjacent to large vessel inflammatory infiltrate that result in retinal thinning without the development of usual stigmata of acute microvascular flow obstruction such as cotton wool spots. This suggests that retinal damage may occur in retinal vasculitis that would not be recognized without using OCT-based imaging modalities. PMID- 27759583 TI - Does Sotalol Still Have a Role in the Management of Arrhythmias? AB - Despite proven effectiveness in treating tachyarrhythmias, sotalol is proarrhythmic and can cause torsades de pointes. Given the emergence of studies that show no benefit from rhythm control strategies in managing atrial fibrillation, as well as the introduction of nonpharmacological approaches to treating arrhythmias, we felt it necessary to ascertain if there was any role for sotalol given its side effects. Review of the literature regarding sotalol use in the prevention and treatment of supraventricular and ventricular tachyarrhythmias seems to show that more effective and safer agents and nonpharmacological alternatives are currently available. However, sotalol still seems to be useful in preventing supraventricular tachyarrhythmias postcardiac surgery and in reverting hemodynamically stable sustained ventricular tachycardias in the setting of coronary artery disease. Its role in the prevention of tachyarrhythmias in the setting of arrhythmogenic right ventricular cardiomyopathy requires further investigation. PMID- 27759584 TI - Use of Rivaroxaban for Mesenteric Vein Thrombosis Secondary to Diverticulitis: A Case Report. PMID- 27759585 TI - Investigation of Microsurgical Technique Combined With Skin Flap Expansion for Ear Reconstruction in Treating Hunter Type III Congenital Microtia. AB - OBJECTIVE: This study aims to observe the efficacies of microsurgical technique combined with the Zhuang's skin soft tissue expander in treating Hunter type III congenital microtia. METHODS: Fifty-eight patients (61 ears) were enrolled from 2003 to 2012; the skin tissue expander was embedded subepidermally in the first stage via the intrahairline longitudinal incision in the postauricular mastoid area, the diseased-side rib cartilage was then taken for preparing the ear bracket in the second stage, and the tragus was surgically reconstructed in the third stage. RESULTS: The mean follow-up lasted 6 months to 10 years, the results were satisfactory for 54 ears and acceptable for 5 ears, and 2 ears (in two patients) appeared with complications, including 1 case of ear flap expansion rupture and 1 case of postoperative lateral helix flap necrosis. CONCLUSIONS: The combination of microsurgical technique, Zhuang's skin soft tissue expander, and autogenous rib cartilage graft could achieve satisfactory results in treating Hunter type III congenital microtia, and the complications were less, so it was worthy of clinical applications. PMID- 27759586 TI - Utilization and Perception of Integrative Medicine Among Plastic Surgery Patients. AB - BACKGROUND: Integrative medicine (IM) is currently used by 40% of Americans. Our objective is to examine the prevalence and perception of IM utilization in patients being evaluated for elective plastic surgery. METHODS: In July 2014, 402 consecutive patients presenting to plastic surgery clinics at the University of Florida, Veterans Affairs (VA), and Private Practices in Gainesville, Florida were requested to complete a survey regarding utilization of and attitudes towards IM. RESULTS: The survey completion rate was 75.5% (n = 331). The respondents' mean age was 48.5 years, and they were primarily white (75%), married (48%), and educated with at least a college degree (58%). The respondents were distributed between the university (74%), VA (15%), and private practice (11%). There was an equal mix of reconstructive (52%) and cosmetic (48%) visits. Overall IM utilization was 80.0%. Integrative medicine use correlated with having a college degree (P = 0.0002) and being middle age (40-64 years, P < 0.005). A higher utilization rate of IM in the private sector (87.0%) compared with the university (76.1%) and VA (71.0%) was not statistically significant (P = 0.17). Similarly, higher IM utilization in cosmetic patients compared with reconstructive patients (81% vs 74%) was not statistically significant (P = 0.56). The majority of patients stated a strong belief in self-healing techniques (71%, P < 0.005), and they desired (61%) that their physician should be familiar with these techniques (P < 0.005). CONCLUSIONS: The IM utilization is highly prevalent among plastic surgery patients regardless of reason for visit (cosmetic versus reconstruction) or practice setting (private versus academic versus VA). Increasing awareness of IM usage and potential impact on outcomes is especially important for academic and VA plastic surgeons. Moreover, an opportunity exists to study how certain aspects of IM can positively impact plastic surgery care. PMID- 27759587 TI - STARplasty for Reconstruction of the Burned Axilla. AB - BACKGROUND: Postburn axillary contractures are common and significantly impact quality of life. Simple release combined with split thickness skin grafting necessitates a donor site, requires immobilization, and may result in poor functional outcome. Common methods of adjacent tissue rearrangement are not well designed to treat broad linear contractures. Flaps from the back, flank, or arm can be used, but may come with significant donor site morbidity. We demonstrate the use of the STARplasty, a novel adjacent tissue rearrangement initially developed to treat neosyndactyly, as a useful reconstructive option for the release of Kurtzman type 1 posterior or anterior axillary contractures. METHODS: A retrospective review was performed to identify patients who underwent STARplasties for treatment of type 1 axillary burn contractures. All reconstructions were performed by a single surgeon at a single ABA burn center (April 2011 to December 2015). A version of the surgical STARplasty technique previously described for treatment of neosyndactyly was modified for use in the axilla. Patient and injury demographics, as well as complications and outcome, were collected. RESULTS: Twelve patients with upper extremity burns underwent 16 primary STARplasties for treatment of axillary contractures. Three patients underwent simultaneous bilateral procedures. The majority (15/16) of the primary procedures were used to address contractures of the anterior axillary fold. Mean patient age was 51 (R 38-63) and average burn size was 35% (R 18-80). Average time from initial injury to primary reconstruction was 11.1 months (R 3-54). One patient required revision for persistent contracture and another experienced wound dehiscence that ultimately required split-thickness skin grafting. No other significant complications were noted, and all remaining patients had closed wounds and full range of motion by 30 days postprocedure. CONCLUSIONS: Axillary contractures remain common despite improvements in physical/occupational therapy. While common techniques, such as z-plasty, continue to be helpful for the surgical release of narrow contractures with bilateral laxity, axillary contractures are typically broad based and often contain only unilateral unburned tissue. Based on our experience, the axillary STARplasty represents a safe and efficacious technique to be considered in the case of broad-based contractures involving either the anterior or posterior axillary fold. PMID- 27759588 TI - Porcine Acellular Dermal Matrix for Hernia Repair in Transplant Patients. AB - PURPOSE: The purpose of this study was to compare clinical outcomes of incisional hernia repair in solid organ transplant patients using non-cross-linked porcine acellular dermal matrix (PADM), human derived acellular dermal matrix (HADM) and synthetic mesh. METHODS: A retrospective review of patients who underwent hernia repair with PADM after pancreas and/or renal transplant at the University of Maryland Medical Center from 2008 to 2012 was conducted. Repair type, postoperative infection, hernia recurrence, mesh removal, and length of follow-up were recorded. Results were compared with our previously published data evaluating HADM and synthetic mesh used in transplant patients between 2000 and 2005. RESULTS: Twenty-seven patients underwent ventral hernia repair with PADM, 34 patients were repaired with HADM and 26 were repaired with synthetic mesh. The rate of wound infection in those repaired with PADM, HADM, and synthetic mesh were 14.8%, 14.7%, and 65.4%, respectively. Rates of recurrence were 13.3%, 23.5%, and 76.9%, respectively. Rate of mesh removal was found to be 7.4%, 11.8%, and 69.2%, respectively. These complication rates were significantly lower in patients who received HADM or PADM compared with patients repaired with synthetic mesh (P < 0.001). There was no statistically significant difference in the outcomes between the groups repaired with HADM or PADM. CONCLUSIONS: The use of PADM for incisional hernia repair after kidney and/or pancreas transplant significantly reduces the incidence of hernia recurrence, wound infection, and need for mesh removal compared to synthetic mesh. No difference in morbidity between HADM and PADM was observed in the study population; however, longer follow-up in the PADM group is warranted. PMID- 27759590 TI - Nipple-Sparing Mastectomy Improves Long-Term Nipple But Not Skin Sensation After Breast Reconstruction: Quantification of Long-Term Sensation in Nipple Sparing Versus Non-nipple Sparing Mastectomy. AB - BACKGROUND: Changes in breast sensation after reconstruction are expected. Return of breast sensation after reconstruction and whether nipple-sparing mastectomy offers a substantial benefit in terms of sensation has been inconsistently documented in the literature. We conducted the current study using the pressure specified sensory device to quantify postoperative breast sensation in patients undergoing nipple-sparing versus non-nipple-sparing mastectomy. METHODS: Consecutive adult women who underwent nipple-sparing (NSM) and non-NSM (NNSM) and were at least 18 months postreconstruction were included. Breast measurements were taken in 4 quadrants (upper/lower lateral, upper/lower medial) and nipple. Averaged skin cutaneous thresholds [(UL+LL+UM+LM)/4] and nipple sensation between NSM and NNSM were compared as the primary outcome measure. A generalized estimating equations model was used; univariate and multivariate variable analyses were done when appropriate. RESULTS: Forty-four patients (74 breasts) were examined (53 NNSM vs 21 NSM). The groups were further subdivided into autologous versus implant-based reconstruction. Averaged cutaneous skin thresholds for quadrants were better for the NSM, 51.8(+/-24.5) g/mm versus NNSM, 56.5(+/-25.7) g/mm, although this difference was not statistically significant. However, NSM breasts measured higher nipple or nipple area sensitivity, 44.5(+/ 30.8) g/mm versus NNSM, 83.8(+/-27.4) g/mm (P < 0.001). In a multivariate regression analysis, a predictor of decreased sensation was the number of revision surgeries, especially after third revision. CONCLUSIONS: Breast sensation is decreased after reconstruction in both NSM and NNSM, but nipple sensation or nipple area is better preserved in NSM breasts. Number of revision surgeries (>3) was a predictor of decreased sensation. PMID- 27759591 TI - Variation in Classification of Infection: A Systematic Review of Recent Plastic Surgery Literature. AB - BACKGROUND: Surgical site infections, also referred to as wound infections, are commonly studied within the plastic surgery literature. The definition of these terms is not standardized in the literature. Individual studies may select criteria to use in identifying infection. This may have important implications upon interpretation of study results. METHODS: Studies evaluating surgical site infection in the plastic surgery literature were identified through search of the MEDLINE database across the five year period ending March 2016. Infection rates were calculated for included studies. Studies were grouped by method of defining infection. Subgroups were compared by calculating percentage of studies reporting greater than 10% infection rates. RESULTS: Three hundred five articles were identified, 77 met study criteria. Thirty-one articles reported criteria for infection and 46 articles did not report criteria for infection. Methods used by studies to define infection were based on treatment received, national/organization definition, characteristics of infection, and International Classification of Diseases, Ninth Revision coding. Studies defining infection by national/organization definition included the greatest percentage reporting infection rates over 10% with 75% of studies. Studies reporting criteria for infection reported infection rates over 10% more often than studies that did not report criteria. 47.5% of studies reporting criteria for infection reported rates over 10% compared with 31.8% of studies which did not. CONCLUSIONS: Criteria used to define infection differs across studies in the plastic surgery literature. Comparison of reported infection rates on the basis of criteria for infection suggests an effect upon infection rate. Many studies do not report criteria used to identify infection and should consider reporting strict criteria for infection. PMID- 27759592 TI - Application for MEDPOR Surgical Implant in Modified Penile Elongation: Review of 19 Cases. AB - OBJECTIVE: To investigate the application of MEDPOR surgical implant in modified penile elongation. METHODS: The suspensory ligaments were divided, and cavernous bodies of crus were partially mobilized, so as to release part of the cavernous bodies from inferior ramus of pubis. Then, the penis was elongated sufficiently. MEDPOR surgical implants (MEDPOR; high-density porous polyethylene, Howmedica Osteonics Corp. Newnan, Ga) were inserted between the cavernous bodies and pubic symphysis. Local fat flap was transposed to fill the front space of pubis to make sure of the effective elongation of penis and improve the appearance of mons pubis. RESULTS: Nineteen cases of micropenis were treated. The average length of the penis was 5.23 cm in the static state and 7.83 cm in erectile state before operation. After the operation, it increased to 8.63 cm in the static state and 11.36 cm in erectile state. CONCLUSIONS: Application for MEDPOR surgical implant in modified penile elongation can make sure of the effective elongation of penis and improve the appearance of mons pubis. PMID- 27759593 TI - A Comparison of the Need for Speech Therapy After 2 Palatal Repair Techniques. AB - BACKGROUND: Reconstruction of the levator musculature during cleft palate repair has been suggested to be important in long-term speech outcomes. In this study, we compare the need for postoperative speech therapy between 2 intravelar veloplasty techniques. METHODS: Chart review was performed for patients with nonsyndromic cleft palate who underwent either primary Kriens or overlapping intravelar veloplasty before 18 months of age. All subjects completed a follow-up visit at approximately 3 years of age. Data obtained included documentation of ongoing or recommended speech therapy at age 3 years and reasons for speech therapy, which were categorized as cleft-related and non-cleft-related by a speech-language pathologist. RESULTS: One surgeon performed all Kriens procedures (n = 81), and the senior author performed all overlapping procedures (n = 25). Mean age at surgery (Kriens = 13.5 +/- 1.4 months; overlapping = 13.1 +/- 1.5 months; P = 0.188) and age at 3-year follow-up (Kriens = 3.0 +/- 0.5 years; overlapping = 2.8 +/- 0.5 years; P = 0.148) were equivalent in both groups. Cleft severity by Veau classification (P = 0.626), prepalatoplasty pure tone averages, (P = 0.237), pure tone averages at 3-year follow-up (P = 0.636), and incidence of prematurity (P = 0.190) were also similar between the 2 groups. At 3 years of age, significantly fewer overlapping intravelar veloplasty patients required cleft-related speech therapy (Kriens = 47%; overlapping = 20%; P = 0.015). The proportions of patients requiring non-cleft-related speech therapy were equivalent (P = 0.906). CONCLUSIONS: At 3 years of age, patients who received overlapping intravelar veloplasty were significantly less likely to need cleft related speech therapy compared with patients who received Kriens intravelar veloplasty. Cleft severity, hearing loss, and prematurity at birth did not appear to explain the difference found in need for speech therapy. PMID- 27759594 TI - The Association of Peripheral Blood Regulatory T-Cell Concentrations With Epithelial Ovarian Cancer: A Brief Report. AB - OBJECTIVE: There is a mounting body of evidence demonstrating higher percentages of regulatory T (Treg) cells in the peripheral blood of patients with cancer in comparison to healthy controls, but there is a paucity of epidemiological literature characterizing circulating Treg cells among patients with epithelial ovarian cancer (EOC). To investigate the role of peripheral Treg cells in ovarian neoplasms, we conducted a case-control study to characterize circulating concentrations of Treg cells among patients with EOC, women with benign ovarian conditions, and healthy controls without a history of cancer. MATERIALS AND METHODS: Participants were identified for inclusion due to their participation in the Data Bank and BioRepository program at Roswell Park Cancer Institute in Buffalo, NY. Patients included 71 women with a primary diagnosis of EOC and 195 women with a diagnosis of benign ovarian conditions. Controls included 101 age- and race-matched women without a history of cancer. Nonfasting, pretreatment peripheral blood levels of CD3+CD4+CD25+FOXP3+ Treg cells were measured using flow cytometric analyses and expressed as a percentage of total CD3+ cells and as a percentage of total CD3+CD4+ cells. RESULTS: Compared to healthy controls and women with benign ovarian conditions, patients with EOC had significantly higher frequency of Treg cells (P < 0.04). In multivariable logistic regression analyses using Treg frequency expressed as a percentage of CD+3 cells, we observed a significant positive association between Treg cell percentage and EOC risk, with each 1% increase associated with a 37% increased risk of EOC (odds ratio, 1.37; 95% confidence interval, 1.04-1.80). We observed a similar trend when Treg frequency was expressed as a percentage of CD3+CD+4 cells (odds ratio, 1.22; 95% confidence interval, 0.99-1.49). CONCLUSIONS: The current study provides support that peripheral Treg cell frequency is elevated in patients with EOC in comparison to women with benign ovarian conditions and healthy controls. PMID- 27759595 TI - Survival Differences Among Uterine Papillary Serous, Clear Cell and Grade 3 Endometrioid Adenocarcinoma Endometrial Cancers: A National Cancer Database Analysis. AB - OBJECTIVES: High-risk histology including UPSC, CC, and high-grade (G3) endometrioid adenocarcinoma (EAC) have a worse prognosis compared to G1-2 EAC. It is unknown whether G3EAC outcomes are more similar to UPSC/CC or to G1-2 EAC. The purpose of this study was to compare overall survival (OS) among UPSC, CC, and G1 3 EAC, for International Federation of Gynecology and Obstetrics stages I to III. METHODS: The National Cancer Data Base was queried for patients diagnosed with International Federation of Gynecology and Obstetrics (1988 classification) Stage I-III UPSC, CC, and EAC from 1998 to 2012 who underwent surgery as definitive treatment. Patients with unknown grade/stage, nonsurgical primary therapy, other histologies, and less than 30-day follow-up were excluded. Overall survival was calculated using the Kaplan-Meier product-limit method and compared using log rank tests. RESULTS: 219,934 patients met our inclusion criteria. For patients with stage I disease (n = 174,361), 5-year OS was for 92.4% for G1EAC, 87.8% for G2EAC, 77.5% for G3EAC, 74.9% for CC, and 74.6% for UPSC. For stage II patients (n = 17,361), 5-year OS was 86.7% for G1EAC, 80.2% for G2EAC, 62.7% for G3EAC, 64.3% for CC, and 56.7% for UPSC. For stage III patients (n = 28,212), 5-year OS was 79.7% for G1EAC, 68.9% for G2EAC, 49.6% for G3EAC, 40.2% for CC, and 35.7% for UPSC (P <0.0001). On multivariate analysis, black race, age 60 years and older, higher stage, higher grade, high-risk histologies, receiving chemotherapy, and higher comorbidity scores were all significantly (P < 0.0001) predictive of death while receiving radiation therapy was protective (hazards ratio, 0.7; 95% confidence interval, 2.6-2.9). CONCLUSIONS: The results suggest that G3 EAC has a slightly more favorable survival than UPSC and CC but predictably does poorer than G1-2 EAC. Further research is warranted to determine if G3 EAC should be reclassified as a type II cancer. PMID- 27759596 TI - PICU Up!: Impact of a Quality Improvement Intervention to Promote Early Mobilization in Critically Ill Children. AB - OBJECTIVE: To determine the safety and feasibility of an early mobilization program in a PICU. DESIGN: Observational, pre-post design. SETTING: PICU in a tertiary academic hospital in the United States. PATIENTS: Critically ill pediatric patients admitted to the PICU. INTERVENTION: This quality improvement project involved a usual-care baseline phase, followed by a quality improvement phase that implemented a multicomponent, interdisciplinary, and tiered activity plan to promote early mobilization of critically ill children. MEASUREMENTS AND MAIN RESULTS: Data were collected and analyzed from July to August 2014 (preimplementation phase) and July to August 2015 (postimplementation). The study sample included 200 children 1 day through 17 years old who were admitted to the PICU and had a length of stay of at least 3 days. PICU Up! implementation led to an increase in occupational therapy consultations (44% vs 59%; p = 0.034) and physical therapy consultations (54% vs 66%; p = 0.08) by PICU day 3. The median number of mobilizations per patient by PICU day 3 increased from 3 to 6 (p < 0.001). More children engaged in mobilization activities after the PICU Up! intervention by PICU day 3, including active bed positioning (p < 0.001), and ambulation (p = 0.04). No adverse events occurred as a result of early mobilization activities. The most commonly reported barriers to early mobilization after PICU Up! implementation was availability of appropriate equipment. The program was positively received by PICU staff. CONCLUSIONS: Implementation of a structured and stratified early mobilization program in the PICU was feasible and resulted in no adverse events. PICU Up! increased physical therapy and occupational therapy involvement in the children's care and increased early mobilization activities, including ambulation. A bundled intervention to create a healing environment in the PICU with structured activity may have benefits for short- and long-term outcomes of critically ill children. PMID- 27759597 TI - Magnetic Resonance Imaging Findings of Ischiofemoral Impingement in Patients With Inflammatory Myositis: An Observational Study. AB - OBJECTIVE: To determine the frequency of magnetic resonance imaging (MRI) findings of ischiofemoral impingement (IFI) in patients with inflammatory myositis (IM) and associated factors. METHODS: Pelvis and thigh MRI studies of 314 consecutive patients (57% women; mean age, 55.5 years; range, 18-85) with suspected muscle disease were reviewed. RESULTS: Ischiofemoral impingement at MRI was present in 11% of patients with a final diagnosis of IM and in 2% of patients with an alternative diagnosis (P = 0.008). In multiple logistic regression analysis, IM, but not age or sex, was independently associated with IFI at MRI (odds ratio, 5.18; 95% confidence interval, 1.19-22.6; P = 0.028). Fatty atrophy of hip stabilizing muscles was independently associated with IFI at MRI (odds ratio per unit increase of fatty atrophy score, 1.03; 95% confidence interval, 1.01-1.05; P = 0.0007). CONCLUSIONS: Magnetic resonance imaging findings of IFI are present in 11% of IM patients and are independently associated with fatty atrophy of hip stabilizing muscles. PMID- 27759598 TI - Incidental Findings in Abdominal Dual-Energy Computed Tomography: Correlation Between True Noncontrast and Virtual Noncontrast Images Considering Renal and Liver Cysts and Adrenal Masses. AB - PURPOSE: To assess correlation between attenuation measurements of incidental findings in abdominal second generation dual-energy computed tomography (CT) on true noncontrast (TNC) and virtual noncontrast (VNC) images. MATERIALS AND METHODS: Sixty-three patients underwent arterial dual-energy CT (Somatom Definition Flash, Siemens; pitch factor, 0.75-1.0; gantry rotation time, 0.28 seconds) after endovascular aneurysm repair, consisting of a TNC single energy CT scan (collimation, 128 * 0.6 mm; 120 kVp) and a dual-energy arterial phase scan (collimation, 32 * 0.6 mm, 140 and 100 kVp; blended, 120 kVp data set). Attenuation measurements in Hounsfield units (HU) of liver parenchyma and incidental findings like renal and hepatic cysts and adrenal masses on TNC and VNC images were done by drawing regions of interest. Statistical analysis was performed by paired t test and Pearson correlation. RESULTS: Incidental findings were detected in 56 (89%) patients. There was excellent correlation for both renal (n = 40) and hepatic cysts (n = 12) as well as adrenal masses (n = 6) with a Pearson correlation of 0.896, 0.800, and 0.945, respectively, and mean attenuation values on TNC and VNC images of 10.6 HU +/- 12.8 versus 5.1 HU +/- 17.5 (attenuation value range from -8.8 to 59.1 HU vs -11.8 to 73.4 HU), 6.4 HU +/- 5.8 versus 6.3 HU +/- 4.6 (attenuation value range from 2.0 to 16.2 HU vs 3.0 to 15.9 HU), and 12.8 HU +/- 11.2 versus 12.4 HU +/- 10.2 (attenuation value range from -2.3 to 27.5 HU vs -2.2 to 23.6 HU), respectively. As proof of principle, liver parenchyma measurements also showed excellent correlation between TNC and VNC (n = 40) images with a Pearson correlation of 0.839 and mean attenuation values on TNC and VNC images of 47.2 HU +/- 10.5 versus 43.8 HU +/- 8.7 (attenuation value range from 21.9 to 60.2 HU vs 4.5 to 65.3 HU). CONCLUSIONS: In conclusion, attenuation measurements of incidental findings like renal cysts or adrenal masses on TNC and VNC images derived from second generation dual-energy CT scans show excellent correlation providing considerable dose savings, favorable for future application in clinical routine. PMID- 27759599 TI - Aortic and Hepatic Contrast Enhancement During Hepatic-Arterial and Portal Venous Phase Computed Tomography Scanning: Multivariate Linear Regression Analysis Using Age, Sex, Total Body Weight, Height, and Cardiac Output. AB - OBJECTIVE: We evaluated the effect of the age, sex, total body weight (TBW), height (HT) and cardiac output (CO) of patients on aortic and hepatic contrast enhancement during hepatic-arterial phase (HAP) and portal venous phase (PVP) computed tomography (CT) scanning. METHODS: This prospective study received institutional review board approval; prior informed consent to participate was obtained from all 168 patients. All were examined using our routine protocol; the contrast material was 600 mg/kg iodine. Cardiac output was measured with a portable electrical velocimeter within 5 minutes of starting the CT scan. We calculated contrast enhancement (per gram of iodine: [INCREMENT]HU/gI) of the abdominal aorta during the HAP and of the liver parenchyma during the PVP. We performed univariate and multivariate linear regression analysis between all patient characteristics and the [INCREMENT]HU/gI of aortic- and liver parenchymal enhancement. RESULTS: Univariate linear regression analysis demonstrated statistically significant correlations between the [INCREMENT]HU/gI and the age, sex, TBW, HT, and CO (all P < 0.001). However, multivariate linear regression analysis showed that only the TBW and CO were of independent predictive value (P < 0.001). Also, only the CO was independently and negatively related to aortic enhancement during HAP and to liver parenchymal enhancement when the contrast material injection protocol was adjusted for the TBW (P < 0.001). CONCLUSION: By multivariate linear regression analysis only the TBW and CO were significantly correlated with aortic and liver parenchymal enhancement; the age, sex, and HT were not. The CO was the only independent factor affecting aortic and liver parenchymal enhancement at hepatic CT when the protocol was adjusted for the TBW. PMID- 27759600 TI - Scout-Based Automated Tube Potential Selection Technique (kV Assist) in Enhanced Chest Computed Tomography: Effects on Radiation Exposure and Image Quality. AB - OBJECTIVE: The aim of our study was to assess radiation dose reduction and image quality for enhanced chest CT examinations with a scout-based automated tube potential selection technique (kV Assist) compared with a standard 120-kV protocol. METHODS: Prospective study of enhanced chest CT examinations was performed in 100 consecutive patients with kV Assist and in 100 consecutive patients with conventional 120-kV protocol on a multislice CT (Discovery CT750 HD). The body mass index, CT dose index volume, and dose length product were recorded from the examination protocol. Image noise and CT value was measured on region of interest, signal-to-noise ratio, and contrast-to-noise ratio was calculated. The subjective image quality was assessed by two radiologists blinded to the respective protocol with the use of a 3-grade scale (3, superior quality; 2, moderate quality; 1, inferior quality). RESULTS: With kV Assist, the percentages of patients being scanned using 80, 100, and 120 kV were 12.0%, 80.0%, and 8.0%, respectively. The kilovolt setting was related with body mass index (r = 0.565, P = 0.000). Compared with the conventional 120 kV protocol, kV Assist allowed for an overall average decrease of 30.6% in CT dose index volume (kV Assist, 11.05 +/- 4.78 mGy; 120 kV, 15.92 +/- 6.89 mGy) (P < 0.001) and 32.3% in dose length product (kV Assist, 386.41 +/- 184.02 mGy cm; 120 kV, 571.14 +/- 286.68 mGy cm) (P < 0.001). In the kV Assist, mean attenuation of regions of interest inside the aorta was significantly higher than that in 120-kV protocols (kV Assist, 310.27 +/- 73.70 HU; 120 kV, 239.44 +/- 47.65 HU) (P < 0.001), resulting in increased contrast-to-noise ratio (kV Assist, 26.69 +/- 7.78; 120 kV, 21.38 +/- 6.05) (P < 0.001). There was no significant difference in subjective image quality scores between the 2 groups. CONCLUSIONS: The use of attenuation-based kV Assist technique enables significant dose reduction in enhanced chest CT scan while improving arterial enhancement and preserving image quality at adequate levels. PMID- 27759601 TI - Computed Tomography and Magnetic Resonance Imaging Findings in a Case of Colonic Intramural Hematoma After Mild Blunt Abdominal Trauma. AB - Intramural hematomas can occur along any part of the gastrointestinal tract, being more common in the duodenum, jejunum, and ileum. Intramural colonic hematomas are very rare, and their main causes include abdominal trauma, anticoagulation, and coagulopathies. We report on a 27-year-old man with right lower quadrant pain for 1 day after a mild blunt trauma sustained during a soccer match. Computed tomography and magnetic resonance imaging evaluation revealed an intramural hematoma of the right colon, subsequently confirmed and drained through laparoscopic surgery. Although computed tomography and magnetic resonance imaging findings in such a context are scarce in the radiological literature, imaging has an important role in the preoperative diagnosis and evaluation of the extent of bowel hematomas to assist in treatment planning. PMID- 27759603 TI - Collaboration and Teamwork are Required for Successful Maternity Care Quality Improvement. PMID- 27759602 TI - Abdominal Multidetector Computed Tomography for Suspected Small-Bowel Obstruction: Multireader Study Comparing Radiologist Performance for Predicting Surgical Outcomes. AB - OBJECTIVE: To compare performance of junior (JR)/senior (SR) abdominal radiologists using multidetector computed tomography (MDCT) to predict surgical intervention, bowel resection, and presence of bowel ischemia in patients with suspected small-bowel obstruction (SBO). METHODS: Retrospective, institutional review board-approved, Health Insurance Portability and Accountability Act compliant, blinded, independent review of MDCT studies for suspected SBO in 179 adults (mean age, 55.8 years; 86 men/93 women) was performed by 12 board certified radiologists (6 JR, 6 SR). Readers rated likelihood of need for surgery, bowel ischemia, and resection. Correlation with clinical outcomes/pathology was performed. RESULTS: Pooled receiver operating characteristic area under the curve for surgery, ischemia, and resection were 0.802, 0.736, and 0.824 and 0.773, 0.851, and 0.751 JR/SR, respectively. Sensitivity/specificity for predicting surgery was 86.7%/65.4% and 79.6%/64.4%. No differences existed between JR/SR performance overall (P = 0.451); highest/lowest performing readers between groups (P < 0.001) and within groups (P = 0.008) varied. CONCLUSIONS: Junior radiologists performed as well as SR in predicting surgical outcomes on MDCT in patients with suspected SBO. PMID- 27759604 TI - Planning, Designing, Building, and Moving a Large Volume Maternity Service to a New Labor and Birth Unit: Commentary and Experiences of Experts. AB - Three teams of perinatal expert nurses participated in planning and designing a new maternity unit, operationalizing the move to the new space, and evaluating care processes and workflows after the move. The hospitals involved were University of California, San Francisco Benioff Children's Hospital, Prentice Women's Hospital of Northwestern Memorial Healthcare in Chicago, IL, and Florida Hospital Orlando, Florida Hospital for Women. Although each team discussed specific details and lessons learned, there is remarkable consistency among the experiences of these teams and with the discussion of the process by the team at Mercy Hospital St. Louis published in this issue of MCN The American Journal of Maternal Child Nursing. Extensive planning, flexibility, involving key stakeholders, evaluating and simulating workflows, and adequate staffing and patient safety on move-day were reported to be essential to success. Reevaluation after settling in to the new unit and making changes as needed were discussed. Being part of the leadership team involved in planning and moving to a new maternity unit in what was likely a once-in-a-lifetime experience was viewed as a career highlight. Their commentary adds to what is known about planning and designing new maternity units, moving into the new space, and adjusting unit operations and care after making the new unit home. PMID- 27759606 TI - The Maternal Fetal Triage Index: A Standardized Approach to OB Triage. PMID- 27759607 TI - Baby-Led Weaning. PMID- 27759605 TI - The Fetal Care Team: Care for Pregnant Women Carrying a Fetus with a Serious Diagnosis. AB - BACKGROUND: Women carrying a fetus with a suspected or known fetal anomaly have complex needs such as emotional and informational support and help with the logistical aspects of arranging care and treatment from numerous specialists. IMPROVEMENT IN QUALITY OF CARE FOR WOMEN CARRYING A FETUS WITH A SUSPECTED OR KNOWN FETAL ANOMALY:: Our fetal care team was initiated in 2012 to meet the needs of this high-risk pregnant population. The fetal care team nurse coordinator supports the woman and her family through all aspects of care during the pregnancy and neonatal period including scheduling appointments with multiple specialists, being there with her as a support person, keeping her updated, making sure she has accurate information about the fetal diagnosis, and helping her to navigate the complex healthcare system. RESULTS: Since the program was started, the number of women enrolled has nearly doubled. Women overwhelmingly are satisfied with the various services and care provided by the nurse coordinators and believe the fetal care team has value for them. CLINICAL IMPLICATIONS: We present the development and operations of our fetal care team with a focus on the role of the fetal care team nurse coordinator. PMID- 27759608 TI - Breastfeeding in the Context of Palliative Care. PMID- 27759609 TI - Strategies to Empower Women Across the Globe: 100 Under 100. PMID- 27759612 TI - Process Improvement to Enhance Quality in a Large Volume Labor and Birth Unit. PMID- 27759611 TI - Length of Second-Stage Labor: Safety Considerations. PMID- 27759613 TI - Maternal Hemorrhage Quality Improvement Collaborative Lessons. PMID- 27759614 TI - Magnetic Surgery: Results From First Prospective Clinical Trial in 50 Patients. AB - OBJECTIVE: To evaluate a new magnetic surgical system during reduced-port laparoscopic cholecystectomy in a prospective, multicenter clinical trial. BACKGROUND: Laparoscopic instrumentation coupled by magnetic fields may enhance surgeon performance by allowing for shaft-less retraction and mobilization. The movements can be performed under direct visualization, generating different angles of traction and reducing the number of trocars to perform the procedure. This may reduce well-known associated complications of trocars, including incisional pain, scarring, infection, bowel, and vascular injuries, among others. METHODS: A prospective, multicenter, single-arm, open-label study was performed to assess the safety and performance of a magnetic surgical system (Levita Magnetics' Surgical System). The investigational device was used during a 3-port laparoscopic technique. The primary endpoints evaluated were safety and feasibility of the device to adequately mobilize the gallbladder to achieve effective exposure of the targeted surgical site. Patients were followed for 30 days postprocedure. RESULTS: Between January 2014 and March 2015, 50 patients presenting with benign gallbladder disease were recruited. Forty-five women and 5 men with an average age of 39 years (18-59), average body mass index of 27 kg/m (20.4-34.1) and an average abdominal wall thickness of 2.6 cm (1.8-4.6). The procedures were successfully performed in all 50 patients. No device-related serious adverse events were reported. Surgeons rated as "excellent" (90%) or "sufficient" (10%) the exposure of the surgical site. CONCLUSIONS: This clinical trial shows that this new magnetic surgical system is safe and effective in reduced-port laparoscopic cholecystectomy. PMID- 27759615 TI - Photochemical Tissue Passivation Attenuates AV Fistula Intimal Hyperplasia. AB - OBJECTIVE: We hypothesized that decreasing vein compliance would protect the vein against stretch injury and reduce intimal hyperplasia (IH). BACKGROUND: Although arteriovenous fistulas (AVFs) are the criterion standard for vascular access, their effectiveness is limited by poor patency with 40% to 60% failing due to IH. Venous stretch injury from exposure to arterial pressure induces IH. Photochemical tissue passivation (PTP) crosslinks adventitial collagen, decreasing vein compliance to resemble that of an artery. METHODS: AVFs were created between the femoral artery and epigastric vein in rats (n = 29). PTP was performed on the vein immediately before vessel anastomosis. AVFs were harvested after four weeks. Venous diameter was measured at the initial procedure and harvest. Intimal area was measured for each segment. Ultrasound was performed at harvest to measure AVF flow. RESULTS: Following AVF construction, venous diameter increased by 10% +/- 18% for PTP-treated vessels and 78% +/- 27% for controls (P <= 0.0001). At one month, PTP reduced AVF dilation by 71% compared to control (69% +/- 29% vs 241% +/- 78%; P <= 0.0001). Both juxta-anastomotic intimal area and total intimal area were reduced in PTP-treated vessels compared to control vessels. Specifically, intimal area was 0.024 +/- 0.018 and 0.095 +/- 0.089 mm for PTP-treated juxta-anastomotic segments of AVF and control, respectively (P < 0.05). Mean total intimal area for PTP-treated and control AVF were 0.080 +/- 0.042 and 0.190 +/- 0.110 mm, respectively (P < 0.03). AVF flow was 46.9 +/- 35.3 and 19.1 +/- 10.1 mL/min for PTP-treated and control AVF, respectively (P < 0.109). CONCLUSIONS: These data demonstrate that PTP represents a promising therapy for the prevention of AVF IH, a process that might improve surgical outcomes for patients receiving hemodialysis. PMID- 27759616 TI - Esophageal Cancer Clinical Presentation: Trends in the Last 3 Decades in a Large Italian Series. AB - OBJECTIVE: The aim of this study was to investigate trends in patients' characteristics and comorbidities in esophageal cancer (EC) patients. BACKGROUND: Identifying changing pattern is essential to understand and predict further changes and to plan surgical procedures and resource allocation. METHODS: Trends in patients' characteristics and comorbidities were evaluated in 4440 EC patients at the Center for Esophageal Diseases in Padova, Italy, during 1980 to 2011. Joinpoint regression analysis was performed to evaluate trends and to estimate annual percentage changes (APCs). RESULTS: During the study period, there has been a statistically significant increment of the rate of esophageal adenocarcinoma (APC 3.70). The rates of elderly and of asymptomatic patients increased over time (APCs 0.98 and 6.24), whereas the rates of malnutrition, alcoholic drinking, and gastric ulcer decreased (APCs -1.50, -1.72, and -5.20). Reflux rate increased until 1997 and decreased thereafter (APCs 6.96 and -4.48), whereas the rate of Barrett esophagus increased until 1992 (APC 35.84) and then leveled. The rates of patients with previous neoplasms increased over time (APCs 3.22 and 4.86). There have been significant changes in systemic comorbidities, with an increase of hypertension and cardiac disease (APCs 7.56 and 1.86) and a decrease of advanced liver disease and pulmonary disease (APCs -2.67 and -1.74). CONCLUSION: The current EC patient has more often an esophageal adenocarcinoma and is more frequently elderly, asymptomatic, a survivor of previous neoplasms, and a patient with hypertension and cardiac disease than 30 years ago. On the contrary, malnutrition, alcoholic drinking, gastric ulcer, pulmonary disease, and advanced liver disease decreased. PMID- 27759617 TI - Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients. AB - OBJECTIVE: The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC). BACKGROUND: HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy. METHODS: A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected. RESULTS: Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be "as expected" by 40% of patients and "better than expected" by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy. CONCLUSION: Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections. PMID- 27759619 TI - Infectious Surgical Complications are Not Dichotomous: Characterizing Discordance Between Administrative Data and Registry Data. AB - OBJECTIVE: To characterize reasons for discordance between administrative data and registry data in the determination of postoperative infectious complications. BACKGROUND: Data regarding the occurrence of postoperative surgical complications are identified through either administrative or registry data. Rates of complications vary significantly between these two types of data; the reasons for this are not well-understood. METHODS: The occurrence of 30-day inpatient infectious complications (pneumonia, sepsis, surgical site infection, and urinary tract infection) was compared between the NSQIP and administrative mechanisms at 4 academic hospitals between 2012 and 2014. In each situation where the NSQIP and administrative data were discordant regarding the occurrence of a specific complication, a 2-clinician chart abstraction was performed to characterize the reasons for discordance as (i) administrative coding error, (ii) NSQIP coding error, (iii) "question of criteria", where the discordance was the result of differences in criteria, or (iv) "dually incorrect", where both data sources coded the complication incorrectly. RESULTS: The cohort included 19,163 patients undergoing surgery in 4 different academic hospitals. Rates of infectious complications varied up to 5-fold between the two data sources. A total of 717 discordant complications were identified. Of these, the greatest portion (43%) was due to "question of criteria," followed by administrative coding error (37%), NSQIP error (15%), and dually incorrect (5%). CONCLUSIONS: With a goal of improving existing mechanisms for measuring surgical quality, definitions for the occurrence of a postoperative complication need to be developed and applied consistently. Progress toward this goal will enable patients and payers to better take advantage of recent advances in healthcare data transparency. PMID- 27759618 TI - Lauren Histologic Type Is the Most Important Factor Associated With Pattern of Recurrence Following Resection of Gastric Adenocarcinoma. AB - OBJECTIVE: To examine sites of initial recurrence in patients after resection of gastric and gastroesophageal junction Siewert II/III adenocarcinoma (GA). BACKGROUND: There are few recent studies on recurrence for Western patients following potentially curative resection of GA. METHODS: A review of a prospectively maintained, single institution database was performed. Clinicopathologic factors, site(s) of initial recurrence, disease-free survival, and overall survival were examined. RESULTS: From January 2000 to June 2010, 957 patients underwent potentially curative resection for GA, 435 patients (46%) had recurrent disease, and complete data on recurrence site(s) could be obtained in 386 patients. Tumors were Lauren intestinal type in 206 (53%) and diffuse or mixed-type in 180 (47%). Median time to recurrence was 12 months and 75% of recurrences occurred within 2 years. There was a significant difference in pattern of initial recurrence between the intestinal and diffuse/mixed cohorts (P < 0.001). For intestinal tumors, distant metastasis was the most common site (54%), followed by locoregional (20%), peritoneal (15%), and multifocal (11%). For diffuse/mixed tumors, peritoneal recurrence was the most common (37%), followed by distant (32%), locoregional (22%), and multifocal (9%). On multivariate analysis, Lauren histologic type was the only significant factor that was associated with both peritoneal recurrence (diffuse, hazard ratio 2.22, confidence interval 1.38-3.94) and distant recurrence (intestinal, hazard ratio 1.888, confidence interval 1.202-2.966). After recurrence, median overall survival was only 8.4 months. CONCLUSIONS: In GA patients who recur after resection, patterns of recurrence vary significantly based on Lauren histologic type. PMID- 27759620 TI - Trainee Involvement in Ivor Lewis Esophagectomy Does Not Negatively Impact Outcomes. AB - OBJECTIVE: The aim of the present study was to determine whether trainee involvement in esophageal cancer resection is associated with adverse patient outcomes. BACKGROUND: Operative experience for surgical trainees is under threat. A number of factors have been implicated in this leading to fewer hours for training. Esophagogastric cancer training is particularly vulnerable due to the publication of individual surgeon results and a perception that dual consultant operating improves patient outcomes. Resectional surgery is increasingly viewed as a subspeciality to be developed after completion of the normal training pathway. METHODS: Data from a prospectively maintained database of consecutive patients undergoing trans-thoracic esophagectomy for potentially curable carcinoma of the esophagus or gastroesophageal junction were reviewed. Patients were divided into 4 cohorts, according to whether a consultant or trainee was the primary surgeon in either the abdominal or thoracic phase. Outcomes including operative time, lymph node yield, blood loss, complications graded by Accordion score, and mortality were recorded. RESULTS: A total of 323 patients underwent esophagectomy during 4 years. The overall in-hospital mortality rate was 1.5%. At least 1 phase of the surgery was performed by a trainee in 75% of cases. There was no significant difference in baseline demographics of age, stage, neoadjuvant treatment, and histology between cohorts. There was no significant difference in blood loss (P = 0.8), lymph node yield (P = 0.26), length of stay (P = 0.24), mortality, and complication rate according to Accordion scores (P = 0.21) between cohorts. Chest operating time was a median 25 minutes shorter when performed by a consultant (P < 0.001). CONCLUSIONS: These findings demonstrate that patient outcomes are not compromised by supervised trainee involvement in transthoracic esophagectomy. Training is an essential role of all surgical units and training data should be more widely reported especially in areas of high-risk surgery. PMID- 27759621 TI - Antibiotics Versus Surgical Therapy for Uncomplicated Appendicitis: Systematic Review and Meta-analysis of Controlled Trials (PROSPERO 2015: CRD42015016882). AB - OBJECTIVE: The aim was to investigate available evidence regarding effectiveness and safety of surgical versus conservative treatment of acute appendicitis. SUMMARY OF BACKGROUND DATA: There is ongoing debate on the merits of surgical and conservative treatment for acute appendicitis. METHODS: A systematic literature search (Cochrane Library, Medline, Embase) and hand search of retrieved reference lists up to January 2016 was conducted to identify randomized and nonrandomized studies. After critical appraisal, data were analyzed using a random-effects model in a Mantel-Haenszel test or inverse variance to calculate risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). RESULTS: Four trials and four cohort studies (2551 patients) were included. We found that 26.5% of patients in the conservative group needed appendectomy within 1 year, resulting in treatment effectiveness of 72.6%, significantly lower than the 99.4% in the surgical group, (RR 0.75; 95% CI 0.7-0.79; P = 0.00001; I = 62%). Overall postoperative complications were comparable (RR 0.95; 95% CI 0.35-2.58; P = 0.91; I = 0%), whereas the rate of adverse events (RR 3.18; 95% CI 1.63-6.21; P = 0.0007; I = 1%) and the incidence of complicated appendicitis (RR 2.52; 95% CI 1.17-5.43; P = 0.02; I = 0%) were significantly higher in the antibiotic treatment group. Randomized trials showed significantly longer hospital stay in the antibiotic treatment group (RR 0.3 days; 95% CI 0.07-0.53; P = 0.009; I = 49%). CONCLUSIONS: Although antibiotics may prevent some patients from appendectomies, surgery represents the definitive, one-time only treatment with a well-known risk profile, whereas the long-term impact of antibiotic treatment on patient quality of life and health care costs is unknown. This systematic review and meta-analysis helps physicians and patients in choosing between treatment options depending on whether they are risk averse or risk takers. PMID- 27759622 TI - Comment on "The Important Role for Intravenous Iron in Perioperative Patient Blood Management in Major Abdominal Surgery: A Randomized Controlled Trial". PMID- 27759623 TI - Duration of Antimicrobial Prophylaxis in Patients Undergoing Major Hepatectomy With Extrahepatic Bile Duct Resection: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the optimal duration of antimicrobial prophylaxis in patients undergoing "complicated"' major hepatectomy with extrahepatic bile duct resection. BACKGROUND: To date, 4 randomized controlled trials (RCTs) have assessed the duration of antimicrobial prophylaxis after hepatectomy. However, all of these previous studies involved only "simple" hepatectomy without extrahepatic bile duct resection. METHODS: Patients with suspected hilar obstruction scheduled to undergo complicated hepatectomy after biliary drainage were randomized to 2-day (antibiotic treatment on days 1 and 2) or 4-day (on days 1 to 4) groups. Antibiotics were selected based on preoperative bile culture. The primary endpoint was the incidence of postoperative infectious complications. RESULTS: In total, 86 patients were included (43 patients in each arm) without between-group differences in baseline characteristics. Bile culture positivity was similar between the 2 groups. No significant between-group differences were observed in surgical variables. The incidence of any infectious complications was similar between the 2 groups (30.2% in the 2-day group and 32.6% in the 4-day group). The positive rate of systemic inflammatory response syndrome and the incidence of additional antibiotic use were almost identical between the 2 groups. According to Clavien-Dindo classification, grade 3a or higher complications occurred in 23 patients (53.5%) in the 2-day group and 29 patients (67.4%) in the 4-day group (P = 0.186). Postoperative hospital stay was not different between the 2 groups. CONCLUSIONS: Two-day administration of antimicrobial prophylaxis is sufficient for patients undergoing hepatectomy with extrahepatic bile duct resection [Registration number: ID 000009800 (University Hospital Medical Information Network, http://www.umin.ac.jp)]. PMID- 27759624 TI - Defining MoRAL After Liver Transplantation. PMID- 27759625 TI - High efficacy of gemifloxacin-containing therapy in Helicobacter Pylori eradication: A pilot empirical second-line rescue therapy. AB - BACKGROUND: Helicobacter pylori (H pylori) is a common gastric pathogen which is associated with chronic gastritis, peptic ulcer, and gastric cancer. It has worldwide distribution with higher incidence in developing countries. Gemifloxacin is a fluoroquinolone antibiotic with documented in vitro activity against H pylori. Considering that there is no clinical data to verify gemifloxacin efficacy in H pylori eradication, this pilot clinical trial was designed. METHODS: This prospective pilot study was performed during February 2014 to February 2015. A regimen of gemifloxacin (320 mg single dose) plus twice daily doses of amoxicillin1g, bismuth 240 mg, and omeprazole 20 mg for 14 days were prescribed for H pylori infected patients in whom a first-line standard quadruple therapy (clarithromycin-amoxicillin-bismuth-omeprazole) had failed. To confirm H pylori eradication a 13C-urea breath test was performed 4 weeks after treatment.Compliance and incidence of adverse effects were evaluated by questionnaires. RESULTS: A total of 120 patients were enrolled consecutively; out of which 106 patients achieved H pylori eradication; per-protocol and intention to-treat eradication rates were 91.4% (95% CI: 85.5-97.6) and 88.3% (95% CI: 75.4 92.4) respectively. Three patients (2.5%) failed to take at least 80% of the drugs and excluded from the final analysis. Adverse effects were reported in 42% of patients, most commonly including nausea (15%) and diarrhea (13.3%), which was intense in 1 patient and led to the discontinuation of treatment. In total, 96.7% (116/120) of the patients took the medications correctly. CONCLUSION: This study revealed that gemifloxacin-containing quadruple therapy provides high H pylori eradication rate (>=90% PP cure rate), and this agent can be included in the list of second-line H pylori therapeutic regimens. PMID- 27759626 TI - Impact of performance grading on annual numbers of acute myocardial infarction associated emergency department visits in Taiwan: Results of segmented regression analysis. AB - To reduce patient boarding time at the emergency department (ED) and to improve the overall quality of the emergent care system in Taiwan, the Minister of Health and Welfare of Taiwan (MOHW) piloted the Grading Responsible Hospitals for Acute Care (GRHAC) audit program in 2007-2009.The aim of the study was to evaluate the impact of the GRHAC audit program on the identification and management of acute myocardial infarction (AMI)-associated ED visits by describing and comparing the incidence of AMI-associated ED visits before (2003-2007), during (2007-2009), and after (2009-2012) the initial audit program implementation.Using aggregated data from the MOHW of Taiwan, we estimated the annual incidence of AMI-associated ED visits by Poisson regression models. We used segmented regression techniques to evaluate differences in the annual rates and in the year-to-year changes in AMI associated ED visits between 2003 and 2012. Medical comorbidities such as diabetes mellitus, hyperlipidemia, and hypertensive disease were considered as potential confounders.Overall, the number of AMI-associated patient visits increased from 8130 visits in 2003 to 12,695 visits in 2012 (P-value for trend < 0.001), corresponding to an average annual growth rate of 5.3% (95%confidence interval [CI]: 0.5-10%). Although age was a major risk factor for AMI-associated ED visits, the statistical association was observed in middle-to-old (aged 40-64; P-value < 0.001) and older aged individuals (aged >=65; P-value <0.001). As compared to 2003-2007, AMI-associated ED visits increased slightly during the intervention roll-in period (2007-2009, slope = 394.5, P-value = 0.117) followed by a dramatic uptake in the early post-intervention period (2010-2012, slope = 1037, P-value = 0.083).There was evidence suggesting for a significant intervention effect of the GRHAC program on identifying critically ill patients with AMI-associated diagnosis at the ED. As the program evaluation is still ongoing, we expect to observe a sustained program effect on hospitals' capacity for timely and correctly diagnosing and managing patients presenting with AMI associated symptoms or signs at the ED. PMID- 27759627 TI - Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials. AB - The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: "nonalcoholic steatohepatitis," "non-alcoholic steatohepatitis," "thiazolidinedione," "pioglitazone," "rosiglitazone," "randomized," and "clinical trial." Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the control patients, TZD treatment had no significant impact on body-mass index, percentage of body fat, or serum levels of cholesterol and triglyceride. Our findings indicate that additional variables should be assessed to obtain a more comprehensive evaluation of the effects of TZD treatment on IR and comorbidity risk factors in NASH patients, and suggest that including lifestyle changes and additional insulin-sensitizing agents in TZD regimens might improve the benefits of TZD therapy for NASH. PMID- 27759628 TI - Steroid-sparing effect and toxicity of dapsone treatment in giant cell arteritis: A single-center, retrospective study of 70 patients. AB - Although a glucocorticoid (GC)-sparing strategy is needed for patients with giant cell arteritis (GCA) suffering from refractory disease or serious treatment related complications, evidence of efficacy in this setting of immunosuppressive drugs and biotherapies is lacking. Herein, we evaluated the GC-sparing effects and tolerability of addition of dapsone (DDS) to prednisone therapy in patients with GCA. We retrospectively assessed data on 18 GCA patients who received DDS as a first-line treatment (DDS-1 group) and 52 patients who received it as a second- or third-line treatment for refractory GCA, with or without excessive GC-related toxicity (DDS-2 group). Of these 70 patients, 63 belonged to an inception cohort of 478 patients, whereas the remaining 7 were referred to our department for resistant GCA. In all, 52 patients were assessable for DDS efficacy. The baseline characteristics of the DDS-1 patients were similar to those of 395 GCA patients (control group) who received prednisone alone. DDS-1 patients had a more sustained decrease in GC dose with a lower mean prednisone dose at 12 months, and they comprised higher proportions who achieved GC withdrawal within the first year, who stopped prednisone treatment, and who recovered from GCA (P < 0.001 for each variable). Patients in the DDS-2 group achieved a mean rate of prednisone reduction of 65% and a prednisone dose reduction of 16.9 +/- 13.3 mg/d. The monthly decreases in the prednisone dose were 2.4 and 1.25 mg in DDS-1 and DDS-2 patients, respectively. DDS-induced side effects were recorded in 44 (64%) assessable patients. These side effects led to lowering of the DDS dose by 25 mg/d in 11 (16%) patients and permanent cessation of DDS in 14 patients (20%), due to allergic skin rash in 7, agranulocytosis in 2, icteric hepatitis in 2, and excessive hemolysis in 2 patients. DDS is a potent GC-sparing agent in GCA that should be evaluated in prospective studies. However, DDS use should be restricted to refractory GCA patients due to its toxicity, and close clinical and laboratory monitoring for 3 months is necessary. PMID- 27759629 TI - Potential role of carbon nanoparticles in protection of parathyroid glands in patients with papillary thyroid cancer. AB - As a novel type of lymphatic tracer, carbon nanoparticles (CNs) were reported not to stain parathyroid glands (PGs) into black, so it may have a clinical potential in protection of PGs during thyroidectomy. The purpose of this study was to investigate the clinical application and significance of CN in protection of PGs from surrounding tissues.A total of 82 consecutive patients were enrolled into this study and were divided into CN group and control group. Parathyroid function (hypoparathyroidism and hypocalcemia) was evaluated.The identification rates of PGs (<=2) and PGs (>=3) were 24.4% and 75.6% in the CN group and 46.3% and 53.7% in the control group, respectively. The difference in the identification rates between the 2 groups was statistically significant (P = 0.038). Pathological results revealed 3 accidental PGs resection occurred in the CN group, whereas 9 accidental PGs removal occurred in the control group. The difference was statistically significant (P = 0.046). Moreover, the incidence of the patients with hypoparathyroidism was statistically significant between the 2 groups (36.6% in CN group vs 53.7% in control group, P = 0.043) at day 1, but not at day 7 (P = 0.424).CN may have a potential in protecting PGs clinically. PMID- 27759630 TI - Risk of hospitalization for hypoglycemia among older Korean people with diabetes mellitus: Interactions between treatment modalities and comorbidities. AB - The objective of this study was to carry out a large population-based study to understand the factors associated with hypoglycemia-related hospitalizations among older Korean adults with diabetes mellitus.This study analyzed data from a subset of the 2013 Health Insurance and Review and Assessment service-Adult Patient Sample. A total of 307,170 subjects, comprising 41.7% men and 58.3% women, had diabetes mellitus. Hypertension (80.8%) was the most common comorbidity, and dyslipidemia (59.0%) and ischemic heart disease (21.3%) were also prevalent. Approximately half of the patients with diabetes had >2 comorbidities, and two-thirds of the patients had >3 comorbidities. The proportion of patients taking insulin or sulfonylureas was 54.9%, and 23.2% of the patients were taking other medications. About 21.9% of the patients were treated nonpharmacologically. A total of 2867 hypoglycemia-related admission occurred, the incident rate was 9.33 per 1000 person. The risk was higher among female patients and older patients with several comorbidities, including cardiovascular disease, cerebrovascular disease, chronic liver disease, chronic kidney disease, dementia, and malignancies. Treatment modalities, including insulin and sulfonylureas, were associated with a high risk of hypoglycemia. After adjustments for age, sex, the different comorbidities, and the treatment modalities, we determined that chronic kidney disease and dementia were associated with a high risk of hypoglycemia-related hospitalization (odds ratio [OR] = 2.52 and OR = 1.93, respectively). Furthermore, patients with chronic kidney disease or dementia who were treated with sulfonylureas and insulin had very high risks of hypoglycemia, and the incident rate was 66.6 and 63.75 per 1000 person, respectively.In conclusion, the presence of comorbidities, especially chronic kidney disease and dementia, increased the risk of hypoglycemia-associated hospitalization within this population of older patients with diabetes. The impact of the treatment modality, for example, insulin or sulfonylureas, on hypoglycemia was much greater among these patients. PMID- 27759631 TI - Does local lavage influence functional recovery during lumber discectomy of disc herniation?: One year's systematic follow-up of 410 patients. AB - Lumbar disc herniation (LDH) is a common disease and lumbar discectomy is the most common surgical procedure carried out for patients with low back pain and leg symptoms. Although most researchers are focusing on the surgical techniques during operation, the aim of this study is to evaluate the effect of local intervertebral lavage during microdiscectomy.In this retrospective study, 410 patients were operated on by microdiscectomy for LDH during 2011 to 2014. Retrospectively, 213 of them (group A) accepted local intervertebral irrigation with saline water before wound closure and 197 patients (group B) only had their operative field irrigated with saline water. Systematic records of visual analog scores (VAS), Oswestry disability Index (ODI) questionnaire scale scores, use of analgesia, and hospital length of stay were done after hospitalization.The majority (80.49%) of the cases were diagnosed with lumber herniation at the levels of L4/5 and L5/S1. Fifty-one patients had herniations at 2 levels. There were significant decreases of VAS scores and ODI in both groups between preoperation and postoperation of different time points. VAS scores decreased more in group A than group B at early stage of postoperation follow-up. However, there were no statistically significant differences between 2 groups in using analgesia, VAS and ODI up to 1 month of follow-up.Microdiscectomy for LDH offers a marked improvement in back and radicular pain. Local irrigation of herniated lumber disc area could relief dick herniation-derived low back pain and leg radicular pain at early stage of post-operation. However, the pain relief of this intervention was not noticeable for a long period. PMID- 27759632 TI - Preoperative evaluation of renal artery in patients with renal tumor: Using noncontrast-enhanced magnetic resonance angiography. AB - To investigate the feasibility of the noncontrast-enhanced magnetic resonance angiography (NCE-MRA) to evaluate renal arteries before partial nephrectomy (PN).Retrospective analyzed 479 patients who underwent renal surgery between January 2013 and December 2015 with NCE-MRA or computed tomographic angiography (CTA) renal artery image reconstruction preoperative in our department. The renal artery reconstruction score (RARS) was based on the level of artery visualization in a 4-class criterion, and the R.E.N.A.L nephrometry score (R.E.N.A.L), arterial based complexity (ABC) were also analyzed.Of the 479 patients, the overall-lever RARS was 3.62, and the average in 2 groups was no significant difference (NCE-MRA vs CTA, P = 0.072). The performance of NCE-MRA in PN group was similar with CTA. Further comparison demonstrated that the efficiency of NCE-MRA in moderate- or low-degree tumor according to the R.E.N.A.L and ABC complexity less than 3S was equal to CTA. However, high degree (P < 0.001), 3S (P = 0.027), or 3H (P < 0.001) would affect the imaging of renal artery. Intragroup analysis showed that tumor complexity such as max tumor size (r = -o.351, P < 0.001), R.E.N.A.L (r = -0.439, P < 0.001), and ABC (r = -0.619, P < 0.001) were closely correlated with the NCE MRA performance. The images of 2 sides of the kidney were compared in single person as well, which was meaningful for NCE-MRA patients only (NCE-MRA, P < 0.001; CTA, P = 0.182).The renal artery reconstruction performed by NCE-MRA is feasible and has a similar achievement in the PN potential recipients, with a lower side effect, and meets the requirements for making surgical decision. It has a broad application prospect in clinical practice; however, it still needs to further improve the ability in more complex tumors. PMID- 27759633 TI - Ultrasound-guided continuous femoral nerve block vs continuous fascia iliaca compartment block for hip replacement in the elderly: A randomized controlled clinical trial (CONSORT). AB - BACKGROUND: Continuous femoral nerve block and fascia iliaca compartment block are 2 traditional anesthesia methods in orthopedic surgeries, but it is controversial which method is better. The objective of this study was to compare the practicality, efficacy, and complications of the 2 modalities in hip replacement surgery in the elderly and to assess the utility of a novel cannula over-needle set. METHODS: In this prospective, randomized controlled clinical investigation, 60 elderly patients undergoing hip replacement were randomly assigned to receive either continuous femoral nerve block or continuous fascia iliaca compartment block. After ultrasound-guided nerve block, all patients received general anesthesia for surgery and postoperative analgesia through an indwelling cannula. Single-factor analysis of variance was used to compare the outcome variables between the 2 groups. RESULTS: There was a significant difference between the 2 groups in the mean visual analog scale scores (at rest) at 6 hours after surgery: 1.0 +/- 1.3 in the femoral nerve block group vs 0.5 +/- 0.8 in the fascia iliaca compartment block group (P < 0.05). The femoral nerve block group had better postoperative analgesia on the medial aspect of the thigh, whereas the fascia iliaca compartment block group had better analgesia on the lateral aspect of the thigh. There were no other significant differences between the groups. CONCLUSIONS: Both ultrasound-guided continuous femoral nerve block and fascia iliaca compartment block with the novel cannula-over-needle provide effective anesthesia and postoperative analgesia for elderly hip replacement patients. PMID- 27759634 TI - Delayed diagnosis with autoimmune polyglandular syndrome type 2 causing acute adrenal crisis: A case report. AB - BACKGROUND: Autoimmune polyglandular syndrome type 2 (APS-2), also known as Schmidt's syndrome, is an uncommon disorder characterized by the coexistence of Addison's disease with thyroid autoimmune disease and/or type 1 diabetes mellitus. Addison's disease as the obligatory component is potentially life threatening. Unfortunately, the delayed diagnosis of Addison's disease is common owing to its rarity and the nonspecific clinical manifestation. METHODS: Here we reported a case of 38-year-old female patient who presented with 2 years' history of Hashimoto's thyroiditis and received levothyroxine replacement. One year later, skin hyperpigmentation, fatigue, loss of appetite, and muscle soreness occurred. She was advised to increase the dose of levothyroxine, but the symptoms were not relieved. After 4 months, the patient accompanied with dizziness, nausea, nonbloody vomiting, and fever. However, she was diagnosed with acute gastroenteritis and fell into shock and ventricular fibrillation subsequently. Further evaluation in our hospital revealed elevated adrenocorticotrophic hormone and low morning serum cortisol, associated with hyponatremia and atrophic adrenal gland. Hypergonadotropic hypogonadism and Hashimoto's thyroiditis were also demonstrated. RESULTS: After the supplementation with hydrocortisone and fludrocortisone was initiated, the physical discomforts were alleviated and plasma electrolytes were back to normal. CONCLUSION: The uncommon case involving 3 endocrine organs reinforced the significance of a timely diagnosis and appropriate treatment of APS-2, and physicians needed to sharpen their awareness of the potentially life-threatening disease. PMID- 27759635 TI - Diffusion tensor imaging detects early brain microstructure changes before and after ventriculoperitoneal shunt in children with high intracranial pressure hydrocephalus. AB - To explore the use of diffusion tensor imaging (DTI) parameters in the quantitative assessment of early brain microstructure changes before and after ventriculoperitoneal shunt in children with high intracranial pressure hydrocephalus.Ten patients with communicating hydrocephalus (age: 2-36 months) and 14 age-/gender-matched controls (age: 2-36 months) were enrolled in this study. All patients underwent the ventriculoperitoneal shunt procedure. The imaging data were collected before and 3 months after the operation. Regions of interests (ROIs) included the white matter near the frontal horn of the lateral ventricles (FHLV), the occipital horn of the lateral ventricles (OHLV), occipital subcortical (OS) area, frontal subcortical (FS) area, and thalamus. Fractional anisotropies (FA) and apparent diffusion coefficients (ADC) of the ROIs before and after ventriculoperitoneal shunt were compared between the patients and the controls.Three months after surgery, the patients recovered from the surgery with ameliorated intracranial pressure and slight improvement of clinical intelligence scale and motor scale. Before ventriculoperitoneal shunt, the FA values (except the right FHLV) were significantly decreased and the ADC values were significantly increased in the patients with hydrocephalus, compared with the controls. After the ventriculoperitoneal shunt, the FA values in the FHLV and OHLV of the patients were similar to the controls, but the FA values in other ROIs were still significantly lower than controls. The ADC values in the FS and OS white matter areas of the patients were similar to the controls; however, the ADC values in other ROIs were still significantly higher in patients.The increase of FA and the reduction in ADC in the ROIs preceded the clinical function improvement in patients with high intracranial pressure hydrocephalus and reflected the early changes in brain tissue microstructure, such as the compression of the white matter areas in the ROIs. PMID- 27759636 TI - Concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis: Case report and review of the literature. AB - BACKGROUND: Herpesvirus infections often complicate the clinical course of patients with inflammatory bowel disease; however, invasive disease due to herpes simplex virus is distinctly uncommon. METHODS: We present a case of herpes simplex virus colitis and hepatitis, review all the previously published cases of herpes simplex virus colitis, and discuss common clinical features and outcomes. We also discuss the epidemiology, clinical manifestations, diagnosis, and management of herpes simplex virus infections, focusing specifically on patients with inflammatory bowel disease. RESULTS: A 43-year-old man with ulcerative colitis, previously controlled with an oral 5-aminosalicylic agent, developed symptoms of a colitis flare that did not respond to treatment with systemic corticosteroid therapy. One week later he developed orolabial ulcers and progressive hepatic dysfunction, with markedly elevated transaminases and coagulopathy. He underwent emergent total colectomy when imaging suggested bowel micro-perforation. Pathology from both the colon and liver was consistent with herpes simplex virus infection, and a viral culture of his orolabial lesions and a serum polymerase chain reaction assay also identified herpes simplex virus. He was treated with systemic antiviral therapy and made a complete recovery. CONCLUSIONS: Disseminated herpes simplex virus infection with concomitant involvement of the colon and liver has been reported only 3 times in the published literature, and to our knowledge this is the first such case in a patient with inflammatory bowel disease. The risk of invasive herpes simplex virus infections increases with some, but not all immunomodulatory therapies. Optimal management of herpes simplex virus in patients with inflammatory bowel disease includes targeted prophylactic therapy for patients with evidence of latent infection, and timely initiation of antiviral therapy for those patients suspected to have invasive disease. PMID- 27759637 TI - A retrospective clinical study of 98 adult idiopathic primary intraventricular hemorrhage cases. AB - The aim of the study is to define the clinical features, risk factors, treatment and prognosis of idiopathic primary intraventricular hemorrhage (IPIVH).We retrospectively collected the data of consecutively admitted patients who were diagnosed and treated for IPIVH in our hospital from January 2010 to December 2014. The clinical information, treatment, and prognosis at the 6-month follow-up were analyzed.Among the 3798 cases of spontaneous intracranial hemorrhage (ICH), 98 IPIVH (2.58%) patients were recruited for the study. The study population consisted of 60 males and 38 females, with an average age (+/- standard deviation, SD) of 51.20 +/- 15.48 years. The initial symptoms were headache (75 cases) and impaired consciousness (23 cases). The surgical treatments included hematoma evacuation under a microscope or an endoscope in 8 cases (8.16%), external ventricular drainage (EVD) in 11 cases (11.22%), lumbar drainage (LD) in 10 cases (10.20%), and a combination of EVD and LD in 11 cases (11.22%). In total, 4 patients died in the hospital (4.08%). At the 6-month follow-up, 73 patients (74.49%) had an improved outcome (modified Rankin scale [mRS] < 3), and 21 patients (21.43%) had a poor outcome (mRS >= 3 points) at the end of the 6 month follow-up.IPIVH is rare in clinical practice, and hypertension is the most common risk factor. Furthermore, the treatment of IPIVH is still controversial. Hematoma evacuation under a microscope or an endoscope, EVD, LD and a combination of EVD and LD could be surgical options for the treatment of IPIVH patients. The outcomes for IPIVH patients could be relatively favorable with individualized treatment. PMID- 27759638 TI - CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART. AB - Plasma HIV viral load is related to declining CD4 lymphocytes. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized so far. We examine if CD8 cell count is a prognostic factor for CD4 cell counts during an HIV infection.A longitudinal analysis is conducted using data from the Swiss HIV cohort study collected between January 2000 and October 2014. Linear mixed regression models were applied to observations from HIV-1-infected treatment naive patients (NAIVE) and cART-treated patients to predict the short-term evolution of CD4 cell counts. For each subgroup, it was quantified to which extent CD8 cell counts or CD4/CD8 ratios are prognostic factors for disease progression.In both subgroups, 2500 NAIVE and 8902 cART patients, past CD4 cells are positively (P < 0.0001) and past viral load is negatively (P < 0.0001) associated with the outcome. Including additionally past CD8 cell counts improves the fit significantly (P < 0.0001) and increases the marginal explained variation 31.7% to 40.7% for the NAIVE and from 44.1% to 50.7% for the cART group. The past CD4/CD8 ratio (instead of the past CD8 level) is positively associated with the outcome, increasing the explained variation further to 41.8% for NAIVE and 51.9% for cART. PMID- 27759639 TI - Double-balloon enteroscopy in small bowel diseases: Eight years single-center experience in China. AB - The aim of the study was to evaluate the diagnostic and therapeutic value of double-balloon entoroscopy (DBE) in small bowel diseases (SBDs) in China.A retrospective review of 674 consecutive patients who underwent DBE between January 2007 and November 2015 was conducted. Patients were divided into 3 groups by age, young group (<45 years), middle-aged group (45-65 years), and elderly group (>65 years). Data were collected with regard to demographics, clinical, endoscopic findings, complications, diagnostic yield, and management.A total of 729 DBE procedures were performed successfully in our series. More than 20 types of SBDs were found with the detection rate of 70.9%(517/729). The majority of patients were Crohn's disease (33.4%,225/674), followed by tumor (18.8%,127/674) and angioectasia (7.9%, 53/674). Endoscopic treatment was performed in 60 patients in which hemostasis (17,28.3%) and polypectomy (15,25%) were the predominant form of intervention used. Adverse events occurred in 6 patients (0.96%,6/729) including perforation, hemorrhage, aspiration pneumonia. No acute pancreatitis or other major complications occurred. Adenocarcinoma, GIST, and lymphoma were the most common tumor detected, the majority of tumors located in the jejunum (56.7%), The detection rate of angioectasia was also higher in the jejunum (54.7%),77.8% of Crohn's disease was located in the ileum. The positive rate of DBE in small bowel tumor and Crohn's disease were significantly higher than that of angioectasia (P<0.05). In young cohort, Crohn's disease (48.1%) was the most commonly diseases followed by tumor (10.4%) and nonspecific enteritis (7.1%). Yet in the elderly group, the majority of patients were tumor (27.6%); angioectasia (21.3%) was also detected frequently. The positive rate of capsule endoscopy was 75.44 %(202/268) which was a little high than DBE (67.9%, 182/268) (P > 0.05). The obscure gastrointestinal bleeding (OGIB) was the most common indication, and the diagnostic yield was 71.8%.DBE is a useful diagnostic and therapeutic tool with high clinical practice value for the investigation of SBDs. With growing experience of endoscopist, we believe that DBE must be kept in mind as the first-line modality for suspected SBDs. PMID- 27759640 TI - Combined inhaled corticosteroid and long-acting beta2-adrenergic agonist therapy for noncystic fibrosis bronchiectasis with airflow limitation: An observational study. AB - BACKGROUND AND OBJECTIVE: There is presently no clear evidence on the effect of combined treatment for non-cystic fibrosis (non-CF) bronchiectasis with inhaled corticosteroid (ICS) and long-acting beta2-adrenergic agonist (LABA). The objective of this study is to assess the efficacy and safety of salmeterol fluticasone combined inhaled therapy for non-CF bronchiectasis with airflow limitation. METHODS: An observational study was performed in 120 non-CF bronchiectasis patients diagnosed by high-resolution computed tomography (HRCT) scanning of the chest. Patients received either routine therapy or salmeterol fluticasone (100/500 MUg daily) combined inhaled therapy on the basis of routine therapy. Clinical symptoms, health-related quality of life (HRQL), lung function, short-acting beta2-adrenergic agonist (SABA) use, and safety were monitored throughout the study. RESULTS: OF the 120 subjects, 60 received combined inhaled therapy and 60 received routine therapy. Compared to the control group, the combined inhaled therapy group showed significant improvement in their clinical symptom scores (-2.21 vs. -0.31, P = 0.002) and a reduction in number of weekly SABA usage (-4.2 vs. 0.1, P < 0.01). In addition, patients in the inhaled therapy group achieved a significant improvement in HRQL based on mMRC (-1.51 vs. -0.31, P < 0.005) and SGRQ (-7.83 vs. -2.16, P < 0.01) scoring accompanied with no severe adverse events. There were fewer exacerbation frequencies in the combined inhaled therapy group over the 12 months of treatment compared to the control group (1 [0-2] vs. 2 [1-4], P = 0.017). Furthermore, stratified analysis indicated that combined inhaled therapy partially improve lung function for patients for whom it is severely impaired and those with pseudomonas aeruginosa isolated. CONCLUSION: Our results show that salmeterol-fluticasone combined inhaled therapy should be effective and safe for non-CF bronchiectasis patients especially for those patients with poor lung function or pseudomonas aeruginosa isolated. PMID- 27759641 TI - Ultrasound screening for neoplasms in children up to 6 years old. AB - The aim of the ultrasound (US) screening program was to detect neoplastic lesions in children, together with other pathologies of the developmental age in the area of the neck, abdomen, female pelvis, and scrotum in boys.US screening scans, including cervical, abdominal, pelvical, and scrotal US, were performed in the population of asymptomatic children aged from 9 months to 6 years. The children were scanned in Mobile Pediatric US Unit, consisting of 2 independent consulting rooms.The scans of 14,324 children were analyzed, 7247 boys and 7077 girls. Totally 42,538 US examinations were performed, including 14,187 cervical scans, 14,259 abdominal scans, 6942 female pelvical scans, and 7150 scrotal scans. Totally 5426 abnormalities were detected, which represent 12.7% of all examinations and 30% of patients. Three tumors were recognized, which are renal malignant tumor diagnosed as Wilms tumor, neurogenic tumor of the rib, and teratoma of the testis.US screening in pediatric population can be used to reveal lesions inaccessible to clinical examination, like tumors or other pathologies of developmental age before the onset of clinical symptoms. Due to the large number of detected abnormalities it should be recommended to the whole population of certain age. PMID- 27759642 TI - Sialodochitis fibrinosa (kussmaul disease) report of 3 cases and literature review. AB - BACKGROUND: Sialodochitis fibrinosa is a rare disease which is characterized by recurring episodes of pain and swelling of the salivary glands due to the formation of mucofibrinous plugs. Analytic studies ascertain elevated levels of eosinophils and immunoglobulin E (IgE). Imaging studies such as magnetic resonance imaging (MRI) and sialography reveal dilation of the main salivary duct (duct ectasia). Treatment is initially supportive, consisting of compressive massages, and use of antihistamines and/or corticosteroids. MATERIAL AND METHODS: In the following, 3 cases of sialodochitis fibrinosa are presented which were diagnosed in a third level hospital during the period of 2008 and 2016, as well as a literature review of all cases reported to our knowledge. RESULTS: Of the 41 cases found, including the 3 of this article, 66% were women with an average age of 45 years old. However, 75% of reported cases were of Japanese heritage. Involvement of the parotid glands was more frequent than the submandibular glands. In more than half of all cases treatment with compressive massages, antihistamines and/or corticosteroids was effective. CONCLUSION: Clinicians should consider sialodochitis fibrinosa as a diagnostic possibility when presented with cases of recurring parotid and submandibular gland tumescence. PMID- 27759643 TI - Epidemiological burden estimates for pathologies with a nonconstant risk: an application to HCV in Italy according to age, Metavir score, and genotype: A systematic review and meta-analysis. AB - Between western European countries, the hepatitis C virus (HCV) endemic is highest in Italy. The main objective of this paper is to estimate the endemic diffusion of hepatitis C at the national level and by geographical area, with an extrapolation at the regional level and by uniform cohorts of subjects (by sex and year of birth). The secondary objective is a stratification by gravity of the estimated statistical figures to provide an overview of possible targets of the new anti-HCV treatments.PubMed and the Cochrane Library were searched for relevant Italian populations studies regarding HCV prevalence. Random and fixed effect models were used for pooling data. To develop the epidemiological model, a meta-analysis of studies of Italian populations and the explicit consideration of the changes in the etiology of the disease in different cohorts (by year of birth) of population and the impact of effective treatments that have been introduced since the 1990s. A Markovian transition model, which is based on the distribution of HCV+ and HCV Ribonucleic Acid (RNA)+ subjects, provides a plausible assessment of the Italian situation. The Meta-analysis of Observational Studies in Epidemiology recommendations/statements were followed.In 2014, 1569,215 HCV+ subjects (95% credible interval [CrI]: 1202,630-2021,261) were estimated in Italy, with a 2.58% prevalence (95% CrI: 1.98%-3.33%). A total of 828,884 HCV RNA+ subjects (95% CrI: 615,892-1081,123), which is equal to a 1.36% prevalence (95% CrI: 1.01%-1.78%), is higher in southern Italy and the islands (1.9%) than in central-northern Italy (1.1%). The predominance of adult and elderly subjects, with an old or very old infection, inevitably entails a significant number of HCV RNA+ subjects in the advanced stages of the illness. According to our estimates, approximately 400,000 subjects have cirrhosis, decompensated cirrhosis, and hepatocarcinoma, with a median age of 70 years.The model aims to support policymakers to define action plans by providing an estimate of both the emerged infected population and nonemerged infected population by age, gender, gravity, genotype, and geographical area. In the future, the model may contribute to simulation of the costs and outcome of different action strategies that can be adopted by health authorities. PMID- 27759644 TI - The research on long-term clinical effects and patients' satisfaction of gabapentin combined with oxycontin in treatment of severe cancer pain. AB - Gabapentin has been used as an adjuvant for treatment of cancer pain. Previous studies showed that opioids combined with gabapentin for management of cancer pain reduced the dosage of opioids.The objective of this study was to explore the clinical effect and patients' satisfaction of oxycontin combined with gabapentin in treatment of severe cancer pain. After titration of morphine, 60 severe cancer patients with visual analog score (VAS) more than 7 were randomly divided into trial group (n = 30) and control group (n = 30). The control group was administered oxycontin and placebo, and the trial group was given oxycontin and gabapentin. VAS score was recorded pre- and post-treatment; while daily dose of oxycontin, daily cost of pain relief and life quality score were observed 1 week, 1 month, 2 months, 3 months, and 6 months post-treatment. We found that daily dose of oxycontin 1 month post was comparable between the 2 groups (P > 0.05). Three months post, compared with control group (58.0 +/- 15.2 mg), average daily dose of oxycontin was significant lower in trial group (33.4 +/- 11 mg) (P < 0.001). Average daily cost of pain relief in trail group (34.5 +/- 10.2 RMB) was less than the control group (52.4 +/- 13.7 RMB) (P < 0.001). Life quality score increased in all of the patients in both group post-treatment (P < 0.05); while life quality score in trail group was greater than in control group 3 months (46.8 +/- 4.5 vs 43.5 +/- 4.6, P = 0.007) and 6 months (46.5 +/- 4.8 vs 41.4 +/- 4.3, P < 0.001) post-treatment. The incidence of drowsiness and dizziness was comparable between the 2 groups (P > 0.05), while the incidence of nausea and vomiting (P = 0.038), and constipation (P < 0.001) was higher in the control group.We concluded that oxycontin combined with gabapentin used in severe cancer pain management can control pain effectively, decreased the dose of oxycontin and the cost of cancer pain relief, and reduced the incidence of nausea and vomiting, and constipation, increased the life quality. PMID- 27759645 TI - Factors associated with previously undiagnosed human immunodeficiency virus infection in a population of men who have sex with men and male-to-female transgender women in Lima, Peru. AB - The aim of the study was to identify factors associated with undiagnosed human immunodeficiency virus (HIV) infection among men who have sex with men (MSM) and male-to-female transgender women in Lima, Peru.We analyzed characteristics of 378 MSM and transgender women recruited from 2 sexually transmitted infection (STI) clinics in Lima, Peru. Descriptive analyses compared: (A) HIV-uninfected, (B) previously undiagnosed HIV-infected, and (C) previously diagnosed HIV-infected participants. Multivariable logistic regression models identified: (1) correlates of previously undiagnosed HIV-infection among participants thought to be HIV uninfected (B vs A); and (2) correlates of previously undiagnosed HIV-infection among HIV-infected participants (B vs C). Subanalysis identified correlates of frequent HIV testing among participants thought to be HIV-uninfected.Among participants, 31.0% were HIV-infected; of those, 35.0% were previously undiagnosed. Among participants thought to be HIV-uninfected (model 1), recent condomless receptive anal intercourse and last HIV test being over 1-year ago (compared to within the last 6-months) were associated with increased odds of being previously undiagnosed HIV-infected (adjusted odds ratio [aOR] = 2.43, 95% confidence interval [95%CI] = 1.10-5.36; aOR = 2.87, 95%CI = 1.10-7.53, respectively). Among HIV-infected participants (model 2), recent condomless receptive anal intercourse was again associated with previously undiagnosed HIV infection (aOR = 2.54, 95%CI = 1.04-6.23). Achieving post-secondary education and prior syphilis infection were associated with lower odds of having previously undiagnosed HIV-infection (aOR = 0.35, 95%CI = 0.15-0.81; aOR = 0.32, 95%CI = 0.14-0.75, respectively).Reporting semiannual testing was associated with higher educational attainment, identifying as a transgender woman, or reporting a history of syphilis (aOR = 1.94, 95%CI = 1.11-3.37; aOR = 2.40, 95%CI = 1.23 4.70; aOR = 2.76, 95%CI = 1.62-4.71, respectively). Lower odds of semiannual testing were associated with recent condomless insertive anal intercourse or reporting a moderate or high self-perceived risk of acquiring HIV (aOR = 0.56, 95%CI = 0.33-0.96; aOR = 0.32, 95%CI = 0.18-0.59 and aOR = 0.43, 95%CI = 0.21 0.86, respectively).In our study, undiagnosed HIV-infection was associated with recent condomless receptive anal intercourse, infrequent HIV testing, lower education, and absence of prior syphilis diagnosis. Infrequent HIV testing was associated with lower education, not identifying as transgender, recent condomless insertive anal intercourse, absence of prior syphilis diagnosis, and higher self-perceived risk of HIV. Further efforts to decrease HIV transmission and increase HIV-serostatus awareness should be directed towards effectively promoting condom use and frequent HIV testing, integrated with STI management. PMID- 27759646 TI - Congenital hepatic cyst with intracystic hemorrhage: Two rare cases reports in the Chinese Han population. AB - INTRODUCTION: Fast-growing congenital hepatic cysts with intracystic hemorrhage are rare in clinical practice. Additionally, the clinical manifestations of and laboratory and imaging findings for this condition are often nonspecific and are particularly difficult to differentiate from those of hepatobiliary cystadenoma and cystadenocarcinoma, thus posing great challenges for diagnosis and treatment. The 2 case reports presented here aim to analyze the diagnosis and treatment of 2 rare cases of congenital hepatic cysts with intracystic hemorrhage in the Chinese Han population to provide an important reference for the clinical diagnosis and treatment of this condition. DIAGNOSES: These 2 case reports present 2 rare cases of congenital hepatic cysts with intracystic hemorrhage. Case 1 involved a 31 year-old patient with a very large, fast-growing hepatic cyst with intracystic hemorrhage and elevated carbohydrate antigen 199. Case 2 involved a patient with intense, paroxysmal right upper abdominal pain; computed tomography suggested a hepatic cyst with intracystic hemorrhage and possibly hepatobiliary cystadenoma. OUTCOMES: Both patients underwent liver resection. Postoperative follow-up showed that for both patients, the symptoms improved, the laboratory findings returned to normal levels, and the surgical outcomes were satisfactory. CONCLUSION: Liver resection is an ideal treatment for patients with congenital hepatic cysts with intracystic hemorrhage, and especially those with fast-growing, symptomatic hepatic cysts or hepatic cysts that are difficult to differentiate from hepatobiliary cystadenoma and cystadenocarcinoma. PMID- 27759647 TI - Clinicopathological and prognostic significance of cancer stem cell markers CD44 and CD133 in patients with gastric cancer: A comprehensive meta-analysis with 4729 patients involved. AB - BACKGROUND: In recent years, CD44 and CD133 have been identified as 2 common used cancer stem cell (CSC) markers in gastric cancer. However, the clinicopathological and prognostic value of these markers in gastric cancer remains controversial; moreover, there is lack of comparison of these 2 markers' roles in clinical applications. A systematic review and meta-analysis was conducted to elucidate these markers' clinicopathological features and association with prognosis in patients with gastric cancer. METHODS: Eligible studies were identified and odds ratios (ORs), hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. Heterogeneity and sensitivity were analyzed as well. Publication bias was assessed using funnel plots and Egger tests. RESULTS: The meta-analysis included 26 studies involving 4729 patients. High expression of CD44 was associated with Lauren type (intestinal type) (OR, 1.53 [95% CI, 1.02-2.30]; P = 0.038) and lymphatic vessel invasion (OR, 1.36 [95% CI, 1.06-1.76]; P = 0.021). CD133 overexpression was related to high TNM stage (III/IV) (OR, 3.18 [95% CI, 2.48-4.07]; P = 0.000), high depth of invasion (T3/T4) (OR, 2.97 [95% CI, 2.20-4.03]; P = 0.000), lymph node metastasis (OR, 2.82 [95% CI, 2.16-3.69]; P = 0.000), vascular invasion (OR, 6.71 [95% CI, 1.63 27.63]; P = 0.008), and distant metastasis (OR, 2.32 [95% CI, 1.64-3.29]; P = 0.000). In addition, survival analysis demonstrated a significant association between CD44, as well as CD133 and poor 5-year overall survival (HR, 1.87 [95% CI, 1.55-2.26]; P = 0.000; HR, 2.07 [95% CI, 1.76-2.44]; P = 0.000, respectively). CONCLUSION: These data suggest that upregulated expression of CD44 and CD133 correlates with several clinicopathological features and poor prognosis. Since the related features do not overlap, combined detection of CD44 and CD133 expression can be an especially effective tool for pathological diagnosis and prognostic prediction of gastric cancer patients in clinical applications. PMID- 27759648 TI - Mechanism and early intervention research on ALI during emergence surgery of Stanford type-A AAD: Study protocol for a prospective, double-blind, clinical trial. AB - BACKGROUND: Stanford type-A acute aortic dissection (AAD) is a severe cardiovascular disease demonstrating the characteristics of acute onset and rapid development, with high morbidity and mortality. The available evidence shows that preoperative acute lung injury (ALI) induced by Stanford type-A AAD is a frequent and important cause for a number of untoward consequences. However, there is no study assessing the incidence of preoperative ALI and its independent determinants before Standford type-A AAD surgery in Chinese adult patients. METHODS/DESIGN: This is a prospective, double-blind, signal-center clinical trial. We will recruit 130 adult patients undergoing Stanford type-A AAD surgery. The incidence of preoperative ALI will be evaluated. Perioperative clinical baselines and serum variables including coagulation, fibrinolysis, inflammatory, reactive oxygen species, and endothelial cell function will be assayed. The independent factors affecting the occurrence of preoperative ALI will be identified by multiple logistic regression analysis. TRIAL REGISTRATION: ClinicalTrials.gov (https://register.clinicaltrials.gov/), Registration number NCT01894334. PMID- 27759649 TI - Erdheim-Chester disease (ECD): Case report, clinical and basic investigations, and review of literature. AB - BACKGROUND: Erdheim-Chester disease (ECD) is an uncommon aggressive, multisystem form of non-Langerhans' cell histocytosis, which was firstly reported by Jakob Erdheim and William chester in 1930. The disease pathological features encompass an aberrant multiplication, overproduction and accumulation of white blood cells called histiocytes within multiple tissues and organs. Herein, we present a case of ECD owing to the rarity of this disease (roughly 550 cases have been described in the literature to date). METHODS: We discussed the clinical course, diagnostic evaluations, and the possible treatments. Our case was encountered in an Arab male in his 30's who has suffered from an ongoing bones pain for years. RESULTS: At our rheumatologic department we compiled his recent medical history, which consisted of diagnosis of central diabetes insipidus, hyperprolactinemia and secondary hypogonadism along with the previously conducted laboratory evaluations and imaging which brought to our mind the possibility of an infiltrative disease such as ECD. The diagnosis of ECD was done based on the combinations of pathognomonic radiographic osteosclerosis, neuroimaging, bones biopsies along with a careful clinical evaluation. Given the protean clinical manifestations, interferon-alpha was considered as our first line treatment of ECD, consequently our patient improved noticeably. CONCLUSION: Clinical presentation, imaging studies, distinctive pathological findings, followed by bone biopsy showed a non Langerhans cell histiocytosis, supported by immunohistochemistry exams are essential for the diagnosis. Radiation therapy and Bisphosphonates in addition to cladribine, anakinra, infliximab and vemurafenib (BRAF Inhibitors) are currently advocated as promising second line treatment for patients whose response to interferon-alpha is unsatisfactory. PMID- 27759650 TI - A new CO2 laser technique for the treatment of pediatric hypertrophic burn scars: An observational study. AB - Treatment of hypertrophic scars arising as a result of thermal burns in children is still a big problem. The results of the treatment are not satisfactory for patients and parents, and new methods of treatment are still investigated.We present the use of one of the most modern carbon dioxide (CO2) lasers (Lumenis Encore laser equipped with a Synergistic Coagulation and Ablation for Advanced Resurfacing module) in the treatment of hypertrophic scars in children after burns.From March to April of 2013, a group of 47 patients aged 6 to 16 years underwent 57 laser surgery treatments. The average time from accident was 7.5 years. The results of treatment were investigated in 114 areas. The assessed areas were divided into 2 groups: 9-cm area 1, where the thickness of the scar measured by physician was the lowest and 9-cm area 2, where the thickness of the scar was the biggest. The results were considered on the Vancouver Scar Scale (VSS) independently by the surgeon and by parents 1, 4, and 8 months after the procedure. In addition, ultrasound evaluation of the scar thickness before and after laser procedure was made.VSS total score improved in all areas assessed by both the physician and parents. The biggest change in total VSS score in area 1 in the evaluation of the investigator was obtained at follow-up after the 1st month of treatment (average 7.23 points before and 5.18 points after the 1st month after surgery-a difference of 2.05 points). Scar ratings by parents and the physician did not differ statistically (P < 0.05). In the ultrasound assessment, the improvement was statistically significant, more frequently for both minimum and maximum thickness of the scars (B-mode measures) (P < 0.05).The use of a CO2 laser in the treatment of hypertrophic scars in children is an effective and safe method. The use of a CO2 laser improves the appearance and morphology of scarring assessed using the VSS by both the parents and the physician. The treatment also reduced the thickness of scars evaluated by ultrasound. PMID- 27759652 TI - Clinicopathological features of choledocholithiasis patients with high aminotransferase levels without cholangitis: Prospective comparative study. AB - Common bile duct (CBD) stones are generally associated with greater elevations of alkaline phosphatase and gamma-glutamyl transpeptidase levels than aspartate aminotransferase and alanine aminotransferase levels. However, some patients with CBD stones show markedly increased aminotransferase levels, sometimes leading to the misdiagnosis of liver disease. Therefore, the aim of this study was to investigate the clinicopathologic features of patients with CBD stones and high aminotransferase levels.This prospective cohort study included 882 patients diagnosed with CBD stones using endoscopic retrograde cholangiopancreatography (ERCP). Among these patients, 38 (4.3%) exhibited aminotransferase levels above 400 IU/L without cholangitis (gallstone hepatitis [GSH] group), and 116 (13.2%) exhibited normal aminotransferase levels (control group). We compared groups in terms of clinical features, laboratory test results, radiologic images, and ERCP findings such as CBD diameter, CBD stone diameter and number, and periampullary diverticulum. Liver biopsy was performed for patients in the GSH group.GSH patients were younger and more likely to have gallbladder stones than control patients, implying a higher incidence of gallbladder stone migration. Also, GSH patients experienced more severe, short-lasting abdominal pain. ERCP showed narrower CBDs in GSH patients than in control patients. Histological analysis of liver tissue from GSH patients showed no abnormalities except for mild inflammation.Compared with control patients, GSH patients were younger and showed more severe, short-lasting abdominal pain, which could be due to a sudden increase of CBD pressure resulting from the migration of gallstones through narrower CBDs. These clinical features could be helpful not only for the differential diagnosis of liver disease but also for investigating the underlying mechanisms of liver damage in obstructive jaundice. Moreover, we propose a new definition of "gallstone hepatitis" based on the specific clinicopathologic characteristics observed in our patients. PMID- 27759651 TI - MMP-2 gene polymorphisms are associated with type A aortic dissection and aortic diameters in patients. AB - Matrix metalloproteinases-2 (MMP-2) plays an important role in the pathogenesis of type A aortic dissection (AD). The aim of this study was to evaluate the association of 3 single nucleotide polymorphisms (SNPs) in the MMP-2 gene with type A AD risk and aortic diameters in patients. We performed a case-control study with 172 unrelated type A AD patients and 439 controls. Three SNPs rs11644561, rs11643630, and rs243865 were genotyped through the MassARRAY platform. Allelic associations of SNPs and SNP haplotypes with type A AD and aortic diameters in patients were evaluated. The frequency of the G allele of the rs11643630 polymorphism was significantly lower in type A AD patients than in control subjects (odds ratio 0.705, 95% confidence interval 0.545-0.912, P = 0.008). The association remained significant after adjusting for clinical covariates (P = 0.008). Carriers of the GG genotype of the rs11643630 polymorphism had significantly smaller aortic diameters than those with GT genotype or TT genotype (P = 0.02). Further haplotype analysis identified 1 protective haplotype (GC; P = 0.008) for development of type A AD. Again, a significant correlation was observed between haplotype GC and AD size (P = 0.020). Our results suggest that MMP-2 gene polymorphisms contribute to type A AD susceptibility. In addition, MMP-2 gene SNPs are associated with AD size, which could be used as a target for the development of new drug therapy. PMID- 27759653 TI - Dislodgement and gastrointestinal tract penetration of bone cement used for spinal reconstruction after lumbosacral vertebral tumor excision: A case report. AB - INTRODUCTION: Polymethylmethacrylate (PMMA) cement is useful for spinal reconstruction, but can cause complications including new vertebral fractures, neurological disorders and pulmonary embolism. We report a case in PMMA cement used for spinal reconstruction after tumor curettage dislodged and penetrated the gastrointestinal tract. DIAGNOSES: The patient was diagnosed with a retroperitoneal extragonadal germ cell tumor at age 27 years. After chemotherapy and tumor resection, the tumor remained. It gradually increased in size and infiltrated lumbosacral vertebrae, causing him to present at age 35 years with increased low back pain. Image findings showed bone destruction in the vertebral bodies accompanied by neoplastic lesions. The left and right common iliac arteries and inferior vena cava were enclosed in the tumor on the anterior side of the vertebral bodies. Lumbosacral bone tumor due to direct extragonadal germ cell tumor infiltration was diagnosed. A 2-step operation was planned; first, fixation of the posterior side of the vertebral bodies, followed by tumor resection using an anterior transperitoneal approach, and spinal reconstruction using PMMA cement. After surgery, the PMMA cement gradually dislodged towards the anterior side and, 2 years 9 months after surgery, it had penetrated the retroperitoneum. The patient subsequently developed nausea and abdominal pain and was readmitted to hospital. The diagnosis was intestinal blockage with dislodged PMMA cement, and an operation was performed to remove the cement present in the small intestine. There was strong intra-abdominal adhesion, the peritoneum between the vertebral bodies and intestine could not be identified, and no additional treatment for vertebral body defects could be performed. After surgery, gastrointestinal symptoms resolved. CONCLUSION: Although this was a rare case, when using bone cement for vertebral body reconstruction, the way of anchoring for the cement must be thoroughly planned to assure no cement dislodgement can occur. PMID- 27759654 TI - Impact of grafting using thin upper pole artery ligation on living-donor adult kidney transplantation: The STROBE study. AB - This study aimed to investigate the impact of grafting using thin upper pole artery ligation for living-donor adult kidney transplantation. Few reports have examined the safety of thin upper pole artery ligation.Between January 2008 and May 2015, 613 consecutive living-donor adult kidney transplantations were performed. We excluded 21 recipients who experienced graft loss due to factors that were unrelated to surgical complications and 3 recipients with grafts treated with arterial reconstruction and thin upper pole artery ligation for 3 arteries. We included 439 kidney grafts with single arteries (Single Artery Group), 123 with reconstructed arteries (Arterial Reconstruction Group) and 27 with ligated thin upper pole arteries (Arterial Ligation Group) in this retrospective cohort study. To evaluate the safety of thin upper pole artery ligation, we compared the Arterial Ligation Group with the Single Artery and Arterial Reconstruction groups. We evaluated the characteristics of the enrolled donors, recipients, and their grafts. Thereafter, we investigated recipients' perioperative and postoperative estimated glomerular filtration rate (eGFR) and complication rates.Significant differences among the 3 groups were identified for donor sex and endoscopic nephrectomy rates. Recipient eGFR and the complication rates were adjusted according to these factors. The perioperative and postoperative eGFR of recipients did not differ significantly in the Arterial Reconstruction and Single Artery groups with low complication rates.Thin upper pole artery ligation is a safe procedure for living-donor adult kidney transplantation and may prevent unnecessary arterial reconstruction and associated complications. PMID- 27759655 TI - Alternation of regional homogeneity in trigeminal neuralgia after percutaneous radiofrequency thermocoagulation: A resting state fMRI study. AB - We used resting-state fMRI to investigate regional homogeneity (ReHo) changes in patients with TN before and after PRT procedure, and to speculate about its possible mechanisms.Thirty-one TN patients underwent the PRT procedure had MRI scans just before and 6 months after surgery. The anatomical and resting-state functional images were all acquired. Patients' visual analog scales (VAS) scores, facial numbness, and disease duration were also recorded. Voxel-wise ReHo analysis was performed to detect the altered regional clusters after surgery. The correlations between the mean ReHo values of each significant cluster and clinical variables were examined.Compared with presurgical condition, patients after the PRT procedure showed a significant ReHo value increases in the right fusiform gyrus (FG) and bilateral anterior cingulate cortex (ACC), but decreases in the left inferior parietal lobule (IPL), right calcarine, right middle temporal gyrus (MTG), left postcentral gyrus (PoCG), and left insula. We demonstrated a positive correlation between ReHo in the left PoCG and VAS scores, a negative correlation between pre-surgical ReHo in the right MTG and VAS changes (DeltaVAS).Alterations of ReHo post-surgical were found in several regions, which are related to sensory, affective, and emotional processes. The MTG may be a specific area that is associated with analgesic efficiency of PRT procedure. PMID- 27759656 TI - Umbilical cord and visceral hemangiomas diagnosed in the neonatal period: A case report and a review of the literature. AB - BACKGROUND: Umbilical cord hemangioma is very rare and may not be detected prenatally. However, it should be considered in differential diagnosis with other umbilical masses because it can cause significant morbidity. METHODS: We report the case of a newborn referred with suspected omphalitis and umbilical hernia. RESULTS: Physical examination showed an irreducible umbilical tumor, the size of olive, with dubious secretion. The initial suspected diagnosis was urachal or omphalomesenteric duct remnants. Abdominal ultrasound and magnetic resonance imaging showed an umbilical and a mesenteric mass. Tumor markers were negative. A definitive diagnosis of umbilical cord and intestinal hemangioma was established after surgical excision and histologic examination of the umbilical mass. Propranolol was prescribed due to the extent of the intestinal lesion. CONCLUSION: This report highlights the diagnostic challenges of hemangiomas in unusual locations. Apart from the rarity of these tumors, few tests are available to guide diagnosis, and surgery and histologic examination are generally required for a definitive diagnosis. Finally, it is essential to rule out associated malformations and hemangiomas in other locations. PMID- 27759657 TI - Clinical presentation and treatment outcome of retinoblastoma in children of South Western China. AB - To study the clinical presentation and treatment outcome among children in South Western China with retinoblastoma (RB) and to determine factors predictive of poor outcome.A retrospective review of children diagnosed with RB from 2006 to 2015 at West China Hospital was undertaken. Demographic and clinical characteristics and treatment outcomes were studied.A total of 253 patients (unilateral 80.2%, bilateral 19.8%) were studied. Twenty six patients (10.3%) were from minority ethnic groups of China. The median onset age was 21 months. Leukocoria was the most common presenting sign (71%). Tumors were intraocular in 91.3% cases, extraocular in 8.7% cases. Extraocular RB patients had a longer median lag period than intraocular patients (9 months vs 2 months, P < 0.0001). In the intraocular group, 89.5% were advanced group D or E diseases. Enucleation was the major treatment for intraocular RB. However, over 10 years, the enucleation rate decreased constantly while more patients received chemotherapy. The Kaplan-Meier survival probability was 87.8%, 81.4%, and 74.8% at 3 years, 5 years, and 10 years, respectively. On Cox regression analysis, extraocular RB (P = 0.0008) and treatment abandonment (P < 0.0001) were associated with poor outcome; bilateral RB (P = 0.0116) and advanced pathological grade pT4 (P = 0.0011) were associated with poor outcome of intraocular RB.Most RB patients from South Western China were diagnosed at advanced clinical stage. Delayed presentation is related to extraocular RB which is a risk factor for poor outcome. Chemotherapy increased the eye salvage but had no effects to overall survival. Education for parents and general physicians for the early signs of RB (such as leukocoria), therapeutic strategy and treatment outcomes of RB may promote early diagnosis, improve the compliance, and outcome. PMID- 27759658 TI - Genome-wide identification of expression quantitative trait loci for human telomerase. AB - A genome-wide association study was conducted to identify expression quantitative trait loci (eQTL) for human telomerase.We tested the genetic associations of nucleotide variants with expression of the genes encoding human telomerase reverse transcriptase (hTERT) and telomerase RNA components (TERC) in lymphoblastoid cell lines derived from 373 Europeans.Our results revealed 6 eQTLs associated with hTERT (P < 5 * 10). One eQTL (rs17755753) was located in the intron 1 of the gene encoding R-spondin-3 (RSPO3), a well-known Wnt signaling regulator. Transcriptome-wide association analysis for these eQTLs revealed their additional associations with the expression of 29 genes (P < 4.75 * 10), including prickle planar cell polarity protein 2 (PRICKLE2) gene important for the Wnt signaling pathway. This concurs with previous studies in which significant expressional relationships between hTERT and some genes (beta-catenin and Wnt-3a) in the Wnt signaling pathway have been observed.This study suggested 6 novel eQTLs for hTERT and the association of hTERT with the Wnt signaling pathway. Further studies are needed to understand their underlying mechanisms to improve our understanding of the role of hTERT in cancer. PMID- 27759659 TI - Mortality in Children With Severe Head Trauma: Predictive Factors and Proposal for a New Predictive Scale. AB - BACKGROUND: Traumatic brain injury is a public health problem around the world, and recognition of systemic sources of secondary brain lesions is crucial to improve outcome. OBJECTIVE: To identify the main predictors of mortality and to propose a grading scale to measure the risk of death. METHODS: This retrospective study was based on medical records of children with severe traumatic brain injury who were hospitalized at a level I pediatric trauma center between January 2000 and December 2005. Multiple logistic regression analysis was done to identify independent factors related to mortality. A receiver-operating characteristics curve was performed to verify the accuracy of the multiple logistic regression, and associations that increased mortality were verified. RESULTS: We identified 315 children with severe head injury. Median Glasgow Coma Scale score was 6, and median Pediatric Trauma Score was 4. Global mortality rate was 30%, and deaths occurred despite adequate medical management within the first 48 hours in 79% of the patients. Age < 2 years (P = .02), Glasgow Coma Scale <= 5 (P < 10), accidental hypothermia (P = .0002), hyperglycemia (P = .0003), and coagulation disorders (P = .02) were all independent factors predicting mortality. A prognostic scale ranging from 0 to 6 that included these independent factors was then calculated for each patient and resulted in mortality rates ranging from 1% with a score of 6 to 100% with a score of 0. CONCLUSION: Independent and modifiable mortality predictors could be identified and used for a new grading scale correlated with the risk of mortality in pediatric traumatic brain injury. PMID- 27759660 TI - The Potential Value of the Disappearance of the Lateral Spread Response During Microvascular Decompression for Predicting the Clinical Outcome of Hemifacial Spasms: A Prospective Study. AB - BACKGROUND: Hemifacial spasm (HFS) is a benign, chronic, involuntary movement of the muscles involved in facial expressions that typically begins in the orbicularis oculi and spreads to the other expression muscles over several years. OBJECTIVE: To clarify the effectiveness of intraoperative electromyogram during microvascular decompression (MVD) for HFS. METHODS: Two hundred ninety-nine consecutive patients with HFS underwent continuous intraoperative monitoring during MVD. The patients were divided into 2 groups based on whether the lateral spread response (LSR) disappeared before or after decompression RESULTS:: In 276 of 299 patients (92.3%), the LSR was observed during intraoperative facial electromyogram monitoring. The mean follow-up period was 17.9 months (range, 12 27 months). Three patients in whom the LSR persisted despite decompression were not included in this study. In 183 of the 273 patients (67%), the LSR disappeared after decompression (group A); in the remaining 90 (33%), the LSR disappeared at dural opening or after drainage of the cerebrospinal fluid before decompression (group B). At the postoperative 3-month and 2-year follow-up visits, there were significant differences in the clinical outcomes between the 2 groups (P < .05). CONCLUSION: The disappearance of the LSR before and after MVD may predict clinical outcomes. This must be considered together with the disappearance or persistence of LSR after decompression as a prognostic factor for HFS after MVD. PMID- 27759661 TI - Three-Dimensional Morphometry of the A1 Segment of the Anterior Cerebral Artery With Neurosurgical Relevance. AB - BACKGROUND: Despite research in the anatomical sciences for the last 200 years, some structures of the human body remain controversial or incompletely described. One of these structures is the A1 segment of the anterior cerebral artery (ACA). OBJECTIVE: To analyze the A1 segment of the ACA using novel stereoscopic methods because the 3-dimensional morphometry of the ACA is important to neurosurgeons. METHODS: A digital-image computer-based system was used to analyze the A1 segment of 230 ACAs derived from computed tomography. Data analysis included the inner diameter, length, and volume and calculation of A1 symmetry, hypoplasia, and deviation, and tortuosity indexes. RESULTS: Hypoplasia of the A1 segment was found in 0.87% and only on the right sides, whereas asymmetry was found in 42.6% and was more common in female patients. Right A1 segments tended to be longer in male patients, and this reached significance. Also of significance was the correlation of an increased length with age. Right A1 segments tended to have greater volumes, and this was significant in a comparison of male and female patients. Tortuosity indexes tended to be greater for left sides, but deviation indexes tended to be greater on the right sides. CONCLUSION: Morphometric data of the A1 segment of the ACA as analyzed in the present study may be of utility to the neurosurgeon. Right A1 segments tend to be more tortuous, more deviated, longer, and narrower than left A1 segments. PMID- 27759662 TI - In Reply. PMID- 27759663 TI - In Reply. PMID- 27759665 TI - ERRATA. PMID- 27759664 TI - In Reply. PMID- 27759666 TI - ERRATA. PMID- 27759671 TI - Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for the Management of Patients With Positional Plagiocephaly: Executive Summary. AB - BACKGROUND: Positional plagiocephaly is a common problem seen by pediatricians, pediatric neurologists, and pediatric neurosurgeons. OBJECTIVE: To create evidence-based guidelines for the treatment of pediatric positional plagiocephaly. METHODS: This guideline was prepared by the Plagiocephaly Guideline Task Force, a multidisciplinary team made up of physician volunteers (clinical experts), medical librarians, and clinical guidelines specialists. The task force conducted a series of systematic literature searches of PubMed and the Cochrane Library, according to standard protocols for each topic addressed in subsequent chapters of this guideline. RESULTS: The systematic literature searches returned 396 abstracts relative to the 4 main topics addressed in this guideline. The results were analyzed and are described in detail in each subsequent chapter included in this guideline. CONCLUSION: Evidence-based guidelines for the management of infants with positional plagiocephaly will help practitioners manage this common disorder. The full guidelines documents can be located at https://www.cns.org/guidelines/guidelines-management-patients positional-plagiocephaly. PMID- 27759672 TI - Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence Based Guideline for the Diagnosis of Patients With Positional Plagiocephaly: The Role of Imaging. AB - BACKGROUND: No evidence-based guidelines exist for the imaging of patients with positional plagiocephaly. OBJECTIVE: The objective of this systematic review and evidence-based guideline is to answer the question, Is imaging necessary for infants with positional plagiocephaly to make a diagnosis? METHODS: The National Library of Medicine Medline database and the Cochrane Library were queried with the use of MeSH headings and key words relevant to imaging as a means to diagnose plagiocephaly. Abstracts were reviewed, and an evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III). Based on the quality of the literature, a recommendation was rendered (Level I, II, or III). RESULTS: A total of 42 full-text articles were selected for review. Of these, 10 were eliminated; thus, 32 full-text were manuscripts selected. There was no Class I evidence, but 2 Class II and 30 Class III studies were included. Three dimensional cranial topographical imaging, ultrasound, skull x-rays, computed tomography, and magnetic resonance imaging were investigated. CONCLUSION: Clinical examination is most often sufficient to diagnose plagiocephaly (quality, Class III; strength, Level III). Within the limits of this systematic review, the evidence suggests that imaging is rarely necessary and should be reserved for cases in which the clinical examination is equivocal. Many of the imaging studies were not designed to address the diagnostic utility of the imaging modality, and authors were actually assessing the utility of the imaging in longitudinal follow up, not initial diagnosis. For this reason, some of the studies reviewed were downgraded in Level of Evidence. When needed, 3-dimensional cranial topographical photo, skull x-rays, or ultrasound imaging is almost always sufficient for definitive diagnosis. Computed tomography scanning should not be used to diagnose plagiocephaly, but it may be necessary to rule out craniosynostosis. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines management-patients-positional-plagiocephaly/Chapter_2. PMID- 27759673 TI - Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence Based Guideline on the Management of Patients With Positional Plagiocephaly: The Role of Repositioning. AB - BACKGROUND: Plagiocephaly, involving positional deformity of the calvarium in infants, is one of the most common reasons for pediatric neurosurgical consultation. OBJECTIVE: To answer the question: "what is the evidence for the effectiveness of repositioning for positional plagiocephaly?" Treatment recommendations are provided based on the available evidence. METHODS: The National Library of Medicine MEDLINE database and the Cochrane Library were queried using MeSH headings and key words relevant to repositioning as a means to treat plagiocephaly and brachycephaly. Abstracts were reviewed to identify which studies met the inclusion criteria. An evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III). Based on the quality of the literature, a recommendation was rendered (Level I, II, or III). RESULTS: There were 3 randomized trials (Class I), 1 prospective cohort study (Class II), and 6 retrospective cohort studies (Class III). Repositioning education was found to be equal to a repositioning device and inferior to a physical therapy program. Five of the 7 cohort studies comparing repositioning with a helmet reported helmets to be better and take less time. CONCLUSION: Within the limits of this systematic review, repositioning education is effective in affording some degree of correction in virtually all infants with positional plagiocephaly or brachycephaly. Most studies suggest that a molding helmet corrects asymmetry more rapidly and to a greater degree than repositioning education. In a Class I study, repositioning education was as effective as repositioning education in conjunction with a repositioning wrap/device. Another Class I study demonstrated that a bedding pillow was superior to physical therapy for some infants. However, in keeping with the American Academy of Pediatrics' warning against the use of soft positioning pillows in the sleeping environment, the Task Force recommends physical therapy over any positioning device. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines management-patients-positional-plagiocephaly/Chapter_3. PMID- 27759674 TI - Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence Based Guideline for the Management of Patients With Positional Plagiocephaly: The Role of Physical Therapy. AB - BACKGROUND: Evidence-based guidelines are not currently available for the treatment of positional plagiocephaly and, in particular, for the use of physical therapy for treatment. OBJECTIVE: To answer the question: "does physical therapy provide effective treatment for positional plagiocephaly?" Treatment recommendations are created based on the available evidence. METHODS: The PubMed and the Cochrane Library were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and recommendations were made based on the quality of the literature (Levels I-III). RESULTS: Three studies met criteria for inclusion. Two randomized, controlled trials (Class I and Class II) and 1 prospective study assessing plagiocephaly as a secondary outcome measure (Class III) were included. CONCLUSION: Within the limits of this systematic review, physical therapy is significantly more effective than repositioning education as a treatment for positional plagiocephaly. There is no significant difference between physical therapy and a positioning pillow as a treatment for positional plagiocephaly. However, given the American Academy of Pediatrics' recommendation against soft pillows in cribs to ensure a safe sleeping environment for infants, physical therapy must be recommended over the use of a positioning pillow. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional plagiocephaly/Chapter_4. PMID- 27759675 TI - Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence Based Guideline on the Role of Cranial Molding Orthosis (Helmet) Therapy for Patients With Positional Plagiocephaly. AB - BACKGROUND: No evidence-based guidelines exist on the role of cranial-molding orthosis (helmet) therapy for patients with positional plagiocephaly. OBJECTIVE: To address the clinical question: "Does helmet therapy provide effective treatment for positional plagiocephaly?" and to make treatment recommendations based on the available evidence. METHODS: The US National Library of Medicine Medline database and the Cochrane Library were queried by using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and, based on the quality of the literature, recommendations were made (Levels I-III). RESULTS: Fifteen articles met criteria for inclusion into the evidence tables. There was 1 prospective randomized controlled trial (Class II), 5 prospective comparative studies (Class II), and 9 retrospective comparative studies (Class II). CONCLUSION: There is a fairly substantive body of nonrandomized evidence that demonstrates more significant and faster improvement of cranial shape in infants with positional plagiocephaly treated with a helmet in comparison with conservative therapy, especially if the deformity is severe, provided that helmet therapy is applied during the appropriate period of infancy. Specific criteria regarding the measurement and quantification of deformity and the most appropriate time window in infancy for treatment of positional plagiocephaly with a helmet remains elusive. In general, infants with a more severe presenting deformity and infants who are helmeted early in infancy tend to have more significant correction (and even normalization) of head shape. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines management-patients-positional-plagiocephaly/Chapter_5. PMID- 27759676 TI - Worse Outcomes After Repeat vs Initial Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations: A Retrospective Matched-Cohort Study. AB - BACKGROUND: Incompletely obliterated cerebral arteriovenous malformations (AVMs) after initial treatment with stereotactic radiosurgery (SRS) can be treated with a repeat session of SRS. However, the relative efficacy of repeat vs initial SRS is not well specified. OBJECTIVE: To retrospectively compare in matched cohorts the outcomes of repeat vs initial SRS for the treatment of matched cohorts with angioarchitecturally similar AVMs. METHODS: We studied a data set of patients with AVM treated with radiosurgery during the period spanning 1989 to 2013. Patients with AVM who underwent repeat SRS with radiologic follow-up of >=2 years or nidus obliteration were identified for the study and matched, in a 1:1 fashion that was blinded to outcome, to patients with previously untreated AVMs who underwent initial SRS. Statistical analyses were performed to compare the outcomes after repeat vs initial SRS. RESULTS: The matching approach resulted in 84 patients for the repeat and the initial SRS cohort (mean margin doses, 20.7 and 20.9 Gy, respectively; P = .74). In the repeat SRS cohort, obliteration was achieved in 67%; the radiologic, symptomatic, and permanent radiation-induced change rates were 35%, 10%, and 4%, respectively; and the post-SRS hemorrhage rate was 3.1%/y. Compared with the initial SRS cohort, the repeat SRS cohort had significantly lower obliteration rates (P = .04) and higher post-SRS hemorrhage rates (P = .04). The radiation-induced change rates of the 2 cohorts were not significantly different. CONCLUSION: Repeat SRS yields considerably poorer outcomes than initial SRS for angioarchitecturally comparable AVMs. Further studies in AVM radiobiology and vascular structure are necessary to elucidate this potentially differential response. ABBREVIATIONS: AVM, arteriovenous malformationRIC, radiation-induced changeRBAS, radiosurgery-based arteriovenous malformation scoreSRS, stereotactic radiosurgeryVRAS, virginia radiosurgery AVM scale. PMID- 27759677 TI - Effect of Surgery on Gait and Sensory Motor Performance in Patients With Cervical Spondylotic Myelopathy. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM) is a common disease of aging that leads to gait instability resulting from loss of leg sensory and motor functions. The results of surgical intervention have been studied using a variety of methods, but no test has been reported that objectively measures integrative leg motor sensory functions in CSM patients. OBJECTIVE: To determine the feasibility of using a novel single leg squat (SLS) test to measure integrative motor sensory functions in patients with CSM before and after surgery. METHODS: Fifteen patients with CSM were enrolled in this prospective study. Clinical data and scores from standard outcomes questionnaires were obtained before and after surgery. Patients also participated in experimental test protocols consisting of standard kinematic gait testing, the Purdue pegboard test, and the novel SLS test. RESULTS: The SLS test protocol was well tolerated by CSM patients and generated objective performance data over short test periods. In patients who participated in postoperative testing, the group measures of mean SLS errors decreased following surgery. Gait velocity measures followed a similar pattern of group improvement postoperatively. Practical barriers to implementing this extensive battery of tests resulted in subject attrition over time. Compared with kinematic gait testing, the SLS protocol required less space and could be effectively implemented more efficiently. CONCLUSIONS: The SLS test provides a practical means of obtaining objective measures of leg motor sensory functions in patients with CSM. Additional testing with a larger cohort of patients is required to use SLS data to rigorously examine group treatment effects. ABBREVIATIONS: BW, body weightCSM, cervical spondylotic myelopathymJOA, modified Japanese Orthopedic AssociationSLS, single leg squat. PMID- 27759678 TI - Failure of Mean Arterial Pressure Goals to Improve Outcomes Following Penetrating Spinal Cord Injury. AB - BACKGROUND: Increased spinal cord perfusion and blood pressure goals have been recommended for spinal cord injury (SCI). Penetrating SCI is associated with poor prognosis, but there is a paucity of literature examining the role of vasopressor administration for the maintenance of mean arterial pressure (MAP) goals in this patient population. OBJECTIVE: To elucidate this topic and to determine the efficacy of vasopressor administration in penetrating SCI by examining a case series of consecutive penetrating SCIs. METHODS: We reviewed consecutive patients with complete penetrating SCI who met inclusion and exclusion criteria, including the administration of vasopressors to maintain MAP goals. We identified 14 patients with complete penetrating SCIs with an admission American Spinal Injury Association grade of A from 2005 to 2011. The neurological recovery, complications, interventions, and vasopressor administration strategies were reviewed and compared with those of a cohort with complete blunt SCI. RESULTS: In our patient population, only 1 patient with penetrating SCI (7.1%) experienced neurological recovery, as determined by improvement in the American Spinal Injury Association grade, despite the administration of vasopressors for supraphysiological MAP goals for an average of 101.07 +/- 34.96 hours. Furthermore, 71.43% of patients with penetrating SCI treated with vasopressors experienced associated cardiogenic complications. CONCLUSION: Given the decreased likelihood of neurological improvement in penetrating injuries, it may be important to re-examine intervention strategies in this population. Specifically, the use of vasopressors, in particular dopamine, with their associated complications is more likely to cause complications than to result in neurological improvement. Our experience shows that patients with acute penetrating SCI are unlikely to recover, despite aggressive cardiopulmonary management. ABBREVIATIONS: ASIA, American Spinal Injury AssociationMAP, mean arterial pressureSCI, spinal cord injury. PMID- 27759679 TI - A Novel Experimental Animal Model of Adult Chronic Hydrocephalus. AB - BACKGROUND: The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown. OBJECTIVE: To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus. METHODS: Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed. RESULTS: Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement. CONCLUSION: Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus. ABBREVIATION: NPH, normal pressure hydrocephalus. PMID- 27759680 TI - Rerupture of a Blister Aneurysm After Treatment With a Single Flow-Diverting Stent. AB - BACKGROUND AND IMPORTANCE: As the use of flow-diverting stents (FDSs) for intracranial aneurysms expands, a small number of case reports have described the successful treatment of blister aneurysms of the internal carotid artery with flow diversion. Blister aneurysms are uncommon and fragile lesions that historically have high rates of morbidity and mortality despite multiple treatment strategies. We report a case of rebleeding after treatment of a ruptured blister aneurysm with deployment of a single FDS. CLINICAL PRESENTATION: A 29-year-old man presented with subarachnoid hemorrhage and a ruptured dorsal variant internal carotid artery aneurysm. Despite a technically successful treatment with a single FDS, a second catastrophic hemorrhage occurred during the course of his hospitalization. CONCLUSION: This case highlights the risk of hemorrhage during the period after deployment of a single FDS. Ruptured aneurysms, especially of the blister type, are at risk for rehemorrhage while the occlusion remains incomplete after flow diversion. ABBREVIATIONS: FDS, flow diverting stentICA, internal carotid arterySAH, subarachnoid hemorrhage. PMID- 27759681 TI - Beyond the Cyst: The Many Contributions of Isadore Tarlov (1905-1977) to Contemporary Neurosurgical Practice. AB - : Isadore Max Tarlov (1905-1977) is primarily remembered for his 1938 description of the eponymous perineural "Tarlov cyst." However, during his long career as a neurosurgeon and researcher, he was responsible for many other observations and inventions that influenced the development of neurosurgery in the 20th century. While studying at Johns Hopkins Medical School he was acquainted with Walter Dandy, and he became the first resident to study under Wilder Penfield at the newly formed Montreal Neurological Institute. He made many novel observations about peripheral and cranial nerve anatomy, pioneered nerve anastomosis and grafting techniques, and introduced the concept of fibrin glue. He developed an animal model of spinal cord injury and used it to establish for the first time that functional neurological reserve is proportional to rapidity of injury, because gradual onset of compression is better tolerated by neural tissue than acute compression. He was the first to describe the use of the knee-chest position for lumbar spine surgery to minimize increases in epidural venous pressure due to abdominal compression. Finally, near the end of his career, he published a collection of thoughtful, philosophical essays entitled The Principle of Parsimony in Medicine and Other Essays, in which he advocated for a humanistic and restrained approach to medical practice. In this article, we discuss the contributions of Tarlov to the field of neurosurgery, including many of his lesser-known accomplishments that have become part of neurosurgery's collective legacy. PMID- 27759682 TI - Journal Club: Outpatient Cervical and Lumbar Spine Surgery Is Feasible and Safe: A Consecutive Single Center Series of 1449 Patients. PMID- 27759683 TI - Letter: Is Intracranial Pressure Monitoring of Patients With Diffuse Traumatic Brain Injury Valuable? An Observational Multicenter Study. PMID- 27759684 TI - Letter: High-Risk Factors in Symptomatic Patients Undergoing Carotid Artery Stenting With Distal Protection: Buffalo Risk Assessment Scale (BRASS). PMID- 27759685 TI - In Reply: High-Risk Factors in Symptomatic Patients Undergoing Carotid Artery Stenting With Distal Protection: Buffalo Risk Assessment Scale (BRASS). PMID- 27759688 TI - An Index Case of Concomitant Tumoral and Ichthyosiform Mycosis Fungoides-Like Presentation of Chronic Adult T-cell Leukemia/Lymphoma Associated With Upregulation of TOX. AB - Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive lymphoid malignancy known to be associated with human T-cell lymphotropic virus type 1. There are 2 broad categories: acute and chronic. In the acute category, there is a leukemic and a lymphomatous variant, whereas in the designated "chronic" form, there is mild peripheral blood lymphocytosis. The intermediate "smoldering" category is without peripheral blood lymphocytosis with only discernible skin involvement. We present a 68-year-old human T-cell lymphotropic virus type 1 seropositive female with a mild peripheral blood atypical lymphocytosis who had indurated nodules on her hands of 2 years duration and a new scaly ichthyosiform eruption on her lower extremities. Histopathologic examination of the hand biopsy revealed coalescing nodules of large atypical noncerebriform lymphocytes with focal areas of epidermotropism. Phenotypically, the infiltrate was positive for beta-F1, CD2, CD4, CD5, CD7, Foxp3, and CD25. In both biopsies, there was striking upregulation of TOX (thymocyte selection-associated high mobility group box factor) in the nuclei of neoplastic cells. The second biopsy taken from the ichthyotic patch on the patient's left leg showed a subtle pattern of epidermal infiltration by atypical noncerebriform lymphocytes and a distinct compact scale consistent with the clinical picture of ichthyosis. The histopathologic appearance was that of a yet undescribed ichthyosiform mycosis fungoides-like presentation of chronic ATLL. In addition, the observed upregulation of nuclear TOX may play an oncogenic role in ATLL. The course to date in this patient has been relatively indolent, although the patients believe that large cell transformation could portend more aggressive disease. PMID- 27759689 TI - Complete Spontaneous Regression of Merkel Cell Carcinoma After Biopsy: A Case Report and Review of the Literature. AB - Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that typically occurs on the head and neck of the elderly and follows an aggressive clinical course. Merkel cell polyomavirus (MCPyV) has been identified in up to 80% of cases and has been shown to participate in MCC tumorigenesis. Complete spontaneous regression of MCC has been rarely reported in the literature. We describe a case of a 79-year-old man that presented with a rapidly growing, 3-cm mass on the left jaw. An incisional biopsy revealed MCC. Additional health issues were discovered in the preoperative workup of this patient which delayed treatment. One month after the biopsy, the lesion showed clinical regression in the absence of treatment. Wide excision of the biopsy site with sentinel lymph node dissection revealed no evidence of MCC 2 months later. The tumor cells in the patient's biopsy specimen were negative for MCPyV by polymerase chain reaction and immunohistochemistry (CM2B4 antibody, Santa Cruz, CA). The exact mechanism for complete spontaneous regression in MCC is unknown. To our knowledge, only 2 previous studies evaluated the presence of MCPyV by polymerase chain reaction in MCC with spontaneous regression. Whether the presence or absence of MCPyV correlates with spontaneous regression warrants further investigation. PMID- 27759690 TI - Loss of Conventional Melanocytic Markers in Malignant Melanoma and Lymph Node Metastasis; an Uncommon but Dangerous Pitfall. AB - Although malignant melanomas exhibit a wide range of immunophenotypes, concurrent loss of all 3 conventional melanocytic markers (S-100, Melan-A, and HMB-45) is relatively rare. We report a case of primary malignant melanoma with lymph node metastasis, both exhibiting loss of immunoreactivity for conventional melanocytic markers, while aberrantly expressing epithelial antigenicity (pancytokeratin, CAM 5.2). PMID- 27759691 TI - A Rare Case of a Primary Cutaneous Desmoplastic Atypical Granular Cell Tumor. AB - Granular cell tumors are uncommon neoplasms and a small number of these neoplasms have been reported as showing malignant behavior. Here, we report a rare case of a solitary granular cell tumor that exhibited atypical histology, including an extensive desmoplastic stroma, in a 69-year-old woman. The surgical specimen revealed localized areas of spindling cells, areas of cellular pleomorphism, and p53 overexpression. Based on previously published criteria, we classified this lesion as an atypical granular cell tumor. To date, only very few case reports have documented this desmoplastic variant of granular cell tumor. However, the classifications of benign, atypical, and malignant granular cell tumors are still controversial, owing to an overlap of morphological and immunohistochemical profiles and lack of consistent histological criteria. Additionally, it is unknown whether the histology of the desmoplastic variant in the present case is significant for the classification of granular cell tumors and prediction of patient prognosis. Regardless of these issues, awareness, and close follow-up are required because of potential recurrences of this rare variant of granular cell tumor. PMID- 27759692 TI - A Case of Onycholemmal Carcinoma in a 77-Year-Old Man. PMID- 27759694 TI - An Aggressive Primary Cutaneous Follicle Center Lymphoma With c-MYC Translocation and CDKN2A (9p21) Deletion: A Case Report and Review of the Literature. AB - Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 1 female patient 85 years of age with an aggressive form of primary cutaneous B cell lymphoma manifesting in multiple firm erythematous indurated solid nodules 1 2 cm each symmetrically on the face periorbitally and on the upper extremities bilaterally. The tumor was a de novo presentation of this aggressive form of lymphoma. The disease demonstrated an aggressive course with only transient improvement of skin lesions after chemotherapy. Punch biopsy taken from a left arm skin lesion showed a diffuse and nodular large cell lymphocytic infiltrate in the 15-20 MUm range exhibiting round to oval nuclei and prominent eosinophilic nucleoli. Phenotypically, the tumor cells were CD10, Bcl-2, Bcl-6, and CD43 positive with a residuum of a follicular dendritic cell network revealed by CD21 staining. There was c-MYC rearrangement and CDKN2A deletion in this sample. The importance in reporting this case is to emphasize that in the context of primary cutaneous B-cell lymphoma, the 9p21 deletion while characteristic of the leg-type lymphoma is not a unique signature of the leg-type lymphoma and is not exclusionary to lymphomas falling under the designation of follicle center lymphoma. As with the leg-type lymphoma, however, this cytogenetic abnormality is a critical determinant to a more aggressive clinical course. PMID- 27759695 TI - Evaluation of Syringomas by In Vivo Reflectance Confocal Microscopy: A Report of Two Cases. AB - Syringomas are benign adnexal tumors that are characterized histologically by the presence of small solid and cystic epithelial structures in the upper half of the reticular dermis. Reflectance confocal microscopy is a noninvasive diagnostic method that enables in vivo visualization of tissues with a resolution that approximates that of conventional histopathology. The use of this method in skin imaging over the past several years has improved dermatological diagnoses, creating the potential for its wide application in such diagnoses, especially for benign and malignant skin tumors. We describe its use in the diagnosis of syringoma in 2 patients and correlate the resulting clinical, histopathological, and digital reflectance confocal microscopy images. PMID- 27759696 TI - Xanthomatized Neutrophilic Dermatosis in a Patient With Myelodysplastic Syndrome. AB - We present an original case report of a 58-year-old man with a history of histiocytoid Sweet and myelodysplastic syndrome who presented with a new onset of tender plaques on his oral commissures. A biopsy revealed a dense dermal neutrophilic infiltrate, leukocytoclasis without frank vasculitis, and, most notably, the presence of many xanthomatized cells. Clinical presentation and histologic features were most consistent with an acute neutrophilic dermatosis, which we believe to be a xanthomized variant of Sweet syndrome. Recent cases have described patients with similar clinical features and neutrophilic dermatosis in the setting of a normolipemic xanthomatosis. These cases were ultimately diagnosed as neutrophilic xanthoma, suggesting a possible histologic overlap between neutrophilic xanthoma and Sweet syndrome. Given these findings, we propose xanthomatized Sweet syndrome as a new histologic variant. PMID- 27759693 TI - Giant Basal Cell Carcinomas Express Neuroactive Mediators and Show a High Growth Rate: A Case-Control Study and Meta-Analysis of Etiopathogenic and Prognostic Factors. AB - BACKGROUND: Giant basal cell carcinomas (GBCCs), (BCC >= 5 cm), are often painless, destructive tumors resulting from poorly understood patient neglect. OBJECTIVES: To elucidate etiopathogenic factors distinguishing GBCC from basal cell carcinoma (BCC) and identify predictors for disease-specific death (DSD). METHODS: Case-control study examining clinicopathologic and neuroactive factors (beta-endorphin, met-enkephalin, serotonin, adrenocorticotropic hormone, and neurofilament expression) in GBCC and BCC. Systematic literature review to determine DSD predictors. RESULTS: Thirteen GBCCs (11 patients) were compared with 26 BCCs (25 patients). GBCC significantly differed in size, disease duration, and outcomes; patients were significantly more likely to live alone, lack concern, and have alcoholism. GBCC significantly exhibited infiltrative/morpheic phenotypes, perineural invasion, ulceration, and faster growth. All neuromediators were similarly expressed. Adenoid phenotype was significantly more common in GBCC. Adenoid tumors expressed significantly more beta-endorphin (60% vs. 18%, P = 0.01) and serotonin (30% vs. 4%, P = 0.02). In meta-analysis (n <= 311: median age 68 years, disease duration 90 months, tumor diameter 8 cm, 18.4% disease-specific mortality), independent DSD predictors included tumor diameter (cm) (hazard ratio (HR): 1.12, P = 0.003), bone invasion (HR: 4.19, P = 0.015), brain invasion (HR: 8.23, P = 0.001), and distant metastases (HR: 14.48, P = 0.000). CONCLUSIONS: GBCC etiopathogenesis is multifactorial (ie, tumor biology, psychosocial factors). BCC production of paracrine neuromediators deserves further study. PMID- 27759697 TI - Anogenital Mammary-Like Glands: A Study of Their Normal Histology With Emphasis on Glandular Depth, Presence of Columnar Epithelial Cells, and Distribution of Elastic Fibers. AB - The normal histology of anogenital mammary-like glands (AGMLG) has been studied previously, but some aspects, including glandular depth, presence of columnar epithelium resembling columnar cell change/hyperplasia as defined in mammary pathology, and distribution of elastic fibers, have not been previously investigated. To address these issues, we studied 148 AGMLG identified in 133 paraffin blocks sampled from 64 vulvar wide excision or vulvectomy specimens (64 patients, various indications for surgery). The depth of AGMLG ranged from 0.64 to 3.9 mm. Epithelial columnar cell change was noted in 33.1% of all AGMLG, whereas columnar cell hyperplasia was detected in 10.1%. Occasionally, combinations of cuboidal epithelium and columnar cell change were seen within 1 histological section. Of 22 specimens stained for elastic fibers, in only 6 (27.3%) cases were elastic fibers found around glands. Periductal elastic fibers were demonstrated around 3 of the only 5 ducts, which were available for analysis in slides stained for elastic fibers. The depth of AGMLG should be taken into account when planning topical and surgical therapies for lesions derived or evolving from AGMLG. Alterations identical to columnar cell change may represent a normal variation of AGMLG. PMID- 27759698 TI - Occlusive Nonvasculitic Vasculopathy. AB - We review the most characteristic clinical and histopathologic findings of the cutaneous manifestations of the occlusive nonvasculitic vasculopathic disorders. Clinically, most of these conditions are characterized by retiform purpura. Histopathologic findings consist of occlusion of the vessel lumina with no vasculitis. Different disorders may produce nonvasculitic occlusive vasculopathy in cutaneous blood and lymphatic vessels, including embolization due to cholesterol and oxalate emboli, cutaneous intravascular metastasis from visceral malignancies, atrial myxomas, intravascular angiosarcoma, intralymphatic histiocytosis, intravascular lymphomas, endocarditis, crystal globulin vasculopathy, hypereosinophilic syndrome, and foreign material. Other times, the occlusive disorder is due to platelet pugging, including heparin necrosis, thrombocytosis secondary to myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, and thrombotic thrombocytopenic purpura. Occlusive vasculopathy may also appear in cold-related gelling agglutination, like that occurring in cryofibrinogenemia, cryoglobulinemia, cold agglutinin syndrome, and crystalglobulinemia. Microorganisms may also occlude the vessels lumina and this is especially frequent in ecthyma gangrenosum, opportunistic fungi as aspergillosis or fusariosis, Lucio phenomenon of lepromatous leprosy and disseminated strongyloidiasis. Systemic coagulopathies due to defects of C and S proteins, coumarin/warfarin-induced skin necrosis, disseminated intravascular coagulation, and antiphospholipid antibody/lupus anticoagulant syndrome may also result in occlusive nonvasculitic vasculopathy. Finally, vascular coagulopathies such as Sneddon syndrome, livedoid vasculopathy, and atrophic papulosis may also cause occlusion of the vessels of the dermis and/or subcutis. Histopathologic study of occlusive vasculopathic lesions is the first step to achieve an accurate diagnosis, and they should be correlated with clinical history, physical examination, and laboratory findings to reach a final diagnosis. PMID- 27759699 TI - A Case of Plasma Cell Granuloma Located on the Gingiva. AB - Plasma cell granuloma (PCG) is an uncommon benign tumor of unknown etiology, primarily located in the lungs. We report a case of PCG on the gingiva mimicking benign and malignant tumors in a 56-year-old woman. Histopathological examination revealed a relatively sharp circumscribed inflammatory cell infiltration under the mucosa-containing plasma cells, predominantly those including Russell bodies. Plasma cells are stained by CD138 immunohistochemistry. Polyclonal status of the lesion was confirmed by kappa and lambda light chaining. The typical histopathological and immunohistochemical findings in combination with the clinical features were consistent with PCG, about which the literature reports very few cases. PMID- 27759700 TI - A Rare Case of Solitary Hemorrhagic Mycosis Fungoides With Angiocentric Features. AB - Unilesional (solitary) mycosis fungoides (MF) is a rare variant characterized clinically by the presence of a single contiguous area of skin involvement covering less than 5% of the body surface and histopathologically by features identical to those seen in classical MF. Angiocentricity (angiodestruction) is mostly a feature of primary or secondary cutaneous lymphomas with an aggressive course and poor outcome, with only very few reports of MF with angiocentric pattern. The authors report an unusual case of solitary patch-stage MF with hemorrhagic features, characterized histologically by epidermotropic and angiocentric (angiodestructive) infiltrate and a reactive B-cell component appearing as lymphoid follicles. PMID- 27759701 TI - Concomitant Cutaneous Langerhans Cell Hystiocytosis and Leukemia Cutis. AB - Leukemia cutis develops in <4% of all acute leukemias. Concurrent acute myeloid leukemia (AML) and Langerhans cell histiocytosis (LCH) is rare, with most cases involving lymph nodes or spleen, and no cutaneous involvement. We report the case of a 59-year-old man who presented with fever, malaise, and fatigue. The CBC showed leukocytosis (30.4 * 10/L, 9% blasts), anemia, and thrombocytopenia. Bone marrow biopsy was diagnosed with AML, not otherwise specified, with mutations of FLT3 and IDH2 (R140Q). The patient developed skin rash on the right flank with the clinical differential diagnosis of herpes simplex virus or varicella-zoster virus infection/reactivation versus leukemia cutis. A skin biopsy showed leukemia cutis in mid and deep dermis. Immunohistochemistry positive for CD4, CD33, CD117, and myeloperoxidase (MPO) supported myeloid and monocytic differentiation. Clusters of Langerhans cells positive for S100, CD1a, CD4, langerin and aberrant CD33 and MPO were found admixed with the AML cells. Langerhans cells were negative for BRAF V600E by immunohistochemistry. The diagnosis of leukemia cutis and concomitant LCH was established. The aberrant expression of CD33 and MPO shared by AML and LCH suggests a possible relationship among these 2 lesions. No LCH or Langerhans cell differentiation was found in the bone marrow. The patient achieved complete remission 4 months after chemotherapy and the skin lesions resolved. To our knowledge, we present for the first time a case of concomitant cutaneous LCH and leukemia cutis. PMID- 27759702 TI - Melanocytic Matrical Carcinoma Mimicking Melanoma. AB - Melanocytic matrical carcinoma is a very uncommon malignant neoplasm with follicular differentiation. The lesion often presents as a solitary nodule on sun exposed skin of elderly patients. Histopathologically, it is characterized by proliferation of atypical matrical cells admixed with an increased number of melanocytes, and some atypical matrical cells may have cytoplasmic pigment. When melanocytic proliferation or melanin pigment is prominent, melanocytic metrical carcinoma can mimic melanoma. Here, we present a novel case of melanocytic matrical carcinoma mimicking melanoma in an 80-year-old man with our findings in histopathologic and immunohistochemical study. PMID- 27759703 TI - p53 Is a Helpful Marker in Distinguishing Langerhans Cell Histiocytosis From Langerhans Cell Hyperplasia. AB - Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells that can be challenging to distinguish histologically from Langerhans cell (LC) hyperplasia, seen in a variety of inflammatory dermatoses. Lesional cells in both entities demonstrate positive staining for CD1a and S100. Previous studies have demonstrated positive staining of fascin, CD31, and p53 in cases of LCH, but currently, no studies have compared the staining profiles of these markers between LCH and LC hyperplasia. The authors compared immunohistochemical staining profiles of LCH (n = 15) and various inflammatory dermatoses with LC hyperplasia (n = 15) using fascin, CD31, and p53. Fascin, CD31, and p53 were graded as a percentage of CD1a staining cells in the epidermis and dermis of each specimen. Fascin showed no significant differences in staining between the 2 entities. CD31 was positive in the dermal infiltrate in 40% of cases of LCH and negative in all cases of LC hyperplasia. p53 was positive in the epidermal infiltrate in 50% of cases of LCH, and positive in the dermal infiltrate in 93% of cases of LCH, whereas negative in all cases of LC hyperplasia. Fascin was not a helpful marker in distinguishing LCH from LC hyperplasia. CD31, if positive in the dermal infiltrate, is suggestive of a diagnosis of LCH, but exhibits a relatively low sensitivity for this purpose. p53 proved to be a helpful and accurate diagnostic immunohistochemical stain when distinguishing between LCH and LC hyperplasia. PMID- 27759704 TI - Sox10-Positive Cells Within Scars: A Potential Diagnostic Pitfall. PMID- 27759707 TI - Can Academic Medicine Lead the Way in the Refugee Crisis? AB - The world is currently in the midst of the largest refugee crisis since World War II, with the highest interval of mass displacement in recorded history according to the United Nations. The United States has pledged to maintain its position as one of the world's top resettlement countries in response to this crisis. These new immigrants will arrive with exceptional chronic and acute medical needs, including higher rates of behavioral health disorders. The author describes the health care challenges experienced by refugees seeking asylum in the United States and outlines the ways in which our health care system is currently deficient in helping refugee patients to overcome these challenges. He argues that the academic medical community can change this dynamic by standardizing and expanding instruction in cross-cultural competence and behavioral health screenings throughout the spectrum of medical education. Ensuring the long-term well-being of refugees in the United States, including meeting their mental health needs, will be the best inoculation against the risks of violent extremism which so many fear. With the absence of national leadership on this issue, academic medicine can and should lead the way. PMID- 27759706 TI - Advancing Women's Health and Women's Leadership With Endowed Chairs in Women's Health. AB - Gender-based bias and conflation of gender and status are root causes of disparities in women's health care and the slow advancement of women to leadership in academic medicine. More than a quarter of women physicians train in internal medicine and its subspecialties, and women physicians almost exclusively constitute the women's health focus within internal medicine. Thus, internal medicine has considerable opportunity to develop women leaders in academic medicine and promote women's health equity.To probe whether holding an endowed chair-which confers status-in women's health may be an effective way to advance women leaders in academic medicine and women's health, the authors explored the current status of endowed chairs in women's health in internal medicine. They found that the number of these endowed chairs in North America increased from 7 in 2013 to 19 in 2015, and all were held by women. The perceptions of incumbents and other women's health leaders supported the premise that an endowed chair in women's health would increase women's leadership, the institutional stature of women's health, and activities in women's health research, education, and clinical care.Going forward, it will be important to explore why not all recipients perceived that the endowed chair enhanced their own academic leadership, whether providing women's health leaders with fundraising expertise fosters future success in increasing the number of women's health endowed chairs, and how the conflation of gender and status play out (e.g., salary differences between endowed chairs) as the number of endowed chairs in women's health increases. PMID- 27759708 TI - TREATMENT OF MACULAR FOLDS COMPLICATING RETINAL DETACHMENT SURGERY USING AIR FOR RETINAL UNFOLDING. AB - PURPOSE: We discuss a modified surgical procedure for the treatment of macular folds complicating retinal reattachment surgery. METHODS: To facilitate the completion of the macular redetachment and the subsequent unrolling of the fold, we propose the subretinal injection, in addition to the conventional balanced salt solution, of filtered air as an original approach. In the presence of a subretinal air bubble, the action of gravity on the perfluorocarbon liquid in the vitreous cavity combined with an active globe manipulation proved to be very effective for flattening the central retina. Short-term tamponade with gas was successful at stabilizing the result. RESULTS: This technique has been used to treat symptomatic macular fold after surgery for rhegmatogenous retinal detachment in 3 consecutive eyes since 2014. Flattening of the macula with progressive visual recovery was achieved in all cases by the end of follow-up. CONCLUSION: Direct injection of air into the macular fold may represent an effective strategy to enhance the surgical management of such a vision threatening complication. Air also minimizes the risks related to the forceful injection of fluid under the macula. An overview of recently reported surgical techniques is included, along with a brief discussion. PMID- 27759709 TI - CHOROIDAL SARCOID GRANULOMA SIMULATING PROSTATE CARCINOMA METASTASIS. AB - PURPOSE: To report a case of choroidal sarcoid granuloma simulating choroidal metastasis in a patient with prostate carcinoma. METHOD: Case report. RESULTS: A 66-year-old man was found to have an asymptomatic choroidal mass in his left eye. He had known history of pulmonary sarcoidosis without systemic involvement and prostate carcinoma without metastasis. On examination, visual acuity was 20/20 in each eye. Anterior segment was normal, without inflammatory sign in either eye. The right fundus was healthy. The left fundus revealed a yellow choroidal mass of 2 mm diameter, temporal to the foveola and without subretinal fluid, retinitis, or vitritis. Optical coherence tomography demonstrated a homogenous hyporeflective choroidal mass with intact retinal pigment epithelium and compression of choroidal vascular structures. Given the medical history and rarity of prostate metastasis to the uvea, choroidal sarcoid granuloma was considered and oral prednisone with a slow taper was given. After 2 months of therapy, tumor resolution with reduction in size was confirmed on optical coherence tomography. CONCLUSION: Choroidal sarcoid granuloma is a rare condition that can simulate choroidal metastasis. Treatment with prednisone can assist in establishing the diagnosis. PMID- 27759710 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY SHOWS INNER CHOROIDAL ISCHEMIA IN ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY. AB - PURPOSE: To describe multimodal imaging findings of an evolving case of acute posterior multifocal placoid pigment epitheliopathy occurring in a young healthy male. METHODS: Case report of a patient with acute posterior multifocal placoid pigment epitheliopathy including comprehensive systemic and ocular examinations. Ultra-widefield autofluorescence, fluorescein angiography, indocyanine green angiography, and serial optical coherence tomography angiography were performed. RESULTS: A 34-year-old male presented with acute vision loss in his left eye for 2 weeks. His best-corrected visual acuity was 20/20 in his right eye and 20/200 in his left eye. Dilated funduscopic examination revealed multiple creamy white deep retinal lesions showing macular involvement of the left eye with a diffuse area of pigmentary changes. The presence of multiple areas of hypoperfusion of the inner choroid were demonstrated with fluorescein and indocyanine green angiography. Serial optical coherence tomography angiography showed multiple evolving areas of decreased flow at the level of the inner choroid. CONCLUSION: Although the pathogenesis of acute posterior multifocal placoid pigment epitheliopathy remains unknown, there is growing evidence of a primary choroidal involvement with secondary damage to the overlying retinal pigment epithelium and the outer retinal layers. Optical coherence tomography angiography may provide valuable information for the diagnosis and follow-up of this condition avoiding invasive angiographic procedures. PMID- 27759711 TI - Can Down-gaze During Near Work Cause Peripheral Deprivation in Asian Eyes? AB - PURPOSE: We hypothesize that the typically narrower palpebral apertures of East Asian eyes in combination with the narrowing of this aperture during down-gaze combine to reduce light levels and image contrast in the inferior retina during near work, thus creating peripheral deprivation in these eyes that could generate deprivation myopia in children culturally encouraged to perform near work. METHODS: We photographed the right eyes of 53 Chinese children during down-gaze (from 10 to 40 degrees) from the fixation point and the primary gaze position. From these images, we determined the size and shape of the effective foveal and superior field entrance pupil at different down-gaze angles. By using an eye model with typical levels of off-axis higher-order aberrations, we quantified the impact of eyelid and eyelash vignetting of the pupil on both retinal illuminance and image quality using Visual Strehl Ratio (VSOTF), and the non-visually weighted Strehl Ratio (SROTF). RESULTS: The effective aperture for the superior visual field is vignetted during down-gaze by lids and lashes, producing reductions in retinal illuminance of 30% and >60% at 20 and 40 degrees, respectively. However, the aperture vignetting effect on peripheral image modulation is small, with neural and aberration changes dominating image quality in the superior field during down-gaze. CONCLUSIONS: Occlusion of the pupil by eyelid and eyelashes during down-gaze is unlikely to produce significant superior field deprivation in East Asian eyes. PMID- 27759712 TI - Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors. AB - OBJECTIVES: The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). METHODS: One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. RESULTS: The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. CONCLUSIONS: Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS. PMID- 27759713 TI - Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated. AB - OBJECTIVES: Emerging data suggest that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. METHODS: Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival were determined. RESULTS: Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median overall survival in G3 WD-panNET patients was 52.2 months (95% confidence interval, 19.3 86.9 months) compared with 10.1 months (95% confidence interval, 6.9-12.4 months) in PDNEC patients (P = 0.0009). Response rate to platinum agents was 10% in G3 WD panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD panNETs and 50% in PDNEC. CONCLUSIONS: Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. Overall survival was significantly greater in G3 WD-panNETs compared with PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology. PMID- 27759716 TI - My patient needs palliative care: Now what? PMID- 27759717 TI - The sacred cow project: Is your practice "udderly" out of date? PMID- 27759718 TI - Back-to-school survival guide. PMID- 27759720 TI - Recognizing and preventing tumor lysis syndrome. PMID- 27759721 TI - Recognizing and preventing tumor lysis syndrome. PMID- 27759722 TI - Synthetic cannabinoid poisoning: A growing health concern. PMID- 27759723 TI - Facing disrespectful behavior. PMID- 27759724 TI - Finding new purpose through volunteering. PMID- 27759725 TI - Caring for hospitalized patients with celiac disease. PMID- 27759726 TI - Introducing the Massachusetts CSI Nursing Delirium Collaborative. PMID- 27759727 TI - Five strategies to combat unconscious bias. PMID- 27759728 TI - Using nurse-led rounds to improve quality measures related to HAPUs. PMID- 27759729 TI - Using transdermal drug patches for older adults. PMID- 27759730 TI - Online resources for Alzheimer disease. PMID- 27759731 TI - Antiepileptic drugs. PMID- 27759734 TI - Contemporary techniques for coronary CTO revascularization. AB - Despite permanent improvement in success rate and technical developments, chronic total occlusion (CTO) remains undertreated by percutaneous coronary intervention (PCI). Dedicated CTO operators from Japan, Europe and USA perform these procedures with success rate beyond 90%, but there is still huge gap between this group of specialists and broader population of PCI operators. Recently proposed CTO scores can be used for patients' selection according to the CTO operators' experience. Patients with low CTO Score values may be suitable for less experienced operators at the beginning of the CTO PCI learning curve, while more complex CTOs (higher CTO Score values) should be differed to CTO experts. As most of CTO scores better predict antegrade procedural success, at the hands of expert CTO operators, lower or intermediate CTO Score values suggest cases which could be started by anterograde techniques. In this paper we review: 1) an impact of CTO on completeness of revascularization; 2) appropriate CTO equipment setting; 3) procedure planning aspects, including the use of computed tomography angiography and CTO scores; 4) current CTO techniques classifying them into A) antegrade, B) retrograde and C) hybrid approach. Further advancements in CTO PCI should not only provide higher rate of complete revascularization, with improved clinical outcome, but also simplify procedure and make it suitable for broader spectrum of interventionalists. PMID- 27759733 TI - No Association Between Single-Nucleotide Polymorphism 56 (SNP56) in Phosphodiesterase 4D (PDE4D) Gene and Susceptibility to Ischemic Stroke: A Meta Analysis of 15 Studies. AB - BACKGROUND Recent studies demonstrated that polymorphisms in the PDE4D gene were associated with several processes involved in the occurrence of ischemic stroke (IS). The association between specific PDE4D single-nucleotide polymorphism 56 (SNP56) and IS risk was initially identified via genome-wide association studies (GWAS), although the GWAS in different populations produced inconclusive results. Thus, we performed a meta-analysis to better explain the association between PDE4D SNP56 and IS risk. MATERIAL AND METHODS A literature search was conducted using PubMed, Embase, and Web of Science up to June 1, 2015. A fixed-effects or random-effects model was used to calculate the pooled odds ratios (ORs) based on the results from the heterogeneity tests. RESULTS Finally, we performed a meta analysis of 15 studies, involving 8731 IS patients and 10,756 controls. The results showed nonsignificant association between PDE4D SNP56 and IS risk (T vs. A: OR=1.01, 95%CI=0.88-1.15, P=0.90). Similarly, in the subgroup analysis by ethnicity, no significant association was observed in Asian (T vs. A: OR=1.08, 95%CI=0.80-1.44, P=0.62) or European (T vs. A: OR=0.96, 95%CI=0.86-1.08, P=0.54) population. Moreover, funnel plots and Egger regression testing showed no evidence of publication bias. CONCLUSIONS In summary, current evidence suggested that PDE4D SNP56 might not be associated with an increased susceptibility to IS. However, this conclusion needs further validation by well-designed studies with large sample sizes. PMID- 27759735 TI - The role of low protein diet in ameliorating proteinuria and deferring dialysis initiation: what is old and what is new. AB - In the management of patients with chronic kidney diseases (CKD), a low-protein diet usually refers to a diet with protein intake of 0.6 to 0.8 grams per kilogram of body weight per day (g/kg/day) and should include at least 50% high biologic-value protein. It may be supplemented with essential acids or nitrogen free ketoanalogues if <0.6 g/kg/d. Low-protein diet can reduce proteinuria especially in non-diabetic CKD patients. In hypoalbuminemic patients it may lead to an increase in serum albumin level. By lowering proteinuria, decreasing nitrogen waste products, ameliorating metabolic burden, mitigating oxidative stress and acidosis, and lowering phosphorus burden, a low-protein diet can help delay dialysis start in advanced CKD. Low-protein diet is safe, since most CKD patients can maintain nitrogen balance by mechanisms of decreasing amino acid oxidation and protein degradation in addition to increased utilization of amino acids for protein synthesis. We suggest a dietary protein intake below 1.0 g/kg/day when estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2 or when there is solitary kidney or proteinuria at any level of GFR. Protein intake should be reduced progressively based on severity and progression of CKD and patient's nutritional status with a target of 0.6-0.8 g/kg/d in most patients with eGFR <45 mL/min/1.73 m2. The risk of protein-energy wasting can be overcome by careful attention to quantity and quality of the ingested proteins, sufficient energy intake of 30-35 Kcal/kg/d, and use of dietary supplements. Long-term observations and individualized approaches are needed to further demonstrate the benefits and safety of low-protein diet. PMID- 27759736 TI - The future of ureteroscopy. AB - Open ureterolithotomy and pyelolithotomy used to be first line therapy for treating kidney and ureteral stones. With the advent of shockwave lithotripsy, open stone surgery became less prevalent, but once ureteroscopy became more prevalent, open stone surgery became all but extinct. Advances in smaller, more flexible endoscopes and improvements in intracorporeal lithotripters, ureteroscopy has become a mainstay of therapy for kidney stones. The holmium:yttrium-aluminium-garnet laser can be utilized through flexible instruments and fragments any stone no matter what it is composed of. Digital image ureteroscopes with chip-on-the-tip technology has improved our visualization during ureteroscopy. What is next? We examine potential directions from current research. Pharmacologic manipulation for ureteral dilation may obviate the need for pre-stenting or balloon dilation. Advances in ureteroscope technology will likely see the biggest advances. Different ureteroscopic platforms and the user interface with the surgeon will progress. Robotic manipulation of the endoscope is an eventual reality with improved ergonomics and improved performance to reach all areas of the kidney. Single-use ureteroscopes are already a reality and offer a digital image with full deflection with every use and without having to worry about sterilization and costly repairs. Lastly, advancements in nanotechnology and robotics will see the potential for miniaturized robots that could be administered intravesically to identify the stone and to disintegrate it. The only prediction that can be made about the future of ureteroscopy is that we do not know how it will look. The future of ureteroscopy is exciting and most definitely will be unrecognizable to the surgeons of today. PMID- 27759737 TI - Ureterorenoscopy: current technology and future outlook. AB - The aim of this paper was to evaluate the current technology and designs of flexible ureterorenoscopes. We will review contemporary fiberoptic and digital ureteroscopes, including a discussion on ureteroscope damage and repair, and lastly present the projected future of flexible ureterorenoscopy. Ureterorenoscopy has evolved dramatically over the past several decades, which has led to landscape reshaping of stone disease treatment and upper tract pathology. Advancements in tip control, miniaturization of scopes, introduction of a digital chip on the tip, disposable devices to augment surgery, surgical experience/familiarity and most recently single use scopes are all independent factors that have increased flexible ureterorenoscopy adoption and success. We therefore detail the aforementioned and provide a view of future innovations. A review of literature from 1980 to 2016 was performed by the two authors focusing on literature that details flexible ureterorenoscopy. Technology has significantly impacted the minimally invasive endourologic management of the urinary system. This review summarizes current literature on advances and modern technical achievements. We include a focus on new perspectives and future outlook in the field of managing upper urinary tract pathology with modern technologies. The advancements in flexible ureterorenoscopy are impressive and yet the challenges of this technology are equally daunting. Obstacles to overcome include improving durability, decreasing cost, further miniaturizing scopes size, and determining the role of single use scopes. Ongoing developments in other technology fields (such as virtual 3D imaging, wireless capsular endoscopy, robotics) continue to create both opportunities to improve the procedure but also threaten to replace ureterorenoscopy over time. This is an exciting time because of past achievements and future innovations in ureterorenoscopy. PMID- 27759738 TI - The relationship between IL-6, ET-1 and cerebral vasospasm, in experimental rabbit subarachnoid hemorrhage. AB - BACKGROUND: In subarachnoid hemorrhage (SAH), occurrence of cerebral vasospasm (CVS) mediated by endothelin (ET)-1 might be a result of a compartmental inflammatory response with interleukin (IL)-6 release. We aim to investigate the relationship between ET-1 and IL-6 in association of CVS. METHODS: A total of 24 New Zealand white rabbits where randomly allocated into 3 groups: SAH (n=10), IL 6 (n=10), and sham (n=4). SAH was induced by a closed cranium extracranial intracranial shunt model. In the IL-6 group, IL-6 was injected into the cisterna magna. CVS of the basilar artery was assessed by digital subtraction angiography. IL-6 and ET-1 concentrations were measured using enzyme-linked immunosorbent assay. Neuronal damage was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling. RESULTS: A significant increase between baseline (day 0) and follow-up (day 3) was found in CSF IL-6 levels of animals in the SAH and IL-6 group. There was a statistically significant correlation between IL-6 and ET-1 levels in the CSF (Pearson's r=0.454, p=0.003). CVS at day 3 was more pronounced in the SAH than in the IL-6 group: 26.0 +/-7.2 % and 16.7 +/-5.0 % respectively. TUNEL positive apoptotic neurons in the hippocampal formation were present in the SAH group and in a lesser degree in the IL-6 group. CONCLUSIONS: The results indicate that IL-6 triggered CVS after SAH is ET-1 dependent. IL-6 may be a target for new therapeutic approaches. PMID- 27759739 TI - Five-year medical expenses of central cord syndrome: analysis using a national cohort. AB - BACKGROUND: This study aimed to investigate the medical expenses and outcomes of central cord syndrome (CCS), comparing patients who received surgical and non surgical management. METHODS: Using a 14-year nationwide database in Taiwan, this study followed-up all patients of CCS at least 5 years. The incidence rates, medical expenses, permanently disabled spinal cord injury (SCI), and mortality rates were compared for patients who underwent surgery and those who were managed conservatively. All CCS patients were further stratified by the level of injury (C1-4 vs. C5-7) in the cost analysis. RESULTS: A total of 1,753 patients with CCS were followed and the incidence of CCS was the highest among males aged between 60 and 70 years, at 42.4 per 1,000,000 person-years. The total medical expenses were higher in the surgery than the non-surgery group (46,586.9 vs 28,472.4, p< 0.001) because of rehabilitation. The surgery group had a significantly lower rate of mortality (Odds Ratio= 0.34, p< 0.05) and lower rates of permanently disabled SCI (OR= 4.92, all p< 0.001). CONCLUSIONS: The highest incidence rates of CCS were observed among males aged between 60 and 70 years. The expenses were higher but the mortality rate was lower for surgically managed patients. Further investigation is required to correlate the neurological outcomes to the management of CCS. PMID- 27759740 TI - Goal-directed fluid management in free flap surgery for cancer of the head and neck. AB - BACKGROUND: Goal-directed fluid management using stroke volume variation (SVV) analysis is not well studied in free flap reconstruction surgery in patients with head and neck cancer. METHODS: Patients operated due to cancer of the head and neck with free flap reconstruction during 2008-2010 and 2012-2014 in Oulu University Hospital were retrospectively evaluated to determine the impact of SVV guided fluid management on perioperative fluid balance, postoperative complications and hospital length of stay (LOS). RESULTS: A total of 104 patients were included in the study and in 48 of them SVV was used to guide intraoperative fluid management. The SVV-guided fluid management led to significant reduction in intraoperative fluid load (6070 mL vs. 8185 mL) and hospital length of stay (11.5 vs. 14.0 days). There was no difference in the number of postoperative complications between the groups. CONCLUSIONS: The SVV-guided fluid management reduces fluid administration in free flap reconstruction surgery with head and neck cancer. PMID- 27759741 TI - Acute kidney injury in liver transplant candidates: a position paper on behalf of the Liver Intensive Care Group of Europe. AB - INTRODUCTION: Acute kidney injury is associated with high mortality in the perioperative period of liver transplantation. The aim of this position paper was to provide an up-to-date overview with special emphases on diagnosis, risk factors, and treatment. EVIDENCE ACQUISITION: The Liver Intensive Care Group of Europe nominated a panel of recognized international experts who reviewed the available literature published from 1990 to January 2016 and produced clinical recommendations. The level of evidence and strength of recommendation were judged according to the Grading of Recommendations Assessment Development and Evaluation system. EVIDENCE SYNTHESIS: Diagnosis of AKI should be based on the KDIGO criteria. The preoperative risk factors are more related to the patient's predisposing factors and post-operative risk factors tend to be difficult to control. Therefore, focusing on intra-operative risk factors it would be important to maintain an adequate hemodynamics and to keep inferior vena cava clamping as short as possible. Biomarkers to identify AKI at an early stage are available; however, there is a lack of robust data that indicates their true beneficial effect. Intraoperative renal replacement therapy may be beneficial in some selective cases whereas its postoperative timing is still under debate. CONCLUSIONS: Perioperative liver transplant risk factors for acute kidney injury are difficult to control. Therefore, the focus should be on intra-operative hemodynamics and nephrotoxic drugs avoidance. Prospective randomized trials are needed to show the beneficial effect of early replacement therapy. In this context, the new biomarkers would be helpful in identifying kidney injury earlier. PMID- 27759742 TI - Reactive oxygen species metabolites in sepsis: markers and mediators. PMID- 27759744 TI - Variation in Acute Medicine Units: Measuring it, understanding it, and reducing it. AB - Although there are national recommendations on the function of Acute Medicine Units (AMUs), there is no single agreed best model of care. Additionally, robust data is not always available to determine whether system changes have resulted in improvement. We designed an Excel file to interface with the hospital patient management system to provide real-time data on a number of metrics including AMU length of stay (AMULOS), mortality and readmissions. This demonstrated that improving consultant continuity of care was associated with a reduction in AMULOS and reduced variation in AMULOS. Additionally, the Excel file provides timely access to consultant and individual patient-level data. These data are clinically owned, and critical for both unit governance and quality improvement work. We would encourage all AMUs to develop a similar dataset to allow standardised comparisons between units, and better understanding of the association between models of care and patient outcomes. PMID- 27759743 TI - Perioperative and periprocedural airway management and respiratory safety for the obese patient: 2016 SIAARTI Consensus. AB - Proper management of obese patients requires a team vision and appropriate behaviors by all health care providers in hospital. Specialist competencies are fundamental, as are specific clinical pathways and good clinical practices designed to deal with patients whose Body Mass Index (BMI) is >=30 kg/m2. Standards of care for bariatric and non-bariatric surgery and for the critical care management of this population exist but are not well defined nor clearly followed in every hospital. Thus every anesthesiologist is likely to deal with this challenging population. Obesity is a multisystem, chronic, proinflammatory disorder. Unfortunately many countries are facing a marked increase in the obese population, defined as "globesity". Obesity presents an added risk in hospital, leading health care organizations to call for action to avoid adverse events and preventable complications. Periprocedural assessment and critical care strategies designed specifically for obese patients are crucial for reducing morbidity and mortality during surgery and in emergency settings, critical care and other particular settings (e.g., obstetrics). Specific care is needed for airway management, as are proactive strategies to reduce the risk of cardiovascular, endocrine, metabolic and infective complications; any effort can be fruitful, including special attention to the science of human factors. The Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) organized a consensus project involving other national scientific societies to increase risk awareness, define the best multidisciplinary approach for treating obese patients in election and emergency, and enable every hospital to provide appropriate levels of care and good clinical practices. The Obesity Project Task Force, a section of the SIAARTI Airway Management Study Group, used a formal consensus process to identify a series of notes, alerts and statements, to be adopted as bundles, to define appropriate clinical pathways for hospitalized obese patients. The consensus, approved by the Task Force and endorsed by several European scientific societies actively operating in this field, is presented herein. PMID- 27759745 TI - Can we predict Acute Medical readmissions using the BOOST tool? A retrospective case note review. AB - BACKGROUND: Readmissions within 30-days of hospital discharge are a problem. The aim was to determine if the Better Outcomes for Older Adults through Safe Transitions (BOOST) risk assessment tool was applicable within the UK. METHODS: Patients over 65 readmitted were identified retrospectively via a casenote review. BOOST assessment was applied with 1 point for each risk factor. RESULTS: 324 patients were readmitted (mean age 77 years) with a median of 7 days between discharge and readmission. The median BOOST score was 3 (IQR 2-4) with polypharmacy evident in 88% and prior hospitalisation in 70%. The tool correctly predicted 90% of readmissions using two or more risk factors and 99.1% if one risk factor was included. CONCLUSION: The BOOST assessment tool appears appropriate in predicting readmissions however further analysis is required to determine its precision. PMID- 27759746 TI - The Relationship Between Social Deprivation and a Weekend Emergency Medical Admission. AB - BACKGROUND: Deprivation increases admission rates; the specific effect of deprivation with regard to weekend admissions is unknown. METHODS: We calculated annual weekend admission rates for each small area population unit and related these to quintiles of Deprivation Index from 2002-2014. Univariate and multivariable risk estimates were calculated using truncated Poisson regression. RESULTS: There were 30,794 weekend admissions in 16,665 patients. The admission rate was substantially higher for more deprived areas, 12.7 per 1000 (95%CI 9.4, 14.7) vs 4.6 per 1000 (95%CI 3.3, 5.8). More deprived patients admitted at the weekend had a significantly lower 30-day in-hospital mortality (10.3% vs 14.5%, p<0.001). CONCLUSION: Deprivation is a powerful determinant of weekend admissions, however these comprise a group of patients with better outcomes. PMID- 27759747 TI - The diagnostic yield of CTPA: pulmonary embolism, alternative diagnoses and incidental findings. AB - AIMS: In this retrospective study we assess the diagnostic yield of computed tomography pulmonary angiogram (CTPA) and the incidence of alterative and incidental diagnoses. METHODS: The results of all CTPA scans performed in our trust over a period of 18 months were reviewed and all diagnoses noted. Data collected was descriptively analysed. RESULTS: A total of 1138 scans were performed (56.5% men, mean age 59 years). A diagnosis of pulmonary embolism (PE) was made in 20.2%, an alternative aetiology for presenting symptoms in 26.4% and incidental findings in 19.5%. The commonest alternative diagnosis was pneumonia (9.5%). CONCLUSIONS: Significant numbers of CTPA yield unexpected findings, which may provide an explanation for the clinical presentation. Furthermore substantial numbers of incidental pathologies are also diagnosed which may lead to inappropriate resource utilization and increased patient anxiety. PMID- 27759748 TI - Frailsafe: from conception to national breakthrough collaborative. AB - The number of people aged over 60 years worldwide is projected to rise from 605 million in 2000 to almost 2 billion by 2050, while those over 80 years will quadruple to 395 million. Two-thirds of UK acute hospital admissions are over 65, the highest consultation rate in general practice is in those aged 85-89 and the average age of elective surgical patients is increasing. Adjusting medical systems to meet the demographic imperative has been recognised by the World Health Organisation to be the next global healthcare priority and is a key feature of discussions on policy, health services structures, workforce reconfiguration and frontline care delivery. PMID- 27759749 TI - Acute generalised exanthematous pustulosis (AGEP)-a potential pitfall for the acute physician. AB - Acute generalised exanthematous pustulosis is a rare drug-induced dermatosis with an incidence of 1-5 cases per million cases per year, characterised by the appearance of hundreds of sterile pustules over erythematous and oedematous skin. Fever and neutrophilia are usually present. It has a rapid course and usually resolves following discontinuation of the precipitating drug or as a result of topical corticosteroid treatment. A patient with AGEP, who presented with generalized pustulosis lesions after the use of Flucloxacillin for cellulitis is described, along with the management and differential diagnosis of this condition. PMID- 27759750 TI - Pheochromocytoma presenting as a mimic of acute coronary syndrome. AB - Chest pain with elevated serum troponin is a common clinical presentation and is normally managed as suspected myocardial infarction or acute coronary syndrome (ACS). We report a 49 year old man who presented with central chest pain sweating and breathlessness. He had a significantly elevated serum troponin I level and a subsequent angiogram showed near normal coronary arteries. He was subsequently investigated for fever and found to have a 3cm right sided adrenal mass consistent with a pheochromocytoma. After confirmation and appropriate blockade laparoscopic adrenalectomy was performed. Pheochromocytoma may present as a mimic of acute coronary syndrome but this is often unrecognized and leaves the patient at risk of future pheo crisis events which may be fatal. PMID- 27759751 TI - Fever, delirium and incontinence: not always a UTI. AB - Unexplained fever and confusion is a common reason for emergency medical admission. When this occurs in the context of new urinary incontinence, a urinary tract infection may be considered to be the most likely cause. However it is also important to consider spinal pathology when this combination of symptoms arises. We present a case of a retropharygeal collection presenting in a patient with this combination of symptoms. PMID- 27759752 TI - Pneumomediastinum as a complication of MDMA (3,4-methylenedioxymetamfetamine, Ecstasy) ingestion. AB - MDMA (3,4-methylenedioxymethamfetamine, Ecstasy) is a widely used recreational drug. We present a case of pneumomediastinum as a complication of MDMA use in a 21-year-old man with no previous history of lung or gastrointestinal pathology. We have performed a literature review, and summarised the symptoms, signs, and prognosis for this under-recognised complication of a commonly used recreational drug. We recommend enquiring about illicit drug use in any patient presenting with spontaneous pneumomediastinum. PMID- 27759753 TI - Improving acute care for adolescents and young adults on medical admission units: The interventions that matter. AB - It had become a familiar routine. My seventh admission with diabetic ketoacidosis (DKA) in a year. Each time I was admitted it was the same; a DKA protocol, a diabetes specialist nurse visit, and a few questions from the doctors checking if "everything is okay?" On each admission, I would be discharged home after a couple of days. We all knew I'd be back again within a month or two. PMID- 27759754 TI - Motion in microfluidic ratchets. AB - The ubiquitous random motion of mesoscopic active particles, such as cells, can be "rectified" or directed by embedding the particles in systems containing local and periodic asymmetric cues. Incorporated on lab-on-a-chip devices, these microratchet-like structures can be used to self-propel fluids, transport particles, and direct cell motion in the absence of external power sources. In this Focus article we discuss recent advances in the use of ratchet-like geometries in microfluidics which could open new avenues in biomedicine for applications in diagnosis, cancer biology, and bioengineering. PMID- 27759755 TI - Direct synthesis of CdSe nanocrystals within a conducting metallopolymer: toward improving charge transfer in hybrid nanomaterials. AB - CdSe nanocrystals with tunable sizes and distributions were synthesized directly from Cd(ii) ions coordinated to the conjugated backbone of a thiophene-based conducting metallopolymer. Using our seeded growth technique, the resulting nanocrystals are in direct electronic communication with the polymer, which leads to effective charge transfer between the donor and acceptor. PMID- 27759756 TI - Stacking of colors in exfoliable plasmonic superlattices. AB - Color printing with plasmonic resonators can overcome limitations in pigment based printing approaches. While layering in pigment-based prints results in familiar color mixing effects, the color effects of stacking plasmonic resonator structures have not been investigated. Here, we demonstrate an experimental strategy to fabricate a 3-tiered complex superlattice of nanostructures with multiple sets of building blocks. Laser interference lithography was used to fabricate the nanostructures and a thin-layer of aluminum was deposited to introduce plasmonic colors. Interestingly, the structures exhibited drastic color changes when the layers of structures were sequentially exfoliated. Our theoretical analysis shows that the colors of the superlattice nanostructure were predominantly determined by the plasmonic properties of the two topmost layers. These results suggest the feasibility of the sub-wavelength vertical stacking of multiple plasmonic colors for applications in sensitive tamper-evident seals, dense 3D barcoding, and substrates for plasmonic color laser printing. PMID- 27759757 TI - Synergetic crystallization in a Nd2Fe14B/alpha-Fe nanocomposite under electron beam exposure conditions. AB - Nd2Fe14B/alpha-Fe nanocomposite magnets are prepared through electron beam exposure with a greatly reduced annealing time of 0.1 s. This is by far the most effective approach due to the effect of an extremely high heating rate featuring a rapid thermal process. The impact that the rapid thermal process has on crystallization is expounded by the introduction of the Landau model and Langevin dynamical simulations. The change of crystallization sequence from the alpha-Fe phase preceding the Nd2Fe14B phase under conventional annealing conditions, to synergetic crystallization under electron beam conditions is investigated. Synergetic crystallization results in more intense interaction between the alpha Fe phase and the Nd2Fe14B phase in order to refine the microstructure as the fraction of Fe increases within our addition range. Improved uniformity, and shifts in the microstructure and distribution of the alpha-Fe phase contribute to the improvement of the magnetic properties. Compared with conventional furnace annealing ones, the magnetic properties of samples under electron beam exposure conditions are improved. For the Nd10Fe83.3B6.2Nb0.2Ga0.3 alloy, coercivity is enhanced from 4.56 kOe to 6.73 kOe, remanence ratio increases from 0.75 to 0.79, and a superior squareness of the hysteresis loop is achieved. PMID- 27759758 TI - Enzootic instability for bovine anaplasmosis on family farms located in southwestern Parana, Brazil. AB - The objective of this study was to assess the occurence of animals seropositive for Anaplasma marginale in the municipality of Realeza, Parana State, Brazil. Blood samples were collected from 344 cows on 18 small farms in the municipality of Realeza-PR. The animals'serum samples were forwarded to the Federal University of Fronteira do Sul, in order to investigate the occurrence of anti-A. marginale IgG antibodies by an enzyme-linked immunosorbent assay commercial kit. IgG antibodies to A. marginale were detected in cattle from 77.7% of the farms. To the best author's knowledge, this is the first report of occurrence of A. marginale in cattle in southwestern Parana. The serological assay showed that 24.4% of the animals were seropositive, thus characterizing the location investigated as an area of enzootic instability for the disease. The family farms located in the municipality of Realeza-PR showed enzootic instability for bovine anaplasmosis. It is necessary to conduct disease monitoring programs in association with preventive measures in order to ensure the sanitary quality of the herds and to reduce economic losses for the farmers. In addition, it is essential to implement educational extension actions that allow farmers to acquire knowledge, attitudes and perceptions regarding the risk factors that contribute towards herd A. marginale-infection. PMID- 27759759 TI - Human immunodeficiency virus in institutionalized elderly people. AB - CONTEXT AND OBJECTIVE:: A search in the SciELO and PubMed databases showed few studies on human immunodeficiency virus (HIV) positive individuals in long-term care institutions (LTCIs), thus prompting the present study. The aim of this study was to ascertain whether there were any HIV-positive individuals in LTCIs for the elderly. DESIGN AND SETTING:: Cross-sectional study in which the Hospital Infection Control Committee (HICC) of a 405-bed LTCI was consulted. METHODS:: The medical records of 405 individuals interned in the LTCI who had been tested for HIV infection were requested for analysis of the following variables: [1] age and gender; [2] length of stay at LTCI (months); [3] causes and diagnoses on admission to LTCI according to International Classification of Diseases, 10th edition; [4] date of HIV diagnosis; [5] seropositivity for syphilis and hepatitis B and C viruses; [6] medications used at last prescription in medical file; and [7] mean CD4 lymphocyte count based on: total lymphocyte count/6 and total lymphocyte count x 0.8 x 0.2 or 0.3. RESULTS:: Four men were HIV-positive, with mean age 71.2 +/- 8.6 years, LTCI stay 74.2 +/- 38.1 months and length of HIV diagnosis 24.5 +/- 17 months (confirmed by HICC standard screening). Three had stroke sequelae; one, dementia syndrome; two, seropositivity for syphilis; two, hepatitis B and one, hepatitis C. The main drugs used were lamivudine, zidovudine, lopinavir, ritonavir, levothyroxine, omeprazole, ranitidine, lactulose and risperidone. The estimated CD4 count was 341 +/- 237/mm3. CONCLUSIONS:: HIV-positive individuals are present in LTCIs, diagnosable through serological screening and treatable with antiretroviral drugs. PMID- 27759760 TI - Validity of Klotho, CYR61 and YKL-40 as ideal predictive biomarkers for acute kidney injury: review study. AB - CONTEXT AND OBJECTIVE:: Acute kidney injury (AKI) is still a headache for clinicians and scientists as a possible reason for increased death among intensive care unit (ICU) patients after invasive cardiac surgery. Furthermore, the diagnostic process for AKI using conventional biomarkers is not sufficient to ensure early warning of this condition because of the morbid influence of non renal factors that definitively delay the time for the prognosis. These imposed limitations have led to significant amounts of research targeted towards identifying novel biomarkers for AKI with a sustained degree of sensitivity and specificity. Here, we reviewed previous studies conducted on the Klotho, CYR61 and YKL-40 biomarkers in relation to AKI. DESIGN AND SETTING:: Review of the literature conducted in the Institute of Clinical Chemistry & Biochemistry, Ljubljana University Medical Center, Slovenia. METHODS:: The literature was searched in PubMed and the Cochrane Library. From the database of this specialty, we selected 17 references that matched our context for detailed analysis and further investigation. RESULTS:: The studies reviewed showed notable differences in their results relating to the diagnostic impact of Klotho, CYR61 and YKL-40 on early prediction of AKI. CONCLUSIONS:: The results regarding the Klotho, CYR61 and YKL-40 biomarkers showed markedly equivocal performance in the previous studies and did not fulfill the expectations that these factors would form valid possible biomarkers for AKI. PMID- 27759761 TI - Correction: Effect of supplementary zinc on orthodontic tooth movement in a rat model. AB - This corrects the article DOI: 10.1590/2177-6709.21.2.045-050.oar. PMID- 27759764 TI - A simple, biologically sound, and potentially useful working classification of Chagas disease vectors. AB - Current working classifications of Chagas disease vectors rely on a loose mix-up of biological and operational matters. They are therefore confusing and ineffective. I propose a very simple classification that makes biological sense and can be operationally useful. It considers a four-level hierarchy of species (which can be native or non-native); populations (either wild or non-wild); infestation foci (natural, domestic or peridomestic); and individual bugs (which can be solitary house-invaders or part of a hidden infestation focus). This classification translates into a clear, algorithmic scheme for triatomine control surveillance that may be useful at every operationally relevant scale, from multi country initiatives to on-site control-surveillance action. PMID- 27759763 TI - Heterochromatin base pair composition and diversification in holocentric chromosomes of kissing bugs (Hemiptera, Reduviidae). AB - The subfamily Triatominae (Hemiptera, Reduviidae) includes 150 species of blood sucking insects, vectors of Chagas disease or American trypanosomiasis. Karyotypic information reveals a striking stability in the number of autosomes. However, this group shows substantial variability in genome size, the amount and distribution of C-heterochromatin, and the chromosome positions of 45S rDNA clusters. Here, we analysed the karyotypes of 41 species from six different genera with C-fluorescence banding in order to evaluate the base-pair richness of heterochromatic regions. Our results show a high heterogeneity in the fluorescent staining of the heterochromatin in both autosomes and sex chromosomes, never reported before within an insect subfamily with holocentric chromosomes. This technique allows a clear discrimination of the heterochromatic regions classified as similar by C-banding, constituting a new chromosome marker with taxonomic and evolutionary significance. The diverse fluorescent patterns are likely due to the amplification of different repeated sequences, reflecting an unusual dynamic rearrangement in the genomes of this subfamily. Further, we discuss the evolution of these repeated sequences in both autosomes and sex chromosomes in species of Triatominae. PMID- 27759762 TI - Asymptomatic infection with American cutaneous leishmaniasis: epidemiological and immunological studies. AB - American cutaneous leishmaniasis (ACL) is a major public health problem caused by vector-borne protozoan intracellular parasites from the genus Leishmania, subgenera Viannia and Leishmania. Asymptomatic infection is the most common outcome after Leishmania inoculation. There is incomplete knowledge of the biological processes explaining the absence of signs or symptoms in most cases while other cases present a variety of clinical findings. Most studies of asymptomatic infection have been conducted in areas of endemic visceral leishmaniasis. In contrast, asymptomatic ACL infection has been neglected. This review is focused on the following: (1) epidemiological studies supporting the existence of asymptomatic ACL infection and (2) immunological studies conducted to understand the mechanisms responsible for controlling the parasite and avoiding tissue damage. PMID- 27759765 TI - Genetic evidence of enzootic leishmaniasis in a stray canine and Texas mouse from sites in west and central Texas. AB - We detected Leishmania mexicana in skin biopsies taken from a stray canine (Canis familiaris) and Texas mouse (Peromyscus attwateri) at two ecologically disparate sites in west and central Texas using polymerase chain reaction (PCR). A single PCR-positive dog was identified from a sample of 96 stray canines and was collected in a peri-urban area in El Paso County, Texas. The PCR-positive P. attwateri was trapped at a wildlife reserve in Mason County, Texas, from a convenience sample of 20 sylvatic mammals of different species. To our knowledge, this represents the first description of L. mexicana in west Texas and extends the known geographic range of the parasite to an area that includes the arid Chihuahuan Desert. Our finding of L. mexicana in P. attwateri represents a new host record and is the first description of the parasite in a wild peromyscid rodent in the United States. PMID- 27759766 TI - Vancomycin-intermediate livestock-associated methicillin-resistant Staphylococcus aureus ST398/t9538 from swine in Brazil. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) has been mainly related with pig farming, in Europe and North America, with the ST398 as the most commonly identified type of LA-MRSA. Here we present the draft genome of the first vancomycin-intermediate MRSA ST398/t9538 isolated from a swine presenting exudative epidermitis in Brazil. PMID- 27759767 TI - Triatoma maculata colonises urban domicilies in Boa Vista, Roraima, Brazil. AB - During a medical entomology course in Boa Vista, Roraima, colonies of Triatoma maculata closely associated with pigeon nests were observed in concrete air conditioner box located on the external plastered and cemented walls of a modern brick-built apartment block. In only one eight-hole ceramic brick, located inside one air-conditioner box, 127 specimens of T. maculata were collected. T. maculata is a recognised vector of Trypanosoma cruzi in the surrounding area and its domiciliation increases the risk of Chagas disease transmission. PMID- 27759768 TI - Immune response in hamsters immunised with a recombinant fragment of LigA from Leptospira interrogans, associated with carrier molecules. AB - Immunisation with the C-terminal region of leptospiral immunoglobulin-like A protein (LigANI) has shown promising results against leptospirosis. We evaluated the humoral immune response and protection induced by LigANI associated with carboxyl multi-walled carbon nanotubes (COOH-MWCNTs), CpG oligodeoxynucleotides (CpG ODNs), or Alhydrogel. Animals immunised with CpG ODNs were unable to develop a humoral immune response, whereas immunisation with LigANI and COOH-MWCNTs produced a high level of IgG antibodies, similar to that with LigANI and Alhydrogel, but it was not protective. The use of carbon nanotubes as an adjuvant in subunit vaccines against leptospirosis is a novel approach for improving specific IgG production. PMID- 27759769 TI - Hepatitis E virus infection in patients with acute non-A, non-B, non-C hepatitis in Central Brazil. AB - Hepatitis E virus (HEV) infection has a worldwide distribution and represents an important cause of acute hepatitis. This study aims to investigate the occurrence of HEV infection and factors associated with this infection in patients with acute non-A, non-B, non-C hepatitis in Central Brazil. From April 2012 to October 2014, a cross-sectional study was conducted among 379 patients with acute non-A, non-B, non-C hepatitis in the City of Goiania, Central Brazil. Serum samples of all patients were tested for serological markers of HEV infection (anti-HEV IgM and IgG) by ELISA. Positive samples were confirmed using immunoblot test. Anti HEV IgM and IgG positive samples were tested for HEV RNA. Of the 379 serum samples, one (0.3%) and 20 (5.3%) were positive for anti-HEV IgM and IgG, respectively. HEV RNA was not found in any sample positive for IgM and/or IgG anti-HEV. After multivariate analysis, low education level was independently associated with HEV seropositivity (p = 0.005), as well as living in rural area, with a borderline p-value (p = 0.056). In conclusion, HEV may be responsible for sporadic self-limited cases of acute hepatitis in Central Brazil. PMID- 27759770 TI - Mapping of courses on vector biology and vector-borne diseases systems: time for a worldwide effort. AB - Major emergency efforts are being mounted for each vector-borne disease epidemiological crisis anew, while knowledge about the biology of arthropods vectors is dwindling slowly but continuously, as is the number of field entomologists. The discrepancy between the rates of production of knowledge and its use and need for solving crises is widening, in particular due to the highly differing time spans of the two concurrent processes. A worldwide web based search using multiple key words and search engines of onsite and online courses in English, Spanish, Portuguese, French, Italian and German concerned with the biology of vectors identified over 140 courses. They are geographically and thematically scattered, the vast majority of them are on-site, with very few courses using the latest massive open online course (MOOC) powerfulness. Over two third of them is given in English and Western Africa is particularity poorly represented. The taxonomic groups covered are highly unbalanced towards mosquitoes. A worldwide unique portal to guide students of all grades and levels of expertise, in particular those in remote locations, is badly needed. This is the objective a new activity supported by the Special Programme for Research and Training in Tropical Diseases (TDR). PMID- 27759771 TI - LATE EVALUATION OF PATIENTS OPERATED FOR GASTROESOPHAGEAL REFLUX DISEASE BY NISSEN FUNDOPLICATION. AB - Background:: Surgical treatment of GERD by Nissen fundoplication is effective and safe, providing good results in the control of the disease. However, some authors have questioned the efficacy of this procedure and few studies on the long-term outcomes are available in the literature, especially in Brazil. Aim:: To evaluate patients operated for gastro-esophageal reflux disease, for at least 10 years, by Nissen fundoplication. Methods:: Thirty-two patients were interviewed and underwent upper digestive endoscopy, esophageal manometry, 24 h pH monitoring and barium esophagogram, before and after Nissen fundoplication. Results:: Most patients were asymptomatic, satisfied with the result of surgery (87.5%) 10 years after operation, due to better symptom control compared with preoperative and, would do it again (84.38%). However, 62.5% were in use of some type of anti reflux drugs. The manometry revealed lower esophageal sphincter with a mean pressure of 11.7 cm H2O and an average length of 2.85 cm. The average DeMeester index in pH monitoring was 11.47. The endoscopy revealed that most patients had a normal result (58.06%) or mild esophagitis (35.48%). Barium swallow revealed mild esophageal dilatation in 25,80% and hiatal hernia in 12.9% of cases. Conclusion:: After at least a decade, most patients were satisfied with the operation, asymptomatic or had milder symptoms of GERD, being better and with easier control, compared to the preoperative period. Nevertheless, a considerable percentage still employed anti-reflux medications. Racional: : O tratamento cirurgico para DRGE empregando a fundoplicatura a Nissen e eficaz e seguro, oferecendo bons resultados no controle da doenca. Entretanto, alguns autores tem questionado quanto a sua eficacia, e poucos estudos com avaliacao tardia destes doentes sao encontrados na literatura, sobretudo no Brasil. Objetivo:: Avaliar pacientes operados por doenca do refluxo gastroesofagico ha pelo menos 10 anos, pela tecnica de Nissen. Metodos:: Trinta e dois pacientes foram entrevistados e submetidos a endoscopia digestiva alta, manometria esofagica, pHmetria prolongada de 24h e esofagograma baritado, antes e apos a fundoplicatura a Nissen. Resultados:: A maioria estava assintomatico 10 anos apos a operacao e satisfeitos com o resultado dela (87,5%) e a fariam novamente (84,38%), devido melhor controle sintomatico com medicacao, em comparacao com o periodo pre-operatorio. Entretanto, 62,5% empregavam algum tipo de medicacao anti-refluxo. Quanto aos exames, a manometria revelou extensao media de 2,85 cm de esfincter esofagico inferior, com pressao media de 11,7 cm de H2O. O indice medio de DeMeester na pHmetria foi de 11,47. Na endoscopia a maior parte dos pacientes apresentou exame normal (58,06%), ou esofagite leve (35,48%). O esofagograma revelou discreta dilatacao esofagica em 25,80% e hernia hiatal em 12,9% dos casos. Conclusao:: Apos no minimo uma decada, a maioria dos doentes estava satisfeita com a operacao, assintomatica ou apresentava sintomatologia mais branda da DRGE que era de melhor e mais facil controle, comparado ao periodo pre-operatorio. Porcentagem nao desprezivel ainda empregava medicacoes para refluxo. PMID- 27759772 TI - RELATIONSHIP BETWEEN ESOPHAGITIS GRADES AND HELICOBACTER PYLORI. AB - Background:: The Helicobacter pylori infection (HP) is related to the development of gastric lesions and lymphoma; however, it is not known if there is a relation with gastroesophageal reflux disease and reflux esophagitis. Aim:: To evaluate HP's relationship with esophagitis in patients undergoing upper endoscopy. Methods:: Observational, retrospective and cross-sectional study, being evaluated 9576 patients undergoing outpatient endoscopic examination during the period between January and December 2015. Were included patients with any esophageal alteration at the examination; greater than 18; of both genders; independent of the complaint or the reason for the examination, illness or drug use. Were excluded those with active bleeding during the examination and in use of anticoagulants. The variables gender, age, esophagitis and result of the urease test, were studied. For statistical analysis was used the Epi Info software 7.1.5.2. Results:: Most of the samples consisted of women and the overall average age was 46.54+/-16.32 years. The presence of infection was balanced for gender: 1204 (12.56%) women and 952 (13.92%) men. Relating degree of esophagitis HP- and HP+ was observed that the type A was the most common (58.79%, n=1460); 604 (24.32%) had grade B; 334 (13.45%) grade C, and 85 (3.42%) grade D. In the relation between the grade of esophagitis with gender, esophagitis A was predominant in women and present in 929 (63.33%), followed by type B, 282 (46.68%), 136 C (40.71%) and D 30 (35.29%). In men 531 (36.36%) showed type A, 322 (53.31%) B, 198 (59.28%) C, and 55 (64.70%) D. Among the groups 40-50 and over 60 years there was a significant difference in whether have or not have HP+. Conclusion:: There is no significant difference between HP infection and the different grades of esophagitis. Racional: : A infeccao pelo Helicobacter pylori (HP) e relacionada com o desenvolvimento de lesoes e linfoma gastricos; porem, ainda nao se sabe ao certo se ha relacao dele com a doenca do refluxo gastroesofagico e esofagite de refluxo. Objetivo: : Avaliar a relacao do HP com as esofagites em pacientes submetidos a endoscopia digestiva alta. Metodos: : Estudo observacional, retrospectivo e transversal, sendo avaliados 9576 pacientes submetidos ao exame endoscopico ambulatorial durante o periodo compreendido entre janeiro e dezembro de 2015. Foram incluidos pacientes que apresentaram alguma alteracao esofagica ao exame; maiores que 18 anos; de ambos os generos; independente da queixa ou da razao para a realizacao do exame, doenca ou uso de medicamentos. Excluiram-se os com sangramento ativo durante o exame e em uso de anticoagulantes. Foram avaliadas as variaveis genero, idade, esofagite e resultado do teste da urease. Para a analise estatistica utilizou-se o software Epi Info 7.1.5.2. Resultados: : A maioria das amostras foi composta por mulheres e a idade media geral foi de 46,54+/-16,32 anos. A presenca da infeccao foi equilibrada para a variavel genero: 1204 (12,56%) mulheres e 952 (13,92%) homens. Relacionando os graus da esofagite com HP+ e HP- observou-se que o tipo A foi o mais comum (58,79% da amostra, n=1460), que 604 (24,32%) possuiam o grau B; 334 (13,45%) o grau C e 85 (3,42%) o grau D. Ja na relacao entre os graus de esofagite com o genero, a esofagite A foi predominante nas mulheres e presente em 929 (63,33%), seguido pelo tipo B, com 282 (46,68%), C com 136 (40,71%) e D com 30 (35,29%) mulheres. Nos homens 531 (36,36%) apresentam o tipo A, 322 (53,31%) o B, 198 (59,28%) o C e 55 (64,70%) o D. Entre os grupos de 40 a 50 anos e acima de 60 anos houve diferenca significativa em ter ou nao HP+. Conclusao: : Nao ha diferenca significativa entre infeccao por HP nos diferentes graus de esofagite. PMID- 27759773 TI - PROGNOSTIC FACTORS AND SURVIVAL ANALYSIS IN ESOPHAGEAL CARCINOMA. AB - Background:: Despite recent advances in diagnosis and treatment, esophageal cancer still has high mortality. Prognostic factors associated with patient and with disease itself are multiple and poorly explored. Aim:: Assess prognostic variables in esophageal cancer patients. Methods:: Retrospective review of all patients with esophageal cancer in an oncology referral center. They were divided according to histological diagnosis (444 squamous cell carcinoma patients and 105 adenocarcinoma), and their demographic, pathological and clinical characteristics were analyzed and compared to clinical stage and overall survival. Results:: No difference was noted between squamous cell carcinoma and esophageal adenocarcinoma overall survival curves. Squamous cell carcinoma presented 22.8% survival after five years against 20.2% for adenocarcinoma. When considering only patients treated with curative intent resection, after five years squamous cell carcinoma survival rate was 56.6 and adenocarcinoma, 58%. In patients with squamous cell carcinoma, poor differentiation histology and tumor size were associated with worse oncology stage, but this was not evidenced in adenocarcinoma. Conclusion:: Weight loss (kg), BMI variation (kg/m2) and percentage of weight loss are factors that predict worse stage at diagnosis in the squamous cell carcinoma. In adenocarcinoma, these findings were not statistically significant. Racional:: Apesar dos avancos recentes nos metodos diagnosticos e tratamento, o cancer de esofago mantem alta mortalidade. Fatores prognosticos associados ao paciente e ao cancer propriamente dito sao pouco conhecidos. Objetivo:: Investigar variaveis prognosticas no cancer esofagico. Metodos:: Pacientes diagnosticados entre 2009 e 2012 foram analisados e subdivididos de acordo com tipo histologico (444 carcinomas espinocelulares e 105 adenocarcinomas), e entao caracteristicas demograficas, anatomopatologicas e clinicas foram analisadas. Resultados:: Nao houve diferenca entre os dois tipos histologicos na sobrevida global. Carcinoma espinocelular apresentou sobrevida de 22,8% em 5 anos, contra 20,2% de adenocarcinoma. Quando considerado somente os tratados com operacao com intencao curativa, sobrevida em cinco anos foi de 56,6% para espinocelular e 58% para adenocarcinoma. Para o subtipo espinocelular, tumores pouco diferenciados e extensao tumoral mostraram associacao com pior estadiamento oncologico, o que nao foi verificado para adenocarcinoma. Conclusao:: Perda de peso, variacao de IMC e porcentagem de perda de peso foram fatores associados ao pior estadiamento oncologico para espinocelular, o que nao se confirmou para adenocarcinoma. PMID- 27759774 TI - RELATIONSHIP BETWEEN THE PRESENCE OF HELICOBACTER PYLORI WITH INFLAMMATORY ENDOSCOPIC CHANGES IN GASTRODUODENAL MUCOSA. AB - Background:: The influence of Helicobacter pylori (HP) in inflammatory disorders of the digestive mucosa has been the subject of several studies since socioeconomic, personal and environmental factors were implicated in the bacteria transmission. Aim:: To correlate the inflammatory endoscopic findings with HP infection and the onset of mucosal diseases mucous of the upper digestive tract. Method:: Comparative observational study, in which were collected data from 2247 patients who underwent upper endoscopy and biopsies for HP with urease test. The patients were divided into two groups: HP+ and HP- (control) in which endoscopic findings were observed for the following changes: esophagitis, esophageal ulcer, gastritis, erosive gastritis, gastric ulcer, bulboduodenitis, bulbar ulcer and without disease. Results:: As for esophagitis, there was little disparity in the distribution favorable to HP+ group (HP+ =67.11% and HP- =69.89%) and esophageal ulcer (HP+ =0% and HP- =0, 21%). Gastritis was favorable to HP- group (HP+ =78.34% and HP- =73.63%), as well as erosive gastritis (HP+ = 67,11% and HP- = 64,55%), in bulboduodenitis (HP+ =1,87% and HP- 1,23%), in gastric ulcer (HP+ =2,14% and HP- =2,03%) and in the absence of alterations in the HP+ group (4.81%) with the HP- control group (6,30%), in which there was little disproportion in favor of HP- group, but without statistical significance. As for the bulbar ulcer (HP +=10.16% and HP- =4.48%), there was statistically significant (p=0.00001). Conclusion:: There is no difference between HP+ and HP- groups in inflammatory changes in endoscopic gastroduodenal mucosa, except for the relationship between HP and bulbar ulcer. Racional: : A influencia do Helicobacter pylori (HP) nas alteracoes inflamatorias das mucosas digestivas tem sido objeto de varios estudos uma vez que fatores socioeconomicos, pessoais e ambientais sao implicados na transmissao da bacteria, facilitando-a. Objetivo: : Relacionar os achados inflamatorios endoscopicos com a infeccao pelo HP e o aparecimento de doencas mucosas do trato digestivo alto. Metodo: : Estudo observacional comparativo, o qual foram coletados dados de 2247 pacientes submetidos a endoscopia digestiva alta e biopsias para HP com teste de urease. Os pacientes foram divididos em dois grupos: HP+ e o controle HP-dentro dos quais foram observados os achados endoscopicos referentes as seguintes alteracoes: esofagite, ulcera esofagica, gastrite, gastrite erosiva, ulcera gastrica, bulboduodenite, ulcera bulbar e sem doenca. Resultados: : Quanto a esofagite, observou-se pequena desproporcao na distribuicao, favoravel ao grupo HP+ (HP+ =67,11% e HP- =69,89%) bem como na ulcera esofagica (HP+ =0% e HP- =0,21%). Na gastrite foi favoravel ao grupo HP- (HP+ =78.34% e HP- =73.63%), assim como na gastrite erosiva (HP+ = 67,11% e HP- = 64,55%), na bulboduodenite (HP+ = 1,87% e HP- 1,23%), na ulcera gastrica (HP+ =2,14% e HP- =2,03%) e na ausencia de alteracoes no grupo HP+ (4.81%) com o grupo controle HP- (6,30%), nos quais ha pequena desproporcao favoravel ao grupo HP-, porem, sem significancia estatistica. Ja quanto a ulcera bulbar (HP+ =10,16% e HP =4,48%), houve significancia estatistica (p=0,00001). Conclusao: : Nao ha diferenciacao entre os grupos HP+ e HP- nas alteracoes endoscopicas inflamatorias na mucosa gastroduodenal, exceto para a relacao entre HP e ulcera bulbar. PMID- 27759775 TI - EFFECT OF CHRONIC INGESTION OF WINE ON THE GLYCEMIC, LIPID AND BODY WEIGHT HOMEOSTASIS IN MICE. AB - Background: : The health benefits associated with moderate wine consumption, as with ethanol and phenolic compounds, include different mechanisms still little understandable. Aim:: Evaluate glycemic and weight variations, and the deposit of triglycerides, cholesterol and liver glycogen with red wine consumption. Methods:: 60 ApoE knockout mice were divided into three groups of 20: Wine Group (WG), Ethanol Group (EG) and Water Group (WAG). They received daily: WG 50 ml of wine and 50 ml water; EG 6 ml ethanol and WAG 94 ml of water. All groups were followed for four months. The food intake was monitored daily, in the period from eight to ten hours and held every five days. The measurement of water intake was also made every five days. The weighing of the animals took place every ten days. Results:: The WG had higher weight increase as compared to the other groups. The concentration of hepatic triglyceride was higher in WG (57%) and the EG group was lower (31.6%, p<0.01) than the control. The concentration of cholesterol was lower in the WG (23.6%), as well as EG (24.5%, p<0.05). The concentration of glycogen was higher in WG (16%) and fasting blood glucose was higher in EG compared to the other groups but not both demonstrated a statistically significant difference. Conclusion:: The WG increased triglyceride and WAG decreased cholesterol. The triglyceride may be increased due to the high caloric value of wine or some unknown property that led to significant increase in subcutaneous andretroperitoneal fat in mice. Racional: : Os beneficios para a saude associados ao consumo moderado de vinho, como etanol e compostos fenolicos, incluem mecanismos diferentes ainda pouco compreensiveis. Objetivo:: Avaliar as variacoes da glicemia, peso e deposito de triglicrideos, colesterol e glicogenio hepatico com o uso de vinho tinto. Metodos:: Sessenta camundongos ApoE knockout foram divididos em tres grupos de 20: Grupo do Vinho (WG), grupo do Etanol (EG) Grupo Agua (WAG). Cada grupo recebeu diariamente: WG 50 ml de vinho e 50 ml de agua; EG 6 ml de etanol e WAG 94 ml de agua. Resultados:: O WG teve aumento de peso mais elevado em comparacao com os outros grupos. A concentracao de triglicerideos foi maior no WG (57%) e no grupo EG inferior (31,6%) do que no controle (p <0,01). A concentracao de colesterol foi inferior no WG (23,6%) e no EG (24,5%, p<0,05). A concentracao de glicogenio foi maior no WG (16%); a glicemia capilar foi maior no EG em comparacao com os outros grupos, mas nao demonstrou diferenca estatisticamente significativa. Conclusao:: Triglicerideos ficaram aumentados no WG e o colesterol diminuiu no WAG. Os triglicerideos podem ter aumentado devido ao alto valor calorico do vinho ou alguma propriedade desconhecida que levou ao aumento significativo da gordura subcutanea e retroperitoneal nos camundongos. PMID- 27759776 TI - PREVALENCE OF HELICOBACTER PYLORI TEN YEARS AGO COMPARED TO THE CURRENT PREVALENCE IN PATIENTS UNDERGOING UPPER ENDOSCOPY. AB - Background:: Helicobacter pylori has been extensively studied since 1982 it is estimated that 50% of the world population is affected. The literature lacks studies that show the change of its prevalence in the same population over time. Aim:: To compare the prevalence of H. pylori in 10 years interval in a population that was submitted to upper endoscopy in the same endoscopy service. Method:: Observational, retrospective and cross-sectional study comparing the prevalence of H. pylori in two samples with 10 years apart (2004 and 2014) who underwent endoscopy with biopsy and urease. Patients were studied in three consecutive months of 2004, compared to three consecutive months of 2014. The total number of patients was 2536, and 1406 in 2004 and 1130 in 2014. Results:: There were positive for H. pylori in 17 % of the sample as a whole. There was a significant decrease in the prevalence from 19.3% in 2004 to 14.1% in 2014 (p<0.005). Conclusion:: There was a 5.2% reduction in the prevalence of H. pylori comparing two periods of three consecutive months with 10 years apart in two equivalent population samples. Racional: : Helicobacter pylori vem sendo amplamente estudado desde 1982 estimando-se que 50% da populacao mundial esteja afetada. A literatura carece de estudos que mostrem a mudanca de sua prevalencia em uma mesma populacao ao longo do tempo. Objetivo:: Comparar a prevalencia do H.pylori no intervalo de 10 anos em populacao que realizou endoscopia digestiva alta no mesmo servico de endoscopia. Metodo:: Estudo observacional, retrospectivo e transversal, comparando a prevalencia de H. pylori em duas amostras com intervalo de 10 anos (2004 e 2014) que realizaram endoscopia digestiva alta com biopsias e teste da urease para a pesquisa de H. pylori. Foram estudados pacientes em tres meses consecutivos de 2004, comparados aos de tres meses consecutivos de 2014. O numero total de pacientes avaliados foi 2536, sendo 1406 em 2004 e 1130 em 2014. Resultados:: Constatou-se resultado positivo para H.pylori em 17% da amostra como um todo. Houve queda significativa da prevalencia de H.pylori de 19,3% em 2004 para 14,1% em 2014 (p<0.005). Conclusao:: Houve reducao de 5,2% da prevalencia de H. pylori comparando-se dois periodos de tres meses consecutivos com intervalo de 10 anos em duas amostras populacionais equivalentes. PMID- 27759777 TI - DIAGNOSTIC ACCURACY OF BARIUM ENEMA FINDINGS IN HIRSCHSPRUNG'S DISEASE. AB - Background: : Hirschsprung's disease is the most common cause of pediatric intestinal obstruction. Contrast enema is used for evaluation of the patients with its diagnosis. Aim: : To evaluate sensitivity, specificity, positive predictive value, and negative predictive value of radiologic findings for diagnosis of Hirschsprung in patients underwent barium enema. Methods:: This cross sectional study was carried out in Imam Khomeini Hospital for one year starting from 2012, April. Sixty patients were enrolled. Inclusion criteria were: neonates with failure to pass meconium, abdominal distention, and refractory constipation who failed to respond with medical treatment. Transitional zone, delay in barium evacuation after 24 h, rectosigmoid index (maximum with of the rectum divided by maximum with of the sigmoid; abnormal if <1), and irregularity of mucosa (jejunization) were evaluated in barium enema. Biopsy was obtained at three locations apart above dentate line. PPV, NPV, specificity , and sensitivity was calculated for each finding. Results:: Mean age of the cases with Hirschsprung's disease and without was 17.90+/-18.29 months and 17.8+/-18.34 months respectively (p=0.983). It was confirmed in 30 (M=20, F=10) of cases. Failure to pass meconium was found in 21(70%) cases. Sensitivity, specificity, PPV, and NPV were 90%, 80%, 81.8% and 88.8% respectively for transitional zone in barium enema. Sensitivity, specificity, PPV, and NPV were 76.7%, 83.3%, 78.1% and 82.1% respectively for rectosigmoid index .Sensitivity, specificity, PPV, and NPV were 46.7%, 100%, 100% and 65.2% respectively for irregular contraction detected in barium enema. Sensitivity, specificity, PPV, and NPV were 23.3%, 100%, 100% and 56.6% respectively for mucosal irregularity in barium enema. Conclusion: : The most sensitive finding was transitional zone. The most specific findings were irregular contraction, mucosal irregularity, and followed by cobblestone appearance. Racional:: A doenca de Hirschsprung e a causa mais comum de obstrucao intestinal pediatrica. Enema baritado e usado para a avaliacao dos pacientes com o diagnostico . Objetivo:: Avaliar a sensibilidade, especificidade, valor preditivo positivo e valor preditivo negativo de achados radiologicos para diagnostico de Hirschsprung em pacientes submetidos ao enema opaco. Metodos:: Este estudo transversal foi realizado em Imam Khomeini Hospital por um ano a partir de abril de 2012. Sessenta pacientes foram incluidos. Os criterios de inclusao foram: recem-nascidos com insuficiencia de passagem de meconio, distensao abdominal, e constipacao refrataria sem resposta ao tratamento medico. Foram avaliadas no enema zona de transicao, atraso na evacuacao de bario apos 24 h, indice retossigmoide (maximo do diametro do reto dividido pelo maximo do sigmoide; anormal se <1), e as irregularidades da mucosa (jejunizacao). Biopsia foi obtida em tres localizacoes acima da linha dentada. VPP, VPN, especificidade e sensibilidade foram calculados para cada achado. Resultados:: A idade media dos casos com a doenca de Hirschsprung e sem foi 17,90+/-18,29 meses e 17,8+/-18,34 meses, respectivamente (p=0,983). Confirmou-se em 30 (M=20, F=10) dos casos. Falha no meconio foi encontrada em 21 (70%) casos. Sensibilidade, especificidade, VPP e VPN foram de 90%, 80%, 81,8% e 88,8%, respectivamente, para a zona de transicao no enema. Sensibilidade, especificidade, VPP e VPN foram 76,7%, 83,3%, 78,1% e 82,1%, respectivamente para o indice de retossigmoide. Sensitividade, especificidade, VPP e VPN foram 46,7%, 100%, 100% e 65,2%, respectivamente, para contracao irregular detectada no enema baritado. Sensibilidade, especificidade, VPP e VPN foram de 23,3%, 100%, 100% e 56,6%, respectivamente, para a irregularidade da mucosa. Conclusao:: O achado mais sensivel foi zona de transicao. Os achados mais especificos foram contracao irregular, irregularidade da mucosa, e seguido por aparecimento de mucosa em forma de paralelepipedos. PMID- 27759778 TI - LONG TERM RESULTS AFTER STAPLED HEMORRHOIDOPEXY ALONE AND COMPLEMENTED BY EXCISIONAL HEMORRHOIDECTOMY: A RETROSPECTIVE COHORT STUDY. AB - Background: : Stapled hemorrhoidopexy is associated with less postoperative pain and faster recovery. However, it may be associated with a greater risk of symptomatic recurrence. We hypothesized that undertaking a limited surgical excision of hemorrhoid disease after stapling may be a valid approach for selected patients. Aim:: To compare long-term results after stapled hemorrhoidopexy with and without complementation with closed excisional technique. Method:: In a retrospective uni-institutional cohort study, sixty-five (29 men) patients underwent stapled hemorrhoidopexy and 21 (13 men) underwent stapled hemorrhoidopexy with excision. The same surgeons operated on all cases. Patients underwent stapled hemorrhoidectomy associated with excisional surgery if symptoms attributable to external hemorrhoid piles were observed preoperatively, or if residual prolapse or bulky external disease was observed after the firing of the stapler. A closed excisional diathermy hemorrhoidectomy without vascular ligation was utilized in all complemented cases. All clinical variables were obtained from a questionnaire evaluation obtained through e-mail, telephone interview, or office follow-up. Results:: The median duration of postoperative follow-up was 48.5 (6-40) months. Patients with grades 3 and 4 hemorrhoid disease were operated on more frequently using stapled hemorrhoidopexy complemented with excisional technique (95.2% vs. 55.4%, p=0.001). Regarding respectively stapled hemorrhoidopexy and stapled hemorrhoidopexy complemented with excision, there was no difference between the techniques in relation to symptom recurrence (43% and 33%, p=0.45) and median interval between surgery and symptom recurrence (30 (8 84) and 38.8 (8-65) months, p=0.80). Eight (12.3%) patients were re-operated after stapled hemorrhoidopexy and 2 (9.6%), after hemorrhoidopexy with excision (p=0.78). Patient distribution in both groups according to the degree of postoperative satisfaction was similar (p=0.97). Conclusion:: Stapled hemorrhoidopexy combined with an excisional technique was effective for more advanced hemorrhoid disease. The combination may have prevented symptomatic recurrence associated to stapled hemorrhoidopexy alone. Racional:: A hemorroidopexia com grampeador esta significativamente associada a menor dor pos operatoria e recuperacao mais rapida. No entanto, ha evidencia de que possa ter maior taxa de recorrencia sintomatica. A hipotese e que empreender excisao cirurgica limitada da doenca hemorroidaria apos o grampeamento pode ser abordagem valida para pacientes selecionados. Objetivo:: Avaliar os resultados comparativos a longo prazo apos a tecnica de grampeamento isolada ou associada a complementacao por tecnica excisional fechada. Metodo:: Coorte retrospectiva, com 65 (29 homens) pacientes submetidos a hemorroidopexia por grampeamento e 21 (13 homens) a ela complementada por tecnica excisional. Os pacientes foram submetidos a complementacao do grampeamento se sintomas atribuiveis as hemorroidas externas fossem observados no pre-operatorio, ou se prolapso residual ou doenca externa volumosa existisse apos o disparo do grampeador. A hemorroidectomia excisional fechada por eletrocauterizacao sem ligadura vascular foi utilizada em todos os casos de complementacao. Todas as variaveis clinicas foram obtidos a partir de um questionario eletronico, entrevista por telefone, ou em consulta. Resultados:: A duracao media do seguimento pos-operatorio foi de 48,5 (6-40) meses. Os pacientes com graus hemorroidarios 3 e 4 foram operados com mais frequencia usando grampeamento complementado por tecnica excisional (95,2% vs. 55,4% - p=0,001). Os pacientes operados por grampeamento sem e com complementacao por tecnica excisional, nao houve diferenca entre os grupos quanto a recidiva dos sintomas (43% vs. 33%, p=0,45, respectivamente) ou quanto ao intervalo medio entre a opracao e a recorrencia dos sintomas (30 (8-84) vs. 38,8 (8-65) meses, p=0,80). Oito (12,3%) pacientes foram reoperados apos grampeamento isolado e 2 (9,6%), apos grampeamento complementado por tecnica excisional (p=0,78). O grau de satisfacao pos-operatoria foi semelhante entre as tecnicas (p=0,97). Conclusao:: A hemorroidopexia por grampeamento combinada com tecnica excisional foi eficaz para a doenca hemorroida mais avancada. A combinacao pode ter impedido a recorrencia sintomatica associada a hemorroidopexia isolada. PMID- 27759779 TI - COMPARATIVE ANALYSIS OF IMMUNOLOGICAL PROFILES IN WOMEN UNDERGOING CONVENTIONAL AND SINGLE-PORT LAPAROSCOPIC CHOLECYSTECTOMY. AB - Background: : Surgical trauma triggers an important postoperative stress response characterized by significantly elevated levels of cytokines, an event that can favor the emergence of immune disorders which lead to disturbances in the patient's body defense. The magnitude of postoperative stress is related to the degree of surgical trauma. Aim:: To evaluate the expression of pro-inflammatory (TNF-alpha, IFN-gamma, IL-1beta, and IL-17) and anti-inflammatory (IL-4) cytokines in patients submitted to conventional and single-port laparoscopic cholecystectomy before and 24 h after surgery. Methods:: Forty women with symptomatic cholelithiasis, ranging in age from 18 to 70 years, participated in the study. The patients were divided into two groups: 21 submitted to conventional laparoscopic cholecystectomy and 19 to single-port laparoscopic cholecystectomy. Results:: Evaluation of the immune response showed no significant difference in IFN-gamma and IL-1beta levels between the groups or time points analyzed. With respect to TNF-alpha and IL-4, serum levels below the detection limit (10 pg/ml) were observed in the two groups and at the time points analyzed. Significantly higher postoperative expression of IL-17A was detected in patients submitted to single-port laparoscopic cholecystectomy when compared to preoperative levels (p=0.0094). Conclusions:: Significant postoperative expression of IL-17 was observed in the group submitted to single-port laparoscopic cholecystectomy when compared to preoperative levels, indicating that surgical stress in this group was higher compared to the conventional laparoscopic cholecystectomy. Racional:: O trauma cirurgico induz resposta de estresse pos-operatorio significativo, evidenciado pelos niveis elevados de citocinas, podendo favorecer o surgimento de disturbios imunologicos. A magnitude de estresse esta relacionada ao grau do trauma cirurgico. Objetivos: : Avaliar a expressao das citocinas pro-inflamatorias (TNF-alpha, IFN-gamma, IL-1beta, IL-17) e da anti-inflamatoria (IL-4) no pre e pos-operatorio de pacientes submetidas a colecistectomia laparoscopica por dois metodos: convencional e por portal unico. Metodos:: Quarenta mulheres com colecistolitiase sintomatica foram operadas, sendo 21 por procedimento laparoscopico convencional e 19 por portal unico. As citocinas TNF-alpha, IFN-gamma, IL-1beta, IL-4, e IL-17 presentes no plasma foram quantificadas pelo metodo de ELISA em dois momentos: no pre-operatorio e apos 24 h da operacao. Resultados:: A avaliacao da resposta imune nao mostrou diferenca estatisticamente significante das citocinas IFN-gamma e IL-1beta na comparacao entre os grupos e tempos analisados. Em relacao as citocinas TNF-alpha e IL-4 os niveis sericos estavam abaixo dos niveis de deteccao (10 pg/ml) em ambos os grupos e tempos analisados. Observou-se que as operadas por portal unico apresentaram expressao significativa da IL-17A do periodo pre para o pos operatorio (p=0,0094). Conclusoes:: A expressao aumentada da IL-17A no pos operatorio do grupo de portal unico pode indicar que o estresse cirurgico foi maior em comparacao ao da colecistectomia laparoscopica convencional. PMID- 27759780 TI - ANTIBIOTIC PROPHYLAXIS IN LAPAROSCOPIC CHOLECISTECTOMY: IS IT WORTH DOING? AB - Background: : Elective laparoscopic cholecystectomy has very low risk for infectious complications, ranging the infection rate from 0.4% to 1.1%. Many surgeons still use routine antibiotic prophylaxis. Aim: : Evaluate the real impact of antibiotic prophylaxis in elective laparoscopic cholecystectomies in low risk patients. Method:: Prospective, randomized and double-blind study. Were evaluated 100 patients that underwent elective laparoscopic cholecystectomy divided in two groups: group A (n=50), patients that received prophylaxis using intravenous Cephazolin (2 g) during anesthetic induction and group B (n=50), patients that didn't receive any antibiotic prophylaxis. The outcome evaluated were infeccious complications at surgical site. The patients were reviewed seven and 30 days after surgery. Results:: There was incidence of 2% in infection complications in group A and 2% in group B. There was no statistical significant difference of infectious complications (p=0,05) between the groups. The groups were homogeneous and comparable. Conclusion:: The use of the antibiotic prophylaxis in laparoscopic cholecystectomy in low risk patients doesn't provide any significant benefit in the decrease of surgical wound infection. Racional: : A colecistectomia laparoscopica eletiva apresenta risco muito baixo para complicacoes infecciosas, com media de infeccao entre 0,4% a 1,1%. Muitos cirurgioes ainda utilizam de rotina profilaxia antibiotica. Objetivo: : Avaliar a real necessidade de profilaxia antibiotica em colecistectomias laparoscopicas eletivas em pacientes de baixo risco para infeccao do sitio cirurgico. Metodo: : Estudo prospectivo, randomizado e duplo-cego, em pacientes submetidos a colecistectomia laparoscopica eletiva, envolvendo 100 pacientes em dois grupos: A (n=50), que receberam profilaxia com cefazolina 2 g intravenoso na inducao anestesica; B (n=50), nao foi utilizado antibiotico. O desfecho avaliado foi presenca de complicacoes infecciosas de sitio cirurgico. Os pacientes foram revisados em sete e 30 dias no pos-operatorio. Resultados: : As taxas de complicacoes infecciosas foi de 2% no grupo A e de tambem 2% no grupo B. Nao houve diferenca estatisticamente significativa (p>0,05) entre os grupos que foram homogeneos e comparaveis. Conclusao:: A antibioticoprofilaxia na colecistectomia laparoscopica em pacientes de baixo risco nao apresenta nenhum beneficio significativo na reducao da incidencia de infeccao do sitio cirurgico. PMID- 27759782 TI - IMMEDIATE COMPLICATIONS AFTER 88 HEPATECTOMIES - BRAZILIAN CONSECUTIVE SERIES. AB - Background:: Hepatectomies have been increasingly recommended and performed in Brazil; they present great differences related to immediate complications. Aim:: Assessing the immediate postoperative complications in a series of 88 open liver resections. Method: : Prospective database of patients subjected to consecutive hepatectomies over nine years. The post-hepatectomy complications were categorized according to the Clavien-Dindo classification; complications presenting grade equal to or greater than 3 were considered major complications. Hepatic resections involving three or more resected liver segments were considered major hepatectomies. Results: : Eighty-four patients were subjected to 88 hepatectomies, mostly were minor liver resections (50 cases, 56.8%). Most patients had malignant diseases (63 cases; 71.6%). The mean hospitalization time was 10.9 days (4-43). Overall morbidity and mortality rates were 37.5% and 6.8%, respectively. The two most common immediate general complications were intra peritoneal collections (12.5%) and pleural effusion (12.5%). Bleeding, biliary fistula and liver failure were identified in 6.8%, 4.5% and 1.1% of the cases, respectively, among the hepatectomy-specific complications. Conclusion: : The patients operated in the second half of the series showed better results, which were apparently influenced by the increased surgical expertise, by the modification of the hepatic parenchyma section method and by the increased organ preservation. Racional: : No Brasil as hepatectomias tem sido cada vez mais indicadas e realizadas, apresentando grandes diferencas relacionadas as complicacoes imediatas. Objetivo:: Avaliar as complicacoes pos-operatorias imediatas em uma serie de 88 resseccoes hepaticas abertas. Metodo:: Foi utilizada uma base de dados prospectiva de pacientes submetidos a hepatectomias consecutivas em nove anos. As complicacoes pos-hepatectomia seguiram a Classificacao de Clavien-Dindo, sendo consideradas complicacoes maiores aquelas as quais apresentaram grau igual ou maior que 3. Foram consideradas hepatectomias maiores as resseccoes hepaticas que envolveram tres ou mais segmentos hepaticos ressecados. Resultados:: Oitenta e quatro pacientes foram submetidos a 88 hepatectomias, sendo a maioria resseccoes hepaticas menores (50 casos; 56,8%). A maior parte dos pacientes apresentou doenca maligna (63 casos; 71,6%). O tempo medio de internacao foi de 10,9 dias (4-43). A taxa de morbidade e mortalidade global foi, respectivamente, de 37,5% e 6,8%. As duas complicacoes gerais imediatas mais frequentes foram as colecoes intraperitoneais (12,5%) e o derrame pleural (12,5%). Ja as complicacoes especificas das hepatectomias - sangramento, fistula biliar e insuficiencia hepatica - foram respectivamente de 6,8%, 4,5% e 1,1% dos casos. Conclusao:: Os pacientes operados na segunda metade da presente casuistica tiveram melhores resultados influenciados, aparentemente, pela maior experiencia cirurgica, modificacao do metodo de seccao do parenquima hepatico e maior preservacao do figado. PMID- 27759781 TI - BRAZILIAN CONSENSUS FOR MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. MODULE 3: CONTROVERSIES AND UNRESECTABLE METASTASES. AB - In the last module of this consensus, controversial topics were discussed. Management of the disease after progression during first line chemotherapy was the first discussion. Next, the benefits of liver resection in the presence of extra-hepatic disease were debated, as soon as, the best sequence of treatment. Conversion chemotherapy in the presence of unresectable liver disease was also discussed in this module. Lastly, the approach to the unresectable disease was also discussed, focusing in the best chemotherapy regimens and hole of chemo embolization. RESUMO Neste ultimo modulo do consenso, abordou-se alguns temas controversos. O primeiro topico discutido foi o manejo da doenca apos progressao na primeira linha de quimioterapia, com foco em se ainda haveria indicacao cirurgica neste cenario. A seguir, o painel debrucou-se sobre as situacoes de resseccao da doenca hepatica na presenca de doenca extra-hepatica, assim como, qual a melhor sequencia de tratamento. O tratamento de conversao para doenca inicialmente irressecavel tambem foi abordado neste modulo, incluindo as importantes definicoes de quando se pode esperar que a doenca se torne ressecavel e quais esquemas terapeuticos seriam mais efetivos a luz dos conhecimentos atuais sobre a biologia tumoral e taxas de resposta objetiva. Por ultimo, o tratamento da doenca nao passivel de resseccao foi discutida, focando-se nos melhores esquemas a serem empregados e seu sequenciamento, bem como o papel da quimioembolizacao no manejo destes pacientes. PMID- 27759783 TI - ESTIMATING BASAL ENERGY EXPENDITURE IN LIVER TRANSPLANT RECIPIENTS: THE VALUE OF THE HARRIS-BENEDICT EQUATION. AB - Background: : Reliable measurement of basal energy expenditure (BEE) in liver transplant (LT) recipients is necessary for adapting energy requirements, improving nutritional status and preventing weight gain. Indirect calorimetry (IC) is the gold standard for measuring BEE. However, BEE may be estimated through alternative methods, including electrical bioimpedance (BI), Harris Benedict Equation (HBE), and Mifflin-St. Jeor Equation (MSJ) that carry easier applicability and lower cost. Aim: : To determine which of the three alternative methods for BEE estimation (HBE, BI and MSJ) would provide most reliable BEE estimation in LT recipients. Methods: : Prospective cross-sectional study including dyslipidemic LT recipients in follow-up at a 735-bed tertiary referral university hospital. Comparisons of BEE measured through IC to BEE estimated through each of the three alternative methods (HBE, BI and MSJ) were performed using Bland-Altman method and Wilcoxon Rank Sum test. Results: : Forty-five patients were included, aged 58+/-10 years. BEE measured using IC was 1664+/-319 kcal for males, and 1409+/-221 kcal for females. Average difference between BEE measured by IC (1534+/-300 kcal) and BI (1584+/-377 kcal) was +50 kcal (p=0.0384). Average difference between the BEE measured using IC (1534+/-300 kcal) and MSJ (1479.6+/-375 kcal) was -55 kcal (p=0.16). Average difference between BEE values measured by IC (1534+/-300 kcal) and HBE (1521+/-283 kcal) was -13 kcal (p=0.326). Difference between BEE estimated through IC and HBE was less than 100 kcal for 39 of all 43patients. Conclusions: : Among the three alternative methods, HBE was the most reliable for estimating BEE in LT recipients. Racional: : Estimativa confiavel do metabolismo basal em pacientes transplantados de figado e necessaria para adaptar os requerimentos energeticos, melhorar o estado nutricional e prevenir ganho de peso. Calorimetria indireta (CI) e o padrao-ouro para a medicao do metabolismo basal. No entanto, ele pode ser estimado utilizando-se metodos alternativos, incluindo a bioimpedancia (BI), a Equacao de Harris-Benedict (EHB), e tambem a Equacao de Mifflin-St. Jeor (MSJ). Esses metodos alternativos possuem aplicabilidade mais facil e custo inferior quando comparados a CI. Objetivo: : Determinar qual dos tres metodos alternativos para a estimativa do metabolismo basal (EHB, BI e MSJ) seria o mais confiavel em pacientes transplantados de figado. Metodos: : Foi realizado estudo transversal prospectivo incluindo pacientes transplantados de figado com dislipidemia, em acompanhamento ambulatorial. Comparacoes dos valores calculados de metabolismo basal via CI aos valores estimados por cada um dos tres metodos alternativos (EHB, BI e MSJ) foram realizadas utilizando o de Bland-Altman e o teste de Wilcoxon-Mann-Whitney. Resultados: : Quarenta e cinco pacientes foram incluidos com idade 58+/-10 anos. O metabolismo basal medido via CI foi 1664+/-319 kcal para pacientes do genero masculino, e 1409+/-221 kcal para o feminino. A diferenca media entre a taxa de metabolismo basal aferida por CI (1534+/-300 kcal) e estimada por BI (1584+/-377 kcal) foi +50 kcal (p=0.0384). A diferenca media entre a taxa de metabolismo basal aferida via CI (1534+/-300 kcal) e estimada por MSJ (1479.6+/-375 kcal) foi -55 kcal (p=0.16). A diferenca media entre os valores de taxa de metabolismo basal medidos via CI (1534+/-300 kcal) e estimados por EHB (1521+/-283 kcal) foi -13 kcal (p=0.326). Alem disso, a diferenca entre a taxa de metabolismo basal estimada via CI e a aferida por EHB foi menor que 100 kcal para 39 de todos os 43 pacientes avaliados. Conclusoes: : A EHB foi o mais confiavel dos tres metodos de estimativa da taxa de metabolismo basal em pacientes transplantados de figado em acompanhamento ambulatorial. PMID- 27759784 TI - POST-REPERFUSION LIVER BIOPSY AND ITS VALUE IN PREDICTING MORTALITY AND GRAFT DYSFUNCTION AFTER LIVER TRANSPLANTATION. AB - Background: : The outcome of the patients after liver transplant is complex and to characterize the risk for complications is not always easy. In this context, the hepatic post-reperfusion biopsy is capable of portraying alterations of prognostic importance. Aim:: To compare the results of liver transplantation, correlating the different histologic features of the hepatic post-reperfusion biopsy with graft dysfunction, primary non-function and patient survival in the first year after transplantation. Method: : From the 377 transplants performed from 1996 to 2008, 164 patients were selected. Medical records were reviewed and the following clinical outcomes were registered: mortality in 1, 3, 6 and 12 months, graft dysfunction in varied degrees and primary graft non-function. The post-reperfusion biopsies had been examined by a blinded pathologist for the outcomes. The following histological variables had been evaluated: ischemic alterations, congestion, steatosis, neutrophilic exudate, monomorphonuclear infiltrate and necrosis. Results:: The variables associated with increased mortality were: steatosis (p=0.02209), monomorphonuclear infiltrate (p=0.03935) and necrosis (p<0.00001). The neutrophilic exudate reduced mortality in this study (p=0.00659). The primary non-function showed significant association (p<0.05) with the necrosis, steatosis and the monomorphonuclear infiltrate. Conclusion:: Post-reperfusion biopsy is useful tool to foresee complications after liver transplant. Racional: : A evolucao dos pacientes apos transplante hepatico e complexa e caracterizar o risco para complicacoes nem sempre e facil. Nesse contexto, a biopsia hepatica pos-reperfusao e capaz de retratar alteracoes de importancia prognostica. Objetivo: : Avaliar os resultados no primeiro ano apos transplante hepatico, correlacionando as alteracoes histologicas a biopsia hepatica pos-reperfusao com a sobrevida, a disfuncao e o nao-funcionamento primario do enxerto. Metodo: : Dos 377 transplantes ocorridos de 1996 a 2008, 164 pacientes foram selecionados para estudo. Os seguintes desfechos clinicos foram registrados: mortalidade em 1, 3, 6 e 12 meses, disfuncao do enxerto em graus variados e o nao-funcionamento primario do enxerto. As biopsias pos-reperfusao foram examinadas por um patologista sem conhecimento dos resultados. As seguintes variaveis histologicas foram avaliadas: alteracoes isquemicas, congestao, esteatose, exsudato neutrofilico, infiltrado monomorfonuclear e necrose. Resultados:: As variaveis associadas com aumento da mortalidade foram: esteatose (p=0.02209), infiltrado monomorfonuclear (p=0.03935) e necrose (p<0.00001). O infiltrado neutrofilico reduziu a mortalidade neste estudo (p=0.00659). O nao funcionamento primario do enxerto mostrou associacao significativa (p<0.05) com a necrose, a esteatose e com o infiltrado monomorfonuclear. Conclusao: : A biopsia hepatica pos-reperfusao e ferramenta util em prever complicacoes apos o transplante hepatico. PMID- 27759785 TI - PYOGENIC LIVER ABSCESS: DIAGNOSTIC AND THERAPEUTIC MANAGEMENT. AB - Background:: The pyogenic liver abscess has an incidence of 1.1/1,000 habitants. Mortality can reach 100%. The use of less invasive procedures diminish morbidity and hospital stay. Aim:: Identify risk factors in patients who underwent percutaneous drainage guided by ultrasound as treatment. Method:: Were analyzed 10 patients submitted to the method. Epidemiological characteristics, laboratory markers and imaging exams (ultrasound and CT) were evaluated. Results:: The majority of the patients were men with mean age of 50 years old. Liver disease, alcoholism and biliary tract disease were the most common prodromes. Abdominal pain (90%), fever (70%) and jaundice (40%) were the most common clinical manifestations. Mortality of 20% was observed in this series. Hypoalbuminemia and days of hospitalization had a statistically significant positive association with death. Conclusion:: The pyogenic liver abscess has subacute evolution which makes the diagnosis difficult. Image exams have high sensitivity in diagnosis, particularly computed tomography. Percutaneous drainage associated with antibiotic therapy is safe and effective therapeutic resource. Racional:: O abscesso hepatico piogenico tem incidencia de 1,1 por 1.000 habitantes com mortalidade podendo chegar a 100%. O uso de recursos menos invasivos diminuem morbimortalidade e tempo de internacao hospitalar. Objetivo:: Identificar fatores de risco no abscesso hepatico piogenico tratado por drenagem percutanea guiada por ultrassom. Metodo:: Total de 10 pacientes foram submetidos ao procedimento. Foram avaliadas caracteristicas epidemiologicas, marcadores laboratoriais exames de imagem (ultrassom e tomografia). Resultados:: Na amostra houve predominancia do sexo masculino, com media de idade de 50 anos. Hepatopatia, etilismo e doenca da via biliar foram os prodromos mais frequentes. Dor abdominal (90%), febre (70%) e ictericia (40%) foram manifestacoes clinicas mais comuns. Houve mortalidade de 20% nesta serie. Hipoalbuminemia e dias de internacao hospitalar tiveram associacao positiva com obito estatisticamente significante. Conclusao:: O abscesso hepatico piogenico tem evolucao subaguda o que dificulta o diagnostico. Exames de imagem tem sensibilidade alta na propedeutica diagnostica, notadamente a tomografia computadorizada. A drenagem percutanea, associada a antibioticoterapia, mostrou ser recurso terapeutico seguro e eficaz. PMID- 27759786 TI - LAPAROSCOPICALLY ASSISTED ANORECTOPLASTY AND THE USE OF THE BIPOLAR DEVICE TO SEAL THE RECTAL URINARY FISTULA. AB - Background:: The anorectal anomalies consist in a complex group of birth defects. Laparoscopic-assisted anorectoplasty improved visualization of the rectal fistula and the ability to place the pull-through segment within the elevator muscle complex with minimal dissection. There is no consensus on how the fistula should be managed. Aim: : To evaluate the laparoscopic-assisted anorectoplasty and the treatment of the rectal urinary fistula by a bipolar sealing device. Method:: It was performed according to the original description by Georgeson1. Was used 10 mm infraumbilical access portal for 30o optics. The pneumoperitoneum was established with pressure 8-10 cm H2O. Two additional trocars of 5 mm were placed on the right and left of the umbilicus. The dissection started on peritoneal reflection using Ligasure(r). With the reduction in the diameter of the distal rectum was identified the fistula to the urinary tract. The location of the new anus was defined by the location of the external anal sphincter muscle complex, using electro muscle stimulator externally. Finally, it was made an anastomosis between the rectum and the new location of the anus. A Foley urethral probe was left for seven days. Results:: Seven males were operated, six with rectoprostatic and one with rectovesical fistula. The follow-up period ranged from one to four years. The last two patients operated underwent bipolar sealing of the fistula between the rectum and urethra without sutures or surgical ligation. No evidence of urethral leaks was identified. Conclusion: : There are benefits of the laparoscopic-assisted anorectoplasty for the treatment of anorectal anomaly. The use of a bipolar energy source that seals the rectal urinary fistula has provided a significant decrease in the operating time and made the procedure be more elegant. Racional: : As anomalias anorretais consistem de um grupo complexo de defeitos congenitos. A anorretoplastia laparoscopica permite melhor visualizacao da fistula retourinaria e propicia o posicionamento do reto abaixado dentro do complexo muscular do elevador do anus com minima disseccao. Nao ha consenso na literatura sobre o melhor tratamento dessa fistula. Objetivo:: Avaliar a anorretoplastia laparoscopica e o selamento bipolar da fistula retourinaria. Metodo:: Ela foi realizada de acordo com a descricao original de Georgeson1. Utilizou-se o acesso infraumbilical com portal de 10 mm para a otica de 30o. O pneumoperitonio foi estabelecido com pressao de 8-10 cm de H2O. Dois trocarteres adicionais de 5 mm foram colocados a direita e a esquerda da cicatriz umbilical. A disseccao foi iniciada na reflexao peritoneal usando Ligasure(r). Com a reducao do calibre do reto distalmente, foi identificada a fistula para a o trato urinario. O local do novo anus foi definido por meio da localizacao do complexo muscular do esfincter anal externo, utilizando-se estimulador eletro muscular externamente. Por fim, foi confeccionada uma anastomose entre o reto e o novo local do anus. Uma sonda uretral de Foley foi deixada durante sete dias. Resultados:: Sete meninos foram operados, seis com fistula retoprostatica e um retovesical. O periodo de seguimento variou de um a quatro anos. Os dois ultimos pacientes operados foram submetidos ao selamento bipolar da fistula entre o reto e a uretra, sem suturas ou ligadura cirurgica com pontos. No seguimento em longo prazo nao houve evidencias de fistulas urinarias. Conclusao:: Ha beneficios da anorretoplastia laparoscopica para o tratamento de anomalia anorretal. O uso de uma fonte de energia bipolar que promova o selamento da fistula retourinaria propiciou reducao significativa do tempo cirurgico e tornou o procedimento mais elegante. PMID- 27759787 TI - MANAGEMENT OF ACUTE SEVERE ULCERATIVE COLITIS: A CLINICAL UPDATE. AB - Introduction: : Acute severe colitis is a potentially lethal medical emergency and, even today, its treatment remains a challenge for clinicians and surgeons. Intravenous corticoid therapy, which was introduced into the therapeutic arsenal in the 1950s, continues to be the first-line treatment and, for patients who are refractory to this, the rescue therapy may consist of clinical measures or emergency colectomy. Objective: : To evaluate the indications for and results from drug rescue therapy (cyclosporine, infliximab and tacrolimus), and to suggest a practical guide for clinical approaches. Methods:: The literature was reviewed using the Medline/PubMed, Cochrane library and SciELO databases, and additional information from institutional websites of interest, by cross correlating the following keywords: acute severe colitis, fulminating colitis and treatment. Results:: Treatments for acute severe colitis have avoided colectomy in 60-70% of the cases, provided that they have been started early on, with multidisciplinary follow-up. Despite the adverse effects of intravenous cyclosporine, this drug has been indicated in cases of greater severity with an imminent risk of colectomy, because of its fast action, short half-life and absence of increased risk of surgical complications. Therapy using infliximab has been reserved for less severe cases and those in which immunosuppressants are being or have been used (AZA/6-MP). Indication of biological agents has recently been favored because of their ease of therapeutic use, their good short and medium-term results, the possibility of maintenance therapy and also their action as a "bridge" for immunosuppressant action (AZA/6-MP). Colectomy has been reserved for cases in which there is still no response five to seven days after rescue therapy and in cases of complications (toxic megacolon, profuse hemorrhage and perforation). Conclusion:: Patients with a good response to rescue therapy who do not undergo emergency operations should be considered for maintenance therapy using azathioprine. A surgical procedure is indicated for selected cases. Racional: : A colite aguda grave e emergencia medica, potencialmente letal e o seu tratamento permanece ainda nos dias de hoje um desafio para o clinico e cirurgiao. A corticoterapia intravenosa introduzida no arsenal terapeutico na decada de 50 permanece como primeira linha de tratamento, e nos pacientes refratarios a tal medida, a terapia de resgate pode ser com medidas clinicas ou colectomia de urgencia. Objetivo: : Avaliar os resultados da terapia de resgate medicamentosa (ciclosporina, infliximabe e tracolimus), suas indicacoes e resultados, e sugerir um guia pratico para abordagem clinica. Metodos:: Foi realizada revisao na literatura utilizando as bases Medline/Pubmed, Cochrane Library, Scielo, e informacoes adicionais em sites institucionais de interesse cruzando os descritores: colite aguda grave, colite fulminante e tratamento. Resultados:: O tratamento da colite aguda grave tem evitado a colectomia em 60- 70% dos casos, desde que iniciado precocemente e com acompanhamento multidisciplinar. A ciclosporina intravenosa apesar de seus efeitos adversos, tem sido indicada naqueles casos mais graves com risco iminente de colectomia, pela sua rapidez de acao, meia-vida curta, e nao aumentar os riscos de complicacoes cirurgicas. A terapia com infliximabe tem sido reservada para os casos menos graves e naqueles em uso ou ja expostos a imunossupressores (AZA/6-MP). A facilidade terapeutica, seus bons resultados a curto e medio prazo, a possibilidade de terapia de manutencao e tambem por agir como "ponte" para acao de imunossupressores (AZA/6-MP) tem recentemente favorecido a indicacao de biologicos. A colectomia fica reservada para casos que nao apresentaram resposta a terapia de resgate apos cinco a sete dias de tratamento e nas complicacoes (megacolon toxico, hemorragia profusa e perfuracao). Conclusoe: s: Os pacientes com boa resposta a terapia de resgate e nao submetidos a operacoes de urgencia, deverao ser considerados para terapia de manutencao com azatioprina, sendo procedimento cirurgico indicado para casos selecionados. PMID- 27759788 TI - UNDERSTANDING THE INTERNATIONAL CONSENSUS FOR ACUTE PANCREATITIS: CLASSIFICATION OF ATLANTA 2012. AB - Introduction: : Contrast computed tomography and magnetic resonance imaging are widely used due to its image quality and ability to study pancreatic and peripancreatic morphology. The understanding of the various subtypes of the disease and identification of possible complications requires a familiarity with the terminology, which allows effective communication between the different members of the multidisciplinary team. Aim:: Demonstrate the terminology and parameters to identify the different classifications and findings of the disease based on the international consensus for acute pancreatitis ( Atlanta Classification 2012). Methods:: Search and analysis of articles in the "CAPES Portal de Periodicos with headings "acute pancreatitis" and "Atlanta Review". Results:: Were selected 23 articles containing radiological descriptions, management or statistical data related to pathology. Additional statistical data were obtained from Datasus and Population Census 2010. The radiological diagnostic criterion adopted was the Radiology American College system. The "acute pancreatitis - 2012 Rating: Review Atlanta classification and definitions for international consensus" tries to eliminate inconsistency and divergence from the determination of uniformity to the radiological findings, especially the terminology related to fluid collections. More broadly as "pancreatic abscess" and "phlegmon" went into disuse and the evolution of the collection of patient fluids can be described as "acute peripancreatic collections", "acute necrotic collections", "pseudocyst" and "necrosis pancreatic walled or isolated". Conclusion: : Computed tomography and magnetic resonance represent the best techniques with sequential images available for diagnosis. Standardization of the terminology is critical and should improve the management of patients with multiple professionals care, risk stratification and adequate treatment. Introducao:: A tomografia computadorizada contrastada e a ressonancia magnetica sao exames amplamente utilizados no estudo da morfologia pancreatica e peripancreatica. O entendimento dos diversos subtipos da doenca e identificacao de suas possiveis complicacoes requer familiaridade com a terminologia padrao, a qual permite comunicacao efetiva entre os diversos membros da equipe multidisciplinar. Objetivo:: Demonstrar terminologia e os parametros para identificacao das diferentes classificacoes da doenca a partir do consenso internacional para as pancreatites agudas (Classificacao de Atlanta 2012. Metodo:: Busca e analise de artigos no "Portal de Periodicos da CAPES" com descritores "pancreatite aguda" e "Revisao de Atlanta". Resultado: : Foram selecionados 23 artigos que continham descricoes radiologicas, manejo ou dados estatisticos relacionados a doenca. Dados estatisticos adicionais foram obtidos no sistema Datasus e Censo Demografico 2010. O criterio de diagnostico radiologico adotado foi o do Colegio Americano de Radiologia. A "Classificacao da pancreatite aguda - 2012: revisao da classificacao de Atlanta e definicoes por consenso internacional" tenta eliminar a inconsistencia e divergencias a partir da determinacao de uniformidade para os achados radiologicos, em especial a terminologia relacionada as colecoes de fluidos. Termos mais abrangentes como "abscesso pancreatico" e "flegmao" entraram em desuso e a evolucao da colecao de fluidos pode ser descrita como: "colecoes peripancreaticas agudas", "colecoes necroticas agudas", "pseudocisto" e "necrose pancreatica murada ou isolada". Conclusao: : A tomografia computadorizada e a ressonancia magnetica representam as melhores tecnicas com cortes sequenciais disponiveis para diagnostico. A adequacao da terminologia e ponto critico e deve permitir o manejo do paciente por multiplos profissionais, estratificacao de risco e adequacao de tratamento. PMID- 27759789 TI - GASTROINTESTINAL SCHWANNOMA: CASE REPORT. PMID- 27759790 TI - SELF-EXTERMINATION ATTEMPTED THROUGH THE 128 NAILS INTAKE. PMID- 27759791 TI - Heatwaves and health: reflections on the El Nino phenomenon in Piura, Peru. PMID- 27759792 TI - The concept of territory in Mental Health. AB - The term "territory" and its correlates have become commonplace in the field of Mental Health since the psychiatric reform, a potentially emancipatory milestone in non-hospital-centered ideals. However, in a previous empirical study, we found a lack of consistent concepts and practices (corresponding to the use of this term) in the territorial reinsertion of persons with mental illness. To clarify the term's various uses and its possible correlations in practice, we have conducted a systematic survey of scientific articles and official documents, comparing them to each other and with the concept of territory from Critical Geography. We conclude that in the Mental Health field in Brazil, despite numerous and repeated critical efforts, a functional notion of territory has prevailed, overlooking power relations and symbolic appropriations, increasing the tendency of subjecting the reinsertion of persons with mental illness to a given territory rather than favoring socio-spatial transformations for the coexistence of differences. PMID- 27759793 TI - Factors associated with the diffusion rate of innovations: a pilot study from the perspective of the Brazilian Unified National Health System. AB - Budget Impact Analyses require a set of essential information on health technology innovation, including expected rates of adoption. There is an absence of studies investigating trends, magnitude of budgetary effects and determinants of diffusion rates for health technology innovations worldwide during the last decades. The present study proposes a pilot assessment on main determinants influencing diffusion rates of pharmaceutical innovations within the Brazilian Unified National Health System (SUS). Data from the Brazilian Health Informatics Department (DATASUS) was gathered to establish the main determinants of diffusion rates of health technology innovations in Brazil, specifically referring to pharmaceutical innovations incorporated in the Brazilian Program for Specialized Pharmaceutical Services (CEAF) at SUS. Information was retrieved on DATASUS relating to patients who had used one of the medicines incorporated into CEAF at least three years prior to the beginning of the study (2015) for treatment of each health condition available. Thus, data from patients adopting 10 different medicines were analyzed in the study. Results from the zero-one inflated beta model showed a higher influence on diffusion rates of pharmaceutical innovations due to: number of pharmaceutical competitors for treatment of the same disease available at CEAF (negative); medicine used in combination with other medication (positive); and innovative medicine within the SUS (positive). Further research on diffusion rates of health technology innovations is required, including wider scope of diseases and medications, potential confusion factors and other variables that may influence rates of adoption in different health systems. PMID- 27759794 TI - [Cross-cultural adaptation of the PRISMA-7 instrument for use in Brazil: evaluation of conceptual, item, and semantic equivalences]. AB - Screening with a simplified instrument is effective for identifying elderly at risk of functional decline, for more comprehensive subsequent evaluation. However, use of a measurement tool in a different sociocultural context from the original requires prior adaptation. The current article aims to describe the initial stages of a cross-cultural adaptation of PRISMA-7, a questionnaire developed to identify community-dwelling elderly at risk of functional decline. Evaluation of conceptual and item equivalences showed pertinence to the Brazilian context. Semantic equivalence covered the correspondence in referential (denotative) and connotative meaning. The pretest showed that the instrument's synthesis version has good acceptability. The results suggest the use of PRISMA-7 in the Brazilian context as a screening tool for identifying risk of functional decline in the elderly. PMID- 27759795 TI - [Differences in mortality in Brazilian youth: the importance of household socioeconomic factors and living conditions in Brazilian municipalities and states]. AB - This study analyzed the relationship between household socioeconomic status and local social conditions and risk of death in Brazilian youth 15 to 29 years of age. Mortality data from the previous 12 months collected by the 2010 Population Census were used for the analysis at the local level. Data analysis was based on hierarchical models that allowed identifying the role of household social conditions and municipality and state of residence on mortality in young Brazilians. Differences in socioeconomic status between households accounted for more than 90% of the variability in risk of death. Residing in socioeconomically deprived areas also increased the odds of death among young people from households of any socioeconomic status. PMID- 27759796 TI - [Trends and inequalities in risk behaviors among adolescents: a comparison of birth cohorts in Pelotas, Rio Grande do Sul State, Brazil]. AB - This study focuses on trends and inequalities in health risk behaviors among adolescents. A cross-sectional study compared two birth cohorts in the city of Pelotas, Rio Grande do Sul State, Brazil. The sample included 1,281 adolescents from the 1982 cohort and 4,106 from the 1993 cohort, followed in 2001 and 2011, respectively. The study recorded alcohol intake, illegal drug use, smoking, sexual initiation < 16 years, lack of condom use, and multiple sex partners. Total prevalence rates were calculated for each cohort, stratified by gender and per capita income, besides absolute and relative measures of inequality. There was a decrease from 2001 to 2011 in prevalence rates for trying alcohol, illegal drug use, smoking, and lack of condom use, and an increase in the number of sex partners. The gap between boys and girls increased for non-use of condoms and decreased for the other behaviors. The gap between income groups decreased for sexual initiation before 16 years of age and increased for episodes of intoxication. Socioeconomic inequalities persist, despite the downward trend in prevalence of risk behaviors. PMID- 27759797 TI - [Socio-demographic and occupational factors associated with gains and losses perceived by employees nearing retirement in a public university]. AB - The aim was to analyze socio-demographic and occupational factors associated with gains and losses perceived by employees nearing retirement in a public university. In an exploratory, cross-sectional, and quantitative survey, employees (n = 164) approaching retirement in a public university in northern Parana State, Brazil, assigned scales of importance to gains and losses. The data were analyzed with simple and multiple linear regression, based on the sizes of the scales, with socio-demographic and occupational variables as predictors. Employees assigned greater importance to retirement gains than losses. Increasing age was associated with less appreciation for total gains and time for relationships. Longer time on the job contributed to appreciation of total losses and tangible aspects of work. It is necessary to create spaces for reflection in employer institutions that promote listening to workers' needs, especially for older employees with longer time on the job. PMID- 27759798 TI - [Building bridges: interdisciplinarity in practice. PopTrans Study: a study with transvestites and transsexual women in Salvador, Bahia State, Brazil]. AB - Trans persons, including transvestites and transsexual women, show disproportionately high HIV/AIDS rates when compared to the rest of the population. However, few quantitative/qualitative studies have addressed trans persons in Brazil. Thus, a team of researchers from different fields is developing an interdisciplinary research project with the objective of shedding light on living conditions and ways of life among transvestites and transsexual women, while investigating determinant factors for HIV infection, syphilis, and hepatitis B and C. The article is intended to describe the experience with the implementation and development of an ethno-epidemiological study in Salvador, Bahia State, Brazil. Mapping the population began with a formative survey that was crucial for orienting the epidemiological survey. The production of ethno epidemiological data posed a daily challenge for the researchers, triggering a series of reflections on the limits of our concepts and categories for translating the diversity of study participants' practices and experiences. PMID- 27759800 TI - Unusual early symptoms of Parkinson's disease. Why do we need to identify them? PMID- 27759801 TI - Unusual motor and non-motor symptoms and signs in the early stage of Parkinson's disease. AB - Objective: Patients with Parkinson's disease (PD) may present with unusual motor and non-motor symptoms and signs in the early stage of the disease. Methods: Cases were collected over a five-year period at two tertiary movement disorders clinics. All had a diagnosis of PD with unusual presentations defined retrospectively as the presence of complaints not objectively related to any of the classic cardinal signs of parkinsonism or the typical early non-motor features of PD. Results: A total of 15 early PD patients fulfilled the proposed criteria, presenting with symptoms such as atypical tremors, shoulder pain, signs related to the rigid akinetic syndrome, as well as cases of asthenia, rhinorrhea, parosmia, dysgeusia, nocturnal sialorrhea, and color discrimination disorders. Conclusions: Unusual motor and non-motor symptoms and signs in the early stage of PD can be difficult to interpret. Specialists should be aware of these conditions as clues to a potential diagnosis. PMID- 27759799 TI - [Basic questionnaire and methodological criteria for Surveys on Working Conditions, Employment, and Health in Latin America and the Caribbean]. AB - This article aimed to present a basic questionnaire and minimum methodological criteria for consideration in future Surveys on Working Conditions, Employment, and Health in Latin America and the Caribbean. A virtual and face-to-face consensus process was conducted with participation by a group of international experts who used the surveys available up until 2013 as the point of departure for defining the proposal. The final questionnaire included 77 questions grouped in six dimensions: socio-demographic characteristics of workers and companies; employment conditions; working conditions; health status; resources and preventive activities; and family characteristics. The minimum methodological criteria feature the interviewee's home as the place for the interview and aspects related to the quality of the fieldwork. These results can help improve the comparability of future surveys in Latin America and the Caribbean, which would in turn help improve information on workers' heath in the region. PMID- 27759802 TI - Working memory and left medial temporal cortical thickness. AB - Objective: To perform a pilot study to investigate the association between working memory and cortical thickness in a sample of attention deficit/hyperactivity disorder (ADHD) children. Methods: Seventeen children aged 7-10 years diagnosed with ADHD and 16 healthy children underwent a magnetic resonance scan for cortical thickness measurements. Data was correlated with working memory performance using the Backwards Digit Span subtest of the Wechsler Intelligence Scale for Children. Results: Working memory impairment, evidenced by lower scores on the Backwards Digit Span, was observed in patients with ADHD compared to healthy controls. There was a direct correlation between working memory and cortical thickness of the left medial temporal lobe (Spearman's correlation coefficient: 0.499; p < 0.005). Conclusions: Our data suggests, for the first time, a correlation between working memory, evaluated by the Backwards Digit Span, and left medial temporal cortical thickness. PMID- 27759803 TI - The relevance of trunk evaluation in Duchenne muscular dystrophy: the segmental assessment of trunk control. AB - The aim was to describe trunk control in ambulant and non-ambulant patients with Duchenne muscular dystrophy (DMD). We conducted a cross-sectional analysis of a sample of 50 DMD patients, (M age = 16.7 years) who underwent the Segmental Assessment of Trunk Control (SATCo). A seven-level scale of trunk control was used (1: head control only; 7: control of entire trunk while unsupported). Static, active and reactive posture control were evaluated in ambulant and non ambulant patients. Inter-rater reliability for all assessments was evaluated by calculating the kappa coefficient. More advanced disease (having higher Vignos scores), was associated with poorer trunk control. Ambulant patients showed better trunk control than non-ambulant patients (p = 0.003). There was strong inter-rater agreement for SATCo scale scores. PMID- 27759804 TI - Autonomic thermoregulatory dysfunction in neurofibromatosis type 1. AB - Objective: Neurofibromatosis type 1 (NF1) causes neural and cutaneous disorders and reduced exercise capacity. Exercise/heat exposure increasing internal temperature must be compensated by eccrine sweat function and warmed skin vasodilation. We suspected NF1 could adversely affect eccrine sweat function and/or vascular thermoregulatory responses (VTR). Methods: The eccrine sweat function and VTR of 25 NF1 volunteers (14 males, 11 females; 16-57 years old) were compared with 23 non-NF1 controls matched by sex, age, height and weight (CG). Sweating was induced by 1) pilocarpine 1% iontophoresis (PILO); and 2) by passive heating (HEAT) via the lower third of the legs being immersed in 42 degrees C water for one hour. Previously established eccrine sweat function and VTR protocols were used. Results: The NF1 group showed: a) lower sweat rate than the CG group during PILO; b) a smaller diastolic pressure decrease; and c) higher tympanic temperatures than controls during HEAT (p < 0.05). Conclusion: Reduced sweating and vascular thermoregulatory responses suggest autonomic dysfunction in NF1 individuals. PMID- 27759806 TI - Red blood cells in cerebrospinal fluid as possible inhibitory factor for enterovirus RT-PCR. AB - The presence of hemoglobin in samples are considered an important inhibitory factor for polymerase chain reaction (PCR). The aim of this study was to examine the influence of red blood cells (RBC)s in cerebrospinal fluid (CSF) as an inhibitory factor to reverse transcription polymerase chain reaction (RT-PCR) for enteroviruses (EV). Forty-four CSF samples from patients showing characteristics of viral meningitis were assessed for EV by RT-PCR. Viral RNA extracted with guanidine isothyocianate buffer and virus detection was performed by in-house nested PCR. Positivity for EV RT-PCR was higher in CSF samples without RBCs than in samples with RBCs: 13(26%) and 36(9.2%), p = 0.001. In the group with positive EV RT-PCR, the mean + SD CSF RBC was 37 +/- 183 cell/mm3; the group with negative results had 580 + 2,890 cell/mm3 (p = 0.007). The acceptable upper limit for CSF RBCs that could not influence RT-PCR was 108 cells/mm3. CSF samples with negative results for EV RT-PCR have more erythrocytes. PMID- 27759805 TI - A simple scoring system for predicting early major complications in spine surgery: the cumulative effect of age and size of surgery. AB - Objective: To analyze the cumulative effect of risk factors associated with early major complications in postoperative spine surgery. Methods: Retrospective analysis of 583 surgically-treated patients. Early "major" complications were defined as those that may lead to permanent detrimental effects or require further significant intervention. A balanced risk score was built using multiple logistic regression. Results: Ninety-two early major complications occurred in 76 patients (13%). Age > 60 years and surgery of three or more levels proved to be significant independent risk factors in the multivariate analysis. The balanced scoring system was defined as: 0 points (no risk factor), 2 points (1 factor) or 4 points (2 factors). The incidence of early major complications in each category was 7% (0 points), 15% (2 points) and 29% (4 points) respectively. Conclusions: This balanced scoring system, based on two risk factors, represents an important tool for both surgical indication and for patient counseling before surgery. PMID- 27759807 TI - Higher positive identification of malignant CSF cells using the cytocentrifuge than the Suta chamber. AB - Objective: To define how to best handle cerebrospinal fluid (CSF) specimens to obtain the highest positivity rate for the diagnosis of malignancy, comparing two different methods of cell concentration, sedimentation and cytocentrifugation. Methods: A retrospective analysis of 411 CSF reports. Results: This is a descriptive comparative study. The positive identification of malignant CSF cells was higher using the centrifuge than that using the Suta chamber (27.8% vs. 19.0%, respectively; p = 0.038). Centrifuge positively identified higher numbers of malignant cells in samples with a normal concentration of white blood cells (WBCs) (< 5 cells/mm3) and with more than 200 cells/mm3, although this was not statistically significant. There was no lymphocyte loss using either method. Conclusions: Cytocentrifugation positively identified a greater number of malignant cells in the CSF than cytosedimentation with the Suta chamber. However, there was no difference between the methods when the WBC counts were within the normal range. PMID- 27759808 TI - The maintenance of modified electroconvulsive therapy combined with risperidone is better than risperidone alone in preventing relapse of schizophrenia and improving cognitive function. AB - Objective: To evaluate the effect of maintenance modified electroconvulsive therapy (MECT) on schizophrenic patients. Methods: From June 2012 to June 2014, 62 patients with schizophrenia, who had recovered from a successful course of acute MECT, were recruited. Thirty-one patients received maintenance MECT and risperidone, as the experimental group. Another 31 patients were enrolled in the control group, and received risperidone only. The effects on cognitive functions, clinical symptoms and relapse rate were determined. Results: Patients in the experimental group had a lower relapse rate and longer relapse-free survival time than the controls. Relative to the baseline evaluation, patients showed statistically significant improvement in verbal memory and visual memory. At the final assessment, the scores of verbal and visual memory were remarkably lower in the experimental group than the controls but there was no significant difference in other tests. Conclusion: Maintenance MECT plus medication is superior to medication alone in preventing relapse and improving cognitive function. PMID- 27759809 TI - Transcranial magnetic stimulation and transcranial direct current stimulation appear to be safe neuromodulatory techniques useful in the treatment of anxiety disorders and other neuropsychiatric disorders. AB - Transcranial magnetic stimulation (TMS) has recently been investigated as a possible adjuvant treatment for many neuropsychiatric disorders, and has already been approved for the treatment of drug-resistant depression in the United States and in Brazil, among other countries. Although its use in other neuropsychiatric disorders is still largely experimental, many physicians have been using it as an off-label add-on therapy for various disorders. More recently, another technique, transcranial direct current stimulation (tDCS), has also become available as a much cheaper and portable alternative to TMS, although its mechanisms of action are different from those of TMS. The use of off-label therapeutic TMS or tDCS tends to occur in the setting of diseases that are notoriously resistant to other treatment modalities. Here we discuss the case of anxiety disorders, namely panic and post-traumatic stress disorders, highlighting the uncertainties and potential problems and benefits of the clinical use of these neuromodulatory techniques at the current stage of knowledge. PMID- 27759810 TI - Disability and progression in Afro-descendant patients with multiple sclerosis. AB - Multiple sclerosis (MS) prevalence is higher in Caucasian (CA) populations, narrowing the analysis of the impact of Afro-descendant (AD) populations in disease outcomes. Even so, recent studies observed that AD patients have a more severe course. The main objective of this study is to confirm and discuss, through a systematic review, that being AD is a risk factor for disability accumulation and/or severe progression in patients with MS. A systematic review of published data in the last eleven years was performed, which evaluated clinical aspects and long term disability in patients with MS. Fourteen studies were included. Of these fourteen articles, thirteen observed a relationship between ancestry and poorer outcome of MS. African ancestry is a condition inherent in the patient and should be considered as an initial clinical characteristic affecting prognosis, and influencing which therapeutic decision to make in initial phases. PMID- 27759811 TI - Ketogenic diet for epilepsy treatment. AB - The ketogenic diet (KD), a high-fat, low-carbohydrate, and adequate-protein diet is an established, effective nonpharmacologic treatment option for intractable childhood epilepsy. The KD was developed in 1921 and even though it has been increasingly used worldwide in the past decade, many neurologists are not familiar with this therapeutic approach. In the past few years, alternative and more flexible KD variants have been developed to make the treatment easier and more palatable while reducing side effects and making it available to larger group of refractory epilepsy patients. This review summarizes the history of the KD and the principles and efficacy of the classic ketogenic diet, medium-chain triglyceride(s) (MCT) ketogenic diet, modified Atkins diet, and low glycemic index treatment. PMID- 27759813 TI - A tribute to Wartenberg's refined neurological examination. AB - Robert Wartenberg was a renowned 20th century neurologist who contributed greatly to our understanding of the neurological examination. This article aims to illustrate his legacy by highlighting five seminal neurological signs. PMID- 27759812 TI - Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis. AB - Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical data regarding its pathophysiological mechanisms, motor neuron disease develops under a complex network of mechanisms not restricted to the unique functions of the alpha motor neurons but which actually involve diverse functions of glial cell interaction. This review aims to expose some of the leading roles of glial cells in the physiological mechanisms of neuron-glial cell interactions and the mechanisms related to motor neuron survival linked to glial cell functions. PMID- 27759814 TI - Itajai, Santa Catarina - Azorean ancestry and spinocerebellar ataxia type 3. AB - The authors present a historical review of spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD), the most common form of spinocerebellar ataxia in Brazil, and consider the high frequency of cases in families from Itajai, a city on the coast of the state of Santa Catarina with a large population of Portuguese/Azorean descent. PMID- 27759815 TI - Drug prices: is the sky the limit? PMID- 27759816 TI - Randomized double-blind clinical trial comparing two anesthetic techniques for ultrasound-guided transvaginal follicular puncture. AB - Objective:: To compare the anesthetic techniques using propofol and fentanyl versus midazolam and remifentanil associated with a paracervical block with lidocaine in performing ultrasound-guided transvaginal oocyte aspiration. Methods:: A randomized double-blind clinical trial (#RBR-8kqqxh) performed in 61 women submitted to assisted reproductive treatment. The patients were divided into two groups: anesthetic induction with 1mcg/kg of fentanyl associated with 1.5mg/kg of propofol (FP Group, n=32), in comparison with anesthetic induction using 0.075mg/kg of midazolam associated with 0.25mcg/kg/min of remifentanil, and paracervical block with 3mL of 2% lidocaine (MRPB Group, n=29). Main outcome measures: human reproduction outcomes, modified Aldrete-Kroulik index, hemodynamic parameters, and salivary cortisol. Results:: The results revealed a higher number of embryos formed in the FP Group (p50=2 versus 1; p=0.025), gestation rate two times higher in the FP Group (44.4% versus 22.2%; p=0.127), less time to reach AK=10 in the MRPB Group (p50=10 versus 2; p<0.001), and lower mean of hemodynamic parameters in the MRPB Group (p<0.05). Conclusion:: Anesthesia with fentanyl and propofol as well as with midazolam, remifentanil, and paracervical block offered satisfactory anesthetic conditions when performing assisted reproduction procedures, providing comfort for the patient and physician. Objetivo:: Comparar as tecnicas anestesicas utilizando propofol e fentanil contra midazolam e remifentanil associados a um bloqueio paracervical com lidocaina na aspiracao de oocitos transvaginal guiada por ultrassom. Metodos:: Ensaio clinico randomizado duplocego (#RBR-8kqqxh) realizado em 61 mulheres submetidas ao tratamento de reproducao assistida. As pacientes foram divididas em dois grupos: um grupo foi submetido a inducao da anestesia com 1mcg/kg de fentanil associada com 1,5mg/kg de propofol (Grupo FP, n=32), em comparacao com ao grupo submetido a inducao da anestesia utilizando 0,075mg/kg de midazolam associada com 0,25mcg/kg/min de remifentanil, e bloqueio paracervical com 3mL de lidocaina a 2% (Grupo MRBP, n=29). Foram avaliados os resultados reprodutivos, indice modificado de Aldrete e Kroulik, parametros hemodinamicos e cortisol salivar. Resultados:: Foi encontrado um numero mais elevado de embrioes formados no Grupo FP (p50=2 versus 1; p=0,025), taxa de gestacao duas vezes mais elevada no Grupo FP (44,4% versus 22,2%; p=0,127), menos tempo para alcancar AK=10 no Grupo MRBP (p50=10 versus 2; p<0,001) e media mais baixa de parametros hemodinamicos do Grupo MRBP (p<0,05). Conclusao:: Ambas as anestesias (com fentanil e propofol, e com midazolam, remifentanil e bloqueio paracervical) ofereceram condicoes anestesicas satisfatorias na realizacao de procedimentos realizados em reproducao assistida, proporcionando conforto para o paciente e medico. PMID- 27759817 TI - Association of gestational age with the option of pregnancy termination for fetal abnormalities incompatible with neonatal survival. AB - Objective:: To identify the profile of women seen in a Fetal Medicine unit, diagnosed with fetal abnormality incompatible with neonatal survival in their current pregnancy, and to check the association of gestational age upon diagnosis with the option of pregnancy termination. Methods:: This is a retrospective cohort study carried out in the Fetal Medicine Outpatients Clinic of a university hospital, in the city of Sao Paulo (SP), Brazil, using medical records of pregnant women with fetus presenting abnormalities incompatible with neonatal survival. The sample comprised 94 medical records. The Statistical Package for the Social Sciences (SPSS), version 19, was used for the data statistical analysis. Results:: The population of the study included young adult women, who had complete or incomplete high school education, employed, with family income of one to three minimum wages, single, nonsmokers, who did not drink alcoholic beverages or used illicit drugs. Women with more advanced gestational age upon fetal diagnosis (p=0.0066) and/or upon admission to the specialized unit (p=0.0018) presented a lower percentage of termination of pregnancy. Conclusion:: Due to characteristics different from those classically considered as of high gestational risk, these women might not be easily identified during the classification of gestational risk, what may contribute to a late diagnosis of fetal diseases. Early diagnosis enables access to specialized multiprofessional care in the proper time for couple's counseling on the possibility of requesting legal authorization for pregnancy termination. Objetivo:: Identificar o perfil de mulheres atendidas em um servico de Medicina Fetal, que receberam diagnostico de anomalia fetal incompativel com a sobrevida neonatal na gestacao atual, e verificar a associacao da idade gestacional no diagnostico com a opcao pela interrupcao da gravidez. Metodos:: Trata-se de um estudo de coorte retrospectivo, realizado no ambulatorio de Medicina Fetal de um hospital universitario da cidade de Sao Paulo (SP), com prontuarios de mulheres com fetos portadores de anomalias incompativeis com a sobrevida neonatal na gestacao atual. A amostra constituiu-se de 94 prontuarios. Para analise estatistica dos dados, utilizou-se o programa Statistical Package for the Social Sciences (SPSS), versao 19. Resultados:: A populacao foi de mulheres adultas jovens, com escolaridade compativel com o Ensino Medio completo/incompleto, empregadas, com renda familiar entre um e tres salarios minimo, solteiras, que nao faziam uso de tabaco, bebidas alcoolicas ou de drogas ilicitas. Verificou-se que mulheres com maior idade gestacional na ocasiao do diagnostico fetal (p=0,0066) e/ou na chegada ao servico especializado (p=0,0018) apresentaram menor percentual de interrupcao gestacional. Conclusao:: Por apresentarem caracteristicas diferentes daquelas classicamente consideradas de alto risco gestacional, e possivel que essas mulheres nao tenham sido facilmente identificadas durante a classificacao de risco gestacional, o que pode ter colaborado para o diagnostico tardio de patologias fetais. O diagnostico precoce possibilita acesso a assistencia multiprofissional especializada em tempo adequado para aconselhamento do casal sobre a possibilidade de solicitacao de autorizacao judicial para a interrupcao gestacional. PMID- 27759818 TI - Frequency and risk factors for the birth of small-for-gestational-age newborns in a public maternity hospital. AB - Objective:: To determine the frequency and risk factors of small-for-gestational age newborns in a high-risk maternity. Methods:: This is an observational, cross sectional, and case-control study, conducted in a public tertiary care maternity hospital. Data from 998 newborns and their mothers were collected through interviews and review of medical records and prenatal care cards. Some placentas underwent histopathological analysis. The variables of small-for-gestational-age and non-small-for-gestational-age newborns and of their mothers were statistically compared by means of Student's t test, Fisher's exact test, and odds ratio. The significance level used was 0.050. Results:: There was a 17.9% frequency of small-for-gestational-age newborns. The statistically significant factors associated with the birth of these babies were female sex (p=0.012); positive history of another small-for-gestational-age child (p=0.006); inadequate prenatal care (p=0.019); smoking (p=0.003); hypertensive disorders of pregnancy (p=0.007); placental bleeding (p=0.009) and infarction (p=0.001). Conclusion:: In the population studied, the frequency of small-for-gestational-age newborns was high and associated with sex, inappropriate prenatal care, presence of maternal diseases and addictions, and placental abnormalities. Objetivo:: Determinar a frequencia e os fatores de risco de recem-nascidos pequenos para idade gestacional em uma maternidade de alto risco. Metodos:: Trata-se de um estudo observacional, transversal e caso-controle, realizado em maternidade publica de nivel terciario. Foram levantados dados de 998 recem-nascidos e de suas respectivas maes por meio de entrevista e analise de prontuarios e de cartoes do pre-natal. Algumas placentas foram submetidas a analise anatomopatologica. As variaveis dos recem-nascidos pequenos e nao pequenos para idade gestacional e de suas respectivas maes foram comparadas estatisticamente pelo teste parametrico t de Student, pelo teste exato de Fisher e por odds ratio. O nivel de significancia adotado foi de 0,050. Resultados:: A frequencia de recem-nascidos pequenos para idade gestacional foi de 17,9%. Os fatores com significado estatistico associados ao nascimento desses bebes foram sexo feminino (p=0,012); historia positiva para filho anterior pequeno para idade gestacional (p=0,006); realizacao de pre-natal inadequado (p=0,019); tabagismo (p=0,003); doenca hipertensiva especifica da gestacao (p=0,007); hemorragia (p=0,009) e infarto (p=0,001) placentarios. Conclusao:: Na populacao estudada, a frequencia de recem-nascidos pequenos para idade gestacional foi elevada e relacionada ao sexo, a inadequacao do pre-natal, a presenca de doencas e vicios maternos e as alteracoes placentarias. PMID- 27759819 TI - Associated factors with mammographic changes in women undergoing breast cancer screening. AB - Objective:: To evaluate association of sociodemographic, anthropometric, and epidemiological factors with result of mammogram in women undergoing breast cancer screening. Methods:: This is a cross-sectional study with data obtained through interviews, anthropometric measurements, and mammography of 600 women aged 40 to 69 years at the Preventive Medicine Department of Hospital de Cancer de Barretos, Brazil, in 2014. The results of these examinations in the BI-RADS categories 1 and 2 were grouped and classified in this study as normal mammogram outcome, and those of BI-RADS categories 3, 4A, 4B, 4C, and 5 were grouped and classified as altered mammogram outcome. The statistical analysis included the Student's t-test to compare means, as well as odds ratios (OR), with their corresponding 95% confidence intervals (95%CI), to verify an association by means of the multivariate analysis. Results:: Of 600 women evaluated, 45% belonged to the age group of 40-49 years-old and 60.2% were classified as BI-RADS category 2. The multivariate analysis showed that women with blood hypertension (OR: 2.64; 95%CI: 1.07-6.49; p<0.05) were more likely to present changes in the mammography, while physical activity was associated with lower chances (OR: 0.30; 95%CI: 0.11 0.81; p<0.05). Conclusion:: Hypertensive women undergoing screening mammography are more likely to present mammographic changes, whereas women practicing physical activity have lower chances (70%) of presenting changes in the breast compared with sedentary individuals. Objetivo:: Avaliar a associacao de fatores sociodemograficos, antropometricos e epidemiologicos com o resultado das mamografias de mulheres submetidas ao rastreamento. Metodos:: Trata-se de um estudo transversal com dados obtidos por meio de entrevistas, avaliacao antropometrica e mamografia de 600 mulheres entre 40 a 69 anos, atendidas no Departamento de Prevencao do Hospital de Cancer de Barretos, em 2014. Os resultados de tais exames nas categorias BI-RADS 1 e 2 foram agrupados e classificados neste estudo como achado mamografico normal, e aqueles das categorias BI-RADS 3, 4A, 4B, 4C e 5 como achado mamografico alterado. Na analise estatistica, utilizou-se o teste t de Student para comparar as medias, bem como odds ratio (OR), com seus respectivos intervalos de confianca de 95% (IC95%), na verificacao de associacao por analise multivariada. Resultados:: Das 600 mulheres avaliadas, 45% pertenciam a faixa etaria dos 40 a 49 anos e 60,2% foram classificadas na categoria BI-RADS 2. Na analise multivariada, verificou-se que as mulheres com hipertensao arterial (OR: 2,64; IC95%: 1,07-6,49; p<0,05) apresentaram maiores chances de alteracao na mamografia, enquanto que atividade fisica foi associada a menor chance (OR: 0,30; IC95%: 0,11-0,81; p<0,05). Conclusao:: Mulheres hipertensas submetidas a mamografia de rastreamento tiveram maiores chances de apresentarem alteracoes mamograficas, ao passo que mulheres praticantes de atividade fisica apresentaram uma chance menor (70%) de terem alteracao na mama em relacao as sedentarias. PMID- 27759820 TI - Disparities in cancer epidemiology and care delivery among Brazilian indigenous populations. AB - Objective:: To assess aspects related to cancer in indigenous population. Methods:: This is a retrospective study developed in a public university hospital. We included patients with 18 or more years of age, diagnosed with solid tumors, and followed between 2005 and 2015. Clinical features were assessed by descriptive statistics, and survival was evaluated by Kaplan-Meier curves and multivariate Cox regression. Results:: Fifty patients were included. The cancer incidence was 15.73 per 100,000. The mean age at diagnosis was 54 years and most patients were female (58%). Cancer of the cervix (28%) and prostate (16%) were the most common. The mean time between the onset of symptoms and the diagnosis was 9 months and from diagnosis to the treatment was 3.4 months. Disease diagnosed at stage IV (17%) had worse overall survival (HR: 11.4; p<0.05). The 5 year survival rate ranged from 88% for prostate cancer to 0% for lung cancer. All 5-year survival rates were lower as compared to other populations. Conclusion:: The most prevalent cancer sites were cervix and prostate. Disease stage and primary site were prognostic factors. Objetivo:: Avaliar os aspectos relacionados a cancer em populacoes indigenas. Metodos:: Estudo retrospectivo conduzido em um hospital universitario publico. Foram incluidos pacientes com 18 anos ou mais, diagnosticados com tumores solidos e acompanhados entre 2005 e 2015. Os aspectos clinicos foram avaliados por meio de estatistica descritiva, e a sobrevida foi avaliada por meio de curvas de Kaplan-Meier e regressao multivariada de Cox. Resultados:: Foram incluidos 50 pacientes. A incidencia de cancer foi 15,73 por 100 mil. A media de idade ao diagnostico foi 54 anos, e a maioria era do sexo feminino (58%). O cancer de colo uterino (28%) e o de prostata (16%) foram os mais frequentes. O tempo medio entre o inicio dos sintomas e o diagnostico foi 9 meses, e entre o diagnostico e o tratamento, de 3,4 meses. Doenca diagnosticada no estagio IV (17%) resultou em pior sobrevida global (HR: 11,4; p<0,05). A sobrevida em 5 anos variou de 88% para o cancer de prostata a 0% para pulmao. Todas as taxas de sobrevida em 5 anos foram menores em comparacao a outras populacoes. Conclusao:: Os locais mais frequentes de neoplasia foram colo de utero e prostata. O estagio da doenca e o sitio primario foram fatores prognosticos. PMID- 27759821 TI - Comparative study of knowledge about oral cancer among undergraduate dental students. AB - Objective:: To evaluate and compare the knowledge of dental undergraduate students about oral cancer. Methods:: The students were divided into two groups according to semester attended in the undergraduate course: Group A, the first semester; and Group B, seventh semester. They were asked to answer a questionnaire about epidemiology, risk factors, clinical aspects, therapeutic solutions and oral self-examination. For statistical analysis, the Fisher's exact test, the Cochran's G test and Kendall's concordance test were used, with significance level set at 0.05. Results:: Regarding the prevalent sex, only 8.0% of Group A and 56.0% of Group B judged males as the frequent affected by the disease (p=0.0006). In terms of age, 84.0% of the Group B and 44.0% of the Group A estimated that most cases were diagnosed over 40 years (p=0.0072). Smoking was identified as the major risk factor for 64.0% and 91.6% of Groups A and B, respectively (p=0.0110). On issues related to sex, ethnicity, age, risk factors, self-examination, treatment, professional responsible for treatment and profile of an individual with the disease, the seventh-semester showed significantly higher correct answer percentages than first-semester undergraduates. Conclusion:: There was significant correlation between the right and wrong answers given by first and seventh semester students, making necessary a specific approach directed to their lack of knowledge. Objetivo:: Avaliar e comparar o conhecimento de academicos de odontologia sobre cancer bucal. Metodos:: Os academicos foram divididos em dois grupos, de acordo com o semestre cursado na graduacao: Grupo A, primeiro semestre; e Grupo B: setimo semestre. Eles foram convidados a responderem um questionario referente a epidemiologia, fatores de risco, aspectos clinicos, solucoes terapeuticas e autoexame bucal. Para a analise estatistica dos resultados, foram utilizados o teste exato de Fisher, o teste G de Cochran e o teste de concordancia de Kendall, com nivel de significancia estabelecido em 0,05. Resultados:: Somente 8,0% do Grupo A e 56,0% do Grupo B julgaram o sexo masculino como aquele frequentemente acometido pela lesao (p=0,0006). Em relacao a faixa etaria, 84,0% do Grupo B e 44,0% do Grupo A estimaram que a maioria dos casos era diagnosticada acima dos 40 anos (p=0,0072). O tabagismo foi apontado como principal fator de risco por 64,0% e 91,6% dos alunos dos Grupos A e B, respectivamente (p=0,0110). Nas questoes referentes a sexo, etnia, faixa etaria, fatores de risco, autoexame, tratamento, profissional responsavel pelo tratamento e perfil de um individuo portador da lesao, os alunos do setimo semestre apresentaram percentagens de respostas corretas significantemente maiores que as dos discentes do primeiro semestre. Conclusao:: Houve significativa concordancia entre os erros e acertos dos discentes do primeiro e setimo semestres, sendo necessaria uma abordagem especifica direcionada a deficiencia por eles apresentadas. PMID- 27759822 TI - Clinical and sociodemographic variables associated with diabetes-related distress in patients with type 2 diabetes mellitus. AB - Objective:: To evaluate the relation between diabetes-related distress and the clinical and sociodemographic characteristics of type 2 diabetes mellitus patients. Methods:: A cross-sectional study based on a secondary analysis of data collected at a specialized care outpatient center in Brazil. Participants completed a questionnaire on sociodemographic and clinical characteristics and the Brazilian version of the Diabetes Distress Scale (B-DDS). Results:: About 31% of the 130 eligible patients reported diabetes distress, and the mean B-DDS score was 2.6. Multiple regression analysis showed the B-DDS score was positively correlated with marital status (p=0.0230), use of diet and physical activities for diabetes management (p=0.0180), and use of insulin therapy (p=0.0030). The "emotional burden", "regimen-related distress", and "interpersonal distress" domains from B-DDS were associated with the use of insulin therapy (p=0.0010), marital status (p=0.0110), and the presence of three or more comorbidities (p=0.0175). Conclusion:: These findings suggest the clinical and sociodemographic variables are relatively weak predictors of diabetes-related distress. The highest scores in the B-DDS were observed in the emotional burden domain, indicating the presence of diabetes distress among the participants of the study. Objetivo:: Avaliar a relacao entre o estresse relacionado ao diabetes e as caracteristicas clinicas e sociodemograficas de pacientes com diabetes mellitus do tipo 2. Metodos:: Estudo transversal com base na analise secundaria de dados coletados em um ambulatorio de atendimento terciario no Brasil. Os participantes preencheram um questionario sobre as caracteristicas sociodemograficas e clinicas, e a versao brasileira da Diabetes Distress Scale (B-DDS). Resultados:: Aproximadamente 31% dos 130 pacientes elegiveis relataram estresse relacionado ao diabetes, e a media do escore da B-DDS foi de 2,6. O modelo de regressao multipla mostrou que a pontuacao B-DDS foi positivamente correlacionada com o estado civil (p=0,0230), realizacao de dieta e atividades fisicas (p=0,0180), e uso de insulina (p=0,0030). Os dominios da B-DDS "carga emocional", "estresse relacionado ao regime terapeutico" e "estresse nas relacoes interpessoais" foram associados a uso de insulina (p=0,0010), estado civil (p=0,0110) e presenca de tres ou mais comorbidades (p=0,0175). Conclusao:: Estes resultados sugerem que as variaveis clinicas e sociodemograficas sao preditores relativamente fracos para o estresse relacionado ao diabetes. No dominio "carga emocional", foi observada a maior pontuacao da B-DDS, indicando a presenca do estresse relacionado ao diabetes entre os pacientes deste estudo. PMID- 27759823 TI - Increased ultrasensitive C-reactive protein is not associated with obesity in hospitalized heart failure patients. AB - Objective:: To evaluate the association between obesity and levels of high sensitivity C-reactive protein (hs-CRP) in patients with heart failure admitted to a tertiary hospital. Methods:: Cross-sectional study with a consecutive sampling of hospitalized patients with heart failure. Sociodemographic and clinical data were collected, and the nutritional status was assessed through indicators such as body mass index (in kg/m2), waist circumference (in cm), waist hip ratio, triceps skinfold (in mm) and subscapularis skinfold (in mm). Neck circumference (in cm) was measured as well as serum levels of hs-CRP, in mg/L. Results:: Among 123 patients, the mean age was 61.9+/-12.3 years and 60.2% were male. The median of hs-CRP was 8.87mg/L (3.34 to 20.01). A tendency to an inverse correlation between neck circumference and hs-CRP was detected (r=-0.167; p=0.069). In the multiple linear regression analysis, after adjustment for age, disease severity (NYHA classification III and IV, low ejection fraction, left ventricular dysfunction during diastole), and infectious conditions there was an inverse association between hs-CRP and neck circumference (beta=-0.196; p=0.03) and subscapularis skinfold (beta=-0.005; p=0.01) in the total sample, which was not maintained after the stratification by sex. Conclusion:: Increased levels of hs-CRP in patients hospitalized for heart failure were not associated with obesity. Objetivo:: Avaliar a associacao entre obesidade e niveis de proteina c reativa ultrassensivel (PCR-us) em pacientes com insuficiencia cardiac admitidos em um hospital terciario. Metodos:: Estudo transversal com amostragem consecutiva de pacientes com insuficiencia cardiaca hospitalizados. Foram coletados dados sociodemograficos e clinicos, e o estado nutricional foi avaliado por meio de indicadores como indice de massa corporal (em kg/m2), circunferencia da cintura (em cm), razao cintura-quadril, dobra cutanea tricipital (em mm) e dobra cutanea subescapular (em mm). Circunferencia do pescoco (em cm) foi aferida bem como niveis sericos de PCR-us, em mg/L. Resultados:: Em 123 pacientes, a media da idade foi 61,9+/-12,3 anos, e 60,2% eram do sexo masculino. A mediana de PCR-us foi de 8,87mg/L (3,34 a 20,01). Detectou-se tendencia a correlacao inversa entre circunferencia do pescoco e PCR-us (r=-0,167; p=0,069). Na analise por regressao linear multipla, apos ajustes para idade, gravidade da doenca (classificacao NYHA III e IV, fracao de ejecao baixa, disfuncao ventricular esquerda durante a diastole) e quadros infecciosos, houve associacao inversa entre PCR-us e circunferencia do pescoco (beta=-0,196; p=0,03) e dobra cutanea subescapular (beta=-0,005; p=0,01) na amostra total, que nao se manteve apos estratificacao para sexo. Conclusao:: O aumento dos niveis de PCR-us em pacientes hospitalizados por insuficiencia cardiaca nao se associou a obesidade. PMID- 27759824 TI - Pharmaceutical orientation at hospital discharge of transplant patients: strategy for patient safety. AB - Objective:: To describe and analyze the pharmaceutical orientation given at hospital discharge of transplant patients. Methods:: This was a cross-sectional, descriptive and retrospective study that used records of orientation given by the clinical pharmacist in the inpatients unit of the Kidney and Liver Transplant Department, at Hospital Universitario Walter Cantidio, in the city of Fortaleza (CE), Brazil, from January to July, 2014. The following variables recorded at the Clinical Pharmacy Database were analyzed according to their significance and clinical outcomes: pharmaceutical orientation at hospital discharge, drug-related problems and negative outcomes associated with medication, and pharmaceutical interventions performed. Results:: The first post-transplant hospital discharge involved the entire multidisciplinary team and the pharmacist was responsible for orienting about drug therapy. The mean hospital discharges/month with pharmaceutical orientation during the study period was 10.6+/-1.3, totaling 74 orientations. The prescribed drug therapy had a mean of 9.1+/-2.7 medications per patient. Fifty-nine drug-related problems were identified, in which 67.8% were related to non-prescription of medication needed, resulting in 89.8% of risk of negative outcomes associated with medications due to untreated health problems. The request for inclusion of drugs (66.1%) was the main intervention, and 49.2% of the medications had some action in the digestive tract or metabolism. All interventions were classified as appropriate, and 86.4% of them we able to prevent negative outcomes. Conclusion:: Upon discharge of a transplanted patient, the orientation given by the clinical pharmacist together with the multidisciplinary team is important to avoid negative outcomes associated with drug therapy, assuring medication reconciliation and patient safety. Objetivo:: Descrever e analisar a orientacao farmaceutica oferecida na alta de pacientes transplantados. Metodos:: Trata-se de um estudo transversal, descritivo e retrospectivo, que utilizou os registros das orientacoes realizadas pelo farmaceutico clinico na unidade de internacao do Servico de Transplante Renal e Hepatico, Hospital Universitario Walter Cantidio, em Fortaleza (CE), de janeiro a julho de 2014. Foram analisadas, de acordo com sua significancia e desfechos clinicos obtidos, as seguintes variaveis registradas no Banco de Dados do Servico de Farmacia Clinica: orientacoes farmaceuticas na alta, problemas e resultados negativos relacionados aos medicamentos, e intervencoes farmaceuticas realizadas. Resultados:: A primeira alta pos-transplante envolveu toda a equipe multiprofissional, sendo o farmaceutico responsavel pela orientacao do tratamento medicamentoso. A media de altas/mes com orientacao farmaceutica no periodo do estudo foi de 10,6+/-1,3, totalizando 74 orientacoes. O tratamento clinico prescrito teve media de 9,1+/-2,7 medicamentos por paciente. Foram identificados 59 problemas relacionados aos medicamentos; 67,8% relacionaram-se com a nao prescricao do medicamento necessario, acarretando 89,8% de risco de resultados negativos associados aos medicamentos por problema de saude nao tratado. A principal intervencao foi a solicitacao de inclusao do medicamento (66,1%), e 49,2% dos medicamentos envolvidos agiam no aparelho digestivo/metabolismo. Todas as intervencoes foram classificadas como apropriadas, e 86,4% foram capazes de prevenir o resultado negativo. Conclusao:: A orientacao do farmaceutico clinico junto a equipe multiprofissional no momento da alta do paciente transplantado e importante, pois previne resultados negativos associados a farmacoterapia, garantindo a conciliacao medicamentosa e a seguranca do paciente. PMID- 27759825 TI - Technical advances in flow cytometry-based diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria. AB - Objective:: To discuss the implementation of technical advances in laboratory diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria for validation of high-sensitivity flow cytometry protocols. Methods:: A retrospective study based on analysis of laboratory data from 745 patient samples submitted to flow cytometry for diagnosis and/or monitoring of paroxysmal nocturnal hemoglobinuria. Results:: Implementation of technical advances reduced test costs and improved flow cytometry resolution for paroxysmal nocturnal hemoglobinuria clone detection. Conclusion:: High-sensitivity flow cytometry allowed more sensitive determination of paroxysmal nocturnal hemoglobinuria clone type and size, particularly in samples with small clones. Objetivo:: Discutir as melhorias tecnicas no diagnostico e no acompanhamento laboratorial de hemoglobinuria paroxistica noturna para a validacao da tecnica de citometria de fluxo de alta sensibilidade. Metodos:: Estudo retrospectivo, que envolveu a analise de dados laboratoriais de 745 pacientes com hipotese diagnostica e/ou acompanhamento de hemoglobinuria paroxistica noturna por citometria de fluxo. Resultados:: Os avancos tecnicos nao so reduziram o custo do ensaio, mas tambem melhoraram a identificacao e a resolucao da citometria de fluxo para a deteccao de clone hemoglobinuria paroxistica noturna. Conclusao:: A citometria de fluxo de alta sensibilidade possibilitou a identificacao do tipo e do tamanho de clone de hemoglobinuria paroxistica noturna, especialmente em amostras com pequeno clone. PMID- 27759826 TI - Multiparametric magnetic resonance imaging findings of prostatic pure leiomyomas. AB - Objective:: To describe the imaging findings of prostatic tumors nonadenocarcinoma on multiparametric magnetic resonance imaging. Methods:: A total of 200 patients underwented multiparametric magnetic resonance imaging of the prostate for screening for prostate cancer, from August 2013 to September 2014, followed by biopsy with ultrasound/magnetic resonance imaging fusion. Results:: We found three pathologic proved cases of prostatic pure leiomyomas (0.02%) in our series and described the multiparametric magnetic resonance imaging features of these prostatic leiomyomas. The imaging findings had similar features to lesions with moderate or high suspicion for significant cancer (Likert 4 or 5) when localized both in the transitional zone or in the peripheral zone of the gland. Conclusion:: Pure prostatic leiomyomas had imaging findings on multiparametric magnetic resonance imaging that mimicked usual adenocarcinomas on this test. Radiologists, urologists and pathologists must be aware of this entity and its imaging features. Objetivo:: Descrever os achados de imagem de tumores prostaticos nao adenocarcinoma na ressonancia magnetica multiparametrica. Metodos:: Realizaram ressonancia magnetica multiparametrica da prostata para deteccao de cancer de prostata 200 pacientes de agosto de 2013 a setembro de 2014, seguida por biopsia com fusao de imagens de ultrassonografia/ressonancia magnetica. Resultados:: Encontramos tres casos confirmados histologicamente de leiomiomas prostaticos puros (0,02%) em nossa casuistica e descrevemos os achados da ressonancia magnetica multiparametrica destes casos de leiomiomas. Os achados de imagem foram semelhantes aos de lesoes com moderada ou alta suspeicao para neoplasia clinicamente significante (Likert 4 ou 5) quando localizados na zona de transicao ou zona periferica da prostata. Conclusao:: Leiomiomas puros da prostata tiveram achados de imagem na ressonancia magnetica multiparametrica que mimetizaram adenocarcinomas. Radiologistas, urologistas e patologistas devem estar cientes destas entidades e seus achados de imagem. PMID- 27759827 TI - Interobserver reproducibility of radiographic evaluation of lumbar spine instability. AB - Objective:: To measure the interobserver reproducibility of the radiographic evaluation of lumbar spine instability. Methods:: Measurements of the dynamic radiographs of the lumbar spine in lateral view were performed, evaluating the anterior translation and the angulation among the vertebral bodies. The tests were evaluated at workstations of the organization, through the Carestream Health Vue RIS (PACS), version 11.0.12.14 Inc. 2009(c) system. Results:: Agreement in detecting cases of radiographic instability among the observers varied from 88.1 to 94.4%, and the agreement coefficients AC1 were all above 0.8, indicating excellent agreement. Conclusion:: The interobserver analysis performed among orthopedic surgeons with different levels of training in dynamic radiographs of the spine obtained high reproducibility and agreement. However, some factors, such as the manual method of measurement and the presence of vertebral osteophytes, might have generated a few less accurate results in this comparative evaluation of measurements. Objetivo:: Mensurar a reprodutibilidade interobservadores da avaliacao radiografica da instabilidade da coluna lombar. Metodos:: Foram realizadas mensuracoes das radiografias dinamicas de coluna lombar na incidencia em perfil, avaliando-se a translacao anterior e a angulacao entre os corpos vertebrais. Os exames foram avaliados em workstations da propria instituicao, por meio do sistema Vue RIS (PACS) da Carestream Health, versao 11.0.12.14 Inc. 2009(c). Resultados:: A proporcao de concordancia em deteccao de casos de instabilidade radiografica entre os observadores variou de 88,1 a 94,4%, e os coeficientes de concordancia AC1 estiveram todos acima de 0,8, indicando concordancia excelente. Conclusao:: A analise interobservadores realizada entre medicos ortopedistas com diferentes niveis de treinamento em radiografias dinamicas da coluna vertebral obteve elevada reprodutibilidade e concordancia. No entanto, alguns fatores, como metodo manual de afericao e a presenca de osteofitos vertebrais, podem ter gerado alguns resultados menos consistentes nessa avaliacao comparativa de medidas. PMID- 27759828 TI - Implementing a clinical pharmacy service in hematology. AB - Objective:: To implement a clinical pharmacy service focused on the comprehensive review of antineoplastic drugs used in therapy of hematological diseases. Methods:: An interventional study was conducted in a Brazilian tertiary teaching hospital in two different periods, with and without a clinical pharmacy service, respectively. This service consisted of an antineoplastic prescription validation (analysis of patients' characteristics, laboratory tests, compliance with the therapeutic protocol and with pharmacotechnical parameters). When problems were detected, the pharmacist intervened with the physician or another health professional responsible for the patient. Inpatients and outpatients with hematological diseases were included. Results:: We found an increased detection of drug-related problem by 106.5% after implementing the service. Comparing the two periods, an increase in patients' age (26.7 years versus 17.6 years), a predominance of outpatients (54% versus 38%), and an increase in multiple myeloma (13% versus 4%) and non-Hodgkin lymphoma (16% versus 3%) was noted. The most commonly found problems were related to dose (33% versus 25%) and cycle day (14% versus 30%). With regard to clinical impact, the majority had a significant impact (71% versus 58%), and in one patient from the second period could have been fatal. The main pharmaceutical interventions were dose adjustment (35% versus 25%) and drug withdrawal (33% versus 40%). Conclusion:: The pharmacy service contributed to increase the detection and resolution of drug-related problems, and it was an effective method to promote the safe and rational use of antineoplastic drugs. Objetivo:: Implementar um servico farmaceutico clinico centrado na revisao completa dos antineoplasicos utilizados no tratamento de doencas hematologicas. Metodos:: Estudo intervencional conduzido em um hospital universitario terciario brasileiro em dois periodos distintos, com base na ausencia e na presenca do servico farmaceutico clinico, respectivamente. O referido servico consistiu na validacao farmaceutica de prescricao de medicamentos antineoplasicos (analise de caracteristicas do paciente, exames laboratoriais, conformidade com o protocolo terapeutico e parametros farmacotecnicos). Apos a deteccao dos problemas, o farmaceutico interveio junto ao medico ou outro profissional de saude responsavel pelo paciente. Foram incluidos pacientes internados e ambulatoriais com doencas hematologicas. Resultados:: Observou-se um aumento de 106,5% na deteccao de problemas relacionados com medicamentos apos a implementacao do servico. Comparando-se os dois periodos, verificou-se aumento na idade dos pacientes (26,7 anos versus 17,6 anos), predominio de pacientes ambulatoriais (54% versus 38%) e aumento de mieloma multiplo (13% versus 4%) e linfoma nao Hodgkin (16% versus 3%). Os problemas mais comumente encontrados foram relacionados a dose (33% versus 25%) e ao dia do ciclo (14% versus 30%). Quanto ao impacto clinico, a maioria apresentou impacto significante (71% versus 58%) e um poderia ter sido fatal no segundo periodo. As principais intervencoes farmaceuticas realizadas foram ajuste de dose (35% versus 25%) e suspensao de medicamento (33% versus 40%). Conclusao:: O servico farmaceutico contribuiu para o aumento da deteccao e resolucao de problemas relacionados com medicamentos, tratando-se de um metodo efetivo para promover o uso seguro e racional de medicamentos antineoplasicos. PMID- 27759829 TI - Analysis of cytokine profile and growth factors in platelet-rich plasma obtained by open systems and commercial columns. AB - Objective:: To evaluate growth factors and cytokines in samples of platelet-rich plasma obtained by three different centrifugation methods. Methods:: Peripheral blood of six individuals with no hematological diseases, aged 18 to 68 years, was drawn to obtain platelet-rich plasma, using the open method and commercial columns by Medtronic and Biomet. The products obtained with the different types of centrifugation were submitted to laboratory analysis, including pro inflammatory cytokines and chemokines by flow cytometry assays, the concentration of fibroblast growth factors-2 (FGF-2) and transforming growth factor-beta1 (TGF beta1). Results:: The diverse separation methods generated systematically different profiles regarding number of platelets and leukocytes. The Medtronic system yielded a product with the highest concentration of platelets, and the open method, with the lowest concentration of platelets. The results of cytokine analysis showed that the different types of centrifugation yielded products with high concentrations of interleukin 8, interleukin 1beta. The open system resulted in a product with high levels of interleukin 6. Other cytokines and chemokines measured were similar between systems. The product obtained with the open method showed higher levels of TGF-beta1 in relation to other systems and low FGF-2 levels. Conclusion:: The formed elements, growth factors and cytokines in samples of platelet-rich plasma varied according to the centrifugation technique used. Objetivo:: Avaliar fatores de crescimento e citocinas em amostras de plasma rico em plaquetas obtidas por tres diferentes metodos de centrifugacao. Metodos:: Foi coletado sangue periferico de seis individuos, sem doenca hematologica, com idades entre 18 e 68 anos, para obtencao de plasma rico em plaquetas, utilizando o metodo aberto e sistemas comerciais das empresas Medtronic e Biomet. Os produtos obtidos com os diferentes tipos de centrifugacao foram submetidos as analises laboratoriais, incluindo citocinas proinflamatorias e quimiocinas, por meio de ensaios de citometria de fluxo, concentracao do fator de crescimento fibroblastico-2 (FGF-2) e fator de crescimento transformador-beta1 (TGF-beta1). Resultados:: As diferentes centrifugacoes geraram perfis sistematicamente diferentes referentes ao numero de plaquetas e de leucocitos. O sistema da Medtronic originou produto com a maior concentracao de plaquetas, e o metodo aberto com a menor concentracao de plaquetas. Os resultados da analise de citocinas demonstraram que os diferentes tipos de centrifugacao originaram produtos com elevadas concentracoes de interleucina 8 e interleucina 1beta. O sistema aberto resultou em produto com elevados niveis de interleucina 6. As demais citocinas e quimiocinas mensuradas foram similares entre os sistemas. O produto obtido com o metodo aberto apresentou niveis superiores de TGF-beta1 em relacao aos demais sistemas e reduzidos niveis de FGF-2. Conclusao:: Os elementos figurados, fatores de crescimento e citocinas, em amostras de plasma rico em plaquetas, variaram conforme a tecnica de centrifugacao utilizada. PMID- 27759830 TI - Phonemic verbal fluency task in adults with high-level literacy. AB - Objective:: To establish normative parameters for the F-A-S form of the phonemic verbal fluency test, in a population of Brazilian Portuguese speaking adults with high-level literacy. Methods:: The sample comprised 40 male and female volunteers aged 19 to 59 years, and at least 8 years of formal education. Volunteers were first submitted to the Mini-Mental State Examination and the Clock Drawing cognitive screening tests, then to the F-A-S Verbal Phonemic Fluency Test; in this test, examinees were given 60 seconds to generate as many words as possible beginning with each of the three test letters. Results:: The means for number of words beginning the letters F, A and S and for total number of words beginning with either letter generated per minute corresponded to 15.3, 14.4, 13.9 and 43.5, respectively. Conclusion:: Reference values obtained from young adults with high levels of literacy submitted to the F-A-S Verbal Phonemic Fluency Test in this study were similar to those reported in the international literature. These reference values can be used for clinical assessment of language disorder and neuropsychological evaluation. Objetivo:: Obter parametros de normalidade na tarefa de fluencia verbal fonemica, versao F-A-S, em uma populacao de alto letramento de adultos falantes do portugues brasileiro. Metodos:: A amostra foi constituida por 40 voluntarios, de ambos os sexos, com idade entre 19 e 59 anos, e com mais de 8 anos de estudo. Todos os voluntarios foram inicialmente submetidos ao Miniexame do Estado Mental e ao Teste do Desenho do Relogio, para fins de rastreio cognitivo, e, entao, ao Teste de Fluencia Verbal Fonemica F-A-S. Neste ultimo, os individuos foram orientados a produzirem o maior numero de palavras que conseguissem, iniciadas com cada uma das tres letras ditas pelo examinador, em um intervalo de 60 segundos cada. Resultados:: As medias das palavras produzidas com as letras F-A-S foram as seguintes: "F" = 15,3 palavras por minuto; "A" = 14,4 palavras por minuto; e "S" = 13,9 palavras por minuto. A media do total de palavras emitidas iniciada com todas as letras do teste foi de 43,5 palavras. Conclusao:: Foram obtidos valores de referencia para o Teste de Fluencia Verbal Fonemica F-A-S para individuos adultos jovens de alto grau de letramento semelhantes aos de estudos internacionais. Tais valores podem ser utilizados na avaliacao clinica de transtornos da linguagem e na avaliacao neuropsicologica. PMID- 27759831 TI - Caregivers' reactions to preoperative procedures in outpatient pediatric surgery. AB - Objective:: To identify pediatric caregivers' reactions in outpatient surgery settings. Methods:: A quantitative descriptive/exploratory survey-based study involving application of a semi-structured questionnaire to 62 caregivers in two hospitals. Results:: Most caregivers (88.7%) were mothers who submitted to preoperative fasting with their children. Nervousness, anxiety and concern were the most common feelings reported by caregivers on the day of the surgery. Conclusion:: Medical instructions regarding preoperative procedures had significant positive impacts on patient care, and on patient and caregiver stress levels. Objetivo:: Identificar as reacoes dos acompanhantes de criancas submetidas a cirurgia ambulatorial. Metodos:: Estudo survey descritivo/ exploratorio, de carater quantitativo, realizado em dois hospitais com 62 acompanhantes que responderam um questionario semiestruturado. Resultados:: Constatou-se que a maioria dos acompanhantes era formada por maes (88,7%) e permaneceu em jejum junto das criancas. Todos os acompanhantes referiram sentimentos identificados como nervosismo, ansiedade e preocupacao. Conclusao:: A orientacao medica aos procedimentos pre-operatorios foi de grande importancia, nao somente para o cuidado da crianca, mas tambem do acompanhante, visando diminuir ao maximo o estresse vivenciado por eles. PMID- 27759832 TI - Preclinical molecular imaging: development of instrumentation for translational research with small laboratory animals. AB - Objective:: To present the result of upgrading a clinical gamma-camera to be used to obtain in vivo tomographic images of small animal organs, and its application to register cardiac, renal and neurological images. Methods:: An updated version of the miniSPECT upgrading device was built, which is composed of mechanical, electronic and software subsystems. The device was attached to a Discovery VH (General Electric Healthcare) gamma-camera, which was retired from the clinical service and installed at the Centro de Imagem Pre-Clinica of the Hospital Israelita Albert Einstein. The combined system was characterized, determining operational parameters, such as spatial resolution, magnification, maximum acceptable target size, number of projections, and acquisition and reconstruction times. Results:: Images were obtained with 0.5mm spatial resolution, with acquisition and reconstruction times between 30 and 45 minutes, using iterative reconstruction with 10 to 20 iterations and 4 projection subsets. The system was validated acquiring in vivo tomographic images of the heart, kidneys and brain of normal animals (mice and adult rats), using the radiopharmaceuticals technetium labeled hexakis-2-methoxy-isobutyl isonitrile (99mTc-Sestamibi), technetium labeled dimercaptosuccinic acid (99mTc-DMSA) and technetium-labeled hexamethyl propyleneamine oxime (99mTc-HMPAO). Conclusion:: This kind of application, which consists in the adaptation for an alternative objective of already existing instrumentation, resulted in a low-cost infrastructure option, allowing to carry out large scale in vivo studies with enhanced quality in several areas, such as neurology, nephrology, cardiology, among others. Objetivo:: Apresentar o resultado da adaptacao de uma gama camara clinica para uso dedicado na obtencao de imagens tomograficas in vivo de orgaos de pequenos animais de experimentacao, e de sua aplicacao na obtencao de imagens cardiacas, renais e neurologicas. Metodos:: Foi construida uma versao atualizada do dispositivo de adaptacao miniSPECT, composto por tres subsistemas: mecanico, eletronico e de software. O dispositivo foi montado em uma camara Discovery VH da General Electric Healthcare, retirada do servico clinico e instalada no Centro de Imagem Pre Clinica do Hospital Israelita Albert Einstein. O sistema combinado foi caracterizado, determinando parametros de funcionamento como resolucao espacial, magnificacao, limites de tamanho dos alvos de estudo, numero de projecoes, tempo de registro e tempo de reconstrucao das imagens tomograficas. Resultados:: Foram obtidas imagens com resolucao espacial de ate 0,5mm, com tempos de registro e reconstrucao de 30 a 45 minutos, utilizando reconstrucao iterativa com 10 a 20 iteracoes e 4 subconjuntos de projecoes. O sistema foi validado obtendo imagens tomograficas in vivo do coracao, dos rins e do cerebro de animais normais (camundongos e ratos adultos), utilizando os radiofarmacos hexaquis-2-metoxi isobutil-isonitrila marcado com 99mTc (Sestamibi-99mTc), acido dimercaptosuccinico marcado com 99mTc (DMSA-99mTc) e hexametil-propileno-amina oxima marcada com 99mTc (HMPAO-99mTc). Conclusao:: Este tipo de aplicacao, que consiste na adaptacao para um objetivo alternativo de instrumentacao ja existente, constituiu-se em uma opcao de infraestrutura de baixo custo, que permite realizar estudos in vivo em larga escala, com qualidade aprimorada, em areas diversas, como neurologia, nefrologia, cardiologia, entre outras. PMID- 27759833 TI - The good pharmacy practice on Einstein Program at Paraisopolis Community. AB - Objectives:: To describe indicators and processes developed and implemented for pharmaceutical assistance at the Einstein Program at Paraisopolis Community pharmacy. Methods:: This was a descriptive study of retrospective data from January 2012 to December 2015. Data were obtained from spreadsheets developed for monitoring the productivity and care quality provided at the pharmacy. The evaluated variables were pharmaceutical assistance to prescription, pharmaceutical intervention, orientation (standard and pharmaceutical) and pharmaceutical orientation rate. Results:: The pharmacy assisted, on average, 2,308 prescriptions monthly, dispensing 4,871 items, including medications, materials and food supplements. Since March 2015, virtually, the pharmacist analyzed all prescriptions, prior to dispensing. In the analyzed period, there was an increase in monthly pharmaceutical interventions from 7 to 32 on average, and, although there was a decrease in the number of standard orientation, the pharmaceutical orientation had an increase, causing a rise of pharmaceutical orientation rate from 4 to 11%. Conclusion:: The processes developed and implemented at the program pharmacy sought to follow the good pharmacy practice, and help patients to make the best use of their medications. Objetivo:: Descrever os indicadores e os processos desenvolvidos e implantados para assistencia farmaceutica na farmacia do Programa Einstein na Comunidade de Paraisopolis. Metodos:: Tratase de um estudo descritivo de dados retrospectivos de janeiro de 2012 a dezembro de 2015. Os dados foram obtidos de planilhas desenvolvidas para acompanhamento da produtividade e da qualidade de assistencia prestada na farmacia. As variaveis avaliadas foram: atencao farmaceutica a prescricao, intervencao farmaceutica, orientacao (padrao e farmaceutica) e taxa de orientacao farmaceutica. Resultados:: A farmacia atendeu, em media, 2.308 prescricoes ao mes, dispensando 4.871 itens, incluindo medicamentos, materiais e suplementos alimentares. Desde marco de 2015, praticamente todas as prescricoes foram analisadas pelo farmaceutico antes da dispensacao. Houve incremento nas intervencoes farmaceuticas mensais, de 7 para 32 em media e, apesar de ter havido diminuicao no numero de orientacoes padrao, a orientacao farmaceutica aumentou, fazendo com que a taxa de orientacao subisse de 4 para 11%. Conclusao:: Os indicadores e os processos desenvolvidos e implantados na farmacia do programa procuraram seguir as boas praticas de farmacia e ajudar os pacientes a fazerem melhor uso de seus medicamentos. PMID- 27759834 TI - Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review. AB - Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are the central nervous system cells that control voluntary muscle movements. The excessive salivation (sialorrhea) is present in approximately 50% of amyotrophic lateral sclerosis cases. Thus, some alternative therapeutic methods are sought, such as anticholinergic drugs and surgery. Recently the use of botulinum toxin applied at a midpoint of the salivary glands, often guided by ultrasound, have demonstrated positive results. The objective was to review the literature to demonstrate an alternative method to treatments of sialorrhea in patients with amyotrophic lateral sclerosis. In recent studies, the efficacy of botulinum toxin is confirmed, although new applications are required. Since the side effects are negligible, this is an alternative to treat amyotrophic lateral sclerosis, and other patients with diseases that present sialorrhea. RESUMO Esclerose lateral amiotrofica e uma doenca neurodegenerativa progressiva e fatal, caracterizada pela degeneracao dos neuronios motores, as celulas do sistema nervoso central que controlam os movimentos voluntarios dos musculos. A salivacao excessiva (sialorreia) esta presente em cerca de 50% dos casos de esclerose lateral amiotrofica. Dessa forma, surgem medidas terapeuticas alternativas como drogas anticolinergicas e cirurgia, e recentemente, o uso da toxina botulinica, aplicada em um ponto central das glandulas salivares, muitas vezes guiado por ultrassonografia, demostrou resultados positivos. Objetivou-se revisar a literatura no intuito de demonstrar um metodo alternativo aos tratamentos de sialorreia em pacientes com esclerose lateral amiotrofica. Em estudos recentes, a eficacia do tratamento com toxina botulinica foi confirmada e, mesmo requerendo novas aplicacoes, os efeitos colaterais sao infimos. Ela surge entao como alternativa nao so ao tratamento de esclerose lateral amiotrofica, mas tambem para outros pacientes com doencas que apresentem a sialorreia. PMID- 27759835 TI - Vesicular lesions in a neonate: what's your diagnosis? PMID- 27759836 TI - Advances in lung ultrasound. AB - Ultrasound examination of the chest has advanced in recent decades. This imaging modality is currently used to diagnose several pathological conditions and provides qualitative and quantitative information. Acoustic barriers represented by the aerated lungs and the bony framework of the chest generate well-described sonographic artifacts that can be used as diagnostic aids. The normal pleural line and A, B, C, E and Z lines (also known as false B lines) are artifacts with specific characteristics. Lung consolidation and pneumothorax sonographic patterns are also well established. Some scanning protocols have been used in patient management. The Blue, FALLS and C.A.U.S.E. protocols are examples of algorithms using artifact combinations to achieve accurate diagnoses. Combined chest ultrasonography and radiography are often sufficient to diagnose and manage lung and chest wall conditions. Chest ultrasonography is a highly valuable diagnostic tool for radiologists, emergency and intensive care physicians. RESUMO O exame ultrassonografico do torax avancou nas ultimas decadas, sendo utilizado para o diagnostico de inumeras condicoes patologicas, e fornecendo informacoes qualitativas e quantitativas. Os pulmoes aerados e o arcabouco osseo do torax representam barreira sonora para o estudo ultrassonografico, gerando artefatos que, bem conhecidos, sao utilizados como ferramentas diagnosticas. Eco pleural normal, linhas A, linhas B, linhas C, linhas E e Z (conhecidas como falsas linhas B) sao artefatos com caracteristicas peculiares. Os padroes de consolidacao e de pneumotorax tambem sao bem estabelecidos. Alguns protocolos tem sido utilizados no manuseio dos pacientes: Blue Protocol, Protocolo FALLS e Protocolo C.A.U.S.E sao exemplos de tres propostas que, por meio da associacao entre os artefatos, permitem sugerir diagnosticos precisos. A ultrassonografia de torax, aliada a radiografia de torax, muitas vezes e suficiente para o diagnostico e a conduta das afeccoes pulmonares e da parede toracica. Trata-se de ferramenta diagnostica de grande valia para medicos radiologistas, emergencistas e intensivistas. PMID- 27759837 TI - Children's oral prevention: a continuum from pregnancy. PMID- 27759838 TI - Emerging Zika virus infection and bioethical considerations. PMID- 27759839 TI - Parkinson's patients in the Brazilian Public Health Policy context. PMID- 27759840 TI - Interpretation of ambiguities by schoolchildren with low birth weight from Embu das Artes, Sao Paulo state, Brazil. AB - Purpose: To assess the development of language regarding the ability to recognize and interpret lexical ambiguity in low-birth-weight schoolchildren enrolled at the school system in the municipality of Embu das Artes, Sao Paulo state, compared with that of schoolchildren with normal birth weight. Methods: A case control, retrospective, cross-sectional study conducted with 378 schoolchildren, both genders, aged 5 to 9.9 years, from the municipal schools of Embu das Artes. Study Group (SG) comprising 210 schoolchildren with birth weight < 2500 g. Control Group (CG) composed of 168 school children with birth weight >= 2500 g. Participants of both groups were compared with respect to the skills of recognition and verbal interpretation of sentences containing lexical ambiguity using the Test of Language Competence. Variables of interest: Age and gender of children; age and schooling of mothers. Statistical analysis: Descriptive analysis to characterize the sample and score per group; Student's t test for comparison between the total scores of each skill/subtest; Chi-square test to compare items within each subtest; multiple regression analysis for the intervening variables. Results: Participants of the SG presented lower scores for ambiguous sentences compared with those of participants of the CG. Multiple regression analysis showed that child's current age was a predictor for all metalinguistic skills regarding interpretation of ambiguities in both groups. Conclusion: Participants of the SG presented lower specific and total scores than those of participants of the CG for ambiguity skills. The child's current age factor positively influenced the ambiguity skills in both groups. PMID- 27759841 TI - Cortical auditory evoked potentials in full-term and preterm neonates. AB - Purpose: To measure the exogenous components of the cortical auditory evoked potential (CAEP) in term and preterm newborns and compare them considering the variables latency and amplitude. Methods: This is a cross-sectional, prospective, comparative, contemporary study. One hundred twenty-seven newborns were evaluated; 96 of these were included in the study after analysis of the exams by three referees. Participants were divided into two groups: Term Group: 66 infants and Preterm Group: 30 neonates. The recordings of CAEP were performed using surface electrodes with newborns comfortably positioned in the lap of their mothers and/or guardians in natural sleep. To this end, binaural verbal stimuli were presented with /ba/ as the frequent stimulation and /ga/ the rare stimulus, at an intensity of 70 dB HL, through insert earphones. The presence or absence of exogenous components and the latency and amplitude of P1 and N1 were analyzed in both groups. Pertinent tests were used in the statistical analysis of data. Results: The latency of the waves P1 and N1 was smaller in participants in the Term Group. However, there were no statistically significant differences in the amplitude of P1 and N1 between the groups. No difference between the groups was found when comparing the presence and absence of the components P2 and N2. Conclusion: It is possible to measure the CAEP in term and preterm neonates. There was influence of the maturational process only on the measure of latency of the components P1, binaurally, and N1, in the left ear, which were smaller in participants in the Term Group. PMID- 27759842 TI - Differential Diagnosis of Solitary Pulmonary Inflammatory Lesions and Peripheral Lung Cancers with Contrast-enhanced Computed Tomography. AB - OBJECTIVES:: To clarify differences between solitary pulmonary inflammatory lesions and peripheral lung cancers with contrast-enhanced computed tomography. METHODS:: In total, 64 and 132 patients with solitary pulmonary inflammatory masses/nodules and peripheral lung cancers, respectively, were enrolled in this study. Their computed tomographic findings were summarized and compared retrospectively. RESULTS:: Compared with the peripheral lung cancers, the inflammatory lesions were located closer to the pleura (p<0.0001). The majority of the inflammatory lesions were patchy and oval-shaped (82.8%), whereas most of the tumors were lobulated (82.6%). Almost all the inflammatory cases were unclear (93.8%), whereas most of the tumors had spiculated margins (72.7%). Computed tomography values were significantly higher for the inflammatory lesions than for the cancers (p<0.0001). More than half of the inflammatory lesions had defined necrosis (59.3%). Furthermore, 49.2% of the cancers enhanced inhomogeneously, but only 24.6% had ill-defined necrosis or cavities. The peripheral zones of 98.4% of the inflammatory lesions and 72.7% of the tumors were unclear, with peripheral scattered patches (92.2%) and beam-shaped opacity (66.7%) being the most common findings, respectively. Adjacent pleural thickening was more frequent for the inflammatory lesions than the cancers (95.3% vs. 21.1%, p<0.0001), whereas pleural indentation was found in 67.4% of the subjects with cancer. In addition, hilar (p=0.034) and mediastinal (p=0.003) lymphadenopathy were more commonly detected in the cancers than in the inflammatory cases. CONCLUSIONS:: Contrast enhanced computed tomography findings for pulmonary inflammatory lesions and peripheral lung cancers were significantly different in many aspects. Developing a comprehensive understanding of these differences is helpful for directing their management. PMID- 27759844 TI - Mother's freedom of choice and the rights of an unborn child: a comparison between the views of freshmen and senior medical school students. AB - OBJECTIVES:: To compare the views of freshman students with senior students of the Faculty of Medicine- University of Sao Paulo concerning the respect for the mother's freedom of choice, the need to protect the unborn child, the proportionality between the mother's freedom of choice and the protection of the unborn child, and issues related to legal abortion. To determine whether the medical knowledge acquired throughout the academic years can influence the views of medical students on these issues. METHODS:: First- and sixth-year students of the Faculty of Medicine - University of Sao Paulo answered a questionnaire; the inclusion criteria were as follows: a first- or sixth-year student of the medical school and a signature on the free informed consent form. To compare the proportions, a chi-square or Fisher's exact test was used. The significance level was set to 5%. RESULTS:: Regarding the mother's freedom of choice, in the case when a pregnant woman undergoes a cesarean section by means of a court order despite her intention to not have a cesarean, 55.7% of the first-year students have answered that the mother's choice should be respected. Among the sixth-year students, only 28.9% believe that the mother's intention should be considered (p<0.0001). With reference to the mother's choice in connection with antiretroviral medication, 38.1% of the first-year students agreed that the mother's intention should be respected, whereas 33% of sixth-year students believed that the mother's intention should be respected (p=0.453). CONCLUSION:: There was a tendency to consider the unborn child's rights over the mother's choice as students spent more time in medical school. PMID- 27759843 TI - Septic Pulmonary Embolism Requiring Critical Care: Clinicoradiological Spectrum, Causative Pathogens and Outcomes. AB - OBJECTIVES:: Septic pulmonary embolism is an uncommon but life-threatening disorder. However, data on patients with septic pulmonary embolism who require critical care have not been well reported. This study elucidated the clinicoradiological spectrum, causative pathogens and outcomes of septic pulmonary embolism in patients requiring critical care. METHODS:: The electronic medical records of 20 patients with septic pulmonary embolism who required intensive care unit admission between January 2005 and December 2013 were reviewed. RESULTS:: Multiple organ dysfunction syndrome developed in 85% of the patients, and acute respiratory failure was the most common organ failure (75%). The most common computed tomographic findings included a feeding vessel sign (90%), peripheral nodules without cavities (80%) or with cavities (65%), and peripheral wedge-shaped opacities (75%). The most common primary source of infection was liver abscess (40%), followed by pneumonia (25%). The two most frequent causative pathogens were Klebsiella pneumoniae (50%) and Staphylococcus aureus (35%). Compared with survivors, nonsurvivors had significantly higher serum creatinine, arterial partial pressure of carbon dioxide, and Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores, and they were significantly more likely to have acute kidney injury, disseminated intravascular coagulation and lung abscesses. The in hospital mortality rate was 30%. Pneumonia was the most common cause of death, followed by liver abscess. CONCLUSIONS:: Patients with septic pulmonary embolism who require critical care, especially those with pneumonia and liver abscess, are associated with high mortality. Early diagnosis, appropriate antibiotic therapy, surgical intervention and respiratory support are essential. PMID- 27759845 TI - Post-operative hemimaxillectomy rehabilitation using prostheses supported by zygoma implants and remaining natural teeth. AB - OBJECTIVES:: This study aimed to evaluate the stability of prostheses supported by zygoma implants and remaining teeth for subjects who had undergone hemi maxillectomy. METHODS:: Ten patients were included in the study. Oral rehabilitation was performed using a temporary prosthesis that was supported by remaining teeth for the first three months. Then, a zygoma implant was placed to provide support for a final prosthesis in addition to the remaining teeth. Each prosthesis was tailor-made according to biomechanical three-dimensional finite element analysis results. The patients were assessed using the prosthesis functioning scale of the Memorial Sloan-Kettering Cancer Center. In addition, retention and bite force were recorded for both the temporary prosthesis and the final prosthesis. RESULTS:: The mean bite force of the prosthetic first molar was increased to 69.2 N. The mean retentive force increased to 13.5 N after zygoma implant insertion. The bite force on the prosthetic first molar was improved to 229.3 N. CONCLUSION:: Bite force increased significantly with the support of a zygoma implant. The use of zygoma implants in the restoration of maxillary defects improved functional outcome and patient satisfaction. PMID- 27759846 TI - Velocity time integral for right upper pulmonary vein in VLBW infants with patent ductus arteriosus. AB - OBJECTIVE:: Early diagnosis of significant patent ductus arteriosus reduces the risk of clinical worsening in very low birth weight infants. Echocardiographic patent ductus arteriosus shunt flow pattern can be used to predict significant patent ductus arteriosus. Pulmonary venous flow, expressed as vein velocity time integral, is correlated to ductus arteriosus closure. The aim of this study is to investigate the relationship between significant reductions in vein velocity time integral and non-significant patent ductus arteriosus in the first week of life. METHODS:: A multicenter, prospective, observational study was conducted to evaluate very low birth weight infants (<1500 g) on respiratory support. Echocardiography was used to evaluate vein velocity time integral on days 1 and 4 of life. The relationship between vein velocity time integral and other parameters was studied. RESULTS:: In total, 98 very low birth weight infants on respiratory support were studied. On day 1 of life, vein velocity time integral was similar in patients with open or closed ductus. The mean vein velocity time integral significantly reduced in the first four days of life. On the fourth day of life, there was less of a reduction in patients with patent ductus compared to those with closed patent ductus arteriosus and the difference was significant. CONCLUSIONS:: A significant reduction in vein velocity time integral in the first days of life is associated with ductus closure. This parameter correlates well with other echocardiographic parameters and may aid in the diagnosis and management of patent ductus arteriosus. PMID- 27759847 TI - A phase III, randomized, non-inferiority study comparing the efficacy and safety of biosimilar filgrastim versus originator filgrastim for chemotherapy-induced neutropenia in breast cancer patients. AB - OBJECTIVES:: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non inferiority of the test drug relative to the originator. METHODS:: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS:: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION:: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa's approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima-). PMID- 27759848 TI - The effect of maternal near miss on adverse infant nutritional outcomes. AB - OBJECTIVES:: To evaluate the association between self-reported maternal near miss and adverse nutritional status in children under one year of age. METHODS:: This study is a secondary analysis of a study in which women who took their children under one year of age to the national vaccine campaign were interviewed. The self reported condition of maternal near miss used the criteria of Intensive Care Unit admission; eclampsia; blood transfusion and hysterectomy; and their potential associations with any type of nutritional disorder in children, including deficits in weight-for-age, deficits in height-for-age, obesity and breastfeeding. The rates of near miss for the country, regions and states were initially estimated. The relative risks of infant adverse nutritional status according to near miss and maternal/childbirth characteristics were estimated with their 95% CIs using bivariate and multiple analyses. RESULTS:: The overall prevalence of near miss was 2.9% and was slightly higher for the Legal Amazon than for other regions. No significant associations were found with nutritional disorders in children. Only a 12% decrease in overall maternal breastfeeding was associated with near miss. Living in the countryside and child over 6 months of age increased the risk of altered nutritional status by approximately 15%, while female child gender decreased this risk by 30%. Maternal near miss was not associated with an increased risk of any alteration in infant nutritional status. CONCLUSIONS:: There was no association between maternal near miss and altered nutritional status in children up to one year of age. The risk of infant adverse nutritional status was greater in women living in the countryside, for children over 6 months of age and for male gender. PMID- 27759849 TI - Long-term Results after CT-Guided Percutaneous Ethanol Ablation for the Treatment of Hyperfunctioning Adrenal Disorders. AB - OBJECTIVES:: To evaluate the safety and long-term efficacy of computed tomography guided percutaneous ethanol ablation for benign primary and secondary hyperfunctioning adrenal disorders. METHOD:: We retrospectively evaluated the long-term results of nine patients treated with computed tomography-guided percutaneous ethanol ablation: eight subjects who presented with primary adrenal disorders, such as pheochromocytoma, primary macronodular adrenal hyperplasia and aldosterone-producing adenoma, and one subject with Cushing disease refractory to conventional treatment. Eleven sessions were performed for the nine patients. The patient data were reviewed for the clinical outcome and procedure-related complications over ten years. RESULTS:: Patients with aldosterone-producing adenoma had clinical improvement: symptoms recurred in one case 96 months after ethanol ablation, and the other patient was still in remission 110 months later. All patients with pheochromocytoma had clinical improvement but were eventually submitted to surgery for complete remission. No significant clinical improvement was seen in patients with hypercortisolism due to primary macronodular adrenal hyperplasia or Cushing disease. Major complications were seen in five of the eleven procedures and included cardiovascular instability and myocardial infarction. Minor complications attributed to sedation were seen in two patients. CONCLUSION:: Computed tomography-guided ethanol ablation does not appear to be suitable for the long-term treatment of hyperfunctioning adrenal disorders and is not without risks. PMID- 27759850 TI - Pediatric minor head trauma: do cranial CT scans change the therapeutic approach? AB - OBJECTIVES:: 1) To verify clinical signs correlated with appropriate cranial computed tomography scan indications and changes in the therapeutic approach in pediatric minor head trauma scenarios. 2) To estimate the radiation exposure of computed tomography scans with low dose protocols in the context of trauma and the additional associated risk. METHODS:: Investigators reviewed the medical records of all children with minor head trauma, which was defined as a Glasgow coma scale >=13 at the time of admission to the emergency room, who underwent computed tomography scans during the years of 2013 and 2014. A change in the therapeutic approach was defined as a neurosurgical intervention performed within 30 days, hospitalization, >12 hours of observation, or neuro-specialist evaluation. RESULTS:: Of the 1006 children evaluated, 101 showed some abnormality on head computed tomography scans, including 49 who were hospitalized, 16 who remained under observation and 36 who were dismissed. No patient underwent neurosurgery. No statistically significant relationship was observed between patient age, time between trauma and admission, or signs/symptoms related to trauma and abnormal imaging results. A statistically significant relationship between abnormal image results and a fall higher than 1.0 meter was observed (p=0.044). The mean effective dose was 2.0 mSv (0.1 to 6.8 mSv), corresponding to an estimated additional cancer risk of 0.05%. CONCLUSION:: A computed tomography scan after minor head injury in pediatric patients did not show clinically relevant abnormalities that could lead to neurosurgical indications. Patients who fell more than 1.0 m were more likely to have changes in imaging tests, although these changes did not require neurosurgical intervention; therefore, the use of computed tomography scans may be questioned in this group. The results support the trend of more careful indications for cranial computed tomography scans for children with minor head trauma. PMID- 27759851 TI - Role of the Neutrophil-Lymphocyte Ratio in the Differential Diagnosis of Exudative Pleural Effusion. AB - OBJECTIVES:: Pleural effusion is a common diagnostic and clinical problem. The differential diagnosis of pleural effusion may be difficult and may require several procedures, including invasive ones. Certain studies have investigated biochemical parameters to facilitate the diagnosis of exudative pleural effusion; however, it remains a challenging problem in clinical practice. We aimed to investigate the potential role of the neutrophil-lymphocyte ratio, which can be easily obtained by determining the cell count of the pleural fluid, in the differential diagnosis of exudative pleural effusion. METHODS:: Records from patients who underwent thoracentesis and pleural fluid analysis between May 1, 2013, and March 1, 2015, were obtained from the electronic database of our hospital. The patients who met the inclusion criteria were divided into five groups according to their diagnosis: malignant pleural effusion, para-malignant pleural effusion, para-pneumonic effusion, tuberculosis-related effusion or other. The neutrophil-lymphocyte ratio value was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The patient groups were compared according to the given parameter. RESULTS:: A total of 465 patients who met the inclusion criteria among 1616 patients with exudative pleural effusion were included in the study. The mean neutrophil-lymphocyte ratio value was significantly lower in tuberculosis-related pleural effusion compared to malignant, para-pneumonic and para-malignant effusions (p=0.001, p=0.001, p=0.012, respectively). The areas under the curve for tuberculosis pleurisy compared to malignant, para-pneumonic and para-malignant effusions were 0.38, 0.36, and 0.37, respectively. Lower cut-off values had higher sensitivity but lower specificity for tuberculosis pleurisy, while higher cut-off values had higher specificity but lower sensitivity for this condition. CONCLUSION:: The pleural fluid neutrophil-lymphocyte ratio, which is an inexpensive, reproducible, and easily calculated hematological parameter, may facilitate the differential diagnosis of pleural effusion. PMID- 27759853 TI - Profibrotic pathways and atrial cardiomyopathy in persistent atrial fibrillation. PMID- 27759852 TI - Functional investigation of bone implant viability using radiotracers in a new model of osteonecrosis. AB - OBJECTIVES:: Conventional imaging methods are excellent for the morphological characterization of the consequences of osteonecrosis; however, only specialized techniques have been considered useful for obtaining functional information. To explore the affinity of radiotracers for severely devascularized bone, a new mouse model of isolated femur implanted in a subcutaneous abdominal pocket was devised. To maintain animal mobility and longevity, the femur was harvested from syngeneic donors. Two technetium-99m-labeled tracers targeting angiogenesis and bone matrix were selected. METHODS:: Medronic acid and a homodimer peptide conjugated with RGDfK were radiolabeled with technetium-99m, and biodistribution was evaluated in Swiss mice. The grafted and control femurs were evaluated after 15, 30 and 60 days, including computed tomography (CT) and histological analysis. RESULTS:: Radiolabeling achieved high (>95%) radiochemical purity. The biodistribution confirmed good blood clearance 1 hour after administration. For 99mTc-hydrazinonicotinic acid (HYNIC)-E-[c(RGDfK)2, remarkable renal excretion was observed compared to 99mTc-methylene diphosphonate (MDP), but the latter, as expected, revealed higher bone uptake. The results obtained in the control femur were equal at all time points. In the implanted femur, 99mTc-HYNIC-E-[c(RGDfK)2 uptake was highest after 15 days, consistent with early angiogenesis. Regarding 99mTc-MDP in the implant, similar uptake was documented at all time points, consistent with sustained bone viability; however, the uptake was lower than that detected in the control femur, as confirmed by histology. CONCLUSIONS:: 1) Graft viability was successfully diagnosed using radiotracers in severely ischemic bone at all time points. 2) Analogously, indirect information about angiogenesis could be gathered using 999mTc-HYNIC-E-[c(RGDfK)2. 3) These techniques appear promising and warrant further studies to determine their potential clinical applications. PMID- 27759854 TI - Toxoplasmosis Retinitis Masquerading as Acute Retinal Necrosis. PMID- 27759855 TI - Choroidal Changes in Anisometropic and Strabismic Children With Unilateral Amblyopia. AB - BACKGROUND AND OBJECTIVE: To detect changes in the choroidal layer at the macular area in amblyopic eyes. PATIENTS AND METHODS: A cross-sectional study of 50 amblyopic patients (20 strabismic and 30 anisometropic) and 50 controls was done. Cross-sectional images using enhanced depth optical coherence tomography (OCT) were taken. Thicknesses were measured subfoveally and at 1,500 um nasally, temporally, inferiorly, and superiorly. Submacular corresponding choroidal areas were also computed. Parameters were compared between amblyopic eyes, fellow eyes, and controls. RESULTS: Significantly thicker choroid was detected in the subfoveal, temporal, and nasal locations (P = .007, .009, and .01, respectively) in amblyopic compared to fellow eyes; areas were also significantly greater temporally, nasally, and inferiorly. Significant differences in all choroidal measurements were found between amblyopic eyes and controls; these persisted only in the anisometropic subgroup. CONCLUSION: Using enhanced depth OCT, the choroid of amblyopic eyes was observed to be thicker compared to normal fellow eyes and controls. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:900-907.]. PMID- 27759856 TI - Optical Coherence Tomography Features in Diabetic Macular Edema and the Impact on Anti-VEGF Response. AB - BACKGROUND AND OBJECTIVE: To assess the relationship between spectral-domain optical coherence tomography (SD-OCT) features and functional outcomes for diabetic macular edema (DME) undergoing treatment with intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA). PATIENTS AND METHODS: Institutional review board-approved, retrospective, consecutive case series of eyes receiving intravitreal bevacizumab (1.25 mg) for DME. SD-OCT features were evaluated and correlated with functional response to anti-vascular endothelial growth factor (VEGF) therapy. RESULTS: One hundred fifty-nine eyes of 159 subjects were included in this study. Mean visual acuity improved from 20/76 to 20/58. The proportion of eyes with 20/40 or greater visual acuity increased with treatment (35% at initial visit, 51% at final visit). SD-OCT factors that were associated with functional outcomes to anti-VEGF therapy include ellipsoid zone integrity and severity of intraretinal fluid. CONCLUSION: SD-OCT features appear to provide important markers for functional response to anti-VEGF therapy in DME. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:908-913.]. PMID- 27759857 TI - Topical Squalamine 0.2% and Intravitreal Ranibizumab 0.5 mg as Combination Therapy for Macular Edema Due to Branch and Central Retinal Vein Occlusion: An Open-Label, Randomized Study. AB - BACKGROUND AND OBJECTIVE: To evaluate the effects of squalamine (OHR-102; Ohr Pharmaceuticals, New York, NY) and ranibizumab (Lucentis; Genentech, South San Francisco, CA) on macular edema (ME) secondary to retinal vein occlusion (RVO). PATIENTS AND METHODS: Twenty consecutive, treatment-naive patients with RVO related ME received topical squalamine and intravitreal ranibizumab 0.5 mg for 10 weeks, followed by randomization to continue or discontinue squalamine. Groups received as-needed ranibizumab from weeks 2 through 34. The primary endpoint was the proportion of eyes gaining 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 38. Safety and tolerability were assessed. Data from 13 treatment-naive control eyes previously enrolled in three similar trials evaluating monthly ranibizumab 0.5 mg for RVO-related ME were included for comparison. RESULTS: At baseline, mean best-corrected visual acuity (BCVA) measures were 55.6 ETDRS letters and 55.0 ETDRS letters in the squalamine and control groups, respectively. At week 38, BCVA improved 25.6 letters in the squalamine group; at month 9, BCVA improved 16.3 letters in the control group. This corresponds to a between-treatment-group difference of 9.2 letters. Squalamine and ranibizumab combination therapy was well-tolerated. CONCLUSIONS: In patients with RVO-related ME, topical squalamine combined with early, as needed ranibizumab appears to enhance visual recovery versus ranibizumab alone. Combination therapy appears safe and was well-tolerated. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:914-923.]. PMID- 27759858 TI - The Effect of Bevacizumab Pretreatment on the Choice of Endotamponade in Diabetic Tractional Retinal Detachment. AB - BACKGROUND AND OBJECTIVE: To evaluate the effect of preoperative intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) injection on the choice of endotamponade at the end of surgery in patients who underwent pars plana vitrectomy (PPV) for diabetic tractional retinal detachment (DTRD). PATIENTS AND METHODS: Seventy-eight patients who had DTRD with macular involvement and underwent PPV by a single surgeon from January 2012 to May 2015 were included. Complete ophthalmological examinations were evaluated at the baseline and during the postoperative follow-up period. RESULTS: The mean age was 55.58 years +/- 9.31 years in bevacizumab group and 56.70 years +/- 9.35 years in the non-bevacizumab group. Preoperative IVB injection was performed in 38 of 78 patients. The complications of intraoperative retinal bleeding and iatrogenic retinal tear were not seen in 26 patients within the bevacizumab group or in 12 patients within the non-bevacizumab group (P = .016). Silicone oil was used as endotamponade in 10 patients (26%) in the bevacizumab group and in 28 patients (70%) in the non-bevacizumab group. The use of silicone oil as endotamponade in the non-bevacizumab group was significantly greater than in the bevacizumab group (P = .039). CONCLUSION: IVB injection reduces the need for the use of silicone oil as endotamponade in the patients who underwent PPV for DTRD at the end of surgery. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:924-929.]. PMID- 27759859 TI - Evaluation and Referral of Diabetic Eye Disease in the Endocrinology and Primary Care Office Settings. AB - BACKGROUND AND OBJECTIVE: The purpose of this study was to identify whether endocrinologists and primary care physicians (PCP) adequately screen for ophthalmic symptoms/signs within office visits and provide timely ophthalmology referrals in patients with diabetes. PATIENTS AND METHODS: Patients between the ages of 18 years and 80 years with diabetes who underwent an office visit with an endocrinologist or a PCP between January 1, 2014, and December 31, 2014, were identified. Demographics, ophthalmic assessments, and referral information were collected. RESULTS: A total of 1,250 patient records were reviewed. Providers asked about ophthalmic symptoms/signs in 95.5% and 71% of endocrinology and primary care office encounters, respectively (P < .0001). Past and/or future ophthalmology appointments were verified in 86.1% and 49.7% of patients during endocrinology and PCP visits, respectively (P < .0001). CONCLUSIONS: Ophthalmic complications from diabetes are not adequately screened, especially within the primary care setting, and further quality improvement measures may improve adherence to recommended screening protocols. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:930-934.]. PMID- 27759860 TI - Value of Optical Coherence Tomography Angiography Imaging in Diagnosis and Treatment of Hemangioblastomas in von Hippel-Lindau Disease. AB - BACKGROUND AND OBJECTIVE: The introduction of optical coherence tomography angiography (OCTA) provides new insights into the retinal vasculature. The aim of this study was to explore the value of OCTA in imaging retinal hemangioblastomas and monitoring laser treatment in patients with von Hippel-Lindau (VHL) disease. PATIENTS AND METHODS: Ten eyes of 10 patients with VHL disease were included in this retrospective case series. All patients underwent complete ophthalmological work-up including OCTA for retinal and optic nerve head hemangioblastoma. RESULTS: Two patients showed retinal scars and no recurrence of hemangioblastoma in OCTA. Three patients revealed recurrent hemangioblastomas. Two patients demonstrated a new hemangioblastoma. Three patients showed hemangioblastomas of the optic nerve head. Successful laser photocoagulation could be monitored with OCTA. CONCLUSIONS: Screening for retinal hemangioblastomas with OCTA alone is not possible. OCTA may help to distinguish hemangioblastomas and other lesions in VHL disease, especially after treatment and allows the differentiation from harmless non-vascular lesions in questionable cases. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:935-946.]. PMID- 27759861 TI - Dehydrated Allogenic Human Amniotic Membrane Graft for Conjunctival Surface Reconstruction Following Removal of Exposed Scleral Buckle. AB - A 54-year-old male developed symptomatic scleral buckle exposure 16 years after placement and presented with large conjunctival defects with fibrosed edges. Following surgical removal of the buckle elements, primary conjunctival closure could not be achieved due to significant wound tension despite undermining the conjunctival edges to mobilize the conjunctiva. A dehydrated amniotic membrane graft (Ambio5; IOP Ophthalmics, Costa Mesa, CA) was placed on the scleral bed and secured in place with fibrin sealant (TISSEEL; Baxter International, Westlake Village, CA). The amniotic membrane allowed successful closure of the large conjunctival defect with a good cosmetic outcome and resolution of symptoms. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:948-951.]. PMID- 27759862 TI - First Travel-Associated Congenital Zika Syndrome in the US: Ocular and Neurological Findings in the Absence of Microcephaly. AB - A 6-day-old female baby with known diagnosis of congenital Zika infection was referred for ophthalmologic examination. The mother (37 years old) was referred for a pruritic rash, conjunctival hyperemia, and malaise at 12 weeks of gestation while still living in Venezuela. Upon arrival to Miami, Zika virus (ZIKV) exposure was confirmed during prenatal screening. At birth, due to the known exposure, a complete congenital ZIKV workup was performed, including brain ultrasound and MRI, which disclosed calcifications in the frontal lobe. Fundus examination revealed a hypopigmented retinal lesion in the left eye that was documented with retinal imaging. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:952-955.]. PMID- 27759863 TI - Stage 1 Type 3 Neovascularization With Choroidal Dilation Unresponsive to Anti VEGF Treatment. AB - Type 3 neovascularization is considered to originate within the retina with subsequent expansion of the neovascular network into the subretinal space. Choroidal circulatory disturbances seem to have a role in Type 3 neovascularization development, but the exact pathophysiology is still under debate. Although eyes with Type 3 neovascularization usually have thinner choroid compared to normal eyes, the increased choroidal thickness associated with Type 3 neovascularization may be a prognostic factor for its recurrence. This case report documents stage 1 Type 3 neovascularization with dilated choroid showing poor response to anti-vascular endothelial growth factor therapy, thus suggesting an active role of choroid in Type 3 lesions. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:956-959.]. PMID- 27759865 TI - Portable Optical Coherence Tomography Detection or Confirmation of Ophthalmoscopically Invisible or Indeterminate Active Retinoblastoma. AB - Portable, hand-held optical coherence tomography (OCT) revealed three clinically relevant yet not ophthalmoscopically detected or confirmed manifestations of retinoblastoma in a single patient with familial bilateral disease. Specifically, OCT showed new retinal tumors, new vitreous seeds, and tumor recurrence before they could be detected or confirmed by ophthalmoscopy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:965-968.]. PMID- 27759864 TI - Analysis of Scleral Feeder Vessel in Myopic Choroidal Neovascularization Using Optical Coherence Tomography Angiography. AB - To describe the appearance of a scleral-derived feeder vessel in a highly myopic eye with secondary choroidal neovascularization (CNV) as visualized on both en face high-speed swept-source (SS) optical coherence tomography angiography (OCTA) prototype, and a commercially available spectral-domain (SD) OCTA, with the corresponding en face and cross-sectional structural OCT images. In this case report, a 60-year-old white male presented with high myopia and secondary CNV in the right eye, previously treated with anti-vascular endothelial growth factor, and was imaged on both SD-OCT and SS-OCT. The neovascular complex could be visualized on both devices. Structural en face SS-OCT images demonstrated a large choroidal-scleral feeder vessel that was not visualized with SD-OCT. The authors concluded that structural en face SS-OCT better visualizes scleral feeder vessel compared to SD-OCT due to the longer wavelength (~1,050 nm) with increased choroidal penetration and decreased sensitivity roll-off in the SS-OCT system. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:960-964.]. PMID- 27759866 TI - Optical Coherence Tomography Angiography Study of Choroidal Neovascularization Associated With Focal Choroidal Excavation. AB - The authors report the use of optical coherence tomography angiography (OCTA) (DRI OCT Triton; Topcon, Tokyo, Japan) to localize, characterize, and confirm the presence of a choroidal neovascular membrane in a patient of focal choroidal excavation (FCE) with recent-onset metamorphopsia and visual blurring. En face OCTA images just above the level of the retinal pigment epithelium-Bruch's membrane complex typically showed the presence of a glomerulus-like neovascular network with an adjacent dark area suggestive of a Type 2 choroidal neovascularization (CNV). OCTA was found to be a very useful, noninvasive, and quick imaging modality to detect secondary CNV formation in a case of FCE. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:969-971.]. PMID- 27759867 TI - Optical Coherence Tomography Angiography Imaging of Congenital Retinal Macrovessel. AB - Congenital retinal macrovessels (CRM) are rarely reported, aberrant, large branches of retinal vessels that can be both arteries and veins; however, they are more commonly veins that cross the horizontal raphe to either supply or drain the macula. In this brief report, the authors discuss optical coherence tomography angiography features of CRM in a 12-year-old male patient presenting with low visual acuity in the right eye since childhood. To the authors' knowledge, this is the first such report published in the literature. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:972-973.]. PMID- 27759868 TI - Dynamic Imaging of a Pigmented Free-Floating Vitreous Cyst. AB - The authors present an incidentally noted pigmented anterior vitreous cyst in an asymptomatic male adult. Observation was elected. Stability during the course of 2 years and mobility of the vitreous cyst using dynamic imaging are demonstrated. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:975-977.]. PMID- 27759869 TI - 8 Questions with Dr. Moshfeghi. PMID- 27759870 TI - Grip strength reference values for Canadians aged 6 to 79: Canadian Health Measures Survey, 2007 to 2013. AB - BACKGROUND: Grip strength is a measure of overall muscular strength and has been associated with disability, morbidity and mortality. Normative data are used to interpret an individual's grip strength measurements, but Canadian reference values are not available for a wide age range. DATA AND METHODS: The data pertain to 11,108 respondents aged 6 to 79 to the 2007-to-2013 Canadian Health Measures Survey, whose right-hand and left-hand grip strength were measured with a handgrip dynamometer. Quantile regression was used to develop reference equations for males and females for maximum, right-hand and left-hand grip strength for selected percentiles as a function of age, height and weight. RESULTS: Reference values for grip strength increased through childhood and adolescence, peaked around age 40, and then declined. Reference values were higher for males than for females; differences between the sexes were smaller during childhood than in adolescence and adulthood. Differences between reference values for maximum, right-hand and left-hand grip strength varied by age and sex. INTERPRETATION: Based on a large, healthy, nationally representative sample, reference equations were developed for grip strength of Canadians from childhood to older adulthood. These equations can be used to determine the reference values that correspond to an individual of a given age, sex, height and weight. PMID- 27759871 TI - Reduced muscular strength among Canadians aged 60 to 79: Canadian Health Measures Survey, 2007 to 2013. AB - BACKGROUND: Reduced muscular strength is associated with an increased risk of all cause, cardiovascular and non-cardiovascular mortality, heart attack and stroke. At older ages, reduced strength is associated with impaired mobility, risk of falls, and disability. Various criteria are used to determine reduced strength. DATA AND METHODS: Data on grip strength among 3,181 respondents aged 60 to 79 from the 2007 to 2013 Canadian Health Measures Survey were used to calculate the prevalence of reduced strength based on sex-specific percentile and t-score cut points and cut-points of the Foundation for the National Institutes of Health. Logistic regression was used to identify significant associations between reduced strength and mobility, disability and self-rated health. RESULTS: Based on stricter criteria, the prevalence of reduced strength among household residents aged 60 to 79 ranged from 3% to 5%; based on less strict criteria, the prevalence ranged from 10% to 18%. Compared with people with normal strength, those with reduced strength had higher odds of impaired mobility (ranging from 3.40 to 8.33, depending on the cut-point), poor or fair self-rated health (2.19 to 4.20), and moderate-to-severe disability (2.21 to 2.60). INTERPRETATION: Estimates of the prevalence of reduced grip strength varied by cut-point. Reduced strength was significantly associated with impaired mobility, moderate-to-severe disability, and poor or fair self-rated health. Further research is required to determine if associations between reduced strength and other health outcomes vary by cut point. PMID- 27759872 TI - Surgical Timing for Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis and Systematic Review. AB - AIM: Despite great advances in treatment of aneurysmal subarachnoid hemorrhage (aSAH), yet, a consensus as to the most optimal timing of surgery has not been reached. In order to identify the most suitable time of surgery for aSAH, the authors conducted a meta-analysis and systematic review. MATERIAL AND METHODS: PubMed and the Cochrane Library were searched for English-language studies published up to May 2015. Two independent reviewers screened abstracts, reviewed full-text articles and extracted data. Before conducting the metaanalysis, the studies were evaluated for publication bias and heterogeneity. Fixed and random effect models were used to estimate relative risks (RR) and the corresponding 95% confidence intervals (CIs). Subgroup analysis and sensitivity analysis were also performed. RESULTS: One randomized controlled trial (RCT) and 33 observational studies of 16,793 participants were included in this paper. The overall methodological quality was satisfying. Results after excluding articles inconsistent with our surgery timing definition showed no significant difference for poor outcome, with early vs intermediate treatment (RR 0.86[0.68,1.09]), early vs late (RR 0.99[0.70,1.40]). Subgroup analysis based on age showed that early surgery could obtain more favorable outcomes for death rate, with non-early group as reference when age ?50 years (RR 0.52[0.29,0.93]). When less than 50 years old, patients could benefit more from early intervention for poor outcome, with intermediate group as reference (RR 0.18[0.04,0.78]). CONCLUSION: Despite the shortcomings of this study, timing of surgery for aSAH did not put a significant impact on overall surgical outcome. But subgroup analysis indicated a trend with more benefits for early treatment. Given the risks of re-bleeding and inpatient stay, early intervention should be performed as soon as possible. However, more randomized trials with long-term followup are necessary, especially in this era of endovascular coiling. PMID- 27759873 TI - Early Endoscopic Ventricular Irrigation for the Treatment of Neonatal Posthemorrhagic Hydrocephalus: A Feasible Treatment Option or Not? A Multicenter Study. AB - AIM: Neonatal intraventricular hemorrhage (IVH) usually results in posthemorrhagic hydrocephalus (PHH). This multicenter study describes the approach of early neuroendoscopic ventricular irrigation for the treatment of IVH/PHH and compares the results with the cases that have been initially treated only with conventional temporary cerebrospinal fluid (CSF) diversion techniques. MATERIAL AND METHODS: The data of 74 neonatal PHH cases, that have been treated at three pediatric neurosurgery centers, were retrospectively analyzed. 23 neonates with PHH underwent early endoscopic ventricular irrigation (Group-A). 29 neonates were initially treated with conventional methods (Group-B). 22 neonates underwent ventriculosubgaleal shunt placement (Group-C). Complications, shunt dependency rates, incidence of multiloculated hydrocephalus and incidence of CSF infection were evaluated and compared retrospectively. RESULTS: Group-A, Group-B and Group-C cases did not differ significantly regarding gestational age and birth weight. In Group-A, 60.8% of the patients required a later shunt insertion, as compared with 93.1% of the cases in Group-B and 77.2% of the cases in Group-C. Group-A patients were also associated with significantly fewer CSF infections as well as significantly lower incidence for multiloculated hydrocephalus development as compared with Group-B and Group-C. CONCLUSION: Early removal of intraventricular blood degradation products and residual hematoma via neuroendoscopic ventricular irrigation is feasible and safe for the treatment of PHH in neonates with IVH. Neuroendoscopic technique seems to offer significantly lower shunt rates and fewer complications such as infection and development of multiloculated hydrocephalus in those cases. PMID- 27759874 TI - Neuroprotective Effect of Genistein in Peripheral Nerve Injury. AB - AIM: To investigate the effects of genistein in a rat model of sciatic nerve crush injury and complete sciatic nerve transection. The effects of genistein were compared with those of gabapentin, which is widely used in clinical practice for peripheral nerve injury. MATERIAL AND METHODS: Forty-eight rats were randomly divided into six groups (8 rats in each group): group 1 (sham); group 2, sciatic nerve crush injury (control); group 3, sciatic nerve crush injury+genistein 20 mg/kg; group 4, sciatic nerve crush injury+gabapentin 90 mg/kg; group 5, sciatic nerve transection+genistein 20 mg/kg; group 6, sciatic nerve transection+gabapentin 90 mg/kg. The effects of genistein and gabapentin were assessed with immunohistochemical staining for growth associated protein-43 (GAP 43) and myelin basic protein (MBP). Interleukin-1beta and tumor necrosis factor alpha levels in the injured nerve specimens were assessed as a measure of inflammatory response; walking track analysis and sciatic function index for neurological recovery and the paw mechanical withdrawal threshold were examined for neuropathic pain. RESULTS: On histopathological examination, genistein use was associated with a greater immunoreactivity for GAP-43 and MBP compared with that associated with gabapentin. Genistein and gabapentin had similar effects on anti-inflammatory activity, functional recovery, and neuropathic pain. CONCLUSION: Genistein and gabapentin exhibit positive effects on histopathology, inflammation, and clinical findings of peripheral nerve injury. When the systemic side effects of gabapentin are considered, genistein (a basic soy isoflavone that has no side effects) can be used as an alternative to medical treatment in peripheral nerve injury. PMID- 27759875 TI - Training in Micro-Vascular Anastomosis Using Rat Femoral Vessels: Comparison of Immediate and Delayed Patency Rates. AB - AIM: Micro-vascular anastomosis is a difficult art. It can be learnt and perfected only by practice using vessels of small animals in the laboratory. The purpose of the study was to practice various anastomotic techniques using rat femoral vessels and study the patency rates. MATERIAL AND METHODS: Sixty-four Sprague-Dawley rats were used in the study. The following procedures were conducted on rat femoral vessels; Femoral artery end-to-end anastomosis- classical method, one way up method, Femoral vein end-to-end anastomosis and end to-side anastomosis. The animals were subsequently sacrificed at a later date to assess delayed patency. RESULTS: The immediate patency rates for femoral artery end-to-end anastomosis- classical method (n=10), one way up method (n=16), femoral vein end-to-end anastomosis (n=12) and end-to-side anastomosis (n=26) were 100%, 81.3%, 58.3% and 53.8% respectively. The delayed patency rates (Mean follow-up=3.6 months) were 66.7%, 69.2%, 83.3% and 16% respectively. The clamp duration and suturing time significantly decreased and patency rates improved significantly in the latter half of the study. CONCLUSION: The clamp duration, suturing time and patency rates improved considerably with time. The need of the hour is to establish well-planned training programs in centers with Animal Research facilities. This will promote younger colleagues and trainees to take up and perfect this difficult art. The present work could be used as a baseline study in this direction. PMID- 27759876 TI - Surgical Value of Neurocysticercosis. PMID- 27759877 TI - Pharmacological Venous Thromboembolism Prophylaxis in Meningioma Patients: Should it be Earlier than in Clinical Practice? PMID- 27759878 TI - The dorsal skinfold chamber: A versatile tool for preclinical research in tissue engineering and regenerative medicine. AB - Previous human study suggested that fresh-frozen intervertebral disc allograft transplantation can relieve neurological symptoms and restore segmental kinematics. Before wide clinical application, research into the pathophysiology of the postoperative disc allograft is needed. One important question that remains to be answered in disc allografting is the healing process of the host graft interface and the subsequent change of the endplates. With the goat model for lumbar disc allografting, histology, micro-computed tomography analysis, scanning electron microscopy and energy-dispersive X-ray spectroscopy mapping were applied to evaluate the healing of the host-graft interfaces, the remodelling of subchondral bone, and the changes of the bony and cartilaginous endplates after transplantation. It was found that healing of the host-graft interfaces started at 1.5 months and was completed at 6 months by natural remodelling. This bony remodelling was also noted in the subchondral bone area after 6 months. The bony endplate was well preserved initially, but was gradually replaced by trabecular bone afterwards; on the other hand, the cartilaginous endplate became atrophic at 6 months and nearly disappeared at the final follow up. Collectively, after intervertebral disc allograft transplantation, bony healing and remodelling were seen which ensured the stability and mobility of the disc-transplanted segment, but the integrity of bony and cartilaginous endplates was gradually lost and nearly disappeared finally. PMID- 27759879 TI - The SPARC protein: an overview of its role in lung cancer and pulmonary fibrosis and its potential role in chronic airways disease. AB - The SPARC (secreted protein acidic and rich in cysteine) protein is matricellular molecule regulating interactions between cells and their surrounding extracellular matrix (ECM). This protein thus governs fundamental cellular functions such as cell adhesion, proliferation and differentiation. SPARC also regulates the expression and activity of numerous growth factors and matrix metalloproteinases essential for ECM degradation and turnover. Studies in SPARC null mice have revealed a critical role for SPARC in tissue development, injury and repair and in the regulation of the immune response. In the lung, SPARC drives pathological responses in non-small cell lung cancer and idiopathic pulmonary fibrosis by promoting microvascular remodelling and excessive deposition of ECM proteins. Remarkably, although chronic airway conditions such as asthma and chronic obstructive pulmonary disease (COPD) involve significant remodelling in both the airway and vascular compartments, the role of SPARC in these conditions has thus far been overlooked. In this review, we discuss the role of SPARC in lung cancer and pulmonary fibrosis, as well as potential mechanisms by which it may contribute to the disease process in asthma and COPD. PMID- 27759881 TI - Endodontic procedures for retreatment of periapical lesions. AB - BACKGROUND: When primary root canal therapy fails, periapical lesions can be retreated with or without surgery. Root canal retreatment is a non-surgical procedure that involves removal of root canal filling materials from the tooth, followed by cleaning, shaping and obturating of the canals. Root-end resection is a surgical procedure that involves exposure of the periapical lesion through an osteotomy, surgical removal of the lesion, removal of part of the root-end tip, disinfection and, commonly, retrograde sealing or filling of the apical portion of the remaining root canal. This review updates one published in 2008. OBJECTIVES: To assess effects of surgical and non-surgical therapy for retreatment of teeth with apical periodontitis.To assess effects of surgical root end resection under various conditions, for example, when different materials, devices or techniques are used. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Trials Register (to 10 February 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE Ovid (1946 to 10 February 2016) and Embase Ovid (1980 to 10 February 2016). We searched the US National Registry of Clinical Trials (ClinicalTrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (to 10 February 2016). We placed no restrictions regarding language and publication date. We handsearched the reference lists of the studies retrieved and key journals in the field of endodontics. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving people with periapical pathosis. Studies could compare surgery versus non-surgical treatment or could compare different types of surgery. Outcome measures were healing of the periapical lesion assessed after one-year follow-up or longer; postoperative pain and discomfort; and adverse effects such as tooth loss, mobility, soft tissue recession, abscess, infection, neurological damage or loss of root sealing material evaluated through radiographs. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies and assessed their risk of bias. We contacted study authors to obtain missing information. We combined results of trials assessing comparable outcomes using the fixed-effect model, with risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, and 95% confidence intervals (CIs). We used generic inverse variance for split-mouth studies. MAIN RESULTS: We included 20 RCTs. Two trials at high risk of bias assessed surgery versus a non-surgical approach: root-end resection with root-end filling versus root canal retreatment. The other 18 trials evaluated different surgical protocols: cone beam computed tomography (CBCT) versus periapical radiography for preoperative assessment (one study at high risk of bias); antibiotic prophylaxis versus placebo (one study at unclear risk); different magnification devices (loupes, surgical microscope, endoscope) (two studies at high risk); types of incision (papilla base incision, sulcular incision) (one study at high risk and one at unclear risk); ultrasonic devices versus handpiece burs (one study at high risk); types of root-end filling material (glass ionomer cement, amalgam, intermediate restorative material (IRM), mineral trioxide aggregate (MTA), gutta-percha (GP), super-ethoxy benzoic acid (EBA)) (five studies at high risk of bias, one at unclear risk and one at low risk); grafting versus no grafting (three studies at high risk and one at unclear risk); and low energy level laser therapy versus placebo (irradiation without laser activation) versus control (no use of the laser device) (one study at high risk).There was no clear evidence of superiority of the surgical or non-surgical approach for healing at one-year follow-up (RR 1.15, 95% CI 0.97 to 1.35; two RCTs, 126 participants) or at four- or 10-year follow-up (one RCT, 82 to 95 participants), although the evidence is very low quality. More participants in the surgically treated group reported pain in the first week after treatment (RR 3.34, 95% CI 2.05 to 5.43; one RCT, 87 participants; low quality evidence).In terms of surgical protocols, there was some inconclusive evidence that ultrasonic devices for root-end preparation may improve healing one year after retreatment, when compared with the traditional bur (RR 1.14, 95% CI 1.00 to 1.30; one RCT, 290 participants; low quality evidence).There was evidence of better healing when root-ends were filled with MTA than when they were treated by smoothing of orthograde GP root filling, after one-year follow-up (RR 1.60, 95% CI 1.14 to 2.24; one RCT, 46 participants; low quality evidence).There was no evidence that using CBCT rather than radiography for preoperative evaluation was advantageous for healing (RR 1.02, 95% CI 0.70 to 1.47; one RCT, 39 participants; very low quality evidence), nor that any magnification device affected healing more than any other (loupes versus endoscope at one year: RR 1.05, 95% CI 0.92 to 1.20; microscope versus endoscope at two years: RR 1.01, 95% CI 0.89 to 1.15; one RCT, 70 participants, low quality evidence).There was no evidence that antibiotic prophylaxis reduced incidence of postoperative infection (RR 0.49, 95% CI 0.09 to 2.64; one RCT, 250 participants; low quality evidence).There was some evidence that using a papilla base incision (PBI) may be beneficial for preservation of the interdental papilla compared with complete papilla mobilisation (one RCT (split-mouth), 12 participants/24 sites; very low quality evidence). There was no evidence of less pain in the PBI group at day 1 post surgery (one RCT, 38 participants; very low quality evidence).There was evidence that adjunctive use of a gel of plasma rich in growth factors reduced postoperative pain compared with no grafting (measured on visual analogue scale: one day postoperative MD 51.60 mm, 95% CI -63.43 to -39.77; one RCT, 36 participants; low quality evidence).There was no evidence that use of low energy level laser therapy (LLLT) prevented postoperative pain (very low quality evidence). AUTHORS' CONCLUSIONS: Available evidence does not provide clinicians with reliable guidelines for treating periapical lesions. Further research is necessary to understand the effects of surgical versus non-surgical approaches, and to determine which surgical procedures provide the best results for periapical lesion healing and postoperative quality of life. Future studies should use standardised techniques and success criteria, precisely defined outcomes and the participant as the unit of analysis. PMID- 27759880 TI - The peptide Phalpha1beta, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice. AB - BACKGROUND AND PURPOSE: Peptides from venomous animals have long been important for understanding pain mechanisms and for the discovery of pain treatments. Here, we hypothesized that Phalpha1beta, a peptide from the venom of the armed spider Phoneutria nigriventer, produces analgesia by blocking the TRPA1 channel. EXPERIMENTAL APPROACH: Cultured rat dorsal root ganglion (DRG) neurons, human fetal lung fibroblasts (IMR90) or HEK293 cells expressing the human TRPA1 (hTRPA1 HEK293), human TRPV1 (hTRPV1-HEK293) or human TRPV4 channels (hTRPV4-HEK293), were used for calcium imaging and electrophysiology. Nociceptive responses induced by TRPA1, TRPV1 or TRPV4 agonists or by bortezomib were investigated in mice. KEY RESULTS: Phalpha1beta selectively inhibited calcium responses and currents evoked by the TRPA1 agonist, allyl isothiocyanate (AITC), on hTRPA1 HEK293, IMR90 fibroblasts and DRG neurons. Phalpha1beta did not affect calcium responses evoked by selective TRPV1 (capsaicin) or TRPV4 (GSK 1016790A) agonists on the various cell types. Intrathecal (i.t.) and intraplantar (i.pl.) administration of low doses of Phalpha1beta (up to 300 pmol per paw) attenuated acute nociception and mechanical and cold hyperalgesia evoked by AITC (i.t. or i.pl.), without affecting responses produced by capsaicin or hypotonic solution. Notably, Phalpha1beta abated the TRPA1-dependent neuropathic pain-like responses induced by bortezomib. In vitro and in vivo inhibition of TRPA1 by Phalpha1beta was reproduced by a recombinant form of the peptide, CTK 01512-2. CONCLUSIONS AND IMPLICATIONS: Phalpha1beta and CTK 01512-2 selectively target TRPA1, but not other TRP channels. This specific action underlines the potential of Phalpha1beta and CTK 01512-2 for pain treatment. PMID- 27759883 TI - The Impact of Early Social Interactions on Later Language Development in Spanish English Bilingual Infants. AB - This study tested the impact of child-directed language input on language development in Spanish-English bilingual infants (N = 25, 11- and 14-month-olds from the Seattle metropolitan area), across languages and independently for each language, controlling for socioeconomic status. Language input was characterized by social interaction variables, defined in terms of speech style ("parentese" vs. standard speech) and social context (one-on-one vs. group). Correlations between parentese one-on-one and productive vocabulary at 24 months (n = 18) were found across languages and in each language independently. Differences are highlighted between previously published monolingual samples, which used the same methods as the current study of bilingual infants. The results also suggest cultural effects on language input and language development in bilingual and bicultural infants. PMID- 27759882 TI - Impairments in Component Processes of Executive Function and Episodic Memory in Alcoholism, HIV Infection, and HIV Infection with Alcoholism Comorbidity. AB - BACKGROUND: Executive functioning and episodic memory impairment occur in HIV infection (HIV) and chronic alcoholism (ALC). Comorbidity of these conditions (HIV + ALC) is prevalent and heightens risk of vulnerability to separate and compounded deficits. Age and disease-related variables can also serve as mediators of cognitive impairment and should be considered, given the extended longevity of HIV-infected individuals in this era of improved pharmacological therapy. METHODS: HIV, ALC, HIV + ALC, and normal controls (NC) were administered traditional and computerized tests of executive function and episodic memory. Test scores were expressed as age- and education-corrected Z-scores; selective tests were averaged to compute Executive Function and Episodic Memory Composite scores. Efficiency scores were calculated for tests with accuracy and response times. RESULTS: HIV, ALC, and HIV + ALC had lower scores than NC on Executive Function and Episodic Memory Composites, with HIV + ALC even lower than ALC and HIV on the Episodic Memory Composite. Impairments in planning and free recall of visuospatial material were observed in ALC, whereas impairments in psychomotor speed, sequencing, narrative free recall, and pattern recognition were observed in HIV. Lower decision-making efficiency scores than NC occurred in all 3 clinical groups. In ALC, age and lifetime alcohol consumption were each unique predictors of Executive Function and Episodic Memory Composite scores. In HIV + ALC, age was a unique predictor of Episodic Memory Composite score. CONCLUSIONS: Disease-specific and disease-overlapping patterns of impairment in HIV, ALC, and HIV + ALC have implications regarding brain systems disrupted by each disease and clinical ramifications regarding the complexities and compounded damping of cognitive functioning associated with dual diagnosis that may be exacerbated with aging. PMID- 27759884 TI - Decreased serum PCSK9 levels after ischaemic stroke predict worse outcomes. AB - BACKGROUND: Soluble mediators have been investigated to predict the prognosis of acute ischaemic stroke (AIS). Among them, proprotein convertase subtilisin/kexin type 9 (PCSK9) might have both clinical and pathophysiological relevance. MATERIALS AND METHODS: All available serum samples from a cohort of patients with first AIS (n = 72) were tested for PCSK9 and included in this substudy analysis. The primary endpoint investigated the predictive value of early PCSK9 level variations (DeltaPCSK9) from AIS onset to day 7 or from day 1 to day 7, towards a 90-day outcome by modified Rankin Scale (mRS). The secondary endpoint explored the association between DeltaPCSK9 and the risk of major adverse cardiovascular events (MACEs). RESULTS: Decreased serum PCSK9 levels at days 1 and 7 were associated with poor clinical outcomes at day 90. At the cut-off point identified by ROC curve analysis (-61.28 ng/mL), DeltaPCSK9 day 7-day 1 predicted a poor mRS at day 90 after AIS. DeltaPCSK9 day 7-day 1 <= -61.28 ng/mL was associated with an increased rate of MACEs. CONCLUSION: A decrease in PCSK9 levels was a predictor for poor outcome and increased MACEs after AIS. Additional studies targeting post-AIS PCSK9 levels and activity are required to clarify the prognostic and pathophysiological relevance of PCSK9 after AIS. PMID- 27759885 TI - gamma-sarcoglycan and dystrophin mutation spectrum in an Algerian cohort. AB - INTRODUCTION: We report the genetic analysis of a large series of 76 Algerian patients from 65 unrelated families who presented with early onset severe muscular dystrophy and a clinical phenotype resembling limb-girdle muscular dystrophy type 2C. METHODS: To define the genetic basis of the diseases in these families, we undertook a series of analyses of the gamma-sarcoglycan (SGCG) and DMD genes. RESULTS: Fifteen families were shown to carry SGCG variants. Only 2 kinds of causative mutations were identified in the population, mostly in the homozygous state: the well-known c.525delT and the previously described c.87dupT. In the DMD gene, 12 distinctive patterns of deletion were identified, mostly affecting the dystrophin central region. CONCLUSIONS: Our data suggest that a simple molecular screen consisting of 2 allele-specific polymerase chain reactions (PCRs) and a set of 3 multiplex PCRs can diagnose half of the patients who present with progressive muscular dystrophy in the developing nation of Algeria. Muscle Nerve 56: 129-135, 2017. PMID- 27759886 TI - Gender Attitudes in Early Childhood: Behavioral Consequences and Cognitive Antecedents. AB - This study examined factors that predicted children's gender intergroup attitudes at age 5 and the implications of these attitudes for intergroup behavior. Ethnically diverse children from low-income backgrounds (N = 246; Mexican-, Chinese-, Dominican-, and African American) were assessed at ages 4 and 5. On average, children reported positive same-gender and negative other-gender attitudes. Positive same-gender attitudes were associated with knowledge of gender stereotypes. In contrast, positive other-gender attitudes were associated with flexibility in gender cognitions (stereotype flexibility, gender consistency). Other-gender attitudes predicted gender-biased behavior. These patterns were observed in all ethnic groups. These findings suggest that early learning about gender categories shape young children's gender attitudes and that these gender attitudes already have consequences for children's intergroup behavior at age 5. PMID- 27759887 TI - Optimizing muscle selection for electromyography in amyotrophic lateral sclerosis. AB - INTRODUCTION: We compared the yield of limb and thoracic paraspinal muscle examination for revealing lower motor neuron (LMN) dysfunction on electromyography (EMG) in amyotrophic lateral sclerosis (ALS). METHODS: A retrospective review of 354 patients with clinically definite or probable ALS was performed. Seventeen limb muscles and thoracic paraspinal muscles were evaluated for the presence of both active and chronic denervation. RESULTS: Distal limb muscles showed the highest electrodiagnostic sensitivities of LMN dysfunction in ALS regardless of onset region and diagnostic certainty at the time of diagnosis. Electrodiagnostic yield is higher in muscles from the onset limb. Noncontiguous spread of lower motor neuron degeneration is present in ALS. Optimally selected 6 upper and 5 lower extremity muscles yielded >98% of potential positive cervical or lumbosacral segments. CONCLUSIONS: An algorithmic approach to needle EMG in ALS based on pretest probability of individual muscles optimizes electrodiagnostic yield, thus possibly minimizing test duration and patient discomfort. Muscle Nerve 56: 36-44, 2017. PMID- 27759888 TI - Dysphagia-related quality of life in oculopharyngeal muscular dystrophy: Psychometric properties of the SWAL-QOL instrument. AB - INTRODUCTION: The Swallowing Quality of Life instrument (SWAL-QOL) is a patient reported outcome measure of swallowing-related quality of life (SR-QoL). Its psychometric properties in oculopharyngeal muscular dystrophy (OPMD) are not known. METHODS: We administered the SWAL-QOL to U.S. OPMD Registry participants. We described SR-QoL profiles and assessed reliability and validity. RESULTS: The mean composite score in 113 individuals with OPMD was 54.4 +/- 20.7, indicating moderate impairment. Severe impairments were observed in eating duration, burden, and fatigue scales. Internal consistency reliability of all scales was found to be satisfactory, and 9 of 10 scales demonstrated adequate test-retest reliability. Data confirmed 86% of hypotheses, supporting construct validity. The SWAL-QOL limitations in OPMD include: floor/ceiling effects in 7 of 10 scales and low specificity of sleep, fatigue, and communication scales for dysphagia. CONCLUSIONS: SR-QoL is reduced in OPMD. Given several limitations of the SWAL QOL, development of an improved dysphagia-specific QoL instrument for OPMD is warranted. Muscle Nerve 56: 28-35, 2017. PMID- 27759889 TI - Sarcopenia, age, atrophy, and myopathy: Mitochondrial oxidative enzyme activities. AB - INTRODUCTION: We studied mitochondrial impairment as a factor in the pathologic equivalent of sarcopenia, muscle fiber atrophy associated with increased age. METHODS: Mitochondrial oxidative enzyme activities and coenzyme Q10 levels were measured in frozen human proximal limb muscles with combined age and atrophy, age alone, atrophy alone, denervation, immune myopathies, and mitochondrial disorders with ophthalmoplegia. RESULTS: Sarcopenia (age and atrophy) had reduced mean activities of mitochondrial Complexes I, II, and II+III, with severe reduction of Complex I activity in 54% of patients. Atrophy, and specific denervation atrophy, had similar patterns of changes. Age alone had moderately reduced Complex I activity. Mitochondrial myopathies had mildly lower Complex IV activity. Immune myopathies had unchanged enzyme activities. CONCLUSIONS: Mitochondrial oxidative enzyme activities, especially Complex I, but also Complexes II and II+III, are reduced in muscles with the pathologic equivalent of sarcopenia. Individually, atrophy and age have different patterns of oxidative enzyme changes. Muscle Nerve 56: 122-128, 2017. PMID- 27759890 TI - Carving Metacognition at Its Joints: Protracted Development of Component Processes. AB - Two experiments investigated the development of metacognitive monitoring and control, and conditions under which children engage these processes. In Experiment 1, 5-year-olds (N = 30) and 7-year-olds (N = 30), unlike adults (N = 30), showed little evidence of either monitoring or control. In Experiment 2, 5 year-olds (N = 90) were given performance feedback (aimed at improving monitoring), instruction to follow a particular strategy (aimed at improving control), or both. Across conditions, feedback improved children's monitoring, and instruction improved both monitoring and control. Thus, children's poor metacognitive performance likely reflects a difficulty engaging the component processes spontaneously rather than a lack of metacognitive ability. These findings also suggest that the component processes are distinct, with both undergoing protracted development. PMID- 27759891 TI - Does change in neuromuscular jitter predict or correlate with clinical change in MG? AB - INTRODUCTION: The objective of this study was to determine if single-fiber electromyography (SFEMG) jitter accurately reflects change in severity in myasthenia gravis (MG). METHODS: We reviewed jitter and outcome data from all MG patients in our clinic who had at least 2 jitter measurements in the extensor digitorum or frontalis muscle. RESULTS: Change in all parameters of jitter measured with SFEMG electrodes predicted clinical change with acceptable accuracy. Absolute and percentage change in mean value of consecutive interval differences were equally accurate in predicting clinical change and were more accurate than change in the proportion of fiber pairs with blocking or normal jitter. CONCLUSIONS: Jitter is a sensitive measure of severity in MG and has a potential role as a biomarker in clinical trials and the clinic. Absolute or percentage change in mean jitter is the best jitter parameter to follow. The accuracy of change in jitter measured with other electrodes has yet to be determined. Muscle Nerve 56: 45-50, 2017. PMID- 27759892 TI - The Photostabilizing Effect of Grape Seed Extract on Three Common Sunscreen Absorbers. AB - The photostabilizing ability of grape seed extract on three common sunscreen absorbers, 2-ethylhexyl-p-methoxycinnamate (EHMC), benzophenone-3 (BP3) and tert butylmethoxy dibenzoylmethane (BMDBM), was investigated. Samples were exposed to simulated solar radiation and monitored by spectrophotometric and chromatographic methods. The chemical composition of the grape seed extract was determined by GC MS and HPLC-MS, and the major secondary metabolites were found to be epicatechin and catechin. Exposure of the extract to UV radiation increased the UV absorption capacity of the extract. All sunscreens showed an improved photostability in the extract. The inherent photo-instability of BMDBM when exposed to UV radiation was almost eliminated in the presence of grape seed extract. A mixture of all three sunscreens in the extract showed very high photostability and a red shift covering the entire UVB and UVA regions, thereby improving the broad-spectrum protection. The incorporation of grape seed extract in sunscreen and other cosmetic formulations for topical application boosts photoprotection by stabilizing the UV filters and enhancing broad-spectrum coverage. This in turn helps in reducing the amounts of absorbers and other additives incorporated in a sunscreen product and consequently lowers the risk of an unprecedented buildup of photoproducts whose toxicities are currently unknown. PMID- 27759893 TI - Addition of a virtual reality component to treadmill training to reduce fall risk in older adults, including individuals with Parkinson's disease. PMID- 27759894 TI - Excessive homework, inadequate sleep, physical inactivity and screen viewing time are major contributors to high paediatric obesity. AB - AIM: This study examined the relationships between energy balance-related behaviours (EBRBs) outside school hours and obesity in Chinese primary school students. We also explored the influence of gender on those relationships. METHODS: The study sample was a cross-sectional cohort of 5032 Chinese children who were enrolled in grades 1-6 in primary schools in five Chinese cities and whose mean ages ranged from seven years and three months to 11.9 years. The children's parents completed a survey on their child's height, weight and EBRBs outside school hours. RESULTS: The response rate was 97%, and the reported rates of overweight and obesity were 13.6% and 13.8%, respectively. The obesity rates were higher in boys and lower grade children. Most EBRBs varied between boys and girls and with increased grade levels. The amount of time spent on academic related activities, screen viewing, outdoor activities and sleep was mostly associated with obesity on weekdays and varied by gender. CONCLUSION: Rate of obesity was alarmingly high in the primary school Chinese children in this cohort, especially in younger children. Excessive time spent on academic-related activities outside school hours, inadequate sleep, physical inactivity and higher levels of screen viewing were major contributors to obesity in these Chinese children. PMID- 27759896 TI - Platelet activation in the presence of neutral protamine Hagedorn insulin: a new feature of antibodies against protamine/heparin complexes. AB - : Essentials Protamine (PRT) is used to stabilize insulin in neutral protamine Hagedorn (NPH) insulin. The interaction between NPH-insulin, anti-PRT/heparin antibodies and platelets was investigated. Anti-PRT/heparin antibodies activate platelets in presence of NPH-insulin dependent on heparin. Cross-reactivity seems to have no major effect on the clinical outcome of medical patients. SUMMARY: Background Protamine (PRT) is used to stabilize insulin in neutral protamine Hagedorn (NPH) insulin, a commonly used therapeutic agent for diabetes mellitus. Immunization against PRT/heparin complexes is common in diabetic patients. Objectives To investigate the impact of NPH-insulin on the interaction between anti-PRT/heparin antibodies and platelets. Methods The interaction between NPH insulin and anti-PRT/heparin antibodies was tested using in-house enzyme immunoassays. The ability of anti-PRT/heparin antibodies to activate platelets in the presence of NPH-insulin (and heparin) was investigated using flow cytometry. Results Twenty-one out of 80 sera containing anti-PRT/heparin IgG showed binding to NPH-insulin. Anti-PRT/heparin IgG from immunized patients bound to platelets in the presence of NPH-insulin, but not in the presence of native insulin. Anti PRT/heparin antibodies induced P-selectin expression in the presence of NPH insulin in a heparin-dependent way (median mean fluorescence intensity in the presence of NPH-insulin: 55, 95% confidence interval [CI] 18.7-100.5 vs. NPH insulin and heparin: 204, 95% CI 106.5-372.8). The clinical relevance of platelet activating anti-PRT/heparin antibodies was assessed by investigating a multicenter study cohort of 332 acutely ill medical patients who received heparin. None of the 21 patients with anti-PRT/heparin IgG developed thrombocytopenia or thromboembolic complications. Conclusions Anti-PRT/heparin antibodies activate platelets in the presence of NPH-insulin in a heparin dependent way. However, results from our preliminary study indicate no major impact of these antibodies on the clinical outcome in medical patients receiving heparin, particularly on thromboembolic complications. PMID- 27759895 TI - Chromosomal inversions and ecotypic differentiation in Anopheles gambiae: the perspective from whole-genome sequencing. AB - The molecular mechanisms and genetic architecture that facilitate adaptive radiation of lineages remain elusive. Polymorphic chromosomal inversions, due to their recombination-reducing effect, are proposed instruments of ecotypic differentiation. Here, we study an ecologically diversifying lineage of Anopheles gambiae, known as the Bamako chromosomal form based on its unique complement of three chromosomal inversions, to explore the impact of these inversions on ecotypic differentiation. We used pooled and individual genome sequencing of Bamako, typical (non-Bamako) An. gambiae and the sister species Anopheles coluzzii to investigate evolutionary relationships and genomewide patterns of nucleotide diversity and differentiation among lineages. Despite extensive shared polymorphism and limited differentiation from the other taxa, Bamako clusters apart from the other taxa, and forms a maximally supported clade in neighbour joining trees based on whole-genome data (including inversions) or solely on collinear regions. Nevertheless, FST outlier analysis reveals that the majority of differentiated regions between Bamako and typical An. gambiae are located inside chromosomal inversions, consistent with their role in the ecological isolation of Bamako. Exceptionally differentiated genomic regions were enriched for genes implicated in nervous system development and signalling. Candidate genes associated with a selective sweep unique to Bamako contain substitutions not observed in sympatric samples of the other taxa, and several insecticide resistance gene alleles shared between Bamako and other taxa segregate at sharply different frequencies in these samples. Bamako represents a useful window into the initial stages of ecological and genomic differentiation from sympatric populations in this important group of malaria vectors. PMID- 27759897 TI - Effect of circular permutation on the structure and function of type 1 blue copper center in azurin. AB - Type 1 copper (T1Cu) proteins are electron transfer (ET) proteins involved in many important biological processes. While the effects of changing primary and secondary coordination spheres in the T1Cu ET function have been extensively studied, few report has explored the effect of the overall protein structural perturbation on active site configuration or reduction potential of the protein, even though the protein scaffold has been proposed to play a critical role in enforcing the entatic or "rack-induced" state for ET functions. We herein report circular permutation of azurin by linking the N- and C-termini and creating new termini in the loops between 1st and 2nd beta strands or between 3rd and 4th beta strands. Characterization by electronic absorption, electron paramagnetic spectroscopies, as well as crystallography and cyclic voltammetry revealed that, while the overall structure and the primary coordination sphere of the circular permutated azurins remain the same as those of native azurin, their reduction potentials increased by 18 and 124 mV over that of WTAz. Such increases in reduction potentials can be attributed to subtle differences in the hydrogen bonding network in secondary coordination sphere around the T1Cu center. PMID- 27759899 TI - Adiposity rebound from three to six years of age was associated with a higher insulin resistance risk at eight-and-a-half years in a birth cohort study. AB - AIM: The association between adiposity rebound and insulin resistance in middle childhood has seldom been studied. We examined the effect of body mass index (BMI) velocity and early adiposity rebound on the insulin resistance of prepubertal children. METHODS: BMI data from a longitudinal follow-up of a birth cohort in Thailand were used. The homoeostatic model assessment of insulin resistance (HOMA-IR) was calculated from 12-hour fasting plasma glucose and serum insulin at eight-and-a-half years of age. BMI velocity was calculated from four periods: zero to one, one to three, three to six and six to eight-and-a-half years of age. A multiple linear regression model was used to assess the association of BMI velocity during these four periods and insulin resistance at the age of eight-and-a-half years. RESULTS: In 814 children - 76.7% of the initial cohort - BMI velocities between years one to three, three to six and six to eight-and-a-half years were positively associated with HOMA-IR levels after adjusting for demographic, behavioural and socio-economic factors. Children who had BMI gains between three and six years had mean HOMA-IR values that were 43% higher than those who did not. CONCLUSION: BMI velocity during early and middle childhood, and early adiposity rebound between three and six years, was associated with a higher insulin resistance risk at eight-and-a-half years. PMID- 27759898 TI - Determining the Optimal Dose of Adenosine for Unmasking Dormant Pulmonary Vein Conduction Following Atrial Fibrillation Ablation: Electrophysiological and Hemodynamic Assessment. DORMANT-AF Study. AB - INTRODUCTION: ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. DORMANT-AF STUDY: The significance of adenosine induced dormant pulmonary vein (PV) conduction in atrial fibrillation (AF) ablation remains controversial. The optimal dose of adenosine to determine dormant PV conduction is yet to be systematically explored. METHODS AND RESULTS: ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. DORMANT-AF STUDY: Consecutive patients undergoing index AF ablation received 3 adenosine doses (12, 18, and 24 mg) in a randomized blinded order, immediately after pulmonary vein isolation (PVI). Electrophysiological (PR prolongation, AV block (AVB) and PV reconnection) and hemodynamic (BP) parameters were measured. A total, 339 doses (113/dose) assessed 191 PVs in 50 patients (66% male, 72% PAF, 52% hypertensive). Dormant PV conduction occurred in 28% of patients (16.5% [32] of PVs). All cases were associated with AVB (AVB: PV reconnection vs. no PV reconnection 100% vs. 83%, P = 0.007). AVB occurred more frequently at 24 mg versus 12 mg (92% vs. 82%, P = 0.019) but not versus 18 mg (91%, P = 0.62). AVB duration progressed between 12 mg (12.0 +/- 8.9 seconds), 18 mg (16.1 +/- 9.1 seconds, P = 0.001), and 24 mg (19.0 +/- 9.3 seconds, P < 0.001) doses. MBP fell further at 24 mg (DeltaMBP: 27 +/- 12 mmHg) and 18 mg (26 +/- 13 mmHg) doses compared to 12 mg (22 +/- 10 mmHg vs., P < 0.001). A significant reduction in AVB in patients >110 kg (65% vs. 91% in 70-110 kg group, P < 0.001) in response to adenosine was seen. CONCLUSION: ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. DORMANT-AF STUDY: An adenosine dose producing AVB is required to unmask dormant PV conduction. AVB is significantly reduced in patients >110 kg. Weight and dosing variability may in part explain the conflicting results of studies evaluating the clinical utility of adenosine in PVI. PMID- 27759900 TI - Near Threshold Effects on Recombination and Vibrational Relaxation in Efimov Systems. AB - We investigate the energy dependence of inelastic processes in systems which possess Efimov states. We consider the three-body recombination rate K3 where three free atoms interact to produce an atom-dimer pair, and the relaxation rate Krel where an atom quenches a weakly bound state of a dimer near an Efimov resonance to more deeply bound levels. Using a model capturing the key features of the Efimov problem, we identify new energy regimes for K3 , namely the near threshold resonance (NTR) regime behavior E-2 for negative scattering lengths and the near threshold suppression (NTS) regime behavior E2 for positive scattering lengths. We also confirm a previously found oscillatory behavior of K3 at higher energy E. Finally, we find that Krel behaves as E-1 in the NTR regime. PMID- 27759901 TI - Human leucocyte antigens B*08, DRB1*03 and DRB1*13 are significantly associated with autoimmune liver and biliary diseases in Finnish children. AB - AIM: The human leucocyte antigen (HLA) allele and haplotype frequencies of the Finnish population are unique because of the restricted and homogenous gene population. There are no published data on HLA genotype associations in paediatric autoimmune liver diseases in Scandinavia. This study characterised the HLA genotypes of children with autoimmune liver or biliary disease in Finland. METHODS: The study cohort comprised 19 paediatric patients (13 female) aged three years to 15 years treated for autoimmune liver or biliary disease at the Children's Hospital, Helsinki University Hospital, between 2000 and 2011, and followed up for four years and three months to 14.6 years. We genotyped HLA-B and HLA-DRB1 in the children, and the HLA antigen frequencies were compared with 19 807 records from the Finnish Bone Marrow Donor Registry. RESULTS: All paediatric patients with autoimmune liver or biliary disease had either autoimmune HLA haplotype B*08;DRB1*03 or DRB1*13. These were significantly more common among patients with autoimmune hepatitis, primary sclerosing cholangitis and autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome than the Finnish control population. HLA RB1*04 was not found in the study cohort. CONCLUSION: Our study found that B*08, DRB1*03 and DRB1*13 were significantly associated with autoimmune liver and biliary diseases in Finnish paediatric patients. PMID- 27759902 TI - Histopathologic features in actinic cheilitis by the comparison of grading dysplasia systems. AB - OBJECTIVE: This study aimed to determine the histopathologic findings in actinic cheilitis (AC) and lip squamous cell carcinomas (LSCC) diagnosed at Federal University of Santa Catarina in order to attempt to predict the evolution from AC to LSCC based on the comparison of two dysplasia classification systems. METHODS: Histopathologic features were evaluated according to the World Health Organization classification of dysplasia and binary system of classification. Also, in LSCC, pattern, stage of invasion, and degree of keratinization were evaluated. A total of 58 cases of AC and 70 cases of LSCC were studied, and data correlation was performed using statistical analysis. RESULTS: The presence of dyskeratosis and keratin pearls was found to be strongly associated with severe dysplasia and could represent higher proximity between the severe dysplasia in AC and LSCC. Also, changes related to the nuclei, such as hyperchromasia, nuclear pleomorphism, anisonucleosis, increase in the number and size of nucleoli, increased number of mitoses, and atypical mitoses, indicate progression in dysplasia spectrum. CONCLUSION: Knowledge of clinical and histological features of AC and LSCC leads to better understanding of factors possibly associated with malignant transformation of epithelial dysplasia. PMID- 27759904 TI - Proposal for Laser Cooling of Complex Polyatomic Molecules. AB - An experimentally feasible strategy for direct laser cooling of polyatomic molecules with six or more atoms is presented. Our approach relies on the attachment of a metal atom to a complex molecule, where it acts as an active photon cycling site. We describe a laser cooling scheme for alkaline earth monoalkoxide free radicals taking advantage of the phase space compression of a cryogenic buffer-gas beam. Possible applications are presented including laser cooling of chiral molecules and slowing of molecular beams using coherent photon processes. PMID- 27759903 TI - Long-term follow up of hospitalized pediatric anorexia nervosa restricting type. AB - BACKGROUND: Information on long-term follow up of childhood-onset anorexia nervosa is scarce. This study investigated long-term (>10 years) course, outcome and prognostic factors for hospitalized childhood-onset anorexia nervosa restricting type (ANR). METHODS: Forty-one ANR girls admitted to a single regional center participated. Median age at first admission was 13.3 years (range, 8.6-15.6 years). The longitudinal clinical course was retrospectively determined for a median follow-up period of 17.1 years (range, 10.4-21.1 years). We analyzed physical, psychological, and social variables to predict partial remission (PR) and full remission (FR). RESULTS: The completion rate of follow up >10 years was high at 97%. At final evaluation (n = 38), distribution of prognosis was as follows: FR, n = 27 (71%); PR, n = 6 (16%); and non-remission, n = 5 (13%). The cumulative ratio of PR and FR increased during the first 5-6 years, and gradually reached a plateau at around 10 years. More than 10 years after the onset, one patient eventually achieved FR, and one patient died. Seven patients were rehospitalized and two died due to suicide during the entire follow up. On multivariate analysis, family disorders/problems rating score was a significant predictor of PR and FR. CONCLUSIONS: This study included hospitalized ANR children aged <=15 years, the youngest cohort ever reported. Long-term prognosis is generally favorable, but the mortality rate was 5%. Careful long term follow up >10 years is needed to evaluate outcome of childhood-onset ANR, and family therapy is important in high-risk patients with family disorders/problems. PMID- 27759905 TI - Ubiquitin Associates with the N-Terminal Domain of Nerve Growth Factor: The Role of Copper(II) Ions. AB - Many biochemical pathways involving nerve growth factor (NGF), a neurotrophin with copper(II) binding abilities, are regulated by the ubiquitin (Ub) proteasome system. However, whether NGF binds Ub and the role played by copper(II) ions in modulating their interactions have not yet been investigated. Herein NMR spectroscopy, circular dichroism, ESI-MS, and titration calorimetry are employed to characterize the interactions of NGF with Ub. NGF1-14 , which is a short model peptide encompassing the first 14 N-terminal residues of NGF, binds the copper binding regions of Ub (KD =8.6 10-5 m). Moreover, the peptide undergoes a random coil-polyproline type II helix structural conversion upon binding to Ub. Notably, copper(II) ions inhibit NGF1-14 /Ub interactions. Further experiments performed with the full-length NGF confirmed the existence of a copper(II)-dependent association between Ub and NGF and indicated that the N-terminal domain of NGF was a valuable paradigm that recapitulated many traits of the full-length protein. PMID- 27759906 TI - Quantitative and functional analysis of CD69+ T regulatory lymphocytes in patients with periodontal disease. AB - BACKGROUND: Periodontal disease is chronic inflammatory process that affects the attachment structures of the teeth and constitutes a significant cause of tooth loss in adults. Although different bacteria play an important role in the triggering of this condition, the progression and severity of the disease are strongly affected by the host immune response, which is under the control of different immune regulatory mechanisms, including T regulatory (Treg) cells. The aim of this study was to assess the frequency and function of CD69+ Treg lymphocytes in patients with chronic periodontal disease. METHODS: Peripheral blood samples (n = 33) and gingival tissue (n = 9) were obtained from patients with chronic periodontal disease. Blood samples from 25 healthy individuals were also studied. Levels of CD69+ Treg lymphocytes in peripheral blood and gingival tissue were determined by six-color multiparametric flow cytometry, immunofluorescence, and immunohistochemistry. The immune regulatory function of CD69+ Treg cells was tested by an in vitro assay of inhibition of lymphocyte activation. RESULTS: Percentages of CD69+ Treg cells were significantly higher in the peripheral blood from patients with active periodontal disease compared to healthy controls, and these percentages inversely correlated with the periodontal attachment loss. Increased numbers of these Treg cells were detected in the gingival tissue from active PD patients compared to their peripheral blood. However, the suppressive function of CD69+ Treg cells was significantly diminished in patients with periodontal disease compared to healthy controls. CONCLUSIONS: Our data suggest that CD69+ Treg cells seem to be another important piece in the complex immunopathogenesis of periodontal disease. PMID- 27759907 TI - Multiscale Computational Study on the Adsorption and Separation of CO2 /CH4 and CO2 /H2 on Li+ -Doped Mixed-Ligand Metal-Organic Framework Zn2 (NDC)2 (diPyNI). AB - The quantum mechanics (QM) method and grand canonical Monte Carlo (GCMC) simulations are used to study the effect of lithium cation doping on the adsorption and separation of CO2 , CH4 , and H2 on a twofold interwoven metal organic framework (MOF), Zn2 (NDC)2 (diPyNI) (NDC=2,6-naphthalenedicarboxylate; diPyNI=N,N'-di-(4-pyridyl)-1,4,5,8-naphthalenetetracarboxydiimide). Second-order Moller-Plesset (MP2) calculations on the (Li+ -diPyNI) cluster model show that the energetically most favorable lithium binding site is above the pyridine ring side at a distance of 1.817 A from the oxygen atom. The results reveal that the adsorption capacity of Zn2 (NDC)2 (diPyNI) for carbon dioxide is higher than those of hydrogen and methane at room temperature. Furthermore, GCMC simulations on the structures obtained from QM calculations predict that the Li+ -doped MOF has higher adsorption capacities than the nondoped MOF, especially at low pressures. In addition, the probability density distribution plots reveal that CO2 , CH4 , and H2 molecules accumulate close to the Li cation site. The selectivity results indicate that CO2 /H2 selectivity values in Zn2 (NDC)2 (diPyNI) are higher than those of CO2 /CH4 . The selectivity of CO2 over CH4 on Li+ -doped Zn2 (NDC)2 (diPyNI) is improved relative to the nondoped MOF. PMID- 27759908 TI - Translocation t(8;14)(q24;q11) with concurrent PTEN alterations and deletions of STIL/TAL1 and CDKN2A/B in a pediatric case of acute T-lymphoblastic leukemia: A genetic profile associated with adverse prognosis. AB - We report a pediatric case of acute T-lymphoblastic leukemia (T-ALL) with NOTCH1wt , FBXW7wt , STIL/TAL1, and PTEN (exons 2, 3, 4, 5) monoallelic deletions, biallelic CDKN2A/B deletion, and a minor t(8;14)(q24;q11)-positive subclone. Undetectable by a flow cytometric minimal residual disease assay, the t(8;14)(q24;q11) subclone expanded as detected by fluorescence in situ hybridization from 5% at diagnosis to 26% before consolidation and 100% at relapse bearing a monoallelic deletion (exons 2, 3) with a new frameshift mutation of PTEN and the same set of remaining molecular alterations. This case documents an unfavorable prognostic potential of a co-occurrence of this set of molecular genetic events and addresses risk stratification in T-ALL. PMID- 27759909 TI - Further delineation of the phenotype of truncating KMT2A mutations: The extended Wiedemann-Steiner syndrome. AB - KMT2A mutations cause Wiedemann-Steiner syndrome (WDSTS), which is characterized by hypertrichosis cubiti, short stature, and distinct facial features in general. Here, we report two Chinese boys with novel nonsense KMT2A mutations. Most of their phenotypes are concordant with WDSTS. They, however, lack the key WDSTS feature-hypertrichosis cubiti. Additionally, their transverse palmar creases are absent. We further summarized the genotypes and phenotypes of the KMT2A mutation carriers. The consensus phenotypes include postnatal growth retardation, developmental delay, short stature, and intellectual disability. The common facial features include thick eyebrows, long eyelashes, downslanting, and narrow palpebral fissures, wide nasal bridge, and broad nasal tip. They have generalized hypertrichosis. A hairy back can be observed as frequently as hairy elbows in patients with KMT2A mutations. Absent palmar proximal transverse creases are only observed in these two Chinese boys. This might be due to the difference in ethnic background. Thus far, all mutations in KMT2A are located before the FYRC domain. They would truncate KMT2A mRNA transcripts. Haploinsufficiency of the histone methyltransferase activity would therefore influence transcriptional regulation. (c) 2016 Wiley Periodicals, Inc. PMID- 27759910 TI - Laryngopharyngeal reflux and herpes simplex virus type 2 are possible risk factors for adult-onset recurrent respiratory papillomatosis (prospective case control study). AB - OBJECTIVE: The human papillomavirus (HPV) causes recurrent respiratory papillomatosis (RRP). Although HPV prevalence is high, the incidence of papillomatosis is low. Thus, factors other than HPV infection probably contribute to RRP. This study investigated whether patients with papillomatosis are more often infected with herpes simplex virus type 2 and chlamydia trachomatis (ChT) and whether laryngopharyngeal reflux (LPR) occurs in this group of patients more often. DESIGN: Prospective case-control study. SETTING: Department of Otorhinolaryngology of University Hospital. PARTICIPANTS: The study included 20 patients with adult-onset RRP and 20 adult patients with vocal cord cyst and no pathology of laryngeal mucosa (control group). MAIN OUTCOME MEASURES: Immunohistochemical analysis of pepsin, HPV, herpes simplex virus type 2 and ChT was performed in biopsy specimens of laryngeal papillomas and of healthy laryngeal mucosa (control group) obtained from medial part of removed vocal cord cyst during microlaryngoscopy procedures. RESULTS: Pathologic LPR (pepsin in tissue) was diagnosed in 8/20 (40.0%) patients with papillomatosis and in 0/20 control patients (P = .003). Herpes simplex virus type 2 was present in 9/20 (45.0%) patients with papillomatosis and in 0/20 control patients (P = .001). Five specimens were positive for both pepsin and herpes simplex virus type 2. No samples were positive for ChT. There were no significant differences between groups for age, body mass index, diabetes mellitus and gastrooesophageal reflux disease. Tobacco exposure was not more frequent in RRP group either (P = .01). CONCLUSIONS: Results show that LPR and herpes simplex virus type 2 are significantly more often present in patients with RRP. LPR and herpes simplex virus type 2 might activate latent HPV infection and thereby be possible risk factors for RRP. PMID- 27759911 TI - Hearing aid fitting for visual and hearing impaired patients with Usher syndrome type IIa. AB - OBJECTIVES: Usher syndrome is the leading cause of hereditary deaf-blindness. Most patients with Usher syndrome type IIa start using hearing aids from a young age. A serious complaint refers to interference between sound localisation abilities and adaptive sound processing (compression), as present in today's hearing aids. The aim of this study was to investigate the effect of advanced signal processing on binaural hearing, including sound localisation. DESIGN AND PARTICIPANTS: In this prospective study, patients were fitted with hearing aids with a nonlinear (compression) and linear amplification programs. Data logging was used to objectively evaluate the use of either program. Performance was evaluated with a speech-in-noise test, a sound localisation test and two questionnaires focussing on self-reported benefit. RESULTS: Data logging confirmed that the reported use of hearing aids was high. The linear program was used significantly more often (average use: 77%) than the nonlinear program (average use: 17%). The results for speech intelligibility in noise and sound localisation did not show a significant difference between type of amplification. However, the self-reported outcomes showed higher scores on 'ease of communication' and overall benefit, and significant lower scores on disability for the new hearing aids when compared to their previous hearing aids with compression amplification. CONCLUSIONS: Patients with Usher syndrome type IIa prefer a linear amplification over nonlinear amplification when fitted with novel hearing aids. Apart from a significantly higher logged use, no difference in speech in noise and sound localisation was observed between linear and nonlinear amplification with the currently used tests. Further research is needed to evaluate the reasons behind the preference for the linear settings. PMID- 27759912 TI - Creation of an international registry to support discovery in schwannomatosis. AB - Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. (c) 2016 Wiley Periodicals, Inc. PMID- 27759914 TI - A retrospective case series of 318 tracheostomy-related adverse events over 6 years - a Scottish context. PMID- 27759913 TI - Accurate MR thermometry by hyperpolarized 129 Xe. AB - PURPOSE: To investigate the temperature dependence of the resonance frequency of lipid-dissolved xenon (LDX) and to assess the accuracy of LDX-based MR thermometry. METHODS: The chemical shift temperature dependence of water protons, methylene protons, and LDX was measured from samples containing tissues with varying fat contents using a high-resolution NMR spectrometer. LDX results were then used to acquire relative and absolute temperature maps in vivo and the results were compared with PRF-based MR thermometry. RESULTS: The temperature dependence of proton resonance frequency (PRF) is strongly affected by the specific distribution of water and fat. A redistribution of water and fat compartments can reduce the apparent temperature dependence of the water chemical shift from -0.01 ppm/ degrees C to -0.006 ppm, whereas the LDX chemical shift shows a consistent temperature dependence of -0.21 ppm/ degrees C. The use of the methylene protons resonance frequency as internal reference improves the accuracy of LDX-based MR thermometry, but degrades that of PRF-based MR thermometry, as microscopic susceptibility gradients affected lipid and water spins differently. CONCLUSION: The LDX resonance frequency, with its higher temperature dependence, provides more accurate and precise temperature measurements, both in vitro and in vivo. More importantly, the resonance frequency of nearby methylene protons can be used to extract absolute temperature information. Magn Reson Med 78:1070-1079, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27759915 TI - Acute lymphoblastic leukemia in a child with a de novo germline gnb1 mutation. PMID- 27759916 TI - Physical and functional interactions between nucleosomes and Rad27, a critical component of DNA processing during DNA metabolism. AB - Highly conserved eukaryotic histones are polybasic proteins that package DNA into nucleosomes, a building block of chromatin, allowing extremely long DNA molecules to form compact and discrete chromosomes. The histone N-terminal tails that extend from the nucleosome core act as docking sites for many proteins through diverse post-translational modifications, regulating various DNA transactions. In this report, we present evidence that the nucleosomes can positively regulate the enzymatic activity of Rad27 (yeast Fen1), a major processing enzyme important for Okazaki fragment in eukaryotes. We found that individual histones, histone octamers, and nucleosomes are able to stimulate Rad27 in a manner dependent on the N-terminal tails of histones. Kinetic analyses suggest that an increase in catalytic efficiency of Rad27 was mainly due to increased affinity between DNA substrates and Rad27. It appears that the physical interaction in vivo between histones and Rad27 results in the enrichment of Rad27 in the vicinity of chromatin, increasing the availability of Rad27 for various DNA metabolisms. These results indicate that nucleosomes are not a mere structural component of chromatin, but an active regulator of DNA metabolisms that serves to ensure the efficient and faithful processing of structural intermediates arising during DNA transactions. PMID- 27759918 TI - Low temperature and dust favour in vitro survival of Mycoplasma hyopneumoniae: time to revisit indirect transmission in pig housing. AB - : Porcine enzootic pneumonia (EP) caused by Mycoplasma hyopneumoniae adversely affects pig welfare and is associated with major economic losses in the pig industry worldwide. Transmission is predominantly by direct contact, but the role of indirect transmission remains poorly understood. This study examined survival of six M. hyopneumoniae isolates dried onto five different surfaces encountered in pig units and exposed to temperatures of 4, 25 and 37 degrees C for up to 12 days. Survival of the organisms was determined by recovering the organism from the surface material and culturing in Friis broth. Data were analysed by logistic regression to identify factors influencing survival of M. hyopneumoniae. Maximum survival was 8 days for all isolates on at least one surface (except stainless steel) at 4 degrees C and was limited to 2 days at 25 and 37 degrees C. Overall, dust and polypropylene copolymer supported M. hyopneumoniae survival the longest when compared with other surface materials. In conclusion, we have demonstrated that M. hyopneumoniae can survive outside the host for at least 8 days. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the transmission of Mycoplasma hyopneumoniae and optimizing biosecurity practices are keys to reducing the use of antimicrobial agents to control this pathogen. Direct transmission of the pathogen between pigs is the main route of spread and its lack of cell wall may compromise its resilience outside the host. The results from our study show that M. hyopneumoniae can survive for up to several days on dry surfaces and therefore may have the potential to infect pigs by indirect transmission. Factors influencing the survival of M. hyopneumoniae outside the host are further elucidated. PMID- 27759917 TI - Implication of LRRC4C and DPP6 in neurodevelopmental disorders. AB - We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. (c) 2016 Wiley Periodicals, Inc. PMID- 27759920 TI - ACS Treatment Continues to Improve: But Price Matters. AB - Over 90% of patients achieve adequate levels of platelet inhibition with both Prasugrel and Ticagrelor. The introduction of Prasugrel was met with some hesitation from physicians because of the significant increase in cost. This pharmaceutically sponsored and authored retrospective study suggests that both agents are effective. PMID- 27759921 TI - Surgical vs. Percutaneous Approaches to Paravalvular Leak: Is Closure Too Little Too Late, or Just Not Soon Enough. PMID- 27759922 TI - Stroke Prevention: Let's Prepare for Generation X TAVR. AB - Stroke leads to significant morbidity, disability, and mortality after TAVR. CKD and prior stroke are risk factors for stroke. Stratification of stroke risk would improve outcomes associated with TAVR. Ongoing prospective randomized trials on embolic protection and post implant anticoagulation are promising strategies to reduce stroke risk and new brain MRI lesions. PMID- 27759923 TI - Impact of Glycoprotein IIb/IIIa Inhibitors Use on Outcomes After Lower Extremity Endovascular Interventions From Nationwide Inpatient Sample (2006-2011). AB - Anticoagulant and antiplatelet medications are necessary in peripheral endovascular intervention, but a standardized approach has not yet been established. Glycoprotein IIb/IIIa inhibitor use in endovascular lower extremity interventions decreased overall amputation rates. Glycoprotein IIb/IIIa inhibitor use in endovascular lower extremity interventions increased postprocedural bleeding and complications requiring intervention. PMID- 27759924 TI - Not just a FREAK finding, but perhaps an important insight. PMID- 27759919 TI - A synthesis of radial growth patterns preceding tree mortality. AB - Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms leading to mortality and the associated changes in tree growth rates are still limited. We compiled a new pan-continental tree ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the mortality events. The extent and duration of these reductions were highly variable (1-100 years in 96% of events) due to the complex interactions among study species and the source(s) of mortality. Strong and long lasting declines were found for gymnosperms, shade- and drought-tolerant species, and trees that died from competition. Angiosperms and trees that died due to biotic attacks (especially bark-beetles) typically showed relatively small and short-term growth reductions. Our analysis did not highlight any universal trade off between early growth and tree longevity within a species, although this result may also reflect high variability in sampling design among sites. The intersite and interspecific variability in growth patterns before mortality provides valuable information on the nature of the mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality. Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or bark-beetle attack, while long-term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth-based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks. PMID- 27759925 TI - Small Acute Mechanical Circulatory Support Pumps for Small People. PMID- 27759926 TI - Paravalvular Leaks: One Size (or Shape) Doesn't Always Fit All? AB - Paravalvular leak (PVL) remains as uncommon but serious complication after surgical prosthetic valve implantation. PVL when associated which congestive heart failure, hemolytic anemia, or infective endocarditis may require percutaneous treatment. High-surgical risk is common in this population. Dedicated PVL devices are lacking often limiting optimal treatment. PMID- 27759927 TI - Fracking the Code to Complete Revascularization. AB - Provisional use of rotational atherectomy (RA) is indicated for procedural success in heavily calcified lesions. In the current study, RA use at three high volume percutaneous coronary intervention (PCI) centers between 2005 and 2013 was 1.4%. MACE rate was 17.8% at median follow-up of 22 months. Peripheral vascular disease (PVD), diabetes mellitus (DM), acute coronary syndrome (ACS), and SYNTAX > 23 were found to be independently associated with MACE. With increasing complexity of disease and SYNTAX score, there is usually an increase in severity of calcification and need for atherectomy. Complete revascularization with residual SYNTAX reduced to < 8 is associated with improved outcomes. Incompleteness of revascularization in patients with SYNTAX > 33 rather than procedural success of the target vessel with atherectomy may have contributed to the adverse outcomes. PMID- 27759928 TI - The Third Rail of Interventional Cardiology: Revascularization of Non-Infarct Related Arteries During Primary PCI. PMID- 27759929 TI - Ischemic Postconditioning: Not Giving Up Yet. AB - Ischemic postconditioning protects against reperfusion injury. Adjunctive use of manual thrombus aspiration improves reperfusion results in patients undergoing primary angioplasty. Combining both strategies (ischemic postconditioning and thrombus aspiration) may have additive effects in terms of myocardial salvage. The PORT trial will study the role of ischemic postconditioning in patients undergoing primary angioplasty with thrombus aspiration. PMID- 27759930 TI - Retraction: 'Beneficial Effect of Intermittent Cyclical Etidronate Therapy in Hemiplegic Patients Following an Acute Stroke' by Y. Sato, T. Asoh, M. Kaji and K. Oizumi. AB - The above article, published online on 1 December 2000 in Wiley Online Library (wileyonlinelibrary.com), and in Volume 15, Issue 12, pages 2487-2494, has been retracted by agreement between the authors, the Journal Editor in Chief, Juliet Compston, and Wiley Periodicals, Inc. The retraction has been agreed due to concerns about the underlying data to which the authors have given no satisfactory response. Dr Sato acknowledges that his co-authors are named as such for honorary reasons and are not responsible for the content of the manuscript. Reference Sato, Y., Asoh, T., Kaji, M. and Oizumi, K. (2000) Beneficial Effect of Intermittent Cyclical Etidronate Therapy in Hemiplegic Patients Following an Acute Stroke. J Bone Miner Res, 15:2487-2494. doi: 10.1359/jbmr.2000.15.12.2487. PMID- 27759931 TI - Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. PMID- 27759933 TI - Corrigendum. PMID- 27759932 TI - Issue Information-Declaration of Helsinki. PMID- 27759934 TI - Abstracts from the 2014 Combined Scientific Meeting: Imaging and Radiation in Personalised Medicine. 4-7 September 2014, Melbourne Convention and Exhibition Centre, Melbourne, Australia. This supplement is a joint publication with the Journal of Medical Imaging & Radiation Oncology: Vol. 58, Suppl. 1, September 2014, Pages 1-352. PMID- 27759935 TI - Pulmonary relaxometry with inversion recovery ultra-fast steady-state free precession at 1.5T. AB - PURPOSE: To present a technique for simultaneous mapping of T1 , T2 , and relative spin density (M0 ) in human lung using inversion recovery ultra-fast steady-state free precession (IR-ufSSFP) imaging. METHODS: Pulmonary relaxometry with IR-ufSSFP is based on an interleaved time series acquisition of 2D images acquired at 1.5T. The technique was tested in a phantom and in four healthy volunteers using breath-hold and electrocardiogram triggering. Typically, 30 transient state images were acquired in a single breath-hold within < 10 s. From the signal time course, voxel-wise nonlinear fitting yielded T1 , T2 , and M0 parameter maps. Furthermore, off-resonance and B1 effects were investigated in a phantom. RESULTS: In the phantom, the observed T1 of 829 +/- 2 ms and T2 of 105 +/- 4 ms were in agreement with the reference T1 of 858 +/- 1 ms and T2 of 104 +/ 1 ms using spin echo methods. In volunteers, the average T1 of 1375 +/- 102 ms and T2 of 66 +/- 26 ms of lung tissue were in good agreement with the literature and were observed to be independent of the respiratory phase. Overall, high reproducibility was shown in a volunteer, yielding coefficient of variations of 0.03 for M0 , 0.004 for T1 , and 0.04 for T2 measurements. CONCLUSION: IR-ufSSFP allows for fast and simultaneous quantitative mapping of the human lung. Magn Reson Med 77:74-82, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27759936 TI - Mass spectrometric analysis of synaptosomal membrane preparations for the determination of brain receptors, transporters and channels. AB - The molecular composition of synaptic signal transduction machineries shapes synaptic neurotransmission. The repertoire of receptors, transporters and channels (RTCs) comprises major signaling events in the brain. RTCs are conventionally studied by candidate immunohistochemistry and biochemistry, which are low throughput with resolution greatly affected by available immunoreagents and membrane interference. Therefore, a comprehensive resource of synaptic brain RTCs is still lacking. In particular, studies on the detergent-soluble synaptosomal fraction, known to contain transporters and channels, are limited. We, therefore, performed sub-synaptosomal fractionation of rat cerebral cortex, followed by trypsin/chymotrypsin sequential digestion of a detergent-soluble synaptosomal fraction and a postsynaptic density preparation, stable-isotope tryptic peptide labeling and liquid chromatography mass spectrometry. Based on the current study, a total of 4784 synaptic proteins were submitted to the ProteomExchange database (PXD001948), including 274 receptors, 394 transporters/channels and 1377 transmembrane proteins. Function-based classification assigned 1781 proteins as probable drug targets with 834 directly linked to brain disorders. The analytical approach identified 499 RTCs that are not listed in the largest, curated database for synaptosomal proteins (SynProt). This is a threefold RTC increase over all other data collected to date. Taken together, we present a protein discovery resource that can serve as a benchmark for future molecular interrogation of synaptic connectivity. PMID- 27759937 TI - Differences in survival for patients with familial and sporadic cancer. AB - Family history of cancer is a well-known risk factor but the role of family history in survival is less clear. The aim of this study was to investigate the association between family history and cancer survival for the common cancers in Sweden. Using the Swedish population-based registers, patients diagnosed with the most common cancers were followed for cancer-specific death during 1991-2010. We used multivariate proportional hazards (Cox) regression models to contrast the survival of patients with a family history of cancer (individuals whose parent or sibling had a concordant cancer) to the survival of patients without a family history. Family history of cancer had a modest protective effect on survival for breast cancer (hazard ratio (HR) = 0.88, 95% confidence interval (95% CI) = 0.81 to 0.96) and prostate cancer (HR = 0.82, 95% CI = 0.75 to 0.90). In contrast, family history of cancer was associated with worse survival for nervous system cancers (HR = 1.24, 95% CI = 1.05 to 1.47) and ovarian cancer (HR = 1.20, 95% CI = 1.01 to 1.43). Furthermore, the poorer survival for ovarian cancer was consistent with a higher FIGO stage and a greater proportion of more aggressive tumors of the serous type. The better survival for patients with a family history of breast and prostate cancer may be due to medical surveillance of family members. The poor survival for ovarian cancer patients with an affected mother or sister is multifactorial, suggesting that these cancers are more aggressive than their sporadic counterparts. PMID- 27759940 TI - Abstracts from the 2014 Combined Scientific Meeting: Imaging and Radiation in Personalised Medicine. 4-7 September 2014, Melbourne Convention and Exhibition Centre, Melbourne, Australia. This supplement is a joint publication with the Journal of Medical Imaging & Radiation Oncology: Vol. 58, Suppl. 1, September 2014, Pages 1-352. PMID- 27759941 TI - Abstracts from the 2014 Combined Scientific Meeting: Imaging and Radiation in Personalised Medicine. 4-7 September 2014, Melbourne Convention and Exhibition Centre, Melbourne, Australia. This supplement is a joint publication with the Journal of Medical Imaging & Radiation Oncology: Vol. 58, Suppl. 1, September 2014, Pages 1-352. PMID- 27759939 TI - Distal limb anomalies in patients with congenital dyserythropoietic anemia. AB - The congenital dyserythropoietic anemias (CDAs) are a group of rare genetic disorders characterized by ineffective erythropoiesis and the development of secondary hemochromatosis. Distal limb anomalies are a well-documented though rare feature of congenital dyserythropoietic anemia type I, that have not been reported so far in other types. We describe a patient with congenital dyserythropoietic anemia type II and four members of a family with clinical features of congenital dyserythropoietic anemia type III with distal limb anomalies. The patient with congenital dyserythropoietic anemia type II presented with bilateral complete osseous syndactyly of the hands, and bilateral complete cutaneous syndactyly of feet. Three of the four affected family members with congenital dyserythropoietic anemia type III had partial absence of fingers, small or absent nails, overlapping toes, and short metatarsals. We suggest that similar to congenital dyserythropoietic anemia type I, distal anomalies may appear in some patients with congenital dyserythropoietic anemia types II and III. Patients presenting with anemia and distal limb anomalies should be further investigated for the presence of congenital dyserythropoietic anemia. (c) 2016 Wiley Periodicals, Inc. PMID- 27759938 TI - Fruit and vegetable consumption, Helicobacter pylori antibodies, and gastric cancer risk: A pooled analysis of prospective studies in China, Japan, and Korea. AB - Epidemiological findings on the association between fruit and vegetable consumption and gastric cancer risk remain inconsistent. The present analysis included 810 prospectively ascertained non-cardia gastric cancer cases and 1,160 matched controls from the Helicobacter pylori Biomarker Cohort Consortium, which collected blood samples, demographic, lifestyle, and dietary data at baseline. Conditional logistic regression adjusting for total energy intake, smoking, and H. pylori status, was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer risk across cohort- and sex-specific quartiles of fruit and vegetable intake. Increasing fruit intake was associated with decreasing risk of non-cardia gastric cancer (OR = 0.71, 95% CI: 0.52-0.95, p trend = 0.02). Compared to low-fruit consumers infected with CagA-positive H. pylori, high-fruit consumers without evidence of H. pylori antibodies had the lowest odds for gastric cancer incidence (OR = 0.12, 95% CI: 0.06-0.25), whereby the inverse association with high-fruit consumption was attenuated among individuals infected with CagA-positive H. pylori (OR = 0.82, 95% CI: 0.66-1.03). To note, the small number of H. pylori negative individuals does influence this finding. We observed a weaker, nondose-response suggestion of an inverse association of vegetable intake with non-cardia gastric cancer risk. High fruit intake may play a role in decreasing risk of non-cardia gastric cancer in Asia. PMID- 27759942 TI - Abstracts from the 2014 Combined Scientific Meeting: Imaging and Radiation in Personalised Medicine. 4-7 September 2014, Melbourne Convention and Exhibition Centre, Melbourne, Australia. This supplement is a joint publication with the Journal of Medical Imaging & Radiation Oncology: Vol. 58, Suppl. 1, September 2014, Pages 1-352. PMID- 27759943 TI - Subclinical dysphagia in persons with Prader-Willi syndrome. AB - Prader-Willi Syndrome (PWS) is caused by a genetic imprinting abnormality resulting from the lack of expression of the paternal genes at 15q11-q13. Intellectual disability, low muscle tone, and life-threatening hyperphagia are hallmarks of the phenotype. The need for the Heimlich maneuver, death from choking, and pulmonary infection occur in a disproportionally high number of persons with PWS. The widely held belief is that eating behaviors are responsible for choking and aspiration; yet, no investigation had sought to determine if swallowing impairments were present in persons with PWS. To address this research and clinical gap, simultaneous videofluoroscopy and nasal respiratory signals were used to record swallowing function and breathing/swallowing coordination in 30 participants with PWS. Subjects consumed thin liquid and barium cookies under two randomized conditions as follows: (i) controlled (cues to swallow and standardized bolus sizes); (ii) spontaneous (no cues or bolus size control). Under videofluoroscopy, the cohort showed disordered pharyngeal and esophageal swallowing in both conditions with disturbances in timing, clearance, and coordination of swallowing with the respiratory cycle. No participant showed a sensory response such as attempting to clear residue or coughing; thereby supporting the lack of overt symptoms. We conclude that the high death rate from choking and pulmonary infection in children and adults with PWS may be related, in part, to underlying, asymptomatic dysphagia. The combination of rapid eating and dysphagia would increase the risk of aspiration-related morbidity and mortality. (c) 2016 Wiley Periodicals, Inc. PMID- 27759944 TI - Review: Prevalence and co-occurrence of addictions in US ethnic/racial groups: Implications for genetic research. AB - BACKGROUND AND OBJECTIVES: We conducted a review of the prevalence and co occurrence of 12 types of addictions in US ethnic/racial groups and discuss the implications of the results for genetic research on addictions. METHODS: We utilized MEDLINE and PsycINFO databases to review the literature on alcohol, tobacco, marijuana, illicit drugs, gambling, eating/food, internet, sex, love, exercise, work, and shopping. We present results for each addiction based on total US prevalence, prevalence within ethnic groups, and co-occurrence of addictions among ethnic groups when available. RESULTS: This review indicates very little research has examined the interrelationships of addictive behaviors among US ethnic groups. The studies that exist have focused nearly exclusively on comorbidity of substances and gambling behaviors. Overall findings suggest differences among US ethnic groups in prevalence of addictions and in prevalence of addiction among those who use substances or engage in gambling. Almost no ethnic group comparisons of other addictive behaviors including eating/food, internet, love, sex, exercise, work, and shopping were identified in the literature. CONCLUSIONS: Despite large-scale research efforts to examine alcohol and substance use disorders in the United States, few studies have been published that examine these addictive behaviors among ethnic groups, and even fewer examine co-occurrence and comorbidity with other addictions. SCIENTIFIC SIGNIFICANCE: Even with the limited studies, these findings have implications for genetic research on addictive behaviors. We include a discussion of these implications, including issues of population stratification, disaggregation, admixture, and the interplay between genetic and environmental factors in understanding the etiology and treatment of addictions. (Am J Addict 2017;26:424 436). PMID- 27759946 TI - Serum soluble urokinase-type plasminogen activator receptor as a serum marker of inflammatory response that leads to tissue damage and surgical complication. AB - Unrestrained activation of the proteolytic systems in anastomotic tissue during repair has been implicated in the pathogenesis of anastomotic leakage. We hypothesized that this mechanism may promote an up-regulation of the urokinase type plasminogen activator system and a spillover of soluble urokinase-type plasminogen activator receptor (suPAR) into blood. In this retrospective analysis patients with anastomotic leakage were compared with a group of matched uncomplicated patients. Anastomotic leakage complicated patients had significantly higher suPAR (p = 0.04) levels until day 3 after surgery. The area under the receiver-operating characteristic (ROC) for suPAR was higher than that CRP (0.874 vs. 0.836). Their analysis suggests the possible use of suPAR as serum marker to characterize the persistent inflammatory response that lead to tissue damage and surgical complication. PMID- 27759948 TI - Selective Angiography Using the Radiofrequency Catheter: An Alternative Technique for Mapping and Ablation in the Aortic Cusps. AB - BACKGROUND: Ablation in aortic cusps could be necessary in up to 15% of the patients, especially in para-Hisian atrial tachycardia and ventricular arrhythmias arising from outflow tracts. Risk of coronary damage has led to recommendation of systematic coronary angiography (CA) during the procedure. Other image tests as intravascular (ICE) or transesophageal echocardiography (TEE) have been proposed. Both methods have limitations: additional vascular access for ICE and need for additional CA in some patients in case of TEE. We describe an alternative method to assess relation of catheter tip and coronary ostia during ablation in aortic cusps without additional vascular accesses by performing selective angiography with the ablation catheter. METHODS AND RESULTS: We prospectively evaluated 12 consecutive patients (69.3 +/- 8.5, 6 female) who underwent ablation in right (1), left (5), and noncoronary cusps (6). We performed angiography through the ablation cooled tip radiofrequency catheter at the ablation site. Ablation was effective in 91.6% of the patients (3 patients needed additional ablation out of coronary cusps: pulmonary cusp, right ventricular outflow tract (RVOT), and coronary sinus and 1 patient underwent a second procedure because recurrence). No complications occurred neither during procedure nor follow-up (6.2 +/- 3.8 months). No technical problems occurred with the ablation catheter after contrast injection. CONCLUSION: Selective angiography through a cooled-tip radiofrequency ablation catheter is feasible to assess relation of coronary ostia and ablation site when ablation in aortic cusps. It allows continuous real-time assessment of this relation, avoids the need for additional vascular accesses and no complications occurred in our series. PMID- 27759945 TI - Review: DNA methylation and alcohol use disorders: Progress and challenges. AB - BACKGROUND AND OBJECTIVES: Risk for alcohol use disorders (AUDs) is influenced by gene-environment interactions. Environmental factors can affect gene expression through epigenetic mechanisms such as DNA methylation. This review outlines the findings regarding the association of DNA methylation and AUDs. METHODS: We searched PubMed (by April 2016) and identified 29 studies that examined the association of DNA methylation and AUDs. We also evaluated the methods used in these studies. RESULTS: Two studies demonstrated elevated global (repetitive element) DNA methylation levels in AUD subjects. Fifteen candidate gene studies showed hypermethylation of promoter regions of six genes (AVP, DNMT3B, HERP, HTR3A, OPRM1, and SNCA) or hypomethylation of the GDAP1 promoter region in AUD subjects. Five genome-wide DNA methylation studies demonstrated widespread DNA methylation changes across the genome in AUD subjects. Six studies showed significant correlations of DNA methylation with gene expression in AUD subjects. Three studies revealed interactive effects of genetic variation and DNA methylation on susceptibility to AUDs. Most studies analyzed AUD-associated DNA methylation changes in the peripheral blood; a few studies examined DNA methylation changes in postmortem brains of AUD subjects. DISCUSSION AND CONCLUSIONS: Chronic alcohol consumption may result in DNA methylation changes, leading to neuroadaptations that may underlie some of the mechanisms of AUD risk and persistence. Future studies are needed to confirm the few existing results, and then to elucidate whether DNA methylation changes are the cause or consequence of AUDs. SCIENTIFIC SIGNIFICANCE: DNA methylation profiles may be used to assess AUD status or monitor AUD treatment response. (Am J Addict 2017;26:502-515). PMID- 27759947 TI - Grit in patients with substance use disorders. AB - BACKGROUND AND OBJECTIVES: Grit is an emerging concept in positive psychology, defined as the ability to be persistent and focused in pursuit of long-term goals. This concept has received a great deal of interest recently because of its robust ability to predict success and well-being across a wide variety of domains. The study aim was to examine the clinical relevance of the construct of grit among patients with substance use disorders. METHODS: Inpatients on a detoxification unit were enrolled from September 2013 to August 2015 (N = 673). Psychometric properties of the Short Grit Scale (Grit-S) were reported. We then examined sociodemographic and clinical variables that might be associated with grit in this population. RESULTS: In this sample of patients with substance use disorders, the total Grit-S demonstrated strong psychometric properties. Grit-S scores were higher among older patients and those who were employed; scores were lower among those never married, diagnosed with a co-occurring psychiatric disorder, or who had used heroin during the past month, according to bivariate analyses. Grit-S scores remained associated with age, employment, and presence of a co-occurring psychiatric disorder in adjusted analysis. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study provides initial support for the utility of the Grit-S among those with substance use disorders; this novel measure has not been previously reported in clinical populations. Research examining grit prospectively is needed to determine whether the links between grit and outcomes observed in other populations apply to patients with substance use disorders. (Am J Addict 2016;25:652-658). PMID- 27759949 TI - Mechanistic Studies of TiO2 Photocatalysis and Fenton Degradation of Hydrophobic Aromatic Pollutants in Water. AB - HO-adduct radicals have been investigated and confirmed as the common initial intermediates in TiO2 photocatalysis and Fenton degradations of water-insoluble aromatics. However, the evolution of HO-adduct radicals to phenols has not been completely clarified. When 4-d-toluene and p-xylene were degraded by TiO2 photocatalysis and Fenton reactions, respectively, a portion of the 4-deuterium or 4-CH3 group (18-100 %) at the attacked ipso position shifted to the adjacent position of the ring in the formed phenols (NIH shift; NIH is short for the National Institutes of Health, to honor the place where this phenomenon was first discovered). The results, combined with the observation of a key dienyl cationic intermediate by in situ attenuated total reflectance FTIR spectroscopy, indicate that, for the evolution of HO-adduct radicals, a mixed mechanism of both the carbocation intermediate pathway and O2 -capturing pathway occurs in both aqueous TiO2 photocatalysis and aqueous Fenton reactions. PMID- 27759950 TI - Molecular Recognition Properties of Biphen[4]arene. AB - Biphen[n]arenes (n=3, 4) are a new family of macrocyclic hosts. Here, we describe the molecular recognition behavior of hydroxylated biphen[4]arene (OHBP4) for the first time. A series of cationic guests with different sizes and shapes, including quaternary ammonium salts (1?PF6 and 2?PF6 ), pyridinium-based guests (3?2 PF6 -6?2 PF6 ), and cobaltocenium hexafluorophosphate (7?PF6 ), were chosen as model guest molecules. OHBP4 exhibits good selectivity towards the 2,7 dibutyldiazapyrenium bis(hexafluorophosphate) (4?2 PF6 ) axle to form a [2]pseudorotaxane-type complex. In contrast, hydroxylated biphen[3]arene (OHBP3) cannot bind with this big guest. In addition, OHBP4 strongly interacts with adamantane derivative 2?PF6 and cobaltocenium 7?PF6 , which have tridimensional shape and relatively large size. The association constant of the 7+ ?OHBP4 complex in 1:1 (v/v) [D6 ]acetone/CD2 Cl2 solution is up to 3100+/-300 m-1 . PMID- 27759951 TI - A particularly useful system to study the ecology of microbes. PMID- 27759953 TI - Abstracts from the 2014 Combined Scientific Meeting: Imaging and Radiation in Personalised Medicine. 4-7 September 2014, Melbourne Convention and Exhibition Centre, Melbourne, Australia. This supplement is a joint publication with the Journal of Medical Imaging & Radiation Oncology: Vol. 58, Suppl. 1, September 2014, Pages 1-352. PMID- 27759954 TI - The prevalence of anxiety and depression in Italian patients with cystic fibrosis and their caregivers. AB - BACKGROUND: Cystic fibrosis, like other chronic diseases, is a risk factor for the development of elevated symptoms of depression and anxiety. The objective of this study was to investigate the prevalence of anxiety and depression in Italian patients with CF and their parents. METHODS: The Hospital Anxiety and Depression Scale (HADS) and Center for Epidemiologic Studies Depression Scale (CES-D) questionnaires were administered to a sample of patients and their parents recruited at the cystic fibrosis centers in Italy. RESULTS: Elevated levels of anxiety were higher in mothers than in fathers, and also higher in female patients than in male patients. A correlation between elevated levels of anxiety/depression and geographical area also emerged. Patient anxiety (OR 2.33) and depression (OR 4.09) were significantly associated with forced expiratory volume in one second (FEV1) <40% and forced vital capacity (FVC) <80% (OR 1.60 and 1.61, respectively). CONCLUSIONS: Cystic fibrosis increases the risk of developing anxiety and depression in female patients and in mothers. Geographical differences were observed, with higher anxiety and depression in southern Italy for parents, but not for patients. Anxiety and depression levels also depend on clinical status. Pediatr Pulmonol. 2016;51:1311-1319. (c) 2016 Wiley Periodicals, Inc. PMID- 27759956 TI - A positive correlation exists between neurotrauma and TGF-beta1-containing microglia in rats. AB - BACKGROUND: Transforming growth factor-beta 1 (TGF-beta1) regulates many processes after traumatic brain injury (TBI). Both Neuro AiDTM (MLC601) and astragaloside (AST) attenuate microglia activation in rats with TBI. The purpose of this study was to investigate whether MLC601 or AST improves output of TBI by affecting microglial expression of TGF-beta1. MATERIALS AND METHODS: Adult male Sprague-Dawley rats (120 in number) were used to investigate the contribution of TGF-beta1-containing microglia in the MLC601-mediated or the AST-mediated neuroprotection in the brain trauma condition using lateral fluid percussion injury. RESULTS: Pearson correlation analysis revealed that there was a positive correlation between brain injury (evidenced by both brain contused volume and neurological severity score) and the cortical numbers of TGF-beta1-containing microglia for the rats (n = 12) 4 days post-TBI. MLC601 or AST significantly (P < 0.05) attenuated TBI-induced brain contused volume (119 +/- 14 mm3 or 108 +/- 11 mm3 vs. 160 +/- 21 mm3 ), neurological severity score (7.8 +/- 0.3 or 8.1 +/- 0.4 vs. 10.2 +/- 0.5) and numbers of TGF-beta1-containing microglia (6% +/- 2% or 11% +/- 3% vs. 79% +/- 7%) for the rats 4 days post-TBI. CONCLUSIONS: There was a positive correlation between TBI and cortical numbers of TGF-beta1-containing microglia which could be significantly attenuated by astragaloside or NeuroAiDTM (MLC601) in rats. PMID- 27759957 TI - Signatures of local adaptation in candidate genes of oaks (Quercus spp.) with respect to present and future climatic conditions. AB - Testing how populations are locally adapted and predicting their response to their future environment is of key importance in view of climate change. Landscape genomics is a powerful approach to investigate genes and environmental factors involved in local adaptation. In a pooled amplicon sequencing approach of 94 genes in 71 populations, we tested whether >3500 single nucleotide polymorphisms (SNPs) in the three most common oak species in Switzerland (Quercus petraea, Q. pubescens, Q. robur) show an association with abiotic factors related to local topography, historical climate and soil characteristics. In the analysis including all species, the most frequently associated environmental factors were those best describing the habitats of the species. In the species-specific analyses, the most important environmental factors and associated SNPs greatly differed among species. However, we identified one SNP and seven genes that were associated with the same environmental factor across all species. We finally used regressions of allele frequencies of the most strongly associated SNPs along environmental gradients to predict the risk of nonadaptedness (RONA), which represents the average change in allele frequency at climate-associated loci theoretically required to match future climatic conditions. RONA is considerable for some populations and species (up to 48% in single populations) and strongly differs among species. Given the long generation time of oaks, some of the required allele frequency changes might not be realistic to achieve based on standing genetic variation. Hence, future adaptedness requires gene flow or planting of individuals carrying beneficial alleles from habitats currently matching future climatic conditions. PMID- 27759958 TI - Response to Letter to the Editor regarding 'establishing advanced practice for medical imaging in New Zealand'. AB - Letter in reply to Mr Hayes' Letter to the Editor, written with respect to the article 'Establishing advanced practice for medical imaging in New Zealand' published in Journal of Medical Radiation Science, 61 (1) 14-21. We raise a number of points in response. PMID- 27759959 TI - Endoscopic versus microscopic management of congenital ossicular chain anomalies: our experiences with 29 patients. PMID- 27759960 TI - Effects of Substrate Heating and Wettability on Evaporation Dynamics and Deposition Patterns for a Sessile Water Droplet Containing Colloidal Particles. AB - Effects of substrate temperature, substrate wettability, and particle concentration are experimentally investigated for evaporation of a sessile water droplet containing colloidal particles. Time-varying droplet shapes and temperature of the liquid-gas interface are measured using high-speed visualization and infrared thermography, respectively. The motion of the particles inside the evaporating droplet is qualitatively visualized by an optical microscope and the profile of the final particle deposit is measured by an optical profilometer. On a nonheated hydrophilic substrate, a ring-like deposit forms after the evaporation, as reported extensively in the literature, while on a heated hydrophilic substrate, a thinner ring with an inner deposit is reported in the present work. The latter is attributed to Marangoni convection, and recorded motion of the particles as well as measured temperature gradient across the liquid-gas interface confirms this hypothesis. The thinning of the ring scales with the substrate temperature and is reasoned to stronger Marangoni convection at larger substrate temperature. In the case of a nonheated hydrophobic substrate, an inner deposit forms due to very early depinning of the contact line. On the other hand, in the case of a heated hydrophobic substrate, the substrate heating as well as larger particle concentration helps in the pinning of the contact line, which results in a thin ring with an inner deposit. We propose a regime map for predicting three types of deposits-namely, ring, thin ring with inner deposit, and inner deposit-for varying substrate temperature, substrate wettability, and particle concentration. A first-order model corroborates the liquid-gas interface temperature measurements and variation in the measured ring profile with the substrate temperature. PMID- 27759961 TI - Absorption and Fluorescence Lineshape Theory for Polynomial Potentials. AB - The modeling of vibrations in optical spectra relies heavily on the simplifications brought about by using harmonic oscillators. However, realistic molecular systems can deviate substantially from this description. We develop two methods which show that the extension to arbitrarily shaped potential energy surfaces is not only straightforward, but also efficient. These methods are applied to an electronic two-level system with potential energy surfaces of polynomial form and used to study anharmonic features such as the zero-phonon line shape and mirror-symmetry breaking between absorption and fluorescence spectra. The first method, which constructs vibrational wave functions as linear combinations of the harmonic oscillator wave functions, is shown to be extremely robust and can handle large anharmonicities. The second method uses the cumulant expansion, which is readily solved, even at high orders, thanks to an ideally suited matrix theorem. PMID- 27759962 TI - Adaptive Encapsulation of omega-Amino Acids and Their Guanidinium-Amide Congeners. AB - The binding and the encapsulation of the 6-aminohexanoic acid (1) and 11 aminoundecanoic acid (2) are achieved in aqueous solution and in crystalline Pyrene-box cages. Unexpectedly, the amino-guanidinium AG+ and the amino acids 1 or 2 are reacting in aqueous solution in the absence and in the presence of Pyrene-box cages. The formation of an amide bond between a carboxylic acid and the amino-guanidine unit under mild acidic conditions in water without the use a coupling reagent is extremely interesting and unexpected. The resulted adducts AG1 and AG2 show adaptive binding behaviors and compressions. PMID- 27759963 TI - Two 3D Isostructural Ln(III)-MOFs: Displaying the Slow Magnetic Relaxation and Luminescence Properties in Detection of Nitrobenzene and Cr2O72. AB - Two new three-dimensional isostructural lanthanide metal-organic frameworks (Ln(III)-MOFs), [LnL(H2O)3].3H2O.0.75DMF (1-Ln; Ln = Dy(III) and Eu(III) ions, H3L = biphenyl-3'-nitro-3,4',5-tricarboxylic acid, DMF = N,N'-dimethylformamide), were synthesized and characterized. The appearance of temperature-dependent out of-phase (chi"M) signal reveals that complex 1-Dy displays slow magnetic relaxation behavior with the energy barrier (DeltaUeff) of 57 K and a pre exponential factor (tau0) of 3.89 * 10-8 s at 1200 Oe direct current field. The luminescence explorations demonstrated that 1-Eu exhibits high quenching efficiency and low detection limit for sensing nitrobenzene and Cr2O72-. Meanwhile, the fluorescence intensity of the quenched 1-Eu samples will be resumed after washing with DMF or water, indicating that 1-Eu may be used as a highly selective and recyclable luminescence sensing material for sensing nitrobenzene and Cr2O72- anion. PMID- 27759964 TI - ? AB - El sobrepeso y la obesidad se definen como un deposito anormal o excesivo de grasa corporal. El aumento de su prevalencia en las ultimas decadas lo convierte en uno de los principales problemas de salud publica que afecta a 42 millones de ninos menores de 5 anos en el mundo. Su presencia durante la infancia puede ser causa de enfermedades metabolicas hasta ahora consideradas tipicas del adulto y mortalidad prematura, por lo que su correcto diagnostico y tratamiento son fundamentales. PMID- 27759965 TI - Enteral feeding through endoscopic gastrostomy in amyotrophic lateral sclerosis patients. AB - BACKGROUND: Dysphagia is common in amyotrophic lateral sclerosis (ALS) and may result in malnutrition. Endoscopic gastrostomy (PEG) is recommended when oral feeding is unsafe. This work aims to assess the effectiveness and safety of PEG feeding on improving nutritional and prognostic parameters in ALS patients. METHODS: Observational and retrospective study using records from ALS patients referred for gastrostomy. Age, gender and mortality data were collected. NRS 2002, body mass index (BMI), serum albumin, transferrin and total cholesterol were recorded at the time of PEG (T0) and repeated after 3 months (T3). The evolution of these parameters was analysed and compared to survival. RESULTS: Data from 37 ALS patients (18 men/19 women) aged 43-88 years (mean: 69 years). All patients presented NRS 2002 >= 3 points. On average, patients underwent gastrostomy 11 months after diagnosis. No major procedural complications occurred. Mean survival after diagnosis was 22.2 months. Mortality rate at 3 months was 21.6% with a mean survival after PEG of 11.2 months. Albumin, transferrin and cholesterol levels increased from T0 to T3 without reaching statistical significance. Higher albumin (R = 0.3) and transferrin (R = 0.4) at admission tend to be positively correlated with survival. Mean BMI was similar at the two moments but higher initial values were associated with better outcome (R2 = 0.39, p < 0.05). CONCLUSIONS: PEG is a safe and effective technique for enteral feeding and should be considered early in ALS patients with dysphagia. Higher BMI predicts longer survival. The association between higher serum proteins and survival must be confirmed in further studies. PMID- 27759966 TI - ? AB - Introduccion: en Murcia, y hasta 2010, la administracion de la nutricion enteral domiciliaria (NED) dictaba cumplir la regulacion marcada en cuanto a los facultativos con competencias para su prescripcion.Objetivos: examinar aspectos esenciales de este recurso en el periodo 2007-2010, caracteristicas de la muestra y evolucion del coste, asi como perspectivas de futuro.Metodos: estudio del perfil de la poblacion NED en un area de salud especifica. Seleccion de recetas facturadas de productos NED en el conjunto de la Region, clasificacion por tipos y analisis de la evolucion en importe y en envases para el periodo 2007 2010.Resultados: respecto al perfil de la muestra del Area I de Salud de la Region, la patologia, via de administracion y tipo de nutricion mas frecuentes resultaron, respectivamente, la enfermedad neurologica, la via oral y la nutricion no especifica. Por otro lado, el gasto sanitario en productos dietoterapicos, en el Servicio Murciano de Salud, aumento alrededor del 50% entre los anos 2007 y 2010. Tanto en envases como en importe, Murcia se situa por encima de la media nacional.Conclusiones: el perfil de la muestra no coincide con trabajos publicados en otras regiones. Este dato, junto a la posicion de Murcia en gasto dietoterapico, y su evidente tendencia al alza en los anos analizados, hace evidente la necesidad de medidas que mejoren la calidad de la NED en la Region de Murcia y, en caso de ser posible, conseguir alcanzar valores nacionales en relacion con el consumo medio y el gasto. PMID- 27759967 TI - Quality indicators for enteral and parenteral nutrition therapy: application in critically ill patients "at nutritional risk". AB - INTRODUCTION: Quality Indicators for Nutritional Therapy (QINT) allow a practical assessment of nutritional therapy (NT) quality. OBJECTIVE: To apply and monitor QINT for critically ill patients at nutritional risk. METHODS: Cross sectional study including critically ill patients > 18 years old, at nutritional risk, on exclusive enteral (ENT) or parenteral nutritional therapy (PNT) for > 72 hours. After three consecutive years, 9 QINT were applied and monitored. Statistical analysis was performed with SPSS version 17.0. RESULTS: A total of 145 patients were included, 93 patients were receiving ENT, among then 65% were male and the mean age was 55.7 years (+/- 17.4); 52 patients were receiving PNT, 67% were male and the mean age was 58.1 years (+/- 17.4). All patients (ENT and PNT) were nutritionally screened at admission and their energy and protein needs were individually estimated. Only ENT was early initiated, more than 70% of the prescribed ENT volume was infused and there was a reduced withdrawal of enteral feeding tube. The frequency of diarrhea episodes and digestive fasting were not adequate in ENT patients. The proper supply of energy was contemplated only for PNT patients and there was an expressive rate of oral intake recovery in ENT patients. CONCLUSION: After three years of research, the percentage of QINT adequacy varied between 55%-77% for ENT and 60%-80% for PNT. The results were only made possible by the efforts of a multidisciplinary team and the continuous re-evaluation of the procedures in order to maintain the nutritional assistance for patients at nutritional risk. PMID- 27759968 TI - Cut-off values for classifying active children and adolescentes using the Physical Activity Questionnaire: PAQ-C and PAQ-ACut-off values for classifying active children and adolescents using the Physical Activity Questionnaire: PAQ-C and PAQ-A. AB - INTRODUCTION: The Physical Activity Questionnaire for children and adolescents (PAQ-C & PAQ-A) has been widely used in research and field settings. However, there is a lack of information about its final score meaning. OBJECTIVE: To determine PAQ-C and PAQ-A score cut-off values using physical activity (PA) thresholds objectively measured as reference criteria. METHODS: 146 children (n = 83 boys, n = 63 girls) and 234 adolescents (n = 115 boys, n = 119 girls) participated in this study. Accelerometers (Actigraph GT3X) were used to assess objectively PA during one-week, afterwards PAQ was filled by the participants. As participants met or not the international PA recommendations for total, moderate vigorous (MVPA) or light PA, three categorical variables of two levels were created. ROC curves procedure were carried out to obtain score cut-off points for identifying the positive category recommendation. RESULTS: ROC curves analysis estimated 2.75 and 2.73 score cut-off points to discriminate > 60 minutes of MVPA for PAQ-A and PAQ-C respectively (PAQ-A AUC = 0.68, p < 0.001 and PAQ-C; AUC = 0.55, p > 0.05). Also 60 minutes of MVPA was achieved with a total volume of 10,664 steps/day in children and 9,701 steps/day in adolescents. CONCLUSIONS: Our results suggest that PAQ-A can be a useful tool to classify adolescents as active or inactive following international recommendations as criteria. However, we could not find a significant cut-off for PAQ-C score. PMID- 27759969 TI - ? AB - Introduccion: bajos niveles de actividad fisica, moderada y vigorosa, son un factor de riesgo conductual importante en la obesidad en ninos.Objetivo: el objetivo del estudio fue determinar el estado nutricional y la condicion fisica de escolares, comparando los resultados obtenidos por genero, obesidad y rendimiento fisico.Material y metodos:578 escolares: 308 hombres de 11,22 +/- 1,93 anos y 270 mujeres de 10,93 +/- 1,92 anos participaron en la investigacion. Fueron evaluados: indice de masa corporal (IMC), porcentaje de masa grasa (%MG), contorno de cintura (CC), razon cintura-estatura (RCE) y rendimiento fisico segun los test del Estudio Nacional de Educacion Fisica de la Agencia de Calidad de la Educacion de Chile.Resultados: el %MG fue mayor en la mujeres (p < 0,001). En el test de abdominales y en el de Navette el rendimiento fue mayor en los hombres, y en el test de flexo-extensiones de brazo el rendimiento fue mayor en las mujeres (p < 0,05). Los escolares en categoria de obeso presentaron inferiores resultados en los test de: abdominales, salto largo, flexo-extensiones de brazo y Navette (p < 0,001). El VO2MAX fue menor en los sujetos con obesidad (p < 0,001). Los estudiantes que necesitan mejorar 3 o 4 test presentan mayor RCE (p < 0,001) y %MG (p < 0,001). Existe una asociacion negativa entre la RCE y el VO2MAX (-0,543, p < 0,001).Conclusiones: existe una elevada prevalencia de sobrepeso y obesidad. Ademas, se aprecia un bajo rendimiento fisico asociado a esta condicion. Los escolares que necesitan mejorar 3 o 4 test de la condicion fisica presentan mayores promedios de %MG y RCE; esta ultima variable es un potente indicador de riesgo cardiovascular. PMID- 27759970 TI - ? AB - Introduccion: a escala mundial y nacional se reporta una alta prevalencia de sobrepeso y obesidad en menores de 5 anos. La etiologia es multifactorial, pero factores ambientales como sedentarismo y el progresivo deterioro de la alimentacion promueven el exceso de peso y conllevan a mayor riesgo de enfermedades cronicas no transmisibles en temprana edad.Objetivo: describir la ingesta de alimentos, energia y nutrientes en los ninos de 2-4 anos con obesidad y eutroficos del programa "Buen Comienzo".Metodo: estudio de corte con 111 ninos con obesidad clasificada segun IMC >3 DE, que fueron pareados por sexo, edad y tipo de atencion con un nino clasificado con estado nutricional normal. Personal entrenado realizo la valoracion antropometrica con equipos y metodos estandarizados y se evaluo la ingesta dietetica a traves de recordatorio de 24 horas. Se aplico la prueba t-student y U de Mann Whitney en el analisis bivariado y para determinar el patron de consumo de alimentos y se efectuo un analisis de clases latentes (ACL).Resultados: los ninos tienen un consumo de energia superior a su requerimiento, pero existe diferencia significativa segun el estado nutricional; el consumo en los ninos obesos es de 1.632 kcal (IQR: 1.475-1.801 kcal) y eutroficos de 1.798 kcal (IQR 1.702-1.632 kcal) (p = 0,00). Los ninos con peso adecuado tienen mayor ingesta de macronutrientes y micronutrientes (p < 0,05); hay una mayor ingesta de proteinas y micronutrientes durante la semana (p < 0,05); el 30% de los ninos no consumio ninguna verdura y el 60% ninguna fruta el dia anterior a la encuesta y tuvieron, ademas, un alto consumo de azucares y dulces.Conclusiones: los ninos estan sometidos a una dieta obesogenica caracterizada por un bajo consumo de frutas y verduras y una alta ingesta de energia, grasas saturadas y carbohidratos concentrados, lo que promueve una ganancia de peso no deseado. PMID- 27759971 TI - Prevalence of overweight and obesity among adolescents in eight Arab countries: comparison between two international standards (ARABEAT-2). AB - OBJECTIVE: The aim of this study was to highlight the prevalence of overweight and obesity among adolescents in eight Arab countries. METHODS: A school-based cross-sectional study was conducted in eight Arab countries: Iraq, Jordan, Kuwait, Libya, Palestine, Saudi Arabia, Sudan and Tunisia. The total sample included was 6,447 adolescents aged 15-18 years (3,111 males, 3,336 females). The International Obesity Task Force (IOTF) and World Health Organization (WHO) reference standards were used to determine obesity levels. RESULTS: The WHO standard provided lower prevalence of overweight but higher prevalence of obesity than the IOTF standard. According to the IOTF standard, overweight among males was highest in Kuwaiti adolescents (24.8%), followed by Saudi Arabian (23.2%). Among females, the highest prevalence was reported in Kuwaiti adolescents (22.1%), followed by Jordanian (20.0%). Regarding obesity, Kuwaiti adolescents showed the highest prevalence of obesity for both males (28.6%) and females (21.1%). CONCLUSION: Findings revealed no progress in reducing prevalence of obesity. PMID- 27759972 TI - ? AB - Objetivo: el proposito del estudio fue relacionar la etapa en el cambio en el comportamiento frente a la actividad fisica y el estado nutricional en escolares de Bogota, Colombia, pertenecientes al estudio FUPRECOL.Metodo: se trata de un estudio transversal, realizado en 8.000 ninos y adolescentes de entre 9 y 17 anos, pertenecientes a 24 instituciones educativas. Se aplico de manera autodiligenciada el cuestionario de cambio de comportamiento en funcion de la intencion de realizar actividad fisica (CCC-FUPRECOL) y se midio el peso y la estatura para determinar el estado nutricional con el indice de masa corporal (IMC).Resultados: el porcentaje de respuesta fue del 82,5% y se consideraron validos 6.606 registros, siendo el 58,3% (n = 3.850) ninas, con un promedio de edad de 12,7 +/- 2,3 anos. En la poblacion general, el 5,3% de los escolares se encontraba en etapa de precontemplacion, el 31,8% en contemplacion, el 26,7% en accion y el 36,2% en etapa de mantenimiento. Al comparar la etapa de cambio con el estado nutricional por IMC, los escolares clasificados como obesos mostraron mayor frecuencia de respuesta en la etapa de precontemplacion, mientras que los escolares con peso saludable acusaron mayores porcentajes en la etapa de mantenimiento.Conclusion: en escolares de Bogota, Colombia, se encontro una relacion estadisticamente significativa entre la intencion de realizar actividad con el estado nutricional medido con el IMC. Fomentar la promocion de la actividad fisica y monitorizar el estado nutricional debera ser una prioridad en las agendas y politicas publicas dentro del ambito escolar. PMID- 27759973 TI - ? AB - Introduccion: la gestacion y lactancia estan relacionadas con perdidas temporales en la densidad mineral osea (DMO) materna. Una suplementacion con calcio podria resultar beneficiosa para evitar la perdida de masa osea del esqueleto materno. Otros nutrientes como los prebioticos han sido identificados como responsables de un incremento en la absorcion de minerales, pudiendo condicionar la mineralizacion osea.Objetivo: estudiar el efecto de la suplementacion de la dieta materna con el prebiotico inulina enriquecida con oligofructosa, durante la gestacion y la lactancia sobre el contenido mineral oseo (CMO) y la DMO al final del periodo de lactancia.Metodos: las ratas gestantes fueron alimentadas con dieta estandar (grupo CC), dieta fortificada en calcio (grupo Ca) o enriquecida con el prebiotico inulina enriquecida con oligofructosa (grupo Pre) hasta el final del periodo de lactancia. Posteriormente se evaluo el CMO y DMO por absorciometria de rayos X (DEXA) y el pH del contenido cecal.Resultados:en terminos generales, el grupo Pre presenta los mayores valores absolutos de CMO y DMO de entre los tres grupos, siendo en la tibia significativamente diferentes en los grupos CC y Pre frente al grupo Ca. El pH del contenido cecal del grupo Pre es significativamente inferior al de los grupos CC y Ca.Conclusion:la suplementacion con inulina enriquecida con oligofructosa, en condiciones nutricionales no deficientes en calcio, durante la gestacion y la lactancia, ejerce una proteccion del esqueleto materno en las ratas y puede ser considerada como una estrategia nutricional para proteger la masa osea materna en el periodo perinatal. PMID- 27759974 TI - Acantosis nigricansis associated with risk factors related to cardiovascular disease in Mexican children with obesity. AB - INTRODUCTION: The prevalence of obesity in Mexican children has increased during the last decade, as has the risk of early onset metabolic disorders and cardiovascular disease. OBJECTIVE: To determine the association ofAcantosis nigricans (AN)with dyslipidemia, high blood pressure, body mass index (BMI), and risk factors related to eating behavior in overweight and obese children. PATIENTS AND METHODS: This transverse analytical study, conducted in two Mexico City primary schools, included 300 boys and girls. Information was gathered on hereditary and perinatal background. A physical examination provided data on the presence/absence of AN, blood pressure, weight and height. The BMI and Z-score were calculated. The serum concentration of glucose, cholesterol and triglycerides was quantified and the lipoprotein profile determined. RESULTS: The prevalence of AN was 41.7%. An association was found between ANand risk factors for cardiovascular disease, including BMI (rS 0.432; p < 0.0001), systolic and diastolic blood pressure above the 90th percentile (rS 0.231, p < 0.0001; rS 0.128, p = 0.026; respectively), hypertriglyceridemia (rS 0.156; p = 0.007), and low levels of cHDL (rS -0.160; p = 0.006). ANwas also associated with risk eating behavior, including dieting to lose weight (p = 0.004), losing control over eating (p = 0.023), and body fat percentage above the 90th percentile (chi2 = 35.1; p = 0.0001). No association was observed between ANand serum glucose concentration (rS -0.018; p = 0.759). Logistic regression analysis demonstrated an association of ANwith a low concentration of cHDL (RM: 1.726; p = 0.041) and a high percentage of body fat (> 48%) (RM: 3.591; p = 0.001). CONCLUSION: A high prevalence of ANwas found in overweight and obese children. There was an association between ANand risk factors of cardiovascular disease, including Z score, BMI, dyslipidemia, and high blood pressure. PMID- 27759975 TI - Body mass index cutoff point estimation as obesity diagnostic criteria in Down syndrome adolescents. AB - INTRODUCTION: Adolescents with Down syndrome (DS) show high rate of overweight and tend to accumulate high amount of fat compared to the same people without the syndrome. OBJECTIVE: To estimate the cutoff point of the Body Mass Index (BMI) for the diagnosis of obesity in adolescents with DS according to different references for BMI in relation to the percentage of body fat (%BF) measured by dual-energy X-ray absorptiometry (DXA). METHODS: The sample was composed of 34 adolescents with DS (aged: 10 to 17 years old). BMI was evaluated according to the references of the International Obesity Task Force (IOTF), the World Health Organization (WHO) for the general population, and Myrelid et al. and Styles et al. for people with DS. The %BF was assessed by whole body DXA and classified according to National Health And Nutrition Examination Survey (NHANES, 2011). RESULTS: The boys were significantly taller than the girls and this %BF higher than boys. All references who have used BMI to assess obesity was positively associated with %BF measured by DXA in the diagnosis of obesity. Using the ROC curve in relation to %BF by DXA, all references showed high sensitivity, but the z-score of BMI by WHO showed better specificity, with the value of the accuracy of 0.82 for the cutoff point above 2.14. CONCLUSIONS: All the references used for the diagnosis of obesity were associated with %BF measured by DXA, and the cutoff point of z-scores above 2.14 by WHO showed better specificity. PMID- 27759976 TI - ? AB - Introduccion: el indice glucemico (IG) y la carga glucemica (CG) de productos lacteos fermentados (PLF) con lactobacilos puede ser una recomendacion util para pacientes diabeticos y para la poblacion en general.Objetivo: el objetivo del estudio fue medir el IG y la CG de PLF con lactobacilos en sujetos sedentarios y deportistas, y evaluar si existe diferencia entre ellos.Metodos: el estudio se realizo en Mexico (DF) de acuerdo con la ISO26642:210 (Organizacion Internacional de Normalizacion). Los participantes fueron: 10 sedentarios y 10 deportistas. Los PLF analizados fueron: Soful, Yakult, Gastroprotect, BeneGastro, Bonacult, Lala Bio 4 y leche descremada con sacarosa (LDS) y la cantidad de alimento que ingirieron dependio de ajustar a 25 g los HC en la porcion.Resultados: el IG de la mayoria de los PLF fue bajo para ambos grupos de sujetos; en los deportistas los PLF Yakult y Bonacult presentaron los mayores IG y solo el Yakult puede considerarse como de IG medio para este grupo; estos dos PLF presentaron la menor relacion de proteina/HC. La LDS, lacteo con los HC no fermentados, presento un IG alto para ambos grupos. La CG de los PLF se encontro entre 4 a 7,6 y solo Gastroprotect presento estadisticamente la menor CG, lo que pudo deberse a su bajo IG, aun cuando su tamano de racion no fue la menor, entre los PLF.Conclusion: en general los valores de IG y CG de los PLF fueron bajos para ambos grupos. Por tanto, su consumo puede recomendarse en forma moderada. El IG y CG entre productos lacteos con azucares fermentados y con azucares no fermentados fueron diferentes. PMID- 27759977 TI - Association of the rs9939609 gene variant in FTO with insulin resistance, cardiovascular risk factor and serum adipokine levels in obese patients. AB - INTRODUCTION: The aim of our study was to analyze the relationship of the rs9939609 FTO gene polymorphism with insulin resistance and serum adipokine levels. MATERIAL AND METHODS: A population of 610 patients with obesity was analyzed in a cross sectional design. Weight, blood pressure, basal glucose, c reactive protein (CRP), insulin, insulin resistance (HOMA), lipid profile and adipocytokines (leptin, adiponectin, resistin, TNF alpha, and interleukin 6) levels were measured. RESULTS: Insulin (122.2 +/- 101.8 pmol/L vs. 104.5 +/- 61.5 pmol/L vs.112.1 +/- 74.3 pmol/L:p < 0.05) and HOMA-IR values (4.76 +/- 4.4 vs. 3.71 +/- 2.5 vs.3.76 +/- 3.1;p < 0.05) were higher in TT group than AT and AA groups. Triglycerides values were higher in TT group than AA group (1.42 +/- 0.71 mmol/L vs.1.39 +/- 0.69 mmol/L vs.1.23 +/- 0.64 mmol/L;p < 0.05). Adiponectin levels were lower in TT genotype group than AA genotype group (35801.2 +/- 35,912.3 ng/L vs.26,718.1 +/- 36,323.1 ng/L vs. 21,112.3 +/- 25,623.1 ng/L p < 0.05). CONCLUSION: The FTO gene polymorphism, rs9939609, was found to be associated with insulin resistance, insulin, triglyceride and adiponectin levels in obese patients with TT variant. PMID- 27759978 TI - Good weight loss responders and poor weight loss responders after Roux-en-Y gastric bypass: clinical and nutritional profiles. AB - BACKGROUND: Bariatric surgery is one of the main treatments for severity obesity, but weight regain after surgery is an important issue. OBJECTIVES: To compare the clinical and nutritional profiles of good and poor weight loss responders in the late postoperative period after bariatric surgery. METHODS: A cross-sectional study with patients undergoing Roux-en-Y gastric bypass in a University Hospital. Patients were divided into good weight loss responders (GWLR) and poor weight loss responders (PWLR) defined as >= 50% or < 50% excess weight loss (EWL), respectively, at least 2 years post-surgery. RESULTS: The sample included 204 individuals (87.7% women; mean age 50.15 +/- 11.1 years; mean time after surgery 67.38 +/- 30.76 months). Two years post-surgery, 71.1% were considered GWLR and 28.9% PWLR (mean EWL 72.33% +/- 13.86%, and 35.06% +/- 12.10%, respectively; p = 0.000). Weight regain was < 10% for 36.3% of patients, 10.1-20% for 36.3%, and > 20% for 21.3%, compared with the lowest post-surgery weight. Among PWLR, 49.0% regained > 20% of the lowest post-surgery weight. GWLR lost most weight at all time points analyzed (p < 0.05). GWLR presented improvement or remission of diabetes, dyslipidemia and hypertension more frequently compared to PWLR (p < 0.05). Eating patterns was similar between GWLR and PWLR (p > 0.05, study's power 100%). Quality of life improved in 79.5% of the total study sample, with greater improvements in the GWLR (p < 0.05). CONCLUSIONS: Greater weight loss correlated with improved remission in comorbidities and better quality of life. PMID- 27759979 TI - Comparison of body fat calculations by sex and puberty status in obese schoolchildren using two and four compartment body composition models. AB - INTRODUCTION: Determine body composition changes in adiposity can assess an individual. OBJECTIVE: The objective of this study was to evaluate total body fat percentage based on two and four compartment models in obese Chilean school children, adjusting for differences in sex and puberty status. METHODS: Sixty-one obese school children (33 boys and 28 girls) between 8 and 13 years of age were evaluated. Two compartment measurements of body fat percentage considered isotope dilution, plethysmography, radiographic absorptiometry and bioelectrical impedance; using the four compartment model as a benchmark. RESULTS: Each method explained between 43-87% of the variance in body fat percentage in Tanner stage I and II children and between 78-96% in Tanner stage III and V children. In both groups of children methods differed significantly for stage I, with the exception of plethysmography. High R2 values were observed for girls in all Tanner stages. Each method explained between 34-92% of the variance in body fat percentage for girls in stages I and II and between 63-93% for stages III and V. In obese boys, R2 values were high for stages III and V. In girls and boys in Tanner stage III and V, the smallest differences were observed for isotopic dilution, and DXA (dual-energy X-ray absorptiometry) scan for stages I and II. CONCLUSIONS: For obese boys and girls, the two compartment model with isotopic dilution and DXA had the best precision and smallest differences in determining body fat percentage compared to the benchmark. PMID- 27759980 TI - Nutritional status and food intake of HCV/HIV coinfected patients. AB - INTRODUCTION: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection may cause nutrient deficiency and affect the nutritional status.Objetive: To assess nutritional status, and energy and macronutrient intake in HCV/HIV coinfected patients. METHODS: Cross-sectional study on HIV/HCV coinfected patients treated in a public hospital. Nutritional status was assessed by measurements of weight, height, waist circumference (WC), arm circumference (AC), triceps skinfold thickness (TST), non-dominant hand gripltrength (NDHGS), body mass index (BMI) and mid-upper arm circumference (MUAC). Dietary intake was assessed by 24-hour recall. RESULTS: Fifty-seven patients (59.6% women) with mean age of 46 +/- 11.2 years were studied. According to BMI, more than half of patients were overweight or obese, and 41% of men and 68% of women had increased or substantially increased WC. The prevalence of malnutrition varied between the methods -10.5% (BMI), 29.8% (AC), 56.2% (TST), 17.6% (MUAC), and 12.3% (NDHGS). We found a high percentage of patients with inadequate intake of protein, fat and energy. The percentage of total energy intake (%TEI) from carbohydrates inversely correlated with WC and AC. A positive correlation was observed between %TEI from protein and NDHGS, and between %TEI from fat and BMI, WC and AC. CONCLUSION: We found a high prevalence of increased body weight and WC, and inadequate dietary intake in HCV/HIV coinfected patients. We observed a positive association between protein intake and muscle function, and between fat intake and obesity. PMID- 27759981 TI - Validity and reliability of beverage intake questionnaire: evaluating hydration status. AB - OBJECTIVE: The purpose of this investigation is to test the validity and reliability the assessment methods for the true beverage consumption of adults. METHODS: This cross-sectional study was carried out 291 healthy volunteers. The beverage intake questionnaire (BIQ) was prepared in combination with a new one which is developed based on basic principles and the existing one developed for the beverages consumed the most with respect to frequency and amount by Turkish populations. During the initial visit the participants completed BIQ1 and then provided a urine sample to determine urinary specific gravity(USG). For validity, participants recorded the type and quantity of foods and beverages consumed on the same day and previous two days. Two weeks later, for reliability, participants completed the same beverage intake questionnaire (BIQ2). RESULTS: Mean daily total fluid intake was estimated at 1,773 +/- 49.4mL using the dietary intake record (DIR), 2,120 +/- 49.5 mL with BIQ1 and 1,990 +/- 46.3 mL for BIQ2. The largest contribution to total fluid intake was plain water. The response on the two assessment tools (DIR and BIQ1) all beverage intakes were significantly correlated (p < 0.01) except for alcoholic beverage intake. One could see a significant correlation between BIQ1 and BIQ2 in relation to total fluid intakes (r = 0.838,p < 0.01). The USG measurement was negatively correlated with three assessment tools (DIR, BIQ1 and BIQ2), the amount of plain water and the amount of total fluid intake. CONCLUSIONS: The self-administered instrument described in this study may be useful for researchers interested in assessing habitual beverage consumption patterns or evaluating hydration status for adults. PMID- 27759982 TI - ? AB - Objetivo: el objetivo de este estudio fue analizar la ingesta nutricional de atletas de alto nivel de las especialidades de fondo y medio fondo, durante una temporada atletica, para detectar posibles deficiencias.Metodos: para llevar a cabo el estudio, se procedio a evaluar la dieta y las diferentes concentraciones de los macronutrientes (glucidos, lipidos y proteinas) y los diferentes tipos de acidos grasos, en cuatro momentos diferentes de la temporada: al inicio y a los 3, 6 y 9 meses de entrenamiento. La muestra estuvo constituida por un grupo formado por 23 atletas de fondo y medio fondo con un minimo de 5 anos de ntrenamiento, una carga semanal de entre 14-20 horas y un volumen de 100-120 km semanales. El procedimiento consistio en el registro nutricional durante un periodo de tres dias consecutivos, en los cuatro momentos establecidos.Resultados: los resultados obtenidos muestran incrementos significativos (p < 0,05) en la ingesta de proteinas entre los 3-9 meses.Conclusion: la ingesta energetica en atletas de fondo y medio fondo va aumentando a lo largo de la temporada deportiva, con cantidades de macronutrientes inferiores a las recomendadas por la comunidad cientifica, y con incrementos en la ingesta de proteinas en periodos de primavera y verano, coincidiendo con momentos de competicion. PMID- 27759983 TI - Impact of the two different iron fortified cookies on treatment of anemia in preschool children in Brazil. AB - INTRODUCTION: Nutritional intervention in pre-school children using cookies prepared with wheat flour enriched with iron and folic acid (CWFFeFA) and cookies prepared with cowpea (Vigna unguiculata (L.) Walp) flour fortified with iron and zinc and wheat flour enriched with iron and folic acid (CCFFeZn + WFFeFA). OBJECTIVE: To assess the impact of the ingestion of CWFFeFA and CCFFeZn + WFFeFA by pre-school children, using the cowpea variety BRS-Xiquexique, to control iron deficiency anaemia. METHODS: Nutritional intervention was conducted in municipal day care centres selected at random (n = 262) involving pre-school children aged 2 to 5 years living in Teresina, state of Piaui, Brazil. To assess the socioeconomic data, BMI-for-age, haemoglobin levels before and after intervention, and dietary intake, the children were divided into group 1 (G1), which received CWFFeFA (30 g), and group 2 (G2), which received CCFFeZn + WFFeFA (30 g). Food acceptance was evaluated daily. RESULTS: The prevalence of anaemia in G1 and G2 before the nutritional intervention was 12.2% (n = 18) and 11.5% (n = 30), respectively. After intervention, the prevalence decreased to 1.4% in G1 (n = 2) and to 4.2% in G2 (n = 11). Food acceptance by pre-school children in G1 and G2 was 97.4% and 94.3%, respectively. CONCLUSION: The use of both types of cookie formulations decreased the prevalence of anaemia among pre-school children, and CCFFeZn + WFFeFA yielded the greatest decrease. PMID- 27759984 TI - Prevalence of overweight, obesity, abdominal-obesity and short stature of adult population of Rosario, Argentina. AB - INTRODUCTION: The aim of this work was to assess the prevalence of overweight, obesity, abdominal-obesity and short stature among Rosario (Argentina) adult population. MATERIALS AND METHODS: A cross-sectional nutritional survey was carried out in Rosario (2012-2013). A random sample (n = 1194) of adult population (18-70 years old) was interviewed. Anthropometric measurements and a general questionnaire incorporating questions related to socio-demographic and lifestyle characteristics, education level and physical activity were used. RESULTS: The current study detected a high prevalence of overweight and obesity among adult population in Rosario. The prevalence of overweight was 32.7% (43.9% in men and 27.6% in women, p < 0.001), of obesity was 23.5% (21.6% in men and 24.3% in women), and of abdominal obesity was 57.5% (63.5% in men vs.54.8% in women, p < 0.005). Multivariate analysis showed that the prevalence of overweight/obesity and abdominal obesity increased according the age and abdominal obesity decreased with high physical activity in men. In women prevalence of overweight/obesity, and abdominal obesity increased with age, marital status (married or coupled), presence of at least one child at home and low educational level. CONCLUSION: The prevalence of short stature was higher in women (16.4% vs. 8.4%, p < 0.001) and was related with age, overweight and abdominal obesity. PMID- 27759985 TI - ? AB - Introduccion: ante las nuevas implicaciones atribuidas a la vitamina D y la asociacion con enfermedades tales como el cancer, diabetes, enfermedades cardiovasculares, autoinmunes y mortalidad, no es de extranar que se haya defendido la medicion de los niveles de vitamina D en la poblacion general. Sin embargo, no existen datos experimentales que demuestren la viabilidad y rentabilidad de la estrategia de cribado en la poblacion y tampoco se ha comprobado la existencia de beneficios para la salud, por lo que en la actualidad solo es aconsejable la medida de 25 (OH) vitamina D en los grupos de personas de alto riesgo como indican las guias clinicas internacionales.Objetivos: analizar las peticiones de vitamina D comprobando si se adecuan a las guias clinicas.Metodos: realizamos un estudio descriptivo transversal en el Area de Salud de Badajoz (Espana) estudiando las peticiones de determinacion de vitamina D durante 12 meses consecutivos (n = 3.907). En dicho estudio revisamos el diagnostico de peticion y la historia clinica del paciente para discriminar entre peticiones que se adecuaban a las guias clinicas y peticiones injustificadas. Por ultimo, realizamos el estudio economico.Resultados: en nuestros resultados encontramos que casi un tercio de peticiones no se adecuaban a las guias clinicas, en patologias tales como diabetes, dislipemias e hipertension en las que no esta recomendada la medicion de los niveles de vitamina D, por lo que suponia un exceso de gasto para el sistema sanitario. Gasto que se incrementa cada ano, tanto es asi que se ha producido un aumento en las peticiones de mas del 1.000% en los ultimos 6 anos.Conclusiones: concluimos la necesidad de crear protocolos de peticion de vitamina D que se ajusten a las guias clinicas hasta que existan mas estudios experimentales sobre las nuevas implicaciones de la vitamina D y asi conseguir una correcta utilizacion de los recursos economicos del hospital. PMID- 27759986 TI - Design and evaluation of a campaign to promote the consumption of vegetables and fruits in Mexican school-age children. AB - INTRODUCTION: In Mexican school-age children the consumption of vegetables and fruits (V&F) is less than 25% of the amount recommended by the World Health Organization. OBJECTIVES: Evaluate the effectiveness of a promotion campaign about the consumption of V&F in urban school children from Hidalgo, Mexico. METHODS: A non controlled community trial in 226 school-age children from private and public schools was conducted, we designed and distributed printed material for promoting the consumption of V&F among the school population, access to V&F was provided through planning and sales at school stores, and consumption was supervised by the teachers. RESULTS: At the end of the intervention vegetable consumption increased by 50 g and plain water in 100 mL (T-test, p < 0.05); the proportion of school-age children who identified the health benefits of the consumption of V&F increased significantly (68% initial, 87% final) and greater support from parents (61% initial, 92 final%) was achieved. CONCLUSIONS: A promotion campaign and improved access to vegetables, fruits and water in the school environment which is supported by parents and teachers can encourage healthier eating at school. PMID- 27759987 TI - ? AB - Introduccion: la alimentacion de los jovenes universitarios se aleja cada vez mas de la dieta mediterranea (DM). El binomio alimentacion-actividad fisica es fundamental para mantener un adecuado estado de salud.Objetivo: comparar la ingesta en un grupo de estudiantes universitarios deportistas frente a otro que no realiza deporte habitualmente.Sujetos y metodos:estudio observacional transversal realizado en 49 voluntarios de la Universidad de Valladolid. Se determinaron peso, talla y actividad fisica (cuestionario GPAQ). La ingesta se evaluo a partir de un cuestionario de frecuencia de consumo y un registro de alimentos de 3 dias. La adherencia a la DM se estimo con el Mediterranean Diet Score. Las diferencias entre las variables en funcion del sexo y la practica deportiva se analizaron con la t de Student o la U-Mann-Whitney. Significacion estadistica: p < 0,05.Resultados: todos los sujetos presentaron normopeso, sin diferencias en funcion de la practica deportiva. El nivel de actividad fisica fue inferior en las mujeres. En todos los estudiantes la dieta fue ligeramente hiperproteica, rica en grasas y colesterol, con un inadecuado perfil lipidico y deficiente en hidratos de carbono y fibra. Se cubren los requerimientos de micronutrientes. Destaca un escaso consumo de frutas-verdurashortalizas, cereales, aceite de oliva, pescado y frutos secos; y un exceso de carne, mantequilla, bolleria-industrial, dulces, snacksy refrescos. El 50% de la muestra tiene una adherencia baja o muy baja a la DM.Conclusion: las dietas de los jovenes universitarios no cumplen los objetivos nutricionales para la poblacion espanola y presentan una adherencia media-baja a la DM, independientemente de la practica deportiva. PMID- 27759988 TI - Lifestyle and vitamin D dosage in women with breast cancer. AB - INTRODUCTION: The prevention strategy of breast cancer is still the key factor for early diagnosis and the most effective method for tracking the disease. OBJECTIVE: This study aimed to evaluate the association vitamin D level with breast cancer in women. METHODS: This hospital case-control study was conducted with 181 women with breast cancer and 197 healthy controls. Vitamin D status, calcium, phosphorus and PTH serum dosage and data collection related to lifestyle and patient's history, besides anthropometric measurements were performed. Univariate analysis (Chi-square and raw odds ratio) and multivariate analysis were performed through multivariate logistic regression. RESULTS: This study shows a higher value of vitamin D in health controls (26.9 mg/dL) than in breast cancer women (24.8 mg/dL). Higher numbers of women with sufficient vitamin D status (34.85%) were found in control group than cancer group. Using the multiple logistic regression model, the family history of breast cancer (OR 36.37, 95%CI 4.75-278.50) and menopause (OR 5.17, 95% CI 2.72-9.80) had a direct association with breast cancer, while the level of vitamin D (OR 0.95, 95%CI 0.91-0.99) and moderate physical activity (OR 0.31, 95%CI 0.10-0.93) maintained the inverse associations with the disease. CONCLUSION: Vitamin D status and the practice of moderate physical activity were considered protective factors for breast cancer. However, menopause and family history of breast cancer were considered a risk factor for breast cancer. PMID- 27759989 TI - ? AB - Objetivos: estimar las actividades preventivas que realizan los pacientes diagnosticados de enfermedad pulmonar obstructiva cronica (EPOC) en la provincia de Leon.Metodos: estudio epidemiologico, transversal, multicentrico (30 centros de salud de la provincia de Leon). Incluyo pacientes mayores de 35 anos diagnosticados y tratados de EPOC. Variables a estudio: edad, sexo, habitat, datos antropometricos, tabaquismo, estado nutricional, ejercicio fisico, vacunacion antigripal, vacunacion, antineumococica (VNP23 y VNC13), fenotipo, gravedad, reagudizaciones y hospitalizaciones. Los resultados se expresan con sus IC al 95,5%.Resultados: se incluyeron 833 pacientes, el 85,8% varones, edad media: 64,69 anos (53,66-75,61) y 20,65 anos (4,47-36,8) de evolucion de la EPOC. El 86,67% (80,30-93,30) tenian antecedentes de tabaquismo (n = 722), de 35,26 anos de evolucion (17,87-52,64), consumian 28,36 paquetes al ano (9,60-46,86), p < 0,001, siendo el 58% fumadores severos. En fumadores activos (n = 288) la intervencion mas efectiva fue terapia cognitivo-conductual mas vareniclina, con abstinencias del 29,86%. En total dejaron de fumar el 51,05% (49,49-52,70) de los pacientes con EPOC, p < 0,001. El 73,67% (71,78-75,65) realizaba ejercicio prescrito, el 88,76% (84,82-90,7) realizaba dieta equilibrada, el 89,7% (87,8 91,8) estaba vacunado frente a la gripe, siendo esta mas frecuente en los mayores de 65 anos y hospitalizados, p < 0,001. El 9,61% (7,7-11,6) de los no vacunados tuvo reagudizaciones que requirieron ingreso hospitalario, p < 0,001. La tasa de vacunacion con VNP23 fue del 52,8% (49,3-56,4) vs.4,97% (3,0-6,61) de VNC13, p < 0,05.Conclusiones: las actividades preventivas en los pacientes con EPOC se realizan de forma optima en nuestro entorno, superior a la media nacional, aunque se deben lograr mayores tasas de cobertura de vacunacion frente al neumococo. PMID- 27759990 TI - Interventions directed at eating habits and physical activity using the Transtheoretical Model: a systematic review. AB - INTRODUCTION: The multi-behavioral Transtheoretical Model (TTM) addresses multiple behaviors and it is a promising strategy to control multifactorial morbidities, such as chronic diseases. The results obtained using the TTM are positive, but are not consistently methodical. OBJECTIVES: The aim of this study was to systematically review the effectiveness of the Transtheoretical Model in multi-behavioral interventions for changing eating habits and levels of physical activity. METHODS: A search on PubMed and SciELO databases was performed with inclusion criteria set for intervention studies before 2016 using the Transtheoretical Model for more than one behavior, including eating habits and/or engaging in physical activity. RESULTS AND CONCLUSION: Eighteen studies were identified; there was a predominance of randomized clinical trials, studies conducted in the United States, and the use of the Internet and/or telephone. The selected studies were aimed at changing eating behaviors; five of the studies did not address physical activity. The main results were reduction of fat consumption, an increase in the consumption of fruit and vegetables, and increases in physical activity, which are progressions in the stages of change and weight loss identified by the Transtheoretical Model. However, the studies showed methodological weaknesses, including high participant loss and the omission of information about randomization and blinding. PMID- 27759991 TI - ? AB - Introduccion: el estado nutricional previo de la embarazada, la adecuada ganancia de peso y la ingesta de ciertos nutrientes pueden tener una influencia importante tanto para la madre como para el recien nacido, a corto y largo plazo. Las recomendaciones de la Organizacion Mundial de la Salud son transmitidas durante el control del embarazo por la matrona.Objetivos: analizar los principales estudios sobre la percepcion de las embarazadas acerca de los consejos nutricionales recibidos e identificar las estrategias utilizadas por las matronas para su implementacion.Metodologia: busqueda bibliografica sobre embarazadas de bajo riesgo controladas por matronas y que reciben consejos nutricionales realizada en WOS, CINHAL y PubMed. Se utilizaron los descriptores: pregnancy, pregnant, midwife, counselling, nutritiony sus diferentes combinaciones. Los criterios de inclusion fueron articulos originales y revisiones en ingles, espanol o portugues de los ultimos diez anos y disponibles en texto completo.Resultados: se encontraron 184 referencias. Solo 11 tratan el tema abordado. Existen multiples articulos con consejos nutricionales en el embarazo, pero muy pocos que incluyan estrategias educativas implementadas por las matronas que aborden recomendaciones dietetico-nutricionales y su utilidad.Conclusion: existen escasos estudios que investiguen los conocimientos que las matronas tienen sobre nutricion en el embarazo y los consejos que aportan sobre el tema. Igualmente sucede con los trabajos que estudian la percepcion que tienen las gestantes sobre los consejos nutricionales recibidos. PMID- 27759992 TI - Eating attitudes, body image and risk for eating disorders in a group of Spanish dancers. AB - INTRODUCTION: Prevalence of eating disorders (ED) and discrepancies between actual weight and weight perception seem much higher in dancers. The aims analysed in 77 dancers were: risk for ED; relationship between eating attitudes and psychological variables; dieting and self-weighing, and body image distortion. METHOD: Weight- and body image-related variables, dieting, self reported physical fitness, specific ED-related variables and other psychological variables were assessed. The robust Huber's model was applied in order to test the inflluence of the variables analysed on the Eating Attitudes Test (EAT-40) scores. In case of categorical variables, the Chi-square (chi2-test) or the Fisher's exact test were applied. RESULTS: Higher risk of ED was not obtained. Despite the relationship between EAT-40 and BMI, body appreciation and drive for thinness, scores on EAT-40 and BMI do not suggest higher risk in dancers. Dancers had a similar weight perception than other populations and body dissatisfaction seems not to be worse than the reported in other types of participants. CONCLUSIONS: Despite some limitations, our study adds some data in this field of study bearing in mind the use of a cluster of variables previously not taken into account as a whole. PMID- 27759993 TI - Hepatic function and antioxidant activity in diabetic rats subjected to diet supplemented with multimixture. AB - INTRODUCTION: Food and dietetic components have received considerable attention as auxiliary feeding resources on controlling of chronic non-transmissible diseases, among them diabetes. This study evaluated the effect of supplementary diet with multimixture based on linseed, sesame, oats and sunflower seeds on the hepatic function and antioxidant activity of diabetic rats. METHODS: Male rats were distributed on groups of seven animals: diabetic control (DC), diabetics subject to multimixture diet (DM), diabetic with insulin (DI), and normal control (NC). The treatment was started on the 5th day after diabetes induction with 40 mg/kg i.v. streptozotocin on tampon citrate and kept during 50 days. RESULTS: The ethereal extract of the supplemented diet showed a higher content of phenolics (p < 0.05) compared to other extracts of the supplemented diet and the ethereal extract of the standard diet. There was no difference in antioxidant in vitro activity of the utilized diets. Concerning to transaminases, significant bigger ALT levels (p < 0.05) were present on diabetic groups compared to NC. The relative liver weight on diabetic groups was significantly higher (p < 0.001) compared to NC group. Non-proteic sulfhydryl group levels were significantly higher (p < 0.05) on DM and I groups when compared to DM and NC. Only the treatment with insulin resulted in an improvement of antioxidant activity concerning to hepatic catalase. The supplementation with multimixture did not improve the metabolic control of diabetes. CONCLUSION: The multimixture treatment showed an isolated improvement on antioxidant activity in the hepatic tissue, evidenced by the increasing on non-proteic sulfhydryl group levels. PMID- 27759994 TI - Calcium supplementation for reducing weight in people with obesity; an overview of systematic reviews AB - Introduccion: actualmente la obesidad es considerada un problema de salud publica, y en la mayor parte de los paises ha evolucionado como una pandemia, presentando un incremento en su prevalencia y severidad.Objetivo:resumir las revisiones sistematicas Cochrane y no Cochrane que evaluen el efecto de la suplementacion de calcio en la disminucion de grasa corporal en personas obesas.Materiales y metodos: se realizo una busqueda en la base de datos Medline (1980-septiembre 2015), Metabuscador TripDatabase y Epistemonikos (hasta septiembre 2015), Cochrane BVS (hasta septiembre 2015), se busco de forma manual en revistas relacionadas con el tema de interes, en actas de congresos, se realizo seguimiento de referencias relevantes y se contacto con expertos en el area.Resultados: la busqueda preliminar arrojo un total de 7.163 articulos potencialmente elegibles, segun los criterios de elegibilidad incluimos 2 revisiones sistematicas de estudios clinicos aleatorizados.Conclusion: el suplemento de calcio al parecer seria efectivo en la disminucion de grasa corporal, DM -0,51 (-1,27, 0,25); (p = 0,19), presentando "baja evidencia" segun la metodologia GRADE, esto quiere decir que "es muy probable que investigaciones adicionales tengan un impacto importante en la confianza de la estimacion del efecto y es probable que cambie". PMID- 27759995 TI - ? AB - Introduccion: la infertilidad es un problema global en aumento. Se estima que aproximadamente un 15% de las parejas en edad reproductiva tiene dificultades a la hora de concebir. De estas, alrededor de la mitad presentan uno o varios factores masculinos asociados a infertilidad o subfertilidad, aislados o en combinacion con problemas de origen femenino. Durante la ultima decada se ha empezado a estudiar la infertilidad desde una perspectiva multifactorial, considerando las interacciones y conexiones entre diferentes situaciones geneticas, epigeneticas, bioquimicas y fisiologicas del paciente.Objetivo: la presente revision pretende describir mecanismos epigeneticos que pueden ser modulados mediante aspectos nutricionales y que estan relacionados con la etiologia de la infertilidad masculina y con la herencia transgeneracional de este fenotipo.Material y metodos: se ha realizado una extensa busqueda de publicaciones cientificas en las principales bases de datos electronicas especializadas: NBCI, Elsevier, Scielo, Scirus y Science Direct.Resultados y conclusion: varios trabajos que muestran la importancia del estado nutricional en la fertilidad del hombre y, mas especificamente, la capacidad de los componentes de la dieta para modificar los perfiles epigeneticos que no unicamente pueden afectar a su fertilidad, sino que tambien pueden ser transmitidos a la descendencia mediante lo que se ha denominado herencia transgeneracional, ocasionandoles problemas de salud diversos entre los que tambien se hallan problemas en la fertilidad. PMID- 27759996 TI - Association between sarcopenic obesity and cardiovascular risk: where are we? AB - INTRODUCTION: The main changes in the body composition refer to the increase of adipose tissue and/or the decrease of muscular mass, and these changes have effect in many clinical outcomes. Sarcopenic obesity (SO) consists of the presence of excessive adipose tissue and deficit of muscular mass simultaneously. People with SO may have synergistic effect due to obesity and sarcopenia, with increases cardiovascular risk more than obesity itself. OBJECTIVE: To describe the findings in the literature about the association between SO and risk factors and/or cardiometabolic disease (CMD) or cardiovascular disease (CVD). METHODS: An electronic search was done on the following databases: MEDLINE, Scopus, SciELO, LILACS and Web of Science, using the matching expressions and Boolean operators: "obesity sarcopenic" OR "sarcopenic obesity", in the titles of the studies, AND "cardiometabolic disease" OR "cardiovascular disease" OR "metabolic syndrome" OR "insulin resistance", in the abstract. RESULTS: Most of studies are cross sectional and present many different diagnosis criteria for SO. It was possible to verify the association of the SO and the risk factors and/or CMD or CVD. CONCLUSION: SO is associated with risk factors and/or CMD or CVD. The lack of a consensus about this definition jeopardizes the effective clinical practice and the research about the subject. PMID- 27759997 TI - Correction: Conclusions of the II International and IV Spanish Hydration Congress. Toledo, Spain, 2nd-4th December, 2015. AB - This corrects the article DOI: 10.20960/nh.308. PMID- 27759998 TI - Presurgical evaluation of bony implant sites using panoramic radiography and cone beam computed tomography-influence of medical education. AB - OBJECTIVES: The aim of this study was to compare the subjective quality rating of panoramic radiography (PAN) and CBCT in the planning of dental implant procedures by clinicians with different educational backgrounds. METHODS: Radiographic images (PAN and CBCT) of 42 patients were examined as follows: the maxillary (MX) anterior region of patients, the MX posterior region of 16 patients and the mandibular (MD) posterior region of 16 patients. These sites were used for planning of dental implant insertion. Data sets were analyzed by examiners with different training backgrounds: three general practitioners (GP), three oral surgeons (OS) and three maxillofacial surgeons (MS). A standardized questionnaire in a standardized setting was answered by participants. RESULTS: The majority of participants rated an additional CBCT as "required" (14.0%) or "reasonable" (56.1%). These ratings depended strongly on the area of interest (MX anterior region: 31.1 and 58.9%; MX posterior region: 14.6 and 62.5%; and MD posterior region: 2.8% and 47.9%). MS classified CBCT as required more often than GP and OS (23.8 vs 10.3 and 7.9%; p < 0.001). With the additional information of CBCT, "therapy affecting" ratings were stated high in all groups. CONCLUSIONS: Especially in the anterior and posterior MX, significant subjective benefits for an additional CBCT were seen for planning of dental implant procedures. Participants with fundamental medical education asked for CBCT more often. The results indicate that an improved education in three-dimensional dental radiology is necessary. PMID- 27759999 TI - The relationship between sleep problems and working memory in children born very preterm. AB - In two studies, the relationship between sleep and working memory performance was investigated in children born very preterm (i.e., gestation less than 32 weeks) and the possible mechanisms underlying this relationship. In Study 1, parent reported measures of snoring, night-time sleep quality, and daytime sleepiness were collected on 89 children born very preterm aged 6 to 7 years. The children completed a verbal working memory task, as well as measures of processing speed and verbal storage capacity. Night-time sleep quality was found to be associated with verbal working memory performance over and above the variance associated with individual differences in processing speed and storage capacity, suggesting that poor sleep may have an impact on the executive component of working memory. Snoring and daytime sleepiness were not found to be associated with working memory performance. Study 2 introduced a direct measure of executive functioning and examined whether sleep problems would differentially impact the executive functioning of children born very preterm relative to children born to term. Parent-reported sleep problems were collected on 43 children born very preterm and 48 children born to term (aged 6 to 9 years). Problematic sleep was found to adversely impact executive functioning in the very preterm group, while no effect of sleep was found in the control group. These findings implicate executive dysfunction as a possible mechanism by which problematic sleep adversely impacts upon cognition in children born very preterm, and suggest that sleep problems can increase the cognitive vulnerability already experienced by many of these children. PMID- 27760000 TI - Who benefits from putting family life into ice? PMID- 27760001 TI - Geometric systematic prostate biopsy. AB - OBJECTIVE: The common sextant prostate biopsy schema lacks a three-dimensional (3D) geometric definition. The study objective was to determine the influence of the geometric distribution of the cores on the detection probability of prostate cancer (PCa). METHODS: The detection probability of significant (>0.5 cm3) and insignificant (<0.2 cm3) tumors was quantified based on a novel 3D capsule model of the biopsy sample. The geometric distribution of the cores was optimized to maximize the probability of detecting significant cancer for various prostate sizes (20-100cm3), number of biopsy cores (6-40 cores) and biopsy core lengths (14-40 mm) for transrectal and transperineal biopsies. RESULTS: The detection of significant cancer can be improved by geometric optimization. With the current sextant biopsy, up to 20% of tumors may be missed at biopsy in a 20 cm3 prostate due to the schema. Higher number and longer biopsy cores are required to sample with an equal detection probability in larger prostates. Higher number of cores increases both significant and insignificant tumor detection probability, but predominantly increases the detection of insignificant tumors. CONCLUSION: The study demonstrates mathematically that the geometric biopsy schema plays an important clinical role, and that increasing the number of biopsy cores is not necessarily helpful. PMID- 27760003 TI - The truth is in the distribution. AB - There may be as many ways to think about the experience of women in science as there are women in science. Indira Raman offers one perspective. PMID- 27760004 TI - First Case of TNF-Receptor-Associated Autoinflammatory Syndrome (TRAPS) in Bulgaria. AB - TRAPS is a very rare disease with an estimated prevalence of about one per million. We present a 53-year-old patient from Bulgaria. The clinical features of the disease are periodic fever, arthralgia, myalgia, rash, abdominal pain and hepatosplenomegaly. Laboratory studies yield leukocytosis, highly elevated levels of CRP, significantly high ESR. Secondary amyloidosis AA is determined. The genetic analysis found a heterozygous T>C nucleotide substance (c.250T>C) in exon 3 of TNFRSF1A gene which is associated with TRAPS (MIM*191190). The presented case of genetic changes and clinical manifestations in the autoinflammatory syndrome TRAPS due to a mutation in the gene encoding the receptor for tumour necrosis factor alpha (TNFRSF1A) is the first documented case of the disease reported in Bulgaria. PMID- 27760005 TI - Subcapsular and Perirenal Hematoma after Ureteroscopy and Pneumatic Lithotripsy. AB - Subcapsular or perirenal hematoma is an unusual complication after semirigid ureteroscopy using pneumatic lithotripsy to treat ureteral stones. We present a patient who developed a large subcapsular and perirenal hematoma following ureteroscopy administered to a stone in the right ureter. PMID- 27760002 TI - Midbrain dopamine neurons signal aversion in a reward-context-dependent manner. AB - Dopamine is thought to regulate learning from appetitive and aversive events. Here we examined how optogenetically-identified dopamine neurons in the lateral ventral tegmental area of mice respond to aversive events in different conditions. In low reward contexts, most dopamine neurons were exclusively inhibited by aversive events, and expectation reduced dopamine neurons' responses to reward and punishment. When a single odor predicted both reward and punishment, dopamine neurons' responses to that odor reflected the integrated value of both outcomes. Thus, in low reward contexts, dopamine neurons signal value prediction errors (VPEs) integrating information about both reward and aversion in a common currency. In contrast, in high reward contexts, dopamine neurons acquired a short-latency excitation to aversive events that masked their VPE signaling. Our results demonstrate the importance of considering the contexts to examine the representation in dopamine neurons and uncover different modes of dopamine signaling, each of which may be adaptive for different environments. PMID- 27760006 TI - Autoimmune Phenomena in Patients with Solid Tumors. AB - INTRODUCTION: Autoimmune disorders have been documented in solid tumors and malignant hematological disorders. They are very common and well studied in lymphomas which are associated with immune imbalance. They are less common in solid tumors and are categorized as paraneoplastic syndromes with unclear pathogenesis. AIM: The aim of the present study was to find the frequency of autoimmune phenomena in solid tumors of various origin, location and status of the tumor. PATIENTS AND METHODS: Between 2000 and 2014 we studied 1083 patients with solid tumors that were diagnosed and treated in St George University Hospital, Plovdiv. RESULTS: We found higher incidence of these phenomena in prostate and ovarian carcinomas (9.01% and 5.6%, respectively) than in other solid tumors. Their distribution by type of autoimmune disease showed that vasculitis, polyneuritis and autoimmune hemolytic anemia have the highest frequency of all. Immune thrombocytopenia, seronegative arthritis, psoriasis, polymyositis are less commonly documented. The autoimmune paraneoplastic phenomena manifest themselves metachronously, less commonly synchronously, with the tumor. In most cases, their clinical manifestation is a progressive disease or metastatic malignant disorder which respond favourably to therapy. CONCLUSION: Paraneoplastic autoimmune phenomena are found very commonly in prostate and ovarian carcinomas. They occur in the course of the evolvement of neoplasm and can regress with medicamentous or surgical treatment of the malignoma. PMID- 27760007 TI - Monitoring of Frequency and Antimicrobial Susceptibility of Pathogens on the Hands of Healthcare Workers in a Tertiary Hospital. AB - OBJECTIVE: To monitor microbes, focusing on drug resistance, on the hands of the personnel of four departments of a tertiary hospital (ICU, neonatal unit, internal medicine ward and surgical ward) and explore differences between departments, professions and genders. MATERIALS AND METHODS: Hand sampling from 125 healthcare employees was conducted followed by isolation, identification and antibiotic resistance profiling of different microbial species. RESULTS: Staphylococcus spp was the most prevalent microbe (76/125, 60.8%), followed by different Gram-negative pathogens (45.6%). ICU employees had a significant probability to have Gram-negative contamination [OR 3.627 (95% CI 1.220-10.782)], independently of gender or profession. Staphylococcus spp presence was associated with working in the internal medicine ward [OR 6.976 (95% CI 1.767-25.540)] and the surgical ward [OR 5.795 (95% CI 1.586-21.178)]. Staphylococcus spp was more prevalent in males vs. females (81.3% vs. 54.9%, p=0.008) and in medical vs. nursing personnel (76.9% vs. 54.8, p=0.019). In the majority of Gram-negative isolates (56.1%), at least one multi-drug resistant (MDR) or extensively drug resistant (XDR) strain was isolated. A statistically significant higher prevalence of XDR Gram-negative microbes was found on the hands of nursing personnel (22.2% vs. 2.3% for medical doctors, p=0.014). Only 2 methicillin resistant Staphylococcus Aureus (MRSA) out of the 12 Staphylococcus aureus positive samples were identified. CONCLUSIONS: Employees in the ICU are more prone to Gram-negative and not to Gram-positive hand contamination. MDR and XDR pathogens are prevalent, and are associated with nursing profession. PMID- 27760008 TI - In Vitro Study of Temperature Changes in Pulp Chamber During Root Planing Procedure Using Er:YAG Laser. AB - AIM: To assess temperature changes at specified time intervals during Er:YAG laser scaling and root planing of surfaces with dental calculus. MATERIALS AND METHODS: Fifteen single-rooted teeth with advanced periodontal disease were extracted and fixed in a cylinder thermostat filled with distilled water at constant temperature (35.5 degrees C). A specially designed thermal probe (type K thermocouple) accurate to +/-0.1 degrees C over the range from 20 degrees C to 80 degrees C was fitted into the pulp chamber of tooth sample. Scaling and root planing of the mesial and distal root surfaces was performed using an Er:YAG laser (Lite Touch, Syneron Dental, Israel) with a wavelength of 2940 nm, provided with a chisel tip, and at the following settings: output energy 100 mJ and 50 Hz, duration of irradiation - 40 sec, the tip in contact mode oblique to the root surface at an angle of approximately 10-15 degrees and water spray level 5-6. The temperature inside the pulp chamber was measured every 10 sec. RESULTS: The temperature in the pulp chamber taken every 10 seconds and compared with the temperature of 35.5 degrees C at baseline decreased by 1.6 degrees C, 2.4 degrees C, 2.5 degrees C, and 2.5 degrees C for the first, second, third and fourth measurement, respectively. These changes did not reach statistical significance. CONCLUSION: The Er:YAG laser does not increase the temperature inside the pulp chamber. The assessed changes do not depend on the duration of irradiation which was kept within 40 seconds. Therefore, this treatment modality causes no thermal damage to the pulp under the above defined conditions and can be considered safe. PMID- 27760009 TI - Relationship between visual field changes and optical coherence tomography measurements in advanced open-angle glaucoma. AB - AIM: To assess relationships between functional changes in visual field and structural changes in advanced open-angle glaucoma (OAG) found using spectral domain optical coherence tomography (SD-OCT). METHODS: Thirty-one eyes of 25 patients with OAG were included in this study. Besides the routine ophthalmological exam the patients underwent standard automated perimetry (SAP) (Humphrey Field Analyzer) and SD-OCT (RTVue-100) performed within 6 months. The global perimetric indices in the study group were as follows: mean deviation (MD) 12.33+/-6.18 dB and pattern standard deviation (PSD) 9.17+/-3.41 dB. The relationship between OCT measurements and MD and PSD was evaluated by correlation analysis (Pearson's correlation coefficient) and regression analysis (linear and nonlinear regression models). RESULTS: Thickness measurements of the lower halves of ganglion cell complex (GCC) and retinal nerve fiber layer by two scanning protocols (ONH and 3.45) showed these to be thinner than the upper halves, but the difference failed to reach statistical significance. The correlations between global indices MD/PSD and most of the analysed quantitative OCT measurements were moderate (r in the range between 0.3 and 0.6). The correlation between MD and GCC showed nonlinear cubic regression (R2=0.417, P=0.004). Good correlation was found between MD and GLV (R2=0.383; P=0.008). Linear regression (P<0.05) was found only between MD and Cup area (R2=0.175, P=0.024) and between MD and RNFL by 3.45 protocol (R2=0.131, P=0.045). CONCLUSION: Nonlinear regressive models appear to be more appropriate in the assessment of the correlations between functional and structural changes in eyes with advanced glaucoma. The correlations we found were moderate. PMID- 27760010 TI - Effect of Nitrates, Thiocyanates and Selenium on the Iron and Iodine Status of Postpartum Women. AB - AIM: To find correlations between high thiocyanate and nitrate levels and low selenium levels and the indicators of the iodine and iron status of postpartum women. MATERIALS AND METHODS: The study included 41 mothers aged 26.4+/-5.9 yrs from Asenovgrad and nearby villages. Urinary iodine was determined by the Sandell Kolthoff reaction and thiocyanate - by the interaction of these ions with acidic solution of KMnO4; for serum nitrates we used the colorimetric method; serum selenium was assessed by electro-thermal atomic-absorption spectrophotometry; thyroxin (FT4), the thyroid stimulating hormone (TSH), serum ferritin (SF), and serum transferrin receptor (sTfR) were determined using ELISA; Hb levels were determined by hematology analyzer. RESULTS: Assessing the iodine status, we found a negative correlation between the levels of iodine and thiocyanates in urine (R= 0.717, r<0.0001), a positive correlation between nitrates and TSH (R=0.487, r=0.003) and a negative correlation between nitrates and FT4 (R=-0.312, r=0.06). For the iron status, we found a negative correlation between nitrates and SF (R= 0.429, r=0.009) and between nitrates and Hb (R=-0.383, r=0.021). The Mann-Whitney U-test showed that in women with nitrate levels higher than the mean value there was low FT4 level (r=0.06), high TSH level (r=0.013), low Hb concentration (r=0.061) and low SF concentration (r=0.005). The combined effects of environmental factors (elevated nitrate levels and low selenium level) on the iodine and iron status are manifested by low concentrations of FT4 (r=0.033), Hb (r=0.06) and SF (r=0.05) and high level of TSH (r=0.05). In conclusion, we found that environmental factors, especially when combined, have a negative impact on the iron and iodine status of females. PMID- 27760011 TI - Global Longitudinal Strain and Strain Rate in Type Two Diabetes Patients with Chronic Heart Failure: Relevance to Osteoprotegerin. AB - BACKGROUND: Biomechanical stress and inflammatory biomarkers relate to global contractility dysfunction; however, adding these biomarkers into a risk model constructed on clinical data does not improve its prediction value in chronic heart failure (CHF). AIM: The aim of this study was to evaluate whether biomarkers predict declining of left ventricular global contractility function in diabetic patients with ischemia-induced CHF. PATIENTS AND METHODS: The study retrospectively evolved 54 diabetic patients who had systolic or diastolic ischemia-induced CHF that was defined as left-ventricular ejection fraction (LVEF) <=45% or 46-55% respectively assessed by quantitative echocardiography and other conventional criteria according to current clinical guidelines. Two dimensional transthoracic echocardiography and tissue Doppler imaging were performed according to a conventional method. Radial, longitudinal, and circumferential strain and strain rate values were obtained by speckle-tracking Imaging analysis of both LV short axis and long axis views. Serum adiponectin, NT pro brain natriuretic peptide (BNP), osteoprotegerin, and hs- C-reactive protein (CRP) were determined at baseline by ELISA. RESULTS: We found lower global longitudinal strain and strain rate in diabetic patients with LVEF <45% than these in diabetic patients that did not have LVEF (R=0.001 for all cases). Multivariate logistic regression analysis showed that NT-proBNP (r=0.432; P=0.001 and r=0.402; P=0.001, respectively), osteoprotegerin (r=0.422; P=0.001 and r=0.401; P=0.001, respectively), hs-CRP (r=0.408; P=0.001 and r=0.404; P=0.001, respectively) were independently inversely associated with global longitudinal strain and strain rate in CHF patients. CONCLUSION: We suggest that osteoprotegerin may be useful in improving the NT-proBNP based model as predictor of decreased global contractility function in diabetic patients with CHF. PMID- 27760012 TI - Cognitive Impairment in Multiple Sclerosis. AB - Multiple sclerosis (MS) is a socially significant immune-mediated disease, characterized by demyelination, axonal transection and oligodendropathy in the central nervous system. Inflammatory demyelination and neurodegeneration lead to brain atrophy and cognitive deficit in up to 75% of the patients. Cognitive dysfunctions impact significantly patients' quality of life, independently from the course and phase of the disease. The relationship between pathological brain findings and cognitive impairment is a subject of intensive research. Summarizing recent data about prevalence, clinical specificity and treatment of cognitive disorders in MS, this review aims to motivate the necessity of early diagnosis and complex therapeutic approach to these disturbances in order to reduce the social burden of the disease. PMID- 27760013 TI - Distant Liver Metastases as a Major Factor Influencing Survival in Patients with Colorectal Cancer. AB - AIM: To assess the effect of the factor 'hepatic metastatic disease' on long-term outcomes in patients with colorectal cancer. MATERIALS AND METHODS: We analysed retrospectively 200 randomly selected patients. Forty-two of them were excluded from the study for different reasons so the study contingent was 158 patients over a period of 23 years. All were diagnosed and treated in the Lozenetz University Hospital, in the Department of General Surgery. 125 of the patients were diagnosed with colorectal cancer without distant metastases and 33 of the patients had liver metastases as a result of colorectal carcinoma. The statistical analysis was performed using SPSS 19 IMB, with a level of significance of P < 0.05 at which the null hypothesis is rejected. We also used descriptive analysis, Kaplan-Meier estimator, Log-Rank Test and Life-Table statistics models. RESULTS: The median survival for patients without metastases was 160 months, and the median was 102 months. The median survival for patients with liver metastases was 28 months and the median was 21 months. One-year survival for patients without metastases was 92% versus 69% in patients with liver metastases. CONCLUSION: Average, annual and median survivals are influenced statistically significantly by the presence of liver metastases compared to overall survival and that of patients without metastatic colorectal cancer. Liver metastatic disease is a proven factor affecting long-term prognosis and survival in patients with colorectal cancer. PMID- 27760014 TI - Vitamin D status in Israeli pediatric type 1 diabetes patients: the AWeSoMe Study Group experience and literature review. AB - BACKGROUND: The prevalence of both vitamin D (VitD) deficiency and type 1 diabetes mellitus (T1DM) has increased worldwide over the last few decades. The objectives of this study were: (1) to evaluate the prevalence of VitD deficiency and insufficiency among Israeli youth with T1DM and (2) to assess the association between VitD status, seasonality and T1D glycemic control characteristics. METHODS: This was a multi-centered, cross-sectional study. VitD levels were routinely tested during the years 2008-2011 in T1DM patients aged up to 21 years. Medical records were reviewed for demographic, clinical and laboratory characteristics. RESULTS: The study population consisted of 199 participants (53% males), mean age 12.24+/-4.11 years, mean T1DM duration 3.77+/-3.43 years. VitD levels were within the normal range in 19.6%, insufficient (15-29 ng/mL, 37-72 nmol/L) in 62.3% and deficient (<15 ng/mL, <37 nmol/L) in 18.1%. Mean VitD level was higher during the summer than during spring, autumn and winter (28.65 ng/mL, 23.16 ng/mL, 21.65 ng/mL, 17.55 ng/mL, respectively, p<0.001). Mean VitD level was higher among secular patients compared to the religious (whole-year heavily dressed) population (23.57 ng/mL, 15.54 ng/mL, respectively, p<0.001). VitD level was negatively associated with body mass index calculation of standard deviation scores (BMI-SDS), high-density lipoprotein (HDL) and age at diagnosis (r=-0.171, p=0.016; r=-0.149, p=0.043; r=-0.150, p=0.037, respectively). No association was demonstrated with disease duration and glycemic control indices and metabolic parameters. CONCLUSIONS: VitD insufficiency is largely prevalent among Israeli youth with T1DM, as is in Israeli youth in general. The VitD level is associated with seasonality, clothing habits and BMI. PMID- 27760015 TI - Evaluation of Acute Phase Proteins in Clinically Healthy Dairy Cows in Perinatal Period and During Lactation. AB - The estimation of acute phase proteins (APP), which are recognized as inflammation markers is a good method for animal health monitoring. Several factors such as obesity, age and sex are also known to modulate APP status. We evaluated the influence of pregnancy and lactation in 65 clinically healthy dairy Holstein-Friesian dairy cows, 2nd/4th lactation, chosen from 3 different dairy farms located in South West part of Poland. Bovine C-reactive protein (CRP), haptoglobin and fibrinogen were assayed using commercial ELISA kits. The highest values of CRP and haptoglobin were observed in cows during the first month after calving. The highest concentrations of fibrinogen was found in a group of cows prior to expected date of parturition and the level of this protein in blood plasma was decreasing during lactation. The significant differences of analyzed APPs among cows before delivery, during first month after calving and in lactation (1-3 months after delivery) suggested that factors like pregnancy and stage of lactation would have an influence on their concentration. PMID- 27760016 TI - Estradiol Reduces Connexin43 Gap Junctions in the Uterus during Adenomyosis in Cows. AB - Adenomyosis is defined as the presence of glandular foci external to the endometrium of the uterus, either in the myometrium or/and perimetrium, depending on the progress of this dysfunction. To date, we showed that steroids secretion and prolactin expression and proliferative processes are disturbed during uterine adenomyosis in cows. During endometriosis in eutopic endometrium in women, gap junctions are down regulated. The transmembrane gap junction protein, connexin (Cx43) is necessary for endometrial morphological, biochemical and angiogenic functions. The aim of this study is recognition of adenomyosis etiology by determination of the role of Cx43 in this process. Immunolocalization and comparison of Cx43 mRNA and protein expression in healthy (N=9) and adenomyotic uterine tissue (N=9), and Cx43 mRNA expression (real time PCR) in uterine stromal - myometrium co-culture under 24-hour stimulation with 17-beta estradiol (10-7M) isolated from healthy (N=5) and adenomyotic (N=5) cows were determined. Cx43 was localized in healthy and adenomyotic uteri. mRNA and protein expression was down regulated in uterine tissue in adenomyotic compared with healthy cows (p<0.05). Estradiol stimulated Cx43 mRNA expression in myometrial cell culture and co culture of stromal and myometrial cells in adenomyotic compared with healthy cows (p<0.05). In summary, down-regulation of Cx43 expression in the junction zone might play an important role in pathogenesis of adenomyosis. Estradiol modulates gap junctions during adenomyosis. PMID- 27760017 TI - Phenotypical and Genotypical Antimicrobial Resistance of Coagulase-negative staphylococci Isolated from Cow Mastitis. AB - The objectives of this study were to determine the prevalence and antimicrobial resistance of coagulase-negative staphylococci (CNS) isolated from dairy cows with subclinical mastitis. Antimicrobial resistance in staphylococci were evaluated by breakpoint values specific to the species (EU-CAST). The presence of resistance-encoding genes was detected by multiplex PCR. A total of 191 CNS isolates were obtained. The CNS isolates were typically resistant to penicillin (67.4%), tetracyc-line (18.9%), and erythromycin (13.7%). CNS isolates (78.0%) were resistant to at least one antimicrobial compound, and 22.0% were multiresistant. The multiresistant isolates were predominantly Staphylococcus chromogenes (28.6%), Staphylococcus warneri (19%) and Staphylococcus haemolyticus (14.3%). According to MIC pattern data, multiresistant isolates showed the highest resistance (p<0.05) rates to penicillin (85.7%), tetracycline (66.7%), and erythromycin (48.2%), but all of them were sensitive to daptomycin, oxacillin, qiunupristin/dalfopristin, and vancomycin. S. chromogenes (9.5%), S. haemolyticus (4.8%), and S. capitis ss capitis (2.4%) strains were resistant to methicillin; their resistance to oxacillin and penicillin was more than 8 mg/l. A high rate of resistance to penicillin was linked to a blaZ gene found in 66.6% of the isolated multiresistant CNS strains. Resistance to tetracycline via the tetK (38.1%) gene and penicillin via the mecA (23.8%) gene were detected less frequently. Gene msrAB was responsible for macrolides and lincosamides resistance and detected in 28.6% of the CNS isolates. Antimicrobial resistance genes were identified more frequently in S. epidermidis, S. chromogenes, and S. warneri. PMID- 27760018 TI - Relevance of Molecular Changes in the ND4 Gene in German Shepherd Dog Tumours. AB - The aim of the study was to identify polymorphisms and mutations in the mitochondrial ND4 gene and to analyse the associations between the occurrence of molecular changes in mtDNA and phenotypic traits in tumours in German Shepherd dogs. Fifty samples obtained from blood and tumour tissues of German Shepherd dogs with diagnosed tumours were analysed. DNA extraction, amplification, and sequencing of the mtDNA ND4 gene, and bioinformatics, statistical, and in silico protein coding SNP analyses were performed. ND4 mutations and/or polymorphisms were noted in eleven nucleotide positions in nearly half of the examined dogs. All the changes were substitution mutations. A majority of the changes identified were homoplasmic. In one dog with osteosarcoma, blood heteroplasmy was detected. In two positions of the ND4 gene, presence of non-synonymous mutations leading to amino acid changes in the ND4 protein was reported. Analyses carried out to determine the deleterious effect of mutations indicated an almost 97 and 62% probability that a single amino acid substitution (p.G239V and p.I401T, respectively) in the protein has a negative impact on its function. The results of statistical analyses indicate a significant association between the occurrence of mutations in three loci of the ND4 gene and the location of tumours. The mutations identified may be a result of cell adaptation to the changes in the environment occurring during carcinogenesis. The high frequency of mutations in the tumours may indicate genetic instability of mtDNA, which may also play a role in carcinogenesis. PMID- 27760019 TI - GP5 Protein-based ELISA for the Detection of PRRSV Antibodies. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important swine pathogen, causing huge economic losses each year worldwide. Immunization with vaccines containing the glycoprotein 5 (GP5) of PRRSV is the main measure to induce neutralizing antibodies and control the disease. Here, we developed a GP5 protein-based ELISA for detecting antibodies against PRRSV. The overall yield of purified GP5 in E. coli flask culture was more than 45 mg/L cell culture. Western blot and IFA indicated that the GP5 protein was highly immunogenic. After optimization and validation with IDEXX PRRS using 566 clinical sera, the DSN, DSP, and accuracy of GP5-ELISA were 81.39%, 75.96%, and 80.39%, respectively. Besides, GP5-ELISA is highly specific, showing no cross-reactions with sera against other important swine pathogens. Hence, GP5 is a good diagnostic antigen and the GP5 protein-based ELISA has the potential to be used in the field. PMID- 27760020 TI - Usefulness of Acidity and Temperature of the Rumen and Abomasum in Diagnosing SARA in Dairy Cows after Calving. AB - The aim of the research was to determine the relationship between the acidity and temperature of the contents of the reticulorumen and abomasum in the first 10 days after calving and to evaluate these factors as predictive traits for the diagnosis of subclinical acidosis. The acidity and temperature of the contents of the reticulorumen and abomasum were measured using specific smaXtec boluses manufactured for animal care. According to the directions of the manufacturer, the boluses were inserted into the reticulorumen of the cows researched with the help of a specific tool. The boluses were inserted into the abomasa by way of surgery, laparotomy and abomasotomy through the right flank. The readings of 7 cows were taken on a total of 10 days, twice a day (at 9 a.m. and at 9 p.m.). In total, 140 measurements were taken. The acidity of the reticulorumen is associated with the acidity of the abomasum. The acidity of the rumen increases, if the acidity of the reticulorumen increases also. A negative correlation was observed between the pH of the contents of the abomasum and this temperature. The increase in the acidity (decrease of pH) of the contents of the reticulorumen increases its temperature and also increases the temperature of the contents of the abomasum. There is a positive statistically significant dependence between the reticulorumen content temperature and the rectal temperature. Through measurement of the ruminoreticular temperature, it is possible to predict the health status of a cow's stomach in regard to acidosis. PMID- 27760021 TI - Feeding Pregnant and Lactating Mice Rhodiola kirilowii Extracts helps to Preserve Thymus Function of their Adult Progeny. AB - Plants belonging to Rhodiola kirilowii species, members of Rhodiola genus and Crassulaceae family, grow wildly in Tibet, Mongolia and China mountains and are traditionally used as adaptogens, antidepressants and anti-inflammatory remedies. Nowadays, R. kirilowii is cultivated in some countries, also in Poland. In our previous papers we reported immuno- and angio-modulatory effects of aqueous and hydro-alcoholic extracts of radix and rhizome of this plant in non-pregnant and pregnant mice. The aim of the present study was to evaluate the effect of feeding pregnant and further lactating mice these extracts on selected thymus function parameters in adult progeny. The counts of M-30+ apoptotic cells, in the thymuses obtained from progeny of mice fed during pregnancy and lactation water or 50% water-alcoholic extract of Rhodiola kirilowii, were significantly lower (p<0.05) than apoptotic cells counts observed in the control mice. No significant differences in the counts of IL-7-positive cells in the thymuses obtained from progeny of the control mice and mothers treated with water or hydro-alcohol extracts of Rhodiola kirilowii were observed. PMID- 27760022 TI - Reproductive Performance of Rabbit does Artificially Inseminated with Semen Supplemented with GnRH Analogue [des-Gly10, D-Ala6]-LH-RH Ethylamide. AB - The aim of the study was to evaluate, the ability of a GnRH synthetic analogue [des-Gly10, D-Ala6]-LH-RH ethylamide to induce ovulation in rabbit does using intravaginal administration. A total of 138 primiparous lactating does were randomly divided into 4 groups that at the time of insemination received following treatments for ovulation induction: 1 MUg of buserelin administered intramuscularly (control group); 5 MUg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D5 group); 10 MUg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D10 group); 15 MUg of [des-Gly10, D-Ala6]-LH RH ethylamide added to the semen dose (D15 group). Kindling rates were 68.8% in D10 and 66.7% in D15 groups and were comparable to that obtained in the control group (72.2%). The kindling rate in group D5 (29.4%) was significantly lower than those recorded in the other groups. The number of live born kits was not significantly affected by the ovulation induction treatment. The results of this study show that [des-Gly10, D-Ala6]-LH-RH ethylamide added directly into the semen dose can effectively stimulate ovulation in rabbits. The dose of 10 MUg of [des-Gly10, D-Ala6]-LH-RH ethylamide per doe was sufficient to produce results comparable to those obtained by intramuscular administration of buserelin. PMID- 27760023 TI - Ultrasonography and Low-field Magnetic Resonance Imaging of the Common Calcanean Tendon in a Rabbit Model for Tendinopathy Research: a Descriptive Study of Normal Anatomy. AB - In spite of recent advances in treatment protocols, tendinopathies continue to challenge orthopaedists and surgeons. Due to the complexity of both tendon injuries and the healing processes, animal models are essential for addressing fundamental questions in tendinopathy research. Diagnostic imaging could contribute to the evaluation of animal models, thus providing information, which could be translated to human tendinopathies. The objective of our study was to evaluate in situ appearance of the rabbit common calcanean tendon with ultrasonography and magnetic resonance imaging. Additionally, we sought to assess and compare the feasibility and usefulness of these techniques in a rabbit model while focusing on the imaging of the particular structures involved in calcaneal tendon disorders. Eight California rabbits were used for post-mortem sonographic and low-field magnetic resonance examination. Morphometry was performed on longitudinal sonograms and sagittal MRI scans. The craniocaudal diameter of the tendon was measured at four points of interest. Ultrasonography and magnetic resonance provided good visualisation of the tendon origin, the paratenon and the pre-Achilles fat pad. Magnetic resonance images presented in more detail the structure of the calcaneal insertion. Both modalities failed to visualise the individual components of the common calcanean tendon and the bursa of the calcaneal tendon. Statistical analysis of measurements obtained showed that the craniocaudal diameter of the common calcanean tendon in a rabbit increases significantly with a growing length from the calcaneal tuber. Both magnetic resonance and ultrasonography are feasible, and should be considered complementary, not alternative imaging techniques in a rabbit common calcanean tendon model. PMID- 27760024 TI - Development and Validation of an Analytical Method for Determination of Ergot Alkaloids in Animal Feedingstuffs with High Performance Liquid Chromatography fluorescence Detection. AB - A high performance liquid chromatography combined with fluorescence detection (HPLC-FLD) method was developed for determination of five ergot alkaloids (EA): ergometrine, ergotamine, ergocornine, ergocrypine and ergocristine in animal feedingstuffs. The method was based on the application of QuEChERS salts for extraction and modified QuEChERS dispersive SPE for the cleanup step. Alkaloids separation was performed on a C18, 250 mm x 4.6 mm, 5 MUm column with the mobile phase containing ammonium carbonate and acetonitrile. The excitation and emission wavelengths were 330 and 420 nm respectively. The method was validated according to the Commission Decision 2002/657/EC and all parameters are in agreement with the requirements of the Decision. Linearity was determined for the concentration range of 25-400 MUg/kg. The coefficient of determination (R2) for all curves was from 0.985 to 0.996. The limit of detection (LOD) was in the range 3.23 to 6.53 MUg/kg and the limit of quantification (LOQ) from 11.78 to 13.06 MUg/kg. The decision limit (CCalpha) ranged from 29.56 to 43.08 MUg/kg and detection capability (CCbeta) from 40.65 to 51.01 MUg/kg. The highest coefficient of variation (CV) for repeatability was 14.3% and for reproducibility 15.4%. PMID- 27760025 TI - Use of Fluorescence Quantitative Polymerase Chain Reaction (PCR) for the Detection of Escherichia coli Adhesion to Pig Intestinal Epithelial Cells. AB - An efficient and accurate method to test Escherichia coli (E. coli) adhesion to intestinal epithelial cells will contribute to the study of bacterial pathogenesis and the function of genes that encode receptors related to adhesion. This study used the quantitative real-time polymerase chain reaction (qPCR) method. qPCR primers were designed from the PILIN gene of E. coli F18ab, F18ac, and K88ac, and the pig beta-ACTIN gene. Total deoxyribonucleic acid (DNA) from E. coli and intestinal epithelial cells (IPEC-J2 cells) were used as templates for qPCR. The 2-DeltaDeltaCt formula was used to calculate the relative number of bacteria in cultures of different areas. We found that the relative numbers of F18ab, F18ac, and K88ac that adhered to IPEC-J2 cells did not differ significantly in 6-, 12-, and 24-well culture plates. This finding indicated that there was no relationship between the relative adhesion number of E. coli and the area of cells, so the method of qPCR could accurately test the relative number of E. coli. This study provided a convenient and reliable testing method for experiments involving E. coli adhesion, and also provided innovative ideas for similar detection methods. PMID- 27760026 TI - 7S Fragment of Type IV Collagen as a Serum Marker of Canine Liver Fibrosis. AB - The aim of this study was to assess whether the serum levels of the 7S fragment of type IV collagen may aid in diagnosing liver fibrosis in dogs. The study was carried out on 20 dogs with liver disease. Serum levels of the 7S fragment of type IV collagen were measured in all dogs. The analysis showed that healthy dogs and dogs with type 1, 2 and 3 liver fibrosis had low serum concentrations of the 7S fragment of type IV collagen compared to dogs with type 4 liver fibrosis. The study revealed that the assessment of serum levels of the 7S fragment of type IV collagen is useful in the diagnosis of advanced liver fibrosis and cirrhosis. PMID- 27760027 TI - Vertical Transmission of PCV2b to Fetuses in Sows Intramuscularly Infected with PCV2b. AB - In order to investigate whether PCV2b can be transmitted across the placenta in sows thereby causing vertical infection of fetuses, six sows in 75 day of pregnancy were either intramuscularly inoculated with a PCV2b culture supernatant (n = 4) or mock infected with cell culture supernatant (n = 2). At parturition, 3 newborn piglets from each litter were randomly selected and euthanatized prior to suckling. Samples of the mesenteric lymph nodes, spleens, kidneys, hearts and lungs were collected for PCR, histopathological and immunohistochemical assays. The results showed that the newborn piglets from PCV2b-infected sows had histopathological lesions in the tested tissues. Moreover, PCV2b antigen and DNA were detected as well. These findings therefore suggested that porcine circovirus type 2b can be transmitted across the placenta of sows, thereby leading to PCV2b vertical infection of the fetuses. PMID- 27760029 TI - Antioxidant and Anti-inflammatory Activities of a Commercial Noni Juice revealed by Carrageenan-induced Paw Edema. AB - This study aimed to investigate antioxidant and anti-inflammatory activities of a commercial product of noni (Morinda citrifolia) juice. Carrageenan-induced rat paw edema was employed as inflammatory model. One control and three experimental groups were formed. Experimental groups were administered noni juice alone, noni juice+carrageenan, and carrageenan alone. Oxidant and antioxidant capacity were determined by d-ROMs test and BAP test, respectively. Plasma concentrations of endothelin-1 and leptin were measured by ELISA. Measurements were performed at zero time and 2nd hour of inflammation. Oxidant capacity decreased in noni received groups at 2nd hour (p=0.019). Antioxidant capacity of the group which received noni alone was found to be higher at 2nd hour (p=0.036). Plasma concentrations of endothelin-1 and leptin were notably lower in noni-received groups (p=0.001 and p=0.021, respectively). The results show that the commercial noni juice investigated has pronounced antioxidant and anti-inflammatory activities. PMID- 27760028 TI - The Effectiveness of Modified Seton and Modified Combat Gauze in Controlling Severe Hemorrhaging during Operations of Uniformed Services. AB - Hemorrhaging from large vessels poses a serious problem in emergency situations when blood loss needs to be immediately controlled. The aim of the study was to compare the effectiveness of two hemostatic dressings in controlling bleeding from a surgically punctured femoral artery. The study was performed on thirteen pigs divided into two groups, of six and seven pigs, respectively. Combat gauze covered with ChitoClear hqg 95 chitosan and Protanal LF10/60 FT sodium alginate was used in the first group, seton covered with identical substances was uses in the second group. Selected hemostatic dressing was applied to the wound 20 seconds after incision and then removed at regular time intervals to evaluate hemostasis. Modified seton was characterized by a shorter time to hemostasis than combat gauze. The result of this experiment indicate that modified seton proved to be a more effective dressing than modified combat gauze. PMID- 27760030 TI - Comparison of High-field and Low-field Magnetic Resonance Imaging of Stifle Joint Disorders in Dogs. AB - The most common cause of hindlimb lameness in dogs is cranial cruciate ligament rupture. In 48-77.3% of the population this trauma leads to secondary damage of the meniscus. Depending on the magnetic strength of the used device, different diagnostic accuracy can be achieved. The examination sensitivity of magnetic resonance imaging is affected by many factors which are independent of diagnostic strength, such as correct positioning of the patient, size of the stifle joint examined, or selection of the right protocol of sequences. Sensitivity of meniscus damage detection was 100% and 90%, respectively, in high- and low-field magnetic resonance. The best results were reported during examination of the stifle in dogs above 10 kg b.w. at a flexion angle of 145 degrees , and in sagittal and dorsal planes. Regardless of the magnetic strength applied, imaging of the whole cranial cruciate ligament is difficult. Moreover, MRI allows the detection of the first signs of osteoarthritis, which were observed 4 and 6 weeks after rupture of the cranial cruciate ligament using high and low-field MRI. This also applies to lesions in the subchondral bone or a bone marrow which occurred in association with insufficiency of the stifle joint, and were mainly localized in the epiphysis of the femur and tibia. The present article provides a comparison of different examination protocols and images of damaged stifle structures, such as menisci, ligaments and bones of the stifle joint visualized with low-field and high-field magnetic resonance. Magnetic resonance arthrography is also discussed. PMID- 27760031 TI - Non-invasive Pregnancy Diagnosis from Urine by the Cuboni Reaction and the Barium Chloride Test in Donkeys (Equus asinus) and Alpacas (Vicugna pacos). AB - The aim of the research was to evaluate two chemical tests for non-invasive pregnancy diagnosis from urine, the Cuboni reaction and the barium chloride test, in donkeys (Equus asinus) and alpacas (Vicugna pacos). The research was carried out from April 2013 to September 2014. Urine samples were collected on five private Czech farms from 18 jennies and 12 alpaca females. Urine was collected non-invasively into plastic cups fastened on a telescopic rod, at 6-9 week intervals. In total, 60 and 54 urine samples from alpacas and jennies, respectively, were collected. The Cuboni reaction was performed by the State Veterinary Institute Prague. The barium chloride test was done with 5 ml of urine mixed together with 5 ml of 1% barium chloride solution. Results of the Cuboni reaction were strongly influenced by the reproductive status of jennies; the test was 100% successful throughout the second half of pregnancy. However, no relationship was found between the real reproductive status of alpaca females and results of the Cuboni reaction. It was concluded that the barium chloride test is not suitable for pregnancy diagnosis either in donkeys, due to significant influence of season on the results, or in alpacas, because no relationship between results of the test and the reproductive status of alpaca females was found. In conclusion, the Cuboni reaction has potential to become a standard pregnancy diagnostic method in donkeys. PMID- 27760032 TI - Efficacy of Topical Therapy with Newly Developed Terbinafine and Econazole Formulations in the Treatment of Dermatophytosis in Cats. AB - In the field of veterinary dermatology dermatophytosis is one of the most frequently occurring infectious diseases, therefore its treatment should be effective, convenient, safe and inexpensive. The aim of this study was to evaluate the efficacy of newly developed topical formulations in the treatment of cats with dermatophytosis. Evaluation of clinical efficacy and safety of terbinafine and econazole formulations administered topically twice a day was performed in 40 cats. Cats, suffering from the most widely spread Microsporum canis-induced dermatophytosis and treated with terbinafine hydrochloride 1% cream, recovered within 20.3+/-0.88 days; whereas when treated with econazole nitrate 1% cream, they recovered within 28.4+/-1.14 days. A positive therapeutic effect was yielded by combined treatment with local application of creams and whole coat spray with enilconazole 0.2% emulsion "Imaverol". Most cats treated with econazole cream revealed redness and irritation of the skin at the site of application. This study demonstrates that terbinafine tended to have superior clinical efficacy (p<0.001) in the treatment of dermatophytosis in cats compared to the azole tested. PMID- 27760033 TI - Cyclosporin A Treatment in Intrinsic Canine Atopic Dermatitis (Atopic-like Dermatitis): Open Trial Study. AB - In this study, dogs were separated into two groups and treated with immunosuppressant (Cyclosporin A: CsA). The first group was the canine atopic dermatitis (CAD) group, which is similar to extrinsic atopic dermatitis (AD) in humans (treated with a CsA dose of 2.5-5.5 mg/kg, n=8), and the second group was the canine atopic-like dermatitis (ALD) group, which is similar to intrinsic AD in humans (treated with a CsA dose of 2.5-6.5 mg/kg, n=14). The canine atopic dermatitis extent and severity index (CADESI)-4 was evaluated before treatment (PRE) and after treatment (POST) to assess the effectiveness of CsA for the two groups. In the CAD group, CADESI-4 showed no change (PRE:79+/-29, POST:77+/-28) and out of the eight dogs, no dogs showed complete remission, three dogs showed partial remission, and five dogs showed no effect. Whereas in the ALD group, CADESI-4 showed a significant reduction (PRE: 61+/-42, POST: 32+/-25, p<0.01) and out of the 14 dogs, 11 dogs showed complete remission, two dogs showed partial remission, and one dog showed no effect. The results indicate that the immunosuppressant showed effectiveness for the dogs diagnosed with ALD. One dog had to be treated for a year and eight months, which was the longest period in the study, this dog presented with hyperplasia of the lymphoidgland and mammary tumor. PMID- 27760034 TI - Application of Matrix-assisted Laser Desorption Ionization Time-of-flight Mass Spectrometry for Identification of Coagulase-negative Staphylococci Isolated from Milk of Cows with Subclinical Mastitis. AB - The aim of this study was to use matrix-assisted laser desorption ionization time of-flight mass spectrometry (MALDI-TOF MS) for the identification of coagulase negative staphylococci (CNS) isolated from the milk of cows with subclinical mastitis. The study material consisted of 33 isolates of CNS, identified by the results of API Staph tests, obtained from the milk of cows with subclinical mastitis. Based on the spectra analyses, MALDI-TOF MS tests of 33 bacterial samples allowed identification of the microorganisms in 27 cases (81.8%). The most frequent cause of subclinical mastitis was found to be Staphylococcus sciuri (39%), while S. vitulinus was detected in 15% of the milk samples. The results obtained indicate that MALDI-TOF MS can be used for the identification of CNS isolated from bovine mastitis as a method supplementary to biochemical tests. PMID- 27760035 TI - Association between SOX5 Genotypes and Semen Quality in Polish Holstein-Friesian Bulls. AB - The aim of this study was to evaluate the effect of C/T missense mutation (SOX5) gene on selected parameters of non-frozen semen in Polish Holstein - Friesian bulls. Three hundred and sixty eight bulls were genotyped by the PCR-Rsa I technique. Semen was collected and evaluated by standardized procedure used in an AI station. Significant associations were found between SOX5 genotypes and sperm concentrations (p=0.020) and sperm motility (p=0.014). Bulls with TT genotype had the lowest values of both traits. Our results demonstrate that C/T missense mutation within the SOX5 gene is involved in bull sperm quality. PMID- 27760036 TI - Three-step Anti-aMPV IgA Expression Profile Evaluation in Turkeys of Different Immunological Status after TRT Vaccination. AB - Maternally derived antibodies (MDA) don not protect turkeys against rhinotracheitis (TRT) but high MDA influences upper respiratory tract (URT) immunity stimulation after avian Metapneumovirus (aMPV) vaccination. Humoral immunity can not be considered as an indicator of protection against TRT, but specific antibodies inhibit aMPV replication and alleviate the course of TRT. Scarce reports indicate the role of IgA in protection against TRT. The aim of our study was to investigate the impact of MDA on stimulation, antigen specificity acquisition of B lymphocytes, and the production of specific IgA after TRT vaccination of turkeys. The results of our study indicate that MDA on the day of TRT vaccination causes disturbances at different levels of specific humoral immunity expression including antigen specificity acquisition of B IgA+ lymphocytes as well as production and secretion of IgA. Vaccine immunity against aMPV associated with sIgA is well expressed in birds not possessing MDA on the day of TRT vaccination, whereas it is inhibited in MDA+ birds. These results corroborate our previous findings and indicate that MDA could be responsible for TRT vaccination failure. These findings could explain the observed frequency of TRT field outbreaks despite aMPV vaccination of turkey flocks. PMID- 27760037 TI - Serological Survey for RHD Antibodies in Rabbits from Two Types of Rabbit Breeding Farms. AB - Seroprevalence studies of RHDV antibodies in domestic rabbits were conducted between 2008-2014. A total of 12,169 sera from the provinces of central, southern and south-east Poland, including 7,570 samples collected from mixed-breed rabbits reared in smallholder farms and nearly 4,600 sera taken mainly from unvaccinated rabbits kept in industrial farms, were examined using ELISA tests. Additionally, cross-reactivity of selected tested and control archival sera using both classic RHDV and RHDVa antigens was determined by HI assay. The overall seroprevalence was 13.3%. In rabbits with unkown history of immunisation or RHD infection which came from small farms, RHDV antibodies were detected in 6.1% ranging between 1.0% to 17.2% of animals. In rabbits of the same group, but with a declared vaccination status, or confirmed exposure to an infectious virus, or coming from exposed females, the seroprevalence ranged from 83% to 100%. Among unvaccinated meat rabbits aged 71 to 90 days from industrial farms, low (1.85%, 4.17%, 11%), medium (34%, 54%) or high rates (98.7%) of seropositivity were detected. The seroconversion recorded in adult vaccinated females from industrial farms was 70% and 95%. Generally, the antibody levels examined by ELISAs and HI were comparable. However, a number of sera from the rabbits from small farms, as well as archival sera, showed clear differences. Several-fold differences in antibody titers, evidenced mainly in the postoutbreak sera, indictaed the contact of animals with RHDVa antigen. The overall results of the survey revealed a great proportion of seronegative rabbits potentially highly susceptible to RHD infection. In combination with the emergence of a novel pathogenic RHD virus type (RHDV2), it poses a severe risk of a next wave of fatal disease cases spreading in the native population of domestic rabbits, especially in farms with a traditional system of husbandry. PMID- 27760038 TI - Bacterial Contamination of Boar Semen and its Relationship to Sperm Quality Preserved in Commercial Extender Containing Gentamicin Sulfate. AB - This study was designed to determine the degree and type of bacterial contamination in boar semen (79 ejaculates from Large White and Landrace boars) and its consequences for sperm quality during storage (27 extended semen samples, 16 degrees C for five days) under practical conditions of artificial insemination (AI). The results revealed the presence of aerobic bacteria in 99% of the ejaculates (from 80 to 370 *106 colony-forming units/mL). Most of the ejaculates contained two or three bacterial contaminants, while the Staphylococcus, Streptococcus, and Pseudomonas bacterial genera were most frequently isolated. Also detected were Enterobacter spp., Bacillus spp., Proteus spp., Escherichia coli, P. fluorescens, and P. aeruginosa. In general, the growth of certain bacterial types isolated prior to semen processing (Enterobacter spp., E. coli, P. fluorescens, and P. aeruginosa) was not discovered on different days of storage, but fluctuations (with a tendency towards increases) were found in the frequencies of Bacillus spp., Pseudomonas spp., and Staphylococcus spp. isolates up to the end of storage. Semen preserved for five days exhibited decreases in sperm motility and increases in the average number of total aerobic bacteria; this was associated with sperm agglutination, plasma membrane disruption, and acrosome damage. We inferred that, due to the different degrees and types of bacterial contaminants in the boar ejaculates, the inhibitory activity of some antimicrobial agents used in swine extenders (such as gentamicin sulfate) may be limited. Because such agents can contribute to the overgrowth of certain aerobic bacteria and a reduction in the quality of stored semen, procedures with high standards of hygiene and microbiological control should be used when processing boar semen. PMID- 27760039 TI - Effects of Neuromedin S on the Proliferation of Splenic Lymphocytes and the Cytokine Secretion by Pulmonary Alveolar Macrophages in Pigs in vitro. AB - Neuromedin S (NMS), a 36-amino acid neuropeptide, has been found to be involved in the regulation of the endocrine activity. It has been also detected in immune tissues in mammals, what suggests that NMS may play an important role in the regulation of immune response. The aim of this study was to demonstrate the presence of NMS receptor 1 (NMU1R) and effect of NMS in pig splenic lymphocytes (SPLs) and pulmonary alveolar macrophages (PAMs). The presence of NMU1R in pig SPLs and PAMs was respectively confirmed by reverse transcription-polymerase chain reaction (RT-PCR), western blot analysis and immunocytochemical methods. Furthermore, SPL proliferation was analyzed using the 3-(4,5)-dimethyl-thiahiazo (-2-yl)-3,5-di-phenytetrazoliumromide (MTT) method. Additionally, the secretion of interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) in PAMs was all measured by enzyme-linked immunosorbent assay (ELISA) kits. In the present study, the results of RT-PCR and western blot analysis revealed that NMU1R mRNA and protein were both expressed in pig SPLs and PAMs, and the immunocytochemical investigations further revealed that the positive signal of NMU1R immunoreactivity was observed in plasma membranes of both SPLs and PAMs. In the in vitro study, we found that at concentrations of 0.001-1000 nM NMS alone or combined with lipopolysaccharide or phytohemagglutinin significantly increased SPL proliferation. Application of ELISA method showed that NMS could induce the secretion of the pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha in PAMs. These results suggest that NMS can act as a potently positive pro-inflammatory factor and immunomodulatory agent that affects the immune response of immune cells by combining with its receptor NMU1R. PMID- 27760040 TI - Comparative Efficacy of Silymarin and Choline Chloride (Liver Tonics) in Preventing the Effects of Aflatoxin B1 in Bovine Calves. AB - Aflatoxins are secondary metabolites produced by Aspergillus spp. which are injurious to animals and humans The aim of this study was to determine the effects of aflatoxin B1 (AFB1) on Average Daily Feed Intake (ADFI), Average Daily Weight Gain (ADWG), haematological and serum biochemical responses of Bovine Calves and to determine the comparative efficacy of two different liver tonics against AFB1. Twenty seven calves were selected from herd and divided into 3 groups. All calves were fed with 1.0 mg/kg AFB1 for a period of 10 days. After that they were fed with liver tonics: Silymarin fed at a rate of 600 mg/kg and Choline chloride 500 mg/kg for 7 days. The results indicate that the ADFI and ADWG of AFB1 treated calves decreased significantly. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine significantly increased due to AFB1. In haematology the total erythrocyte count (TEC), total leukocyte count (TLC), haemoglobin concentration (HGB), haematocrit levels (HCT), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV) and mean corpuscular haemoglobin concentration (MCHC), lymphocyte %, neutrophil % and monocyte % significantly decreased in AFB1 treated calves after 10 days of feeding. Both liver tonics significantly (p<0.05) improved all the parameters, including ADFI, ADWG, hematologial and serum biochemical test. However, Silymarin comparatively more efficiently ameliorate the effects induced by AFB1 than choline chloride. PMID- 27760041 TI - Comparison of Fecal Egg Counts and ELISA for the Diagnosis of Dicrocoelium Dendriticum Infection. AB - From economical point of view, Dicrocoelium Dendriticum (D. dendriticum) causes a lot of damages to the livestock industry annually. So, the rapid diagnosis of infection is very important. The diagnosis is based on egg per count of feces (EPG) test because detection according to clinical symptoms is difficult. Since EPG is not accurate and sensitive, the serological methods become important for the diagnosis of this parasite as they are more accurate in comparison to EPG test and they are able to diagnose infection in a short time. In this study, somatic and Excretory-secretory antigens (EsAg) were isolated. The ELISA test was set up according to positive and negative sera and the results which were obtained compared to those obtained by the EPG test. The prevalence of infection in 550 samples by ELISA and EPG methods were 56% and 7% respectively, which shows the significant difference between these methods in examining the rate of infection. Based on the results, the specificity and sensitivity in ELISA test were 95% and 94%, respectively. The results showed that the ELISA is a more reliable test in comparison to EPG test for the rapid diagnosis of D. dendriticum infection. PMID- 27760042 TI - Use of Elements of the Stewart Model (Strong Ion Approach) - SID3, SID4, Atot/A-, SIDe and SIG for the Diagnostics of Respiratory Acidosis in Brachycephalic Dogs. AB - : Buffer systems of blood and tissues, which have the ability to bind with and give up hydrogen ions, participate in maintaining the acid-base balance (ABB) of the organism. According to the classic model, the system of carbonic acid and bicarbonates, where the first component serves the role of an acid and the second a base, determines plasma pH. The so-called Stewart model, which assumes that ions in blood serum can be separated into completely dissociated - nonbuffer and not dissociated - buffer ions which may give up or accept H+ions, also describes the ABB of the organism. The goal of the study was to find out whether, during respiratory acidosis, the values of SID3, SID4, Atot/A-, SIDe and SIG change. The study was carried out on 60 adult dogs of the boxer breed (32 males and 28 females) in which, on the basis of an arterial blood test, respiratory acidosis was found. A strong overgrowth of the soft palate tissue requiring a surgical correction was the cause of the ABB disorder. Prior to surgery and on the 14th day after the surgery, venous and arterial blood was drawn from each dog. ABB parameters were determined in the arterial blood sample: the blood pH, pCO2 and HCO3-. In the venous blood, concentration of Na+, K+, Cl-, lactate-, albumins, and Pinorganic was determined. On the basis of the obtained data, the values of SID3, SID4, SIDe, A- and SIG, before and after the surgery, were calculated. In spite of the fact that the average concentration of ions, albumins, Pinorganic and lactate in the blood serum of dogs before and after the surgical procedure was similar and within the physiological norms, the values of SID3, SIDe and SIG, calculated on the basis of the former, displayed statistically significant differences. CONCLUSION: On the basis of the results obtained, it can be stated that the values of SID3, SIDe and SIG change during respiratory acidosis and may be helpful in the diagnostics of ABB disorders in brachycephalic dogs. PMID- 27760043 TI - Detection of Schmallenberg Virus RNA in Bull Semen in Poland. AB - The detection of Schmallenberg virus (SBV) in the breeding bull semen raised the question of the possibility of venereal transmission of SBV which could result in cost-intensive restrictions in the trade of bovine semen. In order to evaluate the presence of SBV RNA in bovine semen, 131 bull semen samples from four locations in Poland collected between 2013 and 2015 were analysed by RT-PCR for viral RNA. SBV RNA was detected in 5.3% of the samples. The study has revealed that application of an appropriate RNA extraction method is crucial to detect virus excretion via semen. PMID- 27760044 TI - The relationship between alexithymia and general symptoms of pregnant women. AB - INTRODUCTION: Alexithymia is related to poor emotion regulation strategies as well as higher rates of somatic disorders. The aim of the present study was to assess the relationship between alexithymia and the general symptoms experienced by the pregnant women. MATERIAL AND METHODS: In a cross-sectional study, a total number of 350 pregnant women, attending the antenatal clinics, were randomly selected. A standardized Toronto Alexithymia Scale (TAS-20) was used to elicit responses from participants with alexithymia. The general symptoms scores were measured using the Iranian version of the Symptom Checklist-90-Revised, 90 items. The statistical associations between alexithymia and the general symptoms were then investigated through liner regression. RESULTS: A total number of 186 of pregnant women with alexithymia were compared with the 164 cases without alexithymia. The high scores on Total Toronto Alexithymia Scale-20 and the difficulties to identify feelings emerged as major predictors for the current psychopathology on all SCL-90-R subscales. The difficulty in describing feelings features of alexithymia is positively associated with interpersonal sensitivity and paranoid ideation, but it is inversely associated with the phobic anxiety dimension. CONCLUSION: This study showed that the pregnant women with difficulty in describing feelings features of alexithymia are likely to show a broad range of psychopathology. Therefore, it is necessary to emphasize the benefits of specific psychotherapeutic techniques to improve self-differentiation so that we can reduce the likelihood of mental illnesses in pregnant women. PMID- 27760046 TI - The long noncoding RNA Tug1 connects metabolic changes with kidney disease in podocytes. AB - An increasing amount of evidence suggests that metabolic alterations play a key role in chronic kidney disease (CKD) pathogenesis. In this issue of the JCI, Long et al. report that the long noncoding RNA (lncRNA) taurine-upregulated 1 (Tug1) contributes to CKD development. The authors show that Tug1 regulates mitochondrial function in podocytes by epigenetic targeting of expression of the transcription factor PPARgamma coactivator 1alpha (PGC-1alpha, encoded by Ppargc1a). Transgenic overexpression of Tug1 specifically in podocytes ameliorated diabetes-induced CKD in mice. Together, these results highlight an important connection between lncRNA-mediated metabolic alterations in podocytes and kidney disease development. PMID- 27760045 TI - Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. AB - Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3-/- mice. Although Neil3-/- mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3-/- mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity. PMID- 27760047 TI - Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. AB - The adoptive transfer of T cells that have been genetically modified to express a CD19-specific chimeric antigen receptor (CAR) is effective for treating human B cell malignancies. However, the persistence of functional CD19 CAR T cells causes sustained depletion of endogenous CD19+ B cells and hypogammaglobulinemia. Thus, there is a need for a mechanism to ablate transferred T cells after tumor eradication is complete to allow recovery of normal B cells. Previously, we developed a truncated version of the epidermal growth factor receptor (EGFRt) that is coexpressed with the CAR on the T cell surface. Here, we show that targeting EGFRt with the IgG1 monoclonal antibody cetuximab eliminates CD19 CAR T cells both early and late after adoptive transfer in mice, resulting in complete and permanent recovery of normal functional B cells, without tumor relapse. EGFRt can be incorporated into many clinical applications to regulate the survival of gene-engineered cells. These results support the concept that EGFRt represents a promising approach to improve safety of cell-based therapies. PMID- 27760048 TI - mTOR has distinct functions in generating versus sustaining humoral immunity. AB - Little is known about the role of mTOR signaling in plasma cell differentiation and function. Furthermore, for reasons not understood, mTOR inhibition reverses antibody-associated disease in a murine model of systemic lupus erythematosus. Here, we have demonstrated that induced B lineage-specific deletion of the gene encoding RAPTOR, an essential signaling adaptor for rapamycin-sensitive mTOR complex 1 (mTORC1), abrogated the generation of antibody-secreting plasma cells in mice. Acute treatment with rapamycin recapitulated the effects of RAPTOR deficiency, and both strategies led to the ablation of newly formed plasma cells in the spleen and bone marrow while also obliterating preexisting germinal centers. Surprisingly, although perturbing mTOR activity caused a profound decline in serum antibodies that were specific for exogenous antigen or DNA, frequencies of long-lived bone marrow plasma cells were unaffected. Instead, mTORC1 inhibition led to decreased expression of immunoglobulin-binding protein (BiP) and other factors needed for robust protein synthesis. Consequently, blockade of antibody synthesis was rapidly reversed after termination of rapamycin treatment. We conclude that mTOR signaling plays critical but diverse roles in early and late phases of antibody responses and plasma cell differentiation. PMID- 27760049 TI - Helicase CHD4 is an epigenetic coregulator of PAX3-FOXO1 in alveolar rhabdomyosarcoma. AB - A vast number of cancer genes are transcription factors that drive tumorigenesis as oncogenic fusion proteins. Although the direct targeting of transcription factors remains challenging, therapies aimed at oncogenic fusion proteins are attractive as potential treatments for cancer. There is particular interest in targeting the oncogenic PAX3-FOXO1 fusion transcription factor, which induces alveolar rhabdomyosarcoma (aRMS), an aggressive cancer of skeletal muscle cells for which patient outcomes remain dismal. In this work, we have defined the interactome of PAX3-FOXO1 and screened 60 candidate interactors using siRNA mediated depletion to identify candidates that affect fusion protein activity in aRMS cells. We report that chromodomain helicase DNA binding protein 4 (CHD4), an ATP-dependent chromatin remodeler, acts as crucial coregulator of PAX3-FOXO1 activity. CHD4 interacts with PAX3-FOXO1 via short DNA fragments. Together, they bind to regulatory regions of PAX3-FOXO1 target genes. Gene expression analysis suggested that CHD4 coregulatory activity is essential for a subset of PAX3-FOXO1 target genes. Depletion of CHD4 reduced cell viability of fusion-positive but not of fusion-negative RMS in vitro, which resembled loss of PAX3-FOXO1. It also caused specific regression of fusion-positive xenograft tumors in vivo. Therefore, this work identifies CHD4 as an epigenetic coregulator of PAX3-FOXO1 activity, providing rational evidence for CHD4 as a potential therapeutic target in aRMS. PMID- 27760052 TI - Genetic cause of immune dysregulation - one gene or two? AB - Some autoimmune disorders are monogenetic diseases; however, clinical manifestations among individuals vary, despite the presence of identical mutations in the disease-causing gene. In this issue of the JCI, Massaad and colleagues characterized a seemingly monogenic autoimmune disorder in a family that was linked to homozygous loss-of-function mutations in the gene encoding the endonuclease Nei endonuclease VIII-like 3 (NEIL3), which has not been previously associated with autoimmunity. The identification of an unrelated healthy individual with the same homozygous mutation spurred more in-depth analysis of the data and revealed the presence of a second mutation in a known autoimmune associated gene. Animals lacking Neil3 had no overt phenotype, but were predisposed to autoantibody production and nephritis following exposure to the TLR3 ligand poly(I:C). Together, these results support further evaluation of the drivers of autoimmunity in supposedly monogenic disorders. PMID- 27760050 TI - Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. AB - Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C epsilon (PKCepsilon) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCepsilon inhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site Thr1160 as a PKCepsilon substrate in the functionally critical INSR kinase activation loop. We hypothesized that Thr1160 phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCepsilon in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue Thr1150 (InsrT1150A mice) were protected from high fat diet-induced hepatic insulin resistance. InsrT1150A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR Thr1160 phosphorylation and provide further mechanistic links between PKCepsilon and INSR in mediating NAFLD-induced hepatic insulin resistance. PMID- 27760051 TI - Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy. AB - The regulatory roles of long noncoding RNAs (lncRNAs) in transcriptional coactivators are still largely unknown. Here, we have shown that the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha, encoded by Ppargc1a) is functionally regulated by the lncRNA taurine-upregulated gene 1 (Tug1). Further, we have described a role for Tug1 in the regulation of mitochondrial function in podocytes. Using a murine model of diabetic nephropathy (DN), we performed an unbiased RNA-sequencing (RNA-seq) analysis of kidney glomeruli and identified Tug1 as a differentially expressed lncRNA in the diabetic milieu. Podocyte-specific overexpression (OE) of Tug1 in diabetic mice improved the biochemical and histological features associated with DN. Unexpectedly, we found that Tug1 OE rescued the expression of PGC-1alpha and its transcriptional targets. Tug1 OE was also associated with improvements in mitochondrial bioenergetics in the podocytes of diabetic mice. Mechanistically, we found that the interaction between Tug1 and PGC-1alpha promotes the binding of PGC-1alpha to its own promoter. We identified a Tug1-binding element (TBE) upstream of the Ppargc1a gene and showed that Tug1 binds with the TBE to enhance Ppargc1a promoter activity. These findings indicate that a direct interaction between PGC-1alpha and Tug1 modulates mitochondrial bioenergetics in podocytes in the diabetic milieu. PMID- 27760053 TI - A murder mystery in the liver: who done it and how? AB - Hepatocyte death, which can be apoptosis or necrosis depending on the context, is a prominent feature of liver disease. The lectin concanavalin A (ConA) activates immune cells, resulting in inflammatory liver injury and hepatocyte necrosis. In this issue of the JCI, Gunther et al. demonstrate that the pseudokinase mixed lineage kinase domain-like protein (MLKL) participates in hepatocyte death in ConA injury and that MLKL-mediated death is independent of the receptor interacting protein kinase RIPK3. RIPK3 was absent in hepatocytes, and MLKL deficient mice, but not RIPK3-deficient mice, were protected from ConA-induced liver injury. The authors also present evidence that an unidentified kinase activates MLKL, as RIPK1 bound MLKL but did not phosphorylate it. Moreover, ConA rapidly induced MLKL, mediated by the IFN-gamma/STAT1 pathway, while activation and translocation to the plasma membrane required TNF. Increased phospho-MLKL staining in liver biopsies from patients with autoimmune hepatitis suggests a role for MLKL in this disease. This study describes a previously unrecognized form of cell death in the liver that should be further explored as a potential therapeutic target in immune-mediated liver injury. PMID- 27760054 TI - Central Sensitization: A Clinical Conundrum. PMID- 27760055 TI - Patient Recollection of ICU Procedural Pain and Post ICU Burden: The Memory Study. AB - OBJECTIVE: To assess patients' recollections of in-ICU procedural pain and its impact on post-ICU burden. DESIGN: Prospective longitudinal study of patients who underwent ICU procedures. SETTING: Thirty-four ICUs in France and Belgium. PATIENTS: Two hundred thirty-six patients who had undergone ICU procedures. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients were interviewed 3-16 months after hospitalization about: 1) recall of procedural pain intensity and pain distress (on 0-10 numeric rating scale); 2) current pain; that is, having pain in the past week that was not present before hospitalization; and 3) presence of traumatic stress (Impact of Events Scale). For patients who could rate recalled procedural pain intensity (n = 56) and pain distress (n = 43), both were significantly higher than their median (interquartile range) in ICU procedural pain scores (pain intensity: 5 [4-7] vs 3 [2.5-5], p < 0.001; pain distress: 5 [2-6] vs 2 [0-6], p = 0.003, respectively.) Current pain was reported in 14% of patients. When comparing patients with and without current pain, patients with current pain recalled even greater ICU procedural pain intensity and pain distress scores than patients without current pain: pain intensity, 8 (6 8) versus 5 (3.25-7); p = 0.002 and pain distress, 7 (5-8) versus 4 (2-6); p = 0.01, respectively. Patients with current pain also had significantly higher Impact of Events Scale scores than those without current pain (8.5 [3.5-24] vs 2 [0-10]; p < 0.001). CONCLUSION: Many patients remembered ICU, with far fewer able to rate procedure-associated pain. For those able to do so, recalled pain intensity and pain distress scores were significantly greater than reported in ICU. One in seven patients was having current pain, recalling even higher ICU procedural pain scores and greater traumatic stress when compared with patients without current pain. Studies are needed to assess the impact of ICU procedural pain on post-ICU pain recall, pain status over time, and the relationship between postdischarge pain status and post-ICU burden. PMID- 27760056 TI - Experimental Study on the Efficacy of Site-Specific PEGylated Human Serum Albumins in Resuscitation From Hemorrhagic Shock. AB - OBJECTIVES: To evaluate the resuscitative efficacy and the effect on reperfusion injury of two site-specific PEGylated human serum albumins modified with linear or branched PEG20kDa, compared with saline, 8% human serum albumin and 25% human serum albumin, in a hemorrhagic shock model. SETTING: Laboratory. SUBJECTS: Male Wistar rats. DESIGN: Prospective study. INTERVENTIONS: Rats were bled to hemorrhagic hypovolemic shock and resuscitated with different resuscitation fluids. MEASUREMENTS AND MAIN RESULTS: The mean arterial pressure and blood gas variables were measured. Hemorheology analysis was performed to evaluate the influence of resuscitation on RBCs and blood viscosity. The microvascular state was indirectly characterized in terms of monocyte chemotactic protein-1 and endothelial nitric oxide synthase that related to shear stress and vasodilation, respectively. The levels of inflammation-related factors and apoptosis-related proteins were used to evaluate the reperfusion injury in lungs. The results showed that PEGylated human serum albumin could improve the level of mean arterial pressure and blood gas variables more effectively at the end of resuscitation. poly(ethylene glycol) modification was able to increase the viscosity of human serum albumin to the level of effectively enhancing the expression of monocyte chemotactic protein-1 and endothelial nitric oxide synthase, which could promote microvascular perfusion. The hyperosmotic resuscitative agents including both 25% human serum albumin and PEGylated human serum albumins could greatly attenuate lung injury. No significant therapeutic advantages but some disadvantages were found for Y shaped poly(ethylene glycol) modification over linear poly(ethylene glycol) modification, such as causing the decrease of erythrocyte deformability. CONCLUSIONS: Linear high molecular weight site-specific PEGylated human serum albumin is recommended to be used as a hyperosmotic resuscitative agent. PMID- 27760057 TI - Atypical Testicular Torsion: We Must be Cautious in the Course of Manual Detorsion. AB - Testicular torsion is a common important urological emergency. Testicles usually undergo various degrees of rotation in a medial (inward) direction. Manual detorsion is a critical maneuver, allowing to prevent testis viability in patients with delay to get into the operation room. Testis torsion rarely occurs in lateral direction. It is important for patients undergoing manual detorsion. Hereby, we present a case of atypical lateral (outward) torsion who performed preoperative manual derotation. PMID- 27760058 TI - Time-of-Arrival Parametric Maps and Virtual Bolus Images Derived From Contrast Enhanced Time-Resolved Radial Magnetic Resonance Angiography Improve the Display of Brain Arteriovenous Malformation Vascular Anatomy. AB - OBJECTIVES: Time-of-arrival (TOA) maps can be derived from high-resolution 4 dimensional (4D) contrast-enhanced magnetic resonance angiography (MRA) data sets to provide a quantitative description of contrast material arrival time in each voxel. This information can further be processed to create a compressed time evolution curve that virtually shortens the contrast bolus (virtual bolus [VB]). The purpose of this project was to determine whether TOA-enhanced 4D MRA and/or VB imaging improve the display of contrast kinetics in patients with vascular disease. METHODS: High-resolution whole-brain contrast-enhanced 4D MRA examinations with 1.2-second temporal reconstruction were acquired by using radial acquisition and highly constrained projection reconstruction (radial 4D contrast-enhanced HYPRFlow, abbreviated as HFMRA in this article) in 10 patients (8 patients with arteriovenous malformations [AVM], 1 patient with an arteriovenous fistula, and 1 patient with a high-grade intracranial stenosis). The TOA for each voxel was defined as the time point when the signal intensity reached 20% of its maximum. In the first method, TOA maps were generated, color encoded, and then multiplied with the time-resolved contrast-enhanced MRA images at each time frame to form new 4D MRA images (TOA-enhanced HFMRA), which contains the contrast arrival times with defined color encoding. In the second method, each time frame was weighted by a Gaussian distribution in the time domain to form a virtual 4D bolus map. This 4D bolus map was then color-coded and multiplied with the HFMRA images to form a digital subtraction angiography (DSA) like VB, where at each time frame, only vessels with certain TOA values within the defined bolus length appear. HFMRA, TOA maps, and VB images were scored qualitatively with regard to delineation of arteries, veins, and nidus, as well as artifacts. Furthermore, diagnostic confidence and arteriovenous overlap were evaluated and compared between techniques. A comparison with DSA was performed where DSA served as the reference standard in terms of number of arterial feeders, draining veins, and Spetzler-Martin score of AVMs. In addition, TOA maps were evaluated quantitatively. RESULTS: Overall, diagnostic confidence score of TOA was significantly higher compared with that of HFMRA (P = 0.03). Virtual bolus showed significantly higher scores for overall diagnostic confidence (P = 0.02) and reduced arteriovenous overlap (0.01) compared with HFMRA. Furthermore, VB-reduced arteriovenous overlap scores were significantly higher compared with TOA (P = 0.04). Agreement regarding AVM draining veins was lower between DSA and HFMRA (kappa = 0.3) compared with TOA and VB (kappa = 0.56). Agreement regarding Spetzler-Martin score was lower between DSA and HFMRA (kappa = 0.56) compared with TOA and VB (kappa = 0.74). CONCLUSIONS: TOA-enhanced HFMRA provides serial images and time of arrival maps in one inclusive display. In this study, TOA mapping combined with Virtual Bolus imaging improved diagnostic confidence in AVM patients and facilitated arteriovenous separation. The VB method further reduced overlap of arterial and venous structures. PMID- 27760062 TI - Cognitive Interventions and Nutritional Supplements (The CINS Trial): A Randomized Controlled, Multicenter Trial Comparing a Brief Intervention With Additional Cognitive Behavioral Therapy, Seal Oil, and Soy Oil for Sick-Listed Low Back Pain Patients. AB - STUDY DESIGN: A randomized controlled trial. OBJECTIVE: The aim of this study was to evaluate whether a tailored and manualized cognitive behavior therapy (CBT) or nutritional supplements of seal oil and soy oil had any additional benefits over a brief cognitive intervention (BI) on return to work (RTW). SUMMARY OF BACKGROUND DATA: Brief intervention programs are clinically beneficial and cost effective for patients with low back pain (LBP). CBT is recommended for LBP, but evidence on RTW is lacking. Seal oil has previously been shown to have a possible effect on muscle pain, but no randomized controlled trials have so far been carried out in LBP patients. METHODS: Four hundred thirteen adults aged 18 to 60 years were included. Participants were sick-listed 2 to 10 months due to LBP. Main outcome was objectively ascertained work participation at 12-month follow up. Participants were randomly assigned to BI (n = 100), BI and CBT (n = 103), BI and seal oil (n = 105), or BI and soy oil (n = 105). BI is a two-session cognitive, clinical examination program followed by two booster sessions, while the CBT program is a tailored, individual, seven-session manual-based treatment. RESULTS: At 12-month follow-up, 60% of the participants in the BI group, 50% in the BI and CBT group, 51% in the BI and seal oil group, and 53% in the BI and soy oil group showed reduced sick leave from baseline, and had either partly or fully RTW. The differences between the groups were not statistically significant (chi = 2.54, P = 0.47). There were no significant differences between the treatment groups at any of the other follow-up assessments either, except for a significantly lower sick leave rate in the BI group than the other groups during the first 3 months of follow-up (chi = 9.50, P = 0.02). CONCLUSION: CBT and seal oil had no additional benefits over a brief cognitive intervention on sick leave. The brief cognitive intervention alone was superior in facilitating a fast RTW. LEVEL OF EVIDENCE: 2. PMID- 27760063 TI - Analysis of Segmental Mobility Following a Novel Posterior Apical Short-Segment Correction for Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A prospective, nonrandomized, multicenter study. OBJECTIVES: The purpose of this study was to evaluate the amount of motion present at instrumented but unfused segments and at motion segments adjacent to the instrumentation following application of a new posterior apical short-segment correction technique for correcting adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: High-density pedicle screw instrumentation and posterior arthrodesis of all instrumented levels is the most common surgical treatment for AIS stabilization. The consequence of long fusion is an abnormal load on adjacent levels with an increased risk of future adjacent segment degeneration. METHODS: This new system applied translational and derotational forces over a short apical segment. The short apical region was prepared for fusion while maintaining motion of unfused vertebral segments. Radiographic data were collected pre-operatively, at surgery, and at 3, 6, and 12 months after surgery. RESULTS: Twenty-one female patients, mean age of 14.2 years (10.6-16.9 years) with Lenke 1A/1B curves, were enrolled. The range of motion in the unfused instrumented segment was significantly higher than the apical fused segment (11 vs. 0.9, P < 0.001). The range of motion of unfused vertebral levels distal to the construct at one year did not differ significantly from their respective pre op values. When the analysis was extended to understand the impact of lower instrumented vertebra (LIV) on motion of unfused segments distal to the construct, it appeared that (1) the change in motion from pre-op to 12 months post-op as a function of LIV is not statistically significant; and (2) The motion of the unfused distal vertebral segments at 12 months does not statistically increase with a lower LIV. CONCLUSION: Through one year, this novel technique achieved and maintained similar AIS correction to current posterior fusion techniques while maintaining the mobility of unfused motion segments with less implant density. LEVEL OF EVIDENCE: 4. PMID- 27760065 TI - Conjunctival Cytological Alterations in Ocular Behcet Disease. AB - PURPOSE: To evaluate the ocular surface alterations and tear film functions in patients with ocular Behcet disease (BD). METHODS: This study included 48 eyes of 48 patients with inactive BD and a control group of 33 age- and sex-matched subjects. Schirmer I and tear break-up time (TBUT) tests were used to evaluate the tear film of the subjects. Impression cytology was used to evaluate morphological changes of the conjunctival surface epithelial cells. RESULTS: The mean Schirmer I test result was 11.6 +/- 5.9 mm/5 minutes and 16.1 +/- 4.6 mm/5 minutes in the Behcet and control groups, respectively. The mean TBUT test result was 9.8 +/- 5.6 seconds and 13.2 +/- 5.7 seconds in the study and control groups, respectively. The Schirmer and TBUT test results were significantly lower in the study group than in the controls (P = 0.001 and P = 0.011, respectively). The mean impression cytology score was 1.3 +/- 0.9 in the study group and significantly higher than the control group value of 0.4 +/- 0.6 (P = 0.001). CONCLUSIONS: Tear film functions and conjunctival surface epithelial morphology were significantly altered in patients with ocular BD. PMID- 27760064 TI - The Association Between Body Mass Index (BMI) and Back or Leg Pain in Patients With Spinal Conditions: Results from the Genodisc Study. AB - STUDY DESIGN: A prospective observational study. OBJECTIVE: The aim of this study was to identify the relationship between obesity, quantified by body mass index (BMI), and both back and leg pain in spinal patients. SUMMARY OF BACKGROUND DATA: Obesity and back pain are massive public health problems. Given the poor correlation between pain and a pathological change in the spine, further investigation is required into other, nonpathological predictors such as obesity. METHODS: The Genodisc Study was one of the largest cross-sectional studies of patients presenting to tertiary spinal units and recruited from six centers in four European countries. In total, 2636 patients were recruited over a 5-year period between 2008 and 2013. Both back and leg pain were scored by patients in the range of 0 to 10. Linear regression was used to model the relationship between BMI and pain. Potential confounders included in the model were age, Zung Depression score, episodes of sport, gender, disability benefit, family history, previous surgery, smoking status, work type, clinical diagnosis, and relevant comorbidities. Back and leg pain outcomes were modeled separately. RESULTS: The study included 1160 men and 1349 women with a mean age of 50.9 years and mean BMI of 27.2 kg/m. In our fully adjusted model, a 5-point increase in BMI was associated with greater leg [0.19 units (95% confidence interval 0.08-0.31)] but not back [0.10 units (95% CI -0.02 to 0.22)] pain scores. Although this relationship was statically significant, given the small magnitude of the relationship, the clinical significance is limited. Similarly, female gender, heavy workload, rheumatoid arthritis, previous spine surgery, and depression were associated with higher back and leg pain. CONCLUSION: In this large observational study of spine patients presenting to tertiary European centers, obesity, as measured by increased BMI, was associated with greater leg pain. LEVEL OF EVIDENCE: 2. PMID- 27760066 TI - The Impact of Allopurinol on Patients With Acute ST Elevation Myocardial Infarction Undergoing Thrombolytic Therapy. AB - Allopurinol may have protective effects over ischemic reperfusion injury and reduce infarct size. In this randomized study, we aimed to evaluate the impact of allopurinol in patients with acute ST elevation myocardial infarction (STEMI) undergoing thrombolytic therapy. Overall, 140 patients with STEMI were randomly assigned to receive 400 mg of allopurinol or placebo before treating with streptokinase. Then, study group received 100 mg of allopurinol daily for 28 days and placebo group received placebo for the same period. ST resolution rate in 90 minutes, in-hospital mortality, and major adverse cardiac events (MACE) were compared. Compared to placebo group, patients receiving allopurinol had significantly higher rate of ST resolution rate >=50% (68.8% vs. 50%, P = 0.04) and lower levels of peak Creatine kinase (CK) (P = 0.003), Creatine Kinase-MB (CK MB) (P = 0.005), and Cardiac Troponin I (CTnI) (P < 0.001). Also, patients in allopurinol group had significantly lower rate of in-hospital MACE (P = 0.03), but there was no significant difference between groups regarding in-hospital mortality and cardiac events. In patients admitted with STEMI who are candidates of thrombolytic therapy, allopurinol is associated with better 90-minute ST resolution, lower enzymatically determined infarct size, and in-hospital MACE. More powerful studies are needed to determine the effect on mortality. PMID- 27760067 TI - Role of Asymmetrical Dimethylarginine in Diabetic Microvascular Complications. AB - Microvascular complications are the leading causes of acquired blindness, end stage renal failure, and varieties of neuropathy associated with diabetes. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is involved in endothelial dysfunction, oxidative stress, and inflammation associated with the progression of diabetic microvascular complications. Elevated ADMA has been detected in experimental animals and patients with diabetic microangiopathy like retinopathy, nephropathy, and neuropathy. In the review, we focus on the role of ADMA in the pathobiology of major microvascular complications of diabetes. PMID- 27760068 TI - Localization of Interictal Epileptic Spikes With MEG: Optimization of an Automated Beamformer Screening Method (SAMepi) in a Diverse Epilepsy Population. AB - PURPOSE: To describe and optimize an automated beamforming technique followed by identification of locations with excess kurtosis (g2) for efficient detection and localization of interictal spikes in patients with medically refractory epilepsy. METHODS: Synthetic aperture magnetometry with g2 averaged over a sliding time window (SAMepi) was performed in seven patients with focal epilepsy and five healthy volunteers. The effect of varied window lengths on detection of spiking activity was evaluated. RESULTS: Sliding window lengths of 0.5 to 10 seconds performed similarly, with 0.5- and 1-second windows detecting spiking activity in 1 of the 3 virtual sensor locations with highest kurtosis. These locations were concordant with the region of eventual surgical resection in these seven patients who remained seizure-free at 1 year. Average g2 values increased with increasing sliding window length in all subjects. In healthy volunteers, kurtosis values stabilized in data sets longer than 2 minutes. CONCLUSIONS: SAMepi using g2 averaged over 1-second sliding time windows in data sets of at least 2 minutes of duration reliably identified interictal spiking and the presumed seizure focus in these seven patients. Screening the five locations with highest kurtosis values for spiking activity is an efficient and accurate technique for localizing interictal activity using magnetoencephalography. SIGNIFICANCE: SAMepi should be applied using the parameter values and procedure described for optimal detection and localization of interictal spikes. Use of this screening procedure could significantly improve the efficiency of magnetoencephalography analysis if clinically validated. PMID- 27760069 TI - Electrodiagnosis of Lesions of Median and Ulnar Nerve Hand Sensory Branches: A Case Series. AB - INTRODUCTION: The authors have recently tested a new electrodiagnostic technique for palmar proper digital nerves sensory nerve action potentials in normal controls. Here the authors explored whether it may offer additional information in comparison to mixed nerve wrist stimulation in a series of patients. METHODS: The authors recorded palmar proper digital nerves sensory nerve action potential to selective antidromic webspace stimulation in a group of 19 patients with suspected lesions of median and ulnar nerve hand sensory branches. Coexistent carpal tunnel syndrome was present in 11 patients. RESULTS: The webspace stimulation technique offered additional information in 89% patients when compared with mixed nerve wrist stimulation. Webspace stimulation was informative even when carpal tunnel syndrome coexisted with damage to hand sensory branches and biased the interpretation of conventional wrist nerve conduction study. CONCLUSIONS: Webspace PaPDN stimulation is feasible in patients with lesion of median and ulnar nerve hand sensory branches and offer additional information in comparison with wrist-mixed nerve conduction study, also in patients with coexisting carpal tunnel syndrome. PMID- 27760070 TI - Ultrasonographic and Electrophysiological Evaluation of the Ulnar Nerve in Patients Diagnosed With Carpal Tunnel Syndrome. AB - PURPOSE: In this study, we evaluated the ulnar nerve of patients diagnosed with carpal tunnel syndrome (CTS) using electrophysiology and ultrasonography. METHODS: The study included 86 patients (136 hands) and 39 controls (78 hands) with normal electrophysiological assessment. According to Bland's classification, patients were divided into group 1 (grades 1-3 CTS) or group 2 (grades 4-6 CTS). The ulnar nerve was evaluated at the wrist using nerve conduction studies and ultrasonography. RESULTS: The sensory velocity was slower in group 2 than in group 1 (P < 0.001), slower in group 2 than in controls (P < 0.001), and slower in group 1 than in controls (P < 0.005). Although the ultrasonography results showed a reduction in the ulnar nerve cross-sectional area in group 1 compared with controls, the difference was not statistically significant. However, the reduction was significant in group 2 compared with group 1 and controls (P < 0.001). CONCLUSIONS: Based on our study results, the ulnar nerve is affected electrophysiologically and morphologically in patients with CTS, especially those with advanced-stage CTS. PMID- 27760071 TI - Isotemporal Substitution Analysis for Sedentary Behavior and Body Mass Index. AB - PURPOSE: This study examined the prospective associations of reallocating time spent in different types of sedentary behavior, physical activity, and sleep with body mass index (BMI) in children using isotemporal substitution analysis. METHODS: Chinese children in grades 1-3 were recruited to a cohort study in 2009 and were followed up over a 2-yr period. Reports were gathered from the parents on children's sedentary behavior, sleep duration, and sociodemographic variables. The reported sedentary behavior types were then grouped into three categories: screen time (e.g., watching TV), academic-related activities (e.g., doing homework), and other sedentary behaviors (e.g., sitting and talking). Moderate-to vigorous physical activity (MVPA) and light-intensity physical activity were assessed by ActiGraph accelerometry (ActiGraph, Pensacola, FL). Isotemporal substitution models were performed to examine the effects of time allocation on BMI. RESULTS: A total of 672 children (359 boys, mean age at recruitment = 7.6 yr) who had provided valid accelerometer data for at least one assessment time point were included in the analysis. Controlling for covariates and total behavior time, isotemporal substitution models indicated that the displacement of 30 min.d of other sedentary behaviors with equal amounts of screen time (B = 0.12; 95% confidence interval, 0.04-0.20) or academic-related activities (B = 0.13; 95% confidence interval, 0.04-0.21) was associated with higher BMI. Reallocating 30 min.d of MVPA with each of the sedentary behavior variables resulted in increased BMI. CONCLUSIONS: The substitution of screen time or academic-related activities with other sedentary behaviors or MVPA was associated with lower BMI in Chinese children. PMID- 27760072 TI - Pediatric Musculoskeletal Infection: Hijacking the Acute-Phase Response. AB - Tissue injury activates the acute-phase response mediated by the liver, which promotes coagulation, immunity, and tissue regeneration. To survive and disseminate, musculoskeletal pathogens express virulence factors that modulate and hijack this response. As the acute-phase reactants required by these pathogens are most abundant in damaged tissue, these infections are predisposed to occur in tissues following traumatic or surgical injury. Staphylococcus aureus expresses the virulence factors coagulase and von Willebrand binding protein to stimulate coagulation and to form a fibrin abscess that protects it from host immune-cell phagocytosis. After the staphylococcal abscess community reaches quorum, which is the colony density that enables cell-to-cell communication and coordinated gene expression, subsequent expression of staphylokinase stimulates activation of fibrinolysis, which ruptures the abscess wall and results in bacterial dissemination. Unlike Staphylococcus aureus, Streptococcus pyogenes expresses streptokinase and other virulence factors to activate fibrinolysis and to rapidly disseminate throughout the body, causing diseases such as necrotizing fasciitis. Understanding the virulence strategies of musculoskeletal pathogens will help to guide clinical diagnosis and decision-making through monitoring of acute-phase markers such as C-reactive protein, erythrocyte sedimentation rate, and fibrinogen. PMID- 27760073 TI - Posttraumatic Elbow Stiffness: A Critical Analysis Review. AB - Open and arthroscopic release are both effective surgical treatments for posttraumatic elbow stiffness. Both static and dynamic bracing are effective for increasing elbow range of motion when heterotopic ossification is not present. Some loss of immediate postoperative range of motion is expected. Recurrence of heterotopic ossification around the elbow is rare. The occurrence of ulnar nerve palsy is rare and often requires transposition. PMID- 27760074 TI - An Algorithm for Diagnosing and Treating Primary and Recurrent Patellar Instability. AB - Major anatomic risk factors for recurrent patellar instability include trochlear dysplasia, patella alta, a lateralized tibial tuberosity, and medial patellofemoral ligament insufficiency. Acute first-time patellar dislocation may be treated nonoperatively in the absence of osteochondral injury. Recurrent patellar instability often requires medial patellofemoral ligament reconstruction, with osseous procedures reserved for patients with substantial underlying anatomic abnormalities. Surgical treatment of patellar instability is complex and should be individualized to address the needs of each patient. PMID- 27760075 TI - Acute Scaphoid Fractures: A Critical Analysis Review. AB - Nondisplaced scaphoid fractures can be effectively treated nonoperatively, with union rates approaching or, in some series, exceeding the rates attained with operative intervention. The evidence supports equal outcomes when using a short arm or long arm cast for the closed treatment of nondisplaced scaphoid fractures. Also, equivalent outcomes have been demonstrated with or without a thumb spica component to the cast. Operative intervention is the recommended treatment for displaced scaphoid fractures. Advanced imaging should be obtained if clinical suspicion is present for a scaphoid fracture with negative radiographs more than 2 weeks after the injury. In some settings, it may even be more cost-effective to obtain advanced imaging sooner. PMID- 27760076 TI - The Bisphosphonate Pamidronate is an Intestinal Antiinflammatory Agent in Rat and Mouse Experimental Colitis. AB - BACKGROUND: Statins have antiinflammatory effects at the cardiovascular level because of inhibition of prenylation, which also probably underlies their therapeutic effects in preclinical models of inflammatory bowel disease. Another inhibitor of prenylation, namely alendronate, reduces colitis in rodents. In this study, we aim to explore the therapeutic potential of second-generation, nitrogen containing bisphosphonates in 3 preclinical models of colitis. METHODS: The trinitrobenzenesulfonic acid and dextran sulfate sodium models of rat colitis and the adoptive lymphocyte transfer model of colitis in mice were used. Pamidronate, alendronate, and ibandronate were tested. Treatments were administered in equimolar doses through the oral or intraperitoneal route. The effect of pamidronate on prenylation and cytokine release was assessed in vivo and in vitro. RESULTS: Pretreatment with pamidronate, but not with ibandronate or alendronate, improves chemically induced trinitrobenzenesulfonic acid and dextran sulfate sodium colitis in rats. Moreover, this beneficial effect is extended to lymphocyte transfer colitis. Pamidronate has no effect on intestinal epithelial cells in vitro in terms of cytokine/chemokine release, but enhances IFN-gamma, IL 6, and IL-10 production by T cells in coculture. Pamidronate also exerts a direct immunomodulatory effect on T cells, favoring Th1 differentiation and impairing Th17 polarization. CONCLUSIONS: Pamidronate presents antiinflammatory and immunomodulatory properties in 3 different models of experimental colitis in rodents. This effect requires oral administration and may involve T cells in the gut mucosa, although the exact mechanism is unclear. PMID- 27760077 TI - The Gut Microbiome of Pediatric Crohn's Disease Patients Differs from Healthy Controls in Genes That Can Influence the Balance Between a Healthy and Dysregulated Immune Response. AB - BACKGROUND: Exclusive enteral nutrition (EEN) is a first-line therapy in pediatric Crohn's disease (CD) thought to induce remission through changes in the gut microbiome. With microbiome assessment largely focused on microbial taxonomy and diversity, it remains unclear to what extent EEN induces functional changes that thereby contribute to its therapeutic effect. METHODS: Fecal samples were collected from 15 pediatric CD patients prior to and after EEN treatment, as well as from 5 healthy controls. Metagenomic data were obtained via next-generation sequencing, and nonhuman reads were mapped to KEGG pathways, where possible. Pathway abundance was compared between CD patients and controls, and between CD patients that sustained remission (SR) and those that did not sustain remission (NSR). RESULTS: Of 132 KEGG pathways identified, 8 pathways differed significantly between baseline CD patients and controls. Examination of these eight pathways showed SR patients had greater similarity to controls than NSR patients in all cases. Pathways fell into one of three groups: 1) no prior connection to IBD, 2) previously reported connection to IBD, and 3) known roles in innate immunity and immunoregulation. CONCLUSIONS: The microbiota of CD patients and controls represent alternative ecological states that have broad differences in functional capabilities, including xenobiotic and environmental pollutant degradation, succinate metavolism, and bacterial HtpG, all of which can affect barrier integrity and immune regulation. Moreover, our finding that SR patients were more similar to healthy controls suggests that community microbial function, as inferred from fecal microbiomes, could serve as a valuable diagnostic tool. PMID- 27760078 TI - Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease. AB - The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6 mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation. PMID- 27760079 TI - Expression of DLG1 and DLG5 in the Intestinal Epithelium of Patients with CD. PMID- 27760080 TI - Barriers to Administration of Herpes Zoster Immunization in Patients with Inflammatory Bowel Disease. PMID- 27760081 TI - Extended-release oxybutynin therapy for vasomotor symptoms in women: a randomized clinical trial. AB - OBJECTIVE: Assess effects of once-daily, extended-release oxybutynin chloride on frequency and severity of vasomotor symptoms in healthy, postmenopausal symptomatic women. METHODS: A 12-week, multicenter, double-blind, placebo controlled, phase 2 clinical trial randomized naturally postmenopausal women experiencing at least seven moderate-to-severe vasomotor symptoms daily to oxybutynin 15 mg once daily (n = 73) or placebo (n = 75). Co-primary outcomes were the change from baseline to week 12 in the frequency and severity of moderate-to-severe vasomotor symptoms. RESULTS: Significant reductions in both frequency and severity of moderate-to-severe vasomotor symptoms in women who received oxybutynin compared with placebo were observed at all weeks of treatment (P <= 0.007, all time points) through week 12. Mean changes in frequency in the oxybutynin and placebo groups were -9.48 and -4.69 episodes/d, respectively, at week 12. Mean changes in severity (scale 0-3) in the oxybutynin and placebo groups were -1.27 and -0.30, respectively, at week 12. At the end of treatment, 73% of women in the oxybutynin group and 26.1% in the placebo group rated symptom improvement "much better" (P <= 0.001). Women treated with oxybutynin showed significant improvement in sleep quality, sleep disturbance, and the global sleep index on the Pittsburgh Sleep Quality Index (P <= 0.023). Dry mouth was reported by 52.1% of participants given oxybutynin and 5.3% of participants given placebo, leading to discontinuation of oxybutynin in 6.8% of participants. CONCLUSIONS: Oxybutynin is an effective, nonhormonal therapy for moderate-to-severe vasomotor symptoms in postmenopausal women. PMID- 27760083 TI - Sleep-disordered breathing and the menopausal transition among participants in the Sleep in Midlife Women Study. AB - OBJECTIVE: Menopause is widely believed to be an established cause of sleep disorders, but evidence for this theory is inconclusive. Attributing any sleep problem to normal processes of menopause may lead to underdiagnosis of treatable sleep disorders in midlife women. This study uses detailed longitudinal data on sleep and menopausal health from participants in the Sleep in Midlife Women Study to investigate whether risk and severity of sleep-disordered breathing increase with progression through menopause, accounting for changes in age and body habitus. METHODS: A total of 219 women aged 38 to 62 years were recruited from participants in the Wisconsin Sleep Cohort Study. Menopause status was determined from daily diaries in which participants reported menstrual flow, hot flashes, and use of hormonal medications. Each participant underwent in-home polysomnography studies every 6 months, to measure the apnea-hypopnea index (AHI) (N = 1,667 studies). Linear models with empirical standard errors were fit for logarithm of AHI on menopause status and years in menopause, adjusting for age, body mass index, waist girth, and neck girth. RESULTS: Compared with women in premenopause, AHI was 21% higher among participants in perimenopause (95% CI, -4 to 54), 31% higher among participants in postmenopause (95% CI, 2-68), and 41% higher among participants whose menopausal stage could not be distinguished between peri- and postmenopause (95% CI, 8-82). Among women who had begun perimenopause, each additional year in menopause was associated with 4% greater AHI (95% CI, 2-6). CONCLUSIONS: Progression through menopause is associated with greater sleep-disordered breathing severity. This association is independent of aging and changes in body habitus. PMID- 27760082 TI - Age at natural menopause genetic risk score in relation to age at natural menopause and primary open-angle glaucoma in a US-based sample. AB - OBJECTIVE: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. METHODS: Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. RESULTS: The genetic risk score was associated with self reported ANM (P = 2.2 * 10) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P >=0.20). Compared to the middle 80 percent, there was also no association with the lowest 10 percentile or highest 90 percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). CONCLUSIONS: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes. PMID- 27760085 TI - An investigation of life circumstances associated with the experience of hot flashes in Campeche, Mexico. AB - OBJECTIVE: The purpose of this study was to better understand the experience of calores (hot flashes) in the state of Campeche, Mexico, and characteristics of women's lives. This study was carried out to understand the sociocultural context of women's lives before conducting a larger semistructured survey in the same communities. METHODS: Eighty-five women from rural and urban settings participated in open-ended interviews about the menopausal transition, with particular attention to hot flashes. Univariate and logistic regression analyses identified potential determinants of hot flashes. Qualitative responses were analyzed for central themes from the 40 women who experienced "calores" associated with menopause at the time of interview. RESULTS: The word "calores" was used to describe a variety of sensations and experiences related to the hot climate, infections, going in and out of air-conditioning, emotional stress, and physical exertion, as well as the symptom associated with menopause. In quantitative analyses, the likelihood of experiencing hot flashes varied by menopause status and rural/urban residence. In qualitative analyses, themes that characterized the lives of women with hot flashes were as follows: the search for, and the availability of, biomedical care; presence or absence of networks of social support; marital status and quality of the relationship; and occupational stress. CONCLUSIONS: Hot flash questionnaires can elicit different symptom frequencies depending on the language used and the sociocultural context of women's lives. Qualitative findings suggest that the themes most likely to influence the perception and experience of hot flashes in Campeche are biomedicine, social support, marriage, and stress. PMID- 27760084 TI - Effect of Gua sha therapy on perimenopausal syndrome: a randomized controlled trial. AB - OBJECTIVE: This study aims to evaluate the effectiveness and safety of Gua sha therapy on perimenopausal symptoms, quality of life, and serum female hormones in participants with perimenopausal syndrome. METHODS: A prospective, randomized, controlled clinical trial was conducted at the First Affiliated Hospital of Nanjing University of Chinese Medicine in China. Eighty women with perimenopausal syndrome were recruited and randomized into an intervention group or a control group. Participants in the intervention group received 15-minute Gua sha treatment sessions once a week plus conventional treatment for 8 weeks, whereas participants in the control group received conventional treatment alone. The primary outcome was the change in perimenopausal symptoms and quality of life as obtained through the modified Kupperman Index (KI) and the Menopause-Specific Quality of Life. The secondary outcome was the change of serum female hormones including estrogen, follicle-stimulating hormone, and luteinizing hormone. RESULTS: Seventy-five out of 80 participants (93.8%) completed the study-38 in the intervention group and 37 in the control group. The baseline levels of demographic and outcome measurements were comparable between the two groups. After eight sessions of intervention, the reduction in the total modified KI score was, however, 16.32 +/- 4.38 in the intervention group and 11.46 +/- 5.96 in the control group, with a difference of 4.86 +/- 6.15 (P < 0.01) between the two groups. Also the reductions of hot flash/sweating, paresthesia, insomnia, nervousness, melancholia, fatigue, and headache were greater in the intervention group than in the control group (P < 0.05). The reduction in the total Menopause Specific Quality of Life score was 17.87 +/- 3.84 in the intervention group and 13.62 +/- 7.40 in the control group, with a difference of 4.46 +/- 7.52 (P < 0.01) between the two groups. And the scores for vasomotor, psychosocial, and physical domains in the intervention group were significantly lower than those in the control group (P < 0.05). There were no significant differences in serum estrogen, follicle-stimulating hormone, and luteinizing hormone between the two groups. CONCLUSIONS: The results of this study suggest that Gua sha therapy was effective and safe in relieving perimenopausal symptoms and improving the quality of life in participants with perimenopausal syndrome. The therapy may serve as a promising, effective, nondrug treatment for perimenopausal syndrome in clinical work. Additional research is needed to better understand its effectiveness and examine its mechanism for treating perimenopausal syndrome. PMID- 27760086 TI - Association between maternal age at childbirth and metabolic syndrome in postmenopausal women: Korea National Health and Nutrition Examination Survey 2010 to 2012. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between maternal age at childbirth and metabolic syndrome in postmenopausal women. METHODS: We carried out a cross-sectional study on 3,956 Korean postmenopausal women who participated in the Korea National Health and Nutrition Examination Survey from 2010 to 2012. Multivariate logistic regression was used to evaluate the association between maternal age at first and last childbirth and metabolic syndrome, with adjustment for potential confounding variables. RESULTS: Women with metabolic syndrome had younger age at first delivery (23.3 +/- 0.1 vs 24.4 +/- 0.1 y, P < 0.001) and an older age at last delivery (30.8 +/- 0.1 vs 30.3 +/- 0.1 y, P = 0.011) than those without metabolic syndrome. After adjustments for confounding factors, earlier ages of first and last childbirth were positively associated with metabolic syndrome. The odds ratio (OR) was 2.157 (95% CI 1.256 3.705) for age at first childbirth, and 1.639 (95% CI 1.118-2.403) for age at last childbirth. Among the components of metabolic syndrome, only fasting glucose was positively associated with early age at first childbirth (OR 1.86; 95% CI 1.065-3.249) and early age at last childbirth (OR 1.71; 95% CI 1.197-2.444). CONCLUSIONS: A younger maternal age at first and last childbirth was independently associated with a higher risk of metabolic syndrome in postmenopausal women. Advanced maternal age at last childbirth was, however, not an independent risk factor for metabolic syndrome. PMID- 27760087 TI - Cultural issues in menopause: an exploratory qualitative study of Macedonian women in Australia. AB - OBJECTIVE: This study explored the attitudes to, and experience of, menopause among Macedonian women living in Australia, including attitudes and responses to hormone therapy (HT) and complementary therapies, as well as related psycho sexual, relationship and other midlife issues. METHODS: Using qualitative methodology, the study was based on seven unstructured, nondirective group discussions. Natural social groups were recruited, meeting wherever each group felt most at home. A total of 81 participants ranged in age from 45 to 75 years. The women included both first-generation immigrants and women born in Australia to Macedonian parents. A bilingual Macedonian researcher conducted the fieldwork. RESULTS: Participants typically claimed they lacked information about menopause in their native language, and their knowledge of HT was highly variable. Some women only felt comfortable approaching Macedonian doctors. Others reported an easing of symptoms when they revisited their homeland. Deeply religious participants claimed their faith helped them through this phase of life, and that they were as likely to consult a priest as a doctor. A recurring theme was that Macedonian men tended to regard their wives differently after menopause, sometimes treating them as "non-sexual." Women regarded this shift in male attitudes as a precipitating factor in domestic violence, extramarital affairs and divorce. Symptoms such as hot flashes and mood swings were associated with negative attitudes toward menopause. CONCLUSIONS: Culturally determined attitudes appear to affect the perception and experience of menopause. Other influencing factors include migration, women's roles, marital status, religion, use of herbal and traditional remedies, social situation, access to information, knowledge and experience of menopausal symptoms. PMID- 27760088 TI - Calcium and vitamin D supplementation for fracture prevention in postmenopausal women: where does the evidence lead? PMID- 27760089 TI - Efficacy of Tribulus terrestris for the treatment of hypoactive sexual desire disorder in postmenopausal women: a randomized, double-blinded, placebo controlled trial. AB - OBJECTIVE: The objective of this study was to evaluate the efficacy of Tribulus terrestris for the treatment of hypoactive sexual desire disorder in postmenopausal women and evaluate its effect on the serum levels of testosterone. METHODS: We performed a prospective randomized, double-blinded, placebo controlled study, during 18 months. A total of 45 healthy sexually active postmenopausal women reporting diminished libido were selected to participate in the study and were randomly assigned to receive 750 mg/d of T terrestris or placebo for 120 days. Randomization was performed using sealed envelopes. All participants answered the Female Sexual Function Index and the Sexual Quotient female version questionnaires and had their serum levels of prolactin, thyroid stimulating hormone, total testosterone, and sex hormone-binding globulin measured. RESULTS: A total of 36 participants completed the study, because 3 from each group were excluded due to side effects and 3 dropped out due to personal reasons. FSFI questionnaire results demonstrated an improvement in all domains in both groups (P < 0.05) except for lubrication which was improved only in the study group. QS-F results showed a significant improvement in the domains of desire (P < 0.01), arousal/lubrication (P = 0.02), pain (P = 0.02), and anorgasmia (P < 0.01) in women who used T terrestris, whereas no improvement was observed in the placebo group (P > 0.05). Moreover, free and bioavailable testosterone levels showed a significant increase in the T terrestris group (P < 0.05). CONCLUSIONS: Tribulus terrestris might be a safe alternative for the treatment of hypoactive sexual desire disorder in postmenopausal women, because it was effective in reducing symptoms with few side effects. Its probable mechanism of action involves an increase in the serum levels of free and bioavailable testosterone. PMID- 27760090 TI - [Technical options of electrotherapy in patients with vasovagal syncope]. AB - Syncope is a symptom of the disease with diverse etiology and can be evidence of both benign and very serious life-threatening conditions. Vasovagal syncope(VVS), with prevalence about 35% of the general population, is most frequent causes of transient loss of consciousness (T-LOC). Most cases of vasovagal syncope requires conservative treatment. Although cardioinhibitory type of VVS characterized by a significant bradycardia or pause of the heart rate and can be treated with continuous electrotherapy. This article discuss cardiac pacing and technical solutions for the treatment of VVS. Available cardiac pacing methods used to detect and break VVS such as Rate Drop Response (RDR), Closed Loop Stimulation (CLS) and rate response driven by variations of myocardial contractility like Peak Endocardial Acceleration (PEA), has been presented. PMID- 27760091 TI - [Body composition analysis performed by bioimpedance in patients with chronic obstructive pulmonary disease]. AB - : Body composition disorders are observed in chronic obstructive pulmonary disease (COPD) patients and have a significant impact the general condition and outcome in this disease. AIM: The aim of the study was to assess body composition in relation to airway obstruction severity in patients with COPD. MATERIALS AND METHODS: The study group consisted of 143 patients (58F, 85M) in the middle age The group was divided to two groups: group A FEV1<50% predicted and group B FEV1 >=50% predicted; both groups were compared. The following anthropometric parameters were assessed: body mass index (BMI), waist/hip ratio and shoulder circumference of the dominant upper limb. Body composition analysis was performed by bioimpedance (Tanita T5896, TANITA Corporation of America, Inc, Arlington Heights, USA). RESULTS: The mean BMI for the whole group was 27.5+/-5.1 kg/m2. None of the patients was underweight, 47 (32.9%) had normal BMI, 55 (38.5%) overweight and 41 (28.6%) were obese. Patients in group A had lower BMI, FFMI and muscle mass index (MMI) than patients in group B. We found the correlation between BMI, FFMI, MMI and FEV1 in the studied group. CONCLUSIONS: Our results confirm the relationship between airflow limitation and body compositions in COPD patients. We suggest that anthropometric measurements should be a part routine COPD management. PMID- 27760092 TI - Anxiety and depression levels in rheumatoid arthritis patients before and after joint replacement procedure. AB - : The progression of the inflammatory process in the course of rheumatoid arthiritis (RA) may cause a permanent destruction of joints, which in case of bigger ones (i.e. hip or knee) may be particularly a psychological burden for a patient. AIM: The aim of the study was to verify whether implantation of hip or knee endoprosthesis affect anxiety and depressive symptoms among patients with RA. MATERIALS AND METHODS: The study enrolled a group of 128 rheumatoid arthritis patients, including 64 patients before and 64 patients after the joint replacement procedure. Anxiety was assessed using State- Trait Anxiety Inventory and depression - Beck Depression Inventory. RESULTS: Patients before the endoprosthesis implantation scored statistically significantly higher on the state anxiety scale than patients after the procedure (43.17+/-10.69 vs 36.95+/ 10.63, p<0.01). There was no statistically significant difference in trait anxiety scores between patients before and after alloplasty (p=0.28). Patients before the procedure scored statistically significantly higher on BDI than patients after the joint replacement (15.28+/-8.99 vs 11.48+/-8.45, p<0.05). CONCLUSIONS: Patients with RA after knee or hip alloplasty had lower levels of anxiety and depressive symptoms than patient before the procedure. Endoprosthesis implantation as a treatment option for severe joint destruction in RA might also improve depressive symptoms and anxiety among patients with RA. PMID- 27760093 TI - [Safety of use of micronized diosmin at daily doses up to 2000 mg per day]. AB - : Formulations of micronized diosmin (MPFF) are widely used in the treatment of chronic venous disease, hemorrhoidal disease and other indications. The usual recommended dose of micronized diosmin is 1000 mg once daily. Numerous studies confirm the superior efficacy and safety of higher doses of diosmin up to 2000 mg per day in a few months therapy. AIM: The aim of the study was to observe the efficacy and safety of micronized diosmine used in a daily dose of 1000 and 2000 mg for 4 months. MATERIALS AND METHODS: The study involved 327 patients meeting the inclusion and exclusion criteria. The parameters were measured immediately prior to the first dose and at 2 and 4 months of therapy. The safety analysis was conducted and the results obtained from measured parameters are presented in tables. RESULTS: No significant abnormalities in the following parameters were observed: complete blood cell count, fibrinogen level, the level of alanine transaminase and aspartate, the level of urea and creatinine, urinalysis. The therapy did not affect the level of systolic and diastolic blood pressure. There was no significant adverse events in the study groups. CONCLUSIONS: Cited in this publication results of a clinical study support the use of micronized diosmin at doses up to 2000 mg per day. PMID- 27760094 TI - [Ocular toxocariasis in a boy with idiopathic nephrotic syndrome - a case report]. AB - : Toxocariasis is a common zoonosis caused by infection with Toxocara canis or cati larvae. Ocular toxocariasis is one of the forms of infestation found in 1/1,000 - 1/10,000 children. Children with idiopathic nephrotic syndrome (INS) are at high risk of infections, also parasitic infestations, which can, in turn, cause relapses of the disease. A CASE REPORT: We present a case of a 6-year-old boy with steroiddependent nephrotic syndrome. The disease started at age of 2, the boy had 9 relapses of INS, and was treated with oral prednisone, levamisole, and cyclophosphamide. During hospitalization with Xth relapse of INS, he was screened for causes of recurrences and IgG antibodies against Toxocara were found. Fundoscopy revealed white, slightly elevated, and discoloured inflammatory lesions in right retina without inflammation in the vitreous. Ocular toxocariasis was diagnosed. The boy was treated for 7 days with albendazole in the dose of 15 mg/kg/24 h with simultaneous increase of the dose of prednisone to 1mg/kg/24 h. In control fundoscopic examinations there was no progression of ocular lesions. CONCLUSIONS: In children on immunosuppressive treatment with possible exposure to animals or raw meet it is advisable to take serological tests for Toxocara infestation also in the absence of clinical symptoms of parasitic infection. PMID- 27760095 TI - [Granuloma on tympanic membrane - a case report]. AB - Granuloma on tympanic membrane is a rare complication after ventilation drainage of tympanic cavity. The paper presents a case of a child for chronic otitis media with effusion with ventilation drainage of the right tympanic cavity, retained for 24 months, and granuloma on tympanic membrane growing all over the ventilation drain, imitating acute inflammation, causing conductive hearing loss. The patient was treated with the vent tube removal together with granulation inflammatory. Spontaneous healing of the perforation of the tympanic membrane and improve hearing were obtained after a four-month follow-up. PMID- 27760096 TI - Haemangiopericytoma-like tumor of the nasal cavity treated by endoscopy - a case report. AB - Haemangiopericytoma (HPC) is an uncommon, vascular tumor derived from Zimmerman pericytes surrounding blood vessels. HPC constitute around 1% of all tumors of vascular origin and may appear anywhere, 5% of them can be situated in nasal cavity. Tumor location within the head and neck predispose to its benign character and improves prognosis. This case report presents the case of 33-year old patient with haemangiopericytoma-like tumor of the nasal cavity, presented symptoms of impaired nasal breathing and recurrent epistaxis. Tumor was excised with 0 degree endoscope. The follow-up recurrence-free period was 2 year 6 months and shows this is effective way of treatment. Described in the literature late recurrences and metastases reminds that regular, life-long observation is mandatory. PMID- 27760097 TI - [Treatment of microscopic colitis - what's new?] AB - Microscopic colitis (MC) is frequent, although still uncommonly diagnosed, cause of chronic diarrhea. The etiopathology of MC is unknown but this disease has strong influence on patient's quality of life (measured by health-related quality of life - HRQoL). MC is characterized by microscopic abnormalities in large bowel's mucosa whereas endoscopic and radiological examination findings are normal. The treatment of MC is an essential social and financial problem due to its frequency in society. Thanks to the results of some controlled research which judged efficiency of some medicines as well as advisory groups recommendations, the MC therapy is nowadays going from empiric to accordance with evidence based medicine. PMID- 27760098 TI - [The impact of the consumption of vegetables, fruits, coffee and tea on the development of colorectal carcinoma]. AB - The development of colorectal carcinoma is a multistep process of accumulation of mutations and epigenetic changes associated with DNA repair, proliferation, apoptosis, intra- and extracellular signaling, adhesion and other physiological functions of cells and tissues. A long period of development, high colorectal carcinoma-related mortality as well as significant social and economic costs due to this condition are prerequisites for seeking efficient methods of cancer prevention, including nutritional approach. A number of bioactive components of food is extensively tested for antitumor activity, however limited number of reliable studies on humans impedes the formulation of unequivocal nutritional recommendations. Plant products represent a rich source of numerous phytochemicals endowed with anticancer potential due to, first of all, their free radical scavenger activity. The purpose of this paper was to present the relationship between consumption of selected foods reach in numerous bioactive compounds with proven or putative anticancer activity - vegetables, fruits, coffee and tea - and the development of colorectal carcinoma, based on selected studies. A number of controversies related to the anti-tumor potential of the above ingredients was also discussed. PMID- 27760100 TI - Allergy in Wiskott-Aldrich syndrome. PMID- 27760101 TI - Caloric restriction and type 2 immunity. PMID- 27760099 TI - Association of Rs2071410 on Furin with Transient Ischemic Attack Susceptibility and Prognosis in a Chinese Population. AB - BACKGROUND Because genotype CG/GG of Furin rs2071410 can increase susceptibility to hypertension, this study investigated whether Furin rs2071410 is correlated with transient ischemic attack (TIA) susceptibility and prognosis. MATERIAL AND METHODS The odds ratios (ORs) and their 95% confidence intervals (95% CIs) were evaluated to assess the association of rs2071410 with TIA risk, and logistic regression was used to estimate the effects of various risk factors (e.g., diabetes, hypertension, and hyperlipidemia) on TIA. RESULTS Compared with the homozygous genotype CC of rs2071410, the frequency of CG + GG genotype in the case group was significantly higher than in the control group (OR=1.47, 95% CI: 1.05-2.05, P<0.05). The CG + GG genotype carriers were observed to have worse 90 day prognosis after TIA treatment than patients carrying CC genotype (OR=12.86, 95% CI: 7.41-22.33, P<0.05). Moreover, logistic regression analysis found that age, diabetes, hypertension, and hyperlipidemia were associated with the onset of TIA (P<0.05, all). Of note, individuals with CG + GG genotype had 49.3% increased risk of TIA compared with individuals with CC genotype (OR=1.49, 95% CI: 1.05 2.12), and patients with CG + GG genotype had worse 90-day prognosis after TIA treatment than patients with CC genotype (OR=11.39, 95% CI: 6.29-20.62). CONCLUSIONS Furin rs2071410 was significantly correlated with TIA occurrence and prognosis in the Chinese population. PMID- 27760102 TI - Hypoxic germinal centers. PMID- 27760103 TI - Immunity without innate lymphoid cells. PMID- 27760105 TI - Negative control of TFH cells. PMID- 27760106 TI - How MAIT cells get their start. PMID- 27760104 TI - Epithelial glycosylation in gut homeostasis and inflammation. AB - Intestinal epithelial cells apically express glycans, especially alpha1,2-fucosyl linkages, which work as a biological interface for the host-microbe interaction. Emerging studies have shown that epithelial alpha1,2-fucosylation is regulated by microbes and by group 3 innate lymphoid cells (ILC3s). Dysregulation of the gene (FUT2) encoding fucosyltransferase 2, an enzyme governing epithelial alpha1,2 fucosylation, is associated with various human disorders, including infection and chronic inflammatory diseases. This suggests a critical role for an interaction between microbes, epithelial cells and ILC3s mediated via glycan residues. In this Review, using alpha1,2-fucose and Fut2 gene expression as an example, we describe how epithelial glycosylation is controlled by immune cells and luminal microbes. We also address the pathophysiological contribution of epithelial alpha1,2-fucosylation to pathogenic and commensal microbes as well as the potential of alpha1,2-fucose and its regulatory pathway as previously unexploited targets in the development of new therapeutic approaches for human diseases. PMID- 27760108 TI - Bile acids block NLRP3. PMID- 27760107 TI - Glioma and microglia, a double entendre. PMID- 27760109 TI - Compartmentalized selection. PMID- 27760110 TI - Corrigendum: Design of a hyperstable 60-subunit protein icosahedron. PMID- 27760112 TI - DNA repair: Telomere-lengthening mechanism revealed. PMID- 27760111 TI - The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. AB - Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3 binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours. PMID- 27760113 TI - Mechanism for DNA transposons to generate introns on genomic scales. AB - The discovery of introns four decades ago was one of the most unexpected findings in molecular biology. Introns are sequences interrupting genes that must be removed as part of messenger RNA production. Genome sequencing projects have shown that most eukaryotic genes contain at least one intron, and frequently many. Comparison of these genomes reveals a history of long evolutionary periods during which few introns were gained, punctuated by episodes of rapid, extensive gain. However, although several detailed mechanisms for such episodic intron generation have been proposed, none has been empirically supported on a genomic scale. Here we show how short, non-autonomous DNA transposons independently generated hundreds to thousands of introns in the prasinophyte Micromonas pusilla and the pelagophyte Aureococcus anophagefferens. Each transposon carries one splice site. The other splice site is co-opted from the gene sequence that is duplicated upon transposon insertion, allowing perfect splicing out of the RNA. The distributions of sequences that can be co-opted are biased with respect to codons, and phasing of transposon-generated introns is similarly biased. These transposons insert between pre-existing nucleosomes, so that multiple nearby insertions generate nucleosome-sized intervening segments. Thus, transposon insertion and sequence co-option may explain the intron phase biases and prevalence of nucleosome-sized exons observed in eukaryotes. Overall, the two independent examples of proliferating elements illustrate a general DNA transposon mechanism that can plausibly account for episodes of rapid, extensive intron gain during eukaryotic evolution. PMID- 27760114 TI - Fluvial sediment supply to a mega-delta reduced by shifting tropical-cyclone activity. AB - The world's rivers deliver 19 billion tonnes of sediment to the coastal zone annually, with a considerable fraction being sequestered in large deltas, home to over 500 million people. Most (more than 70 per cent) large deltas are under threat from a combination of rising sea levels, ground surface subsidence and anthropogenic sediment trapping, and a sustainable supply of fluvial sediment is therefore critical to prevent deltas being 'drowned' by rising relative sea levels. Here we combine suspended sediment load data from the Mekong River with hydrological model simulations to isolate the role of tropical cyclones in transmitting suspended sediment to one of the world's great deltas. We demonstrate that spatial variations in the Mekong's suspended sediment load are correlated (r = 0.765, P < 0.1) with observed variations in tropical-cyclone climatology, and that a substantial portion (32 per cent) of the suspended sediment load reaching the delta is delivered by runoff generated by rainfall associated with tropical cyclones. Furthermore, we estimate that the suspended load to the delta has declined by 52.6 +/- 10.2 megatonnes over recent years (1981-2005), of which 33.0 +/- 7.1 megatonnes is due to a shift in tropical cyclone climatology. Consequently, tropical cyclones have a key role in controlling the magnitude of, and variability in, transmission of suspended sediment to the coast. It is likely that anthropogenic sediment trapping in upstream reservoirs is a dominant factor in explaining past, and anticipating future, declines in suspended sediment loads reaching the world's major deltas. However, our study shows that changes in tropical-cyclone climatology affect trends in fluvial suspended sediment loads and thus are also key to fully assessing the risk posed to vulnerable coastal systems. PMID- 27760115 TI - TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling. AB - Mammalian genomes undergo epigenetic modifications, including cytosine methylation by DNA methyltransferases (DNMTs). Oxidation of 5-methylcytosine by the Ten-eleven translocation (TET) family of dioxygenases can lead to demethylation. Although cytosine methylation has key roles in several processes such as genomic imprinting and X-chromosome inactivation, the functional significance of cytosine methylation and demethylation in mouse embryogenesis remains to be fully determined. Here we show that inactivation of all three Tet genes in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signalling. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signalling contributes to the gastrulation failure of Tet mutants. Increased Nodal signalling is probably due to diminished expression of the Lefty1 and Lefty2 genes, which encode inhibitors of Nodal signalling. Moreover, reduction in Lefty gene expression is linked to elevated DNA methylation, as both Lefty-Nodal signalling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a and Dnmt3b genes are disrupted. Additionally, a point mutation in Tet that specifically abolishes the dioxygenase activity causes similar morphological and molecular abnormalities as the null mutation. Taken together, our results show that TET-mediated oxidation of 5 methylcytosine modulates Lefty-Nodal signalling by promoting demethylation in opposition to methylation by DNMT3A and DNMT3B. These findings reveal a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation crucial to regulation of key signalling pathways in early body plan formation. PMID- 27760117 TI - Wild monkeys flake stone tools. AB - Our understanding of the emergence of technology shapes how we view the origins of humanity. Sharp-edged stone flakes, struck from larger cores, are the primary evidence for the earliest stone technology. Here we show that wild bearded capuchin monkeys (Sapajus libidinosus) in Brazil deliberately break stones, unintentionally producing recurrent, conchoidally fractured, sharp-edged flakes and cores that have the characteristics and morphology of intentionally produced hominin tools. The production of archaeologically visible cores and flakes is therefore no longer unique to the human lineage, providing a comparative perspective on the emergence of lithic technology. This discovery adds an additional dimension to interpretations of the human Palaeolithic record, the possible function of early stone tools, and the cognitive requirements for the emergence of stone flaking. PMID- 27760118 TI - Behavioural biology: Stones that could cause ripples. PMID- 27760116 TI - Chromosome conformation elucidates regulatory relationships in developing human brain. AB - Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders. PMID- 27760119 TI - Corrigendum: Fumarate is an epigenetic modifier that elicits epithelial-to mesenchymal transition. PMID- 27760120 TI - Break-induced telomere synthesis underlies alternative telomere maintenance. AB - Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10-15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase delta (Pol delta) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC-PCNA Pol delta axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology directed telomere maintenance. PMID- 27760121 TI - The RTR Complex Partner RMI2 and the DNA Helicase RTEL1 Are Both Independently Involved in Preserving the Stability of 45S rDNA Repeats in Arabidopsis thaliana. AB - The stability of repetitive sequences in complex eukaryotic genomes is safeguarded by factors suppressing homologues recombination. Prominent in this is the role of the RTR complex. In plants, it consists of the RecQ helicase RECQ4A, the topoisomerase TOP3alpha and RMI1. Like mammals, but not yeast, plants harbor an additional complex partner, RMI2. Here, we demonstrate that, in Arabidopsis thaliana, RMI2 is involved in the repair of aberrant replication intermediates in root meristems as well as in intrastrand crosslink repair. In both instances, RMI2 is involved independently of the DNA helicase RTEL1. Surprisingly, simultaneous loss of RMI2 and RTEL1 leads to loss of male fertility. As both the RTR complex and RTEL1 are involved in suppression of homologous recombination (HR), we tested the efficiency of HR in the double mutant rmi2-2 rtel1-1 and found a synergistic enhancement (80-fold). Searching for natural target sequences we found that RTEL1 is required for stabilizing 45S rDNA repeats. In the double mutant with rmi2-2 the number of 45S rDNA repeats is further decreased sustaining independent roles of both factors in this process. Thus, loss of suppression of HR does not only lead to a destabilization of rDNA repeats but might be especially deleterious for tissues undergoing multiple cell divisions such as the male germline. PMID- 27760123 TI - Household Coverage of Fortified Staple Food Commodities in Rajasthan, India. AB - A spatially representative statewide survey was conducted in Rajasthan, India to assess household coverage of atta wheat flour, edible oil, and salt. An even distribution of primary sampling units were selected based on their proximity to centroids on a hexagonal grid laid over the survey area. A sample of n = 18 households from each of m = 252 primary sampling units PSUs was taken. Demographic data on all members of these households were collected, and a broader dataset was collected about a single caregiver and a child in the first 2 years of life. Data were collected on demographic and socioeconomic status; education; housing conditions; recent infant and child mortality; water, sanitation, and hygiene practices; food security; child health; infant and young child feeding practices; maternal dietary diversity; coverage of fortified staples; and maternal and child anthropometry. Data were collected from 4,627 households and the same number of caregiver/child pairs. Atta wheat flour was widely consumed across the state (83%); however, only about 7% of the atta wheat flour was classified as fortifiable, and only about 6% was actually fortified (mostly inadequately). For oil, almost 90% of edible oil consumed by households in the survey was classified as fortifiable, but only about 24% was fortified. For salt, coverage was high, with almost 85% of households using fortified salt and 66% of households using adequately fortified salt. Iodized salt coverage was also high; however, rural and poor population groups were less likely to be reached by the intervention. Voluntary fortification of atta wheat flour and edible oil lacked sufficient industry consolidation to cover significant portions of the population. It is crucial that appropriate delivery channels are utilized to effectively deliver essential micronutrients to at-risk population groups. Government distribution systems are likely the best means to accomplish this goal. PMID- 27760122 TI - Tanscriptomic Study of the Soybean-Fusarium virguliforme Interaction Revealed a Novel Ankyrin-Repeat Containing Defense Gene, Expression of Whose during Infection Led to Enhanced Resistance to the Fungal Pathogen in Transgenic Soybean Plants. AB - Fusarium virguliforme causes the serious disease sudden death syndrome (SDS) in soybean. Host resistance to this pathogen is partial and is encoded by a large number of quantitative trait loci, each conditioning small effects. Breeding SDS resistance is therefore challenging and identification of single-gene encoded novel resistance mechanisms is becoming a priority to fight this devastating this fungal pathogen. In this transcriptomic study we identified a few putative soybean defense genes, expression of which is suppressed during F. virguliforme infection. The F. virguliforme infection-suppressed genes were broadly classified into four major classes. The steady state transcript levels of many of these genes were suppressed to undetectable levels immediately following F. virguliforme infection. One of these classes contains two novel genes encoding ankyrin repeat-containing proteins. Expression of one of these genes, GmARP1, during F. virguliforme infection enhances SDS resistance among the transgenic soybean plants. Our data suggest that GmARP1 is a novel defense gene and the pathogen presumably suppress its expression to establish compatible interaction. PMID- 27760124 TI - rasbhari: Optimizing Spaced Seeds for Database Searching, Read Mapping and Alignment-Free Sequence Comparison. AB - Many algorithms for sequence analysis rely on word matching or word statistics. Often, these approaches can be improved if binary patterns representing match and don't-care positions are used as a filter, such that only those positions of words are considered that correspond to the match positions of the patterns. The performance of these approaches, however, depends on the underlying patterns. Herein, we show that the overlap complexity of a pattern set that was introduced by Ilie and Ilie is closely related to the variance of the number of matches between two evolutionarily related sequences with respect to this pattern set. We propose a modified hill-climbing algorithm to optimize pattern sets for database searching, read mapping and alignment-free sequence comparison of nucleic-acid sequences; our implementation of this algorithm is called rasbhari. Depending on the application at hand, rasbhari can either minimize the overlap complexity of pattern sets, maximize their sensitivity in database searching or minimize the variance of the number of pattern-based matches in alignment-free sequence comparison. We show that, for database searching, rasbhari generates pattern sets with slightly higher sensitivity than existing approaches. In our Spaced Words approach to alignment-free sequence comparison, pattern sets calculated with rasbhari led to more accurate estimates of phylogenetic distances than the randomly generated pattern sets that we previously used. Finally, we used rasbhari to generate patterns for short read classification with CLARK-S. Here too, the sensitivity of the results could be improved, compared to the default patterns of the program. We integrated rasbhari into Spaced Words; the source code of rasbhari is freely available at http://rasbhari.gobics.de/. PMID- 27760125 TI - Unsupervised Learning in an Ensemble of Spiking Neural Networks Mediated by ITDP. AB - We propose a biologically plausible architecture for unsupervised ensemble learning in a population of spiking neural network classifiers. A mixture of experts type organisation is shown to be effective, with the individual classifier outputs combined via a gating network whose operation is driven by input timing dependent plasticity (ITDP). The ITDP gating mechanism is based on recent experimental findings. An abstract, analytically tractable model of the ITDP driven ensemble architecture is derived from a logical model based on the probabilities of neural firing events. A detailed analysis of this model provides insights that allow it to be extended into a full, biologically plausible, computational implementation of the architecture which is demonstrated on a visual classification task. The extended model makes use of a style of spiking network, first introduced as a model of cortical microcircuits, that is capable of Bayesian inference, effectively performing expectation maximization. The unsupervised ensemble learning mechanism, based around such spiking expectation maximization (SEM) networks whose combined outputs are mediated by ITDP, is shown to perform the visual classification task well and to generalize to unseen data. The combined ensemble performance is significantly better than that of the individual classifiers, validating the ensemble architecture and learning mechanisms. The properties of the full model are analysed in the light of extensive experiments with the classification task, including an investigation into the influence of different input feature selection schemes and a comparison with a hierarchical STDP based ensemble architecture. PMID- 27760126 TI - Self-Reported Side Effects and Adherence to Antiretroviral Therapy in HIV Infected Pregnant Women under Option B+: A Prospective Study. AB - BACKGROUND: Antiretroviral therapy (ART) regimens containing efavirenz (EFV) are recommended as part of universal ART for pregnant and breastfeeding women. EFV may have appreciable side effects (SE), and ART adherence in pregnancy is a major concern, but little is known about ART SE and associations with adherence in pregnancy. METHODS: We investigated the distribution of patient-reported SE (based on Division of AIDS categories) and the association of SE with missed ART doses in a cohort of 517 women starting EFV+3TC/FTC+TDF during pregnancy. In analysis, SE were considered in terms of their overall frequency, by systems category, and by latent classes. RESULTS: Overall 97% of women reported experiencing at least one SE after ART initiation, with 48% experiencing more than five SE. Gastrointestinal, central nervous system, systemic and skin SE were reported by 81%, 85%, 79% and 31% of women, respectively, with considerable overlap across groups. At least one missed dose was reported by 32% of women. In multivariable models, ART non-adherence was associated with systemic SE compared to other systems categories, and measures of the overall burden of SE experienced were most strongly associated with missed ART doses. CONCLUSION: These data demonstrate very high levels of SE in pregnant women initiating EFV-based ART and a strong association between SE burden and ART adherence. ART regimens with reduced SE profiles may enhance adherence, and as countries expand universal ART for all adult patients, counseling must include preparation for ART SE. PMID- 27760127 TI - Human Germline Mutation and the Erratic Evolutionary Clock. AB - Our understanding of the chronology of human evolution relies on the "molecular clock" provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not "a mutation rate" but a precise characterization of how mutations accumulate in development in males and females-knowledge that remains elusive. PMID- 27760128 TI - Enrichment of Phosphatidylethanolamine in Viral Replication Compartments via Co opting the Endosomal Rab5 Small GTPase by a Positive-Strand RNA Virus. AB - Positive-strand RNA viruses build extensive membranous replication compartments to support replication and protect the virus from antiviral responses by the host. These viruses require host factors and various lipids to form viral replication complexes (VRCs). The VRCs built by Tomato bushy stunt virus (TBSV) are enriched with phosphatidylethanolamine (PE) through a previously unknown pathway. To unravel the mechanism of PE enrichment within the TBSV replication compartment, in this paper, the authors demonstrate that TBSV co-opts the guanosine triphosphate (GTP)-bound active form of the endosomal Rab5 small GTPase via direct interaction with the viral replication protein. Deletion of Rab5 orthologs in a yeast model host or expression of dominant negative mutants of plant Rab5 greatly decreases TBSV replication and prevents the redistribution of PE to the sites of viral replication. We also show that enrichment of PE in the viral replication compartment is assisted by actin filaments. Interestingly, the closely related Carnation Italian ringspot virus, which replicates on the boundary membrane of mitochondria, uses a similar strategy to the peroxisomal TBSV to hijack the Rab5-positive endosomes into the viral replication compartments. Altogether, usurping the GTP-Rab5-positive endosomes allows TBSV to build a PE-enriched viral replication compartment, which is needed to support peak-level replication. Thus, the Rab family of small GTPases includes critical host factors assisting VRC assembly and genesis of the viral replication compartment. PMID- 27760130 TI - A Reliability Test of a Complex System Based on Empirical Likelihood. AB - To analyze the reliability of a complex system described by minimal paths, an empirical likelihood method is proposed to solve the reliability test problem when the subsystem distributions are unknown. Furthermore, we provide a reliability test statistic of the complex system and extract the limit distribution of the test statistic. Therefore, we can obtain the confidence interval for reliability and make statistical inferences. The simulation studies also demonstrate the theorem results. PMID- 27760129 TI - Efficacy and Safety of Once-Daily Insulin Degludec/Insulin Aspart versus Insulin Glargine (U100) for 52 Weeks in Insulin-Naive Patients with Type 2 Diabetes: A Randomized Controlled Trial. AB - PURPOSE: The efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily (OD) compared with insulin glargine U100 (IGlar) OD over 52 weeks in insulin-naive adults with type 2 diabetes mellitus (T2DM) was investigated. METHODS: In this open-label, parallel-group treat-to-target trial, participants were randomized (1:1) to receive IDegAsp OD (breakfast, n = 266) or IGlar OD (as per label, n = 264). Participants then entered a 26-week extension phase (IDegAsp OD, n = 192; IGlar OD, n = 221). The primary endpoint was change from baseline to Week 26 in HbA1c. RESULTS: After 26 and 52 weeks, mean HbA1c decreased to similar levels in both groups. After 52 weeks, the mean estimated treatment difference was -0.08% (-0.26, 0.09 95%CI), confirming the non-inferiority of IDegAsp OD versus IGlar OD evaluated at Week 26. After 52 weeks, there was a similar reduction in mean fasting plasma glucose in both treatment groups. The rate of confirmed hypoglycemic episodes was 86% higher (p < 0.0001) whereas the rate of nocturnal hypoglycemia was 75% lower (p < 0.0001) for IDegAsp versus IGlar. CONCLUSION: Nocturnal-confirmed hypoglycemia was higher with IGlar whereas overall and diurnal hypoglycemia were higher with IDegAsp dosed at breakfast. These results highlight the importance of administration of IDegAsp with the main meal of the day, tailored to the individual patient's needs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01045707 [core]) and NCT01169766 [ext]. PMID- 27760131 TI - Use of Linear Programming to Develop Cost-Minimized Nutritionally Adequate Health Promoting Food Baskets. AB - BACKGROUND: Food-Based Dietary Guidelines (FBDGs) are developed to promote healthier eating patterns, but increasing food prices may make healthy eating less affordable. The aim of this study was to design a range of cost-minimized nutritionally adequate health-promoting food baskets (FBs) that help prevent both micronutrient inadequacy and diet-related non-communicable diseases at lowest cost. METHODS: Average prices for 312 foods were collected within the Greater Copenhagen area. The cost and nutrient content of five different cost-minimized FBs for a family of four were calculated per day using linear programming. The FBs were defined using five different constraints: cultural acceptability (CA), or dietary guidelines (DG), or nutrient recommendations (N), or cultural acceptability and nutrient recommendations (CAN), or dietary guidelines and nutrient recommendations (DGN). The variety and number of foods in each of the resulting five baskets was increased through limiting the relative share of individual foods. RESULTS: The one-day version of N contained only 12 foods at the minimum cost of DKK 27 (? 3.6). The CA, DG, and DGN were about twice of this and the CAN cost ~DKK 81 (? 10.8). The baskets with the greater variety of foods contained from 70 (CAN) to 134 (DGN) foods and cost between DKK 60 (? 8.1, N) and DKK 125 (? 16.8, DGN). Ensuring that the food baskets cover both dietary guidelines and nutrient recommendations doubled the cost while cultural acceptability (CAN) tripled it. CONCLUSION: Use of linear programming facilitates the generation of low-cost food baskets that are nutritionally adequate, health promoting, and culturally acceptable. PMID- 27760132 TI - Harmful Effect of Beer on Bovine Enamel Microhardness - In Vitro Study. AB - This study aimed to evaluate the effect of beers on the bovine enamel microhardness. Fifty rectangular (1 x 3 x 1 mm-height x width x thickness) enamel specimens were obtained from permanent bovine incisors, and divided into five groups (n = 10) according to the treatment employed: Saliva, Coke, Brahma, Heineken, and Budweiser. Microhardness (Knoop) were obtained before; after 5, 30 and 60 min of immersion in each solution. The data were analyzed using repeated two-way ANOVA and Tukey's test (p<0.05). Coke decreased the microhardness in all immersion times, and Heineken, showed low values after 60 minutes. Beers tested have low potential to cause enamel erosion when compared to Coke. PMID- 27760133 TI - Diversity in the Toll-Like Receptor Genes of the African Penguin (Spheniscus demersus). AB - The African penguin, Spheniscus demersus, is listed as Endangered by the IUCN Red List of Threatened Species due to the drastic reduction in population numbers over the last 20 years. To date, the only studies on immunogenetic variation in penguins have been conducted on the major histocompatibility complex (MHC) genes. It was shown in humans that up to half of the genetic variability in immune responses to pathogens are located in non-MHC genes. Toll-like receptors (TLRs) are now increasingly being studied in a variety of taxa as a broader approach to determine functional genetic diversity. In this study, we confirm low genetic diversity in the innate immune region of African penguins similar to that observed in New Zealand robin that has undergone several severe population bottlenecks. Single nucleotide polymorphism (SNP) diversity across TLRs varied between ex situ and in situ penguins with the number of non-synonymous alterations in ex situ populations (n = 14) being reduced in comparison to in situ populations (n = 16). Maintaining adaptive diversity is of vital importance in the assurance populations as these animals may potentially be used in the future for re-introductions. Therefore, this study provides essential data on immune gene diversity in penguins and will assist in providing an additional monitoring tool for African penguin in the wild, as well as to monitor diversity in ex situ populations and to ensure that diversity found in the in situ populations are captured in the assurance populations. PMID- 27760134 TI - Audiovisual Interval Size Estimation Is Associated with Early Musical Training. AB - Although pitch is a fundamental attribute of auditory perception, substantial individual differences exist in our ability to perceive differences in pitch. Little is known about how these individual differences in the auditory modality might affect crossmodal processes such as audiovisual perception. In this study, we asked whether individual differences in pitch perception might affect audiovisual perception, as it relates to age of onset and number of years of musical training. Fifty-seven subjects made subjective ratings of interval size when given point-light displays of audio, visual, and audiovisual stimuli of sung intervals. Audiovisual stimuli were divided into congruent and incongruent (audiovisual-mismatched) stimuli. Participants' ratings correlated strongly with interval size in audio-only, visual-only, and audiovisual-congruent conditions. In the audiovisual-incongruent condition, ratings correlated more with audio than with visual stimuli, particularly for subjects who had better pitch perception abilities and higher nonverbal IQ scores. To further investigate the effects of age of onset and length of musical training, subjects were divided into musically trained and untrained groups. Results showed that among subjects with musical training, the degree to which participants' ratings correlated with auditory interval size during incongruent audiovisual perception was correlated with both nonverbal IQ and age of onset of musical training. After partialing out nonverbal IQ, pitch discrimination thresholds were no longer associated with incongruent audio scores, whereas age of onset of musical training remained associated with incongruent audio scores. These findings invite future research on the developmental effects of musical training, particularly those relating to the process of audiovisual perception. PMID- 27760135 TI - DREISS: Using State-Space Models to Infer the Dynamics of Gene Expression Driven by External and Internal Regulatory Networks. AB - Gene expression is controlled by the combinatorial effects of regulatory factors from different biological subsystems such as general transcription factors (TFs), cellular growth factors and microRNAs. A subsystem's gene expression may be controlled by its internal regulatory factors, exclusively, or by external subsystems, or by both. It is thus useful to distinguish the degree to which a subsystem is regulated internally or externally-e.g., how non-conserved, species specific TFs affect the expression of conserved, cross-species genes during evolution. We developed a computational method (DREISS, dreiss.gerteinlab.org) for analyzing the Dynamics of gene expression driven by Regulatory networks, both External and Internal based on State Space models. Given a subsystem, the "state" and "control" in the model refer to its own (internal) and another subsystem's (external) gene expression levels. The state at a given time is determined by the state and control at a previous time. Because typical time-series data do not have enough samples to fully estimate the model's parameters, DREISS uses dimensionality reduction, and identifies canonical temporal expression trajectories (e.g., degradation, growth and oscillation) representing the regulatory effects emanating from various subsystems. To demonstrate capabilities of DREISS, we study the regulatory effects of evolutionarily conserved vs. divergent TFs across distant species. In particular, we applied DREISS to the time-series gene expression datasets of C. elegans and D. melanogaster during their embryonic development. We analyzed the expression dynamics of the conserved, orthologous genes (orthologs), seeing the degree to which these can be accounted for by orthologous (internal) versus species-specific (external) TFs. We found that between two species, the orthologs have matched, internally driven expression patterns but very different externally driven ones. This is particularly true for genes with evolutionarily ancient functions (e.g. the ribosomal proteins), in contrast to those with more recently evolved functions (e.g., cell-cell communication). This suggests that despite striking morphological differences, some fundamental embryonic-developmental processes are still controlled by ancient regulatory systems. PMID- 27760136 TI - Combined Use of Genome-Wide Association Data and Correlation Networks Unravels Key Regulators of Primary Metabolism in Arabidopsis thaliana. AB - Plant primary metabolism is a highly coordinated, central, and complex network of biochemical processes regulated at both the genetic and post-translational levels. The genetic basis of this network can be explored by analyzing the metabolic composition of genetically diverse genotypes in a given plant species. Here, we report an integrative strategy combining quantitative genetic mapping and metabolite-transcript correlation networks to identify functional associations between genes and primary metabolites in Arabidopsis thaliana. Genome-wide association study (GWAS) was used to identify metabolic quantitative trait loci (mQTL). Correlation networks built using metabolite and transcript data derived from a previously published time-course stress study yielded metabolite-transcript correlations identified by covariation. Finally, results obtained in this study were compared with mQTL previously described. We applied a statistical framework to test and compare the performance of different single methods (network approach and quantitative genetics methods, representing the two orthogonal approaches combined in our strategy) with that of the combined strategy. We show that the combined strategy has improved performance manifested by increased sensitivity and accuracy. This combined strategy allowed the identification of 92 candidate associations between structural genes and primary metabolites, which not only included previously well-characterized gene metabolite associations, but also revealed novel associations. Using loss-of function mutants, we validated two of the novel associations with genes involved in tyrosine degradation and in beta-alanine metabolism. In conclusion, we demonstrate that applying our integrative strategy to the largely untapped resource of metabolite-transcript associations can facilitate the discovery of novel metabolite-related genes. This integrative strategy is not limited to A. thaliana, but generally applicable to other plant species. PMID- 27760137 TI - Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors. AB - Autosomal dominant lateral temporal epilepsy (ADTLE) is a focal epilepsy syndrome caused by mutations in the LGI1 gene, which encodes a secreted protein. Most ADLTE-causing mutations inhibit LGI1 protein secretion, and only a few secretion positive missense mutations have been reported. Here we describe the effects of four disease-causing nonsynonymous LGI1 mutations, T380A, R407C, S473L, and R474Q, on protein secretion and extracellular interactions. Expression of LGI1 mutant proteins in cultured cells shows that these mutations do not inhibit protein secretion. This finding likely results from the lack of effects of these mutations on LGI1 protein folding, as suggested by 3D protein modelling. In addition, immunofluorescence and co-immunoprecipitation experiments reveal that all four mutations significantly impair interaction of LGI1 with the ADAM22 and ADAM23 receptors on the cell surface. These results support the existence of a second mechanism, alternative to inhibition of protein secretion, by which ADLTE causing LGI1 mutations exert their loss-of-function effect extracellularly, and suggest that interactions of LGI1 with both ADAM22 and ADAM23 play an important role in the molecular mechanisms leading to ADLTE. PMID- 27760138 TI - Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease. AB - Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO. PMID- 27760139 TI - Local Adaptation of Sun-Exposure-Dependent Gene Expression Regulation in Human Skin. AB - Sun-exposure is a key environmental variable in the study of human evolution. Several skin-pigmentation genes serve as classical examples of positive selection, suggesting that sun-exposure has significantly shaped worldwide genomic variation. Here we investigate the interaction between genetic variation and sun-exposure, and how this impacts gene expression regulation. Using RNA-Seq data from 607 human skin samples, we identified thousands of transcripts that are differentially expressed between sun-exposed skin and non-sun-exposed skin. We then tested whether genetic variants may influence each individual's gene expression response to sun-exposure. Our analysis revealed 10 sun-exposure dependent gene expression quantitative trait loci (se-eQTLs), including genes involved in skin pigmentation (SLC45A2) and epidermal differentiation (RASSF9). The allele frequencies of the RASSF9 se-eQTL across diverse populations correlate with the magnitude of solar radiation experienced by these populations, suggesting local adaptation to varying levels of sunlight. These results provide the first examples of sun-exposure-dependent regulatory variation and suggest that this variation has contributed to recent human adaptation. PMID- 27760140 TI - Estimated Prevalence of Cryptococcus Antigenemia (CrAg) among HIV-Infected Adults with Advanced Immunosuppression in Namibia Justifies Routine Screening and Preemptive Treatment. AB - BACKGROUND: Cryptococcal meningitis is common and associated with high mortality among HIV infected persons. The World Health Organization recommends that routine Cryptococcal antigen (CrAg) screening in ART-naive adults with a CD4+ count <100 cells/MUL followed by pre-emptive antifungal therapy for CrAg-positive patients be considered where CrAg prevalence is >=3%. The prevalence of CrAg among HIV adults in Namibia is unknown. We estimated CrAg prevalence among HIV-infected adults receiving care in Namibia for the purpose of informing routine screening strategies. METHODS: The study design was cross-sectional. De-identified plasma specimens collected for routine CD4+ testing from HIV-infected adults enrolled in HIV care at 181 public health facilities from November 2013 to January 2014 were identified at the national reference laboratory. Remnant plasma from specimens with CD4+ counts <200 cells/MUL were sampled and tested for CrAg using the IMMY(r) Lateral Flow Assay. CrAg prevalence was estimated and assessed for associations with age, sex, and CD4+ count. RESULTS: A total of 825 specimens were tested for CrAg. The median (IQR) age of patients from whom specimens were collected was 38 (32-46) years, 45.9% were female and 62.9% of the specimens had CD4 <100 cells/MUL. CrAg prevalence was 3.3% overall and 3.9% and 2.3% among samples with CD4+ counts of CD4+<100 cells/MUL and 100-200 cells/MUL, respectively. CrAg positivity was significantly higher among patients with CD4+ cells/MUL < 50 (7.2%, P = 0.001) relative to those with CD4 cells/MUL 50-200 (2.2%). CONCLUSION: This is the first study to estimate CrAg prevalence among HIV infected patients in Namibia. CrAg prevalence of >=3.0% among patients with CD4+<100 cells/MUL justifies routine CrAg screening and preemptive treatment among HIV-infected in Namibia in line with WHO recommendations. Patients with CD4+<100 cells/MUL have a significantly greater risk for CrAg positivity. Revised guidelines for ART in Namibia now recommend routine screening for CrAg. PMID- 27760141 TI - Correlation Between HLA-A, B and DRB1 Alleles and Severe Fever with Thrombocytopenia Syndrome. AB - OBJECTIVE: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever caused by a tick-borne bunyavirus (SFTSV) in East Asian countries. The role of human leukocyte antigen (HLA) in resistance and susceptibility to SFTSV is not known. We investigated the correlation of HLA locus A, B and DRB1 alleles with the occurrence of SFTS. METHODS: A total of 84 confirmed SFTS patients (patient group) and 501 unrelated non-SFTS patients (healthy individuals as control group) from Shandong Province were genotyped by PCR-sequence specific oligonucleotide probe (PCR-SSOP) for HLA-A, B and DRB1 loci.Allele frequency was calculated and compared using chi2 test or the Fisher's exact test. A corrected P value was calculated with a bonferronis correction. Odds Ratio (OR) and 95% confidence intervals (CI) were calculated by Woolf's method. RESULTS: A total of 11 HLA-A, 23 HLA-B and 12 HLA-DRB1 alleles were identified in the patient group, whereas 15 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles were detected in the control group. The frequencies of A*30 and B*13 in the SFTS patient group were lower than that in the control group (P = 0.0341 and 0.0085, Pc = 0.5115 and 0.252). The ORs of A*30 and B*13 in the SFTS patient group were 0.54 and 0.49, respectively. The frequency of two-locus haplotype A*30 B*13 was lower in the patient group than in the control group(5.59% versus 12.27%, P = 0.037,OR = 0.41, 95%CI = 0.18-0.96) without significance(Pc>0.05). A*30-B*13-DRB1*07 and A*02-B*15-DRB1*04 had strong associations with SFTS resistance and susceptibility respectively (Pc = 0.0412 and 0.0001,OR = 0.43 and 5.07). CONCLUSION: The host HLA class I polymorphism might play an important role with the occurrence of SFTS. Negative associations were observed with HLA-A*30, HLA-B*13 and Haplotype A*30-B*13, although the associations were not statistically significant. A*30-B*13-DRB1*07 had negative correlation with the occurrence of SFTS; in contrast, haplotype A*02-B*15-DRB1*04 was positively correlated with SFTS. PMID- 27760142 TI - Identification of Aedes aegypti Long Intergenic Non-coding RNAs and Their Association with Wolbachia and Dengue Virus Infection. AB - Long intergenic non-coding RNAs (lincRNAs) are appearing as an important class of regulatory RNAs with a variety of biological functions. The aim of this study was to identify the lincRNA profile in the dengue vector Aedes aegypti and evaluate their potential role in host-pathogen interaction. The majority of previous RNA Seq transcriptome studies in Ae. aegypti have focused on the expression pattern of annotated protein coding genes under different biological conditions. Here, we used 35 publically available RNA-Seq datasets with relatively high depth to screen the Ae. aegypti genome for lincRNA discovery. This led to the identification of 3,482 putative lincRNAs. These lincRNA genes displayed a slightly lower GC content and shorter transcript lengths compared to protein encoding genes. Ae. aegypti lincRNAs also demonstrate low evolutionary sequence conservation even among closely related species such as Culex quinquefasciatus and Anopheles gambiae. We examined their expression in dengue virus serotype 2 (DENV-2) and Wolbachia infected and non-infected adult mosquitoes and Aa20 cells. The results revealed that DENV-2 infection increased the abundance of a number of host lincRNAs, from which some suppress viral replication in mosquito cells. RNAi mediated silencing of lincRNA_1317 led to enhancement in viral replication, which possibly indicates its potential involvement in the host anti-viral defense. A number of lincRNAs were also differentially expressed in Wolbachia-infected mosquitoes. The results will facilitate future studies to unravel the function of lncRNAs in insects and may prove to be beneficial in developing new ways to control vectors or inhibit replication of viruses in them. PMID- 27760143 TI - Protective Efficacy of Plasmodium vivax Radiation-Attenuated Sporozoites in Colombian Volunteers: A Randomized Controlled Trial. AB - BACKGROUND: Immunizing human volunteers by mosquito bite with radiation attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. METHODOLOGY/PRINCIPAL FINDINGS: A randomized, single-blinded trial was conducted. Duffy positive (Fy+; Pv susceptible) individuals were enrolled: 14 received bites from irradiated (150 +/- 10 cGy) Pv-infected Anopheles mosquitoes (RAS) and 7 from non-irradiated non-infected mosquitoes (Ctl). An additional group of seven Fy- (Pv refractory) volunteers was immunized with bites from non irradiated Pv-infected mosquitoes. A total of seven immunizations were carried out at mean intervals of nine weeks. Eight weeks after last immunization, a controlled human malaria infection (CHMI) with non-irradiated Pv-infected mosquitoes was performed. Nineteen volunteers completed seven immunizations (12 RAS, 2 Ctl, and 5 Fy-) and received a CHMI. Five of 12 (42%) RAS volunteers were protected (receiving a median of 434 infective bites) compared with 0/2 Ctl. None of the Fy- volunteers developed infection by the seventh immunization or after CHMI. All non-protected volunteers developed symptoms 8-13 days after CHMI with a mean pre-patent period of 12.8 days. No serious adverse events related to the immunizations were observed. Specific IgG1 anti-PvCS response was associated with protection. CONCLUSION: Immunization with PvRAS was safe, immunogenic, and induced sterile immunity in 42% of the Fy+ volunteers. Moreover, Fy- volunteers were refractory to Pv malaria. TRIAL REGISTRATION: Identifier: NCT01082341. PMID- 27760145 TI - Correction: Supported Telemonitoring and Glycemic Control in People with Type 2 Diabetes: The Telescot Diabetes Pragmatic Multicenter Randomized Controlled Trial. AB - [This corrects the article DOI: 10.1371/journal.pmed.1002098.]. PMID- 27760144 TI - Rift Valley Fever Virus Circulating among Ruminants, Mosquitoes and Humans in the Central African Republic. AB - BACKGROUND: Rift Valley fever virus (RVFV) causes a viral zoonosis, with discontinuous epizootics and sporadic epidemics, essentially in East Africa. Infection with this virus causes severe illness and abortion in sheep, goats, and cattle as well as other domestic animals. Humans can also be exposed through close contact with infectious tissues or by bites from infected mosquitoes, primarily of the Aedes and Culex genuses. Although the cycle of RVFV infection in savannah regions is well documented, its distribution in forest areas in central Africa has been poorly investigated. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate current circulation of RVFV among livestock and humans living in the Central African Republic (CAR), blood samples were collected from sheep, cattle, and goats and from people at risk, such as stock breeders and workers in slaughterhouses and livestock markets. The samples were tested for anti-RVFV immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies. We also sequenced the complete genomes of two local strains, one isolated in 1969 from mosquitoes and one isolated in 1985 from humans living in forested areas. The 1271 animals sampled comprised 727 cattle, 325 sheep, and 219 goats at three sites. The overall seroprevalence of anti-RVFV IgM antibodies was 1.9% and that of IgG antibodies was 8.6%. IgM antibodies were found only during the rainy season, but the frequency of IgG antibodies did not differ significantly by season. No evidence of recent RVFV infection was found in 335 people considered at risk; however, 16.7% had evidence of past infection. Comparison of the nucleotide sequences of the strains isolated in the CAR with those isolated in other African countries showed that they belonged to the East/Central African cluster. CONCLUSION AND SIGNIFICANCE: This study confirms current circulation of RVFV in CAR. Further studies are needed to determine the potential vectors involved and the virus reservoirs. PMID- 27760146 TI - Alignment of Homologous Chromosomes and Effective Repair of Programmed DNA Double Strand Breaks during Mouse Meiosis Require the Minichromosome Maintenance Domain Containing 2 (MCMDC2) Protein. AB - Orderly chromosome segregation during the first meiotic division requires meiotic recombination to form crossovers between homologous chromosomes (homologues). Members of the minichromosome maintenance (MCM) helicase family have been implicated in meiotic recombination. In addition, they have roles in initiation of DNA replication, DNA mismatch repair and mitotic DNA double-strand break repair. Here, we addressed the function of MCMDC2, an atypical yet conserved MCM protein, whose function in vertebrates has not been reported. While we did not find an important role for MCMDC2 in mitotically dividing cells, our work revealed that MCMDC2 is essential for fertility in both sexes due to a crucial function in meiotic recombination. Meiotic recombination begins with the introduction of DNA double-strand breaks into the genome. DNA ends at break sites are resected. The resultant 3-prime single-stranded DNA overhangs recruit RAD51 and DMC1 recombinases that promote the invasion of homologous duplex DNAs by the resected DNA ends. Multiple strand invasions on each chromosome promote the alignment of homologous chromosomes, which is a prerequisite for inter-homologue crossover formation during meiosis. We found that although DNA ends at break sites were evidently resected, and they recruited RAD51 and DMC1 recombinases, these recombinases were ineffective in promoting alignment of homologous chromosomes in the absence of MCMDC2. Consequently, RAD51 and DMC1 foci, which are thought to mark early recombination intermediates, were abnormally persistent in Mcmdc2-/- meiocytes. Importantly, the strand invasion stabilizing MSH4 protein, which marks more advanced recombination intermediates, did not efficiently form foci in Mcmdc2-/- meiocytes. Thus, our work suggests that MCMDC2 plays an important role in either the formation, or the stabilization, of DNA strand invasion events that promote homologue alignment and provide the basis for inter-homologue crossover formation during meiotic recombination. PMID- 27760148 TI - Instrument for Real-Time Digital Nucleic Acid Amplification on Custom Microfluidic Devices. AB - Nucleic acid amplification tests that are coupled with a digital readout enable the absolute quantification of single molecules, even at ultralow concentrations. Digital methods are robust, versatile and compatible with many amplification chemistries including isothermal amplification, making them particularly invaluable to assays that require sensitive detection, such as the quantification of viral load in occult infections or detection of sparse amounts of DNA from forensic samples. A number of microfluidic platforms are being developed for carrying out digital amplification. However, the mechanistic investigation and optimization of digital assays has been limited by the lack of real-time kinetic information about which factors affect the digital efficiency and analytical sensitivity of a reaction. Commercially available instruments that are capable of tracking digital reactions in real-time are restricted to only a small number of device types and sample-preparation strategies. Thus, most researchers who wish to develop, study, or optimize digital assays rely on the rate of the amplification reaction when performed in a bulk experiment, which is now recognized as an unreliable predictor of digital efficiency. To expand our ability to study how digital reactions proceed in real-time and enable us to optimize both the digital efficiency and analytical sensitivity of digital assays, we built a custom large-format digital real-time amplification instrument that can accommodate a wide variety of devices, amplification chemistries and sample-handling conditions. Herein, we validate this instrument, we provide detailed schematics that will enable others to build their own custom instruments, and we include a complete custom software suite to collect and analyze the data retrieved from the instrument. We believe assay optimizations enabled by this instrument will improve the current limits of nucleic acid detection and quantification, improving our fundamental understanding of single molecule reactions and providing advancements in practical applications such as medical diagnostics, forensics and environmental sampling. PMID- 27760147 TI - Diagnostic Potential of Cell-Free and Exosomal MicroRNAs in the Identification of Patients with High-Risk Colorectal Adenomas. AB - BACKGROUND: Although there is a growing interest in developing circulating microRNA (miRNA) as noninvasive diagnostic biomarkers for the detection of high risk colorectal adenomas and early-stage CRCs, but the comparative diagnostic significance of serum vs. exosomal miRNAs remains unexplored. METHODS: Based upon published literature, we performed an initial discovery step by investigating the expression of a miRNA panel in 20 normal colonic mucosa, 27 adenomas, and 19 CRC tissues. We performed subsequent validation by quantifying expression of candidate miRNAs in total serum and in exosomes from 26 adenoma patients and 47 healthy controls, and evaluated their clinical significance and potential diagnostic value in colorectal adenomas. RESULTS: We observed that the expression of four miRNAs, miR-21, miR-29a, miR-92a, and miR-135b, was significantly higher in colorectal adenomas vs. normal colonic mucosa. During validation, expression of miR-21, miR-29a and miR-92a in serum was significantly higher in adenomas vs. healthy controls, significantly correlated with adenoma size and total adenoma number within the colorectum, and significantly discriminated patients with advanced adenomas. In contrast, although exosomal miR-21 and miR-29a levels in adenoma patients were significantly higher than those of healthy volunteers, only exosomal miR-21 significantly correlated with adenoma size and total adenoma number, and could discriminate patients with high-risk adenomas. CONCLUSION: Compared to exosomal miRNAs, serum levels of miR-21, miR-29a and miR-92a are superior diagnostic biomarkers in patients with high-risk adenomatous polyps. PMID- 27760149 TI - BEST: Next-Generation Biomedical Entity Search Tool for Knowledge Discovery from Biomedical Literature. AB - As the volume of publications rapidly increases, searching for relevant information from the literature becomes more challenging. To complement standard search engines such as PubMed, it is desirable to have an advanced search tool that directly returns relevant biomedical entities such as targets, drugs, and mutations rather than a long list of articles. Some existing tools submit a query to PubMed and process retrieved abstracts to extract information at query time, resulting in a slow response time and limited coverage of only a fraction of the PubMed corpus. Other tools preprocess the PubMed corpus to speed up the response time; however, they are not constantly updated, and thus produce outdated results. Further, most existing tools cannot process sophisticated queries such as searches for mutations that co-occur with query terms in the literature. To address these problems, we introduce BEST, a biomedical entity search tool. BEST returns, as a result, a list of 10 different types of biomedical entities including genes, diseases, drugs, targets, transcription factors, miRNAs, and mutations that are relevant to a user's query. To the best of our knowledge, BEST is the only system that processes free text queries and returns up-to-date results in real time including mutation information in the results. BEST is freely accessible at http://best.korea.ac.kr. PMID- 27760150 TI - The Effects of Restricted Peripheral Field-of-View on Spatial Learning while Navigating. AB - Recent work with simulated reductions in visual acuity and contrast sensitivity has found decrements in survey spatial learning as well as increased attentional demands when navigating, compared to performance with normal vision. Given these findings, and previous work showing that peripheral field loss has been associated with impaired mobility and spatial memory for room-sized spaces, we investigated the role of peripheral vision during navigation using a large-scale spatial learning paradigm. First, we aimed to establish the magnitude of spatial memory errors at different levels of field restriction. Second, we tested the hypothesis that navigation under these different levels of restriction would use additional attentional resources. Normally sighted participants walked on novel real-world paths wearing goggles that restricted the field-of-view (FOV) to severe (15 degrees , 10 degrees , 4 degrees , or 0 degrees ) or mild angles (60 degrees ) and then pointed to remembered target locations using a verbal reporting measure. They completed a concurrent auditory reaction time task throughout each path to measure cognitive load. Only the most severe restrictions (4 degrees and blindfolded) showed impairment in pointing error compared to the mild restriction (within-subjects). The 10 degrees and 4 degrees conditions also showed an increase in reaction time on the secondary attention task, suggesting that navigating with these extreme peripheral field restrictions demands the use of limited cognitive resources. This comparison of different levels of field restriction suggests that although peripheral field loss requires the actor to use more attentional resources while navigating starting at a less extreme level (10 degrees ), spatial memory is not negatively affected until the restriction is very severe (4 degrees ). These results have implications for understanding of the mechanisms underlying spatial learning during navigation and the approaches that may be taken to develop assistance for navigation with visual impairment. PMID- 27760151 TI - New Species of the Fern Genus Lindsaea (Lindsaeaceae) from New Guinea with Notes on the Phylogeny of L. sect. Synaphlebium. AB - To determine the taxonomic identities and the systematic positions of some collections of Lindsaea sect. Synaphlebium (Lindsaeaceae) from Papua New Guinea, we conducted morphological comparisons and phylogenetic analyses on the whole section. A total of 22 morphological characters were selected and coded for each of all known taxa in L. sect. Synaphlebium, and were analyzed using maximum parsimony. The datasets containing either of or combined two plastid DNA sequences (trnL-trnF spacer and trnH-psbA spacer) of 37 taxa were analyzed using maximum parsimony, maximum likelihood, and Bayesian inference. Morphological comparisons revealed two new species which are formally published here as L. subobscura and L. novoguineensis. Lindsaea subobscura is similar to sympatric L. obscura and L. modesta but differs in the obviously reduced upper pinnules and other characters. Lindsaea novoguineensis is most similar to L. pacifica from Melanesia but differs in having rhomboid pinnules with truncate apices and concave soral receptacles. Molecular analyses resolved L. sect. Synaphlebium and allied species into five well-supported clades, namely L. rigida clade, L. obtusa clade, L. pulchella clade, L. multisora clade, and L. cultrata clade. The new species L. novoguineensis is included in L. obtusa clade; L. subobscura is in L. pulchella clade; whereas the majority of L. sect. Synaphlebium is clustered in L. cultrata clade. As the section Synaphlebium sensu Kramer is strongly suggested as polyphyletic, we propose the concept of a monophyletic L. sect. Synaphlebium in a broad sense that comprises five lineages. The morphological circumscription of L. sect. Synaphlebium sensu lato and the divergence in morphology, habit, and distribution between the five lineages are briefly discussed. Further molecular study is needed to test the systematic positions of 16 other species which are supposed to be within L. sect. Synaphlebium sensu lato but have not been included in this and previous molecular analyses. PMID- 27760152 TI - Mapping the Elephants of the 19th Century East African Ivory Trade with a Multi Isotope Approach. AB - East African elephants have been hunted for their ivory for millennia but the nineteenth century witnessed strongly escalating demand from Europe and North America. It has been suggested that one consequence was that by the 1880s elephant herds along the coast had become scarce, and to meet demand, trade caravans trekked farther into interior regions of East Africa, extending the extraction frontier. The steady decimation of elephant populations coupled with the extension of trade networks have also been claimed to have triggered significant ecological and socio-economic changes that left lasting legacies across the region. To explore the feasibility of using an isotopic approach to uncover a 'moving frontier' of elephant extraction, we constructed a baseline isotope data set (delta13C, delta15N, delta18O and 87Sr/86Sr) for historic East African elephants known to have come from three distinct regions (coastal, Rift Valley, and inland Lakes). Using the isotope results with other climate data and geographical mapping tools, it was possible to characterise elephants from different habitats across the region. This baseline data set was then used to provenance elephant ivory of unknown geographical provenance that was exported from East Africa during the late nineteenth and early twentieth centuries to determine its likely origin. This produced a better understanding of historic elephant geography in the region, and the data have the potential to be used to provenance older archaeological ivories, and to inform contemporary elephant conservation strategies. PMID- 27760154 TI - Freshwater Fossil Pearls from the Nihewan Basin, Early Early Pleistocene. AB - Fossil blister pearls attached to the shells of an Anodonta mollusk from China, early Early Pleistocene, are reported here for the first time. The pearls were investigated in detail using a variety of methods. Micro-CT scanning of the fossil pearls was carried out to discover the inner structure and the pearl nucleus. Using CTAn software, changes in the gray levels of the biggest pearl, which reflect the changing density of the material, were investigated. The results provide us with some clues on how these pearls were formed. Sand grains, shell debris or material with a similar density could have stimulated the development of these pearls. X-ray diffraction analysis of one fossil pearl and the shell to which it was attached reveals that only aragonite exists in both samples. The internal structures of our fossil shells and pearls were investigated using a Scanning Electron Microscope. These investigations throw some light on pearl development in the past. PMID- 27760153 TI - Formin DAAM1 Organizes Actin Filaments in the Cytoplasmic Nodal Actin Network. AB - A nodal cytoplasmic actin network underlies actin cytoplasm cohesion in the absence of stress fibers. We previously described such a network that forms upon Latrunculin A (LatA) treatment, in which formin DAAM1 was localized at these nodes. Knock down of DAAM1 reduced the mobility of actin nodes but the nodes remained. Here we have investigated DAAM1 containing nodes after LatA washout. DAAM1 was found to be distributed between the cytoplasm and the plasma membrane. The membrane binding likely occurs through an interaction with lipid rafts, but is not required for F-actin assembly. Interesting the forced interaction of DAAM1 with plasma membrane through a rapamycin-dependent linkage, enhanced F-actin assembly at the cell membrane (compared to the cytoplasm) after the LatA washout. However, immediately after addition of both rapamycin and LatA, the cytoplasmic actin nodes formed transiently, before DAAM1 moved to the membrane. This was consistent with the idea that DAAM1 was initially anchored to cytoplasmic actin nodes. Further, photoactivatable tracking of DAAM1 showed DAAM1 was immobilized at these actin nodes. Thus, we suggest that DAAM1 organizes actin filaments into a nodal complex, and such nodal complexes seed actin network recovery after actin depolymerization. PMID- 27760155 TI - Spatiotemporal Variation in Distance Dependent Animal Movement Contacts: One Size Doesn't Fit All. AB - The structure of contacts that mediate transmission has a pronounced effect on the outbreak dynamics of infectious disease and simulation models are powerful tools to inform policy decisions. Most simulation models of livestock disease spread rely to some degree on predictions of animal movement between holdings. Typically, movements are more common between nearby farms than between those located far away from each other. Here, we assessed spatiotemporal variation in such distance dependence of animal movement contacts from an epidemiological perspective. We evaluated and compared nine statistical models, applied to Swedish movement data from 2008. The models differed in at what level (if at all), they accounted for regional and/or seasonal heterogeneities in the distance dependence of the contacts. Using a kernel approach to describe how probability of contacts between farms changes with distance, we developed a hierarchical Bayesian framework and estimated parameters by using Markov Chain Monte Carlo techniques. We evaluated models by three different approaches of model selection. First, we used Deviance Information Criterion to evaluate their performance relative to each other. Secondly, we estimated the log predictive posterior distribution, this was also used to evaluate their relative performance. Thirdly, we performed posterior predictive checks by simulating movements with each of the parameterized models and evaluated their ability to recapture relevant summary statistics. Independent of selection criteria, we found that accounting for regional heterogeneity improved model accuracy. We also found that accounting for seasonal heterogeneity was beneficial, in terms of model accuracy, according to two of three methods used for model selection. Our results have important implications for livestock disease spread models where movement is an important risk factor for between farm transmission. We argue that modelers should refrain from using methods to simulate animal movements that assume the same pattern across all regions and seasons without explicitly testing for spatiotemporal variation. PMID- 27760156 TI - Moss Mediates the Influence of Shrub Species on Soil Properties and Processes in Alpine Tundra. AB - In tundra ecosystems, bryophytes influence soil processes directly and indirectly through interactions with overstory shrub species. We experimentally manipulated moss cover and measured seasonal soil properties and processes under two species of deciduous shrubs with contrasting canopy structures, Salix planifolia pulchra and Betula glandulosa-nana complex. Soil properties (seasonal temperature, moisture and C:N ratios) and processes (seasonal litter decomposition and soil respiration) were measured over twelve months. Shrub species identity had the largest influence on summer soil temperatures and soil respiration rates, which were higher under Salix canopies. Mosses were associated with lower soil moisture irrespective of shrub identity, but modulated the effects of shrubs on winter soil temperatures and soil C:N ratios so that moss cover reduced differences in soil winter temperatures between shrub species and reduced C:N ratios under Betula but not under Salix canopies. Our results suggest a central role of mosses in mediating soil properties and processes, with their influence depending on shrub species identity. Such species-dependent effects need to be accounted for when forecasting vegetation dynamics under ongoing environmental changes. PMID- 27760157 TI - Dual Inhibition of Topoisomerase II and Tyrosine Kinases by the Novel Bis Fluoroquinolone Chalcone-Like Derivative HMNE3 in Human Pancreatic Cancer Cells. AB - Both tyrosine kinase and topoisomerase II (TopII) are important anticancer targets, and their respective inhibitors are widely used in cancer therapy. However, some combinations of anticancer drugs could exhibit mutually antagonistic actions and drug resistance, which further limit their therapeutic efficacy. Here, we report that HMNE3, a novel bis-fluoroquinolone chalcone-like derivative that targets both tyrosine kinase and TopII, induces tumor cell proliferation and growth inhibition. The viabilities of 6 different cancer cell lines treated with a range of HMNE3 doses were detected using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was determined using Hoechst 33258 fluorescence staining and the terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. The expression of activated Caspase-3 was examined by immunocytochemistry. The tyrosine kinase activity was measured with a human receptor tyrosine kinase (RTK) detection kit using a horseradish peroxidase (HRP)-conjugated phosphotyrosine (pY20) antibody as the substrate. The topoisomerase II activity was measured using agarose gel electrophoresis with the DNA plasmid pBR322 as the substrate. The expression levels of the P53, Bax, Bcl-2, Caspase-3, -8, -9, p-cSrc, c-Src and topoisomerase II proteins were detected by western blot analysis. The proliferation of five of the six cancer cell lines was significantly inhibited by HMNE3 at 0.312 to 10 MUmol/L in a time- and dose-dependent manner. Treatment of the Capan-1 and Panc-1 cells with 1.6 to 3.2 MUM HMNE3 for 48 h significantly increased the percentage of apoptotic cells (P<0.05), and this effect was accompanied by a decrease in tyrosine kinase activity. HMNE3 potentially inhibited tyrosine kinase activity in vitro with an IC50 value of 0.64+/-0.34 MUmol/L in Capan-1 cells and 3.1+/-0.86 MUmol/L in Panc-1 cells. The activity of c-Src was significantly inhibited by HMNE3 in a dose- and time-dependent manner in different cellular contexts. Compared with the control group, HMNE3 induced increased expression of cellular apoptosis-related proteins. Consistent with cellular apoptosis data, a significant decrease in topoisomerase IIbeta activity was noted following treatment with HMNE3 for 24 h. Our data suggest that HMNE3 induced apoptosis in Capan-1 and Panc-1 cells by inhibiting the activity of both tyrosine kinases and topoisomerase II. PMID- 27760158 TI - Optogenetically Blocking Sharp Wave Ripple Events in Sleep Does Not Interfere with the Formation of Stable Spatial Representation in the CA1 Area of the Hippocampus. AB - During hippocampal sharp wave/ripple (SWR) events, previously occurring, sensory input-driven neuronal firing patterns are replayed. Such replay is thought to be important for plasticity-related processes and consolidation of memory traces. It has previously been shown that the electrical stimulation-induced disruption of SWR events interferes with learning in rodents in different experimental paradigms. On the other hand, the cognitive map theory posits that the plastic changes of the firing of hippocampal place cells constitute the electrophysiological counterpart of the spatial learning, observable at the behavioral level. Therefore, we tested whether intact SWR events occurring during the sleep/rest session after the first exploration of a novel environment are needed for the stabilization of the CA1 code, which process requires plasticity. We found that the newly-formed representation in the CA1 has the same level of stability with optogenetic SWR blockade as with a control manipulation that delivered the same amount of light into the brain. Therefore our results suggest that at least in the case of passive exploratory behavior, SWR-related plasticity is dispensable for the stability of CA1 ensembles. PMID- 27760159 TI - Variations of Phosphorous Accessibility Causing Changes in Microbiome Functions in the Gastrointestinal Tract of Chickens. AB - The chicken gastrointestinal tract (GIT) harbours a complex microbial community, involved in several physiological processes such as host immunomodulation and feed digestion. For the first time, the present study analysed dietary effects on the protein inventory of the microbiome in crop and ceca of broilers. We performed quantitative label-free metaproteomics by using 1-D-gel electrophoresis coupled with LC-MS/MS to identify the structural and functional changes triggered by diets supplied with varying amount of mineral phosphorous (P) and microbial phytase (MP). Phylogenetic assessment based on label-free quantification (LFQ) values of the proteins identified Lactobacillaceae as the major family in the crop section regardless of the diet, whereas proteins belonging to the family Veillonellaceae increased with the P supplementation. Within the ceca section, proteins of Bacteroidaceae were more abundant in the P-supplied diets, whereas proteins of Eubacteriaceae decreased with the P-addition. Proteins of the Ruminococcaceae increased with the amount of MP while proteins of Lactobacillaceae were more abundant in the MP-lacking diets. Classification of the identified proteins indicated a thriving microbial community in the case of P and MP supplementation, and stressed microbial community when no P and MP were supplied. Data are available via ProteomeXchange with identifier PXD003805. PMID- 27760160 TI - Molecular Differences in Hepatic Metabolism between AA Broiler and Big Bone Chickens: A Proteomic Study. AB - Identifying the metabolic differences in the livers of modern broilers and local chicken breeds is important for understanding their biological characteristics, and many proteomic changes in their livers are not well characterized. We therefore analyzed the hepatic protein profiles of a commercial breed, Arbor Acres (AA) broilers, and a local dual purpose breed, Big Bone chickens, using two dimensional electrophoresis combined with liquid chromatography-chip/electrospray ionization-quadruple time-of-flight/mass spectrometry (LC-MS/MS). A total of 145 proteins were identified as having differential abundance in the two breeds at three growth stages. Among them, 49, 63 and 54 belonged to 2, 4, and 6 weeks of age, respectively. The higher abundance proteins in AA broilers were related to the energy production pathways suggesting enhanced energy metabolism and lipid biosynthesis. In contrast, the higher abundance proteins in Big Bone chickens showed enhanced lipid degradation, resulting in a reduction in the abdominal fat percentage. Along with the decrease in fat deposition, flavor substance synthesis in the meat of the Big Bone chickens may be improved by enhanced abundance of proteins involved in glycine metabolism. In addition, the identified proteins in nucleotide metabolism, antioxidants, cell structure, protein folding and transporters may be critically important for immune defense, gene transcription and other biological processes in the two breeds. These results indicate that selection pressure may have shaped the two lines differently resulting in different hepatic metabolic capacities and extensive metabolic differences in the liver. The results from this study may help provide the theoretical basis for chicken breeding. PMID- 27760161 TI - The Transcriptome of Rhabdomyosarcoma Cells Infected with Cytolytic and Non Cytolytic Variants of Coxsackievirus B2 Ohio-1. AB - The transcriptomes of cells infected with lytic and non-lytic variants of coxsackievirus B2 Ohio-1 (CVB2O) were analyzed using next generation sequencing. This approach was selected with the purpose of elucidating the effects of lytic and non-lytic viruses on host cell transcription. Total RNA was extracted from infected cells and sequenced. The resulting reads were subsequently mapped against the human and CVB2O genomes. The amount of intracellular RNA was measured, indicating lower proportions of human RNA in the cells infected with the lytic virus compared to the non-lytic virus after 48 hours. This may be explained by reduced activity of the cellular transcription/translation machinery in lytic enteroviral replication due to activities of the enteroviral proteases 2A and/or 3C. Furthermore, differential expression in the cells infected with the two virus variants was identified and a number of transcripts were singled out as possible answers to the question of how the viruses interact with the host cells, resulting in lytic or non-lytic infections. PMID- 27760164 TI - Risk, Reliability and Resilience: Phytolith Evidence for Alternative 'Neolithization' Pathways at Kharaneh IV in the Azraq Basin, Jordan. AB - 'Neolithization' pathway refers to the development of adaptations that characterized subsequent Neolithic life, sedentary occupations, and agriculture. In the Levant, the origins of these human behaviors are widely argued to have emerged during the Early Epipaleolithic (ca. 23 ka cal BP). Consequently, there has been a pre-occupation with identifying and modeling the dietary shift to cereal and grains during this period, which is considered to have been a key development that facilitated increasing sedentism and, eventually, agriculture. Yet, direct evidence of plant use in the form of macrobotanical remains is extremely limited at Epipaleolithic sites and the expected 'Neolithization' pathway has not been robustly demonstrated. However, new direct microbotanical phytolith evidence from the large aggregation site of Kharaneh IV, in the Azraq Basin, suggests that increasingly settled occupation was not the result of wild grass and cereal use, but rather the result of a typical hunter-gatherer balance, based on the use of mostly reliable resources supplemented by some risky resources. Moreover, and illustrating this balance, the direct botanical evidence emphases the importance of the wetlands as an under-recognized reliable plant resource. Significantly, the use of these reliable wetland plant resources at Kharaneh IV represents an unexpected 'Neolithization' pathway. PMID- 27760163 TI - Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression. AB - The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity. A higher state of inflammation was observed in liver cancer tissues as evident from upregulation of inflammatory cytokines IL-6 and TNF-alpha along with NF-kappaB and STAT3. Our data in mouse model suggested a negative correlation between down-regulation of PXR and its target genes with that of higher expression of inflammatory proteins (like IL-6, TNF-alpha, NF kappaB). In conjunction, our findings with relevant cell culture based assays showed that higher expression of PXR is involved in reduction of tumorigenic potential in hepatic cancer. Overall, the findings suggest that inflammation influences the expression of hepatic proteins important in drug metabolism while higher PXR level reduces tumorigenic potential in hepatic cancer. PMID- 27760162 TI - Transcriptome Analysis of the Hepatopancreas in the Pacific White Shrimp (Litopenaeus vannamei) under Acute Ammonia Stress. AB - In the practical farming of Litopenaeus vannamei, the intensive culture system and environmental pollution usually results in a high concentration of ammonia, which usually brings large detrimental effects to shrimp, such as increasing the susceptibility to pathogens, reducing growth, decreasing osmoregulatory capacity, increasing the molting frequency, and even causing high mortality. However, little information is available on the molecular mechanisms of the detrimental effects of ammonia stress in shrimp. In this study, we performed comparative transcriptome analysis between ammonia-challenged and control groups from the same family of L. vannamei to identify the key genes and pathways response to ammonia stress. The comparative transcriptome analysis identified 136 significantly differentially expressed genes that have high homologies with the known proteins in aquatic species, among which 94 genes are reported potentially related to immune function, and the rest of the genes are involved in apoptosis, growth, molting, and osmoregulation. Fourteen GO terms and 6 KEGG pathways were identified to be significantly changed by ammonia stress. In these GO terms, 13 genes have been studied in aquatic species, and 11 of them were reported potentially involved in immune defense and two genes were related to molting. In the significantly changed KEGG pathways, all the 7 significantly changed genes have been reported in shrimp, and four of them were potentially involved in immune defense and the other three were related to molting, defending toxicity, and osmoregulation, respectively. In addition, majority of the significantly changed genes involved in nitrogen metabolisms that play an important role in reducing ammonia toxicity failed to perform the protection function. The present results have supplied molecular level support for the previous founding of the detrimental effects of ammonia stress in shrimp, which is a prerequisite for better understanding the molecular mechanism of the immunosuppression from ammonia stress. PMID- 27760165 TI - The Role of the Trypanosoma cruzi TcNRBD1 Protein in Translation. AB - The regulation of gene expression in trypanosomatids occurs mainly at the post transcriptional level. Despite the importance of this type of control in Trypanosoma cruzi, few RNA binding proteins have been characterized. The RRM domain (RNA Recognition Motif) is one of the most abundant domains found in RNA binding proteins in higher eukaryotes. Proteins containing the RRM domain are involved in the majority of post-transcriptional processes regulating gene expression. In this work, we aimed to characterize the protein TcNRBD1 from T. cruzi. TcNRBD1 is an RNA-binding protein that contains 2 RRM domains and is the ortholog of the P34 and P37 proteins from Trypanosoma brucei. The TcNRBD1 protein is expressed in all developmental stages of T. cruzi, and its localization pattern is concentrated at the perinuclear region. TcNRBD1 is associated with polysomes and with the 80S monosomes. Furthermore, sequencing of the mRNAs bound to TcNRBD1 allowed the identification of several transcripts that encode ribosomal proteins. Immunoprecipitation assays followed by mass spectrometry showed that the protein complexes with several ribosomal proteins from both the 40S and 60S subunits. In summary, the results indicate that TcNRBD1 is associated with different parts of the translation process, either by regulating mRNAs that encode ribosomal proteins or by acting in some step of ribosome assembly in T. cruzi. PMID- 27760166 TI - Reliable Dual Tensor Model Estimation in Single and Crossing Fibers Based on Jeffreys Prior. AB - PURPOSE: This paper presents and studies a framework for reliable modeling of diffusion MRI using a data-acquisition adaptive prior. METHODS: Automated relevance determination estimates the mean of the posterior distribution of a rank-2 dual tensor model exploiting Jeffreys prior (JARD). This data-acquisition prior is based on the Fisher information matrix and enables the assessment whether two tensors are mandatory to describe the data. The method is compared to Maximum Likelihood Estimation (MLE) of the dual tensor model and to FSL's ball and-stick approach. RESULTS: Monte Carlo experiments demonstrated that JARD's volume fractions correlated well with the ground truth for single and crossing fiber configurations. In single fiber configurations JARD automatically reduced the volume fraction of one compartment to (almost) zero. The variance in fractional anisotropy (FA) of the main tensor component was thereby reduced compared to MLE. JARD and MLE gave a comparable outcome in data simulating crossing fibers. On brain data, JARD yielded a smaller spread in FA along the corpus callosum compared to MLE. Tract-based spatial statistics demonstrated a higher sensitivity in detecting age-related white matter atrophy using JARD compared to both MLE and the ball-and-stick approach. CONCLUSIONS: The proposed framework offers accurate and precise estimation of diffusion properties in single and dual fiber regions. PMID- 27760167 TI - Genomic Regions Associated with Feed Efficiency Indicator Traits in an Experimental Nellore Cattle Population. AB - The objective of this study was to identify genomic regions and metabolic pathways associated with dry matter intake, average daily gain, feed efficiency and residual feed intake in an experimental Nellore cattle population. The high density SNP chip (Illumina High-Density Bovine BeadChip, 777k) was used to genotype the animals. The SNP markers effects and their variances were estimated using the single-step genome wide association method. The (co)variance components were estimated by Bayesian inference. The chromosome segments that are responsible for more than 1.0% of additive genetic variance were selected to explore and determine possible quantitative trait loci. The bovine genome Map Viewer was used to identify genes. In total, 51 genomic regions were identified for all analyzed traits. The heritability estimated for feed efficiency was low magnitude (0.13+/-0.06). For average daily gain, dry matter intake and residual feed intake, heritability was moderate to high (0.43+/-0.05; 0.47+/-0.05, 0.18+/ 0.05, respectively). A total of 8, 17, 14 and 12 windows that are responsible for more than 1% of the additive genetic variance for dry matter intake, average daily gain, feed efficiency and residual feed intake, respectively, were identified. Candidate genes GOLIM4, RFX6, CACNG7, CACNG6, CAPN8, CAPN2, AKT2, GPRC6A, and GPR45 were associated with feed efficiency traits. It was expected that the response to selection would be higher for residual feed intake than for feed efficiency. Genomic regions harboring possible QTL for feed efficiency indicator traits were identified. Candidate genes identified are involved in energy use, metabolism protein, ion transport, transmembrane transport, the olfactory system, the immune system, secretion and cellular activity. The identification of these regions and their respective candidate genes should contribute to the formation of a genetic basis in Nellore cattle for feed efficiency indicator traits, and these results would support the selection for these traits. PMID- 27760168 TI - Abundance and Diversity of Crypto- and Necto-Benthic Coastal Fish Are Higher in Marine Forests than in Structurally Less Complex Macroalgal Assemblages. AB - In Mediterranean subtidal rocky reefs, Cystoseira spp. (Phaeophyceae) form dense canopies up to 1 m high. Such habitats, called 'Cystoseira forests', are regressing across the entire Mediterranean Sea due to multiple anthropogenic stressors, as are other large brown algae forests worldwide. Cystoseira forests are being replaced by structurally less complex habitats, but little information is available regarding the potential difference in the structure and composition of fish assemblages between these habitats. To fill this void, we compared necto benthic (NB) and crypto-benthic (CB) fish assemblage structures between Cystoseira forests and two habitats usually replacing the forests (turf and barren), in two sampling regions (Corsica and Menorca). We sampled NB fish using Underwater Visual Census (UVC) and CB fish using Enclosed Anaesthetic Station Vacuuming (EASV), since UVC is known to underestimate the diversity and density of the 'hard to spot' CB fish. We found that both taxonomic diversity and total density of NB and CB fish were highest in Cystoseira forests and lowest in barrens, while turfs, that could be sampled only at Menorca, showed intermediate values. Conversely, total biomass of NB and CB fish did not differ between habitats because the larger average size of fish in barrens (and turfs) compensated for their lower densities. The NB families Labridae and Serranidae, and the CB families Blenniidae, Cliniidae, Gobiidae, Trypterigiidae and Scorpaenidae, were more abundant in forests. The NB taxa Diplodus spp. and Thalassoma pavo were more abundant in barrens. Our study highlights the importance of using EASV for sampling CB fish, and shows that Cystoseira forests support rich and diversified fish assemblages. This evidence suggests that the ongoing loss of Cystoseira forests may impair coastal fish assemblages and related goods and services to humans, and stresses the need to implement strategies for the successful conservation and/or recovery of marine forests. PMID- 27760170 TI - Three-Dimensional Visualization and Imaging of the Entry Tear and Intimal Flap of Aortic Dissection Using CT Virtual Intravascular Endoscopy. AB - AIMS: Conventional computed tomography (CT) approaches provides limited visualization of the entire endoluminal changes of aortic dissection (AD), which is essential for its treatment. As an important supplement, three-dimensional CT virtual intravascular endoscopy (VIE) can show relevant details. This study aims to determine the value of VIE in displaying the entry tear and intimal flap of AD. METHODS AND RESULTS: Among 127 consecutive symptomatic patients with suspected AD who underwent CT angiography (CTA), 84 subjects were confirmed to have AD and were included in the study. Conventional CT and VIE images were observed and evaluated. From the 92 entry tears revealed via conventional CT, 88 (95.7%) tears appeared on VIE with round (n = 26), slit-shaped (n = 9), or irregular (n = 53) shapes, whereas the intimal flaps were sheetlike (n = 34), tubular (n = 34), wavelike (n = 13), or irregular (n = 7) in shape. The VIE also showed the spatial relationship between the torn flap and adjacent structures. Among 58 entry tears with multiple-line type flap shown on conventional CT, 41 (70.7%) appeared with an irregular shape on VIE, whereas among 30 tears with single-line type flap, 17 (56.7%) appeared as round or slit-shaped on VIE. These results demonstrated a significant difference (P < 0.05). The poor display of tears on VIE was related to the low CT attenuation values in lumen or in neighboring artifacts (P < 0.01). CONCLUSION: CT VIE presents the complete configurations and details of the intimal tears and flaps of AD better than conventional CT approaches. Accordingly, it should be recommended as a necessary assessment tool for endovascular therapy and as part of strategy planning in pre surgical patients. PMID- 27760169 TI - Responses of Bovine Innate Immunity to Mycobacterium avium subsp. paratuberculosis Infection Revealed by Changes in Gene Expression and Levels of MicroRNA. AB - Paratuberculosis in cattle is a chronic granulomatous gastroenteritis caused by Mycobacterium avium subsp. paratubercolosis (MAP) which is endemic worldwide. In dairy herds, it is responsible for huge economic losses. However, current diagnostic methods do not detect subclinical infection making control of the disease difficult. The identification of MAP infected animals during the sub clinical phase of infection would play a key role in preventing the dissemination of the pathogen and in reducing transmission. Gene expression and circulating microRNA (miRNA) signatures have been proposed as biomarkers of disease both in the human and veterinary medicine. In this paper, gene expression and related miRNA levels were investigated in cows positive for MAP, by ELISA and culture, in order to identify potential biomarkers to improve diagnosis of MAP infection. Three groups, each of 5 animals, were used to compare the results of gene expression from positive, exposed and negative cows. Overall 258 differentially expressed genes were identified between unexposed, exposed, but ELISA negative and positive groups which were involved in biological functions related to inflammatory response, lipid metabolism and small molecule biochemistry. Differentially expressed miRNA was also found among the three groups: 7 miRNAs were at a lower level and 2 at a higher level in positive animals vs unexposed animals, while 5 and 3 miRNAs were respectively reduced and increased in the exposed group compared to the unexposed group. Among the differentially expressed miRNAs 6 have been previously described as immune-response related and two were novel miRNAs. Analysis of the miRNA levels showed correlation with expression of their target genes, known to be involved in the immune process. This study suggests that miRNA expression is affected by MAP infection and play a key role in tuning the host response to infection. The miRNA and gene expression profiles may be biomarkers of infection and potential diagnostic of MAP infection earlier than the current ELISA based diagnostic tests. PMID- 27760171 TI - Friendship Concept and Community Network Structure among Elementary School and University Students. AB - We use complex network theory to study the differences between the friendship concepts in elementary school and university students. Four friendship networks were identified from surveys. Three of these networks are from elementary schools; two are located in the rural area of Yucatan and the other is in the urban area of Merida, Yucatan. We analyzed the structure and the communities of these friendship networks and found significant differences among those at the elementary schools compared with those at the university. In elementary schools, the students make friends mainly in the same classroom, but there are also links among different classrooms because of the presence of siblings and relatives in the schools. These kinds of links (sibling-friend or relative-friend) are called, in this work, "mixed links". The classification of the communities is based on their similarity with the classroom composition. If the community is composed principally of students in different classrooms, the community is classified as heterogeneous. These kinds of communities appear in the elementary school friendship networks mainly because of the presence of relatives and siblings. Once the links between siblings and relatives are removed, the communities resembled the classroom composition. On the other hand, the university students are more selective in choosing friends and therefore, even when they have friends in the same classroom, those communities are quite different to the classroom composition. Also, in the university network, we found heterogeneous communities even when the presence of sibling and relatives is negligible. These differences made up a topological structure quite different at different academic levels. We also found differences in the network characteristics. Once these differences are understood, the topological structure of the friendship network and the communities shaped in an elementary school could be predicted if we know the total number of students and the ties between siblings and relatives. However, at the university, we cannot do the same. This discovery implies that friendship is a dynamic concept that produces several changes in the friendship network structure and the way that people make groups of friends; it provides the opportunity to give analytic support to observational studies. Communities were also studied by gender and we found that when the links among relatives and siblings were removed, the number of communities formed by one gender alone increased. At the university, many communities formed by students of the same gender were also found. PMID- 27760172 TI - Inhibition of Snail Family Transcriptional Repressor 2 (SNAI2) Enhances Multidrug Resistance of Hepatocellular Carcinoma Cells. AB - China accounts for almost half of the total number of liver cancer cases and deaths worldwide, and hepatocellular carcinoma (HCC) is the most primary liver cancer. Snail family transcriptional repressor 2 (SNAI2) is known as an epithelial to mesenchymal transition-inducing transcription factor that drives neoplastic epithelial cells into mesenchymal phenotype. However, the roles of endogenous SNAI2 remain controversial in different types of malignant tumors. Herein, we surprisingly identify that anchorage-independent growth, including the formation of tumor sphere and soft agar colony, is significantly increased when SNAI2 expression is inhibited by shRNAs in HCC cells. Suppression of SNAI2 suffices to up-regulate several cancer stem genes. Although unrelated to the metastatic ability, SNAI2 inhibition does increase the efflux of Hoechst 33342 and enhance multidrug resistance in vitro and in vivo. In agreement with this data, we demonstrate for the first time that decreasing SNAI2 level can transcriptionally upregulate several ATP binding cassette (ABC) transporter genes such as ABCB1. Moreover, ABC transporters' inhibitor verapamil can rescue the multidrug resistance induced by SNAI2 inhibition. Our results implicate that SNAI2 behaves as a tumor suppressor by inhibiting multidrug resistance via suppressing ABC transporter genes in HCC cells. PMID- 27760173 TI - Filtration and Normalization of Sequencing Read Data in Whole-Metagenome Shotgun Samples. AB - Ever-increasing affordability of next-generation sequencing makes whole metagenome sequencing an attractive alternative to traditional 16S rDNA, RFLP, or culturing approaches for the analysis of microbiome samples. The advantage of whole-metagenome sequencing is that it allows direct inference of the metabolic capacity and physiological features of the studied metagenome without reliance on the knowledge of genotypes and phenotypes of the members of the bacterial community. It also makes it possible to overcome problems of 16S rDNA sequencing, such as unknown copy number of the 16S gene and lack of sufficient sequence similarity of the "universal" 16S primers to some of the target 16S genes. On the other hand, next-generation sequencing suffers from biases resulting in non uniform coverage of the sequenced genomes. To overcome this difficulty, we present a model of GC-bias in sequencing metagenomic samples as well as filtration and normalization techniques necessary for accurate quantification of microbial organisms. While there has been substantial research in normalization and filtration of read-count data in such techniques as RNA-seq or Chip-seq, to our knowledge, this has not been the case for the field of whole-metagenome shotgun sequencing. The presented methods assume that complete genome references are available for most microorganisms of interest present in metagenomic samples. This is often a valid assumption in such fields as medical diagnostics of patient microbiota. Testing the model on two validation datasets showed four-fold reduction in root-mean-square error compared to non-normalized data in both cases. The presented methods can be applied to any pipeline for whole metagenome sequencing analysis relying on complete microbial genome references. We demonstrate that such pre-processing reduces the number of false positive hits and increases accuracy of abundance estimates. PMID- 27760174 TI - BAR Proteins PSTPIP1/2 Regulate Podosome Dynamics and the Resorption Activity of Osteoclasts. AB - Bone resorption in vertebrates relies on the ability of osteoclasts to assemble F actin-rich podosomes that condense into podosomal belts, forming sealing zones. Sealing zones segregate bone-facing ruffled membranes from other membrane domains, and disassemble when osteoclasts migrate to new areas. How podosome/sealing zone dynamics is regulated remains unknown. We illustrate the essential role of the membrane scaffolding F-BAR-Proline-Serine-Threonine Phosphatase Interacting Proteins (PSTPIP) 1 and 2 in this process. Whereas PSTPIP2 regulates podosome assembly, PSTPIP1 regulates their disassembly. PSTPIP1 recruits, through its F-BAR domain, the protein tyrosine phosphatase non-receptor type 6 (PTPN6) that de-phosphophorylates the phosphatidylinositol 5-phosphatases SHIP1/2 bound to the SH3 domain of PSTPIP1. Depletion of any component of this complex prevents sealing zone disassembly and increases osteoclast activity. Thus, our results illustrate the importance of BAR domain proteins in podosome structure and dynamics, and identify a new PSTPIP1/PTPN6/SHIP1/2-dependent negative feedback mechanism that counterbalances Src and PI(3,4,5)P3 signalling to control osteoclast cell polarity and activity during bone resorption. PMID- 27760175 TI - Chicken Immune Response after In Ovo Immunization with Chimeric TLR5 Activating Flagellin of Campylobacter jejuni. AB - Campylobacter jejuni is the main cause of bacterial food-borne diseases in developed countries. Chickens are the most important source of human infection. Vaccination of poultry is an attractive strategy to reduce the number of C. jejuni in the intestinal tract of chickens. We investigated the immunogenicity and protective efficacy of a recombinant C. jejuni flagellin-based subunit vaccine with intrinsic adjuvant activity. Toll-like receptor activation assays demonstrated the purity and TLR5 stimulating (adjuvant) activity of the vaccine. The antigen (20-40 MUg) was administered in ovo to 18 day-old chicken embryos. Serum samples and intestinal content were assessed for antigen-specific systemic and mucosal humoral immune responses. In ovo vaccination resulted in the successful generation of IgY and IgM serum antibodies against the flagellin-based subunit vaccine as determined by ELISA and Western blotting. Vaccination did not induce significant amounts of flagellin-specific secretory IgA in the chicken intestine. Challenge of chickens with C. jejuni yielded similar intestinal colonization levels for vaccinated and control animals. Our results indicate that in ovo delivery of recombinant C. jejuni flagellin subunit vaccine is a feasible approach to yield a systemic humoral immune response in chickens but that a mucosal immune response may be needed to reduce C. jejuni colonization. PMID- 27760176 TI - Hepatitis C Virus Screening and Emergency Department Length of Stay. AB - BACKGROUND: Recent studies demonstrate high rates of previously undiagnosed hepatitis C virus (HCV) infection among patients screened in urban emergency departments (ED). Experts caution, however, that public health interventions, such as screening for infectious diseases, must not interfere with the primary mission of EDs to provide timely acute care. Increases in ED length of stay (LOS) have been associated with decreased quality of ED care. OBJECTIVE: In this study, we assess the influence of an integrated HCV screening protocol on ED LOS. METHODS: This was a retrospective cohort study analyzing timestamp data for all discharged patients over a 1-year period. The primary outcome compared the median LOS in minutes between patients who completed HCV screening and those who did not. Further analysis compared LOS for HCV screening by whether or not complete blood count (CBC) testing was conducted. RESULTS: Of 69,639 visits, 2,864 (4%) had HCV screening tests completed and 272 (9.5%) were antibody positive. The median LOS for visits that included HCV screening was greater than visits that did not include screening (151 versus 119 minutes, P < 0.001). Among the subset of visits in which CBC testing was conducted, there was no significant difference in median LOS between visits that also included HCV screening and those that did not (240 versus 242 minutes, P = 0.68). CONCLUSION: Integrated HCV screening modestly prolongs ED LOS. However, among patients undergoing other blood tests, screening had no effect on LOS. Programs may consider routinely offering HCV screening to patients who are undergoing laboratory testing. PMID- 27760177 TI - Discriminating the Difference between Remote and Close Association with Relation to White-Matter Structural Connectivity. AB - Remote association is a core ability that influences creative output. In contrast to close association, remote association is commonly agreed to be connected with more original and unique concepts. However, although existing studies have discovered that creativity is closely related to the white-matter structure of the brain, there are no studies that examine the relevance between the connectivity efficiencies and creativity of the brain regions from the perspective of networks. Consequently, this study constructed a brain white matter network structure that consisted of cerebral tissues and nerve fibers and used graph theory to analyze the connection efficiencies among the network nodes, further illuminating the differences between remote and close association in relation to the connectivity of the brain network. Researchers analyzed correlations between the scores of 35 healthy adults with regard to remote and close associations and the connectivity efficiencies of the white-matter network of the brain. Controlling for gender, age, and verbal intelligence, the remote association positively correlated with the global efficiency and negatively correlated with the levels of small-world. A close association negatively correlated with the global efficiency. Notably, the node efficiency in the middle temporal gyrus (MTG) positively correlated with remote association and negatively correlated with close association. To summarize, remote and close associations work differently as patterns in the brain network. Remote association requires efficient and convenient mutual connections between different brain regions, while close association emphasizes the limited connections that exist in a local region. These results are consistent with previous results, which indicate that creativity is based on the efficient integration and connection between different regions of the brain and that temporal lobes are the key regions for discriminating remote and close associations. PMID- 27760178 TI - Outcome of Breast Cancer in Moroccan Young Women Correlated to Clinic Pathological Features, Risk Factors and Treatment: A Comparative Study of 716 Cases in a Single Institution. AB - BACKGROUND: Breast cancer in young women is quite uncommon and shows more aggressive characteristics with major disparities between worldwide populations. Prognosis and outcome of breast cancer in young patients are widely studied, but still no consensus is available. METHODS: We retrospectively included 716 cases of breast cancer women diagnosed in 2009 at the National Institute of Oncology of Rabat. Patients were divided into two groups according to their age: women aged <=40 years (Group 1) and women aged >40 years (Group 2). Data were recorded from patients' medical files and analyzed using SPSS 13.0 software (IBM). RESULTS: Young patients represent 24.9% of all patients with breast cancer. The comparison between the two groups displayed significant differences regarding nulliparity (p = 0.001) and progesterone receptor negativity (p = 0.01). Moreover, more progression (Metastases/Relapse) was registered in young women as compared to older women with breast cancer (p = 0.03). The estimated median follow-up period was 31 months. The 5-years Event-Free Survival (EFS) of patients with local disease was 64.6% in young women and 71.5% in older women with breast cancer (p = 0.04). Multivariate analysis in young women showed that nulliparity (HR: 7.2; 95%CI: 1.16-44.54; p = 0.03), T3 tumors (HR: 17.39; 95%CI: 1.74-173.34; p = 0.01) and negative PgR status (HR: 19.85; 95%CI: 1.07-366.54; p = 0.04) can be considered as risk factors for poorer event free survival while hormone therapy was associated with better EFS (HR: 0.11; 95%CI: 0.00-0.75; p = 0.03). In Group 2, multivariate analysis showed that patients with inflammatory breast cancer, N+ status, absence of radiotherapy, absence of chemotherapy, and absence of hormone therapy are at increased risk of recurrence. CONCLUSIONS: In Morocco, breast cancer is more frequent in young women as compared to western countries. Breast cancer in young women is more aggressive and is diagnosed late, leading to an intensive treatment. Moreover, the main factors associated with breast cancer development in young women would be hormonal and reproductive status. Analysis of other genetic biomarkers is needed to explain the high prevalence of breast cancer in young women to improve breast cancer management in Morocco. PMID- 27760179 TI - Genome-Wide Analysis, Classification, Evolution, and Expression Analysis of the Cytochrome P450 93 Family in Land Plants. AB - Cytochrome P450 93 family (CYP93) belonging to the cytochrome P450 superfamily plays important roles in diverse plant processes. However, no previous studies have investigated the evolution and expression of the members of this family. In this study, we performed comprehensive genome-wide analysis to identify CYP93 genes in 60 green plants. In all, 214 CYP93 proteins were identified; they were specifically found in flowering plants and could be classified into ten subfamilies-CYP93A-K, with the last two being identified first. CYP93A is the ancestor that was derived in flowering plants, and the remaining showed lineage specific distribution-CYP93B and CYP93C are present in dicots; CYP93F is distributed only in Poaceae; CYP93G and CYP93J are monocot-specific; CYP93E is unique to legumes; CYP93H and CYP93K are only found in Aquilegia coerulea, and CYP93D is Brassicaceae-specific. Each subfamily generally has conserved gene numbers, structures, and characteristics, indicating functional conservation during evolution. Synonymous nucleotide substitution (dN/dS) analysis showed that CYP93 genes are under strong negative selection. Comparative expression analyses of CYP93 genes in dicots and monocots revealed that they are preferentially expressed in the roots and tend to be induced by biotic and/or abiotic stresses, in accordance with their well-known functions in plant secondary biosynthesis. PMID- 27760180 TI - Clinical Nomogram for Predicting Survival Outcomes in Early Mucinous Breast Cancer. AB - BACKGROUND: The features related to the prognosis of patients with mucinous breast cancer (MBC) remain controversial. We aimed to explore the prognostic factors of MBC and develop a nomogram for predicting survival outcomes. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was searched to identify 139611 women with resectable breast cancer from 1990 to 2007. Survival curves were generated using Kaplan-Meier methods. The 5-year and 10-year cancer specific survival (CSS) rates were calculated using the Life-Table method. Based on Cox models, a nomogram was constructed to predict the probabilities of CSS for an individual patient. The competing risk regression model was used to analyse the specific survival of patients with MBC. RESULTS: There were 136569 (97.82%) infiltrative ductal cancer (IDC) patients and 3042 (2.18%) MBC patients. Patients with MBC had less lymph node involvement, a higher frequency of well differentiated lesions, and more estrogen receptor (ER)-positive tumors. Patients with MBC had significantly higher 5 and10-year CSS rates (98.23 and 96.03%, respectively) than patients with IDC (91.44 and 85.48%, respectively). Univariate and multivariate analyses showed that MBC was an independent factor for better prognosis. As for patients with MBC, the event of death caused by another disease exceeded the event of death caused by breast cancer. A competing risk regression model further showed that lymph node involvement, poorly differentiated grade and advanced T-classification were independent factors of poor prognosis in patients with MBC. The Nomogram can accurately predict CSS with a high C-index (0.816). Risk scores developed from the nomogram can more accurately predict the prognosis of patients with MBC (C-index = 0.789) than the traditional TNM system (C-index = 0.704, P< 0.001). CONCLUSIONS: Patients with MBC have a better prognosis than patients with IDC. Nomograms could help clinicians make more informed decisions in clinical practice. The competing risk regression model, as a more rational model, is recommended for use in the survival analysis of patients with MBC in the future. PMID- 27760181 TI - Discordance between MTB/RIF and Real-Time Tuberculosis-Specific Polymerase Chain Reaction Assay in Bronchial Washing Specimen and Its Clinical Implications. AB - The prevalence and clinical implications of discordance between Xpert MTB/RIF assays and the AdvanSure TB/NTM real-time polymerase chain reaction (PCR) for bronchial washing specimens have not been studied in pulmonary TB (PTB) patients. The discordant proportion and its clinical impact were evaluated in 320 patients from the bronchoscopy registry whose bronchial washing specimens were tested simultaneously with Xpert MTB/RIF and the TB/NTM PCR assay for three years, and the accuracy of the assays, including the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were studied. The clinical risk factors for discordance and false positivity of assays were also studied. Among 130 patients who were clinically diagnosed with PTB, 64 patients showed positive acid-fast bacilli culture results, 56 patients showed positive results in molecular methods and clinician diagnosed PTB without results of microbiology in 10 patients. The sensitivity, specificity, PPV, and NPV were 80.0%, 98.95%, 98.1%, and 87.9%, respectively, for Xpert MTB/RIF and 81.5%, 92.6%, 88.3%, and 88.0%, respectively, for TB/NTM PCR. The discordant proportion was 16.9% and was higher in culture-negative PTB compared to culture-confirmed PTB (24.3% vs. 9.4%, p = 0.024). However, there were no significant differences in the clinical characteristics, regardless of the discordance. The diagnostic yield increased with an additional assay (7.7% for Xpert MTB/RIF and 9.2% for TB/NTM PCR). False positivity was less common in patients tested with Xpert MTB/RIF (1.05% vs. 7.37%, p = 0.0035). No host-related risk factor for false positivity was identified. The Xpert MTB/RIF and TB/NTM PCR assay in bronchial washing specimens can improve the diagnostic yields for PTB, although there were considerable discordant results without any patient-related risk factors. PMID- 27760182 TI - Revisiting Recombination Signal in the Tick-Borne Encephalitis Virus: A Simulation Approach. AB - The hypothesis of wide spread reticulate evolution in Tick-Borne Encephalitis virus (TBEV) has recently gained momentum with several publications describing past recombination events involving various TBEV clades. Despite a large body of work, no consensus has yet emerged on TBEV evolutionary dynamics. Understanding the occurrence and frequency of recombination in TBEV bears significant impact on epidemiology, evolution, and vaccination with live vaccines. In this study, we investigated the possibility of detecting recombination events in TBEV by simulating recombinations at several locations on the virus' phylogenetic tree and for different lengths of recombining fragments. We derived estimations of rates of true and false positive for the detection of past recombination events for seven recombination detection algorithms. Our analytical framework can be applied to any investigation dealing with the difficult task of distinguishing genuine recombination signal from background noise. Our results suggest that the problem of false positives associated with low detection P-values in TBEV, is more insidious than generally acknowledged. We reappraised the recombination signals present in the empirical data, and showed that reliable signals could only be obtained in a few cases when highly genetically divergent strains were involved, whereas false positives were common among genetically similar strains. We thus conclude that recombination among wild-type TBEV strains may occur, which has potential implications for vaccination with live vaccines, but that these events are surprisingly rare. PMID- 27760183 TI - A Novel Index Using Ankle Hemodynamic Parameters to Assess the Severity of Peripheral Arterial Disease: A Pilot Study. AB - In peripheral arterial disease (PAD) of the lower extremities, the presence of flow-limiting stenoses can be objectively detected by the ankle-brachial index (ABI). However, the severity of ischemic symptoms is not necessarily associated with the ABI value. Atherosclerotic plaque in lower extremity PAD induces ankle arterial stiffness and reduces ankle vascular resistance, which may decrease ankle blood flow and cause ischemic symptoms. We hypothesized that the ankle hemodynamic index (AHI), defined as the ratio of ankle arterial stiffness to ankle vascular resistance, could be used to assess the blood supply deficiency in a diseased lower limb in patients with PAD. The 85 consecutive patients with PAD who were retrospectively analyzed in this study had Rutherford grade 1 to grade 6 ischemia diagnosed as PAD and significant stenotic lesions (>50% diameter stenosis) of the lower extremity on contrast angiography. The AHI was calculated as the product of the ankle pulse pressure and the ratio of heart rate to ankle mean arterial pressure (ankle pulse pressure * heart rate/ankle mean arterial pressure). The Rutherford grade was significantly correlated with the AHI (r = 0.50, P < 0.001), but not with the ABI (r = 0.07, P = 0.52). Multiple ordinal regression analysis showed that anemia (odds ratio 0.66, P = 0.002) and AHI (odds ratio 1.04, P = 0.02) were independently associated with Rutherford grade. Our study shows that AHI, a novel parameter based on the ABI measurement, is well correlated with ischemic symptoms, and may be a useful means to assess the arterial blood supply of the lower extremities of patients with PAD. PMID- 27760185 TI - Effects of Geostrophic Kinetic Energy on the Distribution of Mesopelagic Fish Larvae in the Southern Gulf of California in Summer/Fall Stratified Seasons. AB - Effects of geostrophic kinetic energy flux on the three-dimensional distribution of fish larvae of mesopelagic species (Vinciguerria lucetia, Diogenichthys laternatus, Benthosema panamense and Triphoturus mexicanus) in the southern Gulf of California during summer and fall seasons of stronger stratification were analyzed. The greatest larval abundance was found at sampling stations in geostrophic kinetic energy-poor areas (<7.5 J/m3), where the distribution of the dominant species tended to be stratified. Larvae of V. lucetia (average abundance of 318 larvae/10m2) and B. panamense (174 larvae/10m2) were mostly located in and above the pycnocline (typically ~ 40 m depth). In contrast, larvae of D. laternatus (60 larvae/10m2) were mainly located in and below the pycnocline. On the other hand, in sampling stations from geostrophic kinetic energy-rich areas (> 21 J/m3), where mesoscale eddies were present, the larvae of the dominant species had low abundance and were spread more evenly through the water column, in spite of the water column stratification. For example, in a cyclonic eddy, V. lucetia larvae (34 larvae/10m2) extended their distribution to, at least, the limit of sampling 200 m depth below the pycnocline, while D. laternatus larvae (29 larvae/10m2) were found right up to the surface, both probably as a consequence mixing and secondary circulation in the eddy. Results showed that the level of the geostrophic kinetic energy flux affects the abundance and the three dimensional distribution of mesopelagic fish larvae during the seasons of stronger stratification, indicating that areas with low geostrophic kinetic energy may be advantageous for feeding and development of mesopelagic fish larvae because of greater water column stability. PMID- 27760184 TI - Production of a Locus- and Allele-Specific Monoclonal Antibody for the Characterization of SLA-1*0401 mRNA and Protein Expression Levels in MHC-Defined Microminipigs. AB - The class I major histocompatibility complex (MHC) presents self-developed peptides to specific T cells to induce cytotoxity against infection. The MHC proteins are encoded by multiple loci that express numerous alleles to preserve the variability of the antigen-presenting ability in each species. The mechanism regulating MHC mRNA and protein expression at each locus is difficult to analyze because of the structural and sequence similarities between alleles. In this study, we examined the correlation between the mRNA and surface protein expression of swine leukocyte antigen (SLA)-1*0401 after the stimulation of peripheral blood mononuclear cells (PBMCs) by Staphylococcus aureus superantigen toxic shock syndrome toxin-1 (TSST-1). We prepared a monoclonal antibody (mAb) against a domain composed of Y102, L103 and L109 in the alpha2 domain. The Hp 16.0 haplotype swine possess only SLA-1*0401, which has the mAb epitope, while other haplotypes possess 0 to 3 SLA classical class I loci with the mAb epitopes. When PBMCs from SLA-1*0401 homozygous pigs were stimulated, the SLA-1*0401 mRNA expression level increased until 24 hrs and decreased at 48 hrs. The kinetics of the interferon regulatory transcription factor-1 (IRF-1) mRNA level were similar to those of the SLA-1*0401 mRNA. However, the surface protein expression level continued to increase until 72 hrs. Similar results were observed in the Hp-10.0 pigs with three mAb epitopes. These results suggest that TSST-1 stimulation induced both mRNA and surface protein expression of class I SLA in the swine PBMCs differentially and that the surface protein level was sustained independently of mRNA regulation. PMID- 27760186 TI - Deciphering Transcriptional Programming during Pod and Seed Development Using RNA Seq in Pigeonpea (Cajanus cajan). AB - Seed development is an important event in plant life cycle that has interested humankind since ages, especially in crops of economic importance. Pigeonpea is an important grain legume of the semi-arid tropics, used mainly for its protein rich seeds. In order to understand the transcriptional programming during the pod and seed development, RNA-seq data was generated from embryo sac from the day of anthesis (0 DAA), seed and pod wall (5, 10, 20 and 30 DAA) of pigeonpea variety "Asha" (ICPL 87119) using Illumina HiSeq 2500. About 684 million sequencing reads have been generated from nine samples, which resulted in the identification of 27,441 expressed genes after sequence analysis. These genes have been studied for their differentially expression, co-expression, temporal and spatial gene expression. We have also used the RNA-seq data to identify important seed specific transcription factors, biological processes and associated pathways during seed development process in pigeonpea. The comprehensive gene expression study from flowering to mature pod development in pigeonpea would be crucial in identifying candidate genes involved in seed traits directly or indirectly related to yield and quality. The dataset will serve as an important resource for gene discovery and deciphering the molecular mechanisms underlying various seed related traits. PMID- 27760187 TI - Genetically Engineered Escherichia coli Nissle 1917 Synbiotics Reduce Metabolic Effects Induced by Chronic Consumption of Dietary Fructose. AB - AIMS: To assess protective efficacy of genetically modified Escherichia coli Nissle 1917 (EcN) on metabolic effects induced by chronic consumption of dietary fructose. MATERIALS AND METHODS: EcN was genetically modified with fructose dehydrogenase (fdh) gene for conversion of fructose to 5-keto-D-fructose and mannitol-2-dehydrogenase (mtlK) gene for conversion to mannitol, a prebiotic. Charles foster rats weighing 150-200 g were fed with 20% fructose in drinking water for two months. Probiotic treatment of EcN (pqq), EcN (pqq-glf-mtlK), EcN (pqq-fdh) was given once per week 109 cells for two months. Furthermore, blood and liver parameters for oxidative stress, dyslipidemia and hyperglycemia were estimated. Fecal samples were collected to determine the production of short chain fatty acids and pyrroloquinoline quinone (PQQ) production. RESULTS: EcN (pqq-glf-mtlK), EcN (pqq-fdh) transformants were confirmed by restriction digestion and functionality was checked by PQQ estimation and HPLC analysis. There was significant increase in body weight, serum glucose, liver injury markers, lipid profile in serum and liver, and decrease in antioxidant enzyme activity in high-fructose-fed rats. However the rats treated with EcN (pqq-glf mtlK) and EcN (pqq-fdh) showed significant reduction in lipid peroxidation along with increase in serum and hepatic antioxidant enzyme activities. Restoration of liver injury marker enzymes was also seen. Increase in short chain fatty acids (SCFA) demonstrated the prebiotic effects of mannitol and gluconic acid. CONCLUSIONS: Our study demonstrated the effectiveness of probiotic EcN producing PQQ and fructose metabolizing enzymes against the fructose induced hepatic steatosis suggesting that its potential for use in treating fructose induced metabolic syndrome. PMID- 27760190 TI - Correction: Full-Length Fibronectin Drives Fibroblast Accumulation at the Surface of Collagen Microtissues during Cell-Induced Tissue Morphogenesis. AB - [This corrects the article DOI: 10.1371/journal.pone.0160369.]. PMID- 27760188 TI - Genotyping and Descriptive Proteomics of a Potential Zoonotic Canine Strain of Giardia duodenalis, Infective to Mice. AB - The zoonotic potential of giardiasis, as proposed by WHO since the late 70's, has been largely confirmed in this century. The genetic assemblages A and B of Giardia duodenalis are frequently isolated from human and canine hosts. Most of the assemblage A strains are not infective to adult mice, which can limit the range of studies regarding to biology of G. duodenalis, including virulence factors and the interaction with host immune system. This study aimed to determine the infectivity in mice of an assemblage A Giardia duodenalis strain (BHFC1) isolated from a dog and to classify the strain in sub-assemblages (AI, AII, AIII) through the phylogenetic analysis of beta-giardin (bg), triose phosphate isomerase (tpi) and glutamate dehydrogenase (gdh) genes. In addition, the proteomic profile of soluble and insoluble protein fractions of trophozoites was analyzed by 2D-electrophoresis. Accordingly, trophozoites of BHFC1 were highly infective to Swiss mice. The phylogenetic analysis of tpi and gdh revealed that BHFC1 clustered to sub-assemblage AI. The proteomic map of soluble and insoluble protein fractions led to the identification of 187 proteins of G. duodenalis, 27 of them corresponding to hypothetical proteins. Considering both soluble and soluble fractions, the vast majority of the identified proteins (n = 82) were classified as metabolic proteins, mainly associated with carbon and lipid metabolism, including 53 proteins with catalytic activity. Some of the identified proteins correspond to antigens while others can be correlated with virulence. Besides a significant complementation to the proteomic data of G. duodenalis, these data provide an important source of information for future studies on various aspects of the biology of this parasite, such as virulence factors and host and pathogen interactions. PMID- 27760189 TI - The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types. AB - Virus homologues of seven-transmembrane receptors (7TMR) are encoded by all beta- and gammaherpesviruses, suggesting important functional roles. M78 of mouse cytomegalovirus (MCMV) is representative of a family of 7TMR conserved in all betaherpesviruses. M78 family members have been found to exhibit cell-type specific effects upon virus replication in tissue culture and to affect virus pathogenesis in vivo. We reported previously that M78, for which no ligands are known, undergoes rapid, constitutive endocytosis. In this study, we have investigated the role of the M78 cytoplasmic C-tail in mediating endocytosis and consequences of C-tail deletion upon replication and pathogenesis. Mutations of M78 (C-tail truncations or point mutations) and CCR5-M78 chimeras identified two distinct regions affecting endocytosis. The first was a classical acidic di leucine motif (DDxxxLL), located close to the C-terminus. The second region, the activity of which was suppressed by downstream sequences, included the putative 8th helix, located close to the 7th transmembrane domain. A recombinant MCMV expressing an endocytosis-deficient M78, lacking most of the C-tail (M78_CDelta155), had a cell-type specific replication phenotype. M78_CDelta155 had restricted replication in bone marrow macrophages, indistinguishable from an M78-null recombinant. In contrast, M78_CDelta155 replicated normally or with enhanced titres to wild type virus in other tested cell-types, whereas M78-null was attenuated. Distinct phenotypes for M78_CDelta155 and M78-null suggest that the C-tail deletion resulted in M78 dysfunction, rather than complete loss of function; furthermore, they highlight a cell-type specific role of M78 during replication. Infection of mice (intranasal) demonstrated that M78_CDelta155, similar to M78-null, was cleared more rapidly from the lungs than wild type virus and was severely attenuated for replication in salivary glands. It may be speculated that attenuation of both M78_CDelta155 and M78-null for replication in macrophages may have contributed to their similar pathogenic phenotypes. PMID- 27760191 TI - A Common Profile of Disordered Angiogenic Factor Production and the Exacerbation of Inflammation in Early Preeclampsia, Late Preeclampsia, and Intrauterine Growth Restriction. AB - Preeclampsia and intrauterine growth restriction are two separate disease entities that, according to numerous reports, share the same pathogenesis. In both, angiogenesis disorders and generalized inflammation are the dominant symptoms. In this study, we hypothesized that both diseases demonstrate the same profile in early preeclampsia, late preeclampsia, and intrauterine growth restriction patients, with the only difference being the degree of exacerbation of lesions. One hundred sixty-seven patients were enrolled in the study and divided into four groups: early preeclampsia, late preeclampsia, and intrauterine growth restriction groups, and one control group. Concentrations of the angiogenesis and inflammatory markers soluble fms-like tyrosine kinase receptor 1, placental growth factor, high-sensitivity C-reactive protein, and interleukin 6 were determined, and the behavior of these markers and correlations among them were studied. Higher concentrations of soluble fms-like tyrosine kinase receptor 1, high-sensitivity C-reactive protein, and interleukin-6 and a lower concentration of placental growth factor were observed in the study groups compared with the control group. No differences in concentrations of the studied markers were found among the study groups but significant correlations were observed. The higher values for the angiogenesis and inflammatory markers both in preeclampsia patients and patients with intrauterine growth restriction of placental origin compared with the control group suggest the existence of the same underlying disorders in the development of these pathologies. The observed mutual correlations for disordered angiogenesis and inflammatory markers are suggestive of a mutual relationship between these processes in the development of pathologies evolving secondary to placental ischemia. The same lesion profile was observed for both preeclampsia and 'placental' intrauterine growth restriction patients, which could be used in developing common diagnostic criteria for pregnant patients. PMID- 27760192 TI - Correction: Ligand Binding at the alpha4-alpha4 Agonist-Binding Site of the alpha4beta2 nAChR Triggers Receptor Activation through a Pre-Activated Conformational State. AB - [This corrects the article DOI: 10.1371/journal.pone.0161154.]. PMID- 27760193 TI - Test Expectation Enhances Memory Consolidation across Both Sleep and Wake. AB - Memory consolidation benefits from post-training sleep. However, recent studies suggest that sleep does not uniformly benefit all memory, but instead prioritizes information that is important to the individual. Here, we examined the effect of test expectation on memory consolidation across sleep and wakefulness. Following reports that information with strong "future relevance" is preferentially consolidated during sleep, we hypothesized that test expectation would enhance memory consolidation across a period of sleep, but not across wakefulness. To the contrary, we found that expectation of a future test enhanced memory for both spatial and motor learning, but that this effect was equivalent across both wake and sleep retention intervals. These observations differ from those of least two prior studies, and fail to support the hypothesis that the "future relevance" of learned material moderates its consolidation selectively during sleep. PMID- 27760194 TI - Kingella kingae Expresses Four Structurally Distinct Polysaccharide Capsules That Differ in Their Correlation with Invasive Disease. AB - Kingella kingae is an encapsulated gram-negative organism that is a common cause of osteoarticular infections in young children. In earlier work, we identified a glycosyltransferase gene called csaA that is necessary for synthesis of the [3) beta-GalpNAc-(1->5)-beta-Kdop-(2->] polysaccharide capsule (type a) in K. kingae strain 269-492. In the current study, we analyzed a large collection of invasive and carrier isolates from Israel and found that csaA was present in only 47% of the isolates. Further examination of this collection using primers based on the sequence that flanks csaA revealed three additional gene clusters (designated the csb, csc, and csd loci), all encoding predicted glycosyltransferases. The csb locus contains the csbA, csbB, and csbC genes and is associated with a capsule that is a polymer of [6)-alpha-GlcpNAc-(1->5)-beta-(8-OAc)Kdop-(2->] (type b). The csc locus contains the cscA, cscB, and cscC genes and is associated with a capsule that is a polymer of [3)-beta-Ribf-(1->2)-beta-Ribf-(1->2)-beta-Ribf-(1 >4)-beta-Kdop-(2->] (type c). The csd locus contains the csdA, csdB, and csdC genes and is associated with a capsule that is a polymer of [P-(O->3)[beta-Galp (1->4)]-beta-GlcpNAc-(1->3)-alpha-GlcpNAc-1-] (type d). Introduction of the csa, csb, csc, and csd loci into strain KK01Deltacsa, a strain 269-492 derivative that lacks the native csaA gene, was sufficient to produce the type a capsule, type b capsule, type c capsule, and type d capsule, respectively, indicating that these loci are solely responsible for determining capsule type in K. kingae. Further analysis demonstrated that 96% of the invasive isolates express either the type a or type b capsule and that a disproportionate percentage of carrier isolates express the type c or type d capsule. These results establish that there are at least four structurally distinct K. kingae capsule types and suggest that capsule type plays an important role in promoting K. kingae invasive disease. PMID- 27760195 TI - Prolyl Oligopeptidase Inhibition Attenuates Steatosis in the L02 Human Liver Cell Line. AB - BACKGROUND: Prolyl oligopeptidase (POP) is a serine endopeptidase that is widely distributed in vivo, particularly in the liver. Significant changes in functional mitochondrial proteins involved with mitochondrial oxidoreductases/transporters and nucleic acid binding proteins were observed after POP inhibition in the liver, which suggested a role of POP in regulating liver energy metabolism. Steatosis in nonalcoholic fatty liver disease (NAFLD) is associated with disturbances in lipid and energy metabolism in hepatocytes. Here, we aimed to study the effect of POP on hepatocyte steatosis. METHODS: The human liver cell line L02 was used to investigate the biological effects of POP. An in vitro cell model of steatosis was successfully induced with oleic acid and palmitic acid. L02 cells were also subjected to S17092 (a POP inhibitor) at different concentrations for 24 or 48 h. Ac-SDKP levels and POP activity were measured to assess the rate of inhibition of POP by S17092. The POP gene and protein expression levels were detected using real-time PCR and Western blots, respectively. Oil red O staining was performed and the triglyceride levels in the L02 cells were also measured. Cell proliferation and apoptosis were detected using CCK-8 and flow cytometry, respectively. The expression of genes involved in lipid metabolism was detected using real-time PCR. The effects of POP inhibition on LC3B II were detected by Western blot. RESULTS: Compared with the control, the POP mRNA levels increased by approximately 30%, and the POP protein levels increased by almost 60% in the steatotic L02 cells. After S17092 (0.026~130 MUM) incubation for 24 or 48 h, cell proliferation was significantly decreased in the free fatty acid (FFA)-treated cells at 26-130 MUM; however, S17092 did not affect the proliferation of L02 cells after 24 h of incubation with S17092 at 0.026-65 MUM without FFA treatment. S17092 treatment (13 and 26 MUM) also elicited no significant effect on apoptosis in normal L02 cells, but FFA treatment increased cell apoptosis, which was attenuated by S17092 incubation. S17092 treatment inhibited intracellular POP activity and decreased the AcSDKP level at the concentration of 0.026-26 MUM. After treatment with FFA for 24 h, oil red O staining revealed significant lipid accumulation in the cells in the model group compared with the controls; however, lipid accumulation was suppressed after the administration of S17092 (13 and 26 MUM). Accordingly, the triglyceride levels in the FFA-treated cells were approximately 5-fold greater than those of the controls and were decreased by approximately 25% and 45% after the administration of S17092 at 13 and 26 MUM, respectively. The mRNA levels of FASN, PPAR-gamma, and SREBP-1c were higher in the FFA-treated cells than in the normal controls, and all of these levels were significantly inhibited in the presence of S17092 at both 13 and 26 MUM. S17092 treatment did not affect LC3B II in the FFA-treated cells compared with FFA treatment alone. CONCLUSION: The expression of POP increases with hepatocyte steatosis, and POP inhibitors can significantly reduce intracellular lipid accumulation, which might be related to the inhibition of genes involved in lipid synthesis. PMID- 27760196 TI - The Impact of the Geometrical Structure of the DNA on Parameters of the Track Event Theory for Radiation Induced Cell Kill. AB - BACKGROUND AND PURPOSE: When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. An alternative to the LQ-model is the track-event theory which is based on the probabilities for one- and two two-track events. A one-track-event (OTE) is always represented by at least two simultaneous double strand breaks. A two-track event (TTE) results in one double strand break. Therefore at least two two-track events on the same or different chromosomes are necessary to produce an event which leads to cell sterilization. It is obvious that the probabilities of OTEs and TTEs must somehow depend on the geometrical structure of the chromatin. In terms of the track-event theory the ratio epsilon of the probabilities of OTEs and TTEs includes the geometrical dependence and is obtained in this work by simple Monte Carlo simulations. MATERIALS AND METHODS: For this work it was assumed that the anchors of loop forming chromatin are most sensitive to radiation induced cell deaths. Therefore two adjacent tetranucleosomes representing the loop anchors were digitized. The probability ratio epsilon of OTEs and TTEs was factorized into a radiation quality dependent part and a geometrical part: epsilon = epsilonion ? epsilongeo. epsilongeo was obtained for two situations, by applying Monte Carlo simulation for DNA on the tetranucleosomes itself and for linker DNA. Low energy electrons were represented by randomly distributed ionizations and high energy electrons by ionizations which were simulated on rays. epsilonion was determined for electrons by using results from nanodosimetric measurements. The calculated epsilon was compared to the epsilon obtained from fits of the track event model to 42 sets of experimental human cell survival data. RESULTS: When the two tetranucleosomes are in direct contact and the hits are randomly distributed epsilongeo and epsilon are 0.12 and 0.85, respectively. When the hits are simulated on rays epsilongeo and epsilon are 0.10 and 0.71. For the linker-DNA epsilongeo and epsilon for randomly distributed hits are 0.010 and 0.073, and for hits on rays 0.0058 and 0.041, respectively. The calculated epsilon fits the experimentally obtained epsilon = 0.64+/-0.32 best for hits on the tetranucleosome when they are close to each other both, for high and low energy electrons. CONCLUSIONS: The parameter epsilongeo of the track event model was obtained by pure geometrical considerations of the chromatin structure and is 0.095 +/- 0.022. It can be used as a fixed parameter in the track-event theory. PMID- 27760197 TI - Pleomorphic Structures in Human Blood Are Red Blood Cell-Derived Microparticles, Not Bacteria. AB - BACKGROUND: Red blood cell (RBC) transfusions are a common, life-saving therapy for many patients, but they have also been associated with poor clinical outcomes. We identified unusual, pleomorphic structures in human RBC transfusion units by negative-stain electron microscopy that appeared identical to those previously reported to be bacteria in healthy human blood samples. The presence of viable, replicating bacteria in stored blood could explain poor outcomes in transfusion recipients and have major implications for transfusion medicine. Here, we investigated the possibility that these structures were bacteria. RESULTS: Flow cytometry, miRNA analysis, protein analysis, and additional electron microscopy studies strongly indicated that the pleomorphic structures in the supernatant of stored RBCs were RBC-derived microparticles (RMPs). Bacterial 16S rDNA PCR amplified from these samples were sequenced and was found to be highly similar to species that are known to commonly contaminate laboratory reagents. CONCLUSIONS: These studies suggest that pleomorphic structures identified in human blood are RMPs and not bacteria, and they provide an example in which laboratory contaminants may can mislead investigators. PMID- 27760198 TI - Absolute Memory for Tempo in Musicians and Non-Musicians. AB - The ability to remember tempo (the perceived frequency of musical pulse) without external references may be defined, by analogy with the notion of absolute pitch, as absolute tempo (AT). Anecdotal reports and sparse empirical evidence suggest that at least some individuals possess AT. However, to our knowledge, no systematic assessments of AT have been performed using laboratory tasks comparable to those assessing absolute pitch. In the present study, we operationalize AT as the ability to identify and reproduce tempo in the absence of rhythmic or melodic frames of reference and assess these abilities in musically trained and untrained participants. We asked 15 musicians and 15 non musicians to listen to a seven-step 'tempo scale' of metronome beats, each associated to a numerical label, and then to perform two memory tasks. In the first task, participants heard one of the tempi and attempted to report the correct label (identification task), in the second, they saw one label and attempted to tap the correct tempo (production task). A musical and visual excerpt was presented between successive trials as a distractor to prevent participants from using previous tempi as anchors. Thus, participants needed to encode tempo information with the corresponding label, store the information, and recall it to give the response. We found that more than half were able to perform above chance in at least one of the tasks, and that musical training differentiated between participants in identification, but not in production. These results suggest that AT is relatively wide-spread, relatively independent of musical training in tempo production, but further refined by training in tempo identification. We propose that at least in production, the underlying motor representations are related to tactus, a basic internal rhythmic period that may provide a body-based reference for encoding tempo. PMID- 27760200 TI - High Production of 2,3-Butanediol (2,3-BD) by Raoultella ornithinolytica B6 via Optimizing Fermentation Conditions and Overexpressing 2,3-BD Synthesis Genes. AB - Biological production of 2,3-butandiol (2,3-BD) has received great attention as an alternative to the petroleum-based 2,3-BD production. In this study, a high production of 2,3-BD in fed-batch fermentation was investigated with a newly isolated bacterium designated as Raoultella ornithinolytica B6. The isolate produced 2,3-BD as the main product using hexoses (glucose, galactose, and fructose), pentose (xylose) and disaccharide (sucrose). The effects of temperature, pH-control schemes, and agitation speeds on 2,3-BD production were explored to optimize the fermentation conditions. Notably, cell growth and 2,3-BD production by R. ornithinolytica B6 were higher at 25 degrees C than at 30 degrees C. When three pH control schemes (no pH control, pH control at 7, and pH control at 5.5 after the pH was decreased to 5.5 during fermentation) were tested, the best 2,3-BD titer and productivity along with reduced by-product formation were achieved with pH control at 5.5. Among different agitation speeds (300, 400, and 500 rpm), the optimum agitation speed was 400 rpm with 2,3-BD titer of 68.27 g/L, but acetic acid was accumulated up to 23.32 g/L. Further enhancement of the 2,3-BD titer (112.19 g/L), yield (0.38 g/g), and productivity (1.35 g/L/h) as well as a significant reduction of acetic acid accumulation (9.71 g/L) was achieved by the overexpression of homologous budABC genes, the 2,3-BD synthesis genes involved in the conversion of pyruvate to 2,3-BD. This is the first report presenting a high 2,3-BD production by R.ornithinolytica which has attracted little attention with respect to 2,3-BD production, extending the microbial spectrum of 2,3-BD producers. PMID- 27760199 TI - Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs. AB - The methylfolate trap, a metabolic blockage associated with anemia, neural tube defects, Alzheimer's dementia, cardiovascular diseases, and cancer, was discovered in the 1960s, linking the metabolism of folate, vitamin B12, methionine and homocysteine. However, the existence or physiological significance of this phenomenon has been unknown in bacteria, which synthesize folate de novo. Here we identify the methylfolate trap as a novel determinant of the bacterial intrinsic death by sulfonamides, antibiotics that block de novo folate synthesis. Genetic mutagenesis, chemical complementation, and metabolomic profiling revealed trap-mediated metabolic imbalances, which induced thymineless death, a phenomenon in which rapidly growing cells succumb to thymine starvation. Restriction of B12 bioavailability, required for preventing trap formation, using an "antivitamin B12" molecule, sensitized intracellular bacteria to sulfonamides. Since boosting the bactericidal activity of sulfonamides through methylfolate trap induction can be achieved in Gram-negative bacteria and mycobacteria, it represents a novel strategy to render these pathogens more susceptible to existing sulfonamides. PMID- 27760201 TI - Catastrophic Decline of World's Largest Primate: 80% Loss of Grauer's Gorilla (Gorilla beringei graueri) Population Justifies Critically Endangered Status. AB - Grauer's gorilla (Gorilla beringei graueri), the World's largest primate, is confined to eastern Democratic Republic of Congo (DRC) and is threatened by civil war and insecurity. During the war, armed groups in mining camps relied on hunting bushmeat, including gorillas. Insecurity and the presence of several militia groups across Grauer's gorilla's range made it very difficult to assess their population size. Here we use a novel method that enables rigorous assessment of local community and ranger-collected data on gorilla occupancy to evaluate the impacts of civil war on Grauer's gorilla, which prior to the war was estimated to number 16,900 individuals. We show that gorilla numbers in their stronghold of Kahuzi-Biega National Park have declined by 87%. Encounter rate data of gorilla nests at 10 sites across its range indicate declines of 82-100% at six of these sites. Spatial occupancy analysis identifies three key areas as the most critical sites for the remaining populations of this ape and that the range of this taxon is around 19,700 km2. We estimate that only 3,800 Grauer's gorillas remain in the wild, a 77% decline in one generation, justifying its elevation to Critically Endangered status on the IUCN Red List of Threatened Species. PMID- 27760202 TI - Type 2 Diabetic Mellitus Is a Risk Factor for Nasopharyngeal Carcinoma: A 1:2 Matched Case-Control Study. AB - BACKGROUND: Diabetes has been identified as an adverse prognostic variable which associated with an increased mortality in various cancers, including colorectal, lung, and breast cancers. However, previous studies provided inconsistent results on the association between diabetes and nasopharyngeal carcinoma (NPC). The main aim of this study was to investigate the associations between diabetes mellitus and the survival of NPC patients. METHODS: This study was designed as a 1:2 matched case-control study. Cases were patients who met the criteria for the diagnosis of type 2 diabetic mellitus (DM) below. Controls, matched 1:2, were patients who were normoglycemic (NDM). The survival rates were assessed by Kaplan Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model. RESULTS: Both locoregional relapse-free survival (LRRFS) and disease-free survival (DFS) in the NDM group were higher than that in the DM group (p = 0.001 and p = 0.033). Additionally, subset analyses revealed that the differences in OS, LRRFS, and DFS were all significant between the two groups in the N0-N1 subset (p = 0.007, p =.000 and p = 0.002). The LRRFS was higher in the NDM group in the III-IV, T3-T4 and N0-N1 subsets (p = 0.004, p = 0.002 and p =.000). In T3 T4 subset, the NDM group experienced higher DFS than the DM group (p = 0.039). In multivariate analysis, T stage and N stage were found to be independent predictors for OS, DMFS and DFS; chemotherapy was a significant prognostic factor for DMFS and DFS, age for OS, and diabetes for LRRFS and DFS. CONCLUSIONS: Type 2 diabetic mellitus is associated with poorer prognosis among patients with NPC. PMID- 27760203 TI - Correction: Preliminary Study of MR Diffusion Tensor Imaging of Pancreas for the Diagnosis of Acute Pancreatitis. AB - [This corrects the article DOI: 10.1371/journal.pone.0160115.]. PMID- 27760204 TI - Fine-Tuning of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle in Neighboring Cells through the RTA-JAG1-Notch Pathway. AB - Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic pathogen that displays latent and lytic life cycles. In KS lesions, infiltrated immune cells, secreted viral and/or cellular cytokines, and hypoxia orchestrate a chronic pro lytic microenvironment that can promote KSHV reactivation. However, only a small subset of viruses spontaneously undergoes lytic replication in this pro-lytic microenvironment while the majority remains in latency. Here, we show that the expression of the Notch ligand JAG1 is induced by KSHV-encoded replication and transcription activator (RTA) during reactivation. JAG1 up-regulation activates Notch signaling in neighboring cells and prevents viral lytic replication. The suppression of JAG1 and Notch1 with inhibitors or small interfering RNA promotes lytic replication in the presence of RTA induction or under conditions of hypoxia. The underlying mechanism involves the Notch downstream effector hairy and enhancer of split 1 (Hes1), which directly binds lytic gene promoters and attenuates viral lytic gene expression. RTA interacts with lymphoid enhancer binding factor 1 (LEF1), disrupts LEF1/Groucho/TLE suppressive complexes and releases LEF1 to activate JAG1 expression. Taken together, our results suggest that cells with viral lytic replication can inhibit KSHV reactivation in neighboring cells through an RTA-JAG1-Notch pathway. These data provide insight into the mechanism by which the virus maintains the balance between lytic and latent infection in the pro-lytic tumor microenvironment. PMID- 27760205 TI - Phylogeny of the Viral Hemorrhagic Septicemia Virus in European Aquaculture. AB - One of the most valuable aquaculture fish in Europe is the rainbow trout, Oncorhynchus mykiss, but the profitability of trout production is threatened by a highly lethal infectious disease, viral hemorrhagic septicemia (VHS), caused by the VHS virus (VHSV). For the past few decades, the subgenogroup Ia of VHSV has been the main cause of VHS outbreaks in European freshwater-farmed rainbow trout. Little is currently known, however, about the phylogenetic radiation of this Ia lineage into subordinate Ia clades and their subsequent geographical spread routes. We investigated this topic using the largest Ia-isolate dataset ever compiled, comprising 651 complete G gene sequences: 209 GenBank Ia isolates and 442 Ia isolates from this study. The sequences come from 11 European countries and cover the period 1971-2015. Based on this dataset, we documented the extensive spread of the Ia population and the strong mixing of Ia isolates, assumed to be the result of the Europe-wide trout trade. For example, the Ia lineage underwent a radiation into nine Ia clades, most of which are difficult to allocate to a specific geographic distribution. Furthermore, we found indications for two rapid, large-scale population growth events, and identified three polytomies among the Ia clades, both of which possibly indicate a rapid radiation. However, only about 4% of Ia haplotypes (out of 398) occur in more than one European country. This apparently conflicting finding regarding the Europe-wide spread and mixing of Ia isolates can be explained by the high mutation rate of VHSV. Accordingly, the mean period of occurrence of a single Ia haplotype was less than a full year, and we found a substitution rate of up to 7.813 * 10-4 nucleotides per site per year. Finally, we documented significant differences between Germany and Denmark regarding their VHS epidemiology, apparently due to those countries' individual handling of VHS. PMID- 27760206 TI - Measuring Cross-Cultural Supernatural Beliefs with Self- and Peer-Reports. AB - Despite claims about the universality of religious belief, whether religiosity scales have the same meaning when administered inter-subjectively-or translated and applied cross-culturally-is currently unknown. Using the recent "Supernatural Belief Scale" (SBS), we present a primer on how to verify the strong assumptions of measurement invariance required in research on religion. A comparison of two independent samples, Croatians and New Zealanders, showed that, despite a sophisticated psychometric model, measurement invariance could be demonstrated for the SBS except for two noninvariant intercepts. We present a new approach for inspecting measurement invariance across self- and peer-reports as two dependent samples. Although supernatural beliefs may be hard to observe in others, the measurement model was fully invariant for Croatians and their nominated peers. The results not only establish, for the first time, a valid measure of religious supernatural belief across two groups of different language and culture, but also demonstrate a general invariance test for distinguishable dyad members nested within the same targets. More effort needs to be made to design and validate cross-culturally applicable measures of religiosity. PMID- 27760207 TI - Which Moral Foundations Predict Willingness to Make Lifestyle Changes to Avert Climate Change in the USA? AB - Jonathan Haidt's Moral Foundations Theory identifies five moral axes that can influence human motivation to take action on vital problems like climate change. The theory focuses on five moral foundations, including compassion, fairness, purity, authority, and ingroup loyalty; these have been found to differ between liberals and conservatives as well as Democrats and Republicans. Here we show, based on the Cornell National Social Survey (USA), that valuations of compassion and fairness were strong, positive predictors of willingness to act on climate change, whereas purity had a non-significant tendency in the positive direction (p = 0.07). Ingroup loyalty and authority were not supported as important predictor variables using model selection ([Formula: see text]). Compassion and fairness were more highly valued by liberals, whereas purity, authority, and in group loyalty were more highly valued by conservatives. As in previous studies, participants who were younger, more liberal, and reported greater belief in climate change, also showed increased willingness to act on climate change. Our research supports the potential importance of moral foundations as drivers of intentions with respect to climate change action, and suggests that compassion, fairness, and to a lesser extent, purity, are potential moral pathways for personal action on climate change in the USA. PMID- 27760208 TI - Characterization of Microbiota in Children with Chronic Functional Constipation. AB - OBJECTIVES: Disruption of the intestinal microbiota is considered an etiological factor in pediatric functional constipation. Scientifically based selection of potential beneficial probiotic strains in functional constipation therapy is not feasible due to insufficient knowledge of microbiota composition in affected subjects. The aim of this study was to describe microbial composition and diversity in children with functional constipation, compared to healthy controls. STUDY DESIGN: Fecal samples from 76 children diagnosed with functional constipation according to the Rome III criteria (median age 8.0 years; range 4.2 17.8) were analyzed by IS-pro, a PCR-based microbiota profiling method. Outcome was compared with intestinal microbiota profiles of 61 healthy children (median 8.6 years; range 4.1-17.9). Microbiota dissimilarity was depicted by principal coordinate analysis (PCoA), diversity was calculated by Shannon diversity index. To determine the most discriminative species, cross validated logistic ridge regression was performed. RESULTS: Applying total microbiota profiles (all phyla together) or per phylum analysis, no disease-specific separation was observed by PCoA and by calculation of diversity indices. By ridge regression, however, functional constipation and controls could be discriminated with 82% accuracy. Most discriminative species were Bacteroides fragilis, Bacteroides ovatus, Bifidobacterium longum, Parabacteroides species (increased in functional constipation) and Alistipes finegoldii (decreased in functional constipation). CONCLUSIONS: None of the commonly used unsupervised statistical methods allowed for microbiota-based discrimination of children with functional constipation and controls. By ridge regression, however, both groups could be discriminated with 82% accuracy. Optimization of microbiota-based interventions in constipated children warrants further characterization of microbial signatures linked to clinical subgroups of functional constipation. PMID- 27760209 TI - Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis. AB - Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNalpha-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease. PMID- 27760210 TI - Early Evidence for the Extensive Heat Treatment of Silcrete in the Howiesons Poort at Klipdrift Shelter (Layer PBD, 65 ka), South Africa. AB - Heating stone to enhance its flaking qualities is among the multiple innovative adaptations introduced by early modern human groups in southern Africa, in particular during the Middle Stone Age Still Bay and Howiesons Poort traditions. Comparatively little is known about the role and impact of this technology on early modern human behaviors and cultural expressions, due, in part, to the lack of comprehensive studies of archaeological assemblages documenting the heat treatment of stone. We address this issue through an analysis of the procedure used for heating and a technological analysis of a lithic assemblage recovered from one Howiesons Poort assemblage at Klipdrift Shelter (southern Cape, South Africa). The resulting data show extensive silcrete heat treatment, which adds a new dimension to our understanding of fire-related behaviors during the Howiesons Poort, highlighting the important role played by a heat treatment stage in the production of silcrete blades. These results are made possible by our new analytical procedure that relies on the analysis of all silcrete artifacts. It provides direct evidence of a controlled use of fire which took place during an early stage of core exploitation, thereby impacting on all subsequent stages of the lithic chaine operatoire, which, to date, has no known equivalent in the Middle Stone Age or Middle Paleolithic record outside of southern Africa. PMID- 27760211 TI - Biological Role of Paenilarvins, Iturin-Like Lipopeptide Secondary Metabolites Produced by the Honey Bee Pathogen Paenibacillus larvae. AB - The Gram-positive bacterium Paenibacillus larvae (P. larvae) is the causative agent of a deadly honey bee brood disease called American Foulbrood (AFB). AFB is a notifiable epizootic in most countries and, hence, P. larvae is of considerable relevance for veterinarians and apiculturists alike. Over the last decade, much progress has been made in the understanding of the (patho)biology of P. larvae. Recently, several non-ribosomally produced peptides (NRP) and peptide/polyketide (NRP/PK) hybrids produced by P. larvae were identified. Among these NRPs were iturin-like lipopeptides, the paenilarvins A-C. Iturins are known to exhibit strong anti-fungal activity; for some iturins, cytotoxic activity towards mammalian erythrocytes and human cancer cell lines are described. We here present our results on the analysis of the natural function of the paenilarvins during pathogenesis of P. larvae infections. We demonstrated production of paenilarvins in infected larvae. However, we could neither demonstrate cytotoxicity of paenilarvins towards cultured insect cells nor towards larvae in feeding assays. Accordingly, exposure bioassays performed with larvae infected by wild-type P. larvae and a knockout mutant of P. larvae lacking production of paenilarvins did not substantiate a role for the paenilarvins as virulence factor. Further experiments are necessary to analyze the relevance of the paenilarvins' anti fungal activity for P. larvae infections in the presence of fungal competitors in the larval midgut or cadaver. PMID- 27760212 TI - Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord. AB - Toll-like receptor 4 (TLR4) is important for the pathogenesis of inflammatory reactions and the promotion of pain processing after ischemia/reperfusion (IR) in spinal cord. Recently, C-X-C chemokine ligand 12 (CXCL12) and its receptor, C-X-C chemokine receptor 4 (CXCR4), were demonstrated to be simultaneously critical for inflammatory reactions, thereby facilitating glial activation. However, whether CXCL12/CXCR4 expression can contribute to IR-induced inflammatory pain via spinal TLR4 remained unclear. A rat model was established by 8 min of aortic arch occlusion. The effects of CXCL12/CXCR4 expression and TLR4 activation on inflammatory hyperalgesia were investigated by pretreatments with CXCL12 neutralizing antibody, CXCR4 antagonist (AMD3100) and TLR4 antagonist (TAK-242) for 5 consecutive days before surgery. The results indicated that IR induced significant and sustained inflammatory pain, observed as decreases in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), throughout the post injury period. The increased levels of TLR4 and proinflammatory chemokine CXCL12, as well as its receptor, CXCR4, were closely correlated with the PWT and PWL trends. Double immunostaining further suggested that TLR4, which is mainly expressed on astrocytes and microglia, was closely co-localized with CXCL12 and CXCR4 in spinal dorsal horn. As expected, intrathecal pretreatment with the TLR4 antagonist, TAK-242 markedly ameliorated pain by inhibiting astrocytic and microglial activation, as shown by decreases in TLR4 immunoreactivity and the percentage of double-labeled cells. These protective effects were likely due in part to the reduced production of the downstream cytokines IL-1beta and TNF alpha, as well as for the recruitment of CXCL12 and CXCR4. Additionally, intrathecal pretreatment with CXCL12-neutralizing antibody and AMD3100 resulted in similar analgesic and anti-inflammatory effects as those receiving TAK-242 pretreatment. These results suggest that intrathecal blockade of CXCL12/CXCR4 expression may attenuate IR-induced pain sensation and the release of inflammatory cytokines by limiting glial TLR4 activation in spinal cord. PMID- 27760213 TI - Inulin Supplementation Lowered the Metabolic Defects of Prolonged Exposure to Chlorpyrifos from Gestation to Young Adult Stage in Offspring Rats. AB - Increasing evidence indicates that chlorpyrifos (CPF), an organophosphorus insecticide, is involved in metabolic disorders. We assess the hypothesis whether supplementation with prebiotics from gestation to adulthood, through a modulation of microbiota composition and fermentative activity, alleviates CPF induced metabolic disorders of 60 days old offspring. 5 groups of Wistar rats, from gestation until weaning, received two doses of CPF pesticide: 1 mg/kg/day (CPF1) or 3.5 mg/kg/day (CPF3.5) with free access to inulin (10g/L in drinking water). Then male pups received the same treatment as dams. Metabolic profile, leptin sensitivity, insulin receptor (IR) expression in liver, gut microbiota composition and short chain fatty acid composition (SCFAs) in the colon, were analyzed at postnatal day 60 in the offspring (PND 60). CPF3.5 increased offspring's birth body weight (BW) but decreased BW at PND60. Inulin supplementation restored the BW at PND 60 to control levels. Hyperinsulinemia and decrease in insulin receptor beta in liver were seen in CPF1 exposed rats. In contrast, hyperglycemia and decrease in insulin level were found in CPF3.5 rats. Inulin restored the levels of some metabolic parameters in CPF groups to ranges comparable with the controls. The total bacterial population, short chain fatty acid (SCFA) production and butyrate levels were enhanced in CPF groups receiving inulin. Our data indicate that developmental exposure to CPF interferes with metabolism with dose related effects evident at adulthood. By modulating microbiota population and fermentative activity, inulin corrected adult metabolic disorders of rats exposed to CPF during development. Prebiotics supply may be thus considered as a novel nutritional strategy to counteract insulin resistance and diabetes induced by a continuous pesticide exposure. PMID- 27760214 TI - Global Transcriptomic Analysis of the Response of Corynebacterium glutamicum to Vanillin. AB - Lignocellulosic biomass is an abundant and renewable resource for biofuels and bio-based chemicals. Vanillin is one of the major phenolic inhibitors in biomass production using lignocellulose. To assess the response of Corynebacterium glutamicum to vanillin stress, we performed a global transcriptional response analysis. The transcriptional data showed that the vanillin stress not only affected the genes involved in degradation of vanillin, but also differentially regulated several genes related to the stress response, ribosome/translation, protein secretion, and the cell envelope. Moreover, deletion of the sigH or msrA gene in C. glutamicum resulted in a decrease in cell viability under vanillin stress. These insights will promote further engineering of model industrial strains, with enhanced tolerance or degradation ability to vanillin to enable suitable production of biofuels and bio-based chemicals from lignocellulosic biomass. PMID- 27760215 TI - Interspecific Differences in Metabolic Rate and Metabolic Temperature Sensitivity Create Distinct Thermal Ecological Niches in Lizards (Plestiodon). AB - Three congeneric lizards from the southeastern United States (Plestiodon fasciatus, P. inexpectatus, and P. laticeps) exhibit a unique nested distribution. All three skink species inhabit the US Southeast, but two extend northward to central Ohio (P. fasciatus and P. laticeps) and P. fasciatus extends well into Canada. Distinct interspecific differences in microhabitat selection and behavior are associated with the cooler temperatures of the more Northern ranges. We hypothesized that interspecific differences in metabolic temperature sensitivity locally segregates them across their total range. Resting oxygen consumption was measured at 20 degrees , 25 degrees and 30 degrees C. Plestiodon fasciatus, from the coolest habitats, exhibited greatly elevated oxygen consumption compared to the other species at high ecologically-relevant temperatures (0.10, 0.17 and 0.83 ml O2. g-1. h-1 at 20 degrees , 25 degrees and 30 degrees C, respectively). Yet, P. inexpectatus, from the warmest habitats, exhibited sharply decreased oxygen consumption compared to the other species at lower ecologically-relevant temperatures (0.09, 0.27 and 0.42 ml O2. g-1. h-1 at 20 degrees , 25 degrees and 30 degrees C, respectively). Plestiodon laticeps, from both open and closed microhabitats and intermediate latitudinal range, exhibited oxygen consumptions significantly lower than the other two species (0.057, 0.104 and 0.172 ml O2. g-1. h-1 at 20 degrees , 25 degrees and 30 degrees C, respectively). Overall, Plestiodon showed metabolic temperature sensitivities (Q10s) in the range of 2-3 over the middle of each species' normal temperature range. However, especially P. fasciatus and P. inexpectatus showed highly elevated Q10s (9 to 25) at the extreme ends of their temperature range. While morphologically similar, these skinks are metabolically distinct across the genus' habitat, likely having contributed to their current distribution. PMID- 27760216 TI - Nitric Oxide Donor Molsidomine Positively Modulates Myogenic Differentiation of Embryonic Endothelial Progenitors. AB - Embryonic VE-Cadherin-expressing progenitors (eVE-Cad+), including hemogenic endothelium, have been shown to generate hematopoietic stem cells and a variety of other progenitors, including mesoangioblasts, or MABs. MABs are vessel associated progenitors with multilineage mesodermal differentiation potential that can physiologically contribute to skeletal muscle development and regeneration, and have been used in an ex vivo cell therapy setting for the treatment of muscular dystrophy. There is currently a therapeutic need for molecules that could improve the efficacy of cell therapy protocols; one such good candidate is nitric oxide. Several studies in animal models of muscle dystrophy have demonstrated that nitric oxide donors provide several beneficial effects, including modulation of the activity of endogenous cell populations involved in muscle repair and the delay of muscle degeneration. Here we used a genetic lineage tracing approach to investigate whether the therapeutic effect of nitric oxide in muscle repair could derive from an improvement in the myogenic differentiation of eVE-Cad+ progenitors during embryogenesis. We show that early in vivo treatment with the nitric oxide donor molsidomine enhances eVE-Cad+ contribution to embryonic and fetal myogenesis, and that this effect could originate from a modulation of the properties of yolk sac hemogenic endothelium. PMID- 27760217 TI - Treatment and Prognosis of Anaplastic Thyroid Carcinoma: A Clinical Study of 50 Cases. AB - INTRODUCTION: Although anaplastic thyroid carcinoma (ATC) is rare, it is one of the most aggressive human cancers. The optimal multimodal therapy policy of ATC is still debated, and a standardized treatment strategy remains to be established. This study aimed to evaluate the management aspect and prognosis of ATC. MATERIALS AND METHODS: The data were analyzed retrospectively for 50 patients with ATC to evaluate the clinical characters, management and factors influencing survival. Survival analysis was performed by Kaplan-Merier method and log-rank test, and multivariate analysis was performed using Cox proportional hazard model. RESULTS: The 1-year and 2-year overall survival rates (OS) were 48.0% and 26.0% respectively in all patients, with the 2-year OS of 40.0% and 31.0% and 6.3% for stage IVA, IVB and IVC respectively (P <0.05). In stage IVA and IVB patients, combined surgery with radiotherapy improved overall survival, and the 2-year OS were 50.0% and 35.7% respectively in the group with combined surgery with radiotherapy and the group with surgery with only (P <0.05). Postoperative radiotherapy improved local control rate in stage IVA and IVB patients (P <0.05). However, surgery, radiotherapy or chemotherapy could not improve the survival of stage IVC patients. Multivariate analysis showed that distant metastases, surgery, radiotherapy and tumor residue could predict the prognosis. CONCLUSION: Combined surgery and radiotherapy could improve overall survival in stage IVA and IVB patients. Patients with ATC have a bad prognosis. Distant metastases, surgery, radiotherapy and tumor residue are the most important factors affecting the prognosis. PMID- 27760218 TI - Anthropogenic Matrices Favor Homogenization of Tree Reproductive Functions in a Highly Fragmented Landscape. AB - Species homogenization or floristic differentiation are two possible consequences of the fragmentation process in plant communities. Despite the few studies, it seems clear that fragments with low forest cover inserted in anthropogenic matrices are more likely to experience floristic homogenization. However, the homogenization process has two other components, genetic and functional, which have not been investigated. The purpose of this study was to verify whether there was homogenization of tree reproductive functions in a fragmented landscape and, if found, to determine how the process was influenced by landscape composition. The study was conducted in eight fragments in southwest Brazil. The study was conducted in eight fragments in southwestern Brazil. In each fragment, all individual trees were sampled that had a diameter at breast height >=3 cm, in ten plots (0.2 ha) and, classified within 26 reproductive functional types (RFTs). The process of functional homogenization was evaluated using additive partitioning of diversity. Additionally, the effect of landscape composition on functional diversity and on the number of individuals within each RFT was evaluated using a generalized linear mixed model. appeared to be in a process of functional homogenization (dominance of RFTs, alpha diversity lower than expected by chance and and low beta diversity). More than 50% of the RFTs and the functional diversity were affected by the landscape parameters. In general, the percentage of forest cover has a positive effect on RFTs while the percentage of coffee matrix has a negative one. The process of functional homogenization has serious consequences for biodiversity conservation because some functions may disappear that, in the long term, would threaten the fragments. This study contributes to a better understanding of how landscape changes affect the functional diversity, abundance of individuals in RFTs and the process of functional homogenization, as well as how to manage fragmented landscapes. PMID- 27760219 TI - Calibration and Cross-Validation of the ActiGraph wGT3X+ Accelerometer for the Estimation of Physical Activity Intensity in Children with Intellectual Disabilities. AB - BACKGROUND: Valid objective measurement is integral to increasing our understanding of physical activity and sedentary behaviours. However, no population-specific cut points have been calibrated for children with intellectual disabilities. Therefore, this study aimed to calibrate and cross validate the first population-specific accelerometer intensity cut points for children with intellectual disabilities. METHODS: Fifty children with intellectual disabilities were randomly assigned to the calibration (n = 36; boys = 28, 9.53+/-1.08yrs) or cross-validation (n = 14; boys = 9, 9.57+/-1.16yrs) group. Participants completed a semi-structured school-based activity session, which included various activities ranging from sedentary to vigorous intensity. Direct observation (SOFIT tool) was used to calibrate the ActiGraph wGT3X+, which participants wore on the right hip. Receiver Operating Characteristic curve analyses determined the optimal cut points for sedentary, moderate, and vigorous intensity activity for the vertical axis and vector magnitude. Classification agreement was investigated using sensitivity, specificity, total agreement, and Cohen's kappa scores against the criterion measure of SOFIT. RESULTS: The optimal (AUC = .87-.94) vertical axis cut points (cpm) were <=507 (sedentary), 1008-2300 (moderate), and >=2301 (vigorous), which demonstrated high sensitivity (81-88%) and specificity (81-85%). The optimal (AUC = .86-.92) vector magnitude cut points (cpm) of <=1863 (sedentary), 2610-4214 (moderate), and >=4215 (vigorous) demonstrated comparable, albeit marginally lower, accuracy than the vertical axis cut points (sensitivity = 80-86%; specificity = 77-82%). Classification agreement ranged from moderate to almost perfect (kappa = .51-.85) with high sensitivity and specificity, and confirmed the trend that accuracy increased with intensity, and vertical axis cut points provide higher classification agreement than vector magnitude cut points. CONCLUSIONS: This study provides the first valid methods of interpreting accelerometer output in children with intellectual disabilities. The calibrated physical activity cut points are notably higher than existing cut points, thus raising questions on the validity of previous low physical activity estimates in children with intellectual disabilities that were based on typically developing cut points. PMID- 27760220 TI - Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model. AB - INTRODUCTION: Ischemia/reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up. METHODS: Unilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI) and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion were included as markers of AKI. RESULTS: Unilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function. CONCLUSIONS: As expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I. PMID- 27760221 TI - Impaired Subset Progression and Polyfunctionality of T Cells in Mice Exposed to Methamphetamine during Chronic LCMV Infection. AB - Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host's innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStoneTM to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection. Furthermore, we have studied in detail the effects of METH on splenic T cell functions, such as cytokine production and degranulation, and how they regulate each other. We used the Probability State Modeling (PSM) program to visualize the differentiation of effector/memory T cell subsets during LCMV infection and analyze the effects of METH on T cell subset progression. We recently demonstrated that METH increased PD-1 expression on T cells during viral infection. In this study, we further analyzed the impact of PD-1 expression on T cell functional markers as well as its expression in the effector/memory subsets. Overall, our study indicates that analyzing polyfunctionality of T cells can provide additional insight into T cell effector functions. Analysis of T cell heterogeneity is important to highlight changes in the evolution of memory/effector functions during chronic viral infections. Our study also highlights the impact of METH on PD-1 expression and its consequences on T cell responses. PMID- 27760222 TI - Mitochondrial Respiration after One Session of Calf Raise Exercise in Patients with Peripheral Vascular Disease and Healthy Older Adults. AB - PURPOSE: Mitochondria are essential for energy production in the muscle cell and for this they are dependent upon a sufficient supply of oxygen by the circulation. Exercise training has shown to be a potent stimulus for physiological adaptations and mitochondria play a central role. Whether changes in mitochondrial respiration are seen after exercise in patients with a reduced circulation is unknown. The aim of the study was to evaluate the time course and whether one session of calf raise exercise stimulates mitochondrial respiration in the calf muscle of patients with peripheral vascular disease. METHODS: One group of patients with peripheral vascular disease (n = 11) and one group of healthy older adults (n = 11) were included. Patients performed one session of continuous calf raises followed by 5 extra repetitions after initiation of pain. Healthy older adults performed 100 continuous calf raises. Gastrocnemius muscle biopsies were collected at baseline and 15 minutes, one hour, three hours and 24 hours after one session of calf raise exercise. A multi substrate (octanoylcarnitine, malate, adp, glutamate, succinate, FCCP, rotenone) approach was used to analyze mitochondrial respiration in permeabilized fibers. Mixed linear model for repeated measures was used for statistical analyses. RESULTS: Patients with peripheral vascular disease have a lower baseline respiration supported by complex I and they increase respiration supported by complex II at one hour post-exercise. Healthy older adults increase respiration supported by electron transfer flavoprotein and complex I at one hour and 24 hours post exercise. CONCLUSION: Our results indicate a shift towards mitochondrial respiration supported by complex II as being a pathophysiological component of peripheral vascular disease. Furthermore exercise stimulates mitochondrial respiration already after one session of calf raise exercise in patients with peripheral vascular disease and healthy older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT01842412. PMID- 27760224 TI - Correction: The Gut Microbiomes of Two Pachysoma MacLeay Desert Dung Beetle Species (Coleoptera: Scarabaeidae: Scarabaeinae) Feeding on Different Diets. AB - [This corrects the article DOI: 10.1371/journal.pone.0161118.]. PMID- 27760223 TI - Asymmetric Spread of SRBSDV between Rice and Corn Plants by the Vector Sogatella furcifera (Hemiptera: Delphacidae). AB - Plant viruses are mostly transmitted by sucking insects via their piercing behaviors, which may differ due to host plant species and their developmental stages. We characterized the transmission of a fijivirus, southern rice black streaked dwarf virus (SRBSDV), by the planthopper vector Sogatella furcifera Horvath (Hemiptera: Delphacidae), between rice and corn plants of varying developmental stages. SRBSDV was transmitted from infected rice to uninfected corn plants as efficiently as its transmission between rice plants, while was acquired by S. furcifera nymphs at a much lower rate from infected corn plants than from infected rice plants. We also recorded a high mortality of S. furcifera nymphs on corn plants. It is evident that young stages of both the virus donor and recipient plants added to the transmission efficiency of SRBSDV from rice to corn plants. Feeding behaviors of the vector recorded by electrical penetration graph showed that phloem sap ingestion, the behavioral event that is linked with plant virus acquisition, was impaired on corn plants, which accounts for the high mortality of and low virus acquisition by S. furcifera nymphs on corn plants. Our results reveal an asymmetric spread of SRBSDV between its two host plants and the underlying behavioral mechanism, which is of significance for assessing SRBSDV transmission risks and field epidemiology, and for developing integrated management approaches for SRBSDV disease. PMID- 27760226 TI - Correction: The Global Epidemiology and Contribution of Cannabis Use and Dependence to the Global Burden of Disease: Results from the GBD 2010 Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0076635.]. PMID- 27760225 TI - Family Practitioners' Advice about Taking Time Off Work for Lower Respiratory Tract Infections: A Prospective Study in Twelve European Primary Care Networks. AB - BACKGROUND: Acute cough and lower respiratory tract infections (LRTIs) are one of the most important causes of lost working hours. AIM: to explore variation and predictors in family practitioners (FPs) advice to patients with LRTIs about taking time off work in different European countries. METHODS: Prospective observational study in primary care networks in 12 countries, with multilevel mixed-effects binomial logistic regression. RESULTS: 324 FPs recruited 1616 employed adults who presented to primary care with LRTIs. The proportion of patients advised to take time off work varied from 7.6% in the Netherlands to 89.2% in Slovakia, and of these, 88.2% overall were advised to stay off work for seven days or less. None of Finnish or Dutch patients were advised to take more than 7 days off, in contrast to 35.5% of Polish and 27.0% of Slovak patients. The strongest predictors of FPs' advice about time off work were: patient symptoms interfering with normal activities (OR 4.43; P<0.001), fever (2.49; P<0.001), patients feeling generally unwell (2.21; P<0.001), antibiotic prescribing (1.51; P = 0.025) and auscultation abnormality (1.50; P = 0.029). Advice to take time off was not associated with patient reported recovery. CONCLUSIONS: There is large variation in FPs' advice given to patients with LRTIs in Europe about taking time off work, which is not explained by differences in patients' reported illness duration, but might be explained by differences in regulations around certification and sick pay. Evidence based guidance for advising patients about taking time off work for this common condition is needed. PMID- 27760228 TI - Mistaken Identity: Another Bias in the Use of Relative Genetic Divergence Measures for Detecting Interspecies Introgression. AB - Measures of genetic divergence have long been used to identify evolutionary processes operating within and between species. However, recent reviews have described a bias in the use of relative divergence measures towards incorrectly identifying genomic regions that are seemingly immune to introgression. Here, we present a novel and opposite bias of relative divergence measures: misidentifying regions of introgression between sister species. We examine two distinct haplotypes of intermediate frequency within Drosophila pseudoobscura at the DPSX009 locus. One of these haplotypes had lower relative divergence than another to sister species D. persimilis. Although we and others initially presumed one haplotype have spread via introgression between D. pseudoobscura and D. persimilis, absolute divergence measures and individual sequence analysis suggest that haplotype structuring occurred as the result of within-species processes. The potential for this type of misinference may occur with any haplotype that recently spread within a species. We conclude that absolute measures of genetic divergence are necessary for confirming putative regions of introgression. PMID- 27760227 TI - Reproducibility of Digital PCR Assays for Circulating Tumor DNA Analysis in Advanced Breast Cancer. AB - Circulating tumor DNA (ctDNA) analysis has the potential to allow non-invasive analysis of tumor mutations in advanced cancer. In this study we assessed the reproducibility of digital PCR (dPCR) assays of circulating tumor DNA in a cohort of patients with advanced breast cancer and assessed delayed plasma processing using cell free DNA preservative tubes. We recruited a cohort of 96 paired samples from 71 women with advanced breast cancer who had paired blood samples processed either immediately or delayed in preservative tubes with processing 48 72 hours after collection. Plasma DNA was analysed with multiplex digital PCR (mdPCR) assays for hotspot mutations in PIK3CA, ESR1 and ERBB2, and for AKT1 E17K. There was 94.8% (91/96) agreement in mutation calling between immediate and delayed processed tubes, kappa 0.88 95% CI 0.77-0.98). Discordance in mutation calling resulted from low allele frequency and likely stochastic effects. In concordant samples there was high correlation in mutant copies per ml plasma (r2 = 0.98; p<0.0001). There was elevation of total cell free plasma DNA concentrations in 10.3% of delayed processed tubes, although overall quantification of total cell free plasma DNA had similar prognostic effects in immediate (HR 3.6) and delayed (HR 3.0) tubes. There was moderate agreement in changes in allele fraction between sequential samples in quantitative mutation tracking (r = 0.84, p = 0.0002). Delayed processing of samples using preservative tubes allows for centralized ctDNA digital PCR mutation screening in advanced breast cancer. The potential of preservative tubes in quantitative mutation tracking requires further research. PMID- 27760229 TI - Demographics, Management Strategies, and Problems in ST-Elevation Myocardial Infarction from the Standpoint of Emergency Medicine Specialists: A Survey-Based Study from Seven Geographical Regions of Turkey. AB - BACKGROUND: This study aimed to explore the ST segment elevation myocardial infarction (STEMI) management practices of emergency medicine specialists working in various healthcare institutions of seven different geographical regions of Turkey, and to examine the characteristics of STEMI presentation and patient admissions in these regions. METHODS: We included 225 emergency medicine specialists working in all geographical regions of Turkey. We e-mailed them a 20 item questionnaire comprising questions related to their STEMI management practices and characteristics of STEMI presentation and patient admissions. RESULTS: The regions were not significantly different with respect to primary percutaneous coronary intervention (PCI) resources (p = 0.286). Sixty six point two percent (66.2%) of emergency specialists stated that patients presented to emergency within 2 hours of symptom onset. Forty three point six percent (43.6%) of them contacted cardiology department within 10 minutes and 47.1% within 30 minutes. In addition, 68.3% of the participants improved themselves through various educational activities. The Southeastern Anatolian region had the longest time from symptom onset to emergency department admission and the least favorable hospital admission properties, not originating from physicians or 112 emergency healthcare services. CONCLUSION: Seventy point seven percent (70.7%) of the emergency specialists working in all geographical regions of Turkey comply with the latest guidelines and current knowledge about STEMI care; they also try to improve themselves, and receive adequate support from 112 emergency healthcare services and cardiologists. While inter-regional gaps between the number of primary PCI capable centers and quality of STEMI care progressively narrow, there are still issues to address, such as delayed patient presentation after symptoms onset and difficulties in patient admission. PMID- 27760230 TI - Surface Properties of Wild-Type Rhizobium leguminosarum bv. trifolii Strain 24.2 and Its Derivatives with Different Extracellular Polysaccharide Content. AB - Rhizobium leguminosarum bv. trifolii is a soil bacterium able to establish symbiosis with agriculturally important legumes, i.e., clover plants (Trifolium spp.). Cell surface properties of rhizobia play an essential role in their interaction with both biotic and abiotic surfaces. Physicochemical properties of bacterial cells are underpinned by the chemical composition of their envelope surrounding the cells, and depend on various environmental conditions. In this study, we performed a comprehensive characterization of cell surface properties of a wild-type R. leguminosarum bv. trifolii strain 24.2 and its derivatives producing various levels of exopolysaccharide (EPS), namely, pssA mutant Rt5819 deficient in EPS synthesis, rosR mutant Rt2472 producing diminished amounts of this polysaccharide, and two EPS-overproducing strains, Rt24.2(pBA1) and Rt24.2(pBR1), under different growth conditions (medium type, bacterial culture age, cell viability, and pH). We established that EPS plays an essential role in the electrophoretic mobility of rhizobial cells, and that higher amounts of EPS produced resulted in greater negative electrophoretic mobility and higher acidity (lower pKapp,av) of the bacterial cell surface. From the tested strains, the electrophoretic mobility was lowest in EPS-deficient pssA mutant. Moreover, EPS produced by rhizobial strains resulted not only in an increase of negative surface charge but also in increased hydrophobicity of bacterial cell surface. This was determined by measurements of water contact angle, surface free energy, and free energy of bacterial surface-water-bacterial surface interaction. Electrophoretic mobility of the studied strains was also affected by the structure of the bacterial population (i.e., live/dead cell ratio), medium composition (ionic strength and mono- and divalent cation concentrations), and pH. PMID- 27760231 TI - Pyruvate Oxidase as a Critical Link between Metabolism and Capsule Biosynthesis in Streptococcus pneumoniae. AB - The pneumococcus is one of the most prodigious producers of hydrogen peroxide amongst bacterial pathogens. Hydrogen peroxide production by the pneumococcus has been implicated in antibiotic synergism, competition between other bacterial colonizers of the nasopharynx, and damage to epithelial cells. However, the role during invasive disease has been less clear with mutants defective in hydrogen peroxide production demonstrating both attenuation and heightened invasive disease capacity depending upon strain and serotype background. This work resolves these conflicting observations by demonstrating that the main hydrogen peroxide producing enzyme of the pneumococcus, SpxB, is required for capsule formation in a strain dependent manner. Capsule production by strains harboring capsules with acetylated sugars was dependent upon the presence of spxB while capsule production in serotypes lacking such linkages were not. The spxB mutant had significantly lower steady-state cellular levels of acetyl-CoA, suggesting that loss of capsule arises from dysregulation of this intermediary metabolite. This conclusion is corroborated by deletion of pdhC, which also resulted in lower steady-state acetyl-CoA levels and phenocopied the capsule expression profile of the spxB mutant. Capsule and acetyl-CoA levels were restored in the spxB and lctO (lactate oxidase) double mutant, supporting the connection between central metabolism and capsule formation. Taken together, these data show that the defect in pathogenesis in the spxB mutant is due to a metabolic imbalance that attenuates capsule formation and not to reduced hydrogen peroxide formation. PMID- 27760232 TI - HCMV Displays a Unique Transcriptome of Immunomodulatory Genes in Primary Monocyte-Derived Cell Types. AB - Human cytomegalovirus (HCMV) is a betaherpesvirus which rarely presents problems in healthy individuals, yet may result in severe morbidity in immunocompromised patients and in immune-naive neonates. HCMV has a large 235 kb genome with a coding capacity of at least 165 open reading frames (ORFs). This large genome allows complex gene regulation resulting in different sets of transcripts during lytic and latent infection. While latent virus mainly resides within monocytes and CD34+ progenitor cells, reactivation to lytic infection is driven by differentiation towards terminally differentiated myeloid dendritic cells and macrophages. Consequently, it has been suggested that macrophages and dendritic cells contribute to viral spread in vivo. Thus far only limited knowledge is available on the expression of HCMV genes in terminally differentiated myeloid primary cells and whether or not the virus exhibits a different set of lytic genes in primary cells compared with lytic infection in NHDF fibroblasts. To address these questions, we used Illumina next generation sequencing to determine the HCMV transcriptome in macrophages and dendritic cells during lytic infection and compared it to the transcriptome in NHDF fibroblasts. Here, we demonstrate unique expression profiles in macrophages and dendritic cells which significantly differ from the transcriptome in fibroblasts mainly by modulating the expression of viral transcripts involved in immune modulation, cell tropism and viral spread. In a head to head comparison between macrophages and dendritic cells, we observed that factors involved in viral spread and virion composition are differentially regulated suggesting that the plasticity of the virion facilitates the infection of surrounding cells. Taken together, this study provides the full transcript expression analysis of lytic HCMV genes in monocyte-derived type 1 and type 2 macrophages as well as in monocyte-derived dendritic cells. Thereby underlining the potential of HCMV to adapt to or influence different cellular environments to promote its own survival. PMID- 27760233 TI - Characterization of the Role of Hexamer AGUAAA and Poly(A) Tail in Coronavirus Polyadenylation. AB - Similar to eukaryotic mRNA, the positive-strand coronavirus genome of ~30 kilobases is 5'-capped and 3'-polyadenylated. It has been demonstrated that the length of the coronaviral poly(A) tail is not static but regulated during infection; however, little is known regarding the factors involved in coronaviral polyadenylation and its regulation. Here, we show that during infection, the level of coronavirus poly(A) tail lengthening depends on the initial length upon infection and that the minimum length to initiate lengthening may lie between 5 and 9 nucleotides. By mutagenesis analysis, it was found that (i) the hexamer AGUAAA and poly(A) tail are two important elements responsible for synthesis of the coronavirus poly(A) tail and may function in concert to accomplish polyadenylation and (ii) the function of the hexamer AGUAAA in coronaviral polyadenylation is position dependent. Based on these findings, we propose a process for how the coronaviral poly(A) tail is synthesized and undergoes variation. Our results provide the first genetic evidence to gain insight into coronaviral polyadenylation. PMID- 27760235 TI - Correction: Literature-Informed Analysis of a Genome-Wide Association Study of Gestational Age in Norwegian Women and Children Suggests Involvement of Inflammatory Pathways. AB - [This corrects the article DOI: 10.1371/journal.pone.0160335.]. PMID- 27760234 TI - Limitations in Activities of Daily Living in Community-Dwelling People Aged 75 and Over: A Systematic Literature Review of Risk and Protective Factors. AB - BACKGROUND: Most older people wish to age in place, for which functional status or being able to perform activities of daily living (ADLs) is an important precondition. However, along with the substantial growth of the (oldest) old, the number of people who develop limitations in ADLs or have functional decline dramatically increases in this part of the population. Therefore, it is important to gain insight into factors that can contribute to developing intervention strategies at older ages. As a first step, this systematic review was conducted to identify risk and protective factors as predictors for developing limitations in ADLs in community-dwelling people aged 75 and over. METHODS: Four electronic databases (CINAHL (EBSCO), EMBASE, PsycINFO and PubMed) were searched systematically for potentially relevant studies published between January 1998 and March 2016. RESULTS: After a careful selection process, 6,910 studies were identified and 25 were included. By far most factors were examined in one study only, and most were considered risk factors. Several factors do not seem to be able to predict the development of limitations in ADLs in people aged 75 years and over, and for some factors ambiguous associations were found. The following risk factors were found in at least two studies: higher age, female gender, diabetes, hypertension, and stroke. A high level of physical activity and being married were protective in multiple studies. Notwithstanding the fact that research in people aged 65 years and over is more extensive, risk and protective factors seem to differ between the 'younger' and 'older' olds. CONCLUSION: Only a few risk and protective factors in community-dwelling people aged 75 years and over have been analysed in multiple studies. However, the identified factors could serve both detection and prevention purposes, and implications for future research are given as well. PMID- 27760237 TI - Behavioral Health Workforce and Private Sector Solutions to Addressing Veterans' Access to Care Issues. PMID- 27760238 TI - Quality Assessment of 7 Cardiovascular Drugs in 10 Sub-Saharan Countries: The SEVEN Study. PMID- 27760236 TI - Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT). AB - Importance: Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. Objective: To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. Design, Setting, and Participants: Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. Main Outcomes and Measures: Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of >=75 associated with a categorical ASD diagnosis); attention deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of >=65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. Results: Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first degree relatives) exceeded that observed in the general population and ASD family samples. Conclusions and Relevance: This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism. PMID- 27760240 TI - An African American Man with Diffuse Erythematous Papules. PMID- 27760241 TI - Refining the Diagnosis of Type 2 Myocardial Infarction. PMID- 27760239 TI - Response to Interleukin (IL)-17 Inhibition in an Adolescent With Severe Manifestations of IL-36 Receptor Antagonist Deficiency (DITRA). PMID- 27760242 TI - Lactation in the Human Breast From a Fluid Dynamics Point of View. AB - This study is a collaborative effort among lactation specialists and fluid dynamic engineers. The paper presents clinical results for suckling pressure pattern in lactating human breast as well as a 3D computational fluid dynamics (CFD) modeling of milk flow using these clinical inputs. The investigation starts with a careful, statistically representative measurement of suckling vacuum pressure, milk flow rate, and milk intake in a group of infants. The results from clinical data show that suckling action does not occur with constant suckling rate but changes in a rhythmic manner for infants. These pressure profiles are then used as the boundary condition for the CFD study using commercial ansys fluent software. For the geometric model of the ductal system of the human breast, this work takes advantage of a recent advance in the development of a validated phantom that has been produced as a ground truth for the imaging applications for the breast. The geometric model is introduced into CFD simulations with the aforementioned boundary conditions. The results for milk intake from the CFD simulation and clinical data were compared and cross validated. Also, the variation of milk intake versus suckling pressure are presented and analyzed. Both the clinical and CFD simulation show that the maximum milk flow rate is not related to the largest vacuum pressure or longest feeding duration indicating other factors influence the milk intake by infants. PMID- 27760243 TI - Treatment of Dupuytren Contracture With Injectable Collagenase Within the Veterans Affairs System. PMID- 27760244 TI - Assessing the Effect of the Affordable Care Act on Surgical Populations. PMID- 27760245 TI - Implications of the Patient Protection and Affordable Care Act on Insurance Coverage and Rehabilitation Use Among Young Adult Trauma Patients. AB - Importance: Trauma is the leading cause of death and disability among young adults, who are also among the most likely to be uninsured. Efforts to increase insurance coverage, including passage of the Patient Protection and Affordable Care Act (ACA), were intended to improve access to care and promote improvements in outcomes. However, despite reported gains in coverage, the ACA's success in promoting use of high-quality care and enacting changes in clinical end points remains unclear. Objectives: To assess for observed changes in insurance coverage and rehabilitation use among young adult trauma patients associated with the ACA, including the Dependent Coverage Provision (DCP) and Medicaid expansion/open enrollment, and to consider possible insurance and rehabilitation differences between DCP-eligible vs -ineligible patients and among stratified demographic and community subgroups. Design, Setting, and Participants: A longitudinal assessment of DCP implementation and Medicaid expansion/open enrollment using risk-adjusted before-and-after, difference-in-difference, and interrupted time-series analyses was conducted. Eleven years (January 1, 2005, to September 31, 2015) of Maryland Health Services Cost Review Commission data, representing complete patient records from all payers within the state, were used to identify all hospitalized young adult (aged 18-34 years) trauma patients in Maryland during the study period. Results: Of the 69 507 hospitalized patients included, 50 548 (72.7%) were male, and the mean (SD) age was 25 (5) years. Before implementation of the DCP, 1 of 4 patients was uninsured. After ACA implementation, the number fell to less than 1 of 10, with similar patterns emerging in emergency department and outpatient settings. The change was primarily driven by Medicaid expansion/open enrollment, which corresponded to a 20.1 percentage-point increase in Medicaid (95% CI, 18.9-21.3) and an 18.2 percentage-point decrease in uninsured (95% CI, 19.3 to -17.2). No changes were detected among privately insured patients. Rehabilitation use increased by 5.4 percentage points (95% CI, 4.5-6.2)-a 60% relative increase from a baseline of 9%. Mortality (-0.5; 95% CI, -0.9 to -0.1) and failure-to-rescue rates (-4.5; 95% CI, -7.4 to -1.6) also significantly declined. Stratified changes point to significant differences in the percentage of uninsured patients and rehabilitation access across the board, mitigating or even eradicating disparities in certain cases. Conclusions and Relevance: For patients who are injured, young, and uninsured, Medicaid expansion/open enrollment in Maryland changed insurance coverage and altered patient outcomes in ways that the DCP alone was never intended to do. Implementation of Medicaid expansion/open enrollment transformed the landscape of trauma coverage, directly affecting the health of one of the country's most vulnerable at-risk groups. PMID- 27760246 TI - An Approach for Assessing Turbulent Flow Damage to Blood in Medical Devices. AB - In this work, contributing factors for red blood cell (RBC) damage in turbulence are investigated by simulating jet flow experiments. Results show that dissipative eddies comparable or smaller in size to the red blood cells cause hemolysis and that hemolysis corresponds to the number and, more importantly, the surface area of eddies that are associated with Kolmogorov length scale (KLS) smaller than about 10 MUm. The size distribution of Kolmogorov scale eddies is used to define a turbulent flow extensive property with eddies serving as a means to assess the turbulence effectiveness in damaging cells, and a new hemolysis model is proposed. This empirical model is in agreement with hemolysis results for well-defined systems that exhibit different exposure times and flow conditions, in Couette flow viscometer, capillary tube, and jet flow experiments. PMID- 27760247 TI - Corrected vs Uncorrected Obesity in Childbearing Women-What Really Drives Fetal Risks? PMID- 27760248 TI - A Precision Medicine Approach to Clinical Trials. PMID- 27760249 TI - Multidirectional In Vivo Characterization of Skin Using Wiener Nonlinear Stochastic System Identification Techniques. AB - A triaxial force-sensitive microrobot was developed to dynamically perturb skin in multiple deformation modes, in vivo. Wiener static nonlinear identification was used to extract the linear dynamics and static nonlinearity of the force displacement behavior of skin. Stochastic input forces were applied to the volar forearm and thenar eminence of the hand, producing probe tip perturbations in indentation and tangential extension. Wiener static nonlinear approaches reproduced the resulting displacements with variances accounted for (VAF) ranging 94-97%, indicating a good fit to the data. These approaches provided VAF improvements of 0.1-3.4% over linear models. Thenar eminence stiffness measures were approximately twice those measured on the forearm. Damping was shown to be significantly higher on the palm, whereas the perturbed mass typically was lower. Coefficients of variation (CVs) for nonlinear parameters were assessed within and across individuals. Individual CVs ranged from 2% to 11% for indentation and from 2% to 19% for extension. Stochastic perturbations with incrementally increasing mean amplitudes were applied to the same test areas. Differences between full scale and incremental reduced-scale perturbations were investigated. Different incremental preloading schemes were investigated. However, no significant difference in parameters was found between different incremental preloading schemes. Incremental schemes provided depth-dependent estimates of stiffness and damping, ranging from 300 N/m and 2 Ns/m, respectively, at the surface to 5 kN/m and 50 Ns/m at greater depths. The device and techniques used in this research have potential applications in areas, such as evaluating skincare products, assessing skin hydration, or analyzing wound healing. PMID- 27760250 TI - Refining the Diagnosis of Type 2 Myocardial Infarction-Reply. PMID- 27760251 TI - Misrepresentation of Data and Typographical Error. PMID- 27760252 TI - Evaluating and Improving the Cardiovascular Drug Supply for Better Global Health. PMID- 27760253 TI - Multiscale Strain as a Predictor of Impact-Induced Fissuring in Articular Cartilage. AB - Mechanical damage is central to both initiation and progression of osteoarthritis (OA). However, specific causal links between mechanics and cartilage damage are incompletely understood, which results in an inability to predict failure. The lack of understanding is primarily due to the difficulty in simultaneously resolving the high rates and small length scales relevant to the problem and in correlating such measurements to the resulting fissures. This study leveraged microscopy and high-speed imaging to resolve mechanics on the previously unexamined time and length scales of interest in cartilage damage, and used those mechanics to develop predictive models. The specific objectives of this study were to: first, quantify bulk and local mechanics during impact-induced fissuring; second, develop predictive models of fissuring based on bulk mechanics and local strain; and third, evaluate the accuracy of these models in predicting fissures. To achieve these three objectives, bovine tibial cartilage was impacted using a custom spring-loaded device mounted on an inverted microscope. The occurrence of fissures was modulated by varying impact energy. For the first objective, during impact, deformation was captured at 10,000 frames per second and bulk and local mechanics were analyzed. For the second objective, data from samples impacted with a 1.2 mm diameter rod were fit to logistic regression functions, creating models of fissure probability based on bulk and local mechanics. Finally, for the third objective, data from samples impacted with a 0.8 mm diameter rod were used to test the accuracy of model predictions. This study provides a direct comparison between bulk and local mechanical thresholds for the prediction of fissures in cartilage samples, and demonstrates that local mechanics provide more accurate predictions of local failure than bulk mechanics provide. Bulk mechanics were accurate predictors of fissure for the entire sample cohort, but poor predictors of fissure for individual samples. Local strain fields were highly heterogeneous and significant differences were determined between fissured and intact samples, indicating the presence of damage thresholds. In particular, first principal strain rate and maximum shear strain were the best predictors of local failure, as determined by concordance statistics. These data provide an important step in establishing causal links between local mechanics and cartilage damage; ultimately, data such as these can be used to link macro- and micro-scale mechanics and thereby predict mechanically mediated disease on a subject-specific basis. PMID- 27760254 TI - Dermatologists' Perceptions, Recommendations, and Use of Sunscreen. PMID- 27760256 TI - Cardiac Rehabilitation After Myocardial Infarction: Unmet Needs and Future Directions. PMID- 27760257 TI - Refining the Diagnosis of Type 2 Myocardial Infarction. PMID- 27760255 TI - Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study. AB - Importance: Pancreatic mucinous cystic neoplasms (MCNs) harbor malignant potential, and current guidelines recommend resection. However, data are limited on preoperative risk factors for malignancy (adenocarcinoma or high-grade dysplasia) occurring in the setting of an MCN. Objectives: To examine the preoperative risk factors for malignancy in resected MCNs and to assess outcomes of MCN-associated adenocarcinoma. Design, Setting, and Participants: Patients who underwent pancreatic resection of MCNs at the 8 academic centers of the Central Pancreas Consortium from January 1, 2000, through December 31, 2014, were retrospectively identified. Preoperative factors of patients with and without malignant tumors were compared. Survival analyses were conducted for patients with adenocarcinoma. Main Outcomes and Measures: Binary logistic regression models were used to determine the association of preoperative factors with the presence of MCN-associated malignancy. Results: A total of 1667 patients underwent resection of pancreatic cystic lesions, and 349 (20.9%) had an MCN (310 women [88.8%]; mean (SD) age, 53.3 [14.7] years). Male sex (odds ratio [OR], 3.72; 95% CI, 1.21-11.44; P = .02), pancreatic head and neck location (OR, 3.93; 95% CI, 1.43-10.81; P = .01), increased radiographic size of the MCN (OR, 1.17; 95% CI, 1.08-1.27; P < .001), presence of a solid component or mural nodule (OR, 4.54; 95% CI, 1.95-10.57; P < .001), and duct dilation (OR, 4.17; 95% CI, 1.63 10.64; P = .003) were independently associated with malignancy. Malignancy was not associated with presence of radiographic septations or preoperative cyst fluid analysis (carcinoembryonic antigen, amylase, or mucin presence). The median serum CA19-9 level for patients with malignant neoplasms was 210 vs 15 U/mL for those without (P = .001). In the 44 patients with adenocarcinoma, 41 (93.2%) had lymph nodes harvested, with nodal metastases in only 14 (34.1%). Median follow-up for patients with adenocarcinoma was 27 months. Adenocarcinoma recurred in 11 patients (25%), with a 64% recurrence-free survival and 59% overall survival at 3 years. Conclusions and Relevance: Adenocarcinoma or high-grade dysplasia is present in 14.9% of resected pancreatic MCNs for which risks include male sex, pancreatic head and neck location, larger MCN, solid component or mural nodule, and duct dilation. Mucinous cystic neoplasm-associated adenocarcinoma appears to have decreased nodal involvement at the time of resection and increased survival compared with typical pancreatic ductal adenocarcinoma. Indications for resection of MCNs should be revisited. PMID- 27760258 TI - Pulmonary Edema Occurring 15 Years After Mitral Valve Replacement. PMID- 27760259 TI - Acute Upper Abdominal Pain With a Distended Cecum in the Left Upper Quadrant. PMID- 27760261 TI - Macular Inner Retinal Layer Thickening and Outer Retinal Layer Damage Correlate With Visual Acuity During Remission in Behcet's Disease. AB - Purpose: To identify macular intraretinal layer changes of patients in remission from Behcet's disease (BD) of short and long duration and evaluate the associations with visual acuity (VA). Methods: Thirty-two eyes from 26 BD patients were enrolled, including 16 eyes with a duration less than 3 years (0.5 2.5 years; BD1) and 16 eyes of longer duration (3-12 years; BD2). Their intraretinal layer thicknesses and integrity of ellipsoid zone (EZ) and interdigitation zone (IZ) were evaluated by spectral-domain optical coherence tomography (SD-OCT). Associations between VA and retinal structural changes were analyzed. Results: Compared to controls, the inner retina was significantly thicker in BD groups, especially the nerve fiber layer (NFL). The outer retinal layer (ORL) was thicker in BD1 in the central and temporal regions and thinner in BD2 compared to controls in all regions. In BD2, there were more eyes with disruption of the EZ and IZ. Worsening VA was correlated with thickening of the NFL and inner nuclear layer (INL), thinning of the ORL, and greater disruption of the EZ and IZ. Multiple linear regression analysis revealed EZ disruption, nasal ORL, inferior NFL, and temporal and nasal INLs were independent predictors of best-corrected (BCVA). Conclusions: Behcet's disease patients in remission had significant changes in the inner and outer retinal structures, associated with worse VA. Thickness and integrity of the intraretinal layers by SD-OCT and segmentation might be useful predictors for the degree of VA damage in BD remission. PMID- 27760260 TI - The Solid Mechanics of Cancer and Strategies for Improved Therapy. AB - Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined. PMID- 27760263 TI - Analysis of Cerebrospinal Fluid Pressure Estimation Using Formulae Derived From Clinical Data. AB - Purpose: To evaluate a frequently used regression model and a new, modified regression model to estimate cerebrospinal fluid pressure (CSFP). Methods: Datasets from the Beijing iCOP study from Tongren Hospital, Beijing, China, and the Mayo Clinic, Rochester, Minnesota, were tested in this retrospective, case control study. An often-used regression model derived from the Beijing iCOP dataset, but without radiographic data, was used to predict CSFP by using demographic and physiologic data. A regression model was created using the Mayo Clinic dataset and tested against a validation group. The Mayo Clinic-derived formula was also tested against the Beijing Eye Study population. Intraclass correlation was used to assess predicted versus actual CSFP. Results: The Beijing derived regression equation was reported to have an intraclass correlation coefficient (ICC) of 0.71, indicating strong correlation between predicted and actual CSFP in the study population. The Beijing iCOP regression model poorly predicted CSFP in the Mayo Clinic population with an ICC of 0.14. The Mayo Clinic derived regression model similarly did not predict CSFP in its Mayo Clinic validation group (ICC 0.28 +/- 0.04) nor in the Beijing Eye Study population (ICC 0.06). Conclusions: Formulae used to predict CSFP derived from clinical data fared poorly against a large retrospective dataset. This may be related to differences in lumbar puncture technique, in the populations tested, or the timing of collection of physiologic variables in the Mayo Clinic dataset. Caution should be used when interpreting results based on formulaic derivation of CSFP. PMID- 27760264 TI - Mucinous Cystic Neoplasms of the Pancreas: A Surgical Disease. PMID- 27760262 TI - Associations Between Retinal Pigment Epithelium and Drusen Volume Changes During the Lifecycle of Large Drusenoid Pigment Epithelial Detachments. AB - Purpose: Drusenoid pigment epithelial detachments (PEDs) are a defined path to atrophy in age-related macular degeneration (AMD). We analyzed the relationships between retinal pigment epithelium (RPE) and drusen volume changes during the PED lifecycle, using spectral-domain optical coherence tomography (SD-OCT). Methods: Twenty-one cases of drusenoid PED tracked using SD-OCT through periods of growth and collapse were evaluated. Volumetric calculations and piece-wise linear regression analysis were used to determine the breakpoint between growth and collapse. Spectral-domain OCT scans were independently evaluated for the appearance of intraretinal hyperreflective foci, acquired vitelliform lesions (AVLs), and disruptions to the RPE+basal lamina band. Timing of these events with respect to the breakpoint was statistically evaluated. Morphometric characteristics of drusenoid PEDs were correlated with rate of PED collapse and final visual acuity. Results: Mean age of subjects was 75.3 years and mean period of follow up was 4.1 years (median 4.5 years; range, 0.6-6.6 years). The lifecycle of drusenoid PEDs was asymmetric, in that the rate of collapse (0.199 mm3/month) is significantly faster (P < 0.001) than the rate of growth (0.022 mm3/month). Appearance of intraretinal hyperreflective foci and AVLs preceded the breakpoint (both P < 0.001). The timing of disruptions to the RPE+basal lamina band did not differ from the breakpoint (P = 0.510). Maximal height, volume, and diameter of drusenoid PEDs were inversely correlated with final visual acuity (all P < 0.001) and positively correlated with the rate of PED collapse (all P < 0.001). Conclusions: Spectral-domain OCT signatures, plausibly attributable to anteriorly migrated RPE and disintegration of the RPE layer, precede or occur simultaneously with changes in volume of drusenoid PED during the lifecycle of this lesion. PMID- 27760265 TI - Bariatric Surgery in Women of Childbearing Age, Timing Between an Operation and Birth, and Associated Perinatal Complications. AB - Importance: Metabolic changes after maternal bariatric surgery may affect subsequent fetal development. Many relevant perinatal outcomes have not been studied in this postoperative population, and the risks associated with short operation-to-birth (OTB) intervals have not been well examined. Objective: To examine the risk for perinatal complications in women with a history of bariatric surgery (postoperative mothers [POMs]) by comparing them with mothers without operations (nonoperative mothers [NOMs]) and examining the association of the OTB interval with perinatal outcomes. Design, Setting, and Participants: This investigation was a population-based retrospective cohort study (January 1, 1980, to May 30, 2013) at hospitals in Washington State. Data were collected from birth certificates and maternally linked hospital discharge data. Participants were all POMs and their infants (n = 1859) and a population-based random sample of NOMs and their infants frequency matched by delivery year (n = 8437). Exposures: Bariatric operation before birth or categories of OTB intervals. Main Outcomes and Measures: The primary outcomes were prematurity, neonatal intensive care unit (NICU) admission, congenital malformation, small for gestational age (SGA), birth injury, low Apgar score (<=8), and neonatal mortality. Poisson regression was used to compute relative risks (RRs) and 95% CIs, with adjustments for maternal body mass index, delivery year, socioeconomic status, age, parity, and comorbid conditions. Results: A total of 10 296 individuals were included in the analyses for this study. In the overall cohort, the median age was 29 years (interquartile range, 24-33 years). Compared with infants from NOMS, infants from POMs had a higher risk for prematurity (14.0% vs 8.6%; RR, 1.57; 95% CI, 1.33-1.85), NICU admission (15.2% vs 11.3%; RR, 1.25; 95% CI, 1.08-1.44), SGA status (13.0% vs 8.9%; RR, 1.93; 95% CI, 1.65-2.26), and low Apgar score (17.5% vs 14.8%; RR, 1.21; 95% CI, 1.06-1.37). Compared with infants from mothers with greater than a 4-year OTB interval, infants from mothers with less than a 2-year interval had higher risks for prematurity (11.8% vs 17.2%; RR, 1.48; 95% CI, 1.00-2.19), NICU admission (12.1% vs 17.7%; RR, 1.54; 95% CI, 1.05-2.25), and SGA status (9.2% vs 12.7%; RR, 1.51; 95% CI, 0.94-2.42). Conclusions and Relevance: Infants of mothers with a previous bariatric operation had a greater likelihood of perinatal complications compared with infants of NOMs. Operation-to-birth intervals of less than 2 years were associated with higher risks for prematurity, NICU admission, and SGA status compared with longer intervals. These findings are relevant to women with a history of bariatric surgery and could inform decisions regarding the optimal timing between an operation and conception. PMID- 27760266 TI - Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations. AB - Importance: We found CARD14 mutations (2 de novo novel mutations and another previously reported mutation) in 3 of 3 patients with pityriasis rubra pilaris (PRP) type V, but not in patients with PRP of other types. Our findings, combined with the published literature, suggest that type V PRP, both familial and sporadic, can be caused by CARD14 mutations. Detailed clinical observation revealed that all 3 patients displayed unique patchy macular brown hyperpigmentation. Objective: To further determine how often patients with PRP have pathogenic mutations in CARD14 and to elucidate which clinical subtype of PRP is caused by CARD14 mutations. Design, Setting, and Participants: We sequenced the entire coding regions of CARD14 in genomic DNA from patients with 5 clinical subtypes of PRP. The detailed clinical features were analyzed in all the patients. The pathogenicity of each mutation was evaluated by several computational predictions. PRP was classified into 6 subgroups, types I to VI, based on clinical criteria. We categorized all the patients with PRP into the clinical subtypes using the classic PRP classification; 22 cases of PRP with varying subtypes were studied. Main Outcomes and Measures: The prevalence of CARD14 mutations in each subtype of PRP was evaluated. Clinical features and characteristics of patients with PRP with CARD14 mutations were analyzed. Results: Overall 22 patients with PRP were included in our study (12 men, 10 women; mean [SD] age, 26 [18] years). Among 3 patients with PRP type V, all were found to have CARD14 mutations: 2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser). All were close to the reported pathogenic domains. In silico analysis of all 3 mutations suggested that they are functionally relevant to pathogenesis. All 3 patients displayed unique patchy macular brown hyperpigmentation additionally to other typical features of PRP. Patients with PRP type I and type IV, 1 patient each, had the rare variants in CARD14. Conclusions and Relevance: Pityriasis rubra pilaris type V is a distinct variant of PRP that is caused by CARD14 mutations. In addition, a rare variant of CARD14 might also be implicated in the pathophysiology of other forms of PRP. PMID- 27760270 TI - Degradation of Visual Performance With Increasing Levels of Retinal Stray Light. AB - Purpose: To quantify the effect of induced stray light on halo size, luminance threshold, and contrast sensitivity. Methods: Retinal stray light was induced in five healthy subjects using different photographic filters. The stray light induced ranged from levels observed in intraocular lenses (IOLs) with glistenings (low) to cataract level (high). The visual impact was measured for halo size, luminance detection threshold, and contrast sensitivity with and without a glare source. Results: The amount of retinal stray light induced by the different filters was similar when measured using the psychophysical method and the optical bench method. Low amounts of induced stray light cause the halo size to increase by 21%, the luminance detection threshold to increase by 156%, and contrast sensitivity to decrease by 10% to 21% dependent on spatial frequency and presence of a glare source. The visual impact percentages for high amounts of induced stray light were, respectively, 76%, 2130%, and 30% to 49%. In the presence of a glare source, contrast sensitivity losses were larger and shifted to lower spatial frequencies. Conclusions: Low levels of retinal stray light can cause significant increases in halo sizes, elevations in luminance detection thresholds, and reductions in contrast sensitivity whether or not a glare source is present. PMID- 27760269 TI - Association Between Cardiac Rehabilitation Participation and Health Status Outcomes After Acute Myocardial Infarction. AB - Importance: Cardiac rehabilitation (CR) improves survival after acute myocardial infarction (AMI), and referral to CR has been introduced as a performance measure of high-quality care. The association of participation in CR with patients' health status (eg, quality of life, symptoms, and functional status) is poorly defined. Objective: To examine the association of participation in CR with health status outcomes after AMI. Design, Setting, and Participants: A retrospective cohort study was conducted of patients enrolled in 2 AMI registries: PREMIER, from January 1, 2003, to June 28, 2004, and TRIUMPH, from April 11, 2005, to December 31, 2008. The analytic cohort was restricted to 4929 patients with data available on baseline health status, 6- or 12- month follow-up health status, and participation in CR. Data analysis was performed from 2014 to 2015. Exposures: Participation in at least 1 CR session within 6 months of hospital discharge. Main Outcomes and Measures: Patient health status was quantified using the Seattle Angina Questionnaire (SAQ) and the 12-Item Short-Form Health Survey (SF 12). The primary outcomes of interest were the mean differences in SAQ domain scores during the 12 months after AMI between patients who did and did not participate in CR. Secondary outcomes were the mean differences in the SF-12 summary scores and all-cause mortality. Results: After successfully matching the cohorts of the 4929 patients (3328 men and 1601 women; mean [SD] age, 60.0 [12.2] years) for the propensity to participate in CR and comparing the groups using linear, mixed-effects models, mean differences in the SAQ and SF-12 domain scores were similar at 6 and 12 months between the 2012 patients participating in CR (3 were unable to be matched) and the 2894 who did not participate (20 were unable to be matched). At 6 months, the mean difference was -0.76 (95% CI, -2.05 to 0.52) for the SAQ quality of life score, -1.53 (95% CI, -2.57 to -0.49) for the SAQ angina frequency score, 0.38 (95% CI, -0.51 to 1.27) for the SAQ treatment satisfaction score, -0.42 (95% CI, -1.65 to 0.79) for the SAQ physical limitation score, 0.50 (95% CI, -0.22 to 1.22) for the SF-12 physical component score, and 0.13 (95% CI, -0.53 to 0.79) for the SF-12 mental component score. At 12 months, the mean difference was -0.89 (95% CI, -2.20 to 0.43) for the SAQ quality of life score, -1.05 (95% CI, -2.12 to 0.02) for the SAQ angina frequency score, 0.38 (95% CI, -0.54 to 1.29) for the SAQ treatment satisfaction score, -0.14 (95% CI, 1.41 to 1.14) for the SAQ physical limitation score, 0.17 (95% CI, -0.57 to 0.92) for the SF-12 physical component score, and 0.12 (95% CI, -0.56 to 0.80) for the SF-12 mental component score. In contrast, the hazard rate of all-cause mortality (up to 7 years) associated with participating in CR was 0.59 (95% CI, 0.46-0.75). Conclusions and Relevance: In a cohort of 4929 patients with AMI, we found that those who did and did not participate in CR had similar reported health status during the year following AMI; however, participation in CR did confer a significant survival benefit. These findings underscore the need for increased use of validated patient-reported outcome measures to further examine if and how health status can be maximized for patients who participate in CR. PMID- 27760271 TI - Spatial Interpolation Enables Normative Data Comparison in Gaze-Contingent Microperimetry. AB - Purpose: To demonstrate methods that enable visual field sensitivities to be compared with normative data without restriction to a fixed test pattern. Methods: Healthy participants (n = 60, age 19-50) undertook microperimetry (MAIA 2) using 237 spatially dense locations up to 13 degrees eccentricity. Surfaces were fit to the mean, variance, and 5th percentile sensitivities. Goodness-of-fit was assessed by refitting the surfaces 1000 times to the dataset and comparing estimated and measured sensitivities at 50 randomly excluded locations. A leave one-out method was used to compare individual data with the 5th percentile surface. We also considered cases with unknown fovea location by adding error sampled from the distribution of relative fovea-optic disc positions to the test locations and comparing shifted data to the fixed surface. Results: Root mean square (RMS) difference between estimated and measured sensitivities were less than 0.5 dB and less than 1.0 dB for the mean and 5th percentile surfaces, respectively. Root mean square differences were greater for the variance surface, median 1.4 dB, range 0.8 to 2.7 dB. Across all participants 3.9% (interquartile range, 1.8-8.9%) of sensitivities fell beneath the 5th percentile surface, close to the expected 5%. Positional error added to the test grid altered the number of locations falling beneath the 5th percentile surface by less than 1.3% in 95% of participants. Conclusions: Spatial interpolation of normative data enables comparison of sensitivity measurements from varied visual field locations. Conventional indices and probability maps familiar from standard automated perimetry can be produced. These methods may enhance the clinical use of microperimetry, especially in cases of nonfoveal fixation. PMID- 27760273 TI - Decisive Steps Toward Patient-Reported Outcomes for Claudication-Tread Lightly or Full Steam Ahead? PMID- 27760272 TI - Conjunctival Neutrophils Predict Progressive Scarring in Ocular Mucous Membrane Pemphigoid. AB - Purpose: Ocular mucous membrane pemphigoid (OcMMP) is a rare autoimmune disorder resulting in progressive conjunctival fibrosis and ocular surface failure leading to sight loss in up to 50%. This study was designed to optimize an ocular surface sampling technique for identification of novel biomarkers associated with disease activity and/or progressive fibrosis. Methods: Fifty-seven patients with OcMMP underwent detailed examination of conjunctival inflammation and fibrosis using fornix depth measurement. Ocular surface impression cytology (OSIC) to sample superior bulbar conjunctiva combined with flow cytometry (OSIC-flow) profiled infiltrating leukocytes. Profiles were compared with healthy controls (HC) and disease controls (primary Sjogren's syndrome, pSS). Thirty-five OcMMP patients were followed every 3 months for 12 months. Results: Overall neutrophils were elevated in OcMMP eyes when compared to pSS or HC (109 [18%] neutrophils/impression [NPI]; 2 [0.2%]; 6 [0.8%], respectively [P < 0.0001]) and in OcMMP patients with no visible inflammation when compared with HC (44.3 [7.9%]; 5.8 [0.8%]; P < 0.05). At 12 months follow-up, 53% of OcMMP eyes progressed, and this was associated with baseline conjunctival neutrophilia (P = 0.004). As a potential biomarker, a value of 44 NPI had sensitivity, specificity, and positive predictive values of 75%, 70%, and 73%, respectively. Notably, eyes with no visible inflammation and raised conjunctival neutrophils were more likely to progress and have a greater degree of conjunctival shrinkage compared to those without raised neutrophils. Conclusions: These data suggest that OSIC-flow cytometric analyses may facilitate repeated patient sampling. Neutrophils may act as a biomarker for monitoring disease activity, progressive fibrosis, and response to therapy in OcMMP even when the eye appears clinically uninflamed. PMID- 27760275 TI - Incorrect Figure Caption. PMID- 27760274 TI - Effectiveness of a Medical vs Revascularization Intervention for Intermittent Leg Claudication Based on Patient-Reported Outcomes. AB - Importance: Intermittent claudication (IC) is the most common presentation of infrainguinal peripheral artery disease. Both medical and revascularization interventions for IC aim to increase walking comfort and distance, but there is inconclusive evidence of the comparative benefit of revascularization given the possible risk of limb loss. Objective: To compare the effectiveness of a medical (walking program, smoking cessation counseling, and medications) vs revascularization (endovascular or surgical) intervention for IC in the community, focusing on outcomes of greatest importance to patients. Design, Setting, and Participants: Longitudinal (12-month follow-up) prospective observational cohort study conducted between July 3, 2011, and November 5, 2014, at 15 clinics associated with 11 hospitals in Washington State. Participants were 21 years or older with newly diagnosed or established IC. Interventions: Medical or revascularization interventions. Main Outcomes and Measures: Primary end points were 12-month change scores on the distance, speed, and stair-climb domains of the Walking Impairment Questionnaire (score range, 0-100). Secondary outcomes were change scores on the Walking Impairment Questionnaire pain domain (score range, 0-100), Vascular Quality of Life Questionnaire (VascuQol) (score range, 1-7), European Quality of Life-5 Dimension Questionnaire (EQ-5D) (score range, 0-1), and Claudication Symptom Instrument (CSI) (score range, 0-4). Results: A total of 323 adults were enrolled, with 282 (87.3%) in the medical cohort. At baseline, the mean duration of disease was longer for participants in the medical cohort, while those in the revascularization cohort reported more severe disease. Other characteristics were well balanced. At 12 months, change scores in the medical cohort reached significance for the following 3 outcomes: speed (5.9; 95% CI, 0.5-11.3; P = .03), VascuQol (0.28; 95% CI, 0.08-0.49; P = .008), and EQ-5D (0.038; 95% CI, 0.011-0.066; P = .006). In the revascularization cohort, there were significant improvements in the following 7 outcomes: distance (19.5; 95% CI, 7.9-31.0; P = .001), speed (12.1; 95% CI, 1.4-22.8; P = .03), stair climb (11.4; 95% CI, 1.3-21.5; P = .03), pain (20.7; 95% CI, 11.0-30.4; P < .001), VascuQol (1.10; 95% CI, 0.80-1.41; P < .001), EQ-5D (0.113; 95% CI, 0.067 0.159; P < .001), and CSI (-0.63; 95% CI, -0.96 to -0.31; P < .001). Relative improvements (percentage changes) at 12 months in the revascularization cohort over the medical cohort were observed as follows: distance (39.1%), speed (15.6%), stair climb (9.7%), pain (116.9%), VascuQol (41%), EQ-5D (18%), and CSI (13.5%). Conclusions and Relevance: Among patients with IC, those in the revascularization cohort had significantly improved function (Walking Impairment Questionnaire), better health-related quality of life (VascuQol and EQ-5D), and fewer symptoms (CSI) at 12 months compared with those in the medical cohort, providing important information to inform treatment strategies in the community. PMID- 27760278 TI - Hazard Characteristics and Patterns of Environmental Injustice: Household-Level Determinants of Environmental Risk in Miami, Florida. AB - Limited systematic comparative knowledge exists about patterns of environmental injustices in exposure to varied natural and technological hazards. To address this gap, we examine how hazard characteristics (i.e., punctuated event/suddenness of onset, frequency/magnitude, and divisibility) influence relationships between race/ethnicity, nativity, socioeconomic status (SES), older age, housing tenure, and residential hazard exposure. Sociodemographic data come from a random sample survey of 602 residents of the tricounty Miami Metropolitan Statistical Area (Florida). Hazard exposure was measured using spatial data from the Federal Emergency Management Agency, the National Air Toxics Assessment, and the Emergency Response Notification System. We specified generalized estimating equations (GEEs)-which account for sociospatial clustering-predicting 100-year flood risk, acute chemical accidental releases, and chronic cancer risk from air toxics from all and on-road mobile sources. We found that for punctuated, sudden onset events, some socially advantaged people were significantly at risk. Racial/ethnic minority variables were significant predictors of greater exposure to the three technological hazards, while higher SES was associated with 100-year flood risk exposure. Black and foreign-born Hispanic residents, and white and U.S.-born Hispanic residents, shared nearly identical risk profiles. Results demonstrate the complexities found in human-hazard associations and the roles of hazard characteristics in shaping disparate risk patterns. PMID- 27760279 TI - Tetrahydrobiopterin redox cycling in nitric oxide synthase: evidence supports a through-heme electron delivery. AB - The nitric oxide synthases (NOS) catalyze a two-step oxidation of l-arginine (Arg) to generate NO. In the first step, O2 activation involves one electron being provided to the heme by an enzyme-bound 6R-tetrahydro-l-biopterin cofactor (H4 B), and the H4 B radical must be reduced back to H4 B in order for NOS to continue catalysis. Although an NADPH-derived electron is used to reduce the H4 B radical, how this occurs is unknown. We hypothesized that the NOS flavoprotein domain might reduce the H4 B radical by utilizing the NOS heme porphyrin as a conduit to deliver the electron. This model predicts that factors influencing NOS heme reduction should also influence the extent and rate of H4 B radical reduction in kind. To test this, we utilized single catalytic turnover and stop freeze methods, along with electron paramagnetic resonance spectroscopy, to measure the rate and extent of reduction of the 5-methyl-H4 B radical formed in neuronal NOS (nNOS) during Arg hydroxylation. We used several nNOS variants that supported either a slower or faster than normal rate of ferric heme reduction. We found that the rates and extents of nNOS heme reduction correlated well with the rates and extents of 5-methyl-H4 B radical reduction among the various nNOS enzymes. This supports a model where the heme porphyrin transfers an electron from the NOS flavoprotein to the H4 B radical formed during catalysis, revealing that the heme plays a dual role in catalyzing O2 activation or electron transfer at distinct points in the reaction cycle. PMID- 27760280 TI - Venous thromboembolism prophylaxis during neoadjuvant therapy for resectable and borderline resectable pancreatic cancer-Is it indicated? AB - PURPOSE: To describe venous thromboembolism (VTE) rates in patients with pancreatic cancer (PC) during neoadjuvant therapy. METHODS: Factors associated with VTE were evaluated using multivariable logistic regression modeling in patients with resectable and BLR PC treated with neoadjuvant therapy between 2009 and 2014. RESULTS: Prevalent VTEs were detected in 13 (5%) of the 260 patients. Incident VTEs were detected in 26 patients (10%); 9 (8%) of the 109 resectable and 17 (11%) of the 151 BLR patients (P = 0.53). Of the 26 incident events, 9 (35%) were PEs, 9 (35%) were extremity DVTs, and 8 (31%) involved the SMV/PV. VTEs were catheter-related in 7 (27%) of the 26 patients. Rh(D) antigen positivity was associated with a decreased risk of incident VTE (OR:0.32, 95%CI:0.11-0.85, P = 0.02). Completion of neoadjuvant therapy to include surgery occurred in 176 (75%) of the 234 patients without incident VTE as compared to 14 (54%) of the 26 patients with incident VTE (P = 0.02). The median survival for all 260 patients was 24.3 months: 17.0 months versus 24.6 months for patients who did and did not develop incident VTE during neoadjuvant therapy (P = 0.11). CONCLUSIONS: Patients with localized PC who receive neoadjuvant therapy are at significant risk of VTE and thromboprophylaxis may be warranted. J. Surg. Oncol. 2016;114:581-586. (c) 2016 Wiley Periodicals, Inc. PMID- 27760281 TI - Physiologically relevant binding affinity quantification of monoclonal antibody PF-00547659 to mucosal addressin cell adhesion molecule for in vitro in vivo correlation. AB - BACKGROUND AND PURPOSE: A monoclonal antibody (PF-00547659) against mucosal addressin cell adhesion molecule (MAdCAM), expressed as both soluble (sMAdCAM) and trans-membrane (mMAdCAM) target forms, showed over 30-fold difference in antibody-target KD between in vitro (Biacore) and clinically derived (KD,in-vivo ) values. Back-scattering interferometry (BSI) was applied to acquire physiologically relevant KD values which were used to establish in vitro and in vivo correlation (IVIVC). EXPERIMENTAL APPROACH: BSI was applied to obtain KD values between PF-00547659 and recombinant human MAdCAM in buffer or CHO cells and endogenous MAdCAM in human serum or colon tissue. CHO cells and tissue were minimally processed to yield homogenate containing membrane vesicles and soluble proteins. A series of binding affinities in serum with various dilution factors was used to estimate both KD,in-vivo and target concentrations; MAdCAM concentrations were also measured using LC-MS/MS. KEY RESULTS: BSI measurements revealed low KD values (higher affinity) for sMAdCAM in buffer and serum, yet a 20-fold higher KD value (lower affinity) for mMAdCAM in CHO, mMAdCAM and sMAdCAM in tissue. BSI predicted KD,in-vivo in serum was similar to clinically derived KD,in-vivo , and the BSI-estimated serum sMAdCAM concentration also matched the measured concentration by LC-MS/MS. CONCLUSIONS AND IMPLICATIONS: Our results successfully demonstrated that BSI measurements of physiologically relevant KD values can be used to establish IVIVC, for PF-00547659 to MAdCAM despite the lack of correlation when using Biacore measured KD and accurately estimates endogenous target concentrations. The application of BSI would greatly enhance successful basic pharmacological research and drug development. PMID- 27760282 TI - Heated insufflation with or without humidification for laparoscopic abdominal surgery. AB - BACKGROUND: Intraoperative hypothermia during both open and laparoscopic abdominal surgery may be associated with adverse events. For laparoscopic abdominal surgery, the use of heated insufflation systems for establishing pneumoperitoneum has been described to prevent hypothermia. Humidification of the insufflated gas is also possible. Past studies on heated insufflation have shown inconclusive results with regards to maintenance of core temperature and reduction of postoperative pain and recovery times. OBJECTIVES: To determine the effect of heated gas insufflation compared to cold gas insufflation on maintaining intraoperative normothermia as well as patient outcomes following laparoscopic abdominal surgery. SEARCH METHODS: We searched Cochrane Colorectal Cancer Specialised Register (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 8), Ovid MEDLINE (1950 to September 2016), Ovid Embase (1974 to September 2016), International Pharmaceutical Abstracts (IPA) (September 2016), Web of Science (1985 to September 2016), Scopus, www.clinicaltrials.gov and the National Research Register (1956 to September 2016). We also searched grey literature and cross references. Searches were limited to human studies without language restriction. SELECTION CRITERIA: Only randomised controlled trials comparing heated (with or without humidification) with cold gas insufflation in adult and paediatric populations undergoing laparoscopic abdominal procedures were included. We assessed study quality in regards to relevance, design, sequence generation, allocation concealment, blinding, possibility of incomplete data and selective reporting. Two review authors independently selected studies for the review, with any disagreement resolved in consensus with a third co-author. DATA COLLECTION AND ANALYSIS: Two review authors independently performed screening of eligible studies, data extraction and methodological quality assessment of the trials. We classified a study as low-risk of bias if all of the first six main criteria indicated in the 'Risk of Bias Assessment' table were assessed as low risk. We used data sheets to collect data from eligible studies. We presented results using mean differences for continuous outcomes and relative risks for dichotomous outcomes, with 95% confidence intervals. We used Review Manager (RevMan) 5.3 software to calculate the estimated effects. We took publication bias into consideration and compiled funnel plots. MAIN RESULTS: We included 22 studies in this updated analysis, including six new trials with 584 additional participants, resulting in a total of 1428 participants. The risk of bias was low in 11 studies, high in one study and unclear in the remaining studies, due primarily to failure to report methodology for randomisation, and allocation concealment or blinding, or both. Fourteen studies examined intraoperative core temperatures among heated and humidified insufflation cohorts and core temperatures were higher compared to cold gas insufflation (MD 0.31 degrees C, 95% CI, 0.09 to 0.53, I2 = 88%, P = 0.005) (low-quality evidence). If the analysis was limited to the eight studies at low risk of bias, this result became non-significant but remained heterogeneous (MD 0.18 degrees C, 95% CI, -0.04 to 0.39, I2= 81%, P = 0.10) (moderate-quality evidence).In comparison to the cold CO2 group, the meta analysis of the heated, non-humidified group also showed no statistically significant difference between groups. Core temperature was statistically, significantly higher in the heated, humidified CO2 with external warming groups (MD 0.29 degrees C, 95% CI, 0.05 to 0.52, I2 = 84%, P = 0.02) (moderate-quality evidence). Despite the small difference in temperature of 0.31 degrees C with heated CO2, this is unlikely to be of clinical significance.For postoperative pain scores, there were no statistically significant differences between heated and cold CO2, either overall, or for any of the subgroups assessed. Interestingly, morphine-equivalent use was homogeneous and higher in heated, non humidified insufflation compared to cold insufflation for postoperative day one (MD 11.93 mg, 95% CI 0.92 to 22.94, I2 = 0%, P = 0.03) (low-quality evidence) and day two (MD 9.79 mg, 95% CI 1.58 to 18.00, I2 = 0%, P = 0.02) (low-quality evidence). However, morphine use was not significantly different six hours postoperatively or in any humidified insufflation groups.There was no apparent effect on length of hospitalisation, lens fogging or length of operation with heated compared to cold gas insufflation, with or without humidification. Recovery room time was shorter in the heated cohort (MD -26.79 minutes, 95% CI 51.34 to -2.25, I2 = 95%, P = 0.03) (low-quality evidence). When the one and only unclear-risk study was removed from the analysis, the difference in recovery-room time became non-significant and the studies were statistically homogeneous (MD 1.22 minutes, 95% CI, -6.62 to 4.17, I2 = 12%, P = 0.66) (moderate-quality evidence).There were also no differences in the frequency of major adverse events that occurred in the cold or heated cohorts.These results should be interpreted with caution due to some limitations. Heterogeneity of core temperature remained significant despite subgroup analysis, likely due to variations in the study design of the individual trials, as the trials had variations in insufflation gas temperatures (35 oC to 37 oC), humidity ranges (88% to 100%), gas volumes and location of the temperature probes. Additionally, some of the trials lacked specific study design information making evaluation difficult. AUTHORS' CONCLUSIONS: While heated, humidified gas leads to mildly smaller decreases in core body temperatures, clinically this does not account for improved patient outcomes, therefore, there is no clear evidence for the use of heated gas insufflation, with or without humidification, compared to cold gas insufflation in laparoscopic abdominal surgery. PMID- 27760283 TI - Hormonal Receptor, Human Epidermal Growth Factor and Its Association with Breast Cancer Tumor Characteristics in Albania. AB - AIM: This retrospective study was designed to analyze expression patterns of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu in Albanian patients with breast carcinoma to identify their relationships with tumor size, histological grade (HG), lymph node metastasis and relapse. METHODS: Patients with either biopsy or metastatic relapse were identified. Demographics, tumor characteristics, ER, PR, and HER2/neu status were retrospectively obtained from the medical records of patients treated with breast cancer during 2006-2011. Hormonal receptors and HER2/neu were assessed by immunohistochemistry. Association of ER, PR and HER2/neu with clinicopathological and molecular characteristics were studied using Fisher's test. P value <=0.05 was considered significant. RESULTS: There were 110 patients included in the study. Mean patient age was 51.08+/-10.75 years. The overall immunoexpression of ER, PR and HER2/neu were found positive in 76 (69%), 73 (67%), and 16 (41%) patients, respectively. ER- was associated with higher histological grade (24% vs. 9.2%) and PR+ with tumor size (T2, 78.3 vs. 64.3) (p=0.02 and 0.05, respectively). ER and PR expression were significantly decreased in HER2/neu positive cases while HER2/neu levels correlated with tumor size (p=0.03) and nodal metastasis (p=0.03). No association was detected between ER, PR, HER2/neu and relapse. CONCLUSION: A combination of ER, PR and HER2/neu and prognostic factors could be of clinical value by defining subgroups in Albanian breast cancer patients that might benefit from more aggressive treatment. PMID- 27760284 TI - Cervical Viral Infections among Asymptomatic Bulgarian Women. AB - AIM: Although sexually transmitted viral infections are significant and increasing public health concern, little is known about their prevalence among Bulgarian women. The aim of this study was to investigate cervical viral infections in asymptomatic women. METHODS: The study group included 52 randomly selected asymptomatic female volunteers from Bulgarian border town Kardzhali. Cervical specimens were tested by real-time PCR for human papillomaviruses (HPV), herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV). RESULTS: The investigation demonstrated a high rate (61.5%) of infection with one or more viruses of uterine cervix of participating women considered at low risk. The most prevalent was HPV, found in 32.7% of all women. The genotyping of high-risk (HR) HPV positive specimens showed that HPV16 was the most prevalent HR type. HSV prevalence (30.8%) was almost as high as that of HPV and most women were HSV1 infected. 9.6% and 5.8% of all specimens were positive for EBV and CMV, respectively. CONCLUSIONS: Our results indicate that women from Kardzhali region, involved in this study, might be at risk for development of genital tract pathology, including cervical cancer, and for transmission of virus infection sexually and perinatally. PMID- 27760285 TI - Estimating the Baseline Incidence of a Seasonal Disease Independently of Epidemic Outbreaks. AB - In epidemiology, it is very important to estimate the baseline incidence of infectious diseases, but the available data are often subject to outliers due to epidemic outbreaks. Consequently, the estimate of the baseline incidence is biased and so is the predicted epidemic threshold which is a crucial reference indicator used to suspect and detect an epidemic outbreak. Another problem is that the "usual" incidence varies in a season dependent manner, i.e. it may not be constant throughout the year, is often periodic, and may also show a trend between years. To take account of these factors, more complicated models adjusted for outliers are used. If not adjusted for outliers, the baseline incidence estimate is biased. As a result, the epidemic threshold can be overestimated and thus can make the detection of an epidemic outbreak more difficult. Classical Serfling's model is based on the sine function with a phase shift and amplitude. Multiple approaches are applied to model the long-term and seasonal trends. Nevertheless, none of them controls for the effect of epidemic outbreaks. The present article deals with the adjustment of the data biased by epidemic outbreaks. Some models adjusted for outliers, i.e. for the effect of epidemic outbreaks, are presented. A possible option is to remove the epidemic weeks from the analysis, but consequently, in some calendar weeks, data will only be available for a small number of years. Furthermore, the detection of an epidemic outbreak by experts (epidemiologists and microbiologists) will be compared with that in various models. PMID- 27760286 TI - Kinetics-Driven Crystal Facets Evolution at the Tip of Nanowires: A New Implementation of the Ostwald-Lussac Law. AB - Nanocrystal facets evolution is critical for designing nanomaterial morphology and controlling their properties. In this work, we report a unique high-energy crystal facets evolution phenomenon at the tips of wurtzite zinc oxide nanowires (NWs). As the zinc vapor supersaturation decreased at the NW deposition region, the NW tip facets evolved from the (0001) surface to the {1013} surface and subsequently to the {1122} surface and eventually back to the flat (0001) surface. A series of NW tip morphology was observed in accordance to the different combinations of exposed facets. Exposure of the high-energy facets was attributed to the fluctuation of the energy barriers for the formation of different crystal facets during the layer-by-layer growth of the NW tip. The energy barrier differences between these crystal facets were quantified from the surface area ratios as a function of supersaturation. On the basis of the experimental observation and kinetics analysis, we argue that at appropriate deposition conditions exposure of the crystal facets at NW growth front is not merely determined by the surface energy. Instead, the NW may choose to expose the facets with minimal formation energy barrier, which can be determined by the Ehrlich-Schwoebel barrier variation. This empirical law for the NW tip facet formation was in analogy to the Ostwald-Lussac law of phase transformation, which brings a new insight toward nanostructure design and controlled synthesis. PMID- 27760287 TI - Polyethyleneimine High-Energy Hydrophilic Surface Interfacial Treatment toward Efficient and Stable Perovskite Solar Cells. AB - The interfacial contact is critical for the performance of perovskite solar cells (PSCs), leading to dense perovskite thin films and efficient charge transport. In this contribution, an effective interfacial treatment solution using polyethyleneimine (PEI) was developed to improve the performance and stability of PSCs. Inserting PEI between the s-VOx and perovskite layers can produce a high energy hydrophilic surface to facilitate the formation of a high-quality perovskite layer by the solution method. Accordingly, the surface coverage of perovskite film on the s-VOx layer increased from 80% to 95%, and the PCE of the device improved from 12.06% (with an average of 10.16%) to 14.4% (with an average value of 12.8%) under an irradiance of 100 mW cm-2 AM 1.5G sunlight. More importantly, the stability of PSCs was further improved after adding another PEI layer between the electron transport layer and LiF/Al layer, less than 10% decay in efficiency during a 10-days observation. Since all layers of the PSCs were fabricated at low temperature (<150 degrees C), these PEI-treated PSCs based on the amorphous VOx layer have the potential to contribute significantly toward the development of efficient and stable solar cells on flexible substrates. PMID- 27760289 TI - Prediction of pKa Using DFT: the Nicotianamine Polyacid Example. AB - The determination of pKa values for molecules containing multiple acidic groups in solution is challenging both experimentally and theoretically. We propose a general method to obtain these values by combining a graphical analysis based on a predominance diagram, for amino acids and nicotianamine polyacid, with first principle DFT calculations. Implicit and semiexplicit water solvent models were included to account for solvation. This strategy enables the investigation of the protonation states of compounds containing acidic moieties in solution depending on the pH domain. The method was first validated on a set of amino acids with pKa values calculated with an accuracy within 0.5-1.0 pKa unit and then on the chalenging nicotianamine polyacid with six pKa values. This approach is particularly well suited for such a complex system including both zwitterionic structures and unknown experimental pKa values. PMID- 27760290 TI - Multiple Staggered Mesh Ewald: Boosting the Accuracy of the Smooth Particle Mesh Ewald Method. AB - The smooth particle mesh Ewald (SPME) method is the standard method for computing the electrostatic interactions in the molecular simulations. In this work, we develop the multiple staggered mesh Ewald (MSME) method, which averages the SPME forces computed on, for example, M, staggered meshes. We prove, from a theoretical perspective, that the MSME is as accurate as the SPME, but uses M2 times less mesh points in a certain parameter range. In the complementary parameter range, the MSME is as accurate as the SPME with twice the interpolation order. The theoretical conclusions are numerically validated both by a uniform and uncorrelated charge system, and by a three-point-charge water system that is widely used as solvent for the biomacromolecules. PMID- 27760291 TI - (n,m)-Specific Absorption Cross Sections of Single-Walled Carbon Nanotubes Measured by Variance Spectroscopy. AB - A new method based on variance spectroscopy has enabled the determination of absolute absorption cross sections for the first electronic transition of 12 (n,m) structural species of semiconducting single-walled carbon nanotubes (SWCNTs). Spectrally resolved measurements of fluorescence variance in dilute bulk samples provided particle number concentrations of specific SWCNT species. These values were converted to carbon concentrations and correlated with resonant components in the absorbance spectrum to deduce (n,m)-specific absorption cross sections (absorptivities) for nanotubes ranging in diameter from 0.69 to 1.03 nm. The measured cross sections per atom tend to vary inversely with nanotube diameter and are slightly greater for structures of mod 1 type than for mod 2. Directly measured and extrapolated values are now available to support quantitative analysis of SWCNT samples through absorption spectroscopy. PMID- 27760292 TI - Bioimaging of Intravenous Polymeric Micelles Based on Discrimination of Integral Particles Using an Environment-Responsive Probe. AB - One of the biggest challenges in bioimaging of nanoparticles is how to identify integral particles from bulk signals of probes. Signals of free probes are always mistakenly counted into total signals of particles. In this study, in vivo fate of intravenous polymeric micelles (PMs, mPEG2.5k-PDLLA2.5k) was explored using a highly sensitive near-infrared environment-responsive fluorescent probe. This probe is able to emit fluorescence when embedded in nanocarriers but quench spontaneously and absolutely upon release into water, based on the aggregation caused quenching effect, which means that the interference generated by free probes can be completely diminished. Analysis of blood-borne fluorescence reveals rapid clearance of PMs from blood following a tricompartmental pharmacokinetic model. Live imaging shows pervasive distribution of PMs throughout the body, and a tendency of accumulation to extremities with fluorescence density 3-5 times higher than the trunk. Ex vivo examination reveals that most PMs are found in vital organs following an order of lung > liver > spleen > heart > kidney in concentration, but an order of liver > lung > spleen > heart ~ kidney in total amount. The distribution to other organs and tissues is even lower, and to brain, negligible. It is concluded that the biodistribution of PMs to vital organs and extremities warns of potential toxicity and can be translated to explain the toxicity of its commercial counterpart with similar chain lengths. PMID- 27760293 TI - Noncovalent Interactions between Superoxide Dismutase and Flavonoids Studied by Native Mass Spectrometry Combined with Molecular Simulations. AB - Misfolding and aggregation of Cu, Zn superoxide dismutase (SOD1) is implicated in the etiology of amyotrophic lateral sclerosis (ALS). The use of small molecules may stabilize the spatial structure of SOD1 dimer, thus, preventing its dissociation and aggregation. In this study, "native" mass spectrometry (MS) was used to study the noncovalent interactions between SOD1 and flavonoid compounds. MS experiments were performed on a quadruple time-of-flight (Q-ToF) mass spectrometer with an electrospray ionization (ESI) source and T-wave ion mobility. ESI-MS was used to detect the SOD1-flavonoid complexes and compare their relative binding strengths. The complement of ion mobility separation allowed comparison in the binding affinities between flavonoid isomers and provided information on the conformational changes. Molecular docking together with molecular dynamics simulations and MM/PBSA methods were applied to gain insights into the binding modes and free energies of SOD1-flavonoid complexes at the molecule level. Among all the flavonoids investigated, flavonoid glycosides preferentially bind to SOD1 than their aglycone counterparts. Naringin, one of the compounds that has the strongest binding affinity to SOD1, was subjected to further characterization. Experiment results show that the binding of naringin can stabilize SOD1 dimer and inhibit the aggregation of SOD1. Molecular simulation results suggest that naringin could reduce the dissociation of SOD1 dimers through direct interaction with the dimer interface. This developed analytical strategy could also be applied to study the interactions between SOD1 and other drug-like molecules, which may have the effect to reduce the aggregation. PMID- 27760294 TI - Investigation of the Differential Capacitance of Highly Ordered Pyrolytic Graphite as a Model Material of Graphene. AB - A study of the differences among the capacitances of freshly exfoliated highly ordered pyrolytic graphite (HOPG, sample denoted FEG), HOPG aged in air (denoted AAG), and HOPG aged in an inert atmosphere (hereafter IAG) is presented in this work. The FEG is found to be more hydrophilic than AAG and IAG because the aqueous electrolyte contact angle (CA) increases from 61.7 degrees to 72.5 degrees and 81.8 degrees after aging in Ar and air, respectively. Electrochemical impedance spectroscopy shows the FEG has an intrinsic capacitance (6.0 MUF cm-2 at the potential of minimum capacitance) higher than those of AAG (4.3 MUF cm-2) and IAG (4.7 MUF cm-2). The observed changes in the electrochemical response are correlated with spectroscopic characterization (Raman spectroscopy and X-ray photoelectron spectroscopy), which show that the surface of HOPG was doped or contaminated after exposure to air. Taken together, these changes upon atmospheric exposure are attributed to oxygen molecule, moisture, and airborne organic contaminations: high-vacuum annealing was applied for the removal of the adsorbed contaminants. It was found that annealing the aged sample at 500 degrees C leads to partial removal of the contaminants, as gauged by the recovery of the measured capacitance. To the best of our knowledge, this is first study of the effect of the airborne contaminants on the capacitance of carbon-based materials. PMID- 27760288 TI - Translesion Synthesis of 2'-Deoxyguanosine Lesions by Eukaryotic DNA Polymerases. AB - With the discovery of translesion synthesis DNA polymerases, great strides have been made in the last two decades in understanding the mode of replication of various DNA lesions in prokaryotes and eukaryotes. A database search indicated that approximately 2000 articles on this topic have been published in this period. This includes research involving genetic and structural studies as well as in vitro experiments using purified DNA polymerases and accessory proteins. It is a daunting task to comprehend this exciting and rapidly emerging area of research. Even so, as the majority of DNA damage occurs at 2'-deoxyguanosine residues, this perspective attempts to summarize a subset of this field, focusing on the most relevant eukaryotic DNA polymerases responsible for their bypass. PMID- 27760295 TI - Selective Morphology Control of Bulk Heterojunction in Polymer Solar Cells Using Binary Processing Additives. AB - We report the effect of binary additives on the fabrication of polymer solar cells (PSCs) based on a bulk heterojunction (BHJ) system. The combination of 1,8 diiodooctane (DIO), a high-boiling and selective solvent, for fullerene derivatives and poly(dimethylsiloxane) (PDMS) precursor, a nonvolatile insulating additive, affords complementary functions on the effective modulation of BHJ morphology. It was found that DIO and PDMS precursor each play different roles in the control of BHJ morphology, and thus, the power conversion efficiency (PCE) can be further enhanced to 7.6% by improving the fill factor (FF) from 6.8% compared to that achieved using a conventional device employing only a DIO additive. In the BHJ of the active layer, DIO suppressed the large phase separation of PBDTTT-CF and PC71BM while allowing the formation of continuous polymer networks in the donor polymer through phase separation of the PDMS precursor and BHJ components. The appropriate amount of PDMS precursor does not disturb charge transport in the BHJ despite having insulating properties. In addition, the dependence of photovoltaic parameters on different light intensities reveals that the charge recombination in the device with DIO and PDMS precursor decreases compared to that achieved using the device with only DIO. PMID- 27760296 TI - Organic Field-Effect Transistors with a Bilayer Gate Dielectric Comprising an Oxide Nanolaminate Grown by Atomic Layer Deposition. AB - We report on top-gate OFETs with a bilayer gate dielectric comprising an Al2O3 /HfO2 nanolaminate layer grown by atomic layer deposition and an amorphous fluoro polymer layer (CYTOP). Top-gate OFETs display average carrier mobility values of 0.9 +/- 0.2 cm2/(V s) and threshold voltage values of -1.9 +/- 0.5 V and high operational and environmental stability under different environmental conditions such as damp air at 50 degrees C (80% relative humidity) and prolonged immersion in water at a temperature up to 95 degrees C. PMID- 27760297 TI - Constructing an Interpolated Potential Energy Surface of a Large Molecule: A Case Study with Bacteriochlorophyll a Model in the Fenna-Matthews-Olson Complex. AB - Constructing a reliable potential energy surface (PES) is a key step toward computationally studying the chemical dynamics of any molecular system. The interpolation scheme is a useful tool that can closely follow the accuracy of quantum chemical means at a dramatically reduced computational cost. However, applying interpolation to building a PES of a large molecule is not a straightforward black-box approach, as it frequently encounters practical difficulties associated with its large dimensionality. Here, we present detailed courses of applying interpolation toward building a PES of a large chromophore molecule. We take the example of S0 and S1 electronic states of bacteriochlorophyll a (BChla) molecules in the Fenna-Matthews-Olson light harvesting complex. With a reduced model molecule that bears BChla's main pi conjugated ring, various practical approaches are designed for improving the PES quality in a stable manner and for fine-tuning the final surface such that the surface can be adopted for long time molecular dynamics simulations. Combined with parallel implementation, we show that interpolated mechanics/molecular mechanics (IM/MM) simulations of the entire complex in the nanosecond time scale can be conducted readily without any practical issues. With 1500 interpolation data points for each chromophore unit, the PES error relative to the reference quantum chemical calculation is found to be ~0.15 eV in the thermally accessible region of the conformational space, together with ~0.01 eV error in S0 - S1 transition energies. The performance issue related to the use of a large interpolation database within the framework of our parallel routines is also discussed. PMID- 27760298 TI - Catalyst Composition Tuning: The Key for the Growth of Straight Axial Nanowire Heterostructures with Group III Interchange. AB - Au-catalyzed III-V nanowire heterostructures based on the group III interchange usually grow straight only in one of the two growth sequences, whereas the other sequence produces kinked geometries; thus, the realization of double heterostructures remains challenging. Here, we investigate the growth of Au assisted InAs-GaAs and GaAs-InAs axial nanowire heterostructures. A detailed study of the heterostructure morphology as a function of growth parameters and chemical composition of the catalyst nanoparticle is performed by means of scanning electron microscopy, transmission electron microscopy, and energy dispersive X-ray analysis. Our results clearly demonstrate that the nanoparticle composition, rather than other growth parameters, as postulated so far, controls the growth mode and the resulting nanowire morphology. Although GaAs easily grows straight on InAs, straight growth of InAs on GaAs is achieved only if the nanoparticle composition is properly tuned. We find that straight InAs segments on GaAs require high group III-to-Au ratios in the nanoparticle (greater than 0.8); otherwise, the droplet wets the sidewalls and the nanowire kinks. We discuss the observed behavior within a theoretical model that relates the nanoparticle stability to the group III-to-Au ratio. Based on this finding, we demonstrate the growth of straight nanowire heterostructures for both sequences. The proposed strategy can be extended to other III-V nanowire heterostructures based on the group III interchange, allowing for straight morphology regardless of the growth sequence, and ultimately for designing nanowire heterostructures with the required properties for different applications. PMID- 27760299 TI - Calibration-free concentration analysis for an analyte prone to self-association. AB - Calibration-free concentration analysis (CFCA) based on surface plasmon resonance uses the diffusion coefficient of an analyte to determine the concentration of that analyte in a bulk solution. In general, CFCA is avoided when investigating analytes prone to self-association, as the heterogeneous diffusion coefficient results in a loss of precision. The derivation for self-association of the analyte was presented here. By using the diffusion coefficient for the monomeric state, CFCA provides the lowest possible concentration even though the analyte is self-associated. PMID- 27760300 TI - Loss of CpSRP54 function leads to a truncated light-harvesting antenna size in Chlamydomonas reinhardtii. AB - The Chlamydomonas reinhardtii truncated light-harvesting antenna 4 (tla4) DNA transposon mutant has a pale green phenotype, a lower chlorophyll (Chl) per cell and a higher Chl a/b ratio in comparison with the wild type. It required a higher light intensity for the saturation of photosynthesis and displayed a greater per chlorophyll light-saturated rate of oxygen evolution than the wild type. The Chl antenna size of the photosystems in the tla4 mutant was only about 65% of that measured in the wild type. Molecular genetic analysis revealed that a single plasmid DNA insertion disrupted two genes on chromosome 11 of the mutant. A complementation study identified the "chloroplast signal recognition particle 54" gene (CpSRP54), as the lesion causing the tla4 phenotype. Disruption of this gene resulted in partial failure to assemble and, therefore, lower levels of light harvesting Chl-binding proteins in the C. reinhardtii thylakoids. A comparative in silico 3-D structure-modeling analysis revealed that the M-domain of the CpSRP54 of C. reinhardtii possesses a more extended finger loop structure, due to different amino acid composition, as compared to that of the Arabidopsis CpSRP54. The work demonstrated that CpSRP54 deletion in microalgae can serve to generate tla mutants with a markedly smaller photosystem Chl antenna size, improved solar energy conversion efficiency, and photosynthetic productivity in high-density cultures under bright sunlight conditions. PMID- 27760301 TI - Estrogen-dependent seasonal adaptations in the immune response of fish. AB - Clinical and experimental evidence shows that estrogens affect immunity in mammals. Less is known about this interaction in the evolutionary older, non mammalian, vertebrates. Fish form an excellent model to identify evolutionary conserved neuroendocrine-immune interactions: i) they are the earliest vertebrates with fully developed innate and adaptive immunity, ii) immune and endocrine parameters vary with season, and iii) physiology is constantly disrupted by increasing contamination of the aquatic environment. Neuro-immuno endocrine interactions enable adaption to changing internal and external environment and are based on shared signaling molecules and receptors. The presence of specific estrogen receptors on/in fish leukocytes, implies direct estrogen-mediated immunoregulation. Fish leukocytes most probably are also capable to produce estrogens as they express the cyp19a and cyp19b - genes, encoding aromatase cytochrome P450, the enzyme critical for conversion of C19 steroids to estrogens. Immunoregulatory actions of estrogens, vary among animal species, and also with dose, target cell type, or physiological condition (e.g., infected/non-infected, reproductive status). They moreover are multifaceted. Interestingly, season-dependent changes in immune status correlate with changes in the levels of circulating sex hormones. Whereas E2 circulating in the bloodstream is perhaps the most likely candidate to be the physiological mediator of systemic immune-reproductive trade-offs, leukocyte-derived hormones are hypothesized to be mainly involved in local tuning of the immune response. Contamination of the aquatic environment with estrogenic EDCs may violate the delicate and precise allostatic interactions between the endogenous estrogen system and the immune system. This has negative effects on fish health, but will also affect the physiology of its consumers. PMID- 27760303 TI - Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury. AB - Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated. In a second model, rats (n=18) received a 30min infusion of lipopolysaccharide (LPS; 2.5mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000U/kg) was administered intravenously (15min before reperfusion, or 90min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial. PMID- 27760302 TI - The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation. AB - Over the past decade, it has become increasingly evident that there are extensive bidirectional interactions between the body and its microbiota. These interactions are evident during stressful periods, where it is recognized that commensal microbiota community structure is significantly changed. Many different stressors, ranging from early life stressors to stressors administered during adulthood, lead to significant, community-wide differences in the microbiota. The mechanisms through which this occurs are not yet known, but it is known that commensal microbes can recognize, and respond to, mammalian hormones and neurotransmitters, including those that are involved with the physiological response to stressful stimuli. In addition, the physiological stress response also changes many aspects of gastrointestinal physiology that can impact microbial community composition. Thus, there are many routes through which microbial community composition might be disrupted during stressful periods. The implications of these disruptions in commensal microbial communities for host health are still not well understood, but the commensal microbiota have been linked to stressor-induced immunopotentiation. The role of the microbiota in stressor-induced immunopotentiation can be adaptive, such as when these microbes stimulate innate defenses against bacterial infection. However, the commensal microbiota can also lead to maladaptive immune responses during stressor exposure. This is evident in animal models of colonic inflammation where stressor exposure increases the inflammation through mechanisms involving the microbiota. It is likely that during stressor exposure, immune cell functioning is regulated by combined effects of both neurotransmitters/hormones and commensal microbes. Defining this regulation should be a focus of future studies. PMID- 27760306 TI - Quality in laboratory medicine: 50years on. AB - The last 50years have seen substantial changes in the landscape of laboratory medicine: its role in modern medicine is in evolution and the quality of laboratory services is changing. The need to control and improve quality in clinical laboratories has grown hand in hand with the growth in technological developments leading to an impressive reduction of analytical errors over time. An essential cause of this impressive improvement has been the introduction and monitoring of quality indicators (QIs) such as the analytical performance specifications (in particular bias and imprecision) based on well-established goals. The evolving landscape of quality and errors in clinical laboratories moved first from analytical errors to all errors performed within the laboratory walls, subsequently to errors in laboratory medicine (including errors in test requesting and result interpretation), and finally, to a focus on errors more frequently associated with adverse events (laboratory-associated errors). After decades in which clinical laboratories have focused on monitoring and improving internal indicators of analytical quality, efficiency and productivity, it is time to shift toward indicators of total quality, clinical effectiveness and patient outcomes. PMID- 27760305 TI - Differences in the Phosphorylation-Dependent Regulation of Prenylation of Rap1A and Rap1B. AB - Two isoforms of the small GTPase Rap1, Rap1A and Rap1B, participate in cell adhesion; Rap1A promotes steady state adhesion, while Rap1B regulates dynamic changes in cell adhesion. These events depend on the prenylation of Rap1, which promotes its membrane localization. Here, we identify previously unsuspected differences in the regulation of prenylation of Rap1A versus Rap1B, due in part to their different phosphorylation-dependent interactions with the chaperone protein SmgGDS-607. Previous studies indicate that the activation of Galphas protein-coupled receptors (GPCRs) phosphorylates S-179 and S-180 in the polybasic region (PBR) of Rap1B, which inhibits Rap1B binding to SmgGDS-607 and diminishes Rap1B prenylation and membrane localization. In this study, we investigate how phosphorylation in the PBR of multiple small GTPases, including K-Ras4B, RhoA, Rap1A, and Rap1B, affects their binding to SmgGDS, with emphasis on differences between Rap1A and Rap1B. We identify the amino acids in SmgGDS-607 necessary for binding of Rap1A and Rap1B, and present homology models examining the binding between Rap1A or Rap1B and SmgGDS-607. Unlike Rap1B, phosphorylation in the PBR of Rap1A does not detectably inhibit its prenylation or its binding to SmgGDS 607. Activation of GPCRs suppresses Rap1A prenylation, but unlike this effect on Rap1B, the GPCR-mediated suppression of Rap1A prenylation can occur independently of Rap1A phosphorylation and does not detectably diminish Rap1A membrane localization. These data demonstrate unexpected evolutionarily conserved differences in the ability of GPCRs to regulate the prenylation of Rap1B compared to Rap1A. PMID- 27760304 TI - Role of phosphatidylinositol-4,5-bisphosphate 3-kinase signaling in vesicular trafficking. AB - Phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks) are regulatory enzymes involved in the generation of lipid species that modulate cellular signaling pathways through downstream effectors to influence a variety of cellular functions. Years of intensive study of PI3Ks have produced a significant body of literature in many areas, including that PI3K can mediate intracellular vesicular trafficking and through these actions contribute to a number of important physiological functions. This review focuses on the crucial roles that PI3K and AKT, a major downstream partner of PI3K, play in the regulation of vesicle trafficking during various forms of vesicular endocytosis and exocytosis. PMID- 27760308 TI - Evaluation of a synthetic peptide from the Taenia saginata 18kDa surface/secreted oncospheral adhesion protein for serological diagnosis of bovine cysticercosis. AB - Bovine cysticercosis is a zoonotic infection widely spread throughout Brazil, creating a burden on hygiene maintenance and the economy. Diagnosis of cysticercosis usually relies on post mortem inspection of carcasses in slaughterhouses. This detection method provides only low sensitivity. Recent advancements have improved the performance of serologic tests, such as ELISA, providing greater sensitivity and specificity. The objective of the current study was to identify and evaluate a synthetic peptide derived from the Taenia saginata 18kDa oncospheric surface protein for the diagnosis of bovine cysticercosis in ELISA. Test performance of the identified peptide was compared to an ELISA based on a heterologous crude Taenia crassiceps antigen (Tcra), widely used for the sero-diagnosis of bovine cysticercosis. Based on the primary sequence of an in silico structural model of the 18kDa protein, an epitope region designated EP1 was selected (46-WDTKDMAGYGVKKIEV-61). The peptide derived from this region yielded 91.6% (CI=80-96%) sensitivity and 90% (CI=82-95%) specificity when used in an ELISA, whereas the crude antigen yielded 70% (CI=56-8%) sensitivity and 82% (CI=73-89%) specificity. Thus, we conclude that EP1 has higher diagnostic potential for detecting bovine cysticercosis than the crude antigen Tcra. PMID- 27760307 TI - Molecular genetics of osteosarcoma. AB - Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogs of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalog of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one 'first driver' and two 'synergistic drivers') may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease. PMID- 27760309 TI - Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue. AB - Previous work indicated that lysine-specific demethylase 1 (Lsd1) can positively regulate the oxidative and thermogenic capacities of white and beige adipocytes. Here we investigate the role of Lsd1 in brown adipose tissue (BAT) and find that BAT-selective Lsd1 ablation induces a shift from oxidative to glycolytic metabolism. This shift is associated with downregulation of BAT-specific and upregulation of white adipose tissue (WAT)-selective gene expression. This results in the accumulation of di- and triacylglycerides and culminates in a profound whitening of BAT in aged Lsd1-deficient mice. Further studies show that Lsd1 maintains BAT properties via a dual role. It activates BAT-selective gene expression in concert with the transcription factor Nrf1 and represses WAT selective genes through recruitment of the CoREST complex. In conclusion, our data uncover Lsd1 as a key regulator of gene expression and metabolic function in BAT. PMID- 27760310 TI - A Glo1-Methylglyoxal Pathway that Is Perturbed in Maternal Diabetes Regulates Embryonic and Adult Neural Stem Cell Pools in Murine Offspring. AB - Maternal diabetes is known to adversely influence brain development in offspring. Here, we provide evidence that this involves the circulating metabolite methylglyoxal, which is increased in diabetes, and its detoxifying enzyme, glyoxalase 1 (Glo1), which when mutated is associated with neurodevelopmental disorders. Specifically, when Glo1 levels were decreased in embryonic mouse cortical neural precursor cells (NPCs), this led to premature neurogenesis and NPC depletion embryonically and long-term alterations in cortical neurons postnatally. Increased circulating maternal methylglyoxal caused similar changes in embryonic cortical precursors and neurons and long-lasting changes in cortical neurons and NPCs in adult offspring. Depletion of embryonic and adult NPCs was also observed in murine offspring exposed to a maternal diabetic environment. Thus, the Glo1-methylglyoxal pathway integrates maternal and NPC metabolism to regulate neural development, and perturbations in this pathway lead to long lasting alterations in adult neurons and NPC pools. PMID- 27760311 TI - ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch. AB - Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-coenzyme A (CoA) plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here, we show that, upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY), cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL) and histone acetylation. A physiological level of acetate is sufficient for cell viability and abundant acetyl-CoA production, although histone acetylation levels remain low in ACLY-deficient cells unless supplemented with high levels of acetate. ACLY deficient adipocytes accumulate lipid in vivo, exhibit increased acetyl-CoA and malonyl-CoA production from acetate, and display some differences in fatty acid content and synthesis. Together, these data indicate that engagement of acetate metabolism is a crucial, although partial, mechanism of compensation for ACLY deficiency. PMID- 27760313 TI - A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function. AB - To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet. The model reproduces the dampened clock gene expression and NAD+ rhythms reported for mice on a high-fat diet and predicts that this effect may be pharmacologically rescued by timed REV-ERB agonist administration. Our model thus identifies altered AMPK signaling as a mechanism leading to clock disruption and its associated metabolic effects and suggests a pharmacological approach to resetting the clock in obesity. PMID- 27760312 TI - Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. AB - Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC. We find that Tsc1/2-deficient neurons accumulate mitochondria in cell bodies, but are depleted of axonal mitochondria, including those supporting presynaptic sites. Axonal and global mitophagy of damaged mitochondria is impaired, suggesting that decreased turnover may act upstream of impaired mitochondrial metabolism. Importantly, blocking mTORC1 or inducing mTOR-independent autophagy restores mitochondrial homeostasis. Our study clarifies the complex relationship between the TSC-mTORC1 pathway, autophagy, and mitophagy, and defines mitochondrial homeostasis as a therapeutic target for TSC and related diseases. PMID- 27760314 TI - Sustained Rhythmic Brain Activity Underlies Visual Motion Perception in Zebrafish. AB - Following moving visual stimuli (conditioning stimuli, CS), many organisms perceive, in the absence of physical stimuli, illusory motion in the opposite direction. This phenomenon is known as the motion aftereffect (MAE). Here, we use MAE as a tool to study the neuronal basis of visual motion perception in zebrafish larvae. Using zebrafish eye movements as an indicator of visual motion perception, we find that larvae perceive MAE. Blocking eye movements using optogenetics during CS presentation did not affect MAE, but tectal ablation significantly weakened it. Using two-photon calcium imaging of behaving GCaMP3 larvae, we find post-stimulation sustained rhythmic activity among direction selective tectal neurons associated with the perception of MAE. In addition, tectal neurons tuned to the CS direction habituated, but neurons in the retina did not. Finally, a model based on competition between direction-selective neurons reproduced MAE, suggesting a neuronal circuit capable of generating perception of visual motion. PMID- 27760315 TI - Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling. AB - Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c+ dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-gamma production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity. PMID- 27760316 TI - HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia. AB - Infectious and sterile inflammatory diseases are correlated with increased levels of high mobility group box 1 (HMGB1) in tissues and serum. Extracellular HMGB1 is known to activate Toll-like receptors (TLRs) 2 and 4 and RAGE (receptor for advanced glycation endproducts) in inflammatory conditions. Here, we find that TLR5 is also an HMGB1 receptor that was previously overlooked due to lack of functional expression in the cell lines usually used for studying TLR signaling. HMGB1 binding to TLR5 initiates the activation of NF-kappaB signaling pathway in a MyD88-dependent manner, resulting in proinflammatory cytokine production and pain enhancement in vivo. Biophysical and in vitro results highlight an essential role for the C-terminal tail region of HMGB1 in facilitating interactions with TLR5. These results suggest that HMGB1-modulated TLR5 signaling is responsible for pain hypersensitivity. PMID- 27760317 TI - Elucidation of the Fanconi Anemia Protein Network in Meiosis and Its Function in the Regulation of Histone Modifications. AB - Precise epigenetic regulation of the sex chromosomes is vital for the male germline. Here, we analyze meiosis in eight mouse models deficient for various DNA damage response (DDR) factors, including Fanconi anemia (FA) proteins. We reveal a network of FA and DDR proteins in which FA core factors FANCA, FANCB, and FANCC are essential for FANCD2 foci formation, whereas BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis. In addition, FA proteins modulate distinct histone marks on the sex chromosomes: FA core proteins and FANCD2 regulate H3K9 methylation, while FANCD2 and RNF8 function together to regulate H3K4 methylation independently of FA core proteins. Our data suggest that RNF8 integrates the FA BRCA pathway. Taken together, our study reveals distinct functions for FA proteins and illuminates the male sex chromosomes as a model to dissect the function of the FA-BRCA pathway. PMID- 27760318 TI - PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation. AB - PHF20 is a core component of the lysine acetyltransferase complex MOF (male absent on the first)-NSL (non-specific lethal) that generates the major epigenetic mark H4K16ac and is necessary for transcriptional regulation and DNA repair. The role of PHF20 in the complex remains elusive. Here, we report on functional coupling between methylation readers in PHF20. We show that the plant homeodomain (PHD) finger of PHF20 recognizes dimethylated lysine 4 of histone H3 (H3K4me2) and represents an example of a native reader that selects for this modification. Biochemical and structural analyses help to explain this selectivity and the preference of Tudor2, another reader in PHF20, for dimethylated p53. Binding of the PHD finger to H3K4me2 is required for histone acetylation, accumulation of PHF20 at target genes, and transcriptional activation. Together, our findings establish a unique PHF20-mediated link between MOF histone acetyltransferase (HAT), p53, and H3K4me2, and suggest a model for rapid spreading of H4K16ac-enriched open chromatin. PMID- 27760319 TI - Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants. AB - Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK-, and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology. PMID- 27760320 TI - Generating Late-Onset Human iPSC-Based Disease Models by Inducing Neuronal Age Related Phenotypes through Telomerase Manipulation. AB - Modeling late-onset disorders such as Parkinson's disease (PD) using iPSC technology remains a challenge, as current differentiation protocols yield cells with the properties of fetal-stage cells. Here, we tested whether it is possible to accelerate aging in vitro to trigger late-onset disease phenotypes in an iPSC model of PD. In order to manipulate a factor that is involved in natural aging as well as in premature aging syndromes, we used telomere shortening as an age inducing tool. We show that shortened telomeres result in age-associated as well as potentially disease-associated phenotypes in human pluripotent stem cell (hPSC)-derived midbrain dopamine (mDA) neurons. Our approach provides proof of concept for the further validation of telomere shortening as an induced-aging tool for late-onset-disease modeling. PMID- 27760322 TI - Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. PMID- 27760321 TI - A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies. PMID- 27760323 TI - Loss of Bin1 Promotes the Propagation of Tau Pathology. AB - Tau pathology propagates within synaptically connected neuronal circuits, but the underlying mechanisms are unclear. BIN1-amphiphysin2 is the second most prevalent genetic risk factor for late-onset Alzheimer's disease. In diseased brains, the BIN1-amphiphysin2 neuronal isoform is downregulated. Here, we show that lowering BIN1-amphiphysin2 levels in neurons promotes Tau pathology propagation whereas overexpression of neuronal BIN1-amphiphysin2 inhibits the process in two in vitro models. Increased Tau propagation is caused by increased endocytosis, given our finding that BIN1-amphiphysin2 negatively regulates endocytic flux. Furthermore, blocking endocytosis by inhibiting dynamin also reduces Tau pathology propagation. Using a galectin-3-binding assay, we show that internalized Tau aggregates damage the endosomal membrane, allowing internalized aggregates to leak into the cytoplasm to propagate pathology. Our work indicates that lower BIN1 levels promote the propagation of Tau pathology by efficiently increasing aggregate internalization by endocytosis and endosomal trafficking. PMID- 27760324 TI - IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-beta42 Aggregation in Adult Zebrafish Brain. AB - Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-beta42 (Abeta42) dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Abeta42 derivatives. Abeta42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Abeta42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Abeta42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains. PMID- 27760325 TI - HSV1 MicroRNA Modulation of GPI Anchoring and Downstream Immune Evasion. AB - Herpes simplex virus 1 (HSV1) is a ubiquitous human pathogen that utilizes variable mechanisms to evade immune surveillance. The glycosylphosphatidylinositol (GPI) anchoring pathway is a multistep process in which a myriad of different proteins are covalently attached to a GPI moiety to be presented on the cell surface. Among the different GPI-anchored proteins there are many with immunological importance. We present evidence that the HSV1-encoded miR H8 directly targets PIGT, a member of the protein complex that covalently attaches proteins to GPI in the final step of GPI anchoring. This results in a membrane down-modulation of several different immune-related, GPI-anchored proteins, including ligands for natural killer-activating receptors and the prominent viral restriction factor tetherin. Thus, we suggest that by utilizing just one of dozens of miRNAs encoded by HSV1, the virus can counteract the host immune response at several key points. PMID- 27760327 TI - Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein. AB - Although well characterized as a transcriptional activator that drives prostate cancer (PCa) growth, androgen receptor (AR) can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb). Significantly, AR also indirectly increases the expression of DNA replication genes through stimulatory effects on other metabolic genes with subsequent CDK activation and Rb hyperphosphorylation. In castration-resistant PCa cells, which are dependent on high-level AR expression, this anti-proliferative repression function might be exploited through treatment with androgen in combination with agents that suppress AR-driven metabolic functions or cell cycle progression. PMID- 27760326 TI - Non-oncogenic Acute Viral Infections Disrupt Anti-cancer Responses and Lead to Accelerated Cancer-Specific Host Death. AB - In light of increased cancer prevalence and cancer-specific deaths in patients with infections, we investigated whether infections alter anti-tumor immune responses. We report that acute influenza infection of the lung promotes distal melanoma growth in the dermis and leads to accelerated cancer-specific host death. Furthermore, we show that during influenza infection, anti-melanoma CD8+ T cells are shunted from the tumor to the infection site, where they express high levels of the inhibitory receptor programmed cell death protein 1 (PD-1). Immunotherapy to block PD-1 reverses this loss of anti-tumor CD8+ T cells from the tumor and decreases infection-induced tumor growth. Our findings show that acute non-oncogenic infection can promote cancer growth, raising concerns regarding acute viral illness sequelae. They also suggest an unexpected role for PD-1 blockade in cancer immunotherapy and provide insight into the immune response when faced with concomitant challenges. PMID- 27760328 TI - Cohesin Removal along the Chromosome Arms during the First Meiotic Division Depends on a NEK1-PP1gamma-WAPL Axis in the Mouse. AB - Mammalian NIMA-like kinase-1 (NEK1) is a dual-specificity kinase highly expressed in mouse germ cells during prophase I of meiosis. Loss of NEK1 induces retention of cohesin on chromosomes at meiotic prophase I. Timely deposition and removal of cohesin is essential for accurate chromosome segregation. Two processes regulate cohesin removal: a non-proteolytic mechanism involving WAPL, sororin, and PDS5B and direct cleavage by separase. Here, we demonstrate a role for NEK1 in the regulation of WAPL loading during meiotic prophase I, via an interaction between NEK1 and PDS5B. This regulation of WAPL by NEK1-PDS5B is mediated by protein phosphatase 1 gamma (PP1gamma), which both interacts with and is a phosphotarget of NEK1. Taken together, our results reveal that NEK1 phosphorylates PP1gamma, leading to the dephosphorylation of WAPL, which, in turn, results in its retention on chromosome cores to promote loss of cohesion at the end of prophase I in mammals. PMID- 27760329 TI - Replication-Independent Histone Variant H3.3 Controls Animal Lifespan through the Regulation of Pro-longevity Transcriptional Programs. AB - Chromatin structure orchestrates the accessibility to the genetic material. Replication-independent histone variants control transcriptional plasticity in postmitotic cells. The life-long accumulation of these histones has been described, yet the implications on organismal aging remain elusive. Here, we study the importance of the histone variant H3.3 in Caenorhabditis elegans longevity pathways. We show that H3.3-deficient nematodes have negligible lifespan differences compared to wild-type animals. However, H3.3 is essential for the lifespan extension of C. elegans mutants in which pronounced transcriptional changes control longevity programs. Notably, H3.3 loss critically affects the expression of a very large number of genes in long-lived nematodes, resulting in transcriptional profiles similar to wild-type animals. We conclude that H3.3 positively contributes to diverse lifespan-extending signaling pathways, with potential implications on age-related processes in multicellular organisms. PMID- 27760331 TI - TLR7 Structure: Cut in Z-Loop. AB - TLRs play central roles in host defense. In this issue of Immunity, Zhang et al. (2016) generate structures of TLR7 bound to multiple ligands and provide insight into the mechanism of TLR7 ligand recognition that highlights the differences in the features of the TLR subfamily. PMID- 27760330 TI - Nono, a Bivalent Domain Factor, Regulates Erk Signaling and Mouse Embryonic Stem Cell Pluripotency. AB - Nono is a component of the para-speckle, which stores and processes RNA. Mouse embryonic stem cells (mESCs) lack para-speckles, leaving the function of Nono in mESCs unclear. Here, we find that Nono functions as a chromatin regulator cooperating with Erk to regulate mESC pluripotency. We report that Nono loss results in robust self-renewing mESCs with epigenomic and transcriptomic features resembling the 2i (GSK and Erk inhibitors)-induced "ground state." Erk interacts with and is required for Nono localization to a subset of bivalent genes that have high levels of poised RNA polymerase. Nono loss compromises Erk activation and RNA polymerase poising at its target bivalent genes in undifferentiated mESCs, thus disrupting target gene activation and differentiation. These findings argue that Nono collaborates with Erk signaling to regulate the integrity of bivalent domains and mESC pluripotency. PMID- 27760332 TI - PKA Has the Gall to Oppose NLRP3. AB - The involvement of the NLRP3 inflammasome in inflammatory diseases has generated interest in identifying endogenous mechanisms that inhibit NLRP3. In this issue of Immunity, Guo et al. (2016) reveal bile acids as negative regulators of the NLRP3 inflammasome. PMID- 27760333 TI - Macrophages' Choice: Take It In or Keep It Out. AB - In tuberculosis, some macrophages in granulomas assume an epitheloid appearance. Using the Mycobacterium marinum-zebrafish model, Cronan et al. (2016) now show that granuloma macrophages undergo reprograming events involving E-cadherin dependent formation of epithelial-like cell-cell junctions. Interference with the function of E-cadherin in macrophages disorganized the granulomas and protected the fish, introducing new ideas and questions about macrophage function and granulomatous diseases. PMID- 27760334 TI - Class II-Restricted CD8s: New Lessons Violate Old Paradigms. AB - CD8+ T cells that recognize peptides presented by MHC class II molecules have been observed in a macaque SIV vaccine model. A new study by Ranasinghe et al. (2016) shows that virus-specific class-II-restricted CD8+ T cells can be found in some HIV-infected patients. PMID- 27760335 TI - Two Bugs a NOD Away from Improving Cancer Therapy Efficacy. AB - It has recently become apparent that the gut microbiota modulates the response to cancer therapy. In this issue of Immunity, Daillere et al. (2016) identified two bacterial species potentiating the anti-tumor effect of cyclophosphamide that are kept in check by the sensor NOD2. PMID- 27760336 TI - Amyloid Cascade into Clarity. AB - In a recent issue of Nature, Sevigny et al. (2016) report findings from a phase 1b clinical trial of aducanumab (a monoclonal antibody targeting misfolded amyloid-beta peptides), revitalizing the "amyloid cascade hypothesis" and bringing mononuclear phagocytes center stage in the treatment of Alzheimer's disease. PMID- 27760338 TI - Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation. AB - Macrophage activation status is intrinsically linked to metabolic remodeling. Macrophages stimulated by interleukin 4 (IL-4) to become alternatively (or, M2) activated increase fatty acid oxidation and oxidative phosphorylation; these metabolic changes are critical for M2 activation. Enhanced glucose utilization is also characteristic of the M2 metabolic signature. Here, we found that increased glucose utilization is essential for M2 activation. Increased glucose metabolism in IL-4-stimulated macrophages required the activation of the mTORC2 pathway, and loss of mTORC2 in macrophages suppressed tumor growth and decreased immunity to a parasitic nematode. Macrophage colony stimulating factor (M-CSF) was implicated as a contributing upstream activator of mTORC2 in a pathway that involved PI3K and AKT. mTORC2 operated in parallel with the IL-4Ralpha-Stat6 pathway to facilitate increased glycolysis during M2 activation via the induction of the transcription factor IRF4. IRF4 expression required both mTORC2 and Stat6 pathways, providing an underlying mechanism to explain how glucose utilization is increased to support M2 activation. PMID- 27760339 TI - The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance. AB - T follicular helper (Tfh) cells are a CD4+ T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection. Furthermore, we demonstrated that expression of Talin-1, an adaptor protein that regulates LFA-1 affinity, dictated Tfh versus Th2 effector cell differentiation. Collectively, our results define unique functions for LFA-1 in the Tfh cell effector program and suggest that integrin activity is important in lineage decision-making events in the adaptive immune system. PMID- 27760341 TI - Clonal Proliferation and Stochastic Pruning Orchestrate Lymph Node Vasculature Remodeling. AB - Lymph node (LN) expansion during an immune response relies on the transient remodeling of its vasculature. Although the mechanisms driving LN endothelial cell division are beginning to be understood, a comprehensive view of LN endothelial cell dynamics at the single-cell level is lacking. Here, we used multicolored fluorescent fate-mapping models to track the behavior of blood endothelial cells during LN expansion upon inflammation and subsequent return to homeostasis. We found that expansion of the LN vasculature relied on the sequential assembly of endothelial cell proliferative units. This segmented growth was sustained by the clonal proliferation of high endothelial venule (HEV) cells, which act as local progenitors to create capillaries and HEV neo-vessels at the periphery of the LN. Return to homeostasis was accompanied by the stochastic death of pre-existing and neo-synthesized LN endothelial cells. Thus, our fate-mapping studies unravel-at a single-cell level-the complex dynamics of vascular-tree remodeling during LN expansion and contraction. PMID- 27760340 TI - Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection. AB - Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response. PMID- 27760337 TI - Functions of Murine Dendritic Cells. AB - Dendritic cells (DCs) play critical roles in activating innate immune cells and initiating adaptive immune responses. The functions of DCs were originally obscured by their overlap with other mononuclear phagocytes, but new mouse models have allowed for the selective ablation of subsets of DCs and have helped to identify their non-redundant roles in the immune system. These tools have elucidated the functions of DCs in host defense against pathogens, autoimmunity, and cancer. This review will describe the mouse models generated to interrogate the role of DCs and will discuss how their use has progressively clarified our understanding of the unique functions of DC subsets. PMID- 27760343 TI - Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. PMID- 27760344 TI - A Dual Probe and Two Tones Reveal Dual Waves in the Cochlea. PMID- 27760342 TI - Antiviral CD8+ T Cells Restricted by Human Leukocyte Antigen Class II Exist during Natural HIV Infection and Exhibit Clonal Expansion. AB - CD8+ T cell recognition of virus-infected cells is characteristically restricted by major histocompatibility complex (MHC) class I, although rare examples of MHC class II restriction have been reported in Cd4-deficient mice and a macaque SIV vaccine trial using a recombinant cytomegalovirus vector. Here, we demonstrate the presence of human leukocyte antigen (HLA) class II-restricted CD8+ T cell responses with antiviral properties in a small subset of HIV-infected individuals. In these individuals, T cell receptor beta (TCRbeta) analysis revealed that class II-restricted CD8+ T cells underwent clonal expansion and mediated killing of HIV-infected cells. In one case, these cells comprised 12% of circulating CD8+ T cells, and TCRalpha analysis revealed two distinct co expressed TCRalpha chains, with only one contributing to binding of the class II HLA-peptide complex. These data indicate that class II-restricted CD8+ T cell responses can exist in a chronic human viral infection, and may contribute to immune control. PMID- 27760345 TI - Theory from the Oster Laboratory Leaps Ahead of Experiment in Understanding Actin Based Cellular Motility. PMID- 27760346 TI - Bending, Pushing, and Ratcheting It Up: Memories of a Modeling Effort. PMID- 27760347 TI - Ccoffinn: Automated Wave Tracking in Cultured Cardiac Monolayers. AB - Cardiac arrhythmias are one of the most frequent causes of death worldwide. A popular biological model used to study arrhythmogenesis is the cultured cardiac cell monolayer, which provides a good trade-off between physiological relevance and experimental access. Excitation wave patterns are imaged using high-bandwidth detectors, producing large data sets that are typically analyzed manually. To make such analysis less time consuming and less subjective, we have designed and implemented a toolkit for segmentation and tracking of cardiac waves in optical mapping recordings. The toolkit is optimized for high-resolution detectors to accommodate the growing availability of inexpensive high-resolution detectors for life science imaging applications (e.g., scientific CMOS cameras). The software extracts key features of propagating waves, such as wavefront speed and entropy. The methods have been validated using synthetic data, and real-world examples are provided, showing a difference in conduction velocity between two different types of cardiac cell cultures. PMID- 27760348 TI - Nanomechanics of Fluorescent DNA Dyes on DNA Investigated by Magnetic Tweezers. AB - Fluorescent DNA dyes are broadly used in many biotechnological applications for detecting and imaging DNA in cells and gels. Their binding alters the structural and nanomechanical properties of DNA and affects the biological processes that are associated with it. Although interaction modes like intercalation and minor groove binding already have been identified, associated mechanic effects like local elongation, unwinding, and softening of the DNA often remain in question. We used magnetic tweezers to quantitatively investigate the impact of three DNA binding dyes (YOYO-1, DAPI, and DRAQ5) in a concentration-dependent manner. By extending and overwinding individual, torsionally constrained, nick-free dsDNA molecules, we measured the contour lengths and molecular forces that allow estimation of thermodynamic and nanomechanical binding parameters. Whereas for YOYO-1 and DAPI the binding mechanisms could be assigned to bis-intercalation and minor groove binding, respectively, DRAQ5 exhibited both binding modes in a concentration-dependent manner. PMID- 27760349 TI - Single-Bond Association Kinetics Determined by Tethered Particle Motion: Concept and Simulations. AB - Tethered particle motion (TPM), the motion of a micro- or nanoparticle tethered to a substrate by a macromolecule, is a system that has proven to be extremely useful for its ability to reveal physical features of the tether, because the thermal motion of the bound particle reports sensitively on parameters like the length, the rigidity, or the folding state of its tether. In this article, we survey the applicability of TPM to probe the kinetics of single secondary bonds, bonds that form and break between the tethered particle and a substrate due, for instance, to receptor/ligand pairs on particle and substrate. Much like the tether itself affects the motion pattern, so do the presence and absence of such secondary connections. Keeping the tether properties constant, we demonstrate how raw positional TPM data may be parsed to generate detailed insights into the association and dissociation kinetics of single secondary bonds. We do this using coarse-grained molecular dynamics simulations specifically developed to treat the motion of particles close to interfaces. PMID- 27760350 TI - Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements. AB - Nipah is an emerging paramyxovirus that is of serious concern to human health. It invades host cells using two of its membrane proteins-G and F. G binds to host ephrins and this stimulates G to activate F. Upon activation, F mediates virus host membrane fusion. Here we focus on mechanisms that underlie the stimulation of G by ephrins. Experiments show that G interacts with ephrin and F through separate sites located on two different domains, the receptor binding domain (RBD) and the F activation domain (FAD). No models explain this allosteric coupling. In fact, the analogous mechanisms in other paramyxoviruses also remain undetermined. The structural organization of G is such that allosteric coupling must involve at least one of the two interfaces-the RBD-FAD interface and/or the RBD-RBD interface. Here we examine using molecular dynamics the effect of ephrin binding on the RBD-RBD interface. We find that despite inducing small changes in individual RBDs, ephrin reorients the RBD-RBD interface extensively, and in a manner that will enhance solvent exposure of the FAD. While this finding supports a proposed model of G stimulation, we also find from additional simulations that ephrin induces a similar RBD-RBD reorientation in a stimulation-deficient G mutant, V209 VG -> AAA. Together, our simulations suggest that while inter-RBD reorientation may be important, it is not, by itself, a sufficient condition for G stimulation. Additionally, we find that the mutation affects the conformational ensemble of RBD globally, including the RBD-FAD interface, suggesting the latter's role in G stimulation. Because ephrin induces small changes in individual RBDs, a proper analysis of conformational ensembles required that they are compared directly-we employ a method we developed recently, which we now release at SimTK, and show that it also performs excellently for non-Gaussian distributions. PMID- 27760351 TI - Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A. AB - Proteins commonly sample a number of conformational states to carry out their biological function, often requiring transitions from the ground state to higher energy states. Characterizing the mechanisms that guide these transitions at the atomic level promises to impact our understanding of functional protein dynamics and energy landscapes. The leucine-99-to-alanine (L99A) mutant of T4 lysozyme is a model system that has an experimentally well characterized excited sparsely populated state as well as a ground state. Despite the exhaustive study of L99A protein dynamics, the conformational changes that permit transitioning to the experimentally detected excited state (~3%, DeltaG ~2 kcal/mol) remain unclear. Here, we describe the transitions from the ground state to this sparsely populated excited state of L99A as observed through a single molecular dynamics (MD) trajectory on the Anton supercomputer. Aside from detailing the ground-to excited-state transition, the trajectory samples multiple metastates and an intermediate state en route to the excited state. Dynamic motions between these states enable cavity surface openings large enough to admit benzene on timescales congruent with known rates for benzene binding. Thus, these fluctuations between rare protein states provide an atomic description of the concerted motions that illuminate potential path(s) for ligand binding. These results reveal, to our knowledge, a new level of complexity in the dynamics of buried cavities and their role in creating mobile defects that affect protein dynamics and ligand binding. PMID- 27760352 TI - Modeling the Role of Epitope Arrangement on Antibody Binding Stoichiometry in Flaviviruses. AB - Cryo-electron-microscopy (cryo-EM) structures of flaviviruses reveal significant variation in epitope occupancy across different monoclonal antibodies that have largely been attributed to epitope-level differences in conformation or accessibility that affect antibody binding. The consequences of these variations for macroscopic properties such as antibody binding and neutralization are the results of the law of mass action-a stochastic process of innumerable binding and unbinding events between antibodies and the multiple binding sites on the flavivirus in equilibrium-that cannot be directly imputed from structure alone. We carried out coarse-grained spatial stochastic binding simulations for nine flavivirus antibodies with epitopes defined by cryo-EM or x-ray crystallography to assess the role of epitope spatial arrangement on antibody-binding stoichiometry, occupancy, and neutralization. In our simulations, all epitopes were equally competent for binding, representing the upper limit of binding stoichiometry that results from epitope spatial arrangement alone. Surprisingly, our simulations closely reproduced the relative occupancy and binding stoichiometry observed in cryo-EM, without having to account for differences in epitope accessibility or conformation, suggesting that epitope spatial arrangement alone may be sufficient to explain differences in binding occupancy and stoichiometry between antibodies. Furthermore, we found that there was significant heterogeneity in binding configurations even at saturating antibody concentrations, and that bivalent antibody binding may be more common than previously thought. Finally, we propose a structure-based explanation for the stoichiometric threshold model of neutralization. PMID- 27760353 TI - Dynamic Response of the C2 Domain of Protein Kinase Calpha to Ca2+ Binding. AB - Ca2+-dependent conserved-region 2 (C2) domains target their host signaling proteins to anionic membranes. The Ca2+-binding event is a prerequisite for membrane association. Here, we investigate multiscale metal-ion-dependent dynamics of the C2 domain of protein kinase Calpha (C2alpha) using NMR spectroscopy. Interactions with metal ions attenuate microsecond-timescale motions of the loop regions, indicating that preorganization of the metal-binding loops occurs before membrane insertion. Binding of a full complement of Ca2+ ions has a profound effect on the millisecond-timescale dynamics of the N- and C terminal regions of C2alpha. We propose that Ca2+ binding allosterically destabilizes the terminal regions of C2alpha and thereby facilitates the conformational rearrangement necessary for full membrane insertion and activation of protein kinase Calpha. PMID- 27760354 TI - A Quantitative Model for cAMP Binding to the Binding Domain of MloK1. AB - Ligand-protein binding processes are essential in biological systems. A well studied system is the binding of cyclic adenosine monophosphate to the cyclic nucleotide binding domain of the bacterial potassium channel MloK1. Strikingly, the measured on-rate for cyclic adenosine monophosphate binding is two orders of magnitude slower than a simple Smoluchowski diffusion model would suggest. To resolve this discrepancy and to characterize the ligand-binding path in structural and energetic terms, we calculated 1100 ligand-binding molecular dynamics trajectories and tested two scenarios: In the first scenario, the ligand transiently binds to the protein surface and then diffuses along the surface into the binding site. In the second scenario, only ligands that reach the protein surface in the vicinity of the binding site proceed into the binding site. Here, a binding funnel, which increasingly confines the translational as well as the rotational degrees of freedom, determines the binding pathways and limits the on rate. From the simulations, we identified five surface binding states and calculated the rates between these surface binding states, the binding site, and the bulk. We find that the transient binding of the ligands to the surface binding states does not affect the on-rate, such that this effect alone cannot explain the observed low on-rate. Rather, by quantifying the translational and rotational degrees of freedom and by calculating the binding committor, our simulations confirmed the existence of a binding funnel as the main bottleneck. Direct binding via the binding funnel dominates the binding kinetics, and only ~10% of all ligands proceed via the surface into the binding site. The simulations further predict an on-rate between 15 and 40MUs-1(mol/l)-1, which agrees with the measured on-rate. PMID- 27760355 TI - Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1. AB - The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels' voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges. We have explored these issues by analyzing the effects of the divalent strontium ion (Sr2+) on the voltage dependence of the G(V) curves of wild-type and chimeric Kv channels expressed in Xenopus oocytes, using the voltage-clamp technique. Out of seven Kv channels, Kv1.2 was found to be most sensitive to Sr2+ (50 mM shifted G(V) by +21.7 mV), and Kv2.1 to be the least sensitive (+7.8 mV). Experiments on 25 chimeras, constructed from Kv1.2 and Kv2.1, showed that the large Sr2+-induced G(V) shift of Kv1.2 can be transferred to Kv2.1 by exchanging the extracellular linker between S3 and S4 (L3/4) in combination with either the extracellular linker between S5 and the pore (L5/P) or that between the pore and S6 (LP/6). The effects of the linker substitutions were nonadditive, suggesting specific structural interactions. The free energy of these interactions was ~20 kJ/mol, suggesting involvement of hydrophobic interactions and/or hydrogen bonds. Using principles from double-layer theory we derived an approximate linear equation (relating the voltage shifts to altered ionic strength), which proved to well match experimental data, suggesting that Sr2+ acts on these channels mainly by screening surface charges. Taken together, these results highlight the extracellular surface potential at the voltage sensor as an important determinant of the channels' voltage dependence, making the extracellular linkers essential targets for evolutionary selection. PMID- 27760356 TI - Full-Length OmpA: Structure, Function, and Membrane Interactions Predicted by Molecular Dynamics Simulations. AB - OmpA is a multidomain protein found in the outer membranes of most Gram-negative bacteria. Despite a wealth of reported structural and biophysical studies, the structure-function relationships of this protein remain unclear. For example, it is still debated whether it functions as a pore, and the precise molecular role it plays in attachment to the peptidoglycan of the periplasm is unknown. The absence of a consensus view is partly due to the lack of a complete structure of the full-length protein. To address this issue, we performed molecular-dynamics simulations of the full-length model of the OmpA dimer proposed by Robinson and co-workers. The N-terminal domains were embedded in an asymmetric model of the outer membrane, with lipopolysaccharide molecules in the outer leaflet and phospholipids in the inner leaflet. Our results reveal a large dimerization interface within the membrane environment, ensuring that the dimer is stable over the course of the simulations. The linker is flexible, expanding and contracting to pull the globular C-terminal domain up toward the membrane or push it down toward the periplasm, suggesting a possible mechanism for providing mechanical stability to the cell. The external loops were more stabilized than was observed in previous studies due to the extensive dimerization interface and presence of lipopolysaccharide molecules in our outer-membrane model, which may have functional consequences in terms of OmpA adhesion to host cells. In addition, the pore-gating behavior of the protein was modulated compared with previous observations, suggesting a possible role for dimerization in channel regulation. PMID- 27760357 TI - Effect of Lung Surfactant Protein SP-C and SP-C-Promoted Membrane Fragmentation on Cholesterol Dynamics. AB - To allow breathing and prevent alveolar collapse, lung surfactant (LS) develops a complex membranous system at the respiratory surface. LS is defined by a specific protein and lipid composition, including saturated and unsaturated phospholipid species and cholesterol. Surfactant protein C (SP-C) has been suggested to be an essential element for sustaining the presence of cholesterol in surfactant without functional impairment. In this work, we used a fluorescent sterol partitioning assay to assess the effect of the surfactant proteins SP-B and SP-C on cholesterol distribution in membranes. Our results suggest that in the LS context, the combined action of SP-B and SP-C appears to facilitate cholesterol dynamics, whereas SP-C does not seem to establish a direct interaction with cholesterol that could increase the partition of free cholesterol into membranes. Interestingly, SP-C exhibits a membrane-fragmentation behavior, leading to the conversion of large unilamellar vesicles into highly curved vesicles ~25 nm in diameter. Sterol partition was observed to be sensitive to the bending of bilayers, indicating that the effect of SP-C to mobilize cholesterol could be indirectly associated with SP-C-mediated membrane remodeling. Our results suggest a potential role for SP-C in generating small surfactant structures that may participate in cholesterol mobilization and pulmonary surfactant homeostasis at the alveolar interfaces. PMID- 27760358 TI - Membrane/Water Partition Coefficients of Bile Salts Determined Using Laurdan as a Fluorescent Probe. AB - The interaction of liposomal membranes composed of soybean phosphatidylcholine with the bile salts (BSs) cholate (Ch), glycocholate (GC), chenodeoxycholate (CDC), and glycochenodeoxycholate (GCDC) was studied. The BSs differed with regard to their lipophilicity, pKa values, and the size of their hydrophilic moiety. Their membrane interactions were investigated using Laurdan as a membrane anchored fluorescent dye. The apparent membrane/water partition coefficient, D, at pH 7.4 was calculated from binding plots and compared with direct binding measurements using ultracentrifugation as a reference. The Laurdan-derived LogD values at pH 7.4 were found to be 2.10 and 2.25 for the trihydroxy BSs, i.e., Ch and GC, and 2.85 and 2.75 for the dihydroxy BSs, i.e., CDC and GCDC, respectively. For the membrane-associated glycine-conjugated GC and GCDC (pKa values of ~3.9), no differences in the Laurdan spectra of the respective BS were found at pH 6.8, 7.4, and 8.2. Unconjugated Ch and CDC (pKa values of ~5.0) showed pronounced differences at the three pH values. Furthermore, the kinetics of membrane adsorption and transbilayer movement differed between conjugated and unconjugated BSs as determined with Laurdan-labeled liposomes. PMID- 27760359 TI - Mode of Action of a Designed Antimicrobial Peptide: High Potency against Cryptococcus neoformans. AB - There is a significant need for developing compounds that kill Cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis in immunocompromised individuals. Here, we report the mode of action of a designed antifungal peptide, VG16KRKP (VARGWKRKCPLFGKGG) against C. neoformans. It is shown that VG16KRKP kills fungal cells mainly through membrane compromise leading to efflux of ions and cell metabolites. Intracellular localization, inhibition of in vitro transcription, and DNA binding suggest a secondary mode of action for the peptide, hinting at possible intracellular targets. Atomistic structure of the peptide determined by NMR experiments on live C. neoformans cells reveals an amphipathic arrangement stabilized by hydrophobic interactions among A2, W5, and F12, a conventional folding pattern also known to play a major role in peptide mediated Gram-negative bacterial killing, revealing the importance of this motif. These structural details in the context of live cell provide valuable insights into the design of potent peptides for effective treatment of human and plant fungal infections. PMID- 27760360 TI - Charge Distribution Fine-Tunes the Translocation of alpha-Helical Amphipathic Peptides across Membranes. AB - Hundreds of cationic antimicrobial and cell-penetrating peptides (CPPs) form amphipathic alpha-helices when bound to lipid membranes. Here, we test two hypotheses for the differences in the ability of these peptides to translocate across membranes. The first, which we now call the hydrophobicity hypothesis, is that peptide translocation is determined by the Gibbs energy of insertion into the bilayer from the membrane interface. The second, which we call the charge distribution hypothesis, is that translocation is determined by whether the distribution of cationic residues in the peptide can transiently stabilize a high energy inserted intermediate by forming salt bridges to the phosphates of lipid headgroups. To test these hypotheses, we measured translocation of two series of peptide variants. The first series was based on TP10W, a peptide derived from the amphipathic CPP transportan 10; the second was based on DL1a, a synthetic peptide derived from staphylococcal delta-lysin. The peptides in those two series had small sequence changes relative to TP10W and DL1a: either single-residue substitutions or two-residue switches, which were designed to increase or decrease translocation differently according to the two hypotheses. We found that with regard to the changes introduced in the sequences, five out of six peptide variants translocated in agreement with the charge-distribution hypothesis, whereas none showed agreement with the hydrophobicity hypothesis. We conclude that large effects on translocation are probably determined by hydrophobicity, but the fine tuning appears to arise from the distribution of cationic residues along the peptide sequence. PMID- 27760361 TI - Bilayer Properties of Lipid A from Various Gram-Negative Bacteria. AB - Lipid A is the lipid anchor of a lipopolysaccharide in the outer leaflet of the outer membrane of Gram-negative bacteria. In general, lipid A consists of two phosphorylated N-acetyl glucosamine and several acyl chains that are directly linked to the two sugars. Depending on the bacterial species and environments, the acyl chain number and length vary, and lipid A can be chemically modified with phosphoethanolamine, aminoarabinose, or glycine residues, which are key to bacterial pathogenesis. In this work, homogeneous lipid bilayers of 21 distinct lipid A types from 12 bacterial species are modeled and simulated to investigate the differences and similarities of their membrane properties. In addition, different neutralizing ion types (Ca2+, K+, and Na+) are considered to examine the ion's influence on the membrane properties. The trajectory analysis shows that (1) the area per lipid is mostly correlated to the acyl chain number, and the area per lipid increases as a function of the acyl chain number; (2) the hydrophobic thickness is mainly determined by the average acyl chain length with slight dependence on the acyl chain number, and the hydrophobic thickness generally increases with the average acyl chain length; (3) a good correlation is observed among the area per lipid, hydrophobic thickness, and acyl chain order; and (4) although the influence of neutralizing ion types on the area per lipid and hydrophobic thickness is minimal, Ca2+ stays longer on the membrane surface than K+ or Na+, consequently leading to lower lateral diffusion and a higher compressibility modulus, which agrees well with available experiments. PMID- 27760362 TI - Cellular Stiffness as a Novel Stemness Marker in the Corneal Limbus. AB - Healthy eyes contain a population of limbal stem cells (LSCs) that continuously renew the corneal epithelium. However, each year, 1 million Americans are afflicted with severely reduced visual acuity caused by corneal damage or disease, including LSC deficiency (LSCD). Recent advances in corneal transplant technology promise to repair the cornea by implanting healthy LSCs to encourage regeneration; however, success is limited to transplanted tissues that contain a sufficiently high percentage of LSCs. Attempts to screen limbal tissues for suitable implants using molecular stemness markers are confounded by the poorly understood signature of the LSC phenotype. For cells derived from the corneal limbus, we show that the performance of cell stiffness as a stemness indicator is on par with the performance of DeltaNP63alpha, a common molecular marker. In combination with recent methods for sorting cells on a biophysical basis, the biomechanical stemness markers presented here may enable the rapid purification of LSCs from a heterogeneous population of corneal cells, thus potentially enabling clinicians and researchers to generate corneal transplants with sufficiently high fractions of LSCs, regardless of the LSC percentage in the donor tissue. PMID- 27760363 TI - The Mitotic Spindle in the One-Cell C. elegans Embryo Is Positioned with High Precision and Stability. AB - Precise positioning of the mitotic spindle is important for specifying the plane of cell division, which in turn determines how the cytoplasmic contents of the mother cell are partitioned into the daughter cells, and how the daughters are positioned within the tissue. During metaphase in the early Caenorhabditis elegans embryo, the spindle is aligned and centered on the anterior-posterior axis by a microtubule-dependent machinery that exerts restoring forces when the spindle is displaced from the center. To investigate the accuracy and stability of centering, we tracked the position and orientation of the mitotic spindle during the first cell division with high temporal and spatial resolution. We found that the precision is remarkably high: the cell-to-cell variation in the transverse position of the center of the spindle during metaphase, as measured by the standard deviation, was only 1.5% of the length of the short axis of the cell. Spindle position is also very stable: the standard deviation of the fluctuations in transverse spindle position during metaphase was only 0.5% of the short axis of the cell. Assuming that stability is limited by fluctuations in the number of independent motor elements such as microtubules or dyneins underlying the centering machinery, we infer that the number is ~1000, consistent with the several thousand of astral microtubules in these cells. Astral microtubules grow out from the two spindle poles, make contact with the cell cortex, and then shrink back shortly thereafter. The high stability of centering can be accounted for quantitatively if, while making contact with the cortex, the astral microtubules buckle as they exert compressive, pushing forces. We thus propose that the large number of microtubules in the asters provides a highly precise mechanism for positioning the spindle during metaphase while assembly is completed before the onset of anaphase. PMID- 27760364 TI - Arbitrary-Region Raster Image Correlation Spectroscopy. AB - Combining imaging with correlation spectroscopy, as in raster image correlation spectroscopy (RICS), makes it possible to extract molecular translational diffusion constants and absolute concentrations, and determine intermolecular interactions from single-channel or multicolor confocal laser-scanning microscopy (CLSM) images. Region-specific RICS analysis remains very challenging because correlations are always calculated in a square region-of-interest (ROI). In this study, we describe a generalized image correlation spectroscopy algorithm that accepts arbitrarily shaped ROIs. We show that an image series can be cleaned up before arbitrary-region RICS (ARICS) analysis. We demonstrate the power of ARICS by simultaneously measuring molecular mobility in the cell membrane and the cytosol. Mobility near dynamic subcellular structures can be investigated with ARICS by generating a dynamic ROI. Finally, we derive diffusion and concentration pseudo-maps using the ARICS method. ARICS is a powerful expansion of image correlation spectroscopy with the potential of becoming the new standard for extracting biophysical parameters from confocal fluorescence images. PMID- 27760365 TI - Nanoscale Imaging of Collagen Gels with Focused Ion Beam Milling and Scanning Electron Microscopy. AB - In vitro polymerized type I collagen hydrogels have been used extensively as a model system for three-dimensional (3D) cell and tissue culture, studies of fibrillogenesis, and investigation of multiscale force transmission within connective tissues. The nanoscale organization of collagen fibrils plays an essential role in the mechanics of these gels and emergent cellular behavior in culture, yet quantifying 3D structure with nanoscale resolution to fully characterize fibril organization remains a significant technical challenge. In this study, we demonstrate that a new imaging modality, focused ion beam scanning electron microscopy (FIB-SEM), can be used to generate 3D image datasets for visualizing and quantifying complex nanoscale organization and morphometry in collagen gels. We polymerized gels at a number of concentrations and conditions commonly used for in vitro models, stained and embedded the samples, and performed FIB-SEM imaging. The resulting image data had a voxel size of 25 nm, which is the highest resolution 3D data of a collagen fibril network ever obtained for collagen gels. This resolution was essential for discerning individual fibrils, fibril paths, and their branching and grouping. The resulting volumetric images revealed that polymerization conditions have a significant impact on the complex fibril morphology of the gels. We segmented the fibril network and demonstrated that individual collagen fibrils can be tracked in 3D space, providing quantitative analysis of network descriptors such as fibril diameter distribution, length, branch points, and fibril aggregations. FIB-SEM 3D reconstructions showed considerably less lateral grouping and overlap of fibrils than standard 2D SEM images, likely due to artifacts in SEM introduced by dehydration. This study demonstrates the utility of FIB-SEM for 3D imaging of collagen gels and quantitative analysis of 3D fibril networks. We anticipate that the method will see application in future studies of structure-function relationships in collagen gels as well as native collagenous tissues. PMID- 27760367 TI - The Effect of Temperature on Microtubule-Based Transport by Cytoplasmic Dynein and Kinesin-1 Motors. PMID- 27760366 TI - Two-Tone Suppression of Simultaneous Electrical and Mechanical Responses in the Cochlea. AB - Cochlear frequency tuning is based on a mildly tuned traveling-wave response that is enhanced in amplitude and sharpness by outer hair cell (OHC)-based forces. The nonlinear and active character of this enhancement is the fundamental manifestation of cochlear amplification. Recently, mechanical (pressure) and electrical (extracellular OHC-generated voltage) responses were simultaneously measured close to the sensory tissue's basilar membrane. Both pressure and voltage were tuned and showed traveling-wave phase accumulation, evidence that they were locally generated responses. Approximately at the frequency where nonlinearity commenced, the phase of extracellular voltage shifted up, to lead pressure by >1/4 cycle. Based on established and fundamental relationships among voltage, force, pressure, displacement, and power, the observed phase shift was identified as the activation of cochlear amplification. In this study, the operation of the cochlear amplifier was further explored, via changes in pressure and voltage responses upon delivery of a second, suppressor tone. Two different suppression paradigms were used, one with a low-frequency suppressor and a swept frequency probe, the other with two swept-frequency tones, either of which can be considered as probe or suppressor. In the presence of a high-level low-frequency suppressor, extracellular voltage responses at probe-tone frequencies were greatly reduced, and the pressure responses were reduced nearly to their linear, passive level. On the other hand, the amplifier-activating phase shift between pressure and voltage responses was still present in probe-tone responses. These findings are consistent with low-frequency suppression being caused by the saturation of OHC electrical responses and not by a change in the power-enabling phasing of the underlying mechanics. In the two-tone swept-frequency suppression paradigm, mild suppression was apparent in the pressure responses, while deep notches could develop in the voltage responses. A simple analysis, based on a two wave differencing scheme, was used to explore the observations. PMID- 27760368 TI - Resveratrol induces mitochondrial respiration and apoptosis in SW620 colon cancer cells. AB - BACKGROUND: The polyphenol resveratrol (RSV) is found in the skin of red grapes and has been reported to exhibit anticancer properties. The antitumor effects of RSV in the gastrointestinal tract have gained considerable interest due to the high exposure of this tissue to this dietary compound. One of the hallmarks of cancer cells is their particular metabolism mainly relying on glycolysis for ATP production rather than mitochondrial oxidative phosphorylation. Although RSV has been described to act as a calorie-restriction mimetic, modulating energy metabolism in normal tissues, little efforts have been done to study the effects of this polyphenol in the metabolism of cancer cells. Taking this into account, the aim of this study was to explore metabolic effects of this polyphenol in colon cancer. METHODS: Oxygen consumption, ATP levels, Western blotting and other molecular biology techniques were carried out to characterize the metabolic signature of RSV in SW620 colon cancer cells. RESULTS: Paradoxically, the cytotoxic effects of RSV were associated with an increase in oxygen consumption supported by mitochondrial biogenesis and increased fatty acid oxidation. This partial reversion of the Warburg effect was followed by hyperpolarization of mitochondrial membrane and ROS production, leading to an increased apoptosis. CONCLUSIONS: Our results propose that the anticancer mechanisms of RSV could reside in targeting cancer cell metabolism, promoting mitochondrial electron transport chain overload and, ultimately, increasing ROS production. GENERAL SIGNIFICANCE: These results shed new light into the anticancer mechanism of RSV supporting the ability of this compound in potentiating the effects of chemotherapy. PMID- 27760369 TI - Autoimmunity to heat shock proteins and vitamin D status in patients with celiac disease without associated dermatitis herpetiformis. AB - Inflammation-induced heat shock proteins (HSPs) and hypovitaminosis D have been reported to impact immune responses and to be associated with autoimmune diseases including celiac disease (CD), a gluten-sensitive enteropathy mediated by autoantibodies against tissue transglutaminase (TG2). Recently, we provided evidence for a role of autoantibodies to HSPs in patients with dermatitis herpetiformis (DH), an inflammatory skin disease induced by underlying latent CD. In this study, we aimed at investigating the humoral autoimmune response to HSPs and vitamin D status in CD patients (n=15) presenting without the cutaneous disease manifestation. In comparison with healthy controls (n=15), circulating autoantibodies against HSP40, HSP60, and HSP90 were increased in these patients, and these autoantibodies, including anti-HSP70, correlated with serum anti-TG2 autoantibodies. Deficient and insufficient vitamin D serum levels were found in 8 out of 15 CD patients and 11 out of 15 healthy controls, and the vitamin D status showed no relationship with levels of circulating anti-TG2 or anti-HSP autoantibodies in the patients. Our results preliminarily suggest a pronounced anti-HSP autoimmune response in CD that is linked to pathophysiological processes in the gut independently of both a potential concomitant disease-related extra intestinal inflammatory manifestation in the skin and the vitamin D status. Future studies on larger groups of patients are needed to confirm the present data and to further clarify whether autoimmunity towards HSPs is primarily related to underlying CD or skin inflammation in DH patients. PMID- 27760370 TI - Stem cell therapy clinical research: A regulatory conundrum for academia. AB - The encouraging pace of discovery and development in the field of regenerative medicine holds tremendous potential for bringing therapies to the clinic that may offer meaningful benefit to patients, particularly in diseases with no or suboptimal therapeutic options. Academic researchers will continue to play a critical role in developing concepts and therapies, thus determining whether regenerative medicine will be able to live up to this potential that clearly excites clinicians, researchers and patients alike. This review summarises recent developments in regulatory frameworks across different countries that aim to ensure adequate oversight of the development of regenerative medicine products, which are unique in structural and functional complexity when compared to traditional chemical drugs and fully characterised biological drugs. It discusses the implications of these developments for researchers aiming to make the challenging transition from laboratory to clinical development of these therapies and considers possible pragmatic solutions that could accelerate this process that is essential to maintain research credibility and ensure patient safety. PMID- 27760371 TI - Who is afraid of the invisible snake? Subjective visual awareness modulates posterior brain activity for evolutionarily threatening stimuli. AB - Snakes were probably one of the earliest predators of primates, and snake images produce specific behavioral and electrophysiological reactions in humans. Pictures of snakes evoke enhanced activity over the occipital cortex, indexed by the "early posterior negativity" (EPN), as compared with pictures of other dangerous or non-dangerous animals. The present study investigated the possibility that the response to snake images is independent from visual awareness. The observers watched images of threatening and non-threatening animals presented in random order during rapid serial visual presentation. Four different masking conditions were used to manipulate awareness of the images. Electrophysiological results showed that the EPN was larger for snake images than for the other images employed in the unmasked condition. However, the difference disappeared when awareness of the stimuli decreased. Behavioral results on the effects of awareness did not show any advantage for snake images. PMID- 27760372 TI - Classification and treatment of antisocial individuals: From behavior to biocognition. AB - Antisocial behavior is a heterogeneous construct that can be divided into subtypes, such as antisocial personality and psychopathy. The adverse consequences of antisocial behavior produce great burden for the perpetrators, victims, family members, and for society at-large. The pervasiveness of antisocial behavior highlights the importance of precisely characterizing subtypes of antisocial individuals and identifying specific factors that are etiologically related to such behaviors to inform the development of targeted treatments. The goals of the current review are (1) to briefly summarize research on the operationalization and assessment of antisocial personality and psychopathy; (2) to provide an overview of several existing treatments with the potential to influence antisocial personality and psychopathy; and (3) to present an approach that integrates and uses biological and cognitive measures as starting points to more precisely characterize and treat these individuals. A focus on integrating factors at multiple levels of analysis can uncover person specific characteristics and highlight potential targets for treatment to alleviate the burden caused by antisocial behavior. PMID- 27760373 TI - Porcine circovirus 2 proliferation can be enhanced by stably expressing porcine IL-2 gene in PK-15 cell. AB - Porcine circovirus 2 (PCV2) is the causative agent of porcine circovirus diseases and porcine circovirus-associated diseases (PCVD/PCVAD), which are widely present in every major swine farm. However, lower propagation rate of PCV2 in vitro seriously hindered the production of PCV2 vaccine. Previously, we found that interleukin-2 (IL-2) can increase PCV2 yield in vitro. In the present study, porcine IL-2 gene was amplified and stably transfected into PK-15 cells. The results demonstrated that PCV2 proliferation can be significantly enhanced in cells stably expressing porcine IL-2 gene, suggesting that porcine IL-2 contributes to proliferation of PCV2. These results indicated that cells overexpressing porcine IL-2 gene can be used as a promising cell line for vaccine development of PCV2. PMID- 27760375 TI - p-Cresyl sulfate affects the oxidative burst, phagocytosis process, and antigen presentation of monocyte-derived macrophages. AB - Immune system dysfunction is a common condition in chronic kidney disease (CKD). The present study investigated the effect of p-Cresyl sulfate (pCS) on human cell line U937 monocyte-derived macrophages (MDM) activity. MDM (1*106 cells/mL) were incubated with pCS (10, 25, or 50MUg/mL), with or without lipopolysaccharide (LPS; 25ng/mL) and then evaluated NO production, phagocytosis and antigen presenting molecules expression (HLA-ABC, HLA-DR, CD80 and CD86). All analyses were performed by flow cytometry. All pCS concentrations were able to increase NO production (49+/-12.1%, 39.8+/-7.75%, 43.7+/-11.9%, respectively) compared to untreated cells (4.35+/-3.34%) after 6h incubation but only the lowest concentration increased this production after 12h (82.9+/-8.6%, 61+/-7.2%, 40.8+/ 11.7%). Combined with LPS, the same results were observed. Regarding to phagocytosis, all concentrations were able to induce bead engulfment (35.4+/ 2.71%, 30+/-3.04%, 23.28+/-4.58%). In addition, pCS (50MUg/mL) was able to increase HLA-ABC and CD80 expression, showed a slight effect on HLA-DR expression and, no difference in basal CD86 levels. pCS can induce an increased oxidative burst and phagocytosis by human macrophages while no modulation of HLA-DR or CD86 expression was induced. Together, these results suggest that pCS induces macrophage activation but interfere in antigen processing, leading to a failure in adaptive immune response in CKD. PMID- 27760376 TI - Discovery of new substrates of the elongation factor-2 kinase suggests a broader role in the cellular nutrient response. AB - Elongation Factor-2 Kinase (eEF2K) in an unusual mammalian enzyme that has one known substrate, elongation factor-2. It belongs to a class of kinases, called alpha kinases, that has little sequence identity to the >500 conventional protein kinases, but performs the same reaction and has similar catalytic residues. The phosphorylation of eEF2 blocks translation elongation, which is thought to be critical to regulating cellular energy usage. Here we report a system for discovering new substrates of alpha kinases and identify the first new substrates of eEF2K including AMPK and alpha4, and determine a sequence motif for the kinase that shows a requirement for threonine residues as the target of phosphorylation. These new substrates suggest that eEF2K has a more diverse role in regulating cellular energy usage that involves multiple pathways and regulatory feedback. PMID- 27760377 TI - Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. AB - Aldehyde dehydrogenase 5a1-deficient (aldh5a1-/-) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1-/- mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR. We observed that multiple metabolites associated with GABA metabolism (gamma-hydroxybutyrate, succinic semialdehyde, D-2-hydroxyglutarate, 4,5-dihydrohexanoate) and oxidative stress were significantly increased in multiple tissues derived from aldh5a1-/- mice. These metabolic perturbations were associated with decreased levels of reduced glutathione (GSH) in brain and liver of aldh5a1-/- mice, as well as increased levels of adducts of the lipid peroxidation by-product, 4-hydroxy-2-nonenal (4-HNE). Decreased liver mRNA levels for multiple genes associated with mTOR signaling and oxidative stress parameters were detected in aldh5a1-/- mice, and several were significantly improved with the administration of mTOR inhibitors (Torin 1/Torin 2). Western blot analysis of selected proteins corresponding to oxidative stress transcripts (glutathione transferase, superoxide dismutase, peroxiredoxin 1) confirmed gene expression findings. Our data provide additional preclinical evidence for the potential therapeutic efficacy of mTOR inhibitors in SSADHD. PMID- 27760378 TI - Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate. AB - The aim of this study was to develop and characterize a novel colloidal system, namely, timolol maleate chitosan coated liposomes (TM-CHL) to enhance the ocular permeation, precorneal residence time and bioavailability. The resulting TM-CHL was the most promising formulation with a mean particle size of 150.7nm and an EE% of 75.83+/-1.61%. In vitro release of the TM-CHL showed an extended drug release profile. The TM-CHL exhibited significant mucin adhesion and compared with commercial eye drops, TM-CHL produced a 3.18-fold increase in the apparent permeability coefficient (Papp), resulting in a significant enhancement of corneal permeation. In addition, the gamma scintigraphic study and the pharmacokinetic study showed that TM-CHL could be retained at the corneal surface for longer time compared with eye drops. The ocular irritation study indicated that the developed liposomes produced no significant irritant effects. Furthermore, pharmacodynamics results showed that the maximum intraocular pressure(IOP) produced by TM-CHL was (19.67+/-1.14) mmHg compared with the (23.80+/-1.49) mmHg for TM eye drops, revealing that TM-CHL was more effective in reducing the IOP. These results demonstrate that CHL is a potentially useful carrier for ocular drug delivery, which could improve the efficacy of TM. PMID- 27760379 TI - A combined biochemical and computational studies of the rho-class glutathione s transferase sll1545 of Synechocystis PCC 6803. AB - Peroxides are one of the most important radicals that cause oxidative stress. Certain Glutathione S-transferases (GSTs) have been reported to show peroxidase activity. We report a novel peroxidase activity of Synechocystis GST- sll1545. The recombinant protein was purified to homogeneity and characterized. Low Km (0.109MUM) and high Vmax (0.663MUmolmin-1) values suggest a high preference of sll1545 for cumenehydroperoxide. Disc inhibition assay confirmed the ability of the enzyme to protect cells against peroxide-induced damage. sll1545 has very low sequence and structural similarity with theta and alpha class GSTs that exhibit glutathione-dependent peroxidase activity. Recent data from our laboratory shows that sll1545 is also strongly active against dichloroacetate (DCA), which is a characteristic of zeta class GST. Interestingly, sll1545 shows less than 20% sequence identity with zeta class GST. Molecular dynamic simulation results show that sll1545 was much more structurally different from alpha/theta classes. Our results suggest that sll1545 shows structural variation from zeta, theta/alpha classes of GSTs but have related enzymatic activity. Phylogenetic analysis reveal that sll1545 is evolutionally very distinct from the known GSTs. Overall, the data suggest that Synechocystis sll1545 does not belong to any known GST class and represent a novel GST class, which we have named rho. PMID- 27760380 TI - In vitro characterization and endocrine regulation of cholesterol and phospholipid transport in the mammary gland. AB - Cell-based studies previously showed that the ATP-binding cassette transporter A1 (ABCA1) transfers cholesterol across mammary epithelial cells (MEC). Data for phospholipid transport are lacking, and it is unclear from which cellular source the transported cholesterol stems, whether this transport activates signaling pathways, and how lactogenic hormones regulate it. To clarify these aspects, lipid transport and expressional analyses were performed in bovine primary (bMEC) and/or immortalized (MAC-T) MEC cultures. Lipid efflux and ABCA1, ABCG1 and liver X receptoralpha mRNA levels were higher in MAC-T than bMEC. In MAC-T, the transported cholesterol originated mainly from the plasma membrane. ABCA1 dependent cholesterol efflux was higher than phosphatidylcholine efflux, was suppressed by probucol (ABCA1 inhibitor), AG490 (janus kinase-2 inhibitor), PD98059 (mitogen activated protein kinase kinase inhibitor) and pretreatment with beta-cyclodextrin (lowering membrane cholesterol). Insulin was the only hormone significantly increasing cholesterol efflux. In conclusion, this study gives novel mechanistic and regulatory insights into the transport of cholesterol and phospholipids in MEC. PMID- 27760381 TI - High-throughput RNAi screen in Ewing sarcoma cells identifies leucine rich repeats and WD repeat domain containing 1 (LRWD1) as a regulator of EWS-FLI1 driven cell viability. AB - A translocation leading to the formation of an oncogenic EWS-ETS fusion protein defines Ewing sarcoma. The most frequent gene fusion, present in 85 percent of Ewing sarcomas, is EWS-FLI1. Here, a high-throughput RNA interference screen was performed to identify genes whose function is critical for EWS-FLI1 driven cell viability. In total, 6781 genes were targeted by siRNA molecules and the screen was performed both in presence and absence of doxycycline-inducible expression of the EWS-FLI1 shRNA in A673/TR/shEF Ewing sarcoma cells. The Leucine rich repeats and WD repeat Domain containing 1 (LRWD1) targeting siRNA pool was the strongest hit reducing cell viability only in EWS-FLI1 expressing Ewing sarcoma cells. LRWD1 had been previously described as a testis specific gene with only limited information on its function. Analysis of LRWD1 mRNA levels in patient samples indicated that high expression associated with poor overall survival in Ewing sarcoma. Gene ontology analysis of LRWD1 co-expressed genes in Ewing tumors revealed association with DNA replication and analysis of differentially expressed genes in LRWD1 depleted Ewing sarcoma cells indicated a role in connective tissue development and cellular morphogenesis. Moreover, EWS-FLI1 repressed genes with repressive H3K27me3 chromatin marks were highly enriched among LRWD1 target genes in A673/TR/shEF Ewing sarcoma cells, suggesting that LRWD1 contributes to EWS-FLI1 driven transcriptional regulation. Taken together, we have identified LRWD1 as a novel regulator of EWS-FLI1 driven cell viability in A673/TR/shEF Ewing sarcoma cells, shown association between high LRWD1 mRNA expression and aggressive disease and identified processes by which LRWD1 may promote oncogenesis in Ewing sarcoma. PMID- 27760382 TI - Regeneration patterns influence hindlimb automutilation after sciatic nerve repair using stem cells in rats. AB - INTRODUCTION: Hindlimb autophagy is common after rat sciatic total axotomy and is considered as a sign of neuropathic pain. We applied adult stem cells in a fibrin conduit in a total sciatic axotomy model to improve nerve regeneration, investigating whether a correlation could be detected between stem cells effects on regeneration and limb autophagy. MATERIAL AND METHODS: After sciatic nerve section, a 1-cm sciatic gap was crossed using fibrin conduits. Experimental groups included empty fibrin conduits, fibrin conduits seeded with primary Schwann cells, and fibrin conduits seeded with Schwann cell-like differentiated mesenchymal or adipose-derived stem cells (dMSCs and dASCs). Controls were represented by autografts and by sham rats (tot n=34). At 16 weeks post implantation, regeneration pattern was analysed on histological sections and related to eventual autophagy. Hindlimbs were evaluated and scored according to autophagy Wall's scale and X-Rays radiological evaluation. RESULTS: All regenerative cell lines significantly improved myelination at the mid conduit level, compared to the empty tubes. However, dMSC could not significantly improve myelination at the distal stump, showing a more chaotic regeneration compared to both other cells groups and controls. Autophagy was correlated to this regeneration patterns, with higher autophagy scores in the empty and dMSC group. CONCLUSION: Hindlimb autophagy can be used as index of neuropathic pain due to nerve lesion or on-going immature regeneration. dMSC group was characterized by a less targeted regeneration comparing to dASC and primary Schwann cells, which confirmed their effectiveness in regeneration and potential in future clinical applications. PMID- 27760383 TI - BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus. AB - Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP LTD and the cellular mechanisms of memory consolidation. PMID- 27760384 TI - Chronic intermittent hybobaric hypoxia protects against cerebral ischemia via modulation of mitoKATP. AB - OBJECTIVE: Providing adequate protection against cerebral ischemia remains an unrealized goal. The present study was aimed at testing whether chronic intermittent hypobaric hypoxia (CIHH) would have protective effects against cerebral ischemia and investigating the potential role of mitochondrial membrane ATP-sensitive potassium channel (mitoKATP) in this effect. METHODS: Ischemia was induced in rats by occlusion of bilateral common carotid arteries for 8min on day 2 after bilateral vertebral arteries were permanently electrocauterized and CIHH was simulated in a hypoxic chamber. Learning and memory impairments were analyzed using the Morris water maze. The delay neuronal death (DND) in the hippocampus CA1 was observed by thionine staining. The expression of the two subunits of mitoKATP, SUR1 and Kir 6.2, and the concentration of cytochrome c (Cyt c) were observed by Western blotting. The mitochondrial membrane potential (Deltaym) was determined by flow cytometry. Morphological changes of the mitochondria were investigated by electron microscopy. The antagonist of mitoKATP, 5 hydroxydecanoate (5-HD), was used to demonstrate the involvement of mitoKATP. RESULTS: CIHH pretreatment ameliorated the learning and memory impairments produced by ischemia, concomitant with reduced DND in the hippocampus CA1 area. Expression levels of SUR1 and Kir6.2 both increased for at least one week after CIHH pretreatment. Levels of the two subunits were higher in the CIHH pretreatment combined with ischemia group than the ischemia only group at 2 d and 7 d after ischemia. Furthermore, the concentration of Cyt c was decreased in mitochondria and increased in the cytoplasm after ischemia which was prevented by CIHH. The decrease of Deltapsim and the destruction of mitochondrial ultrastructure were both rescued by CIHH pretreatment. The above protective effects of CIHH were blocked by 5-HD intraperitoneal injection 30min before ischemia. CONCLUSION: CIHH pretreatment can reduce cerebral ischemic injury, which is mediated by upregulating the expression and activity of mitoKATP. PMID- 27760374 TI - Metabolism disrupting chemicals and metabolic disorders. AB - The recent epidemics of metabolic diseases, obesity, type 2 diabetes(T2D), liver lipid disorders and metabolic syndrome have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence that other environmental factors may contribute to the rapid increase in the incidence of these metabolic diseases. This review will examine changes to the incidence of obesity, T2D and non-alcoholic fatty liver disease (NAFLD), the contribution of genetics to these disorders and describe the role of the endocrine system in these metabolic disorders. It will then specifically focus on the role of endocrine disrupting chemicals (EDCs) in the etiology of obesity, T2D and NAFLD while finally integrating the information on EDCs on multiple metabolic disorders that could lead to metabolic syndrome. We will specifically examine evidence linking EDC exposures during critical periods of development with metabolic diseases that manifest later in life and across generations. PMID- 27760387 TI - Bacterial lipid diversity. AB - The glycerophospholipids phosphatidylethanolamine, phosphatidylglycerol (PG), and cardiolipin (CL) are major structural components of bacterial membranes. In some bacteria, phosphatidylcholine or phosphatidylinositol and its derivatives form part of the membrane. PG or CL can be modified with the amino acid residues lysine, alanine, or arginine. Diacylglycerol is the lipid anchor from which syntheses of phosphorus-free glycerolipids, such as glycolipids, sulfolipids, or homoserine-derived lipids initiate. Many membrane lipids are subject to turnover and some of them are recycled. Other lipids associated with the membrane include isoprenoids and their derivatives such as hopanoids. Ornithine-containing lipids are widespread in Bacteria but absent in Archaea and Eukarya. Some lipids are probably associated exclusively with the outer membrane of many bacteria, i.e. lipopolysaccharides, sphingolipids, or sulfonolipids. For certain specialized membrane functions, specific lipid structures might be required. Upon cyst formation in Azotobacter vinelandii, phenolic lipids are accumulated in the membrane. Anammox bacteria contain ladderane lipids in the membrane surrounding the anammoxosome organelle, presumably to impede the passage of highly toxic compounds generated during the anammox reaction. Considering that present knowledge on bacterial lipids was obtained from only a few bacterial species, we are probably only starting to unravel the full scale of lipid diversity in bacteria. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 27760385 TI - Recent advances in the development and function of type II spiral ganglion neurons in the mammalian inner ear. AB - In hearing, mechanically sensitive hair cells (HCs) in the cochlea release glutamate onto spiral ganglion neurons (SGNs) to relay auditory information to the central nervous system (CNS). There are two main SGN subtypes, which differ in morphology, number, synaptic targets, innervation patterns and firing properties. About 90-95% of SGNs are the type I SGNs, which make a single bouton connection with inner hair cells (IHCs) and have been well described in the canonical auditory pathway for sound detection. However, less attention has been given to the type II SGNs, which exclusively innervate outer hair cells (OHCs). In this review, we emphasize recent advances in the molecular mechanisms that control how type II SGNs develop and form connections with OHCs, and exciting new insights into the function of type II SGNs. PMID- 27760386 TI - Spatiotemporal expression and transcriptional regulation of heme oxygenase and biliverdin reductase genes in zebrafish (Danio rerio) suggest novel roles during early developmental periods of heightened oxidative stress. AB - Heme oxygenase 1 (HMOX1) degrades heme into biliverdin, which is subsequently converted to bilirubin by biliverdin reductase (BVRa or BVRb) in a manner analogous to the classic anti-oxidant glutathione-recycling pathway. To gain a better understanding of the potential antioxidant roles the BVR enzymes may play during development, the spatiotemporal expression and transcriptional regulation of zebrafish hmox1a, bvra and bvrb were characterized under basal conditions and in response to pro-oxidant exposure. All three genes displayed spatiotemporal expression patterns consistent with classic hematopoietic progenitors during development. Transient knockdown of Nrf2a did not attenuate the ability to detect bvra or bvrb by ISH, or alter spatial expression patterns in response to cadmium exposure. While hmox1a:mCherry fluorescence was documented within the intermediate cell mass, a transient location of primitive erythrocyte differentiation, expression was not fully attenuated in Nrf2a morphants, but real time RT-PCR demonstrated a significant reduction in hmox1a expression. Furthermore, Gata-1 knockdown did not attenuate hmox1a:mCherry fluorescence. However, while there was a complete loss of detection of bvrb expression by ISH at 24hpf, bvra expression was greatly attenuated but still detectable in Gata-1 morphants. In contrast, 96 hpf Gata-1 morphants displayed increased bvra and bvrb expression within hematopoietic tissues. Finally, temporal expression patterns of enzymes involved in the generation and maintenance of NADPH were consistent with known changes in the cellular redox state during early zebrafish development. Together, these data suggest that Gata-1 and Nrf2a play differential roles in regulating the heme degradation enzymes during an early developmental period of heightened cellular stress. PMID- 27760389 TI - Lipopolysaccharide biogenesis and transport at the outer membrane of Gram negative bacteria. AB - The outer membrane (OM) of Gram-negative bacteria is an asymmetric lipid bilayer containing a unique glycolipid, lipopolysaccharide (LPS) in its outer leaflet. LPS molecules confer to the OM peculiar permeability barrier properties enabling Gram-negative bacteria to exclude many toxic compounds, including clinically useful antibiotics, and to survive harsh environments. Transport of LPS poses several problems to the cells due to the amphipatic nature of this molecule. In this review we summarize the current knowledge on the LPS transport machinery, discuss the challenges associated with this process and present the solutions that bacterial cells have evolved to address the problem of LPS transport and assembly at the cell surface. Finally, we discuss how knowledge on LPS biogenesis can be translated for the development of novel antimicrobial therapies. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 27760388 TI - Major roles for minor bacterial lipids identified by mass spectrometry. AB - Mass spectrometry of lipids, especially those isolated from bacteria, has ballooned over the past two decades, affirming in the process the complexity of the lipidome. With this has come the identification of new and interesting lipid structures. Here is an overview of several novel lipids, from both Gram-negative and Gram-positive bacteria with roles in health and disease, whose structural identification was facilitated using mass spectrometry. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 27760390 TI - MS imaging and mass spectrometric synaptosome profiling identify PEP-19/pcp4 as a synaptic molecule involved in spatial learning in mice. AB - The Morris water maze (MWM) spatial learning task has been demonstrated to involve a cognitive switch of action control to serve the transition from an early towards a late learning phase. However, the molecular mechanisms governing this switch are largely unknown. We employed MALDI MS imaging (MSI) to screen for changes in expression of small proteins in brain structures implicated in the different learning phases. We compared mice trained for 3days and 30days in the MWM, reflecting an early and a late learning phase in relation to the acquisition of a spatial learning task. An ion with m/z of 6724, identified as PEP-19/pcp4 by top-down tandem MS, was detected at higher intensity in the dorsal striatum of the late learning phase group compared with the early learning phase group. In addition, mass spectrometric analysis of synaptosomes confirmed the presence of PEP-19/pcp4 at the synapse. PEP-19/pcp4 has previously been identified as a critical determinant of synaptic plasticity in locomotor learning. Our findings extend PEP-19/pcp4 function to spatial learning in the forebrain and put MSI forward as a valid and unbiased research strategy for the discovery and identification of the molecular machinery involved in learning, memory and synaptic plasticity. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 27760392 TI - Nanoscale analysis of degradation processes of cellulose fibers. AB - Mapping the morphological and nano-mechanical properties of cellulose fibers within paper sheets or textile products at the nano-scale level by using atomic force microscopy is a challenging task due to the huge surface level variation of these materials. However this task is fundamental for applications in forensic or cultural heritage sciences and for the industrial characterization of materials. In order to correlate between nano-mechanical properties and local nanometer scale morphology of different layers of cellulose fibers, a new strategy to prepare samples of isolated cellulose fibers was designed. This approach is based on immobilizing isolated fibers onto glass slides chemically pretreated so as to promote cellulose adhesion. The experiments presented here aim at the nano-scale characterization of fibers in paper samples aged under different external agents (relative humidity, temperature) in such a way as to promote hydrolysis and oxidation of polymers. The observed variability of local mechanical properties of paper fibers was related to varying degrees of cellulose polymerization induced by artificial aging. PMID- 27760397 TI - A thermo-degradable hydrogel with light-tunable degradation and drug release. AB - The development of thermo-degradable hydrogels is of great importance in drug delivery. However, it still remains a huge challenge to prepare thermo-degradable hydrogels with inherent degradation, reproducible, repeated and tunable dosing. Here, we reported a thermo-degradable hydrogel that is rapidly degraded above 44 degrees C by a facile chemistry. Besides thermo-degradability, the hydrogel also undergoes rapid photolysis with ultraviolet light. By embedding photothermal nanoparticles or upconversion nanoparticles into the gel, it can release the entrapped cargoes such as dyes, enzymes and anticancer drugs in an on-demand and dose-tunable fashion upon near-infrared light exposure. The smart hydrogel works well both in vitro and in vivo without involving sophisticated syntheses, and is well suited for clinical cancer therapy due to the high transparency and non invasiveness features of near-infrared light. PMID- 27760393 TI - Social networks, social participation, and health among youth living in extreme poverty in rural Malawi. AB - Extensive research documents that social network characteristics affect health, but knowledge of peer networks of youth in Malawi and sub-Saharan Africa is limited. We examine the networks and social participation of youth living in extreme poverty in rural Malawi, using in-depth interviews with 32 youth and caregivers. We describe youth's peer networks and assess how gender and the context of extreme poverty influence their networks and participation, and how their networks influence health. In-school youth had larger, more interactive, and more supportive networks than out-of-school youth, and girls described less social participation and more isolation than boys. Youth exchanged social support and influence within their networks that helped cope with poverty-induced stress and sadness, and encouraged protective sexual health practices. However, poverty hampered their involvement in school, religious schools, and community organizations, directly by denying them required material means, and indirectly by reducing time and emotional resources and creating shame and stigma. Poverty alleviation policy holds promise for improving youth's social wellbeing and mental and physical health by increasing their opportunities to form networks, receive social support, and experience positive influence. PMID- 27760396 TI - A hydrated phospholipid polymer-grafted layer prevents lipid-related oxidative degradation of cross-linked polyethylene. AB - The surface and substrate of a cross-linked polyethylene (CLPE) liner are designed to achieve resistance against oxidative degradation in the construction of hip joint replacements. In this study, we aimed to evaluate the oxidative degradation caused by lipid absorption of a highly hydrophilic nanometer-scaled thickness layer prepared by grafting a poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) layer and a high-dose gamma-ray irradiated CLPE with vitamin E blending (HD-CLPE[VE]). The HD-CLPE(VE) and PMPC-grafted HD-CLPE(VE) exhibited extremely high oxidation resistance regardless of lipid absorption, even though residual-free radical levels were detectable. The water wettability of the PMPC-grafted CLPE and PMPC-grafted HD-CLPE(VE) surfaces was considerably greater than that of untreated surfaces. The hydrated PMPC-grafted layer also exhibited extremely low solubility for squalene. Lipids such as squalene and cholesterol esters diminished the oxidation resistance of CLPE despite the vitamin E improvement. Notably, the PMPC-grafted surface was resistant to lipid absorption and diffusion as well as subsequent lipid-related oxidative degradation, likely because of the presence of the hydrated PMPC-grafted layer. Together, these results provide preliminary evidence that the resistance against lipid absorption and diffusion of a hydrated PMPC-grafted layer might positively affect the extent of resistance to the in vivo oxidation of orthopedic implants. PMID- 27760395 TI - Carbon nanotube electrodes for retinal implants: A study of structural and functional integration over time. AB - The choice of electrode material is of paramount importance in neural prosthetic devices. Electrodes must be biocompatible yet able to sustain repetitive current injections in a highly corrosive environment. We explored the suitability of carbon nanotube (CNT) electrodes to stimulate retinal ganglion cells (RGCs) in a mouse model of outer retinal degeneration. We investigated morphological changes at the bio-hybrid interface and changes in RGC responses to electrical stimulation following prolonged in vitro coupling to CNT electrodes. We observed gradual remodelling of the inner retina to incorporate CNT assemblies. Electrophysiological recordings demonstrate a progressive increase in coupling between RGCs and the CNT electrodes over three days, characterized by a gradual decrease in stimulation thresholds and increase in cellular recruitment. These results provide novel evidence for time-dependent formation of viable bio-hybrids between CNTs and the retina, demonstrating that CNTs are a promising material for inclusion in retinal prosthetic devices. PMID- 27760391 TI - Molecular profiles of thyroid cancer subtypes: Classification based on features of tissue revealed by mass spectrometry imaging. AB - Determination of the specific type of thyroid cancer is crucial for the prognosis and selection of treatment of this malignancy. However, in some cases appropriate classification is not possible based on histopathological features only, and it might be supported by molecular biomarkers. Here we aimed to characterize molecular profiles of different thyroid malignancies using mass spectrometry imaging (MSI) which enables the direct annotation of molecular features with morphological pictures of an analyzed tissue. Fifteen formalin-fixed paraffin embedded tissue specimens corresponding to five major types of thyroid cancer were analyzed by MALDI-MSI after in-situ trypsin digestion, and the possibility of classification based on the results of unsupervised segmentation of MALDI images was tested. Novel method of semi-supervised detection of the cancer region of interest (ROI) was implemented. We found strong separation of medullary cancer from malignancies derived from thyroid epithelium, and separation of anaplastic cancer from differentiated cancers. Reliable classification of medullary and anaplastic cancers using an approach based on automated detection of cancer ROI was validated with independent samples. Moreover, extraction of spectra from tumor areas allowed the detection of molecular components that differentiated follicular cancer and two variants of papillary cancer (classical and follicular). We concluded that MALDI-MSI approach is a promising strategy in the search for biomarkers supporting classification of thyroid malignant tumors. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 27760398 TI - ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals. AB - The accumulation of extracellular amyloid-beta (Abeta) and intracellular neurofibrillary tangles (hyper-phosphorylated Tau) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). Active and passive immunotherapy may limit cerebral Abeta deposition and/or accelerate its clearance. With the aid of a newly characterized monoclonal anti-Abeta antibody we constructed immunoPEGliposomes with high avidity for capturing Abeta in the periphery. The functionality of these vesicles in modulating Abeta uptake by both human brain capillary endothelial hCMEC/D3 cells (suppressing uptake) and THP-1 phagocytes (stimulating uptake) was confirmed in vitro. The multivalent immunoliposomes dramatically reduced circulating and brain levels of Abeta1-40, and particularly Abeta1-42, in "aged" (16 month-old), but not "adult" (10 month old) APP/PS1 transgenic mice on repeated intraperitoneal administration. Furthermore, the immunoPEGliposome-mediated reduction in amyloidosis correlated with lower levels of glial fibrillary acidic protein (GFAP) and reactive glia (GFAP-positive cells). This treatment also lowered the ratio of phosphorylated Tau to total Tau. The therapeutic efficacy of immunoliposome treatment was superior to free monoclonal antibody administration (at an equivalent antibody dose). The potential mechanisms and significance of age-dependent immunoliposome therapy in AD is discussed. PMID- 27760400 TI - Improving simultaneously the quality and safety of cooked and peeled shrimp using a cocktail of bioprotective lactic acid bacteria. AB - Tropical shrimp is of considerable economic importance in the world but is highly perishable due to microbial and chemical degradation. Biopreservation is a food preservation technology based on the addition of "positive" bacteria able to kill or prevent the growth of undesirable microorganisms. Two strains of lactic acid bacteria (LAB) have previously been selected for a biopreservation strategy: Lactococcus piscium CNCM I-4031, for its ability to prevent the sensory deterioration of seafood and Carnobacterium divergens V41, which inhibits growth of Listeria monocytogenes. The objective was to test the association of the two strains to improve both the quality and safety of shrimp. In a first trial, the two LAB were inoculated alone or in a cocktail in cooked and peeled shrimp (CPS) Penaeus vannamei at 5*105CFU/g. Chemical, sensory and microbiological analyses by culture-dependent and -independent methods were performed during storage under modified atmosphere packaging (MAP) at 8 degrees C. The results were compared to a non-inoculated batch. In a second trial, the same experiments were repeated in the presence of 102CFU/g of L. monocytogenes RF191. The microbiota of CPS was composed of LAB, Shewanella spp. and Enterobacteriaceae. Brochothrix thermosphacta was not detected. L. piscium and C. divergens reached 108 and 109CFU/g, respectively, in 7days and did not inhibit each other when co inoculated. L. piscium reduced L. monocytogenes by 1Log (CFU/g) for 28days. C. divergens had an immediate listericidal effect lasting 7days. A regrowth of L. monocytogenes was then observed but the count was always 2 to 5Log (CFU/g) lower than in the control. No additional or synergic effect between protective strains was observed and the cocktail had the same inhibitory effect as C. divergens alone. C. divergens was very effective at preventing the sensory deterioration of CPS. This may be related to the inhibition of Shewanella and Enterobacteriaceae. However, the panelists could detect the presence of C. divergens during the first 10days of storage, with slight unpleasant odors and flavors. L. piscium improved the sensory quality of CPS for 14days only. In co-culture, L. piscium eliminated the off-odors and flavors released by C. divergens in the early stage of storage and the co-culture allowed maintaining a good quality of CPS throughout the storage. Therefore, the use of a cocktail of L. piscium CNCM I-4031 and C. divergens V41 is recommended in a strategy of biopreservation of shrimp. PMID- 27760394 TI - Two benzimidazole resistance-associated SNPs in the isotype-1 beta-tubulin gene predominate in Haemonchus contortus populations from eight regions in China. AB - Haemonchus contortus is one of the most important parasitic nematodes of small ruminants around the world, particularly in tropical and subtropical regions. The control of haemonchosis relies mainly on anthelmintics, but the excessive and prolonged use of anthelmintics is causing serious drug resistance issues in many countries. As benzimidazole (BZ) anthelmintics have been broadly used in China, we hypothesized that resistance is widespread. Given the link between three known single nucleotide polymorphisms (SNPs, designated F167Y, E198A and F200Y) in the isotype-1 beta-tubulin gene and BZ resistance, our goal here was to explore the presence of these mutations in H. contortus from small ruminants (sheep and goats) from eight provinces in China using PCR-coupled sequencing. In addition, the genetic diversity and genetic relationship of isotype-1 beta-tubulin sequence haplotypes were also investigated. Among 192 H. contortus adult individuals representing the eight populations, we identified six distinct sequence types, five of which had SNP E198A (GCA) and/or F200Y (TAC). Sequence analysis showed that the frequencies of SNPs E198A and F200Y were 0-70% and 0-31%, respectively. SNP F167Y (TAC) was not detected in any population. In addition, high haplotype diversities (0.455-0.939) and nucleotide diversities (0.018-0.039) were calculated. A network analysis of the isotype-1 beta-tubulin gene sequences showed that SNPs E198A and F200Y occurred in multiple distinct groupings, suggesting multiple independent origins of these SNPs. The findings of this first study of SNPs in the isotype-1 beta-tubulin gene of H. contortus populations suggest that BZ resistance is prevalent in some regions of China, and that any control strategy might focus on monitoring BZ resistance in this country. PMID- 27760401 TI - Relation of serum homocysteine levels to cerebral artery calcification and atherosclerosis. AB - BACKGROUND AND AIMS: Elevated serum homocysteine level is known to be associated with increased risk of vascular event due to endothelial senescence. We investigated the association between serum homocysteine level and cerebral arteriosclerosis status including intracranial vascular calcification and atherosclerosis burden. METHODS: We identified 1193 consecutive patients (mean age = 68.6 +/- 12.7, 537 female patients) who were admitted with acute cerebral infarction or transient ischemic attack from a single university medical center. The patients were categorized into three groups according to their serum homocysteine level. Cerebral artery calcification was assessed from the cavernous portion of both internal carotid arteries, and cerebral atherosclerosis burden was derived as the sum of stenosis degree of major intracranial arteries from brain computed tomography angiography. RESULTS: The mean homocysteine level was 14.1 +/- 6.2 MUmol/L, and intracranial cerebral artery calcification was present in 974 patients (81.6%), with 339 cases of advanced calcification (28.4%). The prevalence of cerebral artery calcification, advanced cerebral artery calcification and cerebral atherosclerosis burden showed increasing tendency throughout the homocysteine tertiles. Multivariable logistic regression analysis including age, sex, vascular risk factors, serum C-reactive protein, estimated glomerular filtration rate and homocysteine tertile disclosed that the highest serum homocysteine tertile was an independent predictor of advanced cerebral artery calcification (odds ratio = 1.45, confidence interval = 1.02-2.05) and advanced cerebral atherosclerosis (odds ratio = 1.42, confidence interval = 1.01 1.99) compared to the lowest group. CONCLUSIONS: An elevated serum homocysteine level was independently associated with intracranial arterial calcification and atherosclerosis burden. Future studies are warranted to test whether lowering serum homocysteine can delay cerebral arteriosclerotic changes. PMID- 27760402 TI - Short term effects of palm-tocotrienol and palm-carotenes on vascular function and cardiovascular disease risk: A randomised controlled trial. AB - BACKGROUND AND AIMS: In vitro, ex vivo and animal studies suggest palm-based tocotrienols and carotenes enhance vascular function, but limited data in humans exists. The aim was to examine the effects of palm-tocotrienols (TRF- 80) and palm-carotene (CC-60) supplementation on vascular function and cardiovascular disease (CVD) risk factors in adults at increased risk of impaired vascular function. METHODS: Ninety men and women (18-70 yr, 20-45 kg/m2) with type 2 diabetes, impaired fasting glucose and/or elevated waist circumference were randomised to consume either TRF-80 (420 mg/day tocotrienol + 132 mg/day tocopherol), CC-60 (21 mg/day carotenes) or placebo (palm olein) supplements for 8 weeks. Brachial artery flow-mediated dilation (FMD), other physiological and circulatory markers of vascular function, lipid profiles, glucose, insulin and inflammatory markers were assessed pre- and post-supplementation. Pairwise comparisons were performed using mixed effects longitudinal models (n = 87, n = 3 withdrew before study commencement). RESULTS: Plasma alpha- and beta-carotene and alpha-, delta- and gamma-tocotrienol concentrations increased in CC-60 and TRF-80 groups, respectively, compared to placebo (mean +/- SE difference in total plasma carotene change between CC-60 and placebo: 1.5 +/- 0.13 MUg/ml, p < 0.0001; total plasma tocotrienol change between TRF-80 and placebo: 0.36 +/- 0.05 MUg/ml, p < 0.0001). Neither FMD (treatment x time effect for CC-60 vs. placebo, p = 0.71; TRF-80 vs. placebo, p = 0.80) nor any other vascular function and CVD outcomes were affected by treatments. CONCLUSIONS: CC-60 and TRF-80 supplementation increased bioavailability of palm-based carotenes and tocotrienols but had no effects, superior or detrimental, on vascular function or CVD risk factors. PMID- 27760399 TI - Shifts in macrophage phenotype at the biomaterial interface via IL-4 eluting coatings are associated with improved implant integration. AB - The present study tests the hypothesis that transient, early-stage shifts in macrophage polarization at the tissue-implant interface from a pro-inflammatory (M1) to an anti-inflammatory/regulatory (M2) phenotype mitigates the host inflammatory reaction against a non-degradable polypropylene mesh material and improves implant integration downstream. To address this hypothesis, a nanometer thickness coating capable of releasing IL-4 (an M2 polarizing cytokine) from an implant surface at early stages of the host response has been developed. Results of XPS, ATR-FTIR and Alcian blue staining confirmed the presence of a uniform, conformal coating consisting of chitosan and dermatan sulfate. Immunolabeling showed uniform loading of IL-4 throughout the surface of the implant. ELISA assays revealed that the amount and release time of IL-4 from coated implants were tunable based upon the number of coating bilayers and that release followed a power law dependence profile. In-vitro macrophage culture assays showed that implants coated with IL-4 promoted polarization to an M2 phenotype, demonstrating maintenance of IL-4 bioactivity following processing and sterilization. Finally, in-vivo studies showed that mice with IL-4 coated implants had increased percentages of M2 macrophages and decreased percentages of M1 macrophages at the tissue-implant interface during early stages of the host response. These changes were correlated with diminished formation of fibrotic capsule surrounding the implant and improved tissue integration downstream. The results of this study demonstrate a versatile cytokine delivery system for shifting early-stage macrophage polarization at the tissue-implant interface of a non-degradable material and suggest that modulation of the innate immune reaction at early stages of the host response may represent a preferred strategy for promoting biomaterial integration and success. PMID- 27760403 TI - Body dysmorphic disorder symptoms and risk for suicide: The role of depression. AB - Body dysmorphic disorder (BDD) is associated with elevated suicidality. Little is known about why BDD patients are at increased risk. The interpersonal psychological theory of suicide (IPTS) could clarify suicidality in BDD, and theorizes that perceived burdensomeness and thwarted belongingness lead to suicidal desire, while an acquired capability for suicide is necessary to attempt suicide. No study has investigated how BDD symptoms relate to IPTS constructs or mediators of the relationship between BDD and suicidality. Individuals (N=235) enrolled in Amazon.com's Mechanical Turk (MTurk), who had appearance concerns, completed questionnaires about BDD, depression, eating pathology, and suicide risk. MTurk is an online data collection platform in which participants complete surveys for payment. BDD symptoms predicted suicidal desire, but not acquired capability for suicide. Depression mediated the relationship between BDD and suicidal desire. Research should examine how fluctuations in BDD affect suicide risk. Replication in a clinical sample may inform treatments for BDD. PMID- 27760404 TI - An improved non-denaturing method for the purification of spiralin, the main membrane lipoprotein of the pathogenic bacteria Spiroplasma melliferum. AB - Spiralin is the most abundant protein of several species of spiroplasmas, helical, motile bacteria pathogenic for arthropods and plants. This amphiphilic protein is anchored to the outer face of the plasma membrane by a lipoylated N terminal cysteine. Although spiroplasma pathogenicity in mammals is controversial, it was shown that spiralin is highly immunogenic and endowed with immunomodulatory activity. In this paper, we describe a high performance method for the purification of Spiroplasma melliferum spiralin under non-denaturing conditions. The protein was selectively extracted with 3-[(3-cholamidopropyl) dimethylammonio]-1-propyl sulfonate (CHAPS) from the membrane pre-treated with sodium dodecyl-N-sarcosinate (Sarkosyl), and purified to homogeneity by cation exchange HPLC with an overall yield of ~60%. Detergent-depleted, water-soluble micelles of spiralin displaying a mean diameter of 170A, as evidenced by transmission electron microscopy, were obtained by dialysis detergent removal. Circular dichroism spectroscopy and cross immunoprecipitation assay of the purified spiralin strongly suggested that this purification method could retain the structural characteristics of the native spiralin. The strategy developed to purify spiralin (two successive selective extractions of membrane proteins with mild detergents followed by ion-exchange chromatography) should prove useful for the purification of membrane lipoproteins of other bacteria of the class Mollicutes including different pathogens for humans, animals and plants. PMID- 27760405 TI - Rapid identification of bile acids in snake bile using ultrahigh-performance liquid chromatography with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. AB - Snake bile, a precious traditional Chinese medicine (TCM), was used as the major ingredient of some Chinese patent drugs, such as Shedan Chuanbei powder and Shedan Chenpi powder for hundred years. However, there is still requirement for the comprehensive and definite composition of bile acids in snake bile. In order to rapidly identify the bile acids constituents in snake bile to avoid the adulteration, ultrahigh-performance liquid chromatography with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC/ESI-QTOF MS/MS) has been applied to conduct a qualitative analysis on snake bile acids. ESI ion source was used for mass spectra, and data were collected in both positive and negative ion mode. 16 kinds of reference standards, attributed to free bile acids, taurine- and glycine- conjugated bile acids, were detected and their MS behaviors were summarized. In negative ion mode, the diagnostic ions of free bile acids were obtained via the neutral losses of H2O and CO2 molecules; the diagnostic ions of taurine-conjugated bile acids were at m/z 124.0068 ([C2H6NO3S]-), m/z 106.9803 ([C2H3O3S]-) and m/z 79.9568 ([SO3]-); the diagnostic ion of glycine-conjugated bile acids was at m/z 74.0242 ([C2H4NO2]-). In positive ion mode, dehydration ions, amide bond cleavage ions, and reversed Diels-Alder at A-ring ions were detected in every kind of reference. These reference MS behaviors were used for identifying bile acids without reference standards in snake bile. As a result, totally 15 compounds, including 4 pairs of isomers, were identified by comparing the retention time, exact molecular mass and fragmentation behaviors with reference standards, respectively. Tauro 3beta,7alpha,12alpha-trihydroxy-5beta-cholenoic acid, Tauro-?8 3beta,7alpha,12alpha- trihydroxy-5beta-cholenoic acid, Tauro 3alpha,7alpha,12alpha,23R-tetrahydroxy-5beta-cholenoic acid, and Tauro 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholenoic acid, Taurocholic acid, Glycocholic acid, Taurochenodeoxycholic acid, Taurodeoxycholic acid and Cholic acid were detected as the common bile acids in snake bile. Tauro-?8 3beta,7alpha,12alpha-trihydroxy-5beta-cholenoic acid, Tauro 3alpha,7alpha,9alpha,16alpha-tetrahydroxy-5beta-cholenoic acid, Tauro 3alpha,12alpha,17R,22R-tetrahydroxy-5beta-cholenoic acid, and Tauro-?1,8 3beta,7beta,12alpha-trihydroxy-5beta-cholenoic acid were firstly reported in this study. PMID- 27760407 TI - Job demands and driving anger: The roles of emotional exhaustion and work engagement. AB - This study aimed to examine the effects of both hindrance and challenge demands on driving anger within the framework of the job demands-resources (JD-R) model. We collected self-reported data from 411 office workers driving to and from work each day in five cities in China. The results from a structural equation modeling analysis indicated that both hindrance and challenge demands were positively related to emotional exhaustion, which was in turn positively correlated with driving anger. Moreover, work engagement was positively correlated with driving anger. Implications of the present findings regarding both the JD-R model and driving safety research are discussed. PMID- 27760406 TI - Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine. AB - Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism. Metformin treatment alone resulted in significant suppression of ROS and mitochondrial respiration with increased glycolysis accompanied by modest cytotoxicity (10-25%). In contrast, 6-BT monotherapy resulted in inhibition of glucose uptake, decreased glycolysis, and decreased ATP with minimal changes in ROS and mitochondrial respiration. The combination of 6-BT with metformin resulted in significant cytotoxicity (60-70%) in monocytic AML cell lines and was associated with inhibition of FLT3-ITD activated STAT5 and reduced c-Myc and GLUT-1 expression. Therefore, although the anti-tumor and metabolic effects of metformin have been limited by the metabolic reprogramming within cells, the novel combination of 6 BT and metformin targets this bypass mechanism resulting in reduced glycolysis, STAT5 inhibition, and increased cell death. PMID- 27760408 TI - A finite element model of a six-year-old child for simulating pedestrian accidents. AB - Child pedestrian protection deserves more attention in vehicle safety design since they are the most vulnerable road users who face the highest mortality rate. Pediatric Finite Element (FE) models could be used to simulate and understand the pedestrian injury mechanisms during crashes in order to mitigate them. Thus, the objective of the study was to develop a computationally efficient (simplified) six-year-old (6YO-PS) pedestrian FE model and validate it based on the latest published pediatric data. The 6YO-PS FE model was developed by morphing the existing GHBMC adult pedestrian model. Retrospective scan data were used to locally adjust the geometry as needed for accuracy. Component test simulations focused only the lower extremities and pelvis, which are the first body regions impacted during pedestrian accidents. Three-point bending test simulations were performed on the femur and tibia with adult material properties and then updated using child material properties. Pelvis impact and knee bending tests were also simulated. Finally, a series of pediatric Car-to-Pedestrian Collision (CPC) were simulated with pre-impact velocities ranging from 20km/h up to 60km/h. The bone models assigned pediatric material properties showed lower stiffness and a good match in terms of fracture force to the test data (less than 6% error). The pelvis impact force predicted by the child model showed a similar trend with test data. The whole pedestrian model was stable during CPC simulations and predicted common pedestrian injuries. Overall, the 6YO-PS FE model developed in this study showed good biofidelity at component level (lower extremity and pelvis) and stability in CPC simulations. While more validations would improve it, the current model could be used to investigate the lower limb injury mechanisms and in the prediction of the impact parameters as specified in regulatory testing protocols. PMID- 27760409 TI - Incidence and recurrence of common mental disorders after abortion: Results from a prospective cohort study. AB - Research in the field of mental health consequences of abortion is characterized by methodological limitations. We used exact matching on carefully selected confounders in a prospective cohort study of 325 women who had an abortion of an unwanted pregnancy and compared them 1-to-1 to controls who did not have this experience. Outcome measures were incidence and recurrence of common DSM-IV mental disorders (mood, anxiety, substance use disorders, and the aggregate measure 'any mental disorder') as measured with the Composite International Diagnostic Interview (CIDI) version 3.0, in the 2.5-3 years after the abortion. Although non-matched data suggested otherwise, women in the abortion group did not show significantly higher odds for incidence of 'any mental disorder', or mood, anxiety and substance use disorders, compared to matched controls who were similar in background variables but did not have an this experience. Having an abortion did not increase the odds for recurrence of the three disorder categories, but for any mental disorder the higher odds in the abortion group remained significant after matching. It is unlikely that termination of an unwanted pregnancy increases the risk on incidence of common mental disorders in women without a psychiatric history. However, it might increase the risk of recurrence among women with a history of mental disorders. PMID- 27760410 TI - Detection of acidification limit in anaerobic membrane bioreactors at ambient temperature. AB - High-volume, low-strength industrial wastewaters constitute a large potential for biogas production, which could be realized by membrane bioreactors operating at the ambient temperature of the wastewater. However, the start-up of low temperature anaerobic processes using unadapted inoculum can be sensitive to overloading, which results in acidification. This study assessed if a novel acidification limit test can be used to identify stable organic loading rates as well as process over-loading. The test is based on easy-to-apply batch experiments for determination of the hydrolysis rate constant and the specific methanogenic activity of the acetotrophic and hydrogenotrophic pathways. For evaluation, two anaerobic membrane bioreactors, treating synthetic dairy wastewater at an ambient temperature of 24 degrees C, were used with a slow or a rapid start-up regime, respectively. Tests for hydrolysis rate and methanogenic activity were performed throughout the experiment and were used to calculate acidification limits for each system throughout the start-up. The acidification limit test was able to successfully identify both stable operation of one reactor and process failure of the other reactor as the organic loading rate increased. The reactor failure was caused by over-loading the acetotrophic pathway and coincided with microbial changes observed in real-time PCR and moving window analysis. Overall, the acidification limit tests seem promising as an easy applicable method for estimating what organic loading rate can be utilized, without risking acidification of anaerobic systems. PMID- 27760411 TI - Mercury in river, estuarine and seawaters - Is it possible to decrease realist environmental concentrations in order to achieve environmental quality standards? AB - Dithiocarbamate-functionalized magnetite nanoparticles (Fe3O4@SiO2/SiDTC) have been investigated as a convenient and effective sorbent for mercury removal from river, estuarine and sea waters, and their capability to decrease realistic environmental concentrations to the new environmental quality standards was evaluated. The sorption kinetics was well described by the Elovich model and the initial sorption rate was dependent of the sorbent dose. Except for river water sample, the Fe3O4@SiO2/SiDTC particles uptake 99.9% or more of the Hg(II) in the waters (initially at the concentration of 50 MUg/L), allowing to reach residual concentrations lower than the new environmental quality standards (70 ng/L) with only 10 mg/L of sorbent material. The distribution coefficients of mercuric ions between the magnetic particles and the different natural water types were above 103 mL/g for the river water and above 105 mL/g for the estuarine and sea waters. The differences observed between the water types can be attributed to different water composition (effect of the matrix), which plays an important role in the efficiency of the water treatment. PMID- 27760412 TI - Anterior temporal lobectomy for older adults with mesial temporal sclerosis. AB - OBJECTIVE: To compare postoperative seizure-free survival between older and younger adults. METHODS: A retrospective cohort of 107 temporal lobe epilepsy patients with a diagnosis of mesial temporal sclerosis (MTS) received anterior temporal lobectomy (ATL) between 1993 and 2014. We divided the lower three quartiles (younger) and top quartile (older, all 47+ years) of patients, then reviewed patient registry and electronic medical records to determine time to first self-reported seizure after ATL, the primary outcome (mean=3.5years of follow-up, SD=3.6). We also assessed Engel classifications, intraoperative and postoperative treatment complications, and social disability. We used Cox proportional hazard models to assess the association between individual traits and time of seizure recurrence. RESULTS: During follow-up, 35/107 (32.7%) patients had post-operative seizure(s). After adjustment for potential confounders there were no significant differences in the probability of post operative seizures between the older and younger groups, though we had limited precision (hazard ratio of 0.67 [0.28-1.59]), (p=0.36). There were more treatment complications and disability in older patients (18% vs. 1.3% for any complications, 84.62% vs. 58.23% for driving disability, and 84.6% vs. 60.7% for work disability, p<0.05). CONCLUSION: Older patients appear to have more complications after ATL, compared with younger patients. Age, however, does not appear to have a large independent association with seizure recurrence. PMID- 27760413 TI - What is the impact of impaired left ventricular ejection fraction in COPD after adjusting for confounders? AB - BACKGROUND: It remains unknown whether and to what extent impaired left ventricular ejection fraction (LVEF) affects physical and psychological status in COPD. We aimed to compare health outcome measures between COPD patients with and without impaired LVEF after adjusting for age, sex, BMI and FEV1. METHODS: Impaired LVEF was defined as values <50%. 85 COPD patients with impaired LVEF and 85 COPD patients with normal LVEF were matched for sex, age, BMI and FEV1. Exercise capacity, quadriceps muscle function, functional mobility, inflammatory status, health status, care dependency, and mood disorders were cross-sectionally assessed. RESULTS: Patients with impaired LVEF had shorter 6-minute walk distance (mean -59 (95% confidence interval: -94, -25)m), lower symptom-limited peak oxygen uptake (-131 (-268, 7)ml/min), weaker quadriceps muscles (-12 (-20, -3)Nm) and had more symptoms of anxiety (+2 (1, 3) points) and depression (+1 (0, 2) points) than those with normal LVEF (all P<0.05). Health status was not statistically different between groups (P>0.05). CONCLUSIONS: Impaired LVEF has a clear impact on physical and psychological status in patients with COPD, even after adjusting for confounders. This reinforces the importance of assessing and treating cardiac problems in COPD. PMID- 27760415 TI - Multimodality evaluation of percutaneous closure of coronary fistula using AMPLATZER Vascular Plug IV. AB - Congenital coronary-pulmonary fistulas are uncommon coronary anomalies. We present a case of a 63-year-old woman with a tortuous fistula between the proximal left anterior descending and main pulmonary artery which was effectively closed using an AMPLATZER Vascular Plug IV. PMID- 27760414 TI - Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+ release. AB - BACKGROUND: Junctophilin-2 (JPH2) is the primary structural protein for the coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type 2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes (JMCs) in cardiomyocytes. Effective signaling between these channels ensures adequate Ca-induced Ca release required for normal cardiac contractility. Disruption of JMC subcellular domains, a common feature of failing hearts, has been attributed to JPH2 downregulation. Here, we tested the hypothesis that adeno associated virus type 9 (AAV9) mediated overexpression of JPH2 could halt the development of heart failure in a mouse model of transverse aortic constriction (TAC). METHODS AND RESULTS: Following TAC, a progressive decrease in ejection fraction was paralleled by a progressive decrease of cardiac JPH2 levels. AAV9 mediated expression of JPH2 rescued cardiac contractility in mice subjected to TAC. AAV9-JPH2 also preserved T-tubule structure. Moreover, the Ca2+ spark frequency was reduced and the Ca2+ transient amplitude was increased in AAV9-JPH2 mice following TAC, consistent with JPH2-mediated normalization of SR Ca2+ handling. CONCLUSIONS: This study demonstrates that AAV9-mediated JPH2 gene therapy maintained cardiac function in mice with early stage heart failure. Moreover, restoration of JPH2 levels prevented loss of T-tubules and suppressed abnormal SR Ca2+ leak associated with contractile failure following TAC. These findings suggest that targeting JPH2 might be an attractive therapeutic approach for treating pathological cardiac remodeling during heart failure. PMID- 27760416 TI - Stem Cell Models: A Guide to Understand and Mitigate Aging? AB - Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms. PMID- 27760417 TI - Early Carotid Artery Stenting for Cerebral Watershed Infarction Is Safe and Effective: A Retrospective Study. AB - BACKGROUND: With carotid artery stenosis, infarcts can occur in the cortical or internal watershed areas, or both. The timing of carotid artery stenting (CAS) after a cerebral watershed infarction (CWI) is not yet codified. In this retrospective study, we analyzed the safety and clinical effect of early CAS for CWI patients due to carotid artery stenosis. METHODS: Between March 2011 and April 2014, 120 CWI patients with ipsilateral carotid artery stenosis were recruited. Of these 120 patients, 63 received CAS within 7 days of the symptom onset (group 1) and 57 received standard medical treatment at the symptom onset (group 2). Periprocedural complications were analyzed in group 1 to evaluate the safety of early CAS. Clinical effects were analyzed by evaluating National Institutes of Health Stroke Scale (NIHSS) score as well as modified Ranking Scale (mRS) score of pre- and post-treatment in 2 groups. RESULTS: There was no significant difference in pre-treatment NIHSS score between the 2 groups (8.52 +/ 2.46 and 7.84 +/- 2.64, p = 0.15). However, group 1 had lower post-treatment NIHSS score as compared to group 2 (3.03 +/- 1.44 and 3.84 +/- 1.73, p = 0.006). In both groups, NIHSS score after treatment was significantly reduced (p < 0.05). Treatment effect in group 1 was larger compared to group 2 (-5.49 +/- 2.12 and 4.00 +/- 1.98, p < 0.05). Before the treatment, both groups had similar patient numbers with mRS score <=2; however, after 30 days of surgery, group 1 had more number of patients with mRS score <=2 than group 2. CONCLUSION: This study suggested that early CAS for CWI can be performed without significant risk. More importantly, early CAS for CWI can improve the prognosis. PMID- 27760418 TI - 4-Year Trajectory of Visceral Adiposity Index in the Development of Type 2 Diabetes: A Prospective Cohort Study. AB - BACKGROUND/AIMS: Our aim was to evaluate whether visceral adiposity index (VAI) could predict the risk of type 2 diabetes (T2D) in different genders and to compare the predictive ability between VAI and other fatness indices. METHODS: Four thousand seventy-eight participants including 1,817 men and 2,261 women, aged 18 and older and free of T2D at baseline were enrolled in 2010 and followed up for 4 years. New cases of T2D were identified via the annual medical examination. Cox regression analysis was used to assess the association between VAI and incidence of T2D. Receiver operating characteristic curve and area under the curves (AUC) were applied to compare the prediction ability of T2D between VAI and other fatness indices. RESULTS: During the 4-year follow-up, 153 (8.42%) of 1,817 men and 88 (3.89%) of 2,261 women developed T2D. The multivariable adjusted hazards ratios for developing T2D in the highest tertile of VAI scores were 2.854 (95% CI 1.815-4.487) in men and 3.551 (95% CI 1.586-7.955) in women. The AUC of VAI was not higher than that of other fatness indices. CONCLUSIONS: VAI could predict the risk of T2D among Chinese adults, especially in women. However, the prediction ability of T2D risk for VAI was not higher than that of the other fatness indices. PMID- 27760419 TI - Relationship between Anemia and Serum Concentrations of Calcium and Phosphorus in Advanced Non-Dialysis-Dependent Chronic Kidney Disease. AB - BACKGROUND/AIMS: Different biochemical abnormalities of metabolic bone disease have been associated with anemia of chronic kidney disease (CKD), mainly in hemodialysis patients. However, all of these abnormalities are closely inter related and their individual effect on the development of anemia is uncertain. This study was aimed to assess the relationship between anemia and a set of metabolic bone disease biomarkers in a cohort of adult patients with advanced non dialysis-dependent CKD. METHODS: The sample consisted of 382 patients submitted to a Nephrology Unit for evaluation of advanced CKD in a tertiary hospital from Gran Canaria during 3 years. Associations between anemia and serum levels of calcium (albumin-corrected), phosphorus, PTH, 25-hydroxivitamin D (25(OH)D3) and alkaline phosphatase were analyzed by using logistic regression models with adjustment for other demographic, clinical and biochemical covariates potentially related to anemia and to bone mineral metabolism. RESULTS: Serum levels of calcium and 25(OH)D3 (negatively) and phosphorus (positively) were significantly associated with anemia in an unadjusted logistic regression model. In a fully adjusted multivariable model, the OR for anemia was 0.29 (95% CI 0.16-0.49; p < 0.0001) for every 1 mg/dl increase in serum calcium and 2.19 (95% CI 1.55-3.15; p < 0.001) for every 1 mg/dl increase in serum phosphorus. Female sex and lower serum albumin levels were also independently associated with anemia. The inclusion of albumin in the adjusted model displaced the significance of 25(OH)D3. CONCLUSIONS: Circulating levels of calcium and phosphorus are strongly linked to anemia in patients with advanced non-dialysis CKD. PMID- 27760421 TI - Skeletal Muscle Regeneration, Repair and Remodelling in Aging: The Importance of Muscle Stem Cells and Vascularization. AB - Sarcopenia is the age-related loss of skeletal muscle mass and strength. Ultimately, sarcopenia results in the loss of independence, which imposes a large financial burden on healthcare systems worldwide. A critical facet of sarcopenia is the diminished ability for aged muscle to regenerate, repair and remodel. Over the years, research has focused on elucidating underlying mechanisms of sarcopenia and the impaired ability of muscle to respond to stimuli with aging. Muscle-specific stem cells, termed satellite cells (SC), play an important role in maintaining muscle health throughout the lifespan. It is well established that SC are essential in skeletal muscle regeneration, and it has been hypothesized that a reduction and/or dysregulation of the SC pool, may contribute to accelerated loss of skeletal muscle mass that is observed with advancing age. The preservation of skeletal muscle tissue and its ability to respond to stimuli may be impacted by reduced SC content and impaired function observed with aging. Aging is also associated with a reduction in capillarization of skeletal muscle. We have recently demonstrated that the distance between type II fibre-associated SC and capillaries is greater in older compared to younger adults. The greater distance between SC and capillaries in older adults may contribute to the dysregulation in SC activation ultimately impairing muscle's ability to remodel and, in extreme circumstances, regenerate. This viewpoint will highlight the importance of optimal SC activation in addition to skeletal muscle capillarization to maximize the regenerative potential of skeletal muscle in older adults. PMID- 27760422 TI - How We Experience Being Alone: Age Differences in Affective and Biological Correlates of Momentary Solitude. AB - BACKGROUND: Spending time alone constitutes a ubiquitous part of our everyday lives. As we get older, alone time increases. Less is known, however, about age differences in the experience of spending time alone (momentary solitude). OBJECTIVES: We examined time-varying associations between momentary solitude, affect quality, and two hypothalamic-pituitary-adrenal axis activity markers [salivary cortisol; dehydroepiandrosterone sulfate (DHEAs)] to better understand the affective and biological correlates of momentary solitude across the adult life span. METHOD: A total of 185 adults aged 20-81 years (mean age = 49 years, 51% female, 74% Caucasian) completed questionnaires on momentary solitude (alone vs. not alone) and current affect on a handheld device, and provided concurrent saliva samples up to seven times a day for 10 consecutive days. Data were analyzed using multilevel models, controlling for the overall amount of time participants spent alone during the study (overall solitude). RESULTS: Greater overall solitude was associated with decreased average high arousal positive affect and increased average cortisol and DHEAs levels. Momentary solitude was associated with reduced high arousal positive affect, increased low arousal positive affect, and increased low arousal negative affect. Age by momentary solitude interactions indicate that greater age was associated with increased high arousal positive affect and reduced low arousal negative affect during momentary solitude. Furthermore, momentary solitude was associated with increased cortisol and DHEAs. With greater age, the association between momentary solitude and cortisol weakened. CONCLUSION: Consistent with the negative connotations to loneliness and objective social isolation, greater overall solitude was associated with negative affective and biological correlates. Spending a large overall amount of time alone in old age might thus have negative ramifications for health and well-being. Momentary solitude, in contrast, can be a double-edged sword as evidenced by both positive and negative well-being implications. Importantly, greater age is linked to more favorable affective and biological correlates of momentary solitude. The momentary state of spending time alone is thus an experience that is not necessarily negative and that may improve with aging. PMID- 27760420 TI - Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease: Lessons Learned from Taiwanese Data. AB - Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates >=30 instead of our recommended >=45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time. PMID- 27760423 TI - Endosonography of a Pulmonary Artery Obstruction in Echinococcosis. AB - A 44-year-old woman with a history of pulmonary embolism and abdominal echinococcosis complained of sudden thoracic pain and shortness of breath. A D dimer of 77.5 mg/l (reference <=0.5 mg/l) was found. Chest CT scan revealed obstruction of the right lower and middle lobe pulmonary artery (PA). Anticoagulation therapy was initiated for the presumed diagnosis of recurrent pulmonary embolism. However, due to persistent symptoms of dyspnea, follow-up CT angiography of the chest was performed 3 months later. A persistent PA obstruction was found and the presumed diagnosis of embolism was questioned. Subsequently, endobronchial ultrasound (EBUS) imaging was performed to support an alternative diagnosis. EBUS imaging showed an inhomogeneous, sharply demarcated, intravascular lesion with round hypoechoic areas compatible with cysts. The diagnosis of embolism was rejected and treatment with albendazole was initiated for pulmonary echinococcosis. Echinococcosis is a parasitic disease and cystic spread in the PA is exceptional. The patient has remained stable for more than 4 years. In case of disease progression, including progressive PA obstruction or life-threatening hemoptysis, surgical resection will be considered. PMID- 27760424 TI - Renal Arterial Spin Labeling Magnetic Resonance Imaging. AB - Arterial spin labeling (ASL) MRI allows the quantification of tissue perfusion without administration of exogenous contrast agents. Patients with reduced renal function or other contraindications to Gadolinium-based contrast media may benefit from the non-invasive monitoring of tissue microcirculation. So far, only few studies have investigated the sensitivity, the specificity and the reliability of the ASL techniques for the assessment of renal perfusion. Moreover, only little is known about the interplay between ASL markers of perfusion and functional renal filtration parameters. In this editorial, we discuss the main technical issues related to the quantification of renal perfusion by ASL and, in particular, the latest results in patients with kidney disorders. PMID- 27760425 TI - Oxygen Saturation of 75%, but No Symptoms! PMID- 27760426 TI - Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity. AB - Alzheimer's disease (AD) is the most abundant tauopathy and is characterized by Abeta-derived plaques and tau-derived tangles, resulting from the unfolding of the corresponding monomeric subunits into ordered beta-sheet oligomers and fibrils. Intervening in the toxic aggregation process is a promising therapeutic approach, but, to date, a disease-modifying therapy is neither available for AD nor for other tauopathies. Along these lines, we have previously demonstrated that a small naphthoquinone-tryptophan hybrid, termed NQTrp, is an effective modulator of tauopathy in vitro and in vivo. However, NQTrp is difficult to synthesize and is not very stable. Therefore, we tested whether a more stable and easier-to-synthesize modified version of NQTrp, containing a Cl ion, namely Cl NQTrp, is also an effective inhibitor of tau aggregation in vitro and in vivo. Cl NQTrp was previously shown to efficiently inhibit the aggregation of various amyloidogenic proteins and peptides. We demonstrate that Cl-NQTrp inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau, and alleviates tauopathy symptoms in a transgenic Drosophila model through the inhibition of tau aggregation-engendered toxicity. These results suggest that Cl-NQTrp could be a unique potential therapeutic for AD since it targets aggregation of both Abeta and tau. PMID- 27760427 TI - Doxapram Treatment for Apnea of Prematurity: A Systematic Review. AB - BACKGROUND: Apnea of prematurity (AOP) is a common complication of preterm birth, for which caffeine is the first treatment of choice. In case of persistent AOP, doxapram has been advocated as an additional therapy. OBJECTIVE: To identify and appraise all existing evidence regarding efficacy and safety of doxapram use for AOP in infants born before 34 weeks of gestational age. METHODS: All studies reporting on doxapram use for AOP were identified by searching electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research. Two reviewers independently assessed study eligibility and quality, and extracted data on study design, patient characteristics, efficacy and safety outcomes. RESULTS: The randomized controlled trials showed less apnea during doxapram treatment when compared to placebo, but no difference in treatment effect when compared to theophylline. No serious adverse effects were reported. We identified 28 observational studies consisting mainly of cohort studies and case series (n = 1,994). There was considerable heterogeneity in study design and quality. Most studies reported a positive effect of doxapram on apnea rate. A few studies reported on long-term outcomes with conflicting results. A range of possible doxapram-related short-term adverse effects were reported, sometimes associated with the use of higher doses. CONCLUSION: Based on the limited number of studies and level of evidence, no firm conclusions on the efficacy and safety of doxapram in preterm infants can be drawn. For this reason, routine use cannot be recommended. A large multicenter randomized controlled trial is urgently needed to provide more conclusive evidence. PMID- 27760428 TI - Response of the Nitric Oxide System to Hypobaric Hypoxia in the Aged Striatum. AB - BACKGROUND: Nitric oxide (NO) appears to play a key role in the hypoxic injury to the brain. We have previously reported that hypoxia/reoxygenation downregulated NO synthases (NOS) in the adult striatum. Until now, no data were available concerning the influence of aging in conjunction with hypoxia/reoxygenation on the NO system in the striatum. OBJECTIVE: The aim of this study was to assess the role of the NO pathway in the hypoxic aged striatum. METHODS: Wistar rats 24-25 months old were submitted to hypobaric hypoxia (20 min)/reoxygenation (0 h, 24 h, 5 days). Expression (PCR, immunohistochemistry/image analysis) and activity (NADPH-diaphorase/image analysis) of NOS isoforms (neuronal NOS or nNOS, endothelial NOS or eNOS, inducible NOS or iNOS) were analyzed together with nitrated protein expression (immunohistochemistry/image analysis). NO levels were indirectly quantified as nitrates/nitrites (NOx). RESULTS: The mRNA levels of NOS isoforms were undetectable at 0 h after hypoxia in the striatum compared to the control. At later reoxygenation times, nNOS mRNA decreased, while eNOS mRNA augmented. Protein levels of nNOS and eNOS rose at 24 h after hypoxia, and iNOS protein increased at 5 days. NOx levels remained unchanged, whereas in situ NOS activity and protein nitration diminished during reoxygenation in the aged striatum. CONCLUSION: The aged striatum may overexpress NOS isoforms as a neuroprotective-adaptive mechanism to hypoxia. However, this mechanism may not work properly in the aged striatum, since no changes in NO levels were detected after hypoxia. This may be related to the low activity of NOS isoforms in the hypoxic striatum. PMID- 27760429 TI - Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN Negative Frontotemporal Dementia. AB - BACKGROUND AND OBJECTIVE: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. METHODS: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). RESULTS: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. CONCLUSIONS: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations. PMID- 27760430 TI - Can Large Hydatid Cysts Resolve with Medical Treatment Alone? AB - A 66-year-old female from a rural area in South Africa presented with non-life threatening haemoptysis. Radiologic and serological investigations attributed her symptoms to bilateral, large echinococcal cysts. She declined surgery despite her lung physiologic parameters, which deemed her eligible. Medical therapy with oral albendazole was initiated with excellent clinical and radiologic response during a follow-up period of 18 months. To our knowledge, this is one of the first reported cases in the literature that shows complete resolution of bilateral large echinococcal cysts with medical treatment alone in an adult patient. PMID- 27760431 TI - Visual Hallucination and Pattern of Brain Degeneration in Parkinson's Disease. AB - BACKGROUND AND OBJECTIVES: The incidence of visual hallucination (VH) increases with Parkinson's disease (PD) progression, and its development is thought to be related to a specific neurodegenerative process in PD. This study aimed to reveal brain degeneration related to VH in PD by analyzing neuroimaging data obtained from patients in their different stages of PD. METHODS: Data from 48 PD patients 21 nondemented without VH (PNV group), 10 nondemented with VH (PV group), and 17 demented with VH (PVD group) - and 30 age-matched healthy controls (HC group) were analyzed. Voxel-based morphometry and tract-based spatial statistics were conducted. Previous magnetic resonance volumetric studies on VH in PD were collectively reviewed. RESULTS: The PV group showed gray matter atrophy in the right inferior parietal lobule and supramarginal gyrus compared with the HC and PNV groups. The PVD group showed a wider range of gray matter atrophies in the temporo-parieto-occipital regions than those in the PV group. White matter changes seemed to be an earlier event than gray matter changes. Fractional anisotropy values diffusely decreased in all three PD subgroups compared with the HC group without significant differences between the PD subgroups. Mean diffusivity was not different between the PNV and HC groups but increased in the parieto-temporal region in the PV group and increased diffusely in the PVD group, additionally including the fronto-occipital regions. A review of previous studies supported our observations. CONCLUSIONS: Gray matter degenerations from the parieto-temporal junction to the parieto-occipital and temporo-occipital regions may be responsible for VH on the typical timeline of PD progression. PMID- 27760433 TI - Chronic Prostatitis Affects Male Reproductive Health and Is Associated with Systemic and Local Epigenetic Inactivation of C-X-C Motif Chemokine 12 Receptor C X-C Chemokine Receptor Type 4. AB - : Background/Aims/Objectives: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has detrimental effects on the quality of life including the aspect of sexual dysfunction. The aim of the study was to identify if there was an adverse effect on the male genital compartment and if there are systemic or compartment specific local signals for epigenetic dysregulation of inflammatory factors in CP/CPPS patients. METHODS: One hundred five NIH IIIb CP/CPPS patients and 41 healthy men were recruited and underwent investigations of urines, semen and blood. Promoter methylation and expression of the chemokine C-X-C motif chemokine 12 and its receptor C-X-C chemokine receptor type 4 (CXCR4) (involved in the recruitment of mast cells) were analyzed in prostate epithelial cell lines and in healthy volunteers' and patients' blood, ejaculate cell pellets, and separated ejaculate fractions (sperm and seminal somatic cells). RESULTS: Independently from age, CP/CPPS NIH IIIb was associated with significant impairment of sperm motility, morphology and semen pH (p < 0.001). Patients older than 33 years showed significantly increased seminal interleukin-8 and serum prostate specific antigen values. In patients, the CXCR4 mRNA-expression was significantly decreased in whole blood and ejaculate cell pellets due to promoter hypermethylation. Analyses on separated fractions of sperm and seminal somatic cells revealed that sperm DNA was unaffected, whereas somatic cell DNA was differentially methylated. CONCLUSIONS: NIH IIIb CP/CPPS has negative effects on surrogate parameters of male fertility and is associated significantly with systemic and local epigenetic inactivation of CXCR4. PMID- 27760432 TI - The Efficacy of Antimuscarinics Alone or in Combination with Alpha-Blockers for the Treatment of Ureteral Stent-Related Symptoms: A Systematic Review and Meta Analysis. AB - INTRODUCTION AND AIM: The purpose of this meta-analysis was to evaluate the efficacy of antimuscarinics alone or in combination with alpha-blockers for the treatment of ureteral stent-related symptoms. METHODS: The databases MEDLINE, EMBASE, PubMed, the Cochrane Controlled Trial Register of Controlled Trials from 2000 to February 2016 were searched to identify randomized controlled trials that referred to the use of a combination of antimuscarinics and alpha-blockers for the treatment of ureteral stent-related symptoms. A systematic review and meta analysis was conducted. RESULTS: Seven publications involving 710 patients were included in the meta-analysis. In the analysis, we found significantly improved total International Prostate Symptom Score, quality of life, body pain and work performance score of the Ureteral Stent Symptom Questionnaire (USSQ) in the combination group compared with antimuscarinics alone (p = 0.00001, p = 0.00001, p = 0.00001 and p = 0.004, respectively). Antimuscarinics alone versus the control group showed significant improvement in urinary symptom, body pain and general health score of USSQ (p = 0.002, p = 0.00001 and p = 0.003, respectively). CONCLUSIONS: Our meta-analysis shows the beneficial effect of antimuscarinics alone in reducing stent-related symptoms. The combined use of antimuscarinics and alpha-blockers results in additive favorable effects in patients with ureteral stent-related symptoms compared with antimuscarinics monotherapy. The alpha-blockers may enhance the efficacy of the antimuscarinics, which is beneficial for the treatment of ureteral stent-related symptoms. PMID- 27760434 TI - Changes in Retinal Thickness after Vitrectomy for Epiretinal Membrane with and without Internal Limiting Membrane Peeling. AB - PURPOSE: To investigate anatomic changes in retinal thickness (RT) and functional changes after vitrectomy for idiopathic epiretinal membranes (ERMs) with and without internal limiting membrane (ILM) peeling. METHODS: The medical records of 100 eyes of 96 patients with ERM who underwent vitrectomy and ERM removal were reviewed retrospectively. The RT was measured by optical coherence tomography, and the area was divided into 9 sections. The best-corrected visual acuity (BCVA), 9 RT areas, and incidence rates of recurrent ERM were compared between the groups with and without ILM peeling before the operation and 12 months postoperatively. RESULTS: Thirty-nine eyes that underwent vitrectomy with ILM peeling and 61 eyes that underwent vitrectomy without ILM peeling met the inclusion criteria. There were no significant differences between the groups in the BCVA and any of the RTs before the operation and 12 months postoperatively. The ERMs recurred in 8 (20.5%) of 39 eyes and 26 (42.6%) of 61 eyes in the groups with and without ILM peeling, respectively, with a difference that reached significance (p = 0.02) 12 months postoperatively. CONCLUSIONS: Vitrectomy for ERM affects the BCVA or the RTs 12 months postoperatively. Additional ILM peeling does not affect them, but it might reduce the ERM recurrence rate. PMID- 27760435 TI - Cap-assisted forward-viewing endoscopy to visualize the ampulla of Vater and the duodenum in patients with familial adenomatous polyposis. AB - Background and study aims Guidelines recommend surveillance endoscopy with both forward- and side-viewing endoscopes to identify duodenal and ampullary adenomas in patients with familial adenomatous polyposis (FAP). We hypothesized that both the duodenum and the ampulla of Vater can be completely visualized during cap assisted forward-viewing endoscopy. Patients and methods A total of 40 patients with FAP underwent forward-viewing endoscopy with a short cap attached to the tip of the gastroscope, with the aim of visualizing both the duodenum and the ampulla of Vater. If unsuccessful, the procedure was followed by a side-viewing endoscopy. Adverse events were reported. Results The duodenum, including the ampulla of Vater, was completely visualized using the cap in 38/40 patients (95.0 %). The ampulla could not be visualized using the cap in two patients, both of whom underwent additional side-viewing endoscopy, which was successful. No adverse events occurred. Conclusions This study showed that cap-assisted endoscopy can be used effectively and safely to visualize both the duodenum and the ampulla of Vater in patients with FAP. This practice might reduce burden, time, and costs of an additional side-viewing endoscopy. PMID- 27760436 TI - Short-type single-balloon enteroscope-assisted ERCP in postsurgical altered anatomy: potential factors affecting procedural failure. AB - Background and study aims Short-type single-balloon enteroscope (short SBE) assisted endoscopic retrograde cholangiopancreatography (ERCP) is a promising alternative treatment in postsurgical altered anatomy. However, it is technically demanding, and factors affecting its technical difficulty have not yet been clarified. This study aimed to examine the procedural success rate of short SBE assisted ERCP and the potential factors affecting procedural failure. Patients and methods A total of 117 consecutive patients (203 procedures) with surgically altered anatomy underwent ERCP using prototype short SBEs. The procedural success rate of short SBE-assisted ERCP and the potential factors affecting procedural failure were examined retrospectively. Results The enteroscopy success rate and procedural success rate were 92.6 % (95 % confidence interval [CI] 88.1 % - 95.8 %) and 81.8 % (95 %CI 75.8 % - 86.8 %), respectively. Multivariate analyses indicated that pancreatic indication (odds ratio [OR] 4.35, 95 %CI 1.67 - 11.4), first ERCP attempt (OR 6.03, 95 %CI 2.17 - 16.8), and no transparent hood (OR 4.61, 95 %CI 1.48 - 14.3) were potential risk factors for procedural failure. Conclusions Short SBE-assisted ERCP was effective in postsurgical altered anatomy. This large case series suggested the potential factors affecting procedural failure. PMID- 27760437 TI - A novel hemostatic powder for upper gastrointestinal bleeding: a multicenter study (the "GRAPHE" registry). AB - : Background and study aims: The hemostatic powder TC-325 (Hemospray; Cook Medical, Winston-Salem, North Carolina, USA) has shown promising results in the treatment of upper gastrointestinal bleeding (UGIB) in expert centers in pilot studies. The aim of this study was to evaluate the feasibility and efficacy of TC 325 in a large prospective registry of use in routine practice. Patients and methods: The data of all patients treated with TC-325 were prospectively collected through a national registry. Outcomes were the immediate feasibility and efficacy of TC-325 application, as well as the rates of rebleeding at Day 8 and Day 30. Multivariate analysis was performed to determine predictive factors of rebleeding. Results: A total of 202 patients were enrolled and 64 endoscopists participated from 20 centers. TC-325 was used as salvage therapy in 108 patients (53.5 %). The etiology of bleeding was an ulcer in 75 patients (37.1 %), tumor in 61 (30.2 %), postendoscopic therapy in 35 (17.3 %), or other in 31 (15.3 %). Application of the hemostatic powder was found to be very easy or easy in 31.7 % and 55.4 %, respectively. The immediate efficacy rate was 96.5 %. Recurrence of UGIB was noted at Day 8 and Day 30 in 26.7 % and 33.5 %, respectively. Predictive factors of recurrence at Day 8 were melena at initial presentation and use of TC 325 as salvage therapy. Conclusion: These multicenter data confirmed the high rate of immediate hemostasis, excellent feasibility, and good safety profile of TC-325, which could become the treatment of choice in bleeding tumors or postendoscopic bleeding but not in bleeding ulcers where randomized studies are needed. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02595853). PMID- 27760438 TI - White Paper: Radiological Curriculum for Undergraduate Medical Education in Germany. AB - Purpose: Radiology represents a highly relevant part of undergraduate medical education from preclinical studies to subinternship training. It is therefore important to establish a content base for teaching radiology in German Medical Faculties. Materials and Methods: The German Society of Radiology (DRG) developed a model curriculum for radiological teaching at German medical universities, which is presented in this article. There is also a European model curriculum for undergraduate teaching (U-level curriculum of the European Society of Radiology). In a modular concept, the students shall learn important radiological core principles in the realms of knowledge, skills and competences as well as core scientific competences in the imaging sciences. Results: The curriculum is divided into two modules. Module 1 includes principles of radiation biology, radiation protection and imaging technology, imaging anatomy as well as the risks and side effects of radiological methods, procedures and contrast media. This module is modality-oriented. Module 2 comprises radiological diagnostic decision making and imaging-based interventional techniques for various disease entities. This module is organ system-oriented. Conclusion: The curriculum is meant as a living document to be amended and revised at regular intervals. The curriculum can be used as a basis for individual curricular development at German Medical Faculties. It can be integrated into traditional or reformed medical teaching curricula. Key Points: * Radiology is an integral and important part of medical education.* The German Society of Radiology (DRG) developed a model curriculum for teaching radiology at German Medical Faculties to help students develop the ability to make medical decisions based on scientific knowledge and act accordingly.* This curriculum can be used for individual curricular development at medical departments. It is divided into two modules with several chapters. Citation Format: * Ertl-Wagner B, Barkhausen J, Mahnken AH et al. White Paper: Radiological Curriculum for Undergraduate Medical Education in Germany. Fortschr Rontgenstr 2016; 188: 1017 - 1023. PMID- 27760439 TI - Pneumatic Distension of Ventricular Mural Architecture Validated Histologically. AB - Purpose: There are ongoing arguments as to how cardiomyocytes are aggregated together within the ventricular walls. We used pneumatic distension through the coronary arteries to exaggerate the gaps between the aggregated cardiomyocytes, analyzing the pattern revealed using computed tomography, and validating our findings by histology. Methods: We distended 10 porcine hearts, arresting 4 in diastole by infusion of cardioplegic solutions, and 4 in systole by injection of barium chloride. Mural architecture was revealed by computed tomography, measuring also the angulations of the long chains of cardiomyocytes. We prepared the remaining 2 hearts for histology by perfusion with formaldehyde. Results: Increasing pressures of pneumatic distension elongated the ventricular walls, but produced insignificant changes in mural thickness. The distension exaggerated the spaces between the aggregated cardiomyocytes, compartmenting the walls into epicardial, central, and endocardial regions, with a feathered arrangement of transitions between them. Marked variation was noted in the thicknesses of the parts in the different ventricular segments, with no visible anatomical boundaries between them. Measurements of angulations revealed intruding and extruding populations of cardiomyocytes that deviated from a surface-parallel alignment. Scrolling through the stacks of tomographic images revealed marked spiraling of the aggregated cardiomyocytes when traced from base to apex. Conclusion: Our findings call into question the current assumption that cardiomyocytes are uniformly aggregated together in a tangential fashion. There is marked heterogeneity in the architecture of the different ventricular segments, with the aggregated units never extending in a fully transmural fashion. Key Points: * Pneumographic computed tomography reveals an organized structure of the ventricular walls.* Aggregated cardiomyocytes form a structured continuum, with marked regional heterogeneity.* Global ventricular function results from antagonistic forces generated by aggregated cardiomyocytes. Citation Format: * Burg MC, Lunkenheimer P, Niederer P et al. Pneumatic Distension of Ventricular Mural Architecture Validated Histologically. Fortschr Rontgenstr 2016; 188: 1045 - 1053. PMID- 27760441 TI - [Reread: Eduard Zeis, Handbook of Plastic Surgery, Berlin 1838]. PMID- 27760440 TI - Bronchial Artery Embolization in Hemoptysis: 10-Year Survival and Recurrence-Free Survival in Benign and Malignant Etiologies - A Retrospective Study. AB - Purpose: The aim of the study was to evaluate safety, effectiveness, recurrence rate and 10-year survival after bronchial artery embolization (BAE) in benign and malignant etiologies. Methods: The retrospective study includes 100 BAE procedures in 88 patients. Underlying disease was classified as benign (n = 67) and malignant (n = 21) etiologies. Immediate bleeding control and procedure safety were evaluated in all patients. In 51 (58 %) patients, follow-up data with a median follow-up time of 1015 days (range, 494 to 3727 days) were acquired to assess overall survival, time-to-recurrence of bleeding and recurrence-free survival, using Kaplan-Maier estimates to compare differences between both subgroups. Results: Immediate bleeding control was achieved after 96/100 procedures (96 %), with a minor complication rate of 5.0 %. No major complications occurred. The overall survival was 74 % after 1 year and 59 % after 5 years and 10 years. There was a significant difference in survival between the malignant and benign groups (p < 0.0001). Survival was 90 %, 80 % and 76 % at 1 year, 3 years and 10 years, respectively, in the benign group and 18 % and 0 % at 1 year and 3 years, respectively in the malignant group. The median time to recurrence of bleeding and recurrence-free survival were 239 days and 94 % after 1 year and 87 % after 10 years in the benign group, compared to 66 days and 34 % after 1 year and 0 % after 3 years in the malignant group (p = 0.0107). Conclusion: BAE is a safe and highly effective treatment option in hemoptysis. However, the recurrence rate and survival are highly dependent on the underlying disease. Key Points: * BAE is a safe and highly effective treatment option in hemoptysis.* Recurrence rate and survival are strongly dependent on the underlying disease with significantly impaired results in patients with malignant diseases. * Coil embolization is an effective BAE treatment method. Nevertheless, it should be mentioned, that reinterventions can be impeded, if embolization is performed in the proximal part of bronchial arteries. Citation Format: * Syha R, Benz T, Hetzel J et al. Bronchial Artery Embolization in Hemoptysis: 10-Year Survival and Recurrence-Free Survival in Benign and Malignant Etiologies - A Retrospective Study. Fortschr Rontgenstr 2016; 188: 1061 - 1066. PMID- 27760442 TI - Metabolomics-Guided Isolation of Anti-trypanosomal Metabolites from the Endophytic Fungus Lasiodiplodia theobromae. AB - Fungal endophytes offer diverse and unique secondary metabolites, making these organisms potential sources of promising drug leads. The application of high resolution-liquid chromatography mass spectrometry and nuclear magnetic resonance based metabolomics to fungal endophytes is practical in terms of dereplication studies and the mining of bioactive compounds. In this paper, we report the application of metabolomics in parallel with anti-trypanosomal assays to determine the ideal conditions for the medium-scale fermentation of the endophyte Lasiodiplodia theobromae. The 1H NMR comparison between the active versus inactive fractions identified several unique chemical fingerprints belonging to the active fractions. Furthermore, by integrating high-resolution-liquid chromatography mass spectrometry data with multivariate data analysis, such as orthogonal partial least squares-discriminant analysis (OPLS-DA) and the bioactivity results of the fractions of L. theobromae, the anti-trypanosomal agents were easily discerned. With available databases such as Antibase and Dictionary of Natural Products coupled to MZmine through in-house algorithms optimized in our laboratory, the predicted metabolites were readily identified prior to isolation. Fractionation was performed on the active fractions and three known compounds were isolated, namely, cladospirone B, desmethyl-lasiodiplodin, and R-(-)-mellein. Cladospirone B and desmethyl-lasiodiplodin were among the predicted compounds generated by the OPLS-DA S-plot, and these compounds exhibited good activity against Trypanosoma brucei brucei with minimum inhibitory concentrations of 17.8 uM and 22.5 uM, respectively. PMID- 27760443 TI - Saponin Interactions with Model Membrane Systems - Langmuir Monolayer Studies, Hemolysis and Formation of ISCOMs. AB - Saponins are used in medicine due to their pharmacological and immunological effects. To better understand interactions of saponins with model membranes and natural membranes of, for example, erythrocytes, Langmuir film balance experiments are well established. For most saponins, a strong interaction with cholesterol was demonstrated in dependence of both the aglycone part and the sugar moieties and is suggested to be correlated with a strong hemolytic activity, high toxicity, and high surface activity, as was demonstrated for the steroid saponin digitonin. In general, changes in the sugar chain or in substituents of the aglycone result in a modification of the saponin properties. A promising saponin with regard to fairly low hemolytic activity and high adjuvant effect is alpha-tomatine, which still shows a high affinity for cholesterol. An interaction with cholesterol and lipids has also been proven for the Quillaja saponin from the bark of Quillaja saponaria Molina. This triterpene saponin was approved in marketed vaccines as an adjuvant due to the formation of immunostimulating complexes. Immunostimulating complexes consist of a Quillaja saponin, cholesterol, phospholipids, and a corresponding antigen. Recently, another saponin from Quillaja brasiliensis was successfully tested in immunostimulating complexes, too. Based on the results of interaction studies, the formation of drug delivery systems such as immunostimulating complexes or similar self-assembled colloids is postulated for a variety of saponins. PMID- 27760444 TI - [Pathobiology, pathology and genetics of pulmonary hypertension: Recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) are also valid for Germany. While the guidelines contain detailed recommendations regarding clinical aspects of pulmonary arterial hypertension (PAH) and other forms of PH, they contain only a relatively short paragraph on novel findings on the pathobiology, pathology, and genetics. However, these are of great importance for our understanding of this complex disease both from a clinical and scientific point of view, and they are essential for the development of novel treatment strategies. To this end, a number of current data are relevant, prompting a detailed commentary to the guidelines, and the consideration of new scientific data. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the pathobiology, pathology and genetics of PH. This article summarizes the results and recommendations of this working group. PMID- 27760445 TI - [Clinical classification and initial diagnosis of pulmonary hypertension: recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed information about the clinical classification and diagnosis of pulmonary hypertension, and furthermore provide novel recommendations for risk stratification and follow-up assessments. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the clinical classification and initial diagnosis of PH. This article summarizes the results and recommendations of this working group. PMID- 27760446 TI - [Risk stratification and follow-up assessment of patients with pulmonary arterial hypertension: Recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed information about the diagnosis of pulmonary hypertension, and furthermore provide novel recommendations for risk stratification and follow-up assessments. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to risk stratification and follow-up assessment of patients with PAH. This manuscript summarizes the results and recommendations of this working group. PMID- 27760447 TI - [General and supportive therapy of pulmonary arterial hypertension]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for the targeted and supportive treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to general and supportive therapy of PAH. This article summarizes the results and recommendations of this working group. PMID- 27760448 TI - [Targeted therapy of pulmonary arterial hypertension: Recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for the targeted treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the targeted therapy of PAH. This article summarizes the results and recommendations of the working group on targeted treatment of PAH. PMID- 27760449 TI - [Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for the targeted treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the management of decompensated right heart failure, intensive care management and perioperative management in patients with pulmonary hypertension. This article summarizes the results and recommendations of the working group on decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension. PMID- 27760450 TI - [Pulmonary hypertension associated with left heart disease: recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more common forms of PH such as PH due to left heart disease. Despite the lack of data, targeted PAH treatments are increasingly being used for PH associated with left heart disease. This development is of concern because of limited ressources and the need to base treatments on scientific evidence. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease, representing an unmet need of targeted PH therapies. It that sense, the practical implementation of the European Guidelines in Germany requires the consideration of several specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, several working groups were initiated, one of which was specifically dedicated to PH associated with left heart disease. This article summarizes the results and recommendations of this working group. PMID- 27760451 TI - [Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper. PMID- 27760452 TI - [Chronic thromboembolic pulmonary hypertension: Recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH), but also other significant subgroups of pulmonary hypertension (PH). In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). In every patient with PH of unknown cause CTEPH should be excluded. The primary treatment option is surgical pulmonary endarterectomy (PEA) in a specialized multidisciplinary CTEPH center. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. For balloon pulmonary angioplasty (BPA), there is currently only limited experience. This option - as PEA - is reserved to specialized centers with expertise for this treatment method. In addition, a brief overview is given on pulmonary artery sarcoma, since its surgical treatment is often analogous to PEA. The recommendations of this working group are summarized in the present paper. PMID- 27760453 TI - [Pulmonary hypertension in grown-ups with congenital heart disease: Recommendations of the Cologne Consensus Conference 2016]. AB - The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for different forms of PH, and specifically address PH associated with congenital heart disease (CHD). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH in grown-ups with congenital heart disease (GUCH). This article summarizes the results and recommendations of this working group. PMID- 27760454 TI - Bisphosphonate therapy for osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Register: 28 April 2016. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias of the included trials. MAIN RESULTS: Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval 2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One trial compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months. AUTHORS' CONCLUSIONS: Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators. PMID- 27760455 TI - Orphan Adhesion GPCR GPR64/ADGRG2 Is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling. AB - Abnormal feedback of serum calcium to parathyroid hormone (PTH) secretion is the hallmark of primary hyperparathyroidism (PHPT). Although the molecular pathogenesis of parathyroid neoplasia in PHPT has been linked to abnormal expression of genes involved in cell growth (e.g., cyclin D1, retinoblastoma, and beta-catenin), the molecular basis of abnormal calcium sensing by calcium-sensing receptor (CaSR) and PTH hypersecretion in PHPT are incompletely understood. Through gene expression profiling, we discovered that an orphan adhesion G protein-coupled receptor (GPCR), GPR64/ADGRG2, is expressed in human normal parathyroid glands and is overexpressed in parathyroid tumors from patients with PHPT. Using immunohistochemistry, Western blotting, and coimmunoprecipitation, we found that GPR64 is expressed on the cell surface of parathyroid cells, is overexpressed in parathyroid tumors, and physically interacts with the CaSR. By using reporter gene assay and GPCR second messenger readouts we identified Galphas, 3',5'-cyclic adenosine monophosphate (cAMP), protein kinase A, and cAMP response element binding protein (CREB) as the signaling cascade downstream of GPR64. Furthermore, we found that an N-terminally truncated human GPR64 is constitutively active and a 15-amino acid-long peptide C-terminal to the GPCR proteolysis site (GPS) of GPR64 activates this receptor. Functional characterization of GPR64 demonstrated its ability to increase PTH release from human parathyroid cells at a range of calcium concentrations. We discovered that the truncated constitutively active, but not the full-length GPR64 physically interacts with CaSR and attenuates the CaSR-mediated intracellular Ca2+ signaling and cAMP suppression in HEK293 cells. Our results indicate that GPR64 may be a physiologic regulator of PTH release that is dysregulated in parathyroid tumors, and suggest a role for GPR64 in pathologic calcium sensing in PHPT. (c) 2016 American Society for Bone and Mineral Research. PMID- 27760456 TI - DLX3-Dependent Regulation of Ion Transporters and Carbonic Anhydrases is Crucial for Enamel Mineralization. AB - Patients with tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia caused by mutations in the homeodomain transcription factor DLX3, exhibit enamel hypoplasia and hypomineralization. Here we used a conditional knockout mouse model to investigate the developmental and molecular consequences of Dlx3 deletion in the dental epithelium in vivo. Dlx3 deletion in the dental epithelium resulted in the formation of chalky hypomineralized enamel in all teeth. Interestingly, transcriptomic analysis revealed that major enamel matrix proteins and proteases known to be involved in enamel secretion and maturation were not affected significantly by Dlx3 deletion in the enamel organ. In contrast, expression of several ion transporters and carbonic anhydrases known to play an important role in enamel pH regulation during maturation was significantly affected in enamel organs lacking DLX3. Most of these affected genes showed binding of DLX3 to their proximal promoter as evidenced by chromatin immunoprecipitation sequencing (ChIP-seq) analysis on rat enamel organ. These molecular findings were consistent with altered pH staining evidenced by disruption of characteristic pH oscillations in the enamel. Taken together, these results show that DLX3 is indispensable for the regulation of ion transporters and carbonic anhydrases during the maturation stage of amelogenesis, exerting a crucial regulatory function on pH oscillations during enamel mineralization. (c) 2016 American Society for Bone and Mineral Research. PMID- 27760459 TI - Drift tube ion mobility and four-dimensional molecular feature extraction enable data-independent tandem mass spectrometric 'omics' analysis without quadrupole selection. AB - RATIONALE: Quadrupole-based tandem mass spectrometry (MS/MS) plays a critical role in 'omics' studies. However, when a particular m/z precursor is selected by the quadrupole, ions other than the precursor are not transmitted through, and the sensitivity and dynamic range thus diminish. Therefore, separation techniques such as ion mobility (IM) are coupled with MS/MS to improve it. METHODS: In this workflow, every IM-mass spectrometry (MS) scan was followed by one high-voltage collision energy (CE) scan. The precursors were separated in IM drift time and dissociated after IM; the four-dimensional molecular feature extraction (4D MFE) algorithm was used to align the precursors and their MS/MS spectra based on retention time and drift time distribution. A complicated peptide mixture was selected to exemplify the workflow in a proteomics study. RESULTS: The new IM-MS based workflow achieved similar performance in finding proteins compared to the traditional quadrupole-based MS/MS method. However, a significant difference was found between the proteins found by these two methods. For the four concentration levels analyzed, at least 23% more proteins were found by combining the new methods than only using the traditional quadrupole-based MS/MS method. CONCLUSIONS: The established workflow used the 4D MFE algorithm to analyze a complicated 4D dataset and was demonstrated to find more proteins not found by the traditional quadrupole-based MS/MS method in proteomics application. It is thus an important complementary MS/MS mode for 'omics' studies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27760458 TI - Chordomas and chondrosarcomas-The role of radiation therapy. AB - Achieving negative surgical margins can be challenging for skull base and spinal/paraspinal sarcomas. Data shows that pre- or post-operative radiation therapy improves local control. Delivery of sufficient dose of radiation can be difficult because of the proximity to normal organs/tissues that are sensitive to radiation therapy and therefore dose-limiting. A comprehensive literature search was conducted using PubMed search engine. The scarcity of prospective, randomized data limits the ability to generate definitive treatment recommendations. J. Surg. Oncol. 2016;114:564-569. (c) 2016 Wiley Periodicals, Inc. PMID- 27760457 TI - Factors affecting parental decisions to terminate pregnancy in the presence of chromosome abnormalities: a Japanese multicenter study. AB - OBJECTIVE: To investigate the rates of termination of pregnancy (TOP) for fetal chromosomal abnormalities and factors related to such parental decision in Japan. METHODS: A multicenter retrospective cohort study of chromosomal abnormalities diagnosed before 22 weeks of gestation between April 2008 and March 2015. The pregnancy outcomes and parental decisions were investigated. RESULTS: Among 931 fetuses with chromosome abnormalities, the total TOP rate was 75.1% (699/931). TOP rates were 89.3% (585/655) in autosomal aneuploidies and 40.8% (51/125) in sex chromosome aneuploidies. Trisomy 21 showed the highest TOP rate (93.8% [390/416]) followed by trisomy 18 (84.5% [163/193]) and trisomy 13 (71.9% [23/32]). Indications for karyotyping were related to a parental decision for TOP (p < 0.01): in cases of autosomal aneuploidy, with fetal abnormal ultrasound findings as the reference value, diagnoses made following positive results at non invasive prenatal testing (adjusted odds ratio [OR]: 13.7, 95% confidence interval [CI] 4.07-45.9) and those because of advanced maternal age (adj. OR 2.91, 95% CI 1.15-7.35) were significantly more frequent. CONCLUSIONS: In Japan, pregnancies with fetal trisomy 21 are more likely to result in TOP when diagnosed in utero than any other chromosome anomaly. The indications for prenatal karyotyping strongly affect the decision to TOP. (c) 2016 John Wiley & Sons, Ltd. PMID- 27760460 TI - Role of Electrochemistry in Desorption Ionization Mass Spectrometry (LS DESI MS) of Aqueous Samples Containing Electrolyte Salts. AB - The ionization of LS samples in desorption ionization mass spectrometry (LS DESI MS), supplied continuously through a LS interface separated in space from the spray emitter, was investigated in this work. The role of electrochemistry (EC) in the ionization process was addressed. The visual (observation) of the operation of the LS DESI MS system showed a thick spray plume generated by the electrosonic spray ionization (ESSI), forming a liquid cone at the LS interface. When the LS interface was grounded the cone collapsed and the MS ion signal was lost, indicating that the LS was carried to the MS inlet by the spray that emerged from the cone. Ion signals in a new in-line LS DESI MS system, in angled LS DESI MS, and in electrospray ionization (ESI) MS, which produced the most intense ion signals from methanol/water solutions, and in ESSI MS, of dopamine (DA), tyrosine (Tyr) and N,N-dimethyl-p-phenylenediamine (DMPA), were evaluated using methanol/water and aqueous (aq) solutions. In addition, the effect on ion signals of geometric parameters and the LS and the spray solution flow rates was tested in in-line LS DESI MS. Of the methods tested, the analysis of aq LS containing electrolytes was simplest by LS DESI MS. The signal intensity was higher in in-line than in angled LS DESI MS. In online electrochemistry (EC)/LS DESI MS, when 0 V was applied to the EC cell Tyr ion signal was detected only at low pH (2). PMID- 27760461 TI - Fabrication of Helical Nanoribbon Polydiacetylene via Supramolecular Gelation: Circularly Polarized Luminescence and Novel Diagnostic Chiroptical Signals for Sensing. AB - Four kinds of commercially available diacetylene (DA) monomers with different chain length, diacetylene positions were fabricated into the organogels via mixing with a chaperone gelator, an amphiphilic l-histidine ester derivative LHC18 that can help the nongelator to form gels. Upon photo irradiation with a 254 nm UV light, the white gels underwent topochemical reaction and turned into red or blue gels, depending on the DA monomer structures. Through the gel formation, the molecular chirality of LHC18 can be transferred to the polydiacetylene (PDA) and helical nanoribbon structures were obtained. The blue gels showed a clear response to stimuli such as pH variation, heating, mechanical force and organic solvents, and turned into red gels. Interestingly, the blue gel showed strong supramolecular chirality, which could be turned off or changed into red phase CD signals. Such changes in chiroptical signals depended on the external heating and various organic solvents. In the case of heating, the blue gel changed into red one, which showed both strong CD signals and circularly polarized luminescence. In the case of organic solvents, although all the tested solvents made the blue gel to red, only some of them could keep the CD signals, thus providing additional sensing capacity of the PDA system. So far, the blue-to red color change and the "fluorescence on" was widely used as colorimetric and fluorogenic diagnostic signals for PDA, here we showed an additional chiroptical diagnostic signal for a more precise sensing by using the helical PDA. PMID- 27760462 TI - A Trimeric Surfactant: Surface Micelles, Hydration-Lubrication, and Formation of a Stable, Charged Hydrophobic Monolayer. AB - The surface structure of the trimeric surfactant tri(dodecyldimethylammonioacetoxy)diethyltriamine trichloride (DTAD) on mica and the interactions between two such DTAD-coated surfaces were determined using atomic force microscopy and a surface force balance. In an aqueous solution of 3 mM, 5 times the critical aggregation concentration (CAC), the surfaces are coated with wormlike micelles or hemimicelles and larger (~80 nm) bilayer vesicles. Repulsive normal interactions between the surfaces indicate a net surface charge and a solution concentration of ions close to that expected from the CAC. Moreover, this surface coating is strongly lubricating up to some tens of atmospheres, attributed to the hydration-lubrication mechanism acting at the exposed, highly hydrated surfactant headgroups. Upon replacement of the DTAD solution with surfactant-free water, the surface structures have changed on the DTAD monolayers, which then jump into adhesive contact on approach, both in water and following addition of 0.1 M NaNO3. This trimeric surfactant monolayer, which is highly hydrophobic, is found to be positively charged, which is evident from the attraction between the DTAD monolayer and negatively charged bare mica across water. These monolayers are stable over days even under a salt solution. The stability is attributed to the several stabilization pathways available to DTAD on the mica surface. PMID- 27760463 TI - Mycobacterium tuberculosis Infection Manipulates the Glycosylation Machinery and the N-Glycoproteome of Human Macrophages and Their Microparticles. AB - Tuberculosis (TB) remains a prevalent and lethal infectious disease. The glycobiology associated with Mycobacterium tuberculosis infection of frontline alveolar macrophages is still unresolved. Herein, we investigated the regulation of protein N-glycosylation in human macrophages and their secreted microparticles (MPs) used for intercellular communication upon M. tb infection. LC-MS/MS-based proteomics and glycomics were performed to monitor the regulation of glycosylation enzymes and receptors and the N-glycome in in vitro-differentiated macrophages and in isolated MPs upon M. tb infection. Infection promoted a dramatic regulation of the macrophage proteome. Most notably, significant infection-dependent down-regulation (4-26 fold) of 11 lysosomal exoglycosidases, e.g., beta-galactosidase, beta-hexosaminidases and alpha-/beta-mannosidases, was observed. Relative weak infection-driven transcriptional regulation of these exoglycosidases and a stronger augmentation of the extracellular hexosaminidase activity demonstrated that the lysosome-centric changes may originate predominantly from infection-induced secretion of the lysosomal content. The macrophages showed heterogeneous N-glycan profiles and displayed significant up regulation of complex-type glycosylation and concomitant down-regulation of paucimannosylation upon infection. Complementary intact N-glycopeptide analysis supported a subcellular-specific manipulation of the glycosylation machinery and altered glycosylation patterns of lysosomal N-glycoproteins within infected macrophages. Interestingly, the corresponding macrophage-derived MPs displayed unique N-glycome and proteome signatures supporting a preferential packaging from plasma membranes. The MPs were devoid of infection-dependent N-glycosylation signatures, but interestingly displayed increased levels of the glyco-initiating oligosaccharyltransferase complex and associated alpha-glucosidases that correlated with increased formation, N-glycan precursor levels and N-glycan density of infected MPs. In conclusion, this system-wide study provides new insight into the host- and pathogen-driven N-glycoproteome manipulation of macrophages in TB. PMID- 27760465 TI - Spotlights: Volume 7, Issue 20. PMID- 27760466 TI - Clinical analysis and treatment of symptomatic intracranial hemorrhage after deep brain stimulation surgery. AB - BACKGROUND: Symptomatic intracranial hemorrhage (ICH) may lead to permanent neurological disability of patients and has impeded the extensive clinical application of deep brain stimulation (DBS). The present study was conducted to discuss the incidence, prevention, and treatment of symptomatic ICH after DBS surgery. METHODS: From January 2009 to December 2014, 396 patients underwent DBS with a total of 691 implanted leads. In all, 10 patients had symptomatic ICH. We analyzed these cases' clinical characteristics, including comorbid diagnoses and coagulation profile. We described the onset of ICH, imaging features, clinical manifestations, treatment, neurological impairment, and outcome of DBS. RESULTS: Of the 10 patients with symptomatic ICH, 2 had hypertension. Three cases of ICH occurred within 12 h of the procedure; four cases within 24 h. Five experienced grand mal seizures concurrently with hemorrhage. Unilateral frontal lobe hemorrhage occurred in all cases. In seven cases, hematomas occurred around the electrodes. Some hematomas were not well-circumscribed and had perihematomal edema. Conservative therapy was administered to 8 patients, and 2 patients underwent craniotomy and hematoma evacuation. All electrodes were successfully preserved. Neurological dysfunction in all patients gradually improved. Nine patients ultimately experienced effective symptom relief of Parkinson's disease with DBS. CONCLUSIONS: Symptomatic ICH should be identified as soon as possible after implantation surgery and treated effectively to limit neurological deficit and preserve DBS leads. PMID- 27760468 TI - Corrigendum. PMID- 27760464 TI - Characterization of Site-Specific N-Glycopeptide Isoforms of alpha-1-Acid Glycoprotein from an Interlaboratory Study Using LC-MS/MS. AB - Glycoprotein conformations are complex and heterogeneous. Currently, site specific characterization of glycopeptides is a challenge. We sought to establish an efficient method of N-glycoprotein characterization using mass spectrometry (MS). Using alpha-1-acid glycoprotein (AGP) as a model N-glycoprotein, we identified its tryptic N-glycopeptides and examined the data reproducibility in seven laboratories running different LC-MS/MS platforms. We used three test samples and one blind sample to evaluate instrument performance with entire sample preparation workflow. 165 site-specific N-glycopeptides representative of all N-glycosylation sites were identified from AGP 1 and AGP 2 isoforms. The glycopeptide fragmentations by collision-induced dissociation or higher-energy collisional dissociation (HCD) varied based on the MS analyzer. Orbitrap Elite identified the greatest number of AGP N-glycopeptides, followed by Triple TOF and Q-Exactive Plus. Reproducible generation of oxonium ions, glycan-cleaved glycopeptide fragment ions, and peptide backbone fragment ions was essential for successful identification. Laboratory proficiency affected the number of identified N-glycopeptides. The relative quantities of the 10 major N glycopeptide isoforms of AGP detected in four laboratories were compared to assess reproducibility. Quantitative analysis showed that the coefficient of variation was <25% for all test samples. Our analytical protocol yielded identification and quantification of site-specific N-glycopeptide isoforms of AGP from control and disease plasma sample. PMID- 27760467 TI - Surgical management of acute subdural haematomas in elderly: report of a single center experience. AB - OBJECTIVE: To evaluate the clinical outcome of patients over 70 years old who have received surgical treatment for traumatic acute subdural haematoma (aSDH) in our Neurosurgical Department. We also disclose related surgical and medical costs. METHODS: A retrospective analysis was performed by analyzing the medical records of patients older than 70 who had undergone surgery for evacuation of traumatic aSDH between June 2011 and December 2014. Through univariate and multivariate analyses, we correlated clinical and radiological pre-operatory features with outcome at one and six months after surgery. Overall costs for each patient were recorded. RESULTS: We observed 67 patients, 36 male and 31 female, with a median age of 80.5 years old (range 71-94). The mortality rate at one month and six months after surgery was respectively 55.1% and 67.2% while functional recovery was respectively 10.4% and 13.4%. Multivariate analysis age and Glasgow Coma Score (GCS) are the most significant parameters in relation to clinical outcome. Age greater than 90, shift midline >20 mm and volume of the haematoma >200 cu cm were independent parameters to predict mortality within 10 days of surgery. CONCLUSION: Our study confirms a poor outcome for patients of 70 years and over who received surgical treatment for traumatic aSDH. PMID- 27760469 TI - Male labor migration, patriarchy, and the awareness-behavior gap: HIV risks and prevention among migrants' wives in Armenia. AB - Unlike in most of the world, HIV incidence in the former Soviet Union continues to rise. While international labor migration has been identified as a potentially important contributor to this trend, most attention has been focused on risks of male migrants themselves. This study uses recent household survey data to examine HIV-related perceptions and actions of migrants' left-behind wives in Armenia. Multivariate logistic regression analyses show that migrants' wives are significantly more likely to suspect their husbands of extramarital sex than are non-migrants' wives. The analyses detect greater worries about HIV infection and a higher likelihood of spousal communication on HIV matters among migrants' wives, compared to non-migrants' wives, but these differences are largely explained by the suspicion of husband's extramarital sex. Finally, no difference between the two categories of women in the probability of consistent condom use with husbands is found. These findings are interpreted within the context of patriarchal culture and unequal gender relations in Armenian society as they are further reinforced by male migration. Implications of these findings for policies to increase women's awareness of HIV risks associated with migration and their ability to reduce those risks are discussed. PMID- 27760470 TI - Testing times: identifying puberty in an identified skeletal sample. AB - BACKGROUND: Identifying the onset of puberty in skeletal remains can provide evidence of social changes associated with the onset of adulthood. AIM: This paper presents the first test of a skeletal method for identifying stages of development associated with the onset of puberty in a skeletal sample of known age and cause of death. MATERIALS AND METHODS: Skeletal methods for assessing skeletal development associated with changes associated with puberty were recorded in the identified skeletal collection in Coimbra, Portugal. Historical data on the onset of menarche in this country are used to test the method. RESULTS: As expected, females mature faster than their male counterparts. There is some side asymmetry in development. Menarche was found to have been achieved by an average age of 15. CONCLUSIONS: Asymmetry must be taken into account when dealing with partially preserved skeletons. Age of menarche is consistent, although marginally higher, than the age expected based on historical data for this time and location. Skeletal development in males could not be tested against historical data, due to the lack of counterpart historical data. The ill health known to be present in this prematurely deceased population may have delayed skeletal development and the onset of puberty. PMID- 27760471 TI - Effect of different cooking methods on nutritional value and antioxidant activity of cultivated mushrooms. AB - Influence of culinary treatments (boiling, microwaving, grilling, and deep frying) on proximate composition and antioxidant capacity of cultivated mushrooms (Agaricus bisporus, Lentinula edodes, Pleurotus ostreatus, and Pleurotus eryngii) was studied. Proximate composition was affected by the cooking method and the mushrooms species. Frying induced more severe losses in protein, ash, and carbohydrates content but increased the fat and energy. Boiling improved the total glucans content by enhancing the beta-glucans fraction. A significant decrease was detected in the antioxidant activity especially after boiling and frying, while grilled and microwaved mushrooms reached higher values of antioxidant activity. Maillard reaction products could be partially responsible, as supported by the absorbance values measured at 420 nm. Since cooking techniques clearly influence the nutritional attributes of mushrooms, the proper selection of treatments is a key factor to prevent/reduce nutritional losses. Microwaving and grilling were established as the best processes to maintain the nutritional profile of mushrooms. PMID- 27760472 TI - Temporal trends for pregnancy length in a hospital setting of Southern Spain. AB - For centuries it has been considered that the due date for delivery in our species is 280 days after the onset of the last menstruation. However, in most cases this statement is not accurate. The main objective of this study was to determine the mean duration of pregnancy in our setting and whether it has experienced changes in recent years. A retrospective, population-based descriptive study was made of 102,169 deliveries assisted in Malaga University Hospital (Malaga, Andalusia, Spain) during the period 1998-2015. The mean gestational age at delivery was 269 days (SD 16 days), with a modal gestational age of 273 days. The mean duration of the singleton and multiple pregnancies was 271 days (SD 17 days) and 242 days (SD 20 days), respectively. A significant shortening of the duration of pregnancy was observed in the course of the study period. PMID- 27760473 TI - Candida chorioamnionitis: Report of two cases and review of literature. PMID- 27760474 TI - Maternal serum vitamin D levels and pregnancy outcomes: from Lagos, Nigeria. AB - In an attempt to investigate the effect of vitamin D deficiency on pregnancy complications including caesarean section and foetal outcome in our population, blood samples of 461 pregnant women who attended antenatal booking clinic between 10 and 28 weeks of pregnancy were taken for vitamin D estimation and followed up. Details concerning pregnancy complications, labour and foetal outcome were obtained after delivery. They were divided into three groups according to the serum vitamin D level: group 1 (0-20)ng/ml (deficiency), group 2 (21-30)ng/ml (insufficiency), and group 3 (more than 30 mg/ml) normal. The prevalence of vitamin D deficiency was 29%. There were no differences between the groups regarding complications during pregnancy, including preeclampsia and rate of caesarean section. A multicenter study was advocated to elucidate further the role of vitamin D during pregnancy in our population. PMID- 27760475 TI - An unusual cause of sciatica. PMID- 27760476 TI - Robust Wavelet Stabilized 'Footprints of Uncertainty' for Fuzzy System Classifiers to Automatically Detect Sharp Waves in the EEG after Hypoxia Ischemia. AB - Currently, there are no developed methods to detect sharp wave transients that exist in the latent phase after hypoxia-ischemia (HI) in the electroencephalogram (EEG) in order to determine if these micro-scale transients are potential biomarkers of HI. A major issue with sharp waves in the HI-EEG is that they possess a large variability in their sharp wave profile making it difficult to build a compact 'footprint of uncertainty' (FOU) required for ideal performance of a Type-2 fuzzy logic system (FLS) classifier. In this paper, we develop a novel computational EEG analysis method to robustly detect sharp waves using over 30[Formula: see text]h of post occlusion HI-EEG from an equivalent, in utero, preterm fetal sheep model cohort. We demonstrate that initial wavelet transform (WT) of the sharp waves stabilizes the variation in their profile and thus permits a highly compact FOU to be built, hence, optimizing the performance of a Type-2 FLS. We demonstrate that this method leads to higher overall performance of [Formula: see text] for the clinical [Formula: see text] sampled EEG and [Formula: see text] for the high resolution [Formula: see text] sampled EEG that is improved upon over conventional standard wavelet [Formula: see text] and [Formula: see text], respectively, and fuzzy approaches [Formula: see text] and [Formula: see text], respectively, when performed in isolation. PMID- 27760477 TI - The Nottingham Expectation and Complication score following Surgery (NECS): an universal scale for surgical outcome audit and peer comparison. AB - BACKGROUND: Consultant Outcomes Publication (COP) is an NHS England initiative for promoting improvements in quality of care. However, at present outcomes are commonly expressed as mortality rates which do not necessarily reflect the performance of surgeons. We developed the Nottingham Expectation and Complication score following Surgery (NECS) to determine the success of surgical treatment from both the clinical perspective and the practical expectations agreed between surgeons and patients during the consent process. METHOD: This was a pilot study to trial the use of the NECS score. It is a simple expression of overall outcome comprising three clinical domains: S - surgical outcome, T - surgical/technical complications and M - medical complications recorded by the treating clinician, and practical outcome determined by a joint clinical/patient assessment. 107 elective neurosurgical patients were included in this prospective study. 95 completed questionnaires were included. RESULTS: 75% patients achieved the best possible treatment score (S3T3M4). Of the 25% of patients who did not achieve this ideal outcome, the most common cause was either medical deterioration 18%, or technical complications of surgery discussed during the consent process 17%, or both. Surgeons rated their outcomes as expectations exceeded in 2% of cases, met in 92%, partially met in 5% and failed in 1%. Patients rated their outcomes as expectations exceeded in 37%, met in 37%, partially met in 18%, and 5% reported that their expectations were not met or they were worse than before the operation. Bivariate correlation analysis (Pearson's r coefficient) between overall 'expectation score' of patients and surgeons showed moderate correlation with r = .25 (p = .014). CONCLUSION: NECS score can be used as an indicator to assess technical performance and patient satisfaction. It provides a more balanced quality indicator of the surgical service delivery than COP. It also offers additional advantages for auditing/planning improving care and may serve as an appraisal/revalidation tool. PMID- 27760478 TI - Prevalence of hypothyroidism during pregnancy in a highly specialised referral centre in Mexico. AB - In order to determine the prevalence of overt and subclinical hypothyroidism, and isolated hypothyroxinemia during pregnancy, thyroid hormone reference values established by UMAE HGO4, IMSS in Mexico City and those suggested by the American Thyroid Association (ATA) were used. All pregnant patients, whose thyroid function was measured and whose pregnancy was monitored and resolved in UMAE HGO4, IMSS from 1 January to 31 December 2013, were included. Significant differences (p = .00419) were observed in the frequency of subclinical hypothyroidism, being higher when using ATA criteria (18.21% vs. 9.66%). The prevalence rate (UMAE HGO4 vs. ATA) for overt hypothyroidism was 1.11 vs. 1.63, for subclinical hypothyroidism 0.84 vs. 1.41 and for isolated hypothyroxinemia 3.17 vs. 2.79 per 1000 consults during the study period. Independently of prevalence rate, it is essential to provide information on the possible risks involved in pregnancy to all women of childbearing age at the time of hypothyroidism diagnosis. PMID- 27760479 TI - Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories. AB - Levetiracetam may induce serious behavioral disturbances, especially after surgical resection of frontal lobe low-grade glioma. Two patients, treated with levetiracetam, developed serious psychiatric complications postoperatively which completely resolved after switching to valproate. We aim to create awareness for this serious but reversible adverse effect of levetiracetam in this specific patient category. PMID- 27760480 TI - Body mass index is linked to cervical length and duration of pregnancy: An observational study in low risk pregnancy. AB - In this prospective cohort study, one hundred participants were allocated into four groups according to their body mass indices. Vaginal ultrasound was performed at enrolment to measure cervical length. The shortest cervical measurement was recorded. Overweight and obese groups had significantly longer mean cervical length than women in the normal weight group when measured at 20-22 weeks of gestation (p < .001). Underweight women had the shortest mean cervical length. The incidence of preterm delivery was the highest in underweight women (RR; 1.5). The incidence of post-term delivery was 10% in total in overweight and obese women. Underweight women were more likely to have short cervical length and subsequent preterm delivery compared to overweight and obese women. PMID- 27760481 TI - Is progestogen supplementation necessary to prevent abortion? AB - A prospective study was conducted to evaluate the effect of progestogens on the pregnancy outcome of threatened abortion (TA). A total of 251 pregnant women less than 20 weeks of gestational age (GA) were included. Group 1 consisted of women with vaginal bleeding who had already been under treatment with progestogens and Group 2 was composed of women with vaginal bleeding who were only followed without progestogen therapy, whereas Group 3 was the control group without any vaginal bleeding or progestogen therapy. The pregnancy outcomes and serum progesterone levels were compared among the groups. The mean serum progesterone concentrations were statistically significantly higher in Group 1 in comparison to Group 2 and 3 (p < 0.001). Abortion rates were similar among the study groups. Although progestogen supplementation leads to increased level of serum progesterone, this finding does not translate to its beneficial effect on the pregnancy outcomes in cases of TAs. PMID- 27760482 TI - Clot behind the blood: Cerebral vein thrombosis presenting with subarachnoid haemorrhage in a 28-week pregnant woman. PMID- 27760483 TI - Management of gynaecologic plasmacytoma: A review article. AB - In contrast to multiple myeloma (MM) which exhibits diffuse bone marrow and other organ involvement, solitary plasmacytomas carry a favourable prognosis. Extramedullary plasmacytomas (EMP) are a unique form of plasma cell neoplasms. These tumours are rare in the female reproductive tract. Only 24 cases of gynaecologic plasmacytomas were reported to date (7 cases were solitary plasmacytomas and 17 cases were either part of disseminated MM with involvement of a gynaecologic organ or were lacking complete work-up to rule out MM). The standard care of gynaecologic solitary EMP is surgical resection alone when feasible. Adjuvant radiation therapy may be considered for adverse prognostic factors such as positive resection margins. MM with gynaecologic organ involvement should be managed with systemic therapy and defer local therapies to symptomatic progression. PMID- 27760484 TI - Electrophysiological/sonographic mapping of the superficial peroneal nerve to facilitate biopsy under local anaesthesia. AB - The anatomical surface markings for the superficial peroneal nerve have been described and it may be preferred for biopsy in cases of suspected vasculitis as biopsy of the peroneus brevis muscle increases diagnostic yield. The procedure is however unfamiliar to many surgeons and the anatomical variability of the subcutaneous part underestimated. Where the nerve has some preserved sensory nerve action potential it may be mapped pre-operatively, greatly facilitating minimally traumatic biopsy with potential logistical and wound healing advantages. We review the literature relating to the anatomical course of the nerve and present a case illustrating the advantages of pre-operative mapping, given its location in the anterior compartment of the leg 26% of the time. PMID- 27760485 TI - Leukemia inhibitory factor stimulates steroidogenesis of rat immature Leydig cells via increasing the expression of steroidogenic acute regulatory protein. AB - Leukemia inhibitory factor (LIF) has many physiological roles. However, its effects on Leydig cell development are still unclear. Rat immature and adult Leydig cells were cultured with different concentrations of LIF alone or in combination with luteinizing hormone (LH) for 24 h. LIF (1 and 10 ng/ml) significantly increased androgen production in immature Leydig cells, but had no effects on testosterone production in adult Leydig cells. Further studies revealed that LIF dose-dependently increased Star and Hsd17b3 expression levels in immature Leydig cells. Gene microarray revealed that the upregulation of anti oxidative genes and Star might contribute to LIF-induced androgen production. In conclusion, LIF has stimulatory effects on androgen production in rat immature Leydig cells. PMID- 27760486 TI - Micro RNA-320 as a novel potential biomarker in renal ischemia reperfusion. AB - AIM: MicroRNAs (miR) are important diagnostic and treatment targets due to their different tissue expressions and their central position in the regulation of gene expressions. miR studies might pioneer emerging of new diagnostic tools and treatment goals in kidney diseases. Captopril (CAP) and telmisartan (TEL) were shown to be effective in ischemia reperfusion (IR) injury. There is not any study about the effect of TEL and CAP over miR-21-320-146a. Our aim was to study the effects of CAP and TEL over miR on renal IR model. METHODS: We used 12-16 weeks old Wistar-Albino rats that weigh 300-350 g. Rats (n, 6) were randomized into four groups (Control, IR, IR + CAP, IR + TEL). Urea, creatinine, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), super oxide dismutase (SOD), and miRs were analyzed. RESULTS: Urea, creatinine, TOS, OSI levels of IR + CAP, and IR + TEL groups were lower comparing to IR group. TAS and SOD levels were higher in IR group than IR + TEL group. miR 21-320-146a showed increase in renal IR injury. miR-320, 146a showed significant decrease in IR + CAP and IR + TEL groups comparing to IR group. We showed histopathological recovery and decreased apoptosis in IR + CAP and IR + T groups than IR group. CONCLUSION: We, for the first time in the literature, showed that miR-320 is increased in IR injury. miR-320 might be a novel diagnosis and treatment target in renal ischemic reperfusion injury. Also, for the first time, we showed that CAP and TEL cause functional and histopathological recovery and lower miR-146a and miR-320. PMID- 27760487 TI - Primary Sjogren's syndrome impact on smell, taste, sexuality and quality of life in female patients: A systematic review and meta-analysis. AB - OBJECTIVES: The aim of this study is to assess the impact of dryness caused by primary Sjogren's Syndrome (pSS) on smell, taste and sexual function in female patients, and its influence on quality of life. METHODS: Electronic databases including MEDLINE via Ovid, Web of Science, SCOUPUS, EMBASE and COCHRANE LIBRARY were searched until April 2016. Studies that assessed the function of smell, taste and sexuality in pSS patients, defined by the American European Consensus Group (AECG) criteria. Standardized mean differences (SMD) for individual studies using random-effects meta-analysis were feasible. RESULTS: Five studies incorporated 378 participants were included in the quantitative synthesis. The impact of pSS vs. healthy controls was: smell SMD -0.78 (95% CI -1.29 to -0.27); taste SMD -1.01 (95% CI -1.54 to -0.49); total sexual function SMD -0.93 (95% CI 1.22 to -0.64); physical and mental component of the quality of life SMD -1.28 (95% CI -1.65 to -0.90) and SMD -0.83 (95% CI -1.27 to -0.40) respectively; anxiety and depression SMD 0.61 (95% CI 0.02, 1.20) and SMD 0.79 (95% CI 0.43 to 1.15), respectively. CONCLUSION: pSS has a negative impact on smell, taste, sexual function and quality of life in women. PMID- 27760488 TI - Systematic investigation of metabolic reprogramming in different cancers based on tissue-specific metabolic models. AB - Cancer cells have different metabolism in contrast to normal cells. The advancement in omics measurement technology enables the genome-wide characterization of altered cellular processes in cancers, but the metabolic flux landscape of cancer is still far from understood. In this study, we compared the well-reconstructed tissue-specific models of five cancers, including breast, liver, lung, renal, and urothelial cancer, and their corresponding normal cells. There are similar patterns in majority of significantly regulated pathways and enriched pathways in correlated reaction sets. But the differences among cancers are also explicit. The renal cancer demonstrates more dramatic difference with other cancer models, including the smallest number of reactions, flux distribution patterns, and specifically correlated pathways. We also validated the predicted essential genes and revealed the Warburg effect by in silico simulation in renal cancer, which are consistent with the measurements for renal cancer. In conclusion, the tissue-specific metabolic model is more suitable to investigate the cancer metabolism. The similarity and heterogenicity of metabolic reprogramming in different cancers are crucial for understanding the aberrant mechanisms of cancer proliferation, which is fundamental for identifying drug targets and biomarkers. PMID- 27760489 TI - Geneva-Seattle collaboration in support of developing country vaccine manufacturing. AB - Vaccines were once produced almost exclusively by state-supported entities. While they remain essential tools for public health protection, the majority of the world's governments have allowed industry to assume responsibility for this function. This is significant because while the international harmonisation of quality assurance standards have effectively increased vaccine safety, they have also reduced the number of developing country vaccine producers, and Northern multinational pharmaceutical companies have shown little interest in offering the range of low-priced products needed in low and middle-income-country contexts. This article examines how public-private collaboration is relevant to contemporary efforts aimed at strengthening developing country manufacturers' capacity to produce high-quality, low-priced vaccines. Specifically, it casts light on the important and largely complimentary roles of the World Health Organization, The Bill and Melinda Gates Foundation, and the Seattle-based non profit PATH, in this process. The take away message is that external support remains critical to ensuring that developing country vaccine manufacturers have the tools needed to produce for both domestic and global markets, and the United Nations supply chain, and collaboration at the public-private interface is driving organisational innovation focused on meeting these goals. PMID- 27760490 TI - The word frequency effect during sentence reading: A linear or nonlinear effect of log frequency? AB - The effect of word frequency on eye movement behaviour during reading has been reported in many experimental studies. However, the vast majority of these studies compared only two levels of word frequency (high and low). Here we assess whether the effect of log word frequency on eye movement measures is linear, in an experiment in which a critical target word in each sentence was at one of three approximately equally spaced log frequency levels. Separate analyses treated log frequency as a categorical or a continuous predictor. Both analyses showed only a linear effect of log frequency on the likelihood of skipping a word, and on first fixation duration. Ex-Gaussian analyses of first fixation duration showed similar effects on distributional parameters in comparing high- and medium-frequency words, and medium- and low-frequency words. Analyses of gaze duration and the probability of a refixation suggested a nonlinear pattern, with a larger effect at the lower end of the log frequency scale. However, the nonlinear effects were small, and Bayes Factor analyses favoured the simpler linear models for all measures. The possible roles of lexical and post-lexical factors in producing nonlinear effects of log word frequency during sentence reading are discussed. PMID- 27760491 TI - Influence of short-term inertial training on swimming performance in young swimmers. AB - The aim of this study was to evaluate the influence of dry-land inertial training (IT) on muscle force, muscle power, and swimming performance. Fourteen young, national-level, competitive swimmers were randomly divided into IT and control (C) groups. The experiment lasted four weeks, during which time both groups underwent their regular swimming training. In addition, the IT group underwent IT using the Inertial Training Measurement System (ITMS) three times per week. The muscle groups involved during the upsweep phase of the arm stroke in front crawl and butterfly stroke were trained. Before and after training, muscle force and power were measured under IT conditions. Simultaneously with the biomechanical measurements on the ITMS, the electrical activity of the triceps brachii was registered. After four weeks of training, a 12.8% increase in the muscle force and 14.2% increase in the muscle power (p < .05) were noted in the IT group. Moreover, electromyography amplitude of triceps brachii recorded during strength measurements increased by 22.7% in the IT group. Moreover, swimming velocity in the 100 m butterfly and 50 m freestyle improved significantly following the four weeks of dry-land IT (-1.86% and -0.76%, respectively). Changes in the C group were trivial. Moreover, values of force and power registered during the ITMS test correlated negatively with the 100 m butterfly and 50 m freestyle swimming times (r value ranged from -.80 to -.91). These results suggest that IT can be useful in swimming practice. PMID- 27760492 TI - Impact of vision impairment and self-reported barriers to vision care: The views of elders in Nuwara Eliya district, Sri Lanka. AB - : The growing burden of vision impairment (VI) among older people is a development challenge in Asian countries. This study aimed to understand older people's views and experiences about the impact of VI and barriers to eye care to inform policies to address this challenge. We conducted 12 focus group discussions in 2013 with retired Tamil and Sinhala elders in Nuwara Eliya district, Sri Lanka (n = 107). Data were analysed thematically. Older people described the broad impacts VI has on their lives. They worry about becoming dependent. VI restricts their ability to contribute to their families and communities, access information, socialise, maintain their health, and earn. Barriers to eye care services include transport difficulties, costs of treatment, fear, lack of knowledge, waiting times, and health staff attitudes. Older people experience and fear the impacts of VI on their health and well-being. Eye health promotion and care services need strengthening and integration with the primary health care system to address the backlog and growing need among older people in an equitable way. Older people should be consulted about how to overcome the economic, social, and cultural barriers to access to eye care and to minimise the impact of VI. ABBREVIATIONS: FGDs: focus group discussions; GBD: global burden of disease; NCDs: non-communicable diseases; VI: vision impairment. PMID- 27760493 TI - alpha-Defensin 5 gene expression is regulated by gut microbial metabolites. AB - alpha-Defensin 5 is important to both maintenance of a gut microbiota and host immunity. While previous reports have shown that gut bacteria are able to upregulate alpha-defensin 5 through Toll-like receptor signaling, we demonstrate here that alpha-defensin 5 expression can also be regulated by microbial metabolites. Among these, lactate appeared to significantly suppress alpha defensin 5 gene transcription. Actually, fractions of <3 kD compounds obtained from the ceca of SPF mice were suppressed alpha-defensin 5 gene transcription at specific concentrations. Our results also suggest that cecal content may include as yet unidentified factors that can enhance alpha-defensin 5 expression. Our data point to a novel function for the gut microbial metabolites in controlling the expression of antimicrobial peptides in the intestine. PMID- 27760495 TI - A new sarasinoside congener, sarasinoside M2, from a marine sponge collected in the Solomon Islands. AB - A new sarasinoside congener (sarasinoside M2) and known sarasinoside B1 were obtained from a marine sponge. Sarasinoside M2 was suggested to have the same aglycon as sarasinoside M although the internal glucose in its sugar moiety is replaced by xylose. Sarasinosides B1 and M2 showed moderate cytotoxicity (approximate IC50 5-18 MUM) toward Neuro-2a and HepG2 cell lines. PMID- 27760494 TI - Influence of dental occlusion on postural control and plantar pressure distribution. AB - OBJECTIVE: The number of studies investigating correlations between the temporomandibular system and body posture, postural control or plantar pressure distribution is continuously increasing. If a connection can be found, it is often of minor influence or for only a single parameter. However, small subject groups are critical. This study was conducted to define correlations between dental parameters, postural control and plantar pressure distribution in healthy males. METHODS: In this study, 87 male subjects with an average age of 25.23 +/- 3.5 years (ranging from 18 to 35 years) were examined. Dental casts of the subjects were analyzed. Postural control and plantar pressure distribution were recorded by a force platform. Possible orthodontic and orthopedic factors of influence were determined by either an anamnesis or a questionnaire. All tests performed were randomized and repeated three times each for intercuspal position (ICP) and blocked occlusion (BO). For a statistical analysis of the results, non parametric tests (Wilcoxon-Matched-Pairs-Test, Kruskall-Wallis-Test) were used. A revision of the results via Bonferroni-Holm correction was considered. RESULTS: ICP increases body sway in the frontal (p <= 0.01) and sagittal planes (p <= 0.03) compared to BO, whereas all other 29 correlations were independent of the occlusion position. For both of the ICP or BO cases, Angle-class, midline displacement, crossbite, or orthodontic therapy were found to have no influence on postural control or plantar pressure distribution (p > 0.05). However, the contact time of the left foot decreased (p <= 0.001) while detecting the plantar pressure distribution in each position. CONCLUSIONS: Persistent dental parameters have no effect on postural sway. In addition, postural control and plantar pressure distribution have been found to be independent postural criteria. PMID- 27760497 TI - Under the Golden Psi. PMID- 27760496 TI - GTR1 is a jasmonic acid and jasmonoyl-l-isoleucine transporter in Arabidopsis thaliana. AB - Jasmonates are major plant hormones involved in wounding responses. Systemic wounding responses are induced by an electrical signal derived from damaged leaves. After the signaling, jasmonic acid (JA) and jasmonoyl-l-isoleucine (JA Ile) are translocated from wounded to undamaged leaves, but the molecular mechanism of the transport remains unclear. Here, we found that a JA-Ile transporter, GTR1, contributed to these translocations in Arabidopsis thaliana. GTR1 was expressed in and surrounding the leaf veins both of wounded and undamaged leaves. Less accumulations and translocation of JA and JA-Ile were observed in undamaged leaves of gtr1 at 30 min after wounding. Expressions of some genes related to wound responses were induced systemically in undamaged leaves of gtr1. These results suggested that GTR1 would be involved in the translocation of JA and JA-Ile in plant and may be contributed to correct positioning of JA and JA-Ile to attenuate an excessive wound response in undamaged leaves. PMID- 27760498 TI - The Case of General Grigorenko. PMID- 27760500 TI - Contents Volume Forty-Three 1980. PMID- 27760501 TI - Psychotherapy and Research: An Anaclitic Depression. PMID- 27760503 TI - Safety and durability of low-density polyethylene bags in solar water disinfection applications. AB - Solar water disinfection (SODIS) is a simple point-of-use process that uses sunlight to disinfect water for drinking. Polyethylene terephthalate (PET) bottles are typically used as water containers for SODIS, but a new SODIS container design has recently been developed with low-density polyethylene (LDPE) bags and can overcome the drawbacks of PET bottles. Two nesting layers of LDPE bags are used in the new design: the inner layer containing the water to be disinfected and the outer one creating air insulation to minimize heat loss from the water to the surroundings. This work investigated the degradation of LDPE bags used in the new design in actual SODIS conditions over a period of 12 weeks. The degradation of the LDPE bags was investigated weekly using a scanning electron microscope, Fourier transform infrared spectroscopy, ultraviolet-visible spectrophotometer, and tensile strength tester. It was found that the LDPE bags gradually degraded under the sunlight due to photo-oxidation reactions, especially in the outer bags, which were directly exposed to the sun and surroundings, leading to the reduction of light transmittance (by 11% at 300 nm) and tensile strength (by 33%). In addition, possible leaching of organic compounds into the water contained in the inner bags was examined using gas chromatography-mass spectrometer. 2,4-Di-tert-butylphenol was found in some SODIS water samples as well as the as-received water samples, in the concentration range of 1-4 MUg/L, which passes the Environmental Protection Agency Drinking Water Guidance on Disinfection By-Products. PMID- 27760504 TI - Relationship between craniocervical orientation and center of force of occlusion in adults. AB - OBJECTIVE: Clinical observation and anecdotal reports suggest changes can occur to dental occlusion following intervention with the National Upper Cervical Chiropractic Association (NUCCA) procedure. This case controlled study discerned if occlusion changes are measurable using a dental force plate (T-Scan(r)) following an adjustment to the craniocervical junction (CCJ). METHODS: A degree of case control was established by active patients being assessed twice prior to and following intervention. Before-after intervention assessment included posture evaluation and dental occlusion (T-Scan(r)). RESULTS: Findings suggest that changes in posture and occlusion can be observed after the NUCCA chiropractic procedure. Not all patients demonstrated a more balanced contact pattern following the adjustment, indicating a need for further investigation. DISCUSSION: These findings may suggest interconnectivity between the CCJ and an individual's occlusal contacts and support the need for further integration between chiropractors and dentists seeking to co-manage temporomandibular joint disorders. PMID- 27760505 TI - Pilot randomized controlled trial to assess a physical therapy program on upper extremity function to counteract inactivity in chronic stroke. AB - BACKGROUND: In chronic stroke, feasible physical therapy (PT) programs are needed to promote function throughout life. OBJECTIVE: This randomized controlled pilot trial investigated the feasibility and effect of a PT program composed of strengthening exercises with elastic bands and bimanual functional training, with clearly defined doses based on the rate of perceived exertion (Borg scale), to counteract inactivity in chronic stroke. METHODS: Fifteen subjects > 6 month post stroke were randomized to three-month of UE function training (UE group), or to lower extremity function training (LE group). At baseline (T0), post-intervention (T1) and three-month follow-up (T2) assessment included the Fugl-Meyer Assessment scale (FMA), Wolf Motor Function test (WMFT), grip strength, and muscle tone. Feasibility was also evaluated. RESULTS: The mixed-model ANOVAs revealed a significant interaction between the time and group factors for FMA (p < .001) and WMFT (p = .009). The UE group improved upper extremity function and motor recovery significantly more than the LE group. There was no significant interaction between treatment group and change in grip strength over time (p = .217). No between-group differences (p > .05) were found in muscle tone. In the UE group, the attendance rate was >=85% for 71.4% of subjects and 85.7% showed high satisfaction. No adverse events were recorded. After treatment, adherence to the program was higher in the UE group. CONCLUSIONS: The suggested PT program may be useful to improve the paretic UE function and motor recovery in chronic stroke. Moreover, it may be helpful to facilitate lifelong active involvement of stroke subjects in exercise. PMID- 27760506 TI - Fifty Shades: ambivalence about birth control in an erotic bestseller and its cultural implications. AB - The Fifty Shades trilogy by E.L. James has taken the world by storm and become a cultural phenomenon. The lack of contraceptive use in the erotic fiction, first pointed out by bloggers, is analysed in this article and compared to medical information. James may be praised for sexualising condom use. However, her protagonist makes poor choices in terms of hormonal contraception and is negligent about its use, resulting in an unintended pregnancy and resolved in marital bliss and motherhood. What is of more interest here than a possible message about contraceptive use, is the outcome that the fiction's negligence in birth control and responsibility affirms an ideology in which female sexuality and sexual experimentation can only be tolerated within the context of procreation and affirmation of motherhood. Subsequently, the cultural significance of the trilogy's popularity and its tension between sexual exploration, birth control and fertility is explored. In a globally popular fantasy published more than five decades after the introduction of the pill, the protagonist's lack of attention to reliable birth control leads to a telling dichotomy that combines adventurous exploration of female sexuality and affirmation of the nuclear family. PMID- 27760507 TI - 'We talk, we do not have shame': addressing stigma by reconstructing identity through enhancing social cohesion among female sex workers living with HIV in the Dominican Republic. AB - This study explores social cohesion as a strategy used by female sex workers to address layered HIV and sex work-related stigma. Data derive from a thematic analysis of 23 in-depth interviews and 2 focus groups with female sex workers living with HIV enrolled in a multi-level HIV/STI prevention, treatment and care intervention in Santo Domingo, Dominican Republic. Drawing on Foucault's conceptualisation of modern power, discipline and resistance, we argue that social cohesion provides the psychosocial space (of trust, solidarity and mutual aid) to subvert oppressive societal norms, enabling the reconstruction of identity. Among study participants, identity reconstruction happened through the production, repetition and performance of new de-stigmatised narratives that emerged and were solidified through collective interaction. Findings highlight that enabling the collective reconstruction of identity through social cohesion - rather than solely attempting to change individual beliefs - is a successful approach to addressing stigma. PMID- 27760509 TI - Brief Communications. PMID- 27760508 TI - Facilitating a Therapeutic Milieu in the Families of Schizophrenics. PMID- 27760511 TI - Benevolent Gambling. PMID- 27760512 TI - Body Feeling in Human Relations. PMID- 27760513 TI - Normal activities of AMP-deaminase and adenylate kinase in patients with McArdle disease. AB - During physical activity in McArdle patients, little or no lactate is released in the skeletal muscle. However, excessive ammonia production has frequently been reported in these patients. Production of ammonia is catalysed by AMP deaminase (AMPD) and adenylate kinase (AK). The activities of AMPD and AK along with housekeeping enzyme phosphoglucoisomerase (PGI) were measured in 11 genetically confirmed McArdle patients and compared with 27 healthy controls. The AMPD and AK activities were not significantly different in patients and controls. The activity of PGI was significantly higher in patients than in controls suggesting compensation of the impaired glycogenolysis in McArdle. The ratios of activities of AMPD and AK over PGI were significantly lower in patients than in controls. High ammonia production in McArdle patients is not based on enzyme induction of AMPD and AK but possibly due to kinetic activation of the enzyme AMPD by increased concentration of the substrate AMP. PMID- 27760514 TI - Biological arsenite oxidation with nitrate as sole electron acceptor. AB - The potential of anoxic biological arsenite oxidation with nitrate as the sole electron acceptor was tested by using the acclimatized activated sludge which was chronically exposed under arsenite and nitrate coexisted aquatic environment. The activated sludge cultivated in a sequencing batch reactor was fed with arsenite and nitrate as the main substrates over six months. A series of batch experiments were conducted with acclimated sludge. Results showed that no obvious inhibition was observed in the anoxic arsenite oxidation linked to nitrate and nitrite reduction at the concentration of arsenite up to 35 mg AsIII L-1. Moreover, it was found that nitrite was accumulated over the reaction probably due to limited availability of arsenite. The kinetic study further suggested that the maximum specific arsenite oxidation rates (qobs, max) with nitrate and nitrite as the electron acceptors were found to be 0.55 +/- 0.10 mg AsIII g-1VSS min-1 and 0.40 +/- 0.04 mg AsIII g-1VSS min-1, respectively. PMID- 27760515 TI - Convert your favorite protein modeling program into a mutation predictor: "MODICT". AB - BACKGROUND: Predict whether a mutation is deleterious based on the custom 3D model of a protein. RESULTS: We have developed MODICT, a mutation prediction tool which is based on per residue RMSD (root mean square deviation) values of superimposed 3D protein models. Our mathematical algorithm was tested for 42 described mutations in multiple genes including renin (REN), beta-tubulin (TUBB2B), biotinidase (BTD), sphingomyelin phosphodiesterase-1 (SMPD1), phenylalanine hydroxylase (PAH) and medium chain Acyl-Coa dehydrogenase (ACADM). Moreover, MODICT scores corresponded to experimentally verified residual enzyme activities in mutated biotinidase, phenylalanine hydroxylase and medium chain Acyl-CoA dehydrogenase. Several commercially available prediction algorithms were tested and results were compared. The MODICT PERL package and the manual can be downloaded from https://github.com/IbrahimTanyalcin/MODICT . CONCLUSIONS: We show here that MODICT is capable tool for mutation effect prediction at the protein level, using superimposed 3D protein models instead of sequence based algorithms used by POLYPHEN and SIFT. PMID- 27760516 TI - The 1.78-kb insertion in the 3'-untranslated region of RXFP2 does not segregate with horn status in sheep breeds with variable horn status. AB - BACKGROUND: The mode of inheritance of horn status in sheep is far more complex than a superficial analysis might suggest. Observations, which were mostly based on crossbreeding experiments, indicated that the allele that results in horns is dominant in males and recessive in females, and some authors even speculated about the involvement of more than two alleles. However, all recent genome-wide association analyses point towards a very strong effect of a single autosomal locus on ovine chromosome 10, which was narrowed down to a putatively causal insertion polymorphism in the 3'-untranslated region of the relaxin/insulin-like family peptide receptor 2 gene (RXFP2). The main objective of this study was to test this insertion polymorphism as the causal mutation in diverse sheep breeds, including breeds with a variable and/or sex-dependent horn status. RESULTS: After re-sequencing a region of about 246 kb that covered the RFXP2 gene and its flanking regions for 24 sheep from six completely horned and six completely polled breeds, we identified the same insertion polymorphism that was previously published as segregating with horn status in these breeds. Multiplex PCR genotyping of 489 sheep from 34 breeds and some crosses between sheep breeds showed a nearly perfect segregation of the insertion polymorphism with horn status in sheep breeds of Central and Western European origin. In these breeds and their crossings, heterozygous males were horned and heterozygous females were polled. However, this segregation pattern was not, or at least not completely, reproducible in breeds with sex-dependent and/or variable horn status, especially in sheep that originated from even more southern European regions and from Africa. In such breeds, we observed almost all possible combinations of genotype, sex and horn status phenotype. CONCLUSIONS: The 1.78-kb insertion polymorphism in the 3'-untranslated region of RXFP2 and SNPs in the 3'-UTR, exon 14 and intron 11 of this gene that we analyzed in this study cannot be considered as the only cause of polledness in sheep and are not useful as a universal marker to define the genetic horn status in sheep. PMID- 27760517 TI - Neuroprotective effects of HTR1A antagonist WAY-100635 on scopolamine-induced delirium in rats and underlying molecular mechanisms. AB - BACKGROUND: Limited surveys have assessed the performance of 5-hydroxytreptamine receptor 1A and its antagonist WAY-100635 in pharmacological manipulations targeting delirium therapies. The purpose of this paper was to assess the central pharmacological activity of WAY-100635 in a rat model of scopolamine-induced delirium and its underlying mechanism. RESULTS: A delirium rat model was established by intraperitoneal injection of scopolamine and behavioral changes evaluated through open field and elevated plus maze experiments. Concentrations of monoamines in the hippocampus and amygdalae were detected by high performance liquid chromatography. The effect of WAY-100635 on the recovery of rats from delirium was assessed by stereotactic injection of WAY-100635 and its mechanism of action determined by measuring mRNA and protein expression via real time PCR and western blotting methods. The total distance and the number of crossing and rearing in the elevated plus maze test and the time spent in the light compartment in the dark/light test of scopolamine-treated rats were significantly increased while the percentage of time spent in the open arms was decreased, showing the validity of the established delirium rat model. The measurement of the concentrations of noradrenaline, 3,4-dihydroxyphenylacetic acid, the homovanillic acid, 5-hydroxy-3-indoleacetic acid and serotonin concentrations in the cerebrospinal fluid (CSF) of scopolamine-induced delirium rats were significantly increased. The intra-hippocampus and intra-BLA injections of WAY 100635 improved the delirium-like behavior of rats by significantly reducing the expression of NLRP3 inflammasome and the release of IL1-beta and IL8 into CSF. CONCLUSIONS: Taken together, these findings indicate that WAY-100635 may exert a therapeutic effect on post-operative delirium by controlling neurotransmission as well as suppressing neuroinflammation in the central nervous system. PMID- 27760518 TI - Fine mapping of a QTL on bovine chromosome 6 using imputed full sequence data suggests a key role for the group-specific component (GC) gene in clinical mastitis and milk production. AB - BACKGROUND: Clinical mastitis is an inflammation of the mammary gland and causes significant costs to dairy production. It is unfavourably genetically correlated to milk production, and, thus, knowledge of the mechanisms that underlie these traits would be valuable to improve both of them simultaneously through breeding. A quantitative trait locus (QTL) that affects both clinical mastitis and milk production has recently been fine-mapped to around 89 Mb on bovine chromosome 6 (BTA6), but identification of the gene that underlies this QTL was not possible due to the strong linkage disequilibrium between single nucleotide polymorphisms (SNPs) within this region. Our aim was to identify the gene and, if possible, the causal polymorphism(s) responsible for this QTL through association analysis of high-density SNPs and imputed full sequence data in combination with analyses of transcript and protein levels of the identified candidate gene. RESULTS: Associations between SNPs and the studied traits were strongest for SNPs that were located within and immediately upstream of the group-specific component (GC) gene. This gene encodes the vitamin D-binding protein (DBP) and has multiple roles in immune defense and milk production. A 12-kb duplication that was identified downstream of this gene covered its last exon and segregated with the QTL allele that is associated with increased mastitis susceptibility and milk production. However, analyses of GC mRNA levels on the available samples revealed no differences in expression between animals having or lacking this duplication. Moreover, we detected no differences in the concentrations of DBP and its ligand vitamin D between the animals with different GC genotypes that were available for this study. CONCLUSIONS: Our results suggest GC as the gene that underlies the QTL for clinical mastitis and milk production. However, since only healthy animals were sampled for transcription and expression analyses, we could not draw any final conclusion on the absence of quantitative differences between animals with different genotypes. Future studies should investigate GC RNA expression and protein levels in cows with different genotypes during an infection. PMID- 27760519 TI - Single nucleotide variant discovery of highly inbred Leghorn and Fayoumi chicken breeds using pooled whole genome resequencing data reveals insights into phenotype differences. AB - BACKGROUND: Analyses of sequence variants of two distinct and highly inbred chicken lines allowed characterization of genomic variation that may be associated with phenotypic differences between breeds. These lines were the Leghorn, the major contributing breed to commercial white-egg production lines, and the Fayoumi, representative of an outbred indigenous and robust breed. Unique within- and between-line genetic diversity was used to define the genetic differences of the two breeds through the use of variant discovery and functional annotation. RESULTS: Downstream fixation test (F ST ) analysis and subsequent gene ontology (GO) enrichment analysis elucidated major differences between the two lines. The genes with high F ST values for both breeds were used to identify enriched gene ontology terms. Over-enriched GO annotations were uncovered for functions indicative of breed-related traits of pathogen resistance and reproductive ability for Fayoumi and Leghorn, respectively. CONCLUSIONS: Variant analysis elucidated GO functions indicative of breed-predominant phenotypes related to genomic variation in the lines, showing a possible link between the genetic variants and breed traits. PMID- 27760520 TI - Health Equity Assessment Toolkit (HEAT): software for exploring and comparing health inequalities in countries. AB - BACKGROUND: It is widely recognised that the pursuit of sustainable development cannot be accomplished without addressing inequality, or observed differences between subgroups of a population. Monitoring health inequalities allows for the identification of health topics where major group differences exist, dimensions of inequality that must be prioritised to effect improvements in multiple health domains, and also population subgroups that are multiply disadvantaged. While availability of data to monitor health inequalities is gradually improving, there is a commensurate need to increase, within countries, the technical capacity for analysis of these data and interpretation of results for decision-making. Prior efforts to build capacity have yielded demand for a toolkit with the computational ability to display disaggregated data and summary measures of inequality in an interactive and customisable fashion that would facilitate interpretation and reporting of health inequality in a given country. METHODS: To answer this demand, the Health Equity Assessment Toolkit (HEAT), was developed between 2014 and 2016. The software, which contains the World Health Organization's Health Equity Monitor database, allows the assessment of inequalities within a country using over 30 reproductive, maternal, newborn and child health indicators and five dimensions of inequality (economic status, education, place of residence, subnational region and child's sex, where applicable). RESULTS/CONCLUSION: HEAT was beta-tested in 2015 as part of ongoing capacity building workshops on health inequality monitoring. This is the first and only application of its kind; further developments are proposed to introduce an upload data feature, translate it into different languages and increase interactivity of the software. This article will present the main features and functionalities of HEAT and discuss its relevance and use for health inequality monitoring. PMID- 27760521 TI - An interspecific assessment of Bergmann's rule in 22 mammalian families. AB - BACKGROUND: Bergmann's rule proposes that animals in cold habitats will be larger than those in warm habitats. This prediction has been tested thoroughly at the intraspecific level, but few studies have investigated the hypothesis with interspecific data using phylogenetic comparative approaches. Many clades of mammals have representatives in numerous distinct biomes, making this order highly suitable for a large-scale interspecific assessment of Bergmann's rule. Here, we evaluate Bergmann's rule within 22 mammalian families-with a dataset that include ~35 % of all described species-using a phylogenetic comparative approach. The method is based on an Ornstein-Uhlenbeck model of evolution that allows for joint estimation of adaptation and constraints (phylogenetic inertia) in the evolution of a trait. We use this comparative method to investigate whether body mass evolves towards phenotypic optima that are functions of median latitude, maximum latitude or temperature. We also assess the closely related Allen's rule in five families, by testing if relative forelimb length evolves as a function of temperature or latitude. RESULTS: Among 22 mammalian families, there was weak support for Bergmann's rule in one family: A decrease in temperature predicted increased body mass in Canidae (canids). We also found latitude and temperature to significantly predict body mass in Geomyidae (pocket gophers); however, the association went in the opposite direction of Bergmann's predictions. Allen's rule was supported in one of the five examined families (Pteropodidae; megabats), but only when forelimb length evolves towards an optimum that is a function of maximum latitude, not median latitude or temperature. CONCLUSIONS: Based on this exhaustive assessment of Bergmann's rule, we conclude that factors other than latitude and temperature are the major drivers of body mass evolution at the family level in mammals. PMID- 27760522 TI - Amniotic fluid embolism as a cause of maternal mortality in China between 1996 and 2013: a population-based retrospective study. AB - BACKGROUND: To analyse the maternal mortality ratio, demographic and pregnancy related details in women who suffered a fatal amniotic fluid embolism (AFE) in China. METHODS: A retrospective population based study using data collected as part of the National Maternal Mortality Surveillance System between 1996 and 2013. Data were collected onto a standardised form from women whose cause of death was listed as being secondary to AFE. RESULTS: Records were available for 640 deaths. Over the 17 year period the maternal mortality ratio for AFE decreased from 4.4 per 100,000 births (95 % confidence interval (CI):2.72-6.12) to 1.9 per 100,000 births (95 % CI:1.35-2.54). Over the same period the proportion of maternal deaths secondary to AFE increased from 6.8 to 12.5 %. The mean age of women who died was 30.1 years and the onset of the AFE occurred prior to delivery in 39 %. The most prominent presenting features included premonitory symptoms (29 %), acute fetal compromise (28 %), maternal haemorrhage (16 %) and shortness of breath (15 %). CONCLUSIONS: Maternal mortality secondary to AFE has decreased in China, however at a slower rate than mortality secondary to other conditions. Active surveillance is recommended to assess case fatality rates, risk factors and other lessons specific to this population. PMID- 27760523 TI - Low level of MAp44, an inhibitor of the lectin complement pathway, and long-term graft and patient survival; a cohort study of 382 kidney recipients. AB - BACKGROUND: Higher incidence of malignancy and infectious diseases in kidney transplant recipients is related to immunosuppressive treatment after transplantation and the recipient's native immune system. The complement system is an essential component of the innate immunity. The aim of the present study was to investigate the association of effector molecules of the lectin complement pathway with graft and patient survival after kidney transplantation. METHODS: Two mannan-binding lectin (MBL) associated proteases, MASP-2 and MASP-3 (activators of the lectin pathway) and two MBL-associated proteins, MAp44 and MAp19 (inhibitors of the lectin pathway) were measured at the time of transplantation in 382 patients (>=17 years old) transplanted in 2000-2001. The cohort was followed until December 31, 2014. Data on patient and graft survival were obtained from the Norwegian Renal Registry. Cox proportional hazard regression models were performed for survival analyses. RESULTS: Low MAp44 level (1st versus 2-4 quartile) was significantly associated with overall mortality; HR 1.52, 95 % CI 1.08-2.14, p = 0.017. In the sub analyses in groups below and above median age (51.7 years), low MAp44 as a predictor of overall mortality was statistically significant only in recipients of <=51.7 years; HR 2.57, 95 % CI 1.42-4.66, p = 0.002. Furthermore, low MAp44 was associated with mortality due to infectious diseases; HR 2.22, 95 % CI 1.11-4.41, p = 0.023. There was no association between MASP-2, MASP-3 or MAp19 levels and patient mortality. No association between any measured biomarkers and death censored graft loss was found. CONCLUSIONS: Low MAp44 level at the time of transplantation was associated with increased overall mortality in kidney recipients of median age of 51.7 years or below and with mortality due to infectious diseases in the whole patient cohort after nearly 14-years of follow up after transplantation. No associations between other effector molecules; MASP-2, MASP-3 or MAp19 and recipient mortality were found, as well as no association of any biomarker with death censored graft loss. PMID- 27760524 TI - A question prompt sheet for adult patients with chronic kidney disease. AB - BACKGROUND: Patients with chronic kidney disease (CKD) commonly have unmet information needs. Greater patient participation in healthcare discussions can address these needs and improve health outcomes. We developed a patient-centered question prompt sheet (QPS) to engage CKD patients in healthcare conversations. METHODS: We conducted a two phase, mixed-methods, cross-sectional study involving semi-structured telephone interviews. Patients with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, on dialysis, or with a kidney transplant were recruited from one Veterans Affairs (VA) nephrology clinic. Phase 1 interviews included open-ended questions assessing patients' CKD-related information needs and generated a preliminary 67-item QPS. Phase 2 interview participants rated the importance of asking each question on a 5-point Likert scale and provided open-ended feedback. All participants rated their willingness to use a CKD-QPS. Input from patient ratings, a multidisciplinary team, and from members of the National Kidney Disease Education Program (NKDEP) Coordinating Panel helped to shorten and refine the QPS. A qualitative thematic approach was used to analyze open-ended responses. Quantitative data were analyzed for means and proportions. RESULTS: Eighty-five patients participated. Most were male (97 %), non-Hispanic white (71 %), and mean age was 67 years. Patients desired more information about CKD, particularly dialysis/transplant, and the relationship between CKD and comorbid medical conditions. The final QPS included 31-questions divided into 7 CKD subtopics. Most patients (88 %) reported being 'completely' or 'very' willing to use a CKD-QPS in future doctor visits. CONCLUSIONS: CKD patients have unmet information needs. We developed a QPS to engage CKD patients in healthcare discussions and to facilitate patient-centered care. Future research should assess whether the CKD-QPS addresses patients' information needs, enhances doctor-patient communication, and improves health outcomes. PMID- 27760525 TI - www.common-metrics.org: a web application to estimate scores from different patient-reported outcome measures on a common scale. AB - BACKGROUND: Recently, a growing number of Item-Response Theory (IRT) models has been published, which allow estimation of a common latent variable from data derived by different Patient Reported Outcomes (PROs). When using data from different PROs, direct estimation of the latent variable has some advantages over the use of sum score conversion tables. It requires substantial proficiency in the field of psychometrics to fit such models using contemporary IRT software. We developed a web application ( http://www.common-metrics.org ), which allows estimation of latent variable scores more easily using IRT models calibrating different measures on instrument independent scales. RESULTS: Currently, the application allows estimation using six different IRT models for Depression, Anxiety, and Physical Function. Based on published item parameters, users of the application can directly estimate latent trait estimates using expected a posteriori (EAP) for sum scores as well as for specific response patterns, Bayes modal (MAP), Weighted likelihood estimation (WLE) and Maximum likelihood (ML) methods and under three different prior distributions. The obtained estimates can be downloaded and analyzed using standard statistical software. CONCLUSIONS: This application enhances the usability of IRT modeling for researchers by allowing comparison of the latent trait estimates over different PROs, such as the Patient Health Questionnaire Depression (PHQ-9) and Anxiety (GAD-7) scales, the Center of Epidemiologic Studies Depression Scale (CES-D), the Beck Depression Inventory (BDI), PROMIS Anxiety and Depression Short Forms and others. Advantages of this approach include comparability of data derived with different measures and tolerance against missing values. The validity of the underlying models needs to be investigated in the future. PMID- 27760526 TI - N-terminal pro-brain natriuretic peptide levels associated with severe hand, foot and mouth disease. AB - BACKGROUND: Severe hand, foot, and mouth disease (HFMD) is sometimes associated with serious complications such as acute heart failure that can cause substantial child mortality. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive and specific biomarker of congestive heart failure. The aim of this study was to use plasma NT-proBNP levels to establish the severity of childhood HFMD. METHODS: A retrospective study was performed in 128 Chinese patients with severe HFMD and 88 patients with mild HFMD treated between January 2014 and October 2015. Univariate and multiple logistic regression analyses were used to analyze the risk factors for severe HFMD. NT-proBNP levels were analyzed in 128 severe HFMD patients, and the predictive value of NT-proBNP was assessed by receiver operating characteristic analyses. RESULTS: Multivariate analysis controlling for several potential confounders showed that enterovirus 71 infection [odds ratio (OR) 19.944, 95 % confidence interval (CI) 6.492-61.271], peripheral WBC count (OR 3.428, 95 % CI 1.186-9.914), fasting glucose (OR 19.428, 95 % CI 2.236-168.784), procalcitonin (OR 9.084, 95 % CI 3.462-23.837, and NT proBNP (>125 pg/mL) (OR 16.649, 95 % CI 4.731-58.585) were each associated with the severity of HFMD. The 45 dead severe patients had higher pre-procedural levels of NT-proBNP than the 83 cured severe patients (12776 +/- 13115 versus 1435 +/- 4201 pg/mL, P < 0.001). An NT-proBNP cutoff value of 982 pg/mL predicted mortality with 87 % sensitivity and 86 % specificity. CONCLUSION: Plasma NT-pro BNP level appears to be a useful biological marker for predicting the severity and mortality of HFMD. PMID- 27760528 TI - Prescribing differences in family practice for diabetic patients in Germany according to statutory or private health insurance: the case of DPP-4-inhibitors and GLP-1-agonists. AB - BACKGROUND: The objective of this study was to analyze prescription decisions for family practice (FP) patients with Diabetes mellitus type 2 (DM2) using the case of the incretin mimetics Dipeptidyl peptidase-4 (DDP-4) inhibitors and Glucagon like peptide-1 (GLP-1) agonists dependent on patients' health insurance status (statutory or private) in Germany. This study is important since the scientific debate is still open with regard to DPP-4-inhibitors and GLP-1-agonists, where some critics are raising questions on potential long-term risks for patients. METHODS: Data for this analysis were sourced from the German health services research register CONTENT (CONTinuous morbidity registration Epidemiologic NeTwork), in which FP health services information, generated by family practitioners, is continuously collated, e.g. patients' health insurance status, morbidity and pharmacotherapy. Patients with Diabetes mellitus type 1 (DM1) were excluded from the study. RESULTS: From the family practices collaborating in the CONTENT research network, there were 7298 patients treated with pharmacotherapeutic agents for DM2 between 01.09.2009 and 31.08.2014. 586 (8.03 %) of these patients had private insurance. Prescriptions for the incretin mimetics were 40.6 % higher (9.7 vs. 6.9 %; p < 0.0001) for patients with private insurance compared to patients with statutory health insurance. This finding was confirmed with multivariable analyses. CONCLUSIONS: There was a statistically significant difference found in prescription patterns according to the patient's health insurance status for the incretin mimetics in this sample population of German patients with DM2. Obviously, these differences result from the eligibility for reimbursement according to patients' health insurance status. Whether incretin mimetics pose specific long term risks for particular patients is yet to be determined. PMID- 27760529 TI - The effect of continuous venovenous hemofiltration on neutrophil gelatinase associated lipocalin plasma levels in patients with septic acute kidney injury. AB - BACKGROUND: It is known that continuous venonenous hemofiltration (CVVH) does not affect the plasma level of neutrophil gelatinase-associated lipocalin (pNGAL) in acute kidney injury (AKI) patients. However, because of the unique pathophysiology underlying AKI caused by sepsis, the effect of CVVH on pNGAL in this clinical setting is less certain. The purpose of this study was to determine the effect of CVVH on pNGAL in sepsis-induced AKI patients. METHODS: Between August 1, 2014, and December 31, 2014, 42 patients with sepsis-induced AKI underwent CVVH in the general intensive care unit of our institution and were consecutively enrolled in this study. Prefilter, postfilter, and ultrafiltrate pNGAL measurements were taken at the initiation of continuous renal replacement therapy (CRRT) and repeated after 2, 4, 8, and 12 h (T0, T2h, T4h, T8h, and T12h, respectively). The mass transfer, plasma clearance, and sieving coefficient were calculated based on the mass conservation principle. RESULTS: Following CVVH initiation, we found that pNGAL in the ultrafiltrate decreased significantly (P = 0.013); however, levels at the inlet and outlet showed no significant change (P > 0.05 for both). Furthermore, there was no change in the total mass removal rate, total mass adsorption rate, and plasma clearance over time (P > 0.05 for all), and a significant decrease in the sieving coefficient (P = 0.007) was seen. CONCLUSIONS: The results of this study show a limited effect of CVVH on pNGAL in sepsis-induced AKI patients. This suggests that pNGAL may be used as an indicator of renal progression in these patients. However, a larger study to confirm these findings is needed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02536027 . Retrospectively registered on 20th August 2015. PMID- 27760527 TI - Outcome of cardiac surgery in patients with low preoperative ejection fraction. AB - BACKGROUND: In patients undergoing cardiac surgery, a reduced preoperative left ventricular ejection fraction (LVEF) is common and is associated with a worse outcome. Available outcome data for these patients address specific surgical procedures, mainly coronary artery bypass graft (CABG). Aim of our study was to investigate perioperative outcome of surgery on patients with low pre-operative LVEF undergoing a broad range of cardiac surgical procedures. METHODS: Data from patients with pre-operative LVEF <=40 % undergoing cardiac surgery at a university hospital were reviewed and analyzed. A subgroup analysis on patients with pre-operative LVEF <=30 % was also performed. RESULTS: A total of 7313 patients underwent cardiac surgery during the study period. Out of these, 781 patients (11 %) had a pre-operative LVEF <=40 % and were included in the analysis. Mean pre-operative LVEF was 33.9 +/- 6.1 % and in 290 patients (37 %) LVEF was <=30 %. The most frequently performed operation was CABG (31 % of procedures), followed by mitral valve surgery (22 %) and aortic valve surgery (19 %). Overall perioperative mortality was 5.6 %. Mitral valve surgery was more frequent among patients who did not survive, while survivors underwent more frequently CABG. Post-operative myocardial infarction occurred in 19 (2.4 %) of patients, low cardiac output syndrome in 271 (35 %). Acute kidney injury occurred in 195 (25 %) of patients. Duration of mechanical ventilation was 18 (12-48) hours. Incidence of complications was higher in patients with LVEF <=30 %. Stepwise multivariate analysis identified chronic obstructive pulmonary disease, pre-operative insertion of intra-aortic balloon pump, and pre-operative need for inotropes as independent predictors of mortality among patients with LVEF <=40 %. CONCLUSIONS: We confirmed that patients with low pre-operative LVEF undergoing cardiac surgery are at higher risk of post-operative complications. Cardiac surgery can be performed with acceptable mortality rates; however, mitral valve surgery, was found to be associated with higher mortality rates in this population. Accurate selection of patients, risk/benefit evaluation, and planning of surgical and anesthesiological management are mandatory to improve outcome. PMID- 27760530 TI - Steatocystoma simplex of the lacrimal caruncle: a case report. AB - BACKGROUND: This is the third reported case of a steatocystoma simplex in the lacrimal caruncle. CASE PRESENTATION: A 60-year-old male presented with a history of a slowly progressing mass in the right lacrimal caruncle since several years before his initial visit. At the first examination, a yellowish, relatively smooth surface mass was observed in the right lacrimal caruncle. The caruncular mass was completely removed under local anesthesia. The pathological findings of this mass were consistent with a steatocystoma. At the 6-month follow-up, there was no sign of recurrence or development of the steatocystoma or any other masses. CONCLUSION: Although steatocystoma simplex rarely occurs in the lacrimal caruncle, it needs to be considered as a possible diagnosis for patients with a mass lesion in the caruncle. PMID- 27760531 TI - The impact of predisposing, enabling, and need factors in utilization of health services among rural residents in Guangxi, China. AB - BACKGROUND: Healthcare in China has significantly improved, meanwhile many socio economic risk factors and health conditions factors affect accessibility and utilization of health services in rural areas. Inequity of health service in China needs to be estimated and reduced. Andersen behavioral model is useful to assess the association of health service utilization with predisposing, enabling, and need factors. METHODS: A survey was conducted among 4634 residents of 897 households in 2012. Logistic regression analysis was performed to explore the association of predisposing (age, gender, marital status, ethnicity and family size), enabling (education level, travel time to the nearest health facility, medical expense per capita, and health insurance coverage), and need factors (chronic disease) with the utilization of health services (i.e. physician visit and hospitalization). RESULTS: We observed a significant association between need factor (chronic diseases) and health service unitization, after adjusting for all predisposing and enabling factors (physician visits: odds ratio (OR) = 5.87, 95 % confidence interval (CI) = 4.71-7.32; hospitalization: OR = 4.04, 95 % CI = 2.90 5.61, respectively). In addition, age, gender, marital status, family size and education level were significant predictors of health service utilization. The travel time to the nearest health facility was associated with the utilization of physician visits, and expenditure on healthcare was a hindering factor of hospitalization. CONCLUSIONS: The predisposing and enabling factors had a minor impact on health service utilization, while the need factor was a dominant predictor of health service utilization among rural residents in China. PMID- 27760532 TI - How do children travel to school in urban India? A cross-sectional study of 5,842 children in Hyderabad. AB - BACKGROUND: Millions of children travel to school every day in India, yet little is known about this journey. We examined the distribution and determinants of school travel in Hyderabad, India. METHODS: We conducted a cross-sectional survey using a two-stage stratified cluster sampling design. School travel questionnaires were used to collect data from children aged 11-14 years, attending private, semi-private and government funded schools in Hyderabad. We used Google Earth to estimate the distance from home to school for each child and modelled the relationship between distance to school and mode of travel, adjusting for confounders. RESULTS: Forty five of the 48 eligible schools that were selected agreed to participate, providing a total sample of 5842 children. The response rate was 99 %. Most children walked (57 %) or cycled (6 %) to school but 36 % used motorised transport (mostly bus). The proportion using motorised transport was higher in children attending private schools (41 %) than in those attending government schools (24 %). Most (90 %) children lived within 5km of school and 36 % lived within 1km. Greater distance to school was strongly associated with the use of motorised transport. Children living close to school were much more likely to walk or cycle. CONCLUSIONS: Most children in Hyderabad walk (57 %) or cycle (6 %) to school. If these levels are to be maintained, there is an urgent need to ensure that walking and cycling are safe and pleasant. Social policies that decrease distances to school could have a large impact on road traffic injuries, air pollution, and physical activity levels. PMID- 27760533 TI - Randomised controlled trial of an iPad based early intervention for autism: TOBY playpad study protocol. AB - BACKGROUND: Evidence for early intensive behavioural interventions (EIBI) by therapists as an effective treatment for children with an Autism Spectrum Disorder (ASD) is growing. High-intensity and sustained delivery of quality EIBI is expensive. The TOBY (Therapy Outcomes by You) Playpad is an App-based platform delivering EIBI to facilitate learning for young children with ASD, while enabling parents to become co-therapists. Intervention targets include increasing joint attention, imitation and communication of children with ASD. The primary aim of the study presented in this protocol is to determine the effectiveness of the TOBY App in reducing ASD symptoms when used as a complement to conventional EIBI. The secondary aim is to examine parental attributes as a result of TOBY App use. METHODS AND DESIGN: Children aged less than 4;3 years diagnosed with ASD and parents will be recruited into this single-blind, randomised controlled trial using a pragmatic approach. Eligible participants will be randomised to the treatment group 'TOBY therapy + therapy as usual' or, the control group 'therapy as usual' for six months. The treatment will be provided by the TOBY App and parent where a combination of learning environments such as on-iPad child only (solo), partner (with parent) and off-iPad - Natural Environment (with parent) Tasks will be implemented. Parents in the treatment group will participate in a TOBY training workshop. Treatment fidelity will be monitored via an App-based reporting system and parent diaries. The primary outcome measure is the Autism Treatment Evaluation Checklist. The secondary outcome measures involve diagnostics, functional and developmental assessments, including parent questionnaires at baseline (T0), three months (T1) and six months (T2). DISCUSSION: This trial will determine the effectiveness of the TOBY App as a therapeutic complement to other early interventions children with ASD receive. The trial will also determine the feasibility of a parent delivered early intervention using the iPad as an educational platform, and assess the impact of the TOBY App on parents' self-efficacy and empowerment in an effort to reduce children's ASD symptoms. The outcomes of this trial may have EIBI services implications for newly diagnosed children with ASD and parents. TRIAL REGISTRATION: ACTRN12614000738628 retrospectively registered on 1st of July, 2014. UTN: U1111-1158-6423. PMID- 27760534 TI - Broader conceptualization of remission assessed by the remission from depression questionnaire and its association with symptomatic remission: a prospective, multicenter, observational study. AB - BACKGROUND: Goals of treating major depressive disorder (MDD) include achieving remission and avoiding relapse. It is possible that patients may have a broader view of remission than what is captured via clinician-rated scales. This patient perspective may, in turn, have an impact on treatment outcomes. METHODS: The association between a broader conceptualization of remission, based on the Remission from Depression Questionnaire (RDQ) score at baseline, and being in symptomatic remission after 6 months was evaluated in subjects (N = 613) with MDD in symptomatic remission at baseline (17-item Hamilton Rating Scale for Depression [HAMD-17] <=7). Specific aspects of depression were assessed from physician and patient perspectives as secondary endpoints. A backwards selection strategy was used to statistically model remission status and determine association of factors with potential to influence remission. RESULTS: At month 6, after adjustment for baseline HAMD-17 score, there was no association between baseline RDQ score and symptomatic remission status (HAMD-17), relapse, composite remission status, healthcare resource utilization, or quality of life. There was no association between functional impairment scores at baseline (Sheehan Disability Scale and Social and Occupational Functioning Assessment Scale) and symptomatic remission status (HAMD-17) at month 6. CONCLUSIONS: This study indicates that RDQ-constructs are independent from symptomatic remission. Symptom severity at study entry appeared to be the only significant predictor of eventual relapse during the 6-month follow-up period. However, our results also suggest that the current definition of remission that is based on symptom reduction should be further elaborated and that alternative or additional definitions should be considered in determining remission. PMID- 27760535 TI - The Haiti Medical Education Project: development and analysis of a competency based continuing medical education course in Haiti through distance learning. AB - BACKGROUND: Recent calls for reform in healthcare training emphasize using competency-based curricula and information technology-empowered learning. Continuing Medical Education programs are essential in maintaining physician accreditation. Haitian physicians have expressed a lack access to these activities. The Haiti Medical Education Project works in alliance with Haitian medical leadership, faculty and students to support the Country's medical education system. We present the creation, delivery and evaluation of a competency-based continuing medical education curriculum for physicians in rural Haiti. METHODS: Real time lectures from local and international institutions were teleconferenced to physicians in remote Haitian sites using VidyoConferencingTM technology. With American Academy of Family Physicians (AAFP) and College of Family Physicians Canada (CFPC) guidelines as references, a competency-derived syllabus was created for a Haitian continuing medical education program. The resulting educational goals were reviewed by a committee of Haitian and North American physician/medical education practitioners to reflect local needs. All authors reviewed lectures and then conferred to establish agreement on competencies presented for each lecture. RESULTS: Sixty-seven lectures were delivered. Human immunodeficiency virus/Acquired Immunodeficiency Syndrome, ophthalmologic, infectious diseases, renal and endocrine competencies were well represented, with more than 50 % of the joint AAFP and CFPC recommended competencies outlined. Areas under-represented included allergy and immunology, cardiology, surgery, pain management, gastroenterology, neurology, pulmonology, men's health and rheumatology; these topics accounted for less than 25 % of AAFP/CFPC recommended competencies. Areas not covered included geriatrics, nutrition, occupational health and women's health. Within practice-based lectures, only disaster medicine, health promotion and information management were included, but only partially covered. CONCLUSIONS: We identified teaching goals covered and competencies that were missing from a CME program for rural Haitian physicians. We aim to use this analysis to provide a competency-based CME lecture series that proportionally meets local needs while following recommendations of recognized national family medicine organizations. PMID- 27760536 TI - A comparative, retrospective study of peri-articular and intra-articular injection of tranexamic acid for the management of postoperative blood loss after total knee arthroplasty. AB - BACKGROUND: Intra-articular injection of tranexamic acid (TXA) is known to be effective in controlling blood loss after total knee arthroplasty (TKA). However, this method has some disadvantages, such as TXA leakage due to soft tissue release. Peri-articular injection provides an alternative to intra-articular administration of TXA. This study aimed to evaluate the effects of peri-articular injection of TXA in reducing blood loss after TKA and compare them to those of intra-articular TXA injection. METHODS: This was a retrospective analysis of 127 patients who underwent primary, unilateral TKA for knee osteoarthritis in our hospital between January 2014 and December 2014. Cases were classified into 3 comparison groups: 49 patients in the peri-articular TXA group, 36 in the intra articular group, and 42 in the control group (TXA not administered). Demographic variables, hemoglobin (Hb) measured before and after surgery, operation time, total amount of drained volume, time of removing drains, units of blood transfused peri- and postoperatively, estimated volume of blood loss, and preoperative comorbidities were retrieved from the patients' medical charts. Statistical analyses were performed using SPSS 19.0 software. RESULTS: There were no significant differences of demographic variables and operation time among three groups (P > 0.05). Compared to the control group, both TXA groups had a significantly reduced volume of blood loss, postoperative knee joint drainage, hemoglobin concentration, time of removing drains, and need for blood transfusion (P < 0.05). The effects of TXA were comparable for the two methods of injection (P > 0.05). There were no deep venous thrombosis or thromboembolic complications in any group. CONCLUSIONS: Peri-articular injection of TXA is as effective as an intra-articular injection in reducing postoperative blood loss during TKA. Both methods had a statistically significant benefit in reducing the change in Hb concentration, volume of joint drainage, and estimated volume of blood loss when compared to the control group. Peri-articular injection of TXA can significantly reduce the blood transfusion rate compared to the control group. PMID- 27760537 TI - The prevalence of Nonsuicidal Self-Injury (NSSI) in a representative sample of the German population. AB - BACKGROUND: Non-suicidal self-injury (NSSI) is a proposed new "condition for further study" in the DSM-5. To date no prevalence data has been available on this diagnostic entity from a representative sample of the general population. METHODS: A representative sample of the German population (N = 2509, mean age = 48.8 years, SD = 18.1, female 55.4 %) completed the NSSI section of the German version of the Self-Injurious Thoughts and Behaviors Interview (SITBI-G). RESULTS: A history of NSSI at least once during lifetime was reported by 3.1 % of all participants, with higher lifetime prevalence rates in younger age groups. DSM-5 NSSI disorder criteria were met by 0.3 %. The most common function of NSSI was automatic negative reinforcement (e.g. to alleviate negative feelings). CONCLUSIONS: To the best of our knowledge, this is the first study reporting rates for the proposed NSSI category in DSM-5 from a representative sample of the general population. In comparison to findings from community samples of adolescents, adults seem to have lower lifetime prevalence rates of NSSI, thus making it necessary to emphasize prevention and treatment efforts in younger age groups. PMID- 27760538 TI - The role of socio-economic status in depression: results from the COURAGE (aging survey in Europe). AB - BACKGROUND: Low socio-economic status (SES) has been found to be associated with a higher prevalence of depression. However, studies that have investigated this association have been limited in their national scope, have analyzed different components of SES separately, and have not used standardized definitions or measurements across populations. The aim of the current study was to evaluate the association between SES and depression across three European countries that represent different regions across Europe, using standardized procedures and measurements and a composite score for SES. METHOD: Nationally-representative data on 10,800 individuals aged >=18 from the Collaborative Research on Ageing in Europe (COURAGE) survey conducted in Finland, Poland and Spain were analyzed in this cross-sectional study. An adapted version of the Composite International Diagnostic Interview was used to identify the presence of depression, and SES was computed by using the combined scores of the total number of years educated (0 22) and the quintiles of the country-specific income level of the household (1 5). Multivariable logistic regression was used to assess the association between SES and depression. RESULTS: Findings reveal a significant association between depression and SES across all countries (p <= 0.001). After adjusting for confounders, the odds of depression were significantly decreased for every unit increase in the SES index for Finland, Poland and Spain. Additionally, higher education significantly decreased the odds for depression in each country, but income did not. CONCLUSION: The SES index seems to predict depression symptomatology across European countries. Taking SES into account may be an important factor in the development of depression prevention strategies across Europe. PMID- 27760540 TI - Open questions: how does Wolbachia do what it does? AB - A common symbiont of insects, the bacterium Wolbachia has been implicated in phenomena as diverse as sex determination, pathogen defence and speciation and is being used in public health programs to prevent mosquitoes transmitting disease. Despite decades of research, we know remarkably little about how it exerts its effects. PMID- 27760539 TI - Chemotherapeutic potentials of the stem bark of Balanite aegyptiaca (L.) Delile: an antiangiogenic, antitumor and antioxidant agent. AB - BACKGROUND: Balanite aegyptiaca (L.) Delile, is a plant with extensive medicinal properties. Its stem bark is traditionally known for its spasmolytic and antiepileptic properties and used to treat yellow fever, jaundice and syphilis. Angiogenesis (sprouting of new blood vessels) is crucial for tumor growth and metastasis. The goal of this study is investigate the antiangiogenic, cytotoxicity and antioxidant activity as well as antitumor in vivo properties of B. aegyptiaca stem bark extracts. METHOD: The dried powder of stem bark was extracted sequentially with n-hexane, chloroform, methanol and water. Rat aorta ring assay (RARA) was used as a platform to screen for antiangiogenic affect. The most active extract was subjected to further confirmatory antiangiogenic tests i.e. cell migration, tube formation and VEGF inhibition and finally evaluated for its in vivo antitumor efficacy in nude mice. The cytotoxicity of extracts on four cancer cell lines (HCT-116, K562, U937 and MCF-7) and one normal cells line (HUVEC) was evaluated. To assess the antioxidant activity screening, four methods were used, (DPPH*) and ABTS radical scavenging activity, as well as total flavonoids and phenolic contents. RESULTS: Methanol extract of B. aegyptiaca stem bark (MBA) showed the highest antiangiogenic, antioxidant and anticancer properties. It was found selectively cytotoxic to leukemia cell lines as well as breast cancer cell line MCF-7. (MBA) thus exhibited antiangiogenic in ex-vivo rat aorta ring model; it was found to excel its antiangiogenic effect via inhibition of the key growth factor (VEGF) as well as to halt HUVEC cell migration and tube formation, furthermore animals bearing colon cancer treated with (MBA) showed significant reduction in tumor growth. CONCLUSION: Different extracts of B. aegyptiaca stem bark showed various anticancer and antiangiogenic properties. MBA demonstrated potent antiangiogenic, antioxidant and antitumor in vivo. The outcome of this study suggests the potential of stem bark of the B. aegyptiaca for developing chemotherapeutic agent against solid tumor as well as leukemia. PMID- 27760541 TI - Insect herbivory in a mature Eucalyptus woodland canopy depends on leaf phenology but not CO2 enrichment. AB - BACKGROUND: Climate change factors such as elevated atmospheric carbon dioxide concentrations (e[CO2]) and altered rainfall patterns can alter leaf composition and phenology. This may subsequently impact insect herbivory. In sclerophyllous forests insects have developed strategies, such as preferentially feeding on new leaf growth, to overcome physical or foliar nitrogen constraints, and this may shift under climate change. Few studies of insect herbivory at elevated [CO2] have occurred under field conditions and none on mature evergreen trees in a naturally established forest, yet estimates for leaf area loss due to herbivory are required in order to allow accurate predictions of plant productivity in future climates. Here, we assessed herbivory in the upper canopy of mature Eucalyptus tereticornis trees at the nutrient-limited Eucalyptus free-air CO2 enrichment (EucFACE) experiment during the first 19 months of CO2 enrichment. The assessment of herbivory extended over two consecutive spring-summer periods, with a first survey during four months of the [CO2] ramp-up phase after which full [CO2] operation was maintained, followed by a second survey period from months 13 to 19. RESULTS: Throughout the first 2 years of EucFACE, young, expanding leaves sustained significantly greater damage from insect herbivory (between 25 and 32 % leaf area loss) compared to old or fully expanded leaves (less than 2 % leaf area loss). This preference of insect herbivores for young expanding leaves combined with discontinuous production of new foliage, which occurred in response to rainfall, resulted in monthly variations in leaf herbivory. In contrast to the significant effects of rainfall-driven leaf phenology, elevated [CO2] had no effect on leaf consumption or preference of insect herbivores for different leaf age classes. CONCLUSIONS: In the studied nutrient-limited natural Eucalyptus woodland, herbivory contributes to a significant loss of young foliage. Leaf phenology is a significant factor that determines the level of herbivory experienced in this evergreen sclerophyllous woodland system, and may therefore also influence the population dynamics of insect herbivores. Furthermore, leaf phenology appears more strongly impacted by rainfall patterns than by e[CO2]. e[CO2] responses of herbivores on mature trees may only become apparent after extensive CO2 fumigation periods. PMID- 27760542 TI - A 10-day vacancy period after cleaning and disinfection has no effect on the bacterial load in pig nursery units. AB - BACKGROUND: Biosecurity measures such as cleaning, disinfection and a vacancy period between production cycles on pig farms are essential to prevent disease outbreaks. No studies have tested the effect of a longer vacancy period on bacterial load in nursery units. METHODS: The present study evaluated the effect of a 10-day vacancy period in pig nursery units on total aerobic flora, Enterococcus spp., Escherichia coli, faecal coliforms and methicillin resistant Staphylococcus aureus (MRSA). Three vacancy periods of 10 days were monitored, each time applied in 3 units. The microbiological load was measured before disinfection and at 1, 4, 7 and 10 days after disinfection. RESULTS: No significant decrease or increase in E. coli, faecal coliforms, MRSA and Enterococcus spp. was noticed. Total aerobic flora counts were the lowest on day 4 after disinfection (i.e. 4.07 log CFU/625 cm2) (P < 0.05), but the difference with other sampling moments was limited (i.e. 0.6 log CFU/625 cm2) and therefore negligible. Furthermore, this observation on day 4 was not confirmed for the other microbiological parameters. After disinfection, drinking nipples were still mostly contaminated with total aerobic flora (i.e. 5.32 log CFU/625 cm2) and Enterococcus spp. (i.e. 95 % of the samples were positive) (P < 0.01); the feeding troughs were the cleanest location (total aerobic flora: 3.53 log CFU/625 cm2 and Enterococcus spp.: 50 % positive samples) (P < 0.01). CONCLUSIONS: This study indicates that prolonging the vacancy period in nursery units to 10 days after disinfection with no extra biosecurity measures has no impact on the environmental load of total aerobic flora, E. coli, faecal coliforms, MRSA and Enterococcus spp.. PMID- 27760543 TI - Risk factors for possible serious bacterial infection in a rural cohort of young infants in central India. AB - BACKGROUND: Possible serious bacterial infection (PBSI) is a major cause of neonatal mortality worldwide. We studied risk factors for PSBI in a large rural population in central India where facility deliveries have increased as a result of a government financial assistance program. METHODS: We studied 37,379 pregnant women and their singleton live born infants with birth weight >= 1.5 kg from 20 rural primary health centers around Nagpur, India, using data from the 2010-13 population-based Maternal and Newborn Health Registry supported by NICHD's Global Network for Women's and Children's Health Research. Factors associated with PSBI were identified using multivariable Poisson regression. RESULTS: Two thousand one hundred twenty-three infants (6 %) had PSBI. Risk factors for PSBI included nulliparity (RR 1.13, 95 % CI 1.03-1.23), parity > 2 (RR 1.30, 95 % CI 1.07-1.57) compared to parity 1-2, first antenatal care visit in the 2nd/3rd trimester (RR 1.46, 95 % CI 1.08-1.98) compared to 1st trimester, administration of antenatal corticosteroids (RR 2.04, 95 % CI 1.60-2.61), low birth weight (RR 3.10, 95 % CI 2.17-4.42), male sex (RR 1.20, 95 % CI 1.10-1.31) and lack of early initiation of breastfeeding (RR 3.87, 95 % CI 2.69-5.58). CONCLUSION: Infants who are low birth weight, born to mothers who present late to antenatal care or receive antenatal corticosteroids, or born to nulliparous women or those with a parity > 2, could be targeted for interventions before and after delivery to improve early recognition of signs and symptoms of PSBI and prompt referral. There also appears to be a need for a renewed focus on promoting early initiation of breastfeeding following delivery in facilities. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov ( NCT01073475 ). PMID- 27760544 TI - The speed of tubule formation of two fijiviruses corresponds with their dissemination efficiency in their insect vectors. AB - BACKGROUND: Rice black-streaked dwarf virus (RBSDV) and Southern rice black streaked dwarf virus (SRBSDV) are two closely related fijiviruses transmitted by the small brown planthopper (SBPH) and white-backed planthopper (WBPH), respectively. SRBSDV has a latent period 4 days shorter than that of RBSDV, implying a more efficient spread in insect vector. Currently, the mechanisms underlying this higher efficiency are poorly understood. However, our recent studies have implicated a role of virus induced tubular structures in the dissemination of fijiiruses within their insect vectors. METHODS: Immunofluorescence labeling was performed to visualize and compare the dynamics of P7-1 tubule formation of the RBSDV and SRBSDV in their own vector insects and nonhost Spodoptera frugiperda (Sf9) cells. RESULTS: Tubule formation of SRBSDV P7 1 was faster than that of RBSDV P7-1. For RBSDV, P7-1 formed tubules were observed at 3-days post-first access to diseased plants (padp) in SBPH. For SRBSDV, these structures were detected as early as 1 day padp in WBPH. Importantly, similar phenomena were observed when P7-1 proteins from the two viruses were expressed alone in Sf9 cells. CONCLUSIONS: Our research revealed a relationship between the speed of P7-1 tubule formation and virus dissemination efficiency and also supports a role of such tubular structures in the spread of reoviruses within insect vectors. PMID- 27760545 TI - Factors associated with the severity and complication of patients with malaria hospitalized between 2009 and 2013 in three municipalities of Colombia, case control study. AB - BACKGROUND: Malaria worldwide annual reported cases range between 250 and 500 million and nearly half a million deaths are reported every year. Colombia has a vast expanse of territory with environmental and social conditions conducive to malaria transmission, which is the reason why it has second place in Latin America for the number of cases of malaria. METHODS: This is a retrospective, paired, case-control study that compares patients with severe malaria and malaria patients without mention of complication. Medical records of patients with confirmed malaria diagnosis were reviewed. The objective of this study was to identify factors associated with complicated malaria in three municipalities of Colombia during the period 2009-2013. RESULTS: A total sample of 180 medical records was collected, 60 corresponding to cases and 120 to controls following a 1:2 ratio. From the total sample, 88.33 % (159) of subjects were originally from Tumaco, 7.78 %, most of the patients of the study (104) were diagnosed and treated in 2013. Among the laboratory findings, the platelet count was found to have statistically significant differences between cases and controls; this was also true for total bilirubin value and transaminases. The most prevalent severity finding was clinical jaundice, followed by elevated bilirubin (25 %) and elevated transaminases (44.4 %). Thrombocytopenia was found in 11/44 cases (20 %) and only five of 60 patients (8.3 %) presented severe anaemia. The multivariate analysis showed that a platelet count <100,000 and clinical jaundice not associated with organ failure, were the two variables associated with severe malaria in the patients described. CONCLUSIONS: Most of the cases studied, despite meeting criteria of severity, were shown not to be as morbid or severe as in other countries. Clinical jaundice and thrombocytopaenia are associated with severe malaria, and they can be used by general practitioners or primary care physicians to promptly identify patients who may have severe malaria. PMID- 27760546 TI - Spatial heterogeneity can undermine the effectiveness of country-wide test and treat policy for malaria: a case study from Burkina Faso. AB - BACKGROUND: Considerable debate has arisen regarding the appropriateness of the test and treat malaria policy broadly recommended by the World Health Organization. While presumptive treatment has important drawbacks, the effectiveness of the test and treat policy can vary considerably across regions, depending on several factors such as baseline malaria prevalence and rapid diagnostic test (RDT) performance. METHODS: To compare presumptive treatment with test and treat, generalized linear mixed effects models were fitted to data from 6510 children under five years of age from Burkina Faso's 2010 Demographic and Health Survey. RESULTS: The statistical model results revealed substantial regional variation in baseline malaria prevalence (i.e., pre-test prevalence) and RDT performance. As a result, a child with a positive RDT result in one region can have the same malaria infection probability as a demographically similar child with a negative RDT result in another region. These findings indicate that a test and treat policy might be reasonable in some settings, but may be undermined in others due to the high proportion of false negatives. CONCLUSIONS: High spatial variability can substantially reduce the effectiveness of a national level test and treat malaria policy. In these cases, region-specific guidelines for malaria diagnosis and treatment may need to be formulated. Based on the statistical model results, proof-of-concept, web-based tools were created that can aid in the development of these region-specific guidelines and may improve current malaria-related policy in Burkina Faso. PMID- 27760547 TI - Secondary bladder amyloidosis with familial Mediterranean fever in a living donor kidney transplant recipient: a case report. AB - BACKGROUND: Secondary bladder amyloidosis is an extremely rare disease, resulting from a chronic systematic inflammatory disorder associated with amyloid deposits. Although uncommon in Japan, familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever of short duration and serositis and is frequently associated with systemic amyloidosis. Here, we present a case of a Japanese patient complaining of fever and macroscopic hematuria after a living donor renal transplantation. Consequently, he was diagnosed with secondary bladder amyloidosis with FMF. CASE PRESENTATION: A 64-year-old Japanese male received a living ABO-incompatible kidney transplant from his wife. The postoperative clinical course was normal, and the patient was discharged 21 days after the transplantation with a serum creatinine level of 0.78 mg/dl. The patient frequently complained of general fatigue and fever of unknown origin. Six months later, the patient presented with continuous general fatigue, macroscopic hematuria, and fever. Cystoscopic examination of the bladder showed an edematous region with bleeding, and a transurethral biopsy revealed amyloid deposits. His wife stated that the patient had a recurrent high fever since the age of 40 years and that his younger brother was suspected to have a familial autoinflammatory syndrome; thus, the patient was also suspected to have a familial autoinflammatory syndrome. Based on his brother's medical history and the genetic tests, which showed a homozygous mutation (M694V/M694V) for the Mediterranean fever protein, he was diagnosed with FMF. Although colchicine treatment for FMF was planned, the patient had an untimely death due to heart failure. We re-evaluated the pathological findings of the various tissue biopsies obtained during the treatment after the renal transplantation. Immunohistochemistry revealed amyloid deposits in the bladder region, renal allograft, and myocardium and the condition was diagnosed as AA amyloidosis associated with FMF. CONCLUSION: We presented a case of systemic amyloidosis with FMF, involving the bladder region, myocardium, and renal allograft, diagnosed after renal transplantation. Bladder amyloidosis should be considered in patients with macroscopic hematuria, particularly in the kidney transplant recipients with idiopathic chronic renal disease. Diagnosis of secondary bladder amyloidosis may result in the early detection of underlying diseases, which may contribute to patient prognosis. PMID- 27760548 TI - ATL-derived exosomes modulate mesenchymal stem cells: potential role in leukemia progression. AB - BACKGROUND: Exosomes are membrane nano-vesicles secreted by a multitude of cells that harbor biological constituents such as proteins, lipids, mRNA and microRNA. Exosomes can potentially transfer their cargo to other cells, implicating them in many patho-physiological processes. Mesenchymal stem cells (MSCs), residents of the bone marrow and metastatic niches, potentially interact with cancer cells and/or their derived exosomes. In this study, we investigated whether exosomes derived from adult T-cell leukemia/lymphoma (ATL) cells act as intercellular messengers delivering leukemia-related genes that modulate the properties of human MSCs in favor of leukemia. We hypothesized that the cargo of ATL-derived exosomes is transferred to MSCs and alter their functional behavior to support the establishment of the appropriate microenvironment for leukemia. RESULTS: We showed that both ATL cells (C81 and HuT-102) and patient-derived cells released Tax-containing exosomes. The cargo of HuT-102-derived exosomes consisted of miR 21, miR-155 and vascular endothelial growth factor. We demonstrated that HuT-102 derived exosomes not only deliver Tax to recipient MSCs, but also induce NF kappaB activation leading to a change in cellular morphology, increase in proliferation and the induction of gene expression of migration and angiogenic markers. CONCLUSIONS: This study demonstrates that ATL-derived exosomes deliver Tax and other leukemia-related genes to MSCs and alter their properties to presumably create a more conducive milieu for leukemia. These findings highlight the contribution of leukemia-derived exosomes in cellular transformation and their potential value as biomarkers and targets in therapeutic strategies. PMID- 27760549 TI - A new timepiece: an epigenetic mitotic clock. AB - A new mitotic clock and mathematical approach that incorporates DNA methylation biology common among human cell types provides a new tool for cancer epigenetics research. PMID- 27760550 TI - Clinicopathological features and BRAFV600E mutations in patients with isolated hypothalamic-pituitary Langerhans cell histiocytosis. AB - BACKGROUND: Isolated hypothalamic-pituitary Langerhans cell histiocytosis (HPLCH) is very rare. We investigated the clinicopathological characteristics, endocrine function changes, BRAFV600E mutations and treatments of isolated HPLCH. METHODS: We identified seven patients with isolated HPLCH by reviewing the clinical and pathological files in our hospital from 2007 to 2015. The clinical characteristics of the seven patients were retrospectively reviewed, especially the endocrine function changes. Immunostaining and mutation profiling of BRAFV600E were performed. RESULTS: The seven HPLCH patients included three men and four women, aged 9-47 years. All patients presented with symptoms of central diabetes insipidus (CDI), and four displayed anterior pituitary hypofunction as well. Magnetic resonance imaging showed hypothalamic-pituitary axis involvement in all patients. There was no evidence for the involvement of other organs in all seven patients. Langerhans cell histiocytosis was confirmed by neuroendoscopic procedures, and immunohistochemical staining showed that all cases (7/7) were positive for CD68, CD1a, Langerin, and S-100. The BRAFV600E mutation was detected in three of the six cases (3/6). Six patients had follow-up information; all received desmopressin acetate and high-dose corticosteroid therapy, and two patients received radiotherapy. CONCLUSIONS: Our study indicated that all patients with isolated HPLCH had CDI as the earliest symptom, and more than half of the patients had anterior pituitary deficiencies. The BRAFV600E mutation is a common genetic change in HPLCH patients. Treatment of HPLCH patients is difficult, and the progressive loss of endocrine function is irreversible in most cases. PMID- 27760551 TI - Understanding dentists' management of deep carious lesions in permanent teeth: a systematic review and meta-analysis. AB - BACKGROUND: Increasing evidence supports selective/incomplete (SE) or stepwise (SW) instead of non-selective/complete tissue removal for deep carious lesions in vital teeth, mainly as pulpal risks are significantly reduced. Our aims were to analyze the proportion of dentists who utilize SE/SW for deep lesions in permanent teeth and to identify barriers and facilitators of utilizing SE/SW. METHODS: We included studies that were original, and reported on the proportion of dentists utilizing SE/SW (quantitative studies), or reported on barriers or facilitators of such utilization (qualitative studies). Electronic databases (PubMed, CENTRAL, Embase, PsycINFO) were searched and screening and data extraction performed by two reviewers. Random-effects meta-analysis and meta regression were used for quantitative synthesis of the proportion of dentists utilizing SE/SW. Thematic analysis was performed to assess barriers and facilitators on SE/SW utilization. Identified themes were translated into the constructs of the theoretical domains framework. RESULTS: From 1728 articles, nine studies were included, all using quantitative methods. Four thousand one hundred ninety-nine dentists had been surveyed. The mean (95% CI) proportion of dentists using SE/SW for deep lesions was 53 % (44/62 %). More recent studies reported significantly higher proportions (p < 0.05). Reported estimates and thematic analysis found dentists' age and an understanding of the disease caries and the scientific rationale behind different removal strategies to affect dentists' behavior. Guidelines, peers, and the social and professional identity were further associated with the motivation of utilizing SE/SW. Environmental incentives, sanctions, or restrictions, mainly of financial but also regulatory character, impacted on decision-making, as did the specific indication (the patient, the tooth) and the beliefs on how well different treatments perform. CONCLUSIONS: Around half of all dentists rejected evidence-based carious tissue removal strategies. A range of factors can be addressed for improving implementation. Future studies should use mixed qualitative-quantitative methods to yield a deeper understanding of dentists' decision-making. TRIAL REGISTRATION: PROSPERO CRD42016038047. PMID- 27760552 TI - Facilitating factors and barriers to malaria research utilization for policy development in Malawi. AB - BACKGROUND: Research on various determinants of health is key in providing evidence for policy development, thereby leading to successful interventions. Utilization of research is an intricate process requiring an understanding of contextual factors. The study was conducted to assess enhancing factors and barriers of research utilization for malaria policy development in Malawi. METHODS: Qualitative research approach was used through in-depth interviews with 39 key informants that included malaria researchers, policy makers, programme managers, and key stakeholders. Purposive sampling and snowballing techniques were used in identifying key informants. Interview transcripts were entered in QSR Nvivo 11 software for coding and analysis. RESULTS: Respondents identified global efforts as key in advancing knowledge translation, while local political will has been conducive for research utilization. Other factors were availability of research, availability of diverse local researchers and stakeholders supporting knowledge translation. While barriers included: lack of platforms for researcher-public engagement, politics, researchers' lack of communication skills, lack of research collaborations, funder driven research, unknown World Health Organization policy position, and the lack of a malaria research repository. CONCLUSION: Overall, the study identified facilitating factors to malaria research utilization for policy development in Malawi. These factors need to be systematically coordinated to address the identified barriers and improve on malaria research utilization in policy development. Malaria research can be key in the implementation of evidence-based interventions to reduce the malaria burden and assist in the paradigm shift from malaria control to elimination in Malawi. PMID- 27760553 TI - Closing the loop: 3C versus DNA FISH. AB - Chromosome conformation capture (3C)-based techniques have revolutionized the field of nuclear organization, partly replacing DNA FISH as the method of choice for studying three-dimensional chromosome architecture. Although DNA FISH is commonly used for confirming 3C-based findings, the two techniques are conceptually and technically different and comparing their results is not trivial. Here, we discuss both 3C-based techniques and DNA FISH approaches to highlight their similarities and differences. We then describe the technical biases that affect each approach, and review the available reports that address their compatibility. Finally, we propose an experimental scheme for comparison of 3C and DNA FISH results. PMID- 27760555 TI - A modulatory role of ASICs on GABAergic synapses in rat hippocampal cell cultures. AB - Rapid acidification occurring during synaptic vesicle release can activate acid sensing ion channels (ASICs) both on pre- and postsynaptic neurons. In the latter case, a fraction of postsynaptic current would be mediated by cation-selective acid-sensing ion channels. Additionally, in both cases, activation of acid sensing ion channels could modulate synaptic strength by affecting transmitter release and/or sensitivity of postsynaptic receptors. To address potential involvement of acid-sensing ion channels in mediation/modulation of synaptic transmission at hippocampal GABAergic synapses, we studied effects of three structurally different blockers of acid-sensing ion channels on evoked postsynaptic currents using the patch-clamp technique. We found that GABAergic postsynaptic currents, recorded below their reversal potential as inward currents, are suppressed by all the employed blockers of acid-sensing ion channels. These currents were suppressed by ~ 20 % in the presence of a novel blocker 5b (1 MUM) and by ~30 % in the presence of either amiloride (25 MUM) or diminazene (20 MUM). In the same cells the suppression of postsynaptic currents, recorded above their reversal potential as outward currents was statistically insignificant. These results imply that the effects of blockers in our experiments are at least partially postsynaptic. On the other hand, in the case of mediation of a fraction of postsynaptic current by acid-sensing ion channels, an increase of outward currents would be expected under our experimental conditions. Our analysis of a bicuculline-resistant fraction of postsynaptic currents also suggests that effects of the blockers are predominantly modulatory. In this work we present evidence for the first time that acid-sensing ion channels play a functional role at hippocampal GABAergic synapses. The suppressing effect of the blockers of acid-sensing ion channels on GABAergic transmission is due, at least partially, to a postsynaptic but (predominantly) modulatory mechanism. We hypothesize that the modulatory effect is due to functional crosstalk between ASICs and GABAA-receptors recently reported in isolated neurons, however, verification of this hypothesis is necessary. PMID- 27760556 TI - The Local Edge Machine: inference of dynamic models of gene regulation. AB - We present a novel approach, the Local Edge Machine, for the inference of regulatory interactions directly from time-series gene expression data. We demonstrate its performance, robustness, and scalability on in silico datasets with varying behaviors, sizes, and degrees of complexity. Moreover, we demonstrate its ability to incorporate biological prior information and make informative predictions on a well-characterized in vivo system using data from budding yeast that have been synchronized in the cell cycle. Finally, we use an atlas of transcription data in a mammalian circadian system to illustrate how the method can be used for discovery in the context of large complex networks. PMID- 27760554 TI - Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. AB - BACKGROUND: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-alpha production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients. METHODS: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-alpha production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non survivors and among those who did and did not develop a secondary infection. RESULTS: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-alpha production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection. CONCLUSIONS: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-alpha production in adult medical and surgical critically ill patients. PMID- 27760557 TI - Chinese herbal medicine for the treatment of primary hypertension: a methodology overview of systematic reviews. AB - BACKGROUND: Chinese herbal medicine has been used to treat hypertension in China and East Asia since centuries. In this study, we conduct an overview of systematic reviews of Chinese herbal medicine in the treatment of primary hypertension to 1) summarize the conclusions of these reviews, 2) evaluate the methodological quality of these reviews, and 3) rate the confidence in the effect on each outcome. METHODS: We comprehensively searched six databases to retrieve systematic reviews of Chinese herbal medicine for primary hypertension from inception to December 31, 2015. We used AMSTAR to evaluate the methodological quality of included reviews, and we classified the quality of evidence for each outcome in included reviews using the GRADE approach. RESULTS: A total of 12 systematic reviews with 31 outcomes were included, among which 11 systematic reviews focus on the therapeutic effect of Chinese herbal medicine combined with conventional medicine or simple Chinese herbal medicine versus simple conventional medicine. Among the 11 items of AMSTAR, the lowest quality was "providing a priori design" item, none review conformed to this item, the next was "stating the conflict of interest" item, only three reviews conformed to this item. Five reviews scored less than seven in AMSTAR, which means that the overall methodological quality was fairly poor. For GRADE, of the 31 outcomes, the quality of evidence was high in none (0 %), moderate in three (10 %), low in 19 (61 %), and very low in nine (29 %). Of the five downgrading factors, risk of bias (100 %) was the most common downgrading factor in the included reviews, followed by imprecision (42 %), inconsistency (39 %), publication bias (39 %), and indirectness (0 %). CONCLUSIONS: The methodological quality of systematic reviews about Chinese herbal medicine for primary hypertension is fairly poor, and the quality of evidence level is low. Physicians should be cautious when applying the interventions in these reviews for primary hypertension patients in clinical practice. PMID- 27760558 TI - Tiny microbes, enormous impacts: what matters in gut microbiome studies? AB - Many factors affect the microbiomes of humans, mice, and other mammals, but substantial challenges remain in determining which of these factors are of practical importance. Considering the relative effect sizes of both biological and technical covariates can help improve study design and the quality of biological conclusions. Care must be taken to avoid technical bias that can lead to incorrect biological conclusions. The presentation of quantitative effect sizes in addition to P values will improve our ability to perform meta-analysis and to evaluate potentially relevant biological effects. A better consideration of effect size and statistical power will lead to more robust biological conclusions in microbiome studies. PMID- 27760560 TI - Chikungunya virus transmission between Aedes albopictus and laboratory mice. AB - BACKGROUND: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus associated with epidemics of acute and chronic arthritic disease in humans. Aedes albopictus has emerged as an important new natural vector for CHIKV transmission; however, mouse models for studying transmission have not been developed. METHODS: Aedes albopictus mosquitoes were infected with CHIKV via membrane feeding and by using infected adult wild-type C57BL/6 mice. Paraffin sections of infected mosquitoes were analysed by immunofluorescent antibody staining using an anti-CHIKV antibody. CHIKV-infected mosquitoes were used to infect adult C57BL/6 and interferon response factor 3 and 7 deficient (IRF3/7-/-) mice. RESULTS: Feeding mosquitoes on blood meals with CHIKV titres > 5 log10CCID50/ml, either by membrane feeding or feeding on infected mice, resulted in >= 50 % of mosquitoes becoming infected. However, CHIKV titres in blood meals >= 7 log10CCID50/ml were required before salivary glands showed significant levels of immunofluorescent staining with an anti-CHIKV antibody. Mosquitoes fed on blood meals of 7.5 (but not 5.9) log10CCID50/ml were able efficiently to transmit virus to adult C57BL/6 and IRF3/7-/- mice, with the latter mice showing overt signs of arthritis post infection. CONCLUSIONS: The results provide a simple in vivo model for studying transmission of CHIKV from mosquitoes to mammals and also argue against a resistance barrier to CHIKV infection in adult mice. PMID- 27760561 TI - Acute transfusion-related abdominal injury in trauma patients: a case report. AB - BACKGROUND: Secondary abdominal compartment syndrome is well known as a life threatening complication in critically ill patients in an intensive care unit. Massive crystalloid fluid resuscitation has been identified as the most important risk factor. The time interval from hospital admittance to the development of manifest abdominal compartment syndrome is usually greater than 24 hours. In the absence of any direct abdominal trauma, we observed a rapidly evolving secondary abdominal compartment syndrome shortly after hospital admittance associated with massive transfusion of blood products and only moderate crystalloid resuscitation. CASE PRESENTATION: We report the case of an acute secondary abdominal compartment syndrome developing within 3 to 4 hours in a 74-year-old polytraumatized white woman. Although multiple fractures of her extremities and a B-type pelvic ring fracture were diagnosed by a full body computed tomography scan, no intra-abdominal injury could be detected. Hemorrhagic shock with a drop in her hemoglobin level to 5.7 g/dl was treated by massive transfusion of blood products and high doses of catecholamines. Shortly afterwards, her pulmonary gas exchange progressively deteriorated and mechanical ventilation became almost impossible with peak airway pressures of up to 60 cmH2O. Her abdomen appeared rigid and tense accompanied by a progressive hemodynamic decompensation necessitating mechanic cardiopulmonary resuscitation. Although preoperative computed tomography scans showed no signs of intra-abdominal fluid, a decompressive laparotomy under cardiopulmonary resuscitation conditions was performed and 2 liters of ascites-like fluid disgorged. Her hemodynamics and pulmonary ventilation improved immediately. CONCLUSIONS: This case report describes for the first time acute secondary abdominal compartment syndrome in a trauma patient, evolving in a very short time period. We hypothesize that the massive transfusion of blood products along with high doses of catecholamines triggered the acute development of abdominal compartment syndrome. Trauma teams need to consider a rapidly developing secondary abdominal compartment syndrome to be a potential cause of hemodynamic decompensation not only in the later phase of treatment but also in the emergency phase of treatment. PMID- 27760559 TI - Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts. AB - BACKGROUND: Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts. METHODS: We queried the U.S. population based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as <=45 (young), 46-65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis. RESULTS: We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas. CONCLUSIONS: Older age at time of melanoma diagnosis is associated with shorter MSS, however age's association with clinicopathologic features is dependent upon specific characteristics of the study population. TIL as a read-out of the host immune response may have greater prognostic impact in patients older than age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly. PMID- 27760562 TI - Relationship between viral dose and outcome of infection in Atlantic salmon, Salmo salar L., post-smolts bath-challenged with salmonid alphavirus subtype 3. AB - Salmonid alphavirus subtype 3 (SAV3) causes pancreas disease (PD) and adversely affects salmonid aquaculture in Europe. A better understanding of disease transmission is currently needed in order to manage PD outbreaks. Here, we demonstrate the relationship between viral dose and the outcome of SAV3 infection in Atlantic salmon post-smolts using a bath challenge model. Fish were challenged at 12 degrees C with 3 different SAV3 doses; 139, 27 and 7 TCID50 L-1 of seawater. A dose of as little as 7 TCID50 L-1 of seawater was able to induce SAV3 infection in the challenged population with a substantial level of variation between replicate tanks and, therefore, likely represents a dose close to the minimum dose required to establish an infection in a population. These data also confirm the highly infectious nature of SAV through horizontal transmission. The outcome of SAV3 infection, evaluated by the prevalence of viraemic fish, SAV3 positive hearts, and the virus shedding rate, was positively correlated to the original SAV3 dose. A maximal shedding rate of 2.4 * 104 TCID50 L-1 of seawater h 1 kg-1 was recorded 10 days post-exposure (dpe) from the highest dose group. The method reported here, for the quantification of infectious SAV3 in seawater, could be useful to monitor PD status or obtain data from SAV3 outbreaks at field locations. This information could be incorporated into pathogen dispersal models to improve risk assessment and to better understand how SAV3 spreads between farms during outbreaks. This information may also provide new insights into the control and mitigation of PD. PMID- 27760563 TI - Evolution of the Tim17 protein family. AB - BACKGROUND: The Tim17 family of proteins plays a fundamental role in the biogenesis of mitochondria. Three Tim17 family proteins, Tim17, Tim22, and Tim23, are the central components of the widely conserved multi-subunit protein translocases, TIM23 and TIM22, which mediate protein transport across and into the inner mitochondrial membrane, respectively. In addition, several Tim17 family proteins occupy the inner and outer membranes of plastids. RESULTS: We have performed comprehensive sequence analyses on 5631 proteomes from all domains of life deposited in the Uniprot database. The analyses showed that the Tim17 family of proteins is much more diverse than previously thought and involves at least ten functionally and phylogenetically distinct groups of proteins. As previously shown, mitochondrial inner membrane accommodates prototypical Tim17, Tim22 and Tim23 and two Tim17 proteins, TIMMDC1 and NDUFA11, which participate in the assembly of complex I of the respiratory chain. In addition, we have identified Romo1/Mgr2 as Tim17 family member. The protein has been shown to control lateral release of substrates fromTIM23 complex in yeast and to participate in the production of reactive oxygen species in mammalian cells. Two peroxisomal proteins, Pmp24 and Tmem135, of so far unknown function also belong to Tim17 protein family. Additionally, a new group of Tim17 family proteins carrying a C terminal coiled-coil domain has been identified predominantly in fungi. CONCLUSIONS: We have mapped the distribution of Tim17 family members in the eukaryotic supergroups and found that the mitochondrial Tim17, Tim22 and Tim23 proteins, as well as the peroxisomal Tim17 family proteins, were all likely to be present in the last eukaryotic common ancestor (LECA). Thus, kinetoplastid mitochondria previously identified as carrying a single Tim17protein family homologue are likely to be the outcome of a secondary reduction. The eukaryotic cell has modified mitochondrial Tim17 family proteins to mediate different functions in multiple cellular compartments including mitochondria, plastids and peroxisomes. Concerning the origin of Tim17 protein family, our analyses do not support the affiliation of the protein family and the component of bacterial amino acid permease. Thus, it is likely that Tim17 protein family is exclusive to eukaryotes. REVIEWERS: The article was reviewed by Michael Gray, Martijn Huynen and Kira Makarova. PMID- 27760564 TI - The diagnostic value of non-contrast enhanced quiescent interval single shot (QISS) magnetic resonance angiography at 3T for lower extremity peripheral arterial disease, in comparison to CT angiography. AB - BACKGROUND: The high incidence of renal insufficiency in patients with Peripheral Arterial Disease raises the concern for nephrogenic systemic fibrosis (NSF) with respect to contrast enhanced MRA. The risk of NSF is eliminated with non-contrast enhanced magnetic resonance angiography. The purpose of the current study is to compare image quality and diagnostic performance of non-contrast enhanced Quiescent Interval Single Shot (QISS) magnetic resonance angiography at 3 T versus CT angiography for evaluation of lower extremity Peripheral Arterial Disease (PAD). METHODS: 32 consecutive patients (23 male, 9 female, age range 40 81 years, average age 61.97 years) with clinically suspected lower extremity PAD underwent QISS MRA and CTA. 19 of 32 patients underwent Digital Subtraction Angiography (DSA). Image quality of MRA was compared with CTA by two radiologists with 10 and 8 years' experience according to a 4-point scale. The Kappa test was used to determine the intermodality agreement between MRA and CTA in stenosis assessment, and interobserver agreement with each method. Sensitivity and specificity of CTA and MRA in detecting hemodynamically significant stenosis (>=50 %) were compared, with DSA serving as reference standard when available. RESULTS: Image quality of QISS MRA was rated 3.70 +/- 0.49 by reader 1, and 3.72 +/- 0.47 by reader 2, significantly lower than that of CTA (3.80 +/- 0.44 and 3.82 +/- 0.42, P < 0.001 for both readers). Intermodality agreement between MRA and CTA was excellent for assessment of stenosis (Kappa = 0.923 +/- 0.013 for reader 1, 0.930 +/- 0.012 for reader 2). Interobserver agreement was 0.936 +/- 0.012 for CTA and 0.935 +/- 0.011 for MRA. For readers 1 and 2 respectively, the sensitivity of QISS was 94.25 and 93.26 % (versus 90.11 and 89.13 % for CTA, P > 0.05), and specificity of QISS was 96.70 and 97.75 % (versus 96.55 and 96.51 % for CTA, P > 0.05). For heavily calcified segments, sensitivity of QISS (95.83 and 95.83 %) was significantly higher than that of CTA (74.19 and 76.67 %, P < 0.05). CONCLUSION: QISS is a reliable alternative to CTA for evaluation of lower extremity PAD, and may be suitable as a first-line screening examination in patients with contraindications to intravenous contrast administration. PMID- 27760565 TI - Erratum to: A method to assess image quality for Low-dose PET: analysis of SNR, CNR, bias and image noise. PMID- 27760567 TI - TransComb: genome-guided transcriptome assembly via combing junctions in splicing graphs. AB - Transcriptome assemblers aim to reconstruct full-length transcripts from RNA-seq data. We present TransComb, a genome-guided assembler developed based on a junction graph, weighted by a bin-packing strategy and paired-end information. A newly designed extension method based on weighted junction graphs can accurately extract paths representing expressed transcripts, whether they have low or high expression levels. Tested on both simulated and real datasets, TransComb demonstrates significant improvements in both recall and precision over leading assemblers, including StringTie, Cufflinks, Bayesembler, and Traph. In addition, it runs much faster and requires less memory on average. TransComb is available at http://sourceforge.net/projects/transcriptomeassembly/files/ . PMID- 27760566 TI - MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis. AB - BACKGROUND: Endometrial carcinoma (EC) is one of the most common malignancies of the female reproductive system. Migration and invasion inhibitory protein (MIIP) gene was recently discovered candidate tumor suppress gene which located at chromosome 1p36.22. 1p36 deletion was found in many types of tumor including EC. In the present study, we will determine the role and mechanism of MIIP in EC metastasis. METHODS: Immunohistochemistry was used to measure MIIP expression in normal and EC tissue. Both gain-of-function (infection) and loss-of-function (siRNA) assays were used to alter MIIP expression levels. The effect of MIIP on cell migration and invasion was measured by transwell assay. F-actin immunofluorescence staining was used to observe the cell morphology. The activation of GTP-loaded Rac1 was evaluated by Rac activity assay kit. Immunoprecipitation/WB was used to measure the interaction between MIIP and PAK1. RESULTS: We demonstrate that MIIP expression was significantly decreased in EC patients comparing to the normal ones, and decreased MIIP expression in EC tissues is associated with deep myometrial invasion, advanced stage, and the presence of lymph node metastasis. Using both gain-of-function (infection) and loss-of-function (siRNA) assays, we show that MIIP markedly blocked EC cell migration, whereas loss of MIIP led to increase in EC cell migration. We demonstrate that elevated expression of MIIP resulted in cytoskeleton reorganization with decreased formation of lamellipodia. We also provide evidence that MIIP is a key molecule in directing Rac1 signaling cascades in EC. Ectopically expressed MIIP consistently competed with Rac1-GTP for binding with the PAK1 p21-binding domain. Our data show that MIIP and PAK1 bind each other and that a C-terminal polyproline domain of MIIP is required for PAK1 binding. Deletion of the PAK1-binding domain of MIIP reduced cell migration-inhibiting activity. CONCLUSIONS: MIIP may function as a tumor suppressor gene for endometrial carcinoma. MIIP attenuates Rac1 signaling through a protein interaction network, and loss of this regulator may contribute to EC metastasis. PMID- 27760568 TI - The impact of life events on adult physical and mental health and well-being: longitudinal analysis using the GoWell health and well-being survey. AB - BACKGROUND: It is recognised that life events (LEs) which have been defined as incidents necessitating adjustment to habitual life either permanently or temporarily, not only have the potential to be detrimental to health and well being, but research suggests some LEs may be beneficial. This study aimed to determine the individual and cumulative occurrence of LEs; and to establish their effect on health and well-being. RESULTS: Demographic factors (gender, age and highest educational attainment), LE occurrence and self-reported health data were collected as part of the longitudinal GoWell community health and wellbeing survey (2008-2011). Self-reported health was measured using the SF-12 questionnaire for physical (SF-12 PCS) and mental health (SF-12 MCS) and the Warwick-Edinburgh mental well-being scale (WEMWBS) for well-being. Statistical analysis was performed using SPSSv21 and level of significance was set at p < 0.05. Results showed that the sample was 61.6 % (n = 768) female; 20.4 % (n = 254) were aged 16-39 years, 46.1 % (n = 575) 40-64 years and 33.5 % (n = 418) were over 65 years; 68.8 % (n = 819) had no qualifications/Scottish leaving certificates, with the remaining 31.2 % (n = 372) having their highest educational qualification above Scottish leaving certificates. Health score means were 49.3 SF-12 mental health component score (SF-12 MCS); 42.1 SF-12 physical health component score (SF-12 PCS); and 49.2 WEMWBS. Participants experienced 0-7 LEs over a three year period, with the most common being: housing improvement (44.9 %), house move (36.8 %), health event (26.3 %) and bereavement (25.0 %). Overall, an increase in LEs was associated with a health score decrease. Five LEs (relationship breakdown, health event, bereavement, victimisation and house move) had negative impacts on SF-12 MCS and two (new job/promotion and parenthood) had positive impacts. For SF-12 PCS only three (health event, bereavement and housing improvement) had a negative impact. Six (health event, victimisation, bereavement, relationship breakdown housing move and improvement) had negative impacts on well-being and two (new job/promotion, marriage) had positive effects. CONCLUSIONS: Findings from the current study confirm LEs have both detrimental and beneficial impacts on health and well-being. Further research is required to disentangle the complexity of LEs and the ways they affect health and well-being. PMID- 27760569 TI - Abdominal ectopic pregnancy after in vitro fertilization and single embryo transfer: a case report and systematic review. AB - BACKGROUND: Ectopic pregnancy is the leading cause of maternal morbidity and mortality during the first trimester and the incidence increases dramatically with assisted-reproductive technology (ART), occurring in approximately 1.5-2.1 % of patients undergoing in-vitro fertilization (IVF). Abdominal ectopic pregnancy is a rare yet clinically significant form of ectopic pregnancy due to potentially high maternal morbidity. While risk factors for ectopic pregnancy after IVF have been studied, very little is known about risk factors specific for abdominal ectopic pregnancy. We present a case of a 30 year-old woman who had an abdominal ectopic pregnancy following IVF and elective single embryo transfer, which was diagnosed and managed by laparoscopy. We performed a systematic literature search to identify case reports of abdominal or heterotopic abdominal ectopic pregnancies after IVF. A total of 28 cases were identified. RESULTS: Patients' ages ranged from 23 to 38 (Mean 33.2, S.D. = 3.2). Infertility causes included tubal factor (46 %), endometriosis (14 %), male factor (14 %), pelvic adhesive disease (7 %), structural/DES exposure (7 %), and unexplained infertility (14 %). A history of ectopic pregnancy was identified in 39 % of cases. A history of tubal surgery was identified in 50 % of cases, 32 % cases having had bilateral salpingectomy. Transfer of two embryos or more (79 %) and fresh embryo transfer (71 %) were reported in the majority of cases. Heterotopic abdominal pregnancy occurred in 46 % of cases while 54 % were abdominal ectopic pregnancies. CONCLUSIONS: Our systematic review has revealed several trends in reported cases of abdominal ectopic pregnancy after IVF including tubal factor infertility, history of tubal ectopic and tubal surgery, higher number of embryos transferred, and fresh embryo transfers. These are consistent with known risk factors for ectopic pregnancy following IVF. Further research focusing on more homogenous population may help in better characterizing this rare IVF complication and its risks. PMID- 27760571 TI - Patients as Patches: Ecology and Epidemiology in Healthcare Environments. AB - The modern healthcare system involves complex interactions among microbes, patients, providers, and the built environment. It represents a unique and challenging setting for control of the emergence and spread of infectious diseases. We examine an extension of the perspectives and methods from ecology (and especially urban ecology) to address these unique issues, and we outline 3 examples: (1) viewing patients as individual microbial ecosystems; (2) the altered ecology of infectious diseases specifically within hospitals; and (3) ecosystem management perspectives for infection surveillance and control. In each of these cases, we explore the accuracy and relevance of analogies to existing urban ecological perspectives, and we demonstrate a few of the potential direct uses of this perspective for altering research into the control of healthcare associated infections. Infect Control Hosp Epidemiol. 2016;1507-1512. PMID- 27760572 TI - Maternal abuse history and reduced fetal heart rate variability: Abuse-related sleep disturbance is a mediator. AB - The consequences of childhood maltreatment are profound and long lasting. Not only does the victim of abuse suffer as a child, but there is mounting evidence that a history of maltreatment places the next generation at risk for significant psychopathology. Research identifies postnatal factors as affecting this intergenerational transmission of trauma. However, emerging evidence suggests that part of this risk may be transmitted before birth, passed on via abuse related alterations in the in utero environment that are as yet largely unidentified. To date, no study has directly assessed the influence of pregnant women's abuse history on fetal neurobehavioral development, nor considered trauma associated poor sleep quality as a mediator reflecting established physiological dysregulation. Using data from 262 pregnant adolescents (ages 14-19), a population at elevated risk for childhood maltreatment, the current study examined maternal emotional abuse history and sleep quality in relation to third trimester fetal resting heart rate variability, an index of parasympathetic nervous system functioning. The results indicate that maternal emotional abuse history is indirectly associated with lower fetal heart rate variability via abuse-related sleep disturbances. These data demonstrate an association between maternal abuse histories and fetal development, showing that at least part of the intergenerational transmission of risk occurs during pregnancy. PMID- 27760570 TI - Rumen metagenome and metatranscriptome analyses of low methane yield sheep reveals a Sharpea-enriched microbiome characterised by lactic acid formation and utilisation. AB - BACKGROUND: Enteric fermentation by farmed ruminant animals is a major source of methane and constitutes the second largest anthropogenic contributor to global warming. Reducing methane emissions from ruminants is needed to ensure sustainable animal production in the future. Methane yield varies naturally in sheep and is a heritable trait that can be used to select animals that yield less methane per unit of feed eaten. We previously demonstrated elevated expression of hydrogenotrophic methanogenesis pathway genes of methanogenic archaea in the rumens of high methane yield (HMY) sheep compared to their low methane yield (LMY) counterparts. Methane production in the rumen is strongly connected to microbial hydrogen production through fermentation processes. In this study, we investigate the contribution that rumen bacteria make to methane yield phenotypes in sheep. RESULTS: Using deep sequence metagenome and metatranscriptome datasets in combination with 16S rRNA gene amplicon sequencing from HMY and LMY sheep, we show enrichment of lactate-producing Sharpea spp. in LMY sheep bacterial communities. Increased gene and transcript abundances for sugar import and utilisation and production of lactate, propionate and butyrate were also observed in LMY animals. Sharpea azabuensis and Megasphaera spp. act as important drivers of lactate production and utilisation according to phylogenetic analysis and read mappings. CONCLUSIONS: Our findings show that the rumen microbiome in LMY animals supports a rapid heterofermentative growth, leading to lactate production. We postulate that lactate is subsequently metabolised mainly to butyrate in LMY animals, producing 2 mol of hydrogen and 0.5 mol of methane per mol hexose, which represents 24 % less than the 0.66 mol of methane formed from the 2.66 mol of hydrogen produced if hexose fermentation was directly to acetate and butyrate. These findings are consistent with the theory that a smaller rumen size with a higher turnover rate, where rapid heterofermentative growth would be an advantage, results in lower hydrogen production and lower methane formation. Together with previous methanogen gene expression data, this builds a strong concept of how animal traits and microbial communities shape the methane phenotype in sheep. PMID- 27760573 TI - Distinctive distribution of HPV genotypes in cervical cancers in multi-ethnic Suriname: implications for prevention and vaccination. AB - Suriname is ranked as high-risk country for cervical cancer, but recent national data of HPV prevalence and distribution in cervical cancer is scarce. In a retrospective cross-sectional study, cervical cancer incidence, HPV prevalence and HPV-type-specific distribution were investigated in all cervical cancer cases (n = 111), diagnosed in two consecutive years. HPV presence and type-specific prevalence were determined in paraffin-embedded biopsies utilizing master-nested multiplex PCR assays, targeting 14 HPV types. The age-standardized incidence rate of cervical cancer was 22.4/100 000 women, justifying revision of the current international ranking of Suriname. Eleven HPV types were detected, with the most common types in descending order of frequency: 16, 18, 45, 66, 58/52/35. HPV16 was predominant, although with markedly low presence (25%). HPV16 or 18 infections were detected in 43% of the cases, while 28% were untyped, implicating a divergent HPV-type distribution in Suriname with significant variation in the prevalence of less common high-risk virus types and/or presence of HPV16 variants. HPV-type distribution differed between ethnic groups. A vaccination efficacy of just 28-30% was anticipated, next to an uneven vaccination impact in different ethnic groups, cautioning Suriname and other multi-ethnic countries to tailor the information presented to different ethnic communities. PMID- 27760574 TI - Optimal vaccine schedules to maintain measles elimination with a two-dose routine policy. AB - Measles was eliminated in the Americas in 2002 by a combination of routine immunizations and supplementary immunization activities. Recent outbreaks underscore the importance of reconsidering vaccine policy in order to maintain elimination. We constructed an age-structured dynamical model for the distribution of immunity in a population with routine immunization and without disease, and analysed the steady state for an idealized age structure and for real age structures of countries in the Americas. We compared the level of immunity maintained by current policy in these countries to the level maintainable by an optimal policy. The optimal age target for the first routine dose of measles vaccine depends on the timing and coverage of both doses. Similarly, the optimal age target for the second dose of measles vaccine depends on the timing and coverage of the first dose. The age targets for the first and second doses of measles vaccine should be adjusted for the post-elimination era, by specifically accounting for current context, including realized coverage of both doses, and altered maternal immunity. Doing so can greatly improve the proportion immune within a population, and therefore the chances of maintaining measles elimination, without changing coverage. PMID- 27760575 TI - The interactive effects of child maltreatment and the FK506 binding protein 5 gene (FKBP5) on dissociative symptoms in adolescence. AB - The FK506 binding protein 5 gene (FKBP5) has been associated with susceptibility to pathogenic effects of childhood trauma including dissociative symptoms. This study examines the impact of maltreatment on dissociative tendencies in adolescence as moderated by the FKBP5 gene. Dissociative symptoms and variation within FKBP5 were assessed in a high-risk, low socioeconomic status community sample of 279 maltreated and 171 nonmaltreated adolescents. Following the assignment of haplotypes across four single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080), individuals with one or more copies of the CATT haplotype (N = 230) were grouped together and compared to individuals with zero copies of this haplotype (N = 185). Analyses of covariance were conducted to test hypotheses regarding the effects of developmental timing and the chronicity of maltreatment and the CATT haplotype. We found a significant interactive effect of timing/chronicity of maltreatment and the CATT haplotype on dissociative symptoms. Among adolescents who had no copies of the CATT haplotype, dissociative symptoms were higher for chronically maltreated adolescents who had an infancy onset compared to those who were not maltreated or whose maltreatment experience was either relatively less chronic or not started in infancy. The groups did not differ significantly among subjects who carry one or more copies of the CATT haplotype. PMID- 27760577 TI - The endocrinology of human caregiving and its intergenerational transmission. AB - Variation in the quality of parental care has a tremendous impact on a child's social-emotional development. Research investigating the predictors of this variability in human caregiving behavior has mostly focused on learning mechanisms. Evidence is currently accumulating for the complementary underlying role of steroid hormones and neuropeptides. An overview is provided of the hormones and neuropeptides relevant for human caregiving behavior. Then the developmental factors are described that stimulate variability in sensitivity to these hormones and neuropeptides, which may result in variability in the behavioral repertoire of caregiving. The role of genetic variation in neuropeptide and steroid receptors, the role of testosterone and oxytocin during fetal development and parturition, and the impact of experienced caregiving in childhood on functioning of the neuroendocrine stress and oxytocin system are discussed. Besides providing a heuristic framework for further research on the ontogenetic development of human caregiving, a neuroendocrine model is also presented for the intergenerational transmission of caregiving practices. Insight into the underlying biological mechanisms that bring about maladaptive caregiving behavior, such as neglect and insensitive parenting, will hopefully result in more efficient approaches to reduce the high prevalence of such behavior and to minimize the impact on those affected. PMID- 27760578 TI - Attachment representations and autonomic regulation in maltreating and nonmaltreating mothers. AB - This study assessed attachment representation and attachment-related autonomic regulation in a sample of 38 maltreating and 35 nonmaltreating mothers. Mothers' state of mind regarding attachment was measured using the Adult Attachment Interview. They further watched an attachment-based comfort paradigm, during which we measured skin conductance and vagal tone. More maltreating mothers (42%) than nonmaltreating mothers (17%) had an unresolved/disoriented attachment classification. Attachment representation was related to physiology during the comfort paradigm: an unresolved state of mind and a nonautonomous classification were associated with a decrease in skin conductance during the comfort paradigm, specifically during the responsive caregiver scenario. However, physiology did not differ between maltreating and nonmaltreating mothers. The decrease in skin conductance of unresolved mothers during the comfort paradigm might be indicative of a deactivating response, which is congruent with the dissociative nature of the unresolved state of mind. The results point to the potential utility of interventions focused on attachment representations for maltreating mothers. PMID- 27760576 TI - Unusual Legionnaires' outbreak in cool, dry Western Canada: an investigation using genomic epidemiology. AB - An outbreak of Legionnaires' disease occurred in an inner city district in Calgary, Canada. This outbreak spanned a 3-week period in November-December 2012, and a total of eight cases were identified. Four of these cases were critically ill requiring intensive care admission but there was no associated mortality. All cases tested positive for Legionella pneumophila serogroup 1 (LP1) by urinary antigen testing. Five of the eight patients were culture positive for LP1 from respiratory specimens. These isolates were further identified as Knoxville monoclonal subtype and sequence subtype ST222. Whole-genome sequencing revealed that the isolates differed by no more than a single vertically acquired single nucleotide variant, supporting a single point-source outbreak. Hypothesis-based environmental investigation and sampling was conducted; however, a definitive source was not identified. Geomapping of case movements within the affected urban sector revealed a 1.0 km common area of potential exposure, which coincided with multiple active construction sites that used water spray to minimize transient dust. This community point-source Legionnaires' disease outbreak is unique due to its ST222 subtype and occurrence in a relatively dry and cold weather setting in Western Canada. This report suggests community outbreaks of Legionella should not be overlooked as a possibility during late autumn and winter months in the Northern Hemisphere. PMID- 27760579 TI - Comprehensive screening for immunodeficiency-associated vaccine-derived poliovirus: an essential oral poliovirus vaccine cessation risk management strategy. AB - If the world can successfully control all outbreaks of circulating vaccine derived poliovirus that may occur soon after global oral poliovirus vaccine (OPV) cessation, then immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) from rare and mostly asymptomatic long-term excretors (defined as ?6 months of excretion) will become the main source of potential poliovirus outbreaks for as long as iVDPV excretion continues. Using existing models of global iVDPV prevalence and global long-term poliovirus risk management, we explore the implications of uncertainties related to iVDPV risks, including the ability to identify asymptomatic iVDPV excretors to treat with polio antiviral drugs (PAVDs) and the transmissibility of iVDPVs. The expected benefits of expanded screening to identify and treat long-term iVDPV excretors with PAVDs range from US$0.7 to 1.5 billion with the identification of 25-90% of asymptomatic long-term iVDPV excretors, respectively. However, these estimates depend strongly on assumptions about the transmissibility of iVDPVs and model inputs affecting the global iVDPV prevalence. For example, the expected benefits may decrease to as low as US$260 million with the identification of 90% of asymptomatic iVDPV excretors if iVDPVs behave and transmit like partially reverted viruses instead of fully reverted viruses. Comprehensive screening for iVDPVs will reduce uncertainties and maximize the expected benefits of PAVD use. PMID- 27760581 TI - Mental health literacy as a mediator in use of mental health services among older korean adults. AB - BACKGROUND: Existing literature suggests that mental health literacy is positively associated with mental health services utilization. Despite an aging population that faces significant mental health concerns in Korea, the role of mental health literacy on mental health services utilization is not known among older adults in Korea. This study aimed to (1) identify whether mental health literacy mediates the association between population characteristics and mental health services utilization and (2) identify an optimal path model for mental health services utilization among Korean older adults. METHODS: Using a cross sectional survey with a quota sampling strategy, we collected and analyzed responses from 596 community-dwelling individuals ages 65 years and older. We used structural equation modeling (SEM) to estimate the effect of mental health literacy as a mediator. RESULTS: When controlling for other relevant covariates in the optimal path model, mental health literacy mediated the relationships between three socio-demographic factors (education, general literacy, and health status) and mental health services utilization. The model fit index shows that the SEM fits very well (CFI = 0.92, NFI = 0.90, RMSEA = 0.07). CONCLUSIONS: Efforts to improve mental health literacy through community-based education programs may need to particularly target Korean older adults with the relevant socio-demographic characteristics to enhance their utilization of appropriate mental health services. PMID- 27760580 TI - Smoking in young adulthood among African Americans: Interconnected effects of supportive parenting in early adolescence, proinflammatory epitype, and young adult stress. AB - We examined two potentially interacting, connected pathways by which parental supportiveness during early adolescence (ages 1-13) may come to be associated with later African American young adult smoking. The first pathway is between parental supportiveness and young adult stress (age 19), with stress, in turn, predicting increased smoking at age 20. The second pathway is between supportive parenting and tumor necrosis factor (TNF) gene methylation (i.e., TNFm), a proinflammatory epitype, with low levels indicating greater inflammatory potential and forecasting increased risk for smoking in response to young adult stress. In a sample of 382 African American youth residing in rural Georgia, followed from early adolescence (age 10-11) to young adulthood (age 20), supportive parenting indirectly predicted smoking via associations with young adult stress, IE = -0.071, 95% confidence interval [-0.132, -0.010]. In addition, supportive parenting was associated with TNFm measured at age 20 (r = .177, p = .001). Further, lower TNFm was associated with a significantly steeper slope (b = 0.583, p = .003) of increased smoking in response to young adult stress compared to those with higher TNFm (b = 0.155, p = .291), indicating an indirect, amplifying role for supportive parenting via TNFm. The results suggest that supportive parenting in early adolescence may play a role in understanding the emergence of smoking in young adulthood. PMID- 27760582 TI - The association between maternal postnatal depressive symptoms and offspring sleep problems in adolescence. AB - BACKGROUND: Sleep problems are associated with increased risk of physical and mental illness. Identifying risk factors is an important method of reducing public health impact. We examined the association between maternal postnatal depression (PND) and offspring adolescent sleep problems. METHOD: The sample was derived from Avon Longitudinal Study of Parents and Children (ALSPAC) participants. A sample with complete data across all variables was used, with four outcome variables. A sensitivity analysis imputing for missing data was conducted (n = 9633). RESULTS: PND was associated with increased risk of sleep problems in offspring at ages 16 and 18 years. The most robust effects were sleep problems at 18 years [adjusted odds ratio (OR) for a 1 s.d. increase in PND, 1.26, 95% confidence interval (CI) 1.15-1.39, p < 0.001] and waking more often (adjusted OR 1.14, 95% CI 1.05-1.25, p = 0.003). This remained after controlling for confounding variables including antenatal depression and early sleep problems in infancy. CONCLUSIONS: PND is associated with adolescent offspring sleep problems. Maternal interventions should consider the child's increased risk. Early sleep screening and interventions could be introduced within this group. PMID- 27760583 TI - Utilization of Health Services Among Adults With Recurrent Clostridium difficile Infection: A 12-Year Population-Based Study. AB - BACKGROUND Considerable efforts have been dedicated to developing strategies to prevent and treat recurrent Clostridium difficile infection (rCDI); however, evidence of the impact of rCDI on patient healthcare utilization and outcomes is limited. OBJECTIVE To compare healthcare utilization and 1-year mortality among adults who had rCDI, nonrecurrent CDI, or no CDI. METHODS We performed a nested case-control study among adult Kaiser Foundation Health Plan members from September 1, 2001, through December 31, 2013. We identified CDI through the presence of a positive laboratory test result and divided patients into 3 groups: patients with rCDI, defined as CDI in the 14-57 days after initial CDI; patients with nonrecurrent CDI; and patients who never had CDI. We conducted 3 matched comparisons: (1) rCDI vs no CDI; (2) rCDI vs nonrecurrent CDI; (3) nonrecurrent CDI vs no CDI. We followed patients for 1 year and compared healthcare utilization between groups, after matching patients on age, sex, and comorbidity. RESULTS We found that patients with rCDI consistently have substantially higher levels of healthcare utilization in various settings and greater 1-year mortality risk than both patients who had nonrecurrent CDI and patients who never had CDI. CONCLUSIONS Patients who develop an initial CDI are generally characterized by excess underlying, severe illness and utilization. However, patients with rCDI experience even greater adverse consequences of their disease than patients who do not experience rCDI. Our results further support the need for continued emphasis on identifying and using novel approaches to prevent and treat rCDI. Infect Control Hosp Epidemiol. 2016;1-8. PMID- 27760584 TI - Assessment of the effect of housing on feather damage in laying hens using IR thermography. AB - Plumage damage represents one of the animal-based measures of laying hens welfare. Damage occurs predominantly due to age, environment and damaging pecking. IR thermography, due to its non-invasiveness, objectivity and repeatability is a promising alternative to feather damage scoring systems such as the system included in the Welfare Quality (r) assessment protocol for poultry. The aim of this study was to apply IR thermography for the assessment of feather damage in laying hens kept in two housing systems and to compare the results with feather scoring. At the start of the experiment, 16-week-old laying hens (n=30) were divided into two treatments such as deep litter pen and enriched cage. During 4 months, feather damage was assessed regularly in 2-week intervals. One more single assessment was done nine and a half months after the start of the experiment. The feather damage on four body regions was assessed by scoring and IR thermography: head and neck, back and rump, belly, and underneck and breast. Two variables obtained by IR thermography were used: the difference between the body surface temperature and ambient temperature (DeltaTB) and the proportion of featherless areas, which were defined as areas with a temperature >33.5 degrees C. Data were analyzed using a GLM model. The effects of housing, time, region and their interactions on feather damage, measured by the feather scoring and by both IR thermography measures, were all significant (P<0.001). The DeltaTB in all assessed regions correlated positively with the feather score. Feather scoring revealed higher damage in enriched cages compared with deep litter pens starting from week 6 of the experiment on the belly and back and rump regions, whereas DeltaTB from week 6 in the belly and from week 8 on the back and rump region. The proportion of featherless areas in the belly region differed significantly between the housings from week 8 of the experiment and on the back and rump region from week 12. The IR thermography assessment of the feather damage revealed differences between hens kept in different housing systems in agreement with the feather scoring. In conclusion, it was demonstrated that the IR thermography is a useful tool for the assessment of poultry feather cover quality that is not biased by the subjective component and provides higher precision than feather damage scoring. PMID- 27760585 TI - The neurobiology of self-processing in abused depressed adolescents. AB - Maltreatment is associated with chronic depression, high negative self attributions, and lifetime psychopathology. Adolescence is a sensitive period for the formation of self-concept. Identifying neurobiomarkers of self-processing in depressed adolescents with and without maltreatment may parse the effects of trauma and depression on self-development and chronic psychopathology. Depressed adolescents (n = 86) maltreated due to omission (DO, n = 13) or commission (DCM, n = 28) or without maltreatment (DC, n = 45), and HCs (HC, n = 37) appraised positive and negative self-descriptors in the scanner. DCM and DO showed hypoactivity in the dorsal anterior cingulate cortex (dACC) while processing positive versus negative self-descriptors compared to DC youth, who in turn showed reduced dACC recruitment versus HC. HC youth showed the highest activation in the dACC and striatum during positive self-descriptors; these regions showed a linear decline in activity across DC, DO, and DCM. Low dACC activity to positive versus negative self-descriptors was linked to inadequate coregulation of children's emotions by parents. Negative self-cognitions prevalent in DCM and DO adolescents may be perpetuated by activity in the dACC and striatum. Reduced activation of the dACC and striatum for positive self-descriptors, coupled with enhanced activity for negative self-descriptors, may heighten the risk for persistent depression. PMID- 27760587 TI - Truncated Bid Overexpression Induced by Recombinant Adenovirus Cre/LoxP System Suppresses the Tumorigenic Potential of CD133+ Ovarian Cancer Stem Cells. AB - Ovarian cancer is one of the most lethal malignant gynecologic tumors with a high relapse rate worldwide. Cancer stem cells (CSCs) have been identified in ovarian cancer and other malignant tumors as a small population of cells that are capable of self-renewal and multidifferentiation. CD133+ ovarian CSCs have been reported to be more tumorigenic and more resistant to chemotherapeutic treatment. Thus, CD133 has emerged as one of the most promising therapeutic markers for ovarian cancer treatment. In the current study, we constructed a recombinant adenovirus Cre/loxP regulation system to selectively introduce truncated Bid (tBid) expression specifically targeting CD133+ in ovarian CSCs. The results demonstrated that the coinfection of Ad-CD133-Cre and Ad-CMV-LoxP-Neo-LoxP-tBid significantly increased tBid expression in CD133+ ovarian CSCs. Moreover, the tBid overexpression induced by a recombinant adenovirus Cre/loxP system dramatically inhibited cell proliferation and invasion, significantly elevated cell apoptosis, and activated the mitochondrial apoptosis pathway in CD133+ ovarian CSCs. Additionally, recombinant adenovirus Cre/loxP system-mediated tBid overexpression suppressed the tumorigenic potential of CD133+ ovarian CSCs in a xenograft mouse model. In conclusion, our study successfully constructed a recombinant adenovirus Cre/loxP system and induced tBid overexpression in CD133+ ovarian CSCs, providing a new therapeutic approach for ovarian cancer treatment. PMID- 27760586 TI - Effects of angiogenin on granulosa and theca cell function in cattle. AB - Angiogenin is a member of the ribonuclease A superfamily of proteins that has been implicated in stimulating angiogenesis but whether angiogenin can directly affect ovarian granulosa or theca cell function is unknown. Therefore, the objective of these studies was to determine the effect of angiogenin on proliferation and steroidogenesis of bovine granulosa and theca cells. In experiments 1 and 2, granulosa cells from small (1 to 5 mm diameter) follicles and theca cells from large (8 to 22 mm diameter) follicles were cultured to evaluate the dose-response effect of recombinant human angiogenin on steroidogenesis. At 30 and 100 ng/ml, angiogenin inhibited (P0.10) granulosa cell estradiol production or theca cell progesterone production, and did not affect numbers of granulosa or theca cells. In experiments 3 and 4, granulosa and theca cells from both small and large follicles were cultured with 300 ng/ml of angiogenin to determine if size of follicle influenced responses to angiogenin. At 300 ng/ml, angiogenin increased large follicle granulosa cell proliferation but decreased small follicle granulosa cell progesterone and estradiol production and large follicle theca cell progesterone production. In experiments 5 and 6, angiogenin stimulated (P<0.05) proliferation and DNA synthesis in large follicle granulosa cells. In experiment 7, 300 ng/ml of angiogenin increased (P<0.05) CYP19A1 messenger RNA (mRNA) abundance in granulosa cells but did not affect CYP11A1 mRNA abundance in granulosa or theca cells and did not affect CYP17A1 mRNA abundance in theca cells. We conclude that angiogenin appears to target both granulosa and theca cells in cattle, but additional research is needed to further understand the mechanism of action of angiogenin in granulosa and theca cells, as well as its precise role in folliculogenesis. PMID- 27760588 TI - Development of Loop-Mediated Isothermal Amplification (LAMP) Assay for the Rapid Detection of Alternaria alternata. AB - Fungi of the Alternaria genus are associated with allergic diseases, with Alternaria alternata being one of the most prevalent species. A. alternata has been frequently reported as the etiologic agent of hypersensitivity pneumonitis, allergic rhinosinusitis, bronchial asthma, and other diseases. In this study, we developed a loop-mediated isothermal amplification (LAMP) assay and a real-time PCR assay to detect low levels of A. alternata in herbal tea samples. The LAMP assay can detect as little as 3 pg/MUL of A. alternata genomic DNA with high specificity. In addition, both the LAMP assay and the real-time PCR assay can be used for quantification of A. alternata. Although the newly developed LAMP assay is more rapid and specific in A. alternata identification, the real-time PCR assay is more precise in quantitation analysis. PMID- 27760589 TI - Bioanalytical Method Validation for Dronedarone and Duloxetine in Blood Serum. AB - The present work relates to the development and validation of reversed-phase HPLC UV-photodiode array methods for the estimation of two drugs in blood serum: dronedarone hydrochloride (DDN), a class III antiarrhythmic drug, and duloxetine hydrochloride (DLX), an antidepressant. Chromatographic analysis of DLX was carried out on a Nucleodur C18 column (250 * 4.6 mm, 5 MUm) using ammonium acetate buffer (32 mM, pH 5.5) and acetonitrile (40 + 60, v/v; flow rate of 1.0 mL/min; detection wavelength of 290 nm) as the mobile phase. A Waters XTerra C18 column (250 * 4.6 mm, 5 MUm) was used for the chromatographic analysis of DDN using an acetonitrile-ammonium formate buffer (20 mM, pH 3.0, with formic acid; 45 + 55, v/v; flow rate 1.0 mL/min) as the mobile phase. Pentazocine and bupropion HCl were used as the internal reference standards for DLX and DDN, respectively. Excellent linearity was observed for DLX (r2 = 0.9996; concentration range 0.2-10.0 MUg/mL) and DDN (r2 = 0.9997; concn. range 2.0-50.0 MUg/mL). The LODs for DLX and DDN were 0.022 and 0.78 MUg/mL, respectively, and the LOQs 0.066 and 2.4 MUg/mL, respectively. PMID- 27760590 TI - The Inhibitory Effect of PDIA6 Downregulation on Bladder Cancer Cell Proliferation and Invasion. AB - Protein disulfide isomerases A6 (PDIA6) belongs to the PDI family. Recently, PDIA6 was found to have a close association with various cancers. However, there has been little investigation into the biological functions of PDIA6 in bladder cancer (BC). In this study, we explored the expression pattern and functional significance of PDIA6 in BC. We found that PDIA6 was overexpressed in BC tissues and cell lines. The in vitro study showed that PDIA6 downregulation significantly inhibited BC proliferation and invasion. In addition, the in vivo experiment demonstrated that PDIA6 downregulation decreased the volume, weight, and metastasis of tumors. Furthermore, PDIA6 downregulation reduced the protein expression of beta-catenin, cyclin D1, and c-Myc and thus suppressed the Wnt/beta catenin signaling pathway. In conclusion, we suggest that PDIA6 could be targeted for the treatment of BC. PMID- 27760591 TI - [Clinical Significance of Tumor Marker Detection in Patients ?with Advanced Squamous Cell Carcimoma of the Lung]. AB - BACKGROUND: Due to it's concealment and no obvious symptoms, lung squamous carcimoma often has advanced disease when diagnosed. The aims of this study were to describe the characteristics of the disease, to evaluate the clinical importance of detection of multiple tumor markers in patients with squamous cell carcinoma of the lung. METHODS: The characteristics of all patients with advanced squamous cell lung cancer treated in Beijing Cancer Hospital of Chinese Academy of Medical Sciences during Jan. 2011 to Dec. 2015 were identified by cases reviewing and data extracting. The characteristics, detection levels and sensitivity of multiple tumor makers among patients were described. RESULTS: The 260 patients were treated with mean age of (59.4+/-9.2) years, 85.8% (n=223) of them were male, 14.2% (n=37) of them were female. 78.1% (n=203) of all were smokers and 3.1% (n=8) of patients had family history of tumor. The positive rate of cytokerantin 19 fragment (CYFRA21-1) was 71.2%, which was the highest among five tumor markers. The five tumor markers median level had no statistical significance between different tumor (T) stages and node (N) stages (all P>0.05), only the positive rate of SCC had statistical significance between different T stages (P=0.035). The combination measurement of CYFRA21-1+carcinogen-embryonic antigen (CEA), CYFRA21-1+CEA+cancer antigen (CA125), CA125+CYFRA21-1+CEA+neuron specific enolase (NSE), and CA125+CYFRA21-1+NSE+CEA+squamous cell carcinoma antigen (SCC) were better and had higher clinical values, the positive rates were 82.7%, 84.6%, 85.0% and 86.2%, respectively. CONCLUSIONS: The positive rate of CYFRA21-1 was the highest and the sensitivity of single test of five tumor markers was low, the combination of multiple tumor markers increased the sensitivity of diagnosis of SQCLC, the combination of CA125, CYFRA21-1 and CEA was the best choice. PMID- 27760593 TI - [Clinicopathologic Features and Prognostic Implications in 72 Cases ?with Lung Adenosquamous Carcinoma]. AB - BACKGROUND: Adenosquamous carcinoma (ASC) is a rare subtype of lung cancer, it is mixed glandular and squamous cell carcinoma with a more aggressive behavior and poor prognosis than the other histologic subtypes. The aim of the study was to explore the clinicopathological characteristics and prognostic factors of ASC. METHODS: A total of 72 patients were enrolled. We investigated clinicalpathological features and prognostic factors retrospectively. RESULTS: The overall 72 ASC patients' median age was 34.7 months, 5-year survival rate was 14.9%. The influence of tumor size, M stage, and N stage, gene mutation and surgery on the prognosis of patients show statistical significance. CONCLUSIONS: ASC is characterized by both histologic aggressiveness and adverse prognosis. We suggest the comprehensive therapy based on surgery, and given small molecule tyrosine kinase inhibitors (TKIs) treatment may prolong patients' overall survival. PMID- 27760594 TI - [Clinical Analysis of 58 Patients with Small Cell Lung Cancer ?Combined with Squamous Cell Cancer]. AB - BACKGROUND: Small cell lung cancer combined with squamous cell carcinoma are rare. The aim of this study was to analyze the clinicopathological characteristics and treatment, and explored the prognostic factors of this disease. METHODS: Between January 2004 and December 2012, 58 patients with cytopathologically confirmed small cell lung cancers combined with squamous cell carcinoma were retrospectively analyzed. Kaplan-Meier methods were used to calculate the survival rate, and Log-rank test was used to examine differences between arms. The Cox regression model was used to analyze the independent factors affecting the overall survival (OS). RESULTS: The OS of the 58 patients was 22.7 months with a range of 0.3 to 124.3 months. In univariate analysis, Karnofsky performance score before treatment, extensive disease, tumor stage were the considered prognostic factors affecting the OS rate (P<0.05). Cox multivariate analysis showed that only the tumor-node-metastasis (TNM) stage was the independent prognostic factor (P=0.019). The majority of the patients received multimodality therapy and chemotherapy was the main treatment. Distant metastasis was the main reasonfor the treatment failure. CONCLUSIONS: Combined therapy with chemotherapy as the main treatment should be adopted in therapeutic regimen of the patients with small cell lung cancers combined with squamous cell carcinoma. TNM stage was the independent prognostic factor influencing the OS.?. PMID- 27760592 TI - [Driven Gene in Patients with Lung Squamous Cell Carcinoma: ?Analysis of Clinicopathologic Characteristics and Prognosis]. AB - BACKGROUND: It has been proven that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS are common driver genes in non-small cell lung cancer (NSCLC). Molecular targeted therapy increases the overall response rate and progression-free survival (PFS) of patients with EGFR-sensitive mutation or echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. However, target and targeted drugs for lung squamous cell carcinoma to indicate clinical therapy remain to be confirmed. The aim of this study was to analyze the relationship between the status of driver genes and the clinicopathologic characteristics of NSCLC. METHODS: A total of 90 patients were recruited and tested for EGFR, ALK and KRAS mutations. The status of EGFR and KRAS was tested by amplification refractory mutation system, and the status of ALK was tested by fluorescence in situ hybridization. RESULTS: Of the 90 patients, 8 patients had EGFR mutation (8.8%), and 2 cases had KRAS mutation (2.2%). EML4-ALK fusion was found in 1 of 18 patients (5.6%). EGFR mutation occurred more frequently in females than in males (P=0.022). Significant differences were observed in pathological stage (P=0.042) and differentiation grade (P=0.003). No significant difference in PFS was observed between EGFR-TKI treatment and chemotherapy in EGFR mutation patients with squamous cell carcinoma of the lung (P=0.607). Patients with EML4-ALK fusion could benefit from targeted therapy. CONCLUSIONS: EML4-ALK fusion occurred more frequently than EGFR and KRAS mutations in patients with lung squamous cell carcinoma. Clinicopathologic characteristics were different between EGFR mutation and EGFR wild-type patients. The relationship between molecular targeted therapy and status of EGFR or ALK genes in patients with lung squamous cell carcinoma needs further investigation. PMID- 27760595 TI - [Nimotuzumab Combined with Chemotherapy as Second- or Later-line ?in the Treatment of Advanced Lung Squamous Cell Carcinoma]. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung squamous cell carcinoma and has been associated with impaired prognosis. The aim of this study was to observe the efficacy and safety of nimotuzumab, a anti EGFR monoclonal antibody, combined with chemotherapy as second- or later-line in the treatment of advanced lung squamous cell carcinoma. METHODS: A retrospective analysis of clinical data was conducted in 13 patients with advanced lung squamous cell carcinoma, who were administered with nimotuzumab combined with chemotherapy as second-line or later-line treatment. The efficacy of therapy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and safety by National Cancer Institute Common Toxicity Criteria (NCI-CTC) 4.0. RESULTS: Of the 13 advanced squamous-cell lung cancer patients, one patient had complete response (CR), 2 patients had partial response (PR), 4 cases had stable disease (SD), and 6 patients had progressive disease. The overall response rate (ORR) was 23.1% and clinical benefit rate (CBR) was 53.8%. EGFR expression were detected by immunohistochemistry in 6 patients and the results showed 5 patients were EGFR 3+ and the other was EGFR 2+. Of these 6 EGFR positive patients, 1 case had CR, 1 case had PR and 4 cases had SD; ORR was 33.3% and CBR was 100.0%. Grade 3/4 hematological toxicities were observed in 3 (23.1%) patients, and non hametological toxicities were mild. Nimotuzumab-associated skin rash was found in 2 (15.4%) patients. CONCLUSIONS: Nimotuzumab combined with chemotherapy as second or later-line therapy for advanced squamous cell lung carcinoma was active and well-tolerated, especially for those patients with EGFR positive. PMID- 27760596 TI - [Recombinant Human Endostatin in the Treatment of Advanced Lung Squamous Cell Carcinoma]. AB - BACKGROUND: Squamous cell carcinoma (SCC) is a common pathological type of non small cell lung cancer, and advanced lung SCC is incurable. Chemotherapy combined with anti-angiogenesis agents can prolong the patients' survival time. The aim of the study was to analyze the efficacy and safety of recombinant human endostatin (Endostar) in treating advanced lung SCC. METHODS: We retrospectively analyzed the short-term efficacy and toxicity of recombinant human endostatin combined with traditional chemotherapy regimens in treating 15 advanced lung squamous cell carcinoma patients in Department of Medical Oncology retrospectively, Cancer Hospital, Chinese Academy of Medical Sciences from November 2011 to May 2015. Treatment-related survival was also analyzed. RESULTS: Among the evaluble 14 patients, the best overall response was partial response in 5 patients (35.7%), stable disease in 7 patients (50.0%), and progressive disease in 2 patients (14.3%). The objective response rate (ORR) was 35.7%, and disease control rate (DCR) was 85.7%. The median progression-free survival (PFS) was 9.3 months. The main grade 3 toxicity was neutropenia (2/15, 13.3%) and vomitting (1/15, 6.7%). CONCLUSIONS: Chemotherapy combined with recombinant human endostatin enabled good objective response in advanced SCC patients and had well security. PMID- 27760597 TI - [Clinicopathologic Characteristics of the Patients in the Elderly Lung Carcinoma]. AB - BACKGROUND: As the prevalence of tobacco and the aging of the population, the incidence of lung cancer in the elderly rises. However, few elderly patients (older than 70 years old) with lung squamous cell carcinoma were involved into the clinical trials, which offered insufficient clinical evidence for these patients. Lung squamous cell carcinoma patients older than 80 years old were included in our study to analyze the clinical characteristics, treatment and prognostic factors, and to explore the optimal treatment choices for these patients. METHODS: We retrospectively analyzed the clinical features of 38 elderly patients with lung squamous carcinoma and summarized the treatment under the clear diagnosis and clinical staging. RESULTS: Elderly patients with squamous cell carcinoma can choose surgery, radiotherapy and chemotherapy based on diagnosis and clinical staging when their physical condition is permitted. CONCLUSIONS: Because of the short life expectancy of patients more than 80 years old, fewer of them could receive completed and effective treatment, comparing with patients between 70 and 80 years old. PMID- 27760598 TI - [Effects of Erlotinib on 34 Patients with Advanced Squamous Cell Lung Cancer]. AB - BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhinitors (EGFR TKIs) inhibit tumor growth by affecting signal transduction, and are well tolerated. The aims of this study was to observe the effect of erlotinib in patients with squamous cell lung cancer. METHODS: The 34 patients with squamous cell lung cancer treated with erlotinib 150 mg orally once daily until disease progression or intolerable adverse reactions. RESULTS: The 7 patients were treated with erlotinib as first-line treatment, 6 patients as maintenance therapy (1 case withdrawal of severe toxicity), 9 patients second-line treatment, 5 patients as third-line and 7 patients as further-line therapy. 11 patients died. The median progression-free survival (PFS) was 3.5 months, ranging from 1 month to 55 months (the patient withdrawal of severe toxicity was not included). CONCLUSIONS: Erlotinib was effective for patients with squamous cell lung cancer who can not tolerate chemotherapy or refused chemotherapy and with unknown EGFR status. Adverse reactions were tolerable. PMID- 27760599 TI - [Progress in Immunotherapy for Squamous Non-small Cell Lung Cancer]. AB - In recent years, squamous non-small cell lung cancer (NSCLC) didn't progress much in chemotherapy or target therapy. However, immunotherapy has made breakthroughs in treating squamous NSCLC. Immunotherapy includes two main broad classes of immune checkpoint inhibitors and therapeutic vaccines. Immune checkpoint inhibitors, including anti cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and anti programmed death receptor 1 (PD-1) antibodies, have been tested in the phase II/III clinical trials and have demonstrated promising outcomes. Immunotherapy will become an important treatment for squamous NSCLC. PMID- 27760601 TI - [Systematic Review of the Methodology Quality in Lung Cancer Screening Guidelines]. AB - BACKGROUND: Lung cancer is the most common malignancy and screening can decrease the mortality. High quality screening guideline is necessary and important for effective work. Our study is to review and evaluate the basic characteristics and methodology quality of the current global lung cancer screening guidelines so as to provide useful information for domestic study in the future. METHODS: Electronic searches were done in English and Chinese databases including PubMed, the Cochrane Library, Web of Science, Embase, CNKI, CBM, Wanfang, and some cancer official websites. Articles were screened according to the predefined inclusion and exclusion criteria by two researchers. The quality of guidelines was assessed by AGREE II. RESULTS: At last, a total of 11 guidelines with methodology were included. The guidelines were issued mainly by USA (81%). Canada and China developed one, respectively. As for quality, the average score in the "Scale and objective" of all guidelines was 80, the average score in the "Participants" was 52, the average score in the "rigorism" was 50, the average score in the "clarity" was 76, the average score in the "application" was 43 and the average score in the "independence" was 59. The highest average score was found in 2013 and 2015. Canada guideline had higher quality in six domains. 7 guidelines were evaluated as A level. CONCLUSIONS: The number of clinical guidelines showed an increasing trend. Most guidelines were issued by developed countries with heavy burden. Multi-country contribution to one guideline was another trend. Evidence based methodology was accepted globally in the guideline development. PMID- 27760600 TI - [Treatment of Advanced Squamous Cell Lung Cancer]. AB - Lung cancer is the deadliest cancer in the worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung tumor diagnoses. Squamous cell lung cancer (SQCLC) is a common pathological type, almost 20%-30% of NSCLC. Surgery, chemotherapy, and molecular targeted therapies are the mainstay of treatment for patients with SQCLC. But most patients are diagnosed at advanced stage so that they miss the chance of operation. While noteworthy outcomes have improved with adenocarcinoma of lung with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), a therapeutic plateau for advanced squamous cell lung cancer patients are still not solved. EGFR-TKIs are unsuitable for or mostly ineffective in advanced SQCLC. Patients with advanced SQCLC ramain treated with platinum based chemotherapy. This reciew systematicly describe the treatment of squamous cell carcinoma of the lung. PMID- 27760602 TI - [Effects of VATS Lobectomy, VATS Anatomic Segmentectomy, and Open Thoracotomy on Pulmonary Function of Patients with Non-small Cell Lung Cancer]. AB - BACKGROUND: Lung cancer is a malignancy with high morbidity and mortality rates worldwide. Surgery is the preferred treatment for non-small cell lung cancer. This study aims to investigate the effects of video-assisted thoracoscopic surgery (VATS) lobectomy, VATS segmentectomy, and open thoracotomy on pulmonary function in the early postoperative stage and compare the difference among three groups. METHODS: Pulmonary function data of patients were collected from September 2015 to February 2016 in Department of Thoracic Surgical Oncology, Cancer Hospital Chinese Academy of Medical Sciences. The patients were categorized according to operation methods into three groups, namely, VATS segmentectomy, VATS lobectomy, and open thoracotomy groups. Pulmonary function was assessed 1 day before the surgery, 3 days after the surgery, and 3 months after the surgery. Statistical analysis was performed with SPSS 20.0 through single-factor analysis of variance. RESULTS: Pulmonary function 3 days after the surgery was compared among the three groups. There was a significant difference in forced vital capacity (FVC), FVC%, forced expiratory volume in one second (FEV1), FEV1%, peak expiratory flow (PEF), maximal voluntary ventilation (MVV), transfer factor for carbon monoxide of lung (TLCO) and TLCO% (P values were as follows: 0.033, 0.042, 0.029, 0.045, 0.039, 0.021, 0.018, 0.024). The comparison of pulmonary function of 3 groups at the time of 3 months after operation showed that there was a significant difference among three groups in FVC, FVC%, FEV1, FEV1%, PEF, MVV, TLCO, TLCO% (P values were as follows: 0.019, 0.024, 0.044, 0.021, 0.037, 0.029, 0.045, 0.017). CONCLUSIONS: No matter in the early stage after surgery or at the time of 3 months after surgery, the patients' pulmonary function in VATS segmentectomy is better than the data of VATS lobectomy group, and the pulmonary function data of VATS lobectomy patients recovered better than the open thoracotomy group.?. PMID- 27760603 TI - [Establishment of A Clinical Prediction Model of Solid Solitary Pulmonary Nodules]. AB - BACKGROUND: The solitary pulmonary nodule (SPN) is a common and challenging clinical problem, especially solid SPN. The object of this study was to explore the predictive factors of SPN appearing as pure solid with malignance and to establish a clinical prediction model of solid SPNs. METHODS: We had a retrospective review of 317 solid SPNs (group A) having a final diagnosis in the department of thoracic surgery, Shanghai Chest Hospital from January 2015 to December 2015, and analyzed their clinical data and computed tomography (CT) images, including age, gender, smoking history, family history of cancer, previous cancer history, diameter of nodule, nodule location (upper lobe or non upper lobe, left or right), clear border, smooth margin, lobulation, spiculation, vascular convergence, pleural retraction sign, air bronchogram sign, vocule sign, cavity and calcification. By using univariate and multivariate analysis, we found the independent predictors of malignancy of solid SPNs and subsequently established a clinical prediction model. Then, another 139 solid SPNs with a final diagnosis were chosen in department of Cardiothoracic Surgery, Affiliated Zhoushan Hospital of Wenzhou Medical University as group B, and used to verify the accuracy of the prediction model. Receiver-operating characteristic (ROC) curves were constructed using the prediction model. RESULTS: Multivariate Logistic regression analysis was used to identify eight clinical characteristics (age, family history of cancer, previous cancer history, clear border, lobulation, spiculation, air bronchogram sign, calcification) as independent predictors of malignancy of in solid SPNs. The area under the ROC curve for our model (0.922; 95%CI: 0.865-0.961). In our model, diagnosis accuration rate was 84.89%. Sensitivity was 90.41%, and specificity was 78.79%, and positive predictive value was 80.50%, and negative predictive value was 88.14%. CONCLUSIONS: Our prediction model could accurately identify malignancy in patients with solid SPNs, thereby it can provide help for diagnosis of solid SPNs. PMID- 27760606 TI - [Prostatic adenocarcinoma: update on 2014 International Society of Urological Pathology Gleason grading system and new prognostic grading groups]. PMID- 27760604 TI - [Progress in the Treatment of Non-small Cell Lung Cancer with BRAF Inhibitors]. AB - In recent years, targeted drugs occupy a pivotal position in the treatment of non small cell lung cancer (NSCLC), drugs targeting epidermal growth factor receptor (EGFR) has been widely used in clinical practice, it is of milestone significance. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors targeted at BRAF gene have obviously clinical efficacy to specific advantages populations with little side-effect, and be well tolerated. It is discovered recently that drug resistance also exists in BRAF inhibitors like other targeted drugs, the mechanism of drug resistance is being studied. In this paper, a review were performed in the mechanism, clinical application, adverse reactions and the drug resistance of BRAF inhibitors. PMID- 27760605 TI - [Present Situation of Lung Cancer Screening Methods]. AB - Lung cancer is the leading cause of cancer mortality currently. Early diagnosis is crucial to the good prognosis of lung cancer. Evidence has shown that low-dose computed tomography (CT) screening can make the decline in the mortality of lung cancer. However, there are still many problems in the screening, such as, high false-positive rates, overdiagnosis and radiation exposure. As another non invasive tumor screening method, blood-based tumor markers showed a high sensitivity and specificity in early diagnosis of lung cancer in recent years. How to establish a comprehensive mode for lung cancer screening by use existing screening methods, we need more clinical research. PMID- 27760607 TI - [Consensus on specimen handling and pathologic diagnosis of prostatic carcinoma]. PMID- 27760608 TI - [Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma: an analysis of 368 radical nephroureterectomy specimens]. AB - Objective: To evaluate the epidemiology, clinicopathological features and prognosis in upper tract urothelial carcinoma (UTUC) patients. Methods: All archival 368 UTUC cases that underwent radical nephroureterectomy between September 1999 and October 2014 were reviewed, and their clinicopathological features were analyzed. Follow-up time was 1-216 months, with a mean follow-up of 41 month. Results: One hundred and twenty-eight male and 240 female patients were included, with a mean age of 68 years ranging from 31 to 88 years. Tumor locations were classified in detail as follows: 148 renal pelvic tumors, 155 ureteral tumors, 58 renal pelvic and ureteral tumors, and 7 transitional tumors. Patients with history of renal transplantation (14.7%, 54/368) were more likely to develop UTUC before the age of 65 (P<0.01), with bilateral tract involved (P<0.01) and multifocal distributed (P=0.004). Histological grade was significantly associated with T stage (P<0.01), lympho-vascular involvement (P=0.001), neural invasion (P=0.005), carcinoma in situ (P=0.001) and extensive necrosis (P=0.020), while high-grade UTUC predominantly occurred in female patients (P=0.010) and histological variants (P<0.01). T stage was positively correlated with tumor size (P<0.01), lympho-vascular involvement (P<0.01), neural invasion (P<0.01) and lymph node metastasis (P=0.001). Furthermore, among the 214 followed-up cases, 76 died of the disease. Histological grade (P=0.002, P=0.005), T stage (P<0.01, P<0.01), lympho-vascular involvement (P=0.001, P=0.008), neural invasion (P<0.01, P=0.001) and extensive necrosis (P=0.017, P=0.023) were significantly associated with shorter overall survival and cancer specific survival of UTUC patients, respectively. In multivariable analyses, T stage (P<0.01, P<0.01) and extensive necrosis (P=0.004, P=0.014) were independent predictive factors of both overall survival and cancer specific survival, while neural invasion (P=0.007) and lymph node metastasis (P=0.007) were independent predictors of the overall survival. Conclusions: Chinese UTUC reveals its unique epidemiology. UTUC more commonly occurs in women and has a similar incidence between the renal pelvic and ureteral carcinoma. Patients with history of renal transplantation are prone to detect UTUC through physical examination rather than hematuria. Histological grade, T stage, lympho-vascular involvement, neural invasion and extensive necrosis are predictors of survival in UTUC patients, while advanced-stage and extensive necrosis are independent predictors of poor outcome. PMID- 27760609 TI - [Clinicopathologic characteristics of thyroid-like follicular carcinoma of the kidney: an analysis of five cases and review of literature]. AB - Objective: To study the clinicopathologic features of thyroid-like follicular renal cell carcinoma. Methods: Clinical data were collected in 5 cases of thyroid like follicular renal cell carcinoma. HE staining and immunohistochemistry were carried out in surgically-removed specimen to analyze the clinical and pathological features with review of the literatures. Results: The patients aged 20-55 years, with one male and four females; the tumor occurred in the left kidney in three cases and right kidney in two cases. One case had a history of thyroid papillary carcinoma 3 years ago, and the patient had left flank pain, macroscopic haematuria for 2 weeks. The rest four cases had no consciousness of clinical symptoms and signs, without history of thyroid gland surgery; the physical examination found a mass in the kidney and normal thyroid glands. Three patients underwent radical nephrectomy, and the other two patients underwent tumor partial nephrectomy. The tumors were 2-4 cm in size. They showed a solitary nodular mass of well circumscribed with taupe and gray on cut surface. Microscopically, most of tumor cells arranged in thyroid follicular pattern in different sizes, with papillary configuration in a small portion, in four cases; the follicular structure was intermixed with the papillary each half in one case. A large amount of thyroid colloid was deposited within follicule-like structure or papillary axis, lined by simple columnar cells or cubic cells, with obvious atypia, ground-glass nuclei, nuclear groove and rare mitosis. Immunohistochemical staining showed tumor cells were positive for PAX8, and negative for thyroid transcription factor 1 (TTF1) and thyroglobulin (Tg). One of five patients presented with lymph node metastases (4/4) of renal hilum the same time in the diagnosis. Five cases were followed up for 5-84 months after operation, and no tumor progression was found. Conclusions: Thyroid-like follicular renal cell carcinoma is primary renal epithelial malignant tumor. The diagnosis mainly depends on its characteristics of histological appearance, namely similar to the histological morphology of well-differentiated thyroid follicular carcinoma and papillary carcinoma, and the metastasis from the thyroid papillary or follicular carcinoma must be excluded. On the premise of clinical history, immunohistochemical markers TTF1 and Tg have certain value in the differential diagnosis. PMID- 27760610 TI - [Diagnostic utility of immunohistochemistry in differential diagnosis of renal tumors with oncocytic features]. AB - Objective: To investigate the morphological features and immunophenotypes of eosinophilic renal tumors in order to provide references for the differential diagnosis of this tumor. Methods: A cohort of 75 cases of eosinophilic renal tumors were collected. The morphological features of the tumors were observed under microscope, and the immunophenotypes of the tumors were detected using tissue microarray and immunoshistochemistry. Results: There were some overlaps between the different types of eosinophilic renal tumors in morphology, but each had its distinct characteristics. Immunohistochemically, renal oncocytoma (RO) and eosinophilic chromophobe renal cell carcinoma (ChRCC) shared some common immumophenotypes, except for the expression of CK7, with the expression rates of 2/19 in RO and 17/20 in eosinophilic ChRCC, respectively. Eosinophilic clear cell renal cell carcinoma mainly showed positive immunostaining for Vimentin and CAIX, whereas negative for CK7 and CD117 in most cases (10/15). AMACR was diffusely expressed in the majority of eosinophilic papillary renal cell carcinoma (PRCC, 10/13). Furthermore, vimentin, CK7 and CD10 were positively expressed in eosinophilic PRCC with the expression rates of 8/13, 9/13 and 6/13, respectively; while CAIX, CD117 and TFE3 were all negatively expressed in eosinophilic PRCC.Epithelioid angiomyolipoma generally showed positive expression of vimentin, SMA and HMB45, but negative expression of CAIX and CK7. Vimentin, CD10, AMACR and TFE3 were strongly expressed in XP11.2 translocation renal cell carcinoma; on the contrary, CK7, CD117 and HMB45 were not expressed in the majority of the tumor. Conclusion: With full understanding of the morphology of different types of eosinophilic renal tumors, the immunostaining of vimentin, CAIX, CK7, CD10, AMACR, CD117, TFE3 and HMB45 could play a crucial role in the differential diagnosis of these tumors. PMID- 27760611 TI - [Clinicopathologic analysis of anastomosing hemangioma of the kidney and adrenal gland]. AB - Objective: To investigate the clinical and histopathologic characteristics, diagnosis, differential diagnosis and prognostic features of anastomosing hemangioma. Methods: Five cases of anastomosing hemangioma of the kidney and adrenal gland were collected, the clinical and radiologic features, histomorphology, immunophenotype and prognosis were analyzed with review of literature. Results: Three patients were male and two were female with ages ranging from 47 to 77 years; three were located in adrenal gland and 2 originated from the kidney. Clinically, 4 tumors were incidentally identified, 1 presented as edema of lower extremity. By radiography, all presented as a well-demarcated, oval, solid and low-density mass. Grossly, the tumors ranged in maximum diameter from 1.6 to 2.5 cm (mean 2.1 cm). Microscopically, the tumors consisted of anastomosing sinusoidal capillary-sized vessels lined by a single layer of flattened, cubical to hobnail endothelial cells, setting in an pauci-cellular stroma of edematous and hyaline changes. Other commonly seen features included vaguely lobular growth pattern (3/5), hemorrhage and thrombosis (5/5), intravascular growth pattern (5/5), eosinophilic intracytoplasmic hyaline globules (1/5) and extramedullary hematopoiesis (3/5). The tumor cells were typically bland-appearing and mitoses were scarce, with 1 case demonstrating cellular foci of tumor with slight pleomorphism and increased mitoses (2/50 HPF). Immunohistochemical studies showed the tumor cells expressed endothelial cells markers. Follow-up information was available for all 5 patients and showed no evidence of tumor recurrence or metastasis within 6 to 52 months (mean 30 months). Conclusions: Anastomosing hemangioma is a rare, benign subtype of capillary hemangioma that predominantly affects the urologic organs and adrenal glands; it is needed to distinguish it histologically from a series of benign or malignant tumors that feature a richly vascular stroma. Careful attentions to its characteristic morphology with the judicious use of immunohistochemistry can help distinguish this tumor from its many mimickers. PMID- 27760612 TI - [Pathology and differential diagnosis of immunotactoid glomerulopathy]. AB - Objective: To study the morphologic changes of immunotactoid glomerulopathy and to investigate the clinical pathological features and differential diagnosis. Methods: Renal biopsy was observed under the light microscope, immunofluorescence and electron microscopy in a case of newly diagnosed immunotactoid glomerulopathy. Results: This patient clinically presented with nephrotic syndrome and hypertension, without family history of renal diseases. Light microscopy showed that diffusely massive and specific protein deposition in the glomerulus in Masson staining. Immunofluorescence revealed IgG, C3 and kappa were deposited along the capillary walls and mesangial regions. Electron microscopic examination showed that a large amount of microtubule like substances and a small amount of long bar-shaped and dense crystal-like substances were deposited in the subendothelial spaces and mesangial areas. Conclusions: Light microscopy and immunofluorescence of immunotactoid glomerulopathy show no specifically pathological changes. Under electron microscope, a large amount of microtubule like substances is deposited in the glomerulus, which is the key point to distinguish this disease from other glomerular diseases. Except for the microtubule-like substances, the present case is accompanied by the deposition of long bar-shaped and dense crystal-like substance, which has not been reported in previous studies. PMID- 27760614 TI - [Clinicopathologic characteristic of myxoid leiomyosarcoma of the uterus: report of five cases]. PMID- 27760613 TI - [Alterations of mTOR pathway and autophagy in early type 2 diabetic cardiomyopathy in rats]. AB - Objective: To investigate the alterations of mTOR signaling pathway and autophagy in the development of type 2 diabetes and early diabetic cardiomyopathy and to study their roles in pathogenesis of diabetic myocardium. Methods: A type 2 diabetes rat model was established by injection of streptozocin after five-week of high fat diet. The rats were randomly divided into control group, experiment group of 2 weeks and experiment group of 4 weeks. Alterations of mTOR, p-mTOR, S6K1, Beclin-1 and LC3-II expression in myocardium were determined by Western blot and immunohistochemistry. Results: Compared with the control group, the expression of mTOR, p-mTOR, S6K1, Beclin-1 and LC3-II level increased significantly in the experiment group of 2 weeks. The expression of p-mTOR and S6K1 increased significantly in the experiment group of 4 weeks compared with those of the experiment group of 2 weeks. Conclusions: mTOR signaling pathway is activated in early diabetic myocardial injury via autophagy. The findings may provide a new therapeutic target for diabetic cardiomyopathy. PMID- 27760615 TI - [Mammary analogue secretory carcinoma of salivary gland: report of a case]. PMID- 27760616 TI - [Myoid hamartoma of the breast: clinicopathologic analysis of four cases]. PMID- 27760617 TI - [Intravascular NK/T-cell lymphoma of testis: report of a case]. PMID- 27760618 TI - [Primary clear cell sarcoma of small intestine: report of a case]. PMID- 27760619 TI - [Pubertal ovarian non-gestational choriocarcinoma: report of a case]. PMID- 27760620 TI - [Solitary fibrous tumor in trachea: report of a case]. PMID- 27760621 TI - [Chronic active Epstein-Barr virus enteritis: report of a case]. PMID- 27760622 TI - [Diagnostic criteria of prostate cancer with neuroendocrine differentiation according to WHO classification]. PMID- 27760623 TI - [Clinicopathologic features of cesarean scar-related complications]. PMID- 27760624 TI - [HPV in head and neck squamous carcinomas: an update]. PMID- 27760625 TI - [Molecular classification of gastric cancer]. PMID- 27760627 TI - [Disorders of ejaculatory duct region and their management by vesiculoscopic technology]. PMID- 27760626 TI - [Gene fusions in epithelial cancers]. PMID- 27760628 TI - [Effectiveness of microsurgical crossover anastomosis in treating complicated obstructive azoospermia]. AB - Objective: To evaluate the efficacy and safety of microsurgical crossover vasovasostomy in treating complicated obstructive azoospermia. Methods: The data of 14 patients with complicated obstructive azoospermia treated with microsurgical crossover vasovasostomy were reviewed from October 2012 to March 2016.Ten of them underwent microsurgical crossover vasovasostomy. Intraoperative exploration revealed that 2 patients had vas deferens injury and contralateral testicular atrophy or epididymal obstruction due to previous hernia repair; 7 patients had obstruction of intracorporeal vas deferens on one side and epididymal obstruction on the other side; the other 1 patient had unilateral vasal obstruction with contralateral epididymal obstruction. Furthermore, 4 patients underwent microsurgical crossover vasoepididymostomy, including 3 patients who had obstruction at caput epididymis on one side, and obstruction at cauda epididymis and distal vas deferens on the other side; the other patient had absence of vas deferens in the scrotum on one side, and testicular atrophy on the other side. Regular follow-up visits were conducted after the surgery. Results: Two patients were lost to follow-up; the other 12 patients were follow-up for an average of 11 (range: 2-23) months. In the 10 cases receiving microsurgical crossover vasovasostomy (including 2 patients lost to follow-up), 1 has not undergone semen re-analysis, 6 were confirmed patent, including 3 reporting spontaneous pregnancy. The patency rate in the 4 patients receiving microsurgical crosseover vasoepididymostomy was 2/4, with 1 patient reporting spontaneous pregnancy. There was no complaint of discomfort or complications following the surgery. Conclusions: Microsurgical crossover anastomosis may be effective and safe for patients with complicated obstructive azoospermia, according to preoperative assessment and intraoperative exploration. It allows natural conception for patients with refractory infertility. The microsurgical crossover anastomosis could be an effective therapy to achieve satisfactory patency of vas deferens. PMID- 27760629 TI - [Effectiveness of transurethral seminal vesiculoscopy in the treatment of persistent hematospermia, and oligoasthenozoospermia and azoospermia from ejaculatory duct obstruction]. AB - Objective: To analyze the effectiveness of transurethral seminal vesiculoscopy in the treatment of persistent hematospermia, and oligoasthenozoospermia and azoospermia from ejaculatory duct obstruction. Methods: The clinical date of 56 cases of persistent hematospermia, or azoospermia/oligoasthenozoospermia from ejaculatory duct obstruction treated with transurethral seminal vesiculoscopy between November 2013 and January 2016 in the First Affiliated Hospital of Fujian Medical University were reviewed. A total of 30 cases were persistent hematospermia for 6 months to 3 years, with no response to routine antibiotic therapy for >4 weeks; 24 cases were obstructive azoospermia; and the other 2 cases were extreme oligoasthenozoospermia. Transrectal ultrasound of the prostate and seminal vesicles, and pelvic magnetic resonance imaging (MRI) were performed before the surgery, finding seminal vesicle dilation in 28 cases, ejaculatory duct dilation in 18 cases, seminal vesicle and ejaculatory duct dilation in 7 cases, seminal vesicle dilation with ejaculatory duct cyst in 2 cases, and bilateral ejaculatory duct dilation with prostatic utricle cyst in 1 case. After the transurethral seminal vesiculoscopy, follow-up examinations were performed to assess the effectiveness of the surgery for >=3 months. Results: The surgery was successful in all the patients, with the duration of surgery ranging from 30 to 148 minutes. Among the 30 patients with hematospermia, calculi in ejaculatory duct or seminal vesicle was found in 20 cases, while inflammation or dark red jelly-like substances in seminal vesicle was seen in all cases. In the follow-up of 9.7 months (3.0-13.0 months), hematospermia in 26 (26/30, 86.7%)patients was relieved or cured after 1-6 times of ejaculation; the other 4 (4/30, 13.3%)cases still had hematospermia. In postoperative semen analysis for the 24 cases of azoospermia from ejaculatory duct obstruction, sperms were detected in 16(16/24, 66.7%)cases, but sperms were not found after 6 months following the surgery in 1 of the 16 case, thus re-obstruction was suspected; in the other 8 (8/24, 33.3%)cases, sperms could not be found in multiple semen analyses in >12 months after the surgery. The 2 cases of extreme oligoasthenozoospermia had obvious improvement in routine semen analysis in 1 and 3 months after the surgery. Except for 1 case of scrotum swelling after surgery, no postoperative complications (retrograde ejaculation, urinary incontinence, or rectal injury) were observed. Conclusions: Transurethral seminal vesiculoscopy was an effective therapy for persistent hematospermia. More strict operation indication and careful performance are necessary for azoospermia oligoasthenozoospermia from ejaculatory duct obstruction. PMID- 27760630 TI - [Expression of transcription factor SOX5 in human semen]. AB - Objective: To study and analyze the transcript and expression pattern of SOX5 in human semen, thus to provide evidence for exploring the role of transcription factor SOX5 in the process of spermatogenesis in testis. Methods: A total of 61 semen samples and 3 blood samples (as controls) collected from healthy volunteer donors at Shanghai Human Sperm Bank in September 2015 were randomly selected. Expression of SOX5 in the semen samples was detected and quantified using agarose gel electrophoresis and real time-quantitative PCR (RT-qPCR) analysis. Results: In the human semen samples, SOX5 was found in two different transcript forms: long transcript (L-SOX5) and short transcript (S-SOX5). Moreover, the S-SOX5 was specifically expressed in human semen, not detected in the control blood samples. L-SOX5 and S-SOX5 were primarily found in seminal plasma, with low expression level in sperms. The results of RT-qPCR analysis showed obviously higher mRNA expression levels of L-SOX5 than S-SOX5 in semen (0.280+/-0.232 vs 0.147+/ 0.103), however, not significantly(P=0.132). Conclusion: SOX5 is expressed as different transcripts in human semen, and different transcripts may play different roles in the process of spermatogenesis in testis. PMID- 27760631 TI - [Relationship between decreased expression of inhibin B and spermatogenesis dysfunction in rats testis]. AB - Objective: To explore the effects of varicocele on the expressions of inhibin B in rat testes and the relationship between expression of inhibin B and spermatogenesis dysfunction. Methods: Twenty specific-pathogen-free Sprague Dawley (SD) male rats were randomly divided into two groups with random number table: 4-week control group (C4) and 4-week experimental group(V4). Experimental varicocele was created by partial ligation of left renal vein in the V4 group; vein isolation without ligation was performed in the C4 group.Spermatogenetic function in the two groups were assessed. The expression of inhibin B in the rat testis was analyzed by immunohistochemistry, the expressions of inhibin B, Fas and Fas ligand(FasL)mRNA measured by reverse transcription-polymerase chain reaction(RT-PCR), and the inhibin B protein expression by Western blot. Results: In comparison of spermatogenetic function in left rat testes, the Johnsen scores in the V4 group were significantly lower than those in the C4 group (9.79+/-0.05 vs 9.97+/-0.02, P=0.023), the seminiferous epithelium in the V4 group was significantly thinner than that in the C4 group [(48.35+/-0.99)MUm vs (57.58+/ 1.98)MUm, P=0.000], and the number of sperms in the left epididymis was significantly lower than in the right one in the V4 group [(933+/-161)*106/(ml.g) vs(1 552+/-184)*106/(ml.g), P=0.017]. Both Western blot and immunohistochemical assay showed that the expression of inhibin B in the rat testes was significantly lower in the V4 group than in the C4 group(0.407+/-0.053 vs 0.608+/-0.076, P=0.038; 0.161+/-0.004 vs 0.183+/-0.005, P=0.008). RT-PCR also detected reduced expression of inhibin B mRNA in the V4 group compared with the C4 group(0.522+/ 0.050 vs 1.106+/-0.210, P=0.003. Compared to the C4 group, the expression of Fas mRNA in the V4 group was significantly lower, while the expression of FasL mRNA in the V4 group was significantly higher(P=0.019, 0.015). Conclusions: Varicocele can lead to decreased expressions of inhibin B in rat testes and cause spermatogenesis dysfunction. There may be a close correlation between down regulation ofinhibin B expression and spermatogenesis dysfunction.Inhibin B may play a significant rolein the mechanisms underlying male infertility due to varicocele. PMID- 27760632 TI - [Expression and significance of miR-210 in the epididymis in rats with varicocele and following varicocelectomy]. AB - Objective: To investigate the expression of microRNA 210 (miR-210) in the epididymis of rats with varicocele and changes in miR-210 expression following high spermatic vein ligation, so as to explore the significance of the surgery in treating varicocele. Methods: A total of 21 male Sprague-Dawley (SD) rats aged 7 weeks were randomly divided into control group (n=7), experimental group (n=7), and surgical group (n=7). Varicocele model was established in both the experimental and surgical groups, while only vein isolation was performed in the control group. After 8 weeks, spermatic vein diameter were measured in the control and experimental rats, and collected the left epididymis (fixed in formaldehyde and frozen in refrigerator at -80 C). In the surgical group, left high spermatic vein ligation was performed, and the left epididymis was collected after 4 weeks as in the control and the experimental groups. The fixed epididymis tissues were treated with HE staining for observation of tissue injuries. The miR 210 expression in the epididymis was detected with reverse transcription polymerase chain reaction (RT-PCR). At last every group had 5 rats. Results: The pathological examination showed that the number and distribution of mature sperms in epididymal duct in the experimental group were lower and less even compared to the control group, while the two indicators in the surgical group were better than those in the experimental group. The diameter of the left spermatic vein in the experimental group and pre-treatment surgical group were significantly enlarged than in the control group (P<0.01). The expression of miR-210 in the left epididymis in the experimental group was significantly higher compared with the control group(1.32+/-0.06 vs 0.98+/-0.14, P<0.01), while the expression of miR-210 in the left epididymis in the surgical group was significantly decreased compared with the experimental group (0.96+/-0.16 vs 1.32+/-0.06, P<0.01); the difference between the control group and the surgical group was not statistically significant (P>0.05). Conclusion: The expression of miR-210 in the epididymis may be increased by varicocele and reduced after high ligation of the affected spermatic vein. PMID- 27760633 TI - [Analysis of correlative factors of serum leptin levels in asthmatic patients]. AB - Objective: To analysis the correlative factors that probably affect serum leptin levels in asthmatic patients. Methods: Seventy-eight patients with asthma and 29 health controls who were admitted into outpatient clinic of Peking University Third Hospital from April 2014 to December 2015 were consecutively enrolled in our study prospectively. Serum leptin level was measured by enzyme-linked immunosorbent assay (ELISA). The sex, body mass index (BMI), onset age of asthma, allergen detection test, induced sputum cell count and classification, lung function test and asthma control level were recorded. Asthmatic patients were further divided into groups according to these factors and serum leptin levels were compared among groups. Results: Serum leptin levels were not different between asthmatic patients and health controls [(15.0+/-10.4) vs (15.2+/-11.7) MUg/L, P=0.939]. Female asthmatic patients had significantly higher serum leptin levels than male [(18.2+/-10.7) vs (7.9+/-4.8) MUg/L, P<0.001]. Asthmatic patients with obesity had significantly higher serum leptin levels than asthmatic patients with overweight, with normal BMI, with underweight and health controls [(29.7+/-10.8) vs (17.1+/-11.1), (11.8+/-7.7), (9.1+/-0.96), (15.2+/-11.7) MUg/L, all P<0.01]. Serum leptin level was positively related to percentage of induced sputum eosinophil in female asthmatic patients (r=0.331, P=0.032). Onset age of asthma, positive allergen detection, airflow limitation or asthma control level did not affect serum leptin level. Conclusion: Sex and BMI are important factors affecting serum leptin levels in patients with asthma. PMID- 27760634 TI - [Efficacy of Bailemian capsule combined with self-help cognitive behavioral therapy in treatment of chronic insomnia]. AB - Objective: To evaluate the efficacy of Bailemian capsule combined with self-help cognitive behavioral therapy (CBTI-SH) in treatment of chronic insomnia. Methods: Approved by the Ethics Committee of the hospital, 60 patients with chronic insomnia were randomly divided into two groups, the test group (Bailemian capsule combined with CBTI-SH) and the control group (CBTI-SH alone). Each group contained 30 cases. After 4 weeks for therapy, the sleep quality, mood and adverse reactions of treatment in patients were evaluated by sleep diary, sleep severity index scale (ISI), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and treatment emergent symptom scale (TESS) respectively. The data were statistically analyzed. Results: The total effective rate in the test group was significantly higher than that of the control group (73.3% vs 46.7%, P<0.05). Compared to the control group, the sleep onset latency was significantly shorten [(38.3+/-13.1) vs (27.5+/-9.8) min, P<0.05], while the sleep efficiency were increased markedly [(76.6+/-5.7)% vs (80.5+/-6.6)%, P<0.05] in the test group. In the test group, the sleep onset latency, the total sleep time, the time in bed and sleep efficiency both improved significantly after treatment [(27.5+/-9.8) vs (56.2+/-19.4) min, (334.4+/-41.6) vs (310.8+/-31.7) min, (415.6+/-38.9) vs (446.9+/-39.9) min, (80.5+/-6.6)% vs (69.6+/-4.9)%, all P<0.05], while in the control group, the sleep onset latency, the time in bed and sleep efficiency also improved significantly after therapy [(38.3+/-13.1) vs (55.2+/-16.2) min, (430.4+/-32.6) vs (452.4+/-34.4) min, (76.6+/-5.7)% vs (69.9+/ 5.2)%, all P<0.05]. After combined treatment, the SAS and SDS scores [(51.5+/ 6.5) vs (55.0+/-5.8), (52.0+/-5.3) vs (55.3+/-4.4), both P<0.05] both decreased significantly than those of the control group, at the same time, the SAS and SDS scores decreased significantly after treatment in both the test group and the control group [(51.5+/-6.5) vs (61.5+/-4.8), (52.0+/-5.3) vs (60.2+/-4.5), (55.0+/-5.8) vs (62.5+/-3.7), (55.3+/-4.4) vs (62.2+/-3.7), all P<0.01]. Conclusion: The efficacy of Bailemian capsule combined with CBTI-SH in the treatment of chronic insomnia is more effective. PMID- 27760635 TI - [Predictive values of pathologic complete response for patient outcome in different molecular subtypes of breast cancer]. AB - Objective: To analyze the predict values of pathologic complete response (pCR) rates for patient outcome according to breast cancer (BC) molecular subtypes. Methods: Four hundred and sixteen patients with confirmed BC who received neoadjuvant chemotherapy (NCT) in The Affiliated Hospital of Military Medical Science Academy of the PLA were enrolled.The clinical and pathological characteristics of patients were collected. The primary endpoint was pCR rate and the secondary endpoint was disease free survival (DFS). We analyzed the predict values of pCR rate for patient outcome, and the predict factors for DFS by univariate and multivariate Analysis. Results: A total of 416 BC patients confirmed by pathology were enrolled and received treatment and assessment in this study. The overall pCR rate was 23.1% (96/416). The pCR rate was 6.9% (14/204) in patients of HR+ /HER2- Subtype, 41.5% (27/65) in HR-/HER2+ Subtype, 30.9% (17/55) in HR+ /HER2+ Subtype, and 41.1% (37/91) in HR-/HER2- Subtype. The correlation of the pathological status and the patient outcome was analyzed in all patients. Compared with no pCR group, pCR group had significant higher DFS rates. In HER2+ Subtype and HR-/HER2- Subtype, DFS rates of patients who achieved pCR was higher than that of who didn't achieved pCR. In HR+ /HER2- Subtype, DFS rates of patients who achieved pCR was higher than that of who didn't achievced pCR, but without statistics difference. The Cox proportional hazards regression analysis revealed that ER status, T stage, pCR affected the patient outcome of BC. Conclusion: So far, pCR was an established prognostic factor: reaching a pCR could predicte improved survival in HER2-enriched BC and triple-negative breast cancer (TNBC) subgroup, while data remain controversial for the luminal subtypes. Our results do not support the use of pCR as a surrogate end point of treatment efficacy in unselected patients with BC submitted to neoadjuvant systemic therapy. PMID- 27760636 TI - [Safety and efficacy of off-pump coronary artery bypass grafting in octogenarians]. AB - Objective: To discuss the clinical safety and efficacy about off-pump coronary artery bypass grafting (OPCABG) in octogenarians. Methods: From June 2005 to July 2014, 252 patients (male 208, female 44, with a mean age of 81.7 years old) underwent OPCABG in Beijing Anzhen Hospital who were aged 80 years or older were enrolled. Results: Eight (3.2%) patients were diagnosed as single vessel coronary artery disease (CAD), 29 cases (11.5%) were diagnosed as bifurcation vessel CAD, and 215 cases (85.3%) were multivessel CAD. One hundred and one cases (40.1%) were diagnosed as left main artery disease, among which 51 cases (20.2%) had old myocardial infarction. Two hundred and forty-eight patients belonged to Canadian Cardiovascular Society (CCS) classI-III and 4 cases to CCS class IV. One hundred and forty-five cases belonged to New York Heart Association (NYHA) classI-II and 107 cases to NYHA class III-IV. Mean graft number was 3. Two hundred and six patients (81.7%) received total vein graft operation. Intra-aortic balloon pump (IABP) was used in 43 patients (17.1%). In-hospital death occurred in 15 cases (6.0%). Major in-hospital complications included reoperation (16 cases), re intubation (16 cases), dialysis (11 cases), sternum infection (2 cases), atrial fibrillation (63 cases). The follow-up time was from 1 to 11 years (with a mean time of 6 years). All-cause mortality was 18.1% (43 cases). The major out-of hospital complications included recurrent myocardial infarction (3 cases), stroke (3 cases), re-admission (27 cases) and recurrent angina pectoris (20 cases). Conclusion: OPCABG is safe and effective for myocardial revascularization in patients aged 80 years and over. PMID- 27760637 TI - [Effects of epicanthoplasty on trichiasis of the lower eyelids with epicanthus]. AB - Objective: To investigate the effects of epicanthoplasty on the trichiasis caused by the entropion of lower eyelid with epicanthus. Methods: Epicanthoplasty was used to correct the trichiasis of lower eyelid with epicanthus from February 2010 to October 2015. Total of 72 patients were enrolled in this study, among whom 42 were male and 30 were female, and aged 8 to 58 years. Among those patients, 64 cases were found with bilateral trichiasis and 8 patients with unilateral trichiasis. And 3 cases received secondary operations for recurrence. All patients were followed-up at 1, 3 and 12 months after the operation for therapeutic evaluation. Results: A total of sixty-three patients completed the follow-up study with 9 withdrew. The trichiasis was corrected with the satisfied palpebral appearance. And the cure rate was 98.4%. Of the patients, 95.3%, 95.2% and 96.9% were satisfied with the effects of the operations at 1, 3 and 12 months postoperatively. Mild retraction of lower eyelid occurred in only 3 patients. Conclusion: Epicanthoplasty is a simple and effective method to correct the trichiasis with epicanthus. PMID- 27760638 TI - [The clinical analysis of 18 cases with bilateral lung transplantation for severe idiopathic pulmonary arterial hypertension]. AB - Objective: To study the clinical efficacy of bilateral lung transplantation treating for severe idiopathic pulmonary hypertension (IPAH). Methods: The clinical data of 18 cases of bilateral lung transplantation for severe IPAH were retrospectively analyzed. Comparative analysis of preoperative and postoperative sets of data was performed. Results: The postoperative 30-day mortality of 18 cases was 11.1%, 3 months mortality 22.2%. The survival rate of 1 year, 3 years, 5 years was 77.8%, 72.2% and 72.2%, respectively. The remaining 13 cases were able to survive for a long time which preoperative cardiac function rating of level III, IV were improved to level Iafter transplantation. Compared preoperative with postoperative, pulmonary artery systolic pressure from preoperative 128.2+/-25.6 mmHg dropped to postoperative 39.7+/-14.8 mmHg; pulmonary artery mean pressure from 75.5+/-13.94 mmHg to 19.61+/-6.43 mmHg; right atrial pressure from 21.5+/-2.43 mmHg to 5.22+/-4.18 mmHg, all P<0.000 1. Conclusion: Bilateral lung transplantation is an effective treatment for severe idiopathic pulmonary arterial hypertension, which has longer survival. PMID- 27760639 TI - [Study on the survival rate of random flap using pre-injection of ADSCs]. AB - Objective: To determine the effects of adipose-derived stem cells (ADSCs) on the survival rate of flaps by transplanting ADSCs into the experimental flaps pre operatively. Methods: ADSCs were isolated from fresh human fat and cultured in vitro. Their morphological characters were observed, and flowcytometry and differentiation test and evaluation were conducted. A total of 40 BALB/c mice were divided into 5 groups randomly with each of 8 mice. 1 cm*4 cm random skin flap was designed on the mice back, ADSCs were injected in advance into subcutaneous tissues of 3 groups, the operation was performed on the 2nd, 5th and 7th day after the ADSCs injection, meanwhile skin flap operation was conducted in the immediate injection group and control group. Survival condition of the skin flaps was observed and von willebrand factor (vWF) staining was used to detect the number of micro-vessels in the skin flap. The enzyme-linked immuno sorbent assay (ELISA) method was used to detect the concentration of vascular endothelial growth factor (VEGF) in the skin flap. Results: The immediate injection group had a significantly higher survival rate of skin flap than the pre-injection groups and the control group [(51.5+/-6.3)% vs (38.3+/-6.7)%, (21.0+/-2.9)%, (30.0+/ 3.9)% and (34.5+/-4.2)%, all P<0.01]. The immediate injection group had a significantly higher number of micro-vessels in the skin flap than the pre injection groups and the control group [(21.0+/-4.3) vs (17.5+/-3.9), (9.9+/ 2.6), (13.9+/-2.6) and (16.1+/-3.3)/LPF, all P<0.01]. The laboratory results of the concentration of VEGF in skin flap kept a consistent tendency with the flap survival rate. Conclusion: Pre-injection with the ADSCs into the skin flap prevents the survival of the flap to a certain extend and does not show the function of promoting tissue angiogenesis. PMID- 27760640 TI - [Current status and influence factors of ACEI/ARB application in elderly coronary heart disease outpatients complicated with diabetes mellitus in China]. AB - Objective: To investigate the current status and influence factors of ACEI/ARB application in elderly coronary heart disease outpatients complicated with diabetes mellitus in 21 provinces of China. Methods: In this multicenter, non intervention and cross-sectional survey, the elderly coronary heart disease patients aged 60 years or over were recruited from 165 hospitals in 21 provinces across China from April to July 2011. Current status and influence factors of ACEI/ARB application among 1 789 cases with diabetes mellitus were investigated in the survey. Results: Totally, 1 069 patients used ACEI/ARB drugs (59.8%); proportion of ACEI (544 cases, 30.4%) drugs were the same as ARB drugs (533 cases, 29.8%) in terms of usage of drug types, and combination of the two drugs were taken by 28 cases (1.6%) at the same time. ACEI/ARB usage decreased with the increasing of age, and the rate of drug usage in male patients was slightly higher than that in female, however there was no statistical difference (both P>0.05); the rate of usage of ACEI/ARB drugs gradually decreased with increasing of coronary heart disease or diabetes duration (P<0.05); the rates of usage of ACEI/ARB drugs in hypertension, dyslipidemia, myocardial infarction, renal insufficiency patients and patients received revascularization therapy were significantly higher (all P<0.05). Multivariable logistic regression analysis showed that hypertension (OR=3.016, 95%CI: 1.376-4.887), dyslipidemia (OR=1.489, 95%CI: 1.114-2.031), revascularization (OR=2.291, 95%CI: 1.276-3.277), myocardial infarction (OR=2.561, 95%CI: 1.571-4.545), renal insufficiency (OR=1.337, 95%CI: 1.145-2.013), and insulin treatment (OR=1.584, 95%CI: 1.084-2.511) were positively correlated with ACEI/ARB usage (P<0.05); and coronary heart disease duration was negatively correlated with ACEI/ARB drugs usage (duration 5-10 years: OR=0.621, 95%CI: 0.416-0.823; duration >10 years, OR=0.664, 95%CI: 0.471 0.840). Conclusions: The rate of usage of ACEI/ARB drugs in elderly coronary heart disease outpatients complicated with diabetes mellitus is still low, however, patients with hypertension, dyslipidemia, myocardial infarction, renal insufficiency and patients received revascularization therapy and insulin treatment are more likely to use ACEI/ARB drugs. PMID- 27760641 TI - [Clinical outcomes of totally endoscopic coronary artery bypass grafting: a system review and meta-analysis]. AB - Objective: To assess the clinical outcomes of totally endoscopic coronary artery bypass grafting (TECABG). Methods: A systematic review of studies reporting clinical outcomes of TECABG was performed. Twelve studies were included in the meta-analysis. R 3.2.3 was used to perform the statistical analysis. Results: Length of hospital stay of TACABG patients ranged from 3.3 to 8.6 days. The rate of recent conversion to thoracotomy was 0-28.1% (from perioperative period to 2 years after surgery); the rate of anastomotic bleeding was 1.7%-8.5%; the case fatality rate of in-hospital or 30 days after surgery was 0-3.8%; the rate of myocardial infarction was 0-3.4%; the rate of stroke was 0-2.2%; the rate of revascularization was 0-6.8%; the patency rate of recent coronary artery bypass graft (CABG) was 89.5%-100%; the mid-time survival rate of TECABG patients (from 2 to 5 years after surgery) was 92.7%-100%; the rate of revascularization was 2.0%-12.2%; the patency rate of mid-time CABG was 71.4%-97.0%. Conclusions: The current data suggests that TECABG is feasible, safe and effective when proper patients are selected. However, randomized controlled trials of TECABG versus conventional CABG are still required due to lack of long-term outcomes. PMID- 27760642 TI - [Attention to the impression cytology in the evaluation of ocular surface tumors]. AB - Impression cytology (IC) has been widely used as a method for evaluating the ocular surface and superficial cells layers in the diagnosis and follow-up after treatment of several ocular surface tumors of both epithelial and melanocytic origin. Compared with exfoliative cytology with spatula, IC is less traumatic to the patient's eye. It provides a precise location of the area being studied and allows accurate observation of the cells the way they exist in vivo. The additional advantage of IC is the preservation of limbal stem cells responsible for continuous corneal epithelium renewal. In certain cases, ophthalmologists may prefer interventions less invasive than surgical biopsy such as impression cytology for both initial diagnosis and therapeutic monitoring of the treatment for ocular surface lesions. The purpose of this article is to comment the effect for the diagnosis and management of ocular surface tumors and to discuss the requirement for further investigation on the subject. (Chin J Ophthalmol, 2016, 52: 721-723). PMID- 27760643 TI - [Development of ophthalmic pathology and precision medicine]. AB - As an indispensable professional, ophthalmic pathology plays an important role in the development of the ophthalmology. With the worldwide attention and promotion of precision medicine and the rapid development of modern medical testing technology, the development of pathology is facing the challenges of survival and development opportunities. We discuss the relationship between the development of pathology and the precision medicine to explain that the precise pathological diagnosis is the basis of the implementation of precision medicine. Ophthalmic pathology workers should be the first to improve the accuracy of the diagnosis of ocular diseases, in order to play a greater role in the future of precision medicine in the diagnosis of pathology. (Chin J Ophthalmol, 2016, 52: 724-727). PMID- 27760644 TI - [Eyeball salvage treatment or enucleation for advanced retinoblastoma]. AB - The management of retinoblastoma (RB) has dramatically changed over the past two decades. The introduction of chemotherapy has transformed treatment algorithms completely. Chemotherapy is currently used as a first line approach for children with RB and can be delivered by intravenous, intra-arterial and intravitreal routes. However, there still remains some controversy on the treatment of advanced RB, especially in eyeball salvage. This article described domestic and international approaches to eyeball salvage treatment. We would like to further discuss our opinion on the management of advanced RB based on our clinical experience for attracting more clinical concern on this issue. Many factors should be considered when choosing the appropriate conservative therapy. The choice of eyeball salvage treatment not only depends upon the tumor staging and laterality but also upon compliance and economic factors. Doctors and parents should not blindly pursue eye saving. However, there are still cases where enucleation is definitely the treatment of choice. (Chin J Ophthalmol, 2016, 52: 728-732). PMID- 27760646 TI - [The efficacy of large spot indirect ophthalmoscopy laser alone or combined with systemic chemotherapy in retinoblastoma therapy]. AB - : Objective: To evaluate the efficacy of large spot indirect ophthalmoscopy laser alone or combined with systemic chemotherapy in the treatment of early and middle stage retinoblastoma. Methods: Retrospective series case study. Clinical data of 21 patients (22 eyes) who were diagnosed as retinoblastoma (RB) in Peking University People's Hospital from March 2009 to August 2014 were collected. Medical and family history, ocular ultrasound, orbital and cranial MRI or CT examination of RB Children were detailed recorded. Ocular examination and laser treatment were performed under general anesthesia, once every 3-4 weeks until the tumor was under control. The observation period was at least 3 months after the last treatment. The ocular examination included intraocular pressure measurement, anterior segment and fundus examination and the fundus photography with Retcam. Laser therapeutic instrument was large spot indirect ophthalmoscopy laser of 810nm wavelength. Results: Of the 21 children, 16 were male and 5 were female. The range of age was 3 to 82 months averaged 17.3 months. Among 22 eyes, four with small tumor, eight with medium tumor, and ten with large tumor. Two eyes underwent laser treatment only and 20 eyes underwent laser treatment combined with systemic chemotherapy. During the average observation period of 33.9 months, 15 tumors were treated successfully, but 7 failed. The total success rate was 68.2%. The number and success rate of small, medium and large tumor eyes were 4 (100%), 5 (62.5%) and 5 (50%), respectively. There was one case of tumor brain metastases, and the classification of contralateral eye of the child was E phase. COMPLICATIONS: Iris burns happened in one eye, obvious vitreous proliferation in one eye and mild vitreous hemorrhage occurred in two eyes, which did not affect the treatment of laser. However, obvious tumor hemorrhage happened in two eyes and affected laser therapy. There was no complicated cataract, iatrogenic retinal hole and tumor intravitreal implant caused by laser blasting effect. Conclusions: Indirect ophthalmoscope laser in 810-nm diode laser with large-spot alone or combined with systemic chemotherapy may be effective treatment for retinoblastoma in earlier than stage C of international classification. It is suitable for large and multiple retinoblastoma.(Chin J Ophthalmol, 2016, 52: 745-748). PMID- 27760645 TI - [The clinical and histopathological analysis of 2 053 cases of conjunctival neoplasms]. AB - Objective: We aimed to identify and describe the clinical and histopathologic characteristics of conjunctival neoplasms. Methods: Retrospective case series study. We collected and analyzed the clinical and histopathologic data of the conjunctival neoplastic specimens including the age, gender, and histopathologic diagnosis of all patients obtained from Beijing Tongren Eye Center between October 2003 and October 2015. All the pathology diagnosis results were divided into two categories which were benign and malignant tumors, according to Shields histopathological classification methods and the pathology diagnosis results in our department. All cases were divided into four groups as 0-17 years old, 18-39 years old, 40-59 years old, aged 60 and above. The chi-square test was used for statistical analysis. Results: Of the 2 053 cases, 1 025 were males and 1 028 were females (male?female=1?1). 1660 cases (80.9%) were benign and 393 cases(19.1%) were premalignant or malignant. The average age at diagnosis was 30.5 years for benign lesions and 53.3 years for premalignant and malignant lesions, which was significant different (P<0.01). The most common benign lesions were nevus, cysts, dermoids and dermolipomas, inflammatory granulomas and squamous cell papillomas. The most common premalignant and malignant tumors were CIN, melanomas, lymphomas and squamous cell carcinoma. The constitution of males and females of cysts, squamous cell papillomas, primary acquired melanosis, CIN and lymphomas were significant different (P<0.01). Moreover, the most common benign and malignant neoplasm were dermoids and dermolipomas, melanomas respectively in group under 18 years old. And nevus and lymphomas were the most common benign and malignant tumors respectively in patients between 18 and 39 years old. While cysts and CIN were the most common benign and malignant tumors respectively in cases over 40 years old. Conclusions: The majority of tumors of the conjunctiva were benign, with the young people being most. The premalignant and malignant tumors were more frequent in the elderly. Nevus and CIN were the most common benign and malignant tumors, respectively.(Chin J Ophthalmol, 2016, 52: 738-744). PMID- 27760647 TI - [Characteristics of retinal and scleral infiltration in uveal melanoma]. AB - Objective: To analyze features of retinal and scleral infiltration of uveal melanoma. Methods: It was a retrospective case series study. The pathological and clinical data of 102 cases of uveal melanoma were analyzed retrospectively, which were collected between Jun. 2001 and Apr. 2013 in Beijing Tongren Hospital, Capital Medical University. The tumor shape, size, cell types, retinal and scleral invasion were recorded and analyzed. The relationship between retinal invasion and scleral invasion was analyzed by trend Chi-square test. Results: There were 44 male patients and 58 female patients with an average age of 45.6+/ 12.4 (range from 15 to 78 years old) in 102 cases. As for tumor size, there were 68 (66.7%) large size tumors, 27 (26.5%) medium size tumors and 7(6.8%) small size tumors; As for cell types, 76 (74.5%) were spindle cell, 6 (5.9%) were epithelioid cell, 16 (15.7%) were mixed cell, and 4 (4.0%) were others; As for tumor location, there were 3 (2.94%) ciliary body melanoma, 28 (27.5%) ciliary body and anterior choroid melanoma, and 71 (69.6%) choroid melanoma. Eighty-six cases (84.3%) showed retinal invasion, in which there were 20 cases of outer nuclear layer invasion (19.6%), 12 cases of inner nuclear layer invasion (11.8%), 30 cases of ganglion cell layer invasion (29.4%), and 24 cases of inner limiting membrane invasion (23.5%). Fifty-five cases (53.9%) showed scleral invasions, in which there were 11 cases (68.8%) of no retinal invasion, 13 cases of outer nuclear layer invasion (65.0%), 5 cases of inner nuclear layer invasion (41.7%), 15 cases of ganglion cell layer invasion (50.0%) and 11 cases of inner limiting membrane invasion (45.8%). In 76 spindle cell cases, the scleral invasion rate of different retinal invasion degree were 72.7% in 8 cases of none retinal invasion, 71.4% in 10 cases of outer nuclear layer invasion, 62.5% in 5 cases of inner nuclear layer invasion, 53.9% in 14 cases of ganglion cell layer invasion and 47.1% in 8 cases of inner limiting membrane invasion. No significant relationship was found between retinal and scleral invasion (gamma=-0.21, P=0.127) . Conclusion: With the increase of scleral invasion, the retinal invasion decreased. However, the correlation show no statistical significance.(Chin J Ophthalmol, 2016, 52: 749-754). PMID- 27760648 TI - [Study on the evaluation of pterygium activity with in vivo confocal microscopy]. AB - Objective: To observe the characteristics of pterygium with in vivo confocal microscopy (IVCM) and understand pterygium activity with the density of inflammatory cells, formation of new blood vessels, and the number of activated keratocytes within the stroma. Methods: A prospective case-controlled study. Thirty-six pterygia from 28 patients were analyzed in this study. A pterygium activity score was obtained by summing four scores of ocular discomfort, pterygium hyperemia, keratitis, and the presence of Fuchs patches. Among them, the low activity of pterygium (PAS score less than 3 points) appeared in 12 eyes and high activity of pterygium (PAS score >= 4 points) in 24 eyes. All Patients underwent pterygium IVCM quantitative analysis by observing the boundaries between the pterygium and the adjacent cornea, the density of goblet cells and dendritiform inflammatory cells and Fuchs patches. The correlation of pterygium activity between IVCM and PAS with slit lamp was analyzed with Spearman correlation analysis. Results: The presence of inflammatory cells, numerous blood vessels, and irregular boundary between the cornea and the pterygium with infiltration of hyper-reflective cells in the adjacent corneal epithelium were signs observed with IVCM associated with pterygium activity. With IVCM technique, epithelial cells, goblet cells, and dendritiform inflammatory cells of various sizes were observed within the pterygium epithelium.The active (PAS >=4) pterygium showed irregular boundaries between the pterygium and the adjacent cornea (score, 0.84+/-0.51) comparing with inactive subjects (score 0.23+/-0.12, t=2.68, P=0.009). Fuchs patches were observed as islets of hyper-reflective polygonal cells in front of the pterygium head with blurred boundary. The score (0.75+/-0.25) in active group showed significant changes as compared with normal subjects (0.23+/-0.12, t=3.79, P=0.001). The score of dendritiform inflammatory cells, activated keratocytes, and goblet cells in active group were 2.75+/-0.76, 1.92+/-0.68, and 2.08+/-0.42, which were significantly higher than those in inactive group (1.25+/-0.55, 0.50+/-0.25, 1.15+/-0.32, P=0.035, 0.030, <0.01). There was significant positive correlation between IVCM activity and traditional slit lamp PAS. Conclusion: Quantitative analysis of dendritiform inflammatory cells, vascular proliferation and activated keratocytes of pterygium by IVCM may be a reliable evaluation method to evaluate the activity of pterygium.(Chin J Ophthalmol, 2016, 52: 755-763). PMID- 27760649 TI - [Clinical and pathological analysis of ocular tumors in 504 children cases]. AB - Objective: To analyze the clinical features and pathological classification of chlidren's ocular tumors. Methods: Retrospective case series study. Five hundred and four cases (506 eyes) of ocular tumor with biopsy-proven in children below 14 years old between January 2002 and December 2014 from Tianjin Eye Hospital were performed to retrospectively investigated the lesion location, clinical features and histopathologic classification of these lesions. Results: Of 504 cases there were 246 boys (248 eyes) and 258 girls (258 eyes) patients. The mean age at diagnosis was 6.4 years, ranged from 4 months to 14 years. Of 328 cases (65.1%) of eyelid and ocular surface, 2 cases (0.6%) were malignant tumors and other tumors were all benign tumors. The leading four tumors were corneal dermoid, dermoid cysts, nevus and pilomatricoma. Of 123 cases (24.4%) of orbital tumors, 13 cases (10.6%) were malignant tumors and other tumors were all benign tumors. The leading four tumors were dermoid cysts, lymphangiomas, hemolymphangioma and venous hemangioma. Of 53 cases (10.5%) of intraocular tumors, 41 cases (77.4%) were malignant tumors which were all retinoblastoma. Conclusions: Most of children's ocular tumors were congenital and embryonic tumors. The most common ocular tumors of 504 children patients were from eyelid and ocular surface. Corneal dermoid and dermoid cysts were the most benign ones. Retinoblastoma and rhabdomyosarcoma were the most malignant ones.(Chin J Ophthalmol, 2016, 52: 764 768). PMID- 27760650 TI - [Clinical and pathologic observation of uveal metastatic carcinoma]. AB - Objective: To observe the clinical and pathological features of uveal metastatic carcinoma. Methods: It was a retrospective case series study. The clinical manifestation, growth pattern, tumor types and relative pathological features of 13 patients visiting from January 1980 to December 2014 with uveal metastatic carcinoma in Tianjin Eye Hospital were analyzed retrospectively. Results: There were 13 cases, 6 cases of male and 7 of female. Age was from 37.0 to 66.0 years old. The mean age was 52.1 years old. all cases were monocular. There were 5 cases with right eye and 8 cases with left eye. Among 13 cases, 10 tumors were in posterior choroid, one tumor was in anterior choroid and ciliary body, 2 tumors were in the iris. There were 5 patients with lung cancer, 4 patients with breast cancer, 1 patient with prostate cancer, 1 patient with thyroid cancer and 1 patient with esophageal cancer. The primary tumor wasn't found in 1 patient. The rapid decrease of visual acuity showed in 10 patients with posterior choroidal metastatic carcinoma, 8 of them accompanied with extensive retinal detachment and 6 of them had secondary glaucoma. The multiple gray-white nodule or pink cauliflower mass on the papillary margin of iris were showed respectively in 2 patients with iris metastatic carcinoma. The pathological examination found that posterior choroidal metastatic carcinoma mainly located in temporal or nasal side choroids in 10 cases, among them, local or diffuse flat choroidal masses showed in 6cases, extensive mass involving choroid and ciliary body showed in 1 case, large nodular or globular choroidal mass showed in 2 cases, choroidal mass surrounded the optic disc in 1 case, optic nerve invasion showed in 3 cases and extraocular or orbital invasion showed in 3 cases. The scleral and subconjunctival invasion showed in 1 case of anterior choroid and ciliary body metastatic carcinoma. Conclusions: Uveal metastatic carcinoma manifested various growth pattern, the rapid decrease of visual acuity, flat or nodular choroidal solid mass, secondary retinal detachment and glaucoma were common clinical features. Some cases might invade extraocular or orbital tissue. (Chin J Ophthalmol, 2016, 52: 769-774). PMID- 27760651 TI - [Clinical and pathological features and surgical treatment of eyelid/conjunctival amyloidosis]. AB - Objective: To study the clinical and pathological features and surgical outcome of eyelid/conjunctival amyloidosis. Methods: It was a retrospective case series study. The clinical and pathological records of 11 patients who were diagnosed as eyelid/conjunctival amyloidosis and had surgical treatment between February 2007 and October 2015 at Beijing Tongren Hospital were analyzed. Routine pathological examinations and Congo red staining were performed. All of the 11 patients received surgical treatment. Seven patients with ptosis underwent surgical excision and ptosis repair. One patient with lower eyelid mass underwent surgical excision and reconstruction of the lower eyelid. One patient with upper eyelid mass underwent surgical excision. Two patients with conjunctival mass underwent surgical excision. Results: In the 11 patients, 6 were male and 5 were female. The mean age was 31 years old, median age was 21 years old, and the range of age was13-59 years old. Eight cases presented as eyelid thickening and nodular growth of the conjunctiva, and 7 of them had ptosis. One case presented as tumor of the upper lid. Two cases presented as conjunctival masses at the semilunar fold. None of the patients were found to have systemic involvement. All of the 11 cases received surgical treatment including excision of the lesions and correction of ptosis when necessary. Pathological examinations confirmed the diagnosis of amyloidosis. Follow up time was 1-9 years. Nine cases were stable, 1 case had progression in the conjunctival lesion and 1 case was lost to follow up. Conclusions: Eyelid/conjunctival amyloidosis usually present as mass or diffuse thickening of the eyelid/conjunctiva. The outcome of surgical treatment was satisfying.(Chin J Ophthalmol, 2016, 52: 775-779). PMID- 27760652 TI - [Role of in vivo confocal microscopy in the diagnosis of keratoconjunctival tumors]. AB - The diagnosis of keratoconjunctival tumors were mainly relied on the examination of the slit lamp microscope and histopathology till now. Making an accurate diagnosis to ocular surface tumor in time was very important for deciding the treatment method and evaluating the prognosis. In recent years, in vivo confocal microscopy (IVCM) has been used in ophthalmic clinical diagnosis as a new evaluation method. It was easy to detect cytological characteristics of ocular surface diseases safely in vivo. More and more researches results have shown that IVCM could provide powerful supports to the diagnosis and management of keratoconjunctival tumors, especially for the pigmented tumors and ocular surface squamous neoplasia. In this paper, the applications of IVCM for diagnosing keratoconjunctival tumors were reviewed. (Chin J Ophthalmol, 2016, 52: 789-793). PMID- 27760653 TI - [Advances in genome-wide association study of myopia]. AB - As the results of both environmental and genetic factors, myopia is one of the most popular refractive errors in the world. In recent years, progressive achievements have been made in genome-wide association study (GWAS) of myopia and refractive error. A lot of susceptibility loci and regions have been found, which means the researches on genetic basis of myopia and refractive error entered a new stage. This review summarized the main advances, and indicated the possible directions of genetic studies of myopia and refractive error in the future. (Chin J Ophthalmol, 2016, 52: 794-800). PMID- 27760654 TI - [Cognitive effectiveness of risperidone and olanzapine in first-episode schizophrenia]. AB - Objective: To study the impairments of cognitive function in first-episode schizophrenia and the potential effectiveness of risperidone and olanzapine monotherapy on first-episode schizophrenia. Methods: A total of 57 first-episode schizophrenia and 30 healthy controls were assessed at baseline, and patients were assessed again after 8-week antipsychotics therapy. Results: The positive and negative symptom scale (PANSS) reductive ratio between the two groups was similar. At baseline, the performance of schizophrenia patients was significant poor than healthy controls in the four domains of cognitive function (P<0.05); after 8-week's antipsychotics therapy, the performance of Trail Making Test (t=3.862, P<0.05) and Verbal Learning (t=-3.073, P<0.05) got significant improvements in patients with risperidone, while in group of patients with olanzapine, the performance of Trail Making Test (t=3.587, P<0.05) and working memory domain (t=-2.891, P<0.05) got significant improvements. Spearman correlation analyses suggested that dosage of risperidone was negatively correlated with the score-reducing rate of the performance of Trail Making Test of patients (r=-0.391, P=0.048). Conclusions: The effects of the two psychotroptic drugs on clinical symptoms and cognitive functions are almost equal. Comprehensive cognitive impairment is found in first-episode schizophrenia, and risperidone and olanzapine could partially improve the performance of cognitive function as well as clinical symptoms. The higher the dosage of risperidone is, the less improvement the patients has in the speed of process domain. PMID- 27760655 TI - [Research of upper arms muscle MRI in patients with Kennedy's disease]. AB - Objective: To investigate whether or not the involvement degree of extensor and flexor muscles in patients with Kennedy's Disease (KD) was different by measuring the diameter of biceps and triceps brachii muscles using Magnetic Resonance Imaging (MRI). Methods: All the subjects were outpatients or hospitalized patients from Department of Neurology, the Third Hospital of Peking University, 2011-2015. Subjects included 30 KD patients and 30 amyotrophic lateral sclerosis (ALS) patients. The right upper arms of all subjects were examined by muscle MRI. The diameters of biceps and triceps brachii muscles were measured, then the ratios were calculated. Additionally, the forces of these muscles were recorded. Results: The ratio of diameters of biceps to triceps brachii muscles were 1.08+/ 0.14 in KD patients and 0.99+/-0.15 in ALS patients. The difference was statistically significant (P<0.05). The ratio of forces of biceps to triceps were 1.17+/-0.12 in KD patients and 0.98+/-0.28 in ALS patients. The difference was statistically significant (P<0.01). In KD patients, the fatty infiltration was more serious in triceps than biceps. At the same time, in ALS patients, the fatty infiltration was similar in triceps and biceps. Conclusion: The involvement degree of extensor and flexor muscles in KD patients is different. PMID- 27760656 TI - [Analysis on clinical features and functional MRI of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes]. AB - Objective: To explore the clinical and perfusion weighted imaging (PWI) characteristics of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) in order to improve the early diagnosis rate. Methods: Clinical and imaging data of 46 patients with final diagnosis of MELAS treated in Henan Province People's Hospital from January 2012 to June 2016 were collected. Results: Patients presented with symptoms of epilepsy, hemiplegia, language disorders, and decreased visual acuity and so on. Diffusion-weighted imaging (DWI) of the lesion area showed a high signal, apparent diffusion coefficient (ADC) chart with the course of disease development can be a high signal, low signal, high and low signal. Vascular stenosis was not seen in all the patients by magnetic resonance angiography (MRA). PWI perfusion increased in acute phase and was normal or decreased in the chronic phase. Conclusions: The clinical manifestations of MELAS patients are complex and various, and lack of specificity. Routine MRI examination is of great significance for the screening of the lesion, which has a characteristic performance and is helpful to improve the early diagnosis rate of the disease. PMID- 27760657 TI - [Application evaluation of multi-parametric MRI in the diagnosis and differential diagnosis of early prostate cancer and prostatitis]. AB - Objective: To evaluate the value of multi-parametric MRI (Mp-MRI) in the diagnosis and differential diagnosis of early prostate cancer(PCa) in the peripheral zone(PZ) and low T2WI signal intensity of prostatitis. Methods: A total of 40 patients with PZ early PCa and 37 with prostatitis of hypointense T2WI signal in PZ were retrospectively analyzed, which were collected from the General Hospital of Ningxia Medical University from Janurary 2009 to June 2015, who underwent T2WI, DWI, and DCE-MRI examination and all patients were confirmed by pathology. All the data was transferred to GE Advanced Workstation AW4.3, the indexes divided into cancerous and prostatitis regions were calculated by Functool2 of signal intensity-time(SI-T) curve and ADC value, to calcuate the time to minimum(Tmax), the whole enhancment degree (SImax). ROC cure was used to determine the cutoff value for PCa detection with the ADC value. Result: On T2WI, 57.5% of PCa (23/40) showed focal nodular homogeneous low signal intensity, 70.3% of prostatitis(26/37) showed diffuse inhomogeneous low signal intensity. DCE-MRI, the distribution of curve types for malignant tumors was type I 2.5%(1/40), typeII32.5%(13/40) and type III 65.0% (26/40). While the numbers for prostatitis was type I 16.2%(6/37) , type II 56.8% (21/37) and type III 27.0% (10/37)respectively.The patterns of curve types in malignant lesions were different from benign lesions significantly(chi2 =12.32, P<0.01). The mean values of Tmax, SImax in cancerous and prostatitis regions were (17.96+/-2.91)s, 1.76%+/ 0.23% and (21.19+/-3.59)s, 1.53%+/-0.18%, respectively (t=5.37, 6.10; P<0.01). On DWI, The mean ADC values in cancerous and prostatitis regions were (0.95+/ 0.13)*10-3 mm2/s and (1.12+/-0.13)*10-3 mm2/s, respectively (t=7.10, P<0.01). According to the ROC analysis, when the cutoff value was 1.01*10-3 mm2/s, the early PCa of diagnostic sensitivity, specificity and accuracy was 79.1%, 72.7% and 76.1% respectively. Conclusion: Combined with morphology and signal characteristics of conventional T2WI, DWI and DCE-MRI improve the power of MR imaging in discriminating prostatitis from early PCa. PMID- 27760658 TI - [Transarterial chemoembolization combined with cryoablation for unresectable large hepatocellular carcinoma: a controlled study]. AB - Objective: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with cryoablation in patients with unresectable large hepatocellular carcinoma (HCC). Methods: A total of 122 patients with unresectable large HCC admitted to the First Affiliated Hospital of Sun Yat-sen University between November 2011 and July 2015 were retrospectively involved.The patients were divided into study group (58 patients who underwent TACE combined with cryoablation) and control group (64 patients who underwent TACE alone). Short-term effect of the initial treatment, long-term effect, prognostic factors for survival and adverse reactions were statistically analyzed. Result: There was no statistical difference in general information between two groups. The effective rates of the study and control group were 29.3% and 10.9% (P=0.011), and the control rates were 79.3% and 62.5% (P=0.042). The median survival time was 11.0 months (95% CI 7.4-14.6) for the study group and 5.0 months (95% CI 4.0 6.0) for the control group, the 6-, 12-, and 18-month overall survival rates for the study and control group were 84.5%, 49.5%, 26.8% and 48.1%, 17.8%, 11.1%, respectively (all P<0.01). On multivariate analysis, negative distant metastasis, Barcelona Clinic Liver Cancer B-stage, neutrophil-to-lymphocyte ratio <=5, alpha fetoprotein<400 MUg/L, combined treatment and effective initial treatment were independent protective factors for survival of patients with large HCC. Conclusions: The prognosis of patients with unresectable large HCC is affected by multiple factors. In comparison with TACE alone, TACE combined with cryoablation has advantage in both short-term and long-term effect with low incidence of serious adverse reactions, it is an effective and safe treatment option for patients with unresectable large HCC. PMID- 27760659 TI - [Study on the impact of labro-chondral complex on development of the acetabulum after close reduction in developmental dysplasia of the hip]. AB - Objective: To explore the influence of the labro-chondral complex (LLC) on the development of the acetabulum after close reduction in developmental dysplasia of the hip (DDH). Methods: Sixty-one cases (72 hips) with DDH presented in Beijing Jishuitan Hospital were reviewed, all the patients were treated by closed reduction, arthrogram and Spica casting from March 2010 to December 2013. The anterior-posterior pelvic radiography was performed to evaluate the morphology of the labro-chondral complex and reduction of the hip. The cases were divided into I, II, III, IV four groups according to the shape of the LLC initially, and when performed the secondary Spica cast after 3 months, these cases were divided into 0-0.4, 0.4-0.6, and >0.6, three groups based on the height difference ratio (HDR) of the LLC. The relationship between the shape and HDR of the LLC was analyzed. The AI and CE angle were used to evaluate development of the hip during the latest follow up. The impact of the shape and HDR of the LLC on the development of the acetabulum was explored as well. Results: The HDR was the least in the type I hips, all cases were less than 0.6, the AI in this group was significantly lower than the others(24.33 degrees +/-3.12 degrees ), and the CE angle was significantly higher in the type I hips(15.22 degrees +/-3.11 degrees ) during the latest follow up. The CE angle was significantly different among the three groups of HDR. The HDR was lower, the CE angle was higher. The AI in 0-0.4 group was significantly lower than the others(14.24 degrees +/-3.10 degrees ). Conclusion: The shape of the LLC is helpful to judge development of the acetabulum when closed reduction was performed in DDH. And the HDR in the secondary cast change could be used as a sensitive index to predict development of the hip. PMID- 27760660 TI - [Comparison of mid-term surgical results between plate and intramedullary nail for humeral shaft fracture]. AB - Objective: To evaluate the mid-term clinical efficacy of plate and intramedullary nail for humeral shaft fracture. Methods: In this retrospective study a total of 122 patients with humeral shaft fracture were divided into 2 groups according to surgery type from May 2010 to July 2012. There were 63 patients in plate group and 59 patients in intramedullary nail group. The factors related to the operation for each group were compared respectively. The clinical outcome was evaluated by the Neer scores, Myao scores and EuroQol 5 dimensions scores (EQ 5D). All the patients were followed up periodically in the next 3 years. Results: There were no significant differences between the two groups on hospital stay and time of returning to work (P>0.05). While the operation time, amount of intraoperative blood loss and complication rate were less in intramedullary nail group. The mean follow-up duration was (41.2+/-4.2) months in plate group and (42.1+/-4.7) months in intramedullary nail group respectively. At the last follow up the postoperative Neer scores, Myao scores and EQ-5D scores showed no significant differences between the 2 groups[Neer: (93.8+/-6.1) vs(92.1+/-4.2); Myao: (94.9+/-2.9) vs(96.2+/-1.5), P>0.05]. There were no cases complicated with nonunion, delayed union, infection and deformity during the follow-up period. Conclusions: The mid-term outcome of open reduction and internal fixation with plate and close reduction with intramedullary nail for humeral shaft fracture is satisfactory. Although both surgeries are safe and effective, they also have some defaults. The doctors should choose the right surgery carefully according to the actual situation of the patients. PMID- 27760661 TI - [Clinical results of the patients with severe kyphosis and paraplegia in different spine segment due to tuberculosis of thoracic and lumbar treated by one stage posterior surgical procedure to debriment of lesion bone fusion with internal fixation by pedicle screw system]. AB - Objective: To evaluate the clinical results of the patients with severe kyphosis and paraplegia in different spine segment due to tuberculosis of thoracic and lumbar had been treated by one stage posterior surgical procedure to debriment of lesion and titian mesh bone fusion with internal fixation by pedicle screw system. Method: From May 2008 to March 2014, there were total 30 patients with severe kyphosis and paraplegia in different spine segment due to tuberculosis of thoracic and lumbar in Department of Orthopaedics, the People's Hospital of Xinjiang Uygur Autonoumy Region.The average age was 27 years, ranging from 11-65 years old, 21 male and 9 female.Tuberculosis lesion were located in differental spine segment: T3-54 four cases, T6-10 ten cases, T11-L2 twelve cases, L3-L5 four cases, two vertebral bodies were involved in 6 cases, three vertebralbodies were involved in 12 cases, and four vertebral bodies were involved in 10 cases.All patients were treated by one stage posterior surgical procedure to debriment of lesion and titian mesh bone fusion with internal fixation of pedicle screw system .There were investigated the period of bone grafting fusion, kyphosis deformity correction degree , ESR, CRP preoperatively and postoperatively were compared before and after operation, and neurological function recovery record postoperatively, and neurological function recovery record postoperatively. Result: In the final follew-up, all patients got solid fusion in a average of eight months.The kyphosis deformity was corrected from(77+/-12) degrees preoperatively to(9.7+/-1.6) degrees postoperatively, in a average of 57 degrees , the result is significant(P<0.05). The value of ESR degraded from(64+/-44)mm/h preoperatively to(15+/-7)mm/h, through statistic analyzing, the change of ESR value between postoperative and preoperative is significant(P<0.05) .The value of CRP degraded from(72+/-40)mg/L preoperatively to(13+/-5)mg/L postoperatively, via statistic analyzing, the change of CRP value between postoperative and preoperative is significant(P<0.05). All Patients neurological function deficiency achieved complete recovery, the longest time being within 8 months.All patients were cured thoroughly and there was no seroius complication. Conclusion: The one stage debriment of lesion and threaded fusion cage with internal fixation of vertebral pedicle surgical procedure, according to the extent of severe kyphosis and paraplegir due to tuberculosis of thoracic and lumbar vertebrae can achieve thoroughly debridement of tuberculosis, solid interbody fusion, good correction of deformity and forever stability of spine with posterior internal fixation, it get successfully rehablitation for neurological function and improve the life quality. PMID- 27760662 TI - [Surgical treatment of pituitary adenomas in childhood and adolescence]. AB - Objective: To investigate the clinical characteristics and treatment of pituitary adenomas of childhood and adolescence. Methods: Thisarticle was a retrospective study of 140 pituitary adenomas of childhood and adolescence that was admitted into Peking Union Medical College Hospital from December 1987 to December 2014, whose clinical manifestations, hormone secretions, images, pathological types, surgical complications and follow-ups were studied. Results: A total of 58 (41.4%) males and 82 females (58.6%) were included, whose mean age was 12.5 years old (age range from 7 to 18). As for the type of tumors, ACTH adenoma, PRL adenoma, GH adenoma, non-functional adenoma and multiple-secreting adenoma accounted for 35.7%, 25.7%, 12.2%, 25.7% and 0.7%, respectively. Microadenoma accounted for 33.6% of total patients, while macroadenoma and giant adenoma accounted for 60.0% and 6.4% respectively. 19.3% of adenomas in our study wereinvasive. Transsphenoidal approach surgery was commonly used and accounted for 97.9% of cases in our study, 2 of which used intraoperative navigation assistance. Total resection was achieved in 93.6% of patients, and the rest achieved subtotal resection. 108 (77.1%) patients got full term follow-up until 1 year after surgery, and tumor recurred in 14 patients (13.0%). Conclusions: ACTH secreting adenoma is the most common pituitary adenoma in childhood and adolescence which need surgical treatment. Transsphenoidal approach surgery is the most commonly used surgical procedure. The recurrence rate is about 13%, and the patients need regular examination of pituitary hormones and image study to confirm the recurrence. PMID- 27760663 TI - [The prognosis of Monochorionic co-twin after single intrauterine fetal demise]. AB - Objective: To analyze the prognosis of surviving monochorionic co-twin after single intrauterine fetal demise (sIUFD). Methods: Retrospectively analyzed the twin pregnancy cases admitted in Peking University Third Hospital between Jan 2008 and Feb 2015. We recorded perinatal characteristics, neuroimage in co-twin, and followed up the neonatal outcome. Results: 47 cases were found, including 45 cases of monochorionic diamniotic (MCDA) and 2 cases of monochorionic monoamniotic (MCMA). Median gestational age at sIUFD was 27 weeks.Median interval between sIUFD and birth was 3.3 weeks.Median gestational age at birth was 34.2 weeks.The causes of sIUFD were: MCMA (2/47, 4.3%), sIUGR (11/47, 23.4%), twin twin transfusion syndrome (TTTS) (16/47, 34.0%) or TTTS complicated with sIUGR (3/47, 6.4%). In the sIUGR pregnancies, sIUFD occurred all in the growth restricted fetus.In the TTTS pregnancies, sIUFD always occurred in donors (15/16, 93.8%). There were 41 (87.2%) live-born co-twins.Among the live births, fetal cranial ultrasound showed that 7 neonatus got intraventricular hemorrhage.There were 6 neonatus dead in first 28 days.All of the 35 survivors whose follow up from 12 to 70 months, responses were all received and nobody had cerebral palsy. Conclusion: sIUFD always occurred in the growth-restricted fetus and the donor twins. There was nobody had cerebral palsy in the survivors. PMID- 27760664 TI - [Interferon alpha sensitizes human osteosarcoma cells to doxorubicin-induced apoptosis through p53-dependent pathway]. AB - Objective: To investigate the effect of IFNalpha on doxorubicin-induced apoptosis in human osteosarcoma cells with its molecular mechanisms to provide evidences for improving the treatment of osteosarcoma. Methods: Osteosacoma U2OS and MG63 cells were treated with IFNalpha and Doxorubicin, alone or in combination, for 72 h . Cytotoxicity was determined with MTT. Apoptosis was evaluated through fluorescence-activated cell sorting, Hoechst33258 staining and DNA ladder assay. The expression of p53, Bax, Bcl-2, Mdm2, p21, caspase-3 and PARP was determined with Western blot. siRNA interference was used to silence p53. Results: IFNalpha treatment for 72 h did not induce cytotoxicity but greatly enhanced doxorubicin induced cytotoxicity and apoptosis in p53-wild U2OS cells but not p53-mutant MG63 cells. Compared with other groups, the combination of IFNalpha and doxorubicin induced more obvious apoptotic morphological changes and DNA ladder. IFNalpha did not alter the expression of the indicate genes. The expression of p53, Bax, Mdm2 and p21 was up-regulated by doxorubicin and further increased in response to combination. The expression of Bcl-2 was down-regulated by doxorubicin and further decreased in response to combination.There were no differences among groups in MG63 cells. The expression of p53 was effectively blocked by p53-siRNA in U2OS cells. The p53 silencing greatly reduced the cytotoxicity mediated by combination for 72 h, compared with non- and control-siRNA groups. The activation of caspase-3 and PARP mediated by combination was largely suppressed by p53 silence. Conclusion: IFNalpha sensitizes human osteosarcoma cells to doxorubicin induced apoptosis through p53-dependent pathway. The combination of IFNalpha and traditional chemotherapy can be used in osteosarcoma treatment. PMID- 27760665 TI - [Effect of quorum sensing system on the infection of MRSA and the intervention of erythromycin on it]. AB - Objective: To investigate the destructive effects of erythromycin on biofilm of MRSA and find the effect of erythromycin on QS related factors. Methods: Tested the MBC of erythromycin on MRSA.Established the model of biofilm.Erythromycin was added into the medium when bacteria were inoculated for 24 h. Tested the biofilm and collected the supernatant or serum of rat at 6, 12, 24, 48, 72 h and 7 d after adding erythromycin to detect the concentration of autoinducing peptides (AIP). Results: The MBC of the erythromycin on standard strains of MRSA was 256 g/L.There is a decreasing tendency of biofilm in a short time after adding erythromycin or TSB and then gradually increase until to a steady state. Biofilm of experimental group(1.348, 1.236, 1.667)were significantly less than the control group(1.789, 1.712, 2.349, P<0.05)at 12, 24, 48 h. Adding erythromycin to the mature biofilm, there was a significant decrease of biofilm.Adding erythromycin within 3 hours after inoculating bacteria, there was no bacterial growth or biofilm formation. The development trend of AIP was similar with biofilm and AIP happened earlier than biofilm.With the intervention of erythromycin, AIP of experimental group(0.891 5, 0.853 9, 0.792 4)were significantly less than the control group(1.023 7, 1.061 6, 1.034 7, P<0.05)at 6, 24, 48 h. Conclusion: Adding erythromycin timely before biofilm formation, then bacteria were killed effectively.Erythromycin was able to destroy biofilm. Biofilm was inhibited by AIP obviously.To some extent, erythromycin can inhibit the synthesis or secretion of AIP. PMID- 27760667 TI - [Drawing experience from the history, proceeding with confidence and staying true to the mission, a Talk in the new book launch of A Century History of Traditional Chinese Medicine: 1912-2015]. PMID- 27760666 TI - [Prognostic significance of systematic retroperitoneal lymphadenectomy in patients with epithelial ovarian cancer: a Meta-analysis]. AB - Objective: To investigate the survival impact of systematic retroperitoneal lymphadenectomy (SL) and unsystematic lymphadenectomy (USL) in patients with epithelial ovarian cancer. Methods: Randomized control trial (RCT) and observational studies about the effects of SL and USL on patients with epithelial ovarian cancer were searched in major online databases including PubMed, Embase, Web of Science, and Cochrane Library. The literature search was performed up to January 2016. The results were analyzed using RevMan 5.0 software. Results: Totally 14 studies including 1 634 patients in SL group and 1 719 patients in USL group were enrolled. Three of the 14 studies were RCTs, and the other 11 were observational studies. Meta analysis showed that SL was a favorable factor for 5 year overall survival rate (5-OS) compared with USL[RR=0.89, 95% CI (0.81, 0.97), P=0.007]. However, the efficacy of SL on increased 5-OS could not be determined in all type of studies owing to the result of RCTs[RR=0.99, 95% CI (0.85, 1.15), P=0.90], whereas SL improved 5-OS of patients in observational studies[RR=0.84, 95% CI (0.76, 0.93), P=0.001]. Moreover, SL increased 5-OS in patients with early stage (FIGO I-II) disease comparing with USL[RR=0.78, 95% CI (0.61, 0.99), P=0.04], as well as it could improve 5-OS statistically in advanced stage (FIGO III-IV) disease[RR=0.90, 95% CI (0.82, 0.99), P=0.03]. But analysis on patients with optimal debulking surgery showed that SL could not improve 5-OS of these patients, regardless of early stage[RR=0.71, 95% CI (0.43, 1.17), P=0.18]or advanced stage[RR=1.01, 95% CI (0.90, 1.14), P=0.86]. Conclusions: The impact of SL on the survival of patients with epithelial ovarian cancer is still extremely controversial, which requires more relevant RCTs. In patients with optimal debulking surgery, SL could hardly improve the survival. PMID- 27760669 TI - [The role of textual research discipline in the formation and development of the learning of warm disease]. AB - The theory of warm disease is basically founded in Su wen (Plain Questions) , with its basis laid down, and developed to mature in the Qing Dynasty. In addition to the developmental rules of medical science itself and the epidemics of warm disease at the turn of the Ming-Qing Dynasties, this theory rapidly developed and became an independent theory, the adoption of methodology of textual research also played an indispensable role. Specialists of warm disease sorted out, checked, and revised previous works, with discerning, annotating all terms and nomenclatures to raise questions, solvingdifficulties, strengthening the integrity, reliability, and precision of works on warm disease, thus deepened the knowledge of the nature of warm disease, promoted the formation of the specific system of diagnosis and treatment for the learning of warm disease. PMID- 27760668 TI - [Hua Shou's social circle and his accomplishments and good medical reputation]. AB - Hua Shou was a very famous physician at the turn of the Yuan and Ming Dynasties. In addition to his medical skills, his social communication was also very helpful to his fame. Under the tutorship of the Confucianist Han Shuo, and physicians such as Wang Juzhong and Gao Dongyang in his early days, Hua Shou obtained two identities: Confucian scholar and doctor. The former helped Hua Shou get acceptance from literati group, meanwhile, Hua Shou's medical skill helped him deepen the communication among them. By means of his double identity, Hua Shou got acquaintance with many local and nation-wide scholars and politicians, including Zhao Lian, Chen Xingzhong, Wang Shuyu, Fang Guozhen, Song Xuanxi, Zhu You, Wang Xiyang, Song Lian, Liu Ji, through them Hua Shou's fame spread throughout the country. The whole set of"Lin xia"(Hermit identity) constructed by Ding Henian, Liu Renben and Dai Liang, help Hua Shou attain his bequeathed reputation. PMID- 27760670 TI - [Textural research on the origin and evolution of the"theory of drying dampness"and its initiator]. AB - There are two different records, namely,"vulnerability to dampness in autumn"and"dryness prevailing"in autumn, in the Neijing (Inner Canon). In the Jin and Yuan Dynasties, Liu Wansu supplemented the pathogenesis of dryness pathogen, whereas Wang Andao explained the contradictory records in the Neijing. In the Qing Dynasty, Yu Chang definitely challenged the theory"vulnerability to dampness in autumn"of the Neijing,triggering a debate on the recognition of"drying dampness". In fact, Yu Guopei was the initiator of"theory of drying dampness", who discussed the nature of Yin and Yang of"drying dampness"based on the laws of correspondence between human body and natural environment, elucidating that drying dampness should be the root of both exogenous disease and internal damage, and elaborating the etiology and pathogenesis of"drying dampness", the diagnosis and the nature of the drugs for drying dampness. Shi Shoutang inherited Yu's theory and made a further development. In modern times, some scholars advocated that"drying dampness"should be consideredalong with Yin and Yang, superficies and interior, excess and deficiency, cold and heat, as the guiding principle for syndrome differentiation. PMID- 27760671 TI - [The first official organization of traditional Chinese medicine in modern China TCM Improvement Research Association]. AB - In modern China, most of the mass organizations of traditional Chinese medicine (TCM) were civilian and established by the individuals with self support financially.The TCM Improvement Research Association of Shanxi Province was the first official TCM organization in modern China. For the purpose of ruling and recognition of TCM, Yan Xishan, the chief executive of Shanxi province, gave a full support to its creation, development, and operation of the Association with the military and political officials in the government served as part-time staff members of a few of important position in the Association. The Association was given funding and policy support by official ways. The local administrative departments cooperated with the Association affairs actively. Because of the stable organization and the abundant fund, the TCM Improvement Research Association developed quickly and steadily. As a result, the Association had been playing an important and increasing role in academic research, TCM education, medical and epidemic prevention and so on. It had become one of the great national TCM academic societies with prolonged existence. As an official Association, it was characterized with a dual property: a better foundation for development and little independency. PMID- 27760672 TI - [Early stage western hospitals in Harbin]. AB - From 1900 to 1932, China Eastern Railway Central Hospital, Harbin Board First Hospital, Harbin Special City Second Hospital, Binjiang Hospital, Jewish Hospital, Kong's Hospital, Mingming Ophthalmic Hospital and other western medicine hospitals were established in Harbin. These Hospitals had different sources of funds and talents, different consumers, including general hospitals and specialized hospitals with integration of clinic, education and academic research, which encouraged the dissemination of western medicine in Harbin at the beginning of the 20th century. PMID- 27760673 TI - [The establishment of Ting Hsien Experimental Project of Rural Health Service and its influence]. AB - Founded by the Chinese Mass Education Movement (MEM) led by Dr.James Yen and Peking Union Medical College(PUMC), the Ting Hsien Experimental Project was a demonstration program for health service in a rural county. Through a 8-year endeavor (1929-1937) and using a bottom-up approach, Dr. Chen Chih-chien and Dr.YaoHsun-yuan took the leadership of a group of dedicated PUMC graduates and students, and created a three-level(village-district-county) system to deliver both curative as well as preventive medical service for rural population. This project, under the full support of MEM and Dr. John Black Grant, Director of the Department of Public Health of PUMC, offered an important example for rural community health care in contemporary China. Moreover, it demonstrated and inspired the concepts of the primary health care advocated by World Health Organization 40 years later. PMID- 27760674 TI - [Investigation of the Campaign of"Eliminating the Four Pests and Paying Attention to Hygiene"in Shanxi province in the 1950s, with special reference to technological innovation]. AB - In order to improve the level of people's living and health standard, increase the output of cereal crops, achieve the country's economic recovery and development, and consolidate the new state power, a Campaign of"Eliminating the Four Pests and Paying Attention to Hygiene"in the field of health was launched by the Central Government in the 1950s. In response to the call of government, Shanxi province actively organized the people to participate in this Campaign. For improving the efficiency of Eliminating the Four Pests, people widely carried out technological innovation, with constant creation and invented advanced tools, and gained fruitful technological achievements. Through technological innovation, the working efficiency and quality were enhanced. More importantly, the interaction between the national and local authorities was promoted. In other words, there was a formation of national political domination and power over the local authority, as well as the"owner"awareness and the formation of the state conception. PMID- 27760675 TI - [Decipherment and annotation of a manuscript of Tibetan medicine in Dunhuang scroll (Part II)-on prescription]. AB - A manuscript of Tibetan medicine, P. t.1054, written on 4 pattra-leaf-like rectangular papers connected together, is collected in the Volume 10 of Dunhuang Tibetan Manuscripts Preserved in France Scroll. The contents on the front pages of the whole set is on pulse-taking of Tibetan medicine, and the back pages, on prescriptions containing 5 recipes of cathartics and medicinal oils, are included in 16 lines on the remained Scroll dealing with its ingredients, processing method, function and indications which can be differentiated into 5 units. There are altogether 30 drugs applied, including plants, animals and mineral. Among them, almost half are transliterated from foreign languages, and some of them are titled with India, Han region, etc. for distinguishing its producing area and breeds. It is preliminarily probative that this whole Scroll is translated-edited from certain part of an Indian formulary. PMID- 27760676 TI - Building research and evaluation capacity in population health: the NSW Health approach. AB - Issue addressed An organisational culture that values and uses research and evaluation (R&E) evidence to inform policy and practice is fundamental to improving health outcomes. The 2016 NSW Government Program Evaluation Guidelines recommend investment in training and development to improve evaluation capacity. The purpose of this paper is to outline the approaches taken by the NSW Ministry of Health to develop R&E capacity and assess these against existing models of practice. Method The Ministry of Health's Centre for Epidemiology and Evidence (CEE) takes an evidence-based approach to building R&E capacity in population health. Strategies are informed by: the NSW Population Health Research Strategy, R&E communities of practice across the Ministry and health Pillar agencies and a review of the published evidence on evaluation capacity building (ECB). An internal survey is conducted biennially to monitor research activity within the Ministry's Population and Public Health Division. One representative from each of the six centres that make up the Division coordinates completion of the survey by relevant staff members for their centre. Results The review identified several ECB success factors including: implementing a tailored multifaceted approach; an organisational commitment to R&E; and offering experiential training and ongoing technical support to the workforce. The survey of research activity found that the Division funded a mix of research assets, research funding schemes, research centres and commissioned R&E projects. CEE provides technical advice and support services for staff involved in R&E and in 2015, 22 program evaluations were supported. R&E capacity building also includes a series of guides to assist policy makers, practitioners and researchers to commission, undertake and use policy-relevant R&E. Staff training includes workshops on critical appraisal, program logic and evaluation methods. From January 2013 to June 2014 divisional staff published 84 peer-reviewed papers and one book chapter. Conclusion A strategic approach to R&E capacity building compares favourably with organisational dimensions of ECB and has facilitated the generation of high quality population health R&E in NSW. So what? An evidence-based multistrategy approach to population health R&E can result in substantial contributions to the population-health evidence base. PMID- 27760677 TI - Challenges in diabetes mellitus type 2 management in Nepal: a literature review. AB - BACKGROUND AND OBJECTIVES: Diabetes has become an increasingly prevalent and severe public health problem in Nepal. The Nepalese health system is struggling to deliver comprehensive, quality treatment and services for diabetes at all levels of health care. This study aims to review evidence on the prevalence, cost and treatment of diabetes mellitus type 2 and its complications in Nepal and to critically assess the challenges to be addressed to contain the epidemic and its negative economic impact. DESIGN: A comprehensive review of available evidence and data sources on prevalence, risk factors, cost, complications, treatment, and management of diabetes mellitus type 2 in Nepal was conducted through an online database search for articles published in English between January 2000 and November 2015. Additionally, we performed a manual search of articles and reference lists of published articles for additional references. RESULTS: Diabetes mellitus type 2 is emerging as a major health care problem in Nepal, with rising prevalence and its complications especially in urban populations. Several challenges in diabetes management were identified, including high cost of treatment, limited health care facilities, and lack of disease awareness among patients. No specific guideline was identified for the prevention and treatment of diabetes in Nepal. CONCLUSIONS: We conclude that a comprehensive national effort is needed to stem the tide of the growing burden of diabetes mellitus type 2 and its complications in Nepal. The government should develop a comprehensive plan to tackle diabetes and other non-communicable diseases supported by appropriate health infrastructure and funding. PMID- 27760678 TI - Involving private healthcare practitioners in an urban NCD sentinel surveillance system: lessons learned from Pune, India. AB - BACKGROUND: Despite the rising impact of non-communicable diseases (NCDs) on public health in India, lack of quality data and routine surveillance hampers the planning process for NCD prevention and control. Current surveillance programs focus largely on communicable diseases and do not adequately include the private healthcare sector as a major source of care in cities. OBJECTIVE: The objective of the study was to conceptualize, implement, and evaluate a prototype for an urban NCD sentinel surveillance system among private healthcare practitioners providing primary care in Pune, India. DESIGN: We mapped all private healthcare providers in three selected areas of the city, conducted a knowledge, attitude, and practice survey with regard to surveillance among 258 consenting practitioners, and assessed their willingness to participate in a routine NCD surveillance system. In total, 127 practitioners agreed and were included in a 6 month surveillance study. Data on first-time diagnoses of 10 selected NCDs alongside basic demographic and socioeconomic patient information were collected onsite on a monthly basis using a paper-based register. Descriptive and regression analyses were performed. RESULTS: In total, 1,532 incident cases were recorded that mainly included hypertension (n=622, 41%) and diabetes (n=460, 30%). Dropout rate was 10% (n=13). The monthly reporting consistency was quite constant, with the majority (n=63, 50%) submitting 1-10 cases in 6 months. Average number of submitted cases was highest among allopathic practitioners (17.4). A majority of the participants (n=104, 91%) agreed that the surveillance design could be scaled up to cover the entire city. CONCLUSIONS: The study indicates that private primary healthcare providers (allopathic and alternate medicine practitioners) play an important role in the diagnosis and treatment of NCDs and can be involved in NCD surveillance, if certain barriers are addressed. Main barriers observed were lack of regulation of the private sector, cross practices among different systems of medicine, limited clinic infrastructure, and knowledge gaps about disease surveillance. We suggest a voluntary augmented sentinel NCD surveillance system including public and private healthcare facilities at all levels of care. PMID- 27760679 TI - Microbial culturomics unravels the halophilic microbiota repertoire of table salt: description of Gracilibacillus massiliensis sp. nov. AB - BACKGROUND: Microbial culturomics represents an ongoing revolution in the characterization of environmental and human microbiome. METHODS: By using three media containing high salt concentration (100, 150, and 200 g/L), the halophilic microbial culturome of a commercial table salt was determined. RESULTS: Eighteen species belonging to the Terrabacteria group were isolated including eight moderate halophilic and 10 halotolerant bacteria. Gracilibacillus massiliensis sp. nov., type strain Awa-1T (=CSUR P1441=DSM 29726), is a moderately halophilic gram-positive, non-spore-forming rod, and is motile by using a flagellum. Strain Awa-1T shows catalase activity but no oxidase activity. It is not only an aerobic bacterium but also able to grow in anaerobic and microaerophilic atmospheres. The draft genome of G. massiliensis is 4,207,226 bp long, composed of 13 scaffolds with 36.05% of G+C content. It contains 3,908 genes (3,839 protein-coding and 69 RNA genes). At least 1,983 (52%) orthologous proteins were not shared with the closest phylogenetic species. Hundred twenty-six genes (3.3%) were identified as ORFans. CONCLUSIONS: Microbial culturomics can dramatically improve the characterization of the food and environmental microbiota repertoire, deciphering new bacterial species and new genes. Further studies will clarify the geographic specificity and the putative role of these new microbes and their related functional genetic content in environment, health, and disease. PMID- 27760681 TI - PrEP in Europe - expectations, opportunities and barriers. AB - INTRODUCTION: In contrast to the global trend showing a decline in new HIV infections, the number reported in the World Health Organization (WHO) region of Europe is increasing. Health systems are disparate, but even countries with free access to screening and treatment observe continuing high rates of new infections in key populations, notably men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) is only available in France. This commentary describes the European epidemics and healthcare settings where PrEP could be delivered, how need might be estimated for MSM and the residual barriers to access. DISCUSSION: Health systems and government commitment to HIV prevention and care, both financial and political, differ considerably between the countries that make up Europe. A common feature is that funds for prevention are a small fraction of funds for care. Although care is generally good, access is limited in the middle income countries of Eastern Europe and central Asia, and only 19% of people living with HIV received antiretroviral therapy in 2014. It is challenging to motivate governments or civil society to implement PrEP in the context of this unmet treatment need, which is driven by limited national health budgets and diminishing assistance from foreign aid. The high-income countries of Western Europe have hesitated to embrace PrEP for different reasons, initially due to key gaps in the evidence. Now that PrEP has been shown to be highly effective in European MSM in two randomized controlled trials, it is clear that the major barrier is the cost of the drug which is still on patent, although inadequate health systems and diminishing investment in civil society are also key challenges to overcome. CONCLUSIONS: The momentum to implement PrEP in European countries is increasing and provides a welcome opportunity to expand and improve clinical services and civil society support focused on HIV and related infections including other sexually transmitted and blood-borne infections. PMID- 27760680 TI - PrEP implementation research in Africa: what is new? AB - INTRODUCTION: Of the two million new HIV infections in adults in 2014, 70% occurred in sub-Saharan Africa. Several African countries have already approved guidelines for pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV as part of combination HIV prevention but key questions remain about how to identify and deliver PrEP to those at greatest need. Throughout the continent, individuals in sero-discordant relationships, and members of key populations (sex workers, men who have sex with men (MSM), transgender women and injection drug users) are likely to benefit from the availability of PrEP. In addition, adolescent girls and young women (AGYW) are at substantial risk in some parts of the continent. It has been estimated that at least three million individuals in Africa are likely to be eligible for PrEP according to WHO's criteria. Tens of demonstration projects are planned or underway across the continent among a range of countries, populations and delivery settings. DISCUSSION: In each of the target populations, there are overarching issues related to (i) creating demand for PrEP, (ii) addressing supply-side issues and (iii) providing appropriate and tailored adherence support. Critical for creating demand for PrEP is the normalization of HIV prevention. Community-level interventions which engage opinion leaders as well as empowerment interventions for those at highest risk will be key. Critical to supply of PrEP is that services are accessible for all, including for stigmatized populations. Establishing accessible integrated services provides the opportunity to address other public health priorities including the unmet need for HIV testing, contraception and sexually transmitted infections treatment. National policies need to include minimum standards for training and quality assurance for PrEP implementation and to address supply chain issues. Adherence support needs to recognize that social and structural factors are likely to have an important influence. Combining interventions that build self-efficacy, empowerment and social cohesion, with evidence-based individualized adherence support for PrEP, are most likely to be effective. CONCLUSIONS: Efficacy of tenfovir-based PrEP is proven but many issues related to implementation remain unclear. Here, we have summarized some of the important implementation questions that need to be assessed as PrEP is rolled out across Africa. PMID- 27760682 TI - PrEP as a feature in the optimal landscape of combination HIV prevention in sub Saharan Africa. AB - INTRODUCTION: The new WHO guidelines recommend offering pre-exposure prophylaxis (PrEP) to people who are at substantial risk of HIV infection. However, where PrEP should be prioritised, and for which population groups, remains an open question. The HIV landscape in sub-Saharan Africa features limited prevention resources, multiple options for achieving cost saving, and epidemic heterogeneity. This paper examines what role PrEP should play in optimal prevention in this complex and dynamic landscape. METHODS: We use a model that was previously developed to capture subnational HIV transmission in sub-Saharan Africa. With this model, we can consider how prevention funds could be distributed across and within countries throughout sub-Saharan Africa to enable optimal HIV prevention (that is, avert the greatest number of infections for the lowest cost). Here, we focus on PrEP to elucidate where, and to whom, it would optimally be offered in portfolios of interventions (alongside voluntary medical male circumcision, treatment as prevention, and behaviour change communication). Over a range of continental expenditure levels, we use our model to explore prevention patterns that incorporate PrEP, exclude PrEP, or implement PrEP according to a fixed incidence threshold. RESULTS: At low-to-moderate levels of total prevention expenditure, we find that the optimal intervention portfolios would include PrEP in only a few regions and primarily for female sex workers (FSW). Prioritisation of PrEP would expand with increasing total expenditure, such that the optimal prevention portfolios would offer PrEP in more subnational regions and increasingly for men who have sex with men (MSM) and the lower incidence general population. The marginal benefit of including PrEP among the available interventions increases with overall expenditure by up to 14% (relative to excluding PrEP). The minimum baseline incidence for the optimal offer of PrEP declines for all population groups as expenditure increases. We find that using a fixed incidence benchmark to guide PrEP decisions would incur considerable losses in impact (up to 7%) compared with an approach that uses PrEP more flexibly in light of prevailing budget conditions. CONCLUSIONS: Our findings suggest that, for an optimal distribution of prevention resources, choices of whether to implement PrEP in subnational regions should depend on the scope for impact of other possible interventions, local incidence in population groups, and total resources available. If prevention funding were to become restricted in the future, it may be suboptimal to use PrEP according to a fixed incidence benchmark, and other prevention modalities may be more cost-effective. In contrast, expansions in funding could permit PrEP to be used to its full potential in epidemiologically driven prevention portfolios and thereby enable a more cost-effective HIV response across Africa. PMID- 27760684 TI - Preventing HIV among adolescents with oral PrEP: observations and challenges in the United States and South Africa. AB - INTRODUCTION: Adolescents and young adults aged <25 are a key population in the HIV epidemic, with very high HIV incidence rates in many geographic settings and a large number who have limited access to prevention services. Thus, any biomedical HIV prevention approach should prepare licensure and implementation strategies for young populations. Oral pre-exposure prophylaxis (PrEP) is the first antiretroviral-based prevention intervention with proven efficacy across many settings and populations, and regulatory and policy approvals at global and national levels are occurring rapidly. We discuss available data from studies in the United States and South Africa on the use of oral PrEP for HIV prevention in adolescent minors, along with some of the implementation challenges. DISCUSSION: Ongoing studies in the United States and South Africa among youth under the age of 18 should provide the safety data needed by the end of 2016 to contribute to licensure of Truvada as daily PrEP in adolescents. The challenges of completing these studies as well as foreseeable broader challenges highlighted by this work are presented. Adherence to daily PrEP is a greater challenge for younger populations, and poor adherence was associated with decreased efficacy in all PrEP trials. Individual-level barriers include limited familiarity with antiretroviral-based prevention, stigma, product storage, and social support. Structural challenges include healthcare financing for PrEP, clinician acceptability and comfort with PrEP delivery, and the limited youth-friendly health services available. These challenges are discussed in the context of the work done to date in the United States and South Africa, but will likely be magnified in the setting of limited resources in many other countries that are heavily impacted by HIV. CONCLUSIONS: Adolescent populations are particularly vulnerable to HIV, and oral PrEP in these populations is likely to have an impact on population-level HIV incidence. The challenges of disseminating an HIV biomedical prevention tool requiring daily usage in adolescents are formidable, but addressing these issues and starting dialogues will lay the groundwork for the many other HIV prevention tools now being developed and tested. PMID- 27760683 TI - The future of PrEP among transgender women: the critical role of gender affirmation in research and clinical practices. AB - INTRODUCTION: Globally, transgender ("trans") women are one of the key populations most disproportionately impacted by HIV. Pre-exposure prophylaxis (PrEP) is the newest and most promising biomedical HIV prevention intervention to date. This paper reviews relevant literature to describe the current state of the science and describes the potential role of PrEP among trans women, including a discussion of unique considerations for maximizing the impact of PrEP for this vulnerable population. METHODS: Available information, including but not limited to existing scientific literature, about trans women and PrEP was reviewed and critiqued based on author expertise, including PrEP clinical trials and rollout. RESULTS: To date, PrEP demonstration projects and clinical trials have largely excluded trans women, or have not included them in a meaningful way. Data collection strategies that fail to identify trans women in clinical trials and research further limit the ability to draw conclusions about trans women's unique needs and devise strategies to meet them. Gender-affirming providers and clinic environments are essential components of any sexual health programme that aims to serve trans women, as they will largely avoid settings that may result in stigmatizing encounters and threats to their identities. While there is currently no evidence to suggest drug-drug interactions between PrEP and commonly used feminizing hormone regimens, community concerns about potential interactions may limit interest in and uptake of PrEP among trans women. CONCLUSIONS: In scaling up PrEP for trans women, it is essential to engage trans communities, utilize trans-inclusive research and marketing strategies and identify and/or train healthcare providers to provide gender-affirming healthcare to trans women, including transition-related care such as hormone provision. PrEP implementation guidelines must consider and address trans women's unique barriers and facilitators to uptake and adherence. PMID- 27760685 TI - Implementation of pre-exposure prophylaxis for human immunodeficiency virus infection: progress and emerging issues in research and policy. AB - BACKGROUND: In this article, we present recent evidence from studies focused on the implementation, effectiveness and cost-effectiveness of pre-exposure prophylaxis (PrEP) for HIV infection; discuss PrEP scale-up to date, including the observed levels of access and policy development; and elaborate on key emerging policy and research issues to consider for further scale-up, with a special focus on lower-middle income countries. DISCUSSION: The 2015 WHO Early Release Guidelines for HIV Treatment and Prevention reflect both scientific evidence and new policy perspectives. Those guidelines present a timely challenge to health systems for the scaling up of not only treatment for every person living with HIV infection but also the offer of PrEP to those at substantial risk. Delivery and uptake of both universal antiretroviral therapy (ART) and PrEP will require nation-wide commitment and could reinvigorate health systems to develop more comprehensive "combination prevention" programmes and support wider testing linked to both treatments and other prevention options for populations at highest risk who are currently not accessing services. Various gaps in current health systems will need to be addressed to achieve strategic scale-up of PrEP, including developing prioritization strategies, strengthening drug regulations, determining cost and funding sources, training health providers, supporting user adherence and creating demand. CONCLUSIONS: The initial steps in the scale-up of PrEP globally suggest feasibility, acceptability and likely impact. However, to prevent setbacks in less well-resourced settings, countries will need to anticipate and address challenges such as operational and health systems barriers, drug cost and regulatory policies, health providers' openness to prescribing PrEP to populations at substantial risk, demand and legal and human rights issues. Emerging problems will require creative solutions and will continue to illustrate the complexity of PrEP implementation. PMID- 27760686 TI - Commentary: the value of PrEP for people who inject drugs. AB - INTRODUCTION: The offer of pre-exposure prophylaxis (PrEP) is recommended as an additional option for HIV prevention for people at substantial risk of HIV infection as part of combination HIV prevention approaches. Implementing this depends on integrating PrEP in public health programmes that address risky practices with evidence-based interventions, and that operate in an enabling legal and policy environment for the delivery of health services to those at higher risk of HIV infection. What does this recommendation mean in terms of the diverse range of HIV prevention needs of key populations, some of whom are so discriminated against that they exist essentially outside formal systems such as national public health services, and for whom a substantial risk of HIV is part of a larger adverse and hostile situation? We discuss this question with reference to people who inject drugs, informed by concerns and comments that emerged from a series of consultations. DISCUSSION: HIV prevention is part of a spectrum of injecting drug users' priorities, and their access and uptake of HIV prevention services is contingent on their wider "risk environment." The need to address structural barriers to services and human rights violations, and to improve access to comprehensive harm reduction programmes are of prime importance and would have higher value than a mono-focus on HIV prevention. Where existing harm reduction activities are inadequate, fragile or dependent on external donors, shifts in funding priorities, including, for example, towards PrEP, could threaten investment in the broader programmes. For these reasons, it cannot be assumed that PrEP promotion will always be supported by people who inject drugs.The sexual partners of people who inject drugs, non-opioid users who also inject and for whom there is no established substitution treatment, as well as drug users who are unable to negotiate safe sex may value PrEP. As for all key populations, the involvement of people who inject drugs in shaping services for their consumption is vital and too often ignored. CONCLUSIONS: For people who inject drugs and who experience discrimination, violence or harassment, implementation of PrEP should be guided by understanding and engaging with their interconnected range of needs, risk practices, priorities and options. The differentiated needs of sub-populations that inject a range of drugs, and their sexual partners, require further exploration. PMID- 27760687 TI - Towards a fair consideration of PrEP as part of combination HIV prevention in Latin America. AB - INTRODUCTION: Despite progress in scaling up antiretroviral treatment, HIV prevention strategies have not been successful in significantly curbing HIV incidence in Latin America. HIV prevention interventions need to be expanded to target the most affected key populations with a combination approach, including new high impact technologies. Oral pre-exposure prophylaxis (PrEP) is recommended as additional prevention choice for individuals at higher risk of infection and could become a cost-effective prevention tool. We discuss the barriers and solutions for a fair consideration of PrEP as part of combination HIV prevention strategies in Latin America. DISCUSSION: Although demonstration projects are ongoing or being planned in a number of countries, to date no Latin American country has implemented a public PrEP programme. The knowledge of policymakers about PrEP implementation needs to be strengthened, and programmatic guidance and cost estimate tools need to be developed to support adequate planning. Despite high levels of awareness among health providers, especially if engaged in HIV or key population care, willingness to prescribe PrEP is still low due to the lack of national policies and guidelines. Key populations, especially men who have sex with men, transgender women and sex workers, have been engaged in demonstration projects, and qualitative research shows high awareness and willingness to use PrEP, especially if accessible in the public sector for free or at affordable price. Concerns of safety, adherence, effectiveness and risk compensation need to be addressed through targeted social communication strategies to improve PrEP knowledge and stimulate demand. Alliance among policymakers, civil society and representatives from key populations, healthcare providers and researchers will be critical for the design and successful implementation of PrEP demonstration projects of locally adapted delivery models. The use of mechanisms of joint negotiation and procurement of antiretrovirals could reduce costs and significantly increase the cost-effectiveness of PrEP. CONCLUSIONS: PrEP is an additional prevention tool and should be implemented in combination and synergy with other prevention interventions. PrEP programmes should target high-risk individuals from key populations for higher cost-effectiveness. Demonstration projects may generate strategic information for and lead to the implementation of full-scale PrEP programmes. PMID- 27760689 TI - PrEP: controversy, agency and ownership. AB - Pre-exposure prophylaxis (PrEP) has been and continues to be an intervention that causes controversy and debate between stakeholders involved in providing or advocating for it, and within communities in need of it. These controversies extend beyond the intrinsically complex issues of making it available. In this commentary, some of the possible roots of the air of dissent and drama that accompanies PrEP are explored. The similarities between the controversies that dogged the earliest human trials of PrEP and the ones we see today in the era of licensing and implementation are explored. We outline five mediating principles or cultural norms that may influence arguments about PrEP differently. Three areas of specific concern are identified: medical risk versus benefit, distrust and fear of healthcare interventions, and fears for individual responsibility and community cohesion. The fear that PrEP may somehow represent a loss of control over one or more of these domains is suggested as an underlying factor. The development of countervailing measures, to institute greater community "ownership" of PrEP, and concomitant improvements in the sense of individual agency over sexual risk are outlined and recommended. PMID- 27760688 TI - PrEP implementation in the Asia-Pacific region: opportunities, implementation and barriers. AB - INTRODUCTION: HIV epidemics in the Asia-Pacific region are concentrated among men who have sex with men (MSM) and other key populations. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention intervention and could be a potential game changer in the region. We discuss the progress towards PrEP implementation in the Asia-Pacific region, including opportunities and barriers. DISCUSSION: Awareness about PrEP in the Asia-Pacific is still low and so are its levels of use. A high proportion of MSM who are aware of PrEP are willing to use it. Key PrEP implementation barriers include poor knowledge about PrEP, limited access to PrEP, weak or non-existent HIV prevention programmes for MSM and other key populations, high cost of PrEP, stigma and discrimination against key populations and restrictive laws in some countries. Only several clinical trials, demonstration projects and a few larger-scale implementation studies have been implemented so far in Thailand and Australia. However, novel approaches to PrEP implementation have emerged: researcher-, facility- and community-led models of care, with PrEP services for fee and for free. The WHO consolidated guidelines on HIV testing, treatment and prevention call for an expanded access to PrEP worldwide and have provided guidance on PrEP implementation in the region. Some countries like Australia have released national PrEP guidelines. There are growing community leadership and consultation processes to initiate PrEP implementation in Asia and the Pacific. CONCLUSIONS: Countries of the Asia Pacific region will benefit from adding PrEP to their HIV prevention packages, but for many this is a critical step that requires resourcing. Having an impact on the HIV epidemic requires investment. The next years should see the region transitioning from limited PrEP implementation projects to growing access to PrEP and expansion of HIV prevention programmes. PMID- 27760690 TI - No one left behind: how are we doing in the roll-out of PrEP as part of combination HIV prevention? PMID- 27760691 TI - Losing self control. AB - Our brain is less able to move one of our hands if an illusion makes us feel like the hand does not belong to us. PMID- 27760692 TI - Decreased motor cortex excitability mirrors own hand disembodiment during the rubber hand illusion. AB - During the rubber hand illusion (RHI), subjects experience an artificial hand as part of their own body, while the real hand is subject to a sort of 'disembodiment'. Can this altered belief about the body also affect physiological mechanisms involved in body-ownership, such as motor control? Here we ask whether the excitability of the motor pathways to the real (disembodied) hand are affected by the illusion. Our results show that the amplitude of the motor-evoked potentials recorded from the real hand is significantly reduced, with respect to baseline, when subjects in the synchronous (but not in the asynchronous) condition experience the fake hand as their own. This finding contributes to the theoretical understanding of the relationship between body-ownership and motor system, and provides the first physiological evidence that a significant drop in motor excitability in M1 hand circuits accompanies the disembodiment of the real hand during the RHI experience. PMID- 27760694 TI - Neurological deficit following stereotactic radiosurgery for trigeminal neuralgia. AB - We report a unique case of neurological deficit from late onset multiple sclerosis (MS), in a 65-year-old woman, after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). At 3.5months post-SRS for TN, the patient developed ataxia and left leg paraesthesiae and brain MRI showed altered signal and enhancement in the vicinity of the right trigeminal root entry zone (REZ). The symptoms remitted following treatment with intravenous methylprednisolone, however, 10months post-SRS, the patient developed gait ataxia and left lower limb weakness. MRI showed persistent T2 changes at the REZ and multiple new non enhancing white matter lesions in the cerebrum and spinal cord; and oligoclonal bands were present in the cerebrospinal fluid but not serum. A diagnosis of multiple sclerosis (MS) was made. This report raises the issue of whether the risk of radiation-induced toxicity is increased in patients with MS treated with SRS. We hypothesise that breakdown in the blood brain barrier secondary to the radiosurgery may have triggered a vigorous local inflammatory response. PMID- 27760693 TI - Iron acquisition pathways and colonization of the inflamed intestine by Salmonella enterica serovar Typhimurium. AB - Salmonella enterica serotype Typhimurium is able to expand in the lumen of the inflamed intestine through mechanisms that have not been fully resolved. Here we utilized streptomycin-pretreated mice and dextran sodium sulfate (DSS)-treated mice to investigate how pathways for S. Typhimurium iron acquisition contribute to pathogen expansion in the inflamed intestine. Competitive infection with an iron uptake-proficient S. Typhimurium strain and mutant strains lacking tonB feoB, feoB, tonB or iroN in streptomycin pretreated mice demonstrated that ferric iron uptake requiring IroN and TonB conferred a fitness advantage during growth in the inflamed intestine. However, the fitness advantage conferred by ferrous iron uptake mechanisms was independent of inflammation and was only apparent in models where the normal microbiota composition had been disrupted by antibiotic treatment. PMID- 27760696 TI - Prevalence of flatfoot among school students and its relationship with BMI. AB - OBJECTIVE: The aim of this study was to analyze the relation between the flat footedness and obesity. MATERIALS AND METHODS: A total of 1158 school children (653 male and 505 female) participated in this cross sectional descriptive study. According to their age, children were divided into three groups for each gender (6-10, 11-13, 14-18 years old). Diagnosis and severity of flatfoot was assessed in using the Dennis method. BMI of children were calculated as body weight divided by height squared (kg*m-2). RESULTS: Majority (83.9%) of respondents had normal feet. The prevalence of flatfoot was 16.1% with a decreasing trend with age. Boys had a higher frequency of flatfoot than girls; however the difference was not significant (p > 0.05). The prevalence of flatfoot was 17.5% in boys and 14.5% in girls. The percentage of overweight and obese children was 10.3%. A significant difference in the prevalence of flatfoot occurred between; under weight (13.9%), normal-weight (16.1%), overweight (26.9%), and obese (30.8%); children. CONCLUSION: The increasing prevalence of childhood obesity is one of the most serious health challenges across the globe, and a positive correlation between increased BMI; and flatfoot is one of the potential complications. PMID- 27760695 TI - Effect of lavage and brush preparation on cement penetration and primary stability in tibial unicompartmental total knee arthroplasty: An experimental cadaver study. AB - BACKGROUND: Unicompartmental total knee arthroplasty (UKA) is a well-established treatment option for unicondylar osteoarthritis, and generally leads to better functional results than tricompartimental total knee arthroplasty (TKA). However, revision rates of UKAs are reported as being higher; a major reason for this is aseptic loosening of the tibial component due to implant-cement-bone interface fatigue. The objective of this study was to determine the effects of trabecular bone preparation, prior to implantation of tibial UKAs, on morphological and biomechanical outcomes in a cadaver study. METHODS: Cemented UKAs were performed in 18 human cadaver knees after the bone bed was cleaned using pulsed lavage (Group A), conventional brush (Group B) or no cleaning at all (Group C, control). Morphologic cement penetration and primary stability were measured. RESULTS: The area proportion under the tibial component without visible cement penetration was significantly higher in Group C (21.9%, SD 11.9) than in both Group A (7.1%, SD 5.8), and Group B (6.5%, SD 4.2) (P=0.007). The overall cement penetration depth did not differ between groups. However, in the posterior part, cement penetration depth was significantly higher in Group B (1.9mm, SD 0.3) than in both Group A (1.3mm, SD 0.3) and Group C (1.4mm, SD 0.3) (P=0.015). The mode of preparation did not show a substantial effect on primary stability tested under dynamic compression-shear test conditions (P=0.910). CONCLUSION: Bone preparation significantly enhances cement interdigitation. The application of a brush shows similar results compared with the application of pulsed lavage. PMID- 27760697 TI - Post-operative Benefit of Compression Therapy after Endovenous Laser Ablation for Uncomplicated Varicose Veins: A Randomised Clinical Trial. AB - OBJECTIVE: The hypothesis that post-operative short-term compression therapy improves operation related complications in patients with uncomplicated varicose veins after endovenous laser ablation (EVLA) treatment was tested. METHODS: In this randomized trial, patients with uncomplicated varicose veins (C2 according to the CEAP classification) treated with EVLA at a single institution from January 2012 to November 2013 were enrolled. Before EVLA, patients were randomized into two groups based on whether or not (control group) they wore an elastic compression stocking (ECS group) post-operatively. The primary end point was the pain score (visual analog scale [VAS], range from 0 to 10), while secondary end points included the severity of operation related complications, the quality of life (Aberdeen Varicose Vein Symptoms Severity Score, AVVSS), and the mean time to return to work. RESULTS: A total of 400 patients (200 patients in each group) were included and analyzed. In the first week after EVLA, patients in the ECS group experienced less pain (p < .001) and edema (p = .01), but by 2 weeks these variables were similar between the groups. There were no significant differences in the quality of life or in the mean time to return to work. CONCLUSIONS: The use of an ECS does not prove to be of greater benefit in the quality of life and the mean time to return to work; ECS therapy does reduce the severity of pain and oedema during the first week after surgery in patients with uncomplicated varicose veins. PMID- 27760698 TI - Contrast Enhanced Ultrasound can Replace Computed Tomography Angiography for Surveillance After Endovascular Aortic Aneurysm Repair. AB - OBJECTIVE/BACKGROUND: Surveillance after endovascular aortic aneurysm repair (EVAR) is mandatory and computed tomography angiography (CTA) is considered the standard imaging modality, although patients are exposed to ionizing radiation and nephrotoxic contrast medium. The primary aim of this study was to determine the diagnostic efficacy of duplex ultrasound (DUS) and contrast enhanced ultrasound (CEUS) using CTA as the gold standard. The secondary aim was to determine the clinical consequences of endoleaks missed by DUS and CEUS, or CTA. METHODS: All patients with EVAR for an aorto-iliac aneurysm between 1 August 2011 and 31 October 2014 were prospectively and consecutively enrolled. CEUS was added to the existing surveillance protocol, which included DUS, plain abdominal X-ray, and CTA at 3 and 12 months after stent implantation. RESULTS: In 278 patients, endoleaks were detected in 68, 69, and 46 cases by CTA, CEUS, and DUS, respectively. The sensitivity and specificity of DUS and CEUS were 46% and 93%, and 85% and 95%, respectively. CEUS and CTA were diagnostically equivalent, as opposed to DUS and CTA (p = .002). Endoleaks detected by CTA led to re intervention in 11 (4%) patients. These endoleaks were also detected by CEUS; however, three out of 11 patients were missed by DUS and underwent re intervention: limb extension, re-cuff, and attempt to coil lumbar leaks. Endoleaks missed by CEUS or CTA were type II endoleaks without sac expansion. CONCLUSION: In surveillance programs after EVAR a diagnostic CEUS examination may replace CTA. PMID- 27760699 TI - Blood cadmium concentrations in Korean adolescents: From the Korea National Health and Nutrition Examination Survey 2010-2013. AB - OBJECTIVE: To assess blood cadmium levels in Korean adolescents with respect to demographic and lifestyle factors. METHODS: We analyzed data from the Korea National Health and Nutrition Examination Survey from 2010 to 2013, totaling 1472 adolescents aged 10-18 years. Geometric means of blood cadmium were calculated using a complex samples general linear model to compare blood levels in different demographic and lifestyle groups. Multivariate logistic regression analyses were also used to find predictors for high blood cadmium (>90th percentile). RESULTS: The geometric mean of the blood cadmium concentrations was 0.30MUg/L in Korean adolescents. Older age, type of housing (multifamily house and commercial building), smoking and alcohol consumption, and iron deficiency/iron deficiency anemia (IDA) were significantly associated with higher blood cadmium concentrations (P<0.05). Blood cadmium concentrations were not significantly affected by gender, region, body mass index status, or household income. In multivariate logistic regression analysis, independent predictors for higher blood cadmium levels included current smoker (OR=7.77), alcohol consumption (OR=4.31), living in a multifamily house or commercial building (OR=3.11-3.46), and IDA (OR=2.64). CONCLUSIONS: Possible associations between blood cadmium levels and type of housing or alcohol consumption in adolescents are suggested for the first time in this study. Further studies are needed to elucidate the mechanism of these findings. PMID- 27760700 TI - Altered interregional correlations between serotonin transporter availability and cerebral glucose metabolism in schizophrenia: A high-resolution PET study using [11C]DASB and [18F]FDG. AB - The purpose of the present study was to investigate the patterns of interregional correlations of serotonin transporter (SERT) availability with glucose metabolism using 7-Tesla magnetic resonance imaging (MRI) and high-resolution positron emission tomography (PET) with 11C-3-amino-4-(2 dimethylaminomethylphenylthio)benzonitrile ([11C]DASB) and [18F]fluorodeoxyglucose ([18F]FDG) in antipsychotic-free patients with schizophrenia in order to shed new light on the disrupted functional connectivity in schizophrenia. Nineteen patients with schizophrenia and 18 healthy controls underwent high-resolution PET and MRI. The binding potential (BPND) of [11C]DASB and standardized uptake value ratio (SUVR) of [18F]FDG were obtained. In SERT availability, the region of interest (ROI)-based analyses showed no significant group differences in any region, except for the anterior hippocampus where the SERT availability was lower in patients with schizophrenia than in controls. The ROI- and voxel-based analyses revealed that the [18F]FDG SUVR values were significantly lower in patients than in controls in the right superior frontal gyrus and medial part of the left superior frontal gyrus. Regarding the interregional correlations of [11C]DASB BPND with [18F]FDG SUVR, more widespread positive correlations across the brain regions were observed in control subjects than in patients with schizophrenia. Notably, the patients and control subjects showed statistically significant differences in correlations between the SERT availability in the parietal and temporal cortices and the glucose metabolism in the posterior cingulate cortex. These results suggest abnormal functional connectivity between the higher-order cortical regions in schizophrenia and a possible important role of the posterior cingulate gyrus and its related circuitry in the pathophysiology of schizophrenia. PMID- 27760701 TI - Course of illness in a sample of patients diagnosed with a schizotypal disorder and treated in a specialized early intervention setting. Findings from the 3.5year follow-up of the OPUS II study. AB - BACKGROUND: Previous studies report that 20% to 30% of those initially diagnosed with schizotypal disorder go on to develop a psychotic disorder (predominantly schizophrenia). Schizotypal disorder share some traits of those used to identify patients at ultra-high risk for psychosis. METHOD: As part of a randomized clinical trial testing the effect of prolonged specialized early intervention, we recruited 83 participants diagnosed with a schizotypal disorder. Participants were recruited 18 months into their two-year treatment program, and follow-up interviews were conducted three and a half year later. They were randomized to either discontinuation after the standard two year treatment or continuation of the specialized treatment for totally five year. The study investigated whether prolonged treatment could affect the rate of transition to psychosis and other clinical outcomes, and what would predict transition to psychosis. RESULTS: Of those 59 who attended the follow-up interview 19 (32%) developed a psychotic disorder at follow-up. There were no differences between the two treatment groups on transition rates or clinical outcomes. We found that lower level of functioning at baseline predicted transition to psychosis. DISCUSSION: Comparable to previous ultra-high risk studies, we found that level of functioning was the strongest predictor of transition to psychosis. Prior studies have found effect of specialized early intervention on transition rates, but we were not able to reproduce this finding. This may be attributable to the intervention in our study occurring at a later stage in the illness than prior studies. PMID- 27760702 TI - Improving the health and welfare of people who live in slums. AB - In the first paper in this Series we assessed theoretical and empirical evidence and concluded that the health of people living in slums is a function not only of poverty but of intimately shared physical and social environments. In this paper we extend the theory of so-called neighbourhood effects. Slums offer high returns on investment because beneficial effects are shared across many people in densely populated neighbourhoods. Neighbourhood effects also help explain how and why the benefits of interventions vary between slum and non-slum spaces and between slums. We build on this spatial concept of slums to argue that, in all low-income and-middle-income countries, census tracts should henceforth be designated slum or non-slum both to inform local policy and as the basis for research surveys that build on censuses. We argue that slum health should be promoted as a topic of enquiry alongside poverty and health. PMID- 27760704 TI - Differences in mental workload between traditional and single-incision laparoscopic procedures measured with a secondary task. AB - INTRO: The mental workload associated with laparoscopic suturing can be assessed with a secondary task that requires the same visual-spatial attentional resources. The purpose of this study was to use a secondary task to measure the incremental workload demands of single-incision laparoscopic surgery (SILS) procedures versus traditional laparoscopic procedures. METHOD: 12 surgery residents and surgical assistants who had met FLS criteria on an FLS and SILS simulator performed one trial each of peg transfer, cutting, and intracorporeal suturing tasks simultaneously with the secondary task and provided subjective workload ratings using the NASA-TLX. RESULTS: SILS procedures resulted in lower primary and secondary task scores, p < 0.001 and higher workload ratings, p < 0.0001. Suturing resulted in lower primary (p < 0.003) and secondary task scores (p < 0.017) and higher workload ratings (p < 0.017) compared to the other tasks. CONCLUSIONS: SILS procedures were significantly more mentally demanding than traditional laparoscopic procedures corroborated by primary and secondary tasks scores and subjective ratings. PMID- 27760705 TI - Clinical effectiveness of a pylorus-preserving procedure on total pancreatectomy with islet autotransplantation. AB - BACKGROUND: The impact of pylorus preserving procedures (PP) on total pancreatectomy with islet autotransplantation (TPIAT) has not been examined. This study aimed to investigate the clinical impact of the PP on TPIAT. METHODS: The Baylor Simmons Transplant Institute database was queried to identify seventy three patients who underwent TPIAT from 2006 to 2014. All patients were investigated in postoperative complications, long-term nutritional status, and graft function. RESULTS: Patients with PP did not face worse outcomes in terms of delayed gastric emptying and length of hospital stay. Also, nutritional status and metabolic outcome, such as body weight, serum albumin level, serum vitamin level, HbA1c level, graft survival rate and insulin independent rate, were similar between both groups. CONCLUSIONS: Clinical results including the graft function indicated that patients undergoing TPIAT with PP did not amplify surgical complications such as delayed gastric emptying and showed no significant advantage of nutrition and metabolic outcome. PMID- 27760703 TI - The history, geography, and sociology of slums and the health problems of people who live in slums. AB - Massive slums have become major features of cities in many low-income and middle income countries. Here, in the first in a Series of two papers, we discuss why slums are unhealthy places with especially high risks of infection and injury. We show that children are especially vulnerable, and that the combination of malnutrition and recurrent diarrhoea leads to stunted growth and longer-term effects on cognitive development. We find that the scientific literature on slum health is underdeveloped in comparison to urban health, and poverty and health. This shortcoming is important because health is affected by factors arising from the shared physical and social environment, which have effects beyond those of poverty alone. In the second paper we will consider what can be done to improve health and make recommendations for the development of slum health as a field of study. PMID- 27760706 TI - Enantioseparation of four amide herbicide stereoisomers using high-performance liquid chromatography. AB - The chirality of herbicides has been the focus of research. However, there is little information on the enantioseparation of amide herbicides with different chiral elements. In this study, the need for different chiral stationary phases (CSPs), mobile phases, temperatures and flow rates for the separation of napropamide, acetochlor and propisochlor was discussed in detail and compared to metolachlor. Resolution of C-chiral enantiomers was easier than that of axial chiral enantiomers. Metolachlor and acetochlor could achieve baseline separation only on AY-H and AS-H columns, respectively. Propisochlor had satisfactory separations on OD-H and AS-H columns. Napropamide was separated on OJ-H, AY-H and AS-H columns. Both the structures of the compounds and CSPs and the interactions between them played significant roles in the enantioseparations. Molecule dockings were also used to elucidate the separation mechanisms. C-chiral enantiomers had perfect symmetry in their optical properties, whereas the axial chiral enantiomers did not. The elution order for napropamide, acetochlor and propisochlor, with a single chiral location, was R- prior to S-. These results were the first that compare the enantioseparations of four amide herbicides with different chirality, and they provided the absolute configurations for the herbicides. The paper also illustrated certain mechanisms for enantioseparations. PMID- 27760707 TI - Survival after pelvic exenteration for uterine malignancy: A National Cancer Data Base study. AB - OBJECTIVE: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for uterine cancer. METHODS: Women with uterine cancer who underwent exenteration (n=1160) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, comorbidity score, insurance status, income, distance from home to treatment center, stage, distant and nodal metastasis, tumor size, surgical margin status, exenteration type, and treatment with radiation and/or chemotherapy. RESULTS: Among women with follow-up data (n=652), median (IQR) OS was 63.1 (42.2-107.2) and 17.6 (14.7-23.9) months for women with node-negative versus node-positive disease, respectively. Histology (p=1.5*10-4), grade (p=7.9*10-14), race (p=0.0002), lymph node status (p=1.0*10-14), surgical node evaluation (p=2.8*10-8), surgery for distant metastasis (p=0.004), distant metastasis at diagnosis (p=1.3*10-10), positive surgical margins (p=1.6*10-9), radiotherapy (p=0.004), and insurance status (p=6.5*10-6) were significantly associated with differential, unadjusted Kaplan Meier OS estimates. Exenteration type was not associated with OS (p=0.357). By multivariate regression, increased age, positive surgical margins, nodal metastasis or unknown nodal status, higher histologic grade, and black race were associated with increased hazards for death. CONCLUSION: Exenteration may be curative for well-selected women with uterine cancer, particularly among women with pathologically negative lymph nodes. PMID- 27760708 TI - Pertussis outbreak among patients and healthcare workers in a provincial dialysis facility in Japan. AB - BACKGROUND: Sixteen pertussis cases in haemodialysis patients and healthcare workers were detected in a 25-bed outpatient haemodialysis facility in Japan between October 2013 and April 2014. AIM: To describe an outbreak of pertussis among patients and healthcare workers, and to identify risk factors for pertussis infection. METHODS: Sputum cultures, loop-mediated isothermal amplification assays performed on nasopharyngeal swabs to detect respiratory pathogens including Bordetella pertussis, and serum anti-pertussis toxin immunoglobulin G measurements were performed for all haemodialysis patients and healthcare workers. A retrospective case-control study was performed to identify the risk factors for pertussis infection in the clinic. FINDINGS: Only six of the 16 pertussis patients (37.5%) had respiratory symptoms. Recent exposure to an unmasked individual with a cough was associated with pertussis infection (odds ratio 6.25, P<0.05). The outbreak was terminated successfully after enforcing the use of surgical masks among both patients and healthcare workers. CONCLUSION: This report demonstrates the risk of pertussis transmission in a haemodialysis facility, and underscores the importance of wearing surgical masks to control a pertussis outbreak. PMID- 27760709 TI - Child discipline in Qatar and Palestine: A comparative study of ICAST-R. AB - To compare the nature and determinants of child discipline in Qatar and Palestine among young adults through retrospective survey to develop legislation, policies and interventions for effective prevention of child maltreatment, and educational materials to promote positive discipline among parents and caregivers. Cross sectional random household surveys were conducted in each country (Qataris N=697, Palestinians N=2064) using ISPCAN Child Abuse Screening Tool-Retrospective (ICAST R) for young adults (18-24 years), to investigate child discipline methods into the maltreatment range. Qatari young adults were more educated (p<0.001) and had more full-time employment (p=0.004) than Palestinian young adults. Qatar reported lower physical and emotional abuse compared to their counterparts in Palestine, e.g. Hit/Punch, Kick (p<0.001) and Insult/Criticize, Threaten to be hurt/killed (p<0.001). Qatari participants found any harsh discipline they received in childhood was not reasonable and not justified compared to Palestinian participants. The more advantaged Qatari population was less likely to experience disciplinary methods that experts developing the ICAST-R defined as abuse compared to Palestinians where the higher incidence of child abuse could be attributed to lower economic advantage, lower level of education and greater exposure to violence. Suggestions are made for future studies in Qatar and Palestine to develop survey methodology with a more culturally appropriate level of intrusion, such as indirect yet meaningful child maltreatment questions. PMID- 27760711 TI - Seasonal variations and sources of sedimentary organic carbon in Tokyo Bay. AB - Total organic carbon (TOC), total nitrogen (TN) contents, their stable C and N isotope ratio (delta13C and delta15N), and chlorophyll a ([Chl a]sed) of surface sediments were investigated monthly to identify the seasonal variations and sources of organic matter in Tokyo Bay. The sedimentary TOC (TOCsed) and TN (TNsed) contents, and the sedimentary delta13C and delta15N (delta13Csed and delta15Nsed) values were higher in summer than other seasons. The seasonal variations were controlled by high primary production in the water column and hypoxic water in the bottom water during summer. The fraction of terrestrial and marine derived organic matter was estimated by Bayesian mixing model using stable isotope data and TOC/TN ratio. Surface sediments in Tokyo Bay are dominated by marine derived organic matter, which accounts for about 69+/-5% of TOCsed. PMID- 27760712 TI - A model study of the effects of river discharges and winds on hypoxia in summer in the Pearl River Estuary. AB - The deterioration of dissolved oxygen conditions in the Pearl River Estuary (PRE) in summer has recently attracted considerable-scientific and political-attention. This paper documents the development, calibration, and verification of a coupled three-dimensional hydrodynamic and water quality model for the PRE. A comparison of the model's performance against field observations indicated that the model is capable of reproducing key hydrodynamic and water quality characteristics of the estuary within an acceptable range of accuracy. Furthermore, a scenario analysis showed that the extent of the hypoxic zone responds differently to changes in the river discharge at different inlets. Moreover, the hypoxic zone also changes in response to variations in the southwest wind in summer; specifically, a larger hypoxic zone develops as southwest winds blow in a more southward direction. However, the hypoxic conditions are much more sensitive to changes in the wind speed than changes in the wind direction. PMID- 27760713 TI - Assessing and managing stressors in a changing marine environment. AB - We are facing a dynamic future in the face of multiple stressors acting individually and in combination: climate change; habitat change/loss; overfishing; invasive species; harmful algal blooms/eutrophication; and, chemical contaminants. Historic assessment and management approaches will be inadequate for addressing risks from climate change and other stressors. Wicked problems (non-linear, complex, competing risks and benefits, not easily solvable), will become increasingly common. We are facing irreversible changes to our planetary living conditions. Agreed protection goals and considering both the negatives (risks) and the positives (benefits) of all any and all actions are required, as is judicious and appropriate use of the Precautionary Principle. Researchers and managers need to focus on: determining tipping points (alternative stable points); maintaining ecosystem services; and, managing competing ecosystem services. Marine (and other) scientists are urged to focus their research on wicked problems to allow for informed decision-making on a planetary basis. PMID- 27760714 TI - Sedimentary records of recent anthropogenic eutrophication and metal contamination in Zhelin Bay, an important mariculture area in Southern China. AB - Dinoflagellate cysts (dinocysts), biogenic elements and metals were analyzed from sediment cores collected from Zhelin Bay of the South China Sea in December 2008 to understand the environmental changes over the past 50years. Dinocyst concentrations ranged from 0cysts/g to 770cysts/g, and they were dominated by heterotrophic taxa. There was a clear increase trend upcore for biogenic elements, except for biogenic silica. Metals originated from both the lithogenic source and human activities, and significantly increased after 1985-1995. Environmental changes in the past 50years can be divided into three stages: (1) before 1985, during which biogenic elements, cyst flux and metals were low; (2) from 1985 to the early 2000s, characterized by an obvious increase of dinocysts, TOC, TN and most metals, while TOC/TN and BSi decreased; and (3) after 2000, the period of rapid increase of dinocysts, TOC and TN but decrease of certain contamination metals. PMID- 27760710 TI - Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. AB - Fanconi anemia (FA) is a rare autosomal and X-linked genetic disease characterized by congenital abnormalities, progressive bone marrow failure (BMF), and increased cancer risk during early adulthood. The median lifespan for FA patients is approximately 33years. The proteins encoded by the FA genes function together in the FA-BRCA pathway to repair DNA damage and to maintain genome stability. Within the past two years, five new FA genes have been identified RAD51/FANCR, BRCA1/FANCS, UBE2T/FANCT, XRCC2/FANCU, and REV7/FANCV-bringing the total number of disease-causing genes to 21. This review summarizes the discovery of these new FA genes and describes how these proteins integrate into the FA-BRCA pathway to maintain genome stability and critically prevent early-onset BMF and cancer. PMID- 27760715 TI - Tracking cardiorespiratory fitness and physical activity in children with and without motor coordination problems. AB - OBJECTIVES: Previous research has shown children with Developmental Coordination Disorder (DCD) have lower cardiorespiratory fitness (CRF) than typically developing (TD) children. This has been hypothesized to be due to an activity deficit, whereby poor motor functioning discourages children from participating in physical activities, but this hypothesis has not been directly tested. In this study, we use longitudinal data to measure the extent to which physical activity explains differences in CRF between children with and without motor coordination deficits. DESIGN: Longitudinal observational study. METHODS: The study sample is an open cohort of children, numbering 2278 at baseline (age 9-10), that was followed for up to 5 years (to age 13-14). Motor skills were assessed once over the study period. Children scoring at or below the 5th percentile (n=103) on the Bruininks-Oseretsky Test of Motor Proficiency-Short Form were considered to have possible DCD (pDCD). CRF (estimated peak VO2) was estimated from performance on the Leger 20m shuttle run test, and physical activity was measured with the Participation Questionnaire. Both fitness and physical activity were measured up to 7 times over the study period. RESULTS: Children with pDCD had significantly lower CRF than their TD peers at each time point. CRF declined for both groups, but this decline was steeper for children with pDCD. Physical activity explained only a small part of the difference in CRF. CONCLUSIONS: The activity deficit did not contribute to the persistent and gradually widening gap in CRF between children with and without possible DCD. Possible reasons for this and future directions are discussed. PMID- 27760716 TI - Proteomic analysis of Trichinella spiralis adult worm excretory-secretory proteins recognized by early infection sera. AB - At the intestinal stage of a Trichinella spiralis (T. spiralis) infection, the excretory-secretory (ES) antigens produced by adult worms (AWs) result in an early exposure to the host's immune system and elicit the production of specific antibodies; the AW ES proteins might provide early diagnostic markers of trichinellosis. The aim of this study was to identify early serodiagnostic markers from T. spiralis AW ES antigens. T. spiralis AWs were collected at 72h post infection, and their ES antigens were analysed by SDS-PAGE and Western blot. Then, the immunoreactive bands were subjected to shotgun LC-MS/MS and bioinformatics analyses. Our results showed that only one protein band (33kDa) was recognized by the sera of mice infected with T. spiralis at 8 days after infection. The shotgun LC-MS/MS analysis identified 23 proteins that were then clustered into 10 types; these proteins had molecular weights of 28.13-71.62kDa and pI 5.05-9.20. Certain enzymes (e.g., serine protease, adult-specific deoxyribonuclease [DNase] II, peptidase S1A subfamily, and multi cystatin-like domain protein) were found to be highly represented. The functions of the 10 proteins were further analysed: of the 6 annotated proteins, 3 had serine hydrolase activity and 2 had DNase II activity. These results provide a valuable basis for identifying early diagnostic antigens and vaccine candidates for trichinellosis. PMID- 27760718 TI - Laboratory detection of intestinal carriage of carbapenemase-producing Enterobacteriaceae - A comparison of algorithms using the Carba NP test. AB - Stool specimens spiked with a panel of 46 carbapenemase-producing Enterobacteriaceae (CPE) and 59 non-carbapenemase producers were used to compare the diagnostic accuracy of 4 testing algorithms for the detection of intestinal carriage of CPE: (1) culture on Brilliance ESBL agar followed by the Carba NP test; (2) Brilliance ESBL followed by the Carba NP test, plus chromID OXA-48 agar with no Carba NP test; (3) chromID CARBA agar followed by the Carba NP test; (4) chromID CARBA followed by the Carba NP test, plus chromID OXA-48 with no Carba NP test. All algorithms were 100% specific. When comparing algorithms (1) and (3), Brilliance ESBL agar followed by the Carba NP test was significantly more sensitive than the equivalent chromID CARBA algorithm at the lower of 2 inoculum strengths tested (84.8% versus 63.0%, respectively [P<0.02]). With the addition of chromID OXA-48 agar, the sensitivity of these algorithms was marginally increased. PMID- 27760719 TI - Diagnostic accuracy of fibrinogen to differentiate appendicitis from nonspecific abdominal pain in children. AB - AIM: The aim of this study was to assess the diagnostic accuracy of the biomarker fibrinogen (FB), along with the more traditional markers white blood cell count (WBC), absolute neutrophil count (ANC), and C-reactive protein (CRP), to discriminate appendicitis from nonspecific abdominal pain (NSAP) in children. METHODS: We prospectively evaluated all children aged 5 to 15 years admitted for suspected appendicitis at an academic pediatric emergency department during 2 years. Diagnostic accuracy of FB (prothrombin time-derived method), WBC, ANC, and CRP was assessed by the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: A total of 275 patients were enrolled in the study (143 NSAP, 100 uncomplicated appendicitis, and 32 complicated appendicitis). WBC and ANC had a moderate diagnostic accuracy for appendicitis vs NSAP (WBC: AUC 0.79, ANC: AUC 0.79). FB and CPR had a poor diagnostic accuracy for appendicitis vs NSAP (FB: AUC 0.63, CRP: AUC 0.64) and a good diagnostic accuracy for complicated vs uncomplicated appendicitis (FB: AUC 0.86, CRP: AUC 0.90). All inflammatory markers had a good diagnostic accuracy for complicated appendicitis vs NSAP. CONCLUSIONS: WBC and ANC are useful inflammatory markers to discriminate appendicitis from NSAP. FB and CRP are not very useful to discriminate appendicitis from NSAP, but they discriminate properly complicated from uncomplicated appendicitis and NSAP, with a similar diagnostic accuracy. In a child with suspected appendicitis, a plasma FB level (prothrombin time-derived method) >520 mg/dL is associated to an increased likelihood of complicated appendicitis. PMID- 27760720 TI - The role of electrocardiogram in diagnosis of acute pericarditis after Wellens syndrome. PMID- 27760721 TI - Virtual water and water self-sufficiency in agricultural and livestock products in Brazil. AB - Virtual water trade is often considered a solution for restricted water availability in many regions of the world. Brazil is the world leader in the production and export of various agricultural and livestock products. The country is either a strong net importer or a strong net exporter of these products. The objective of this study is to determine the volume of virtual water contained in agricultural and livestock products imported/exported by Brazil from 1997 to 2012, and to define the water self-sufficiency index of agricultural and livestock products in Brazil. The indexes of water scarcity (WSI), water dependency (WDI) and water self-sufficiency (WSSI) were calculated for each Brazilian state. These indexes and the virtual water balance were calculated following the methodology developed by Chapagain and Hoekstra (2008) and Hoekstra and Hung (2005). The total water exports and imports embedded in agricultural and livestock products were 5.28 * 1010 and 1.22 * 1010 Gm3 yr-1, respectively, which results in positive virtual water balance of 4.05 * 1010 Gm3 yr-1. Brazil is either a strong net importer or a strong net exporter of agricultural and livestock products among the Mercosur countries. Brazil has a positive virtual water balance of 1.85 * 1010 Gm3 yr-1. The indexes used in this study reveal that Brazil is self-sufficient in food production, except for a few products such as wheat and rice. Horticultural products (tomato, onion, potato, cassava and garlic) make up a unique product group with negative virtual water balance in Brazil. PMID- 27760722 TI - Corrigendum to "Gentile-Solomon JM, Abbott JA. Conventional echocardiographic assessment of the canine right heart: reference intervals and repeatability" [J Vet Cardiol 18 (3) (2016) 234-247]. PMID- 27760717 TI - Anxiety sensitivity and racial differences in sleep duration: Results from a national survey of adults with cardiovascular disease. AB - Although Blacks sleep between 37 and 75min less per night than non-Hispanic Whites, research into what drives racial differences in sleep duration is limited. We examined the association of anxiety sensitivity, a cognitive vulnerability, and race (Blacks vs. White) with short sleep duration (<7h of sleep/night), and whether anxiety sensitivity mediated race differences in sleep duration in a nationally representative sample of adults with cardiovascular disease. Overall, 1289 adults (115 Black, 1174 White) with a self-reported physician/health professional diagnosis of >=1 myocardial infarction completed an online survey. Weighted multivariable logistic regressions and mediation analyses with bootstrapping and case resampling were conducted. Anxiety sensitivity and Black vs. White race were associated with 4%-84% increased odds, respectively, of short sleep duration. Anxiety sensitivity mediated Black-White differences in sleep duration. Each anxiety sensitivity subscale was also a significant mediator. Implications for future intervention science to address sleep disparities are discussed. PMID- 27760723 TI - OspTAC2 encodes a pentatricopeptide repeat protein and regulates rice chloroplast development. AB - Functional chloroplast generation depends on the precise coordination of gene expression between the plastid and the nucleus and is essential for plant growth and development. In this study, a rice (Oryza sativa) mutant that exhibited albino and seedling-lethal phenotypes was isolated from a60Co-irradiated rice population. The mutant gene was identified as an ortholog of the Arabidopsis plastid transcriptionally active chromosome protein 2 (pTAC2) gene, and the mutant strain was designated osptac2. Sequence and transcription analyses showed that OspTAC2 encodes a putative chloroplast protein consisting of 10 pentratricopeptide repeat (PPR) domains and a C-terminal small MutS-related (SMR) domain. Cytological observations via microscopy showed that the OspTAC2-green fluorescent fusion protein is localized in the chloroplasts. Transmission electron microscopy revealed that the chloroplast of the osptac2 mutant lacks an organized thylakoid membrane. The transcript levels of all investigated PEP (plastid-encoded RNA polymerase)-dependent genes were dramatically reduced in the osptac2 mutant, whereas the transcript levels of NEP (nuclear-encoded polymerase) dependent genes were increased. These results suggest that OspTAC2 plays a critical role in chloroplast development and indicate that the molecular function of the OspTAC2 gene is conserved in rice and Arabidopsis. PMID- 27760725 TI - Estimating the cost of operating cancer registries: Experience in Colombia. AB - BACKGROUND: Maintaining population-based registries requires adequate and sustained resources; however, to date there has been no systematic evaluation to identify the resource needs for cancer registration in most countries, including Colombia. A systematic assessment of the costs can quantify the funding required and identify processes to improve efficiency of cancer registries. METHODS: The Centers for Disease Control and Prevention's (CDC's) International Registry Costing Tool (IntRegCosting Tool) was tailored specifically for the Colombian registries and was used to collect resource use data from five regional population-based cancer registries: Barranquilla, Bucaramanga, Cali, Manizales, and Pasto. The registries provided cost data for the year 2013 and cancer cases corresponding to the year 2010. RESULTS: We identified an almost threefold variation in the average cost per case (77,932 to 214,082 Colombian pesos or US $41 to US $113 in 2013) across the registries, but there were also substantial differences in data collection approaches, types of data collected, and activities performed. Cost per inhabitant varied between 95 and 415 Colombian pesos (US $0.05 to US $0.22). Between 20% and 45% of the total cost was due to fixed cost activities. CONCLUSIONS: The detailed economic information presented in this study constitutes a valuable source of activity-based cost data that registries can use to compare operations, assess key factors that lead to differences in cost per case, and identify potential approaches to improve efficiencies. Furthermore, the knowledge gained from studying the Colombian registries can help inform the planning and operations of other registries in the region. PMID- 27760724 TI - Managing threats to respiratory health in urban slums. PMID- 27760727 TI - To operate or not to operate, that is the question: The proximal humerus fracture. PMID- 27760726 TI - Integrating Patient-Generated Health Data Into Clinical Care Settings or Clinical Decision-Making: Lessons Learned From Project HealthDesign. AB - BACKGROUND: Patient-generated health data (PGHD) are health-related data created or recorded by patients to inform their self-care and understanding about their own health. PGHD is different from other patient-reported outcome data because the collection of data is patient-driven, not practice- or research-driven. Technical applications for assisting patients to collect PGHD supports self management activities such as healthy eating and exercise and can be important for preventing and managing disease. Technological innovations (eg, activity trackers) are making it more common for people to collect PGHD, but little is known about how PGHD might be used in outpatient clinics. OBJECTIVE: The objective of our study was to examine the experiences of health care professionals who use PGHD in outpatient clinics. METHODS: We conducted an evaluation of Project HealthDesign Round 2 to synthesize findings from 5 studies funded to test tools designed to help patients collect PGHD and share these data with members of their health care team. We conducted semistructured interviews with 13 Project HealthDesign study team members and 12 health care professionals that participated in these studies. We used an immersion-crystallization approach to analyze data. Our findings provide important information related to health care professionals' attitudes toward and experiences with using PGHD in a clinical setting. RESULTS: Health care professionals identified 3 main benefits of PGHD accessibility in clinical settings: (1) deeper insight into a patient's condition; (2) more accurate patient information, particularly when of clinical relevance; and (3) insight into a patient's health between clinic visits, enabling revision of care plans for improved health goal achievement, while avoiding unnecessary clinic visits. Study participants also identified 3 areas of consideration when implementing collection and use of PGHD data in clinics: (1) developing practice workflows and protocols related to PGHD collection and use; (2) data storage, accessibility at the point of care, and privacy concerns; and (3) ease of using PGHD data. CONCLUSIONS: PGHD provides value to both patients and health care professionals. However, more research is needed to understand the benefit of using PGHD in clinical care and to identify the strategies and clinic workflow needs for optimizing these tools. PMID- 27760728 TI - UK lung cancer care must improve drastically, says report. PMID- 27760729 TI - A portable infrared photoplethysmograph: heartbeat of Mytilus galloprovincialis analyzed by MRI and application to Bathymodiolus septemdierum. AB - Infrared photoplethysmogram (IR-PPG) and magnetic resonance image (MRI) of the Mytilus galloprovincialis heart were obtained simultaneously. Heart rate was varied by changing temperature, aerial exposure and hypoxia. Higher heart rates (35-20 beat min-1) were usually observed at 20 degrees C under the aerobic condition, and typical IR-PPG represented a single peak (peak v). The upward and downward slopes of the peak v corresponded to the filling and contracting of the ventricle, respectively. A double-peak IR-PPG was observed in a wide range of heart rates (5 to 35 beats min-1) under various conditions. The initial peak v corresponded to the filling of the ventricle, and the origin of the second peak (v') varied with the heart rate. A flat IR-PPG with a noise-level represented cardiac arrest. Although large movement of the shells and the foot caused slow waves or a baseline drift of the IR-PPG, the heart rate can be calculated from the v-v interval. Based on these results, we assembled a portable IR-PPG recording system, and measured the heartbeats of Bathymodiolus septemdierum (Mytilidae) for 24 h on a research vessel just after sampling from the deep sea, showing that IR-PPG is a noninvasive, economical, robust method that can be used in field experiments. PMID- 27760730 TI - Home care services should give patients more responsibility for medicines, NICE says. PMID- 27760731 TI - Delaying surgery for obese patients or smokers is a bad idea. PMID- 27760733 TI - The BMJ launches ninth medical awards. PMID- 27760732 TI - Maternal vascular responses to hypoxia in a rat model of intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) is a common pregnancy complication and is a leading cause of fetal morbidity and mortality. Placental hypoxia contributes to adverse fetal consequences, such as IUGR. Exposing pregnant rats to hypoxia can lead to IUGR; however, assessment of maternal vascular function in a rat model of hypoxia, and the mechanisms that may contribute to adverse pregnancy outcomes, has not been extensively studied. We hypothesized that exposing pregnant rats to hypoxia will affect maternal systemic vascular function and increase the uterine artery resistance index (RI), which will be associated with IUGR. To test this hypothesis, pregnant rats were kept in normoxia (21% O2) or hypoxia (11% O2) from gestational day (GD) 6 to 20 Maternal blood pressure, uteroplacental resistance index (RI) (ultrasound biomicroscopy), and vascular function (wire myography) were assessed in uterine and mesenteric arteries. Fetal weight was significantly reduced (P < 0.001), while maternal blood pressure was increased (P < 0.05) in rats exposed to hypoxia. Maternal vascular function was also affected after exposure to hypoxia, including impaired endothelium-dependent vasodilation responses to methacholine in isolated uterine arteries (pEC50 normoxia: 6.55 +/- 0.23 vs. hypoxia: 5.02 +/- 0.35, P < 0.01) and a reduced uterine artery RI in vivo (normoxia: 0.63 +/- 0.04 vs. hypoxia: 0.53 +/- 0.01, P < 0.05); associated with an increase in umbilical vein RI (normoxia: 0.35 +/- 0.02 vs. hypoxia: 0.45 +/- 0.04, P < 0.05). These data demonstrate maternal and fetal alterations in vascular function due to prenatal exposure to hypoxia. Further, although there was a compensatory reduction in uterine artery RI in the hypoxia groups, this was not sufficient to prevent IUGR. PMID- 27760734 TI - Aortic stenosis: diagnosis and management. PMID- 27760735 TI - Industry sponsorship hits the headlines. PMID- 27760736 TI - A case treated with nivolumab after small cell lung cancer transformation of mutant EGFR non-small cell lung cancer. PMID- 27760737 TI - Genome-wide DNA methylation analysis identifies candidate epigenetic markers and drivers of hepatocellular carcinoma. AB - The alteration of DNA methylation landscape is a key epigenetic event in cancer. As the accumulation of large-scale genome-wide DNA methylation data from clinical samples, we are able to characterize the patterns of DNA methylation alterations for identifying candidate epigenetic markers and drivers. In this survey, we take hepatocellular carcinoma (HCC) as an example to show the basic steps of analyzing the DNA methylation patterns in cancer across multiple data sets. We collected three genome-wide DNA methylation data sets with ~800 clinical samples and the corresponding gene expression data sets. First, by quantitatively analyzing two global methylation alterations, it is found that about 90% tumors acquire either genome-wide DNA hypo-methylation or CpG island methylator phenotype. Second, probe-level analysis identified 267, 228 and 197 hyper-methylated sites in promoter regions for the three data sets, respectively. These local hyper methylated patterns are highly consistent: 84 sites (from 61 promoters) are hyper methylated in all the three studied data sets, including many previously reported genes, such as CDKL2, TBX15 and NKX6-2. Then, these hyper-methylated sites were used as candidate markers to classify tumor and non-tumor samples. The classifiers based on only 10 selected probes can achieve high discriminative ability across different data sets. Finally, by integrative analyzing DNA methylation and gene expression data, we identified 222 candidate epigenetic drivers, which are enriched in inflammatory response and multiple metabolic pathways. A set of high-confidence candidates, including SFN, SPP1 and TKT, are significantly associated with patients' overall survivals. In summary, this study systematically characterized the DNA methylation alterations and their impacts on gene expressions in HCCs based on multiple data sets. PMID- 27760738 TI - The framework for population epigenetic study. AB - At present, understanding of DNA methylation at the population level is still limited. Here, we first extended the classical framework of population genetics, such as single nucleotide polymorphism allele frequency, linkage disequilibrium (LD), LD block and haplotype, to epigenetics. Then, as an example, we compared the DNA methylation disequilibrium (MD) maps between HapMap CEU (Caucasian residents of European ancestry from Utah) population and YRI (Yoruba people from Ibadan) population (lymphoblastoid cell lines). We analyzed the differences and similarities between CEU and YRI from the following aspects: SMP (single methylation polymorphism) allele frequency, SMP allele association, MD, MD block and methylation haplotype (meplotype) frequency. The results showed that CEU and YRI had similar distribution of SMP allele frequency, and shared many MD block region. We believe that the framework of population genetics can be used in the population epigenetics. The population epigenetic framework also has potential prospects in the study of complex diseases, such as epigenome-wide association study. PMID- 27760739 TI - New technology gives insights into diarrhoeal disease in low or middle income countries. PMID- 27760740 TI - Effects of juglone and lawsone on oxidative stress in maize coleoptile cells treated with IAA. AB - Naphthoquinones are secondary metabolites widely distributed in nature and produced by bacteria, fungi and higher plants. Their biological activity may result from induction of oxidative stress, caused by redox cycling or direct interaction with cellular macromolecules, in which quinones act as electrophiles. The redox homeostasis is known as one of factors involved in auxin-mediated plant growth regulation. To date, however, little is known about the crosstalk between reactive oxygen species (ROS) produced by quinones and the plant growth hormone auxin (IAA). In this study, redox cycling properties of two naphthoquinones, juglone (5-hydroxy-1,4-naphthoquinone) and lawsone (2-hydroxy-1,4 naphthoquinone), were compared in experiments performed on maize coleoptile segments incubated with or without the addition of IAA. It was found that lawsone was much more effective than juglone in increasing both H2O2 production and the activity of antioxidative enzymes (SOD, POX and CAT) in coleoptile cells, regardless of the presence of IAA. An increase in the activity of Cu/Zn-SOD isoenzymes induced by both naphthoquinones suggests that juglone- and lawsone generated H2O2 was primarily produced in the cytosolic and cell wall spaces. The cell potential to neutralize hydrogen peroxide, determined by POX and CAT activity, pointed to activity of catalase as the main enzymatic mechanism responsible for degradation of H2O2 Therefore, we assumed that generation of H2O2, induced more efficiently by LW than JG, was the major factor accounting for differences in the toxicity of naphthoquinones in maize coleoptiles. The role of auxin in the process appeared negligible. Moreover, the results suggested that oxidative stress imposed by JG and LW was one of mechanisms of allelopathic action of the studied quinones in plants. PMID- 27760742 TI - Andrew Potter: Restoring sight and dignity in Benin. PMID- 27760741 TI - Nerve Growth Factor Protects Against Alcohol-Induced Neurotoxicity in PC12 Cells via PI3K/Akt/mTOR Pathway. AB - AIMS: To study whether autophagy participates in the neuroprotective effect of nerve growth factor (NGF) on neurons treated with alcohol. METHODS: The autophagy related markers were used to explore the role of autophagy in PC12 cells exposed to alcohol or pre-incubated with NGF before initiating the treatment with alcohol (100 mM; 6 h). PC12 cells were pre-incubated with 3-methyladenine (3-MA) (10 mM; 1 h) or rapamycin (100 nM; 1 h) before co-incubated with alcohol (100 mM; 6 h) in order to investigate the relationship between apoptosis and autophagy. PC12 cells were pre-incubated with LY294002 (50 MUM; 30 min) before co-incubated with NGF and alcohol in order to analyze the protein expression of PI3K/Akt/mTOR pathway via western blotting. RESULT: By methylthiazoltetrazolium, western blotting and flow cytometry assays, we found that cell viability decreased in a dose- and time dependent manner after treatment with alcohol in PC12 cells. As cells were exposed to alcohol, the levels of LC3-II proteins became elevated, likewise, pre treatment with 3-methyladenine (3-MA, an autophagic inhibitor) or rapamycin (an autophagic inducer) resulted in an increased or decreased percentage of apoptosis in contrast to other alcohol-treated groups, respectively. NGF markedly increased LC3-II production after treatment with alcohol in a dose-dependent manner. Moreover, NGF remarkably attenuated the phosphorylation effect of alcohol exposure on PI3K/Akt/mTOR pathway, which was suppressed by LY294002 (Akt inhibitor). CONCLUSIONS: NGF protects against alcohol-induced neurotoxicity via PI3K/Akt/mTOR pathway. SHORT SUMMARY: In this study, we chose the PC12 cell line as a neuronal model, and our results demonstrate that nerve growth factor can induce autophagy with the neuroprotective effect and regulatory mechanisms of alcohol-induced autophagy in PC12 cells. PMID- 27760743 TI - David Oliver: Four riders of the NHS apocalypse. PMID- 27760744 TI - A girl with an abnormal gait. PMID- 27760745 TI - Computed tomography findings in a confused patient. PMID- 27760746 TI - Evidence-based policy in palliative care: time to learn from our mistakes. PMID- 27760747 TI - Thank you letter to David Bowie from a palliative care doctor. PMID- 27760749 TI - Circulating miRNAs as Potential Alternative Cell Signaling Associated with Maternal Recognition of Pregnancy in the Mare. AB - During early pregnancy, the conceptus and mare communicate to establish pregnancy. Cell-secreted vesicles (e.g., exosomes) have been reported in serum. Exosomes contain bioactive materials, such as miRNA, that can mediate cell responses. We hypothesized that a) exosomes are present in mare circulation and quantity varies with pregnancy status, b) exosomes contain miRNAs unique to pregnancy status, and c) miRNAs target pathways in endometrium based upon pregnancy status of the mare. First, serum samples were obtained from mares in a crossover design, with each mare providing samples from a pregnant and nonmated control cycle (n = 3/sample day) on Days 12, 14, 16, and 18 postovulation. Flow cytometry revealed the presence of serum microvesicles in mares in two different sized populations (greater than or less than 100 nm), validated by transmission electron microscopy. Second, serum was collected on Days 9, 11, and 13 (n = 4/day), and endometrial biopsies were collected on Days 11 and 13 (n = 3/day) from pregnant and nonmated mares. Total RNA from serum exosomes was evaluated with quantitative RT-PCR using equine-specific miRNA sequences. A total of 12 miRNAs were found in different quantities on the specified days. Pathway analysis suggested that miRNAs targeted focal adhesion molecules (FAMs). Transcripts corresponding to FAMs were evaluated in endometrial biopsies. Protein levels and localization for PAK6 and RAF1 were further evaluated. Our data suggest that serum exosomes contain miRNA that differ based upon pregnancy status, and may affect mRNA expression related to focal adhesion pathway in the endometrium, with a potential role in maternal recognition of pregnancy. PMID- 27760748 TI - The Local and Systemic Immune Response to Intrauterine LPS in the Prepartum Mouse. AB - Inflammation plays a key role in human term and preterm labor (PTL). Intrauterine LPS has been widely used to model inflammation-induced complications of pregnancy, including PTL. It has been shown to induce an intense myometrial inflammatory cell infiltration, but the role of LPS-induced inflammatory cell activation in labor onset and fetal demise is unclear. We investigated this using a mouse model of PTL, where an intrauterine injection of 10 MUg of LPS (serotype 0111:B4) was given at E16 of CD1 mouse pregnancy. This dose induced PTL at an average of 12.7 h postinjection in association with 85% fetal demise. Flow cytometry showed that LPS induced a dramatic systemic inflammatory response provoking a rapid and marked leucocyte infiltration into the maternal lung and liver in association with increased cytokine levels. Although there was acute placental inflammatory gene expression, there was no corresponding increase in fetal brain inflammatory gene expression until after fetal demise. There was marked myometrial activation of NFkappaB and MAPK/AP-1 systems in association with increased chemokine and cytokine levels, both of which peaked with the onset of parturition. Myometrial macrophage and neutrophil numbers were greater in the LPS-injected mice with labor onset only; prior to labor, myometrial neutrophils and monocytes numbers were greater in PBS-injected mice, but this was not associated with an earlier onset of labor. These data suggest that intrauterine LPS induces parturition directly, independent of myometrial inflammatory cell infiltration, and that fetal demise occurs without fetal inflammation. Intrauterine LPS provokes a marked local and systemic inflammatory response but with limited inflammatory cell infiltration into the myometrium or placenta. PMID- 27760750 TI - Random Allocation of Blastomere Descendants to the Trophectoderm and ICM of the Bovine Blastocyst. AB - The first lineage specification during mammalian embryo development can be visually distinguished at the blastocyst stage. Two cell lineages are observed on the embryonic-abembryonic axis of the blastocyst: the inner cell mass and the trophectoderm. The timing and mechanisms driving this process are still not fully understood. In mouse embryos, cells seem prepatterned to become certain cell lineage because the first cleavage plane has been related with further embryonic abembryonic axis at the blastocyst stage. Nevertheless, this possibility has been very debatable. Our objective was to determine whether this would be the case in another mammalian species, the bovine. To achieve this, cells of in vitro produced bovine embryos were traced from the 2-cell stage to the blastocyst stage. Blastocysts were then classified according to the allocation of the labeled cells in the embryonic and/or abembryonic part of the blastocyst. Surprisingly, we found that there is a significant percentage of the embryos (~60%) with labeled and nonlabeled cells randomly distributed and intermingled. Using time-lapse microscopy, we have identified the emergence of this random pattern at the third to fourth cell cycle, when cells started to intermingle. Even though no differences were found on morphokinetics among different embryos, these random blastocysts and those with labeled cells separated by the embryonic abembryonic axis (deviant pattern) are significantly bigger; moreover deviant embryos have a significantly higher number of cells. Interestingly, we observed that daughter cells allocation at the blastocyst stage is not affected by biopsies performed at an earlier stage. PMID- 27760751 TI - Phospholipid Profile and Distribution in the Receptive Oviduct and Uterus During Early Diestrus in Cattle. AB - Phospholipid metabolism and signaling influences on early pregnancy events in cattle are unknown. This study aimed to characterize global phospholipid composition of oviduct and uterus during early diestrus in a model of contrasting embryo receptivity. Beef cows were treated to ovulate a larger (LF-LCL group, associated with greater receptivity) or smaller (SF-SCL group) follicle and, consequently, to present greater or smaller plasma concentrations of estradiol during proestrus-estrus, as well as progesterone during early diestrus. Oviduct and uterus (4 days after gonadotropin-releasing hormone-induced ovulation; D4) as well as the uterus (D7) were collected, and lipid profiles were monitored by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). This technique allowed the identification and tissue localization of sphingomyelins (SM), phosphatidylcholines (PC), ceramides (Cer), and phosphatidylethanolamines (PE). Multivariate statistics were used to separate samples into groups with distinctly different phospholipid profiles in the uterus at D4 and D7. Different abundance of ions corresponding to specific lipids were detected on D4 (Cer [42:1], PC [31:0], PC [32:1], PC [34:4], and PC [36:4] greater for LF-LCL group; and PC [38:7], PC [38:5], PC [38:4], PC [40:7], and PC [40:6] greater for SF-SCL group) and D7 (SM [34:2], SM [34:1], PC [32:1], and PC [35:2] greater for LF-LCL group). The MALDI-MS imaging showed the spatial distributions of major phospholipids. In conclusion, distinct phospholipid profiles were associated with animals treated to show contrasting receptivity to the embryo. Functional roles of the identified phospholipids on uterine function and preimplantation embryo development deserve further studies. PMID- 27760753 TI - Myosin light chain kinase mediates intestinal barrier dysfunction via occludin endocytosis during anoxia/reoxygenation injury. AB - Intestinal anoxia/reoxygenation (A/R) injury induces loss of barrier function followed by epithelial repair. Myosin light chain kinase (MLCK) has been shown to alter barrier function via regulation of interepithelial tight junctions, but has not been studied in intestinal A/R injury. We hypothesized that A/R injury would disrupt tight junction barrier function via MLCK activation and myosin light chain (MLC) phosphorylation. Caco-2BBe1 monolayers were subjected to anoxia for 2 h followed by reoxygenation in 21% O2, after which barrier function was determined by measuring transepithelial electrical resistance (TER) and FITC dextran flux. Tight junction proteins and MLCK signaling were assessed by Western blotting, real-time PCR, or immunofluorescence microscopy. The role of MLCK was further investigated with select inhibitors (ML-7 and peptide 18) by using in vitro and ex vivo models. Following A/R injury, there was a significant increase in paracellular permeability compared with control cells, as determined by TER and dextran fluxes (P < 0.05). The tight junction protein occludin was internalized during A/R injury and relocalized to the region of the tight junction after 4 h of recovery. MLC phosphorylation was significantly increased by A/R injury (P < 0.05), and treatment with the MLCK inhibitor peptide 18 attenuated the increased epithelial monolayer permeability and occludin endocytosis caused by A/R injury. Application of MLCK inhibitors to ischemia injured porcine ileal mucosa induced significant increases in TER and reduced mucosal-to-serosal fluxes of 3H-labeled mannitol. These data suggest that MLCK induced occludin endocytosis mediates intestinal epithelial barrier dysfunction during A/R injury. Our results also indicate that MLCK-dependent occludin regulation may be a target for the therapeutic treatment of ischemia/reperfusion injury. PMID- 27760752 TI - Ectopic Trophoblast Allografts in the Horse Resist Destruction by Secondary Immune Responses. AB - Invasive trophoblast from Day 34 horse conceptuses survives in extrauterine sites in allogeneic recipients that are immunologically naive to donor major histocompatibility complex class I antigens. The ectopic trophoblast retains its in utero characteristics, including similar lifespan, physiologic effect of its secreted product (equine chorionic gonadotropin) upon the recipient's ovaries, and induction of host immune responses. Immunologic memory has not been considered previously in this experimental system. We hypothesized that primary exposure to ectopic trophoblast would affect the recipient's immune status such that the survival time of subsequent transplants would be altered. Secondary transplant lifespans could be shortened by destructive memory responses, as has been observed in ectopic trophoblast studies in rodents, or lengthened, as occurs when male skin grafts follow multiple syngeneic pregnancies in mice. Eight mares received two closely spaced trophoblast transplants. Both grafts for each recipient were obtained from conceptuses sired by the same stallion to provide consistency in histocompatibility antigen exposure. Donor stallions were major histocompatibility complex class I homozygotes. Cytotoxic antibody production was tracked to monitor recipients' immune responses to the transplants. Detection of serum equine chorionic gonadotropin was used as a proxy for transplant lifespan. There was no significant difference between the distributions of primary and secondary transplant lifespans, despite evidence of immunologic memory. These data demonstrate that secondary ectopic trophoblast transplants in horses do not experience earlier destruction or prolonged survival following immune priming of recipients. Mechanisms responsible for the eventual demise of the transplants remain unperturbed by secondary immune responses or chronic antigenic exposure. PMID- 27760754 TI - Lysophosphatidic acid-induced vascular neointimal formation in mouse carotid arteries is mediated by the matricellular protein CCN1/Cyr61. AB - Vascular smooth muscle cell (SMC) migration is an essential step involved in neointimal formation in restenosis and atherosclerosis. Lysophosphatidic acid (LPA) is a bioactive component of oxidized low-density lipoprotein and is produced by activated platelets, implying that LPA influences vascular remodeling. Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro. Here we examined the role of CCN1 in LPA-induced neointimal formation. By using LPA infusion of carotid artery in a mouse model, we demonstrated that LPA highly induced CCN1 expression (approximately six- to sevenfold) in neointimal lesions. Downregulation of CCN1 expression with the specific CCN1 siRNA in carotid arteries blocked LPA-induced neointimal formation, indicating that CCN1 is essential in LPA-induced neointimal formation. We then used LPA receptor knockout (LPA1-/-, LPA2-/-, and LPA3-/-) mice to examine LPA receptor function in CCN1 expression in vivo and in LPA-induced neointimal formation. Our data reveal that LPA1 deficiency, but not LPA2 or LPA3 deficiency, prevents LPA induced CCN1 expression in vivo in mouse carotid arteries. We also observed that LPA1 deficiency blunted LPA infusion-induced neointimal formation, indicating that LPA1 is the major mediator for LPA-induced vascular remodeling. Our in vivo model of LPA-induced neointimal formation established a key role of the ECM protein CCN1 in mediating LPA-induced neointimal formation. Our data support the notion that the LPA1-CCN1 axis may be the central control for SMC migration and vascular remodeling. CCN1 may serve as an important vascular disease marker and potential target for vascular therapeutic intervention. PMID- 27760755 TI - Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels. AB - Hyperactivated DEG/ENaC channels cause neuronal death mediated by intracellular Ca2+ overload. Mammalian ASIC1a channels and MEC-4(d) neurotoxic channels in Caenorhabditis elegans both conduct Na+ and Ca2+, raising the possibility that direct Ca2+ influx through these channels contributes to intracellular Ca2+ overload. However, we showed that the homologous C. elegans DEG/ENaC channel UNC 8(d) is not Ca2+ permeable, yet it is neurotoxic, suggesting that Na+ influx is sufficient to induce cell death. Interestingly, UNC-8(d) shows small currents due to extracellular Ca2+ block in the Xenopus oocyte expression system. Thus, MEC 4(d) and UNC-8(d) differ both in current amplitude and Ca2+ permeability. Given that these two channels show a striking difference in toxicity, we wondered how Na+ conductance vs. Ca2+ permeability contributes to cell death. To address this question, we built an UNC-8/MEC-4 chimeric channel that retains the calcium permeability of MEC-4 and characterized its properties in Xenopus oocytes. Our data support the hypothesis that for Ca2+-permeable DEG/ENaC channels, both Ca2+ permeability and Na+ conductance contribute to toxicity. However, for Ca2+ impermeable DEG/ENaCs (e.g., UNC-8), our evidence shows that constitutive Na+ conductance is sufficient to induce toxicity, and that this effect is enhanced as current amplitude increases. Our work further refines the contribution of different channel properties to cellular toxicity induced by hyperactive DEG/ENaC channels. PMID- 27760756 TI - How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. AB - Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy. CMV resistance is diagnosed by detecting specific genetic mutations. UL97 mutations confer resistance to ganciclovir and valganciclovir, and a UL54 mutation confers multidrug resistance. Risk factors for resistance include prolonged or previous anti-CMV drug exposure or inadequate dosing, absorption, or bioavailability. Host risk factors include type of HCT and degree of immunosuppression. Depending on the genotyping results, multiple strategies can be adopted to treat resistant CMV infections, albeit no randomized clinical trials exist so far, after reducing immunosuppression (if possible): ganciclovir dose escalation, ganciclovir and foscarnet combination, and adjunct therapy such as CMV-specific cytotoxic T lymphocyte infusions. Novel therapies such as maribavir, brincidofovir, and letermovir should be further studied for treatment of resistant CMV. PMID- 27760759 TI - KIR gene haplotype: an independent predictor of clinical outcome in MDS patients. AB - Myelodysplastic syndromes (MDSs) are a group of hematopoietic disorders affecting the myeloid lineage, characterized by cytopenias and clonal evolution to acute myeloid leukemia (AML). We hypothesized that natural killer (NK) cells and their activating killer immunoglobulin-like receptors (aKIRs) influence the immune surveillance and clinical outcome of patients with MDSs. Here, we first examined the distribution of aKIR genes and haplotype in 2 independent cohorts of MDS and AML patients. The median number of aKIR genes was lower in MDS patients than healthy controls (2 vs 3 genes; P = .001), and lower in patients with secondary AML (progressed from MDSs) compared with de novo AML patients (2 vs 3; P = .008) and healthy controls (2 vs 3; P = .006). In a multivariate analysis, the presence of KIR haplotype A (characterized by low aKIR content 0-1) independently predicted a higher risk of conversion to AML (relative risk [RR] with 95% confidence interval [CI], 2.67 [1.13-6.71]; P = .02) and worse adjusted progression-free survival (RR with 95% CI, 2.96 [1.59-5.52]; P = .001) and overall survival (2.25 [1.17-4.31]; P = .02), compared with KIR haplotype B (multiple aKIR genes). These novel findings may help to identify MDS patients with a high risk of disease progression who would likely benefit from adoptive NK cell therapy. PMID- 27760757 TI - Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma. AB - CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37-) in ~60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-kappaBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63-, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37- status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL. PMID- 27760758 TI - Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation. AB - Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266). PMID- 27760760 TI - DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. AB - CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. We recently demonstrated that a single treatment of the agonistic antibody to DR3 (death receptor 3, alphaDR3) to donor mice resulted in the expansion of donor-derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3-activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25+Foxp3+ subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of alphaDR3 to recipient mice expanded recipient-derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T-cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T-cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical effect of the state of T cell activation on clinical outcomes after activation of DR3. PMID- 27760763 TI - The total number of acini remains constant throughout postnatal rat lung development. AB - The pulmonary airways are subdivided into conducting and gas-exchanging airways. The small tree of gas-exchanging airways which is fed by the most distal conducting airway represents an acinus. Very little is known about the development of the number of acini. The goal of this study was to estimate their number throughout rat postnatal development. Right middle rat lung lobes were obtained at postnatal day 4-60, stained with heavy metals, paraffin embedded, and scanned by synchrotron radiation-based X-ray tomographic microscopy or imaged with micro computed tomography after critical point drying. The acini were counted by detection of the transitional bronchioles [bronchioalveolar duct junction (BADJ)] by using morphological criteria (thickness of the walls of airways and appearance of alveoli) during examination of the resulting three dimensional (3D) image stacks. Between postnatal days 4-60, the number of acini per lung remained constant (5,840 +/- 547 acini), but their volume increased significantly. We concluded that the acini are formed before the end of the saccular stage (before postnatal day 4) and that the developmental increase of the lung volume is achieved by an increase of the acinar volume and not by an increase of their number. Furthermore, our results propose that the bronchioalveolar stem cells, which are residing in the BADJ, are as constant in their location as the BADJ itself. PMID- 27760761 TI - MVA vaccine encoding CMV antigens safely induces durable expansion of CMV specific T cells in healthy adults. AB - Attenuated poxvirus modified vaccinia Ankara (MVA) is a useful viral-based vaccine for clinical investigation, because of its excellent safety profile and property of inducing potent immune responses against recombinant (r) antigens. We developed Triplex by constructing an rMVA encoding 3 immunodominant cytomegalovirus (CMV) antigens, which stimulates a host antiviral response: UL83 (pp65), UL123 (IE1-exon4), and UL122 (IE2-exon5). We completed the first clinical evaluation of the Triplex vaccine in 24 healthy adults, with or without immunity to CMV and vaccinia virus (previous DryVax smallpox vaccination). Three escalating dose levels (DL) were administered IM in 8 subjects/DL, with an identical booster injection 28 days later and 1-year follow-up. Vaccinations at all DL were safe with no dose-limiting toxicities. No vaccine-related serious adverse events were documented. Local and systemic reactogenicity was transient and self-limiting. Robust, functional, and durable Triplex-driven expansions of CMV-specific T cells were detected by measuring T-cell surface levels of 4-1BB (CD137), binding to CMV-specific HLA multimers, and interferon-gamma production. Marked and durable CMV-specific T-cell responses were also detected in Triplex vaccinated CMV-seronegatives, and in DryVax-vaccinated subjects. Long-lived memory effector phenotype, associated with viral control during CMV primary infection, was predominantly found on the membrane of CMV-specific and functional T cells, whereas off-target vaccine responses activating memory T cells from the related herpesvirus Epstein-Barr virus remained undetectable. Combined safety and immunogenicity results of MVA in allogeneic hematopoietic stem cell transplant (HCT) recipients and Triplex in healthy adults motivated the initiation of a placebo-controlled multicenter trial of Triplex in HCT patients. This trial was registered at www.clinicaltrials.gov as #NCT02506933. PMID- 27760762 TI - Endothelin-1-Rho kinase interactions impair lung structure and cause pulmonary hypertension after bleomycin exposure in neonatal rat pups. AB - Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through Rho kinase (ROCK) activation, ET-1 impairs endothelial cell function; however, whether ET-1-ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intraperitoneal bleomycin with and without selective ETA (BQ123/BQ610) and ETB (BQ788) receptor blockers, nonselective ET receptor blocker (ETRB) (bosentan), or fasudil (ROCK inhibitor). At day 14, lungs were harvested for morphometrics, and measurements of Fulton's index (RV/LV+S), medial wall thickness (MWT), and vessel density. Lung ET-1 protein and ROCK activity (phospho-MYPT-1:total MYPT-1 ratio) were also measured by Western blot analysis. Bleomycin increased lung ET-1 protein expression by 65%, RV/LV+S by 60%, mean linear intercept (MLI) by 212%, and MWT by 140% and decreased radial alveolar count (RAC) and vessel density by 40 and 44%, respectively (P < 0.01 for each comparison). After bleomycin treatment, fasudil and bosentan partially restored RAC and vessel density and decreased MLI, RV/LV+S, and MWT to normal values. Bleomycin increased ROCK activity by 120%, which was restored to normal values by bosentan but not selective ETRB. We conclude that ET-1-ROCK interactions contribute to decreased alveolar and vascular growth and PH in experimental BPD. We speculate that nonselective ETRB and ROCK inhibitors may be effective in the treatment of infants with BPD and PH. PMID- 27760764 TI - BNP, troponin I, and YKL-40 as screening markers in extremely preterm infants at risk for pulmonary hypertension associated with bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is often complicated by pulmonary hypertension (PH). We investigated three biomarkers potentially suitable as screening markers for extremely preterm infants at risk of BPD-associated PH. In this prospective observational cohort study conducted in a tertiary neonatal intensive care unit, 83 preterm infants with BPD born <28-wk gestation and still inpatients at 36-wk corrected age received an echocardiogram and blood tests of B-type natriuretic peptide (BNP), troponin I, and YKL-40. Infants were analyzed according to echocardiographic evidence of tricuspid regurgitation (TR). Thirty infants had evidence of TR on echocardiogram at 36-wk corrected age. Infants with or without TR had similar baseline demographics: mean +/- SD gestational age 261 +/- 12 vs. 261 +/- 11 wk and birth weight 830 +/- 206 vs. 815 +/- 187 g, respectively. There was no difference in duration of respiratory support. The right ventricular systolic pressure of infants with evidence of TR was 40 +/- 16 mmHg. BNP was the only biomarker that proved to be significantly higher in infants with evidence of TR: median (interquartile range) serum level 54.5 (35-105) vs. 41.5 (30-59) pg/ml, P = 0.043. Subgroup analysis of infants with severe BPD requiring discharge on home oxygen or BPD-related mortality revealed similar results. There was no difference between groups for troponin I and YKL-40. In conclusion, increased serum levels of BNP were associated with evidence of TR at 36-wk corrected gestational age in extremely preterm infants, suggesting a potential role as a screening biomarker for BPD-associated PH. PMID- 27760765 TI - Deletion of protein kinase C-epsilon attenuates mitochondrial dysfunction and ameliorates ischemic renal injury. AB - Previously, we documented that activation of protein kinase C-epsilon (PKC epsilon) mediates mitochondrial dysfunction in cultured renal proximal tubule cells (RPTC). This study tested whether deletion of PKC-epsilon decreases dysfunction of renal cortical mitochondria and improves kidney function after renal ischemia. PKC-epsilon levels in mitochondria of ischemic kidneys increased 24 h after ischemia. Complex I- and complex II-coupled state 3 respirations were reduced 44 and 27%, respectively, in wild-type (WT) but unchanged and increased in PKC-epsilon-deficient (KO) mice after ischemia. Respiratory control ratio coupled to glutamate/malate oxidation decreased 50% in WT but not in KO mice. Activities of complexes I, III, and IV were decreased 59, 89, and 61%, respectively, in WT but not in KO ischemic kidneys. Proteomics revealed increases in levels of ATP synthase (alpha-subunit), complexes I and III, cytochrome oxidase, alpha-ketoglutarate dehydrogenase, and thioredoxin-dependent peroxide reductase after ischemia in KO but not in WT animals. PKC-epsilon deletion prevented ischemia-induced increases in oxidant production. Plasma creatinine levels increased 12-fold in WT and 3-fold in KO ischemic mice. PKC-epsilon deletion reduced tubular necrosis, brush border loss, and distal segment damage in ischemic kidneys. PKC-epsilon activation in hypoxic RPTC in primary culture exacerbated, whereas PKC-epsilon inhibition reduced, decreases in: 1) complex I- and complex II-coupled state 3 respirations and 2) activities of complexes I, III, and IV. We conclude that PKC-epsilon activation mediates 1) dysfunction of complexes I and III of the respiratory chain, 2) oxidant production, 3) morphological damage to the kidney, and 4) decreases in renal functions after ischemia. PMID- 27760766 TI - The native TRPP2-dependent channel of murine renal primary cilia. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening monogenic renal disease. ADPKD results from mutations in either of two proteins: polycystin-1 (also known as PC1 or PKD1) or transient receptor potential cation channel, subfamily P, member 2 (TRPP2, also known as polycystin 2, PC2, or PKD2). Each of these proteins is expressed in the primary cilium that extends from many renal epithelial cells. Existing evidence suggests that the cilium can promote renal cystogenesis, while PC1 and TRPP2 counter this cystogenic effect. To better understand the function of TRPP2, we investigated its electrophysiological properties in the native ciliary membrane. We recorded directly from the cilia of mIMCD-3 cells, a murine cell line of renal epithelial origin. In one-third of cilia examined, a large-conductance channel was observed. The channel was not permeable to Cl- but conducted cations with permeability ratios PK:PCa:PNa of 1:0.55:0.14. The single-channel conductance ranged from 97 pS in typical physiological solutions to 189 pS in symmetrical 145 mM KCl. Open probability of the channel was very sensitive to membrane depolarization or increasing cytoplasmic free Ca2+ in the low micromolar range, with the open probability increasing in either case. Knocking out TRPP2 by CRISPR/Cas9 genome editing eliminated the channel current, establishing it as TRPP2 dependent. Possible mechanisms for activating the TRPP2-dependent channel in the renal primary cilium are discussed. PMID- 27760767 TI - Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. AB - STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 * 106/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, alpha-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, alpha-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production. PMID- 27760768 TI - ILK and cytoskeletal architecture: an important determinant of AQP2 recycling and subsequent entry into the exocytotic pathway. AB - Within the past decade tremendous efforts have been made to understand the mechanism behind aquaporin-2 (AQP2) water channel trafficking and recycling, to open a path toward effective diabetes insipidus therapeutics. A recent study has shown that integrin-linked kinase (ILK) conditional-knockdown mice developed polyuria along with decreased AQP2 expression. To understand whether ILK also regulates AQP2 trafficking in kidney tubular cells, we performed in vitro analysis using LLCPK1 cells stably expressing rat AQP2 (LLC-AQP2 cells). Upon treatment of LLC-AQP2 cells with ILK inhibitor cpd22 and ILK-siRNA, we observed increased accumulation of AQP2 in the perinuclear region, without any significant increase in the rate of endocytosis. This perinuclear accumulation did not occur in cells expressing a serine-256-aspartic acid mutation that retains AQP2 in the plasma membrane. We then examined clathrin-mediated endocytosis after ILK inhibition using rhodamine-conjugated transferrin. Despite no differences in overall transferrin endocytosis, the endocytosed transferrin also accumulated in the perinuclear region where it colocalized with AQP2. These accumulated vesicles also contained the recycling endosome marker Rab11. In parallel, the usual vasopressin-induced AQP2 membrane accumulation was prevented after ILK inhibition; however, ILK inhibition did not measurably affect AQP2 phosphorylation at serine-256 or its dephosphorylation at serine-261. Instead, we found that inhibition of ILK increased F-actin polymerization. When F-actin was depolymerized with latrunculin, the perinuclear located AQP2 dispersed. We conclude that ILK is important in orchestrating dynamic cytoskeletal architecture during recycling of AQP2, which is necessary for its subsequent entry into the exocytotic pathway. PMID- 27760769 TI - A small molecule screening to detect potential therapeutic targets in human podocytes. AB - WIDMEIER E, TAN W, AIRIK M, HILDEBRANDT F: A small molecule screening to detect potential therapeutic targets in human podocytes. Am J Physiol Renal Physiol 312: F157-F171, 2017. First published October 19, 2016; doi:10.1152/ajprenal.00386.2016. Steroid-resistant nephrotic syndrome (SRNS) inevitably progresses to end-stage kidney disease, requiring dialysis or transplantation for survival. However, treatment modalities and drug discovery remain limited. Mutations in over 30 genes have been discovered as monogenic causes of SRNS. Most of these genes are predominantly expressed in the glomerular epithelial cell, the podocyte, placing it at the center of the pathogenesis of SRNS. Podocyte migration rate (PMR) represents a relevant intermediate phenotype of disease in monogenic causes of SRNS. We therefore adapted PMR in a high throughput manner to screen small molecules as potential therapeutic targets for SRNS. We performed a high-throughput drug screening of a National Institutes of Health Clinical Collection (NCC) library (n = 725 compounds) measuring PMR by videomicroscopy. We used the Woundmaker to perform individual 96-well scratch wounds and screened compounds using a quantitative kinetic live cell imaging migration assay using IncuCyte ZOOM technology. Using a normal distribution for the average PMR in wild-type podocytes with a vehicle control (DMSO), we applied a 90% confidence interval to define "distinct" compounds (5% faster/slower PMR) and found that 12 of 725 compounds (at 10 MUM) reduced PMR. Clusters of drugs that alter PMR included actin/tubulin modulators such as the azole class of antifungals and antineoplastic vinca-alkaloids. We hereby identify compounds that alter PMR. The PMR assay provides a new avenue to test therapeutics for nephrotic syndrome. Positive results may reveal novel pathways in the study of glomerular diseases such as SRNS. PMID- 27760770 TI - Inflammation drives renal scarring in experimental pyelonephritis. AB - Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis. The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden. Transcriptome analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis. The integration of histopathology, quantification of cellular immune influx, and unbiased transcriptional profiling begins to define potential mechanisms of tissue injury during pyelonephritis in the context of an intact immune response. The clear relationship between inflammatory cell recruitment and fibrosis supports the hypothesis that acquired renal scarring arises as a consequence of excessive host inflammation and suggests that immunomodulatory therapies should be investigated to reduce renal scarring in patients with pyelonephritis. PMID- 27760772 TI - Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms. AB - Chronic kidney disease (CKD) is associated to an increased risk of death, CKD progression, and acute kidney injury (AKI) even from early stages, when glomerular filtration rate (GFR) is preserved. The link between early CKD and these risks is unclear, since there is no accumulation of uremic toxins. However, pathological albuminuria and kidney inflammation are frequent features of early CKD, and the production of kidney protective factors may be decreased. Indeed, Klotho expression is already decreased in CKD category G1 (normal GFR). Klotho has anti-aging and nephroprotective properties, and decreased Klotho levels may contribute to increase the risk of death, CKD progression, and AKI. In this review, we discuss the downregulation by mediators of inflammation of molecules with systemic and/or renal local protective functions, exemplified by Klotho and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a transcription factor that promotes mitochondrial biogenesis. Cytokines such as TWEAK, TNF-alpha, or transforming growth factor -beta1 produced locally during kidney injury or released from inflammatory sites at other organs may decrease kidney expression of Klotho and PGC-1alpha or lead to suboptimal recruitment of these nephroprotective proteins. Transcription factors (e.g., Smad3 and NF kappaB) and epigenetic mechanisms (e.g., histone acetylation or methylation) contribute to downregulate the expression of Klotho and/or PGC-1alpha, while histone crotonylation promotes PGC-1alpha expression. NF-kappaBiz facilitates the repressive effect of NF-kappaB on Klotho expression. A detailed understanding of these mediators may contribute to the development of novel therapeutic approaches to prevent CKD progression and its negative impact on mortality and AKI. PMID- 27760773 TI - Stop that podocyte! PMID- 27760774 TI - Associations of Accelerometry-Assessed and Self-Reported Physical Activity and Sedentary Behavior With All-Cause and Cardiovascular Mortality Among US Adults. AB - The US physical activity (PA) recommendations were based primarily on studies in which self-reported data were used. Studies that include accelerometer-assessed PA and sedentary behavior can contribute to these recommendations. In the present study, we explored the associations of PA and sedentary behavior with all-cause and cardiovascular disease (CVD) mortality in a nationally representative sample. Among the 2003-2006 National Health and Nutrition Examination Survey cohort, 3,809 adults 40 years of age or older wore an accelerometer for 1 week and self reported their PA levels. Mortality data were verified through 2011, with an average of 6.7 years of follow-up. We used Cox proportional hazards models to obtain adjusted hazard ratios and 95% confidence intervals. After excluding the first 2 years, there were 337 deaths (32% or 107 of which were attributable to CVD). Having higher accelerometer-assessed average counts per minute was associated with lower all-cause mortality risk: When compared with the first quartile, the adjusted hazard ratio was 0.37 (95% confidence interval: 0.23, 0.59) for the fourth quartile, 0.39 (95% confidence interval: 0.27, 0.57) for the third quartile, and 0.60 (95% confidence interval: 0.45, 0.80) second quartile. Results were similar for CVD mortality. Lower all-cause and CVD mortality risks were also generally observed for persons with higher accelerometer-assessed moderate and moderate-to-vigorous PA levels and for self-reported moderate-to vigorous leisure, household and total activities, as well as for meeting PA recommendations. Accelerometer-assessed sedentary behavior was generally not associated with all-cause or CVD mortality in fully adjusted models. These findings support the national PA recommendations to reduce mortality. PMID- 27760775 TI - Invited Commentary: Little Steps Lead to Huge Steps-It's Time to Make Physical Inactivity Our Number 1 Public Health Enemy. AB - The analysis plan and article in this issue of the Journal by Evenson et al. (Am J Epidemiol 2016;184(9):621-632) is well-conceived, thoughtfully conducted, and tightly written. The authors utilized the National Health and Nutrition Examination Survey data set to examine the association between accelerometer measured physical activity level and mortality and found that meeting the 2013 federal Physical Activity Guidelines resulted in a 35% reduction in risk of mortality. The timing of these findings could not be better, given the ubiquitous nature of personal accelerometer devices. The masses are already equipped to routinely quantify their activity, and now we have the opportunity and responsibility to provide evidenced-based, tailored physical activity goals. We have evidenced-based physical activity guidelines, mass distribution of devices to track activity, and now scientific support indicating that meeting the physical activity goal, as assessed by these devices, has substantial health benefits. All of the pieces are in place to make physical inactivity a national priority, and we now have the opportunity to positively affect the health of millions of Americans. PMID- 27760771 TI - Molecular mechanisms regulating aquaporin-2 in kidney collecting duct. AB - The kidney collecting duct is an important renal tubular segment for regulation of body water homeostasis and urine concentration. Water reabsorption in the collecting duct principal cells is controlled by vasopressin, a peptide hormone that induces the osmotic water transport across the collecting duct epithelia through regulation of water channel proteins aquaporin-2 (AQP2) and aquaporin-3 (AQP3). In particular, vasopressin induces both intracellular translocation of AQP2-bearing vesicles to the apical plasma membrane and transcription of the Aqp2 gene to increase AQP2 protein abundance. The signaling pathways, including AQP2 phosphorylation, RhoA phosphorylation, intracellular calcium mobilization, and actin depolymerization, play a key role in the translocation of AQP2. This review summarizes recent data demonstrating the regulation of AQP2 as the underlying molecular mechanism for the homeostasis of water balance in the body. PMID- 27760776 TI - Direct Participation in and Indirect Exposure to the Occupy Central Movement and Depressive Symptoms: A Longitudinal Study of Hong Kong Adults. AB - Despite the extensive history of social movements around the world, the evolution of population mental health before, during, and after a social movement remains sparsely documented. We sought to assess over time the prevalence of depressive symptoms during and after the Occupy Central movement in Hong Kong and to examine the associations of direct and indirect exposures to Occupy Central with depressive symptoms. We longitudinally administered interviews to 909 adults who were randomly sampled from the population-representative FAMILY Cohort at 6 time points from March 2009 to March 2015: twice each before, during, and after the Occupy Central protests. The Patient Health Questionnaire-9 was used to assess depressive symptoms and probable major depression (defined as Patient Health Questionnaire-9 score >=10). The absolute prevalence of probable major depression increased by 7% after Occupy Central, regardless of personal involvement in the protests. Higher levels of depressive symptoms were associated with online and social media exposure to protest-related news (incidence rate ratio (IRR) = 1.28, 95% confidence interval (CI): 1.06, 1.55) and more frequent Facebook use (IRR = 1.38, 95% CI: 1.12, 1.71). Higher levels of intrafamilial sociopolitical conflict was associated with more depressive symptoms (IRR = 1.05, 95% CI: 1.01, 1.09). The Occupy Central protests resulted in substantial and sustained psychological distress in the community. PMID- 27760778 TI - Morphine exposure in preterm infants correlates with impaired cerebellar growth and poorer neurodevelopmental outcome. PMID- 27760777 TI - Alternative lengthening of human telomeres is a conservative DNA replication process with features of break-induced replication. AB - Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells. Furthermore, depletion of PolD3 or PolD4, two subunits of human DNA polymerase delta that are essential for BIR, reduced the frequency of conservatively replicated telomeric DNA ends and led to shorter telomeres and chromosome end-to-end fusions. Taken together, these results suggest that BIR is associated with conservative DNA replication in human cells and mediates ALT in cancer. PMID- 27760779 TI - Role of Serum Mycoplasma pneumoniae IgA, IgM, and IgG in the Diagnosis of Mycoplasma pneumoniae-Related Pneumonia in School-Age Children and Adolescents. AB - Mycoplasma pneumoniae is an important causative pathogen of community-acquired pneumonia in children. Rapid and reliable laboratory diagnosis of M. pneumoniae infection is important so that appropriate antibiotic treatment can be initiated to reduce the misuse of drugs and resistance rates. Anti-M. pneumoniae immunoglobulin M (IgM) is an indicator of recent primary infection but can persist for several months after initial infection. It has been suggested that anti-M. pneumoniae immunoglobulin A (IgA) can be a reliable indicator for recent M. pneumoniae infection in adults. We investigated the clinical diagnostic value of M. pneumoniae IgA in school-age children and adolescents with M. pneumoniae related pneumonia. Eighty children with pneumonia and seropositive for M. pneumoniae IgM or with a 4-fold increase of anti-M. pneumoniae immunoglobulin G (IgG) were enrolled from May 2015 to March 2016. The titers of M. pneumoniae IgA, IgM, and IgG, the clinical features, and laboratory examinations of blood, C reactive protein, and liver enzymes were analyzed. The initial positivity rates for M. pneumoniae IgM and IgA upon admission to the hospital were 63.6 and 33.8%, respectively. One week after admission, the cumulative positivity rates for M. pneumoniae IgM and IgA increased to 97.5 and 56.3%, respectively. Detection of M. pneumoniae IgM was more sensitive than detection of M. pneumoniae IgA for the diagnosis of M. pneumoniae-related pneumonia in school-age children and adolescents; however, paired sera are necessary for a more accurate diagnosis. PMID- 27760780 TI - Use of a Toxin Neutralization Assay To Characterize the Serologic Response to Adenylate Cyclase Toxin after Infection with Bordetella pertussis. AB - Adenylate cyclase toxin (ACT) is an essential virulence factor of Bordetella pertussis, and antibodies to ACT protect against B. pertussis infection in mice. The toxin is therefore a strong candidate antigen for addition to future acellular pertussis vaccines. In order to characterize the functionality of the immunologic response to ACT after infection, we developed an assay for testing the ability of serum samples from subjects infected with B. pertussis to neutralize ACT-induced cytotoxicity in J774 macrophage cells. Baboons develop neutralizing anti-ACT antibodies following infection with B. pertussis, and all sera from baboons with positive anti-ACT IgG enzyme-linked immunosorbent assay (ELISA) results neutralized ACT cytotoxicity. The toxin neutralization assay (TNA) was positive in some baboon sera in which ELISA remained negative. Of serum samples obtained from humans diagnosed with pertussis by PCR, anti-ACT IgG ELISA was positive in 72%, and TNA was positive in 83%. All samples positive for anti ACT IgG ELISA were positive by TNA, and none of the samples from humans without pertussis neutralized toxin activity. These findings indicate that antibodies to ACT generated following infection with B. pertussis consistently neutralize toxin induced cytotoxicity and that TNA can be used to improve understanding of the immunologic response to ACT after infection or vaccination. PMID- 27760781 TI - Biomarkers for Clinical Decision-Making in the Management of Pulmonary Embolism. AB - BACKGROUND: Pulmonary embolism (PE) is associated with high all-cause and PE related mortality and requires individualized management. After confirmation of PE, a refined risk stratification is particularly warranted among normotensive patients. Previous prognostic models favored combinations of echocardiography or computed tomography suggestive of right ventricular (RV) dysfunction together with biomarkers of RV dysfunction (natriuretic peptides) or myocardial injury (cardiac troponins) to identify candidates for thrombolysis or embolectomy. In contrast, current predictive models using clinical scores such as the Pulmonary Embolism Severity Index (PESI) or its simplified version (sPESI) rather seek to identify patients, not only those at higher risk requiring observation for early detection of hemodynamic decompensation, and the need for initiation of rescue reperfusion therapy, but also those at low risk qualifying for early discharge and outpatient treatment. Almost all prediction models advocate the additional measurement of biomarkers along with imaging of RV dysfunction as part of a comprehensive algorithm. CONTENT: The following mini-review will provide an updated overview on the individual components of different algorithms with a particular focus on guideline-recommended and new, less-established biomarkers for risk stratification, and how biomarkers should be implemented and interpreted. SUMMARY: Ideally, biomarkers should be part of a comprehensive risk stratification algorithm used together with clinical risk scores as a basis, and/or imaging. For this purpose, cardiac troponins, including high-sensitivity troponin generations, natriuretic peptides, and h-FABP (heart-type fatty acid binding protein) are currently recommended in guidelines. There is emerging evidence for several novel biomarkers that require further validation before being applied in clinical practice. PMID- 27760783 TI - Preprint Deja Vu. PMID- 27760782 TI - Determinants of Light and Intermittent Smoking in the United States: Results from Three Pooled National Health Surveys. AB - BACKGROUND: Light and/or intermittent smokers have been the fastest growing segment of cigarette smokers in the United States over the past two decades. Defining their behavioral characteristics is a critical public health priority. METHODS: Our sample included 78,229 U.S. adults from three pooled contemporary population-based surveys: the 2012 NHIS, 2012 NSDUH, and 2011-2012 NHANES. We classified current smokers into four categories (light and intermittent [LITS], light-daily, heavier-intermittent, and heavier-daily) and assessed smoking behaviors, illicit drug use, and mental health indicators using weighted analyses. RESULTS: Analyses associated smoking categories with nicotine dependence, age of smoking initiation, race/ethnicity, and other demographic and behavioral factors. Compared with heavier-daily smokers, smokers who were LITS were most likely to have mild or no nicotine dependence (weighted odds ratio [OR], 16.92; 95% confidence interval [CI], 13.10-21.85), to start smoking cigarettes regularly after age 21 (OR, 3.42; 95% CI, 2.84-4.12), and to be Hispanic (OR, 5.38; 95% CI, 4.38-6.61). Additional significant results were found for other categories of smokers. CONCLUSIONS: Based on pooled data from three large national surveys, light and/or intermittent smokers differed in smoking, drug use, and mental health behaviors from heavier-daily, former, and never smokers. Notable differences by level of smoking frequency and intensity were observed for nicotine dependence, age of smoking initiation, and race/ethnicity. IMPACT: Our results may help focus preventive measures and policies for the growing number of light and/or intermittent smokers in the United States because smoking patterns vary by behavioral and socioeconomic factors. Cancer Epidemiol Biomarkers Prev; 26(2); 228-39. (c)2016 AACR. PMID- 27760784 TI - Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System. AB - In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process. PMID- 27760785 TI - Monitoring and Detecting the Cigarette Beetle (Coleoptera: Anobiidae) Using Ultraviolet (LED) Direct and Reflected Lights and/or Pheromone Traps in a Laboratory and a Storehouse. AB - The cigarette beetle, Lasioderma serricorne (F.), is an important stored-product pest worldwide because it damages dry foods. Detection and removal of the female L. serricorne will help to facilitate the control of the insect by removal of the egg-laying populations. In this manuscript, we examined the responses by L. serricorne to direct and reflected light in transparent cube (50 m3) set in a chamber (200 m3) and a stored facility with both direct and reflected UV-LED lights. The study also examined the responses by the beetles to light in the presence or absence of pheromone in traps that are placed at different heights. Reflected light attracted more beetles than the direct light in the experimental chamber, but the direct light traps attracted more beetles than the reflected light traps in the storehouse. Pheromone traps attracted only males; UV-LED traps attracted both sexes. The UV-LED traps with a pheromone, i.e., combined trap, attracted more males than UV-LED light traps without a pheromone, whereas the attraction of UV-LED traps with and without the pheromone was similar in females. The results suggest that UV-LED light trap combined with a sex pheromone is the best solution for monitoring and controlling L. serricorne. PMID- 27760786 TI - Anthranilic Diamide Insecticides Delivered via Multiple Approaches to Control Vegetable Pests: A Case Study in Snap Bean. AB - Many vegetable insect pests are managed using neonicotinoid and pyrethroid insecticides. Unfortunately, these insecticides are toxic to many bees and natural enemies and no longer control some pests that have developed resistance. Anthranilic diamide insecticides provide systemic control of many herbivorous arthropod pests, but exhibit low toxicity to beneficial arthropods and mammals, and may be a promising alternative to neonicotinoids and pyrethroids. Anthranilic diamides may be delivered to vegetable crops via seed, in-furrow, or foliar treatments; therefore, it would be desirable to identify which application method provides high levels of pest control while minimizing the amount of active ingredient. As a case study, chlorantraniliprole and cyantraniliprole applied via the methods listed above were evaluated for managing seedcorn maggot, Delia platura (Meigen) (Diptera: Anthomyiidae), and European corn borer, Ostrinia nubilalis (Hubner) (Lepidoptera: Crambidae), in snap bean. Chlorantraniliprole and cyantraniliprole delivered as seed and in-furrow treatments reduced D. platura damage to the same level as the standard neonicotinoid seed treatment. Both diamides applied via all three methods significantly reduced O. nubilalis damage, but only the foliar application provided similar control as the standard pyrethroid spray. Results from laboratory bioassays revealed that both diamides applied as seed and in-furrow treatments caused high O. nubilalis neonate mortality up to 44 d after application. While the diamides provided equivalent control of these pests as the neonicotinoid and pyrethroid standards when applied in the same manner, chlorantraniliprole delivered as a seed treatment showed the most promise for managing both pests. PMID- 27760788 TI - Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma. AB - Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 3' untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. Cancer Res; 76(24); 7140-50. (c)2016 AACR. PMID- 27760790 TI - MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves' orbitopathy - lessons from randomized control trials. AB - Rituximab (RTX) use in open-label series has been associated with very encouraging responses in patients with active and moderate-to-severe Graves' orbitopathy (GO). Recently, randomized controlled trials of RTX have been performed in such patients to answer the question of clinical efficacy and the safety profile of this agent. That data, reported separately, focused on Clinical Activity Score (CAS) and indicated in one trial a strong benefit of RTX in comparison with IV glucocorticoids, whereas the other trial noted the absence of a benefit by comparison with placebo. The outcome was reanalyzed post hoc here, using EUGOGO criteria, and the results were not significantly different. The authors comment further on the differences between the two trials regarding populations treated, methodology, analysis of outcomes and the adverse effect profile of RTX. The populations treated appear different with younger patients, lower TRAb and shorter duration of disease prevalent in the Italian trial, all elements favoring a better response. Smoking, usually diminishing a response, was also more prevalent in some patients. The combined outcome proposed by EUGOGO revealed similar results with CAS regarding RTX efficacy; yet, it might be a more comprehensive outcome. The adverse events of concern relate mainly to the risk of DON, which seems to be increased by the use of RTX in a certain subset of patients. Based on available data, a multicenter trial using the EUGOGO-proposed outcomes might be the next best step to define the role of RTX in GO therapy. PMID- 27760789 TI - The Biodistribution and Immune Suppressive Effects of Breast Cancer-Derived Exosomes. AB - Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45+ bone marrow-derived cells. Subsequent long-term conditioning of naive mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer-derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816-27. (c)2016 AACR. PMID- 27760791 TI - TERT promoter mutations: a genetic signature of benign and malignant thyroid tumours occurring in the context of tinea capitis irradiation. AB - OBJECTIVE: The aim of this study is to evaluate the frequency and molecular characteristics of TERTp mutations in thyroid adenomas and carcinomas occurring in the low-dose radiation exposure tinea capitis setting. DESIGN AND METHODS: Twenty-seven patients with 34 well-differentiated thyroid carcinomas and 28 patients with 29 follicular adenomas diagnosed in a Portuguese tinea capitis cohort were studied. Blood samples were obtained from all the patients. Screening for TERTp mutations was performed by PCR amplification followed by Sanger sequencing. A series of 33 sporadic thyroid adenomas was used as control. RESULTS: TERTp mutations were detected in six of the 28 patients with adenoma (21.4%) and in four of the 27 patients with carcinoma (14.8%). Three tumours (two carcinomas and one adenoma) had the tandem mutation -124/-125 GG>AA (30.0%), whereas the remaining seven had the -124G > A. The 20.7% frequency of TERTp mutations in adenomas contrasts with the absence of mutations in the adenomas from the control group and from most series on record, whereas the one found in carcinomas (11.8%) is similar to those reported in the literature for sporadic carcinomas. CONCLUSION: TERTp mutations, including the tandem mutation -124/-125 GG>AA not described previously in thyroid tumours, appear to represent a genetic signature for thyroid tumours in patients submitted to low-dose X-ray irradiation. The high frequency of TERTp mutations in the adenomas of our cohort contrasts with their absence in sporadically occurring, as well as in adenomas of the Chernobyl series. PMID- 27760792 TI - Elevated TSH in adults treated for hypothyroidism is associated with increased mortality. AB - CONTEXT: Numerous studies investigated the link between hypothyroidism and mortality, but a definite conclusion is hard to reach as these were limited by a number of factors, including age of participants, comorbidities and single measurement of thyroid function. OBJECTIVE: To evaluate the association between TSH and fT4 levels and mortality in patients with levothyroxine-treated hypothyroidism. DESIGN AND SETTING: Observational data of hospitalized patients (2011-2014). TSH and fT4 levels obtained between at least 30 days after discharge and until death or end of follow-up were collected. Median TSH and fT4 levels were stratified into categories. PATIENTS: In total, 611 patients with treated hypothyroidism, aged 60-80 years (72% females, mean age 71 +/- 6 years) were included in the study. MAIN OUTCOME MEASURE: All-cause mortality up to 66 months after discharge, by TSH and fT4 categories. RESULTS: During follow-up, the average numbers of TSH and fT4 measurements were 5.5 +/- 3.8 and 2.5 +/- 4.2 per patient respectively. Mortality rates were 28%, 29% and 54% with median TSH of 0.5-2.5, 2.5-5.0 and 5.0-10.0 IU/L respectively. Adjusted hazard ratios for mortality with median TSH between 5.0 and 10.0 IU/L were 2.3 (95% CI: 1.6-3.4) and 2.2 (95% CI: 1.6-3.2) compared with patients with TSH between 0.5-2.5 IU/L and 2.5-5 IU/L respectively. There was no difference in mortality between patients with median fT4 10-15 or 15-20 pmol/L. CONCLUSION: In treated hypothyroid adult patients and serial measurements of thyroid function tests, median TSH levels of 5-10 IU/L are associated with increased mortality with no effect of fT4 levels. Treatment should aim at achieving euthyroidism to improve survival. PMID- 27760793 TI - A Genetic Screen To Assess Dopamine Receptor (DopR1) Dependent Sleep Regulation in Drosophila. AB - Sleep is an essential behavioral state of rest that is regulated by homeostatic drives to ensure a balance of sleep and activity, as well as independent arousal mechanisms in the central brain. Dopamine has been identified as a critical regulator of both sleep behavior and arousal. Here, we present results of a genetic screen that selectively restored the Dopamine Receptor (DopR/DopR1/dumb) to specific neuroanatomical regions of the adult Drosophila brain to assess requirements for DopR in sleep behavior. We have identified subsets of the mushroom body that utilizes DopR in daytime sleep regulation. These data are supported by multiple examples of spatially restricted genetic rescue data in discrete circuits of the mushroom body, as well as immunohistochemistry that corroborates the localization of DopR protein within mushroom body circuits. Independent loss of function data using an inducible RNAi construct in the same specific circuits also supports a requirement for DopR in daytime sleep. Additional circuit activation of discrete DopR+ mushroom body neurons also suggests roles for these subpopulations in sleep behavior. These conclusions support a new separable function for DopR in daytime sleep regulation within the mushroom body. This daytime regulation is independent of the known role of DopR in nighttime sleep, which is regulated within the Fan-Shaped Body (FSB). This study provides new neuroanatomical loci for exploration of dopaminergic sleep functions in Drosophila, and expands our understanding of sleep regulation during the day vs. night. PMID- 27760794 TI - Evolutionary Insights into Taste Perception of the Invasive Pest Drosophila suzukii. AB - Chemosensory perception allows insects to interact with the environment by perceiving odorant or tastant molecules; genes encoding chemoreceptors are the molecular interface between the environment and the insect, and play a central role in mediating its chemosensory behavior. Here, we explore how the evolution of these genes in the emerging pest Drosophila suzukii correlates with the peculiar ecology of this species. We annotated approximately 130 genes coding for gustatory receptors (GRs) and divergent ionotropic receptors (dIRs) in D. suzukii and in its close relative D. biarmipes We then analyzed the evolution, in terms of size, of each gene family as well of the molecular evolution of the genes in a 14 Drosophila species phylogenetic framework. We show that the overall evolution of GRs parallels that of dIRs not only in D. suzukii, but also in all other analyzed Drosophila Our results reveal an unprecedented burst of gene family size in the lineage leading to the suzukii subgroup, as well as genomic changes that characterize D. suzukii, particularly duplications and strong signs of positive selection in the putative bitter-taste receptor GR59d. Expression studies of duplicate genes in D. suzukii support a spatio-temporal subfunctionalization of the duplicate isoforms. Our results suggest that D. suzukii is not characterized by gene loss, as observed in other specialist Drosophila species, but rather by a dramatic acceleration of gene gains, compatible with a highly generalist feeding behavior. Overall, our analyses provide candidate taste receptors specific for D. suzukii that may correlate with its specific behavior, and which may be tested in functional studies to ultimately enhance its control in the field. PMID- 27760795 TI - Association Between a Prolonged PR Interval and Outcomes of Cardiac Resynchronization Therapy: A Report From the National Cardiovascular Data Registry. AB - BACKGROUND: A prolonged PR interval is common among cardiac resynchronization therapy (CRT) candidates; however, the association between PR interval and outcomes is unclear, and the data are conflicting. METHODS: We conducted inverse probability weighted analyses of 26 451 CRT-eligible (ejection fraction <=35, QRS >=120 ms) patients from the National Cardiovascular Data Registry ICD Registry to assess the association between a prolonged PR interval (>=230 ms), receipt of CRT with defibrillator (CRT-D) versus implantable cardioverter defibrillator (ICD), and outcomes. We first tested the association between a prolonged PR interval and outcomes among patients stratified by device type. Next, we performed a comparative effectiveness analysis of CRT-D versus ICD among patients when stratified by PR interval. Using Medicare claims data, we followed up with patients up to 5 years for incident heart failure hospitalization or death. RESULTS: Patients with a PR>=230 ms (15%; n=4035) were older and had more comorbidities, including coronary artery disease, atrial arrhythmias, diabetes mellitus, and chronic kidney disease. After risk adjustment, a PR>=230 ms (versus PR<230 ms) was associated with increased risk of heart failure hospitalization or death among CRT-D (hazard ratio, 1.23; 95% confidence interval, 1.14-1.31; P<0.001) but not ICD recipients (hazard ratio, 1.08; 95% confidence interval, 0.97-1.20; P=0.17) (Pinteraction=0.043). CRT-D (versus ICD) was associated with lower rates of heart failure hospitalization or death among patients with PR<230 ms (hazard ratio, 0.79; 95% confidence interval, 0.73-0.85; P<0.001) but not PR>=230 ms (hazard ratio, 1.01; 95% confidence interval, 0.87-1.17; P=0.90) (Pinteraction=0.0025). CONCLUSIONS: A PR>=230 ms is associated with increased rates of heart failure hospitalization or death among CRT-D patients. The real world comparative effectiveness of CRT-D (versus ICD) is significantly less among patients with a PR>=230 ms in comparison with patients with a PR<230 ms. PMID- 27760796 TI - Association Between Duration of Resuscitation and Favorable Outcome After Out-of Hospital Cardiac Arrest: Implications for Prolonging or Terminating Resuscitation. AB - BACKGROUND: Little evidence guides the appropriate duration of resuscitation in out-of-hospital cardiac arrest, and case features justifying longer or shorter durations are ill defined. We estimated the impact of resuscitation duration on the probability of favorable functional outcome in out-of-hospital cardiac arrest using a large, multicenter cohort. METHODS: This was a secondary analysis of a North American, single-blind, multicenter, cluster-randomized, clinical trial (ROC-PRIMED [Resuscitation Outcomes Consortium Prehospital Resuscitation Using an Impedance Valve and Early Versus Delayed]) of consecutive adults with nontraumatic, emergency medical services-treated out-of-hospital cardiac arrest. Primary exposure was duration of resuscitation in minutes (onset of professional resuscitation to return of spontaneous circulation [ROSC] or termination of resuscitation). Primary outcome was survival to hospital discharge with favorable outcome (modified Rankin scale [mRS] score of 0-3). Subjects were additionally classified as survival with unfavorable outcome (mRS score of 4-5), ROSC without survival (mRS score of 6), or without ROSC. Subject accrual was plotted as a function of resuscitation duration, and the dynamic probability of favorable outcome at discharge was estimated for the whole cohort and subgroups. Adjusted logistic regression models tested the association between resuscitation duration and survival with favorable outcome. RESULTS: The primary cohort included 11 368 subjects (median age, 69 years [interquartile range, 56-81 years]; 7121 men [62.6%]). Of these, 4023 (35.4%) achieved ROSC, 1232 (10.8%) survived to hospital discharge, and 905 (8.0%) had an mRS score of 0 to 3 at discharge. Distribution of cardiopulmonary resuscitation duration differed by outcome (P<0.00001). For cardiopulmonary resuscitation duration up to 37.0 minutes (95% confidence interval, 34.9-40.9 minutes), 99% with an eventual mRS score of 0 to 3 at discharge achieved ROSC. The dynamic probability of an mRS score of 0 to 3 at discharge declined over elapsed resuscitation duration, but subjects with initial shockable cardiac rhythm, witnessed cardiac arrest, and bystander cardiopulmonary resuscitation were more likely to survive with favorable outcome after prolonged efforts (30-40 minutes). After adjustment for prehospital (odds ratio, 0.93; 95% confidence interval, 0.92-0.95) and inpatient (odds ratio, 0.97; 95% confidence interval, 0.95-0.99) covariates, resuscitation duration was associated with survival to discharge with an mRS score of 0 to 3. CONCLUSIONS: Shorter resuscitation duration was associated with likelihood of favorable outcome at hospital discharge. Subjects with favorable case features were more likely to survive prolonged resuscitation up to 47 minutes. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00394706. PMID- 27760797 TI - The Effects of Music on Pain: A Meta-Analysis. AB - BACKGROUND: Numerous meta-analyses have been conducted on the topic of music and pain, with the latest comprehensive study published in 2006. Since that time, more than 70 randomized controlled trials (RCTs) have been published, necessitating a new and comprehensive review. OBJECTIVE: The aim of this meta analysis was to examine published RCT studies investigating the effect of music on pain. METHODS: The present study included RCTs published between 1995 and 2014. Studies were obtained by searching 12 databases and hand-searching related journals and reference lists. Main outcomes were pain intensity, emotional distress from pain, vital signs, and amount of analgesic intake. Study quality was evaluated according to the Cochrane Collaboration guidelines. RESULTS: Analysis of the 97 included studies revealed that music interventions had statistically significant effects in decreasing pain on 0-10 pain scales (MD = 1.13), other pain scales (SMD = -0.39), emotional distress from pain (MD = 10.83), anesthetic use (SMD = -0.56), opioid intake (SMD = -0.24), non-opioid intake (SMD = -0.54), heart rate (MD = -4.25), systolic blood pressure (MD = 3.34), diastolic blood pressure (MD = -1.18), and respiration rate (MD = -1.46). Subgroup and moderator analyses yielded additional clinically informative outcomes. CONCLUSIONS: Considering all the possible benefits, music interventions may provide an effective complementary approach for the relief of acute, procedural, and cancer/chronic pain in the medical setting. PMID- 27760798 TI - Trainee Needs in Pediatric Transplant Infectious Diseases Education. AB - Background: Pediatric transplant infectious diseases (PTID) is emerging as an area of expertise within pediatric infectious diseases. Although guidelines for training in PTID have been published, no prior national survey has been conducted to identify trainee-described needs for instruction in PTID. Methods: A survey was designed through collaboration between the American Society of Transplantation and the Pediatric Infectious Diseases Society, to assess trainee exposure, self-knowledge, and self-competency in PTID. Results: Sixty of 169 trainees replied (response rate 35%) with 93% of respondents from centers that performed transplants. Eighty-two percent of trainees were unaware of the recommended curriculum for PTID. Although a majority of trainees (78%) indicated they had received structured teaching in PTID, most (>50%) ranked their knowledge in donor selection, donor-derived infections, and candidate risk assessment as poor or fair. A majority (>50%) also reported their competency in areas regarding pre- and posttransplant guidance as poor or fair. Trainees identified the following strategies to augment their PTID training: additional rotations, teaching by experts, case-based learning, and a reference guide. Conclusions: This survey highlights significant trainee-identified gaps in PTID knowledge and competency. Limitations include low survey response rate but appears weighted towards centers with transplantation. Suggested strategies can inform the development of learner-specific initiatives and curriculum in PTID. PMID- 27760799 TI - Vertical Transmission of Dengue Virus in the Peripartum Period and Viral Kinetics in Newborns and Breast Milk: New Data. AB - Summary: We investigated 10 mother-newborn pairs and found a 90% rate of dengue virus (DENV) transmission during the perinatal period. Here, we describe DENV kinetics in the sera of newborns before the onset of disease. Of the breast-milk samples analyzed, 75% tested positive for DENV. Background: Dengue is the most common mosquito-borne viral disease in humans. With this study, we aimed to investigate the risk of vertical (DENV) transmission during the peripartum period and to describe its viral kinetics in serum and breast milk. Methods: We carried out a prospective study during the 2012-2013 dengue epidemic in New Caledonia, its most severe on record. All mothers hospitalized at the Centre Hospitalier Territorial in Noumea, New Caledonia, with symptoms of dengue infection between 7 days before and 2 days after delivery and/or whose infant was infected during breastfeeding were investigated. DENV was detected and quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in sera and breast milk (mothers), sera and gastric fluid (newborns), cord blood, and placentas. DENV kinetics and sequences in sera and breast milk were studied. Clinical presentation and biological evolution in mother-newborn pairs were analyzed. Results: Ten mother-newborn pairs were investigated over an 11-month period. One premature birth, 3 hemorrhagic complications, and 1 maternal death occurred. Nine newborns were infected and symptomatic. One case of deep thrombocytopenia and 1 case of anoxic encephalopathy occurred. DENV was detected in breast milk samples from 9 (75%) of 12 infected breastfeeding mothers. Original DENV kinetics in sera and breast milk were described. Conclusions: The occurrence of vertical DENV transmission was high (90%) in viremic mothers at delivery, and these mothers and their infants were at major risk for obstetric and neonatal complications. The modes of viral transmission are difficult to clarify. The risk of DENV transmission through breast milk seems plausible. Close follow-up of mothers and prolonged surveillance of their newborns are required for minimizing complications. Complementary studies are needed to elaborate preventive recommendations. PMID- 27760800 TI - Sustained High Effectiveness of RotaTeq on Hospitalizations Attributable to Rotavirus-Associated Gastroenteritis During 4 Years in Finland. AB - Key points: The effectiveness of pentavalent rotavirus vaccine against rotavirus associated hospitalization was more than 90% 4 years after introduction into the national immunization program in Finland. A major impact on hospitalization for all-cause gastroenteritis was observed also. Background: Rotavirus vaccination with exclusive use of RotaTeq was added to the National Immunization Programme (NIP) of Finland in September 2009. The objective of our study was to estimate the effectiveness and impact of RotaTeq after 4 years of follow-up. Methods: Between 2009 and 2013, we conducted a prospective surveillance study of children aged <16 years with acute gastroenteritis (AGE) and admitted in 2 hospitals in Finland. Rotavirus and other gastroenteritis viruses were detected in stool samples by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assays. The effectiveness of RotaTeq was investigated by using a case-control design; wild-type rotavirus-positive children were classified as "cases" and rotavirus-negative children as "controls." Hospital discharge records were used to estimate the impact of RotaTeq on rotavirus associated AGE (RV-AGE) and all-cause AGE (AC-AGE) hospitalizations of age eligible children in the NIP by comparing the prevaccination (2001-2006) and post NIP seasons (2009-2013). Results: The crude estimate of the effectiveness of RotaTeq to prevent RV-AGE hospitalization in NIP age-eligible children was 94.4% (95% confidence interval, 79.8%-98.4%). No change in prevalent wild-type rotavirus genotypes was observed. Vaccine-derived rotaviruses were detected in 8% of the children with RV-AGE, with a probable causal association in 2 children. Hospital discharge records revealed that RV-AGE and AC-AGE hospitalizations in children aged <16 years decreased in the two post-NIP seasons by 79% and 58%, respectively, compared to those in the prevaccination seasons. Conclusions: Over 4 years of follow-up, high rotavirus vaccine coverage in the NIP (>95%) has led to a major reduction in RV-AGE and AC-AGE hospitalizations without a resurgence of rotavirus activity. However, rotavirus continues to circulate in older unvaccinated children. PMID- 27760802 TI - CD127 Expression in Naive and Memory T Cells in HIV Patients Who Have Undergone Long-Term HAART. AB - OBJECTIVE: To evaluate cluster of differentiation (CD)127 expression in T cells of patients with HIV-1 and the relationship of CD127 expression with disease progression. METHODS: We divided 139 patients infected with human immunodeficiency virus type 1 (HIV-1) who had undergone highly active antiretroviral therapy (HAART) into 3 groups: patients with poor recovery (CD4+T < 350/MU;L, patients with general recovery (CD4+T = 350 - ~600/MUL) and patients with good recovery (CD4+T > 600/MUL). Counts and percentages of naive (CD45RA+) and memory (CD45RO+) T cells and CD127 expression were determined using flow cytometry. RESULTS: CD4+CD45RO+, CD4+CD45RA+, CD4+ CD45RO+ CD127+, and CD4+CD45RA+CD127+T-cell counts in patients with good recovery were higher than in patients with poor recovery and those with general recovery patients (P <.05). Percentages of CD45RO+ were increased, and percentages of CD45RA+ and CD127 in T cells were decreased in patients with poor and general recovery (P <.05). CD127 values were positively correlated with CD4+T-cell counts and percentages of CD45RA+ subsets (P <.05). CONCLUSION: CD127 expression in T cells is decreased in patients with HIV-1 and is related to recovery of CD4+T-cell counts and to naive subsets. PMID- 27760801 TI - Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses. AB - Titanium dioxide nanoparticles (TiO2NPs) induce lung inflammation in experimental animals. In this study, we conducted a comprehensive toxicogenomic analysis of lung responses in mice exposed to six individual TiO2NPs exhibiting different sizes (8, 20 and 300nm), crystalline structure (anatase, rutile or anatase/rutile) and surface modifications (hydrophobic or hydrophilic) to investigate whether the mechanisms leading to TiO2NP-induced lung inflammation are property specific. A detailed histopathological analysis was conducted to investigate the long-term disease implications of acute exposure to TiO2NPs. C57BL/6 mice were exposed to 18, 54, 162 or 486 ug of TiO2NPs/mouse via single intratracheal instillation. Controls were exposed to dispersion medium only. Bronchoalveolar lavage fluid (BALF) and lung tissue were sampled on 1, 28 and 90 days post-exposure. Although all TiO2NPs induced lung inflammation as measured by the neutrophil influx in BALF, rutile-type TiO2NPs induced higher inflammation with the hydrophilic rutile TiO2NP showing the maximum increase. Accordingly, the rutile TiO2NPs induced higher number of differentially expressed genes. Histopathological analysis of lung sections on Day 90 post-exposure showed increased collagen staining and fibrosis-like changes following exposure to the rutile TiO2NPs at the highest dose tested. Among the anatase, the smallest TiO2NP of 8nm showed the maximum response. The anatase TiO2NP of 300nm was the least responsive of all. The results suggest that the severity of lung inflammation is property specific; however, the underlying mechanisms (genes and pathways perturbed) leading to inflammation were the same for all particle types. While the particle size clearly influenced the overall acute lung responses, a combination of small size, crystalline structure and hydrophilic surface contributed to the long-term pathological effects observed at the highest dose (486 ug/mouse). Although the dose at which the pathological changes were observed is considered physiologically high, the study highlights the disease potential of certain TiO2NPs of specific properties. PMID- 27760803 TI - Understanding the role of phosphorylation in the binding mechanism of a PDZ domain. AB - The PDZ domain is one of the most common protein-protein interaction domains in mammalian species. While several studies have demonstrated the importance of phosphorylation in interactions involving PDZ domains, there is a paucity of detailed mechanistic data addressing how the PDZ interaction is affected by phosphorylation. Here, we address this question by equilibrium and kinetic binding experiments using PDZ2 from protein tyrosine phosphatase L1 and its interaction with a peptide from the natural ligand RIL. The results show that phosphorylation of a serine residue in the RIL peptide has dual and opposing effects: it increases both the association and dissociation rate constants, which leads to an overall weakening of binding. Furthermore, we performed binding experiments with a RIL peptide in which the serine was replaced by a glutamate, a commonly used method to mimic phosphorylation in proteins. Strikingly, both the affinity and the ionic strength dependence of the affinity differed markedly for the phosphoserine and glutamate peptides. These results show that, in this particular case, glutamate is a poor mimic of serine phosphorylation. PMID- 27760806 TI - Short-term results of isolated phlebectomy with preservation of incompetent great saphenous vein (ASVAL procedure) in primary varicose veins disease. AB - Objective To establish an effect of isolated phlebectomy in patients with incompetent great saphenous vein (Ambulatory Selective Varices Ablation under Local anesthesia (ASVAL) procedure) on the reflux and diameter of the trunk and to assess recurrence rate of varicose veins at one year. Material and methods We conducted a prospective study on patients with primary varicose veins and with C2 or C2,3 or C2,3,4 or C2,4 classes of chronic venous disease and great saphenous vein incompetence. The study included 67 patients (51 women and 16 men; 75 limbs in total). Age varied from 17 to 71 years; mean age was 46.8 years (SD 13.9). We recorded the presence or absence of reflux in the great saphenous vein with duplex ultrasound before and after surgery. The recurrence of varicose veins was evaluated at 12 months. All the patients underwent isolated phlebectomy with preservation of incompetent great saphenous vein (ASVAL procedure) under local anesthesia. Results At one year after removing of tributaries of the incompetent trunk, 66% of them were competent. Reflux persisted in 17% of great saphenous veins with reflux above mid-thigh and in 61% of trunks with reflux extended below the mid-thigh (p = 0.0004). The diameter of all the veins decreased significantly no matter reflux disappeared or not. Varicose veins reoccurred in 13.5% cases. In 6.5% of limbs with a reflux above the mid-thigh, the recurrence was registered at one year, while in the limbs with the reflux below the mid-thigh at a baseline, the recurrence rate was 25% (p = 0.036). Conclusion Isolated phlebectomy with a preservation of incompetent great saphenous vein leads to disappearance of reflux in a majority of cases and to significant decrease of vein diameter in all the cases. ASVAL procedure could be considered as a less aggressive and less expensive approach in selected cases. Clear indications for isolated phlebectomy need to be established. PMID- 27760807 TI - Intercoder Reliability and Validity of WebPlotDigitizer in Extracting Graphed Data. AB - Quantitative synthesis of data from single-case designs (SCDs) is becoming increasingly common in psychology and education journals. Because researchers do not ordinarily report numerical data in addition to graphical displays, reliance on plot digitizing tools is often a necessary component of this research. Intercoder reliability of data extraction is a commonly overlooked, but potentially important, step of this process. The purpose of this study was to examine the intercoder reliability and validity of WebPlotDigitizer (Rohatgi, 2015), a web-based plot digitizing tool for extracting data from a variety of plots, including XY coordinates of interrupted time-series data. Two coders extracted 3,596 data points from 168 data series in 36 graphs across 18 studies. Results indicated high levels of intercoder reliability and validity. Implications of and recommendations based on these results are discussed in relation to researchers involved in quantitative synthesis of data from SCDs. PMID- 27760805 TI - The Minimum Open Reading Frame, AUG-Stop, Induces Boron-Dependent Ribosome Stalling and mRNA Degradation. AB - Upstream open reading frames (uORFs) are often translated ahead of the main ORF of a gene and regulate gene expression, sometimes in a condition-dependent manner, but such a role for the minimum uORF (hereafter referred to as AUG-stop) in living organisms is currently unclear. Here, we show that AUG-stop plays an important role in the boron (B)-dependent regulation of NIP5;1, encoding a boric acid channel required for normal growth under low B conditions in Arabidopsis thaliana High B enhanced ribosome stalling at AUG-stop, which was accompanied by the suppression of translation and mRNA degradation. This mRNA degradation was promoted by an upstream conserved sequence present near the 5'-edge of the stalled ribosome. Once ribosomes translate a uORF, reinitiation of translation must take place in order for the downstream ORF to be translated. Our results suggest that reinitiation of translation at the downstream NIP5;1 ORF is enhanced under low B conditions. A genome-wide analysis identified two additional B responsive genes, SKU5 and the transcription factor gene ABS/NGAL1, which were regulated by B-dependent ribosome stalling through AUG-stop. This regulation was reproduced in both plant and animal transient expression and cell-free translation systems. These findings suggest that B-dependent AUG-stop-mediated regulation is common in eukaryotes. PMID- 27760808 TI - Analysis of Behavioral Indicators as a Measure of Satiation. AB - Providing noncontingent access to a stimulus until an individual displays behavioral indicators of satiation has been used to determine when an abolishing operation is in effect, but there has been variation in its application in the literature. Four males diagnosed with autism spectrum disorder with tangibly maintained challenging behavior participated in this study. Individualized behavioral indicators were identified and verified to determine when each participant was finished playing with his/her preferred item. Three presession conditions were manipulated including restricted access to the tangible stimulus for 30 min, access to the tangible stimulus until the display of one behavioral indicator, and access to the tangible stimulus until the display of three behavioral indicators. Each presession condition was followed by a tangible condition of the functional analysis to measure challenging behavior. Results indicated that presession access to a tangible stimulus until the display of three behavioral indicators produced a greater abative effect on challenging behavior than one behavioral indicator. PMID- 27760804 TI - The Reverse Transcriptase/RNA Maturase Protein MatR Is Required for the Splicing of Various Group II Introns in Brassicaceae Mitochondria. AB - Group II introns are large catalytic RNAs that are ancestrally related to nuclear spliceosomal introns. Sequences corresponding to group II RNAs are found in many prokaryotes and are particularly prevalent within plants organellar genomes. Proteins encoded within the introns themselves (maturases) facilitate the splicing of their own host pre-RNAs. Mitochondrial introns in plants have diverged considerably in sequence and have lost their maturases. In angiosperms, only a single maturase has been retained in the mitochondrial DNA: the matR gene found within NADH dehydrogenase 1 (nad1) intron 4. Its conservation across land plants and RNA editing events, which restore conserved amino acids, indicates that matR encodes a functional protein. However, the biological role of MatR remains unclear. Here, we performed an in vivo investigation of the roles of MatR in Brassicaceae. Directed knockdown of matR expression via synthetically designed ribozymes altered the processing of various introns, including nad1 i4. Pull-down experiments further indicated that MatR is associated with nad1 i4 and several other intron-containing pre-mRNAs. MatR may thus represent an intermediate link in the gradual evolutionary transition from the intron-specific maturases in bacteria into their versatile spliceosomal descendants in the nucleus. The similarity between maturases and the core spliceosomal Prp8 protein further supports this intriguing theory. PMID- 27760809 TI - Active haematological manifestations of systemic lupus erythematosus lupus are associated with a high rate of in-hospital mortality. AB - The aim of this study was to estimate the impact of the haematological manifestations of systemic lupus erythematosus (SLE) on mortality in hospitalized patients. For that purpose a case-control study of hospitalized patients in a medical referral centre from January 2009 to December 2014 was performed. For analysis, patients hospitalized for any haematological activity of SLE ( n = 103) were compared with patients hospitalized for other manifestations of SLE activity or complications of treatment ( n = 206). Taking as a variable outcome hospital death, an analysis of potential associated factors was performed. The most common haematological manifestation was thrombocytopenia (63.1%), followed by haemolytic anaemia (30%) and neutropenia (25.2%). In the group of haematological manifestations, 17 (16.5%) deaths were observed compared to 10 (4.8%) deaths in the control group ( P < 0.001). The causes of death were similar in both groups. In the analysis of the variables, it was found that only haematological manifestations were associated with intra-hospital death (odds ratio 3.87, 95% confidence interval 1.8-88, P < 0.001). Our study suggests that apparently any manifestation of haematological activity of SLE is associated with poor prognosis and contributes to increased hospital mortality. PMID- 27760810 TI - Promotoras and the Semantic Gap Between Latino Community Health Researchers and Latino Communities. AB - Promotoras are identified as a unique group of community health workers adept at reducing health disparities. This qualitative study was conducted to better understand perceptions of the term promotora, broadly used in research but not well documented in everyday Latina vocabulary. Six focus groups to better understand perceptions of the term promotora were conducted with 36 Latina women living in three nonmetropolitan areas in Illinois. Results suggest that Latina participants in the study do not understand the meaning of "promotora" in the same way as it is used in the literature. Latina participants understood "promotoras" as referring to people who sell or deliver information, or organize events in the community that are not necessarily related to health events or community health work. Furthermore, they usually understood the term to refer to paid work rather than volunteering. Results underscore the importance of being sensitive to Latinas' perceptions of community health terminology by assessing their context, needs, and expectations. These findings call researchers' attention to the need to educate certain Latino communities about the concept of promotoras, with implications for the implementation and dissemination of promotora-led community health programs, as the semantic discrepancy could affect the recruitment of promotoras as well as community participation in the programs they deliver. PMID- 27760811 TI - Cost savings analysis and toxicity audit of a bevacizumab dose rounding policy at a community cancer center. AB - Purpose To evaluate the potential cost savings incurred from a policy to round doses of bevacizumab to the nearest vial size. Secondarily, to determine differences in rates of adverse events between patients who had their doses rounded up compared with those who had doses rounded down. Methods This study is a retrospective chart review of all patients who received at least one rounded dose of bevacizumab over a period of 22 months. Doses of bevacizumab were calculated based on actual body weight. The calculated dose was then rounded to the nearest 400 or 100 mg vial size. The predicted effect on cost was calculated in US dollars for both the pre-rounded dose and the rounded dose. Adverse events including hypertension, proteinuria, and vascular events were compared between those that received a dose that was rounded up and those with a dose rounded down. Results A total of 55 patients received at least one dose bevacizumab between 1 August 2014 and 31 May 2016. A total of 470 doses were administered. The estimated cost savings by rounding bevacizumab doses to the nearest 100 mg during the study time period was $164,617.92. Patients receiving either a dose that was rounded up or rounded down to the nearest 100 mg experienced similar rates of adverse events. Conclusion Dose rounding of bevacizumab to the nearest vial size resulted in significant cost savings and did not significantly impact the incidence of adverse events. PMID- 27760812 TI - Analysis of Risk Factors for Early Type I Endoleaks After Thoracic Endovascular Aneurysm Repair. AB - PURPOSE: To evaluate risk factors for early (<30 days) type I endoleak following thoracic endovascular aortic repair (TEVAR). METHODS: A retrospective study was conducted of 439 consecutive patients (mean age 74.0+/-10.0 years; 333 men) who underwent TEVAR at a single center between June 2006 and June 2013. Pathologies included 237 aortic arch aneurysms and 202 descending thoracic aortic aneurysms (dTAA). Maximum TAA diameter was 63.6+/-13.7 mm. Among the distal aortic arch aneurysms, 124 required coverage of the left subclavian artery (LSA), while the remaining 113 arch aneurysms had debranching (n=40), the chimney technique (n=52), and a branched stent-graft (n=13). Eight patients with dilatation of the ascending aorta underwent arch replacement with elephant trunk prior to TEVAR. Predictive factors for type I endoleak were explored in univariate analysis and examined for each outcome using logistic regression models; results are given as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Among 439 TEVAR cases, 37 (8.4%) had type I endoleaks on imaging at 1 month; 31 were in the 237 arch cases (13.1%). Endoleak investigation by site indicated a low incidence (3.0%) for dTAAs and markedly low (1.4%) in zone 4. Significantly more endoleaks were observed in zones 0-2 than in zone 4 (p<0.001). On univariate analysis, significant associations were found between endoleak and LSA coverage (OR 5.8, 95% CI 2.4 to 14.4, p<0.001), operative time >=240 minutes (OR 3.7, 95% CI 1.5 to 6.2, p=0.002), and >=270 mL of contrast (OR 2.8, 95% CI 1.4 to 5.8, p=0.004). Among the aortic branch reconstruction procedures, the chimney technique was the only maneuver associated with a significant risk of endoleak (OR 5.3, 95% CI 2.3 to 11.2, p<0.001). Arch state was not correlated with endoleaks, but >=38-mm proximal neck diameter (OR 3.6, 95% CI 1.2 to 10.8, p=0.023), stent-graft diameter >=40 mm (OR 9.9, 95% CI 1.4 to 30.5, p=0.015), and excessively oversized (>=14%) stent-grafts (OR 3.5, 95% CI 1.2 to 10.3, p=0.020) were; the proximal neck length was not correlated with endoleaks if a proximal neck length >10 mm can be secured. CONCLUSION: Risks for early type I endoleaks after TEVAR for aneurysm were landing zone 0-2, LSA coverage, large proximal neck and stent-graft diameters, excessive oversizing, and the use of the chimney technique. PMID- 27760813 TI - Foot placement relies on state estimation during visually guided walking. AB - : As we walk, we must accurately place our feet to stabilize our motion and to navigate our environment. We must also achieve this accuracy despite imperfect sensory feedback and unexpected disturbances. In this study we tested whether the nervous system uses state estimation to beneficially combine sensory feedback with forward model predictions to compensate for these challenges. Specifically, subjects wore prism lenses during a visually guided walking task, and we used trial-by-trial variation in prism lenses to add uncertainty to visual feedback and induce a reweighting of this input. To expose altered weighting, we added a consistent prism shift that required subjects to adapt their estimate of the visuomotor mapping relationship between a perceived target location and the motor command necessary to step to that position. With added prism noise, subjects responded to the consistent prism shift with smaller initial foot placement error but took longer to adapt, compatible with our mathematical model of the walking task that leverages state estimation to compensate for noise. Much like when we perform voluntary and discrete movements with our arms, it appears our nervous systems uses state estimation during walking to accurately reach our foot to the ground. NEW & NOTEWORTHY: Accurate foot placement is essential for safe walking. We used computational models and human walking experiments to test how our nervous system achieves this accuracy. We find that our control of foot placement beneficially combines sensory feedback with internal forward model predictions to accurately estimate the body's state. Our results match recent computational neuroscience findings for reaching movements, suggesting that state estimation is a general mechanism of human motor control. PMID- 27760815 TI - Beat-to-beat control of human optokinetic nystagmus slow phase durations. AB - : This study provides the first clear evidence that the generation of optokinetic nystagmus fast phases (FPs) is a decision process that is influenced by performance of a concurrent disjunctive reaction time task (DRT). Ten subjects performed an auditory DRT during constant velocity optokinetic stimulation. Eye movements were measured in three dimensions with a magnetic search coil. Slow phase (SP) durations were defined as the interval between FPs. There were three main findings. Firstly, human optokinetic nystagmus SP durations are consistent with a model of a Gaussian basic interval generator (a type of biological clock), such that FPs can be triggered randomly at the end of a clock cycle (mean duration: 200-250 ms). Kolmogorov-Smirnov tests could not reject the modeled cumulative distribution for any data trials. Secondly, the FP need not be triggered at the end of a clock cycle, so that individual SP durations represent single or multiple clock cycles. Thirdly, the probability of generating a FP at the end of each interval generator cycle decreases significantly during performance of a DRT. These findings indicate that the alternation between SPs and FPs of optokinetic nystagmus is not purely reflexive. Rather, the triggering of the next FP is postponed more frequently if a recently presented DRT trial is pending action when the timing cycle expires. Hence, optokinetic nystagmus FPs show dual-task interference in a manner usually attributed to voluntary movements, including saccades. NEW & NOTEWORTHY: This study provides the first clear evidence that the generation of optokinetic nystagmus (OKN) fast phases is a decision process that is influenced by performance of a concurrent disjunctive reaction time task (DRT). The slow phase (SP) durations are consistent with a Gaussian basic interval generator and multiple interval SP durations occur more frequently in the presence of the DRT. Hence, OKN shows dual-task interference in a manner observed in voluntary movements, such as saccades. PMID- 27760814 TI - Independent coding of absolute duration and distance magnitudes in the prefrontal cortex. AB - : The estimation of space and time can interfere with each other, and neuroimaging studies have shown overlapping activation in the parietal and prefrontal cortical areas. We used duration and distance discrimination tasks to determine whether space and time share resources in prefrontal cortex (PF) neurons. Monkeys were required to report which of two stimuli, a red circle or blue square, presented sequentially, were longer and farther, respectively, in the duration and distance tasks. In a previous study, we showed that relative duration and distance are coded by different populations of neurons and that the only common representation is related to goal coding. Here, we examined the coding of absolute duration and distance. Our results support a model of independent coding of absolute duration and distance metrics by demonstrating that not only relative magnitude but also absolute magnitude are independently coded in the PF. NEW & NOTEWORTHY: Human behavioral studies have shown that spatial and duration judgments can interfere with each other. We investigated the neural representation of such magnitudes in the prefrontal cortex. We found that the two magnitudes are independently coded by prefrontal neurons. We suggest that the interference among magnitude judgments might depend on the goal rather than the perceptual resource sharing. PMID- 27760816 TI - Thalamic state control of cortical paired-pulse dynamics. AB - : Sensory stimulation drives complex interactions across neural circuits as information is encoded and then transmitted from one brain region to the next. In the highly interconnected thalamocortical circuit, these complex interactions elicit repeatable neural dynamics in response to temporal patterns of stimuli that provide insight into the circuit properties that generated them. Here, using a combination of in vivo voltage-sensitive dye (VSD) imaging of cortex, single unit recording in thalamus, and optogenetics to manipulate thalamic state in the rodent vibrissa pathway, we probed the thalamocortical circuit with simple temporal patterns of stimuli delivered either to the whiskers on the face (sensory stimulation) or to the thalamus directly via electrical or optogenetic inputs (artificial stimulation). VSD imaging of cortex in response to whisker stimulation revealed classical suppressive dynamics, while artificial stimulation of thalamus produced an additional facilitation dynamic in cortex not observed with sensory stimulation. Thalamic neurons showed enhanced bursting activity in response to artificial stimulation, suggesting that bursting dynamics may underlie the facilitation mechanism we observed in cortex. To test this experimentally, we directly depolarized the thalamus, using optogenetic modulation of the firing activity to shift from a burst to a tonic mode. In the optogenetically depolarized thalamic state, the cortical facilitation dynamic was completely abolished. Together, the results obtained here from simple probes suggest that thalamic state, and ultimately thalamic bursting, may play a key role in shaping more complex stimulus-evoked dynamics in the thalamocortical pathway. NEW & NOTEWORTHY: For the first time, we have been able to utilize optogenetic modulation of thalamic firing modes combined with optical imaging of cortex in the rat vibrissa system to directly test the role of thalamic state in shaping cortical response properties. PMID- 27760817 TI - Effects of ion channel noise on neural circuits: an application to the respiratory pattern generator to investigate breathing variability. AB - : Neural activity generally displays irregular firing patterns even in circuits with apparently regular outputs, such as motor pattern generators, in which the output frequency fluctuates randomly around a mean value. This "circuit noise" is inherited from the random firing of single neurons, which emerges from stochastic ion channel gating (channel noise), spontaneous neurotransmitter release, and its diffusion and binding to synaptic receptors. Here we demonstrate how to expand conductance-based network models that are originally deterministic to include realistic, physiological noise, focusing on stochastic ion channel gating. We illustrate this procedure with a well-established conductance-based model of the respiratory pattern generator, which allows us to investigate how channel noise affects neural dynamics at the circuit level and, in particular, to understand the relationship between the respiratory pattern and its breath-to-breath variability. We show that as the channel number increases, the duration of inspiration and expiration varies, and so does the coefficient of variation of the breath-to-breath interval, which attains a minimum when the mean duration of expiration slightly exceeds that of inspiration. For small channel numbers, the variability of the expiratory phase dominates over that of the inspiratory phase, and vice versa for large channel numbers. Among the four different cell types in the respiratory pattern generator, pacemaker cells exhibit the highest sensitivity to channel noise. The model shows that suppressing input from the pons leads to longer inspiratory phases, a reduction in breathing frequency, and larger breath-to-breath variability, whereas enhanced input from the raphe nucleus increases breathing frequency without changing its pattern. NEW & NOTEWORTHY: A major source of noise in neuronal circuits is the "flickering" of ion currents passing through the neurons' membranes (channel noise), which cannot be suppressed experimentally. Computational simulations are therefore the best way to investigate the effects of this physiological noise by manipulating its level at will. We investigate the role of noise in the respiratory pattern generator and show that endogenous, breath-to-breath variability is tightly linked to the respiratory pattern. PMID- 27760818 TI - Descending propriospinal neurons mediate restoration of locomotor function following spinal cord injury. AB - : Following spinal cord injury (SCI) in the lamprey, there is virtually complete recovery of locomotion within a few weeks, but interestingly, axonal regeneration of reticulospinal (RS) neurons is mostly limited to short distances caudal to the injury site. To explain this situation, we hypothesize that descending propriospinal (PS) neurons relay descending drive from RS neurons to indirectly activate spinal central pattern generators (CPGs). In the present study, the contributions of PS neurons to locomotor recovery were tested in the lamprey following SCI. First, long RS neuron projections were interrupted by staggered spinal hemitransections on the right side at 10% body length (BL; normalized from the tip of the oral hood) and on the left side at 30% BL. For acute recovery conditions (<=1 wk) and before axonal regeneration, swimming muscle burst activity was relatively normal, but with some deficits in coordination. Second, lampreys received two spaced complete spinal transections, one at 10% BL and one at 30% BL, to interrupt long-axon RS neuron projections. At short recovery times (3-5 wk), RS and PS neurons will have regenerated their axons for short distances and potentially established a polysynaptic descending command pathway. At these short recovery times, swimming muscle burst activity had only minor coordination deficits. A computer model that incorporated either of the two spinal lesions could mimic many aspects of the experimental data. In conclusion, descending PS neurons are a viable mechanism for indirect activation of spinal locomotor CPGs, although there can be coordination deficits of locomotor activity. NEW & NOTEWORTHY: In the lamprey following spinal lesion-mediated interruption of long axonal projections of reticulospinal (RS) neurons, sensory stimulation still elicited relatively normal locomotor muscle burst activity, but with some coordination deficits. Computer models incorporating the spinal lesions could mimic many aspects of the experimental results. Thus, after disruption of long axon projections from RS neurons in the lamprey, descending propriospinal (PS) neurons appear to be a viable compensatory mechanism for indirect activation of spinal locomotor networks. PMID- 27760820 TI - Vestibular implants studied in animal models: clinical and scientific implications. AB - Damage to the peripheral vestibular system can result in debilitating postural, perceptual, and visual symptoms. A potential new treatment for this clinical problem is to replace some aspects of peripheral vestibular function with an implant that senses head motion and provides this information to the brain by stimulating branches of the vestibular nerve. In this review I consider animal studies performed at our institution over the past 15 years, which have helped elucidate how the brain processes information provided by a vestibular (semicircular canal) implant and how this information could be used to improve the problems experienced by patients with peripheral vestibular damage. PMID- 27760821 TI - Does the sensorimotor system minimize prediction error or select the most likely prediction during object lifting? AB - : The human sensorimotor system is routinely capable of making accurate predictions about an object's weight, which allows for energetically efficient lifts and prevents objects from being dropped. Often, however, poor predictions arise when the weight of an object can vary and sensory cues about object weight are sparse (e.g., picking up an opaque water bottle). The question arises, what strategies does the sensorimotor system use to make weight predictions when one is dealing with an object whose weight may vary? For example, does the sensorimotor system use a strategy that minimizes prediction error (minimal squared error) or one that selects the weight that is most likely to be correct (maximum a posteriori)? In this study we dissociated the predictions of these two strategies by having participants lift an object whose weight varied according to a skewed probability distribution. We found, using a small range of weight uncertainty, that four indexes of sensorimotor prediction (grip force rate, grip force, load force rate, and load force) were consistent with a feedforward strategy that minimizes the square of prediction errors. These findings match research in the visuomotor system, suggesting parallels in underlying processes. We interpret our findings within a Bayesian framework and discuss the potential benefits of using a minimal squared error strategy. NEW & NOTEWORTHY: Using a novel experimental model of object lifting, we tested whether the sensorimotor system models the weight of objects by minimizing lifting errors or by selecting the statistically most likely weight. We found that the sensorimotor system minimizes the square of prediction errors for object lifting. This parallels the results of studies that investigated visually guided reaching, suggesting an overlap in the underlying mechanisms between tasks that involve different sensory systems. PMID- 27760819 TI - Optimizing computer models of corticospinal neurons to replicate in vitro dynamics. AB - : Corticospinal neurons (SPI), thick-tufted pyramidal neurons in motor cortex layer 5B that project caudally via the medullary pyramids, display distinct class specific electrophysiological properties in vitro: strong sag with hyperpolarization, lack of adaptation, and a nearly linear frequency-current (F I) relationship. We used our electrophysiological data to produce a pair of large archives of SPI neuron computer models in two model classes: 1) detailed models with full reconstruction; and 2) simplified models with six compartments. We used a PRAXIS and an evolutionary multiobjective optimization (EMO) in sequence to determine ion channel conductances. EMO selected good models from each of the two model classes to form the two model archives. Archived models showed tradeoffs across fitness functions. For example, parameters that produced excellent F-I fit produced a less-optimal fit for interspike voltage trajectory. Because of these tradeoffs, there was no single best model but rather models that would be best for particular usages for either single neuron or network explorations. Further exploration of exemplar models with strong F-I fit demonstrated that both the detailed and simple models produced excellent matches to the experimental data. Although dendritic ion identities and densities cannot yet be fully determined experimentally, we explored the consequences of a demonstrated proximal to distal density gradient of Ih, demonstrating that this would lead to a gradient of resonance properties with increased resonant frequencies more distally. We suggest that this dynamical feature could serve to make the cell particularly responsive to major frequency bands that differ by cortical layer. NEW & NOTEWORTHY: We developed models of motor cortex corticospinal neurons that replicate in vitro dynamics, including hyperpolarization-induced sag and realistic firing patterns. Models demonstrated resonance in response to synaptic stimulation, with resonance frequency increasing in apical dendrites with increasing distance from soma, matching the increasing oscillation frequencies spanning deep to superficial cortical layers. This gradient may enable specific corticospinal neuron dendrites to entrain to relevant oscillations in different cortical layers, contributing to appropriate motor output commands. PMID- 27760822 TI - Rhythm generation, coordination, and initiation in the vocal pathways of male African clawed frogs. AB - : Central pattern generators (CPGs) in the brain stem are considered to underlie vocalizations in many vertebrate species, but the detailed mechanisms underlying how motor rhythms are generated, coordinated, and initiated remain unclear. We addressed these issues using isolated brain preparations of Xenopus laevis from which fictive vocalizations can be elicited. Advertisement calls of male X. laevis that consist of fast and slow trills are generated by vocal CPGs contained in the brain stem. Brain stem central vocal pathways consist of a premotor nucleus [dorsal tegmental area of medulla (DTAM)] and a laryngeal motor nucleus [a homologue of nucleus ambiguus (n.IX-X)] with extensive reciprocal connections between the nuclei. In addition, DTAM receives descending inputs from the extended amygdala. We found that unilateral transection of the projections between DTAM and n.IX-X eliminated premotor fictive fast trill patterns but did not affect fictive slow trills, suggesting that the fast and slow trill CPGs are distinct; the slow trill CPG is contained in n.IX-X, and the fast trill CPG spans DTAM and n.IX-X. Midline transections that eliminated the anterior, posterior, or both commissures caused no change in the temporal structure of fictive calls, but bilateral synchrony was lost, indicating that the vocal CPGs are contained in the lateral halves of the brain stem and that the commissures synchronize the two oscillators. Furthermore, the elimination of the inputs from extended amygdala to DTAM, in addition to the anterior commissure, resulted in autonomous initiation of fictive fast but not slow trills by each hemibrain stem, indicating that the extended amygdala provides a bilateral signal to initiate fast trills. NEW & NOTEWORTHY: Central pattern generators (CPGs) are considered to underlie vocalizations in many vertebrate species, but the detailed mechanisms underlying their functions remain unclear. We addressed this question using an isolated brain preparation of African clawed frogs. We discovered that two vocal phases are mediated by anatomically distinct CPGs, that there are a pair of CPGs contained in the left and right half of the brain stem, and that mechanisms underlying initiation of the two vocal phases are distinct. PMID- 27760824 TI - RNA Interference Directed against the Transglutaminase Gene Triggers Dysbiosis of Gut Microbiota in Drosophila. AB - We recently reported that transglutaminase (TG) suppresses immune deficiency pathway-controlled antimicrobial peptides (IMD-AMPs), thereby conferring immune tolerance to gut microbes, and that RNAi of the TG gene in flies decreases the lifespan compared with non-TG-RNAi flies. Here, analysis of the bacterial composition of the Drosophila gut by next-generation sequencing revealed that gut microbiota comprising one dominant genus of Acetobacter in non-TG-RNAi flies was shifted to that comprising two dominant genera of Acetobacter and Providencia in TG-RNAi flies. Four bacterial strains, including Acetobacter persici SK1 and Acetobacter indonesiensis SK2, Lactobacillus pentosus SK3, and Providencia rettgeri SK4, were isolated from the midgut of TG-RNAi flies. SK1 exhibited the highest resistance to the IMD-AMPs Cecropin A1 and Diptericin among the isolated bacteria. In contrast, SK4 exhibited considerably lower resistance against Cecropin A1, whereas SK4 exhibited high resistance to hypochlorous acid. The resistance of strains SK1-4 against IMD-AMPs in in vitro assays could not explain the shift of the microbiota in the gut of TG-RNAi flies. The lifespan was reduced in gnotobiotic flies that ingested both SK4 and SK1, concomitant with the production of reactive oxygen species and apoptosis in the midgut, whereas the survival rate was not altered in gnotobiotic flies that mono-ingested either SK4 or SK1. Interestingly, significant amounts of reactive oxygen species were detected in the midgut of gnotobiotic flies that ingested SK4 and SK2, concomitant with no significant apoptosis in the midgut. In gnotobiotic flies that co-ingested SK4 and SK1, an additional unknown factor(s) may be required to cause midgut apoptosis. PMID- 27760823 TI - Modulation of activity and conduction in single dorsal column axons by kilohertz frequency spinal cord stimulation. AB - : Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a potential paresthesia-free treatment for chronic pain. However, the effects of KHF-SCS on spinal dorsal column (DC) axons and its mechanisms of action remain unknown. The objectives of this study were to quantify activation and conduction block of DC axons by KHF-SCS across a range of frequencies (1, 5, 10, or 20 kHz) and waveforms (biphasic pulses or sinusoids). Custom platinum electrodes delivered SCS to the T10/T11 dorsal columns of anesthetized male Sprague-Dawley rats. Single DC axons and compound action potentials were recorded during KHF-SCS to evaluate SCS-evoked activity. Responses to KHF-SCS in DC axons included brief onset firing, slowly accommodating asynchronous firing, and conduction block. The effects of KHF-SCS mostly occurred well above motor thresholds, but isolated units were activated at amplitudes shown to reduce behavioral sensitivity in rats. Activity evoked by SCS was similar across a range of frequencies (5-20 kHz) and waveforms (biphasic and sinusoidal). Stimulation at 1-kHz SCS evoked more axonal firing that was also more phase-synchronized to the SCS waveform, but only at amplitudes above motor threshold. These data quantitatively characterize the central nervous system activity that may modulate pain perception and paresthesia, and thereby provide a foundation for continued investigation of the mechanisms of KHF-SCS and its optimization as a therapy for chronic pain. Given the asynchronous and transient nature of DC activity, it is unlikely that the same mechanisms underlying conventional SCS (i.e., persistent, periodic DC activation) apply to KHF-SCS. NEW & NOTEWORTHY: Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a new mode of SCS that may offer better pain relief than conventional SCS. However, the mechanism of action is poorly characterized, especially the effects of stimulation on dorsal column (DC) axons, which are the primary target of stimulation. This study provides the first recordings of single DC axons during KHF-SCS to quantify DC activity that has the potential to mediate the analgesic effects of KHF-SCS. PMID- 27760828 TI - How the Non-Work Environment Can Affect Worker and Family Health. AB - Occupational health nurses are familiar with environmental exposures workers encounter in their workplaces. However, employees are only "on-the-job" about one third of each workday, with a multitude of potential exposures in other environments that can affect their health. This article addresses some of the major exposures employees encounter outside the workplace-air, water, and soil pollution, and hazardous wastes-including a discussion of several well-known national and international environmental incidents. The major sources of these pollutants and how they contaminate the environment were investigated. Finally, risk assessment and communication along with effective strategies for educating employees and the community are presented. PMID- 27760827 TI - In Vivo and in Vitro Synthesis of Phosphatidylglycerol by an Escherichia coli Cardiolipin Synthase. AB - Phosphatidylglycerol (PG) makes up 5-20% of the phospholipids of Escherichia coli and is essential for growth in wild-type cells. PG is synthesized from the dephosphorylation of its immediate precursor, phosphatidylglycerol phosphate (PGP) whose synthase in E. coli is PgsA. Using genetic, biochemical, and highly sensitive mass spectrometric approaches, we identified an alternative mechanism for PG synthesis in E. coli that is PgsA independent. The reaction of synthesis involves the conversion of phosphatidylethanolamine and glycerol into PG and is catalyzed by ClsB, a phospholipase D-type cardiolipin synthase. This enzymatic reaction is demonstrated herein both in vivo and in vitro as well as by using the purified ClsB protein. When the growth medium was supplemented with glycerol, the expression of E. coli ClsB significantly increased PG and cardiolipin levels, with the growth deficiency of pgsA null strain also being complemented under such conditions. Identification of this alternative mechanism for PG synthesis not only expands our knowledge of bacterial anionic phospholipid biosynthesis, but also sheds light on the biochemical functions of the cls gene redundancy in E. coli and other bacteria. Finally, the PGP-independent PG synthesis in E. coli may also have important implications for the understanding of PG biosynthesis in eukaryotes that remains incomplete. PMID- 27760825 TI - Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis. AB - Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumorigenesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63+ and CK5+ basal/progenitor cell population, induced by the concomitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo The differentiation process led to suppression of p63-expressing cells with a decreased number of CK5+ basal cells but an increase of CK8+ luminal tumorigenic cells and revealed a hierarchal lineage pattern consisting of p63+/CK5+ progenitor, CK5+/CK8+ transitional progenitor, and CK8+ differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli transcription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63+ and CK5+ basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited different functions in the regulation of p63 expression or proliferation of p63+ cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of targeting prostate cancer progression by inhibiting Gli signaling. PMID- 27760829 TI - Synergistic effect of anidulafungin combined with posaconazole in experimental aspergillosis. AB - Clinical and experimental data have shown discrepancies on the efficacy of combinations between triazoles and echinocandins. In this study, anidulafungin plus posaconazole have shown efficacy against a murine systemic infection by three strains of Aspergillus fumigatus. The combination increased mice survival and reduced burden in the kidneys over the corresponding monotherapies and voriconazole. Clearance of kidneys was observed in 62% to 100% of animals (strain dependant). We observed good in vitro- in vivo correlation when a cutoff < 1 was indicative of synergy. Our results showed that the combination could be a therapeutical option, especially against infections refractory to the first line therapy. PMID- 27760826 TI - Pleckstrin Homology (PH) Domain Leucine-rich Repeat Protein Phosphatase Controls Cell Polarity by Negatively Regulating the Activity of Atypical Protein Kinase C. AB - The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures as indicated by the formation of aberrant multi-lumen structures. Overexpression of PHLPP resulted in a decrease in aPKC phosphorylation at both the activation loop and the turn motif sites; conversely, knockdown of PHLPP increased aPKC phosphorylation. Moreover, in vitro dephosphorylation experiments revealed that both aPKC isoforms were substrates of PHLPP. Interestingly, knockdown of PKCzeta, but not PKCiota, led to similar disruption of the polarized lumen structure, suggesting that PKCzeta likely controls the polarization process of Caco2 cells. Furthermore, knockdown of PHLPP altered the apical membrane localization of aPKCs and reduced the formation of aPKC-Par3 complex. Taken together, our results identify a novel role of PHLPP in regulating aPKC and cell polarity. PMID- 27760830 TI - Modeling dermatophytosis in reconstructed human epidermis: A new tool to study infection mechanisms and to test antifungal agents. AB - Dermatophytosis is a superficial fungal infection of keratinized structures that exhibits an increasing prevalence in humans and is thus requesting novel prophylactic strategies and therapies. However, precise mechanisms used by dermatophytes to adhere at the surface of the human epidermis and invade its stratum corneum are still incompletely identified, as well as the responses provided by the underlying living keratinocytes during the infection. We hereby report development of an in vitro model of human dermatophytosis through infection of reconstructed human epidermis (RHE) by arthroconidia of the anthropophilic Trichophyton rubrum species or of the zoophilic Microsporum canis and Arthroderma benhamiae species. By modulating density of arthroconidia in the inoculum and duration of exposure to such pathogens, fungal infection limited to the stratum corneum was obtained, mimicking severe but typical in vivo situation. Fungal elements in infected RHE were monitored over time by histochemical analysis using periodic-acid Schiff-staining or quantified by qPCR-detection of fungal genes inside RHE lysates. This model brings improvements to available ones, dedicated to better understand how dermatophytes and epidermis interact, as well as to evaluate preventive and therapeutic agents. Indeed, miconazole topically added to RHE was demonstrated to inhibit fungal infection in this model. PMID- 27760831 TI - Identification of the causative dermatophyte of tinea capitis in children attending Mbarara Regional Referral Hospital in Uganda by PCR-ELISA and comparison with conventional mycological diagnostic methods. AB - Tinea capitis is a dermatophyte infection common among prepubertal children in sub-Saharan Africa and mainly caused by Trichophyton and Microsporum species. Accurate identification is challenging as conventional methods like culture and microscopy are slow and mostly based on morphological characteristics, which make them less sensitive and specific. Modern molecular methods, like polymerase chain reaction (PCR) assays, are gaining acceptance and are quick as well as accurate. The aim of this study was to investigate the clinical patterns of tinea capitis and to accurately identify the most common causative dermatophytes affecting the scalps of children aged 1 to 16 years attending the Skin Clinic at Mbarara University of Science and Technology (MUST), Mbarara, Uganda, East Africa, using both conventional mycological methods and PCR-ELISA for detection of dermatophyte DNA. One hundred fifteen clinical samples from children from Western Uganda attending the MUST Skin Clinic with a clinical diagnosis of tinea capitis were analyzed. T. violaceum was identified as the most common causative agent, followed by M. audouinii, T. soudanense, and T. rubrum. The early identification of the causative agent of tinea capitis is a prerequisite for the effective management of the disease, the identification of probable source and the prevention of spreading. Children with tinea capitis in Western Uganda should be treated by systemic therapy rather than topical preparations to ensure high cure rates as the most common causative dermatophytes T. violaceum exhibits an endothrix rather than ectothrix invasion of the hair follicle. PMID- 27760833 TI - Statin Effect on Platelet to Lymphocyte Ratio. PMID- 27760832 TI - An outcomes-based grading scale for the evaluation of cerebral aneurysms treated with flow diversion. AB - OBJECT: Despite the popularity of flow-diverting stents for the treatment of cerebral aneurysms, there is no widely accepted scale for the characterization of results. We present an outcomes-based grading scale that considers factors related to failure of flow diversion. METHODS: The grading scale was developed using the results from consecutive patients at two institutions who were treated with flow diversion for a cerebral aneurysm. The initial treatment results were graded on patient, aneurysm, and treatment characteristics. A 6-point grading scale was developed based on these data. RESULTS: One hundred and seventy-one patients were included in the patient cohort. When compared by multivariate analysis with patients without residuals, patients with aneurysm residuals were found to be older (age >=60 years, p=0.01, OR 1.17, 95% CI 1.03 to 1.33), to have larger aneurysms (size >=15 mm, p<0.01, OR 1.38, 95% CI 1.17 to 1.62), to have aneurysms with associated side branches (p=0.02, OR 1.17, 95% CI 1.03 to 1.33), and to have a post-treatment Raymond score of 2 or 3 (p=0.01, OR 1.28, 95% CI 1.06 to 1.56). Using the Raymond score (1-3) as the foundation for the grading scale, additional points (0 or 1) were given for the other three identified factors, creating a 6-point scale. We found that patients with residual aneurysms had statistically higher final tabulated scores (p<0.01). CONCLUSIONS: We propose a novel straightforward outcomes-based scale to characterize results after flow diversion treatment of cerebral aneurysms. This scale may provide the basis for the common reporting of results in future studies. PMID- 27760834 TI - Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer. AB - Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase specific replication-competent adenovirus (TRAD), which carries the tumor specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing short-hairpin RNA against Dicer (shDicer; TRAD shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity. Mol Cancer Ther; 16(1); 251 9. (c)2016 AACR. PMID- 27760835 TI - N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation. AB - RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers. Mol Cancer Ther; 16(1); 57-67. (c)2016 AACR. PMID- 27760836 TI - Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET. AB - Antibody-drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3*2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis of mesothelin expression was performed using immunohistochemistry. AMA-MMAE showed the greatest growth inhibition in OVCAR-3*2.1, Capan-2, and HPAC tumors, which showed target-specific tumor uptake of 89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show 89Zr-AMA uptake despite confirmed mesothelin expression. ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer Ther; 16(1); 134 42. (c)2016 AACR. PMID- 27760837 TI - 6alpha-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells. AB - The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6alpha-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA-treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared with the anticancer drug vinblastine, which included pathways involved in mitosis, microtubule spindle organization, and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced cellular microtubule polymer mass. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids (vinblastine/vincristine) or 2-methoxyestradiol did not confer resistance to 6-AA, suggesting a different mechanism of microtubule interaction. 6-AA is a first-in-class microtubule inhibitor that features the unique anopterine scaffold. This study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease. Mol Cancer Ther; 16(1); 3-15. (c)2016 AACR. PMID- 27760838 TI - Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line-Specific Effects from P-Glycoprotein-Induced Toxicity. AB - Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgp-dependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1-/-;p53-/- spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer. Mol Cancer Ther; 16(1); 45-56. (c)2016 AACR. PMID- 27760839 TI - Sofosbuvir-based antiviral therapy in hepatitis C virus patients with severe renal failure. AB - Background: Chronic hepatitis C virus (HCV) infection is the most common chronic liver disease in patients with end-stage renal disease (ESRD). Over the last few years, second-generation direct-acting antivirals have been revolutionary in the treatment of hepatitis C, and sofosbuvir (SOF) is the backbone of most modern treatment strategies. Since SOF is eliminated through the kidney, the aim of this multicentre retrospective study was to assess its antiviral efficacy and safety in HCV-infected patients with severe renal failure [including haemodialysis (HD) patients]. Methods: Fifty patients (36 males, mean age +/- standard deviation 60.5 +/- 7.5 years) with chronic HCV infection (G1: 28/56%, cirrhosis: 27/54%) and severe renal failure [i.e. MDRD estimated glomerular filtration rate (eGFR) <35 mL/min], including 35 on HD, were enrolled. Antiviral treatment consisted of SOF/ribavirin (RBV) (n = 7), SOF/RBV/pegylated interferon (n = 2), SOF/daclatasvir +/- RBV (n = 30) or SOF/simeprevir +/- RBV (n = 11) for 12 or 24 weeks. A reduced dose of SOF (400 mg three times a week or 400 mg every other day) was given to all HD patients. Initial dose of RBV (n = 12) ranged from 400 to 4200 mg/week. Results: On an intent-to-treat-based analysis, sustained virological response rate was 86% at 12 weeks. During therapy, haemoglobin levels were not significantly modified, but recombinant erythropoietin (rEPO) dose significantly increased in patients treated with RBV. Two patients (4%) required blood transfusion. No patient had treatment discontinuation due to side effects. Dose of RBV was reduced in two patients (16.7%) during antiviral therapy. Dose of SOF was reduced in two non-HD patients because of side effects. In non-HD patients, median eGFR was not significantly modified during treatment. Conclusions: Our results strongly suggest that SOF-based antiviral therapy, with a reduced dose of SOF, is safe and effective for the treatment of HCV patients with ESRD, including HD patients. PMID- 27760840 TI - mTORC1 signalling and eIF4E/4E-BP1 translation initiation factor stoichiometry influence recombinant protein productivity from GS-CHOK1 cells. AB - Many protein-based biotherapeutics are produced in cultured Chinese hamster ovary (CHO) cell lines. Recent reports have demonstrated that translation of recombinant mRNAs and global control of the translation machinery via mammalian target of rapamycin (mTOR) signalling are important determinants of the amount and quality of recombinant protein such cells can produce. mTOR complex 1 (mTORC1) is a master regulator of cell growth/division, ribosome biogenesis and protein synthesis, but the relationship between mTORC1 signalling, cell growth and proliferation and recombinant protein yields from mammalian cells, and whether this master regulating signalling pathway can be manipulated to enhance cell biomass and recombinant protein production (rPP) are not well explored. We have investigated mTORC1 signalling and activity throughout batch culture of a panel of sister recombinant glutamine synthetase-CHO cell lines expressing different amounts of a model monoclonal IgG4, to evaluate the links between mTORC1 signalling and cell proliferation, autophagy, recombinant protein expression, global protein synthesis and mRNA translation initiation. We find that the expression of the mTORC1 substrate 4E-binding protein 1 (4E-BP1) fluctuates throughout the course of cell culture and, as expected, that the 4E BP1 phosphorylation profiles change across the culture. Importantly, we find that the eIF4E/4E-BP1 stoichiometry positively correlates with cell productivity. Furthermore, eIF4E amounts appear to be co-regulated with 4E-BP1 amounts. This may reflect a sensing of either change at the mRNA level as opposed to the protein level or the fact that the phosphorylation status, as well as the amount of 4E-BP1 present, is important in the co-regulation of eIF4E and 4E-BP1. PMID- 27760841 TI - Loss of lamin B receptor is necessary to induce cellular senescence. AB - Cellular transition to senescence is associated with extensive chromatin reorganization and changes in gene expression. Recent studies appear to imply an association of lamin B1 (LB1) reduction with chromatin rearrangement in human fibroblasts promoted to senescence, while the mechanisms and structural features of these relationships have not yet been clarified. In this work, we examined the functions of LB1 and the lamin B receptor (LBR) in human cancer cells. We found that both LB1 and LBR tend to deplete during cancer cell transfer to senescence by gamma-irradiation. A functional study employing silencing of LBR by small hairpin ribonucleic acid (shRNA) constructs revealed reduced LB1 levels suggesting that the regulation of both proteins is interrelated. The reduced expression of LBR resulted in the relocation of centromeric heterochromatin (CSH) from the inner nuclear membrane (INM) to the nucleoplasm and is associated with its unfolding. This indicates that LBR tethers heterochromatin to INM in cycling cancer cells and that LB1 is an integral part of this tethering. Down-regulation of LBR and LB1 at the onset of senescence are thus necessary for the release of heterochromatin binding to lamina, resulting in changes in chromatin architecture and gene expression. However, the senescence phenotype was not manifested in cell lines with reduced LBR and LB1 expression suggesting that other factors, such as deoxyribonucleic acid (DNA) damage, are needed to trigger senescence. We conclude that the primary response of cells to various stresses leading to senescence consists of the down-regulation of LBR and LB1 to attain reversal of the chromatin architecture. PMID- 27760842 TI - Molecular mapping of alpha-thrombin (alphaT)/beta2-glycoprotein I (beta2GpI) interaction reveals how beta2GpI affects alphaT functions. AB - beta2-Glycoprotein I (beta2GpI) is the major autoantigen in the antiphospholipid syndrome, a thrombotic autoimmune disease. Nonetheless, the physiological role of beta2GpI is still unclear. In a recent work, we have shown that beta2GpI selectively inhibits the procoagulant functions of human alpha-thrombin (alphaT; i.e. prolongs fibrin clotting time, tc, and inhibits alphaT-induced platelet aggregation) without affecting the unique anticoagulant activity of the protease, i.e. the proteolytic generation of the anticoagulant protein C (PC) from the PC zymogen, which interacts with alphaT exclusively at the protease catalytic site. Here, we used several different biochemical/biophysical techniques and molecular probes for mapping the binding sites in the alphaT-beta2GpI complex. Our results indicate that alphaT exploits the highly electropositive exosite-II, which is also responsible for anchoring alphaT on the platelet GpIbalpha (platelet receptor glycoprotein Ibalpha) receptor, for binding to a continuous negative region on beta2GpI structure, spanning domain IV and (part of) domain V, whereas the protease active site and exosite-I (i.e. the fibrinogen-binding site) remain accessible for substrate/ligand binding. Furthermore, we provided evidence that the apparent increase in tc, previously observed with beta2GpI, is more likely caused by alteration in the ensuing fibrin structure rather than by the inhibition of fibrinogen hydrolysis. Finally, we produced a theoretical docking model of alphaT-beta2GpI interaction, which was in agreement with the experimental results. Altogether, these findings help to understand how beta2GpI affects alphaT interactions and suggest that beta2GpI may function as a scavenger of alphaT for binding to the GpIbalpha receptor, thus impairing platelet aggregation while enabling normal cleavage of fibrinogen and PC. PMID- 27760844 TI - Injuries in an Extreme Conditioning Program. AB - BACKGROUND: Extreme conditioning programs (ECPs) are fitness training regimens relying on aerobic, plyometric, and resistance training exercises, often with high levels of intensity for a short duration of time. These programs have grown rapidly in popularity in recent years, but science describing the safety profile of these programs is lacking. HYPOTHESIS: The rate of injury in the extreme conditioning program is greater than the injury rate of weightlifting and the majority of injuries occur to the shoulder and back. STUDY DESIGN: Cross sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: This is a retrospective survey of injuries reported by athletes participating in an ECP. An injury survey was sent to 1100 members of Iron Tribe Fitness, a gym franchise with 5 locations across Birmingham, Alabama, that employs exercises consistent with an ECP in this study. An injury was defined as a physical condition resulting from ECP participation that caused the athlete to either seek medical treatment, take time off from exercising, or make modifications to his or her technique to continue. RESULTS: A total of 247 athletes (22%) completed the survey. The majority (57%) of athletes were male (n = 139), and 94% of athletes were white (n = 227). The mean age of athletes was 38.9 years (+/-8.9 years). Athletes reported participation in the ECP for, on average, 3.6 hours per week (+/- 1.2 hours). Eighty-five athletes (34%) reported that they had sustained an injury while participating in the ECP. A total of 132 injuries were recorded, yielding an estimated incidence of 2.71 per 1000 hours. The shoulder or upper arm was the most commonly injured body site, accounting for 38 injuries (15% of athletes). Athletes with a previous shoulder injury were 8.1 times as likely to injure their shoulder in the ECP compared with athletes with healthy shoulders. The trunk, back, head, or neck (n = 29, 12%) and the leg or knee (n = 29, 12%) were the second most commonly injured sites. The injury incidence rate among athletes with <6 months of experience in the ECP was 2.5 times greater than that of more experienced athletes (>=6 months of experience). Of the 132 injuries, 23 (17%) required surgical intervention. Squat cleans, ring dips, overhead squats, and push presses were more likely to cause injury. Athletes reported that 35% of injuries were due to overexertion and 20% were due to improper technique. CONCLUSION: The estimated injury rate among athletes participating in this ECP was similar to the rate of injury in weightlifting and most other recreational activities. The shoulder or upper arm was the most commonly injured area, and previous shoulder injury predisposed to new shoulder injury. New athletes are at considerable risk of injury compared with more experienced athletes. CLINICAL RELEVANCE: Extreme conditioning programs are growing in popularity, and there is disagreement between science and anecdotal reports from athletes, coaches, and physicians about their relative safety. This study estimates the incidence of injury in extreme conditioning programs, which appears to be similar to other weight-training programs. PMID- 27760845 TI - External Iliac Artery Vasospasm in an Elite Female Runner. AB - A 33-year-old elite female runner presented to a tertiary care sports medicine clinic with a 2-year history of progressive anterior thigh and circumferential leg pain with associated foot paresthesias brought on by high-intensity running. She had both external iliac artery vasospasm and chronic exertional compartment syndrome. External iliac artery vasospasm is a rare cause of exertional leg pain, particularly in the running population. This case highlights the unique features of this condition, addresses the multidisciplinary approach that led to the accurate diagnoses, and demonstrates that more than 1 etiology for exertional leg pain can coexist in an athlete. PMID- 27760843 TI - Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis. AB - : Tumor-derived exosomes are emerging mediators of tumorigenesis and tissue specific metastasis. Proteomic profiling has identified Annexin II as one of the most highly expressed proteins in exosomes; however, studies focused on the biological role of exosomal Annexin II (exo-Anx II) are still lacking. In this study, mechanistic insight was sought regarding exo-Anx II and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-Anx II in angiogenesis. Using atomic force microscopy and Western blotting, exo-Anx II expression was characterized in normal and breast cancer cells. In addition, organ-specific metastatic breast cancer cells and animal models were used to define the role exo Anx II in breast cancer metastasis. Results revealed that exo-Anx II expression is significantly higher in malignant cells than normal and premetastatic breast cancer cells. In vitro and in vivo studies demonstrated that exo-Anx II promotes tPA-dependent angiogenesis. Furthermore, in vivo analysis indicated that metastatic exosomes create a favorable microenvironment for metastasis, and exo Anx II plays an important role in this process, as priming with Anx II-depleted exosomes reduces brain (~4-fold) and lung (~2-fold) metastasis. Upon delineating the mechanism, it was discovered that exo-Anx II causes macrophage-mediated activation of the p38MAPK, NF-kappaB, and STAT3 pathways and increased secretion of IL6 and TNFalpha. These data demonstrate an important role for exo-Anx II in breast cancer pathogenesis. IMPLICATIONS: Exosome-associated Annexin II plays an important role in angiogenesis and breast cancer metastasis, which can be exploited as a potential biomarker as well as a therapeutic target for diagnosis and treatment of metastatic breast cancer. Mol Cancer Res; 15(1); 93-105. (c)2016 AACR. PMID- 27760846 TI - T/Tn immunotherapy avoiding immune deviation. AB - Tumor immunotherapy, capable of inducing both cellular and humoral immune responses, is an attractive treatment strategy for cancer. It has been reported that the inactivation of cell-mediated immunity by hyper-activation of humoral immunity-referred to as immune deviation-does not inhibit tumor growth. We investigated the ability of several adjuvants to elicit Thomsen-Friedenreich (T/Tn)-specific humoral immunity while avoiding immune deviation and conferring protection against tumorigenesis. T/Tn (9:1) antigen was purified from blood type O erythrocytes donated by healthy Korean volunteers. Immunization was performed using T/Tn only, T/Tn mixed with Freund's adjuvant (T/Tn+FA), keyhole limpet hemocyanin (KLH)-conjugated T/Tn mixed with FA (KLH-T/Tn+FA), or oxidized mannan conjugated T/Tn mixed with FA (ox-M-T/Tn+FA). Anti-T/Tn antibodies were generated in the T/Tn+FA, KLH-T/Tn+FA, and ox-M-T/Tn+FA groups. The antibody level was highest in the KLH-T/Tn+FA group. Mice immunized with ox-M-T/Tn+FA showed specific complement-dependent cytotoxicity, and were protected against T/Tn positive mammary adenocarcinoma cell challenge, although anti-T/Tn antibody levels were the highest in the KLH-T/Tn+FA group. These results demonstrate that an ox-M-conjugated T/Tn vaccine mixed with FA can promote cellular immunity while moderating the humoral immune response, thereby effectively inhibiting tumor growth. PMID- 27760847 TI - Levels of circulating soluble receptor activator of NF-kappaB and interleukins-1 predicting outcome of locally advanced basal cell carcinoma. AB - Decreasing levels of cytokines are associated with better responses to therapies, while increasing levels are related to progression or recurrence and decreased survival. NF-kappaB's role in the cell cycle and its ubiquity are only stressed out by the evidence for the importance of activation (aberrant activation in the majority of cancers) of both canonical and non-canonical pathways in advanced basal cell carcinomas (aBCCs), a subset of basal cell carcinoma (BCC). NF-kappaB acts through its canonical, or classical, form activated by interleukin-1 (IL-1), regulates cytoprotective, innate, and adaptive immune responses. However, NF kappaB2 often acts through its non-canonical or alternate pathway. During the two year study period, we selected 21 patients presenting with aBCCs due to delay in accessing medical attention with an advanced form of BCCs (n = 19) and infiltrative BCCs (n = 2). Initial diagnosis of BCCs of head and neck was made clinically and verified by skin biopsy. Venous blood was drawn and serum was obtained. Samples were collected at baseline and every three days thereafter (days 3, 6, 9, etc. until surgery). Antigenes' quantities (cytokines) were determined by ELISA kits. Initially, the mean value of all cytokine subjects was significantly different related to the control group (P <0.05). Changes in serum levels of circulating soluble receptor activator of NF-kappaB and interleukins-1 (alpha and beta) were observed following the surgery. Changes in serum levels of circulating soluble receptor activator of NF-kappaB and interleukins-1 (alpha and beta) are evident throughout our study period and a certain regularity in its dynamics is evident as the follow-up period moves away. It was therefore concluded that measurement of these factors might be useful in predicting the overall outcome of patients with aBCCs. This study highlights the systemic effects of aBCCs, but further studies are required on this topic. PMID- 27760848 TI - Five new species of the obligate mycoparasite Syncephalis (Zoopagales, Zoopagomycotina) from soil. AB - More than 520 soil samples were surveyed for species of the mycoparasitic zygomycete genus Syncephalis using a culture-based approach. These fungi are relatively common in soil using the optimal conditions for growing both the host and parasite. Five species obtained in dual culture are unknown to science and are described here: (i) S. digitata with sporangiophores short, merosporangia separate at the apices, simple, 3-5 spored; (ii) S. floridana, which forms galls in the host and has sporangiophores up to 170 um long with unbranched merosporangia that contain 2-4 spores; (iii) S. pseudoplumigaleta, with an abrupt apical bend in the sporophore; (iv) S. pyriformis with fertile vesicles that are long-pyriform; and (v) S. unispora with unispored merosporangia. To facilitate future molecular comparisons between species of Syncephalis and to allow identification of these fungi from environmental sampling datasets, we used Syncephalis-specific PCR primers to generate internal transcribed spacer (ITS) sequences for all five new species. PMID- 27760849 TI - ITS phylogeny and taxonomy of Phyllachora species on native Myrtaceae from the Brazilian Cerrado. AB - Nine Phyllachora species found on hosts belonging to the family Myrtaceae native to the Brazilian Cerrado were described and illustrated. We sequenced nuc rDNA internal transcribed spacer barcode regions for representatives of seven species and conducted phylogenetic analyses, which provided strong support for four new species that we describe as Phyllachora cerradensis, P. ermidensis, P. furnasensis, and P. myrciariae. Catacauma nigerrimum was recombined into P. nigerrima, and a key to the common Phyllachora species on myrtaceous hosts from the Brazilian Cerrado was also included. PMID- 27760851 TI - Carbon utilization profile of the filamentous fungal species Fusarium fujikuroi, Penicillium decumbens, and Sarocladium strictum isolated from marine coastal environments. AB - Facultative marine filamentous fungi have recently emerged as a functional component in coastal marine systems. However, little is known about their ecological role and functions in biogeochemical cycles. Penicillium decumbens, S. strictum, and F. fujikuroi were isolated from the coastal upwelling zone off south-central Chile. Their carbon profiles were characterized using Biolog FF MicroPlates. These species used a wide range of carbon sources, mainly carbohydrates, but also amino acids, suggesting the use of metabolic routes that include glycolysis/gluconeogenesis. Substrate richness revealed a great capacity for the utilization of nutritional sources, reflected by the following Shannon Indices of utilization of specific substrates: 4.02 for S. strictum, 4.01 for P. decumbes, and 3.91 for F. fujikuroi, which reveals a high physiological capacity for oxidizing different substrates. Significant differences were found between 18 substrates utilized by all three species. Results suggest that filamentous fungi should be considered an integral part of the marine microbial community and included in biogeochemical cycling models of upwelling ecosystems. PMID- 27760850 TI - Multilocus phylogenetic and coalescent-based methods reveal dilemma in generic limits, cryptic species, and a prevalent intercontinental disjunct distribution in Geopyxis (Pyronemataceae s. l., Pezizomycetes). AB - Species limits in the small genus Geopyxis are debatable because of problems with interpreting the few phenotypic features and poor documentation of types. To clarify species boundaries and diversity, we studied the morphology of 74 specimens of Geopyxis from the Northern Hemisphere, including five types, and sequenced four loci for 57 representatives: the nuc rDNA ITS1-5.8S-ITS2 (ITS), D1 D2 domains of nuc 28S rDNA (28S), translation elongation factor (tef1), and (or) part of the second largest subunit of the RNA polymerase II (rpb2) (5-7 region). Eight species are delimited. Six species are shown to be highly supported as reciprocally monophyletic: G. aleurioides sp. nov., G. alpina s. l., G. carbonaria, G. delectans, G. korfii, and G. majalis. In addition, coalescent based Bayesian species delimitation shows G. alpina s. l. constitutes three cryptic species: G. alpina s. str., G. deceptiva sp. nov., and G. rehmii. ITS-28S sequences of type material show that G. vulcanalis and G. foetida are synonyms of G. carbonaria. A lectotype is designated for Humaria delectans and the name is combined in Geopyxis. Morphological characters that can be used to distinguish Geopyxis species are presence/absence of a long stipe, spore size and shape, and pigmented resinous exudates in medullary and ectal excipulum. Geopyxis carbonaria and G. delectans produce apothecia almost exclusively on burned ground. Bayesian analyses detected highly supported conflicts among different loci regarding generic delimitation and species relationships. Two hypogeous genera, Stephensia and Hydnocystis, are confirmed to nest within Geopyxis. The relationships between species of Geopyxis and Tarzetta, Stephensia shanorii and Paurocotylis pila, are unresolved. Six out of eight species of Geopyxis recognized in this study have intercontinental disjunct distributions. PMID- 27760852 TI - Molecular and morphological characterization of three new species of Pythium from Iran: P. ershadii, P. pyrioosporum, and P. urmianum. AB - Three new species of Pythium: P. ershadii, P. pyrioosporum, and P. urmianum from soils of various regions in Iran are described and illustrated. These species are morphologically distinct from all other known species. Pythium ershadii is morphologically characterized by pyriform ornamented oogonia and rarely production of pyriform oospores. Pythium pyrioosporum differs from other species of the genus by the production of pyriform oospores and smooth walled oogonia, oospores with a tapering elongation toward a hypogynous antheridium and intercalary hypogynous antheridia. Pythium urmianum is distinguished by the presence of intercalary hypogynous antheridia, smooth walled oogonia formed laterally on hyphae or on short side branches and peanut-shaped oospores. Phylogenetic relationships of these new taxa with other Pythium species were investigated using internal transcribed spacers rDNA and partial coxI sequence data. The three species reside in clade E1 and are separated from closely related species. PMID- 27760853 TI - The pH-responsive transcription factor PacC regulates mycelial growth, fruiting body development, and ganoderic acid biosynthesis in Ganoderma lucidum. AB - Ganoderma lucidum is a medicinal macrofungus that is widely used in traditional Chinese medicine. Nonetheless, the scarcity of basic biological studies of this organism has hindered the further development of its commercial value. The pH responsive transcription factor PacC/Rim101 governs the adaptation to environmental pH, the development and the secondary metabolism of many fungi. In this study, a homologue of PacC/Rim101 that encodes GlPacC was identified in the higher basidiomycete G. lucidum. GlPacC is composed of 807 amino acids and contains three typical C2H2 zinc-finger domains, two potential PEST domains, a putative PKA phosphorylation site, and a putative nuclear localization signal (NLS). GlPacC was transcribed at a high level when the fungus was under neutral and alkaline conditions, and silencing of GlPacC impaired the fungal response to ambient pH. The distance between the hyphal branches (of vegetative hyphae and aerial hyphae) was significantly increased in the GlPacC-silenced strains. The GlPacC-silenced strains grew abnormally or became sickly on solid culture medium and were unable to form primordia and fruiting bodies. The ganoderic acid content, levels of the sqs and ls transcripts, and contents of the metabolic intermediates squalene and lanosterol were all up-regulated in the GlPacC silenced strains. Our results indicate that GlPacC is functional and plays complex roles in mycelial growth, fruiting body development and ganoderic acid biosynthesis in G. lucidum. PMID- 27760854 TI - Sequence-based classification and identification of Fungi. AB - Fungal taxonomy and ecology have been revolutionized by the application of molecular methods and both have increasing connections to genomics and functional biology. However, data streams from traditional specimen- and culture-based systematics are not yet fully integrated with those from metagenomic and metatranscriptomic studies, which limits understanding of the taxonomic diversity and metabolic properties of fungal communities. This article reviews current resources, needs, and opportunities for sequence-based classification and identification (SBCI) in fungi as well as related efforts in prokaryotes. To realize the full potential of fungal SBCI it will be necessary to make advances in multiple areas. Improvements in sequencing methods, including long-read and single-cell technologies, will empower fungal molecular ecologists to look beyond ITS and current shotgun metagenomics approaches. Data quality and accessibility will be enhanced by attention to data and metadata standards and rigorous enforcement of policies for deposition of data and workflows. Taxonomic communities will need to develop best practices for molecular characterization in their focal clades, while also contributing to globally useful datasets including ITS. Changes to nomenclatural rules are needed to enable validPUBLICation of sequence-based taxon descriptions. Finally, cultural shifts are necessary to promote adoption of SBCI and to accord professional credit to individuals who contribute to community resources. PMID- 27760855 TI - Phylogenetic assessment of global Suillus ITS sequences supports morphologically defined species and reveals synonymous and undescribed taxa. AB - The genus Suillus represents one of the most recognizable groups of mushrooms in conifer forests throughout the Northern Hemisphere. Although for decades the genus has been relatively well defined morphologically, previous molecular phylogenetic assessments have provided important yet preliminary insights into its evolutionary history. We present the first large-scale phylogenetic study of the boundaries of each species in the genus Suillus based on the most current internal transcribed spacer (ITS) barcode sequences available inPUBLIC databases, as well as sequencing of 224 vouchered specimens and cultures, 15 of which were type specimens from North America. We found that species boundaries delimited by morphological data are broadly congruent with those based on ITS sequences. However, some species appear to have been described several times under different names, several species groups cannot be resolved by ITS sequences alone, and undescribed taxa are apparent, especially in Asia. Therefore, we elevated S. tomentosus var. discolor to S. discolor; proposed synonymies of S. neoalbidipes with S. glandulosipes, S. borealis with S. brunnescens, Boletus serotinus and B. solidipes with Suillus elbensis, S. lactifluus with S. granulatus, S. himalayensis with S. americanus; and proposed usage of the names S. clintonianus in the place of the North American S. grevillei, S. weaverae for North American S. granulatus, S. ampliporus in the place of the North American S. cavipes, and S. elbensis in place of the North American S. viscidus. We showed that the majority of Suillus species have strong affinities for particular host genera. Although deep node support was low, geographic differentiation was apparent, with species from North America, Eurasia, and Asia often forming their own clades. Collectively, this comprehensive genus-level phylogenetic integration of currently available Suillus ITS molecular data and metadata will aid future taxonomic and ecological work on an important group of ectomycorrhizal fungi. PMID- 27760857 TI - Reply. PMID- 27760856 TI - High-Throughput Screens to Discover Small-Molecule Modulators of Ryanodine Receptor Calcium Release Channels. AB - Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca2+ channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca2+ regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca2+], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders. This leaky state of the RyR is an attractive target for pharmacological agents to treat such pathologies. Our FRET-based HTS detects RyR binding of accessory proteins calmodulin (CaM) or FKBP12.6. Under conditions that mimic a pathological state, we carried out a screen of the 727-compound NIH Clinical Collection, which yielded six compounds that reproducibly changed FRET by >3 SD. Dose-response of FRET and [3H]ryanodine binding readouts reveal that five hits reproducibly alter RyR1 structure and activity. One compound increased FRET and inhibited RyR1, which was only significant at nM [Ca2+], and accentuated without CaM present. These properties characterize a compound that could mitigate RyR1 leak. An excellent Z' factor and the tight correlation between structural and functional readouts validate this first HTS method to identify RyR modulators. PMID- 27760858 TI - The ethos of caring within midwifery: A history of ideas study. AB - BACKGROUND: The midwifery profession in Sweden has a history since the early 1700s when government training for midwives began. Midwifery is historically well described, but the idea of caring within midwifery is not described. AIM: The aim was to describe the patterns of ideas of caring as they appeared in midwifery during the first half of the 20th century. RESEARCH DESIGN: This study has a hermeneutic approach and the method is history of ideas. Sources of material are taken from the journal Jordemodern (Midwifery), textbooks for midwives, and midwifery regulations. The study has a caring science perspective according to Eriksson. Ethical considerations: This study is conducted in accordance with the ethical guidelines for good scientific practice issued by The Finnish Advisory Board on Research Integrity. The special demands on approach to the analyzed text in history of ideas have been met. FINDINGS: Three themes were identified: Serving as a way of life, Acting in a redemptive spirit, and Having independence with heavy responsibility. The various themes are not refined, but current ideas are woven into the weave that were characteristic of midwifery during the first half of the 20th century. CONCLUSION: History of ideas is a fruitful method for understanding and re-finding valuable cultural goods. We can once more stress the manner of being within the midwife's profession where inner values, ethos, shape the manner of conduct in the care of women in childbirth. PMID- 27760859 TI - Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis. AB - OBJECTIVE: To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. METHODS: Whole and sub regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. RESULTS: Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. CONCLUSION: Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level. PMID- 27760860 TI - Imaging of microglial activation in MS using PET: Research use and potential future clinical application. AB - Multiple sclerosis (MS) is a complex disease, where several processes can be selected as a target for positron emission topography (PET) imaging. Unlike magnetic resonance imaging (MRI), PET provides specific and quantitative information, and unlike neuropathology, it can be non-invasively applied to living patients, which enables longitudinal follow-up of the MS pathology. In the study of MS, PET can be useful for in vivo evaluation of specific pathological characteristics at various stages of the disease. Increased understanding of the progressive MS pathology will enhance the treatment options of this undertreated condition. The ultimate goal of developing and expanding PET in the study of MS is to have clinical non-invasive in vivo imaging biomarkers of neuroinflammation that will help to establish prognosis and accurately measure response to therapeutics. This topical review provides an overview of the promises and challenges of the use of PET in MS. PMID- 27760861 TI - Clinical-radiological-pathological spectrum of central nervous system-idiopathic inflammatory demyelinating disease in the elderly. AB - BACKGROUND: The spectrum of central nervous system-idiopathic inflammatory demyelinating disease (CNS-IIDD) in the elderly is uncertain. OBJECTIVE: To describe the clinical, radiological, and pathological features of a cohort of 30 pathologically proven CNS-IIDD patients ?65 years. METHODS: Elderly multiple sclerosis (MS)/clinically isolated syndrome (CIS) patients were compared to a cohort of 125 patients with pathologically proven MS/CIS and symptom onset <65 years. RESULTS: Median age at symptom onset was 69 years (interquartile range (IQR) = 68-75). Median follow-up was 1.9 years (IQR = 1.0-5.6). Diagnoses were MS (14/30), CIS (11/30), neuromyelitis optica (NMO; 4/30), and acute disseminated encephalomyelitis (ADEM; 1/30). Disability was higher in patients with MS/CIS ?65 compared to patients <65 (median Expanded Disability Status Scale (EDSS) 4 (IQR = 2.5-7) vs 2.5 (IQR = 1.5-4); p = 0.002). When compared to patients <65 years, there was no difference in the lesion size, number of patients fulfilling Barkhof's criteria, edema, or mass effect. Confluent demyelination was observed in 27 patients (MS/CIS (23/25), NMO (4)), 2 had a mixed perivenular/confluent pattern (MS (1), ADEM (1)), and 1 patient with MS had a mixed confluent/perivenular/coalescent pattern. Early active lesions were found in 19/30 patients ((MS (4), CIS (13), NMO (2); 53%). Cortical demyelination was present in 7/12 (58%) patients (MS (3), CIS(3), ADEM (1)). CONCLUSION: A spectrum of CNS-IIDD can develop in the elderly, with presenting symptoms similar to younger patients. Early diagnosis of CNS demyelinating disease is essential to avoid invasive and disabling procedures. PMID- 27760863 TI - Primary laryngeal leishmaniasis: an unusual diagnosis at an unusual site. PMID- 27760862 TI - Gender effect on neuromyelitis optica spectrum disorder with aquaporin4 immunoglobulin G. AB - BACKGROUND: Neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G (NMOSD-AQP4) is an inflammatory disease characterised by a high female predominance. However, the effect of gender in patients with NMOSD-AQP4 has not been fully evaluated. OBJECTIVE: The aim of this study was to determine the effect of gender in clinical manifestations and prognosis of patients with NMOSD AQP4. METHODS: The demographics, clinical and radiological characteristics, pattern reversal visual evoked potential (VEP) test results, and prognosis of 102 patients (18 males) with NMOSD-AQP4 were assessed. RESULTS: Male patients had a higher age at onset (48.7 vs 41 years, p = 0.037) and less optic neuritis as the onset attack (17% vs 44%, p = 0.026), higher tendency to manifest as isolated myelitis over the follow-up period (67% vs 28%, p = 0.005), fewer optic neuritis attacks per year (0.08 vs 0.27, p < 0.001), and shorter relative P100 latency on VEP testing (97.1% vs 108.3%, p = 0.001). Moreover, male gender was significantly associated with the absence of optic neuritis attacks over the follow-up period independent of their age of onset. CONCLUSION: In NMOSD-AQP4 patients, gender impacts on disease onset age and site of attack. This may be an important clue in identifying NMOSD-AQP4 patients with limited manifestations as well as in predicting their clinical courses. PMID- 27760864 TI - Assessing Mental Models of Emergencies Through Two Knowledge Elicitation Tasks. AB - OBJECTIVE: The goals of this study were to assess the risk identification aspect of mental models using standard elicitation methods and how university campus alerts were related to these mental models. BACKGROUND: People fail to follow protective action recommendations in emergency warnings. Past research has yet to examine cognitive processes that influence emergency decision-making. METHOD: Study 1 examined 2 years of emergency alerts distributed by a large southeastern university. In Study 2, participants listed emergencies in a thought-listing task. Study 3 measured participants' time to decide if a situation was an emergency. RESULTS: The university distributed the most alerts about an armed person, theft, and fire. In Study 2, participants most frequently listed fire, car accident, heart attack, and theft. In Study 3, participants quickly decided a bomb, murder, fire, tornado, and rape were emergencies. They most slowly decided that a suspicious package and identify theft were emergencies. CONCLUSION: Recent interaction with warnings was only somewhat related to participants' mental models of emergencies. Risk identification precedes decision-making and applying protective actions. Examining these characteristics of people's mental representations of emergencies is fundamental to further understand why some emergency warnings go ignored. APPLICATION: Someone must believe a situation is serious to categorize it as an emergency before taking the protective action recommendations in an emergency warning. Present-day research must continue to examine the problem of people ignoring warning communication, as there are important cognitive factors that have not yet been explored until the present research. PMID- 27760865 TI - Effects of Rest-Break Intention on Rest-Break Frequency and Work-Related Fatigue. AB - OBJECTIVES: The present paper presents findings from two studies addressing the effects of the employee's intention to have rest breaks on rest-break frequency and the change of well-being during a workday. BACKGROUND: Rest breaks are effective in avoiding an accumulation of fatigue during work. However, little is known about individual differences in rest-break behavior. METHOD: In Study 1, the association between rest-break intention and the daily number of rest breaks recorded over 4 consecutive workdays was determined by generalized linear model in a sample of employees ( n = 111, 59% females). In Study 2, professional geriatric nurses ( n = 95 females) who worked over two consecutive 12-hour day shifts recorded well-being (fatigue, distress, effort motivation) at the beginning and the end of their shifts. The effect of rest-break intention on the change of well-being was determined by multilevel modeling. RESULTS: Rest-break intention was positively associated with the frequency of rest breaks (Study 1) and reduced the increase of fatigue and distress over the workday (Study 2). CONCLUSION: The results indicate that individual differences account for the number of breaks an employee takes and, as a consequence, for variations in the work-related fatigue and distress. APPLICATION: Strengthening rest-break intentions may help to increase rest-break behavior to avoid the buildup of fatigue and distress over a workday. PMID- 27760866 TI - Serum Trefoil Factor 3 as a Protein Biomarker for the Diagnosis of Colorectal Cancer. AB - Colorectal cancer is one of the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for timely diagnosis and effective treatment. Our aim in the present study was to detect the serum level of trefoil factor 3 protein and evaluate the diagnostic accuracy of trefoil factor 3 in patients with colorectal cancer. We collected serum samples from 204 participants (127 patients with colorectal cancer, 35 patients with polyps, and 42 healthy controls). The levels of serum trefoil factor 3 and carcinoembryonic antigen expression were measured by enzyme-linked immunosorbent assay. Receiver operating characteristic curves were plotted to calculate the diagnostic accuracy of trefoil factor 3 in patients with colorectal cancer. The serum levels of trefoil factor 3 in patients with colorectal cancer (6.66 +/- 2.4 ng/mL; P < .00l) and polyps (3.86 +/- 1.3 ng/mL; P < .00l) were significantly increased compared to healthy controls (2.09 +/- 1.0 ng/mL). Moreover, the area under the receiver operating characteristic curve for trefoil factor 3 was greater than carcinoembryonic antigen (0.889 vs 0.715). At a cutoff value of 5.591 ng/mL, the diagnostic sensitivity, specificity, and likelihood ratio of serum trefoil factor 3 for colorectal cancer was 74.2%, 94.8%, and 14.25, respectively. Furthermore, the serum trefoil factor 3 levels in early colorectal cancer (TNM stage I, 3.67 +/- 1.27 ng/mL) were significantly increased compared to healthy controls ( P < .001); however, there was no significant difference compared to patients with polyps ( P = .576). We observed that the serum trefoil factor 3 levels decreased after surgery (6.66 +/- 2.4 vs 4.48 +/- 1.80 ng/mL; P < .001). In addition, high serum trefoil factor 3 levels were associated with poor tumor differentiation and clinical TNM stage ( P < .05). In conclusion, serum trefoil factor 3 is a promising biomarker for the diagnosis of colorectal cancer and prognosis of patients. PMID- 27760867 TI - Practice advisory: The utility of EEG theta/beta power ratio in ADHD diagnosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To evaluate the evidence for EEG theta/beta power ratio for diagnosing, or helping to diagnose, attention-deficit/hyperactivity disorder (ADHD). METHODS: We identified relevant studies and classified them using American Academy of Neurology criteria. RESULTS: Two Class I studies assessing the ability of EEG theta/beta power ratio and EEG frontal beta power to identify patients with ADHD correctly identified 166 of 185 participants. Both studies evaluated theta/beta power ratio and frontal beta power in suspected ADHD or in syndromes typically included in an ADHD differential diagnosis. A bivariate model combining the diagnostic studies shows that the combination of EEG frontal beta power and theta/beta power ratio has relatively high sensitivity and specificity but is insufficiently accurate. CONCLUSIONS: It is unknown whether a combination of standard clinical examination and EEG theta/beta power ratio increases diagnostic certainty of ADHD compared with clinical examination alone. RECOMMENDATIONS: Level B: Clinicians should inform patients with suspected ADHD and their families that the combination of EEG theta/beta power ratio and frontal beta power should not replace a standard clinical evaluation. There is a risk for significant harm to patients from ADHD misdiagnosis because of the unacceptably high false-positive diagnostic rate of EEG theta/beta power ratio and frontal beta power. Level R: Clinicians should inform patients with suspected ADHD and their families that the EEG theta/beta power ratio should not be used to confirm an ADHD diagnosis or to support further testing after a clinical evaluation, unless such diagnostic assessments occur in a research setting. PMID- 27760868 TI - Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. AB - OBJECTIVE: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). METHODS: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. RESULTS: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades >=2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. CONCLUSIONS: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective. PMID- 27760869 TI - Aerobic exercise and vascular cognitive impairment: A randomized controlled trial. AB - OBJECTIVE: To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). METHODS: This was a proof-of concept single-blind randomized controlled trial comparing a 6-month, thrice weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT 25]), and activities of daily living (Alzheimer's Disease Cooperative Study Activities of Daily Living [ADCS-ADL]). RESULTS: Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS Cog performance compared with the usual care plus education group (-1.71 point difference, 95% confidence interval [CI] -3.15 to -0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (-0.63 point difference, 95% CI -2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference, 95% CI 5.82 to 54.86, p = 0.02) and in diastolic blood pressure (-6.89 mm Hg difference, 95% CI -12.52 to -1.26, p = 0.02). CONCLUSIONS: This study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education. CLINICALTRIALSGOV IDENTIFIER: NCT01027858. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with mild SIVCI, an aerobic exercise program for 6 months results in a small, significant improvement in ADAS-Cog performance. PMID- 27760871 TI - Rituximab for treating multiple sclerosis: Off-label but on target. PMID- 27760870 TI - Increasing comorbidity and health services utilization in older adults with prior stroke. AB - OBJECTIVE: To characterize comorbid chronic conditions, describe health services use, and estimate health care costs among community-dwelling older adults with prior stroke. METHODS: This is a retrospective cohort study using administrative data from Ontario, Canada. We identified all community-dwelling individuals aged 66 and over on April 1, 2008 (baseline), who had experienced a stroke at least 6 months prior. We estimated the prevalence of 14 comorbid conditions at baseline; we captured all physician visits, emergency department visits, hospital admissions, home care contacts, and associated costs over 5 years stratifying by number of comorbid conditions. Where possible, we distinguished between health services use for stroke- and non-stroke-related reasons. RESULTS: A total of 29,673 individuals met our criteria. Only 1% had no comorbid conditions, while 74.9% had 3 or more. The most common conditions were hypertension (89.8%) and arthritis (65.8%); 5 other conditions had a prevalence of 20% or more (ischemic heart disease, diabetes, chronic obstructive pulmonary disease, inflammatory bowel disease, and dementia). Use of all health services doubled with increasing comorbidity and was largely attributed to non-stroke-related reasons. Total and per-patient costs increased with comorbidity. Main cost drivers shifted from physician and home care visits to hospital admissions with greater comorbidity. CONCLUSIONS: Our findings demonstrate the importance of community-based patient centered care strategies for stroke survivors that address their range of health needs and prevent more costly acute care use. PMID- 27760872 TI - The eternal promise of EEG-based biomarkers: Getting closer? PMID- 27760873 TI - Aerobic exercise: A possible therapy for vascular cognitive impairment. PMID- 27760876 TI - Comparison of the CADRI and CTS2 for Measuring Psychological and Physical Dating Violence Perpetration and Victimization. AB - Advancing dating violence (DV) research requires consistent conceptualization and measurement. However, empirical sudies on the measurement of psychological and physical DV perpetration and victimization are uncommon. There were three aims of the current study: (a) to examine the construct validity of psychological and physical DV perpetration and victimization on the Conflict in Adolescent Dating Relationships Inventory (CADRI) and Revised Conflict Tactics Scales (CTS2) using factor analysis; (b) to compare empirically derived DV scales with ones using face valid definitions of psychological and physical DV within each measure; and (c) to compare results obtained from the CADRI with those obtained from the CTS2. A diverse sample of undergraduates ( N = 512; 63.9% female, 50.0% White, 16.2% Black, and 22.9% Latino) completed an online survey. There were two-factor solutions for each survey and DV perpetration and victimization: moderate psychological DV and severe psychological/physical DV on the CADRI; and moderate psychological and physical DV and severe psychological and physical DV on the CTS2. Multiple regression analyses showed that results were similar for empirically and rationally derived scoring methods with one exception: On the CTS2, risk factors associated with moderate DV were not the same as those associated with psychological DV. Moreover, the unique contribution of risk factors to each form of DV depended on which survey was used. In multivariate studies of risk factors associated with psychological and physical DV, the CADRI and CTS2 do not appear to be interchangeable, and may lead to different conclusions about the relative importance of risk factors. PMID- 27760874 TI - Heterogeneous cortical atrophy patterns in MCI not captured by conventional diagnostic criteria. AB - OBJECTIVE: We investigated differences in regional cortical thickness between previously identified empirically derived mild cognitive impairment (MCI) subtypes (amnestic MCI, dysnomic MCI, dysexecutive/mixed MCI, and cluster-derived normal) in order to determine whether these cognitive subtypes would show different patterns of cortical atrophy. METHODS: Participants were 485 individuals diagnosed with MCI and 178 cognitively normal individuals from the Alzheimer's Disease Neuroimaging Initiative. Cortical thickness estimates were computed for 32 regions of interest per hemisphere. Statistical group maps compared each MCI subtype to cognitively normal participants and to one another. RESULTS: The pattern of cortical thinning observed in each MCI subtype corresponded to their cognitive profile. No differences in cortical thickness were found between the cluster-derived normal MCI subtype and the cognitively normal group. Direct comparison between MCI subtypes suggested that the cortical thickness patterns reflect increasing disease severity. CONCLUSIONS: There is an ordered pattern of cortical atrophy among patients with MCI that coincides with their profiles of increasing cognitive dysfunction. This heterogeneity is not captured when patients are grouped by conventional diagnostic criteria. Results in the cluster-derived normal group further support the premise that the conventional MCI diagnostic criteria are highly susceptible to false-positive diagnostic errors. Findings suggest a need to (1) improve the diagnostic criteria by reducing reliance on conventional screening measures, rating scales, and a single memory measure in order to avoid false-positive errors; and (2) divide MCI samples into meaningful subgroups based on cognitive and biomarkers profiles-a method that may provide better staging of MCI and inform prognosis. PMID- 27760875 TI - Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials? AB - The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial. PMID- 27760877 TI - Attitudes of Young Adult Men Toward Domestic Violence and Factors Affecting Their Attitudes in Turkey. AB - Domestic violence is commonly observed worldwide; however, exposure to violence is not often mentioned directly. Prevention of domestic violence may be one of the most important social problems and requires much time and effort to resolve. This study was conducted to determine the attitudes toward domestic violence of Turkish males who are young adult and undertake military service, and the factors that affect these attitudes. A cross-sectional study design was used. This study was conducted with 221 young adult men who applied to Sarikamis Military Hospital between December 2012 and February 2013. A questionnaire and the Attitude Toward Domestic Violence Scale were used for the collection of data. One-way ANOVA, T test, Kruskal-Wallis test, and Mann-Whitney U test were used in the process of analyzing the data. In the study, it was found that 10% of the young adult men were exposed to violence within their own family and the average of their total scores from the Attitude Toward Domestic Violence Scale was 49.41 +/- 7.27. It was confirmed that undereducated men have more negative attitudes toward domestic violence than other groups. The present study determined that men who have negative attitudes toward domestic violence and who have a low education level affected attitudes toward domestic violence negatively. It is important that violence is prevented before it occurs. In this respect, health professionals, politicians, teachers, academics, and all community leaders have an important role in preventing initiatives on violence. PMID- 27760878 TI - The Role of Shame in the Relation Between Peer Victimization and Mental Health Outcomes. AB - Youth who experience peer victimization are at risk of developing mental health problems. However, little is known about the emotional causal mechanisms linking peer victimization with these negative outcomes. This study investigated whether shame mediated this relationship. At three time points (T1-T3), 396 10- to 13 year-olds completed measures of peer victimization, shame (characterological, bodily, and behavioral; shame proneness), and mental health (depression, social anxiety, and externalizing behavior). Three multiple mediation models tested the indirect effects of T1 victimization on T3 mental health through the four T2 shame-related variables. Analyses revealed indirect effects for the shame-related mediators on depression, social anxiety, and externalizing behaviors. Specifically, indirect positive effects for characterological and bodily shame on depression and social anxiety were found, with greater bodily shame linked to higher levels of social anxiety in girls but not boys. In addition, an indirect negative effect for behavioral shame on externalizing problems was found, with higher levels of externalizing problems in victimized boys but not in girls. Finally, an indirect positive effect for shame proneness and externalizing problems was found. To clarify the directionality, three additional mediation models were run with mental health symptoms as predictors of shame and subsequent victimization. Indirect effects for the shame-related mediators were found for all outcomes, specifically bodily shame and shame proneness as mediators between internalizing and externalizing symptoms and victimization. These three models were compared and contrasted with the hypothesized models. In sum, findings support the role of shame as an underlying emotional mechanism of peer victimization, and may guide intervention programs to address the mental health concerns of victimized youth. PMID- 27760879 TI - Investigating the Performance of Second Language Medical Students on Lengthy Clinical Vignettes. AB - This study evaluated the extent to which medical students with limited English language experience are differentially impacted by the additional reading load of test items consisting of long clinical vignettes. Participants included 25,012 examinees who completed Step 2 of the U.S. Medical Licensing Examination(r). Test items were categorized into five levels based on the number of words per item, and examinee scores at each level were evaluated as a function of English language experience (English as a second language [ESL] status and scores on a test of English-speaking proficiency). The longest items were more difficult than the shortest items across all examinee groups, and examinees with more English language experience scored higher than those with less experience across all five levels of word count. The effect of primary interest-the interaction of word count with English-language experience-was statistically significant, indicating that score declines for longer items were larger for examinees with less English language experience; however, the magnitude of this interaction effect was barely detectable (eta2 = .0004, p < .001). Additional analyses supported the conclusion that the differential effect for examinees with less English-language experience was small but worthy of continued monitoring. PMID- 27760880 TI - Transcriptome and Degradome Sequencing Reveals Dormancy Mechanisms of Cunninghamia lanceolata Seeds. AB - Seeds with physiological dormancy usually experience primary and secondary dormancy in the nature; however, little is known about the differential regulation of primary and secondary dormancy. We combined multiple approaches to investigate cytological changes, hormonal levels, and gene expression dynamics in Cunninghamia lanceolata seeds during primary dormancy release and secondary dormancy induction. Light microscopy and transmission electron microscopy revealed that protein bodies in the embryo cells coalesced during primary dormancy release and then separated during secondary dormancy induction. Transcriptomic profiling demonstrated that expression of genes negatively regulating gibberellic acid (GA) sensitivity reduced specifically during primary dormancy release, whereas the expression of genes positively regulating abscisic acid (ABA) biosynthesis increased during secondary dormancy induction. Parallel analysis of RNA ends revealed uncapped transcripts for ~55% of all unigenes. A negative correlation between fold changes in expression levels of uncapped versus capped mRNAs was observed during primary dormancy release. However, this correlation was loose during secondary dormancy induction. Our analyses suggest that the reversible changes in cytology and gene expression during dormancy release and induction are related to ABA/GA balance. Moreover, mRNA degradation functions as a critical posttranscriptional regulator during primary dormancy release. These findings provide a mechanistic framework for understanding physiological dormancy in seeds. PMID- 27760883 TI - Evaluating mobile phone applications for health behaviour change: A systematic review. AB - Introduction Increasing smartphones access has allowed for increasing development and use of smart phone applications (apps). Mobile health interventions have previously relied on voice or text-based short message services (SMS), however, the increasing availability and ease of use of apps has allowed for significant growth of smartphone apps that can be used for health behaviour change. This review considers the current body of knowledge relating to the evaluation of apps for health behaviour change. The aim of this review is to investigate approaches to the evaluation of health apps to identify any current best practice approaches. Method A systematic review was conducted. Data were collected and analysed in September 2016. Thirty-eight articles were identified and have been included in this review. Results Articles were published between 2011- 2016, and 36 were reviews or evaluations of apps related to one or more health conditions, the remaining two reported on an investigation of the usability of health apps. Studies investigated apps relating to the following areas: alcohol, asthma, breastfeeding, cancer, depression, diabetes, general health and fitness, headaches, heart disease, HIV, hypertension, iron deficiency/anaemia, low vision, mindfulness, obesity, pain, physical activity, smoking, weight management and women's health. Conclusion In order to harness the potential of mobile health apps for behaviour change and health, we need better ways to assess the quality and effectiveness of apps. This review is unable to suggest a single best practice approach to evaluate mobile health apps. Few measures identified in this review included sufficient information or evaluation, leading to potentially incomplete and inaccurate information for consumers seeking the best app for their situation. This is further complicated by a lack of regulation in health promotion generally. PMID- 27760881 TI - Impaired Cyclic Electron Flow around Photosystem I Disturbs High-Light Respiratory Metabolism. AB - The cyclic electron flow around photosystem I (CEF-PSI) increases ATP/NADPH production in the chloroplast, acting as an energy balance mechanism. Higher export of reducing power from the chloroplast in CEF-PSI mutants has been correlated with higher mitochondrial alternative oxidase (AOX) capacity and protein amount under high-light (HL) conditions. However, in vivo measurements of AOX activity are still required to confirm the exact role of AOX in dissipating the excess of reductant power from the chloroplast. Here, CEF-PSI single and double mutants were exposed to short-term HL conditions in Arabidopsis (Arabidopsis thaliana). Chlorophyll fluorescence, in vivo activities of the cytochrome oxidase (nucyt) and AOX (nualt) pathways, levels of mitochondrial proteins, metabolite profiles, and pyridine nucleotide levels were determined under normal growth and HL conditions. nualt was not increased in CEF-PSI mutants, while AOX capacity was positively correlated with photoinhibition, probably due to a reactive oxygen species-induced increase of AOX protein. The severe metabolic impairment observed in CEF-PSI mutants, as indicated by the increase in photoinhibition and changes in the levels of stress-related metabolites, can explain their lack of nualt induction. By contrast, nucyt was positively correlated with photosynthetic performance. Correlations with metabolite changes suggest that nucyt is coordinated with sugar metabolism and stress-related amino acid synthesis. Furthermore, changes in glycine-serine and NADH-NAD+ ratios were highly correlated to nucyt Taken together, our results suggest that nucyt can act as a sink for the excess of electrons from the chloroplast, probably via photorespiratory glycine oxidation, thus improving photosynthetic performance when nualt is not induced under severe HL stress. PMID- 27760882 TI - Low-Phosphate Induction of Plastidal Stromules Is Dependent on Strigolactones But Not on the Canonical Strigolactone Signaling Component MAX2. AB - Stromules are highly dynamic protrusions of the plastids in plants. Several factors, such as drought and light conditions, influence the stromule frequency (SF) in a positive or negative way. A relatively recently discovered class of plant hormones are the strigolactones; strigolactones inhibit branching of the shoots and promote beneficial interactions between roots and arbuscular mycorrhizal fungi. Here, we investigate the link between the formation of stromules and strigolactones. This research shows a strong link between strigolactones and the formation of stromules: SF correlates with strigolactone levels in the wild type and strigolactone mutants (max2-1 max3-9), and SF is stimulated by strigolactone GR24 and reduced by strigolactone inhibitor D2. PMID- 27760884 TI - Embolization with larger-caliber coils can increase packing density: Evidence from the pilot phase of a randomized trial. AB - Background and purpose Endovascular coil embolization of cerebral aneurysms is associated with suboptimal angiographic results in up to 20-30% of patients. Coil packing density has been used as an index of the success of the initial procedure. The trial sought to study the effects of using 15-caliber coils, as compared with 10-caliber coils, on packing density. Methods Does Embolization with Larger coils lead to better Treatment of Aneurysms (DELTA) is an investigator-initiated multicenter prospective, randomized, controlled clinical trial. Patients are randomized 1:1 to embolization with either 10-caliber coils exclusively (control group) or the highest safely achievable proportion of 15 caliber coils and 10-caliber coils if necessary (intervention group) in 4-12-mm aneurysms. The endpoint of the pilot phase of the trial was the capacity to increase packing density of the initial procedure, calculated using a mathematical transformation of the dimensions entered into the case report forms. Secondary outcomes included the total number of coils used per aneurysm, total fluoroscopy time, initial angiographic outcomes and any adverse or undesirable event. Results Seventy patients were recruited between June 2014 and November 2015. Compared with 10-caliber coils, the 15-caliber coil group had a higher median packing density (44% vs 24%, p = 0.017). Results of other outcome measures were similar for the two groups. Conclusion Coiling of small and medium aneurysms randomized to 15-caliber coils achieved higher packing densities compared with coiling using 10-caliber coils. PMID- 27760886 TI - An Empirical Study of Design Parameters for Assessing Differential Impacts for Students in Group Randomized Trials. AB - BACKGROUND: Prior research has investigated design parameters for assessing average program impacts on achievement outcomes with cluster randomized trials (CRTs). Less is known about parameters important for assessing differential impacts. OBJECTIVES: This article develops a statistical framework for designing CRTs to assess differences in impact among student subgroups and presents initial estimates of critical parameters. RESEARCH DESIGN: Effect sizes and minimum detectable effect sizes for average and differential impacts are calculated before and after conditioning on effects of covariates using results from several CRTs. Relative sensitivities to detect average and differential impacts are also examined. SUBJECTS: Student outcomes from six CRTs are analyzed. MEASURES: Achievement in math, science, reading, and writing. RESULTS: The ratio of between cluster variation in the slope of the moderator divided by total variance-the "moderator gap variance ratio"-is important for designing studies to detect differences in impact between student subgroups. This quantity is the analogue of the intraclass correlation coefficient. Typical values were .02 for gender and .04 for socioeconomic status. For studies considered, in many cases estimates of differential impact were larger than of average impact, and after conditioning on effects of covariates, similar power was achieved for detecting average and differential impacts of the same size. CONCLUSIONS: Measuring differential impacts is important for addressing questions of equity, generalizability, and guiding interpretation of subgroup impact findings. Adequate power for doing this is in some cases reachable with CRTs designed to measure average impacts. Continuing collection of parameters for assessing differential impacts is the next step. PMID- 27760885 TI - Prasugrel versus clopidogrel in stent-assisted coil embolization of unruptured intracranial aneurysms. AB - Background Thromboembolic complications are the main problem in stent-assisted coil embolization of unruptured intracranial aneurysms. The combination of aspirin and clopidogrel is generally used to decrease these complications, but some patients do not respond to clopidogrel and have a higher risk of stent thrombosis. In cardiology, clinical trials have shown that prasugrel reduced the incidence of ischaemic events in patients with acute coronary syndrome compared with clopidogrel but, according to several authors, prasugrel would produce an increased risk of cerebral haemorrhagic complications. Objective The purpose of this study was to determine whether prasugrel would be more effective than clopidogrel in reducing procedural events in patients with an unruptured aneurysm treated endovascularly with coils and stent. Materials and methods Two hundred consecutive patients with intracranial aneurysms were treated using coiling and stenting procedures. The first 100 patients were administered a dual antiplatelet of aspirin and clopidogrel, while the remaining 100 patients were administered a dual antiplatelet of aspirin and prasugrel. In each group data were collected on procedural and periprocedural haemorrhagic and ischaemic complications. Results Aneurysmal occlusion and haemorrhagic complications rates were identical in both groups. The number of thromboembolic events observed in the two groups of our study did not differ significantly, but the prasugrel group included more wide neck aneurysms and more flow-diverted stents. Moreover, complications in the prasugrel group were more benign, explaining the significant difference in clinical outcomes between the two groups on Day 30. Conclusions Prasugrel reduces the clinical consequences of thromboembolic complications of endovascular treatment with stenting and coiling of unruptured intracranial aneurysms. PMID- 27760887 TI - Comparative Effectiveness of Three Occupational Therapy Sleep Interventions: A Randomized Controlled Study. AB - Although sleep intervention is within the domain of occupational therapy, few studies exist supporting practice. Effectiveness of three sleep interventions was compared: Dreampad Pillow(r), iRest(r) meditation, and sleep hygiene. Twenty-nine participants were randomly assigned to the Dreampad Pillow(r) ( n = 10), iRest(r) meditation ( n = 9), and sleep hygiene ( n = 10) groups. In Phase 1, all participants used a 7-day sleep hygiene regimen to reduce poor sleep habits. In Phase 2 (14 days), 10 participants used the Dreampad Pillow(r) and sleep hygiene, nine used the iRest meditation and sleep hygiene, and 10 continued sleep hygiene only. At intervention-end, the iRest meditation group experienced statistically greater time asleep than both the Dreampad Pillow(r) ( p < .006, d = 1.87) and sleep hygiene groups ( p < .03, d = 1.80). The Dreampad Pillow(r) group experienced statistically fewer nighttime awakenings than the iRest(r) meditation ( p < .04, d = -1.53) and sleep hygiene ( p < .004, d = -1.43) groups. No differences were found between groups in perceived sleep quality, length of time needed to fall asleep, and fatigue level next day. This study provides support for sleep interventions within occupational therapy's domain. PMID- 27760888 TI - Elevated thyroid stimulating hormone levels are associated with metabolic syndrome in a Chinese community-based population of euthyroid people aged 40 years and older AB - This study investigated whether high-normal thyrotropin (TSH) levels are associated with metabolic syndrome in euthyroid Chinese people>=40 years old. Clinical and metabolic factors were assessed in 2,356 subjects (40-77 years old) with TSH levels in the normal range (0.35-5.00 mU/L). Using 2.50 mU/L as the cut off point of TSH level within the normal range, we divided subjects into the high TSH (2.50-5.00 mU/L; n = 1,064) and low-TSH (0.35-2.50 mU/L; n = 11,292) group. The results showed that the mean levels of body mass index (BMI), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and fasting plasma glucose (FPG) were higher in the high-TSH group and TSH levels were significantly positively correlated with BMI, LDL-C, TC, and FPG. The prevalence of central obesity, hypertriglyceridemia, low high density lipoprotein cholesterol (HDL-C), and high FPG (>5.60 mmol/L) was significantly higher in females and subjects with high-TSH levels. Metabolic syndrome was also more prevalent in the high-TSH group. People over the age of 40 years with high-normal TSH levels had a 1.2-fold increased risk of metabolic syndrome, compared with those with low-normal TSH levels, after adjusting for age and gender. In conclusion, high normal TSH is a risk factor for metabolic syndrome in people>=40 years old. PMID- 27760889 TI - G-Aminobutyric acid promotes methionine-choline deficient diet-induced nonalcoholic steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and a major cause of liver fibrosis worldwide. G-Aminobutyric acid (GABA) is one of the most abundant inhibitory neurotransmitters in the central nervous system. Recently, it has been reported that GABAergic signaling pathways are found in various non-neuronal tissues including the immune system and play a functional role. In the present study, we investigated whether administration of GABA has effects on NASH through its immunomodulatory effects. To test this hypothesis, C57BL/6 mice were fed a methionine-choline-deficient (MCD) diet for 8 weeks. After four weeks into MCD feeding, mice were provided with plain water (control) or water containing 2 mg/mL of GABA for the subsequent 4 weeks. Using this MCD diet-induced NASH model, we found that mice receiving GABA showed more severe steatohepatitis and liver fibrosis than control mice. This increased liver damage was confirmed by higher levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) compared to the control group. In accordance with increased liver steatohepatitis, NASH-related and inflammatory gene expression (collagen alpha1, tissue inhibitor of metalloproteinase-1, TNF-alpha) in the liver was markedly increased in GABA-treated mice. Furthermore, GABA directly enhanced production of inflammatory cytokines including IL-6 and TNF-alpha in LPS activated RAW macrophage cells and increased TIB-73 hepatocyte death. Such effects were abolished when GABA was treated with bicuculline, a competitive antagonist of GABA receptors. These results suggest that oral administration of GABA may be involved in changes of the liver immune milieu and conferred detrimental effects on NASH progression. PMID- 27760891 TI - Slowly progressive insulin-dependent (type 1) diabetes positive for anti-GAD antibody ELISA test may be strongly associated with a future insulin-dependent state. AB - Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM), believed to be caused by beta-cell destruction through islet-cell autoimmunity, gradually progresses to an insulin-dependent state over time. Although the presence of anti-glutamic acid decarboxylase antibody (GADA) is required for the diagnosis of SPIDDM, a recent change in the GADA assay kit from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) yields mismatched GADA test results between the two kits, leading to confusion in understanding the pathological conditions of SPIDDM in Japan. Thus, this study aimed to clarify the difference in the clinical characteristics of GADA-ELISA-positive and GADA-ELISA negative patients originally diagnosed as SPIDDM by GADA-RIA test. As a result, 42 of 63 original GADA-RIA-positive SPIDDM patients (66.7%) were found to be GADA ELISA-positive, whereas the remaining 21 patients (33.3%) were found to be GADA ELISA-negative. In patients with shorter disease duration, GADA-ELISA-positive patients showed significantly lower serum C-peptide levels than GADA-ELISA negative patients. Meanwhile, in patients with longer disease duration, serum C peptide levels were comparably decreased in GADA-ELISA-positive and GADA-ELISA negative patients. A significant inverse correlation between serum C-peptide level and disease duration was observed in GADA-ELISA-negative patients, but not in GADA-ELISA-positive patients, suggesting that insulin secretory capacity may be gradually impaired over time also in GADA-ELISA-negative SPIDDM patients. In conclusion, physicians should be aware that GADA-ELISA-positive SPIDDM may be strongly associated with a future insulin-dependent state. Meanwhile, physicians should be careful in treating GADA-ELISA-negative SPIDDM patients diagnosed as type 2 DM, and cautiously follow the clinical course, in accordance with SPIDDM. PMID- 27760890 TI - Pathology and molecular characterization of recent Leucocytozoon caulleryi cases in layer flocks. AB - Leucocytozoonosis was found in three layer farms in chickens with suspected fatty liver or fatty liver hemorrhagic syndrome in Korea between 2009 and 2011. These layer chicken flocks showed both mortality and decreased egg production for one or two weeks when they were between 59 and 82 weeks old. At the necropsy, the most prominent gross lesions were found in the liver, which was enlarged, had a fragile texture, exhibited yellowish discolorations, and had various hemorrhagic lesions. Tissue reactions associated with megaloschizonts specific for Leucocytozoon caulleryi were prominent upon microscopic examination of the liver without significant lipidosis. In addition, the ovaries and uterus were the most affected organs for Leucocytozoon caulleryi multiplication, which led to decreased egg productions. Molecular studies with formalin-fixed, paraffin embedded tissues were performed in search of a partial region of the cytochrome b gene for hemosporidian parasites. Based on these results, the causal agent was determined to be closely related to Leucocytozoon caulleryi reported in Japan and Malaysia. In this study, we describe recently re-occurring leucocytozoonosis in layer chickens, which required histopathology for disease diagnosis. To prevent outbreaks and maintain chicken health and egg production, layer chickens need to be monitored for symptoms of leucocytozoonosis. PMID- 27760892 TI - Investigation of sleep-wake rhythm in non-human primates without restraint during data collection. AB - To understand sleep mechanisms and develop treatments for sleep disorders, investigations using animal models are essential. The sleep architecture of rodents differs from that of diurnal mammals including humans and non-human primates. Sleep studies have been conducted in non-human primates; however, these sleep assessments were performed on animals placed in a restraint chair connected via the umbilical area to the recording apparatus. To avoid restraints, cables, and other stressful apparatuses and manipulations, telemetry systems have been developed. In the present study, sleep recordings in unrestrained cynomolgus monkeys (Macaca fascicularis) and common marmoset monkeys (Callithrix jacchus) were conducted to characterize normal sleep. For the analysis of sleep-wake rhythms in cynomolgus monkeys, telemetry electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG) signals were used. For the analysis of sleep-wake rhythms in marmosets, telemetry EEG and EOG signals were used. Both monkey species showed monophasic sleep patterns during the dark phase. Although non-rapid eye movement (NREM) deep sleep showed higher levels at the beginning of the dark phase in cynomolgus monkeys, NREM deep sleep rarely occurred during the dark phase in marmosets. Our results indicate that the use of telemetry in non-human primate models is useful for sleep studies, and that the different NREM deep sleep activities between cynomolgus monkeys and common marmoset monkeys are useful to examine sleep functions. PMID- 27760893 TI - The effects of workplace psychosocial factors on whether Japanese dual-earner couples with preschool children have additional children: a prospective study. AB - This study explored the effect of workplace psychosocial factors (job demand, job control, and workplace social support) on dual-earner couples in Japan having additional children, using a prospective study design. We conducted a 2-year prospective cohort study with 103 dual-earner couples with preschool children in Japan, as part of the Tokyo Work-Family Interface Study II. We used multivariable logistic regression analyses to evaluate the prospective association of job strain (categorized into low-strain job, active job, passive job, and strain job groups) and workplace social support (high and low) with couples having additional children during the follow-up period, adjusting for age, for men and women separately. Men in the active job group (i.e., with high job demands and high job control) had a significantly higher odds ratio (OR) of having additional children during the follow-up period, after controlling for age (OR 9.07, 95% confidence interval: 1.27-64.85). No significant association between any workplace psychosocial factor and having additional children was confirmed among women. Having an active job may have a positive influence on having additional children among men in dual-earner couples. PMID- 27760895 TI - Endophilin A2 Influences Volume-Regulated Chloride Current by Mediating ClC-3 Trafficking in Vascular Smooth Muscle Cells. AB - BACKGROUND: Previous research has demonstrated that ClC-3 is responsible for volume-regulated Cl-current (ICl.vol) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration ofICl.vol.Methods and Results:Volume-regulated chloride current (ICl.vol) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction. Live cell imaging was used to observe ClC-3 transporting. The results showed that an overexpression of endophilin A2 could increaseICl.vol, while endophilin A2 knockdown decreasedICl.vol. In addition, the SH3 domain of endophilin A2 mediated its interaction with ClC-3 and promotes ClC-3 transportation from the cytoplasm to cell membranes. The regulation of ClC-3 channel activity was also verified in basilar arterial smooth muscle cells (BASMCs) isolated from endophilin A2 transgenic mice. Moreover, endophilin A2 increase VSMCs proliferation induced by endothelin-1 or hypo osmolarity. CONCLUSIONS: The present study identified endophilin A2 as a ClC-3 channel partner, which serves as a new ClC-3 trafficking insight in regulatingICl.volin VSMCs. This study provides a new mechanism by which endophilin A2 regulates ClC-3 channel activity, and sheds light on how ClC-3 is transported to cell membranes to play its critical role as a chloride channel in VSMCs function, which may be involved in cardiovascular diseases. (Circ J 2016; 80: 2397-2406). PMID- 27760894 TI - Development of reproductive engineering techniques at the RIKEN BioResource Center. AB - Reproductive engineering techniques are essential for assisted reproduction of animals and generation of genetically modified animals. They may also provide invaluable research models for understanding the mechanisms involved in the developmental and reproductive processes. At the RIKEN BioResource Center (BRC), I have sought to develop new reproductive engineering techniques, especially those related to cryopreservation, microinsemination (sperm injection), nuclear transfer, and generation of new stem cell lines and animals, hoping that they will support the present and future projects at BRC. I also want to combine our techniques with genetic and biochemical analyses to solve important biological questions. We expect that this strategy makes our research more unique and refined by providing deeper insights into the mechanisms that govern the reproductive and developmental systems in mammals. To make this strategy more effective, it is critical to work with experts in different scientific fields. I have enjoyed collaborations with about 100 world-recognized laboratories, and all our collaborations have been successful and fruitful. This review summarizes development of reproductive engineering techniques at BRC during these 15 years. PMID- 27760897 TI - A Term Infant of Neonatal Toxic Shock Syndrome-Like Exanthematous Disease Complicated with Hemophagocytic Syndrome. AB - Neonatal toxic shock syndrome-like exanthematous disease (NTED) is a newly recognized neonatal infectious disease, caused by the superantigen toxic shock syndrome toxin-1 (TSST-1). TSST-1 is mainly produced by methicillin-resistant Staphylococcus aureus, and the immune responses to TSST-1 are known to cause toxic shock syndrome, a life-threatening infectious disease. The clinical symptoms of NTED are skin rash, fever, and thrombocytopenia, but severe thrombocytopenia is rare in term infants with NTED. Although the cause of NTED is the same as that of toxic shock syndrome, the clinical symptoms of NTED are milder than toxic shock syndrome. The mild phenotype of NTED has been explained by selectively elevated serum levels of anti-inflammatory cytokine interleukin (IL)-10, which suppress immune responses to TSST-1. In the present study, we report a term female infant of NTED complicated with hemophagocytic syndrome (HPS). HPS is characterized by systemic inflammation and hemophagocytosis, caused by uncontrolled activation of T cells and macrophages. The serum IL-10 level of the patient at 4 days of age was relatively low (67 pg/mL) for NTED but still higher than normal controls (< 2.0 pg/mL). The patient also showed severe thrombocytopenia. We speculate that the serum IL-10 level of the patient was enough to supress immune responses to TSST-1, thereby resulting in NTED, but not enough to suppress the onset of HPS. This is the first reported case of NTED complicated with HPS. If a physician encounters an NTED patient with severe cytopenia, microscopic examination of peripheral blood smear should be carried out to exclude HPS. PMID- 27760896 TI - Gustatory Salivation Is Associated with Body Mass Index, Daytime Sleepiness, and Snoring in Healthy Young Adults. AB - The taste detection system for oral fatty acid may be related to obesity. In addition, sleep is intrinsically and closely related to food intake and metabolism. However, the association of gustatory salivation with body mass index (BMI), daytime sleepiness, or sleep habits is largely unknown. Therefore, we evaluated the relationship between gustatory salivation and BMI, Epworth sleepiness scale (ESS, a daytime sleepiness scale) or sleep habits among 26 healthy young individuals (20 males and 6 females; mean age: 26.0 +/- 4.3 years). We also measured the saliva flow rate (SFR) that was induced by gum-chewing or each of three prototypical tastants (acetic acid, sucrose, and NaCl). Further, the SFR was induced by fatty acid, provided as oleic acid (OA) homogenized in non fat milk. All participants showed normal rates of salivation during resting and gum-chewing states. The increase in the SFR induced by OA, but not by each of the three tastants, was associated with BMI. Moreover, both daytime sleepiness level and frequency of snoring were associated with the increase in the SFR induced by NaCl. These results suggest that BMI is associated with salivation induced by oral fatty acid exposure. Additionally, the regulatory mechanism for the NaCl induced salivation reflex may have a relationship with impairments of the respiratory control system that are related to snoring during sleep and lead to daytime sleepiness because of insufficient sleep. Thus, measurement of gustatory salivation might contribute to the evaluation and prevention of obesity and sleep related breathing disorders. PMID- 27760898 TI - Activation of G protein-coupled estrogen receptor 1 mimics, but does not mediate, the anti-proliferative action of estradiol on pituitary lactotrophs in primary culture. AB - Estrogen binds to nuclear estrogen receptors (ERs) to modulate transcription of target genes in estrogen-responsive cells. However, recent studies have shown that estrogen also binds to cytoplasmic membrane ERs to modulate protein kinase signaling cascades, leading to non-genomic actions. We investigated whether either nuclear or membrane ERs, including G protein-coupled estrogen receptor 1 (Gper1), mediate the inhibitory action of estrogen on insulin-like growth factor 1 (IGF-1)-induced proliferation of pituitary lactotrophs in primary culture. The cytoplasmic membrane-impermeable bovine serum albumin-conjugated estradiol (BSA E2) at 1 nM, an equimolar concentration at which 17beta-estradiol (E2) exerts anti-proliferative effects, did not inhibit IGF-1-induced lactotroph proliferation. In contrast, diethylstilbestrol, which is known to selectively activate nuclear ERs but not membrane ERs, inhibited IGF-1-induced proliferation and modulated mRNA expression of estrogen-responsive genes to a similar degree as E2. Activation of Gper1 by its agonist G-1 inhibited IGF-1-induced proliferation in a dose-dependent manner, but it had little effect on modulation of mRNA expression of estrogen-responsive genes. However, blockade of Gper1 by its antagonist G-15 did not affect the inhibitory action of E2 on IGF-1-induced proliferation. Here, we demonstrate that E2 inhibition of lactotroph proliferation is due to nuclear ER-mediated genomic action. Our results suggest that activation of Gper1 mimics, but does not mediate, the anti-proliferative action of E2 on lactotrophs. PMID- 27760899 TI - Small nonfunctional parathyroid cysts: single institution experience. AB - Parathyroid cysts (PCs) account for less than 1% of all parathyroid lesions and are most commonly located along thyroid lobes, rarely at ectopic sites. PCs are important because they can pose a differential diagnostic challenge against other cystic formations of the neck. PCs can be functional (elevated serum parathyroid hormone level) and nonfunctional. Four cases of nonfunctional PCs are presented. All four female patients underwent physical examination and ultrasonography of the neck with ultrasound-guided fine-needle aspiration biopsy (UG-FNA). The material thus obtained was stained by the standard May-Grunwald-Giemsa method. Parathyroid hormone level was determined in aspirate and serum, along with serum levels of total calcium, inorganic phosphates. In two asymptomatic patients, remission occurred after initial aspiration biopsy; one patient had compression syndrome with vocal cord paresis that required surgical treatment; and one patient had cyst recurrence that was surgically removed. Cystic neck masses can pose a major differential diagnostic problem considering different approach, treatment method, and preoperative and postoperative follow up. Surgical treatment is necessary in case of functional and large nonfunctional PCs (due to compression syndrome), whereas individualized therapeutic approach is used in case of small nonfunctional PCs. Ultrasonography with UG-FNA, cytologic analysis of the material obtained, and determination of parathyroid hormone level in aspirate and serum are crucial for making an accurate diagnosis. PMID- 27760900 TI - The Difference in Backscatter Factors of Diagnostic X-rays by the Difference in the Scattering Medium and in the Objective Dose. AB - The diagnostic reference levels (DRLs) of the general X-ray radiography are defined by the absorbed dose of air at the entrance surface with backscattered radiation from a scattering medium. Generally, the entrance surface dose of the general X-ray radiography is calculated from measured air kerma of primary X-ray multiplied by a backscatter factor (BSF). However, the BSF data employed at present used water for scattering medium, and was calculated based on the water absorbed dose by incident primary photons and backscattered photons from the scattering medium. In the calculation of air dose at the entrance surface defined in DRLs, there are no theoretical consistencies for using BSF based on water dose, and this may be a cause of calculation error. In this paper, we verified the difference in BSF by the difference in the scattering medium and by the difference in the objective dose by means of the Monte Carlo simulation. In this calculation, the scattering medium was set as water and the soft-tissue, and the objective dose was set as air dose, water dose, soft-tissue dose, and skin dose. The difference in BSF calculated by the respective combination was at most about 1.3% and was less than 1% in most cases. In conclusion, even if the entrance surface dose defined by DRLs of general X-ray radiography is calculated using BSF, which set both the scattering medium and the object substance of the absorbed dose as water, a so big error doesn't show. PMID- 27760901 TI - Image Format Conversion to DICOM and Lookup Table Conversion to Presentation Value of the Japanese Society of Radiological Technology (JSRT) Standard Digital Image Database. AB - Japanese Society of Radiological Technology (JSRT) standard digital image database contains many useful cases of chest X-ray images, and has been used in many state-of-the-art researches. However, the pixel values of all the images are simply digitized as relative density values by utilizing a scanned film digitizer. As a result, the pixel values are completely different from the standardized display system input value of digital imaging and communications in medicine (DICOM), called presentation value (P-value), which can maintain a visual consistency when observing images using different display luminance. Therefore, we converted all the images from JSRT standard digital image database to DICOM format followed by the conversion of the pixel values to P-value using an original program developed by ourselves. Consequently, JSRT standard digital image database has been modified so that the visual consistency of images is maintained among different luminance displays. PMID- 27760902 TI - MRI Claustrophobia: Assessment and Management. PMID- 27760903 TI - 5. Japanese Society of Radiological Technology Code of Ethics. PMID- 27760904 TI - 9. Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma. PMID- 27760906 TI - About that The Japan Fair Trade Council of the Medical Devices Industry (JFTC) Shall Perform the Following Functions; Matters Pertaining to Promotion of Greater Awareness and Understanding of The Fair Competition Code (FCC). PMID- 27760905 TI - C-programing for Image Processing: Introduction of the Experience-based E learning. PMID- 27760907 TI - Deblurring Algorithm for Blurred Images Caused by Patient Motion in Radiography. AB - In radiography, when a blurred image caused by patient motion was acquired, radiologists retake an image as needed. However, retaking an image leads to extra radiation exposure to patients and reducing work efficiency. This study proposes the deblurring algorithm for blurred images caused by patient motion in radiography. In the proposed algorithm, we first take a video using an optical device during radiography. Second, we calculate the optical flow between each frame, and estimate a point spread function (PSF) based on the optical flows. Finally, we restore the blurred image by deconvolution processing. In this study, blurred images with the blur width from 1.0 mm to 5.0 mm at 0.5 mm intervals were obtained by using own moving body phantom, and applied proposed algorithm for each blurred image. To evaluate the algorithm, we measured blur area and structural similarity (SSIM) of the blurred images and deblurred images, and compared the values. As a result, a significant decrease in blur area and a significant increase in SSIM were confirmed in each blur condition. These results suggest the usefulness of the proposed algorithm. PMID- 27760908 TI - Trends for the Geographic Distribution of Radiological Resources in Hokkaido, Japan: Data Analysis Using Gini Coefficient and Herfindahl-Hirschman Index. AB - The aim of this study is to analyze the maldistribution and the trends in the geographic distribution of radiological resources in secondary medical areas of Hokkaido. The distribution was measured by combining the Gini coefficient (GC), which is an indicator of inequality of distribution, and the Herfindahl-Hirschman index (HHI), which is mainly used to assess market concentration. Data concerning the distribution of radiological resources, such as CT, MRI, radiotherapy facilities (RTF), radiological technologists (RT), and medical doctors were obtained from official publications. CT was more equally distributed, and RTF was more inequality than other radiological resources in 2014. Radiological resources excluded CT were higher degree of concentration than population distribution, and it showed that they were located relatively more intensively in urban areas than in rural areas. During the period 1999-2014, the GC for CT, MRI, RTF, and RT decreased, while the HHI increased. These trends indicated increased equality of distribution of CT, MRI, RTF, and RT and the concentration in urban areas. This study suggested that GC and HHI could be powerful indicators for allocation planning of medical resources with further analysis of the maldistribution of medical resources. PMID- 27760909 TI - Evaluation of Resolution Recovery for Each Collimator in Brain Perfusion Image. AB - PURPOSE: This study aimed to verify the resolution recovery for each collimator in the brain perfusion image. METHOD: To verify the effect of the resolution recovery for each collimator, we evaluated via the three-dimensional brain phantom (phantom) and the normal brain perfusion single photon emission computed tomography (SPECT) data. These data were reconstructed using the three dimensional ordered subset expectation maximization method (3D-OSEM) (Evolution for boneTM) that was performed with scatter correction, attenuation correction, and resolution recovery (RR). The performance of resolution recovery was evaluated in the two collimator systems (ELEGP and MEGP) reconstruction condition via the contrast value, mean counts, normalized mean square error (NMSE), and regional brain activity. RESULT: In the "with resolution recovery (+RR)", the NMSE indicated minimum value with SI (subset*iteration) = 100, cut-off frequency (Fc) = 0.50 cycles/cm. The contrast value in the "+RR" increased 20% for the cortical region and decreased 28% and 6% at ELEGP collimator and MEGP collimator for the central region, as compared to the "without resolution recovery (-RR)". In the phantom study, the error of the brain activity using MEGP collimator at the temporal lobe and sub-lobar decreased 15%, compared with ELEGP collimator in the + RR. In the clinical study, the error of the regional brain activity using MEGP collimator in the "+RR" increased from 3% to 8%, compared with "-RR". DISCUSSION: The accurate resolution recovery was obtained at SI = 100 and Fc = 0.50 cycles/cm. The contrast value and regional brain activity at the central region decreased due to incomplete resolution recovery by use of ELEGP collimator. PMID- 27760910 TI - Decontamination of the Activation Product Based on a Legal Revision of the Cyclotron Vault Room on the Non-self-shield Compact Medical Cyclotron. AB - The non-self-shield compact medical cyclotron and the cyclotron vault room were in operation for 27 years. They have now been decommissioned. We efficiently implemented a technique to identify an activation product in the cyclotron vault room. Firstly, the distribution of radioactive concentrations in the concrete of the cyclotron vault room was estimated by calculation from the record of the cyclotron operation. Secondly, the comparison of calculated results with an actual measurement was performed using a NaI scintillation survey meter and a high-purity germanium detector. The calculated values were overestimated as compared to the values measured using the NaI scintillation survey meter and the high-purity germanium detector. However, it could limit the decontamination area. By simulating the activation range, we were able to minimize the concrete core sampling. Finally, the appropriate range of radioactivated area in the cyclotron vault room was decontaminated based on the results of the calculation. After decontamination, the radioactive concentration was below the detection limit value in all areas inside the cyclotron vault room. By these procedures, the decommissioning process of the cyclotron vault room was more efficiently performed. PMID- 27760911 TI - Vessel Visibility Assessment of Low Tube Voltage Coronary Computed Tomography Angiography Determined with Contrast-to-Noise Ratio. AB - PURPOSE: The purpose of this study was to investigate the association of vessel visibility and radiation dose using contrast-to-noise ratio (CNR) method with low tube voltage in coronary computed tomography angiography (c-CTA). METHODS: We performed electrocardiogram-gated scan of 2.0-mm diameter simulated vessel in the center of the cardiac phantom by the use of a 64-detector CT scanner. Reference CNR was calculated from the target coronary CT number (CTnumberA; 350 Hounsfield units [HU]), epicardial fat CT number (CTnumberB; -100 HU), and target epicardial fat standard deviation (SD) number (SDB; 25 HU) at the 120 kV. We obtained the tube current at low tube voltage (100 and 80 kV) to perform the similar reference CNR at 120 kV. The full widths at half maximum from axial images were evaluated with quantitative evaluation and three types of visualizations of the vessel phantom were evaluated with the qualitative evaluations. RESULTS: CTnumberA of 100 and 80 kV were increased by 26% and 50%, respectively, compared with 120 kV (P<0.01). SDB was also increased by a similar ratio (P<0.01). CTDIvol of 100 and 80 kV were decreased by 39% and 51%, respectively, compared with 120 kV (P<0.05). There were no significant voltage differences among three tubes in quantitative and qualitative evaluations at the same CNR (P> 0.05). CONCLUSION: In this phantom study, these results show that the CNR method with low tube voltage achieves radiation dose reduction without decreasing the image quality. PMID- 27760912 TI - Challenge to Increase Original Research Papers. PMID- 27760913 TI - Is the Effect of Omega-3 Polyunsaturated Fatty Acids Dependent on Life-Style, Severity of Disease, and Use of Concomitant Medications? PMID- 27760914 TI - Erratum: J Reprod Dev, Vol. 59, No. 3, p. 266-272, Dynorphin-Kappa Opioid Receptor Signaling Partly Mediates Estrogen Negative Feedback Effect on LH Pulses in Female Rats. AB - Figure 3(a) have been corrected. PMID- 27760915 TI - Identification of an antiviral host transmembrane protein MARCH8. AB - Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins; however, its physiological roles remain unknown. Here we identify MARCH8 as a novel antiviral factor. The overexpression of MARCH8 in virus producing cells did not affect levels of lentivirus production, but markedly reduced viral infectivity. MARCH8 blocked the incorporation of HIV-1 envelope glycoprotein into virions by downregulating it from the cell surface, probably through their interaction, resulting in reduced viral entry efficiency. The inhibitory effect of MARCH8 on vesicular stomatitis virus G-glycoprotein was even more remarkable, suggesting a broad-spectrum inhibition of enveloped viruses by MARCH8. Importantly, the endogenous expression of MARCH8 was high in monocyte-derived macrophages and dendritic cells, and MARCH8 depletion in macrophages significantly increased the infectivity of virions produced from these cells. Our findings thus indicate that MARCH8, which is highly expressed in terminally differentiated myeloid cells, is a potent antiviral host transmembrane protein that reduces virion incorporation of viral envelope glycoproteins. PMID- 27760916 TI - The significance of Hsp70 subnetwork for Dengue virus lifecycle. AB - Viruses hijack host machineries for replicating themselves efficiently. Host protein quality control machineries (QC) not only assist protein folding to form bona fide proteins with active functions but also get rid of un/misfolded proteins via degradation to maintain the protein homeostasis. Previous studies have reported that viruses utilize QC at various steps for their lifecycles. Recently we defined Hsp70s and their cochaperones, DnaJs functions on Dengue lifecycle. Here we summarize the significance of QC on Dengue virus. PMID- 27760917 TI - Host-adaptive mechanism of H5N1 avian influenza virus hemagglutininn. AB - The H5N1 subtype is a highly pathogenic avian influenza virus currently circulating in birds in parts of Asia and northeast Africa, which has caused fatal human infections since 1997. Continuous circulation of the virus in endemic areas has allowed genetically diverse viruses to emerge, increasing the risk of H5N1 human infection. Although human infections with H5N1 have to date been limited, experimental evidence of the aerosol transmission of mutated viruses in a mammalian infection model has revealed the pandemic potential of H5N1 virus. One of the most important viral factors for host-adaptation of influenza virus is hemagglutinin (HA), which is the principal antigen on the viral surface and is responsible for viral binding to host receptors as well as endosomal membrane fusion. Our recent reports suggest that a fine balance of the HA properties, including receptor binding specificity and pH stability, is crucial for replication in human respiratory epithelia. This review provides an overview of current knowledge on the host-adaptive mechanism of H5N1 virus HA. PMID- 27760918 TI - R-gene-mediated resistance to plant viruses. AB - Most of the reported dominant disease-resistance genes in plants, R genes, encode NB-LRR immune receptors. Plant genomes carry many NB-LRR type R genes that recognize specific pathogens and induce resistance against them. Thus, this immune system in plants is thought to perform similar functions as the adaptive immune system in animals. In this review, we provide an overview of the resistance mechanisms, evolution, and agricultural applications of R genes against plant viruses. We also introduce recent advances in research into the regulatory mechanisms of R gene expression, focusing on regulation by microRNAs and introns. One of the most intriguing phenomena that occur following R gene mediated recognition of viruses is programmed cell death around the initial infection site, although its significance in the survival strategies of plants remains to be elucidated. We discuss the possible benefits for plants of inducing such programmed cell death based on our empirical observations and some hypotheses from an ecological point of view. PMID- 27760919 TI - Unique symbiotic viruses in plants: Endornaviruses. AB - Linear double-stranded RNAs (dsRNAs) of about 15 kbp in length are often found from healthy plants, such as bell pepper and rice plants. Nucleotide sequencing and phylogenetic analyses reveal that these dsRNAs are not transcribed from host genomic DNAs, encode a single long open reading frame (ORF) with a viral RNA dependent RNA polymerase domain, and contain a site-specific nick in the 5' region of their coding strands. Consequently the International Committee on Taxonomy of Viruses has approved that these dsRNAs are viruses forming a distinct taxon, the family Endornaviridae the genus Endornavirus. Endornaviruses have common properties that differ from those of conventional viruses: they have no obvious effect on the phenotype of their host plants, and they are efficiently transmitted to the next generation via both pollen and ova, but their horizontal transfer to other plants has never been proven. Conventional single-stranded RNA viruses, such as cucumber mosaic virus, propagate hugely and systemically in host plants to sometime kill their hosts eventually and transmit horizontally (infect to other plants). In contrast, copy numbers of endornaviruses are low and constant (about 100 copies/cell), and they symbiotically propagate with host plants and transmit vertically. Therefore, endornaviruses are unique plant viruses with symbiotic properties. PMID- 27760920 TI - Molecular genetics and Biochemical analyses of mycoviruses in rice blast fungus, Magnaporthe oryzae. AB - We have found a novel mycovirus, MoCV1 in the rice blast fungus, Magnaporthe oryzae. MoCV1 has five dRNA segments as genome, and belong to Chrysoviridae tentatively. Using micro-spin column method or one-step reverse-transcription PCR (RT-PCR) assay, we detected a MoCV1-related virus from M. oryzae in Japan, whose sequence shares considerable identity with that of the MoCV1 Vietnamese isolate. To establish a system for comprehensive survey of MoCV1 infection in the field, we developed a reverse-transcription loop-mediated isothermal amplification (RT LAMP) assay for direct detection of the virus. In this review, we introduce our current knowledges of MoCV1 properties for biochemical and molecular genetic aspects and also describe its negative effects to host fungus, which imply potentiality to utilize MoCV1 as bio-controller. Heterologous gene-expression system in yeast is employed to investigate biological activities or functions of mycoviral proteins in fungal host cells. MoCV1-A infection caused hypovirulence to the host fungus, unexpectedly, also resulted in the change of pathogenic races in several differential rice lines, namely S (compatible) to R (incompatible) reaction or R to S. The cause of epigenetic alteration is also discussed. PMID- 27760921 TI - Migration of plant viruses: Time correlations with the agriculture history and human immigration. AB - In this review, I made the phylodynamic comparisons of three plant viruses, Turnip mosaic virus (TuMV), Cauliflower mosaic virus (CaMV) and Cucumber mosaic virus (CMV), using the genomic sequences of a large numbers of isolates collected worldwide. We analyzed these genomic nucleotide sequences, in combination with published sequences, to estimate the timescale and rate of evolution of the individual genes of TuMV, CaMV and CMV. The main hosts of the viruses are Brassicaceae crops. We also compared these estimates from complete sequences with those from which non-synonymous and invariate codons had been removed. Our analyses provided a preliminary definition of the present geographical structure of three plant virus populations in the world, and showed that the time of migration of three plant viruses correlate well with agriculture history and human immigration. PMID- 27760922 TI - Advances in drug development for hepatitis C. AB - Chronic infection with hepatitis C virus (HCV) is a global public health burden. It has been only several decades since this virus was first identified. In the meantime, a lot of progress has been made in the fight against HCV. Although the development of pegylated interferon (PEG-IFN) and its combination with ribavirin (RBV) has significantly increased effectiveness of IFN-based treatment, candidate patients must be assessed for eligibility prior to the treatment due to side effects of the regimens and the rates of sustained virological response (SVR) were only around 50%. In 2011, the protease inhibitor (PI) Telaprevir was firstly approved as a direct-acting antiviral (DAA) for hepatitis C. The second generation of PIs was subsequently introduced and, by adding PI to Peg-IFN/RBV, the SVR rates were found to be raised to up to 80%. Further, with the recent approval of the NS5A inhibitors and the NS5B polymerase inhibitors and with the SVR rates reaching 90% or greater using IFN-free, DAA combination regimens, it is now expected that the majority of patients with chronic hepatitis C can be cured of infection in the near future. PMID- 27760923 TI - Anti-hepatitis C virus strategy targeting host entry factor claudin-1. AB - Chronic hepatitis C virus (HCV) infection is a major threat to global public health, because it is significantly correlated with the development of severe liver diseases including cirrhosis and hepatocellular carcinomas. Host molecules as well as viral factors are promising targets for anti-HCV preventive and therapeutic strategies. Multiple host factors such as CD81, SRBI, claudin-1, and occludin are involved in HCV entry into hepatocytes. In this paper, I first introduce our anti-HCV strategy targeting for host tight junction protein claudin 1. And this review also summarizes developments of other entry inhibitors to prevent initiation of HCV infection and spread. Entry inhibitors might be useful in blocking primary infections, such those as after liver transplantation, and in combination therapies with other anti-HCV agents such as direct-acting antivirals. PMID- 27760924 TI - Animal model for hepatitis C virus infection. AB - Hepatitis C virus (HCV) infects more than 170 million people in the world and chronic HCV infection develops into cirrhosis and hepatocellular carcinoma (HCC). Recently, the effective compounds have been approved for HCV treatment, the protease inhibitor and polymerase inhibitor (direct acting antivirals; DAA). DAA based therapy enabled to cure from HCV infection. However, development of new drug and vaccine is still required because of the generation of HCV escape mutants from DAA, development of HCC after treatment of DAA, and the high cost of DAA. In order to develop new anti-HCV drug and vaccine, animal infection model of HCV is essential. In this manuscript, we would like to introduce the history and the current status of the development of HCV animal infection model. PMID- 27760925 TI - Hepatitis C virus-induced glucose metabolic disorder. AB - Hepatitis C virus (HCV) infection often causes intrahepatic diseases, such as chronic hepatitis, liver chirrohsis, and hepatocellular carcinoma (HCC). Moreover, HCV infection exhibits various extrahepatic manifestations, such as thyroiditis, glucose and lipid metabolic disorder, and iron metabolic disorder. HCV infection is often associated with type 2 diabetes, involving hepatic fibrosis and poor prognosis. Type 2 diabetes increases the risk of HCC. We have been investigating molecular mechanisms of HCV-induced glucose metabolic disorder and we reported that HCV infection promotes hepatic gluconeogenesis through forkhead box O1 (FoxO1)-dependent pathway and that HCV infection suppresses the cell surface expression of glucose transporter 2 (GLUT2), resulting in suppression of glucose uptake. We have found that HCV NS5A protein plays important roles in these two independent pathways. Here we discuss the roles of HCV NS5A in HCV-induced glucose metabolic disorder. PMID- 27760926 TI - Roles of lipoprotein and apolipoprotein in HCV infection. AB - Although chronic infection of hepatitis C virus (HCV) induces disorders of lipid metabolism, HCV is known to utilize lipid metabolism for efficient propagation in the liver. Due to the morphological and physiological similarities of HCV particles to lipoproteins, lipid-associated HCV particles are named lipoviroparticles. Previous reports have shown that lipoprotein receptors or cholesterol transporter participate in the entry of lipoviroparticles. In addition, recent analyses revealed that exchangeable apolipoproteins directly interact with the viral membrane to generate infectious HCV particles. In this review, we would like to discuss about involvement of lipoprotein and apolipoprotein in HCV lifecycle. PMID- 27760927 TI - Regulation of hepatitis C virus genome replication by microRNA-122. AB - microRNA-122 (miR-122) is an abundant, liver-specific miRNA that regulates gene expression post-transcriptionally, typically by binding to the 3' untranslated region (UTR) of mRNAs, repressing their translation and mediating their degradation. Hepatitis C virus (HCV) is uniquely dependent on miR-122. Similar to conventional miRNA action, miR-122 recruits Argonaute-2 (AGO2) protein to the 5' UTR of the viral genome. However, in contrast to typical miRNA function, this stabilizes HCV RNA and slows its decay in infected cells. We found that HCV RNA is degraded primarily by the cytoplasmic 5' exonuclease XRN1 and that miR-122 acts to protect the viral RNA from XRN1-mediated 5' exonucleolytic decay. However, HCV replication still requires miR-122 in XRN1-depleted cells, suggesting additional functions. We also showed that miR-122 enhances HCV RNA synthesis by reducing viral genomes engaged in translation while increasing the fraction available for RNA synthesis. In this review, we summarize the recent progress on the regulatory mechanisms of HCV genome replication by miR-122. PMID- 27760928 TI - Developments in Biosecurity in the Netherlands. PMID- 27760929 TI - Trends in U.S. Policy on Dual Use Research of Concern. PMID- 27760930 TI - [Screening for Pain in Cancer Patients]. AB - The newly revised 2014 Set of Standards for"Designated Cancer Care Hospitals"mandated the screening of all cancer patients6 for their physical and psychological suffering systematically in both outpatient and inpatient settings as well as rapid response to the suffering detected. It is a step forward as a cancer control policy, but because the pain associated with cancer changes by time depending on factors such as disease progression and treatment, it must be evaluated repeatedly. Simply complying with the standard by measuring once, say on admission or at the initial visit, will not help patients. It is necessary to continuously monitor how the pain was treated and improved or worsened, and whether any new pain develops after admission. In the United States, campaigns to regard pain as the"fifth vital sign"have been are in action since 2001. They made the patient pain intensity be recorded on a numeric scale along with the body temperature on the same daily vital sign charts. However, the US experiences indicated that the simple screening for pain is not enough. One study reported that physicians took action to pain of moderate or greater intensity in only one sixth of the time. Numerical evaluation of pain intensity captures only one aspect of pain. What matters more to patients with pain, thus is more important to their clinicians, is the degree of impairment of patients in their daily lives due to pain. Our study group set as the goal of pain treatment the elimination of"things one is unable to do or has trouble doing because of pain". We systematically presented the attending physicians the degree of impairment of patient lifestyle due to pain rather than numbers, and physicians became more engaged in the prescribing or increasing the dose of opioids. PMID- 27760931 TI - [The Role of Preoperative Chemotherapy Depending on Breast Cancer Subtype]. AB - Following the discovery that the prognostic impact of preoperative chemotherapy depends on the primary breast cancer subtype, the treatment strategy for primary breast cancer changed. Pathologic complete response(pCR)with preoperative chemotherapy is predictive of a favorable prognosis in patients with HER2 type or triple-negative type breast cancer, but not in patients with ER-positive/HER2 negative, the so-called Luminal type, breast cancer. However, the role of preoperative chemotherapy in patients with Luminal-B type breast cancer who may need chemotherapy should be further assessed. Recent studies have reported severalsubtypes of triple-negative breast cancer, distinguishable by gene expression analysis, which may respond differently to treatment. Furthermore, novel agents, including pertuzumab or T-DM1 for HER2 type breast cancer, bevacizumab or PARP inhibitors for triple negative-breast cancer, or combination regimens with these novelagents, are expected to achieve higher pCR rates and improve patient prognosis. The tumor microenvironment may also play an important role in predicting treatment response or prognosis. It is important that tailor made treatment strategies for patients with primary breast cancer, especially for patients who will not respond favorably to current standard therapies, consider both the treatment effects and the medicaleconomic effects. PMID- 27760932 TI - [Neoadjuvant Chemotherapy for Gastric Cancer]. AB - Adjuvant chemotherapy aims to eradicate residual micro-metastatic tumor cells existing at distant sites outside the surgical field. The current standard adjuvant chemotherapy is S-1 for 1 year or capecitabine plus oxaliplatin for 6 months after D2 gastrectomy. However, there are some rooms in the overall survival of Stage III. Neoadjuvant chemotherapy(NAC)is a promising approach that combines intensive chemotherapy with high compliance; however, it is under development in Japan. Two JCOG phase II trials suggested that NAC was effective for bulky nodal disease. For scirrhous-type malignancy, a JCOG phase III trial is currently ongoing investigating the efficacy of a NAC regimen of S-1 plus CDDP. Another group is conducting 2 randomized phase II trials to compare different regimens and courses of NAC. So far, 2 courses of S-1 plus CDDP or 3 courses of S 1 plus oxaliplatin can be recommended as candidates for the test arm of future phase III studies of NAC. PMID- 27760933 TI - [Neoadjuvant Therapy in Multimodal Surgical Treatment for Squamous Cell Carcinoma of the Esophagus]. AB - Postoperative chemotherapy was initially conducted with surgical treatment as part of a multimodal treatment strategy for esophageal squamous cell carcinoma. Subsequently, a randomized trial comparing post- versus pre-operative chemotherapy with cisplatin and 5-fluorouracil demonstrated the superior efficacy of neoadjuvant treatment with FP(CF). However, the results of subgroup analysis based on T factor revealed no efficacy for cT3 tumors. To improve the survival rate in patients with cT3 tumors, treatments with neoadjuvant chemotherapy using FP(CF)plus docetaxel and concurrent FP(CF)plus radiation were conducted to assess the feasibility of preoperative adjuvant treatment and surgery after neoadjuvant treatment. These neoadjuvant regimens are expected to improve outcomes following surgical treatment. A randomized controlled phase III trial comparing FP(CF)versus DCF versus FP(CF)-RT as neoadjuvant treatments for locally advanced esophageal cancer is currently under investigation. PMID- 27760934 TI - [Neoadjuvant Chemotherapy Using S-1 for Pancreatic Cancer - Mid-Term Results]. AB - BACKGROUND: Although surgical resection is the only curative strategy for pancreatic cancer, the prognosis of patients with pancreatic cancer remains poor. Recently, neoadjuvant treatment has been frequently employed as a promising treatment. Here, the mid-term results of neoadjuvant chemoradiotherapy(NACRT)using S-1, which has been performed in our hospital since 2008, are reported. METHODS: Seventy-nine patients with resectable or borderline resectable pancreatic ductal adenocarcinoma, who had been intended to undergo NACRT treatment using S-1, were enrolled. The NACRT comprised radiotherapy( 1.8 Gy*28 days)and full-dose twice-daily oral S-1 given on the same days as the radiotherapy. The results of the NACRT and pancreatectomy and the patients' prognoses were evaluated. RESULTS: Fifty-five patients(69.6%)underwent pancreatectomy, with no case of mortality. The curative resection rate was 94.5%. Postoperative adjuvant chemotherapy was administered in 46 patients(83.6%). The 3 year survival rates of all 79 patients and 55 pancreatectomy patients were 40.1% and 50.4%, respectively. CONCLUSION: NACRT using S-1 was found to be feasible, and good mid-term outcomes were obtained. However, analysis of the long-term outcomes and comparisons with other novel anti-cancer drugs are still required. PMID- 27760935 TI - [A Multivariate Analysis of the Efficacy of Adjuvant Chemotherapy in Triple Negative Breast Cancer]. AB - Triple-negative breast cancers(TNBCs)are associated with early recurrence after surgery and unfavorable prognoses. To date, no effective therapies for TNBCs have been established. The present study was designed to evaluate the efficacy of adjuvant chemotherapy(ACT)for 111 TNBCs using a retrospective multivariate analysis(MVA). The intravenous(iv)ACTs included docetaxel, epirubicin, gemcitabine, and vinorelbine. The oral ACTs included UFT, doxifluridine, and cyclophosphamide. The 10-year disease-free survival(DFS)and overall survival(OS)rates were 77.5% and 86.0%, respectively. Recurrences were observed in 17 patients, and the first recurrence was most frequently located in the lung. MVA revealed that pT was a significant independent variable for poor DFS and OS. UFT was the only significant independent variable for improved DFS. The survival analysis also demonstrated that UFT alone may be an effective option for Stage I TNBCs. Furthermore, it suggested that the addition of further iv ACTs to UFT could improve the outcome in patients with Stage II-III TNBCs. PMID- 27760936 TI - [Clinical Experience of Ramucirumab for Treating Advanced Gastric Cancer]. AB - BACKGROUND: The REGARD and RAINBOW trials showed that ramucirumab(RAM)alone and RAM plus paclitaxel(PTX) were effective therapies for advanced gastric cancer patients previously treated with chemotherapy. In this retrospective study, we evaluated the safety and efficacy of RAM alone and PTX plus RAM in such patients. METHODS: Patients who were received RAM at 8mg/kg or RAM plus PTX at 80mg/m2(on days 1, 8, and 15 of a 28-day cycle)between June 2015 and March 2016 were enrolled in this study. We compared the clinical outcome of RAM alone(RAM group, n=10)with that of RAM plus PTX(PTX+RAM group, n=13). RESULTS: The RAM group contained many more patients with poor performance status or prior chemotherapy of 2 or more regimens than the PTX+RAM group. All patients in both groups received chemotherapy on an outpatient basis. One case of grade 3 or 4 hematological adverse events was found in the RAM group and 6 cases were found in the PTX+RAM group. The overall response rate was 10% in the RAM group and 30% in the PTX+RAM group. Progression-free survival was 54 days in the RAM group and 187 days in the PTX+RAM group(p=0.0374). Overall survival was 158 days in the RAM group and was not reached in the PTX+RAM group(p=0.1091). CONCLUSIONS: RAM alone and RAM plus PTX can be administered safely on an outpatient basis and are beneficial for advanced gastric cancer patients previously treated with chemotherapy. PMID- 27760937 TI - [A Retrospective Case Study of Combination Chemotherapy with Bevacizumab for Recurrent Ovarian Cancer]. AB - OBJECTIVES: Treatment for ovarian cancer with bevacizumab(Bmab)has been covered by public medical insurance in Japan since November 2013. It is recommended that the use of Bmab is limited to the first treatment for FIGO stage III or IV ovarian cancer. The OCEAN trial for platinum sensitivity in relapsed patients and the AURELIA trial for platinum-resistance in relapsed patients were performed, and both significantly improved progression-free survival. METHOD: We retrospectively studied patients receiving Bmab with an anticancer agent for recurrent ovarian cancer. Written informed consent was obtained from all patients. RESULTS: Between November 2013 and September 2015, Bmab at 15mg/kg/3-4 week was administered to 20 patients with recurrent ovarian cancer. The median age was 58 years(range 32-81)and the median performance status was 0-2. Platinum sensitive recurrence occurred in 6 patients. The response rate and disease control rate of combination chemotherapy with Bmab was 50.0% and 57.1%. However, 11 patients stopped treatment with Bmab due to serious adverse events. CONCLUSION: Combination chemotherapy with Bmab for recurrent ovarian cancer may be feasible. PMID- 27760938 TI - [Comparison of the Cost-Effectiveness of the SOX and COX Regimens in Patients with Unresectable Advanced and Recurrent Colorectal Cancer Using a Clinical Decision Analysis Approach]. AB - Phase III clinical trials have comfirmed that the S-1 plus oxaliplatin(SOX)is inferior to the capecitabine plus oxaliplatin (COX)regimen in the treatment of metastatic colorectal cancer.On the basis of these findings, we compared, using a clinical decision analysis-based approach, the cost-effectiveness of the SOX and COX regimens.Herein, we simulated the expected effects and costs of the SOX and COX regimens using the markov model.Clinical data were obtained from Hong's 2012 report.The cost data comprised the costs for pharmacist labor, material, inspection, and treatment for adverse event, as well as the total cost of care at the advanced stage.The result showed that the expected cost of the SOX and COX regimen was 1,538,330 yen, and 1,429,596 yen, respectively, with an expected survival rate of 29.18 months, and 28.63 months, respectively.The incremental cost-effectiveness ratio of the SOX regimen was 197,698 yen/month; thus, the SOX regimen was found to be more cost-effective that the COX regimen. PMID- 27760939 TI - [Remarkable Response to Trastuzumab Observed in a Case of Gastric Cancer with HER2-Negative Conversion]. AB - A 64-year-old woman was diagnosed with advanced gastric cancer with solitary liver metastasis. Although the HER2 status of the tumor was IHC2+, no further examination for HER2 status using FISH was performed. Four courses of S-1 and cisplatin chemotherapy were administered. The primary lesion and metastatic lesion were confirmed to have partially regressed. After 4 courses of chemotherapy, an open total gastrectomy, D2 dissection, pancreatosplenectomy, and posterior segmental hepatectomy were performed. Her postoperative course was uneventful. On histopathology, cancer cells were found in the resected stomach and resected liver. However, the HER2 statuses of the resected specimens were negative. After discharge, she received S-1 therapy for 1 year. Upon evaluation 1 year and 1 month postoperatively, the tumor marker CA19-9 was elevated. An enhanced CT scan showed multiple lung metastases and lymph node metastases in the pancreatic tail. Three courses of XELOX therapy(capecitabine and oxaliplatin)were administered. However, tumor marker levels continued to increase, and the metastasis continued to enlarge. Although the HER2 status of the resected site was negative, the HER2 status of the biopsy specimen before chemotherapy was positive on FISH. Therefore, weekly paclitaxel and trastuzumab therapy was initiated and repeated for 6 courses, after which an enhanced CT showed significant reduction(nearly CR)of multiple lung metastases and lymph node metastases. This suggests that HER2-negative conversion had occurred at the resected site. However, the HER2 status of the metastatic sites was considered positive. PMID- 27760940 TI - [A Case of HER2-Positive Advanced Gastric Cancer with Multiple Liver Metastases Effectively Treated with Trastuzumab, Capecitabine, and Cisplatin Combination Therapy]. AB - We reported a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer with multiple liver metastases that responded well to a combination of trastuzumab, capecitabine, and cisplatin(T-XP therapy)as first line chemotherapy. A 73-year-old man was admitted to our hospital in December 2012 for liver dysfunction. Based on computed tomography(CT)and gastroendoscopy findings, he was diagnosed with advanced gastric cancer with multiple liver metastases. Because HER2 protein overexpression was observed in the primary tumor, he was treated with T-XP therapy. After 5 courses of treatment, the sizes of the primary tumor and multiple liver metastases were reduced on CT scans. In March 2013, a Billroth I distal gastrectomy with D2 lymph node dissection was performed. Liver metastasis was not detected. No residual cancer cells were found in the stomach or lymph nodes. The patient subsequently received oral administration of S-1 alone for 2 weeks followed by a 2-week rest period as 1 course. This was repeated for 19 courses. The postoperative course was uneventful, and there was no detectable liver metastasis 36 months after the original diagnosis. Therefore, T-XP therapy is an option for the management of HER2-positive advanced gastric cancer with liver metastasis. PMID- 27760941 TI - [A Case of Long-Term Survival after Combination Therapy for Gastric Cancer with Synchronous Multiple Liver Metastasis]. AB - A 63-year-old man was admitted to our hospital owing to weight loss and vertigo. Endoscopic examination revealed advanced gastric cancer type 2. Abdominal CT showed a 62mm liver tumor in segment 4 and a 26mm tumor in segment 8. Distal gastrectomy and D2 lymph node dissection were performed. After surgery, he was administered chemotherapy with S- 1. After 2 courses of treatment, the tumors' in segments 4 and 8 were reduced to 52mm and 16mm, respectively. No other metastases were detected. Left lobectomy and partial resection of segment 8 were performed. The pathological therapeutic effects were rated as Grade 1b for the tumor in segment 4 and Grade 3 for the tumor in segment 8. After hepatectomy, he was administered adjuvant chemotherapy with S-1 for 1 year. No recurrence has been detected for 4 years and 6months after hepatectomy. PMID- 27760942 TI - [Ethinylestradiol Following Everolimus plus Exemestane Was Effective in Postmenopausal Endocrine-Responsive Metastatic Breast Cancer - A Case Report]. AB - A 71-year-old woman diagnosed with left breast cancer underwent mastectomy and axillary dissection in 1987. Pathological findings showed invasive ductal carcinoma that was ER and PgR positive and HER2 negative.5 -FU and tamoxifen were administered for 2 years as adjuvant therapy.Bone metastasis was found in 2002, and endocrine therapy was started, using anastrozole, exemestane, letrozole, medroxyprogesterone acetate, and fulvestrant.However, liver, lung, pleural, penetiral, and lymph-node metastases were observed, and the following chemotherapy regimen was administered: CAF, capecitabine, paclitaxel, vinorelbine, gemcitabine, methotrexate plus mitomycin C, and eribulin.Then, estrogen therapy with ethinylestradiol( EE2)was started in December 2013.T he pleural effusion disappeared and the liver metastases were reduced.After 11 months of progression-free survival(PFS), regrowth of the liver metastases was seen.Thus, everolimus plus exemestane was administered, and approximately 8 months of PFS was obtained.Therefore, both EE2 and everolimus are effective therapy even for heavily pretreated metastatic breast cancer. PMID- 27760943 TI - [Chronic Myelomonocytic Leukemia with Myelofibrosis Resulting in Sudden Massive Pleural Effusion during Cytoreductive Therapy with Hydroxycarbamide]. AB - Pleural effusion may occur as a rare complication associated with myeloid hematological malignancies. However, it occasionally occurs in patients with myelodysplastic/myeloproliferative neoplasms(MDS/MPN), especially in chronic myelomonocytic leukemia(CMML)with marked leukocytosis. Pleural effusion can also develop in hematological disorders with bone marrow fibrosis. Here, we report a case of CMML with bone marrow fibrosis, in which massive pleural effusion developed rapidly during cytoreductive therapy with hydroxycarbamide(HU). At the same time, the patient's leukocytosis was well controlled by the HU treatment. Although the cause of the patient's pleural effusion was unclear, despite a detailed thoracoscopic investigation, it is suspected that the invasion of leukemia cells or extramedullary hematopoiesis in the thoracic cavity may have led to this complication. Our findings suggest that in MPN and hematological disorders with bone marrow fibrosis, pleural effusion should be considered as a possible complication and should be carefully monitored, even when cytoreductive therapy is effective. PMID- 27760944 TI - [A Case of Axillary Nodal Metastasis of Adenocarcinoma of an Unknown Primary Site Effectively Treated with Anti-HER2plus AC plus Paclitaxel Therapy]. AB - A 68-year-old woman who presented with a left axillary mass was admitted. A computed tomography scan showed swelling ofthe left axillary and supraclavicular lymph nodes, but magnetic resonance imaging(MRI)and fluorodeoxyglucose positron emission tomography(FDG-PET)did not reveal these primary sites. Histological findings of the axillary mass revealed a HER2-positive adenocarcinoma. We diagnosed the patient with axillary nodal metastasis ofadenocarcinoma ofan unknown primary site and treated her with neoadjuvant chemotherapy including paclitaxel and trastuzumab followed by doxorubicin and cyclophosphamide. The lesions almost disappeared after 3 courses of chemotherapy and she showed a pathologically complete response(CR)after surgery. The patient has been recurrence-free since the operation owing to treatment with adjuvant trastuzumab. PMID- 27760945 TI - [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Multiple Metastatic Breast Cancer Patients]. AB - We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)during fulvestrant therapyfor multiple metastatic breast cancer patients. IDO activitycan be measured using the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured using high-performance liquid chromatography(HPLC). The serum Trp/Kyn level in patients with multiple metastatic breast cancer was lower than in patients without metastases. IDO activityincreased after breast cancer metastases developed. IDO activitywas correlated with the number of metastatic lesions during toremifene and fulvestrant therapy. These results suggested that measurement of the Trp/Kyn ratio is useful to evaluate immunological metastatic status during endocrine therapy. PMID- 27760946 TI - [Novel HER2-Targeted Therapy Combined with Gold Nanoparticles]. AB - Trastuzumab(Tmab)is a humanized monoclonalantibody that binds to the human epidermalgrowth factor receptor 2 (HER2). It is clinically used for HER2-positive breast and gastric cancers; however, the use of Tmab is restricted to tumors expressing high levels of HER2(accounting for only 20%of tumors), and Tmab cannot be used for tumors resistant to Tmab. Although novel HER2-targeted agents have been developed to treat Tmab-resistant tumors, none of these have shown clinical efficacy in gastric cancer patients. Recent developments in nanotechnology have had a significant impact on the field of medicine. Gold nanoparticles(AuNPs), which show characteristics such as in vivo stability and ease of surface functionalization, have been developed as therapeutic and contrast agents for medical applications. Previous studies show that AuNPs exert cytotoxic effects through autophagy and apoptosis; therefore, AuNPs in combination with tumor targeting antibodies are attractive therapeutic agents. In this study, we developed HER2-targeted AuNPs(Tmab-AuNPs)and showed that they had a potent antitumor effect on Tmab-resistant cell lines. In addition, Tmab-AuNPs were effective against HER2-negative gastric cancer cell lines when HER2 was artificially overexpressed. Thus, our results indicate that Tmab-AuNPs may overcome the shortcomings of Tmab-based therapy. PMID- 27760947 TI - [A Case of HER2-Positive Siewert Type I Adenocarcinoma of the Esophagogastric Junction Treated via Neoadjuvant Chemotherapy Followed by Radical Resection]. AB - A 63-year-old man with dysphagia was referred to our hospital. He was found to have a type 2 tumor extending from the lower thoracic esophagus to the esophagogastric junction via upper gastrointestinal endoscopy. A biopsy revealed adenocarcinoma with overexpression of the human epidermal growth factor type 2(HER2). The tumor was type I according to Siewert's classification, as the epicenter of the tumor was 27mm to the oral side from the esophago-gastric junction. The clinical diagnosis was T3N1M1, stage IV according to the Japanese Classification of Gastric Carcinoma, and T3N2M0, stage III per the Japanese Classification of Esophageal Cancer. He was treated with neoadjuvant chemotherapy consisting of 6 courses of capecitabine(1,000mg/m / / 2: days 1-14)plus cisplatin(80mg/m2: day 1)and trastuzumab(8mg/kg: day 1 of the first course, 6mg/kg: day 1 after the second course). Computed tomography(CT)and upper gastrointestinal endoscopy showed shrinkage of the primary esophagogastric cancer and lymph node metastases. The patient had a partial response and underwent radical esophagectomy. The pathological findings revealed a T3N2M0, stage III tumor; the tumor was determined to be Grade 1b owing to the chemotherapeutic effect. At a follow-up examination 1 year and 7 months after the start of chemotherapy, the patient is alive without recurrence. PMID- 27760948 TI - [Significance of Perioperative Neutrophil Lymphocyte Ratio(NLR)in Gastric Cancer and Colon Cancer]. AB - BACKGROUND: We examined the significance of neutrophil lymphocyte ratio(NLR)in gastric cancer and colon cancer in the perioperative period. METHOD: There were 46 patients(21 with gastric cancer and 25 with colon cancer). We examined the association between preoperative NLR and other indicators of nutritional status, as well as the relationship between preoperative NLR and the incidence of postoperative complications(all complications/infectious complications). RESULT: NLR was higher in those with zinc<65 mg, prognostic nutritional index(PNI)<=40, and modified Glasgow prognostic score(mGPS)of 2 (p<0.05). NLR showed no difference among all patients with complications(12 cases), but was higher in patients with infectious complications(p<0.05). CONCLUSION: Preoperative NLR is correlated with PNI as a predictor of infectious complications. PMID- 27760949 TI - [Study of the Relationship between Obesity and Lymphocytes in Breast Cancer Patients Undergoing Chemotherapy]. AB - Obesitychanges the regulatorymechanisms of the immune system, resulting in impaired immunity. In cancer immune mechanisms, the greater the degree of obesity, the lower the activity of the lymphocytes. Herein, we examined the relationship between obesity and lymphocytes in breast cancer patients undergoing chemotherapy. We recruited 10 recurrent or metastatic breast cancer patients who were administered eribulin. Using bodymass index(BMI), we classified these patients into a non-obese group(BMI<25)and an obese group(BMI>25). We measured the number of lymphocytes before chemotherapy and 8 days after eribulin administration. We examined the decreasing rates of lymphocytes before and after eribulin administration in the 2 groups. The average age was 63.1 years. Non obese and obese groups comprised 6 and 4 cases, respectively. The average rates of lymphocyte decrease before and after eribulin administration were 13.3%and 12.3% in the non-obese and obese groups, respectively. There were no significant differences between the 2 groups. PMID- 27760950 TI - [Development of Peptide Vaccines for Triple-Negative Breast Cancer Treatment]. AB - Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated. PMID- 27760951 TI - [WT1 Class I Peptide/WT1 Class II Peptide Pulsed Dendritic Cell Therapy Efficacy in 60 Patients with a Wide Range of Advanced Cancers]. AB - We assessed the efficacy of WT1 class I peptide and WT1 class II peptide pulsed dendritic cell(DC)therapy for a wide range of advanced cancers. This retrospective study included 60 advanced cancer patients who were vaccinated 5times or more in this clinic between September 2013 and December 2015. The clinical response was examined. This treatment was approved by the ethics panel at this institution. Sixty patients were injected an average of 6.15times with dendritic cells(DCs) (2.6*10 / 7 cells/injection). Overall, 55of 60(92%)patients achieved a clinical benefit per the RECIST v1.1 criteria. The median survival time(MST)from diagnosis was 26.9 months, and the MST from the first admission at this institution was 12.2 months. Complete response(CR)was achieved in 5patients(9.1%), partial response(PR)in 12(22%), and stable disease(SD) in 21(38%), with confirmed progressive disease(PD)in 17(31%). In 11 cases of pancreatic cancer, the response(RR)and disease control rates(DCR)were 27%and 55%,respectively. In 8 cases of colorectal cancer, the rates were 25% and 75%; in 7 cases of lung cancer, the rates were 29% and 43%; in 7 cases of gastric cancer, the rates were 71% and 86%; in 22 other types, the rates were 23% and 74%. These results demonstrated the potential clinical efficacy of DC-based immunotherapy. PMID- 27760952 TI - [A Case of Stage IV Colon Cancer Relapsed 10 Years after Curative Resection with Adjuvant Chemotherapy Using Long-Term, Low-Dose Leucovorin and 5 Fluorouracil(LV/5-FU)]. AB - A 57-year-old woman had been diagnosed with sigmoid colon cancer at surgery for ovarian cancer, and underwent simultaneous radical resection. Because of the pathological diagnosis of sigmoid cancer with ovarian metastasis, adjuvant chemotherapy was scheduled, with Leucovorin(LV)25 mg. This was immediately followed with 5-fluorouracil(5-FU)500 mg, via a 2-hour systemic intravenous infusion daily for 5 consecutive days, with courses repeated at 5 weeks, followed by maintenance once every 1 or 2 weeks for 2 years. There had been no evidence of recurrence for 10 years after surgery; however, peritoneal recurrence and a thyroid tumor were found using computed tomography(CT)at the 10-yearsur veillance. Chemotherapy with mFOLFOX6+bevacizumab was initiated because the peritoneal recurrence was determined to be unresectable and because of the metastasis to the thyroid. Chemotherapy was maintained, except for oxaliplatin(L OHP)due to toxicity, with shrinkage of the peritoneal tumor; however, it was difficult to maintain the chemotherapy due to toxicity. Eleven months after initiation of chemotherapy, lung and bone metastases were detected, and she subsequently died. PMID- 27760953 TI - [A Case of Laparoscopic Transhiatal Esophagectomy for Esophageal Cancer after Chemoradiotherapy]. AB - Patients with esophageal cancer often have various comorbidities, and these sometimes limit treatment choices. We report a case of esophageal cancer surgically treated using laparoscopic transhiatal esophagectomy after chemoradiotherapy in an elderly man with interstitial lung disease. A 77-year-old man who had undergone upper gastrointestinal endoscopic examination was admitted to our hospital with a diagnosis of esophageal cancer and interstitial lung disease. We diagnosed T4 esophageal cancer, and administered chemoradiotherapy. The chemoradiotherapy reduced the size of the tumor, but an esophageal stricture remained. A non-transthoracic approach was thought to be an appropriate choice for a patient at high risk for postoperative respiratory complications. Laparoscopic transhiatal esophagectomy was performed safely and successfully. In the postoperative course, temporary tracheotomy was necessary, but the tracheotomy tube was ultimately removed, after which he was able to consume food. PMID- 27760954 TI - [A Case of Synchronous Esophageal and Gastric Cancer Successfully Treated Using Multimodal Therapy]. AB - We report a case of advanced esophageal and gastric cancer that was successfully treated via multimodal therapy. A 65- year-old man with hoarseness was referred to our hospital. He was diagnosed with clinical T4aN2M0, Stage IV esophageal squamous cell carcinoma and clinical T3N1M0, Stage II B gastric adenocarcinoma. He was treated with 3 courses of chemotherapy, administered over 4weeks, with S 1(80mg/m / / 2: day 1-14), cisplatin(60mg/m2: day 1), and docetaxel(40mg/m2: day 1). Computed tomography(CT)revealed shrinkage of the primary esophageal tumor, gastric tumor, and lymph node metastases. Next, we selected definitive radiation chemotherapy(CRT), because lymph node metastases remained around the bilateral recurrent laryngeal nerves. After CRT with a total 60 Gy plus administration of 5 fluorouracil and cisplatin, CT showed that the primary esophageal tumor and lymph node metastases had disappeared. Then, distal gastrectomy was performed for the remaining gastric cancer, as part of the multimodal therapy. After gastrectomy, no systemic chemotherapy was performed. At a follow-up examination 5 years and 6 months after the start of chemotherapy, the patient is alive without recurrence. PMID- 27760955 TI - [Prognostic Factors in Elderly Patients with Stage II/III Colorectal Carcinomas with Invasion of pT3 or Deeper]. AB - Three hundred and fourteen patients with pT3 or deeper, Stage II/IIIcolorectal carcinoma who underwent curative operation were divided into two groups: age 75 years and more(elderly)and 74 years and less(non-elderly), to identify prognostic factors and risk factors for postoperative complications. Higher comorbidity rates and poorer nutritional status where found in the elderly group, which led to a shorter operation time and less lymph node dissection. There were no significant differences in 5-year OS and 3-year RFS between the two groups. These results suggest that elderly patients with colorectal carcinoma can achieve outcomes equal to the non-elderly group by curative resection even if it is not standard radical resection. PMID- 27760956 TI - [Changes in Endocrine Function in Patients after Pancreatic Surgery]. AB - We investigated glucose metabolism in patients who underwent pancreatoduodenectomy(PD), distal pancreatectomy (DP), and partial resection(PR). Fifteen patients(36%)were diabetic(HbA1c>=6.5%)before PD, 16(38%)were diabetic after PD, and 6(60%)were diabetic both before and after DP. The level of HbA1c was not significantly different preoperatively( PD: 7.5+/-2.7%, DP: 7.5+/-1.3%)vs postoperatively(PD: 6.7+/-1.1%, DP: 6.3+/-0.7%). These results suggest that pancreatic endocrine function was fairly preserved in patients who underwent pancreatic surgery. PMID- 27760957 TI - [Administration of Immune Checkpoint Inhibitor for Cancer except for Melanoma and Lung Cancer]. AB - We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses. Three remarkably effective responses were seen in cases of pancreatic cancer, esophageal cancer, and brain malignant lymphoma. In every effective case, dendritic cell therapy was administered prior to nivolumab. PMID- 27760958 TI - [Study of the Immunological Stress Caused by Breast Surgery Methods]. AB - To determine the role of immunosuppressive acidic protein(IAP)in the host defense of surgical patients, we investigated the kinetics of the post-operative elevation of IAP, as well as factors influencing the increase in serum IAP concentration, in 17 patients who underwent breast surgery. IAP was not increased in the pre-operation phase, post-operation phase, or 2 weeks after surgery, byvarious breast surgerymethods. In contrast, IL-6 was increased in the post operation phase byall breast surgerymethods. IL-6 correlated with anesthesia time. These results suggest that breast surgical methods are less immunologicallyinvasive than other major surgery. PMID- 27760959 TI - [The Efficiency of Postoperative Endoscopy for Anastomotic Leakage after Total Gastrectomy]. AB - An 81-year-old man underwent total gastrectomy with Roux-en-Y reconstruction for cardiac cancer in our department. He developed high fever on postoperative day 3, and pathological examination showed WBC and CRP level of 12,000/mL and 29.983mg/dL, respectively. A diagnosis of anastomotic leakage was confirmed using enhanced abdominal CT scanning that demonstrated free air around the esophagojejunalanastomosis after totalgastrectomy. The drainage tube was replaced by a 12 Fr sump tube because of leakage on postoperative day 10. Nasal endoscopy performed on postoperative day 13 revealed anastomotic leakage from the sump tube in the abdominal cavity. Endoscopy performed on postoperative day 20 confirmed the anastomotic leakage as a fistula that allowed air to leak into the abdominal cavity. On postoperative day 28, the sump tube was removed and oralintake was started. In conclusion, postoperative endoscopy might be usefulfor the assessment and drainage of anastomotic leakage. PMID- 27760960 TI - [Analysis of Short-Term Outcomes after Laparoscopy-Assisted Pylorus-Preserving Gastrectomy]. AB - BACKGROUND: Pylorus-preserving gastrectomy(PPG)has long been used for the treatment of early gastric cancer, and its survival benefits, postoperative symptoms, and functional outcomes have already been reported in several studies. This study aimed to evaluate the short-term outcomes after LAPPG in our hospital. METHODS: Ten patients with early gastric cancer underwent LAPPG from 2013 to 2015 in our hospital. Their short-term outcomes after LAPPG were retrospectively analyzed. RESULTS: No intraoperative complications were observed, and no patient required conversion to open surgery or reoperation. At 1 year after the operation, the relative body weight(present/preoperative)of the patients was 94.8%, and the incidence of nausea, diarrhea, abdominal fullness, and vomiting was, each, 1 in 7. CONCLUSION: The short-term results show that LAPPG seems to be beneficial in terms of postoperative symptoms and functional outcomes. PMID- 27760962 TI - [A Case of Long-Term Survival after Gastrectomy and Metachronous Brain Metastasis]. AB - A30 -year-old woman underwent total gastrectomy with D2 lymph node dissection after being diagnosed with clinical T3, N2, M0, Stage III B gastric cancer. The postoperative pathological findings revealed a T3(SE), N2, M0, Stage III B tumor. Headache, dizziness, and vomiting occurred during chemotherapy for peritoneal recurrence, using weekly paclitaxel on days 1, 8, and 15. Head CT showed a solitary tumor with a diameter of 28mm in the cerebellum, as well as cerebellar swelling and hydrocephalus. She underwent an emergency craniotomy and tumor enucleation. Pathological examination revealed a metastatic brain tumor from the gastric cancer. She received 12 courses of CPT-11 plus cisplatin until discontinuation because of an adverse event. The patient is alive 6 years after the diagnosis of the cerebellar metastasis without recurrence. PMID- 27760961 TI - [Clinical Evaluation of Immunosuppressive Acidic Protein in the Serum of Patients with Locally Advanced Breast Cancer during Mohs Paste Treatment]. AB - Locallyadvanced breast cancer lesions often compromise the patient's qualityof life(QOL). Mohs paste is a histopathological fixative containing zinc chloride as the main ingredient. It has been applied to perform chemosurgeryon skin tumors. In recent years, this paste has reportedlybeen veryeffective for controlling various symptoms of skin metastases in inoperable advanced cancer, such as pungent odor and hemorrhage, in the field of palliative care. We evaluated the clinical significance of immunosuppressive acidic protein(IAP)and C-reactive protein(CRP)in the serum of patients with locallyadvanced breast cancer duringMohs paste treatment. The tryptophan(Trp)/kynurenine(Kyn)ratio measures IDO activity. Trp and Kyn were measured byhigh performance liquid chromatography(HPLC). We took serum samples from 3 locallyadvanced breast cancer cases, in the pre-treatment phase, 2 times after the treatment phase, and 5 times after the treatment phase. Then, we measured IAP and CRP in these samples during Mohs paste treatment. Serum IAP values did not differ significantlybetween each of the phases; however, serum CRP values were decreased byMohs paste treatment. These results suggested that Mohs paste treatment for locallyadvanced breast cancer lesions was useful for enhancing the patient QOL, without immunosuppression. PMID- 27760963 TI - [A Case of Pancreatic Cancer Associated with Autoimmune Pancreatitis]. AB - A 74-year-old man with IgG4-related cholangitis had been treated with steroids for 1 year. In the outpatient clinic, elevated levels of the tumor marker CA19-9 and serum IgG4 were observed. Abdominal enhanced CT showed a 20mm hypovascular tumor in the pancreatic head. ERCP showed narrowingof the main pancreatic duct in the pancreatic head with slight caudal dilation and stricture of the lower common bile duct. We made a diagnosis of pancreatic cancer, and the patient underwent pancreaticoduodenectomy. Pathological examination of the resected tissue revealed a well-differentiated adenocarcinoma surrounded by autoimmune pancreatitis, characteristic of lymphoplasmacytic sclerosingpancreatitis. He is receiving adjuvant chemotherapy with S-1 in the outpatient clinic. PMID- 27760964 TI - [A Case of Early Anal Canal Cancer with Pagetoid Spread with Different Antitumor Effects of Chemotherapy on Different Metastatic Sites]. AB - A 78-year-old man visited our hospital with a prolapsed hemorrhoid. He was referred to the dermatology unit due to the thickness and redness of the perianal skin. He was diagnosed as having extra mammary Paget's disease by skin biopsy. After a biopsy of the anal polyp was performed to investigate the primary site, he was diagnosed with early anal canal cancer with Pagetoid spread and underwent a radical operation. Abdominoperineal resection with skin(D2 prx D3 lymphadenectomy) was performed with perineal reconstruction using a gracilis muscle graft. Postoperative surveillance without adjuvant therapy was performed because the pathological stage was stage I. Two years and 2 months after surgery, multiple liver metastases were found, and the patient was diagnosed with multiple liver, bone, and lymph node metastases(K-ras and UGT1A1 wild type)on PET. XELOX plus bevacizumab was used as first-line treatment and the liver metastases showed remarkable shrinkage; however, disease progression occurred in the bone. IRIS plus bevacizumab was started as second-line therapy but grade 3 hematotoxicity was observed during the first course. After 4 courses, it was difficult to maintain the therapy due to toxicity and cancer-related pain. The liver metastases had almost disappeared but the patient died 11 months after the initiation of chemotherapy. PMID- 27760965 TI - [Indoleamine 2,3-Dioxygenase Activity in Intracystic Breast Tumors]. AB - We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)in intra-cystic tumors of the breast. IDO activitycan be measured byusing the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured by high performance liquid chromatography(HPLC). We took liquid from 3 intra-cystic papilloma cases and 5 intra-cystic breast cancer cases. Then, we measured the Trp/Kyn ratio in these samples, and we evaluated the difference in the Trp/Kyn ratio between the papilloma group and the breast cancer group. The Trp/Kyn ratio was significantly lower in the breast cancer group than in the papilloma group. These results suggest that measuring the Trp/Kyn ratio in cystic liquid from intra-cystic breast lesions is useful to distinguish benign intra-cystic lesions from malignant intra-cystic lesions. PMID- 27760966 TI - [Incidence and Characteristics of Mismatch Repair Protein Deficiency in Elderly Gastric Cancer Patients]. AB - The loss of mismatch repair(MMR)function as a result of MLH1 promoter methylation is closely correlated with high frequency microsatellite instability, and tumors with such characteristics are resistant to anticancer drugs such as 5-FU. We examined the incidence and characteristics of deficient MMR(dMMR)in elderly gastric cancer patients by performing a comprehensive immunohistochemical screening. The study was conducted in 199 patients diagnosed with gastric cancer, aged 75 years or older, who underwent a gastrectomy between April 2005 and January 2014. dMMR was detected in 23 patients(12%). All the tumors with dMMR were deficient in MLH1 and PMS2. dMMR was significantly more common compared to proficient MMR(pMMR)in patients with a more advanced age(p=0.03), women(p<0.01), and a tumor location corresponding to the lower region(p<0.01). Considering the incidence of dMMR in elderly gastric cancer patients, only a limited proportion of patients are likely to be eligible for immune checkpoint inhibitor therapy, which is expected to become more popular in the near future. PMID- 27760967 TI - [Clinical Significance of Serum p53 Antibody Measurement in Colorectal Cancer Patients]. AB - We investigated the significance of serum p53 antibody in colorectal cancer. The subjects included 239 patients with colorectal cancerwithout any history of priortr eatment. Patients with multiple cancerordouble cancerwer e excluded. Serum p53 antibodies and relationships with clinicopathological factors and prognosis were examined. The preoperative positive rate of serum p53 antibody was 28.9%. There was no relationship between p53 antibody and clinicopathological factors or degree of progression. Examination of a possible relationship with prognosis revealed that p53 antibody was not related to whether recurrence occurred, and there was no difference observed for survival rate. Examination of the cases in which serum p53 antibody was measured continuously after curative resection revealed that there was a tendency to find a low incidence of cancer recurrence in cases in which serum p53 antibody became negative postoperatively. Furthermore, cancer recurred at a low incidence in the cases in which p53 antibody was on the decrease postoperatively(p=0.0008). Thus, ourr esults show that serum p53 antibody in colorectal cancer cases is not related to clinicopathological factors or prognosis. However, in cases positive for preoperative serum p53 antibody, changes in postoperative levels of the titer could be a marker for recurrence. PMID- 27760968 TI - [Clinical Outcomes of Anteroposterior Dissection Holmium Laser Enucleation of the Prostate for Benign Prostatic Hyperplasia]. AB - Holmium laser enucleation of the prostate (HoLEP) is a standard surgical procedure for treatment of benign prostatic hyperplasia (BPH). A low incidence of postoperative urinary incontinence in association with anteroposterior dissection HoLEP was recently reported. We evaluated 66 patients with BPH who underwent anteroposterior dissection HoLEP from March 2013 to November 2014. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, maximum flow rate (Qmax), and post-void residual urine volume (PVR) were assessed preoperatively and at 1 and 3 months after treatment. The incidence of postoperative urinary incontinence, which was defined as the requirement of more than one pad per day, was compared between the first and second half of the patient population. Postoperative urination parameters (IPSS, QOL index, Qmax, and PVR) were significantly improved. The incidence of urinary incontinence at 3 months was significantly lower in the second half (4%) than first half (28%) of the patient population (p=0.020). In conclusion, anteroposterior dissection HoLEP is an effective procedure for the treatment of BPH and can reduce the rate of postoperative urinary incontinence, even in low-volume institutes. PMID- 27760969 TI - [Spontaneous Infection of an Atrophic Ureter with an Ectopic Ureteral Opening after Living-Donor Renal Transplantation in a Patient with Kabuki Syndrome]. AB - A 24-year-old woman with a high fever presented at our hospital. She had been diagnosed with Kabuki syndrome at the age of 4 years because she had the typical facial features of the condition ; she had undergone living donor renal transplantation 12 years prior. She was prescribed a course of antibiotics to treat pyelonephritis of the transplanted kidney and the high fever disappeared, but the fever developed again 3 days after the discharge. Abdominal computed tomography revealed a tubular structure of recent onset running from the left dorsal side to the lower part of the bladder. This structure was filled with pus, which we drained. We also performed laparoscopic ureterectomy of the left ureter to achieve a complete cure. No complication was observed after the surgery and the graft renal function did not deteriorate further. PMID- 27760970 TI - [Neuroendocrine Tumor Possibly Originating from the Kidney : A Case Report]. AB - A 40-year-old woman was referred to our hospital with right lower back pain as the chief complaint. Contrast-enhanced computed tomography (CT) showed a partially-solid tumor within a cyst measuring approximately 6 cm in diameter in the right renal hilum. The solid part was enhanced in the early phase and contrast medium was washed out earlier in the solid part than in the parenchyma in the equilibrium phase. Plain CT revealed partial cyst wall calcification. A soft tissue shadow approximately 10 mm in diameter in the dorsal inferior vena cava at the upper pole of the kidney and a solid tumor adjacent to the iliopsoas muscle and the kidney were detected. We performed radical nephrectomy and lymph node dissection with transperitoneal approach. The histopathological diagnosis was neuroendocrine tumor. Her clinical course has since been observed on an outpatient basis, for nearly 10 months to date, without any recurrence. PMID- 27760971 TI - [Metastatic Renal Cell Carcinoma in Paranasal Sinus for which Periodic Drug Withdrawal Schedule of Axitinib was Effective : A Case Report]. AB - A 73-year-old male patient underwent a right nephrectomy for renal cell carcinoma in 2008, and interferon-alpha was initiated as adjuvant treatment. Computed tomography (CT) scans showed lymphadenopathy above the left diaphragm, and treatment with interferon-2 was subsequently initiated in 2009. Nasal bleeding manifested in February 2010, and CT scans showed a soft-tissue density mass mainly located in the ethmoid sinus. A biopsy of the lesion was performed, and metastatic renal cell carcinoma was diagnosed. Treatment with sorafenib was consequently initiated and the paranasal metastasis showed a temporary partial response (PR). However, the metastatic lesion increased in size and caused repeated nasal bleeding that required blood transfusion. Although treatment with everolims was initiated, adverse events, such as rush, hypertensionnemia, and anemia due to nasal bleeding, developed. Treatment with axitinib was subsequently initiated. However, because adverse events, such as severe diarrhea, renal dysfunction and proteinuria manifested, the dose of axitinib was gradually decreased, and a periodic drug withdrawal schedule (11 days on, 3 days off) was finally initiated, which controlled these adverse events. The metastatic lesions showed a PR for 31months following axitinib administration. PMID- 27760972 TI - [A Case of Synchronous Multiple Metastases in which the Origin Could Not Be Identified by Routine Examination]. AB - A 67-year-old man presented at our hospital with severe edema on the left side of his neck, chest and brachial regions. He had a history of right radical nephrectomy due to renal cell carcinoma (RCC, clear cell subtype, stage II) 15 years earlier. Thereafter, metastases to the pancreatic tail and right lung, and left lung metastasis were removed at 8 years and 11 years, respectively, after the nephrectomy. Four years earlier, he had also undergone total gastrectomy for gastric carcinoma (poorly differentiated adenocarcinoma, stage IV) and subsequent maintenance chemotherapy for gastric carcinoma. Follow-up computed tomography (CT) disclosed bilateral lung metastases and a pancreatic head metastasis. Cytology of pleural effusion on admission suggested pleuritis carcinomatosa from RCC. Clinical diagnosis was bilateral lung and pancreatic head metastases, pleuritis carcinomatosa and left subclavian vein thrombosis due to RCC metastasis. Maintenance chemotherapy for gastric carcinoma was replaced by Sunitinib 50 mg for RCC but he died of progressive disease 20 days later. Immunohistochemical study of the tissue from autopsy revealed lung metastasis and pancreatic head metastasis from both RCC and gastric carcinoma as well as multiple visceral metastases, pleuritis carcinomatosa and left subclavian vein thrombosis due to gastric carcinoma. Cause of death was acute respiratory failure due to pulmonary tumor embolism and pulmonary edema. Immunohistochemical study from autopsy was able to reveal the exact diagnosis, and immunohistochemical studies may be helpful in diagnosing the exact origin of metastasis and selecting appropriate treatmentsin patientswith multiple cancers. PMID- 27760973 TI - [Urinary Diversion Using an Appendicovesicostomy for Idiopathic Urethral Stricture : A Case Report]. AB - A 55-year-old woman was referred to our hospital with dysuria. We were unable to catheterize her using a nelaton catheter because of a urethral stricture, resulting in a large residual urine volume on ultrasonography. The circumference of the periurethral tissue was also thickened and the entire length of the urethra was stenotic, without apparent cause, on magnetic resonance imaging. Biopsy did not reveal malignancy. The pathological diagnosis of the periurethral tissue was simply fibrosis, and there was no definitive diagnosis. We decided to place a guidewire to attempt transurethral dilation, but it was unsuccessful because of the urethral stricture. The patient then underwent Mitrofanoff appendicovesicostomy. Three years later, there was no difficulty with catheterization through the appendix, despite her suffering from a bladder stone during the interim. We consider the Mitrofanoff appendicovesicostomy a good substitute technique for catheterization in patients with very severe urethral stricture. PMID- 27760974 TI - [Severe Acute Myocardial Infarction during Induction Chemotherapy for Retroperitoneal Germ Cell Tumor : A Case Report]. AB - A 37-year-old man presented at our hospital. Pathological examination of a right orchiectomy specimen, radiographic examination, and tumor marker profile resulted in a diagnosis of retroperitoneal nonseminomatous germ cell tumor (intermediate risk according to IGCC classification). Laboratory testing revealed mild elevation of low density lipoprotein cholesterol. Induction chemotherapy with bleomycin, etoposide and cisplatin (BEP) was started, but he complained of chest pain on day 10 of the second cycle of BEP. We immediately started cardiac monitoring. One hour later, he suffered cardiac arrest due to ventricular fibrillation. Fortunately, sinus rhythm was restored after defibrillation. A diagnosis of acute myocardial infarction (AMI) with total occlusion at the mid portion of the left anterior descending coronary artery was established by coronary angiography. After percutaneous transluminal coronary angioplasty was successfully performed, he recovered uneventfully. The induction chemotherapy was re-started 19 days after AMI. To avoid endothelial damage by bleomycin, we elected to treat with etoposide, ifosfamide, and cisplatin (VIP). After two further courses of VIP, the patient underwent resection of retoperitoneal tumor and achieved complete remission. The patient has remained disease-free during 3 years follow up without recurrence of AMI. PMID- 27760975 TI - [Two Cases of Germ Cell Tumors with Hyperthyroidism Due to High Serum hCGLevels]. AB - We reported two cases of hyperthyroidism that developed during induction chemotherapy for advanced germ cell tumors with high serum human chorionic gonadotropin (hCG) levels. Case 1 : An 18-year-old man with mediastinal choriocarcinoma complained of tachycardia and tremor. His pretreatment serum hCG level was 1.37 million mIU/ml. The free thyroxine (fT4) level measured on day 2 of the first course of bleomycin, etoposide and cisplatin (BEP) was elevated to 7.8 ng/dl (<1.7 ng/dl), whereasthe thyroidstimulating hormone (TSH) level was undetectable. We diagnosed the patient with hyperthyroidism and started oral propranolol and thiamazole. Subsequently, his tachycardia and tremor disappeared. On day 12 of the first course of BEP, his hCG level decreased to less than 50,000 mIU/ml. Also, his fT4 level returned to the normal range. Case 2 : A 29-year-old man presented with a left scrotal mass. He was diagnosed with non-seminoma testicular cancer (embryonal carcinoma and choriocarcinoma) with multiple lung, liver and lymph node metastases. On the admission day, his serum hCG and fT4 levels were high ; 3.23 million mIU/ml and 2.2 ng/dl, respectively. The TSH level was low at 0.011 mIU/ml. On day 3 of the first course of BEP, his hCG and fT4 levels increased to 4.5 million mIU/ml and 3.0 ng/dl, respectively. He complained of tachycardia, tremor and hyperhydrosis. He was started on propranolol and potassium iodide. After the treatment, histachycardia, tremor and hyperhidrosisdis appeared. HisfT4 level normalized on day 17 of the first course of BEP. The TSH-like activity of hCG is considered to be responsible for paraneoplastic hyperthyroidism among germ cell cancer patients with high hCG levels. To our knowledge, thisisthe first report of such a case in Japan. However, thisphenomenon isnot rare among patients with extremely high hCG levels. Therefore, we should be careful of these patients. PMID- 27760976 TI - [A Case of Intrascrotal Liposarcoma]. AB - A 69-year-old man was referred to our hospital with the chief complaint of a painless right scrotal swelling gradually increasing in size during the past 10 years. Testicular tumor markers were within the normal range. Ultrasonography showed an intrascrotal homogeneous mass. Computed tomography and magnetic resonance imaging revealed an inguinal mass, which mainly consisted of fat signal area and partially well enhanced in vascular density. Pre-surgical diagnosis was liposarcoma of spermatic cord estimated by radiographic examination and resection of the right intrascrotal tumor with high inguinal orchitectomy was performed. Histopathological diagnosis revealed well-differentiated liposarcoma. No recurrence phenomenon has been observed after 12 months without any adjuvant therapy. This case is the 129th report of intrascrotal liposarcoma in the Japanese literature. PMID- 27760977 TI - [Two Cases of Penile Fracture Diagnosed by Magnetic Resonance Imaging]. AB - We report two cases of penile fracture. Case 1 was in a 22-year-old male. He heard a cracking sound during urination and experienced acute penile pain and detumescence. He was admitted to our hospital on that day. Case 2 was in a 52 year-old male. He heard a cracking sound during sexual intercourse and experienced detumescence. He was admitted to our hospital on the next day. In both cases, magnetic resonance imaging (MRI) showed disruption of the tunica albuginea. We performed immediate surgical repair through localized incision. They had no perioperative complications. Several months after surgery, they reported subjectively good erection without penile curvature or pain. We found that MRI is a useful tool for the assessment of location of the tunica rupture and minimization of the surgical incision. PMID- 27760978 TI - Efficacy and Safety of Danshen Compound Tablets in Preventing Thalidomide Associated Thromboembolism in Patients with Multiple Myeloma: A Multicenter Retrospective Study. AB - BACKGROUND Currently available antithrombotic prophylaxis is not perfectly reliable in elderly patients. The aim of this retrospective study was to evaluate the efficacy and safety of Compound Danshen Tablet (CDT) in preventing thromboembolism in multiple myeloma (MM) patients treated with thalidomide-based regimens. MATERIAL AND METHODS MM patients treated with thalidomide-based regimens were retrospectively reviewed between January 2008 and March 2015. Patients were categorized into 3 cohorts based on thromboembolic prophylaxis used: CDT, Warfarin Tablet, and no prophylaxis. Venous thromboembolism (VTE), other adverse effects (AEs), and the changes of D-dimer and fibrinogen levels were monitored. RESULTS Seven out of 313 MM patients (2.24%) developed venous thrombosis events (VTE) in this retrospective study, all clustering in the no prophylaxis cohort. Three patients of the Warfarin cohort (3.19%) experienced hemorrhage. Neither VTE events nor serious AEs were observed in the CDT cohort. Following Compound Danshen or Warfarin treatment for 3 months, the D-dimer and fibrinogen levels (in particular the D-dimer level) (all P<0.05), were obviously decreased relative to their respective baselines and the no prophylaxis cohort. In contrast, the 2 blotting parameters were significantly increased in the no prophylaxis cohort relative to the baseline level (All P<0.05), and were even higher in the patients experiencing VTE compared to the no VTE patients (P<0.0001 and P=0.016, respectively). CONCLUSIONS Our findings indicate CDT is an effective therapy for preventing VTE in MM patients treated with thalidomide-based regimens, and is well tolerated in long-term use. PMID- 27760979 TI - Intra-Amniotic Hemorrhage Imitating Gastroschisis: A Case Report and Review of the Literature. AB - BACKGROUND A spontaneous intra-amniotic hemorrhage is rarely encountered during pregnancy. The correct diagnosis and management are problematic because of the infrequency of this condition and the high likelihood of a misdiagnosis. CASE REPORT A primigravida with an uncomplicated pregnancy and a normal targeted ultrasound presented late in the second trimester of pregnancy with antepartum bleeding of unknown origin. A repeat ultrasound was suggestive of an abdominal wall defect (gastroschisis). The patient continued to have antepartum bleeding and developed uterine contractions and abdominal pain necessitating frequent visits to labor and delivery. An MRI ruled out gastroschisis and diagnosed intra amniotic hematoma. The patient presented with acute abdominal pain and was clinically considered to be having an abruption, and was delivered by cesarean. Old blood was noted in the abdominal cavity and within the uterine cavity. At the time of the cesarean, an area of intra-amniotic hematoma was identified, as well as a retroplacental blood clot. CONCLUSIONS An intra-amniotic hematoma is unusual and may be misdiagnosed. MRI may be helpful in determining the correct diagnosis and subsequent management. PMID- 27760980 TI - Upper limb ischemia: an uncommon clinical situation? PMID- 27760981 TI - Arterial thoracic outlet syndrome: rare and triggering. AB - Arterial thoracic outlet syndrome (TOS) is the least common type of TOS. Patient's symptoms, clinical examination and duplex ultrasonography usually suffice in deciding patient's management. Our proposed treatment strategies are based on the Scher classification. The choice of the procedure and approach should depend on surgeon's experience and need for arterial reconstruction. PMID- 27760982 TI - Simple and effective reverse bent wiring technique for side branch access after crush stenting. PMID- 27760983 TI - ST-elevation myocardial infarction due to spontaneous coronary artery dissection: to touch or not to touch? The conundrum of invasive versus conservative treatment. PMID- 27760984 TI - The worsening renal failure in a chronic cardio-renal syndrome type II: efficacy of a single levosimendan infusion. PMID- 27760985 TI - A myocardial infarction in a patient with previous myocardial revascularization presenting with tachyarrhythmia. Is it type 1, 2 or 4c myocardial infarction? PMID- 27760986 TI - Symptomatic in-stent restenosis due to complete stent fracture treated with drug coated balloon. PMID- 27760987 TI - Left internal mammary artery graft stenosis and post-angioplasty restenosis: follow-up through multi-slice cardiac computed tomography angiography. PMID- 27760988 TI - Left main coronary artery thrombosis with distal coronary embolization in a patient with methyltetrahydrofolate reductase C677T mutation presenting with STEMI. PMID- 27760989 TI - Mechanisms underlying the endogenous dopaminergic inhibition of spinal locomotor circuit function in Xenopus tadpoles. AB - Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5-100 MUM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2 like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel. PMID- 27760990 TI - Aggregation of soy protein-isoflavone complexes and gel formation induced by glucono-delta-lactone in soymilk. AB - This study investigated the glucono-delta-lactone (GDL)-induced aggregation of isoflavones and soy proteins in soymilk. High-performance liquid chromatography (HPLC) analysis indicated that isoflavones mixed with beta-conglycinin (7S) and glycinin (11S) proteins formed 7S-isoflavone and 11S-isoflavone complexes in soymilk supernatant fraction (SSF). Most of the soy protein-isoflavone complexes then precipitated into the soymilk pellet fraction (SPF) following the addition of 4 mM GDL, whereupon the pH value of the soymilk dropped from 6.6 to 5.9. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and HPLC analysis suggest that the addition of 4 mM GDL induced the aggregation of most 7S (alpha', alpha and beta subunits), 11S acidic and 11S basic proteins as well as isoflavones, including most aglycones, including daidzein, glycitein, genistein and a portion of glucosides, including daidzin, glycitin, genistin, malonyldaidzin and malonylgenistin. These results provide an important reference pertaining to the effects of GDL on the aggregation of soy protein-isoflavone complexes and could benefit future research regarding the production of tofu from soymilk. PMID- 27760992 TI - Genome stability: Cyclin' on mRNA. PMID- 27760991 TI - Identification of a regulation network in response to cadmium toxicity using blood clam Tegillarca granosa as model. AB - Clam, a filter-feeding lamellibranch mollusk, is capable to accumulate high levels of trace metals and has therefore become a model for investigation the mechanism of heavy metal toxification. In this study, the effects of cadmium were characterized in the gills of Tegillarca granosa during a 96-hour exposure course using integrated metabolomic and proteomic approaches. Neurotoxicity and disturbances in energy metabolism were implicated according to the metabolic responses after Cd exposure, and eventually affected the osmotic function of gill tissue. Proteomic analysis showed that oxidative stress, calcium-binding and sulfur-compound metabolism proteins were key factors responding to Cd challenge. A knowledge-based network regulation model was constructed with both metabolic and proteomic data. The model suggests that Cd stimulation mainly inhibits a core regulation network that is associated with histone function, ribosome processing and tight junctions, with the hub proteins actin, gamma 1 and Calmodulin 1. Moreover, myosin complex inhibition causes abnormal tight junctions and is linked to the irregular synthesis of amino acids. For the first time, this study provides insight into the proteomic and metabolomic changes caused by Cd in the blood clam T. granosa and suggests a potential toxicological pathway for Cd. PMID- 27760993 TI - Long Term Surgical Outcome and Prognostic Factors of Atypical and Malignant Meningiomas. AB - Atypical and malignant meningiomas are rare. Our aim was to examine the treatment outcomes following surgical resection, and analyze associations between clinical characteristics and overall survival (OS) or relapse free survival (RFS). 102 patients with atypical or malignant meningiomas underwent microsurgical resection between June 2001 and November 2009 were analyzed retrospectively. We compared demographics, clinical characteristics, treatment, and complications. The five year and ten-year overall survival rates were 93.5% and 83.4%, respectively. Three factors significantly reduced OS: Malignant meningiomas (p < 0.001), which also decreased RFS (p < 0.001); female patients (p = 0.049), and patients with Karnofsky Performance Status (KPS) < 70 at diagnosis (p = 0.009). Fifty two patients (51%) experienced tumor relapse. Total resection of tumors significantly impacted RFS (p = 0.013). Tumors located at parasagittal and posterior fossa area lead to higher relapse rate (p = 0.004). Subtotal resection without adjuvant radiotherapy lead to the worst local control of tumor (p = 0.030). An MIB-1 index <8% improved OS and RFS (p = 0.003). Total resection of atypical and malignant meningiomas provided better outcome and local control. Adjuvant radiation therapy is indicated for patients with malignant meningiomas, with incompletely excised tumors; or with tumors in the parasagittal or posterior fossa area. The MIB-1 index of the tumor is an independent prognostic factor of clinical outcome. PMID- 27760994 TI - Nutrient supplements boost yeast transformation efficiency. AB - Efficiency of yeast transformation is determined by the rate of yeast endocytosis. The aim of this study was to investigate the effect of introducing amino acids and other nutrients (inositol, adenine, or p-aminobenzoic acid) in the transformation medium to develop a highly efficient yeast transformation protocol. The target of rapamycin complex 1 (TORC1) kinase signalling complex influences the rate of yeast endocytosis. TORC signaling is induced by amino acids in the media. Here, we found that increasing the concentration of amino acids and other nutrients in the growth media lead to an increase yeast transformation efficiency up to 107 CFU per MUg plasmid DNA and per 108 cells with a 13.8 kb plasmid DNA. This is over 130 times that of current published methods. This improvement may facilitate more efficient experimentation in which transformation efficiency is critical, such as yeast two-hybrid screening. PMID- 27760996 TI - Coverage recommendation for genotyping analysis of highly heterologous species using next-generation sequencing technology. AB - Next-generation sequencing (NGS) technology is being applied to an increasing number of non-model species and has been used as the primary approach for accurate genotyping in genetic and evolutionary studies. However, inferring genotypes from sequencing data is challenging, particularly for organisms with a high degree of heterozygosity. This is because genotype calls from sequencing data are often inaccurate due to low sequencing coverage, and if this is not accounted for, genotype uncertainty can lead to serious bias in downstream analyses, such as quantitative trait locus mapping and genome-wide association studies. Here, we used high-coverage reference data sets from Crassostrea gigas to simulate sequencing data with different coverage, and we evaluate the influence of genotype calling rate and accuracy as a function of coverage. Having initially identified the appropriate parameter settings for filtering to ensure genotype accuracy, we used two different single-nucleotide polymorphism (SNP) calling pipelines, single-sample and multi-sample. We found that a coverage of 15* was suitable for obtaining sufficient numbers of SNPs with high accuracy. Our work provides guidelines for the selection of sequence coverage when using NGS to investigate species with a high degree of heterozygosity and rapid decay of linkage disequilibrium. PMID- 27760995 TI - Differential effects of L-tryptophan and L-leucine administration on brain resting state functional networks and plasma hormone levels. AB - Depending on their protein content, single meals can rapidly influence the uptake of amino acids into the brain and thereby modify brain functions. The current study investigates the effects of two different amino acids on the human gut brain system, using a multimodal approach, integrating physiological and neuroimaging data. In a randomized, placebo-controlled trial, L-tryptophan, L leucine, glucose and water were administered directly into the gut of 20 healthy subjects. Functional MRI (fMRI) in a resting state paradigm (RS), combined with the assessment of insulin and glucose blood concentration, was performed before and after treatment. Independent component analysis with dual regression technique was applied to RS-fMRI data. Results were corrected for multiple comparisons. In comparison to glucose and water, L-tryptophan consistently modifies the connectivity of the cingulate cortex in the default mode network, of the insula in the saliency network and of the sensory cortex in the somatosensory network. L-leucine has lesser effects on these functional networks. L-tryptophan and L-leucine also modified plasma insulin concentration. Finally, significant correlations were found between brain modifications after L-tryptophan administration and insulin plasma levels. This study shows that acute L tryptophan and L-leucine intake directly influence the brain networks underpinning the food-reward system and appetite regulation. PMID- 27760997 TI - Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension. AB - The kidney has a central role in long-term control of blood pressure, and decreased kidney function is a common but difficult-to-treat cause of hypertension. Conversely, elevated blood pressure contributes to the progression of chronic kidney disease. Steroid hormone aldosterone and its receptor mineralocorticoid receptor (MR) contribute to hypertension by increasing renal salt reabsorption and promote kidney dysfunction through direct effects on renal parenchymal cells. Accumulating data indicate that various mechanisms affect aldosterone-MR signaling. Using a genetically engineered mouse model, we identified crosstalk between small GTPase Rac1 and MR. This crosstalk pathway promotes glomerular podocyte injury, and is also involved in the pathogenesis of hypertension. Notably, salt loading increases renal Rac1 activity in several models of salt-sensitive hypertension, which, in the presence of aldosterone, synergistically activates MR signaling, causing hypertension and kidney injury. There is also a mechanism regulating MR in a cell-selective manner. In the principal cells of the collecting duct, aldosterone directly binds and activate MR. In neighboring intercalated cells, however, binding of aldosterone to MR is regulated by phosphorylation at the ligand-binding domain. This mechanism serves as a switch to turn on electrolyte flux pathways in intercalated cells, allowing aldosterone to exert distinct effects in different physiological contexts. Given the potential benefit of MR blockade in hypertensive kidney disease, the delineation of these pathways may lead to the identification of alternative therapeutic targets. In this review, we discuss the roles of MR in mediating kidney disease and hypertension, with a focus on the crosstalk among related signaling pathways. PMID- 27760998 TI - Effective uric acid-lowering treatment for hypertensive patients with hyperuricemia. AB - Uric acid (UA) has been associated with hypertension, renal disease and cardiovascular disease. The aim of the present study was to compare the UA lowering effects of a standard dose of the UA synthesis inhibitor febuxostat to a standard dose of the uricosuric agent benzbromarone, and to investigate the effects of a low-dose combination of both agents in hypertensive patients with hyperuricemia. Twenty hypertensive patients with inadequate UA control were administered febuxostat 40 mg (Feb), benzbromarone 50 mg (Ben) and febuxostat 20 mg and benzbromarone 25 mg (feb/ben) for 3 months each in a randomized modified crossover manner. UA metabolism, blood pressure (BP) and the indices of organ damage were assessed at baseline and the end of each treatment period. No significant changes were observed in BP or estimated glomerular filtration rate (eGFR) after the treatment with each UA-lowering regimen. The change in UA was significantly greater with feb/ben than with Feb. The excretion of UA and clearance of UA were higher with Ben than with Feb and feb/ben. Urinary 8 hydroxydeoxyguanosine and liver-type fatty-acid-binding protein levels were slightly lower with Ben, whereas flow-mediated dilation was slightly higher with feb/ben and Ben. The UA-lowering effects of the low-dose combination of the UA synthesis inhibitor and uricosuric agent were greater than those of the standard dose of each agent alone. The uricosuric agent may be more effective at improving vascular function than the UA synthesis inhibitor. Thus, the appropriate management of hyperuricemia with uricosuric drugs appears to be useful for hypertensive patients with hyperuricemia. PMID- 27760999 TI - Feeling the pressure: (patho) physiological mechanisms of weight gain and weight loss in humans. AB - Obesity is an ongoing global epidemic and has adverse consequences for cardiovascular health. Obesity is often associated with hypertension, which is, itself, a common condition and an important cause of morbidity and mortality worldwide. Although animal models of obesity have provided extensive data on the links between obesity and hypertension, a greater understanding of the pathways linking obesity and hypertension in humans is likely to assist translation of animal data, and may, itself, identify important treatment strategies. Ultimately, this could have a substantial impact on human health, both at an individual and population level. The current review will focus specifically on studies of experimental weight gain and weight loss in humans and the following key areas, which are strongly related to blood pressure: cardiovascular function, autonomic nervous system function, metabolic function and the impact of cardiorespiratory fitness. PMID- 27761000 TI - Effect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study. AB - The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ?20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5. PMID- 27761001 TI - Comparison of invasive and brachial cuff-based noninvasive measurements for the assessment of blood pressure amplification. AB - Our aim was to assess the discrepancy in the blood pressure amplification (BPA) value defined as the aortic-to-brachial increase in systolic BP (SBP) between invasive and noninvasive brachial cuff-based methods. In 45 patients undergoing cardiac catheterization, BP in the brachial artery and ascending aorta were measured with an invasive catheter and a brachial cuff-based oscillometric device. To calculate aortic SBP, brachial waveforms were calibrated by the brachial systolic and diastolic BP (DBP) (C1 calibration) or by the brachial mean BP and DBP (C2 calibration). C1 calibration underestimated aortic SBP (-17.7 mm Hg (95% confidence interval: -21.9 to -13.5)), whereas C2 calibration generated an approximately accurate aortic SBP (1.8 mm Hg (-2.4 to 5.9)). Regarding brachial SBP, noninvasively measured values were markedly underestimated (22.2 mm Hg (-26.4 to -18.0)), resulting in a slightly low BPA value in C1 calibration (11.9+/-6.3 mm Hg) and a paradoxical negative BPA value in C2 calibration (-7.6+/ 6.7 mm Hg). Multiple linear regression analysis showed that the cuff-catheter difference of BPA was positively correlated with the cuff-catheter difference of brachial SBP in both calibrations (C1 calibration: beta=0.51; C2 calibration: beta=0.50; both P<0.01). Although noninvasively measured BPA was associated with invasively measured BPA only in C1 calibration (r=0.33, P=0.03), when using invasively measured brachial SBP instead of a cuff-based measurement, the BPA was well associated with invasively measured BPA in both calibrations (C1 calibration: r=0.57; C2 calibration: r=0.52; both P<0.001). In conclusion, there was a trade-off in accuracy between brachial cuff-based noninvasive aortic SBP and BPA because of the inherent inaccuracies in the cuff-based method. This finding should be fully considered in establishing standardized reference values for aortic BP. PMID- 27761003 TI - Synaptic plasticity: Spinal signals. PMID- 27761002 TI - Intrarenal renin-angiotensin system activity is augmented after initiation of dialysis. AB - Circulating renin-angiotensin system (RAS) activation is maintained after renal function has deteriorated. The activation of the intrarenal RAS plays a critical role in the pathophysiology of chronic kidney disease (CKD), independently of the circulating RAS. However, the activation of intrarenal RAS and the chymase dependent pathway after initiation of dialysis has not been clarified. We recruited 19 CKD patients (10 without dialysis and 9 with dialysis) who underwent a heminephrectomy. Circulating RAS was investigated before nephrectomy. The levels of intrarenal RAS components and chymase-positive cells were investigated using radioimmunoassay or immunoblot analysis on samples collected from the removed kidney. Renal damage was evaluated by the extent of tubulointerstitial fibrosis. No significant differences in circulating RAS between nondialysis and dialysis patients were found. However, intrarenal angiotensin II (AngII) and the extent of tubulointerstitial fibrosis in dialysis patients were significantly increased when compared with nondialysis patients. Prorenin and angiotensin converting enzyme (ACE) levels were dramatically decreased in accordance with renal dysfunction. On the other hand, chymase-positive cells and AngII type 1 receptor (AT1R) expression was significantly increased in dialysis patients when compared with nondialysis patients. In multiple linear regression analyses, there were significant positive and negative relationships between the extent of interstitial fibrosis and angiotensinogen (beta=0.45, P=0.042) and prorenin levels (beta=-0.85, P<0.01), respectively. In summary, a decrease in prorenin and ACE expression and an increase in chymase, angiotensinogen and AT1R expression in the kidney may augment the intrarenal RAS activation and be associated with renal damage, even after initiation of dialysis. PMID- 27761005 TI - Regimes of turbulence without an energy cascade. AB - Experiments and numerical simulations of turbulent 4He and 3He-B have established that, at hydrodynamic length scales larger than the average distance between quantum vortices, the energy spectrum obeys the same 5/3 Kolmogorov law which is observed in the homogeneous isotropic turbulence of ordinary fluids. The importance of the 5/3 law is that it points to the existence of a Richardson energy cascade from large eddies to small eddies. However, there is also evidence of quantum turbulent regimes without Kolmogorov scaling. This raises the important questions of why, in such regimes, the Kolmogorov spectrum fails to form, what is the physical nature of turbulence without energy cascade, and whether hydrodynamical models can account for the unusual behaviour of turbulent superfluid helium. In this work we describe simple physical mechanisms which prevent the formation of Kolmogorov scaling in the thermal counterflow, and analyze the conditions necessary for emergence of quasiclassical regime in quantum turbulence generated by injection of vortex rings at low temperatures. Our models justify the hydrodynamical description of quantum turbulence and shed light into an unexpected regime of vortex dynamics. PMID- 27761004 TI - The mirror mechanism: a basic principle of brain function. AB - The mirror mechanism is a basic brain mechanism that transforms sensory representations of others' behaviour into one's own motor or visceromotor representations concerning that behaviour. According to its location in the brain, it may fulfil a range of cognitive functions, including action and emotion understanding. In each case, it may enable a route to knowledge of others' behaviour, which mainly depends on one's own motor or visceromotor representations. PMID- 27761006 TI - The JAK2V617F mutation is a target for specific T cells in the JAK2V617F-positive myeloproliferative neoplasms. PMID- 27761007 TI - Only child syndrome in snakes: Eggs incubated alone produce asocial individuals. AB - Egg-clustering and communal nesting behaviours provide advantages to offspring. Advantages range from anti-predatory benefits, maintenance of moisture and temperature levels within the nest, preventing the eggs from rolling, to enabling hatching synchrony through embryo communication. It was recently suggested that embryo communication may extend beyond development fine-tuning, and potentially convey information about the quality of the natal environment as well as provide an indication of forthcoming competition amongst siblings, conspecifics or even heterospecifics. Here we show that preventing embryos from communicating not only altered development rates but also strongly influenced post-natal social behaviour in snakes. Clutches of water snakes, Natrix maura, were split evenly into half-clutches and incubated as (1) clusters (i.e. eggs in physical contact with each other) or (2) as single eggs placed in individual goblets (i.e. no physical contact amongst sibling eggs). Single incubated eggs produced less sociable young snakes than their siblings that were incubated in a cluster: the former were more active, less aggregated and physically contacted each other less often than the latter. Potential long-term effects and evolutionary drivers for this new example of informed dispersal are discussed. PMID- 27761018 TI - Investigation of bacterial effects of Asian dust events through comparison with seasonal variability in outdoor airborne bacterial community. AB - Atmospheric bacterial dispersion with aeolian dust has been reported to have a potential impact on public health and ecosystems. Asian dust is a major aeolian event that results in an estimated 4 million tons of Asian dust particles falling in Japan annually, 3,000-5,000 km away from their source regions. However, most studies have only investigated the effects of Asian dust during dust seasons. Therefore, in this study, outdoor bacterial abundance and community composition were determined by 16S rRNA quantitative PCR and amplicon sequencing, respectively, and compared on Asian and non-Asian dust days (2013-2015; 44 samples over four seasons). Seasonal variations in bacterial abundance of non Asian dust days were not observed. Bacterial abundance of individual samples collected on non-Asian dust days changed dynamically relative to Asian dust days, with bacterial abundance occasionally reaching those of Asian dust days. The bacterial community composition on non-Asian dust days was rather stable seasonally, and did not differ from that on Asian dust days. These results indicate that bacteria in Asian dust does not immediately influence indigenous bacterial communities at the phylum/class level in distant downwind areas; accordingly, further studies of bacterial communities in downwind areas closer to the dust source are warranted. PMID- 27761020 TI - Vasculitis syndromes: Kawasaki disease is IL-1beta-mediated. PMID- 27761019 TI - Novel mutation of ND4 gene identified by targeted next-generation sequencing in patient with Leigh syndrome. AB - By using next-generation sequencing targeted to MitoExome including the entire mtDNA and exons of 1033 genes encoding the mitochondrial proteome, we described here a novel m.11240C>T mutation in the mitochondrial ND4 gene from a patient with Leigh syndrome. High mutant loads of m.11240C>T were detected in blood, urinary epithelium, oral mucosal epithelium cells, and skin fibroblasts of the patient. Decreased mitochondrial complex I activity was found in transmitochondrial cybrids containing the m.11240C>T mutation with biochemical analysis. Furthermore, functional investigations confirmed that mitochondria with the m.11240C>T variant exhibited lower adenosine triphosphate-related mitochondrial respiration. However, complex I assembly in mutant cybrids was not affected. While this mutation was located in the fourth hydrophobic trans membrane region of ND4 gene, we suggested that mutation of m.11240C>T might impair the proton pumping channel of complex I but had little effect on the complex I assembly. In conclusion, we identified m.11240C>T as a novel mitochondrial disease-related mtDNA mutation. PMID- 27761021 TI - Clinical trials: The rise of IL-2 therapy - a novel biologic treatment for SLE. PMID- 27761022 TI - Circular Dichroism Microscopy Free from Commingling Linear Dichroism via Discretely Modulated Circular Polarization. AB - In this work, we developed a circular dichroism (CD) imaging microscope with a device to suppress the commingling of linear birefringence (LB) and linear dichroism (LD) signals. CD signals are, in principle, free from the commingling influence of LD and LB if the sample is illuminated with pure circularly polarized light, with no linear polarization contribution. Based on this idea, we here propose a novel circular polarization modulation method to suppress the contribution of linear polarization, which enables high-sensitivity CD detection (10-4 level in optical density unit or mdeg level in ellipticity) for microscopic imaging at a nearly diffraction limited spatial resolution (sub-MUm level). The highly sensitive, diffraction-limited local CD detection will make direct analyses of chiral structures and spatial mappings of optical activity feasible for MUm- to sub-MUm-sized materials and may yield a number of applications as a unique optical imaging method. PMID- 27761023 TI - MicroRNA-574-5p promotes metastasis of non-small cell lung cancer by targeting PTPRU. AB - Dysregulation of microRNAs (miRNAs) has been associated with malignant behavior in a variety of cancers. Our previous study demonstrated that miRNA expression profiles are predictors for patients with advanced non-small cell lung cancer (NSCLC). We also showed that miRNAs are involved in small-cell lung cancer metastasis. Here, we used qRT-PCR to re-analyze our previous microarray results using serum samples from 75 patients with NSCLC. Surprisingly, we found that miR 574-5p and miR-874 were overexpressed in patients with metastatic advanced NSCLC but not in patients with non-metastatic advanced NSCLC. Additionally, miR-574-5p expression was correlated between matched serum and tissue samples from 68 patients. However, these 2 miRNAs are not prognostic factors for NSCLC. Transwell and wound-healing assays showed that miR-574-5p promotes the migration and invasion of NSCLC cells. Furthermore, miR-574-5p enhanced the tyrosine phosphorylation of beta-catenin by repressing PTPRU expression in vitro. In conclusion, this study explored the expression of miR-574-5p in clinical samples and its molecular mechanisms in the metastasis of advanced NSCLC. PMID- 27761024 TI - Eating disinhibition and vagal tone moderate the postprandial response to glycemic load: a randomised controlled trial. AB - Reducing the glycemic load (GL) of the diet may benefit appetite control but its utility is complicated by psychological influences on eating. Disinhibited behaviour, a risk factor for overconsumption, is characterized by reduced prefrontal cortex activity, which in turn modulates vagal tone; a phenomenon associated with glucoregulation. This double blind randomised controlled trial explored for the first time the influence of disinhibited eating and vagal tone (heart rate variability (HRV)) on hunger and the postprandial response to GL. Blood glucose (BG) and hunger were measured 30 and 150 min after consumption of water, glucose or isomaltulose (low glycemic sugar). After consuming glucose, independently of BMI or habitual diet, those with the highest levels of disinhibition had higher BG levels after thirty minutes (B = 0.192, 95% CI LL. 086, UL 0.297), and lower BG after one hundred and fifty minutes (B = -0.240, 95% CI LL -0.348, UL -0.131). BG was related to hunger but only in low disinhibited eaters. Disinhibited eaters were characterised by a reduced HRV which was related to greater BG excursions (B = 0.407, 95% CI LL 0.044, UL 1.134). These findings highlight novel mechanisms by which disinhibited eating leads to obesity and insulin resistance. This trial was registered at clinicaltrials.gov NCT02827318. PMID- 27761025 TI - The Clinical Relevance of Beta Blockers in Ovarian Carcinoma: A Systematic Review. AB - The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma. There is a great need for new treatment strategies, and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response. This systematic review summarizes the current state of knowledge and research on the topic: A database analysis identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course. The 13 preclinical studies identified showed almost without exception both that catecholamines had detrimental effects on tumour progression, and that these effects could be influenced by pharmacological blockade. Overall the available evidence does not justify the use of beta blockers in clinical practice for ovarian carcinoma at the present time. This article also outlines details of research design required for further studies needed on the subject. Preclinical research findings are however very impressive: They not only form an important basis for the development of future clinical studies but also, through revealing new pathomechanisms, they already make an important contribution towards the development of new treatment strategies for ovarian carcinoma. PMID- 27761026 TI - Surgical Aspects of Ovarian Tissue Removal and Ovarian Tissue Transplantation for Fertility Preservation. AB - Introduction: The removal of ovarian tissue prior to starting oncologic treatment and the subsequent transplantation of this tissue after completing therapy have become increasingly important surgical fertility-preserving techniques. The aim of this review was to investigate the different surgical techniques used for this method reported in the literature to date and to discuss the advantages and disadvantages of the respective techniques. Review: A search was done in MEDLINE using a defined algorithm to find studies published between January 2004 and December 2015. All study designs were included in our review if they contained statements on the surgical technique used. We found 16 publications (8 retrospective cohort studies, 6 case reports and 2 systematic reviews) with a total of 1898 female patients which reported on the surgical technique used for ovarian biopsy and 15 publications (7 retrospective cohort studies, 6 case reports and 2 systematic reviews) with a total of 455 women which mentioned the surgical technique used for ovarian transplantation. Different surgical techniques can be used both for ovarian biopsy and for the transplantation of ovarian tissue. A number of different surgical routes have been used, and the amount of tissue extracted, the instruments used, the treatment of the ovary, the transplantation site, the blood supply to the transplanted ovarian tissue and the procedure used for simultaneous surgical interventions vary. Conclusion: In future, one of the tasks will be to establish a standard surgical method for ovarian extraction and transplantation which will have a low rate of complications and a high pregnancy and birth rate while ensuring that the transplanted tissue is fully functional. PMID- 27761028 TI - HPV Vaccination: Attitude and Knowledge among German Gynecologists. AB - Purpose: In order to achieve a higher vaccination rate, education on HPV as well as options for prophylaxis performed by doctors is of great importance. One opportunity to increase the protection against HPV would be vaccinating boys. This study evaluated attitude and knowledge among German gynecologists regarding HPV vaccination, especially in boys. Material and Methods: A questionnaire with 42 questions about demographics, attitude and knowledge about HPV and HPV vaccination was sent to members of the German Society for Gynecology and Obstetrics (DGGG). Results: 998 out of 6567 addressed gynecologists participated. Knowledge about HPV, associated diseases and possible HPV vaccines was high among participants. The attitude towards vaccination in boys as well as girls was positive. Only 8.2 % refused to vaccinate their sons whereas 2.2 % refused to do this for their daughters. However, only few gynecologists vaccinated their daughters and sons against HPV. Main reason for girls was an age outside of vaccination guidelines; for boys it was the lack of cost coverage. Conclusion: The willingness of gynecologists to perform HPV vaccination in boys is as high as for girls. However, sons of gynecologists are only rarely vaccinated against HPV. Main reason is the lack of cost coverage. Vaccinating boys could decrease the disease burden in males, as well as protect women by interrupting ways of transmission. Since the main argument against vaccination of boys is only of financial nature, the necessity of a vaccination recommendation for boys needs to be re-evaluated taking into account the cost-reduced 2-dose vaccination scheme. PMID- 27761027 TI - Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients. AB - Introduction: When cancer patients have advanced disease and a primary cure is no longer possible, the focus is on maintaining the patient's quality of life. Recent therapeutic advances in breast cancer treatment mean that even patients with metastatic disease can remain stable for long periods of time. The aim of this study was to look at the health-related quality of life (HRQL) of these patients and compare it with data for the general population and to show the differences in outcomes for different survey instruments used to measure quality of life. Material and Methods: A total of 96 breast cancer patients with metastatic disesae or receiving adjuvant therapy were questioned about their quality of life. Patients were investigated using the established survey instruments EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L and EQ VAS. All patients filled out questionnaires. Statistical analysis was done using MS Excel and SPSS. Results: Although the questionnaires were completed at the same time, the different questionnaires showed significant differences with regard to the level of stress experienced by the patient. When the EQ VAS questionnaire was used, the patient's current state of health was assessed as significantly better than with the EORTC QLQ-C30. Overall, all aspects of patients' quality of life were found to be in need of optimization and HRQL of patients was significantly poorer in all areas compared to the reference population. Conclusion: To improve the quality of life of patients with metastatic disease, it is necessary to continuously monitor the success of therapy. The choice of survey tools is highly relevant as assessments differ considerably depending on the choice of questionnaire. PMID- 27761029 TI - Systematic Comparison of Different Meta-analyses, Systematic Reviews and HTA Reports on Cervical Cancer Screening based on Cytology or HPV Test. AB - Introduction: Cervical cancer screening programs all over the world are being radically revised; preventive screening is increasingly based on detecting infection with human papillomavirus (HPV). This change was driven by large international studies (comparing cytological and HPV-based screening), which were then summarized in systematic reviews or HTA reports. We carried out a systematic comparison of these meta-analyses, comparing their contents, quality, results and recommendations. Material and Methods: A systematic search in MEDLINE identified eight meta-analyses. Seven more papers were also included in our analysis. The quality of these publications was reviewed using the AMSTAR criteria and presented in tabular form. Results: There were significant differences with regard to the primary studies included in the meta-analyses, the quality of the meta-analyses, the endpoints, and the outcomes and recommendations based on these endpoints. Conclusion: Different meta-analyses on the same or similar issues sometimes came to quite different conclusions because they used different approaches. This is quite significant because the underlying primary data did not change. The data indicated that HPV-based screening was superior. The heterogeneity of the meta-analyses affects the decisions taken by policymakers in the healthcare system. PMID- 27761030 TI - Routine Treatment of Cervical Cytological Cell Changes: Diagnostic Standard, Prevention and Routine Treatment of Cervical Cytological Cell Changes - An Assessment of Primary and Secondary Prevention and Routine Treatment Data in the Context of an Anonymous Data Collection from Practicing Gynaecologists; an Academic, Non-Interventional Study. AB - Introduction: Diagnosis and treatment of vaginal and cervical cytological cell changes are described in European and national guidelines. The aim of this data collection was to evaluate the remission rates of PAP III and PAP III D cytological findings in patients over a period of 3-4 months. Method: The current state of affairs in managing suspicious and cytological findings (PAP III, and III D) in gynecological practice was assessed in the context of a data collection survey. An evaluation over a period of 24 months was conducted on preventative measures, the occurrence and changes to normal/suspect/pathological findings and therapy management (for suspicious or pathological findings). Results: 307 female patients were included in the analysis. At the time of the survey 186 patients (60.6 %) had PAP III and 119 (38.8 %) had PAP III D findings. The spontaneous remission rate of untreated PAP III patients was 6 % and that of untreated PAP III D patients was 11 %. The remission rates of patients treated with a vaginal gel were 77 % for PAP III and 71 % for PAP III D. Conclusion: A new treatment option was used in gynecological practice on patients with PAP III and PAP III D findings between confirmation and the next follow-up with excellent success. PMID- 27761031 TI - Melatonin - marvel in the making? PMID- 27761032 TI - Ultrasound-guided truncal blocks: A new frontier in regional anaesthesia. AB - The practice of regional anaesthesia is rapidly changing with the introduction of ultrasound into the working domain of the anaesthesiologist. New techniques are being pioneered. Among the recent techniques, notable are the truncal blocks, for example, the transversus abdominis plane block, rectus sheath block, hernia block and quadratus lumborum block in the abdomen and the pectoral nerves (Pecs) block 1 and 2, serratus anterior plane block and intercostal nerve block. This narrative review covers the brief anatomical discourse along with technical description of the ultrasound-guided truncal blocks. PMID- 27761033 TI - Role of melatonin in attenuation of haemodynamic responses to laryngoscopy and intubation. AB - BACKGROUND AND AIMS: Laryngoscopy and endotracheal intubation are considered as potent stimuli which lead to an increase in heart rate and blood pressure. Melatonin (N-acetyl-5-methoxytryptamine) has been studied for pre-operative anxiolysis and sedation in Intensive Care Unit. We made a hypothesis that melatonin can provide haemodynamic stability during laryngoscopy and intubation when given 120 min before the procedure. METHODS: Sixty American Society of Anesthesiologists physical status Grade I and II patients of either gender, 20-45 years old, 40-65 kg body weight, scheduled to undergo elective surgical procedures under general anaesthesia were assigned into two equal groups - Group C (control) and Group M (melatonin). They received oral placebo or melatonin tablets 6 mg, respectively, 120 min before surgery. The haemodynamic parameters were recorded preoperatively, during laryngoscopy and endotracheal intubation and thereafter at 1, 3, 5 and 10 min. Unpaired t-test was used for between-group comparison of ratio and interval scale data. For within-group comparison of ratio and interval scale data, repeated-measures ANOVA and post hoc Bonferroni t-tests were used. RESULTS: It was observed that in the control group, there was a significant increase in heart rate and blood pressure at laryngoscopy and intubation and persisted till 10 min post-intubation. In melatonin group, there was an insignificant increase in heart rate at the time of laryngoscopy and intubation which however settled within 1 min post-intubation. CONCLUSION: Melatonin is an effective drug for attenuation of cardiovascular responses to laryngoscopy and endotracheal intubation. PMID- 27761034 TI - Metabolic profile in right lobe living donor hepatectomy: Comparison of lactated Ringer's solution and normal saline versus acetate based balanced salt solution - a pilot study. AB - BACKGROUND AND AIMS: Lactate levels predict outcomes after hepatectomy. We compared metabolic effects of lactated versus lactate free solutions in living donor hepatectomy. METHODS: Consecutive right lobe donors (n = 53) were alternatively allotted to lactated Ringer's solution and normal saline (Group L control) or acetated crystalloid (Sterofundin B Braun(r) Group S -study group) in an observational prospective randomised study. The primary outcome measure was lactate level, and secondary outcomes were base excess, bicarbonate, glucose and chloride intra- and post-operatively. Mann-Whitney and Chi-square tests were used for analysis. RESULTS: The intraoperative, post-operative lactate levels and the time for normalisation were comparable. Group L had significantly lower intraoperative bicarbonate levels (mmol/L) at 6 and 8 h (20.0 +/- 2.14 vs. 21.3 +/- 1.6, P = 0.0471; 18.68 +/- 2.04 vs. 20.39 +/- 17, P = 0.002), base excess at 4 and 6 h (mmol/L) (-3.64 +/- 2.73 vs. -3.0 +/- 1.52, P = 0.031; -6.64 +/- 2.76 vs. -4.35 +/- 1.7 P = 0.006). The intraoperative chloride levels (mmol/L) were higher in group L at 4 and 8 h (108 +/- 5.9 vs. 105.99 +/- 2.76, P = 0.0471; 109.51 +/- 3.86 vs. 106.93 +/- 3.09, P = 0.002). Intraoperative glucose (mg/dL) at 6 h was higher in group L, 160.55 +/- 31.52 vs. 145.5 +/- 24.29, P = 0.043. The highest post-operative chloride (mmol/L) was higher in Group L (112.3 +/- 3.86 vs. 109.81 +/- 3.72, P = 0.034). Post-operative base excess and bicarbonate showed an improved profile in Group S (-7.37 +/- 2.99 vs. -5.06 +/- 1.71 P = 0.001 and 17.79 +/- 2.23 vs. 19.68 +/- 1.51 P = 0.005). CONCLUSION: Acetated fluids were associated with higher levels of bicarbonate, lesser base deficit, glucose and chloride but no difference in lactate levels in comparison with Ringer's lactate and normal saline in living donor hepatectomy. PMID- 27761035 TI - A randomised trial to compare i-gel and ProSealTM laryngeal mask airway for airway management in paediatric patients. AB - BACKGROUND AND AIMS: i-gelTM is a newer supraglottic airway device with a unique non-inflatable cuff. We aimed to compare i-gelTM with ProSealTM laryngeal mask airway (PLMATM) in children scheduled for surgery under general anaesthesia (GA) with controlled ventilation. METHODS: This prospective, randomised controlled study was conducted in 100 surgical patients, aged 2-6 years of American Society of Anesthesiologists Physical Status I-II scheduled under GA. Patients were randomly allocated to receive either size 2 i-gelTM or PLMATM as an airway device. The primary aim was oropharyngeal leak pressure assessed at 5 min following correct placement of the device. Secondary outcomes measured included number of attempts, ease of insertion, time of insertion, quality of initial airway, fibre-optic grading and effects on pulmonary mechanics. Statistical analysis was done using paired t-test and Chi-square test. RESULTS: The demographic data were similar in both the groups. The oropharyngeal leak pressure in the i-gelTM group was 29.5 +/- 2.5 cmH2 O as compared to 26.1 +/- 3.8 cmH2 O in PLMATM group (P = 0.002). The time taken for successful insertion in PLMATM was longer as compared to i-gel (12.4 +/- 2.7 vs. 10.2 +/- 1.9 s, P = 0.007). The quality of initial airway was superior with i-gelTM. The number of attempts, ease of insertion of supraglottic device, insertion of orogastric tube and pulmonary mechanics were similar in both the groups. CONCLUSION: Size 2 i-gelTM exhibited superior oropharyngeal leak pressure and quality of airway in paediatric patients with controlled ventilation as compared to PLMATM although the pulmonary mechanics were similar. PMID- 27761036 TI - Does C-MAC(r) video laryngoscope improve the nasotracheal intubating conditions compared to Macintosh direct laryngoscope in paediatric patients posted for tonsillectomy surgeries? AB - BACKGROUND AND AIMS: C-MAC(r) video laryngoscope (VL) with Macintosh blade has been found to improve Cormack-Lehane (C-L) laryngoscopic view as well as intubating conditions for orotracheal intubation. However, studies done on the performance of C-MAC(r) VL for nasotracheal intubation (NTI) are very few in number. Hence, we compared laryngoscopy and intubating conditions between Macintosh direct laryngoscope and C-MAC(r) VL for NTI. METHODS: Sixty American Society of Anesthesiologists Physical Status I, II patients, aged 8-18 years, posted for tonsillectomy surgeries under general anaesthesia with NTI were randomised, into two groups. Patients in group 1 were intubated using Macintosh direct laryngoscope and group 2 with C-MAC(r) VL. C-L grading, time required for intubation, need for additional manoeuvres and haemodynamic changes during and after intubation were compared between the groups. RESULTS: C-L grade 1 views were obtained in 26 and 29 patients in group 1 and group 2, respectively (86.7% vs. 96.7%). Remaining patients were having C-L grade 2 (13.3% vs. 3.3%). Duration of intubation was less than a minute in group 2 (93.3%). Need for additional manoeuvres (M1-M5) were more in group 1 (97% vs. 77%). M1 (external manipulation) was needed more in group 2 compared to group 1 (53.3% vs. 30%). Magill's forceps alone (M4) and M4 with additional external manipulation (M5) were needed more in group 1 compared to group 2 (60% vs. 16%). CONCLUSION: The overall performance of C-MAC(r) VL was better when compared to conventional direct Macintosh laryngoscope during NTI in terms of glottis visualisation, intubation time and need for additional manoeuvres. PMID- 27761037 TI - Prevalence of acute post-operative pain in patients in adult age-group undergoing inpatient abdominal surgery and correlation of intensity of pain and satisfaction with analgesic management: A cross-sectional single institute-based study. AB - BACKGROUND AND AIMS: Considering the paucity of regional data, this study was designed to investigate the prevalence of post-operative pain and determine if there exists any correlation between the intensity of post-operative pain and patient's level of satisfaction with their pain management after inpatient abdominal surgery at an academic tertiary care government centre. METHODS: Pain intensity was measured in 120 patients with numeric rating scale at the fifth post-operative hour, second and third post-operative day. A questionnaire was used to measure the level of satisfaction with nurse's and doctor's response to their pain and overall pain management. RESULTS: The prevalence of post-operative pain was 84.17%, 92.5% and 96.66% at the fifth post-operative hour, second and third post-operative day, respectively. Less number of patients experienced severe intensity pain on the third post-operative day (P = 0.00046), whereas the number of patients experiencing mild pain increased (P < 0.000) compared to the fifth post-operative hour. The number of patients with complete analgesia decreased on the third post-operative day (P = 0.001 compared to fifth post operative day). The Spearman correlation coefficient between pain score on the third post-operative day and level of satisfaction with nurse's response, doctor's response to pain and the overall pain management was - 0.0218 (P = 0.8107), 0.1307 (P = 0.1553) and 0.0743 (P = 0.4195), respectively. CONCLUSION: There is a high prevalence of acute post-operative pain in patients undergoing inpatient abdominal surgery at our institute. There is a weak correlation between the intensity of pain and level of satisfaction with pain management. PMID- 27761038 TI - A comparison of the effect of two doses of oral melatonin with oral midazolam and placebo on pre-operative anxiety, cognition and psychomotor function in children: A randomised double-blind study. AB - BACKGROUND AND AIMS: Melatonin (MT), a naturally occurring pituitary hormone has a sleep promoting effect. There are very few studies on pre-operative oral MT (0.2-0.5 mg/kg) in children. We planned a study to assess the efficacy of oral MT in two doses and compare it with oral midazolam and placebo for pre-operative anxiolysis, sedation, maintenance of cognition and psychomotor skills, parental separation behaviour and venepuncture compliance. METHODS: This prospective double-blind randomised study was conducted after ethical committee approval on 100 children aged 5-15 years, American Society of Anaesthesiologists physical status I and II undergoing elective surgery at our hospital from January 1, 2014, to December 31, 2014. Mentally disordered children were excluded from the study. They were randomised into four groups of 25 each (A, B, C, D) to receive either oral MT 0.5 mg/kg or 0.75 mg/kg or oral midazolam 0.5 mg/kg or placebo 45-60 min, respectively, before induction. The child's anxiety, cognition and psychomotor function before and after pre-medication, behaviour during the parental separation and venepuncture were appropriately scored. Kruskal-Wallis analysis of variance for intergroup and Wilcoxon matched pairs tests for intragroup comparisons of data were applied. RESULTS: The four groups were comparable regarding mean age, weight and sex. The anxiety score reductions in the three groups when compared to placebo were statistically significant. Children receiving MT 0.75 mg/kg had maximum anxiolysis and venepuncture compliance (P < 0.05). Cognition was decreased with maximum sedation, successful parental separation and psychomotor impairment in the midazolam group (P < 0.05). CONCLUSION: Oral MT (0.5 mg/kg and 0.75 mg/kg) in children decreases pre operative anxiety without impairing cognitive and psychomotor functions, the 0.75 mg/kg dose being most effective. PMID- 27761039 TI - A survey on the use of low flow anaesthesia and the choice of inhalational anaesthetic agents among anaesthesiologists of India. AB - BACKGROUND AND AIMS: With the availability of modern workstations and heightened awareness on the environmental effects of waste anaesthesia gases, anaesthesiologists worldwide are practicing low flow anaesthesia (LFA). Although LFA is being practiced in India, hard evidence on the current practice of the same from anaesthesiologists practicing in India is lacking and hence, we conducted this survey. METHODS: A questionnaire containing 16 questions was distributed among a subgroup of anaesthesiologists who attended the 2014 National Conference of Indian Society of Anaesthesiologists. The filled-in questionnaires were computed and analysed with SPSS version 11. RESULTS: The response rate to the survey was 82%. About 73% of the respondents practiced LFA routinely, with 65% having workstations. Most of the anaesthesiologists used fresh gas flows <1.5 L/min with 45.1% using O2 concentrations at a range of 30-40%. ETCO2 monitoring was used routinely by most whereas use of agent analysers and bispectral index monitoring were restricted. The availability of scavenging system was also limited to only 33.5%. Majority preferred N2 O as carrier gas and sevoflurane as volatile agent of their choice. CONCLUSION: Our survey revealed that practice of LFA in India has numerous lacunae. Provision of better monitoring facilities, workstations as well as awareness regarding the environmental issues of waste anaesthetic gases need to be addressed. PMID- 27761040 TI - A comparison of intraperitoneal bupivacaine-tramadol with bupivacaine-magnesium sulphate for pain relief after laparoscopic cholecystectomy: A prospective, randomised study. AB - BACKGROUND AND AIMS: In laparoscopic surgeries, intraperitoneal instillation of local anaesthetics and opioids is gaining popularity, for better pain relief. This study compared the quality and duration of post-operative analgesia using intraperitoneal tramadol plus bupivacaine (TB) or magnesium plus bupivacaine (MB). METHODS: In this study, 186 patients undergoing laparoscopic cholecystectomy were randomly divided into two groups: group TB received intraperitoneal tramadol with bupivacaine and group MB received intraperitoneal magnesium sulphate (MgSO4) with bupivacaine. The visual analogue scale (VAS) to assess pain, haemodynamic variables and side effects were noted and compared at different time points. The primary outcome was to compare the analgesic efficacy and duration of pain relief. The secondary outcomes included comparison of haemodynamic parameters and side effects among the two groups. The data analysis was carried out with unpaired Student's t-test and Chi-square test using software SPSS 20.0 version. RESULTS: The mean of VAS pain score after 1, 2, 4, 6 and 24 h of surgery was more in TB group compared to MB group, and the difference was statistically significant (P < 0.05). The total rescue analgesia consumption in 24 h after surgery was 2.4 g (mean) of paracetamol in TB group and 1.4 g (mean) of paracetamol in MB group which was statistically significant (P < 0.05). There were no statistically significant differences in the secondary outcomes. CONCLUSION: Intraperitoneal instillation of bupivacaine-MgSO4 renders patients relatively pain-free in first 24 h after surgery, with longer duration of pain free period and less consumption of rescue analgesic as compared to bupivacaine tramadol combination. PMID- 27761041 TI - Acute post-operative diabetic ketoacidosis: Atypical harbinger unmasking latent diabetes mellitus. AB - Hyperglycaemia following surgical and anaesthetic stress is a well-established entity which might have undesirable clinical consequences in known diabetics. We encountered a rare event where an undiagnosed diabetic patient developed ketoacidosis in the immediate post-operative period which was her initial presenting symptom of deranged glucoregulation. Presumably, the stress induced by surgery and anaesthesia lead to the genesis of this event. We discuss the management of this case. In addition, we highlight the importance of glycosylated haemoglobin as a subject of future research in identifying such "at risk" patients and for stratifying the risk of hyperglycaemic complications in perioperative settings. PMID- 27761042 TI - Quality of post-operative analgesia after epidural dexmedetomidine and ketamine: A comparative pilot study. PMID- 27761043 TI - Successful first swap renal transplant in a public hospital. PMID- 27761044 TI - Internet use among anaesthesiologists: A cross-sectional survey. PMID- 27761045 TI - Ultrasonographic optic nerve sheath diameter measurement in overweight parturient with intracranial tumour: Guiding choice of anaesthesia. PMID- 27761046 TI - Treatment of upper airway oedema prior to extubation. PMID- 27761047 TI - Green colour donor plasma. PMID- 27761048 TI - Anaesthetic considerations in an orphan disease with skeletal anomalies. PMID- 27761049 TI - Post-spinal headache in a parturient - look beyond post-dural puncture headache. PMID- 27761050 TI - A 'Y'-shaped connector as an indispensable component of paediatric bronchoscopy mask: A novel innovation! PMID- 27761051 TI - Left molar approach using adult C-MAC videolaryngoscope for airway management of a child with nasopharyngeal carcinoma extending to hypopharynx. PMID- 27761053 TI - Erratum: Basic statistical tools in research and data analysis. AB - [This corrects the article on p. 662 in vol. 60, PMID: 27729694.]. PMID- 27761052 TI - Peri-operative management of a neonate with tracheo-oesophageal fistula and anorectal malformation: Survival of the fittest. PMID- 27761054 TI - Pharmacotherapy for Body Dysmorphic Disorder. PMID- 27761056 TI - Dreaming in Spain: Parental Determinants of Immigrant Children's Ambition. AB - We examine determinants of educational and occupational aspirations and expectations among children of immigrants in Spain on the basis of a unique data set that includes statistically representative data for foreign-origin secondary students in Madrid and Barcelona plus a sample of one-fourth of their parents. Independently collected data for both generations allow us to establish effects of parental characteristics on children's orientations without the confounding potential inherent in children's reports about parents. We analyze first determinants of parental ambition and, through a series of step-wise regressions, the effects of these goals and other parental and family characteristics on children's aspirations and expectations. A structural equations model synthesizes results of the analysis. The model confirms predictions from the research literature, especially those based on the Wisconsin status attainment model, but rejects others, including the predicted significance of private vs. public school attendance. Parental ambition, knowledge of Spanish by parents and children, gender, and children's age are major determinants of youths' educational and occupational goals. These results have direct implications for policy; these are discussed in the conclusion. PMID- 27761057 TI - Behavior Problems Among Adolescents Exposed to Family and Community Violence in Chile. AB - Research that simultaneously examines the relationship of multiple types of family and community violence with youth outcomes is limited in the previous research literature, particularly in Latin America. This study examined the relationship of youth exposure to family and community violence-parental use of corporal punishment, violence in the community, intimate partner physical aggression-with eight subscales of the Youth Self Report among a Chilean sample of 593 youth-mother pairs. Results from multilevel models indicated a positive association between youth exposure to violence in the family and community, and a wide range of behavior problem outcomes, in particular, aggression. With growing evidence concerning the detrimental effect of violence on youth's well-being, these findings highlight the need for a more comprehensive understanding of the various kinds of violence youth are exposed to within the family and community and the concomitant need to reduce multiple forms of violence. PMID- 27761058 TI - Silicon technologies for arrays of Single Photon Avalanche Diodes. AB - In order to fulfill the requirements of many applications, we recently developed a new technology aimed at combining the advantages of traditional thin and thick silicon Single Photon Avalanche Diodes (SPAD). In particular we demonstrated single-pixel detectors with a remarkable improvement in the Photon Detection Efficiency in the red/near-infrared spectrum (e.g. 40% at 800nm) while maintaining a timing jitter better than 100ps. In this paper we discuss the limitations of such Red-Enhanced (RE) technology from the point of view of the fabrication of small arrays of SPAD and we propose modifications to the structure aimed at overcoming these issues. We also report the first preliminary experimental results attained on devices fabricated adopting the improved structure. PMID- 27761055 TI - Life Stress and Health: A Review of Conceptual Issues and Recent Findings. AB - Life stress is a central construct in many models of human health and disease. The present article reviews research on stress and health, with a focus on (a) how life stress has been conceptualized and measured over time, (b) recent evidence linking stress and disease, and (c) mechanisms that might underlie these effects. Emerging from this body of work is evidence that stress is involved in the development, maintenance, or exacerbation of several mental and physical health conditions, including asthma, rheumatoid arthritis, anxiety disorders, depression, cardiovascular disease, chronic pain, human immunodeficiency virus/AIDS, stroke, and certain types of cancer. Stress has also been implicated in accelerated biological aging and premature mortality. These effects have been studied most commonly using self-report checklist measures of life stress exposure, although interview-based approaches provide a more comprehensive assessment of individuals' exposure to stress. Most recently, online systems like the Stress and Adversity Inventory (STRAIN) have been developed for assessing lifetime stress exposure, and such systems may provide important new information to help advance our understanding of how stressors occurring over the life course get embedded in the brain and body to affect lifespan health. PMID- 27761059 TI - Key Barriers to Community Cohesion: Views from Residents of 20 London Deprived Neighbourhoods. AB - The notion of community has been central to the political project of renewal of New Labour in the UK. The paper explores how the discourses of community are framed within New Labour and discusses these in the light of the results from research which focuses on how people within urban deprived areas construct their community. It draws upon the results of one part of a larger research project (the 'Well London' programme) which aimed to capture the views of residents from 20 disadvantaged neighbourhoods throughout London using an innovative qualitative method known as the 'World Cafe'. Our results show the centrality of young people to the development of cohesive communities, the importance of building informal relationships between residents alongside encouraging greater participation to policy making, and the need to see these places as fragile and temporary locations but with considerable social strengths. Government policies are only partially addressing these issues. They pay greater attention to formally encouraging citizens to become more involved in policy making, largely ignore the contribution young people could make to the community cohesion agenda, and weakly define the shared norms and values that are crucial in building cohesive communities. Thus, the conclusion is that whilst an emphasis of the government on 'community' is to be welcome, more needs to be done in terms of considering the 'voices' of the community as well as enabling communities to determine and act upon their priorities. PMID- 27761060 TI - Clinical Application of Autologous Adipose Stem Cells in Patients with Multiple Sclerosis: Preliminary Results. AB - The clinical outcome of autologous adipose stem cell (ASC) treatment of patients with multiple sclerosis (MS) was investigated following one year of observation. Methods. The clinical and MRI outcomes of 16 ASC-treated patients with RRMS and SPMS are reported after a one-year follow-up period. Results. At 18 months of follow-up, some patients showed "enticing" improvements on some exploratory efficacy measures, although a significant benefit was not observed for any measure across the entire group. Neither the progression of disability nor relapses were observed in any cases. In four patients, we found new gadolinium+ (Gd+) lesions on MRI. Our results indicate that ASC therapy is safe and does not produce any substantial side effects. Disease progression-free survival (PFS) of 18 months was seen in all patients with RRMS and SPMS. In these patients, EDSS scores did not progress above baseline scores. Gd-enhancing lesions were observed in two cases with RRMS, but these patients did not exhibit changes in EDSS score. Conclusion. Intrathecal treatment with ASCs is an attractive form of therapy for patients with MS but should be reserved for cases with aggressive disease progression, for cases that are still in the inflammatory phase, and for the malignant form. PMID- 27761061 TI - Inhibitory Effect of Loranthus parasiticus on IgE-Mediated Allergic Responses in RBL-2H3 Cells. AB - The mistletoe Loranthus parasiticus has been used as a compound for traditional medicine in Northeast Asia for a long time and is known to possess neuroprotective action. Nonetheless, the effect of Loranthus parasiticus on allergic responses remains unknown. In the present study, we evaluated whether the water extract of Loranthus parasiticus (LPE) could inhibit IgE-mediated allergic responses in RBL-2H3 cells. LPE inhibited the release of beta hexosaminidase (IC50, 184.5 MUg/mL) and the formation of tumor necrosis factor alpha (IC50, 84.27 MUg/mL), interleukin-4 (IC50, 93.43 MUg/mL), prostaglandin E2 (IC50, 84.10 MUg/mL), prostaglandin D2, and leukotriene C4 (IC50, 43.27 MUg/mL) in a concentration-dependent manner. Moreover, LPE inhibited phosphorylation of Syk, PLCgamma1/2, PKCdelta, ERK, JNK, p38, and Akt. In the late phase, LPE decreased 5-lipoxygenase phosphorylation and COX-2 expression but not cPLA2 phosphorylation. Additionally, LPE included total phenolic compounds (10.72 mg/g dry weight) and total flavonoids (56.20 mg/g dry weight). These results suggest that the phenolic compounds or flavonoids contained in LPE may be associated with antiallergic activity. The phenolic compounds and flavonoids in LPE are antiallergic phytochemicals capable of inhibiting the activation of the FcepsilonRI signaling cascade in mast cells. Such effects may provide further information for the development of a phytomedicine for allergic diseases. PMID- 27761062 TI - Dietary Chitosan Supplementation Increases Microbial Diversity and Attenuates the Severity of Citrobacter rodentium Infection in Mice. AB - C57BL/6 mice were tested in order to investigate the effects of dietary chitosan (COS) supplements on intestinal microflora and resistance to Citrobacter rodentium infection. The findings reveal that, after consuming a 300 mg/kg COS diet for 14 days, microflora became more diverse as a result of the supplement. Mice receiving COS exhibited an increase in the percentage of Bacteroidetes phylum and a decrease in the percentage of Firmicutes phylum. After Citrobacter rodentium infection, the histopathology scores indicated that COS feeding resulted in less severe colitis. IL-6 and TNF-alpha were significantly lower in colon from COS-feeding mice than those in the control group. Furthermore, mice in COS group were also found to experience inhibited activation of nuclear factor kappa B (NF-kappaB) in the colonic tissue. Overall, the findings revealed that adding 300 mg/kg COS to the diet changed the composition of the intestinal microflora of mice, resulting in suppressed NF-kappaB activation and less production of TNF-alpha and IL-6; and these changes led to better control of inflammation and resolution of infection with C. rodentium. PMID- 27761064 TI - Human Cytochrome P450 Enzyme Modulation by Gymnema sylvestre: A Predictive Safety Evaluation by LC-MS/MS. AB - BACKGROUND: Traditionally GS is used to treat diabetes mellitus. Drug-herb interaction of GS via cytochrome P450 enzyme system by substrate cocktail method using HLM has not been reported. OBJECTIVE: To evaluate the in-vitro modulatory effects of GS extracts (aqueous, methanol, ethyl acetate, chloroform and n hexane) and deacylgymnemic acid (DGA) on human CYP1A2, 2C8, 2C9, 2D6 and 3A4 activities in HLM. MATERIAL AND METHODS: Probe substrate-based LCMS/MS method was established for all CYPs. The metabolite formations were examined after incubation of probe substrates with HLM in the presence or absence of extracts and DGA. The inhibitory effects of GS extracts and DGA were characterized with kinetic parameters IC50 and Ki values. RESULTS: GS extracts showed differential effect on CYP activities in the following order of inhibitory potency: ethyl acetate > Chloroform > methanol > n-hexane > aqueous > DGA. This differential effect was observed against CYP1A2, 2C9 and less on CYP3A4 and 2C8 but all CYPs were unaffected by aqueous extract and DGA. The ethyl acetate and chloroform extract exhibited moderate inhibition towards CYP1A2 and 3A4. The aqueous extract and DGA however showed negligible inhibition towards all five major human CYPs with very high IC50 values (>90MUg/ml). CONCLUSION: The results of our study revealed that phytoconstituents contained in GS, particularly in ethyl acetate and chloroform extracts, were able to inhibit CYP1A2, 3A4 and 2C9. The presence of relatively small, lipophillic yet slightly polar compounds within the GS extracts may be attributed for inhibition activities. These suggest that the herb or its extracts should be examined for potential pharmacokinetic drug interactions in vivo. Abbreviations used: GS: Gymnema sylvestre, GSE: Gymnema sylvestre extract, DGA: deacyl gymnemic acid, CYP: cytochrome P450, DMSO: dimethylsulphoxide, HLM: human liver microsomes, LC-MS/MS: liquid chromatography tandem mass spectroscopy, NADPH: reduced nicotinamide adeninedinucleotide phosphate, NRS: nicotinamide adeninedinucleotide phosphate regenerating system, CHE: chloroform extract, EAE: ethyl acetate extract, NHE- n-hexane extract, AE: aqueous extract, ME: methanol extract. PMID- 27761065 TI - Evaluation of the Genotoxicity and Cytotoxicity of Semipurified Fractions from the Mediterranean Brown Algae, Dictyopteris membranacea. AB - : Dictyopteris membranacea, a species of Mediterranean brown algae, is believed to have potential pharmacological and nutritional applications. However, such potentials only make sense when devoid of any adverse health consequences. The present study should be seen in this context. It aimed at evaluating the genotoxicity and cytoxicity of its organic extract (F0) and semi purified fractions (F4, F5, and F6). Extracts were tested using the bacterial Vitotox(r) test and micronucleus assay in different concentrations (from 1.25 MUg/mL up to 100 MUg/mL, depending on the test and the extract). Applied concentrations were based on a preliminary dose-finding test with the neutral red uptake assay. The results show that all extracts were not genotoxic in the presence or absence of a rat metabolic enzyme fraction (S9). This is encouraging and justifies further investigations on the therapeutic and other values of this algae. SUMMARY: Dictyopteris membranacea extracts and some of their semi purified fractions have important antibacterial properties.The organic extract (F0) and semi purified fractions (F4, F5, and F6) were not genotoxic according to the bacterial Vitotox test.They were also not genotoxic according to the micronucleus test in human C3A cells.Applied concentrations were based on the in-vitro neutral red uptake (NRU) test. PMID- 27761063 TI - IL-33 Effect on Quantitative Changes of CD4+CD25highFOXP3+ Regulatory T Cells in Children with Type 1 Diabetes. AB - IL-33 is an IL-1 cytokine family member, with ability to induce both Th1 and Th2 immune responses. It binds to ST2 receptor, whose deficiency is associated with enhanced inflammatory response. The most recent studies have shown the immunoregulatory effect of IL-33 on Tregs in animal models. As type 1 diabetes is an autoimmune, inflammatory disease, where Treg defects have been described, we aimed to analyze the in vitro influence of recombinant IL-33 on quantitative properties of regulatory CD4+CD25highFOXP3+ T cells. CD4+CD25highFOXP3+ as well as CD4+CD25highFOXP3+ST2+ Tregs were analyzed by flow cytometry. In a group of patients with type 1 diabetes in vitro IL-33 treatment induced regulatory CD4+CD25highFOXP3+ cell frequencies as well as upregulating the surface expression of ST2 molecule. In addition, the number of CD4+CD25highFOXP3+ cells carrying ST2 receptor increased significantly. Similar effect was observed in case of the FOXP3 expression. We did not observe any significant changes in IL-33 treated cells of healthy controls. The level of ST2 was higher in serum of patients with type 1 diabetes in comparison to their healthy counterparts. We propose that IL-33 becomes an additional immunostimulatory factor used to induce Treg expansion in future clinical trials of adoptive therapy in type 1 diabetes. PMID- 27761066 TI - In vitro Accumulation of Polyphenols in Tea Callus Derived from Anther. AB - BACKGROUND: Tea is an economic important crop with high medicinal value due to rich polyphenols content. In the present research we studied the accumulation of polyphenols of in vitro regenerated callus from anthers. OBJECTIVE: Callus induction of tea anthers and in vitro accumulation of phenolic compounds from the anther-derived callus. MATERIALS AND METHODS: Standardization of callus induction for tea anthers. In vitro generated callus was screened for in vivo accumulation of catechins and its isomers were screened by FC reagent staining technique. The methanol extract of dry and green callus obtained were estimated qualitatively by Fourier transform infrared spectroscopy (FTIR)-alternative total reflection (ATR) and quantitatively by HPLC method. RESULTS: Anthers inoculated on half strength MS media fortified with 2,4-dichloro acetic acid (2 mg/L), Kn (1 mg/L), and BAP (1 mg/L) induced callus under photoperiod of 9:15 h light. The in vivo histochemical studies revealed the accumulation of polyphenols in the callus. The in vitro generated fresh and dry callus were used for extraction and screened for accumulated polyphenols [galic acid, (+)-catechin (C), (-)-epicatechin, (-) epigallocatechin, (-)-epigallocatechin gallate, (-)-gallocatechins, (-) epicatechin gallate] were estimated qualitatively by FTIR-ATR method and quantitatively by HPLC method. CONCLUSION: The FC staining technique used here helps in localization of polyphenol compounds accumulation in the tissues by instant microscopic studies. The study have scope in large-scale isolation of various medicinally important flavonol by using anther culture. Abbreviations used: HPLC: high pressure liquid chromatography; FTIR: Fourier transform infrared spectroscopy; 2,4-D: 2,4-dichloro acetic acid; BAP: N6-benzyl amino purine; kn: kinetin. PMID- 27761067 TI - Genetic and Chemical Profiling of Gymnema sylvestre Accessions from Central India: Its Implication for Quality Control and Therapeutic Potential of Plant. AB - BACKGROUND: Gymnema sylvestre, a vulnerable plant species, is mentioned in Indian Pharmacopeia as an antidiabetic drug. OBJECTIVE: Study of genetic and chemical diversity and its implications in accessions of G. sylvestre. MATERIALS AND METHODS: Fourteen accessions of G. sylvestre collected from Central India and assessment of their genetic and chemical diversity were carried out using ISSR (inter simple sequence repeat) and HPLC (high performance liquid chromatography) fingerprinting methods. RESULTS: Among the screened 40 ISSR primers, 15 were found polymorphic and collectively produced nine unique accession-specific bands. The maximum and minimum numbers of amplicones were noted for ISSR-15 and ISSR-11, respectively. The ISSR -11 and ISSR-13 revealed 100% polymorphism. HPLC chromatograms showed that accessions possess the secondary metabolites of mid polarity with considerable variability. Unknown peaks with retention time 2.63, 3.41, 23.83, 24.50, and 44.67 were found universal type. Comparative hierarchical clustering analysis based on foresaid fingerprints indicates that both techniques have equal potential to discriminate accessions according to percentage gymnemic acid in their leaf tissue. Second approach was noted more efficiently for separation of accessions according to their agro-climatic/collection site. CONCLUSION: Highly polymorphic ISSRs could be utilized as molecular probes for further selection of high gymnemic acid yielding accessions. Observed accession specific bands may be used as a descriptor for plant accessions protection and converted into sequence tagged sites markers. Identified five universal type peaks could be helpful in identification of G. sylvestre-based various herbal preparations. SUMMARY: Nine accession specific unique bandsFive marker peaks for G. sylvestre.Suitability of genetic and chemical fingerprinting Abbreviations used: HPLC: High Performance Liquid Chromatography, ISSR: Inter Simple Sequence Repeats, CTAB: Cetyl Trimethylammonium Bromide, DNTP: Deoxynucleotide Triphosphates. PMID- 27761068 TI - Potential Therapeutic Agents for the Treatment of Fatty Degeneration of Liver and Atheromatous Plaques: An Experimental Study in Rats. AB - BACKGROUND: Since long high fat diet (HFD) is being blamed for causing fatty degeneration of liver and formation of atheromatous plaques. At present, no proper pharmacotherapy is available for both the conditions. In this study, different substances containing monounsaturated fatty acids were used to observe their protective effects in the HFD induced damage to liver and coronary vessels. OBJECTIVES: To discover effective therapeutic agents for HFD induced fatty degeneration of liver and atheromatous plaques. MATERIALS AND METHODS: The study was conducted from September 2015 to April 2016. In this study, rats were divided into nine groups according to dietary regimen. Each group comprised six rats. Saturated fat was given in the form of butter, and unsaturated fat was given in the form of corn oil, olive oil, Nigella sativa oil, and crushed garlic. Serum samples were taken to estimate lipid profile, liver functions, cardiac functions, and kidney functions. Visceras were removed after animal sacrifice, and histopathological examination was done. RESULTS AND CONCLUSION: During the study period, the weight of animals changed significantly in some groups. Those animals which were given crushed garlic along with high saturated fat diet, showed protection against accumulation of lipids in the hepatocytes. Olive oil and Nigella sativa oil were comparatively less effective. SUMMARY: Consumption of Garlic, Nigella Sativa and Olive oil significantly improved/revised the Fatty Degeneration of liver induced by intake of High Fat Diet.No fat deposition was found in the liver when Garlic, Nigella Sativa and Olive oil, were given concomitantly with HFD.Hepatocytes functioned better even in comparison to control and a decrease in liver enzymes was found with use of Garlic.Use of Garlic, Nigella Sativa and Olive oil, prevented the plaque formation in the vessels and decreased serum lipids.Beneficial effects of Garlic were significant in comparison to Nigella Sativa and Olive oil. Abbreviations used: HFD: High Fat Diet; NS: Nigella Sativa; TQ: Thymoquinone; KFMRC: King Fahad Medical Research Center; BUN: Blood Urea Nitrogen; BNF: Buffered Neutral Formalin; G: Group. PMID- 27761069 TI - Influence of Extracting Solvent on Pharmacological Activity and Cytotoxicity of Polygonum minus, a Commonly Consumed Herb in Southeast Asia. AB - OBJECTIVE: To investigate the antihyperlipidemic, antioxidant, and cytotoxic effect of aqueous and methanol extract of leaves of Polygonum minus. MATERIALS AND METHODS: Acute antihyperlipidemic effect was studied on chemically induced hyperlipidemic rat model. Treated groups received aqueous and methanol extract of leaves of P. minus respectively (1000 mg/kg; oral) whereas standard treated group received atorvastatin (60 mg/kg; oral) for 3 consecutive days. Blood samples were collected at fixed intervals for lipid profile analysis. Antioxidant effects were studied using 1,1-diphenyl-2-picrylhydrazyl, 2,2-azinobis 3-ethylbenzothiazoline 6-sulfonate, and ferric reducing antioxidant power assays. The total flavonoids content and total phenolic contents were also estimated. Cytotoxicity of both extracts was studied on one normal and three cancer cell lines using 3-(4,5 Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay method. RESULTS: The methanol extract showed significant reduction in total cholesterol (P < 0.001), triglycerides (P < 0.01), LDL (P < 0.05), VLDL (P < 0.01), atherogenic index (P < 0.001), and elevation of HDL (P < 0.05) levels than the aqueous extract. Similarly, the antioxidant investigations also demonstrated that the methanol extract had higher antioxidant capacity than aqueous extract. Both extracts were not toxic to normal (EA.hy926) as well as to cancer (HCT116, HT29, and HeLa) cells. Significant correlation was demonstrated between total phenolic and total flavonoids contents with the antioxidant activity but not with the antihyperlipidemic effect, suggesting other groups of chemical constituents may be mainly responsible for the antihyperlipidemic effect of this plant. CONCLUSION: The study demonstrated that the presence and extent of bioactivities are influenced by solvents used for extraction. This study confirmed the antihyperlipidemic effect of leaves of P. minus in acute hyperlipidemic rat model. SUMMARY: Polygonum minus is an herbaceous flowering plant.This plant possess high amount of phenolics and flavonoidsThis study focused on the antioxidant, cytotoxicity and antihyperlipidemic effect of aqueous and methanol extracts of leaves of P. minusThe extracts possess significant antioxidant activity and antihyperlipidemic activity but they are not toxic to normal and cancer cells tested.The antioxidant activity is well correlated with phenolic and flavonoids contents but the antihyperlipidemic activity is not correlated with antioxidant effect. Abbreviations used: CVDs: Cardiovascular diseases, LDL: Low density lipoprotein, DDPH: 1,1-Diphenyl-2-picrylhydrazyl radical, TPTZ: 2,4,6, tris(1-pyridyl)-5-triazine, ABTS: 2,2'-Azino-di-[3-ethylbenzthiazoline Sulfonate], HDL: High-density lipoprotein, VLDL: Very low-density lipoprotein, TC: Total cholesterol, TG: Triglycerides, EC50: Half maximal effective concentration, LD50: Median lethal dose. PMID- 27761070 TI - Phytochemicals and Cytotoxicity of Launaea procumbens on Human Cancer Cell Lines. AB - BACKGROUND: The plant Launaea procumbens belongs to the family Asteraceae and traditionally used in the treatment rheumatism, kidney, liver dysfunctions and eye diseases. In the present study Phytochemical analysis and fractions of methanolic extract of L. procumbens leaves were tested in vitro for their cytotoxicity. OBJECTIVES: Phytochemical analysis and cytotoxic activity of methanolic extract and fractions of Launaea procumbens against four cancer cell lines K562, HeLa, MIA-Pa-Ca-2 and MCF-2 by SRB assay. MATERIALS AND METHODS: Powdered leaves of Launaea procumbens were extracted sequentially with hexane, ethyl acetate, butanol and water by cold extraction. Phytochemical analysis and cytotoxicity assay were carried out for these fractions using SRB assay against four human cancer cell lines, namely leukemia (K562), cervix (HeLa), pancreatic (MIA-Pa-Ca-2) and breast (MCF-7). RESULTS: Ethyl acetate extract exerts potent cytotoxicity against human leukemia (K562), cervix (HeLa) and breast (MCF-7) cell lines IC50 value of 25.30+/-0.50, 19.80+/-0.10 and 36.90+/-4.90 MUg/ml respectively. Moderately cytotoxic effect found in hexane extract IC50 value of 41+/-8 and 48.20+/-0.50 MUg/ml against leukemia (K562), and breast (MCF-7) cancer cell line respectively. The Chemical composition analyzed by GC-MS showed considerable differences in solvent fractions of Launaea procumbens. CONCLUSION: This study revealed the cytotoxic potential of ethyl acetate and hexane fractions of L. procumbens leaves on different cancer cell lines. SUMMARY: Ethyl acetate and Hexane fractions of Launaea procumbens plant exhibit cytotoxicity. Among the different fractions Ethyl acetate showed relatively higher cytotoxicity.Ethyl acetate found more cytotoxic against leukemia (K 562), cervix (HeLa) and breast (MCF-7) cancer cell lines. Moderete cytotoxicity found in hexane fraction against leukemia (K 562) and breast (MCF-7) cancer cell line.GC-MS results showed L. procumbens is a rich source of 1-H- pyrazole, 1-H-imidazole, beta -amyrin, alpha amyrin and lupeol. These compounds may be attributed for the cytotoxic activity. Abbreviations used: SRB: Sulforhodamine B assay, MW: Molecular weight. PMID- 27761071 TI - Inhibitory and Cytotoxic Activities of Chrysin on Human Breast Adenocarcinoma Cells by Induction of Apoptosis. AB - OBJECTIVES: Chrysin, an active natural bioflavonoid found in honey and many plant extracts, was first known for its antioxidant and anti-inflammatory effects. The fact that antioxidants have several inhibitory effects against different diseases, such as cancer, led to search for food rich in antioxidants. In this study, we investigated the antiproliferative and apoptotic effects of chrysin on the cultured human breast cancer cells (MCF-7). MATERIALS AND METHODS: Cells were cultured in Roswell Park Memorial Institute medium and treated with different chrysin concentrations for three consecutive days. Cell viability was quantitated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The percentage of apoptotic cells was determined by flow cytometry using Annexin V-fluorescein isothiocyanate. RESULTS: The MTT assay showed that chrysin had an antiproliferative effect on MCF-7 cells in a dose- and time-dependent manner. The 50% cell growth inhibition values for chrysin against MCF-7 cells were 19.5 and 9.2 MUM after 48 and 72 h, respectively. Chrysin induced apoptosis in MCF-7 cells as determined by flow cytometry. Chrysin inhibits the growth of the breast cancer cells by inducing cancer cell apoptosis which may, in part, explain its anticancer activity. CONCLUSION: This study shows that chrysin could also be considered as a promising chemotherapeutic agent and anticancer activity in treatment of the breast cancer cells in future. SUMMARY: Chrysin had an antiproliferative effect on human breast cancer cells (MCF-7) cells in a dose- and time-dependent mannerChrysin induced apoptosis in MCF-7 cells, as determined by flow cytometryChrysin inhibits the growth of the breast cancer cells by inducing cancer cell apoptosisChrysin may have anticancer activity. Abbreviations used: Human breast cancer cells (MCF-7), 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT), phosphate-buffered saline (PBS), normal fibroblast mouse (L929). PMID- 27761073 TI - Antihepatotoxic Effect and Metabolite Profiling of Panicum turgidum Extract via UPLC-qTOF-MS. AB - BACKGROUND: Panicum turgidum, desert grass, has not reported any detailed phytochemical or biological study as yet. OBJECTIVE: To establish P. turgidum secondary metabolite profile and to assess its antihepatotoxic effect. MATERIALS AND METHODS: Ultra-performance liquid chromatography (UPLC) coupled to quadrupole high-resolution time of flight mass spectrometry (qTOF-MS) was used for large scale secondary metabolites profiling in P. turgidum extract, alongside assessing median lethal dose (LD50) and hepatoprotective effect against carbon tetrachloride (CCl4) intoxication. RESULTS: A total of 39 metabolites were identified with flavonoids as the major class present as O/C-glycosides of luteolin, apigenin, isorhamnetin and naringenin, most of which are first time to be reported in Panicum sp. Antihepatotoxic effect of P. turgidum crude extract was revealed via improving several biochemical marker levels and mitigation against oxidative stress in the serum and liver tissues, compared with CCl4 intoxicated group and further confirmed by histopathological examination. CONCLUSION: This study reveals that P. turgidum, enriched in C-flavonoids, presents a novel source of safe antihepatotoxic agents and further demonstrates the efficacy of UPLC-MS metabolomics in the field of natural products drug discovery. SUMMARY: UPLC coupled to qTOF-MS was used for large scale secondary metabolites profiling in P. turgidum.A total of 39 metabolites were identified with flavonoids amounting as the major metabolite class.Anti-hepatotoxic effect of P. turgidum extract was revealed via several biochemical markers and histopathological examination.This study reveals that P. turgidum, enriched in C flavonoids, present a novel source of antihepatotoxic agents. Abbreviations used: UPLC: Ultra-performance liquid chromatography (UPLC), LD50: median lethal dose, MDA: malondialdehyde, GSH: glutathione reductase, CAT: catalase, SOD: superoxide dismutase, ALT: alanine aminotransferase, AST: aspartate aminotransferase, ALP: alkaline phosphatase, TG: triglycerides. PMID- 27761072 TI - Sambar, an Indian Dish Prevents the Development of Dimethyl Hydrazine-Induced Colon Cancer: A Preclinical Study. AB - BACKGROUND: Colon cancer (CC) is the third commonly diagnosed cancer and the second leading cause of mortality in the US when compared to India where prevalence is less. Possible reason could be the vegetarian diet comprising spices used in curry powders. Researchers believe that 70% of the cases are associated with diet. Spices have inherited a rich tradition for their flavor and medicinal properties. Researchers have been oriented towards spices present in food items for their antitumorigenic properties. OBJECTIVE: We investigated the effects of sambar as a preventive measure for 1,2-dimethyl hydrazine (DMH) induced CC in Wistar albino rats. MATERIALS AND METHODS: The animals were divided into three groups (n = 6) namely control, DMH, and sambar. At the end of the experimental period, the animals were killed using anesthesia and the colons and livers were examined. RESULTS: All the treatment groups exhibited a significant change in the number of aberrant crypt foci (ACF). Sambar group showed a significant change in the colonic GSH when compared to both normal and DMH groups. A significant reduction in the liver GSH was noted in the sambar group. Only sambar group showed a significant change in the liver catalase levels when compared to DMH. There was a significant reduction in the colonic nitrite in the sambar-treated group; 2.94 +/- 0.29 when compared to DMH control at 8.09 +/- 1.32. On the contrary, a significant rise in the liver nitrite levels was observed in the sambar-treated rats. CONCLUSION: Sambar may prevent the risk of CC when consumed in dietary proportions. SUMMARY: Consumption of sambar significantly reduced aberrant crypt foci in DMH-induced colon cancer modelSambar treatment prevented DMH-induced oxidative changes in the colonic tissue, indicating its antioxidant roleSambar comprises a variety of spices that exhibited both pro- and antioxidant properties in different tissues, leading to its overall beneficial effect in this model. Abbreviations used: ACF: aberrant crypt foci, CC: colon cancer, DMH: 1,2-dimethyl hydrazine, GSH: glutathione, IL 6: Interleukin-6, TNF-alpha: Tumor necrosis factor-alpha. PMID- 27761074 TI - Catha edulis (khat) Induces Apoptosis in Madin-Darby Bovine Kidney Cell Line. AB - BACKGROUND: Khat (Catha edulis) is a controversial plant having a euphoretic effect, at the same time part of culture in many countries such as Africa and Arabian Peninsula. The presence of amphetamine-like substance, cathinone and cathine make this plant banned in many countries. Many neurological and other system related studies have been carried out in this plant, but the lack of toxicity studies are there especially the mechanism. OBJECTIVE: In this study, Madin-Darby Bovine Kidney cell line was used as an in vitro model to study the cell death mechanism. Crude extract of fresh Khat plant leaves were prepared and exposed to cells. MATERIALS AND METHODS: Trypan blue assay, phase-contrast microscopy, fluorescent microscopy, clonogenic assay, annexin-V assay, and hematoxylin and eosin (H and E) staining were employed to check the objectives. RESULTS: Reductions in cellular viability were observed at concentrations above 1.25 mg/ml while using Trypan blue assay. The results of the clonogenic assay had shown that the untreated control with the highest number of colonies (100% survival) and the 0.1562 concentration could not prevent the colony formation significantly. The high concentrations reduced the colony formation at concentration dependent manner 27.4% and 24.9%, for 0.625 mg/ml and 1.25 mg/ml concentrations, respectively. The acridine orange/ethidium bromide experiment had observed the cells were intact with round nucleus while the apoptosis features such as blebbing and nuclear chromatin condensation were clearly observed in treatment. The shrinkage of cells was clearly observed in H and E staining. CONCLUSION: In addition, annexin-V binding confirmed the presence of apoptosis significantly on Khat treatment. SUMMARY: Khat (Catha edulis) is a controversial plant having euphoretic effectReductions in cellular viability were observed at concentrations above 1.25 mg/ml while using Trypan blue assayThe high concentrations of khat extract had reduced the colony formation at concentration dependent mannerThe acridine orange/ethidium bromide experiment had observed the apoptosis features such as blebbing and nuclear chromatin in treatmentAnnexin-V binding confirmed the presence of apoptosis significantly on Khat treatment. Abbreviation used: PS: Phosphatidylserine (PS); MDBK: Madin-Darby Bovine Kidney; DMEM: Dulbecco's modified Eagle's medium; PI: propidium iodide; EB: ethidium bromide; PBS: Phosphate Buffer saline; FITC: fluorescein isothiocyante; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling. PMID- 27761075 TI - Induction, Subculture Cycle, and Regeneration of Callus in Safed Musli (Chlorophytum borivilianum) using Different Types of Phytohormones. AB - BACKGROUND: Chlorophytum borivilianum is an industrially valued medicinal crop. Propagation through seeds is not feasible because of low germination percentage and long dormancy period. Therefore, callus culture and plant regeneration can be an alternative to improve this crop production. Also, callus can serve as an alternative source of bioactive compounds. OBJECTIVE: To evaluate the effect of different phytohormones on callus induction, subculture cycle, and regeneration studies of callus in C. borivilianum. MATERIALS AND METHODS: Young shoot buds of C. borivilianum were inoculated on Murashige and Skoog medium fortified with 3% sucrose and different concentrations (0, 1, 5, 10, and 15 mg/L) of either naphthalene acetic acid or 2,4-dichlorophenoxyacetic acid or indole-3-acetic acid and callus induction was evaluated up to four subcultures cycles. Shoot regeneration from callus was studied on Murashige and Skoog media fortified with 6-benzylaminopurine andkinetin or thidiazuron at varied levels (0, 0.5, 1, 2, and 3 mg/L). Microshoots were rooted on Murashige and Skoog media supplemented with 1.0 mg/L indole-3-butyric acid and plantlets were acclimatized before transferred to the natural conditions. RESULTS: Callus induction was better evidenced on Murashige and Skoog media containing 5 mg/L 2,4-dichlorophenoxyacetic acid up to fourth subculture. Callus differentiated into shoots on Murashige and Skoog media fortified with 6-benzylaminopurine or kinetin, whereas thidiazuron completely failed to regenerate shoots. Furthermore, microshoots rooted on 1.0 mg/L indole-3 butyric acid containing Murashige and Skoog media. The rooted plantlets were successfully acclimatized and established in soil with 88.3% survivability. CONCLUSION: The type of auxins played an important role in inducing callus tissue from shoot bud explants of Safed musli. In future, this in vitro protocol could benefit in crop improvement programs and serve as a new source of bioactive compounds from Safed musli callus tissue for various therapeutic applications. SUMMARY: Explants de-differentiated to form callus on Murashige and Skoog media containing 5 mg/L 2,4-D up to fourth subculture.Callus re-differentiated into shoots on Murashige and Skoog media fortified with 0.5 mg/L BAP.In vitro rooting of shoots was achieved on 1.0 mg/L IBA containing Murashige and Skoog media.The rooted plantlets were successfully acclimatized and established in soil with 88.3% survivability. Abbreviations used: MS: Murashige and Skoog, NAA: naphthalene acetic acid, 2,4-D: 2,4-dichlorophenoxyacetic acid, IAA: indole-3 acetic acid, BAP: 6-benzylaminopurine, Kn: Kinetin, TDZ: thidiazuron, IBA: indole 3-butyric acid, RCBD: Randomized Complete Block Design, DMRT: Duncan's Multiple Range Test. PMID- 27761076 TI - Elicitation of Phenolics from the Micropropagated Endangered Medicinal Plant Calligonum polygonoides L. (Polygonoaceae). AB - BACKGROUND: Calligonum polygonoides L. subsp. comosum (L'Her.) Sosk. is a plant species belonging to family Polygonaceae. Susceptibility to threaten, presence of various chemical constituents, and many medicinal effects reported for this plant in addition to rareness of in vitro culture studies have fuelled the need for its micropropagation and phytochemical investigations of the produced cultures. OBJECTIVES: To employ in vitro culture technique for ex situ conservation of C. polygonoides, using the fruit as an explant; establish callus and cell suspension cultures from in vitro germinated plantlets; investigate the production of phenolics through callus, redifferentiated shoot, and cell suspension cultures; attempt to enhance cell capacity to accumulate phenolics using salicylic acid and yeast extract and provide a brief demonstration of biosynthetic pathway leading to phenolic production. MATERIALS AND METHODS: Modified Murashige and Skoog media supplemented with growth hormones such as kinetin, 1-naphthaleneacetic acid, 6 benzylaminopurine, and indole-3-acetic acid were used to establish callus, redifferentiated shoots, and cell suspension cultures. Elicitation of cell suspension culture was performed using salicylic acid and yeast extracts. A reversed phase-high performance liquid chromatography method for determination of phenolic content in the aforementioned cultures was developed. RESULTS: The unorganized callus and cell suspension cultures contained fewer amounts of phenolic compounds than redifferentiated shoots. Elicitation produced massive quantitative reprogramming of phenolic content. CONCLUSION: The present study offers an alternative and renewable source for this valuable natural plant, provide a chance to improve secondary metabolite yield and serve as a useful tool for studying the biosynthesis of these compounds and its regulation in plant cells. SUMMARY: In vitro culture techniques provided a strategy for ex situ conservation of the endangered C. polygonoides.Unorganized callus and cell suspension cultures accumulated less phenolic content than re-differentiated shoots.Elicitation produced massive quantitative reprogramming of phenolic content.Phenolic biosynthesis was discussed briefly. Abbreviation used: H2O2: Hydrogen peroxide, Kin: Kinetin, NAA: Naphthaleneacetic acid, BAP: 6 benzylaminopurine, IAA: Indole-3-acetic acid, HPLC: High-performance liquid chromatography. PMID- 27761077 TI - Assessment of In vitro Antibacterial Activity and Cytotoxicity Effect of Nigella sativa Oil. AB - BACKGROUND: Methicillin resistance is a serious health concern since it has spread among Staphylococcus aureus and coagulase-negative Staphylococci (CoNS) that are frequent community and nosocomial pathogens worldwide. Methicillin resistant strains are often resistant to other classes of antibiotics, making their treatment difficult. Nigella sativa oil is known to be active against Gram positive cocci, yet its in vitro cytotoxicity is rarely investigated, is a proper and powerful candidate for treatment of methicillin-resistant isolates. OBJECTIVES: The aim of this study is to evaluate the in vitro antibacterial activity and cytotoxicity effect of N. sativa oil. MATERIALS AND METHODS: The minimal inhibitory concentrations (MICs) of N. sativa oil were determined by broth microdilution method against four different American Type Culture Collection strains, 45 clinical isolates of methicillin-resistant S. aureus (MRSA), and 77 methicillin-resistant CoNS (MRCoNS). The effects of different dilutions (0.25 MUg/mL, 0.5 MUg/mL, and 1 MUg/mL) of N. sativa oil on the proliferation of gingival fibroblasts were evaluated. RESULTS: The MIC values of N. sativa oil against clinical isolates of Staphylococci were between <0.25 MUg/mL and 1.0 MUg/mL. Compared to the control group, there was no cytotoxic effect on the proliferation of the gingival fibroblasts. CONCLUSION: In the present study, the oil of N. sativa was very active against MRSA and MRCoNS and had no in vitro cytotoxicity at relevant concentrations. These findings emphasize that there is a requirement for further clinical trials on N. sativa oil for "safe" medical management of infections caused by methicillin-resistant Staphylococci. SUMMARY: The minimal inhibitory concentration (MIC) values of Nigella sativa oil against Staphylococcus aureus American Type Culture Collection (ATCC) 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 standard strains were 0.5 MUg/mL, 2 MUg/mL, 64 MUg/mL, and 64 MUg/mL, respectivelyThe N. sativa oil showed an excellent antibacterial activity against clinical isolates of methicillin-resistant S. aureus and methicillin-resistant coagulase-negative Staphylococci with very low MIC range of <0.25-1.0 ug/mLThe N. sativa oil exhibited no cytotoxic effect on the proliferation of the gingival fibroblasts. Abbreviation used: ATCC: American Type Culture Collection; CLSI: Clinical and Laboratory Standards Institute; CoNS: Coagulase-negative Staphylococci; DMEM: Dulbecco's modified Eagle's medium; DMSO: Dimethyl sulfoxide; FBS: Fetal bovine serum; HGF: Human gingival fibroblast; MIC: Minimal inhibitory concentration; MRCoNS: Methicillin-resistant CoNS; MRSA: Methicillin-resistant S. aureus. PMID- 27761078 TI - Postprandial Antihyperglycemic And Antioxidant Activities of Acalypha indica Linn Stem Extract: An In-vivo Study. AB - BACKGROUND: alpha-glucosidase inhibitors controls postprandial hyperglycemia (PPHG) by lowering sharp rise in blood glucose levels after ingestion of carbohydrate rich meal in type 2 diabetic (T2D) individuals. Acalypha indica commonly known as Indian copper leaf is used in traditional medicinal system to treat various diseases. In our previous in-vitro investigation, methanolic extract of A. indica stems (AIS) proved to be an effective a-glucosidase inhibitor, antioxidant, and well tolerated in acute and subchronic toxicity studies in albino wistar rats. OBJECTIVE: In this perspective, this study was designed to evaluate postprandial antihyperglycemic potential of AIS in maltose, sucrose, and glucose loaded streptozotocin (STZ)-induced normal and diabetic rats. As, the acute hyperglycemia at postprandial period has more triggering effect on oxidative stress, study was also aimed to evaluate the antioxidant potential of AIS on STZ-induced Albino-Wistar rats. MATERIALS AND METHODS: Rats were treated with AIS (300-600 mg/kg b.w.) to investigate effect of AIS in controling PPHG after carbohydrate loading. Hepatoprotective activity of AIS is evaluated in diabetic rats by treating them at the dosages 300-600 mg/kg b.w. RESULTS: Studies revealed 69.10 and 80.35% blood glucose-lowering effect of AIS in maltose and sucrose loaded diabetic rats in comparison with the diabetic control group. AIS recovered the liver damage caused by streptozotocin. CONCLUSION: The present study confirmed high potential of AIS in controling PPHG by inhibiting a-glucosidase enzyme in maltose and sucrose loaded diabetic rats. AIS also exhibited hepatoprotective activity in STZ-induced diabetic rats. Thus, AIS could be used as a nutraceutical supplement to treat T2D effectively. SUMMARY: AIS extract is effective in suppressing maltose and sucrose-induced postprandial hyperglycemic spikes in ratsAIS treat ment showed a 69.10 and80.35% blood glucose-lowering effect in maltose and sucrose loaded diabetic rats in comparison with the diabetic control group.AIS also improved the antioxidant status in diabetic rats and also has recovered the liver damage caused by streptozotocin.The alpha-glucosidase inhibitor isolated from AIS is a good supplement to control postprandial blood glucose level in the management of type 2 diabetes. Abbreviations used: AIS: Acalypha indica Stems, ALP: Alkaline Phosphatase, b/w: Body Weight, PPHG: Postprandial hyperglycemia, SE: Standard Error, SGOT: Serum glutamate oxaloacetate transaminase, SGPT: Serum glutamate pyruvate transaminase, SOD: Superoxide dismutase, STZ: Streptozotocin, TB: Total Bilirubin, T2D: Type 2 diabetes. PMID- 27761079 TI - Elucidation of Molecular Mechanism(s) of Cognition Enhancing Activity of Bacomind(r): A Standardized Extract of Bacopa Monnieri. AB - BACKGROUND: Bacopa monnieri (L.) Wettst., commonly known as Brahmi, is renowned in Indian traditional system for its potent memory enhancing activity, which has been validated by various scientific studies. OBJECTIVE: The objective of this study was to understand the molecular mechanism of memory enhancing activity of BacoMind(r) (BM), a standardized extract of B. monnieri. MATERIALS AND METHODS: BM was screened in vitro in a panel of cell-free and receptor-transfected cell assays. The purified enzymes/membrane homogenates/cells were incubated with substrate/standard ligand in the absence or presence of the test compound. The IC50 values and EC50 values were determined by nonlinear regression analysis of the concentration-response curves generated with mean replicate values using Hill equation curve fitting. RESULTS: BM was found to inhibit three enzymes; Catechol O-methyl transferase (COMT), Prolyl endopeptidase (PEP), and Poly (ADP-ribose) polymerase (PARP). It also had an antagonistic effect on serotonin 6 and 2A (5 HT6 and 5-HT2A) receptors, known to influence the different neurological pathways, associated with memory and learning disorders, age-associated memory impairment. CONCLUSION: BM was found to inhibit three enzymes namely, Catechol-O methyl transferase (COMT), Prolyl endopeptidase (PEP), and Poly (ADP-ribose) polymerase (PARP). It also exhibited an antagonistic effect on 5-HT6 and 5-HT2A receptors. SUMMARY: This study was conducted to understand the molecular mechanism of memory enhancing activity of a standardized extract of B. monnieri by was screening it in vitro in a panel of cell-free and receptor-transfected cell assays. The purified enzymes/membrane homogenates/cells were incubated with substrate/standard ligand in the absence or presence of the test compound. BM was found to inhibit three enzymes; Catechol-O-methyl transferase (COMT), Prolyl endopeptidase (PEP), and Poly (ADP-ribose) polymerase (PARP). It also had an antagonistic effect on serotonin6 and2A (5-HT6 and 5-HT2A) receptors, known to influence the different neurological pathways, associated with memory and learning disorders, age-associated memory impairment. Abbreviations used: HTRF: Homogenous time resolved fluorescence, cAMP: Cyclic adenosine monophosphate, CHO: Chinese hamster ovary, RFU: Relative fluorescence unit, pNP: Para nitro phenol, AMC: 7-amino-4-methylcoumarin, ELISA: Enzyme linked immunosorbent assay, Z-Pro Pro-CHO: Z-prolyl-prolinal, HEK: Human embryonic kidney, TE: Trolox equivalent. PMID- 27761080 TI - Free radical scavenging, alpha-glucosidase inhibitory and anti-inflammatory constituents from Indian sedges, Cyperus scariosus R.Br and Cyperus rotundus L. AB - BACKGROUND: Cyperus scariosus R. Br and Cyperus rotundus L are widely used in ayurvedic preparation for the treatment of diabetes and other diseases. The early literature, so far, does not indicate the presence of any bioactive principle isolated from these plants. OBJECTIVE: To identify free radical scavenging, anti diabetic and anti- inflammatory principles from these two species. MATERIALS AND METHODS: The bioassay guided fractionation and isolation of active constituents was done by chromatographic techniques. They also evaluated their anti-oxidant activity by DPPH and ABTS. The anti-diabetic activity was screened by alpha- glucosidase and alpha- amylase assays. Also, the further evaluation of in vitro anti-inflammatory activity using THP-1 monocytic cells and in vivo anti- inflammatory activity, was confirmed by carrageenan induced rat paw edema as model. RESULTS: The activity guided isolation led to isolation of twelve compounds Which are: Stigmasterol[1], beta- sitosterol[2], Lupeol[3], Gallic acid[4], Quercetin[5], beta- amyrin[6], Oleanolic acid[7], beta- amyrin acetate[8], 4- hydroxyl butyl cinnamate[9], 4- hydroxyl cinnamic acid[10], Caffeic acid,[11] and Kaempferol[12] respectively. Among the isolates, the compounds 4 and 5 displayed potent radical scavenging activity with an IC50 values of 0.43 and 0.067 ?g/ml. The compounds 4, 5 and 10 showed significant anti diabetic activities. while lupeol[3] showed potent IL-1 beta activity inhibition in THP-1 monocytic cells and also displayed significant (p<0.0025) in vivo anti inflammatory activity. CONCLUSION: Inbrief, we isolated twelve compounds from both the species. Collectively, our results suggested that aromatic compounds showed good anti-oxidant and anti-diabetic activities. SUMMARY: The study investigates the free radical scavenging, alpha-glucosidase inhibitory and anti inflammatory effects of constituents isolated from Indian sedges viz. C. scariosus and C. rotundus. The results indicated that phenolic compounds displayed potent fee radical scavenging activty and alpha-glucosidase inhibition activity. While terpene constituent, Lupeol[3] showed good IL-1beta activity inhibition in THP-1 monocytic cells and also displayed significant (p<0.0025) in vivo anti inflammatory activity in carrageenan induced rat paw edema. However, further studies are required to know the exact molecular mechanism. Abbreviations used: DPPH: 2,2- Diphenyl-1-1-picryl hydrazyl, ABTS: 2,2-Azinobis-3-ethylbenzo thiazoline-6-sulfonic acid, THP-1: Human leukaemia monocytic cell line, IL-1beta: Interleukin-1beta, IC50-Inhibitory concentration 50%. PMID- 27761081 TI - Optimising Wound Healing in Aesthetic Surgery: From the Laboratory to the Clinic. PMID- 27761082 TI - Retinoids: Literature Review and Suggested Algorithm for Use Prior to Facial Resurfacing Procedures. AB - Vitamin A-containing products have been used topically since the early 1940s to treat various skin conditions. To date, there are four generations of retinoids, a family of Vitamin A-containing compounds. Tretinoin, all-trans-retinoic acid, is a first-generation, naturally occurring, retinoid. It is available, commercially, as a gel or cream. The authors conducted a complete review of all studies, clinical- and basic science-based studies, within the literature involving tretinoin treatment recommendations for impending facial procedures. The literature currently lacks definitive recommendations for the use of tretinoin-containing products prior to undergoing facial procedures. Tretinoin pretreatment regimens vary greatly in terms of the strength of retinoid used, the length of the pre-procedure treatment, and the ideal time to stop treatment before the procedure. Based on the current literature and personal experience, the authors set forth a set of guidelines for the use of tretinoin prior to various facial procedures. PMID- 27761083 TI - Neocollagenesis and Neoelastinogenesis: From the Laboratory to the Clinic. AB - An internet search was made looking for articles about chemical and physical modalities that are known to induce collagen and elastin formation. Textbooks, independent articles, journals and books on pathology, biochemistry, aesthetic medicine and cosmetic and plastic surgery were used as references. Here, we take a look at various studies, in vitro and in vivo, that lend credence to the products and procedures used in clinical practice to induce neocollagenesis and neoelastinogenesis. PMID- 27761084 TI - Role of Adipose-derived Stem Cells in Fat Grafting and Reconstructive Surgery. AB - Autologous fat grafting is commonly utilised to reconstruct soft tissue defects caused by ageing, trauma, chronic wounds and cancer resection. The benefits of fat grafting are minimal donor site morbidity and ease of availability through liposuction or lipectomy. Nonetheless, survival and longevity of fat grafts remain poor post-engraftment. Various methods to enhance fat graft survival are currently under investigation and its stem cell constituents are of particular interest. Cell-assisted lipotransfer refers to the addition of adipose-derived stem cell (ASC) rich component of stromal vascular fraction to lipoaspirate, the results of which have proven promising. This article aims to review the role of ASCs in fat grafting and reconstructive surgery. PMID- 27761085 TI - Outcome of Intra-operative Injected Platelet-rich Plasma Therapy During Follicular Unit Extraction Hair Transplant: A Prospective Randomised Study in Forty Patients. AB - CONTEXT: Platelet-rich plasma (PRP) therapy is finding importance in aesthetic medicine. AIM: The objective of this study was to study efficacy of PRP therapy in follicular unit extraction (FUE) hair transplant. MATERIALS AND METHODS: It is a single-blind, prospective randomised study on 40 FUE hair transplant subjects, allocated in two groups (PRP and non-PRP) alternately. PRP was injected intra operatively immediately after creating slits over the recipient area in PRP group; and normal saline in non-PRP group. Two groups were evaluated at 2, 4 and 8 weeks, 3 and 6 months of the procedure. STATISTICAL ANALYSIS: It was done using Chi-square test and test of significance was set as P < 0.05. RESULTS: In PRP group, all subjects had >75% hair regrowth at 6 months, density of >75% grafts was noticed in 12 patients at 4 weeks meaning reduced fall of transplanted hair during catagen phase. New hair growth started at 8 weeks in 16 patients and redness over recipient area completely disappeared in 19 patients at 3 months of surgery and activity in dormant follicles as fine thread like hair was noticed besides the thick transplanted hair in all subjects. In non-PRP group, four patients had >75% hair regrowth at 6 months; none showed >75% graft density at 4 weeks, and 13 subjects showed dormant follicle activity at 4 months. The number of patients having lengthier hairs was significantly more in PRP group. CONCLUSION: Intra-operative PRP therapy is beneficial in giving faster density, reducing the catagen loss of transplanted hair, recovering the skin faster and activating dormant follicles in FUE transplant subjects. PMID- 27761086 TI - Stem Cell Markers (Cytokeratin 17 and Cytokeratin 19) in Scarring and Nonscarring Alopecia. AB - BACKGROUND: Alopecia is one of the most important hair follicle (HF) disorders, which is divided into scarring (cicatricial) and nonscarring (noncicatricial) types. OBJECTIVE: The aim of this study is to investigate the expression of stem cell (SC) markers such as cytokeratin (CK) 17 and CK19 in scarring and nonscarring alopecia. MATERIALS AND METHODS: Thirty patients with scalp alopecia (15 with scarring alopecia and 15 without) together with ten healthy volunteers were included in this study. Biopsies were taken from all participants and stained for CK17 and CK19 using immunohistochemistry. RESULTS: There was a statistically significant difference between the nonscarring group and the control group with regard to CK17 expression in the outer layers of the HFs (P = 0.00) and CK19 staining of the inner layers of the HFs (P = 0.008). There was a statistically significant difference between the scarring and the control groups regarding CK17 expression in the outer (P = 0.00) and the inner layers (P = 0.00) of the HFs and CK19 expression in the inner layers of the HFs (P = 0.00). CK17 expression in the outer layers (P = 0.02) and the inner layers of the HFs (P = 0.00) together with CK19 expression in the inner layers of the HFs (P = 0.00) showed statistically significant differences between scarring and nonscarring alopecia groups. CONCLUSIONS: The presence of SC markers (CK17 and CK19) in the HFs was affected in both scarring and nonscarring alopecia, but the defect in scarring alopecia is more evident than that of nonscarring alopecia. The persistence of SC markers in some types of scarring alopecia could give a hope for the recovery of these lesions. Further studies are recommended to clarify the benefit from using HF SCs in the treatment of alopecia. PMID- 27761087 TI - Tattoo Practices in North-East India: A Hospital-based Cross-sectional Study. AB - BACKGROUND: Tattooing has become increasingly popular, particularly among young people. However, little is known about the tattoo practices in North-East India. OBJECTIVES: The primary objective of this study was to know the reasons and motivations of tattoo application and tattoo removal in individuals asking for tattoo removal. The secondary objective was to identify the demography, methods and safety of tattoo practices in these tattooed individuals. MATERIALS AND METHODS: A hospital-based cross-sectional study was carried out in 212 consecutive individuals seeking tattoo removal. Chi-square and Fisher's exact tests were performed for intergroup comparisons. RESULTS: There were 178 (84%) males and 34 (16%) females. The mean +/- standard deviation (SD) age of individuals seeking tattoo removal was 21.8 +/- 4 years. The mean +/- SD age of doing tattoo was 15.8 +/- 3 years. Most individuals possessed an amateur tattoo (94.3%), 4.2% a professional one and 1.4% had a combination. Sewing needle was the most common instrument used for making tattoos in 51.4%. The individuals made their tattoos in an unsterile manner in 49.1%. The most common reason for doing tattoo was for fashion in 87.7%. The participants wanted tattoo removal to qualify for jobs, especially in armed forces in 49.5% and due to regret in 21.7%. Black was the most preferred colour in 37.3% followed by green in 28.3%. The fabric ink was the choice of ink in maximum number of individuals, i.e. 93.9%. LIMITATIONS: It was a hospital-based study done only on individuals seeking tattoo removal. It needs caution to generalise the findings in population. In addition, there may be recall bias in the participants. CONCLUSION: The tattoo was done mostly below 18 years of age in a crude unsterile way. The individuals had poor risk perceptions about various infections and complications of tattooing. There is an urgent need to caution and educate the youngsters and school-going children about safe tattooing and consequences of tattooing. PMID- 27761088 TI - Salient Points in Reconstruction of Nasal Skin after Tumor Ablation with Local Flaps. AB - OBJECTIVE: A variety of nasal skin reconstruction methods are available to meet the esthetic patient's needs. In this article, we review some of modifications of these procedures and share our experience in reconstruction of different parts of the nasal skin following skin tumor ablation. PATIENTS AND METHODS: From January 2010 to January 2014, 171 patients underwent nasal skin reconstruction after excising cancerous lesions of the involved nasal skin. The patient's history, pre and post-operation photographs, and the surgery data were collected and assessed. Demographic data related to the type of cancer, defect size and location, type of reconstruction were collected. RESULTS: A variety of local flaps were used based on location and defect features. Nearly all flaps healed primarily without postsurgical significant complications. CONCLUSION: According to the results and the outcomes of the operations, we concluded that a certain flaps are more effective than others in nasal skin reconstruction. Local flap reconstruction of the nose has good esthetic result with low complication rate. PMID- 27761089 TI - Evaluation of Carbon Dioxide Laser in the Treatment of Epidermal Nevi. AB - BACKGROUND: Epidermal naevi are benign hamartomatous growths of the skin which are generally asymptomatic with a benign course but are cosmetically disagreeable. Topical treatments such as steroids, calcipotriol, 5 fluorouracil, podophyllin, retinoids and cryotherapy are ineffective and surgical excision results in scar formation. Therapy is often challenging. AIM OF THE STUDY: To study the response of carbon dioxide (CO2) laser in the management of epidermal naevi. SUBJECTS AND METHODS: We conducted a study of CO2 laser treatment on 15 patients of epidermal naevi, eight with verrucous epidermal naevi and seven with sebaceous naevi. A thorough history and examination was done to rule out any epidermal naevus syndrome. The diagnosis was confirmed by histopathology. The number of treatment sessions varied from 1 to 8. RESULTS: Response was excellent (>90% reduction in lesion size) in three patients, very good (>75% reduction) in five, good (>50% reduction in lesion size) in five and poor (<50% reduction in lesion size) in two patients. The side effects were hyperpigmentation and scarring. Long-term follow-up over a period of 10 months showed a recurrence rate of 20%. CONCLUSION: We conclude that CO2 laser treatment might be an effective option with long-term safety, minimal discomfort and rapid recovery. PMID- 27761091 TI - Ahmad's NPRT System: A Practical Innovation for Documenting Male Pattern Baldness. AB - Various classifications for male pattern baldness are mentioned in the literature. The 'Norwood's classification is the most commonly used but it has certain limitations. The new system has included 'three' extra features which were not mentioned in any other classification. It provides an opportunity to document the full and correct picture while documenting male pattern baldness. It also aids in assessing the treatment for various degrees of baldness. PMID- 27761090 TI - Screening for Body Dysmorphic Disorder in a Dermatology Outpatient Setting at a Tertiary Care Centre. AB - CONTEXT: A distressing pre-occupation with an imagined or slight defect in appearance with a marked negative effect on the patient's life is the core symptom of body dysmorphic disorder (BDD). AIM: To screen the patients attending a dermatology clinic at a tertiary care centre for BDD using the BDD-dermatology version (DV) questionnaire. SETTINGS AND DESIGN: This cross-sectional study enrolled 245 consecutive patients from the dermatology outpatients clinic. METHODS: The demographic details were collected and the DV of BDD screening questionnaire was administered. A 5-point Likert scale was used for objective scoring of the stated concern and patients who scored >=3 were excluded from the study. STATISTICAL ANALYSIS USED: The results were statistically analysed. Differences between the groups were investigated by Chi-square analysis for categorical variables, and Fisher exact test wherever required. RESULTS: A total of 177 patients completed the study, and of these, eight patients screened positive for BDD. The rate of BDD in patients presenting with cosmetic complaints was 7.5% and in those with general dermatology, complaints were 2.1%, with no significant difference between the two groups (P = 0.156). Facial flaws (62.5%) were the most common concern followed by body asymmetry (25%). CONCLUSION: The rates of BDD found in this study are comparable but at a lower rate than that reported in literature data. PMID- 27761093 TI - Finger-shaped Red Light Emitting Diode to Ascertain the Depth of Periungual Wart. AB - Management of periungual wart is a great challenge, especially when there is subungual extension. The major cause of recurrence of wart is improper clinical assessment of its extent and not directing therapy against the entire wart. This difficulty of ascertaining its extent could be overcome with this finger-shaped red light emitting diode device. Red light in the device penetrates the thick palmar skin and dark constitutive skin colour due to its longer wavelength. PMID- 27761092 TI - Clinical and Histologic Evaluation of Platelet-Rich Fibrin Accelerated Epithelization of Gingival Wound. AB - The foremost indication for gingival depigmentation is patient demand for improved aesthetics. In most cases after the removal of pigmented layer, the area is covered with periodontal packs. These dressings have no curative properties. They only minimise the likelihood of surface trauma during mastication. However, platelet-rich fibrin (PRF) accelerates wound healing by effective neovascularisation and promoting fast cicatricial tissue remodelling. In the present split mouth study, PRF membrane was applied in the first quadrant and non eugenol dressing (Coe-Pack) in the second quadrant after depigmentation. Clinical evaluation of epithelization with toluidine blue revealed that PRF treated sites stained substantially less indicating better wound healing as compared to Coe Pack sites, which appeared more erythematous after 5 days. The histologic evaluation also revealed greater inflammatory cell infiltrate on Coe-Pack sites as compared to PRF. Thus, PRF membrane as a periodontal dressing is a successful approach to protect the raw wound area of the depigmented site to reduce healing time and patient discomfort. PMID- 27761094 TI - Syringocystadenoma Papilliferum of the Scalp Arising from a Nevus Sebaceous. AB - Syringocystadenoma papilliferum (SCAP) is a rare, benign tumour with varied presentations that arises from the apocrine glands and at times can lead to a diagnostic dilemma. A 53-year-old male presented with a 40-year history of a scalp nodule and a recent 2-year change in its character, and a sanguinopurulent discharge. Examination revealed a 4 cm * 2 cm firm nodule upon left side of the scalp vertex, actively discharging pus and blood. No regional lymph nodes were noticeably palpable. Incision biopsy performed elsewhere showed evidence of a squamous cell carcinoma-in-situ. He underwent a wide local excision with a bilobed flap reconstruction. Histopathologically, the lesion was reported to be SCAP. On follow-up, the patient has since remained asymptomatic with an acceptable cosmetic recovery. PMID- 27761095 TI - Subungual Glomus Tumour Excision with Transungual Approach with Partial Proximal Nail Avulsion. PMID- 27761096 TI - White Hair Removal with Follicular Unit Extraction. PMID- 27761097 TI - Erratum: Facial Rejuvenation with Fillers: The Dual Plane Technique. AB - [This corrects the article on p. 127 in vol. 8, PMID: 26644734.]. PMID- 27761098 TI - MODEL AVERAGING BASED ON KULLBACK-LEIBLER DISTANCE. AB - This paper proposes a model averaging method based on Kullback-Leibler distance under a homoscedastic normal error term. The resulting model average estimator is proved to be asymptotically optimal. When combining least squares estimators, the model average estimator is shown to have the same large sample properties as the Mallows model average (MMA) estimator developed by Hansen (2007). We show via simulations that, in terms of mean squared prediction error and mean squared parameter estimation error, the proposed model average estimator is more efficient than the MMA estimator and the estimator based on model selection using the corrected Akaike information criterion in small sample situations. A modified version of the new model average estimator is further suggested for the case of heteroscedastic random errors. The method is applied to a data set from the Hong Kong real estate market. PMID- 27761100 TI - Crystal and Molecular Structure of Dichloro(ethylenediamine)gold(III) Nitrate: [Au(NH2CH2CH2NH2)Cl2]NO3. AB - The gold(III) atom in [Au(NH2CH2CH2NH2) Cl2]NO3 is chelated by the ethylenediamine (en) ligand and the approximately square planar geometry is completed by two chloride atoms. Weak Au?O and Au?Cl contacts are noted above and below the square plane leading to a tetragonally distorted octahedron for the gold(III) center. Extensive charge-assisted hydrogen bonding of the type N-H?O leads to the formation of a 2-D array and layers are consolidated into a 3-D network via C-H?O and C-H?Cl contacts. The compound crystallizes in the orthorhombic space group Pbca with a = 10.3380(11) A, b = 8.2105(7) A, c = 19.625(2) A, and Z = 8. PMID- 27761099 TI - Estimated Risk of Developing Selected DSM-IV Disorders Among 5-Year-Old Children with Prenatal Cocaine Exposure. AB - This study estimated childhood risk of developing selected DSM-IV Disorders, including Attention-Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Separation Anxiety Disorder (SAD), in children with prenatal cocaine exposure (PCE). Children were enrolled prospectively at birth (n=476) with prenatal drug exposures documented by maternal interview, urine and meconium assays. Study participants included 400 African-American children from the birth cohort, 208 cocaine-exposed (CE) and 192 non-cocaine-exposed (NCE) who attended a 5-year follow-up assessment and whose caregiver completed the Computerized Diagnostic Interview Schedule for Children. Under a generalized linear model (logistic link), Fisher's exact methods were used to estimate the CE-associated relative risk (RR) of these disorders. Results indicated a modest but statistically robust elevation of ADHD risk associated with increasing levels of PCE (p<0.05). Binary comparison of CE versus NCE children indicated no CE associated RR. Estimated cumulative incidence proportions among CE children were 2.9% for ADHD (vs 3.1% NCE); 1.4% for SAD (vs 1.6% NCE); and 4.3% for ODD (vs 6.8% NCE). Findings offer suggestive evidence of increased risk of ADHD (but not ODD or SAD) in relation to an increasing gradient of PCE during gestation. PMID- 27761101 TI - Measures of Kindergarten Spelling and Their Relations to Later Spelling Performance. AB - Learning the orthographic forms of words is important for both spelling and reading. To determine whether some methods of scoring children's early spellings predict later spelling performance better than do other methods, we analyzed data from 374 U.S. and Australian children who took a 10-word spelling test at the end of kindergarten (mean age 6 years, 2 months) and a standardized spelling test approximately two years later. Surprisingly, scoring methods that took account of phonological plausibility did not outperform methods that were based only on orthographic correctness. The scoring method that is most widely used in research with young children, which allots a certain number of points to each word and which considers both orthographic and phonological plausibility, did not rise to the top as a predictor. Prediction of Grade 2 spelling performance was improved to a small extent by considering children's tendency to reverse letters in kindergarten. PMID- 27761102 TI - Proteome profiling reveals insights into cold-tolerant growth in sea buckthorn. AB - BACKGROUND: Low temperature is one of the crucial environmental factors limiting the productivity and distribution of plants. Sea buckthorn (Hippophae rhamnoides L.), a well recognized multipurpose plant species, live successfully in in cold desert regions. But their molecular mechanisms underlying cold tolerance are not well understood. METHODS: Physiological and biochemical responses to low temperature stress were studied in seedlings of sea buckthorn. Differentially expressed protein spots were analyzed using multiplexing fluorescent two dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization (MALDI) time-of-flight/time-of-flight (TOF/TOF) mass spectrometry (MS), the concentration of phytohormone was measured using enzyme-linked immunosorbent assay, and a spectrophotometric assay was used to measure enzymatic reactions. RESULTS: With the increase of cold stress intensity, the photosynthesis rate, transpiration rate, stomatal conductance in leaves and contents of abscisic acid (ABA) and indole acetic acid (IAA) in roots decreased significantly; however, water-use efficiency, ABA and zeatin riboside in leaves increased significantly, while cell membrane permeability, malondialdehyde and IAA in leaves increased at 7 d and then decreased at 14 d. DIGE and MS/MS analysis identified 32 of 39 differentially expressed protein spots under low-temperature stress, and their functions were mainly involved in metabolism, photosynthesis, signal transduction, antioxidative systems and post translational modification. CONCLUSION: The changed protein abundance and corresponding physiological-biochemical response shed light on the molecular mechanisms related to cold tolerance in cold-tolerant plants and provide key candidate proteins for genetic improvement of plants. PMID- 27761103 TI - Shape Tracking of a Dexterous Continuum Manipulator Utilizing Two Large Deflection Shape Sensors. AB - Dexterous continuum manipulators (DCMs) can largely increase the reachable region and steerability for minimally and less invasive surgery. Many such procedures require the DCM to be capable of producing large deflections. The real-time control of the DCM shape requires sensors that accurately detect and report large deflections. We propose a novel, large deflection, shape sensor to track the shape of a 35 mm DCM designed for a less invasive treatment of osteolysis. Two shape sensors, each with three fiber Bragg grating sensing nodes is embedded within the DCM, and the sensors' distal ends fixed to the DCM. The DCM centerline is computed using the centerlines of each sensor curve. An experimental platform was built and different groups of experiments were carried out, including free bending and three cases of bending with obstacles. For each experiment, the DCM drive cable was pulled with a precise linear slide stage, the DCM centerline was calculated, and a 2D camera image was captured for verification. The reconstructed shape created with the shape sensors is compared with the ground truth generated by executing a 2D-3D registration between the camera image and 3D DCM model. Results show that the distal tip tracking accuracy is 0.40 +/- 0.30 mm for the free bending and 0.61 +/- 0.15 mm, 0.93 +/- 0.05 mm and 0.23 +/- 0.10 mm for three cases of bending with obstacles. The data suggest FBG arrays can accurately characterize the shape of large-deflection DCMs. PMID- 27761104 TI - ACCURATE CHEMICAL MASTER EQUATION SOLUTION USING MULTI-FINITE BUFFERS. AB - The discrete chemical master equation (dCME) provides a fundamental framework for studying stochasticity in mesoscopic networks. Because of the multi-scale nature of many networks where reaction rates have large disparity, directly solving dCMEs is intractable due to the exploding size of the state space. It is important to truncate the state space effectively with quantified errors, so accurate solutions can be computed. It is also important to know if all major probabilistic peaks have been computed. Here we introduce the Accurate CME (ACME) algorithm for obtaining direct solutions to dCMEs. With multi-finite buffers for reducing the state space by O(n!), exact steady-state and time-evolving network probability landscapes can be computed. We further describe a theoretical framework of aggregating microstates into a smaller number of macrostates by decomposing a network into independent aggregated birth and death processes, and give an a priori method for rapidly determining steady-state truncation errors. The maximal sizes of the finite buffers for a given error tolerance can also be pre-computed without costly trial solutions of dCMEs. We show exactly computed probability landscapes of three multi-scale networks, namely, a 6-node toggle switch, 11-node phage-lambda epigenetic circuit, and 16-node MAPK cascade network, the latter two with no known solutions. We also show how probabilities of rare events can be computed from first-passage times, another class of unsolved problems challenging for simulation-based techniques due to large separations in time scales. Overall, the ACME method enables accurate and efficient solutions of the dCME for a large class of networks. PMID- 27761106 TI - A Comparison of Medical Birth Register Outcomes between Maternity Health Clinics and Integrated Maternity and Child Health Clinics in Southwest Finland. AB - INTRODUCTION: Primary maternity care services are globally provided according to various organisational models. Two models are common in Finland: a maternity health clinic and an integrated maternity and child health clinic. The aim of this study was to clarify whether there is a relation between the organisational model of the maternity health clinics and the utilisation of maternity care services, and certain maternal and perinatal health outcomes. METHODS: A comparative, register-based cross-sectional design was used. The data of women (N = 2741) who had given birth in the Turku University Hospital area between 1 January 2009 and 31 December 2009 were collected from the Finnish Medical Birth Register. Comparisons were made between the women who were clients of the maternity health clinics and integrated maternity and child health clinics. RESULTS: There were no clinically significant differences between the clients of maternity health clinics and integrated maternity and child health clinics regarding the utilisation of maternity care services or the explored health outcomes. CONCLUSIONS: The organisational model of the maternity health clinic does not impact the utilisation of maternity care services or maternal and perinatal health outcomes. Primary maternity care could be provided effectively when integrated with child health services. PMID- 27761105 TI - Fibrinogen alpha C chain 5.9 kDa fragment (FIC5.9), a biomarker for various pathological conditions, is produced in post-blood collection by fibrinolysis and coagulation factors. AB - BACKGROUND: Fibrinogen alpha C chain 5.9 kDa fragment (FIC5.9) is a new serum biomarker for chronic hepatitis that was discovered by proteomics analysis. Previous studies have shown that FIC5.9 is derived from the C-terminal region of fibrinogen alpha chain and the serum levels of FIC5.9 decrease in chronic hepatitis. It also have been reported that FIC5.9 cannot be detected in the blood stream of the systemic circulation and it is released from fibrinogen during blood clotting in collecting tube. However, the mechanism of FIC5.9 releasing from fibrinogen is unclear. METHODS: We formulated a hypothesis that FIC5.9 is released by enzymes that are activated by post-blood collection and may be coagulation and fibrinolysis factors. In this study, we analyzed the mechanisms of FIC5.9 releasing from fibrinogen in healthy blood. RESULTS: Our analysis showed that thrombin acts as an initiator for FIC5.9 releasing, and that mainly plasmin cleaves N-terminal end of FIC5.9 and neutrophil elastase cleave C terminal end of FIC5.9. CONCLUSION: FIC5.9 reflects minute changes in coagulation and fibrinolysis factors and may be associated with pathological conditions. PMID- 27761107 TI - Design of microfluidic channels for magnetic separation of malaria-infected red blood cells. AB - This study is motivated by the development of a blood cell filtration device for removal of malaria-infected, parasitized red blood cells (pRBCs). The blood was modeled as a multi-component fluid using the computational fluid dynamics discrete element method (CFD-DEM), wherein plasma was treated as a Newtonian fluid and the red blood cells (RBCs) were modeled as soft-sphere solid particles which move under the influence of drag, collisions with other RBCs, and a magnetic force. The CFD-DEM model was first validated by a comparison with experimental data from Han et al. 2006 (Han and Frazier 2006) involving a microfluidic magnetophoretic separator for paramagnetic deoxygenated blood cells. The computational model was then applied to a parametric study of a parallel plate separator having hematocrit of 40% with a 10% of the RBCs as pRBCs. Specifically, we investigated the hypothesis of introducing an upstream constriction to the channel to divert the magnetic cells within the near-wall layer where the magnetic force is greatest. Simulations compared the efficacy of various geometries upon the stratification efficiency of the pRBCs. For a channel with nominal height of 100 um, the addition of an upstream constriction of 80% improved the proportion of pRBCs retained adjacent to the magnetic wall (separation efficiency) by almost 2 fold, from 26% to 49%. Further addition of a downstream diffuser reduced remixing, hence improved separation efficiency to 72%. The constriction introduced a greater pressure drop (from 17 to 495 Pa), which should be considered when scaling-up this design for a clinical-sized system. Overall, the advantages of this design include its ability to accommodate physiological hematocrit and high throughput - which is critical for clinical implementation as a blood-filtration system. PMID- 27761109 TI - Saccadic and Postsaccadic Disconjugacy in Zebrafish Larvae Suggests Independent Eye Movement Control. AB - Spontaneous eye movements of zebrafish larvae in the dark consist of centrifugal saccades that move the eyes from a central to an eccentric position and postsaccadic centripetal drifts. In a previous study, we showed that the fitted single-exponential time constants of the postsaccadic drifts are longer in the temporal-to-nasal (T->N) direction than in the nasal-to-temporal (N->T) direction. In the present study, we further report that saccadic peak velocities are higher and saccadic amplitudes are larger in the N->T direction than in the T >N direction. We investigated the underlying mechanism of this ocular disconjugacy in the dark with a top-down approach. A mathematic ocular motor model, including an eye plant, a set of burst neurons and a velocity-to-position neural integrator (VPNI), was built to simulate the typical larval eye movements in the dark. The modeling parameters, such as VPNI time constants, neural impulse signals generated by the burst neurons and time constants of the eye plant, were iteratively adjusted to fit the average saccadic eye movement. These simulations suggest that four pools of burst neurons and four pools of VPNIs are needed to explain the disconjugate eye movements in our results. A premotor mechanism controls the synchronous timing of binocular saccades, but the pools of burst and integrator neurons in zebrafish larvae seem to be different (and maybe separate) for both eyes and horizontal directions, which leads to the observed ocular disconjugacies during saccades and postsaccadic drifts in the dark. PMID- 27761108 TI - Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological Diseases. AB - D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs). A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements. The receptor/multireceptor affinity and functional profiles for the examined compounds have been covered, together with their most significant pharmacological applications. PMID- 27761110 TI - Magnitude Processing in the Brain: An fMRI Study of Time, Space, and Numerosity as a Shared Cortical System. AB - Continuous dimensions, such as time, space, and numerosity, have been suggested to be subserved by common neurocognitive mechanisms. Neuroimaging studies that have investigated either one or two dimensions simultaneously have consistently identified neural correlates in the parietal cortex of the brain. However, studies investigating the degree of neural overlap across several dimensions are inconclusive, and it remains an open question whether a potential overlap can be conceptualized as a neurocognitive magnitude processing system. The current functional magnetic resonance imaging study investigated the potential neurocognitive overlap across three dimensions. A sample of adults (N = 24) performed three different magnitude processing tasks: a temporal discrimination task, a number discrimination task, and a line length discrimination task. A conjunction analysis revealed several overlapping neural substrates across multiple magnitude dimensions, and we argue that these cortical nodes comprise a distributed magnitude processing system. Key components of this predominantly right-lateralized system include the intraparietal sulcus, insula, premotor cortex/SMA, and inferior frontal gyrus. Together with previous research highlighting intraparietal sulcus, our results suggest that the insula also is a core component of the magnitude processing system. We discuss the functional role of each of these components in the magnitude processing system and suggest that further research of this system may provide insight into the etiology of neurodevelopmental disorders where cognitive deficits in magnitude processing are manifest. PMID- 27761112 TI - Hospitalizations Due to Adverse Drug Events in the Elderly-A Retrospective Register Study. AB - Adverse drug events (ADEs) are more likely to affect geriatric patients due to physiological changes occurring with aging. Even though this is an internationally recognized problem, similar research data in Finland is still lacking. The aim of this study was to determine the number of geriatric medication-related hospitalizations in the Finnish patient population and to discover the potential means of recognizing patients particularly at risk of ADEs. The study was conducted retrospectively from the 2014 emergency department patient records in Oulu University Hospital. A total number of 290 admissions were screened for ADEs, adverse drug reactions (ADRs) and drug-drug interactions (DDIs) by a multi-disciplinary research team. Customized Naranjo scale was used as a control method. All admissions were categorized into "probable," "possible," or "doubtful" by both assessment methods. In total, 23.1% of admissions were categorized as "probably" or "possibly" medication-related. Vertigo, falling, and fractures formed the largest group of ADEs. The most common ADEs were related to medicines from N class of the ATC-code system. Age, sex, residence, or specialty did not increase the risk for medication-related admission significantly (min p = 0.077). Polypharmacy was, however, found to increase the risk (OR 3.3; 95% CI, 1.5-6.9; p = 0.01). In conclusion, screening patients for specific demographics or symptoms would not significantly improve the recognition of ADEs. In addition, as ADE detection today is largely based on voluntary reporting systems and retrospective manual tracking of errors, it is evident that more effective methods for ADE detection are needed in the future. PMID- 27761113 TI - Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing. AB - Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in aconitine-induced dynorphin A expression, anti-hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of aconitine and benzoylaconine (but not aconine) attenuated mechanical allodynia and heat hyperalgesia, with normalized ED50 values of 35 pmol and 3.6 nmol, respectively. Aconitine and benzoylaconine anti-allodynia was completely blocked by the microglial inhibitor, dynorphin A antiserum, and kappa-opioid receptor antagonist. Aconitine and benzoylaconine, but not aconine, stimulated dynorphin A expression in cultured primary spinal microglia, with EC50 values of 32 nM and 3 MUM, respectively. Intrathecal aconitine, benzoylaconine and aconine induced flaccid paralysis and death, with normalized TD50 values of 0.5 nmol, 0.2 MUmol, and 1.6 MUmol, respectively. The TD50/ED50 ratios of aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for aconitine to stimulate spinal microglial dynorphin A expression and subsequent anti-hypersensitivity, which can be separated from neurotoxicity, because both benzoylaconine and aconine differentially produced anti hypersensitivity and neurotoxicity due to their different stimulatory ability on dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to avoid overprocessing and excess hydrolysis of benzolyaconine to aconine. PMID- 27761114 TI - Prolonged Calorie Restriction Downregulates Skeletal Muscle mTORC1 Signaling Independent of Dietary Protein Intake and Associated microRNA Expression. AB - Short-term (5-10 days) calorie restriction (CR) downregulates muscle protein synthesis, with consumption of a high protein-based diet attenuating this decline. Benefit of increase protein intake is believed to be due to maintenance of amino acid-mediated anabolic signaling through the mechanistic target of rapamycin complex 1 (mTORC1), however, there is limited evidence to support this contention. The purpose of this investigation was to determine the effects of prolonged CR and high protein diets on skeletal muscle mTORC1 signaling and expression of associated microRNA (miR). Twelve-week old male Sprague Dawley rats consumed ad libitum (AL) or calorie restricted (CR; 40%) adequate (10%, AIN-93M) or high (32%) protein milk-based diets for 16 weeks. Body composition was determined using dual energy X-ray absorptiometry and muscle protein content was calculated from muscle homogenate protein concentrations expressed relative to fat-free mass to estimate protein content. Western blot and RT-qPCR were used to determine mTORC1 signaling and mRNA and miR expression in fasted mixed gastrocnemius. Independent of dietary protein intake, muscle protein content was 38% lower (P < 0.05) in CR compared to AL. Phosphorylation and total Akt, mTOR, rpS6, and p70S6K were lower (P < 0.05) in CR vs. AL, and total rpS6 was associated with muscle protein content (r = 0.64, r2 = 0.36). Skeletal muscle miR expression was not altered by either energy or protein intake. This study provides evidence that chronic CR attenuates muscle protein content by downregulating mTORC1 signaling. This response is independent of skeletal muscle miR and dietary protein. PMID- 27761111 TI - Sexual Dimorphism and Aging in the Human Hyppocampus: Identification, Validation, and Impact of Differentially Expressed Genes by Factorial Microarray and Network Analysis. AB - Motivation: In the brain of elderly-healthy individuals, the effects of sexual dimorphism and those due to normal aging appear overlapped. Discrimination of these two dimensions would powerfully contribute to a better understanding of the etiology of some neurodegenerative diseases, such as "sporadic" Alzheimer. Methods: Following a system biology approach, top-down and bottom-up strategies were combined. First, public transcriptome data corresponding to the transition from adulthood to the aging stage in normal, human hippocampus were analyzed through an optimized microarray post-processing (Q-GDEMAR method) together with a proper experimental design (full factorial analysis). Second, the identified genes were placed in context by building compatible networks. The subsequent ontology analyses carried out on these networks clarify the main functionalities involved. Results: Noticeably we could identify large sets of genes according to three groups: those that exclusively depend on the sex, those that exclusively depend on the age, and those that depend on the particular combinations of sex and age (interaction). The genes identified were validated against three independent sources (a proteomic study of aging, a senescence database, and a mitochondrial genetic database). We arrived to several new inferences about the biological functions compromised during aging in two ways: by taking into account the sex-independent effects of aging, and considering the interaction between age and sex where pertinent. In particular, we discuss the impact of our findings on the functions of mitochondria, autophagy, mitophagia, and microRNAs. Conclusions: The evidence obtained herein supports the occurrence of significant neurobiological differences in the hippocampus, not only between adult and elderly individuals, but between old-healthy women and old-healthy men. Hence, to obtain realistic results in further analysis of the transition from the normal aging to incipient Alzheimer, the features derived from the sexual dimorphism in hippocampus should be explicitly considered. PMID- 27761115 TI - TRPA1 Channels in Drosophila and Honey Bee Ectoparasitic Mites Share Heat Sensitivity and Temperature-Related Physiological Functions. AB - The transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is conserved between many arthropods, and in some has been shown to function as a chemosensor for noxious compounds. Activation of arthropod TRPA1 channels by temperature fluctuations has been tested in only a few insect species, and all of them were shown to be activated by heat. The recent identification of chemosensitive TRPA1 channels from two honey bee ectoparasitic mite species (VdTRPA1 and TmTRPA1) have provided an opportunity to study the temperature dependent activation and the temperature-associated physiological functions of TRPA1 channels in non-insect arthropods. We found that both mite TRPA1 channels are heat sensitive and capable of rescuing the temperature-related behavioral defects of a Drosophila melanogaster trpA1 mutant. These results suggest that heat-sensitivity of TRPA1 could be conserved between many arthropods despite its amino acid sequence diversity. Nevertheless, the ankyrin repeats (ARs) 6 and 7 are well-conserved between six heat-sensitive arthropod TRPA1 channels and have critical roles for the heat activation of VdTRPA1. PMID- 27761116 TI - BdorOBP83a-2 Mediates Responses of the Oriental Fruit Fly to Semiochemicals. AB - The oriental fruit fly, Bactrocera dorsalis (Diptera: Tephritidae), is one of the most destructive pests throughout tropical and subtropical regions in Asia. This insect displays remarkable changes during different developmental phases in olfactory behavior between sexually immature and mated adults. The olfactory behavioral changes provide clues to examine physiological and molecular bases of olfactory perception in this insect. We comparatively analyzed behavioral and neuronal responses of B. dorsalis adults to attractant semiochemicals, and the expression profiles of antenna chemosensory genes. We found that some odorant binding proteins (OBPs) were upregulated in mated adults in association with their behavioral and neuronal responses. Ligand-binding assays further showed that one of OBP83a orthologs, BdorOBP83a-2, binds with high affinity to attractant semiochemicals. Functional analyses confirmed that the reduction in BdorOBP83a-2 transcript abundance led to a decrease in neuronal and behavioral responses to selected attractants. This study suggests that BdorOBP83a-2 mediates behavioral responses to attractant semiochemicals and could be a potential efficient target for pest control. PMID- 27761117 TI - The Effect of Expert Performance Microtiming on Listeners' Experience of Groove in Swing or Funk Music. AB - This study tested the influence of expert performance microtiming on listeners' experience of groove. Two professional rhythm section performances (bass/drums) in swing and funk style were recorded, and the performances' original microtemporal deviations from a regular metronomic grid were scaled to several levels of magnitude. Music expert (n = 79) and non-expert (n = 81) listeners rated the groove qualities of stimuli using a newly developed questionnaire that measures three dimensions of the groove experience (Entrainment, Enjoyment, and the absence of Irritation). Findings show that music expert listeners were more sensitive to microtiming manipulations than non-experts. Across both expertise groups and for both styles, groove ratings were high for microtiming magnitudes equal or smaller than those originally performed and decreased for exaggerated microtiming magnitudes. In particular, both the fully quantized music and the music with the originally performed microtiming pattern were rated equally high on groove. This means that neither the claims of PD theory (that microtiming deviations are necessary for groove) nor the opposing exactitude hypothesis (that microtiming deviations are detrimental to groove) were supported by the data. PMID- 27761118 TI - Sexual Well-Being in Patients with Blepharospasm, Spasmodic Torticollis, and Hemifacial Spasm: A Pilot Study. AB - Mood, anxiety, and other psychological symptoms are common in dystonic patients suffering from blepharospasm (BSP) and spasmodic torticollis (ST). Since sexual well-being is an important aspect of mental health, here, we investigated whether these patients may also experience a worsening of their sexual life. In particular, quality of sexual life was evaluated in patients suffering from BSP (N = 30), ST (N = 30), and in a control group of patient with Hemifacial spasm (HFS; N = 30), undergoing botulinum toxin type A therapy. A group of 30 age matched healthy volunteers constituted an additional control group. Patients were evaluated just before the periodic injection of botulinum toxin. Sexual functioning was assessed using the Sexual Functioning Inventory, a reduced form of the Golombok Rust Inventory, previously employed in patients with Parkinson's disease. Depression (Beck Depression Inventory) and anxiety (STAI-X1/X2) were also assessed. Results revealed that sexual functioning was significantly affected in patients with BSP, ST, and HFS with respect to healthy controls. Dystonic patients manifested more sexual dysfunction than patients with HFS. Overall, females had a poorer quality of sexual life than males and, among females, women with BSP were the most dysfunctional. Psychological symptoms were present in patients with dystonia, but not in patients with HFS. As discussed in the paper, several factors might be taken into account to explain worse quality of sexual life in patients with dystonia compared to patients with hemifacial spasm. Among them an important role might be played by the central origin of dystonia pathophysiology (i.e., altered activity of cortico-striato-thalamic cortical circuits). Future investigations are necessary to further explore these preliminary findings, considering that this is the first time that sexual well being is evaluated in patients with BSP, ST, and HFS, and comparable data are not available. PMID- 27761119 TI - Using Behavioral Consensus to Learn about Social Conventions in Early Childhood. AB - Adults make inferences about the conventionality of others' behaviors based on their prevalence across individuals. Here, we look at whether children use behavioral consensus as a cue to conventionality, and whether this informs which cultural models children choose to learn from. We find that 2- to 5-year old children exhibit increasing sensitivity to behavioral consensus with age, suggesting that like adults, young humans use behavioral consensus to identify social conventions. However, unlike previous studies showing children's tendencies to prefer and to learn from members of a consensus, the present study suggests that there are contexts in which children prefer and learn from unconventional individuals. The implications of these different preferences are discussed. PMID- 27761120 TI - Soft-assembled Multilevel Dynamics of Tactical Behaviors in Soccer. AB - This study aimed to identify the tactical patterns and the timescales of variables during a soccer match, allowing understanding the multilevel organization of tactical behaviors, and to determine the similarity of patterns performed by different groups of teammates during the first and second halves. Positional data from 20 professional male soccer players from the same team were collected using high frequency global positioning systems (5 Hz). Twenty-nine categories of tactical behaviors were determined from eight positioning-derived variables creating multivariate binary (Boolean) time-series matrices. Hierarchical principal component analysis (PCA) was used to identify the multilevel structure of tactical behaviors. The sequential reduction of each set level of principal components revealed a sole principal component as the slowest collective variable, forming the global basin of attraction of tactical patterns during each half of the match. In addition, the mean dwell time of each positioning-derived variable helped to understand the multilevel organization of collective tactical behavior during a soccer match. This approach warrants further investigations to analyze the influence of task constraints on the emergence of tactical behavior. Furthermore, PCA can help coaches to design representative training tasks according to those tactical patterns captured during match competitions and to compare them depending on situational variables. PMID- 27761121 TI - Iconic Native Culture Cues Inhibit Second Language Production in a Non-immigrant Population: Evidence from Bengali-English Bilinguals. AB - We examined if iconic pictures belonging to one's native culture interfere with second language production in bilinguals in an object naming task. Bengali English bilinguals named pictures in both L1 and L2 against iconic cultural images representing Bengali culture or neutral images. Participants named in both "Blocked" and "Mixed" language conditions. In both conditions, participants were significantly slower in naming in English when the background was an iconic Bengali culture picture than a neutral image. These data suggest that native language culture cues lead to activation of the L1 lexicon that competed against L2 words creating an interference. These results provide further support to earlier observations where such culture related interference has been observed in bilingual language production. We discuss the results in the context of cultural influence on the psycholinguistic processes in bilingual object naming. PMID- 27761122 TI - What's in a Word? On Weight Stigma and Terminology. PMID- 27761123 TI - Intuitive Participation in Aggressive Intergroup Conflict: Evidence of Weak Versus Strong Parochial Altruism. PMID- 27761124 TI - Executive Cognitive Functioning and Cardiovascular Autonomic Regulation in a Population-Based Sample of Working Adults. AB - Objective: Executive cognitive functioning is essential in private and working life and is sensitive to stress and aging. Cardiovascular (CV) health factors are related to cognitive decline and dementia, but there is relatively few studies of the role of CV autonomic regulation, a key component in stress responses and risk factor for cardiovascular disease (CVD), and executive processes. An emerging pattern of results from previous studies suggest that different executive processes may be differentially associated with CV autonomic regulation. The aim was thus to study the associations between multiple measures of CV autonomic regulation and measures of different executive cognitive processes. Method: Participants were 119 healthy working adults (79% women), from the Swedish Longitudinal Occupational Survey of Health. Electrocardiogram was sampled for analysis of heart rate variability (HRV) measures, including the Standard Deviation of NN, here heart beats (SDNN), root of the mean squares of successive differences (RMSSD), high frequency (HF) power band from spectral analyses, and QT variability index (QTVI), a measure of myocardial repolarization patterns. Executive cognitive functioning was measured by seven neuropsychological tests. The relationships between CV autonomic regulation measures and executive cognitive measures were tested with bivariate and partial correlational analyses, controlling for demographic variables, and mental health symptoms. Results: Higher SDNN and RMSSD and lower QTVI were significantly associated with better performance on cognitive tests tapping inhibition, updating, shifting, and psychomotor speed. After adjustments for demographic factors however (age being the greatest confounder), only QTVI was clearly associated with these executive tests. No such associations were seen for working memory capacity. Conclusion: Poorer CV autonomic regulation in terms of lower SDNN and RMSSD and higher QTVI was associated with poorer executive cognitive functioning in terms of inhibition, shifting, updating, and speed in healthy working adults. Age could largely explain the associations between the executive measures and SDNN and RMSSD, while associations with QTVI remained. QTVI may be a useful measure of autonomic regulation and promising as an early indicator of risk among otherwise healthy adults, compared to traditional HRV measures, as associations between QTVI and executive functioning was not affected by age. PMID- 27761125 TI - Prosocial Reward Learning in Children and Adolescents. AB - Adolescence is a period of increased sensitivity to social contexts. To evaluate how social context sensitivity changes over development-and influences reward learning-we investigated how children and adolescents perceive and integrate rewards for oneself and others during a dynamic risky decision-making task. Children and adolescents (N = 75, 8-16 years) performed the Social Gambling Task (SGT, Kwak et al., 2014) and completed a set of questionnaires measuring other regarding behavior. In the SGT, participants choose amongst four card decks that have different payout structures for oneself and for a charity. We examined patterns of choices, overall decision strategies, and how reward outcomes led to trial-by-trial adjustments in behavior, as estimated using a reinforcement learning model. Performance of children and adolescents was compared to data from a previously collected sample of adults (N = 102) performing the identical task. We found that that children/adolescents were not only more sensitive to rewards directed to the charity than self but also showed greater prosocial tendencies on independent measures of other-regarding behavior. Children and adolescents also showed less use of a strategy that prioritizes rewards for self at the expense of rewards for others. These results support the conclusion that, compared to adults, children and adolescents show greater sensitivity to outcomes for others when making decisions and learning about potential rewards. PMID- 27761126 TI - Motivation toward Physical Exercise and Subjective Wellbeing: The Mediating Role of Trait Self-Control. AB - Motivation toward physical exercise (MPE) and trait self-control (TSC) were identified as key predictors of subjective wellbeing (SWB). However, there has not been any research designed to examine the mediating role of TSC in the relationship between MPE and SWB. The present study utilizes self-determination theory, control-process theory of self-regulation, and theory of multiple pathways of TSC in order to examine whether TSC mediates the relationships of autonomous MPE (A-MPE), controlled MPE (C-MPE), and impersonal MPE (NO-MPE) with SWB using structural equation modeling (XLSTAT PLS). Three hundred seventeen adult American individuals (Mage = 32.97, SDage = 11.30), who reported to be regular exercisers, voluntarily answered questionnaires assessing MPE, TSC, and SWB. Correlational analyses revealed positive relationships between A-MPE, TSC, and SWB, and negative relationships of C-MPE and NO-MPE with TSC and SWB. Mediation analyses revealed that TSC mediated the relationships of A-MPE (partial mediation) and C-MPE (full mediation) with SWB, but did not mediate the relationship between NO-MPE and SWB. The estimates of the quality of the hypothesized model were acceptable (outer model GoF = 0.935; absolute GoF = 0.330; relative GoF = 0.942; inner model GoF = 1.008; R2 = 36.947%). Finally, this study supports the view that MPE can influence SWB through TSC, and incites to pursue the examination of the relationships between self-determined motivation, self-regulation mechanisms, and health-related outcomes. PMID- 27761127 TI - Is there any Influence of Variations in Context on Object-Affordance Effects in Schizophrenia? Perception of Property and Goals of Action. AB - The simple perception of an object can potentiate an associated action. This affordance effect depends heavily on the action context in which the object is presented. In recent years, psychologists, psychiatrists, and phenomenologists have agreed that subjects with schizophrenia may not perceive the affordances of people or objects that could lead to a loss of ease in their actions. We examined whether the addition of contextually congruent elements, during the perception of everyday objects, could promote the emergence of object-affordance effects in subjects with schizophrenia and controls. Participants performed two Stimulus Response-Compatibility tasks in which they were presented with semantic primes related to sense of property (Experiment 1) or goal of action (Experiment 2) prior to viewing each graspable object. Controls responded faster when their response hand and the graspable part of the object were compatibly oriented, but only when the context was congruent with the individual's needs and goals. When the context operated as a constraint, the affordance-effect was disrupted. These results support the understanding that object-affordance is flexible and not just intrinsic to an object. However, the absence of this object-affordance effect in subjects with schizophrenia suggests the possible impairment of their ability to experience the internal simulation of motor action potentialities. In such case, all activities of daily life would require the involvement of higher cognitive processes rather than lower level sensorimotor processes. The study of schizophrenia requires the consideration of concepts and methods that arise from the theories of embodied and situated cognition. PMID- 27761128 TI - Positive Association between Tinnitus and Arterial Hypertension. AB - INTRODUCTION: Tinnitus is the perception of noise in the absence of an external source and is considered by most authors as a multifactorial symptom. A systematic review concerning the association of tinnitus and systemic arterial hypertension retrieved suggestions of a positive association, but the articles included failed to perform a detailed analysis on the theme. PURPOSE: To analyze the presence of arterial hypertension in tinnitus and non-tinnitus patients, to analyze differences between tinnitus impact and psychoacoustic measurements in hypertensive and normotensive patients, and to evaluate the association between the presence of tinnitus and the diverse antihypertensive drugs employed. MATERIALS AND METHODS: This includes cross-sectional transversal study, comparing two groups of subjects (144 in the study group with tinnitus and 140 in the control group without tinnitus). Clinical, demographical, audiometrical, and psychoacoustics characteristics of the subjects were compared. RESULTS: Hypertension prevalence in tinnitus subjects was 44.4% against 31.4% in subjects without tinnitus (p = 0.024). Positive associations with tinnitus were found with hypertension treatment with angiotensin-converting enzyme (ACE) inhibitors (p = 0.006), tiazidic diuretics (p < 0.0001), potassium-sparing diuretics (p = 0.016), and calcium channels blockers (p = 0.004). CONCLUSION: There is an association between tinnitus and arterial hypertension. This association is particularly strong in older patients. Hypertension treatment with diuretics, ACE inhibitors, and calcium channels blockers were more prevalent in tinnitus patients, suggesting that an eventual ototoxicity of these drugs may be involved in tinnitus pathophysiology, a hypothesis that should be evaluated in further studies. PMID- 27761129 TI - Functional, Structural, and Neurotoxicity Biomarkers in Integrative Assessment of Concussions. AB - Concussion is a complex, heterogeneous process affecting the brain. Accurate assessment and diagnosis and appropriate management of concussion are essential to ensure that athletes do not prematurely return to play or others to work or active military duty, risking re-injury. To date, clinical diagnosis relies primarily on evaluating subjects for functional impairment using instruments that include neurocognitive testing, subjective symptom report, and neurobehavioral assessments, such as balance and vestibular-ocular reflex testing. Structural biomarkers, defined as advanced neuroimaging techniques and biomarkers assessing neurotoxicity and immunoexcitotoxicity, may complement the use of functional biomarkers. We hypothesize that neurotoxicity AMPA, NMDA, and kainite receptor biomarkers might be utilized as a part of comprehensive approach to concussion evaluations, with the goal of increasing diagnostic accuracy and facilitating treatment planning and prognostic assessment. PMID- 27761130 TI - Production Strategies and Applications of Microbial Single Cell Oils. AB - Polyunsaturated fatty acids (PUFAs) of the omega-3 and omega-6 class (e.g., alpha linolenic acid, linoleic acid) are essential for maintaining biofunctions in mammalians like humans. Due to the fact that humans cannot synthesize these essential fatty acids, they must be taken up from different food sources. Classical sources for these fatty acids are porcine liver and fish oil. However, microbial lipids or single cell oils, produced by oleaginous microorganisms such as algae, fungi and bacteria, are a promising source as well. These single cell oils can be used for many valuable chemicals with applications not only for nutrition but also for fuels and are therefore an ideal basis for a bio-based economy. A crucial point for the establishment of microbial lipids utilization is the cost-effective production and purification of fuels or products of higher value. The fermentative production can be realized by submerged (SmF) or solid state fermentation (SSF). The yield and the composition of the obtained microbial lipids depend on the type of fermentation and the particular conditions (e.g., medium, pH-value, temperature, aeration, nitrogen source). From an economical point of view, waste or by-product streams can be used as cheap and renewable carbon and nitrogen sources. In general, downstream processing costs are one of the major obstacles to be solved for full economic efficiency of microbial lipids. For the extraction of lipids from microbial biomass cell disruption is most important, because efficiency of cell disruption directly influences subsequent downstream operations and overall extraction efficiencies. A multitude of cell disruption and lipid extraction methods are available, conventional as well as newly emerging methods, which will be described and discussed in terms of large scale applicability, their potential in a modern biorefinery and their influence on product quality. Furthermore, an overview is given about applications of microbial lipids or derived fatty acids with emphasis on food applications. PMID- 27761131 TI - Genome Sequencing and Comparative Genomics Analysis Revealed Pathogenic Potential in Penicillium capsulatum as a Novel Fungal Pathogen Belonging to Eurotiales. AB - Penicillium capsulatum is a rare Penicillium species used in paper manufacturing, but recently it has been reported to cause invasive infection. To research the pathogenicity of the clinical Penicillium strain, we sequenced the genomes and transcriptomes of the clinical and environmental strains of P. capsulatum. Comparative analyses of these two P. capsulatum strains and close related strains belonging to Eurotiales were performed. The assembled genome sizes of P. capsulatum are approximately 34.4 Mbp in length and encode 11,080 predicted genes. The different isolates of P. capsulatum are highly similar, with the exception of several unique genes, INDELs or SNPs in the genes coding for glycosyl hydrolases, amino acid transporters and circumsporozoite protein. A phylogenomic analysis was performed based on the whole genome data of 38 strains belonging to Eurotiales. By comparing the whole genome sequences and the virulence-related genes from 20 important related species, including fungal pathogens and non-human pathogens belonging to Eurotiales, we found meaningful pathogenicity characteristics between P. capsulatum and its closely related species. Our research indicated that P. capsulatum may be a neglected opportunistic pathogen. This study is beneficial for mycologists, geneticists and epidemiologists to achieve a deeper understanding of the genetic basis of the role of P. capsulatum as a newly reported fungal pathogen. PMID- 27761133 TI - The Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles. AB - Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress. Deletion of any of them resulted in hypersensitivity to azoles and heat. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that the toxic sterols eburicol and 14alpha-methyl-3,6-diol were significantly accumulated in the sti1 and p23 deletion mutants after ketoconazole treatment, which has been shown before to led to cell membrane stress. At the transcriptional level, Aha1, Sti1, and P23 positively regulate responses to ketoconazole stress by erg11 and erg6, key genes in the ergosterol biosynthetic pathway. Aha1, Sti1, and P23 are highly conserved in fungi, and sti1 and p23 deletion also increased the susceptibility to azoles in Fusarium verticillioides. These results indicate that Hsp90-cochaperones Aha1, Sti1, and P23 are critical for the basal azole resistance and could be potential targets for developing new antifungal agents. PMID- 27761132 TI - Diversification of Gene Expression during Formation of Static Submerged Biofilms by Escherichia coli. AB - Many bacteria primarily exist in nature as structured multicellular communities, so called biofilms. Biofilm formation is a highly regulated process that includes the transition from the motile planktonic to sessile biofilm lifestyle. Cellular differentiation within a biofilm is a commonly accepted concept but it remains largely unclear when, where and how exactly such differentiation arises. Here we used fluorescent transcriptional reporters to quantitatively analyze spatio temporal expression patterns of several groups of genes during the formation of submerged Escherichia coli biofilms in an open static system. We first confirm that formation of such submerged biofilms as well as pellicles at the liquid-air interface requires the major matrix component, curli, and flagella-mediated motility. We further demonstrate that in this system, diversification of gene expression leads to emergence of at least three distinct subpopulations of E. coli, which differ in their levels of curli and flagella expression, and in the activity of the stationary phase sigma factor sigmaS. Our study reveals mutually exclusive expression of curli fibers and flagella at the single cell level, with high curli levels being confined to dense cell aggregates/microcolonies and flagella expression showing an opposite expression pattern. Interestingly, despite the known sigmaS-dependence of curli induction, there was only a partial correlation between the sigmaS activity and curli expression, with subpopulations of cells having high sigmaS activity but low curli expression and vice versa. Finally, consistent with different physiology of the observed subpopulations, we show striking differences between the growth rates of cells within and outside of aggregates. PMID- 27761134 TI - Microbial Sulfate Reduction Potential in Coal-Bearing Sediments Down to ~2.5 km below the Seafloor off Shimokita Peninsula, Japan. AB - Sulfate reduction is the predominant anaerobic microbial process of organic matter mineralization in marine sediments, with recent studies revealing that sulfate reduction not only occurs in sulfate-rich sediments, but even extends to deeper, methanogenic sediments at very low background concentrations of sulfate. Using samples retrieved off the Shimokita Peninsula, Japan, during the Integrated Ocean Drilling Program (IODP) Expedition 337, we measured potential sulfate reduction rates by slurry incubations with 35S-labeled sulfate in deep methanogenic sediments between 1276.75 and 2456.75 meters below the seafloor. Potential sulfate reduction rates were generally extremely low (mostly below 0.1 pmol cm-3 d-1) but showed elevated values (up to 1.8 pmol cm-3 d-1) in a coal bearing interval (Unit III). A measured increase in hydrogenase activity in the coal-bearing horizons coincided with this local increase in potential sulfate reduction rates. This paired enzymatic response suggests that hydrogen is a potentially important electron donor for sulfate reduction in the deep coalbed biosphere. By contrast, no stimulation of sulfate reduction rates was observed in treatments where methane was added as an electron donor. In the deep coalbeds, small amounts of sulfate might be provided by a cryptic sulfur cycle. The isotopically very heavy pyrites (delta34S = +430/00) found in this horizon is consistent with its formation via microbial sulfate reduction that has been continuously utilizing a small, increasingly 34S-enriched sulfate reservoir over geologic time scales. Although our results do not represent in-situ activity, and the sulfate reducers might only have persisted in a dormant, spore-like state, our findings show that organisms capable of sulfate reduction have survived in deep methanogenic sediments over more than 20 Ma. This highlights the ability of sulfate-reducers to persist over geological timespans even in sulfate-depleted environments. Our study moreover represents the deepest evidence of a potential for sulfate reduction in marine sediments to date. PMID- 27761135 TI - The Influence of Genotype and Environment on Small RNA Profiles in Grapevine Berry. AB - Understanding the molecular mechanisms involved in the interaction between the genetic composition and the environment is crucial for modern viticulture. We approached this issue by focusing on the small RNA transcriptome in grapevine berries of the two varieties Cabernet Sauvignon and Sangiovese, growing in adjacent vineyards in three different environments. Four different developmental stages were studied and a total of 48 libraries of small RNAs were produced and sequenced. Using a proximity-based pipeline, we determined the general landscape of small RNAs accumulation in grapevine berries. We also investigated the presence of known and novel miRNAs and analyzed their accumulation profile. The results showed that the distribution of small RNA-producing loci is variable between the two cultivars, and that the level of variation depends on the vineyard. Differently, the profile of miRNA accumulation mainly depends on the developmental stage. The vineyard in Riccione maximizes the differences between the varieties, promoting the production of more than 1000 specific small RNA loci and modulating their expression depending on the cultivar and the maturation stage. In total, 89 known vvi-miRNAs and 33 novel vvi-miRNA candidates were identified in our samples, many of them showing the accumulation profile modulated by at least one of the factors studied. The in silico prediction of miRNA targets suggests their involvement in berry development and in secondary metabolites accumulation such as anthocyanins and polyphenols. PMID- 27761136 TI - Exogenous Melatonin Suppresses Dark-Induced Leaf Senescence by Activating the Superoxide Dismutase-Catalase Antioxidant Pathway and Down-Regulating Chlorophyll Degradation in Excised Leaves of Perennial Ryegrass (Lolium perenne L.). AB - Leaf senescence is a typical symptom in plants exposed to dark and may be regulated by plant growth regulators. The objective of this study was to determine whether exogenous application of melatonin (N-acetyl-5 methoxytryptamine) suppresses dark-induced leaf senescence and the effects of melatonin on reactive oxygen species (ROS) scavenging system and chlorophyll degradation pathway in perennial grass species. Mature perennial ryegrass (Lolium perenne L. cv. 'Pinnacle') leaves were excised and incubated in 3 mM 2-(N morpholino) ethanesulfonic buffer (pH 5.8) supplemented with melatonin or water (control) and exposed to dark treatment for 8 days. Leaves treated with melatonin maintained significantly higher endogenous melatonin level, chlorophyll content, photochemical efficiency, and cell membrane stability expressed by lower electrolyte leakage and malondialdehyde (MDA) content compared to the control. Exogenous melatonin treatment also reduced the transcript level of chlorophyll degradation-associated genes and senescence marker genes (LpSAG12.1, Lph36, and Lpl69) during the dark treatment. The endogenous O2- production rate and H2O2 content were significantly lower in these excised leaves treated with melatonin compared to the water control. Exogenous melatonin treatment caused increases in enzymatic activity and transcript levels of superoxide dismutase and catalase but had no significant effects on ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, and monohydroascorbate reductase. The content of non enzymatic antioxidants, such as ascorbate and dehydroascorbate, were decreased by melatonin treatment, while the content of glutathione and oxidized glutathione was not affected by melatonin. These results suggest that the suppression of dark induced leaf senescence by exogenous melatonin may be associated with its roles in regulating ROS scavenging through activating the superoxide dismutase-catalase enzymatic antioxidant pathway and down-regulating chlorophyll degradation in perennial ryegrass. PMID- 27761137 TI - Selection of Reliable Reference Genes for Gene Expression Analysis under Abiotic Stresses in the Desert Biomass Willow, Salix psammophila. AB - Salix psammophila is a desert shrub willow that has extraordinary adaptation to abiotic stresses and plays an important role in maintaining local ecosystems. Moreover, S. psammophila is regarded as a promising biomass feedstock because of its high biomass yields and short rotation coppice cycle. However, few suitable reference genes (RGs) for quantitative real-time polymerase chain reaction (qRT PCR) constrain the study on normalization of gene expression in S. psammophila until now. Here, we investigated the expression stabilities of 14 candidate RGs across tissue types and under four abiotic stress treatments, including heat, cold, salt, and drought treatments. After calculation of PCR efficiencies, three different software, NormFinder, geNorm, and BestKeeper were employed to analyze systematically the qRT-PCR data, and the outputs were merged by RankAggreg software. The optimal RGs selected for gene expression analysis were EF1alpha (Elongation factor-1 alpha) and OTU (OTU-like cysteine protease family protein) for different tissue types, UBC (Ubiquitin-conjugating enzyme E2) and LTA4H (Leukotriene A-4 hydrolase homolog) for heat treatment, HIS (Histone superfamily protein H3) and ARF2 (ADP-ribosylation factor 2) for cold treatment, OTU and ACT7 (Actin 7) for salt treatment, UBC and LTA4H for drought treatment. The expression of UBC, ARF2, and VHAC (V-type proton ATPase subunit C) varied the least across tissue types and under abiotic stresses. Furthermore, the relative genes expression profiles of one tissue-specific gene WOX1a (WUSCHEL-related homeobox 1a), and four stress-inducible genes, including Hsf-A2 (Heat shock transcription factors A2), CBF3 (C-repeat binding factor 3), HKT1 (High-Affinity K+ Transporter 1), and GST (Glutathione S-transferase), were conducted to confirm the validity of the RGs in this study. These results provided an important RGs application guideline for gene expression characterization in S. psammophila. PMID- 27761139 TI - Recent Advances in Brain Signal Analysis: Methods and Applications. PMID- 27761140 TI - Advances in Eye Tracking Technology: Theory, Algorithms, and Applications. PMID- 27761138 TI - Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains. AB - A central challenge in pharmaceutical research is to investigate genetic variation in response to drugs. The Collaborative Cross (CC) mouse reference population is a promising model for pharmacogenomic studies because of its large amount of genetic variation, genetic reproducibility, and dense recombination sites. While the CC lines are phenotypically diverse, their genetic diversity in drug disposition processes, such as detoxification reactions, is still largely uncharacterized. Here we systematically measured RNA-sequencing expression profiles from livers of 29 CC lines under baseline conditions. We then leveraged a reference collection of metabolic biotransformation pathways to map potential relations between drugs and their underlying expression quantitative trait loci (eQTLs). By applying this approach on proximal eQTLs, including eQTLs acting on the overall expression of genes and on the expression of particular transcript isoforms, we were able to construct the organization of hepatic eQTL-drug connectivity across the CC population. The analysis revealed a substantial impact of genetic variation acting on drug biotransformation, allowed mapping of potential joint genetic effects in the context of individual drugs, and demonstrated crosstalk between drug metabolism and lipid metabolism. Our findings provide a resource for investigating drug disposition in the CC strains, and offer a new paradigm for integrating biotransformation reactions to corresponding variations in DNA sequences. PMID- 27761142 TI - Pulmonary Hilar Tumor: An Unusual Presentation of Sclerosing Hemangioma. AB - Pulmonary sclerosing hemangioma is an uncommon benign tumor of the lung; however, on rare occasions it can arise from the pulmonary hilar region. Herein, we report a 53-year-old female patient who presented with a round opacity in the right upper lung field on a radiograph. Chest computed tomography scanning revealed a 3.1 cm mass in the right pulmonary hilum. Thoracoscopic tumor excision was subsequently performed. On pathohistologic study, the tumor was well defined and composed of round stromal cells and surface cells arranged in a papillary, sclerotic, solid, and hemorrhagic pattern. In immunochemical study, the round cells were positive for thyroid transcription factor-1 (TTF-1) and epithelial membrane antigen (EMA) and negative for cytokeratin. The surface cells were positive for TTF-1, EMA, and cytokeratin. Therefore, a final diagnosis of sclerosing hemangioma was confirmed. In conclusion, pulmonary sclerosing hemangioma is uncommon and rare in the pulmonary hilar region. CT scanning is useful to determine its benignity, although imaging features are not specific for a definite differential diagnosis from other pulmonary tumors. Therefore, tissue diagnosis is usually necessary, and pulmonary sclerosing hemangioma should be listed in the differential diagnoses of pulmonary hilar tumors. PMID- 27761141 TI - Knowledge, Attitudes, and Practices Related to Preoperative Chemoradiotherapy in Rectal Cancer Patients. AB - Background. The aim of this study is to assess the knowledge, attitudes, and practices related to pre-CRT in patients of stage II/III rectal cancer. Materials and Methods. Questionnaires regarding the knowledge, attitudes, and practices of pre-CRT were mailed to 145 rectal cancer patients in II/III stage between January 2012 and December 2014, and 111 agreed to participate and returned completed questionnaires to the researcher. Logistic regression model was used to compare sociodemographic characteristics, knowledge, and attitude with practice, respectively. Results. A total of 145 patients were approached for interview, of which 111 responded and 48.6% (54) had undergone pre-CRT. Only 31.5% of the participants knew that CRT is a treatment of rectal cancer and 39.6% were aware of the importance of CRT. However, the vast majority of participants (68.5%) expressed a positive attitude toward rectal cancer. Multivariate logistic regression analysis revealed that knowledge level (p = 0.006) and attitudes (p = 0.001) influence the actual practice significantly. Furthermore, age, gender, and income were potential predictors of practice (all p < 0.05). Conclusion. This study shows that, despite the fact that participants had suboptimal level of knowledge on rectal cancer, their attitude is favorable to pre-CRT. Strengthening the professional health knowledge and realizing the importance of attitudes may deepen patients' understanding of preoperative therapy. PMID- 27761143 TI - Altered Concentrations of Copper, Zinc, and Iron are Associated With Increased Levels of Glycated Hemoglobin in Patients With Type 2 Diabetes Mellitus and Their First-Degree Relatives. AB - BACKGROUND: The altered levels of some essential trace elements and antioxidant minerals have been observed in diabetic patients. OBJECTIVES: The aim of the present study was to compare the concentrations of essential trace elements, copper (Cu), zinc (Zn), and iron (Fe) in the serum of patients who have type 2 diabetes mellitus (T2DM) with those of their non-diabetic first-degree relatives (FDR) and control subjects. The association between glycated hemoglobin (HbA1c) and levels of metals was also evaluated. PATIENTS AND METHODS: We studied 46 subjects with T2DM, 46 FDR, and 50 control subjects matched for age and sex. Serum concentrations of Cu, Zn, and Fe were measured by colorimetric kit. Fasting blood glucose (FBG) and HbA1c were assayed using the standard kit. RESULTS: An imbalance in the levels of the studied metals was observed in both patients with T2DM and FDR. We found significantly decreased levels of Zn and higher levels of Cu and Fe in the patients with T2DM and FDR when compared with the control subjects (P < 0.05). HbA1c levels were positively correlated with Cu and Fe and inversely correlated with Zn in the patients with T2DM and FDR (P < 0.05). CONCLUSIONS: The patients with T2DM and FDR had altered contents of Cu, Zn, and Fe that might be a predisposing factor to the development of diabetes in future or vice versa the result of diabetes development. Impaired metabolism of these elements may contribute to the augmented risk of developing type 2 diabetes mellitus later in the life of their first-degree relatives. PMID- 27761144 TI - Obesity Paradox and Recurrent Coronary Heart Disease in a Population-Based Study: Tehran Lipid and Glucose Study. AB - BACKGROUND: Although current data shows a positive association between obesity and development of coronary heart disease (CHD) in general population, there is limited data on the important protective role of central or general obesity in patients with prevalent CHD or the "obesity paradox", from this region. OBJECTIVES: The objective of the present investigation was to describe the relationship between BMI categories and the recurrence of CHD in patients with a history of CHD using data from a large population-based study, the Tehran lipid and glucose study (TLGS). PATIENTS AND METHODS: The study was conducted on 440 adults, aged >= 30 years, with a history of CHD at baseline who attended the first (1999 - 2001) or second (2001 - 2003) phases of the Tehran Lipid and Glucose Study and had at least one year of follow-up until March 31, 2010. Cox proportional hazard models were used to evaluate the association among various BMI groups and recurrent CHD incidence. RESULTS: During a median follow-up of 8.44 years, 169 new cases of CHD occurred (incidence density of: 54.53 per 1000 person-years). The incidence of recurrent CHD was higher in the normal BMI compared with overweight and obese categories (68.71, 47.56 and 54.46 per 1000 person-years, respectively). In multivariable models, using the forward stepwise selection approach, compared to the overweight group (0.48 95% CI, 0.30-0.80), the obese group (0.55 95% CI, 0.28-1.06) lost its significant protective effect. CONCLUSIONS: Results of this study demonstrated an apparently protective effect for overweight in comparison with normal weight against long-term recurrent CHD in patients with history of CHD. PMID- 27761145 TI - Neuroprotective Effects of the Herbal Formula B401 in Both Cell and Mouse Models of Alzheimer's Disease. AB - In this study, we have reported the herbal formula B401 that has neuroprotective effects via multifunction, multitarget characteristics. It is possible that the herbal formula B401 may also provide new insights for AD. Here, we studied protective effects in the Tet-On Abeta42-GFP SH-SY5Y cell model and the APP/PS1/Tau triple transgenic mouse model by the herbal formula B401. In in vitro experiments, we showed that the herbal formula B401 treatment effectively reduces glutamate-induced excitotoxicity and acetylcholinesterase activity in Tet-On Abeta42-GFP SH-SY5Y cells. In in vivo experiments, we found that oral B401 treatment effectively ameliorates neurocognitive dysfunctions of 3* Tg-AD mice via motor and cognitive behavior tests. By using magnetic resonance imaging, moorFLPI instruments, and chemiluminescence methods, we reported that oral B401 treatment effectively alleviates brain atrophy, improves subcutaneous blood flow, and reduces blood ROS in 3* Tg-AD mice. As observed from results of immunohistochemistry staining and western blotting, we found that oral B401 treatment significantly enhances expressions of neuroprotective proteins, while reducing expressions of AD derived proteins such as amyloid beta, phosphorylated Tau, neurofibrillary tangles, and 3-nitrotyrosine in the brain of 3* Tg-AD mice. Thus, the herbal formula B401 may have the potential to be developed into optimum TCM for AD patients. PMID- 27761147 TI - The Rhizome Mixture of Anemarrhena asphodeloides and Coptis chinensis Attenuates Mesalazine-Resistant Colitis in Mice. AB - We investigated the effect of DWac on the gut microbiota composition in mice with 2,3,6-trinitrobenzenesulfonic acid- (TNBS-) induced colitis. Treatment with DWac restored TNBS-disturbed gut microbiota composition and attenuated TNBS-induced colitis. Moreover, we examined the effect of DWac in mice with mesalazine resistant colitis (MRC). Intrarectal injection of TNBS in MRC mice caused severe colitis, as well as colon shortening, edema, and increased myeloperoxidase activity. Treatment with mesalazine (30 mg/kg) did not attenuate TNBS-induced colitis in MRC mice, whereas treatment with DWac (30 mg/kg) significantly attenuated TNBS-induced colitis. Moreover, treatment with the mixture of mesalazine (15 mg/kg) and DWac (15 mg/kg) additively attenuated colitis in MRC mice. Treatment with DWac and its mixture with mesalazine inhibited TNBS-induced activation of NF-kappaB and expression of M1 macrophage markers but increased TNBS-suppressed expression of M2 macrophage markers. Furthermore, these inhibited TNBS-induced T-bet, RORgammat, TNF-alpha, and IL-17 expression but increased TNBS suppressed Foxp3 and IL-10 expression. However, Th2 cell differentiation and GATA3 and IL-5 expression were not affected. These findings suggest that DWac can ameliorate MRC by increasing the polarization of M2 macrophage and correcting the disturbance of gut microbiota and Th1/Th17/Treg, as well as additively attenuating MRC along with mesalazine. PMID- 27761148 TI - Oncocytic variant of poorly differentiated thyroid carcinoma: "Is diagnosis possible by fine-needle aspiration?" AB - Poorly differentiated thyroid carcinoma (PDTC) is a very rare entity, and the diagnosis can be made on histopathology specimens. However, recognition of characteristic features of PDTC is significant on fine-needle aspirations (FNAs) to differentiate this entity from well-differentiated and anaplastic thyroid carcinomas. Here, we present an FNA case concordant with "oncocytic variant of PDTC" and discuss whether definitive diagnosis can be given on FNAs to assess the prognosis in clinically inoperable patients. PMID- 27761146 TI - The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo and In Vitro. AB - Nobiletin (NOB) chemically known as 5,6,7,8,3',4'-hexamethoxyflavone is a dietary polymethoxylated flavonoid found in Citrus fruits. Recent evidences show that NOB is a multifunctional pharmaceutical agent. The various pharmacological activities of NOB include neuroprotection, cardiovascular protection, antimetabolic disorder, anticancer, anti-inflammation, and antioxidation. These events may be underpinned by modulation of signaling cascades, including PKA/ERK/MEK/CREB, NF kappaB, MAPK, Ca2+/CaMKII, PI3K/Akt1/2, HIF-1alpha, and TGFbeta signaling pathways. The metabolites may exhibit stronger beneficial effects than NOB on diseases pathogenesis. The biological activities of NOB have been clarified on many systems. This review aims to discuss the pharmacological effects of NOB with specific mechanisms of actions. NOB may become a promising candidate for potential drug development. However, further investigations of NOB on specific intracellular targets and clinical trials are still needed, especially for in vivo medical applications. PMID- 27761149 TI - Endoscopic ultrasound-guided fine needle aspiration cytology of metastatic renal cell carcinoma to the pancreas: A multi-center experience. AB - INTRODUCTION: The increasing use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology to examine pancreatic neoplasms has led to an increase in the diagnosis of metastases to the pancreas. Renal cell carcinoma (RCC) is the most common metastasis to the pancreas. Our study examines 33 cases of metastatic RCC to the pancreas sampled by EUS-FNA from four large tertiary care hospitals. MATERIALS AND METHODS: We searched the cytopathology database for RCC metastatic to the pancreas diagnosed by EUS-FNA from January 2005 to January 2015. Patient age, history of RCC, nephrectomy history, follow-up postnephrectomy, radiological impression, and EUS-FNA cytologic diagnosis were reviewed. RESULTS: Thirty-three patients were identified. The average age was 67.5 years (range, 49-84 years). Thirty-two patients had a previous documented history of RCC. One patient had the diagnosis of pancreatic metastasis at the same time of the kidney biopsy. Thirty-one patients had been treated with nephrectomy. Twenty-seven patients were being monitored annually by computed tomography or magnetic resonance imaging. Twenty-five patients had multiple masses by imaging, but 8 patients had a single mass in the pancreas at the time of EUS-FNA. EUS-FNA of 20 cases showed classic morphology of RCC. Thirteen cases had either "atypical" clinical-radiologic features or morphologic overlaps with primary pancreatic neoplasms or other neoplasms. Cell blocks were made on all 13 cases and immunochemical stains confirmed the diagnosis. CONCLUSIONS: EUS-FNA cytology is useful for the diagnosis of metastatic RCC to the pancreas. Cytomorphology can be aided with patient history, imaging analyses, cell blocks, and immunochemical stains. PMID- 27761150 TI - Erratum: CytoJournal Quiz Cases: Publishing open access, PubMed searchable cytopathology cases with educational messages. AB - [This corrects the article on p. 15 in vol. 13, PMID: 27563338.]. PMID- 27761151 TI - Erratum to: The loop-less tmCdc34 E2 mutant defective polyubiquitination in vitro and in vivo supports yeast growth in a manner dependent on Ubp14 and Cka2. AB - [This corrects the article DOI: 10.1186/1747-1028-6-7.]. PMID- 27761152 TI - Improvement of free fatty acid production using a mutant acyl-CoA thioesterase I with high specific activity in Escherichia coli. AB - BACKGROUND: Microbial production of oleochemicals has been actively studied in the last decade. Free fatty acids (FFAs) could be converted into a variety of molecules such as industrial products, consumer products, and fuels. FFAs have been produced in metabolically engineered Escherichia coli cells expressing a signal sequence-deficient acyl-CoA thioesterase I ('TesA). Nonetheless, increasing the expression level of 'TesA seems not to be an appropriate approach to scale up FFA production because a certain ratio of each component including fatty acid synthase and 'TesA is required for optimal production of FFAs. Thus, the catalytic activity of 'TesA should be rationally engineered instead of merely increasing the enzyme expression level to enhance the production of FFAs. RESULTS: In this study, we constructed a sensing system with a fusion protein of tetracycline resistance protein and red fluorescent protein (RFP) under the control of a FadR-responsive promoter to select the desired mutants. Fatty acid dependent growth and RFP expression allowed for selection of FFA-overproducing cells. A 'TesA mutant that produces a twofold greater amount of FFAs was isolated from an error-prone PCR mutant library of E. coli 'TesA. Its kinetic analysis revealed that substitution of Arg64 with Cys64 in the enzyme causes an approximately twofold increase in catalytic activity. CONCLUSIONS: Because the expression of 'TesA in E. coli for the production of oleochemicals is almost an indispensable process, the proposed engineering approach has a potential to enhance the production of oleochemicals. The use of the catalytically active mutant 'TesAR64C should accelerate the manufacture of FFA-derived chemicals and fuels. PMID- 27761153 TI - Involvement of Fenton chemistry in rice straw degradation by the lignocellulolytic bacterium Pantoea ananatis Sd-1. AB - BACKGROUND: Lignocellulolytic bacteria have revealed to be a promising source for biofuel production, yet the underlying mechanisms are still worth exploring. Our previous study inferred that the highly efficient lignocellulose degradation by bacterium Pantoea ananatis Sd-1 might involve Fenton chemistry (Fe2+ + H2O2 + H+ > Fe3+ + OH. + H2O), similar to that of white-rot and brown-rot fungi. The aim of this work is to investigate the existence of this Fenton-based oxidation mechanism in the rice straw degradation process of P. ananatis Sd-1. RESULTS: After 3 days incubation of unpretreated rice straw with P. ananatis Sd-1, the percentage in weight reduction of rice straw as well as its cellulose, hemicellulose, and lignin components reached 46.7, 43.1, 42.9, and 37.9 %, respectively. The addition of different hydroxyl radical scavengers resulted in a significant decline (P < 0.001) in rice straw degradation. Pyrolysis gas chromatography-mass spectrometry and Fourier transform infrared spectroscopy analysis revealed the consistency of chemical changes of rice straw components that exists between P. ananatis Sd-1 and Fenton reagent treatment. In addition to the increased total iron ion concentration throughout the rice straw decomposition process, the Fe3+-reducing capacity of P. ananatis Sd-1 was induced by rice straw and predominantly contributed by aromatic compounds metabolites. The transcript levels of the glucose-methanol-choline oxidoreductase gene related to hydrogen peroxide production were significantly up-regulated (at least P < 0.01) in rice straw cultures. Higher activities of GMC oxidoreductase and less hydrogen peroxide concentration in rice straw cultures relative to glucose cultures may be responsible for increasing rice straw degradation, which includes Fenton-like reactions. CONCLUSIONS: Our results confirmed the Fenton chemistry assisted degradation model in P. ananatis Sd-1. We are among the first to show that a Fenton-based oxidation mechanism exists in a bacteria degradation system, which provides a new perspective for how natural plant biomass is decomposed by bacteria. This degradative system may offer an alternative approach to the fungi system for lignocellulosic biofuels production. PMID- 27761154 TI - Molecular genetics have opened a new era for arrhythmia research, but also Pandora's box? PMID- 27761156 TI - Left cardiac sympathetic denervation: An important treatment option for patients with hereditary ventricular arrhythmias. AB - Medications such as beta-blockers are currently the primary treatment for patients with hereditary arrhythmia syndromes such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, these drugs are ineffective in some patients, and the other treatment option, that is implantable cardioverter defibrillator (ICD) implantation, is associated with significant complications in young and active patients. Left cardiac sympathetic denervation (LCSD) may reduce the wide gap between life-long beta-blocker medication and ICD implantation. Although LCSD is highly effective in prevention of cardiac events in patients with LQTS and CPVT, it is rarely used. The recently introduced procedure video-assisted thoracoscopic LCSD is associated with short hospital stays and low morbidity. Thus, LCSD is an important therapeutic option for patients with LQTS and CPVT. PMID- 27761157 TI - Current topics in catecholaminergic polymorphic ventricular tachycardia. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is induced by emotions or exercise in patients without organic heart disease and may be polymorphic or bidirectional in nature. The prognosis of CPVT is not good, and therefore prevention of sudden death is of utmost importance. Genetic variants of CPVT include RyR2, CASQ2, CALM2, TRD, and possibly KCNJ2 and ANK2 gene mutations. Hypotheses that suggest the causes of CPVT include weakened binding of FKBP12.6 and RyR2, a store overload-induced Ca2+ release (SOICR), unzipping of intramolecular domain interactions in RyR2, and molecular and functional abnormalities caused by mutations in the CASQ2 gene. The incidence of an RyR2 anomaly in CPVTs is about 35-79%, whereas anomalies in the CASQ2 gene account for 3-5% CPVTs. The ping-pong theory, suggesting that reciprocating delayed after depolarization induces bigeminy of the right and left bundle branches, may explain the pathogenesis of bidirectional ventricular tachycardia. Flecainide, carvedilol, left sympathetic nerve denervation, and catheter ablation of the PVC may serve as new therapeutic strategies for CPVT while gene-therapy may be applied to some types of CPVT in the future. Although, not all sudden cardiac deaths in CPVT patients are currently preventable, new medical and interventional therapies may improve CPVT prognosis. PMID- 27761158 TI - Inherited bradyarrhythmia: A diverse genetic background. AB - Bradyarrhythmia is a common heart rhythm abnormality comprising number of diseases and is associated with decreased heart rate due to the failure of action potential generation and propagation at the sinus node. Permanent pacemaker implantation is often used therapeutically to compensate for decreased heart rate and cardiac output. The vast majority of bradyarrhythmia cases are attributable either to aging or to structural abnormalities of the cardiac conduction system, caused by underlying structural heart disease. However, there is a subset of bradyarrhythmia primarily caused by genetic defects in the absence of aging or underlying structural heart disease. These include several genes that play principal roles in cardiac electrophysiology, heart development, cardioprotection, and the structural integrity of the membrane and sarcomere. Recent advances in the functional analysis of mutations using a heterologous expression system and genetically engineered animal models have provided significant insights into the underlying molecular mechanisms responsible for inherited arrhythmia. In this review, current understandings of the genetic and molecular basis of inherited bradyarrhythmia are presented. PMID- 27761159 TI - Molecular autopsy in victims of inherited arrhythmias. AB - Sudden cardiac death (SCD) is a rare but devastating complication of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM). In up to 40% of young SCD victims (defined as 1-40 years old, excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS), no cause of death is identified at postmortem [so-called "autopsy negative" or "sudden arrhythmic death syndrome" (SADS)]. Management of families following a SCD includes the identification of the cause of death, based either on premorbid clinical details or the pathological findings at the postmortem. When no cause of death is identified, genetic testing of DNA extracted from postmortem tissue (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Targeted clinical testing in a specialized multidisciplinary clinic in surviving family members combined with the results from genetic testing, provide the optimal setting for the identification of relatives who may be at risk of having the same inherited heart disease and are therefore also predisposed to an increased risk of SCD. PMID- 27761160 TI - Atrial arrhythmias in inherited arrhythmogenic disorders. AB - Atrial arrhythmias are being increasingly recognized in inherited arrhythmogenic disorders particularly in patients with Brugada syndrome and short QT syndrome. Atrial arrhythmias in inherited arrhythmogenic disorders have significant epidemiologic, clinical, and prognostic implications. There has been progress in the understanding of underlying genetic characteristics and the mechanistic link between atrial arrhythmias and inherited arrhythmogenic disorders. Appropriate management of these patients is of paramount importance. PMID- 27761161 TI - Molecular pathogenesis of long QT syndrome type 2. AB - The molecular mechanisms underlying congenital long QT syndrome (LQTS) are now beginning to be understood. New insights into the etiology and therapeutic strategies are emerging from heterologous expression studies of LQTS-linked mutant proteins, as well as inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from LQTS patients. This review focuses on the major molecular mechanism that underlies LQTS type 2 (LQT2). LQT2 is caused by loss of function (LOF) mutations in KCNH2 (also known as the human Ether-a-go-go-Related Gene or hERG). Most LQT2-linked mutations are missense mutations and functional studies suggest that ~90% of them disrupt the intracellular transport (trafficking) of KCNH2-encoded Kv11.1 proteins to the cell membrane. Trafficking deficient LQT2 mutations disrupt Kv11.1 protein folding and misfolded Kv11.1 proteins are retained in the endoplasmic reticulum (ER) until they are degraded in the ER associated degradation pathway (ERAD). This review focuses on the quality control mechanisms in the ER that contribute to the folding and ERAD of Kv11.1 proteins; the mechanism for ER export of Kv11.1 proteins in the secretory pathway; different subclasses of trafficking deficient LQT2 mutations; and strategies being developed to mitigate or correct trafficking deficient LQT2 related phenotypes. PMID- 27761162 TI - Molecular pathogenesis of long QT syndrome type 1. AB - Long QT syndrome type 1 (LQT1) is a subtype of a congenital cardiac syndrome caused by mutation in the KCNQ1 gene, which encodes the alpha-subunit of the slow component of delayed rectifier K+ current (IKs) channel. Arrhythmias in LQT1 are characterized by prolongation of the QT interval on ECG, as well as the occurrence of life-threatening cardiac events, frequently triggered by adrenergic stimuli (e.g., physical or emotional stress). During the past two decades, much advancement has been made in understanding the molecular pathogenesis underlying LQT1. Uncovering the genotype-phenotype correlations in LQT1 is of clinical importance to better understand the gene-specific differences that may influence the propensity for developing life-threatening arrhythmias under specific conditions. Elucidation of these mechanisms will also help to improve the diagnosis and management of this cardiac disorder based on gene-specific considerations. This review describes the current medical consensus and recent developments regarding the molecular pathogenesis of LQT1 and provides a novel insight into the adrenergic regulation of this disease. PMID- 27761163 TI - Recent advances in genetic testing and counseling for inherited arrhythmias. AB - Inherited arrhythmias, such as cardiomyopathies and cardiac ion channelopathies, along with coronary heart disease (CHD) are three most common disorders that predispose adults to sudden cardiac death. In the last three decades, causal genes in inherited arrhythmias have been successfully identified. At the same time, it has become evident that the genetic architectures are more complex than previously known. Recent advancements in DNA sequencing technology (next generation sequencing) have enabled us to study such complex genetic traits. This article discusses indications for genetic testing of patients with inherited arrhythmias. Further, it describes the benefits and challenges that we face in the era of next generation sequencing. Finally, it briefly discusses genetic counseling, in which a multidisciplinary approach is required due to the increased complexity of the genetic information related to inherited arrhythmias. PMID- 27761164 TI - The genetic background of arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by degeneration of the right ventricle and ventricular tachycardia originating from the right ventricle. Additionally, the disease is an inherited cardiomyopathy that mainly follows the autosomal dominant pattern. More than 10 genes have been reported as causative genes for ARVC, and more than half of ARVC patients carry mutations in desmosome related genes. The desmosome is one of the structures involved in cell adhesion and its disruption leads to various diseases, including a skin disease called pemphigus. Among desmosome genes, mutations in PKP2 are most frequently identified in ARVC patients. Although the genotype-phenotype correlations remain to be fully studied, many studies have reported clinical manifestations of, prognosis for, and appropriate therapies for ARVC from the perspective of gene mutations. A collective review of these reports would enhance the understanding of ARVC pathogenesis and clinical manifestation. This review discusses the clinical issues of ARVC from the genetic background. PMID- 27761155 TI - J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. PMID- 27761165 TI - Catheter ablation for ventricular tachyarrhythmia in patients with channelopathies. AB - Drug treatment and/or implantable cardioverter defibrillator (ICD) implantation are the most widely accepted first-line therapies for channelopathic patients who have recurrent syncope, sustained ventricular tachycardia (VT), or documented ventricular fibrillation (VF), or are survivors of cardiac arrest. In recent years, there have been significant advances in mapping techniques and ablation technology, coupled with better understanding of the mechanisms of ventricular tachyarrhythmia in channelopathies. Catheter ablation has provided important insights into the role of the Purkinje network and the right ventricular outflow tract in the initiation and perpetuation of VT/VF, and has evolved as a promising treatment modality for ventricular tachyarrhythmia even in channelopathies. When patients are exposed to a high risk of sudden cardiac death or deterioration of their quality of life due to episodes of tachycardia and frequent ICD discharges, catheter ablation may be an effective treatment option to reduce the risk of sudden cardiac death and decrease the frequency of cardiac events. In this review, we summarize the current understanding of catheter ablation for VT/VF in patients with channelopathies including Brugada syndrome, idiopathic VF, long QT syndrome, and catecholaminergic polymorphic VT. PMID- 27761166 TI - Cardiac dynamics: Alternans and arrhythmogenesis. AB - Pre-existing heterogeneities present in cardiac tissue are essential for maintaining the normal electrical and mechanical functions of the heart. Exacerbation of such heterogeneities or the emergence of dynamic factors can produce repolarization alternans, which are beat-to-beat alternations in the action potential time course. Traditionally, this was explained by restitution, but additional factors, such as cardiac memory, calcium handling dynamics, refractory period restitution, and mechano-electric feedback, are increasingly recognized as the underlying causes. The aim of this article is to review the mechanisms that generate cardiac repolarization alternans and convert spatially concordant alternans to the more arrhythmogenic spatially discordant alternans. This is followed by a discussion on how alternans generate arrhythmias in a number of clinical scenarios, and concluded by an outline of future therapeutic targets for anti-arrhythmic therapy. PMID- 27761168 TI - Autonomic and cardio-respiratory responses to exercise in Brugada Syndrome patients. AB - BACKGROUND: Imbalances of the autonomic nervous (ANS), the cardiovascular system, and ionics might contribute to the manifestation of The Brugada Syndrome (BrS). Thus, this study has aimed to investigate the cardio-respiratory fitness and the responses of the ANS both at rest and during a sub-maximal exercise stress test, in BrS patients and in gender-matched and age-matched healthy sedentary controls. METHODS: Eleven BrS patients and 23 healthy controls were recruited in Khon Kaen, Thailand. They performed an exercise test on a cycle ergometer, and during the exercise, expired gas samples and electrocardiograms were collected. Blood glucose and electrolyte concentrations were analyzed before and after exercise. Then the heart rate variability (HRV) and the heart rate recovery (HRR) were analyzed from the electrocardiograms. RESULTS: The BrS patients showed a higher parasympathetic activation during exercise recovery than baseline. They had a smaller level of sympathetic activation during the period of exercise recovery than the controls did. They also showed a significantly lower peak HR, HRR, and peak oxygen consumption than the controls (p<0.05). All subjects had a significantly lower percentage of peak oxygen consumption and respiratory exchange ratio during low-intensity (p<0.01) and moderate-intensity (p<0.05) exercise than during high-intensity exercise. The BrS patients had mild hyperkalemia which is reduced according to the exercise. CONCLUSION: Thai BrS patients had a more rapid rate of restoration of the parasympathetic and smaller level of sympathetic activation after exercise. They had mild hyperkalemia which is reduced according to the exercise. Furthermore, they exhibited impaired cardio respiratory fitness. PMID- 27761167 TI - Genetics of Brugada syndrome. AB - In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology >= 2 mm in >=1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occurring either spontaneously or after a provocative drug test by the intravenous administration of Class I antiarrhythmic drugs. With accumulated findings, the BrS inheritance model is believed to be an autosomal dominant inheritable model with incomplete penetrance, although most patients with BrS were sporadic cases. SCN5A, which was identified as the first BrS associated gene in 1998, has emerged as the most common gene associated with BrS, and more than 10 BrS-associated genes have been identified thereafter. Mutation specific genetic testing is recommended for the family members and appropriate relatives following the identification of BrS-causative mutations in an index patient. In addition, comprehensive or BrS1 (SCN5A) targeted genetic testing could be useful for patients in whom a cardiologist has established a clinical index of suspicion for BrS based on the patient's clinical history, family history, and the expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype. Over the past 20 years, extensive research in this field has allowed better understanding of the pathophysiology, genetic background, and management of BrS even though controversies still exist. In this review article, a background of genetics, the genetic background of BrS, the genotype and phenotype relationship, the role of genetic screening in clinical practice, and the interpretation of the identified genetic variants have been addressed based on this understanding. PMID- 27761169 TI - Characterization of the novel mutant A78T-HERG from a long QT syndrome type 2 patient: Instability of the mutant protein and stabilization by heat shock factor 1. AB - BACKGROUND: The human ether-a-go-go-related gene (HERG) encodes the alpha-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). METHODS: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein. A78T HERG and wild-type HERG (WT-HERG) were expressed in HEK293 cells and analyzed by immunoblotting, immunoprecipitation, immunofluorescence, and whole-cell patch clamping. RESULTS: When expressed in HEK293 cells, WT-HERG gave rise to immature and mature forms of the protein at 135 and 155 kDa, respectively. A78T-HERG gave rise only to the immature form, which was heavily ubiquitinated. The proteasome inhibitor MG132 increased the expression of immature A78T-HERG and increased both the immature and mature forms of WT-HERG. WT-HERG, but not A78T-HERG, was expressed on the plasma membrane. In whole-cell patch clamping experiments, depolarizing pulses evoked E4031-sensitive HERG channel currents in cells transfected with WT-HERG, but not in cells transfected with A78T-HERG. The A78V mutant, but not A78G mutant, remained in the immature form similarly to A78T. Maturation of the A78T-HERG protein was facilitated by HS, expression of HSF-1, or exposure to geranyl geranyl acetone. CONCLUSIONS: A78T-HERG was characterized by protein instability and reduced expression on the plasma membrane. The stability of the mutant was partially restored by HSF-1, indicating that HSF-1 is a target for the treatment for LQT2 caused by the A78T mutation in HERG. PMID- 27761170 TI - Erratum to '2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing' [Journal of Arrhythmia 32/1 (2016) 1-28]. AB - [This corrects the article DOI: 10.1016/j.joa.2015.12.001.]. PMID- 27761171 TI - Shprintzen-Goldberg syndrome: a rare disorder. AB - Shprintzen-Goldberg Syndrome is an extremely infrequent disorder of connective tissue, characterized by craniosynostosis and marfanoid features, also known as Marfanoid Craniosynostosis syndrome. The syndrome was first introduced by Sugarman and Vogel' (1981) however, Shprintzen and Goldberg established this as a separate clinical entity in the year 1982. Since then, approximately sixty such cases have been set down in writing in the medical literature. Herein, we present a short review of literature of this rare connective disorder, in order to create awareness about this condition, as the magnitude of this disorder is not measured properly due to the paucity of literature. PMID- 27761172 TI - The novel concept of creating awareness about tuberculosis at the metro stations. AB - Tuberculosis is an infectious disease and is a major health problem in developing countries like India. The disease is prevalent mainly in the underprivileged sections of the society. However, the same is not always true and even the well to do sections are also affected by this disease. The lack of knowledge in the masses and the communities is a factor that contributes largely to the spread of the disease. In such a scenario, there is always a need for new and innovative ideas to create mass awareness about tuberculosis. PMID- 27761173 TI - Evaluating the Reliability of Expert Evidence in Compensation Procedures: Are Diagnosticians Influenced by the Narrative Fallacy when Assessing the Psychological Injuries of Trauma Victims? AB - The current study investigated whether mental health practitioners are influenced by the narrative fallacy when assessing the psychological injuries of trauma victims. The narrative fallacy is associated with our tendency to establish logical links between different facts. In psychodiagnostic assessments, this tendency may result in overdiagnosis of mental disorders when psychological symptoms can be attributed to a traumatic event. Consequently, legal decision makers may be at risk of awarding compensation for psychological injuries which are not severe enough to justify financial reimbursement. To explore this topic, we asked Dutch mental health practitioners whether they would assign a diagnosis of mental disorder to fictitious symptoms of psychological injury. Each participant was presented with two vignettes. The first vignette described symptoms in terms of a generalized anxiety disorder; the second in terms of a major depressive episode. The vignettes varied in the cause (trauma versus cause not specified) and severity (near threshold of DSM diagnosis versus below threshold of DSM diagnosis) of the symptoms. Results indicated that participants more often assigned a diagnosis of mental disorder if the psychological symptoms had been caused by a traumatic event than if that had not been the case. Further analysis of the data suggested that this difference was due to the high numbers of assigned diagnoses of posttraumatic stress and acute stress disorder in the trauma conditions. It was speculated that participants filled in missing information to justify the assignment of such diagnoses, for example by imagining symptoms of intrusion and avoidance. PMID- 27761174 TI - Spinal Metastases of Extramammary Paget Disease with Radiologic-Pathologic Correlation. AB - Extramammary Paget disease (EMPD) is an uncommon malignancy. It manifests either in the primary form in the skin as an intraepithelial neoplasm, or in secondary form as pagetoid (intraepithelial) spread of an underlying internal carcinoma to the skin. Although local invasion and recurrence of primary extramammary Paget disease are relatively frequent, widespread metastases are rare. As such, there are very few reports and little characterization of the radiologic features of widespread spinal metastases. To our knowledge, there are no prior reports of a metastatic extramammary Paget disease presenting as a painful pathologic vertebral body compression fracture. We report the radiological features of a case of primary extramammary Paget disease with subsequent spinal metastases presenting as a painful compression fracture. PMID- 27761175 TI - MR Imaging Findings in Xp21.2 Duplication Syndrome. AB - Xp21.2 duplication syndrome is a rare genetic disorder of undetermined prevalence and clinical relevance. As the use of chromosomal microarray has become first line for the work-up of childhood developmental delay, more gene deletions and duplications have been recognized. To the best of our knowledge, the imaging findings of Xp21.2 duplication syndrome have not been reported. We report a case of a 33 month-old male referred for developmental delay that was found to have an Xp21.2 duplication containing IL1RAPL1 and multiple midline brain malformations. PMID- 27761176 TI - Middle Lobe Torsion after Unilateral Lung Transplant. AB - Lobar torsion is well documented after pneumonectomy, but is very rare after lung transplant. To the best of our knowledge, this is the twelfth reported case of lobar torsion after lung transplant. In our case, bronchoscopies and chest radiographs were inconclusive; however, CT scan clearly demonstrated findings consistent with right middle lobe torsion. We review the literature and discuss the epidemiology, clinical presentation, imaging features, and treatment considerations for this condition. We also propose that if a clinical picture could be secondary to torsion and bronchoscopies and chest x ray are inconclusive that a CT scan should be obtained as soon as possible since early recognition increases the likelihood of being able to successfully detorse the lung and avoid lobectomy. PMID- 27761177 TI - Case Report: Gallbladder Varices in a Patient with Portal Vein Thrombosis Secondary to Hepatocellular Carcinoma. AB - Gallbladder varices are a rare form of collateralization that develop in patients with portal hypertension. We present here a case of gallbladder varices accurately diagnosed by contrast enhanced CT imaging of the abdomen and confirmed by Color Doppler Sonography. A 76-year-old patient with hepatocellular carcinoma developed portal vein thrombosis due to tumor extension during the course of treatment and was incidentally discovered to have gallbladder varices. While most commonly asymptomatic, gallbladder varices are associated with increased risk of massive bleeding, either spontaneously or during cholecystectomy. As a result, the existence of such varices should be well documented if the patient is to undergo any abdominal surgical procedures. In addition, because of a particular association with portal vein thrombosis, patients with portal hypertension that are found to possess gallbladder varices should be evaluated for portal vein thrombosis. PMID- 27761178 TI - Intravenous leiomyomatosis disguised as a large deep vein thrombosis. AB - Intravenous leiomyomatosis is a benign smooth muscle tumor which despite its histology can have devastating consequences. Furthermore, the clinical manifestations are variable and nonspecific, typically leading to delayed or missed diagnosis. Thus, it is critical for clinicians to be aware of this condition and have a high index of suspicion in a middle-aged woman with a history of uterine leiomyoma presenting with an inferior vena cava mass to enable early diagnosis and treatment. We report a case of a large intravenous leiomyoma which was initially considered to be a very large deep venous thrombosis; with thorough preoperative planning, it was successfully removed intact and in entirety with a single-stage operation. PMID- 27761179 TI - Carotid Stent Fracture from Stylocarotid Syndrome. AB - Eagle syndrome is a rare condition resulting from elongation of the temporal styloid process or calcification of its associated stylohyoid ligaments. Although usually presenting with pain or odynophagia, Eagle syndrome has been reported to cause a multitude of neurologic symptoms or vascular complications, some of which can be life-threatening. We present a case in which an endovascularly placed internal carotid artery stent in close proximity to a calcified stylohyoid ligament resulted in stent fracture with subsequent stent and vessel occlusion. We review and discuss the presentation, diagnosis, etiology, complications and treatment options of the syndrome. PMID- 27761180 TI - Incisional Hernia Following Ventriculoperitoneal Shunt Positioning. AB - Incisional hernia represents a rare complication after ventriculoperitoneal shunt positioning due to failure of the fascial suture in the site of abdominal entrance of ventriculoperitoneal catheter. Clinical presentation can be extremely variable, according to patient's performance status, herniated material constitution (i.e. mesenteric fat, bowel loops or both) and complication occurrence (e.g. strangulation or intestinal obstruction). Early diagnosis is fundamental in order to surgically repair the defect and prevent further complications. We present the case of a paucisymptomatic incisional hernia following ventriculoperitoneal shunt positioning. Diagnosis was made by means of ultrasound and confirmed by means of computed tomography. The patient was successfully managed by means of surgical repositioning of herniated loop and re suture. PMID- 27761181 TI - Currarino Syndrome and the Effect of a Large Anterior Sacral Meningocele on Distal Colostogram in an Anorectal Malformation. AB - Currarino syndrome is a congenital disorder, consisting of a triad of anomalies including an anorectal malformation, sacral anomaly, and a presacral mass. Anterior sacral meningoceles are the most common presacral mass. A young child presented to our institution with an unrepaired anorectal malformation and a large anterior sacral meningocele. We describe how the anterior meningocele affected the imaging work-up. PMID- 27761182 TI - Intra-articular osteoid osteoma at the femoral trochlea treated with osteochondral autograft transplantation. AB - We present the case of an intra-articular osteoid osteoma at the femoral trochlea. Intra-articular osteoid osteoma can present a diagnostic challenge both clinically and with imaging because it presents differently from the classic cortical osteoid osteoma. Given the lesion's proximity to overlying cartilage, the patient underwent resection of the lesion with osteochondral autograft transplantation at the surgical defect. A comprehensive literature review and discussion of intra-articular osteoma will be provided. PMID- 27761183 TI - Small bowel perforation: a rare complication of ventriculoperitoneal shunt placement. AB - Small bowel perforation is a rare complication of ventriculoperitoneal (VP) shunt placement. When seen, it most commonly affects the stomach or colon. We describe a case and image findings of an 8-year-old female who presented with sepsis and erosion of the VP shunt into the small bowel. The imaging findings were confirmed surgically. We also provide an overview of the current literature discussing previously reported cases, clinical features, and treatment. PMID- 27761184 TI - Diffusion, Perfusion, and Histopathologic Characteristics of Desmoplastic Infantile Ganglioglioma. AB - We present a case series of a rare tumor, the desmoplastic infantile ganglioglioma (DIG) with MRI diffusion and perfusion imaging quantification as well as histopathologic characterization. Four cases with pathologically-proven DIG had diffusion weighted imaging (DWI) and two of the four had dynamic susceptibility contrast imaging. All four tumors demonstrate DWI findings compatible with low-grade pediatric tumors. For the two cases with perfusion imaging, a higher relative cerebral blood volume was associated with higher proliferation index on histopathology for one of the cases. Our results are discussed in conjunction with a literature review. PMID- 27761185 TI - Fishbone Perforated Appendicitis. AB - Ingested foreign bodies tend to pass through the gastrointestinal tract without incidence, and vast majority of cases do not need intervention. Rarely, these foreign bodies drop into the appendix and not likely to re-enter the normal digestive tract. We describe a case of a 72-year-old male patient who presented with right iliac fossa pain of 3-day duration. Clinical examination suggested classic acute appendicitis. Blood test results revealed leukocytosis. Computed tomography of the abdomen and pelvis showed evidence of acute appendicitis and a linear hyperdensity (foreign body) perforating the appendix. The patient was managed successfully with prompt laparoscopic appendectomy and removal of the foreign body which was confirmed to be a fish bone measuring about 10mm. While imaging diagnosis of fishbone in the appendix has been published, reports are few. To the best of the author's knowledge, fishbone induced perforated appendicitis has been described only in 2 cases (including this case) in the literature. PMID- 27761186 TI - Paediatric post-traumatic osseous cystic lesion following a distal radial fracture. AB - Post-traumatic osseous cystic lesions are a rare complication in children. An aetiology of intramedullary fat seepage through the damaged bone cortex and its entrapment within the subperiosteum has been proposed. These lesions run a benign course and usually resolve spontaneously. The presence of fatty marrow gives it a distinct appearance which aids in its diagnosis and differentiation from other bone lesions. This case demonstrates a fat-fluid level within the subperiosteal cystic lesion in Magnetic Resonance Imaging (MRI) and this is a typical feature of post-traumatic cystic lesion in a child. Recognition of this imaging feature allows for a confident diagnosis, cutting down on unnecessary, potentially invasive investigations. PMID- 27761187 TI - Delayed Presentation of a Chronic Morel-Lavallee Lesion. AB - Morel-Lavellee lesions are soft tissue degloving injuries resulting from shearing trauma that induces separation of the superficial and deep fascias creating a potential space that becomes filled with hemolymph. Here we present a case of a 28-year-old male presenting with a persistent Type I Morel-Lavallee lesion 2.5 years after an automobile versus pedestrian accident. These lesions can be visualized via computed tomography, plain film and ultrasound, but magnetic resonance imaging is the modality of choice for their identification and characterization. PMID- 27761188 TI - Percutaneous Retrieval of an Embolized Kyphoplasty Cement Fragment From the Pulmonary Artery: A Case Report and Literature Review. AB - We present a case of a 41-year-old man with symptomatic pulmonary cement embolism following percutaneous vertebral augmentation, which was successfully retrieved via a percutaneous endovascular approach, a novel technique with only two prior cases reported. Cement leakage, including venous embolization of cement into the cardiopulmonary circulation, is a known potential complication following percutaneous kyphoplasty and vertebroplasty. While many patients with pulmonary cement embolism are asymptomatic and likely go undiagnosed, others experience respiratory distress and hemodynamic compromise requiring surgical and medical intervention. The optimal management for pulmonary cement embolism must be tailored to fit each individual patient, dependent upon the acuity of the clinical presentation, coexisting patient comorbidities, and the risks of systemic anticoagulation. In our patient, cement migration was visualized in real time during vertebral augmentation. Endovascular retrieval by our Interventional Radiology section obviated the need for anticoagulation therapy or more invasive open surgical procedures. PMID- 27761189 TI - Intracranial Migration of Silicone Delaying Life Saving Surgical Management: A Mimicker of Hemorrhage. AB - We present a case in which intraocular silicone injection for complex retinal detachment resulted in migration and distribution of silicone along the intracranial visual pathway, and ultimately throughout the ventricular system. Misinterpretation of this material as intracranial hemorrhage on outside computed tomography imaging delayed emergent repair of a Type A aortic dissection until the diagnosis was made on repeat imaging. A discussion of this case and salient computed tomography and magnetic resonance imaging characteristics of silicone is provided. PMID- 27761190 TI - Left Anterior Descending Coronary Artery and Multiple Peripheral Mycotic Aneurysms Due to Mycobacterium Bovis Following Intravesical Bacillus Calmette Guerin Therapy: A Case Report. AB - The use of live attenuated intravesicular Bacillus Calmette-Guerin (BCG) therapy is a generally accepted safe and effective method for the treatment of superficial transitional cell carcinoma (TCC) of the bladder. Although rare, < 5% of patient's treated with intravesicular BCG therapy may develop potentially serious complications, including localized infections to the genitourinary tract, mycotic aneurysms and osteomyelitis. We present here a case of a 63-year-old male who developed left coronary and multiple peripheral M. Bovis mycotic aneurysms as a late complication of intravesicular BCG therapy for superficial bladder cancer. The patient initially presented with acute onset pain and swelling in the left knee > 2 years following initial therapy, and initial workup revealed a ruptured saccular aneurysm of the left popliteal artery as well as incidental bilateral common femoral artery aneurysms. Following endovascular treatment and additional workup, the patient was discovered to have additional aneurysms in the right popliteal artery and left anterior descending artery (LAD). Surgical pathology and bacterial cultures obtained from the excised femoral aneurysms and surgical groin wounds were positive for Mycobacterium Bovis, and the patient was initiated on a nine-month antimycobacterial course of isoniazid, rifampin and ethambutol. Including the present case, there has been a total of 32 reported cases of mycotic aneurysms as a complication from intravesicular BCG therapy, which we will review here. The majority of reported cases involve the abdominal aorta; however, this represents the first known reported case of a coronary aneurysm. PMID- 27761191 TI - Adult pancreatoblastoma - Case report and review of literature. AB - Most cases of pancreatoblastoma, a rare malignant epithelial tumor of the pancreas, are seen in the pediatric population. The rarity of pancreatoblastoma, the similar radiologic findings to those seen in other pancreatic lesions, and its histopathologic heterogeneity, make its preoperative diagnosis in adults a real challenge. We report ultrasound, computed tomography and magnetic resonance imaging correlative findings of a histologically proven pancreatoblastoma in a 37 year-old woman. Pancreatoblastoma should be considered in the differential diagnosis of a pancreatic mass presenting uncommon imaging features. PMID- 27761192 TI - CHAOS: Prenatal imaging findings with post mortem contrast radiographic correlation. AB - Congenital high airway obstruction syndrome is a rare fetal anomaly with characteristic constellation of prenatal findings on ultrasound and MRI. The typical triad of imaging features are enlarged and echogenic lungs, flattening or inversion of diaphragm and fetal hydrops. Early prenatal recognition of congenital high airway obstruction syndrome by ultrasound and/or MRI is mandatory for the appropriate perinatal management. We report a case of a male fetus with typical imaging findings of congenital high airway obstruction syndrome on ultrasound and MRI at 19 weeks of gestation. The role of contrast radiographs of fetal airways, including retrograde laryngogram, in confirming the postnatal diagnosis of this fetal condition is demonstrated. The prenatal imaging findings were correlated with contrast radiographs of upper airways, sonography of aborted fetus and fetal autopsy findings. PMID- 27761193 TI - Multiple hereditary exostoses: A pseudoaneurysm masquerading as tumor. AB - Multiple hereditary exostoses is an autosomal dominant condition characterized by numerous benign osteochondromas. Complications are rare and can include deformity, growth abnormality, fracture, adventitial bursa formation, local mass effect on a nerve, malignant degeneration, and vascular complications including stenosis, occlusion, arteriovenous fistula, and pseudoaneurysm. We present a case of multiple hereditary exostoses leading to a deep femoral artery pseudoaneurysm in the proximal medial thigh with subsequent rupture and hematoma, masquerading as tumor. PMID- 27761194 TI - ALK positive Anaplastic Large Cell Lymphoma of the Thoracic Spine. AB - Primary bone lymphoma (PBL) is an uncommon extra nodal disease that represents about 1-3% of lymphoma cases. Imaging findings are variable and non-specific. Computed tomography may demonstrate lytic lesions with sequestra and periosteal reaction. On magnetic resonance imaging, lesions are T1WI hypointense and T2WI hyperintense, related to peritumoral edema or bone marrow replacement. Rarely lesions may have associated fibrosis and show a more hypointense signal pattern on T2WI. After administration of contrast, PBL tends to enhance avidly. We present a case of a 24 years old African American female patient with history of back pain. Initial imaging examinations showed lesions involving the T12 and T11 vertebral bodies with initial negative biopsy results. One month later, the patient returned with worsening back pain, and the follow up studies depicted collapse of the T12 vertebral body. A diagnosis of anaplastic large cell lymphoma in T12 was made. A brief review of the literature, imaging and pathological findings, and treatment options are also discussed. PMID- 27761195 TI - Impact of Isometric Contraction of Anterior Cervical Muscles on Cervical Lordosis. AB - OBJECTIVE: This study investigates the impact of isometric contraction of anterior cervical muscles on cervical lordosis. METHODS: 29 volunteers were randomly assigned to an anterior head translation (n=15) or anterior head flexion (n=14) group. Resting neutral lateral cervical x-rays were compared to x-rays of sustained isometric contraction of the anterior cervical muscles producing anterior head translation or anterior head flexion. RESULTS: Paired sample t tests indicate no significant difference between pre and post anterior head translation or anterior head flexion. Analysis of variance suggests that gender and peak force were not associated with change in cervical lordosis. Chamberlain's to atlas plane line angle difference was significantly associated with cervical lordosis difference during anterior head translation (p=0.01). CONCLUSION: This study shows no evidence that hypertonicity, as seen in muscle spasms, of the muscles responsible for anterior head translation and anterior head flexion have a significant impact on cervical lordosis. PMID- 27761197 TI - Endometrial stromal sarcoma: An aggressive uterine malignancy. AB - Endometrial stromal sarcoma (ESS) is an aggressive uterine sarcoma. We report a case of a large endometrial stromal sarcoma in a 42 year nulliparous woman with chronic kidney disease presenting with acute urinary retention and irregular per vaginal bleeding. Ultrasound and Doppler imaging revealed a heterogeneous mass in the endometrial cavity with internal vascularity. Magnetic resonance imaging (MRI) revealed a large lobulated mass in the endometrial cavity extending into the vagina, causing local mass effect. Multiple linear hypointense bands on magnetic resonance T2 weighted (T2wt) images were characteristic of ESS. MRI is a very useful imaging modality in characterizing the lesion and also for the staging. It is necessary to distinguish these tumors from benign as well as other uterine malignancies for better management. We also review relevant literature discussing imaging findings of ESS. PMID- 27761196 TI - Factitious Disorder Presenting with Attempted Simulation of Fournier's Gangrene. AB - Fournier's gangrene is a severe polymicrobial necrotizing fasciitis of the perineal, genital, or perianal regions. The classic presentation is severe pain and swelling with systemic signs. Crepitus and cutaneous necrosis are often seen. Characteristic CT findings include subcutaneous gas and inflammatory stranding. Unless treated aggressively, patients can rapidly become septic and die. Factitious Disorder is the falsification of one's own of medical or psychological signs and symptoms. Many deceptive methods have been described, from falsely reporting physical or psychological symptoms, to manipulating lab tests, or even injecting or ingesting foreign substances in order to induce illness. We present a case of a 35-year-old man with factitious disorder who attempted to simulate Fournier's gangrene by injecting his scrotum with air and fluid. We will review the clinical presentation and diagnosis of Factitious Disorder, as well as Fournier's gangrene. PMID- 27761198 TI - Percutaneous Transhepatic Embolization of Bleeding Rectal Varices Using A New Embolic And Sclerotic Mixture Augmented By Amplatzer Vascular Plug 2. AB - We report a case of 59-year-old female with non-alcoholic-steato-hepatitis (NASH) induced cirrhosis, who presented with hematochezia. The patient had a history of bleeding esophageal varices treated with endoscopic variceal ligation (EVL). Colonoscopy showed large rectal varices which were the source of her lower gastrointestinal bleeding (LGIB). Since endoscopic treatment for LGIB are limited, and because the patient had portal vein thrombosis which contraindicated transjugular intrahepatic portosystemic shunt (TIPS), we performed percutaneous transhepatic embolization of her rectal varices using a new mixture of embolic and sclerotic agents, followed by Amplatzer plug 2 (AVP 2). To our knowledge, the use of this new mixture with the AVP 2 in the rectal varices treatment has not been previously published in literature. Our case provides an alternative treatment modality that can be used for rectal varices treatment, when TIPS and endoscopic management fails or is contraindicated. PMID- 27761199 TI - ON THE DISTRIBUTION OF THE GREATEST COMMON DIVISOR OF GAUSSIAN INTEGERS. AB - For a pair of random Gaussian integers chosen uniformly and independently from the set of Gaussian integers of norm x or less as x goes to infinity, we find asymptotics for the average norm of their greatest common divisor, with explicit error terms. We also present results for higher moments along with computational data which support the results for the second, third, fourth, and fifth moments. The analogous question for integers is studied by Diaconis and Erdos. PMID- 27761200 TI - Catch me if you can: Leukemia Escape after CD19-Directed T Cell Immunotherapies. AB - Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells. The anti-CD19/CD3 bispecific antibody blinatumomab and anti-CD19 chimeric antigen receptor T cells (CART19) have produced deep responses in patients with relapsed and refractory B-cell acute leukemias. However, although the majority of these patients responds to anti-CD19 immunotherapy, a subset of them still relapses. Interestingly, a novel family of leukemia escape mechanisms has been described, all characterized by the apparent loss of CD19 on the surface of leukemic blasts. This extraordinary finding demonstrates the potent selective pressure of CART19/blinatumomab that drives extreme and specific escape strategies by leukemic blasts. Patients with CD19-negative relapsed leukemia have very poor prognosis and novel approaches to treat and ideally prevent antigen-loss are direly needed. In this review we discuss the incidence, mechanisms and therapeutic approaches for CD19-negative leukemia relapses occuring after CD19 directed T cell immunotherapies and present our future perspective. PMID- 27761202 TI - Novel Echocardiographic Indices for Assessing the Left Main Coronary Artery in Children With Kawasaki Disease. AB - BACKGROUND: Kawasaki disease (KD) is the most common cause of acquired myocardial infarction in children. Coronary artery involvement is the most serious feature of this vasculitis syndrome. Timely diagnosis of coronary artery involvement is of utmost importance since it can prevent long-term morbidity and mortality. The current methods for the diagnosis of coronary artery dilation in KD are inconsistent and are also not capable of detecting all the abnormal coronary arteries or the so-called occult dilations present. OBJECTIVES: The aim of this study was to determine the sensitivity and specificity of three novel allometric indices for the diagnosis of left main coronary artery (LMCA) involvement in KD. METHODS: We performed a prospective case-control study in 69 children (38 with KD and 31 healthy children). All the followed up patients underwent two complete echocardiographic examinations at the time of admission and 4 - 6 weeks later. We measured the size of the LMCA, coronary sinus (CS) and aorta (A) and calculated the LMCA/CS, LMCA/A and LMCA/CS/A ratios. We also calculated the cut-off scores for each index using receiver operating characteristic curves both in the acute phase and 4 - 6 weeks later. RESULTS: In the acute phase, the cut-off scores for the LMCA/A ratio was > 0.23; LMCA/CS, > 0.44; and LMCA/CS/A, > 0.03. This implied 60% sensitivity and 80% specificity for the detection of abnormal LMCA in KD. Four to six weeks after the acute phase, the LMCA/A cut-off score was > 0.23; LMCA/CS, > 0.73; and LMCA/CS/A, > 0.73. This implied 100% sensitivity and 100% specificity for the detection of abnormal LMCA. There was a significant decrease in the size of the CS in comparison with the control group (1.92 +/- 0.363 mm; P = 0.007 and 0.023). CONCLUSIONS: The LMCA/A, LMCA/CS and LMCA/CS/A ratios seem to provide simple and patient-specific indices for the detection of abnormal LMCA in KD, both in the acute and subacute phase. Further, a decrease in the size of the CS may imply a decrease in coronary artery flow in the acute and subacute phases of KD. PMID- 27761201 TI - The promises of quantitative systems pharmacology modelling for drug development. AB - Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response. Here we review QSP, pharmacometrics and systems biology models with respect to the diseases covered as well as their clinical relevance and applications. Overall, the majority of modelling focus was aligned with the priority of drug-discovery and clinical trials. However, a few clinically important disease categories, such as Immune System Diseases and Respiratory Tract Diseases, were poorly covered by computational models. This suggests a possible disconnect between clinical and modelling agendas. As a standard element of the drug discovery pipeline the uptake of QSP might help to increase the efficiency of drug development across all therapeutic indications. PMID- 27761203 TI - Anti-Proliferative Activity of lambda-Carrageenan Through the Induction of Apoptosis in Human Breast Cancer Cells. AB - BACKGROUND: Sulfated Polysaccharides (SPs) possess spectrum of pharmacological and therapeutic properties that could attributed to their origins variation, chemical structures and biological activities. Various studies have shown the impact of SPs on proliferation in different cancer cell lines. OBJECTIVES: In this study, we have evaluated the biological effects of lambda-carrageenan, a highly SP, extracted from the red seaweed Laurencia papillosa, on MDA-MB-231 cancer cell line. MATERIALS AND METHODS: MDA-MB-231 cells have treated with lambda-carrageenan, the viability and apoptosis have assessed by the appropriate florescent probes on flow cytometer. The expression levels of mRNA of apoptotic genes have detected by real-time PCR analysis. RESULTS: Our results have indicated that the signaling pathway of lambda-carrageenan inhibited the proliferation of MDA-MB-231 cells by up-regulating the pro-apoptotic genes caspase-8, caspase-9, caspase-3 which have been resulting the increased levels of active caspase-3 protein. Furthermore, This SP had that capacity to disrupt the mitochondrial function by altering the bax/bcl-2 ratio of expression which has considered an important element in apoptosis induction. CONCLUSIONS: The presented results have signposted that lambda-carrageenan was a promising bioactive polymer which could be a potential candidate in preventing or treating breast cancer. PMID- 27761204 TI - The Role of Psychological Hardiness and Marital Satisfaction in Predicting Posttraumatic Growth in a Sample of Women With Breast Cancer in Isfahan. AB - BACKGROUND: Posttraumatic growth (PTG) refers to positive psychological change experienced as a result of the struggle with highly challenging life circumstances. PTG in cancer survivors is related to several psychosocial factors such as psychological hardiness and marital satisfaction. OBJECTIVES: The purpose of this study was to examine the prediction of posttraumatic growth based on psychological hardiness and marital satisfaction. PATIENTS AND METHODS: A total of 120 women with breast cancer were recruited from several hospitals in Isfahan using convenience sampling. Participants completed the research questionnaires including the posttraumatic growth inventory (PTGI), the Ahvaz psychological hardiness scale and the Enrich's marital satisfaction scale (EMS). Statistical analysis including means, standard deviation, Pearson's correlation and multiple regression analysis were carried out using SPSS software (version 16). RESULTS: Results indicated that the majority of patients with cancer experienced posttraumatic growth. Findings also showed that psychological hardiness, marital satisfaction and longer time since diagnosis of cancer significantly predicted posttraumatic growth. CONCLUSIONS: This study highlights the significant role of psychological hardiness and marital support in personal growth of breast cancer survivors. PMID- 27761205 TI - Psychological Predictors of Prostate Cancer Screening Behaviors Among Men Over 50 Years of Age in Hamadan: Perceived Threat and Efficacy. AB - BACKGROUND: Prostate cancer is the fourth most common cancer worldwide and is the second most lethal cancer. OBJECTIVES: The aim of this study was to investigate psychological predictors of prostate cancer screening behaviors among men over 50 years of age in Hamadan. MATERIALS AND METHODS: This cross-sectional study was carried out on 200 men over 50 years of age in Hamadan, west of Iran. Participants were recruited with a cluster sampling method. The subjects completed a self-administered questionnaire including demographic characteristics, prostate cancer screening behaviors and psychological factors related to prostate cancer. Data was analyzed by SPSS-18 using chi-square, fisher exact test, and logestic regression. RESULTS: According to the results, 8.5 and 7.5 percent of participants reported history of digital rectal exam and prostate specific antigen test, respectively. Also, the subjects reported 18.5%, 49.3% and 50.3% of receivable scores of knowledge, perceived threat, and perceived efficacy of prostate cancer screening behaviors, respectively. There was a significant association between prostate cancer screening behaviors and age groups (P < 0.05). CONCLUSIONS: The results showed that providing analytical studies in this field helps to surface the hidden aspects of this context and the health care providers and administrators will hopefully consider them in planning for identification of psychological factors, such as barriers and facilitators factors. PMID- 27761206 TI - Effects of Chrysin-PLGA-PEG Nanoparticles on Proliferation and Gene Expression of miRNAs in Gastric Cancer Cell Line. AB - BACKGROUND: Recently, Chrysin, as a flavone, has revealed cancer chemo-preventive activity. The present experiment utilized the PLGA-PEG-chrysin complex, and free chrysin, to evaluation of the expression of miR-22, miR-34a and miR-126 in human gastric cell line. OBJECTIVES: The purpose of this study was to examine whether nano encapsulating chrysin improves the anti-cancer effect of free chrysin on AGS human gastric cell line. METHODS: Properties of the chrysin encapsulated in PLGA PEG nanoparticles were investigated by SEM, H NMR, and FTIR. The assessment of cytotoxicity on the growth of the human gastric cell line was carried out through MTT assay. After treating the cells with a prearranged amount of pure and encapsulated chrysin, RNA was extracted and the expressions of miR-22, miR-34a and miR-126 were measured by using real-time PCR. RESULTS: With regard to the amount of the chrysin loaded in PLGA-PEG nanoparticles, IC50 value was significantly decreased in nanocapsulatedchrysin, in comparison with free chrysin. This finding has been proved through the further increase of miR-22, miR 34a and miR-126 gene expression of nanocapsulatedchrysin, in comparison with free chrysin. CONCLUSIONS: In this study, we revealed that the PLGA-PEG-chrysin is more effective than free chrysin in inhibiting the growth of human gastric cell line. PMID- 27761207 TI - A Rare Presentation of Primary Nasopharyngeal Carcinoma (NPC) in Mediastinum. AB - INTRODUCTION: Nasopharyngeal carcinoma among the children has been rare accounting for only 1% of all pediatric malignancies. Both genetic and environmental factors have contributed to the development of nasopharyngeal carcinoma. Among the children there was a higher rate of undifferentiated histology. The mean age of nasopharyngeal carcinoma diagnosis has been 11 years old age; and the most common site was nasopharynx. Palpable lymphadenopathy, dysphasia and neural defect were common associated signs. CASE PRESENTATION: A 15 year-old boy has presented with a mass that located near by the heart in the left side of mediastinum with invasion to anterior mediastinum from two years ago. In biopsy, nasopharyngeal carcinoma, non-keratinizing type, has diagnosed while there was no involvement of nasopharyngeal region. Patient has treated by 70 Gy (2.0 Gy/fraction) radiotherapy plus concomitant chemotherapy with base of docetaxel. But the mass had no regression. Then, the patient has treated with Cisplatin 100 mg/m2 IV on days 1, 22, and 43 with radiation, then cisplatin 80 mg/m2 IV on day 1 plus fluorouracil (5-FU) 1000 mg/m2/day by continuous IV infusion on days 1 - 4 every 4wk for 3 cycles and after remission interferon beta has added to treatment for 6 months duration as a maintenance therapy. After 1 year follow up; the patient was in complete remission. In the course of therapy, only hypothyroidism has occurred. CONCLUSIONS: Nasopharyngeal carcinoma in childhood, without nasopharyngeal involvement, initially could be detected in other sites such as pericardium. Also good results could be respected by cisplatin and 5-fluorouracil based neoadjuvant chemotherapy before radiotherapy plus interferon beta as a maintenance therapy in childhood aggressive nasopharyngeal carcinoma. PMID- 27761208 TI - Evaluation of MAGE-1 Cancer-Testis Antigen Expression in Invasive Breast Cancer and its Correlation with Prognostic Factors. AB - BACKGROUND: Aberrant expression of cancer-testis antigens (CTA) in breast carcinoma tissue, and its natural expression in the testis, the tissue away from the immune system, makes them good candidates for cancer immunotherapy and vaccines designing. OBJECTIVES: The aim of this study was to assess the expression of a CTA (MAGE-1) in invasive breast cancer and its correlation with prognostic factors. METHODS: Paraffin blocks of breast cancer tissues from 113 patients operated in 2011 - 2013 were stained for MAGE-1expression by immunohistochemistry (IHC). The associations of MAGE-1 expression with known prognostic factors were assessed by statistical analysis using SPSS 16. RESULTS: MAGE-1 expression was found in cancer cell cytoplasms of 30.1% of patients, with different degrees of intensity, (23.9% moderate and 6.2% strong). Nuclear staining turned positive in 31.8%, stratified from moderate in 26.5%to to strong in 5.3%. There was a significant association between the number of lymph nodes involved and both nuclear (P = 0.042) and cytoplasmic (P = 0.003) MAGE-1 expression. There was also a significant correlation between the nuclear expression of MAGE-1 and tumor size (P = 0.018). Cytoplasmic expression of MAGE-1 increased with increasing pathologic grade of tumors although the association was not statistically significant (P = 0.119). CONCLUSIONS: CTA MAGE-1 has significant association with some prognostic factors in breast cancer and may have the role of a prognostic factor. PMID- 27761209 TI - Malignant Tumors of Tongue in Iranian Population. AB - BACKGROUND: The incidence of oral cancers varies from one country to another, which can be clarified by the difference in the distribution of the risk factors and the possible etiologies. Tongue is a main segment of oral cavity and malignant lesions of this region accounts for nearly 30% of all oral cancers. OBJECTIVES: In the present study, we evaluated the pattern of tongue cancer in Iranian population and compared these findings with those previously reported in the other countries. METHODS: In this multicenter, retrospective cross-sectional study recorded cases of the malignant tongue tumors in the cancer research center (CRC) of Shahid Beheshti University of Medical Sciences were extracted. The patient records and their microscopic reports were retrieved from the archives and age, sex and microscopic types were evaluated. It is to be noted that the CRC has been serving as a cancer registry center for major hospitals all over the country since the year of 2003. Thus, the obtained statistics are highly reliable. RESULTS: During the years 2003 to 2008, a total number of 952 new cases of the tongue cancer were recorded in the CRC. Most cases are diagnosed in the sixth and seventh decades of life. 450 cases (47.2%) occurred in men and 489 cases (51.36%) in women. Four different types of malignant lesions (epithelial, salivary gland, hematopoietic and mesenchymal) were diagnosed. Epithelial tumors were the most prevalent malignancies (93%) of which squamous cell carcinoma (SCC) made up 87.39% of all lesions. Salivary gland tumors had the second place with 3.15% of the total lesions. CONCLUSIONS: In Iranian population, squamous cell carcinoma is the most prevalent malignancy of tongue and it is notable that the ratio of female to male population was equal. These lesions were prevalent in the sixth and seventh decades of life. Thus screening examination of tongue by dentist especially in elderly patients is necessary for early detection of cancerous lesions. PMID- 27761210 TI - The Relationship Between Risk Factors and Survival in Adult Acute Lymphoblastic Leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is aggressive cancer, especially in adults as only 20-40% is cured with current treatment regimens. OBJECTIVES: The aim of this study is to evaluate prognostic factors and their effects on survival in ALL patients in the Northeast of Iran. METHODS: In a descriptive and retrospective study from 2009 to 2015, 48 ALL patients referred to hematology oncology clinic. Age, sex, fever, blood group, type of ALL and consumption of amphotericin B, forms of cytogenetic, survival in the patients, WBC, hemoglobin, and platelet were checked in the first referral for every patient. The mean follow-up was 27.3 months in which 28 patients (59.3%) died. overall survival (OS) was plotted by GraphPad Prism 5 and the Log-rank test was used for analysis of survival with risk factors. RESULTS: The mean age for all the ALL patients at diagnosis was 32.3 years (range, 15-71 years), and 81.3% were male. Of all patients, 62.5% had fever and 25% consumed amphotericin B. 1-, 2-, 3-, 4-, 5-year OS rates were 62.2%, 52.7%, 40.6%, 39.1%, 22.2%, respectively. 75%, 29.2% and 39.6% of patients had WBC < 20 * 103/MUl, Hb < 7 g/dL and platelet < 30 * 103/MUL, respectively. There was a significant difference in survival based on age (P = 0.000). CONCLUSIONS: Based on the results, age > 35 years is the most prognostic factor in ALL patients. Also, patients who received amphotericin B had lower life expectancy because these patients were suffering from fungal infection or due to lack of response to antibacterial drugs, they have been treated with amphotericin B. PMID- 27761211 TI - Designing and Psychometric Evaluation of Adjustment to Illness Measurement Inventory for Iranian Women With Breast Cancer. AB - BACKGROUND: Cancer diagnosis for everybody may be perceived as crisis and breast cancer, as the most common malignancy in women, can influence their well-being and multiple aspects of their health. So understanding that how women in various contexts and communities adjust to the illness is necessary to facilitate this adjustment and improve their quality of life. OBJECTIVES: The aim of this study was to: 1) identify the core components of coping strategies to adjust to the illness in Iranian women with breast cancer perspective, 2) to develop and determine psychometric properties of a native self-report instrument to assess coping behaviors and measure the degree of adjustment with the breast cancer. METHODS: The present exploratory mixed method study was conducted in two consecutive stages: 1) the hermeneutic phenomenological study was done to explore the life experiences of coping styles to adjust with the breast cancer using in depth interviews with patients that lead to item generation; 2) psychometric properties (validity and reliability) of the instrument were evaluated recruiting 340 eligible women. The item pool was reduced systematically and resulted in a 49 item instrument. RESULTS: From the qualitative stage, item pool containing 78 items related to coping strategies to adjust with the breast cancer. After eliminating unwanted statements from the results, qualitative and quantitative face and content validity, the 10 factors extracted employing construct validity were: feeling of guilt, abstention-diversion, role preservation and seeking support, efforts for threat control, confronting, fear and anxiety, role wasting, maturation and growth, isolation, and fatalism. These factors accounted for the 59.1% of variance observed. The Cronbach reliability test was carried out and alpha value of 10 factors was calculated from 0.78 to 0.87 confirming all factors were internally consistent. The scale's stability was tested using the test retest method. CONCLUSIONS: The 49-item AIMI-IBC revealed acceptable psychometric properties. This instrument provides healthcare professionals to systematically assess the coping strategies of Iranian women with breast cancer and measure the degree of adjustment with illness. PMID- 27761212 TI - Are Estrogen Receptor Genomic Aberrations Predictive of Hormone Therapy Response in Breast Cancer? AB - CONTEXT: Breast cancer is the most common cancer in women worldwide. Estrogen receptor (ER) positive breast cancer constitutes the majority of these cancers. Hormone therapy has significantly improved clinical outcomes for early- and late stage hormone receptor positive breast cancer. Although most patients with early stage breast cancer are treated with curative intent, approximately 20% - 30% of patients eventually experience a recurrence. During the last two decades, there have been tremendous efforts to understand the biological mechanisms of hormone therapy resistance, with the ultimate goal of implementing new therapeutic strategies to improve the current treatments for ER positive breast cancer. Several mechanisms of hormone therapy resistance have been proposed, including genetic alterations that lead to altered ER expression or ERs with changed protein sequence. EVIDENCE ACQUISITION: A Pubmed search was performed utilizing various related terms. Articles over the past 20 years were analyzed and selected for review. RESULTS: On the basis of published studies, the frequencies of ESR1 (the gene encoding ER) mutations in ER positive metastatic breast cancer range from 11% to 55%. Future larger prospective studies with standardized mutation detection methods may be necessary to determine the true incidence of ESR1 mutations. ESR1 amplification in breast cancer remains a controversial issue, with numerous studies either confirmed or challenged the reports of ESR1 amplification. The combination of intra-tumor heterogeneity regarding ESR1 copy number alterations and low level ESR1 copy number increase may account for these discrepancies. CONCLUSIONS: While numerous unknown issues on the role of ESR1 mutations in advanced breast cancer remain, these new findings will certainly deepen current knowledge on molecular evolution of breast cancer and acquired resistance to hormone therapy. PMID- 27761213 TI - Alanine to Serine Variant at Position 986 of Calcium Sensing Receptor and Colorectal Cancer Risk. AB - BACKGROUND: With regard to the effect of calcium against colorectal cancer (CRC) and considering the key role of calcium sensing receptor (CaSR) in calcium homeostasis, this study investigated whether CaSR gene rs1801725 or A986S variant was associated with susceptibility to CRC risk. METHODS: This study was conducted as a case-control study and 303 cases with CRC and 354 controls were enrolled. All 657 subjects were genotyped for CaSR gene A986S variant using PCR-RFLP method. RESULTS: No significant difference was observed for the A986S variant of CaSR gene in either genotype or allele frequencies between the cases and the controls and this lack of difference remained non-significant even after adjustment for age, BMI, sex, smoking status, and family history of CRC. No evidence for the effect modification of the association A986S variant and CRC by BMI, sex, or tumor site was also observed. Furthermore, the risk of obesity in relation to the A986S variant in the controls and the cases was separately analyzed and we observed no significant difference between normal weight (BMI < 25kg/m2) and overweight/obese (BMI >= 25kg/m2) subjects. CONCLUSIONS: Our findings do not support a role for effect of the CaSR gene A986S variant on CRC risk; nevertheless, this finding requires confirmation and the role of the gene variant in carcinogenesis needs to be further investigated. PMID- 27761214 TI - Antidepressant Activity of Enicostemma littorale Blume in Shp2 (Protein Tyrosine Phosphatase)-inhibited Animal Model of Depression. AB - BACKGROUND: The objective of this study is to develop a new animal model based on signaling pathways to understand the pathophysiology, therapy of depression, and to investigate the antidepressant activity of Enicostemma littorale which is not yet established. METHODS: Animal models of depression were raised by physical methods and administration of methyl isobutyl ketone (100 mg/kg b.w., i.p.,) and a protein tyrosine phosphatase inhibitor, sodium orthovanadate (30 mg/kg b.w., i.p.,) to young Wistar rats. E. littorale aqueous extract (100 mg/kg b.w., oral) was administered. Forced swimming test (FST), biochemical, and histopathological parameters were performed with reference to fluoxetine (20 mg/kg b.w., oral) treatment. RESULTS: High-performance thin-layer chromatography confirmed the presence of swertiamarin, a unique glycoside present in the Gentianaceae family. FST indicated high rates of immobility in depressed groups and low rates in plant extract-administered group with reference to fluoxetine. Biochemical assays indicated significantly (P < 0.05) increased levels of total protein, superoxide dismutase, triglycerides, and total serum cholesterol, whereas significant reduction (P < 0.05) of glutathione peroxidase, catalase, and lipid peroxidation in plant extract-administered groups in comparison to the depressed groups. Histopathological analysis indicated disorganized neuronal architecture during depression whereas rejuvenation of neuronal patterns was observed during treatment with plant extract and fluoxetine. CONCLUSIONS: This study shows that sodium orthovanadate induces depression in animals and also establishes the antidepressant activity of E. littorale. PMID- 27761215 TI - Comparison of Optimal Cardiovascular Risk Factor Management in Patients with Type 2 Diabetes Who Attended Urban Medical Health Center with those Attended a Tertiary Care Center: Experiences from Tehran, Iran. AB - BACKGROUND: Diabetes is a leading cause of cardiovascular disease (CVD). Moreover, CVD accounts for primary cause of death among diabetic patients. Physicians, especially in the primary care setting, have effective role in the management of cardiovascular risk factors. Therefore, we aimed to compare the prevalence of modifiable cardiovascular risk factors in Type 2 diabetic patients attending to an urban health center as a primary care center with Institute of Endocrinology and Metabolism Diabetes Clinic (IEMDC) as a tertiary center. METHODS: This cross-sectional study was performed on 200 adult diabetic patients attending urban health center (Abouzar Health Center) and 201 diabetic patients in a tertiary center. The patients' cardiovascular risk factors including lipid profile, systolic and diastolic blood pressure (BP), and smoking history were recorded. The number of patients who did not achieve the target according to the American Diabetes Association guidelines was determined and compared. RESULTS: The patients in urban health center were older than those who attending IEMDC (P = 0.004). The duration of diabetes was longer among urban center patients (P < 0.001). Comparison of cardiovascular risk factors between two groups of patients showed a significant number of patients with poor-controlled low-density lipoprotein (75% vs. 44.7%) and triglyceride (74% vs. 51.7%) in patients attending primary center (P < 0.001). However, the prevalence of high diastolic BP (60.6% vs. 44.5%) was significantly higher in patients attending IEMDC (P = 0.001). There was no significant difference between the two centers' findings in glycosylated hemoglobin level, high-density lipoprotein level, and systolic BP. CONCLUSIONS: Both centers have failure in target achievement in some risk factors; however, the inability of the primary care center in controlling hyperlipidemia in comparison with the tertiary center is a serious warning to provide training about managing dyslipidemia in these centers. PMID- 27761216 TI - Comparative Study on the Effect of Plantago psyllium and Ocimum basilicum Seeds on Anthropometric Measures in Nonalcoholic Fatty Liver Patients. AB - BACKGROUND: Due to the attribution of fatty liver with some chronic diseases such as obesity, finding a way to control obesity can be useful for the management of fatty liver. This study was performed to assess the effects of Plantago psyllium (PP) and Ocimum basilicum (OB) on anthropometric measurements in people with hepatic steatosis. METHODS: All patients with nonalcoholic fatty liver disease (NAFLD) were enrolled in this four-arm parallel, randomized, and single blind trial. They randomly assigned into four groups receiving (1) OB 10 g/day; (2) PP 10 g/day; (3) mix of OB and PP 10 g/day; and (4) control group without placebo for 12 weeks. Anthropometric measurements were assessed during study baseline and after 12 weeks intervention. The data were analyzed using paired sample t-test for within group and analysis of covariance for between groups. RESULTS: In within group analysis, weight and body mass index show a significant reduction after 12 weeks intervention. In addition, soft lean mass and lean body mass were decreased in PP and mixed of PP and OB groups significantly; another group (OB) shows the same result for mass body fat. Although in intervention groups, we see considerable reduction, between group changes did not demonstrate the same consequences. CONCLUSIONS: The results of this study showed that administration of OB, PP, or mix of them for 12 weeks does not affect any of the anthropometric measures in NAFLD. PMID- 27761217 TI - "Theory Based Health Education: Application of Health Belief Model for Iranian Obese and Overweight Students about Physical Activity" in Urmia, Iran. AB - BACKGROUND: Obesity is a major problem in both developed and underdeveloped countries. The aim of this study is to investigate the effects of a physical education program (PEP) on promoting health belief model (HBM) scores, increasing physical activity (PA), and reducing obesity among Iranian high school students. METHODS: This quasi-experimental study was accomplished at four high schools that were randomly divided into two groups of experiment (forty) and control (forty) male students in junior high schools in Urmia, Iran. Students in the experimental group received a PEP during 6 months. The essential parameters were used for evaluating the effects of educational program on HBM, PA, and body mass index (BMI) of students. RESULTS: After the intervention of 3 and 6 months, the experimental group showed a significant difference on the results of HBM constructs. According to the result of repeated-measures ANOVA, there is a significant difference between the experimental and control groups about the components of PA constructs. Analysis of covariance showed that although BMI reduced in 6 months after intervention, there was no significant difference in BMI. CONCLUSIONS: Results of the study revealed that implementation of PEP was effective on increasing the score of the components of HBM and PA of students. PMID- 27761218 TI - Bilateral Scapulothoracic Osteochondromas in a Patient With Hereditary Multiple Exostosis: A Case Report and Review of the Literature. AB - Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by two or more benign growing, cartilage capped tumors of long bones called osteochondromas. If abnormal growth and clinical symptoms of osteochondromas newly appear in adults, malignant transformation of the usually benign growing tumors should be suspected and diagnostic testing should be initiated. Against the background of hypothesized higher malignant transformation of osteochondromas into chondrosarcoma in individuals with shoulder exostoses, we report a case of bilateral scapulothoracic osteochondromas in a patient suffering from HME. A 60-year-old female with HME complained of chest pain while being hospitalized for bilateral femoral fractures. A computed tomography scan of the chest was performed to rule out pulmonary embolism. However, bilateral osteochondromas in the scapulothoracic spaces were detected. Due to absence of radiographic evidences for malignant transformation in the patient, invasive diagnostic procedures such as biopsy and histological examination were recommended in order to exclude malignant transformation of both osteochondromas. Physicians should be aware that patients with HME who present with shoulder pain should be examined for osteochondromas in the scapulothoracic space. Due to possible sarcomatous transformation, regular follow-ups are necessary for adolescents and adults. PMID- 27761220 TI - Targeted Screening of Hip Dysplasia in Newborns: Experience at a District General Hospital in Scotland. AB - National Health Service Quality Improvement Scotland (NHS QIS) published a health technology scoping report in 2006 acknowledging that there are serious concerns within Scotland in relation to Developmental Dysplasia of Hip (DDH) as there is no formal screening program in place and there are significant variations between NHS boards leading to confusion for staff and parents. NHS QIS identified need for audit work to improve hip screening in Scotland. The aim of this study is review of current practice of selective screening for DDH. All newborns who had their first hip scan during one year period (2014) were included in this retrospective study and followed up until June 2015 to include any surgical intervention for dysplastic hip. Out of 428 babies (856 hip scans), abnormality was seen in 119 babies/147 hips (134 Graf 2a/2b, 10 hips were 2c and 3 hips were Graf grade 3). Average age when first scan was performed was 5 weeks (range 3 weeks to 22 weeks). Analysis of risk factors in 119 babies with abnormal scan was consistent with literature (83 breech, 12 family history, 12 HBW, 10 instability and 2 twins of breech). Twelve babies (16 hips) required treatment and were successfully treated in Pavlik harness. There was one case of missed/late dislocation, which lived in outside catchment area for 3 years since birth. During this study period there was no case of avascular necrosis or femoral nerve palsy as a result of treatment. In our experience, selective hip screening by ultrasound scan is useful in avoiding overtreatment and minimizing late presentations. PMID- 27761219 TI - Personal Trainer Demographics, Current Practice Trends and Common Trainee Injuries. AB - Increasing emphasis on maintaining a healthy lifestyle has led many individuals to seek advice on exercise from personal trainers. There are few studies to date that evaluate personal trainer education, practice trends, and injuries they have seen while training clients. A survey was distributed to personal trainers using Survey Monkey(r) (Palo Alto, CA, USA) with 605 personal trainers accessing the survey. An exercise related bachelor's degree was held by 64.2% of survey participants and a certification in personal training by 89.0%. The most common personal trainer certifications were from American College of Sports Medicine (59.2%) and National Strength and Conditioning Association (28.9%). Only 2.9% of all personal trainers surveyed had no exercise-related bachelor's degree and no personal trainer certification. The most common injuries seen by personal trainers during sessions were lumbar muscle strain (10.7%), rotator cuff tear/tendonitis (8.9%), shin splints (8.1%), ankle sprain (7.5%), and cervical muscle strain (7.4%). There is variability in the practices between different personal trainers when analyzing differences in collegiate education, personal trainer certifications, and strength and conditioning certifications. The clinical implication of the differences in practices is unknown as to the impact on injuries or exercise prescription effectiveness. PMID- 27761221 TI - The Basic Science of Bone Marrow Aspirate Concentrate in Chondral Injuries. AB - There has been great interest in bone marrow aspirate concentrate (BMAC) as a cost effective method in delivering mesenchymal stem cells (MSCs) to aid in the repair and regeneration of cartilage defects. Alongside MSCs, BMAC contains a range of growth factors and cytokines to support cell growth following injury. However, there is paucity of information relating to the basic science underlying BMAC and its exact biological role in supporting the growth and regeneration of chondrocytes. The focus of this review is the basic science underlying BMAC in relation to chondral damage and regeneration. PMID- 27761222 TI - Comparative Analysis of Surgical Options for Medial Collateral Ligament Repair in Terrible Triad Injury of the Elbow. AB - The aim of our study is to evaluate the clinical and radiologic outcomes in patients with terrible triad injury, who underwent surgical treatment with or without the medial collateral ligament (MCL) repair. Fourteen patients who underwent surgery with a minimum of 12-month follow-up (mean, 17 months) were reviewed. Based on the systematic treatment protocol, radial head fracture, lateral collateral ligament, and coracoid fracture were treated. Subsequently, torn MCL was repaired in 7 patients, whereas in the remaining 7 patients, the MCL was not treated. Range of motion, elbow function, and radiographs regarding the arthrosis and heterotopic ossification were assessed. At final follow-up, no significant differences were found in elbow motion or function between the groups with and without MCL repair; except the pronation and supination which had superior range in repair group. In contrast, radiologic findings such as the arthrosis were seen more frequently in patients without MCL repair than those with repair. Our results indicate the effect of MCL repair on elbow motion and function might be small, whereas osteoarthritic changes occurred more frequently in elbows without MCL repair. PMID- 27761223 TI - Topical Versus Intravenous Administration of Tranexamic Acid in Primary Total Hip Arthroplasty: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Tranexamic acid (TA) is widely used by orthopedic surgeons to decrease blood loss and the need for transfusion following total hip arthroplasty (THA). Although both intravenous and topical applications are described in the literature, there remains no consensus regarding the optimal regimen, dosage and method of delivery of TA during THA. In addition, concerns still exist regarding the risk of thromboembolic events with intravenous administration. The purpose of this meta analysis was to compare the efficacy and safety of topical versus intravenous administration of TA in THA. A systemic review of the electronic databases PubMed, CENTRAL, EMBASE and Google Scholar was undertaken to identify all randomized controlled trials (RCTs) comparing the topical and intravenous administration of TA during THA, in terms of total blood loss, rate of blood transfusion and incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) post-operatively. A meta-analysis was performed to evaluate and compare the efficacy and safety of both methods of administration. Of 248 potentially relevant papers, three RCTs comprising (482) were eligible for data extraction and meta-analysis. The results showed a slightly higher amount of blood loss [Mean Difference (MD) - 46.37, P=0.12, 95% confidence interval (CI) - 12.54 to 105.29] and rate of transfusion (Risk Ratio 1.30, P=0.39, 95%CI 0.71 to 2.37) postoperatively in the topical TA group, but both did not reach statistical significance. There were 3 cases (1.2%) of DVT/PE in the intravenous group and one case (0.4%) in the topical group. Topical TA is an effective and safe method to reduce blood loss and the rate of transfusion following primary THA. It has comparative effectiveness to IV administration with slightly less post-operative thromboembolic complications. Larger and better-designed RCTs are required to establish the optimum dosage and regimen for topical use. PMID- 27761224 TI - Neuro-Ophthalmological Manifestations after Intramuscular Medroxyprogesterone: A Forme Fruste of Idiopathic Intracranial Hypertension? AB - We report a case of a 22-year-old female student nurse who presented to hospital with an acute neuro-ophthalmological syndrome characterized by papilledema, ataxia, ophthalmoplegia and headache after a single first time use of 150 mg medroxyprogesterone intramuscular injection. Clinical, laboratory, radiological and ophthalmological investigations were in keeping with the diagnosis of idiopathic intracranial hypertension but lumbar puncture did not show a raised cerebrospinal fluid pressure suggesting a forme fruste of this entity. Her neuro ophthalmological clinical features responded well to acetazolamide and diagnostic/therapeutic lumbar puncture. Full recovery was achieved three months after medroxyprogesterone usage. Health care providers must be aware of this adverse drug reaction. PMID- 27761225 TI - Multiple Sclerosis Patients Valuing Their Own Health Status: Valuation and Psychometric Properties of the 15D. AB - An ongoing debate on decision and cost-utility analyses is whether to use preferences of general public or patients. The aim of this study was to replicate the valuation procedure of the multi-attribute utility generic measure, 15D, using a sample of multiple sclerosis (MS) patients and to assess its psychometric properties. Consecutive outpatient MS patients were recruited from two MS centers in Greece. The three-stage valuation procedure was applied and, with the use of elicited preference weights, an MS patients' algorithm was developed. The original Finnish value set derived from healthy individuals was also used to calculate scores and a comparison between the two algorithms was made. A total of 64 MS patients were evaluated. The 15D scores obtained with the MS patients' valuation algorithm were higher than the original one. The derived utilities differed significantly with respect to age, depressive symptoms, Expanded Disability Status Scale score and clinical form. MS patients indicated as most important domains mobility, mental functioning and vitality. Cronbach's alpha was estimated 0.876 and correlations between relevant dimensions of the instruments were moderate to high. The 15D was generally feasible and reliable in patients with MS and the valuation system yielded acceptable psychometric properties. PMID- 27761226 TI - Injectable Disease Modifying Agents in Multiple Sclerosis: Pattern of Medication Use and Clinical Effectiveness. AB - The objective of this study was to assess long-term use, adherence and efficacy of injectable disease modifying agents (DMAs). Multiple Sclerosis (MS) patients diagnosed during 2002-2010 with early treatment start and at least one year in first choice medication were included in a large university district in Finland. Annualized relapse rates (ARR) during each treatment period were studied, and number of switches by medication evaluated. Use of health care facilities during 2002-2010 was assessed. In the study were included 113 MS patients; 15 (13%) switched medication. The mean duration of treatment period (128) was 3.8 years. In 77% (98/128) the treatment continued with the first DMA for (mean) 3.8 years, in 19% (25/128) with the second for 3.5 years and in 4% (5/128) with the third for 4.8 years. Mean ARR was 0.26, with 54% (69/128) of the periods relapse free. Mean ARR during the treatment periods with product switch was 0.41 before, and 0.28 after the switch, showing a trend towards better efficacy with the second DMA. The usage of health care resources remained within the guidelines. Long-term adherence to first choice DMA was observed, and a switch of product within the DMAs showed continuous adherence and efficacy. The efforts to seek a clinically effective and well tolerated agent within the first-line DMAs is warranted, leading to continued adherence and increased clinical effectiveness. PMID- 27761227 TI - The Chronic Encephalopathy of Parry Romberg Syndrome and En Coupe De Sabre with a 31-Year-History in a West Indian Woman: Clinical, Immunologic and Neuroimaging Abnormalities. AB - We describe a case of Parry Romberg syndrome/en coupe de sabre in a woman whose disease started as seizures at age 8 but was diagnosed at the age 39. During these 31 years she got married, completed a first degree at university, had two successful pregnancies and has been gainfully employed. The features of generalized tonic-clonic seizures, autoimmune abnormalities, ocular abnormalities, morphea en coup de sabre and brain imaging abnormalities were present. Areas of parietal lobe cerebral calcification were encountered on the computed tomographic scan and bilateral periventricular white matter changes on the magnetic resonance imaging with frontal, temporal and parietal lobe brain atrophy ipsilateral to the facial hemiatrophy. Clinical, immunologic and neuroradiological abnormalities are discussed. In some cases, this illness can run a benign and stable course. PMID- 27761228 TI - Hereditary Neuropathy With Liability to Pressure Palsies: A Single-Center Experience in Southern Brazil. AB - The spectrum of clinical and electrophysiological features in hereditary neuropathy with liability to pressure palsies (HNPP) is broad. We analyze a series of Brazilian patients with HNPP. Correlations between clinical manifestations, laboratory features, electrophysiological analyze, histological and molecular findings were done. In five cases, more than one episode occurred before diagnosis. Median nerve in the carpal tunnel at the wrist, ulnar nerve in its groove at the elbow, fibular nerve in the head of the fibula at the knee, radial nerve in its groove of the humerus and suprascapular nerve in its notch at the supraspinous fossa were found as focal neuropathies. One patient presented with persistent writer's cramp after ulnar nerve palsy. Nerve conduction studies showed focal neuropathy in all patients and concomitant generalized symmetrical neuropathy in eight patients. Molecular analysis of the PMP22 gene detected deletion of the 1.5-Mb fragment in all patients. PMID- 27761229 TI - Neurosyphilis With Normal Pressure Hydrocephalus and Dementia Paralytica: Serial Clinical, Laboratory and Radiological Correlations in the 21st Century. AB - We report a case of a 46-year-old man presenting with a progressive cognitive decline, ataxic gait, urinary incontinence for 4 months and neuroimaging consistent with normal pressure hydrocephalus. The atypical presentation of a progressively worsening dysphasia and a right hemiparesis dismissed as a vascular event 1 month earlier associated with normal pressure hydrocephalus prompted further investigations confirming neurosyphilis also manifesting as dementia paralytica. Treatment using consensus guidelines led to resumption of activities of daily living. Neurosyphilis, considered rare in the neuroimaging era, must still be considered a reversible cause of dementia and other neurological manifestations in contemporary neurological practice. PMID- 27761230 TI - Therapeutic potential of the renin angiotensin system in ischaemic stroke. AB - The renin angiotensin system (RAS) consists of the systemic hormone system, critically involved in regulation and homeostasis of normal physiological functions [i.e. blood pressure (BP), blood volume regulation], and an independent brain RAS, which is involved in the regulation of many functions such as memory, central control of BP and metabolic functions. In general terms, the RAS consists of two opposing axes; the 'classical axis' mediated primarily by Angiotensin II (Ang II), and the 'alternative axis' mediated mainly by Angiotensin-(1-7) (Ang-(1 7)). An imbalance of these two opposing axes is thought to exist between genders and is thought to contribute to the pathology of cardiovascular conditions such as hypertension, a stroke co-morbidity. Ischaemic stroke pathophysiology has been shown to be influenced by components of the RAS with specific RAS receptor antagonists and agonists improving outcome in experimental models of stroke. Manipulation of the two opposing axes following acute ischaemic stroke may provide an opportunity for protection of the neurovascular unit, particularly in the presence of pre-existing co-morbidities where the balance may be shifted. In the present review we will give an overview of the experimental stroke studies that have investigated pharmacological interventions of the RAS. PMID- 27761231 TI - Faecal biomarker patterns in patients with symptoms of irritable bowel syndrome. AB - OBJECTIVE: To determine rates of faecal biomarker results capable of suggesting potentially treatable causes of irritable bowel syndrome (IBS) symptomatology in a population of patients with symptoms of IBS who meet Rome III criteria for that condition. DESIGN: Descriptive, retrospective study in which faecal biomarker results (dichotomised into 'normal' and 'abnormal' values) were related to data from patient-completed questionnaire data identifying demographics, Rome III criteria for IBS and IBS phenotype (IBS-D, IBS-C, IBS-M and IBS-U). SETTING: Commercial reference laboratory. PATIENTS: Individuals whose physicians ordered faecal biomarker testing for evaluation of chronic abdominal symptoms consistent with IBS. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Rates of occurrence of abnormal results on any of seven faecal biomarkers suggesting a treatable cause for IBS symptoms. RESULTS: Abdominal symptoms meeting Rome III criteria for IBS were present in 3553 records (the population), which were subjected to further analysis. Abnormal biomarker results (the outcomes) occurred in 94% of cases; 73% and 65% of records indicated growth of a bacterial potential pathogen and low growth of beneficial organisms, respectively. Abnormal results for all other faecal biomarkers occurred with frequencies from 5% to 13%. Frequency of abnormal results for elastase, calprotectin, eosinophil protein X, and beneficial organisms rose significantly with age, and differed significantly across IBS phenotypes. CONCLUSIONS: A large proportion of patients manifesting symptoms meeting Rome III IBS diagnostic criteria have faecal biomarker results indicating potential underlying, treatable causes of their symptoms. Faecal biomarker testing is an appropriate means of identifying potentially treatable causes of IBS symptoms. PMID- 27761232 TI - Monitoring the premalignant potential of Barrett's oesophagus'. AB - The landscape for patients with Barrett's oesophagus (BE) has changed significantly in the last decade. Research and new guidelines have helped gastroenterologists to better identify those patients with BE who are particularly at risk of developing oesophageal adenocarcinoma. In parallel, developments in endoscopic image enhancement technology and optical biopsy techniques have improved our ability to detect high-risk lesions. Once these lesions have been identified, the improvements in minimally invasive endoscopic therapies has meant that these patients can potentially be cured of early cancer and high-risk dysplastic lesions without the need for surgery, which still has a significant morbidity and mortality. The importance of reaching an accurate diagnosis of BE remains of paramount importance. More work is needed, however. The vast majority of those undergoing surveillance for their BE do not progress towards cancer and thus undergo a regular invasive procedure, which may impact on their psychological and physical well-being while incurring significant cost to the health service. New work that explores cheaper endoscopic or non-invasive ways to identify the at-risk individual provides exciting avenues for research. In future, the diagnosis and monitoring of patients with BE could move away from hospitals and into primary care. PMID- 27761233 TI - Using best practice to create a pathway to improve management of irritable bowel syndrome: aiming for timely diagnosis, effective treatment and equitable care. AB - BACKGROUND: Irritable bowel syndrome (IBS) costs the National Health Service almost L12 million per annum. Despite national guidelines advising primary care management, these have failed to stem secondary care referrals of patients with likely IBS for unnecessary and costly assessment and investigation without necessarily achieving resolution of their symptoms. METHODS: In 2011, an integrated team from primary and secondary care developed a business case using baseline data to create a Somerset-wide IBS pathway using Clinical Commissioning Group funding. This provided face-to-face general practitioners (GP) education, developed a diagnostic pathway and funded faecal calprotectin (FC) testing to exclude inflammatory pathology for patients aged 16-45 years with likely IBS and no alarm symptoms. For those with FC<=50 MUg/g, we provided a management algorithm and community-based dietetic treatment. Audit results measured usage and outcomes from FC testing, changes in patterns and costs of new patients reviewed in gastroenterology outpatients and dietetic IBS treatment outcomes. RESULTS: The proportion of new patient slots used reduced from 14.3% to 8.7% over 10 months while overall costs reduced by 25% for patients with no alarm symptoms and likely IBS aged 16-45 years. FC results confirmed research findings with no inflammatory pathology, if FC<=50 MUg/g over 2 years. 63% of patients had satisfactory control of their IBS after specialist dietetic input with 74% reporting improved quality of life. CONCLUSIONS: The combination of GP education, providing diagnosis and management pathways, using FC to exclude inflammatory pathology and providing an effective treatment for patients with likely IBS appeared successful in our pilot. This proved cost-effective, reduced secondary care involvement and improved patient care. PMID- 27761234 TI - The elimination half-life of crystalloid fluid is shorter in female than in male volunteers: a retrospective population kinetic analysis. AB - BACKGROUND: A recent review article suggests that elimination of infused crystalloid fluid might occur faster in females than in males. To study this question, a population kinetic analysis was performed to compare the turnover of buffered Ringer's solution when infused at different rates in males and females. METHODS: Data were retrieved from seven series of experiments where 44 intravenous infusions of Ringer's acetate had been given to female volunteers and 67 to male volunteers. Frequent measurements of the blood hemoglobin and the urinary excretion were used as input in a kinetic two-volume model with micro constants and covariates, using a nonlinear mixed effects software. The key outcome measure was the rate of irreversible elimination of infused fluid, which was expressed as the half-life, obtained as the excreted urine divided by the modeled plasma volume expansion over time. RESULTS: The half-life amounted to 24 min (95 % confidence interval, 21-27) in the females and 38 min (33-42) in the males. The urinary excretion differed somewhat less than suggested by these figures during the experimental period (3-4 h) because the plasma volume became less expanded in the females. This was due to that fluid that had been distributed peripheral tissues (the interstitium) returned slightly more slowly to the central fluid space (the plasma) in the females. Gender did not serve as a statistically significant covariate to other rate constants in the kinetic model. CONCLUSIONS: The half-life of infused Ringer's acetate was 60 % longer in healthy male volunteers than in female volunteers. PMID- 27761235 TI - Keratinocytes at the uppermost layer of epidermis might act as sensors of atmospheric pressure change. AB - It has long been suggested that climate, especially atmospheric pressure change, can cause health problems ranging from migraine to myocardial infarction. Here, I hypothesize that the sensory system of epidermal keratinocytes mediates the influence of atmospheric pressure change on the human physiological condition. We previously demonstrated that even subtle changes of atmospheric pressure (5-20 hPa) induce elevation of intracellular calcium level in cultured human keratinocytes (excitation of keratinocytes). It is also established that communication occurs between epidermal keratinocytes and peripheral nerve systems. Moreover, various neurotransmitters and hormones that influence multiple systems (nervous, cardiovascular, endocrine, and immune systems) are generated and released from epidermal keratinocytes in response to various external stimuli. Thus, I suggest that pathophysiological phenomena induced by atmospheric pressure changes might be triggered by epidermal keratinocytes. PMID- 27761237 TI - The effectiveness of conservative management for retropharyngeal abscesses greater than 2 cm. AB - OBJECTIVES: Conservative management for retropharyngeal abscesses <2 cm is now a first line option. It is unclear if conservative management can be used to manage larger abscesses without increased morbidity and mortality. STUDY DESIGN: A prospective case series was performed from 2012 to 2015 by the Otolaryngology department of the San Fernando General Hospital involving pediatric patients who presented with retropharyngeal abscesses. All patients were initially treated with antibiotics alone. METHODS: Patients with clinical features and CT scan confirmation of a retropharyngeal abscess were included in the study. Those who improved clinically and biochemically within 48 h continued to be treated conservatively and those who deteriorated had surgical intervention. RESULTS: Sixteen patients fulfilled the inclusion criteria. Most patients were Afro Trinidadian males between the ages of two and five who were also found to be iron deficient. Drooling was a sensitive predictor for the presence of an abscess but did not indicate the need for drainage. Hoarseness was the clinical feature that prompted surgical intervention. Sixty three percent of patients had an abscess >2 cm of which 90% improved within 48 h. One patient required surgical drainage with no increase in morbidity or mortality. CONCLUSION: Conservative management of retropharyngeal abscesses >2 cm can be offered to patients during the first 48 h. If the patient demonstrates clinical and biochemical improvement, antibiotics alone can be continued. If the patient deteriorates, surgical drainage can be subsequently performed with no increase in morbidity and mortality. PMID- 27761238 TI - Clinical report: variable phenotypic expression in a large sibling cohort with a deletion of 4p16.1. AB - We report a half-sibling cohort with deletion of 4p16.1, astigmatism, gross and fine motor delay, variable intellectual disability, and variable behavioral concerns. However, two siblings without the deletion also had learning delays and psychological concerns. Thus, variable phenotypic expression was seen and the significance of deletion of 4p16.1 remains unclear. PMID- 27761236 TI - Utility of susceptibility-weighted imaging in Parkinson's disease and atypical Parkinsonian disorders. AB - In the clinic, the diagnosis of Parkinson's disease (PD) largely depends on clinicians' experience. When the diagnosis is made, approximately 80% of dopaminergic cells in the substantia nigra (SN) have been lost. Additionally, it is rather challenging to differentiate PD from atypical parkinsonian disorders (APD). Clinially-available 3T conventional MRI contributes little to solve these problems. The pathologic alterations of parkinsonism show abnormal brain iron deposition, and therefore susceptibility-weighted imaging (SWI), which is sensitive to iron concentration, has been applied to find iron-related lesions for the diagnosis and differentiation of PD in recent decades. Until now, the majority of research has revealed that in SWI the signal intensity changes in deep brain nuclei, such as the SN, the putamen (PUT), the globus pallidus (GP), the thalamus (TH), the red nucleus (RN) and the caudate nucleus (CN), thereby raising the possibility of early diagnosis and differentiation. Furthermore, the signal changes in SN, PUT and TH sub-regions may settle the issues with higher accuracy. In this article, we review the brain iron deposition of PD, MSA-P and PSP in SWI in the hope of exhibiting a profile of SWI features in PD, MSA and PSP and its clinical values. PMID- 27761239 TI - Discordant monoamniotic twins with Pena-Shokeir phenotype. AB - Pena-Shokeir phenotype is a rare disorder. However, its etiology is incompletely understood. It may be familial or may be due to anoxic-ischemic etiology. Although rare, it can affect one twin in a monoamniotic pregnancy, most likely due to early cord entanglement. PMID- 27761240 TI - Multiple endocrine neoplasia phenocopy revealed as a co-occurring neuroendocrine tumor and familial hypocalciuric hypercalcemia type 3. AB - Familial hypocalciuric hypercalcemia type 3 should be considered as differential diagnosis in patients with suspected primary hyperparathyroidism and/or suspected multiple neoplasia syndrome, as correct diagnosis will spare the patients for going through multiple futile parathyroidectomies and for the worry of being diagnosed with a cancer susceptibility syndrome. PMID- 27761241 TI - The potential role of HER2 upregulation in metastatic breast cancer to the uterus: a case report. AB - Abnormal uterine bleeding in a patient on maintenance hormonal therapy for breast cancer should raise concern for endometrial abnormalities including rare uterine metastasis from the breast. Hormonal receptor profile changes in metastatic lesions favoring human epidermal growth factor receptor 2 (HER2) overexpression may be involved in the pathogenesis of metastasis to the uterus. PMID- 27761242 TI - Idiopathic sclerosing orbital inflammation mimicking a malignant spindle cell tumor in a dog. AB - A dog presented with a retrobulbar mass, diagnosed histopathologically as malignant spindle cell neoplasia. Emergence of analogous findings in the contralateral orbit prompted extended immunohistochemistry of the original mass and reassignment to idiopathic sclerosing orbital inflammation. Early incisional biopsy with extended immunohistochemical analysis should be considered for canine orbital tumors. PMID- 27761243 TI - Common electrocardiogram variations pre- and post-marathon. AB - Electrocardiographic changes can be present in marathon runners. These findings may be misinterpreted as malignant by healthcare providers. For example, incomplete right bundle branch block, early ventricular repolarization, and left ventricular hypertrophy by voltage criteria alone are quite common in athletes, yet considered benign. PMID- 27761244 TI - Right parietal source in Mahjong-induced seizure: a system epilepsy of focal origin. AB - Mahjong, a game similar to bridge and chess in Western cultures, can cause reflex seizure. We report a case of Mahjong-induced seizures with the first documentation of ictal electroencephalography (EEG) findings, which showed secondarily generalized partial seizure of the right parietal origin. PMID- 27761245 TI - Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities. AB - This report constitutes the first report of a cryptic exonic splice-donor site in CDK5RAP2, highlights the importance of evaluating novel splice mutations, and suggests that the phenotypic range associated with CDK5RAP2 mutations may include skin pigmentary abnormalities. PMID- 27761246 TI - Bipolar irrigated radiofrequency ablation of resistant ventricular tachycardia with a septal intramural origin: the initial experience and a description of the method. AB - Bipolar radiofrequency (RF) ablation is effective in treatment of ventricular tachycardia originating from thick interventricular septum. The RF generator and CARTO system can be used to precisely and safely perform ablation. Standard ablation catheter can be used with indifferent ablation electrode connected to the electrode receptacle in RF generator with custom-made cable. PMID- 27761247 TI - Immature gastric teratoma in an infant: a case report and review of the literatures. AB - Immature gastric teratoma is an uncommon germ cell tumor of the stomach. We report a rare case of immature gastric teratoma in an infant with down syndrome with clinically presenting with hematemesis and severe anemia. Complete surgical resection remains the cornerstone of treatment. PMID- 27761248 TI - Importance of genetic testing in global health during the evaluation of familial microcephaly. AB - A focused genetic workup is useful in determining the cause of familial microcephaly, especially in the setting of mildly different phenotypes. As illustrated by this case from an impoverished international urban location, one must not assume the etiology for the apparent familial microcephaly is the same for all affected members. PMID- 27761250 TI - Intrapancreatic accessory spleen: a rare cause of recurrence of immune thrombocytopenic purpura. AB - Accessory splenectomy should be considered in any patient with recurrence of immune thrombocytopenic purpura, if studies (scintigraphy using heat-damaged Tc99m-labeled red blood cells) are suggestive of residual functional splenic tissue. The most common benefit after removal of accessory spleen seems to be the reduction of dose in medical treatment. PMID- 27761249 TI - Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2. AB - Recurrent lethal perinatal osteogenesis imperfecta may result from asymptomatic parental mosaicism. A previously unreported mutation in COL1A2 leads to recurrent cases of fetal osteogenesis imperfecta Sillence type IIA, which emphasizes the importance of clinical and genetic evaluation of mosaicism in asymptomatic parents as verified mosaicism highly increases recurrence risk. PMID- 27761252 TI - Marked ST-segment elevation during permanent pacemaker implantation. AB - Some acute complications are known during permanent pacemaker implantation such as pneumothorax, lead perforation, lead dislodgement, and hemorrhage. ST-segment elevation in electrocardiogram during implantation is rare, but it might indicate critical complication like myocardial ischemia or ventricular perforation. Physicians should pay attention about ST-segment change during pacemaker implantation. PMID- 27761251 TI - Reconstruction of massive full-thickness abdominal wall defect: successful treatment with nonabsorbable mesh, negative pressure wound therapy, and split skin grafting. AB - We demonstrate that it is possible to use a nonabsorbable mesh for abdominal wall reconstruction after total wound rupture and successfully split-skin graft directly on the mesh. Sufficient granulation tissue formation prior to skin grafting was obtained with long-term use of negative pressure wound therapy (NPWT). PMID- 27761253 TI - A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome. AB - Little is known about the influence of pregnancy on pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome. We experienced a rare case of pregnancy complicated with PAPA syndrome. The patient had various histories of skin and joint disorders and experienced subarachnoid hemorrhage during pregnancy; however, her skin lesion was unaffected. PMID- 27761254 TI - Acute cardiac decompensation in a patient with beta-thalassemia and diabetes mellitus following cessation of chelation therapy. AB - Patients with higher liver iron stores are likely to have a worse cardiac outcome following noncompliance with chelation. Cardiovascular magnetic resonance identifies myocardial siderosis allowing optimization of iron chelation regimes. Diabetes puts thalassemic patients at increased risk of myocardial fibrosis. Dual chelation therapy with deferoxamine and deferiprone offers improved cardiac outcomes. PMID- 27761255 TI - Congenital insensitivity to pain and anhydrosis due to a rare mutation and that is complicated by inflammatory bowel disease and amyloidosis: a case report. AB - Patients with congenital insensitivity to pain and anhydrosis syndrome are at risk for renal amyloidosis and inflammatory bowel disease. Physicians caring for such patients should be aware of these complications. PMID- 27761257 TI - Totally submuscular implantation of subcutaneous implantable cardioverter defibrillator: a safe and effective solution for obese or oversized patients. AB - The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a safe alternative to transvenous ICD. We describe a submuscular S-ICD placement technique in a severely obese with an oversized chest. Submuscular configuration allows optimal system positioning and impendence values warranting a safe and effective shock transmission. This technique is safe and improves patients comfort. PMID- 27761256 TI - Hypercalcemia in pregnancy - a multifaceted challenge: case reports and literature review. AB - Hypercalcemia in pregnancy is an uncommon event that can cause major maternal morbidity and/or fetal or neonatal morbidity and mortality. Management is a challenge for the clinicians, especially as regards to investigations in pregnancy, surgery, and the use of cinacalcet and bisphosphonates. We present three case reports and discuss management. PMID- 27761258 TI - Papillomatosis cutis lymphostatica. AB - Papillomatosis cutis lymphostatica is a benign, usually asymptomatic and underreported condition resulting from primary lymphedema or damage of lymphatic vessels due to diabetes. Cases have only been published sporadically. The presented image may help future colleagues to establish the diagnosis. PMID- 27761259 TI - Partial splenectomy for a giant epidermoid cyst of the spleen. AB - The splenic epidermoid cysts are rare benign tumors, and a definitive treatment remains unclear. Although some spleen-preserving approaches have been reportedly used, splenic cyst recurrence usually occurs in true cyst cases, wherein the cyst is incompletely removed. In our case, partial splenectomy was performed and the giant cyst was completely removed. PMID- 27761260 TI - Hemophagocytic lymphohistiocytosis as an unusual cause of prolonged bicytopenia after chemotherapy. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare cause of cytopenia and is often associated with lymphoma. The occurrence of HLH in the course of lymphoma treatment could be an indicator for refractory disease. PMID- 27761261 TI - Experiences of women in secure care who have been prescribed clozapine for borderline personality disorder. AB - BACKGROUND: Clozapine is an atypical antipsychotic medicine which can cause significant side-effects. It is often prescribed off-license in severe cases of borderline personality disorder contrary to national treatment guidelines. Little is known about the experiences of those who take clozapine for borderline personality disorder. We explored the lived-experience of women in secure inpatient care who were prescribed clozapine for borderline personality disorder. FINDINGS: Adult females (N = 20) participated in audio-taped semi-structured interviews. Transcripts were subject to thematic analysis. The central themes related to evaluation, wellbeing, understanding and self-management; for many, their subjective wellbeing on clozapine was preferred to prior levels of functioning and symptomatology, sometimes profoundly so. The negative and potentially adverse effects of clozapine were explained as regrettable but relatively unimportant. CONCLUSIONS: When psychological interventions are, at least initially, ineffective then clozapine treatment is likely to be evaluated positively by a group of women with borderline personality disorder in secure care despite the potential disadvantages. PMID- 27761262 TI - Women with exposure to childhood interpersonal violence without psychiatric diagnoses show no signs of impairment in general functioning, quality of life and sexuality. AB - BACKGROUND: Childhood interpersonal violence is a major risk factor for developing Posttraumatic Stress Disorder (PTSD), other axis-I disorders or Borderline Personality Disorder (BPD). Individuals with a history of childhood sexual abuse (CSA) and childhood physical abuse (CPA) who meet the criteria of any axis-I disorder usually also exhibit general psychopathologic symptoms and impairments in quality of life and sexuality. The present study investigates whether women with a history of potentially traumatic CSA/CPA without any axis-I disorder or BPD show subthreshold symptoms of PTSD-specific and general psychopathology and impairments in global functioning, quality of life, and sexuality. METHODS: Data were obtained from N = 92 female participants: n = 31 participants with a history of potentially traumatic CSA/CPA (defined as fulfilling PTSD criterion A) without any axis-I disorder or BPD; n = 31 participants with PTSD related to CSA/CPA; and n = 30 healthy controls without any traumatic experiences. All three groups were matched for age and education. Those with a history of CSA/CPA with and without PTSD were further matched with regard to severity of physical and sexual abuse. RESULTS: While women with a history of potentially traumatic CSA/CPA without axis-I disorder or BPD clearly differed from the PTSD-group in the collected measures, they did not differ from healthy controls (e.g., GAF:87, BSI:0.3, BDI-II:4.5). They showed neither PTSD specific nor general subthreshold symptoms nor any measurable restrictions in quality of life or sexual satisfaction. CONCLUSIONS: Women with a history of potentially traumatic childhood interpersonal violence without axis-I disorder or BPD show a high level of functioning and a low level of pathological impairment that are comparable to the level of healthy controls. Further studies are needed to identify what helped these women survive these potentially traumatic experiences without developing any mental disorders. TRIAL REGISTRATION: German Clinical Trials Registration ID: DRKS00006095. Registered 21 May 2014. PMID- 27761264 TI - Monitoring of pesticides water pollution-The Egyptian River Nile. AB - BACKGROUND: Persistent organic pollutants represent about 95 % of the industrial sector effluents in Egypt. Contamination of the River Nile water with various pesticides poses a hazardous risk to both human and environmental compartments. Therefore, a large scale monitoring study was carried on pesticides pollution in three geographical main regions along the River Nil water stream, Egypt. METHODS: Organochlorine and organophosphorus pesticides were extracted by liquid-liquid extraction and analyzed by GC-ECD. RESULTS: Organochlorine pesticides mean concentrations along the River Nile water samples were 0.403, 1.081, 1.209, 3.22, and 1.192 MUg L-1 for endrin, dieldrin, p, p'-DDD, p, p'-DDT, and p, p'-DDE, respectively. Dieldrin, p, p'-DDT, and p, p'-DDE were above the standard guidelines of the World Health Organization. Detected organophosphorus pesticides were Triazophos (2.601 MUg L-1), Quinalphos (1.91 MUg L-1), fenitrothion (1.222 MUg L-1), Ethoprophos (1.076 MUg L-1), chlorpyrifos (0.578 MUg L-1), ethion (0.263 MUg L-1), Fenamiphos (0.111 MUg L-1), and pirimiphos-methyl (0.04 MUg L 1). Toxicity characterization of organophosphorus pesticides according to water quality guidelines indicated the hazardous risk of detected chemicals to the public and to the different environmental compartments. The spatial distribution patterns of detected pesticides reflected the reverse relationship between regional temperature and organochlorine pesticides distribution. However, organophosphorus was distributed according to the local inputs of pollutant compounds. CONCLUSIONS: Toxicological and water quality standards data revealed the hazardous risk of detected pesticides in the Egyptian River Nile water to human and aquatic life. Thus, our monitoring data will provide viewpoints by which stricter legislation and regulatory controls can be admitted to avoid River Nile pesticide water pollution. PMID- 27761263 TI - Towards the just and sustainable use of antibiotics. AB - The emergence and spread of antibiotic resistant pathogens poses a big challenge to policy-makers, who need to oversee the transformation of health systems that evolved to provide easy access to these drugs into ones that encourage appropriate use of antimicrobials, whilst reducing the risk of resistance. This is a particular challenge for low and middle-income countries with pluralistic health systems where antibiotics are available in a number of different markets. This review paper considers access and use of antibiotics in these countries from a complex adaptive system perspective. It highlights the main areas of intervention that could provide the key to addressing the sustainable long term use and availability of antibiotics. A focus on the synergies between interventions addressing access strategies, antibiotic quality, diagnostics for low-resource settings, measures to encourage just and sustainable decision making and help seeking optimal therapeutic and dosing strategies are key levers for the sustainable future of antibiotic use. Successful integration of such strategies will be dependent on effective governance mechanisms, effective partnerships and coalition building and accurate evaluation systems at national, regional and global levels. PMID- 27761265 TI - Relationship between thyroid stimulating hormone and night shift work. AB - BACKGROUND: Night shift work has well-known adverse effects on health. However, few studies have investigated the relationship between thyroid diseases and night shift work. This study aimed to examine night shift workers and their changes in thyroid stimulating hormones (TSH) levels over time. METHODS: Medical check-up data (2011-2015) were obtained from 967 female workers at a university hospital in Incheon, Korea. Data regarding TSH levels were extracted from the records, and 2015 was used as a reference point to determine night shift work status. The relationships between TSH levels and night shift work in each year were analyzed using the general linear model (GLM). The generalized estimating equation (GEE) was used to evaluate the repeated measurements over the 5-year period. RESULTS: The GEE analysis revealed that from 2011 to 2015, night shift workers had TSH levels that were 0.303 mIU/L higher than the levels of non-night shift workers (95 % CI: 0.087-0.519 mIU/L, p = 0.006) after adjusting for age and department. When we used TSH levels of 4.5 >= mIU/L to identify subclinical hypothyroidism, night shift workers exhibited a 1.399 fold higher risk of subclinical hypothyroidism (95 % CI: 1.050-1.863, p = 0.022), compared to their non-night shift counterparts. CONCLUSIONS: This result of this study suggests that night shift workers may have an increased risk of thyroid diseases, compared to non night shift workers. PMID- 27761266 TI - Ambulatory heart rate of professional taxi drivers while driving without their typical psychosocial work stressors: a pilot study. AB - BACKGROUND: Few studies have examined ambulatory cardiovascular physiological parameters of taxi drivers while driving in relation to their occupational hazards. This study aims to investigate and quantify the impact of worksite physical hazards as a whole on ambulatory heart rate of professional taxi drivers while driving without their typical worksite psychosocial stressors. METHODS: Ambulatory heart rate (HRdriving) of 13 non-smoking male taxi drivers (24 to 67 years old) while driving was continuously assessed on their 6-hour experimental on-road driving in Los Angeles. Percent maximum HR range (PMHRdriving) of the drivers while driving was estimated based on the individual HRdriving values and US adult population resting HR (HRrest) reference data. For analyses, the HRdriving and PMHRdriving data were split and averaged into 5-min segments. Five physical hazards inside taxi cabs were also monitored while driving. Work stress and work hours on typical work days were self-reported. RESULTS: The means of the ambulatory 5-min HRdriving and PMHRdriving values of the 13 drivers were 80.5 bpm (11.2 bpm higher than their mean HRrest) and 10.7 % (range, 5.7 to 19.9 %), respectively. The means were lower than the upper limits of ambulatory HR and PMHR for a sustainable 8-hour work (35 bpm above HRrest and 30 % PMHR), although 15-27 % of the 5-min HRdriving and PMHRdriving values of one driver were higher than the limits. The levels of the five physical hazards among the drivers were modest: temperature (26.4 +/- 3.0 degrees C), relative humidity (40.7 +/- 10.4 %), PM2.5 (21.5 +/- 7.9 MUg/m3), CO2 (1,267.1 +/- 580.0 ppm) and noise (69.7 +/- 3.0 dBA). The drivers worked, on average, 72 h per week and more than half of them reported that their job were often stressful. CONCLUSIONS: The impact of physical worksite hazards alone on ambulatory HR of professional taxi drivers in Los Angeles generally appeared to be minor. Future ambulatory heart rate studies including both physical and psychosocial hazards of professional taxi drivers are warranted. PMID- 27761267 TI - The association between long working hours and hearing impairment in noise unexposed workers: data from the 5th Korea National Health and Nutrition Examination Survey (KNHANES 2010-2012). AB - BACKGROUND: This study is aimed at finding out the relationship between long working hours, one of major job stress elements, and hearing impairment in unexposed workers to occupational and environmental noise. METHODS: This study was performed on 1628 regular, full-time wage workers between the age of 25-64 who indicated in the survey of having no experience of exposure to noise, normal otoscopic findings, and not suffering from diabetes based on the data from the fifth Korea National Health and Nutrition Examination Survey (KNHANES 2010-2012). The average working hours per week was categorized into 40 h and lower group, more than 40 to 48 h group, more than 48 to 60 h group, and more than 60 h group. The groups were defined as suffering from low or high frequencies hearing impairment if the average hearing threshold for 0.5, 1, 2 kHz or 3, 4, 6 kHz in both ears exceeds 25 dB based on the pure tone audiometry. The association between average weekly working hours and hearing impairment was analyzed using logistic regression after gender stratification. RESULTS: The prevalences of low and high frequencies hearing impairment in male workers were 4.3 and 28.6 %, respectively, which were much higher than female's prevalence of 2.7 and 11.1 %. For male workers, no significant association was found between average weekly working hours and low and high frequencies hearing impairment. For female workers, odds ratios (OR) of low and high frequencies hearing impairment were 4.22 (95 % confidence interval (CI) 1.09-16.27) and 4.49 (95 % CI 1.73-11.67), respectively, after controlling for several related factors, such as, age, Body Mass Index (BMI), socio-economic status, health-related behavioral, and occupational characteristics variables, in the final model in the group working more than 60 h compared to the group working 40 h and lower. In addition, a dose response relationship was observed that ORs of low and high frequencies hearing impairment were increased according to increasing average weekly working hours. CONCLUSIONS: The association between long working hours and hearing impairment in both low and high frequencies was significant in Korean female workers with a dose-response relationship. Therefore, the law to change the culture of long working hours should be enacted in order to protect the workers' health and improve the quality of life in Korean workers. PMID- 27761268 TI - Promising New Wart Treatment: A Randomized, Placebo-Controlled, Clinical Trial. AB - BACKGROUND: Warts are common dermatological lesion caused by skin epithelial cells' infection with human Papillomavirus (HPV). OBJECTIVES: This study aimed to assess the efficacy of a new method for the treatment of dermal warts. PATIENTS AND METHODS: In this clinical trial study, 60 patients (older than 10 years) with dermal warts living in Baneh city, west of Iran, were allocated into the intervention and control groups using the block randomized method in 2012. In the intervention group, outer layers of the dermal wart carved using scalpel and HD tablet set on it and covered with adhesive. In the second and third days, it was repeated again. All stages in the intervention group were similar to the placebo group. Placebo was prepared by a pharmacologist, which was similar to the HD tablet. In both groups, patients were examined one week and one month after taking the last tablet by the physician in terms of improvement or lack of improvement. Data were analyzed by SPSS software version 18 using chi-square test, Fisher's exact test, Mann-Whitney test and ANOVA for repeated measures. RESULTS: In the first week after the intervention, warts were changed in 93.3% of the cases; however, no changes were recorded in the control group. One month after follow-up, the mean was 0.4 +/- 0.7 in the intervention group and 5.5 +/- 4.9 in the control group (P = 0.0001). Based on ANOVA for repeated measures and t test, the average number of warts, before, one week and one month after the intervention was statistically significant for both intervention (P = 0.009) and control groups (P = 0.0001). CONCLUSIONS: This method is recommended for the treatment of dermal warts, owing to the effectiveness, short duration of treatment, and low cost of topical treatment for dermal warts using HD tablets. PMID- 27761269 TI - Phytochemical Analysis and Antioxidant Activity of Salvia chloroleuca Aerial Extracts. AB - BACKGROUND: Salvia, known as Maryam Goli in the Persian language, is an important genus that includes approximately 900 species in the Lamiaceae family. There are 58 Salvia species growing naturally in Iran, including Salvia chloroleuca Rech. f. and Allen., which grows wild in the northeastern and central parts of the country. OBJECTIVES: This study was designed to determine the chemical composition, in vitro antioxidant activity, and total phenol content of various extracts of S. chloroleuca. MATERIALS AND METHODS: Dried aerial parts of the plant were crushed, then sequentially extracted with n-hexane, ethyl acetate, and methanol. The fractions of S. chloroleuca were subjected to silica gel column chromatography and Sephedex LH-20. The antioxidant activities of these extracts were measured by ferric reducing antioxidant power (FRAP), and the total phenolic contents of the extracts were evaluated using Folin-Ciocalteu reagent. RESULTS: The separation and purification processes were carried out using different chromatographic methods. Structural elucidation was on the basis 1H-NMR and 13C NMR spectral data, in comparison with that reported in the literature. The isolated compounds were salvigenin (1), luteolin (2), cirsiliol (3), beta sitosterol (4), and daucosterol (5). Ethyl acetate extract displayed the highest level of total antioxidants and total polyphenols compared to the other analyzed extracts (n-hexane and methanol). In the FRAP assay, ethyl acetate extract had the highest (230.4+/-10.5) FRAP value, followed by methanol (211.4 +/- 8.3) and n hexane (143.4 +/- 12.04). Total phenol contents were calculated to be 13.8 +/- 0.3, 58.25 +/- 0.05, and 43.48 +/- 0.38 mg of gallic acid/100 g in the n-hexane, ethyl acetate, and methanol extracts, respectively. CONCLUSIONS: The above mentioned compounds were isolated for the first time from S. chloroleuca. The antioxidant activity of this plant could be in part related to isolated flavonoids and sterols. The results of this study indicated that S. chloroleuca could be an important dietary source of phenolic compounds with high antioxidant capacity. PMID- 27761271 TI - Late-Developing Supernumerary Premolars: Analysis of Different Therapeutic Approaches. AB - This case series describes the different potential approaches to late-developing supernumerary premolars (LDSP). LDSP are supernumerary teeth (ST) formed after the eruption of the permanent dentition; usually they develop in the premolar region of the upper and lower jaw. The choice to extract or to monitor the LDSP depends on many factors and has to be carefully planned due to the several risks that either the monitoring or the extraction could provoke. These four cases of LDSP showed different treatment plan alternatives derived from a scrupulous assessment of the clinical and radiographic information. PMID- 27761270 TI - Cardiovascular Disease Risk Factors Profile in Individuals With Diabetes Compared With Non-Diabetic Subjects in North-East of Iran. AB - BACKGROUND: Diabetes mellitus is assumed to be a strong risk factor for cardiovascular diseases (CVD) and is frequently associated with other CVD risk factors. OBJECTIVES: The aims of this study were to assess the prevalence of different patterns of dyslipidemia in individuals with diabetes compared with non diabetic subjects and evaluate other accompanied CVD risk factors between the two groups. PATIENTS AND METHODS: This was an analytical cross-sectional study on 230 participants, aged 28 - 66 years old, who were referred to different urban health centers of Khorasan Razavi province (north-east of Iran). Data from the participants were collected during their first visit by primary care physicians. Statistical package for social science (version 11.5) was used to analyze the data. The chi-square or Fisher's exact, student's t or the Mann-Whitney U and correlation tests were used in the analysis. RESULTS: The age and gender of the participants were not different between the two groups (P = 0.1 and P = 0.4, respectively). The most common patterns of dyslipidemia in both groups were isolated dyslipidemia followed by combined dyslipidemia. Prevalence of dyslipidemia as a whole (one, two or three lipid profile abnormalities) in patients with diabetes and non-diabetic participants was 89.3% and 82.6%, respectively and the difference between the two groups was not statistically significant (P = 0.1). Subjects with diabetes had higher systolic blood pressure (P < 0.001), higher diastolic blood pressure (P = 0.002) and higher body mass index (P = 0.09) compared to non-diabetics. Moreover, they were more likely to have higher levels of total cholesterol (P = 0.01), triglycerides (P = 0.001) and low density lipoprotein cholesterol (P = 0.009) and lower levels of high density lipoprotein cholesterol (P = 0.2). CONCLUSIONS: Cardiovascular diseases risk factors are more common in patients with diabetes; however, non-diabetic individuals also had a high prevalence of risk factors in our region, predisposing them to diabetes. Therefore, further attention by the medical community is necessary to choose effective strategies for a more a aggressive approach to prevent and manage these risk factors. PMID- 27761272 TI - Clinical Heterogeneity of Guillain-Barre Syndrome in the Emergency Department: Impact on Clinical Outcome. AB - Guillain-Barre syndrome (GBS) is mainly classified into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Although diagnosis of GBS requires progressive weakness and universal areflexia or hyporeflexia, cases of GBS with preserved or increased deep tendon reflexes (DTRs) have been increasingly recognized. We report three cases of GBS, presenting at a single unit in six months. Our first case presented with pure sensory symptoms. The second case had nonspecific generalized weakness, while the third presented with typical ascending weakness. One of our patients had preserved DTRs, while the other two had increased DTRs. Our two cases with hyperreflexia were found to have a preceding Campylobacter jejuni infection and anti-ganglioside antibodies, and their electrophysiological studies revealed AMAN. The other case had an AIDP. Only one case was offered a diagnosis and treatment from the first emergency department (ED) visit and had a better clinical outcome. Clinical diagnosis of GBS in the ED can be challenging. Delay in diagnosis of GBS in the ED is common due to cases with intact or increased DTRs, atypical pattern of weakness, or pure sensory symptoms. Emergency physicians should be aware of GBS clinical heterogeneity, because early diagnosis and treatment improve clinical outcome. PMID- 27761273 TI - Unusual Case of a Proptosed Eye: Isolated Right Maxillary Neurofibroma. AB - Neurofibroma is a slow growing benign tumour of the peripheral nerve sheath which is frequently associated with neurofibromatosis type 1 (Prakash et al., 2014). Isolated solitary occurrence of neurofibroma in the maxillary sinus is rare with only 29 reported cases in the literature. We present a rare case of a 70-year-old gentleman who was referred to ENT with a right maxillary sinus neurofibroma with extension into the right inferior orbit. He has significant proptosis, ptosis, and limitation in abduction of the right eye. He has a complicated past history of multiple neurofibromas which were completely excised. Craniofacial MRI shows a large mass filling the right maxillary antrum extending anteriorly into subcutaneous tissue towards nasal ala and posterolaterally into inferior temporal fossa and superiorly into orbit and cavernous sinus involvement. Biopsy of the right maxillary mass revealed cellular spindle cell tumour with wavy collagen bundles within myxoid stroma which is consistent with a neurofibroma. Patient's case was discussed in the skull-base MDT and he has been referred to a specialist center for surgical removal of the neurofibroma with reconstructive surgery. Despite the rarity of this disease, otorhinolaryngologist should consider a possibility of neurofibroma of the paranasal sinuses. PMID- 27761274 TI - A New Cornerstone of Education of Authorship and Biomedical Project Design: International Research Interdisciplinary School, Slovakia, 2016. PMID- 27761275 TI - Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage. AB - BACKGROUND: Matrix metalloproteinase (MMP) inhibitors decrease inflammation in normal tissues and suppress cancer progress in normal tissues. Valproic acid (VA) and doxycycline (DX) are MMP inhibitors that have radio-protective effects. Their ability to inhibit MMPs in irradiated tissue is unknown and the role of MMPs in radio-protective effects has not been tested to date. AIMS: The purpose of this study was to examine whether administration of VA and DX to rats before irradiation affects tissue inflammation and apoptosis in the early phase of radiation, and whether the effect of these drugs is mediated by MMP inhibition. STUDY DESIGN: Animal experimentation. METHODS: Twenty-six Wistar rats were randomized into four groups: control (CTRL), radiation (RT), VA plus radiation (VA+RT), and DX plus radiation (DX+RT). Three study groups were exposed to a single dose of abdominal 10 Gy gamma radiation; the CTRL group received no radiation. Single doses of VA 300 mg/kg and DX 100 mg/kg were administered to each rat before radiation and all rats were sacrificed 8 hours after irradiation, at which point small intestine tissue samples were taken for analyses. Levels of inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and matrix metal loproteinases (MMP-2 and MMP 9) were measured by ELISA, MMP activities were measured by gelatin and casein zymography and apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. RESULTS: VA decreased the levels of TNF-alpha and IL-1beta proteins insignificantly and decreased apoptosis significantly in the irradiated tissue, but did not inhibit MMPs. In contrast, VA protected the basal MMP activities, which decreased in response to irradiation. No effect of DX was observed on the levels of inflammatory cytokines or activities of MMPs in the early phases of radiation apoptosis. CONCLUSION: Our findings indicated that VA protects against inflammation and apoptosis, and DX exhibits anti-apoptotic effects in early radiation and these effects are independent from MMP inhibition. PMID- 27761276 TI - Advantages of Pressurized-Spray Cryosurgery in Giant Cell Tumors of the Bone. AB - BACKGROUND: Giant Cell Tumor is considered a benign, local and aggressive tumor. Although considered a benign bone tumor, it is still the subject of discussion and research because of the associated local bone destruction, as well as high rates of recurrence and distant metastases. Options are being developed for both surgical techniques and adjuvant therapies. AIMS: The present study evaluated the administration of cryotherapy via a pressurized-spray technique in giant cell tumors of the bone. STUDY DESIGN: Cross-sectional study. METHODS: The study included 40 patients who were treated with extensive curettage and cryotherapy at various locations during the period from February 2006 to December 2013. Informed consent forms were obtained from the participants and ethics committee approval was taken from the local ethics committee of Ondokuz Mayis University. The pressurized-spray technique was performed using liquid nitrogen. The patients were evaluated with respect to age, gender, radiological appearance, treatment modality, duration of follow-up, skin problems and recurrence. RESULTS: Twenty one patients were female; 19 were male. The average age of the patients was 33 years (range: 16-72 years), and the average duration of follow-up was 43 months (range: 12-80 months). The average time from the onset of the complaints to the diagnosis was 6 months (range: 2-12 months). Based on the Campanacci classification: 9 patients were Grade I; 25 patients were Grade II; six patients were Grade III. The lesion was located in the femur in 14 patients, in the tibia in 11 patients, in the radius in 5 patients, in the pelvis in 4 patients, in the fibula in 3 patients, in the metatarsal in 2 patients and in the phalanges of the hand in one patient. One patient had postoperative early fracture. None of the patients had skin problems and infection. Three (7.5%) of the patients had recurrence. CONCLUSION: It was found that cryotherapy was highly effective in the lesions, especially those located in the femur and tibia and remained insufficient in the lesions expanded outside the cortex. Wound healing problems, infection and fracture risk are lower with this technique. PMID- 27761277 TI - Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats. AB - BACKGROUND: Cisplatin (Cis) is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-alpha). Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. AIMS: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis. STUDY DESIGN: Animal experimentation. METHODS: Male Wistar albino rats were divided in three groups as follows: Cis group, infliximab + Cis (CIN) group and the control group. Each group comprised 10 animals. Animals in the Cis group received an intraperitoneal single-dose injection of Cis (7 mg/kg). In the CIN group, a single dose of infliximab (7 mg/kg) was administered 72 h prior to the Cis injection. After 72 h, a single dose of Cis (7 mg/kg) was administered. All rats were sacrificed five days after Cis injection. RESULTS: TNF-alpha levels in the Cis group were significantly higher (345.5+/-40.0 pg/mg protein) than those of the control (278.7+/-62.1 pg/mg protein, p=0.003) and CIN groups (239.0+/-64.2 pg/mg protein, p=0.013). The Cis group was found to have high carbonic anhydrase (CA)-II and low carbamoyl phosphate synthetase-1 (CPS-1) levels. Aspartate transaminase (AST) and alanine transaminase (ALT) levels were lower in the CIN group as compared to the Cis group. Total histological damage was greater in the Cis group as compared to the control and CIN groups. CONCLUSION: Cis may lead to liver damage by increasing cytokine levels. It may increase oxidative stress-induced tissue damage by increasing carbonic anhydrase II (CA-II) enzyme levels and decreasing CPS-1 enzyme levels. Infliximab decreases Cis-induced hepatic damage by blocking TNF-alpha and it may also protect against liver damage by regulating CPS-1 and CA-II enzyme levels. PMID- 27761278 TI - Autosomal Dominant Polycystic Disease is Associated with Depressed Levels of Soluble Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple, large renal cysts and impaired kidney function. Although the reason for the development of kidney cysts is unknown, ADPKD is associated with cell cycle arrest and abundant apoptosis of renal tubular epithelial cells. AIMS: We asked whether serum-soluble TNF-related apoptosis-inducing ligand (sTRAIL) might underlie ADPKD. STUDY DESIGN: Case-control study. METHODS: Serum sTRAIL levels were measured in 44 patients with ADPKD and 18 healthy volunteers. The human soluble TRAIL/Apo2L ELISA kit was used for the in vitro quantitative determination of sTRAIL in serum samples. RESULTS: Mean serum sTRAIL levels were lower in patients with ADPKD as compared to the control group (446.9+/-103.1 and 875.9+/-349.6 pg/mL, p<0.001). Serum sTRAIL levels did not differ among stages of renal failure in patients with ADPKD. There was no correlation between serum sTRAIL levels and estimated glomerular filtration rate in patients with ADPKD (p>0.05). CONCLUSION: Our results show that ADPKD patients have depressed sTRAIL levels, indicating apoptosis unrelated to the stage of chronic renal failure. PMID- 27761279 TI - Predictive and Prognostic Factors in Ovarian and Uterine Carcinosarcomas. AB - BACKGROUND: Prognostic factors and the standard treatment approach for gynaecological carcinosarcomas have not yet been clearly defined. Although carcinosarcomas are more aggressive than pure epithelial tumours, they are treated similarly. Serous/clear cell and endometrioid components may be predictive factors for the efficacy of adjuvant chemotherapy (CT) or radiotherapy (RT) or RT in patients with uterine and ovarian carcinosarcomas. Heterologous carcinosarcomas may benefit more from adjuvant CT. AIMS: We aimed to define the prognostic and predictive factors associated with treatment options in ovarian (OCS) and uterine carcinosarcoma (UCS). STUDY DESIGN: Retrospective cross sectional study. METHODS: We retrospectively reviewed the medical records of patients with ovarian and uterine carcinosarcoma from 2000 to 2013, and 127 women were included in this study (24 ovarian and 103 uterine). Patients admitted to seventeen oncology centres in Turkey between 2000 and December 2013 with a histologically proven diagnosis of uterine carcinosarcoma with FIGO 2009 stage I III and patients with sufficient data obtained from well-kept medical records were included in this study. Stage IV tumours were excluded. The patient records were retrospectively reviewed. Data from 104 patients were evaluated for this study. RESULTS: Age (>=70 years) was a poor prognostic factor for UCS (p=0.036). Pelvic+/-para aortic lymph node dissection did not affect overall survival (OS) (p=0.35). Macroscopic residual disease was related with OS (p<0.01). The median OS was significantly longer in stage I-II patients than stage III patients (p=0.03). Adjuvant treatment improved OS (p=0.013). Adjuvant radiotherapy tended to increase the median OS (p=0.075). However, this tendency was observed in UCS (p=0.08) rather than OCS (p=0.6).Adjuvant chemotherapy had no effect on OS (p=0.15).Adjuvant radiotherapy significantly prolonged the median OS in patients with endometrioid component (p=0.034). A serous/clear cell component was a negative prognostic factor (p=0.035). Patients with serous/clear cell histology for whom adjuvant chemotherapy was applied had significantly longer OS (p=0.019), and there was no beneficial effect of adjuvant radiotherapy (p=0.4). Adjuvant chemotherapy was effective in heterologous tumours (p=0.026). In multivariate analysis, the stage and chemotherapy were prognostic factors for all patients. Age was an independent prognostic factor for UCS. However, serous/clear cell histology and radiotherapy tended to be significant prognostic factors. CONCLUSION: The primary location, the histological type of sarcomatous and the epithelial component may be predictive factors for the efficacy of chemotherapy or radiotherapy in UCS and OCS. PMID- 27761280 TI - Does Short Message Service Increase Adherence to Smoking Cessation Clinic Appointments and Quitting Smoking? AB - BACKGROUND: Using innovative and scientific methods increases the rate of quitting in smokers. Short message service (SMS) is a communication tool widely used and well integrated in many people's daily lives. To increase adherence to appointments in smoking cessation clinics (SCC), it is thought that increased compliance could be achieved by falling outside the traditional methods. SMS has been shown to increase the compliance of patients with SCC appointments. AIMS: In this study, we aimed to evaluate the effect of SMS in the compliance of patients with SCC follow-up visits and smoking cessation success. STUDY DESIGN: Case control study. METHODS: Our study was a controlled, open, prospective study. We enrolled 436 cases applied to SCC of Yedikule Training and Research Hospital between 01.10.2013-30.06.2014 and agreed to follow-up with SMS. SMS was sent to the patients to remind them of appointments at the SCC and to query their smoking state. RESULTS: Two hundred-and-eighty seven (65.8%) of the patients were male and 149 (34.2%) were female. The mean age was 45+/-12 years. In this study, 296 (67.9%) patients had graduated from primary school. Our patients' smoking state was queried by telephone at the 6-month follow-up and we contacted 348 patients. According to this, 88 (25.3%) patients were not smoking, and 260 (74.7%) patients were smokers. Therefore, the smoking cessation rate was 24% (n=60) in patients who did not respond to SMS reminders at all, and 28.6% (n=28) in patients answering any SMS at least once (p=0.377). Smoking cessation rate of the patients invited by SMS but who did not attend any control visits was 19.1%, and it was 34.5% in patients coming to a control visit at least once. This difference was statistically significant (p=0.001). CONCLUSION: In our study, there was increased success of smoking cessation in patients coming to control visits. We think that this may result from the possibly increased compliance to SCC appointments following reminders by SMS, and that this may also increase smoking cessation success. PMID- 27761281 TI - Assessment of the Speech Intelligibility Performance of Post Lingual Cochlear Implant Users at Different Signal-to-Noise Ratios Using the Turkish Matrix Test. AB - BACKGROUND: Spoken word recognition and speech perception tests in quiet are being used as a routine in assessment of the benefit which children and adult cochlear implant users receive from their devices. Cochlear implant users generally demonstrate high level performances in these test materials as they are able to achieve high level speech perception ability in quiet situations. Although these test materials provide valuable information regarding Cochlear Implant (CI) users' performances in optimal listening conditions, they do not give realistic information regarding performances in adverse listening conditions, which is the case in the everyday environment. AIMS: The aim of this study was to assess the speech intelligibility performance of post lingual CI users in the presence of noise at different signal-to-noise ratio with the Matrix Test developed for Turkish language. STUDY DESIGN: Cross-sectional study. METHODS: The thirty post lingual implant user adult subjects, who had been using implants for a minimum of one year, were evaluated with Turkish Matrix test. Subjects' speech intelligibility was measured using the adaptive and non-adaptive Matrix Test in quiet and noisy environments. RESULTS: The results of the study show a correlation between Pure Tone Average (PTA) values of the subjects and Matrix test Speech Reception Threshold (SRT) values in the quiet. Hence, it is possible to asses PTA values of CI users using the Matrix Test also. However, no correlations were found between Matrix SRT values in the quiet and Matrix SRT values in noise. Similarly, the correlation between PTA values and intelligibility scores in noise was also not significant. Therefore, it may not be possible to assess the intelligibility performance of CI users using test batteries performed in quiet conditions. CONCLUSION: The Matrix Test can be used to assess the benefit of CI users from their systems in everyday life, since it is possible to perform intelligibility test with the Matrix test using a material that CI users experience in their everyday life and it is possible to assess their difficulty in speech discrimination in noisy conditions they have to cope with. PMID- 27761282 TI - School Board Policies on Prevention and Management of Anaphylaxis in Istanbul: Where Do We Stand? AB - BACKGROUND: Allergic diseases with a potential for anaphylaxis pose a critical public health issue in schools. AIMS: This study was carried out to identify the current status of prevention and management of anaphylaxis in school children with the main goal of establishing such an action plan. STUDY DESIGN: Cross sectional study. METHODS: Schools were randomly selected from 11 different regions of Istanbul. A questionnaire was filled out by 2596 teachers/school principals from 232 public schools. RESULTS: A school safety committee was absent in 80% of elementary schools (ES) and 60.8% of preschools (PS). Although some form of health recording system was available in many schools, no such system was available in 24.5% of ESs and 10% of PSs. A specific inquiry for detecting children with food allergies was a routine practice in only 4% of ES and 10% of PS. Approximately 27% of teachers stated that monitoring children in school places was not possible at all times. Eighty four percent stated that no written anaphylaxis treatment protocol was available in their school and only around 2.3% in ES and 3.1% in PS stated that they would perform an epinephrine injection in the event of anaphylaxis. CONCLUSION: Our survey demonstrated critical gaps in the organization of schools for the management of children at risk of anaphylaxis. Data derived from this study would provide the initiative for legislators to review the current situation of school health policies along with the relevant authorities to establish school anaphylaxis guidelines. PMID- 27761283 TI - Efficiency of Direct Microscopy of Stool Samples Using an Antigen-Specific Adhesin Test for Entamoeba Histolytica. AB - BACKGROUND: E. histolytica is among the common causes of acute gastroenteritis. The pathogenic species E. histolytica and the nonpathogenic species E. dispar cannot be morphologically differentiated, although correct identification of these protozoans is important for treatment and public health. In many laboratories, the screening of leukocytes, erythrocytes, amoebic cysts, trophozoites and parasite eggs is performed using Native-Lugol's iodine for pre diagnosis. AIMS: In this study, we aimed to investigate the frequency of E. histolytica in stool samples collected from 788 patients residing in the Anatolian region of Istanbul who presented with gastrointestinal complaints. We used the information obtained to evaluate the effectiveness of microscopic examinations when used in combination with the E. histolytica adhesin antigen test. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Preparations of stool samples stained with Native-Lugol's iodine were evaluated using the E. histolytica adhesin test and examined using standard light microscopy at *40 magnification. Pearson's Chi-square and Fisher's exact tests were used for statistical analysis. Logistic regression analysis was used for multivariate analysis. RESULTS: Of 788 samples, 38 (4.8%) were positive for E. histolytica adhesin antigens. When evaluated together with the presences of erythrocytes, leukocytes, cysts, and trophozoites, respectively, using logistic regression analysis, leukocyte positivity was significantly higher. The odds ratio of leukocyte positivity increased adhesin test-positivity by 2,530-fold (95% CI=1.01 6.330). Adhesin test-positivity was significant (p=0.047). CONCLUSION: In line with these findings, the consistency between the presence of cysts and erythrocytes and adhesin test-positivity was found to be highly significant, but that of higher levels of leukocytes was found to be discordant. It was concluded that leukocytes and trophozoites were easily misjudged using direct microscopy. Although microscopic examination of samples stained with Native-Lugol's iodine is a cheap and simple method, the confusion of trophozoites with leukocytes may direct the clinician toward an incorrect pre-diagnosis. Because trichrome staining is difficult and time consuming, and results may vary depending on the technician, this method is not preferred in most laboratories. Therefore, an enzyme-linked immunosorbent assay method, which is a more advanced method than polymerase chain reaction, should be used to distinguish between E. histolytica and E. dispar in order to achieve an accurate diagnosis. PMID- 27761284 TI - Evaluation of Serum S100A8/S100A9 Levels in Patients with Autoimmune Thyroid Diseases. AB - BACKGROUND: The correlation of S100A8/S100A9 with various inflammatory conditions, including autoimmune diseases have been reported. There is no study investigating the levels of S100A8/S100A9 in autoimmune thyroid diseases (AITD). AIMS: We aimed to evaluate the level of serum S100A8/S100A9 in AITD. STUDY DESIGN: Case control study. METHODS: Fifty patients with AITD (25 Hashimoto's thyroiditis (HT) and 25 Graves' disease (GD)) were included in the study. Twenty seven healthy subjects participated as a control group. Blood samples were obtained in the 3 months after the initiation of medical treatment. Serum levels of total antioxidant status (TAS), total oxidative status (TOS), total free sulfhydryl (SH), lipid hydroperoxide (LOOH) and S100A8/S100A9 were analyzed. RESULTS: The patients with AITD had significantly higher S100A8/S100A9, OSI, LOOH and TOS levels than the healthy control group. There was no significant difference between GD and HT patients in terms of S100A8/S100A9, TOS and OSI levels. S100A8/S100A9 level was positively correlated with LOOH, TOS and OSI levels but negatively correlated with -SH level in the patients with AITD. CONCLUSION: Serum S100A8/S100A9 levels were increased in patients with AITD and positively correlated with LOOH, TOS and OSI whereas negatively correlated with SH. PMID- 27761285 TI - Revisiting the Anatomy of the Facial Recess: The Boundaries of the Round Window Exposure. AB - BACKGROUND: The exposure of the round window (RW) through the facial recess (FR) is sometimes partial. The anatomic variations that alter RW exposure during cochleostomy have not been clearly defined to date. AIMS: The aim of this study was to assess the best FR position in which to achieve the widest exposure of the RW niche and to define the topographic relationship between two other important anatomical structures, the facial nerve (FN) and the chorda tympani (CT). STUDY DESIGN: Cadaver study. METHODS: Twenty-four temporal bones were included in the study. Anterior and posterior epitympanectomy and posterior tympanotomy were performed after mastoidectomy. Bone was removed until the FN and CT were skeletonized and the CT branching point was visible. Two pictures were taken. The first was taken when the facial recess was at its widest exposure, while the second was taken when the RW niche was maximally exposed through the facial recess. Various measurements were taken. RESULTS: The RW niche was totally visible in 19 temporal bones (79.2%). The RW was partially visible in the remaining five bones (20.8%). The unexposed part of the RW lay posteromedial to the FN in these five bones. While the branching point of the CT could be visualized in all cases at the widest exposure of RW, the part of the FN distal to the branching point was hidden in eight subjects (33.3%) under the posterior wall of the external ear canal. CONCLUSIONS: The RW niche was totally visible in most of the temporal bones. The RW lay posteromedial to the FN in some cases and total exposure was impossible. PMID- 27761286 TI - Brucella Infection Associated with Complete Atrioventricular Block. AB - BACKGROUND: The clinical spectrum of Brucella infection is quite diverse and characterized by multi-system involvement. Patients present with myocarditis, endocarditis, or pericarditis. Infective endocarditis is the most common cardiovascular complication in patients with brucellosis. Although conduction abnormalities are seen in cases with endocarditis, they are reported very rarely in the setting of cardiac Brucella infection. CASE REPORT: An eight and a half year-old male patient was referred to our clinic due to inadequate response to cotrimaxazole plus streptomycin treatment at the 15th day of admission. Although local hospital records on the patient showed a heart rate of 80 bpm, we determined a heart rate of 46 bpm. The electrocardiogram showed complete atrioventricular (AV) block. The average heart rate was determined as 48 bpm with 24-hour Holter electrocardiogram (ECG) monitoring. The echocardiographic examination showed normal-sized heart chambers and the absence of valvular involvement. An agglutination test for brucellosis was found to be positive with a titer of 1/320. High fever, arthralgia, and splenomegaly regressed following doxycycline plus rifampicin therapy, but there was no improvement in the AV block. A permanent pacemaker was implanted because of the detection of an average heart rate of 48 bpm. CONCLUSION: Because cardiac failure and rhythm abnormalities are reported in the course of Brucella infection and may be associated with significant outcomes, cases with brucellosis should be evaluated carefully in terms of cardiac involvement. This report aims to draw attention to complete AV block as an extremely rare complication of Brucella infection. PMID- 27761287 TI - Oleander Poisoning as an Example of Self-Medication Attempt. AB - BACKGROUND: There is an increasing interest in herbal products as a self medication method in recent years. Some plant extracts either turn into drugs over time or are consumed directly without treatment. One of these plants is Nerium oleander L., which is a potentially lethal plant, since it has cardiac glycosides. However, numerous researches of its extracts have been performed against cancer cell lines in recent literature. This contradiction leads to misinterpretation and induces the prevalence of intoxication or fatal cases. CASE REPORT: This case is associated with an oleander-poisoned patient, who was admitted to the Emergency unit 20 hours after the first dose, and 8 hours after the second dose. Although she lives in a metropolis and has a higher level of education and numerous hospital facilities available, she had decided to take self-medication for her Hashimoto's thyroiditis and malignant thyroid disease which was caused by her apprehensive thoughts. Oleandrin was detected in the urine at a concentration of 3.2 ng/mL and in the serum at a concentration of 8.4 ng/mL by chromatographic analysis at the time of admission. CONCLUSION: This case represents the misunderstanding of herbal treatments by the community. Promoting awareness of the potential toxicity of this plant among the public may help to reduce the incidence of poisoning due to Nerium species. PMID- 27761288 TI - A Case of Biotinidase Deficiency in an Adult with Respiratory Failure in the Intensive Care Unit. AB - BACKGROUND: Biotinidase deficiency (BD) is a rare, inherited autosomal recessive disorder that is treatable within childhood. We present a patient with pneumonia and respiratory acidosis who was not diagnosed with any systemic disorders; the patient was finally diagnosed as BD. CASE REPORT: A thirty-year-old woman was admitted to the emergency department with respiratory failure that had persisted for a few days and progressively weakening over the previous six months. Then, the patient was admitted to the intensive care unit with marked respiratory acidosis, respiratory failure and alterations in consciousness. At the follow-up, the patient was not diagnosed with a systematic disorder. Rather, the patient's historical clinical findings suggested a metabolic disorder. Finally, the patient was diagnosed with biotinidase deficiency. CONCLUSION: Even though biotinidase deficiency is not frequently seen in the intensive care unit, metabolic syndromes such as biotinidase deficiency should be considered. Patients should be evaluated holistically with attention to medical history, family history and clinical findings. PMID- 27761289 TI - Canal of Nuck Hernia in a Female Infant Containing Uterus, Bilateral Adnexa and Bowel. AB - BACKGROUND: The canal of Nuck is a fold of peritoneum that invaginates into the inguinal canal and closes at or just before birth. If the canal of Nuck remains open in female infants, herniation of the uterus, adnexa and/or bowel loops may arise through the inguinal canal into the labia majora. CASE REPORT: The present case is a 12-week-old female infant with complaints of left groin swelling and discomfort. Ultrasonographic examination revealed a left inguinal hernia containing both adnexa (ovaries and fallopian tubes), uterus and small bowel loops with fluid. CONCLUSION: A hernia containing ovary and uterus should be considered as a possible cause in a female infant with a groin mass. Ultrasonography of the inguinal mass lesions should be performed routinely in a female infant for accurate diagnosis. PMID- 27761290 TI - A Rare Cause of Hemifacial Spasm: Papillary Oncocytic Cystadenoma. AB - BACKGROUND: Hemifacial spasm is a sudden, involuntary and synchronous spasm of the facial muscles. The most frequent cause of this condition is compression of the facial nerves due to vascular pathologies. The most commonly used method of treatment is Botulinum toxin injection. However, the gold standard treatment is surgical treatment. CASE REPORT: A 64-year-old male patient with hemifacial spasms, which had occurred due to a rare parotid mass that had been surgically treated, is presented in this case. CONCLUSION: This case report demonstrates that longstanding parotid gland masses may compress the facial nerves and cause demyelination in the nerve and thus may cause spasms in the facial muscles. PMID- 27761291 TI - Langerhans Cell Histiocytosis with Atypical Intervertebral Disc and Sacroiliac Joint Involvement Mimicking Osteoarticular Tuberculosis in an Adult. AB - BACKGROUND: Langerhans cell histiocytosis (LCH), typically found in children, is a rare single or multisystem disorder with a wide range of clinical and radiological manifestations. Unusual presentations of LCH are occasionally encountered and it may be difficult to distinguish LCH from an infection or a benign or malignant tumor. RESULTS: A 35-year-old female presented with pain in her back and left buttock, malaise, and weight loss, with a duration of several months. Her laboratory test results were within the normal ranges except for the levels of acute phase reactants, which were elevated. Magnetic resonance imaging and computed tomography revealed a unilateral destructive sacroiliac lesion, and multiple vertebral lesions with adjacent discal involvement and extensive soft tissue extensions. She was initially misdiagnosed with multifocal osteoarticular tuberculosis. An open biopsy and joint curettage was performed. Histopathological examination showed that she had LCH. CONCLUSION: To the best of our knowledge, this is the first case of LCH associated with a destructive unilateral sacroiliac lesion, discal involvement, and involvement of the adjacent vertebrae, in an adult patient; the LCH mimicked osteoarticular tuberculosis. Disease onset in adulthood is rare, and this can potentially delay diagnosis. Familiarity with the imaging features of unusual LCH manifestations is necessary to ensure accurate diagnosis and appropriate treatment. PMID- 27761292 TI - Pediatric Fulminant Leptospirosis Complicated by Pericardial Tamponade, Macrophage Activation Syndrome and Sclerosing Cholangitis. AB - BACKGROUND: Leptospirosis is a zoonotic infectious disease caused by pathogenic spirochetes of the genus Leptospira. Although it is usually asymptomatic and self limited, severe potentially fatal illness accompanied by multi-organ failure may occur. CASE REPORT: Here we report an unusual case of severe leptospirosis successfully treated with continuous venovenous hemofiltration (CVVHF) and therapeutic plasma exchange (TPE). The patient presented with pericardial tamponade, renal failure and macrophage activation syndrome, and later suffered prolonged jaundice and sclerosing cholangitis during hospitalization in the pediatric intensive care unit (PICU). To the best of our knowledge, sclerosing cholangitis due to leptospirosis has not been reported in the literature. CONCLUSION: Leptospirosis should be kept in mind in the differential diagnosis of sepsis and septic shock with fever, thrombocytopenia, jaundice and renal failure. TPE and CVVHF should start early after the diagnosis of leptospirosis with multiorgan failure. PMID- 27761293 TI - Testicular Involvement in Relapsed Hodgkin Lymphoma. PMID- 27761294 TI - Neutrophil-to-Lymphocyte Ratio and Non-arteritic Anterior Ischemic Optic Neuropathy. PMID- 27761295 TI - The Association of Mounier-Kuhn Syndrome and Pulmonary Aspergillomas: A Case Report. PMID- 27761297 TI - Erratum: Antibody supervised deep learning for quantification of tumor infiltrating immune cells in hematoxylin and eosin stained breast cancer samples. AB - [This corrects the article on p. 38 in vol. 7, PMID: 27688929.]. PMID- 27761296 TI - Ingested Foreign Body Causing Pylephlebitis Identified by Trans-abdominal Ultrasound. PMID- 27761298 TI - Palladium-Catalyzed Oxidative Domino Carbocyclization-Arylation of Bisallenes. AB - Herein we report a highly efficient and site-selective palladium-catalyzed oxidative carbocyclization-arylation reaction of bisallenes and arylboronic acids under operationally simple conditions for the selective synthesis of cyclohexadiene derivatives. The palladium source and the solvent proved to be crucial for the selectivity and the reactivity displayed. Interestingly, in the absence of the nucleophile, an oxidative carbocyclization-beta-elimination pathway predominates. The reaction conditions are compatible with a wide range of functional groups, and the reaction exhibits broad substrate scope. Furthermore, key information regarding the mechanism was obtained using control experiments and kinetic studies. PMID- 27761299 TI - Improving Formate and Methanol Fuels: Catalytic Activity of Single Pd Coated Carbon Nanotubes. AB - The oxidations of formate and methanol on nitrogen-doped carbon nanotubes decorated with palladium nanoparticles were studied at both the single-nanotube and ensemble levels. Significant voltammetric differences were seen. Pd oxide formation as a competitive reaction with formate or methanol oxidation is significantly inhibited at high overpotentials under the high mass transport conditions associated with single-particle materials in comparison with that seen with ensembles, where slower diffusion prevails. Higher electro-oxidation efficiency for the organic fuels is achieved. PMID- 27761300 TI - Extramedullary Plasmacytoma of the Gallbladder Detected on Fluorine 18 fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Extramedullary plasmacytoma is rare in patients with diagnosed multiple myeloma. Soft tissue plasmacytoma of the gallbladder is particularly uncommon and has been described in only a handful of cases. Diagnosis of gallbladder plasmacytoma with fluorine 18-fluorodeoxyglucose (F18-FDG) positron emission tomography/computed tomography (PET/CT) has not previously been reported. We present a 65-year-old female with a history of multiple myeloma who underwent a restaging F18-FDG PET/CT which showed a focal area of hypermetabolic activity, corresponding to a nodular lesion within the posterior gallbladder wall. The patient underwent successful cholecystectomy, with surgical pathology revealing gallbladder plasmacytoma. A follow-up scan was negative for active malignancy. This is a novel case of gallbladder plasmacytoma diagnosed on whole-body F18-FDG PET/CT - thus demonstrating the clinical value of this imaging modality in staging, restaging, and surveillance for patients with multiple myeloma. PMID- 27761301 TI - Occult Primary Neuroendocrine Tumor Metastasis to the Breast Detected on Screening Mammogram. AB - Metastatic tumors are rare in the breast. Well-differentiated neuroendocrine tumors (WDNETs) are slow-growing neoplasms that arise from neuroendocrine cells, particularly in the gastrointestinal tract and bronchial tree. Metastatic WDNET to the breast is a rare entity. We present a case report of ileal WDNET metastatic to the breast which was initially identified as a small mass in the patient's left breast on screening mammography. Targeted ultrasound identified a suspicious mass, and ultrasound-guided percutaneous core biopsy was performed. Pathology revealed metastatic WDNET. Breast magnetic resonance imaging (MRI) was then performed and demonstrated left axillary Level 2 lymphadenopathy, and liver lesions were suspicious for metastasis. The patient underwent abdominal computed tomography (CT) to evaluate for distant metastatic disease. A spiculated mass was found near the ileocecal valve, suggestive of primary ileal WDNET. In addition, CT identified multiple liver lesions, most compatible with metastasis. Indium 111 OctreoScan confirmed radiotracer uptake in the ileum consistent with primary neuroendocrine tumor. In this report, we review the imaging characteristics of metastatic WDNET to the breast by different imaging modalities including mammogram, ultrasound, and breast MRI. PMID- 27761302 TI - Are Gait Stereotypies a Marker for Neurodegeneration in Down Syndrome? A Prospective Observation. PMID- 27761303 TI - Ecomorphological analysis of the astragalo-calcaneal complex in rodents and inferences of locomotor behaviours in extinct rodent species. AB - Studies linking postcranial morphology with locomotion in mammals are common. However, such studies are mostly restricted to caviomorphs in rodents. We present here data from various families, belonging to the three main groups of rodents (Sciuroidea, Myodonta, and Ctenohystrica). The aim of this study is to define morphological indicators for the astragalus and calcaneus, which allow for inferences to be made about the locomotor behaviours in rodents. Several specimens were dissected and described to bridge the myology of the leg with the morphology of the bones of interest. Osteological characters were described, compared, mechanically interpreted, and correlated with a "functional sequence" comprising six categories linked to the lifestyle and locomotion (jumping, cursorial, generalist, fossorial, climber and semi-aquatic). Some character states are typical of some of these categories, especially arboreal climbers, fossorial and "cursorial-jumping" taxa. Such reliable characters might be used to infer locomotor behaviours in extinct species. Linear discriminant analyses (LDAs) were used on a wider sample of species and show that astragalar and calcaneal characters can be used to discriminate the categories among extant species whereas a posteriori inferences on extinct species should be examined with caution. PMID- 27761304 TI - Local-scale models reveal ecological niche variability in amphibian and reptile communities from two contrasting biogeographic regions. AB - Ecological Niche Models (ENMs) are widely used to describe how environmental factors influence species distribution. Modelling at a local scale, compared to a large scale within a high environmental gradient, can improve our understanding of ecological species niches. The main goal of this study is to assess and compare the contribution of environmental variables to amphibian and reptile ENMs in two Spanish national parks located in contrasting biogeographic regions, i.e., the Mediterranean and the Atlantic area. The ENMs were built with maximum entropy modelling using 11 environmental variables in each territory. The contributions of these variables to the models were analysed and classified using various statistical procedures (Mann-Whitney U tests, Principal Components Analysis and General Linear Models). Distance to the hydrological network was consistently the most relevant variable for both parks and taxonomic classes. Topographic variables (i.e., slope and altitude) were the second most predictive variables, followed by climatic variables. Differences in variable contribution were observed between parks and taxonomic classes. Variables related to water availability had the larger contribution to the models in the Mediterranean park, while topography variables were decisive in the Atlantic park. Specific response curves to environmental variables were in accordance with the biogeographic affinity of species (Mediterranean and non-Mediterranean species) and taxonomy (amphibians and reptiles). Interestingly, these results were observed for species located in both parks, particularly those situated at their range limits. Our findings show that ecological niche models built at local scale reveal differences in habitat preferences within a wide environmental gradient. Therefore, modelling at local scales rather than assuming large-scale models could be preferable for the establishment of conservation strategies for herptile species in natural parks. PMID- 27761305 TI - Performance of maximum likelihood mixture models to estimate nursery habitat contributions to fish stocks: a case study on sea bream Sparus aurata. AB - BACKGROUND: Mixture models (MM) can be used to describe mixed stocks considering three sets of parameters: the total number of contributing sources, their chemical baseline signatures and their mixing proportions. When all nursery sources have been previously identified and sampled for juvenile fish to produce baseline nursery-signatures, mixing proportions are the only unknown set of parameters to be estimated from the mixed-stock data. Otherwise, the number of sources, as well as some/all nursery-signatures may need to be also estimated from the mixed-stock data. Our goal was to assess bias and uncertainty in these MM parameters when estimated using unconditional maximum likelihood approaches (ML-MM), under several incomplete sampling and nursery-signature separation scenarios. METHODS: We used a comprehensive dataset containing otolith elemental signatures of 301 juvenile Sparus aurata, sampled in three contrasting years (2008, 2010, 2011), from four distinct nursery habitats. (Mediterranean lagoons) Artificial nursery-source and mixed-stock datasets were produced considering: five different sampling scenarios where 0-4 lagoons were excluded from the nursery-source dataset and six nursery-signature separation scenarios that simulated data separated 0.5, 1.5, 2.5, 3.5, 4.5 and 5.5 standard deviations among nursery-signature centroids. Bias (BI) and uncertainty (SE) were computed to assess reliability for each of the three sets of MM parameters. RESULTS: Both bias and uncertainty in mixing proportion estimates were low (BI <= 0.14, SE <= 0.06) when all nursery-sources were sampled but exhibited large variability among cohorts and increased with the number of non-sampled sources up to BI = 0.24 and SE = 0.11. Bias and variability in baseline signature estimates also increased with the number of non-sampled sources, but tended to be less biased, and more uncertain than mixing proportion ones, across all sampling scenarios (BI < 0.13, SE < 0.29). Increasing separation among nursery signatures improved reliability of mixing proportion estimates, but lead to non-linear responses in baseline signature parameters. Low uncertainty, but a consistent underestimation bias affected the estimated number of nursery sources, across all incomplete sampling scenarios. DISCUSSION: ML-MM produced reliable estimates of mixing proportions and nursery-signatures under an important range of incomplete sampling and nursery-signature separation scenarios. This method failed, however, in estimating the true number of nursery sources, reflecting a pervasive issue affecting mixture models, within and beyond the ML framework. Large differences in bias and uncertainty found among cohorts were linked to differences in separation of chemical signatures among nursery habitats. Simulation approaches, such as those presented here, could be useful to evaluate sensitivity of MM results to separation and variability in nursery-signatures for other species, habitats or cohorts. PMID- 27761307 TI - Diversity of planktonic fish larvae along a latitudinal gradient in the Eastern Atlantic Ocean estimated through DNA barcodes. AB - Mid-trophic pelagic fish are essential components of marine ecosystems because they represent the link between plankton and higher predators. Moreover, they are the basis of the most important fisheries resources; for example, in African waters. In this study, we have sampled pelagic fish larvae in the Eastern Atlantic Ocean along a latitudinal gradient between 37 degrees N and 2 degrees S. We have employed Bongo nets for plankton sampling and sorted visually fish and fish larvae. Using the cytochrome oxidase I gene (COI) as a DNA barcode, we have identified 44 OTUs down to species level that correspond to 14 families, with Myctophidae being the most abundant. A few species were cosmopolitan and others latitude-specific, as was expected. The latitudinal pattern of diversity did not exhibit a temperate-tropical cline; instead, it was likely correlated with environmental conditions with a decline in low-oxygen zones. Importantly, gaps and inconsistencies in reference DNA databases impeded accurate identification to the species level of 49% of the individuals. Fish sampled from tropical latitudes and some orders, such as Perciformes, Myctophiformes and Stomiiformes, were largely unidentified due to incomplete references. Some larvae were identified based on morphology and COI analysis for comparing time and costs employed from each methodology. These results suggest the need of reinforcing DNA barcoding reference datasets of Atlantic bathypelagic tropical fish that, as main prey of top predators, are crucial for ecosystem-based management of fisheries resources. PMID- 27761306 TI - Prevention of necrotizing enterocolitis with probiotics: a systematic review and meta-analysis. AB - CONTEXT: Necrotizing enterocolitis (NEC) is the most frequent gastrointestinal emergency in neonates. The microbiome of the preterm gut may regulate the integrity of the intestinal mucosa. Probiotics may positively contribute to mucosal integrity, potentially reducing the risk of NEC in neonates. OBJECTIVE: To perform an updated systematic review and meta-analysis on the efficacy and safety of probiotics for the prevention of NEC in premature infants. DATA SOURCES: Structured searches were performed in: Medline, Embase, and the Cochrane Central Register of Controlled Trials (all via Ovid, from 2013 to January 2015). Clinical trial registries and electronically available conference materials were also searched. An updated search was conducted June 3, 2016. STUDY SELECTION: Randomized trials including infants less than 37 weeks gestational age or less than 2,500 g on probiotic vs. standard therapy. DATA EXTRACTION: Data extraction of the newly-identified trials with a double check of the previously-identified trials was performed using a standardized data collection tool. RESULTS: Thirteen additional trials (n = 5,033) were found. The incidence of severe NEC (RR 0.53 95% CI [0.42-0.66]) and all-cause mortality (RR 0.79 95% CI [0.68-0.93]) were reduced. No difference was shown in culture-proven sepsis RR 0.88 95% CI [0.77 1.00]. LIMITATIONS: Heterogeneity of organisms and dosing regimens studied prevent a species-specific treatment recommendation from being made. CONCLUSIONS: Preterm infants benefit from probiotics to prevent severe NEC and death. PMID- 27761308 TI - Corallimorpharians are not "naked corals": insights into relationships between Scleractinia and Corallimorpharia from phylogenomic analyses. AB - Calcification is one of the most distinctive traits of scleractinian corals. Their hard skeletons form the substratum of reef ecosystems and confer on corals their remarkable diversity of shapes. Corallimorpharians are non-calcifying, close relatives of scleractinian corals, and the evolutionary relationship between these two groups is key to understanding the evolution of calcification in the coral lineage. One pivotal question is whether scleractinians are a monophyletic group, paraphyly being an alternative possibility if corallimorpharians are corals that have lost their ability to calcify, as is implied by the "naked-coral" hypothesis. Despite major efforts, relationships between scleractinians and corallimorpharians remain equivocal and controversial. Although the complete mitochondrial genomes of a range of scleractinians and corallimorpharians have been obtained, heterogeneity in composition and evolutionary rates means that mitochondrial sequences are insufficient to understand the relationship between these two groups. To overcome these limitations, transcriptome data were generated for three representative corallimorpharians. These were used in combination with sequences available for a representative range of scleractinians to identify 291 orthologous single copy protein-coding nuclear markers. Unlike the mitochondrial sequences, these nuclear markers do not display any distinct compositional bias in their nucleotide or amino-acid sequences. A range of phylogenomic approaches congruently reveal a topology consistent with scleractinian monophyly and corallimorpharians as the sister clade of scleractinians. PMID- 27761309 TI - Phylogenetic relationships and evolutionary history of the greater horseshoe bat, Rhinolophus ferrumequinum, in Northeast Asia. AB - The greater horseshoe bat, Rhinolophus ferrumequinum, is an important model organism for studies on chiropteran phylogeographic patterns. Previous studies revealed the population history of R. ferrumequinum from Europe and most Asian regions, yet there continue to be arguments about their evolutionary process in Northeast Asia. In this study, we obtained mitochondrial DNA cyt b and D-loop data of R. ferrumequinum from Northeast China, South Korea and Japan to clarify their phylogenetic relationships and evolutionary process. Our results indicate a highly supported monophyletic group of Northeast Asian greater horseshoe bats, in which Japanese populations formed a single clade and clustered into the mixed branches of Northeast Chinese and South Korean populations. We infer that R. ferrumequinum in Northeast Asia originated in Northeast China and South Korea during a cold glacial period, while some ancestors likely arrived in Japan by flying or land bridge and subsequently adapted to the local environment. Consequently, during the warm Eemian interglaciation, the Korea Strait, between Japan and South Korea, became a geographical barrier to Japanese and inland populations, while the Changbai Mountains, between China and North Korea, did not play a significant role as a barrier between Northeast China and South Korea populations. PMID- 27761310 TI - A comprehensive investigation of mesophotic coral ecosystems in the Hawaiian Archipelago. AB - Although the existence of coral-reef habitats at depths to 165 m in tropical regions has been known for decades, the richness, diversity, and ecological importance of mesophotic coral ecosystems (MCEs) has only recently become widely acknowledged. During an interdisciplinary effort spanning more than two decades, we characterized the most expansive MCEs ever recorded, with vast macroalgal communities and areas of 100% coral cover between depths of 50-90 m extending for tens of km2 in the Hawaiian Archipelago. We used a variety of sensors and techniques to establish geophysical characteristics. Biodiversity patterns were established from visual and video observations and collected specimens obtained from submersible, remotely operated vehicles and mixed-gas SCUBA and rebreather dives. Population dynamics based on age, growth and fecundity estimates of selected fish species were obtained from laser-videogrammetry, specimens, and otolith preparations. Trophic dynamics were determined using carbon and nitrogen stable isotopic analyses on more than 750 reef fishes. MCEs are associated with clear water and suitable substrate. In comparison to shallow reefs in the Hawaiian Archipelago, inhabitants of MCEs have lower total diversity, harbor new and unique species, and have higher rates of endemism in fishes. Fish species present in shallow and mesophotic depths have similar population and trophic (except benthic invertivores) structures and high genetic connectivity with lower fecundity at mesophotic depths. MCEs in Hawai'i are widespread but associated with specific geophysical characteristics. High genetic, ecological and trophic connectivity establish the potential for MCEs to serve as refugia for some species, but our results question the premise that MCEs are more resilient than shallow reefs. We found that endemism within MCEs increases with depth, and our results do not support suggestions of a global faunal break at 60 m. Our findings enhance the scientific foundations for conservation and management of MCEs, and provide a template for future interdisciplinary research on MCEs worldwide. PMID- 27761311 TI - Judgement bias in goats (Capra hircus): investigating the effects of human grooming. AB - Animal emotional states can be investigated by evaluating their impact on cognitive processes. In this study, we used a judgement bias paradigm to determine if short-term positive human-animal interaction (grooming) induced a positive affective state in goats. We tested two groups of goats and trained them to discriminate between a rewarded and a non-rewarded location over nine training days. During training, the experimental group (n = 9) was gently groomed by brushing their heads and backs for five min over 11 days (nine training days, plus two testing days, total time 55 min). During training, the control group (n = 10) did not experience any direct interaction with the experimenter, but was kept unconstrained next to him for the same period of time. After successful completion of the training, the responses (latency time) of the two groups to reach ambiguous locations situated between the two reference locations (i.e., rewarded/non-rewarded) were compared over two days of testing. There was not a positive bias effect after the animals had been groomed. In a second experiment, 10 goats were tested to investigate whether grooming induced changes in physiological activation (i.e., heart rate and heart rate variability). Heart rate increased when goats were groomed compared to the baseline condition, when the same goats did not receive any contact with the experimenter. Also, subjects did not move away from the experimenter, suggesting that the grooming was positively accepted. The very good care and the regular positive contacts that goats received from humans at the study site could potentially account for the results obtained. Good husbandry outcomes are influenced by animals' perception of the events and this is based on current circumstances, past experiences and individual variables. Taking into account animals' individual characteristics and identifying effective strategies to induce positive emotions could increase the understanding and reliability of using cognitive biases paradigms to investigate and promote animal welfare. PMID- 27761312 TI - Geographical and altitudinal distribution of Brachycephalus (Anura: Brachycephalidae) endemic to the Brazilian Atlantic Rainforest. AB - Mountains of the Brazilian Atlantic Forest can act as islands of cold and wet climate, leading to the isolation and speciation of species with low dispersal capacity, such as the toadlet species of the genus Brachycephalus. This genus is composed primarily by diurnal species, with miniaturized body sizes (<2.5 cm), inhabiting microhabitats in the leaf litter of montane forests. Still, little is known about the geographical distribution, altitudinal range, and ecological limits of most Brachycephalus species. In this study, we review the available data on the geographical and altitudinal distribution of Brachycephalus based on occurrence records compiled from literature and museums, both for the genus as a whole and separately for the three recently proposed groups of species (ephippium, didactylus, and pernix). The final ensemble dataset comprised 333 records, 120 localities, 28 described species, and six undescribed ones. Species were recorded in six relief units, the richest of which being the Serra do Mar, with 30 species. When the Serra do Mar is subdivided into three subunits, Northern, Central and Southern Serra do Mar, the number of species increase from north to the south, with records of six, nine, and 16 species, respectively. We were able to estimate the extent of occurrence of nearly half of the described species, and the resulting estimates indicate that many of them show remarkably small ranges, some of which less than 50 ha. Brachycephalus species are present from sea level to roughly 1,900 m a.s.l., with the highest richness being found between 751 and 1,000 m a.s.l. (21 spp.). The species with the broadest altitudinal range were B. didactylus (1,075 m) and Brachycephalus sp. 1 (1,035 m), both in the didactylus group, and B. ephippium (1,050 m), of the ephippium group. The broadest altitudinal amplitude for species of the pernix group was recorded for B. brunneus (535 m). The lowest altitudinal records for the pernix group were at 845 m a.s.l. in the state of Parana and at 455 m a.s.l. in the state of Santa Catarina. The altitudinal occurrence in the pernixspecies group seems to decrease southward. Syntopy between species is also reviewed. PMID- 27761313 TI - Comparative functional characterization of novel non-syndromic GJB2 gene variant p.Gly45Arg and lethal syndromic variant p.Gly45Glu. AB - We characterized a novel GJB2 missense variant, c.133G>A, p.Gly45Arg, and compared it with the only other variant at the same amino acid position of the connexin 26 protein (Cx26) reported to date: c.134G>A, p.Gly45Glu. Whereas both variants are associated with hearing loss and are dominantly inherited, p.Gly45Glu has been implicated in the rare fatal keratitis-ichthyosis-deafness (KID) syndrome, which results in cutaneous infections and septicemia with premature demise in the first year of life. In contrast, p.Gly45Arg appears to be non-syndromic. Subcellular localization experiments in transiently co-transfected HeLa cells demonstrated that Cx26-WT (wild-type) and p.Gly45Arg form gap junctions, whereas Cx26-WT with p.Gly45Glu protein does not. The substitution of a nonpolar amino acid glycine in wildtype Cx26 at position 45 with a negatively charged glutamic acid (acidic) has previously been shown to interfere with Ca2+ regulation of hemichannel gating and to inhibit the formation of gap junctions, resulting in cell death. The novel variant p.Gly45Arg, however, changes this glycine to a positively charged arginine (basic), resulting in the formation of dysfunctional gap junctions that selectively affect the permeation of negatively charged inositol 1,4,5-trisphosphate (IP3) and contribute to hearing loss. Cx26 p.Gly45Arg transfected cells, unlike cells transfected with p.Gly45Glu, thrived at physiologic Ca2+ concentrations, suggesting that Ca2+ regulation of hemichannel gating is unaffected in Cx26 p.Gly45Arg transfected cells. Thus, the two oppositely charged amino acids that replace the highly conserved uncharged glycine in p.Gly45Glu and p.Gly45Arg, respectively, produce strikingly different effects on the structure and function of the Cx26 protein. PMID- 27761314 TI - Highly divergent mussel lineages in isolated Indonesian marine lakes. AB - Marine lakes, with populations in landlocked seawater and clearly delineated contours, have the potential to provide a unique model to study early stages of evolution in coastal marine taxa. Here we ask whether populations of the mussel Brachidontes from marine lakes in Berau, East Kalimantan (Indonesia) are isolated from each other and from the coastal mangrove systems. We analyzed sequence data of one mitochondrial marker (Cytochrome Oxidase I (COI)), and two nuclear markers (18S and 28S). In addition, we examined shell shape using a geometric morphometric approach. The Indonesian populations of Brachidontes spp. harbored four deeply diverged lineages (14-75% COI corrected net sequence divergence), two of which correspond to previously recorded lineages from marine lakes in Palau, 1,900 km away. These four lineages also showed significant differences in shell shape and constitute a species complex of at least four undescribed species. Each lake harbored a different lineage despite the fact that the lakes are separated from each other by only 2-6 km, while the two mangrove populations, at 20 km distance from each other, harbored the same lineage and shared haplotypes. Marine lakes thus represent isolated habitats. As each lake contained unique within lineage diversity (0.1-0.2%), we suggest that this may have resulted from in situdivergence due to isolation of founder populations after the formation of the lakes (6,000-12,000 years before present). Combined effects of stochastic processes, local adaptation and increased evolutionary rates could produce high levels of differentiation in small populations such as in marine lake environments. Such short-term isolation at small spatial scales may be an important contributing factor to the high marine biodiversity that is found in the Indo-Australian Archipelago. PMID- 27761316 TI - A new hynobiid-like salamander (Amphibia, Urodela) from Inner Mongolia, China, provides a rare case study of developmental features in an Early Cretaceous fossil urodele. AB - A new fossil salamander, Nuominerpeton aquilonaris (gen. et sp. nov.), is named and described based on specimens from the Lower Cretaceous Guanghua Formation of Inner Mongolia, China. The new discovery documents a far northern occurrence of Early Cretaceous salamanders in China, extending the geographic distribution for the Mesozoic fossil record of the group from the Jehol area (40th-45th parallel north) to near the 49th parallel north. The new salamander is characterized by having the orbitosphenoid semicircular in shape; coracoid plate of the scapulocoracoid greatly expanded with a convex ventral and posterior border; ossification of two centralia in carpus and tarsus; and first digit being about half the length of the second digit in both manus and pes. The new salamander appears to be closely related to hynobiids, although this inferred relationship awaits confirmation by research in progress by us on a morphological and molecular combined analysis of cryptobranchoid relationships. Comparison of adult with larval and postmetamorphic juvenile specimens provides insights into developmental patterns of cranial and postcranial skeletons in this fossil species, especially resorption of the palatine and anterior portions of the palatopterygoid in the palate and the coronoid in the mandible during metamorphosis, and postmetamorphic ossification of the mesopodium in both manus and pes. Thus, this study provides a rare case study of developmental features in a Mesozoic salamander. PMID- 27761315 TI - Metagenomic survey of methanesulfonic acid (MSA) catabolic genes in an Atlantic Ocean surface water sample and in a partial enrichment. AB - Methanesulfonic acid (MSA) is a relevant intermediate of the biogeochemical cycle of sulfur and environmental microorganisms assume an important role in the mineralization of this compound. Several methylotrophic bacterial strains able to grow on MSA have been isolated from soil or marine water and two conserved operons, msmABCD coding for MSA monooxygenase and msmEFGH coding for a transport system, have been repeatedly encountered in most of these strains. Homologous sequences have also been amplified directly from the environment or observed in marine metagenomic data, but these showed a base composition (G + C content) very different from their counterparts from cultivated bacteria. The aim of this study was to understand which microorganisms within the coastal surface oceanic microflora responded to MSA as a nutrient and how the community evolved in the early phases of an enrichment by means of metagenome and gene-targeted amplicon sequencing. From the phylogenetic point of view, the community shifted significantly with the disappearance of all signals related to the Archaea, the Pelagibacteraceae and phylum SAR406, and the increase in methylotroph-harboring taxa, accompanied by other groups so far not known to comprise methylotrophs such as the Hyphomonadaceae. At the functional level, the abundance of several genes related to sulfur metabolism and methylotrophy increased during the enrichment and the allelic distribution of gene msmA diagnostic for MSA monooxygenase altered considerably. Even more dramatic was the disappearance of MSA import related gene msmE, which suggests that alternative transporters must be present in the enriched community and illustrate the inadequacy of msmE as an ecofunctional marker for MSA degradation at sea. PMID- 27761317 TI - Effects of elevated CO2 on predator avoidance behaviour by reef fishes is not altered by experimental test water. AB - Pioneering studies into the effects of elevated CO2 on the behaviour of reef fishes often tested high-CO2 reared fish using control water in the test arena. While subsequent studies using rearing treatment water (control or high CO2) in the test arena have confirmed the effects of high CO2 on a range of reef fish behaviours, a further investigation into the use of different test water in the experimental arena is warranted. Here, we used a fully factorial design to test the effect of rearing treatment water (control or high CO2) and experimental test water (control or high CO2) on antipredator responses of larval reef fishes. We tested antipredator behaviour in larval clownfish Amphiprion percula and ambon damselfish Pomacentrus amboinensis, two species that have been used in previous high CO2 experiments. Specifically, we tested if: (1) using control or high CO2 water in a two channel flume influenced the response of larval clownfish to predator odour; and (2) using control or high CO2 water in the test arena influenced the escape response of larval damselfish to a startle stimulus. Finally, (3) because the effects of high CO2 on fish behaviour appear to be caused by altered function of the GABA-A neurotransmitter we tested if antipredator behaviours were restored in clownfish treated with a GABA antagonist (gabazine) in high CO2 water. Larval clownfish reared from hatching in control water (496 uatm) strongly avoided predator cue whereas larval clownfish reared from hatching in high CO2 (1,022 uatm) were attracted to the predator cue, as has been reported in previous studies. There was no effect on fish responses of using either control or high CO2 water in the flume. Larval damselfish reared for four days in high CO2 (1,051 uatm) exhibited a slower response to a startle stimulus and slower escape speed compared with fish reared in control conditions (464 uatm). There was no effect of test water on escape responses. Treatment of high CO2 reared clownfish with 4 mg l-1 gabazine in high CO2 seawater restored the normal response to predator odour, as has been previously reported with fish tested in control water. Our results show that using control water in the experimental trials did not influence the results of previous studies on antipredator behaviour of reef fishes and also supports the results of novel experiments conducted in natural reef habitat at ambient CO2 levels. PMID- 27761318 TI - The effect of CO2 enrichment on net photosynthesis of the red alga Furcellaria lumbricalis in a brackish water environment. AB - Anthropogenic carbon dioxide (CO2) emissions to the atmosphere are causing reduction in the global ocean pH, also known as ocean acidification. This change alters the equilibrium of different forms of dissolved inorganic carbon in seawater that macroalgae use for their photosynthesis. In the Baltic Sea, benthic macroalgae live in a highly variable environment caused by seasonality and rapid changes in meteorological conditions. The effect of increasing water CO2 concentration on the net photosynthesis of the red macroalgae Furcellaria lumbricalis (Hudson) Lamouroux was tested in short-term mesocosm experiments conducted in Koiguste Bay (N Gulf of Riga) in June-July 2012 and 2013. Separate mesocosms were maintained at different pCO2 levels: ca. 2,000, ca. 1,000 and ca. 200 uatm. In parallel, different environmental factors were measured such as nutrients, light and water temperature. Thus, the current study also investigated whether elevated pCO2 and different environmental factors exerted interactive effects on the photosynthetic rate of F. lumbricalis. In addition, laboratory experiments were carried out to determine the optimal temperature for photosynthesis of F. lumbricalis. The results of our field experiments demonstrated that elevated pCO2 levels may remarkably enhance the photosynthetic rate of F. lumbricalis. However, the magnitude of this effect is altered by different environmental factors, mainly by changes in water temperature. PMID- 27761319 TI - Exploring the socio-emotional factors associated with subjective well-being in the unemployed. AB - In this study, we examined the relations between dimensions of Perceived Emotional Intelligence (PEI) and classic constructs, such as social support, on depression, stress, and subjective well-being indicators (life satisfaction and happiness). The study also sought to determine whether PEI dimensions accounted for a significant portion of the variance beyond that of classic constructs in the study of depression, stress, and well-being outcomes in a sample of 442 unemployed subjects. Results indicated that social support and all PEI dimensions are found to be significant and negatively related to depression and stress, and these variables were also found to be significant and positively associated with life satisfaction and happiness. Additionally, results using regression analysis indicated that PEI, and specifically use of emotions and regulation of emotions, explain a significant amount of the variance of all outcomes after controlling for socio-demographics and social support dimensions. Finally, theoretical and practical implications of these constructs and their relation with psychological adjustment and well-being in unemployed people are discussed. PMID- 27761320 TI - Mutation of the rice XA21 predicted nuclear localization sequence does not affect resistance to Xanthomonas oryzae pv. oryzae. AB - BACKGROUND: The rice receptor kinase XA21 confers robust resistance to the bacterial pathogen Xanthomonas oryzaepv. oryzae(Xoo). We previously reported that XA21 is cleaved in transgenic plants overexpressing XA21 with a GFP tag (Ubi-XA21 GFP) and that the released C-terminal domain is localized to the nucleus. XA21 carries a predicted nuclear localization sequence (NLS) that directs the C terminal domain to the nucleus in transient assays, whereas alanine substitutions in the NLS disrupt the nuclear localization. METHODS: To determine if the predicted NLS is required for XA21-mediated immunity in planta, we generated transgenic plants overexpressing an XA21 variant carrying the NLS with the same alanine substitutions (Ubi-XA21nls-GFP). RESULTS: Ubi-XA21nls-GFP plants displayed slightly longer lesion lengths, higher Xoobacterial populations after inoculation and lower levels of reactive oxygen species production compared with the Ubi-XA21-GFP control plants. However, the Ubi-XA21nls-GFP plants express lower levels of protein than that observed in Ubi-XA21-GFP. DISCUSSION: These results demonstrate that the predicted NLS is not required for XA21-mediated immunity. PMID- 27761321 TI - Positive effect of dietary lutein and cholesterol on the undirected song activity of an opportunistic breeder. AB - Song is a sexually selected trait that is thought to be an honest signal of the health condition of an individual in many bird species. For species that breed opportunistically, the quantity of food may be a determinant of singing activity. However, it is not yet known whether the quality of food plays an important role in this respect. The aim of the present study was to experimentally investigate the role of two calorie-free nutrients (lutein and cholesterol) in determining the expression of a sexually selected behavior (song rate) and other behaviors (locomotor activity, self-maintenance activity, eating and resting) in male zebra finches (Taeniopygia guttata). We predicted that males supplemented with lutein and cholesterol would sing at higher rates than controls because both lutein and cholesterol have important health-related physiological functions in birds and birdsong mirrors individual condition. To control for testosterone secretion that may upregulate birdsong, birds were exposed to a decreasing photoperiod. Our results showed that control males down-regulated testosterone in response to a decreasing photoperiod, while birds treated with lutein or cholesterol maintained a constant singing activity. Both lutein- and cholesterol-supplemented groups sang more than control groups by the end of the experiment, indicating that the quality of food can affect undirected song irrespective of circulating testosterone concentrations. None of the other measured behaviors were affected by the treatment, suggesting that, when individuals have full availability of food, sexually selected song traits are more sensitive to the effect of food quality than other behavioral traits. Overall the results support our prediction that undirected song produced by male zebra finches signals access to high quality food. PMID- 27761322 TI - Antibacterial and anti-adherence effects of a plant extract mixture (PEM) and its individual constituent extracts (Psidium sp., Mangifera sp., and Mentha sp.) on single- and dual-species biofilms. AB - BACKGROUND: Plant extracts mixture (PEM) and its individual constituent plant extracts(Psidium sp., Mangifera sp., Mentha sp.) are known to have an anti adhering effect towards oral bacteria in the single-species biofilm. To date, the adhering ability of the early and late plaque colonisers (Streptococcus sanguinis and Streptococcus mutans) to PEM-treated experimental pellicle have not been investigated in dual-species biofilms. METHODS: Fresh leaves of these plants were used in the preparation of the respective aqueous extract decoctions. The minimum inhibitory concentration (MIC) of the extracts towards S. sanguinis ATCC BAA-1455 and S. mutans ATCC 25175 was determined using a two-fold serial microdilution method. The sum of fractional inhibitory concentration (SigmaFIC) index of PEM and its constituent plant extracts was calculated using the MIC values of the plants. The minimum bactericidal concentration (MBC) of the plant extracts was also determined. The anti-adherence effect of the plant extracts (individually and mixed) was carried out by developing simulated S. sanguinis and S. mutans respectively in single- and dual-species of biofilms in the Nordini's Artificial Mouth (NAM) model system in which the experimental pellicle was pretreated with the plant extract before bacterial inoculation. The bacterial population in the respective biofilms was quantified using ten-fold serial dilutions method and expressed as colony forming unit per ml (CFU/ml). The bacterial population was also viewed using Scanning Electron Microscope (SEM). All experiments were done in triplicate. RESULTS: The PEM compared with its respective constituent plants showed the lowest MIC towards S. sanguinis (3.81 mg/ml) and S. mutans (1.91 mg/ml) and exhibited a synergistic effect. The Psidium sp. (15.24 mg/ml) and, PEM and Psidium sp. (30.48 mg/ml) showed the lowest MBC towards S. sanguinis and S. mutans respectively. The anti-adherence effect of the PEM and its respective constituent plants (except Psidium sp.) was different for the two bacteria in the single-species biofilm. In the dual-species biofilms, PEM demonstrated similar anti-adherence effect towards S. sanguinis and S. mutans. The proportions of the bacterial population viewed under SEM appeared to be in agreement with the quantified population. DISCUSSION: The combination of the active constituents of the individual plant extracts in PEM may contribute to its low MIC giving rise to the synergistic effect. The different anti-adherence effect towards S. sanguinis and S. mutans in both single- and dual-species biofilms could be due to the different proportion of the active constituents of the extracts and the interaction between different bacteria. The better adhering ability of S. sanguinis towards the PEM-treated pellicle when present together with S. mutans in the dual-species biofilms may suggest the potential of PEM in controlling the balance between the early and late colonisers in biofilms. PMID- 27761323 TI - A transcriptomic scan for potential candidate genes involved in osmoregulation in an obligate freshwater palaemonid prawn (Macrobrachium australiense). AB - BACKGROUND: Understanding the genomic basis of osmoregulation (candidate genes and/or molecular mechanisms controlling the phenotype) addresses one of the fundamental questions in evolutionary ecology. Species distributions and adaptive radiations are thought to be controlled by environmental salinity levels, and efficient osmoregulatory (ionic balance) ability is the main mechanism to overcome the problems related to environmental salinity gradients. METHODS: To better understand how osmoregulatory performance in freshwater (FW) crustaceans allow individuals to acclimate and adapt to raised salinity conditions, here we (i), reviewed the literature on genes that have been identified to be associated with osmoregulation in FW crustaceans, and (ii), performed a transcriptomic analysis using cDNA libraries developed from mRNA isolated from three important osmoregulatory tissues (gill, antennal gland, hepatopancreas) and total mRNA from post larvae taken from the freshwater prawn, Macrobrachium australiense using Illumina deep sequencing technology. This species was targeted because it can complete its life cycle totally in freshwater but, like many Macrobrachium sp., can also tolerate brackish water conditions and hence should have genes associated with tolerance of both FW and saline conditions. RESULTS: We obtained between 55.4 and 65.2 million Illumina read pairs from four cDNA libraries. Overall, paired end sequences assembled into a total of 125,196 non-redundant contigs (>=200 bp) with an N50 length of 2,282 bp and an average contig length of 968 bp. Transcriptomic analysis of M. australiense identified 32 different gene families that were potentially involved with osmoregulatory capacity. A total of 32,597 transcripts were specified with gene ontology (GO) terms identified on the basis of GO categories. Abundance estimation of expressed genes based on TPM (transcript per million) >=20 showed 1625 transcripts commonly expressed in all four libraries. Among the top 10 genes expressed in four tissue libraries associated with osmoregulation, arginine kinase and Na+/K+- ATPase showed the highest transcript copy number with 7098 and 660, respectively in gill which is considered to be the most important organ involved in osmoregulation. DISCUSSION: The current study provides the first broad transcriptome from M. australiense using next generation sequencing and identifies potential candidate genes involved in salinity tolerance and osmoregulation that can provide a foundation for investigating osmoregulatory capacity in a wide variety of freshwater crustaceans. PMID- 27761324 TI - Expediting evidence synthesis for healthcare decision-making: exploring attitudes and perceptions towards rapid reviews using Q methodology. AB - BACKGROUND: Rapid reviews expedite the knowledge synthesis process with the goal of providing timely information to healthcare decision-makers who want to use evidence-informed policy and practice approaches. A range of opinions and viewpoints on rapid reviews is thought to exist; however, no research to date has formally captured these views. This paper aims to explore evidence producer and knowledge user attitudes and perceptions towards rapid reviews. METHODS: A Q methodology study was conducted to identify central viewpoints about rapid reviews based on a broad topic discourse. Participants rank-ordered 50 text statements and explained their Q-sort in free-text comments. Individual Q-sorts were analysed using Q-Assessor (statistical method: factor analysis with varimax rotation). Factors, or salient viewpoints on rapid reviews, were identified, interpreted and described. RESULTS: Analysis of the 11 individual Q sorts identified three prominent viewpoints: Factor A cautions against the use of study design labels to make judgements. Factor B maintains that rapid reviews should be the exception and not the rule. Factor C focuses on the practical needs of the end-user over the review process. CONCLUSION: Results show that there are opposing viewpoints on rapid reviews, yet some unity exists. The three factors described offer insight into how and why various stakeholders act as they do and what issues may need to be resolved before increase uptake of the evidence from rapid reviews can be realized in healthcare decision-making environments. PMID- 27761325 TI - Controlled-release of Bacillus thurigiensis formulations encapsulated in light resistant colloidosomal microcapsules for the management of lepidopteran pests of Brassica crops. AB - Bacillus thuringiensis (B. t.) based formulations have been widely used to control lepidopteran pests in agriculture and forestry. One of their weaknesses is their short residual activity when sprayed in the field. Using Pickering emulsions, mixtures of spores and crystals from three B. t. serovars were successfully encapsulated in colloidosomal microparticles (50 MUm) using innocuous chemicals (acrylic particles, sunflower oil, iron oxide nanoparticles, ethanol and water). A pH trigger mechanism was incorporated within the particles so that B. t. release occurred only at pH > 8.5 which corresponds to the midgut pH of the target pests. Laboratory assays performed on Trichoplusia ni (T. ni) larvae demonstrated that the microencapsulation process did not impair B. t. bioactivity. The best formulations were field-tested on three key lepidopteran pests that attack Brassica crops, i.e., the imported cabbageworm, the cabbage looper and the diamondback moth. After 12 days, the mean number of larvae was significantly lower in microencapsulated formulations than in a commercial B. t. formulation, and the effect of microencapsulated formulations was comparable to a chemical pesticide (lambda-cyhalothrin). Therefore, colloidosomal microcapsule formulations successfully extend the bioactivity of B. t. for the management of lepidopteran pests of Brassica crops. PMID- 27761326 TI - Transcriptome response to elevated atmospheric CO2 concentration in the Formosan subterranean termite, Coptotermes formosanus Shiraki (Isoptera: Rhinotermitidae). AB - BACKGROUND: Carbon dioxide (CO2) is a pervasive chemical stimulus that plays a critical role in insect life, eliciting behavioral and physiological responses across different species. High CO2 concentration is a major feature of termite nests, which may be used as a cue for locating their nests. Termites also survive under an elevated CO2 concentration. However, the mechanism by which elevated CO2 concentration influences gene expression in termites is poorly understood. METHODS: To gain a better understanding of the molecular basis involved in the adaptation to CO2 concentration, a transcriptome of Coptotermes formosanus Shiraki was constructed to assemble the reference genes, followed by comparative transcriptomic analyses across different CO2 concentration (0.04%, 0.4%, 4% and 40%) treatments. RESULTS: (1) Based on a high throughput sequencing platform, we obtained approximately 20 GB of clean data and revealed 189,421 unigenes, with a mean length and an N50 length of 629 bp and 974 bp, respectively. (2) The transcriptomic response of C. formosanus to elevated CO2 levels presented discontinuous changes. Comparative analysis of the transcriptomes revealed 2,936 genes regulated among 0.04%, 0.4%, 4% and 40% CO2 concentration treatments, 909 genes derived from termites and 2,027 from gut symbionts. Genes derived from termites appears selectively activated under 4% CO2 level. In 40% CO2 level, most of the down-regulated genes were derived from symbionts. (3) Through similarity searches to data from other species, a number of protein sequences putatively involved in chemosensory reception were identified and characterized in C. formosanus, including odorant receptors, gustatory receptors, ionotropic receptors, odorant binding proteins, and chemosensory proteins. DISCUSSION: We found that most genes associated with carbohydrate metabolism, energy metabolism, and genetic information processing were regulated under different CO2 concentrations. Results suggested that termites adapt to ~4% CO2 level and their gut symbionts may be killed under high CO2 level. We anticipate that our findings provide insights into the transcriptome dynamics of CO2 responses in termites and form the basis to gain a better understanding of regulatory networks. PMID- 27761327 TI - Greater than X kb: a quantitative assessment of preservation conditions on genomic DNA quality, and a proposed standard for genome-quality DNA. AB - Advances in biodiversity genomic sequencing will increasingly depend on the availability of DNA samples-and their quantifiable metadata-preserved in large institutional biorepositories that are discoverable to the scientific community. Improvements in sequencing technology constantly provide longer reads, such that longer fragment length, higher molecular weight, and overall "genome-quality" DNA (gDNA) will be desirable. Ideally, biorepositories should publish numerical scale measurements of DNA quality useful to the user community. However, the most widely used technique to evaluate DNA quality, the classic agarose gel, has yet to be quantified. Here we propose a simple and economical method using open source image analysis software to make gDNA gel images quantifiable, and propose percentage of gDNA "greater than X kb" as a standard of comparison, where X is a band from any widely used DNA ladder with desirably large band sizes. We employ two metadata standards ("DNA Threshold" and "Percent above Threshold") introduced as part of the Global Genome Biodiversity Network (GGBN) Darwin Core extension. We illustrate the method using the traditionally used HindIII ladder and the 9,416 base-pair (bp) band as a standard. We also present data, for two taxa, a vertebrate (fish) and an invertebrate (crab), on how gDNA quality varies with seven tissue preservation methods, time since death, preservation method (i.e. buffers vs. cold temperatures), and storage temperature of various buffers over time. Our results suggest that putting tissue into a buffer prior to freezing may be better than directly into ultra-cold conditions. PMID- 27761328 TI - Did the 1918 influenza cause the twentieth century cardiovascular mortality epidemic in the United States? AB - During most of the twentieth century, cardiovascular mortality increased in the United States while other causes of death declined. By 1958, the age-standardized death rate (ASDR) for cardiovascular causes for females was 1.84 times that for all other causes, combined (and, for males, 1.79*). Although contemporary observers believed that cardiovascular mortality would remain high, the late 1950s and early 1960s turned out to be the peak of a roughly 70-year epidemic. By 1988 for females (1986 for males), a spectacular decline had occurred, wherein the ASDR for cardiovascular causes was less than that for other causes combined. We discuss this phenomenon from a demographic point of view. We also test a hypothesis from the literature, that the 1918 influenza pandemic caused the cardiovascular mortality epidemic; we fail to find support. PMID- 27761330 TI - Ontogenetic foraging activity and feeding selectivity of the Brazilian endemic parrotfish Scarus zelindae. AB - Parrotfish are fundamental species in controlling algal phase-shifts and ensuring the resilience of coral reefs. Nevertheless, little is known on their ecological role in the south-western Atlantic Ocean. The present study analysed the ontogenetic foraging activity and feeding selectivity of the Brazilian endemic parrotfish Scarus zelindae using behavioural observation and benthic composition analyses. We found a significant negative relationship between fish size and feeding rates for S. zelindae individuals. Thus, terminal phase individuals forage with lower feeding rates compared to juveniles and initial phase individuals. The highest relative foraging frequency of S. zelindae was on epilithic algae matrix (EAM) with similar values for juveniles (86.6%), initial phase (88.1%) and terminal phase (88.6%) individuals. The second preferred benthos for juveniles was sponge (11.6%) compared with initial (4.5%) and terminal life phases (1.3%). Different life phases of S. zelindae foraged on different benthos according to their availability. Based on Ivlev's electivity index, juveniles selected EAM and sponge, while initial phase and terminal phase individuals only selected EAM. Our findings demonstrate that the foraging frequency of the endemic parrotfish S. zelindae is reduced according to body size and that there is a slight ontogenetic change in feeding selectivity. Therefore, ecological knowledge of ontogenetic variations on resource use is critical for the remaining parrotfish populations which have been dramatically reduced in the Southwestern Atlantic Ocean. PMID- 27761329 TI - Transcriptome analysis reveals candidate genes involved in luciferin metabolism in Luciola aquatilis (Coleoptera: Lampyridae). AB - Bioluminescence, which living organisms such as fireflies emit light, has been studied extensively for over half a century. This intriguing reaction, having its origins in nature where glowing insects can signal things such as attraction or defense, is now widely used in biotechnology with applications of bioluminescence and chemiluminescence. Luciferase, a key enzyme in this reaction, has been well characterized; however, the enzymes involved in the biosynthetic pathway of its substrate, luciferin, remains unsolved at present. To elucidate the luciferin metabolism, we performed a de novo transcriptome analysis using larvae of the firefly species, Luciola aquatilis. Here, a comparative analysis is performed with the model coleopteran insect Tribolium casteneum to elucidate the metabolic pathways in L. aquatilis. Based on a template luciferin biosynthetic pathway, combined with a range of protein and pathway databases, and various prediction tools for functional annotation, the candidate genes, enzymes, and biochemical reactions involved in luciferin metabolism are proposed for L. aquatilis. The candidate gene expression is validated in the adult L. aquatilis using reverse transcription PCR (RT-PCR). This study provides useful information on the bio production of luciferin in the firefly and will benefit to future applications of the valuable firefly bioluminescence system. PMID- 27761331 TI - Occurrence of Blastocystis sp. in water catchments at Malay villages and Aboriginal settlement during wet and dry seasons in Peninsular Malaysia. AB - In the tropics, there are too few studies on isolation of Blastocystis sp. subtypes from water sources; in addition, there is also an absence of reported studies on the occurrence of Blastocystis sp. subtypes in water during different seasons. Therefore, this study was aimed to determine the occurrence of Blastocystis sp. subtypes in river water and other water sources that drained aboriginal vicinity of highly endemic intestinal parasitic infections during wet and dry seasons. Water samples were collected from six sampling points of Sungai Krau (K1-K6) and a point at Sungai Lompat (K7) and other water sources around the aboriginal villages. The water samples were collected during both seasons, wet and dry seasons. Filtration of the water samples were carried out using a flatbed membrane filtration system. The extracted DNA from concentrated water sediment was subjected to single round polymerase chain reaction and positive PCR products were subjected to sequencing. All samples were also subjected to filtration and cultured on membrane lactose glucuronide agar for the detection of faecal coliforms. During wet season, Blastocystis sp. ST1, ST2 and ST3 were detected in river water samples. Blastocystis sp. ST3 occurrence was sustained in the river water samples during dry season. However Blastocystis sp. ST1 and ST2 were absent during dry season. Water samples collected from various water sources showed contaminations of Blastocystis sp. ST1, ST2, ST3 and ST4, during wet season and Blastocystis sp. ST1, ST3, ST8 and ST10 during dry season. Water collected from all river sampling points during both seasons showed growth of Escherichia coli and Enterobacter aerogenes, indicating faecal contamination. In this study, Blastocystis sp. ST3 is suggested as the most robust and resistant subtype able to survive in any adverse environmental condition. Restriction and control of human and animal faecal contaminations to the river and other water sources shall prevent the transmission of Blastocystis sp. to humans and animals in this aboriginal community. PMID- 27761332 TI - Age, growth, and natural mortality of schoolmaster (Lutjanus apodus) from the southeastern United States. AB - Ages of schoolmaster (n = 136) from the southeastern Florida coast from 1981-2015 were determined using sectioned sagittal otoliths. Opaque zones were annular, forming March-July (peaking in May-June). Schoolmaster ranged in age from 1-42 years; the largest fish measured 505 mm total length (TL) and was 19 years old. The oldest fish measured 440 mm TL. Estimated body size relationships for schoolmaster were: W = 9.26 * 10-6TL3.11 (n = 256, r2 = 0.95); W = 2.13 * 10 5FL2.99 (n = 161, r2 = 0.95); TL = 1.03 FL + 10.36 (n = 143, r2 = 0.99); and FL = 0.96 TL - 8.41 (n = 143, r2 = 0.99), where W = whole weight in g, FL = fork length in mm, and TL in mm. The fitted von Bertalanffy growth equation was: Lt = 482 (1 - e-0.12(t+2.79)) (n = 136). Based on published life history relationships, a point estimate of natural mortality for schoolmaster was M = 0.10, while age-specific estimates of M ranged from 1.57-0.18 for ages 1-42. PMID- 27761333 TI - Aboveground and belowground arthropods experience different relative influences of stochastic versus deterministic community assembly processes following disturbance. AB - BACKGROUND: Understanding patterns of biodiversity is a longstanding challenge in ecology. Similar to other biotic groups, arthropod community structure can be shaped by deterministic and stochastic processes, with limited understanding of what moderates the relative influence of these processes. Disturbances have been noted to alter the relative influence of deterministic and stochastic processes on community assembly in various study systems, implicating ecological disturbances as a potential moderator of these forces. METHODS: Using a disturbance gradient along a 5-year chronosequence of insect-induced tree mortality in a subalpine forest of the southern Rocky Mountains, Colorado, USA, we examined changes in community structure and relative influences of deterministic and stochastic processes in the assembly of aboveground (surface and litter-active species) and belowground (species active in organic and mineral soil layers) arthropod communities. Arthropods were sampled for all years of the chronosequence via pitfall traps (aboveground community) and modified Winkler funnels (belowground community) and sorted to morphospecies. Community structure of both communities were assessed via comparisons of morphospecies abundance, diversity, and composition. Assembly processes were inferred from a mixture of linear models and matrix correlations testing for community associations with environmental properties, and from null-deviation models comparing observed vs. expected levels of species turnover (Beta diversity) among samples. RESULTS: Tree mortality altered community structure in both aboveground and belowground arthropod communities, but null models suggested that aboveground communities experienced greater relative influences of deterministic processes, while the relative influence of stochastic processes increased for belowground communities. Additionally, Mantel tests and linear regression models revealed significant associations between the aboveground arthropod communities and vegetation and soil properties, but no significant association among belowground arthropod communities and environmental factors. DISCUSSION: Our results suggest context dependent influences of stochastic and deterministic community assembly processes across different fractions of a spatially co-occurring ground-dwelling arthropod community following disturbance. This variation in assembly may be linked to contrasting ecological strategies and dispersal rates within above- and below ground communities. Our findings add to a growing body of evidence indicating concurrent influences of stochastic and deterministic processes in community assembly, and highlight the need to consider potential variation across different fractions of biotic communities when testing community ecology theory and considering conservation strategies. PMID- 27761334 TI - The ethnobotany of psychoactive plant use: a phylogenetic perspective. AB - Psychoactive plants contain chemicals that presumably evolved as allelochemicals but target certain neuronal receptors when consumed by humans, altering perception, emotion and cognition. These plants have been used since ancient times as medicines and in the context of religious rituals for their various psychoactive effects (e.g., as hallucinogens, stimulants, sedatives). The ubiquity of psychoactive plants in various cultures motivates investigation of the commonalities among these plants, in which a phylogenetic framework may be insightful. A phylogeny of culturally diverse psychoactive plant taxa was constructed with their psychotropic effects and affected neurotransmitter systems mapped on the phylogeny. The phylogenetic distribution shows multiple evolutionary origins of psychoactive families. The plant families Myristicaceae (e.g., nutmeg), Papaveraceae (opium poppy), Cactaceae (peyote), Convolvulaceae (morning glory), Solanaceae (tobacco), Lamiaceae (mints), Apocynaceae (dogbane) have a disproportionate number of psychoactive genera with various indigenous groups using geographically disparate members of these plant families for the same psychoactive effect, an example of cultural convergence. Pharmacological traits related to hallucinogenic and sedative potential are phylogenetically conserved within families. Unrelated families that exert similar psychoactive effects also modulate similar neurotransmitter systems (i.e., mechanistic convergence). However, pharmacological mechanisms for stimulant effects were varied even within families suggesting that stimulant chemicals may be more evolutionarily labile than those associated with hallucinogenic and sedative effects. Chemically similar psychoactive chemicals may also exist in phylogenetically unrelated lineages, suggesting convergent evolution or differential gene regulation of a common metabolic pathway. Our study has shown that phylogenetic analysis of traditionally used psychoactive plants suggests multiple ethnobotanical origins and widespread human dependence on these plants, motivating pharmacological investigation into their potential as modern therapeutics for various neurological disorders. PMID- 27761335 TI - Higher central fat and poor self-body image in short-stature overweight/obese women living in Brazilian shantytowns. AB - BACKGROUND: Short stature in adult life, a possible consequence of poor perinatal conditions, is associated with higher risk of mortality and social disabilities. We aimed to determine whether low-income, overweight/obese, short-stature (SS) women show alterations in body composition, self-body-image perception, and biochemical profile compared to their non-short (NS) counterparts. METHODS: A cross-sectional study was conducted with women living in shantytowns and mother or relatives to undernourished children treated in a center for recuperation and nutritional education. Inclusion criteria were: (1) age, 19-45 years; (2) stature < 152.3 cm or > 158.7 cm; and (3) body mass index > 25 kg/m2. Socioeconomic, anthropometric, biochemical, and body image data were collected. We analyzed 56 SS and 57 NS women. RESULTS: The SS group showed a higher waist-to-height ratio (WHtR) (mean: 0.63; standard deviation: 0.06 for SS and mean: 0.60; standard deviation: 0.07 for the NS group; p = 0.02), and, in the adjusted analysis, showed lower fat-free mass (Estimated Marginal Mean for the SS group: 45.7 kg 95% confidence intervals (CI) (45.2-46.2) and for the NS group: 46.9 kg 95% CI (46.4 47.4); p < 0.01) and higher fat mass (Estimated Marginal Mean for the SS group: 32.5 95% CI (31.9-33.0) and for the NS group: 31.4 kg 95% CI (30.9-31.9); p < 0.01). Body mass index was a better predictor of current self-body-image perception for NS women. The SS coefficient values were beta = 0.141, SE = 0.059, and R2-Nagelkerke = 0.107, and the NS coefficients values were beta = 0.307, SE = 0.058, and R2-Nagelkerke = 0.491 (Z = 2.006; p < 0.05). Considering the obese subgroup, six out of 32 (18.8%) SS women and 14 out of 33 (42.4%) NS women perceived themselves as obese (chi2 = 4.27; p = 0.03). This difference remained significant even after adjustment by age, schooling, and number of children (p = 0.04). Only the total thyroxin showed significant differences between groups, lower in SS women (p = 0.04). DISCUSSION: Overweight/obese, low-income SS women have more central adiposity and impaired self-body image perception, and the body mass index is a weaker predictor of it, compared to NS women. Misperception about body size may be linked with an overestimation of health and underestimation of risk, which may lead to a lower utilization of the health care system and inadequate physician counseling. These features may account, at least partially, for the higher mortality risk seen in SS adults. PMID- 27761336 TI - Histology and gametogenesis in Heleobia piscium (Cochliopidae) from the Multiple Use Reserve "Isla Martin Garcia," Buenos Aires, Argentina. AB - Heleobia piscium (d'Orbigny, 1835), a member of the Cochliopidae family found only in South America, is distributed from Entre Rios, Delta del Parana, and the littoral of the Rio de la Plata down as far as to Punta Indio (Buenos Aires), the southernmost limit of the snail's geographical distribution. To date, little information is available regarding the reproductive cycle of species within this family either in Argentina or throughout South America. The present work analyzed the histology of the reproductive system of the gonochoric species H. piscium and determined the stages oogenesis and spermatogenesis under natural conditions. Specimens of H. piscium were collected in the Multiple-Use Natural Reserve Isla Martin Garcia, located in the Upper Rio de la Plata estuary to the south of the mouth of the Uruguay River. The gametogenic cycle in both sexes was found to consist of the following stages: early maturation, maturation, and evacuation. The maturation period was found to extend from January to October and evacuation of the gametes to start in November and end in February (summer in the Southern Hemisphere). The results indicated the H. piscium exhibit a reproductive cycle without a resting period. PMID- 27761338 TI - Environmental and spatial drivers of taxonomic, functional, and phylogenetic characteristics of bat communities in human-modified landscapes. AB - BACKGROUND: Assembly of species into communities following human disturbance (e.g., deforestation, fragmentation) may be governed by spatial (e.g., dispersal) or environmental (e.g., niche partitioning) mechanisms. Variation partitioning has been used to broadly disentangle spatial and environmental mechanisms, and approaches utilizing functional and phylogenetic characteristics of communities have been implemented to determine the relative importance of particular environmental (or niche-based) mechanisms. Nonetheless, few studies have integrated these quantitative approaches to comprehensively assess the relative importance of particular structuring processes. METHODS: We employed a novel variation partitioning approach to evaluate the relative importance of particular spatial and environmental drivers of taxonomic, functional, and phylogenetic aspects of bat communities in a human-modified landscape in Costa Rica. Specifically, we estimated the amount of variation in species composition (taxonomic structure) and in two aspects of functional and phylogenetic structure (i.e., composition and dispersion) along a forest loss and fragmentation gradient that are uniquely explained by landscape characteristics (i.e., environment) or space to assess the importance of competing mechanisms. RESULTS: The unique effects of space on taxonomic, functional and phylogenetic structure were consistently small. In contrast, landscape characteristics (i.e., environment) played an appreciable role in structuring bat communities. Spatially-structured landscape characteristics explained 84% of the variation in functional or phylogenetic dispersion, and the unique effects of landscape characteristics significantly explained 14% of the variation in species composition. Furthermore, variation in bat community structure was primarily due to differences in dispersion of species within functional or phylogenetic space along the gradient, rather than due to differences in functional or phylogenetic composition. DISCUSSION: Variation among bat communities was related to environmental mechanisms, especially niche-based (i.e., environmental) processes, rather than spatial mechanisms. High variation in functional or phylogenetic dispersion, as opposed to functional or phylogenetic composition, suggests that loss or gain of niche space is driving the progressive loss or gain of species with particular traits from communities along the human-modified gradient. Thus, environmental characteristics associated with landscape structure influence functional or phylogenetic aspects of bat communities by effectively altering the ways in which species partition niche space. PMID- 27761339 TI - Evaluation of reference genes for gene expression in red-tailed phascogale (Phascogale calura) liver, lung, small intestine and spleen. AB - BACKGROUND: Reference genes serve an important role as an endogenous control/standard for data normalisation in gene expression studies. Although reference genes have recently been suggested for marsupials, independent analysis of reference genes on different immune tissues is yet to be tested. Therefore, an assessment of reference genes is needed for the selection of stable, expressed genes across different marsupial tissues. METHODS: The study was conducted on red tailed phascogales (Phascogale calura) using five juvenile and five adult males. The stability of five reference genes (glyceraldehyde-3-phosphate dehydrogenase, GAPDH; beta-actin, ACTB; 18S rRNA, 18S; 28S rRNA, 28S; and ribosomal protein L13A, RPL13A) was investigated using SYBR Green and analysed with the geNorm application available in qBasePLUS software. RESULTS: Gene stability for juvenile and adult tissue samples combined show that GAPDH was most stable in liver and lung tissue, and 18S in small intestine and spleen. While all reference genes were suitable for small intestine and spleen tissues, all reference genes except 28S were stable for lung and only 18S and 28S were stable for liver tissue. Separating the two age groups, we found that two different reference genes were considered stable in juveniles (ACTB and GAPDH) and adults (18S and 28S), and RPL13A was not stable for juvenile small intestine tissue. Except for 28S, all reference genes were stable in juvenile and adult lungs, and all five reference genes were stable in spleen tissue. DISCUSSION: Based on expression stability, ACTB and GAPDH are suitable for all tissues when studying the expression of marsupials in two age groups, except for adult liver tissues. The expression stability between juvenile and adult liver tissue was most unstable, as the stable reference genes for juveniles and adults were different. Juvenile and adult lung, small intestine and spleen share similar stable reference genes, except for small intestine tissues where all reference genes were stable in adults but RPL13A was not suitable in juveniles. PMID- 27761337 TI - Mitochondrial DNA hyperdiversity and its potential causes in the marine periwinkle Melarhaphe neritoides (Mollusca: Gastropoda). AB - We report the presence of mitochondrial DNA (mtDNA) hyperdiversity in the marine periwinkle Melarhaphe neritoides (Linnaeus, 1758), the first such case among marine gastropods. Our dataset consisted of concatenated 16S-COI-Cytb gene fragments. We used Bayesian analyses to investigate three putative causes underlying genetic variation, and estimated the mtDNA mutation rate, possible signatures of selection and the effective population size of the species in the Azores archipelago. The mtDNA hyperdiversity in M. neritoides is characterized by extremely high haplotype diversity (Hd = 0.999 +/- 0.001), high nucleotide diversity (pi = 0.013 +/- 0.001), and neutral nucleotide diversity above the threshold of 5% (pisyn = 0.0677). Haplotype richness is very high even at spatial scales as small as 100m2. Yet, mtDNA hyperdiversity does not affect the ability of DNA barcoding to identify M. neritoides. The mtDNA hyperdiversity in M. neritoides is best explained by the remarkably high mutation rate at the COI locus (MU = 5.82 * 10-5 per site per year or MU = 1.99 * 10-4 mutations per nucleotide site per generation), whereas the effective population size of this planktonic-dispersing species is surprisingly small (Ne = 5, 256; CI = 1,312 3,7495) probably due to the putative influence of selection. Comparison with COI nucleotide diversity values in other organisms suggests that mtDNA hyperdiversity may be more frequently linked to high MU values and that mtDNA hyperdiversity may be more common across other phyla than currently appreciated. PMID- 27761340 TI - LIMK1/2 inhibitor LIMKi 3 suppresses porcine oocyte maturation. AB - LIMKi 3 is a specific selective LIMK inhibitor against LIMK1 and LIMK2, while LIMK1 and LIMK2 are the main regulators of actin cytoskeleton to participate in many cell activities. However, the effect of LIMKi 3 in porcine oocyte meiosis is still unclear. The present study was designed to investigate the effects of LIMKi 3 and potential regulatory role of LIMK1/2 on porcine oocyte meiotic maturation. Immunofluorescent staining of p-LIMK1/2 antibody showed that LIMK1/2 was localized mainly to the cortex of porcine oocyte, which co-localized with actin. After LIMKi 3 treatment, the diffusion of COCs became weak and the rate of polar body extrusion was decreased. This could be rescued by moving oocytes to fresh medium. After prolonging the culture time of oocytes, the maturation rate of porcine oocyte increased in LIMKi 3 groups, indicating that LIMKi 3 may suppress the cell cycle during porcine oocyte maturation. We also found that after LIMKi 3 treatment actin distribution was significantly disturbed at porcine oocyte membranes and cytoplasm, indicating the conserved roles of LIMK1/2 on actin dynamics. Next we examined the meiotic spindle positioning in porcine oocyte, and the results showed that a majority of spindles were not attached to the cortex of porcine oocyte, indicating that LIMKi 3 may affect actin-mediated spindle positioning. Taken together, these results showed that LIMK1/2 inhibitor LIMKi 3 had a repressive role on porcine oocyte meiotic maturation. PMID- 27761341 TI - Identification and temporal expression of putative circadian clock transcripts in the amphipod crustacean Talitrus saltator. AB - BACKGROUND: Talitrus saltator is an amphipod crustacean that inhabits the supralittoral zone on sandy beaches in the Northeast Atlantic and Mediterranean. T. saltator exhibits endogenous locomotor activity rhythms and time-compensated sun and moon orientation, both of which necessitate at least one chronometric mechanism. Whilst their behaviour is well studied, currently there are no descriptions of the underlying molecular components of a biological clock in this animal, and very few in other crustacean species. METHODS: We harvested brain tissue from animals expressing robust circadian activity rhythms and used homology cloning and Illumina RNAseq approaches to sequence and identify the core circadian clock and clock-related genes in these samples. We assessed the temporal expression of these genes in time-course samples from rhythmic animals using RNAseq. RESULTS: We identified a comprehensive suite of circadian clock gene homologues in T. saltator including the 'core' clock genes period (Talper), cryptochrome 2 (Talcry2), timeless (Taltim), clock (Talclk), and bmal1 (Talbmal1). In addition we describe the sequence and putative structures of 23 clock-associated genes including two unusual, extended isoforms of pigment dispersing hormone (Talpdh). We examined time-course RNAseq expression data, derived from tissues harvested from behaviourally rhythmic animals, to reveal rhythmic expression of these genes with approximately circadian period in Talper and Talbmal1. Of the clock-related genes, casein kinase IIbeta (TalckIIbeta), ebony (Talebony), jetlag (Taljetlag), pigment dispensing hormone (Talpdh), protein phosphatase 1 (Talpp1), shaggy (Talshaggy), sirt1 (Talsirt1), sirt7 (Talsirt7) and supernumerary limbs (Talslimb) show temporal changes in expression. DISCUSSION: We report the sequences of principle genes that comprise the circadian clock of T. saltator and highlight the conserved structural and functional domains of their deduced cognate proteins. Our sequencing data contribute to the growing inventory of described comparative clocks. Expression profiling of the identified clock genes illuminates tantalising targets for experimental manipulation to elucidate the molecular and cellular control of clock-driven phenotypes in this crustacean. PMID- 27761342 TI - Variation in habitat soundscape characteristics influences settlement of a reef building coral. AB - Coral populations, and the productive reef ecosystems they support, rely on successful recruitment of reef-building species, beginning with settlement of dispersing larvae into habitat favourable to survival. Many substrate cues have been identified as contributors to coral larval habitat selection; however, the potential for ambient acoustic cues to influence coral settlement responses is unknown. Using in situ settlement chambers that excluded other habitat cues, larval settlement of a dominant Caribbean reef-building coral, Orbicella faveolata, was compared in response to three local soundscapes, with differing acoustic and habitat properties. Differences between reef sites in the number of larvae settled in chambers isolating acoustic cues corresponded to differences in sound levels and reef characteristics, with sounds at the loudest reef generating significantly higher settlement during trials compared to the quietest site (a 29.5 % increase). These results suggest that soundscapes could be an important influence on coral settlement patterns and that acoustic cues associated with reef habitat may be related to larval settlement. This study reports an effect of soundscape variation on larval settlement for a key coral species, and adds to the growing evidence that soundscapes affect marine ecosystems by influencing early life history processes of foundational species. PMID- 27761343 TI - Effect of orthodontic debonding and residual adhesive removal on 3D enamel microroughness. AB - BACKGROUND: Termination of fixed orthodontic treatment is associated with bracket debonding and residual adhesive removal. These procedures increase enamel roughness to a degree that should depend on the tool used. Enamel roughening may be associated with bacterial retention and staining. However, a very limited data exists on the alteration of 3D enamel roughness resulting from the use of different tools for orthodontic clean-up. AIMS: 1. To perform a precise assessment of 3D enamel surface roughness resulting from residual adhesive removal following orthodontic debonding molar tubes. 2. To compare enamel surfaces resulting from the use of tungsten carbide bur, a one-step polisher and finisher and Adhesive Residue Remover. MATERIAL AND METHODS: Buccal surfaces of forty-five extracted human third molars were analysed using a confocal laser microscope at the magnification of 1080* and 3D roughness parameters were calculated. After 20 s etching, molar tubes were bonded, the teeth were stored in 0.9% saline solution for 24 hours and debonded. Residual adhesive was removed using in fifteen specimen each: a twelve-fluted tungsten carbide bur, a one-step finisher and polisher and Adhesive Residue Remover. Then, surface roughness analysis was repeated. Data normality was assessed using Shapiro-Wilk test. Analysis of variance (ANOVA) was used to compare between variables of normal distribution and for the latter-Kruskal-Wallis test. RESULTS: Sa (arithmetical mean height) was significantly different between the groups (p = 0, 01326); the smoothest and most repeatable surfaces were achieved using Adhesive Residue Remover. Similarly, Sq (root mean square height of the scale-limited surface) had the lowest and most homogenous values for Adhesive Residue Remover (p = 0, 01108). Sz (maximum height of the scale-limited surface) was statistically different between the groups (p = 0, 0327), however no statistically significant differences were found concerning Ssk (skewness of the scale-limited surface). DISCUSSION: Confocal laser microscopy allowed 3D surface analysis of enamel surface, avoiding the limitations of contact profilometry. Tungsten carbide burs are the most popular adhesive removing tools, however, the results of the present study indicate, that a one step polisher and finisher as well as Adhesive Residue Remover are less detrimental to the enamel. This is in agreement with a recent study based on direct 3D scanning enamel surface. It proved, that a one-step finisher and polisher as well as Adhesive Residue Remover are characterized by a similar effectiveness in removing residual remnants as tungsten carbide bur, but they remove significantly less enamel. CONCLUSION: Orthodontic debonding and removal of adhesive remnants increases enamel roughness. The smoothest surfaces were achieved using Adhesive Residue Remover, and the roughest using tungsten carbide bur. PMID- 27761344 TI - Form and function of long-range vocalizations in a Neotropical fossorial rodent: the Anillaco Tuco-Tuco (Ctenomys sp.). AB - The underground environment poses particular communication challenges for subterranean rodents. Some loud and low-pitched acoustic signals that can travel long distances are appropriate for long-range underground communication and have been suggested to be territorial signals. Long-range vocalizations (LRVs) are important in long-distance communication in Ctenomys tuco-tucos. We characterized the LRV of the Anillaco Tuco-Tuco (Ctenomys sp.) using recordings from free living individuals and described the behavioral context in which this vocalization was produced during laboratory staged encounters between individuals of both sexes. Long-range calls of Anillaco tuco-tucos are low-frequency, broad band, loud, and long sounds composed by the repetition of two syllable types: series (formed by notes and soft-notes) and individual notes. All vocalizations were initiated with series, but not all had individual notes. Males were heavier than females and gave significantly lower-pitched vocalizations, but acoustic features were independent of body mass in males. The pronounced variation among individuals in the arrangement and number of syllables and the existence of three types of series (dyads, triads, and tetrads), created a diverse collection of syntactic patterns in vocalizations that would provide the opportunity to encode multiple types of information. The existence of complex syntactic patterns and the description of soft-notes represent new aspects of the vocal communication of Ctenomys. Long-distance vocalizations by Anillaco Tuco-Tucos appear to be territorial signals used mostly in male-male interactions. First, emission of LRVs resulted in de-escalation or space-keeping in male-male and male-female encounters in laboratory experiments. Second, these vocalizations were produced most frequently (in the field and in the lab) by males in our study population. Third, males produced LRVs with greater frequency during male-male encounters compared to male-female encounters. Finally, males appear to have larger home ranges that were more spatially segregated than those of females, suggesting that males may have greater need for long-distance signals that advertise their presence. Due to their apparent rarity, the function and acoustic features of LRV in female tuco-tucos remain inadequately known. PMID- 27761345 TI - Associations between different components of fitness and fatness with academic performance in Chilean youths. AB - OBJECTIVES: To analyze the associations between different components of fitness and fatness with academic performance, adjusting the analysis by sex, age, socio economic status, region and school type in a Chilean sample. METHODS: Data of fitness, fatness and academic performance was obtained from the Chilean System for the Assessment of Educational Quality test for eighth grade in 2011 and includes a sample of 18,746 subjects (49% females). Partial correlations adjusted by confounders were done to explore association between fitness and fatness components, and between the academic scores. Three unadjusted and adjusted linear regression models were done in order to analyze the associations of variables. RESULTS: Fatness has a negative association with academic performance when Body Mass Index (BMI) and Waist to Height Ratio (WHR) are assessed independently. When BMI and WHR are assessed jointly and adjusted by cofounders, WHR is more associated with academic performance than BMI, and only the association of WHR is positive. For fitness components, strength was the variable most associated with the academic performance. Cardiorespiratory capacity was not associated with academic performance if fatness and other fitness components are included in the model. CONCLUSIONS: Fitness and fatness are associated with academic performance. WHR and strength are more related with academic performance than BMI and cardiorespiratory capacity. PMID- 27761346 TI - Boundary curves of individual items in the distribution of total depressive symptom scores approximate an exponential pattern in a general population. AB - BACKGROUND: Previously, we proposed a model for ordinal scale scoring in which individual thresholds for each item constitute a distribution by each item. This lead us to hypothesize that the boundary curves of each depressive symptom score in the distribution of total depressive symptom scores follow a common mathematical model, which is expressed as the product of the frequency of the total depressive symptom scores and the probability of the cumulative distribution function of each item threshold. To verify this hypothesis, we investigated the boundary curves of the distribution of total depressive symptom scores in a general population. METHODS: Data collected from 21,040 subjects who had completed the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire as part of a national Japanese survey were analyzed. The CES-D consists of 20 items (16 negative items and four positive items). The boundary curves of adjacent item scores in the distribution of total depressive symptom scores for the 16 negative items were analyzed using log-normal scales and curve fitting. RESULTS: The boundary curves of adjacent item scores for a given symptom approximated a common linear pattern on a log normal scale. Curve fitting showed that an exponential fit had a markedly higher coefficient of determination than either linear or quadratic fits. With negative affect items, the gap between the total score curve and boundary curve continuously increased with increasing total depressive symptom scores on a log-normal scale, whereas the boundary curves of positive affect items, which are not considered manifest variables of the latent trait, did not exhibit such increases in this gap. DISCUSSION: The results of the present study support the hypothesis that the boundary curves of each depressive symptom score in the distribution of total depressive symptom scores commonly follow the predicted mathematical model, which was verified to approximate an exponential mathematical pattern. PMID- 27761347 TI - Common metabolic constraints on dive duration in endothermic and ectothermic vertebrates. AB - Dive duration in air-breathing vertebrates is thought to be constrained by the volume of oxygen stored in the body and the rate at which it is consumed (i.e., "oxygen store/usage hypothesis"). The body mass-dependence of dive duration among endothermic vertebrates is largely supportive of this model, but previous analyses of ectothermic vertebrates show no such body mass-dependence. Here we show that dive duration in both endotherms and ectotherms largely support the oxygen store/usage hypothesis after accounting for the well-established effects of temperature on oxygen consumption rates. Analyses of the body mass and temperature dependence of dive duration in 181 species of endothermic vertebrates and 29 species of ectothermic vertebrates show that dive duration increases as a power law with body mass, and decreases exponentially with increasing temperature. Thus, in the case of ectothermic vertebrates, changes in environmental temperature will likely impact the foraging ecology of divers. PMID- 27761348 TI - Invasion of the tropical earthworm Pontoscolex corethrurus (Rhinodrilidae, Oligochaeta) in temperate grasslands. AB - The tropical earthworm Pontoscolex corethrurus (Rhinodrilidae, Oligochaeta) presents a broad distribution (e.g., 56 countries from four continents). It is generally assumed that temperature appears to limit the success of tropical exotic species in temperate climates. However, the distribution range of this species could advance towards higher elevations (with lower temperatures) where no tropical species currently occur. The aim of this study was to evaluate the soil and climatic variables that could be closely associated with the distribution of P. corethrurus in four sites along an altitudinal gradient in central Veracruz, Mexico. We predicted that the distribution of P. corethrurus would be more related to climate variables than edaphic parameters. Five sampling points (in the grassland) were established at each of four sites along an altitudinal gradient: Laguna Verde (LV), La Concepcion (LC), Naolinco (NA) and Acatlan (AC) at 11-55, 992-1,025, 1,550-1,619 y 1,772-1,800 masl, respectively. The climate ranged from tropical to temperate along the altitudinal gradient. Ten earthworm species (5 Neotropical, 4 Palearctic and 1 Nearctic) were found along the gradient, belonging to three families (Rhinodrilidae, Megascolecide and Lumbricidae). Soil properties showed a significant association (positive for Ngrass, pH, permanent wilting point, organic matter and P; and negative for Total N, K and water-holding capacity) with the abundance of the earthworm community. Also there seems to be a relationship between climate and earthworm distribution along the altitudinal gradient. P. corethrurus was recorded at tropical (LV and LC) and temperate sites (NA) along the altitudinal gradient. Our results reveal that soil fertility determines the abundance of earthworms and site (climate) can act as a barrier to their migration. Further research is needed to determine the genetic structure and lineages of P. corethrurus along altitudinal gradients. PMID- 27761349 TI - YUCCA auxin biosynthetic genes are required for Arabidopsis shade avoidance. AB - Plants respond to neighbor shade by increasing stem and petiole elongation. Shade, sensed by phytochrome photoreceptors, causes stabilization of PHYTOCHROME INTERACTING FACTOR proteins and subsequent induction of YUCCA auxin biosynthetic genes. To investigate the role of YUCCA genes in phytochrome-mediated elongation, we examined auxin signaling kinetics after an end-of-day far-red (EOD-FR) light treatment, and found that an auxin responsive reporter is rapidly induced within 2 hours of far-red exposure. YUCCA2, 5, 8, and 9 are all induced with similar kinetics suggesting that they could act redundantly to control shade-mediated elongation. To test this hypothesis we constructed a yucca2, 5, 8, 9 quadruple mutant and found that the hypocotyl and petiole EOD-FR and shade avoidance responses are completely disrupted. This work shows that YUCCA auxin biosynthetic genes are essential for detectable shade avoidance and that YUCCA genes are important for petiole shade avoidance. PMID- 27761350 TI - Monte Carlo simulation of OLS and linear mixed model inference of phenotypic effects on gene expression. AB - BACKGROUND: Self-contained tests estimate and test the association between a phenotype and mean expression level in a gene set defined a priori. Many self contained gene set analysis methods have been developed but the performance of these methods for phenotypes that are continuous rather than discrete and with multiple nuisance covariates has not been well studied. Here, I use Monte Carlo simulation to evaluate the performance of both novel and previously published (and readily available via R) methods for inferring effects of a continuous predictor on mean expression in the presence of nuisance covariates. The motivating data are a high-profile dataset which was used to show opposing effects of hedonic and eudaimonic well-being (or happiness) on the mean expression level of a set of genes that has been correlated with social adversity (the CTRA gene set). The original analysis of these data used a linear model (GLS) of fixed effects with correlated error to infer effects of Hedonia and Eudaimonia on mean CTRA expression. METHODS: The standardized effects of Hedonia and Eudaimonia on CTRA gene set expression estimated by GLS were compared to estimates using multivariate (OLS) linear models and generalized estimating equation (GEE) models. The OLS estimates were tested using O'Brien's OLS test, Anderson's permutation [Formula: see text]-test, two permutation F-tests (including GlobalAncova), and a rotation z-test (Roast). The GEE estimates were tested using a Wald test with robust standard errors. The performance (Type I, II, S, and M errors) of all tests was investigated using a Monte Carlo simulation of data explicitly modeled on the re-analyzed dataset. RESULTS: GLS estimates are inconsistent between data sets, and, in each dataset, at least one coefficient is large and highly statistically significant. By contrast, effects estimated by OLS or GEE are very small, especially relative to the standard errors. Bootstrap and permutation GLS distributions suggest that the GLS results in downward biased standard errors and inflated coefficients. The Monte Carlo simulation of error rates shows highly inflated Type I error from the GLS test and slightly inflated Type I error from the GEE test. By contrast, Type I error for all OLS tests are at the nominal level. The permutation F-tests have ~1.9X the power of the other OLS tests. This increased power comes at a cost of high sign error (~10%) if tested on small effects. DISCUSSION: The apparently replicated pattern of well being effects on gene expression is most parsimoniously explained as "correlated noise" due to the geometry of multiple regression. The GLS for fixed effects with correlated error, or any linear mixed model for estimating fixed effects in designs with many repeated measures or outcomes, should be used cautiously because of the inflated Type I and M error. By contrast, all OLS tests perform well, and the permutation F-tests have superior performance, including moderate power for very small effects. PMID- 27761352 TI - Exclusions for resolving urban badger damage problems: outcomes and consequences. AB - Increasing urbanisation and growth of many wild animal populations can result in a greater frequency of human-wildlife conflicts. However, traditional lethal methods of wildlife control are becoming less favoured than non-lethal approaches, particularly when problems involve charismatic species in urban areas. Eurasian badgers (Meles meles) excavate subterranean burrow systems (setts), which can become large and complex. Larger setts within which breeding takes place and that are in constant use are known as main setts. Smaller, less frequently occupied setts may also exist within the social group's range. When setts are excavated in urban environments they can undermine built structures and can limit or prevent safe use of the area by people. The most common approach to resolving these problems in the UK is to exclude badgers from the problem sett, but exclusions suffer a variable success rate. We studied 32 lawful cases of badger exclusions using one-way gates throughout England to evaluate conditions under which attempts to exclude badgers from their setts in urban environments were successful. We aimed to identify ways of modifying practices to improve the chances of success. Twenty of the 32 exclusion attempts were successful, but success was significantly less likely if a main sett was to be excluded in comparison with another type of sett and if vegetation was not completely removed from the sett surface prior to exclusion attempts. We recommend that during exclusions all vegetation is removed from the site, regardless of what type of sett is involved, and that successful exclusion of badgers from a main sett might require substantially more effort than other types of sett. PMID- 27761353 TI - Histological variability in the limb bones of the Asiatic wild ass and its significance for life history inferences. AB - The study of bone growth marks (BGMs) and other histological traits of bone tissue provides insights into the life history of present and past organisms. Important life history traits like longevity or age at maturity, which could be inferred from the analysis of these features, form the basis for estimations of demographic parameters that are essential in ecological and evolutionary studies of vertebrates. Here, we study the intraskeletal histological variability in an ontogenetic series of Asiatic wild ass (Equus hemionus) in order to assess the suitability of several skeletal elements to reconstruct the life history strategy of the species. Bone tissue types, vascular canal orientation and BGMs have been analyzed in 35 cross-sections of femur, tibia and metapodial bones of 9 individuals of different sexes, ages and habitats. Our results show that the number of BGMs recorded by the different limb bones varies within the same specimen. Our study supports that the femur is the most reliable bone for skeletochronology, as already suggested. Our findings also challenge traditional beliefs with regard to the meaning of deposition of the external fundamental system (EFS). In the Asiatic wild ass, this bone tissue is deposited some time after skeletal maturity and, in the case of the femora, coinciding with the reproductive maturity of the species. The results obtained from this research are not only relevant for future studies in fossil Equus, but could also contribute to improve the conservation strategies of threatened equid species. PMID- 27761351 TI - Metabolic control in patients with type 2 diabetes mellitus in a public hospital in Peru: a cross-sectional study in a low-middle income country. AB - OBJECTIVE: The objective of this study was to assess patients' achievement of ADA (American Diabetes Association) guideline recommendations for glycosylated hemoglobin, lipid profile, and blood pressure in a type 2 diabetes mellitus (T2DM) outpatient clinic in a low-middle income country (LMIC) setting. METHODS: This is a descriptive cross-sectional study with 123 ambulatory T2DM patients who are being treated at a public hospital in Lima, Peru. Data was gathered via standardized interviews, clinical surveys, and anthropomorphic measurements for each patient. Blood samples were drawn in fasting state for measures of glucose, glycosylated hemoglobin (HbA1c), and lipid profile. Laboratory parameters and blood pressure were evaluated according to ADA recommendations. RESULTS: Of the 123 patients, 81 were women and the mean age was 61.8 years. Glycemic control was abnormal in 82 (68.33%) participants, and 45 (37.50%) were unable to control their blood pressure. Lipid profile was abnormal in 73 (60.83%) participants. Only nine (7.50%) participants fulfilled ADA recommendations for glycemic, blood pressure, and lipid control. CONCLUSIONS: Amongst individuals with type 2 diabetes, there was poor attainment of the ADA recommendations (HbA1c, blood pressure and LDL-cholesterol) for ambulatory T2DM patients. Interventions are urgently needed in order to prevent long-term diabetic complications. PMID- 27761354 TI - USING RESPONDENT DRIVEN SAMPLING TO RECRUIT SEXUAL MINORITY WOMEN. PMID- 27761355 TI - Occurrence and transformation of veterinary pharmaceuticals and biocides in manure: a literature review. AB - The spread of veterinary medicinal products (VMPs) and biocides via manure onto agriculturally used areas represents a very important emission into the environment for these product groups. Within this literature study, publicly available transformation studies with liquid manure are summarized. Transformation studies were evaluated regarding the transformation fate of tested substances, the origin and characteristics of used manure, the experimental setup, and the measured parameters. As main topics within the 42 evaluated transformation studies, the high dependency of transformation on temperature, redox potential, dry matter content, and other parameters is reported. Test duration throughout the studies ranged from 2 to 374 days and study temperature ranged from 5 to 55 degrees C. Only seven publications gave information on the redox potential of the manure. Further, the characterization of the matrix in many cases was inadequate due to missing parameters such as dry matter content or pH. Only three publications studied transformation of biocides. To allow for a consistent assessment of studies within the registration process, a harmonized internationally accepted and validated test method is needed. Additionally, monitoring data of VMPs in manure were collected from literature and evaluated regarding the origin and characteristics of the manure, the minimum/maximum found concentrations, and the percentage of identified compounds. Within the 27 evaluated publications, 1568 manure samples were analyzed and 39 different active substances for VMPs and 11 metabolites and transformation products of VMPs could be found in manure. Most often, the samples were analyzed for sulfonamides, tetracyclines, and fluoroquinolones. Not one study searched for biocides or worked with a non-target approach. For sulfadiazine and chlortetracycline, concentrations exceeding the predicted environmental concentrations were found. PMID- 27761356 TI - Cycling in Sao Paulo, Brazil (1997-2012): Correlates, time trends and health consequences. AB - The purpose of the study was to describe cyclists and cycling trips, and to explore correlates, time trends and health consequences of cycling in Sao Paulo, Brazil from 1997 to 2012. Cross-sectional analysis using repeated Sao Paulo Household Travel Surveys (HTS). At all time periods cycling was a minority travel mode in Sao Paulo (1174 people with cycling trips out of 214,719 people). Poisson regressions for individual correlates were estimated using the entire 2012 HTS sample. Men were six times more likely to cycle than women. We found rates of bicycle use rising over time among the richest quartile but total cycling rates dropped from 1997 to 2012 due to decreasing rates among the poor. Harms from air pollution would negate benefits from physical activity through cycling only at 1997 air pollution levels and at very high cycling levels (>= 9 h of cycling per day). Exposure-based road injury risk decreased between 2007 and 2012, from 0.76 to 0.56 cyclist deaths per 1000 person-hours travelled. Policies to reduce spatial segregation, measures to tackle air pollution, improvements in dedicated cycling infrastructure, and integrating the bicycle with the public transport system in neighborhoods of all income levels could make cycling safer and prevent more individuals from abandoning the cycling mode in Sao Paulo. PMID- 27761357 TI - The importance of evolutionarily conserved C-terminal basic residues for the stability of proapoptotic Bax protein. AB - Bax is a protein that promotes apoptosis (a form of cell death). The atomistic details of the mechanism by which Bax is activated during apoptosis remain a subject of debate. C-terminal basic residues in the sequence of Bax show remarkable conservation across a variety of species. The role of these charged residues in the stability of Bax was investigated by submitting substituted mutants to molecular dynamics simulations at high temperatures. Mutation of either or both K189 and K190 led to dramatic changes in helical content, radius of gyration, proximity of the C terminus to the core of the protein, exposure of the BH3 domain, and bundling of the core. These results suggest a critical role of positively charged residues close to the C terminus in the structural stability of Bax. PMID- 27761358 TI - Stabilization of tryptophan hydroxylase 2 by l-phenylalanine-induced dimerization. AB - Tryptophan hydroxylase 2 (TPH2) catalyses the initial and rate-limiting step in the biosynthesis of serotonin, which is associated with a variety of disorders such as depression, obsessive compulsive disorder, and schizophrenia. Full-length TPH2 is poorly characterized due to low purification quantities caused by its inherent instability. Three truncated variants of human TPH2 (rch TPH2; regulatory and catalytic domain, NDelta47-rch TPH2; truncation of 47 residues in the N terminus of rch TPH2, and ch TPH2; catalytic domain) were expressed, purified, and examined for changes in transition temperature, inactivation rate, and oligomeric state. ch TPH2 displayed 14- and 11-fold higher half-lives compared to rch TPH2 and NDelta47-rch TPH2, respectively. Differential scanning calorimetry experiments demonstrated that this is caused by premature unfolding of the less stable regulatory domain. By differential scanning fluorimetry, the unfolding transitions of rch TPH2 and NDelta47-rch TPH2 are found to shift from polyphasic to apparent two-state by the addition of l-Trp or l-Phe. Analytical gel filtration revealed that rch TPH2 and NDelta47-rch TPH2 reside in a monomer dimer equilibrium which is significantly shifted toward dimer in the presence of l-Phe. The dimerizing effect induced by l-Phe is accompanied by a stabilizing effect, which resulted in a threefold increase in half-lives of rch TPH2 and NDelta47-rch TPH2. Addition of l-Phe to the purification buffer significantly increases the purification yields, which will facilitate characterization of hTPH2. PMID- 27761359 TI - Effect of nordihydroguaiaretic acid on cell viability and glucose transport in human leukemic cell lines. AB - The polyphenol nordihydroguaiaretic acid (NDGA) has antineoplastic properties, hence it is critical to understand its action at the molecular level. Here, we establish that NDGA inhibits glucose uptake and cell viability in leukemic HL-60 and U-937 cell lines. We monitored hexose uptake using radio-labeled 2 deoxyglucose (2DG) and found that the inhibition by NDGA followed a noncompetitive mechanism. In addition, NDGA blocked hexose transport in human red blood cells and displaced prebound cytochalasin B from erythrocyte ghosts, suggesting a direct interaction with the glucose transporter GLUT1. We propose a model for the mechanism of action of NDGA on glucose uptake. Our study shows for the first time that NDGA can act as inhibitor of the glucose transporter GLUT1. PMID- 27761360 TI - Ezetimibe reduced hepatic steatosis induced by dietary oxysterols in nonhuman primates. AB - Oxidized cholesterol (oxysterols) plays an important and multifaceted role in lipid metabolism. Here we examined whether dietary oxysterols accelerate hepatic lipid accumulation and inflammation in nonhuman primates. We also examined the effect of the Niemann-Pick C1-like1 inhibitor, ezetimibe (Ez). Macaca fascicularis (5-year-old males) were fed either regular cholesterol + high-fat diet (control-HFD) or oxysterols + high-fat diet (ox-HFD; with 0.015% of oxysterols cholesterol) for 24 weeks. Compared with control-HFD, ox-HFD did not affect plasma lipid levels, but it did affect hepatic lipid levels [total cholesterol, 40.9 mg.g-1 (ox-HFD) versus 3.2 (control-HFD) mg.g-1; triglycerides, 28.0 (ox-HFD) versus 5.7 (control-HFD) mg.g-1]. Ox-HFD increased lipid accumulation as well as recruitment of inflammatory cells when compared to control-HFD. We then examined the effects of Ez, 0.2 mg.kg-1.day-1 for 12 weeks. In addition to a significant reduction in dyslipidemia, Ez alleviated biochemical and pathological aspects of steatosis. Dietary oxysterols aggravate steatosis in nonhuman primates. Treatment with Ez may be a novel therapeutic approach to NAFLD by alleviating dyslipidemia. PMID- 27761361 TI - Paradoxical delay of senescence upon depletion of BRCA2 in telomerase-deficient worms. AB - BRCA2 is a multifunctional tumor suppressor involved in homologous recombination (HR), mitotic checkpoint regulation, and telomere homeostasis. Absence of Brca2 in mice results in progressive shortening of telomeres and senescence, yet cells are prone to neoplastic transformation with elongated telomeres, suggesting that BRCA2 has positive and negative effects on telomere length regulation along the path to tumorigenesis. Using Caenorhabditis elegans as a model, we show here that depletion of BRC-2, an ortholog of BRCA2, paradoxically delays senescence in telomerase-deficient mutant worms. Telomerase-deficient worms (trt-1) exhibit early replication senescence due to short telomeres. It should be noted that worms mutated in brc-2 are not viable as well due to massive genotoxic insults. However, when BRC-2 is depleted by RNA interference in trt-1 mutant worms, the number of generations is unexpectedly increased with telomere length maintained, compared to telomerase mutants. Interestingly, depletion of other HR genes such as rad-51 and rad-54 exhibited similar effects. In worms doubly deficient of telomerase and brc-2, rad-51, or rad-54, extra telomeric C-circles were generated, suggesting that abrogation of HR induces an alteration in telomere environment favorable to illegitimate telomere maintenance when telomerase is absent. Collectively, absence of BRC-2 in telomerase-deficient background first leads to telomere shortening, followed by an induction of an as-yet-unknown telomere maintenance pathway, resulting in delay of senescence. The results have implications in the understanding of dysfunctional BRCA2-associated tumorigenesis. PMID- 27761362 TI - The bone microenvironment - Multiple players involved in cancer progression. PMID- 27761364 TI - The role of osteoclasts in breast cancer bone metastasis. AB - Breast cancer frequently metastasises to the skeleton, interfering with the normal bone remodelling process and inducing bone degradation. Bone degradation is caused by osteoclasts, the normal bone-resorbing cells. Osteoclast-mediated bone degradation subsequently leads to the release of bone-derived factors that promote skeletal tumour growth. Osteoclasts themselves stimulate tumour growth. This Review describes the molecular mechanisms through which osteoclasts and breast cancer cells collaborate with each other, triggering the formation of osteolytic bone metastasis. PMID- 27761363 TI - Bone targeted treatments in cancer - The story so far. PMID- 27761365 TI - The unresolved role of systemic factors in bone metastasis. AB - Systemic factors including cytokines, cell-free nucleic acids, microvesicles, and platelets are appreciated as important regulators of adenocarcinoma progression. Research findings using pre-clinical mouse models have revealed that many such systemically acting factors are either secreted by or responsive to peripheral tumors and impact bone and bone marrow (collectively referred to as the bone microenvironment) to initiate processes that ultimately govern disease progression, even in the absence of detectable bone metastases. In some cases, cancer-driven modulation of the bone microenvironment involves mobilization of bone marrow hematopoietic and mesenchymal cells into the circulation that are subsequently recruited into peripheral tissues and tumors. In other cases, systemic factors alter bone marrow cell (BMC) differentiation and/or gene expression to render the BMCs pro-tumorigenic even prior to their mobilization into the circulation. Given their effect on the bone microenvironment, it stands to reason that such systemic factors might also influence metastases in the bone; however, this hypothesis remains to be comprehensively tested. Here, we briefly review what is known, and not known, about systemic factors that regulate the bone microenvironment and thereby influence bone metastases. We also pose a number of currently unanswered questions in this active area of research. A better understanding of systemic processes that influence bone metastasis should aid discovery of therapeutic approaches that aim to eradicate or reduce disease burden in the bone, which is the cause of significant patient mortality and morbidity and is currently incurable. PMID- 27761366 TI - The role of lysyl oxidase, the extracellular matrix and the pre-metastatic niche in bone metastasis. AB - Most deaths from solid cancers occur as a result of secondary metastasis to distant sites. Bone is the most frequent metastatic site for many cancer types and can account for up to 80% of cancer-related deaths in certain tumours. The progression from a discrete solid primary tumour to devastating and painful bone metastases is a complex process involving multiple cell types and steps. There is increasing evidence that modulation of the extracellular matrix plays an important role in the lethal transition from a primary to disseminated metastatic bone tumour. This review provides an overview of the current understanding on the role of role of lysyl oxidase, the extracellular matrix and the pre-metastatic niche in bone metastasis. PMID- 27761367 TI - The role of microRNAs in bone metastasis. AB - The skeleton represents a common site of metastases for osteotropic cancers such as prostate and breast tumors and novel therapeutic targets and new markers for the monitoring of bone lesions are urgently needed. The formation of bone metastases is a complex process that starts at the level of the confined tumor and that is characterized by a dynamic crosstalk between the primary cancer and the future metastatic site, the bone. Factors released by the primary tumor contribute to prepare a fertile "soil", where a "pre-metastatic niche" is established prior to future colonization by cancer cells. When the primary cancer progress from the confined disease to its invasive phase, tumor cells will acquire an invasive phenotype, enter into the circulation and colonize the previously prepared site where they will establish a "metastatic niche". Among the variety of molecules that participate in the metastatic cascade, microRNAs are a class of small non-coding RNA that play an important role in the development of metastatic bone lesions. Many studies have addressed the role of small non-coding RNAs (miRs) in metastasis in osteotropic cancers and have highlighted the role of miRs as oncogenes (oncomiRs) or tumor suppressor miRs. In this review we present describe the role of miRs in the processing of the supportive bone microenvironment prior and after the bone colonization by cancer cells. Finally, future therapeutic strategies and perspectives are also discussed. PMID- 27761368 TI - The role of platelets and megakaryocytes in bone metastasis. AB - Blood platelets have been known for more than a century as important partners for successful metastatic dissemination of solid tumors. Cancer cell-induced platelet activation is a key event responsible for prometastatic activity of platelets. Blocking platelet aggregation inhibits the progression of skeletal metastases through mechanisms that are not fully understood. The establishment and progression of bone metastases are strongly influenced by the bone remodeling process. Growth factors and cytokines released upon platelet activation may contribute to both skeletal tumor growth and osteolytic lesions. Megakaryocytes are platelet precursors located in the bone marrow that control bone mass through direct stimulation of osteoblast functions and indirect inhibition of osteoclast activities. Considering growing evidence for their role in the metastatic cascade, platelets and/or megakaryocytes may provide new therapeutic opportunities to help limit bone metastases. PMID- 27761369 TI - Vascular niches for disseminated tumour cells in bone. AB - The vasculature of the skeletal system regulates osteogenesis and hematopoiesis, in addition to its primary function as a transportation network. Recent studies suggest that the vasculature in bone regulates multiple steps involved in the metastatic cascade. Matrix and growth factor abundant vascular microenvironments in bone not only provide a fertile soil for the metastatic growth but also support the dormancy of Disseminated Tumour Cells (DTCs). Interestingly, vasculature also seems to direct the reactivation of dormant DTCs. Targeting such early steps of bone metastasis by directing therapies against vascular niches can lead to the development of effective therapeutic strategies that delay or even prevent the metastatic relapse. However, this would require a detailed understanding of the regulatory mechanisms that govern the interaction between endothelial cells and DTCs in the early stages of bone metastasis. This review aims to highlight the importance of vascular niches and outline their newly identified roles during bone metastasis. PMID- 27761370 TI - The role of hematopoietic stem cell niche in prostate cancer bone metastasis. AB - Approximately 80% of prostate cancers exhibit some degree of bone metastasis. The role of the bone marrow and the hematopoietic stem cell (HSC) niche in attracting metastatic cells and maintaining dormancy of disseminated tumor cells (DTCs) is an increasingly important topic towards the development of novel prostate cancer therapies. This paper reviews aspects of the HSC niche that lead to prostate cancer cell homing and dormancy in the bone marrow. This review also discusses the role of DTCs in the niche environment and discusses the role of erythropoietin in targeting DTCs within the HSC niche. PMID- 27761371 TI - The role of bone marrow adipocytes in bone metastasis. AB - Adipocytes are a significant component of the bone marrow microenvironment. Although bone marrow adipocytes were first identified more than 100 years ago, it is only in recent years that an understanding of their complex physiological role is emerging. Bone marrow adipocytes act as local regulators of skeletal biology and homeostasis, with recent studies suggesting that marrow adipose tissue is metabolically active, and can function as an endocrine organ. As such, bone marrow adipocytes have the potential to interact with tumour cells, influencing both tumour growth and bone disease. This review discusses the current evidence for the role of bone marrow adipocytes in tumour growth within the bone marrow microenvironment and the development of the associated bone disease. PMID- 27761372 TI - The role of osteoblasts in bone metastasis. AB - The primary role of osteoblasts is to lay down new bone during skeletal development and remodelling. Throughout this process osteoblasts directly interact with other cell types within bone, including osteocytes and haematopoietic stem cells. Osteoblastic cells also signal indirectly to bone resorbing osteoclasts via the secretion of RANKL. Through these mechanisms, cells of the osteoblast lineage help retain the homeostatic balance between bone formation and bone resorption. When tumour cells disseminate in the bone microenvironment, they hijack these mechanisms, homing to osteoblasts and disrupting bone homeostasis. This review describes the role of osteoblasts in normal bone physiology, as well as interactions between tumour cells and osteoblasts during the processes of tumour cell homing to bone, colonisation of this metastatic site and development of overt bone metastases. PMID- 27761373 TI - Cancer-associated fibroblasts - Not-so-innocent bystanders in metastasis to bone? PMID- 27761374 TI - Role of sympathetic nerves in the establishment of metastatic breast cancer cells in bone. AB - The bone marrow microenvironment is characterized by its multicellular nature, and perhaps less obviously by the high mobility of multiple transient and stationary cell lineages present in this environment. The trafficking of hematopoietic and mesenchymal cells between the bone marrow and blood compartments is regulated by a number of bone marrow-derived factors. It is suspected that transformed metastatic cells "hijack" these processes to engraft into the skeleton and eventually cause the skeletal complications associated with metastatic disease. In this short review, experimental and association data supporting the contribution of a less recognized cell type of the bone marrow - the nerves of the sympathetic nervous system - to early events of the breast cancer bone metastatic process, are summarized. PMID- 27761375 TI - The role of tumour-associated macrophages in bone metastasis. AB - This overview addresses the recent research developments in the role of tumour associated macrophages (TAM) in bone metastasis biology and management of breast and prostate cancer as well as in primary and lung metastatic osteosarcoma. Immunosuppressive M2-type TAMs have been shown to associate with poor prognosis. Throughout their life cycle, macrophages (Macs) can adapt to environmental cues and influence the surroundings by secreting different cytokines and enzymes crucial to matrix remodelling, infection fighting, immune regulation and/or inflammation. In general terms, there is a broad and complex spectrum of Mac polarization statuses from M1 (classically activated/inflammatory) to M2 (alternatively activated/wound healing/immune regulating) Macs. Often the activation status of TAMs resembles more the M2-type. Considering the physiological functions of M2 Macs, it is no surprise that TAMs appear to have a role in metastasis, participating in almost every step of the metastatic cascade, which we review and explore in selected bone tropic cancers. PMID- 27761378 TI - Clinical photography. PMID- 27761376 TI - Reproductive hormones in breast cancer bone metastasis: The role of inhibins. AB - The spread of breast cancer cells to bone and survival in this new metastatic environment is influenced not only by the genetic signature of the cells, but also multiple host cells and soluble factors produced locally (paracrine) or from distant sites (endocrine). Disrupting this metastatic process has been evaluated in clinical trials of the bone targeted agents bisphosphonates and denosumab and have shown that these agents reduce the recurrence of breast cancer in postmenopausal women only, suggesting the efficacy of the drugs are influenced by levels of reproductive endocrine hormones. The molecular mechanism driving this differential effect has not been definitively identified, however, there is evidence that both reproductive hormones and bisphosphonates can affect similar paracrine factors and cellular components of the bone metastatic niche. This review focuses on how the ovarian endocrine hormone, inhibin, interacts with the paracrine factors activin and follistatin, abundant in the primary tumour and bone microenvironment, with subsequent effects on tumour cell survival. Inhibin also affects the cellular components of the bone microenvironment primarily the osteoblastic niche. Recent evidence has shown that bisphosphonates also alter this niche, which may represent a common mechanism by which inhibin and bisphosphonates interact to influence disease outcomes in early breast cancer. Further research is needed to fully elucidate these molecular mechanisms to enable understanding and future development of alternative bone targeted treatments with anti-tumour efficacy in premenopausal women. PMID- 27761377 TI - The role of extracellular calcium in bone metastasis. AB - This review summarizes the role of extracellular calcium, as found present in the bone tissue, in the process of bone metastasis. PMID- 27761379 TI - Editorial. PMID- 27761380 TI - Clinical use of the resorbable bioscaffold poly lactic co-glycolic acid (PLGA) in post-extraction socket for maintaining the alveolar height: A prospective study. AB - BACKGROUND: A common sequel of tooth extraction is alveolar bone resorption. It makes the placement of dental implants difficult and creates an esthetic problem for the fabrication of conventional prostheses. Therefore, alveolar bone following tooth extraction should be preserved. AIMS AND OBJECTIVES: The present prospective study was conducted to evaluate the efficacy of the resorbable bioscaffold poly lactic co-glycolic acid (PLGA) in maintaining the alveolar height in post-extraction socket. MATERIAL AND METHODS: 20 patients were selected based on inclusion and exclusion criteria and were randomly divided into two groups: cases and control comprising of 10 patients each. Atraumatic tooth extraction was done in all patients. PLGA bioscaffold was placed in cases and socket was closed with 3-0 vicryl. In control group, socket was directly closed with 3-0 vicryl. The patients were kept on follow-up and complications such as dry socket, pain, and swelling were recorded. IOPA were taken at 1st, 4th, 12th, and 24th week to record changes in the height of alveolar bone. The radiographic measurements were compared and the differences were statistically analyzed. RESULTS: Reduction in alveolar bone height after placement of PLGA bioscaffold was significantly less in cases as compared to controls at 4th, 12th, and 24th week following extraction. No complications were observed throughout the follow up period. CONCLUSION: PLGA scaffold significantly reduces bone resorption. Application is very simple and can be easily performed in a dental setup. However, PLGA scaffold adds significantly to the cost of treatment. PMID- 27761381 TI - Prevalence of oral ulcers and its association with addictions in rural population of western Uttar Pradesh and eastern Rajasthan. AB - BACKGROUND: Head and neck cancer in Indian perspective predominantly relates to tobacco use. The present study explores the prevalence of oral ulcers and its association with addictions among the population of Uttar Pradesh and Rajasthan, India. METHODOLOGY: The screening method in early detection of head and neck cancer is broadly symptom based. 1399 subjects from Uttar Pradesh and Rajasthan were screened by trained personnel between April and June 2015. RESULTS: Study findings showed, mouth ulcers and trismus were common symptoms and tobacco chewing and smoking were common addictions. There were statistically significant associations among the symptoms and addictions as well as predominance in rural populations. The majority of smokers (27.1%) belonged to age >=55 years whereas the tobacco chewers (29.2%) and alcohol abusers (45.8%) in the age group 25-34 years. Also the risk of developing mouth ulcers and trismus in this area are approximately 35 (MRR: 35.7, 95% CI: 15.5-81.9) and nearly eight (MRR: 7.7, 95% CI: 2.2-26.6) times higher respectively in males. However, joint use of smoked and smokeless tobacco increases nearly three times more risk of either mouth ulcers or trismus. CONCLUSION: Male individuals are more exposed to certain addictions such as tobacco (smoked and smokeless) and alcohol. The prevalence of oral ulcers is primarily associated with the addictions. Therefore, these persons are more at risk of further developing head neck cancer. A large level community screening and awareness are required especially among the rural population of India. PMID- 27761382 TI - Role of podoplanin expression in deciding the invasive potential of ameloblastoma - A retrospective IHC study. AB - BACKGROUND: The aim of this study was to investigate the podoplanin expression in epithelial odontogenic tumors both non-aggressive and aggressive, tumors with and without ectomesenchyme and remnants of the odontogenic epithelium from dental follicles (DF) of unerupted teeth and to examine its role in progression and invasion of tumors. METHOD: Thirty paraffin embedded specimens AM (15 were non aggressive ameloblastomas and 15 ameloblastoma showing aggressive behavior), 15 paraffin embedded specimens of AOT, 15 paraffin embedded specimens of CEOT, 15 paraffin embedded specimens of CCOT were obtained and were analyzed by immunohistochemistry using anti-human podoplanin. Podoplanin expression in odontogenic epithelial cells was evaluated using a scoring method, along with calculation of the percentage of positive odontogenic cells. RESULTS: Podoplanin was expressed strongly at the invasive front (in the peripheral odontogenic epithelial cells) of most tumors and dental follicles. Membranous expression of podoplanin in ameloblastomas was stronger in cases of ameloblastomas showing aggressive behavior than (NA) non-aggressive ameloblastomas. CONCLUSION: Expression of podoplanin at the invasive front (in peripheral cells) of odontogenic tumors considered to be associated with neoplastic odontogenic tissues. This molecule might play a role in progression and local invasion of odontogenic tumors. The migration and invasion mediated by podoplanin in odontogenic tumors could be related to cytoskeletal reorganization. PMID- 27761383 TI - Histologic and immunohistochemical evaluation of mirror image biopsies in oral squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVE: The concept of field cancerization has frequently been quoted to explain the occurrence of multiple primary cancers in the head and neck region and recurrence following complete excision of the original tumor. The main objective is to study the occurrence of field changes in mirror image biopsy in relation to histopathological changes in the oral mucosa among oral cancer patients using hematoxylin and eosin and to study the expression pattern of cytokeratin, Ki-67 and p53 in oral squamous cell carcinoma and mirror image biopsy. MATERIALS AND METHODS: A pilot study of 15 patients clinically diagnosed with carcinoma lesion and their corresponding mirror image sites were taken and stained using immunohistochemistry method for the expression of cytokeratin, Ki 67 and p53. RESULTS: Primary tumors showed strong positive staining for cytokeratin throughout both the epithelium and malignant epithelial islands but absence of staining for Ki-67 and p53. CONCLUSION: CK may be useful in predicting epithelial differentiation and Ki-67 and p53 act as weak indicators of malignant disease progression in oral tissues. PMID- 27761384 TI - Estimation of gingival crevicular blood glucose level for the screening of diabetes mellitus: A simple yet reliable method. AB - AIM: This study was designed to assess the reliability of blood glucose level estimation in gingival crevicular blood(GCB) for screening diabetes mellitus. MATERIALS AND METHOD: 70 patients were included in study. A randomized, double blind clinical trial was performed. Among these, 39 patients were diabetic (including 4 patients who were diagnosed during the study) and rest 31 patients were non-diabetic. GCB obtained during routine periodontal examination was analyzed by glucometer to know blood glucose level. The same patient underwent for finger stick blood (FSB) glucose level estimation with glucometer and venous blood (VB) glucose level with standardized laboratory method as per American Diabetes Association Guidelines.1 All the three blood glucose levels were compared. Periodontal parameters were also recorded including gingival index (GI) and probing pocket depth (PPD). RESULTS: A strong positive correlation (r) was observed between glucose levels of GCB with FSB and VB with the values of 0.986 and 0.972 in diabetic group and 0.820 and 0.721 in non-diabetic group. As well, the mean values of GI and PPD were more in diabetic group than non-diabetic group with the statistically significant difference (p < 0.005). CONCLUSION: GCB can be reliably used to measure the blood glucose level as the values were closest to glucose levels estimated by VB. The technique is safe, easy to perform and non invasive to the patient and can increase the frequency of diagnosing diabetes during routine periodontal therapy. PMID- 27761385 TI - A cephalometric evaluation of the effect of glenoid fossa location on craniofacial morphology. AB - AIM: The purpose of this study was to assess the effect of glenoid fossa location in various skeletal malocclusions on craniofacial morphology. METHODS: Cephalometric data of 84 subjects were analyzed for four linear and two angular variables for assessing glenoid fossa location in cranial base and eight linear and eight angular variables for evaluating the corresponding effect on craniofacial morphology using statistical software STATA 12 for windows. Regression analysis was done to see the effect of glenoid fossa location on the parameters measuring craniofacial morphology. RESULTS: Significant association between glenoid fossa location and craniofacial morphology was demonstrated in skeletal class I, class II, and class III malocclusion subjects by the regression analysis. CONCLUSIONS: Glenoid fossa location varies significantly among skeletal malocclusions and glenoid fossa location has a profound effect on craniofacial morphology of skeletal class I, class II, and class III malocclusions. PMID- 27761386 TI - Nickel release from stainless steel and nickel titanium archwires - An in vitro study. AB - AIMS: This study was conducted to evaluate and compare the nickel release from stainless steel and nickel titanium archwires in artificial saliva over three months with the use of simulated fixed orthodontic appliances. METHODS AND MATERIALS: Fifty simulated fixed orthodontic appliances representing half of the dental arch were used for this study. Five groups of ten samples each were made. Group A was the control group without archwires. Groups B and C contained stainless steel archwires from American Orthodontics (Sheboygan, WI, USA) and Dentaurum (Remanium, Ispringen, Germany) respectively. Groups D and E contained NiTi archwires from American Orthodontics (Sheboygan, WI, USA) and copper NiTi from Ormco (Glendora, CA) respectively. The amount of nickel released from the appliances into the artificial saliva were measured after 1 day, 7 days, 1 month, 2 months and 3 months. The mean release from each group was calculated and compared using Kruskal-Wallis test and Mann-Whitney U test. RESULTS: Significant release of nickel was seen in all groups up to the end of first month (p < 0.05), the median values of which were; Control Group A (without archwire); 13.75 ppb, Group B; 15.2 ppb, Group C; 14.16 ppb, Group D; 18.6 ppb, Group E; 17.45 ppb respectively. On comparing the nickel release between all groups at each time interval, the result was not significant (p > 0.05). CONCLUSION: The highest amount of nickel was released from nickel titanium archwires, however, the quantity of nickel released from both NiTi and stainless steel archwires were not significant. The rate of nickel released was high within the first week and continued up to the first month after which the nickel content was stable in all the groups. PMID- 27761387 TI - Efficacy of azithromycin and metronidazole combined therapy on rats' gingival overgrowth induced by cyclosporine-A: An experimental animal study. AB - AIMS: To evaluate the therapeutic efficacy of azithromycin (azm) and/or metronidazole (mtz) on the histopathological features of rats' gingival overgrowth (GO) induced by cyclosporine-A (CsA) in an animal model. METHODS: Ninety male albino rats were divided randomly into six equal groups. The rats of group I received corn oil via gastric feeding for 7 weeks. Group II rats were administered CsA for the same period. Groups III, IV, and V rats received CsA for 6 weeks and simultaneously in the 7th week received a monotherapy of placebo gel, azm suspension, mtz gel, respectively. Group VI rats were handled as groups III, IV, and V and instead received a combined therapy of azm suspension, and mtz gel. Rats were euthanized at the end of the experiment and routine tissue processing was carried out. The obtained specimens were stained with H&E, TGF-beta, MMP-1, and IL-6 antibodies. RESULTS: One-way MANOVA test for TGF-beta, MMP-1, and IL-6 revealed an overall significant difference between the different groups (P = 0.000). LSD post hoc test for multiple comparisons of TGF-beta revealed nonsignificant difference between groups I and VI and between groups IV and V. Nonsignificant difference was found between groups II and III considering the amount of MMP-1 immune expression. In addition, nonsignificant difference was found between groups V and VI regarding the amount of immune expression for IL-6. CONCLUSION: Combined therapy of azm suspension and mtz gel significantly improved the histopathological features of CsA-induced GO better than a monotherapy of azm suspension or mtz gel. PMID- 27761388 TI - Influence of the impacted mandibular third molars on fractures of the mandibular angle and condyle - A prospective clinical study. AB - AIMS: This study was set out to evaluate the relationship between the presence and absence of unerupted mandibular third molar and fracture of mandibular angle/condyle, and to analyse if prophylactic removal of symptom-free unerupted mandibular third molar is beneficial. METHODS: Hundred patients of mandible fracture were selected randomly irrespective of age, sex, caste, creed and socio economic status. Data were collected from the patients on the basis of history, clinical examination and radiographs for the following information: age, sex, aetiology of fracture, presence and status of the mandibular third molar and location of mandible fracture. RESULTS: In group A (partially/completely unerupted mandibular 3rd molar), the incidence of angle and condylar fracture was 44.44% and 13.33%, respectively, whereas in group B (fully erupted/missing mandibular third molar), the incidence of angle fracture was 14.45% and the incidence of condylar fractures was 31.77%. CONCLUSION: Practice of prophylactic removal of mandibular third molar and resultant strengthening of angle region should be reconsidered, as it increases the risk of fracture at condylar region which is difficult to treat and associated with more morbidity. PMID- 27761390 TI - Melanotic neuroectodermal tumour of infancy - A rare entity. AB - Melanotic neuroectodermal tumour of infancy (MNTI) is rare, rapidly growing, pigmented neoplasm of neural crest origin. It is generally accepted as a benign tumour despite of its rapid and locally destructive growth. It primarily affects the maxilla of infants during the first year of life. Surgical excision is considered as the treatment of choice. The recurrence rate varies between 10% and 15%, and malignant behaviour has been reported in 6.5% of cases. We report a case of MNTI, associated with an erupted primary tooth in a 5-month-old male child. We discuss the clinical, radiographic and histologic features of this rare tumour, as well as its surgical management and the follow-up. PMID- 27761389 TI - Immunohistochemical expression of vascular endothelial growth factor in orofacial lesions - A review. AB - Angiogenesis is considered to be an important biological process in disease progression and tumorigenesis. Among the various factors associated with angiogenesis, vascular endothelial growth factor (VEGF) is a leading candidate. VEGF induces the proliferation, differentiation, and migration of vascular endothelial cells, increases capillary permeability, and enhances endothelial cell survival by preventing apoptosis. This article reviews and highlights the role of VEGF in health, and various oral diseases. PMID- 27761391 TI - A novel step osteotomy for correction of hemifacial microsomia - A case report. AB - Facial asymmetry is one of the commonest facial anomalies, with reported incidence as high as 34%. Hemifacial microsomia (HFM) has an incidence of 1 in every 4000-5600 children and is one of the commonest causes of facial asymmetry. The standard treatment of HFM is orthognathic surgery by bilateral saggital split osteotomy (BSSO) or distraction osteogenesis (DO) of the mandible, both of which involve prolonged periods of occlusal adjustments by an orthodontist. Here, we present distraction of the mandible by means of a novel modified step osteotomy to correct the facial asymmetry in a case of hemifacial microsomia without disturbing the occlusion. This novel technique can prove to be a new tool in the maxillofacial surgeons armamentarium to treat facial asymmetry. PMID- 27761392 TI - Periosteum as a lateral pedicle graft for the treatment of single tooth root recession: A novel approach. AB - The treatment of gingival recession defects is indicated for esthetic and functional reasons to reduce root sensitivity, to remove muscle pull, to create or augment keratinized tissue, and to prevent disease progression. The presence of sufficient amount of periosteum adjacent to gingival recession defects makes it a suitable graft. The adult human periosteum is a highly vascular connective tissue with immense regenerative potential. It contains fibroblasts, osteogenic progenitor cells, and stem cells as a result of which it has the ability to differentiate into fibroblast, osteoblast, chondrocytes, adipocytes, and skeletal myocytes. The tissue provided by these cells includes cementum with periodontal ligament fibers and bone. Therefore, in the present case, periosteum has been used as a lateral pedicle graft for the coverage of the single tooth gingival recession (mandibular central incisor). The procedure is justified by the evidence that periosteum is capable of proliferation and osteogenesis after injury. PMID- 27761393 TI - Mandibular metastasis of cutaneous melanoma. AB - Melanoma is a malignant neoplasm of melanocytes that can metastasize to every organ of the body, but metastasis to the oral cavity is uncommon. We describe a case of metastatic malignant melanoma to the mandible in a 33-years-old woman. The patient had a 2 cm * 4 cm firm, ulcerated nodule, distal to the second mandibular right molar. Incisional biopsy revealed epithelioid cells and immunohistochemistry was positive for HMB-45, S-100 protein and vimentin. The patient was referred to the local cancer hospital for treatment but died 3 months later. Metastatic malignant melanomas of the oral cavity are rare and unusual. Early diagnosis of the primary tumor is essential for successful treatment and to improvement of patient prognosis. PMID- 27761394 TI - Management of 'labial' type of dens invaginatus: A rare case report. AB - Dens invaginatus is a developmental anomaly resulting in an infolding of the enamel organ into the dental papilla prior to calcification of the dental tissues. The invagination predisposes the tooth for the development of dental caries. Conventional radiographs do not provide detailed information concerning the three-dimensional image, which would help the clinician in making a confirmatory diagnosis and planning the treatment before undertaking the actual treatment. This report describes a case where Oehlers type II dens invaginatus was diagnosed with the help of spiral computed tomography. The locations of the primary root canal and the invagination were assessed from spiral computed tomography scan images. Usually, the invagination is present on palatal/lingual side. However, in this case, the invagination was unusually located on labial side, which has yet not been reported. The tooth also showed certain unusual morphological features. PMID- 27761395 TI - Hypertonic saline solution for management of parotid fistula: A case report. AB - The management of parotid fistulae has been unsatisfactory in the past, and numerous methods of treatment with varying success and morbidity have been described. A case of parotid fistula caused by damage to glandular elements during a transparotid approach for a subcondylar fracture reduction is reported. This paper presents a simple but effective and conservative method of treating this complication with the use of hot hypertonic saline. PMID- 27761396 TI - Plagiarism: Concern. PMID- 27761397 TI - Interhemispheric connectivity in amyotrophic lateral sclerosis: A near-infrared spectroscopy and diffusion tensor imaging study. AB - PURPOSE: Aim of the present study was to investigate potential impairment of non motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non motor associated cortical areas correlates with clinical parameters and disease specific degeneration of the corpus callosum (CC) in ALS. MATERIAL AND METHODS: Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains. RESULTS: ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs (p = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (rho = - 0.85, p = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI (p < 0.05). CONCLUSIONS: The present study further supports involvement of non-motor areas in ALS. Our results render homotopic rs-FC as assessed by NIRS a potential clinical marker for disease progression rate in ALS patients without executive dysfunction and a potential anatomical marker for ALS-specific degeneration of the CC and CSTs. PMID- 27761398 TI - Automated quantification of cerebral edema following hemispheric infarction: Application of a machine-learning algorithm to evaluate CSF shifts on serial head CTs. AB - Although cerebral edema is a major cause of death and deterioration following hemispheric stroke, there remains no validated biomarker that captures the full spectrum of this critical complication. We recently demonstrated that reduction in intracranial cerebrospinal fluid (CSF) volume (? CSF) on serial computed tomography (CT) scans provides an accurate measure of cerebral edema severity, which may aid in early triaging of stroke patients for craniectomy. However, application of such a volumetric approach would be too cumbersome to perform manually on serial scans in a real-world setting. We developed and validated an automated technique for CSF segmentation via integration of random forest (RF) based machine learning with geodesic active contour (GAC) segmentation. The proposed RF + GAC approach was compared to conventional Hounsfield Unit (HU) thresholding and RF segmentation methods using Dice similarity coefficient (DSC) and the correlation of volumetric measurements, with manual delineation serving as the ground truth. CSF spaces were outlined on scans performed at baseline (< 6 h after stroke onset) and early follow-up (FU) (closest to 24 h) in 38 acute ischemic stroke patients. RF performed significantly better than optimized HU thresholding (p < 10- 4 in baseline and p < 10- 5 in FU) and RF + GAC performed significantly better than RF (p < 10- 3 in baseline and p < 10- 5 in FU). Pearson correlation coefficients between the automatically detected ? CSF and the ground truth were r = 0.178 (p = 0.285), r = 0.876 (p < 10- 6) and r = 0.879 (p < 10- 6) for thresholding, RF and RF + GAC, respectively, with a slope closer to the line of identity in RF + GAC. When we applied the algorithm trained from images of one stroke center to segment CTs from another center, similar findings held. In conclusion, we have developed and validated an accurate automated approach to segment CSF and calculate its shifts on serial CT scans. This algorithm will allow us to efficiently and accurately measure the evolution of cerebral edema in future studies including large multi-site patient populations. PMID- 27761399 TI - Disruptions in neural connectivity associated with reduced susceptibility to a depth inversion illusion in youth at ultra high risk for psychosis. AB - Patients with psychosis exhibit a reduced susceptibility to depth inversion illusions (DII) in which a physically concave surface is perceived as convex (e.g., the hollow mask illusion). Here, we examined the extent to which lessened susceptibility to DII characterized youth at ultra high risk (UHR) for psychosis. In this study, 44 UHR participants and 29 healthy controls judged the apparent convexity of face-like human masks, two of which were concave and the other convex. One of the concave masks was painted with realistic texture to enhance the illusion; the other was shown without such texture. Networks involved with top-down and bottom-up processing were evaluated with resting state functional connectivity magnetic resonance imaging (fcMRI). We examined regions associated with the fronto-parietal network and the visual system and their relations with susceptibility to DII. Consistent with prior studies, the UHR group was less susceptible to DII (i.e., they were characterized by more veridical perception of the stimuli) than the healthy control group. Veridical responses were related to weaker connectivity within the fronto-parietal network, and this relationship was stronger in the UHR group, suggesting possible abnormalities of top-down modulation of sensory signals. This could serve as a vulnerability marker and a further clue to the pathogenesis of psychosis. PMID- 27761400 TI - Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder. AB - BACKGROUND: Despite considerable effort, the neurobiological underpinnings of hyper-responsive threat processing specific to patients suffering from generalized anxiety disorder (GAD) remain poorly understood. The current functional magnetic resonance imaging (fMRI) study aims to delineate GAD-specific brain activity during immediate threat processing by comparing GAD patients to healthy controls (HC), to social anxiety disorder (SAD) and to panic disorder (PD) patients. METHOD: Brain activation and functional connectivity patterns to threat vs. neutral pictures were investigated using event-related fMRI. The sample consisted of 21 GAD, 21 PD, 21 SAD and 21 HC. RESULTS: GAD-specific elevated activity to threat vs. neutral pictures was found in cingulate cortex, dorsal anterior insula/frontal operculum (daI/FO) and posterior dorsolateral prefrontal cortex (dlPFC). Defining these effects as seed regions, we detected GAD-specific increased functional connectivity to threat vs. neutral pictures between posterior dlPFC and ventrolateral prefrontal cortex, between cingulate cortex and amygdala, between cingulate cortex and anterior insula, as well as decreased functional connectivity between daI/FO and mid-dlPFC. CONCLUSION: The findings present the first evidence for GAD-specific neural correlates of hyper responsive threat processing, possibly reflecting exaggerated threat sensitivity, maladaptive appraisal and attention-allocation processes. PMID- 27761401 TI - A fractional motion diffusion model for grading pediatric brain tumors. AB - OBJECTIVES: To demonstrate the feasibility of a novel fractional motion (FM) diffusion model for distinguishing low- versus high-grade pediatric brain tumors; and to investigate its possible advantage over apparent diffusion coefficient (ADC) and/or a previously reported continuous-time random-walk (CTRW) diffusion model. MATERIALS AND METHODS: With approval from the institutional review board and written informed consents from the legal guardians of all participating patients, this study involved 70 children with histopathologically-proven brain tumors (30 low-grade and 40 high-grade). Multi-b-value diffusion images were acquired and analyzed using the FM, CTRW, and mono-exponential diffusion models. The FM parameters, Dfm , phi, psi (non-Gaussian diffusion statistical measures), and the CTRW parameters, Dm , alpha, beta (non-Gaussian temporal and spatial diffusion heterogeneity measures) were compared between the low- and high-grade tumor groups by using a Mann-Whitney-Wilcoxon U test. The performance of the FM model for differentiating between low- and high-grade tumors was evaluated and compared with that of the CTRW and the mono-exponential models using a receiver operating characteristic (ROC) analysis. RESULTS: The FM parameters were significantly lower (p < 0.0001) in the high-grade (Dfm : 0.81 +/- 0.26, phi: 1.40 +/- 0.10, psi: 0.42 +/- 0.11) than in the low-grade (Dfm : 1.52 +/- 0.52, phi: 1.64 +/- 0.13, psi: 0.67 +/- 0.13) tumor groups. The ROC analysis showed that the FM parameters offered better specificity (88% versus 73%), sensitivity (90% versus 82%), accuracy (88% versus 78%), and area under the curve (AUC, 93% versus 80%) in discriminating tumor malignancy compared to the conventional ADC. The performance of the FM model was similar to that of the CTRW model. CONCLUSIONS: Similar to the CTRW model, the FM model can improve differentiation between low- and high-grade pediatric brain tumors over ADC. PMID- 27761403 TI - Rangelia vitalii in a free-ranging maned wolf (Chrysocyon brachyurus) and co infections. AB - An adult free-ranged female maned wolf was rescued from a periurban area subject to anthropogenic disturbances in the Minas Gerais, Brazil. The animal presented poor body condition and anemia. The clinical condition rapidly deteriorated culminating in dead and a necropsy was performed. The main gross lesions were marked anemia and blood content in the intestines accompanied by many types of parasites. The protozoa Rangelia vitalii was identified by histopathological analysis predominantly within the cytoplasm of endothelial cells of capillaries of the small intestine. The lymph nodes, spleen, bone marrow, dermis, lungs and kidney had similar protozoal forms but with mild or moderate intensity. Rangelia vitalii was confirmed by molecular assays. Hepatozoon sp., Leishmania sp., and Entamoeba spp., apparently not related to the clinical signs were also detected. The myriad parasites found in the intestines included nematodes (Ancylostoma caninum, A. braziliensis,, Molineus sp., Pterygodermatites sp., and Trichuris sp.), cestodes (Spirometra sp.) and (acanthocephalans. To our knowledge, R. vitalii was identified in C. brachyurus for the first time. These findings emphasize the fragility of Brazilian ecosystems, especially in disturbed areas, reinforcing the necessity of efforts to preserve these areas and wild carnivores, some of which are threatened with extinction, such as the maned wolf. PMID- 27761402 TI - Neural changes in extinction recall following prolonged exposure treatment for PTSD: A longitudinal fMRI study. AB - BACKGROUND: Neurobiological models of posttraumatic stress disorder (PTSD) implicate fear processing impairments in the maintenance of the disorder. Specific deficits in extinction recall, the retention of learned extinction, have been demonstrated. While deficient extinction recall, and the associated activation pattern of prefrontal and hippocampal regions, distinguishes individuals with PTSD from controls, research has not yet examined changes following treatment. We examined the behavioral and neural correlates of extinction recall before and after cognitive behavioral treatment of PTSD. METHODS: Fifty-eight participants (30 with PTSD, 28 trauma-exposed matched controls) underwent a 2-day behavioral fear conditioning, extinction, and recall paradigm during functional magnetic resonance imaging (fMRI). The same procedures were repeated 10 weeks later, after PTSD patients had completed prolonged exposure treatment. We analyzed fMRI data from 32 subjects (16 PTSD; 16 controls) and skin conductance response (SCR) data from 33 subjects (16 PTSD; 17 controls). Neural activity during extinction recall, SCR, and PTSD symptoms were compared across groups and over time. RESULTS: PTSD patients exhibited pre- to post treatment reduction in rostral anterior cingulate cortex (rACC) activation during extinction recall, and increase in functional coherence between the rACC and the ventromedial prefrontal cortex (vmPFC) and subgenual anterior cingulate cortex (sgACC). Reduced PTSD symptom severity from pre- to post-treatment was significantly associated with reduced subgenual ACC and parahippocampal activation during this task. SCR during the extinction recall phase did not significantly change with treatment in the PTSD group, but change in SCR was associated with reduction in PTSD symptom severity. CONCLUSIONS: Prolonged exposure treatment appears to alter neural activation in PTSD patients during recall of fear extinction, and change in extinction recall (measured by SCR) is associated with symptom reduction. We discuss results in the context of neural systems involved in response to affective stimuli. PMID- 27761404 TI - Influence of management and biological factors on the parasitic invasions in the wild-spread of blood-sucking nematode Ashworthius sidemi in European bison (Bison bonasus). AB - The full course of new parasite introductions in wild animals is difficult to accurately trace. We documented and analysed the invasive blood-sucking nematode Ashworthius sidemi (Trichostrongylidae) introduction and spread in European bison (Bison bonasus) from the initial phase of its progression. In the Polish part of the Bialowieza Primeval Forest (BPF) the parasite was first found in 2000. From 2002 to 2015, 165 culled bison were investigated. The prevalence and intensity of A. sidemi Schulz, 1933 infection increased over the following years, reaching 100% of investigated bison four years after introduction and a maximal median intensity of 8200 nematodes per animal in the winter of 2008/2009. Afterwards, a significant decline of median infection intensity was observed to the minimum value of 410 nematodes per animal. Between 2011 and 2014 prevalence varied from 89 to 100%. Among the factors analysed, the number of years since introduction, herd size, age and sex proved to significantly influence infection intensity. A higher infection intensity was recorded in sub-adults compared to juveniles and adults. Males had significantly lower infection intensity than females, but this was the case for adults only. The highest infection intensities were recorded in the biggest bison herds, where the winter supplementary feeding of bison is intense. Moreover, the longer the parasite was present in the host population, the more important herd size became as a factor. Our study indicates that it is not solely biological factors that determine the spread of a newly detected parasite in wildlife, but that management practices can also have a strong influence. This is especially important in endangered species under intensive human care as the management practices may pose a threat to the species. PMID- 27761406 TI - Special issue introduction: Photoacoustic microscopy. PMID- 27761405 TI - Draft genome sequence of Mycobacterium tuberculosis strain B9741 of Beijing B0/W lineage from HIV positive patient from Siberia. AB - We report a draft genome sequence of Mycobacterium tuberculosis strain B9741 belonging to Beijing B0/W lineage isolated from a HIV patient from Siberia, Russia. This clinical isolate showed MDR phenotype and resistance to isoniazid, rifampin, streptomycin and pyrazinamide. We analyzed SNPs associated with virulence and resistance. The draft genome sequence and annotation have been deposited at GenBank under the accession NZ_LVJJ00000000. PMID- 27761407 TI - Near-infrared multispectral photoacoustic microscopy using a graded-index fiber amplifier. AB - We demonstrate optical resolution photoacoustic microscopy (OR-PAM) of lipid-rich tissue using a multi-wavelength pulsed laser based on nonlinear fiber optics. 1047 nm laser pulses are converted to 1098, 1153, 1215, and 1270 nm pulses via stimulated Raman scattering in a graded-index multimode fiber. Multispectral PAM of a lipid phantom is demonstrated with our low-cost and simple technique. PMID- 27761408 TI - All-optical optoacoustic microscopy based on probe beam deflection technique. AB - Optoacoustic (OA) microscopy using an all-optical system based on the probe beam deflection technique (PBDT) for detection of laser-induced acoustic signals was investigated as an alternative to conventional piezoelectric transducers. PBDT provides a number of advantages for OA microscopy including (i) efficient coupling of laser excitation energy to the samples being imaged through the probing laser beam, (ii) undistorted coupling of acoustic waves to the detector without the need for separation of the optical and acoustic paths, (iii) high sensitivity and (iv) ultrawide bandwidth. Because of the unimpeded optical path in PBDT, diffraction-limited lateral resolution can be readily achieved. The sensitivity of the current PBDT sensor of 22 MUV/Pa and its noise equivalent pressure (NEP) of 11.4 Pa are comparable with these parameters of the optical micro-ring resonator and commercial piezoelectric ultrasonic transducers. Benefits of the present prototype OA microscope were demonstrated by successfully resolving micron-size details in histological sections of cardiac muscle. PMID- 27761409 TI - Multimodal optoacoustic and multiphoton microscopy of human carotid atheroma. AB - Carotid artery atherosclerosis is a main cause of stroke. Understanding atherosclerosis biology is critical in the development of targeted prevention and treatment strategies. Consequently, there is demand for advanced tools investigating atheroma pathology. We consider hybrid optoacoustic and multiphoton microscopy for the integrated and complementary interrogation of plaque tissue constituents and their mutual interactions. Herein, we visualize human carotid plaque using a hybrid multimodal imaging system that combines optical resolution optoacoustic (photoacoustic) microscopy, second and third harmonic generation microscopy, and two-photon excitation fluorescence microscopy. Our data suggest more comprehensive insights in the pathophysiology of atheroma formation and destabilization, by enabling congruent visualization of structural and biological features critical for the atherosclerotic process and its acute complications, such as red blood cells and collagen. PMID- 27761411 TI - 30 months follow-up of an early enzyme replacement therapy in a severe Morquio A patient: About one case. AB - : Patients under 5 years were not evaluated in the phase-3 study for enzyme replacement therapy (ERT) in MPS IV A. Here we describe the evolution of a severe Morquio A pediatric patient who was diagnosed at 19 months old and treated by ERT at 21 months old for the next 30 months. Applying the standard ERT protocol on this very young patient appeared to reduce his urinary excretion of glycosaminoglycans (GAGs); the improvements in both the 6 minute-walk test (6MWT) and the stair climb test, however, were no different than those reported in the nature history study. Additionally, this young patient experienced many ERT associated side effects, and as a result a specific corticosteroid protocol (1 mg/kg of betamethasone the day before and 1 h before the ERT infusion) was given to avoid adverse events. Under these treatments, the height of this patient increased during the first year of the ERT although no more height gain was observed thereafter for 18 months. However, despite of ERT, his bone deformities (including severe pectus carinatum) actually worsened and his medullar cervical spine compression showed no improvement (thus needed decompression surgery). CONCLUSION: early ERT treatment did not improve the bone outcome in this severe MPS IV A patient after the 30 months-long treatment. A longer term follow up is required to further assess the efficacy of ERT on both the motor and the respiratory function of the patient. PMID- 27761412 TI - Plasma amino acid and urine organic acid profiles of Filipino patients with maple syrup urine disease (MSUD) and correlation with their neurologic features. AB - BACKGROUND: Maple syrup urine disease (MSUD) is the most common inborn error of metabolism in the country. The cause of the neuropathology is still not well established although accumulation of branched chain amino acids (BCAA) and alteration in large neutral amino acids (LNAA) as well as energy deprivation are suggested. It is therefore the aim of this study to determine the plasma amino acid and urine organic acid profiles of patients with MSUD and correlate the findings with their neurologic features. METHODOLOGY: Twenty six Filipino patients with MSUD were studied in terms of their plasma amino acid and urine organic acid profiles. Their results were compared with 26 age and sex matched controls. The neurologic features were correlated with the results of the plasma amino acids and urine organic acids. RESULTS: Majority of the patients with MSUD had developmental delay/intellectual disability (88%), speech delay (69%), and seizures (65%). Their amino acid profiles revealed low glutamine and alanine with high levels of leucine, isoleucine, phenylalanine, threonine and alloisoleucine compared to controls (p < 0.05). The urine organic acids showed significantly elevated excretion of the branched chain ketoacids and succinate (p < 0.05). However there were no biochemical markers that correlated significantly with the neurologic features. CONCLUSION: The findings suggest that there could still be altered LNAA metabolism among patients with MSUD when the BCAAs are elevated. Although the biochemical findings were not significantly correlated with the neurologic features, the study showed that prevention and avoidance of neurologic disturbances may still rely primarily on early diagnosis and prompt institution of treatment, along with strict compliance with the dietary regimen and maintenance of good metabolic control over time. PMID- 27761410 TI - Photoacoustic imaging of the eye: A mini review. AB - The eye relies on the synergistic cooperation of many different ocular components, including the cornea, crystalline lens, photoreceptors, and retinal neurons, to precisely sense visual information. Complications with a single ocular component can degrade vision and sometimes cause blindness. Immediate treatment and long-term monitoring are paramount to alleviate symptoms, restore vision, and cure ocular diseases. However, successful treatment requires understanding ocular pathological mechanisms, precisely detecting and monitoring the diseases. The investigation and diagnosis of ocular diseases require advanced medical tools. In this mini review, we discuss non-invasive photoacoustic (PA) imaging as a potential research tool and medical screening device. In the research setting, PA imaging can provide valuable information on the disease progression. In the clinical setting, PA imaging can potentially aid in disease detection and treatment monitoring. PMID- 27761413 TI - Liver-specific knockout of arginase-1 leads to a profound phenotype similar to inducible whole body arginase-1 deficiency. AB - Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ~ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype. Liver selective Arg1 deletion was induced by using an adeno-associated viral (AAV) thyroxine binding globulin (TBG) promoter-Cre recombinase vector administered to Arg1 "floxed" mice; Arg1fl/fl ). An AAV vector expressing an Arg1-enhanced green fluorescent protein (Arg1-eGFP) transgene was used for gene delivery, while intrasplenic injection of wild-type (WT) C57BL/6 hepatocytes after partial hepatectomy was used for cell delivery to "rescue" tamoxifen-treated Arg1-Cre mice. The results indicate that liver-selective loss of Arg1 (> 90% deficient) leads to a phenotype resembling the whole body knockout of Arg1 with lethality ~ 3 weeks after Cre-induced gene disruption. Delivery of Arg1-eGFP AAV rescues more than half of Arg1 global knockout male mice (survival > 4 months) but a significant proportion still succumb to the enzyme deficiency even though liver expression and enzyme activity of the fusion protein reach levels observed in WT animals. Significant Arg1 enzyme activity from engrafted WT hepatocytes into knockout livers can be achieved but not sufficient for rescuing the lethal phenotype. This raises a conundrum relating to liver-specific expression of Arg1. On the one hand, loss of expression in this organ appears to be both necessary and sufficient to explain the lethal phenotype of the genetic disorder in mice. On the other hand, gene and cell-directed therapies suggest that rescue of extra hepatic Arg1 expression may also be necessary for disease correction. Further studies are needed in order to illuminate the detailed mechanisms for pathogenesis of Arg1-deficiency. PMID- 27761415 TI - Preemptive Oral Clonidine Provides Better Sedation Than Intravenous Midazolam in Brachial Plexus Nerve Blocks. AB - BACKGROUND: Preemptive analgesia is the blocking of pain perception afferent pathways before noxious painful stimuli. Clonidine is an alpha agonist drug that is partially selective for alpha-2 adrenoreceptors. Clonidine is used as anti anxiety medication and an, analgesic, and it prolongs the duration of the block in the brachial plexus block. OBJECTIVES: To compare the effect of preemptive clonidine with midazolam on intraoperative sedation, duration of block, and postoperative pain scores. PATIENTS AND METHODS: In a randomized clinical trial, 80 patients with orthopedic fractures of an upper extremity who underwent supraclavicular nerve block were randomly assigned to receive 0.2 mg oral clonidine or 2 mg oral midazolam. Intraoperative sedation was measured at one hour after the start of urgery and again in the PACU (Post-Anesthesia Care Unit) using the Ramsay scale. The duration of sensory blockade was measured. Postoperative pain scores were measured using the VAS (Visual Analogue Scale) after entrance to recovery up to 2 hours. RESULTS: The percentages of patients in the calm and sedated scale were significantly higher in clonidine group (35 and 42.5%, respectively), compared to the midazolam group (17.5 and 17.5%, respectively) (P = 0.042, 0.029; respectively). Those administered fentanyl in the clonidine group 105 +/- 30.8 was significantly lower than that for the midazolam group 165 +/- 34.5 (P = 0.0018). The percentages of patients in the calm scale were significantly higher in the clonidine group (52.5), compared to the midazolam group (17.5) (P = 0.001) in the post-operative period. VAS scores were significantly lower at one (P = 0.01) and two hours (P = 0.001) after operation in the clonidine group, compared to the midazolam group. CONCLUSIONS: Preemptive clonidine has many marvelous advantages over midazolam, including better sedation inside the operating room and then in the post-operative care unit, lower fentanyl doses are required during surgery, more stable heart rate and blood pressure are observed during the procedure, and patients report lower post-operative pain scores. PMID- 27761416 TI - The Incidence and Predictors of Headache and Myalgia in Patients After Electroconvulsive Therapy (ECT). AB - BACKGROUND: Electroconvulsive therapy (ECT) is a safe and effective mode of therapy for a wide variety of psychiatric disorders. However, it is associated with some disturbing side effects, such as nausea and vomiting, dental and tongue injury, confusion, dizziness, headache, and myalgia. OBJECTIVES: The present study focused on the evaluation of myalgia and headache and their predictors after ECT. PATIENTS AND METHODS: A prospective analytical descriptive study was conducted from October 2014 to January 2015, in an academic hospital in northern Iran. Before sampling, the study was approved by the ethics committee of Guilan University of Medical Sciences. 621 patients with psychiatric disorders who were referred to Shafa hospital enrolled in the study. They were evaluated based on a verbal rating scale (4 point scales) 6 hours after ECT, regarding headache and myalgia side effects. RESULTS: 6 hours after ECT, 126 patients (21.9%) reported headaches, and 56 patients (9%) reported myalgia. The presence of headache or myalgia 6 hours after ECT was not correlated to the duration of convulsion, treatment sessions, sex, or age. But myalgia at 2 hours after treatment was correlated with sex (0.04). Sex, age, duration of seizure, and treatment sessions were not predictors of headache and myalgia 6 hours after ECT (log regression, enter mode). The intensity and frequency of headaches decreased during 6 hours after ECT (P = 0.0001 and P = 0.0001, respectively), and myalgia frequency decreased (P = 0.062) but the intensity increased (P = 0.87). CONCLUSIONS: The results of the present study demonstrate that headache after ECT procedures was more common than myalgia, but it was mild, tolerable, and decreased within 6 hours of the treatment. It is also notable that we did not found any predictors for post-ECT headache and myalgia. PMID- 27761417 TI - Capparis spinosa reduces Doxorubicin-induced cardio-toxicity in cardiomyoblast cells. AB - OBJECTIVE: Doxorubicin (DOX) is an effective anticancer drug but its clinical application is limited because it induces apoptosis in cardiomyocytes and leads to permanent degenerative cardiomyopathy and heart failure possibly due to oxidative stress. Recent studies showed that Capparis spinosa (C. spinose) exhibits potent antioxidant activity. So, in this study, we explored the protective effect of hydro-alcoholic extract of C. spinosa against DOX-induced cytotoxicity in H9c2 cells. MATERIALS AND METHODS: Cell viability was quantified by MTT assay. Apoptotic cells were determined using flow cytometry (sub-G1 peak) evaluation of DNA fragmentation following PI staining. Cells were cultured with 5 MUM DOX for 24 hr to induce cell damage. H9c2 cells were pretreated with different concentrations (6-200 MUg/ml) of C. spinosa extract for 4 hr before DOX treatment in all trials. RESULTS: Pretreatment with 25, 50, 100 and 200 ug/ml of C. spinosa could increase the viability of H9C2 cells to 72.63+/-2.8% (p<0.05), 77.37+/-1.8% (p<0.05), 83.56+/-2.6% (p<0.001) and 90.9+/-0.5% (p<0.001) of control, respectively. Also, C. spinosa decreased apoptotic induction significantly, at the doses of 50 ug/ml (p<0.05), 100 ug/ml (p<0.01) and 200 ug/ml (p<0.001). CONCLUSION: Our results showed that C. spinosa could exert cardioprotective effects against DOX-induced toxicity that might be mediated via its antioxidant activity. PMID- 27761414 TI - Controversies and evidence of hepatic resection for hepatocellular carcinoma. AB - Symptoms of early hepatocellular carcinoma (HCC) often go unnoticed, so more than half of patients with primary HCC are diagnosed after their disease has already reached an intermediate or advanced stage, or after portal hypertension has appeared. While hepatic resection is widely recognized as a first-line therapy to treat very early or early HCC, its use in treating intermediate or advanced HCC or HCC involving portal hypertension remains controversial. Here we review PubMed indexed literature covering the use of hepatic resection for such patients. The available evidence strongly suggests that, as a result of improvements in surgical techniques and perioperative care, hepatic resection can benefit many patients with intermediate or advanced HCC or with HCC associated with portal hypertension. PMID- 27761419 TI - Urological recommedations of Hadji Pasha's, a Turkish aged doctor in Anatolia. AB - OBJECTIVE: Urinary tract conditions have been an important part of diseases from antiquity until today. Historically, many plants and herbs have been used for the treatment of urinary disorders. METHODS: Celaluddin Hizir bin Ali el-Konevi (Hadji Pasha) is one of the most famous physician who lived in Anatolia between 13th and 14th centuries. He has written one of the most important medical books of that era, "Muntehab-iSifa" (solution of wellness) in Turkish. General medical information about the diseases in this book, focus on diagnosis and treatment. RESULTS: The herbal solutions for urological disorders such as, urinary incontinence, urinary stones or erection problems are told in this section. CONCLUSION: Many of the herbal medicines addressed in this book are being widely used in current medicine, but the usage of these herbals in daily urology practice is limited. In this study, we aimed to share the advices for the urological diseases and the related herbal medicines that are named in Hadji Pasha's book, "Muntehab-iSifa ", with today's physicians. PMID- 27761418 TI - Assessment of antibacterial effect of garlic in patients infected with Helicobacter pylori using urease breath test. AB - OBJECTIVE: Helicobacter pylori (H. pylori) is the most common pathogenic bacteria in the stomach. The aim of the current study was to explore the effect of oral garlic administration on bacterial urease activity inside the stomach and its contribution to the treatment of H. pylori infection. MATERIALS AND METHODS: In this clinical trial, 15 patients were studied quantitatively with Urease Breath Test (UBT). The patients with gastrointestinal symptoms and a positive serum H. pylori IgG were enrolled. UBT was performed for each patient in three sessions as follows: at the beginning of the study, an initial UBT was performed based on which, the positive cases entered the study and the negative ones were excluded. Second UBT was done three days later in patients who were not receiving any treatment and were considered as the control, whereas the third UBT was performed three days after prescribing two medium-sized cloves of garlic (3 g) with their meal, twice a day (at noon and in the evening). The collected data were analyzed using ANOVA and Bonferroni tests and the significance level was set at p<0.05. RESULTS: the mean UBT significantly differed before and after treatment with garlic cloves, being significantly lower after garlic consumption. No meaningful difference was observed in the mean UBT without garlic consumption between the first and second steps. CONCLUSION: Raw garlic has anti-bacterial effects against H. pylori residing in the stomach and may be prescribed along with routine drugs for the treatment of gastric H. pylori infection. PMID- 27761420 TI - A review study on the effect of Iranian herbal medicines against in vitro replication of herpes simplex virus. AB - OBJECTIVE: There are a number of published data indicating in vitro anti-HSV activity of some of Iranian herbal extracts with no systematic review to discuss these results. Therefore, this article was aimed to review and discuss the methods carried out and the phytochemistry and bioactivity of the extracts used and also conclusions provided in these publications. MATERIALS AND METHODS: Published articles both in English (from Medline, Science Direct, EMBASE, Scopus, Pro Quest, Google scholar, Cochrane Library) and in Persian (from SID, Iran Medex and Magiran) databases, from 1966 to October 2014 were incorporated in this review. The in vitro studies that lacked CC50, IC50, were excluded. RESULTS: Only 42 published reports were found to examine Iranian herbs against HSV replication in vitro. Seventeen out of 42 studies in which 23 kinds of medicinal plants were subjected to crude extraction were included. The review of data showed that some of the herbal extracts including Hyssopus officinalis methanolic extract, Melissa officinalis aqueous extract, Quercus persica L. hydroalcoholic extract and Securigeras ecuridaca methanolic extract with selective index (SI) of 234, 877, >778 and 250, respectively were highly effective against HSV in vitro. CONCLUSION: More comprehensive studies using more advanced methods are needed to be done to achieve promising anti-HSV agents from the bioactive compounds isolated from these herbs. PMID- 27761422 TI - Estragole and methyl-eugenol-free extract of Artemisia dracunculus possesses immunomodulatory effects. AB - OBJECTIVE: Some evidence suggests that chronic uptake of estragole and methyl eugenol, found in the essential oil of Artemisia dracunculus (tarragon), may be associated with an increased risk of hepato-carcinogenicity. The present study was conducted to investigate the immumodulatory and anti-inflammatory potentials of estragole and methyl-eugenol free extract of tarragon. MATERIALS AND METHODS: Aqueous, hydroalcoholic, methanol and hexane extracts of dried and milled tarragon was prepared and analyzed by GC-MS. The estragole and methyl-eugenol free extract was characterized and used for evaluation of immunity in NMRI mice after challenging with sheep red blood cells. RESULTS: It was shown that the aqueous extract of tarragon was free from potentially harmful estragole or methyl eugenol. Moreover, the immunomodulatory effect of the aqueous extract of tarragon (100 mg/kg for 21 consecutive days) was investigated. The extract significantly increased the level of anti-sheep red blood cells (SRBC (antibody and simultaneously decreased the level of cellular immunity in the treatment group. Moreover, tarragon caused a significant reduction in the production of pro inflammatory IL-17 and IFN-gamma in parallel with a reduction in the ratio of INF gamma to Il-10 or IL-17 to IL-10 in the splenocytes. In addition, the levels of the respiratory burst and nitric oxide production in peritoneal macrophages were significantly decreased. Additionally, the phagocytosis potential of macrophages was significantly increased in treated mice. CONCLUSION: These data showed that the aqueous extract of tarragon may be used as a natural source to modulate the immune system, because it can inhibit pro-inflammatory cytokines and induce anti inflammatory macrophages. PMID- 27761423 TI - Effect of virgin olive oil versus piroxicam phonophoresis on exercise-induced anterior knee pain. AB - OBJECTIVE: The main purpose of this study was to evaluate the effects of virgin olive oil phonophoresis on female athletes' anterior knee pain (AKP). MATERIALS AND METHODS: A double blinded randomized clinical trial was conducted. Ninety three female athletes suffering from AKP voluntarily participated in this study. Patients were randomly assigned into olive oil (n=31), piroxicam (n=31) or base gel phonophoresis (n=31) groups. At the baseline visit, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire was filled by subjects who were then treated with olive oil, piroxicam or pure phonophoresis for 12 sessions. After 6 and 12 sessions of physiotherapy, subjects filled the questionnaire again. Main outcomes were significant improvement in pain, stiffness, physical function, and total WOMAC scores. RESULTS: Although, there was a significant reduction in symptoms of AKP at the end of the therapy in all groups (p<0.05), but in olive oil group, this improvement was seen after 6 sessions of treatment (p<0.001). A significant difference between olive oil group and piroxicam and/or phonophoresis group was observed after 6 sessions of therapy (p<0.05). CONCLUSION: It could be proposed that phonophoresis with virgin olive oil is as effective as piroxicam gel on lowering WOMAC scores of AKP in female athletes and also has several beneficial properties including faster effect and shorter duration of therapy. The exact mechanism of beneficial action of virgin olive oil on AKP is not clear and requires further studies. PMID- 27761421 TI - Anti-oxidant and anti-hyperlipidemic activity of Hemidesmus indicus in rats fed with high-fat diet. AB - OBJECTIVE: Dietary changes play major risk roles in oxidative stress and cardiovascular disease and modulate normal metabolic function. The present study was designed to investigate the ameliorative potential of different extracts of Hemidesmus indicus to experimental high-fat diet in wistar rats, and their possible mechanism of action. MATERIALS AND METHODS: Male wistar rats were divided into 6 groups (n=6/group) and fed with a standard diet (control), high fat diet (HFD), high-fat diet supplemented with different extracts and positive control for 9 weeks. High-fat diet induced changes in average body weight and oxidative stress and elevated levels of plasma lipid profile in rats. RESULTS: Oral administration of methanolic extract of H. indicus (200 mg/kg) offered a significant dose-dependent protection against HFD-induced oxidative stress, as reflected in the levels of catalase (p<0.001 in the aorta, heart and liver), superoxide dismutase (p<0.001 in the aorta, heart and liver), and glutathione peroxidase (p<0.001 in the aorta, heart and liver). Hyperlipidemia condition assessed in terms of body weight, total cholesterol, free cholesterol, ester cholesterol, phospholipids, triglycerides, and atherogenic index and the results showed significant differences between HFD and non-HFD fed rats (p<0.001). High fat diet treated rats showed changes in hepatic tissue architecture such as micro and macrovascular steatosis, increased fatty infiltration, and inflammation. CONCLUSION: The present study revealed that the methanolic extract of H. indicus protects against oxidative stress, hyperlipidemia and liver damage. PMID- 27761424 TI - Teratogenic effects of silymarin on mouse fetuses. AB - OBJECTIVE: Silybum marianum has been used for centuries in herbal medicine for treatment of liver diseases. Currently, there is no data available on the possible effects of silymarin on fetal development. This study aimed to investigate the teratogenic effect of silymarin on BALB/c mice fetuses. MATERIALS AND METHODS: A total of 40 pregnant mice were divided into 4 groups of 10 mice each. Three groups received silymarin at three different doses of 50, 100 and 200 mg/kg/day during gestational days (GDs). The control group received normal saline and tween (solvent). Dams were sacrificed on GD 18 and all fetuses were examined for gross malformations, size and body weight. Malformed fetuses were double stained with alizarin red and alcian blue. RESULTS: Silymarin administration at all doses resulted in reduction of the mean fetal body weights. The abnormalities included limb, vertebral column and craniofacial malformations. Craniofacial malformations were the most common abnormalities, but they were not observed in a dose-dependent manner. The percentage of fetal resorption significantly increased (up to 15%) in all treatment groups. CONCLUSION: Based on our results, silymarin, especially at high doses can lead to fetal resorption, intrauterine growth retardation and limb, vertebral column and craniofacial abnormalities. More precise studies should be conducted about the teratogenic effects of herbal medicine investigating the underlying mechanisms. Thus, caution should be taken when administering S. marianum to pregnant woman. PMID- 27761425 TI - Comparison of antiplatelet activity of garlic tablets with cardio-protective dose of aspirin in healthy volunteers: a randomized clinical trial. AB - OBJECTIVE: Some of the adverse effects of aspirin including peptic ulcers, gastrointestinal bleeding and aspirin resistance compelled researchers to find a suitable alternative with fewer adverse effects. In this clinical trial, we aimed to find the effective antiplatelet dose of garlic. MATERIALS AND METHODS: This randomized controlled clinical trial (RCT) was conducted on 62 healthy volunteers of 20-50 years old. All volunteers used 80 mg aspirin per day for 1 week and at the end of this time, platelet aggregation (PA) induced by 4 agonists acting in aggregation pathway including adenosinediphosphate (20 MUmol/l), epinephrine (20 MUmol/l), collagen(0.19 mg/ ml) and arachidonic acid (0.5mg/ ml) was measured by Light Transmittance Aggregometry (LTA) in all participants. After one month washout period, volunteers were randomized into 3 groups and each received 1, 2 or 3 garlic tablets (1250 mg) a day for 1 month. After one month, PA was examined in all groups. RESULTS: The mean +/-SD of the age of all volunteers was 28.60 +/- 9.00 years. In addition, 52.00 % of our volunteers were male and 48.00% of them were female. Garlic tablet didnot have significant effect on PA at any dose. However, 30% of volunteers in the group that used 3 garlic tablets/day reported adverse effect (i.e. bleeding). No significant association between sex, age and PA was observed. CONCLUSION: In this study, we were unable to determine the effective anti-platelet dose of garlic which that could be equal to that of aspirin anti-platelet activity, as assessed LTA method. PMID- 27761426 TI - Evaluation of acute and sub-acute toxicity of Pinus eldarica bark extract in Wistar rats. AB - OBJECTIVE: Pinus eldarica (P. eldarica) is one of the most common pines in Iran which has various bioactive constituents and different uses in traditional medicine. Since there is no documented evidence for P. eldarica safety, the acute and sub-acute oral toxicities of hydroalcoholic extract of P. eldarica bark were investigated in male and female Wistar rats in this study. MATERIALS AND METHODS: In the acute study, a single dose of extract (2000 mg/kg) was orally administered and animals were monitored for 7 days. In the sub-acute study, repeated doses (125, 250 and 500 mg/kg/day) of the extract were administered for 28 days and biochemical, hematological and histopathological parameters were evaluated. RESULTS: Our results showed no sign of toxicity and no mortality after single or repeated administration of P. eldarica. The median lethal dose (LD50) of P. eldarica was determined to be higher than 2000 mg/kg. The mean body weight and most of the biochemical and hematological parameters showed normal levels. There were only significant decreases in serum triglyceride levels at the doses of 250 and 500 mg/kg of the extract in male rats (p<0.05 and p<0.01, respectively) and in monocyte counts at the highest dose of the extract in both male and female rats (p<0.05). Mild inflammation was also found in histological examination of kidney and liver tissues at the highest dose of extract. CONCLUSION: Oral administration of the hydroalcoholic extract of P. eldarica bark may be considered as relatively non-toxic particularly at the doses of 125 and 250 mg/kg. PMID- 27761427 TI - The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in diabetic subjects: a randomized clinical trial. AB - OBJECTIVE: Diabetes mellitus is defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both or insulin resistance. Curcumin inhibits NF-kappaB signaling pathway. The aim of this study is evaluation of the effect of Nano curcumin on HbA1C, fast blood glucose and lipid profile in diabetic patients. MATERIALS AND METHODS: Seventy type-2 diabetic patients (fasting blood glucose (FBG) >= 126 mg/dL or 2-hr postprandial blood glucose >=200 mg/dl) randomly receivedeither Curcumin (as nano-micelle 80 mg/day) or placebo for 3 months in a double blind randomized clinical trial. Fasting blood glucose, HbA1C, and lipids profile were checked before and after the intervention. Data analyses, including parametric and nonparametric tests were done using the SPSS 11.5 software. A p value < 0.05 was regarded as statistically significant. (RCT registration code: IRCT2013081114330N1). RESULTS: Mean age, BMI, FBG, total cholesterol (TC), triglyceride (TG), LDL, HDL, HbA1c , and sex and had no significant difference at the baseline between the groups. In Nano-curcumin group, a significant decrease was found in HbA1C, FBG, TG, and BMI comparing results of each subject before and after the treatment (p<0.05). By comparing pre- and post-treatment values among the groups, HbA1c, eAG, LDL-C, and BMI variables showed significant differences (p<0.05). CONCLUSION: These findings suggest an HbA1c lowering effect for Nano curcumin in type-2 diabetes; also, it is partially decrease in serum LDL-C and BMI. PMID- 27761428 TI - Effects of flavonoids from Martynia annua and Tephrosia purpurea on cutaneous wound healing. AB - OBJECTIVE: Martynia annua L. (M. annua), (Martyniaccae) has been traditionally used in the treatment of epilepsy, sore throat and inflammatory disorders. The leaf paste is used topically on Tuberculosis of the lymphatic glands and wounds of domestic animals. Tephrosia purpurea (T. purpurea), (Fabaceae) has been used traditionally as a remedy for asthma, gonorrhea, rheumatism and ulcers. This study aimed to evaluate the potential wound healing effects of different fractions ofethanol extract of M. annua leaves and aerial parts of T. purpurea. MATERIALS AND METHODS: Methanol fraction of M. annua (MAF-C) and ethyl acetate fraction of T. purpurea (TPF-A) were evaluated for healing potential in dead space and burn wound models. An ointment (5% w/w) of MAF-C and TPF-A, pongamol (0.2 and 0.5% w/w) and luteolin (0.2 and 0.5% w/w) was applied topically twice a day. The effects were compared with Povidone Iodine ointment with respect to protein, collagen content, enzymatic assay and histopathological finding of granuloma tissues. RESULTS: Ethanol extracts of M. annua and T. purpureawere exhibited total flavonoid contents of 126.2 +/- 4.69 and 171.6 +/- 6.38 mg (quercetin equivalent), respectively. HPLC fingerprinting confirmed the presence of luteolin in M. annua and quercetin in T. purpurea. TPF-A and MAF-C ointments (5% w/w) significantly increases the hydroxyproline and protein contents. Luteolin and pongamol ointments were also found to be effective in both wound models. CONCLUSION: Our findings suggested that 5% w/w ointment of TPF-A and MAF C fractions were more effective than isolated flavonoids in wound healing which may be due to synergistic interactions between the flavonoids and other constituents. PMID- 27761429 TI - Identification and Characterization of a Gene stp17 Located on the Linear Plasmid pBSSB1 as an Enhanced Gene of Growth and Motility in Salmonella enterica Serovar Typhi. AB - The linear plasmid pBSSB1 mediates the flagellar phase variation in H:z66 positive Salmonella enterica serovar Typhi (S. Typhi). The gene named stp17 (S. Typhi plasmid number 17 gene) is located on pBSSB1 and encodes the protein STP17. The expression pattern at the protein-level and function of STP17 remains unknown. In this study, the recombinant protein STP17His6 was expressed, purified and used to prepare the polyclonal anti-STP17 antibody. We detected protein-level expression of stp17 in S. Typhi and further investigated the protein expression characteristics of stp17 in different growth phases by western blot analysis. The effects of STP17 on bacterial growth and motility were analyzed. In addition, the structure of STP17 was predicted and the active site of STP17 was identified by site-directed mutagenesis. The results showed that STP17 was expressed stably in the wild type strain of S. Typhi. STP17 expression at the protein level peaks when cultures reach an OD600 value of 1.2. The growth rate and motility of the Deltastp17 strain were significantly decreased compared with the wild type strain (P < 0.05) and this phenotype was restored in the stp17 complementary strain. Moreover, the growth rate and motility of the stp17 over-expression strain was greater than the wild type strain. STP17 contains nine Helix segments, six Stand segments and some Coil segments in the secondary structural level. The top-ranked 3-D structure of STP17 predicted by I-TASSER contains a putative ATPase domain and the amino acid residues of GLY16, GLY19, LYS20, ASN133, LYS157, and LYS158 may be the active site residues of STP17. Finally, STP17 was able to catalyze the ATP to ADP reaction, suggesting that STP17 may be an ATPase. To our knowledge, this is the first report describing the protein expression characteristics of STP17 in S. Typhi, showing that STP17 promotes bacterial growth and motility, which may be associated with its potential ATPase activity. PMID- 27761430 TI - Association between ELMO1 gene polymorphisms and diabetic nephropathy in an Iranian population. AB - BACKGROUND: Diabetic nephropathy (DN) is one of the leading causes of death in patients with type 2 diabetes mellitus (T2DM). Several genome-wide association studies have introduced Engulfment and Cell Motility 1 (ELMO1) as a candidate gene which is associated with DN. This study assessed the association of ELMO1 gene polymorphisms with DN in order to investigate the effects of ELMO1 gene on susceptibility to DN in an Iranian population. METHODS: In the present study, 100 patients with T2DM, 100 patients with DN and 100 healthy subjects who were matched for sex were selected. Allele and genotype frequencies were determined by Tetra-ARMS PCR technique. In all groups, levels of FBS, creatinine, urea, HbA1C, urine levels of albumin creatinine ratio and glomerular filtration rate were measured. RESULTS: A statistically significant association was shown between G allele of rs741301 (odds ratio (OR) = 1.7 [95 % CI 1.17-2.63]; p value = 0.005), and GG genotypes of rs741301 (OR = 2.5 [95 % CI 1.2-5.4]; p value = 0.01) and DN. A significant association was not detected between allelic and genotypic frequencies of rs1345365 and DN. Linkage Disequilibrium (LD) between two variants was weak (D' = 0.11, r2 = 0.008). rs1345365A/rs741301A haplotypes were more frequent in patients with T2DM as compared to DN (OR = 0.5 [95 % CI 0.3-0.7]; p value = 0.0006). Also, genotypes of variant rs741301 in all subjects had significant difference with respect to the mean of ACR (p Value < 0.05). CONCLUSION: This study first investigated the association of ELMO1 gene polymorphisms (rs741301) with DN in an Iranian population, supporting its key role as a candidate gene in the susceptibility to DN. PMID- 27761431 TI - Evaluate the growth and adhesion of osteoblast cells on nanocomposite scaffold of hydroxyapatite/titania coated with poly hydroxybutyrate. AB - BACKGROUND: The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. MATERIALS AND METHODS: In this paper, hydroxyapatite (HA) powder was made out of bovine bone by thermal analysis at 900 degrees C and first, and then, porous HA (50 weight percentage) was produced by polyurethane sponge replication method. In order to improve the scaffold mechanical properties, they have been coated with poly hydroxybutyrate. In terms of phase studies, morphology, and specifying agent groups, the specific characterization devices such as X-ray diffraction and Fourier transform infrared, were employed. To compare the behavior of cellular scaffolds, they were divided into four groups of scaffolds. The osteoblast cells were cultured. To perform phase studies, analysis of Methylthiazole tetrazolium (MTT) and Trypan blue were carried out for the viability and attachment on the surface of the scaffold, and the specification of Scanning electron microscopy was employed for the morphology of the cells. RESULTS: The results of MTT analysis performed on four groups of scaffolds have shown that Titanium oxide (Tio2) had no effect on cell growth alone and HA was the main factor of growth and cell osteoblast adhesion on the scaffold. Moreover, the results showed that the use of coating with poly-3-hydroxybutyrate saved the factors and placed the osteoblasts within the pore. Since the main part of bone consists of HA, the TiO2 accelerates the formation of apatite crystals at the scaffold surface which is the evidence for bone tissue regeneration. CONCLUSIONS: It is likely that the relation between HA and TiO2 leads to an increase in osteoblast adhesion and growth of cells on the scaffold surface. PMID- 27761432 TI - Validity and reliability of "Persian Weaning Tool" in mechanically ventilated patients. AB - BACKGROUND: "Persian Weaning Tool" (PWT) is the only specific, national protocol designed to assess patients' readiness for weaning from mechanical ventilation in Iran. This study was developed to determine the validity and reliability of this protocol. MATERIALS AND METHODS: This is a psychometric study conducted on 31 patients connected to mechanical ventilation were ready from weaning according to anesthesiologist's diagnosis and was selected through convenient sampling. The patients selected from Intensive Care Units (ICUs) of Al-Zahra Hospital in Isfahan. The sheet data collection includes demographic data, PWT; Burn's Wean Assessment Program (BWAP), and Morganroth's scale. To determine the inter-rater reliability between researcher and his partner, Pearson correlation and paired t test were used. To assess the criterion validity of the PWT in relation to Burn's and Morganroth's weaning scales (as criteria), Pearson correlation and McNemar tests were used. To specify a minimum acceptable score of the PWT for weaning from mechanical ventilation, receiver operating characteristic curve was used. RESULTS: The results showed that there was statistically significant correlation between score of PWT and BWAP (r = 0.370 with P < 0.05) and there were no statistically significant differences between these tools in terms of identification of patients' readiness for weaning (P = 0.453). There was statistically significant correlation between PWT score obtained by researcher and his colleague (r = 0.928), and the reliability of this tool was approved. The PWTs cut of point was calculated as 57 (sensitivity = 0.679, specificity = 1). CONCLUSIONS: The reliability and validity of the PWT were confirmed for this study's sample size. Consequently, the findings of this study can be used to measure the PWTs effectiveness and applicability in ICUs. PMID- 27761433 TI - Life stressors, coping strategies, and social supports in patients with irritable bowel syndrome. AB - BACKGROUND: The frequency and the perceived intensity of life stressors, coping strategies, and social supports are very important in everybody's well-being. This study intended to estimate the relation of irritable bowel syndrome (IBS) and these factors. MATERIALS AND METHODS: This was a cross-sectional study carried out in Isfahan on 2013. Data were extracted from the framework of the study on the epidemiology of psychological, alimentary health, and nutrition. Symptoms of IBS were evaluated by Talley bowel disease questionnaire. Stressful life event, modified COPE scale, and Multidimensional Scale of Perceived Social Support were also used. About 4763 subjects were completed questionnaires. Analyzing data were done by t-test and multivariate logistic regression. RESULTS: Of all returned questionnaire, 1024 (21.5%) were diagnosed with IBS. IBS and clinically-significant IBS (IBS-S) groups have significantly experienced a higher level of perceived intensity of stressors and had a higher frequency of stressors. The mean score of social supports and the mean scores of three coping strategies (problem engagement, support seeking, and positive reinterpretation and growth) were significantly lower in subjects with either IBS-S or IBS than in those with no IBS. Multivariate logistic regression revealed a significant association between frequency of stressors and perceived intensity of stressors with IBS (odds ratio [OR] =1.09 and OR = 1.02, respectively) or IBS-S (OR = 1.09 and OR = 1.03, respectively). CONCLUSIONS: People with IBS had higher numbers of stressors, higher perception of the intensity of stressors, less adaptive coping strategies, and less social supports which should be focused in psychosocial interventions. PMID- 27761434 TI - TNF-alpha/IL-10 Ratio Correlates with Burn Severity and May Serve as a Risk Predictor of Increased Susceptibility to Infections. AB - Severe burn injury renders patients susceptible to multiple infection episodes; however, identifying specific patient groups at high risk remains challenging. Burn-induced inflammatory response dramatically modifies the levels of various cytokines. Whether these changes could predict susceptibility to infections remains unknown. The aim of this study was to determine the early changes in the pro- to anti-inflammatory cytokine ratio and investigate its ability to predict susceptibility to repeated infections after severe burn trauma. The patient population consisted of 34 adult patients having early (<=48 h since injury) blood draws following severe (>=20% total burn surface area (TBSA)) burn injury and suffering from a first infection episode at least 1 day after blood collection. Plasma TNF-alpha and IL-10 levels were measured to explore the association between the TNF-alpha/IL-10 ratio, hypersusceptibility to infections, burn size (TBSA), and common severity scores (Acute Physiology and Chronic Health Evaluation II (APACHEII), Baux, modified Baux (R-Baux), Ryan Score, and Abbreviated Burn Severity Index (ABSI)). TNF-alpha/IL10 plasma ratio measured shortly after burn trauma was inversely correlated with burn size and the injury severity scores investigated, and was predictive of repeated infections (>=3 infection episodes) outcome (AUROC [95%CI] of 0.80 [0.63-0.93]). Early measures of circulating TNF-alpha/IL10 ratio may be a previously unidentified biomarker associated with burn injury severity and predictive of the risk of hypersusceptibility to repeated infections. PMID- 27761435 TI - 13C Metabolic Flux Analysis for Systematic Metabolic Engineering of S. cerevisiae for Overproduction of Fatty Acids. AB - Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption. These genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg/L of free fatty acids. With the addition of ATP citrate lyase and downregulation of malate synthase, the engineered strain produced 26% more free fatty acids. Further increases in free fatty acid production of 33% were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by ~70%. PMID- 27761436 TI - High-Sensitivity Mass Spectrometry for Probing Gene Translation in Single Embryonic Cells in the Early Frog (Xenopus) Embryo. AB - Direct measurement of protein expression with single-cell resolution promises to deepen the understanding of the basic molecular processes during normal and impaired development. High-resolution mass spectrometry provides detailed coverage of the proteomic composition of large numbers of cells. Here we discuss recent mass spectrometry developments based on single-cell capillary electrophoresis that extend discovery proteomics to sufficient sensitivity to enable the measurement of proteins in single cells. The single-cell mass spectrometry system is used to detect a large number of proteins in single embryonic cells in the 16-cell embryo of the South African clawed frog (Xenopus laevis) that give rise to distinct tissue types. Single-cell measurements of protein expression provide complementary information on gene transcription during early development of the vertebrate embryo, raising a potential to understand how differential gene expression coordinates normal cell heterogeneity during development. PMID- 27761437 TI - MERS-CoV at the Animal-Human Interface: Inputs on Exposure Pathways from an Expert-Opinion Elicitation. AB - Nearly 4 years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV) and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and more than risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert-opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios, e.g., camels-camels, camels-human, bats/other species to camels/humans, and the role of diverse biological substances (milk, urine, etc.) and potential fomites. Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods) on transmission risk. All experts thought that MERS-CoV-infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated "most likely" incidence risks of at least 22 and 13% for direct and indirect contact, respectively. The results of our study are consistent with available, yet very limited, published data regarding the potential pathways of transmission of MERS-CoV at the animal-human interface. These results identify key knowledge gaps and highlight the need for more comprehensive, yet focused research to be conducted to better understand transmission between dromedaries and humans. PMID- 27761438 TI - Treatment for hepatitis B in patients with drug resistance. AB - Persistent hepatitis B virus (HBV) infections affect about 240 million patients worldwide that are at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes and a unique life cycle, which involves the generation of an RNA template for replication via reverse transcription. Mutations occur frequently during chronic infection, and particular selection pressures select distinct mutants. Nucleoside and nucleotide analogues like lamivudine (LMV), entecavir (ETV), telbivudine (LdT), adefovir dipivoxil (ADV) and tenofovir (TDF) are used to achieve long-term suppression of viral replication. Importantly, these drugs have different barriers to resistance, explaining the higher incidence of treatment failure in the past due to drug resistant viral strains for the older compounds LMV, LdT and ADV. On a molecular level, drug resistant mutations usually affect the reverse transcriptase domain of the HBV polymerase protein. Secondary compensatory mutations restore the replication fitness of the mutant virus. From a clinical point of view, patients undergoing antiviral therapy require regular testing for HBV DNA (every 3-6 months). In case of insufficient viral suppression or viral breakthrough (>1 log increase in HBV DNA above nadir), strict adherence to therapy needs to be ensured. If drug resistance is suspected or even molecularly confirmed, rescue therapy strategies exist, usually switching to a noncross-resistant antiviral drug. LMV, LdT and ETV resistant HBV can be treated with TDF monotherapy, ADV resistance with ETV or TDF, and insufficient responses to TDF may require ETV either as mono- or combination therapy. Complex treatment histories with many antivirals may sometimes necessitate the combination of highly effective antivirals like ETV and TDF. Novel treatment targets such as core (capsid) inhibitors, siRNA targeting protein translation, entry inhibitors or immune modulators aim at improving the efficacy of antivirals in order to (functionally) cure hepatitis B. PMID- 27761440 TI - Treatment strategies according to genotype for chronic hepatitis B in children. AB - This review article was requested by editor-in-chief of this journal as 'pediatric CHB treatment' for the upcoming special issue. The main objective of chronic hepatitis B (CHB) treatment is diminishing the risk of complications related to chronic liver disease. In Asia, there are already some reports about hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected children. The key points of treatment in children with CHB infections are selection of which patients to treat and conformation of the optimal therapy time that would reduce viral resistance. The choice of therapy is determined by the district (Western/Eastern), HBV genotype, medical accessibility, and economic state of the country. Newly developed nucleos(t)ide analogues (NAs) are potent in children with CHB. However, to improve therapeutic efficacy, physicians are recommended to follow treatment guidelines and determine the specific genotype in the CHB patient. In this article, the treatment of pediatric CHB is reviewed according to differences in genotype. PMID- 27761439 TI - Immune therapy for hepatitis B. AB - Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries. Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients. Immune therapy seems to be an alternate therapeutic approach for CHB patients because impaired or distorted or diminished immune responses have been detected in most of these patients. Also, investigators have shown that restoration or induction of proper types of immune responses may have therapeutic implications in CHB. Various immunomodulatory agents have been used to treat patients with CHB around the world and the outcomes of these clinical trials show that the properties of immune modulators and nature and designing of immune therapeutic regimens seem to be highly relevant in the context of treatment of CHB patients. In this review, the general properties and specific features of immune therapy for CHB have been discussed for developing the guidelines of effective regimens of immune therapy for CHB. PMID- 27761441 TI - Hepatitis B: progress in understanding chronicity, the innate immune response, and cccDNA protection. AB - Hepatitis B virus (HBV) infection is a serious health threat around the world. Despite the availability of an effective hepatitis B vaccine, the number of HBV carriers is estimated to be as high as 240 million worldwide. Global mortality due to HBV-related liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) may be as high as 1 million deaths per year. HBV is transmitted via blood and body fluids, and is much more infectious than both human immunodeficiency virus (HIV) and hepatitis C virus. While HBV infection exhibits a variety of clinical presentations, even asymptomatic carriers can develop HCC without liver fibrosis. Current therapeutic options against HBV include pegylated interferon (Peg-IFN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs), with clinical studies showing a significant association between loss of HBV DNA and a decrease in cancer risk. However, the ultimate goal of HBV therapy is a complete cure of HBV-including the elimination of covalently closed circular DNA (cccDNA)-in order to further decrease the risk of developing HCC. The development of hepatitis B is associated with the host immune response to virus-infected hepatocytes, as HBV is understood to lack direct cytotoxicity. While HBV-specific CD8+ T cells are thus involved in hepatitis development, they also play an important role in eliminating HBV infection. Indeed, the innate immune response during the initial phase of HBV infection is essential to the induction of acquired immunity. However, the innate immune response to HBV infection, including the roles of specific immunocompetent cells and associated molecules, is not well understood. In this review, we focus on the current understanding of the mechanisms underlying hepatitis development by HBV infection. We also address the mechanisms by which HBV protects cccDNA. PMID- 27761442 TI - Diagnosis of hepatitis B. AB - Hepatitis B virus (HBV) infection is a major global health problems leading to severe liver disease such as cirrhosis and hepatocellular carcinoma (HCC). HBV is a circular, partly double-stranded DNA virus with various serological markers: hepatitis B surface antigen (HBsAg) and anti-HBs, anti-HBc IgM and IgG, and hepatitis B e antigen (HBeAg) and anti-HBe. It is transmitted by sexual, parenteral and vertical route. One significant method to diminish the burden of this disease is timely diagnosis of acute, chronic and occult cases of HBV. First step of HBV diagnosis is achieved by using serological markers for detecting antigens and antibodies. In order to verify first step of diagnosis, to quantify viral load and to identify genotypes, quantitative or qualitative molecular tests are used. In this article, the serological and molecular tests for diagnosis of HBV infection will be reviewed. PMID- 27761443 TI - Patient satisfaction at 2 months following total knee replacement using a second generation medial-pivot system: follow-up of 250 consecutive cases. AB - BACKGROUND: Patient dissatisfaction following total knee replacement (TKR) has been reported as high as 24%. Most previous studies have focused on satisfaction for TKR overall, with few reporting satisfaction for specific implant designs. The purpose of this study was to assess patient satisfaction for TKRs performed using a second generation medial-pivot system (EVOLUTION(r), MicroPort Orthopedics Inc., Arlington, TN, USA). METHODS: Of a single surgeon's first 250 consecutive TKRs performed using the subject system, 224 completed a patient satisfaction assessment, the Knee Injury and Osteoarthritis Outcome Score (KOOS), range of motion, and radiographs at 2 months follow-up. RESULTS: The overall very satisfied/satisfied rate was 94.6% at 2 months. Following the first 50 TKRs, the satisfied rate improved to 99.4% suggesting a bias towards the initial cases potentially due to learning the system and instrumentation. Overall KOOS, range of motion, and radiographic outcomes were satisfactory at final follow-up. CONCLUSIONS: In conclusion, more subjects implanted with a second generation medial-pivot system were satisfied compared to previous reports for TKR. PMID- 27761444 TI - Outcomes of off-pump versus on-pump coronary artery bypass graft surgery in patients with severely dilated left ventricle. AB - BACKGROUND: Currently, off-pump coronary artery bypass (OPCAB) grafting has been the standard procedure for surgical revascularization in patients with coronary artery disease (CAD). This study aimed to examine the safety and applicability of OPCAB compared with on-pump coronary artery bypass (ONCAB) in patients with severely dilated left ventricle. METHODS: A retrospective study of giant left ventricle patients [left ventricular end diastolic diameter (LVEDD) >= VE mm] undergoing coronary bypass grafting from 2009 through 2015 at a single center was conducted. Preoperative and intraoperative risk factors, and postoperative outcomes were analyzed. Survival analysis was carried to analyze survival rate during follow-up. RESULTS: A total of 24 patients underwent ONCAB, and 26 underwent OPCAB. Both groups had similar preoperative profiles. Two cases from each group died during in-hospital time. In comparison to OPCAB, there was longer operation and post-surgery intubation time and more renal dysfunction in ONCAB group (P<0.05). One-year survival between OPCAB and ONCAB were not significantly different (87.5% vs. 92.3%, P>0.05). CONCLUSIONS: OPCAB is a safe and feasible alternative for CAD patients with giant left ventricle, offering a significant advantage over ONCAB with regards to renal function, operation duration and length of ventilation. PMID- 27761445 TI - Case-crossover design and its implementation in R. AB - Case-crossover design is a variation of case-control design that it employs persons' history periods as controls. Case-crossover design can be viewed as the hybrid of case-control study and crossover design. Characteristic confounding that is constant within one person can be well controlled with this method. The relative risk and odds ratio, as well as their 95% confidence intervals (CIs), can be estimated using Cochran-Mantel-Haenszel method. R codes for the calculation are provided in the main text. Readers may adapt these codes to their own task. Conditional logistic regression model is another way to estimate odds ratio of the exposure. Furthermore, it allows for incorporation of other time varying covariates that are not constant within subjects. The model fitting per se is not technically difficult because there is well developed statistical package. However, it is challenging to convert original dataset obtained from case report form to that suitable to be passed to clogit() function. R code for this task is provided and explained in the text. PMID- 27761446 TI - Laparoscopic repair of abdominal incisional hernia. AB - Abdominal incisional hernia is a common complication after open abdominal operations. Laparoscopic procedures have obvious mini-invasive advantages for surgical treatment of abdominal incisional hernia, especially to cases with big hernia defect. Laparoscopic repair of incisional hernia has routine mode but the actual operations will be various according to the condition of every hernia. Key points of these operations include design of the position of trocars, closure of defects and fixation of meshes. The details of these issues and experiences of perioperative evaluation and treatment will be talked about in this article. PMID- 27761447 TI - Laparoscopic hernioplasty of hiatal hernia. AB - Laparoscopic surgery is a good choice for surgical treatment of hiatal hernia because of its mini-invasive nature and intraperitoneal view and operating angle. This article will talk about the surgical procedures, technical details, precautions and complications about laparoscopic hernioplasty of hiatal hernia. PMID- 27761448 TI - Non-intubated simultaneous en bloc resection of pulmonary nodule and rib chondrosarcoma. AB - Adequate surgical resection was required for patients with rib chondrosarcoma. A 61-year-old woman was presented with a palpable chest wall mass. Computed tomography (CT) of the chest revealed an isolated pulmonary nodule about 0.9 cm, and a giant rib tumor about 12 cm * 9 cm which penetrated through the 7th rib into thorax. CT reconstruction and simulated surgery was utilized for disease free surgical margin (R0 resection), then a simultaneous en bloc resection of pulmonary nodule and rib tumor was performed along with chest wall reconstruction under local anesthesia and intravenous sedation without endotracheal intubation. And the recovery was encouragingly uneventful. PMID- 27761449 TI - Tracheoesophageal fistula induced by invasive pulmonary aspergillosis. AB - Invasive pulmonary aspergillosis (IPA) is commonly seen in immunocompromised patients, and tracheoesophageal fistula (TEF) induced by IPA is rare and seldom reported. Management of these critically ill patients is challenging and often requires a multidisciplinary approach. The authors reported an adult suffering from aplastic anemia who developed TEF caused by IPA. The diagnosis was confirmed following bronchoscopy and histopathological examination. Antifungal and bronchoscopic intervention provided a cure without any recurrence as yet. PMID- 27761450 TI - Pulmonary nodule follow-up: be careful with volumetry between contrast enhanced and unenhanced CT. AB - Incident pulmonary nodules are a frequent finding on chest computed tomography (CT) of the lungs requiring follow-up. This case illustrates the importance of taking differences in CT scanning techniques (contrast versus non-contrast enhanced) into account. Comparing nodule size on unenhanced follow-up CT's with initial contrast-enhanced CT may consequently underestimate growth and mask malignant growth rates as demonstrated by our case report. PMID- 27761451 TI - Glucose management in the intensive care unit: are we looking for the right sweet spot? AB - In a recently published issue of Critical Care Medicine, Kar and colleagues investigated glucose management of critically ill patients with type 2 diabetes. In this commentary, we discuss the challenges of investigating glucose control in the critically ill, why so many internally valid studies in this field lead to conflicting results, and the obstacles preventing investigators from reaching a conclusive answer. PMID- 27761452 TI - A new horizon for the use of non-invasive ventilation in patients with acute respiratory distress syndrome. AB - Non-invasive ventilation (NIV) has assumed an important role in the management of acute respiratory failure (ARF). NIV, compared with standard medical therapy, improves survival and reduces complications in selected patients with ARF. NIV represents the first-line intervention for some forms of ARF, such as chronic obstructive pulmonary disease (COPD) exacerbations and acute cardiogenic pulmonary edema. The use of NIV is also well supported for immunocompromised patients who are at high risk for infectious complications from endotracheal intubation. Selection of appropriate patients is crucial for optimizing NIV success rates. Appropriate ventilator settings, a well-fitting and comfortable interface, and a team skilled and experienced in managing NIV are key components to its success. In a recent issue of the Journal of the American Medical Association, Patel et al. reported the results of their single-center trial of 83 patients with acute respiratory distress syndrome (ARDS) who were randomly assigned to NIV delivered via a helmet or face mask. Patients assigned to the helmet group exhibited a significantly lower intubation rate and were more likely to survive through 90 days. This perspective reviews the findings of this trial in the context of current clinical practice and in light of data from the literature focused on the potential reasons for success of NIV delivered through a helmet compared to face mask. The implications for early management of patients with ARDS are likewise discussed. PMID- 27761454 TI - Noninvasive ventilatory management of the acute respiratory distress syndrome: a new era or just another tease! PMID- 27761453 TI - Non-invasive ventilation in acute respiratory distress syndrome: helmet use saves lives? PMID- 27761455 TI - Should we carry out noninvasive ventilation using a helmet in acute respiratory distress syndrome? PMID- 27761456 TI - Improving diagnostic accuracy for invasive pulmonary aspergillosis in the intensive care unit. PMID- 27761457 TI - The role of galactomannan testing to diagnose invasive pulmonary aspergillosis in critically ill patients. PMID- 27761458 TI - Timing of renal replacement therapy in critically ill patients: where are the hands on the clock? PMID- 27761459 TI - When to start a renal replacement therapy in acute kidney injury (AKI) patients: many irons in the fire. PMID- 27761460 TI - Do we really need more intensive care unit beds? PMID- 27761461 TI - Towards a practical clinical use of fractioned exhaled nitric oxide levels in chronic cough. PMID- 27761462 TI - Liberal glucose targets for critically ill diabetic patients: is it time for large clinical trials with more personalized endpoints? PMID- 27761463 TI - Non-invasive ventilation in hypoxemic patients: does the interface make a difference? PMID- 27761464 TI - Erratum to PillCam colon capsule endoscopy (PCCE) in colonic diseases. AB - [This corrects the article DOI: 10.21037/atm.2016.08.28.]. PMID- 27761465 TI - In Vitro and In Vivo Biofilm Characterization of Methicillin-Resistant Staphylococcus aureus from Patients Associated with Pharyngitis Infection. AB - The present investigation was deliberately aimed at evaluating the biofilm forming ability of 63 clinical MRSA isolates recovered from pharyngitis patients through different phenotypic assays. The molecular detection of adhesion (icaA/icaD/icaB/icaC), adhesins (fnbA/fnbB, clfA, and cna), staphylococcal accessory regulator (sarA), and alpha-toxin (hla) genes was done by employing polymerase chain reaction (PCR). Out of 63 isolates, 49 (77.8%) were found slime positive by the Congo red agar (CRA) method and 44 (69.8%) as biofilm positive by the quantitative microtitre plate assays. The results of MATH assay showed that most of the test pathogens are hydrophilic in nature. The molecular investigation of biofilm-associated genes revealed that 84.13% (n = 53) of isolates were found positive for icaADBC genes. The fnbA and fnbB genes were present in 49 (77.8%) and 51 (81%) MRSA isolates, respectively. In addition, 58.7% (n = 37), 73% (n = 46), and 69.8% (n = 44) of the isolates harboured the clfA, cna, and hla genes, respectively. Further, nearly 81% (n = 51) of the isolates were found positive for the gene sarA and all the ica negative isolates were also negative for the gene. Furthermore, the results of in vivo adherence assay unveiled the factual commonness in the in vitro adherence method. PMID- 27761466 TI - Late Presentation of HIV Infection: Prevalence, Trends, and the Role of HIV Testing Strategies in Guangzhou, China, 2008-2013. AB - Background. The prevalence, trends, and the role of different HIV testing strategies in late presentation of HIV infection in China were unknown. Methods. Data of newly reported HIV cases in Guangzhou between 2008 and 2013 was analyzed to examine the prevalence, trends, and characteristics of late presentation of HIV infection by three types of HIV testing strategies. Results. Overall, 53.2% (1412/2653) and 27.3% (724/2653) met the criteria of late presentation and presentation with advanced HIV disease. The overall trend of late presentation of HIV infection within the study period was declining. Late presentation was 62.9% in 2008 and dropped to 43.3% in 2013 (P < 0.001); presentation with advanced HIV disease was 40.3% in 2008 and dropped to 15.2% in 2013 (P < 0.001). Of the three testing strategies, PITC presented higher odds of both late presentation [AOR (95% CI): PITC versus VCT: 1.37 (1.09, 1.73); PITC versus MHT: 3.09 (2.16, 4.42)] and presentation with advanced HIV disease [AOR (95% CI): PITC versus VCT: 1.65 (1.29, 2.11); PITC versus MHT: 13.14 (8.47, 20.39)]. Conclusions. Although the late presentation of HIV infection was declining, it was still high in Guangzhou. The worse situation among PITC cases urges the policy adjustment in medical settings to increase early HIV diagnosis. PMID- 27761467 TI - Analysis of Relationship between the Body Mass Composition and Physical Activity with Body Posture in Children. AB - Introduction. Excessive body mass in turn may contribute to the development of many health disorders including disorders of musculoskeletal system, which still develops intensively at that time. Aim. The aim of this study was to assess the relationship between children's body mass composition and body posture. The relationship between physical activity level of children and the parameters characterizing their posture was also evaluated. Material and Methods. 120 school age children between 11 and 13 years were enrolled in the study, including 61 girls and 59 boys. Each study participant had the posture evaluated with the photogrammetric method using the projection moire phenomenon. Moreover, body mass composition and the level of physical activity were evaluated. Results. Children with the lowest content of muscle tissue showed the highest difference in the height of the inferior angles of the scapulas in the coronal plane. Children with excessive body fat had less slope of the thoracic-lumbar spine, greater difference in the depth of the inferior angles of the scapula, and greater angle of the shoulder line. The individuals with higher level of physical activity have a smaller angle of body inclination. Conclusion. The content of muscle tissue, adipose tissue, and physical activity level determines the variability of the parameter characterizing the body posture. PMID- 27761468 TI - Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. AB - Diabetic macular edema (DME) can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). DM parameters controls (glycemia, arterial tension, and lipids) are the gold standard for preventing DR and DME. Although the vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF overexpression is a cause or a consequence of inflammation. This paper provides a review of the data currently available, focusing on VEGF, angiogenesis, and inflammation. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. Knowledge of DME etiology seems to be important in treatments with anti-VEGF or anti-inflammatory drugs. Current diagnostic techniques do not permit us to differentiate between both etiologies. In the future, diagnosing the physiopathology of each patient with DME will help us to select the most effective drug. PMID- 27761469 TI - Effect of Alkaloids from Nelumbinis Plumula against Insulin Resistance of High Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice. AB - This study aimed to investigate the effects of total alkaloids from Nelumbinis Plumula (NPA) on insulin resistance (IR) of high-fat diet- (HFD-) induced nonalcoholic fatty liver disease (NAFLD). Rats were fed with HFD for 8 weeks to induce NAFLD. Then, the effect of NPA on ameliorating IR in HFD-induced NAFLD was evaluated. Fasting serum insulin was determined using an enzyme-linked immunosorbent assay (ELISA) kit for insulin following the manufacturer's protocol. Some inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) were determined using ELISA kits to assess the inflammatory burden in rats. The results showed that HFD could induce a significant increase in blood glucose and IR in rats. However, rats treated with NPA (400 or 600 mg/kg) showed improved IR and reduction in serum inflammatory cytokines TNF-alpha and IL-6. Further investigation indicated that NPA could inhibit IR by restoring the insulin receptor substrate-1 (IRS-1) and suppressing the expression of c-Jun N-terminal kinase (JNK) phosphorylation. The present results supported the view that the pathogenesis of NAFLD was complex with inflammation, together with increasing serum glucose and IR. Also, JNK and IRS phosphorylation were suggested for their involvement in the modulating of IR during NAFLD progression. Therefore, NPA may serve as a potential natural remedy against IR in NAFLD. PMID- 27761470 TI - Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFkappaB Pathway Suppression. AB - Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha)) mRNA expression, RAGE expression, and NFkappaB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects. In conclusion, metformin inhibits AGEs-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFkappaB pathway suppression. PMID- 27761471 TI - Exercise Therapy for Management of Type 2 Diabetes Mellitus: Superior Efficacy of Activity Monitors over Pedometers. AB - We compared the efficacy of activity monitor (which displays exercise intensity and number of steps) versus that of pedometer in exercise therapy for patients with type 2 diabetes. The study subjects were divided into the activity monitor group (n = 92) and pedometer group (n = 95). The primary goal was improvement in hemoglobin A1c (HbA1c). The exercise target was set at 8,000 steps/day and 20 minutes of moderate-intensity exercise (>=3.5 metabolic equivalents). The activity monitor is equipped with a triple-axis accelerometer sensor capable of measuring medium-intensity walking duration, number of steps, walking distance, calorie consumption, and total calorie consumption. The pedometer counts the number of steps. Blood samples for laboratory tests were obtained during the visits. The first examination was conducted at the start of the study and repeated at 2 and 6 months. A significant difference in the decrease in HbA1c level was observed between the two groups at 2 months. The results suggest that the use of activity level monitor that displays information on exercise intensity, in addition to the number of steps, is useful in exercise therapy as it enhances the concept of exercise therapy and promotes lowering of HbA1c in diabetic patients. PMID- 27761472 TI - Rapid Acting Insulin Use and Persistence among Elderly Type 2 Diabetes Patients Adding RAI to Oral Antidiabetes Drug Regimens. AB - We examined the real-world utilization and persistence of rapid acting insulin (RAI) in elderly patients with type 2 diabetes who added RAI to their drug (OAD) regimen. Insulin-naive patients aged >=65 years, with >=1 OAD prescription during the baseline period, who were continuously enrolled in the US Humana Medicare Advantage insurance plan for 18 months and initiated RAI were included. Among patients with >=2 RAI prescriptions (RAIp), persistence during the 12-month follow-up was assessed. Multivariate logistic regression analyses identified factors affecting RAI use and persistence. Of 3734 patients adding RAI to their OAD regimen, 2334 (62.5%) had a RAIp during follow-up. Factors associated with RAIp included using <=2 OADs; cognitive impairment, basal insulin use during follow-up; and higher RAI out-of-pocket costs ($36 to <$56 versus $0 to $6.30). Patients were less likely to persist with RAI when on <=2 OADs versus >=3 OADs and when having higher RAI out-of-pocket costs ($36 to <$56 versus $0 to $6.30) and more likely to persist when they had cognitive impairment and basal insulin use during follow-up. Real-world persistence of RAI in insulin-naive elderly patients with type 2 diabetes was very poor when RAI was added to an OAD regimen. PMID- 27761473 TI - The Relationship between Health Literacy and Health Behaviour in People with Diabetes: A Danish Population-Based Study. AB - Background. People with diabetes who have poor health behaviours are at greater risk for a range of adverse health outcomes. We aimed to investigate the relationship between health literacy and health behaviour (smoking, alcohol, physical activity, and diet) in people with diabetes. Methods. The study was based on respondents aged 25 years or older from a population-based survey in 2013 who reported having diabetes (n = 1685). Two dimensions from the Health Literacy Questionnaire were used: "understand health information" and "actively engage with healthcare providers." We used logistic regression to examine the association between health literacy and health behaviour. Results. After adjustment for sociodemographic factors, individuals with diabetes who found it difficult to understand information about health had higher odds of being physically inactive (OR: 3.43, 95% CI: 2.14-5.51) and having unhealthy dietary habits (OR: 3.01, 95% CI: 1.63-5.58). Similar results were observed for individuals who found it difficult to actively engage with healthcare providers. No associations were found between the two dimensions of health literacy and smoking and alcohol consumption. Conclusion. When developing health services and interventions to improve health behaviour among people with diabetes, our results suggest that they may benefit by including focus on health literacy. PMID- 27761475 TI - Firing of an Implantable Cardiac Defibrillator: An Unusual Presentation of Celiac Crisis. AB - Celiac crisis, an atypical presentation of celiac disease, is characterized by acute diarrhea and severe metabolic derangements. This diagnosis is often missed in the differential of acute diarrheal illness. Our patient is a 69-year-old man who presented with ICD firing and was found to have profound metabolic derangements. Further evaluation revealed undiagnosed celiac disease and his symptoms resolved with a gluten-free diet. Celiac crisis should be considered in all patients presenting with acute diarrhea, metabolic acidosis, and severe electrolyte abnormalities as management can be life-saving. PMID- 27761476 TI - An Uncommon and Challenging Case of Duodenal Variceal Bleeding. PMID- 27761477 TI - Adult-Onset Esophageal Crohn's Disease. AB - Crohn's disease (CD) is an idiopathic inflammatory bowel disease that can involve any part of the gastrointestinal tract. Esophageal involvement is rarely seen in adults, especially at the initial diagnosis of CD. Esophageal symptoms as primary manifestations of the disease are extremely rare. We report a case of a CD with esophageal involvement at the time of her initial diagnosis of CD. PMID- 27761474 TI - Generalized Joint Laxity and Ligament Injuries in High School-Aged Female Volleyball Players in Japan. AB - BACKGROUND: Generalized joint laxity has been linked to ligamentous injuries such as anterior cruciate ligament tear and ankle sprain. PURPOSE/HYPOTHESIS: The purpose of this study was to investigate generalized joint laxity and incidence of ligament injuries in high school-aged female volleyball players. It was hypothesized that volleyball players with a past history of sprains would have increased generalized joint laxity compared with those without any history and that athletes with multiple sprains would demonstrate with a higher generalized joint laxity score than those who had only 1 sprain. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Forty-seven subjects were tested for generalized joint laxity using the Beighton and Horan Joint Mobility Index (BHJMI). They were categorized into 2 groups based on the presence of past ligament injury: injury group (IG) and noninjury group (NG). The IG group was further divided into 2 groups based on whether they had a single ligamentous injury (IGS) or multiple injuries (IGM) in the past to study whether there was any difference in scores between the subgroups. The collected data were analyzed statistically with 1-way analysis of variance. RESULTS: Subjects in the IG group scored significantly higher on the BHJMI than those in the NG group. The mean score for the IG group was 2.40 +/- 1.42, as opposed to 1.24 +/- 1.09 for the NG group (P = .006). Eleven subjects in the IG group had suffered multiple injuries or recurrent injuries (IGM) and scored significantly higher than the remaining 19 individuals in the IG group, who had only sustained a single injury (IGS). The mean BHJMI scores were 3.18 +/- 1.47 and 1.95 +/- 1.22 for IGM and IGS, respectively (P = .02). CONCLUSION: Female athletes with a high generalized joint laxity score may be more prone to ligament injury and potentially to recurrent ligament injuries. PMID- 27761478 TI - Fatal Streptococcus pneumoniae Sepsis in a Patient With Celiac Disease-Associated Hyposplenism. AB - We present a 59-year-old male with poorly controlled celiac disease (CD) and fatal Streptococcus pneumoniae sepsis, describe the morphologic findings, and stress the need for monitoring splenic function and pneumococcal vaccination in these patients. PMID- 27761479 TI - The Klatskin Tumor That Wasn't: An Unusual Presentation of Sarcoidosis. AB - We present the case of a patient who presented with signs and symptoms associated with a Klatskin tumor. After endoscopic retrograde cholangiopancreatography (ERCP) and biopsy, she was found instead to have granulomatous infiltration of the extrahepatic biliary tree consistent with biliary sarcoidosis. The patient was treated successfully with systemic corticosteroids and azathioprine. She later developed cutaneous, lymphatic, and pulmonary granulomatous disease. Isolated biliary disease is a rare initial presentation of systemic sarcoidosis. PMID- 27761480 TI - The Interview Process for Gastroenterology Fellowship. PMID- 27761481 TI - Keys to Success in the Match: The Rank Order List. PMID- 27761482 TI - Immunology of neuromyelitis optica during pregnancy. AB - Anti-aquaporin-4 (AQP4) autoantibody plays a key role in the pathogenesis of neuromyelitis optica (NMO). Studies have shown increased relapse rates in patients with NMO during pregnancy and postpartum. High estrogen levels during pregnancy can increase activation-induced cytidine deaminase expression, which is responsible for immunoglobulin production. Additionally, sex hormones may influence antibody glycosylation, with effects on antibody function. Estrogen decreases apoptosis of self-reactive B cells, through upregulation of antiapoptotic molecules. Furthermore, high estrogen levels during pregnancy can boost B-cell activating factor and type 1 interferon (IFN) production, facilitating development of self-reactive peripheral B cells in association with increased disease activity. Elevated levels of estrogen during pregnancy decrease IFN-gamma generation, which causes a shift toward T helper (Th) 2 immunity, thereby propagating NMO pathogenesis. Women with NMO have an elevated rate of pregnancy complications including miscarriage and preeclampsia, which are associated with increased Th17 cells and reduction of T-regulatory cells. These in turn can enhance inflammation in NMO. Increased regulatory natural killer cells (CD56-) during pregnancy can enhance Th2-mediated immunity, thereby increasing inflammation. In the placenta, trophoblasts express AQP4 antigen and are exposed to maternal blood containing anti-AQP4 antibodies. Animal models have shown that anti-AQP4 antibodies can bind to AQP4 antigen in placenta leading to complement deposition and placental necrosis. Reduction of regulatory complements has been associated with placental insufficiency, and it is unclear whether these are altered in NMO. Further studies are required to elucidate the specific mechanisms of disease worsening, as well as the increased rate of complications during pregnancy in women with NMO. PMID- 27761483 TI - Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy. AB - OBJECTIVE: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy. METHODS: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies. RESULTS: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive. In relation with cancer, there were 12 patients (statin-exposed, n = 4) with cancers detected within 3 years of myopathy diagnosis (cancer association), 3 patients (all statin naive) with cancers detected more than 3 years before myopathy diagnosis (cancer history), 10 cancer-free patients followed up for more than 3 years (all statin naive), and 8 patients without cancer detection but followed up for less than 3 years (statin-exposed, n = 3). Therefore, 12 patients with cancer association (36%) formed a larger group than that of 7 statin-exposed patients (21%). Among 12 patients with cancer association, 92% had cancer detection within 1 year of myopathy diagnosis (after 1.3 years in the remaining patient), 83% had advanced cancers, and 75% died of cancers within 2.7 years. Of interest, 1 patient with cancer history had sustained increase in creatine kinase level over 12 years from cancer removal to the development of weakness. CONCLUSIONS: Patients with cancer association formed a large group with poor prognosis in our series of patients with anti-HMGCR Ab+ myopathy. The close synchronous occurrence of cancers and myopathies suggested that cancer association is one of the risk factors for developing anti-HMGCR Ab+ myopathy. PMID- 27761484 TI - Erratum: Serotonin-norepinephrine reuptake inhibitors may exacerbate stiff-person syndrome. AB - [This corrects the article on p. e281 in vol. 3, PMID: 27606356.]. PMID- 27761485 TI - Erratum: Comprehensive evaluation of serum microRNAs as biomarkers in multiple sclerosis. AB - [This corrects the article on p. e267 in vol. 3, PMID: 27606352.]. PMID- 27761486 TI - Simultaneous multiview capture and fusion improves spatial resolution in wide field and light-sheet microscopy. AB - Most fluorescence microscopes are inefficient, collecting only a small fraction of the emitted light at any instant. Besides wasting valuable signal, this inefficiency also reduces spatial resolution and causes imaging volumes to exhibit significant resolution anisotropy. We describe microscopic and computational techniques that address these problems by simultaneously capturing and subsequently fusing and deconvolving multiple specimen views. Unlike previous methods that serially capture multiple views, our approach improves spatial resolution without introducing any additional illumination dose or compromising temporal resolution relative to conventional imaging. When applying our methods to single-view wide-field or dual-view light-sheet microscopy, we achieve a twofold improvement in volumetric resolution (~235 nm * 235 nm * 340 nm) as demonstrated on a variety of samples including microtubules in Toxoplasma gondii, SpoVM in sporulating Bacillus subtilis, and multiple protein distributions and organelles in eukaryotic cells. In every case, spatial resolution is improved with no drawback by harnessing previously unused fluorescence. PMID- 27761487 TI - Shelf life stability comparison in air for solution processed pristine PDPP3T polymer and doped spiro-OMeTAD as hole transport layer for perovskite solar cell. AB - This data in brief includes forward and reverse scanned current density-voltage (J-V) characteristics of perovskite solar cells with PDPP3T and spiro-OMeTAD as HTL, stability testing conditions of perovskite solar cell shelf life in air for both PDPP3T and spiro-OMeTAD as HTL as per the description in Ref. [1], and individual J-V performance parameters acquired with increasing time exposed in ambient air are shown for both type of devices using PDPP3T and spiro-OMeTAD as HTL. The data collected in this study compares the device stability with time for both PDPP3T and spiro-OMeTAD based perovskite solar cells and is directly related to our research article "solution processed pristine PDPP3T polymer as hole transport layer for efficient perovskite solar cells with slower degradation" [2]. PMID- 27761489 TI - Data supporting attempted caveolae-mediated phagocytosis of surface-fixed micro pillars by human osteoblasts. AB - The provided data contains the phagocytic interaction of human MG-63 osteoblasts with micro-particles 6 um in size as well as geometric micro-pillared topography with micro-pillar sizes 5 um of length, width, height and spacing respectively related to the research article entitled "Attempted caveolae-mediated phagocytosis of surface-fixed micro-pillars by human osteoblasts" in the Biomaterials journal. [1] Micro-particle treatment was used as positive control triggering phagocytosis by the osteoblasts. Caveolin-1 (Cav-1) as major structural component of caveolae [2] plays an important role in the phagocytic process of micro-particles and -pillars. Data related to the experiments in [1] with siRNA-mediated knockdown are presented here as well as micro-particle control experiments, tubulin analysis on the micro-pillared topography and initial cell interaction with the micro-pillars. PMID- 27761488 TI - Data on common variants associated with coronary artery disease/myocardial infarction in ethnic Arabs. AB - The data shows results acquired in a large cohort of 5668 ethnic Arabs involved in a common variants association study for coronary artery disease (CAD) and myocardial infarction (MI) using the Affymetrix Axiom Genotyping platform ("A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs" Wakil et al. (2015) [1] ). Several loci were described that conferred risk for CAD or MI, some of which were validated in an independent set of samples. Principal Component (PCA) analysis suggested that the Saudi Cohort was close to the CEU and TSI populations, thus pointing to similarity with European populations. PMID- 27761490 TI - Data in support of preparation and functionalization of a clickable polycarbonate monolith. AB - This data article provides supplementary figures to the research article entitled, "Phase separation approach to a reactive polycarbonate monolith for "click" modifications" (Xin et al., Polymer, 2015, doi:10.1016/j.polymer.2015.04.008). Here, the nitrogen adsorption/desorption isotherms of the prepared porous polycarbonate monolith are shown to classify its inner structure and calculate the specific surface area. The monoliths were modified by using the thiol-ene click chemistry and the olefin metathesis, which was examined by contact angle measurements, FT-IR, solid state 13C NMR spectroscopy as well as thermogravimetric analysis. PMID- 27761491 TI - "Eyes Open - Eyes Closed" EEG/fMRI data set including dedicated "Carbon Wire Loop" motion detection channels. AB - This data set contains electroencephalography (EEG) data as well as simultaneous EEG with functional magnetic resonance imaging (EEG/fMRI) data. During EEG/fMRI, the EEG cap was outfitted with a hardware-based add-on consisting of carbon-wire loops (CWL). These yielded six extra'CWL' signals related to Faraday induction of these loops in the main magnetic field "Measurement and reduction of motion and ballistocardiogram artefacts from simultaneous EEG and fMRI recordings" (Masterton et al., 2007) [1]. In this data set, the CWL data make it possible to do a direct regression approach to deal with the BCG and specifically He artifact. The CWL-EEG/fMRI data in this paper has been recorded on two MRI scanners with different Helium pump systems (4 subjects on a 3 T TIM Trio and 4 subjects on a 3T VERIO). Separate EEG/fMRI data sets have been recorded for the helium pump ON as well as the helium pump OFF conditions. The EEG-only data (same subjects) has been recorded for a motion artifact-free reference EEG signal outside of the scanner. This paper also links to an EEGlab "EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis" (Delorme and Makeig, 2004) [2] plugin to perform a CWL regression approach to deal with the He pump artifact, as published in the main paper "Carbon-wire loop based artifact correction outperforms post-processing EEG/fMRI corrections-A validation of a real-time simultaneous EEG/fMRI correction method" (van der Meer et al., 2016) [3]. PMID- 27761492 TI - Data on the effect of Cytopiloyne against Listeria monocytogenes infection in mice. AB - Cytopiloyne (CP), a novel polyacetylene compound extracted from B. pilosa, shows a multi-bioactivity, including immunomodulatory and antidiabetes. Here, we investigated the anti-Listeria effect of cytopiloyne in mice by assessing mortality, clearance of L. monocytogenes, and pathology examination. The data presented herein are supplemental to our research article entitled "Cytopiloyne, a polyacetylenic glucoside from Bidens pilosa, acts as a novel anticandidial agent via regulation of macrophages" [1]. PMID- 27761493 TI - Proteome data from a host-pathogen interaction study with Staphylococcus aureus and human lung epithelial cells. AB - To simultaneously obtain proteome data of host and pathogen from an internalization experiment, human alveolar epithelial A549 cells were infected with Staphylococcus aureus HG001 which carried a plasmid (pMV158GFP) encoding a continuously expressed green fluorescent protein (GFP). Samples were taken hourly between 1.5 h and 6.5 h post infection. By fluorescence activated cell sorting GFP-expressing bacteria could be enriched from host cell debris, but also infected host cells could be separated from those which did not carry bacteria after contact (exposed). Additionally, proteome data of A549 cells which were not exposed to S. aureus but underwent the same sample processing steps are provided as a control. Time-resolved changes in bacterial protein abundance were quantified in a label-free approach. Proteome adaptations of host cells were monitored by comparative analysis to a stable isotope labeled cell culture (SILAC) standard. Proteins were extracted from the cells, digested proteolytically, measured by nanoLC-MS/MS, and subsequently identified by database search and then quantified. The data presented here are related to a previously published research article describing the interplay of S. aureus HG001 and human epithelial cells (Surmann et al., 2015 [1]). They have been deposited to the ProteomeXchange platform with the identifiers PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD002384 for the S. aureus HG001 proteome dataset and PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD002388 for the A549 proteome dataset. PMID- 27761494 TI - Data on correlation between CT-derived and MRI-derived myocardial extracellular volume. AB - This article describes data related to a research article titled "Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study", Kurita et al. (in press) [1]. Myocardial extracellular volume fraction (ECV) is an imaging biomarker that can elevate in various heart diseases. This article describes correlation between CT-derived and MRI-derived ECV in 24 myocardial segments in 8 patients. CT derived ECV was obtained from pre-contrast and delayed-phase images acquired by using dual-source CT system. MRI-derived ECV was obtained by using modified Look Locker inversion recovery sequence implemented on a 3 T MRI system. PMID- 27761495 TI - Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. AB - This data set is composed of transcriptomics analyses of (i) liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF) and (ii) hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC). Data from primary human hepatocytes was also added to the data set "Open TG-GATEs: a large-scale toxicogenomics database" (Igarashi et al., 2015) [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article "Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems" (Rodrigues et al., 2016) [2]. PMID- 27761496 TI - Tourism trends in the world's main destinations before and after the 2008 financial crisis using UNWTO official data. AB - The first decade of the present century has been characterized by several economic shocks such as the 2008 financial crisis. In this data article we present the annual percentage growth rates of the main tourism indicators in the world's top tourist destinations: the United States, China, France, Spain, Italy, United Kingdom, Germany, Turkey, Mexico and Austria. We use data from the Compendium of Tourism Statistics provided by the World Tourism Organization (http://www2.unwto.org/content/data-0). It has been demonstrated that the dynamics of growth in the tourism industry pose different challenges to each destination in the previous study "Positioning and clustering of the world's top tourist destinations by means of dimensionality reduction techniques for categorical data" (Claveria and Poluzzi, 2016, [1]). We provide a descriptive analysis of the variables over the period comprised between 2000 and 2010. We complement the analysis by graphing the evolution of the main variables so as to visually represent the co-movements between tourism variables and economic growth. PMID- 27761497 TI - Small power and lighting load time series data for 27 departments across 8 UK hospitals. AB - The electricity consumption of 27 departments was measured across 8 medium to large General Acute hospitals in England (largely by the authors, some data was donated and authorised for publication by the respective hospitals). The departments fall into 6 different categories which have been selected due to their prevalence in General Acute Hospitals (wards), their high energy intensities (theatres, laboratories, imaging and radiotherapy) or their distinct operating hours (day clinics). This data article provides floor areas and the time series of departmental power loads, mostly encompassing lighting and small power (but excluding central electricity use for ventilation, pumping and medical gas services). Comparative interpretations of the data are published in doi: 10.1016/j.enbuild.2016.02.052 [1]. PMID- 27761498 TI - Ecological data in support of an analysis of Guinea-Bissau's medicinal flora. AB - This dataset presents an annotated list of medicinal plants used by local communities in Guinea-Bissau (West Africa), in a total of 218 species. Data was gathered by means of herbarium and bibliographic research, as well as fieldwork. Biological and ecological information is provided for each species, including in country distribution, geographical range, growth form and main vegetation types. The dataset was used to prepare a paper on the medicinal plants of Guinea-Bissau "Medicinal plants of Guinea-Bissau: therapeutic applications, ethnic diversity and knowledge transfer" (Catarino et al., 2016) [1]. The table and figures provide a unique database for Guinea-Bissau in support of ethno-medical and ethno pharmacological research, and their ecological dimensions. PMID- 27761500 TI - Biokinetic datasets of PEI F25-LMW complexed and non-complexed 32P-siRNA within different lung compartments. AB - Biokinetics data of lung-administered PEI F25-LMW/siRNA polyplexes within different lung compartments are presented. Thereby, at three different timepoints (1 h, 3 h, 8 h), the data was determined by calculations to the 32P-radioactivity in the whole mouse body. Additionally, data was optimized to the available PEI F25-LMW/siRNA polyplexes in the target organ and therefore normalized to the sum of all lung compartments. Methods, other biokinetics data and the discussion of the results are published in "Biokinetic studies of non-complexed siRNA versus nano-sized PEI F25-LMW/siRNA polyplexes following intratracheal instillation into mice" (Lipka et al., 2016 [1]). PMID- 27761499 TI - Data including GROMACS input files for atomistic molecular dynamics simulations of mixed, asymmetric bilayers including molecular topologies, equilibrated structures, and force field for lipids compatible with OPLS-AA parameters. AB - In this Data in Brief article we provide a data package of GROMACS input files for atomistic molecular dynamics simulations of multicomponent, asymmetric lipid bilayers using the OPLS-AA force field. These data include 14 model bilayers composed of 8 different lipid molecules. The lipids present in these models are: cholesterol (CHOL), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE), 1-stearoyl-2 oleoyl-sn-glycero-3-phosphatidyl-ethanolamine (SOPE), 1-palmitoyl-2-oleoyl-sn glycero-3-phosphatidylserine (POPS), 1-stearoyl-2-oleoyl-sn-glycero-3 phosphatidylserine (SOPS), N-palmitoyl-D-erythro-sphingosyl-phosphatidylcholine (SM16), and N-lignoceroyl-D-erythro-sphingosyl-phosphatidylcholine (SM24). The bilayers' compositions are based on lipidomic studies of PC-3 prostate cancer cells and exosomes discussed in Llorente et al. (2013) [1], showing an increase in the section of long-tail lipid species (SOPS, SOPE, and SM24) in the exosomes. Former knowledge about lipid asymmetry in cell membranes was accounted for in the models, meaning that the model of the inner leaflet is composed of a mixture of PC, PS, PE, and cholesterol, while the extracellular leaflet is composed of SM, PC and cholesterol discussed in Van Meer et al. (2008) [2]. The provided data include lipids' topologies, equilibrated structures of asymmetric bilayers, all force field parameters, and input files with parameters describing simulation conditions (md.mdp). The data is associated with the research article "Interdigitation of Long-Chain Sphingomyelin Induces Coupling of Membrane Leaflets in a Cholesterol Dependent Manner" (Rog et al., 2016) [3]. PMID- 27761501 TI - Synchronization of networks of chaotic oscillators: Structural and dynamical datasets. AB - We provide the topological structure of a series of N=28 Rossler chaotic oscillators diffusively coupled through one of its variables. The dynamics of the y variable describing the evolution of the individual nodes of the network are given for a wide range of coupling strengths. Datasets capture the transition from the unsynchronized behavior to the synchronized one, as a function of the coupling strength between oscillators. The fact that both the underlying topology of the system and the dynamics of the nodes are given together makes this dataset a suitable candidate to evaluate the interplay between functional and structural networks and serve as a benchmark to quantify the ability of a given algorithm to extract the structural network of connections from the observation of the dynamics of the nodes. At the same time, it is possible to use the dataset to analyze the different dynamical properties (randomness, complexity, reproducibility, etc.) of an ensemble of oscillators as a function of the coupling strength. PMID- 27761502 TI - Data on the potential impact of food supplements on the growth of mouse embryonic stem cells. AB - The use of new compounds as dietary supplements is increasing, but little is known in terms of possible consequences of their use. Pluripotent stem cells are a promising research tool for citotoxicological research for evaluation of proliferation, cell death, pluripotency and differentiation. Using the mouse embryonic stem cell (mESC) model, we present data on three different compounds that have been proposed as new potential supplements for co-adjuvant disease treatments: kaempferol, berberine and Tauroursodeoxycholic acid (TUDCA). Cell number and viability were monitored following treatment with increased concentrations of each drug in pluripotent culture conditions. PMID- 27761503 TI - Kinetics data from bovine sex-specific embryo development from three different bulls. AB - Here we present kinetics data from bovine sex-specific embryo development. Embryos were originated using sex-sorted semen from three different Nelore bulls, and semen from the same batch was used for X-and Y-chromosome spermatozoa sorting. Data was obtained for six time points (24, 48, 96, 120, and 144 h.p.i.). Analyses for each bull's embryos (1, 2 and 3) is presented for female and male groups separately. Also, grouped data analysis, considering bull and sex interaction, is shown. For further interpretation and discussion, see "Cell death is involved in sexual dimorphism during preimplantation development" (Oliveira et al., 2015 [1]). PMID- 27761504 TI - Data on medicinal plants used in Central America to manage diabetes and its sequelae (skin conditions, cardiovascular disease, kidney disease, urinary problems and vision loss). AB - The data described in this article is related to the review article "Medicinal plants used in the traditional management of diabetes and its sequelae in Central America: a review" (Giovannini et al., 2016) [1]. We searched publications on the useful plants of Central America in databases and journals by using selected relevant keywords. We then extracted reported uses of medicinal plants within the disease categories: diabetes mellitus, kidney disease, urinary problems, skin diseases and infections, cardiovascular disease, sexual dysfunction, vision loss, and nerve damage. The following countries were included in our definition of Central America: Belize, Guatemala, Honduras, El Salvador, Nicaragua, Costa Rica and Panama. Data were compiled in a bespoke Access database. Plant names from the published sources were validated against The Plant List (TPL, (The Plant List, 2013) [2]) and accepted names and synonyms were extracted. In total, the database includes 607 plant names obtained from the published sources which correspond to 537 plant taxa, 9271 synonyms and 1055 use reports. PMID- 27761505 TI - Structural dataset for the PPARgamma V290M mutant. AB - Loss-of-function mutation V290M in the ligand-binding domain of the peroxisome proliferator activated receptor gamma (PPARgamma) is associated with a ligand resistance syndrome (PLRS), characterized by partial lipodystrophy and severe insulin resistance. In this data article we discuss an X-ray diffraction dataset that yielded the structure of PPARgamma LBD V290M mutant refined at 2.3 A resolution, that allowed building of 3D model of the receptor mutant with high confidence and revealed continuous well-defined electron density for the partial agonist diclofenac bound to hydrophobic pocket of the PPARgamma. These structural data provide significant insights into molecular basis of PLRS caused by V290M mutation and are correlated with the receptor disability of rosiglitazone binding and increased affinity for corepressors. Furthermore, our structural evidence helps to explain clinical observations which point out to a failure to restore receptor function by the treatment with a full agonist of PPARgamma, rosiglitazone. PMID- 27761506 TI - Data for the gene expression profiling and alternative splicing events during the chondrogenic differentiation of human cartilage endplate-derived stem cells under hypoxia. AB - This article contains relevant data of the research article titled Global profiling of the gene expression and alternative splicing events during the hypoxia-regulated chondrogenic differentiation in human cartilage endplate derived stem cells (Yao et al., 2016) [1]. The data show global profiling of the DEGs (Differentially expressed genes) and AS (Alternative splicing) events during the hypoxia-regulated chondrogenesis of CESCs (human cartilage endplate-derived stem cells) by using Affymetrix Human Transcriptome Array 2.0 (HTA 2.0) system. In addition, the enriched GO (Gene Ontology) functions and signaling pathways are listed. The information presented here includes the information of patients from which the clinical samples are obtained, the list of primers used for validation, the identification, GO and KEGG analysis of DEG and AS events. PMID- 27761507 TI - Mass spectrometry analysis of PPIP5K1 interactions and data on cell motility of PPIP5K1-deficient cells. AB - Inositol pyrophosphates are cellular signals that are created by the actions of inositol kinases and are degraded by highly active inositol phosphatases. The potent actions of these phosphatases suggest these signals must be created near their sites of action. To identify sites where the inositol kinase, PPIP5K1 acts, we performed affinity purification of PPIP5K1 from HEK293 cells and analyzed these samples using mass spectrometry to identify the proteins pesent (10.1016/j.cellsig.2016.02.002) [1]. We further decreased PPIP5K1 levels in HeLa cells and treated these with PPIP5K1 siRNA. We then monitored the motility of these cells in Scratch assays. PMID- 27761508 TI - Dataset of the Botrytis cinerea phosphoproteome induced by different plant-based elicitors. AB - Phosphorylation is one of the main post-translational modification (PTM) involved in signaling network in the ascomycete Botrytis cinerea, one of the most relevant phytopathogenic fungus. The data presented in this article provided a differential mass spectrometry-based analysis of the phosphoproteome of B. cinerea under two different phenotypical conditions induced by the use of two different elicitors: glucose and deproteinized Tomate Cell Walls (TCW). A total 1138 and 733 phosphoproteins were identified for glucose and TCW culture conditions respectively. Raw data are deposited at the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier (PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD003099). Further interpretation and discussion of these data are provided in our research article entitled "Phosphoproteome analysis of B.cinerea in response to different plant-based elicitors" (Lineiro et al., 2016) [1]. PMID- 27761509 TI - Small-area deprivation measure datasets for Scotland, 2001 and 2011. AB - These data present a new small-area deprivation measure, but also include a variety of other indicators, such as the Scottish Index of Multiple Deprivation (SIMD) and the Carstairs score. The data are for Scottish 2001 Datazones and for the years 2001 and 2011. In addition the data provide standardised self-reported measures of general health and limiting long-term illness. The theoretical background for developing the new deprivation measure, and the implications of using different measures to study health inequalities are discussed in "Developing a new small-area measure of deprivation using 2001 and 2011 census data from Scotland" (Allik et al., 2016) [1]. PMID- 27761510 TI - Data on Vietnamese patients' behavior in using information sources, perceived data sufficiency and (non)optimal choice of health care provider. AB - This data article introduces a data set containing 1459 observations that can enable researchers to examine issues related to and perform statistical investigations into questions of relationships between sources of health care information, data sufficiency, trust levels between patients and healthcare experts (and the advice). The data set also records assessment of Vietnamese patients on whether their choice of health care provider is best available (optimal vs. nonoptimal). The data come from a survey in many hospitals in Hanoi and several neighboring provinces/cities in the North of Vietnam, during the last quarter of 2015. Variables that can be useful for future analysis include sources and availability of information, cost, and amount of time for seeking information. The quality of information and health professionals' credibility are critical factors in helping patients choose a health care provider. Mendeley Data, v1 http://dx.doi.org/10.17632/gmbz53tpwc.1; and can enable the modeling after useful discrete data models such as BCL, with one example being provided in this data article. PMID- 27761511 TI - Data for peptide-binding assay with oriented immobilization of GRP78 in Biacore. AB - To develop peptide-conjugated liposomes for cancer imaging and therapy, the label free surface plasmon resonance (SPR) biosensor (BiacoreTM) is a practical and also preferred strategy to examine protein-peptide interaction. A new Biacore protocol with "oriented immobilization" for peptide-binding assay, which overcomes the drawbacks of conventional protocols, was presented in this data article. These results were complementary to the research article Wang at al., [1], which reported a series of new cancer-targeting peptides found with HotLig software (Wang et al., 2013) [2], and this newly developed Biacore protocol. PMID- 27761513 TI - Insulin stimulated MCF7 breast cancer cells: Proteome dataset. AB - The proteome data provided in this article were acquired from MCF7 breast cancer cells stimulated with insulin, and were generated by using a 2D-SCX (strong cation exchange)/RPLC (reversed phase liquid chromatography) separation protocol followed by tandem mass spectrometry (MS) detection. To facilitate data re processing by more advanced search engines and the extraction of additional information from already existing files, both raw and processed data are provided. The sample preparation, data acquisition and processing protocols are described in detail. The raw data relate to work published in "Proteome profile of the MCF7 cancer cell line: a mass spectrometric evaluation" (Sarvaiya et al., 2006) [1] and are made available through the PRIDE (PRoteomics IDEntifications)/ProteomeXchange public repository with identifier PRIDE: PXD004051 ("2016 update of the PRIDE database and tools" (Vizcaino et al., 2016) [2]). PMID- 27761512 TI - Data on the purification and crystallization of the loss-of-function von Willebrand disease variant (p.Gly1324Ser) of the von Willebrand factor A1 domain. AB - von Willebrand factor's (VWF) primary hemostatic responsibility is to deposit platelets at sites of vascular injury to prevent bleeding. This function is mediated by the interaction between the VWF A1 domain and the constitutively active platelet receptor, GPIbalpha. The crystal structure of the A1 domain harboring the von Willebrand disease (vWD) type 2M mutation p.Gly1324Ser has been recently published in the Journal of Biological Chemistry describing its effect on the function and structural stability of the A1 domain of VWF, "Mutational constraints on local unfolding inhibit the rheological adaptation of von Willebrand factor" [1]. The mutation introduces a side chain that thermodynamically stabilizes the domain by reducing the overall flexibility of the A1-GPIbalpha binding interface resulting in loss-of-function and bleeding due to the inability of A1 to adapt to a binding competent conformation under the rheological shear stress blood flow. In this data article we describe the production, quality control and crystallization of the p.Gly1324Ser vWD variant of the A1 domain of VWF. p.Gly1324Ser A1 was expressed in Escherichia coli as insoluble inclusion bodies. After the preparation of the inclusion bodies, the protein was solubilized, refolded, purified by affinity chromatography and crystallized. The crystal structure of the p.Gly1324Ser mutant of the A1 domain is deposited at the Protein Data Bank PDB: 5BV8. PMID- 27761514 TI - Data on the value of elevated circulating mimecan levels for detecting poor coronary collateralization in patients with stable angina and chronic total occlusion. AB - The data presented here support the research article "Association of serum mimecan with angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion" (Shen et al., 2016) [1] where elevated circulating mimecan levels reflected poor angiographic coronary collateralization in such patients. The data included in this article are composed by one figure and consist of (1) validation of serum mimecan measurement by assessing inter- and intra-assay variability in 45 samples; (2) findings on the relation of clinical and angiographic characteristics and biochemical parameters to coronary collateralization in 559 patients; (3) the diagnostic value of serum mimecan for poor collateralization, which was derived from plotting receiver-operating characteristic curves and logistic regression analysis. PMID- 27761515 TI - SWATH-MS proteome profiling data comparison of DJ-1, Parkin, and PINK1 knockout rat striatal mitochondria. AB - This article reports changes in the striatal non-synaptic mitochondrial proteome of DJ-1, Parkin, and PINK1 knockout (KO) rats at 3 months of age. DJ-1, Parkin, and PINK1 mutations cause autosomal-recessive parkinsonism. It is thought that loss of function of these proteins contributes to the onset and pathogenesis of Parkinson's disease (PD). As DJ-1, Parkin, and PINK1 have functions in the regulation of mitochondria, the dataset generated here highlights protein expression changes, which can be helpful for understanding pathological mitochondrial alterations. In total, 1281 proteins were quantified and 25, 37, and 15 proteins were found to exhibit differential expression due to DJ-1, Parkin, and PINK1 deficiency, respectively. All quantification can be found in the supplemental table and can be searched online at http://genome.unmc.edu/mitorat/index.html. Further, mitochondrial respiration was measured to evaluate mitochondrial function in the striatum of DJ-1, Parkin, and PINK1 KO rats, which was significantly changed only in the DJ-1 KOs. PMID- 27761516 TI - The data of GDP and exchange rate used in the Balassa-Samuelson hypothesis. AB - This article introduces the data of the log real GDP per capita ratio and the log real exchange rate which are used to revisit the Balassa-Samuelson Hypothesis. We acquired the data from IMF and World Bank database, and provide the name and source of the data. All data are openly accessible. Besides, we describe the value of data as well as the method to process the data which can also be found in "The Balassa-Samuelson Hypothesis in the developed and developing countries revisited" (Weiguo Wang, Jing Xue, Chonghua Du, 2016) [1]. PMID- 27761517 TI - Evaluating pH in the Extracellular Tumor Microenvironment Using CEST MRI and Other Imaging Methods. AB - Tumor acidosis is a consequence of altered metabolism, which can lead to chemoresistance and can be a target of alkalinizing therapies. Noninvasive measurements of the extracellular pH (pHe) of the tumor microenvironment can improve diagnoses and treatment decisions. A variety of noninvasive imaging methods have been developed for measuring tumor pHe. This review provides a detailed description of the advantages and limitations of each method, providing many examples from previous research reports. A substantial emphasis is placed on methods that use MR spectroscopy and MR imaging, including recently developed methods that use chemical exchange saturation transfer MRI that combines some advantages of MR spectroscopy and imaging. Together, this review provides a comprehensive overview of methods for measuring tumor pHe, which may facilitate additional creative approaches in this research field. PMID- 27761518 TI - Pilot and Feasibility Test of a Mobile Health-Supported Behavioral Counseling Intervention for Weight Management Among Breast Cancer Survivors. AB - BACKGROUND: Health behavior and weight management interventions for cancer survivors have the potential to prevent future cancer recurrence and improve long term health; however, their translation can be limited if the intervention is complex and involves high participant burden. Mobile health (mHealth) offers a delivery modality to integrate interventions into daily life routines. OBJECTIVE: The objective of this study was to evaluate the effects of a one-group trial with a pre-post evaluation design on engagement (use and acceptability), physiological (weight), behavioral (diet and physical activity), and other secondary outcomes. METHODS: The 10-week intervention consisted of mHealth components (self monitoring of selected diet behaviors via daily text messages, wireless devices to automatically track weight and steps) and 4 motivational interviewing-based technology-assisted phone sessions with a nonprofessionally trained counselor. Participants were overweight breast cancer survivors who had completed treatment and owned a smartphone. Weight was measured objectively; diet and physical activity were measured with brief self-reported questionnaires. RESULTS: Ten women participated; they had a mean age of 59 years (SD 6), 50% belonged to a racial or ethnic minority group, 50% had some college or less, and 40% reported using Medicaid health insurance. Engagement was high: out of 70 days in total, the mean number of days recording steps via the wristband pedometer was 64 (SD 7), recording a weight via the scale was 45 (SD 24), and responding to text messages was 60 (SD 13); 100% of participants completed all 4 calls with the counselor. Most (90%) were very likely to participate again and recommend the program to others. Mean weight in pounds decreased (182.5 to 179.1, mean change 3.38 [SD 7.67]), fruit and vegetable daily servings increased (2.89 to 4.42, mean change 1.53 [SD 2.82]), and self-reported moderate physical activity increased in metabolic equivalent of task (MET) minutes per week (2791 to 3336, mean change 545 [SD 1694]). CONCLUSIONS: Findings support the conduct of a fully powered trial to evaluate the efficacy of mHealth as a feasible intervention modality for breast cancer survivors. Future research should employ accelerometer-based physical activity assessment and consider development of an all-in-one app to integrate devices, messaging, and educational content and other mHealth approaches to support behavioral counselors conducting weight management interventions. PMID- 27761520 TI - Assessing Stigma among African Americans Living with HIV. AB - PURPOSE: In the present study, we validated a culturally adapted stigma scale designed to assess stigma among African Americans living with HIV. METHODS: We collected data on the scale using an audio computer assisted self-interview (ACASI) format. We validated the scale with a sample of 62 African American participants living with HIV. RESULTS: Findings demonstrated that stigma can be measured succinctly and effectively in a 14-item scale with two subscales measuring enacted and internalized stigma. DISCUSSION: We identified many advantages to using the scale, which demonstrated good psychometric properties when used with an audio computer assisted self-interview format and with an African American sample. We recommend this scale's use in both clinical practice and research study of HIV-stigma reduction interventions with African American populations. PMID- 27761521 TI - The Self-Stigma Process in Criminal Offenders. AB - Upon conviction, individuals receive the stigmatizing label "criminal offender." Existing stereotypes about criminal offenders may be integrated into the self concept, a phenomenon known as self-stigma. In many stigmatized groups, self stigma is a robust predictor of poor functioning (Livingston & Boyd, 2010; Schomerus et al., 2011). However, little is known about how self-stigma occurs (Corrigan et al., 2006), and there has been limited research with criminal offenders. This study examines a theoretical model of self-stigma in which perceived stigma leads to stereotype agreement, internalized stigma, and then to anticipated stigma. A sample of 203 male jail inmates completed assessments of these constructs just prior to release. Results show a significant indirect path from perceived stigma to stereotype agreement to internalized stigma, but not to anticipated stigma. However, perceived stigma was directly related to anticipated stigma. In conclusion, perceived stigma affects the self through two processes: it indirectly leads to internalized stigma through one avenue, and directly leads to anticipated stigma through a separate avenue. Race, criminal identity, and attitudes toward criminals were examined as moderators. PMID- 27761519 TI - The Largest Response Component in the Motor Cortex Reflects Movement Timing but Not Movement Type. AB - Neural activity in monkey motor cortex (M1) and dorsal premotor cortex (PMd) can reflect a chosen movement well before that movement begins. The pattern of neural activity then changes profoundly just before movement onset. We considered the prediction, derived from formal considerations, that the transition from preparation to movement might be accompanied by a large overall change in the neural state that reflects when movement is made rather than which movement is made. Specifically, we examined "components" of the population response: time varying patterns of activity from which each neuron's response is approximately composed. Amid the response complexity of individual M1 and PMd neurons, we identified robust response components that were "condition-invariant": their magnitude and time course were nearly identical regardless of reach direction or path. These condition-invariant response components occupied dimensions orthogonal to those occupied by the "tuned" response components. The largest condition-invariant component was much larger than any of the tuned components; i.e., it explained more of the structure in individual-neuron responses. This condition-invariant response component underwent a rapid change before movement onset. The timing of that change predicted most of the trial-by-trial variance in reaction time. Thus, although individual M1 and PMd neurons essentially always reflected which movement was made, the largest component of the population response reflected movement timing rather than movement type. PMID- 27761522 TI - Outdated risk assessment in a family with Duchenne dystrophy: Implications for duty to reassess. AB - Carrier risk assessment for Duchenne muscular dystrophy (DMD) is necessary to counsel women at risks of developing cardiomyopathy and having a child with DMD. Comprehensive molecular testing for dystrophin gene mutations has only been available since 20031; women counseled earlier have outdated risk assessments. We present a 5-generation family in whom results of familial mutation testing for DMD newly identified 10 obligate carriers and 28 women at risk to be carriers for DMD. PMID- 27761523 TI - Reassessing carrier status for dystrophinopathies. AB - The cloning of the DMD gene, and the identifications of mutations in it as the cause of Duchenne muscular dystrophy (DMD), makes a compelling story that is aptly told elsewhere.1 The locus-the largest in the human genome-consists of 79 exons, distributed over 2.5 million nucleotides on the X chromosome, which are assembled into a complementary DNA (cDNA) of around 14 kb encoding the predominant muscle isoform of the dystrophin protein.2 The size of the gene, and the number of exons, had historically made mutation analysis challenging. For more than a decade, the standard clinical assay was a multiplex PCR test that amplified sequences from a limited number of exons; nevertheless, because it included exons within the deletion hotspots of the gene, this method could confirm the presence of mutations in up to 98% of boys with exonic deletions.3,4. PMID- 27761524 TI - An Analysis of and Recommendations for the Peruvian Blood Collection and Transfusion System. AB - BACKGROUND: Peru experienced a crisis in its blood collection and supply system in the mid-2000s, as contaminated blood led to several transfusion-transmitted infections (TTI), occurring in the backdrop of extremely low voluntary donation rates and a national blood supply shortage. Thus, the Peruvian Ministry of Health (MINSA) implemented a national investigation on the safety and quality of the Peruvian blood collection/transfusion network. METHODS: Every Peruvian blood bank was evaluated by MINSA from 2007-2008. These evaluations consisted of an update of the national registry of blood banks and visits to each blood bank from MINSA oversight teams. Information was collected on the condition of the blood bank personnel, equipment, supplies, and practices. Further, previously-collected blood at each blood bank was randomly selected and screened for TTI-causing pathogens. RESULTS: Uncovered in this investigation was a fragmented, under equipped, and poorly-staffed blood collection and transfusion network, consisting of 241 independent blood banks and resulting in suboptimal allocation of resources. Further, blood with evidence of TTI-causing pathogens (including Hepatitis B, Hepatitis C, and syphilis) and set for transfusion was discovered at three separate blood banks as part of the random screening process. CONCLUSION: Using the successful reorganizations of national blood supply systems in other Latin American countries as examples, Peru would be well-served to form large, high-volume, regional blood collection and transfusion centers, responsible for blood collection and screening for the entire country. The small, separate blood banks would then be transformed into a network of blood transfusion centers, not responsible for blood collection. This reorganization would allow Peru to better utilize its resources, standardize the blood collection and transfusion process, and increase voluntary donation, resulting in a safer, more abundant national blood product. PMID- 27761526 TI - Multifunctional single-layered vesicles derived from Cu(ii)-metal-organic polyhedra. AB - Cu(ii) metal-organic-polyhedra (MOP) derived from a tris-pyridyl ligand gave stable single-layered vesicles capable of encapsulating an anti-cancer drug (doxorubicin - DOX) and its pH responsive release. While encapsulation of DOX was further confirmed by MTT assay and cellular imaging, alpha-chymotrypsin inhibition assay corroborated well with the single crystal structures of the MOP. The MOP derived vesicles reported herein not only represent the rare examples of such hierarchical architectures derived from MOP but also provide the first example of multifunctional organic-inorganic synthetic bio-membranes. PMID- 27761525 TI - A simple check valve for microfluidic point of care diagnostics. AB - Check valves are often essential components in microfluidic devices, enabling automated sample processing for diagnostics at the point of care. However, there is an unmet need for a check valve design that is compatible with rigid thermoplastic devices during all stages of development-from initial prototyping with a laser cutter to final production with injection molding. Here, we present simple designs for a passive, normally closed check valve that is manufactured from commonly available materials with a CO2 laser and readily integrated into prototype and production thermoplastic devices. The check valve consists of a thermoplastic planar spring and a soft elastomeric pad that act together to seal against fluid backflow. The valve's cracking pressure can be tuned by modifying the spring's planar geometry and thickness. Seal integrity is improved with the addition of a raised annular boss beneath the elastomeric pad. To demonstrate the valve's usefulness, we employ these valves to create a finger-operated on-chip reagent reservoir and a finger-actuated pneumatic pump. We also apply this check valve to passively seal a device to enable portable detection of RNA from West Nile virus in a laser-cut device. PMID- 27761527 TI - Cu(ii)/Cu(0)@UiO-66-NH2: base metal@MOFs as heterogeneous catalysts for olefin oxidation and reduction. AB - Two copper-loaded MOF materials, namely Cu(ii)@Ui-O-66-NH2 (1) and Cu(0)@UiO-66 NH2 (2), are reported. They can, respectively, serve as highly efficient heterogeneous catalysts for olefin oxidation and hydrogenation under mild conditions. Complete styrene hydrogenation occurs in 15 min at ambient temperature with quantitative yield. PMID- 27761528 TI - Bimodal self-assembly of an amphiphilic gelator into a hydrogel-nanocatalyst and an organogel with different morphologies and photophysical properties. AB - We design a flexible, amphiphilic LMWG consisting of donor and acceptor pi chromophores which self-assembles into a hydrogel and an organogel with different nano-morphologies. Different mechanisms of self-assembly evolve charge transfer (CT) emission in the hydrogel and LMWG-based emission in the organogel. Moreover, the hydrogel-nanostructure with surface exposed amide groups is explored for catalyzing Knoevenagel condensation reaction. PMID- 27761529 TI - Unconventional micro-/nanofabrication technologies for hybrid-scale lab-on-a chip. AB - Micro-/nanofabrication-based lab-on-a-chip (LOC) technologies have recently been substantially advanced and have become widely used in various inter /multidisciplinary research fields, including biological, (bio-)chemical, and biomedical fields. However, such hybrid-scale LOC devices are typically fabricated using microfabrication and nanofabrication processes in series, resulting in increased cost and time and low throughput issues. In this review, after briefly introducing the conventional micro-/nanofabrication technologies, we focus on unconventional micro-/nanofabrication technologies that allow us to produce either in situ micro-/nanoscale structures or master molds for additional replication processes to easily and conveniently create novel LOC devices with micro- or nanofluidic channel networks. In particular, microfabrication methods based on crack-assisted photolithography and carbon-microelectromechanical systems (C-MEMS) are described in detail because of their superior features from the viewpoint of the throughput, batch fabrication process, and mixed-scale channels/structures. In parallel with previously reported articles on conventional micro-/nanofabrication technologies, our review of unconventional micro-/nanofabrication technologies will provide a useful and practical fabrication guideline for future hybrid-scale LOC devices. PMID- 27761531 TI - Thermally rearranged (TR) bismaleimide-based network polymers for gas separation membranes. AB - Highly permeable, thermally rearranged polymer membranes based on bismaleimide derivatives that exhibit excellent CO2 permeability up to 5440 Barrer with a high BET surface area (1130 m2 g-1) are reported for the first time. In addition, the membranes can be easily used to form semi-interpenetrating networks with other polymers endowing them with superior gas transport properties. PMID- 27761530 TI - Spatial assessment of soil nitrogen availability and varying effects of related main soil factors on soil available nitrogen. AB - To effectively understand the availability of soil nitrogen and assist in soil nitrogen control at the regional scale, it is essential to understand the accurate spatial distribution patterns of the three soil nitrogen parameters [i.e., total nitrogen (TN), available nitrogen (AN) and nitrogen availability ratio (NAR)] and explore the spatially varying influences of major impact factors on soil AN. Land use affects the spatial distributions of soil TN, AN and NAR (i.e., AN/TN). To explore the effects of different land use types and improve mapping accuracy, residual kriging with land use information and ordinary kriging (without land use information) were compared based on the sample data of soil TN and AN in Hanchuan county, China. A local regression technique, geographically weighted regression (GWR), was adopted to explore the varying relationships between soil AN and its major impact factors in soil (i.e., soil TN and soil pH), due to the advantages of GWR over the traditional ordinary least squares regression (OLS) model. The results showed that (1) land use types as auxiliary information obviously improved the prediction accuracies of the three soil nitrogen parameters; (2) GWR performed much better than OLS in terms of fitting accuracy; and (3) GWR effectively revealed the spatially varying influences of the impact factors on soil AN, which were ignored by OLS. Based on the results, suggestions for soil nitrogen control measures in different subareas were proposed. PMID- 27761532 TI - Octahedral Werner complexes with substituted ethylenediamine ligands: a stereochemical primer for a historic series of compounds now emerging as a modern family of catalysts. AB - As reported by Alfred Werner in 1911-1912, salts of the formally D3 symmetric [Co(en)3]3+ (en = ethylenediamine) trication were among the first chiral inorganic compounds to be resolved into enantiomers, the absolute configurations of which are denoted Lambda (left handed helix) or Delta (right handed helix). After a >100 year dormant period during which few useful reactions of these substitution inert complexes were described, carbon substituted derivatives have recently been found to be potent catalysts for enantioselective organic synthesis. This review systematically outlines the fascinating range of stereoisomers that can arise, such as conformers associated with the five membered chelate rings (lambda/delta), alignment modes of the C-C bonds with the C3 symmetry axis (lel/ob), geometric isomers (fac/mer), and configurational diastereomers (R/S) arising from carbon stereocenters. These analyses demonstrate a profound stereochemical diversity that can be applied in catalyst optimization. Efforts are made to bridge the often orthogonal nomenclature systems inorganic and organic chemists employ to describe these phenomena. PMID- 27761533 TI - Reduction of hypervalent iodine by coordination to iron(iii) and the crystal structures of PhIO and PhIO2. AB - The iodine L3-edge X-ray Absorption Near Edge Structure (XANES) of organic and inorganic iodine compounds with formal iodine oxidation states ranging from -1 to +7 shows edge energies spanning from 4560.8 eV to 4572.5 eV. These were used to calibrate the oxidation state of iodine in a unique iron complex of iodosylbenzene (PhIO), [Fe(tpena)OIPh]2+ (tpena- = N,N,N'-tris(2 pyridylmethyl)ethylenediamine-N'-acetate), which was found to be +1.6. Thus the iodine oxidation state is reduced by 1.4 compared with that in precursor uncoordinated PhIO. On the basis of a combination of X-ray diffraction and Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy, we have determined the unknown crystal structure of PhIO, along with a new phase of iodylbenzene (beta-PhIO2) using the Rietveld method. Analogous 1-D chains of halogen bonded [O IO-I] motifs are the dominant supramolecular interactions between PhIO and PhIO2 monomers in each structure respectively and the polymeric structures rationalise the general insolubility of these oxygen atom transfer reagents. A double stack of phenyl units in PhIO is found between the layers of the halogen bonded O/I chains. In the case of PhIO, C-Hpi interactions between adjacent phenyl groups result in the alternate phenyl groups lying in parallel planes. Supplementing the strong polymerizing halogen bonds, this supramolecular interaction must exacerbate the insolubility of PhIO. The pillared structure of the new rhombohedral beta-PhIO2 differs significantly from the known monoclinic lamellar phase, alpha-PhIO2, described 36 years ago in which the chains form lamellar stacks [N. W. Alcock and J. F. Sawyer, J. Chem. Soc., Dalton Trans., 1980, 115 120]. PMID- 27761534 TI - A chemical-structural model for coherent martensite/parent interface in Mn-based antiferromagnetic shape memory alloys. AB - The martensite/parent coherent interface of Mn-based shape memory alloys (SMAs) is a significant part in the research of their martensitic transformation, reversible shape memory effect and magnetic shape memory effect. In the present work, a chemical-structural model was proposed to calculate the martensite/parent coherent interfacial energy of Mn-X (X = Cu, Fe) alloys. In this model, the coherent heterophase interfacial energy consists of chemical and structural parts. Resulting from the formation process of the heterophase interface, the chemical interfacial energy is expressed as the incremental value of bond energy, while the structural part is obtained by calculating the interfacial strain energy. The results show that the structural interfacial energy plays the chief role in the total interfacial energy, and the total interfacial energy decreases as the temperature rises when the alloy composition is fixed. In addition, the preferred orientation has noteworthy influence on the total interfacial energy. Using the proposed model, interfacial energy, interfacial entropy, interfacial enthalpy and interfacial heat capacity are found to be correlated with temperature and interface preferred orientation. Furthermore, the influences of alloy composition, modulus softening, and the index of the habit plane on the results were discussed. PMID- 27761535 TI - Detection of an explosive simulant via electrical impedance spectroscopy utilizing the UiO-66-NH2 metal-organic framework. AB - Electrical impedance spectroscopy, in conjunction with the metal-organic framework (MOF) UiO-66-NH2, is used to detect trace levels of the explosive simulant 2,6-dinitrotoluene. The combination of porosity and functionality of the MOF provides an effective dielectric structure, resulting in changes of impedance magnitude and phase angle. The promising data indicate that MOFs may be used in low-cost, robust explosive detection devices. PMID- 27761536 TI - Highly efficient blue solid emitters and tautomerization-induced ON/OFF fluorescence switching based on structurally simple 3(5)-phenol-1H-pyrazoles. AB - 3(5)-Phenyl-1H-pyrazoles are employed in this study to develop highly efficient organic crystalline solids with deep-blue ESIPT fluorescence as well as provide novel experimental insight into the mechanism of ESIPT fluorescence and generate an intriguing fluorescence "ON/OFF" switching. PMID- 27761537 TI - Oligo(aryl-triazole)s CHCl- interactions guide chloride efficient and selective transmembrane transport. AB - A series of oligo(aryl-triazole)s (compounds 1-8) have been synthesized and served as transmembrane anion transporters by only CHCl- interactions. This work confirms their role in the activity of anion transport. By changing the lipophilicity and anion affinity of the compounds, efficient anion transport with remarkable Cl-vs. HCO3- selectivity was achieved. PMID- 27761538 TI - A process to enhance the specific surface area and capacitance of hydrothermally reduced graphene oxide. AB - The impact of post-synthesis processing in reduced graphene oxide materials for supercapacitor electrodes has been analyzed. A comparative study of vacuum, freeze and critical point drying was carried out for hydrothermally reduced graphene oxide demonstrating that the optimization of the specific surface area and preservation of the porous network are critical to maximize its supercapacitance performance. As described below, using a supercritical fluid as the drying medium, unprecedented values of the specific surface area (364 m2 g-1) and supercapacitance (441 F g-1) for this class of materials have been achieved. PMID- 27761539 TI - First-principles study of relative stability of rutile and anatase TiO2 using the random phase approximation. AB - The relative stability of TiO2 in the rutile and anatase structure is wrongly described by density functional theory in various local, semilocal, or even hybrid functional approximations. In this work, we have found that by considering high-order correlations in the adiabatic connection fluctuation-dissipation theory with the random phase approximation (ACFDT-RPA), rutile is correctly predicted to be more stable than anatase, which can be physically attributed to different characters in the electronic band structure of rutile and anatase, including, in particular, that rutile has a smaller band gap than anatase. We further consider the zero-point energy and finite-temperature effects based on the harmonic approximation, and we found that the inclusion of the zero-point energy correction can further increase the relative stability of rutile, and leads to a better quantitative agreement with available experimental measurements. Our study indicates the importance of considering high-order dynamical correlation effects to correctly predict the relative phase stability of polymorphic materials, especially for those systems in which the less stable phase as predicted by conventional local, semilocal or even hybrid density functional approximations has a smaller band gap than the more stable one. PMID- 27761540 TI - Dehydrative condensation of carbonyls with non-acidic methylenes enabled by light: synthesis of benzofurans. AB - Condensation of carbonyls with non-acidic methylenes such as those adjacent to heteroatoms and allylic types to generate C[double bond, length as m-dash]C bonds is challenging but highly desirable. Inventing novel methods that can accomplish such condensations can enrich synthetic chemists' toolbox. Herein, we report a simple, clean, and high yielding protocol promoted by light to achieve condensation of non-acidic methylenes with carbonyls. As examples to demonstrate the power of this methodology, one class of ubiquitous and highly important heterocycles, i.e. benzofurans, were synthesized with broad functional group compatibility. Furthermore, intermolecular condensations were also briefly investigated. PMID- 27761541 TI - A series of robust metal-porphyrinic frameworks based on rare earth clusters and their application in N-H carbene insertion. AB - We herein report a series of microporous metal-porphyrinic frameworks (MPFs), denoted as NUPF-2M, based on rare earth (RE) clusters. NUPF-2M represent the first examples of RE cluster-based MPFs, possessing a rarely seen shp-a topology and exhibiting high thermal and thermal stabilities. After a post-metallization process with FeCl3, NUPF-2M is catalytically active as an efficient heterogeneous catalyst for intermolecular N-H carbene insertion. PMID- 27761542 TI - Concluding remarks: single entity electrochemistry one step at a time. AB - This article provides a summary of the Faraday Discussion on single entity electrochemistry held in York, U.K., in early September, 2016. The introduction provides some context for thinking about electrochemical studies of single entities. The next four sections follow the themes of the meeting as they relate to single-entity electrochemistry: (1) nanoparticles, nanotubes, and nanowires; (2) nanopores and nanofluidics; (3) complex surfaces and reactions at the nanoscale; and (4) molecular electroanalysis. Each paper presented at the Discussion is summarized, and some personal thoughts as to the significance of the findings, the technical advances that made the experiments possible, and common themes between articles are interspersed. Finally, at the end, I round-up my impressions and provide them in a succinct list. PMID- 27761543 TI - Maximizing the health effects of strawberry anthocyanins: understanding the influence of the consumption timing variable. AB - Strawberries, rich in anthocyanins, attenuate meal-induced postprandial increases in inflammation and oxidative stress as well as improved post-meal insulin responses. While previous studies have focused on the health effects of strawberry consumption ingested with a meal, this study aimed to determine if consuming strawberries at alternative times near a meal would influence meal induced oxidative-immuno-metabolic outcomes. Fourteen overweight healthy adults participated in a 3-arm, single-blinded, crossover clinical trial delivering a strawberry drink at 1 of 3 different time points: 2 hours before a standard meal, with the meal, or 2 hours after the meal. Control drinks were provided at the alternative time points so that 3 drinks were consumed at each study visit. Blood samples were collected over 10 h. Comparisons of plasma analytes were between strawberry "timing" groups and secondarily with a demographically matched reference group that ingested only control drinks (no strawberry). The study results showed significant reduction in postprandial glucose when strawberry was consumed before the meal compared to having the strawberry drink with the meal, p < 0.05. Compared to the reference group, consuming strawberries before and after the meal attenuated postprandial glucose without additional insulin, suggesting improved insulin sensitivity. Interleukin-6 was significantly lower after consuming the strawberry drink before the meal (p = 0.048) compared to the reference group. This study provides data suggesting that strawberries have a role in glycemic control and attenuating the pro-inflammatory effect of a modern diet. There may be particular advantages when strawberries are consumed before a meal. PMID- 27761544 TI - Rb2SeOCl4.H2O: a polar material among the alkali metal selenite halides with a strong SHG response. AB - An alkali metal selenite chloride, Rb2SeOCl4.H2O, has been hydrothermally synthesized and structurally characterized. It is the first example of an alkali metal selenite halide in the literature. The compound crystallizes in the noncentrosymmetric (NCS) space group, Cmc21(36), of the orthorhombic system with a = 10.342(3) A, b = 10.124(3) A, c = 9.158(3) A, and alpha = beta = gamma = 90 degrees . The anionic [SeOCl4]2- groups are arranged in the crystal in nearly the same direction, giving rise to a relatively large macroscopic dipole moment, causing the compound to display second harmonic generation (SHG) eight times as strong as that of KDP, measured using the Kurtz-Perry method on powders. First principle density functional theory (DFT) calculations were carried out to interpret the relationship between the crystal structure and properties. PMID- 27761546 TI - A significant enhancement of color transition from an on-off type achromatic colorimetric nanosensor for highly sensitive multi-analyte detection with the naked eye. AB - Here, we report the development of an achromatic nanoparticle-based colorimetric sensor (achromatic nanosensor) with an on-off type color change that significantly enhances the color transition and increases the sensitivity of the sensor for naked-eye inspection. The achromatic nanosensor was prepared via a modified CMYK (CRYK) subtractive color model by combining DNA-functionalized gold nanoparticles (AuNPs-DNA), silver nanoparticles (AgNPs-DNA), and gold nanorods (AuNRs-DNA). The initially black-colored achromatic nanosensor not only allowed multiplexed detection by generating target-specific diverse color changes, but also improved the recognition of color changes by the naked eye. Thus, this on off type color change enabled analysis near the limit of detection (LOD) with the naked eye. In addition, we developed a new image processing method adapted for this achromatic sensor. By quantifying the saturation value of the color images of the achromatic sensor, we could significantly amplify the color signal of the samples, which is difficult to achieve with general colorimetric sensors. The practical application of this achromatic nanosensor for biomarker detection was demonstrated with thrombin and platelet-derived growth factor (PDGF) in human blood plasma. These results provide a new sensing platform that is applicable to most NP-based colorimetric sensing systems for a wide range of applications, including biomolecular diagnosis, chemical pollutant sensing, environmental monitoring, etc. PMID- 27761549 TI - Complexation between a triptycene-derived oxacalixarene and pi-extended viologens: linker-length-dependent orientation of the macrocycles in pseudo[3]rotaxanes. AB - With an expanded electron-rich cavity and a fixed conformation, macrocycle H was found to encapsulate pi-extended viologens G1-G4 to form the first case of pseudo[3]rotaxanes based on oxacalixarenes. The complexation was investigated in detail both in solution and in the solid state using NMR spectroscopy and X-ray crystallography. Due to the three-dimensional nonsymmetric structure of H, three orientational isomers of the pseudorotaxanes could be expected theoretically. However, as the crystal structure analysis revealed, only one of the three isomers was obtained with either G1 or G3. Moreover, with regard to the different lengths of the linkers in the guest molecules, completely opposite orientations of the macrocycles on the axles were observed, which could be explained by different complexation modes between the components in the pseudo[3]rotaxanes. Additionally, the complexation between the host and the guest could be reversibly switched on and off using a suitable acid and base. These results will provide us with the opportunity to design and elaborately regulate high-order molecular devices. PMID- 27761550 TI - Fabrication of zero to three dimensional nanostructured molybdenum sulfides and their electrochemical and photocatalytic applications. AB - Transition metal dichalcogenides (TMDs) are emerging as promising materials, particularly for electrochemical and photochemical catalytic applications, and among them molybdenum sulfides have received tremendous attention due to their novel electronic and optoelectronic characteristics. Several review articles have summarized the recent progress on TMDs but no critical and systematic summary exists about the nanoscale fabrication of MoS2 with different dimensional morphologies. In this review article, first we will summarize the recent progress on the morphological tuning and structural evolution of MoS2 from zero-dimension (0D) to 3D. Then the different engineering methods and the effect of synthesis conditions on structure and morphology of MoS2 will be discussed. Moreover, the corresponding change in the electronic and physicochemical properties of MoS2 induced by structure tuning will also be presented. Further, the applications of MoS2 in various electrochemical systems e.g. hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), oxygen evolution reaction (OER) and supercapacitors as well as photocatalytic hydrogen evolution will be highlighted. The review article will also critically focus on challenges faced by researchers to tune the MoS2 nanostructures and the resulting electrochemical mechanism to enhance their performances. At the end, concluding remarks and future prospects for the development of better MoS2 based nanostructured materials for the aforementioned applications will be presented. PMID- 27761545 TI - Stiffness of pancreatic cancer cells is associated with increased invasive potential. AB - Metastasis is a fundamentally physical process in which cells are required to deform through narrow gaps as they invade surrounding tissues and transit to distant sites. In many cancers, more invasive cells are more deformable than less invasive cells, but the extent to which mechanical phenotype, or mechanotype, can predict disease aggressiveness in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here we investigate the invasive potential and mechanical properties of immortalized PDAC cell lines derived from primary tumors and a secondary metastatic site, as well as noncancerous pancreatic ductal cells. To investigate how invasive behavior is associated with cell mechanotype, we flow cells through micron-scale pores using parallel microfiltration and microfluidic deformability cytometry; these results show that the ability of PDAC cells to passively transit through pores is only weakly correlated with their invasive potential. We also measure the Young's modulus of pancreatic ductal cells using atomic force microscopy, which reveals that there is a strong association between cell stiffness and invasive potential in PDAC cells. To determine the molecular origins of the variability in mechanotype across our PDAC cell lines, we analyze RNAseq data for genes that are known to regulate cell mechanotype. Our results show that vimentin, actin, and lamin A are among the most differentially expressed mechanoregulating genes across our panel of PDAC cell lines, as well as a cohort of 38 additional PDAC cell lines. We confirm levels of these proteins across our cell panel using immunoblotting, and find that levels of lamin A increase with both invasive potential and Young's modulus. Taken together, we find that stiffer PDAC cells are more invasive than more compliant cells, which challenges the paradigm that decreased cell stiffness is a hallmark of metastatic potential. PMID- 27761554 TI - To what extent should dental implant placement be adopted as a standard for diabetic patients? AB - Diabetes mellitus (DM) is considered one of the major chronic diseases in the world. Long-term hyperglycemia considerably affects the body tissues, and consequently, can lead to morbidity and mortality. Moreover, many oral complications have been observed with DM but little consideration in relation to the placement of dental implants has been investigated. Dental research has analyzed the relation of dental implants and bone osseointegration in diabetic patients. Theoretically, an impaired immune system and delayed wound healing of these patients might decrease the success rate of implant placement; however, with noticeable advances in evidence-based dentistry and statistically significant results, successful implant treatment could be achieved significantly in well-controlled diabetic patients. PMID- 27761555 TI - Erlotinib for advanced hepatocellular carcinoma. A systematic review of phase II/III clinical trials. AB - OBJECTIVES: To evaluate the efficacy and safety of erlotinib for the treatment of advanced hepatocellular carcinoma (HCC). METHODS: A systematic literature search was undertaken in June 2015. Phase II/III trials of erlotinib for the treatment of advanced HCC were included. A descriptive analysis was applied. The study was conducted in College of Medicine, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China, between June 2015 and January 2016. RESULTS: Ten trials, comprising 9 phase II and one phase III trial, were included in the systematic review. The tumor response rate was 0% in 4 of the phase II trials, less than 10% in 3 of the phase II trials and the phase III trial, and greater than 20% in 2 of the phase II trials. The disease control rate was 42.5-79.6% in most studies. Three studies reported a median progression-free survival (PFS) of 6.5-9.0 months, although PFS was less than 3.5 months in most studies. Most trials reported a median overall survival of 6.25-15.65 months. The most frequent grade 3/4 toxicities were fatigue (11.9%), diarrhea (10%), increased alanine and aspartate transaminases (7.3%), and rash/desquamation (6.9%). Conclusion: Erlotinib provides efficacious and well-tolerated treatment for advanced HCC. However, more detailed investigations of HCC pathogenesis and evaluation of sensitive patient subsets are needed to improve outcomes of patients with advanced HCC. Additional well designed, randomized, controlled trials are needed to evaluate the efficacy and safety of erlotinib as monotherapy or combination with other drugs for advanced HCC. PMID- 27761556 TI - Alfentanil versus ketamine combined with propofol for sedation during upper gastrointestinal system endoscopy in morbidly obese patients. AB - OBJECTIVES: To observe the effects of both propofol/alfentanil and propofol/ketamine on sedation during upper gastrointestinal system endoscopy in morbidly obese patients (UGSEMOP). METHODS: In a prospective, double-blinded, randomized clinical study, 52 patients scheduled for UGSEMOP were assigned to either group A (n=26; 10 ug/kg intravenous [IV] alfentanil) or group K (n=26; 0.5 mg/kg IV ketamine). Each patient was administered 0.7 mg/kg propofol for induction. If it was needed, the patients were administered an additional dose of IV propofol. This study was performed in Sehitkamil State Hospital, Gaziantep, Turkey, between January 2014-2015. Total propofol consumption, time to achieve Modified Aldrete Scores (MAS) of 5 and 10 following the procedure, physician and patient satisfaction scores, and instances of side effects, such as bradycardia and hypotension were recorded. Results: Time to onset of sedation and duration of sedation were both significantly shorter in group A. Patients in group A also required less time to achieve an MAS of 5. Total propofol consumption was significantly lower in group A. CONCLUSION: Both propofol/alfentanil and propofol/ketamine combinations provided appropriate hypnosis and analgesia during UGSEMOP. However, propofol consumption was significantly higher using the propofol/ketamine combination. PMID- 27761558 TI - A profile of out-of-hospital cardiac arrests in Northern Emirates, United Arab Emirates. AB - OBJECTIVES: To report the characteristics of out-of-hospital cardiac arrest patients and their outcomes in the emirates of Sharjah, Ras-al-Khaimah, Umm Al Quwain, Fujairah, and Ajman in the United Arab Emirates (collectively known as the Northern Emirates). Methods: This is a prospective descriptive cohort study of out-of-hospital cardiac arrest incidents transported by the national ambulance crews between February 2014 and March 2015 in the Northern Emirates. Results: A total of 384 patients were enrolled in this study. Male victims of out-of hospital cardiac arrest represented 76% of the participants. The mean age of the study population was 50.9 years. An over-all prehospital return of spontaneous circulation rate of 3.1% was documented, as well as a 30% rate of bystander cardiopulmonary resuscitation being performed. Public access defibrillators were applied in 0.5% of cases. Data is presented according to Utstein reporting criteria. Conclusion: Baseline data for out-of-hospital cardiac arrest was established for the first time in the Northern Emirates of the United Arab Emirates. A low survival rate for out-of-hospital cardiac arrest, low rates of bystander cardiopulmonary resuscitation, and low public access defibrillator use were discovered. Although low by comparison to established western systems results are similar to other systems in the region. Determining the baseline data presented in this study is essential in recommending and implementing strategies to reduce mortality from out-of-hospital cardiac arrest. PMID- 27761557 TI - Safety and efficacy of transthoracic versus transesophageal echocardiography in transcatheter closure of atrial septal defects. Reporting a single center experience from Saudi Arabia. AB - OBJECTIVES: To assess the safety and effectiveness of transthoracic echocardiography (TTE) in monitoring transcatheter closure of atrial septal defect (ASD), in comparison with conventional technique using transesophageal echocardiography (TEE). Methods: A retrospective review of all cases of transcatheter closure of isolated ostium secundum ASDs operated from 2005 to 2015, at the Pediatric Interventional Cardiology Department, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. Exclusion criteria included age <=3 years at the time of the procedure and rim size <=3 mm. Patients were divided into 2 groups: TTE and TEE group. Demographic and clinical baseline data, procedure data, and outcomes were compared between the 2 groups. RESULTS: We included 77 cases: 45 in TTE group and 28 in TEE (mean +/- standard deviation age=8.18 +/- 5.85 versus 17.68 +/- 14.88), with no significant difference in ASD size, rim adequacy, or other anatomical difficulties. All (100%) patients in TEE group underwent general anesthesia, versus 8.9% in TTE group. Device deployment was comparably successful (97.8% versus 92.9%, p=0.554); while procedure time (76.27 +/- 31.80 versus 119.85 +/- 19.90 minutes, p less than 0.001) and fluoroscopy time (11.29 +/- 9.04 versus 18.73 +/- 11.54 minutes, p=0.003) were significantly reduced in TTE versus TEE. Prevalence of postprocedural complications was comparable in the 2 groups. Conclusion: Transthoracic echocardiography has non-inferior efficacy in device deployment with reference to TEE and superior safety features including significant reduction of procedure and fluoroscopy times and lesser use of general anesthesia. PMID- 27761559 TI - Lung cancer in Basrah, Iraq during 2005-2012. Incidence and time trend. AB - OBJECTIVES: To study the incidence rate of lung cancer and its time trend in Basrah during 2005-2012. METHODS: This was a cancer registry-based retrospective study including all Basrah inhabitant patients diagnosed with primary lung cancer during the period from January 2005 to December 2012. The crude incidence rate was calculated in addition to the age standardized incidence rate (ASIR)/100,000 using the world standard population. Results: Out of 746 registered cases of lung cancer in Basrah, 75.9% were males and 24.1% were females with a male: female gender ratio of 3.1:1. The crude incidence rate was 3.93/100,000 (5.89/100,000 for males and 1.93/100,000 for females). The ASIR was 8.25/100,000 (13.30/100,000 for males and 4.08/100,000 for females). The time trend showed a decrease in incidence rate in the last 2 years (2011 and 2012) compared with the preceding years. CONCLUSION: The incidence rate of lung cancer in Basrah did not differ greatly from that reported for some Arab and neighboring countries. No definite time trend could be identified apart from a tendency for the incidence rate to decline in 2011 and 2012. PMID- 27761560 TI - Tall Cell Variant Papillary Thyroid Carcinoma in Saudi Patients: A clinicopathological and Outcomes Analysis. AB - OBJECTIVES: To evaluate the clinicopathological features and treatment outcomes of papillary thyroid carcinoma tall cell variant (PTC-TCV) in Saudi population. Methods: This retrospective study were medical records of 776 treated PTC patients between December 2007 and 2015, at King Fahad Medical City and King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia was probed for PTC TCV. Total 42 (5.4%) patients were found to have PTC-TCV, which were investigated for demographic, symptoms, histopathological features, and treatment outcomes locoregional control (LRC), distant metastasis control (DMC), disease free survival (DFS), and overall survival (OS) rates. Results: Mean age of cohort was 52.3 years (range: 46-80), with female predominance (73.8%). Mean tumor size was 3.62 cm (range: 0.4-10). Rates of LVSI (59.5%), positive pathological lymph nodes (66.7%), multifocality (42.9%) and extrathyroidal extension, (45.3%). Median follow-up was 37.4 months (range: 6-60). Local recurrence rate were seen in 6/42 (14.2%) patients and 8/42 (19%) developed distant metastasis. The 5 year rates of LRC (82.3%), DMC (77.8%), DFS (69.2%), and OS (86.7%) multivariate analysis showed PTC-TVC as an important independent prognosticator (odds ratio: 4.2; 95% confidence interval: 1.79-7.3; p=0.03) Conclusion: Papillary thyroid carcinoma tall cell variant is associated with aggressive biological behavior. PMID- 27761561 TI - Low bone mineral density among young healthy adult Saudi women. Prevalence and associated factors in the age group of 20 to 36 years. AB - OBJECTIVES: To screen for low bone mineral density among young adult Saudi women using quantitative ultrasound (QUS) and exploring the high risk groups. Methods: A cross-sectional study was performed on 279, 20-36 years old female students and employees of Taibah University, Al Madinah Al Munawwarah, Kingdom of Saudi Arabia between January and May 2014. The study included bone status assessed using QUS, a structured self-reported questionnaire, anthropometric measurements, and evaluation of bone markers of bone metabolism. Results: The prevalence of low bone mineral density was 9%. Serum osteocalcin was found significantly higher in candidates with low bone mineral density, 20.67 ng/ml versus 10.7 ng/ml, and it was negatively correlated with T-scores. At any given point in time the exposed subjects to low calcium intake and inadequate sun exposure in the population were 11 times and 3 times more likely to have low bone mineral density, (adjusted odds ratio [OR], 11.0; 95%confidence interval [CI]=3.16, 38.34; p=0.001) and (adjusted OR, 3.32, 95%CI=1.27, 8.66, p less than 0.01). Conclusion: Early detection screening programs for low bone mineral density are needed in Saudi Arabia as it affects young Saudi women specially the high-risk group that includes young women with insufficient calcium intake and insufficient sun exposure. Serum osteocalcin as a biomarker for screening for low bone mineral density could be introduced. PMID- 27761562 TI - Diverse etiology of hyperlipidemia among hospitalized children in Western region of Saudi Arabia. AB - OBJECTIVES: To determine the various etiologies of primary and secondary hyperlipidemia among children visiting the pediatric endocrine clinic. Methods: This is a retrospective, cross-sectional, cohort study conducted at King Abdulaziz University Hospital (KAUH), Jeddah, Kingdom of Saudi Arabia from January 2010 to 2015 that included 253 children aged from birth to 12 years old. Data were obtained by reviewing medical reports of patients who presented with hyperlipidemia to the clinic, and their laboratory investigation results using KAUH electronic "Phoenix" system. Results: Of the 253 children who were reviewed, those who have shown to have abnormal lipid metabolism with nephrotic syndrome were 35.6%, diabetes mellitus 17.8%, primary/idiopathic hyperlipidemia 19.4%, hypothyroidism 7.1%, obesity 4.3%, metabolic syndrome 2.8%, chronic liver disease 2% and chronic renal failure 1.2%. The body mass index relative to gender and age in this group of children showed that 23.2% were underweight, 38.4% were normal weight, 8.9% were overweight, and 29.5% were obese. Conclusion: The highest prevalence of hyperlipidemia was in nephrotic syndrome, followed by primary/idiopathic hyperlipidemia and diabetes mellitus. PMID- 27761564 TI - Physical activity and major non-communicable diseases among physicians in Central Saudi Arabia. AB - OBJECTIVES: To evaluate levels of physical activity among physicians in Riyadh, Saudi Arabia and to study the possible factors affecting physical inactivity. In addition, the study aims to estimate the prevalence of major non-communicable diseases (NCDs) and a possible correlation between physical inactivity and major NCDs. Method: A cross-sectional approach was used for this study conducted on 370 randomly-selected outpatient physicians of both genders working at 4 leading healthcare institutions in Riyadh, Kindom of Saudi Arabia between December 2013 and January 2014. Using a modified World Health Organization (WHO) STEPwise questionnaire. Data was analyzed using the Statistical Package for Social Sciences version 21. Results: The findings of the present study demonstrated a prevalence of physical activity among Riyadh physicians (63%), which is higher than the general population (32.4%). The main reason for not engaging in physical activity was lack of time (58.1%) followed by work duties (22.5%). The prevalence of the most frequently reported NCDs (cardiovascular diseases, diabetes, chronic respiratory diseases, and cancers) was 21.9%. No significant association between physical inactivity and major NCDs among physicians in our sample was found. Conclusion: The participating physicians are physically active and suffer from a small percentage of the most reported NCDs. The main factor associated with physical inactivity was lack of time. No association was detected between physical inactivity and major NCDs. PMID- 27761563 TI - Effect of iron overload on renal functions and oxidative stress in beta thalassemia patients. AB - OBJECTIVES: To check the amount of cellular damage caused by serial transfusions of blood in thalassemia patients. Methods: A cross-sectional study was conducted in the University of Lahore, Lahore, Pakistan between August 2012 and December 2012. A total of 43 thalassemia patients underwent at least 10 blood transfusions. Comprehensive biochemical analysis of blood was performed to record the levels of creatinine, urea, uric acid, albumin, liver function tests, malondialdehyde (MDA), and ferritin. Results: Serum creatinine (0.732+/ 0.23mg/dl) and uric acid (6.7+/-0.94mg/dl, p less than 0.05) were significantly higher in patient groups as compared with the control. Ferritin levels were significantly higher in patients as compared with the control (3103.9+/-1747.4, p less than 0.05). Hemoglobin levels were observed in controls 14+/-1.3g/dl and in patients 7.1+/-1.03g/dl. No clear relationship exists between age and hematological parameters of thalassemic patients. Serum ferritin level is positively related with serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase and MDA (p less than 0.05). Conclusion: Serum MDA and serum ferritin of patients (r=0.593, p less than 0.05) reflects that both are crucial parameters estimating the cellular damage in patients suffering from thalassemia. PMID- 27761565 TI - Institute for Scientific Information-indexed biomedical journals of Saudi Arabia. Their performance from 2007-2014. AB - OBJECTIVES: To compare the journal impact factor (JIF) and Eigenfactor score (ES) of Institute for Scientific Information (ISI)-indexed biomedical journals published from the Kingdom of Saudi Arabia (KSA) over the last 8 years. Methods: This is a retrospective study, conducted at Alfaisal University, Riyadh, KSA from January to March 2016. The Journal Citation Reports of ISI Web of Knowledge were accessed, and 6 Saudi biomedical journals were included for analysis. Results: All Saudi journals have improved their IF compared with their baseline. However, the performance of the Journal of Pharmaceutical Sciences and Neurosciences has been exceptionally good. The biggest improvement in percent growth in JIF was seen in the Saudi Pharmaceutical Journal (approximately 887%) followed by Neurosciences (approximately 462%). Interestingly, the ES of all biomedical journals, except Saudi Journal of Gastroenterology and Saudi Medical Journal, increased over the years. The greatest growth in ES (more than 5 fold) was noted for Neurosciences and Saudi Pharmaceutical Journal. Conclusion: This study shows that the overall quality of all Saudi biomedical journals has improved in the last 8 years. PMID- 27761566 TI - Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation in Saudi Arabia. AB - Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare disease, but could be fatal if not diagnosed early. It mimics many other diseases and it may take few years after the onset of rapid obesity to have the other clinical features. Therefore, any patient with rapid-onset obesity after the age of 2 years should have high index of suspicion and long term follow up. We report a case of ROHHAD in Saudi Arabia and we highlight the clinical features and the importance of early diagnosis and management. PMID- 27761567 TI - An extraordinary case of syphilis presenting with a labial ulcer. AB - In the differential diagnosis of patients with ulcers on the lips characteristics like the duration of the ulcer, number, size, depth, shape, base, margins, and distribution are considered. Such ulcers arise from many diseases particularly, viral and bacterial infections, malignancies can also be responsible. Classic syphilitic chancres are painless erosions settled on hard papule; these are evident in the genital area in more than 90% of patients. This study describes a case of a 38-year-old female patient presenting with a painful ulcer covering 3 quarters of the upper lip showing settlement on erythematous, edematous, and indurated plaque covered with hemorrhagic crusts. The aim of this study was to consider differences between the classic syphilitic chancre typically found in the genital region from extragenital chancres and to raise awareness of the possibility of primary syphilis when patients present with painful ulcers on the lip. PMID- 27761568 TI - Adult onset Still's disease with dermatopathic lymphadenopathy. AB - Adult onset Still's disease (AOSD) is a chronic inflammatory disorder involving multiple systems. The symptoms mimic those of lymphomas, therefore, the diagnosis of lymphoma needs to be excluded prior to establishing the diagnosis of AOSD. Another similar condition is dermatopathic lymphadenopathy (DL). In DL, the histopathological appearance of lymph node biopsy may also mimic AOSD. The DL is associated with several systemic pathologies, such as malignant lymphomas, and rarely AOSD. We present a case of a 43-year-old male presented with 3 months history of fatigue, fever, and lymphadenopathy. Initial work-up satisfactorily met the criteria for diagnosis of AOSD. But considering the well-known association of DL with hematological malignancies, detailed pathological studies were considered, including tumor markers to rule out the possibility of malignancy. The patient was started on steroids and showed remarkable recovery within 2 weeks. Evaluation of malignant lymphomas in a patient with DL is important, in order to diagnose AOSD and rule out hematological malignancy. PMID- 27761569 TI - Distribution of various pathogenic bacteria from pediatric ward settings. AB - OBJECTIVES: To test various items in hospital environment as reservoirs of bacteria. Methods: This simple descriptive study was conducted between June and December 2014. Pediatric wards of 4 different hospitals of Faisalabad, Pakistan were selected and 8 different items per hospital were sampled (n=160). Poisson regression analysis was carried out with R software and using lme4 package. Results: There were no differences between the hospitals regarding total number of bacterial isolates or bacterial isolates per sample source or prevalent bacterial species. Utensile tables were significantly the least contaminated source when comparing all sample sources from all hospitals (p=0.05). When testing if the bacterial species differed significantly between sample sources, Escherichia coli (p=0.05) and Bacillus (p=0.04) were found significantly high on utensils, while Pseudomonas was found significantly less on curtains (p=0.03) and doors (p=0.02). Conclusion: Due to unhygienic practices in hospitals children are exposed to pathogens steers to life threatening infection. A good control strategy should be implemented to avoid health care-associated infection. PMID- 27761570 TI - The significance of anthropometric and endocrine parameters in ovulation induction with clomiphene citrate in women with polycystic ovary syndrome. AB - OBJECTIVES: To investigate factors associated with the response to ovarian stimulation in patients with polycystic ovary syndrome. Methods: The records of patients with polycystic ovary syndrome and infertility who underwent ovulation induction with clomiphene citrate were reviwed between January 2011 and December 2014 in Etlik Zubeyde Hanim Women's Health Training and Research Hospital Ankara, Turkey. The anthropometric and endocrine factors of patients who were resistant to treatment at a dose of 150 mg/day (n=84) were compared with those who responded with growth of at least one graaffian follicle at a dose of 50 mg/day (n=342). Results: Of the parameters examined, body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio were significantly higher in the clomiphene citrate-resistant group compared with the responsive group. Conclusion: Reproductive treatment in patients with polycystic ovary syndrome show different outcomes. Significantly higher body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio observed in clomiphene citrate resistant group can be a possible explanation for this impedance. PMID- 27761571 TI - Pediatric foreign body ingestion and esophageal impaction. AB - [No Abstract Available]. PMID- 27761572 TI - The Saudi clinical practice guideline for the prophylaxis of venous thromboembolism in medical and critically ill patients. AB - Venous thromboembolism (VTE) acquired during hospitalization is common, yet preventable by the proper implementation of thromboprophylaxis which remains to be underutilized worldwide. As a result of an initiative by the Saudi Ministry of Health to improve medical practices in the country, an expert panel led by the Saudi Association for Venous Thrombo Embolism (SAVTE; a subsidiary of the Saudi Thoracic Society) with the methodological guidance of the McMaster University Guideline working group, produced this clinical practice guideline to assist healthcare providers in VTE prevention. The expert part panel issued ten recommendations addressing 10 prioritized questions in the following areas: thromboprophylaxis in acutely ill medical patients (Recommendations 1-5), thromboprophylaxis in critically ill medical patients (Recommendations 6-9), and thromboprophylaxis in chronically ill patients (Recommendation 10). The corresponding recommendations were generated following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. PMID- 27761573 TI - The spectrum of congenital heart diseases in down syndrome. A retrospective study from Northwest Saudi Arabia. AB - [No abstract available]. PMID- 27761574 TI - The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis. AB - Some studies suggest that patients with cirrhosis have an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, available data on this association are contrasting. It was the objective of this study to perform a systematic review and meta-analysis of literature to evaluate the risk of venous thromboembolism (VTE) associated with cirrhosis. Studies reporting on VTE risk associated with cirrhosis were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. Eleven studies (15 data-sets) showed a significantly increased VTE risk in 695,012 cirrhotic patients as compared with 1,494,660 non-cirrhotic controls (OR: 1.703; 95 %CI: 1.333, 2.175; P<0.0001). These results were confirmed when specifically considering the risk of DVT (7 studies, OR: 2.038; 95 %CI: 1.817, 2.285; P<0.0001) and the risk of PE (5 studies, OR: 1.655; 95 %CI: 1.042, 2.630; p=0.033). The increased VTE risk associated with cirrhosis was consistently confirmed when analysing nine studies reporting adjusted risk estimates (OR: 1.493; 95 %CI: 1.266, 1.762; p<0.0001), and after excluding studies specifically enrolling populations exposed to transient risk factors for VTE (OR: 1.689; 95 %CI: 1.321, 2.160; p<0.0001). Meta regression models suggested that male gender may significantly impact on the risk of VTE associated with cirrhosis. Results of our meta-analysis suggest that cirrhotic subjects may exhibit an increased risk of VTE. This should be considered to plan specific prevention strategies in this clinical setting. PMID- 27761575 TI - Capillary blood samples for anti-Xa monitoring of heparin in paediatric patients. PMID- 27761576 TI - Evaluation of inertial measurement units as a novel method for kinematic gait evaluation in dogs. AB - OBJECTIVE: To evaluate the use of inertial measurement units (IMU) for quantification of canine limb kinematics. METHODS: Sixteen clinically healthy, medium-sized dogs were enrolled. Baseline kinematic data were acquired using an optical motion capture system. Following this baseline data acquisition, a harness system was used for attachment of IMU to the animals. Optical kinematic data of dogs with and without the harness were compared to evaluate the influence of the harness on gait parameters. Sagittal plane joint kinematics acquired simultaneously with IMU and the optical system were compared for the carpal, tarsal, stifle and hip joints. Comparisons of data were made using the concordance correlation coefficient (CCC) test and evaluation of root mean squared errors (RMSE). RESULTS: No significant differences were demonstrated in stance duration, swing duration or stride length between dogs instrumented with or without the harness, however, mean RMSE values ranged from 4.90 degrees to 14.10 degrees across the various joints. When comparing simultaneously acquired optical and IMU kinematic data, strong correlations were found for all four joints evaluated (CCC: carpus = 0.98, hock = 0.95, stifle = 0.98, hip = 0.96) and median RMSE values were similar across the joints ranging from 2.51 degrees to 3.52 degrees . CONCLUSIONS AND CLINICAL RELEVANCE: Canine sagittal plane motion data acquisition with IMU is feasible, and optically acquired and IMU acquired sagittal plane kinematics had good correlation. This technology allows data acquisition outside the gait laboratory and may provide an alternative to optical kinematic gait analysis for the carpal, tarsal, stifle, and hip joints in the dog. Further investigation into this technology is indicated. PMID- 27761577 TI - Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system. AB - Patients with type 3 von Willebrand disease (VWD-3) have no measurable levels of VW factor (VWF) and usually require treatment with VWF-FVIII concentrate to prevent and/or stop bleeding. Even though the patients are treated prophylactically, they may experience bleeding symptoms. The aim of this study was to evaluate the effect of VWF-FVIII concentrate treatment in VWD-3 patients with the Total Thrombus Analysis System (T-TAS(r)), which measures thrombus formation under flow conditions. Coagulation profiles of 10 VWD-3 patients were analysed using T-TAS before and 30 minutes after VWF-FVIII concentrate (Haemate(r)) injection. Results were compared to VWF- and FVIII activity in plasma, and results with thromboelastometry and ristocetin-activated platelet impedance aggregometry (Multiplate(r)) in whole blood. For comparison, 10 healthy controls were also analysed with T-TAS. A median dose of 27 (range 15-35) IU/kg of VWF-FVIII concentrate increased VWF- and FVIII activity as expected. T-TAS thrombus formation was enhanced when a tissue factor/collagen-coated flow chamber was used at low shear, but treatment effects at high shear using a collagen coated flow chamber were minimal. Whole blood coagulation assessed by thromboelastometry was normal and did not change (p > 0.05) but ristocetin induced platelet aggregation improved (p < 0.001). In conclusion, T-TAS detects effects of VWF-FVIII concentrate treatment on coagulation-dependent thrombus formation at low shear, but minor effects are observed on platelet-dependent thrombus formation at high shear. The poor prediction of bleeding by conventional laboratory monitoring in VWD-3 patients might be related to insufficient restoration of platelet-dependent thrombus formation. PMID- 27761578 TI - One-stage revision of an infected cementless total hip replacement. AB - A two-year-old, 44 kg dog with a right Helica cementless total hip replacement (THR) was radiographically diagnosed with implant loosening eight months after the index total hip replacement procedure. Subsequent synoviocentesis and synovial fluid culture revealed a methicillin-resistant coagulase-negative Staphylococcus spp infection of the right THR. A one-stage revision using a hybrid BFX cementless acetabular cup and CFX cemented femoral stem was performed. Vancomycin and micro-silver antimicrobial powder impregnated cement were used in the revision. At re-evaluation 27 months following the revision procedure, the patient did not exhibit any signs of lameness. Radiographic images confirmed stable implants, with bone ingrowth into the cup and no signs of implant loosening. Our report demonstrates the success of a one-stage THR revision when faced with a multi-drug resistant periprosthetic infection, when combined with the use of micro-silver antimicrobial powder and culture-based antibiotic impregnated cement therapy. PMID- 27761579 TI - The MAP kinase JNK2 mediates cigarette smoke-induced arterial thrombosis. AB - Despite public awareness of its deleterious effects, smoking remains a major cause of death. Indeed, it is a risk factor for atherothrombotic complications and in line with this, the introduction of smoking ban in public areas reduced smoking-associated cardiovascular complications. Nonetheless, smoking remains a major concern, and molecular mechanisms by which it causes cardiovascular disease are not known. Peripheral blood monocytes from healthy smokers displayed increased JNK2 and tissue factor (TF) gene expression compared to non-smokers (n=15, p<0.05). Similarly, human aortic endothelial cells exposed to cigarette smoke total particulate matter (CS-TPM) revealed increased TF expression mediated by JNK2 (n=4; p<0.05). Wild-type and JNK2-/- mice were exposed to cigarette smoke for two weeks after which arterial thrombosis was investigated. Wild-type mice exposed to smoke displayed reduced time to thrombotic arterial occlusion (n=8; p<0.05) and increased tissue factor activity (n=7; p<0.05) as compared to wild type controls (n=6), while JNK2-/-mice exposed to smoke maintained an unaltered thrombotic potential (n=8; p=NS) and tissue factor activity (n=8) comparable to that of JNK2-/- and wild-type controls (n=6; p=NS). Smoking caused an increased production of reactive oxygen species (ROS) in wild-type but not in JNK2-/- mice (n=7; p<0.05 for wild-type mice and n=5-6; p=NS for JNK2-/- mice). In conclusion, the MAP kinase JNK2 mediates cigarette smoke-induced TF activation, arterial thrombosis and ROS production. These results underscore a major role of JNK2 in smoke-mediated thrombus formation and may offer an attractive target to prevent smoke-related thrombosis in those subjects which do not manage quitting. PMID- 27761580 TI - Decreased platelet reactivity in patients with cancer is associated with high risk of venous thromboembolism and poor prognosis. AB - Platelets are suggested to play a crucial role in cancer progression and the prothrombotic state of cancer patients. Here, we aimed to examine the activation status of platelets in cancer patients and investigate their association with risk of death and occurrence of venous thromboembolism (VTE) in a prospective observational cohort study. We measured platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregate (MPA) formation in vivo and platelet response to ex vivo stimulation with agonists of protease activated receptor (PAR) -1, -4, and GPVI, by whole blood flow cytometry, before beginning of chemotherapy and repeatedly during the first six months thereafter (total number of samples analysed: 230). Endpoints of the study were occurrence of death or VTE during a two-year follow-up, respectively. Of 62 patients (median age [interquartile range, IQR]: 63 [54-70] years, 48 % female), 32 (51.6 %) died and nine (14.5 %) developed VTE. Association with a higher risk of death was found for lower platelet surface expression of P-selectin and activated GPIIb/IIIa in vivo and in response to PAR-1, -4 and GPVI activation, but not for MPA formation. Furthermore, reduced platelet responsiveness to PAR-1 and GPVI agonists was associated with higher risk of VTE (hazard ratio per decile increase of percentage P-selectin positive platelets: 0.73 [0.56-0.92, p=0.007] and 0.77 [0.59-0.98, p=0.034], respectively). In conclusion, cancer patients with a poor prognosis showed decreased platelet reactivity, presumably as a consequence of continuous activation. Our data suggest that decreased platelet reactivity is associated with increased mortality and VTE in cancer. PMID- 27761581 TI - Evaluation of an overlapping pubic and ischiatic osteotomy for the improvement of acetabular ventroversion in dogs: an ex vivo study. AB - OBJECTIVES: To assess the potential of a new single-session surgical procedure, the overlapping pubic and ischiatic osteotomy (OPIO) for modification of bilateral hip conformation. We hypothesized that OPIO would be simple to perform with currently available surgical equipment, through a single surgical approach, with minimal potential morbidity, and that it would allow adequate simultaneous bilateral improvement of coxofemoral joint conformation in patients at risk of canine hip dysplasia. METHODS: The OPIO procedure was performed in the pelves of five large breed canine cadavers. Computed tomography images of each cadaver were compared by measurement of the dorsal acetabular rim angle (DARA), acetabular angle (AA), dorso-ventral sacroiliac ratio (SR), and pubic inlet area before and after OPIO. RESULTS: Coxofemoral joint conformation was improved after OPIO. Postoperative DARA was significantly decreased (mean: -5.09 degrees ) and AA was significantly increased (mean: 3.54 degrees ) after OPIO. The SR was not significantly different after OPIO, indicating minimal impact on the sacro-illiac joints by the procedure. Pubic inlet dimensions and area were significantly decreased after OPIO, but the overall effect on pelvic inlet area was clinically insignificant. CLINICAL SIGNIFICANCE: An OPIO allows some improvement of coxofemoral joint conformation in canine cadavers. PMID- 27761582 TI - A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. The CAPITAL OPTI-CROSS Study. AB - Ticagrelor has been endorsed by guidelines as the P2Y12 inhibitor of choice in patients with acute coronary syndrome. Clinically, some patients on ticagrelor will require a switch to clopidogrel; however, the optimal strategy and pharmacodynamics effects of switching remain unknown. Patients with an indication to switch were randomly assigned to either a bolus arm (Clopidogrel 600 mg bolus followed by 75 mg daily, n=30) or a no-bolus arm (Clopidogrel 75 mg daily, n=30). Blood samples were collected at baseline, 12, 24, 48, 54, 60 and 72 hours (h) for assessment of platelet reactivity. The primary outcome was P2Y12 reactivity units (PRU) at 72 h. Secondary outcomes included: PRUs at each time point, incidence of high on-treatment platelet reactivity (HPR), major adverse cardiac events (MACE) and TIMI bleeding at 30 days. Serial PRUs increased after switching to clopidogrel in both groups. At 72 h, no difference in PRU was observed (165.8 +/- 71.0 vs 184.1 +/- 67.7, bolus vs no bolus, respectively, p=0.19). At 48 h the PRUs were significantly lower in the bolus arm (114 +/- 73.1 vs 165.1 +/- 70.5, respectively; p=0.0076) and at 72 h, there was a significant reduction in incidence of HPR (26.7 % vs 56.7 %, p=0.02). No differences in MACE or TIMI bleeding were observed. Although a bolus strategy was not associated with improved platelet inhibition at 72 h; at 48 h, platelet inhibition was superior with reduced incidence of HPR. Larger studies will be required to determine its clinical significance. Until then, decision for giving a bolus of clopidogrel at the time of a switch may in part be dependent on the indication for switching, especially if there are concerns for bleeding risk. PMID- 27761583 TI - Several adaptor proteins promote intracellular localisation of the transporter MRP4/ABCC4 in platelets and haematopoietic cells. AB - The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as an important transporter for signalling molecules including cyclic nucleotides and several lipid mediators in platelets and may thus represent a novel target to interfere with platelet function. Besides its localisation in the plasma membrane, MRP4 has been also detected in the membrane of dense granules in resting platelets. In polarised cells it is localised at the basolateral or apical plasma membrane. To date, the mechanism of MRP4 trafficking has not been elucidated; protein interactions may regulate both the localisation and function of this transporter. We approached this issue by searching for interacting proteins by in vitro binding assays, followed by immunoblotting and mass spectrometry, and by visualising their co-localisation in platelets and haematopoietic cells. We identified the PDZ domain containing scaffold proteins ezrin-binding protein 50 (EBP50/NHERF1), postsynaptic density protein 95 (PSD95), and sorting nexin 27 (SNX27), but also the adaptor protein complex 3 subunit beta3A (AP3B1) and the heat shock protein HSP90 as putative interaction partners of MRP4. The knock-down of SNX27, PSD95, and AP3B1 by siRNA in megakaryoblastic leukaemia cells led to a redistribution of MRP4 from intracellular structures to the plasma membrane. Inhibition of HSP90 led to a diminished expression and retention of MRP4 in the endoplasmic reticulum. These results indicate that MRP4 localisation and function are regulated by multiple protein interactions. Changes in the adaptor proteins can hence lead to altered localisation and function of the transporter. PMID- 27761584 TI - Adenosine Generated in the Bone Marrow Niche Through a CD38-Mediated Pathway Correlates with Progression of Human Myeloma. AB - Human myeloma cells express CD38 at high levels and grow in hypoxic niches inside the bone marrow. Myeloma cells respond to hypoxia with metabolic changes leading to aerobic glycolysis, thus reducing ATP and increasing NAD+. Our hypothesis is that these conditions favor the enzymatic pathways involved in the production of adenosine in the niche. Within the niche, NAD+ is able to activate a discontinuous adenosinergic pathway that relies upon CD38, CD203a, and CD73 or TRACP, according to the environmental pH. The observed variability in adenosine concentrations in bone marrow aspirates is a result of the interactions taking place among myeloma and other cells in the bone marrow niche. A pilot study showed that adenosine profiles differ during disease progression. Adenosine levels were significantly higher in the bone marrow plasma of patients with symptomatic myeloma and correlated with ISS staging, suggesting that adenosine is produced in the myeloma niche at micromolar levels by an ectoenzymatic network centered on CD38. Adenosine levels increase with disease aggressiveness, a finding that supports adenosine as a potential marker of myeloma progression. PMID- 27761585 TI - Sigmoid-vaginal fistula as a rare complication following vaginal surgery. PMID- 27761587 TI - Professor Miloslav Krsiak 1939 - 2016. PMID- 27761586 TI - Reducing obstetric anal sphincter injuries using perineal support: our preliminary experience. AB - INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injuries (OASIs) are associated with significant short-term and long-term morbidity. Over the past decade, there has been a steady rise in the rate of OASIs. There is therefore a compelling need to identify strategies to minimize OASIs. The objective of this study was to determine if perineal support at the time of vaginal delivery can reduce the incidence and severity of OASIs. METHODS: All labour ward staff including midwives and doctors were invited to train in the technique of perineal support during vaginal delivery. Two experts from Norway conducted workshops with practical hands-on training on pelvic models. The midwives and doctors underwent further training with women in labour, and mandatory training was continued within the department. All midwives and doctors were instructed to support the perineum during both spontaneous and assisted vaginal delivery. RESULTS: From April 2011 to November 2014, 11,135 women underwent vaginal delivery. The OASI rate decreased from 4.7 % to 4.1 % (p = 0.11). There was a significant reduction (0.9 % to 0.3 %, p < 0.001) in 3c third-degree and fourth-degree tears (major OASIs). In a multivariate analysis, perineal support was associated with a significant reduction in the rates of OASIs (23 %; OR 0.77, 95 % CI 0.63 - 0.95, p = 0.01]) and major OASIs (71 %; OR 0.34, 95 % CI 0.17 - 0.69, p = 0.03). CONCLUSIONS: This interventional study showed that perineal support during vaginal delivery can reduce the risk of major OASIs. With sustained reinforcement of this intervention programme, we anticipate a further reduction in OASI rates. PMID- 27761588 TI - Post-treatment changes in permanent retention. AB - OBJECTIVES: While permanent retention is today the method of choice to stabilize orthodontic treatment outcomes, recent studies have increasingly reported posttreatment changes in tooth position during permanent retention. We conducted this study to analyze changes in the anterior mandible, whether the changes follow an underlying movement pattern, and, aiming for a preventive strategy, whether any risk factors could be identified comparing findings with the pretreatment situations. METHODS: We included 30 patients who had worn fixed Twistflex retainers (UK 3-3) extending from canine to canine in the mandible. Casts reflecting the intraoral situations before orthodontic treatment (T0), directly after completion of active therapy (T1), and 6 months later (T2) were scanned and superimposed using Imageware Surfacer software. Posttreatment changes (T2-T1) of tooth position within the retainer block were analyzed on 3D virtual models and were compared to pretreatment (T0) and treatment-related (T1-T0) findings to identify potential risk factors. RESULTS: Almost all analyzed patients revealed three-dimensional changes in tooth position within the retainer block. Comparing these movements, we repeatedly found rotated retainer blocks in labio-oral direction, while the center of rotation was located at the first incisors. This pattern was associated with intercanine expansion and excessive overjet correction during orthodontic treatment. The canines underwent the most pronounced (rotational and translational) movements. CONCLUSIONS: In general permanent lingual retainers are safe but in special clinical cases retainers can induce undesired tooth movement. Risk factors seem to be intercanine expansion and excessive overjet correction during orthodontic treatment. In specific cases an additional retention device might be needed. PMID- 27761589 TI - [Minimally invasive treatment of benign prostatic hyperplasia]. AB - Novel minimally invasive treatment options for the management of male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction (BOO) aim to provide equal efficacy compared to standard techniques with a more favourable safety profile. The preservation of all aspects of male sexual function including antegrade ejaculation is increasingly important to patients. It should be ideally performed in an outpatient setting under local anesthesia to assure a short recovery time. Novel injectables for intraprostatic application (botulinum neurotoxin A, NX-1207, PRX302) have emerged and first phase III results could not confirm the promising initial data. For mechanical devices like Urolift(r) the early and mid-term benefits demonstrate a rapid and durable symptom relief without compromising sexual function. Novel innovative procedures like aquablation (AquaBeam(r)) are entering the scene, but their feasibility, efficacy and safety still need to be addressed in randomized controlled trials. PMID- 27761591 TI - Randomised trials of vitamin D3 for critically ill patients in adults: systematic review and meta-analysis with trial sequential analysis. PMID- 27761592 TI - Hyperglycemia and outcomes of medical intensive care unit patients with and without a history of diabetes mellitus in a Chinese population. PMID- 27761590 TI - The role of calcium supplementation in healthy musculoskeletal ageing : An expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF). AB - The place of calcium supplementation, with or without concomitant vitamin D supplementation, has been much debated in terms of both efficacy and safety. There have been numerous trials and meta-analyses of supplementation for fracture reduction, and associations with risk of myocardial infarction have been suggested in recent years. In this report, the product of an expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF), we review the evidence for the value of calcium supplementation, with or without vitamin D supplementation, for healthy musculoskeletal ageing. We conclude that (1) calcium and vitamin D supplementation leads to a modest reduction in fracture risk, although population level intervention has not been shown to be an effective public health strategy; (2) supplementation with calcium alone for fracture reduction is not supported by the literature; (3) side effects of calcium supplementation include renal stones and gastrointestinal symptoms; (4) vitamin D supplementation, rather than calcium supplementation, may reduce falls risk; and (5) assertions of increased cardiovascular risk consequent to calcium supplementation are not convincingly supported by current evidence. In conclusion, we recommend, on the basis of the current evidence, that calcium supplementation, with concomitant vitamin D supplementation, is supported for patients at high risk of calcium and vitamin D insufficiency, and in those who are receiving treatment for osteoporosis. PMID- 27761593 TI - CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor. AB - Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression. PMID- 27761595 TI - Biosensors and their applications in detection of organophosphorus pesticides in the environment. AB - This review discusses the past and recent advancements of biosensors focusing on detection of organophosphorus pesticides (OPs) due to their exceptional use during the last decades. Apart from agricultural benefits, OPs also impose adverse toxicological effects on animal and human population. Conventional approaches such as chromatographic techniques used for pesticide detection are associated with several limitations. A biosensor technology is unique due to the detection sensitivity, selectivity, remarkable performance capabilities, simplicity and on-site operation, fabrication and incorporation with nanomaterials. This study also provided specifications of the most OPs biosensors reported until today based on their transducer system. In addition, we highlighted the application of advanced complementary materials and analysis techniques in OPs detection systems. The availability of these new materials associated with new sensing techniques has led to introduction of easy-to-use analytical tools of high sensitivity and specificity in the design and construction of OPs biosensors. In this review, we elaborated the achievements in sensing systems concerning innovative nanomaterials and analytical techniques with emphasis on OPs. PMID- 27761594 TI - Assembly and regulation of ASC specks. AB - The inflammasome adapter ASC links activated inflammasome sensors to the effector molecule pro-caspase-1. Recruitment of pro-caspase-1 to ASC promotes the autocatalytic activation of caspase-1, which leads to the release of pro inflammatory cytokines, such as IL-1beta. Upon triggering of inflammasome sensors, ASC assembles into large helical fibrils that interact with each other serving as a supramolecular signaling platform termed the ASC speck. Alternative splicing, post-translational modifications of ASC, as well as interaction with other proteins can perturb ASC function. In several inflammatory diseases, ASC specks can be found in the extracellular space and its presence correlates with poor prognosis. Here, we review the role of ASC in inflammation, and focus on the structural mechanisms that lead to ASC speck formation, the regulation of ASC function during inflammasome assembly, and the importance of ASC specks in disease. PMID- 27761597 TI - [Objective audiometry with DPOAEs : New findings for generation mechanisms and clinical applications. German version]. AB - BACKGROUND: Distortion product otoacoustic emissions (DPOAEs) and transient evoked otoacoustic emissions (TEOAEs) are sound waves generated as byproducts of the cochlear amplifier. These are measurable in the auditory canal and represent an objective method for diagnosing functional disorders of the inner ear. Conventional DPOAE and TEOAE methods permit detection of hearing impairment, but with less than desirable accuracy. OBJECTIVE: By accounting for DPOAE generation mechanisms, the aim is to improve the accuracy of inner-ear diagnosis. MATERIALS AND METHODS: DPOAEs consist of two components, which emerge at different positions along the cochlea and which may cause artifacts due to mutual interference. Here, the two components are separated in the time domain using short stimulus pulses. Optimized stimulus levels facilitate the acquisition of DPOAEs with maximum amplitudes. DPOAE and Bekesy audiograms were recorded from 41 subjects in a clinically relevant frequency range of 1.5 to 6 kHz. RESULTS: The short stimulus pulses allowed artifact-free measurement of DPOAEs. Semilogarithmic input-output functions yielded estimated distortion product thresholds, which were significantly correlated with the subjectively acquired Bekesy thresholds. In addition, they allowed detection of hearing impairment from 20 dB HL, with 95 % sensitivity and only a 5 % false-positive rate. This accuracy was achieved with a measurement time of about 1-2 min per frequency. CONCLUSIONS: Compared to conventional DPOAE and TEOAE methods, separation of DPOAE components using short-pulse DPOAEs in combination with optimized stimulus parameters considerably enhances the accuracy of DPOAEs for diagnosing impairment of the cochlear amplifier. PMID- 27761596 TI - Protective Effects of Calcium on Cadmium Accumulation in Co-Cultured Silver Carp (Hypophthalmichthys molitrix) and Triangle Sail Mussel (Hyriopsis cumingii). AB - Discovering cost effective strategies to reduce cadmium (Cd) uptake is of great concern for consumer food safety in the aquaculture industry. This study investigated the protective effects of calcium (Ca) on Cd uptake in co-cultured silver carp (Hypophthalmichthys molitrix) and triangle sail mussel (Hyriopsis cumingii). The results show that Ca-depending on its applied concentration-caused a significant decrease in the Cd uptake into muscle (by 48 %-72 %), gills (by 51 %-57 %), liver (by 52 %-81 %) and kidney (by 54 %-81 %) of silver carp (p < 0.001), as well as foot (by 8 %-32 %) and visceral mass (by 40 %-47 %) of triangle sail mussels (p < 0.05). The results indicate that Ca treatment is an effective means of reducing Cd accumulation in aquaculture. Since Ca is often used to increase the quality of pearls produced by triangle sail mussel, the quality of co-cultured edible fish might improve as a consequence of the potentially reduced Cd uptake. PMID- 27761598 TI - Seeing the sound after visual loss: functional MRI in acquired auditory-visual synesthesia. AB - Acquired auditory-visual synesthesia (AVS) is a rare neurological sign, in which specific auditory stimulation triggers visual experience. In this study, we used event-related fMRI to explore the brain regions correlated with acquired monocular sound-induced phosphenes, which occurred 2 months after unilateral visual loss due to an ischemic optic neuropathy. During the fMRI session, 1-s pure tones at various pitches were presented to the patient, who was asked to report occurrence of sound-induced phosphenes by pressing one of the two buttons (yes/no). The brain activation during phosphene-experienced trials was contrasted with non-phosphene trials and compared to results obtained in one healthy control subject who underwent the same fMRI protocol. Our results suggest, for the first time, that acquired AVS occurring after visual impairment is associated with bilateral activation of primary and secondary visual cortex, possibly due to cross-wiring between auditory and visual sensory modalities. PMID- 27761599 TI - Comorbidity of schizophrenia and infection: a population-based cohort study. AB - PURPOSE: In this paper, we investigate the hypothesis that there is an overlap between infection and schizophrenia. Infections have been identified as a risk factor for schizophrenia, but the possible overlap between schizophrenia and infections remains unidentified so far. Here, we describe the use of the comorbidity index, a method for objectively integrating associations into a single measure estimating overlap. METHODS: Data were drawn from three population based registers, the Civil Registration Register, the Danish Psychiatric Central Research Register, and the Danish National Hospital Register. We selected a cohort of 1,403,183 persons born in Denmark 1977-2002. RESULTS: Our results indicate that persons who have had a hospital contact with an infection (IRR 1.53, CI 1.46-1.61) are more likely to develop schizophrenia than persons who have not had such a contact. Persons who have had a diagnosis with schizophrenia are more likely to have had a hospital contact with an infection (IRR 1.73, 95 % CI 1.57-1.91) than persons who have had no schizophrenia diagnosis. A comorbidity index of 1.40 (95 % CI 1.34-1.46) was found, indicating an overlap between schizophrenia and infection. CONCLUSION: Our findings indicate that schizophrenia and infections overlap and that they share risk factors. The comorbidity index showed that the co-occurrence of schizophrenia and infection was 40 % higher than if the two disorders had occurred independently. Although the incidence of schizophrenia and infection was associated with each factor, the overlap could not be explained by urbanicity, parental history of psychiatric admission and infection. PMID- 27761601 TI - KV7 channels in the human detrusor: channel modulator effects and gene and protein expression. AB - Voltage-gated type 7 K+ (KV7 or KCNQ) channels regulate the contractility of various smooth muscles. With this study, we aimed to assess the role of KV7 channels in the regulation of human detrusor contractility, as well as the gene and protein expression of KV7 channels in this tissue. For these purposes, the isolated organ technique, RT-qPCR, and Western blot were used, respectively. XE 991, a selective KV7 channel blocker, concentration-dependently contracted the human detrusor; mean EC50 and Emax of XE-991-induced concentration-response curve were 14.1 MUM and 28.8 % of the maximal bethanechol-induced contraction, respectively. Flupirtine and retigabine, selective KV7.2-7.5 channel activators, induced concentration-dependent relaxations of bethanechol-precontracted strips, with maximal relaxations of 51.6 and 51.8 % of the precontraction, respectively. XE-991 blocked the relaxations induced by flupirtine and retigabine. All five KCNQ genes were found to be expressed in the detrusor with KCNQ4 being the most expressed among them. Different bands, having sizes similar to some of reported KV7.1, 7.4, and 7.5 channel subunit isoforms, were detected in the detrusor by Western blot with the KV7.4 band being the most intense among them. In conclusion, KV7 channels contribute to set the basal tone of the human detrusor. In addition, KV7 channel activators significantly relax the detrusor. The KV7.4 channels are probably the most important KV7 channels expressed in the human detrusor. These data suggest that selective KV7.4 channel activators might represent new pharmacological tools for inducing therapeutic relaxation of the detrusor. PMID- 27761600 TI - Education as a social pathway from parental socioeconomic position to depression in late adolescence and early adulthood: a Finnish population-based register study. AB - PURPOSE: There is inconsistent evidence for social differentials in the risk of depression in youth, and little is known about how education at this age influences the risk. We assess how parental socioeconomic position (SEP) and education predict depression from late adolescence to early adulthood, a time of major educational transitions. METHODS: We followed a nationally representative 20 % sample of Finnish adolescents born in 1986-1990 (n = 60,829) over two educational transitory stages at the age of 17-19 and 20-23 covering the years 2003-2011. We identified incident depression using health care register data. We estimated the risk of depression by parental SEP and personal education using Cox regression, adjusting for family structure, parental depression and the individual's own psychiatric history. RESULTS: Lower parental income was associated with up to a twofold risk of depression. This effect was almost fully attributable to other parental characteristics or mediated by the individual's own education. Educational differences in risk were attenuated following adjustment for prior psychiatric history. Adjusted for all covariates, not being in education increased the risk up to 2.5-fold compared to being enrolled in general upper secondary school at the age of 17-19 and in tertiary education at the age of 20-23. Vocationally oriented women experienced a 20 % higher risk than their academically oriented counterparts in both age groups. CONCLUSIONS: Education constitutes a social pathway from parental SEP to the risk of depression in youth, whereby educational differences previously shown in adults are observed already before the establishment of adulthood SEP. PMID- 27761602 TI - Calcified synovial metastasis in the knee from renal cell carcinoma: a case report. AB - We present the case of an 83-year-old man who had painful swelling of right knee for 6 months. Radiographs showed a large intra-articular soft-tissue mass with small calcifications, whereas MRI detected a multilobulated intra-articular tumor with bone erosions at the distal femur. Histopathology of ultrasound-guided biopsy specimen of the synovial mass revealed it to be a poorly differentiated metastatic carcinoma. Abdominal computed tomography with intravenous contrast medium administration found a heterogeneously enhancing large right renal mass with calcifications, which was shown to be a renal cell carcinoma on histopathology. No metastases were found elsewhere. To our knowledge, this is the first reported case with MRI findings of a calcified intra-articular synovial metastasis from renal cell carcinoma. PMID- 27761603 TI - Does the initiation of urate-lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review. AB - The aim of this study was to systematically review the literature on effect of initiating urate-lowering treatment (ULT) during an acute attack of gout on duration of index attack and persistence on ULT. OVID (Medline), EMBASE and AMED were searched to identify randomized controlled trials (RCTs) of ULT initiation during acute gout attack published in English language. Two reviewers appraised the study quality and extracted data independently. Standardized mean difference (SMD) and relative risk (RR) were used to pool continuous and categorical data. Meta-analysis was carried out using STATA version 14. A total of 537 studies were selected. A total of 487 titles and abstracts were reviewed after removing duplicates. Three RCTs were identified. There was evidence from two high-quality studies that early initiation of allopurinol did not increase pain severity at days 10-15 [SMDpooled (95 % CI) 0.18 (-0.58, 0.93)]. Data from three studies suggested that initiation of ULT during an acute attack of gout did not associate with dropouts [RRpooled (95 % CI) 1.16 (0.58, 2.31)]. There is moderate-quality evidence that the initiation of ULT during an acute attack of gout does not increase pain severity and risk of ULT discontinuation. Larger studies are required to confirm these findings so that patients with acute gout can be initiated on ULT with confidence. PMID- 27761604 TI - Characterization of beta-amino- and gamma-amino butyric acid-induced citrus seeds germination under salinity using nanoLC-MS/MS analysis. AB - KEY MESSAGE: BABA or GABA induces salinity acclimation during citrus seeds germination via alternation of specific proteins (e.g., citrin). The impact of four elicitors, namely hydrogen peroxide (H2O2), beta-amino butyric acid (BABA), gamma-amino butyric acid (GABA) and hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS), in citrus seed germination under salinity (150 mM NaCl) was tested. The germination potential was adversely affected by NaCl-alone treatment. Pretreatment with H2O2 or the NaHS-H2S donor prior to salinity had no significant effect in germination process, however, BABA and GABA substantially improved seed acclimation to salinity, as evidenced by increased germination percentage and radicle length. Total soluble proteins of radicle and cotyledons were separated by 1DE SDS-PAGE and proteins zones were analyzed by mass spectrometry. In total, 27 and 3 proteins were identified in radicle and cotyledons, respectively. The identified proteins mainly include redox-regulated enzymes (i.e., glutathione S transferase, dehydroascorbate reductase, Mn-superoxide dismutase, glutathione peroxidase), energy-related proteins (i.e., isocitrate lyase, malate synthase, pyruvate decarboxylase), stress proteins (i.e., stress-related protein, miraculin, thaumatin, disulfide isomerase), storage proteins (i.e., vicilin, Pis v 1 allergen 2S albumin) and transcriptional regulators (i.e., MarR family transcriptional regulator, MADS544 protein). Pretreatments with BABA or GABA altered the accumulation of protein zones exclusively corresponding to citrin, indicating that this protein may serve as a marker for salinity acclimation in citrus seeds. PMID- 27761605 TI - Primary neurolymphomatosis as clinical onset of chronic lymphocytic leukemia. PMID- 27761606 TI - BCR-ABL-positive acute myeloid leukemia: About one case treated with ponatinib. PMID- 27761607 TI - Outcome of allogeneic hematopoietic stem cell transplantation in cases of mature T/NK-cell neoplasms: a single-center retrospective analysis. PMID- 27761608 TI - Cyclin A2 as a potential differential marker of splenic diffuse red pulp small B cell lymphoma: a report of the first case. PMID- 27761609 TI - A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. AB - Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung. We will also provide a brief literature review of other rarely reported cases of type 1 diabetes presenting after treatment with pembrolizumab and nivolumab, as well as discussion regarding potential mechanisms of this adverse effect and its importance as these drugs continue to become even more widespread. PMID- 27761610 TI - Avoiding Psychological Pitfalls in Aesthetic Medical Procedures. AB - OBJECTIVE: To assess the prevalence of body dysmorphic disorder (BDD) in an aesthetic surgery setting in the region of Southwest China, and to ascertain the differences in terms of body images between patients in the aesthetic setting and general Chinese population. This study tracked patient satisfaction with their body image changes while undergoing aesthetic medical procedures to identify whether the condition of patients who were presenting with BDD symptoms or their psychological symptoms could be improved by enhancing their appearance. Additionally, this study explored whether there was improvement in quality of life (QoL) and self-esteem after aesthetic medical procedures. METHODS: A total of 106 female patients who were undergoing aesthetic medical procedures for the first time (plastic surgery, n = 26; minimally invasive aesthetic treatment, n = 42; and aesthetic dermatological treatment, n = 38) were classified as having body dysmorphic disorder symptoms or not having body dysmorphic disorder symptoms, based on the body dysmorphic disorder examination (BDDE), which was administered preoperatively. These patients were followed up for 1 month after the aesthetic procedures. The multidimensional body self-relations questionnaire appearance scales (MBSRQ-AS) and rosenberg self-esteem scale (RSE-S) were used to assess patients' preoccupation with appearance and self-esteem pre-procedure and 1 month post-procedure. Additionally, 100 female healthy control participants were recruited as a comparative group into this study and they were also assessed using BDDE, MBSRQ-AS, and RSE-S. RESULTS: A total of 14.2 % of 106 aesthetic patients and 1 % of 100 healthy controls were diagnosed with BDD to varying extents. BDDE scores were 72.83 (SD +/- 30.7) and 68.18 (SD +/- 31.82), respectively, before and after the procedure for the aesthetic patient group and 43.44 (SD +/- 15.65) for the healthy control group (F = 34.28; p < 0.001). There was a significant difference between the groups in subscales of MBSRQ-AS, i.e. appearance evaluation (F = 31.31; p < 0.001), appearance orientation (F = 31.65; p < 0.001), body areas satisfaction (F = 27.40; p < 0.001), and RSE-S scores (F = 20.81; p < 0.001). There was no significant difference, however, in subscales of MBSRQ-AS, i.e. overweight preoccupation (F = 1.685; p = 0.187), self-classified weight (F = 0.908; p = 0.404) between groups. All the subscales of MBSRQ-AS showed significant differences between the aesthetic patients (pre-procedure) and female adult norms from Dr. Cash's result given in Table 4 (p < 0.001). The study also showed that there were no significant differences in the scores of BDDE, MBSRQ-AS, and RSE-S of those fifteen aesthetic patients diagnosed with BDD after aesthetic procedures lasting one month. CONCLUSION: There was a high prevalence rate (14.2 %) of body dysmorphic disorder in aesthetic procedure seekers, and it seemed that those patients suffering from BDD were more likely to be dissatisfied with the results of the aesthetic medical procedures. However, general aesthetic patients showed improvement in most assessments which indicated that aesthetic medical procedures could not only enhance patient appearance, but also patient low self-esteem and QoL. Self-satisfaction could also be promoted. A screening procedure for BDD including suitable screening questionnaires might be considered for routine use in aesthetic clinical settings to minimize dissatisfaction and complaints. LEVEL OF EVIDENCE IV: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors. www.springer.com/00266 . PMID- 27761611 TI - Nasopharyngeal carcinoma in a low incidence European area : A prospective observational analysis from the Head and Neck Study Group of the Italian Society of Radiation Oncology (AIRO). AB - PURPOSE: To evaluate the outcomes with respect to long-term survival and toxicity in patients with nasopharyngeal carcinoma (NPC) treated in a European country with low incidence. MATERIALS AND METHODS: A prospective observational study carried out by the AIRO Head and Neck group in 12 Italian institutions included 136 consecutive patients treated with radiotherapy (RT) +/- chemotherapy (CHT) for NPC (without distant metastasis) between January 1, 2008 and December 31, 2010. RESULTS: The disease-specific survival (DSS), overall survival (OS), and disease-free survival (DFS) at 5 years were 92 (+/-2), 91 (+/-3), and 69 % (+/-5 %), respectively. Distant failure was the most frequent modality of relapse. The local, regional, and locoregional control at 5 years were 89 (+/-3), 93 (+/-3), and 84 % (+/-4 %), respectively. The incidence of acute and late toxicity and the correlations with different clinical/technical variables were analyzed. Neoadjuvant CHT prolongs radiotherapy overall treatment time (OTT) and decreases treatment adherence during concomitant chemoradiotherapy. An adequate minimum dose coverage to PTV(T) is a predictive variable well related to outcome. CONCLUSION: Our data do not substantially differ in terms of survival and toxicity outcomes from those reported in larger series of patients treated in countries with higher incidences of NPC. The T stage (TNM 2002 UICC classification) is predictive of DSS and OS. The GTV volume (T +/- N) and an adequate minimum PTV(T) coverage dose (D95 %) were also identified as potential predictive variables. Sophisticated technologies of dose delivery (IMRT) with image-guided radiotherapy could help to obtain better minimum PTV(T) coverage dose with increased DFS; distant metastasis after treatment still remains an unresolved issue. PMID- 27761612 TI - Dynamic contrast-enhanced MRI for automatic detection of foci of residual or recurrent disease after prostatectomy. AB - PURPOSE: This study aimed to develop an automated procedure for identifying suspicious foci of residual/recurrent disease in the prostate bed using dynamic contrast-enhanced-MRI (DCE-MRI) in prostate cancer patients after prostatectomy. MATERIALS AND METHODS: Data of 22 patients presenting for salvage radiotherapy (RT) with an identified gross tumor volume (GTV) in the prostate bed were analyzed retrospectively. An unsupervised pattern recognition method was used to analyze DCE-MRI curves from the prostate bed. Data were represented as a product of a number of signal-vs.-time patterns and their weights. The temporal pattern, characterized by fast wash-in and gradual wash-out, was considered the "tumor" pattern. The corresponding weights were thresholded based on the number (1, 1.5, 2, 2.5) of standard deviations away from the mean, denoted as DCE1.0, ..., DCE2.5, and displayed on the T2-weighted MRI. The resultant four volumes were compared with the GTV and maximum pre-RT prostate-specific antigen (PSA) level. Pharmacokinetic modeling was also carried out. RESULTS: Principal component analysis determined 2-4 significant patterns in patients' DCE-MRI. Analysis and display of the identified suspicious foci was performed in commercial software (MIM Corporation, Cleveland, OH, USA). In general, DCE1.0/DCE1.5 highlighted larger areas than GTV. DCE2.0 and GTV were significantly correlated (r = 0.60, p < 0.05). DCE2.0/DCA2.5 were also significantly correlated with PSA (r = 0.52, 0.67, p < 0.05). Ktrans for DCE2.5 was statistically higher than the GTV's Ktrans (p < 0.05), indicating that the automatic volume better captures areas of malignancy. CONCLUSION: A software tool was developed for identification and visualization of the suspicious foci in DCE-MRI from post-prostatectomy patients and was integrated into the treatment planning system. PMID- 27761613 TI - Differential diagnosis of gastric cancer and gastritis: the role of contrast enhanced ultrasound (CEUS). AB - OBJECTIVES: To evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in differential diagnosis of gastric cancer and gastritis, with histological results as reference standard. METHODS: From September 2011 to August 2014, 82 patients (50 males and 32 females; mean age +/- SD, 59.5 +/- 15.0 years; range 19-91 years) with gastric cancer or gastritis were included in this Ethics Committee-approved prospective study. Conventional ultrasonography (US) and CEUS were applied to distinguish the two lesions, and both qualitative and quantitative features were evaluated. RESULTS: Of the 82 histopathologic-proven lesions, 58 were cancer and 24 were gastritis. For US, the gastric wall stratification was not preserved in about one-third of cancer (21/58, 36.2%) compared with gastritis (0/24, 0%) (p < 0.001). Blurred, angular, or spiculated serosa margin and increased echogenicity in perigastric fat appeared only in cancer (10/58, 17.2%), and all of them proved to be pathologic T3 or T4 stage. On CEUS, gastric cancer usually manifested as diffused enhancement without comb teeth-like vessels (parallel curvilinear structures representing arterial branching within the gastric wall) (56/58, 96.6%), while these vessels presented in most gastritis (19/24, 79.2%, p < 0.001). For quantitative analysis, the malignant lesions showed later and lower enhancement (p < 0.001), and they also had slower speed to reach the peak intensity (p < 0.001). On CEUS, the absence of comb-teeth-like vessel is most reliable for diagnosing malignancy, and the sensitivity, specificity, and accuracy were 96.5%, 79.2%, and 91.5%, respectively. CONCLUSIONS: Our results demonstrated the usefulness and accuracy of US and CEUS in differential diagnosis of gastric cancer and gastritis. CEUS has the potential to make the diagnosis more accurate. PMID- 27761614 TI - Monitoring cell secretions on microfluidic chips using solid-phase extraction with mass spectrometry. AB - Microfluidics is an enabling technology for both cell biology and chemical analysis. We combine these attributes with a microfluidic device for on-line solid-phase extraction (SPE) and mass spectrometry (MS) analysis of secreted metabolites from living cells in culture on the chip. The device was constructed with polydimethylsiloxane (PDMS) and contains a reversibly sealed chamber for perfusing cells. A multilayer design allowed a series of valves to control an on chip 7.5 MUL injection loop downstream of the cell chamber with operation similar to a six-port valve. The valve collects sample and then diverts it to a packed SPE bed that was connected in-line to treat samples prior to MS analysis. The valve allows samples to be collected and injected onto the SPE bed while preventing exposure of cells to added back pressure from the SPE bed and organic solvents needed to elute collected chemicals. Here, cultured murine 3T3-L1 adipocytes were loaded into the cell chamber and non-esterified fatty acids (NEFAs) that were secreted by the cells were monitored by SPE-MS at 30 min intervals. The limit of detection for a palmitoleic acid standard was 1.4 MUM. Due to the multiplexed detection capabilities of MS, a variety of NEFAs were detected. Upon stimulation with isoproterenol and forskolin, secretion of select NEFAs was elevated an average of 1.5-fold compared to basal levels. Despite the 30-min delay between sample injections, this device is a step towards a miniaturized system that allows automated monitoring and identification of a variety of molecules in the extracellular environment. PMID- 27761615 TI - A strategy for simultaneous determination of fatty acid composition, fatty acid position, and position-specific isotope contents in triacylglycerol matrices by 13C-NMR. AB - Triacylglycerols, which are quasi-universal components of food matrices, consist of complex mixtures of molecules. Their site-specific 13C content, their fatty acid profile, and their position on the glycerol moiety may significantly vary with the geographical, botanical, or animal origin of the sample. Such variables are valuable tracers for food authentication issues. The main objective of this work was to develop a new method based on a rapid and precise 13C-NMR spectroscopy (using a polarization transfer technique) coupled with multivariate linear regression analyses in order to quantify the whole set of individual fatty acids within triacylglycerols. In this respect, olive oil samples were analyzed by means of both adiabatic 13C-INEPT sequence and gas chromatography (GC). For each fatty acid within the studied matrix and for squalene as well, a multivariate prediction model was constructed using the deconvoluted peak areas of 13C-INEPT spectra as predictors, and the data obtained by GC as response variables. This 13C-NMR-based strategy, tested on olive oil, could serve as an alternative to the gas chromatographic quantification of individual fatty acids in other matrices, while providing additional compositional and isotopic information. Graphical abstract A strategy based on the multivariate linear regression of variables obtained by a rapid 13C-NMR technique was developed for the quantification of individual fatty acids within triacylglycerol matrices. The conceived strategy was tested on olive oil. PMID- 27761616 TI - Quantitative analysis of cow whole milk and whey powder adulteration percentage in goat and sheep milk products by isotopic dilution-ultra-high performance liquid chromatography-tandem mass spectrometry. AB - The aim of the study was to develop a method for quantification of cow's whey and whole milk powder in goat or sheep milk products including infant formula. A ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method was established for simultaneous quantification of four caseins and two major whey proteins by detecting their signature peptides, which were able to act as markers for differentiating goat or sheep from cow whey and whole milk powder in infant formulas. The signature peptides were screened based on the computational prediction by Biolynx software, and confirmed by database searching after analysis of liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (LC-Q-TOF-MS). The isotopic-labeled signature peptide was used as internal standard to compensate the matrix effect. The limits of quantification were 0.01-0.05 g/100 g for target proteins. The observed recovery rates ranged from 82.3 to 116.6 % and the reproducibility was excellent (RSD <12 %) at different spiking levels. The RSDs of intra- and inter-day precision were 2.8-6.2 and 3.3-9.8 %, respectively. The multiple reaction monitoring method was successfully applied to milk powder with different composition, showing high specificity and accuracy in detection of species involved. The calculating formula was designed to assess the composition of adulteration in the actual detection of infant formulas. These results highlight applicability of this method for the detection of infant formulas with complicated matrix. PMID- 27761617 TI - Reconstruction of undergraduate analytical chemistry laboratory course. PMID- 27761618 TI - Salinivibrio costicola GL6, a Novel Isolated Strain for Biotransformation of Caffeine to Theobromine Under Hypersaline Conditions. AB - The present study has been conducted towards isolation of moderately halophilic bacteria capable of transforming caffeine into theobromine. A total of 45 caffeine-degrading moderate halophiles were enriched from hypersaline lakes and examined for the biotransformation of caffeine to theobromine by thin-layer chromatography (TLC) and high-performance liquid chromatography analyses. Strain GL6, giving the highest yield of theobromine, was isolated from the Hoz Soltan Lake, 20 % w/v salinity, central Iran, and identified as Salinivibrio costicola based on morphological and biochemical features as well as its 16S rRNA gene sequence analysis (GeneBank Accession No. KT378066) and DNA-DNA relatedness. The biotransformation of caffeine with strain GL6 leads to the formation of two metabolites, identified as theobromine and paraxanthine, but the yield of paraxanthine was much lower. Further study on the production of theobromine from caffeine under resting cell experiment was carried out subsequently. The optimal yield of theobromine (56 %) was obtained after a 32-h incubation using 5 mM of caffeine and 15 g l-1 (wet weight) of biomass in 0.1 M saline phosphate buffer (pH 7.0 and 10 % w/v NaCl) under agitation 180 rpm at 30 degrees C. The biotransformed theobromine was purified by preparative TLC and subjected to FTIR and mass spectroscopy for chemical identification. This is the first evidence for biotransformation of caffeine into theobromine by strains of the genus Salinivibrio. PMID- 27761620 TI - Do paraneoplastic changes in diffuse FDG organ uptake predict relapse? - Wait for confirmation study : Reply to Jorgov et al. Eur J Nucl Med Mol Imaging. 2016 Jul;43(7):1220--30. PMID- 27761619 TI - Genetic Diversity and Virulence Potential of Staphylococcus aureus Isolated from Crayfish (Procambarus clarkii). AB - Staphylococcus aureus, a commensal and a pathogenic bacterium, causes a wide variety of diseases in humans and animals with a high impact on public health and the livestock industry. The risk of zoonotic transmission to humans highlights the need to understand the molecular ecology of S. aureus in foods. In this study, we obtained 25 S. aureus isolates from 39 crayfish samples in Hubei, China. PCR was applied for detection of presence of virulence and methicillin resistance genes in the pathogen genome. The result revealed that all of the 25 S. aureus isolates harbored at least four virulence genes, and 64 % of them were positive for five or more virulence genes. The most predominant virulence genes were coa, alpha-HL and beta-HL genes (100 %), followed by sea (68 %), fnbA (60 %), tsst-1 (36 %), while none of the examined isolates presented positive for mecA gene conferring methicillin resistance. Subsequently, all of the isolates were assessed for phenotypic biofilm formation with the microtiter plate assay. The results showed 92 % isolates could produce biofilm with different forming capacity. Multilocus sequence typing divided the isolates into five sequence types (STs), three of which (ST1920, ST188 and ST398) were the same with the isolates from livestock and clinic in China. This study provides preliminary insights into the genetic diversity and virulence gene profiles of S. aureus from crayfish, suggesting that S. aureus isolates from crayfish is a potential hazard for consumers and deserves further attention. PMID- 27761621 TI - Radioiodine - the success story of Nuclear Medicine : 75th Anniversary of the first use of Iodine-131 in humans. PMID- 27761622 TI - Joint awareness after ACL reconstruction: patient-reported outcomes measured with the Forgotten Joint Score-12. AB - PURPOSE: To measure joint awareness in patients who have undergone anterior cruciate ligament (ACL) reconstruction and to investigate medium- and long-term results of the procedure. METHODS: All patients who had undergone ACL reconstruction with the same arthroscopic surgical technique at our institution between 2011 and 2014 (medium-term follow-up group (Group I)) or between 2000 and 2005 (long-term follow-up group (Group II)) were considered for inclusion in the study. A group of healthy controls were recruited to obtain reference values for the FJS-12 (Forgotten Joint Score-12). Propensity score matching was applied to improve comparability of patients and healthy controls in terms of sex and age. RESULTS: Fifty-eight patients of the Group I (mean follow-up 31.5 (SD13.4) months, range 12-54), 57 patients of the Group II (mean follow-up 139 (SD15.2) months, range 120-179), and the healthy control samples (100 individuals) were analysed. Significantly lower FJS-12 was found in both groups (Group I: 71.6 and Group II: 70.1), compared to the two matched control groups (88.1 and 90.0). CONCLUSIONS: The concept of joint awareness was successfully applied to evaluate medium- and long-term results of ACL reconstruction. The clinical relevance of this study is that it extends the construct of joint awareness as a patient reported outcome parameter to ACL reconstruction surgery. LEVEL OF EVIDENCE: Level III. PMID- 27761623 TI - Clinical advantages of image-free navigation system using surface-based registration in anatomical anterior cruciate ligament reconstruction. AB - PURPOSE: To evaluate the clinical advantages of a navigation system developed with an emphasis on attaining an appropriate femoral tunnel length and posterior wall margin with no posterior wall blowout, as well as having accurate tunnel positioning, in anatomical anterior cruciate ligament reconstruction (ACLR). METHODS: Ten freshly frozen human knees were transected at mid-femur and mid tibia. Each knee specimen underwent arthroscopic single-bundle anterior cruciate ligament reconstruction using the outside-in technique, with two knees by manual ACLR (control group) and another eight knees by only the navigational ACLR without arthroscopic assistance (experimental group). The position/orientation information of tunnel entry point, tunnel length, and posterior wall distance of pre-, intra-, and postoperative tunnel were recorded, and the reliability and errors among them were evaluated. RESULTS: From comparison of the 3D models for preoperative planning and postoperative reconstruction, the mean differences for navigational femoral tunnelling and arthroscopic-assisted femoral tunnelling were recorded, respectively: (1) tunnel entry position, 1.4 mm (SD 0.3) versus 4.9 mm; (2) tunnel length, 0.7 mm (SD 0.2), similar to 0.6 mm in arthroscopic-assisted femoral tunnelling, and (3) posterior wall distance, 0.5 mm (SD 0.2), much smaller than 4.7 mm for arthroscopic-assisted femoral tunnelling. The intraclass correlation coefficients, calculated to determine the accuracy and reliability of navigational femoral tunnelling, showed excellent internal consistency that ranged from 0.965 to 0.989 for tunnel length and from 0.810 to 0.953 for posterior wall distance. CONCLUSION: Navigation systems with enhancement of the registration accuracy by the developed system are feasible in anatomical ACLR, in reducing surgical failures such as short tunnel length or posterior wall breakage of distal femur. The present study revealed that computer navigation could aid in avoiding major mistakes in exact positioning and posterior wall blowout and help in attaining appropriate length for femoral tunnelling in anatomical ACLR. PMID- 27761624 TI - Comparison of the efficiency of an extra-articular absorber system and high tibial osteotomy for unloading the medial knee compartment: an in vitro study. AB - PURPOSE: The unloading effect of an extra-articular absorber system on the knee joint medial compartment was compared with high tibial osteotomy (HTO) under physiological conditions in vitro. METHODS: Seven fresh-frozen cadaveric knees were used to test isokinetic flexion-extension motions under physiological loading using a biomechanical knee simulator. Tibiofemoral area contact and peak contact pressures were measured using pressure-sensitive film in the untreated medial compartment. Pressures were measured after KineSpring System implantation and HTO (5 degrees and 10 degrees correction angles) performed with an angular stable internal fixator (Tomofix). RESULTS: Implantation of the unloading device resulted in significantly decreased medial compartment area contact pressure (Delta0.02 +/- 0.01 MPa, p = 0.001) and peak contact pressure (Delta0.3 +/- 0.1 MPa, p = 0.001) compared with the first test cycle results in the untreated knee. HTO significantly decreased the pressure (p = 0.001). Compared with the first test cycle, HTO (5 degrees correction angle) decreased the mean contact pressure by Delta0.03 +/- 0.01 MPa and peak contact pressure by Delta0.3 +/- 0.01 MPa. With a 10 degrees correction angle, HTO decreased contact pressure by Delta0.04 +/- 0.02 MPa and peak contact pressure by Delta0.4 +/- 0.1 MPa compared with that at the 5 degrees correction angle. CONCLUSION: Implantation of an extra-capsular unloading device resulted in a significant unloading effect on the medial compartment comparable to that achieved with HTO at 5 degrees and 10 degrees correction angles. Thus, implantation of an extra-articular, extra-capsular absorber could become the method of choice when treating patients with unicompartmental osteoarthritis that cannot be adequately treated by HTO because of their straight-leg axis. PMID- 27761626 TI - Erratum to: The need for secondary resurfacing is affected by trochlear height in total knee arthroplasty. PMID- 27761625 TI - Non-operative management of medial meniscus posterior horn root tears is associated with worsening arthritis and poor clinical outcome at 5-year follow up. AB - PURPOSE: Medial meniscus posterior root tears (MMPRTs) are a significant source of pain and dysfunction, but little is known about the natural history and outcome and for non-operative management of these lesions. The purpose of this study was to evaluate (1) the mid-term clinical and radiographic outcomes of non operative treatment of MMPRTs and (2) risk factors for worse outcomes. METHODS: A retrospective review was performed for patients with symptomatic, unrepaired MMPRTs and a minimum 2-year follow-up for IKDC and Tegner outcome scores. Baseline and final radiographs were reviewed and graded according to Kellgren Lawrence scores. Baseline MRIs were reviewed for the presence of meniscal extrusion, subchondral oedema, and insufficiency fractures. Failure was defined as conversion to arthroplasty or severely abnormal patient subjective IKDC score. RESULTS: Fifty-two patients (21M:31F) with a mean age of 58 +/- 10 years were diagnosed with symptomatic MMPRTs clinically and confirmed by MRI and followed for a mean of 62 +/- 30 months. Sixteen patients (31 %) underwent total knee arthroplasty at a mean of 30 +/- 32 months after diagnosis with higher Kellgren Lawrence grades associated with increased rates of arthroplasty (p = 0.01). Mean IKDC scores for the remaining patients were 61.2 +/- 21 with significantly lower scores in females compared to males (75 +/- 12 vs. 49 +/- 20; p = 0.03). Mean Kellgren-Lawrence grades and rates of arthritis progressed over time on radiographs (1.5 +/- 0.7 vs. 2.4 +/- 1.0; p < 0.001 and 78 % vs. 51 %; p = 0.01). Overall, 87 % of patients failed non-operative treatment. CONCLUSIONS: Non operative treatment of medial meniscus posterior horn root tears is associated with poor clinical outcome, worsening arthritis, and a relatively high rate of arthroplasty at 5-year follow-up. Female gender was associated with lower subjective scores and higher rate of arthroplasty. The current study provides a natural history benchmark for clinical outcomes that can be expected in patients with medial meniscus posterior horn root tears undergoing non-operative treatment and helps in counselling patients with these types of injuries. LEVEL OF EVIDENCE: IV. PMID- 27761627 TI - The effect of total knee arthroplasty on patients' balance and incidence of falls: a systematic review. AB - PURPOSE: Despite the high incidence of falls in patients with OA, few studies have explored whether falls risk is affected after patients undergo total knee arthroplasty (TKA). Therefore, the aim of this systematic review was to identify the extent of the effects of TKA on balance and incidence of falls by critically reviewing the available literature. METHODS: A systematic review of published literature sources was conducted up to March 2014. All studies assessing balance and incidence of falls after TKA (without physiotherapeutic intervention) were included. The methodological quality of each study was reviewed using the Critical Appraisal Skill Programme tool. RESULTS: Thirteen studies were included, comprising of ten cohort studies (Level II) and three studies with Level of evidence III. CONCLUSIONS: Findings provide evidence that TKA improves significantly single-limb standing balance (~60%) and dynamic balance up to 1 year following surgery (Level of evidence II). Moreover, TKA influences positively fear of falling and incidence of falls by switching 54.2 % of pre operative fallers to post-operative non-fallers (Level of evidence II-III). It is highlighted that knee extension strength, proprioception and symmetrization of postural strategies have not fully recovered post-TKA and influence balance performance. Clinically, these persistent deficits need to be mitigated by physiotherapy even before TKA takes place. PMID- 27761628 TI - Radiological and functional 24-month outcomes of resurfacing versus stemmed anatomic total shoulder arthroplasty. AB - PURPOSE: This study compared clinical and radiographic outcomes of patients undergoing resurfacing total shoulder arthroplasty (TSA) with those treated with a stemmed TSA. METHODS: Patients with primary osteoarthritis who underwent humeral resurfacing (RES) or stemmed (STA) TSA were identified in our shoulder arthroplasty register for retrospective analysis. Standard radiographs and clinical/patient-rated assessments were made up to 24 months post-surgery. Implant revisions were assessed. Patients were frequency-matched in a 1:1 (RES:STA) ratio based on gender and age, and compared with regard to operation time and shoulder function (Constant, SPADI and Quick DASH scores). Mixed models with statistical adjustments were applied. RESULTS: From 2006 to 2014, 44 RES and 137 STA operations were performed in 157 patients; one and two revisions were recorded in the RES and STA group, respectively. The final matched cohort included a total of 69 patients and 37 operations per treatment group. Resurfacing TSA was 17 min shorter (95%CI: 5-28) compared to the stemmed procedure (p = 0.005). RES and STA patients showed significant functional improvement six months post-implantation, yet all measured scores did not differ between the groups at 2 years (p >= 0.131). The status of static centering of the humeral head, acromiohumeral distance, and a lack of signs of implant loosening were also similar between treatments. CONCLUSION: Similar 24-month post-operative radiological and functional outcome is achieved by RES and STA patients, even with a shorter RES surgery time. Larger cohorts and longer follow-up are required to better assess implant survival. PMID- 27761629 TI - Metal-on-metal total hip arthroplasty: risk factors for pseudotumours and clinical systematic evaluation. AB - The potential advantages of contemporary MoM THA implants include less volumetric wear with subsequent reduction of polyethylene wear-induced osteolysis and greater component stability with use of large-diameter femoral heads. However, there have been concerns regarding significantly elevated revision rates in MoM THA due to MoM-related complications such as adverse local tissue reaction (pseudotumour) formation. The increased failure rate in MoM hip arthroplasty is associated with the generation of biologically active, nanometer sized metal particles from the MoM bearing surfaces and taper junctions, which result in the development of a localized, adverse periprosthetic soft tissue response. The focus of this article is to provide an update on (1) implant, surgical and patient factors associated with adverse local tissue reactions (pseudotumours) and (2) the clinical systematic evaluation and management of patients with MoM hip arthroplasty based on the currently available evidence. There should be a low threshold to conduct a systematic clinical evaluation of patients with MoM hip arthroplasty as early recognition and diagnosis will allow the initiation of prompt and appropriate treatment. As a symptomatic MoM total hip arthroplasty may have intrinsic and extrinsic causes, patients should be evaluated systematically, utilizing risk stratification algorithms. Although specialized laboratory tests such as metal ion levels and cross sectional imaging modalities such as MARS MRI can be used to facilitate clinical decision making, over-reliance on any single investigative tool in the clinical decision-making process should be avoided. Further research is required to obtain a better understanding of implant and patient risk factors associated with tribocorrosion in MoM total hip arthroplasty. PMID- 27761630 TI - Long term results after arthroscopic resection of medial plicae of the knee-a prospective study. AB - PURPOSE: The medial plica (MP) is a normal anatomic structure consisting of a fold in the synovial layer of the joint. Arthroscopic resection is currently used as a gold standard procedure in patients with medial plica syndrome (MPS), but there are few prospective studies that analyze the long-term functional outcomes of plica resection. METHODS: The purpose of this prospective study was to evaluate the long-term results of arthroscopic resection of the medial plicae of the knee. Between 1999 and 2014 we included 267 patients that showed MRI evidence of MP out of the 5682 knee arthroscopies that we performed. We recorded pre and post-operative Tegner Lysholm knee scale scores (TLKSS) for up to 36 (3, 6, 12, 24, 36) months. The EQ-5D questionnaire was used to measure the patients' generic health status. RESULTS: The mean values of the TLKSS were 68 (61-82) pre operative, 87 (81-94) at the 3-month follow-up and 94 (92-97) at the 6-month follow-up. The long term results (TLKSS at 12, 24, and 36 months post operatively) were 94.8 (91-98), 94.8 (90-97), and 94.5 (92-97) respectively. The EQ-5D and EQ-VAS showed significant improvement between each of the first three data registering moments (pre-operative, 3 and 6 month follow-up). CONCLUSION: The quality of the treatment and the final functional result is directly influenced by the type of plica that creates the symptomatology. We have achieved good overall results for our patients, the ones with less cartilage damage having the fastest recovery time. The arthroscopic resection is a very good option for medial plicae that do not respond to conservative treatment, and it must be initiated as a first option when cartilage damage is suspected. PMID- 27761632 TI - Comparative risk of chronic kidney diseases in patients with urolithiasis and urological interventions: a longitudinal population-based study. AB - Large cohort studies on whether any association existed between urological interventions for urolithiasis and the development of CKD are lacking. From claims data of the National Health Insurance (NHI) program of Taiwan, we identified 54,433 patients newly diagnosed with urolithiasis during 1998-2010. For each case, four individuals without urolithiasis were randomly selected and frequency matched by age, sex, and diagnosis year. Both groups were followed up until the end of 2010. Incident CKD events were identified by the International Classification of Diseases, Ninth Revision (ICD-9) code in the NHI registration database. The overall incidence of periodontal diseases was 1.85-fold greater in the urolithiasis group than in the comparison group (33.9 vs 18.3 per 10,000 person-years; 95 % confidence interval [CI] 1.81-1.90). Compared with the adjusted hazard ratios (aHRs) of nonurolithiasis patients, those of patients with urolithiasis increased with the number of medical visits (from 0.91 [95 % CI 0.83 1.00] to 10.6 [95 % CI 9.48-11.8]) and urological interventions (from 1.22 [95 % CI 1.10-1.35] to 86.4 [95 % CI 67.6-110.6]). The aHR was similar in different urological intervention methods, extracorporeal shock wave lithotripsy, ureteroscopy, percutaneous nephrostolithotomy, and open stone surgery. The urological intervention for urolithiasis is associated with an increased risk of CKD. We should be aware of the risk for CKD, especially in patients who have received multiple urological interventions and those elderly. PMID- 27761631 TI - Dual-mobility implants prevent hip dislocation following hip revision in obese patients. AB - PURPOSE: Revision total hip arthroplasty (THA) is associated with increased rates of dislocation in obese patients. It is not known whether dual-mobility implants decrease dislocation in these patients with obesity. METHODS: We retrospectively reviewed two groups of revision THAs to compare the dislocation rate between 32 obese patients (BMI >30 kg/m2) with standard cups, and 35 obese patients (BMI >30 kg/m2) with dual-mobility cups. All patients received the same implants except for diameter head (32-mm head with standard cups and 28-mm head with dual mobility) and had the same cemented stem that was not changed at revision. The patients were followed at routine intervals and were specifically queried about dislocation. The two groups were similar in terms of age, gender, causes of revision and follow-up since the primary arthroplasty. RESULTS: With standard liners, more hips in obese patients dislocated than did hips in obese patients who received dual-mobility implants. The number of dislocations in standard hips was at one year follow-up 15.6 % (5 of 32) compared with 0 % in dual-mobility hips and was at five year follow-up 21.8 % (7 of 32) compared with 2.8 % (1 of 35). After a mean follow-up of seven years no cases of loosening were found. Five patients in the obese group with a standard liner underwent re-revision surgery, the additional re-operations being necessary to treat recurrent postoperative dislocation. CONCLUSIONS: Obese patients should be counselled about the important risk of dislocation that occurs with standard liners after revision THA. Dual mobility liners in these patients with hip revision is an efficient technique to prevent post-operative hip dislocation. PMID- 27761633 TI - Does a retropulsion prevention device equalize the surgical success of Ho:YAG laser and pneumatic lithotripters for upper ureteral stones? A prospective randomized study. AB - To establish if a retropulsion prevention device for ureteral stones equalizes surgical success and push-back rates of Ho:YAG laser and pneumatic lithotripters for upper ureteral stones. Patients with upper ureteral stones (n = 267) were treated endoscopically at the Department of Urology between April 2014 and December 2015. Patients were randomly assigned to pneumatic and Ho:YAG laser lithotripters as group-1 and group-2, respectively. Lithotripsy was performed with Stone ConeTM in both groups. The surgical success rate on the first postoperative day was 81.5 % (n = 106) and 90.6 % (n = 116) for group-1 and group 2, respectively, and the difference between the groups was statistically significant (p < 0.05). The relation between stone size and surgical success was statistically significant for both groups (p < 0.01). Surgical success for the stones closer than 2 cm to the UPJ was 23.1 % for the pneumatic group versus 64 % for the laser group (p < 0.01). Lithotripsy time was significantly longer in group-2 (16.48 +/- 4.74 min) than group-1 (12.24 +/- 3.95 min) (p < 0.01). Ho:YAG laser lithotripsy is more successful than pneumatic lithotripsy for upper ureteral stones and a retropulsion prevention device does not equalize the surgical success of Ho:YAG laser and pneumatic lithotripters for upper ureteral stones on the first postoperative day and one month after surgery. Although the success rate of the first month after surgery is higher in group-2, the difference is not statistically significant. PMID- 27761634 TI - Multi-modular engineering of 1,3-propanediol biosynthesis system in Klebsiella pneumoniae from co-substrate. AB - 1,3-Propanediol (1,3-PDO) is a monomer for the synthesis of various polyesters. It is widely used in industries including cosmetics, solvents, and lubricants. Here, the multi-modular engineering was used to improve the concentration and tolerance of 1,3-PDO in Klebsiella pneumoniae. Firstly, the concentration of 1,3 PDO was increased by 25 %, while the concentrations of by-products were reduced considerably through one-step evolution which focused on the glycerol pathway. In addition, the 1,3-PDO tolerance was improved to 150 g L-1. Secondly, co-substrate transport system was regulated, and the 1,3-PDO concentration, yield, and productivity of the mutant were improved to 76.4 g L-1, 0.53 mol mol-1, and 2.55 g L-1 h-1, respectively. Finally, NADH regeneration was introduced and the recombinant strain was successfully achieved with a high productivity of 2.69 g L 1 h-1. The concentration and yield of 1,3-PDO were also improved to 86 g L-1 and 0.59 mol mol-1. This strategy described here provides an approach of achieving a superior strain which is able to produce 1,3-PDO with high productivity and yield. PMID- 27761635 TI - The application of biotechnology on the enhancing of biogas production from lignocellulosic waste. AB - Anaerobic digestion of lignocellulosic waste is considered to be an efficient way to answer present-day energy crisis and environmental challenges. However, the recalcitrance of lignocellulosic material forms a major obstacle for obtaining maximum biogas production. The use of biological pretreatment and bioaugmentation for enhancing the performance of anaerobic digestion is quite recent and still needs to be investigated. This paper reviews the status and perspectives of recent studies on biotechnology concept and investigates its possible use for enhancing biogas production from lignocellulosic waste with main emphases on biological pretreatment and bioaugmentation techniques. PMID- 27761637 TI - Bacterial membrane vesicles (MVs): novel tools as nature- and nano-carriers for immunogenic antigen, enzyme support, and drug delivery. AB - It is becoming well-known that bacterial cells produce membrane vesicles (MVs) from the cell surface in a budding manner, whereas the detailed mechanisms of MV biogenesis remain unclear. MVs are not authentic cells, since they are observed to be between 20 and 300 nm in size but have a structure close to the subcellular compartments. In a sense, the structure of MVs containing biogenic and cellular substances and their behavior look similar to those of viruses. Due to these scientific facts, several potent applications employing MVs as a promising tool have been proposed and reported. This review introduces a few outstanding examples for promising applications of MVs to biotechnology. PMID- 27761636 TI - Bacterial community radial-spatial distribution in biofilms along pipe wall in chlorinated drinking water distribution system of East China. AB - Biofilms in the pipe wall may lead to water quality deterioration and biological instability in drinking water distribution systems (DWDSs). In this study, bacterial community radial-spatial distribution in biofilms along the pipe wall in a chlorinated DWDS of East China was investigated. Three pipes of large diameter (300, 600, and 600 mm) were sampled in this DWDS, including a ductile cast iron pipe (DCIP) with pipe age of 11 years and two gray cast iron pipes (GCIP) with pipe ages of 17 and 19 years, and biofilms in the upper, middle, and lower parts of each pipe wall were collected. Real-time quantitative polymerase chain reaction (qPCR) and culture-based method were used to quantify bacteria. 454 pyrosequencing was used for bacterial community analysis. The results showed that the biofilm density and total solid (TS) and volatile solid (VS) contents increased gradually from the top to the bottom along the pipe wall. Microorganisms were concentrated in the upper and lower parts of the pipe wall, together accounting for more than 80 % of the total biomass in the biofilms. The bacterial communities in biofilms were significantly different in different areas of the pipe wall and had no strong interaction. Compared with the upper and lower parts of the pipe wall, the bacterial community in the middle of the pipe wall was distributed evenly and had the highest diversity. The 16S rRNA genes of various possible pathogens, including Escherichia coli, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Salmonella enterica, were detected in the biofilms, and the abundances of these possible pathogens were highest in the middle of the pipe wall among three areas. The detachment of the biofilms is the main reason for the deterioration of the water quality in DWDSs. The results of this study suggest that the biofilms in the middle of the pipe wall have highly potential risk for drinking water safety, which provides new ideas for the study of the microbial ecology in DWDS. PMID- 27761638 TI - Exploiting non-conserved residues to improve activity and stability of Halothermothrix orenii beta-glucosidase. AB - beta-glucosidase (EC 3.2.1.21; BG) cleaves beta-glucosidic linkages in disaccharide or glucose-substituted molecules. In an effort towards designing better BGs, we focused on the role of non-conserved residues across an otherwise homologous BG active site tunnel and designed mutants across the aglycone-binding site (V169C) and the gatekeeper residues (I246A) of the active site tunnel. We expressed in Escherichia coli, the Hore_15280 gene encoding a beta-glucosidase (BG) in Halothermothrix orenii. The overexpressed and purified wild-type (B8CYA8) has a high specific activity of 345 MUmol/min/mg on pNPGlc and a half-life of 1.13 h when assayed with pNPGlc at pH 7.1 and 70 degrees C. The specific activities of V169C and I246A were 1.7 and 1.2 times higher than that of wild type (WT) enzyme with the model substrate pNPGlc, while the activity on the natural substrate cellobiose was slightly higher to the WT. The two mutants were kinetically stable with 4.4- to 11-fold longer half-life compared to the WT enzyme. When the two mutations were combined to generate the V169C/I246A mutant, the specific activity increased to nearly twofold higher than WT on both substrates and the half-life increased fivefold. The two single mutants also show enhanced saccharification of insoluble natural biomass on supplementation of Trichoderma viride cellulase cocktail. These enhanced properties suggest the need for a closer look at the active site tunnel of these enzymes, especially across residues that are not conserved towards improving catalytic efficiencies. PMID- 27761639 TI - Current advances in molecular methods for detection of nitrite-dependent anaerobic methane oxidizing bacteria in natural environments. AB - Nitrite-dependent anaerobic methane oxidation (n-damo) process uniquely links microbial nitrogen and carbon cycles. Research on n-damo bacteria progresses quickly with experimental evidences through enrichment cultures. Polymerase chain reaction (PCR)-based methods for detecting them in various natural ecosystems and engineered systems play a very important role in the discovery of their distribution, abundance, and biodiversity in the ecosystems. Important characteristics of n-damo enrichments were obtained and their key significance in microbial nitrogen and carbon cycles was investigated. The molecular methods currently used in detecting n-damo bacteria were comprehensively reviewed and discussed for their strengths and limitations in applications with a wide range of samples. The pmoA gene-based PCR primers for n-damo bacterial detection were evaluated and, in particular, several incorrectly stated PCR primer nucleotide sequences in the published papers were also pointed out to allow correct applications of the PCR primers in current and future investigations. Furthermore, this review also offers the future perspectives of n-damo bacteria based on current information and methods available for a better acquisition of new knowledge about this group of bacteria. PMID- 27761640 TI - An autopsy confirmed case of progressive supranuclear palsy with predominant cerebellar ataxia. PMID- 27761641 TI - Impulse control behaviors and subthalamic deep brain stimulation in Parkinson disease. AB - To determine the clinical and demographic correlates of persistent, remitting, and new-onset impulse control behaviors (ICBs) before and after subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD). We compared the pre- and post-surgical prevalence of ICBs, classified as impulse control disorders (ICD), dopamine dysregulation syndrome (DDS), and punding in 150 consecutive PD STN-DBS treated patients and determined the association with motor, cognitive, neuropsychological, and neuropsychiatric endpoints. At baseline (before STN-DBS), ICBs were associated with younger age (p = 0.045) and male gender (85 %; p = 0.001). Over an average follow-up of 4.3 +/- 2.1 years of chronic STN-DBS there was an overall trend for reduction in ICBs (from 17.3 to 12.7 %; p = 0.095) with significant improvement in hypersexuality (12-8.0 %; p = 0.047), gambling (10.7 5.3 %; p = 0.033), and DDS (4.7-0 %; p < 0.001). ICB remitted in 18/26 patients (69 %) and persisted in 8/26 (31 %); the latter group was characterized by higher levodopa equivalent daily dose. Patients who developed a new-onset ICB during follow-up (n = 11/150) were characterized by younger age (p = 0.042), lower dyskinesia improvement (p <= 0.035), and a gender distribution with higher prevalence of women (p = 0.018). In addition, new-onset ICB was more common among patients with borderline, schizoid, and/or schizotypal traits of personality disorders; persistent ICB in those with obsessive-compulsive traits. PD-related ICBs exhibit a complex outcome after STN-DBS, with a tendency for overall reduction but with age, gender, dopaminergic therapy, and neuropsychiatric features exerting independent effects. PMID- 27761642 TI - Hans Queckenstedt (1876-1918). PMID- 27761643 TI - Letter to the Editor concerning "Treating multi-level cervical disc disease with hybrid surgery compared to anterior cervical discectomy and fusion: a systematic review and meta-analysis'' by Lu, V.M., Zhang, L., Scherman, D.B. et al. Eur Spine J (2016). doi:10.1007/s00586-016-4791-y. PMID- 27761644 TI - Reply to the Letter to the Editor of Yongzhao Zhao et al. concerning "Treating multi-level cervical disc disease with hybrid surgery compared to anterior cervical discectomy and fusion: a systematic review and meta-analysis" by Lu VM, Zhang L, Scherman DB et al. Eur Spine J (2016). doi:10.1007/s00586-015-4324-0. PMID- 27761645 TI - Rod fracture and lengthening intervals in traditional growing rods: is there a relationship? AB - PURPOSE: Is there any relationship between lengthening intervals and rod fracture in traditional growing rod (TGR) surgery? METHODS: A multicenter EOS database was queried for patients who had: (1) dual growing rods for EOS; (2) minimum 2-year follow-up; (3) a minimum of 2 lengthenings; and (4) revision surgery due to rod fracture. Of 138 patients who met the criteria: 56 patients experienced at least one-rod fracture (RF group) and 82 patients had no rod fractures (NRF group). In addition to each patient's lengthening intervals, demographics, construct details, and radiographic parameters were compared. RESULTS: RF and NRF patients had a mean pre-op age of 5.7 years (range 1.3-10.7) and 7.3 years (range 1.6 12.8), respectively (p < 0.001). There was no significant association between etiologies and rod fracture or between BMI and rod fracture (p = 0.979). There was no significant difference between lengthening intervals between the RF and NRF groups (p > 0.05). RF and NRF patients had statistically similar mean pre-op major curve size and max kyphosis (p = 0.279; p = 0.619, respectively). Stainless steel rods fractured more frequently compared with Titanium rods (SS 49.2 % vs. Ti 38 %; p = 0.004). Rod fracture occurred more in rods smaller than 4 mm (p = 0.011). CONCLUSIONS: Lengthening intervals were not statistically different in RF and NRF groups and there was no association between lengthening interval and rod fracture in TGR cases. It was shown that patients who had rod fracture were younger and were more likely to have SS rods with smaller than 4 mm diameter. PMID- 27761646 TI - [Viral arthritis and vasculitis]. AB - Viral arthritis and vasculitis are important differential diagnoses primarily in patients with acute polyarticular arthritis in association with fever and rash, in populations specially at risk and in returning travellers. Parvovirus B19 is the most frequent cause of viral arthritis in Europe, whereas rubella, hepatitis B and C viruses have become less common. Due to worldwide tourism arthritogenic alphaviruses, which are transmitted by mosquito vectors have come into the focus of tropical medicine and rheumatology. Viral arthritis is typically self-limiting but due to severe pain often requires symptomatic therapy with nonsteroidal antirheumatic drugs; however, arthritis and vasculitis may also be a manifestation of an important treatable viral infection, such as hepatitis B, C and human immunodeficiency viruses (HIV). PMID- 27761647 TI - The Pattern of Elastic Fiber Breakdown in Bleomycin-Induced Pulmonary Fibrosis May Reflect Microarchitectural Changes. AB - INTRODUCTION: Desmosine and isodesmosine (DID) are unique elastin crosslinks that may serve as biomarkers for elastic fiber degradation in chronic obstructive pulmonary disease. Previously, our laboratory found that the ratio of free to peptide-bound DID in bronchoalveolar lavage fluid (BALF) showed a significant positive correlation with the extent of airspace enlargement in an elastase model of pulmonary emphysema. To further evaluate this hypothesis, our laboratory measured this ratio in a bleomycin (BLM) model of pulmonary fibrosis, which involved different microarchitectural changes than those associated with pulmonary emphysema. METHODS: Syrian hamsters were instilled intratracheally with 1.0 unit BLM in 0.2 ml of normal saline (controls received the vehicle alone), and BALF was analyzed for both free and total DID, using a combination of liquid chromatography and tandem mass spectrometry. RESULTS: Total BALF DID was significantly increased in hamsters receiving BLM at 1 week post-treatment (92 vs 13 pg/ml; p < 0.001), consistent with elastic fiber degradation. However, in contrast to elastase-induced emphysema, free/bound DID was lower in BLM-treated animals compared to controls at both 1 week (0.76 vs 0.84) and 2 weeks post treatment (0.69 vs 0.86), though the differences were not statistically significant. CONCLUSIONS: These results indicate that it may be possible to identify specific pulmonary microarchitecture changes, based on the ratio of free to peptide-bound DID. It is speculated that the proportionate decrease in free DID in BLM-induced fibrosis may be due to preservation of intact elastic fibers as the lung injury progresses. PMID- 27761649 TI - [Selectively implement defibrillator implantation]. PMID- 27761648 TI - Structural and functional characterisation of a class I endochitinase of the carnivorous sundew (Drosera rotundifolia L.). AB - MAIN CONCLUSION: Chitinase gene from the carnivorous plant, Drosera rotundifolia , was cloned and functionally characterised. Plant chitinases are believed to play an important role in the developmental and physiological processes and in responses to biotic and abiotic stress. In addition, there is growing evidence that carnivorous plants can use them to digest insect prey. In this study, a full length genomic clone consisting of the 1665-bp chitinase gene (gDrChit) and adjacent promoter region of the 698 bp in length were isolated from Drosera rotundifolia L. using degenerate PCR and a genome-walking approach. The corresponding coding sequence of chitinase gene (DrChit) was obtained following RNA isolation from the leaves of aseptically grown in vitro plants, cDNA synthesis with a gene-specific primer and PCR amplification. The open reading frame of cDNA clone consisted of 978 nucleotides and encoded 325 amino acid residues. Sequence analysis indicated that DrChit belongs to the class I group of plant chitinases. Phylogenetic analysis within the Caryophyllales class I chitinases demonstrated a significant evolutionary relatedness of DrChit with clade Ib, which contains the extracellular orthologues that play a role in carnivory. Comparative expression analysis revealed that the DrChit is expressed predominantly in tentacles and is up-regulated by treatment with inducers that mimick insect prey. Enzymatic activity of rDrChit protein expressed in Escherichia coli was confirmed and purified protein exhibited a long oligomer specific endochitinase activity on glycol-chitin and FITC-chitin. The isolation and expression profile of a chitinase gene from D. rotundifolia has not been reported so far. The obtained results support the role of specific chitinases in digestive processes in carnivorous plant species. PMID- 27761650 TI - Examining the socioeconomic effects on third molar maturation in a Portuguese sample of children, adolescents and young adults. AB - INTRODUCTION: The impact of socioeconomic status (SES) on tooth mineralization has seldom been evaluated. This is important because SES can be used as a proxy for quantifying factors in the environmental that can impact mineralization but that can be difficult to measure directly, such as nutrition. OBJECTIVE: The objective of this study was to examine the effects of SES on third molar mineralization, using a sample of children, adolescents and young adults from Porto, Portugal. METHODS: Panoramic x-rays from 1747 patients (842 males and 904 females) were used in this study. Eight hundred and fifteen individuals were patients attending a private practice and were classified as high SES (384 males and 458 females), whereas the remaining 932 subjects (458 males and 474 females) were patients attending the dental clinic at the Faculty of Dental Medicine, University of Porto and were classified as low SES. Inclusion of individuals on the each SES group was also based on parental and own occupation. The mandibular third molar was assessed for its maturation using Demirjian's stages. The median age of attainment of root stages was calculated for stages D to H, using logistic regression and compared between the high and low SES samples. RESULTS: Boys from the higher SES group show an earlier median age of attainment for stages D, E, and F. Girls from the higher SES group also show an earlier median age of attainment, but for stages D and E. Stages G and H did not show SES differences in both sexes. CONCLUSIONS: Patients from the higher SES group showed a consistent advancement in maturation of the third molar, although SES differences diminish and eventually disappear in the last stages of root maturation. An accelerated effect related to overweight and obesity is suggested as the primary explanation. PMID- 27761651 TI - SUMO proteases OTS1 and 2 control filament elongation through a DELLA-dependent mechanism. AB - KEY MESSAGE: SUMOylation and anther growth. During fertilization, stamen elongation needs to be synchronized with pistil growth. The phytohormone gibberellic acid (GA) promotes stamen growth by stimulating the degradation of growth repressing DELLA proteins. DELLA accumulation is negatively regulated by GAs through the ubiquitin-proteasome system. In Arabidopsis thaliana, a proportion of DELLAs is also conjugated to the small ubiquitin-like modifier (SUMO) protein, which stabilizes DELLAs. Increased DELLA levels occur in the SUMO protease-deficient OVERLY TOLERANT TO SALT 1 and 2 (ots1 ots2) double mutants, especially under salt stress conditions. Here, we show that OTS genes play a redundant role in the control of plant fertility under non-stress conditions. Mutants of ots1 ots2 display reduced fertility compared with the wild type, owing to reduced stamen elongation. Stamen growth, pollination rate and seed production are restored in ots1 ots2 della mutants, thus linking OTS1 function to the control of DELLA activity in the context of filament elongation. OTS levels appear to be developmentally regulated as OTS1/2 transcript upregulation during stamen development overlaps with GAs accumulations. We propose that OTS genes enable synchronization of stamen development by facilitating DELLA degradation at a specific developmental stage. PMID- 27761652 TI - Stigmatization of psychiatric symptoms and psychiatric service use: a vignette based representative population survey. AB - Background There is evidence for two different types and/or sources of mental illness stigma, namely the display of psychiatric symptoms and the use of psychiatric service institutions. However, no current study has compared the two. Furthermore, gaps exist in our knowledge of both types of stigma. Little is known about the perceived stigma of specific psychiatric service treatment environments, for instance forensic settings. In addition, systematic research on stigma attached to symptoms of personality disorders in the general population is scarce, and for borderline personality disorder, nonexistent. Methods We conducted a representative survey of the general population (N = 2207) in the canton of Basel-Stadt, Switzerland. Participants were asked to read a vignette depicting either the psychiatric symptoms of a fictitious character or a psychiatric service institution to which the character had been admitted, and indicate desired social distance (an indicator for stigma). Type of symptoms, type of psychiatric service, dangerousness, and gender were systematically varied between vignettes. Findings Desired social distance was significantly lower in relation to psychiatric service use than to psychiatric symptoms. Overall, symptoms of alcohol dependency, behavior endangering others, and the fictitious character's being male tend to increase stigmatization. Interestingly, the character's being hospitalized in a psychiatric unit at a general hospital and also respondent familiarity with psychiatric services tend to decrease stigmatization. Interpretation Familiarity of the general population with psychiatric patients should be increased. Furthermore, treatment in psychiatric units located within general hospitals should be promoted, as such treatment is associated with decreased stigma. PMID- 27761654 TI - Cellotriose-hydrolyzing activity conferred by truncating the carbohydrate-binding modules of Cel5 from Hahella chejuensis. AB - Processivity is a typical characteristic of cellobiohydrolases (CBHs); it enables the enzyme to successively hydrolyze the ends of cellulose chains and to produce cellobiose as the major product. Some microbes, which do not have CBHs, utilize endoglucanases (EGs) that exhibit processivity, commonly referred to as processive EGs. A processive EG identified from Hahella chejuensis, HcCel5, has a catalytic domain (CD) belonging to the glycoside hydrolase family 5 (GH5) and two carbohydrate-binding modules (CBM6s). In this study, we compared HcCel5-CD with the CD of Saccharophagus degradans Cel5H (SdCel5H-CD), which is a processive EG reported previously. Our results showed that in comparison to SdCel5H-CD, HcCel5 CD has more suitable characteristics for cellulose hydrolysis, such as higher hydrolytic activity, thermostability (40-80 degrees C), and processivity. Noticeably, HcCel5-CD is capable of hydrolyzing cellotriose, unlike HcCel5. These features of HcCel5-CD for cellulose hydrolysis could be employed for efficient saccharification of lignocellulose to produce cellobiose and glucose, which may be used to produce renewable fuels and chemicals. PMID- 27761653 TI - Sex-related differences in matrix remodeling and early osteogenic markers in aortic valvular interstitial cells. AB - Calcific aortic valve disease (CAVD) is a major cardiovascular disorder in the developed countries. Male is a known risk factor in this disease; unfortunately, how sex contributes to CAVD is mostly unknown. The objective of this study is to determine whether valvular interstitial cells (VICs) isolated from male versus female aortic valves demonstrate difference in osteogenic differentiation and/or extracellular matrix (ECM) remodeling. VICs were isolated from male and female rat or porcine aortic valves and cultured in osteogenic media for 10, 15 and 20 days. The proliferation among male and female VICs was assessed by a cell growth assay. The matrix remodeling of the VIC samples was quantified using glycosaminoglycan (GAG), collagen type I and gelatin zymography assays. Early osteogenic marker expression was assessed using alkaline phosphatase (ALP) staining and enzyme activity assay and Alizarin Red S staining. Our result showed that proliferation of VICs was significantly greater in female than male after 12 days of culture in regular media. Additionally, male VICs showed elevated amounts of normalized GAG, collagen I, and activated matrix metallopreoteniase-2 expression compared to female. Similarly, ALP content was greater in male VICs than female at all time points. In addition, male VICs formed calcific nodules with greater size, % area and integrated density than females. The results from this research suggest that there is a sex-related difference in the events associated with osteogenic differentiation of the aortic VICs, where male VICs are more prone to calcification. PMID- 27761655 TI - Alkaline-assisted screw press pretreatment affecting enzymatic hydrolysis of wheat straw. AB - Screw press processing of biomass can be considered as a suitable mechanically based pretreatment for biofuel production since it disrupts the structure of lignocellulosic biomass with high shear and pressure forces. The combination with chemical treatment has been suggested to increase the conversion of lignocellulosic biomass to fermentable sugars. Within the study, the synergetic effect of alkaline (sodium hydroxide, NaOH) soaking and screw press pretreatment on wheat straw was evaluated based on, e.g., sugar recovery and energy efficiency. After alkaline soaking (at 0.1 M for 30 min) and sequential screw press pretreatment with various screw press configurations and modified screw barrel, the lignin content of pretreated wheat straw was quantified. In addition, the structure of pretreated wheat straw was investigated by scanning electron microscopy and measurement of specific surface area. It could be shown that removal of lignin is more important than increase of surface area of the biomass to reach a high sugar recovery. The rate constant of the enzymatic hydrolysis increased from 1.1 * 10-3 1/h for the non-treated material over 2.3 * 10-3 1/h for the alkaline-soaked material to 26.9 * 10-3 1/h for alkaline-assisted screw press pretreated material, indicating a nearly 25-fold improvement of the digestibility by the combined chemo-mechanical pretreatment. Finally, the screw configuration was found to be an important factor for improving the sugar recovery and for reducing the specific energy consumption of the screw press pretreatment. PMID- 27761658 TI - A recent experience as neurosurgical registrar in UK. "Legal" differences with the Italian system and on-call duties. PMID- 27761656 TI - HOXB8 promotes tumor metastasis and the epithelial-mesenchymal transition via ZEB2 targets in gastric cancer. AB - PURPOSE: The homeobox B8 (HOXB8) functions as a sequence-specific transcription factor that is involved in development. Increased expression of this gene is associated with a wide variety of tumor; however, its function in gastric cancer has not been clarified. In the present study, the expression of HOXB8 in gastric cancer tissues and influence of HOXB8 on gastric cancer cellular were evaluated. METHODS: The expression levels of HOXB8 mRNA in human gastric cancer tissues were analyzed through quantitative RT-PCR. To test the role of HOXB8 in gastric cancer metastasis, the cell transwell assay was performed. Microarray, ChIP-qPCR, and Western blot were used to explore the possible mechanism that HOXB8 promotes gastric cancer cells metastasis. RESULTS: In this study, we found that HOXB8 showed higher expression in metastatic tissues than no-metastatic tissues. Overexpression of HOXB8 can promote gastric cancer cells migration and invasion, while silencing HOXB8 leads to the opposite results. Overexpression of HOXB8 also increases the rate of metastasis in NCI-N87 mice, while silencing HOXB8 has the opposite results. Furthermore, HOXB8 promotes epithelial-mesenchymal transformation of AGS cells. We also found that ZEB2 can interact with HOXB8 and may be a downstream factor of HOXB8 by using microarray. Knockdown of ZEB2 can inhibit HOXB8-induced migration and invasion capacity, as well as the epithelial mesenchymal transformation in gastric cancer cells. CONCLUSIONS: The results showed that HOXB8 plays an important role in the development and metastasis of gastric carcinoma. PMID- 27761657 TI - High-intensity Interval training enhances mobilization/functionality of endothelial progenitor cells and depressed shedding of vascular endothelial cells undergoing hypoxia. AB - PURPOSE: Exercise training improves endothelium-dependent vasodilation, whereas hypoxic stress causes vascular endothelial dysfunction. Monocyte-derived endothelial progenitor cells (Mon-EPCs) contribute to vascular repair process by differentiating into endothelial cells. This study investigates how high intensity interval (HIT) and moderate-intensity continuous (MCT) exercise training affect circulating Mon-EPC levels and EPC functionality under hypoxic condition. METHODS: Sixty healthy sedentary males were randomized to engage in either HIT (3-min intervals at 40 and 80 % VO2max for five repetitions, n = 20) or MCT (sustained 60 % VO2max, n = 20) for 30 min/day, 5 days/week for 6 weeks, or to a control group (CTL) that did not received exercise intervention (n = 20). Mon-EPC characteristics and EPC functionality under hypoxic exercise (HE, 100 W under 12 % O2) were determined before and after HIT, MCT, and CTL. RESULTS: The results demonstrated that after the intervention, the HIT group exhibited larger improvements in VO2peak, estimated peak cardiac output (QC), and estimated peak perfusions of frontal cerebral lobe (QFC) and vastus lateralis (QVL) than the MCT group. Furthermore, HIT (a) increased circulating CD14++/CD16-/CD34+/KDR+ (Mon-1 EPC) and CD14++/CD16+/CD34+/KDR+ (Mon-2 EPC) cell counts, (b) promoted the migration and tube formation of EPCs, (c) diminished the shedding of endothelial (CD34-/KDR+/phosphatidylserine+) cells, and (d) elevated plasma nitrite plus nitrate, stromal cell-derived factor-1, matrix metalloproteinase-9, and vascular endothelial growth factor-A concentrations at rest or following HE, compared to those of MCT. In addition, Mon-1 and -2 EPC counts were directly related to VO2peak and estimated peak QC, QFC, and QVL. CONCLUSIONS: HIT is superior to MCT for improving hemodynamic adaptation and Mon-EPC production. Moreover, HIT effectively enhances EPC functionality and suppresses endothelial injury undergoing hypoxia. PMID- 27761659 TI - Reasons for scientific rigor and skepticism revisited. PMID- 27761661 TI - Comparison of short-axis out-of-plane versus long-axis in-plane ultrasound-guided radial arterial cannulation in adult patients: a randomized controlled trial. AB - BACKGROUND: The current available literature is not unanimous in reporting the utility of short-axis and long-axis techniques for radial artery cannulation in both adults and children. This study was designed to compare short-axis out-of plane (SA-OOP) and long-axis in-plane (LA-IP) techniques in ultrasound-guided radial artery cannulation in adults. METHODS: In this prospective randomized controlled trial, 150 adult patients of American Society of Anesthesiologists physical status I-III aged between 18 and 70 years were included. All patients were randomized into two groups (group SA-OOP) and (group LA-IP) of 75 each undergoing ultrasound-guided radial artery cannulation. The primary outcome was successful cannulation in the first attempt. Secondary outcomes included antero posterior arterial diameter, skin-to-artery distance, ultrasonic localization time, cannulation time, no of attempts to cannulate artery, cannula insertion failure, and vascular complications. RESULTS: First-attempt arterial cannulation was successful in 80 % of patients in the SA-OOP group as opposed to 82.6 % patients in the LA-IP group (p = 0.67). The time to cannulate the artery was similar between the two groups, but the time to localize artery was significantly higher in the long-axis technique (p < 0.001). CONCLUSIONS: The first-attempt cannulation success rate and cannulation time in adult patients are similar in ultrasound-guided radial artery cannulation with both short-axis as well as long axis techniques. Trial registration Clinical Trial Registry of India (CTRI/2015/02/005552). PMID- 27761660 TI - Timing of renal replacement therapy does not influence survival and growth in children with congenital nephrotic syndrome caused by mutations in NPHS1: data from the ESPN/ERA-EDTA Registry. AB - BACKGROUND: Congenital nephrotic syndrome (CNS) of the Finnish type, NPHS1, is the most severe form of CNS. Outcomes of renal replacement therapy (RRT) in NPHS1 patients in Europe were analysed using data from the ESPN/ERA-EDTA Registry. As NPHS1 is most prevalent in Finland and the therapeutic approach differs from that in many other countries, we compared outcomes in Finnish and other European patients. METHODS: NPHS1 mutations were confirmed in 170 children with CNS who initiated RRT (dialysis or renal transplantation) between 1991 and 2012. Finnish (n = 66) and non-Finnish NPHS1 patients (n = 104) were compared with respect to treatment policy, age at first RRT and renal transplantation (RTX), patient and graft survival, estimated glomerular filtration rate (eGFR) and growth. Age matched patients with congenital anomalies of the kidney and urinary tract (CAKUT) served as controls. RESULTS: Finnish NPHS1 patients were significantly younger than non-Finnish patients, both at the start of RRT and at the time of RTX. We found similar overall 5-year patient survival on RRT (91 %) and graft survival (89 %) in both NPHS1 groups and CAKUT controls. At the start of RRT, height standard deviation score (SDS) was higher in Finnish patients than in non Finnish patients (mean [95 % CI]: -1.31 [-2.13 to -0.49] and -3.0 [-4.22 to 1.91], p < 0.01 respectively), but not at 5 years of age. At 5 years of age height and body mass index (BMI) SDS were similar to those of CAKUT controls. CONCLUSIONS: Overall, 5-year patient and graft survival of both Finnish and non Finnish NPHS1 patients on RRT were excellent and comparable with CAKUT patients with equally early RRT onset and was independent of the timing of RRT initiation and RTX. PMID- 27761662 TI - Non-vascularized bone grafting in scaphoid nonunion: principles and type of fixation. AB - In scaphoid fractures, delayed diagnosis and nonunion are fairly common as a result of several factors, including the difficulty of radiographic diagnosis of non-displaced fractures and underestimation of the injury by the patient. Main factors to consider when deciding treatment are the type of fracture and fracture stability. In the stable nonunion (Type D1 according to the Filan and Herbert classification, or linear type of Ikeda's classification), percutaneous screw fixation without bone graft is recommended. The indications of non-vascularized bone grafting are as follows: (1) arthroscopic cancellous bone graft in type D1 and cystic type of Ikeda's classification. (2) tricortical bone graft from the iliac crest in type D2 or D3 if the possibility of avascular necrosis of the proximal fragment is excluded. In this paper, our non-vascularized bone grafting for scaphoid nonunion would like to be described mainly about principles and type of fixation. PMID- 27761663 TI - A shift from arbuscular mycorrhizal to dark septate endophytic colonization in Deschampsia flexuosa roots occurs along primary successional gradient. AB - Soil fungal community and dominant mycorrhizal types are known to shift along with plant community changes during primary succession. However, it is not well understood how and why root fungal symbionts and colonization types vary within the plant host when the host species is able to thrive both at young and at old successional stages with different light and nutrient resource availability. We asked (i) how root fungal colonization of Deschampsia flexuosa (Poaceae) by arbuscular mycorrhizal (AM) fungi and dark septate endophytes (DSE) changes along a postglacial primary successional land uplift gradient. As neighboring vegetation may play a role in root fungal colonization, we also asked (ii) whether removal of the dominant neighbor, Empetrum nigrum ssp. hermaphroditum (Ericaceae), affects root fungal colonization of Deschampsia. We also studied whether (iii) foliar carbon (C) and nitrogen (N) concentration of Deschampsia is related to successional changes along a land uplift gradient. AM colonization decreased (-50 %), DSE colonization increased (+200 %), and foliar C declined in Deschampsia along with increasing successional age, whereas foliar N was not affected. Empetrum removal did not affect AM colonization but increased DSE sclerotial colonization especially at older successional stages. The observed decrease in foliar C coincides with an increase in canopy closure along with increasing successional age. We suggest that the shift from an AM-dominated to a DSE-dominated root fungal community in Deschampsia along a land uplift successional gradient may be related to different nutritional benefits gained through these root fungal groups. PMID- 27761664 TI - Increasing Performance of Professional Soccer Players and Elite Track and Field Athletes with Peak Performance Training and Biofeedback: A Pilot Study. AB - The aim of this pilot study was to investigate the effects of an intervention consisting of mental coaching combined with either electro encephalogram (EEG) alpha power feedback or heart rate variability (HRV) feedback on HRV, EEG outcomes and self-reported factors related to stress, performance, recovery and sleep quality in elite athletes. A prospective pilot study was performed with two distinct cohorts. Soccer players were provided with four sessions of mental coaching combined with daily HRV biofeedback (Group A); track and field athletes were provided with four sessions of mental coaching in combination with daily neurofeedback (Group B). Measurements were performed at baseline, post intervention and at 5 weeks follow-up. Objective measures: EEG and ECG. Subjective measures: Numeric Rating Scale for performance, Pittsburgh Sleep Quality Index, Rest and Stress Questionnaire and Sports Improvement-60. Group characteristics were too distinct to compare the interventions. Linear mixed models were used to analyze differences within groups over time. In Group A, significant changes over time were present in alpha power at 5 of 7 EEG locations (p < 0.01-0.03). LF/HF ratio significantly increased (p = 0.02) and the concentration (p = 0.02) and emotional scale (p = 0.03) of the SIM-60 increased significantly (p = 0.04). In Group B, the HRV low frequency power and recovery scale of the REST-Q significantly increased (p = 0.02 and <0.01 resp.). Other measures remained stable or improved non-significantly. A mental coaching program combined with either HRV or EEG alpha power feedback may increase HRV and alpha power and may lead to better performance-related outcomes and stress reduction. Further research is needed to elucidate the effects of either type of feedback and to compare effects with a control group. PMID- 27761665 TI - Somatosensory Brain Function and Gray Matter Regional Volumes Differ According to Exercise History: Evidence from Monozygotic Twins. AB - Associations between long-term physical activity and cortical function and brain structure are poorly known. Our aim was to assess whether brain functional and/or structural modulation associated with long-term physical activity is detectable using a discordant monozygotic male twin pair design. Nine monozygotic male twin pairs were carefully selected for an intrapair difference in their leisure-time physical activity of at least three years duration (mean age 34 +/- 1 years). We registered somatosensory mismatch response (SMMR) in EEG to electrical stimulation of fingers and whole brain MR images. We obtained exercise history and measured physical fitness and body composition. Equivalent electrical dipole sources of SMMR as well as gray matter (GM) voxel counts in regions of interest indicated by source analysis were evaluated. SMMR dipolar source strengths differed between active and inactive twins within twin pairs in postcentral gyrus, medial frontal gyrus and superior temporal gyrus and in anterior cingulate (AC) GM voxel counts differed similarly. Compared to active twins, their inactive twin brothers showed greater dipole strengths in short periods of the deviant elicited SMMR and larger AC GM voxel counts. Stronger activation in early unattended cortical processing of the deviant sensory signals in inactive co twins may imply less effective gating of somatosensory information in inactive twins compared to their active brothers. Present findings indicate that already in 30's long-term physical activity pattern is linked with specific brain indices, both in functional and structural domains. PMID- 27761666 TI - The 4th International One Health Congress and 6th Biennial Congress of the International Association for Ecology and Health 2016. PMID- 27761668 TI - Decrowding of lower anterior segment with and without photobiomodulation: a single center, randomized clinical trial. AB - The aim of this study was to evaluate the effect of low-level light therapy using light-emitting diodes (LEDs) on the speed of tooth movements that were required for the leveling and aligning of the lower anterior segment during non-extraction orthodontic treatment. The sample was comprised of patients (n = 40) with lower anterior crowding who were treated with self-ligating orthodontic brackets and a standardized wire sequence. A test group of patients (n = 20) who were treated with extraoral infrared light therapy for 20 min daily with at least 80 % compliance was compared to a control group (n = 20). The date of the first arch wire placement was recorded as T1, and the date of the completion of the lower anterior segment decrowding was recorded as T2. A final impression was also taken at T2. The time between T1 and T2 was significantly reduced by 22 % in the test group compared to the control group (68.3 vs. 87.8 days, respectively, p < 0.043). The use of photobiomodulation for 20 min daily at a wavelength of 850 nm might reduce the time required to resolve lower anterior crowding. This trial and its protocol were not registered on a publicly accessible registry. PMID- 27761667 TI - CO2 laser increases the regenerative capacity of human adipose-derived stem cells by a mechanism involving the redox state and enhanced secretion of pro-angiogenic molecules. AB - CO2 laser has a beneficial effect on stem cells by mechanisms that are not clearly elucidated. We hypothesize that the effect of fractional CO2 laser on human adipose-derived stem cells (ADSC) could be due to changes in redox homeostasis and secretion of factors contributing to cellular proliferation and angiogenic potential. ADSC incubated in medium containing 0.5 or 10 % FBS were exposed to a single irradiation of a 10,600-nm fractional CO2 laser; non irradiated ADSC were used as control. Viability/proliferation of ADSC was assessed by MTT assay; the intracellular reactive oxygen species (ROS) levels and the mitochondrial membrane potential (?Psim) were determined with DCFH-DA and JC 1 fluorescent probes, respectively. Molecules secreted by ADSC in the medium were determined by ELISA assay, and their capacity to support endothelial tube-like formation by the Matrigel assay. The results showed that compared to controls, ADSC kept in low FBS medium and irradiated with CO2 laser at 9 W exhibited: (a) increased proliferation (~20 %), (b) transient increase of mitochondrial ROS and the capacity to restore Deltapsim after rotenone induced depolarization, and (c) augmented secretion in the conditioned medium of MMP-2 (twofold), MMP-9 (eightfold), VEGF (twofold), and adiponectin (~50 %) that have the capacity to support angiogenesis of endothelial progenitor cells. In conclusion, the mechanisms underlying the benefic effect of CO2 laser on ADSC are the activation of the redox pathways which increases cell proliferation and enhances secretion of angiogenic molecules. These results explain, in part, the mechanisms involved in the increased regenerative potential of CO2 laser-exposed ADSC that could be exploited for clinical applications. PMID- 27761669 TI - Relationship between metal and pigment concentrations in the Fe-hyperaccumulator moss Scopelophila ligulata. AB - Scopelophila ligulata is known to be a Fe-hyperaccumulator moss; however, its mechanism of accumulation and the effects of Fe on pigments remain unclear. To clarify the effects, we measured its metal and pigment concentrations. The Fe concentration in S. ligulata was 10-61 times higher than that in normal mosses, confirming that the moss is a Fe-hyperaccumulator. The black samples of S. ligulata had the highest Fe concentration (2.9 wt%) and the second in the order of decreasing Fe concentration (2.2 wt%), which explains their color and indicates that the excess amount of Fe is distributed through the plant body. Moreover, we observed that the concentration of Ca is negatively correlated with the concentrations of pigments and, conversely, that the concentration of K is positively correlated with the concentrations of pigments. This inverse relationship between Ca and K can be explained by the reduced uptake of K in S. ligulata in response to Ca stress, which is supported by the fact that the concentration of Ca is negatively correlated with that of K. These findings provide a better understanding of the relationships between metals and pigments in the Fe-hyperaccumulator moss S. ligulata. PMID- 27761670 TI - The association between urinary liver-type fatty acid-binding protein and chronic kidney disease classification in HIV-infected Japanese patients. AB - BACKGROUND: Renal dysfunction is recognized with increasing frequency among the noninfectious comorbidities associated with human immunodeficiency virus (HIV) infection. Urinary liver-type fatty acid-binding protein (L-FABP) has been shown to be a new biomarker to screen for not only tubulointerstitial damage but also kidney dysfunction. METHODS: We performed a cross-sectional study to determine the association between the urinary L-FABP and chronic kidney disease (CKD) among 77 HIV-infected Japanese patients by backward-stepwise multivariable logistic regression. RESULTS: The prevalence of individuals in the low risk was 80 %. Urinary L-FABP level was not associated with antiretroviral therapy and tenofovir disoproxil fumarate. On the other hand, urinary L-FABP level was independently associated with the CKD classification. CONCLUSION: Urinary L-FABP may be used as an adjunct to diagnose the CKD stage. PMID- 27761671 TI - Preemptive kidney transplantation: a propensity score matched cohort study. AB - BACKGROUND: The reasons for improved outcomes associated with preemptive kidney transplantation (PKT) are incompletely understood, and post-transplant complications have been scarcely investigated. METHODS: We evaluated the outcomes of PKT in both unmatched (n = 1060) and propensity score matched cohorts (n = 186) of adults who underwent living kidney transplant between 2000 and 2014. Outcomes were estimated glomerular filtration rate (eGFR), biopsy-proven rejection, cytomegalovirus (CMV) infection, post-transplant diabetes mellitus (PTDM), cardiovascular disease (CVD), graft failure (non-censored for death), and malignancy. Primary endpoint was post-transplant renal function assessed with eGFR. RESULTS: A total of 95 patients (9.0 %) underwent PKT. The 2-week mean eGFR after transplant was comparable between the matched PKT and non-PKT groups (45.2 vs. 46.5 mL/min/1.73 m2, respectively, P = 0.56). Sensitivity analysis using various formulas did not change the results. PKT was not superior to non-PKT in reducing the risk of biopsy-proven rejection, CMV, PTDM, and malignancy, regardless of matching. The risk of graft failure and CVD was significantly reduced in the unmatched PKT group (ARR, -6.2 %; 95 % CI, -8.6 to -0.7; P = 0.03, and ARR, -6.7 %; 95 % CI, -9.6 to -0.7, P = 0.03, respectively); nevertheless, the corresponding ARRs were -3.2 % (95 % CI, -10.0 to 2.9; P = 0.44) and -2.2 % (95 % CI, -9.1 to 4.4; P = 0.72) after matching. CONCLUSIONS: PKT was associated with neither improvement of post-transplant renal function nor a lower rate of common post-transplant complications than non-PKT among patients with end-stage renal disease who underwent living KT. PMID- 27761673 TI - Detection of unsuspected pelvic DVTs on abdominopelvic CT scans: a potentially life-saving diagnosis. AB - Venous thromboembolism (VTE) is a serious common disorder with substantial cost and morbidity to society and can be life threatening in some cases. The majority of VTE is diagnosed on lower extremity ultrasound or CT pulmonary angiography, but some cases of deep venous thrombosis (DVT) may be occasionally diagnosed on CT of the abdomen and pelvis by the alert radiologist. The purpose of our study was to determine the fraction of new/unsuspected DVTs diagnosed on CTAP and the subsequent management and clinical course of these patients. After Institutional Review Board approval, a retrospective search of an institutional imaging database was performed for all cases of DVTs diagnosed on CTs of the abdomen and pelvis. Patients with positive studies were further investigated via clinical chart review for their subsequent management and clinical course. The 90-day mortality of the patients diagnosed with DVT on CTAP was also recorded. Sixty-two patients met the criteria for positive DVT on CTAP. Of these 62 cases, 26 (42 %) were new. Management was substantially changed in 24 out of 26 cases (92 %), most commonly initiation of anticoagulation. The 90-day mortality rate of patients diagnosed with pelvic DVTs on CTAP in our cohort was 21 %. Timely detection of pelvic DVTs can have serious implications for patient management, morbidity, and mortality. The pelvic veins should be included in the search pattern of all radiologists who review CTs of the abdomen and pelvis. PMID- 27761672 TI - Histologic tissue response to furcation perforation repair using mineral trioxide aggregate or dental pulp stem cells loaded onto treated dentin matrix or tricalcium phosphate. AB - OBJECTIVES: The aim of this study is to compare the effect of treated dentine matrix (TDM) and tricalcium phosphate (TCP) scaffolds on odontogenic differentiation and mineralization of dental pulp stem cells (DPSCs) in furcation perforations created in the pulp chamber floor of premolar teeth in dogs. MATERIAL AND METHODS: DPSCs were isolated and cultured from the dental pulp of the maxillary left second and third premolars of dogs. The DPSCs were loaded on TCP (SC+TCP) and TDM (SC+TDM) scaffolds and inserted into intentionally perforated pulp chamber floors of premolars in dogs; six teeth were used for each group. Three more groups of six specimens were created, and mineral trioxide aggregate (MTA), TDM, and TCP were inserted into the perforations to act as controls. An intact premolar and no treatment in the perforation site were used as positive and negative controls respectively. After 3 months, the animals were sacrificed and the type of inflammation, presence of dentine, continuation and type of cementum, type of connective tissue, and presence of foreign body reaction were evaluated, and significant differences were between groups determined using the Fisher's exact test. The evaluation of the amount of inflammation and the percentage of new bone formation was evaluated using the Mann-Whitney U test. RESULTS: The negative control group was associated with severe inflammation and granulation tissue formation. In the positive control group, intact periodontal tissues and no inflammation were observed. Dentine bridge formation was not seen in specimens of any group. The specimens in the SC+TDM group were associated with significantly more bone formation than other groups (P < 0.001). The amount of inflammation was less than 10 % in specimens of all groups with the exception of three specimens in the TCP group that were categorized as 10-30 %. Chronic inflammation without foreign body reactions was the major pattern of inflammation in groups. Formation of cementum with a cellular and continuous appearance was seen in all specimens. CONCLUSIONS: SC+TDM was associated with significantly more bone formation when used to repair uninfected furcation perforations in the premolar teeth of dogs. CLINICAL RELEVANCE: Application of TDM as a biological scaffold in combination with DPSCs may offer an advantage during the repair of root perforation defects. PMID- 27761674 TI - Autonomic dysfunction in pediatric patients with headache: migraine versus tension-type headache. AB - PURPOSE: To examine symptoms indicating central nervous system (CNS) autonomic dysfunction in pediatric patients with migraine and tension-type headache. METHODS: A retrospective chart review assessed six symptoms (i.e. constipation, insomnia, dizziness, blurry vision, abnormal blood pressure, and cold and clammy palms and soles) indicating central nervous system (CNS) autonomic dysfunction in 231 patients, ages 5-18 years, diagnosed with migraine, tension-type headache (TTH), or Idiopathic Scoliosis (IS). RESULTS: Higher frequencies of "insomnia," "dizziness," and "cold and clammy palms and soles" were found for both migraine and TTH patients compared to the IS control group (P < 0.001). Frequencies of all six symptoms were greater in TTH than migraine patients with "cold and clammy palms and soles" reaching significance (P < 0.001). CONCLUSIONS: The need for prospective research investigating autonomic dysfunction in pediatric headache patients is discussed. PMID- 27761675 TI - A Greedy Algorithm for Brain MRI's Registration. AB - This document presents a non-rigid registration algorithm for the use of brain magnetic resonance (MR) images comparison. More precisely, we want to compare pre operative and post-operative MR images in order to assess the deformation due to a surgical removal. The proposed algorithm has been studied in Chesseboeuf et al. ((Non-rigid registration of magnetic resonance imaging of brain. IEEE, 385-390. doi: 10.1109/IPTA.2015.7367172 , 2015), following ideas of Trouve (An infinite dimensional group approach for physics based models in patterns recognition. Technical Report DMI Ecole Normale Superieure, Cachan, 1995), in which the author introduces the algorithm within a very general framework. Here we recalled this theory from a practical point of view. The emphasis is on illustrations and description of the numerical procedure. Our version of the algorithm is associated with a particular matching criterion. Then, a section is devoted to the description of this object. In the last section we focus on the construction of a statistical method of evaluation. PMID- 27761678 TI - Circulating tumor cells in breast cancer: applications in personalized medicine. AB - Recent technological advancements in rare cell analysis have facilitated the detection of circulating tumor cells (CTCs) in the blood of patients diagnosed with breast and other types of cancers. Numerous clinical studies involving the enumeration of CTCs in breast cancer patients have unequivocally demonstrated the prognostic value of these cells. Evidence from recent molecular studies indicates that CTCs may be potential surrogate markers for systemic disease. As such, real time assessment of therapeutic biomarkers in breast CTCs, such as the estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2), may have a tremendous impact in guiding-targeted cancer therapy. In this review, we discuss the clinical implications of CTC detection and its potential utility for personalized medicine in breast cancer. PMID- 27761676 TI - Multicompartment analysis of protein-restricted phenylketonuric mice reveals amino acid imbalances in brain. AB - BACKGROUND: The mainstay of therapy for phenylketonuria (PKU) remains dietary protein restriction. Developmental and neurocognitive outcomes for patients, however, remain suboptimal. We tested the hypothesis that mice with PKU receiving protein-restricted diets would reveal disruptions of brain amino acids that shed light on these neurocognitive deficits. METHOD: Phenylalanine hydroxylase deficient (PKU) mice and parallel controls (both wild-type and heterozygous) were fed custom diets containing 18, 6, and 4 % protein for 3 weeks, after which tissues (brain, liver, sera) were collected for amino acid analysis profiling. RESULTS: Phenylalanine (phe) was increased in all tissues (p < 0.0001) of PKU mice and improved with protein restriction. In sera, decreased tyrosine (p < 0.01) was corrected (defined as not significantly different from the level in control mice receiving 18 % chow) with protein restriction, whereas protein restriction significantly increased many other amino acids. A similar trend for increased amino acid levels with protein restriction was also observed in liver. In brain, the effects of protein restriction on large neutral amino acids (LNAAs) were variable, with some deficit correction (threonine, methionine, glutamine) and no correction of tyrosine under any dietary paradigm. Protein restriction (4 % diet) in PKU mice significantly decreased lysine, arginine, taurine, glutamate, asparagine, and serine which had been comparable to control mice under 18 % protein intake. CONCLUSION: Depletion of taurine, glutamate, and serine in the brain of PKU mice with dietary protein restriction may provide new insight into neurocognitive deficits of PKU. PMID- 27761677 TI - Tissue recovery practices and bioburden: a systematic review. AB - For successful transplantation, allografts should be free of microorganisms that may cause harm to the allograft recipient. Before or during recovery and subsequent processing, tissues can become contaminated. Effective tissue recovery methods, such as minimizing recovery times (<24 h after death) and the number of experienced personnel performing recovery, are examples of factors that can affect the rate of tissue contamination at recovery. Additional factors, such as minimizing the time after asystole to recovery and the total time it takes to perform recovery, the type of recovery site, the efficacy of the skin prep performed immediately prior to recovery of tissue, and certain technical recovery procedures may also result in control of the rate of contamination. Due to the heterogeneity of reported recovery practices and experiences, it cannot be concluded if the use of other barriers and/or hygienic precautions to avoid contamination have had an effect on bioburden detected after tissue recovery. Qualified studies are lacking which indicates a need exists for evidence-based data to support methods that reduce or control bioburden. PMID- 27761679 TI - Improved Adherence to Antiretroviral Therapy Observed Among HIV-Infected Children Whose Caregivers had Positive Beliefs in Medicine in Sub-Saharan Africa. AB - A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART. PMID- 27761680 TI - Design of a multi-enzyme reaction on an electrode surface for an L-glutamate biofuel anode. AB - OBJECTIVES: To design and construct a novel bio-anode electrode based on the oxidation of glutamic acid to produce 2-oxoglutarate, generating two electrons from NADH. RESULTS: Efficient enzyme reaction and electron transfer were observed owing to immobilization of the two enzymes using a mixed self-assembled monolayer. The ratio of the immobilized enzymes was an important factor affecting the efficiency of the system; thus, we quantified the amounts of immobilized enzyme using a quartz crystal microbalance to further evaluate the electrochemical reaction. The electrochemical reaction proceeded efficiently when approximately equimolar amounts of the enzyme were on the electrode. The largest oxidation peak current increase (171 nA) was observed under these conditions. CONCLUSION: Efficient multi-enzyme reaction on the electrode surface has been achieved which is applicable for biofuel cell application. PMID- 27761682 TI - Investigating acculturation orientations of patients with an immigration background and doctors in Canada: implications for medical advice adherence. AB - BACKGROUND: Increased immigration requires successful interaction of different cultures in various life domains, such as health. This study investigates acculturation orientation (AO) of immigrant patients and doctors native to the country, as a potential factor related to perceived medical advice adherence. DATA AND METHODS: N = 171 immigrant patients (M = 54.38 years, SD = 17.94, range = 23-96, 74.3 % female) and their N = 12 doctors (M = 38.88 years, SD = 13.42, range = 27-66, 83 % female) from a hospital in Montreal, Canada, participated in a paper-based survey to assess AOs, patients' perceived expectations of their doctor (regarding adopting the new culture or keeping their previous culture), doctors' actual expectations, perceived quality of care and perceived adherence. RESULTS: AO of patients significantly related to perceived adherence, via a path model involving perceptions of doctors' expectations and perceived quality of care. Integration was positively related to perceived adherence, while Marginalization was negatively related to it. Doctors' AOs were not significant. CONCLUSION: Patient perceptions seem to be a significant factor to be considered when striving to improve immigrant medical advice adherence. PMID- 27761683 TI - The Association of Minority Self-Rated Health with Black versus White Gentrification. AB - There exists controversy as to the impact gentrification of cities has on the well-being of minorities. Some accuse gentrification of causing health disparities for disadvantaged minority populations residing in neighborhoods that are changing as a result of these socioeconomic shifts. Past scholarship has suggested that fears of displacement and social isolation associated with gentrification lead to poorer minority health. However, there is a lack of research that directly links gentrification to minority health outcomes. We address this gap with individual data from the 2008 Philadelphia Health Management Corporation's Southeastern Pennsylvania Household Health Survey and census tract data from the 2000 Decennial Census and the 2006-2010 American Community Survey. We implement logistic multilevel models to determine whether and how a resident's self-rated health is affected by gentrification of their neighborhoods. We find that while gentrification does have a marginal effect improving self-rated health for neighborhood residents overall, it leads to worse health outcomes for Blacks. Accounting for racial change, while gentrification leading to increases in White population has no measurable effect on minority health, "Black gentrification" leads to marginally worse health outcomes for Black respondents. These results demonstrate the limitations that improvements of neighborhood socioeconomic character have in offsetting minority health disparities. PMID- 27761681 TI - Diadenosine tetraphosphate (Ap4A) inhibits ATP-induced excitotoxicity: a neuroprotective strategy for traumatic spinal cord injury treatment. AB - Reducing cell death during the secondary injury is a major priority in the development of a cure for traumatic spinal cord injury (SCI). One of the earliest processes that follow SCI is the excitotoxicity resulting from the massive release of excitotoxicity mediators, including ATP, which induce an excessive and/or prolonged activation of their receptors and a deregulation of the calcium homeostasis. Diadenosine tetraphosphate (Ap4A) is an endogenous purinergic agonist, present in both extracellular and intracellular fluids, with promising cytoprotective effects in different diseases including neurodegenerative processes. In a search for efficient neuroprotective strategies for SCI, we have tested the capability of Ap4A to reduce the excitotoxic death mediated by the ATP induced deregulation of calcium homeostasis and its consequences on tissue preservation and functional recovery in a mouse model of moderate contusive SCI. Our analyses with the murine neural cell line Neuro2a demonstrate that treatment with Ap4A reduces ATP-dependent excitotoxic death by both lowering the intracellular calcium response and decreasing the expression of specific purinergic receptors. Follow-up analyses in a mouse model of contusive SCI showed that acute administration of Ap4A following SCI reduces tissue damage and improves motor function recovery. These results suggest that Ap4A cytoprotection results from a decrease of the purinergic tone preventing the effects of a massive release of ATP after SCI, probably together with a direct induction of anti-apoptotic and pro-survival pathways via activation of P2Y2 proposed in previous studies. In conclusion, Ap4A may be a good candidate for an SCI therapy, particularly to reduce excitotoxicity in combination with other modulators and/or inhibitors of the excitotoxic process that are being tested. PMID- 27761684 TI - Subcutaneous malignant mast cell tumor in a Japanese macaque (Macaca fuscata). AB - The histopathological, immunohistochemical, and ultrastructural morphologic characteristics of a tumor in the subcutaneous tissue of the chest of a 19-year old female Japanese macaque were investigated. Consequently, the mass was diagnosed as a malignant mast cell tumor (MCT). Tumors were present in both mammary gland portions of the anterior thorax. Both tumors showed the same histopathological findings. The tumor tissue was defined by the presence of delicate connective tissue, and the tumor cells grew in a cord-like or cobblestone pattern. The tumor cell cytoplasm was very clear. The nuclei were relatively uniform and the cells showed a low nucleus-cytoplasm ratio. The cytoplasmic granules stained blue with Alcian blue and eosinophils had infiltrated into the tumor tissue. Furthermore, immunohistochemical analysis revealed that the tumor cell membrane was positive for the anti-c-kit antibody. In ultrastructural morphologic analyses, all tumor cells showed a rich cytoplasm and, occasionally, granules wrapped in a limiting membrane of high electron density. The tumor cells had metastasized to the axillary lymph nodes, the kidney, and the peritoneum. Based on these results, the mass was diagnosed as a malignant MCT originating from the subcutaneous tissue of the chest. Since cases of MCTs in macaques are very rare, this report presents important new knowledge of neoplastic lesions in this species. PMID- 27761686 TI - Genetic Counseling, Professional Values, and Habitus: An Analysis of Disability Narratives in Textbooks. AB - This article analyzes narrative illustrations in genetic counseling textbooks as a way of understanding professional habitus--the dispositions that motivate professional behavior. In particular, this analysis shows that there are significant differences in how the textbooks' expository and narrative portions represent Down syndrome, genetic counseling practice, and patient behaviors. While the narrative portions of the text position the genetic counseling profession as working in service to the values of genetic medicine, the expository portions represent genetic counselors as neutral parties. Ultimately, this article argues that this ambiguity is harmful to the production of a professional habitus that is consistent with espoused professional values concerning respect for persons with disabilities and the promotion of psychosocial counseling. PMID- 27761685 TI - The Relationship Between Social Support, HIV Serostatus, and Perceived Likelihood of Being HIV Positive Among Self-Settled Female, Foreign Migrants in Cape Town, South Africa. AB - Female cross-border migrants experience elevated risks for HIV, and migrants in South Africa may face additional risks due to the country's underlying HIV prevalence. These risks may be mitigated by the receipt of social support. A behavioral risk-factor survey was administered using respondent-driven sampling. Multivariable regression models assessed the relationships between social support and two HIV outcomes: HIV serostatus and perceived HIV status. Low social support was not significantly associated with HIV status (aOR = 1.03, 95 % CI 0.43-2.46), but was significantly related to a perception of being HIV positive (aPR = 1.36, 95 % CI 1.04-1.78). Age, marital status, and education level were significantly associated with HIV serostatus. Illegal border-crossing, length of time in South Africa, anal sex, and transactional sex were significantly associated with aperception of being HIV positive. Future research should investigate how HIV risks and the receipt of social support change throughout the migration process. PMID- 27761687 TI - Bad Mothers and Monstrous Sons: Autistic Adults, Lifelong Dependency, and Sensationalized Narratives of Care. AB - Sensationalized representations of autistic families in film and other media frequently feature violent encounters between mothers and sons. This essay analyzes two media stories and three films that suggest how limited-and therefore misleading-popular representations of the autism family are. Except for one of the films, these representations blame the problem of adult autistic dependency on either monstrous autism or bad mothering. Doing so elides collective social responsibility for autism care and denies the reality that autistic adults continue to have complex dependency needs that families cannot always meet. Narratives that sensationalize youth and adults with autism or scapegoat their maternal caregivers also diminish opportunities for social inclusion and for autistic people to live fully and dependently. PMID- 27761688 TI - Whose Values? Whose Risk? Exploring Decision Making About Trial of Labor After Cesarean. AB - In this article, we discuss decision making during labor and delivery, specifically focusing on decision making around offering women a trial of labor after cesarean section (TOLAC). Many have discussed how humans are notoriously bad at assessing risks and how we often distort the nature of various risks surrounding childbirth. We will build on this discussion by showing that physicians make decisions around TOLAC not only based on distortions of risk, but also based on personal values (i.e. what level of risk are you comfortable with or what types of risks are you willing to take) rather than medical data (or at least medical data alone). As a result of this, we will further suggest that the party who is best epistemically situated to make decisions about TOLAC is the woman herself. PMID- 27761690 TI - Innocent or Intentional?: Interpreting Oppositional Defiant Disorder in a Preschool Mental Health Clinic. AB - Based on 9 months of ethnographic fieldwork in a U.S. mental health clinic focused on the treatment of preschool-aged children who exhibited extremely disruptive behavior, this article examines the contradictions clinicians faced when trying to identify and attribute "intentionality" to very young children. Disruptive, aggressive behavior is one of the central symptoms involved in a wide range of childhood psychopathology and the number one reason young children are referred to mental health clinics in the United States. In the clinic where I conducted my research, clinicians were especially interested in diagnosing these children with oppositional defiant disorder (ODD), in order to identify those at risk for more serious mental illness later in the lifecourse. In this article, I look at the different strategies clinicians used in interpreting whether aggressive, defiant behavior was a part of the child's "self," a biologically driven symptom of a disease, or a legitimate reaction to problematic social environments. I argue that conceptualizing intentionality as a developmental, interpersonal process may help to make sense of the multiple discourses and practices clinicians used to try to reconcile the contradictions inherent in diagnosing ODD. PMID- 27761691 TI - "Hunger Hurts, but Starving Works". The Moral Conversion to Eating Disorders. AB - This article aims to shed light on the self-perceptions of people with eating disorders in Malta and Italy through a deep understanding of their narratives. In contrast to the biomedical perception of the phenomenon and in opposition with the prevalent feminist theories on the subject, I consider eating disorders as the result of self-transformative processes. I suggest that anorexics, bulimics and binge eaters are actively and deliberately engaged in a project of moral self transformation that is culturally defined. The moral transformations of women with eating disorders in Malta and Italy, the two considered contexts of this research, reflect the social expectations of women in these societies. The drastic changes in personal attitudes towards both food and the body that characterise eating disorders are the result of a complete dedication to the moral values embodied in thinness, namely the control of bodily needs and pleasure. The self-transformative process of people with eating disorders can be understood as a form of moral conversion along a continuum of increasing control over hunger: the higher the control, the higher the level of satisfaction and the degree of moral conversion achieved. Considering the general low recovery rates of people with eating disorders, this approach helps in the understanding of why people who are diagnosed with an eating disorder accept medical definitions and treatments to different extents. PMID- 27761689 TI - Limitations to Work-Related Functioning of People with Persistent "Medically Unexplained" Physical Symptoms: A Modified Delphi Study Among Physicians. AB - Purpose The purpose of this study was to obtain consensus among physicians of several medical specialties on the level of limitations to work-related functioning of people with persistent "medically unexplained" physical symptoms (PPS). Methods A modified Delphi study was conducted with 15 physicians of five different medical specialties. The study involved two email rounds and one meeting. In each round, the physicians prioritized the level of limitations in 78 work-related functioning items for four different PPS cases. These items were based on the Dutch Functional Ability List, national guidelines and scientific literature regarding the International Classification of Functioning. Results In all four cases, the physicians reached consensus on the level of limitations to work-related functioning in 49 items. The physicians reported the highest number and level of limitations for PPS of the back and lower extremities, but they reported hardly any limitations for PPS of the abdomen and genitals. For PPS of the head, they reported mainly limitations to personal and social functioning; for PPS of the neck, back and upper or lower extremities, they reported mainly limitations to dynamic movements and static postures. The physicians could not reach consensus on limitations in the category of working hours. Conclusion Physicians reached consensus on the level of limitations in a substantial part of work-related functioning items for PPS. There was a difference in the number and severity of limitations between different cases of PPS. The assessment of functioning seems to be based more on the specific impairment than on the disease. PMID- 27761692 TI - Plausible anti-inflammatory mechanism of resveratrol and caffeic acid against chronic stress-induced insulin resistance in mice. AB - Stress is associated with many diseases and dysfunctions, such as depression, cardiovascular alterations, immunological function disorder, inflammation, obesity, and insulin resistance. Stress-induced inflammation is associated with the genesis of insulin resistance. Stress activates hypothalamic pituitary adrenal axis, Renin Angiotensin System pathway, and sympatho-adrenal system, all of which are involved in the production of cytokines, causing the negative downregulation of insulin signaling either by phosphorylating serine residues of IRS or by inhibiting the activity of Akt leading to insulin resistance. In this study, male LACA mice (20-30 g) were subjected to 2 h of chronic restraint stress daily for 30 days at variable time. Resveratrol, caffeic acid, glibenclamide, and their combinations were administered 45 min prior to restraint stress daily for 30 days and their anti-inflammatory effect was examined on CRS-induced behavioral, biochemical, and metabolic alterations. Induction of stress in mice was evident by increased corticosterone and decreased bodyweight. Chronic restraint stress for 30 days developed insulin resistance characterized by hyperglycemia, hyperinsulinemia, increased glycosylated haemoglobin (HbA1c), and homeostasis model assessment of insulin resistance index, hyperlipidemia, increased inflammatory cytokines, and TNF-alpha. Treatment with resveratrol, caffeic acid, and their combinations has attenuated stress-induced insulin resistance by reducing inflammation. PMID- 27761693 TI - Curcuma longa extract reduces inflammatory and oxidative stress biomarkers in osteoarthritis of knee: a four-month, double-blind, randomized, placebo controlled trial. AB - BACKGROUND AND PURPOSE: Curcuma longa L. (CL), an Indian herb, has been used to treat many disorders because of its wide spectrum of pharmacological activities. It has been shown to exhibit anti-oxidant and anti-inflammatory properties, and is being used as herbal remedy since ancient times. Osteoarthritis of knee (KOA) is a chronic painful disorder in which prolong use of non-steroidal anti inflammatory drugs (NSAIDs) or steroids may result into many serious side effects; hence, there is a need to develop herbal drugs, having good analgesia without side effects. Therefore, we planned to evaluate the efficacy of CL in KOA. METHODS: The study was designed as a randomized, double-blind, placebo controlled trial in patients of KOA. After obtaining ethical clearance and written informed consent, a total of 160 patients of KOA were randomly enrolled into two groups to receive either CL extract or placebo along with the standard drug regimen. The patients were assessed on day 0, day 60, and day 120. On the days of their visit, the clinical prognosis was assessed by visual analog scale (VAS) and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis index. On these days, the radiographs were also taken for Kellgren and Lawrence grading and blood samples were collected for assessing the changes in levels of IL-1beta and biomarkers of oxidative stress, such as reactive oxygen species and malondialdehyde (MDA). RESULTS: Over all significant improvement was observed in the patients of CL extract group as compared to placebo group. Clinically, the VAS and WOMAC scores became better, and simultaneously, the levels of biomarkers, viz., IL-1beta, ROS, and MDA, were also significantly (p < 0.05) improved. CONCLUSION: It may be concluded that on chronic administration, CL suppresses inflammation and brings clinical improvement in patients of KOA, which may be observed by decreased level of IL-1beta and VAS/WOMAC scores, respectively. At the same time, CL decreases the oxidative stress also. PMID- 27761694 TI - Chodatiionosides A and B: two new megastigmane glycosides from Chorisia chodatii leaves. AB - Phytochemical investigation of Chorisia chodatii Hassl. leaves led to the isolation of an unusual rearranged megastigmane glycoside; chodatiionoside A (1) and another new megastigmane glycoside; chodatiionoside B (2), together with three known megastigmane glycosides (3-5) and one known flavonoid glycoside (6). Their structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments (1H, 13C, DEPT, COSY, HSQC and HMBC) in combination with HR-ESI-MS, CD and modified Mosher's method. As a result, chodatiionoside A has been elucidated as a first example of an unusual rearranged form of megastigmane. PMID- 27761695 TI - Cryosurgery, an alternative treatment option for organ-confined prostate cancer: current beliefs and practice patterns of urologists. AB - PURPOSE: We aim to evaluate the current beliefs and practice patterns of urologists in regard to use of cryosurgery for management of PCa. METHODS: An anonymous 13-point survey was designed and sent out to members of the Society of Urologic Oncology (SUO), Endourological Society (ES) and American College of Cryosurgery (ACC). Descriptive statistics and univariate analyses were used to determine variables associated with the use of cryosurgery. RESULTS: Of the 206 responses received [81 (39.2 %) SUO; 106 (51.5 %) ES; 19 (9.2 %) ACC], 83 (40.3 %) performed cryosurgery. The majority of respondents who utilize cryosurgery do so in unilateral (80.3 %) and bilateral (77.6 %) intermediate-risk PCa. Also, users of this technology indicated significant use in primary treatment (>72 %), salvage treatment (>83 %), in patients who prefer cryosurgery (89.9 %) have a life expectancy >=10 years (65.8 %) and poor erections (74.7 %). The main reason for not utilizing cryosurgery was the lack of technical expertise (56.7 %). A urologist in a non-academic practice setting was 3.2 times more likely to perform cryosurgery compared to a urologist in an academic setting, p = 0.0001. CONCLUSION: Cryosurgery is increasingly being accepted among urologists. However, the need for large-scale studies as well as randomized clinical trials to further delineate the benefits of cryosurgery and convince the non-users and institutions cannot be overemphasized. PMID- 27761696 TI - Histone methyltransferase TXR1 is required for both H3 and H3.3 lysine 27 methylation in the well-known ciliated protist Tetrahymena thermophila. AB - DNA replication elongation is tightly controlled by histone-modifying enzymes. Our previous studies showed that the histone methytransferase TXR1 (Tetrahymena Trithorax related protein 1) specifically catalyzes H3K27 monomethylation and affects DNA replication elongation in Tetrahymena thermophila. In this study, we investigated whether TXR1 has a substrate preference to the canonical H3 over the replacement variant H3.3. We demonstrated by histone mutagenesis that K27Q mutation in H3.3 further aggravated the replication stress phenotype of K27Q mutation in canonical H3, supporting H3.3 as a physiologically relevant substrate of TXR1. This result is in apparent contrast to the strong preference for canonical H3 recently reported in Arabidopsis homologues ATXR5 and ATXR6, and further corroborates the role of TXR1 in DNA replication. PMID- 27761697 TI - Differential expression analysis of the broiler tracheal proteins responsible for the immune response and muscle contraction induced by high concentration of ammonia using iTRAQ-coupled 2D LC-MS/MS. AB - Ammonia has been considered the contaminant primarily responsible for respiratory disease in poultry. Even though it can cause tracheal lesions, its adverse effects on the trachea have not been sufficiently studied. The present study investigated tracheal changes in Arbor Acres broilers (Gallus gallus) induced by high concentration of ammonia using isobaric tag for relative and absolute quantification (iTRAQ)-based proteome analysis. In total, 3,706 proteins within false discovery rate of 1% were identified, including 119 significantly differentially expressed proteins. Functional analysis revealed that proteins related to immune response and muscle contraction were significantly enriched. With respect to the immune response, up-regulated proteins (like FGA) were pro inflammatory, while down-regulated proteins participated in antigen processing and antigen presenting (like MYO1G), immunoglobulin and cathelicidin production (like fowlicidin-2), and immunodeficiency (like PTPRC). Regarding muscle contraction, all differentially expressed proteins (like TPM1) were up-regulated. An over-expression of mucin, which is a common feature of airway disease, was also observed. Additionally, the transcriptional alterations of 6 selected proteins were analyzed by quantitative RT-PCR. Overall, proteomic changes suggested the onset of airway obstruction and diminished host defense in trachea after ammonia exposure. These results may serve as a valuable reference for future interventions against ammonia toxicity. PMID- 27761698 TI - Collective Cell Behaviour with Neighbour-Dependent Proliferation, Death and Directional Bias. AB - Collective cell migration and proliferation are integral to tissue repair, embryonic development, the immune response and cancer. Central to collective cell migration and proliferation are interactions among neighbouring cells, such as volume exclusion, contact inhibition and adhesion. These individual-level processes can have important effects on population-level outcomes, such as growth rate and equilibrium density. We develop an individual-based model of cell migration and proliferation that includes these interactions. This is an extension of a previous model with neighbour-dependent directional bias to incorporate neighbour-dependent proliferation and death. A deterministic approximation to this individual-based model is derived using a spatial moment dynamics approach, which retains information about the spatial structure of the cell population. We show that the individual-based model and spatial moment model match well across a range of parameter values. The spatial moment model allows insight into the two-way interaction between spatial structure and population dynamics that cannot be captured by traditional mean-field models. PMID- 27761699 TI - The Impact of Microfibril Orientations on the Biomechanics of Plant Cell Walls and Tissues. AB - The microscopic structure and anisotropy of plant cell walls greatly influence the mechanical properties, morphogenesis, and growth of plant cells and tissues. The microscopic structure and properties of cell walls are determined by the orientation and mechanical properties of the cellulose microfibrils and the mechanical properties of the cell wall matrix. Viewing the shape of a plant cell as a square prism with the axis aligning with the primary direction of expansion and growth, the orientation of the microfibrils within the side walls, i.e. the parts of the cell walls on the sides of the cells, is known. However, not much is known about their orientation at the upper and lower ends of the cell. Here we investigate the impact of the orientation of cellulose microfibrils within the upper and lower parts of the plant cell walls by solving the equations of linear elasticity numerically. Three different scenarios for the orientation of the microfibrils are considered. We also distinguish between the microstructure in the side walls given by microfibrils perpendicular to the main direction of the expansion and the situation where the microfibrils are rotated through the wall thickness. The macroscopic elastic properties of the cell wall are obtained using homogenization theory from the microscopic description of the elastic properties of the cell wall microfibrils and wall matrix. It is found that the orientation of the microfibrils in the upper and lower parts of the cell walls affects the expansion of the cell in the lateral directions and is particularly important in the case of forces acting on plant cell walls and tissues. PMID- 27761700 TI - Stability of Ecosystems Under Invasions. AB - This paper considers a model of foodwebs taking into account species extinction and invasion. We show that system stability depends not only on usual parameters (mortality rates, self-limitation coefficients, and resource abundances), but also on an additional parameter ("biodiversity potential"). The main result is as follows. For foodwebs with random parameters, we obtain an estimate of probability that the foodweb exposed to invasion survives. This estimate involves different system parameters, size and its topological properties. PMID- 27761701 TI - Application of a Loop-Mediated Isothermal Amplification Assay for Rapid Detection of Cow Components Adulterated in Buffalo Milk/Meat. AB - Loop-mediated isothermal amplification (LAMP) is a diagnostic method for amplification of DNA with rapid and minimal equipment requirement. In the present study, we applied the LAMP assay for rapid detection of cow components adulteration in buffalo milk/meat samples. The test can be completed within around 1 h 40 min starting from DNA extraction and can be performed in water bath without requirement of thermocycler. The cow DNA in buffalo samples were identified in the developed LAMP assay by either visualizing with SYBR Green I/HNB dyes or observing the typical ladder pattern on gel electrophoresis. The test can detect up to 5 % level of cow milk/meat mixed in buffalo counterparts. Due to the simplicity and specificity, the developed LAMP test can be easily adapted in any laboratory for rapid detection of cow species identification in livestock by products. PMID- 27761702 TI - Clinical features and outcomes of patients with primary myelofibrosis in Japan: report of a 17-year nationwide survey by the Idiopathic Disorders of Hematopoietic Organs Research Committee of Japan. AB - We conducted a 17-year nationwide survey (1999-2015) to elucidate the clinical outcomes of patients with primary myelofibrosis (PMF) in Japan. Questionnaires were sent annually to approximately 500 hematology departments. Newly diagnosed patients with PMF were enrolled in this study, and were followed up annually to collect prognostic information. Approximately 50 patients were enrolled per year, yielding a total of 780 patients with PMF included in this study. The median age at diagnosis was 66 years. At the time of analysis, the median survival duration was 47 months, and the 3-year overall survival rate was 59 %. Infection and disease transformation into acute leukemia were the most frequent causes of death. Of the proposed prognostic models for predicting the outcomes of PMF patients in Japan, the Dynamic International Prognostic Scoring System of PMF plus model was the most feasible. Forty-three patients received allogeneic hematopoietic stem cell transplantation (alloSCT) at a median of 343 days after diagnosis. This treatment significantly prolonged the survival of PMF patients, and the 3-year overall survival rate after first alloSCT was 84 %. A long-term registration study is required for further evaluation of prognosis and the impact of treatments on survival. PMID- 27761703 TI - Intraoperative floppy iris syndrome and its association with various concurrent medications, bulbus length, patient age and gender. AB - PURPOSE: To evaluate the association between intraoperative floppy iris syndrome (IFIS) and concurrent medications containing selective alpha1A receptor antagonists as well as nonselective alpha1-adrenergic receptor antagonists, bulbus length, patient age and gender. METHODS: We performed a prospective data acquisition of IFIS occurrence and grading, and retrospective evaluation of concurrent medications, bulbus length, patient age and gender of all patients undergoing cataract surgery over a 6-month period. RESULTS: IFIS was observed in 119 of 947 cases (12.6 %). 31 of those 119 patients (26.1 %) had a concurrent medication with a drug that is associated with a higher risk of causing IFIS. Tamsulosin was the drug most commonly associated with IFIS (n = 11), followed by a combination of drugs (n = 7), doxazosin (n = 4), quetiapine (n = 4), finasterid (n = 2), prothipendyl (n = 2), and mianserin (n = 1). Bulbus length and age did not show any significant association with occurrence or grade of IFIS. Gender distribution among IFIS cases was 57.1 % males (n = 68) and 42.9 % (n = 51) females. CONCLUSIONS: The occurrence of IFIS has to be expected with a variety of concurrent medications. The number of IFIS cases and the percentage of females in this series are higher compared to previous reports. The observations might be due to a rising awareness of surgeons or to an increasing number of causative medications on the market. PMID- 27761704 TI - Limbal conjunctival versus amniotic membrane in the intraoperative application of mitomycin C for recurrent pterygium: a randomized controlled trial. AB - PURPOSE: This study compared the outcomes of a limbal conjunctival autograft (LCAG) with those of an amniotic membrane graft (AMG) followed by intraoperative 0.02 % mitomycin C (MMC) to treat recurrent pterygium. METHODS: In this randomized controlled trial, ninety-six eyes with recurrent pterygium were enrolled and randomly allocated into two groups using a computer-generated random number table. Pterygium removal was followed by intraoperative 0.02 % MMC for 3 min and then either LCAG or AMG transplantation. The major outcomes were recurrence rate, conjunctival inflammation grade, healing time of the corneal epithelial defect, eye-movement amplitude (EMA), uncorrected distance visual acuity (UDVA), and complications. RESULTS: A follow-up of 12 months was conducted for 93 eyes of 82 patients. Grade D (recurrence) presented in one eye of the LCAG group and five eyes of the AMG group, with no between-group difference (p = 0.196). However, Grades A, B, and C presented in 46, zero and zero eyes of the LCAG group respectively, and in 37, two and two eyes of the AMG group respectively, with the surgical bed generally showing a better appearance in the LCAG group than in the AMG group (p = 0.008). Compared with baseline values, the postoperative EMA improved significantly in both groups (p < 0.001 for the LCAG group; p = 0.001 for the AMG group), as did UDVA (p = 0.005 for the LCAG group; p = 0.012 for the AMG group). No between-group differences were found in terms of the healing time for epithelial defect, conjunctival inflammation grade, or the frequency of complications such as punctate epithelial keratitis, episcleral melting, corneal pannus, and delayed corneal epithelium healing. CONCLUSIONS: LCAG transplantation with intraoperative 0.02 % MMC is as efficacious in treating recurrent pterygium as AMG transplantation with MMC. The former procedure results in an attractive cosmetic appearance but might result in limbal damage in some eyes. The surgeon's familiarity with these procedures should determine the method of treatment. PMID- 27761706 TI - Aerodynamic Droplet Stream Expansion for the Production of Spray Freeze-Dried Powders. AB - In spray freeze-srying (SFD), a solution is sprayed into a refrigerant medium, frozen, and subsequently sublimation dried, which allows the production of flowable lyophilized powders. SFD allows commonly freeze-dried active pharmaceutical ingredients (e.g., proteins and peptides) to be delivered using new applications such as needle-free injection and nasal or pulmonary drug delivery. In this study, a droplet stream was injected into a vortex of cold gas in order to reduce the risk of droplet collisions and therefore droplet growth before congelation, which adversely affects the particle size distribution. Droplets with initial diameters of about 40-50 MUm were frozen quickly in a swirl tube at temperatures around -75 degrees C and volumetric gas flow rates between 17 and 34 L/min. Preliminary studies that were focused on the evaluation of spray cone footprints were performed prior to SFD. A 23 factorial design with a model solution of mannitol (1.5% m/V) and maltodextrin (1.5% m/V) was used to create flowable, low density (0.01-0.03 g/cm3) spherical lyophilisate powders. Mean particle diameter sizes of the highly porous particles ranged between 49.8 +/- 6.6 and 88.3 +/- 5.5 MUm. Under optimal conditions, the mean particle size was reduced from 160 to 50 MUm (decrease of volume by 96%) compared to non-expanded streams, whereas the SPAN value did not change significantly. This method is suitable for the production of lyophilized powders with small particle sizes and narrow particle size distributions, which is highly interesting for needle-free injection or nasal delivery of proteins and peptides. PMID- 27761705 TI - Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease. AB - PURPOSE OF REVIEW: Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an independent and causal risk factor for cardiovascular diseases including coronary artery disease, ischemic stroke, and calcific aortic valve stenosis. This review summarizes the rationale for Lp(a) lowering and surveys relevant clinical trial data using a variety of agents capable of lowering Lp(a). RECENT FINDINGS: Contemporary guidelines and recommendations outline populations of patients who should be screened for elevated Lp(a) and who might benefit from Lp(a) lowering. Therapies including drugs and apheresis have been described that lower Lp(a) levels modestly (~20 %) to dramatically (~80 %). Existing therapies that lower Lp(a) also have beneficial effects on other aspects of the lipid profile, with the exception of Lp(a)-specific apheresis and an antisense oligonucleotide that targets the mRNA encoding apolipoprotein(a). No clinical trials conducted to date have managed to answer the key question of whether Lp(a) lowering confers a benefit in terms of ameliorating cardiovascular risk, although additional outcome trials of therapies that lower Lp(a) are ongoing. It is more likely, however, that Lp(a)-specific agents will provide the most appropriate approach for addressing this question. PMID- 27761707 TI - Online Spectroscopic Monitoring of Drug Release Kinetics from Nanostructured Dual Stimuli-Responsive Conducting Polymer. AB - PURPOSE: The potential of electrochemical/temperature dual stimuli-responsive conducting polymer to be used as general drug delivery systems. It allows on demand release of incorporated drug is kinetically investigated in real time. METHODS: Online spectroscopic monitoring was used to investigate the electrochemically/thermally controlled release behavior of a model drug (naproxen) from drug-doped polypyrrole (DDPPy) film. Avrami's equation has been used to study the kinetics and further analyzing has been carried out using the Arrhenius and the Eyring equations. Furthermore, drug release behavior, with two other electrochemical techniques was investigated. RESULTS: It was observed both temperature and electrical stimuli increase the rate of release while electrical potential has a greater effect as revealed in the values of release rate constant (from 0.0068 to 0.018 min-1 at 37 degrees C). It was also shown that a linear relationship exists between the applied electrical potentials and release activation parameters. CONCLUSION: The electronic properties of the conducting polymer has an important role in release kinetics, there might be a single mechanism with the same limiting step. In addition, it was demonstrated the rate of drug release from DDPPy dramatically depends on the amounts as well as modes of applying potential which provides enhanced control of drug-release kinetics which can be accelerated or even sustained. PMID- 27761708 TI - Diagnosis of sub-centimetre breast lesions: combining BI-RADS-US with strain elastography and contrast-enhanced ultrasound-a preliminary study in China. AB - OBJECTIVES: To compare the diagnostic efficacies of B-mode ultrasound (US), strain elastography (SE), contrast-enhanced ultrasound (CEUS) and the combination of these modalities for breast lesions <1 cm in size. METHODS: Between January 2013 and October 2015, 203 inpatients with 209 sub-centimetre breast lesions categorised as BI-RADS-US (Breast Imaging Reporting and Data System for Ultrasound) 3-5 were included. US, SE and CEUS were performed to evaluate each lesion. The diagnostic performances of different ultrasonic modalities were compared. The diagnostic efficacies of BI-RADS-US and our re-rating systems were also compared. The pathology findings were used as the reference standard. RESULTS: The specificities of US, SE and CEUS for tumour differentiation were 17.4 %, 56.2 % and 86.0 %, respectively (P < 0.05); and the sensitivities were 100 %, 93.2 % and 93.2 % for US, SE and CEUS, respectively (P < 0.05). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.867 for original BI-RADS-US, 0.882 for BI-RADS-US combined with only SE, 0.953 for BI-RADS-US combined with only CEUS and 0.924 for BI-RADS-US combined with both SE and CEUS. The best combination was BI-RADS-US combined with only CEUS. CONCLUSIONS: Evaluating sub-centimetre breast lesions with SE and CEUS could increase the diagnostic specificity while retaining high sensitivity compared with B-mode ultrasound. KEY POINTS: * Evaluating breast lesions with SE and CEUS could increase the diagnostic specificity * SE and CEUS offer alternatives to biopsy and possibly allow shorter-interval follow-ups * BI-RADS-US combined with CEUS exhibited the best diagnostic performance. PMID- 27761709 TI - Magnetic Resonance Parkinsonism Index: diagnostic accuracy of a fully automated algorithm in comparison with the manual measurement in a large Italian multicentre study in patients with progressive supranuclear palsy. AB - OBJECTIVES: To investigate the reliability of a new in-house automatic algorithm for calculating the Magnetic Resonance Parkinsonism Index (MRPI), in a large multicentre study population of patients affected by progressive supranuclear palsy (PSP) or Parkinson's disease (PD), and healthy controls (HC), and to compare the diagnostic accuracy of the automatic and manual MRPI values. METHODS: The study included 88 PSP patients, 234 PD patients and 117 controls. MRI was performed using both 3T and 1.5T scanners. Automatic and manual MRPI values were evaluated, and accuracy of both methods in distinguishing PSP from PD and controls was calculated. RESULTS: No statistical differences were found between automated and manual MRPI values in all groups. The automatic MRPI values differentiated PSP from PD with an accuracy of 95 % (manual MRPI accuracy 96 %) and 97 % (manual MRPI accuracy 100 %) for 1.5T and 3T scanners, respectively. CONCLUSION: Our study showed that the new in-house automated method for MRPI calculation was highly accurate in distinguishing PSP from PD. Our automatic approach allows a widespread use of MRPI in clinical practice and in longitudinal research studies. KEY POINTS: * A new automatic method for calculating the MRPI is presented. * Automatic MRPI values are in good agreement with manual values. * Automatic MRPI can distinguish patients with PSP from patients with PD. * The automatic method overcomes MRPI application limitations in routine practice. * The automatic method may allow a more widespread use of MRPI. PMID- 27761710 TI - Malignancy rates and diagnostic performance of the Bosniak classification for the diagnosis of cystic renal lesions in computed tomography - a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review the literature on the Bosniak classification system in CT to determine its diagnostic performance to diagnose malignant cystic lesions and the prevalence of malignancy in Bosniak categories. METHODS: A predefined database search was performed from 1 January 1986 to 18 January 2016. Two independent reviewers extracted data on malignancy rates in Bosniak categories and several covariates using predefined criteria. Study quality was assessed using QUADAS-2. Meta-analysis included data pooling, subgroup analyses, meta-regression and investigation of publication bias. RESULTS: A total of 35 studies, which included 2,578 lesions, were investigated. Data on observer experience, inter-observer variation and technical CT standards were insufficiently reported. The pooled rate of malignancy increased from Bosniak I (3.2 %, 95 % CI 0-6.8, I2 = 5 %) to Bosniak II (6 %, 95 % CI 2.7-9.3, I2 = 32 %), IIF (6.7 %, 95 % CI 5-8.4, I2 = 0 %), III (55.1 %, 95 % CI 45.7-64.5, I2 = 89 %) and IV (91 %, 95 % CI 87.7-94.2, I2 = 36). Several study design-related influences on malignancy rates and subsequent diagnostic performance indices were identified. CONCLUSION: The Bosniak classification is an accurate tool with which to stratify the risk of malignancy in renal cystic lesions. KEY POINTS: * The Bosniak classification can accurately rule out malignancy. * Specificity remains moderate at 74 % (95 % CI 64-82). * Follow-up examinations should be considered in Bosniak IIF and Bosniak II cysts. * Data on the influence of reader experience and inter-reader variability are insufficient. * Technical CT standards and publication year did not influence diagnostic performance. PMID- 27761711 TI - Computed tomography features and predictive findings of ruptured gastrointestinal stromal tumours. AB - OBJECTIVES: To evaluate the CT features of ruptured GISTs and factors that might be predictive of rupture through comparison with CTs taken prior to rupture and CTs of non-ruptured GIST. METHODS: Forty-nine patients with ruptured GIST and forty-nine patients with non-ruptured GIST matched by age, gender and location were included. Clinical data including pharmacotherapy were reviewed. The imaging features were analyzed. Prior CT obtained before rupture were evaluated. RESULTS: The most common location of ruptured GIST was small bowel with mean size of 12.1 cm. Ruptured GIST commonly showed wall defects, >40 % eccentric necrosis, lobulated shaped, air density in mass, pneumoperitoneum, peritonitis, hemoperitoneum and ascites (p < 0.001-0.030). Twenty-seven of 30 patients with follow up imaging received targeted therapy. During follow-up, thickness of the tumour wall decreased. Increase in size and progression of necrosis were common during targeted therapy (p = 0.017). Newly developed ascites, peritonitis and hemoperitoneum was more common (p < 0.001-0.036). CONCLUSION: Ruptured GISTs commonly demonstrate large size, >40 % eccentric necrosis, wall defects and lobulated shape. The progression of necrosis with increase in size and decreased wall thickness during targeted therapy may increase the risk of rupture. Rupture should be considered when newly developed peritonitis, hemoperitoneum, or ascites are noted during the follow-up. KEY POINTS: * Ruptured GISTs demonstrate large size, eccentric necrosis, wall defects, and lobulated shape. * Rupture should be considered when peritonitis or hemoperitoneum/adjacent hematoma newly appears. * Progression of necrosis with increase in size increases the risk of rupture. PMID- 27761712 TI - 3D vs. 2D imaging in laparoscopic surgery-an advantage? Results of standardised black box training in laparoscopic surgery. AB - PURPOSE: 3D imaging is an upcoming technology in laparoscopic surgery, and recent studies have shown that the modern 3D technique is superior in an experimental setting. METHODS: All 14 members of the Asklepios Klinik Langen Department of Visceral and Thoracic Surgery, as well as two gynaecologists, were asked to undertake 2D vs. 3D laparoscopic black box skill training. The black box training was adapted to the "fundamentals of laparoscopic surgery" programme provided by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). First, the participants categorised themselves as beginner, advanced or expert in laparoscopic surgery. Then, they were randomised in terms of whether the black box training commenced with 2D or 3D vision. The exercises included peg transfer with the dominant hand and the non-dominant hand (with and without transfer between the graspers), needle capping and cutting a sutured knot. The time taken to complete these exercises was measured. After the training, each participant was asked to describe his/her personal impression of the imaging systems employed. RESULTS: Overall, for the participants in all groups, the time required for all exercises showed a significant advantage for 3D imaging (3D vs. 2D; Wilcoxon matched pair test; mean 68.0 +/- 94.9 s (3D) vs. 90.1 +/- 69.4 s (2D); p = 0.002). Regarding the subgroups, the experts significantly improved their time in completing the exercises in 3D vs. 2D by a margin of 25.8 % (mean 30.8 +/- 20.1 s (3D) vs. 41.5 +/- 25.0 s (2D); p = 0.010). In the group of advanced surgeons, the results were similar, showing an improvement of 23.6 % for 3D, but without significance (mean 61.5 +/- 41.1 s (3D) vs. 80.4 +/- 72.8 s (2D); p = 0.123). The results for the beginner group also showed an improvement in the 3D exercises of 24.8 %; here, the result also showed a trend towards 3D but did not reach significance (mean 93.9 +/- 90.7 s (3D) vs. 124.8 +/- 118.72 (2D); p = 0.062). CONCLUSION: In our opinion, 3D imaging could be an advantage in laparoscopic surgery, especially in the surgical education of upcoming surgical generations. To determine whether these ex vivo results can be transferred to the clinical situation, our group has initiated a randomised controlled study. PMID- 27761713 TI - Rescue ALPPS is efficient and safe after failed portal vein occlusion in patients with colorectal liver metastases. AB - PURPOSE: The aim of this study was to investigate whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can be used as an effective and safe rescue procedure in patients with colorectal liver metastases (CRLM) and insufficient effect on the future liver remnant (FLR) after previous portal vein occlusion (PVO). METHODS: Eleven patients with bilobar CRLM treated with neoadjuvant chemotherapy and previous PVO with insufficient effect on the FLR were analyzed retrospectively from a prospective database. FLR was evaluated with computed tomography volumetry 6 days after stage 1, and stage 2 was performed on day seven. RESULTS: Six days after stage 1, the median increase of the FLR was 209 ml (range 87-314, P < 0.001). This corresponded to a median FLR growth of 61.8 % (range 19.3-120) resulting in an FLR/BW ratio >0.5 % in all patients and successful subsequent removal of the tumor bearing liver (segments IV-VIII) in all patients with no 90-day mortality. No patient had a 3b complication or more according to Clavien-Dindo. No patient developed severe posthepatectomy liver failure. CONCLUSIONS: The powerful hypertrophy of the FLR associated with ALPPS seems to be maintained in patients with CRLM and previous failed PVO. PMID- 27761715 TI - Feasibility and safety of augmented reality-assisted urological surgery using smartglass. AB - PURPOSE: To assess the feasibility, safety and usefulness of augmented reality assisted urological surgery using smartglass (SG). METHODS: Seven urological surgeons (3 board urologists and 4 urology residents) performed augmented reality assisted urological surgery using SG for 10 different types of operations and a total of 31 urological operations. Feasibility was assessed using technical metadata (number of photographs taken/number of videos recorded/video time recorded) and structured interviews with the urologists on their use of SG. Safety was evaluated by recording complications and grading according to the Clavien-Dindo classification. Usefulness of SG for urological surgery was queried in structured interviews and in a survey. RESULTS: The implementation of SG use during urological surgery was feasible with no intrinsic (technical defect) or extrinsic (inability to control the SG function) obstacles being observed. SG use was safe as no grade 3-5 complications occurred for the series of 31 urological surgeries of different complexities. Technical applications of SG included taking photographs/recording videos for teaching and documentation, hands-free teleconsultation, reviewing patients' medical records and images and searching the internet for health information. Overall usefulness of SG for urological surgery was rated as very high by 43 % and high by 29 % of surgeons. CONCLUSIONS: Augmented reality-assisted urological surgery using SG is both feasible and safe and also provides several useful functions for urological surgeons. Further developments and investigations are required in the near future to harvest the great potential of this exciting technology for urological surgery. PMID- 27761714 TI - Advantages of laparoscopic compared to conventional surgery are not related to an innate immune response of peritoneal immune activation: an animal study in rats. AB - PURPOSE: Laparoscopic surgery (LS) has proved superior compared to conventional surgery (CS) regarding morbidity, length of hospital stay, rate of wound infection and time until recovery. An improved preservation of the postoperative immune function is assumed to contribute to these benefits though the role of the local peritoneal immune response is still poorly understood. Our study investigates the peritoneal immune response subsequent to abdominal surgery and compares it between laparoscopic and conventional surgery to find an immunological explanation for the clinically proven benefits of LS. METHODS: Wistar rats (N = 140) underwent laparoscopic cecum resection (LCR; N = 28), conventional cecum resection (CCR; N = 28), laparoscopic sham operation (LSO; N = 28), conventional sham operation (CSO; N = 28), or no surgical treatment (CTRL; N = 28). Postoperatively, peritoneal lavages were performed, leukocytes isolated and analyzed regarding immune function and phagocytosis activity. RESULTS: Immune function was inhibited postoperatively in animals undergoing LCR or CCR compared to CTRL reflected by a lower TNF-alpha (CTRL 3956.65 pg/ml, LCR 2018.48 pg/ml (p = 0.023), CCR 2793.78 pg/ml (n.s.)) and IL-6 secretion (CTRL 625.84 pg/ml, LCR 142.84 pg/ml (p = 0.009), CCR 169.53 pg/ml (p = 0.01)). Phagocytosis was not affected in rats undergoing any kind of surgery compared to CTRL. Neither cytokine secretion nor phagocytosis activity differed significantly between laparoscopic and conventional surgery. CONCLUSIONS: According to our findings the benefits associated with LS compared to CS cannot be explained by differences in the postoperative peritoneal innate immune response. Further studies are needed to elucidate the causes for a more favorable postoperative outcome in patients after LS compared to CS. PMID- 27761716 TI - Description of Citharodactylus gagei n. gen. et n. sp. (Monogenea: Gyrodactylidae) from the moon fish, Citharinus citharus (Geoffroy Saint-Hilaire), from Lake Turkana. AB - A new genus and species of monogenean belonging to the Gyrodactylidae, Citharodactylus gagei n. gen. et n. sp. (Plathyhelminthes, Monogenea), is described from the gills of the moon fish, Citharinus citharus (Geoffroy Saint Hilaire), a characiform fish collected from Lake Turkana in northern Kenya. The new viviparous genus can be readily distinguished from the six other gyrodactylid genera recorded from Africa and from the other viviparous genera within the Gyrodactylidae based on the morphology of the male copulatory organ (MCO), which consists of a muscular ovate organ with an opening onto the tegument through which the narrow tapered end of a sclerotised curved cone-shaped structure protrudes. The tegumental opening of the MCO is surrounded by a collar of short spines. Sequencing of the nuclear ribosomal DNA internal transcribed spacers 1 and 2, the 5.8S and the 18S rDNA genes and a comparison with the gyrodactylid species listed in GenBank confirmed the specimens are unique and do not match with any existing entry. When phylogenies for each genomic region were conducted (i.e. 0.064 gamma-corrected pairwise genetic distance based on a alignment of 1750 bp of the 1857 bp long 18S rDNA gene), the most similar match was that of Afrogyrodactylus sp. [= A. girgifae (Folia Parasitol 61:529-536, 2014)] from Brycinus nurse (Ruppell). The proposed name of the new parasite is Citharodactylus n. gen. which represents the seventh gyrodactylid genus to be found in Africa and the 25th viviparous genus and the 32nd genus to be added to the Gyrodactylidae. PMID- 27761717 TI - Filarial infection caused by Onchocerca boehmi (Supperer, 1953) in a horse from Italy. AB - Equids can be infected by a range of skin-dwelling filarial nematodes, including four species of the genus Onchocerca. Current literature on equine onchocercosis is fragmentary and often limited to isolated case reports. The present study aimed to describe a clinical case of equine onchocercosis caused by Onchocerca boehmi (Supperer, 1953) (syn. Elaeophora boehmi) in an 8-year-old gelding Belgian show jumper from northern Italy. The horse was presented with a firm and painless mass on the proximal third of the right metacarpal region. Ultrasound examination showed a peritendinous enlargement around the palmaro-lateral area of the tendons, characterized by an elongated hypoechoic and well-defined structure, embedding a coiled hyperechoic line. The metacarpal nodule was resected and histologically examined. Fragments of a parasitic nematode were detected, isolated and examined. The morphological analysis allowed identifying the nematode as O. boehmi. In addition, total genomic DNA was extracted from individual fragments using a commercial kit for the nematode identification and a comparative sequence analysis of the nematode cytochrome oxidase subunit 1 (cox1) sequence with data available in the GenBankTM database revealed the closest identity (i.e. 91 %) with that of Onchocerca lupi. Thus far, O. boehmi has only been reported in Austria and Iran, and information about its life-cycle and vectors is lacking. The systematic position of this species within the genus Onchocerca, not in Elaeophora where it was originally described, is in concordance with the morphological and molecular analysis. In this article, we describe the first autochthonous case of equine onchocercosis in Italy caused by O. boehmi and discuss novel parasitological, clinical, and pathological data on these pathogens of horses. PMID- 27761718 TI - Gene migration for re-emerging amebiasis in Iran's northwest-Iraq borders: a microevolutionary scale for reflecting epidemiological drift of Entamoeba histolytica metapopulations. AB - In the microevolutionary scales of Entamoeba isolates, the gene migration shows how Entamoeba spp. has epidemiologically drifted among border countries. Five hundred fecal samples were taken from patients suffering gastrointestinal disorders, abdominal pain, and diarrhea at Saggez, northwest Iran located within the border Iraq country. Following parasitological techniques, DNA samples were extracted and amplified by polymerase chain reaction (PCR) of 18S rRNA region to identify Entamoeba infections. To distinguish the Entamoeba spp., a multiplex PCR was conducted. Amplicons were sequenced to reconfirm their heterogeneity traits and phylogenetic analysis. Additionally, Entamoeba histolytica sequences of Iraq were retrieved from GenBank database. The suspected isolates were diagnosed as E. histolytica (2.2 %), Entamoeba moshkovskii (1 %), and Entamoeba dispar (0.4 %). Mixed Entamoeba infections did not detect among isolates. A parsimonious network of the sequence haplotypes displayed star-like features in the overall isolates containing E.h1, E.d2, and E.m3 as the most common haplotypes. According to analysis of molecular variance (AMOVA) test, high partial value of haplotype diversity (0.700 to 0.800) of E. histolytica was shown the total genetic variability within populations while nucleotide diversity was low among Iranian and Iraqi metapopulations. Neutrality indices of the 18S rRNA were shown negative values in E. histolytica populations which indicating significant deviations from neutrality. A pairwise fixation index (F-statistics [Fst]) as a degree of gene flow had a low value for all populations (0.001) while the number of migrants was 2.48. The statistically Fst value indicates that E. histolytica isolates are not genetically differentiated among shared isolates of Iran and Iraq. Occurrence of E.h1 between two regional populations indicates that there is dawn of Entamoeba flow due to transfer of alleles from one population to another population through host mobility and ecological alterations. To evaluate the hypothetical evolutionary scenario, further study is required to analyze Entamoeba spp. in the neighboring Middle East countries. PMID- 27761719 TI - Ixodes ventalloi: morphological and molecular support for species integrity. AB - Despite their medical and veterinary importance, some tick species are so poorly studied, that their role within pathogen vector transmission cycles is difficult to assess. The tick Ixodes ventalloi is one such species, and its biology and phylogenetic status remain an issue of debate. In the present study, specimens of adult I. ventalloi (n = 65 females; n = 31 males) infesting cats in the Lipari Island (Aeolian archipelago, Sicily, southern Italy) were characterized morphologically and molecularly, the latter based on mitochondrial 16S rRNA and cytochrome c oxidase subunit 1 (cox1) genes. The genetic data and phylogenetic analyses for both mitochondrial genes suggest the existence of two distinct genogroups. The ecological and epidemiological significance of the genetic structure within the I. ventalloi endemic population remains to be determined. The results highlight the need for further analysis of this tick species, including whole mitochondrial genome sequencing and crossbreeding studies, which will be pivotal to complement features of its status as a vector of pathogens. PMID- 27761720 TI - Further Evaluation of Covariate Analysis using Empirical Bayes Estimates in Population Pharmacokinetics: the Perception of Shrinkage and Likelihood Ratio Test. AB - Covariate analysis based on population pharmacokinetics (PPK) is used to identify clinically relevant factors. The likelihood ratio test (LRT) based on nonlinear mixed effect model fits is currently recommended for covariate identification, whereas individual empirical Bayesian estimates (EBEs) are considered unreliable due to the presence of shrinkage. The objectives of this research were to investigate the type I error for LRT and EBE approaches, to confirm the similarity of power between the LRT and EBE approaches from a previous report and to explore the influence of shrinkage on LRT and EBE inferences. Using an oral one-compartment PK model with a single covariate impacting on clearance, we conducted a wide range of simulations according to a two-way factorial design. The results revealed that the EBE-based regression not only provided almost identical power for detecting a covariate effect, but also controlled the false positive rate better than the LRT approach. Shrinkage of EBEs is likely not the root cause for decrease in power or inflated false positive rate although the size of the covariate effect tends to be underestimated at high shrinkage. In summary, contrary to the current recommendations, EBEs may be a better choice for statistical tests in PPK covariate analysis compared to LRT. We proposed a three step covariate modeling approach for population PK analysis to utilize the advantages of EBEs while overcoming their shortcomings, which allows not only markedly reducing the run time for population PK analysis, but also providing more accurate covariate tests. PMID- 27761721 TI - Linking functional group richness and ecosystem functions of dung beetles: an experimental quantification. AB - Dung beetles form an insect group that fulfils important functions in terrestrial ecosystems throughout the world. These include nutrient cycling through dung removal, soil bioturbation, plant growth, secondary seed dispersal and parasite control. We conducted field experiments at two sites in the northern hemisphere temperate region in which dung removal and secondary seed dispersal were assessed. Dung beetles were classified in three functional groups, depending on their size and dung manipulation method: dwellers, large and small tunnelers. Other soil inhabiting fauna were included as a fourth functional group. Dung removal and seed dispersal by each individual functional group and combinations thereof were estimated in exclusion experiments using different dung types. Dwellers were the most diverse and abundant group, but tunnelers were dominant in terms of biomass. All dung beetle functional groups had a clear preference for fresh dung. The ecosystem services in dung removal and secondary seed dispersal provided by dung beetles were significant and differed between functional groups. Although in absolute numbers more dwellers were found, large tunnelers were disproportionally important for dung burial and seed removal. In the absence of dung beetles, other soil inhabiting fauna, such as earthworms, partly took over the dung decomposing role of dung beetles while most dung was processed when all native functional groups were present. Our results, therefore, emphasize the need to conserve functionally complete dung ecosystems to maintain full ecosystem functioning. PMID- 27761722 TI - Robotic-Assisted Laparoscopic Biliopancreatic Diversion, Vertical Sleeve Gastrectomy with Traditional Roux-en-Y Duodenal Switch. AB - BACKGROUND: Although effective, duodenal switch can be a complicated and time consuming operation for surgeons. PURPOSE: The purpose of this article is to present our technique of biliopancreatic diversion and vertical sleeve gastrectomy, creating a 150-cm common channel and a 100-cm alimentary limb. MATERIAL AND METHODS: A robot-assisted technique was utilized in creating a biliopancreatic diversion and vertical sleeve gastrectomy. RESULTS: Laparoscopy was used for marking stitches and then the robot was docked. After creating a window behind the duodenum, sleeve gastrectomy is performed followed by duodeno ileal anastomosis and ileo-ileal anastomosis. CONCLUSION: With the adoption of robots and the described technique, it can be easier to be achieved in less time. PMID- 27761723 TI - Preoperative Medical Weight Management in Bariatric Surgery: a Review and Reconsideration. AB - Bariatric surgery is the most robust treatment for extreme obesity. The impact of preoperative medical weight management sessions designed, in theory, with the primary goal of promoting preoperative weight loss, is unclear. This paper reviews studies that have investigated the relationship between preoperative weight loss and bariatric surgical outcomes, both with respect to postoperative weight loss and complications. We conclude that the most robust of preoperative interventions has not been implemented or evaluated in a manner which would conclusively assess the value of this element of care. We offer a reconsideration of the role of preoperative medical weight management and provide recommendations for future research in this area. PMID- 27761724 TI - Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass. Data from IFSO-European Chapter Center of Excellence Program. AB - BACKGROUND: The purpose of this study is to compare sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGBP) performed in Institutions participating in IFSO European Chapter, Center of Excellence (COE) program. METHODS: Since the initiation of the program in January 2010, 6413 SGs and 10,622 RYGBPs performed as primary procedures by December 31, 2014, with at least 12-month follow-up, were retrospectively compared. RESULTS: There were steadily increasing numbers of patients underwent SG from 2010 to 2015. Early (<30 days) postoperative complication rate of 3.02 % for RYGBP was significantly higher than 2.12 % seen after SG (p = 0.0006). Only two patients, one in each group, died in the first 30 postoperative days (0.016 % mortality for SG vs 0.009 % for RYGBP-NS). From SG group, 103 patients, 1.61 %, and 206 patients, 1.94 %, from RYGBP group required readmission following hospital discharge in the first 30 days following bariatric surgery-NS. From the readmitted patients in the SG group, 75.72 % were reoperated vs 50.50 % in the RYGBP group (p < 0.0001). SG patients were heavier (BMI 44.93 vs 43.96 kg/m2, p < 0.0001). However, significantly better % excess weight loss were seen following RYGBP in all postoperative years (60.36 vs 67.72 %, p = 0.002 at fifth year). Better remission rates were seen for diabetes, arterial hypertension, dyslipidemia, and sleep apnea syndrome after RYGBP in the first postoperative year. CONCLUSIONS: Both procedures were performed with very low complications, mortality, readmissions, and reoperations rate. Better weight loss was observed following RYGBP, the first five postoperative years. PMID- 27761725 TI - Evaluation of antimicrobial resistance among Salmonella and Shigella isolates in the University Hospital "St. George," Plovdiv, Bulgaria. AB - The aim of this work is to study the epidemiology and antimicrobial resistance to the most commonly used antibiotics for the treatment of acute gastroenteritis caused by Salmonella and Shigella at the largest Bulgarian hospital-University Hospital "St. George," Plovdiv-for the period 2009-2013. Two hundred ninety strains were in vitro tested for resistance to 15 antimicrobial agents. The presence of extended-spectrum beta-lactamases (ESBLs) was demonstrated by a variety of specialized tests. For comparison, a collection of 28 strains submitted by the National Reference Laboratory (NRL) "Enteric Infections" at the National Center of Infectious and Parasitic Diseases (NCIPD), Sofia, was also tested for the production of ESBLs. In isolates, phenotypically demonstrated as ESBL producers, polymerase chain reaction (PCR) detection of the genes bla-CTX-M, bla-SHV, and bla-TEM was performed. Among the 290 tested isolates, only two- Salmonella serotype Livingstone and Shigella flexneri-were phenotypically proven to be ESBL producers. Only 4 strains from the collection of 28, submitted from the NRL "Intestinal Infections" in NCIPD, Sofia, were phenotypically confirmed as ESBL producers. The presence of the bla-CTX-M gene was detected in all of the tested strains (4 from NRL, NCIPD, Sofia, and 2 from the University Hospital St. George, Plovdiv), the bla-SHV gene only in strain S. Livingstone from Plovdiv, and the bla-TEM gene in two from Sofia and one (again S. Livingstone) from Plovdiv. In conclusion, Salmonella and Shigella isolates from patients hospitalized at the University Hospital St. George, Plovdiv, with acute gastroenteritis demonstrate good susceptibility to the most commonly used antibiotic agents, including azithromycin. PMID- 27761726 TI - Vitamin D Status and Recurrent Wheezing in Infancy: Is There a Link? PMID- 27761727 TI - The Role of CD90 in the Differential Diagnosis of Pleural Malignant Mesothelioma, Pulmonary Carcinoma and Comparison with Calretinin. AB - Pleural Malignant Mesothelioma (MM) is a fatal disease that has been associated with asbestos exposure. Differential diagnosis between the pleural infiltration of pulmonary carcinomas and MM is rather difficult particularly for epitheloid type mesothelioma.We aimed to investigate the utility of CD90, a cancer stem cell marker, in the differential diagnosis of MM and lung carcinoma, its prognostic significance and compare its value with that of Calretinin. Ninety pathology specimens including MM (n:30), pulmonary adenocarcinoma (n:30) and pulmonary squamous cell carcinoma (n:30) were used in this study. Immunohistochemical comparision of CD 90 and Calretinin was made in all groups. Calretinin was positive in 20 cases with MM (64.5 %), and was negative in 10 (32.3 %). CD 90 was positive in 25 of these cases (80 %) and negative in 5 (16 %). On the other hand pulmonary adenocarcinomas and squamous cell carcinomas showed positivity with CD90, 63,6 % and 73 %, respectively. We think that CD 90 has no place in the differential diagnosis between mesothelioma and pulmonary carcinoma because of the low specificity in spite of the high sensitivity. PMID- 27761728 TI - Postpartum Depression among African-American and Latina Mothers Living in Small Cities, Towns, and Rural Communities. AB - BACKGROUND: The presence of postpartum depression can lead to poor maternal-child attachment, failure to thrive, and even infant death. Postpartum depression affects 13-19 % of parturients. However, among racial and ethnic minority parturients, postpartum depression rates have been shown to reach up to 35-67 % (as reported by O'Hara and McCabe, Annu Rev Clin Psychol 9:379-407, 2013; Boury et al., Women Health. 39(3):19-34, 2004; Ramos-Marcuse et al.. J Affect Disord. 122(1-2):68-75, 2010; Lucero et al., J Am Acad Nurse Pract. 24(12):726-34, 2012). This is more concerning when considering the fact that these mothers are also hardest to reach because they are usually marginalized and displaced within mainstream US society. The current study assesses potential risk factors that contribute to postpartum depression among African-American and Latina mothers. METHODS: We analyze data from 3317 Healthy Start participants living in small cities, towns, and rural areas in Pennsylvania using a logistic regression analysis controlling for known contributing risk factors, including maternal health, family life, social support, socioeconomic and demographic characteristics, and community of residence. We use a multiple imputation multivariate analysis to account for the potential effects of missing data. RESULTS: The results show that the odds of a risk of postpartum depression is nearly 80 and 40 % greater for African-American (OR = 1.80, p < .001) and Latina mothers (OR = 1.41, p < .01), respectively, as compared to white mothers. While the higher risks of postpartum depression for Latinas is explained in part by socioeconomic status, community of residence, and immigrant status, the significantly higher risk among African-American mothers cannot be completely ameliorated by the controlled variables. Our study highlights the need for further research into the impact of social and environmental stressors on postpartum depression among racial and ethnic minority populations living in small cities, towns, and rural areas. PMID- 27761729 TI - Curvilinear associations of sleep patterns during weekdays and weekends with glycemic control in type 2 diabetes: the Hong Kong Diabetes Registry. AB - AIMS: We aimed to explore the associations of sleep patterns during weekdays and weekends with glycemic control in patients with type 2 diabetes. METHODS: We examined the association between indices of glycemic control [glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG)] and sleep parameters (sleep duration, bedtime, and differences of sleep duration during weekdays and weekends) from adults with type 2 diabetes recruited in a prospective cohort enrolling from hospital medical clinics. Restricted cubic spline regression was used to examine the relationships between the glycemic indices and sleep parameters. RESULTS: Excluding shift workers, a total of 3508 patients enrolled between July 2010 and July 2014 were included in this analysis. Mean age was 53.9 [standard deviation (SD) 8.7] years, and mean disease duration of diabetes was 8.3 (SD 7.1) years. Fifty-nine percentage were men. Mean sleep duration during weekdays and difference of sleep durations between weekdays and weekends were 7.7 (SD 1.3) hours and 0.6 (SD 1.2) hours, respectively. Mean HbA1c and FPG were 7.6 (1.5) % and 7.6 (2.5) mmol/L, respectively. Using restricted cubic spline regressions with successive adjustments of potential confounders, sleep duration difference between weekdays and weekends remained significantly associated with both HbA1c and FPG in a curvilinear manner. Sleep duration of about 1 h more during weekends when compared to weekdays was associated with beneficial effect in HbA1c (-0.13 %, 95 % confidence interval -0.24 to -0.02). CONCLUSIONS: In type 2 diabetes, regular sleeping habit with modest sleep compensation during weekends has positive impact on glycemic control. PMID- 27761731 TI - An overview of maternal and fetal short and long-term impact of physical activity during pregnancy. AB - PURPOSE: To explore information available in the literature about the possible benefits resulting from physical activity (PA) in non-risky pregnant women, repercussion on maternal organism, fetal development, and on long-term offspring health. METHODS: Critical narrative review using online databases. RESULTS: Through critical discussion of studies focused on PA practiced during pregnancy, it was observed that some of the outcomes investigated on both mother and offspring showed conflicting findings. Considering the impact of maternal PA in certain offspring characteristics, due to the fact that their findings come from studies with small samples, they do not allow the stablishment of scientific evidence. However, a feature that shows broad consensus among studies is the view of PA during pregnancy as a safe intervention for mother and fetus. In situations where studies employing PA of moderate-intensity have not enough power to ensure a positive influence on certain clinical outcomes, what is observed is the lack of their influence, not negative impacts. Regarding epigenetic modulations measured late in the offspring, it has been attributed to PA a positive modulatory role on metabolic, hemodynamic and even on behavioral characteristics. However, possible mechanisms involved in these epigenetic changes have not been sufficiently explored. CONCLUSION: Maternal PA appears to be safe for both mother and fetus, and additional studies are needed to confirm the real influence of this practice in the offspring, as well as the perpetuation and transfer of these features between generations. PMID- 27761730 TI - Influence of Glycemic Control on Endogenous Circulating Ketone Concentrations in Adults Following Traumatic Brain Injury. AB - BACKGROUND: The objective was to investigate the impact of targeting tight glycemic control (4.4-6.1 mM) on endogenous ketogenesis in severely head-injured adults. METHODS: The data were prospectively collected during a randomized, within-patient crossover study comparing tight to loose glycemic control, defined as 6.7-8.3 mM. Blood was collected periodically during both tight and loose glycemic control epochs. Post hoc analysis of insulin dose and total nutritional provision was performed. RESULTS: Fifteen patients completed the crossover study. Total ketones were increased 81 MUM ([38 135], p < 0.001) when blood glucose was targeted to tight (4.4-6.1 mM) compared with loose glycemic control (6.7-8.3 mM), corresponding to a 60 % increase. There was a significant decrease in total nutritional provisions (p = 0.006) and a significant increase in insulin dose (p = 0.008). CONCLUSIONS: Permissive underfeeding was tolerated when targeting tight glycemic control, but total nutritional support is an important factor when treating hyperglycemia. PMID- 27761732 TI - Comparison of four protocols for luteal phase support in frozen-thawed Embryo transfer cycles: a randomized clinical trial. AB - PURPOSE: To compare the pregnancy outcomes between four regimens of luteal phase support (LPS), including vaginal progesterone, oral dydrogesterone, combination of oral dydrogesterone and gonadotropin releasing hormone analog (GnRH-alpha), and combination of oral dydrogesterone and human chorionic gonadotrophin (hCG), in Frozen-thawed Embryo Transfer (FET) cycles. METHODS: This randomized clinical trial was performed during a 6-month period, including candidates for FET. Patients were randomly assigned to four groups for LPS: 400 mg vaginal progesterone suppository twice daily, 10 mg oral dydrogesterone twice daily, 10 mg oral dydrogesterone twice daily combined with injection of 0.1 mg GnRH-alpha, and 10 mg oral dydrogesterone twice daily combined with injection of 1500 IU hCG. Primary endpoint included clinical pregnancy rate, ongoing pregnancy rate (OPR), and miscarriage rate (MR). RESULTS: A total of 400 FET cycles were analyzed. CPR was significantly lower in dydrogesterone group (9 %) when compared to vaginal progesterone (20 %), dydrogesterone and GnRH-alpha (25 %), and dydrogesterone and hCG (17 %). Logistic regression showed that only dydrogesterone group had significantly lower CPR in comparison with vaginal progesterone (OR = 0.39; p = 0.03), while it was comparable between other three groups. There were no significant difference between four groups regarding to OPR and MR. CONCLUSION: Vaginal progesterone provides appropriate LPS. Yet, combination of oral dydrogesterone and GnRH-alpha or hCG can be more suitable option compared to vaginal progesterone for LPS in women with vaginal irritation or discharge at a lower cost. PMID- 27761733 TI - Part-time employment of gynecologists and obstetricians: a sub-group analysis of a Germany-wide survey of residents. AB - BACKGROUND: Combining family and career is increasingly taken for granted in many fields. However, the medical profession in Germany has inadequately developed structures. Little is known regarding the satisfaction of physicians working part time (PT). METHODS: This Germany-wide on-line survey collected information on the working situation of PT employees (PTE) in gynecology. An anonymous questionnaire with 95 items, nine of which concerned PT work, was sent to 2770 residents and physicians undergoing further specialist training. RESULTS: Of the 481 participants, 104 (96 % female, 4 % male) stated they worked PT, which is greater than the national average. 94 % of all women and 60 % of all men would work PT for better compatibility between work and family life. The PTE regularly work night shifts (NS) (96 %) and weekends (98 %). The number of monthly NS (median 5 9) was not different between the full-time (FT) employees and the PTE who work >75 %. Only when the working hours are reduced by 25 % or more, there are fewer NS (median 1-4) PTE that have a desire for fewer NS. The classic PT model is seldom realized; over 70 % of PTE work whole days, while other working models do not play a major role in Germany. On-call models were subjectively declared to have the best family friendly work-life balance. OUTLOOK: The results obtained indicated that structures must be developed that to address the problem of childcare and the long working hours to ensure comprehensive medical care from specialists. PMID- 27761734 TI - Successful treatment of annular rupture during transcatheter aortic valve implantation. AB - Annular rupture presents a rare but potentially fatal complication of transcatheter aortic valve implantation (TAVI). Although it can be subtle and subclinical in presentation, most severe forms present with hemodynamic instability and represent true emergencies requiring a more invasive treatment, even conventional surgery. We present a case of successful treatment of annular rupture by left ventricular outflow tract patch and surgical aortic valve replacement. PMID- 27761735 TI - Can we still stop the migration of physicians from Austria? : An evaluation of clinical internships by students of the Medical University of Vienna. AB - The increasing emigration of graduates of the Medical University of Vienna presents a serious problem. This study examined students' evaluation of clinical rotations, their self-rated performance, and where they felt the most deficits exist. Medical students answered an online questionnaire surveying the following aspects: an evaluation of their internship; supervision; integration in the team and improvement of field-specific knowledge; the qualities of taking a patient's medical history by empathy; patient-centeredness; structure; target orientation; and the ability to integrate field-specific knowledge into anamnesis. The data collected indicate that rotations in Austria, especially in Vienna, were evaluated significantly worse than those abroad. Particularly the lack of supervision and integration in the team were criticized. These data stress a dire need for the reform of curricular structures during clinical rotation in the latter years of medical education. PMID- 27761736 TI - The medical and scientific responsibility of pollen information services. AB - Pollen information as such is highly valuable and was considered so far as a self evident good free for the public. The foundation for reliable and serious pollen information is the careful, scientific evaluation of pollen content in the air. However, it is essential to state and define now the requirements for pollen data and qualifications needed for institutions working with pollen data in the light of technical developments such as automated pollen counting and various political interests in aerobiology including attempts to finally acknowledge pollen and spores as relevant biological particles in the air worth being considered for pollution and health directives. It has to be emphasized that inadequate pollen forecasts are a considerable health risk for pollen allergy sufferers. Therefore, the responsibility of institutions involved in pollen monitoring and forecasting is high and should be substantiated with respective qualifications and know-how. We suggest here for the first time a portfolio of quality criteria and demand rigorous scientific monitoring and certification of such institutions in the interest and for the protection of persons affected by a pollen allergy. PMID- 27761737 TI - Middle ear adenoma with neuroendocrine differentiation : A pediatric case report. AB - BACKGROUND: Middle ear adenoma with neuroendocrine differentiation (MEA-ND), also known as carcinoid tumor of the middle ear, is an extremely rare neoplasm, especially when located within the tympanic cavity. To the best of our knowledge, this represents the first pediatric case of a MEA-ND described in Europe. Excluding the present case, only three other pediatric cases of this disease have been published globally. CASE REPORT: We report on a 15-year-old female patient who presented with conductive hearing loss of the right ear. A tympanogram was flat. Ear microscopy revealed bulging of the right posterior superior tympanic quadrant. Computed tomography depicted an opacification of the middle ear and mastoid air cells without evidence of bone erosion. Paracentesis was performed assuming a serous otitis media. Since there was no liquid found the patient underwent an atticoantrotomy and mastoidectomy as therapy for cholesteatoma. Histologic examination revealed a highly differentiated neuroendocrine tumor. Immunohistochemical evaluation showed strong positivity for synaptophysin. On the basis of these results, the patient underwent a middle ear revision surgery. After 15 months, magnetic resonance imaging and octreotide scans suggested disease recurrence, prompting a second surgical revision. The histologic examination confirmed a recurrence of only 1 mm, but postoperative imaging still showed pathological diffuse enhancement. Eight years after the initial diagnosis there has been no evidence of recurrence or metastasis. CONCLUSION: In our opinion a pathological radiological result is insufficient to identify recurrent or residual disease within the tympanic cavity. PMID- 27761738 TI - Mortality and readmissions in heart failure: an analysis of 36,824 elderly patients from the Slovenian national hospitalization database. AB - BACKGROUND: In heart failure (HF), comorbidity burden and prognostic risks increase with age. Studies investigating outcome in elderly patients from large datasets are lacking, particularly in central and eastern European countries. We analyzed the Slovenian data on mortality and readmissions after first HF hospitalization in patients aged 65 years or over. METHODS: In this observational epidemiological study, the Slovenian national hospitalization database was searched for HF patients aged >=65 years with first HF hospitalization between 2008 and 2012. All-cause mortality and readmissions were compared in young-olds (65-74 years), middle-olds (75-84 years), and old-olds (>=85 years) using cumulative probability plots and log rank test. The prognostic value of comorbidities on mortality and readmissions for age groups were assessed using multiple Cox proportional hazards models. RESULTS: Overall, 36,824 patients were included (median age 80 years, 41 % men, 20 % in-hospital mortality). The proportions of young-olds, middle-olds, and old-olds were 26, 48, and 26 %, respectively. Arterial hypertension (60 %), pulmonary disease (44 %), and atrial fibrillation (38 %) were the most prevalent comorbidities, with little variation over age. While age group was associated with higher mortality (P < 0.001), no such associations were seen for readmissions at any time points (P > 0.1 for all). Importance of comorbidities as a predictor for mortality faded with increasing age while only small decrease in hazard ratios for readmissions were seen. CONCLUSIONS: Age is an independent predictor of mortality but not readmissions in elderly patients with first HF hospitalization. Comorbidities are important predictors for mortality and readmissions in elderly. PMID- 27761740 TI - Aftereffects of Intense Low-Frequency Sound on Spontaneous Otoacoustic Emissions: Effect of Frequency and Level. AB - The presentation of intense, low-frequency (LF) sound to the human ear can cause very slow, sinusoidal oscillations of cochlear sensitivity after LF sound offset, coined the "Bounce" phenomenon. Changes in level and frequency of spontaneous otoacoustic emissions (SOAEs) are a sensitive measure of the Bounce. Here, we investigated the effect of LF sound level and frequency on the Bounce. Specifically, the level of SOAEs was tracked for minutes before and after a 90-s LF sound exposure. Trials were carried out with several LF sound levels (93 to 108 dB SPL corresponding to 47 to 75 phons at a fixed frequency of 30 Hz) and different LF sound frequencies (30, 60, 120, 240 and 480 Hz at a fixed loudness level of 80 phons). At an LF sound frequency of 30 Hz, a minimal sound level of 102 dB SPL (64 phons) was sufficient to elicit a significant Bounce. In some subjects, however, 93 dB SPL (47 phons), the lowest level used, was sufficient to elicit the Bounce phenomenon and actual thresholds could have been even lower. Measurements with different LF sound frequencies showed a mild reduction of the Bounce phenomenon with increasing LF sound frequency. This indicates that the strength of the Bounce not only is a simple function of the spectral separation between SOAE and LF sound frequency but also depends on absolute LF sound frequency, possibly related to the magnitude of the AC component of the outer hair cell receptor potential. PMID- 27761739 TI - Muscle wasting in heart failure : The role of nutrition. AB - Muscle wasting and malnutrition are common complications in patients with advanced heart failure (HF); however, both remain underdiagnosed and undertreated although they both play relevant roles in the progression of HF. The risk of muscle wasting in patients with HF increases in those patients with malnutrition or at risk of malnutrition. Muscle wasting and malnutrition are thought to be positively influenced by adequate therapeutic interventions such as physical activity and nutritional support. Consequently, early detection of malnutrition in patients with HF is recommended. This review discusses muscle wasting and nutritional status, describing the effects of malnutrition on muscle wasting in patients with HF. We review specific issues related to muscle wasting and nutritional status in patients with HF; however, no established strategies currently exist to focus on patients suffering from muscle wasting with malnutrition. PMID- 27761743 TI - Immunogenic decapeptide in melanoma immunotherapy. AB - Melanoma is a cancer associated with melanocytes of epidermis. There has been a consistent increase in the number of melanoma patients because of the depletion of the ozone layer which makes it of paramount importance to explore the immunogenic potential of various peptides in melanoma therapy. In the current study, a mutated decapeptide (ELAGIGILTV) epitope ID 12941 was taken from the melanoma antigen recognized by T-cells. This epitope displayed relatively better affinity for histocompatibility leukocyte antigen influencing the proliferation of cytotoxic T-cells. Immunogenicity of the oligopeptide can be further intensified by its simultaneous binding to the programmed death receptor of the T lymphocytes. We have used the molecular dynamics (MD) simulation approach to reveal the dynamics of the decapeptide and its consequences to immunogenic effects. The dynamics have ensembled various conformations of the peptide which have been clustered in their representative conformers. During the dynamics, the peptide was found to fold to its conformation with a minimum free energy. Moreover, multiple analysis of the MD trajectory has provided many physiochemical features involved in the biological activity to improve the immunogenicity of this antigenic peptide. The manuscript concludes by proposing this decapeptide as a potential vaccine for the melanoma cancer. PMID- 27761742 TI - Cementless metaphyseal sleeves without stem in revision total knee arthroplasty. AB - INTRODUCTION: Revision total knee arthroplasty with a cementless metaphyseal sleeve is suggested to be used without stem in revision total knee arthroplasty (rTKA). To the best of our knowledge, no papers investigating this have been published. The purpose of this study was to evaluate clinical outcome. METHOD: In this retrospective study, 71 patients operated with rTKA with sleeves without stem in the period 2009-2011 were identified; 63 were examined. All patients with the prosthesis still in place were invited to a medical examination including X rays. American Knee Society Score (AKSS) and Oxford Knee Score (OKS) were used as primary clinical outcome scores. RESULTS: Mean number of revisions including the revision with sleeve was 1.7. AKSS increased significantly from 62.7 to 109.6; (p value <0.0001). The overall satisfaction was 2.5 on a four-stage scale, going from very satisfied to dissatisfied (range 1-4). The Anderson Orthopaedic Research Institute (AORI) classification showed 63 % of the tibias and 56 % of the femurs to be type 2B, whereas 19 % tibias and 5 % femurs were type 3. Review of the X-rays showed all prostheses fixed. Mean tibiofemoral alignment was 6.0 degrees valgus, and 51 % were outside optimal alignment (2.4 degrees -7.2 degrees ). Six patients were excluded from the study. CONCLUSIONS: We found that the prostheses were overall well fixed and patients' AKSS increased significantly. Many patients had pain conditions, both comorbid pain and pain that might be alignment-related, and adding a stem thus seems to be a good idea in terms of alignment. Level of evidence Level IV, case series without control group. PMID- 27761741 TI - The added value of auditory cortex transcranial random noise stimulation (tRNS) after bifrontal transcranial direct current stimulation (tDCS) for tinnitus. AB - Tinnitus is the perception of a sound in the absence of a corresponding external sound source. Research has suggested that functional abnormalities in tinnitus patients involve auditory as well as non-auditory brain areas. Transcranial electrical stimulation (tES), such as transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex and transcranial random noise stimulation (tRNS) to the auditory cortex, has demonstrated modulation of brain activity to transiently suppress tinnitus symptoms. Targeting two core regions of the tinnitus network by tES might establish a promising strategy to enhance treatment effects. This proof-of-concept study aims to investigate the effect of a multisite tES treatment protocol on tinnitus intensity and distress. A total of 40 tinnitus patients were enrolled in this study and received either bifrontal tDCS or the multisite treatment of bifrontal tDCS before bilateral auditory cortex tRNS. Both groups were treated on eight sessions (two times a week for 4 weeks). Our results show that a multisite treatment protocol resulted in more pronounced effects when compared with the bifrontal tDCS protocol or the waiting list group, suggesting an added value of auditory cortex tRNS to the bifrontal tDCS protocol for tinnitus patients. These findings support the involvement of the auditory as well as non-auditory brain areas in the pathophysiology of tinnitus and demonstrate the idea of the efficacy of network stimulation in the treatment of neurological disorders. This multisite tES treatment protocol proved to be save and feasible for clinical routine in tinnitus patients. PMID- 27761744 TI - Predominance of CRF63_02A1 and multiple patterns of unique recombinant forms of CRF63_A1 among individuals with newly diagnosed HIV-1 infection in Kemerovo Oblast, Russia. AB - Kemerovo Oblast (KO) has had the highest rate of HIV spread in Russia since 2011. The aim of this work was to study the genetic variation of HIV-1 in Kemerovo Oblast. Blood was sampled from a total of 91 HIV-positive antiretroviral-therapy naive individuals in 2013 (38) and 2015 (53). HIV-1 subtypes, pol gene drug resistance mutations, and viral tropism were analyzed. In 2013-2015, the prevalence of HIV-1 subtype A decreased in KO from 60.5 to 7.5 %. The samples collected in 2015 from the patients with newly diagnosed HIV demonstrate the current dominance of HIV-1 CRF63_02A1 (71.7 %) and HIV-1 URF63_A1 (20.8 %), their parental viruses being CRF63_02A1 and subtype A. The initially predominant genetic variant, HIV-1 subtype A, was replaced in KO. An unusually high incidence of HIV-1 unique recombinant forms is probably the result of HIV-1 CRF63_02A1 introduction in the group of injection drug users with the initial HIV-1 subtype A infection and the practice of risky behavior that promotes reinfection. HIV-1 CRF63_02A1, which recently emerged in Siberia, and its recombinant forms have an ever-increasing impact on the current HIV epidemic in Russia, making urgent the need for in-depth study of this HIV-1 genetic variant. PMID- 27761745 TI - Evidence of circulation of the novel border disease virus genotype 8 in chamois. AB - Evidence of association between the novel putative border disease virus genotype 8 (BDV-8) and fatal disease in an Alpine chamois (Rupicapra rupicapra) is reported. Diagnostically, we also demonstrated, as already previously reported, the failure of BDV-specific primers (PDB1 and PDB2) to detect BDV-8. PMID- 27761746 TI - Imaging of Paget's disease of bone. AB - Paget's disease of bone is a disorder of bone remodelling, leading to changes in the architecture and overall appearance of the bone. The disorder may be monostotic or polyostotic and affect any bone in the body, although most commonly it involves the spine, pelvis, skull and femur. This article explores the different imaging modalities used in the assessment of Paget's disease of bone in its different phases. The relative merits of each imaging modality is discussed with illustrative examples, in particular with respect to radiographs, nuclear medicine bone scan, computed tomography (CT) and magnetic resonance imaging (MRI). PMID- 27761747 TI - Endoclip therapy of post-sphincterotomy bleeding using a transparent cap-fitted forward-viewing gastroscope. AB - BACKGROUND: The incidence of post-endoscopic sphincterotomy (ES) bleeding is reportedly 2.0-5.0 %. Among various hemostatic methods, endoclip therapy is an effective modality in gastrointestinal bleeding. However, endoclip application for post-ES hemorrhage has not been widely studied, partly because of the difficulty in placing of clips using a duodenoscope. A cap-fitted forward-viewing gastroscope can easily visualize the major papilla and overcome the technical difficulty in applying endoclips. We aimed to determine the efficacy and safety of endoclips for the treatment of post-ES hemorrhage using a cap-fitted forward viewing gastroscope. METHODS: From January 2011 to December 2015, a total of 1448 endoscopic retrograde cholangiopancreatography procedures with ES were retrospectively assessed and followed-up. Patients with post-ES hemorrhage who did not respond to balloon compression or to spray or injection of a diluted epinephrine solution at the bleeding focus underwent endoclip therapy using a cap fitted forward-viewing gastroscope. Bleeding patterns (oozing, pulsatile, and exposed vessel) were recorded. RESULTS: ES-induced uncontrolled hemorrhage occurred in 57 patients (3.93 %). The mean age was 68.9 +/- 14.5 years, and the sex ratio (male/female) was 37 (64.9 %):20 (35.1 %) in 57 patients. Of the 57 cases of hemorrhage, early uncontrolled and delayed hemorrhage occurred in 45 (3.1 %) and 12 (0.82 %), respectively. Visible bleeding patterns following ES were: 50 oozing (57.7 %), 6 pulsatile (10.5 %), and 1 exposed vessel (1.8 %). Hemostasis was achieved by endoclipping using a cap-fitted forward-viewing gastroscope in 57 of 57 patients (100 %). The median number of clips used was 1.8 (range 1-3). No evidence of further bleeding or procedure-related complications was seen. CONCLUSIONS: We concluded that endoclip application using a cap-fitted forward-viewing gastroscope is feasible and safe and may be an effective technique for the treatment and/or prevention of post-ES hemorrhage. PMID- 27761748 TI - Ammonium acrylate biomanufacturing by an engineered Rhodococcus ruber with nitrilase overexpression and double-knockout of nitrile hydratase and amidase. AB - Rhodococcus ruber TH was selected as a parent strain to engineer for biomanufacturing of ammonium acrylate; the characteristics of this strain included accelerated growth rate, high cell tolerance and natively overexpressed nitrile hydratase (NHase). Transcriptome analysis revealed that the transcription levels of the native NHase, amidase and nitrilase were extremely high, moderate and extremely low, respectively. Through NHase-amidase double-knockout and amidase single-knockout, the engineered strains R. ruber THdAdN and R. ruber THdA were obtained for overexpression of a heterologous nitrilase from R. rhodochrous tg1-A6 using a urea-induced Pa2 promoter. The nitrilase activity toward substrate acrylonitrile in the engineered THdAdN(Nit) reached 187.0 U/mL at 42 h, threefold of that R. rhodochrous tg1-A6 and 2.3-fold of that of THdA(Nit). The optimal catalysis temperature and pH of the nitrilases in different cells exhibited no significant difference. Using the cells as catalysts, biomanufacturing of ammonium acrylate was performed under room temperature. When catalyzed by the engineered THdAdN(Nit), the titer and productivity of ammonium acrylate dramatically increased to 741.0 g/L and 344.9 g/L/h, which are the highest results reported to date. PMID- 27761749 TI - Predictors of acute scaffold recoil after implantation of the everolimus-eluting bioresorbable scaffold: an optical coherence tomography assessment in native coronary arteries. AB - This study investigated the predictors of acute recoil after implantation of everolimus-eluting BRS based on optical coherence tomography (OCT). Thirty-nine patients (56 scaffolds) were enrolled. Acute absolute recoil by quantitative coronary angiography was defined as the difference between the mean diameter of the last inflated balloon (X) and the mean lumen diameter of BRS immediately after balloon deflation (Y). Acute percent recoil was defined as (X - Y) * 100/X. Plaque eccentricity (PE) and plaque composition (PC) were assessed by OCT. PC was classified into two different types: calcific (score = 1), fibrous and lipid (score = 0). Based on the mean acute scaffold recoil value of the present study, scaffolds were divided into two groups: the low acute recoil group (LAR, n = 34) and the high acute recoil group (HAR, n = 22). Acute percent and absolute recoil were 6.4 +/- 3.0 % and 0.19 +/- 0.11 mm. PE, PC score and scaffold/artery ratio were significantly higher in HAR than in LAR. In multivariate logistic regression analysis, PE > 1.49, PC score (score 1) and scaffold/artery ratio >1.07 were significant positive predictors for the occurrence of acute scaffold recoil (OR 10.7, 95 % CI 2.2-51.4, p < 0.01; OR 5.6, 95 % CI 1.9-22.0, p = 0.04; OR 12.4, 95 % CI 2.6-65.4, p < 0.01, respectively). Acute recoil of BRS is influenced by BRS sizing as well as OCT-derived plaque characteristics. PMID- 27761750 TI - Comparison of vascular responses after different types of second-generation drug eluting stents implantation detected by optical coherence tomography. AB - : Few studies have directly compared vascular responses to second-generation drug eluting stents (DESs). We performed optical coherence tomography examinations in 56 consecutive patients with implanted single stent [19 cobalt-chromium everolimus-eluting stents (CoCr-EES), 22 platinum-chromium EES (PtCr-EES), and 15 resolute zotarolimus-eluting stents (R-ZES)] for de novo lesions, and who did not have restenosis at their 9-month follow-up. Neointimal thickness (NIT), stent apposition, and neointimal coverage were assessed in every strut. A neointimal unevenness score [(NUS), maximum NIT/average NIT in the same cross-section] was determined for every 1-mm cross-section (CS). A total of 8350 struts and 1159 CSs were analyzed. The CoCr- and PtCr-EES had significantly fewer malapposed struts compared to the R-ZES (CoCr-EES: 0.19 % vs. PtCr-EES: 0.19 % vs. R-ZES: 0.61 %, p = 0.007). Furthermore, the PtCr-EES had a lower frequency of uncovered struts compared to the others (CoCr-EES: 2.0 % vs. PtCr-EES: 1.4 % vs. R-ZES: 2.3 %, p = 0.047). The NUS correlated with the frequency of uncovered struts (p < 0.001, r = 0.54). The EESs demonstrated more homogenous neointimal growth, as shown in the NUS, compared to the R-ZES [CoCr-EES: 1.66 (1.38-1.97) vs. PtCr-EES: 1.67 (1.41 2.00) vs. R-ZES: 1.94 (1.56-2.28), p < 0.001]. Our results demonstrate that unevenness neointimal growth may relate with strut coverage after second generation DES implantation. The PtCr-EES had a high frequency of strut coverage with a homogeneous neointima, suggesting fewer risks for stent thrombosis. PMID- 27761751 TI - Myositis-specific autoantibodies and their association with malignancy in Italian patients with polymyositis and dermatomyositis. AB - This study aims to characterize myositis-specific antibodies in a well-defined cohort of patients with idiopathic inflammatory myopathy and to determine their association with cancer. Sera from 40 patients with polymyositis, dermatomyositis, and controls were tested by protein and RNA immunoprecipitation to detect autoantibodies, and immunoprecipitation-Western blot was used for anti MJ/NXP-2, anti-MDA5, and anti-TIF1gamma/alpha identification. Medical records were re-evaluated with specific focus on cancer. Anti-MJ/NXP-2 and anti TIF1gamma/alpha were the most common antibodies in dermatomyositis. In six dermatomyositis cases, we found five solid forms of cancer and one Hodgkin's lymphoma in long-term remission. Among patients with cancer-associated dermatomyositis, three were positive for anti-TIF1gamma/alpha, two for anti-Mi-2, and one for anti-MJ/NXP-2. The strongest positivity of anti-TIF1gamma was seen in two active forms of cancer, and this antibody was either negative or positive at low titers in the absence of cancer or in the 7-year remission Hodgkin's lymphoma. Four out of twenty (20 %) patients with polymyositis had solid cancer, but no specific association with autoantibodies was identified; further, none of the four cases of antisynthetase syndrome had a history of cancer. No serum myositis-associated autoantibody was observed in control sera, resulting in positive predictive value 75 %, negative predictive value 78.5 %, sensitivity 50 %, specificity 92 %, and area under the ROC curve 0.7083 for the risk of paraneoplastic DM in anti-TIF1gamma/alpha (+) patients. Myositis-specific autoantibodies can be identified thanks to the use of immunoprecipitation, and their association with cancer is particularly clear for anti-TIF1gamma/alpha in dermatomyositis. This association should be evaluated in a prospective study by immunoprecipitation in clinical practice. PMID- 27761752 TI - A3K2A3-induced apoptotic cell death of Leishmania amazonensis occurs through caspase- and ATP-dependent mitochondrial dysfunction. AB - Leishmaniasis is a neglected tropical disease that affects millions of people worldwide. Current therapies mainly rely on antimonial drugs that are inadequate because of their high toxicity and increased drug resistance. An urgent need exists to discover new, more effective, more affordable, and more target-specific drugs. Pathways that are associated with apoptosis-like cell death have been identified in unicellular eukaryotes, including protozoan parasites. In the present study, we studied the mechanism of cell death that is induced by A3K2A3 against L. amazonensis. A3K2A3 is a dibenzylideneacetone that has an acyclic dienone that is attached to aryl groups in both beta-positions, which is similar to curcuminoids and chalcone structures. This compound was previously shown to be safe with regard to cytotoxicity and active against the parasite. Biochemical and morphological approaches were used in the present study. The results suggested that A3K2A3 caused mitochondrial dysfunction in L. amazonensis promastigotes, leading to mechanisms of cell death that share some common phenotypic features with metazoan apoptosis, such as an increase in reactive oxygen species production, a decrease in the adenosine triphosphate ratio, phosphatidylserine exposure, a decrease in cell volume, caspase production, and DNA fragmentation. Altogether, these findings indicate that apoptosis can indeed be triggered by chemotherapeutic agents. PMID- 27761753 TI - A commentary on the paper: Facial trauma in the Trojan War. PMID- 27761755 TI - beta-Conglycinin enhances autophagy in porcine enterocytes. AB - beta-Conglycinin (beta-CG) is well known for inducing intestinal allergies and dysfunction in neonates and young pigs. However, the underlying mechanisms are largely unknown. In this study, to clarify the role of autophagy in beta-CG induced cytotoxicity, we investigated the effects of beta-CG on cell viability and autophagy activity in porcine enterocytes (IPEC-1 cells). The results indicated that the cell viability was decreased with the increasing levels of beta-CG. beta-CG treatment enhanced the eGFP-LC3 puncta per cells and LC3-II/LC3 I, and the latter was further increased in IPEC-1 cells cultured with bafilomycin A1. We conclude that beta-CG enhances autophagy activity in enterocytes. PMID- 27761754 TI - Review of Osteosarcoma and Current Management. AB - Osteosarcoma is the most common primary malignancy of bone in children and young adults. This tumor has a very heterogeneous genetic profile and lacks any consistent unifying event that leads to the pathogenesis of osteosarcoma. In this review, some of the important genetic events involved in osteosarcoma will be highlighted. Additionally, the clinical diagnosis of osteosarcoma will be discussed, as well as contemporary chemotherapeutic and surgical management of this tumor. Finally, the review will discuss some of the novel approaches to treating this disease. PMID- 27761757 TI - Development of a sandwich ELISA assay for quantification of human tissue transglutaminase in cell lysates and tissue homogenates. AB - Tissue transglutaminase (tTG) belongs to the multigene transglutaminase family of Ca2+-dependent protein cross-linking enzymes. There is a strong evidence that tTG is involved in pathology, such as neurodegenerative diseases, cancer, and celiac disease. To study physiopathological implication of tTG, a sandwich immunoassay has been developed with a new monoclonal antibody for the capture and polyclonal antibody both generated in house. Using this ready to use assay, the tTG protein level can be measured in human tissue homogenates and cells extracts easily in about 4 h. The limit of detection is 1.7 ng/ml; the coefficients of intra- and inter-assay variations range from 1 to 2 % and from 7 to 10 %, respectively. The assay is specific to tTG, and no cross reactivity with TG1, TG3, TG6, TG7, or factor XIIIa was observed. Finally, in the addition to the tTG activity assay previously developed, this assay should be a valuable tool to increase our knowledge of the tTG involvement in physiological and pathological states. PMID- 27761756 TI - Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat. AB - Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca2+ dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential. We demonstrated that the anti-proliferative effect of the HDACi vorinostat is paralleled by the induction of TG2 mRNA and protein expression in cancer cells but not in ex vivo treated peripheral blood lymphocytes. This effect was also shared by other pan-HDACi and resulted in increased TG2 transamidating activity. Notably, high TG2 basal levels in a panel of cancer cell lines correlated with lower vorinostat antiproliferative activity. Notably, in TG2-knockdown cancer cells vorinostat anti-proliferative and pro apoptotic effects were enhanced, whereas in TG2-full-length transfected cells were impaired, suggesting that TG2 could represent a mechanism of intrinsic or acquired resistance to vorinostat. In fact, co-treatment of tumor cells with inhibitors of TG2 transamidating activity potentiated the antitumor effect of vorinostat. Moreover, vorinostat-resistant MCF7 cells selected by stepwise increasing concentrations of the drug, significantly overexpressed TG2 protein compared to parental cells, and co-treatment of these cells with TG2 inhibitors reversed vorinostat-resistance. Taken together, our data demonstrated that TG2 is involved in the resistance of cancer cells to vorinostat, as well as to other HDACi. PMID- 27761758 TI - Good for All? Hardly! Attending Church Does Not Benefit Religiously Unaffiliated. AB - The existing literature addressing Religion and Spirituality supports the idea that attending church is positively associated with health outcomes. However, within this literature there has been an impoverished effort to determine whether the Religiously Unaffiliated will report these positive relationships. Using representative data from Ontario (N = 3620), the relationships between Religious/Spiritual variables (Attendance, Prayer/Meditation, and Religiosity) and health outcomes (Happiness, Self-Rated Health, and Satisfaction with Life) were assessed. Results focused on three recurring trends: the Religiously Unaffiliated experienced attending church less positively than Christians; when compared at the highest level of Attendance, the Religiously Unaffiliated were less healthy than Christians; and when only considering the Religiously Unaffiliated, Religious/Spiritual variables were not significant and positive predictors of health outcomes. The discussion focused on the need to delineate between how Christians and the Religiously Unaffiliated experience Religious/Spiritual variables, and the need to stop over-generalizing the positive relationship between Religious/Spiritual variables and health. PMID- 27761759 TI - Caring for critically ill oldest old patients: a clinical review. AB - Despite technological advances, the mortality rate for critically ill oldest old patients remains high. The intensive caring should be able to combine technology and a deep humanity considering that the patients are living the last part of their lives. In addition to the traditional goals of ICU of reducing morbidity and mortality, of maintaining organ functions and restoring health, caring for seriously oldest old patients should take into account their end-of-life preferences, the advance or proxy directives if available, the prognosis, the communication, their life expectancy and the impact of multimorbidity. The aim of this review was to focus on all these aspects with an emphasis on some intensive procedures such as mechanical ventilation, noninvasive mechanical ventilation, cardiopulmonary resuscitation, renal replacement therapy, hemodynamic support, evaluation of delirium and malnutrition in this heterogeneous frail ICU population. PMID- 27761761 TI - Addressing heterogeneity of individual blood cancers: the need for single cell analysis. AB - Cancer heterogeneity is a significant factor in response to treatment and escape leading to relapse. Within an individual cancer, especially blood cancers, there exists multiple subclones as well as distinct clonal expansions unrelated to the clinically detected, dominant clone. Over time, multiple subclones and clones undergo emergence, expansion, and extinction. Although sometimes this intra clonal and inter-clonal heterogeneity can be detected and/or quantified in tests that measure aggregate populations of cells, frequently, such heterogeneity can only be detected using single cell analysis to determine its frequency and to detect minor clones that may subsequently emerge to become drug resistant and dominant. Most genetic/genomic tests look at the pooled tumor population as a whole rather than at its individual cellular components. Yet, minor clones and cancer stem cells are unlikely to be detected against the background of expanded major clones. Because selective pressures are likely to govern much of what is seen clinically, single cell analysis allows identification of otherwise cryptic compartments of the malignancy that may ultimately mediate progression and relapse. Single cell analysis can track intra- or inter-clonal heterogeneity and provide useful clinical information, often before changes in the disease are detectable in the clinic. To a very limited extent, single cell analysis has already found roles in clinical care. Because inter- and intra-clonal heterogeneity likely occurs more frequently than can be currently appreciated on a clinical level, future use of single cell analysis is likely to have profound clinical utility. PMID- 27761760 TI - Thymol improves high-fat diet-induced cognitive deficits in mice via ameliorating brain insulin resistance and upregulating NRF2/HO-1 pathway. AB - The impaired insulin signaling has been recognized as a common pathogenetic mechanism between diabetes and Alzheimer's disease (AD). In the progression of AD, brain is characterized by defective insulin receptor substrate-1 (IRS-1) and increased oxidative stress. Thymol, a monoterpene phenol isolated from medicinal herbs, has exhibited robust neuroprotective effects. The present study was designed to investigate the protective effect of thymol on HFD-induced cognitive deficits, and explore the possible mechanisms. C57BL/6 J mice were fed for 12 weeks with either HFD or normal diet. The mice fed with HFD were dosed with metformin (200 mg/kg) or thymol (20, 40 mg/kg) daily. It was observed that thymol treatment significantly reversed the gain of body weight and peripheral insulin resistance induced by HFD. Meanwhile, thymol improved the cognitive impairments in the Morris Water Maze (MWM) test and decreased HFD-induced Abeta deposition and tau hyperphosphorylation in the hippocampus, which may be correlated with the inhibition of hippocampal oxidative stress and inflammation. In addition, thymol down-regulated the level of P-Ser307 IRS-1, and hence enhancing the expression of P-Ser473 AKT and P-Ser9 GSK3beta. We further found that the protective effects of thymol on cognitive impairments were associated with the up-regulation of nuclear respiratory factor (Nrf2)/heme oxygenase-1(HO-1) pathway. In conclusion, thymol exhibited beneficial effects on HFD-induced cognitive deficits through improving hippocampal insulin resistance, and activating Nrf2/HO-1 signaling. PMID- 27761762 TI - Sarcoid-like reaction in a patient with uveitis and underlying cancer. AB - PURPOSE: Sarcoidosis is a granulomatous disease of unknown etiology. Occasionally, triggering causes are identified, such as neoplasms, and they are termed sarcoid-like reactions, which may appear in any sarcoidotic target tissue. Choroidal metastases appear as part of widespread metastatic disease or as the first suggestion of neoplastic disease. They can also be a part of the differential diagnosis of a spectrum of inflammatory eye diseases. We present a case in which a lung carcinoma, pulmonary and eye sarcoid-like reactions, and choroidal metastasis take place in the same patient. CASE REPORT: A 60-year-old male with a past history of pulmonary sarcoidosis and associated anterior uveitis was diagnosed with a lung carcinoma with no regional lymph nodes extension, so that the resection surgery was performed without additional systemic treatment. At the same time, he complained of visual acuity loss and pain in his right eye. An intense ocular inflammatory reaction and a choroidal mass compatible with metastasis were identified. A vitrectomy with an accompanied histological exam of the lesion was deemed inconclusive. Ocular symptoms progressively worsened showing mass growth, and as a result, an enucleation was performed and the histological study subsequently revealed metastasis from his lung carcinoma. CONCLUSION: Sarcoid-like reactions may be due to incipient malignancies. Any diagnosis of sarcoidosis requires ruling out other diseases that can produce secondary sarcoid-like reactions. In addition, any choroidal mass suggestive of metastasis requires exclusion of metastatic disease even in the absence of clinical signs indicating tumor extension. PMID- 27761763 TI - Synthesis and antibacterial evaluation of new N- and S-glycosides analogues with dinitrophenyl-substituted heterocyclic bases. AB - Four N- and S-glycosides 13-16 having nucleobases 7-12 binding to sugar molecules from one side and to 3,5-dinitrophenyl moieties from another side were synthesized from 3,5-dinitrobenzoic acid 2. The synthetic intermediates, hydrazide 5 and thiosemicarbazide 6 regarded as important key compounds for the synthesis of nucleobases 7-12, each was obtained by two approaches. Structures of synthesized compounds were determined spectroscopically. Antibacterial activities for synthetic intermediates and glycosides were assessed using the paper disk diffusion method against Gram-negative bacteria: Pseudomonas aeruginosa, Pseudomonas fluorescens, and Escherichia coli and Gram-positive bacteria: Bacillus cereus and Staphylococcus aureus. Some of the synthetic compounds showed variant activity against some of the microorganisms tested. Nucleobases 8-10 and 12 showed moderate to slight activity against microorganisms under test at relatively high concentration, while the N-glycosides 14 and 15 exhibited persistent effect even at lower concentrations. Commercially available antibiotics polymyxine and oxytetracycline were used as positive controls. PMID- 27761764 TI - UV-mediated Chlamydomonas mutants with enhanced nuclear transgene expression by disruption of DNA methylation-dependent and independent silencing systems. AB - KEY MESSAGE: In this investigation, we succeeded to generate Chlamydomonas mutants that bear dramatically enhanced ability for transgene expression. To yield these mutants, we utilized DNA methyltransferase deficient strain. These mutants must be useful as a plant cell factory. Chlamydomonas reinhardtii (hereafter Chlamydomonas) is a green freshwater microalga. It is a promising cell factory for the production of recombinant proteins because it rapidly grows in simple salt-based media. However, expression of transgenes integrated into the nuclear genome of Chlamydomonas is very poor, probably because of severe transcriptional silencing irrespective of the genomic position. In this study, we generated Chlamydomonas mutants by ultraviolet (UV)-mediated mutagenesis of maintenance-type DNA methyltransferase gene (MET1)-null mutants to overcome this disadvantage. We obtained several mutants with an enhanced ability to overexpress various transgenes irrespective of their integrated genomic positions. In addition, transformation efficiencies were significantly elevated. Our findings indicate that in addition to mechanisms involving MET1, transgene expression is regulated by a DNA methylation-independent transgene silencing system in Chlamydomonas. This is in agreement with the fact that DNA methylation occurs rarely in this organism. The generated mutants may be useful for the low-cost production of therapeutic proteins and eukaryotic enzymes based on their rapid growth in simple salt-based media. PMID- 27761766 TI - De Novo Synthesis and Functional Analysis of Polyphosphate-Loaded Poly(Ethylene) Glycol Hydrogel Nanoparticles Targeting Pyocyanin and Pyoverdin Production in Pseudomonas aeruginosa as a Model Intestinal Pathogen. AB - The human gastrointestinal tract is the primary site of colonization of multidrug resistant pathogens and the major source of life-threatening complications in critically ill and immunocompromised patients. Eradication measures using antibiotics carry further risk of antibiotic resistance. Furthermore, antibiotic treatment can adversely shift the intestinal microbiome toward domination by resistant pathogens. Therefore, approaches directed to prevent replacement of health promoting microbiota with resistant pathogens should be developed. The use of non-microbicidal drugs to create microenvironmental conditions that suppress virulence of pathogens is an attractive strategy to minimize the negative consequences of intestinal microbiome disruption. We have previously shown that phosphate is depleted in the intestinal tract following surgical injury, that this depletion is a major "cue" that triggers bacterial virulence, and that the maintenance of phosphate abundance prevents virulence expression. However, the use of inorganic phosphate may not be a suitable agent to deliver to the site of the host-pathogen interaction since it is readily adsorbed in small intestine. Here we propose a novel drug delivery approach that exploits the use of nanoparticles that allow for prolonged release of phosphates. We have synthesized phosphate (Pi) and polyphosphate (PPi) crosslinked poly (ethylene) glycol (PEG) hydrogel nanoparticles (NP-Pi and NP-PPi, respectively) that result in sustained delivery of Pi and PPi. NP-PPi demonstrated more prolonged release of PPi as compared to the release of Pi from NP-Pi. In vitro studies indicate that free PPi as well NP-PPi are effective compounds for suppressing pyoverdin and pyocyanin production, two global virulence systems of virulence of P. aeruginosa. These studies suggest that sustained release of polyphosphate from NP-PPi can be exploited as a target for virulence suppression of lethal pathogenic phenotypes in the gastrointestinal tract. PMID- 27761767 TI - Pre-Exposure Prophylaxis: A Narrative Review of Provider Behavior and Interventions to Increase PrEP Implementation in Primary Care. AB - Since FDA approval of HIV pre-exposure prophylaxis (PrEP) for HIV prevention, attention has been focused on PrEP implementation. The CDC estimates that 1.2 million U.S. adults might benefit from PrEP, but only a minority are using PrEP, so there is a significant unmet need to increase access for those at risk for HIV. Given the large numbers of individuals who have indications for PrEP, there are not enough practicing specialists to meet the growing need for providers trained in providing PrEP. Moreover, since PrEP is a preventive intervention for otherwise healthy individuals, primary care providers (PCPs) should be primary prescribers of PrEP. There are important clinical considerations that providers should take into account when planning to prescribe PrEP, which are highlighted in the clinical case discussed. A growing body of research also suggests that some providers may be cautious about prescribing PrEP because of concerns regarding its "real-world" effectiveness, anticipated unintended consequences associated with its use, and ambiguity as to who should prescribe it. This review summarizes findings from studies that have assessed prescriber behavior regarding provision of PrEP, and offers recommendations on how to optimize PrEP implementation in primary care settings. Development and dissemination of educational interventions for PCPs and potential PrEP users are needed, including improved methods to assist clinicians in identifying appropriate PrEP candidates, and programs to promote medication adherence and access to social and behavioral health services. PCPs are well-positioned to prescribe PrEP and coordinate health related services to improve the sexual health of their patients, but tailored educational programs are needed. PMID- 27761769 TI - Metoprolol-induced Total Body Erythroderma. PMID- 27761768 TI - Comparing VA to Non-VA Care. PMID- 27761770 TI - Capsule Commentary on Thorp et al., Implementation of 2011 Duty Hours Regulations Through a Workload Reduction Strategy and Impact on Residency Training. PMID- 27761771 TI - Cryoprotection synergism between glycerol and dimethyl sulfoxide improves the mitochondrial transmembrane potential, plasmalemma, acrosomal and DNA integrities, and in vivo fertility of water buffalo (Bubalus bubalis) spermatozoa. AB - The objective of the study was to devise a cryoprotection synergism between glycerol and dimethyl sulfoxide (DMSO) for water buffalo spermatozoa. Additionally, the effect of best evolved concentrations of glycerol and DMSO in extender was assessed on in vivo fertility of buffalo spermatozoa. Ejaculates (n = 30) were equally distributed into five aliquots; first aliquot was diluted at 37 degrees C in extender having 7 % glycerol (control); second aliquot was diluted at 37 degrees C as well as at 4 degrees C in extender having 3.5 % DMSO (Group 1); third aliquot was diluted at 37 degrees C in extender having 3.5 % glycerol and then at 4 degrees C in extender having 3.5 % DMSO (Group 2); fourth aliquot was diluted at 37 degrees C in extender having 3.5 % DMSO and then at 4 degrees C in extender having 3.5 % glycerol (Group 3); fifth aliquot was diluted in extenders having 1.75 % glycerol and 1.75 % DMSO at 37 as well as at 4 degrees C (Group 4). At post thawing, sperm progressive motility (%), rapid velocity (%), average path velocity (um/s), curved line velocity (um/s), in vitro longevity (%), structural and functional integrity of plasmalemma (%), mitochondrial transmembrane potential (%) and viable sperm with intact acrosome (%) were higher (P < 0.05) in Group 4 compared to other treatment groups and control. Regarding sperm DNA integrity (%); it was higher (P < 0.05) in Group 4 compared to Group 1, 3 and control. The in vivo fertility (%) of buffalo spermatozoa was significantly higher with Group 4 compared to control (69.45 vs. 59.81). In conclusion, synergism exists between glycerol and DMSO (Group 4) in improving the quality and in vivo fertility of cryopreserved water buffalo spermatozoa. PMID- 27761772 TI - Toxicity of antimony, copper, cobalt, manganese, titanium and zinc oxide nanoparticles for the alveolar and intestinal epithelial barrier cells in vitro. AB - Heavy metals are found naturally on Earth and exposure to them in the living environment is increasing as a consequence of human activity. The toxicity of six different metal oxide nanoparticles (NP) at different points in time was compared using resazurin assay. After incubating Caco2 and A549 cells with 100 MUg/mL of Sb2O3, Mn3O4 and TiO2 nanoparticles (NPs) for 24 h no toxic effects were observed while Co3O4 and ZnO NPs had moderate effects and CuO NPs were toxic below 100 MUg/mL (24 h EC25 = 11 for A549 and 71 MUg/mL for Caco2). The long-term monitoring (up to 9 days) of cells to NPs revealed that the toxic effects of Mn3O4 and Sb2O3 NPs remarkably increased over time. The 9 day EC50 values for Sb2O3 NPs were 22 and 48 MUg/mL for A549 and Caco2 cells; and for Mn3O4 NPs were 47 and 29 MUg/mL for A549 and Caco2 cells, respectively. In general, the sensitivity of the cell lines in the resazurin assay was comparable. Trans epithelial electrical resistance (TEER) measurements were performed for both cell types exposed to Co3O4, Sb2O3 and CuO NPs. In TEER assay, the Caco2 cells were more susceptible to the toxic effects of these NPs than A549 cells, where the most toxic NPs were the Sb2O3 NPs: the permeability of the Caco2 cell layer exposed to 10 MUg/mL Sb2O3 NPs already increased after 24 h of exposure. PMID- 27761773 TI - Morphological study of Socorro Island Merino sheep and its crosses with hair breeds. AB - A study was conducted with the objective to characterize the morphology of Socorro Island Merino sheep. A total of 67 sheep, 62 females, 26 purebred and 36 crossbred with hair breeds, and five males were scored for 10 body measurements in addition to live weight, and four racial and seven functional indices were calculated. The influence of sex and crossbreeding on the body measurements and indices was analyzed by one-way analysis of variance, and morphological harmony was determined using Spearman correlation. With exception of rump length, body measurements and live weight were significantly greater in males than in females. Sexual dimorphism was 1.21, with males being 78 % heavier than females. Socorro Island Merino sheep were dolichocephalous, elipometric, with a convex curve rump, and with a high and low morphological harmony for females and males, respectively. They had undefined zootechnical aptitude tended toward dairy phenotype as long as crossbreeding with hair breeds did not affect their functional or productive aptitude. It can be concluded that Socorro Island Merino sheep is a new biotype of the Merino breed, which is necessary to preserve and evaluate as a source of genetic characteristics such as adaptation to harsh environmental conditions. PMID- 27761774 TI - Foot-and-mouth disease (FMD) in the Maghreb and its threat to southern European countries. AB - Foot-and-mouth disease (FMD) is a highly contagious and transboundary viral disease of domesticated and wild cloven-hoofed animals. The present study summarizes the knowledge generated from the epidemiology, diagnosis, and surveillance of the disease in the Maghreb (2014-2015) in assessing its threat to southern European countries. Currently, two serotypes of the FMD virus (O and SAT 2) and four lineages are circulating in the Maghreb region. The introduction of serotype SAT-2 in Libya and Mauritania in 2012 and 2015 respectively sets their neighbors and subsequently south European countries at constant risk of FMD re emergence. The potential pathways of FMD introduction to southern European countries from the Maghreb are the illegal introduction of infected animals and animal products, particularly meat or meat products carried by refugees. PMID- 27761775 TI - Improving smallholder cattle reproductive efficiency in Cambodia to address expanding regional beef demand. AB - This study aimed to identify factors associated with cattle reproductive output in rural smallholder farms in Cambodia in order to determine the main causes of reproductive failure and design efficient interventions for improvement. The majority of the nation's beef is produced on smallholder farms where productivity is constrained by poor animal reproductivity reflected in the recent livestock population decline of approximately 13 % from 2009 to 2013. Farmers (n = 240) from 16 villages from five provinces were surveyed in mid-2015 to determine their baseline knowledge, attitude and practices (KAP) associated with cattle reproduction. In addition, 16 case studies from three of these provinces were conducted to provide a more detailed assessment of current cattle reproductive husbandry practices. In order to assess the reproductive impact of previously implemented interventions, an endpoint KAP survey and longitudinal health and husbandry study from three Cambodian provinces conducted between 2008 and 2013 were also analysed. Three multivariable prediction models (two KAP and one longitudinal) identified the following significant factors associated with the reproductive outcomes 'number of calves born' or probability that cows 'gave birth': target feeding (P = 0.074), growing vegetables (P = 0.005), attitudes towards cattle vaccination (P = 0.010), improving bull selection (P = 0.032), local breed use (P = 0.005), number of joining attempts (P < 0.001), discontinuation of animal draught practices (P = 0.003) and retention of breeding animals (P < 0.001). The identification of significant factors and interventions in this study has led to intervention recommendations that can potentially improve reproductive efficiency, combat the declining cattle population and improve smallholder capacity to supply to expanding regional meat demand in South East Asia and China. PMID- 27761776 TI - Prospective study of avian influenza H9 infection in commercial poultry farms of Punjab Province and Islamabad Capital Territory, Pakistan. AB - A prospective study was conducted from November 2013 to February 2014 to estimate the spatial clustering; cumulative incidence and risk factors associated with avian influenza (AI) subtype H9 infection on commercial poultry farms of Pakistan. A total of 400 farms were enrolled and followed during the study period. Among these, 109 farms submitted samples suspected for AI to the laboratory, and only 47 farms were confirmed positive by hemagglutinin inhibition (HI) test. Data was collected from these 109 farms about their demography, management, and biosecurity practices. The cumulative incidence of H9N2 was 11.75 % (95 % confidence interval (CI) 8.76-15.23). The highest number of cases (40.42 %) was reported in January. One most likely cluster (p = 0.009, radius = 4.61 km) occurred in the Kasur district. Multivariable logistic regression analyses showed that the presence of wild birds on the farms (odds ratio (OR) = 16.18; 95 % CI 3.94-66.45) was independently associated with H9N2 infection. Cleaning of cages before delivery on farm (OR = 0.16; 95 % CI = 0.06-0.47), presence of a footbath at the entrance of farm (OR = 0.24; 95 % CI 0.08-0.79), and changing of gloves (OR = 0.33; 95 % CI 0.11-0.99) were protective factors against H9N2 infection. Reducing the exposure to risk factors and adapting biosecurity measures may reduce the risk of AI H9N2 infection on commercial poultry farms in Pakistan. PMID- 27761777 TI - Validation of a Brief Structured Interview: The Children's Interview for Psychiatric Syndromes (ChIPS). AB - Evidence-based assessment is important in the treatment of childhood psychopathology. While researchers and clinicians frequently use structured diagnostic interviews to ensure reliability, the most commonly used instrument, the Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS) is too long for most clinical applications. The Children's Interview for Psychiatric Syndromes (ChIPS/P-ChIPS) is a highly-structured brief diagnostic interview. The present study compared K-SADS and ChIPS/P-ChIPS diagnoses in an outpatient clinical sample of 50 parent-child pairs aged 7-14. Agreement between most diagnoses was moderate to high between the instruments and with consensus clinical diagnoses. ChIPS was significantly briefer to administer than the K SADS. Interviewer experience level and participant demographics did not appear to affect agreement. Results provide further evidence for the validity of the ChIPS and support its use in clinical and research settings. PMID- 27761778 TI - Antibiotic Resistance in Pediatric Urinary Tract Infections. AB - Urinary tract infections (UTIs) are a common problem in pediatric patients. Resistance to common antibiotic agents appears to be increasing over time, although resistance rates may vary based on geographic region or country. Prior antibiotic exposure is a pertinent risk factor for acquiring resistant organisms during a first UTI and recurrent UTI. Judicious prescribing of antibiotics for common pediatric conditions is needed to prevent additional resistance from occurring. Complex pediatric patients with histories of hospitalizations, prior antibiotic exposure, and recurrent UTIs are also at high risk for acquiring UTIs due to extended spectrum beta-lactamase-producing organisms. Data regarding the impact of in vitro antibiotic susceptibility testing interpretation on UTI treatment outcomes is lacking. PMID- 27761779 TI - Azole Resistance in Candida glabrata. AB - Candida infections have increased due to the growth and expansion of susceptible patient populations. The azole fluconazole is the most widely prescribed antifungal, but rising rates of clinical resistance among Candida glabrata isolates have greatly limited its utility. A better understanding of the mechanisms of azole antifungal resistance will provide information needed to overcome this clinical problem and reclaim this antifungal class as an option for empiric treatment of Candida infections. By far, the most frequent mechanism of azole resistance in C. glabrata is the overexpression of multidrug transporters due to activating mutations in the gene encoding transcription factor Pdr1. In this review, we will discuss the molecular and genetic basis of azole resistance in C. glabrata with particular attention given to the most recent discoveries in this field. PMID- 27761780 TI - Translocation of a granular chain in a horizontally vibrated saw-tooth channel. AB - We study the translocation mechanism of a granular chain in a horizontally vibrated saw-tooth channel using MD simulations and macro-scale experiments and show that the translocation speed is independent of the chain length as long as the chain length is larger than the spatial period of the saw-tooth. With the help of simulation, we explore the effect of geometry of the container and frequency and amplitude of vibration as well as chain flexibility on the chain drift speed. We observe that the most efficient transport is achieved when one of the channel walls is shifted with respect to the other wall by an amount equal to half the spatial period of the saw-tooth. We define a persistence length for the chain and show that the translocation speed depends on the ratio of persistence length over the spatial period of the saw-tooth. The optimum translocation occurs when this ratio is about 0.4. We also determine the optimum saw-tooth angle for the translocation of the chain as well as the optimum distance between the two walls. Some properties of this system are similar to those of polymer systems. PMID- 27761782 TI - Editorial: CORR (r) Thanks its Peer Reviewers. PMID- 27761781 TI - Water populations in restricted environments of lipid membrane interphases. AB - We employ molecular dynamics simulations to study the hydration properties of Dipalmitoylphosphatidylcholine (DPPC) bilayers, both in the gel and the liquid crystalline states. We show that while the tight hydration centers (PO and CO moieties) are significantly hydrated in both phases, the gel-fluid transition involves significant changes at the second hydration shell, particularly at the buried region between the hydrocarbon tails. Thus, while almost no buried water population exists in the gel state below the carbonyls, this hydrophobic region becomes partially water accesible in the liquid crystalline state. We shall also show that such water molecules present a lower H-bond coordination as compared to the molecules at the primary hydration shell. This means that, while the latter are arranged in relatively compact nanoclusters (as already proposed), the buried water molecules tend to organize themselves in less compact structures, typically strings or branched strings, with a scarce population of isolated molecules. This behavior is similar to that observed in other hydration contexts, like water penetrating carbon nanotubes or model hydrophobic channels or pores, and reflects the reluctance of water to sacrifice HB coordination. PMID- 27761783 TI - Examining the Course of Suicidal and Nonsuicidal Self-Injurious Thoughts and Behaviors in Outpatient and Inpatient Adolescents. AB - Suicidal and nonsuicidal self-injurious thoughts and behaviors (SITBs) among youth are major public health concerns. Although a growing body of research has focused on the complex association between nonsuicidal and suicidal self-injury, the temporal relationship between these two classes of behaviors is unclear. The current study addresses this empirical gap by examining the course of SITBs in adolescents receiving outpatient (N = 106; 82.1 % female) and inpatient (N = 174; 75.9 % female) treatment. SITBs (co-occurrence, age-of-onset, and time lag between SITBs) and major psychiatric disorders were assessed at a single time point with well-validated structured interviews. Adolescents in both clinical samples reported high co-occurrence of SITBs: most adolescents reported both lifetime nonsuicidal self-injury (NSSI) and suicidal thoughts. A similar temporal pattern of SITBs was reported in the two samples: thoughts of NSSI and suicide ideation had the earliest age-of-onset, followed by NSSI behaviors, suicide plans, and suicide attempts. However, the age-of-onset for each SITB was younger in the inpatient sample than in the outpatient sample. In terms of time lag between SITBs, suicide ideation occurred on average before initial engagement in NSSI, suggesting that pathways to NSSI and suicidal behavior may occur simultaneously rather than in succession from nonsuicidal to suicidal self injury. Results also indicated that the time to transition between SITBs was relatively fast, and that a key period for intervention and prevention is within the first 6-12 months after the onset of suicidal thinking. Taken together, these findings have important implications for understanding the time-lagged relationship between nonsuicidal and suicidal self-injury. PMID- 27761784 TI - Effect of C-type natriuretic peptide pretreatment on in vitro bovine oocyte maturation. AB - C-type natriuretic peptide (CNP) has been considered as a physiological meiotic inhibitor that stimulates the cGMP production by cumulus cell natriuretic peptide receptor 2 (NPR2), which inhibits oocyte phosphodiesterase type 3 activity and increases cAMP. In this study, we explored the effect of CNP pretreatment on the in vitro maturation (IVM) of bovine oocytes by examining changes in cleavage rate, blastocyst formation, mitochondrial DNA (mtDNA) copy number, reactive oxygen species (ROS) level, glutathione (GSH) content, and redox state. Our results showed that 200 nM CNP could effectively maintain meiotic arrest of bovine oocytes in vitro within 6 h. The two-step IVM system in which oocytes were pretreated with 200 nM CNP for 6 h and then cultured IVM for 28 h yielded a significantly (P < 0.05) increased blastocyst rate and cell number after in vitro fertilization (IVF) while compared to the conventional one-step IVM method. In addition, in comparison with the conventional 24-h matured oocyte, oocytes pretreated with 200 nM CNP for 6 h followed by 28 h IVM resulted in significantly (P < 0.05) higher mtDNA copy number and ROS levels in oocytes, while GSH level significantly (P < 0.05) decreased. Remarkably, regardless of treatment, no changes were observed in FAD++, NAD(P)H autofluorescence intensity, and redox ratio (FAD++/NAD(P)H) within the oocytes, maintaining a healthy metabolic equilibrium of redox throughout the two-step IVM. In conclusion, these results indicate that CNP pretreatment could dramatically improve the quality of bovine oocytes during in vitro maturation. PMID- 27761785 TI - Physical and psychological health in rare cancer survivors. AB - PURPOSE: Registries provide a unique tool for tracking quality of life in rare cancer survivors, whose survivorship experience is less known than for common cancers. This paper reports on these outcomes in 321 patients enrolled in the Rare Cancer Genetics Registry diagnosed with rare gastrointestinal, genitourinary, gynecologic, sarcoma, head/neck, or hematologic cancers. METHODS: Four outcomes were assessed, reflecting registrants' self-reported physical and mental health, psychological distress, and loneliness. Combining all patients into a single analysis, regression was used to evaluate the association between outcomes and socio-demographic and clinical factors. RESULTS: Median time since diagnosis was 3 years (range 0-9); 69 % were no longer in treatment. Poorer physical health was reported in registrants who were older at diagnosis, unmarried, and still in treatment. Poorer mental status was associated with younger diagnosis age and unmarried status. Psychological distress varied by cancer type and was higher among currently treated and unmarried registrants. Greater loneliness was reported in registrants with gynecological cancers, and those who were less educated or unmarried. The physical and mental health profile of rare cancer survivors is similar to what is reported for common cancers. CONCLUSIONS: Unmarried participants reported poorer outcomes on all measures of quality of life. Furthermore, physical and mental health were not significantly different by cancer type after adjustment for diagnosis age, whether currently in treatment and marital status. Thus, the combined analysis performed here is a useful way to analyze outcomes in less common diseases. Our findings could be valuable in guiding evaluation and intervention for issues impacting quality of life. IMPLICATIONS FOR CANCER SURVIVORS: Rare cancer survivors, particularly those without spousal support, should be monitored for challenges to the physical as well as psychological aspects of quality of life. PMID- 27761786 TI - Post-pericardiotomy Syndrome. AB - Post-pericardiotomy syndrome (PPS) occurs in a subgroup of patients who have undergone cardiothoracic surgery and is characterized by fever, pleuritic pain, pleural effusion, and pericardial effusion. It is associated with significant morbidity, and the leading complications include tamponade and constrictive pericarditis. Epidemiologic studies have found that PPS often occurs among younger patients; however, there is a lack of comprehensive risk stratification. It is therefore important to be able to identify patients who are at high risk for developing this disease. The diagnosis is made if patients present with 2 out of the following 5 criteria; fever, pericardial or pleuritic chest pain, pericardial or pleural friction rub, pericardial effusion, and pleural effusion with elevated C-reactive protein (CRP). Pericardial effusion associated with PPS is detected by echocardiography, and cardiac MRI is used for evaluation of pericardial thickening as well as inflammation associated with PPS. These imaging modalities have been invaluable for monitoring the efficacy of treatment in PPS. Aspirin, nonsteroidal anti-inflammatory agents (NSAID), and colchicine are the mainstay of the current treatment for PPS. Although steroids are used for refractory cases of PPS, they are associated with significant side effects when used for long-term treatment of this disease. It is important for future research to focus on identification of clinical, serologic, and genetic markers that may predispose patients to PPS. There is also a need for clinical trials to address the use of targeted immunomodulatory treatment for this disease. PMID- 27761788 TI - Overexpression of Tau Rescues Nogo-66-Induced Neurite Outgrowth Inhibition In Vitro. AB - Nogo-66 plays a central role in the myelin-mediated inhibition of neurite outgrowth. Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. It remains unverified whether tau interacts directly with growth factor receptors, or engages in cross-talk with regeneration inhibitors like Nogo-66. Here, we report that plasmid overexpression of tau significantly elevated the protein levels of total tau, phosphorylated tau, and microtubule-affinity regulating kinase (MARK). Nogo-66 transiently elevated the total tau protein level and persistently reduced the level of p-S262 tau (tau phosphorylated at serine 262), whereas it had little influence on the level of p T205 tau (tau phosphorylated at threonine 205). Nogo-66 significantly decreased the protein level of MARK. Hymenialdisine, an inhibitor of MARK, significantly reduced the level of p-S262 tau. Overexpression of tau rescued the Nogo-66 induced inhibition of neurite outgrowth in neuroblastoma 2a (N2a) cells and primary cortical neurons. However, concomitant inhibition of MARK abolished the rescue of neurite outgrowth by tau in N2a cells. We conclude that dephosphorylation of tau at S262 is able to regulate Nogo-66 signaling, and that overexpression of tau can rescue the Nogo-66-induced inhibition of neurite outgrowth in vitro. PMID- 27761787 TI - Telomeres and telomerase in the clinical management of colorectal cancer. AB - Colorectal cancer (CRC) is the third most common cancer worldwide. Our aim is to describe the state of the art about the role of telomeres and telomerase in the clinical management of CRC and its potential utility as prognostic and diagnostic biomarkers and targets of new treatments. Telomere length could be a new diagnostic marker as an anomalous behavior is observed in peripheral blood cells when CRC patients and healthy people are compared. Moreover, telomeres and telomerase may be used as diagnostic markers considering that universal changes appear along the CRC process. Currently, new therapeutic cancer approaches are focused on inhibiting the maintenance of telomere length, choosing as targets telomerase -or its subunits- or the Shelterin complex. The goal of these therapies is the shortening of telomeres and the induction of cell senescence. Telomeres and telomerase emerge as useful molecular tools in the clinical management of CRC. PMID- 27761790 TI - Adrenal disorders: Is there Any role for vitamin D? AB - An emerging branch of research is examining the linkage between Vitamin D and nonskeletal disorders, including endocrine diseases. In this regard, a still little studied aspect concerns the involvement of vitamin D in adrenal gland disorders. Adrenal gland disorders, which might be theoretically affected by vitamin D unbalance, include adrenal insufficiency, Cushing's syndrome, adrenocortical tumors and hyperaldosteronism. In this review, we provide an updated document, which tries to collect and discuss the limited evidence to be found in the literature about the relationship between vitamin D and adrenal disorders. We conclude that there is insufficient evidence proving a causal relationship between vitamin D levels and adrenal disorders. Evidence coming from cross-sectional clinical studies can hardly clarify what comes first between vitamin D unbalance and adrenal disease. On the other hand, longitudinal studies monitoring the levels of vitamin D in patients with adrenal disorders or, conversely, the possible development of adrenal pathologies in subjects affected by impaired vitamin D levels would be able to elucidate this still unclear issue. PMID- 27761792 TI - Questioning the preparatory function of counterfactual thinking. AB - Why do individuals mentally modify reality (e.g., "If it hadn't rained, we would have won the game")? According to the dominant view, counterfactuals primarily serve to prepare future performance. In fact, individuals who have just failed a task tend to modify the uncontrollable features of their attempt (e.g., "If the rules of the game were different, I would have won it"), generating counterfactuals that are unlikely to play any preparatory role. By contrast, they generate prefactuals that focus on the controllable features of their ensuing behavior (e.g., "If I concentrate more, I will win the next game"). Here, we test whether this tendency is robust and general. Studies 1a and 1b replicate this tendency and show that it occurs regardless of whether individuals think about their failures or their successes. Study 2 shows that individuals generate relatively few controllable counterfactuals, unless explicitly prompted to do so. These results raise some questions regarding the generality of the dominant view according to which counterfactuals mainly serve a preparatory function. PMID- 27761789 TI - Skin steroidogenesis in health and disease. AB - The skin is an important extra-gonadal steroidogenic organ, capable of metabolizing various hormones from their precursors, as well as of synthesizing de novo a broad palette of sex steroids and glucocorticoids from cholesterol. In this manuscript, we review the major steroidogenic properties of human skin and we suggest steroidogenesis' impairment as a cardinal factor for various pathological conditions such as acne, rosacea, atopic dermatitis, and androgenic alopecia. PMID- 27761793 TI - Can the age at onset give a clue to the pathogenesis of ALS? AB - Pathogenesis could play an important role in the mid- to late-life onset of symptoms in amyotrophic lateral sclerosis (ALS). An analysis of the age at onset of ALS among the incident cases occurring in the population in the Health District of Ferrara, Italy, in the period 1064-2009 was carried out. Two subsequent 23-year time intervals (1964-1986 and 1987-2009) were considered. The mean age at onset (MAAO) was estimated in relation to gender, onset type and area of residence (urban or extra-urban) at disease onset among the incident cases which occurred in the two subsequent time intervals. An uneven increase in the MAAO over time was observed as it was significant only among the female cases (from 56.7 95 % CI 51.6-61.7 years to 65.4 95 % CI 61.8-69.0 years), the overall bulbar onset cases (from 58.0 95 % CI 54.0-62.1 years to 69.3 95 % CI 66.2-72.4 years), the overall cases occurring in the extra-urban population (from 54.5 95 % CI 49.0-60.1 years to 65.1 95 % CI 60.4-69.8 years) and the bulbar onset cases occurring in the extra-urban population (from 57.1 95 % CI 53.5-60.7 years to 69.6 95 % CI 66.3-73.7 years). Although the increasing age of the population combined with improvements in ALS diagnosis among the elderly may have played a part, these uneven findings among the incident cases occurring in a well-defined homogeneous population with a stable ALS incidence would seem to suggest the involvement of risk factors associated with the extra-urban environment. PMID- 27761794 TI - Nitrogen Sources Screening for Ethanol Production Using Carob Industrial Wastes. AB - Nowadays, bioethanol production is one of the most important technologies by the necessity to identify alternative energy resources, principally when based on inexpensive renewable resources. However, the costs of 2nd-generation bioethanol production using current biotechnologies are still high compared to fossil fuels. The feasibility of bioethanol production, by obtaining high yields and concentrations of ethanol, using low-cost medium, is the primary goal, leading the research done today. Batch Saccharomyces cerevisiae fermentation of high density sugar from carob residues with different organic (yeast extract, peptone, urea) and inorganic nitrogen sources (ammonium sulfate, ammonium nitrate) was performed for evaluating a cost-effective ethanol production, with high ethanol yield and productivity. In STR batch fermentation, urea has proved to be a very promising nitrogen source in large-scale production of bioethanol, reaching an ethanol yield of 44 % (w/w), close to theoretical maximum yield value and an ethanol production of 115 g/l. Urea at 3 g/l as nitrogen source could be an economical alternative with a great advantage in the sustainability of ethanol production from carbohydrates extracted from carob. Simulation studies, with experimental data using SuperPro Design software, have shown that the bioethanol production biorefinery from carob wastes could be a very promising way to the valorization of an endogenous resource, with a competitive cost. PMID- 27761791 TI - Evaluation of the potential inhibitory activity of a combination of L. acidophilus, L. rhamnosus and L. sporogenes on Helicobacter pylori: A randomized double-blind placebo-controlled clinical trial. AB - OBJECTIVES: To investigate whether three strains of probiotics, L. acidophilus, L. rhamnosus, and L. sporogenes, had signifificant inhibitive effects on Helicobacter pylori (H. pylori). METHODS: This is a 4-week, randomly assigned, parallel-group, doubled-blind, and placebo-controlled study. Fifty patients with a positive H. pylori infection urea breath test (?UBT) result > 10% and without ulcer symptoms were randomized into a treatment group and a placebo group by a computer generated allocation sheet with 1:1. These subjects took one capsule of probiotics or placebo twice daily. The primary measurement was the change in ?UBT values. RESULTS: The ?UBT values during the 4-week treatment period and the 2 week follow-up period were not signifificantly different between the treatment group and the placebo group, indicating that the inhibitive effects on H. pylori were comparable between both groups. The monocyte count (%) was 5.77+/-1.11 in the treatment group versus 5.09+/-1.12 in the placebo group (P=0.044), and the basophile count was 0.55+/-0.32 in the treatment group versus 0.36+/-0.23 in the placebo group (P=0.024) at week 2 of the treatment period, both of which reached statistical signifificance. The monocyte count was 5.75+/-1.26 in the treatment group and 4.72+/-0.99 in the placebo group at the end of the follow-up period (P=0.003). CONCLUSION: There was no signifificant inhibitive effects of the three probiotic strains (L. acidophilus, L. rhamnosus, and L. sporogenes) on H. pylori. Probiotics can not play the same role as antibiotics in the eradication of H. pylori, the role of probiotics is likely to be important as adjuvant to the triple or quadruple therapy for H. pylori, especially in resistance cases. PMID- 27761795 TI - Neuroprotective Effect of Low Frequency-Pulsed Electromagnetic Fields in Ischemic Stroke. AB - Low frequency-pulsed electromagnetic fields (LF-PEMFs) affect many biological processes; however, the fundamental mechanisms responsible for these effects remain unclear. Our study aimed to investigate the effect of LF-PEMFs on neuroprotection after ischemic stroke. C57B6 mice were exposed to LF-PEMF (F = 60 Hz, Bm = 10 mT) after photothrombotic occlusion. We measured the BDNF/TrkB/Akt signaling pathway, pro-apoptotic and pro-survival protein and gene expressions, and the expression of inflammatory mediators and performed behavioral tests in both LF-PEMF-treated and untreated ischemic stroke mice. Our results showed that LF-PEMF treatment promotes activation of the BDNF/TrkB/Akt signaling pathway. Subsequently, pro-survival proteins were significantly increased, while pro apoptotic proteins and inflammatory mediators were decreased in ischemic stroke mice after LF-PEMF treatment. The results demonstrated that LF-PEMF exposure has a neuroprotective effect after ischemic stroke in mice during the recovery process. PMID- 27761796 TI - Molecular Cloning, Characterization, and Expression Analysis of Lignin Genes from Sugarcane Genotypes Varying in Lignin Content. AB - Sugarcane (Saccharum spp.) is one of the highest biomass-producing plant and the best lignocellulosic feedstock for ethanol production. To achieve more efficient conversion of biomass to ethanol, a better understanding of the main factors affecting biomass recalcitrance is needed. Therefore, with this objective, here, we report a systematic study on lignin content, deposition, identification, and cloning of genes involved in lignin biosynthesis and their differential expression in five sugarcane clones, EC11003, EC11010, IK 76-91, IK 76-99, and Co 86032. Lignin content among the clones varied from 26.87 to 23.19 % with the highest in the clone EC11010 and the lowest in high sugar Co86032. Lignin deposition studied through phloroglucinol staining of the cell walls implied that the sclerenchyma cells of the energy canes (EC11010 and EC11003) have more lignin deposition followed by the Erianthus (IK 76-91 and IK 76-99) clones whereas Co86032 has the minimum amount of lignin deposition. We cloned partial coding regions of important genes of lignification COMT (650 bp), CCR (332 bp), and PAL (650 bp) from Erianthus, wild relative of sugarcane followed by the expression analysis through real-time PCR. Differential expression analysis showed high level of expression for the three genes in the energy cane EC11010. PMID- 27761797 TI - Regression analysis of clustered failure time data with informative cluster size under the additive transformation models. AB - This paper discusses regression analysis of clustered failure time data, which occur when the failure times of interest are collected from clusters. In particular, we consider the situation where the correlated failure times of interest may be related to cluster sizes. For inference, we present two estimation procedures, the weighted estimating equation-based method and the within-cluster resampling-based method, when the correlated failure times of interest arise from a class of additive transformation models. The former makes use of the inverse of cluster sizes as weights in the estimating equations, while the latter can be easily implemented by using the existing software packages for right-censored failure time data. An extensive simulation study is conducted and indicates that the proposed approaches work well in both the situations with and without informative cluster size. They are applied to a dental study that motivated this study. PMID- 27761798 TI - Colonisation with extended-spectrum beta-lactamase (ESBL) not detected in a prevalence study. AB - BACKGROUND: The Mid-West of Ireland has higher than average national rates of invasive extended-spectrum beta-lactamase (ESBL) bloodstream infections and carbapenemase-producing Enterobacteriaceae (CPE), with increasing numbers of ESBL isolates detected in community-dwelling patients. AIMS: To conduct a point prevalence study in a convenience sample of the Mid-West population with the aim of determining the extent of ESBL colonisation. METHODS: Utilising anonymised community stool samples that had completed routine analysis, we conducted a point prevalence study over a 4-week period on all samples that met defined inclusion and exclusion criteria. Limited epidemiological data was recorded: (1) age of patient, (2) gender, and (3) sender location. From these stool specimens, rectal swabs were inoculated (eSwabTM 480CE, Copan, Italy), which were subsequently cultured on selective chromogenic agar (ColorexTM ESBL). Culture plates were incubated aerobically at 37 degrees C for 24 h. RESULTS: Of 195 samples processed, 58 % (n = 112) were from females. The median patient age was 62.4 years (range 20-94 years). 186 samples (95 %) originated from general practitioner clinics. During the study period, only nine eligible stool samples were received from LTCF (6 public). From 195 ColorexTM ESBL chromogenic agar plates cultured, no ESBL-producing organisms were detected. CONCLUSIONS: This community point prevalence study did not identify ESBL colonisation despite high numbers of patients with invasive ESBL bloodstream infections presenting for admission in our institution. We believe this may be because of our small sample size. Data regarding antimicrobial exposure and other risk factors for ESBL colonisation were also not available. We remain vigilant for ESBL-producing organisms. PMID- 27761799 TI - Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma. AB - Calcitonin Gene-related Peptide (CGRP), Vasoactive Intestinal Peptide (VIP) and Substance P (SP) are sensory neuropeptides which may alter cancer growth through modulation of chronic inflammation. We recently reported that SP suppresses breast cancer growth and metastasis through neuroimmune modulation. These neuropeptides are hydrolyzed by Neprilysin (NEP) to bioactive fragments. Decreased activity of NEP was reported in clear cell and chromophobe type renal cell carcinoma (RCC). It is however not known how the levels of neuropeptides hydrolyzed with NEP changes in RCC. Decrease activity of SP and CGRP containing sensory nerve endings was previously reported to increase cancer metastasis in animal models. It is however not known how peptidergic nerve endings are altered in RCC. Hence we here evaluated the levels of neuronal and non-neuronal neuropeptides and NEP activity in RCC including papillary type as well as neighboring uninvolved kidney. A cross-sectional study was conducted in 57 patients undergoing radical nephrectomy and diagnosed with RCC. NEP activity, levels and expression were determined using flourogenic substrate, western blot and qPCR respectively in freshly-frozen tissues. Immunohistochemical analyses were also performed. Neuronal and non-neuronal levels of CGRP, SP and VIP levels were determined using two-step acetic acid extraction. Levels and activity of NEP were markedly decreased in RCC regardless of subtype. Similar levels of VIP were detected in first and second extractions. VIP levels were higher in clear cell and papillary RCC compared to nearby kidney tissue. VIP levels of neighboring kidney tissue of papillary type RCC was significantly lower compared to kidney samples from clear cell RCC. CGRP levels were higher in second extraction. Similar to VIP levels, CGRP levels of neighboring kidney tissue from clear cell and chromophobe type RCC was significantly lower compared to corresponding tumor samples, an effect observed in the second extraction. VIP and CGRP levels of nearby kidney tissue varied subtype dependently demonstrating that different subtypes of RCC alter their local environment differently. Furthermore NEP-induce hydrolysis of VIP creates selective VPAC-1 receptor agonist which has anti proliferative and anti-inflammatory effects. Hence loss of NEP activity may prevent anti-tumoral effects of VIP on RCC. PMID- 27761800 TI - Investigation of biomimetic shear stress on cellular uptake and mechanism of polystyrene nanoparticles in various cancer cell lines. AB - Cancer cells in the tumor microenvironment are affected by fluid shear stress generated by blood flow in the vascular microenvironment and interstitial flows in the tumor microenvironment. Thus, we investigated how fluidic shear stress affects cellular uptake as well as the endocytosis mechanism of nanoparticles using a biomimetic microfluidic system that mimics the human dynamic environment. Positively charged amino-modified polystyrene nanoparticles (PSNs) at 100 MUg/mL were delivered to cancer cells under static and biomimetic dynamic conditions (0.5 dyne/cm2). Additionally, the experiment was done in the presence of endocytosis inhibitors specific for one of the endocytosis pathways. To evaluate cellular uptake of cationic PSNs, the fluorescence intensity of cationic PSNs in cancer cells was measured by flow cytometer and fluorescence images were taken using confocal laser scanning microscopy. Cancer cells in dynamic conditions exhibited higher cellular uptake of PSNs and showed different cellular uptake mechanisms compared with those in static conditions. From these results, it suggested that biomimetic dynamic conditions stimulated specific endocytosis and prompted cellular uptake. It was also important to consider fluidic shear stress as one of the critical factors because cellular uptake and drug delivery could play a key role in cancer cells and metastasis. PMID- 27761802 TI - Contribution of LATS1 and LATS2 promoter methylation in OSCC development. AB - The aberrant DNA methylation of the tumor suppressor genes involved in DNA Damage Response (DDR) signaling and cell cycle regulation may lead to the tumorigenesis. Our purpose here is to analyze the promoter methylation and mRNA expression levels of LATS1 and LATS2 (LATS1/2) genes in OSCC. Promoter methylation status of LATS1/2 genes was evaluated in 70 OSCC paraffin-embedded tissues and 70 normal oral samples, using Methylation Specific PCR (MSP). LATS1/2 mRNA expression profiles were also investigated in 14 OSCC patients and 14 normal samples, using real-time PCR. In both candidate genes, promoter methylation assessment revealed significant relationship between cases and controls (OR = 2.24, 95 % CI = 1.40 3.54, P = 0.001; LATS1 and OR = 15.5, 95%CI = 3.64-64.76, P < 0.001; LATS2). As well as, the evaluation of mRNA expression levels showed decreased expression in OSCC tissues in compare to control tissues. (Mean +/- SD 1.74 +/- 0.14 in OSCC versus 2.10 +/- 0.24 in controls, P < 0.001; LATS1 and Mean +/- SD 1.36 +/- 0.077 in OSCC versus 1.96 +/- 0.096 in controls, P < 0.001; LATS2). To the best our knowledge, this is the first report regarding the down-regulation of LATS1/2 through promoter methylation in OSCC. It is suggested to explore the down-stream transcription factors of both genes for finding the molecular mechanism of this deregulation in OSCC. PMID- 27761801 TI - Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters. AB - Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography. The purpose of this study was to determine if the nature of the respiratory deficits in WNV-infected rodents is neurological and if deficits are due to a disorder of brainstem respiratory centers, cervical spinal cord (CSC) phrenic motor neuron (PMN) circuitry, or both. We recorded phrenic nerve (PN) activity and found that in WNV-infected mice, PN amplitude is reduced, corroborating a neurological basis for respiratory deficits. These results were associated with a reduction in CSC motor neuron number. We found no dramatic deficits, however, in brainstem mediated breathing rhythm generation or responses to hypercapnia. PN frequency and pattern parameters were normal, and all PN parameters changed appropriately upon a CO2 challenge. Histological analysis revealed generalized microglia activation, astrocyte reactivity, T cell and neutrophil infiltration, and mild histopathologic lesions in both the brainstem and CSC, but none of these were tightly correlated with PN function. Similar results in PN activity, brainstem function, motor neuron number, and histopathology were seen in WNV-infected hamsters, except that histopathologic lesions were more severe. Taken together, the results suggest that respiratory deficits in acute WNV infection are primarily due to a lower motor neuron disorder affecting PMNs and the PN rather than a brainstem disorder. Future efforts should focus on markers of neuronal dysfunction, axonal degeneration, and myelination. PMID- 27761803 TI - The pivotal role of CCN2 in mammalian palatogenesis. AB - Mammalian palatogenesis is a complex process involving a temporally and spatially regulated myriad of factors. Together these factors control the 3 vital processes of proliferation, elevation and fusion of the developing palate. In this study, we show for the first time the unequivocally vital role of CCN2 in development of the mammalian palate. We utilized CCN2 knockout (KO) mice and cranial neural crest derived mesenchymal cells from these CCN2 KO mice to investigate the 3 processes crucial to normal palatogenesis. Similar to previously published reports, the absence of CCN2 inhibits proliferation of cells in the palate specifically at the G1/S transition. Absence of CCN2 also inhibited palatal shelf elevation from the vertical to horizontal position. CCN2 KO mesenchymal cells demonstrated deficiencies in adhesion and spreading owing to an inability to activate Rac1 and RhoA. On the contrary, CCN2 KO mesenchymal cells exhibited increased rates of migration compared to WT cells. The addition of exogenous CCN2 to KO mesenchymal cells restored their ability to spread normally on fibronectin. Finally, utilizing an organ culture model we show that the palatal shelves of the CCN2 KO mice demonstrate an inability to fuse when apposed. Together, these data signify that CCN2 plays an indispensible role in normal development of the mammalian palate and warrants additional studies to determine the precise mechanism(s) responsible for these effects. PMID- 27761804 TI - The Presence of the Neuronal Nitric Oxide Synthase Isoform in the Intervertebral Disk. AB - Intervertebral disk degeneration is a progressive and debilitating disease with multifactorial causes. Nitric oxide (NO) might contribute to the cell death pathway. We evaluated the presence of the constitutive form of the neuronal NOS (nNOS) in both health and degenerated intervertebral disk through qPCR and immunohistochemistry. We also analyzed the potential role of nNOS modulation in the tail needle puncture model of intervertebral disk degeneration. Male Wistar rats were submitted to percutaneous disk puncture with a 21-gauge needle of coccygeal vertebras. The selective nNOS pharmacological inhibitor N (omega) propyl-L-arginine (NPLA) or a nNOS-target siRNA (siRNAnNOShum_4400) was injected immediately after the intervertebral disk puncture with a 30-gauge needle. Signs of disk degeneration were analyzed by in vivo magnetic resonance imaging and histological score. We found that intact intervertebral disks express low levels of nNOS mRNA. Disk injury caused a 4 fold increase in nNOS mRNA content at 5 h post disk lesion. However, NPLA or nNOS-target siRNA slight mitigate the intervertebral disk degenerative progress. Our data show evidence of the nNOS presence in the intervertebral disk and its upregulation during degeneration. Further studies would disclose the nNOS role and its potential therapeutical value in the intervertebral disk degeneration. PMID- 27761805 TI - Focal Therapy for Prostate Cancer: Pending Questions. AB - Focal therapy (FT) represents a potential shift in clinical practice by featuring a tissue-sparing approach for prostate cancer (PCa) treatment. It stands midway between active surveillance (AS) and more aggressive options like radical prostatectomy (RP) or radiotherapy. The field has enormously evolved in the last few years but there are still pending questions to answer in the future. The manuscript overlooks FT in terms of indications, available energies, situation of tumor microenvironment, follow-up, re-interventions, and the future of this approach for PCa. PMID- 27761806 TI - Mechanisms for attentional modulation by threatening emotions of fear, anger, and disgust. AB - Appropriately attending to threatening environmental stimuli is evolutionarily adaptive and crucial for survival. This study revealed that nonconscious attentional modulation of disgust has different behavioral and event-related potential (ERP) patterns, as compared to fear and anger. To facilitate its evolutionary purpose of avoidance, disgust first diverts rather than attracts attention. Accordingly, the N1 was smaller in a validly than in an invalidly disgust-cued condition. Furthermore, the frontal P3a for disgust, anger, and fear was found to be larger in the valid than in the invalid condition, which was interpreted as an involuntary switching of attention toward threat-related events to mobilize cognitive resources for action or defense. On the contrary, the parietal P3b only occurred at the conscious level; the enhanced P3b indicated that more cognitive resources were being allocated toward the task-relevant but previously less attended location, to ensure the effective achievement of task goals. In addition, group comparisons between individuals with low and high disgust sensitivity showed that the ERP differences between the disgust and the anger/fear conditions at the unconscious level may be attributed only to individuals with high disgust sensitivity. These findings, together with previous knowledge of the effects of fear and anger on attention, strengthen our confidence in the two-stage scheme of attentional modulation by threats, which consists of an early stage of bottom-up response scaling of sensory processing (reflected by the P1 and N1) and a later stage of top-down integration and regulation of emotion and behavior (reflected by the P3). PMID- 27761807 TI - Identification of Potential Therapeutics to Conquer Drug Resistance in Salmonella typhimurium: Drug Repurposing Strategy. AB - BACKGROUND: Salmonella typhimurium is the main cause of gastrointestinal illness in humans, and treatment options are decreasing because drug-resistant strains have emerged. OBJECTIVE: The objective of this study was to use computational drug repurposing to identify a novel candidate with an effective mechanism of action to circumvent the drug resistance. METHODS: We used the Mantra 2.0 database to initially screen drug candidates that share similar gene expression profiles to those of quinolones. Data were further reduced using pharmacophore mapping theory. Finally, we employed molecular-simulation studies to calculate the binding affinity of the screened candidates with DNA gyrase, alongside an analysis of side effects. RESULTS: A total of 16 drug candidates from the Mantra 2.0 database were screened. The pharmacophoric features of the screened candidates were examined and nalidixic acid features compared using the PharamGist program. A total of 11 compounds with the highest pharmacophore score were considered for binding energy calculation. Finally, we analysed the side effects of the eight drug candidates that showed significant binding affinity in the simulation study. CONCLUSION: Overall, flufenamic acid and sulconazole may be potential drug candidates that could be studied in vitro to assess their resistance profile against Salmonella enterica Typhimurium. PMID- 27761808 TI - Genome-wide piggyBac transposon mediated screening reveals genes related to reprogramming. PMID- 27761809 TI - Detection of Autophagy Induction After HDAC Inhibitor Treatment in Leukemic Cells. AB - Autophagy is a lysosome-dependent, intracellular pathway for the recycling of cellular components. It plays a pivotal role in both cancer development and the response to chemotherapy. Here we describe how autophagy can be monitored in living cells by flow cytometry using the cationic amphiphilic tracer dye Cyto ID(r) Green. The detection of autophagy induction in the human leukemia cell line K562 after the treatment with the HDAC class I inhibitor MS-275 serves as an example for this approach. PMID- 27761810 TI - Assessment of HDACi-Induced Protein Cleavage by Caspases. AB - Aberrant histone deacetylase (HDAC) activity often correlates with neoplastic transformation and inhibition of HDACs by small molecules has emerged as a promising strategy to treat hematological malignancies in particular. Treatment with HDAC inhibitors (HDACis) often prompts tumor cells to undergo apoptosis, thereby causing a caspase-dependent cleavage of target proteins. An unexpectedly large number of proteins are in vivo caspase substrates and defining caspase mediated substrate specificity is a major challenge. In this chapter we demonstrate that the hematopoietic transcription factor PU.1 becomes cleaved after treatment of acute myeloid leukemia (AML) cells with the HDACis LBH589 (panobinostat) or MS-275 (entinostat). To define caspase specificity for PU.1, an in vitro caspase assay including caspases 1-10 with in vitro-translated PU.1 is described in detail. PMID- 27761811 TI - Assessment of HDACi-Induced Cytotoxicity. AB - The chromatin contains the genetic and the epigenetic information of a eukaryotic organism. Posttranslational modifications of histones, such as acetylation and methylation, regulate their structure and control gene expression. Histone acetyltransferases (HATs) acetylate lysine residues in histones while histone deacetylases (HDACs) remove this modification. HDAC inhibitors (HDACi) can alter gene expression patterns and induce cytotoxicity in cancer cells. Here we provide an overview of methods to determine the cytotoxic effects of HDACi treatment. Our chapter describes colorimetric methods, like trypan blue exclusion test, crystal violet staining, lactate dehydrogenase assay, MTT and Alamar Blue assays, as well as fluorogenic methods like TUNEL staining and the caspase-3/7 activity assay. Moreover, we summarize flow cytometric analysis of propidium iodide uptake, annexin V staining, cell cycle status, ROS levels, and mitochondrial membrane potential as well as detection of apoptosis by Western blot. PMID- 27761813 TI - Analysis of Histone Deacetylase-Dependent Effects on Cell Migration Using the Stripe Assay. AB - For normal embryonic development/morphogenesis, cell migration and homing are well-orchestrated and important events requiring specific cellular mechanisms. In diseases such as cancer deregulated cell migration represents a major problem. Therefore, numerous efforts are under way to understand the molecular mechanisms of tumor cell migration and to generate more efficient tumor therapies. Cell migration assays are one of the most commonly used functional assays. The wound healing assay or the Boyden chamber assay are variations of these assays. Nearly all of them are two-dimensional assays and the cells can only migrate on one substrate at a time. This is in contrast to the in vivo situation where the cells are faced simultaneously with different surfaces and interact with different cell types. To approach this in vivo situation we used a modified version of the stripe assay designed by Bonhoeffer and colleagues to examine mechanisms of axonal guidance. The design of this assay allows cells to decide between two different substrates offered at the same time. Utilizing alternating neuronal substrates for migration analyses we can partially mimic the complex in vivo situation for brain tumor cells. Here we describe the detailed protocol to perform a modified version of the stripe assay in order to observe substrate dependent migration effects in vitro, to analyze the effect of Rho-dependent kinases (ROCKS), of histone deacetylases (HDACs) and of other molecules on glioma cells. PMID- 27761812 TI - Analysis of HDACi-Induced Changes in Chromosomal Passenger Complex Localization. AB - The chromosomal passenger complex (CPC) is a key regulator of cell division. Its proper localization during the different phases of mitosis and cytokinesis is crucial for the exertion of its various functions. HDACi treatment has been demonstrated to disturb the centromeric localization of the CPC in tumor cells, thus leading to severe mitotic defects often followed by apoptosis. In this chapter, we describe how HDACi-induced changes of the CPC localization can be analyzed by indirect immunofluorescence using CPC-specific primary and fluorophore-coupled secondary antibodies followed by confocal microscopy. PMID- 27761814 TI - Using Histone Deacetylase Inhibitors to Analyze the Relevance of HDACs for Translation. AB - Gene expression is regulated in part through the reversible acetylation of histones, by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). HAT activity results in the addition of acetyl groups on the lysine residues of histone tails leading to decondensation of the chromatin, and increased gene transcription in general, whereas HDACs remove these acetyl groups, thus leading to an overall suppression of gene transcription. Recent evidence has elucidated that histones are not the only components of the proteome that are targeted by HATs and HDACs. A large number of nonhistone proteins undergo posttranslational acetylation. They include proteins involved in mRNA stability, protein localization and degradation, as well as protein-protein and protein-DNA interactions. In recent years, numerous studies have discovered increased HDAC expression and/or activity in numerous disease states, including cancer, where the upregulation of HDAC family members leads to dysregulation of genes and proteins involved in cell proliferation, cell cycle regulation, and apoptosis. These observations have pushed HDAC inhibitors (HDACi) to the forefront of therapeutic development of oncological conditions. HDACi, such as Vorinostat (Suberoylanilide hydroxamic acid (SAHA)), affect cancer cells in part by suppressing the translation of key proteins linked to tumorigenesis, such as cyclin D1 and hypoxia inducible factor 1 alpha (HIF-1alpha). Herein we describe methodologies to analyze the impact of the HDACi Vorinostat on HIF-1alpha translational regulation and downstream effectors. PMID- 27761815 TI - Effects of HDACi on Immunological Functions. AB - Histone deacetylase inhibitors (HDACi) are used as therapeutics for several B cell-derived malignancies. Furthermore, they have been shown to modulate the response of the immune system, like the B cell function. HDACi treatment affects differentiation, proliferation, and survival of B cells. Here we describe how to investigate the effects of HDACi treatment on naive B cells regarding class switch recombination (CSR) in vitro using flow cytometry. PMID- 27761816 TI - DNA Fiber Spreading Assay to Test HDACi Effects on DNA and Its Replication. AB - DNA fiber spreading assay is an invaluable technique to visualize and follow the spatial and temporal progress of individual DNA replication forks. It provides information on the DNA replication progress and its regulation under normal conditions as well as on replication stress induced by environmental genotoxic agents or cancer drugs. The method relies on the detection of incorporated thymidine analogues during DNA synthesis in the S phase of the cell cycle by indirect immunofluorescence. Here, we describe the procedure established in our laboratories for sequential pulse labeling of human cells with 5-chloro-2' deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU), cell lysis, and DNA fiber spreading on slides and sequential immunodetection of the incorporated thymidine analogues by primary antibodies recognizing specifically CldU or IdU alone. We describe also the laser scanning imaging, classification, and measurement of the detected DNA fiber tracks. The obtained quantitative data can be evaluated statistically to reveal the immediate or long-term effects of DNA-damaging agents, DNA repair inhibitors, and epigenetic modulators like HDAC inhibitors on DNA replication in normal and tumor cells. PMID- 27761817 TI - Assessing the Effect of Class I Histone Deacetylase Activity on DNA Double-Strand Break Repair by Homologous Recombination. AB - Here we describe the method used in our laboratory for determining the activity of homologous recombination repair of DNA double-strand breaks in cell lines. This plasmid-based method, first published by Pierce et al. 1999 from Maria Jasin's laboratory, is used along with flow cytometry for demonstrating the positive regulation of class I histone deacetylases on the repair of DNA double strand breaks by homologous recombination. PMID- 27761818 TI - Establishment and Characterization of Long-Term Cultures Derived from Primary Acute Myeloid Leukemia Cells for HDAC Inhibitor Research. AB - Histone deacetylase (HDAC) inhibitors are promising drugs. These agents lead to growth inhibition, cell cycle arrest, premature senescence, and apoptosis of malignant cells. Aim of our studies was to determine the efficacy of HDAC inhibitors on the clinically most relevant population of human leukemic progenitor cells in vitro. We here present stroma-free long-term cultures (LTC) of primary acute myeloid leukemia (AML) cells as a useful system for drug sensitivity testing in functional assays. AML-LTC are established by isolating mononuclear cells from peripheral blood samples of AML patients followed by selection of CD34+ progenitor cells. AML-LTC cells can be maintained in liquid culture supplemented with cytokines and utilized for in vitro analyses to assess proliferation, apoptosis, expression of surface proteins or intracellular proteins and signal transduction, respectively. PMID- 27761819 TI - Assessing the Histone Deacetylase Activity of SIRT6 in Primary Murine Hepatocytes via Proximity Ligation Assay. AB - Generation of primary cell culture of hepatocytes by mouse liver perfusion (MLP) combines the advantages of in vivo and in vitro models. It provides hepatocytes that grow under physiological conditions in mice, with the genotype of the whole organism or a specific gene knockout. In contrast to immortalized cell cultures, primary murine hepatocytes (pmHep) are non-cancerous cells with a limited lifespan but still amenable to classical in vitro methods such as treatment with drugs, small molecule inhibitors, and agonistic/antagonistic antibodies of surface receptors as well as transfection. One technique, which has gained popularity recently, is the analysis of protein-protein interactions by the proximity ligation assay (PLA). Here, we describe a liver perfusion protocol and the detection of the histone deacetylase function of Sirtuin 6 (SIRT6) using PLA in pmHep. PMID- 27761820 TI - Purification and Analysis of Male Germ Cells from Adult Mouse Testis. AB - Isolation of pools of spermatogenic cells at specific developmental stages is essential for the investigations of molecular events controlling critical transitions during spermatogenesis. Large-scale cell purification techniques allow for combined proteomics, genomics, and transcriptomics studies. Herein, we describe a procedure for the purification of meiotic and post-meiotic male germ cells from adult mouse testes. We also describe how the fractionated cell populations could be used for further studies. In our laboratory, these protocols are routinely used to specifically investigate the molecular basis of histone acetylation/acylation-driven epigenetic programming. PMID- 27761822 TI - Engineering of Conditional Class I Hdac Knockout Mice and Generation of a Time Spatial Knockout by a Dual Recombination System. AB - The protein sequences of class I HDACs in mice and humans are 96-99 % identical. These highly conserved proteins have crucial roles in biological processes, such as proliferation and development, which is reflected in the lethality that occurs in conventional whole body knockout mice. Therefore, conditional knockouts are inevitable to investigate the functions of class I HDACs in mice. Here, we describe the generation of conditional class I Hdac knockout mice, using Hdac1 as an example. We explain a relatively quick procedure to generate the necessary target vectors by recombination-mediated genetic engineering and gateway techniques. Furthermore, we show how to culture, target, and screen for positively recombined ES cells. Additionally, we present a dual recombination system, which allows the deletion of class I Hdacs at any time by a tamoxifen inducible Cre. PMID- 27761821 TI - Generation of Tissue-Specific Mouse Models to Analyze HDAC Functions. AB - Histone deacetylases (HDACs) play crucial roles during mammalian development and for cellular homeostasis. In addition, these enzymes are promising targets for small molecule inhibitors in the treatment of cancer and neurological diseases. Conditional HDAC knock-out mice are excellent tools for defining the functions of individual HDACs in vivo and for identifying the molecular targets of HDAC inhibitors in disease. Here, we describe the generation of tissue-specific HDAC knock-out mice and delineate a strategy for the generation of conditional HDAC knock-in mice. PMID- 27761823 TI - Xenografting of Cancer Cell Lines for In Vivo Screening of the Therapeutic Potential of HDAC Inhibitors. AB - Histone deacetylase inhibitor application is lethal to many cancer types. To screen for the therapeutic potential of HDIs it is necessary to analyze their ability to target and kill cancer cells in vivo. Here, we describe the xenografting of (germ cell) cancer cell lines into the flank of nude mice and the subsequent intravenous application of HDIs. PMID- 27761824 TI - Generation of Xenotransplants from Human Cancer Biopsies to Assess Anti-cancer Activities of HDACi. AB - Human tumor in vivo cancer models raised in immunodeficient mice, the so-called patient-derived xenografts, are increasingly in use in preclinical development and evaluation of novel drug candidates including HDAC inhibitors. Here, we describe the techniques needed to generate novel patient-derived xenografts. The focus lies on vitally frozen tumor biopsies as starting material. First, the preparative steps on the animals, followed by the engraftment procedure itself, the tumor growth surveillance, the explantation procedure, and finally the handling of obtained xenograft tissues are described step by step. This technical description is completed by numerous tips and alternatives designed to allow for an easy adaptation and transfer to other laboratories. PMID- 27761825 TI - Phospho-Flow Analysis of Primary Mouse Cells After HDAC Inhibitor Treatment. AB - Flow cytometric techniques allow fast, sensitive, and multiparametric analyses at the single cell level. This makes it possible to distinguish subsets of cells within heterogeneous samples. Moreover, flow cytometry has become a frequently used method for the evaluation of therapeutic effects. Here, we describe the analysis of the phosphorylation status of signal transducer and activator of transcription-1 (STAT-1) in primary mouse cells after treatment with histone deacetylase inhibitors (HDACi) that are currently considered anticancer agents. We provide detailed protocols for the preparation of murine bone marrow cells and the staining of HDACi-treated cells, as well as an insight into the concepts of flow cytometry analysis. PMID- 27761827 TI - Assessing HDAC Function in the Regulation of Signal Transducer and Activator of Transcription 5 (STAT5) Activity Using Chromatin Immunoprecipitation (ChIP). AB - Transcriptional activation by STAT5 is repressed by deacetylase inhibitors. Investigating the role of deacetylases (HDACs) in STAT5-mediated transcription implies the analysis of molecular events taking place at the chromatin level. We describe here two alternative methods of chromatin immunoprecipitation that allow the characterization of chromatin modifications ensuing STAT5 activation and its inhibition by deacetylase inhibitors, in particular changes in histone acetylation, in histone occupancy, and in the association/dissociation of transcription factors and other chromatin-associated factors. PMID- 27761826 TI - Evaluation of Innate Immune Gene Expression Following HDAC Inhibitor Treatment by High Throughput qPCR and PhosFlow Cytometry. AB - The dynamics of chromatin structure contribute to the regulation of gene transcription and in part, the changes in chromatin structure associated with gene activation/repression are a function of the state of histone acetylation. Histone deacetylases (HDACs) deacetylate histone tails leading to a more compact structure of chromatin that in turn represses gene transcription. Given the rapid activation and/or repression of gene networks following microbial infection, the role of HDACs in the epigenetic regulation of genes involved in the innate and adaptive immune responses has become an area of extensive research. In relation to the immune-modulatory properties of HDAC inhibitors, we provide in the following methodological article an extended description of two techniques-a high throughput qPCR assay combined with PhosFlow cytometry-to evaluate the modulation of antiviral and inflammatory signaling cascades following HDAC inhibitor treatment. The high-throughput qPCR assay is based on the nanofluidic Fluidigm BioMark system that permits the analysis of up to 9216 qPCR reactions at once in a self-design open array chip. Together with the more refined analysis provided with the Phosflow technique, these two strategies offer invaluable tools to measure modulation of innate immune gene networks. PMID- 27761828 TI - Modulation of STAT1-Driven Transcriptional Activity by Histone Deacetylases. AB - The luciferase (LUC) reporter assay is commonly used to study gene expression at the transcriptional level. It is convenient, fast, sensitive, inexpensive, and provides quantitative data about small changes in transcription. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that plays a crucial role in signaling by interferons (IFNs). Here, we describe LUC reporter studies that address the role of histone deacetylase (HDAC) activity in STAT1-dependent gene activation. These experiments include overexpression of HDAC1, HDAC2, HDAC3, and HDAC4 as well as silencing of HDAC1, HDAC2, and HDAC3 through RNA interference in mammalian cancer cells. PMID- 27761829 TI - Proximity Ligation Assay to Quantify Foxp3 Acetylation in Regulatory T Cells. AB - Determining protein acetylation by immunoprecipitation and immunoblotting can be challenging, especially if the tissue of interest is low in quantity, and when good quality acetylation site-specific antibodies are not available. Proximity ligation assays allow a sensitive and quantitative method to assess Foxp3 acetylation in regulatory T cells, with as little as 1.5 * 105 cells within two days turnaround time. This method is of potential use in other similar scenarios, when post-translational modifications of a protein of interest need to be determined with only a small amount of sample and in the absence of specific antibodies that can assess the post-translational modification in the protein of interest. PMID- 27761830 TI - Testing the Effects of SIAH Ubiquitin E3 Ligases on Lysine Acetyl Transferases. AB - The family of seven-in-absentia (SIAH) ubiquitin E3 ligases functions in the control of numerous key signaling pathways. These enzymes belong to the RING (really interesting new gene) group of E3 ligases and mediate the attachment of ubiquitin chains to substrates, which then leads to their proteasomal degradation. Here, we describe a protocol that allows measuring SIAH-mediated ubiquitination and degradation of its client proteins as exemplified by acetyl transferases using simple overexpression experiments. The impact of SIAH expression on the relative amounts of target proteins and their mRNAs can be quantified by Western blotting and quantitative PCR (qPCR) as described here. PMID- 27761831 TI - Assessment of HDACi-Induced Acetylation of Nonhistone Proteins by Mass Spectrometry. AB - Posttranslational acetylation of lysine residues has been discovered as multifaceted regulatory modification for various nuclear, cytoplasmic, and mitochondrial proteins. The implementation of high-resolution and high-throughput mass spectrometry (MS) approaches has led to the identification of a hitherto underappreciated, large number of acetylation sites for a broad spectrum of cellular proteins. In this chapter, we describe a comprehensive protocol for the purification of an in vivo-acetylated, ectopically expressed, FLAG-epitope tagged nonhistone protein through immunoprecipitation (IP). The protocol also covers the sample preparation by SDS-PAGE, proteolytic digestion, and the analysis by LC-ESI MS. The success of this methodology, however, strongly depends on the physico chemical properties of the respective protein(s) and the quality of selected peptide mass spectra. PMID- 27761833 TI - Analysis of Histone Deacetylases Sumoylation by Immunoprecipitation Techniques. AB - Histone deacetylases (HDACs) are controlling dynamic protein acetylation by removing acetyl moieties from lysine. Histone deacetylases themselves are regulated on the posttranslational level, including modifications with small ubiquitin-like modifier (SUMO) proteins. Detecting SUMO modifications of deacetylases by immunoblotting is technically challenging due to the typically low ratio of the modified compared to the unmodified species. Here, we describe a set of methods for the detection of endogenous sumoylated HDACs by immunoprecipitation and immunoblotting techniques. PMID- 27761832 TI - Assessing the Role of Paralog-Specific Sumoylation of HDAC1. AB - Attachment of ubiquitin or ubiquitin-like (Ubl) modifiers, such as the small ubiquitin-related modifier SUMO, is a posttranslational modification (PTM) that reversibly regulates the function and the stability of target proteins. The SUMO paralogs SUMO1 and SUMO2/3, although sharing a common conjugation pathway, seem to play different roles in the cell. Many regulatory mechanisms, which contribute to SUMO-paralog-specific modification, have emerged. We have recently found that cell environment affects SUMO-paralog-specific sumoylation of HDAC1, whose conjugation to SUMO1 and not to SUMO2 facilitates its protein turnover. Here, we describe how to identify SUMO-paralog-specific conjugation of HDAC1 and how the different expression of SUMO E3 ligases in the cell plays an important role in this mechanism. PMID- 27761834 TI - How to Distinguish Between the Activity of HDAC1-3 and HDAC6 with Western Blot. AB - Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in their target proteins. This biochemical modification can have profound effects on the functions of these proteins and a dysregulation of HDAC activity contributes to severe diseases, including neoplastic transformation. In the following chapter, we present a strategy that allows to distinguish between the inhibition of the class I HDACs HDAC1, 2, and 3 and of the class IIb HDAC HDAC6. This method is based on Western blot and relies on the detection of hyperacetylated substrates of class I or class IIb HDACs in lysates from cells that were treated with histone deacetylase inhibitors (HDACi). PMID- 27761835 TI - Evaluating the Effect of HDAC8 Inhibition in Malignant Peripheral Nerve Sheath Tumors. AB - Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive disease with a dismal prognosis. The disease can occur sporadically or in patients with inherited neurofibromatosis (NF-1). MPNST is typically resistant to therapeutic intervention. Hence, the need for improved therapies is warranted. Several broad spectrum histone deacetylase (HDAC) inhibitors have a high affinity for class I HDAC isoforms. Inhibition of multiple HDAC isoforms often results in undesirable side effects, while inhibiting a single isoform could possibly improve the therapeutic window and limit toxicity. Recently, HDAC8 inhibitors have been developed and in initial preclinical studies, they demonstrate anticancer efficacy. Little is known about the role of HDAC8 in MPNST. We recently revealed an anticancer effect of HDAC8 inhibition in human and murine MPNST models. The goal of our previous study was to determine the potential therapeutic efficacy of HDAC8 inhibition in MPNST. In this chapter, we briefly describe the methods for determining the role of pharmacological HDAC inhibition in MPNST. PMID- 27761836 TI - Analyzing the Impact of Pan- and Class-Specific HDACi on Differentiation Associated Factors. AB - The differentiation of hematopoietic stem cells into mature blood cells is a highly ordered process and dysregulation of this process can lead to leukemogenesis. Agents that are used to cure acute promyelocytic leukemia (APL) can induce differentiation and/or apoptosis. Here, we describe how effects of all trans retinoic acid (ATRA) and histone deacetylase inhibitors (HDACi) on APL cell differentiation can be evaluated by immunoblotting and by flow cytometry. We show how the levels of differentiation-associated transcription factors of the CCAAT enhancer binding protein (C/EBP) family can be determined by Western blot and we explain how the cell surface expression of the leukocyte surface antigen CD11b can be measured by flow cytometry. PMID- 27761837 TI - Encapsulation of the HDACi Ex527 into Liposomes and Polymer-Based Particles. AB - Incorporation of drugs into particles can improve their therapeutic effectiveness. Solubility, half-life time, targeting, and the release of the drug can be modified by the encapsulation into a particle. Histone deacetylase inhibitors have a great potential to be used as therapeutics for many different diseases. In this chapter, we describe the inclusion of the low molar mass HDACi Ex527 into polymer-based particles and liposomes. PMID- 27761838 TI - Preparation of Histone Deacetylase Inhibitor Vorinostat-Loaded Poly D, L-Lactide co-Glycolide Polymeric Nanoparticles by Nanoprecipitation Method. AB - Nanotechnology is a comparatively new branch of science that includes harnessing the unique properties of particles that are nanometers in scale. Nanoparticles can be tailored in a precise fashion where their size, composition, and surface chemistry can be carefully controlled. The nanoprecipitation is a simple, powerful, and low-energy requiring technique, commonly used for the preparation of defined nanoparticles. Histone deacetylase inhibitor Vorinostat-loaded Poly D, L-lactide-co-glycolide (PLGA) polymeric nanoparticles were prepared by the nanoprecipitation technique. The technique commonly relies on the precipitation of a solvent-dissolved material as nanosize particles after the addition to a non solvent-containing stabilizer. The particle size and size distribution of the Vorinostat polymeric nanoparticles are significantly influenced by the surfactants used in the fabrication process of the formulation. The surfactants prevent aggregate formation and improve the stability of the nanoparticles. The partitioning and evaporation of organic solvents allowed the formation of Vorinostat-loaded polymeric nanoparticles. PMID- 27761839 TI - Generation and Assessment of Fusions Between HDACi and TKi. AB - Chimeric compounds combine the structural features of inhibitors of histone deacetylases (HDACi) and tyrosine kinase inhibitors (TKi), and therefore unite the effects of a dual-targeting strategy in one compound. Here, we describe the generation of such hybrid molecules. Small molecules, known as TKi, are combined with a Zn2+ chelating motive, preferentially a hydroxamic acid, in addition. The resulting small molecules also can inhibit histone deacetylases, which are dependent on the catalytically active Zn2+. Moreover, we summarize how the growth inhibitory effects of these combined compounds can be determined with a simple proliferation assay with a leukemic cell line. PMID- 27761840 TI - Differences in sleep architecture between left and right temporal lobe epilepsy. AB - To investigate whether seizure lateralization affects sleep macrostructure in patients with left and right temporal lobe epilepsy (TLE), as rapid eye movement (REM) sleep is shorter in patients with right hemispheric cerebral infarction than with left. We retrospectively analyzed data from 16 patients with TLE (6 men and 10 women aged 34.9 +/- 11.4 years) who underwent polysomnography as well as long-term video electroencephalography. Ten patients were diagnosed with left TLE and six patients with right TLE. Sleep stages and respiratory events were scored based on the American Academy of Sleep Medicine criteria. Sleep and respiratory parameters were compared between the patient groups. Percentage of REM stage sleep was significantly (p < 0.05) lower in patients with left TLE (median 8.8 %, interquartile range 5.5-13.8 %) than in patients with right TLE (median 17.0 %, interquartile range 14.1-18.3 %). The other parameters showed no significant differences. Shorter REM sleep in patients with left TLE sharply contrasts with the previous report of shorter REM sleep in patients with right cerebral infarction. Laterality of the irritative epileptic focus versus destructive lesion may have different effects on the sleep macrostructures. PMID- 27761841 TI - Adverse working events in patients with multiple sclerosis. AB - Multiple sclerosis (MS) and working status have recently arisen great interest. Fatigue, physical disability, cognition, and psychological disturbances have been linked to unemployment, as well to accidents during daily activities. The aim of our study was to determine frequency of different types of accidents at workplace (AWE) and possible clinical differences among employed (MSe) and unemployed (MSu) MS patients. Sixty MS patients (31 employed, 29 unemployed) and twenty healthy control subjects were recruited. All employed participants were requested to complete an ad-hoc questionnaire to collect AWE and related risks occurring at workplace in the past 2 months. Physical, cognitive, mood, and fatigue evaluations were also assessed. Illness and bumps along with risk of bumps and near falls resulted the most frequent AWE and risks occurring in MSe. Interestingly, those AWE were mostly observed among subjects with anxiety, depression, and cognitive fatigue rather than depending on severity of physical impairment. Moreover, psychological aspects, like anxiety and anger, seemed to play a crucial role in determining AWE. This study provides data on AWE occurrence and suggests possible mechanisms underlying negative events at workplace in MS. This might be important for planning strategies of AWE prevention in MS patients. PMID- 27761842 TI - The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma. AB - To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P < 0.05). Downregulated the expression of CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies. PMID- 27761843 TI - Automatic Diagnosis of Obstructive Sleep Apnea/Hypopnea Events Using Respiratory Signals. AB - Obstructive sleep apnea is a sleep disorder which may lead to various results. While some studies used real-time systems, there are also numerous studies which focus on diagnosing Obstructive Sleep Apnea via signals obtained by polysomnography from apnea patients who spend the night in sleep laboratory. The mean, frequency and power of signals obtained from patients are frequently used. Obstructive Sleep Apnea of 74 patients were scored in this study. A visual scoring based algorithm and a morphological filter via Artificial Neural Networks were used in order to diagnose Obstructive Sleep Apnea. After total accuracy of scoring was calculated via both methods, it was compared with visual scoring performed by the doctor. The algorithm used in the diagnosis of obstructive sleep apnea reached an average accuracy of 88.33 %, while Artificial Neural Networks and morphological filter method reached a success of 87.28 %. Scoring success was analyzed after it was grouped based on apnea/hypopnea. It is considered that both methods enable doctors to reduce time and costs in the diagnosis of Obstructive Sleep Apnea as well as ease of use. PMID- 27761844 TI - High-Precision (MC-ICPMS) Isotope Ratio Analysis Reveals Contrasting Sources of Elevated Blood Lead Levels of an Adult with Retained Bullet Fragments, and of His Child, in Milwaukee, Wisconsin. AB - Exposure to the neurotoxic element lead (Pb) continues to be a major human health concern, particularly for children in US urban settings, and the need for robust tools for assessment of exposure sources has never been greater. The latest generation of multicollector inductively coupled plasma mass spectrometry (MC ICPMS) instrumentation offers the capability of using Pb isotopic signatures as a tool for environmental source tracking in public health. We present a case where MC-ICPMS was applied to isotopically resolve Pb sources in human clinical samples. An adult male and his child residing in Milwaukee, Wisconsin, presented to care in August 2015 with elevated blood lead levels (BLLs) (>200 MUg/dL for the adult and 10 MUg/dL for the child). The adult subject is a gunshot victim who had multiple bullet fragments embedded in soft tissue of his thigh for approximately 10 years. This study compared the high-precision isotopic fingerprints (<1 0/00 2sigma external precision) of Pb in the adult's and child's whole blood (WB) to the following possible Pb sources: a surgically extracted bullet fragment, household paint samples and tap water, and a Pb water distribution pipe removed from servicing a house in the same neighborhood. Pb in the bullet and adult WB were nearly isotopically indistinguishable (matching within 0.05-0.56 0/00), indicating that bullet fragments embedded in soft tissue could be the cause of both acute and chronic elevated blood Pb levels. Among other sources investigated, no single source dominated the child's exposure profile as reflected in the elevated BLL. PMID- 27761845 TI - Effects of Excess Cr3+ on Trace Element Contents in the Brain and Serum in Chicken. AB - This study aimed to investigate the effects of chromic chloride (CrCl3) on Ca, Mg, Mn, Fe, Cu, and Zn contents in the brain and serum of chicken. Seventy-two chickens were randomly divided into four groups and treated with different doses of CrCl3 via drinking water: 0, 1/8, 1/4, and 1/2 LD50 for 42 days. The contents of the elements were evaluated through inductively coupled plasma mass spectrometry. Results showed that Cr contents in the brain and serum were higher than those in the control groups, although no significant dose-dependent changes (P > 0.05) in brain of the Cr-treated groups were observed at 42 days. As exposure time was prolonged and CrCl3 dosage was increased, Ca contents increased (P < 0.05). Mg and Cu contents in serum decreased; by contrast, Mg and Cu contents initially increased and then decreased in the brain. Fe and Zn contents in the serum increased; conversely, Fe and Zn contents in the brain decreased. CrCl3 exposure did not significantly affect Mn contents at 14 or 28 days, but significantly decreased (P < 0.05) at 42 days. Therefore, excess Cr3+ intake can disrupt absorption and deposition of other trace elements in the brain and serum; the blood-brain barrier may prevent the accumulation of these elements in the brain exposed to CrCl3. PMID- 27761846 TI - The Effects of Cerium Oxide Incorporation in Calcium Silicate Coating on Bone Mesenchymal Stem Cell and Macrophage Responses. AB - Ideal coatings for orthopedic implants should be able to induce excellent osseointegration with host bone tissue, which requires good osteogenic responses and limited inflammatory reactions. Cerium oxide (CeO2) ceramics have anti oxidative properties and can be used to decrease mediators of inflammation, making them attractive for biomedical application. In this study, two kinds of CeO2 incorporated calcium silicate coatings (CS-10Ce and CS-30Ce) were prepared via plasma spraying technique, and the effects of CeO2 addition on the responses of bone mesenchymal stem cells (BMSCs) and RAW264.7 macrophages were evaluated. The CS-10Ce and CS-30Ce coatings were characterized by X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy. An increase in CeO2 content in the coatings resulted in enhanced chemical stability and better BMSCs osteogenic behaviors in terms of cell adhesion, proliferation, ALP activity, and mineralized nodule formation. With respect to either ZrO2-added or unmodified CS coating, the CS-30Ce coating elicited higher effects on the macrophages, suppressing the gene expressions of pro-inflammatory (M1) markers (CCR7, IL-6, and TNF-alpha), while upregulating the expressions of anti inflammatory (M2) markers (CD206, IL-1ra, and IL-10); moreover, it could also increase the expression of osteoinductive molecules (BMP2 and TGF-beta1) by the macrophages. The results suggested that the regulation of BMSCs behaviors and macrophage-mediated responses at the coating's surface was related to CeO2 incorporation. The incorporation of CeO2 in CS coatings can be a valuable strategy to promote osteogenic responses and mitigate inflammatory reactions. PMID- 27761848 TI - Dexamethasone-induced cardiac deterioration is associated with both calcium handling abnormalities and calcineurin signaling pathway activation. AB - Dexamethasone is a potent and widely used anti-inflammatory and immunosuppressive drug. However, recent evidences suggest that dexamethasone cause pathologic cardiac remodeling, which later impairs cardiac function. The mechanism behind the cardiotoxic effect of dexamethasone is elusive. The present study aimed to verify if dexamethasone-induced cardiotoxicity would be associated with changes in the cardiac net balance of calcium handling protein and calcineurin signaling pathway activation. Wistar rats (~400 g) were treated with dexamethasone (35 ug/g) in drinking water for 15 days. After dexamethasone treatment, we analyzed cardiac function, cardiomyocyte diameter, cardiac fibrosis, and the expression of proteins involved in calcium handling and calcineurin signaling pathway. Dexamethasone-treated rats showed several cardiovascular abnormalities, including elevated blood pressure, diastolic dysfunction, cardiac fibrosis, and cardiomyocyte apoptosis. Regarding the expression of proteins involved in calcium handling, dexamethasone increased phosphorylation of phospholamban at threonine 17, reduced protein levels of Na+/Ca2+ exchanger, and had no effect on protein expression of Serca2a. Protein levels of NFAT and GATA-4 were increased in both cytoplasmic and nuclear faction. In addition, dexamethasone increased nuclear protein levels of calcineurin. Altogether our findings suggest that dexamethasone causes pathologic cardiac remodeling and diastolic dysfunction, which is associated with impaired calcium handling and calcineurin signaling pathway activation. PMID- 27761849 TI - A Relational Approach to Genetic Counseling for Hereditary Breast and Ovarian Cancer. AB - Ethical issues arise for genetic counselors when a client fails to disclose a genetic diagnosis of hereditary disease to family: they must consider the rights of the individual client to privacy and confidentiality as well as the rights of the family to know their genetic risk. Although considerable work has addressed issues of non-disclosure from the client's perspective, there is a lack of qualitative research into how genetic counselors address this issue in practice. In this study, a qualitative approach was taken to investigate whether genetic counselors in Australia use a relational approach to encourage the disclosure of genetic information from hereditary breast and ovarian cancer (HBOC) clients among family members; and if so, how they use it. Semi-structured qualitative interviews were conducted with 16 genetic counselors from selected states across Australia. Data collection and analysis were guided by a basic iterative approach incorporating a hybrid methodology to thematic analysis. The findings provide indicative evidence of genetic counselors employing a relational approach in three escalating stages--covert, overt and authoritative--to encourage the disclosure of genetic information. The findings lend credence to the notion that genetic counselors envision a form of relational autonomy for their clients in the context of sharing genetic information, and they depart from individualistic conceptions of care/solely client-centered counseling when addressing the needs of other family members to know their genetic status. PMID- 27761847 TI - Triazole RGD antagonist reverts TGFbeta1-induced endothelial-to-mesenchymal transition in endothelial precursor cells. AB - Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor beta1 (TGFbeta1) play a central role. When exposed to TGFbeta1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of alphav integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFbeta1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with alphavbeta3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFbeta1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFbeta1, and reduces both ALK5/TGFbeta1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing alpha-smooth muscle actin (alpha-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment. PMID- 27761850 TI - Patients with Amyotrophic Lateral Sclerosis Have High Interest in and Limited Access to Genetic Testing. AB - Although genetic testing for amyotrophic lateral sclerosis (ALS) is widely available, it is unknown what proportion of patients with ALS have access to genetic counseling and testing, and patient attitudes towards ALS genetic testing have not been studied. We conducted a national survey of ALS patients enrolled in the Agency for Toxic Substances and Disease Registry, which consisted of multiple choice questions and two 12 item Likert scale series assessing respondents' experience with and attitude toward genetic testing. The survey had an 8 % response rate, with 449 completed responses. Genetic testing was offered to 33.4 % and completed by 67.1 % of those offered. A minority of respondents (12.5 %) saw a genetic counselor, and were much more likely to be offered genetic testing (p = 0.0001). Respondents with a family history of ALS (8.4 %) were more likely to be offered testing (p = 0.0001) and complete testing (p = 0.05). Respondents with a family history of ALS were more likely to report a favorable attitude towards genetic testing (p = 0.0003), as were respondents who saw a genetic counselor (p = 0.02). The majority of respondents (82.7 %) felt that genetic testing should be offered to all patients with ALS. Our results indicate that ALS patients may have limited access to genetic testing, but perceive benefit from this service. Development of practice guidelines for genetic testing in ALS, to include the routine offer of genetic counseling, may result in broader and more consistent access to these services. PMID- 27761851 TI - Microbial community structure of a freshwater system receiving wastewater effluent. AB - Despite our dependency on treatment facilities to condition wastewater for eventual release to the environment, our knowledge regarding the effects of treated water on the local watershed is extremely limited. Responses of lotic systems to the treated wastewater effluent have been traditionally investigated by examining the benthic macroinvertebrate assemblages and community structure; however, these studies do not address the microbial diversity of the water systems. In the present study, planktonic and benthic bacterial community structure were examined at 14 sites (from 60 m upstream to 12,100 m downstream) and at two time points along an aquatic system receiving treated effluent from the Charleston Wastewater Treatment Plant (Charleston, IL). Total bacterial DNA was isolated and 16S rRNA sequences were analyzed using a metagenomics platform. The community structure in planktonic bacterial communities was significantly correlated with dissolved oxygen concentration. Benthic bacterial communities were not correlated with water quality but did have a significant geographic structuring. A local restructuring effect was observed in both planktonic and benthic communities near the treated wastewater effluent, which was characterized by an increase in abundance of sphingobacteria. Sites further downstream from the wastewater facility appeared to be less influenced by the effluent. Overall, the present study demonstrated the utility of targeted high-throughput sequencing as a tool to assess the effects of treated wastewater effluent on a receiving water system, and highlighted the potential for this technology to be used for routine monitoring by wastewater facilities. PMID- 27761853 TI - Prevalence and predictors of orthorexia nervosa among German students using the 21-item-DOS. AB - PURPOSE: Orthorexia nervosa (ON) describes the constant pathological preoccupation with "healthy" nutrition. The current results regarding the prevalence of ON differ widely possibly because of invalid measurement tools. This study aimed to investigate ON prevalence in a sample of German students and to examine age, gender, semester, and nutritional knowledge as potential predictors of ON by comparing nutrition science (NS) with economics (ES) students. METHODS: A total of 446 university students participated in the survey (NS 188, ES 268). ON was determined using the 21-item-DOS, which is a well constructed, validated, and reliability-tested questionnaire. Age, gender, and semester were also assessed. RESULTS: Of the total sample, 3.3 % were classified as having ON and 9.0 % were at risk of developing ON. Older students scored significantly higher on the subscale "avoidance of additives" compared with younger students and students of lower semester suffered significantly more often from ON than students of higher semester. In addition, comparing field of study showed no significant difference in the prevalence of ON or the risk of developing ON between female NS and ES students. However, mean values for the three DOS subscales were higher among female NS students, albeit far below values indicating pathological behavior. CONCLUSIONS: The prevalence of ON appears to be low in this sample of German university students. Female NS students do not seem to have higher prevalence of ON or risk of developing ON. PMID- 27761852 TI - Optimizing cultivation of agricultural products using socio-economic and environmental scenarios. AB - The combination of degrading natural conditions and resources, climate change, growing population, urban development, and competition in a global market complicate optimization of land for agricultural products. The use of pesticides and fertilizers for crop production in the agricultural fields has become excessive in the recent years and Golestan Province of Iran is no exception in this regard. For this, effective management with an efficient and cost-effective practice should be undertaken, maintaining public service at a high level and preserving the environment. Improving the production efficiency of agriculture, efficient use of water resources, decreasing the use of pesticides and fertilizers, improving farmer revenue, and conservation of natural resources are the main objectives of the allocation, ranking, and optimization of agricultural products. The goal of this paper is to use an optimization procedure to lower the negative effects of agriculture while maintaining a high production rate, which is currently a gap in the study area. We collected information about fertilizer and pesticide consumption and other data in croplands of eastern Golestan Province through face-to-face interviews with farmers to optimize cultivation of the agricultural products. The toxicity of pesticides according to LD50 was also included in the optimization model. A decision-support software system called multiple criteria analysis tool was used to simultaneously minimize consumption of water, chemical fertilizers, and pesticides and maximize socio-economic returns. Three scenarios for optimization of agricultural products were generated that alternatively emphasized on environmental and socio-economic goals. Comparing socio-economic and environmental performance of the optimized agricultural products under the three scenarios illustrated the conflict between social, economic, and environmental objectives. Of the six crops studied (wheat, barley, rice, soybeans, oilseed rape, and maize), rice ranked second in the social and fifth in the economic scenarios. Soybeans had the lowest rank for economic and social scenarios and its cultivation in the study area, in terms of economic and social goals, was rejected by the model. However, cultivation of soybeans continues in the area as a responsibility to cater for the major need of the country. Because of subsidized prices of water, fertilizers, and pesticides, the use of these items are far from optimized in the current agricultural practices in the area. PMID- 27761854 TI - Calcium polysulphide, its applications and emerging risk of environmental pollution-a review article. AB - Easy availability, preparation technique, and economic value make calcium polysulphide (CaS x ) a very useful inorganic chemical for various field and industrial applications. In this article, disparate applications of CaS x solution have been reviewed to suggest potential and future consolidation. This article also encompasses the physiochemical properties and production of CaS x solution, with critical appraisal on research focusing on CaS x application in agriculture industries and removal of potentially toxic elements (PTEs) from the environment. The kinetics of CaS x , technical issues associated with optimization of its dosage and environmental fate is also discussed in detail. This study covers almost all of the peer-reviewed research that has been performed since 1914. Some of the critiques in this article include the lack of integration between the exposure effect and the efficiency of treatment method, effects of oxidizing environments on the long-term performance of CaS x solution, and kinetics of CaS x solution with the PTEs. The working model of CaS x with PTEs is still system dependent, and therefore cannot be used with other applications. The kinetics of CaS x is described in detail with various phase stoichiometric reactions. Environmental fate is discussed based on applications, government reports, peer-reviewed articles and kinetics of CaS x , which provides a clear picture of emerging contaminants in the environment in relation to the insect resistance and ecotoxicology. Real time, lab based research articles are needed to identify toxicity limits of CaS x in environment in order to describe its effective permissible limit in environmental system. This review article provides a risk assessment of environmental pollution by CaS x based on its physicochemical characteristic, stoichiometry, kinetics, field, and industrial applications. PMID- 27761855 TI - Whole blood and hair trace elements and minerals in children living in metal polluted area near copper smelter in Karabash, Chelyabinsk region, Russia. AB - The primary aim of the study is assessment of hair and whole blood trace element and mineral levels in children living in a polluted area near a copper smelter (Karabash) and two control locations (Varna, Tomino) using inductively coupled plasma mass spectrometry. The obtained data indicates that both blood and hair As, Pb, and Fe levels in children living in Karabash significantly exceeded the control values. Whole blood levels of copper in children living in Varna exceeded that in Tomino (p = 0.155) and Karabash (p < 0.001) by 16 %. Oppositely, hair concentration of Cu was maximal in children from Karabash. Blood Ca and Mg content in children from Varna exceeded the respective values from Tomino and Karabash by 32 % (p = 0.021) and 42 % (p < 0.001), and 19 % (p < 0.001) and 9 % (p < 0.001), respectively. Similar differences were observed in hair mineral content. Oppositely, children living in Tomino and Karabash were characterized by 10 (p = 0.002) and 23 % (p < 0.001) higher levels of blood phosphorus. At the same time, hair P content was maximal in a polluted area. Therefore, children living in a polluted area near a copper smelter had significantly higher values of heavy metals and decreased Mg and Ca content in biosamples. It is supposed that adverse health effects in persons living near a copper smelter may be associated not only with toxic metal overexposure but also with altered mineral homeostasis. PMID- 27761856 TI - Global estimates of carbon monoxide emissions from 1960 to 2013. AB - The quantification of carbon monoxide (CO) emissions is necessary for atmospheric research and has been studied extensively. Aiming to build an inventory with both high spatial resolution and detailed source information, this study estimated the monthly nation-level CO emissions from 79 major sources from 1960 to 2013, based on which a 0.1 degrees * 0.1 degrees gridded emission map was developed for 2011 using a recent energy product. The high sectorial resolution of this inventory can help scientists to study the influence of socioeconomic development on emissions, help decision makers to formulate abatement strategies, and potentially benefit emission-reduction scenario modeling and cost-benefit analysis. Our estimate for 2011 was 888.17 Tg (745.67 Tg-1112.80 Tg), with a much higher contribution from anthropogenic activities (68 %) than wildfire and deforestation (32 %). The anthropogenic emissions in recent years were dominated by developing countries due to the continuously increasing industrial production intensity and/or population explosion. Further discussion of the spatial and temporal variation of emissions was conducted, and a decreased emission intensity was observed, which was attributed to related policies and technological progress. PMID- 27761858 TI - miR-21 is involved in skeletal deficiencies of zebrafish embryos exposed to polychlorinated biphenyls. AB - Polychlorinated biphenyl (PCB) exposure increases the incidence and severity of skeletal diseases, but little is known about the mechanisms that mediate this relationship. We exposed zebrafish embryos to PCB1254 and assessed the changes in bone morphology protein receptor II (BMPRII), which is involved in bone formation and embryonic development, miRNA-21, for which BMPRII is a known target, and calcium metabolism. PCB1254 upregulated the expression of miR-21 and suppressed BMPRII expression. The inhibition of miR-21 reversed the downregulation of BMPRII and alleviated the PCB1254-induced loss of calcium. These findings suggest new biomarkers of developmental defects of the skeleton caused by PCBs. PMID- 27761857 TI - Heavy metals and metalloids in the surface sediments of the Xiangjiang River, Hunan, China: distribution, contamination, and ecological risk assessment. AB - Here, we aim to determine the distribution, ecological risk and sources of heavy metals and metalloids in the surface sediments of the Xiangjiang River, Hunan Province, China. Sixty-four surface sediment samples were collected in 16 sites of the Xiangjiang River, and the concentrations of ten heavy metals and metalloids (Mn, Zn, Cr, V, Pb, Cu, As, Ni, Co, and Cd) in the sediment samples were investigated using an inductively coupled plasma mass spectrometer (ICP-MS) and an atomic fluorescence spectrophotometer (AFS), respectively. The results showed that the mean concentrations of the ten heavy metals and metalloids in the sediment samples followed the order Mn > Zn > Cr > V > Pb > Cu > As ~ Ni >Co > Cd. The geoaccumulation index (I geo), enrichment factor (EF), modified degree of contamination (mCd), and potential ecological risk index (RI) revealed that Cd, followed by Pb, Zn, and Cu, caused severely contaminated and posed very highly potential ecological risk in the Xiangjiang River, especially in Shuikoushan of Hengyang, Xiawan of Zhuzhou, and Yijiawan of Xiangtan. The Pearson's correlation coefficient (PCC) analysis, principal component analysis (PCA), and hierarchical cluster analysis (HCA) indicated that the ten heavy metals and metalloids in the sampling sediments of the Xiangjiang River were classified into three groups: (1) Cd, Pb, Zn, and Cu which possibly originated from Shuikoushan, Xiawan, and Yijiawan clustering Pb-Zn mining and smelting industries; (2) Co, V, Ni, Cr, and Al from natural resources; and (3) Mn and As. Therefore, our results suggest that anthropogenic activities, especially mining and smelting, have caused severe contamination of Cd, Pb, Zn, and Cu and posed very high potential ecological risk in the Xiangjiang River. PMID- 27761860 TI - Molecular and cellular response of earthworm Eisenia andrei (Oligochaeta, Lumbricidae) to PCDD/Fs exposure. AB - The acute toxicity of polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) was investigated in the earthworm Eisenia andrei using filter paper toxicity test. Protein content, catalase (CAT) activity, and histology of intestinal wall (chloragogen cells and intestinal epithelium) were investigated in earthworms exposed for 48 h to 0 (control), 0.5, 1.0, and 1.5 ng/cm2 PCDD/Fs. The results showed an increase in the total protein content 1.56- (p = 0.104), 1.66- (p = 0.042), and 2.26-fold (p < 0.001), respectively, compared to control. The average +/- standard deviation of tissular CAT activity showed no significant differences; it was 36.01 +/- 7.65, 36.17 +/- 9.45, 36.08 +/- 9.80, and 40.01 +/- 6.98 U/g tissue, respectively. However, the average specific activity of CAT +/- standard deviation was significantly decreased (p < 0.001) at all doses compared to control; it was 2.93 +/- 0.42, 1.93 +/- 0.53, 1.80 +/- 0.38, and 1.53 +/- 0.44 U/mg protein, respectively. There was a progressive damage in both of the intestinal villi and the chloragogenous tissue associated with the incrementing doses. Since the toxic mixture altered the investigated biomarkers of E. andrei within 48 h, the cellular and molecular alterations resulted from the filter paper contact test could be utilized as a rapid toxicity assessment tool of environmental contamination with dioxins/furans and to assess consequent potential adverse effects on soil biota and other organisms in the ecosystem. PMID- 27761859 TI - Incentive effect of bentonite and concrete admixtures on stabilization/solidification for heavy metal-polluted sediments of Xiangjiang River. AB - Solidification is a very effective way to alleviate heavy metal impacts to the environment. In this paper, an improved method was adopted herein for the solidification/stabilization (S/S) of sediments with cement-based additives and low content of cement in S/S materials. Sediments in Xiangjiang River, containing high concentrations of Cu, Cd, and Pb, were solidified/stabilized by binders of cement, fly ash, and bentonite. Admixtures such as sodium lignosulfonate, sodium lauryl sulfate, and triethanolamine were used to improve the bonding properties of S/S, which had never been investigated before. Results demonstrated that the addition of concrete admixtures had significant effects on the S/S of sediments. Sequential extraction method indicates that the concentrations of heavy metals changed significantly after solidification and were more stable over time, with the exception of Pb. In addition, SEM images indicated that the main hydrated product was ettringite. Large quantities of calcium silicate hydrates (CSH) formed and filled the solidified sediment in 60 days. The results provide further insights into the transformation of heavy metals during S/S. PMID- 27761861 TI - Identifying effective factors on consumers' choice behavior toward green products: the case of Tehran, the capital of Iran. AB - The environment is increasingly turning to a vital and very important issue for all people. By increasing environmental concerns as well as legislating and regulating rules on the protection of the environment and the emergence of green consumers, implementing green marketing approach for organizations seems to be more crucial and essential. As a result, the need for ecological products and green business activities compels companies to combine environmental issues with marketing strategies. The first step in the success of companies and organizations is to identify consumers and their consumption behaviors correctly and accurately. So, the purpose of this study is to identify effective factors for the choice of consumers of green products. We used consumption values (functional value, social value, emotional value, conditional value, epistemic value, and environmental value) as the effective factor for choosing green products. The original place of this research was in Tehran, capital city of Iran, which is one of the most polluted cities in the world due to environmental issues. The results from the survey questionnaires are analyzed using confirmatory factor analysis and structural equation modelling. The results indicated that functional value-price, functional value-quality, social value, epistemic value, and environmental value had significantly positive effects on the choice of green products; also, conditional value and emotional value had no influence on it. It was concluded that the main influential factors for consumers' choice behavior regarding green products included environmental value and epistemic value. This study emphasized the proper pricing of green products by producers and sellers. PMID- 27761862 TI - Accelerated eutrophication and toxicity in tropical reservoir water and sediments: an ecotoxicological approach. AB - The aim of this study was to jointly show the results of three independent ecotoxicological studies performed to investigate pollutants in three Brazilian tropical reservoirs undergoing accelerated eutrophication. In order to accomplish this goal, the full toxicity identification and evaluation procedure (TIE approach) was performed, at Pampulha (Minas Gerais State) and Salto Grande and Barra Bonita reservoirs (Sao Paulo State). Acute and chronic toxicity tests were performed using the cladocerans Daphnia similis and Ceriodaphnia dubia (exotic) and Daphnia laevis and Ceriodaphnia silvestrii (native) as test organisms. Results from TIE procedure stage I indicated the existence of nonpolar organic and filterable compounds in the water from Pampulha, probably cyanotoxins, and oxidants as part of the toxic agents. TIE results for sediments identified ammonia (Pampulha and Salto Grande), organic compounds (Pampulha), metals (Pampulha, Barra Bonita, and Salto Grande), and acidity (Salto Grande) as responsible for toxicity. Whole-sediment remediation experiments for Pampulha reservoir confirmed, through reproduction decrease, ammonia and organic compounds as contaminants. Such pollutants represent threats to aquatic biota and must be prevented. Higher temperatures as predicted from global climate change will severely affect tropical shallow reservoirs, accelerating eutrophication, the release of contaminants from sediments, and increasing toxicity. PMID- 27761863 TI - Preparation, characterization, and bio-efficacy evaluation of controlled release carbendazim-loaded polymeric nanoparticles. AB - Synthesis and controlled release study of polymeric nanoformulation of carbendazim (2-benzimidazole carbamic acid methyl ester) using chitosan and pectin is reported in this article. The formulation was subjected to morphological, physiological, in vitro fungicide release and bio-efficacy evaluation studies. The average size of nanoparticles was found to be in the range of 70-90 nm as confirmed by transmission electron microscopy. The in vitro fungicide release of nanoformulated carbendazim was compared with pure carbendazim at different pH values. The results confirmed sustained release of nanoformulated carbendazim. The bio-efficacy evaluation of the carbendazim nanoformulation was carried out against Fusarium oxysporum and Aspergillus parasiticus. The nanoformulation showed 100 % inhibition of test fungi at both concentrations (0.5 and 1.0 ppm) while pure carbendazim showed 80 +/- 0 % and 97.2 +/- 1.1 % inhibition at 0.5 and 1.0 ppm concentration respectively against Fusarium oxysporum and 86.0 +/- 0.6 % inhibition and 100.0 % inhibition at 0.5 and 1.0 ppm concentration respectively against Aspergillus parasiticus. The commercial formulation (WP 50) showed 42 % and 58.0 +/- 0.1 % inhibition at 0.5 and 1 ppm concentration respectively against Aspergillus parasiticus and 50.5 +/- 0.7 % and 70.0 +/- 0 % inhibition at 0.5 and 1.0 ppm concentrations respectively against Fusarium oxysporum. Phytotoxicity evaluation of nanoformulated fungicide confirmed that the nanoformulated carbendazim is safer for germination and root growth of the seeds of Cucumis sativa, Zea mays, and Lycopersicum esculantum. PMID- 27761865 TI - Appraisal of a hybrid air cleaning process. AB - Nowadays, there is an amplified interest in maintaining suitable indoor air quality (IAQ). Besides a wide range of available interventions, air cleaners are considered a valuable tool, since based on inexpensive and easily implementing technologies to improve IAQ. The purpose of this work is to combine the TiO2 photocatalysis with the electrostatic and adsorption processes, in order to improve efficiency and reliability. A TiO2-photocatalytic oxidation combined with an electrostatic filter has been studied. Nitrogen oxides reduction and degradation of many VOC over different catalyst support were monitored jointly with CO and CO2 production. The coupling of photocatalysis with an external electric field enhances efficiency of the process. The choice of materials with diversified adsorptive characteristics plays an important role in the durability of the process over time. PMID- 27761866 TI - Health risk assessment of heavy metals in wheat using different water qualities: implication for human health. AB - In the recent years, the use of sewage water for irrigation has attracted the attention of arid and semi-arid countries where the availability of fresh water is poor. Despite the potential use of sewage water in crop irrigation as effective and sustainable strategy, the environmental and human risks behind this use need to be deeply investigated. In this regard, an experiment was carried out under field conditions in Nursery, University College of Agriculture Sargodha, to evaluate the possible health risks of undesirable metals in wheat grains. Wheat variety Sarang was cultivated and irrigated with different combinations of ground (GW) and sewage water (SW). The concentrations of heavy metals (Cr, Cd, Ni, and Pb) and trace elements (Cu, Zn, and Fe) in wheat grains as well as in soil were determined. Moreover, the pollution load index (PLI), accumulation factor (AF), daily intake of metals (DIM), and health risk index (HRI) were calculated. Results showed that the concentration trend of heavy metals was Pb5 and swirling sheets could be considered diagnostic for PTCs. CONCLUSIONS: Our study suggests that IOCs using nuclear features and additional figures could be useful with decreasing the likelihood of inconclusive results. PMID- 27761887 TI - Erratum to: Cost of a lymphedema treatment mandate-10 years of experience in the Commonwealth of Virginia. PMID- 27761886 TI - Comparison between effects of pressure support and pressure-controlled ventilation on lung and diaphragmatic damage in experimental emphysema. AB - BACKGROUND: In patients with emphysema, invasive mechanical ventilation settings should be adjusted to minimize hyperinflation while reducing respiratory effort and providing adequate gas exchange. We evaluated the impact of pressure controlled ventilation (PCV) and pressure support ventilation (PSV) on pulmonary and diaphragmatic damage, as well as cardiac function, in experimental emphysema. METHODS: Emphysema was induced by intratracheal instillation of porcine pancreatic elastase in Wistar rats, once weekly for 4 weeks. Control animals received saline under the same protocol. Eight weeks after first instillation, control and emphysema rats were randomly assigned to PCV (n = 6/each) or PSV (n = 6/each) under protective tidal volume (6 ml/kg) for 4 h. Non-ventilated control and emphysema animals (n = 6/group) were used to characterize the model and for molecular biology analysis. Cardiorespiratory function, lung histology, diaphragm ultrastructure alterations, extracellular matrix organization, diaphragmatic proteolysis, and biological markers associated with pulmonary inflammation, alveolar stretch, and epithelial and endothelial cell damage were assessed. RESULTS: Emphysema animals exhibited cardiorespiratory changes that resemble human emphysema, such as increased areas of lung hyperinflation, pulmonary amphiregulin expression, and diaphragmatic injury. In emphysema animals, PSV compared to PCV yielded: no changes in gas exchange; decreased mean transpulmonary pressure (Pmean,L), ratio between inspiratory and total time (Ti/Ttot), lung hyperinflation, and amphiregulin expression in lung; increased ratio of pulmonary artery acceleration time to pulmonary artery ejection time, suggesting reduced right ventricular afterload; and increased ultrastructural damage to the diaphragm. Amphiregulin correlated with Pmean,L (r = 0.99, p < 0.0001) and hyperinflation (r = 0.70, p = 0.043), whereas Ti/Ttot correlated with hyperinflation (r = 0.81, p = 0.002) and Pmean,L (r = 0.60, p = 0.04). CONCLUSIONS: In the model of elastase-induced emphysema used herein, PSV reduced lung damage and improved cardiac function when compared to PCV, but worsened diaphragmatic injury. PMID- 27761888 TI - A lifelong competitive training practice attenuates age-related lipid peroxidation. AB - The effect of exercise-induced oxidative stress on health and aging is not clearly explained. This study examined the effects of habitual sport practice, age, and submaximal exercise on the blood markers of oxidative stress, muscle damage, and antioxidant response. Seventy-two healthy men were grouped by their habitual sport practice: inactive (<1.5 h/week), recreational (3-8 h/week), and trained athletes (>8 h/week), and further divided by age: young (18-25 years), adult (40-55 years), and senior (>55 years). Blood samples were collected at rest and after submaximal effort. Hydroperoxides and superoxide dismutase, glutathione peroxidase, and catalase activities were measured by spectrophotometry. Nuclear DNA damage was analyzed by comet assay. The alpha-actin release was analyzed by Western blot. Alpha-tocopherol, retinol, and coenzyme-Q10 were quantified by high performance liquid chromatography analysis. Data was analyzed through a factorial ANOVA and the Bonferroni post hoc test. Lipid peroxidation increased significantly with age and submaximal effort (p < 0.05). However, the trained athlete group presented lower lipid peroxidation compared with the recreational group (MD = 2.079, SED = 0.58, p = 0.002) and inactive group (MD = 1.979, SED = 0.61, p = 0.005). Trained athletes showed significant higher alpha-actin levels (p < 0.001) than the other groups. Recreational group showed lower nuclear DNA damage than trained athletes (MD = 3.681, SED = 1.28, p = 0.015). Nevertheless, the inactive group presented significantly higher superoxide dismutase and catalase (p < 0.05) than the other groups. Data suggested that habitual competitive training practice could prevent age-related increases of plasma lipid peroxidation, which, according with our results, cannot be entirely attributed to blood antioxidant defense systems. PMID- 27761890 TI - A little less conversation. PMID- 27761889 TI - MicroRNA-155 in serum-derived extracellular vesicles as a potential biomarker for hematologic malignancies - a short report. AB - PURPOSE: The use of extracellular vesicles (EVs) from body fluids as "liquid biopsies" is emerging as a promising approach for the diagnosis, prognosis and therapeutic monitoring of cancer patients. MicroRNA-155 (miR155), a non-coding transcript of the B-cell integration cluster (BIC) gene, has been reported to play a critical role in the pathogenesis of several types of hematologic malignancies (HMs) in which high miR155 levels have been found. At yet, however, the EV miR155 level and its putative clinical relevance in sera of HM patients have not been reported. METHODS: EVs from sera of representative patients with eight different HMs and healthy subjects (controls) were isolated using differential centrifugation. The identity and quality of the EVs were verified by atomic force and transmission electron microscopy. The EV miR155 levels were measured by quantitative RT-PCR. The sensitivity, specificity and area under the curve (AUC) of differences in EV miR155 levels were determined using ROC curve analyses. RESULTS: We found that the EV miR155 levels were significantly higher in chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and Waldenstrom's macroglobulinemia (WM) cases compared to controls. Conversely, we found that the EV miR155 levels were significantly lower in myelodysplastic syndrome (MDS) and multiple myeloma (MM) cases. No differences were found in follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) or Hodgkin's Lymphoma (HL) cases compared to controls. EV miR155 ROC curve analyses revealed significantly different patterns in CLL and AML cases compared to controls, and in AML cases compared to MDS cases (p = 0.004, p = 0.01 and p = 0.04, respectively). In addition, we found that high EV miR155 levels correlated with high white blood cell counts in AML patients. CONCLUSION: Our data indicate that EV miR155 may serve as an attractive new, non-invasive diagnostic biomarker in human hematologic malignancies. PMID- 27761891 TI - Superantigens and adhesins of infant gut commensal Staphylococcus aureus strains and association with subsequent development of atopic eczema. AB - BACKGROUND: According to the hygiene hypothesis, insufficient immune activation by microbes increases the risk of allergy development. Staphylococcus aureus, which is part of the skin and gut microbiota of infants in Western countries, produces a variety of T-cell-activating enterotoxins, called superantigens. OBJECTIVES: To investigate whether early (0-2 months of age) gut colonization by S. aureus strains that carry specific superantigens and adhesins was related to subsequent development of atopic eczema in a Swedish birth cohort. METHODS: Staphylococcus aureus was isolated from rectal swabs and cultured quantitatively from faecal samples, with individual strains being tested for carriage of genes for superantigens and adhesins. Atopic eczema was diagnosed at onset of symptoms and at 18 months of age. RESULTS: Although the frequency of early gut colonization by S. aureus was not related to subsequent eczema development, the S. aureus strains that were found to colonize those infants who developed atopic eczema were less likely to carry the gene encoding the superantigen SElM (P = 0.008) and the gene for elastin-binding protein (P = 0.03), compared with strains that were isolated from infants who had not developed atopic eczema by 18 months of age. CONCLUSIONS: Gut colonization by S. aureus strains carrying a certain combination of superantigen and adhesin genes was negatively associated with subsequent development of atopic eczema. Such strains may provide stimulation and promote maturation of the infant immune system. PMID- 27761892 TI - Integrated analysis of rice transcriptomic and metabolomic responses to elevated night temperatures identifies sensitivity- and tolerance-related profiles. AB - Transcript and metabolite profiling were performed on leaves from six rice cultivars under high night temperature (HNT) condition. Six genes were identified as central for HNT response encoding proteins involved in transcription regulation, signal transduction, protein-protein interactions, jasmonate response and the biosynthesis of secondary metabolites. Sensitive cultivars showed specific changes in transcript abundance including abiotic stress responses, changes of cell wall-related genes, of ABA signaling and secondary metabolism. Additionally, metabolite profiles revealed a highly activated TCA cycle under HNT and concomitantly increased levels in pathways branching off that could be corroborated by enzyme activity measurements. Integrated data analysis using clustering based on one-dimensional self-organizing maps identified two profiles highly correlated with HNT sensitivity. The sensitivity profile included genes of the functional bins abiotic stress, hormone metabolism, cell wall, signaling, redox state, transcription factors, secondary metabolites and defence genes. In the tolerance profile, similar bins were affected with slight differences in hormone metabolism and transcription factor responses. Metabolites of the two profiles revealed involvement of GABA signaling, thus providing a link to the TCA cycle status in sensitive cultivars and of myo-inositol as precursor for inositol phosphates linking jasmonate signaling to the HNT response specifically in tolerant cultivars. PMID- 27761893 TI - Cardiac involvement in female carriers of duchenne or becker muscular dystrophy. AB - INTRODUCTION: The significance of abnormal cardiac measures in asymptomatic females who harbor dystrophin gene mutations is controversial. METHODS: Echo measures of ventricular function were compared with published norms in a cross sectional study of 130 (age, 39 +/- 15.7 years) "carriers" of Duchenne or Becker muscular dystrophy (DMD/BMD). Correlations between cardiomyopathy (CM) and mutation, creatine kinase (CK) levels, age, and muscle symptoms were investigated. RESULTS: Depending on definition, CM prevalence was 3-33%. Ejection fraction (Simpson method) was < 55% in 9 (13%) and < 40% in 2 (2.9%). Eleven (8.5%) had wall motion abnormalities. Left ventricular end-systolic dimensions were increased in 7 (5.7%) and end-diastolic in 17 (13.9%). CM did not correlate with mutation type, DMD or BMD phenotype, CK level, muscle symptoms, or age. CONCLUSIONS: Occult CM can be found by screening in DMD/BMD carriers. Its lack of age-correlation suggests that not all abnormalities progress. Optimum screening schedules require a better understanding of progressive CM. Muscle Nerve 55: 810 818, 2017. PMID- 27761894 TI - A novel computer algorithm for modeling and treating mandibular fractures: A pilot study. AB - OBJECTIVES/HYPOTHESIS: To describe a novel computer algorithm that can model mandibular fracture repair. To evaluate the algorithm as a tool to model mandibular fracture reduction and hardware selection. STUDY DESIGN: Retrospective pilot study combined with cross-sectional survey. METHODS: A computer algorithm utilizing Aquarius Net (TeraRecon, Inc, Foster City, CA) and Adobe Photoshop CS6 (Adobe Systems, Inc, San Jose, CA) was developed to model mandibular fracture repair. Ten different fracture patterns were selected from nine patients who had already undergone mandibular fracture repair. The preoperative computed tomography (CT) images were processed with the computer algorithm to create virtual images that matched the actual postoperative three-dimensional CT images. A survey comparing the true postoperative image with the virtual postoperative images was created and administered to otolaryngology resident and attending physicians. They were asked to rate on a scale from 0 to 10 (0 = completely different; 10 = identical) the similarity between the two images in terms of the fracture reduction and fixation hardware. RESULTS: Ten mandible fracture cases were analyzed and processed. There were 15 survey respondents. The mean score for overall similarity between the images was 8.41 +/- 0.91; the mean score for similarity of fracture reduction was 8.61 +/- 0.98; and the mean score for hardware appearance was 8.27 +/- 0.97. There were no significant differences between attending and resident responses. There were no significant differences based on fracture location. CONCLUSION: This computer algorithm can accurately model mandibular fracture repair. Images created by the algorithm are highly similar to true postoperative images. The algorithm can potentially assist a surgeon planning mandibular fracture repair. LEVEL OF EVIDENCE: 4. Laryngoscope, 2016 127:331-336, 2017. PMID- 27761895 TI - Patient-centered outcomes to decide treatment strategy for patients with low rectal cancer. AB - BACKGROUND: For patients with low-lying rectal cancer, the feasibility of anus preserving surgery in combination with neoadjuvant chemoradiotherapy (NACRT) has been not well established from the perspective of patient-centered outcomes. METHODS: We investigated 278 patients with low-lying rectal adenocarcinoma from 2005 to 2012. We compared their symptoms and QOL scores of patients who underwent anus-preserving surgery with (n = 88) and without (n = 143) NACRT according to the Wexner scale, EORTC QLQ C-30, CR29, and the modified fecal incontinence quality life scale (mFIQL). Furthermore, to assess the rationale for intersphincteric resection (ISR) with NACRT, we also compared QOL of patients who underwent ISR with NACRT (n = 31) and abdominoperineal resection (APR, n = 47). RESULTS: The adjusted mean differences of the Wexner score estimates of the patients who underwent ISR and very low anterior resection (VLAR) with or without NACRT were 5.29 (P = 0.004) and 2.67 (P = 0.009), respectively. No significant difference was observed in the QOL scores of two treatment groups. Furthermore, there were no significant differences in the QOL or function scores of patients who underwent ISR with NACRT and APR. CONCLUSION: The incontinence was significantly worse in patients who receive NACRT. However, there were no significant differences in their QOL or function scores. J. Surg. Oncol. 2016;114:630-636. (c) 2016 Wiley Periodicals, Inc. PMID- 27761896 TI - Transitory cystic cavities in the developing mammalian brain - normal or anomalous? AB - Transitory cavities associated with the ventricular system represent probably one of the most unique features in the developing mammalian brain. In rodents, the cavities exist transiently in the developing brain and do not appear to be associated with any pathological events. Among the various cavities, the pyramidal-shaped cavum septum pellucidum (CSP) located beneath the corpus callosum and between the lateral ventricles is most well defined. In addition to the CSP are the bilateral subependymal cysts that are consistently associated with the third and fourth ventricles as well as the aqueduct. The cavities/cysts contain a large number of amoeboid microglia expressing surface receptors and hydrolytic enzymes common to tissue macrophages. The significance of these cavities in the developing brain remains a conjecture. Firstly, the cavity walls are free of an apparent epithelial lining; hence, it is speculated that the cavities that appear to communicate with the widened neighboring interstitial tissue spaces may have resulted from physical traction due to the rapid growth of the perinatal brain. Secondly, the cavities contain prominent clusters of amoeboid microglia that may be involved in clearing the debris of degenerating axons and cells resulting from the early brain tissue remodeling. With the increase in brain tissue compactness following the beginning of myelination in the second postnatal week, all cavities are obliterated; concomitantly, the number of amoeboid microglia in them diminishes and all this might signal further maturation of the brain. PMID- 27761897 TI - Self-reported levels of education and disability progression in multiple sclerosis. AB - OBJECTIVES: The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). MATERIALS AND METHODS: We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. RESULTS: Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. CONCLUSIONS: Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS. PMID- 27761899 TI - Self-preserving personal care products. AB - OBJECTIVE: As questions on the safety of some popular preservatives are on the rise, there is a growing interest in developing 'self-preserving' personal care products. Use of multifunctional ingredients/actives with antimicrobial properties has been explored as replacements for conventional preservatives. This study explores the use of combinations of multifunctional actives (MFA) and other cosmetic ingredients in various personal care formulations, to deliver microbiologically safe self-preserving products. Products studied in this study include face wash, gel-based leave-on skin care product and face mask. METHODS: Minimum inhibitory concentration (MIC) of several cosmetic ingredients was determined to identify multifunctional actives with antimicrobial activity. Personal care formulations made with multifunctional actives and other cosmetic ingredients were studied for preservative efficacy by challenging the product with six multiple cycles of microbial challenge. RESULTS: Formulations with combinations of multifunctional actives with antioxidant (AO) and chelators (CHL) were found to work synergistically and were highly efficacious in controlling multiple microbial challenges as observed in the preservative efficacy test (PET) studies. The effective combinations were able to withstand up to six multiple microbial challenges without product degradation. The preservative efficacy profile was similar to control formula containing preservatives. CONCLUSION: Self preserving personal care/cosmetic products can be developed which are as efficacious as preserved products by a prudent selection of multifunctional actives, antioxidants and chelators as a part of the formulation. PMID- 27761898 TI - An automated method for coding sleep states in human infants based on respiratory rate variability. AB - A novel quantitative method for coding epochs of active and quiet sleep in infants using respiration is reported. The approach uses the variance of the instantaneous breathing rate within brief epochs of sleep. Variances are normalized within subject by dividing by the 75th percentile variance across epochs. Then, a normalized variance active sleep threshold of 0.29 was determined to produce the highest concordance with a method based on visual inspection of respiratory variability (100% and 90% for quiet and active sleep, respectively). The method was independently validated by comparing to standard polysomnographic state coding (87% and 80% concordance for quiet and active sleep) as well as with behavioral state coding (92% and 78% for quiet and active sleep). Validity was also demonstrated by showing that sleep states identified by the method resulted in the expected state differences in infant heart rate variability and electrocortical activity. PMID- 27761900 TI - Immunophenotypic and prognostic analysis of PAX8 and TTF-1 expressions in neuroendocrine carcinomas of thymic origin: A comparative study with their pulmonary counterparts. AB - OBJECTIVES: To investigate the immunoreactivity of TTF-1 and PAX8 in neuroendocrine carcinoma of thymic (TNEC) and pulmonary origins (PNEC), and whether their immunophenotyping could be used to distinguish between NEC of the two sites, as well as prognosis of patients with TNEC. METHODS: Twenty-two cases of TNEC and 20 cases of PNEC were selected for immunohistochemical analysis using PAX8 and TTF-1. Clinical data and follow-up information were obtained for survival analyses. RESULTS: TTF-1 immunoreactivity was seen in 19 PNEC cases (95%) and 13 TNEC cases (59.1%). PAX8 was negative in all pulmonary tumors while positive in 19 thymic cases (86.4%). TTF-1 positivity was associated with high sensitivity but low specificity for PNEC, and adding PAX8 negativity significantly increased the specificity. PAX8 positivity alone showed essentially 100% specificity and 86.4% sensitivity for TNEC. Survival analysis showed lung metastasis as a significant prognostic factor in TNEC. CONCLUSION: Our study demonstrated that TTF-1/PAX8 immunophenotyping may be helpful for differential diagnosis of NECs of pulmonary and thymic origins. TTF-1+/PAX8- immunophenotyping showed high specificity for PNECs, while PAX8+ alone showed a good diagnostic accuracy for TNEC. Lung metastasis was a predictive factor that associated with survival of TNEC patients. J. Surg. Oncol. 2016;114:697-702. (c) 2016 Wiley Periodicals, Inc. PMID- 27761901 TI - The Visible-Light Photocatalytic Activity and Antibacterial Performance of Ag/AgBr/TiO2 Immobilized on Activated Carbon. AB - Visible-light-driven Ag/AgBr/TiO2 /activated carbon (AC) composite was prepared by solgel method coupled with photoreduction method. For comparison, TiO2 , TiO2 /AC, and Ag/AgBr/TiO2 were also synthesized. Their characteristics were analyzed by XRD, SEM-EDS, TG-DSC and UV-vis techniques. Photocatalytic activity and antibacterial performance under visible-light irradiation were investigated by ICP-AES, ATR-FT-IR and spectrophotometry methods using methylene blue and Escherichia coli as target systems, respectively. The results showed that Ag/AgBr was successfully deposited on anatase TiO2 /AC surface, and exhibited a distinct light absorption in the visible region. Ag/AgBr/TiO2 /AC displayed excellent antibacterial performance both in dark and under visible-light illumination. The growth of E. coli cell was inhibited in the presence of Ag/AgBr/TiO2 /AC in dark. Moreover, upon visible-light illumination, a significant damage of cell membrane was noticed. Ag/AgBr/TiO2 /AC was also shown higher photocatalytic efficiency for methylene blue degradation than those of TiO2 , TiO2 /AC, and Ag/AgBr/TiO2 . This is attributed to the synergetic effect between AC and Ag/AgBr/TiO2 , of which AC acts as the role of increasing reaction areas, continuous enriching, and transferring the adsorbed MB molecules to the surface of supported photocatalysts, and the Ag/AgBr/TiO2 acts as a highly active photocatalyst for degrading MB molecules under visible-light irradiation. PMID- 27761902 TI - Substantial role for carbonic anhydrase in latitudinal variation in mesophyll conductance of Populus trichocarpa Torr. & Gray. AB - In Populus trichocarpa (black cottonwood), net photosynthesis (An ) varies with latitude and, in northern genotypes, is supported by higher stomatal conductance (gs ). We report here a parallel cline in mesophyll conductance (gm ) and link this variation to carbonic anhydrase (CA) activity. Using concurrent carbon isotope discrimination and chlorophyll fluorescence methods, we examined the effects of acetazolamide, an inhibitor of CA, on gm in six representative genotypes (three from either end of the north-south cline). Acetazolamide reduced CA activity, gm , gs , chloroplast CO2 concentration (Cc ) and An at normal CO2 (400 MUmol mol-1 ), the latter being reversible at saturating CO2 . Absolute reductions in An , gm and CA activity were greater in northern genotypes than in southern genotypes (P < 0.025) but percent reductions were similar. In contrast, northern genotypes showed lower percent reduction in Cc compared to southern genotypes (P < 0.025). The northern genotypes had greater CA activity relative to both leaf area (two-fold) and mass (1.8-fold) (P < 0.016). The relationship between CA activity and gm was similar whether the variation was inherent or inhibitor induced. We suggest that greater CA activity contributes to higher gm in northern P. trichocarpa genotypes, but other diffusion pathway components may also be involved. PMID- 27761904 TI - Language, life praxis and scenic understanding in psychoanalytic therapy. AB - Freud held that the repressed unconscious arose from the separation of thing presentations from word-presentations. The author divests these terms of the implication that they are objectively existing entities by citing some of Freud's other texts. Thing-presentations are memory-traces of (as yet) non-language-based interactions - that is, precipitates of actions that have been experienced and models of future actions. Scenic understanding, which, on the basis of participation by the therapist in the patient's play, treats all material presented by the patient by an approach analogous to the interpretation of dreams, is therefore the royal road to the unconscious. PMID- 27761905 TI - Letter from Colombia. PMID- 27761906 TI - On: Existential crises in two religious patients - vicissitudes of faith and the emergence of the true self. PMID- 27761907 TI - Introduction to Alfred Lorenzer's paper 'Language, life praxis and scenic understanding in psychoanalytic therapy'. PMID- 27761908 TI - Bridging gaps between conscious and unconscious. PMID- 27761903 TI - The role of perivascular adipose tissue in obesity-induced vascular dysfunction. AB - : Under physiological conditions, perivascular adipose tissue (PVAT) attenuates agonist-induced vasoconstriction by releasing vasoactive molecules including hydrogen peroxide, angiotensin 1-7, adiponectin, methyl palmitate, hydrogen sulfide, NO and leptin. This anticontractile effect of PVAT is lost under conditions of obesity. The central mechanism underlying this PVAT dysfunction in obesity is likely to be an 'obesity triad' (consisting of PVAT hypoxia, inflammation and oxidative stress) that leads to the impairment of PVAT-derived vasoregulators. The production of hydrogen sulfide, NO and adiponectin by PVAT is reduced in obesity, whereas the vasodilator response to leptin is impaired (vascular leptin resistance). Strikingly, the vasodilator response to acetylcholine is reduced only in PVAT-containing, but not in PVAT-free thoracic aorta isolated from diet-induced obese mice, indicating a unique role for PVAT in obesity-induced vascular dysfunction. Furthermore, PVAT dysfunction has also been observed in small arteries isolated from the gluteal/visceral fat biopsy samples of obese individuals. Therefore, PVAT may represent a new therapeutic target for vascular complications in obesity. A number of approaches are currently being tested under experimental conditions. Potential therapeutic strategies improving PVAT function include body weight reduction, enhancing PVAT hydrogen sulfide release (e.g. rosiglitazone, atorvastatin and cannabinoid CB1 receptor agonists) and NO production (e.g. arginase inhibitors), inhibition of the renin-angiotensin aldosterone system, inhibition of inflammation with melatonin or cytokine antagonists, activators of AMP-activated kinase (e.g. metformin, resveratrol and diosgenin) and adiponectin releasers or expression enhancers. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc. PMID- 27761910 TI - On: The couch and the chador. PMID- 27761911 TI - Choline and dimethylglycine produce superoxide/hydrogen peroxide from the electron transport chain in liver mitochondria. AB - Here, we report that choline and dimethylglycine can stimulate reactive oxygen species (ROS) production in liver mitochondria. Choline stimulated O2 - /H2 O2 formation at a concentration of 5 MUm. We also observed that Complex II and III inhibitors, atpenin A5 and myxothiazol, collectively induced a 95% decrease in O2 - /H2 O2 production indicating both sites serve as the main sources of ROS during choline oxidation. Dimethylglycine, an intermediate of choline oxidation, was a more effective ROS generator. Rates of production were ~ 43% higher than choline mediated O2 - /H2 O2 production. The main site for dimethylglycine-mediated ROS production was via reverse electron transfer to Complex I. Our results demonstrate that metabolism of essential metabolites involved in methionine and folic acid biosynthesis can stimulate mitochondrial ROS production. PMID- 27761912 TI - How adults with a profound intellectual disability engage others in interaction. AB - Using video records of everyday life in a residential home, we report on what interactional practices are used by people with severe and profound intellectual disabilities to initiate encounters. There were very few initiations, and all presented difficulties to the interlocutor (support staff; the recording researcher); one (which we call 'blank recipiency') gave the interlocutor virtually no information at all on which to base a response. Only when the initiation was of a new phase in an interaction already under way (for example, the initiation of an alternative trajectory of a proposed physical move) was it likely to be successfully sustained. We show how interlocutors responded to initiations verbally, as if to neuro-typical speakers - but inappropriately for people unable to comprehend, or to produce well-fitted next turns. This mis reliance on ordinary speakers' conversational practices was one factor that contributed to residents abandoning the interaction in almost all cases. We discuss the dilemma confronting care workers. PMID- 27761913 TI - Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling? AB - Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases. PMID- 27761914 TI - Activities of daily living and quality of life during treatment with neoadjuvant chemoradiotherapy and after surgery in patients with esophageal cancer. AB - BACKGROUND AND OBJECTIVES: Neoadjuvant chemoradiation (nCRT) followed by esophagectomy is a treatment with curative intent for resectable esophageal cancer. The aim of this study was to measure activities of daily living (ADL) and quality of life (QoL), and to examine correlates of changes in ADL and QoL. METHODS: A prospective study was performed with three time points (baseline, 1 week after the end of nCRT, 3-months post-surgery) together with a cross sectional post-treatment study. ADL was measured with the Amsterdam Linear Disability Score (ALDS), and QoL with the EORTC QLQ-C30 and the OES-18. Regression analysis was performed to identify factors associated with changes in ADL and QoL. RESULTS: Seventy-six patients were included in the prospective study, 79 in the cross-sectional study. After nCRT, ALDS decreased from 90 to 88 (P < 0.01) and remained stable after surgery. Global QoL decreased from 75 to 61 (P < 0.01); no significant changes were observed after surgery. Only timing of the measurement of ALDS was negatively associated with non-maximum ALDS (n = 155, based on both studies) and QoL (n = 76) (P < 0.01). CONCLUSIONS: Patients who undergo nCRT plus surgery should be prepared to experience a short-term decline in ADL and QoL. The findings of this study can support patients and healthcare workers to guide expectations. J. Surg. Oncol. 2016;114:684-690. (c) 2016 Wiley Periodicals, Inc. PMID- 27761915 TI - Respiratory sinus arrhythmia moderates the impact of maternal prenatal anxiety on infant negative affectivity. AB - Maternal prenatal anxiety is associated with infants' temperamental negative affectivity (NA), but it is unclear to what extent children vary in their susceptibility to prenatal influences. We tested a hypothesis that infants' respiratory sinus arrhythmia (RSA), an index of parasympathetic vagal tone and a potential marker of differential susceptibility to environmental influences, moderates the effects of maternal prenatal anxiety on the development of infant NA. Prenatal anxiety was assessed during the last trimester of pregnancy in a low risk community sample. Infant NA, baseline RSA, and maternal postnatal anxiety were assessed at 8-10 months of infant age. Regression analyses were performed to predict infant NA on the basis of prenatal anxiety, infant baseline RSA, and their interaction (N = 173). Maternal prenatal anxiety and infant RSA interactively predicted infant NA at 8-10 months. Among infants with high RSA, a significant positive association between prenatal anxiety and infant NA was observed, whereas prenatal anxiety did not predict infant NA among infants with low RSA. Vagal tone, as indexed by baseline RSA, may provide a promising marker of differential susceptibility to the long-term effects of varying intrauterine conditions. PMID- 27761916 TI - The role of genetics in fisheries management under the E.U. common fisheries policy. AB - Exploitation of fish and shellfish stocks by the European Union fishing fleet is managed under the Common Fisheries Policy (CFP), which aims to ensure that fishing and aquaculture are environmentally, economically and socially sustainable and that they provide a source of healthy food for E.U. citizens. A notable feature of the CFP is its legally enshrined requirement for sound scientific advice to underpin its objectives. The CFP was first conceived in 1970 when it formed part of the Common Agricultural Policy. Its formal inception as a stand-alone regulation occurred in 1983 and since that time, the CFP has undergone reforms in 1992, 2002 and 2013, each time bringing additional challenges to the scientific advisory process as the scope of the advice increased in response to changing objectives arising from E.U. regulations and commitments to international agreements. This paper reviews the influence that genetics has had on fish stock assessments and the provision of management advice for European fisheries under successive reforms of the CFP. The developments in genetics since the inception of the CFP have given rise to a diverse and versatile set of genetic techniques that have the potential to provide significant added value to fisheries assessments and the scientific advisory process. While in some cases, notably Pacific salmon Oncorhynchus spp., genetics appear to be very well integrated into existing management schemes, it seems that for marine fishes, discussions on the use of genetics and genomics for fisheries management are often driven by the remarkable technological progress in this field, rather than imminent needs emerging from policy frameworks. An example is the recent suggestion to use environmental (e)DNA for monitoring purposes. While there is no denying that state-of-the-art genetic and genomic approaches can and will be of value to address a number of issues relevant for the management and conservation of marine renewable natural resources, a focus on technology rather than policy and management needs is prone to widen the gap between science and policy, governance and management, thereby further impeding the effective integration of genetic and genomic information into the fisheries management decision making process. Hence, rather than focusing on what is technically achievable, this review outlines suggestions as to which modern genetic and genomic approaches are likely to help address some of the most pressing fisheries management challenges under the CFP. PMID- 27761917 TI - Improved outcomes in acute myeloid leukemia patients treated with washed transfusions. PMID- 27761919 TI - Genome-wide copy number analysis on DNA from fetal cells isolated from the blood of pregnant women. AB - OBJECTIVE: Non-invasive prenatal testing (NIPT) based on fetal cells in maternal blood has the advantage over NIPT based on circulating cell-free fetal DNA in that there is no contamination with maternal DNA. This will most likely result in better detection of chromosomal aberrations including subchromosomal defects. The objective of this study was to test whether fetal cells enriched from maternal blood can be used for cell-based NIPT. METHODS: We present a method for enriching fetal cells from maternal blood, subsequent amplification of the fetal genome and detection of chromosomal and subchromosomal variations in the genome. RESULTS: An average of 12.8 fetal cells from 30 mL of maternal blood were recovered using our method. Subsequently, whole genome amplification on fetal cells resulted in amplified fetal DNA in amounts and quality high enough to generate array comparative genomic hybridization as well as next-generation sequencing profiles. From one to two fetal cells, we were able to demonstrate copy number differences of whole chromosomes (21, X-, and Y) as well as subchromosomal aberrations (ring X). CONCLUSION: Intact fetal cells can be isolated from every maternal blood sample. Amplified DNA from isolated fetal cells enabled genetic analysis by array comparative genomic hybridization and next-generation sequencing. (c) 2016 John Wiley & Sons, Ltd. PMID- 27761918 TI - Exploring the structure and stability of cholesterol dimer formation in multicomponent lipid bilayers. AB - For 40 years, the existence and possible functional importance of cholesterol dimer formation has been discussed. Due to challenges associated with structural studies of membrane lipids, there has as yet been no direct experimental verification of the existence and relevance of the cholesterol dimer. Building on recent advances in lipid force fields for molecular simulation, in this work the structure and stability of the cholesterol dimer is characterized in POPC bilayers in absence and presence of sphingomyelin. The cholesterol dimer structural ensemble is found to consist of sub-states that reflect, but also differ from, previously proposed dimer structures. While face-to-face dimer structures predominate, no evidence is found for the existence of tail-to-tail dimers in POPC lipid bilayers. Near stoichiometric complex formation of cholesterol with sphingomyelin is found to effect cholesterol dimer structure without impacting population. Comparison with NMR-derived order parameters provide validation for the simulation model employed and conclusions drawn related to the structure and stability of cholesterol dimers in multicomponent lipid bilayers. (c) 2016 Wiley Periodicals, Inc. PMID- 27761920 TI - Isoflurane prevents acquired epilepsy in rat models of temporal lobe epilepsy. AB - OBJECTIVE: Acquired epilepsy is a devastating long-term risk of various brain insults, including trauma, stroke, infections, and status epilepticus (SE). There is no preventive treatment for patients at risk. Attributable to the complex alterations involved in epileptogenesis, it is likely that multitargeted approaches are required for epilepsy prevention. We report novel preclinical findings with isoflurane, which exerts various nonanesthetic effects that may be relevant for antiepileptogenesis. METHODS: The effects of isoflurane were investigated in two rat models of SE-induced epilepsy: intrahippocampal kainate and systemic administration of paraoxon. Isoflurane was either administered during (kainate) or after (paraoxon) induction of SE. Magnetic resonance imaging was used to assess blood-brain barrier (BBB) dysfunction. Positron emission tomography was used to visualize neuroinflammation. Long-term electrocorticographic recordings were used to monitor spontaneous recurrent seizures. Neuronal damage was assessed histologically. RESULTS: In the absence of isoflurane, spontaneous recurrent seizures were common in the majority of rats in both models. When isoflurane was administered during kainate injection, duration and severity of SE were not affected, but only few rats developed spontaneous recurrent seizures. A similar antiepileptogenic effect was found when paraoxon treated rats were exposed to isoflurane after SE. Moreover, in the latter model, isoflurane prevented BBB dysfunction and neurodegeneration, whereas isoflurane reduced neuroinflammation in the kainate model. INTERPRETATION: Given that isoflurane is a widely used volatile anesthetic, and is used for inhalational long-term sedation in critically ill patients at risk to develop epilepsy, our findings hold a promising potential to be successfully translated into the clinic. Ann Neurol 2016;80:896-908. PMID- 27761921 TI - Repeat-associated non-AUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome. AB - OBJECTIVE: Repeat-associated non-AUG (RAN) translation drives production of toxic proteins from pathogenic repeat sequences in multiple untreatable neurodegenerative disorders. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such condition, resulting from a CGG trinucleotide repeat expansion in the 5' leader sequence of the FMR1 gene. RAN proteins from the CGG repeat accumulate in ubiquitinated inclusions in FXTAS patient brains and elicit toxicity. In addition to the CGG repeat, an antisense mRNA containing a CCG repeat is also transcribed from the FMR1 locus. We evaluated whether this antisense CCG repeat supports RAN translation and contributes to pathology in FXTAS patients. METHODS: We generated a series of CCG RAN translation-specific reporters and utilized them to measure RAN translation from CCG repeats in multiple reading frames in transfected cells. We also developed antibodies against predicted CCG RAN proteins and used immunohistochemistry and immunofluorescence on FXTAS patient tissues to measure their accumulation and distribution. RESULTS: RAN translation from CCG repeats is supported in all 3 potential reading frames, generating polyproline, polyarginine, and polyalanine proteins, respectively. Their production occurs whether or not the natural AUG start upstream of the repeat in the proline reading frame is present. All 3 frames show greater translation at larger repeat sizes. Antibodies targeted to the antisense FMR polyproline and polyalanine proteins selectively stain nuclear and cytoplasmic aggregates in FXTAS patients and colocalize with ubiquitinated neuronal inclusions. INTERPRETATION: RAN translation from antisense CCG repeats generates novel proteins that accumulate in ubiquitinated inclusions in FXTAS patients. Ann Neurol 2016;80:871-881. PMID- 27761922 TI - Urticarial exanthema due to hepatitis B in a pregnant woman, mimicking a polymorphic eruption of pregnancy. AB - Hepatitis B virus (HBV) infection in pregnant women is very rare in western countries, thus, cutaneous manifestation of HBV infection may be confused with a dermatosis specific of pregnancy. We report a 39-year-old woman who presented in her 20th week of pregnancy with a pruritic rash, which consisted of generalized erythematous plaques, some of them with a purple centre. Serology testing showed acute HBV infection, and a biopsy revealed a superficial and interstitial perivascular inflammatory infiltrate of lymphocytes and eosinophils. A diagnosis of exanthema due to acute hepatitis B infection was established. The patient delivered a clinically healthy boy, who was given the first dose of the HBV vaccine and intravenous specific immunoglobulin, followed by the second dose 2 months later, and did not get infected with HBV. To our knowledge, this is the first case describing HBV exanthema in a pregnant woman, which led to early action for the newborn, avoiding vertical transmission and its high prevalence of cirrhosis and hepatocellular carcinoma. PMID- 27761923 TI - Biotransformation and metabolic profile of anemoside B4 with rat small and large intestine microflora by ultra-performance liquid chromatography-quadrupole time of-flight tandem mass spectrometry. AB - Pulsatilla chinensis (Bunge) Regel is commonly used in Asia, and anemoside B4 (AB4) is its major saponin, with diverse pharmaceutical effects. Previous studies showed that intestinal flora plays an important role in the metabolism of herbs administered orally. In this study, the metabolic profile of AB4 with microflora in rat small and large intestines in vitro was investigated. Gut microflora was collected from different intestinal segments and anaerobically incubated with AB4 at 37 degrees C for 24, 48, 72 and 96 h, respectively. A total of 10 metabolites were detected and identified by ultra- performance liquid chromatography/quadrupole time-of-flight mass spectrometry, involving the products of oxygenation and deglycosylation reactions. Gut microflora in the large intestine generated more comprehensive metabolic pathways, which appears to be attributable to the wider range of bacterial types and numbers of bacteria. Human cancer cell lines SMMC-7721, Hela and MCF-7 were treated with metabolite pools by MTT assay, together with M6 as the greatest deglycosylation product. As a result, M6 exhibited a reduction in cell viability of SMMC-7721 with an IC50 value of 22.28 +/- 1.26 MUg/mL. The present study provided scientific evidence for AB4 metabolism in small and large intestines, which is helpful to reveal the active forms of AB4 in vivo. PMID- 27761924 TI - Visualizing dispersion interactions through the use of local orbital spaces. AB - The interpretation of chemical properties/phenomena can often be aided through the use of imagery. The mapping of molecular electrostatic potentials is a prime example, serving as a guideline in the design of novel compounds or understanding transition state stabilization effects. It is today a common tool for theoreticians and experimentalists alike. With the emergence of concepts such as dispersion energy donors, and the overall importance of dispersion in chemical systems, representations targeting such a class of interactions are warranted. In this work, we make use of local orbital analysis to extract dispersion interactions and represent them in a scalar quantity, the Dispersion Interaction Density (DID). A particular advantage of the method is the possibility to represent at the same footing intermolecular and intramolecular interactions in a straightforward fashion from wave function calculations. We present examples for the benzene dimer, several substituted benzenes and a coupled diamondoid molecule. (c) 2016 Wiley Periodicals, Inc. PMID- 27761925 TI - Psychiatric disorders prior to amyotrophic lateral sclerosis. AB - It is recognized that neuropsychiatric conditions are overrepresented in amyotrophic lateral sclerosis (ALS) patient kindreds and psychiatric symptoms may precede the onset of motor symptoms. Using a hospital record linkage database, hospitalization with a diagnosis of schizophrenia, bipolar disorder, depression, or anxiety was significantly associated with a first diagnosis of ALS within the following year. This is likely to specifically reflect the clinicopathological overlap of ALS with frontotemporal dementia. A diagnosis of depression was significantly associated with a first record of ALS >=5 years later, in keeping with growing evidence for major depressive disorder as an early marker of cerebral neurodegeneration. Ann Neurol 2016;80:935-938. PMID- 27761926 TI - Preoperative differentiation between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and non-NIFTP. AB - BACKGROUND: A recent concept was proposed that the noninvasive encapsulated follicular variant of papillary thyroid carcinoma reclassified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" is benign. Our aim was to identify the differences between NIFTP and non-NIFTP preoperatively. METHODS: This retrospective study included a total of 208 patients with 208 follicular variant of papillary thyroid carcinomas (FVPTC) that were surgically confirmed at three university hospitals from 2008 to 2014. Clinical factors, the biopsy techniques and ultrasonography (US) imaging characteristics were compared between the NIFTP and non-NIFTP groups. RESULTS: A total of 34 NIFTP (16.3%) and 174 non-NIFTP (83.7%) were observed. For NIFTPs, the need for surgery was indicated by ultrasonography-guided fine needle aspiration (US-FNA) in 54.3% and by ultrasonography-guided core needle biopsy (US CNB) in 100% (P = 0.008). For non-NIFTP, no significant difference was noted in the rates of surgical indication between US-FNA and US-CNB (62.6% vs 78.9%, P = 0.054). The most common biopsy diagnosis of NIFTP was Bethesda category V (28.6%) in the US-FNA group and category IV (45.5%) in the US-CNB group. US diagnosis of NIFTP had a significantly lower rate of the high suspicion of malignancy than that of non-NIFTP (14.7% vs 37.9%, P = 0.024). Central nodal metastasis was found in only one case (2.9%) of NIFTP patients, but none had distance metastasis or recurrence. CONCLUSION: Noninvasive follicular thyroid neoplasm with papillary like nuclear features lacks malignant US features and is better triaged using US CNB than using US-FNA to facilitate the surgical management. US evaluation is pivotal in determining the next step of FVPTC management. PMID- 27761927 TI - Hypercalcaemia-induced kidney injury caused by the vitamin D analogue calcitriol for psoriasis: a note of caution when prescribing topical treatment. AB - A 55-year-old man with severe plaque psoriasis presented with a 2-week history of feeling generally unwell with lethargy and thirst. His symptoms had developed 6 weeks after commencement of the topical vitamin D3 analogue calcitriol. Investigations revealed hypercalcaemia and acute-on-chronic kidney injury, probably directly induced by systemic absorption of vitamin D3 following extensive topical use. Topical calcitriol had been started as a steroid-sparing agent to reduce the patient's liberal potent corticosteroid usage during anti tumour necrosis factor-alfa therapy. Topical vitamin D analogues are commonly prescribed in dermatological and general practice, with hypercalcaemia being a rare but potentially serious adverse effect. This case serves to outline key factors that may predispose to hypercalcaemia, such as disease extent, quantity of drug applied, comorbidities and concurrent medications, and it highlights the importance of considering these factors when prescribing topical therapies. PMID- 27761929 TI - The space-math link in preschool boys and girls: Importance of mental transformation, targeting accuracy, and spatial anxiety. AB - Spatial abilities are pertinent to mathematical competence, but evidence of the space-math link has largely been confined to older samples and intrinsic spatial abilities (e.g., mental transformation). The roles of gender and affective factors are also unclear. This study examined the correlations between counting ability, mental transformation, and targeting accuracy in 182 Hong Kong preschoolers, and whether these relationships were weaker at higher spatial anxiety levels. Both spatial abilities related with counting similarly for boys and girls. Targeting accuracy also mediated the male advantage in counting. Interestingly, spatial anxiety moderated the space-math links, but differently for boys and girls. For boys, spatial abilities were irrelevant to counting at high anxiety levels; for girls, the role of anxiety on the space-math link is less clear. Results extend the evidence base of the space-math link to include an extrinsic spatial ability (targeting accuracy) and have implications for intervention programmes. Statement of contribution What is already known on this subject? Much evidence of a space-math link in adolescent and adult samples and for intrinsic spatial abilities. What does this study add? Extended the space math link to include both intrinsic and extrinsic spatial abilities in a preschool sample. Showed how spatial anxiety moderated the space-math link differently for boys and girls. PMID- 27761928 TI - Assessment of the link between endothelin K198n Snp, endothelin concentration and acute myocardial infarction in Egyptians. AB - The aim of the current study was to assess the link between EDN K198N SNP, ET-1 serum concentration and acute myocardial infarction (AMI) in Egyptians. The study cohort consisted of 84 patients at AMI onset and 84 age-matched healthy controls. Endothelin genotypes and concentrations were determined by sequencing and ELISA, respectively. Genotype distribution was not significantly different between AMI patients and controls (P=.8341). The mean serum ET-1 concentration of patients (13.83+/-0.7 pg/mL) was significantly higher than controls (7.26+/-0.2 pg/mL) (P<.0001). ET-1 serum concentrations did not vary significantly among various EDN genotypes in patients (P=.378) and controls (P=.6164). Hence, we conclude that EDN K198N genotypes were not related to either ET-1 concentration or incidence of early-onset AMI in Egyptians. But, AMI patients had higher ET-1 concentrations than controls. PMID- 27761930 TI - Concurrent STAT3, DNMT3A, and TET2 mutations in T-LGL leukemia with molecularly distinct clonal hematopoiesis of indeterminate potential. PMID- 27761931 TI - The rising toll of homicide by psychiatric patients: have we reached 'peak community care'? PMID- 27761933 TI - Immunogenicity and protective efficacy of recombinant iron superoxide dismutase protein from Bordetella pertussis in mice models. AB - Whooping cough (pertussis) is a highly contagious respiratory infection caused by Bordetella pertussis. Although availability of effective pertussis vaccines reportedly decreases the incidence of the disease, B. pertussis circulation in populations has not been eliminated. Thus, it is necessary to find new protein candidates with greater immune protective capacities than the currently available acellular pertussis vaccines. In this study, iron superoxide dismutase (FeSOD) gene (sodB) was cloned, expressed in Escherichia coli and recombinant FeSOD protein thence purified. The recombinant protein (rFeSOD) was formulated with aluminum hydroxide (Alum) or monophosphoryl lipid A (MPLA) and injected intraperitoneally to immunize mice, after which IgG1, IgG2a and IFN-gamma titers were measured to assess humoral and cellular responses, respectively, to these immunizations. The extent of bacterial colonization in lungs of intranasally challenged mice was determined 5, 8 and 14 days post-challenge. IgG1 and IgG2a responses were significantly stronger in mice that had been immunized with rFeSOD MPLA than in those that had received rFeSOD-Alum (P < 0.05). Additionally, IgG2a titers were higher in mice vaccinated with recombinant protein FeSOD (rFeSOD) formulated with MPLA, especially after the second immunization. Immunization with rFeSOD-MPLA also provided a modest, but significant decrease in bacterial counts in lungs of mice (P < 0.05). Antigen specific-IFN-gamma responses were significantly stronger in the group vaccinated with rFeSOD-MPLA, which could account for the lower bacterial counts. These findings suggest that rFeSOD protein formulated with MPLA has potential as an acellular pertussis vaccine candidate component. PMID- 27761932 TI - Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective, population-based cohort. AB - The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sbeta0 thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009 2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77 81, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27761934 TI - Allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: a retrospective single-center study. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of hematopoietic stem cell characterized by complement mediated intravascular hemolysis. There are different treatment modalities available for PNH, such as supportive care, eculizumab, and hematopoietic stem cell transplantation (HSCT); only the last one has a potential curative role. This study reported the outcome of HSCT transplanted PNH patients. Thirteen PNH patients between 2002 and 2014 participated in this study. All had full-matched sibling donors, and the conditioning regimen was Bu/Cy (busulfan plus cyclophosphamide), and the source of stem cells was peripheral blood of the donors. Mean age at transplant was 27.46 years, and mean time to transplant was 41.30 months. Three were female and 10 were male. Three patients died at the end of follow-up time, and the cause of death was graft versus host disease (GVHD) for all 3 cases. Survival analysis showed a 5-year and a 13-year survival rate of 74.07% and a significant relationship between a positive history of thrombosis and a higher mortality rate. HSCT has curative role in management of PNH with an acceptable survival rate and therefore can be considered as an acceptable choice for selected cases. PMID- 27761935 TI - Alpha blockade-not to be underdone. PMID- 27761936 TI - Epigenetic Treatment of Persistent Viral Infections. AB - Preclinical Research Approximately 2,500 years ago, Hippocrates used the word herpes as a medical term to describe lesions that appeared to creep or crawl on the skin, advocating heat as a possible treatment. During the last 50 years, pharmaceutical research has made great strides, and therapeutic options have expanded to include small molecule antiviral agents, protease inhibitors, preventive vaccines for a handful of the papillomaviruses, and even cures for hepatitis C virus infections. However, effective treatments for persistent and recurrent viral infections, particularly the highly prevalent herpesviruses, continue to represent a significant unmet medical need, affecting the majority of the world's population. Exploring the population diversity of the human microbiome and the effects its compositional variances have on the immune system, health, and disease are the subjects of intense investigational research and study. Among the collection of viruses, bacteria, fungi, and single-cell eukaryotes that comprise the human microbiome, the virome has been grossly understudied relative to the influence it exerts on human pathophysiology, much as mitochondria have until recently failed to receive the attention they deserve, given their critical biomedical importance. Fortunately, cellular epigenetic machinery offers a wealth of druggable targets for therapeutic intervention in numerous disease indications, including those outlined above. With advances in synthetic biology, engineering our body's commensal microorganisms to seek out and destroy pathogenic species is clearly on the horizon. This is especially the case given recent breakthroughs in genetic manipulation with tools such as the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR associated) gene-editing platforms. Tying these concepts together with our previous work on the microbiome and neurodegenerative and neuropsychiatric diseases, we suggest that, because mammalian cells respond to a viral infection by triggering a cascade of antiviral innate immune responses governed substantially by the cell's mitochondria, small molecule carnitinoids represent a new class of therapeutics with potential widespread utility against many infectious insults. Drug Dev Res 78 : 24-36, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27761937 TI - Chronic spontaneous urticaria in an 8-year-old girl treated with omalizumab. PMID- 27761938 TI - Cutaneous malignant melanoma and Parkinson disease: Common pathways? AB - The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated alpha-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820. PMID- 27761939 TI - Association of IL-37 gene polymorphisms with susceptibility to tuberculosis in Saudi subjects. AB - Tuberculosis (TB) is one of the most common infectious diseases worldwide. IL-37, a novel member of the IL-1 family, has anti-inflammatory activity. Various cytokine genes polymorphisms are reportedly associated with susceptibility to TB infection. However, an association between genetic variations in the IL-37 gene and susceptibility to TB infection has not been investigated. The aim of this case-control study was therefore to identify such an association in Saudi subjects, in which five single-nucleotide polymorphisms (SNPs) in the IL-37 gene were assessed. Serum concentrations of IL-37 were evaluated using ELISA, and genetic variants genotyped by multiplex PCR and ligase detection reaction. It was found that the C/C genotype of rs2723176 (-6962 A/C) occurs significantly more frequently in patients with active TB and that the C allele of this SNP is associated with TB. In addition, the C allele of rs2723176 SNP was associated with high circulating concentrations of IL-37. However, the genotype and allele frequency of the other four SNPs (rs3811046, rs3811047, rs2723186 and rs2723187) were not significantly associated with TB infection. In conclusion, the present data suggest that rs2723176 SNP of IL-37 is involved in the development of TB infection. Furthermore, high circulating concentrations of IL-37 may have a negative effect on protective immunity against TB infection. PMID- 27761940 TI - Ferrocenyl-Coupled N-Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs. AB - Four gold(I) carbene complexes featuring 4-ferrocenyl-substituted imidazol-2 ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug-resistant ones, with low micromolar or nanomolar IC50 (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular-disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %. PMID- 27761942 TI - Effects of advanced carbohydrate counting guided by an automated bolus calculator in Type 1 diabetes mellitus (StenoABC): a 12-month, randomized clinical trial. AB - AIMS: To test whether concomitant use of an automated bolus calculator for people with Type 1 diabetes carrying out advanced carbohydrate counting would induce further improvements in metabolic control. METHODS: We conducted a 12-month, randomized, parallel-group, open-label, single-centre, investigator-initiated clinical study. We enrolled advanced carbohydrate counting-naive adults with Type 1 diabetes and HbA1c levels 64-100 mmol/mol (8.0-11.3%), who were receiving multiple daily insulin injection therapy. In a 1:1-ratio, participants were randomized to receive training in either advanced carbohydrate counting using mental calculations (MC group) or advanced carbohydrate counting using an automated bolus calculator (ABC group) during a 3.5-h group training course. For 12 months after training, participants attended a specialized diabetes centre quarterly. The primary outcome was change in HbA1c from baseline to 12 months. RESULTS: Between August 2012 and September 2013, 168 participants (96 men and 72 women) were recruited and randomly assigned to the MC group (n = 84) and the ABC group (n = 84). Drop-out rates were 23.8 and 21.4%, respectively (P = 0.712); 130 participants completed the study. The baseline HbA1c was 75 +/- 9 mmol/mol (9.0 +/- 0.8%) in the MC group and 74 +/- 8 mmol/mol (8.9 +/- 0.7%) in the ABC group. At 12 months, change in HbA1c was significant within both groups: MC group: -2 mmol/mol (95% CI -4 to -1) or -0.2% (95% CI -0.4 to -0.1; P = 0.017) and ABC group: -5 mmol/mol (95% CI -6 to -3) or -0.5% (95% CI -0.6 to -0.3; P < 0.0001), but HbA1c reductions were significantly greater in the ABC group (P = 0.033). No episodes of severe hypoglycaemia were reported. CONCLUSIONS: People with Type 1 diabetes initiating advanced carbohydrate counting obtained significantly greater HbA1c reductions when guided by an automated bolus calculator (NCT02084498). PMID- 27761941 TI - Continental-level population differentiation and environmental adaptation in the mushroom Suillus brevipes. AB - Recent advancements in sequencing technology allowed researchers to better address the patterns and mechanisms involved in microbial environmental adaptation at large spatial scales. Here we investigated the genomic basis of adaptation to climate at the continental scale in Suillus brevipes, an ectomycorrhizal fungus symbiotically associated with the roots of pine trees. We used genomic data from 55 individuals in seven locations across North America to perform genome scans to detect signatures of positive selection and assess whether temperature and precipitation were associated with genetic differentiation. We found that S. brevipes exhibited overall strong population differentiation, with potential admixture in Canadian populations. This species also displayed genomic signatures of positive selection as well as genomic sites significantly associated with distinct climatic regimes and abiotic environmental parameters. These genomic regions included genes involved in transmembrane transport of substances and helicase activity potentially involved in cold stress response. Our study sheds light on large-scale environmental adaptation in fungi by identifying putative adaptive genes and providing a framework to further investigate the genetic basis of fungal adaptation. PMID- 27761944 TI - Maternal dietary linoleic acid supplementation promotes muscle fibre type transformation in suckling piglets. AB - As meat quality is basically dependent on muscle fibre characteristics, it is important to know how muscle fibres are regulated and transformed. This study aimed to investigate the effect of maternal dietary supplementation on muscle fibre types using 3% saturated fatty acid (palmitic acid, PA) or 3% unsaturated fatty acid (linoleic acid, LA) from 80 days of gestation to the weaning of offspring (25 days post-natal). The results indicated that higher mRNA levels of MyHCI type genes were found in the soleus muscles of piglets that suckled from LA supplemented sows than from PA-supplemented sows. In addition, LA treatment increased the gene expression of the type I muscle fibre marker troponin I (p < 0.01), suggesting that LA promoted muscle fibre type transformation to type I fibres. Moreover, PGC-1alpha (p < 0.01) and MEF2c (p < 0.05) mRNA levels were higher in the piglets from the LA treatment group than in those from the PA treatment group. Furthermore, LA supplementation also significantly increased AMP activated protein kinase (AMPK) mRNA levels (p < 0.05), which is an upstream regulator of PGC-1alpha. Collectively, these findings demonstrated that maternal dietary LA supplementation promoted muscle fibre transformation to type I fibre and that this process may be mediated through an AMPK-dependent pathway. PMID- 27761943 TI - Adaptive working memory training improved brain function in human immunodeficiency virus-seropositive patients. AB - OBJECTIVE: We aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls. METHODS: A total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near-transfer WM tests (Digit-Span, Spatial Span), self-reported executive functioning, and functional magnetic resonance images during 1-back and 2-back tasks were performed at baseline and each follow up visit, and LMX1A-rs4657412 was genotyped in all participants. RESULTS: Although HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p < 0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p <= 0.001), but not after nonadaptive WMT (training by training type corrected, p = 0.01 to p = 0.05) 1 month later. HIV participants (especially LMX1A-G carriers) also had poorer self-reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p = 0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p < 0.0001), with normalization of brain activation in HIV participants, especially the LMX1A-AA carriers (LMX1A genotype by HIV status, cluster-corrected-p < 0.0001). INTERPRETATION: Adaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV-LMX1A-AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17-34. PMID- 27761945 TI - Crowded Star Mesogens: Guest-Controlled Stability of Mesophases from Unconventional Liquid-Crystal Molecules. AB - The molecular design of crowded hexasubstituted star mesogens based on a benzene core and alternating substitution with oligo(phenylenevinylene) arms and aryl units generates free space between the conjugated arm scaffolds. Various arylcarboxy building blocks, decorated with alkoxy chains, have been incorporated in the void by mixing, hydrogen bonding or covalent bonds to the aryl groups. The mesogens assemble in columnar stacks ranging from soft crystals to rectangular and hexagonal columnar liquid crystals, revealed by polarized optical microscopy, differential scanning calorimetry, X-ray scattering and modelling. The stability of the mesophases is crucially influenced by the binding mode of the arylcarboxy guest building blocks. The origin of the variation in clearing temperature is unravelled by modelling, cohesive energy density considerations and solid-state NMR spectroscopy. The control over the transition temperature is important for the formation of aligned thin films and thus for potential applications. PMID- 27761946 TI - Profile of diabetes in men aged 79-97 years: the Western Australian Health in Men Study. AB - AIMS: To investigate behavioural, physical and biochemical characteristics associated with diabetes in the oldest age group of elderly men. METHODS: We conducted a cross-sectional analysis of community-dwelling men aged 79-97 years from Perth, Western Australia. Lifestyle behaviours, self-rated health, physical function, and fasting glucose and HbA1c levels were assessed. RESULTS: Of 1426 men, 315 had diabetes (22%). Men with diabetes were of similar age to men without (84.9 vs 84.5 years; P = 0.14). Only 26.5% of men with diabetes self-rated their health as excellent or very good, compared with 40.6% of men without diabetes (P < 0.001). Diabetes was associated with less involvement with recreational walking (32.7 vs 41.0%; P < 0.01) and leisure activities (19.0 vs 26.5%; P < 0.01). Men with diabetes had poorer physical function on multiple measures, including longer times for the Timed Up-and-Go test (15.0 +/- 6.9 s vs 13.4 +/- 5.3 s; P < 0.001) and weaker knee extension (20.2 vs 21.9 kg; P < 0.001). In multivariate analyses, diabetes was associated with an increased prevalence of myocardial infarction (odds ratio 1.80, 95% CI 1.25-2.60; P < 0.001) and falls resulting in injury (odds ratio 1.55, 95% CI 1.06-2.26; P = 0.02). Average HbA1c was 49 +/- 8 mmol/mol (6.6 +/- 0.8%) in men with diabetes, with 90.6% of these men on diet or oral hypoglycaemic therapy. CONCLUSIONS: In older men, diabetes is associated with poorer self-perceived health, reduced healthy lifestyle behaviours and physical function, heart disease and injurious falls. The majority of these men with diabetes had good glycaemic control. Encouraging healthy lifestyle behaviours and improving physical function should be evaluated as interventions to improve quality-of-life and health outcomes. PMID- 27761947 TI - Effect of ensiling whole crop oat with lucerne in different ratios on fermentation quality, aerobic stability and in vitro digestibility on the Tibetan plateau. AB - The objective of this study was to determine the effect of ensiling different ratios of whole crop oat to lucerne on fermentation quality, aerobic stability and in vitro digestibility of silage on the Tibetan plateau. Four experimental treatments were produced varying in the ratio of forages on a fresh matter (FM) basis: 1) 100% oat (control, dry matter (DM) content: 317 g/kg), 2) 90% oat + 10% lucerne (OL10, DM content: 316 g/kg), 3) 80% oat+ 20% lucerne (OL20, DM content: 317 g/kg) and 4) 70% oat+ 30% lucerne (OL30, DM content: 318 g/kg). All treatments were packed into laboratory-scale silos and ensiled for 60 days and then subjected to an aerobic stability test for 15 days. Further, the four experimental treatments were incubated in vitro with buffered rumen fluid to study the nutrient digestibility. All silages were well preserved with low pH and NH3 -N contents, and high lactic acid contents and V-scores (evaluation of silage quality). Increasing the lucerne proportion increased (p < 0.05) crude protein (CP) content of silage, whereas neutral (NDF) and acid (ADF) detergent fibre contents were not affected. Under aerobic conditions, the control silage showed higher (p < 0.05) yeast counts (>105 cfu/g FM) followed by OL10 silage, and OL10 silage improved aerobic stability for 74 h. OL20 and OL30 silages showed fewer (p < 0.05) yeasts (<105 cfu/g FM) and markedly (p < 0.05) improved the aerobic stability (>360 h). After 48-h incubation, OL30 silage increased (p < 0.05) in vitro dry matter digestibility (IVDMD) and neutral detergent fibre digestibility (IVNDFD) compared with the control silage. These results suggest that replacing oat with lucerne had no unfavourable effects on fermentation quality of silage, but improved CP content, aerobic stability IVDMD and IVNDFD. OL30 silage was the best among the three mixed silages. PMID- 27761948 TI - Skin permeation of econazole nitrate formulated in an enhanced hydrophilic multiple emulsion. AB - Local delivery of imidazolic antifungals is limited by its extreme lipophilicity. Multiple emulsions (ME) are a potential vehicle to enhance the delivery of econazole nitrate (ECN), an antifungal targeted to deep-seated epidermal yeast infections. An 1% ECN hydrophilic ME was compared with a commercial formulation in terms of rheology, droplet size and in vitro antifungal activity against Candida species. Comparative in vitro drug release, human skin permeation and drug retention were investigated using vertical diffusion cells. Rheology demonstrated a pseudoplastic shear thinning with thixotropy facilitating skin residence. No significant aggregation or droplet size variations were observed during a 6-month stability storage. Both formulations exhibited similar release levels achieving asymptotic values in 5 h. ECN skin permeation levels from the multiple emulsion resulted to be significantly higher than those of the commercial formulation, attributable to differences in formulation polarity and excipients composition. Conversely, similar drug accumulation levels in skin were obtained (40-130 ppm). These concentrations resulted to be comparable with obtained MIC values (2-78 ppm), confirming the in vitro antimicrobial efficacy of both formulations. A similar skin retention and a higher permeation rate over the existing formulations is considered an improved approach to target the drug to deep epidermis. PMID- 27761949 TI - Pairwise contact energy statistical potentials can help to find probability of point mutations. AB - To adopt a particular fold, a protein requires several interactions between its amino acid residues. The energetic contribution of these residue-residue interactions can be approximated by extracting statistical potentials from known high resolution structures. Several methods based on statistical potentials extracted from unrelated proteins are found to make a better prediction of probability of point mutations. We postulate that the statistical potentials extracted from known structures of similar folds with varying sequence identity can be a powerful tool to examine probability of point mutation. By keeping this in mind, we have derived pairwise residue and atomic contact energy potentials for the different functional families that adopt the (alpha/beta)8 TIM-Barrel fold. We carried out computational point mutations at various conserved residue positions in yeast Triose phosphate isomerase enzyme for which experimental results are already reported. We have also performed molecular dynamics simulations on a subset of point mutants to make a comparative study. The difference in pairwise residue and atomic contact energy of wildtype and various point mutations reveals probability of mutations at a particular position. Interestingly, we found that our computational prediction agrees with the experimental studies of Silverman et al. (Proc Natl Acad Sci 2001;98:3092-3097) and perform better prediction than iMutant and Cologne University Protein Stability Analysis Tool. The present work thus suggests deriving pairwise contact energy potentials and molecular dynamics simulations of functionally important folds could help us to predict probability of point mutations which may ultimately reduce the time and cost of mutation experiments. Proteins 2016; 85:54 64. (c) 2016 Wiley Periodicals, Inc. PMID- 27761950 TI - Melanoma risk alleles are associated with downregulation of the MTAP gene and hypermethylation of a CpG island upstream of the gene in dermal fibroblasts. AB - Several association studies and GWAS on melanoma skin cancer risk have reported statistically significant signals on 9p21.3 region, where MTAP gene maps. None of the associated SNPs identified in these studies lie in the coding region of the gene and the causative relation of risk alleles with melanoma predisposition has not been elucidated. MTAP has a tumor suppressor activity and epigenetic silencing has been described in melanoma cell lines. In the present study, we show that melanoma risk alleles correlate with a MTAP allele-specific hyper methylation and down-regulation of gene expression. PMID- 27761952 TI - Wy14643, an agonist for PPARalpha, downregulates expression of TARC and RANTES in cultured human keratinocytes. AB - Beneficial effects of Wy14643, an agonist for peroxisome proliferator-activated receptor (PPAR)alpha, on permeability barrier homeostasis-related functions of keratinocytes such as up-regulation of epidermal differentiation-related molecules and lipid synthesis, have been demonstrated. The present study demonstrated that Wy14643 reduced the expression of thymus and activation-related chemokine (TARC) and regulated on activation normal T cell expressed (RANTES) in both single- and 3D-cultured human keratinocytes. The combined data of the present and previous studies support the notion that Wy14643 could be a therapeutic agent that might simultaneously and directly modulate permeability barrier dysfunction and allergic inflammation in the pathogenesis of atopic dermatitis. As for the anti-microbial barrier function, the present study demonstrated that Wy14643 up-regulated expression of the anti-microbial peptide, human beta defensin 3, in cultured human keratinocytes only in mRNA levels but not in protein ones, suggesting that Wy14643 might not directly account for the up-regulation of the anti-microbial peptide which has been reported in vivo. PMID- 27761951 TI - A systematic review of interventions to improve outcomes for young adults with Type 1 diabetes. AB - BACKGROUND: Many young adults with Type 1 diabetes experience poor outcomes. The aim of this systematic review was to synthesize the evidence regarding the effectiveness of interventions aimed at improving clinical, behavioural or psychosocial outcomes for young adults with Type 1 diabetes. METHODS: Electronic databases were searched. Any intervention studies related to education, support, behaviour change or health service organizational change for young adults aged between 15-30 years with Type 1 diabetes were included. A narrative synthesis of all studies was undertaken due to the large degree of heterogeneity between studies. RESULTS: Eighteen studies (of a possible 1700) were selected and categorized: Health Services Delivery (n = 4), Group Education and Peer Support (n = 6), Digital Platforms (n = 4) and Diabetes Devices (n = 4). Study designs included one randomized controlled trial, three retrospective studies, seven feasibility/acceptability studies and eight studies with a pre/post design. Continuity, support, education and tailoring of interventions to young adults were the most common themes across studies. HbA1c was the most frequently measured outcome, but only 5 of 12 studies that measured it showed a significant improvement. CONCLUSION: Based on the heterogeneity among the studies, the effectiveness of interventions on clinical, behavioural and psychosocial outcomes among young adults is inconclusive. This review has highlighted a lack of high quality, well-designed interventions, aimed at improving health outcomes for young adults with Type 1 diabetes. PMID- 27761953 TI - Kinetically Trapped Supramolecular Assembly of Perylene Dianhydride Derivative in Methanol: Optical Spectra, Morphology, and Mechanisms. AB - Supramolecular self-assembly has attracted increasing attention as a breakthrough methodology in the fields of nanoscience and nanotechnology. Herein, a perylene dianhydride derivative (TP-PDA) self-assembles into well-defined nanospheres through a nucleation-growth process. The mechanisms of this process were explored by using spectral analysis, dynamic light scattering (DLS), and scanning electron microscopy (SEM). In situ DLS and in situ SEM both revealed that the size of the aggregated nanospheres increases with time until the formation of equilibrium H aggregates. This shows that TP-PDA undergoes a kinetically trapped assembly with a rapid transformation into the thermodynamically favored form, and this process can be finely tuned by reducing the concentration and increasing the temperature. Weak intermolecular forces, such as pi-pi stacking, hydrogen bonding, and solvophobic interactions, play an important role in the formation of nanostructures. This work inspired us to explore other kinetically trapped supramolecular assemblies that might be easily ignored due to the short trapping time of commonly used experimental timescales. PMID- 27761954 TI - Novel insights into role of miR-320a-VDAC1 axis in astrocyte-mediated neuronal damage in neuroAIDS. AB - Astroglia are indispensable component of the tripartite synapse ensheathing innumerous soma and synapses. Its proximity to neurons aids the regulation of neuronal functions, health and survival through dynamic neuroglia crosstalk. Susceptibility of astrocyte to HIV-1 infection and subsequent latency culminates in compromised neuronal health. The viral protein HIV-1 transactivator of transcription (Tat) is neurotoxic. HIV-1 Tat is detected in brain of AIDS patients even in cases where viral load is non-detectable due to successful HAART therapy. Recently, we demonstrated that HIV-1 Tat triggers excess ATP release from astrocytes that causes neuronal death by activating purinergic receptor system. Using well-characterized model system of human primary astrocytes and neurons, we probed into the molecular mechanism for enhanced ATP release in HIV-1 Tat affected astrocytes. HIV-1 Tat modulated the miRNA machinery in astrocytes and perturbed the levels of voltage dependent anion channel 1 (VDAC1), a channel present in the outer mitochondrial membrane and plasma membrane that regulates extracellular ATP release. Our studies with autopsy tissue sections also showed concordantly dysregulated VDAC1 and miR-320a levels in HIV-1 patients suffering from mild cognitive impairment (MCI). We report a novel molecular cascade of miRNA-mediated ATP release through regulation of VDAC1. Downregulation of VDAC1 either with miR-320a mimic or VDAC1 siRNA in HIV-1 Tat-affected astroglia could rescue the neurons from glia-mediated indirect death. Our findings reveal a novel upstream therapeutic target that could be employed to thwart the astroglia mediated neurotoxicity in HIV-1 neuropathogenesis. GLIA 2017;65:250-263. PMID- 27761956 TI - Explaining the accreditation process from the institutional isomorphism perspective: a case study of Jordanian primary healthcare centers. AB - BACKGROUND: While the main focus of accreditation initiatives has been on hospitals, the implementation of these programs is a relatively new notion among other types of healthcare facilities. Correspondingly, this study aims to understand how accreditation is perceived among primary public healthcare centers using an isomorphic institutional theory. DESIGN/METHODOLOGY: Semi-structured, in depth interviews were conducted with 56 healthcare professionals and administrative staff from seven non-profit healthcare centers in Jordan using an explanatory case-study approach. RESULTS: The informants' narratives revealed that all three components of institutional theory: coercive, mimetic, and normative pressure, were drivers for institutional change in seeking accreditation. There was an overlapping and blending between the three various types of pressure. While participants perceived that healthcare centers faced formal and informal pressures to achieve accreditation, health centers were reluctant about the time, amount of effort, and their ability to achieve the accreditation. Ambiguity and fear of failure forced them to model successful ones. Moreover, the findings revealed that normative values of health professionals enhanced institutional isomorphism and influenced the accreditation process. CONCLUSION: Identifying these isomorphic changes may help key stakeholders to develop plans, policies, and procedures that could improve the quality of healthcare and enhance accreditation as an organizational strategic plan. Moreover, the study provided explanations of why and how organizations move to adopt new interventions and grow over time. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27761955 TI - Are fingernails a key to unlocking the puzzle of mammalian limb regeneration? AB - Some mammalian digit tips, including those of mice and human children, can regenerate following amputation, whereas mammalian limb regeneration does not occur. One major difference between the digit tip and the rest of the limb is the presence of the nail, which is necessary for this type of regeneration. This couples well with the finding that canonical Wnt signalling and Lgr6, an agonist of Wnt signalling that marks nail stem cells, are necessary for digit tip regeneration. This viewpoint essay discusses the role of the nail in digit tip regeneration and explores whether nail stem cells and their presumptive niche can be solely accountable for why regeneration is possible in the digit tip, but not the rest of the limb. PMID- 27761957 TI - Pure shift 1 H NMR: what is next? AB - Currently, pure shift nuclear magnetic resonance (NMR) is an area of high interest. The aim of this contribution is to describe briefly how this technique has evolved, where it is now and what could be the next challenges in the amazing adventure of the development and application of pure shift NMR experiments. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27761958 TI - Validity of administrative data for identification of obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a common condition associated with significant morbidity and health-care utilization. We determined the validity of an algorithm derived from administrative data for identifying OSA using the respiratory disturbance index (RDI) as the reference standard. We conducted a retrospective cohort study of adults in Alberta, Canada referred for facility and community based sleep diagnostic testing between July 2005 and August 2007. Validity indices were estimated for several case definitions of OSA derived from outpatient physician billing claims and hospital discharge codes. For each algorithm, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated against several reference standards for OSA (RDI >= 5 h-1 , RDI >= 15 h-1 or RDI >= 30 h-1 ). For the 2149 patients included in the study, an algorithm requiring one hospital discharge code or two outpatient billing claims identifying OSA in a 2-year period had a sensitivity of 24.1%, specificity of 67.8%, PPV of 74.8% and NPV of 18.3% (reference standard RDI >= 5 h-1 ). When comorbidities were included in the case definition, the specificity was 90.5% and PPV was 83.3% (reference standard RDI >= 5 h-1 ). Similar findings were observed using RDI >= 15 h-1 and >=30 h-1 as the reference standard. We identify a claims-based algorithm that identifies OSA with a high degree of specificity in patients referred for sleep diagnostic testing. This validated algorithm has a good PPV and may be useful when identifying patients with OSA for population studies within a single-payer health care system. PMID- 27761960 TI - Inferring paternal history of rural African-derived Brazilian populations from Y chromosomes. AB - OBJECTIVES: Quilombo remnants are relics of communities founded by runaway or abandoned African slaves, but often with subsequent extensive and complex admixture patterns with European and Native Americans. We combine a genetic study of Y-chromosome markers with anthropological surveys in order to obtain a portrait of quilombo structure and history in the region that has the largest number of quilombo remnants in the state of Sao Paulo. METHODS: Samples from 289 individuals from quilombo remnants were genotyped using a set of 17 microsatellites on the Y chromosome (AmpFlSTR-Yfiler). A subset of 82 samples was also genotyped using SNPs array (Axiom Human Origins-Affymetrix). We estimated haplotype and haplogroup frequencies, haplotype diversity and sharing, and pairwise genetic distances through FST and RST indexes. RESULTS: We identified 95 Y chromosome haplotypes, classified into 15 haplogroups. About 63% are European, 32% are African, and 6% Native American. The most common were: R1b (European, 34.2%), E1b1a (African, 32.3%), J1 (European, 6.9%), and Q (Native American, 6.2%). Genetic differentiation among communities was low (FST = 0.0171; RST = 0.0161), and haplotype sharing was extensive. Genetic, genealogical and oral surveys allowed us to detect five main founder haplotypes, which explained a total of 27.7% of the Y chromosome lineages. CONCLUSIONS: Our results showed a high European patrilineal genetic contribution among the founders of quilombos, high amounts of gene flow, and a recent common origin of these populations. Common haplotypes and genealogical data indicate the origin of quilombos from a few male individuals. Our study reinforces the importance of a dual approach, involving the analysis of both anthropological and genetic data. PMID- 27761959 TI - Long-term dynamics in microbial eukaryotes communities: a palaeolimnological view based on sedimentary DNA. AB - Assessing the extent to which changes in lacustrine biodiversity are affected by anthropogenic or climatic forces requires extensive palaeolimnological data. We used high-throughput sequencing to generate time-series data encompassing over 2200 years of microbial eukaryotes (protists and Fungi) diversity changes from the sedimentary DNA record of two lakes (Lake Bourget in French Alps and Lake Igaliku in Greenland). From 176 samples, we sequenced a large diversity of microbial eukaryotes, with a total 16 386 operational taxonomic units distributed within 50 phylogenetic groups. Thus, microbial groups, such as Chlorophyta, Dinophyceae, Haptophyceae and Ciliophora, that were not previously considered in lacustrine sediment record analyses appeared to be potential biological markers of trophic status changes. Our data suggest that shifts in relative abundance of extant species, including shifts between rare and abundant taxa, drive ecosystem responses to local and global environmental changes. Community structure shift events were concomitant with major climate variations (more particularly in Lake Igaliku). However, this study shows that the impacts of climatic fluctuations may be overpassed by the high-magnitude eutrophication impacts, as observed in the eutrophicated Lake Bourget. Overall, our data show that DNA preserved in sediment constitutes a precious archive of information on past biodiversity changes. PMID- 27761961 TI - Using expert elicitation to estimate the potential impact of improved diagnostic performance of laboratory tests: a case study on rapid discharge of suspected non ST elevation myocardial infarction patients. AB - Early health technology assessment can provide insight in the potential cost effectiveness of new tests to guide further development decisions. This can increase their potential benefit but often requires evidence which is lacking in early test development stages. Then, expert elicitation may be used to generate evidence on the impact of tests on patient management. This is illustrated in a case study on a new triple biomarker test (copeptin, heart-type fatty acid binding protein, and high-sensitivity troponin [HsTn]) at hospital admission. The elicited evidence enables estimation of the impact of using the triple biomarker on time to exclusion of non-ST elevation myocardial infarction compared with current serial HsTn measurement (performed 0, 2, and 6 h after admission). Cardiologists were asked to estimate the effect of the triple biomarker on patient's discharge rates and interventions performed, depending on its diagnostic performance. This elicited evidence was combined with Dutch reimbursement data and published evidence into a decision analytic model. Direct hospital costs and patients' discharge rates were assessed for 3 testing strategies including this triple biomarker (ie, only at admission or combined with HsTn measurements after 2 and 6 h). Direct hospital costs of suspected non ST elevation myocardial infarction patients using serial HsTn measurements are estimated at ?1825 per patient. Combining this triple biomarker with HsTn measurements after 2 and 6 hours is expected to be the most cost-effective strategy. Depending on the diagnostic performance of the triple biomarker, this strategy is estimated to reduce costs with ?66 to ?205 per patient (ie, 3.6% 11.3% reduction). Expert elicitation can be a valuable tool for early health technology assessment to provide an initial estimate of the cost-effectiveness of new tests prior to their implementation in clinical practice. As demonstrated in our case study, improved diagnostic performance of the triple biomarker may have benefits that should be further explored. PMID- 27761962 TI - European retrospective study of real-life haemophilia treatment. AB - INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels <=5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated >=3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care. PMID- 27761965 TI - Analyses of joint health and influencing factors in different age groups of Chinese children with haemophilia. PMID- 27761964 TI - Recombinant B-domain-deleted porcine sequence factor VIII (r-pFVIII) for the treatment of bleeding in patients with congenital haemophilia A and inhibitors. AB - INTRODUCTION: Development of inhibitors to human FVIII (hFVIII) significantly complicates the control of bleeding events in patients with haemophilia A. AIM: This prospective, multicentre, open-label, non-comparative, Phase II study evaluated the haemostatic activity of a recombinant B-domain-deleted porcine FVIII (r-pFVIII), in the treatment of non-life/non-limb-threatening bleeding in individuals with haemophilia A and FVIII inhibitors. METHODS: Acute bleeding episodes in patients with pFVIII inhibitor titres <0.8 BU mL-1 were treated with 50 U kg-1 body weight r-pFVIII. Those with pFVIII inhibitor titres of >0.8 BU mL 1 received an initial calculated r-pFVIII loading dose followed by 50 U kg-1 treatment dose. Treatment continued at 6-hourly intervals until bleeding was determined, controlled or till a maximum of eight doses was reached. RESULTS: All 25 bleeding episodes in nine patients (mean age: 23.7 years; range: 14-34 years) were controlled successfully with eight or fewer injections of r-pFVIII. The median time from bleeding onset to the administration of r-pFVIII was 5.7 h (range: 1.5-20.0 h). Twenty of the bleeding episodes (80%) were controlled with one treatment dose of r-pFVIII (with or without a loading dose, median dose: 200.8 U kg-1 ; range: 50-576 U kg-1 ) regardless of pFVIII level. r-pFVIII was well tolerated and no treatment-emergent serious adverse events were considered by the investigator to be related to r-pFVIII administration. CONCLUSION: The results suggest that FVIII replacement therapy with r-pFVIII could be a viable alternative to bypassing agents for the treatment of bleeding episodes in individuals with haemophilia A and FVIII inhibitors. PMID- 27761963 TI - Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/beta-catenin signaling pathway. AB - We previously reported that celecoxib, a selective COX-2 inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/beta catenin signaling pathway. 2,5-Dimethylcelecoxib (DM-celecoxib), a celecoxib analog that does not inhibit COX-2, has also been reported to have an antitumor effect. In the present study, we elucidated whether DM-celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM-celecoxib with that of celecoxib on the human colon cancer cell lines HCT-116 and DLD-1. 2,5-Dimethylcelecoxib suppressed cell proliferation and inhibited T-cell factor 7-like 2 expression with almost the same strength as celecoxib. 2,5-Dimethylcelecoxib also inhibited the T-cell factor-dependent transcription activity and suppressed the expression of Wnt/beta catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM-celecoxib using the Mutyh-/- mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM-celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated treatment with celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer effect of celecoxib derivatives is the suppression of the Wnt/beta catenin signaling pathway but not the inhibition of COX-2, and that DM-celecoxib might be a better lead compound candidate than celecoxib for the development of novel anticancer drugs. PMID- 27761966 TI - Efficacy of Occupational Therapy Task-oriented Approach in Upper Extremity Post stroke Rehabilitation. AB - There is a need for more effective rehabilitation methods for individuals post stroke. Occupational Therapy Task-Oriented (TO) approach has not been evaluated in a randomized clinical trial. The purpose of this study was to evaluate functional and impairment efficacies of TO approach on the more-affected Upper Extremity (UE) of persons post-stroke. A randomized single-blinded cross-over trial recruited 20 participants post-stroke (mean chronicity = 62 months) who demonstrated at least 10 degrees active more-affected shoulder flexion and abduction and elbow flexion-extension. Participants were randomized into immediate (n = 10) and delayed intervention (n = 10) groups. Immediate group had 6 weeks of 3 hr/week TO intervention followed by 6 weeks of no-intervention control. Delayed intervention group underwent the reversed order. Functional measures included Canadian Occupational Performance Measure (COPM), Motor Activity Log (MAL), and Wolf Motor Function Test (WMFT). Impairment measures included UE Active Range of Motion (AROM) and handheld dynamometry strength. Measurements were obtained at baseline, cross over, and end of the study. TO intervention showed statistically higher functional change scores. COPM performance and satisfaction scores were 2.83 and 3.46 units greater respectively (p < .001), MAL amount of use and quality of use scores were 1.1 and 0.87 units greater, respectively (p < .001), WMFT time was 8.35 seconds faster (p = .009). TO impairment outcomes were not significantly larger than control ones. TO approach appears to be an effective UE post-stroke rehabilitation approach inducing clinically meaningful functional improvements. More studies are needed with larger samples and specific stroke chronicity and severity. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27761968 TI - Expression and release of platelet protein disulphide isomerase in patients with haemophilia A. AB - INTRODUCTION: Despite similar residual factor VIII activity, patients with haemophilia A (HA) show significant interindividual variability with regard to bleeding frequency and severity, suggesting that additional factors modulate thrombin generation and fibrin deposition. Protein disulphide isomerase (PDI) is an abundant oxidoreductase that exerts pleiotropic effects in primary and secondary haemostasis and contributes to thrombosis and vascular inflammation. AIM: We conducted a pilot study to explore a potential role of platelet PDI in patients with HA. METHODS: Expression and release of platelet PDI were studied by flow cytometry and enzyme-linked immunosorbent assay, respectively. RESULTS: Compared to healthy male controls (n = 12), patients with HA (n = 24) showed significantly increased expression of PDI antigen on ADP- or TRAP-6-, but not on buffer-treated platelets, a finding that could not be explained by enhanced platelet activation, as indicated by expression of the alpha-granule protein, CD62P (P-selectin). While platelet agonists did not affect PDI secretion in healthy male controls, increased levels of PDI antigen were found in supernatants of TRAP-6-treated platelets from patients with HA. Importantly, in two patients with exceedingly high TRAP-6-induced PDI release over baseline, findings were consistent when platelets were isolated and stimulated on a separate occasion. No obvious association was found between platelet PDI and bleeding phenotype in this patient cohort. CONCLUSION: Agonist-induced expression and release of platelet PDI were increased in patients with HA. Larger studies are needed to clarify if variations in this platelet response contribute to the diversity in bleeding frequency and severity among patients with congenital factor VIII deficiency. PMID- 27761967 TI - Changes in the tumor microenvironment during lymphatic metastasis of lung squamous cell carcinoma. AB - Metastasis and growth in neoplastic lesions requires the multistep regulation of microenvironmental factors. We aimed to elucidate the microenvironmental changes in the process of lymphatic metastasis of lung squamous cell carcinoma. We examined the morphological characteristics of 102 cases of primary tumor (PT), 50 of intralymphatic tumor (ILT), 51 of lymph node (LN) micrometastasis (LN-Mic; <=2 mm in size), and 82 of LN macrometastasis (LN-Mac; >=10 mm in size). Afterwards we evaluated the expression of nine molecules (epidermal growth factor receptor, fibroblast growth factor receptor 2, CD44, aldehyde dehydrogenase 1, Podoplanin, E-cadherin, S100A4, geminin, and ezrin) in matched PT, ILT, LN-Mic, and LN-Mac from 23 of these cases. The number of smooth muscle actin alpha-positive fibroblasts, CD34-positive microvessels and CD204-positive macrophages were also examined. As a result, the mitotic index of tumor cells was significantly lower in ILT and LN-Mic than PT and LN-Mac (P < 0.001). Moreover, stromal reaction in ILT and LN-Mic was less prominent than in PT and LN-Mac (P < 0.001). Immunohistochemical study revealed that epidermal growth factor receptor expression level and frequency of geminin-positive cells in ILT and LN-Mic were significantly lower than in PT and LN-Mac (P < 0.05). The number of stromal cells indicated by staining of CD34, CD204, and smooth muscle actin alpha in ILT and LN Mic was also significantly lower than in PT and LN-Mac (P < 0.05). In lung squamous cell carcinoma, drastic microenvironmental changes (e.g., growth factor receptor expression and proliferative capacity of tumor cells and structural changes in stromal cells) occur during both the process of lymphatic permeation and the progression into macrometastases. PMID- 27761969 TI - The possible FAT1-mediated apoptotic pathways in porcine cumulus cells. AB - Porcine cumulus cells are localized around oocytes and act as a specific type of granulosa that plays essential roles in the development and maturation of oocytes, the development and atresia of follicles, and the development of embryos. Studies of FAT1 have demonstrated its functions in cell-cell contact, actin dynamics, and cell growth suppression. To understand whether the FAT1 gene affects the apoptosis of porcine cumulus cells and to elucidate the mechanism of this potential action, FAT1 was knocked down using RNA interference. The lack of FAT1 resulted in stable expression of CTNNB, enhanced expression of cleaved CASP3, but decreased the BCL2/BAX ratios at both the mRNA and protein levels. These results indicated that FAT1 inhibited porcine cumulus cell apoptosis via different pathways. Taken together, these data provide new insights into the mechanisms of the association between FAT1 and porcine cumulus cell apoptosis. PMID- 27761970 TI - Feasibility of video consultations in case of acute complications in children with haemophilia. PMID- 27761971 TI - Response diversity, nonnative species, and disassembly rules buffer freshwater ecosystem processes from anthropogenic change. AB - Integrating knowledge of environmental degradation, biodiversity change, and ecosystem processes across large spatial scales remains a key challenge to illuminating the resilience of earth's systems. There is now a growing realization that the manner in which communities will respond to anthropogenic impacts will ultimately control the ecosystem consequences. Here, we examine the response of freshwater fishes and their nutrient excretion - a key ecosystem process that can control aquatic productivity - to human land development across the contiguous United States. By linking a continental-scale dataset of 533 fish species from 8100 stream locations with species functional traits, nutrient excretion, and land remote sensing, we present four key findings. First, we provide the first geographic footprint of nutrient excretion by freshwater fishes across the United States and reveal distinct local- and continental-scale heterogeneity in community excretion rates. Second, fish species exhibited substantial response diversity in their sensitivity to land development; for native species, the more tolerant species were also the species contributing greater ecosystem function in terms of nutrient excretion. Third, by modeling increased land-use change and resultant shifts in fish community composition, land development is estimated to decrease fish nutrient excretion in the majority (63%) of ecoregions. Fourth, the loss of nutrient excretion would be 28% greater if biodiversity loss was random or 84% greater if there were no nonnative species. Thus, ecosystem processes are sensitive to increased anthropogenic degradation but biotic communities provide multiple pathways for resistance and this resistance varies across space. PMID- 27761973 TI - Do inhaled corticosteroids protect against lung cancer in patients with COPD? A systematic review. AB - Inhaled corticosteroids (ICS) are commonly prescribed to COPD patients, particularly those with more advanced stages of the disease. These patients are also at increased risk of lung cancer. A systematic review was undertaken to identify studies that examined the association between lung cancer risk and ICS therapy in COPD patients. The search strategy was created in MEDLINE and extended to EMBASE as well as other relevant databases. Both randomized controlled trials (RCTs) and observational studies were considered for inclusion. Studies were required to have incident lung cancer or deaths from lung cancer as an outcome in order to be included in the review. Six studies met the inclusion criteria. Two observational studies directly addressed the specific research. Four RCTs presented sufficient data to calculate the relative risk of lung cancer in COPD patients. None of the identified RCTs showed a statistically significant association of ICS use with lung cancer risk. Observational studies showed a protective effect from ICS use, particularly at high doses. Given the observational evidence and the low numbers of lung cancer events in the RCTs, these results may be prone to type II error. The observational studies dealt with very specific patient populations and exposure definitions, which might not have adequately captured the complex relationship between ICS exposure and lung cancer risk. Results from RCTs suggest no effect of ICS on the risk of lung cancer. However, results from observational studies suggest the potential that ICS may confer a protective effect, particularly at high doses. PMID- 27761972 TI - Suppressing the epimerization of endothioamide peptides during Fmoc/t-Bu-based solid phase peptide synthesis. AB - Despite a number of intriguing utilities associated with thioamide-containing peptides and proteins in the context of biophysics, pharmacology and chemical biology, it has hitherto remained as one of the underexplored territories of peptidomimetics. The synthesis of long mono to multiply substituted endothioamide peptides is invariably accompanied with severe epimerization, oxoamide formation and various other undesired side reactions, resulting in messy product profiles. This has completely restrained their use as novel chemical tools for biological studies. During the chain elongation of an N-terminally located thioamide peptide using the Fmoc/t-Bu chemistry, it becomes vulnerable to the repetitive basic treatments as required for such chemistry. The incompatibility of thioamide moiety with bases as well as strong coupling reagents leads to epimerization as well as other side reactions due to its nucleophilicity, resulting in the loss of the stereochemical identity of the thioamidated amino acid residue. An easy-to implement and efficient protocol to synthesize long (>10-mer) endothioamide peptides, significantly suppressing epimerization and other side reactions using 10% piperidine/dimethylformamide for 1 min, is reported herein. The novelty of the protocol is shown through the efficient synthesis of a number of 10-12-mer mono to multiply thioamide-substituted peptides with broad substrate scopes. The utility of the protocol in the context of protein engineering and chemical protein synthesis is also shown through the synthesis of a thioamide version of the 16-mer peptide from the B1 domain of protein G. Such a protocol to synthesize long endothioamide peptides would open up avenues toward engineering and accessing novel thiopeptide and thioprotein-based chemical tools, the synthesis of which had been a serious hurdle thus far. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27761975 TI - Grazing effects on surface energy fluxes in a desert steppe on the Mongolian Plateau. AB - Quantifying the surface energy fluxes of grazed and ungrazed steppes is essential to understand the roles of grasslands in local and global climate and in land use change. We used paired eddy-covariance towers to investigate the effects of grazing on energy balance (EB) components: net radiation (Rn ), latent heat (LE), sensible heat (H), and soil heat (G) fluxes on adjacent grazed and ungrazed areas in a desert steppe of the Mongolian Plateau for a two-year period (2010-2012). Near 95% of Rn was partitioned as LE and H, whereas the contributions of G and other components of the EB were 5% at an annual scale. H dominated the energy partitioning and shared ~50% of Rn . When comparing the grazed and the ungrazed desert steppe, there was remarkably lower Rn and a lower H, but higher G at the grazed site than at the ungrazed site. Both reduced available energy (Rn - G) and H indicated a "cooling effect" feedback onto the local climate through grazing. Grazing reduced the dry year LE but enhanced the wet year LE. Energy partitioning of LE/Rn was positively correlated with the canopy conductivity, leaf area index, and soil moisture. H/Rn was positively correlated with the vapor pressure deficit but negatively correlated with the soil moisture. Boosted regression tree results showed that LE/Rn was dominated by soil moisture in both years and at both sites, while grazing shifted the H/Rn domination from temperature to soil moisture in the wet year. Grazing not only caused an LE shift between the dry and the wet year, but also triggered a decrease in the H/Rn because of changes in vegetation and soil properties, indicating that the ungrazed area had a greater resistance while the grazed area had a greater sensitivity of EB components to the changing climate. PMID- 27761974 TI - Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability. AB - Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 degrees C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded oligomers. Consequently we examined the utility of the non-reducible cystine isostere, cystathionine, within the A-chain. Reported herein is an efficient method for forming this mimic using simple monomeric building blocks. The intra-A-chain cystathionine insulin analogue was obtained in good overall yield, chemically characterized and demonstrated to possess native binding affinity for the insulin receptor isoform B. It was also shown to possess significantly enhanced thermal stability indicating potential application to next-generation insulin analogues. PMID- 27761976 TI - Degradation and Crystallization of Cellulose in Hydrogen Chloride Vapor for High Yield Isolation of Cellulose Nanocrystals. AB - Despite the structural, load-bearing role of cellulose in the plant kingdom, countless efforts have been devoted to degrading this recalcitrant polysaccharide, particularly in the context of biofuels and renewable nanomaterials. Herein, we show how the exposure of plant-based fibers to HCl vapor results in rapid degradation with simultaneous crystallization. Because of the unchanged sample texture and the lack of mass transfer out of the substrate in the gas/solid system, the changes in the crystallinity could be reliably monitored. Furthermore, we describe the preparation of cellulose nanocrystals in high yields and with minimal water consumption. The study serves as a starting point for the solid-state tuning of the supramolecular properties of morphologically heterogeneous biological materials. PMID- 27761979 TI - Maternal systemic or cord blood inflammation is associated with birth anthropometry in a Tanzanian prospective cohort. AB - OBJECTIVES: HIV infection is associated with chronic systemic inflammation, with or without antiretroviral therapy. Consequences for foetal growth are not understood, particularly in settings where multiple maternal infections and malnutrition are common. The study was designed to examine maternal systemic circulating and umbilical cord blood cytokine concentrations in relation to birth anthropometry in a Tanzanian prospective cohort. METHODS: A 9-plex panel of maternal plasma cytokines in HIV-positive (n = 44) and HIV-negative (n = 70) mothers and the same cytokines in umbilical cord blood collected at delivery was assayed. Linear regression modelled associations between maternal or cord blood cytokines and birth anthropometry. RESULTS: Health indicators (haemoglobin, mid upper-arm circumference, body mass index) in HIV-positive mothers without considerable immunosuppression did not differ from HIV-negative women. Despite this, HIV-exposed infants had lower birthweight and length. Subgroup analyses indicated that HIV management using HAART was associated with lower plasma TNF alpha, as were longer durations of any antiretroviral therapy (>=2 months). Greater maternal plasma TNF-alpha was associated with earlier delivery (-1.7 weeks, P = 0.039) and lower birthweights (-287 g; P = 0.020), while greater umbilical cord TNF-alpha (-1.43 cm; P = 0.036) and IL-12p70 (-2.4 cm; P = 0.008) were associated with shorter birth length. Birthweight was inversely associated with cord IL-12p70 (-723 g; P = 0.001) and IFN-gamma (-482 g, P = 0.007). Maternal cytokines during pregnancy did not correlate with umbilical cord cytokines at delivery. CONCLUSIONS: Systemic inflammation identified in maternal plasma or umbilical cord blood was associated with poorer birth anthropometrics in HIV-exposed and HIV-unexposed infants. Controlling maternal and/or foetal systemic inflammation may improve birth anthropometry. PMID- 27761978 TI - Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase-7 (MMP-7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP-7 was predictive of mortality in an independent cohort of IPF patients. METHODS: MMP-7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP-7 threshold of 12.1 ng/mL with all-cause mortality or transplant-free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m-PCMI). RESULTS: MMP-7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 +/- 6.55 ng/mL vs 6.03 +/- 2.51 ng/mL, P < 0.001). The plasma MMP-7 threshold of 12.1 ng/mL was significantly associated with both all cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91-61.23 and 5.41-44.34, respectively, P < 0.001). MMP-7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP-7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DLCO ) (r = -0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DLCO (r = 0.32, P = 0.001). CONCLUSION: This study confirms that MMP-7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied. PMID- 27761980 TI - The effects of administration of the Lactobacillus gasseri strain CP2305 on quality of life, clinical symptoms and changes in gene expression in patients with irritable bowel syndrome. AB - AIMS: To clarify the effects of Lactobacillus gasseri CP2305 (CP2305) on quality of life and clinical symptoms and its functional mechanisms in patients with irritable bowel syndrome (IBS). METHODS AND RESULTS: After the patients were administered CP2305 daily for 4 weeks, the IBS-severity index score was significantly improved compared with that of the placebo group, and this improvement was accompanied by a reduction in health-related worry and changes in intestinal microbiota. The gene expression profiling of the peripheral blood leucocytes showed that CP2305 treatment significantly up-regulated genes related to eukaryotic initiation factor 2 (EIF2) signalling. Eighty-two genes were down regulated in IBS patients compared with healthy controls. The expression of 23 of these genes exhibited a CP2305-dependent increase associated with an improvement in IBS severity. The majority of the restored genes were related to EIF2 signalling. CONCLUSIONS: CP2305 administration is a potential candidate therapeutic option for patients with IBS. SIGNIFICANCE AND IMPACT OF THE STUDY: Although probiotics have been proposed to benefit IBS patients, objective clinical evidence and elucidation of the functional mechanism remain insufficient. Our study demonstrated that CP2305 administration beneficially influences IBS patients in both subjective and objective evaluations, and gene expression profiling provided insights into the functional mechanism. PMID- 27761981 TI - Dialysate bicarbonate variation in maintenance hemodiafiltration patients: Impact on serum bicarbonate, intradialytic hypotension and interdialytic weight gain. AB - INTRODUCTION: The dialysate bicarbonate (DB) influences the acid-base balance in dialysis patients. Very low and high serum bicarbonate (SB) have been related with a higher mortality. Acid-base balance also has been associated with hemodynamic effects in these patients. The trial aim was to compare the effect of DB concentration variation on SB levels in maintenance hemodiafiltration (HDF) patients and the effect on intradialytic hypotension and interdialytic weight gain. METHODS: A prospective study, with 9 months of follow-up, involving 93 patients, divided in two groups: group 1 and group 2 with a DB of 34 mmol/L and 30 mmol/L, respectively, with monitoring of pre and post HDF SB, intradialytic hypotension, and interdialytic weight gain. FINDINGS: Pre dialysis SB was higher in group 1: median concentration of 22.7 mmol/L vs. 21.1 mmol/L (P < 0.001). Post dialysis SB levels were higher in group 1: median concentration of 28.0 mmol/L vs. 25.3 mmol/L (P < 0.001). Post dialysis SB in alkalotic range was only detected in group 1 (51.2% of the patients). No significant differences were detected in intradialytic hypotension rate [28.0 vs. 27.4 episodes per 1000 sessions in group 1 and 2, respectively, (P = 0.906)] or in average interdialytic weight gain [2.9% vs. 3.0% in group 1 and 2, respectively, (P = 0.710)]. DISCUSSION: DB of 30 mmol/L appears to be associated with SB levels closer to physiological levels than 34 mmol/L. The bicarbonate dialysate, in the tested concentrations, did not appear to have a significant impact on intradialytic hypotension and interdialytic weight gain in maintenance HDF patients. PMID- 27761982 TI - Assessment of tear film osmolarity using the TearLabTM osmometer in normal dogs and dogs with keratoconjunctivitis sicca. AB - OBJECTIVE: To evaluate repeatability and reproducibility of tear osmolarity measured using the TearLabTM osmometer in normal dogs and to assess its diagnostic potential in dogs with keratoconjunctivitis sicca (KCS). ANIMALS STUDIED: Beagle dogs; six normal and five with KCS. PROCEDURES: Tear osmolarity and Schirmer tear test-1 (STT-1) values were obtained at various times. Normal dogs were assessed for diurnal variation and repeatability and reproducibility of measurements. Dogs with KCS were evaluated before and after 5 months' topical twice-daily therapy with 2% cyclosporine. RESULTS: Mean +/- SD tear osmolarity (mOsm/L) was significantly higher in normal dogs (337.4 +/- 16.2) than in dogs with KCS before therapy (306.2 +/- 18.0; P < 0.0001), but not following therapy with 2% cyclosporine (330.5 +/- 13.7; P = 1.00). Osmolarity readings lower than 325.5 mOsm/L were suggestive of KCS (84.8% sensitivity and 87.1% specificity). In normal dogs, tear osmolarity readings were stable during the daytime (P = 0.99). Repeated measurements revealed high variability and typically poor-to-moderate repeatability and reproducibility, although this was improved by taking three successive measurements at each session. Considering combined data from all dogs, a positive correlation existed between STT-1 and tear osmolarity measurements (Pearson's correlation test, P = 0.04, r = 0.62). CONCLUSIONS: Canine tear osmolarity as determined by TearLabTM osmometer was variable, required multiple readings to be informative, and differed from values reported for humans. Dogs with KCS had a lower tear osmolarity than did normal dogs, and this increased following cyclosporine therapy. PMID- 27761977 TI - Concomitant differentiation of a population of mouse embryonic stem cells into neuron-like cells and schwann cell-like cells in a slow-flow microfluidic device. AB - BACKGROUND: To send meaningful information to the brain, an inner ear cochlear implant (CI) must become closely coupled to as large and healthy a population of remaining spiral ganglion neurons (SGN) as possible. Inner ear gangliogenesis depends on macrophage migration inhibitory factor (MIF), a directionally attractant neurotrophic cytokine made by both Schwann and supporting cells (Bank et al., 2012). MIF-induced mouse embryonic stem cell (mESC)-derived "neurons" could potentially substitute for lost or damaged SGN. mESC-derived "Schwann cells" produce MIF, as do all Schwann cells (Huang et al., a; Roth et al., 2007; Roth et al., 2008) and could attract SGN to a "cell-coated" implant. RESULTS: Neuron- and Schwann cell-like cells were produced from a common population of mESCs in an ultra-slow-flow microfluidic device. As the populations interacted, "neurons" grew over the "Schwann cell" lawn, and early events in myelination were documented. Blocking MIF on the Schwann cell side greatly reduced directional neurite outgrowth. MIF-expressing "Schwann cells" were used to coat a CI: Mouse SGN and MIF-induced "neurons" grew directionally to the CI and to a wild-type but not MIF-knockout organ of Corti explant. CONCLUSIONS: Two novel stem cell-based approaches for treating the problem of sensorineural hearing loss are described. Developmental Dynamics 246:7-27, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27761983 TI - Feasibility and Acceptability of the 'HABIT' Group Programme for Comorbid Bipolar and Alcohol and Substance use Disorders. AB - OBJECTIVES: We investigated the feasibility and acceptability of an integrated group therapy (called HABIT) for comorbid bipolar disorder (BD) and alcohol and substance use disorders (ASUD) (BD-ASUD), a disabling clinical presentation for which no specific treatment has been validated. The 14-session HABIT programme employs psychoeducation-oriented cognitive-behaviour therapy (CBT) followed by mindfulness-based relapse prevention (MBRP) therapy. METHOD: Potential group participants were recruited from adult clients with a DSM-IV diagnosis of BD and an ASUD who were referred by their treating clinician. Observer-rated changes in mood symptoms and ASUD, attendance rates and subjective feedback are reported. RESULTS: Eight of 12 clients referred to the programme initially agreed to join the group, six attended the first group session and five clients completed the programme. Group mean scores for mood symptoms improved over time, with slightly greater reductions in depression during the first module. About 50% of individuals showed clinically significant improvement (>=30% reduction) in alcohol and substance use. Attendance rates showed some variability between individuals and across sessions, but the average attendance rate of the group was marginally higher for the first module (86%) as compared with the second module (77%). Most clients reported high levels of general satisfaction with a group specifically targeted at individuals with BD-ASUD. CONCLUSION: This small pilot study suggests our intensive group therapy is acceptable and feasible. If findings are replicated, we may have identified a therapy that, for the first time, leads to improvement in both mood and substance use outcomes in clients with difficult-to-treat comorbid BD-ASUD. Copyright (c) 2016 John Wiley & Sons, Ltd. Key Practitioner Message Comorbidity between bipolar and alcohol and substance use disorders (BD-ASUD) is frequent and highly disabling; Therapeutic research on approaches that can simultaneously help BD and ASUD is lacking; Previous research highlights the need for integrated treatment of both conditions but showed improvements limited to either element of the comorbid disorder; This pilot study supports the feasibility and acceptability of an intensive, 14 session group therapy programme that integrates CBT and mindfulness approaches. PMID- 27761985 TI - Alternating Sequence Control for Carboxylic Acid and Hydroxy Pendant Groups by Controlled Radical Cyclopolymerization of a Divinyl Monomer Carrying a Cleavable Spacer. AB - By utilizing features of the hemiacetal ester (HAE) bond: easy formation from vinyl ether and carboxylic acid and easy cleavage into different functional groups (-COOH and -OH), we achieved control of the alternating sequence of two functional pendant groups of a vinyl copolymer. Methacrylate- and acrylate-based vinyl groups were connected through HAE bonds to prepare a cleavable divinyl monomer, which was cyclo-polymerized under optimized conditions in a ruthenium catalyzed living radical polymerization. Subsequent cleavage of the HAE bonds in the resultant cyclo-pendant led to a copolymer consisting of alternating methacrylic acid and 2-hydroxyethyl acrylate units as analyzed by 13 C NMR spectroscopy. The alternating sequence of -COOH and -OH pendants specifically provided a lower critical solution temperature (LCST) in an ether solvent, which was not observed with the random copolymer of same composition ratio. PMID- 27761984 TI - Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes. AB - In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon-like peptide-1 (GLP-1) secretion. We evaluated the effects of metformin on serum 3-O methylglucose (3-OMG; a marker of glucose absorption) and plasma total GLP-1 concentrations during a standardized intraduodenal infusion of glucose and 3-OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double-blind, randomized, crossover design (14 days' washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3-OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3-OMG ( P < .001) and higher plasma total GLP-1 ( P = .003) concentrations. The increment in plasma GLP-1 after metformin vs placebo was related to the reduction in serum 3-OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP-1 secretion in type 2 diabetes. PMID- 27761986 TI - Power Difference and Risk Perception: Mapping Vulnerability within the Decision Process of Pregnant Women towards Clinical Trial Participation in an Urban Middle Income Setting. AB - To address the burden of maternal morbidity and mortality in low- and middle income countries (LMICs), research with pregnant women in these settings is increasingly common. Pregnant women in LMIC-context may experience vulnerability related to giving consent to participate in a clinical trial. To recognize possible layers of vulnerability this study aims to identify factors that influence the decision process towards clinical trial participation of pregnant women in an urban middle-income setting. This qualitative research used participant observation, in-depth interviews, and focus group discussion with medical staff and pregnant women eligible for trial participation, at a regional hospital in Accra, Ghana. Besides lack of familiarity with modern scientific concepts, specific factors influencing the decision-making process were identified. These include a wide power difference between health provider and patient, and a different perception of risk through externalization of responsibility of risk management within a religious context as well as a context shaped by authority. Also, therapeutic misconception was observed. The combination of these factors ensued women to rely on the opinion of the medical professional, rather than being guided by their own motivation to participation. Although being a (pregnant) woman per se should not render the label of being vulnerable, this study shows there are factors that influence the decision process of pregnant woman towards trial participation in a LMIC context that can result in vulnerability. The identification of context-specific factors that can create vulnerability facilitates adaptation of the design and conduct of research in a culturally competent manner. PMID- 27761987 TI - Long-term effect of exercise on improving fatty liver and cardiovascular risk factors in obese adults: A 1-year follow-up study. AB - Exercise training can reduce hepatic fat accumulation and cardiovascular risk among patients with non-alcoholic fatty liver disease (NAFLD), but how long these benefits extend beyond the period of active intervention is unclear. Intrahepatic triglyceride (IHTG) content, measured by proton magnetic resonance spectroscopy, and metabolic risk factors among 220 obese people with NAFLD, who were randomly assigned to vigorous/moderate exercise, moderate exercise or no exercise (control), were assessed at 1 year after the 12-month exercise intervention. IHTG content was significantly reduced in the 2 exercise groups compared with the control group over the 12-month active intervention. It was significantly lower (by -2.39%) in the vigorous/moderate exercise group compared with the control group at the 1-year follow-up (95% confidence interval -4.72 to -0.05%; P = .045). Waist circumference and blood pressure remained significantly lower in the vigorous/moderate exercise group and the moderate exercise group compared with the control group at the 1-year follow-up. Visceral adipose fat remained significantly reduced, but with no differences among 3 groups. These findings suggest 12-month exercise intervention induced reductions in hepatic fat accumulation, abdominal obesity and blood pressure for up to 1 year after the active intervention, with some attenuation of the benefits. PMID- 27761988 TI - Delivering Structural Information on the Polar Face of Membrane-Active Peptides: 19 F-NMR Labels with a Cationic Side Chain. AB - Conformationally constrained non-racemizing trifluoromethyl-substituted lysine isosteres [(E)- and (Z)-TCBLys] with charged side chains are presented as a new type of 19 F-NMR labels for peptide studies. Design of the labels, their synthesis, incorporation into peptides and experimental demonstration of their application for solid state NMR studies of membrane-active peptides are described. A series of fluorine-labeled analogues of the helical amphipathic antimicrobial peptide PGLa(Nle) was obtained, in which different lysine residues in the original peptide sequence were replaced, one at a time, by either (E)- or (Z)-TCBLys. Antimicrobial activities of the synthesized analogues were practically the same as those of the parent peptide. The structural and orientational parameters of the helical PGLa(Nle) peptide in model bilayers, as determined using the novel labels confirmed and refined the previously known structure. (E)- and (Z)-TCBLys, as a set of cationic 19 F-NMR labels, were shown to deliver structural information about the charged face of amphipathic peptides by solid state 19 F-NMR, previously inaccessible by this method. PMID- 27761989 TI - The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. AB - AIMS: Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on beta-cell function in humans and the direct effects of propionate on isolated human islets in vitro. MATERIALS AND METHODS: For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon. Acute insulin, GLP-1 and non-esterified fatty acid (NEFA) levels were quantified pre- and post-supplementation in response to a mixed meal test. Expression of the SCFA receptor FFAR2 in human islets was determined by western blotting and immunohistochemistry. Dynamic insulin secretion from perifused human islets was quantified by radioimmunoassay and islet apoptosis was determined by quantification of caspase 3/7 activities. RESULTS: Colonic propionate delivery in vivo was associated with improved beta-cell function with increased insulin secretion that was independent of changes in GLP-1 levels. Human islet beta-cells expressed FFAR2 and propionate potentiated dynamic glucose-stimulated insulin secretion in vitro, an effect that was dependent on signalling via protein kinase C. Propionate also protected human islets from apoptosis induced by the NEFA sodium palmitate and inflammatory cytokines. CONCLUSIONS: Our results indicate that propionate has beneficial effects on beta-cell function in vivo, and in vitro analyses demonstrated that it has direct effects to potentiate glucose stimulated insulin release and maintain beta-cell mass through inhibition of apoptosis. These observations support ingestion of propiogenic dietary fibres to maintain healthy glucose homeostasis. PMID- 27761991 TI - Energetic N-Nitramino/N-Oxyl-Functionalized Pyrazoles with Versatile pi-pi Stacking: Structure-Property Relationships of High-Performance Energetic Materials. AB - N-Nitramino/N-oxyl functionalization strategies were employed to investigate structure-property relationships of energetic materials. Based on single-crystal diffraction data, pi-pi stacking of pyrazole backbones can be tailored effectively by energetic functionalities, thereby resulting in diversified energetic compounds. Among them, hydroxylammonium 4-amino-3,5-dinitro-1H-pyrazol 1-olate and dipotassium N,N'-(3,5-dinitro-1H-pyrazol-1,4-diyl)dinitramidate, with unique face-to-face pi-pi stacking, can be potentially used as a high-performance explosive and an energetic oxidizer, respectively. PMID- 27761990 TI - Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase-4 inhibitor, evogliptin (DA-1229). AB - Evogliptin is a novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin in participants with renal impairment (RI). An open-label, parallel-group clinical study was conducted in participants with mild, moderate and severe RI and in matched participants with normal renal function (NRF). A single oral 5-mg dose of evogliptin was administered and serial blood and urine samples were obtained to assess the PK and PD characteristics of evogliptin. Baseline urine samples were collected to evaluate endogenous CYP3A metabolic markers. The plasma exposure to evogliptin and degree of DPP-4 activity inhibition increased with decreasing renal function. The mean areas under the concentration-time curves from 0 to 120 hours were increased 1.2-, 1.8- and 1.98-fold in the mild, moderate and severe RI groups, respectively, compared with the NRF group. The levels of CYP3A metabolic markers were lower in the RI group than in the NRF group. The increase in the plasma concentration of evogliptin is unlikely to result in changes in its efficacy or safety, considering the results of previous clinical studies. PMID- 27761992 TI - Obesity and hypertension in Australian young people: results from the Australian Health Survey 2011-2012. AB - BACKGROUND: Few studies have focused on the prevalence of obesity and hypertension among young people (ages 15-24). AIM: To characterise the prevalence of obesity and systolic hypertension in young people aged 15-24 years across Australia. METHODS: Using data from the 2011-2012 Australian Health Survey, a national cross-sectional population-based survey, we included 2163 young people aged 15-24 years. Risk factors were estimated using multinomial logistic regression. RESULTS: The prevalence of obesity increased from 8% to 15% through the ages of 15-24 among males, but the prevalence of overweight and obesity were both 14% for females across all age groups. Low levels of physical activity were a strong risk factor for obesity for both males (odds ratio (OR) 5.95, 95% confidence intervals (CI)1.83-19.36) and females (OR 3.20 95% CI 0.69-14.87). Low socioeconomic status was associated with obesity among females only (first quintile OR 4.65, 95% CI 1.97-10.99). Although the prevalence of hypertension was low (4% males, 3% females), the prevalence of high normal blood pressure was substantial, especially among males (28% males, 14% females). CONCLUSIONS: Overweight, obesity and high normal blood pressure were highly prevalent among Australian young people. Low levels of physical activity were identified as a risk factor for obesity for both male and females. Programmes targeting physical activity participation may need to be tailored differently for males and females, with a focus on females during early adolescence but early adult life for males. PMID- 27761993 TI - Implementing an 'Interprofessional fair' for pre-clinical medical undergraduates. PMID- 27761994 TI - The dilemma of the women's health educator. PMID- 27761995 TI - The feedback game: missed opportunities in workplace-based learning. PMID- 27761996 TI - Student-as-teacher: the creation of a medical student-driven education elective. PMID- 27761997 TI - Implementation of point-of-care tools for assessment of teaching. PMID- 27761998 TI - BROWnies: bioethics rounds on the wards. PMID- 27762000 TI - Novel mobile application to improve student feedback. PMID- 27762001 TI - A near-peer talk to allay Year 1 student anxieties and misconceptions over assessments. PMID- 27762003 TI - The hospital mortuary: learning about death... and life. PMID- 27762002 TI - Teaching is the best way to learn: student-led screencasting. PMID- 27762004 TI - SBAR: towards a common interprofessional team-based communication tool. PMID- 27762005 TI - Revising residents' addiction experience: a 1-week intensive course. PMID- 27762007 TI - The case for intimate partner violence education: early, essential and evidence based. PMID- 27762006 TI - Resident grand rounds. PMID- 27762009 TI - Digital interactive learning during idle time at work. PMID- 27762010 TI - Host community perspectives on trainees participating in short-term experiences in global health. AB - CONTEXT: High-income country (HIC) trainees are undertaking global health experiences in low- and middle-income country (LMIC) host communities in increasing numbers. Although the benefits for HIC trainees are well described, the benefits and drawbacks for LMIC host communities are not well captured. OBJECTIVES: This study evaluated the perspectives of supervising physicians and local programme coordinators from LMIC host communities who engaged with HIC trainees in the context of the latter's short-term experiences in global health. METHODS: Thirty-five semi-structured interviews were conducted with LMIC host community collaborators with a US-based, non-profit global health education organisation. Interviews took place in La Paz, Bolivia and New Delhi, India. Interview transcripts were assessed for recurrent themes using thematic analysis. RESULTS: Benefits for hosts included improvements in job satisfaction, local prestige, global connectedness, local networks, leadership skills, resources and sense of efficacy within their communities. Host collaborators called for improvements in HIC trainee attitudes and behaviours, and asked that trainees not make promises they would not fulfil. Findings also provided evidence of a desire for parity between the opportunities afforded to US-based staff and those available to LMIC-based partners. CONCLUSIONS: This study provides important insights into the perspectives of LMIC host community members in the context of short-term experiences in global health for HIC trainees. We hope to inform the behaviour of HIC trainees and institutions with regard to international partnerships and global health activities. PMID- 27762011 TI - Measuring resilience in palliative care workers using the situational judgement test methodology. AB - OBJECTIVES: Relatively little research has been directed toward the assessment of resilience in the health care context. Given the stressors associated with the provision of health care, the present study describes the development and evaluation of a situational judgement test (SJT) designed to assess resilience in palliative care health care workers. METHODS: An SJT was developed to measure behaviours associated with resilience in a palliative care context. Next, SJT reliability and validity analyses were assessed in a sample of acute ward, hospice and community palliative care workers (n = 284). RESULTS: Findings showed the SJT to have a negative association with self-reported sickness absence and a positive association with well-being and employee attitudes (in terms of turnover intention, organisational commitment and job satisfaction). A series of two-wave longitudinal (hierarchical) regressions showed the SJT was predictive of well being and employee attitudes at two time-points (4 weeks apart) over and above self-report measures of resilience, education and experience, and the Big Five personality dimensions of Emotional Stability and Openness. Reliability analyses showed the SJT to have acceptable test-retest scores (rho = 0.71) and high internal consistency (alpha = 0.91). CONCLUSIONS: The study findings suggest that the SJT is a valid assessment of resilience in at-risk workers and can be used in either summative or formative assessment under the right set of conditions. More research is needed to test the hypothesis that the SJT might be used as a formative tool to develop workplace resilience. PMID- 27762012 TI - A quick and easy makeshift suture pad. PMID- 27762013 TI - A novel approach to virtual patient simulation using natural language processing. PMID- 27762014 TI - Identifying teaching award criteria for health professional educators. PMID- 27762015 TI - Using high-fidelity simulation for critical event training. PMID- 27762017 TI - Shared team leadership training through pre-clerkship team-based learning. PMID- 27762016 TI - SkypeTM : a platform for remote, interactive skills instruction. PMID- 27762018 TI - South American investigation on professionalism: a theoretical framework. PMID- 27762019 TI - Art and movement in nutrition education. PMID- 27762020 TI - Health care disparities education using the implicit association test. PMID- 27762021 TI - Healing conversations in medicine: Making Every Encounter Therapeutic. PMID- 27762022 TI - Game theory and strategy in medical training. AB - OBJECTIVE: This paper analyses how game theory can provide a framework for understanding the strategic decision-making that occurs in everyday scenarios in medical training and practice, and ultimately serves as a tool for improving the work environment and patient care. Game theory has been applied to a variety of fields outside of its native economics, but has not been thoroughly studied in the context of health care provision. METHODS: The paper discusses four of the most common 'games' and applies each to a scenario in medicine to provide new insight on the incentives and drivers for certain types of behaviour and a deeper understanding of why certain results are valued more strongly than others. CONCLUSIONS: Using game theory as an integrative tool, in conjunction with good judgement and a sound knowledge base, trainees and physicians can work to better recognise where competing priorities exist, understand the motivations and interactions of the various players, and learn to adjust their approaches in order to 'change the game' when their preferred outcome is not the most likely one. PMID- 27762023 TI - Scientific speaker apprenticeship programme. PMID- 27762024 TI - Using critical friends to build writing success. PMID- 27762025 TI - Facilitating guided reflections on leadership activities. PMID- 27762026 TI - A national collaboration to improve OSCE delivery. PMID- 27762027 TI - Reflections on our current history. PMID- 27762028 TI - Computer dissection program to enhance understanding of ultrasound anatomy. PMID- 27762029 TI - Basic life support: students teaching community health workers. PMID- 27762030 TI - More productive ways to think about learning, knowledge and education. PMID- 27762031 TI - Boosters for clerkship professionalism curriculum: online self-learning modules. PMID- 27762032 TI - Use of WhatsApp in assisting psychiatry learning. PMID- 27762033 TI - Getting SMART about teaching objective writing. PMID- 27762034 TI - Interprofessional education: 50 years and counting. PMID- 27762035 TI - Teaching medical law and ethics using letter-based narrative. PMID- 27762036 TI - A systematic review of intimate partner violence educational interventions delivered to allied health care practitioners. AB - CONTEXT: Intimate partner violence (IPV) is a significant cause of morbidity and mortality in women worldwide. Numerous health organisations have called for increased education for health care practitioners who encounter IPV patients and the first clinical guidelines for health services responding to IPV were recently published. This renewed focus has created a need to examine the current evidence for IPV education so that it may inform the next generation of educational interventions. OBJECTIVES: This study was designed to examine the effects of IPV educational interventions on the knowledge, attitudes, skills and behaviours of allied health care practitioners (AHCPs). METHODS: We conducted a systematic search of multiple databases up to the end of May 2015. We selected studies that included IPV educational interventions for AHCPs and that measured knowledge, attitude, skill or behavioural outcomes. Studies were evaluated based on methodological quality, education context and outcome measurement. RESULTS: We found 2757 articles from which 18 were selected for inclusion. Study participants included nurses, dentists, social workers and paramedics. Educational interventions ranged widely in length, delivery format and topics covered. Findings indicate that improvements in some knowledge, attitudes, skills and behaviours are associated with education, although the lack of high-quality studies indicates that conclusions should be treated with caution. CONCLUSIONS: Future studies should be conducted using rigorous methodology and validated instruments to measure evidence-based outcomes and should target a wider range of AHCPs. Recommendations are provided on education content and delivery, study methodology and outcome measurement based on insights gained from selected studies. PMID- 27762038 TI - Really Good Stuff reviewers for 2016. PMID- 27762037 TI - Licence to commence clinical day: the L-Plate test. PMID- 27762039 TI - Changing the culture of the morbidity and mortality conference. PMID- 27762040 TI - Photoassisted Oxygen Reduction Reaction in H2 -O2 Fuel Cells. AB - The oxygen reduction reaction (ORR) is a key step in H2 -O2 fuel cells, which, however, suffers from slow kinetics even for state-of-the-art catalysts. In this work, by making use of photocatalysis, the ORR was significantly accelerated with a polymer semiconductor (polyterthiophene). The onset potential underwent a positive shift from 0.66 to 1.34 V, and the current was enhanced by a factor of 44 at 0.6 V. The improvement was further confirmed in a proof-of-concept light driven H2 -O2 fuel cell, in which the open circuit voltage (Voc ) increased from 0.64 to 1.18 V, and the short circuit current (Jsc ) was doubled. This novel tandem structure combining a polymer solar cell and a fuel cell enables the simultaneous utilization of photo- and electrochemical energy, showing promising potential for applications in energy conversion and storage. PMID- 27762041 TI - Acute resistance exercise using free weights on aortic wave reflection characteristics. AB - Aortic wave reflection characteristics such as the augmentation index (AIx), wasted left ventricular pressure energy (DeltaEw ) and aortic haemodynamics, such as aortic systolic blood pressure (ASBP), strongly predict cardiovascular events. The effects of acute resistance exercise (ARE) using free-weight exercises on these characteristics are unknown. Therefore, we sought to determine the effects of acute free-weight resistance exercise on aortic wave reflection characteristics and aortic haemodynamics in resistance-trained individuals. Fifteen young, healthy resistance-trained (9 +/- 3 years) individuals performed two randomized sessions consisting of an acute bout of free-weight resistance exercise (ARE) or a quiet control (CON). The ARE consisted of three sets of 10 repetitions at 75% one repetition maximum for squat, bench press and deadlift. In CON, the participants rested in the supine position for 30 min. Measurements were made at baseline before sessions and 10 min after sessions. A two-way ANOVA was used to compare the effects of condition across time. There were no significant interactions for aortic or brachial blood pressures. Compared to rest, there were significant increases in augmentation pressure (rest: 5.7 +/- 3.0 mmHg; recovery: 10.4 +/- 5.7 mmHg, P = 0.002), AIx (rest: 116.8 +/- 4.2%; recovery: 123.2 +/- 8.4%, P = 0.002), AIx normalized at 75 bpm (rest: 5.2 +/- 7.6%; recovery: 27.3 +/ 13.2%, P<0.0001), DeltaEw (rest: 1215 +/- 674 dynes s cm-2 ; recovery: 2096 +/- 1182 dynes s cm-2 , P = 0.008), and there was a significant decrease in transit time of the reflected wave (rest: 150.7 +/- 5.8 ms; recovery 145.5 +/- 5.6 ms, P<0.001) during recovery from ARE compared to CON. These data suggest that ARE using free-weight exercises may have no effect on aortic and brachial blood pressure but may significantly alter aortic wave reflection characteristics. PMID- 27762042 TI - Electrophilic Aromatic Substitution with Silicon Electrophiles: Catalytic Friedel Crafts C-H Silylation. AB - Electrophilic aromatic substitution is a fundamental reaction in synthetic chemistry. It converts C-H bonds of sufficiently nucleophilic arenes into C-X and C-C bonds using either stoichiometrically added or catalytically generated electrophiles. These reactions proceed through Wheland complexes, cationic intermediates that rearomatize by proton release. Hence, these high-energy intermediates are nothing but protonated arenes and as such strong Bronsted acids. The formation of protons is an issue in those rare cases where the electrophilic aromatic substitution is reversible. This situation arises in the electrophilic silylation of C-H bonds as the energy of the intermediate Wheland complex is lowered by the beta-silicon effect. As a consequence, protonation of the silylated arene is facile, and the reverse reaction usually occurs to afford the desilylated arene. Several new approaches to overcome this inherent challenge of C-H silylation by SE Ar were recently disclosed, and this Minireview summarizes this progress. PMID- 27762043 TI - TLR4-induced B7-H1 on keratinocytes negatively regulates CD4+ T cells and CD8+ T cells responses in oral lichen planus. AB - Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4+ T cells and CD8+ T cells. B7-H1 induced by Toll-like receptors (TLRs) can suppress T-cell immune reaction, thereby resulting in immune tolerance. However, the role of TLR mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-kappaB or PI3K/mTOR pathway downregulated B7 H1 transcriptional expression. Moreover, TLR4-stimulated oral keratinocytes inhibited the proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and simultaneously prompted their apoptosis. Blockade of keratinocyte-associated B7 H1 restored the declined proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and prevented their increased apoptosis. Therefore, TLR4-upregulated B7-H1 on keratinocytes could decelerate immune responses of CD4+ T cells and CD8+ T cells in OLP. PMID- 27762044 TI - Cathepsin B-Specific Metabolic Precursor for In Vivo Tumor-Specific Fluorescence Imaging. AB - Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor-specific metabolic precursors that can generate unnatural glycans on the tumor-cell surface. A cathepsin B-specific cleavable substrate (KGRR) conjugated with triacetylated N-azidoacetyl-d-mannosamine (RR-S-Ac3 ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR-S-Ac3 ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye-labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor-bearing mice. Therefore, our RR-S-Ac3 ManNAz is promising for research in tumor-specific imaging or drug delivery. PMID- 27762045 TI - Exploiting the Imidazolium Effect in Base-free Ammonium Enolate Generation: Synthetic and Mechanistic Studies. AB - N-Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition-cyclization reactions using different alpha,beta-unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the "imidazolium" effect in ammonium enolate formation and have highlighted key differences with traditional base-mediated processes. PMID- 27762047 TI - A Responsive Battery with Controlled Energy Release. AB - A new type of responsive battery with the fascinating feature of pressure perceptibility has been developed, which can spontaneously, timely and reliably control the power outputs (e.g., current and voltage) in response to pressure changes. The device design is based on the structure of the Zn-air battery, in which graphene-coated sponge serves as pressure-sensitive air cathode that endows the whole system with the capability of self-controlled energy release. The responsive batteries exhibit superior battery performance with high open-circuit voltage (1.3 V), and competitive areal capacity of 1.25 mAh cm-2 . This work presents an important move towards next-generation intelligent energy storage devices with energy management function. PMID- 27762046 TI - Immunochip analysis identifies novel susceptibility loci in the human leukocyte antigen region for acquired thrombotic thrombocytopenic purpura. AB - Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02 3.27, P = 1.64 * 10-14 ). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 * 10-5 to 7.60 * 10-5 ). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 * 10-19 ). Imputation of classic HLA genes followed by stepwise conditional analysis revealed that the combination of rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in acquired TTP. Our results refined the association of the HLA class II locus with acquired TTP, confirming its importance in the etiology of this autoimmune disease. PMID- 27762048 TI - Production of RbCs Molecules in the Rovibronic Ground State via Short-Range Photoassociation to the 2 1 Pi1 , 2 3 Pi1 , and 3 3 Sigma1+ States. AB - We report the production of ultracold 85 Rb133 Cs molecules in their rovibronic ground state X 1 Sigma+ (v=0; J=0), by short-range photoassociation (PA) to the 2 1 Pi1 , 2 3 Pi1 , and 3 3 Sigma1+ states. In the PA frequency range from 11650 to 12150 cm-1 (corresponding to energy levels 15500-16000 cm-1 above the bottom of the X potential), we have observed 40 sets of new PA lines. For selected PA states, we investigate vibrational branching, rotational branching, and saturation behavior. Among these 40 new PA lines, the 3 3 Sigma1+ (v=3) state has the highest molecule production rate of 2 x 103 molecules s-1 into the rovibronic ground state. PMID- 27762049 TI - Testing genotyping strategies for ultra-deep sequencing of a co-amplifying gene family: MHC class I in a passerine bird. AB - Characterization of highly duplicated genes, such as genes of the major histocompatibility complex (MHC), where multiple loci often co-amplify, has until recently been hindered by insufficient read depths per amplicon. Here, we used ultra-deep Illumina sequencing to resolve genotypes at exon 3 of MHC class I genes in the sedge warbler (Acrocephalus schoenobaenus). We sequenced 24 individuals in two replicates and used this data, as well as a simulated data set, to test the effect of amplicon coverage (range: 500-20 000 reads per amplicon) on the repeatability of genotyping using four different genotyping approaches. A third replicate employed unique barcoding to assess the extent of tag jumping, that is swapping of individual tag identifiers, which may confound genotyping. The reliability of MHC genotyping increased with coverage and approached or exceeded 90% within-method repeatability of allele calling at coverages of >5000 reads per amplicon. We found generally high agreement between genotyping methods, especially at high coverages. High reliability of the tested genotyping approaches was further supported by our analysis of the simulated data set, although the genotyping approach relying primarily on replication of variants in independent amplicons proved sensitive to repeatable errors. According to the most repeatable genotyping method, the number of co-amplifying variants per individual ranged from 19 to 42. Tag jumping was detectable, but at such low frequencies that it did not affect the reliability of genotyping. We thus demonstrate that gene families with many co-amplifying genes can be reliably genotyped using HTS, provided that there is sufficient per amplicon coverage. PMID- 27762050 TI - Paediatric tracheostomy speaking valves: our experience of forty-two children with an adapted Passy-Muir(r) speaking valve. PMID- 27762051 TI - Proceedings of the 20th Annual Conference of the European Society for Domestic Animal Reproduction (ESDAR) and the 13th Conference of the Spanish Association for Animal Reproduction (AERA), Lisbon, Portugal, 27-29 October 2016. PMID- 27762052 TI - Generation of human organs in pigs via interspecies blastocyst complementation. AB - More than eighteen years have passed since the first derivation of human embryonic stem cells (ESCs), but their clinical use is still met with several challenges, such as ethical concerns regarding the need of human embryos, tissue rejection after transplantation and tumour formation. The generation of human induced pluripotent stem cells (iPSCs) enables the access to patient-derived pluripotent stem cells (PSCs) and opens the door for personalized medicine as tissues/organs can potentially be generated from the same genetic background as the patient recipients, thus avoiding immune rejections or complication of immunosuppression strategies. In this regard, successful replacement, or augmentation, of the function of damaged tissue by patient-derived differentiated stem cells provides a promising cell replacement therapy for many devastating human diseases. Although human iPSCs can proliferate unlimitedly in culture and harbour the potential to generate all cell types in the adult body, currently, the functionality of differentiated cells is limited. An alternative strategy to realize the full potential of human iPSC for regenerative medicine is the in vivo tissue generation in large animal species via interspecies blastocyst complementation. As this technology is still in its infancy and there remains more questions than answers, thus in this review, we mainly focus the discussion on the conceptual framework, the emerging technologies and recent advances involved with interspecies blastocyst complementation, and will refer the readers to other more in-depth reviews on dynamic pluripotent stem cell states, genome editing and interspecies chimeras. Likewise, other emerging alternatives to combat the growing shortage of human organs, such as xenotransplantation or tissue engineering, topics that has been extensively reviewed, will not be covered here. PMID- 27762053 TI - Editorial. PMID- 27762055 TI - Workshops. PMID- 27762054 TI - Ovulation-inducing factor (OIF/NGF) in seminal plasma: a review and update. AB - The ovulation-inducing effect of seminal plasma was first reported in Bactrian camels over 30 years ago, and the entity responsible was dubbed 'ovulation inducing factor' (OIF). More recent studies, primarily in llamas and alpacas, characterized the biological and chemical properties of OIF and ultimately identified it as betaNGF. This recent discovery has allowed a convergence of knowledge previously separated by discipline and by mechanism; that is, neurobiology and reproductive biology, and autocrine/paracrine vs endocrine. To preserve this link, we have referred to the seminal factor as OIF/NGF. As a highly conserved protein, the implications of discoveries related to OIF/NGF in reproductive tissues extend beyond the camelid species, and results of recent studies show that the presence and function of OIF/NGF in seminal plasma are conserved among species considered to be induced ovulators as well as those considered to be spontaneous ovulators. The abundance of OIF/NGF in seminal plasma and the effects of seminal plasma on ovarian function strongly support the idea of an endocrine mode of action (i.e. systemic distribution with distant target tissues). This review is intended to provide an update on the progress in our understanding of the nature of OIF/NGF in seminal plasma and its effects on reproductive function in the female, including the effects of dose and route of administration, evidence for ovarian effects in other species, tissue sources of OIF/NGF and early findings related to the mechanism of action of OIF. PMID- 27762056 TI - Parturition effects on reproductive health in the gilt and sow. AB - In this review, we address significant characteristics of parturition in the pig and their connection to post-partum reproductive health and fertility. We discuss the normal physiology and behaviour around parturition and the effect of the second phase (expulsion of foetuses) on the third phase of parturition (expulsion of foetal membranes). In addition, we intend to cover retained placenta, and the connection to post-partum uterine health and fertility in the contemporary prolific sow. We also explore factors that support successful parturition or can cause potential problems. Successful parturition in the pig includes the possibility to express adequate maternal behaviour, rapid expulsion of the piglets, complete expulsion of the placenta, neonatal activity and colostrum intake. Abnormal incidents during any phase of parturition can cause subsequent problems. Duration of the expulsion phase of foetuses can be used as a simple measure of whether parturition is considered successful. Prolonged parturition can impair health of the sow and piglet and fertility after weaning. New insights, such as adding more fibre to sow diets during pregnancy, and especially during the period prior to farrowing, may prevent constipation, increase water intake of the sow around parturition and increase milk intake and performance of piglets. Maternal characteristics, including maternal behaviour, ease of parturition, colostrum production and piglet quality parameters, may be utilized to improve success rate of reproductive management during farrowing and early lactation. Additionally, we share some of the recent developments in methods, including ultrasonography in evaluation of post-partum uterine health. In conclusion, successful farrowing is of the greatest importance for reproductive health of the sow and survival of the piglets. We suggest connections exist among prolonged farrowing and yield of colostrum, retained placenta, development of PDS, and impaired involution of the uterus and reduced subsequent fertility. PMID- 27762057 TI - Placental metabolism: substrate requirements and the response to stress. AB - The placenta is a dynamic, metabolically active organ with significant nutrient and energy requirements for growth, nutrient transfer and protein synthesis. It uses a range of substrates to meet its energy needs and has a higher rate of oxygen (O2 ) consumption than many other foetal and adult tissues. Placental metabolism varies with species and alters in response to a range of nutritional and endocrine signals of adverse environmental conditions. The placenta integrates these signals and adapts its metabolic phenotype to help maintain pregnancy and to optimize offspring fitness by diversifying the sources of carbon and nitrogen available for energy production, hormone synthesis and foeto placental growth. The metabolic response of the placenta to adversity depends on the nature, severity and duration of the stressful challenge and on whether the insult is maternal, placental or foetal in origin. This review examines placental metabolism and its response to stresses common in pregnancy with particular emphasis on farm species like the sheep. It also considers the consequences of changes in placental metabolism for the supply of O2 and nutrients to the foetus. PMID- 27762058 TI - Improving outcome of acute lymphoblastic leukemia with a simplified protocol: report from a tertiary care center in north India. AB - BACKGROUND: The outcome of malignancies in low- and middle-income countries (LMICs) is hampered owing to numerous factors. Current protocols are complex, demanding supportive care, often not optimally available. We de-escalated the UKALL 2003 protocol to improve the outcome of acute lymphoblastic leukemia (ALL) at our center. METHODS: In 2007-2009, children were treated as per the UKALL 2003 protocol (protocol 1). In 2010 and 2011, a modified version of the UKALL 2003 (protocol 2) was followed. RESULTS: Three hundred and seventy-four children aged 5.71+3.1 (1-13) years were treated. Remission was achieved in 335 of the 338 who completed induction. Treatment-related mortality decreased significantly with the modified protocol (P <= 0.001). Relapses were similar with both protocols. Protocol used, regimen, counts at diagnosis, weight for age, gender, education of parents and occupation of caregiver were associated with the outcome of death (P < 0.05). On Cox proportional hazard analysis, patients on protocol 1, female gender and weight <=5th centile had a greater hazard of dying (0.46 [P < 0.0001]; 1.5 [P = 0.04] and 1.64 [P = 0.01]). The 3 years overall survival (OS) with protocols 1 and 2 was 54.8% (95% CI 47.4-61.7%) and 73.9% (95% CI 66-79%) (P < 0.001), respectively. The event-free survival with protocols 1 and 2 was 50.8% (95% CI 43-57%) and 65.7% (95% CI 58-72%) (P < 0.001), respectively. CONCLUSIONS: A steady improvement in survival has been observed at our center to a 3-year present OS of 73.9% with reduction in treatment intensity. The way forward for LMICs is to formulate rational treatment protocols at par with resources. PMID- 27762059 TI - Iridium(III) Complexes Bearing Pyrene-Functionalized 1,10-Phenanthroline Ligands as Highly Efficient Sensitizers for Triplet-Triplet Annihilation Upconversion. AB - "Chemistry-on-the-complex" synthetic methods have allowed the selective addition of 1-ethynylpyrene appendages to the 3-, 5-, 3,8- and 5,6-positions of IrIII coordinated 1,10-phenanthroline via Sonogashira cross-coupling. The resulting suite of complexes has given rise to the first rationalization of their absorption and emission properties as a function of the number and position of the pyrene moieties. Strong absorption in the visible region (e.g. 3,8 substituted Ir-3: lambdaabs =481 nm, epsilon=52 400 m-1 cm-1 ) and long-lived triplet excited states (e.g. 5-substituted Ir-2: tauT =367.7 MUs) were observed for the complexes in deaerated CH2 Cl2 . On testing the series as triplet sensitizers for triplet-triplet annihilation upconversion, those IrIII complexes bearing pyrenyl appendages at the 3- and 3,8-positions (Ir-1, Ir-3) were found to give optimal upconversion quantum yields (30.2 % and 31.6 % respectively). PMID- 27762060 TI - The value of direct audiology access for magnetic resonance imaging: an audit of 40 cases. PMID- 27762062 TI - Measuring primary tumor response in neuroblastoma: More than using a ruler. PMID- 27762063 TI - Peritoneal dialysis in patients with failed kidney transplant: Single centre experience. AB - AIM: To determine if patients with failing kidney transplants who opt to have peritoneal dialysis (PD) have poor short-term PD technique survival and increased rates of peritonitis. METHODS: We performed a retrospective analysis comparing 50 consecutive patients starting PD after a failed kidney transplant to 93 incident patients starting PD (matching for age, gender, diabetes causing renal failure, ethnicity and year of starting PD). RESULTS: The mean follow-up period was 26 months. PD technique survival was lower for the post-transplant cohort. However, this did not appear to be related to PD peritonitis risk; infection rate was lower in the post-transplant group albeit not statistically significant (1 in 23.6 patient months vs 1 in 22.5 patient months). There were no differences in the proportion of Gram positive: Gran negative: Culture Negative infections. The only fungal peritonitis occurred in a Control patient. Results of baseline Peritoneal Equilibration Tests were not different; D/Pcr was 0.69 for post-TP versus 0.64 for Control (P = ns), and net UF was 250 mL for post-TP versus 310 mL for Control (P = ns). PET results after 12 months were also similar. CONCLUSION: Our study found a small but significantly higher rate of PD technique failure in the post-transplant cohort, but this did not appear to be related to peritonitis rates or peritoneal membrane function. Further studies are required to explore reasons for PD technique failure in patients who have had kidney transplant, but our study supports the use of PD in selected patient from this cohort. PMID- 27762061 TI - Sero-epidemiologic study of influenza A(H7N9) infection among exposed populations, China 2013-2014. AB - BACKGROUND: The first human infections of novel avian influenza A(H7N9) virus were identified in China in March 2013. Sentinel surveillance systems and contact tracing may not identify mild and asymptomatic human infections of influenza A(H7N9) virus. OBJECTIVES: We assessed the seroprevalence of antibodies to influenza A(H7N9) virus in three populations during the early stages of the epidemic. PATIENTS/METHODS: From March 2013 to May 2014, we collected sera from the general population, poultry workers, and contacts of confirmed infections in nine Chinese provinces reporting human A(H7N9) infections and, for contacts, second sera 2-3 weeks later. We screened for A(H7N9) antibodies by advanced hemagglutination inhibition (HI) assay and tested sera with HI titers >=20 by modified microneutralization (MN) assay. MN titers >=20 or fourfold increases in paired sera were considered seropositive. RESULTS: Among general population sera (n=1480), none were seropositive. Among poultry worker sera (n=1866), 28 had HI titers >=20; two (0.11%, 95% CI: 0.02-0.44) were positive by MN. Among 61 healthcare and 117 non-healthcare contacts' sera, five had HI titers >=20, and all were negative by MN. There was no seroconversion among 131 paired sera. CONCLUSIONS: There was no evidence of widespread transmission of influenza A(H7N9) virus during March 2013 to May 2014, although A(H7N9) may have caused rare, previously unrecognized infections among poultry workers. Although the findings suggest that there were few undetected cases of influenza A(H7N9) early in the epidemic, it is important to continue monitoring transmission as virus and epidemic evolve. PMID- 27762065 TI - 32 years of experience with CO2 -LASER-assisted treatment for Zenker's Diverticulum - an update of 227 patients treated in Kiel. AB - OBJECTIVES: To underline the value of the microendoscopic CO2 -LASER-assisted treatment (MEDCO2 ) for Zenker's diverticulum by investigating a large patient cohort treated in a single medical centre. DESIGN: Retrospective cohort study of consecutive patients. SETTING: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University Kiel, Germany. PARTICIPANTS: A total of 227 patients with Zenker's diverticulum were treated by MEDCO2 , and the results were compared with those reported in the literature for the open transcervical approach (OTA) and the endoscopic staple-assisted oesophagodiverticulostomy (ESED). OUTCOME MEASUREMENTS: Data assessment regarding preoperative symptoms, perioperative management, morbidity, mortality and longtime results. Comparison of results with data from the literature regarding MEDCO2 , ESED and OTA. RESULTS: Operation duration: 25 min median; morbidity: 4.7%; mortality: 0%; mediastinitis: 0.9%; hospitalisation: 7 days; feeding tube dependency: 4 days; recurrence rate: 6.1%. Rise of body temperature above 38 degrees C and 39 degrees C in 36.7% and 12.2% of cases on first postoperative day, respectively. CONCLUSIONS: The results identify MEDCO2 as superior in comparison with ESED and OTA concerning the treatment for Zenker's diverticulum especially in terms of excellent long-term functional results and a low morbidity and mortality. The short operation time qualifies MEDCO2 as specifically suitable for the treatment of the characteristic patient cohort with Zenker's diverticulum, namely the elderly, whereas OTA should be reserved for cases with sophisticated or impossible endoscopic exposure of the pouch. The occurrence of perioperative fever can be managed with a systemic antibiotic and antipyretic medication. Although a mediastinitis as major complication is a rare event, the early introduction of its diagnosis with CT scans and consecutive therapy including thoracotomies can be lifesaving. PMID- 27762064 TI - CCND1-BCL2 Gene Network: A direct target of Amifostine in human acute megakaryocytic leukemia cells. AB - Amifostine, 2-(3-aminopropyl) aminoethyl phosphorothioate, is a broad-spectrum cytoprotective agent used to treat nuclear radiation and chemical weapon injuries. Recently, amifostine has been shown to have a profound biological influence on tumor cells. To examine the effects and mechanisms underlying the effects of amifostine on human acute megakaryocytic leukemia, we evaluated the efficacy of amifostine against Dami cells and observed a cell cycle arrest in G2 /M phase. Amifostine treatment also induced cell apoptosis of Dami cells which corresponds to formal studies. Through whole-genome microarray and bioinformatics analyses, we found that amifostine affected the gene expression of CCND1, BCL2, and CASP3 which revealed the mechanism amifostine acted on Dami cells. Thus, CCND1-BCL2 Gene Network is predicted to be a direct target of amifostine treating human acute megakaryocytic leukemia, which may provide a novel potential target for the therapy of several subtypes of human AML. PMID- 27762066 TI - A new brain dopamine-deficient Drosophila and its pharmacological and genetic rescue. AB - Dopamine (DA) is a neurotransmitter with conserved behavioral roles between invertebrate and vertebrate animals. In addition to its neural functions, in insects DA is a critical substrate for cuticle pigmentation and hardening. Drosophila tyrosine hydroxylase (DTH) is the rate limiting enzyme for DA biosynthesis. Viable brain DA-deficient flies were previously generated using tissue-selective GAL4-UAS binary expression rescue of a DTH null mutation and these flies show specific behavioral impairments. To circumvent the limitations of rescue via binary expression, here we achieve rescue utilizing genomically integrated mutant DTH. As expected, our DA-deficient flies have no detectable DTH or DA in the brain, and show reduced locomotor activity. This deficit can be rescued by l-DOPA/carbidopa feeding, similar to human Parkinson's disease treatment. Genetic rescue via GAL4/UAS-DTH was also successful, although this required the generation of a new UAS-DTH1 transgene devoid of most untranslated regions, as existing UAS-DTH transgenes express in the brain without a Gal4 driver via endogenous regulatory elements. A surprising finding of our newly constructed UAS-DTH1m is that it expresses DTH at an undetectable level when regulated by dopaminergic GAL4 drivers even when fully rescuing DA, indicating that DTH immunostaining is not necessarily a valid marker for DA expression. This finding necessitated optimizing DA immunohistochemistry, showing details of DA innervation to the mushroom body and the central complex. When DA rescue is limited to specific DA neurons, DA does not diffuse beyond the DTH-expressing terminals, such that DA signaling can be limited to very specific brain regions. PMID- 27762067 TI - SUMO E3 Ligases GmSIZ1a and GmSIZ1b regulate vegetative growth in soybean . AB - SIZ1 is a small ubiquitin-related modifier (SUMO) E3 ligase that mediates post translational SUMO modification of target proteins and thereby regulates developmental processes and hormonal and environmental stress responses in Arabidopsis. However, the role of SUMO E3 ligases in crop plants is largely unknown. Here, we identified and characterized two Glycine max (soybean) SUMO E3 ligases, GmSIZ1a and GmSIZ1b. Expression of GmSIZ1a and GmSIZ1b was induced in response to salicylic acid (SA), heat, and dehydration treatment, but not in response to cold, abscisic acid (ABA), and NaCl treatment. Although GmSIZ1a was expressed at higher levels than GmSIZ1b, both genes encoded proteins with SUMO E3 ligase activity in vivo. Heterologous expression of GmSIZ1a or GmSIZ1b rescued the mutant phenotype of Arabidopsis siz1-2, including dwarfism, constitutively activated expression of pathogen-related genes, and ABA-sensitive seed germination. Simultaneous downregulation of GmSIZ1a and GmSIZ1b (GmSIZ1a/b) using RNA interference (RNAi)-mediated gene silencing decreased heat shock-induced SUMO conjugation in soybean. Moreover, GmSIZ1RNAi plants exhibited reduced plant height and leaf size. However, unlike Arabidopsis siz1-2 mutant plants, flowering time and SA levels were not significantly altered in GmSIZ1RNAi plants. Taken together, our results indicate that GmSIZ1a and GmSIZ1b mediate SUMO modification and positively regulate vegetative growth in soybean. PMID- 27762068 TI - Procalcitonin and cytokine profiles in engraftment syndrome in pediatric stem cell transplantation. AB - BACKGROUND: Diagnosis of engraftment syndrome (ES) following allogeneic hematopoietic stem cell transplantation (HSCT) can be a challenge due to the systemic presentation and alternative etiologies. With a goal of establishing biomarkers to more accurately distinguish ES, we prospectively analyzed levels of cytokines during HSCT. PROCEDURES: We performed a prospective study of children <=21 years who underwent allogeneic HSCT. Blood samples for interleukin (IL)-6, IL-8, IL-10, IL-1b, IL-12p70, interferon-gamma, tumor necrosis factor alpha (TNF alpha) and procalcitonin were obtained from each subject prior to conditioning, at day 0, and then biweekly through engraftment and at days 30, 60 and 100. Patients were evaluated for ES, infection and acute graft-versus-host disease. Cytokines were analyzed by values at engraftment, and also compared to pre conditioning and day 0 values to evaluate for change from baseline. RESULTS: A total of 30 subjects (median age: 7 years, min.-max.: 1-21 years) were enrolled of whom 5 had ES. Characterization of the cytokine profile revealed differences between day 0 from pre-HSCT, with a trend towards differences in IL-10, IL-12p70, interferon-gamma and TNF-alpha at the time of ES. For IL8 and procalcitonin, there was evidence that the absolute difference (or fold change) between engraftment and pre-conditioning or day 0 differed according to ES. In particular, procalcitonin increased from baseline (15.1 median fold increase in ES+ versus 2.31 median fold increase in ES-, P = 0.0006, median difference: 13.8, 95% confidence interval: 6.33, 65.6). CONCLUSIONS: Our data provide one of the first prospective studies evaluating cytokines in pediatric allogeneic HSCT and suggest that elevated procalcitonin may serve as a biomarker for ES. Further studies to evaluate this finding are warranted. PMID- 27762069 TI - An introduction to microbiome analysis for human biology applications. AB - Research examining the gut microbiota is currently exploding, and results are providing new perspectives on human biology. Factors such as host diet and physiology influence the composition and function of the gut microbiota, which in turn affects human nutrition, health, and behavior via interactions with metabolism, the immune system, and the brain. These findings represent an exciting new twist on familiar topics, and as a result, gut microbiome research is likely to provide insight into unresolved biological mechanisms driving human health. However, much remains to be learned about the broader ecological and evolutionary contexts within which gut microbes and humans are affecting each other. Here, I outline the procedures for generating data describing the gut microbiota with the goal of facilitating the wider integration of microbiome analyses into studies of human biology. I describe the steps involved in sample collection, DNA extraction, PCR amplification, high-throughput sequencing, and bioinformatics. While this review serves only as an introduction to these topics, it provides sufficient resources for researchers interested in launching new microbiome initiatives. As knowledge of these methods spreads, microbiome analysis should become a standard tool in the arsenal of human biology research. PMID- 27762070 TI - Loss of algal Proton Gradient Regulation 5 increases reactive oxygen species scavenging and H2 evolution. AB - We have identified hpm91, a Chlamydomonas mutant lacking Proton Gradient Regulation5 (PGR5) capable of producing hydrogen (H2 ) for 25 days with more than 30-fold yield increase compared to wild type. Thus, hpm91 displays a higher capacity of H2 production than a previously characterized pgr5 mutant. Physiological and biochemical characterization of hpm91 reveal that the prolonged H2 production is due to enhanced stability of PSII, which correlates with increased reactive oxygen species (ROS) scavenging capacity during sulfur deprivation. This anti-ROS response appears to protect the photosynthetic electron transport chain from photo-oxidative damage and thereby ensures electron supply to the hydrogenase. PMID- 27762071 TI - Immunohistochemical studies and fluorodeoxyglucose uptake on positron emission tomography in pharyngeal cancer for predicting radiotherapy-based treatment outcomes. AB - OBJECTIVES: This study correlated immunohistochemical studies with fluorodeoxyglucose (FDG) uptake on positron emission tomography-computed tomography (PET-CT) and identified prognostic factors for radiotherapy (RT)-based treatment outcomes in patients with squamous cell carcinoma of the oropharynx and hypopharynx. METHODS: Genomic data from pre-treatment biopsy specimens (Glut1, CAIX, VEGF, HIF-1alpha, EGFR, Ki-67, Bcl-2, CLAUDIN-4, YAP-1, c-Met and p16) of 76 patients were analysed using tissue microarrays. FDG uptake was evaluated using the maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG). RESULTS: The overexpression of Glut1 positively associated with increased values of the SUVmax, MTV and TLG, whereas VEGF and HIF-1alpha expression with the MTV and TLG, respectively. A VEGF immunoreactive score (IRS) >2 (P = 0.001, hazard ratio [HR] = 3.94) and an MTV defined by an SUV of 2.5 (MTV2.5) >14.5 mL (P = 0.004, HR = 3.31) were prognostic factors for low cause-specific survival, whereas a VEGF IRS >2 (P = 0.02, HR = 2.83) for low primary relapse-free survival. CONCLUSION: The overexpression of Glut1, VEGF and HIF-1alpha associated with increased FDG uptake. For patients with pharyngeal cancer requiring RT, the treatment outcome can be stratified by VEGF and MTV2.5. PMID- 27762072 TI - Characterizing restriction enzyme-associated loci in historic ragweed (Ambrosia artemisiifolia) voucher specimens using custom-designed RNA probes. AB - Population genetic studies of nonmodel organisms frequently employ reduced representation library (RRL) methodologies, many of which rely on protocols in which genomic DNA is digested by one or more restriction enzymes. However, because high molecular weight DNA is recommended for these protocols, samples with degraded DNA are generally unsuitable for RRL methods. Given that ancient and historic specimens can provide key temporal perspectives to evolutionary questions, we explored how custom-designed RNA probes could enrich for RRL loci (Restriction Enzyme-Associated Loci baits, or REALbaits). Starting with genotyping-by-sequencing (GBS) data generated on modern common ragweed (Ambrosia artemisiifolia L.) specimens, we designed 20 000 RNA probes to target well characterized genomic loci in herbarium voucher specimens dating from 1835 to 1913. Compared to shotgun sequencing, we observed enrichment of the targeted loci at 19- to 151-fold. Using our GBS capture pipeline on a data set of 38 herbarium samples, we discovered 22 813 SNPs, providing sufficient genomic resolution to distinguish geographic populations. For these samples, we found that dilution of REALbaits to 10% of their original concentration still yielded sufficient data for downstream analyses and that a sequencing depth of ~7m reads was sufficient to characterize most loci without wasting sequencing capacity. In addition, we observed that targeted loci had highly variable rates of success, which we primarily attribute to similarity between loci, a trait that ultimately interferes with unambiguous read mapping. Our findings can help researchers design capture experiments for RRL loci, thereby providing an efficient means to integrate samples with degraded DNA into existing RRL data sets. PMID- 27762073 TI - Cognitive analysis of schizophrenia risk genes that function as epigenetic regulators of gene expression. AB - Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression, to orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to schizophrenia pathophysiology. A core feature of schizophrenia is cognitive dysfunction. For genetic disorders where cognitive impairment is more severe such as intellectual disability, there are a disproportionally high number of genes involved in the epigenetic regulation of gene transcription. Evidence now supports some shared genetic aetiology between schizophrenia and intellectual disability. GWAS have identified 108 chromosomal regions associated with schizophrenia risk that span 350 genes. This study identified genes mapping to those loci that have epigenetic functions, and tested the risk alleles defining those loci for association with cognitive deficits. We developed a list of 350 genes with epigenetic functions and cross-referenced this with the GWAS loci. This identified eight candidate genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE, SATB2. Using a dataset of Irish psychosis cases and controls (n = 1235), the schizophrenia risk SNPs at these loci were tested for effects on IQ, working memory, episodic memory, and attention. Strongest associations were for rs6984242 with both measures of IQ (P = 0.001) and episodic memory (P = 0.007). We link rs6984242 to CHD7 via a long range eQTL. These associations were not replicated in independent samples. Our study highlights that a number of genes mapping to risk loci for schizophrenia may function as epigenetic regulators of gene expression but further studies are required to establish a role for these genes in cognition. (c) 2016 Wiley Periodicals, Inc. PMID- 27762074 TI - NARROW AND ROLLED LEAF 2 regulates leaf shape, male fertility, and seed size in rice. AB - Grain yield in rice (Oryza sativa L.) is closely related to leaf and flower development. Coordinative regulation of leaf, pollen, and seed development in rice as a critical biological and agricultural question should be addressed. Here we identified two allelic rice mutants with narrow and semi-rolled leaves, named narrow and rolled leaf 2-1 (nrl2-1) and nrl2-2. Map-based molecular cloning revealed that NRL2 encodes a novel protein with unknown biochemical function. The mutation of NRL2 caused pleiotropic effects, including a reduction in the number of longitudinal veins, defective abaxial sclerenchymatous cell differentiation, abnormal tapetum degeneration and microspore development, and the formation of more slender seeds compared with the wild type (WT). The NRL2 protein interacted with Rolling-leaf (RL14), causing the leaves of the nrl2 mutants to have a higher cellulose content and lower lignin content than the WT, which may have been related to sclerenchymatous cell differentiation and tapetum degeneration. Thus, this gene is an essential developmental regulator controlling fundamental cellular and developmental processes, serving as a potential breeding target for high-yielding rice cultivars. PMID- 27762076 TI - Clinical efficacy of desensitizing mouthwashes for the control of dentin hypersensitivity and root sensitivity: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review aimed to evaluate the scientific evidence on the efficacy of desensitizing mouthwashes for the treatment of dentin hypersensitivity (DH) and root sensitivity (RS). MATERIAL AND METHODS: A thorough search in MEDLINE, PubMed and Cochrane Plus Library was conducted up to February 2015. Randomized clinical trials, parallel, double-blinded and placebo controlled, with a follow-up of at least 6 weeks, reporting changes on response to tactile stimuli, thermal/evaporative stimuli or patients' subjective assessment of the pain experienced during their daily life after the home use of desensitizing mouthwashes were considered for inclusion. RESULTS: The screening of titles and abstracts resulted in seven publications meeting the eligibility criteria. The desensitizing agents evaluated were potassium nitrate (n = 5), aluminium lactate (n = 1) and sodium fluoride (n = 1). A meta-analysis for each of the hypersensitivity stimuli was performed. Results demonstrated statistically significant reduction in sensitivity scores favouring test group when DH was assessed by means of patients' self-reported pain experience (SMD at 8 weeks = 0.77; 95% CI [0.23; 1.31]; P = 0.005). No significant effects were detected in response to tactile or thermal/evaporative stimuli. Meta-regression analysis demonstrated a tendency towards an increased effect favouring test group for the patients' subjective perception, whereas tactile and thermal/evaporative stimuli showed a slight tendency towards a reduction in the efficacy of the test mouthwash. CONCLUSIONS: There exists a tendency towards a decrease in DH or RS scores with time in both treatment groups, with significant differences in favour of test group when sensitivity is evaluated in terms of patients' self-reported sensitivity symptoms. PMID- 27762075 TI - Sex-specific linkage scans in opioid dependence. AB - Sex influences risk for opioid dependence (OD). We hypothesized that sex might interact with genetic loci that influence the risk for OD. Therefore we performed an analysis to identify sex-specific genomic susceptibility regions for OD using linkage. Over 6,000 single nucleotide polymorphism (SNP) markers were genotyped for 1,758 African- and European-American (AA and EA) individuals from 739 families, ascertained via affected sib-pairs with OD and/or cocaine dependence. Autosomewide non-parametric linkage scans, stratified by sex and population, were performed. We identified one significant linkage region, segregating with OD in EA men, at 71.1 cM on chromosome 4 (LOD = 3.29; point-wise P = 0.00005; empirical autosome-wide P = 0.042), which significantly differed from the linkage signal at the same location in EA women (empirical P = 0.002). Three suggestive linkage signals were identified at 181.3 cM on chromosome 7 (LOD = 2.18), 104 cM on chromosome 11 (LOD = 1.85), and 60.9 cM on chromosome 16 (LOD = 1.93) in EA women. In AA men, four suggestive linkage signals were detected at 201.1 cM on chromosome 3 (LOD = 2.32), 152.9 cM on chromosome 6 (LOD = 1.86), 16.8 cM on chromosome 7 (LOD = 1.95), and 36.1 cM on chromosome 17 (LOD = 1.99). The significant region, mapping to 4q12-4q13.1, harbors several OD candidate genes with interconnected functionality, including VEGFR, CLOCK, PDCL2, NMU, NRSF, and IGFBP7. In conclusion, these results provide an evidence for the existence of sex specific and population-specific differences in OD. Furthermore, these results provide positional information that will facilitate the use of targeted next generation sequencing to search for genes that contribute to sex-specific differences in OD. (c) 2016 Wiley Periodicals, Inc. PMID- 27762077 TI - In Vivo 3D Analysis of Thoracic Kinematics: Changes in Size and Shape During Breathing and Their Implications for Respiratory Function in Recent Humans and Fossil Hominins. AB - The human ribcage expands and contracts during respiration as a result of the interaction between the morphology of the ribs, the costo-vertebral articulations and respiratory muscles. Variations in these factors are said to produce differences in the kinematics of the upper thorax and the lower thorax, but the extent and nature of any such differences and their functional implications have not yet been quantified. Applying geometric morphometrics we measured 402 three dimensional (3D) landmarks and semilandmarks of 3D models built from computed tomographic scans of thoraces of 20 healthy adult subjects in maximal forced inspiration (FI) and expiration (FE). We addressed the hypothesis that upper and lower parts of the ribcage differ in kinematics and compared different models of functional compartmentalization. During inspiration the thorax superior to the level of the sixth ribs undergoes antero-posterior expansion that differs significantly from the medio-lateral expansion characteristic of the thorax below this level. This supports previous suggestions for dividing the thorax into a pulmonary and diaphragmatic part. While both compartments differed significantly in mean size and shape during FE and FI the size changes in the lower compartment were significantly larger. Additionally, for the same degree of kinematic shape change, the pulmonary thorax changes less in size than the diaphragmatic thorax. Therefore, variations in the form and function of the diaphragmatic thorax will have a strong impact on respiratory function. This has important implications for interpreting differences in thorax shape in terms of respiratory functional differences within and among recent humans and fossil hominins. Anat Rec, 300:255 264, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27762078 TI - Phenotypic Resistance to Disinfectants and Antibiotics in Methicillin-Resistant Staphylococcus aureus Strains Isolated from Pigs. AB - The aim of this research was to study the phenotypic resistances to disinfectants and antibiotics in strains of methicillin-resistant Staphylococcus aureus (MRSA) obtained from Canary black pigs. Analyses were performed on 54 strains of MRSA, isolated in Canary black pigs from the province of Tenerife (Spain); all of them carried the mecA gene. The strains were isolated by means of nasal swab samples of healthy pigs, collected under veterinarian supervision. Bactericidal activity of antiseptics and disinfectants was tested by means of the dilution neutralization method. Susceptibility to the disinfectants glutaraldehyde, peracetic acid and silver nitrate was assessed, as well as to the antiseptics chlorhexidine, benzalkonium chloride and povidone iodine. Susceptibility to a wide array of antibiotics representing the main groups was determined by means of the disc diffusion method. All the strains demonstrated susceptibility to the disinfectants tested at the recommended concentration, and even to dilutions equal to or lesser than 1/16. The most effective antiseptic and disinfectant were, respectively, chlorhexidine and silver nitrate. With regard to the antibiotics, the strains proved to be multiresistant. All presented phenotypic resistance to the beta-lactam antibiotics ampicillin, penicillin and cefoxitin, as well as to numerous aminoglycosides, tetracycline and trimethoprim sulfamethoxazole. It was also observed that 61.1% of the strains were carriers of plasmids. Our results underline that in the strains such as MRSA, which show multiple resistances to antibiotics, the antiseptics and disinfectants show great efficacy. Moreover, as other authors also suggest, for the treatment and prevention of infections caused by MRSA, the use of beta-lactam and aminoglycoside antibiotics may be less effective. PMID- 27762080 TI - A proposed approach for quantitative benefit-risk assessment in diagnostic radiology guideline development: the American College of Radiology Appropriateness Criteria Example. AB - The American College of Radiology develops evidence-based practice guidelines to aid appropriate utilization of radiological procedures. Panel members use expert opinion to weight trade-offs and consensus methods to rate appropriateness of imaging tests. These ratings include an equivocal range, assigned when there is disagreement about a technology's appropriateness and the evidence base is weak or for special circumstances. It is not clear how expert consensus merges with the evidence base to arrive at an equivocal rating. Quantitative benefit-risk assessment (QBRA) methods may assist decision makers in this capacity. However, many methods exist and it is not clear which methods are best suited for this application. We perform a critical appraisal of QBRA methods and propose several steps that may aid in making transparent areas of weak evidence and barriers to consensus in guideline development. We identify QBRA methods with potential to facilitate decision making in guideline development and build a decision aid for selecting among these methods. This study identified 2 families of QBRA methods suited to guideline development when expert opinion is expected to contribute substantially to decision making. Key steps to deciding among QBRA methods involve identifying specific benefit-risk criteria and developing a state-of evidence matrix. For equivocal ratings assigned for reasons other than disagreement or weak evidence base, QBRA may not be needed. In the presence of disagreement but the absence of a weak evidence base, multicriteria decision analysis approaches are recommended; and in the presence of weak evidence base and the absence of disagreement, incremental net health benefit alone or combined with multicriteria decision analysis is recommended. Our critical appraisal further extends investigation of the strengths and limitations of select QBRA methods in facilitating diagnostic radiology clinical guideline development. The process of using the decision aid exposes and makes transparent areas of weak evidence and barriers to consensus. PMID- 27762079 TI - Methamphetamine Induces Anhedonic-Like Behavior and Impairs Frontal Cortical Energetics in Mice. AB - INTRODUCTION: We recently showed that a single high dose of methamphetamine (METH) induces a persistent frontal cortical monoamine depletion that is accompanied by helpless-like behavior in mice. However, brain metabolic alterations underlying both neurochemical and mood alterations remain unknown. AIMS: Herein, we aimed at characterizing frontal cortical metabolic alterations associated with early negative mood behavior triggered by METH. Adult C57BL/6 mice were injected with METH (30 mg/kg, i.p.), and their frontal cortical metabolic status was characterized after probing their mood and anxiety-related phenotypes 3 days postinjection. RESULTS: Methamphetamine induced depressive-like behavior, as indicated by the decreased grooming time in the splash test and by a transient decrease in sucrose preference. At this time, METH did not alter anxiety-like behavior or motor functions. Depolarization-induced glucose uptake was reduced in frontocortical slices from METH-treated mice compared to controls. Consistently, astrocytic glucose transporter (GluT1) density was lower in the METH group. A proton high rotation magic angle spinning (HRMAS) spectroscopic approach revealed that METH induced a significant decrease in N-acetyl aspartate (NAA) and glutamate levels, suggesting that METH decreased neuronal glutamatergic function in frontal cortex. CONCLUSIONS: We report, for the first time, that a single METH injection triggers early self-care and hedonic deficits and impairs frontal cortical energetics in mice. PMID- 27762081 TI - Pilot study on 18 F-FDG PET/CT for detection of inflammatory changes in blood induced knee arthropathy in a rabbit model. AB - RATIONALE: 18 F-FDG-PET/CT has a potential role in the early detection of haemophilic arthritis, at a time when treatment may still avoid further joint degeneration. The purposes of this pilot study were to determine the ability of 18 F-FDG-PET/CT to detect inflammatory changes associated with blood-induced arthropathy in knees of a rabbit model. METHODS: Ten juvenile rabbits were imaged at baseline and weeks 5 and 17 post intraarticular autologous blood injections (ABI). Five rabbits in group 1 (G1) had ABI into the same knee joint every 2 weeks (total, eight injections). Five rabbits in group 2 (G2) had only two injections into the same knee, at weeks 5 and 17. Images were assessed visually and semi-quantitatively by measuring maximal standardized uptake values (SUVmax) and standardized uptake ratio (SUR = SUVmax in affected knee/SUVmax in non affected knee). RESULTS: More rabbits in G1 than G2 presented with positive chronic inflammatory synovial scores at week 17. Mean iron staining scores in injected knees were greater for G1 than for G2 (P = 0.049). No increased uptake was identified in the injected knees in any of the rabbits at baseline or at week 5. At week 17, all G1 rabbits demonstrated increased uptake in their affected knees with higher mean SUVmax (1.5) than normal knees (1.0) (P < 0.02). None of the G2 rabbits showed asymmetric increased uptake. The SUR of G1 was higher at week 17 compared to baseline (P < 0.01) and week 5 (P < 0.01). The SUR at week 17 was higher for G1 than for G2 (1.13) rabbits (P < 0.01). CONCLUSION: 18 F-FDG-PET is able to detect the inflammatory changes associated with haemophilic arthropathy in this experimental model. PMID- 27762082 TI - A New Species of Centrohelid Heliozoan Acanthocystis amura n. sp. Isolated From Two Remote Locations in Russia. AB - A new species of centrohelid heliozoan Acanthocystis amura from the Amur River, the Far East of Russia was studied with light- and electron microscopy. Acanthocystis amura has simple oval plate scales (1.2-2.6 * 1.0-1.8 MUm) with an axial thickening and a thin border as well as two types of spine scales. The spine scales of type 1 were 1.3-4.8 MUm long and had four small hooks on their tips. The spine scales of type 2 were shorter, 1.0-3.6 MUm long and had four teeth at the distal end. The morphology of A. amura resembles that of Acanthocystis quadrifurca. They both have similar spine scales but their plate scales are completely different. Acanthocystis valdiviense differs from the new species in absence of hook-bearing scales. Molecular phylogeny based on 18S rDNA consistently placed A. amura into Acanthocystis nichollsi/Acanthocystis costata clade, but relationships between those three species were not resolved. Morphology of another centrohelid strain from another location (the South Urals) has been compared with that of the original strain and few minor differences in size characteristics of the scales have been revealed. PMID- 27762083 TI - The Rhodococcus equi virulence protein VapA disrupts endolysosome function and stimulates lysosome biogenesis. AB - Rhodococcus equi (R. equi) is an important pulmonary pathogen in foals that often leads to the death of the horse. The bacterium harbors a virulence plasmid that encodes numerous virulence-associated proteins (Vaps) including VapA that is essential for intracellular survival inside macrophages. However, little is known about the precise function of VapA. Here, we demonstrate that VapA causes perturbation to late endocytic organelles with swollen endolysosome organelles having reduced Cathepsin B activity and an accumulation of LBPA, LC3 and Rab7. The data are indicative of a loss of endolysosomal function, which leads cells to upregulate lysosome biogenesis to compensate for the loss of functional endolysosomes. Although there is a high degree of homology of the core region of VapA to other Vap proteins, only the highly conserved core region of VapA, and not VapD of VapG, gives the observed effects on endolysosomes. This is the first demonstration of how VapA works and implies that VapA aids R. equi survival by reducing the impact of lysosomes on phagocytosed bacteria. PMID- 27762084 TI - Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress. AB - One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 (CB1 receptors) playing a major role. In the present study, we investigated whether the effect of the CB1 receptor coding CNR1 gene on migraine and its symptoms is conditional on life stress. In a cross-sectional European population (n = 2426), recruited from Manchester and Budapest, we used the ID-Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events (RLE), and covered the CNR1 gene with 11 SNPs. The main genetic effects and the CNR1 * RLE interaction with age and sex as covariates were tested. None of the SNPs showed main genetic effects on possible migraine or its symptoms, but 5 SNPs showed nominally significant interaction with RLE on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression- and anxiety-related phenotypes. In addition, a Bayesian systems-based analysis demonstrated that in the development of headache with nausea all SNPs were more relevant with higher a posteriori probability in those who experienced recent life stress. In summary, the CNR1 gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone. PMID- 27762086 TI - Bacterial community assembly in activated sludge: mapping beta diversity across environmental variables. AB - Effect of ecological variables on community assembly of heterotrophic bacteria at eight full-scale and two pilot-scale activated sludge wastewater treatment plants (AS-WWTPs) were explored by pyrosequencing of 16S rRNA gene amplicons. In total, 39 samples covering a range of abiotic factors spread over space and time were analyzed. A core bacterial community of 24 families detected in at least six of the eight AS-WWTPs was defined. In addition to the core families, plant-specific families (observed at <50% AS-WWTPs) were found to be also important in the community structure. Observed beta diversity was partitioned with respect to ecological variables. Specifically, the following variables were considered: influent wastewater characteristics, season (winter vs. summer), process operations (conventional, oxidation ditch, and sequence batch reactor), reactor sizes (pilot-scale vs. full-scale reactors), chemical stresses defined by ozonation of return activated sludge, interannual variation, and geographical locations. Among the assessed variables, influent wastewater characteristics and geographical locations contributed more in explaining the differences between AS WWTP bacterial communities with a maximum of approximately 26% of the observed variations. Partitioning of beta diversity is necessary to interpret the inherent variability in microbial community assembly and identify the driving forces at play in engineered microbial ecosystem. PMID- 27762087 TI - Exploring the Binding Proteins of Glycolipids with Bifunctional Chemical Probes. AB - Glycolipids are important structural components of biological membranes and perform crucial functions in living systems, including signaling transduction and interaction with extracellular environment. However, the mechanistic exploration of glycolipids in vivo is challenging because they are not genetically encoded. Herein, we designed and synthesized a series of bifunctional monogalactosyldiacylglycerol (MGDG) probes as a model by introducing diazirine and terminal alkyne moieties on an aliphatic chain. In combination with proteome profiling and molecular modeling, we have demonstrated that MGDG alleviates inflammation by antagonizing TLR4. PMID- 27762088 TI - Preventive effect of ipragliflozin on nocturnal hypoglycemia in patients with type 2 diabetes treated with basal-bolus insulin therapy: An open-label, single center, parallel, randomized control study. AB - The efficacy of the administration of sodium-glucose co-transporter 2 inhibitor or the co-administration of sodium-glucose co-transporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor to insulin therapy is not well known. A total of 58 patients with type 2 diabetes, admitted for glycemic control, were randomized to basal-bolus insulin therapy (BBT) alone or BBT plus 50 mg ipragliflozin and/or 20 mg teneligliptin. Insulin doses were adjusted to maintain normal blood glucose levels. Plasma glucose profiles were estimated by continuous glucose monitoring before discharge. Required insulin doses were not significantly different among the treatment groups. The frequency of nocturnal hypoglycemia was significantly lower in the groups treated with ipragliflozin (6.5 +/- 10.6%) and ipragliflozin plus teneligliptin (6.9 +/- 14.3%) than in the group treated with BBT alone (42 +/- 43.6%). The administration of sodium-glucose co-transporter 2 inhibitor with or without dipeptidyl peptidase-4 inhibitor prevented nocturnal hypoglycemia in type 2 diabetes patients with BBT. PMID- 27762089 TI - Improvement of Ligand Affinity and Thermodynamic Properties by NMR-Based Evaluation of Local Dynamics and Surface Complementarity in the Receptor-Bound State. AB - The thermodynamic properties of a ligand in the bound state affect its binding specificity. Strict binding specificity can be achieved by introducing multiple spatially defined interactions, such as hydrogen bonds and van der Waals interactions, into the ligand-receptor interface. These introduced interactions are characterized by restricted local dynamics and improved surface complementarity in the bound state. In this study, we experimentally evaluated the local dynamics and the surface complementarity of weak-affinity ligands in the receptor-bound state by forbidden coherence transfer analysis in free-bound exchange systems (Ex-FCT), using the interaction between a ligand, a myocyte enhancer factor 2A (MEF2A) docking peptide, and a receptor, p38alpha, as a model system. The Ex-FCT analyses successfully provided information for the rational design of a ligand with higher affinity and preferable thermodynamic properties for p38alpha. PMID- 27762091 TI - Reexamining the Prohibition of Gestational Surrogacy in Sunni Islam. AB - Advances in reproductive medicine have provided new, and much needed, hope for millions of people struggling with infertility. Gestational surrogacy is one such development that has been gaining popularity with infertile couples, especially those unable to benefit from other reproductive procedures such as In Vitro Fertilization. For many Muslim couples, however, surrogacy remains a nonviable option. Islamic scholars have deemed the procedure incompatible with Islam and have prohibited its use. This paper examines the arguments presented for proscribing surrogacy arrangements in Sunni Islam in particular. These include preservation of lineage, exclusion of third parties in reproduction, upholding the rights of the child, and protection from the negative effects of surrogacy arrangements. The rationales for banning surrogacy are subsequently refuted utilizing Islamic law "Sharia", bioethics, and medical evidence. The paper also presents reasons for why surrogacy is not only consistent with Sunni Islamic teachings, but is also both ethically justified and medically necessary. Lastly, Islamic scholars are urged to take into account the arguments presented in this paper and reconsider their rulings on the permissibility of surrogacy. PMID- 27762090 TI - Wnt5b-associated exosomes promote cancer cell migration and proliferation. AB - Wnt5b is a member of the same family of proteins as Wnt5a, the overexpression of which is associated with cancer aggressiveness. Wnt5b is also suggested to be involved in cancer progression, however, details remain unclarified. We analyzed the biochemical properties of purified Wnt5b and the mode of secretion of Wnt5b by cancer cells. Wnt5b was glycosylated at three asparagine residues and lipidated at one serine residue, and these post-translational modifications of Wnt5b were essential for secretion. Purified Wnt5b showed Dvl2 phosphorylation and Rac activation abilities to a similar extent as Wnt5a. In cultured-cell conditioned medium, Wnt5b was detected in supernatant or precipitation fractions that were separated by centrifugation at 100 000 g. In PANC-1 pancreatic cancer cells, 55% of secreted endogenous Wnt5b was associated with exosomes. Exosomes from wild-type PANC-1 cells, but not those from Wnt5b-knockout PANC-1 cells, activated Wnt5b signaling in CHO cells and stimulated migration and proliferation of A549 lung adenocarcinoma cells, suggesting that endogenous, Wnt5b-associated exosomes are active. The exosomes were taken up by CHO cells and immunoelectron microscopy revealed that Wnt5b is indeed associated with exosomes. In Caco-2 colon cancer cells, most Wnt5b was recovered in precipitation fractions when Wnt5b was ectopically expressed (Caco-2/Wnt5b cells). Knockdown of TSG101, an exosome marker, decreased the secretion of Wnt5b-associated exosomes from Caco 2/Wnt5b cells and inhibited Wnt5b-dependent cell proliferation. Exosomes secreted from Caco-2/Wnt5b cells stimulated migration and proliferation of A549 cells. These results suggest that Wnt5b-associated exosomes promote cancer cell migration and proliferation in a paracrine manner. PMID- 27762092 TI - Rationale of cerebral protection devices in left atrial appendage occlusion. AB - AIMS: Aims of this case-series were to assess the feasibility of cerebral protection devices in interventional left atrial appendage occlusion (iLAAO) procedures and to yield insight into the pathomorphological correlate of early, procedural cerebral embolization during iLAAO. METHODS AND RESULTS: Five consecutive patients underwent iLLO flanked by the Sentinel CPS(r) (Claret Medical, Inc., Santa Rosa, CA) cerebral protection system. Placement and recapture of the Sentinel(r) device as well as the iLAAO were successful and safe in all cases. Histomorphometric analysis of the collected filters showed embolized debris in all patients. Acute thrombus was found in three patients, organizing thrombus in four. Interestingly, two patients had endocardial or myocardial tissue in their filters. CONCLUSIONS: Cerebral protection during iLAAO with the Sentinel CPS(r) device is feasible. Furthermore, this dataset identifies the formation and embolization of thrombus and cardiac tissue as emboligeneic sources and potential future targets to reduce procedural complications. (c) 2016 Wiley Periodicals, Inc. PMID- 27762094 TI - A Metallaanthracene and Derived Metallaanthraquinone. AB - Metalla-analogues of archetypal aromatic molecules are attracting ever increasing interest. Although metallabenzenes (which fall within this class) have been well studied, fused-ring metallabenzenes are rare and of the linear polycyclic metallaaromatic hydrocarbons, only metallanaphthalene is known. Herein we report the first metallaanthracene, [Ir(C13 H8 {CH2 CO2 Me-5})Cl(PPh3 )2 ]O3 SCF3 (5), which represents the next member of this series of polycyclic compounds. Structurally, 5 has a number of features in common with anthracene including fused-ring planarity and bond-length alternation. In analogues of classic reactions of anthracene, 5 forms a Diels-Alder adduct with maleic anhydride and on oxidation the unprecedented fused-ring metallaanthraquinone, [Ir(C15 H6 O{Br 6}{OMe-7}{=O-8}{=O-15})Br(PPh3 )2 ], is obtained. PMID- 27762093 TI - Linagliptin as add-on to empagliflozin and metformin in patients with type 2 diabetes: Two 24-week randomized, double-blind, double-dummy, parallel-group trials. AB - AIM: To evaluate the efficacy and safety of linagliptin vs placebo as add-on to empagliflozin and metformin in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with inadequate glycaemic control despite stable-dose metformin received open-label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add-on therapy for 16 weeks. Subsequently, those with HbA1c >=7.0 and <=10.5% (>53 and <=91 mmol/mol) (N = 482) were randomized to 24 weeks' double-blind, double-dummy treatment with linagliptin 5 mg or placebo in study 1, or to linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2). The primary endpoint was change from baseline (defined as the last value before first intake of randomized, double-blind treatment) in HbA1c at week 24. RESULTS: At week 24, HbA1c (mean baseline 7.82-8.04 [62-64 mmol/mol]) was significantly reduced with linagliptin vs placebo; adjusted mean (SE) differences in change from baseline in HbA1c with linagliptin vs placebo were -.32% (.10) (-3.59 [1.08] mmol/mol) ( P = .001) for patients on empagliflozin 10 mg and metformin, and 0.47% (0.10) (-5.15 [1.04] mmol/mol) ( P < 0.001) for patients on empagliflozin 25 mg and metformin. Adverse events were reported in more patients receiving placebo than in those receiving linagliptin: 55.5% vs 48.4% in study 1 and 58.9% vs 52.7% in study 2. CONCLUSIONS: Linagliptin as add-on to empagliflozin and metformin for 24 weeks improved glycaemic control vs placebo, and was well tolerated. PMID- 27762095 TI - Evaluation of new chlorhexidine- and cetylpyridinium chloride-based mouthrinse formulations adjunctive to scaling and root planing: pilot study. AB - OBJECTIVE: To compare the effect of two newly formulated chlorhexidine (CHX) and cetylpyridinium chloride (CPC) mouthrinses after scaling and root planing (SRP) in terms of clinical, microbiological, patient-based variables and adverse events, with a positive control with the same active components, already marketed and tested. METHODS: A pilot, randomized clinical trial, double-blind, parallel design with 1-month follow-up was conducted. Chronic periodontitis patients requiring non-surgical periodontal therapy were enrolled and randomly assigned to: (i) SRP and test-1 (new reformulation: 0.12% CHX and 0.05% CPC); (ii) SRP and test-2 (new formulation: 0.03% CHX and 0.05% CPC); or (iii) SRP and positive control (commercial product: 0.12% CHX and 0.05% CPC). All variables were evaluated at baseline and 1 month after SRP. Quantitative variables were compared by means of anova or Kruskal-Wallis test and qualitative variables by chi-square or McNemar tests. RESULTS: Thirty patients (10 per group) were included. After 1 month, there were significant differences among groups in plaque levels (P = 0.016) as test-1 showed less sites with plaque than test-2 (31.15% [standard error-SE 2.21%] versus 49.39% [SE 4.60%), respectively). No significant differences were found for global patient perception of the product or in adverse effects. Test groups showed better results in levels and proportions (P = 0.022) of Capnocytophaga spp. CONCLUSIONS: Within the limitations of this pilot study, it can be concluded that the newly formulated 0.12% CHX and 0.05% CPC mouthrinse showed larger plaque level reductions, without showing more adverse effects, when compared to the other two mouthrinses, after SRP. PMID- 27762096 TI - Beneficial effect of lixisenatide after 76 weeks of treatment in patients with type 2 diabetes mellitus: A meta-analysis from the GetGoal programme. AB - AIMS: To evaluate the long-term efficacy and safety of lixisenatide, a short acting, prandial glucagon-like peptide-1 receptor agonists (GLP-1 RA) as add-on therapy in type 2 diabetes mellitus. METHODS: A meta-analysis of 76-week results of 5 placebo-controlled clinical trials from the GetGoal programme was performed, including 3000 inadequately controlled adult diabetic patients where lixisenatide 20 ug once-daily was administered in combination with metformin (GetGoal-M and GetGoal-F1), sulphonylurea +/- metformin (GetGoal-S), basal insulin +/- metformin (GetGoal-L) or pioglitazone +/- metformin (GetGoal-P). RESULTS: A significant reduction in HbA1c at 76 weeks was observed in the intervention arm compared to placebo (LSM difference: -0.41%, 95%CI: -0.51, -0.32, P < .00001). Compared to placebo, lixisenatide induced a larger decrease in fasting plasma glucose (LSM difference -0.49 mmol/L, 95% CI -0.71, -0.27, P < .0001) and postprandial glucose excursion after a standard test meal (LSM difference -3.29 mmol/L, 95% CI -4.17, 2.42, P < .00001). A bodyweight reduction was observed in the lixisenatide arm (LSM difference -0.40 kg, 95%CI: -0.8, -0.01, P = .05). The risk of hypoglycaemia was slightly higher with lixisenatide vs placebo (risk difference +0.02, 95% CI: 0, 0.04, P = .04). The most commonly observed non-severe adverse events were nausea and vomiting, which after week 16 and week 8, were steadily <4% and <1% in the lixisenatide arm, respectively. CONCLUSIONS: Lixisenatide, a once-daily prandial GLP-1 RA, provides long-term glycaemic control, a sustained beneficial effect on weight and with a good safety profile. PMID- 27762097 TI - Comparative retrospective study on the modalities of biopsying peripheral neuroblastic tumors: a report from the Italian Pediatric Surgical Oncology Group (GICOP). AB - BACKGROUND: Peripheral neuroblastic tumors are the most common extracranial solid neoplasms in children. Early and adequate tissue sampling may speed up the diagnostic process and ensure a prompt start of optimal treatment whenever needed. Different biopsy techniques have been described. The purpose of this multi-center study is to evaluate the accuracy and safety of the various examined techniques and to determine whether a preferential procedure exists. METHODS: All children who underwent a biopsy, from January 2010 to December 2014, as a result of being diagnosed with a peripheral neuroblastic tumor, were retrospectively reviewed. Data collected included patients' demographics, clinical presentation, intraoperative technical details, postoperative parameters, complications, and histology reports. The Mann-Whitney U and Fisher's exact tests were used for statistical analysis. RESULTS: The cohort included 100 patients, 32 of whom underwent an incisional biopsy (performed through open or minimally invasive access) (Group A), and the remaining 68 underwent multiple needle-core biopsies (either imaging-guided or laparoscopy/thoracoscopy-assisted) (Group B). Comparing the two groups revealed that Group A patients had a higher rate of complications, a greater need for postoperative analgesia, and required red blood cell transfusion more often. Overall adequacy rate was 94%, without significant differences between the two groups (100% vs. 91.2% for Group A and Group B, respectively, P = 0.0933). CONCLUSIONS: Both incision and needle-core biopsying methods provided sub-optimal to optimal sampling adequacy rates in children affected by peripheral neuroblastic tumors. However, the former method was associated with a higher risk of both intraoperative and postoperative complications compared with the latter. PMID- 27762098 TI - Paralogs are revealed by proportion of heterozygotes and deviations in read ratios in genotyping-by-sequencing data from natural populations. AB - Whole-genome duplications have occurred in the recent ancestors of many plants, fish, and amphibians, resulting in a pervasiveness of paralogous loci and the potential for both disomic and tetrasomic inheritance in the same genome. Paralogs can be difficult to reliably genotype and are often excluded from genotyping-by-sequencing (GBS) analyses; however, removal requires paralogs to be identified which is difficult without a reference genome. We present a method for identifying paralogs in natural populations by combining two properties of duplicated loci: (i) the expected frequency of heterozygotes exceeds that for singleton loci, and (ii) within heterozygotes, observed read ratios for each allele in GBS data will deviate from the 1:1 expected for singleton (diploid) loci. These deviations are often not apparent within individuals, particularly when sequence coverage is low; but, we postulated that summing allele reads for each locus over all heterozygous individuals in a population would provide sufficient power to detect deviations at those loci. We identified paralogous loci in three species: Chinook salmon (Oncorhynchus tshawytscha) which retains regions with ongoing residual tetrasomy on eight chromosome arms following a recent whole-genome duplication, mountain barberry (Berberis alpina) which has a large proportion of paralogs that arose through an unknown mechanism, and dusky parrotfish (Scarus niger) which has largely rediploidized following an ancient whole-genome duplication. Importantly, this approach only requires the genotype and allele-specific read counts for each individual, information which is readily obtained from most GBS analysis pipelines. PMID- 27762099 TI - Microvascular dysfunction affects the development and prognosis of sudden idiopathic hearing loss. AB - OBJECTIVE: The aim of our study is to investigate whether systemic microvascular function affects the development and prognosis of sudden idiopathic hearing loss (SHL). TYPE OF STUDY: A prospective case-control study. MATERIALS AND METHODS: Fifty patients diagnosed with SHL at our hospital between September 2015 and May 2016 were included as the SHL group, and 50 healthy volunteers who came to the hospital for medical screening were included in the control group. Thirty-one patients from the SHL group who responded to treatment and 19 patients who did not respond to treatment were identified according to the Siegel criteria and were grouped. Patients with comorbid disorders were excluded from the study. To determine microvascular function, the videocapillaroscopic examination was conducted from the nailfold, measuring the capillary density (CD) and post occlusive reactive hyperaemia (PORH) values and statistical analysis was performed between the groups. RESULT: While CD was an average of 83.1 +/- 6 in the SHL group, it was measured as 96.2 +/- 10 in the control group. The CD value was significantly lower in the SHL group than the control group (P < 0.05). While the average PORH value in the SHL group was 80.5 +/- 7.7, it was measured as 97.5 +/- 10 in the control group. The PORH value was significantly lower in the SHL group than the control group (P < 0.05). The CD value did not differ significantly (P > 0.05) between the group that responded to treatment (83.4 +/- 5.5) and the group that did not respond to treatment (82.7 +/- 6.9). The PORH value was significantly lower (P < 0.05) in the group that did not respond to treatment (75.2 +/- 7.9) than the group that did (83.8 +/- 5.6). CONCLUSION: To our best knowledge, our study is the first study in the literature. Although the role of specific mechanisms in SHL is not entirely understood, the capillaroscopic examination can show the importance of microvascular function in SHL. CD and PORH values were found to be low in SHL patients, and a low PORH value was found to be a factor of poor prognosis. PMID- 27762100 TI - Inhibition of DNA methyltransferases regulates cocaine self-administration by rats: a genome-wide DNA methylation study. AB - DNA methylation is a major epigenetic process which regulates the accessibility of genes to the transcriptional machinery. In the present study, we investigated whether modifying the global DNA methylation pattern in the brain would alter cocaine intake by rats, using the cocaine self-administration test. The data indicate that treatment of rats with the DNA methyltransferase inhibitors 5-aza 2'-deoxycytidine (dAZA) and zebularine enhanced the reinforcing properties of cocaine. To obtain some insights about the underlying neurobiological mechanisms, a genome-wide methylation analysis was undertaken in the prefrontal cortex of rats self-administering cocaine and treated with or without dAZA. The study identified nearly 189 000 differentially methylated regions (DMRs), about half of them were located inside gene bodies, while only 9% of DMRs were found in the promoter regions of genes. About 99% of methylation changes occurred outside CpG islands. Gene expression studies confirmed the inverse correlation usually observed between increased methylation and transcriptional activation when methylation occurs in the gene promoter. This inverse correlation was not observed when methylation took place inside gene bodies. Using the literature based Ingenuity Pathway Analysis, we explored how the differentially methylated genes were related. The analysis showed that increase in cocaine intake by rats in response to DNA methyltransferase inhibitors underlies plasticity mechanisms which mainly concern axonal growth and synaptogenesis as well as spine remodeling. Together with the Akt/PI3K pathway, the Rho-GTPase family was found to be involved in the plasticity underlying the effect of dAZA on the observed behavioral changes. PMID- 27762101 TI - Synthesis and evaluation of novel amonafide-polyamine conjugates as anticancer agents. AB - With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three-position of amonafide aromatic ring was modified by coupling with different amine/polyamine motifs via two linkers. Two series of naphthalimide derivatives were designed and synthesized and evaluated for their antitumor properties in vitro and in vivo. The preliminary in vitro trials revealed that compounds with urea as the linker were not active, and the presence of aspirin elevated the potency of 6k against tumor cells, wound healing, and the protein expression of cyclic D1 and MMP9. The in vivo trials on three H22 tumor transplant models demonstrated that the combination of 6k and aspirin markedly improved the efficacy in terms of inhibitive effect, pulmonary metastasis, and extension of the life span. More importantly, the combination of 6k and aspirin displayed the reduced side-effects compared to that of amonafide. PMID- 27762103 TI - Management of Snake Bite in India. PMID- 27762104 TI - A Clinico-Epidemiological Profile of Neuroparalytic Snake Bite: Using Low Dose ASV in a Tertiary Care Centre from North India. AB - OBJECTIVE: Snake bite in India is a common medical emergency and an occupational hazard for majority of Indian population especially farmers. Epidemiological data on snake bite from the North India is sparse. Hence we conducted this study to find clinico-epidemiological profile of neuroparalytic snake bite. METHODS: This is a record-based, descriptive study carried out at the Department of Medicine, M.L.N. Medical College and associated Swaroop Rani Nehru Hospital, Allahabad, U.P. (India) which is a tertiary care hospital of north India.. This study describes the epidemiology, arrival delays and the outcome of neuroparalytic snakebites with low dose ASV along with ventilatory support. RESULTS: Among the total 113 cases of neuroparalytic snake bite victims (56.63%) were males aged 21 40 years. Majorities of the victims were bitten outdoor (63.71%) and most of the bites occurred on the lower limbs (83%). The highest number of cases occurred during the monsoon season of July-September. Most of the victims were farmers (53.44%) and labourers (30.55%), which suggested that snake bite was an occupational hazard. Mean dose of ASV administered was 16.99 vials. The percentage of patients requiring intensive care and ventilatory support were (40.70%) and the total percentage of patients showing recovery was (84.07%). The most important positive prognostic factor was reaching hospital within 7 hours. CONCLUSIONS: Snake bite can be viewed as an occupational hazard among farmers and labourers. Delay in reaching hospital in time where definite treatment and care can be done was identified as the most important cause of mortality. Low dose ASV administration and ventilatory support can provide sufficient cure if patients reach on time. Public health programs regarding the prevention and the importance of the early arrival to the hospital should be emphasized. PMID- 27762105 TI - Clinical Profile and Laboratory Parameters in 1051 Victims of Snakebite from a Single Centre in Kerala, South India. AB - INTRODUCTION: Snakebite is an occupational hazard causing considerable morbidity and mortality worldwide, particularly so in tropical countries like India. OBJECTIVE: The aim of this study is to (i) review the demographic, clinical and laboratory findings in patients (1051) admitted with venomous snakebite (ii) to correlate mortality, morbidity and duration of hospital stay with clinical signs, symptoms and laboratory parameters. METHODS: A retrospective study of 1051 patients treated for snakebite over 10 years (2000 - 2009) in Little Flower Hospital, Angamaly, Kerala. RESULTS: Of the 1051 cases, haemotoxic bites outnumbered 586 (56%) neurotoxic ones 435 (41%). Most victims were males 706 (70%), 792 (75%) of the victims were between 20-60 years of age, lower limb bites predominated, 883 (84%). Among laboratory tests, haemoconcentration (>15 gm/dl), low platelets (<100,000 cmm), proteinuria (3+), raised creatinine (>4 mg/dl) and elevated d-Dimer (>200 ug/ml) were associated with an adverse prognosis. Major complications include death in 38 (3.6%) victims, Acute Respiratory Distress Syndrome 20 (1.9%), Acute Renal Failure 220 (20.9%), needing haemodialysis in 110 (10.4%). Ventilator support was needed in 41 (3.9%) victims and gangrene was seen in 43 (4%). 891 (85%) patients received ASV with adverse reactions in 379 (37%) with 3 having anaphylaxis. The mean dose of antivenom given for neuroparalytic snakebite was 12.26 vials (range 0-32) and 16.79 vials (range 2-52) for hemotoxic bites. 45% of the victims had a hospital stay of <5 days, 40% between 6-14 days and 15% victims of >15 days. CONCLUSIONS: This study highlights that snakebite is an occupational hazard, and the time between bite and treatment determines the prognosis. The low mortality observed in our study is probably due to early admission to hospital, early and adequate ASV administration and better management of complications. The study also indicates that the use of PT and APTT tests along with 20 min WBCT, helped in initiating early treatment. Symptoms of abdominal pain, vomiting, local excruciating pain at the bite site with regional lymphadenopathy even before the prolongation of the clotting time was taken as a sign of systemic envenomation. In the absence of a diagnostic kit, a definite protocol for treatment of snakebite has to be devised. ABBREVIATIONS: Intensive Care Unit (ICU); Polyvalent Anti-snake venom (ASV); whole blood clotting test (WBCT); Acute Respiratory Distress Syndrome (ARDS) ; Acute Kidney Injury(AKI); Disseminated Intravascular Coagulation (DIC); Anterior Wall myocardial infarction (AMI); Cerebro-Vascular Accidents (CVA). PMID- 27762106 TI - The Ever Increasing Reservoirs of Infection in the Health Care Environment - Time for a Sixth Moment of Hygiene. AB - OBJECTIVES: The study was carried out to determine the extent and type of contamination of the hands and accessories of staff from different settings and also to determine the phenotypic similarity between the isolates recovered from the same staff. DESIGN: Prospective cross-sectional study. SETTING: Tertiary care center. PARTICIPANTS: Health care workers (HCWs') and administrative staff. METHODS: Samples were collected and processed for bacteriology from the dominant hand, mobiles, aprons, stethoscopes and computer keyboards of 280 staff working in different settings after consent. Isolates were identified and antimicrobial susceptibility testing was carried out. A comparison of data sets was performed using chi square test. p value < 0.05 was considered significant. RESULTS: 817 samples were screened, 616 yielded growth. Contamination rate was found to be 75%. Of the 1254 isolates recovered, Gram positive and gram negative accounted for 80% and 18% respectively. Hands and accessories of HCWs from clinical settings showed significant contamination with potential pathogens as compared to the non-clinical settings. (p<0.0001) All computer keyboards and stethoscopes used by ICU doctors were contaminated. MRSA was recovered only from clinical settings. Two salmonella isolates were isolated from apron of laboratory health care workers. In 102 staff, similar isolates were recovered from hand and any accessory. CONCLUSIONS: The risk of contamination of any accessory with potential pathogens is high in the clinical setting. The five moments of hand hygiene should be strengthened. A policy for decontamination of all accessories should be formulated. PMID- 27762107 TI - Sensitivity and Specificity of Pulse Oximetry and Ankle-Brachial Index for Screening Asymptomatic Peripheral Vascular Diseases in Type 2 Diabetes Mellitus. AB - OBJECTIVES: To compare pulse oximetry and Ankle-Brachial Index (ABI) with duplex ultrasonography as reference standard to determine the diagnostic accuracy for screening asymptomatic PVD in type 2 diabetes mellitus. METHODS: This cross sectional study was conducted in 2012 at tertiary hospital in Madurai among diabetic patients attending the medicine outpatient department (OPD). Type 2 Diabetes Mellitus patients, asymptomatic with regards to symptoms and signs of PVD, aged above 40 years were included. Pulse Oximetry was performed using a pulse oximeter and ABI using sphygmomanometer cuffs and duplex ultrasonography of femoral, popliteal, tibial, posterior tibial and dorsalis pedis arteries. A diagnosis of PVD was based on: monophasic waveforms in any artery by duplex ultrasonography, toe saturation being less than finger saturation by >2% or if foot saturation decreased by >2% in an elevated position and an ABI <0.9. RESULTS: Among 120 patients included in the study, prevalence of PVD was 22.5% (95% CI: 15.9, 30.8). The PVD group had a higher proportion of elderly, males, current smokers, long-standing diabetics and comorbidities. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of pulse oximetry were 74.1% (95% CI: 55.3, 86.8), 95.7% (89.4, 98.3), 83.3% (64.1, 93.3) and 92.7% (85.7, 96.4) respectively, while those of ABI were 70.3% (51.5, 84.2), 87.1 (78.8, 92.5), 61.3% (43.8, 76.3) and 91.0% (83.3, 95.4) respectively. Parallel testing had net sensitivity increased to 92.3% and net specificity decreased to 83.3%. Performances did not differ across the subgroups. CONCLUSIONS: Pulse oximetry was atleast as good as ABI for the screening for asymptomatic PVD among diabetics. PMID- 27762102 TI - Multiple roles for a novel RND-type efflux system in Acinetobacter baumannii AB5075. AB - Colony opacity phase variation in Acinetobacter baumannii strain AB5075 is regulated by a reversible high-frequency switch. Transposon mutagenesis was used to generate mutations that decreased the opaque to translucent switch and a gene encoding a predicted periplasmic membrane fusion component of a resistance nodulation-cell division (RND)-type efflux system was isolated. This gene was designated arpA and immediately downstream was a gene designated arpB that encodes a predicted membrane transporter of RND-type systems. A nonpolar, in frame deletion in arpA resulted in a 70-fold decrease in the opaque to translucent switch. An arpB::Tc mutant exhibited a 769-fold decrease in the opaque to translucent switch. However, the translucent to opaque switch was largely unchanged in both the arpA and arpB mutants. The arpA and arpB mutants also exhibited increased surface motility in the opaque form and the arpB mutant exhibited increased susceptibility to aminoglycosides. The arpA and arpB mutants were both attenuated in a Galleria mellonella model of virulence. A divergently transcribed TetR-type regulator ArpR was capable of repressing the arpAB operon when this TetR regulator was overexpressed. The arpR gene was also involved in regulating the opaque to translucent switch as an in-frame arpR mutation decreased this switch by 1,916-fold. PMID- 27762108 TI - Clinical and Laboratory Profile of Hospitalized Malarial Patients: An Agra-Based Study. AB - OBJECTIVE: The clinical presentations and laboratory profile of malaria has been changing over the years. Therefore this study was undertaken to study the clinical profile and laboratory parameters of malarial patients. METHODS: This prospective observational study was undertaken in military hospital with high prevalence of malaria. A total of 320 patients were studied. All patients tested positive by peripheral blood smear or rapid diagnostic test were included. Clinical presentations, hematological and biochemical parameters were noted. RESULTS: Of the total 320 patients, 249 had P vivax, 43 had P falciparum and 28 had mixed malaria.79% patients were male. Maximum (51.56%) patients were in 21-30 age group. The mean duration of symptoms was 2.54 days in vivax to 3.03 days in mixed malaria. Fever was observed in 97.8% of patients of vivax. Thrombocytopenia was observed in 99% of all patients. Splenomegaly was noticed in 24.84% patients of vivax and 34.5% of falciparum malaria. Herpes labialis was observed in 23.64% patients of vivax and 5.94% had urticaria. CONCLUSIONS: High index of suspicion should be maintained in picking up the diagnosis. Any patient with thrombocytopenia, leucopenia, headache, herpes labialis, pain epigastrium and urticaria deserves exclusion of malaria. PMID- 27762109 TI - A Comparative Study of Concurrent Dengue and Malaria Infection with their Monoinfection in a Teaching Hospital in Mumbai. AB - OBJECTIVE: This comparative cross sectional study was conducted in a teaching hospital in Mumbai during the monsoon of 2014.A significant number of dengue and malaria co-infection cases, along with dengue, malaria and other infective causes of acute febrile illnesses were noted. The objective of the present study was to understand the interplay of both infections. Since the first such reported case in 2005, studies and data on such cases are scarce, hence this study. AIM: To compare the clinical course, laboratory features, severity and outcome of coinfection with monoinfection of malaria and dengue. Malaria sub species too were included in the study. RESULTS: In the study period of April-Nov 2014, a comparative cross sectional retrospective study of co-infections of concurrent malaria and dengue (Group A), isolated Dengue (Group B) and isolated Malaria (Group C) was carried out. Out of 156 febrile cases included, 85 (54.48%) were dengue monoinfection, 55 (35.25%) isolated malaria, (P. falciparum- 23 -41.81%, P. vivax 16-29.09% and mixed -16-29.09%) and 16 (10.25%) were co infection cases. The coinfection and dengue groups presented with a similar clinical picture though in the coinfection group, epigastric distress was notable. Among compared laboratory parameters, transaminitis was statistically significant in the co infection group (p value <0.001). Anaemia was significant in the malaria group whereas the dengue group presented with raised haematocrit. The coinfection group with low haemoglobin and haematocrit, was consistent with concurrent malaria co infection. Among the severity parameters, bleeding manifestations, renal dysfunction and jaundice, were notable in the coinfection group, compared to the malaria group (12% and 3.6%, 6.3% and 3.6% and 6.3% and 3.6% respectively). Dengue monoinfection group, despite being the largest and with significant incidence of thrombocytopenia (p<0.001), recovered fully. One death was encountered in the coinfection group, with a mortality of 6.3% (1/16) compared to 5.5% (3/55) in the malaria group. PMID- 27762110 TI - Executive Summary: A Consensus Statement - Part I: Recommendations for the Management of Chronic Venous Disease (CVD) in India and Key Role of Primary Care Doctors. PMID- 27762111 TI - Management of Pregnancy in Lupus Patients. AB - Systemic lupus erythematosus (SLE) mostly affects young women of reproductive age group. SLE patients may conceive as any normal woman but complication may occur in these patients if the disease is active. Pregnancy in SLE may lead to 1. Aggravation of SLE (Lupus flare) 2. Pre-term delivery, intrauterine growth retardation and foetal loss (in presence of antiphospholipid antibodies) 3. Neonatal lupus especially in presence of Anti-Ro / La antibody. For a successful pregnancy, both from maternal and foetal aspects, disease should be quiescent for at least six months before the conception. Lupus patients with pregnancy require specific management to improve the maternal and fetal outcomes. Many safe drugs are available for the management of pregnancy in SLE. PMID- 27762112 TI - Importance of Therapeutic Drug Monitoring of Rifampicin. AB - Therapeutic Drug Monitoring (TDM) is a routinely practised clinical laboratory technique which aids the clinicians with a clear clinical judgement of the drug therapy and optimize the doses if necessary. Rifampicin is the most important and potent component of first line therapy of tuberculosis (TB). Several factors like age, weight, gender, doses and formulations, gastro-intestinal disorders, ethnicity etc alter the absorption and bioavailability of rifampicin thus altering the drug levels. Low plasma levels of rifampicin may play a plausible role in slow response to therapy, treatment failure or relapse or acquired drug resistance. TB Patients with further complicated conditions like diabetes or HIV are at an increased risk for poor drug absorption and drug-drug interactions. A standard treatment regimen may be inadequate for some cases as the clinical status of patients vary from case to case. TDM can be used as a clinical tool for identifying patients at high risk of treatment failure, delayed response, drug drug interactions and help optimization of therapy. In the past two decades numerous reports of TDM of anti-tuberculosis drugs have been reported wherein low rifampicin levels have been a major concern. Rifampicin exhibit concentration dependent killing of mycobacteria. A 2 hour post-dose sample approximates the peak plasma rifampicin concentration (Cmax) and is recommended for TDM of rifampicin. An additional 6 hour sample may be collected to distinguish between delayed absorption and malabsorption. Combined with clinical and bacteriological data, TDM can help clinicians treat slow response / complicated TB patients. PMID- 27762113 TI - Normal Distribution, "p" Value and Confidence Intervals. PMID- 27762114 TI - Dyke-Davidoff-Masson Syndrome. PMID- 27762115 TI - Recurrent Respiratory Infection and Hemoptysis in a Young Lady from Rural South India. PMID- 27762116 TI - Cerebellar Toxoplasmosis in an Immunocompetent Patient with G6PD Deficiency. AB - We report a case of an immunocompetent patient who presented with a short history of unilateral cerebellar lesion later proven as toxoplasmosis on histopathology. The case highlights that patients with G6PD deficiency are more prone to develop fatal toxoplasma infections than those individuals with normal G6PD activity. PMID- 27762117 TI - Bilateral Coronary Artery Fistula. AB - Coronary artery anomalies include anomalies of origin, termination, structure or course. Coronary artery fistulae (CAF) are classified as abnormalities of termination and are considered a major congenital anomaly. A coronary artery fistula involves a sizable communication between a coronary artery, bypassing the myocardial capillary bed and entering either a chamber of the heart (coronary cameral fistula) or a great vessel. Bilateral coronary artery fistula, are a rare variant. We describe a bilateral CAF with angina and significant coronary artery disease requiring percutaneous coronary intervention. PMID- 27762118 TI - Fahr's Disease with Seizure Presentation. AB - Fahr's disease or Fahr's syndrome is a rare neurodegenerative disorder characterized by abnormal symmetrical calcifications of the basal ganglia, thalami, sub-cortical hemispheric white matter and deep cerebellar nuclei. It can be idiopathic or associated with an endocrinopathy, frequently with parathyroid disorder. Clinical spectrum of the disease is wide ranging from neurological features like seizure, syncope, stroke like events, extra-pyramidal symptoms often combined with frontal sub-cortical pattern of behavioural dysfunction and psychiatric symptoms such as psychosis, mood disorder and dementia. Diagnosis is based on the clinical features, progressive neurological dysfunction, absence of biochemical abnormality and characteristic radiological imaging. PMID- 27762119 TI - Life-Threatening Thrombo-embolic Events in a Case of Dengue Hemorrhagic Fever. AB - In Dengue Hemorrhagic Fever (DHF), hemorrhagic manifestations are common but thrombotic events are uncommonly reported, despite the wide range of increased procoagulant activity during Dengue Fever illness. We report a case of a 55-year old man of Asian Indian ethnicity who developed large vein thrombotic event -Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in the acute phase of DHF. His condition was further complicated by associated thrombocytopenia. The etiological connections between dengue viral infection with thrombocytopenia, DVT/PE and abnormal thrombophilia profile as well as the treatment dilemmas posed in treating a patient of DF with hemorrhagic manifestations and associated DVT/PE, and the role of eltrombopag are discussed. PMID- 27762120 TI - Sudden Simultaneous Cerebellar Infarction in the Territories of the Medial Division of Posterior Inferior Cerebellar Arteries. AB - Strokes involving posterior inferior cerebellar arteries (PICA) are rare and usually unilateral. They can involve either the lateral division or the medial division of PICA. Sudden simultaneous cerebellar infarctions in the medial PICA territories are extremely rare. We report one such patient who presented with acute bilateral cerebellar infarctions in the medial PICA territories. She was a diabetic and had features of diffuse atherosclerotic vertebrobasilar disease. We discuss the anatomical peculiarities of PICA and its blood supply along with the clinical features differentiating the medial and lateral PICA infarctions. We also list out the possible mechanisms of bilateral medial PICA territory infarction. Though bilateral they generally have a good prognosis considering the very small area of blood supply. PMID- 27762121 TI - Cartap Hydrochloride Poisoning. AB - Cartap hydrochloride is a moderately hazardous nereistoxin insecticide that is increasingly used for deliberate self-harm in India. It can cause neuromuscular weakness resulting in respiratory failure. We report a patient with 4% Cartap hydrochloride poisoning who required mechanical ventilation for 36-hours. He recovered without any neurological deficits. We also review literature on Cartap hydrochloride poisoning. PMID- 27762122 TI - Hemoptysis due to Tracheal Diverticulum. AB - Tracheal diverticulum is a rare entity with only 79 symptomatic cases reported till date. We herein describe the case of a 38 year old male who presented with recurrent dry cough and hemoptysis and was diagnosed to have tracheal diverticulum on High Resolution Computed Tomography (HRCT) of chest. This was further confirmed on fibre optic bronchoscopy. PMID- 27762123 TI - Jaundice Heralding the Onset of Thyrotoxic Crisis. AB - Thyrotoxic crisis is a life threatening medical condition that requires urgent diagnosis and treatment. Because of the wide variety of presenting symptoms, its diagnosis can be difficult in some cases and a high index of suspicion is required for diagnosis. We present a case of 53 year old patient who presented with fever, jaundice and passage of loose stools. Upon investigations other etiologies for hepatic injury were ruled out and she was found to be in thyrotoxic crisis causing liver injury. PMID- 27762124 TI - Systolic Murmur Due to Systolic Gradient Across Moderator Band. AB - A 14 years asymptomatic male was evaluated for a grade 3/6 systolic murmur along lower left parasternal region. Color Doppler evaluation revealed turbulent systolic flow across moderator band with a peak systolic gradient of 127.2 mm hg. There was no other abnormality. This anomaly should be considered in differential diagnosis of systolic murmur in tricuspid area. PMID- 27762125 TI - Bortezomib Based Chemotherapy for Light Chain Deposition Disease. AB - Light chain deposition disease (LCDD) is a rare systemic disorder in which monoclonal light chains are abnormally secreted due to clonal proliferation of plasma cells and get deposited in various organs; the kidneys being the common one to be affected leading to renal failure. Advocated therapeutic options include chemotherapy with alkylating agents and steroids, High-Dose Melphalan (HDM) with Autologous Stem Cell Transplantation. Recently, Bortezomib has proven to be a novel therapeutic option in these patients when combined with dexamethasone. Here, we report a patient who presented with acute renal failure, was diagnosed to have LCDD and treated with bortezomib and dexamethasone. PMID- 27762127 TI - Stroke. PMID- 27762126 TI - Dengue Encephalitis. AB - Dengue infection accompanied by unusual complications and manifestations has been described before. Here we report a case of dengue encephalitis who was IgM positive for dengue serology and had presented to us with only motor weakness after an acute febrile episode. Dengue presenting as encephalitis is in itself a very rare feature and that too, pure motor weakness has hardly ever been reported before. PMID- 27762128 TI - August Krogh and Gas Exchange. PMID- 27762129 TI - CA-125 Testing in Females with Ascites: A Red Herring. PMID- 27762130 TI - Diagnostic Dilemma of Tubercular Ascites, where we are. PMID- 27762131 TI - Vitamin D Deficiency Presenting as Fatigue. PMID- 27762132 TI - Gas-Particle Partitioning of Vehicle Emitted Primary Organic Aerosol Measured in a Traffic Tunnel. AB - We measured the gas-particle partitioning of vehicle emitted primary organic aerosol (POA) in a traffic tunnel with three independent methods: artifact corrected bare-quartz filters, thermodenuder (TD) measurements, and thermal desorption gas-chromatography mass-spectrometry (TD-GC-MS). Results from all methods consistently show that vehicle emitted POA measured in the traffic tunnel is semivolatile under a wide range of fleet compositions and ambient conditions. We compared the gas-particle partitioning of POA measured in both tunnel and dynamometer studies and found that volatility distributions measured in the traffic tunnel are similar to volatility distributions measured in the dynamometer studies, and predict similar gas-particle partitioning in the TD. These results suggest that the POA volatility distribution measured in the dynamometer studies can be applied to describe gas-particle partitioning of ambient POA emissions. The POA volatility distribution measured in the tunnel does not have significant diurnal or seasonal variations, which indicate that a single volatility distribution is adequate to describe the gas-particle partitioning of vehicle emitted POA in the urban environment. PMID- 27762133 TI - Replacement of 2'-Deoxycytidine by 2'-Deoxycytidine Analogues in the E. coli Genome. AB - Several modified bases have been observed in the genomic DNA of bacteriophages, prokaryotes, and eukaryotes that play a role in restriction systems and/or epigenetic regulation. In our efforts to understand the consequences of replacing a large fraction of a canonical nucleoside with a modified nucleoside, we previously replaced around 75% of thymidine (T) with 5'-hydroxymethyl-2' deoxyuridine (5hmU) in the Escherichia coli genome. In this study, we engineered the pyrimidine nucleotide biosynthetic pathway using T4 bacteriophage genes to achieve approximately 63% replacement of 2'-deoxycytidine (dC) with 5 hydroxymethyl-2'-deoxycytidine (5hmC) in the E. coli genome and approximately 71% replacement in plasmids. We further engineered the glucose metabolic pathway to transform the 5hmC into glucosyl-5-hydroxymethyl-2'-deoxycytidine (5-gmC) and achieved 20% 5-gmC in the genome and 45% 5-gmC in plasmid DNA. PMID- 27762134 TI - Photo-Carrier Multi-Dynamical Imaging at the Nanometer Scale in Organic and Inorganic Solar Cells. AB - Investigating the photocarrier dynamics in nanostructured and heterogeneous energy materials is of crucial importance from both fundamental and technological points of view. Here, we demonstrate how noncontact atomic force microscopy combined with Kelvin probe force microscopy under frequency-modulated illumination can be used to simultaneously image the surface photopotential dynamics at different time scales with a sub-10 nm lateral resolution. The basic principle of the method consists in the acquisition of spectroscopic curves of the surface potential as a function of the illumination frequency modulation on a two-dimensional grid. We show how this frequency-spectroscopy can be used to probe simultaneously the charging rate and several decay processes involving short-lived and long-lived carriers. With this approach, dynamical images of the trap-filling, trap-delayed recombination and nongeminate recombination processes have been acquired in nanophase segregated organic donor-acceptor bulk heterojunction thin films. Furthermore, the spatial variation of the minority carrier lifetime has been imaged in polycrystalline silicon thin films. These results establish two-dimensional multidynamical photovoltage imaging as a universal tool for local investigations of the photocarrier dynamics in photoactive materials and devices. PMID- 27762135 TI - Contribution of Mass Spectrometry-Based Proteomics to the Understanding of TNF alpha Signaling. AB - NF-kappaB is a family of ubiquitous dimeric transcription factors that play a role in a myriad of cellular processes, ranging from differentiation to stress response and immunity. In inflammation, activation of NF-kappaB is mediated by pro-inflammatory cytokines, in particular the prototypic cytokines IL-1beta and TNF-alpha, which trigger the activation of complex signaling cascades. In spite of decades of research, the system level understanding of TNF-alpha signaling is still incomplete. This is partially due to the limited knowledge at the proteome level. The objective of this review is to summarize and critically evaluate the current status of the proteomic research on TNF-alpha signaling. We will discuss the merits and flaws of the existing studies as well as the insights that they have generated into the proteomic landscape and architecture connected to this signaling pathway. Besides delineating past and current trends in TNF-alpha proteomic research, we will identify research directions and new methodologies that can further contribute to characterize the TNF-alpha associated proteome in space and time. PMID- 27762136 TI - A Second-Generation Synthesis of the Cyanthiwigin Natural Product Core. AB - An improved synthesis of the cyanthiwigin natural product core enabled by new catalytic technology is reported. The key double catalytic enantioselective alkylation has been reoptimized using a recently developed protocol employing low loadings of palladium catalyst, thereby facilitating large-scale production of the tricyclic cyanthiwigin framework. Additionally, preparation of the penultimate aldehyde intermediate is expedited through the application of anti Markovnikov Tsuji-Wacker oxidation. PMID- 27762137 TI - Oxidative Stability of Pomegranate (Punica granatum L.) Seed Oil to Simulated Gastric Conditions and Thermal Stress. AB - The fatty acid composition of pomegranate (Punica granatum L.) seed oil (PSO) is dominated by punicic acid, a conjugated linolenic acid (18:3omega-5). As a free fatty acid, punicic acid is rapidly oxidized in air and extensively isomerizes upon acid-catalyzed methylation at 90 degrees C. In contrast, triacylglycerol bound punicic acid in PSO was unchanged by simulated gastric conditions and was degraded by 5-7% by severe heating (up to 170 degrees C for 4 h), as herein assessed by gas chromatography, attenuated total reflectance-Fourier transform infrared spectroscopy, 1H and 13C NMR, and high-resolution electrospray ionization mass spectrometry. Total polar compounds of PSO were slightly affected by thermal stress, accounting for 5.71, 6.35, and 9.53% (w/w) in the unheated, heated at mild temperature (50 degrees C, 2 h), and heated at frying temperature (170 degrees C, 4 h) PSO, respectively. These findings support from a structural standpoint the potential use of PSO as a health-promoting edible oil. PMID- 27762138 TI - Model System-Guided Protein Interaction Mapping for Virus Isolated from Phloem Tissue. AB - Phloem localization of plant viruses is advantageous for acquisition by sap sucking vectors but hampers host-virus protein interaction studies. In this study, Potato leafroll virus (PLRV)-host protein complexes were isolated from systemically infected potato, a natural host of the virus. Comparing two different co-immunoprecipitation (co-IP) support matrices coupled to mass spectrometry (MS), we identified 44 potato proteins and one viral protein (P1) specifically associated with virus isolated from infected phloem. An additional 142 proteins interact in complex with virus at varying degrees of confidence. Greater than 80% of these proteins were previously found to form high confidence interactions with PLRV isolated from the model host Nicotiana benthamiana. Bioinformatics revealed that these proteins are enriched for functions related to plasmodesmata, organelle membrane transport, translation, and mRNA processing. Our results show that model system proteomics experiments are extremely valuable for understanding protein interactions regulating infection in recalcitrant pathogens such as phloem-limited viruses. PMID- 27762139 TI - Extremely Low-Cost, Scalable Oxide Semiconductors Employing Poly(acrylic acid) Decorated Carbon Nanotubes for Thin-Film Transistor Applications. AB - In this study, we report for the first time a simple bar-coating process of soluble metal oxide semiconductors, consuming the 0.1 g of precursor solution in 4 in. sized devices with a cost of only $0.05. To resolve the issue of critical degradation in device performance observable in slow-evaporation-based film formation processes, we incorporate the unprecedentedly developed, poly(acrylic acid)-decorated multiwalled carbon nanotubes (MWNTs) in oxide semiconductors. It is demonstrated that a field-effect mobility is improved to the value of 7.34 cm2/(V s) (improvement by a factor of 2) without any critical variation in threshold voltage and on/off current ratio. PMID- 27762140 TI - Solution-Processed Rare-Earth Oxide Thin Films for Alternative Gate Dielectric Application. AB - Previous investigations on rare-earth oxides (REOs) reveal their high possibility as dielectric films in electronic devices, while complicated physical methods impede their developments and applications. Herein, we report a facile route to fabricate 16 REOs thin insulating films through a general solution process and their applications in low-voltage thin-film transistors as dielectrics. The formation and properties of REOs thin films are analyzed by atomic force microscopy (AFM), X-ray diffraction (XRD), spectroscopic ellipsometry, water contact angle measurement, X-ray photoemission spectroscopy (XPS), and electrical characterizations, respectively. Ultrasmooth, amorphous, and hydrophilic REO films with thickness around 10 nm have been obtained through a combined spin coating and postannealing method. The compositional analysis results reveal the formation of RE hydrocarbonates on the surface and silicates at the interface of REOs films annealed on Si substrate. The dielectric properties of REO films are investigated by characterizing capacitors with a Si/Ln2O3/Au (Ln = La, Gd, and Er) structure. The observed low leakage current densities and large areal capacitances indicate these REO films can be employed as alternative gate dielectrics in transistors. Thus, we have successfully fabricated a series of low voltage organic thin-film transistors based on such sol-gel derived REO films to demonstrate their application in electronics. The optimization of REOs dielectrics in transistors through further surface modification has also been studied. The current study provides a simple solution process approach to fabricate varieties of REOs insulating films, and the results reveal their promising applications as alternative gate dielectrics in thin-film transistors. PMID- 27762141 TI - Omniphobic Polyvinylidene Fluoride (PVDF) Membrane for Desalination of Shale Gas Produced Water by Membrane Distillation. AB - Microporous membranes fabricated from hydrophobic polymers such as polyvinylidene fluoride (PVDF) have been widely used for membrane distillation (MD). However, hydrophobic MD membranes are prone to wetting by low surface tension substances, thereby limiting their use in treating challenging industrial wastewaters, such as shale gas produced water. In this study, we present a facile and scalable approach for the fabrication of omniphobic polyvinylidene fluoride (PVDF) membranes that repel both water and oil. Positive surface charge was imparted to an alkaline-treated PVDF membrane by aminosilane functionalization, which enabled irreversible binding of negatively charged silica nanoparticles (SiNPs) to the membrane through electrostatic attraction. The membrane with grafted SiNPs was then coated with fluoroalkylsilane (perfluorodecyltrichlorosilane) to lower the membrane surface energy. Results from contact angle measurements with mineral oil and surfactant solution demonstrated that overlaying SiNPs with ultralow surface energy significantly enhanced the wetting resistance of the membrane against low surface tension liquids. We also evaluated desalination performance of the modified membrane in direct contact membrane distillation with a synthetic wastewater containing surfactant (sodium dodecyl sulfate) and mineral oil, as well as with shale gas produced water. The omniphobic membrane exhibited a stable MD performance, demonstrating its potential application for desalination of challenging industrial wastewaters containing diverse low surface tension contaminants. PMID- 27762142 TI - Synthesis, structural studies, and cytotoxic evaluation of novel ursolic acid hybrids with capabilities to arrest breast cancer cells in mitosis. AB - Some novel chemically modified frameworks of ursolic acid have been designed and synthesized. The key step was the cycloaddition of azidopropyl-3beta-hydroxy-urs 12-en-28-oate with the appropriate C28 propargyl esters of ursolic, corosolic, asiatic, oleanolic, and betulinic acid under Click reaction conditions, and the products were obtained in 74-84% yields. In view of their intriguing structural diversity, they have been subjected to detailed 1D and 2D NMR studies and their structures are thoroughly assigned. The synthesized compounds were screened for their anticancer potential against two human breast cancer cell lines (MCF-7 & MDA-MB-231) using sulforhodamine B cell proliferation assay. The GI50 data revealed that the synthesized compounds exhibit highly potent activities against the two tested cell lines. Interestingly, the synthesized compounds showed selectivity and higher activity against MDA-MB-231 cell line than MCF-7. Among the tested compounds, compound 17 is the most potent one with GI50 value of 1.4 +/- 0.1 MUM and showed 2.9 times more activity than the standard doxorubicin against MDA-MB-231. In addition, 17 arrests cells in mitotic phase of cell cycle, resulting in a change in cell phenotype. In view of the selective and highly promising activity against breast cancer cell lines, these compounds can serve as promising leads for further development. PMID- 27762143 TI - Diagnostic value of serum squamous cell carcinoma antigen for hepatocellular carcinoma: a systematic review and meta-analysis. AB - The aim of this study was to ascertain the diagnostic value of serum squamous cell carcinoma antigen (SCCA) and SCCA-IgM for hepatocellular carcinoma (HCC). After a comprehensive search of PubMed and Web of Science databases, we identified eligible studies on the diagnostic value serum SCCAs for HCC. The quality of the eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool. The overall diagnostic value of SCCAs for HCC was pooled using a bivariate model. Twelve studies were included in this systematic review and meta-analysis. The pooled sensitivities for SCCA and SCCA-IgM were 0.61 (95% confidence interval [CI], 0.37-0.81) and 0.70 (95% CI, 0.55-0.82), respectively. The corresponding specificities were 0.80 (95% CI, 0.52-0.94) and 0.62 (95% CI, 0.51-0.72), respectively. The areas under summary receiver operating characteristic (sROC) curves for SCCA and SCCA-IgM were 0.76 (95% CI, 0.72-0.80) and 0.70 (95% CI, 0.66-0.74), respectively. Major design deficiencies of the included studies were two-gate design and partial verification bias. Therefore, we concluded that both serum SCCA and SCCA-IgM have a fair diagnostic value for HCC. PMID- 27762144 TI - Impacts of regulated competition on pricing in Chinese pharmaceutical market under urban employee basic medical insurance. AB - BACKGROUND: Examine the effects of regulated competition on the drug pricing in China. METHODS: Based on product-level data, a regression method was employed for pricing by using data from Tianjin Urban Employee Basic Medical Insurance (UEBMI) database. The market competition measures distinguished generic competition within the same molecule from therapeutic competition within the same therapeutic class. RESULTS: The increases in pricing are inversely related to the number of generic competitions. The generic sub-group results vary from the originator sub group. For the generics, generic competition has a significantly reduced effect on the price; however, only therapeutic competition has a significantly reduced effect on the originator price. CONCLUSIONS: Regulated competition has a positive role in shaping the pharmaceutical market. Furthermore, regulated competition affects the price differently for the sub-groups. The promotion of competition between generic and originator in order to reap full competition benefit and reduce frictions among policies are necessary. PMID- 27762145 TI - Elevated prostate specific antigen and reduced 10-year survival among a cohort of Danish men consecutively referred from primary care to an urological department during 2005-2006. AB - It remains unclear whether total prostate specific antigen (tPSA) or complex PSA (cPSA) has the best diagnostic performance. Additionally, the utility of percentage free PSA (%fPSA) is still debated. Our objectives were to compare the diagnostic performances of tPSA, cPSA, and %fPSA among patients referred from GP to an Urological Specialist and to investigate prognostic factors and survival in the cohort. A total of 1261 consecutive male patients without previously known prostate cancer (PCa) were referred to the same Department of Urology during June 2005 to August 2006. Some 299 patients were diagnosed with PCa and 962 patients were found without PCa. Among the PCa patients, the median age, tPSA, cPSA, and %fPSA levels were 70.8 years, 13.4 MUg/L, 10.8 MUg/L, and 12.6%. For patients without PCa the results were 67.5 years, 2.5 MUg/L, 1.9 MUg/L, and 24.9%. The sensitivity, specificity, PVpos, PVneg, and efficiency of tPSA and cPSA were overlapping (p > .05). In the tPSA interval >4 MUg/L - <=20 MUg/L, %fPSA excluded PCa with a PVneg of 72.4%; 38.5% of PCa patients had a tPSA concentration >20 MUg/L at the time of referral and these patients had a reduced 10-year survival as compared to patients with tPSA concentrations <=20 MUg/L. In conclusion, tPSA and cPSA showed similar diagnostic performances. %fPSA provided additional diagnostic information at tPSA concentrations >4 MUg - <=20 MUg/L. The high percentage of patients with tPSA concentrations >20 MUg/L indicate delayed use of tPSA resulting in advanced disease at presentation and reduced patient survival. PMID- 27762146 TI - Combined QSAR-based virtual screening and fluorescence binding assay to identify natural product mediators of Interferon Regulatory Factor 7 (IRF-7) in pulmonary infection. AB - Interferon regulatory factor-7 (IRF-7) is involved in pulmonary infection and pneumonia. Here, a synthetic strategy that combined quantitative structure activity relationship (QSAR)-based virtual screening and in vitro binding assay was described to identify new and potent mediator ligands of IRF-7 from natural products. In the procedure, a QSAR scoring function was developed and validated using Gaussian process (GP) regression and a structure-based set of protein ligand affinity data. By integrating hotspot pocket prediction, pharmacokinetics profile analysis and molecular docking calculations, the scoring function was successfully applied to virtual screening against a large library of structurally diverse, drug-like natural products. With the method we were able to identify a number of potential hits, from which several compounds were found to have moderate or high affinity to IRF-7 using fluorescence binding assays, with dissociation constants Kd at micromolar level. We have also examined the structural basis and noncovalent interactions of computationally modelled IRF-7 complex with its potent ligands. It is revealed that hydrophobic forces and van der Waals contacts play a central role in stabilization of the complex architecture, while few hydrogen bonds confer additional specificity for the protein-ligand recognition. PMID- 27762147 TI - Effects of icon size and location on speed and accuracy of SGD access. AB - Increasing speed and accuracy of communication via a speech-generating device (SGD) is an important clinical goal in augmentative and alternative communication (AAC). The current study, conducted with adults without disabilities using a within-subject experimental design, compared the effects of two different SGD trainings on speed and accuracy of locating words via an SGD interface. During size-centered training, participants were introduced to six large icons that completely filled an SGD screen. During location-centered training, participants were introduced to six small icons on a 40-location screen where other icons were hidden. After the training, participants were asked to find the trained items on a 40-location screen with all 40 icons visible. Accuracy and speed of response were analyzed, and the study found that participants located targets faster and more accurately following location-centered training vs. following size-centered training. If similar effects are found with individuals with complex communication needs, clinicians should consider implementing SGD grid designs that facilitate location-centered learning. PMID- 27762148 TI - Strategies to limit immune-activation in HIV patients. AB - INTRODUCTION: Antiretroviral treatment of HIV infection reduces, but does not eliminate, viral replication and down modulates immune activation. The persistence of low level HIV replication in the host, nevertheless, drives a smouldering degree of immune activation that is observed throughout the natural history of disease and is the main driving force sustaining morbidity and mortality. Areas covered: Early start of antiretroviral therapy (ART) and intensive management of behavioural risk factors are possible but, at best, marginally successful ways to manage immune activation. We review alternative, possible strategies to reduce immune activation in HIV infection including timing of ART initiation and ART intensification to reduce HIV residual viremia; switch of ART to newer molecules with reduced toxicity; use of anti inflammatory/immunomodulatory agents and, finally, interventions aimed at modifying the composition of the microbiota. Expert commentary: Current therapeutic strategies to limit immune activation are only marginally successful. Because HIV eradication is currently impossible, intensive studies are needed to determine if and how immune activation can be silenced in HIV infection. PMID- 27762149 TI - Post-cholecystectomy syndrome and sphincter of Oddi dysfunction: past, present and future. AB - INTRODUCTION: Post-cholecystectomy syndrome and the concept of a causal relationship to sphincter of Oddi dysfunction, despite the controversy, has presented a clinically relevant conflict for decades. Historically surgeons, and now gastroenterologists have expended tremendous efforts towards trying to better understand the dilemma that is confounded by unique patient phenotypes. Areas covered: This review encompasses the literature from a century of experience on the topic of post-cholecystectomy syndrome. Relevant historical and anecdotal experiences are examined in the setting of insights from evaluation of recently available controlled data. Expert commentary: Historical observations and recent data suggest that patients with post-cholecystectomy syndrome can be categorized as follows. Patients with sphincter of Oddi stenosis will most often benefit from treatment with sphincterotomy. Patients with classic biliary pain and some objective evidence of biliary obstruction may have a sphincter of Oddi disorder and should be considered for endoscopic evaluation and therapy. Patients with atypical post-cholecystectomy pain, without any evidence consistent with biliary obstruction, and/or with evidence for another diagnosis or dysfunction should not undergo ERCP. PMID- 27762150 TI - Epigenetic regulation of hepatic stellate cell activation and liver fibrosis. AB - INTRODUCTION: Chronic liver injury to hepatocytes or cholangiocytes, when left unmanaged, leads to the development of liver fibrosis, a condition characterized by the excessive intrahepatic deposition of extracellular matrix proteins. Activated hepatic stellate cells constitute the predominant source of extracellular matrix in fibrotic livers and their transition from a quiescent state during fibrogenesis is associated with important alterations in their transcriptional and epigenetic landscape. Areas covered: We briefly describe the processes involved in hepatic stellate cell activation and discuss our current understanding of alterations in the epigenetic landscape, i.e DNA methylation, histone modifications and the functional role of non-coding RNAs that accompany this key event in the development of chronic liver disease. Expert commentary: Although great progress has been made, our understanding of the epigenetic regulation of hepatic stellate cell activation is limited and, thus far, insufficient to allow the development of epigenetic drugs that can selectively interrupt liver fibrosis. PMID- 27762151 TI - The development of an observational screening tool to assess safe, effective and appropriate walking aid use in people with multiple sclerosis. AB - PURPOSE: The purpose of this study was to identify potential items for an observational screening tool to assess safe, effective and appropriate walking aid use among people with multiple sclerosis (MS). Such a tool is needed because of the association between fall risk and mobility aid use in this population. METHODS: Four individuals with MS were videotaped using a one or two straight canes, crutches or a rollator in different settings. Seventeen health care professionals from Canada, Ireland and the United States were recruited, and viewed the videos, and were then interviewed about the use of the devices by the individuals in the videos. Interview questions addressed safety, effectiveness and appropriateness of the device in the setting. Data were analyzed qualitatively. Coding consistency across raters was evaluated and confirmed. RESULTS: Nineteen codes were identified as possible items for the screening tool. The most frequent issues raised regardless of setting and device were "device used for duration/abandoned", "appropriate device", "balance and stability", "device technique", "environmental modification" and "hands free." CONCLUSION: With the identification of a number of potential tool items, researchers can now move forward with the development of the tool. This will involve consultation with both healthcare professionals and people with MS. Implications for rehabilitation Falls among people with multiple sclerosis are associated with mobility device use and use of multiple devices is associated with greater falls risk. The ability to assess for safe, effective and efficient use of walking aids is therefore important, no tools currently exist for this purpose. The codes arising from this study will be used to develop a screening tool for safe, effective and efficient walking aid use with the aim of reducing falls risk. PMID- 27762152 TI - MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development. AB - INTRODUCTION: Macrophage migration inhibitory factor (MIF) has emerged as a promising drug target in diseases including sepsis, rheumatoid arthritis, and cancer. MIF has multiple properties that favor development of specific, targeted therapies: it is expressed broadly among human cells, has noted roles in diverse inflammatory and oncological processes, and has intrinsic enzymatic activity amenable to high-throughput screening. Despite these advantages, anti-MIF therapy remains well behind other cytokine-targeted therapeutics, with no small molecules in the pipeline for clinical development and anti-MIF antibodies only recently beginning clinical trials. Areas covered: In this review we summarize current literature regarding MIF structure and function-including challenges and controversies that have arisen in studies of anti-MIF therapeutics-and propose a strategy for development of clinically relevant anti-MIF drugs. Expert opinion: We believe that the field of anti-MIF therapeutics would benefit from capitalizing on the protein's multiple assets while acknowledging their flaws. The tautomerase enzymatic site of MIF may not be active biologically, but can nonetheless offer a high-throughput method to highlight molecules of interest that can affect its other, frequently intertwined bioactivities. Future work should also focus on developing more robust assays for MIF bioactivity that can be used for second-pass screening and specificity studies. PMID- 27762153 TI - Olive polyphenols: new promising agents to combat aging-associated neurodegeneration. AB - INTRODUCTION: Clinical trials and population studies indicate the healthy virtues of the Mediterranean diet and its main lipid component, extra-virgin olive oil (EVOO). Olive leaves and EVOO contain many phenolics effective against several aging and lifestyle-related diseases, including neurodegeneration, both in animal models and in humans. Recent research has shown that such protection stems from several effects, including (i.) the interference with the aggregation of peptides/proteins found in amyloid diseases, particularly in Alzheimer's and Parkinson's diseases; (ii.) the protection of cells and tissues against aging associated functional derangement (ion/redox homeostasis, aberrant cell signaling, etc.); (iii.) the transcriptional modulation through epigenetic modifications. Area covered: We used MEDLINE for literature reference; we also searched ClinicalTrials.gov to select clinical trials with olive oil and/or its polyphenols that suggested their potential particularly for what neuroprotective therapy is concerned. Expert commentary: We focus the relation between diet components, particularly olive polyphenols, and protection against the occurrence of the most widespread neurodegenerative conditions associated with aging. The need of more clinical studies in humans to confirm the results obtained in animal and cell models to definitely support the utility of these molecules to combat or to delay the symptoms associated to aging-associated neurodegeneration is also stressed. PMID- 27762154 TI - Corrigendum. PMID- 27762155 TI - Improving confidence in (Q)SAR predictions under Canada's Chemicals Management Plan - a chemical space approach. AB - One of the key challenges of Canada's Chemicals Management Plan (CMP) is assessing chemicals with limited/no empirical hazard data for their risk to human health. In some instances, these chemicals have not been tested broadly for their toxicological potency; as such, limited information exists on their potential to induce human health effects following exposure. Although (quantitative) structure activity relationship ((Q)SAR) models are able to generate predictions to address data gaps for certain toxicological endpoints, the confidence in predictions also needs to be addressed. One way to address this issue is to apply a chemical space approach. This approach uses international toxicological databases, for example, those available in the Organisation for Economic Co-operation and Development (OECD) QSAR Toolbox. The approach,assesses a model's ability to predict the potential hazards of chemicals that have limited hazard data that require assessment under the CMP when compared to a larger, data-rich chemical space that is structurally similar to chemicals of interest. This evaluation of a model's predictive ability makes (Q)SAR analysis more transparent and increases confidence in the application of these predictions in a risk-assessment context. Using this approach, predictions for such chemicals obtained from four (Q)SAR models were successfully classified into high, medium and low confidence levels to better inform their use in decision-making. PMID- 27762156 TI - Strategies for managing transient tachypnoea of the newborn - a systematic review. AB - OBJECTIVE: To conduct a systematic review of strategies for the management of transient tachypnoea of the newborn (TTN). METHODS: The Cochrane Collaboration and PRISMA guidelines were used for conducting and reporting this systematic review, respectively. The Cochrane Central Register of Controlled Trials, PubMed, CINAHL and EMBASE databases were searched in February 2016. Only randomised and quasi-randomised controlled trials (RCTs) assessing any intervention for the management of TTN in infants <7 days of age, born at 35 or more weeks with a clinical diagnosis of TTN were eligible for inclusion. Primary outcomes included the duration of respiratory support, oxygen support, tachypnoea and hospitalisation. RESULTS: Nine RCTs with moderate risk of bias were included. The interventions assessed included furosemide (2 trials, n = 100), inhaled salbutamol (2 trials, n = 94), inhaled epinephrine (1 trial, n = 20), restrictive fluids (2 trials, n = 146) and non-invasive ventilation (2 trials, n = 80). Amongst all interventions, inhaled salbutamol significantly reduced the duration of hospitalisation (2 trials, n = 94) [mean difference (MD) - 1.63 days (95% CI 2.71 to -0.55); p = 0.003] and duration of oxygen requirement (1 trial, n = 37) [MD - 43.10 h (95% CI -81.82 to -4.38; p = 0.03] without adverse effects. CONCLUSION: Limited low-quality evidence exists on the effects of different management strategies for TTN. The safety and efficacy of inhaled salbutamol in the treatment of TTN can be assessed in a large RCT. PMID- 27762157 TI - Individualizing management of extensively drug-resistant tuberculosis: diagnostics, treatment, and biomarkers. AB - INTRODUCTION: Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure. Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of XDR-TB. Improved diagnostic procedures and rapid molecular tests help to select appropriate drugs and dosages. Drugs dosages can be further tailored to the specific conditions of the patient based on quantitative susceptibility testing of the M. tuberculosis isolate and use of therapeutic drug monitoring. Pharmacovigilance is important for preserving activity of the novel drugs bedaquiline and delamanid. Furthermore, biomarkers of treatment response must be developed and validated to guide therapeutic decisions. Expert commentary: Given the currently poor treatment outcomes and the association of XDR-TB with HIV in endemic regions, a more patient oriented approach regarding diagnostics, drug selection and tailoring and treatment evaluation will improve treatment outcome. The different areas of expertise should be covered by a multidisciplinary team and may involve the transition of patients from hospitalized to home or community-based treatment. PMID- 27762158 TI - Perception and description of New World non-human primates in the travel literature of the fifteenth and sixteenth centuries: a critical review. AB - The current work presents the results of a review of most of the European diaries and travel chronicles containing reports of New World non-human primates dating from the discovery of America in 1492 until the end of the sixteenth century. We report the integral texts translated into English of these literary sources, giving a critical interpretation from a historical and scientific point of view. We note the ways these primates were perceived and described, with attention to the most important characteristics that were highlighted by the first explorers. Ethnotaxonomy and vernacular names used to designate non-human primates are also provided. This new body of knowledge, based largely on empirical reports full of details and first-hand observations, emerged as the first nucleus in the natural history of Neotropical Primates. PMID- 27762159 TI - Experience of plastic surgery registrars in a European Working Time Directive compliant rota. AB - BACKGROUND: Surgical training requires exposure to clinical decision-making and operative experience in a supervised environment. It is recognised that learning ability is compromised when fatigued. The European Working Time Directive requires a decrease in working hours, but compliance reduces trainees' clinical exposure, which has profound implications for plastic surgery training. The aim of this study was to evaluate plastic surgery registrars' experience of an EWTD compliant rota, and to examine its impact on patient care, education, and logbook activity. METHODS: An electronic survey was distributed to plastic surgery registrars in a university teaching hospital. Registrars were asked to rate 31 items on a five-point Likert scale, including statements on patient care, clinical and operative duties, training, and quality-of-life. Interquartile deviations explored consensus among responses. Operative caseload was objectively evaluated using eLogbook data to compare activity at equal time points before and after implementation of the EWTD rota. RESULTS: Highest levels of consensus among respondents were found in positive statements addressing alertness and preparation for theatre, as well as time to read and study for exams. Registrars agreed that EWTD compliance improved their quality-of-life. However, it was felt that continuity of patient care was compromised by work hours restriction. Registrars were concerned about their operative experience. eLogbook data confirmed a fall-off in mean caseload of 31.8% compared to activity prior to EWTD rota implementation. CONCLUSION: While EWTD compliant rotas promote trainee quality-of-life and satisfaction with training, attention needs to be paid to optimising operative opportunities. PMID- 27762160 TI - 'I thought if I marry the prophet I would not die': The significance of religious affiliation on marriage, HIV testing, and reproductive health practices among young married women in Zimbabwe. AB - This study examines the association between religious affiliation and reasons for marriage, perceived church attitudes, and reproductive health-seeking behaviors, including HIV testing, among young women in eastern rural Zimbabwe. The sample comprised women (N = 35) who had married by 2012 while participating in a larger randomized controlled trial (RCT) to test the effects of school support on HIV related risk. The RCT sample was identified in 2007 as all female sixth graders in 25 rural eastern Zimbabwe primary schools whose parents, one or both, had died (N = 328). In our previous RCT analyses, we found that participants who affiliated with an Apostolic church were more than four times more likely to marry than those from non-Apostolic churches and that control group participants were twice as likely to marry as those in the intervention group. Other studies had found that marriage greatly increased the odds of HIV infection among adolescent women. Given the link between Apostolic affiliation and marriage, we conducted semi-structured interviews to explore type of marriage, reasons for marrying, church affiliation and attitudes, family planning, HIV testing, schooling, and family life. We were interested in differences, as perceived by our sample of young married women congregants, among Apostolic sects and other denominations in their attitudes about marriage and health-seeking behaviors. We were also interested in the influence of church affiliation on intervention participants' decision to marry, since they had comprehensive school support and education is highly valued in Zimbabwe, but costly and often out of financial reach. Interviews were conducted from October 2012 through November 2013; data were analyzed using a general inductive approach. We found that pressure or perceived deception for coitus or marriage was reported only by intervention participants affiliated with Apostolic denominations. Other reasons for marriage were similar between Apostolic and non-Apostolic adherents, as well as intervention and control conditions. All participants believed HIV testing was important, but while all non-Apostolic denominations encouraged HIV testing and clinic/hospital care, there was considerable heterogeneity in attitudes among Apostolics, with ultraconservative denominations most likely to proscribe non religious health care. We conclude that some, but not all, Apostolic-affiliated women are afforded discretion in their health-seeking behaviors. Since HIV screening and treatment depend on access to clinic/hospital care, continued public health efforts to engage Apostolic leaders is needed, along with monitoring of progress in access and outcomes. PMID- 27762161 TI - Structural brain changes in first episode mania with and without psychosis: Data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM). AB - OBJECTIVES: The neurobiological underpinnings of bipolar I disorder are not yet understood. Previous structural neuroimaging studies of bipolar disorder have produced rather conflicting results. We hypothesise that clinical sub-phenotypes of bipolar I disorder defined by their psychotic symptoms, especially those with mood-incongruent psychotic features, may have more extensive structural brain abnormalities. METHODS: We investigated structural brain alterations in patients with first-episode mania (n = 55) with mood-congruent (n = 16) and mood incongruent (n = 32) psychotic features, as well as those without psychotic symptoms (n = 7), relative to healthy subjects (n = 56). RESULTS: Total intracranial volume was significantly reduced in patients with mood-incongruent psychosis compared to healthy subjects while cerebrospinal fluid (CSF) volume was significantly increased. Patients with mood-congruent psychosis showed significant reduction in total white matter volume and significant CSF volume increase. Patients with psychosis had significant volume reduction in anterior cingulate and medial prefrontal cortices. Relative to mood-congruent psychotic features, mood-incongruent psychotic features were associated with volume reduction in the left middle temporal gyrus, right inferior parietal gyrus, right fusiform gyrus, left middle orbitofrontal gyrus and cerebellum. CONCLUSIONS: While preliminary, our findings suggest that the presence and type of psychosis in first-episode mania may be phenotypic markers of underlying biological variants of bipolar disorder. PMID- 27762163 TI - Spontaneous recovery of memory functions in an untreated case of anti NMDAR encephalitis - a reason to maintain hope. AB - OBJECTIVE: Anti N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder that was only fully discovered recently and neuropsychological outcome data remains sparse. We present the case of BA, a 19 year-old male, which illustrates the cognitive outcome in an untreated case over a time period of over 21/2 years. METHOD: We conducted three cognitive assessments, including tests of memory and executive functioning, over this time period and considered the evidence for reliable change in memory function using the Wechsler Advanced Clinical Solutions (ACS) serial assessment package. RESULTS: Our findings revealed mild memory problems 6 months post-discharge with, at best, static and potentially declining memory functioning at follow-up assessment 12 months post-discharge. However, the results of testing at 30 months post-discharge revealed significant improvements in immediate and delayed memory index performances. CONCLUSIONS: Our report of a case of anti-NMDAR encephalitis provides evidence for spontaneous improvements in memory functioning occurring more than 2 years after initial assessment and also demonstrates both the utility and potential limitations of the ACS serial assessment software when used in a relatively typical clinical assessment situation. PMID- 27762162 TI - Pfeiffer syndrome: literature review of prenatal sonographic findings and genetic diagnosis. AB - PURPOSE: Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in FGFR1 and FGFR2 genes. Given its wide range of clinical expression and severity, early prenatal diagnosis is difficult and genetic counseling is desirable. We report a literature review of all prenatal diagnosis of PS and a case report, with a focused description of ultrasound findings. METHODS: After literature search, we selected 14 studies of antenatal diagnosis of PS. Prenatal ultrasound findings, outcome, maternal and obstetrical data and genetic tests were recorded and analyzed. RESULTS: A total of 18 cases including the one we present were selected. Among the most frequent sonographic features, skull shape anomalies were evident in 72.2% of cases, nasal abnormalities in 50%, proptosis and hypertelorism in 44.4% and frontal bossing in 22.2%. Thumbs' anomalies were present in 33.3% of cases and toes' abnormalities in 38.9%. In all cases, postnatal or postmortem examination confirmed the prenatal diagnosis of PS. CONCLUSIONS: We provide a literature review of prenatal diagnosis of PS to identify ultrasound features that may be supportive in the diagnosis of this rare disease, helping in making a differential diagnosis with the other possible craniosynostosis syndromes and in suggesting gene molecular testing. PMID- 27762164 TI - Maternal diet and breastfeeding duration of infants after NICU hospitalization in Greece: a cohort study. AB - OBJECTIVES: To investigate the role of maternal diet, personal characteristics and willingness to breastfeed on breastfeeding duration of hospitalized neonates as well as to evaluate the mothers' dietetic intake based on the national recommendations. METHODS: A sample of 161 pregnant women from Athens, Greece was followed up during pregnancy, labor and the first 40 weeks of lactation. The participants attended breastfeeding classes and were interviewed regarding their nutritional habits, personal characteristics and breastfeeding intention. A multivariable logistic regression, adjusted for maternal age, smoking, weeks of gestation, body mass index, mode of delivery was conducted in order to estimate the adjusted odds ratios of breastfeeding for at least 6 months for consuming additional serves of fruit or vegetables from the recommended by the national guidelines. RESULTS: The adjusted odds ratios for breastfeeding at 6 months was 2.15 (p = 0.05) for women consumed >=3.5 servings of fruits/day. Moreover, the participants reported low conformity with the national dietetic guidelines. CONCLUSIONS: Mothers who consumed the recommended by the NDG fruit servings/day breast-fed their hospitalized newborns for a longer period. Despite the fact that our participants were highly motivated and willing to breast-feed, we argue that this relationship is highly unlikely to be biological. PMID- 27762165 TI - Haemostatic disorders in reproductive age women with menorrhagia and effects on quality of life. AB - The aim of this study was to determine the frequency of haemostatic abnormalities in women with menorrhagia and to evaluate their effect on quality of life (QoL). The study population was composed of patients with menorrhagia seen in the outpatient clinic, having a score of >185 with a pictorial blood assessment chart. Structured questionnaires were used in the assessment of demographic characteristics and QoL, and patients were tested for bleeding disorders. Ninety women were recruited for the study. Bleeding disorders were detected in 40% of them: 11.1% had von Willebrand disease, 2.2% had low von Willebrand factor and 26.7% had platelet function disorders (PFD). In 22 (91.6%) cases with PFD the, defect was non-specific and impaired aggregation response to ristocetine (37.5%) was the most commonly detected problem. Bleeding disorders were not associated with any significant reduction in QoL (p > .05). Hereditary bleeding disorders may be the cause of unexplained menorrhagia even in the middle-aged women, but they had no prominent effect on QoL. PMID- 27762166 TI - Birth weight centiles, risk of intrapartum compromise, and adverse perinatal outcomes in term infants. AB - OBJECTIVE: The objective of this study is to evaluate the association between birth weight centiles and the risk of intrapartum compromise and adverse neonatal outcomes in term pregnancies. METHODS: Retrospective study of 32 468 term singleton births at a major tertiary maternity hospital in Australia. Data comprised gestation, mode, and indication for delivery and adverse perinatal outcomes. Fetal sex and gestational age-specific birth weight centiles were the main exposure variable. RESULTS: Neonates <21st birth weight centile had an increased risk of intrapartum compromise, the highest risk was in babies <3rd centile (OR 4.04, 95% CI 3.34-4.89). The risk of adverse perinatal outcomes was increased in neonates <21st and >91st birth weight centiles. The highest risk was in those <3rd centile (OR 2.35, 95% CI 2.00-2.75). CONCLUSIONS: Fetal size measurements near term may be used as part of screening test for identifying fetuses at an increased risk of intrapartum compromise and adverse perinatal outcomes. PMID- 27762168 TI - Laboratory-scale assessment of vacuum-degassed activated sludge for improved settling properties. AB - Vacuum degassing of activated sludge was tested at eight different Swedish wastewater treatment plants with laboratory-scale equipment in batch mode in order to evaluate its efficiency on improvement of sludge compaction and settling properties. The results show that the efficiency of the degassing technique is mainly dependent on the initial sludge volume index (SVI) of the target sludge which was found to be related to its process configuration. Facilities with full activated sludge-based nitrogen removal processes, including both nitrification and denitrification, had high SVIs (>300 mL g-1) and were strongly affected by vacuum degassing with reduction of SVI up to 30%. Nitrogen removal facilities also including biological phosphorus removal showed better compaction and settling properties with relatively lower SVIs and were affected to a lesser extent by degassing with SVI reduction of 10-20%. Wastewater treatment plants without full biological nitrogen removal, lacking either nitrification or denitrification (or both) processes in the activated sludge had the lowest SVIs observed with almost no effect of vacuum degassing. PMID- 27762167 TI - Demographic and clinical characteristics of persons with spinal cord injury in Turkey: One-year experience of a primary referral rehabilitation center. AB - OBJECTIVE: To define the demographic and clinical characteristics of persons with spinal cord injury, rehabilitated in a primary referral rehabilitation center in Turkey. DESIGN: Retrospective study. SETTING: Ankara Physical Medicine and Rehabilitation Training and Research Hospital, Ankara, Turkey. METHODS: Medical records of all patients with spinal cord injury (acute-subacute-chronic) at a single academic referral center over the course of one year were reviewed. Variables of each patient were recorded, including: age, sex, etiology, length of rehabilitation stay, neurological level of injury, level of neurological impairment and severity of injury. RESULTS: Among 262 persons with spinal cord injury, 69.8% were male (male:female ratio is 2.31 : 1). Mean age was 38.3 +/- 17.6 years. Falls were the most common cause of injury. The majority of falls were falls from a height (93.3%). More than 20% of falls from a height were related to occupational injury. The most common neurological level of injury was L1. Of all persons 46.2% had thoracic, 27.5% had lumbar and 26.3% had cervical lesions. The mean length of rehabilitation stay was 52.1 +/- 25.5 days. Persons with motor complete injury and with a shorter (<12 months) time since injury had longer length of rehabilitation stay. CONCLUSION: The mean age of SCI population is increasing. Falls constitute the majority of etiologic factors and are more common in persons >60 years old. More than 20% of falls from a height are related to occupational injury. Male-female ratio is decreasing. Thoraco-lumbar injures are more common than cervical injuries. PMID- 27762169 TI - Gaucher disease epidemiology and natural history: a comprehensive review of the literature. AB - OBJECTIVES: The objectives of this research were: (1) to heighten awareness of Gaucher disease (GD), a rare lysosomal storage disorder with highly heterogeneous patterns of organ involvement and disease severity, to clinicians most likely to encounter these patients, and; (2) to summarize the published evidence on GD epidemiology which is essential to accurately depict the total societal burden of this rare worldwide disorder. METHODS: A comprehensive literature review was undertaken to summarize the published evidence on the epidemiology of GD. MEDLINE, EMBASE, CENTRAL, and 'grey' literature sources published in English between January 1990 and March 2015 were searched to identify relevant publications. RESULTS: In total, 188 full-text articles were reviewed and findings from 49 studies are summarized herein. The standardized birth incidence of GD in the general population varied from 0.39 to 5.80 per 100 000, and prevalence ranged from 0.70 to 1.75 per 100 000, respectively. Time from onset of GD symptoms to clinical diagnosis was highly variable, with median delays of up to 7 years reported. DISCUSSION: The incidence and prevalence of GD is substantially higher among the Ashkenazi Jewish population than the general population. Limited epidemiologic information was available from Latin America, Africa, Asia, and developed nations such as the United States, Germany, and the United Kingdom. CONCLUSIONS: Signs and symptoms of GD frequently mimic more common hematologic conditions resulting in missed or delayed diagnosis. Early diagnosis and prompt initiation of treatment when indicated is crucial to prevent or minimize life-altering or life-threatening liver and skeletal complications. PMID- 27762170 TI - The impact of stakeholder involvement in hospital policy decision-making: a study of the hospital's business processes. AB - INTRODUCTION: In many health care systems, strategies are currently deployed to engage patients and other stakeholders in decisions affecting hospital services. In this paper, a model for stakeholder involvement is presented and evaluated in three Flemish hospitals. In the model, a stakeholder committee advises the hospital's board of directors on themes of strategic importance. OBJECTIVES: To study the internal hospital's decision processes in order to identify the impact of a stakeholder involvement committee on strategic themes in the hospital decision processes. METHODS: A retrospective analysis of the decision processes was conducted in three hospitals that implemented a stakeholder committee. The analysis consisted of process and outcome evaluation. RESULTS: Fifteen themes were discussed in the stakeholder committees, whereof 11 resulted in a considerable change. None of these were on a strategic level. The theoretical model was not applied as initially developed, but was altered by each hospital. Consequentially, the decision processes differed between the hospitals. Despite alternation of the model, the stakeholder committee showed a meaningful impact in all hospitals on the operational level. As a result of the differences in decision processes, three factors could be identified as facilitators for success: (1) a close interaction with the board of executives, (2) the inclusion of themes with a more practical and patient-oriented nature, and (3) the elaboration of decisions on lower echelons of the organization. CONCLUSION: To effectively influence the organization's public accountability, hospitals should involve stakeholders in the decision-making process of the organization. The model of a stakeholder committee was not applied as initially developed and did not affect the strategic decision-making processes in the involved hospitals. Results show only impact at the operational level in the participating hospitals. More research is needed connecting stakeholder involvement with hospital governance. PMID- 27762172 TI - The effect of display movement angle, indicator type and display location on control/display stereotype strength. AB - Much research on stereotype strength relating display and control movements for displays moving in the vertical or horizontal directions has been reported. Here we report effects of display movement angle, where the display moves at angles (relative to the vertical) of between 0 degrees and 180 degrees . The experiment used six different controls, four display locations relative to the operator and three types of indicator. Indicator types were included because of the strong effects of the 'scale-side principle' that are variable with display angle. A directional indicator had higher stereotype strength than a neutral indicator, and showed an apparent reversal in control/display stereotype direction beyond an angle of 90 degrees . However, with a neutral indicator this control reversal was not present. Practitioner Summary: The effects of display moving at angles other than the four cardinal directions, types of control, location of display and types of indicator are investigated. Indicator types (directional and neutral) have an effect on stereotype strength and may cause an apparent control reversal with change of display movement angle. PMID- 27762171 TI - Decrease of spasticity after hybrid assistive limb(r) training for a patient with C4 quadriplegia due to chronic SCI. AB - CONTEXT: Recently, locomotor training with robotic assistance has been found effective in treating spinal cord injury (SCI). Our case report examined locomotor training using the robotic suit hybrid assistive limb (HAL) in a patient with complete C4 quadriplegia due to chronic SCI. This is the first report examining HAL in complete C4 quadriplegia. FINDINGS: The patient was a 19 year-old man who dislocated C3/4 during judo 4 years previously. Following the injury, he underwent C3/4 posterior spinal fusion but remained paralyzed despite rehabilitation. There was muscle atrophy under C5 level and no sensation around the anus, but partial sensation of pressure remained in the limbs. The American Spinal Injury Association impairment scale was Grade A (complete motor C4 lesion). HAL training was administered in 10 sessions (twice per week). The training sessions consisted of treadmill walking with HAL. For safety, 2 physicians and 1 therapist supported the subject for balance and weight-bearing. The device's cybernic autonomous control mode provides autonomic physical support based on predefined walking patterns. We evaluated the adverse events, walking time and distance, and the difference in muscle spasticity before and after HAL training using a modified Ashworth scale (mAs). No adverse events were observed that required discontinuation of rehabilitation. Walking distance and time increased from 25.2 meters/7.6 minutes to 148.3 meter/15 minutes. The mAs score decreased after HAL training. CONCLUSION: Our case report indicates that HAL training is feasible and effective for complete C4 quadriplegia in chronic SCI. PMID- 27762173 TI - Phylogenetic patterns of Haemonchus contortus and related trichostrongylid nematodes isolated from Egyptian sheep. AB - Haemonchus contortus is a major parasite of small ruminants and its blood-feeding behaviour causes effects ranging from mild anaemia to death. Knowledge of the genetic variation within and among H. contortus populations can provide the foundation for understanding transmission patterns and aid in the control of haemonchosis. Adult male H. contortus were collected from three geographical regions in Egypt. The second internal transcribed spacer (ITS2) of nuclear ribosomal DNA was amplified using the polymerase chain reaction (PCR) and sequenced directly. The population genetic diversity and sequence variations were determined. Nucleotide sequence analyses revealed one genotype (ITS2) in all worms, without genetic differentiation. The similarity in population genetic diversity and genetic patterns observed among the three geographical regions could be attributed to possible movement between the sites. This is the first study of genetic variation in H. contortus in Egypt. The present results could have implications for the rapid characterization of H. contortus and other trichostrongyloid nematodes, and evaluation of the epidemiology of H. contortus in Egypt. PMID- 27762174 TI - Childhood atopy and mental health: a prospective, longitudinal investigation. AB - BACKGROUND: Prior studies have suggested a relationship between atopy and mental health, although methodological barriers have limited the generalizability of these findings. The objective of this study was to investigate the relationship between early-life atopy and vulnerability to mental health problems among youth in the community. METHOD: Data were drawn from the Raine Study (N = 2868), a population-based birth cohort study in Western Australia. Logistic regression and generalized estimating equations were used to examine the relationship between atopy at ages 1-5 years [using parent report and objective biological confirmation (sera IgE)], and the range of internalizing and externalizing mental health problems at ages 5-17 years. RESULTS: Atopy appears to be associated with increased vulnerability to affective and anxiety problems, compared to youth without atopy. These associations remained significant after adjusting for a range of potential confounders. No relationship was evident between atopy and attention deficit hyperactivity disorder or externalizing problems. CONCLUSIONS: Findings are the first linking atopy (measured by both parent report and objective verification) with increased vulnerability to affective and anxiety problems. Therefore, replication is required. If replicated, future research aimed at understanding the possible biological and/or social and environmental pathways underlying these links is needed. Such information could shed light on shared pathways that could lead to more effective treatments for both atopy and internalizing mental health problems. PMID- 27762175 TI - Predictability of helminth parasite host range using information on geography, host traits and parasite community structure. AB - Host-parasite associations are complex interactions dependent on aspects of hosts (e.g. traits, phylogeny or coevolutionary history), parasites (e.g. traits and parasite interactions) and geography (e.g. latitude). Predicting the permissive host set or the subset of the host community that a parasite can infect is a central goal of parasite ecology. Here we develop models that accurately predict the permissive host set of 562 helminth parasites in five different parasite taxonomic groups. We developed predictive models using host traits, host taxonomy, geographic covariates, and parasite community composition, finding that models trained on parasite community variables were more accurate than any other covariate group, even though parasite community covariates only captured a quarter of the variance in parasite community composition. This suggests that it is possible to predict the permissive host set for a given parasite, and that parasite community structure is an important predictor, potentially because parasite communities are interacting non-random assemblages. PMID- 27762176 TI - In vitro and ex vivo activity of Melaleuca alternifolia against protoscoleces of Echinococcus ortleppi. AB - Cystic echinococcosis is a zoonotic disease of difficult diagnosis and treatment. The use of protoscolicidal agents in procedures is of utmost importance for treatment success. This study was aimed at analysing the in vitro and ex vivo activity of Melaleuca alternifolia oil (tea tree oil - TTO), its nanoemulsion formulation (NE-TTO) and its major component (terpinen-4-ol) against Echinococcus ortleppi protoscoleces obtained from cattle. Concentrations of 2.5, 5 and 10 mg mL-1 of TTO, 10 mg mL-1 of NE-TTO and 1, 1.5 and 2 mg mL-1 of terpinen-4-ol were evaluated in vitro against protoscoleces at 5, 10, 15 and 30 min. TTO was also injected directly into hydatid cysts (ex vivo analysis, n = 20) and the viability of protoscoleces was evaluated at 5, 15 and 30 min. The results indicated protoscolicidal effect at all tested formulations and concentrations. Terpinen-4 ol (2 mg mL-1) activity was superior when compared with the highest concentration of TTO. NE-TTO reached a gradual protoscolicidal effect. TTO at 20 mg mL-1 showed 90% protoscolicidal action in hydatid cysts at 5 min. The results showed that TTO affects the viability of E. ortleppi protoscoleces, suggesting a new protoscolicidal option to the treatment of cystic equinococcosis. PMID- 27762178 TI - Role of targeted magnetic resonance imaging sequences in the surgical management of anterior skull base pathology. AB - BACKGROUND: The skull base is a highly complex anatomical region that provides passage for important nerves and vessels as they course into and out of the cranial cavity. Key to the management of pathology in this region is a thorough understanding of the anatomy, with its variations, and the relationship of various neurovascular structures to the pathology in question. Targeted high resolution magnetic resonance imaging on high field strength magnets can enable the skull base surgeon to understand this intricate relationship and deal with the pathology from a position of relative advantage. OBJECTIVE: With the help of case studies, this paper illustrates the application of specialised magnetic resonance techniques to study pathology of the orbital apex in particular. CONCLUSION: The fine anatomical detail provided gives surgeons the ability to design an endonasal endoscopic procedure appropriate to the anatomy of the pathology. PMID- 27762177 TI - Childhood adversity and midlife suicidal ideation. AB - BACKGROUND: Childhood adversity predicts adolescent suicidal ideation but there are few studies examining whether the risk of childhood adversity extends to suicidal ideation in midlife. We hypothesized that childhood adversity predicts midlife suicidal ideation and this is partially mediated by adolescent internalizing disorders, externalizing disorders and adult exposure to life events and interpersonal difficulties. METHOD: At 45 years, 9377 women and men from the UK 1958 British Birth Cohort Study participated in a clinical survey. Childhood adversity was prospectively assessed at the ages of 7, 11 and 16 years. Suicidal ideation at midlife was assessed by the depressive ideas subscale of the Revised Clinical Interview Schedule. Internalizing and externalizing disorders were measured by the Rutter scales at 16 years. Life events, periods of unemployment, partnership separations and alcohol dependence were measured through adulthood. RESULTS: Illness in the household, paternal absence, institutional care, parental divorce and retrospective reports of parental physical and sexual abuse predicted suicidal ideation at 45 years. Three or more childhood adversities were associated with suicidal ideation at 45 years [odds ratio (OR) 4.31, 95% confidence interval (CI) 2.67-6.94]. Psychological distress at 16 years partially mediated the associations of physical abuse (OR 3.41, 95% CI 2.29-5.75), sexual abuse (OR 4.99, 95% CI 2.90-11.16) with suicidal ideation. Adult life events partially mediated the association of parental divorce (OR 6.34, 95% CI -7.16 to 36.75) and physical (OR 9.59, 95% CI 4.97-27.88) and sexual abuse (OR 6.59, 95% CI 2.40-38.36) with suicidal ideation at 45 years. CONCLUSIONS: Adversity in childhood predicts suicidal ideation in midlife, partially mediated by adolescent internalizing and externalizing disorders, adult life events and interpersonal difficulties. Understanding the pathways from adversity to suicidal ideation can inform suicide prevention and the targeting of preventive interventions. PMID- 27762179 TI - Laryngeal manifestations of pachyonychia congenita: a clinical case and discussion on management for the otolaryngologist. AB - BACKGROUND: Pachyonychia congenita is a rare keratinising disorder, which typically presents during the first three years of life and usually affects the nails and palmoplantar surfaces. It can involve the larynx and potentially result in life-threatening airway obstruction. METHODS: A case report is presented and the findings of a literature review are reported. The review involved a PubMed search using the keywords 'pachyonychia congenita' together with 'larynx', 'laryngeal involvement', 'laryngeal obstruction', 'airway obstruction', 'hoarseness' and/or 'stridor'. RESULTS: A five-year-old boy, with confirmed pachyonychia congenita, presented with complications of laryngeal involvement over a four-year period. He required three intubations and a tracheostomy for acute airway obstruction. Treatment with potassium titanyl phosphate laser laryngoscopy stabilised the progression of laryngeal disease. CONCLUSION: Patients with pachyonychia congenita and laryngeal involvement can have a varied presentation, ranging from hoarseness to acute airway obstruction. Management can be a challenge, requiring early evaluation, regular surveillance and aggressive treatment. This paper reports our experience in managing and treating the laryngeal complications of a child with pachyonychia congenita. PMID- 27762180 TI - How Cognitive Genetic Factors Influence Fertility Outcomes: A Mediational SEM Analysis. AB - Utilizing a newly released cognitive Polygenic Score (PGS) from Wave IV of Add Health (n = 1,886), structural equation models (SEMs) examining the relationship between PGS and fertility (which is approximately 50% complete in the present sample), employing measures of verbal IQ and educational attainment as potential mediators, were estimated. The results of indirect pathway models revealed that verbal IQ mediates the positive relationship between PGS and educational attainment, and educational attainment in turn mediates the negative relationship between verbal IQ and a latent fertility measure. The direct path from PGS to fertility was non-significant. The model was robust to controlling for age, sex, and race; furthermore, the results of a multigroup SEM revealed no significant differences in the estimated path coeficients across sex. These results indicate that those predisposed towards higher verbal IQ by virtue of higher PGS values are also predisposed towards trading fertility against time spent in education, which contributes to those with higher PGS values producing fewer offspring at this stage in their life course. PMID- 27762181 TI - Prenatal maternal bereavement and mortality in the first decades of life: a nationwide cohort study from Denmark and Sweden. AB - BACKGROUND: The loss of a close relative is one of the most stressful life events. In pregnancy, this experience has been associated with a higher risk of fetal death and under-five mortality, but little is known about potential effects on long-term mortality in offspring. We examined the association between prenatal maternal bereavement and mortality in a cohort of 5.3 million children followed until up to 37 years of age. METHOD: The population-based cohort study included 5 253 508 live singleton births in Denmark (1973-2004) and Sweden (1973-2006). Children born to mothers who lost a child, spouse, sibling, or parent during or 1 year before pregnancy were categorized as exposed. RESULTS: Prenatal maternal bereavement was associated with a 10% increased all-cause mortality risk in offspring [mortality rate ratio (MRR) 1.10, 95% confidence interval (CI) 1.03 1.18]. The association was the most pronounced for children of mothers who lost a child/spouse (MRR 1.28, 95% CI 1.14-1.44) and was stronger during the first 10 years of life. Prenatal maternal bereavement may have stronger effects on natural causes of death in offspring, including infectious/parasitic disease (MRR 1.86, 95% CI 1.07-3.23), endocrine/nutritional/metabolic diseases (MRR 3.23, 95% CI 2.02-5.17), diseases of nervous system (MRR 3.36, 95% CI 2.47-4.58), and congenital malformations (MRR 1.39, 95% CI 1.08-1.80). No excess mortality risk in offspring was observed for unnatural causes of death. CONCLUSION: Prenatal maternal bereavement was associated with an increased long-term mortality risk in offspring, particularly for selected natural causes of diseases and medical conditions. Our results support the fetal programming hypothesis that prenatal stress may contribute to ill health from physical diseases later in life. PMID- 27762182 TI - Ultrastructural changes to the tegumental system and gastrodermal cells of adult Fasciola hepatica following treatment in vivo with a commercial preparation of myrrh (Mirazid). AB - An in vivo study in the laboratory rat model has been carried out to monitor changes to the tegument and gut of adult Fasciola hepatica following treatment with myrrh ('Mirazid'). Rats infected with the triclabendazole-resistant Dutch isolate were dosed orally with Mirazid at a concentration of 250 mg/kg and flukes recovered 2, 3 and 7 days post-treatment (pt). The flukes were processed for examination by scanning and transmission electron microscopy. A variety of changes to the external surface were observed, culminating in the sloughing of the tegumental syncytium. Internal changes to the syncytium and tegumental cell bodies were more severe and were evident from 2 days pt onwards. Swelling of the basal infolds (leading to flooding of the surface layer) and a decline in secretory body production were the major changes seen. The gastrodermal cells were less severely affected than the tegument, pointing to a trans-tegumental route of uptake for Mirazid by the fluke. Some loss of muscle fibres in the main somatic muscle layers was observed, which may be correlated with the decline in movement of flukes seen at recovery. PMID- 27762183 TI - Spatial and temporal variation in macroparasite communities of three-spined stickleback. AB - Patterns in parasite community structure are often observed in natural systems and an important question in parasite ecology is whether such patterns are repeatable across time and space. Field studies commonly look at spatial or temporal repeatability of patterns, but they are rarely investigated in conjunction. We use a large dataset on the macroparasites of the three-spined stickleback, Gasterosteus aculeatus L., collected from 14 locations on North Uist, Scotland over an 8-year period to investigate: (1) repeatability of patterns in parasite communities among populations and whether variation is consistent across years, (2) whether variation between years can be explained by climatic variation and progression of the season and (3) whether variation in habitat characteristics explain population differences. Differences in relative abundance and prevalence across populations were observed in a number of parasites investigated indicating a lack of consistency across years in numerous parasite community measures; however, differences between populations in the prevalence and abundance of some parasites were consistent throughout the study. Average temperature did not affect parasite community, and progression of the season was only significant for two of 13 community measures. Two of the six habitat characteristics investigated (pH and calcium concentration) significantly affected parasite presence. PMID- 27762184 TI - Gender and Intergroup Helping: Forms of Prosocial Behavior as Differential Social Control Mechanisms for Women and Men. AB - The present research, drawing on the Intergroup Helping as Power Relations Model (Nadler, 2002), investigated the ways in which different forms of helping behavior can strategically affect responses to women and men who display socially valued or devalued characteristics. Participants read scenarios about concrete problems faced by a woman or man in need, who displayed positive (i.e., prosocial) or negative (i.e., antisocial) characteristics, and indicated the extent to which they would be willing to support small tax increases if that money were used to help address the target's issues. The predicted Target Gender * Target History * Type of Support interaction, controlling for political orientation, was obtained, F(1, 149) = 6.49, p = .012, eta p 2 = .04. Participants tended to give less autonomy-oriented (i.e., empowering) help to a man displaying antisocial (vs. prosocial) characteristics, F(1, 36) = 3.39, p = .074, eta p 2 = .09.; they also tended to off more dependency-oriented (i.e., disempowering) help to a woman women exhibiting prosocial (vs. antisocial) qualities, F(1, 38) = 3.42, p = .072, eta p 2 = .08. The role of seemingly positive forms of social behavior as a mechanism for social control and the relation of helping to processes of group-hierarchy and system-justifying processes are considered. PMID- 27762185 TI - Loads of trematodes: discovering hidden diversity of paramphistomoids in Kenyan ruminants. AB - Paramphistomoids are ubiquitous and widespread digeneans that infect a diverse range of definitive hosts, being particularly speciose in ruminants. We collected adult worms from cattle, goats and sheep from slaughterhouses, and cercariae from freshwater snails from ten localities in Central and West Kenya. We sequenced cox1 (690 bp) and internal transcribed region 2 (ITS2) (385 bp) genes from a small piece of 79 different adult worms and stained and mounted the remaining worm bodies for comparisons with available descriptions. We also sequenced cox1 and ITS2 from 41 cercariae/rediae samples collected from four different genera of planorbid snails. Combining morphological observations, host use information, genetic distance values and phylogenetic methods, we delineated 16 distinct clades of paramphistomoids. For four of the 16 clades, sequences from adult worms and cercariae/rediae matched, providing an independent assessment for their life cycles. Much work is yet to be done to resolve fully the relationships among paramphistomoids, but some correspondence between sequence- and anatomically based classifications were noted. Paramphistomoids of domestic ruminants provide one of the most abundant sources of parasitic flatworm biomass, and because of the predilection of several species use Bulinus and Biomphalaria snail hosts, have interesting linkages with the biology of animal and human schistosomes to in Africa. PMID- 27762186 TI - Future Achievements, Passion and Motivation in the Transition from Junior-to Senior Sport in Spanish Young Elite Soccer Players. AB - Within the context of the transition from junior-to-senior sport, this study aims in first place to explore differences in young Spanish elite soccer players based on the importance given to getting different achievements in their future (including sport, studies and private life) and, in second place, to explore differences among those players in levels of passion, motivation and basic psychological need. 478 elite youth soccer filled out a questionnaire based on the presented theoretical models. A cluster analysis shows a sport oriented group (N = 98) only interested in becoming a professional, a life spheres balance group (N = 288) characterized by balancing the importance of achievements in the sport sphere, as well as in education and a private life and a group (N = 91) only interested in private life achievements. The life spheres balance group shows higher levels of harmonious passion (eta2 = .06, F(2, 475) = 9.990, p < .001) than the players of the other groups. The life spheres balance group shows higher levels of autonomous motivation (eta2 = .10, F(2, 475) = 13.597, p < .001), autonomy (eta2 = .07, F(2, 475) = 6.592, p < .01) and relatedness satisfaction (eta2 = .07, F(2, 475) = 5.603, p < .01) than the sport oriented group as well as lower levels of amotivation (eta2 = .04, F(2, 475) = 6.665, p < .01) than the private life oriented group. This study suggests players who perceive equal future importance in their life spheres appear to be more resourceful than the other two groups regarding athletes' internal resources, such as passion and motivation, to cope with the transition to professional soccer. PMID- 27762187 TI - RADAI-5 and electronic monitoring tools. AB - Tighter monitoring of patients is regarded one of the key approaches to improve management of rheumatoid arthritis (RA). It could be demonstrated that the patient relevant disease course is not simply the linear link between two observation points, but fluctuates significantly in up to 80% of patients surveyed three times over two months, which understandably compromises quality of life. Patient self-report questionnaires such as the Rheumatoid Arthritis Disease Activity Index-Five (RADAI-5) have been shown to provide reliable information about disease activity, functionality, and other important aspects of daily life. The internal consistency of such questionnaires was shown to be significantly higher than the one of the DAS28 or the CDAI. Innovative electronic tools can be easily foreseen to constitute the media to enhance the dialogue between healthcare professionals and patients to improve disease care. These tools collect patient-recorded outcomes (PROs) data, through which physicians can monitor the course of the individual disease. Electronic versions can enable patients to receive additional medical attention between visits and provide a more detailed record of disease course over time. Applying the RADAI-5 or other questionnaires in electronic assessment tools will allow for the individual assessment of health levels, well-being, joint pain and the quality of life. Such tools will enable more frequent patient monitoring, with the potential to improve the patient's situation as well as to enhance physicians' time management, and to prioritise patients who may need further attention. PMID- 27762188 TI - Information technology in paediatric rheumatology. AB - Information technology in paediatric rheumatology has seen several exciting developments in recent years. The new multidimensional questionnaires for juvenile idiopathic arthritis, juvenile dermatomyositis, and juvenile autoinflammatory diseases integrate all major parent- and child-reported outcomes (PCROs) used in these diseases into a single tool, and provide an effective guide to manage, document change in health, assess effectiveness of therapeutic interventions, and verify the parent and child satisfaction with illness outcome. The Pharmachild registry is aimed to gain information concerning the long-term effectiveness and safety of the medications currently used in juvenile idiopathic arthritis, particularly biologic agents, through collection of prospective data in a large, multinational sample of patients. Children and their parents are directly involved in the data collection by means of the regular completion of a digital version of a multidimensional questionnaire. The Patient-Reported Outcomes Measurement Information System (PROMIS) employs modern measurement science to advance assessment of PCROs, particularly HRQL, and offers multidimensional profile measures. The conceptual link of paediatric PROMIS with adult instruments facilitates harmonisation of assessments made in children and adolescents with those carried out in young adults in the process of transition of medical care. Development of electronic versions of questionnaires that permit their completion through smartphones or touch-screen devices will revolutionise information collection from parents and children, foster the regular collection of PCROs in routine care, and ultimately improve the quality of self-reported health data, and patient outcomes. PMID- 27762189 TI - The Disease Activity Score (DAS) and the Disease Activity Score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. AB - In rheumatoid arthritis (RA), disease activity cannot be measured in all individual patients according to a single variable. The Disease Activity Score (DAS) and the DAS28 have been developed to measure disease activity in RA both in daily clinical practice as well as in clinical trials on a group as well as individual level. The DAS/DAS28 is a continuous measure of RA disease activity that combines information from swollen joints, tender joints, acute phase response and general health. The DAS-based EULAR response criteria were primarily developed to be used in clinical trials. The EULAR response criteria classify individual patients as non-, moderate, or good responders, dependent on the magnitude of change and level of disease activity reached. In addition, already in the early nineties, cut points were developed to categorise patients in remission. The DAS28 is incorporated in several electronic patient records and web-based systems for monitoring purposes in daily clinical practice. In addition to this, it is being used in combination with patient-reported outcome measures (PROMs) to facilitate self-monitoring. PMID- 27762190 TI - Automated joint space width quantification of hand and wrist joints: a proof of concept study. AB - OBJECTIVES: To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. METHODS: Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125). Of those 134 patients, 70 started with methotrexate and prednisone (MTX+Pred) and 64 with MTX and placebo (MTX+Plac). JSW change over 1 and 2 years of the hands and wrists was assessed, applying both the joint space narrowing (JSN) subscore of the SHS by 2 readers and the automated assessment with the JSW quantification software 'JSQ'. For both methods, progression of JSW change of the hand and wrist was analysed using linear mixed modelling (dependent variable 'JSW', factor 'strategy group', covariate 'follow-up time in years', interaction term 'strategy group*follow-up time'; radiographs of baseline, year 1 and year 2 were used). For each method the standardised mean difference (SMD) for the change in JSW from baseline to year 2 between the treatment strategies was obtained using a non-parametric method. RESULTS: Patient characteristics of the current subpopulation were similar to those of the whole study population. JSN of the hand and wrist according to SHS at 2 years was present in 16 vs. 23% in the MTX+Pred group vs. the MTX+Plac group. The mean yearly progression rates of JSW change of the hands and wrists using JSQ were -0.00mm (95% confidence interval (CI) -0.01; 0.01) for MTX+Pred vs. -0.02mm (95%CI -0.03; -0.01) for MTX+Plac, p=0.045, and using SHS JSN they were 0.19 units (95%CI 0.09; 0.30) vs. 0.30 units (95%CI 0.14; 0.45) for MTX+Pred vs. MTX+Plac, p=0.271. The SMD for the change from baseline to year 2 between the treatment strategies was 0.37 for JSQ and 0.13 for SHS JSN. CONCLUSIONS: In this proof of concept study the yearly progression rate of JSW change of hand and wrist joints, according to the automated JSW quantification software package 'JSQ', was higher in the group initiating MTX+Plac than in the group initiating MTX+Pred. A similar trend was seen with the JSN assessment according to the SHS method of the hand and wrist. However, JSN of the hand and wrist according to SHS, the current gold standard to assess radiographic progression, was seen in only about 20%. Therefore, further studies are needed to conclude firmly that JSQ should be incorporated into quantitative scoring of radiographs in RA. PMID- 27762191 TI - Electronic health records in rheumatology: emphasis on automated scoring and additional use. AB - Electronic health records are increasingly used and frequently required from various regulatory authorities. Apart from their day-to-day use by health care professionals for routine clinical practice and/or the improvement of quality of care processes, patients with chronic inflammatory disease may become increasingly involved in the data retrieval process by self-monitoring and providing patient-reported (outcome) data. Among key features of electronic health records are automated scoring, visualisation of validated measures, and long-term systematic patient-centered data collection in a structured and standardised manner. Data derived from electronic health records are increasingly incorporated into patient-centered research, registries, and other secondary uses. Thus, electronic health records offer opportunities to improve knowledge and to create new process flows in rheumatology health care. The article summarises some of these opportunities in patient care, as well as an overview of secondary use scenarios. In addition, the article focuses on patients' active involvement in the disease management process via health information applications, reports on patients' perspectives, as well as some legal and regulatory matters concerning electronic health records. PMID- 27762192 TI - The Computer Assisted Management in Early Rheumatoid Arthritis programme tool used in the CAMERA-I and CAMERA-II studies. AB - The history, issues and result of the development of the computer decision software tool used for the two tight control and treat-to-target CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) studies are described. The software tool is simple and can be used with various protocolled strategies and visit intervals both in clinical trials and daily practice, because it does not dictate strategy steps and is independent of visit intervals. The tool gives information on whether enough improvement since the last visit is present and whether there is remission or not. With this information, strategy steps according to various protocols and treatment arms can be taken. PMID- 27762193 TI - Implementing the findings of the TICOPA trial in clinical practice: challenges in implementation and how information technology can bridge the gap. AB - As in rheumatoid arthritis, treating to target in psoriatic arthritis (PsA) has been shown to improve outcomes over standard therapy. As a result of this, the European League Against Rheumatism (EULAR) updated recommendations for the management of PsA now recommend a treat-to-target approach for all patients with PsA. However, translating the results of this research remains challenging in clinical practice. Prolonged consultation time associated with implementing this into practice can be minimised using a simple to calculate but inclusive target for treatment and assessing this within information technology (IT) systems. IT systems can combine physician and patient-reported outcomes, use algorithms to calculate any target and even be used to suggest follow up times based on previous data. Utilising these tools can help to make optimal treatment of arthritis feasible in routine clinical practice. PMID- 27762194 TI - Information technology concerning SDAI and CDAI. AB - Disease activity assessment of rheumatoid arthritis has never been trivial. Composite indices like the Disease Activity Score using 28 joint counts 28 (DAS28) and the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI) attempted to integrate several core set variables into one readout, which eventually laid the grounds for implementation strategies that targeted disease activity levels, like remission. While CDAI and SDAI were clearly simpler at times when a calculator was needed, this has likely become less relevant in the era of digital records, where core set variables are entered into a computed device after measurement. However, DAS28 has faced new challenges, which are derived from its lack of specificity when it comes to assessing remission. Digital technology has advanced the management of patients with RA in clinical practice, since the disease activity levels can now be followed for each patient over adjustable time periods interesting for the clinician, such as since start of the last treatment. Also for research purposes, the digital records have allowed a more rapid course of projects from the scientific hypothesis to publication, simply by allowing to go to the digital database and select the items and observation needed. This has made clinical research much more efficient. In the digital era, the CDAI and SDAI can still be used on a piece of paper without the necessity of any electronic device, and it is exactly this flexibility and versatility of these two scores that account for their continued success. PMID- 27762196 TI - The National Data Bank for Rheumatic Diseases (NDB). AB - The National Data Bank for Rheumatic Diseases (NDB) is a longitudinal observational patient-driven database, founded as a non-profit research organization in 1998 by Dr. Frederick Wolfe. Patients are sent a primary questionnaire twice a year. More than 50,000 patients with more than 100 various rheumatic diseases under the care of more than 1,500 rheumatologists have completed at least one 6-month questionnaire. Many important publications concerning rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, fibromyalgia, and pharmaco-epidemiology have resulted from NDB research. PMID- 27762195 TI - Electronic multidimensional health assessment questionnaire (eMDHAQ): past, present and future of a proposed single data management system for clinical care, research, quality improvement, and monitoring of long-term outcomes. AB - An MDHAQ/RAPID3 (multidimensional health assessment questionnaire/routine assessment of patient index data) was developed from the HAQ over 25 years, based on observations made from completion by every patient (with all diagnoses) at every routine rheumatology visit since 1980. Modification of the HAQ was viewed as similar to improving a laboratory test, with a primary focus on clinical value for diagnosis, prognosis, and/or management, as well as feasibility for minimal effect on clinical workflow. Rigorous attention, was also directed to validity, reliability, other methodologic and technological considerations, but after clinical value and feasibility were established. A longer "intake" MDHAQ was introduced for new patients to record a complete past medical history - illnesses, hospitalisations, surgeries, allergies, family history, social history and medications. MDHAQ scales not found on the HAQ record complex activities, sleep quality, anxiety, depression, self-report joint count, fatigue, symptom checklist, morning stiffness, exercise status, recent medical history, social history and demographic data within 2 pages on one sheet of paper. An electronic eMDHAQ/RAPID3 provides a similar platform to pool data from multiple sites. A patient may be offered a patient-administered, password-protected, secure, web site, to store the medical history completed on the eMDHAQ. This eMDHAQ would allow a patient to complete a single general medical history questionnaire rather than different intake questionnaires in different medical settings. The eMDHAQ would be available for updates and correction by the patient for future visits, regardless of electronic medical record (EMR). The eMDHAQ is designed to interface with an EMR using HL7 (health level seven) and SMART (Substitutable Medical Apps, Reusable Technology) on FHIR (Fast Healthcare Interoperability Resources), although implementation requires collaboration with the EMR vendor. Advanced features include reports for the physician formatted as a medical record note of past medical history for entry into any EMR without typing or dictation, and a periodic "tickler" function to monitor long-term outcomes with minimal effort of the physician and staff. Nonetheless, clinical use of an eMDHAQ should be guided primarily not by the latest technology, but by value and feasibility in clinical care, the same principles that guided development of the pencil-and paper MDHAQ/RAPID3. PMID- 27762197 TI - The Corrona US registry of rheumatic and autoimmune diseases. AB - The Corrona US national registry collects data concerning patient status from both the rheumatologist and patient at routine clinical encounters. Corrona has functioning disease registries in rheumatoid arthritis, psoriatic arthritis, spondyloarthropathies, psoriasis and inflammatory bowel disease. Corrona merges data concerning long-term effectiveness and safety, as well as comparative and cost effectiveness of agents to treat these autoimmune diseases. PMID- 27762198 TI - Digital health assessment in rheumatology: current and future possibilities. AB - Digital assessment and graphical feedback of patient-reported outcome measures such as the Health Assessment Questionnaire (HAQ) could increase empowerment and involvement of patients in their own care process. The App ecosystem that Reade is building is an example of how digital assessment using mobile devices can be integrated into existing hospital IT infrastructure. PMID- 27762199 TI - Using an electronic platform interactively to improve treatment outcome in patients with rheumatoid arthritis: new developments from the DANBIO registry. AB - OBJECTIVES: Electronic platforms have been developed to help the clinician monitor disease activity in rheumatoid arthritis (RA) to support at treat-to target strategy. We present an initiative to interactively improve disease control in patients with rheumatoid arthritis. METHODS: In patients who presented with one or more swollen joints AND moderate/high disease activity (i.e. either CDAI>=10.1 and/or DAS-28CRP>3.2, which is automatically calculated in the DANBIO registry), a red alert was shown, which activated a pop-up: "This patient has at least one swollen joint AND either CDAI>= 10.1 or DAS28CRP>3.2. Which action do you as a physician take today: ? Intensify treatment, ? Treatment intensification is not possible currently/awaiting results of additional investigations, ? No further treatment intensification is possible, ? The patient does not want to intensify treatment, ? Other decisions taken" RESULTS: Of 21,056 patients with RA, 40% fulfilled the criteria for getting the alert message. The pop-up was activated and completed by the physician in 65% of those (5,428 patients). Treatment was intensified in 67%. In 2% of patients, no additional treatment intensification was possible, and 8% of the patients objected to intensification. CONCLUSIONS: In >8,000 RA patients who presented with objective signs of active disease in routine care, an interactive feature of the DANBIO registry was introduced, which prompted the physician to take action and consider treatment intensification. In two-thirds of the cases, the treating physician reported that treatment was intensified. PMID- 27762200 TI - Primary and secondary patient data in contrast: the use of observational studies like RABBIT. AB - The study of secondary patient data, particularly represented by claims data, has increased in recent years. The strength of this approach involves easy access to data that have been generated for administrative purposes. By contrast, collection of primary data for research is time-consuming and may therefore appear outdated. Both administrative data and data collected prospectively in clinical care can address similar research questions concerning effectiveness and safety of treatments. Therefore, why should we invest the precious time of rheumatologists to generate primary patient data? This article will outline some features of primary patient data collection illustrated by the German biologics register RABBIT (Rheumatoid arthritis: observation of biologic therapy). RABBIT is a long-term observational cohort study that was initiated more than 15 years ago. We will discuss as quality indicators: (i) study design, (ii) type of documentation, standardisation of (iii) clinical and (iv) safety data, (v) monitoring of the longitudinal follow-up, (vi) losses to follow-up as well as (vii) the possibilities to link the data base. The impact of these features on interpretation and validity of results is illustrated using recent publications. We conclude that high quality and completeness of data prospectively-collected offers many advantages over large quantities of non-standardised data collected in an unsupervised manner. We expect the enthusiasm about the use of secondary patient data to decline with more awareness of their methodological limitations while studies with primary patient data like RABBIT will maintain and broaden their impact on daily clinical practice. PMID- 27762201 TI - Ten years of METEOR (an international rheumatoid arthritis registry): development, research opportunities and future perspectives. AB - OBJECTIVES: Ten years ago, the METEOR tool was developed to simulate treatment-to target and create an international research database. The development of the METEOR tool and database, research opportunities and future perspectives are described. METHODS: The METEOR tool is a free, online, internationally available tool in which daily practice visits of all rheumatoid arthritis patients visiting a rheumatologist can be registered. In the tool, disease characteristics, patient and physician-reported outcomes and prescribed treatment could be entered. These can be subsequently displayed in powerful graphics, facilitating treatment decisions and patient-physician interactions. An upload facility is also available, by which data from local electronic health record systems or registries can be integrated into the METEOR database. This is currently being actively used in, among other countries, the Netherlands, Portugal and India. RESULTS: Since an increasing number of hospitals use electronic health record systems, the upload facility is being actively used by an increasing number of sites, enabling them to benefit from the benchmark and research opportunities of METEOR. Enabling a connection between local registries and METEOR is a well established but time-consuming process for which an IT-specialist of METEOR and the local registry are necessary. However, once this process has been finished, data can be uploaded regularly and relatively easily according to a pre-specified format. The METEOR database currently contains data from >39,000 patients and >200,000 visits, from 32 different countries and is ever increasing. Continuous efforts are being undertaken to increase the quality of data in the database. CONCLUSIONS: Since METEOR was founded 10 years ago, many rheumatologists worldwide have used the METEOR tool to follow-up their patients and improve the quality of care they provide to their patients. Combined with uploaded data, this has led to an extensive growth of the database. It now offers a unique opportunity to study daily practice care and to perform research regarding cross country differences in a large, worldwide setting, which could provide important knowledge about disease and its treatment in different geographic and clinical settings. PMID- 27762202 TI - Go, go, GoTreatIT! AB - Patient monitoring has been emphasised in rheumatology for decades. However, many obstacles must be overcome before successful monitoring is part of routine care. We describe one model: GoTreatIT. PMID- 27762203 TI - Electronic assessment of disease activity and functioning in patients with axial spondyloarthritis: challenges and unmet needs. AB - The dynamic clinical course of rheumatic conditions indicates a need for regular collection of information on health status to monitor disease activity and functional status. Patient-reported outcomes measures (PROMs) are playing a key role in the evaluation of symptoms and functioning and health, and are crucial in the initiation of treatment in those patients. In recent years, electronic assessments of PROMs (so called ePROMs) have been introduced. This report summarises some of the rationale, opportunities, and results using ePROMs in patients with spondyloarthritis (SpA). PMID- 27762204 TI - Health information technologies in systemic lupus erythematosus: focus on patient assessment. AB - Recent advances in health information technologies (HIT) in systemic lupus erythematosus have included electronic databases and registries, computerised clinical charts for patient monitoring, computerised diagnostic tools, computerised prediction rules and, more recently, disease-specific applications for mobile devices for physicians, health care professionals, and patients. Traditionally, HIT development has been oriented primarily to physicians and public administrators. However, more recent development of patient-centered Apps could improve communication and empower patients in the daily management of their disease. Economic advantages could also result from the use of HIT, including these Apps by collecting real life data that could be used in both economic analyses and to improve patient care. PMID- 27762205 TI - Overview of the American College of Rheumatology's Electronic Health Record Enabled Registry: The Rheumatology Informatics System for Effectiveness. AB - The Rheumatology Informatics System for Effectiveness (RISE) Registry was developed by the American College of Rheumatology (ACR) to serve US rheumatologists for the significant challenges of a rapidly changing healthcare environment. More than 400 rheumatologists have sent data from more than 3 million encounters of more than 650,000 patients as of August 11, 2016, through their electronic medical records (EMRs), with no additional work or interference with workflow on the part of the rheumatologists. RISE includes patients with all diagnoses seen by participating rheumatologists, at no cost to the rheumatologist. PMID- 27762206 TI - Electronic eRAPID3 (Routine Assessment of Patient Index Data): opportunities and complexities. AB - RAPID3 (routine assessment of patient index data) is an index found within a multi-dimensional health assessment questionnaire (MDHAQ) for routine clinical care, composed only of 3 self-report scores for physical function, pain, and patient global estimate, each scored 0-10, for a total of 0-30. RAPID3 is correlated significantly with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index), and distinguishes active from control treatments as efficiently as these indices in clinical trials involving adalimumab, abatacept, certolizumab, infliximab, and rituximab. Many versions of an electronic RAPID3 (eRAPID3) have been developed, which are incompatible with one another, as seen for electronic medical records (EMR). Therefore, opportunities are lost to pool data from many sites for advancement of patient care and outcomes. Interfaces for linkage to EMRs and pooling of data are available as Health Level Seven (HL7) standards, FHIR (Fast Health Interoperability Resources), and innovative open platforms like SMART (Substitutable Medical Apps, Reusable Technology), but many eRAPID3 versions do not have this capacity. RAPID3 scores may be elevated in many patients due to damage or distress, rather than, or in addition to, inflammation, a problem that also affects DAS28, CDAI, and all RA indices which include a patient global estimate, even if they include a formal joint count. A full MDHAQ, of which RAPID3 is a component, provides clues to the presence of damage, and/or distress and adds much further information, with no more work for the health professional and little more time for the patient. A RheuMetric physician checklist of global scores for inflammation, damage, and distress is also useful to recognise damage and/or distress, but not available with most available eRAPID3 versions. Many eRAPID3 versions also are limited by the absence of flowsheets to monitor scores over time, the absence of strategies to convey data to health professionals to improve care, and the absence of advanced features for patients and doctors which are available in some versions of an eRAPID3. It is recommended that eRAPID3 should include a full MDHAQ, RheuMetric checklist, a longitudinal flowsheet of scores, and a defined strategy for management of the data to be available to the physician for improved patient care, to enhance value and quantitative interpretation of RAPID3 scores. PMID- 27762207 TI - Information technology in rheumatology. PMID- 27762209 TI - Letter to the editor: A norovirus intervariant GII.4 recombinant in Victoria, Australia, June 2016: the next epidemic variant? Reflections and a note of caution. PMID- 27762208 TI - The potential impact of media reporting in syndromic surveillance: an example using a possible Cryptosporidium exposure in North West England, August to September 2015. AB - During August 2015, a boil water notice (BWN) was issued across parts of North West England following the detection of Cryptosporidium oocysts in the public water supply. Using prospective syndromic surveillance, we detected statistically significant increases in the presentation of cases of gastroenteritis and diarrhoea to general practitioner services and related calls to the national health telephone advice service in those areas affected by the BWN. In the affected areas, average in-hours general practitioner consultations for gastroenteritis increased by 24.8% (from 13.49 to 16.84) during the BWN period; average diarrhoea consultations increased by 28.5% (from 8.33 to 10.71). Local public health investigations revealed no laboratory reported cases confirmed as being associated with the water supply. These findings suggest that the increases reported by syndromic surveillance of cases of gastroenteritis and diarrhoea likely resulted from changes in healthcare seeking behaviour driven by the intense local and national media coverage of the potential health risks during the event. This study has further highlighted the potential for media-driven bias in syndromic surveillance, and the challenges in disentangling true increases in community infection from those driven by media reporting. PMID- 27762210 TI - Authors' reply: A norovirus intervariant GII.4 recombinant in Victoria, Australia, June 2016: the next epidemic variant? Reflections and a note of caution. PMID- 27762211 TI - Improving influenza virological surveillance in Europe: strain-based reporting of antigenic and genetic characterisation data, 11 European countries, influenza season 2013/14. AB - Influenza antigenic and genetic characterisation data are crucial for influenza vaccine composition decision making. Previously, aggregate data were reported to the European Centre for Disease Prevention and Control by European Union/European Economic Area (EU/EEA) countries. A system for collecting case-specific influenza antigenic and genetic characterisation data was established for the 2013/14 influenza season. In a pilot study, 11 EU/EEA countries reported through the new mechanism. We demonstrated feasibility of reporting strain-based antigenic and genetic data and ca 10% of influenza virus-positive specimens were selected for further characterisation. Proportions of characterised virus (sub)types were similar to influenza virus circulation levels. The main genetic clades were represented by A/StPetersburg/27/2011(H1N1)pdm09 and A/Texas/50/2012(H3N2). A(H1N1)pdm09 viruses were more prevalent in age groups (by years) < 1 (65%; p = 0.0111), 20-39 (50%; p = 0.0046) and 40-64 (55%; p = 0.00001) while A(H3N2) viruses were most prevalent in those >= 65 years (62%*; p = 0.0012). Hospitalised patients in the age groups 6-19 years (67%; p = 0.0494) and >= 65 years (52%; p = 0.0005) were more frequently infected by A/Texas/50/2012 A(H3N2)-like viruses compared with hospitalised cases in other age groups. Strain-based reporting enabled deeper understanding of influenza virus circulation among hospitalised patients and substantially improved the reporting of virus characterisation data. Therefore, strain-based reporting of readily available data is recommended to all reporting countries within the EU/EEA. PMID- 27762212 TI - Seroprevalence of Toxoplasma gondii in goats in Hunan province, China. AB - Toxoplasma gondii infections are prevalent in animals and humans worldwide. In the present investigation, the seroprevalence of T. gondii in goats was investigated in Hunan province, subtropical China between March 2014 and December 2015. A total of 1,028 serum samples collected from 14 administrative regions of Hunan province were evaluated by the indirect hemagglutination test (IHAT) for the detection of specific antibodies. Antibodies to T. gondii were detected in 124 serum samples (12%). The T. gondii seroprevalence ranged from 1.7% to 19% among different regions in subtropical China, and the differences were statistically significant (p < 0.01). The results of the present survey indicated that T. gondii infection is prevalent in goats in Hunan, which poses a potential risk for human infection with T. gondii in this province. PMID- 27762213 TI - Comparison of Toxoplasma gondii IgG avidity Architect and Vidas assays with the estimated date of infection in pregnant women. AB - A maternal Toxoplasma gondii infection during pregnancy is a risk for congenital infection through maternal-fetal transplacental transmission. Estimation of the date of infection is of the utmost importance for management and treatment recommendations. In this setting, IgG avidity has been shown to be useful as high avidity rules out an infection dating less than 4 months. The estimated date of infection can also be obtained by the ratio of T. gondii IgG titers measured by the Vidas (bioMerieux) assay versus T. gondii IgG titers measured by the Architect (Abbott Laboratories) test, together with T. gondii IgM and IgA antibody responses. In this study, using 117 serum samples from pregnant women, we compared the IgG avidity values obtained by Architect and Vidas with the presumed date of T. gondii infection established by the T. gondii IgG ratio of IgG Vidas and IgG Architect plus the IgM and IgA results. To date, IgG avidity Vidas seems to exhibit better performance than Architect. For both assays, gray zone results were most likely obtained from patients infected more than 4 months before sampling. These data should be taken into account for a possible reconsideration of the interpretation of avidity results in the gray zone. PMID- 27762214 TI - Bullous pemphigoid in infancy with spontaneous remission. PMID- 27762215 TI - Objective and subjective treatment evaluation of scars using optical coherence tomography, sonography, photography, and standardised questionnaires. AB - BACKGROUND: Currently, different types of treatments for pathological scars are available, however, to date, there is no established method of measurement to objectively assess therapeutic outcome. Treatment success is usually evaluated clinically by the physician and patient. Non-invasive imaging techniques, such as HD-OCT (high-definition optical coherence tomography), may represent a valuable diagnostic tool to objectively measure therapeutic outcome. OBJECTIVES: To compare HD-OCT with ultrasound and subjective evaluation tools, such as questionnaires. MATERIALS & METHODS: In total, eight patients with pathological scars were treated in this pilot study with cryotherapy and intralesional steroid injections, and evaluated pre- and post-treatment using clinical examination, photography, sonography, and HD-OCT. The analysis of objective and subjective measuring methods was used to draw direct comparisons. RESULTS: HD-OCT revealed reduced epidermal and dermal thickness of the scar after four treatments with triamcinolone acetonide and cryotherapy. Based on sonography, a total reduction in scar height and reduction in scar depth was demonstrated. Both methods correlated well with the injected amount of triamcinolone acetonide. In addition, a positive correlation between well-established subjective and objective evaluation methods was found. CONCLUSION: We demonstrate that HD-OCT may be used as an objective diagnostic instrument to evaluate skin thickness under therapy for pathological scars, and serves as a valuable adjunctive device in combination with ultrasound and subjective evaluation tools. This provides additional information for the therapist concerning the quality and success of the applied treatment. PMID- 27762216 TI - Predicting adverse health outcomes in older emergency department patients: the APOP study. AB - BACKGROUND: Older patients experience high rates of adverse outcomes after an emergency department (ED) visit. Early identification of those at high risk could guide preventive interventions and tailored treatment decisions, but available models perform poorly in discriminating those at highest risk. The present study aims to develop and validate a prediction model for functional decline and mortality in older patients presenting to the ED. METHODS: A prospective follow up study in patients aged >= 70, attending the EDs of the LUMC, the Netherlands (derivation) and Alrijne Hospital, the Netherlands (validation) was conducted. A baseline assessment was performed and the main outcome, a composite of functional decline and mortality, was obtained after 90 days of follow-up. RESULTS: In total 751 patients were enrolled in the Leiden University Medical Center of whom 230 patients (30.6%) experienced the composite outcome and 71 patients (9.5%) died. The final model for the composite outcome resulted in an area under the curve (AUC) of 0.73 (95% CI 0.67-0.77) and was experienced in 69% of the patients at highest risk. For mortality the AUC was 0.79 (95% CI 0.73-0.85) and 36% of the patients at highest risk died. External validation in 881 patients of Alrijne Hospital showed an AUC of 0.71 (95% CI 0.67-0.75) for the composite outcome and 0.67 (95% CI 0.60-0.73) for mortality. CONCLUSION: We successfully developed and validated prediction models for 90-day composite outcome and 90-day mortality in older emergency patients. The benefits for patient management by implementing these models with preventive interventions have to be investigated. PMID- 27762217 TI - The use of ultrasound during and after central venous catheter insertion versus conventional chest X-ray after insertion of a central venous catheter. AB - BACKGROUND: After insertion of a central venous catheter (CVC) a conventional chest X-ray (CXR) is usually taken to check for complications and correct position. Ultrasound might be equally effective as CXR and is less time consuming. We studied the use of ultrasound versus CXR after insertion of a CVC in general ward patients. METHODS: General ward patients in need of a CVC were included. CVCs were inserted under direct ultrasound guidance. After insertion, ultrasound was performed and compared with CXR to check for complications and position. The waiting time for CXR was noted. RESULTS: In total, 53 patients were included. In 52/53 patients ultrasound was feasible. The results of ultrasound and CXR only differed in 3 of 53 patients. The sensitivity of ultrasound in detecting the correct CVC position was 98% (89.4-100%). No complications were detected (ultrasound or CXR). The median waiting time for CXR was 24.5 minutes. CONCLUSIONS: Our study shows that an integral use of ultrasound during and after CVC insertion is effective in establishing that the CVC is correctly positioned and for identifying post-procedural complications in patients from the general ward when compared with CXR. PMID- 27762218 TI - Coloenteric fistula in a young patient with recurrent diverticulitis: A case report and review of the literature. AB - The development of colonic diverticula is common in developed countries and complications of colonic diverticulosis are responsible for a remarkable burden of the disease. The natural history and management of complicated and recurrent diverticulitis in young patients are still a matter of debate. Coloenteric fistula is a rare complication of diverticulitis in young adults. In this report, and utilising a case study, we will review the natural history, outcome and management of acute diverticulitis in the young. PMID- 27762219 TI - Coxiella burnetii chronic pericarditis: a case report. AB - Coxiella burnetii is capable of causing a variety of acute and chronic infections. We present a case of pericarditis with serologically confirmed chronic C. burnetii infection. This case report emphasises the justification of serological testing for chronic C. burnetii infection in patients with prolonged or recurrent pericarditis, particularly in countries endemic for C. burnetii infection. PMID- 27762220 TI - The diagnostic work-up in patients with ascites: current guidelines and future prospects. AB - Accumulation of fluid in the peritoneal cavity - ascites - is commonly encountered in clinical practice. Ascites can originate from hepatic, malignant, cardiac, renal, and infectious diseases. This review discusses the current recommended diagnostic approach towards the patient with ascites and summarises future diagnostic targets. PMID- 27762222 TI - Pragmatic barriers to assessing post-emergency department vulnerability for poor outcomes in an ageing society. PMID- 27762221 TI - Human metapneumovirus in haematopoietic stem cell transplantation recipients: a case series and review of the diagnostic and therapeutic approach. AB - Human metapneumovirus (hMPV) is a paramyxovirus that causes respiratory tract infections ranging from mild upper airway infection to severe pneumonia. Patients with haematological disease, especially haematopoietic stem cell transplantation (HSCT) recipients, are more likely to develop more severe infections. We describe three cases of hMPV infection in HSCT patients. The most reliable diagnostic procedure for hMPV is multiplex ligation-dependent probe amplification (MLPA) on a nasopharyngeal swab. Sensitivity and specificity of MLPA to detect hMPV is high and time to diagnosis is short. A number of other respiratory pathogens can be tested in one test run. Treatment is mainly supportive and only a few antiviral agents are available for treating paramyxovirus infections. Ribavirin and immunoglobulins were reported to be effective in cases of HSCT patients with hMPV pneumonia but their efficacy has not been studied in randomised trials. PMID- 27762223 TI - A fatty cause of acute renal failure. PMID- 27762224 TI - Answer to Photo Quiz: A fatty cause of acute renal failure. PMID- 27762225 TI - What does the skin tell us in this haemodialysis patient? PMID- 27762226 TI - Answer to Photo Quiz: What does the skin tell us in this haemodialysis patient? PMID- 27762227 TI - Pathological fracture and osteolysis of the rib with pleural effusion - is this malignant? PMID- 27762228 TI - Answer to Photo Quiz: Pathological fracture and osteolysis of the rib with pleural effusion - is this malignant? PMID- 27762229 TI - Levetiracetam (Keppra), urinary retention and literature search. PMID- 27762230 TI - Guest Editorial. PMID- 27762232 TI - Impact of negative feedback in metabolic noise propagation. AB - Synthetic biology combines different branches of biology and engineering aimed at designing synthetic biological circuits able to replicate emergent properties useful for the biotechnology industry, human health and environment. The role of negative feedback in noise propagation for a basic enzymatic reaction scheme is investigated. Two feedback control schemes on enzyme expression are considered: one from the final product of the pathway activity, the other from the enzyme accumulation. Both schemes are designed to provide the same steady-state average values of the involved players, in order to evaluate the feedback performances according to the same working mode. Computations are carried out numerically and analytically, the latter allowing to infer information on which model parameter setting leads to a more efficient noise attenuation, according to the chosen scheme. In addition to highlighting the role of the feedback in providing a substantial noise reduction, our investigation concludes that the effect of feedback is enhanced by increasing the promoter sensitivity for both schemes. A further interesting biological insight is that an increase in the promoter sensitivity provides more benefits to the feedback from the product with respect to the feedback from the enzyme, in terms of enlarging the parameter design space. PMID- 27762231 TI - Lung cancer prediction from microarray data by gene expression programming. AB - Lung cancer is a leading cause of cancer-related death worldwide. The early diagnosis of cancer has demonstrated to be greatly helpful for curing the disease effectively. Microarray technology provides a promising approach of exploiting gene profiles for cancer diagnosis. In this study, the authors propose a gene expression programming (GEP)-based model to predict lung cancer from microarray data. The authors use two gene selection methods to extract the significant lung cancer related genes, and accordingly propose different GEP-based prediction models. Prediction performance evaluations and comparisons between the authors' GEP models and three representative machine learning methods, support vector machine, multi-layer perceptron and radial basis function neural network, were conducted thoroughly on real microarray lung cancer datasets. Reliability was assessed by the cross-data set validation. The experimental results show that the GEP model using fewer feature genes outperformed other models in terms of accuracy, sensitivity, specificity and area under the receiver operating characteristic curve. It is concluded that GEP model is a better solution to lung cancer prediction problems. PMID- 27762233 TI - Modular bond-graph modelling and analysis of biomolecular systems. AB - Bond graphs can be used to build thermodynamically-compliant hierarchical models of biomolecular systems. As bond graphs have been widely used to model, analyse and synthesise engineering systems, this study suggests that they can play the same role in the modelling, analysis and synthesis of biomolecular systems. The particular structure of bond graphs arising from biomolecular systems is established and used to elucidate the relation between thermodynamically closed and open systems. Block diagram representations of the dynamics implied by these bond graphs are used to reveal implicit feedback structures and are linearised to allow the application of control-theoretical methods. Two concepts of modularity are examined: computational modularity where physical correctness is retained and behavioural modularity where module behaviour (such as ultrasensitivity) is retained. As well as providing computational modularity, bond graphs provide a natural formulation of behavioural modularity and reveal the sources of retroactivity. A bond graph approach to reducing retroactivity, and thus inter module interaction, is shown to require a power supply such as that provided by the ATP ? ADP + Pi reaction. The mitogen-activated protein kinase cascade (Raf MEK-ERK pathway) is used as an illustrative example. PMID- 27762234 TI - Expanding the (kaleido)scope: exploring current literature trends for translating electroencephalography (EEG) based brain-computer interfaces for motor rehabilitation in children. AB - Rehabilitation applications using brain-computer interfaces (BCI) have recently shown encouraging results for motor recovery. Effective BCI neurorehabilitation has been shown to exploit neuroplastic properties of the brain through mental imagery tasks. However, these applications and results are currently restricted to adults. A systematic search reveals there is essentially no literature describing motor rehabilitative BCI applications that use electroencephalograms (EEG) in children, despite advances in such applications with adults. Further inspection highlights limited literature pursuing research in the field, especially outside of neurofeedback paradigms. Then the question naturally arises, do current literature trends indicate that EEG based BCI motor rehabilitation applications could be translated to children? To provide further evidence beyond the available literature for this particular topic, we present an exploratory survey examining some of the indirect literature related to motor rehabilitation BCI in children. Our goal is to establish if evidence in the related literature supports research on this topic and if the related studies can help explain the dearth of current research in this area. The investigation found positive literature trends in the indirect studies which support translating these BCI applications to children and provide insight into potential pitfalls perhaps responsible for the limited literature. Careful consideration of these pitfalls in conjunction with support from the literature emphasize that fully realized motor rehabilitation BCI applications for children are feasible and would be beneficial. * BCI intervention has improved motor recovery in adult patients and offer supplementary rehabilitation options to patients. * A systematic literature search revealed that essentially no research has been conducted bringing motor rehabilitation BCI applications to children, despite advances in BCI. * Indirect studies discovered from the systematic literature search, i.e. neurorehabilitation in children via BCI for autism spectrum disorder, provide insight into translating motor rehabilitation BCI applications to children. * Translating BCI applications to children is a relevant, important area of research which is relatively barren. PMID- 27762235 TI - BDNF gene delivery within and beyond templated agarose multi-channel guidance scaffolds enhances peripheral nerve regeneration. AB - OBJECTIVE: We combined implantation of multi-channel templated agarose scaffolds with growth factor gene delivery to examine whether this combinatorial treatment can enhance peripheral axonal regeneration through long sciatic nerve gaps. APPROACH: 15 mm long scaffolds were templated into highly organized, strictly linear channels, mimicking the linear organization of natural nerves into fascicles of related function. Scaffolds were filled with syngeneic bone marrow stromal cells (MSCs) secreting the growth factor brain derived neurotrophic factor (BDNF), and lentiviral vectors expressing BDNF were injected into the sciatic nerve segment distal to the scaffold implantation site. MAIN RESULTS: Twelve weeks after injury, scaffolds supported highly linear regeneration of host axons across the 15 mm lesion gap. The incorporation of BDNF-secreting cells into scaffolds significantly increased axonal regeneration, and additional injection of viral vectors expressing BDNF into the distal segment of the transected nerve significantly enhanced axonal regeneration beyond the lesion. SIGNIFICANCE: Combinatorial treatment with multichannel bioengineered scaffolds and distal growth factor delivery significantly improves peripheral nerve repair, rivaling the gold standard of autografts. PMID- 27762237 TI - Clinical applications of penetrating neural interfaces and Utah Electrode Array technologies. AB - This paper briefly describes some of the recent progress in the development of penetrating microelectrode arrays and highlights the use of two of these devices, Utah electrode arrays and Utah slanted electrode arrays, in two therapeutic interventions: recording volitional skeletal motor commands from the central nervous system, and recording motor commands and evoking somatosensory percepts in the peripheral nervous system (PNS). The paper also briefly explores other potential sites for microelectrode array interventions that could be profitably pursued and that could have important consequences in enhancing the quality of life of patients that has been compromised by disorders of the central and PNSs. PMID- 27762236 TI - Nerve cuff electrode using embedded magnets and its application to hypoglossal nerve stimulation. AB - OBJECTIVE: A novel nerve cuff electrode with embedded magnets was fabricated and developed. In this study, a pair of magnets was fully embedded and encapsulated in a liquid crystal polymer (LCP) substrate to utilize magnetic force in order to replace the conventional installing techniques of cuff electrodes. In vitro and in vivo experiments were conducted to evaluate the feasibility of the magnet embedded nerve cuff electrode (MENCE). Lastly, several issues pertaining to the MENCE such as the cuff-to-nerve diameter ratio, the force of the magnets, and possible concerns were discussed in the discussion section. APPROACH: Electrochemical impedance spectrum and cyclic voltammetry assessments were conducted to measure the impedance and charge storage capacity of the cathodal phase (CSCc). The MENCE was installed onto the hypoglossal nerve (HN) of a rabbit and the movement of the genioglossus was recorded through C-arm fluoroscopy while the HN was stimulated by a pulsed current. MAIN RESULTS: The measured impedance was 0.638 ? -67.8 degrees kOmega at 1 kHz and 5.27 ? -82.1 degrees kOmega at 100 Hz. The average values of access resistance and cut-off frequency were 0.145 kOmega and 3.98 kHz, respectively. The CSCc of the electrode was measured as 1.69 mC cm-2 at the scan rate of 1 mV s-1. The movement of the genioglossus contraction was observed under a pulsed current with an amplitude level of 0.106 mA, a rate of 0.635 kHz, and a duration of 0.375 ms applied through the MENCE. SIGNIFICANCE: A few methods to close and secure cuff electrodes have been researched, but they are associated with several drawbacks. To overcome these, we used magnetic force as a closing method of the cuff electrode. The MENCE can be precisely installed on a target nerve without any surgical techniques such as suturing or molding. Furthermore, it is convenient to remove the installed MENCE because it requires little force to detach one magnet from the other, enabling repeatable installation and removal. We anticipate that the MENCE will become a very useful tool given its unique properties as a cuff electrode for neural engineering. PMID- 27762239 TI - A pipeline of spatio-temporal filtering for predicting the laterality of self initiated fine movements from single trial readiness potentials. AB - OBJECTIVE: In recent years, the readiness potential (RP), a type of pre-movement neural activity, has been investigated for asynchronous electroencephalogram (EEG)-based brain-computer interfaces (BCIs). Since the RP is attenuated for involuntary movements, a BCI driven by RP alone could facilitate intentional control amid a plethora of unintentional movements. Previous studies have attempted single trial classification of RP via spatial and temporal filtering methods, or by combining the RP with event-related desynchronization. However, RP feature extraction remains challenging due to the slow non-oscillatory nature of the potential, its variability among participants and the inherent noise in EEG signals. Here, we propose a participant-specific, individually optimized pipeline of spatio-temporal filtering (PSTF) to improve RP feature extraction for laterality prediction. APPROACH: PSTF applies band-pass filtering on RP signals, followed by Fisher criterion spatial filtering to maximize class separation, and finally temporal window averaging for feature dimension reduction. Optimal parameters are simultaneously found by cross-validation for each participant. Using EEG data from 14 participants performing self-initiated left or right key presses as well as two benchmark BCI datasets, we compared the performance of PSTF to two popular methods: common spatial subspace decomposition, and adaptive spatio-temporal filtering. MAIN RESULTS: On the BCI benchmark data sets, PSTF performed comparably to both existing methods. With the key press EEG data, PSTF extracted more discriminative features, thereby leading to more accurate (74.99% average accuracy) predictions of RP laterality than that achievable with existing methods. SIGNIFICANCE: Naturalistic and volitional interaction with the world is an important capacity that is lost with traditional system-paced BCIs. We demonstrated a significant improvement in fine movement laterality prediction from RP features alone. Our work supports further study of RP-based BCI for intuitive asynchronous control of the environment, such as augmentative communication or wheelchair navigation. PMID- 27762238 TI - OptoZIF Drive: a 3D printed implant and assembly tool package for neural recording and optical stimulation in freely moving mice. AB - OBJECTIVE: Behavioral neuroscience studies in freely moving rodents require small, light-weight implants to facilitate neural recording and stimulation. Our goal was to develop an integrated package of 3D printed parts and assembly aids for labs to rapidly fabricate, with minimal training, an implant that combines individually positionable microelectrodes, an optical fiber, zero insertion force (ZIF-clip) headstage connection, and secondary recording electrodes, e.g. for electromyography (EMG). APPROACH: Starting from previous implant designs that position recording electrodes using a control screw, we developed an implant where the main drive body, protective shell, and non-metal components of the microdrives are 3D printed in parallel. We compared alternative shapes and orientations of circuit boards for electrode connection to the headstage, in terms of their size, weight, and ease of wire insertion. We iteratively refined assembly methods, and integrated additional assembly aids into the 3D printed casing. MAIN RESULTS: We demonstrate the effectiveness of the OptoZIF Drive by performing real time optogenetic feedback in behaving mice. A novel feature of the OptoZIF Drive is its vertical circuit board, which facilities direct ZIF-clip connection. This feature requires angled insertion of an optical fiber that still can exit the drive from the center of a ring of recording electrodes. We designed an innovative 2-part protective shell that can be installed during the implant surgery to facilitate making additional connections to the circuit board. We use this feature to show that facial EMG in mice can be used as a control signal to lock stimulation to the animal's motion, with stable EMG signal over several months. To decrease assembly time, reduce assembly errors, and improve repeatability, we fabricate assembly aids including a drive holder, a drill guide, an implant fixture for microelectode 'pinning', and a gold plating fixture. SIGNIFICANCE: The expanding capability of optogenetic tools motivates continuing development of small optoelectric devices for stimulation and recording in freely moving mice. The OptoZIF Drive is the first to natively support ZIF-clip connection to recording hardware, which further supports a decrease in implant cross-section. The integrated 3D printed package of drive components and assembly tools facilities implant construction. The easy interfacing and installation of auxiliary electrodes makes the OptoZIF Drive especially attractive for real time feedback stimulation experiments. PMID- 27762240 TI - "TEE or not to TEE?" PMID- 27762241 TI - Utility of perioperative transesophageal echocardiography. PMID- 27762242 TI - The utility of live video capture to enhance debriefing following transcatheter aortic valve replacement. AB - BACKGROUND: The surgical and procedural specialties are continually evolving their methods to include more complex and technically difficult cases. These cases can be longer and incorporate multiple teams in a different model of operating room synergy. Patients are frequently older, with comorbidities adding to the complexity of these cases. Recording of this environment has become more feasible recently with advancement in video and audio capture systems often used in the simulation realm. AIMS: We began using live capture to record a new procedure shortly after starting these cases in our institution. This has provided continued assessment and evaluation of live procedures. The goal of this was to improve human factors and situational challenges by review and debriefing. SETTING AND DESIGN: B-Line Medical's LiveCapture video system was used to record successive transcatheter aortic valve replacement (TAVR) procedures in our cardiac catheterization/laboratory. An illustrative case is used to discuss analysis and debriefing of the case using this system. RESULTS AND CONCLUSIONS: An illustrative case is presented that resulted in long-term changes to our approach of these cases. The video capture documented rare events during one of our TAVR procedures. Analysis and debriefing led to definitive changes in our practice. While there are hurdles to the use of this technology in every institution, the role for the ongoing use of video capture, analysis, and debriefing may play an important role in the future of patient safety and human factors analysis in the operating environment. PMID- 27762243 TI - Echo for diastology. AB - Diastolic dysfunction ranging from impaired relaxation of the left ventricle to heart failure with preserved ejection fraction (HFpEF) is a common finding in the cardiac surgery population. It is important for the peri-operative echocardiographer to have a developed understanding of the pathophysiology of diastolic dysfunction and the echocardiographic features that determine where on the spectrum of diastolic function and dysfunction a patient lies. PMID- 27762244 TI - Perioperative management of left ventricular assist devices. AB - The use of mechanical circulatory support for patients with severe heart failure is on the rist. The poeoperative, intraoperative and postoperative challenges the anaesthesiologists skills. These are discussed in this review. PMID- 27762245 TI - Transesophageal echocardiography evaluation of tricuspid and pulmonic valves. AB - The tricuspid is the lost valve and the pulmonary being the most anterior, is not visualized well on TEE; The Pulmonary valve is a semilunar valve that separates the right ventricle from the pulmonary artery. It is situated anterior and superior to the aortic valve, almost at right angle to the aortic valve and parallel to the beam of the ultrasound. PMID- 27762246 TI - Left ventricular global systolic function assessment by echocardiography. AB - The left ventricle, with its thickened myocardial walls, unlike the right ventricle has no measurable geometric shape. It has a conical apex and its function quantification, needs intensive, 2D, 3D and M mode transesophageal echocardiography, which is described in this review. PMID- 27762247 TI - Three-dimensional transesophageal echocardiography: Principles and clinical applications. AB - A basic understanding of evolving 3D technology enables the echocardiographer to master the new skills necessary to acquire, manipulate, and interpret 3D datasets. Single button activation of specific 3D imaging modes for both TEE and transthoracic echocardiography (TTE) matrix array probes include (a) live, (b) zoom, (c) full volume (FV), and (d) color Doppler FV. Evaluation of regional LV wall motion by RT 3D TEE is based on a change in LV chamber subvolume over time from altered segmental myocardial contractility. Unlike standard 2D TEE, there is no direct measurement of myocardial thickening or displacement of individual segments. PMID- 27762248 TI - Transesophageal echocardiography evaluation of the thoracic aorta. AB - Transesophageal echocardiography (TEE) can be used to identify risk factors such as aortic atherosclerosis [2] before any sort of surgical manipulations involving aorta and its related structures. TEE has become an important noninvasive tool to diagnose acute thoracic aortic pathologies. TEE evaluation of endoleaks helps early detection and immediate corrective interventions. TEE is an invaluable imaging modality in the management of aortic pathology. TEE has to a large extent improved the patient outcomes. PMID- 27762249 TI - An update on transesophageal echocardiography views 2016: 2D versus 3D tee views. AB - In 1980, Transesophageal Echocardiography (TEE) first technology has introduced the standard of practice for most cardiac operating rooms to facilitate surgical decision making. Transoesophageal echocardiography as a diagnostic tool is now an integral part of intraoperative monitoring practice of cardiac anaesthesiology. Practice guidelines for perioperative transesophageal echocardiography are systematically developed recommendations that assist in the management of surgical patients, were developed by Indian Association of Cardiac Anaesthesiologists (IACTA). This update relates to the former IACTA practice guidelines published in 2013 and the ASE/EACTA guidelines of 2015. The current authors believe that the basic echocardiographer should be familiar with the technical skills for acquiring 28 cross sectional imaging planes. These 28 cross sections would provide also the format for digital acquisition and storage of a comprehensive TEE examination and adds 5 more additional views, introduced for different clinical scenarios in recent times. A comparison of 2D TEE views versus 3D TEE views is attempted for the first time in literature, in this manuscript. Since, cardiac anaesthesia variability exists in the precise anatomic orientation between the heart and the oesophagus in individual patients, an attempt has been made to provide specific criteria based on identifiable anatomic landmarks to improve the reproducibility and consistency of image acquisition for each of the standard cross sections. PMID- 27762250 TI - Guidelines of the Indian Association of Cardiovascular and Thoracic Anaesthesiologists and Indian College of Cardiac Anaesthesia for perioperative transesophageal echocardiography fellowship examination. AB - During current medical care, perioperative transesophageal echocardiography (TEE) has become a vital component of patient management, especially in cardiac operating rooms and in critical care medicine. Information derived from echocardiography has an important bearing on the patient's outcome. The Indian Association of Cardiovascular and Thoracic Anaesthesiologists (IACTA) has promoted the use of TEE during routine clinical care of patients undergoing cardiac surgery. An important mission of IACTA is to oversee training and certify anesthesiologists in the perioperative and intensive care use of TEE. The provision of "Fellowship" is by way of conducting IACTA - TEE fellowship (F-TEE) examination. This has been done annually for the past 7 years using well established curriculums by accredited national and international societies. Now, with the transformation and reconstitution of IACTA education and research cell into the newly formed Indian College of Cardiac Anaesthesia, F-TEE is bound to meet international standards. To ensure that the examinations are conducted in a transparent and foolproof manner, the guideline committee (formulated in 2010) of IACTA has taken the onus of formulating the guidelines for the same. These guidelines have been formally reviewed and updated since 2010 and are detailed here to serve as a guide to both the examinee and examiner ensuring standardization, efficiency, and competency of the IACTA F-TEE certification process. PMID- 27762252 TI - The effect of room acoustics on the sleep quality of healthy sleepers. AB - INTRODUCTION: Noise is one of the factors that can seriously disturb sleep, and sound volume is an important factor in this context. One strategy involves avoiding exposure to sounds in the night, while entail the minimization of background noise in a bedroom. The goal of this study was to investigate the effect of systematic sound attenuation on nocturnal sleep by influencing sound volume and reverberation within the context of room acoustics. MATERIALS AND METHODS: On this basis, we designed a randomized, controlled crossover trial investigating 24 healthy sleepers (15 men and 9 women, aged 24.9 +/- 4.1 years) with a body mass index (BMI) of 21.9 +/- 1.6 kg/m2. Each participant slept for three consecutive nights at three different locations: (a) at our sleep lab, (b) at the participant's home, and (c) at an acoustically isolated room. In addition to conduct of polysomnography (PSG), subjective sleep quality and nocturnal noise level were measured at each location. We likewise measured room temperature and relative humidity. RESULTS: Under conditions of equal sleep efficiency, a significant increase in deep sleep, by 16-34 min, was determined in an acoustically isolated room in comparison to the two other sleep locations. Fewer arousal events and an increase in rapid eye movement (REM) latency became evident in an acoustically isolated environment. Sleep in a domestic environment was subjectively better than sleep under the two test conditions. DISCUSSION: For healthy sleepers, room acoustics influence the microstructure of sleep, without subjective morning benefit. Reduction of noise level and of reverberation leads to an increase in the amount of deep sleep and to reduction of nocturnal arousal events, which is especially important for poor sleepers. PMID- 27762251 TI - Disorders induced by direct occupational exposure to noise: Systematic review. AB - BACKGROUND: To review the available scientific literature about the effects on health by occupational exposure to noise. MATERIALS AND METHODS: A systematic review of the retrieved scientific literature from the databases MEDLINE (via PubMed), ISI-Web of Knowledge (Institute for Scientific Information), Cochrane Library Plus, SCOPUS, and SciELO (collection of scientific journals) was conducted. The following terms were used as descriptors and were searched in free text: "Noise, Occupational," "Occupational Exposure," and "Occupational Disease." The following limits were considered: "Humans," "Adult (more than 18 years)," and "Comparative Studies." RESULTS: A total of 281 references were retrieved, and after applying inclusion/exclusion criteria, 25 articles were selected. Of these selected articles, 19 studies provided information about hearing disturbance, four on cardiovascular disorders, one regarding respiratory alteration, and one on other disorders. CONCLUSIONS: It can be interpreted that the exposure to noise causes alterations in humans with different relevant outcomes, and therefore appropriate security measures in the work environment must be employed to minimize such an exposure and thereby to reduce the number of associated disorders. PMID- 27762253 TI - The Protective effect of the endoplasmic reticulum stress-related factors BiP/GRP78 and CHOP/Gadd153 on noise-induced hearing loss in guinea pigs. AB - CONTEXT: The audiological features and cochlear morphology of individuals with noise-induced hearing loss (NIHL) are well characterized. However, the molecular processes in the cochlea are not well understood. AIMS: To explore the role of the endoplasmic reticulum stress (ERS) response in the guinea pig model of cochlear damage induced by exposure to intense noise. SETTINGS AND DESIGN: A pilot case-control study. SUBJECTS AND METHODS: Forty-eight guinea pigs were divided into four equal groups. At 1, 4, or 14 days (d) post-exposure, the auditory brainstem responses (ABRs) were tested before sacrificing the subjects. The expression levels of the binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78) and C/EBP-homologous protein/growth arrest and DNA damage inducible gene 153 (CHOP/Gadd153) proteins were evaluated using immunohistochemistry and Western blotting. The number of cochlear hair cells with altered nuclei was counted using confocal fluorescence microscopy. STATISTICAL ANALYSIS USED: One-way analysis of variance (ANOVA) and the least squares difference (LSD) test. RESULTS: The outer hair cells (OHCs) showed changes of apoptosis, necrosis, and loss after noise exposure. In the 1- and 4-d groups, more apoptotic cells were found than necrotic cells (P < 0.01). The level of BiP/GRP78 was significantly higher in all three experimental groups compared to the control group (P < 0.01). The level of CHOP/Gadd153 was increased at 1 d post exposure, achieving a peak that was maintained until 4 d, after which it returned to baseline levels by 14 d post-exposure. CONCLUSIONS: ERS response was activated by inducing the expression of BiP/GRP78 to lessen the extent of the resulting cellular damage and activating the CHOP/Gadd153 pathway to eliminate the most severely damaged cells. PMID- 27762254 TI - Determination of the level of noise in nurseries and pre-schools and the teachers' level of annoyance. AB - OBJECTIVE: The aim of this article is to determine the level of noise in nurseries and pre-schools and also to compare measured levels with standard levels and evaluate the teachers' level of annoyance. MATERIALS AND METHODS: The level of noise was measured in three different schools. A total of 162 students, whose ages were between 3 and 6 years, and 12 teachers were included the study. Every age groups' level of noise was measured during sleeping, gaming, and eating activity. In addition, teachers' annoyance was assessed in different age groups. RESULTS: The 4- to 6-year-old groups were found to have higher level of sounds than 3-year-old group. Eating period was found to be the highest level of sound whereas sleeping was found the lowest. Furthermore, teachers' annoyance was found higher as the age decreased. CONCLUSION: Nurseries and pre-schools have noisy environment both for the students and the teachers. High level of noise, which has bad effects on health, is a public health problem. Both the students' families and teachers must be aware of this annoying situation. PMID- 27762255 TI - Auditory brainstem responses for click and CE-chirp stimuli in individuals with and without occupational noise exposure. AB - INTRODUCTION: Encoding of CE-chirp and click stimuli in auditory system was studied using auditory brainstem responses (ABRs) among individuals with and without noise exposure. MATERIALS AND METHODS: The study consisted of two groups. Group 1 (experimental group) consisted of 20 (40 ears) individuals exposed to occupational noise with hearing thresholds within 25 dB HL. They were further divided into three subgroups based on duration of noise exposure (0-5 years of exposure-T1, 5-10 years of exposure-T2, and >10 years of exposure-T3). Group 2 (control group) consisted of 20 individuals (40 ears). Absolute latency and amplitude of waves I, III, and V were compared between the two groups for both click and CE-chirp stimuli. T1, T2, and T3 groups were compared for the same parameters to see the effect of noise exposure duration on CE-chirp and click ABR. RESULT: In Click ABR, while both the parameters for wave III were significantly poorer for the experimental group, wave V showed a significant decline in terms of amplitude only. There was no significant difference obtained for any of the parameters for wave I. In CE-Chirp ABR, the latencies for all three waves were significantly prolonged in the experimental group. However, there was a significant decrease in terms of amplitude in only wave V for the same group. DISCUSSION: Compared to click evoked ABR, CE-Chirp ABR was found to be more sensitive in comparison of latency parameters in individuals with occupational noise exposure. Monitoring of early pathological changes at the brainstem level can be studied effectively by using CE-Chirp stimulus in comparison to click stimulus. CONCLUSION: This study indicates that ABR's obtained with CE-chirp stimuli serves as an effective tool to identify the early pathological changes due to occupational noise exposure when compared to click evoked ABR. PMID- 27762256 TI - Occupational noise exposure on a Royal Navy warship during weapon fire. AB - INTRODUCTION: Measurements were made of the sound pressure levels on a military ship HMS Grimsby during firing of a Heavy Machine Gun (HMG) mounted on the starboard bridge wing. The measurement positions comprised three locations on the ship's bridge (the wheelhouse) and one location on the starboard bridge wing. Equipment and Procedure: The three locations on the bridge were the starboard door, centre and port door. A total of 255 burst firings were measured during the survey comprising 850 rounds with each burst encompassing from 1 to 10 rounds. ANALYSIS: The data have been assessed and interpreted in accordance with the Control of Noise at Work Regulations 2005. RESULTS: The highest peak sound pressure levels measured on the bridge wing and on the bridge were 160.7 dB(C) (2170 Pa) and 122.7 dB(C) (27.3 Pa), respectively. The highest sound exposure levels measured on the bridge wing and on the bridge corresponding to one round being fired were 127.8 dB(A) and 88.9 dB(A), respectively. The ship's structure provided about 40 dB attenuation in the transmitted noise. DISCUSSION: The operator of the weapon would be required to wear some form of hearing protection. On the basis of the measured peak noise levels, there would be no requirement for bridge crew to wear any hearing protection during firing of a HMG. However, crew exposure to noise on the bridge is likely to exceed the upper exposure action value corresponding to 85 dB(A) after about 11,750 rounds. CONCLUSIONS: Measurements made on the bridge wings are likely to be affected by reflections from the ship's structure. PMID- 27762257 TI - Soft tissue conduction as a possible contributor to the limited attenuation provided by hearing protection devices. AB - CONTEXT: Damage to the auditory system by loud sounds can be avoided by hearing protection devices (HPDs) such as earmuffs, earplugs, or both for maximum attenuation. However, the attenuation can be limited by air conduction (AC) leakage around the earplugs and earmuffs by the occlusion effect (OE) and by skull vibrations initiating bone conduction (BC). AIMS: To assess maximum attenuation by HPDs and possible flanking pathways to the inner ear. SUBJECTS AND METHODS: AC attenuation and resulting thresholds were assessed using the real ear attenuation at threshold (REAT) procedure on 15 normal-hearing participants in four free-field conditions: (a) unprotected ears, (b) ears covered with earmuffs, (c) ears blocked with deeply inserted customized earplugs, and (d) ears blocked with both earplugs and earmuffs. BC thresholds were assessed with and without earplugs to assess the OE. RESULTS: Addition of earmuffs to earplugs did not cause significantly greater attenuation than earplugs alone, confirming minimal AC leakage through the external meatus and the absence of the OE. Maximum REATs ranged between 40 and 46 dB, leading to thresholds of 46-54 dB HL. Furthermore, calculation of the acoustic impedance mismatch between air and bone predicted at least 60 dB attenuation of BC. CONCLUSION: Results do not support the notion that skull vibrations (BC) contributed to the limited attenuation provided by traditional HPDs. An alternative explanation, supported by experimental evidence, suggests transmission of sound to inner ear via non-osseous pathways such as skin, soft tissues, and fluid. Because the acoustic impedance mismatch between air and soft tissues is smaller than that between air and bone, air-borne sounds would be transmitted to soft tissues more effectively than to bone, and therefore less attenuation is expected through soft tissue sound conduction. This can contribute to the limited attenuation provided by traditional HPDs. The present study has practical implications for hearing conservation protocols. PMID- 27762258 TI - Supporting the global initiative of preventing childhood hearing loss: Act now, here's how! PMID- 27762259 TI - Inferior Vena Cava Collapsibility Index is a Valuable and Non-Invasive Index for Elevated General Heart End-Diastolic Volume Index Estimation in Septic Shock Patients. AB - BACKGROUND This study aimed to investigate the relationship between the inferior vena cava respirophasic variation (IVC collapsibility index [IVCCI]) and the general heart end-diastolic volume index (GEDVI). By determining the above relationship, we could evaluate the utility of IVCCI as an indicator. MATERIAL AND METHODS Forty-two septic patients were finally enrolled in this study. The inferior vena cava's diameter was measured with the largest at the end of expiration (IVC3) and with the smallest at the end of inspiration (IVCi) on the ultrasound (IVCCI=[(IVCD e - IVCD i)/IVCD e] *100%). The central venous pressure (CVP), cardiac index (CI), and GEDVI were also measured at least 3 times. After fluid resuscitation therapy, the patients with a CI increase induced by more than 15% and less than 15% were classified as the positive response group (PRG) and the negative response group (NRG), respectively. RESULTS After treatment, the average levels of CVP, CI, and GEDVI were significantly higher (P<0.01) in both groups, whereas the IVCCI was reduced. CVP, CI, and GEDVI were negatively correlated with IVCCI in both groups. The correlation coefficient between IVCCI and GEDVI was the greatest (correlation coefficient in the PRG group was 0.889 and in the NRG group it was 0.672). The ROC curve analysis indicated that IVCCI illustrated the best area under the curve, with a sensitivity of 100% and specificity of 100%, and a cut-off value of 12.9% to predict GEDVI <600 ml/m2 in the PRG group. CONCLUSIONS IVCCI was a good predictor of low-volume state. The IVCCI appears to be a valuable and non-invasive index for the estimation of elevated GEDVI during fluid resuscitation in septic shock patients. PMID- 27762260 TI - Field-induced spin-density wave beyond hidden order in URu2Si2. AB - URu2Si2 is one of the most enigmatic strongly correlated electron systems and offers a fertile testing ground for new concepts in condensed matter science. In spite of >30 years of intense research, no consensus on the order parameter of its low-temperature hidden-order phase exists. A strong magnetic field transforms the hidden order into magnetically ordered phases, whose order parameter has also been defying experimental observation. Here, thanks to neutron diffraction under pulsed magnetic fields up to 40 T, we identify the field-induced phases of URu2Si2 as a spin-density-wave state. The transition to the spin-density wave represents a unique touchstone for understanding the hidden-order phase. An intimate relationship between this magnetic structure, the magnetic fluctuations and the Fermi surface is emphasized, calling for dedicated band-structure calculations. PMID- 27762261 TI - A sulfur host based on titanium monoxide@carbon hollow spheres for advanced lithium-sulfur batteries. AB - Lithium-sulfur batteries show advantages for next-generation electrical energy storage due to their high energy density and cost effectiveness. Enhancing the conductivity of the sulfur cathode and moderating the dissolution of lithium polysulfides are two key factors for the success of lithium-sulfur batteries. Here we report a sulfur host that overcomes both obstacles at once. With inherent metallic conductivity and strong adsorption capability for lithium-polysulfides, titanium monoxide@carbon hollow nanospheres can not only generate sufficient electrical contact to the insulating sulfur for high capacity, but also effectively confine lithium-polysulfides for prolonged cycle life. Additionally, the designed composite cathode further maximizes the lithium-polysulfide restriction capability by using the polar shells to prevent their outward diffusion, which avoids the need for chemically bonding all lithium-polysulfides on the surfaces of polar particles. PMID- 27762262 TI - Age and structure of a model vapour-deposited glass. AB - Glass films prepared by a process of physical vapour deposition have been shown to have thermodynamic and kinetic stability comparable to those of ordinary glasses aged for thousands of years. A central question in the study of vapour deposited glasses, particularly in light of new knowledge regarding anisotropy in these materials, is whether the ultra-stable glassy films formed by vapour deposition are ever equivalent to those obtained by liquid cooling. Here we present a computational study of vapour deposition for a two-dimensional glass forming liquid using a methodology, which closely mimics experiment. We find that for the model considered here, structures that arise in vapour-deposited materials are statistically identical to those observed in ordinary glasses, provided the two are compared at the same inherent structure energy. We also find that newly deposited hot molecules produce cascades of hot particles that propagate far into the film, possibly influencing the relaxation of the material. PMID- 27762263 TI - A centrifugation-based physicochemical characterization method for the interaction between proteins and nanoparticles. AB - Nanomedicine requires in-depth knowledge of nanoparticle-protein interactions. These interactions are studied with methods limited to large or fluorescently labelled nanoparticles as they rely on scattering or fluorescence-correlation signals. Here, we have developed a method based on analytical ultracentrifugation (AUC) as an absorbance-based, label-free tool to determine dissociation constants (KD), stoichiometry (Nmax), and Hill coefficient (n), for the association of bovine serum albumin (BSA) with gold nanoparticles. Absorption at 520 nm in AUC renders the measurements insensitive to unbound and aggregated proteins. Measurements remain accurate and do not become more challenging for small (sub-10 nm) nanoparticles. In AUC, frictional ratio analysis allows for the qualitative assessment of the shape of the analyte. Data suggests that small nanoparticles/protein complexes significantly deviate from a spherical shape even at maximum coverage. We believe that this method could become one of the established approaches for the characterization of the interaction of (small) nanoparticles with proteins. PMID- 27762265 TI - Peak-ring structure and kinematics from a multi-disciplinary study of the Schrodinger impact basin. AB - The Schrodinger basin on the lunar farside is ~320 km in diameter and the best preserved peak-ring basin of its size in the Earth-Moon system. Here we present spectral and photogeologic analyses of data from the Moon Mineralogy Mapper instrument on the Chandrayaan-1 spacecraft and the Lunar Reconnaissance Orbiter Camera (LROC) on the LRO spacecraft, which indicates the peak ring is composed of anorthositic, noritic and troctolitic lithologies that were juxtaposed by several cross-cutting faults during peak-ring formation. Hydrocode simulations indicate the lithologies were uplifted from depths up to 30 km, representing the crust of the lunar farside. Through combining geological and remote-sensing observations with numerical modelling, we show that a Displaced Structural Uplift model is best for peak rings, including that in the K-T Chicxulub impact crater on Earth. These results may help guide sample selection in lunar sample return missions that are being studied for the multi-agency International Space Exploration Coordination Group. PMID- 27762264 TI - TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe-/- mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD) induced monocytosis and synergizes with HFCD serum-derived factors to promote pro inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1-/-Apoe-/- mice exhibit substantially attenuated diet induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-atherogenic cytokine production and foam cell formation. PMID- 27762267 TI - Single-catalyst high-weight% hydrogen storage in an N-heterocycle synthesized from lignin hydrogenolysis products and ammonia. AB - Large-scale energy storage and the utilization of biomass as a sustainable carbon source are global challenges of this century. The reversible storage of hydrogen covalently bound in chemical compounds is a particularly promising energy storage technology. For this, compounds that can be sustainably synthesized and that permit high-weight% hydrogen storage would be highly desirable. Herein, we report that catalytically modified lignin, an indigestible, abundantly available and hitherto barely used biomass, can be harnessed to reversibly store hydrogen. A novel reusable bimetallic catalyst has been developed, which is able to hydrogenate and dehydrogenate N-heterocycles most efficiently. Furthermore, a particular N-heterocycle has been identified that can be synthesized catalytically in one step from the main lignin hydrogenolysis product and ammonia, and in which the new bimetallic catalyst allows multiple cycles of high weight% hydrogen storage. PMID- 27762266 TI - Semi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy. AB - Haematopoietic stem cell (HSC) gene therapy has demonstrated potential to treat many diseases. However, current state of the art requires sophisticated ex vivo gene transfer in a dedicated Good Manufacturing Practices facility, limiting availability. An automated process would improve the availability and standardized manufacture of HSC gene therapy. Here, we develop a novel program for semi-automated cell isolation and culture equipment to permit complete benchtop generation of gene-modified CD34+ blood cell products for transplantation. These cell products meet current manufacturing quality standards for both mobilized leukapheresis and bone marrow, and reconstitute human haematopoiesis in immunocompromised mice. Importantly, nonhuman primate autologous gene-modified CD34+ cell products are capable of stable, polyclonal multilineage reconstitution with follow-up of more than 1 year. These data demonstrate proof of concept for point-of-care delivery of HSC gene therapy. Given the many target diseases for gene therapy, there is enormous potential for this approach to treat patients on a global scale. PMID- 27762268 TI - Chromosome biorientation produces hundreds of piconewtons at a metazoan kinetochore. AB - High-fidelity transmission of the genome through cell division requires that all sister kinetochores bind to dynamic microtubules (MTs) from opposite spindle poles. The application of opposing forces to this bioriented configuration produces tension that stabilizes kinetochore-microtubule (kt-MT) attachments. Defining the magnitude of force that is applied to kinetochores is central to understanding the mechano-molecular underpinnings of chromosome segregation; however, existing kinetochore force measurements span orders of magnitude. Here we measure kinetochore forces by engineering two calibrated force sensors into the Drosophila kinetochore protein centromere protein (CENP)-C. Measurements of both reporters indicate that they are, on average, under ~1-2 piconewtons (pNs) of force at metaphase. Based on estimates of the number of CENP-C molecules and MTs per Drosophila kinetochore and envisioning kinetochore linkages arranged such that they distribute forces across them, we propose that kinetochore fibres (k fibres) exert hundreds of pNs of poleward-directed force to bioriented kinetochores. PMID- 27762269 TI - A direct-sensing galactose chemoreceptor recently evolved in invasive strains of Campylobacter jejuni. AB - A rare chemotaxis receptor, Tlp11, has been previously identified in invasive strains of Campylobacter jejuni, the most prevalent cause of bacterial gastroenteritis worldwide. Here we use glycan and small-molecule arrays, as well as surface plasmon resonance, to show that Tlp11 specifically interacts with galactose. Tlp11 is required for the chemotactic response of C. jejuni to galactose, as shown using wild type, allelic inactivation and addition mutants. The inactivated mutant displays reduced virulence in vivo, in a model of chicken colonization. The Tlp11 sensory domain represents the first known sugar-binding dCache_1 domain, which is the most abundant family of extracellular sensors in bacteria. The Tlp11 signalling domain interacts with the chemotaxis scaffolding proteins CheV and CheW, and comparative genomic analysis indicates a likely recent evolutionary origin for Tlp11. We propose to rename Tlp11 as CcrG, Campylobacter ChemoReceptor for Galactose. PMID- 27762270 TI - beta-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways. AB - Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on beta-adrenergic receptors (betaARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that betaAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that betaAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations. PMID- 27762271 TI - Thermally enhanced photoluminescence for heat harvesting in photovoltaics. AB - The maximal Shockley-Queisser efficiency limit of 41% for single-junction photovoltaics is primarily caused by heat dissipation following energetic-photon absorption. Solar-thermophotovoltaics concepts attempt to harvest this heat loss, but the required high temperatures (T>2,000 K) hinder device realization. Conversely, we have recently demonstrated how thermally enhanced photoluminescence is an efficient optical heat-pump that operates in comparably low temperatures. Here we theoretically and experimentally demonstrate such a thermally enhanced photoluminescence based solar-energy converter. Here heat is harvested by a low bandgap photoluminescent absorber that emits thermally enhanced photoluminescence towards a higher bandgap photovoltaic cell, resulting in a maximum theoretical efficiency of 70% at a temperature of 1,140 K. We experimentally demonstrate the key feature of sub-bandgap photon thermal upconversion with an efficiency of 1.4% at only 600 K. Experiments on white light excitation of a tailored Cr:Nd:Yb glass absorber suggest that conversion efficiencies as high as 48% at 1,500 K are in reach. PMID- 27762272 TI - Pressure-induced commensurate stacking of graphene on boron nitride. AB - Combining atomically-thin van der Waals materials into heterostructures provides a powerful path towards the creation of designer electronic devices. The interaction strength between neighbouring layers, most easily controlled through their interlayer separation, can have significant influence on the electronic properties of these composite materials. Here, we demonstrate unprecedented control over interlayer interactions by locally modifying the interlayer separation between graphene and boron nitride, which we achieve by applying pressure with a scanning tunnelling microscopy tip. For the special case of aligned or nearly-aligned graphene on boron nitride, the graphene lattice can stretch and compress locally to compensate for the slight lattice mismatch between the two materials. We find that modifying the interlayer separation directly tunes the lattice strain and induces commensurate stacking underneath the tip. Our results motivate future studies tailoring the electronic properties of van der Waals heterostructures by controlling the interlayer separation of the entire device using hydrostatic pressure. PMID- 27762273 TI - Approaching the standard quantum limit of mechanical torque sensing. AB - Reducing the moment of inertia improves the sensitivity of a mechanically based torque sensor, the parallel of reducing the mass of a force sensor, yet the correspondingly small displacements can be difficult to measure. To resolve this, we incorporate cavity optomechanics, which involves co-localizing an optical and mechanical resonance. With the resulting enhanced readout, cavity-optomechanical torque sensors are now limited only by thermal noise. Further progress requires thermalizing such sensors to low temperatures, where sensitivity limitations are instead imposed by quantum noise. Here, by cooling a cavity-optomechanical torque sensor to 25 mK, we demonstrate a torque sensitivity of 2.9 yNm/. At just over a factor of ten above its quantum-limited sensitivity, such cryogenic optomechanical torque sensors will enable both static and dynamic measurements of integrated samples at the level of a few hundred spins. PMID- 27762274 TI - Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers. AB - Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity. PMID- 27762275 TI - A unique peptide deformylase platform to rationally design and challenge novel active compounds. AB - Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate. PMID- 27762276 TI - 3D mapping of elastic modulus using shear wave optical micro-elastography. AB - Elastography provides a powerful tool for histopathological identification and clinical diagnosis based on information from tissue stiffness. Benefiting from high resolution, three-dimensional (3D), and noninvasive optical coherence tomography (OCT), optical micro-elastography has the ability to determine elastic properties with a resolution of ~10 MUm in a 3D specimen. The shear wave velocity measurement can be used to quantify the elastic modulus. However, in current methods, shear waves are measured near the surface with an interference of surface waves. In this study, we developed acoustic radiation force (ARF) orthogonal excitation optical coherence elastography (ARFOE-OCE) to visualize shear waves in 3D. This method uses acoustic force perpendicular to the OCT beam to excite shear waves in internal specimens and uses Doppler variance method to visualize shear wave propagation in 3D. The measured propagation of shear waves agrees well with the simulation results obtained from finite element analysis (FEA). Orthogonal acoustic excitation allows this method to measure the shear modulus in a deeper specimen which extends the elasticity measurement range beyond the OCT imaging depth. The results show that the ARFOE-OCE system has the ability to noninvasively determine the 3D elastic map. PMID- 27762278 TI - Isothermal anisotropic magnetoresistance in antiferromagnetic metallic IrMn. AB - Antiferromagnetic spintronics is an emerging field; antiferromagnets can improve the functionalities of ferromagnets with higher response times, and having the information shielded against external magnetic field. Moreover, a large list of aniferromagnetic semiconductors and metals with Neel temperatures above room temperature exists. In the present manuscript, we persevere in the quest for the limits of how large can anisotropic magnetoresistance be in antiferromagnetic materials with very large spin-orbit coupling. We selected IrMn as a prime example of first-class moment (Mn) and spin-orbit (Ir) combination. Isothermal magnetotransport measurements in an antiferromagnetic-metal(IrMn)/ferromagnetic insulator thin film bilayer have been performed. The metal/insulator structure with magnetic coupling between both layers allows the measurement of the modulation of the transport properties exclusively in the antiferromagnetic layer. Anisotropic magnetoresistance as large as 0.15% has been found, which is much larger than that for a bare IrMn layer. Interestingly, it has been observed that anisotropic magnetoresistance is strongly influenced by the field cooling conditions, signaling the dependence of the found response on the formation of domains at the magnetic ordering temperature. PMID- 27762277 TI - Allosteric regulation by cooperative conformational changes of actin filaments drives mutually exclusive binding with cofilin and myosin. AB - Heavy meromyosin (HMM) of myosin II and cofilin each binds to actin filaments cooperatively and forms clusters along the filaments, but it is unknown whether the two cooperative bindings are correlated and what physiological roles they have. Fluorescence microscopy demonstrated that HMM-GFP and cofilin-mCherry each bound cooperatively to different parts of actin filaments when they were added simultaneously in 0.2 MUM ATP, indicating that the two cooperative bindings are mutually exclusive. In 0.1 mM ATP, the motor domain of myosin (S1) strongly inhibited the formation of cofilin clusters along actin filaments. Under this condition, most actin protomers were unoccupied by S1 at any given moment, suggesting that transiently bound S1 alters the structure of actin filaments cooperatively and/or persistently to inhibit cofilin binding. Consistently, cosedimentation experiments using copolymers of actin and actin-S1 fusion protein demonstrated that the fusion protein affects the neighboring actin protomers, reducing their affinity for cofilin. In reciprocal experiments, cofilin-actin fusion protein reduced the affinity of neighboring actin protomers for S1. Thus, allosteric regulation by cooperative conformational changes of actin filaments contributes to mutually exclusive cooperative binding of myosin II and cofilin to actin filaments, and presumably to the differential localization of both proteins in cells. PMID- 27762279 TI - Universal stress protein Rv2624c alters abundance of arginine and enhances intracellular survival by ATP binding in mycobacteria. AB - The universal stress protein family is a family of stress-induced proteins. Universal stress proteins affect latency and antibiotic resistance in mycobacteria. Here, we showed that Mycobacterium smegmatis overexpressing M. tuberculosis universal stress protein Rv2624c exhibits increased survival in human monocyte THP-1 cells. Transcriptome analysis suggested that Rv2624c affects histidine metabolism, and arginine and proline metabolism. LC-MS/MS analysis showed that Rv2624c affects the abundance of arginine, a modulator of both mycobacteria and infected THP-1 cells. Biochemical analysis showed that Rv2624c is a nucleotide-binding universal stress protein, and an Rv2624c mutant incapable of binding ATP abrogated the growth advantage in THP-1 cells. Rv2624c may therefore modulate metabolic pathways in an ATP-dependent manner, changing the abundance of arginine and thus increasing survival in THP-1 cells. PMID- 27762281 TI - Widespread occurrence of lysine methylation in Plasmodium falciparum proteins at asexual blood stages. AB - Post-transcriptional and post-translational modifications play a major role in Plasmodium life cycle regulation. Lysine methylation of histone proteins is well documented in several organisms, however in recent years lysine methylation of proteins outside histone code is emerging out as an important post-translational modification (PTM). In the present study we have performed global analysis of lysine methylation of proteins in asexual blood stages of Plasmodium falciparum development. We immunoprecipitated stage specific Plasmodium lysates using anti methyl lysine specific antibodies that immunostained the asexual blood stage parasites. Using liquid chromatography and tandem mass spectrometry analysis, 570 lysine methylated proteins at three different blood stages were identified. Analysis of the peptide sequences identified 605 methylated sites within 422 proteins. Functional classification of the methylated proteins revealed that the proteins are mainly involved in nucleotide metabolic processes, chromatin organization, transport, homeostatic processes and protein folding. The motif analysis of the methylated lysine peptides reveals novel motifs. Many of the identified lysine methylated proteins are also interacting partners/substrates of PfSET domain proteins as revealed by STRING database analysis. Our findings suggest that the protein methylation at lysine residues is widespread in Plasmodium and plays an important regulatory role in diverse set of the parasite pathways. PMID- 27762280 TI - Protease induced plasticity: matrix metalloproteinase-1 promotes neurostructural changes through activation of protease activated receptor 1. AB - Matrix metalloproteinases (MMPs) are a family of secreted endopeptidases expressed by neurons and glia. Regulated MMP activity contributes to physiological synaptic plasticity, while dysregulated activity can stimulate injury. Disentangling the role individual MMPs play in synaptic plasticity is difficult due to overlapping structure and function as well as cell-type specific expression. Here, we develop a novel system to investigate the selective overexpression of a single MMP driven by GFAP expressing cells in vivo. We show that MMP-1 induces cellular and behavioral phenotypes consistent with enhanced signaling through the G-protein coupled protease activated receptor 1 (PAR1). Application of exogenous MMP-1, in vitro, stimulates PAR1 dependent increases in intracellular Ca2+ concentration and dendritic arborization. Overexpression of MMP-1, in vivo, increases dendritic complexity and induces biochemical and behavioral endpoints consistent with increased GPCR signaling. These data are exciting because we demonstrate that an astrocyte-derived protease can influence neuronal plasticity through an extracellular matrix independent mechanism. PMID- 27762282 TI - Application of Targeted Mass Spectrometry for the Quantification of Sirtuins in the Central Nervous System. AB - Sirtuin proteins have a variety of intracellular targets, thereby regulating multiple biological pathways including neurodegeneration. However, relatively little is currently known about the role or expression of the 7 mammalian sirtuins in the central nervous system. Western blotting, PCR and ELISA are the main techniques currently used to measure sirtuin levels. To achieve sufficient sensitivity and selectivity in a multiplex-format, a targeted mass spectrometric assay was developed and validated for the quantification of all seven mammalian sirtuins (SIRT1-7). Quantification of all peptides was by multiple reaction monitoring (MRM) using three mass transitions per protein-specific peptide, two specific peptides for each sirtuin and a stable isotope labelled internal standard. The assay was applied to a variety of samples including cultured brain cells, mammalian brain tissue, CSF and plasma. All sirtuin peptides were detected in the human brain, with SIRT2 being the most abundant. Sirtuins were also detected in human CSF and plasma, and guinea pig and mouse tissues. In conclusion, we have successfully applied MRM mass spectrometry for the detection and quantification of sirtuin proteins in the central nervous system, paving the way for more quantitative and functional studies. PMID- 27762283 TI - Hepatitis C RNA assay differences in results: Potential implications for shortened therapy and determination of Sustained Virologic Response. AB - Approval of Ledipasvir/Sofosbuvir for the treatment of chronic hepatitis C (HCV) includes the truncation of therapy from 12 to 8 weeks in treatment naive, non cirrhotic patients with baseline HCV RNA levels <6 million IU/mL (6.8 log10 IU/mL). The aim of this study was to evaluate this clinical cutoff with a different widely used commercially available HCV RNA test. Results from samples tested prospectively with Roche High Pure TaqMan HCV 2.0 test (HPS) were compared to those tested retrospectively with the Abbott RealTime HCV RNA test (ART). Using 6 million IU/mL as the cut-off, pre-treatment results were concordant in 70.4% of cases. When results with the same test measured at screening and baseline, clinical decisions could be impacted in 14.4% and 6.2% of cases for HPS and ART respectively. Using only HCV RNA cutoff of 6 million IU/mL, 29.55% of subjects would receive a different and potentially incorrect treatment duration based solely on HCV RNA test method used. A further 6-14% of subjects would have treatment decision change based on the day the sample was taken. PMID- 27762284 TI - PolyHIPE Derived Freestanding 3D Carbon Foam for Cobalt Hydroxide Nanorods Based High Performance Supercapacitor. AB - The current paper describes enhanced electrochemical capacitive performance of chemically grown Cobalt hydroxide (Co(OH)2) nanorods (NRs) decorated porous three dimensional graphitic carbon foam (Co(OH)2/3D GCF) as a supercapacitor electrode. Freestanding 3D porous GCF is prepared by carbonizing, high internal phase emulsion (HIPE) polymerized styrene and divinylbenzene. The PolyHIPE was sulfonated and carbonized at temperature up to 850 degrees C to obtain graphitic 3D carbon foam with high surface area (389 m2 g-1) having open voids (14 MUm) interconnected by windows (4 MUm) in monolithic form. Moreover, entangled Co(OH)2 NRs are anchored on 3D GCF electrodes by using a facile chemical bath deposition (CBD) method. The wide porous structure with high specific surface area (520 m2 g 1) access offered by the interconnected 3D GCF along with Co(OH)2 NRs morphology, displays ultrahigh specific capacitance, specific energy and power. The Co(OH)2/3D GCF electrode exhibits maximum specific capacitance about ~1235 F g-1 at ~1 A g-1 charge-discharge current density, in 1 M aqueous KOH solution. These results endorse potential applicability of Co(OH)2/3D GCF electrode in supercapacitors and signifies that, the porous GCF is a proficient 3D freestanding framework for loading pseudocapacitive nanostructured materials. PMID- 27762285 TI - Changes in Central Asia's Water Tower: Past, Present and Future. AB - The Tienshan Mountains, with its status as "water tower", is the main water source and ecological barrier in Central Asia. The rapid warming affected precipitation amounts and fraction as well as the original glacier/snowmelt water processes, thereby affecting the runoff and water storage. The ratio of snowfall to precipitation (S/P) experienced a downward trend, along with a shift from snow to rain. Spatially, the snow cover area in Middle Tienshan Mountains decreased significantly, while that in West Tienshan Mountains increased slightly. Approximately 97.52% of glaciers in the Tienshan Mountains showed a retreating trend, which was especially obvious in the North and East Tienshan Mountains. River runoff responds in a complex way to changes in climate and cryosphere. It appears that catchments with a higher fraction of glacierized area showed mainly increasing runoff trends, while river basins with less or no glacierization exhibited large variations in the observed runoff changes. The total water storage in the Tienshan Mountains also experienced a significant decreasing trend in Middle and East Tienshan Mountains, but a slight decreasing trend in West Tienshan Mountains, totally at an average rate of -3.72 mm/a. In future, water storage levels are expected to show deficits for the next half-century. PMID- 27762286 TI - Simultaneous generation of high-efficiency broadband asymmetric anomalous refraction and reflection waves with few-layer anisotropic metasurface. AB - Optical metasurfaces consisting of single-layer nanostructures have immensely promising applications in wavefront control because they can be used to arbitrarily manipulate wave phase, and polarization. However, anomalous refraction and reflection waves have not yet been simultaneously and asymmetrically generated, and the limited efficiency and bandwidth of pre existing single-layer metasurfaces hinder their practical applications. Here, a few-layer anisotropic metasurface is presented for simultaneously generating high efficiency broadband asymmetric anomalous refraction and reflection waves. Moreover, the normal transmission and reflection waves are low and the anomalous waves are the predominant ones, which is quite beneficial for practical applications such as beam deflectors. Our work provides an effective method of enhancing the performance of anomalous wave generation, and the asymmetric performance of the proposed metasurface shows endless possibilities in wavefront control for nanophotonics device design and optical communication applications. PMID- 27762287 TI - Neurons in the pigeon caudolateral nidopallium differentiate Pavlovian conditioned stimuli but not their associated reward value in a sign-tracking paradigm. AB - Animals exploit visual information to identify objects, form stimulus-reward associations, and prepare appropriate behavioral responses. The nidopallium caudolaterale (NCL), an associative region of the avian endbrain, contains neurons exhibiting prominent response modulation during presentation of reward predicting visual stimuli, but it is unclear whether neural activity represents valuation signals, stimulus properties, or sensorimotor contingencies. To test the hypothesis that NCL neurons represent stimulus value, we subjected pigeons to a Pavlovian sign-tracking paradigm in which visual cues predicted rewards differing in magnitude (large vs. small) and delay to presentation (short vs. long). Subjects' strength of conditioned responding to visual cues reliably differentiated between predicted reward types and thus indexed valuation. The majority of NCL neurons discriminated between visual cues, with discriminability peaking shortly after stimulus onset and being maintained at lower levels throughout the stimulus presentation period. However, while some cells' firing rates correlated with reward value, such neurons were not more frequent than expected by chance. Instead, neurons formed discernible clusters which differed in their preferred visual cue. We propose that this activity pattern constitutes a prerequisite for using visual information in more complex situations e.g. requiring value-based choices. PMID- 27762289 TI - Comparative Study of the Catalytic Activities of Three Distinct Carbonaceous Materials through Photocatalytic Oxidation, CO Conversion, Dye Degradation, and Electrochemical Measurements. AB - In order to compare the catalytic activities of reduced graphene oxide (rGO), graphene oxide (GO), and graphene, we conducted oxidation of 2-aminothiophenol (2 ATP) and reduction of nitrobenzene (NB) in their presence by using high resolution photoemission spectroscopy (HRPES). In addition, we determined conversion rates of CO to CO2 in the presence of these catalysts by performing a residual gas analyzer (RGA) under a UHV condition, Orange II and methylene blue degradations UV-vis spectrophotometry, and electrochemistry (EC) measurements in an aqueous solution, as well as by obtaining cyclic voltammograms and determining the change of the condition of electrodes before and after the oxidation of 2 ATP. We found that we can successively fabricate GO (oxidation) and graphene (reduction) from rGO by controlling the oxidation or reduction procedure time and then clearly comparing the critical properties among them as we perform various oxidation and reduction activities. PMID- 27762288 TI - The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism. AB - Puerarin, a known isoflavone, is commonly found as a Chinese herb medicine. It is widely used in China to treat cardiac diseases such as angina, cardiac infarction and arrhythmia. However, its cardioprotective mechanism remains unclear. In this study, puerarin significantly prolonged ventricular action potential duration (APD) with a dosage dependent manner in the micromolar range on isolated rat ventricular myocytes. However, submicromolar puerarin had no effect on resting membrane potential (RMP), action potential amplitude (APA) and maximal velocity of depolarization (Vmax) of action potential. Only above the concentration of 10 mM, puerarin exhibited more aggressive effect on action potential, and shifted RMP to the positive direction. Millimolar concentrations of puerarin significantly inhibited inward rectified K+ channels in a dosage dependent manner, and exhibited bigger effects upon Kir2.1 vs Kir2.3 in transfected HEK293 cells. As low as micromolar range concentrations of puerarin significantly inhibited Kv7.1 and IKs. These inhibitory effects may due to the direct inhibition of puerarin upon channels not via the PKA-dependent pathway. These results provided direct preclinical evidence that puerarin prolonged APD via its inhibitory effect upon Kv7.1 and IKs, contributing to a better understanding the mechanism of puerarin cardioprotection in the treatment of cardiovascular diseases. PMID- 27762290 TI - Dim light at night disturbs the daily sleep-wake cycle in the rat. AB - Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150-200lux):12 h dark (LD) schedule or a 12 h light (150-200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16-19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia. PMID- 27762292 TI - Electromagnetic Model Reliably Predicts Radar Scattering Characteristics of Airborne Organisms. AB - The radar scattering characteristics of aerial animals are typically obtained from controlled laboratory measurements of a freshly harvested specimen. These measurements are tedious to perform, difficult to replicate, and typically yield only a small subset of the full azimuthal, elevational, and polarimetric radio scattering data. As an alternative, biological applications of radar often assume that the radar cross sections of flying animals are isotropic, since sophisticated computer models are required to estimate the 3D scattering properties of objects having complex shapes. Using the method of moments implemented in the WIPL-D software package, we show for the first time that such electromagnetic modeling techniques (typically applied to man-made objects) can accurately predict organismal radio scattering characteristics from an anatomical model: here the Brazilian free-tailed bat (Tadarida brasiliensis). The simulated scattering properties of the bat agree with controlled measurements and radar observations made during a field study of bats in flight. This numerical technique can produce the full angular set of quantitative polarimetric scattering characteristics, while eliminating many practical difficulties associated with physical measurements. Such a modeling framework can be applied for bird, bat, and insect species, and will help drive a shift in radar biology from a largely qualitative and phenomenological science toward quantitative estimation of animal densities and taxonomic identification. PMID- 27762291 TI - THz-circuits driven by photo-thermoelectric, gate-tunable graphene-junctions. AB - For future on-chip communication schemes, it is essential to integrate nanoscale materials with an ultrafast optoelectronic functionality into high-frequency circuits. The atomically thin graphene has been widely demonstrated to be suitable for photovoltaic and optoelectronic devices because of its broadband optical absorption and its high electron mobility. Moreover, the ultrafast relaxation of photogenerated charge carriers has been verified in graphene. Here, we show that dual-gated graphene junctions can be functional parts of THz circuits. As the underlying optoelectronic process, we exploit ultrafast photo thermoelectric currents. We describe an immediate photo-thermoelectric current of the unbiased device following a femtosecond laser excitation. For a picosecond time-scale after the optical excitation, an additional photo-thermoelectric contribution shows up, which exhibits the fingerprint of a spatially inverted temperature profile. The latter can be understood by the different time-constants and thermal coupling mechanisms of the electron and phonon baths within graphene to the substrate and the metal contacts. The interplay of the processes gives rise to ultrafast electromagnetic transients in high-frequency circuits, and it is equally important for a fundamental understanding of graphene-based ultrafast photodetectors and switches. PMID- 27762293 TI - Antigen-affinity controls pre-germinal center B cell selection by promoting Mcl-1 induction through BAFF receptor signaling. AB - Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF. Moreover, expression of BAFF receptor CD268 is regulated in a BCR-affinity dependent fashion. High affinity responses via BAFF correlated with PI3K activation, which controlled expression of the pro-survival protein Mcl-1, and thereby increased survival. In the presence of excess BAFF, or in absence of the Mcl-1 antagonist Noxa, more low-affinity B cells survived the first two days after antigen encounter. This resulted in increased numbers of antigen-specific B cells of low affinity upon immunization and reduced the overall affinity of cells that contributed to the germinal center reaction. Our findings elucidate a crucial molecular pathway of B cell selection in the earliest phases of activation by identifying a novel link between BCR affinity and BAFF-R signaling towards Mcl-1. PMID- 27762294 TI - The role of ion transport phenomena in memristive double barrier devices. AB - In this work we report on the role of ion transport for the dynamic behavior of a double barrier quantum mechanical Al/Al2O3/NbxOy/Au memristive device based on numerical simulations in conjunction with experimental measurements. The device consists of an ultra-thin NbxOy solid state electrolyte between an Al2O3 tunnel barrier and a semiconductor metal interface at an Au electrode. It is shown that the device provides a number of interesting features such as an intrinsic current compliance, a relatively long retention time, and no need for an initialization step. Therefore, it is particularly attractive for applications in highly dense random access memories or neuromorphic mixed signal circuits. However, the underlying physical mechanisms of the resistive switching are still not completely understood yet. To investigate the interplay between the current transport mechanisms and the inner atomistic device structure a lumped element circuit model is consistently coupled with 3D kinetic Monte Carlo model for the ion transport. The simulation results indicate that the drift of charged point defects within the NbxOy is the key factor for the resistive switching behavior. It is shown in detail that the diffusion of oxygen modifies the local electronic interface states resulting in a change of the interface properties. PMID- 27762295 TI - Inferring neutral biodiversity parameters using environmental DNA data sets. AB - The DNA present in the environment is a unique and increasingly exploited source of information for conducting fast and standardized biodiversity assessments for any type of organisms. The datasets resulting from these surveys are however rarely compared to the quantitative predictions of biodiversity models. In this study, we simulate neutral taxa-abundance datasets, and artificially noise them by simulating noise terms typical of DNA-based biodiversity surveys. The resulting noised taxa abundances are used to assess whether the two parameters of Hubbell's neutral theory of biodiversity can still be estimated. We find that parameters can be inferred provided that PCR noise on taxa abundances does not exceed a certain threshold. However, inference is seriously biased by the presence of artifactual taxa. The uneven contribution of organisms to environmental DNA owing to size differences and barcode copy number variability does not impede neutral parameter inference, provided that the number of sequence reads used for inference is smaller than the number of effectively sampled individuals. Hence, estimating neutral parameters from DNA-based taxa abundance patterns is possible but requires some caution. In studies that include empirical noise assessments, our comprehensive simulation benchmark provides objective criteria to evaluate the robustness of neutral parameter inference. PMID- 27762297 TI - Early Detection of T cell Transfer-induced Autoimmune Colitis by In Vivo Imaging System. AB - Inflammatory bowel disease is a chronic and progressive inflammatory intestinal disease that includes two major types, namely ulcerative colitis and Crohn's disease (CD). CD is characterized by intestinal epithelial hyperplasia and inflammatory cell infiltration. Transfer of CD25-CD45RBhiCD4+ (naive) T cells into immunodeficiency mice induces autoimmune colitis with pathological lesions similar to CD and loss of body weight 4 weeks after cell transfer. However, weight loss neither has sufficient sensitivity nor totally matches the pathological findings of CD. To establish an early and sensitive indicator of autoimmune colitis model, the transferred T cell-induced colitis mouse model was modified by transferring luciferase-expressing donor T cells and determining the colitis by in vivo imaging system (IVIS). Colitis was detected with IVIS 7-10 days before the onset of body weight loss and diarrhea. IVIS was also applied in the dexamethasone treatment trial, and was a more sensitive indicator than body weight changes. All IVIS signals were parallel to the pathological abnormalities of the gut and immunological analysis results. In summary, IVIS provides both sensitive and objective means to monitor the disease course of transferred T cell induced CD and fulfills the 3Rs principle of humane care of laboratory animals. PMID- 27762296 TI - Integrated mRNA and miRNA transcriptome reveal a cross-talk between developing response and hormone signaling for the seed kernels of Siberian apricot. AB - Recently, our transcriptomic analysis has identified some functional genes responsible for oil biosynthesis in developing SASK, yet miRNA-mediated regulation for SASK development and oil accumulation is poorly understood. Here, 3 representative periods of 10, 30 and 60 DAF were selected for sRNA sequencing based on the dynamic patterns of growth tendency and oil content of developing SASK. By miRNA transcriptomic analysis, we characterized 296 known and 44 novel miRNAs in developing SASK, among which 36 known and 6 novel miRNAs respond specifically to developing SASK. Importantly, we performed an integrated analysis of mRNA and miRNA transcriptome as well as qRT-PCR detection to identify some key miRNAs and their targets (miR156-SPL, miR160-ARF18, miR164-NAC1, miR171h-SCL6, miR172-AP2, miR395-AUX22B, miR530-P2C37, miR393h-TIR1/AFB2 and psi-miRn5-SnRK2A) potentially involved in developing response and hormone signaling of SASK. Our results provide new insights into the important regulatory function of cross-talk between development response and hormone signaling for SASK oil accumulation. PMID- 27762298 TI - PD-L1 is a critical mediator of regulatory B cells and T cells in invasive breast cancer. AB - Regulatory T cells (Tregs), a key mediator in regulating anti-tumor immune suppression, tumor immune escape, metastasis and relapse, are considered an important therapeutic target in immunotherapy of human cancers. In the present investigation, elevated CD19+ CD24+ CD38+ regulatory B cells (Bregs) were observed in PBMCs of invasive carcinoma of breast (IBCa) patients compared with that in patients with fibroadenoma (FIBma) or healthy individuals, and the positive correlation existed between Bregs and CD4+ CD25+ CD127- Tregs (r = 0.316, P = 0.001). We found that PD-L1 expression was higher on Bregs in IBCa patients compared with patients with FIBma or healthy individuals (P < 0.05, respectively), and that a tight correlation exists between CD19+ CD24+ CD38+ PD L1+ Bregs and CD19+ CD24+ CD38+ Bregs (r = 0.267, P = 0.007), poor TNM phases and up-regulated expression of PD-L1 on Bregs. The pattern of PD-1 expression on CD4+ T cells indicated that high level of PD-1hi expressed on CD4+ CD25+ CD127+ effector T cells (P < 0.001). More importantly, the presence of PD-L1 on Bregs was positively correlated with Tregs (r = 0.299, P = 0.003), but negatively correlated with PD-1hi effector T cells (r = -0.22, P = 0.031). Together, results of the present study indicated that PD-L1 is an important molecule on Bregs, mediated the generation of Tregs in IBCa. PMID- 27762299 TI - Quantitative analysis of echogenicity for patients with thyroid nodules. AB - Hypoechogenicity has been described qualitatively and is potentially subject to intra- and inter-observer variability. The aim of this study was to clarify whether quantitative echoic indexes (EIs) are useful for the detection of malignant thyroid nodules. Overall, 333 participants with 411 nodules were included in the final analysis. Quantification of echogenicity was performed using commercial software (AmCAD-UT; AmCad BioMed, Taiwan). The coordinates of three defined regions, the nodule, thyroid parenchyma, and strap muscle regions, were recorded in the database separately for subsequent analysis. And the results showed that ultrasound echogenicity (US-E), as assessed by clinicians, defined hypoechogenicity as an independent factor for malignancy. The EI, adjusted EI (EIN-T; EIN-M) and automatic EI(N-R)/R values between benign and malignant nodules were all significantly different, with lower values for malignant nodules. All of the EIs showed similar percentages of sensitivity and specificity and had better accuracies than US-E. In conclusion, the proposed quantitative EI seems more promising to constitute an important advancement than the conventional qualitative US-E in allowing for a more reliable distinction between benign and malignant thyroid nodules. PMID- 27762300 TI - Lipid remodelling in the reef-building honeycomb worm, Sabellaria alveolata, reflects acclimation and local adaptation to temperature. AB - Acclimation and adaptation, which are key to species survival in a changing climate, can be observed in terms of membrane lipid composition. Remodelling membrane lipids, via homeoviscous adaptation (HVA), counteracts membrane dysfunction due to temperature in poikilotherms. In order to assess the potential for acclimation and adaptation in the honeycomb worm, Sabellaria alveolata, a reef-building polychaete that supports high biodiversity, we carried out common garden experiments using individuals from along its latitudinal range. Individuals were exposed to a stepwise temperature increase from 15 degrees C to 25 degrees C and membrane lipid composition assessed. Our results suggest that S. alveolata was able to acclimate to higher temperatures, as observed by a decrease in unsaturation index and 20:5n-3. However, over the long-term at 25 degrees C, lipid composition patterns are not consistent with HVA expectations and suggest a stress response. Furthermore, unsaturation index of individuals from the two coldest sites were higher than those from the two warmest sites, with individuals from the thermally intermediate site being in-between, likely reflecting local adaptation to temperature. Therefore, lipid remodelling appears limited at the highest temperatures in S. alveolata, suggesting that individuals inhabiting warm environments may be close to their upper thermal tolerance limits and at risk in a changing climate. PMID- 27762302 TI - Machine-learned pattern identification in olfactory subtest results. AB - The human sense of smell is often analyzed as being composed of three main components comprising olfactory threshold, odor discrimination and the ability to identify odors. A relevant distinction of the three components and their differential changes in distinct disorders remains a research focus. The present data-driven analysis aimed at establishing a cluster structure in the pattern of olfactory subtest results. Therefore, unsupervised machine-learning was applied onto olfactory subtest results acquired in 10,714 subjects with nine different olfactory pathologies. Using the U-matrix, Emergent Self-organizing feature maps (ESOM) identified three different clusters characterized by (i) low threshold and good discrimination and identification, (ii) very high threshold associated with absent to poor discrimination and identification ability, or (iii) medium threshold, i.e., in the mid-range of possible thresholds, associated with reduced discrimination and identification ability. Specific etiologies of olfactory (dys)function were unequally represented in the clusters (p < 2.2 . 10-16). Patients with congenital anosmia were overrepresented in the second cluster while subjects with postinfectious olfactory dysfunction belonged frequently to the third cluster. However, the clusters provided no clear separation between etiologies. Hence, the present verification of a distinct cluster structure encourages continued scientific efforts at olfactory test pattern recognition. PMID- 27762301 TI - Comparative profiling of microRNAs in the winged and wingless English grain aphid, Sitobion avenae (F.) (Homoptera: Aphididae). AB - MicroRNAs (miRNAs) are short single-stranded non-coding RNAs that regulate gene expression, particularly during development. In this study, 345 miRNAs were identified from the English green aphid, Sitobion avenae (F.), of which 168 were conserved and 177 were S. avenae-specific. Quantitative comparison of miRNA expression levels indicated that 16 and 12 miRNAs were significantly up-regulated in winged and wingless S. avenae small RNA libraries, respectively. Differential expression of these miRNAs was confirmed by real-time quantitative RT-PCR validation. The putative transcript targets for these candidate miRNAs were predicted based on sequences from a model species Drosophila melanogaster and four aphid species Acyrthosiphon pisum, Myzus persicae, Toxoptera citricida, and Aphis gosspii. Gene Ontology and KEGG pathway analyses shed light on the potential functions of these miRNAs in the regulation of genes involved in the metabolism, development and wing polyphenism of S. avenae. PMID- 27762303 TI - AKT/GSK3beta signaling pathway is critically involved in human pluripotent stem cell survival. AB - Human embryonic and induced pluripotent stem cells are self-renewing pluripotent stem cells (PSC) that can differentiate into a wide range of specialized cells. Basic fibroblast growth factor is essential for PSC survival, stemness and self renewal. PI3K/AKT pathway regulates cell viability and apoptosis in many cell types. Although it has been demonstrated that PI3K/AKT activation by bFGF is relevant for PSC stemness maintenance its role on PSC survival remains elusive. In this study we explored the molecular mechanisms involved in the regulation of PSC survival by AKT. We found that inhibition of AKT with three non-structurally related inhibitors (GSK690693, AKT inhibitor VIII and AKT inhibitor IV) decreased cell viability and induced apoptosis. We observed a rapid increase in phosphatidylserine translocation and in the extent of DNA fragmentation after inhibitors addition. Moreover, abrogation of AKT activity led to Caspase-9, Caspase-3, and PARP cleavage. Importantly, we demonstrated by pharmacological inhibition and siRNA knockdown that GSK3beta signaling is responsible, at least in part, of the apoptosis triggered by AKT inhibition. Moreover, GSK3beta inhibition decreases basal apoptosis rate and promotes PSC proliferation. In conclusion, we demonstrated that AKT activation prevents apoptosis, partly through inhibition of GSK3beta, and thus results relevant for PSC survival. PMID- 27762304 TI - Bone Marrow Stem/Progenitor Cells Attenuate the Inflammatory Milieu Following Substitution Urethroplasty. AB - Substitution urethroplasty for the treatment of male stricture disease is often accompanied by subsequent tissue fibrosis and secondary stricture formation. Patients with pre-existing morbidities are often at increased risk of urethral stricture recurrence brought upon in-part by delayed vascularization accompanied by overactive inflammatory responses following surgery. Within the context of this study, we demonstrate the functional utility of a cell/scaffold composite graft comprised of human bone marrow-derived mesenchymal stem cells (MSC) combined with CD34+ hematopoietic stem/progenitor cells (HSPC) to modulate inflammation and wound healing in a rodent model of substitution urethroplasty. Composite grafts demonstrated potent anti-inflammatory effects with regards to tissue macrophage and neutrophil density following urethral tissue analyses. This was accompanied by a significant reduction in pro-inflammatory cytokines TNFalpha and IL-1beta and further resulted in an earlier transition to tissue remodeling and maturation with a shift in collagen type III to I. Grafted animals demonstrated a progressive maturation and increase in vessel size compared to control animals. Overall, MSC/CD34+ HSPC composite grafts reduce inflammation, enhance an earlier transition to wound remodeling and maturation concurrently increasing neovascularization in the periurethral tissue. We demonstrate the feasibility and efficacy of a stem cell-seeded synthetic graft in a rodent substitution urethroplasty model. PMID- 27762305 TI - Novel mutations in FKBP10 in Chinese patients with osteogenesis imperfecta and their treatment with zoledronic acid. AB - Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. OI cases of autosomal recessive inheritance are rare, and OI type XI is attributable to mutation of the FKBP10 gene. Here, we used next-generation sequencing and Sanger sequencing to detect mutations in FKBP10 and to analyze their relation to the phenotypes of OI type XI in three Chinese patients. We also evaluated the efficacy of zoledronic acid treatment in these patients. Two of the affected patients had novel compound heterozygous mutations, one patient with c.343C>T (p.R115X) in exon 2 and c.1085delC (p.A362fsX1) in exon 7, and the other patient with c.879C>G (p.Y293X) in exon 5 and c.918-3C>G in intron 5. In the third proband, we identified a homozygous single base-pair duplication, c.831dupC (p.G278RfsX95) in exon 5. In conclusion, we report for the first time that these novel pathogenic mutations of FKBP10 can lead to the extremely rare type XI OI without contractures, which expands the genotypic spectrum of OI. The phenotypes of these patients are similar to patients with types III or IV OI, and zoledronic acid is effective in increasing BMD, inhibiting bone resorption biomarkers and reducing fractures of these patients. PMID- 27762306 TI - Integrated analysis of bacterial and microeukaryotic communities from differentially active mud volcanoes in the Gulf of Cadiz. AB - The present study assesses the diversity and composition of sediment bacterial and microeukaryotic communities from deep-sea mud volcanoes (MVs) associated with strike-slip faults in the South-West Iberian Margin (SWIM). We used a 16S/18S rRNA gene based pyrosequencing approach to characterize and correlate the sediment bacterial and microeukaryotic communities from MVs with differing gas seep regimes and from an additional site with no apparent seeping activity. In general, our results showed significant compositional changes of bacterial and microeukaryotic communities in sampling sites with different seepage regimes. Sediment bacterial communities were enriched with Methylococcales (putative methanotrophs) but had lower abundances of Rhodospirillales, Nitrospirales and SAR202 in the more active MVs. Within microeukaryotic communities, members of the Lobosa (lobose amoebae) were enriched in more active MVs. We also showed a strong correlation between Methylococcales populations and lobose amoeba in active MVs. This study provides baseline information on the diversity and composition of bacterial and microeukaryotic communities in deep-sea MVs associated with strike slip faults. PMID- 27762307 TI - White matter microstructural characteristics in newly diagnosed Parkinson's disease: An unbiased whole-brain study. AB - Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Findings on specific white matter (WM) alterations in PD have been inconsistent. We hypothesized that WM changes occur in early PD patients and unbiased whole-brain analysis may provide additional evidence of pathological WM changes in PD. In this study, we examined various indexes of WM microstructure in newly diagnosed PD patients at the whole-brain level. 64 PDs with Hoehn &Yahr stage 1 (HY1PDs), 87 PDs with Hoehn &Yahr stage 2 (HYPD2s), and 60 controls (HCs) were recruited. Tract-based spatial statistics (TBSS) and diffusion connectometry were used to identify changes of WM pathways associated with PD. There were no significant differences in axial diffusivity, but HY1PDs exhibited greater fractional anisotropy (FA) and decreased mean and radial diffusivities (MD and RD) in callosal, projection, and association fibres than HCs and HY2PDs. Motor severity was inversely correlated with FA, but positively correlated with MD and RD in PD patients. Connectometry analysis also revealed increased WM density in the aforementioned tracts in PD patients, compared with HCs. Our study reveals WM enhancement, suggesting neural compensations in early PD. Longitudinal follow-up studies are warranted to identify the trajectory of WM changes alongside the progression of PD. PMID- 27762308 TI - Dynamic Drug-Induced Sleep Computed Tomography in Adults With Obstructive Sleep Apnea. AB - Surgical success for obstructive sleep apnea (OSA) depends on identifying sites of obstruction in the upper airway. In this study, we investigated sites of obstruction by evaluating dynamic changes in the upper airway using drug-induced sleep computed tomography (DI-SCT) in patients with OSA. Thirty-five adult patients with OSA were prospectively enrolled. Sleep was induced with propofol under light sedation (bispectral index 70-75), and low-dose 320-detector row CT was performed for 10 seconds over a span of 2-3 respiratory cycles with supporting a continuous positive airway pressure model. Most (89%) of the patients had multi-level obstructions. Total obstruction most commonly occurred in the velum (86%), followed by the tongue (57%), oropharyngeal lateral wall (49%), and epiglottis (26%). There were two types of anterior-posterior obstruction of the soft palate, uvular (94%) and velar (6%), and three types of tongue obstruction, upper (30%), lower (37%), and upper plus lower obstruction (33%). DI-SCT is a fast and safe tool to identify simulated sleep airway obstruction in patients with OSA. It provides data on dynamic airway movement in the sagittal view which can be used to differentiate palate and tongue obstructions, and this can be helpful when planning surgery for patients with OSA. PMID- 27762309 TI - Visit-to-visit blood pressure variability, average BP level and carotid arterial stiffness in the elderly: a prospective study. AB - In a cross-sectional study, visit-to-visit blood pressure (BP) variability was shown to be associated with artery remodelling. Here, we investigated the impact of visit-to-visit BP variability and average BP on the carotid artery remodelling progression in high-risk elderly according to different classes of antihypertension medication use/non-use. BP measurements and carotid ultrasound were performed in the common carotid artery in 164 subjects (mean age 79.7 years at baseline, 74.7% females) with one or more cardiovascular risk factors. Based on 12 visits (1 * /month for 1 year), we calculated visit-to-visit BP variability expressed as the standard deviation (s.d.), coefficient of variation (CV), maximum BP, minimum BP and delta (maximum-minimum) BP. We measured mean intima media thickness (IMT) as well as stiffness parameter beta were measured at baseline and at the mean 4.2-year follow-up. In a multiple regression analysis, the maximum, minimum, s.d. and average of systolic BP (SBP) were significantly associated with a change in beta-values between the baseline and follow-up after adjustment for age, smoking, lower high-density lipoprotein level, baseline beta value and follow-up period. There were no significant associations between the visit-to-visit BP variability measures and the change in mean IMT. Significant associations of maximum, minimum, s.d. and average SBP were found with increased beta-values in the subjects without calcium channel blocker (CCB) use and in the subjects using renin-angiotensin system inhibitors (RASIs). Thus, exaggerated visit-to-visit SBP variability and a high average SBP level were significant predictors of progression in carotid arterial stiffness in high-risk elderly without CCBs use and in those using a RASI. PMID- 27762310 TI - Chromatin accessibility contributes to simultaneous mutations of cancer genes. AB - Somatic mutations of many cancer genes tend to co-occur (termed co-mutations) in certain patterns during tumor initiation and progression. However, the genetic and epigenetic mechanisms that contribute to the co-mutations of these cancer genes have yet to be explored. Here, we systematically investigated the association between the somatic co-mutations of cancer genes and high-order chromatin conformation. Significantly, somatic point co-mutations in protein coding genes were closely associated with high-order spatial chromatin folding. We propose that these regions be termed Spatial Co-mutation Hotspots (SCHs) and report their occurrence in different cancer types. The conserved mutational signatures and DNA sequences flanking these point co-mutations, as well as CTCF binding sites, are also enriched within the SCH regions. The genetic alterations that are harboured in the same SCHs tend to disrupt cancer driver genes involved in multiple signalling pathways. The present work demonstrates that high-order spatial chromatin organisation may contribute to the somatic co-mutations of certain cancer genes during tumor development. PMID- 27762311 TI - Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease. AB - The concept of the 'vulnerable plaque' originated from pathological observations in patients who died from acute coronary syndrome. This recognition spawned a generation of research that led to greater understanding of how complicated atherosclerotic plaques form and precipitate thrombotic events. In current practice, an increasing number of patients who survive their first event present with non-ST-segment elevation myocardial infarction (NSTEMI) rather than myocardial infarction (MI) with ST-segment elevation (STEMI). The culprit lesions that provide the pathological substrate for NSTEMI can vary considerably from the so-called 'vulnerable plaque'. The shift in clinical presentation of MI and stroke corresponds temporally to a progressive change in the characteristics of human plaques away from the supposed characteristics of vulnerability. These alterations in the structure and function of human atherosclerotic lesions might mirror the modifications that are produced in experimental plaques by lipid lowering, inspired by the vulnerable plaque construct. The shift in the clinical presentations of the acute coronary syndromes mandates a critical reassessment of the underlying mechanisms, proposed risk scores, the results and interpretation of preclinical experiments, as well as recognition of the limitations of the use of population data and samples collected before the application of current preventive interventions. PMID- 27762313 TI - Intraoperative electrophysiological evaluations of macular function during peripheral scleral indentation. AB - Scleral indentation is widely used to examine the peripheral fundus, however it can increase the intraocular pressure (IOP) to high levels which can then affect retinal function. We evaluated the effects of scleral indentation on the macular function electrophysiologically. Intraoperative focal macular electroretinograms (iFMERGs) were recorded with and without controlling the IOP in 7 eyes. Without IOP control, the IOP increased from 21.7 +/- 4.9 to 92.7 +/- 20.2 mmHg significantly (P = 0.020) and the amplitudes of the b-wave (from 6.29 +/- 1.160 to 3.71 +/- 1.98 uV, P = 0.007), on-photopic negative response (from 2.29 +/- 0.99 to 0.72 +/- 0.47 uV, on-PhNR, P = 0.005), and d-wave (from 2.57 +/- 0.41 to 1.64 +/- 0.69 uV, P = 0.007) decreased significantly soon after beginning the indentation. All values returned to the baseline levels after releasing the indentation. In the eyes with IOP controlled, the IOP and the amplitude of all components did not change significantly during and after the indentation except the on-PhNR amplitude which was significantly reduced during the indentation. The changes in the iFMERGs and macular function caused by scleral indentation were transient and reversible. The changes can be minimized by controlling the IOP. PMID- 27762312 TI - Cardiovascular effects of bariatric surgery. AB - Obesity is a major global health problem, and its multisystem effects are inextricably linked with elevated cardiovascular risk and adverse outcomes. The cardiovascular benefits of reversing obesity in adults are well-established. Compared with other weight-loss strategies, programmes that incorporate bariatric surgery for weight loss are beneficial for sustained BMI reduction. A marked improvement in cardiovascular risk factors, including hypertension, dyslipidaemia, inflammation, and type 2 diabetes mellitus, has been observed after bariatric surgery. This broad improvement in cardiovascular risk profile has led to substantial reductions in the risk of myocardial infarction, stroke, and death. As with all procedures, the benefits of bariatric surgery must be weighed against its potential risks. Modern bariatric surgery has an excellent safety profile, but important limitations remain, including the potential for surgical complications and nutritional deficiencies, and the lifelong requirement for nutritional supplementation. Surgery should be considered in patients with severe obesity, especially those with cardiovascular comorbidities. In this Review, we summarize the current management options for patients with obesity, and discuss the effects of bariatric surgery on cardiovascular risk factors and outcomes. PMID- 27762314 TI - Aberration-free volumetric high-speed imaging of in vivo retina. AB - Certain topics in research and advancements in medical diagnostics may benefit from improved temporal and spatial resolution during non-invasive optical imaging of living tissue. However, so far no imaging technique can generate entirely diffraction-limited tomographic volumes with a single data acquisition, if the target moves or changes rapidly, such as the human retina. Additionally, the presence of aberrations may represent further difficulties. We show that a simple interferometric setup-based on parallelized optical coherence tomography-acquires volumetric data with 10 billion voxels per second, exceeding previous imaging speeds by an order of magnitude. This allows us to computationally obtain and correct defocus and aberrations resulting in entirely diffraction-limited volumes. As demonstration, we imaged living human retina with clearly visible nerve fiber layer, small capillary networks, and photoreceptor cells. Furthermore, the technique can also obtain phase-sensitive volumes of other scattering structures at unprecedented acquisition speeds. PMID- 27762315 TI - Biologically templated assembly of hybrid semiconducting nanomesh for high performance field effect transistors and sensors. AB - Delicately assembled composites of semiconducting nanomaterials and biological materials provide an attractive interface for emerging applications, such as chemical/biological sensors, wearable health monitoring devices, and therapeutic agent releasing devices. The nanostructure of composites as a channel and a sensing material plays a critical role in the performance of field effect transistors (FETs). Therefore, it is highly desirable to prepare elaborate composite that can allow the fabrication of high performance FETs and also provide high sensitivity and selectivity in detecting specific chemical/biological targets. In this work, we demonstrate that high performance FETs can be fabricated with a hydrodynamically assembled composite, a semiconducting nanomesh, of semiconducting single-walled carbon nanotubes (S SWNTs) and a genetically engineered M13 phage to show strong binding affinity toward SWNTs. The semiconducting nanomesh enables a high on/off ratio (~104) of FETs. We also show that the threshold voltage and the channel current of the nanomesh FETs are sensitive to the change of the M13 phage surface charge. This biological gate effect of the phage enables the detection of biologically important molecules such as dopamine and bisphenol A using nanomesh-based FETs. Our results provide a new insight for the preparation of composite material platform for highly controllable bio/electronics interfaces. PMID- 27762316 TI - Long-Term Homeostatic Properties Complementary to Hebbian Rules in CuPc-Based Multifunctional Memristor. AB - Most simulations of neuroplasticity in memristors, which are potentially used to develop artificial synapses, are confined to the basic biological Hebbian rules. However, the simplex rules potentially can induce excessive excitation/inhibition, even collapse of neural activities, because they neglect the properties of long-term homeostasis involved in the frameworks of realistic neural networks. Here, we develop organic CuPc-based memristors of which excitatory and inhibitory conductivities can implement both Hebbian rules and homeostatic plasticity, complementary to Hebbian patterns and conductive to the long-term homeostasis. In another adaptive situation for homeostasis, in thicker samples, the overall excitement under periodic moderate stimuli tends to decrease and be recovered under intense inputs. Interestingly, the prototypes can be equipped with bio-inspired habituation and sensitization functions outperforming the conventional simplified algorithms. They mutually regulate each other to obtain the homeostasis. Therefore, we develop a novel versatile memristor with advanced synaptic homeostasis for comprehensive neural functions. PMID- 27762318 TI - Polarization of an electroactive functional film on titanium for inducing osteogenic differentiation. AB - To enhance the surface bioactivity of titanium (Ti) prostheses, an electroactive polyvinylidene fluoride (PVDF) film was prepared on a Ti substrate to provide a mimetic of the electrical microenvironment, which facilitated the performance of cell functions. The results of cell proliferation and differentiation assays indicated that polarization of the PVDF-Ti (PTi) altered its surface charge, thus inducing adhesion, proliferation and osteogenic differentiation of cells. The polarized PVDF-Ti (PPTi) may therefore find applications in bone regeneration. PMID- 27762317 TI - Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. AB - Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) play a central role in tryptophan metabolism and are involved in many cellular and disease processes. Here we report the crystal structure of human TDO (hTDO) in a ternary complex with the substrates L-Trp and O2 and in a binary complex with the product N-formylkynurenine (NFK), defining for the first time the binding modes of both substrates and the product of this enzyme. The structure indicates that the dioxygenation reaction is initiated by a direct attack of O2 on the C2 atom of the L-Trp indole ring. The structure also reveals an exo binding site for L Trp, located ~42 A from the active site and formed by residues conserved among tryptophan-auxotrophic TDOs. Biochemical and cellular studies indicate that Trp binding at this exo site does not affect enzyme catalysis but instead it retards the degradation of hTDO through the ubiquitin-dependent proteasomal pathway. This exo site may therefore provide a novel L-Trp-mediated regulation mechanism for cellular degradation of hTDO, which may have important implications in human diseases. PMID- 27762320 TI - Enhancing electric-field control of ferromagnetism through nanoscale engineering of high-Tc MnxGe1-x nanomesh. AB - Voltage control of magnetism in ferromagnetic semiconductor has emerged as an appealing solution to significantly reduce the power dissipation and variability beyond current CMOS technology. However, it has been proven to be very challenging to achieve a candidate with high Curie temperature (Tc), controllable ferromagnetism and easy integration with current Si technology. Here we report the effective electric-field control of both ferromagnetism and magnetoresistance in unique MnxGe1-x nanomeshes fabricated by nanosphere lithography, in which a Tc above 400 K is demonstrated as a result of size/quantum confinement. Furthermore, by adjusting Mn doping concentration, extremely giant magnetoresistance is realized from ~8,000% at 30 K to 75% at 300 K at 4 T, which arises from a geometrically enhanced magnetoresistance effect of the unique mesh structure. Our results may provide a paradigm for fundamentally understanding the high Tc in ferromagnetic semiconductor nanostructure and realizing electric-field control of magnetoresistance for future spintronic applications. PMID- 27762321 TI - Reconfigurable Complementary Logic Circuits with Ambipolar Organic Transistors. AB - Ambipolar organic electronics offer great potential for simple and low-cost fabrication of complementary logic circuits on large-area and mechanically flexible substrates. Ambipolar transistors are ideal candidates for the simple and low-cost development of complementary logic circuits since they can operate as n-type and p-type transistors. Nevertheless, the experimental demonstration of ambipolar organic complementary circuits is limited to inverters. The control of the transistor polarity is crucial for proper circuit operation. Novel gating techniques enable to control the transistor polarity but result in dramatically reduced performances. Here we show high-performance non-planar ambipolar organic transistors with electrical control of the polarity and orders of magnitude higher performances with respect to state-of-art split-gate ambipolar transistors. Electrically reconfigurable complementary logic gates based on ambipolar organic transistors are experimentally demonstrated, thus opening up new opportunities for ambipolar organic complementary electronics. PMID- 27762319 TI - Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease. AB - The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders. PMID- 27762322 TI - Purification and Characterization of a Novel Cold Shock Protein-Like Bacteriocin Synthesized by Bacillus thuringiensis. AB - Bacillus thuringiensis (Bt), one of the most successful biopesticides, may expand its potential by producing bacteriocins (thuricins). The aim of this study was to investigate the antimicrobial potential of a novel Bt bacteriocin, thuricin BtCspB, produced by Bt BRC-ZYR2. The results showed that this bacteriocin has a high similarity with cold-shock protein B (CspB). BtCspB lost its activity after proteinase K treatment; however it was active at 60 degrees C for 30 min and was stable in the pH range 5-7. The partial loss of activity after the treatments of lipase II and catalase were likely due to the change in BtCspB structure and the partial degradation of BtCspB, respectively. The loss of activity at high temperatures and the activity variation at different pHs were not due to degradation or large conformational change. BtCspB did not inhibit four probiotics. It was only active against B. cereus strains 0938 and ATCC 10987 with MIC values of 3.125 MUg/mL and 0.781 MUg/mL, and MBC values of 12.5 MUg/mL and 6.25 MUg/mL, respectively. Taken together, these results provide new insights into a novel cold shock protein-like bacteriocin, BtCspB, which displayed promise for its use in food preservation and treatment of B. cereus-associated diseases. PMID- 27762324 TI - Maternal and Live-birth Outcomes of Pregnancies following Assisted Reproductive Technology: A Retrospective Cohort Study. AB - This study was carried out to explore associations between assisted reproductive technology (ART) and maternal and neonatal outcomes compared with similar outcomes following spontaneously conceived births. We conducted a retrospective cohort study of pregnancies conceived by ART (N = 2641) during 2006-2014 compared to naturally conceived pregnancies (N = 5282) after matching for maternal age and birth year. Pregnancy complications, perinatal complications and neonatal outcomes of enrolled subjects were investigated and analysed by multivariate logistic regression. We found that pregnancies conceived by in vitro fertilization (IVF) were associated with a significantly increased incidence of gestational diabetes mellitus, gestational hypertension, preeclampsia, intrahepatic cholestasis of pregnancy, placenta previa, placental abruption, preterm premature rupture of membranes, placental adherence, postpartum haemorrhage, polyhydramnios, preterm labour, low birth weight, and small-for-date infant compared with spontaneously conceived births. Pregnancies conceived by intracytoplasmic sperm injection (ICSI) showed similar elevated complications, except some of the difference narrowed or disappeared. Singleton pregnancies or nulliparous pregnancies following ART still exhibited increased maternal and neonatal complications. Therefore, we conclude that pregnancies conceived following ART are at increased risks of antenatal complications, perinatal complications and poor neonatal outcomes, which may result from not only a higher incidence of multiple pregnancy, but also the manipulation involved in ART processes. PMID- 27762323 TI - Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma. AB - Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues. PMID- 27762325 TI - Performance and microbial ecology of a nitritation sequencing batch reactor treating high-strength ammonia wastewater. AB - The partial nitrification (PN) performance and the microbial community variations were evaluated in a sequencing batch reactor (SBR) for 172 days, with the stepwise elevation of ammonium concentration. Free ammonia (FA) and low dissolved oxygen inhibition of nitrite-oxidized bacteria (NOB) were used to achieve nitritation in the SBR. During the 172 days operation, the nitrogen loading rate of the SBR was finally raised to 3.6 kg N/m3/d corresponding the influent ammonium of 1500 mg/L, with the ammonium removal efficiency and nitrite accumulation rate were 94.12% and 83.54%, respectively, indicating that the syntrophic inhibition of FA and low dissolved oxygen contributed substantially to the stable nitrite accumulation. The results of the 16S rRNA high-throughput sequencing revealed that Nitrospira, the only nitrite-oxidizing bacteria in the system, were successively inhibited and eliminated, and the SBR reactor was dominated finally by Nitrosomonas, the ammonium-oxidizing bacteria, which had a relative abundance of 83%, indicating that the Nitrosomonas played the primary roles on the establishment and maintaining of nitritation. Followed by Nitrosomonas, Anaerolineae (7.02%) and Saprospira (1.86%) were the other mainly genera in the biomass. PMID- 27762327 TI - Flaky FeSiAl alloy-carbon nanotube composite with tunable electromagnetic properties for microwave absorption. AB - Flaky FeSiAl alloy/multi-wall carbon nanotube (FeSiAl/MWCNT) composite was fabricated by facile and scalable ball milling method. The morphology and electromagnetic properties of the FeSiAl alloy can be well tuned by controlling the milling time. It is found that the magnetic loss of the FeSiAl alloy is improved by optimizing the milling time due to the increased anisotropy field. Meanwhile the addition of MWCNTs enhances the dielectric loss of the composite by increasing the interfacial polarizations, dipolar polarizations and conductive paths. Relative to conventional FeSiAl absorbers, the FeSiAl/MWCNT composite exhibits greatly improved microwave absorption performance with advantages of strong absorption and small thickness. The minimum reflection loss of the composite reaches -42.8 dB at 12.3 GHz at a very thin thickness of 1.9 mm. PMID- 27762326 TI - Imaging hydrogen peroxide in Alzheimer's disease via cascade signal amplification. AB - In brains of Alzheimer's disease (AD), reactive oxygen species (ROS) levels are significantly higher than that of healthy brains. Evidence suggests that, during AD onset and progression, a vicious cycle revolves around amyloid beta (Abeta) production, aggregation, plaque formation, microglia/immunological responses, inflammation, and ROS production. In this cycle, ROS species play a central role, and H2O2 is one of the most important ROS species. In this report, we have designed a fluorescent imaging probe CRANAD-88, which is capable of cascade amplifying near infrared fluorescence (NIRF) signals at three levels upon interacting with H2O2 in AD brains. We demonstrated that the amplification was feasible in vitro and in vivo. Remarkably, we showed that, for the first time, it was feasible to monitor the changes of H2O2 concentrations in AD brains before and after treatment with an H2O2 scavenger. Our method opens new revenues to investigate H2O2 in AD brains and can be very instructive for drug development. PMID- 27762329 TI - The universal characteristics of a thermodynamic model to conform to the Gibbs Duhem equation. AB - In a multi-component homogeneous system, the relationship between partial molar and molar quantity (RPMQ) is proved to be an equivalent relation of the Gibbs Duhem equation. The universal characteristics of a thermodynamic model to conform to the Gibbs-Duhem equation are inferred from the RPMQ. Based on the inference, an asymmetric regular solution model is suggested to deal with those systems that exhibit strong negative deviation, strong positive deviation, and both strong positive and negative deviation from ideality. PMID- 27762328 TI - Nuclear receptor nhr-48 is required for pathogenicity of the second stage (J2) of the plant parasite Meloidogyne incognita. AB - Nuclear receptors (NRs) are a diverse class of transcription factors, which are involved in regulating a large number of physiological events in metazoans. However, the function of NRs is poorly understood in plant-parasitic nematodes. Here, members of the NR1J+K group of NRs in nematodes, including the free-living and plant parasites, were examined and phylogenetically analyzed. We found that the number of members of the NR1J+K group in plant-parasitic nematodes was less than that in the free-living nematodes, suggesting this reduction of NR1J+K group members in plant parasites maybe arose during the separation of the free-living and intermediately plant parasitic nematodes (Bursaphelenchus xylophilus). Interestingly, the DNA-binding domain (DBD) and ligand-binding domain (LBD) of NR1J+K members were separated into two gene locations in the plant parasites. Knockdown of Meloidogyne incognita WBMinc13296, the ortholog of Caenorhabditis elegans nhr-48 DBD, reduced infectivity, delayed development, and decreased reproductivity. J2 of M. incognita subjected to silencing of WBMinc13295, the orthologs of B. xylophilus nhr-48 LBD, exhibited developmental lag within the host and reduced reproductivity. This study provides new insights into the function of NRs and suggests that NRs are potential targets for developing effective strategies for biological control of plant-parasitic nematodes. PMID- 27762330 TI - Strontium isotope evidence for a highly mobile population on the Pamir Plateau 2500 years ago. AB - Archeological researches have proposed arguments for human mobility and long distance trading over the Eurasia before the Silk Roads. Here we utilize biologically available strontium isotope analysis to assess the extent of pre Silk Road population movements and cultural communications across the Asian interior. From an early Iron Age cemetery (ca. 2500 yr B.P.) on the eastern Pamir Plateau, mean 87Sr/86Sr ratios from 34 individuals display considerable isotopic variability, and 10 individuals are distinguished as migrants based on the local strontium isotope range of 0.710296-0.710572 defined by 12 ovicaprine bones. Comparison of the proportion (10/34) with the regional census data completed in 1909 A.D. (3% non-locals) suggests a highly migratory behavior on the plateau 2500 years ago. Furthermore, exotic mortuary objects, such as silk fabrics from eastern China and angular harp originated from the Near East, clearly demonstrate an interaction between different cultures on the plateau before the establishment of the Silk Road. PMID- 27762333 TI - Macroscopic irreversibility and microscopic paradox: A Constructal law analysis of atoms as open systems. AB - The relation between macroscopic irreversibility and microscopic reversibility is a present unsolved problem. Constructal law is introduced to develop analytically the Einstein's, Schrodinger's, and Gibbs' considerations on the interaction between particles and thermal radiation (photons). The result leads to consider the atoms and molecules as open systems in continuous interaction with flows of photons from their surroundings. The consequent result is that, in any atomic transition, the energy related to the microscopic irreversibility is negligible, while when a great number of atoms (of the order of Avogadro's number) is considered, this energy related to irreversibility becomes so large that its order of magnitude must be taken into account. Consequently, macroscopic irreversibility results related to microscopic irreversibility by flows of photons and amount of atoms involved in the processes. PMID- 27762331 TI - DCE-MRI Perfusion and Permeability Parameters as predictors of tumor response to CCRT in Patients with locally advanced NSCLC. AB - In this prospective study, 36 patients with stage III non-small cell lung cancers (NSCLC), who underwent dynamic contrast-enhanced MRI (DCE-MRI) before concurrent chemo-radiotherapy (CCRT) were enrolled. Pharmacokinetic analysis was carried out after non-rigid motion registration. The perfusion parameters [including Blood Flow (BF), Blood Volume (BV), Mean Transit Time (MTT)] and permeability parameters [including endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), fractional plasma volume (Vp)] were calculated, and their relationship with tumor regression was evaluated. The value of these parameters on predicting responders were calculated by receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis was conducted to find the independent variables. Tumor regression rate is negatively correlated with Ve and its standard variation Ve_SD and positively correlated with Ktrans and Kep. Significant differences between responders and non-responders existed in Ktrans, Kep, Ve, Ve_SD, MTT, BV_SD and MTT_SD (P < 0.05). ROC indicated that Ve < 0.24 gave the largest area under curve of 0.865 to predict responders. Multivariate logistic regression analysis also showed Ve was a significant predictor. Baseline perfusion and permeability parameters calculated from DCE-MRI were seen to be a viable tool for predicting the early treatment response after CCRT of NSCLC. PMID- 27762332 TI - Climatic, Geographic and Operational Determinants of Trihalomethanes (THMs) in Drinking Water Systems. AB - Trihalomethanes (THMs) are conditionally carcinogenic compounds formed during chlorine disinfection in water treatment processes around the world. THMs occur especially when source waters are subject to marine influences, high and-or regular precipitation, and elevated levels of organic matter. THMs formation is then rooted in geographic, operational and climatic factors, the relative importance of which can only be derived from large datasets and may change in the future. Ninety three full-scale Scottish water treatment plants (WTPs) were assessed from Jan 2011 to Jan 2013 to identify factors that promote THMs formation. Correlation analysis showed that ambient temperature was the primary THMs formation predictor in potable water (r2 = 0.66, p < 0.05) and water distribution systems (r2 = 0.43, p = 0.04), while dissolved organic carbon (r2 = 0.55, p < 0.001) and chloride (indicating marine influence; r2 = 0.41, p < 0.001) also affected THMs formation. GIS mapping of median THMs levels indicated brominated THMs were most prevalent in coastal areas and on islands. This real world dataset confirms both geographic and climatic factors are key to THMs formation. If ambient temperatures increase, THMs control will become more challenging, substantiating concerns about the impact of global warming on water quality. PMID- 27762334 TI - A liquid-liquid transition can exist in monatomic transition metals with a positive melting slope. AB - Liquid-liquid transitions under high pressure are found in many elemental materials, but the transitions are known to be associated with either sp-valent materials or f-valent rare-earth elements, in which the maximum or a negative slope in the melting line is readily suggestive of the transition. Here we find a liquid-liquid transition with a positive melting slope in transition metal Ti from structural, electronic, and thermodynamic studies using ab-initio molecular dynamics calculations, showing diffusion anomaly, but no density anomaly. The origin of the transition in liquid Ti is a pressure-induced increase of local structures containing very short bonds with directionality in electronic configurations. This behavior appears to be characteristic of the early transition metals. In contrast, the late transition metal liquid Ni does not show the L-L transition with pressure. This result suggests that the possibility of the L-L transition decreases from early to late transition metals as electronic structures of late transition metals barely have a Jahn-Teller effect and bond directionality. Our results generalize that a phase transition in disordered materials is found with any valence band regardless of the sign of the melting slope, but related to the symmetry of electronic structures of constituent elements. PMID- 27762335 TI - An inhibitory receptor of VLRB in the agnathan lamprey. AB - Lamprey, the primitive jawless vertebrate, uses variable lymphocyte receptor (VLR) as alternative adaptive immune system instead of immunoglobulin (Ig)-based receptors used in jawed vertebrates. In the present study, we characterized a potential inhibitory receptor of VLRB from leucocytes in lamprey. It is a novel ITIM-containing IgSF protein and was therefore named as NICIP. NICIP has two Ig like domains in extracellular region, a transmembrane domain and two classical ITIM motifs in cytoplasmic domain. It is mainly expressed on the surface of granulocytes and monocytes and can interact with VLRB. In transiently transfected HEK293T cells, it was confirmed again that it could interact with VLRB and the two phosphorylated ITIM motifs could recruit SHP-1 and SHP-2. These results imply that NICIP may play a role as a potential inhibitory receptor of VLRB and involve in negative regulation of immune response mediated by VLRB. PMID- 27762336 TI - Microfluidic co-culture system for cancer migratory analysis and anti-metastatic drugs screening. AB - Tumour metastasis is an important reason for cancer death, and cancer cell migration is an important step in the process of tumour metastasis. Studying cancer cell migration is of great significance. Here, we present a novel microfluidic co-culture system and establish mild, moderate and severe cancer models by using HMEpiC and MDA-MB-231 cells to study cancer cell migration and anti-cancer drug screening. Using this device, we achieved high cell viability (over 90%) and a stable analysis of the migration ability of cancer cells. We observed that the density of the cancer cells determined the probability of the occurrence of metastatic cells and that the induction of normal cells affected the metastatic velocity of each cancer cell. We verified that the increase in the migration ability of MDA-MB-231 cells co-cultured with HMEpiC cells was relative to the increased secretion of IL-6 and that this was verified by an IL-6 inhibitor assay. This co-culture also led to decreased CK-14 secretion and morphological changes in HMEpiC cells. Finally, significant inhibition of paclitaxel and tamoxifen on cancer migration was observed. Taken together, our microfluidic device could be a useful tool for the quantitation of the migratory capability and anti-metastatic drug screening. PMID- 27762338 TI - Development of a membrane-anchored ligand and receptor yeast two-hybrid system for ligand-receptor interaction identification. AB - Identifying interactions between ligands and transmembrane receptors is crucial for understanding the endocrine system. However, the present approaches for this purpose are still not capable of high-throughput screening. In this report, a membrane-anchored ligand and receptor yeast two-hybrid (MALAR-Y2H) system was established. In the method, an extracellular ligand is linked with an intracellular split-ubiquitin reporter system via a chimeric transmembrane structure. Meanwhile, the prey proteins of transmembrane receptors are fused to the other half of the split-ubiquitin reporter system. The extracellular interaction of ligands and receptors can lead to the functional recovery of the ubiquitin reporter system in yeast, and eventually lead to the expression of report genes. Consequently, the system can be used to detect the interactions between extracellular ligands and their transmembrane receptors. To test the efficiency and universality of the method, interactions between several pairs of ligands and receptors of mouse were analyzed. The detecting results were shown to be thoroughly consistent with the present knowledge, indicating MALAR-Y2H can be utilized for such purpose with high precision, high efficiency and strong universality. The characteristics of the simple procedure and high-throughput potential make MALAR-Y2H a powerful platform to study protein-protein interaction networks between secreted proteins and transmembrane proteins. PMID- 27762337 TI - Formaldehyde impairs transepithelial sodium transport. AB - Unsaturated oxidative formaldehyde is a noxious aldehyde in cigarette smoke that causes edematous acute lung injury. However, the mechanistic effects of formaldehyde on lung fluid transport are still poorly understood. We examined how formaldehyde regulates human epithelial sodium channels (ENaC) in H441 and expressed in Xenopus oocytes and exposed mice in vivo. Our results showed that formaldehyde reduced mouse transalveolar fluid clearance in vivo. Formaldehyde caused a dose-dependent inhibition of amiloride-sensitive short-circuit Na+ currents in H441 monolayers and of alphabetagamma-ENaC channel activity in oocytes. alpha-ENaC protein was reduced, whereas phosphorylation of the extracellular regulated protein kinases 1 and 2 (ERK1/2) increased significantly post exposure. Moreover, both alpha- and gamma-ENaC transcripts were down regulated. Reactive oxygen species (ROS) was elevated significantly by formaldehyde in addition to markedly augmented membrane permeability of oocytes. These data suggest that formaldehyde contributes to edematous acute lung injury by reducing transalveolar Na+ transport, through decreased ENaC activity and enhanced membrane depolarization, and by elevating ROS production over long-term exposure. PMID- 27762339 TI - Genomic, physiologic, and proteomic insights into metabolic versatility in Roseobacter clade bacteria isolated from deep-sea water. AB - Roseobacter clade bacteria are ubiquitous in marine environments and now thought to be significant contributors to carbon and sulfur cycling. However, only a few strains of roseobacters have been isolated from the deep-sea water column and have not been thoroughly investigated. Here, we present the complete genomes of phylogentically closed related Thiobacimonas profunda JLT2016 and Pelagibaca abyssi JLT2014 isolated from deep-sea water of the Southeastern Pacific. The genome sequences showed that the two deep-sea roseobacters carry genes for versatile metabolisms with functional capabilities such as ribulose bisphosphate carboxylase-mediated carbon fixation and inorganic sulfur oxidation. Physiological and biochemical analysis showed that T. profunda JLT2016 was capable of autotrophy, heterotrophy, and mixotrophy accompanied by the production of exopolysaccharide. Heterotrophic carbon fixation via anaplerotic reactions contributed minimally to bacterial biomass. Comparative proteomics experiments showed a significantly up-regulated carbon fixation and inorganic sulfur oxidation associated proteins under chemolithotrophic conditions compared to heterotrophic conditions. Collectively, rosebacters show a high metabolic flexibility, suggesting a considerable capacity for adaptation to the marine environment. PMID- 27762340 TI - Juvenile hormone regulation of female reproduction in the common bed bug, Cimex lectularius. AB - To begin studies on reproduction in common bed bug, Cimex lectularius, we identified three genes coding for vitellogenin (Vg, a protein required for the reproductive success of insects) and studied their hormonal regulation. RNA interference studied showed that expression of Vg3 gene in the adult females is a prerequisite for successful completion of embryogenesis in the eggs laid by them. Juvenile hormone (JH) receptor, Methoprene-tolerant (Met), steroid receptor coactivator (SRC) and GATAa but not ecdysone receptor (EcR) or its partner, ultraspiracle (USP) are required for expression of Vg genes. Feeding and mating working through Vg, Met, SRC, EcR, and GATAa regulate oocyte development. Knockdown of the expression of Met, SRC, EcR, USP, BR-C (Broad-Complex), TOR (target of rapamycin), and GATAa in female adults resulted in a reduction in the number eggs laid by them. Interestingly, Kruppel homolog 1 (Kr-h1) knockdown in the adult females did not reduce their fecundity but affected the development of embryos in the eggs laid by females injected with Kr-h1 double-stranded RNA. These data suggest that JH functioning through Met and SRC regulate both vitellogenesis and oogenesis in C. lectularius. However, JH does not work through Kr-h1 but may work through transcription factors not yet identified. PMID- 27762342 TI - Thermal treatment of hair for the synthesis of sustainable carbon quantum dots and the applications for sensing Hg2. AB - A facile, simple and low-cost approach for synthesizing highly fluorescent carbon quantum dots (CQDs) from thermal treatment of sustainable hair has been developed. The resultant CQDs exhibited strong blue emission with a quantum yield of 10.75%, excellent photostability and high stability in high salt conditions. As the fluorescence of CQDs can be efficiently quenched by Hg2+, the CQDs can be constructed as a nanosensor for Hg2+ with good sensitivity and selectivity. And as low as 10 nM Hg2+ can be successfully detected. PMID- 27762341 TI - SparRec: An effective matrix completion framework of missing data imputation for GWAS. AB - Genome-wide association studies present computational challenges for missing data imputation, while the advances of genotype technologies are generating datasets of large sample sizes with sample sets genotyped on multiple SNP chips. We present a new framework SparRec (Sparse Recovery) for imputation, with the following properties: (1) The optimization models of SparRec, based on low-rank and low number of co-clusters of matrices, are different from current statistics methods. While our low-rank matrix completion (LRMC) model is similar to Mendel Impute, our matrix co-clustering factorization (MCCF) model is completely new. (2) SparRec, as other matrix completion methods, is flexible to be applied to missing data imputation for large meta-analysis with different cohorts genotyped on different sets of SNPs, even when there is no reference panel. This kind of meta-analysis is very challenging for current statistics based methods. (3) SparRec has consistent performance and achieves high recovery accuracy even when the missing data rate is as high as 90%. Compared with Mendel-Impute, our low rank based method achieves similar accuracy and efficiency, while the co clustering based method has advantages in running time. The testing results show that SparRec has significant advantages and competitive performance over other state-of-the-art existing statistics methods including Beagle and fastPhase. PMID- 27762343 TI - Cryo-EM structure of the large subunit of the spinach chloroplast ribosome. AB - Protein synthesis in the chloroplast is mediated by the chloroplast ribosome (chloro-ribosome). Overall architecture of the chloro-ribosome is considerably similar to the Escherichia coli (E. coli) ribosome but certain differences are evident. The chloro-ribosome proteins are generally larger because of the presence of chloroplast-specific extensions in their N- and C-termini. The chloro ribosome harbours six plastid-specific ribosomal proteins (PSRPs); four in the small subunit and two in the large subunit. Deletions and insertions occur throughout the rRNA sequence of the chloro-ribosome (except for the conserved peptidyl transferase center region) but the overall length of the rRNAs do not change significantly, compared to the E. coli. Although, recent advancements in cryo-electron microscopy (cryo-EM) have provided detailed high-resolution structures of ribosomes from many different sources, a high-resolution structure of the chloro-ribosome is still lacking. Here, we present a cryo-EM structure of the large subunit of the chloro-ribosome from spinach (Spinacia oleracea) at an average resolution of 3.5 A. High-resolution map enabled us to localize and model chloro-ribosome proteins, chloroplast-specific protein extensions, two PSRPs (PSRP5 and 6) and three rRNA molecules present in the chloro-ribosome. Although comparable to E. coli, the polypeptide tunnel and the tunnel exit site show chloroplast-specific features. PMID- 27762344 TI - Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism. AB - The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 and TH17 cell formation and controls peripheral CD8+ T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4-/- mice generated only marginal numbers of listeria-specific TH1 cells. After transfer into infected mice, IRF4-/- CD4+ T cells failed to differentiate into TH1 cells as indicated by reduced T-bet and IFN-gamma expression, and showed limited proliferation. Activated IRF4-/- CD4+ T cells exhibited diminished uptake of the glucose analog 2-NBDG, limited oxidative phosphorylation and strongly reduced aerobic glycolysis. Insufficient metabolic adaptation contributed to the limited proliferation and TH1 differentiation of IRF4-/- CD4+ T cells. Our study identifies IRF4 as central regulator of TH1 responses and cellular metabolism. We propose that this function of IRF4 is fundamental for the initiation and maintenance of all TH cell responses. PMID- 27762345 TI - Metabolomic Responses of Arabidopsis Suspension Cells to Bicarbonate under Light and Dark Conditions. AB - Global CO2 level presently recorded at 400 ppm is expected to reach 550 ppm in 2050, an increment likely to impact plant growth and productivity. Using targeted LC-MS and GC-MS platforms we quantified 229 and 29 metabolites, respectively in a time-course study to reveal short-term responses to different concentrations (1, 3, and 10 mM) of bicarbonate (HCO3-) under light and dark conditions. Results indicate that HCO3- treatment responsive metabolomic changes depend on the HCO3- concentration, time of treatment, and light/dark. Interestingly, 3 mM HCO3- concentration treatment induced more significantly changed metabolites than either lower or higher concentrations used. Flavonoid biosynthesis and glutathione metabolism were common to both light and dark-mediated responses in addition to showing concentration-dependent changes. Our metabolomics results provide insights into short-term plant cellular responses to elevated HCO3- concentrations as a result of ambient increases in CO2 under light and dark. PMID- 27762346 TI - Study to explore the mechanism to form inclusion complexes of beta-cyclodextrin with vitamin molecules. AB - Host-guest inclusion complexes of beta-cyclodextrin with two vitamins viz., nicotinic acid and ascorbic acid in aqueous medium have been explored by reliable spectroscopic, physicochemical and calorimetric methods as stabilizer, carrier and regulatory releaser of the guest molecules. Job's plots have been drawn by UV visible spectroscopy to confirm the 1:1 stoichiometry of the host-guest assembly. Stereo-chemical nature of the inclusion complexes has been explained by 2D NMR spectroscopy. Surface tension and conductivity studies further support the inclusion process. Association constants for the vitamin-beta-CD inclusion complexes have been calculated by UV-visible spectroscopy using both Benesi Hildebrand method and non-linear programme, while the thermodynamic parameters have been estimated with the help of van't Hoff equation. Isothermal titration calorimetric studies have been performed to determine the stoichiometry, association constant and thermodynamic parameters with high accuracy. The outcomes reveal that there is a drop in DeltaSo, which is overcome by higher negative value of DeltaHo, making the overall inclusion process thermodynamically favorable. The association constant is found to be higher for ascorbic acid than that for nicotinic acid, which has been explained on the basis of their molecular structures. PMID- 27762348 TI - Atomically Thin B doped g-C3N4 Nanosheets: High-Temperature Ferromagnetism and calculated Half-Metallicity. AB - Since the graphitic carbon nitride (g-C4N3), which can be seen as C-doped graphitic-C3N4 (g-C3N4), was reported to display ferromagnetic ground state and intrinsic half-metallicity (Du et al., PRL,108,197207,2012), it has attracted numerous research interest to tune the electronic structure and magnetic properties of g-C3N4 due to their potential applications in spintronic devices. In this paper, we reported the experimentally achieving of high temperature ferromagnetism in metal-free ultrathin g-C3N4 nanosheets by introducing of B atoms. Further, first-principles calculation results revealed that the current flow in such a system was fully spin-polarized and the magnetic moment was mainly attributed to the p orbital of N atoms in B doped g-C3N4 monolayer, giving the theoretic evidence of the ferromagnetism and half-metallicity. Our finding provided a new perspective for B doped g-C3N4 spintronic devices in future. PMID- 27762347 TI - Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-kappaB/HIF-1alpha signal axis. AB - Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-kappaB/HIF-1alpha signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers. PMID- 27762350 TI - Erratum: Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. PMID- 27762349 TI - Hypericum perforatum as a cognitive enhancer in rodents: A meta-analysis. AB - Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have nootropic potential. We quantitatively reviewed the pre-clinical literature to examine if there is a cognitive-enhancing effect of H. perforatum in healthy rodents. Additionally, within these studies, we compared the effects observed in intact rodents versus those whose performance has been impaired, mostly through stress manipulations. The meta-analysis incorporated studies that examined the effect of H. perforatum versus placebo on memory indices of task performance. All analyses were based on weighting different studies according to their inverse variance. Thirteen independent studies (published 2000-2014) involving 20 experimental comparisons met our inclusion criteria. The results showed a large positive effect of H. perforatum on cognitive performance for intact, healthy rodents (d = 1.11), though a larger effect emerged for stress-impaired rodents (d = 3.10 for restraint stress). The positive effect on intact rodents was observed in tasks assessing reference memory as well as working memory, and was not moderated by the type of memory or motivation (appetitive versus aversive). Thus, while primarily considered as a medication for depression, H. perforatum shows considerable nootropic potential in rodents. PMID- 27762351 TI - Ultraluminous X-ray bursts in two ultracompact companions to nearby elliptical galaxies. AB - A flaring X-ray source was found near the galaxy NGC 4697 (ref. 1). Two brief flares were seen, separated by four years. During each flare, the flux increased by a factor of 90 on a timescale of about one minute. There is no associated optical source at the position of the flares, but if the source was at the distance of NGC 4697, then the luminosities of the flares were greater than 1039 erg per second. Here we report the results of a search of archival X-ray data for 70 nearby galaxies looking for similar flares. We found two ultraluminous flaring sources in globular clusters or ultracompact dwarf companions of parent elliptical galaxies. One source flared once to a peak luminosity of 9 * 1040 erg per second; the other flared five times to 1040 erg per second. The rise times of all of the flares were less than one minute, and the flares then decayed over about an hour. When not flaring, the sources appear to be normal accreting neutron-star or black-hole X-ray binaries, but they are located in old stellar populations, unlike the magnetars, anomalous X-ray pulsars or soft gamma repeaters that have repetitive flares of similar luminosities. PMID- 27762354 TI - Climate change: Wildfires burn more US forest. PMID- 27762353 TI - Multi-petahertz electronic metrology. AB - The frequency of electric currents associated with charge carriers moving in the electronic bands of solids determines the speed limit of electronics and thereby that of information and signal processing. The use of light fields to drive electrons promises access to vastly higher frequencies than conventionally used, as electric currents can be induced and manipulated on timescales faster than that of the quantum dephasing of charge carriers in solids. This forms the basis of terahertz (1012 hertz) electronics in artificial superlattices, and has enabled light-based switches and sampling of currents extending in frequency up to a few hundred terahertz. Here we demonstrate the extension of electronic metrology to the multi-petahertz (1015 hertz) frequency range. We use single cycle intense optical fields (about one volt per angstrom) to drive electron motion in the bulk of silicon dioxide, and then probe its dynamics by using attosecond (10-18 seconds) streaking to map the time structure of emerging isolated attosecond extreme ultraviolet transients and their optical driver. The data establish a firm link between the emission of the extreme ultraviolet radiation and the light-induced intraband, phase-coherent electric currents that extend in frequency up to about eight petahertz, and enable access to the dynamic nonlinear conductivity of silicon dioxide. Direct probing, confinement and control of the waveform of intraband currents inside solids on attosecond timescales establish a method of realizing multi-petahertz coherent electronics. We expect this technique to enable new ways of exploring the interplay between electron dynamics and the structure of condensed matter on the atomic scale. PMID- 27762355 TI - Neuroscience: Why mole rats don't feel the heat. PMID- 27762357 TI - Animal cognition: Bees learn and 'teach' others. PMID- 27762358 TI - Species loss: learn from health metrics. PMID- 27762359 TI - Biodiversity: Two African elephant species, not just one. PMID- 27762360 TI - Electronics: Shortest transistor made. PMID- 27762356 TI - Genome evolution in the allotetraploid frog Xenopus laevis. AB - To explore the origins and consequences of tetraploidy in the African clawed frog, we sequenced the Xenopus laevis genome and compared it to the related diploid X. tropicalis genome. We characterize the allotetraploid origin of X. laevis by partitioning its genome into two homoeologous subgenomes, marked by distinct families of 'fossil' transposable elements. On the basis of the activity of these elements and the age of hundreds of unitary pseudogenes, we estimate that the two diploid progenitor species diverged around 34 million years ago (Ma) and combined to form an allotetraploid around 17-18 Ma. More than 56% of all genes were retained in two homoeologous copies. Protein function, gene expression, and the amount of conserved flanking sequence all correlate with retention rates. The subgenomes have evolved asymmetrically, with one chromosome set more often preserving the ancestral state and the other experiencing more gene loss, deletion, rearrangement, and reduced gene expression. PMID- 27762361 TI - Cell biology: The organelle replication connection. PMID- 27762363 TI - Genomics: A matched set of frog sequences. PMID- 27762364 TI - Optical physics: Speedy electrons exposed in a flash. PMID- 27762365 TI - Social science: Include social equity in California Biohub. PMID- 27762367 TI - Astronomy: Two stars have three disks. PMID- 27762368 TI - Astrobiology: Martian dance of fiction and fact. PMID- 27762369 TI - Astrophysics: Unexpected X-ray flares. PMID- 27762370 TI - Deborah S. Jin 1968-2016. PMID- 27762373 TI - Drug discovery: Bacteria in humans yield drug. PMID- 27762372 TI - Clarification. PMID- 27762375 TI - Plant biology: RNA spray fights fungus. PMID- 27762377 TI - Chemistry: Meteorite makes good catalyst. PMID- 27762376 TI - Neurotechnology: Paralysed man with implant feels touch. PMID- 27762378 TI - China: Soil clean-up needs cash and clarity. PMID- 27762379 TI - The polling crisis: How to tell what people really think. PMID- 27762380 TI - Mouse eggs made from skin cells in a dish. PMID- 27762381 TI - One sharp edge does not a tool make. PMID- 27762382 TI - The power of prediction markets. PMID- 27762383 TI - Arecibo Observatory hit with discrimination lawsuit. PMID- 27762384 TI - Effort to wrangle geoscience data faces uncertain future. PMID- 27762385 TI - How Republicans reshaped the House science committee. PMID- 27762386 TI - Women need to be seen and heard at conferences. PMID- 27762387 TI - Hillary Clinton will make a fine US president. PMID- 27762388 TI - Science group seeks to guide Silicon Valley philanthropists. PMID- 27762389 TI - Program good ethics into artificial intelligence. PMID- 27762390 TI - Mars excitement, campus riots and a freeze on refrigerants. PMID- 27762391 TI - There is a blind spot in AI research. PMID- 27762392 TI - The scientists who support Donald Trump. PMID- 27762393 TI - Intramedullary Nailing Versus Plate Fixation for the Treatment Displaced Midshaft Clavicular Fractures: A Systematic Review and Meta-Analysis. AB - The two commonly performed surgical techniques used to repair displaced midshaft clavicle fractures are plate fixation or intramedullary nailing; however, despite recent evidence, the optimal method to treat such fractures remains a continued topic of debate. A meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate long term function, complications, and operative duration in adult patients receiving intramedullary nailing in comparison to plating. Seven RCTs and three quasi-randomized trials were included. No significant difference was found in long-term function between the two groups (MD: -0.66, 95% CI: -2.03 to 0.71, I2 = 62%, p = 0.34). Patients who received plating had a 2.19 times increased risk of treatment failure, but this failed to reach significance (95% CI: 0.93 to 5.15, I2 = 0%, p = 0.07). The risk of non-operative complications was 2.11 times higher in patients who received plating and this reached statistical significance (95% CI: 1.38 to 3.23, I2 = 53%, p = 0.0006). Finally, plating significantly prolonged operative duration by 20.16 minutes (95% CI: 16.87 to 23.44, I2 = 56%, p < 0.00001). Our results suggest that intramedullary nailing and plating provide equivalent long-term functional outcomes; however, plating may lead to a higher risk of treatment failure and non operative complications. PMID- 27762394 TI - Gold Nanoparticle Monolayers from Sequential Interfacial Ligand Exchange and Migration in a Three-Phase System. AB - Using a three-phase system, centimeter-scale monolayer gold nanoparticle (Au NP) films have been prepared that have long-range order and hydrophobic ligands. The system contains an interface between an aqueous phase containing Au NPs and an oil phase containing one of various types of amine ligands, and a water/air interface. As the Au NPs diffuse to the water/oil interface, ligand exchange takes place which temporarily traps them at the water/oil interface. The ligand exchanged particles then spontaneously migrate to the air/water interface, where they self-assemble, forming a monolayer under certain conditions. The spontaneous formation of the NP film at the air/water interface was due to the minimization of the system Helmholtz free energy. However, the extent of surface functionalization was dictated by kinetics. This decouples interfacial ligand exchange from interfacial self-assembly, while maintaining the simplicity of a single system. The interparticle center-to-center distance was dictated by the amine ligand length. The Au NP monolayers exhibit tunable surface plasma resonance and excellent spatial homogeneity, which is useful for surface-enhanced Raman scattering. The "air/water/oil" self-assembly method developed here not only benefits the fundamental understanding of NP ligand conformations, but is also applicable to the manufacture of plasmonic nanoparticle devices with precisely designed optical properties. PMID- 27762395 TI - Differential protein structural disturbances and suppression of assembly partners produced by nonsense GABRG2 epilepsy mutations: implications for disease phenotypic heterogeneity. AB - Mutations in GABAA receptor subunit genes are frequently associated with epilepsy, and nonsense mutations in GABRG2 are associated with several epilepsy syndromes including childhood absence epilepsy, generalized tonic clonic seizures and the epileptic encephalopathy, Dravet syndrome. The molecular basis for the phenotypic heterogeneity of mutations is unclear. Here we focused on three nonsense mutations in GABRG2 (GABRG2(R136*), GABRG2(Q390*) and GABRG2(W429*)) associated with epilepsies of different severities. Structural modeling and structure-based analysis indicated that the surface of the wild-type gamma2 subunit was naturally hydrophobic, which is suitable to be buried in the cell membrane. Different mutant gamma2 subunits had different stabilities and different interactions with their wild-type subunit binding partners because they adopted different conformations and had different surface hydrophobicities and different tendency to dimerize. We utilized flow cytometry and biochemical approaches in combination with lifted whole cell patch-clamp recordings. We demonstrated that the truncated subunits had no to minimal surface expression and unchanged or reduced surface expression of wild-type partnering subunits. The amplitudes of GABA-evoked currents from the mutant alpha1beta2gamma2(R136*), alpha1beta2gamma2(Q390*) and alpha1beta2gamma2(W429*) receptors were reduced compared to the currents from alpha1beta2gamma2 receptors but with differentially reduced levels. This thus suggests differential protein structure disturbances are correlated with disease severity. PMID- 27762396 TI - Revealing Deactivation Pathways Hidden in Time-Resolved Photoelectron Spectra. AB - Time-resolved photoelectron spectroscopy is commonly employed with the intention to monitor electronic excited-state dynamics occurring in a neutral molecule. With the help of theory, we show that when excited-state processes occur on similar time scales the different relaxation pathways are completely obscured in the total photoionization signal recorded in the experiment. Using non-adiabatic molecular dynamics and Dyson norms, we calculate the photoionization signal of cytosine and disentangle the transient contributions originating from the different deactivation pathways of its tautomers. In the simulations, the total signal from the relevant keto and enol tautomers can be decomposed into contributions either from the neutral electronic state populations or from the distinct mechanistic pathways across the multiple potential surfaces. The lifetimes corresponding to these contributions cannot be extracted from the experiment, thereby illustrating that new experimental setups are necessary to unravel the intricate non-adiabatic pathways occurring in polyatomic molecules after irradiation by light. PMID- 27762397 TI - A unified theory of calcium alternans in ventricular myocytes. AB - Intracellular calcium (Ca2+) alternans is a dynamical phenomenon in ventricular myocytes, which is linked to the genesis of lethal arrhythmias. Iterated map models of intracellular Ca2+ cycling dynamics in ventricular myocytes under periodic pacing have been developed to study the mechanisms of Ca2+ alternans. Two mechanisms of Ca2+ alternans have been demonstrated in these models: one relies mainly on fractional sarcoplasmic reticulum Ca2+ release and uptake, and the other on refractoriness and other properties of Ca2+ sparks. Each of the two mechanisms can partially explain the experimental observations, but both have their inconsistencies with the experimental results. Here we developed an iterated map model that is composed of two coupled iterated maps, which unifies the two mechanisms into a single cohesive mathematical framework. The unified theory can consistently explain the seemingly contradictory experimental observations and shows that the two mechanisms work synergistically to promote Ca2+ alternans. Predictions of the theory were examined in a physiologically detailed spatial Ca2+ cycling model of ventricular myocytes. PMID- 27762398 TI - A New Time-varying Concept of Risk in a Changing Climate. AB - In a changing climate arising from anthropogenic global warming, the nature of extreme climatic events is changing over time. Existing analytical stationary based risk methods, however, assume multi-dimensional extreme climate phenomena will not significantly vary over time. To strengthen the reliability of infrastructure designs and the management of water systems in the changing environment, multidimensional stationary risk studies should be replaced with a new adaptive perspective. The results of a comparison indicate that current multi dimensional stationary risk frameworks are no longer applicable to projecting the changing behaviour of multi-dimensional extreme climate processes. Using static stationary-based multivariate risk methods may lead to undesirable consequences in designing water system infrastructures. The static stationary concept should be replaced with a flexible multi-dimensional time-varying risk framework. The present study introduces a new multi-dimensional time-varying risk concept to be incorporated in updating infrastructure design strategies under changing environments arising from human-induced climate change. The proposed generalized time-varying risk concept can be applied for all stochastic multi-dimensional systems that are under the influence of changing environments. PMID- 27762400 TI - The copepod Calanus spp. (Calanidae) is repelled by polarized light. AB - Both attraction and repulsion from linearly polarized light have been observed in zooplankton. A dichotomous choice experiment, consisting of plankton light traps deployed in natural waters at a depth of 30 m that projected either polarized or unpolarized light of the same intensity, was used to test the hypothesis that the North Atlantic copepod, Calanus spp., is linearly polarotactic. In addition, the transparency of these copepods, as they might be seen by polarization insensitive vs. sensitive visual systems, was measured. Calanus spp. exhibited negative polarotaxis with a preference ratio of 1.9:1. Their transparency decreased from 80% to 20% to 30% in the unpolarized, partially polarized, and electric (e-) vector orientation domains respectively - that is, these copepods would appear opaque and conspicuous to a polarization-sensitive viewer looking at them under conditions rich in polarized light. Since the only difference between the two plankton traps was the polarization cue, we conclude that Calanus spp. are polarization sensitive and exhibit negative polarotaxis at low light intensities (albeit well within the sensitivity range reported for copepods). We hypothesize that Calanus spp. can use polarization vision to reduce their risk of predation by polarization-sensitive predators and suggest that this be tested in future experiments. PMID- 27762399 TI - Molecular characterization of host-parasite cell signalling in Schistosoma mansoni during early development. AB - During infection of their human definitive host, schistosomes transform rapidly from free-swimming infective cercariae in freshwater to endoparasitic schistosomules. The 'somules' next migrate within the skin to access the vasculature and are surrounded by host molecules that might activate intracellular pathways that influence somule survival, development and/or behaviour. However, such 'transactivation' by host factors in schistosomes is not well defined. In the present study, we have characterized and functionally localized the dynamics of protein kinase C (PKC) and extracellular signal regulated kinase (ERK) activation during early somule development in vitro and demonstrate activation of these protein kinases by human epidermal growth factor, insulin, and insulin-like growth factor I, particularly at the parasite surface. Further, we provide evidence that support the existence of specialized signalling domains called lipid rafts in schistosomes and propose that correct signalling to ERK requires proper raft organization. Finally, we show that modulation of PKC and ERK activities in somules affects motility and reduces somule survival. Thus, PKC and ERK are important mediators of host-ligand regulated transactivation events in schistosomes, and represent potential targets for anti-schistosome therapy aimed at reducing parasite survival in the human host. PMID- 27762402 TI - Selective molecular recognition on calixarene-functionalized 3D surfaces. AB - Host-guest recognition plays an important role in biological analysis and biosensing. Accordingly, great efforts have been devoted to the development of sensors using versatile 3D surface materials. These functionalized nanomaterials possess the advantages of high selectivity and visual signals, enabling the selective detection of ions, amino acids, proteins, and other biological molecules. Therefore, in this feature article, we present some significant and representative examples of molecular recognition on calixarene functionalized 3D surface nanomaterials. By virtue of host-guest interactions, the functional interfaces displaying high selectivity and featuring a reversible switch response towards the environmental stimuli with various signal output (electrochemical and optical signals) are herein introduced. Furthermore, various 3D surface materials with unique signal amplification in molecular recognition are presented, including quantum dots (QDs), metal nanoparticles (NPs), nanotubes, and mesoporous silica. These excellent properties enable calixarene-functionalized 3D materials to become an outstanding platform for molecular recognition, offering convenient approaches for sensing and separation. PMID- 27762401 TI - Achievement of over 1.4 V photovoltage in a dye-sensitized solar cell by the application of a silyl-anchor coumarin dye. AB - A dye-sensitized solar cell (DSSC) fabricated by using a novel silyl-anchor coumarin dye with alkyl-chain substitutes, a Br3-/Br- redox electrolyte solution containing water, and a Mg2+-doped anatase-TiO2 electrode with twofold surface modification by MgO and Al2O3 exhibited an open-circuit photovoltage over 1.4 V, demonstrating the possibility of DSSCs as practical photovoltaic devices. PMID- 27762405 TI - In situ rapid growth of fluorescent silicon nanoparticles at room temperature and under atmospheric pressure. AB - Herein, we demonstrate that at room temperature (20-25 degrees C) and under atmospheric pressure, small-sized (~3.1 nm) SiNPs can be rapidly formed in aqueous phase within 60 min, with high photoluminescence quantum yield (PLQY) of ~50%. This approach is readily scalable and could potentially be used to produce high-quality SiNPs at an industrial level. PMID- 27762408 TI - A review of stereochemical implications in the generation of secondary organic aerosol from isoprene oxidation. AB - The atmospheric reactions leading to the generation of secondary organic aerosol (SOA) from the oxidation of isoprene are generally assumed to produce only racemic mixtures, but aspects of the chemical reactions suggest this may not be the case. In this review, the stereochemical outcomes of published isoprene degradation mechanisms contributing to high amounts of SOA are evaluated. Despite evidence suggesting isoprene first-generation oxidation products do not contribute to SOA directly, this review suggests the stereochemistry of first generation products may be important because their stereochemical configurations may be retained through to the second-generation products which form SOA. Specifically, due to the stereochemistry of epoxide ring-opening mechanisms, the outcome of the reactions involving epoxydiols of isoprene (IEPOX), methacrylic acid epoxide (MAE) and hydroxymethylmethyl-alpha-lactone (HMML) are, in principle, stereospecific which indicates the stereochemistry is predefined from first-generation precursors. The products from these three epoxide intermediates oligomerise to form macromolecules which are proposed to form chiral structures within the aerosol and are considered to be the largest contributors to SOA. If conditions in the atmosphere such as pH, aerosol water content, relative humidity, pre-existing aerosol, aerosol coatings and aerosol cation/anion content (and other) variables acting on the reactions leading to SOA affect the tacticity (arrangement of chiral centres) in the SOA then they may influence its physical properties, for example its hygroscopicity. Chamber studies of SOA formation from isoprene encompass particular sets of controlled conditions of these variables. It may therefore be important to consider stereochemistry when upscaling from chamber study data to predictions of SOA yields across the range of ambient atmospheric conditions. Experiments analysing the stereochemistry of the reactions under varying conditions of the above variables would help elucidate whether there is stereoselectivity in SOA formation from isoprene and if the rates of SOA formation are affected. PMID- 27762409 TI - Photochemical recovery of europium from non-aqueous solutions. AB - The photochemical recovery of europium from non-aqueous media, more specifically alcohols, is studied. The recovery was performed by photochemical reduction of europium(iii) to europium(ii) and subsequent removal as the insoluble EuCl2. Two charge transfer bands are present in the UV-C region, one originating from the alcohol (around 230 nm) and the other from the chloride anion (at 271 nm), which are responsible for the photochemical reduction when the solution is illuminated by a medium-pressure mercury lamp. When using different alcohol solvents, a trend is observed with regards to the removal rate and efficiency, following methanol (MeOH) < ethanol (EtOH) < isopropanol (IPA) <50/50 v/v ethanol/isopropanol (EtOH/IPA). This trend can be explained by the solubility of EuCl2 in the different solvents, and by the photon absorption at the wavelengths which provoke the reduction. In a 50/50 v/v EtOH/IPA solution, it is observed that addition of chloride ions (as LiCl) intensifies the chloride-to-europium(iii) CT band, effectively increasing the photon absorption in the 260-340 nm wavelength region. Moreover, addition of extra chloride ions decreases the solubility of EuCl2, which in turn accounts for a better recovery efficiency. However, this beneficial effect disappears when the water content rises above 1.5 wt%. For an EtOH/IPA solution with a high chloride concentration and low water content, it is feasible to recover europium from binary europium/yttrium mixtures with an efficiency of up to 94.7% and a purity of 96.7-99.8%, depending on the Eu/Y molar ratio. For higher yttrium excess, the removal rate of europium is higher, which is explained by the ability of yttrium to coordinate water molecules, decreasing the free water content in the solution. The fact that a large excess of yttrium does not compromise the removal rate of europium from the solution, proves that this technique has potential for europium recovery from red lamp phosphors (Y2O3:Eu3+), which consist entirely of europium and yttrium with a Eu/Y molar ratio of 1/20-1/30. PMID- 27762410 TI - Highly regioselective synthesis of 4-tosylthiomorpholine via intramolecular cyclization of N-tethered thioalkenols. AB - A one-pot, metal-free procedure has been developed for the synthesis of 4 tosylthiomorpholine from N-tethered thioalkenols via bromination, cyclization and subsequent elimination reaction in good yields. The reaction is found to be highly regioselective. PMID- 27762411 TI - Photochemical synthesis and photophysical features of ethynylphenanthrenes studied by emission and transient absorption measurements. AB - Phenanthrenes substituted with trimethylsilylethynyl and phenylethynyl groups were photochemically prepared, and their photophysical properties were systematically investigated based on measurements of fluorescence quantum yields, lifetimes, and transient absorption. Introducing ethynyl groups into the phenanthrene skeleton caused an increase in the fluorescence quantum yields compared to that of phenanthrene. The quantum yields and rates of fluorescence were dependent on the substituting position(s) and the terminating group for the C-C triple bond. The observation of the triplet-triplet absorption of the substituted phenanthrenes was evident for the nonradiative process being intersystem crossing competitive with the fluorescence process. The mechanism of increasing the fluorescence abilities by substituting with the ethynyl group(s) was discussed with the aid of TD-DFT calculations. PMID- 27762413 TI - Characterization of NO non-covalent interactions involving sigma-holes: "electrostatics" or "dispersion". AB - In this article, the existence of NO noncovalent interactions was explored in per halo substituted ammonia-water complexes. Optimized geometry at the MP2/aug-cc pVTZ level shows that the NO distance in all complexes is less than the sum of the vdW radii of N and O. The strength of these contacts was directly dependent on the extent of chlorine substitution on N or O atoms. Also, the level of theory and the basis set employed for the binding energy calculations have a direct effect on the strength of the NO contacts. Energy decomposition analysis reveals that dispersion was the major contributor towards the stability of these contacts followed by electrostatic energy. The topological analysis further confirmed the existence of NO contacts due to the presence of a bond critical point between the N and the O atom in all the complexes. These contacts have characteristics of a sigma-hole interaction with the NBO analysis revealing that the primary charge transfer in all the complexes is occurring from O(lp) to sigma*(N-X) orbitals, confirming these interactions to be predominantly in the category of pnicogen bonds. PMID- 27762412 TI - Slowing the translocation of single-stranded DNA by using nano-cylindrical passage self-assembled by amphiphilic block copolymers. AB - We report a novel approach to slow the translocation of single-stranded DNA (ssDNA) by employing polyethylene oxide (PEO) filled nano-cylindrical domains as transportation channels. DNA strands were demonstrated to electrophoretically translocate through PEO filled cylindrical domains with diameters of 2 and 9 nm, which were self-assembled by amphiphilic liquid crystalline block copolymers. The average translocation rate of ssDNA strands was effectively reduced to an order of 10 MUs per nucleotide, which was 1-2 orders slower than that attained by utilizing conventional solid-state nanopore devices. PMID- 27762414 TI - Enantioselective total synthesis and structural assignment of callyspongiolide. AB - We have elucidated the complete absolute configuration of callyspongiolide and unambiguously assigned its stereochemistry at the C-21 center through synthesis. Four stereoisomers of callyspongiolide were synthesized in a convergent and enantioselective manner. A late-stage Sonogashira coupling forges the diene-ynic side chain. Other notable reactions are Yonemitsu's variation of Yamaguchi macrolactonization to cyclize an alkynic seco acid, highly trans-selective Julia Kocienski olefination, CBS reduction to set the C-21 stereocenter, and methyl cuprate addition to an unsaturated pyranone to install the C-5 methyl center. PMID- 27762415 TI - A novel 2-step ALD route to ultra-thin MoS2 films on SiO2 through a surface organometallic intermediate. AB - The lack of scalable-methods for the growth of 2D MoS2 crystals, an identified emerging material with applications ranging from electronics to energy storage, is a current bottleneck against its large-scale deployment. We report here a two step ALD route with new organometallic precursors, Mo(NMe2)4 and 1,2 ethanedithiol (HS(CH2)2SH) which consists in the layer-by-layer deposition of an amorphous surface Mo(iv) thiolate at 50 degrees C, followed by a subsequent annealing at higher temperature leading to ultra-thin MoS2 nanocrystals (~20 nm large) in the 1-2 monolayer range. In contrast to the usual high-temperature growth of 2D dichalcogenides, where nucleation is the key parameter to control both thickness and uniformity, our novel two-step ALD approach enables chemical control over these two parameters, the growth of 2D MoS2 crystals upon annealing being ensured by spatial confinement and facilitated by the formation of a buffer oxysulfide interlayer. PMID- 27762417 TI - Ion induced dewetting of Au-Si on a SiO2 surface: composite nanodot evolution and wettability transition. AB - A nanodot array morphology gradually develops on SiO2 surface when a thin bi layer of Au and Si undergoes ion irradiation. An increasing amount of gold silicide is detected as islands on the insulator surface evolve into nanodots as a function of increasing ion fluence. Different stages of evolution from islands to nanodots are found to be driven by the localized melting of Au along the ion track and dewetting of the metal film. Dewetting is accompanied by sputter erosion and mixing of Au and Si at the bi-layer interface due to ion energy deposition. Interestingly, a gradual transition in wettability of the surface from the hydrophilic to the hydrophobic one is observed with the growth of nanodots, which is correlated with the compositional variation. The experimental results indicate a route towards the controlled growth of composite nanodots on an insulator surface having hydrophobic properties using ion irradiation. PMID- 27762416 TI - Nanoscale dynamics of phospholipids reveals an optimal assembly mechanism of pore forming proteins in bilayer membranes. AB - Cell membranes are believed to be highly complex dynamical systems having compositional heterogeneity involving several types of lipids and proteins as the major constituents. This dynamical and compositional heterogeneity is suggested to be critical to the maintenance of active functionality and response to chemical, mechanical, electrical and thermal stresses. However, delineating the various factors responsible for the spatio-temporal response of actual cell membranes to stresses can be quite challenging. In this work we show how biomimetic phospholipid bilayer membranes with variable lipid fluidity determine the optimal assembly mechanism of the pore-forming protein, listeriolysin O (LLO), belonging to the class of cholesterol dependent cytolysins (CDCs). By combining atomic force microscopy (AFM) and super-resolution stimulated emission depletion (STED) microscopy imaging on model membranes, we show that pores formed by LLO in supported lipid bilayers can have variable conformation and morphology depending on the fluidity of the bilayer. At a fixed cholesterol concentration, pores formed in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membranes were larger, flexible and more prone to coalescence when compared with the smaller and more compact pores formed in the lower fluidity 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) membranes. In contrast, 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) membranes did not show any evidence of pore formation. Fluorescence correlation spectroscopy (FCS) in STED mode revealed the appearance of a length scale, xi, below which lipid dynamics, under the influence of LLO protein binding and assembly, becomes anomalous. Interestingly, the magnitude of xi is found to correlate with both lipid fluidity and pore dimensions (and flexibility) in DOPC and POPC bilayers. However this length scale dependent crossover, signalling the onset of anomalous diffusion, was not observed in DMPC bilayers. Our study highlights the subtle interplay of lipid membrane mediated protein assembly and lipid fluidity in determining proteo-lipidic complexes formed in biomembranes and the significant insight that STED microscopy provides in unraveling critical aspects of nanoscale membrane biophysics. PMID- 27762418 TI - Local NH-pi interactions involving aromatic residues of proteins: influence of backbone conformation and pipi* excitation on the pi H-bond strength, as revealed from studies of isolated model peptides. AB - Conformer-selective IR gas phase spectroscopy and high level quantum chemistry methods have been used to characterise the diversity of local NH-pi interactions between the pi ring of a phenylalanine aromatic residue and the nearby main chain amide groups. The study of model systems shows how the amide NH stretch vibrational features, in the 3410-3460 cm-1 frequency range, can be used to monitor the strength of these local pi H-bonds, which is found to depend on both the backbone conformation and the aromatic side chain orientation. This is rationalized in terms of partial electron transfer between the pi cloud and the main chain NH bonds, with the help of analysis tools based on Natural Bonding Orbitals and Non-Covalent Interactions plots. The experimental study, extended to the NH-pi interactions when the Phe residue is excited in its first pipi* electronic state, also demonstrates the principle of the pipi* labelling technique, i.e. a selective labelling of those NH bonds in a peptide molecule that are in close contact with an aromatic ring, as an elegant tool for IR spectroscopic assignments. The validation of theoretical predictions against experimental data (frequency change upon excitation) eventually qualifies the use of the CC2 method for the description of the pipi* excited states of systems having a phenyl ring, both in terms of structure, vibrational modes and nature of excited states. PMID- 27762420 TI - Probing driving forces in aerolysin and alpha-hemolysin biological nanopores: electrophoresis versus electroosmosis. AB - The transport of macromolecules through nanopores is involved in many biological functions and is today at the basis of promising technological applications. Nevertheless the interpretation of the dynamics of the macromolecule/nanopore interaction is still misunderstood and under debate. At the nanoscale, inside biomimetic channels under an external applied voltage, electrophoresis, which is the electric force acting on electrically charged molecules, and electroosmotic flow (EOF), which is the fluid transport associated with ions, contribute to the direction and magnitude of the molecular transport. In order to decipher the contribution of the electrophoresis and electroosmotic flow, we explored the interaction of small, rigid, neutral molecules (cyclodextrins) and flexible, non ionic polymers (poly(ethylene glycol), PEG) that can coordinate cations under appropriate experimental conditions, with two biological nanopores: aerolysin (AeL) and alpha-hemolysin (aHL). We performed experiments using two electrolytes with different ionic hydration (KCl and LiCl). Regardless of the nature of the nanopore and of the electrolyte, cyclodextrins behaved as neutral analytes. The dominant driving force was attributed to EOF, acting in the direction of the anion flow and stronger in LiCl than in KCl. The same qualitative behaviour was observed for PEGs in LiCl. In contrast, in KCl, PEGs behaved as positively charged polyelectrolytes through both AeL and aHL. Our results are in agreement with theoretical predictions about the injection of polymers inside a confined geometry (ESI). We believe our results to be of significant importance for better control of the dynamics of analytes of different nature through biological nanopores. PMID- 27762421 TI - Remarkable acceleration of template-directed photodimerisation of 9 phenylethynylanthracene derivatives assisted by complementary salt bridge formation. AB - The photoirradiation of 9-phenylethynylanthracene in degassed chloroform and benzene afforded not only a [4 + 2]-anti Diels-Alder addition dimer, but also a [4 + 4]-anti-dimer as a minor product for the first time as revealed by single crystal X-ray analysis, while the anthracene residue was quantitatively oxidised in undegassed dilute chloroform, giving the corresponding endoperoxides. The photochemical reactions of carboxylic acid monomers bearing a 9 phenylethynylanthracene unit at one and both ends were further investigated in the presence and absence of the complementary amidine dimer as the template. It was found that a similar photooxidation reaction of the monomers was significantly suppressed in the presence of the template even in undegassed chloroform. In addition, the template-directed photodimerisation of the mono- and di-9-phenylethynylanthracene-bound monomers was remarkably accelerated 30- or 61 fold in the degassed chloroform, giving the [4 + 2]-anti- and [4 + 4]-anti-dimers as major and minor products, respectively, whereas the di-9 phenylethynylanthracene-bound monomer was preferentially photo-polymerised in the absence of the template. PMID- 27762422 TI - Computationally efficient error estimate for evaluation of regularization in photoacoustic tomography. AB - The model-based image reconstruction techniques for photoacoustic (PA) tomography require an explicit regularization. An error estimate (?2) minimization-based approach was proposed and developed for the determination of a regularization parameter for PA imaging. The regularization was used within Lanczos bidiagonalization framework, which provides the advantage of dimensionality reduction for a large system of equations. It was shown that the proposed method is computationally faster than the state-of-the-art techniques and provides similar performance in terms of quantitative accuracy in reconstructed images. It was also shown that the error estimate (?2) can also be utilized in determining a suitable regularization parameter for other popular techniques such as Tikhonov, exponential, and nonsmooth (?1 and total variation norm based) regularization methods. PMID- 27762423 TI - Comparison of different cutaneous carotenoid sensors and influence of age, skin type, and kinetic changes subsequent to intake of a vegetable extract. AB - In the last decade, cutaneous carotenoid measurements have become increasingly popular, as carotenoids were found to be a biomarker of nutrition rich in fruits and vegetables, permitting monitoring of the influence of various stress factors. For such measurements, in addition to the specific and selective resonance Raman spectroscopy (RRS), newly developed low expensive small and mobile sensors that are based on spatially resolved reflectance spectroscopy (SRRS) are used for cutaneous carotenoid measurements. Human volunteers of different age exhibiting skin types I to III were investigated using RRS and two SRRS-based sensors to determine the influence of these parameters on the measuring results. In two studies on volunteers of either the same age or skin type, however, the respective other parameter being varied and no significant influences of age or skin type could be detected. Furthermore, the kinetic changes resulting from the intake and discontinued intake of a vegetable extract rich in carotenoids showed a good correlation among the three sensors and with the detected blood carotenoids. This illustrates that the SRRS-based sensors and RRS device provide reliable cutaneous carotenoid values independent of age and skin types I to III of the volunteers. PMID- 27762424 TI - Monitoring of airborne biological particles in outdoor atmosphere. Part 1: Importance, variability and ratios. AB - The first part of this review ("Monitoring of airborne biological particles in outdoor atmosphere. Part 1: Importance, variability and ratios") describes the current knowledge on the major biological particles present in the air regarding their global distribution, concentrations, ratios and influence of meteorological factors in an attempt to provide a framework for monitoring their biodiversity and variability in such a singular environment as the atmosphere. Viruses, bacteria, fungi, pollen and fragments thereof are the most abundant microscopic biological particles in the air outdoors. Some of them can cause allergy and severe diseases in humans, other animals and plants, with the subsequent economic impact. Despite the harsh conditions, they can be found from land and sea surfaces to beyond the troposphere and have been proposed to play a role also in weather conditions and climate change by acting as nucleation particles and inducing water vapour condensation. In regards to their global distribution, marine environments act mostly as a source for bacteria while continents additionally provide fungal and pollen elements. Within terrestrial environments, their abundances and diversity seem to be influenced by the land-use type (rural, urban, coastal) and their particularities. Temporal variability has been observed for all these organisms, mostly triggered by global changes in temperature, relative humidity, et cetera. Local fluctuations in meteorological factors may also result in pronounced changes in the airbiota. Although biological particles can be transported several hundreds of meters from the original source, and even intercontinentally, the time and final distance travelled are strongly influenced by factors such as wind speed and direction. [Int Microbiol 2016; 19(1):1-1 3]. PMID- 27762425 TI - Haloalkalitolerant Actinobacteria with capacity for anthracene degradation isolated from soils close to areas with oil activity in the State of Veracruz, Mexico. AB - The use of native strains of microorganisms from soils is an excellent option for bioremediation. To our knowledge, until now there has been no other group working on the isolation of Actinobacteria from contaminated soils in Mexico. In this study, samples of soils close to areas with oil activity in the State of Veracruz, Mexico, were inoculated for the isolation of Actinobacteria. The strains isolated were characterized morphologically, and the concentrations of NaCl and pH were determined for optimal growth. Strain selection was performed by the detection of a phylogenetic marker for Actinobacteria located at the 23S rRNA gene, followed by species identification by sequencing the 16S rRNA gene. Several haloalkalitolerant Actinobacteria were isolated and identified as: Kocuria rosea, K. palustris, Microbacterium testaceum, Nocardia farcinica and Cellulomonas denverensis. Except for C. denverensis, the biomass of all strains increased in the presence of anthracene. The strains capacity to metabolize anthracene (at 48 h), determined by fluorescence emission, was in the range of 46-54%. During this time, dihydroxy aromatic compounds formed, characterized by attenuated total reflectance Fourier transform infrared spectroscopy bands of 1205 cm-1 and 1217 cm-1. Those Actinobacteria are potentially useful for the bioremediation of saline and alkaline environments contaminated with polycyclic aromatic hydrocarbon compounds. [Int Microbiol 2016; 19(1):15-26]. PMID- 27762426 TI - Genetic and serologic surveillance of rotavirus with P[8] and P[4] genotypes in feces from children in the city of Chihuahua, northern Mexico. AB - Rotavirus vaccine was developed using the most prominent G and P genotypes circulating in children population. Therefore, severe gastroenteritis has been reduced around the world. This study investigated the G and P rotavirus genotypes circulating in children from two hospitals in the city of Chihuahua, Mexico. Additionally, polyclonal antibodies against Rotavirus Wa strain were used to determine their homotypic and heterotypic reactivity to both P[8] and P[4] genotypes. G1, G2, and G3 VP7 genotypes and P[8] and P[4] VP4 genotypes were detected in common and uncommon combinations as well as mixed infectious. The predominant combination was G1P[8]. Phylogenetic analysis of VP4 gene revealed the presence of P[8]-1 and P[8]-3 lineages of P[8] genotype and P[4]-5 lineage of P[4] genotype. All but five G1P[8] rotavirus were detected by polyclonal anti Rotavirus Wa strain. Mutation analysis revealed differences in three of the four neutralizing epitopes previously reported to VP8* subunit of VP4 protein. Results of this study offer insights over genetic variants of field rotavirus that could be detected in a homotypic and heterotypic way by antibodies elicited to rotavirus with P[8] genotype. [Int Microbiol 2016; 19(1):27-32]. PMID- 27762427 TI - Prevalence of Campylobacter spp. in diarrhoea samples from patients in New South Wales, Australia. AB - Campylobacteriosis is a leading cause of bacterial foodborne disease in many industrialized countries including Australia. New South Wales (NSW) is the most populous state in Australia yet the lack of any Campylobacter species surveillance programs has led to a knowledge gap in the importance of these pathogens as causes of diarrhoea. The data collected in this study demonstrated a need for such programs. In this study, 400 human clinical fecal samples were collected from two NSW locations, Western Sydney and Wagga Wagga, and tested for the presence of Campylobacter spp. Patients were clustered by location, age and gender to assess Campylobacter spp. prevalence within these groups between the two regions. The frequency of Campylobacter spp. was higher in males compared to females in the age groups 0-4 and 5-14 years; 6.4% and 1.0%, and 8.2% and none, respectively. A second peak was noted in elderly adults compared with those in younger age groups. Based on the findings of the quantitative PCR analysis it was estimated that the age-adjusted prevalence of Campylobacter spp. associated diarrhoea was 159 cases per 100,000 persons. [Int Microbiol 2016; 19(1):33-37]. PMID- 27762428 TI - De novo synthesis and functional analysis of the phosphatase-encoding gene acI-B of uncultured Actinobacteria from Lake Stechlin (NE Germany). AB - The National Center for Biotechnology Information [http://www.ncbi.nlm.nih.gov/guide/taxonomy/] database enlists more than 15,500 bacterial species. But this also includes a plethora of uncultured bacterial representations. Owing to their metabolism, they directly influence biogeochemical cycles, which underscores the the important status of bacteria on our planet. To study the function of a gene from an uncultured bacterium, we have undertaken a de novo gene synthesis approach. Actinobacteria of the acI-B subcluster are important but yet uncultured members of the bacterioplankton in temperate lakes of the northern hemisphere such as oligotrophic Lake Stechlin (NE Germany). This lake is relatively poor in phosphate (P) and harbors on average ~1.3 x 10 6 bacterial cells/ml, whereby Actinobacteria of the ac-I lineage can contribute to almost half of the entire bacterial community depending on seasonal variability. Single cell genome analysis of Actinobacterium SCGC AB141-P03, a member of the acI-B tribe in Lake Stechlin has revealed several phosphate metabolizing genes. The genome of acI-B Actinobacteria indicates potential to degrade polyphosphate compound. To test for this genetic potential, we targeted the exoP-annotated gene potentially encoding polyphosphatase and synthesized it artificially to examine its biochemical role. Heterologous overexpression of the gene in Escherichia coli and protein purification revealed phosphatase activity. Comparative genome analysis suggested that homologs of this gene should be also present in other Actinobacteria of the acI lineages. This strategic retention of specialized genes in their genome provides a metabolic advantage over other members of the aquatic food web in a P-limited ecosystem. [Int Microbiol 2016; 19(1):39-47]. PMID- 27762429 TI - A functional ferric uptake regulator (Fur) protein in the fish pathogen Piscirickettsia salmonis. AB - Piscirickettsia salmonis, a Gram-negative fastidious facultative intracellular pathogen, is the causative agent of the salmonid rickettsial septicemia (SRS). The P. salmonis iron acquisition mechanisms and its molecular regulation are unknown. Iron is an essential element for bacterial pathogenesis. Typically, genes that encode for the iron acquisition machinery are regulated by the ferric uptake regulator (Fur) protein. P. salmonis fur sequence database reveals a diversity of fur genes without functional verification. Due to the fastidious nature of this bacterium, we evaluated the functionality of P. salmonis fur in the Salmonella Deltafur heterologous system. Although P. salmonis fur gene strongly differed from the common Fur sequences, it restored the regulatory mechanisms of iron acquisition in Salmonella. We concluded that P. salmonis LF-89 has a conserved functional Fur protein, which reinforces the importance of iron during fish infection. [Int Microbiol 2016; 49-55]. PMID- 27762430 TI - Antimicrobial activity of Lactobacillus strains of chicken origin against bacterial pathogenss. AB - This study was conducted to identify and evaluate the antimicrobial activity of some Lactobacillus isolates of chicken origin. Among 90 isolates 14 Lactobacillus species were distinguished using MALDI-TOF mass spectrometry and 16S-ARDRA. The dominant species was L. salivarius (34.4%), followed by L. johnsonii (23.3%), L. crispatus (13.3%) and L. reuteri (11.1%). All lactobacilli were screened for antimicrobial activity against wild-type strains of Salmonella enterica, Escherichia coli, and Clostridium perfringens. Results from the agar slab method showed that all Lactobacillus isolates were able to produce active compounds on solid media with antagonistic properties against these pathogens. The highest sensitivity to lactobacilli was observed in C. perfringens strains, and the lowest in E. coli. Lactobacillus salivarius exhibited particularly strong antagonism towards all of the indicator bacteria. Strains of L. ingluviei and L. johnsonii and one strain of L. salivarius (10d) selectively inhibited the growth of C. perfringens. No antimicrobial activity of many Lactobacillus isolates was observed when cell-free culture supernatant was used in a well diffusion assay. All Lactobacillus isolates exhibited the ability to produce H2O2 and proved to be hydrophobic (excluding one of L. salivarius). [Int Microbiol 19(1):57-67 (2016)]. PMID- 27762431 TI - Classification of Headache Disorders: Extending to a Multiaxial System. AB - This article argues for extending the International Classification of Headache Disorders to include information that goes beyond diagnosis. The obvious model is a multiaxial system as has been developed for other taxonomies. An axis for recording disability and impact on functioning, and an axis for recording the triggers of headache/migraine, are perhaps the strongest contenders for adding to the system, but there are other possibilities such as lifestyle factors relevant to headache. Extensions such as these would contribute to headache management, provide clear targets for change, and encourage adoption of a biopsychosocial perspective. PMID- 27762432 TI - Oncological impact of anastomotic leakage after laparoscopic mesorectal excision. AB - BACKGROUND: The effect of anastomotic leakage on oncological outcomes after total mesorectal excision (TME) is controversial. This study aimed to assess the influence of symptomatic and asymptomatic anastomotic leakage on oncological outcomes after laparoscopic TME. METHODS: All patients who underwent restorative laparoscopic TME for rectal adenocarcinoma with curative intent from 2005 to 2014 were identified from an institutional database. Asymptomatic anastomotic leakage was defined by CT performed systematically 4-8 weeks after rectal surgery, with no relevant clinical symptoms or laboratory examination findings during the postoperative course. RESULTS: Of a total of 428 patients, anastomotic leakage was observed in 120 (28.0 per cent) (50 asymptomatic, 70 symptomatic). After a mean follow-up of 40 months, local recurrence was observed in 36 patients (8.4 per cent). Multivariable Cox regression identified three independent risk factors for reduced local recurrence-free survival (LRFS): symptomatic anastomotic leakage (odds ratio (OR) 2.13, 95 per cent c.i. 1.29 to 3.50; P = 0.003), positive resection margin (R1) (OR 2.41, 1.40 to 4.16; P = 0.001) and pT3-4 category (OR 1.77, 1.08 to 2.90; P = 0.022). Patients with no risk factor for reduced LRFS had an estimated 5-year LRFS rate of 87.7(s.d. 3.2) per cent, whereas the rate dropped to 75.3(4.3) per cent with one risk factor, 67(7) per cent with two risk factors, and 14(13) per cent with three risk factors (P < 0.001). Asymptomatic anastomotic leakage was not significantly associated with LRFS in multivariable analysis. CONCLUSION: Symptomatic anastomotic leakage is a risk factor for disease recurrence in patients with rectal adenocarcinoma. PMID- 27762433 TI - A case of stroke-like migraine attacks after radiation therapy. PMID- 27762434 TI - Randomized open-label phase II study comparing oxycodone-naloxone with oxycodone in early return of gastrointestinal function after laparoscopic colorectal surgery. AB - BACKGROUND: Combined oral modified-release oxycodone-naloxone may reduce opioid induced postoperative gut dysfunction. This study examined the feasibility of a randomized trial of oxycodone-naloxone within the context of enhanced recovery for laparoscopic colorectal resection. METHODS: In a single-centre open-label phase II feasibility study, patients received analgesia based on either oxycodone naloxone or oxycodone. Primary endpoints were recruitment, retention and protocol compliance. Secondary endpoints included a composite endpoint of gut function (tolerance of solid food, low nausea/vomiting score, passage of flatus or faeces). RESULTS: Eighty-two patients were screened and 62 randomized (76 per cent); the attrition rate was 19 per cent (12 of 62), leaving 50 patients who received the allocated intervention with 100 per cent follow-up and retention (modified intention-to-treat cohort). Protocol compliance was more than 90 per cent. Return of gut function by day 3 was similar in the two groups: 13 (48 per cent) of 27 in the oxycodone-naloxone group and 15 (65 per cent) of 23 in the control group (95 per cent c.i. for difference -10.0 to 40.7 per cent; P = 0.264). However, patients in the oxycodone-naloxone group had a shorter time to first bowel movement (mean(s.d.) 87(38) h versus 111(37) h in the control group; 95 per cent c.i. for difference 2.3 to 45.4 h, P = 0.031) and reduced total (oral plus parenteral) opioid consumption (mean(s.d.) 78(36) versus 94(56) mg respectively; 95 per cent c.i. for difference -10.2 to 42.8 mg, P = 0.222). CONCLUSION: High participation, retention and protocol compliance confirmed feasibility. Potential benefits of oxycodone-naloxone in reducing time to bowel movement and total opioid consumption could be tested in a randomized trial. Registration number: NCT02109640 (https://www.clinicaltrials.gov/). PMID- 27762435 TI - ECSPECT prospective multicentre registry for single-port laparoscopic colorectal procedures. AB - BACKGROUND: The international multicentre registry ECSPECT (European Consensus of Single Port Expertise in Colorectal Treatment) was established to evaluate the general feasibility and safety of single-port colorectal surgery with regard to preoperative risk assessment. METHODS: Consecutive patients undergoing single port colorectal surgery were enrolled from 11 European centres between March 2010 and March 2014. Data were analysed to assess patient-, technique- and procedure dependent parameters. A validated sex-adjusted risk chart was developed for prediction of single-port colorectal surgery-related conversion and complications. RESULTS: Some 1769 patients were enrolled, 937 with benign and 832 with malignant conditions. Procedures were completed without additional trocars in 1628 patients (92.0 per cent). Conversion to open surgery was required in 75 patients (4.2 per cent) and was related to male sex and ASA fitness grade exceeding I. Conversions were more frequent in pelvic procedures involving the rectum compared with abdominal procedures (8.1 versus 3.2 per cent; odds ratio 2.69, P < 0.001). Postoperative complications were observed in a total of 224 patients (12.7 per cent). Independent predictors of complications included male sex (P < 0.001), higher ASA grade (P = 0.006) and rectal procedures (P = 0.002). The overall 30-day mortality rate was 0.5 per cent (8 of 1769 patients); three deaths (0.2 per cent; 1 blood loss, 2 leaks) were attributable to surgical causes. CONCLUSION: The feasibility and safety, conversion and complication profile demonstrated here provides guidance for patient selection. PMID- 27762436 TI - Network meta-analysis of protocol-driven care and laparoscopic surgery for colorectal cancer. AB - BACKGROUND: Laparoscopic approaches and standardized recovery protocols have reduced morbidity following colorectal cancer surgery. As the optimal regimen remains inconclusive, a network meta-analysis was undertaken of treatments for the development of postoperative complications and mortality. METHODS: MEDLINE, Embase, trial registries and related reviews were searched for randomized trials comparing laparoscopic and open surgery within protocol-driven or conventional perioperative care for colorectal cancer resection, with complications as a defined endpoint. Relative odds ratios (ORs) for postoperative complications and mortality were estimated for aggregated data. RESULTS: Forty trials reporting on 11 516 randomized patients were included with the network. Open surgery within conventional perioperative care was the index for comparison. The OR relating to complications was 0.77 (95 per cent c.i. 0.65 to 0.91) for laparoscopic surgery within conventional care, 0.69 (0.48 to 0.99) for open surgery within protocol driven care, and 0.43 (0.28 to 0.67) for laparoscopic surgery within protocol driven care. Sensitivity analyses excluding trials of low rectal cancer and those with a high risk of bias did not affect the treatment estimates. Meta-analyses demonstrated that mortality risk was unaffected by perioperative strategy. CONCLUSION: Laparoscopic surgery combined with protocol-driven care reduces colorectal cancer surgery complications, but not mortality. The reduction in complications with protocol-driven care is greater for open surgery than for laparoscopic approaches. Registration number: CRD42015017850 (https://www.crd.york.ac.uk/PROSPERO). PMID- 27762438 TI - The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. AB - Acute respiratory distress syndrome is associated with high mortality and morbidity. Inhaled nitric oxide has been used to improve oxygenation but its role remains controversial. Our primary objective in this systematic review was to examine the effects of inhaled nitric oxide administration on mortality in adults and children with acute respiratory distress syndrome. We included all randomised, controlled trials, irrespective of date of publication, blinding status, outcomes reported or language. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effect of inhaled nitric oxide. There was no statistically significant effect of inhaled nitric oxide on longest follow-up mortality (inhaled nitric oxide group 250/654 deaths (38.2%) vs. control group 221/589 deaths (37.5%; relative risk (95% CI) 1.04 (0.9-1.19)). We found a significant improvement in PaO2 /FI O2 ratio at 24 h (mean difference (95% CI) 15.91 (8.25-23.56)), but not at 48 h or 72 h, while four trials indicated improved oxygenation in the inhaled nitric oxide group at 96 h (mean difference (95% CI) 14.51 (3.64-25.38)). There were no statistically significant differences in ventilator-free days, duration of mechanical ventilation, resolution of multi-organ failure, quality of life, length of stay in intensive care unit or hospital, cost-benefit analysis and methaemoglobin and nitrogen dioxide levels. There was an increased risk of renal impairment (risk ratio (95% CI) 1.59 (1.17-2.16)) with inhaled nitric oxide. In conclusion, there is insufficient evidence to support inhaled nitric oxide in any category of critically ill patients with acute respiratory distress syndrome despite a transient improvement in oxygenation, since mortality is not reduced and it may induce renal impairment. PMID- 27762437 TI - Symptomatic and presumed symptomatic focal epilepsies in childhood: An observational, prospective multicentre study. AB - OBJECTIVE: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. METHODS: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: <=3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. RESULTS: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age <=3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. SIGNIFICANCE: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone. PMID- 27762439 TI - Identification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence. AB - BACKGROUND: Fetal akinesia deformation sequence (FADS) refers to a broad spectrum of disorder with the absent fetal movement as the unifying feature. The etiology of FADS is heterogeneous, and the majority remains unknown. Prenatal diagnosis of FADS because of neuromuscular origin has relied on clinical features and fetal muscle pathology, which can be unrevealing. The recent advance of next-generation sequencing (NGS) can provide definitive molecular diagnosis effectively. METHODS AND RESULTS: An 18-week-old fetus presented with akinesia and multiple contractures of joints. The mother had two previously aborted similarly affected fetuses. Clinical diagnosis of FADS was made. Molecular diagnosis using cord blood by NGS of genes related to neuromuscular diseases revealed two compound heterozygous mutations; c.602G > A(p.W201*) and c.1516A > C(p.T506P), in the Kelch-like 40 (KLHL40) gene. Based on this information, prenatal diagnosis was performed on the CVS of the subsequent pregnancy that resulted in an unaffected female baby, heterozygous for the c.1516A > C(p.T506P) mutation. CONCLUSION: Identification of KLHL40 mutations in one of the aborted fetuses provided a confirmative diagnosis of FADS, facilitating the prenatal diagnosis of the subsequent pregnancy. This report underscores the importance of target NGS in providing FADS families with an affordable, precise molecular diagnosis for genetic counseling and options of prenatal diagnosis. (c) 2016 John Wiley & Sons, Ltd. PMID- 27762440 TI - Group differences in the legitimization of inequality: Questioning the role of social dominance orientation. AB - Social dominance orientation (SDO) is conceived as an individual's level of support for group-based hierarchy in general that causes support for more specific group hierarchies. According to social dominance theory, group differences in SDO underpin ideological and behavioural group differences related to specific group hierarchies. Using representative 5-year longitudinal panel data from New Zealand (N = 3,384), we test whether SDO mediates effects of sex and ethnicity on legitimizing myths (LMs) relating to gender and ethnic hierarchy over time. The SDO mediation hypothesis is supported in the case of hostile sexism. However, it is unsupported in the case of benevolent sexism and LMs relating to ethnic hierarchy, where there was no cross-lagged effect of SDO. Moreover, being in the dominant ethnic group is associated with more legitimization of ethnic hierarchy but less legitimization of gender hierarchy, which is inconsistent with the notion of a general orientation underpinning group differences in legitimation. There was mixed evidence for a reverse path whereby specific LMs mediate group differences in SDO across time. We argue for the need to find alternative ways to theorize ideological consensus and difference between groups. PMID- 27762441 TI - Free fillet flap application to cover forequarter or traumatic amputation of an upper extremity: A case report. AB - Reusing tissue of amputated or unsalvageable limbs to reconstruct soft tissue defects is one aspect of the "spare parts concept." Using a free fillet flap in such situations enables the successful formation of a proximal stump with the length needed to cover a large defect from forequarter amputation without risking additional donor-site morbidity. The use of free fillet flaps for reconstruction after forequarter and traumatic upper extremity amputations is illustrated here in a case report. A 41-year old patient required a forequarter amputation to resect a desmoid tumor, resulting in an extensive soft-tissue defect of the upper extremity. A free fillet flap of the amputated arm and an additional local epaulette flap were used to reconstruct the defect. At 9 months after the procedure, a satisfactory result with a very well healed flap was attained. Free fillet flaps can be used successfully for reconstruction of large upper extremity defects, without risking additional donor-site morbidity. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:700-704, 2016. PMID- 27762443 TI - Efficient isolation of human parainfluenza viruses 1 and 3 using MNT-1, a human malignant melanoma cell line system that exhibits an apparent cytopathic effect. AB - Isolation of human parainfluenza virus (HPIV) serotypes 1 and 3 from clinical specimens is not very efficient because of the lack of a cell culture system capable of inducing CPE. In this study, the utility of a melanoma cell line, MNT 1, that allows HPIV growth and displays CPE was demonstrated. In particularly, the efficiency of isolating HPIV1 and HPIV3 using MNT-1 was greater than for cell lines conventionally used for HPIV isolation. Our demonstrated efficacy of HPIV1 and HPIV3 isolation with apparent CPE using the MNT-1 cell culture system has the potential to improve virus isolation from clinical specimens. PMID- 27762442 TI - Paediatric ocular and adnexal injuries requiring hospitalisation in Western Australia. AB - BACKGROUND: The aim was to investigate the characteristics and outcomes of ocular and adnexal injuries requiring hospitalisation in children in Perth, Western Australia. METHODS: This is a hospital-based retrospective review of children admitted to Princess Margaret Hospital for Children with diagnoses of ocular and/or adnexal trauma from 2002-2013. Hospital charts were reviewed for demographic information, injury and management details, follow-up and visual outcome. Final visual acuity was categorised into three groups: 6/12 or better, from 6/12 to 6/60, worse than 6/60. Ordinal logistic regression was used to compute odds ratios and predicted probabilities for each category of final visual outcome. RESULTS: Over the 12-year time period, 482 children were admitted with ocular or adnexal injuries - an average of 40 admissions per year. The mean age of the cohort was 7.1 years (range 0.09 to 16.47 years) with a male to female ratio of 2.6:1.0. There were 185 closed-globe injuries, 72 open-globe injuries and 293 adnexal injuries. Fourteen per cent of the cohort sustained a combined globe and adnexal injury. Children in the up to five-year age group were most susceptible to injury. Eighty-two per cent of the group had a final visual acuity of 6/12 or better. Factors associated with poor visual outcomes included younger age (p < 0.01), open-globe injury (p < 0.01) and lens injury (p < 0.01). CONCLUSIONS: Based on the outcomes of our review, paediatric ocular and adnexal trauma are significant causes for hospital attendance in childhood. Identifying associated risk factors will help develop injury prevention strategies to promote eye safety for children. PMID- 27762444 TI - A major locus involved in the formation of the radial oxygen loss barrier in adventitious roots of teosinte Zea nicaraguensis is located on the short-arm of chromosome 3. AB - A radial oxygen loss (ROL) barrier in roots of waterlogging-tolerant plants promotes oxygen movement via aerenchyma to the root tip, and impedes soil phytotoxin entry. The molecular mechanism and genetic regulation of ROL barrier formation are largely unknown. Zea nicaraguensis, a waterlogging-tolerant wild relative of maize (Zea mays ssp. mays), forms a tight ROL barrier in its roots when waterlogged. We used Z. nicaraguensis chromosome segment introgression lines (ILs) in maize (inbred line Mi29) to elucidate the chromosomal region involved in regulating root ROL barrier formation. A segment of the short-arm of chromosome 3 of Z. nicaraguensis conferred ROL barrier formation in the genetic background of maize. This chromosome segment also decreased apoplastic solute permeability across the hypodermis/exodermis. However, the IL and maize were similar for suberin staining in the hypodermis/exodermis at 40 mm and further behind the root tip. Z. nicaraguensis contained suberin in the hypodermis/exodermis at 20 mm and lignin at the epidermis. The IL with ROL barrier, however, did not contain lignin in the epidermis. Discovery of the Z. nicaraguensis chromosomal region responsible for root ROL barrier formation has improved knowledge of this trait and is an important step towards improvement of waterlogging tolerance in maize. PMID- 27762445 TI - Phylogeny of the jacchus group of Callithrix marmosets based on complete mitochondrial genomes. AB - OBJECTIVES: Two subgroups make up the marmoset genus Callithrix. The "aurita" group is composed of two species, whereas evolutionary relationships among the four species of the "jacchus" group remain unclear. To uncover these relationships, we first sequenced mitochondrial genomes for C. kuhlii and C. penicillata to complement data available for congeners. We then constructed a phylogenetic tree based on mtDNA heavy chain protein coding genes from several primates to untangle species relationships and estimate divergence times of the jacchus group. MATERIALS AND METHODS: MtDNA genomes of C. kuhlii and C. penicillata were Sanger sequenced. These Callithrix mitogenomes were combined with other publically available primate mtDNA genomes. Phylogenies were produced using maximum likelihood and Bayesian inference. Finally, divergence times within the jacchus group of marmosets were estimated with Bayesian inference. RESULTS: In our phylogenetic tree, C. geoffroyi was the sister to all other jacchus group species, followed by C. kuhlii, while C. jacchus and C. penicillata diverged most recently. Bayesian inference showed that C. jacchus and C. penicillata diverged approximately 0.70 MYA and that the jacchus group radiated approximately 1.30 MYA. DISCUSSION: Callithrix nuclear and mtDNA phylogenies frequently result in polytomies and paraphyly. Here, we present a well-supported phylogenetic tree based on mitochondrial genome sequences, which facilitates the understanding of the divergence of the jacchus marmosets. Our results demonstrate how mitochondrial genomes can enrich Callithrix phylogenetic studies by alleviating some of the difficulties faced by previous mtDNA studies and allow formulation of hypotheses to test further under larger genomic-scale analyses. PMID- 27762446 TI - The purple acid phosphatase GmPAP21 enhances internal phosphorus utilization and possibly plays a role in symbiosis with rhizobia in soybean. AB - Induction of secreted and intracellular purple acid phosphatases (PAPs; EC 3.1.3.2) is widely recognized as an adaptation of plants to phosphorus (P) deficiency. The secretion of PAPs plays important roles in P acquisition. However, little is known about the functions of intracellular PAP in plants and nodules. In this study, we identified a novel PAP gene GmPAP21 in soybean. Expression of GmPAP21 was induced by P limitation in nodules, roots and old leaves, and increased in roots with increasing duration of P starvation. Furthermore, the induction of GmPAP21 in nodules and roots was more intensive than in leaves in both P-efficient genotype HN89 and P-inefficient genotype HN112 in response to P starvation, and the relative expression in the leaves and nodules of HN89 was significantly greater than that of HN112 after P deficiency treatment. Further functional analyses showed that over-expressing GmPAP21 significantly enhanced both acid phosphatase activity and growth performance of hairy roots under P starvation condition, indicating that GmPAP21 plays an important role in P utilization. Moreover, GUS expression driven by GmPAP21 promoter was shown in the nodules besides roots. Overexpression of GmPAP21 in transgenic soybean significantly inhibited nodule growth, and thereby affected plant growth after inoculation with rhizobia. This suggests that GmPAP21 is also possibly involved in regulating P metabolism in nodules. Taken together, our results suggest that GmPAP21 is a novel plant PAP that functions in the adaptation of soybean to P starvation, possibly through its involvement in P recycling in plants and P metabolism in nodules. PMID- 27762447 TI - Emerging new tools to study and treat muscle pathologies: genetics and molecular mechanisms underlying skeletal muscle development, regeneration, and disease. AB - Skeletal muscle is the most abundant tissue in our body, is responsible for generating the force required for movement, and is also an important thermogenic organ. Skeletal muscle is an enigmatic tissue because while on the one hand, skeletal muscle regeneration after injury is arguably one of the best-studied stem cell-dependent regenerative processes, on the other hand, skeletal muscle is still subject to many degenerative disorders with few therapeutic options in the clinic. It is important to develop new regenerative medicine-based therapies for skeletal muscle. Future therapeutic strategies should take advantage of rapidly developing technologies enabling the differentiation of skeletal muscle from human pluripotent stem cells, along with precise genome editing, which will go hand in hand with a steady and focused approach to understanding underlying mechanisms of skeletal muscle development, regeneration, and disease. In this review, I focus on highlighting the recent advances that particularly have relied on developmental and molecular biology approaches to understanding muscle development and stem cell function. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27762449 TI - Visual and personal characteristics are associated with reading performance in normally sighted adults. AB - BACKGROUND: Visual acuity (VA) only slightly explains variability in reading performance, whereas other visual and non-visual parameters have been reported to influence reading performance; however, in ophthalmologic and optometric clinical practice and research, where standardised reading tests are used, many of these parameters are often neglected. The purpose of this study was to give insight into how various visual and non-visual parameters are associated with reading performance in normally sighted subjects. In addition, reading speed over time was investigated to observe the influence of prolonged reading on standardised test performance. METHODS: Reading speed and the number of mistakes were assessed with long text paragraphs obtained from the International Reading Speed Texts (IReST) and short sentences obtained from the Radner Reading Charts in 71 persons (mean age: 55 years, range: 18 to 86 years) with a binocular distance VA of logMAR 0.20 or better. For each of the variables (distance and near VA, contrast sensitivity, stray light, age, sex, educational level, habitual reading hours and reading affinity), the association with reading performance was investigated with multivariate linear regression models. Reading performance over time was assessed with linear mixed models. RESULTS: Contrast sensitivity was independently associated with reading speed (IReST paragraphs p = 0.002, Radner sentences p = 0.021). An interaction between age and education was found for both reading tests (p = 0.001), at an older age, reading speed was less influenced by educational level. Reading speed remained stable over time. CONCLUSION: The present study shows that contrast sensitivity was independently associated with reading speed and an interaction effect was found between age and education. As these tests are easy to administer, it is recommended to assess them in clinical practice and scientific research. When using standardised tests in healthy subjects, prolonged reading proved not to be an issue for reading durations up to about 23 minutes. PMID- 27762451 TI - Erratum. PMID- 27762452 TI - Trends in Hospitalization of Older Adults with Traumatic Brain Injury. PMID- 27762454 TI - Erratum. PMID- 27762455 TI - Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. AB - : Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-alpha (+/ corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational drugs: Recent data confirms midostaurin's significant anti-MC activity in patients with advanced SM. Am. J. Hematol. 91:1147-1159, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27762456 TI - Hovenia Dulcis Extract Reduces Lipid Accumulation in Oleic Acid-Induced Steatosis of Hep G2 Cells via Activation of AMPK and PPARalpha/CPT-1 Pathway and in Acute Hyperlipidemia Mouse Model. AB - Hovenia dulcis Thunb. (HDT) was known to have anti-fatigue, anti-diabetes, neuroprotective, and hepatoprotective effects. In the present study, the anti fatty liver mechanism of HDT was elucidated in oleic acid (OA)-treated Hep G2 cells and acute hyperlipidemia mouse model using Triton WR-1339. Here, HDT activated p-AMP-activated protein kinase (p-AMPK), proliferator activated receptor-alpha, carnitine palmitoyltransferase and also inhibited the expression of lipogenesis and cholesterol synthesis proteins, such as 3-hydroxy-3 methylglutaryl-CoA reductase, sterol regulatory element binding protein-1c, SREBP 2, and fatty acid synthase in OA-treated Hep G2 cells. Conversely, AMPK inhibitor compound C blocked the anti-fatty liver effect of HDT to induce AMPK phosphorylation and decrease 3-hydroxy-3-methylglutaryl-CoA reductase and lipid accumulation by oil red O staining in OA-treated Hep G2 cells. Additionally, HDT pretreatment protected against the increase of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol and phospholipid in an acute hyperlipidemia mouse model with enhancement of glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase activities. Taken together, HDT inhibits OA-induced hepatic lipid accumulation via activation of AMPK and proliferator activated receptor-alpha/carnitine palmitoyltransferase signaling and enhancement of antioxidant activity as a potent candidate for nonalcoholic fatty liver disease and hyperlipidemia. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27762457 TI - Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy. AB - OBJECTIVE: Hypertensive pregnant women who do not respond to treatment with labetalol to control blood pressure (BP), but require vasodilatory therapy, progress rapidly to severe hypertension. This could be delayed by early recognition and individualized treatment. In this study, we sought to create prediction models from data at presentation and at 1 h and 24 h after commencement of treatment to identify patients who will not have a sustained response to labetalol and therefore need vasodilatory therapy. METHODS: The study population comprised 134 women presenting with hypertension at a UK hospital. Treatment with oral labetalol was administered when BP was > 150/100 mmHg or > 140/90 mmHg with systemic disease. BP and hemodynamic parameters were recorded at presentation and at 1 h and 24 h after commencement of treatment. Labetalol doses were titrated to maintain BP around 135/85 mmHg. Women with unresponsive BP, despite labetalol dose maximization (2400 mg/day), received additional vasodilatory therapy with nifedipine. Binary logistic and longitudinal (mixed model) data analyses were performed to create prediction models anticipating the likelihood of hypertensive women needing vasodilatory therapy. The prediction models were created from data at presentation and at 1 h and 24 h after treatment, to assess the value of central hemodynamics relative to the predictive power of BP, heart rate and demographic variables at these intervals. RESULTS: Twenty-two percent of our cohort required additional vasodilatory therapy antenatally. These women had higher rates of severe hypertension and delivered smaller babies at earlier gestational ages. The unresponsive women were more likely to be of black ethnicity, had higher BP and peripheral vascular resistance (PVR), and lower heart rate and cardiac output (CO) at presentation. Those who needed vasodilatory therapy showed an initial decrease in BP and PVR, which rebounded at 24 h, whereas BP and PVR in those who responded to labetalol showed a sustained decrease at 1 h and 24 h. Stroke volume and CO did not decrease during the acute phase of treatment in either group. The best model for prediction of the need for vasodilators was provided at 24 h by combining ethnicity and longitudinal BP and heart rate changes. The model achieved a detection rate of 100% for a false-positive rate of 20% and an area under the receiver-operating characteristics curve of 0.97. CONCLUSION: Maternal demographics and hemodynamic changes in the acute phase of labetalol monotherapy provide a powerful tool to identify hypertensive pregnant patients who are unlikely to have their BP controlled by this therapy and will consequently need additional vasodilatory therapy. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. RESUMEN OBJETIVO: Las embarazadas hipertensas que no responden al tratamiento con labetalol para el control de la presion arterial (PA), pero que requieren terapia vasodilatadora, evolucionan rapidamente hacia una hipertension severa. Esta se puede retrasar mediante un diagnostico precoz y un tratamiento individual. En este estudio se ha tratado de crear modelos de prediccion a partir de datos al inicio del tratamiento y al cabo de 1 hora y de 24 horas despues del mismo, para identificar a las pacientes que no mostraran una respuesta constante al labetalol y que por lo tanto necesitaran terapia vasodilatadora. METODOS: La poblacion de estudio incluyo 134 mujeres con hipertension en un hospital del Reino Unido. El tratamiento con labetalol por via oral se administro cuando la PA fue >150/100 mm de Hg o >140/90 mm de Hg con enfermedad multisistemica. Se registro la PA y los parametros hemodinamicos tanto al inicio como al cabo de 1 h y de 24 h despues del inicio del tratamiento. Las dosis de Labetalol se ajustaron para mantener la PA en torno a los 135/85 mm de Hg. Las mujeres cuya PA no produjo respuesta, a pesar de haberles administrado la dosis maxima de labetalol (2400 mg/dia), recibieron terapia vasodilatadora adicional con nifedipino. Se realizaron analisis de datos mediante logistica binaria y longitudinal (modelo mixto), para crear modelos de prediccion con los que pronosticar la probabilidad de la necesidad de terapia vasodilatadora en mujeres hipertensas. Los modelos de prediccion se crearon a partir de datos al inicio y al cabo de 1 hora y 24 horas del tratamiento, para evaluar el valor de los parametros hemodinamicos principales con respecto a la capacidad predictiva de la PA, la frecuencia cardiaca y las variables demograficas en estos intervalos. RESULTADOS: El 22 % de la cohorte necesito terapia vasodilatadora adicional antes del parto. Estas mujeres tuvieron tasas mas altas de hipertension grave y neonatos mas pequenos en edades gestacionales mas tempranas. Las mujeres que no respondieron al tratamiento fueron con mas frecuencia de raza negra, tuvieron la PA y la resistencia vascular periferica (RVP) mas alta, y la frecuencia cardiaca y el gasto cardiaco (GC) mas bajos al inicio del tratamiento. Aquellas que necesitaron terapia vasodilatadora mostraron un descenso inicial de la PA y la RVP, que se recupero al cabo de 24 h, mientras que la PA y la RVP en las que respondieron al labetalol mostraron una disminucion constante al cabo de 1 h y de 24 h. El volumen sistolico y el GC no disminuyeron durante la fase aguda del tratamiento en ninguno de los grupos. El mejor modelo para la prediccion de la necesidad de vasodilatadores se obtuvo a las 24 h mediante la combinacion de la etnia con los cambios longitudinales de la PA y la frecuencia cardiaca. El modelo alcanzo una tasa de deteccion del 100% para una tasa de falsos positivos del 20% y un area bajo la curva de caracteristicas operativas del receptor de 0,97. CONCLUSION: Los datos demograficos maternos y los cambios hemodinamicos en la fase aguda de la monoterapia con labetalol constituyen una herramienta poderosa para identificar a las pacientes embarazadas hipertensas con pocas probabilidades de que se les pueda controlar su PA mediante esta terapia y que por lo tanto necesitaran terapia vasodilatadora adicional. : ,(blood pressure,BP),??,1 h24 h,? : 134?BP>150/100 mmHgBP>140/90 mmHg?1 h24 hBP?,BP135/85 mmHg?BP,()?logistic(),?1 h24 h,,BP,? : 22%??,BP(peripheral vascular resistance,PVR),(cardiac output,CO)?BPPVR,24 h,1 h24 hBPPVR?CO?24hBP?100%,20%,0.97? : ,BP?. PMID- 27762458 TI - Role of Medicinal Plants for Liver-Qi Regulation Adjuvant Therapy in Post-stroke Depression: A Systematic Review of Literature. AB - Current evidence demonstrated certain beneficial effects of medicinal herbs as an adjuvant therapy for post-stroke depression (PSD) in China; Chai-hu (Chinese Thorowax Root, Radix Bupleuri) is an example of a medicinal plant for Liver-Qi regulation (MPLR) in the treatment of PSD. Despite several narrative reports on the antidepressant properties of MPLR, it appears that there are no systematic reviews to summarize its outcome effects. Therefore, the aim of this review was to assess the effectiveness and safety of MPLR adjuvant therapy in patients with PSD. Seven databases were extensively searched from January 2000 until July 2016. Randomized control trials (RCTs) involving patients with PSD that compared treatment with and without MPLR were taken into account. The pooled effect estimates were calculated based on Cochrane Collaboration's software RevMan 5.3. Finally, 42 eligible studies with 3612 participants were included. Overall, MPLR adjuvant therapy showed a significantly higher effective rate (RR = 1.23; 95% CI = 1.19, 1.27; p < 0.00001) compared to those without. Moreover, the administration of MPLR was superior to abstainers regarding Hamilton Depression Scale (HAMD) score changes after 3 weeks (WMD = -4.83; 95% CI = -6.82, -2.83; p < 0.00001), 4 weeks (WMD = -3.25; 95% CI = -4.10, -2.40; p < 0.00001), 6 weeks (WMD = -4.04; 95% CI = -5.24, -2.84; p < 0.00001), 8 weeks (WMD = -4.72; 95% CI = 5.57, -3.87; p < 0.00001), and 12 weeks (WMD = -3.07; 95% CI = -4.05, -2.09; p < 0.00001). In addition, there were additive benefits in terms of response changes for the National Institutes of Health Stroke Scale (NIHSS) and other self-rating scores. No frequently occurring or serious adverse events were reported. We concluded that there is supporting evidence that adjuvant therapy with MPLR is effective in reducing the depressive symptoms and enhancing quality of life for patients with PSD. More well-designed RCTs are necessary to explore the role of MPLR in the treatment of PSD. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27762459 TI - The Effect of Moisture on the Hydrolysis of Basic Salts. AB - A great deal of information exists concerning the hydration of ions in bulk water. Much less noticeable, but equally ubiquitous is the hydration of ions holding on to several water molecules in nanoscopic pores or in natural air at low relative humidity. Such hydration of ions with a high ratio of ions to water molecules (up to 1:1) are essential in determining the energetics of many physical and chemical systems. Herein, we present a quantitative analysis of the energetics of ion hydration in nanopores based on molecular modeling of a series of basic salts associated with different numbers of water molecules. The results show that the degree of hydrolysis of basic salts in the presence of a few water molecules is significantly different from that in bulk water. The reduced availability of water molecules promotes the hydrolysis of divalent and trivalent basic ions (S2- , CO32- , SO32- , HPO42- , SO42- , PO43- ), which produces lower valent ions (HS- , HCO3- , HSO3- , H2 PO4- , HSO4- , HPO42- ) and OH- ions. However, reducing the availability of water inhibits the hydrolysis of monovalent basic ions (CN- , HS- ). This finding sheds some light on a vast number of chemical processes in the atmosphere and on solid porous surfaces. The discovery has wide potential applications including designing efficient absorbents for acidic gases. PMID- 27762460 TI - Cobalt-Catalyzed Reductive Cross-Coupling Between Styryl and Benzyl Halides. AB - A simple and efficient protocol for the direct reductive cross-coupling between alkenyl and benzyl halides using a Co/Mn system has been developed. This reaction proceeds smoothly in the presence of [CoBr2 (PPh3 )2 ] as the catalyst, with NaI as an additive in acetonitrile with a broad scope of functionalized alkenyl and benzyl halides. Different functional groups are tolerated on both coupling partners, thus, significantly extending the general scope of transition-metal catalyzed benzylation of alkenyl halides. Moderate to excellent yields were also obtained. From a mechanistic point of view, a radical chain mechanism was proposed. This reaction is stereospecific and some studies suggest the retention of the double-bond configuration. PMID- 27762461 TI - Restoration of autophagy by puerarin in lead-exposed primary rat proximal tubular cells via regulating AMPK-mTOR signaling. AB - Previous study has demonstrated that puerarin (PU) exerts nephroprotective effect against Pb-induced cytotoxicity in primary rat proximal tubular (rPT) cells. Autophagy can protect cells from various cytotoxic stimuli, but its role in the process of PU against Pb-induced nephrotoxicity is still unknown. This study aims to investigate whether PU can alleviate Pb-induced renal damage by recovering autophagy. Data showed that Pb inhibited the autophagic flux, as evidenced by the accumulation of LC3-II and p62 as well as the confocal microscopy analysis of GFP LC3 puncta and punctate spots of monodansylcadaverine staining, whereas coadministration of PU could restore Pb-induced autophagy inhibition. Moreover, PU dramatically enhanced the phosphorylation of 5'AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its target proteins p70S6 kinase (p70S6K) and 4E-binding protein 1 (4E-BP1) in Pb-exposed rPT cells. Collectively, these evidence suggested that PU restored the impaired autophagic flux in Pb-treated rPT cells partly by activating autophagy via AMPK/mTOR-mediated signaling pathway. PMID- 27762462 TI - The binding properties of metandienone and human serum albumin by comparing with other five similar compounds. AB - Metandienone (MET) is an exogenous anabolic androgenic steroid. The interaction between MET and human serum albumin (HSA) was investigated by molecular modeling and different optical techniques. There was no possibility of energy transfer, and the fluorescence quenching of HSA induced by MET was mainly due to the complex formation. The differences of binding ability between MET and compounds 1 5 were significantly caused by space steric hindrance. The single crystallographic data of two steroids (compounds 4 and 5) were obtained in the methanol at the first time. In addition, the binding ability was slightly affected by -OH, -CH3 , and -COCH3 . The results of displacement experiment demonstrated that the MET binding site was mainly located in site 1 of HSA. H bonding and van der Waals forces were significant in the MET-HSA binding. MET played an insignificant role on the local conformation change in HSA. PMID- 27762463 TI - Differential expression of thioredoxin binding protein-2/Txnip in human placenta: Possible involvement of hypoxia in its suppression during early pregnancy. AB - AIM: Thioredoxin binding protein-2 (TBP-2), which is identical to thioredoxin interacting protein (Txnip), controls cellular proliferation and differentiation. The aim of the present study was to compare TBP-2 protein and mRNA expression in human placenta during the three trimesters of pregnancy and to investigate the role of hypoxia in the change of these expressions in placental tissue. A secondary objective was to determine the gene expression of peroxisome proliferator-activated receptors (PPARs) in TBP-2 deficient placenta using TBP-2 gene disrupted mice (TBP-2-/- ). METHODS: Protein and mRNA expression of TBP-2 in human placenta from each trimester were analyzed by immunohistochemistry, Western blots, and by quantitative reverse-transcriptase-polymerase chain reaction. The effect of hypoxia on TBP-2 expression was tested using an explant culture of human placenta. In TBP-2-/- mouse placenta, we detected PPAR mRNA expression. RESULTS: TBP-2 was located in syncytiotrophoblasts and cytotrophoblasts, and also in the endothelium in human placenta. Its expression in the placenta was low in the first trimester, and increased in the second and third trimesters. Hypoxia decreased TBP-2 mRNA and protein expression in human placental explant culture. In TBP-2-/- mice, placental mRNA levels of PPARalpha and gamma were significantly suppressed compared with those in wild-type mice. CONCLUSION: Hypoxia suppresses TBP-2 gene expression, which may ultimately alter placental development. PMID- 27762464 TI - Enzymatic Degradation of Oligo(epsilon-caprolactone)s End-Capped with Phenylboronic Acid Derivatives at the Air-Water Interface. AB - The influence of terminal functionalization of oligo(epsilon-caprolactone)s (OCL) with phenylboronic acid pinacol ester or phenylboronic acid on the enzymatic degradation behavior at the air-water interface is investigated by the Langmuir monolayer degradation technique. While the unsubstituted OCL immediately degrades after injection of the enzyme lipase from Pseudomonas cepacia, enzyme molecules are incorporated into the films based on end-capped OCL before degradation. This incorporation of enzymes does not inhibit or suppress the film degradation, but retards it significantly. A specific binding of lipase to the polymer monolayer allows studying the enzymatic activity of bound proteins and the influence on the degradation process. The functionalization of a macromolecule with phenyl boronic acid groups is an approach to investigate their interactions with diol-containing biomolecules like sugars and to monitor their specified impact on the enzymatic degradation behavior at the air-water interface. PMID- 27762465 TI - Ultrasound sclerotherapy pretreatment could obtain a similar effect to surgical intervention on improving the outcomes of in vitro fertilization for patients with hydrosalpinx. AB - AIM: The aim of this study was to compare the clinical outcomes of in vitro fertilization (IVF) for patients with hydrosalpinx between ultrasound sclerotherapy and surgical intervention. METHODS: The data of 482 IVF/intracytoplasmic sperm injection (ICSI) cycles were divided into three groups according to different intervention protocols before IVF/ICSI. Group A included 265 cycles in which ultrasound sclerotherapy pretreatment was carried out before controlled ovarian hyperstimulation. Group B included 109 cycles in which hydrosalpinx aspiration was carried out under ultrasound guidance on the day of oocyte retrieval. Croup C included 108 cycles in which bilateral salpingectomy was carried out before IVF/ICSI. RESULTS: The rates of embryo implantation, biochemical pregnancy, clinical pregnancy, multiple pregnancy, and early abortion showed no significant differences between groups A and C (P > 0.05); whereas the rates of embryo implantation, biochemical pregnancy, and clinical pregnancy in group B were significantly lower than those in groups A and C (P < 0.05), and that of early abortion in group B was significantly higher than that in groups A and C (P < 0.05). CONCLUSION: Ultrasound sclerotherapy on patients with hydrosalpinx before IVF-embryo transfer could obtain a similar clinical outcome to surgical intervention. PMID- 27762466 TI - Hepatoprotective role of vardenafil against experimentally induced hepatitis in mice. AB - Vardenafil is a selective phosphodiesterase-5 inhibitor used for erectile dysfunction treatment. The hepatoprotective role of vardenafil against acute hepatitis is not reported yet. Hence, this study aims to explore the protective role of vardenafil against concanavalin A (Con A) induced acute liver injury. Mice were pretreated with vardenafil (0.17 mg/kg/day) for seven consecutive days, and then subjected to a single IV injection of Con A. The results demonstrated that the vardenafil pretreatment significantly reduced the elevated serum levels of transaminases and alkaline phosphatase. Histopathological examination showed marked necrosis and inflammation in Con A-treated mice which was significantly ameliorated in vardenafil pretreated animals. Vardenafil pretreatment significantly alleviated the expression of nuclear factor kappa-B and inducible nitric oxide synthase in the hepatic tissue. Additionally, serum levels of nitric oxide and tumor necrosis factor-alpha were decreased in vardenafil pretreated animals compared to the Con A group. Therefore, our results demonstrate that vardenafil has hepatoprotective effect and this could be linked to decrease inflammatory mediators. PMID- 27762467 TI - Immunoglobulin M indirect-fluorescent antibody test for the diagnosis of acute toxoplasmosis during pregnancy in the avidity era: A 14-year experience at the Tuscany Reference Center for Infectious Diseases in Pregnancy, Florence, Italy. AB - AIM: The aim of this study was to evaluate immunoglobulin M indirect-fluorescent antibody test (IgM IFAT) for the diagnosis of acute or chronic Toxoplasma infection in pregnancy. METHODS: Pregnant women with suspected acute toxoplasmosis referred to the Tuscany Reference Center for Infectious Diseases in Pregnancy during the period 1998-2012 were retrospectively enrolled. All women were tested with a panel of serological tests, including enzyme-linked immunosorbent assay for IgG avidity and IgM IFAT. On the basis of anamnestic, clinical, and serological criteria, pregnant women were classified into three groups: recently infected (RI), latently infected (LI), and doubtful latently infected (DLI). Patients classified as DLI were excluded from the analysis. The association between IgM IFAT (positive or negative) and the diagnosis of infection (acute or chronic) was assessed. Positive predictive value and negative predictive value of the IgM IFAT were calculated. RESULTS: A total of 810 pregnant women were enrolled in the study: 302 in the RI group and 508 in the LI group. Fifty-two women classified as DLI were excluded. IgM IFAT was positive in 172 out of 302 (56.9%) pregnant women in the RI group and in 29 out of 508 (5.7%) in the LI group. The positive predictive value and negative predictive value of IgM IFAT in predicting RI was 85.6% and 78.6%, respectively. CONCLUSION: IgM IFAT has reasonable sensitivity and specificity in diagnosing recent infection and, mostly in case of borderline avidity test, could be considered as a further aid for an accurate diagnosis of acute toxoplasmosis in pregnancy. PMID- 27762468 TI - Thrombelastography coagulation index may be a predictor of venous thromboembolism in gynecological oncology patients. AB - AIM: Venous thromboembolism (VTE) is a well-recognized complication in gynecological oncology patients, and has an impact on the overall outcome. The purpose of this study was to identify whether thrombelastography (TEG) predicts VTE in gynecological oncology patients. METHODS: This retrospective study included patients with gynecological oncology who were hospitalized at the Fujian Provincial Cancer Hospital from May 2014 to April 2016. Univariate and logistic regression multivariate analyses were performed to determine the clinical and laboratorial factors for VTE in gynecological oncology patients. The sensitivity and specificity of predictors was calculated using receiver operating characteristic curve. RESULTS: The study included 376 patients; 39 (10.37%) developed VTE. Logistic regression multivariate analysis revealed that TEG coagulation index (CI) value, D-dimer, arrhythmia, coronary heart disease, surgery within four weeks and chemotherapy within four weeks were independent risk factors for VTE. The area under the curve values were 0.71 (95% confidence interval 0.63-0.79, P = 0.000) for TEG CI and 0.67 (95% confidence interval 0.58 0.76, P = 0.000) for D-Dimer. The TEG CI cut-off value was 2.55, which had 53.8% sensitivity and 75.4% specificity for VTE. CONCLUSIONS: These results indicated that the TEG CI value may be predictive of VTE in gynecological oncology patients. PMID- 27762469 TI - Medical emergency team may reduce obstetric intensive care unit admissions. AB - AIM: Some recent studies have reported that early intervention by a medical emergency team (MET) for clinical deterioration before intensive care unit (ICU) admission was associated with a survival benefit in critically ill cancer patients. We hypothesized that early MET intervention for an obstetric crisis in the general wards would be related to favorable outcomes in critically ill obstetric patients. METHODS: Data of obstetric patients who were managed by a MET were collected retrospectively from 1 March 2008 to 30 April 2015. A total of 69 obstetric patients were enrolled. Among them, 48 (69.6%) were treated successfully in the general wards and 21 (30.4%) were transferred to the ICU. RESULTS: Major causes of MET activation were pulmonary edema (n = 23, 33.3%), hypovolemic shock (n = 19, 27.5%), and septic shock (n = 8, 11.6%). Compared with the patients treated in the general ward, the patients transferred to the ICU had significantly higher severity of illness score. Sequential Organ Failure Assessment score was the most useful for prediction of ICU admission of obstetric patients (AUC, 0.810, P < 0.001), and the ideal cut-off was 4 (sensitivity, 81%; specificity, 60%). During the study period, in-hospital mortality of the obstetric patients was 2.9% (2/69). CONCLUSION: After MET activation many obstetric patients could be successfully treated in the general wards without mortality. Therefore, MET may reduce ICU admissions in critically ill obstetric patients. PMID- 27762448 TI - Cost-effectiveness of emergency versus delayed laparoscopic cholecystectomy for acute gallbladder pathology. AB - BACKGROUND: The optimal timing of cholecystectomy for patients admitted with acute gallbladder pathology is unclear. Some studies have shown that emergency cholecystectomy during the index admission can reduce length of hospital stay with similar rates of conversion to open surgery, complications and mortality compared with a 'delayed' operation following discharge. Others have reported that cholecystectomy during the index acute admission results in higher morbidity, extended length of stay and increased costs. This study examined the cost-effectiveness of emergency versus delayed cholecystectomy for acute benign gallbladder disease. METHODS: Using data from a prospective population-based cohort study examining the outcomes of cholecystectomy in the UK and Ireland, a model-based cost-utility analysis was conducted from the perspective of the UK National Health Service, with a 1-year time horizon for costs and outcomes. Probabilistic sensitivity analysis was used to investigate the impact of parameter uncertainty on the results obtained from the model. RESULTS: Emergency cholecystectomy was found to be less costly (L4570 versus L4720; ?5484 versus ?5664) and more effective (0.8868 versus 0.8662 QALYs) than delayed cholecystectomy. Probabilistic sensitivity analysis showed that the emergency strategy is more than 60 per cent likely to be cost-effective across willingness to-pay values for the QALY from L0 to L100 000 (?0-120 000). CONCLUSION: Emergency cholecystectomy is less costly and more effective than delayed cholecystectomy. This approach is likely to be beneficial to patients in terms of improved health outcomes and to the healthcare provider owing to the reduced costs. PMID- 27762471 TI - Impact of human papilloma virus vaccination on adolescent knowledge, perception of sexual risk and need for safer sexual behaviors in Bali, Indonesia. AB - AIM: To determine the impact of human papilloma virus (HPV) vaccination on knowledge, perception of sexual risk and need for continued safe sexual behavior among Indonesian girls. METHODS: A comparative cross-sectional study was carried on in Denpasar, the capital city of Bali, Indonesia, during September 2015 February 2016. A total of 828 adolescent girls (12-16 years) were recruited to assess their knowledge on HPV/HPV vaccine, perception of sexual risks and need for continued safe sexual behavior. RESULTS: A total of 419 girls (50.7%) had received HPV vaccination prior to the study, 76.4% of whom (320/419) had sufficient knowledge about HPV. HPV vaccination was a strong and independent predictor of higher HPV/HPV vaccine knowledge (adjusted OR [AOR], 9.358; 95%CI: 6.816-12.849, P < 0.001). HPV vaccination (AOR, 0.107; 95%CI: 0.074-0.155, P < 0.001) and higher knowledge level (AOR, 0.667; 95%CI: 0.464-0.958, P = 0.028) were associated with lower perceived HPV risk. Despite the low risk perception, most of the vaccinated girls (408/419, 97.4%) continued to perceive higher need for safe sexual behaviors. On multivariate analysis, higher knowledge was the independent predictor for higher perceived need for safe sexual behaviors (AOR, 4.260; 95%CI: 2.016-9.001, P < 0.001). CONCLUSION: The HPV vaccination was associated with higher knowledge and appropriately lower perception of HPV risk. Despite the vaccination, most of the adolescents continued to perceive a need for safer sexual behavior. All adolescent girls should receive HPV vaccination in order to reduce cervical cancer burden in the future. PMID- 27762470 TI - Association of urodynamics and lower urogenital tract nerve growth factor after synthetic vaginal mesh implantation on a rat model. AB - AIM: By investigating the association of urodynamics and urogenital nerve growth factor (NGF) levels in vaginal mesh surgery, we may be able to associate the likelihood of postoperative lower urinary tract symptoms developing as a result of synthetic mesh implanted for pelvic floor reconstructive surgery. METHODS: Thirty-eight female Sprague-Dawley rats were divided into three groups: mesh, sham (no mesh), and control. Urodynamic study and NGF analysis of the urogenital tissues were done and results were compared among all groups. The urodynamic studies of the mesh and sham groups were further divided into the 4th and 10th days. A P-value < 0.05 was considered statistically significant. RESULTS: All rats survived and no complications were observed during the post-implantation period. Histological evaluation showed intense acute inflammatory reaction on days 4 and 7 in the mesh and sham groups when compared to the control. The mesh group showed a larger area of inflammation as compared to the sham. The NGF levels increased significantly in the mesh and sham groups on the 4th and 10th days when compared to the control (P < 0.001, P < 0.001, respectively). Both the mesh and sham groups had shorter voiding interval and lower voiding volume on days 4 and 10 when compared to the control group (P < 0.001, P < 0.001, respectively). The magnitude on increasing NGF level and decreasing voiding interval and voiding volume was significantly more on the mesh group than the sham group. CONCLUSION: A higher level of NGF in the early days post-transvaginal mesh implantation is associated with a shorter voiding interval and a smaller bladder capacity, which represents abnormal lower urinary tract symptoms following transvaginal mesh implantation. PMID- 27762472 TI - Treatment of total pelvic organ prolapse using a whole biological patch: A pilot study of 17 patients. AB - AIM: A complete and non-splice porcine small-intestine submucosa (SIS) patch was used for total pelvic anatomical repair of organ prolapse. METHODS: This study included a total of 17 patients with severe total pelvic organ prolapse, including five patients with combined stress urinary incontinence (SUI). Panhysterectomy was performed, and then a porcine SIS patch was placed on the anterior (posterior) vaginal wall. The top of the vaginal wall was moved to the corresponding side of the vaginal wall, and the patch was sutured to bilateral uterosacral ligaments, the sacrospinous ligament, and arcus tendineus fasciae pelvis. SUI was addressed at the same time. 'Failure' was defined as anterior or posterior wall prolapse beyond the hymen. RESULTS: The mean follow-up duration was 11.6 +/- 7.45 months (2-24 months). No symptom recurrence was observed in the five patients with combined SUI. One patient who underwent porcine SIS patch placement on the posterior wall experienced stage II anterior vaginal wall prolapse after surgery. The vaginal wall and fornix of the remaining patients with patches were restored to stable anatomical positions (92.85%). No organ damage, infection, erosion, or rejection was observed, and no blood transfusion was necessary. CONCLUSION: This study is the first to implement total pelvic anatomical repair using a complete and non-splice SIS. Our results suggest that this new surgical method is safe and can achieve satisfactory therapeutic effects, especially for patients with combined SUI. PMID- 27762473 TI - Oxidative damage of the male reproductive system induced by paraquat. AB - The effects of paraquat (PQ) on the male reproductive system are unclear. In this study, male rats were divided into four groups (0, 0.5, 2, and 8 mg/kg) and treated with PQ by oral gavage for 8 weeks. At the end of the experiment, a significant decline in sperm count, motility, and viability and an increase in teratospermia were observed in the PQ-treated group (P < 0.05). Further investigation found that PQ resulted in enhanced lipid peroxidation and more apoptosis in the testis tissues, and apoptosis was likely to be associated with activation of the mitochondrial pathway. In summary, our study demonstrated oxidative damage due to PQ on the male reproductive system. PMID- 27762475 TI - Enlarged uterine corpus volume in women with endometriosis: Assessment using three-dimensional reconstruction of pelvic magnetic resonance images. AB - AIM: To assess and compare the uterine volume and endometrium length between women with and without endometriosis, using pelvic magnetic resonance imaging scans. METHODS: In this case-control study, a total of 75 nulligravid women (aged 20-45 years) with regular menstrual cycles whose uterus were free of any surgically confirmed lesions were enrolled. The endometriosis group underwent surgery for endometrioma (n = 39), and the control group underwent surgery for non-endometrioma ovarian cysts (n = 36). The primary outcome was uterine corpus volume, which was assessed using three-dimensional reconstructions of preoperative pelvic magnetic resonance imaging scans. RESULTS: The mean uterine volume was significantly larger in the endometriosis group than in the control group (mean +/- standard deviation, 50.9 +/- 14.4 cm3 vs 41.7 +/- 14.3 cm3 ; P < 0.01). The longitudinal length and transverse diameter of the corpus and the longitudinal length of the endometrium were also significantly greater in the endometriosis group (all, P < 0.01). CONCLUSIONS: An increase in uterine volume and endometrium length was observed in women with endometriosis. PMID- 27762474 TI - Accuracy of Voltage Signal Measurement During Radiofrequency Delivery Through the SMARTTOUCH Catheter. AB - INTRODUCTION: Current methods for measuring voltage during radiofrequency (RF) ablation (RFA) necessitate turning off the ablation catheter. If voltage could be accurately read without signal attenuation during RFA, turning off the catheter would be unnecessary, allowing continuous ablation. We evaluated the accuracy of the Thermocool SMARTTOUCH catheter for measuring voltage while RF traverses the catheter. METHODS AND RESULTS: We studied 26 patients undergoing RFA for arrhythmias. A 7.5F SMARTTOUCH catheter was used for sensing voltage and performing RFA. Data were collected from the Carto-3 3-dimensional mapping system. Voltages were measured during ablation (RF-ON) and immediately before or after ablation (RF-OFF). In evaluating the accuracy of RF-ON measurements, we utilized the RF-OFF measure as the gold standard. We measured 465 voltage signals. The median values were 0.2900 and 0.3100 for RF-ON and RF-OFF, respectively. Wilcoxon signed rank testing showed no significant difference in these values (P = 0.608). The intraclass correlation coefficient (ICC) was 0.96, indicating that voltage measurements were similarly accurate during RF-OFF versus RF-ON. Five patients had baseline atrial fibrillation (AF), for whom 82 ablation points were measured; 383 additional ablation points were measured for the remaining patients. The voltages measured during RF-ON versus RF-OFF were similar in the presence of AF (P = 0.800) versus non-AF rhythm (P = 0.456) (ICC, 0.96 for both). CONCLUSION: Voltage signal measurement was similarly accurate during RF-ON versus RF-OFF independent of baseline rhythm. Physicians should consider not turning off the SMARTTOUCH ablation catheter when measuring voltage during RFA. PMID- 27762476 TI - Normogram of umbilical artery Doppler indices in singleton pregnancies in south western Nigerian women. AB - AIM: To determine the Doppler indices of the umbilical arteries in normal singleton pregnancy with a view to generating local reference ranges. METHODS: In this prospective, cross-sectional study, 400 pregnant women at 15-39 weeks' gestational age, with estimated fetal weight within the 10th and 90th percentile, no fetal malformation(s), and without any history of maternal medical disease, were recruited. Umbilical arteries were assessed on ultrasound, with the subjects in the supine position. Resistivity index (RI), pulsatility index (PI) and systolic/diastolic (S/D) ratio were recorded and analyzed. RESULTS: All the umbilical arteries were paired; no single umbilical artery was seen. Mean RI, PI, and S/D ratio declined with gestational age, and decreased from 1.265 to 0.829, from 0.760 to 0.585 and from 4.068 to 2.365, respectively, from 15 to 39 weeks of gestation. With regard to correlation between gestational age and Doppler indices, r = - 0.598 for PI (P < 0.05), - 0.437 for RI (P < 0.05), and - 0.538 for S/D ratio (P < 0.05). Decline in the Doppler indices was progressive with gestational age. CONCLUSION: A normogram of umbilical artery Doppler indices was constructed, which showed that the indices decreased with gestational age. These normative data could serve as reference ranges for evaluation of the umbilical artery circulation in this locality. PMID- 27762477 TI - Effects of Ginsenoside Rg1 on Learning and Memory in a Reward-directed Instrumental Conditioning Task in Chronic Restraint Stressed Rats. AB - Ginsenoside Rg1 is one of the major active ingredients of Panax ginseng and has showed notable improving learning and memory effects in several behavioral tasks, such as water maze, shuttle-box, and step-through, based on avoidance. However, there was no report about the role of Rg1 on the performance of reward-directed instrumental conditioning, which could reflect the adaptive capacity to ever changing environments. Thus, in this study, the reward devaluation test and conditional visual discrimination task were conducted to study the ameliorating effects of Rg1 on cognitive deficits, especially the loss of adaptation capacity in chronic restraint stress (CRS) rat model. Our results showed that rat subjected to CRS became insensitive to the changes in outcome value, and it significantly harmed the rat's performance in conditional visual discrimination task. Moreover, the levels of BDNF, TrkB, and Erk phosphorylation were decreased in the prefrontal cortex of CRS rats. However, these changes were effectively reversed by Rg1 (5 and 10 mg/kg, i.p.). Therefore, it demonstrated that Rg1 has a good ability to improve learning and memory and also ameliorate impaired adaptive capacity induced by CRS. This amelioration effect of Rg1 might be mediated partially by BDNF/TrkB/Erk pathway in prefrontal cortex. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27762478 TI - BK polyomavirus infection in pediatric heart transplant recipients: a prospective study. AB - BKV infection and nephropathy complicate pediatric HTx, but the incidence and time course of the disease are unknown. We assessed the incidence of BKV infection and its association with kidney dysfunction in pediatric HTx recipients. A single center prospective study compared pediatric (<18 years) HTx recipients, with and without BKV infection, who received an allograft between September 2013 and December 2014. Screening of urine for BKV was performed prior to transplant, and at week 1, and at months 3, 6, 9, 12, and 15 months post transplantation. Serum for BKV DNA was assayed if BK viruria was present. Statistics included Fisher's exact test and Student's t test. Twelve patients were enrolled. Two patients were removed per parent request. Two (20%) had BK viruria and one (10%) had BK viremia. No patients developed BKVN. BK viruria was present within 2 months following transplantation. There were no identifiable risk factors for BKV infection and no statistically significant difference in renal function between the groups; however, there was a trend toward worsening renal function in those with BKV infection. BKV infection can occur early following heart transplantation. Screening for BK viruria should be considered in HTx recipients. PMID- 27762480 TI - Variation in resource utilization in liver transplantation at freestanding children's hospitals. AB - We sought to examine the relationship between liver transplant-related total cost, patient outcome, and hospital resource utilization at freestanding children's hospitals. Using the PHIS database, a retrospective study of 374 patients that underwent liver transplantation at 15 freestanding children's hospitals from July 2010 to December 2012 was performed. One-year graft failure and patient mortality rates from July 2010 to December 2012 for each center were also obtained from the SRTR. There was a 5.1-fold difference in median cost (median $146 444, range $59 487-302 058, P<.001) between all centers. A 2.4-fold difference existed in median LOS (median 15 days, range 9-22 days, P<.001) across centers. Median postoperative ICU stay varied from 0 to 7 days (median 4 days, P<.001). Overall, 30-day readmission rate was 55% (31.3%-100%, P<.001). One-year graft failure varied from 0% to 19.1%, with an overall rate of 5.5% (P=.279). One year patient mortality for all centers was 2.3% (range 0%-11.1%, P=.016). Higher total cost did not correlate with lower readmission rates, patient mortality, graft failure, or any other variable. These data suggest that identifying practice patterns at low-cost centers and implementing them at higher-cost centers may decrease the cost of pediatric liver transplantation without compromising outcomes. PMID- 27762479 TI - Transition to adult care for pediatric liver transplant recipients: the Western Australian experience. AB - Transition to adult care is a vulnerable period for pediatric transplant recipients and is associated with reduced medication compliance, graft loss, and increased mortality. Psychosocial outcomes in young adults differ between pediatric transplant recipients and their healthy peers. We conducted a single center, retrospective cohort study of all pediatric liver transplant recipients who were transitioned through our center. This study aimed to assess the outcomes of transitioned pediatric liver transplant recipients at an Australian center, including mortality, adherence, and psychosocial morbidity. The 1- and 5-year survival rates following transition were 100% and 92%, respectively. There were no episodes of late rejection. In total, 66.7% of patients were compliant with immunosuppression and 61.1% of patients were compliant with clinic attendance. There was a significant relationship between medication compliance and clinic attendance, as well as presence of psychological issues with clinic non attendance. Psychosocial outcomes were in keeping with age-matched data from the general population. All patients were employed or studying following transition. This is the first study of its kind in the Australian population, and outcomes were superior to published international data. Despite the demonstrated good outcomes, transition programs may improve healthcare engagement in this cohort. PMID- 27762481 TI - Jejunal varices diagnosed by capsule endoscopy in patients with post-liver transplant portal hypertension. AB - Portal hypertension secondary to portal vein obstruction following liver transplant occurs in 5%-10% of children. Jejunal varices are uncommon in this group. We present a case series of children with significant GI blood loss, negative upper endoscopy, and jejunal varices detected by CE. Case series of patients who had CE for chronic GI blood loss following liver transplantation. Three patients who had their initial transplants at a median age of 7 months were identified at our institution presenting at a median age of 8 years (range 7-16 years) with a median Hgb of 2.8 g/dL (range 1.8-6.8 g/dL). Upper endoscopy was negative for significant esophageal varices, gastric varices, and bleeding portal gastropathy in all three children. All three patients had significant jejunal varices noted on CE in mid-jejunum. Jejunal varices were described as large prominent bluish vessels underneath visualized mucosa, one with evidence of recent bleeding. The results led to venoplasty of the portal vein in two patients and a decompressive shunt in one patient with resolution of GI bleed and anemia. CE is useful to diagnose intestinal varices in children with portal hypertension and GI bleeding following liver transplant. PMID- 27762482 TI - Treatment of erythematotelangiectatic rosacea with the fractionation of high fluence, long-pulsed 595-nm pulsed dye laser. AB - Various lasers have been used for the treatment of erythematotelangiectatic rosacea (ETR) that does not respond to systemic or topical therapy. The pulsed dye lasers (PDLs) are an effective option for ETR, and the purpuragenic fluence proved to be superior until now. Given that purpura and subsequent possible postinflammatory hyperpigmentation (PIH) are occasionally unbearable in some patients, and several studies using the low nonpurpuragenic fluence were reported. To deliver the sufficient high fluence of a PDL without generating purpura, we designed the fractionation of high fluence using five passes and longer pulse duration (6 milliseconds) of a PDL in succession. A total of eight patients with ETR were enrolled in this study; all patients were treated with PDL 10 times at 2-week intervals. Erythema and telangiectasia scores, as well as improvement, were assessed by two physicians using the digital photographs. Moderate-to-marked improvement was achieved in most of the patients, and erythema and telangiectasia scores were significantly decreased. Purpura and PIH were not reported in all patients. The fractionation of high-fluence, long-pulsed 595 nm PDL is a very safe and effective treatment for ETR. PMID- 27762483 TI - Range shifts or extinction? Ancient DNA and distribution modelling reveal past and future responses to climate warming in cold-adapted birds. AB - Global warming is predicted to cause substantial habitat rearrangements, with the most severe effects expected to occur in high-latitude biomes. However, one major uncertainty is whether species will be able to shift their ranges to keep pace with climate-driven environmental changes. Many recent studies on mammals have shown that past range contractions have been associated with local extinctions rather than survival by habitat tracking. Here, we have used an interdisciplinary approach that combines ancient DNA techniques, coalescent simulations and species distribution modelling, to investigate how two common cold-adapted bird species, willow and rock ptarmigan (Lagopus lagopus and Lagopus muta), respond to long term climate warming. Contrary to previous findings in mammals, we demonstrate a genetic continuity in Europe over the last 20 millennia. Results from back-casted species distribution models suggest that this continuity may have been facilitated by uninterrupted habitat availability and potentially also the greater dispersal ability of birds. However, our predictions show that in the near future, some isolated regions will have little suitable habitat left, implying a future decrease in local populations at a scale unprecedented since the last glacial maximum. PMID- 27762484 TI - Non-hemolytic enterotoxin of Bacillus cereus induces apoptosis in Vero cells. AB - Bacillus cereus is an opportunistic pathogen that often causes foodborne infectious diseases and food poisoning. Non-hemolytic enterotoxin (Nhe) is the major toxin found in almost all enteropathogenic B. cereus and B. thuringiensis isolates. However, little is known about the cellular response after Nhe triggered pore formation on cell membrane. Here, we demonstrate that Nhe induced cell cycle arrest at G0 /G1 phase and provoked apoptosis in Vero cells, most likely associated with mitogen-activated protein kinase (MAPK) and death receptor pathways. The influx of extracellular calcium ions and increased level of reactive oxygen species in cytoplasm were sensed by apoptosis signal-regulating kinase 1 (ASK1) and p38 MAPK. Extrinsic death receptor Fas could also promote the activation of p38 MAPK. Subsequently, ASK1 and p38 MAPK triggered downstream caspase-8 and 3 to initiate apoptosis. Our results clearly demonstrate that ASK1, and Fas-p38 MAPK-mediated caspase-8 dependent pathways are involved in apoptotic cell death provoked by the pore-forming enterotoxin Nhe. PMID- 27762486 TI - 12th Key Symposium Introduction: insulin resistance in common diseases. PMID- 27762485 TI - Associations among stress, gender, sources of social support, and health in emerging adults. AB - This study aimed to examine how sources of social support intersect with stress and health by testing two theoretical models. Three relationship-specific sources of social support (family, friends, and romantic partners) and two health indicators (self-rated physical health and depressive symptoms) were investigated. The sample consisted of 636 emerging adults attending college (age range: 18-25). Results suggest that only support from family was a stress-buffer, in that it buffered the adverse association between stress and depressive symptoms. Holding stress constant, only support from family was related to self rated physical health and only support from friends or romantic partners was associated with depressive symptoms. There were no gender differences in the mean levels of self-rated physical health and depressive symptoms. However, gender moderations were found, in that the positive relationship between friends support and physical health was observed only in women, that the association between friends support and depressive symptoms was greater in men than in women, and that family support buffered the negative relationship between stress and physical health only in men. Findings of this study suggest that the associations among stress, social support, and health vary by the sources of support, the health outcome, and gender. PMID- 27762488 TI - Curvilinear relationships between resource allocation and life domain-specific interference. AB - This study investigated the inherent complexities of the work-life interface (WLI) by examining the relationship between resource allocation (i.e., time and energy dedicated to a particular domain) and perceived interference of individual life domains. Much of the research on the WLI is based on the assumption that a linear pattern best describes the relationship between resource allocation and the interference caused by various life domains; however, this study examined the possibility that curvilinear relationships may be a more appropriate representation. Results indicated that resource allocation is a meaningful predictor of interference, and for many life domains a curvilinear relationship accounts for more variance than a linear one; a breakdown of the sample also revealed this relationship varies by gender. Overall, findings suggest that the nature of the WLI is more individualized and complex than is currently conceptualized in the field. PMID- 27762489 TI - Comparison of the therapeutic efficacy and safety of combined oral tranexamic acid and topical hydroquinone 4% treatment vs. topical hydroquinone 4% alone in melasma: a parallel-group, assessor- and analyst-blinded, randomized controlled trial with a short-term follow-up. AB - BACKGROUND: Melasma's high prevalence and profound psychological impact on patients necessitate efficacious, economical, and safe therapeutic interventions. Adjunctive therapies such as tranexamic acid (TA) can enhance the therapeutic effect of standard treatments like hydroquinone 4% cream (HQ). OBJECTIVE: To conduct an assessor- and analyst-blinded, parallel, superiority, randomized controlled trial to compare the clinical efficacy and safety of oral TA plus HQ vs. HQ alone in melasma treatment. MATERIALS AND METHODS: A total of 100 eligible patients with symmetric facial melasma were assigned to the intervention (250 mg thrice daily oral TA plus HQ 4% cream nightly) or the control group (HQ 4% cream only). Following 3 months of treatment, MASI (melasma area and severity index) score reduction was calculated as the primary outcome measure. After a 3-month follow-up, relapse was also assessed. RESULTS: A total of 88 patients completed the study. At the end of the 6-month period, the overall mean of the MASI score in the intervention group was 1.8 points lower than in the controls (95% confidence interval, 0.36-3.24, P = 0.015) but the relapse rate was not significantly different (30% vs. 26% in the treatment vs. control group, respectively). Side effect occurrence was also similar, but treatment satisfaction was higher in the intervention group than the controls, with 82.2% vs. 34.95 of patients reporting moderate-to-complete satisfaction, respectively (P < 0.001). CONCLUSIONS: Oral TA can enhance the efficacy of hydroquinone 4% cream in melasma treatment, but the high incidence of relapse suggests that treatment effects may be temporary, warranting more investigation. PMID- 27762491 TI - Resolution of non-alcoholic steatohepatitis after growth hormone replacement in a pediatric liver transplant patient with panhypopituitarism. AB - NAFLD is a common condition linked to obesity, type 2 diabetes, and metabolic syndrome. Simple hepatic steatosis is a risk factor for inflammatory reactions in the liver (NASH), which may lead to cirrhosis. While the mechanism is unclear, NAFLD and NASH are associated with panhypopituitarism, which in the pediatric population often results from craniopharyngioma or pituitary adenoma and the sequelae of treatment, causing hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism, and GH deficiency. Refractory NAFLD in panhypopituitarism may be amenable to GH replacement. Here, we report a pediatric case of NASH secondary to panhypopituitarism from craniopharyngioma, which recurred by 11 months after LDLT. Despite low-dose GH replacement, the patient remained GH deficient. Pubertal dosed GH therapy led to rapid and complete resolution of hepatic steatosis, which we tracked using serial 1 H MRS. Pediatric patients with NASH cirrhosis secondary to panhypopituitarism can be good candidates for liver transplantation, but hormone deficiencies predispose to recurrence after transplant. High-dose GH replacement should be considered in pediatric patients with GH deficiency and recurrent disease. A multidisciplinary team approach is essential for successful outcomes. PMID- 27762490 TI - Lessons from two high CO2 worlds - future oceans and intensive aquaculture. AB - Exponentially rising CO2 (currently ~400 MUatm) is driving climate change and causing acidification of both marine and freshwater environments. Physiologists have long known that CO2 directly affects acid-base and ion regulation, respiratory function and aerobic performance in aquatic animals. More recently, many studies have demonstrated that elevated CO2 projected for end of this century (e.g. 800-1000 MUatm) can also impact physiology, and have substantial effects on behaviours linked to sensory stimuli (smell, hearing and vision) both having negative implications for fitness and survival. In contrast, the aquaculture industry was farming aquatic animals at CO2 levels that far exceed end-of-century climate change projections (sometimes >10 000 MUatm) long before the term 'ocean acidification' was coined, with limited detrimental effects reported. It is therefore vital to understand the reasons behind this apparent discrepancy. Potential explanations include 1) the use of 'control' CO2 levels in aquaculture studies that go beyond 2100 projections in an ocean acidification context; 2) the relatively benign environment in aquaculture (abundant food, disease protection, absence of predators) compared to the wild; 3) aquaculture species having been chosen due to their natural tolerance to the intensive conditions, including CO2 levels; or 4) the breeding of species within intensive aquaculture having further selected traits that confer tolerance to elevated CO2 . We highlight this issue and outline the insights that climate change and aquaculture science can offer for both marine and freshwater settings. Integrating these two fields will stimulate discussion on the direction of future cross-disciplinary research. In doing so, this article aimed to optimize future research efforts and elucidate effective mitigation strategies for managing the negative impacts of elevated CO2 on future aquatic ecosystems and the sustainability of fish and shellfish aquaculture. PMID- 27762492 TI - Triple Redox Responsive Poly(Ethylene Glycol)-Polycaprolactone Polymeric Nanocarriers for Fine-Controlled Drug Release. AB - Stimuli-responsive nanocarriers with the ability to respond to tumorous heterogeneity have been extensively developed for drug delivery. However, the premature release during blood circulation and insufficient intracellular drug release are still a significant issue. Herein, three disulfide bonds are introduced into the amphiphilic poly(ethylene glycol)-polycaprolactone copolymer blocks to form triple-sensitive cleavable polymeric nanocarrier (tri-PESC NPs) to improve its sensitivity to narrow glutathione (GSH) concentration. The tri-PESC NPs keep intact during blood circulation due to the limited cleaving of triple disulfide bonds, whereas the loaded drug is efficiently released at tumor cells with the increased concentration of GSH. In vitro studies of doxorubicin-loaded tri-PESC NPs show that the nanocarriers achieve sufficient drug release in cancerous cells and inhibit the tumor cells growth, though they only bring minimum damage to normal cells. Therefore, the tri-PESC NPs with triple-sensitive cleavable bonds hold great promise to improve the therapeutic index in cancer therapy. PMID- 27762493 TI - Quinacrine Mediated Sensitization of Glioblastoma (GBM) Cells to TRAIL through MMP-Sensitive PEG Hydrogel Carriers. AB - Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix-metalloproteinase (MMP)-sensitive and arg-gly-asp-ser (RGDS) peptide functionalized poly (ethylene glycol) (PEG) particles which are synthesized via visible-light-induced water-in water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP sensitive particles are cytocompatible and superior to promote TRAIL-induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC-loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC-loaded particles, but not QC or PEG hydrogels alone, enhance apoptosis as is measured through expression of apoptosis related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy. PMID- 27762494 TI - Thin Poly(Di(Ethylene Glycol)Methyl Ether Methacrylate) Homopolymer Brushes Allow Controlled Adsorption and Desorption of PaTu 8988t Cells. AB - Poly(di(ethylene glycol)methyl ether methacrylate) (PDEGMA) brushes, which are known to suppress protein adsorption and prevent cell attachment, are reported here to possess interesting and tunable thermoresponsive behavior, if the brush thickness is reduced or the grafting density is altered. PDEGMA brushes with a dry ellipsometric thickness of 5 +/- 1 nm can be switched from cell adherent behavior at 37 degrees C to cell nonadherent at 25 degrees C. This behavior coincides with the temperature-dependent irreversible adsorption of fibronectin from phosphate saline buffer and proteins present in the cell culture medium, as unveiled by surface plasmon resonance measurements. Unlike for tissue culture polystyrene reference surfaces, swelling of the PDEGMA chains below the lower critical solution temperature results in the absence of paxillin and actin containing cellular filaments responsible for cell attachment. These tunable properties of very thin homopolymer PDEGMA brushes render this system interesting as an alternative thermoresponsive layer for continuous cell culture or enzyme free cell culture systems. PMID- 27762495 TI - Targeted Co-delivery of PTX and TR3 siRNA by PTP Peptide Modified Dendrimer for the Treatment of Pancreatic Cancer. AB - A new type of tumor-targeted nanovehicle peptide-conjugated PSPG (PSPGP) is successfully synthesized for co-delivery of paclitaxel (PTX) and TR3 small interfering RNA (siRNA). In vitro and in vivo investigations demonstrate that the redox-responsive PSPGP exhibit enhanced endosomal escape and intracellular degradation, which facilitate PTX and TR3 siRNA release, effectively improving the antitumor efficacy. PMID- 27762496 TI - Metal-Organic Frameworks for CO2 Chemical Transformations. AB - Carbon dioxide (CO2 ), as the primary greenhouse gas in the atmosphere, triggers a series of environmental and energy related problems in the world. Therefore, there is an urgent need to develop multiple methods to capture and convert CO2 into useful chemical products, which can significantly improve the environment and promote sustainable development. Over the past several decades, metal-organic frameworks (MOFs) have shown outstanding heterogeneous catalytic activity due in part to their high internal surface area and chemical functionalities. These properties and the ability to synthesize MOF platforms allow experiments to test structure-function relationships for transforming CO2 into useful chemicals. Herein, recent developments are highlighted for MOFs participating as catalysts for the chemical fixation and photochemical reduction of CO2 . Finally, opportunities and challenges facing MOF catalysts are discussed in this ongoing research area. PMID- 27762497 TI - Characterization of a novel HLA-B*18 variant allele, HLA-B*18:122, by genome sequencing. AB - The HLA-B*18:122 allele showed four nucleotide differences from HLA B*18:01:01:01. PMID- 27762499 TI - MoS2 /Rubrene van der Waals Heterostructure: Toward Ambipolar Field-Effect Transistors and Inverter Circuits. AB - 2D transition metal dichalcogenides are promising channel materials for the next generation electronic device. Here, vertically 2D heterostructures, so called van der Waals solids, are constructed using inorganic molybdenum sulfide (MoS2 ) few layers and organic crystal - 5,6,11,12-tetraphenylnaphthacene (rubrene). In this work, ambipolar field-effect transistors are successfully achieved based on MoS2 and rubrene crystals with the well balanced electron and hole mobilities of 1.27 and 0.36 cm2 V-1 s-1 , respectively. The ambipolar behavior is explained based on the band alignment of MoS2 and rubrene. Furthermore, being a building block, the MoS2 /rubrene ambipolar transistors are used to fabricate CMOS (complementary metal oxide semiconductor) inverters that show good performance with a gain of 2.3 at a switching threshold voltage of -26 V. This work paves a way to the novel organic/inorganic ultrathin heterostructure based flexible electronics and optoelectronic devices. PMID- 27762498 TI - Graphene Oxide Nanosheets Retard Cellular Migration via Disruption of Actin Cytoskeleton. AB - Graphene and graphene-based nanomaterials are broadly used for various biomedical applications due to their unique physiochemical properties. However, how graphene based nanomaterials interact with biological systems has not been thoroughly studied. This study shows that graphene oxide (GO) nanosheets retard A549 lung carcinoma cell migration through nanosheet-mediated disruption of intracellular actin filaments. After GO nanosheets treatment, A549 cells display slower migration and the structure of the intracellular actin filaments is dramatically changed. It is found that GO nanosheets are capable of absorbing large amount of actin and changing the secondary structures of actin monomers. Large-scale all atom molecular dynamics simulations further reveal the interactions between GO nanosheets and actin filaments at molecular details. GO nanosheets can insert into the interstrand gap of actin tetramer (helical repeating unit of actin filament) and cause the separation of the tetramer which eventually leads to the disruption of actin filaments. These findings offer a novel mechanism of GO nanosheet induced biophysical responses and provide more insights into their potential for biomedical applications. PMID- 27762501 TI - Genomic full-length sequence of two HLA-A alleles, A*33:01:01 and A*33:03:01, identified by cloning and sequencing. AB - Genomic full-length sequences of HLA-A*33:01:01 and A*33:03:01, were identified by cloning and sequencing. PMID- 27762500 TI - Microwave-induced porosity and bioactivation of chitosan-PEGDA scaffolds: morphology, mechanical properties and osteogenic differentiation. AB - In this study, a new foaming method, based on physical foaming combined with microwave-induced curing, is proposed in combination with a surface bioactivation to develop scaffold for bone tissue regeneration. In the first step of the process, a stable physical foaming was induced using a surfactant (Pluronic) as blowing agent of a homogeneous blend of Chitosan and polyethylene glycol diacrylate (PEGDA700) solutions. In the second step, the porous structure of the foaming was chemically stabilized by radical polymerization induced by homogeneous heating of the sample in a microwave reactor. In this step, 2,2 azobis[2-(2-imidazolin-2yl)propane]dihydrochloride was used as thermoinitiator (TI). Chitosan and PEGDA were mixed in different blends to investigate the influence of the composition on the final properties of the material. The chemical properties of each sample were evaluated by infrared attenuated total reflectance analysis, before and after curing in order to maximize reaction yield and optimize kinetic parameters (i.e. time curing, microwave power). Absorption capacity, elastic modulus, porosity and morphology of the porous structure were measured for each sample. The stability of materials was evaluated in vitro by degradation test in phosphate-buffered saline. To improve the bioactivity and biological properties of chitosan scaffold, a biomineralization process was used. Biological characterization was carried out with the aim to prove the effect of biomineralization scaffold on human mesenchymal stem cells behaviour. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27762502 TI - Methods for suspension culture, protoplast extraction, and transformation of high biomass yielding perennial grass Arundo donax. AB - Arundo donax L. is a promising biofuel feedstock in the Mediterranean region. Despite considerable interest in its genetic improvement, Arundo tissue culture and transformation remains arduous. The authors developed methodologies for cell- and tissue culture and genetic engineering in Arundo. A media screen was conducted, and a suspension culture was established using callus induced from stem axillary bud explants. DBAP medium, containing 9 uM 2,4-D and 4.4 uM BAP, was found to be the most effective medium among those tested for inducing cell suspension cultures, which resulted in a five-fold increase in tissue mass over 14 days. In contrast, CIM medium containing 13 uM 2,4-D, resulted in just a 1.4 fold increase in mass over the same period. Optimized suspension cultures were superior to previously-described solidified medium-based callus culture methods for tissue mass increase. Suspension cultures proved to be very effective for subsequent protoplast isolation. Protoplast electroporation resulted in a 3.3 +/- 1.5% transformation efficiency. A dual fluorescent reporter gene vector enabled the direct comparison of the CAMV 35S promoter with the switchgrass ubi2 promoter in single cells of Arundo. The switchgrass ubi2 promoter resulted in noticeably higher reporter gene expression compared with that conferred by the 35S promoter in Arundo. PMID- 27762503 TI - Translocation Pathway-Dependent Assembly of Streptavidin- and Antibody-Binding Filamentous Virus-Like Particles. AB - Compared to well-tolerated p3 fusion, the display of fast-folding proteins fused to the minor capsid p7 and the major capsid p8, as well as in vivo biotinylation of biotin acceptor peptide (AP) fused to p7, are found to be markedly inefficient using the filamentous phage. Here, to overcome such limitations, the effect of translocation pathways, amber mutation, and phage and phagemid display systems on p7 and p8 display of antibody-binding domains are examined, while comparing the level of in vivo biotinylation of AP fused to p7 or p3. Interestingly, the in vivo biotinylation of AP occurs only in p3 fusion and the fast-folding antibody binding scaffolds fused to p7 and p8 are best displayed via a twin-arginine translocation pathway in TG1 cells. The lower the expression level of the wild type p8 and the smaller the size of the guest protein, the better the display of Z-domain fused to the recombinant p8. The in vivo biotinylated multifunctional filamentous virus-like particles can be vertically immobilized on streptavidin (SAV)-coated microspheres to resemble cellular microvilli-like structures, which reportedly enhance protein-protein interactions due to dramatically expanded flexible surface area. PMID- 27762504 TI - Improved pan-specific prediction of MHC class I peptide binding using a novel receptor clustering data partitioning strategy. AB - Pan-specific prediction of receptor-ligand interaction is conventionally done using machine-learning methods that integrates information about both receptor and ligand primary sequences. To achieve optimal performance using machine learning, dealing with overfitting and data redundancy is critical. Most often so called ligand clustering methods have been used to deal with these issues in the context of pan-specific receptor-ligand predictions, and the MHC system the approach has proven highly effective for extrapolating information from a limited set of receptors with well characterized binding motifs, to others with no or very limited experimental characterization. The success of this approach has however proven to depend strongly on the similarity of the query molecule to the molecules with characterized specificity using in the machine-learning process. Here, we outline an alternative strategy with the aim of altering this and construct data sets optimal for training of pan-specific receptor-ligand predictions focusing on receptor similarity rather than ligand similarity. We show that this receptor clustering method consistently in benchmarks covering affinity predictions, MHC ligand and MHC epitope identification perform better than the conventional ligand clustering method on the alleles with remote similarity to the training set. PMID- 27762505 TI - Use of 5-Fluorouracil Loaded Micelles and Cisplatin in Thermosensitive Chitosan Hydrogel as an Efficient Therapy against Colorectal Peritoneal Carcinomatosis. AB - Colorectal peritoneal carcinomatosis (CRPC) is a common systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy against CRPC is at present the preferred treatment. The aim of this study is to develop a novel hydrogel drug delivery system through the combination of 5-fluorouracil (5-FU) loaded polymeric micelles and cisplatin (DDP) in biodegradable thermosensitive chitosan (CS) hydrogel. The prepared CS hydrogel drug is a free-flowing solution at room temperature and forms a stationary gel at body temperature. Therefore, a CRPC mouse model is established to investigate the antitumor activity of CS hydrogel drug system. The results suggest that intraperitoneal administration of CS hydrogel drug can inhibit tumor growth and metastasis, and prolong survival time compared with other groups, thus improving the chemotherapeutic effect. Ki-67 immunohistochemical analysis reveals that tumors in the CS hydrogel drug group has lower cell proliferation in contrast to other groups (P < 0.001). Furthermore, hematoxylin-eosin staining of liver and lung tissue indicates that the CS hydrogel drug has also a certain inhibitory effect on colorectal cancer metastasis to the liver and lung. Hence, the work highlights the potential clinical applications of the CS hydrogel drug. PMID- 27762506 TI - Crosslinked Platform Coatings Incorporating Bioactive Signals for the Control of Biointerfacial Interactions. AB - Control over biointerfacial interactions on material surfaces is of significant interest in many biomedical applications and extends from the modulation of protein adsorption and cellular responses to the inhibition of bacterial attachment and biofilm formation. Effective control over biointerfaces is best achieved by reducing nonspecific interactions on the surface while also displaying specific bioactive signals. A poly(ethylene glycol) (PEG)-based multifunctional coating has been developed that provides effective reduction of protein fouling while enabling covalent immobilization of peptides in a one or two-step manner. The highly protein resistant properties of the coating, synthesized via the crosslinking of PEG diepoxide and diaminopropane, are confirmed via europium-labeled fibronectin adsorption and cell attachment assays. The ability to covalently incorporate bioactive signals is demonstrated using the cyclic peptides cRGDfK and cRADfK. L929 cells show enhanced attachment on the biologically active cRGDfK containing surfaces, while the surface remains nonadhesive when the nonbiologically active cRADfK peptide is immobilized. The crosslinked PEG-based coating also demonstrates excellent resistance toward Staphylococcus aureus attachment in a 48 h biofilm assay, achieving a >96% reduction compared to the control surface. Additionally, incorporation of the antimicrobial peptide melimine during coating formation further significantly decreases biofilm formation (>99%). PMID- 27762507 TI - The plant microbiome in biotechnology: An annotated selection of World Wide Websites relevant to the topics in microbial biotechnology. PMID- 27762508 TI - Measuring Anti-drug Antibodies: A Step Towards Optimization of Biologic Therapy. PMID- 27762509 TI - Analytical and Clinical Evaluation of an Immunoassay for Estimating Immunogenicity of Infliximab and Etanercept in Indian Population. AB - BACKGROUND / OBJECTIVES: Biologic anti-TNFs in India have improved the patient management. Significant proportions of patients lose response over time or do not respond. Possible explanations are suboptimal trough anti-TNFa concentrations or antibodies to anti-TNFs. The aim of this project was to set up and standardize an independent laboratory to test immunogenicity of anti-TNF biologics (infliximab and etanercept). METHODS: Three rheumatologists piloted this project approved by independent ethics committee and carried out in compliance with ICH/GCP guidelines. Pfizer supplied immunogenicity kits (Promonitor(r) - ELISA) to the independent laboratory (SRL labs). After informed consent, blood (5 mL) was collected before infusion of infliximab (n=8) or injection of etanercept (n=8). RESULTS: Mean age of 16 patients was 42.06 +/- 12.89 years. While 4 patients tested negative for infliximab, one patient tested low positive and 3 patients were positive. Anti-infliximab antibody was detected in 1/8 patient (12.5%) and the blood level of infliximab was negligible. DISCUSSION: Anti-infliximab antibodies are found in 12%-44% of patients vis-a'-vis anti-etanercept antibodies (0%-18%). Anti-etanercept antibodies are without apparent effect on effectiveness or adverse events. When anti-TNFa are used, therapeutic drug monitoring is of help for optimal clinical outcomes. It might be more cost effective to adjust anti TNFa dosages according to serum drug concentrations. Clinicians should have access to immunogenicity testing facility in India. The results of the study were as per the observed percentages across the world. CONCLUSIONS: This study met its objective of setting up and standardizing an independent laboratory for immunogenicity testing of anti-TNF biologics in India. PMID- 27762510 TI - Long-term Mortality in Patients with Permanent Pacemaker Implantation. AB - INTRODUCTION: The development of implantable technology for cardiac rhythm management remains one of the seminal achievements of the second half of the 20th century. The development of artificial pacemakers for the electrical control of the cardiac rhythm has greatly enhanced the physician's ability to treat cardiac dysrhythmias. An ageing population and the extension of indications will in all probability result in an increasing number of cardiac device implantations. OBJECTIVE OF STUDY: To study mortality and morbidity in patients with permanent pacemaker implantation at a tertiary care hospital in North India. MATERIAL ANDF METHODS: This was a two year prospective observational study conducted in the Department of Cardiology of Christian Medical College and Hospital, Ludhiana. This included a retrospective period of ten years from 1st July 2002 to 30th June 2012, and a prospective period of two years from 1st July 2012 to 31st July 2014. All patients admitted to Christian Medical College and Hospital, Ludhiana, who received a permanent pacemaker for bradyarrhythmias were included in the study. A detailed analysis of demographic profile, indications, complications and mortality data was performed. RESULTS: A total of 323 patients were included in the study of which more than 75% of the patients receiving the pacemaker were in the age group 56-85 yrs. Males received more pacemakers than females. The commonest presenting symptom was syncope. Complete heart block was the commonest ECG finding. Acquired A-V block was the most common indication of pacing. VVI was the commonest mode of pacemaker implantation. Complications were seen in 3.72% patients. During the entire study period death occurred in 7.1% patients. CONCLUSIONS: Permanent pacemaker implantation is a relatively safe procedure with low complication rates and low mortality particularly in patients who have been on a regular follow up. PMID- 27762511 TI - A Study of Effects of Pioglitazone and Rosiglitazone on Various Parameters in Patients of Type-2 Diabetes Mellitus with Special Reference to Lipid Profile. AB - OBJECTIVES: To study the complete fasting lipid profile and other parameters (weight, body mass index, HbA1c, fasting blood sugar and postprandial blood sugar)in Type 2 diabetes mellitus patients on OHA/insulin, to study the effect of addition of pioglitazone on lipid profile and other parameters in Type 2 diabetes mellitus patients on OHA/insulin, to study the effect of addition of rosiglitazone on lipid profile and other parameters in Type 2 diabetes mellitus patients on OHA/insulin and to compare the effect of pioglitazone and rosiglitazone on lipid profile and other parameters in Type 2 diabetes mellitus patients on OHA/insulin. MATERIAL AND METHODS: In the study, 100 Type 2 diabetes cases on oral hypoglycemic agent/insulin with deranged lipid profile were chosen and divided into 2 groups 50 and 50 in group A and group B respectively.Pioglitazone was given initially 15mg/day then if required increasing upto 45mg/day in group A for period of 18 weeks and rosiglitazone was given initially 2 mg/day then if required increasing upto 8 mg/day in group B for period of 18 weeks. Detailed clinical history was obtained and thorough physical examination was done and following parameters were established-Age, Height, Weight, Body mass index, Fasting and Postprandial blood sugar, HbA1c levels and fasting complete lipid profile done at 0 and 18 weeks. Each patient itself served as a control for this study. RESULTS: Maximum no. of patients were in sixth decade (53.30%) and minimum patients were in seventh decade (6.6%). Males were 63.3% and females were 36.8%. Fasting blood sugar levels decreased by 23% with pioglitazone in group A and 14.07% with rosiglitazone in group B. The postprandial blood sugar levels decreased by 29.9% with pioglitazone in group A and 20.17% with rosiglitazone in group B.The mean HbA1c decreased by 2.13 % pioglitazone in group A and 3.8% with rosiglitazone in group B after 18 weeks of therapy. The effects of both drugs on BMI and weight were not significant. In group A the total cholesterol level decreased by 8.62% with pioglitazone but in group B there was no significant decrease in total cholesterol level after 18 weeks of therapy with rosiglitazone. There was no significant reduction in mean LDL cholesterol level in both groups. HDL-c level increased by 17.14% with pioglitazone in group A and decreased by 1.2% with rosiglitazone in group B. Triglycerides levels decreased by 12.33% with pioglitazone in group A and 6.16% with rosiglitazone in group B. CONCLUSIONS: Treatment with pioglitazone and rosiglitazone both were associated with reduction in fasting and postprandial blood sugar levels but more with pioglitazone. There was significant reduction in HbA1c with both pioglitazone and rosiglitazone but more with rosiglitazone. The total cholesterol level decreased by pioglitazone significantly but not with rosiglitazone. The LDL levels were not affected much by both drugs, while HDL levels were significantly increased with pioglitazone. Triglycerides levels were decreased with both pioglitazone and rosiglitazone but more with pioglitazone. Both drugs are useful but pioglitazone proved to be more beneficial on deranged lipid profile as compared to rosiglitazone in Type 2 Diabetes mellitus patients on OHA/insulin. PMID- 27762512 TI - Noradrenaline is as Effective as Terlipressin in Hepatorenal Syndrome Type 1: A Prospective, Randomized Trial. AB - OBJECTIVES: Hepatorenal syndrome (HRS) is a functional renal failure occurring in end stage liver disease, which is associated with poor prognosis. Terlipressin has been shown to be effective in treatment of HRS. More recently, it was suggested that noradrenaline, an alpha-adrenergic drug may be also effective in HRS. We aimed to compare the efficacy of noradrenaline versus terlipressin in treatment of HRS type 1. METHODS: Consecutive patients with cirrhosis and HRS type 1 were enrolled and randomised into 2 groups- Group A received intravenous noradrenaline infusion (0.5-3 mg/h) and group B received intravenous terlipressin (0.5-2 mg/6h) for 2 weeks. Intravenous albumin (20 g/day) was given to both groups. RESULTS: Out of 55 cirrhotics screened, 41 were randomised into group A (n=21) or group B (n=20). Baseline characteristics of the two groups were similar. HRS reversal was seen in 47.6%(10/21) patients in group A, and 45% (9/20) patients in group B (p=1.00). In both groups, there was a significant decrease in serum creatinine from baseline (group A- 3.1+/-1.4 mg/dl to 2.2+/-1.3 mg/dl, p=0.028; group B- 3.4+/-1.6 mg/dl to 2.3+/-1.3 mg/dl, p=0.035). Both the groups showed a significant increase in mean arterial pressure (group A- 77.3+/ 8.6 mmHg to 103.4+/-8.3 mmHg, p=0.0001; group B- 76.8+/-11.6 mmHg to 100+/-9.4 mmHg, p=0.0001). Noradrenaline was associated with fewer adverse events and was significantly cheaper than terlipressin. Lower baseline MELD score was an independent predictor of response to treatment. CONCLUSIONS: Noradrenaline is as effective and safe as terlipressin in the treatment of HRS type 1. PMID- 27762513 TI - Etiology and Left Ventricular Functions in Left Bundle Branch Block- A Prospective Observational Study. AB - PURPOSE OF STUDY: Left bundle branch (LBBB) is common ECG finding. Common causes of LBBB are coronary artery disease (CAD), hypertension and dilated cardiomyopathy (DCM). Purpose of the study was to find out the etiology and left ventricular function in patients coming to a territory care hospital. MATERIAL AND METHODS: All consecutive patients coming to our hospital as indoor or outdoor patients with ECG suggestive of LBBB were studied. The detail history and examination was done. Echocardiography was done in all patients. RESULTS: 132 patients with LBBB were studied. Mean age was 61.65+/-13.02 yrs. 70 were male (53.03%) and 62 were female (44.97%). 40 patients presented with dyspnea ((30.3%) and 34 with chest pain ((24.24%). 23 patients were asymptomatic (17.4%). 63 were hypertensive (47.7%) and 6 were diabetic (4.5%). Left ventricular hypertrophy (LVH) was present in 42 patients (31.8%), with 33 having diastolic and 9 systolic dysfunction. 33 patients had DCM (25%) and 31 patients had evidence of myocardial infarction (23.48%). 20 patients had normal echocardiography (15.15%). 75 patients had systolic dysfunction (56.8%). CONCLUSIONS: Commonest presentation in patients wih LBBB was dyspnea followed by chest pain. Majority had hypertension. LVH was the commonest echocardiographic finding followed by global hypokinesia and regional wall motion abnormality. More than 50% patients had left ventricular systolic dysfunction. PMID- 27762514 TI - A Prospective Analysis of the Efficacy and Safety of Sodium Glucose Cotransporter 2 Inhibitors: Real World Evidence from Clinical Practice in India. AB - BACKGROUND AND AIM: The number of patients with type 2 diabetes (T2DM) is increasing. Most patients with T2DM are uncontrolled and fail to achieve their target Hba1c. In recent years, newer agents such as SGLT2 inhibitors (SGLT2i) have been approved for clinical use. Though data from clinical trials and sub set analysis of Indian patients in global studies are promising, real world evidence from standard clinical practice in India is lacking. The aim of this study was to analyze the metabolic parameters in patients with T2DM on SGLT2i in real world clinical practice. MATERIAL AND METHODS: This was a prospective, longitudinal study of 100 patients with uncontrolled T2DM attending the outpatient of a specialized diabetes hospital. Their metabolic parameters were evaluated at baseline and after 3 months of follow up. They were categorized based on their baseline anti diabetic medications into four groups (25 in each).The groups were as follows: metformin plus sulfonylurea, metformin plus DPP4 inhibitor, triple drug regimen with metformin plus DPP4 inhibitor plus sulfonylurea, and patients on insulin and on triple drug therapy with metformin plus sulfonylurea plus DPP4 inhibitor. Patients in each group were initiated with an SGLT2i. Descriptive statistical analysis was carried out using Microsoft excel. T test was used to calculate the p value at 5 % level of significance. RESULTS: The mean age of the subjects in the study population was 53.20+/-12.1 years and the duration of diabetes was 13.1+/-7.26 years. The mean Hba1c reduction and weight reduction observed was 1.02+/-0.24% and 2.64+/-1.27 kg respectively. Genital pruritis was reported in 4% of the patients. There was a 16.6% reduction in the daily insulin requirement at follow up when compared to baseline. No other side effects were observed. The reductions in Hba1c and weight were statistically significant (p<0.05) across all groups. CONCLUSIONS: This study demonstrates that when SGLT2i are added at any stage of the disease spectrum with any of the preexisting therapeutic agents for patients with uncontrolled T2DM, there is an improvement in glycemic control and body weight, with minimal side effects. The real world study data on Indian patients appears to be promising. PMID- 27762515 TI - A Cross-sectional Cohort Analyses Assessing Response to Levosalbutamol Bronchodilatory Cough Formulations in Outpatient Community Settings of India: 'BUS' analyses. AB - INTRODUCTION: Cough is significant health problem with greater implication for impaired quality of life. Acute and chronic cough due to infective (viral/bacterial), allergic conditions or bronchial asthma including cough variant asthma are often treated with combination of mucolytics, expectorants and bronchodilators. Bronchodilators reduces cough sensitivity, promotes clearance of cough secretions while reducing protrusive inflammatory mediator release. AIMS AND OBJECTIVES: To further understand the clinical utility and safety of Bronchodilatory cough formulations (BCF) containing Levosalbutamol in real world settings. MATERIAL AND METHODS: A prospective, cross sectional, cohort analyses (Bronchodilatory coUgh formulary Survey, BUS) assessing Levosalbutamol cough formulations utilization at 40 centers involving general and consultant physicians across India. RESULTS: Consecutive prescription records (n=1367) involving Levosalbutamol were collated for analyses. Baseline demographics included adults (21%) and children (79%) with mean age 11.1 yrs, male (60%) and female(40%). Levosalbutamol BCF was commonly prescribed for LRTI (69.7%), AECB (14.8%), Bronchial asthma (8.5%), Allergic rhinitis (5%). The predominant risk factors in both adults and children included smoking and allergic rhinitis respectively. In most cases cough severity was assessed utilizing Fisman scale score (0-4). Mean cough score improved from baseline score of 3 to 0.8 with parallel improvement in associated symptoms of wheeze and sputum. Antibiotics were prescribed in most of LRTI or acute exacerbation cases with purulent sputum. Side effects noted included tremor (1%), palpitation (0.9%), vomiting (0.7%) that were mild and transient in most cases with none requiring treatment withdrawal. In two cases (0.1%), further treatment with nebulization and antibiotics were provided. CONCLUSIONS: Levosalbutamol containing Bronchodilatory Cough formulation remains as safe and effective option for adults and children while managing acute or chronic cough primarily due to allergic rhinitis, bronchial asthma or COPD. PMID- 27762516 TI - Significance of BP Control in Reducing Stroke Events: Role of Amlodipine in an Indian Perspective. AB - While the incidence and prevalence of stroke is gradually decreasing in the western world, a parallel increase is seen in the developing world. It is a matter of special concern to us as approximately 20-30% of stroke occur in people younger than 45 years in India. Indians are prone to higher stroke risk because of urbanization, diabetes, cigarette smoking and high incidence of hypertension. Unfortunately, there is an inadequate awareness about the risk of stroke with hypertension among general public. Hypertension is considered to be the most important risk factor for stroke, and all forms of hypertension are associated with an increased risk of both ischemic and haemorrhagic stroke. The presence of hypertension also worsens mortality in stroke. Recently, it has been increasingly observed that controlling blood pressure variability (BPV) is equally important as achieving BP reduction, and an increased BPV has been shown to increase stroke risk. Thus, effective treatment option for stroke prevention should include drugs which can reduce BPV as well. The landmark ASCOT-BPLA trial reported that the calcium channel blocker amlodipine decreases stroke risk in hypertensive patients, and attributed this beneficial effect to its effective lowering of BPV. Such beneficial effects of amlodipine were replicated in other trials as well and thus it becomes an important drug from an Indian perspective. In this review, we analyse published literature and present a picture on the effect of amlodipine in the stroke prevention in hypertensive patients. PMID- 27762517 TI - Strategies for Better Hypertension Control in India and Other Lower Middle Income Countries. AB - Hypertension is the most important cause of global burden of disease. It is highly prevalent in India and other low and lower-middle income countries. Prevalence of uncontrolled hypertension varies from 70-90% and is significantly greater in rural vs urban locations. Guidelines based treatment strategy has improved blood pressure (BP) control in high income countries but no context specific guidelines exist in low and lower-middle income countries such as India. There are numerous barriers to proper BP control in these countries and include political apathy, bureaucratic inertia, weak health systems, overburdened healthcare providers and unempowered patients. Hypertension control can be improved in these countries by better political focus on social determinants of health such as education, development of health systems, proper healthcare financing, free or low-cost BP medicines, healthcare provider education for hypertension management, free primary care, task sharing with trained community health workers, patient empowerment and use of technological innovations. PMID- 27762518 TI - Samples and their Size: The Bane of Researchers (Part I). PMID- 27762519 TI - Public Health - the 'black hole' in Indian Medical Services. PMID- 27762520 TI - Differing Presentations of Familial Tuberous Sclerosis. PMID- 27762521 TI - Conus Medullaris Injury following Spinal Anaesthesia. PMID- 27762522 TI - Lingual Thyroid Presenting as Life Threatening Haematemesis in Pregnancy. PMID- 27762523 TI - Acute Rhinosinusitis Complicated by Cortical Venous Thrombosis and Multiple Subdural Empyemas. PMID- 27762524 TI - Multifocal Tuberculosis. AB - Multifocal Tuberculosis represents the many faces of an age old disease. It is characterized by the presence of large multifocal tuberculous areas in same or different organs. A 50 year old male patient, presented with features suggestive of renal failure, low grade fever and cough with mucoid expectoration. He was found to have pulmonary TB, genitourinary TB and tuberculous lymphadenitis. He was started on antituberculous treatment to which he showed good response. PMID- 27762525 TI - Myelopathy following Cypermethrin Poisoning. AB - Cypermethrin is a synthetic pyrethroid and pyrimethrin analogue. Cypermethrin poisoning produces neurological manifestations due to its primary target on sodium channels.1 Neuropathy following cypermethrin poisoning is common. But myelopathy is rare and not reported so far. We report a 17 year old healthy male who developed myelopathy following cypermethrin ingestion. The possible mechanism for the myelopathy in this patient is discussed. PMID- 27762526 TI - Unstable Angina: A Serious Adverse Event following Gemcitabine-Cisplatin Based Chemotherapy. AB - A 29 year male, with an inoperable adenocarcinoma of gall bladder was initiated on gemcitabine and a platinum compound based chemotherapy. During 4th cycle of chemotherapy, patient complained of chest pain following cisplatin and gemcitabine infusion. ECG was suggestive of acute coronary syndrome, which was successfully managed by antianginal therapy. Fifth cycle of chemotherapy was uneventful. Patient died of cardiovascular collapse before receiving the 6th cycle of chemotherapy. As per Naranjo adverse drug reaction probability scale, causal association of the event with cisplatin and gemcitabine was probable and possible respectively. It is advised to routinely assess the cardiovascular status of patients before and during cisplatin and/or gemcitabine based chemotherapy. PMID- 27762527 TI - Post-Partum Angiopathy presenting as Ischemic Stroke. AB - Post-partum angiopathy is grouped within the category of reversible cerebral vasoconstriction syndromes. It is considered to be a rare but under-recognized cause of stroke especially in pregnancy. We present the case of a 24 year old female who presented with hemiparesis and seizure, and turned out to be a case of post partum angiopathy. PMID- 27762528 TI - Delayed Haemothorax Resulting from Indwelling Right Internal Jugular Central Venous Catheter: A Rare Complication. AB - Haemothorax is an uncommon and serious complication, occurring most often during or immediately after percutaneous internal jugular and subclavian vein catheterizations. Delayed haemothorax is a rare complication, especially following right-sided catheterization. We report a case of acute yellow phosphorus poisoning with acute liver failure (resulting from rat killer paste ingestion) in a 28-year-old male who developed right-sided haemothorax eight days after placement of right internal jugular central venous catheter. The proposed pathogenesis involves vascular wall erosion by the indwelling catheter tip. Awareness of this complication perhaps avoids unnecessary investigations for other causes of haemothorax such as pulmonary embolism. PMID- 27762529 TI - Acute Antero-Inferior Wall Ischaemia with Acute Ischaemic Stroke Caused by Oral Ingestion of Cannabis in a Young Male. AB - Cannabis is a frequently used illicit recreational drug that is known to be associated with a variety of psychopharmacological effects. Negative somatic effects such as myocardial infarction and stroke have been reported, though, less frequently. Most of the literature available has focused on the complications due to smoked forms of cannabis (ganja and charas). Here we report a case of acute myocardial ischaemia with acute ischaemic stroke developing after oral ingestion of 'Bhang', a preparation of cannabis. PMID- 27762530 TI - Acute Transverse Myelitis and Nicolau Syndrome after Benzathine Penicillin Injection. AB - Rare complications have been documented due to inadvertent intravascular administration of penicillin such as Nicolau syndrome (lipoatrophy), transverse myelitis, injury to sciatic nerve as well as Hoigne syndrome (transient central nervous system dysfunction).1 We present a case report where a young male developed Nicolau syndrome and transverse myelitis after receiving benzathine penicillin injection. PMID- 27762531 TI - Epilepsy. PMID- 27762532 TI - Alan Lloyd Hodgkin- Nerve impulses. PMID- 27762533 TI - Tubercular Addison' Disease- an Under-Diagnosed Entity. PMID- 27762534 TI - Polycythemia causing Cerebral Venous Thrombosis-A Case Series. PMID- 27762535 TI - Evident Enhancement of Photoelectrochemical Hydrogen Production by Electroless Deposition of M-B (M = Ni, Co) Catalysts on Silicon Nanowire Arrays. AB - Modification of p-type Si surface by active and stable earth-abundant electrocatalysts is an effective strategy to improve the sluggish kinetics for the hydrogen evolution reaction (HER) at p-Si/electrolyte interface and to develop highly efficient and low-cost photocathodes for hydrogen production from water. To this end, Si nanowire (Si-NW) array has been loaded with highly efficient electrocatalysts, M-B (M = Ni, Co), by facile and quick electroless plating to build M-B catalyst-modified Si nanowire-array-textured photocathodes for water reduction to H2. Compared with the bare Si-NW array, composite Si-NWs/M B arrays display evidently enhanced photoelectrochemical (PEC) performance. The onset potential (Vphon) of cathodic photocurrent is positively shifted by 530-540 mV to 0.44-0.45 V vs RHE, and the short-circuit current density (Jsc) is up to 19.5 mA cm-2 in neutral buffer solution under simulated 1 sun illumination. Impressively, the half-cell photopower conversion efficiencies (etahc) of the optimized Si-NWs/Co-B (2.53%) and Si-NWs/Ni-B (2.45%) are comparable to that of Si-NWs/Pt (2.46%). In terms of the large Jsc, Vphon, and etahc values, as well as the high Faradaic efficiency, Si-NWs/M-B electrodes are among the top performing Si photocathodes which are modified with HER electrocatalysts but have no buried solid/solid junction. PMID- 27762536 TI - UV-Mediated Photochemical Treatment for Low-Temperature Oxide-Based Thin-Film Transistors. AB - Solution processing of amorphous metal oxides has lately been used as an option to implement in flexible electronics, allowing a reduction of the associated costs and high performance. However, the research has focused more on the semiconductor layer rather than on the insulator layer, which is related to the stability and performance of the devices. This work aims to evaluate amorphous aluminum oxide thin films produced by combustion synthesis and the influence of far-ultraviolet (FUV) irradiation on the properties of the insulator on thin-film transistors (TFTs) using different semiconductors, in order to have compatibility with flexible substrates. An optimized dielectric layer was obtained for an annealing of 30 min assisted by FUV exposure. These thin films were applied in gallium-indium-zinc oxide TFTs as dielectrics showing the best results for TFTs annealed at 180 degrees C with FUV irradiation: good reproducibility with a subthreshold slope of 0.11 +/- 0.01 V dec -1 and a turn-on voltage of -0.12 +/- 0.05 V, low operating voltage, and good stability over time. Finally, the dielectric layer was applied in solution-processed indium oxide (In2O3) TFTs at low temperature, 180 degrees C, with a short processing time being compatible with flexible electronic applications. PMID- 27762537 TI - Biomimetic Hydrogel Composites for Soil Stabilization and Contaminant Mitigation. AB - We have developed a novel method to synthesize a hyper-branched biomimetic hydrogel network across a soil matrix to improve the mechanical strength of the loose soil and simultaneously mitigate potential contamination due to excessive ammonium. This method successfully yielded a hierarchical structure that possesses the water retention, ion absorption, and soil aggregation capabilities of plant root systems in a chemically controllable manner. Inspired by the robust organic-inorganic composites found in many living organisms, we have combined this hydrogel network with a calcite biomineralization process to stabilize soil. Our experiments demonstrate that poly(acrylic acid) (PAA) can work synergistically with enzyme-induced carbonate precipitation (EICP) to render a versatile, high-performance soil stabilization method. PAA-enhanced EICP provides multiple benefits including lengthening of water supply time, localization of cementation reactions, reduction of harmful byproduct ammonium, and achievement of ultrahigh soil strength. Soil crusts we have obtained can sustain up to 4.8 * 103 kPa pressure, a level comparable to cementitious materials. An ammonium removal rate of 96% has also been achieved. These results demonstrate the potential for hydrogel-assisted EICP to provide effective soil improvement and ammonium mitigation for wind erosion control and other applications. PMID- 27762538 TI - Heat Transfer Organic Materials: Robust Polymer Films with the Outstanding Thermal Conductivity Fabricated by the Photopolymerization of Uniaxially Oriented Reactive Discogens. AB - For the development of advanced heat transfer organic materials (HTOMs) with excellent thermal conductivities, triphenylene-based reactive discogens, 2,3,6,7,10,11-hexakis(but-3-enyloxy)triphenylene (HABET) and 4,4',4",4''',4'''',4'''''-(triphenylene-2,3,6,7,10,11 hexaylhexakis(oxy))hexakis(butane-1-thiol) (THBT), were synthesized as discotic liquid crystal (DLC) monomers and cross-linkers, respectively. A temperature composition phase diagram of HABET-THBT mixtures was first established based on their thermal and microscopic analyses. From the experimental results, it was realized that the thermal conductivity of DLC HTOM was strongly affected by the molecular organizations on a macroscopic length scale. Macroscopic orientation of self-assembled columns in DLC HTOMs was effectively achieved under the rotating magnetic fields and successfully stabilized by the photopolymerization. The DLC HTOM polymer-stabilized at the LC phase exhibited the remarkable thermal conductivity above 1 W/mK. When the DLC HTOM was macroscopically oriented, the thermal conductivity was estimated to be 3 W/mK along the in-plane direction of DLC molecule. The outstanding thermal conductivity of DLC HTOM should be originated not only from the high content of two-dimensional aromatic discogens but also from the macroscopically oriented and self-assembled DLC. The newly developed DLC HTOM with an outstanding thermal conductivity as well as with an excellent mechanical sustainability can be applied as directional heat dissipating materials in electronic and display devices. PMID- 27762539 TI - Relationships between Poly(ethylene glycol) Modifications on RNA-Spherical Nucleic Acid Conjugates and Cellular Uptake and Circulation Time. AB - Two synthetic approaches that allow one to control PEG content within spherical nucleic acids (SNAs) have been developed. One approach begins with RNA-modified gold nanoparticles followed by a backfill of PEG 2K alkanethiols, and the other involves co-adsorption of the two entities on a gold nanoparticle template. These two methods have been used to explore the role of PEG density on the chemical and biological properties of RNA-SNAs. Such studies show that while increasing the extent of PEGylation within RNA-SNAs extends their blood circulation half-life in mice, it also results in decreased cellular uptake. Modified ELISA assays show that constructs, depending upon RNA and PEG content, have markedly different affinities for class A scavenger receptors, the entities responsible, in part, for cellular internalization of SNAs. In designing SNAs for therapeutic purposes, these competing factors must be considered and appropriately adjusted depending upon the desired use. PMID- 27762540 TI - Electro-Photodynamic Visualization of Singlet Oxygen Induced by Zinc Porphyrin Modified Microchip in Aqueous Media. AB - A porphyrin-based electro-photodynamic imaging system was fabricated for monitoring the concentration of oxygen. Distinct from the electrochemiluminescent (ECL) inability of numerous organic species in aqueous solutions, a strong and stable red irradiation at 634 nm could be stimulated electrochemically on zinc(II) meso-tetra(4-carboxyphenyl) porphine (ZnTCPP)/tetraoctylammonium bromide (TOAB) in the physiological condition. In terms of in situ electron paramagnetic resonance and ECL spectroscopies, the nature of ECL was thoroughly investigated, being exactly the chemiluminescence from singlet oxygen (1O2) produced during the successive electro-reduction of ZnTCPP. Meanwhile, the excellent film-making capacity of amphiphilic TOAB as a potent ion barrier granted the luminophores a micro-order and patternable electrode modification. Such platform was exceptionally tolerant of pH variation, facilitating a durable solid-state ECL visualization under potentiostatic electrolysis and time exposure in the charge coupled device (CCD) camera. For flow-injection and real-time detection, a chip mounted microfluidic cell was customized and manufactured. A sensitive and simple vision-sensing of O2 was further achieved with a real determination limit as low as a few micromolar level. The developed ECL imaging system is a good prototype and an eco-friendly technique in the cathodic range, and thus, it would supplement the primary anodic imaging library, showing great promise for multiplexed and colorimetric assays as well as oxygen-involved activity studies in the future. PMID- 27762542 TI - Simultaneous Graphite Exfoliation and N Doping in Supercritical Ammonia. AB - We report the exfoliation of graphite and simultaneous N doping of graphene by two methods: supercritical ammonia treatment and liquid-phase exfoliation with NH4OH. While the supercritical ammonia allowed N doping at a level of 6.4 atom % in 2 h, the liquid-phase exfoliation with NH4OH allowed N doping at a level of 2.7 atom % in 6 h. The N doped graphene obtained via the supercritical ammonia route had few layers (<5) and showed large lateral flake size (~8 MUm) and low defect density (ID/IG < 0.6) in spite of their high level of N doping. This work is the first demonstration of supercritical ammonia as an exfoliation agent and N doping precursor for graphene. Notably, the N doped graphene showed electrocatalytic activity toward oxygen reduction reaction with high durability and good methanol tolerance compared to those of commercial Pt/C catalyst. PMID- 27762543 TI - A One Donor-Two Acceptor Lipid Bilayer FRET Assay Based on Asymmetrically Labeled Liposomes. AB - The fusion of two opposing membranes is essential in biological functions such as fertilization, viral entry, membrane trafficking and synaptic transmission. Before the membrane bilayers are fully connected, at some stage a hemifusion intermediate-when the outer leaflets are merged but not the inner leaflets-is formed. However, the position of hemifusion in the energy landscape and the duration of it vary and have not been fully mapped out. To date, there has not been a way to differentiate lipid mixing of the two leaflets directly in a single experiment. Herein we demonstrate labeling of the outer and inner leaflets with different fluorophores, which can be distinguished by their fluorescence lifetimes. As a proof of concept, the asymmetrically labeled liposomes were used as acceptor liposomes in a novel one donor-two acceptor Forster resonance energy transfer (FRET) assay to monitor membrane fusion reactions mediated by the synaptic proteins soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) in microfluidic devices. Initial hemifusion was clearly indicated by the acceptor fluorescence lifetime originating solely from FRET acceptors on the outer leaflet (Oregon Green 488; tauFl ~ 4.8 ns). Progression to full fusion was then indicated by the significantly increasing lifetime contribution from acceptors on the inner leaflet (nitrobenzoxadiazole; tauFl ~ 6.7 ns). The new labeling strategy creates many possibilities in the design of bulk and single-molecule experiments. PMID- 27762544 TI - Enhancing Cycling Stability of Aqueous Polyaniline Electrochemical Capacitors. AB - Electrochemical capacitors fabricated with polyaniline nanofibers are cycled 150 000 times with 98% capacitance retention. These devices maintain an energy density of 11.41 Wh/kg at a power density of 4000 W/kg, 64 times greater than that of an identically fabricated device based on activated carbon (0.177 Wh/kg at 4600 W/kg). For applications requiring a higher specific energy, 33.39 Wh/kg at a specific power of 600 W/kg is obtained by widening the voltage window; this device retains 93% capacitance after 10 000 cycles. We achieve a high cycling stability through careful device engineering paired with a renewed focus on the electrochemical processes occurring at the positive and negative electrodes during cycling. PMID- 27762545 TI - New Solid-Base Cu-MgO for CO2 Capture at 473 K and Removal of Nitrosamine. AB - To fabricate a new solid base with high efficiency in the adsorption of CO2 at 473 K and catalytic activity in the degradation of nitrosamines, magnesium oxalate and copper nitrate are mixed with the assistance of microwave irradiation followed by calcination to immobilize CuO among MgO particles. The binary solid base CuO-MgO is thus moderately reduced to form the Cu-inserted MgO composite with highly exposed strong basic sites, and it can capture 34.6 mg g-1 of CO2 in the harsh instantaneous adsorption at 473 K and keep a high strong basicity while trapping the CO2 mixed with SO2 and NO. Besides this, the new solid base exhibits high activity in the removal of volatile nitrosamine N-nitrosopyrrolidine (NPYR), for the first time expanding the application of solid bases to environmental catalysis. PMID- 27762546 TI - Microsized Porous SiOx@C Composites Synthesized through Aluminothermic Reduction from Rice Husks and Used as Anode for Lithium-Ion Batteries. AB - Microsized porous SiOx@C composites used as anode for lithium-ion batteries (LIBs) are synthesized from rice husks (RHs) through low-temperature (700 degrees C) aluminothermic reduction. The resulting SiOx@C composite shows mesoporous irregular particle morphology with a high specific surface area of 597.06 m2/g under the optimized reduction time. This porous SiOx@C composite is constructed by SiOx nanoparticles uniformly dispersed in the C matrix. When tested as anode material for LIBs, it displays considerable specific capacity (1230 mAh/g at a current density of 0.1 A/g) and excellent cyclic stability with capacity fading of less than 0.5% after 200 cycles at 0.8 A/g. The dramatic volume change for the Si anode during lithium-ion (Li+) insertion and extraction can be successfully buffered because of the formation of Li2O and Li4SiO4 during initial lithiation process and carbon coating layer on the surface of SiOx. The porous structure could also mitigate the volume change and mechanical strains and shorten the Li+ diffusion path length. These characteristics improve the cyclic stability of the electrode. This low-cost and environment-friendly SiOx@C composite anode material exhibits great potential as an alternative for traditional graphite anodes. PMID- 27762541 TI - Nanoyeast and Other Cell Envelope Compositions for Protein Studies and Biosensor Applications. AB - Rapid progress in disease biomarker discovery has increased the need for robust detection technologies. In the past several years, the designs of many immunoaffinity reagents have focused on lowering costs and improving specificity while also promoting stability. Antibody fragments (scFvs) have long been displayed on the surface of yeast and phage libraries for selection; however, the stable production of such fragments presents challenges that hamper their widespread use in diagnostics. Membrane and cell wall proteins similarly suffer from stability problems when solubilized from their native environment. Recently, cell envelope compositions that maintain membrane proteins in native or native like lipid environment to improve their stability have been developed. This cell envelope composition approach has now been adapted toward stabilizing antibody fragments by retaining their native cell wall environment. A new class of immunoaffinity reagents has been developed that maintains antibody fragment attachment to yeast cell wall. Herein, we review recent strategies that incorporate cell wall fragments with functional scFvs, which are designed for easy production while maintaining specificity and stability when in use with simple detection platforms. These cell wall based antibody fragments are globular in structure, and heterogeneous in size, with fragments ranging from tens to hundreds of nanometers in size. These fragments appear to retain activity once immobilized onto biosensor surfaces for the specific and sensitive detection of pathogen antigens. They can be quickly and economically generated from a yeast display library and stored lyophilized, at room temperature, for up to a year with little effect on stability. This new format of scFvs provides stability, in a simple and low-cost manner toward the use of scFvs in biosensor applications. The production and "panning" of such antibody cell wall composites are also extremely facile, enabling the rapid adoption of stable and inexpensive affinity reagents for emerging infectious threats. PMID- 27762548 TI - Toward Molecular Magnets of Organic Origin via Anion-pi Interaction Involving m Aminyl Diradical: A Theoretical Study. AB - Here we study a set of novel magnetic organic molecular species with different halide ions (fluoride, chloride, bromide) absorbed ~2 A above or below the center of an aromatic pi-ring in an m-aminyl diradical. Focus is on the nature of anion pi interaction and its impact on magnetic properties, specifically on magnetic anisotropy and on intramolecular magnetic exchange coupling. In the development of single molecule magnets, magnetic anisotropy is considered to be the most influential factor. A new insight regarding the magnetic anisotropy that determines the barrier height for relaxation of magnetization of m-aminyl diradical-derived anionic complexes is obtained from calculations of the axial zero-field-splitting (ZFS) parameter D. The noncovalent anion-pi interaction strongly influences magnetic anisotropy in m-aminyl-halide diradical complexes. In particular, the change of D values from positive (for the m-aminyl diradical, m-aminyl diradical/fluoride, and m-aminyl diradical/chloride complexes) to negative D-values in m-aminyl diradical complexes containing bromide signals a change from oblate to prolate type of spin-density distribution. Furthermore, the noncovalent halide-pi interactions lead to large values of intramolecular magnetic exchange coupling coefficients J exhibiting a ferromagnetic sign. The magnitude of J steadily increases going from anionic complexes containing fluoride to chloride and then to bromide. Relations are sought between the magnetic exchange coupling coefficients J and aromaticity, namely structural HOMA (harmonic oscillator model of aromaticity) and magnetic NICS (nucleus independent chemical shift) aromaticity indices, in particular, the NICSzz(+1) component. Finally, possible numerical checks on the conditions relating to validity of the well-known Yamaguchi's formula for calculating the exchange coupling coefficient J in diradical systems are discussed. PMID- 27762547 TI - Impact of Collagen/Heparin Multilayers for Regulating Bone Cellular Functions. AB - Bone cell interaction with extracellular matrix (ECM) microenvironment is of critical importance when engineering surface interfaces for bone regeneration. In this work layer-by-layer films of type I collagen (coll), the major constituent of bone ECM, and heparin (hep), a glycosaminoglycan, were assembled on poly(l lactic acid) (PLLA) substrates to evaluate the impact of the biomacromolecular coating on cell activity. The surface modification of PLLA demonstrated that the hep/coll multilayer is stable after 10 bilayers (confirmed by contact angle, infrared spectroscopy, and morphological analysis). This simple approach provided novel information on the effect of heparin on type I collagen hierarchical organization and subsequent cell response of osteoblast-like (MC3T3-E1) and human bone marrow-derived mesenchymal stem cells (hMSCs). Interestingly, the number of deposited heparin layers (1 or 10) appeared to play an important role in the self assembly of collagen into fibrils, stabilizing the fibrous collagen layer, and potentially impacting hMSCs activity. PMID- 27762549 TI - Enantioselective Formation of All-Carbon Quaternary Centers via C-H Functionalization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation. AB - The first catalytic enantioselective C-C couplings of methanol (>30 * 106 tons/year) are reported. Insertion of 2-substituted dienes into the methanol C-H bond occurs in a regioselective manner to form all-carbon quaternary centers with excellent levels of enantioselectivity using an iridium-PhanePhos catalyst. Mechanistic studies corroborate a Curtin-Hammett scenario in which methanol dehydrogenation triggers rapid, reversible diene hydrometalation en route to regioisomeric allyliridium-formaldehyde pairs, yet single constitutional isomers are formed. PMID- 27762550 TI - First-Principle Characterization of the Adsorption Configurations of Cyanoacrylic Dyes on TiO2 Film for Dye-Sensitized Solar Cells. AB - The loading of sensitizers on a semiconductor is crucial for determining the light-harvesting efficiency of dye-sensitized solar cells (DSSCs). The interfacial properties of dyes adsorbed on a TiO2 film, such as adsorption configurations and adsorption energy, can influence the total amount of dye sensitizers that loads and the stability of a DSSC device. Therefore, it is important to characterize the adsorption properties of sensitizers on TiO2 films atomically and electronically to ensure rational structure-based dye design for high-performance DSSCs. Due to the complex properties of interfacial dyes, previous works on the identification of adsorption configurations of dyes on TiO2 have sometimes been controversial, in particular, the essential IR band assignments. In this study, we employed density functional theory to investigate the adsorption energies, geometries, and vibrational frequencies of various adsorption configurations of 2-cyano-3-(thiophen-2-yl)acrylic acid adsorbed on TiO2. We performed a comparative assignment of the calculated vibrational peaks of tridentate and bidentate configurations to the experimental FT-IR spectra simultaneously. Our work backs up the coexistence of tridentate and bidentate bridging configurations, first proposed by Meng and co-workers. Moreover, our comparative IR mode assignments provide clues for further studies of the interfacial properties of dyes adsorbed on TiO2. Study of the transformation mechanisms between tridentate and bidentate modes suggests that the bidentate bridging configuration is a kinetically trapped adsorption mode and the tridentate configuration is thermodynamically the most stable one. Finally, we investigated the photophysical properties of a D-pi-A dye in tridentate and bidentate adsorption configurations. PMID- 27762551 TI - Preparation of Polyethylene Composites Containing Silver(I) Acylpyrazolonato Additives and SAR Investigation of their Antibacterial Activity. AB - Novel composite materials PEn (n = 1-9) have been prepared by an easily up scalable embedding procedure of three different families of Ag(I) acylpyrazolonato complexes in polyethylene (PE) matrix. In details, PE1-PE3 composites contain polynuclear [Ag(QR)]n complexes, PE4-PE6 contain mononuclear [Ag(QR)(L)m] complexes and PE7-PE9 are loaded with mononuclear [Ag(QR) (PPh3)2] complexes, respectively (where L = 1-methylimidazole or 2-ethylimidazole, m = 1 or 2, and HQR = 1-phenyl-3-methyl-4-RC(?O)-5-pyrazolone, where in detail HQfb, R = -CF2CF2CF3; HQcy, R = -cyclo-C6H11; HQbe, R = -C(H)?C(CH3)2). The PEn composites, prepared by using a 1:1000 w/w silver additive/polyethylene ratio, have been characterized in bulk by IR spectroscopy and TGA analyses, which confirmed that the properties of polyethylene matrix are essentially unchanged. AFM, SEM, and EDX surface techniques show that silver additives form agglomerates with dimensions 10-100 MUm on the polyethylene surface, with a slight increment of surface roughness of pristine plastic within 50 nm. However, the elastic properties of the composites are essentially the same of PE. The antibacterial activity of all composites has been tested against three bacterial strains (E. coli, P. aeruginosa and S. aureus) and results show that two classes of composites, PE1-PE3 and PE4-PE6, display high and persistent bactericidal and bacteriostatic activity, comparable to PE embedded with AgNO3. By contrast, composites PE7-PE9 exhibit a reduced antibacterial action. Contact and release tests in several conditions for specific migration of Ag+ from plastics, indicate a very limited but time persistent release of silver ions from PE1-PE6 composites, thus suggesting that they are potential antibacterial materials for future applications. Instead, PE7-PE9 almost do not release silver, only trace levels of silver ions being detected, in accordance with their reduced antibacterial action. None of the composites is toxic against higher organisms, as confirmed by D. magna test of ecotoxicity. PMID- 27762552 TI - Conformational Polymorphism of Lithium Pinacolone Enolate. AB - A metastable, polymorphic hexameric crystal structure of lithium pinacolone enolate (LiOPin) is reported along with three preparation methods. NMR-based structural characterization implies that the lithium pinacolate hexamer deaggregates to a tetramer in toluene but retains mainly the hexameric structure in nonaromatic hydrocarbon solvents such as cyclohexane. Moreover, the presence of a small amount of lithium aldolate (LiOA) dramatically influences the aggregation state of LiOPin by forming a mixed aggregate with a 3:1 ratio (LiOPin3.LiOA). PMID- 27762553 TI - Theoretical Study on the Mechanism of the Thermal Retro-Cycloaddition of Isoxazolinofullerenes. AB - The retro-cycloaddition thermal reaction of isoxazolino[4,5:1,2][60]fullerenes to pristine fullerene seems to be guided by the electronic nature of the substituted nitrile oxide 1,3-dipole in the isoxazoline ring. Trapping experiments proved that the reaction mechanism occurs by thermal removal of the nitrile oxide 1,3 dipole in a process that is favored in the presence of a big excess of a highly efficient dipolarophile such as maleic anhydride. Theoretical gas phase calculations carried out at the B3LYP/6-31G(d) and M06-2X/6-31G(d) levels of theory underpin the experimental findings and predict that compound 1c, bearing the p-(CH3)2N-Ph substituent on the isoxazoline ring and with a remarkable experimental conversion efficiency in just 12 h, showed the lowest activation energy. Solvent calculations have predicted the same behavior in gas phase. Different approaches such as electrostatic natural population analysis and Houk's distortion/interaction model have been applied to understand how the electronic nature of these substituents affects the retro-cycloaddition reaction process. Analysis of the values of the condensed Fukui functions and dual descriptor shed light on the mechanism of the retro-cycloaddition reaction. PMID- 27762554 TI - Performance of Dark Chemical Matter in High Throughput Screening. AB - A statistical analysis of 203 high-throughput screens was conducted studying the propensity of small molecules in the Boehringer Ingelheim screening deck to show biological activity after having tested as inactive previously in a growing number of screening assays. Dark chemical matter (DCM) compounds, which have been tested and found to be inactive in 50 or more assays, exhibit hit rates that are comparable to those of compounds tested in much fewer assays. Only compounds tested as inactive in 125 or more assays started showing a hit rate deterioration of up to 40% compared to compounds tested in less than 25 assays. The observed large number of DCM compounds in the BI screening deck is found to be in line with the expected fraction of DCM calculated based on a probability analysis. The analysis suggests not only that DCM compounds have the chance to occasionally provide valuable hits associated with higher selectivity as recently shown by Novartis ( Nat. Chem. Biol. 2015 , 11 , 958 ) but that there is little compelling reason to exclude DCM compounds from screening decks in favor of previously untested or less tested compounds. PMID- 27762555 TI - Synthesis of Gly-psi[(Z)CF?CH]-Phe, a Fluoroalkene Dipeptide Isostere, and Its Incorporation into a Leu-enkephalin Peptidomimetic. AB - A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepared and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-psi[(Z)CF?CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane extracts of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the electrically induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biological activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes. PMID- 27762556 TI - Full-Dimensional Potential Energy and Dipole Moment Surfaces of GeH4 Molecule and Accurate First-Principle Rotationally Resolved Intensity Predictions in the Infrared. AB - Nine-dimensional potential energy surface (PES) and dipole moment surface (DMS) of the germane molecule are constructed using extended ab initio CCSD(T) calculations at 19 882 points. PES analytical representation is determined as an expansion in nonlinear symmetry adapted products of orthogonal and internal coordinates involving 340 parameters up to eighth order. Minor empirical refinement of the equilibrium geometry and of four quadratic parameters of the PES computed at the CCSD(T)/aug-cc-pVQZ-DK level of the theory yielded the accuracy below 1 cm-1 for all experimentally known vibrational band centers of five stable isotopologues of 70GeH4, 72GeH4, 73GeH4, 74GeH4, and 76GeH4 up to 8300 cm-1. The optimized equilibrium bond re = 1.517 594 A is very close to best ab initio values. Rotational energies up to J = 15 are calculated using potential expansion in normal coordinate tensors with maximum errors of 0.004 and 0.0006 cm 1 for 74GeH4 and 76GeH4. The DMS analytical representation is determined through an expansion in symmetry-adapted products of internal nonlinear coordinates involving 967 parameters up to the sixth order. Vibration-rotation line intensities of five stable germane isotopologues were calculated from purely ab initio DMS using nuclear motion variational calculations with a full account of the tetrahedral symmetry of the molecules. For the first time a good overall agreement of main absorption features with experimental rotationally resolved Pacific Northwest National Laboratory spectra was achieved in the entire range of 700-5300 cm-1. It was found that very accurate description of state-dependent isotopic shifts is mandatory to correctly describe complex patterns of observed spectra at natural isotopic abundance resulting from the superposition of five stable isotopologues. The data obtained in this work will be made available through the TheoReTS information system. PMID- 27762557 TI - Parallel Control over Surface Charge and Wettability Using Polyelectrolyte Architecture: Effect on Protein Adsorption and Cell Adhesion. AB - Surface charge and wettability, the two prominent physical factors governing protein adsorption and cell adhesion, have been extensively investigated in the literature. However, a comparison between these driving forces in terms of their independent and cooperative effects in affecting adhesion is rarely explored on a systematic and quantitative level. Herein, we formulate a protocol that features two-dimensional control over both surface charge and wettability with limited cross-parameter influence. This strategy is implemented by controlling both the polyion charge density in the layer-by-layer (LbL) assembly process and the polyion side-chain chemical structures. The 2D property matrix spans surface isoelectric points ranging from 5 to 9 and water contact angles from 35 to 70 degrees , with other interferential factors (e.g., roughness) eliminated. The interplay between these two surface variables influences protein (bovine serum albumin, lysozyme) adsorption and 3T3 fibroblast cell adhesion. For proteins, we observe the presence of thresholds for surface wettability and electrostatic driving forces necessary to affect adhesion. Beyond these thresholds, the individual effects of electrostatic forces and wettability are observed. For fibroblast, both surface charge and wettability have an effect on its adhesion. The combined effects of positive charge and hydrophilicity lead to the highest cell adhesion, whereas negative charge and hydrophobicity lead to the lowest cell adhesion. Our design strategy can potentially form the basis for studying the distinct behaviors of electrostatic force or wettability driven interfacial phenomena and serve as a reference in future studies assessing protein adsorption and cell adhesion to surfaces with known charge and wettability within the property range studied here. PMID- 27762558 TI - Engineered Solution-Liquid-Solid Growth of a "Treelike" 1D/1D TiO2 Nanotube-CdSe Nanowire Heterostructure: Photoelectrochemical Conversion of Broad Spectrum of Solar Energy. AB - This work presents a hitherto unreported approach to assemble a 1D oxide-1D chalcogenide heterostructured photoactive film. As a representative system, bismuth (Bi) catalyzed 1D CdSe nanowires are directly grown on anodized 1D TiO2 nanotube (T_NT). A combination of the reductive successive-ionic-layer-adsorption reaction (R-SILAR) and the solution-liquid-solid (S-L-S) approach is implemented to fabricate this heterostructured assembly, reported in this 1D/1D form for the first time. XRD, SEM, HRTEM, and elemental mapping are performed to systematically characterize the deposition of bismuth on T_NT and the growth of CdSe nanowires leading to the evolution of the 1D/1D heterostructure. The resulting "treelike" photoactive architecture demonstrates UV-visible light driven electron-hole pair generation. The photoelectrochemical results highlight: (i) the formation of a stable n-n heterojunction between TiO2 nanotube and CdSe nanowire, (ii) an excellent correlation between the absorbance vis-a-vis light conversion efficiency (IPCE), and (iii) a photocurrent density of 3.84 mA/cm2. This proof-of-concept features the viability of the approach for designing such complex 1D/1D oxide-chalcogenide heterostructures that can be of interest to photovoltaics, photocatalysis, environmental remediation, and sensing. PMID- 27762559 TI - Group 12 Metal Complexes of an 18-Membered N2O2S2 Macrocycle Incorporating Two Pyridines: First Examples of an Infinite Mercury(I) Complex and a Dumbbell-Shaped Heteronuclear Complex with a Macrocyclic Ligand. AB - Homo- and heteronuclear group 12 metal (Zn2+, Cd2+, and Hg2+) complexes 1-6 containing a newly designed 18-membered N2O2S2 macrocycle incorporating two pyridine subunits (L) were prepared and structurally characterized. The individual complexes isolated exhibit unusual stoichiometries, geometries, oxidation states, and structural topologies and include an infinite mercurous complex and a heteronuclear dumbbell-shaped complex. Both the Zn(II) complex [Zn(L)][ZnBr4] (1) and the Cd(II) complex [Cd(L)Br2] (2) are mononuclear, with the metal ion located inside the macrocyclic cavity. The six-coordinated Zn(II) center in 1 adopts an octahedral geometry and is shielded from the anion and solvent by the strongly bound macrocycle. The Cd(II) center in 2 is seven coordinate, being bound equatorially to two N donors, two O donors, and a S donor from the macrocycle and axially to two bromide ions on opposite sides of the macrocyclic plane, adopting a pentagonal-bipyramidal geometry. In the Hg(II) complexations, the configuration adopted by the macrocycle L shows a dependence of the nuclearity on the anion used. When mercury(II) bromide was used, the dinuclear complex [HgII2(L)Br4] (3) was obtained, while the reaction with mercury(II) nitrate afforded the unexpected Hg(I) complex {[HgI2(L)](NO3)2}n (4) with a one-dimensional polymeric structure. In heterometallic complexation experiments, one-pot reaction of L with a mixture of ZnBr2 and CdBr2.4H2O resulted in the stepwise isolation of two pure solubility-dependent Cd(II) complexes (2 and 5), including the half-dumbbell-type complex [Cd(L)(MU Br)(CdBr3)] (5), while a mixture of CdBr2.4H2O and HgBr2 yielded the heterometallic bis(macrocycle) product [(CdL)2(MU-Hg2Br6)](Hg2Br6) (6). This is the first example of a heteronuclear dumbbell-shaped complex in which two terminal macrocyclic Cd(II) complexes are linked by a hexabromodimercury(II) cluster via Cd-Br-Hg bonds. The heterometallic dumbbell 6 can be considered as a good example of competition and collaboration between Cd(II) and Hg(II) ions because its formation is associated with the higher coordination affinity of Cd(II) toward the macrocycle and the formation of the (Hg2Br6)2- cluster, which links the two endocyclic Cd(II) complexes directly. Both NMR titration and comparative NMR data indicate a relatively higher coordination affinity of Cd(II) toward the macrocycle than occurs for Hg(II), in parallel to the situation observed in the solid state. PMID- 27762560 TI - Injectable, Biomolecule-Responsive Polypeptide Hydrogels for Cell Encapsulation and Facile Cell Recovery through Triggered Degradation. AB - Injectable hydrogels have been widely investigated in biomedical applications, and increasing demand has been proposed to achieve dynamic regulation of physiological properties of hydrogels. Herein, a new type of injectable and biomolecule-responsive hydrogel based on poly(l-glutamic acid) (PLG) grafted with disulfide bond-modified phloretic acid (denoted as PLG-g-CPA) was developed. The hydrogels formed in situ via enzymatic cross-linking under physiological conditions in the presence of horseradish peroxidase and hydrogen peroxide. The physiochemical properties of the hydrogels, including gelation time and the rheological property, were measured. Particularly, the triggered degradation of the hydrogel in response to a reductive biomolecule, glutathione (GSH), was investigated in detail. The mechanical strength and inner porous structure of the hydrogel were influenced by the addition of GSH. The polypeptide hydrogel was used as a three-dimensional (3D) platform for cell encapsulation, which could release the cells through triggered disruption of the hydrogel in response to the addition of GSH. The cells released from the hydrogel were found to maintain high viability. Moreover, after subcutaneous injection into rats, the PLG-g-CPA hydrogels with disulfide-containing cross-links exhibited a markedly faster degradation behavior in vivo compared to that of the PLG hydrogels without disulfide cross-links, implying an interesting accelerated degradation process of the disulfide-containing polypeptide hydrogels in the physiological environment in vivo. Overall, the injectable and biomolecule-responsive polypeptide hydrogels may serve as a potential platform for 3D cell culture and easy cell collection. PMID- 27762561 TI - General Approach To Construct Photoresponsive Self-Assembly in a Light-Inert Amphiphilic System. AB - The ability to modulate amphiphilic aggregation reversibly with external stimuli, especially using light as a trigger, is of great importance. This has greatly contributed to the development of applications using self-assembly. However, most previously described systems are based on a specific molecular design and have shown difficultly in their application to light-inert aggregation. Here, we developed a general and effective approach to control the morphology of amphiphilic aggregates by light, which is suitable for different assemblies such as micelles, vesicles, and helixes. Our strategy is to construct a photoresponsive factor into light-inert self-assemblies. On the basis of the different capabilities to form host-guest inclusions between photoresponsive azobenzene sodium and light-inert molecules with cyclodextrin, the transformation of the corresponding amphiphilic aggregation can be controlled easily and reversibly by light stimuli. Not only the nanostructure of the aggregates but also the phase behavior, such as gel formation, can be modulated upon light irradiation using this method. PMID- 27762563 TI - Mesoscopic Simulations of Adsorption and Association of PEO-PPO-PEO Triblock Copolymers on a Hydrophobic Surface: From Mushroom Hemisphere to Rectangle Brush. AB - The dissipative particle dynamics (DPD) method is used to investigate the adsorption behavior of PEO-PPO-PEO triblock copolymers at the liquid/solid interface. The effect of molecular architecture on the self-assembled monolayer adsorption of PEO-PPO-PEO triblock copolymers on hydrophobic surfaces is elucidated by the adsorption process, film properties, and adsorption morphologies. The adsorption thicknesses on hydrophobic surfaces and the diffusion coefficient as well as the aggregation number of Pluronic copolymers in aqueous solution observed in our simulations agree well with previous experimental and numerical observations. The radial distribution function revealed that the ability of self-assembly on hydrophobic surfaces is P123 > P84 > L64 > P105 > F127, which increased with the EO ratio of the Pluronic copolymers. Moreover, the shape parameter and the degree of anisotropy increase with increasing molecular weight and mole ratio of PO of the Pluronic copolymers. Depending on the conformation of different Pluronic copolymers, the morphology transition of three regimes on hydrophobic surfaces is present: mushroom or hemisphere, progressively semiellipsoid, and rectangle brush regimes induced by decreasing molecular weight and mole ratio of EO of Pluronic copolymers. PMID- 27762564 TI - Active and Recyclable Catalytic Synthesis of Indoles by Reductive Cyclization of 2-(2-Nitroaryl)acetonitriles in the Presence of Co-Rh Heterobimetallic Nanoparticles with Atmospheric Hydrogen under Mild Conditions. AB - A cobalt-rhodium heterobimetallic nanoparticle-catalyzed reductive cyclization of 2-(2-nitroaryl)acetonitriles to indoles has been achieved. The tandem reaction proceeds without any additives under the mild conditions (1 atm H2 and 25 degrees C). This procedure could be scaled up to the gram scale. The catalytic system is significantly stable under these reaction conditions and could be reused more than ten times without loss of catalytic activity. PMID- 27762562 TI - Quantitative Proteomics Reveals the Dynamics of Protein Phosphorylation in Human Bronchial Epithelial Cells during Internalization, Phagosomal Escape, and Intracellular Replication of Staphylococcus aureus. AB - Internalization of Staphylococcus aureus by nonprofessional phagocytic cells is a major suspected cause of persistent and difficult-to-treat infections, including pneumonia. In this study, we established an infection model with 16HBE14o- human bronchial epithelial cells and demonstrated internalization, escape from phagosomal clearance, and intracellular replication of S. aureus HG001 within the first 4 h postinfection. We used quantitative phosphoproteomics to identify characteristic signaling networks in the host at different infection stages. Although we found only minor changes in protein abundance, the infection was accompanied by highly dynamic alterations in phosphorylation events primarily in proteins that are associated with pathways of cytoskeleton dynamics, cell-cell and cell-matrix contacts, vesicle trafficking, autophagy, and GTPase signaling. Analyses of host protein kinases by kinase-substrate mapping, active regulatory site immunoblotting, and prediction algorithms highlighted known and novel host kinases with putative critical roles in S. aureus infection-accompanied signaling including FAK, PKA, PKC, and CDK. Targeted pharmacological inhibition of these kinases resulted in a significant reduction of intracellular S. aureus cells. The current study constitutes a valuable resource for better understanding the infection-relevant molecular pathomechanisms of airway cells and for developing novel host-centric anti-infective strategies for treating S. aureus infections. PMID- 27762565 TI - Does parental sexual orientation matter? A longitudinal follow-up of adoptive families with school-age children. AB - Controversy continues to surround parenting by lesbian and gay (LG) adults and outcomes for their children. As sexual minority parents increasingly adopt children, longitudinal research about child development, parenting, and family relationships is crucial for informing such debates. In the psychological literature, family systems theory contends that children's healthy development depends upon healthy family functioning more so than family structure. From the framework of family stress theory, it was expected that longitudinal outcomes for school-age children adopted in infancy could be distinct among those with same sex versus other-sex parents (N = 96 families). Similar findings were hypothesized in terms of parent adjustment, couple relationships, and family functioning in comparing same-sex and other-sex parent families. Results indicated that adjustment among children, parents, and couples, as well as family functioning, were not different on the basis of parental sexual orientation (lesbian, gay, or heterosexual) when children were school-age. Rather, children's behavior problems and family functioning during middle childhood were predicted by earlier child adjustment issues and parenting stress. These findings are consistent with and extend previous literature about families headed by LG parents, particularly those that have adopted children. The results have implications for advancing supportive policies, practices, and laws related to adoption and parenting by sexual minority adults. (PsycINFO Database Record PMID- 27762566 TI - Comparing within-person effects from multivariate longitudinal models. AB - Several multivariate models are motivated to answer similar developmental questions regarding within-person (intraindividual) effects between 2 or more constructs over time, yet the within-person effects tested by each model are distinct. In this article, the authors clarify the types of within-person inferences that can be made from each model. Whereas previous research has focused on detecting whether within-person effects exist over development, the present work can be used to understand the nature of these relationships. The authors compare each modeling approach using an example investigating the concurrent development of mother-child closeness and mother-child conflict. The findings demonstrate that fundamentally different conclusions about developmental processes may be reached depending on which model is used, and a framework is demonstrated for making sense of seemingly contradictory findings. (PsycINFO Database Record PMID- 27762567 TI - Partner expressed emotion and diabetes management among spouses living with Type 2 diabetes. AB - INTRODUCTION: Expressed emotion has been consistently shown to be a significant predictor of relapse and poor disease management across numerous physical and mental health conditions, however very little research has been conducted on its relationship to the management practices of individuals living with Type 2 diabetes. This study examines the relationship between expressed emotion (EE) and diabetes management among couples where 1 spouse has Type 2 diabetes. METHODS: The authors surveyed 106 couples where 1 partner was diagnosed with Type 2 diabetes. Partners without diabetes completed questionnaires about their level of criticism, emotional involvement, and warmth toward their partners. Partners with diabetes completed questionnaires on diabetes control, diabetes management practices and attitude toward their diabetes. RESULTS: The authors found that, individuals living with diabetes who had partners with high EE reported significantly poorer diabetes management in all areas (diet, physical activity, and attitude toward diabetes). Diabetes management was found to mediate the relationship between EE and diabetes control. Results suggest that partners with high EE may have a significant influence on diabetes management practices in their partner. DISCUSSION: These findings highlight the important role couple interactions may play in diabetes management. Findings also emphasize the potential benefit of conceptualizing diabetes management from a systems/relational perspective. In addition, greater consideration should be given to using family-based approaches for diabetes management and treatment among coupled individuals living with Type 2 diabetes. (PsycINFO Database Record PMID- 27762568 TI - Validating emotional attention regulation as a component of emotional intelligence: A Stroop approach to individual differences in tuning in to and out of nonverbal cues. AB - Emotional intelligence (EI) has captivated researchers and the public alike, but it has been challenging to establish its components as objective abilities. Self report scales lack divergent validity from personality traits, and few ability tests have objectively correct answers. We adapt the Stroop task to introduce a new facet of EI called emotional attention regulation (EAR), which involves focusing emotion-related attention for the sake of information processing rather than for the sake of regulating one's own internal state. EAR includes 2 distinct components. First, tuning in to nonverbal cues involves identifying nonverbal cues while ignoring alternate content, that is, emotion recognition under conditions of distraction by competing stimuli. Second, tuning out of nonverbal cues involves ignoring nonverbal cues while identifying alternate content, that is, the ability to interrupt emotion recognition when needed to focus attention elsewhere. An auditory test of valence included positive and negative words spoken in positive and negative vocal tones. A visual test of approach-avoidance included green- and red-colored facial expressions depicting happiness and anger. The error rates for incongruent trials met the key criteria for establishing the validity of an EI test, in that the measure demonstrated test-retest reliability, convergent validity with other EI measures, divergent validity from factors such as general processing speed and mostly personality, and predictive validity in this case for well-being. By demonstrating that facets of EI can be validly theorized and empirically assessed, results also speak to the validity of EI more generally. (PsycINFO Database Record PMID- 27762569 TI - Augmenting brief interventions for adolescent marijuana users: The impact of motivational check-ins. AB - OBJECTIVE: Brief interventions for adolescent marijuana users offered in schools reach users who would not otherwise present for treatment. The current study builds on previous trials of a school-based, 2-session motivational enhancement therapy (MET) intervention by adding periodic, brief motivational check-ins to reinforce gains and bolster motivation. METHOD: Adolescent participants were randomly assigned to a motivational check-in (MCI; n = 128) or assessment-only check-in (ACI; n = 124) comparison condition. Both conditions received 2 sessions of MET. Participants in the MCI condition then attended 3 MET-based check-in sessions at 4, 7, and 10 months after baseline, whereas the ACI condition participants attended assessment-only check-ins at the same time points. Optional cognitive behavior therapy (CBT) sessions were available as needed for 12 months from baseline in both conditions. RESULTS: Outcomes were assessed at 6, 9, 12, and 15 months after baseline. Participants (59% Caucasian; 68% male; mean age = 15.84) reported using marijuana on an average of 37 of the last 60 days, and 70% met diagnostic criteria for a marijuana use disorder. Both conditions were associated with reduced use and negative consequences that were sustained throughout the 15 months of follow-up. The MCI condition resulted in greater reductions at the 6 months follow-up, but differences between conditions were not found at later follow-ups, and MCI participation did not increase engagement in CBT as predicted. CONCLUSIONS: Results replicated the efficacy of the brief intervention for adolescent marijuana use and provided mixed evidence on the utility of adding repeated check-in sessions. (PsycINFO Database Record PMID- 27762570 TI - A biphasic process of resistance among suspects: The mobilization and decline of self-regulatory resources. AB - We conducted two experiments to test whether police interrogation elicits a biphasic process of resistance from suspects. According to this process, the initial threat of police interrogation mobilizes suspects to resist interrogative influence in a manner akin to a fight or flight response, but suspects' protracted self-regulation of their behavior during subsequent questioning increases their susceptibility to interrogative influence in the long-run. In Experiment 1 (N = 316), participants who were threatened by an accusation of misconduct exhibited responses indicative of mobilization and more strongly resisted social pressure to acquiesce to suggestive questioning than did participants who were not accused. In Experiment 2 (N = 160), self-regulatory decline that was induced during questioning about misconduct undermined participants' ability to resist suggestive questioning. These findings support a theoretical account of the dynamic and temporal nature of suspects' responses to police interrogation over the course of questioning. (PsycINFO Database Record PMID- 27762571 TI - How suspect race affects police use of force in an interaction over time. AB - Although studies often find racial disparities in policing outcomes, less is known about how suspect race biases police interactions as they unfold. This study examines what is differentially occurring during police-suspect interactions for White, Black, and Latino suspects across time. It is hypothesized that racial bias may be more evident earlier in interactions, when less information about the situation is available. One hundred thirty-nine (62 White, 42 Black, and 35 Latino) use-of-force case files and associated written narratives from a medium to large size urban police department in the United States were analyzed. Trained coders broke down the interaction narratives into discrete "sequences," or dyadic action-reaction steps involving a suspect action (level of resistance) and an officer response (level of force). A linear mixed effects model was run on amount of police use of force by suspect race and time, with suspect resistance and suspect actions toward third-party/self as controls. Results demonstrated that Black and Latino suspects receive more force in the beginning stages of the interaction, whereas Whites escalated in level of force faster after initial levels. By breaking down police-suspect interactions into discrete sequences, the current study reveals a better understanding of when bias originates in police use of force and informs how to focus policing interventions. (PsycINFO Database Record PMID- 27762572 TI - Mock juror sampling issues in jury simulation research: A meta-analysis. AB - The advantages and disadvantages of jury simulation research have often been debated in the literature. Critics chiefly argue that jury simulations lack verisimilitude, particularly through their use of student mock jurors, and that this limits the generalizabilty of the findings. In the present article, the question of sample differences (student v. nonstudent) in jury research was meta analyzed for 6 dependent variables: 3 criminal (guilty verdicts, culpability, and sentencing) and 3 civil (liability verdicts, continuous liability, and damages). In total, 53 studies (N = 17,716) were included in the analysis (40 criminal and 13 civil). The results revealed that guilty verdicts, culpability ratings, and damage awards did not vary with sample. Furthermore, the variables that revealed significant or marginally significant differences, sentencing and liability judgments, had small or contradictory effect sizes (e.g., effects on dichotomous and continuous liability judgments were in opposite directions). In addition, with the exception of trial presentation medium, moderator effects were small and inconsistent. These results may help to alleviate concerns regarding the use of student samples in jury simulation research. (PsycINFO Database Record PMID- 27762573 TI - The interrogation decision-making model: A general theoretical framework for confessions. AB - This article presents a new model of confessions referred to as the interrogation decision-making model. This model provides a theoretical umbrella with which to understand and analyze suspects' decisions to deny or confess guilt in the context of a custodial interrogation. The model draws upon expected utility theory to propose a mathematical account of the psychological mechanisms that not only underlie suspects' decisions to deny or confess guilt at any specific point during an interrogation, but also how confession decisions can change over time. Findings from the extant literature pertaining to confessions are considered to demonstrate how the model offers a comprehensive and integrative framework for organizing a range of effects within a limited set of model parameters. (PsycINFO Database Record PMID- 27762574 TI - Do we spontaneously form stable trustworthiness impressions from facial appearance? AB - It is widely assumed among psychologists that people spontaneously form trustworthiness impressions of newly encountered people from their facial appearance. However, most existing studies directly or indirectly induced an impression formation goal, which means that the existing empirical support for spontaneous facial trustworthiness impressions remains insufficient. In particular, it remains an open question whether trustworthiness from facial appearance is encoded in memory. Using the 'who said what' paradigm, we indirectly measured to what extent people encoded the trustworthiness of observed faces. The results of 4 studies demonstrated a reliable tendency toward trustworthiness encoding. This was shown under conditions of varying context relevance, and salience of trustworthiness. Moreover, evidence for this tendency was obtained using both (experimentally controlled) artificial and (naturalistic varying) real faces. Taken together, these results suggest that there is a spontaneous tendency to form relatively stable trustworthiness impressions from facial appearance, which is relatively independent of the context. As such, our results further underline how widespread influences of facial trustworthiness may be in our everyday life. (PsycINFO Database Record PMID- 27762576 TI - "Does reading a single passage of literary fiction really improve theory of mind? An attempt at replication": Correction to Panero et al. (2016). AB - Reports an error in "Does Reading a Single Passage of Literary Fiction Really Improve Theory of Mind? An Attempt at Replication" by Maria Eugenia Panero, Deena Skolnick Weisberg, Jessica Black, Thalia R. Goldstein, Jennifer L. Barnes, Hiram Brownell and Ellen Winner (Journal of Personality and Social Psychology, Advanced Online Publication, Sep 19, 2016, np). In the article, due to an error in stimulus construction, four items (three authors, one foil) were omitted from the ART presented to all participants tested by Research Group 1. These omissions do not undermine the results in the primary analyses, which all included ART and ART Condition (as covariates). Any variation across research groups, including this difference in reading exposure measurement, is accounted for in the multilevel analyses. Therefore, the Table 2 title should appear as Reading the Mind in the Eyes Test (RMET) Scores by Condition and Overall Unadjusted Means for the Current Study and Kidd and Castano (2013), as Well as the Zero-Order Pearson's Correlations Between RMET and ART Scores Overall and by Condition. The ART data columns should be deleted, and the table note should begin as follows: RMET scores were transformed to correct for skew prior to correlational analyses. The section title above the Discussion section should appear as Comparison of Our RMET Scores to Kidd and Castano Data, with the first two sentences appearing as follows: To determine whether the responses in our sample were similar to what Kidd and Castano (2013) found, we compared our mean performance on the RMET to theirs. Our grand mean (26.28) was significantly higher than theirs (25.18), t(1=, 374) = 3.71, p< .001, d = 0.21. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2016-44825-001.) Fiction simulates the social world and invites us into the minds of characters. This has led various researchers to suggest that reading fiction improves our understanding of others' cognitive and emotional states. Kidd and Castano (2013) received a great deal of attention by providing support for this claim. Their article reported that reading segments of literary fiction (but not popular fiction or nonfiction) immediately and significantly improved performance on the Reading the Mind in the Eyes Test (RMET), an advanced theory-of-mind test. Here we report a replication attempt by 3 independent research groups, with 792 participants randomly assigned to 1 of 4 conditions (literary fiction, popular fiction, nonfiction, and no reading). In contrast to Kidd and Castano (2013), we found no significant advantage in RMET scores for literary fiction compared to any of the other conditions. However, as in Kidd and Castano and previous research, the Author Recognition Test, a measure of lifetime exposure to fiction, consistently predicted RMET scores across conditions. We conclude that the most plausible link between reading fiction and theory of mind is either that individuals with strong theory of mind are drawn to fiction and/or that a lifetime of reading gradually strengthens theory of mind, but other variables, such as verbal ability, may also be at play. (PsycINFO Database Record PMID- 27762575 TI - Using wise interventions to motivate deliberate practice. AB - Deliberate practice leads to world-class excellence across domains. In the current investigation, we examined whether psychologically "wise" interventions targeting expectancies and values-stock antecedents of ordinary effortful behaviors-could motivate nonexperts to engage in deliberate practice and improve their achievement. As a preliminary, we developed and validated a novel task measure of deliberate practice and confirmed its association with (a) expectancy value beliefs, and (b) achievement in the nonexpert setting (Study 1). Next, across 4 longitudinal, randomized-controlled, field experiments, we intervened. Among lower-achievers, wise deliberate practice interventions improved math performance for 5th and 6th graders (Study 2), end-of-semester grades for undergraduates (Study 3), and end-of-quarter grades for 6th graders (Study 4); the same pattern of results emerged in end-of-quarter grades for 7th graders (Study 5). Following the intervention, expectancy-value beliefs and deliberate practice improved for 1 month (Study 4), but not 4 (Study 5). Treatment proved beneficial over and above 2 control conditions: 1 that taught standard study skills (Studies 2 and 3), and 1 that discussed deep interests, generalized motivation, and high achievement (Studies 4 and 5). Collectively, these findings provide preliminary support for the heretofore untested hypothesis that deliberate practice submits to the same laws that govern typical forms of effortful behavior, and that wise interventions that tap into these laws can spur short-term gains in adaptive beliefs, deliberate practice, and objectively measured achievement. (PsycINFO Database Record PMID- 27762577 TI - Saccadic eye movements impose a natural bottleneck on visual short-term memory. AB - Visual short-term memory (VSTM) is a crucial repository of information when events unfold rapidly before our eyes, yet it maintains only a fraction of the sensory information encoded by the visual system. Here, we tested the hypothesis that saccadic eye movements provide a natural bottleneck for the transition of fragile content in sensory memory to VSTM. In 4 experiments, we show that saccades, planned and executed after the disappearance of a memory array, markedly bias visual memory performance. First, items that had appeared at the saccade target were more readily remembered than items that had appeared elsewhere, even though the saccade was irrelevant to the memory task (Experiment 1). Second, this influence was strongest for saccades elicited right after the disappearance of the memory array and gradually declined over the course of a second (Experiment 2). Third, the saccade stabilized memory representations: The imposed bias persisted even several seconds after saccade execution (Experiment 3). Finally, the advantage for stimuli congruent with the saccade target occurred even when that stimulus was far less likely to be probed in the memory test than any other stimulus in the array, ruling out a strategic effort of observers to memorize information presented at the saccade target (Experiment 4). Together, these results make a strong case that saccades inadvertently determine the content of VSTM, and highlight the key role of actions for the fundamental building blocks of cognition. (PsycINFO Database Record PMID- 27762579 TI - Belief in corrective feedback for common misconceptions: Implications for knowledge revision. AB - When correcting a common misconception, it seems likely that for corrective feedback to be effective, it needs to be believed. In 2 experiments, we assessed how participants' belief in the validity of corrective feedback regarding individual misconceptions influenced knowledge revision. After responding about the validity of a set of misconceptions, participants received either a refutation alone (feedback that they were correct or incorrect) or a refutation accompanied by a supporting explanation, and then rated their belief in the corrective feedback. One week later, participants once again responded about the validity of the misconceptions. Across both experiments, participants corrected their misconceptions more often when they believed the corrective feedback. In addition, participants corrected their misconceptions more often when they had earlier received a refutation with a supporting explanation than when they had received the refutation only. This benefit of supportive explanations on knowledge revision was mediated by belief in the feedback, suggesting that explanations enhance the effectiveness of a correction by increasing belief in the feedback. These findings imply that successful correction of common misconceptions is likely enhanced by techniques that increase people's belief in the validity of the corrective feedback. (PsycINFO Database Record PMID- 27762580 TI - The role of gist and verbatim memory in complex decision making: Explaining the unconscious-thought effect. AB - Previous research showed that the unconscious-thought effect, which refers to an improvement in complex decision making following a distraction period, was moderated by the presentation format of pieces of information about different options. The aim of the current study was to replicate this finding and further examine the memory representations underlying decision making following a distraction or a deliberation period. Results showed that, when the information was presented blocked per option, participants were better able to differentiate the best option from the others after a distraction period than immediately after the information presentation or after a deliberation period. In addition, distracted participants retrieved more gist representations of the options when the information was presented per option. By contrast, participants were better able to differentiate the best option from the others after a deliberation period when the information was presented per attribute. Participants who deliberated also retrieved more verbatim representations when the information was presented per attribute. Finally, mediation analyses indicated that the accuracy of the evaluations of the options depends on gist memory when distracted but on verbatim memory when deliberating. These findings suggest that the effectiveness of distraction or deliberation depends on the memory representations of the different options. (PsycINFO Database Record PMID- 27762578 TI - Verb biases are shaped through lifelong learning. AB - Verbs often participate in more than 1 syntactic structure, but individual verbs can be biased in terms of whether they are used more often with 1 structure or the other. For instance, in a sentence such as "Bop the bunny with the flower," the phrase "with the flower" is more likely to indicate an instrument with which to "bop," rather than which "bunny" to bop. Conversely, in a sentence such as "Choose the cow with the flower," the phrase "with the flower" is more likely to indicate which "cow" to choose. An open question is where these biases come from and whether they continue to be shaped in adulthood in a way that has lasting consequences for real-time processing of language. In Experiment 1 we replicated previous findings that these language-wide biases guide online syntactic processing in a computer-based visual-world paradigm. In Experiment 2, we tested the malleability of these biases by exposing adults to initially unbiased verbs situated in unambiguous contexts that led to either instrument or modifier interpretations. During test, participants interpreted sentences containing either modifier- or instrument-trained verbs in ambiguous contexts. Eye-movement and action data show that participants' considerations of the candidate interpretations of the ambiguous with-phrases were guided by the newly learned verb biases. These results suggest that co-occurrence information about specific verbs and syntactic structures embedded in language experiences plays a role in forming, and continuously shaping, the verb biases that constitute a part of the broader representation of the language. (PsycINFO Database Record PMID- 27762582 TI - Peptide-targeted polymer cancerostatics. AB - A tumor-targeting drug delivery system consists of a tumor recognition moiety and a directly linked cytotoxic agent or an agent attached to a water-soluble synthetic polymer carrier through a suitable linker. Conjugation of a drug with a polymer carrier can change its solubility, toxicity, biodistribution, blood clearance and therapeutic specificity. Increased therapeutic specificity of a polymer drug can be achieved by the attachment of a targeting moiety (e.g. a lectin, protein, antibody, or peptide) that specifically interacts with receptors on the target cells. A large number of tumor-specific peptides were described in recent years. After a short introduction, some important examples of peptide targeted conjugates will be described and discussed. PMID- 27762583 TI - Supramolecular structures and self-association processes in polymer systems. AB - Self-organization in a polymer system appears when a balance is achieved between long-range repulsive and short-range attractive forces between the chemically different building blocks. Block copolymers forming supramolecular assemblies in aqueous media represent materials which are extremely useful for the construction of drug delivery systems especially for cancer applications. Such formulations suppress unwanted physicochemical properties of the encapsulated drugs, modify biodistribution of the drugs towards targeted delivery into tissue of interest and allow triggered release of the active cargo. In this review, we focus on general principles of polymer selforganization in solution, phase separation in polymer systems (driven by external stimuli, especially by changes in temperature, pH, solvent change and light) and on effects of copolymer architecture on the self-assembly process. PMID- 27762584 TI - High-molecular-weight HPMA-based polymer drug carriers for delivery to tumor. AB - In this work, design and synthesis of high-molecular-weight N-(2 hydroxypropyl)methacrylamide-based polymer drug delivery systems tailored for cancer therapy is summarized. Moreover, the influence of their architecture on tumor accumulation and in vivo anti-cancer efficacy is discussed. Mainly, the high-molecular-weight delivery systems, such as branched, grafted, multi-block, star-like or micellar systems, with molecular weights greater than the renal threshold are discussed and reviewed in detail. PMID- 27762581 TI - Reading sky and seeing a cloud: On the relevance of events for perceptual simulation. AB - Previous research has shown that processing words with an up/down association (e.g., bird, foot) can influence the subsequent identification of visual targets in congruent location (at the top/bottom of the screen). However, as facilitation and interference were found under similar conditions, the nature of the underlying mechanisms remained unclear. We propose that word comprehension relies on the perceptual simulation of a prototypical event involving the entity denoted by a word in order to provide a general account of the different findings. In 3 experiments, participants had to discriminate between 2 target pictures appearing at the top or the bottom of the screen by pressing the left versus right button. Immediately before the targets appeared, they saw an up/down word belonging to the target's event, an up/down word unrelated to the target, or a spatially neutral control word. Prime words belonging to target event facilitated identification of targets at a stimulus onset asynchrony (SOA) of 250 ms (Experiment 1), but only when presented in the vertical location where they are typically seen, indicating that targets were integrated in the simulations activated by the prime words. Moreover, at the same SOA, there was a robust facilitation effect for targets appearing in their typical location regardless of the prime type. However, when words were presented for 100 ms (Experiment 2) or 800 ms (Experiment 3), only a location nonspecific priming effect was found, suggesting that the visual system was not activated. Implications for theories of semantic processing are discussed. (PsycINFO Database Record PMID- 27762585 TI - Seven years of radionuclide laboratory at IMC - important achievements. AB - For many important research topics in polymer science the use of radionuclides brings significant benefits concerning nanotechnology, polymer drug delivery systems, tissue engineering etc. This contribution describes important achievements of the radionuclide laboratory at Institute of Macromolecular Chemistry of the Academy of Sciences of the Czech Republic (IMC) in the area of polymers for biomedical applications. Particular emphasis will be given to water soluble polymer carriers of radionuclides, thermoresponsive polymer radionuclide carriers, thermoresponsive polymers for local brachytherapy, polymer scaffolds modified with (radiolabeled) peptides and polymer copper chelators for the therapy of Wilson's disease. PMID- 27762586 TI - Macromolecular systems for vaccine delivery. AB - Vaccines have helped considerably in eliminating some life-threatening infectious diseases in past two hundred years. Recently, human medicine has focused on vaccination against some of the world's most common infectious diseases (AIDS, malaria, tuberculosis, etc.), and vaccination is also gaining popularity in the treatment of cancer or autoimmune diseases. The major limitation of current vaccines lies in their poor ability to generate a sufficient level of protective antibodies and T cell responses against diseases such as HIV, malaria, tuberculosis and cancers. Among the promising vaccination systems that could improve the potency of weakly immunogenic vaccines belong macromolecular carriers (water soluble polymers, polymer particels, micelles, gels etc.) conjugated with antigens and immunistumulatory molecules. The size, architecture, and the composition of the high molecular-weight carrier can significantly improve the vaccine efficiency. This review includes the most recently developed (bio)polymer based vaccines reported in the literature. PMID- 27762587 TI - Intracellular fate of polymer therapeutics investigated by fluorescence lifetime imaging and fluorescence pattern analysis. AB - Nanocarriers bearing anticancer drugs are promising candidates to improve the efficacy of cancer therapy and minimize side effects. The most potent cytostatics used in the treatment of various cancers are anthracyclines, e.g. doxorubicin or pirarubicin. Recently, polymer therapeutics carrying anthracyclines have been intensively studied. The precise characterization of in vitro nanocarrier biological behavior brings a better understanding of the nanocarrier characteristics and enables prediction of the behavior of the nanocarrier during in vivo application. Advanced fluorescence detection methods, e.g. fluorescence lifetime imaging microscopy (FLIM), were successfully exploited to describe the properties of various polymeric nano-systems and contributed to a complex view of anthracyclines' intracellular transport and DNA intercalation. Here, we report the application of a specific technique for processing FLIM images, called fluorescence pattern decomposition, to evaluate early events after doxorubicin or pirarubicin treatment of cells. Moreover, we characterized changes in the intracellular localization and release of the anthracyclines during the incubation of cells with polymer nanotherapeutics based on poly[N-(2 hydroxypropyl)-methacrylamide] (pHPMA). PMID- 27762588 TI - The pH-dependent and enzymatic release of cytarabine from hydrophilic polymer conjugates. AB - Cytarabine is one of the most efficient drugs in the treatment of hematological malignancies. In this work, we describe the synthesis and characterization of two different polymer conjugates of cytarabine that were designed for the controlled release of cytarabine within the leukemia cells. Reactive copolymers of N-(2 hydroxypropyl)methacrylamide (HPMA) and 3-(3-methacrylamidopropa noyl)thiazolidine-2-thione) or 3-(Nmethacryloylglycyl phenylalanylleucylglycyl)thiazolidine-2-thione were used in the study as reactive polymer precursors for reaction with cytarabine. The enzymatic release of cytarabine from the conjugate containing a GFLG spacer utilizing cathepsin B was verified. In addition to enzymolysis, the pH-dependent hydrolysis of cytarabine from both copolymers was also confirmed. Approximately 40 % and 20 % of the drug was released by spontaneous hydrolysis at pH 7.4 within 72 h from the polymer conjugates with the GFLG and beta-Ala spacers, respectively. At pH 6.0, the spontaneous hydrolysis slowed down, and less than 10 % of the drug was liberated within 72 h. The results of the cytotoxicity evaluation of the polymer conjugates in vitro against various cell lines showed that the cytotoxicity of the polymer conjugates is approximately three times lower in comparison to free cytarabine. PMID- 27762589 TI - HPMA copolymer-based polymer conjugates for the delivery and controlled release of retinoids. AB - In this paper, we describe the synthesis, physicochemical characterization, drug release kinetics and preliminary biological evaluation of several N-(2 hydroxypropyl)methacrylamide (HPMA)-based polymer-retinoid conjugates designed for solid tumor immunotherapy. The conjugates are supposed to inhibit the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) accumulated in the solid tumor microenvironment. All-trans retinoic acid (ATRA) was derivatized to hydrazide (AtrHy) and then attached to the polymer backbone via a spacer that is stable at the normal pH of blood (7.4) and hydrolytically degradable in mildly acidic environments (e.g. in endosomes or lysosomes, pH~5.0 6.5). Polymer-AtrHy conjugates were designed to achieve prolonged blood circulation and release of the immunomodulator intracellularly or extracellularly in solid tumor tissue. Three types of polymer precursors, differing in the structure of the keto acid-containing side chains, were synthesized. A linkage susceptible to hydrolytic cleavage was formed by the conjugation reaction of the carbonyl group-terminated side chains of the polymer precursors with the hydrazide group of a drug derivative. In vitro incubation of the conjugates in buffers resulted in much faster release of the drugs or their derivatives from the polymer at pH 5.0 than at pH 7.4, with the rate depending on the detailed structure of the spacer. Both the AtrHy derivative and its polymer conjugates showed the ability to induce the differentiation of retinoid-responsive HL-60 cells, thus demonstrating the required biological activity. PMID- 27762591 TI - Protein interactions with quaternized chitosan/heparin multilayers. AB - Understanding the behavior of single proteins at the polyelectrolyte multilayer film/solution interface is of prime importance for the designing of bio functionalized surface coatings. In the present paper, we study the adsorption of the model proteins, albumin and lysozyme, as well as basic fibroblast growth factor (FGF-2) on a polysaccharide multilayer film composed of quaternized chitosan and heparin. Several analytical methods were used to describe the formation of the polysaccharide film and its interactions with the proteins. Both albumin and lysozyme adsorbed on quaternized chitosan/heparin films, however this process strongly depended on the terminating polysaccharide. Protein adsorption was driven mainly by electrostatic interactions between protein and the terminal layer of the film. The effective binding of FGF-2 by the heparin-terminated film suggested that other interactions could also contribute to the adsorption process. We believe that this FGF-2-presenting polysaccharide film may serve as a biofunctional surface coating for biologically-related applications. PMID- 27762590 TI - Carbohydrate-modified magnetic nanoparticles for radical scavenging. AB - Maghemite (gamma-Fe2O3) nanoparticles, 12 nm in size, were prepared by co precipitation of Fe(II) and Fe(III) chlorides with ammonium hydroxide and oxidation with hydrogen peroxide. To achieve stability and biocompatibility, obtained particles were coated with silica, to which glucose and ascorbic acid were bound by different mechanisms. The composite particles were thoroughly characterized by transmission electron microscopy, dynamic light scattering, elemental analysis, and FT-Raman and fluorescence spectroscopy to determine composition, morphology, size and its distribution, zeta-potential, and scavenging of peroxyl and hydroxyl radicals. As the particles showed promising antioxidative properties, they may have a possible application as a stable magnetically controlled scavenger of reactive oxygen species. PMID- 27762592 TI - Fibrin nanostructures for biomedical applications. AB - Fibrin is a versatile biopolymer that has been extensively used in tissue engineering. In this paper fibrin nanostructures prepared using a technique based on the catalytic effect of fibrin-bound thrombin are presented. This technique enables surface-attached thin fibrin networks to form with precisely regulated morphology without the development of fibrin gel in bulk solution. Moreover, the influence of changing the polymerization time, along with the antithrombin III and heparin concentrations on the morphology of fibrin nanostructures was explored. The binding of bioactive molecules (fibronectin, laminin, collagen, VEGF, bFGF, and heparin) to fibrin nanostructures was confirmed. These nanostructures can be used for the surface modification of artificial biomaterials designed for different biomedical applications (e.g. artificial vessels, stents, heart valves, bone and cartilage constructs, skin grafts, etc.) in order to promote the therapeutic outcome. PMID- 27762593 TI - The Expression Level of Neutrophil CD64 Is a Useful Marker of Systemic Inflammation Associated with HIV Infection. AB - CD64 is an Fc-gamma-receptor type 1. The expression level of neutrophil CD64 (nCD64) is a known bacterial infection marker, and it also increases in viral infections. We examined the absolute nCD64 before and after the initiation of antiretroviral therapy (ART) to determine its role as an infection and inflammation marker of human immunodeficiency virus (HIV) infection. In this prospective observational study, 94 HIV-infected patients were enrolled and classified into ART (n = 62), ART naive (n = 24), and acute/early phase groups (n = 8). The median nCD64 was 1,430 molecules/cell in the ART group, 2,994 in the ART naive group, 4,625 in the acute/early phase group, and 1,196 in the healthy control group. The nCD64 in the ART group was significantly higher compared with the healthy controls (p = .041), and the nCD64 in the ART naive and acute/early phase groups was significantly higher compared with the ART group (both p < .001). In the ART naive group, nCD64 was significantly higher in patients with than without concomitant infections (3,942 +/- 1,519 vs. 2,300 +/- 784, p = .004). However, this was influenced by the fact that nCD64 elevated as the stage of HIV infection progressed. nCD64 decreased significantly during the 24 weeks after starting ART (p = .004), although an upward trend in nCD64 was observed at weeks 2 and 4, without symptoms. When immune reconstitution inflammatory syndrome occurred, nCD64 elevated with a wider range than did C-reactive protein. This preliminary study suggests that nCD64 would be useful as a marker of the systemic inflammation of HIV-infected patients. PMID- 27762594 TI - Metastatic Patterns of Solitary Fibrous Tumors: A Single-Institution Experience. AB - OBJECTIVE: The objective of our study was to evaluate the metastatic patterns and imaging features of solitary fibrous tumors (SFTs). MATERIALS AND METHODS: This retrospective study included 139 patients with pathologically proven SFT, 49 of whom developed metastases. Electronic medical records and all available images were reviewed to record the pattern and imaging appearances of metastatic disease, and comparisons of thoracic SFTs and extrathoracic SFTs were also performed. Associations of metastatic spread were studied using univariate and multivariate Cox regression analyses. RESULTS: A total of 49 (35%) patients developed metastases at a median of 124 months (interquartile range [IQR], 66-195 months) after SFT diagnosis; 11 patients (8%) had metastases at presentation. Of these 49 patients, 40 patients died at a mean of 183 months after diagnosis. The associations with metastatic disease on univariate analysis were tumor size >= 10 cm (p = 0.01) and malignant pathology or mitotic count >= 4 per 10 high-power fields (HPF) (p < 0.001). Malignant pathology and a mitotic count of >= 4 per 10 HPF were also associated with metastatic disease on multivariate analysis (p = 0.01; hazard ratio, 0.22; 95% CI, 0.05-0.73). The most common sites of metastasis were the lungs (30/49, 61%) followed by the pleura (24/49, 49%) and then the liver (20/49, 41%), bones (20/49, 41%), and peritoneum (20/49, 41%). A significantly higher proportion of patients with extrathoracic SFT had metastatic disease (37/139, 27%) compared with those with thoracic SFT (12/139, 9%) (p = 0.003). The overall metastasis-free survival was a median of 117 months (IQR, 33 169 months) in patients with extrathoracic SFT and a median of 120 months (IQR, 82-169 months) in patients with thoracic SFT (p = 0.01). CONCLUSION: A mitotic count of >= 4 per 10 HPF or malignant pathology was significantly associated with metastatic disease on both univariate and multivariate analyses. The sites of metastatic disease differed depending on the site of the primary SFT but were most commonly the lung and pleura. Patients with extrathoracic SFT were statistically more likely to develop metastatic disease than those with thoracic SFT. PMID- 27762595 TI - An Official American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. Rehabilitation Protocols, Ventilator Liberation Protocols, and Cuff Leak Tests. AB - BACKGROUND: Interventions that lead to earlier liberation from mechanical ventilation can improve patient outcomes. This guideline, a collaborative effort between the American Thoracic Society and the American College of Chest Physicians, provides evidence-based recommendations to optimize liberation from mechanical ventilation in critically ill adults. METHODS: Two methodologists performed evidence syntheses to summarize available evidence relevant to key questions about liberation from mechanical ventilation. The methodologists appraised the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach and summarized the results in evidence profiles. The guideline panel then formulated recommendations after considering the balance of desirable consequences (benefits) versus undesirable consequences (burdens, adverse effects, and costs), the certainty in the evidence, and the feasibility and acceptability of various interventions. Recommendations were rated as strong or conditional. RESULTS: The guideline panel made four conditional recommendations related to rehabilitation protocols, ventilator liberation protocols, and cuff leak tests. The recommendations were for acutely hospitalized adults mechanically ventilated for more than 24 hours to receive protocolized rehabilitation directed toward early mobilization, be managed with a ventilator liberation protocol, be assessed with a cuff leak test if they meet extubation criteria but are deemed high risk for postextubation stridor, and be administered systemic steroids for at least 4 hours before extubation if they fail the cuff leak test. CONCLUSIONS: The American Thoracic Society/American College of Chest Physicians recommendations are intended to support healthcare professionals in their decisions related to liberating critically ill adults from mechanical ventilation. PMID- 27762597 TI - MRI of Placenta Accreta, Placenta Increta, and Placenta Percreta: Pearls and Pitfalls. AB - OBJECTIVE: The purpose of this article is to provide a primer for radiologists performing MRI for suspected placenta accreta, illustrating normal and abnormal findings and diagnostic pitfalls. Appropriate examination indications and recommendations for optimizing image acquisition and interpretation are summarized. CONCLUSION: MRI increases the accuracy of the workup of high-risk patients and aids in multidisciplinary delivery planning to improve maternal outcome. Reader accuracy and confidence require adherence to examination performance, image interpretation criteria, and awareness of common pitfalls. PMID- 27762596 TI - Short Communication: Phylogenetic Evidence of HIV-1 Transmission Between Adult and Adolescent Men Who Have Sex with Men. AB - HIV-1 incidence among youth, especially men who have sex with men (MSM), is increasing in the United States. We aimed to better understand the patterns of adolescent HIV-1 acquisition, to help guide future prevention interventions. We conducted a study combining epidemiologic and HIV-1 pol sequence data from a retrospective cohort of HIV-infected adults and adolescents in Seattle, WA between 2000 and 2013. Adolescents were defined as 13-24 years of age at the time of first HIV-1 care. Maximum-likelihood phylogenetic trees were reconstructed to identify putative viral transmission clusters of two or more individuals, followed by multivariable regression tests of associations between clustering and demographic and clinical parameters. The dataset included 3,102 sequences from 1,953 individuals; 72 putative transmission clusters were identified, representing 168 individuals (8.6%). MSM and MSM/intravenous drug use (IDU) were positively associated with clustering, with aOR 3.18 (95% CI: 1.34-7.55) and 2.59 (95% CI: 1.04-6.49), respectively. African American race was negatively associated with clustering (aOR 0.54 95% CI: 0.32-0.91). Twenty-five clusters contained one adolescent and five clusters contained two adolescents. Other individuals who clustered with adolescents were predominantly male (95%), white (85%), and either MSM (66%) or MSM/IDU (16%), with a greater mean age (34 years vs. 22 years; p < .01). In this Seattle cohort, HIV-1 transmission linkages were identified between white male adolescents and older MSM adults. Interventions aimed at age-discrepant pairs may reduce HIV-1 infections in adolescent males. PMID- 27762598 TI - Identification of Two New HIV-1 Circulating Recombinant Forms (CRF87_cpx and CRF88_BC) from Reported Unique Recombinant Forms in Asia. AB - The on-going generation of HIV-1 intersubtype recombination has led to new circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in Asia. In this study, we evaluated whether previously reported URFs were actually CRFs. All available complete or near full-length HIV-1 URF sequences from Asia were retrieved from the HIV Los Alamos National Laboratory Sequence database, and phylogenetic, transmission cluster, and bootscan analyses were performed using MEGA 6.0, Cluster Picker 1.2.1, and SimPlot3.5.1. According to the criterion of new CRFs, two new HIV-1 CRFs (CRF87_cpx and CRF88_BC) were identified from these available URFs. CRF87_cpx comprised HIV-1 subtypes B, C, and CRF01_AE, and CRF88_BC comprised subtypes B and C. HIV Blast and bootscan analysis revealed that besides the three representative strains, there were two additional CRF87_cpx strains. Furthermore, we defined seven dominant URFs (dURF01-dURF07), each of which contained two strains sharing same recombination map and can be used as sequence references to facilitate the finding of new potential CRFs in future. These results will benefit the molecular epidemiological investigation of HIV-1 in Asia. PMID- 27762599 TI - Dose Reduction in Tomosynthesis of the Wrist. AB - OBJECTIVE: The purpose of this study was to quantitatively and qualitatively determine the impact of radiation dose reduction on the image noise and quality of tomosynthesis studies of the wrist. MATERIALS AND METHODS: Imaging of six cadaver wrists was performed with tomosynthesis in anteroposterior position at a tube voltage of 60 kV and tube current of 80 mA and subsequently at 60 or 50 kV with different tube currents of 80, 40, or 32 mA. Dose-area products (DAP) were obtained from the electronically logged protocol. Image noise was measured with an ROI. Two independent and blinded readers evaluated all images. Interreader agreement was measured with a Cohen kappa. Readers assessed overall quality and delineation of soft tissue, cortical bone, and trabecular bone on a 4-point Likert scale. RESULTS: The highest DAP (3.892 +/- 0.432 Gy . cm2) was recorded for images obtained with 60 kV and 80 mA; the lowest (0.857 +/- 0.178 Gy . cm2) was recorded for images obtained with 50 kV and 32 mA. Noise was highest when a combination of 50 kV and 32 mA (389 +/- 26.6) was used and lowest when a combination of 60 kV and 80 mA (218 +/- 12.3) was used. The amount of noise on images acquired using 60 kV and 80 mA was statistically significantly different from the amount measured on all other images (p < 0.0001). Interreader agreement was excellent (kappa = 0.93). Delineation of anatomy and overall quality were scored best on images obtained with 60 kV and 80 mA and worst on images obtained with 50 kV and 32 mA. The difference in delineation and quality on images obtained using 50 kV and 40 mA was not statistically significantly different compared with images obtained using 60 kV and 80 mA. CONCLUSION: Significant dose reduction for tomosynthesis of the wrist is possible while image quality and delineation of anatomic structures remain preserved. PMID- 27762600 TI - Trends of HIV-1 Subtypes Among Young People in Hangzhou, China. AB - To investigate the HIV-1 molecular epidemiology among young people (18 to 25 years old) in Hangzhou. Plasma samples from 262 newly diagnosed HIV-1-infected patients were collected between 2009 and 2013 from Hangzhou of Zhejiang province. HIV-1 nucleotide sequences of pol gene regions were amplified using a nested polymerase chain reaction method and sequenced. Phylogenetic and recombination analyses were used to determine the HIV-1 genotypes. Based on all sequences generated, the subtype/circulating recombinant forms (CRFs) distribution was as follows: CRF01_AE (68.70%), CRF07_BC (21.54%), subtype B (3.66%), CRF08_BC (2.44%), 01B (2.03%), BC (0.81%), and C (0.41%). We found that the percentage of CRF07_BC was increasing year by year among young people in Hangzhou. Novel CRFs such as CRF67_01B (HZ2011-15 CD4-4516) and CRF68_01B (HZ2011-20 CD4-4530 and HZ2011-29 CD4-4087) were first discovered in the area in this study. Our study presents a molecular epidemiology investigation describing the structure of HIV-1 strains cocirculating in young people in Hangzhou. Increasing CRF07_BC and new CRFs popular in young people are a challenge for future prevention in Hangzhou. PMID- 27762602 TI - Class II subdivision treatment with the Forsus Fatigue Resistant Device vs intermaxillary elastics. AB - OBJECTIVE: To compare the effectiveness of comprehensive fixed appliance treatments implemented in combination with Forsus or intermaxillary elastics in Class II subdivision subjects. MATERIALS AND METHODS: Twenty-eight Class II subdivision patients were allocated to two groups using matched randomization: Forsus group (mean age, 14.19 +/- 1.02 years) and elastics group (mean age, 13.75 +/- 1.16 years). Patients received fixed appliance therapy in combination with either Forsus or intermaxillary elastics. The study was conducted on lateral cephalograms and digital models acquired before orthodontic treatment and 10-12 weeks after the fixed appliances were removed. RESULTS: The treatment phase comprising the use of Forsus (4.53 +/- 0.91 months) was significantly shorter compared with elastics application (6.85 +/- 1.08 months). This was also true for comparing duration of overall comprehensive treatment in both groups. Extrusion and palatal tipping of maxillary incisors and clockwise rotation of the occlusal plane were greater in the elastics group (P < .05). The mandibular incisors were proclined in both groups (P < .001), but no significant difference was observed between groups (P > .05). The mandibular incisors showed intrusion in the Forsus group and extrusion in the elastics group; the difference between groups was significant (P < .05). Overbite was decreased in both groups (P < .001) in similar amounts. Improvement in overjet, mandibular midline deviation, and correction of molar relationship on the Class II side were greater in the Forsus group (P < .05). CONCLUSION: Forsus is more effective for correcting Class II subdivision malocclusion in a shorter treatment period with minimal patient compliance required. PMID- 27762601 TI - Stereotactic CT-Guided Percutaneous Microwave Ablation of Liver Tumors With the Use of High-Frequency Jet Ventilation: An Accuracy and Procedural Safety Study. AB - OBJECTIVE: The purpose of the present study is to evaluate the accuracy and safety of antenna placement performed with the use of a CT-guided stereotactic navigation system for percutaneous ablation of liver tumors and to assess the safety of high-frequency jet ventilation for target motion control. MATERIALS AND METHODS: Twenty consecutive patients with malignant liver lesions for which surgical resection was contraindicated or that were not readily visible on ultrasound or not accessible by ultrasound guidance were included in the study. Patients were treated with percutaneous microwave ablation performed using a CT guided stereotactic navigation system. High-frequency jet ventilation was used to reduce liver motion during all interventions. The accuracy of antenna placement, the number of needle readjustments required, overall safety, and the radiation doses were assessed. RESULTS: Microwave ablation was completed for 20 patients (28 lesions). Performance data could be evaluated for 17 patients with 25 lesions (mean [+/- SD] lesion diameter, 14.9 +/- 5.9 mm; mean lesion location depth, 87.5 +/- 27.3 mm). The antennae were placed with a mean lateral error of 4.0 +/- 2.5 mm, a depth error of 3.4 +/- 3.2 mm, and a total error of 5.8 +/- 3.2 mm in relation to the intended target. The median number of antenna readjustments required was zero (range, 0-1 adjustment). No major complications were related to either the procedure or the use of high-frequency jet ventilation. The mean total patient radiation dose was 957.5 +/- 556.5 mGy * cm, but medical personnel were not exposed to irradiation. CONCLUSION: Percutaneous microwave ablation performed with CT-guided stereotactic navigation provides sufficient accuracy and requires almost no repositioning of the needle. Therefore, it is technically feasible and applicable for safe treatments. PMID- 27762603 TI - Update on Image-Guided Percutaneous Ablation of Breast Cancer. AB - OBJECTIVE: The purpose of this article is to delineate the potential techniques for percutaneous ablation of breast cancer, discuss the advantages and disadvantages of each technique, and provide results from recent studies on these technologies. The techniques discussed are cryotherapy, laser irradiation, microwave irradiation, radiofrequency ablation, high-intensity focused ultrasound ablation, and irreversible electroporation. CONCLUSION: Although percutaneous ablation techniques have some promising potential for less-invasive treatment of breast cancer, larger multicenter trials are needed to confirm their efficacy, especially in comparison with the reference standard of lumpectomy. The use of these techniques also leads to other remaining unanswered questions, including how to manage the axilla and which patients are the best candidates for these treatments. PMID- 27762604 TI - Focal Benign Disorders of the Pediatric Mandible With Radiologic-Histopathologic Correlation: Mandibular Development and Lucent Lesions. AB - OBJECTIVE: Lucent lesions of the pediatric mandible may present variably. Cysts, neoplasms, and developmental and inflammatory conditions have a host of possible causes. There is also substantial overlap in the imaging appearance of cysts and that of benign but locally aggressive tumors that need to undergo resection. CONCLUSION: The purpose of this article is to present common and uncommon lucent lesions of the mandible in children, with an emphasis on benign abnormalities. Discussions of imaging and histopathologic features are provided. PMID- 27762605 TI - Variation in Attenuation in L1 Trabecular Bone at Different Tube Voltages: Caution Is Warranted When Screening for Osteoporosis With the Use of Opportunistic CT. AB - OBJECTIVE: The purpose of this study is to investigate the variation in attenuation values (expressed as Hounsfield units) for L1 vertebral body trabecular bone at different tube voltages used in dual-energy CT (DECT) and to remind physicians to consider changes in attenuation values when they approach opportunistic screening for osteoporosis. MATERIALS AND METHODS: Consecutive patients who underwent DECT examination of the abdomen and pelvis for suspected urolithiasis were included in the study. Attenuation noted on CT of the L1 trabecular bone performed with the use of tube voltages of 80, 100, and 140 kV was recorded. The correlation between the attenuation noted when the tube voltage was 140 kV and the attenuation noted when the tube voltage was either 80 or 100 kV was calculated, and differences in the mean CT attenuation values were compared. RESULTS: The mean attenuation values from L1 trabecular bone measurement performed for 191 patients were analyzed. As expected, the mean attenuation values decreased as the tube voltage increased. There was a strong correlation between the attenuation values noted when tube voltages of 80 and 140 kV were used (r2 = 0.97) and those noted when 100 and 140 kV were used (r2 = 0.96). The mean attenuation value noted at 80 kV was 76.4 HU (65%) higher than that noted at 140 kV (p < 0.001). The mean attenuation value at 100 kV was 45.5 HU (39.9%) higher than that noted at 140 kV (p < 0.001). CONCLUSION: We confirmed that attenuation values of L1 trabecular bone, unlike attenuation values of fat, fluid, or soft tissue, vary at different CT x-ray tube voltages. Therefore, standard reference attenuation values for trabecular bone seen at 120 kV cannot be applied to other single-energy settings, DECT, or CT examinations where dose modulation software automatically raises or lowers the tube voltage from 120 kV. Knowledge of the specific energy spectra used is essential before performing opportunistic CT evaluation for osteoporosis. PMID- 27762606 TI - Geometric morphometric analysis of the palatal morphology in children with impacted incisors: A three-dimensional evaluation. AB - OBJECTIVE: To analyze variations in palatal morphology in subjects presenting unilaterally impacted maxillary permanent central incisors compared with a control group of subjects without eruption anomalies using a three-dimensional (3D) analysis. MATERIALS AND METHODS: Twenty-six white subjects (10 girls and 16 boys; mean age 9.5 +/- 1.5 years) with unilaterally impacted maxillary permanent central incisors (impacted incisor group [IIG]) were compared with a control group (CG) of 26 subjects (14 girls and 12 boys, mean age 8.7 +/- 1.6 years) presenting no eruption disorders. For each subject, dental casts were taken and the upper arch was scanned using a 3D laser scanner. To study the entirety of the shape of the palate in any point of the surface, 3D geometric morphometrics was applied. RESULTS: Subjects with impacted maxillary incisors showed skeletal adaptations of the maxilla. In the IIG, both the superior palatal region and lateral palatal surface showed significantly different morphology when compared with CG, with a narrower and higher palatal vault. CONCLUSION: The absence of maxillary central incisors over the physiological age of eruption influenced the development of the palatal morphology compared with subjects without eruption anomalies. PMID- 27762607 TI - Molecular Breast Imaging for Screening in Dense Breasts: State of the Art and Future Directions. AB - OBJECTIVE: The purposes of this review are to discuss the motivation for supplemental screening, to address molecular breast imaging (MBI) radiation dose concerns, and to provide an updated guide to current MBI technology, clinical protocols, and screening performance. Future directions of MBI are also discussed. CONCLUSION: MBI offers detection of mammographically occult cancers in women with dense breasts. Although MBI has been under investigation for nearly 15 years, it has yet to gain widespread adoption in breast screening. PMID- 27762608 TI - Official Executive Summary of an American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. AB - BACKGROUND: This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society and the American College of Chest Physicians. METHODS: A multidisciplinary panel posed six clinical questions in a Population, Intervention, Comparator, and Outcomes format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the certainty in the evidence (i.e., the quality of evidence) using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, the confidence in the evidence, the certainty about how much the public values the main outcomes, the magnitude and balance of desirable and undesirable outcomes, the resources and costs associated with the intervention, the impact on health disparities, and the acceptability and feasibility of the intervention. RESULTS: Evidence-based recommendations were formulated and graded initially by subcommittees and then modified after full panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. CONCLUSIONS: The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and Chest. PMID- 27762609 TI - AcroangiodermatitisA Presentation of Two Cases of Nonhealing Ulcerations in the Lower Extremity. AB - Acroangiodermatitis (AAD), also known as pseudo-Kaposi's sarcoma, is an uncommon benign angioproliferative condition most commonly seen in the lower extremities. This condition often presents as discolored patches that progress to painful ulcerations. The list of vascular conditions associated with this diagnosis is vast. Acroangiodermatitis presents similarly to more aggressive conditions such as Kaposi's sarcoma, making histopathologic examination helpful in its diagnosis. We present two cases of AAD in the setting of chronic venous insufficiency. PMID- 27762611 TI - Gift-Giving in the Podiatric Medical Student-Patient Relationship. AB - We sought to explore the relationship between the podiatric medical student and the patient as it relates to the act of gift-giving as a sign of gratefulness for the services provided. This article presents the clinical case of a man who visited a podiatric medical student because of pain in his feet and subsequently presented the student with several gifts. Philanthropy, empathy, a positive attitude, treatment instructions, and the time devoted to the patient are some of the reasons why patients offer gifts to podiatric medical students. The relationship between the podiatric medical student and the patient and the act of gift-giving by patients are of ethical concern. PMID- 27762613 TI - Effect of Vibram FiveFingers Minimalist Shoes on the Abductor Hallucis Muscle. AB - BACKGROUND: This study investigated the effect of Vibram FiveFingers Bikila minimalist shoes on intrinsic foot musculature. We hypothesized that a gradual transition into minimalist shoes will increase the thickness of the abductor hallucis muscle. METHODS: Forty-one individuals were divided into four groups: control (traditional shod) (n = 9), restricted walking in Vibram FiveFingers (n = 11), running in Vibram FiveFingers (n = 10), and unlimited walking in Vibram FiveFingers (n = 11). At baseline, 12 weeks, and 24 weeks, the thickness of the abductor hallucis muscle was determined using ultrasound. Statistical analysis was performed to determine the significance of differences in muscle thickness at the three different time points. RESULTS: The mean thickness of the abductor hallucis muscle at 24 weeks was significantly greater than that at baseline for the restricted walking (P = .005) and running (P < .001) groups. In the unlimited walking group, the mean thickness of the muscle at 12 weeks was significantly greater than that at baseline (P < .05) but not at 24 weeks. There were no significant differences in muscle thickness among the three time points for the control group (P = .432). CONCLUSIONS: This study demonstrated that wearing Vibram FiveFinger Bikila footwear over a controlled period of time, an unlimited amount of time, as well as transitioning runners over a 6-month period of time using the 10% philosophy for increasing mileage, significantly increases intrinsic muscle thickness of the abductor hallucis. The abductor hallucis muscle aids in support of the medial longitudinal arch, and an increase in this muscle thickness may help reduce running-related injuries thought to arise from arch weakness. PMID- 27762614 TI - The Design, Development, and Reliability Testing of a New Innovative Device to Measure Ankle Joint Dorsiflexion. AB - BACKGROUND: In clinical and research settings, ankle joint dorsiflexion needs to be reliably measured. Dorsiflexion is often measured by goniometry, but the intrarater and interrater reliability of this technique have been reported to be poor. Many devices to measure dorsiflexion have been developed for clinical and research use. An evaluation of 12 current tools showed that none met all of the desirable criteria. The purpose of this study was to design and develop a device that rates highly in all of the criteria and that can be proved to be highly reliable. METHODS: While supine on a treatment table, 14 participants had a foot placed in the Charles device and ankle joint dorsiflexion measured and recorded three times with a digital inclinometer. The mean of the three readings was determined to be the ankle joint dorsiflexion. RESULTS: The analysis used was intraclass correlation coefficient (ICC). There was very little difference in ICC single or average measures between left and right feet, so data were pooled (N = 28). The single-measure ICC was 0.998 (95% confidence interval, 0.996-0.998). The average-measure ICC was 0.998 (95% confidence interval, 0.995-0.999). Limits of agreement for the average measure were also very good: -1.30 degrees to 1.65 degrees . CONCLUSIONS: The Charles device meets all of the desirable criteria and has many innovative features, increasing its appropriateness for clinical and research applications. It has a suitable design for measuring dorsiflexion and high intrarater and interrater reliability. PMID- 27762616 TI - Surgical Treatment of Lateral Malleolar Fractures Using the Compression Cerclage System. AB - Background Lateral malleolar fractures (Weber type B or OTA 44-B) account for 60% of all ankle fractures. To achieve anatomic restoration, surgical stabilization provides better results than conservative treatment. Various fixation methods are available to treat these fractures; however, the best method is still unknown. Our objectives were to present a new, useful, and efficient surgical technique for stabilizing lateral malleolar fractures and to analyze the outcomes of patients treated with the compression cerclage system. Methods The surgical technique consists of a Kirschner wire that is passed percutaneously and perpendicular to the fracture line, and a cerclage wire that is passed in a semi circular fashion over the ends of the Kirschner wire on the lateral side of the bone, leaving loops on each side to allow bilateral compression while twisting both wires. We retrospectively evaluated patients treated with this technique, with or without additional fractures. Follow-up of <24 months and bilateral ankle fractures were the exclusion criteria. Fractures were examined clinically and radiologically in comparison to the uninjured side and were rated according to the criteria reported by McLennon and Ungersma. Olerud and Molander ankle score was used to evaluate functional outcome. Results At the final follow-up, 15 out of 21 patients (9 women and 6 men; mean age, 48.2 years [range, 19-78 years]) were evaluated. The mean follow-up was 5.16 years (28-129 months). Five patients had an isolated lateral malleolar fracture; eight had lateral and medial malleolar fractures; and two had trimalleolar fractures. At the final follow-up, 11 patients were rated good functionally and four were fair, and all patients were rated good radiographically according to the criteria by McLennon and Ungersma. Mean Olerud and Molander ankle score was 93.3 (range, 80-100). Conclusions The compression cerclage system provides good functional and radiological outcomes in patients with lateral malleolus fractures. This method is useful, safe, and efficient with minimum hardware. It can be applied through limited soft-tissue stripping, which is especially important in patients with a high risk for wound complications. PMID- 27762617 TI - Let's Start a Revolution. PMID- 27762618 TI - Improving Diabetes Knowledge and Self-Care Practices. AB - BACKGROUND: This study sought to identify the nature and extent of diabetes related knowledge and self-care practices in people living with type 2 diabetes who attend primary-care clinics and to determine whether a correlation between the two exists. METHODS: In a nonexperimental prospective study, the Diabetes Knowledge Questionnaire and the Summary of Diabetes Self-care Activities were used to assess knowledge and self-management in 50 patients. RESULTS: The mean diabetes knowledge score was 14.40 out of a total of 24 and the mean self-care activities score was 2.89 out of a total of 7, indicating a deficit in a number of key areas in the management of diabetes. There was no statistically significant correlation between diabetes knowledge score and diabetes self-care activities (r = 0.190, P = 0.187). On analysis of the individual subscales, a significant relationship resulted between diabetes knowledge score and diet (r = 0.324, P = 0.022) but physical activity (r = 0.179, P = 0.214), blood sugar testing (r = 0.231, P = 0.107) and footcare (r = 0.189, P = 0.189) gave no significant results. On further analysis, education level was significantly correlated to diabetes knowledge score (r = 0.374, P = 0.007) and self-care activities score (r = 0.317, P = 0.025) while age was significantly correlated to diabetes knowledge score (P = 0.008) and self-care activities score (P = 0.035). CONCLUSIONS: Integrating theories of behavior change into educational interventions at the primary-care level may translate to improved care, reduced long-term complications, and better quality of life. PMID- 27762620 TI - Reinforcement of the Flexor Tendon Repair Using Human Amniotic MembraneA Biomechanical Evaluation Using the Modified Kessler Method of Tendon Repair. AB - BACKGROUND: Human amniotic membrane is used to prevent peritendinous adhesions after tendon injuries. This study compares the mechanical properties of modified Kessler repairs and modified Kessler repairs strengthened using multiple layers of human amniotic membrane. METHODS: Twenty flexor digitorum profundus tendons of sheep forelimbs were sutured by the two-strand modified Kessler technique (group A) and by the two-strand modified Kessler repair reinforced with multiple layers of human amniotic membrane (group B). To assess the mechanical performance of the repairs, tendons were subjected to a linear noncyclic load-to-failure test using a material testing machine. Outcome measures included ultimate forces and the mode of failure. RESULTS: The mean +/- SD value of the failure strength was 34.6 +/- 1.64 N for group A and 50.6 +/- 5.60 N for group B. The reinforced repair provided a significantly higher ultimate load compared with the nonreinforced group (P < .001). All of the specimens failed due to suture breakage at the repair site. CONCLUSIONS: The results of this study show that the modified Kessler repair can be reinforced effectively with human amniotic membrane. PMID- 27762619 TI - Simultaneous Bilateral FractureUnilateral Dislocation of the Talus. AB - In this study, we present the case of a 42-year-old man with a fracture and dislocation of the left talus neck, and a fracture of the right talus neck due to a fall. This kind of fracture can be considered rare, and thus few cases have been reported. Fracture fixation was provided through cannulated screws on either side. Splints were removed after 6 weeks, and passive/active joint movement exercises were started. The patient was able to walk with partial weightbearing at 2 months and with full weightbearing at 3 months. The magnetic resonance imaging scan at 1 year postoperatively revealed the presence of avascular necrosis on the left, whereas it did not exist on the right. Range of motion in both of the ankles was satisfactory. The patient expressed that he was able to perform daily activities without any difficulty and run for 30 minutes without pain. In this case report, in addition to providing a review of the relevant literature on the subject, we set out to show the importance of rigid fixation and early mobilization in these rare injuries. PMID- 27762621 TI - A Case Report of an Osteoid Osteoma on the Bearing Surface of the Talus Treated with Arthroscopic Resection Associated with Autologous Iliac Crest Graft. AB - Osteoid osteomas are most likely to occur in the talar neck and can be classified as cortical, cancellous, or subperiosteal according to the position of the tumor nidus. However, cases located on the bearing surface of the talus are rare. Herein, the patient presented with an osteoid osteoma on the bearing surface of the talus and achieved good curative effects with arthroscopic resection associated with autologous iliac crest graft. PMID- 27762622 TI - First Metatarsal Head and Medial Eminence Widths with and Without Hallux Valgus. AB - BACKGROUND: Resection of the medial eminence in hallux valgus surgery is common. True hypertrophy of the medial eminence in hallux valgus is debated. No studies have compared metatarsal head width in patients with hallux valgus and control patients. METHODS: We reviewed 43 radiographs with hallux valgus and 27 without hallux valgus. We measured medial eminence width, first metatarsal head width, and first metatarsal shaft width in patients with and without radiographic hallux valgus. RESULTS: Medial eminence width was 1.12 mm larger in patients with hallux valgus (P < .0001). Metatarsal head width was 2.81 mm larger in patients with hallux valgus (P < .001). Metatarsal shaft width showed no significant difference (P = .63). CONCLUSIONS: Metatarsal head width and medial eminence width are significantly larger on anteroposterior weightbearing radiographs in patients with hallux valgus. However, frontal plane rotation of the first metatarsal likely accounts for this difference. PMID- 27762623 TI - AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE EVALUATION AND TREATMENT OF HYPERTHYROIDISM AND HYPOTHYROIDISM. AB - These clinical practice guidelines summarize the recommendations of the American Association of Clinical Endocrinologists for the diagnostic evaluation of hyperthyroidism and hypothyroidism and for treatment strategies in patients with these disorders. The sensitive thyroid-stimulating hormone (TSH or thyrotropin) assay has become the single best screening test for hyperthyroidism and hypothyroidism, and in most outpatient clinical situations, the serum TSH is the most sensitive test for detecting mild thyroid hormone excess or deficiency. Therapeutic options for patients with Graves' disease include thyroidectomy (rarely used now in the United States), antithyroid drugs (frequently associated with relapses), and radioactive iodine (currently the treatment of choice). In clinical hypothyroidism, the standard treatment is levothyroxine replacement, which must be tailored to the individual patient. Awareness of subclinical thyroid disease, which often remains undiagnosed, is emphasized, as is a system of care that incorporates regular follow-up surveillance by one physician as well as education and involvement of the patient. PMID- 27762624 TI - Laparoscopic Partial Nephrectomy with a Remotely Activated Bulldog Clamp in a Pig Model. AB - PURPOSE: Saving warm ischemia time (WIT) in laparoscopic partial nephrectomy (LPN) is important. We have designed a new device, a remotely activated bulldog clamp, to facilitate LPN. In present study, the effectiveness, convenience, and safety of the new design device were compared with that of standard bulldog vascular clamp in a pig model. MATERIALS AND METHODS: Fifteen cases of LPN were bilaterally operated on upper or lower pole of kidneys in five pigs. As the test group, eight cases involved the remotely activated bulldog clamp, whereas the remaining seven cases, as the control group, involved the common standard vascular bulldog clamp. The mean operative time, blood lost, and mean WIT were compared between the two groups. RESULTS: The mean operative time and blood lost were not significantly different between the groups (p < 0.05). Continuous artery clamping was used in the two groups. With on-demand clamping, the mean WIT in the test group was 19.0 +/- 3.42 minutes, which was significantly less compared with the control group (31.54 +/- 5.23 minutes, p < 0.05). CONCLUSIONS: The newly designed device can remotely control the renal artery, which made clamping and unclamping much easier. It is effective and safe in LPN. PMID- 27762625 TI - Implantable cardioverter defibrillator management: an update. AB - Implantable cardioverter defibrillator (ICD) is the cornerstone of primary and secondary prevention of sudden cardiac death. In 35 years of technologic improvement and clinical trials, there has been a continuous increase in implantation rate. Purpose of this review is to point out and discuss every aspect related to actual ICD management, investigating implantation procedure and predischarge care, office and remote monitoring follow-up, diagnostic evaluations, management of patients with suspected therapies or malfunctions, heart failure, surgery, radiotherapy and endoscopic procedures. Also, ICD backface such as infections and other complications will be discussed. Finally, we will focus on interesting future perspectives for this setting of patients. PMID- 27762626 TI - Genome-wide DNA methylation in saliva and body size of adolescent girls. AB - AIM: We performed an epigenome-wide association study within the Finnish Health in Teens cohort to identify differential DNA methylation and its association with BMI in adolescents. MATERIALS & METHODS: Differential DNA methylation analyses of 3.1 million CpG sites were performed in saliva samples from 50 lean and 50 heavy adolescent girls by genome-wide targeted bisulfite-sequencing. RESULTS: We identified 100 CpG sites with p-values < 0.000524, seven regions by 'bumphunting' and five CpG islands that differed significantly between the two groups. The ten CpG sites and regions most strongly associated with BMI substantially overlapped with obesity- and insulin-related genes, including MC2R, IGFBPL1, IP6K1 and IGF2BP1. CONCLUSION: Our findings suggest an association between the saliva methylome and BMI in adolescence. PMID- 27762627 TI - miR-22 Inhibits CD34+ Cell Expansion Through Decreasing beta-Catenin in Osteoblasts. AB - The bone marrow (BM) microenvironment, heavily composed of osteoblasts, plays a key role during the normal development of hematopoiesis. Endogenous miR-22 has an important function in the hematopoietic development and osteoblastic differentiation. It is unclear whether miR-22 in osteoblasts from the BM microenvironment also has an important function in the development of hematopoiesis. This study found that the capacity of hTERT-transduced fetal bone marrow osteoblasts (FBMOB-hTERT) cells to expand human cord blood (CB) CD34+ cells and maintain the multipotency of CB CD34+ cells is decreased upon ectopic expression of miR-22. Further experiments revealed that with the existence of CB CD34+ cells, the expression of beta-catenin in FBMOB-hTERT cells is decreased upon ectopic expression of miR-22. The reduced ability of FBMOB-hTERT cells to expand human CB CD34+ cells and maintain the multipotency of CB CD34+ cells upon ectopic miR-22 was partly rescued by overexpression of beta-catenin. The study indicated that the ability of osteoblasts to expand human CB CD34+ cells and maintain the multipotency of CB CD34+ cells is decreased upon ectopic expression of miR-22. The decreased expression of beta-catenin is, at least partly, responsible for the reduced ability of osteoblasts for expanding and supporting CB CD34+ cells upon ectopic expression of miR-22. PMID- 27762628 TI - A Prospective Randomized Study Comparing the Effect of Different Kidney Protection Treatment Protocols on Acute Renal Injury After Extracorporeal Shockwave Lithotripsy. AB - OBJECTIVES: To perform a prospective study to evaluate the renal protective effects of ramping protocol and pause protocol for extracorporeal shockwave lithotripsy (SWL) in human subjects. PATIENTS AND METHODS: Three hundred twenty patients with solitary renal stone <15 mm were randomized to receive one of four protocols: (1) 80% power from beginning until the end of treatment; (2) the first 100 shockwaves (SWs) at 40% power, and then 80% power until the end of treatment; (3) the first 100 shocks at 40% power, followed by a 3-minute pause, and then further SWs at 80% power until the end of treatment; and (4) the first 100 shocks at 80% power, followed by a 3-minute pause, and then further SWs at 80% power until the end of treatment. The primary endpoint was the incidence of renal hematoma assessed by imaging on day 2. Spot urine samples were also collected before and after treatment for acute renal injury marker measurement. RESULTS: The baseline information and treatment parameters of the four groups were comparable. The overall incidence of hematoma formation was 7.69% (24 patients). The number of patients developing hematoma in the four groups was 8 (10.26%), 7 (8.97%), 6 (7.59%), and 3 (3.90%), respectively, and the incidence of hematoma among the four groups was not significantly different. Only patient's body mass index and mean blood pressure during treatment were predictors for hematoma formation. There was also no significant difference in changes in the levels of all markers and complication and hospitalization rates between the four groups. CONCLUSION: Comprehensive assessment of clinical parameters, imaging results, and urinary markers showed no obvious improvement in post-SWL renal insult by either protocol. PMID- 27762629 TI - Enhanced High-Rate Shockwave Lithotripsy Stone Comminution in an In Vivo Porcine Model Using Acoustic Bubble Coalescence. AB - Cavitation plays a significant role in the efficacy of stone comminution during shockwave lithotripsy (SWL). Although cavitation on the surface of urinary stones helps to improve fragmentation, cavitation bubbles along the propagation path may shield or block subsequent shockwaves (SWs) and potentially induce collateral tissue damage. Previous in vitro work has shown that applying low-amplitude acoustic waves after each SW can force bubbles to consolidate and enhance SWL efficacy. In this study, the feasibility of applying acoustic bubble coalescence (ABC) in vivo was tested. Model stones were percutaneously implanted and treated with 2500 lithotripsy SWs at 120 SW/minute with or without ABC. Comparing the results of stone comminution, a significant improvement was observed in the stone fragmentation process when ABC was used. Without ABC, only 25% of the mass of the stone was fragmented to particles <2 mm in size. With ABC, 75% of the mass was fragmented to particles <2 mm in size. These results suggest that ABC can reduce the shielding effect of residual bubble nuclei, resulting in a more efficient SWL treatment. PMID- 27762630 TI - Enhancing Graduate and Postdoctoral Education To Create a Sustainable Biomedical Workforce. AB - PhD-trained biomedical scientists are moving into an increasingly diverse variety of careers within the sciences. However, graduate and postdoctoral training programs have historically focused on academic career preparation, and have not sufficiently prepared trainees for transitioning into other scientific careers. Advocates for science have raised the concern that the collective disregard of the broader career-development needs for predoctoral and postdoctoral trainees could drive talent away from science in upcoming generations. A shift is occurring, wherein universities are increasingly investing in centralized career development programs to address this need. In this Perspective, I reflect on the movement that brought biomedical PhD career development to the spotlight in recent years, and how this movement has influenced both the academic biomedical community and the field of career development. I offer recommendations for universities looking to establish or strengthen their career development programs, including recommendations for how to develop a campus culture that values career development as part of pre- and postdoctoral training. I also suggest steps that faculty might take to facilitate the career development of their mentees, regardless of the mentee's career aspirations. Finally, I reflect on recent national efforts to incentivize innovation, evaluation, and research in the field of biomedical PhD career development, and propose actions that the scientific community can take to support biomedical career development further as a scholarly discipline. These investments will enable new approaches to be rigorously tested and efficiently disseminated to support this rapidly growing field. Ultimately, strengthening biomedical career development will be essential for attracting the best talent to science and helping them efficiently move into careers that will sustain our nation's scientific enterprise. PMID- 27762631 TI - Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs. AB - CONTEXT: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. OBJECTIVE: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. METHODS: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. RESULTS: Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. DISCUSSION: The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. CONCLUSION: The optimized setup uses FaSSIFmod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B. PMID- 27762632 TI - The role of speech-language pathologists in adult palliative care. AB - PURPOSE: Given minimal studies describing the role and practice of speech language pathologists (SLPs) in adult palliative care, the aim of this review was to compile a database of research literature, examine the potential research gaps and to consider material that specifically discussed the need for and/or use of procedures and protocols for SLPs working in palliative care that would support the development of SLP palliative care guidelines. METHOD: A scoping review was conducted utilising Arksey and O'Malley's framework with the goal of exploring any key concepts and approaches utilised by SLPs in adult palliative care, plus any literature and/or recommendations regarding SLP practice in adult palliative care settings. RESULT: Over 1200 articles were initially identified. Of the 1200 articles, 13 academic papers were considered relevant as they recommended, or at least suggested, the need for speech-language pathology therapy guidelines to be implemented within adult palliative care settings. CONCLUSION: The main focus of these articles was on ethical considerations and clinical recommendations for SLPs. Recommendations arising from this scoping review include providing goals to support current practising SLP clinicians and developing clinical guidelines to manage swallowing and/or communication needs of people receiving palliative care. PMID- 27762634 TI - Fatigue in facioscapulohumeral muscular dystrophy: a qualitative study of people's experiences. AB - PURPOSE: The aim of this article is to describe how fatigue affects the lives of people with facioscapulohumeral dystrophy (FSHD), how they experience fatigue, and how they deal with it in order to attune rehabilitation care to patients' needs. METHOD: A qualitative study, consisting of 25 semistructured interviews with patients with FSHD and severe fatigue (as measured with the checklist individual strength (CIS) fatigue questionnaire), was conducted to gain insight into the experiences of patients with fatigue. Data were inductively analyzed. RESULTS: Patients describe fatigue as an overwhelming and unpredictable experience and they make a distinction between actual experienced fatigue and fear of becoming tired. Fatigue can, according to patients, be the result of weak muscles, physical overachieving or underachieving and stress. But most of the time patients do not know the actual causes of the fatigue, which makes it hard to deal with. The experienced fatigue has a large impact on participation, social contacts, and the quality of life of patients, and patients try to use many strategies to adapt themselves to the constantly changing situations. CONCLUSIONS: Fatigue is a severe problem in FSHD and has a huge impact on patients' lives. Patients should be helped to reduce fatigue, for instance by offering evidence-based therapies such as aerobic exercise training or cognitive behavioral therapy. Implications for Rehabilitation Fatigue has significant influence on the quality of lives and participation of people with FSHD. Patients with FSHD are insufficient supported in coping with their fatigue. More attention for fatigue in patients with FSHD in rehabilitation is needed, for instance by a broader implementation of aerobic exercise training or cognitive behavioral therapy. PMID- 27762635 TI - RBANS factor structure in older adults with suspected cognitive impairment: Evidence for a 5-factor structure. AB - Previous research has yielded minimal empirical support for the theoretically formulated five-factor structure of the RBANS, a brief, yet comprehensive standardized neuropsychological test battery used to assess cognitive impairment. The present study tested the theoretically formulated five-factor structure, as well as three alternative factor solutions, using a combination of exploratory and confirmatory factor analytic approaches. The present study utilized archival data from a clinical sample of 150 older adults who were evaluated at an outpatient neuropsychological service. A total of four RBANS models were specified using confirmatory factor analysis. Results of the five-factor model demonstrated good to excellent fit following modifications to the model. Results of chi-square difference tests demonstrated that the five-factor model was statistically superior to the two- and three-factor models (p < .001). In summary, results provide support for the theoretically derived five-factor structure of the RBANS in a clinical sample of older adults. Cautious interpretation of the RBANS index scores as five distinct cognitive domains may be warranted, particularly when there is minimal discrepancy across performance on the tests that comprise each index. PMID- 27762633 TI - Developmental epigenetic programming of adult germ cell death disease: Polycomb protein EZH2-miR-101 pathway. AB - AIM: The Developmental Origin of Health and Disease refers to the concept that early exposure to toxicants or nutritional imbalances during perinatal life induces changes that enhance the risk of developing noncommunicable diseases in adulthood. Patients/materials & methods: An experimental model with an adult chronic germ cell death phenotype resulting from exposure to a xenoestrogen was used. RESULTS: A reciprocal negative feedback loop involving decreased EZH2 protein level and increased miR-101 expression was identified. In vitro and in vivo knockdown of EZH2 induced an apoptotic process in germ cells through increased levels of apoptotic factors (BIM and BAD) and DNA repair alteration via topoisomerase 2B deregulation. The increased miR-101 levels were observed in the animal blood, meaning that miR-101 may be a part of a circulating mark of germ cell death. CONCLUSION: miR-101-EZH2 pathway deregulation could represent a novel pathophysiological epigenetic basis for adult germ cell disease with environmental and developmental origins. PMID- 27762636 TI - Predicting factors associated with frailty in aged patients with bone-arthrosis pain in the clinic. AB - OBJECTIVES: To identify frail and pre-frail patients in a group of patients older than 60 years. METHODS: The phenotype model of Fried's method was used to identify frailty and pre-frailty in total of 78 participants. Cognitive ability and psychosocial function tests were also given to 59 of the 78 patients. RESULTS: Prevalence of frailty and pre-frailty was 14.1% (11/78) and 46.2% (36/78), respectively. Of the 5 phenotype variables, weak grip strength was the most commonly seen variable with 53.8% of all participants and 100% in the frail group. Low energy expenditure, however, was not self-reported by any participant in the current study (0%). Prevalence of frailty in the present study is associated with chronological age. The current study indicates that 4 phenotypic variables (unintentional weight loss, self-reported exhaustion, gait speed and grip strength) contribute to the development to frailty, and that cognitive impairment and psychosocial frailty also predict frailty or pre-frailty in the patients older than 60 years old irrespective of chronic pain or osteoarthritis. The findings of the current study suggest frailty and pre-frailty are common in senior Chinese patients with chronic diseases. CONCLUSION: Recognition and identification of frailty in a rehabilitation clinic or hospital might help physicians to provide appropriate counseling to patients and families about adverse outcomes of certain treatments such as surgery, and could optimize management of coexisting chronic diseases that might contribute to or be affected by frailty. PMID- 27762637 TI - Dextranase from Arthrobacter oxydans KQ11-1 inhibits biofilm formation by polysaccharide hydrolysis. AB - Dental plaque is a biofilm of water-soluble and water-insoluble polysaccharides, produced primarily by Streptococcus mutans. Dextranase can inhibit biofilm formation. Here, a dextranase gene from the marine microorganism Arthrobacter oxydans KQ11-1 is described, and cloned and expressed using E. coli DH5alpha competent cells. The recombinant enzyme was then purified and its properties were characterized. The optimal temperature and pH were determined to be 60 degrees C and 6.5, respectively. High-performance liquid chromatography data show that the final hydrolysis products were glucose, maltose, maltotriose, and maltotetraose. Thus, dextranase can inhibit the adhesive ability of S. mutans. The minimum biofilm inhibition and reduction concentrations (MBIC50 and MBRC50) of dextranase were 2 U ml-1 and 5 U ml-1, respectively. Scanning electron microscopy and confocal laser scanning microscope (CLSM) observations confirmed that dextranase inhibited biofilm formation and removed previously formed biofilms. PMID- 27762638 TI - Body habitus in heart failure: understanding the mechanisms and clinical significance of the obesity paradox. AB - The prevalence of obesity among adults and children worldwide has reached epic proportions and has become a major independent risk factor for the development of heart failure (HF), in addition to a contributor of hypertension and cardiovascular disease. The implications of obesity in the development of HF involve adverse effects on cardiac structure and function. Despite all of this, in the setting of chronic HF, excess body mass is associated with improved clinical outcomes, demonstrating the presence of an obesity paradox. In this review, we will discuss the gender differences, global application, potential mechanisms and role of interventions based on fitness and purposeful weight loss as potential therapeutic strategies. PMID- 27762639 TI - Stem Cells for Modeling and Therapy of Parkinson's Disease. AB - Parkinson's disease (PD) is the second most frequent neurodegenerative disease after Alzheimer's disease, which is characterized by a low level of dopamine being expressing in the striatum and a deterioration of dopaminergic neurons (DAn) in the substantia nigra pars compacta. Generation of PD-derived DAn, including differentiation of human embryonic stem cells, human neural stem cells, human-induced pluripotent stem cells, and direct reprogramming, provides an ideal tool to model PD, creating the possibility of mimicking key essential pathological processes and charactering single-cell changes in vitro. Furthermore, thanks to the understanding of molecular neuropathogenesis of PD and new advances in stem-cell technology, it is anticipated that optimal functionally transplanted DAn with targeted correction and transgene-free insertion will be generated for use in cell transplantation. This review elucidates stem-cell technology for modeling PD and offering desired safe cell resources for cell transplantation therapy. PMID- 27762640 TI - How to prepare a systematic review of economic evaluations for informing evidence based healthcare decisions: data extraction, risk of bias, and transferability (part 3/3). AB - INTRODUCTION: This article is part of the series "How to Prepare a Systematic Review (SR) of Economic Evaluations (EE) for Informing Evidence-based Healthcare Decisions" in which a five-step-approach for conducting a SR of EE is proposed. Areas covered: This paper explains the data extraction process, the risk of bias assessment and the transferability of EEs by means of a narrative review and expert opinion. SRs play a critical role in determining the comparative cost effectiveness of healthcare interventions. It is important to determine the risk of bias and the transferability of an EE. Expert commentary: Over the past decade, several criteria lists have been developed. This article aims to provide recommendations on these criteria lists based on the thoroughness of development, feasibility, overall quality, recommendations of leading organizations, and widespread use. PMID- 27762641 TI - The immediate effects of robot-assistance on energy consumption and cardiorespiratory load during walking compared to walking without robot assistance: a systematic review. AB - PURPOSE: The integration of sufficient cardiovascular stress into robot-assisted gait (RAG) training could combine the benefits of both RAG and aerobic training. The aim was to summarize literature data on the immediate effects of RAG compared to walking without robot-assistance on metabolic-, cardiorespiratory- and fatigue related parameters. METHODS: PubMed and Web of Science were searched for eligible articles till February 2016. Means, SDs and significance values were extracted. Effect sizes were calculated. RESULTS: Fourteen studies were included, concerning 155 participants (85 healthy subjects, 39 stroke and 31 spinal cord injury patients), 9 robots (2 end-effectors, 1 treadmill-based and 6 wearable exoskeletons), and 7 outcome parameters (mostly oxygen consumption and heart rate). Overall, metabolic and cardiorespiratory parameters were lower during RAG compared to walking without robot-assistance (moderate to large effect sizes). In healthy subjects, when no body-weight support (BWS) was provided, RAG with an end effector device was more energy demanding than walking overground (p > .05, large effect sizes). CONCLUSIONS: Generally, results suggest that RAG is less energy consuming and cardiorespiratory stressful than walking without robot-assistance, but results depend on factors such as robot type, walking speed, BWS and effort. Additional research is needed to draw firm conclusions. Implications for Rehabilitation Awareness of the energy consumption and cardiorespiratory load of robot-assisted gait (RAG) training is important in the rehabilitation of (neurological) patients with impaired cardiorespiratory fitness and patients who are at risk of cardiovascular diseases. On the other hand, the integration of sufficient cardiometabolic stress in RAG training could combine the effects of both RAG and aerobic training. Energy consumption and cardiorespiratory load during walking with robot-assistance seems to depend on factors such as robot type, walking speed, body-weight support or amount of effort. These parameters could be adjusted in RAG rehabilitation to make RAG more or less energy-consuming and cardiorespiratory stressful. Overall, short duration exoskeleton walking seems less energy-consuming and cardiorespiratory stressful than walking without robot-assistance. This might implicate that the exercise intensity is safe for (neurological) patients at risk of cardiovascular diseases. How this changes in extended walking time is unclear. PMID- 27762642 TI - Efficacy and safety of mascara dyeing as an adjunct to Alexandrite and Nd:YAG laser applications for removing thin and white-colored facial and axillary hair. AB - INTRODUCTION: There is no satisfactory and efficient method for long-term removal of white-colored and thin hair. METHODS: We conducted a randomised clinical trial of hirsute patients with excessive white and/or thin hair on the face and/or axilla. In Group I (n: 16), the facial hair on one side of the face was painted with a black eyelash mascara immediately before Nd:YAG laser and the other half was only treated by Nd:YAG. In Group II (n: 20), the axillary hair on one side was painted with the mascara before the Alexandrite laser with the other side being only treated by Alexandrite. RESULTS: The terminal hair counts on the painted facial and axillary sides were significantly lower than those on the control sides throughout the study except for the first month. The decrease in the terminal hair count was significant from the beginning of treatment to the second and sixth months on the painted and control facial sides and to the first and sixth months on the axillary sides. CONCLUSION: Hair coloring with black eyelash mascara is a simple, efficient and safe adjunct to Alexandrite and Nd:YAG laser applications to enhance their clinical efficacy in eliminating white and thin facial or axillary hair. PMID- 27762643 TI - Intense pulsed light (IPL) treatment for the skin in the eye area - clinical and cutometric analysis. AB - OBJECTIVE: The aim of the research was to establish the influence of IPL treatment on skin ageing in the eye area. MATERIAL AND METHODS: This study included 24 women, aged 38-63 years (mean age was 48.04) with Fitzpatrick skin type II and III who underwent five successive treatment sessions with an IPL in two-week intervals. The Cutometer (Courage + Khazaka electronic) reference test was an objective method for the assessment of the biomechanical properties of the skin. The measurements were made in three places around the eye. The photo documentation was used to compare state of skin before and after three months of treatments. Additionally, patients filled in a questionnaire, which contained questions concerning self-assessment of the procedure effects. RESULTS: Cutometric analysis showed significant improvement of skin elasticity (statistical significance level is mostly < 0.0001). The comparison of clinical changes in the therapy, based on photo documentation, showed a 25% improvement. CONCLUSIONS: This treatment was used in order to improve skin elasticity and decrease the amount and depth of wrinkles. It is a non-invasive treatment, with low risk of complications. PMID- 27762644 TI - Adapting a robotics program to enhance participation and interest in STEM among children with disabilities: a pilot study. AB - PURPOSE: Youth with disabilities are under-represented in science, technology, engineering, and math (STEM) in school and in the workforce. One encouraging approach to engage youth's interest in STEM is through robotics; however, such programs are mostly for typically developing youth. The purpose of this study was to understand the development and implementation of an adapted robotics program for children and youth with disabilities and their experiences within it. METHOD: Our mixed methods pilot study (pre- and post-workshop surveys, observations, and interviews) involved 41 participants including: 18 youth (aged 6-13), 12 parents and 11 key informants. The robotics program involved 6, two-hour workshops held at a paediatric hospital. RESULTS: Our findings showed that several adaptations made to the robotics program helped to enhance the participation of children with disabilities. Adaptations addressed the educational/curriculum, cognitive and learning, physical and social needs of the children. In regards to experiences within the adapted hospital program, our findings highlight that children enjoyed the program and learned about computer programming and building robots. CONCLUSIONS: Clinicians and educators should consider engaging youth with disabilities in robotics to enhance learning and interest in STEM. Implications for Rehabilitation Clinicians and educators should consider adapting curriculum content and mode of delivery of LEGO(r) robotics programs to include youth with disabilities. Appropriate staffing including clinicians and educators who are knowledgeable about youth with disabilities and LEGO(r) robotics are needed. Clinicians should consider engaging youth with disabilities in LEGO(r) to enhance learning and interest in STEM. PMID- 27762645 TI - Morphological features of fascia lata in relation to fascia diseases. AB - Fascia lata is an important element of the fascial system, which forms the continuum of connective tissue throughout the body. This deep fascia envelops the entire thigh and hip area and its main function is to transmit mechanical forces generated by the musculoskeletal system of the lower extremities. Fascia lata is also known as a useful and easily harvested graft material. Despite its crucial role in lower extremity biomechanics and wide-ranging applications in plastic and reconstructive surgery, both the structure of fascia lata and particularly the cells populating this tissue are relatively unexplored and therefore poorly understood. The aim of this study was to characterize the main cell populations encountered within human fascia lata and to try to understand their role in health and diseases. Pathologically unchanged human fascia lata was obtained post mortem from adult males. The specimens were analyzed under light, electron, and confocal microscopy. On the basis of different visualization techniques, we were able to characterize in detail the cells populating human fascia lata. The main cells found were fibroblasts, fibrocytes, mast cells, cells showing myoid differentiation, nerve cells, and most interestingly, telocytes. Our results supplement the formerly inadequate information in the literature regarding the cellular components of deep fascial structure, may contribute to a better understanding of the pathogenesis of fascial disorders and improve fascia lata application as a graft material. PMID- 27762646 TI - Rejuvenation of the perioral and lip regions with two new dermal fillers: The Italian experience with VycrossTM Technology. AB - BACKGROUND: Hyaluronic acid fillers are frequently used for maintenance of youthful appearance of perioral and lip region. The introduction of Juvederm(r) VolbellaTM with lidocaine and Juvederm(r) VoliftTM with lidocaine to the European aesthetic market in 2012 increased the options of fillers to be used and it appears to be a new solution to improve this area. OBJECTIVE: the aim of this study is to demonstrate how to correct this area using two new dermal fillers: Juvederm(r) VoliftTM with lidocaine, and Juvederm(r) VolbellaTM with lidocaine, based on the experience of two Italian phycians. MATERIAL AND METHODS: 510 patients were enrolled, 195 were treated with Juvederm(r) VolbellaTM with Lidocaine, 160 with Juvederm(r) VoliftTM with lidocaine and 150 with both dermal fillers. Patients were photographed before and immediately after the treatment. RESULTS: All patients were extremely satisfied with their treatments. There were no immediate or delayed complications with either of the dermal fillers when used alone, or in combination. CONCLUSION: The dermal filler portfolio in Europe is among the largest and most varied available. ( 5 ) We propose here two new 15mg/ml and 17.5mg/ml hyaluronic acid fillers that utilize VycrossTM technology, that are suitable for lip and perioral region. According to the severity of the wrinkles and to the lip augmentation that we want to obtain we can select either one filler or another. PMID- 27762647 TI - Clinical comparison of salicylic acid peel and LED-Laser phototherapy for the treatment of Acne vulgaris in teenagers. AB - Acne vulgaris treatments usually cause sensitivity, teratogenicity and bacterial resistance. Investigations of other therapeutic techniques, such as phototherapy, are highly relevant. Thus, we compared the effectiveness of two Acne vulgaris treatments in adolescents: peeling with salicylic acid (SA) and phototherapy. Teens were randomly divided into: group I, treatment with SA peels (10%) and group II, treatment with phototherapy (blue LED and red laser lights). Photographs were taken before and after ten sessions of each treatment, carried out weekly, and compared. To compare the differences between the treatments, the Student t-test was used. P values < 0.05 were considered significant. Both techniques are effective therapies for the treatment of acne in teenagers since the number of comedones, papules and pustules decreased significantly at the end of the session. However, when the two treatments were compared, phototherapy showed a significant difference in reducing the number of pustules. The combined use of red and blue lights due to their anti-inflammatory and wound-healing properties is a more efficient alternative for treating Acne vulgaris in relation to SA and proves more reliable and without side effects, improving the adolescents' skin health. PMID- 27762648 TI - Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013. AB - BACKGROUND: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the 'Luminal A-like' and 'Luminal B-like (HER2-negative)' subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined. PATIENTS AND METHODS: Six hundred seventy-one patients (>=35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included. RESULTS: 'Luminal A-like' tumors were mostly G1 or G2 (90%) whereas 'Luminal B-like' tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In 'Luminal B-like' tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 'Luminal A-like' tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95-3.4) and 1.5 (0.80-2.8), respectively. CONCLUSIONS: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of 'Luminal A-like', while those with ER-positive/HER2 negative/G3 breast cancer have a worse prognosis, similar to that of 'Luminal B like', when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2. PMID- 27762649 TI - Skin permeation and retention of topical bead formulation containing tranexamic acid. AB - The objective of this study is to develop a topical bead formulation of tranexamic acid (TA) which can be used concomitantly with laser treatment. The bead formulation of TA (TAB) was successfully prepared by fluidized bed drying method. Physicochemical properties of the TAB were evaluated in terms of chemical stability of TA and differential scanning calorimetry. TA in the bead was stable up to six months at 25 degrees C and existed as amorphous state. In vitro skin permeation and in vivo skin retention of TA in the beads were significantly higher compared to a commercial product. When the bead was dissolved into distilled water and applied concomitantly with laser treatment, the amount of TA retained in the skin in the in vivo study was inversely proportional to the energy levels of laser treatment, indicating absorption into subcutaneous tissue and drainage to systemic circulation. Therefore, when laser treatment is used concomitantly with TAB, energy level should be very carefully monitored to avoid possible adverse events associated with systemic side effects of TA. PMID- 27762650 TI - Antiviral Defense Involves AGO4 in an Arabidopsis-Potexvirus Interaction. AB - In plants, RNA silencing regulates gene expression through the action of Dicer like (DCL) and Argonaute (AGO) proteins via micro RNAs and RNA-dependent DNA methylation (RdDM). In addition, RNA silencing functions as an antiviral defense mechanism by targeting virus-derived double-stranded RNA. Plants encode multiple AGO proteins with specialized functions, including AGO4-like proteins that affect RdDM and AGO2, AGO5, and AGO1, which have antiviral activities. Here, we show that AGO4 is also required for defense against the potexvirus Plantago asiatica mosaic virus (PlAMV), most likely independent of RdDM components such as DCL3, Pol IV, and Pol V. Transient assays showed that AGO4 has direct antiviral activity on PlAMV and, unlike RdDM, this activity does not require nuclear localization of AGO4. Furthermore, although PlAMV infection causes a decrease in AGO4 expression, PlAMV causes a change in AGO4 localization from a largely nuclear to a largely cytoplasmic distribution. These results indicate an important role for AGO4 in targeting plant RNA viruses as well as demonstrating novel mechanisms of regulation of and by AGO4, independent of its canonical role in regulating gene expression by RdDM. PMID- 27762651 TI - A Clinically Relevant Closed-Head Model of Single and Repeat Concussive Injury in the Adult Rat Using a Controlled Cortical Impact Device. AB - Repeat concussions (RC) can result in significant long-term neurological consequences and increased risk for neurodegenerative disease compared with single concussion (SC). Mechanisms underlying this difference are poorly understood and best elucidated using an animal model. To the best of our knowledge, there is no closed-head model in the adult rat using a commercially available device. We developed a novel and clinically relevant closed-head injury (CHI) model of both SC and RC in the adult rat using a controlled cortical impact (CCI) device. Adult rats received either a single or repeat CHI (three injuries, 48 h apart), and acute deficits in sensorimotor and locomotor function (foot fault; open field), memory (novel object), and anxiety (open field; corticosterone [CORT]) were measured. Assessment of cellular pathology was also conducted. Within the first week post-CHI, rats with SC or RC showed similar deficits in motor coordination, decreased locomotion, and higher resting CORT levels. Rats with an SC had memory deficits post-injury day (PID) 3 that recovered to sham levels by PID 7; however, rats with RC continued to show memory deficits. No obvious gross pathology was observed on the cortical surface or in coronal sections. Further examination showed thinning of the cortex and corpus callosum in RC animals compared with shams and increased axonal pathology in the corpus callosum of both SC and RC animals. Our data present a model of CHI that results in clinically relevant markers of concussion and an early differentiation between SC and RC. PMID- 27762652 TI - Polydeoxyribonucleotide improves wound healing of fractional laser resurfacing in rat model. AB - BACKGROUND: Polydeoxyribonucleotide (PDRN) is an active compound that can promote wound healing. PDRN stimulates wound healing by enhancing angiogenesis and increasing fibroblast growth rates. Laser skin resurfacing is a popular cosmetic procedure for skin rejuvenation. Despite excellent improvement of photo-damaged skin and acne scarring, it is accompanied with drawbacks, such as prolonged erythema and crusting. OBJECTIVE: This study was designed to assess the effect of PDRN on wounds induced by fractional laser resurfacing. METHODS: Twelve male rats aged 8 weeks were randomly assigned to the PDRN treatment group and the control group. Wounds were induced using a fractional ablative CO2 laser. The treatment group received daily injections of PDRN and the control group received injections of the vehicle. Wound healing assessed by clinical features and histopathologic findings. RESULTS: The process of wound healing was faster in the treatment group than in the control group. In the histopathological examination, the granulation tissue thickness score of the treatment group was significantly higher than that of the control group. Results of immunohistochemical staining showed a marked increase of VEGF-positive cells and PECAM-1/CD31-positive microvessels in the treatment group. CONCLUSION: PDRN may be a beneficial option to promote wound healing after laser treatment. PMID- 27762653 TI - Resting-State Magnetoencephalography Reveals Different Patterns of Aberrant Functional Connectivity in Combat-Related Mild Traumatic Brain Injury. AB - Blast mild traumatic brain injury (mTBI) is a leading cause of sustained impairment in military service members and veterans. However, the mechanism of persistent disability is not fully understood. The present study investigated disturbances in brain functioning in mTBI participants using a source-imaging based approach to analyze functional connectivity (FC) from resting-state magnetoencephalography (rs-MEG). Study participants included 26 active-duty service members or veterans who had blast mTBI with persistent post-concussive symptoms, and 22 healthy control active-duty service members or veterans. The source time courses from regions of interest (ROIs) were used to compute ROI to whole-brain (ROI-global) FC for different frequency bands using two different measures: 1) time-lagged cross-correlation and 2) phase-lock synchrony. Compared with the controls, blast mTBI participants showed increased ROI-global FC in beta, gamma, and low-frequency bands, but not in the alpha band. Sources of abnormally increased FC included the: 1) prefrontal cortex (right ventromedial prefrontal cortex [vmPFC], right rostral anterior cingulate cortex [rACC]), and left ventrolateral and dorsolateral prefrontal cortex; 2) medial temporal lobe (bilateral parahippocampus, hippocampus, and amygdala); and 3) right putamen and cerebellum. In contrast, the blast mTBI group also showed decreased FC of the right frontal pole. Group differences were highly consistent across the two different FC measures. FC of the left ventrolateral prefrontal cortex correlated with executive functioning and processing speed in mTBI participants. Altogether, our findings of increased and decreased regionalpatterns of FC suggest that disturbances in intrinsic brain connectivity may be the result of multiple mechanisms, and are associated with cognitive sequelae of the injury. PMID- 27762654 TI - Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy. AB - BACKGROUND: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision. MATERIAL AND METHODS: A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000 2013 from the National Oncology Data AllianceTM (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR. RESULTS: On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT. CONCLUSION: Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery. PMID- 27762655 TI - Traumatic Brain Injury and Post-Deployment Binge Drinking among Male and Female Army Active Duty Service Members Returning from Operation Enduring Freedom/Operation Iraqi Freedom. AB - This study examines whether the relationship between traumatic brain injury (TBI) and post-deployment binge drinking is independent of screening positive for mental health problems among male and female service members. Data are from the Substance Use and Psychological Injury Combat Study of Army members returning from deployment to Afghanistan or Iraq in fiscal years 2008-2011. The sample consists of 240,694 male and 26,406 female active duty members who completed initial and follow-up questionnaires. The initial questionnaire, completed at the end of deployment, included screens for TBI and mental health problems (post traumatic stress disorder, depression, harmful thoughts). The dependent variable, frequent binge drinking (six or more drinks on one occasion, at least monthly), was assessed on the follow-up questionnaire on average 3-9 months post deployment. More than 21% of males and 7% of females reported frequent binge drinking. Male members were more likely to screen positive for TBI, compared with females (7.5% vs. 4.4%). Females with both TBI and mental health positive screens had more than double the risk of frequent binge drinking, compared with those without either problem (15.8% vs. 6.6%), and males with both problems had almost double the risk, compared with males with neither problem (33.6% vs. 19.7%). In multivariable logistic regression models, having a TBI and a comorbid positive mental health screen was associated with increased odds of frequent binge drinking among both males and females (adjusted odds ratio [AOR] = 1.59, CI: 1.50 1.69, and AOR = 2.11, CI: 1.57-2.83, respectively), compared with those with neither condition. More research is needed on the interaction of gender and binge drinking, especially when TBI and mental health problems co-exist. PMID- 27762658 TI - Effects of Stem Cell Factor on Cell Homing During Functional Pulp Regeneration in Human Immature Teeth. AB - Conventional root canal treatment in immature permanent teeth can lead to early tooth loss in children because root formation is discontinued. We investigated whether the stem cell factor (SCF) could facilitate cell homing in the pulpless immature root canal and promote regeneration of a functional pulp. In vitro, human mesenchymal stem cells (hMSCs) were exposed to SCF at various concentrations for assessing cell migration, proliferation, and differentiation toward odonto/osteoblasts by 3D-chemotaxis slides, WST-1 assay, and alkaline phosphatase activity, respectively. Fibrin gels were used to deliver 15 MUg/mL SCF for in vivo experiments. The release kinetic of SCF was assessed in vitro. Two corresponding human immature premolars, with or without SCF, were placed at rat calvariae for 6 and 12 weeks. All tooth specimens were either analyzed histologically and the percentage of tissue ingrowth determined or the cells were extracted from the pulp space, and the mRNA level of DMP1, DSPP, Col1, NGF, and VEGF were assessed by quantitative polymerase chain reaction. In the presence of SCF, we saw an increase in hMSCs directional migration, proliferation, and odonto/osteogenic differentiation. SCF also increased the extent of tissue ingrowth at 6 weeks but not at 12 weeks. However, at this time point, the formed tissue appeared more mature in samples with SCF. In terms of gene transcription, DMP1, Col1, and VEGF were the significantly upregulated genes, while DSPP and NGF were not affected. Our results suggest that SCF can accelerate cell homing and the maturation of the pulp-dentin complex in human immature teeth. PMID- 27762660 TI - Time-Dependent Effects of Arginine-Vasopressin V1 Receptor Inhibition on Secondary Brain Damage after Traumatic Brain Injury. AB - Arginine-vasopressin (AVP) V1 receptors are known to mediate brain edema formation after traumatic brain injury (TBI). So far, however, AVP V1 receptors were only inhibited by genetic deletion or prior to trauma. Therefore, the current study aimed to determine the therapeutic window of AVP V1 receptor antagonization after TBI. Male C57BL/6 mice (n = 7 per group) were subjected to controlled cortical impact (CCI), and 500 ng of a selective peptide V1 receptor antagonist (V1880) were applied by intracerebroventricular injection 5 min, and 1, 3, and 6 h thereafter. After 24 h, brain water content (BWC), intracranial pressure (ICP), and secondary contusion expansion volume were assessed. Neurological function was assessed daily for 7 days after trauma. Inhibition of AVP V1 receptors within 1 h after TBI significantly reduced BWC from 81.6 +/- 0.7 to 80.6 +/- 0.7% (mean +/- SD; p < 0.05). Reduction of brain edema resulted in a significant decrease in ICP from 25.9 +/- 1.8 mm Hg to 21.0 +/- 1.5 mm Hg (p < 0.05) and a reduction in contusion volume (26.1 +/- 2.5 mm3 vs. 30.1 +/- 2.0 mm3 in controls; p < 0.05). This reduction of brain injury resulted in a significantly improved neurological function 7 days after trauma. Treatments initiated 6 h after TBI had no effect. The results of the current study demonstrate that inhibition of AVP V1 receptors improve outcome after experimental TBI when given within a clinically relevant time window. Therefore, AVP V1 receptors may represent a therapeutic target with clinical potential. PMID- 27762659 TI - Neurobiological Effects of Morphine after Spinal Cord Injury. AB - Opioids and non-steroidal anti-inflammatory drugs are used commonly to manage pain in the early phase of spinal cord injury (SCI). Despite its analgesic efficacy, however, our studies suggest that intrathecal morphine undermines locomotor recovery and increases lesion size in a rodent model of SCI. Similarly, intravenous (IV) morphine attenuates locomotor recovery. The current study explores whether IV morphine also increases lesion size after a spinal contusion (T12) injury and quantifies the cell types that are affected by early opioid administration. Using an experimenter-administered escalating dose of IV morphine across the first seven days post-injury, we quantified the expression of neuron, astrocyte, and microglial markers at the injury site. SCI decreased NeuN expression relative to shams. In subjects with SCI treated with IV morphine, virtually no NeuN+ cells remained across the rostral-caudal extent of the lesion. Further, whereas SCI per se increased the expression of astrocyte and microglial markers (glial fibrillary acidic protein and OX-42, respectively), morphine treatment decreased the expression of these markers. These cellular changes were accompanied by attenuation of locomotor recovery (Basso, Beattie, Bresnahan scores), decreased weight gain, and the development of opioid-induced hyperalgesia (increased tactile reactivity) in morphine-treated subjects. These data suggest that morphine use is contraindicated in the acute phase of a spinal injury. Faced with a lifetime of intractable pain, however, simply removing any effective analgesic for the management of SCI pain is not an ideal option. Instead, these data underscore the critical need for further understanding of the molecular pathways engaged by conventional medications within the pathophysiological context of an injury. PMID- 27762661 TI - Clinical Profile of Patients with Necrotizing Scleritis in a Tertiary Eye Care Center in Southern India. AB - PURPOSE: To report the clinical profile of a series of necrotizing scleritis in an Indian population. METHODS: A retrospective medical record review of 27 consecutive patients with necrotizing scleritis. Patient demographics, ocular and systemic findings, treatment modalities, and visual outcome were recorded. RESULTS: There were 19 males and 8 females (31 eyes) with mean age at presentation of 49.5 years (range: 30-84 years). Underlying immunologically induced disorders was present in 37%. In 70% of the cases with immunologically induced disorders, necrotizing scleritis was the initial presentation. Complicated cataract (25.8%) and exudative retinal detachment (9.6%) were the most common anterior and posterior segment complications, respectively. Cyclophosphamide was the most commonly used immunosuppressive (55.56%) and proved to be the most effective. But even with the best available treatment, globe perforation was encountered in two eyes. CONCLUSIONS: Necrotizing scleritis can be the initial presentation of immunologically induced disorders. This disease entity is plagued with a high rate of ocular complications, especially those which can be devastating, such as globe perforation. Early and intensive therapy can be helpful in salvaging the eye. PMID- 27762657 TI - Rehabilitation Strategies after Spinal Cord Injury: Inquiry into the Mechanisms of Success and Failure. AB - Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems' responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans. PMID- 27762662 TI - Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine. AB - This study examined effects of 4 weeks of caffeine supplementation on endurance performance. Eighteen low-habitual caffeine consumers (<75 mg . day-1) were randomly assigned to ingest caffeine (1.5-3.0 mg . kg-1day-1; titrated) or placebo for 28 days. Groups were matched for age, body mass, VO2peak and Wmax (P > 0.05). Before supplementation, all participants completed one VO2peak test, one practice trial and 2 experimental trials (acute 3 mg . kg-1 caffeine [precaf] and placebo [testpla]). During the supplementation period a second VO2peak test was completed on day 21 before a final, acute 3 mg . kg-1 caffeine trial (postcaf) on day 29. Trials consisted of 60 min cycle exercise at 60% VO2peak followed by a 30 min performance task. All participants produced more external work during the precaf trial than testpla, with increases in the caffeine (383.3 +/- 75 kJ vs. 344.9 +/- 80.3 kJ; Cohen's d effect size [ES] = 0.49; P = 0.001) and placebo (354.5 +/- 55.2 kJ vs. 333.1 +/- 56.4 kJ; ES = 0.38; P = 0.004) supplementation group, respectively. This performance benefit was no longer apparent after 4 weeks of caffeine supplementation (precaf: 383.3 +/- 75.0 kJ vs. postcaf: 358.0 +/- 89.8 kJ; ES = 0.31; P = 0.025), but was retained in the placebo group (precaf: 354.5 +/- 55.2 kJ vs. postcaf: 351.8 +/- 49.4 kJ; ES = 0.05; P > 0.05). Circulating caffeine, hormonal concentrations and substrate oxidation did not differ between groups (all P > 0.05). Chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers. Therefore, individuals with low habitual intakes should refrain from chronic caffeine supplementation to maximise performance benefits from acute caffeine ingestion. PMID- 27762663 TI - A New Genus and Two New Species of Proteocephalidean Tapeworms (Cestoda) from Cichlid Fish (Perciformes: Cichlidae) in the Neotropics. AB - Cichlidocestus n. gen. is proposed to accommodate 2 new species of proteocephalidean cestodes, Cichlidocestus gillesi n. sp. from Cichlasoma amazonarum in Peru (type species) and Cichlidocestus janikae n. sp. from Hypsophrys nicaraguensis (all Perciformes: Cichlidae) in Costa Rica. The new genus is unique among all but 1 proteocephalidean genera in the position of the ovary that occupies the middle and posterior thirds of the median region of proglottids (vs. the ovary in the posterior third of proglottids near their posterior margin in all but 1 remaining taxa). In addition, Cichlidocestus is typified by the presence of a voluminous, spherical, internal seminal vesicle, several pairs of ventral excretory canals in the medulla, a pyramidal, quadrilobed scolex with an apical muscular sucker, and the posterior extent of the testes that may reach almost to the posterior margin of proglottids. The new genus shares the position of the ovary and its extension with Sciadocephalus (also a parasite of cichlids in the Neotropics as the new taxon); in all remaining proteocephalideans the ovary occupies the posterior third only. Sciadocephalus differs from Cichlidocestus by a different morphology of the scolex, which possesses an umbrella-like metascolex that is markedly wider than the strobila, the number of ventral osmoregulatory canals, and development of the uterus, which forms capsule-like formations filled with eggs in Sciadocephalus megalodiscus (vs. simple lateral diverticula in Cichlidocestus spp.). Both new species of Cichlidocestus can be easily distinguished from one another by the anterior extent of the poral vitelline follicles (anterior to the cirrus-sac, i.e., preporal, in C. gillesi vs. posterior, i.e., only postporal in C. janikae), size of the eggs (diameter of the external layer of the embryophore of C. gillesi 30-33 MUm vs. 44-46 MUm in C. janikae), and the number of uterine lateral diverticula (16-21 on 1 side in C. gillesi vs. only 8-12 in C. janikae) and the testes (37-46 in C. gillesi vs. 63-74 in C. janikae). Based on a phylogenetic analysis of the 28S rRNA gene (lsrDNA) sequences, C. gillesi forms a lineage sister to S. megalodiscus, thus supporting the morphological similarity of both genera that occur in fishes of the same family in the same zoogeographical region. PMID- 27762664 TI - Limited Immunogenicity of Human Induced Pluripotent Stem Cell-Derived Cartilages. AB - Articular cartilage damage does not spontaneously heal and could ultimately result in a loss of joint function. Damaged cartilage can be repaired with cell/tissue sources that are transplanted, however, autologous chondrocytes are limited in number as a cell source. Induced pluripotent stem cells (iPSCs) are a relatively new and abundant cell source and can be made from the patient, but at a considerable cost. Because cartilage is immunoprivileged tissue, allogeneic cartilages have been transplanted effectively without matching for human leukocyte antigen (HLA), but are difficult to acquire due to scarcity of donors. In this study, we examined the immunogenicity of human iPSC-derived cartilages (hiPS-Carts) in vitro to evaluate whether allogeneic hiPS-Carts can be a new cell/tissue source. The cells in hiPS-Carts expressed limited amounts of major histocompatibility complex (MHC) class I (HLA-ABC) and MHC class II (HLA-DRDQDP). Treatment with interferon gamma (IFNgamma) induced the expression of MHC class I, but not MHC class II in hiPS-Carts. A mixed lymphocyte reaction assay showed that hiPS-Carts stimulated the proliferation of neither T cells nor the activation of NK cells. Furthermore, hiPS-Carts suppressed the proliferation of T cells stimulated with interleukin 2 and phytohemagglutinin (PHA). Together with previously reported findings, these results suggest that hiPS-Carts are no more antigenic than human cartilage. Additionally, in combination with the fact that iPSCs are unlimitedly expandable and thus can supply unlimited amounts of iPS Carts from even one iPSC line, they suggest that allogeneic hiPS-Carts are a candidate source for transplantation to treat articular cartilage damage. PMID- 27762665 TI - Sutures Possess Strong Regenerative Capacity for Calvarial Bone Injury. AB - Repair of calvarial bony defects remains challenging for craniofacial surgeons. Injury experiments on animal calvarial bones are widely used to study healing mechanisms and test tissue engineering approaches. Previously, we identified Gli1+ cells within the calvarial sutures as stem cells supporting calvarial bone turnover and injury repair. In this study, we tested the regenerative capacity of the suture region compared with other areas of calvarial bone. Injuries were made to mouse sagittal sutures or other areas of the calvarial bone at varying distances from the suture. Samples were collected at different time points after injury for evaluation. MicroCT and histological analyses were conducted. EdU incorporation analysis was performed to assay cell proliferation. Gli1 CreERT2;Tdtomatoflox mice were used to trace the fate of Gli1+ stem cells after injury. Calvarial sutures possess much stronger regeneration capability than the nonsuture bony areas of the calvaria. The healing rate of the calvarial bone is inversely proportional to the distance between the suture and injury site: injuries closer to the suture heal faster. After complete removal of the sagittal suture, regeneration and restoration of normal organization occur within 6 weeks. Gli1+ cells within the suture mesenchyme are the cellular source for injury repair and bone regeneration. These results demonstrate that calvarial bone healing is not an evenly distributed event on the calvarial surface. Sutures contain stem cells and are the origin of calvarial bone tissue regeneration. Therefore, current practice in calvarial surgery needs to be reevaluated and modified. These findings also necessitate the design of new approaches for repairing calvarial bony defects. PMID- 27762666 TI - Different Donors Mesenchymal Stromal Cells Secretomes Reveal Heterogeneous Profile of Relevance for Therapeutic Use. AB - Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder caused by null mutations in the dystrophin gene. Although the primary defect is the deficiency of muscle dystrophin, secondary events, including chronic inflammation, fibrosis, and muscle regeneration failure are thought to actively contribute to disease progression. Despite several advances, there is still no effective therapy for DMD. Therefore, the potential regenerative capacities, and immune-privileged properties of mesenchymal stromal cells (MSCs), have been the focus of intense investigation in different animal models aiming the treatment of these disorders. However, these studies have shown different outcomes according to the sources from which MSCs were obtained, which raise the question whether stem cells from distinct sources have comparable clinical effects. Here, we analyzed the protein content of the secretome of MSCs, isolated from three different sources (adipose tissue, skeletal muscle, and uterine tubes), obtained from five donors and evaluated their in vitro properties when cocultured with DMD myoblasts. All MSC lineages showed pathways enrichment related to protein metabolic process, oxidation-reduction process, cell proliferation, and regulation of apoptosis. We found that MSCs secretome proteins and their effect in vitro vary significantly according to the tissue and donors, including opposite effects in apoptosis assay, indicating the importance of characterizing MSC secretome profile before its use in animal and clinical trials. Despite the individual differences a pool of conditioned media from all MSCs lineages was able to delay apoptosis and enhance migration when in contact with DMD myoblasts. PMID- 27762667 TI - Asymptomatic Herpes Simplex Virus Infection in Iranian Mothers and Their Newborns. AB - This study aims to determine the prevalence of herpes simplex virus (HSV) infection among pregnant women as well as congenital infection of their newborns in Tehran. One hundred samples of blood sera from pregnant women were analyzed for the presence of HSV specific antibodies. Umbilical cord blood samples from the newborns were analyzed for the presence of HSV DNA using real-time PCR. HSV IgG and IgM antibodies were found in 97% and 2% of pregnant women, respectively. Of all the 100 cord blood samples, 6 were positive for HSV DNA in which 2 cases were from mothers who had detectable IgM. It was notable that all corresponding mothers of six HSV positive infants had detectable IgG antibodies in their sera. It was demonstrated that the presence of HSV DNA in cord blood of newborns could be a risk marker for maternal-fetal transmission of the virus in asymptomatic pregnant women. PMID- 27762668 TI - Platynosomum illiciens (Trematoda: Dicrocoeliidae) in Captive Black-Tufted Marmoset Callithrix penicillata (Primates: Cebidae) from Brazil: A Morphometric Analyses with Taxonomic Comments on Species of Platynosomum from Nonhuman Primates. AB - The trematodes belonging to the genus Platynosomum are biliary parasites of birds and mammals (domestic and wildlife) in tropical and subtropical areas of the globe. Despite several reports on platynosomosis in captive nonhuman primates, mainly in South America, the taxonomy of species of Platynosomum that infect these hosts remains confused, and it is not clear whether the species found in cats is the same that infects nonhuman primates. Because a detailed morphological study of Platynosomum from nonhuman primates is lacking, in this study we analyzed specimens of Platynosomum recovered from the biliary system of Callithrix penicillata kept in captivity in an animal facility. The helminths were submitted to morphological and morphometric analyses in a light microscope and measurements of 16 morphological traits were taken. A kernel density estimation (KDE) was used to estimate density distributions of the measurements obtained as well as the occurrence of overlap with the ranges of the measurements known to 2 other species of Platynosomum previously described from South American marmosets, Platynosomum amazonensis and Platynosomum marmoseti. A principal component analysis (PCA) was also performed in order to evaluate the position of each of the 3 species in the multivariate gradient of morphometric measurements. The occurrence of a growth gradient was also evaluated by analysis of correlation between the measurements. Besides a great morphological variability, all specimens obtained from marmosets in this study were identified as Platynosomum illiciens (Braun, 1901). In addition, the published ranges of the measurements of P. amazonensis and P. marmoseti were completely contained within the ranges found in this study as revealed by KDE. The PCA did not show the formation of groups, and the 3 species were distributed along a growth continuum, also corroborated by correlation analysis. Therefore, P. amazonensis and P. marmoseti are here synonymized with P. illiciens. The involvement of wildlife hosts to the epidemiology of feline platynosomosis and implications for its control are briefly discussed. PMID- 27762669 TI - The validation and application of Inertial Measurement Units to springboard diving. AB - Inertial Measurement Units (IMUs) may offer an ecologically valid, reliable, and practical method for biomechanical performance analysis. With such potential in mind, Part 1 of this study examined the accuracy of IMUs gyroscopes with an optical system (Cortex 3.3). A calibration formula standardised the IMUs angular velocity output with the optical system. The percentage differences between the two measures = 0.5% (p < 0.05), suggest IMU's efficacy for application. In Part 2, the aim was to examine and understand how dive flight angular velocity time series plots change and increase according to dive degree of difficulty. With IMUs attached to three competitive divers performing forward somersault dives, dive flight kinematics were assessed. Biomechanically, a 41/2 tuck somersault dive differed to lower degree of difficulty dives in terms of: (1) a rotational delay immediately after takeoff (to gain greater vertical translation); (2) increased total time of flight; (3) greater muscle effort to resist increased centrifugal forces produced by the increased angular velocity (1,090 degrees /s); and (4) greater eccentric control during deceleration allow a safe and vertical entry into the water. IMUs can be effectively utilised and integrated into contexts such as springboard diving for performance analysis and optimisation purposes. PMID- 27762670 TI - Estimation of Second Primary Cancer Risk After Treatment with Radioactive Iodine for Differentiated Thyroid Carcinoma. AB - BACKGROUND: An increase in the incidence of second primary cancers is the late effect of greatest concern that could occur in differentiated thyroid carcinoma (DTC) patients treated with radioactive iodine (RAI). The decision to treat a patient with RAI should therefore incorporate a careful risk-benefit analysis. The objective of this work was to adapt the risk-estimation models developed by the Biological Effects of Ionizing Radiation Committee to local epidemiological characteristics in order to assess the carcinogenesis risk from radiation in a population of Brazilian DTC patients treated with RAI. Absorbed radiation doses in critical organs were also estimated to determine whether they exceeded the thresholds for deterministic effects. METHODS: A total of 416 DTC patients treated with RAI were retrospectively studied. Four organs were selected for absorbed dose estimation and subsequent calculation of carcinogenic risk: the kidney, stomach, salivary glands, and bone marrow. Absorbed doses were calculated by dose factors (absorbed dose per unit activity administered) previously established and based on standard human models. The lifetime attributable risk (LAR) of incidence of cancer as a function of age, sex, and organ-specific dose was estimated, relating it to the activity of RAI administered in the initial treatment. RESULTS: The salivary glands received the greatest absorbed doses of radiation, followed by the stomach, kidney, and bone marrow. None of these, however, surpassed the threshold for deterministic effects for a single administration of RAI. Younger patients received the same level of absorbed dose in the critical organs as older patients did. The lifetime attributable risk for stomach cancer incidence was by far the highest, followed in descending order by salivary-gland cancer, leukemia, and kidney cancer. CONCLUSION: RAI in a single administration is safe in terms of deterministic effects because even high administered activities do not result in absorbed doses that exceed the thresholds for significant tissue reactions. The Biological Effects of Ionizing Radiation Committee mathematical models are a practical method of quantifying the risks of a second primary cancer, demonstrating a marked decrease in risk for younger patients with the administration of lower RAI activities and suggesting that only the smallest activities necessary to promote an effective ablation should be administered in low-risk DTC patients. PMID- 27762671 TI - Examining the Role of Preoperative Positron Emission Tomography/Computerized Tomography in Combination with Ultrasonography in Discriminating Benign from Malignant Cytologically Indeterminate Thyroid Nodules. AB - BACKGROUND: Cytologically defined indeterminate thyroid nodules are a diagnostic challenge. Surgical lobectomy remains the gold standard for definitive diagnosis. However, 70-85% of nodules are ultimately benign. The primary objective of this study was to evaluate the negative predictive value (NPV) of F18 fluorodeoxyglucose (FDG) positron emission computed tomography (PET/CT) in excluding cancer among cytologically indeterminate thyroid nodules within the authors' institution using surgical pathology as the gold-standard reference. In addition, a systematic review was performed of published prospective studies on the NPV of PET/CT in evaluating indeterminate thyroid nodules. METHODS: A retrospective review was performed of all patients aged >=18 years seen at the Mayo Clinic between January 1, 2000, and December 31, 2014, with cytologically defined indeterminate thyroid nodules (suspicious for Hurthle cell neoplasm or follicular neoplasm; N = 858), who had a PET/CT within one year of fine-needle aspiration (n = 80) and underwent definitive diagnostic lobectomy (n = 51). Nodules were considered PET negative if they had a standardized uptake value (SUV) <5. Additionally, a systematic review was performed of published prospective studies on the NPV of PET/CT across multiple sites. RESULTS: Fifty one patients met the eligibility criteria. The retrospective review combined with a systematic review of eight prospective studies suggests that indeterminate nodules with a negative PET (SUV <5) have a low risk of malignancy (NPV 94%). The cancer prevalence in the institution is 14% and 27% in the combined prospective studies. CONCLUSIONS: PET/CT represents a preoperative, non-invasive tool that when combined with sonographic features can identify indeterminate nodules at low risk for malignancy. PMID- 27762673 TI - Lessons Learned After 1000 Cases of Transcutaneous Laryngeal Ultrasound (TLUSG) with Laryngoscopic Validation: Is There a Role of TLUSG in Patients Indicated for Laryngoscopic Examination Before Thyroidectomy? AB - INTRODUCTION: Patients with hoarseness of voice, previous neck operation, or suspicion of malignancy are at high risk of having pre-thyroidectomy vocal cord (VCP) palsy. Therefore, vocal cord (VC) functions should be evaluated before surgery. This study aimed to evaluate the accuracy of hoarseness, a voice-related questionnaire (Voice Handicap Index [VHI]-30), and transcutaneous laryngeal ultrasound (TLUSG) in diagnosing VCP, as well as the role of TLUSG in the evaluation of high-risk patients. METHODS: A total of 1000 patients undergoing thyroidectomy or other endocrine-related neck procedures were prospectively included. Symptoms of hoarseness, the VHI-30 score, and TLUSG were evaluated. Validation laryngoscopies were performed by a separate endoscopist after performing TLUSG. All the assessments were performed one to seven days before surgery. The findings of hoarseness, the VHI-30 score, and TLUSG were correlated with laryngoscopic findings to evaluate the diagnostic accuracy. RESULTS: Of 1000 patients, nine preoperative VCP were diagnosed with laryngoscopy. Sensitivity in detecting VCP by hoarseness, the VHI-30 score, and TLUSG were 33.3%, 62.5%, and 88.9%, respectively. A total of 342 patients were considered as high risk, and eight preoperative VCP were confirmed with laryngoscopy. Despite it not being possible to visualize the VCs in 26 (7.7%) patients, TLUSG had a higher accuracy in detecting VCP than the VHI-30 did (96.8% vs. 74.2%; p < 0.001). If patients had been selected who were unassessable or who had had VCP on assessment for confirmatory laryngoscopy, TLUSG saved more patients from laryngoscopic examinations than the VHI-30 did (87.7% vs. 71.3%; p < 0.001). A history of neck operation and suspicion of malignancy did not affect the assessment by TLUSG (p > 0.05). CONCLUSION: TLUSG is a feasible, non-invasive, and sensitive tool in detecting VCP in high-risk patients. It has safely precluded 87.7% high-risk patients from laryngoscopy. TLUSG should be incorporated as a part of the ultrasound examination of the thyroid. PMID- 27762674 TI - Friends and Groups Matter When it Comes to Leisure-Time Physical Activity. PMID- 27762672 TI - Transfer of pyrrolizidine alkaloids from various herbs to eggs and meat in laying hens. AB - To investigate the potential transfer of pyrrolizidine alkaloids (PAs), laying hens were fed for 14 days with diets containing 0.5% of dried common ragwort, common groundsel, narrow-leaved ragwort or viper's bugloss, or 0.1% of common heliotrope. This resulted in total PA levels in feed of respectively 5.5, 11.1, 53.1, 5.9 and 21.7 mg kg-1, with varying composition. PAs were transferred to eggs, in particular yolk, with steady-state levels of respectively 12, 21, 216, 2 and 36 ug kg-1. Overall transfer rates for the sum of PAs were estimated between 0.02% and 0.23%, depending on the type of PAs in the feed. In animals slaughtered shortly after the last exposure, levels in meat were slightly lower than those in eggs, levels in livers somewhat higher. When switched to clean feed, levels in eggs gradually decreased, but after 14 days were still above detection limits in the hens exposed to higher PA levels. Similar was the case for meat and especially kidneys and livers. It is concluded that the intake of PA containing herbs by laying hens may result in levels in eggs and meat that could be of concern for consumers, and as such should be avoided. PMID- 27762675 TI - An ergonomic evaluation of city police officers: an analysis of perceived discomfort within patrol duties. AB - The purpose of this study was to assess the perceived discomfort of patrol officers related to equipment and vehicle design and whether there were discomfort differences between day and night shifts. A total of 16 participants were recruited (10 males, 6 females) from a local police force to participate for one full day shift and one full night shift. A series of questionnaires were administered to acquire information regarding comfort with specific car features and occupational gear, body part discomfort and health and lifestyle. The discomfort questionnaires were administered three times during each shift to monitor discomfort progression within a shift. Although there were no significant discomfort differences reported between the day and night shifts, perceived discomfort was identified for specific equipment, vehicle design and vehicle configuration, within each 12-h shift. PMID- 27762727 TI - Should Level V Be Routinely Dissected in N1b Papillary Thyroid Carcinoma? AB - BACKGROUND: For N1b papillary thyroid carcinoma (PTC) patients, modified radical neck dissection (MRND) encompassing levels II-V is generally recommended. However, routine level V dissection is controversial because of the low incidence of metastasis/recurrence in level V and the increased morbidities associated with level V dissection. METHODS: This study retrospectively reviewed 646 N1b PTC patients who underwent unilateral MRND between January 1997 and June 2015. Specifically, to assess surgery-related outcomes of level V dissection, outcomes from N1b PTC patients who underwent unilateral MRND (levels II-V) were compared with those who underwent unilateral selective neck dissection (SND; levels II-IV) using propensity score matching. RESULTS: Overall and occult level V metastases were observed in 13.9% and 8.6% of patients, respectively. Level V recurrences were observed in only 2.26 (7.7%) recurred N1b PTC patients who underwent unilateral MRND. In multivariate analysis, three-level (II, III, and IV) simultaneous metastasis (adjusted odds ratio = 3.079, p = 0.003) was an independent predictor for level V metastasis. Under a matched condition, "shoulder syndrome" encompassing shoulder dysfunction and pain (9.1% vs. 2.7%, p = 0.002) was significantly more frequent in the MRND group than it was in the SND group. CONCLUSIONS: Because of the low incidence of metastasis/recurrence in level V and the clear evidence of increased morbidities, level V dissection in N1b PTC patients may be reserved for those with three-level simultaneous metastasis or clinically/radiologically evident level V metastasis. PMID- 27762676 TI - Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells. AB - Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8-/- NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/- NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/- NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8+/- NSCs, Dgcr8-/- NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8-/- NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8-/- NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8-/- NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs. PMID- 27762728 TI - miR-138/miR-222 Overexpression Characterizes the miRNome of Amniotic Mesenchymal Stem Cells in Obesity. AB - Clinical findings and data obtained in animal models indicate that nutrient uptake and exposure to environmental agents during pregnancy may affect fetal/newborn gestational programming, thereby resulting in obesity and/or obesity-related disorders in offspring. Human amniotic mesenchymal stem cells (hA MSCs) differentiate into adipocytes and are thus a suitable model to investigate adipocyte functions in obesity. The aim of this study was to elucidate the miRNome of hA-MSCs and its contribution to obesity in pregnancy. To this aim we used the following: (i) high-resolution small RNA sequencing to characterize the microRNA (miRNA) profiles of hA-MSCs of 13 obese (Ob-) and 7 control (Co-) pregnant women at delivery; (ii) multiple-method integrated bioinformatics to predict the metabolic pathways potentially miRNA deregulated in Ob-hA-MSCs; and (iii) microarray mRNA expression profiling to verify obese-associated mRNA alterations. In summary, 12 miRNAs were differentially expressed between Ob-hA MSCs and Co-hA-MSCs, with a multiple-methods bioinformatic consensus on miR-138 5p and miR-222-3p, which were overexpressed in Ob-hA-MSCs versus Co-hA-MSCs. The top 20 significant pathways predicted to be deregulated through miR-138-5p and/or miR-222-3p/target interaction included fat cell differentiation and deposits, lipid/carbohydrate homeostasis, response to stress, metabolic syndrome, heart disease, and ischemia. In conclusion, our finding of miR-138-5p/miR-222-3p overexpression in Ob-hA-MSCs, together with the transcriptomic data, suggests that these miRNAs in obese pregnancy could derange metabolic pathways previously found impaired in tissues from obese adults or in obesity-associated disorders and concur to modify gestational programming as has been demonstrated in animal models. This raises the possibility of using diet-based strategies to normalize the perinatal miRNome in obesity. PMID- 27762729 TI - Thyroglobulin as a Functional Biomarker of Iodine Status in a Cohort Study of Pregnant Women in the United Kingdom. AB - BACKGROUND: Though iodine deficiency in pregnancy is a matter of public-health concern, a functional measure of iodine status is lacking. The thyroid-specific protein thyroglobulin (Tg), which reflects thyroid size, has shown promise as a functional measure in studies of children and adults, but data in pregnancy are sparse. In a cohort of mildly to moderately iodine-deficient pregnant women, this study aimed to explore whether serum Tg is a sensitive functional biomarker of iodine status and to examine longitudinal change in Tg with gestational age. METHOD: A total of 230 pregnant women were recruited at an antenatal clinic at 12 weeks of gestation to the Selenium in PRegnancy INTervention study, in Oxford, United Kingdom. Repeated measures of urinary iodine-to-creatinine ratio, serum thyrotropin (TSH), and Tg at 12, 20, and 35 weeks of gestation were made. Women were dichotomized by their iodine-to-creatinine ratio (<150 or >=150 MUg/g) to group them broadly as iodine deficient or iodine sufficient. Women with thyroid antibodies were excluded; data and samples were available for 191 women. RESULTS: Median Tg concentrations were 21, 19, and 23 MUg/L in the first, second, and third trimesters, respectively. In a linear mixed model, controlling for confounders, Tg was higher in the <150 MUg/g group than it was in the >=150 MUg/g group (p < 0.001) but there was no difference in TSH (p = 0.27). Gestational week modified the effect of iodine status on TSH (p = 0.01) and Tg (p = 0.012); Tg did not increase with gestational week in the >=150 MUg/g group, but it did in the <150 MUg/g group, and TSH increased more steeply in the <150 MUg/g group. CONCLUSIONS: Low iodine status (<150 MUg/g) in pregnancy is associated with higher serum Tg, suggesting that the thyroid is hyperstimulated by iodine deficiency, which causes it to enlarge. Tg is a more sensitive biomarker of iodine status in pregnancy than is TSH. PMID- 27762731 TI - Strain-Specific Impact of Fusobacterium nucleatum on Neutrophil Function. AB - BACKGROUND: Neutrophil function is critical for initiation and progression of infecto-inflammatory diseases. Key quorum-sensing plaque bacteria, such as Fusobacterium nucleatum, act as bridging species between early and late colonizer pathogens, such as Porphyromonas gingivalis, as the biofilm ages and periodontal inflammation increases. This study is designed to determine impact of different F. nucleatum strains on neutrophil function. METHODS: Cells of human promyelocytic leukemia cell line-60 were differentiated into neutrophil-like cells and cultured with F. nucleatum strains of subspecies (ssp.) nucleatum ATCC 25586, ssp. polymorphum ATCC 10953, and ssp. vincentii ATCC 49256. Neutrophil phagocytosis of F. nucleatum strains and neutrophil apoptosis were analyzed by flow cytometry. Superoxide generation was measured by cytochrome C reduction in the presence and absence of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) (1 MUM) stimulation. Proinflammatory cytokine release was determined after 2, 6, and 24 hours of culture in the presence/absence of different F. nucleatum strains. Expression of Toll-like receptor (TLR)2, TLR4, and nuclear factor (NF) kappa B mRNA levels were analyzed using real-time quantitative polymerase chain reaction. Each experiment was repeated at least three times in triplicate. Data were analyzed using analysis of variance followed by post hoc Bonferroni correction. RESULTS: All strains of F. nucleatum significantly increased phagocytic capacity of neutrophils. Neutrophil phagocytosis of F. nucleatum ssp. polymorphum was significantly greater than that of F. nucleatum ssp. vincentii and ssp. nucleatum (P <0.001). F. nucleatum ssp. nucleatum and ssp. polymorphum significantly blocked fMLP-induced superoxide generation (P <0.001). Although F. nucleatum vincentii also reduced superoxide generation (25%), the impact was not as strong as that of ssp. nucleatum (83%) and ssp. polymorphum (100%). All F. nucleatum strains stimulated significant increase in neutrophil apoptosis compared with control (P <0.001) and significantly increased expression of NF kappaB mRNA in neutrophils (P <0.05). Levels of interleukin-8 and tumor necrosis factor-alpha produced by neutrophils were significantly increased in all F. nucleatum groups compared with control (P <0.001). CONCLUSIONS: These findings suggest that different strains of F. nucleatum impact neutrophil function in different ways. Two of three subspecies blocked neutrophil superoxide generation in response to a secondary stimulus, preventing oxidative killing by neutrophils. The direct role of bridging species in pathogenesis of periodontitis may be greater than previously suspected in which they create a favorable environment for pathogenic transition of the dental ecosystem. PMID- 27762730 TI - TSHR Gene Polymorphisms in the Enhancer Regions Are Most Strongly Associated with the Development of Graves' Disease, Especially Intractable Disease, and of Hashimoto's Disease. AB - BACKGROUND: Graves' disease (GD) and Hashimoto's disease (HD) are autoimmune thyroid disorders distinguished by the presence or absence of antithyrotropin receptor (TSHR) antibodies (TRAb). TSHR gene polymorphisms determine the amount of TSHR expressed, which may in turn influence TRAb production. The FANTOM5 project identified six GD-associated single nucleotide polymorphisms (SNPs) within the enhancer regions of the TSHR and unknown genes. This study examined the association of 11 TSHR and unknown gene polymorphisms, five of which are located in TSHR enhancer regions, with the development and prognosis of GD and HD. METHODS: SNPs of the TSHR and unknown genes were genotyped in 180 GD patients, including 62 patients with intractable GD and 48 patients with GD in remission; 151 HD patients, including 65 patients with severe HD and 40 patients with mild HD; and 111 healthy controls. RESULTS: The rs4411444 GG genotype and G allele, the rs2300519 AA genotype, and the rs179247 AA genotype and A allele were more frequent in GD patients than they were in controls. These same genotypes and alleles, in addition to the rs2300519 A allele and rs4903961 GG genotype and G allele, were more frequent in patients with intractable GD than they were in controls and patients with GD in remission. Interestingly, the rs2300519 TT genotype and T allele, rs4903961 CC genotype and C allele, and rs179247 GG genotype, all of which are minor genotypes and alleles among the evaluated SNPs, were more frequent in HD patients than they were in controls, but there were no differences in the frequencies of these genotypes and alleles between patients with severe HD and mild HD. Among the evaluated SNPs, the rs4411444 GG genotype and the rs4903961 C allele in the enhancer regions of the TSHR gene were most strongly associated with the development of GD, especially intractable disease, and that of HD, respectively. CONCLUSIONS: Among the evaluated TSHR gene SNPs, the rs4411444 GG genotype and the rs4903961 C allele in the enhancer regions of the TSHR gene were most strongly associated with the development of GD, especially intractable disease, and that of HD, respectively. PMID- 27762732 TI - Epithelial Cells Secrete Interferon-gamma Which Suppresses Expression of Receptor Activator of Nuclear Factor Kappa-B Ligand in Human Mandibular Osteoblast-Like Cells. AB - BACKGROUND: Prostaglandin (PG)E2 accumulates in inflamed periodontal tissue and induces receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK osteoprotegerin (OPG) signaling associated with bone resorption. Although oral epithelial cells maintain tissue homeostasis, the role of these cells in RANKL regulation remains unknown. METHODS: To mimic an inflamed condition, RANKL upregulation in human mandibular osteoblast-like cells (HMOBs) were stimulated with PGE2. Effect of recombinant human interferon (IFN)-gamma or epithelial derived IFN-gamma in constitutively released or Porphyromonas gingivalis lipopolysaccharide (PgLPS)-stimulated epithelial supernatant was investigated in HMOBs. Some HMOBs were pretreated with an anti-IFN-gamma antibody before PGE2 stimulation. THP-1 human monocytes and HMOBs were cocultured in a transwell system to investigate RANKL-driven THP-1 osteoclastic activity. RESULTS: PGE2 significantly increased RANKL messenger RNA (mRNA) and protein in HMOBs in a dose dependent manner, while OPG protein remained similar to baseline. Epithelial cells constitutively released IFN-gamma, which was substantially increased by PgLPS. HMOBs treated with epithelial supernatant or recombinant IFN-gamma, concurrently with PGE2 stimulation, reduced RANKL, but not OPG, expression. In contrast, anti-IFN-gamma antibody reversed the effect of epithelial mediators on RANKL expression. When cocultured with THP-1, RANKL released by PGE2-stimulated HMOBs is adequate to drive THP-1 differentiation as osteoclastogenic gene expression and bone resorption pit are increased. However, recombinant IFN-gamma, or IFN-gamma derived from oral epithelial cells, suppressed RANKL expression at both the mRNA and protein level, resulting in decreased THP-1-derived osteoclastic activity. CONCLUSION: Oral epithelial cells interact with HMOBs by releasing IFN-gamma to regulate RANKL expression and contribute to osteoclastogenesis. PMID- 27762733 TI - Proteolytic Mediators in Gestational Diabetes Mellitus and Gingivitis. AB - BACKGROUND: This study evaluates levels of matrix metalloproteinase (MMP)-8, MMP 9, and tissue inhibitor of MP-1 (TIMP-1) in biofluids of women with gestational diabetes mellitus (GDM) and systemically healthy counterparts with different statuses of periodontal health. METHODS: Seventy-one women with GDM and gingivitis (Gg), 30 women with GDM and healthy periodontium (Gh), 28 systemically and periodontally healthy women (Hh), and 37 systemically healthy women with gingivitis (Hg) were evaluated. MMP-8, MMP-9, and TIMP-1 levels were determined in gingival crevicular fluid (GCF), saliva, and serum by immunofluorometric and enzyme-linked immunosorbent assays. Full-mouth clinical periodontal parameters were recorded. RESULTS: GCF and serum MMP-8 concentrations, serum MMP-9 concentrations, and serum MMP-8/MMP-1 and MMP-9/MMP-1 molar ratios were significantly higher in Gg compared with Hg group (P <0.05). Serum MMP-8 levels and salivary TIMP-1 levels were higher in Gh compared with Hg group (P <0.05) whereas salivary MMP-8/TIMP-1 molar ratio was lower in Gh compared with Hg group (P <0.05). Elevated concentrations of GCF MMP-8 and MMP-9 were found in Gg compared with Gh group (P <0.05). Significant correlations were found between local levels of biomarkers and clinical periodontal parameters in only GDM group. CONCLUSION: GDM may modulate both local and circulating levels of MMP-8 especially when associated with gingivitis. PMID- 27762734 TI - A Japanese Family with Central Hypothyroidism Caused by a Novel IGSF1 Mutation. AB - BACKGROUND: Hemizygous mutations in the immunoglobulin superfamily member 1 (IGSF1) gene have been demonstrated to cause congenital central hypothyroidism in males. This study reports a family with a novel mutation in the IGSF1 gene located on the long arm of the X chromosome. PATIENT FINDINGS: A two-month-old boy was diagnosed with central hypothyroidism because of prolonged jaundice. A thyrotropin-releasing hormone (TRH) stimulation test indicated dysfunction in both the hypothalamus and the pituitary gland, and prompted the IGSF1 gene to be analyzed. The patient had a novel nonsense variant, c.2713C>T (p.Q905X), in exon 14 of the IGSF1 gene. Studies of the family revealed that the patient's sister and mother were heterozygous carriers of the IGSF1 mutation. The patient's maternal uncle carried the same mutation as the proband but had no overt symptoms. The mother and uncle started levothyroxine supplementation because of subclinical hypothyroidism. SUMMARY: A novel mutation (c.2713C>T, p.Q905X) of the IGSF1 gene was identified that causes congenital central hypothyroidism in a Japanese family. The findings further expand the clinical heterogeneity of this entity. PMID- 27762791 TI - miR-146a gene polymorphism and susceptibility to gastric cancer. PMID- 27762892 TI - Evaluating the Past, Present, and Future of Regenerative Medicine: A Global View. AB - "Evaluating the Past and Present of Regenerative Medicine (RM)" was the first part of an Industry Symposium dedicated to the subject during the 2015 TERMIS World Congress in Boston. This working session presented a critical review of the current RM landscape in Europe and North America with possible projections for the future. Interestingly, the RM development cycle seems to obey the Gartner hype cycle, now at the enlightenment phase, after past exaggerated expectations and discouragements, as suggested by increasing numbers of clinical trials and recent market approvals of RM solutions in both Europe (Glybera and Holoclar(r) from Chiesi Pharma and Strimvelis(r) from GSK) and Japan (Remestemcel-L from Mesoblast(r)). The successful commercial translation of RM research is governed by five major drivers: (i) fully validated manufacturing capability for autologous or allogeneic products, (ii) reimbursement for targeted clinical indications with high and demonstrable medico-economic benefits versus standard of care, (iii) implication of regulatory bodies in the design and development plan of any RM solution, which should be well characterized, robust, with proven consistent efficacy and an acceptable and controlled positive benefit/risk ratio, (iv) collaborations facilitated by multicompetence hubs/consortia of excellence, (v) well-thought-out clinical development plans for reducing the risk of failure. Benefiting from past and present experience, the RM burgeoning industry is expected to accelerate the market release of cost-effective RM products with real curative potential for specific clinical indications with high unmet needs. This should be achieved by wisely leveraging all possible synergies of the different stakeholders, for example, patients, clinicians, reimbursement and health technology assessment (HTA) agencies, regulatory authorities, public/private investors, academia, and companies. PMID- 27762949 TI - Student life - Tips for managing stress. AB - Being a nursing student can take its toll on our well-being. Now in my third year of training, I have experienced the pressure to succeed academically and clinically. PMID- 27762951 TI - Inspirational songs chosen by celebrated nurse Elizabeth Anionwu. AB - An Irish polka tune, 1950s rock and roll and African music were among the songs chosen by celebrated nurse Elizabeth Anionwu at a Desert Island Discs-style event for Black History Month. PMID- 27762950 TI - How to be a good role model. AB - The Cambridge dictionary defines a role model as 'a person who someone admires and whose behaviour they try to copy'. When considering what professional traits you would like to portray to others, it might help to think of colleagues who inspire you. PMID- 27762952 TI - Nurse Awards are a chance to share your innovations and successes. AB - Let me tell you something you already know: nurses are extraordinary people who do extraordinary things every day. Yet how many times do you hear nurses playing this down, saying they are 'just doing their job', or giving the credit to others in the team? PMID- 27762953 TI - RCN highlights critical role of overseas nurses in NHS. AB - The NHS would not cope without its growing cohort of nurses from European Union (EU) countries, says the RCN. PMID- 27762955 TI - Compassion in a crisis. AB - As a third-year nursing student my final placement was with an anaesthetic team. Two months into the placement, the emergency telephone rang at 4am, with the message 'obstetric airway emergency' - a call that no nurse or midwife wants to receive. PMID- 27762957 TI - Free e-learning next step for 'isolated' care home nurses. AB - New research involving more than 350 care home nurses, managers, community healthcare professionals and nurse educators has identified priority areas for CPD - with personal care, dementia care and managing long-term conditions top of the list. PMID- 27762959 TI - A fantastic opportunity to develop the clinical leaders of the future. AB - After qualifying as a registered nurse in 1985, Nicky Hayes held clinical and academic posts before becoming consultant nurse for older people at London's King's College Hospital NHS Foundation Trust in 2001. PMID- 27762958 TI - Ankylosing spondylitis. AB - Essential facts About 200,000 people in the UK have ankylosing spondylitis, and there are around 2,300 new diagnoses each year in England and Wales. A form of arthritis, the chronic condition causes inflammation in the spine and other areas of the body. It is about three times more common in men than in women. PMID- 27762960 TI - Guidance outlines how to stay safe when working alone in the community. AB - The RCN has published guidance for nurses who work alone, after research revealed almost half of community nurses have faced abuse. PMID- 27762962 TI - Healthy diet helps children perform better in reading skills. AB - Research from Finland suggests a healthy diet is linked to better reading skills in the first 3 years of school. PMID- 27762963 TI - Living with spouse halves risk of being overweight in type 2 diabetes. AB - Single patients with type 2 diabetes are twice as likely to be overweight as those with the condition who live with their spouse, new research suggests. PMID- 27762965 TI - Prescription painkillers linked to greater risk of heart failure. AB - An international research team has found that traditional non-steroidal anti inflammatory drugs (NSAIDs) and new generation anti-inflammatories COX-2 inhibitors raise the risk of heart failure. PMID- 27762964 TI - Smoking linked to shorter survival after diagnosis of motor neurone disease. AB - Survival time after diagnosis with amyotrophic lateral sclerosis (ALS) is 10 months shorter, on average, for smokers than non-smokers, an Italian study has found. PMID- 27762966 TI - The perfect blend of compassion, knowledge and practical ability. AB - Macmillan breast cancer nurse Caroline Mercer has been at my side since I was diagnosed with cancer in March 2014. PMID- 27762967 TI - 'Far too many' Fitness to Practise referrals are unnecessary, says former RCN head. AB - Employers are needlessly adding to the Nursing and Midwifery Council (NMC) caseload with complaints that should be handled internally, a former head of the RCN claims. PMID- 27762968 TI - Keeping the team happy. AB - Emergency team leader Nikola J Gipp asks what she can do to protect colleagues from a deluge of difficulties when morale is low and fatigue is setting in. She says a simple 'thank you' is a good start. PMID- 27762969 TI - Disadvantage passed down through the generations. AB - Heather Henry talks about the role public health nurses can play bridging the gaps in a broken community. She reflects on her own experiences working with a market town community, which she quickly realised was divided by prejudice. Young people's voices were not heard, and many mothers spoke about disadvantaged children, so she sought to challenge the troubling situations that continued to be ignored. PMID- 27762971 TI - Paralympic parity in the Games. AB - 'There will only be equal esteem when the Paralympic and the Olympic Games run simultaneously and the two competitions merge'. PMID- 27762970 TI - Down's screening: the right to informed choice. AB - Antenatal screening for Down's syndrome, and particularly the potential NHS implementation of the more sensitive cell-free DNA screening known as NIPT (non invasive prenatal testing), has had intense media coverage recently, prompted by the BBC2 documentary A World Without Down's Syndrome. PMID- 27762972 TI - Facing Down's syndrome myths. AB - Layla Haidrani, writing in Learning Disability Practice, aims to debunk the myths and misconceptions that parents of children with Down's syndrome face. PMID- 27762973 TI - Readers' panel - Should IVF funding be given higher priority in the NHS? AB - Our experts consider a hot topic of the day. PMID- 27762974 TI - There's no place for 'blamers' in our work. AB - When I was pooped on by a bird the size of a light aircraft, I knew how my companion would react. Not with a baby wipe and sympathy, but with reproach. PMID- 27762975 TI - District nursing vision will require resources. AB - At the Queen's Nursing Institute (QNI) annual conference in London last month, NHS England chief executive Simon Stevens spoke about his aspiration for the NHS to become a 'neighbourhood health service', as well as a national one. PMID- 27762977 TI - Lack of symptom awareness linked to poor cancer survival. AB - In regions with poor cancer survival rates, people tend to have a lower awareness of symptoms, say researchers. PMID- 27762976 TI - Can I read my own hospital notes? AB - Notes made about you while you are in any health setting are not yours. If it is an NHS hospital, they belong to the health secretary; if it is a private hospital, they belong to the consultant or the hospital itself. If something belongs to someone else, you do not have a right to it. The Data Protection Act 1998 allows you to access your health records, but this usually means you receive a copy rather than obtaining and holding the originals. PMID- 27762978 TI - Holistic approach to breast cancer and palliative care. AB - At The Christie NHS Foundation Trust, Manchester, concerns that end of life care discussions were occurring too late in breast cancer cases led to earlier introduction of palliative care. Benefits include reduced hospital admissions during end of life and improved symptom management. The authors encourage nurses to support an integrated approach to enhance care provision for patients. PMID- 27762979 TI - It is up to us to improve care. AB - Over the past few decades, international interest in quality improvement in health and social care has grown exponentially. PMID- 27762981 TI - Share your innovations in our 2017 Nurse Awards. AB - Nominations are now open for the 2017 RCNi Nurse Awards, the UK nursing profession's highest accolade for nursing excellence. PMID- 27762982 TI - Over-reliance on students. AB - I identify with the nursing students who have reported high stress levels on the Facebook page 'Support for Nurses, Midwives and Frontline Staff in Ireland'. PMID- 27762983 TI - Diabetes research. AB - I began watching the BBC's Panorama documentary Diabetes: The Hidden Killer but got frustrated and had to turn it off. I have had type 1 diabetes for 28 years and am shocked at the resources thrown at people with type 2, which can easily be prevented. This funding would be better used on research into type 1 diabetes and its treatment. PMID- 27762985 TI - Suicide risk higher in community care. AB - People with mental health problems who are cared for by community crisis teams are far more likely to take their own life than those treated in hospital, research shows. PMID- 27762986 TI - Watch your pension. AB - At the age of 56, I am glad I never entered into discussion or read any information about altering or tampering with my NHS pension scheme (news, 21 September, page 10 ). I feel the NHS is acting like a loan shark, encouraging people to stop contributing so they have more money in their pocket today, but this will be paid back four-fold in years to come through lost pension income. PMID- 27762987 TI - Managing irritable bowel syndrome in children. AB - Irritable bowel syndrome (IBS) is the most common cause of non-organic recurrent abdominal pain in children. IBS is a clinical diagnosis, which is based on the Rome IV criteria for functional gastrointestinal disorders in children, as well as the patient's history. The diagnosis of IBS is established following the exclusion of organic causes of recurrent abdominal pain. Staggered investigations should be avoided because they might increase the child's and family's anxiety in the absence of an organic diagnosis. In most cases, providing a positive diagnosis of IBS and explaining the current understanding of the functional pathophysiology of the condition and management strategies gives reassurance to the child and their family. Management is based on dietary, pharmacological and biopsychosocial interventions. IBS can be a debilitating condition, with effects on activities of daily living, education and social interactions. Nurses working in various clinical settings will encounter children with IBS and have an important role in the management of children with this condition. PMID- 27762989 TI - Learning disabilities care reviews 'could do better'. AB - Too many people with learning disabilities are still being admitted to hospital as inpatients, according to an NHS nurse leader. PMID- 27762991 TI - Understanding Sociology in Nursing Allan Helen Traynor Michael Kelly Daniel and Smith Pam Understanding Sociology in Nursing 200pp L21.99 Sage 9781473913592 1473913594 [Formula: see text]. AB - The intention behind this book is to help the reader understand the complexities of modern nursing and health care, and the authors have succeeded brilliantly in this difficult task. PMID- 27762990 TI - Never stop nursing. AB - Well done to 83-year-old nurse Monica Bulman (news, 14 September, page 7 ). At 71 and working on an orthopaedic rehabilitation ward at a hospital in Birmingham, I thought I was getting near to being the oldest nurse practising on a ward. PMID- 27762992 TI - We need to inspire students. AB - The 1914 message 'Your Country Needs You' was an attempt to attract recruits to the military. The message has resonance for nursing today. Imagine answering the call full of enthusiasm but then being asked by a senior colleague: 'What do you want to come into nursing for?' PMID- 27762994 TI - D-A-S-H. AB - This simple-to-use app is a useful resource for all those supporting victims of abuse, and offers particular local information for Kent. PMID- 27762995 TI - Step up to a ward sister role. AB - It's an absolutely huge challenge,' Mary Callaghan says of her shift to a ward sister role in an elderly medical ward. 'It was a huge shock to the system. It makes me feel proud, but it is a very hard job.' PMID- 27762996 TI - Thousands sign nurse's petition demanding end to 1% pay cap. AB - Thousands of people have signed a petition urging the government to scrap the NHS pay cap, which limits staff to a rise of just 1% each year. PMID- 27762997 TI - The truth about race discrimination in the NHS. AB - When NHS England chief executive Simon Stevens launched the first report of the NHS Workforce Race Equality Standard (WRES) in June, he described the findings as 'unvarnished feedback' to every hospital and trust about the experiences of their black and minority ethnic staff. PMID- 27762998 TI - Self-management of diabetes. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article provided an insight into some of the challenges associated with self-management of diabetes, and discussed strategies that can be used to improve patient outcomes. PMID- 27762999 TI - Identifying different learning styles to enhance the learning experience. AB - Identifying your preferred learning style can be a useful way to optimise learning opportunities, and can help learners to recognise their strengths and areas for development in the way that learning takes place. It can also help teachers (educators) to recognise where additional activities are required to ensure the learning experience is robust and effective. There are several models available that may be used to identify learning styles. This article discusses these models and considers their usefulness in healthcare education. Models of teaching styles are also considered. PMID- 27763000 TI - New NMC rule: protecting reputations or a 'mockery'? AB - Allegations against nurses and midwives will no longer be available for public scrutiny ahead of disciplinary hearings, the Nursing and Midwifery Council (NMC) has announced. PMID- 27763207 TI - Potential Use of Antiapoptotic Proteins and Noncoding RNAs for Efficient In Vitro Follicular Maturation and Ovarian Bioengineering. AB - In vitro culture of ovarian follicles is a promising bioengineering technique for preserving fecundity in reproductive-aged female by providing fertilizable oocytes. Successful clinical application should be preceded by developing the protocols that can efficiently overcome follicular cell apoptosis since the apoptosis is a critical phenomenon in in vivo folliculogenesis and in in vitro follicular maturation. Numerous prosurvival and antiapoptotic molecules, including follicular developmental regulators, have been reported to be involved in the intraovarian apoptosis. The authors searched literature and analyzed the current knowledge of these proteins and noncoding RNAs, and their antiapoptotic roles in the dynamics of follicular development in vivo and in vitro. Two dimensional (2D) culture method has widely been used, however, with recent emergence of various biomaterials, three-dimensional (3D) culture is also considered a proper environment for maintenance of solid structure of ovarian follicles. The identification of candidate paracrine and endocrine intracellular effectors that are responsible for the coordination occurring between oocyte, granulosa, and theca cells during follicular development was explored in this review, to assess the possibility of their use as antiapoptotic factors in establishing more efficacious 2D or 3D in vitro follicular microenvironment. The retrieved information will provide an inventory and the insight for defining more sophisticated culture conditions that are essential for functional artificial ovarian bioengineering. PMID- 27763249 TI - Comment on "Obesity and weight gain among former World Trade Center workers and volunteers" by Napier et al. PMID- 27763250 TI - Psychometric evaluation of a new instrument in Spanish to measure the wellness of university nursing faculty. AB - The aim of this study was to design and validate an instrument to measure the wellness among university nursing faculty. The study was performed in two phases. Phase I consisted of the development of the instrument with discussion groups and participant consensus. We designed an instrument including the 21 items or psychosocial risk factors identified and estimated an index by evaluating the frequency and intensity of each item. The items were grouped into 3 dimensions: teaching work demands, curricular demands, and organizational difficulties. Phase II, we evaluated the psychometric properties of the tool in a sample of 263 participants. Exploratory factor analysis showed a 3-factor structure that explained 53% of the total variance. The internal consistency of the instrument was 0.91 for the whole instrument. The results indicate that the tool developed is valid and reliable and may be a good instrument to monitor the wellness of university nursing faculty. PMID- 27763251 TI - Factors associated with use of psychiatric intensive care and seclusion in adult inpatient mental health services. AB - AIMS: Within acute psychiatric inpatient services, patients exhibiting severely disturbed behaviour can be transferred to a psychiatric intensive care unit (PICU) and/or secluded in order to manage the risks posed to the patient and others. However, whether specific patient groups are more likely to be subjected to these coercive measures is unclear. Using robust methodological and statistical techniques, we aimed to determine the demographic, clinical and behavioural predictors of both PICU and seclusion. METHODS: Data were extracted from an anonymised database comprising the electronic medical records of patients within a large South London mental health trust. Two cohorts were derived, (1) a PICU cohort comprising all patients transferred from general adult acute wards to a non-forensic PICU ward between April 2008 and April 2013 (N = 986) and a randomly selected group of patients admitted to general adult wards within this period who were not transferred to PICU (N = 994), and (2) a seclusion cohort comprising all seclusion episodes occurring in non-forensic PICU wards within the study period (N = 990) and a randomly selected group of patients treated in these wards who were not secluded (N = 1032). Demographic and clinical factors (age, sex, ethnicity, diagnosis, admission status and time since admission) and behavioural precursors (potentially relevant behaviours occurring in the 3 days preceding PICU transfer/seclusion or random sample date) were extracted from electronic medical records. Mixed effects, multivariable logistic regression analyses were performed with all variables included as predictors. RESULTS: PICU cases were significantly more likely to be younger in age, have a diagnosis of bipolar disorder and to be held on a formal section compared with patients who were not transferred to PICU; female sex and longer time since admission were associated with lower odds of transfer. With regard to behavioural precursors, the strongest predictors of PICU transfer were incidents of physical aggression towards others or objects and absconding or attempts to abscond. Secluded patients were also more likely to be younger and legally detained relative to non secluded patients; however, female sex increased the odds of seclusion. Likelihood of seclusion also decreased with time since admission. Seclusion was significantly associated with a range of behavioural precursors with the strongest associations observed for incidents involving restraint or shouting. CONCLUSIONS: Whilst recent behaviour is an important determinant, patient age, sex, admission status and time since admission also contribute to risk of PICU transfer and seclusion. Alternative, less coercive strategies must meet the needs of patients with these characteristics. PMID- 27763253 TI - Fungal Sex: The Ascomycota. AB - This article provides an overview of sexual reproduction in the ascomycetes, a phylum of fungi that is named after the specialized sacs or "asci" that hold the sexual spores. They have therefore also been referred to as the Sac Fungi due to these characteristic structures that typically contain four to eight ascospores. Ascomycetes are morphologically diverse and include single-celled yeasts, filamentous fungi, and more complex cup fungi. The sexual cycles of many species, including those of the model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe and the filamentous saprobes Neurospora crassa, Aspergillus nidulans, and Podospora anserina, have been examined in depth. In addition, sexual or parasexual cycles have been uncovered in important human pathogens such as Candida albicans and Aspergillus fumigatus, as well as in plant pathogens such as Fusarium graminearum and Cochliobolus heterostrophus. We summarize what is known about sexual fecundity in ascomycetes, examine how structural changes at the mating-type locus dictate sexual behavior, and discuss recent studies that reveal that pheromone signaling pathways can be repurposed to serve cellular roles unrelated to sex. PMID- 27763254 TI - Macrophages and Iron Metabolism. AB - Macrophages exert multiple important roles in iron metabolism. As scavengers, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recycle iron, predominantly for the production of hemoglobin in new erythrocytes. Splenic red pulp macrophages are specialized for iron recycling, with increased expression of proteins for the uptake of hemoglobin, breakdown of heme, and export of iron. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. As regulators and effectors of antimicrobial host defense, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. Macrophages also have an important trophic role in the bone marrow, supporting efficient erythropoiesis. PMID- 27763252 TI - Myeloid Cell Origins, Differentiation, and Clinical Implications. AB - The hematopoietic stem cell (HSC) is a multipotent stem cell that resides in the bone marrow and has the ability to form all of the cells of the blood and immune system. Since its first purification in 1988, additional studies have refined the phenotype and functionality of HSCs and characterized all of their downstream progeny. The hematopoietic lineage is divided into two main branches: the myeloid and lymphoid arms. The myeloid arm is characterized by the common myeloid progenitor and all of its resulting cell types. The stages of hematopoiesis have been defined in both mice and humans. During embryological development, the earliest hematopoiesis takes place in yolk sac blood islands and then migrates to the fetal liver and hematopoietic organs. Some adult myeloid populations develop directly from yolk sac progenitors without apparent bone marrow intermediates, such as tissue-resident macrophages. Hematopoiesis also changes over time, with a bias of the dominating HSCs toward myeloid development as animals age. Defects in myelopoiesis contribute to many hematologic disorders, and some of these can be overcome with therapies that target the aberrant stage of development. Furthermore, insights into myeloid development have informed us of mechanisms of programmed cell removal. The CD47/SIRPalpha axis, a myeloid-specific immune checkpoint, limits macrophage removal of HSCs but can be exploited by hematologic and solid malignancies. Therapeutics targeting CD47 represent a new strategy for treating cancer. Overall, an understanding of hematopoiesis and myeloid cell development has implications for regenerative medicine, hematopoietic cell transplantation, malignancy, and many other diseases. PMID- 27763256 TI - Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals. AB - All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age related diseases. Studies of the TOR pathway unraveled a complex growth regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms. PMID- 27763257 TI - Mycobacterium bovis BCG and New Vaccines for the Prevention of Tuberculosis. AB - Tuberculosis infects millions of people worldwide and remains a leading global killer despite widespread neonatal administration of the tuberculosis vaccine, bacillus Calmette-Guerin (BCG). BCG has clear and sustained efficacy, but after 10 years, its efficacy appears to wane, at least in some populations. Fortunately, there are many new tuberculosis vaccines in development today, some in advanced stages of clinical trial testing. Here we review the epidemiological need for tuberculosis vaccination, including evolving standards for administration to at risk individuals in developing countries. We also examine proven sources of immune protection from tuberculosis, which to date have exclusively involved natural or vaccine exposure to whole cell mycobacteria. After summarizing evidence for the use and efficacy of BCG, we detail the most promising new candidate vaccines against tuberculosis. The global need for a new tuberculosis vaccine is acute and huge, but clinical trials to be completed in the coming few years are likely either to identify a new tuberculosis vaccine or to substantially reframe how we understand immune protection from this historical scourge. PMID- 27763258 TI - Tuberculosis Diagnostics: State of the Art and Future Directions. AB - Rapid and accurate diagnosis is critical for timely initiation of anti tuberculosis (TB) treatment, but many people with TB (or TB symptoms) do not have access to adequate initial diagnosis. In many countries, TB diagnosis is still reliant on sputum microscopy, a test with known limitations. However, new diagnostics are starting to change the landscape. Stimulated, in part, by the success and rollout of Xpert MTB/RIF, an automated, molecular test, there is now considerable interest in new technologies. The landscape looks promising with a pipeline of new tools, particularly molecular diagnostics, and well over 50 companies actively engaged in product development, and many tests have been reviewed by WHO for policy endorsement. However, new diagnostics are yet to reach scale, and there needs to be greater convergence between diagnostics development and the development of shorter TB drug regimens. Another concern is the relative absence of non-sputum-based diagnostics in the pipeline for children, and of biomarker tests for triage, cure, and latent TB progression. Increased investments are necessary to support biomarker discovery, validation, and translation into clinical tools. While transformative tools are being developed, high-burden countries will need to improve the efficiency of their health care delivery systems, ensure better uptake of new technologies, and achieve greater linkages across the TB and HIV care continuum. While we wait for next-generation technologies, national TB programs must scale up the best diagnostics currently available, and use implementation science to get the maximum impact. PMID- 27763259 TI - Antifungal Drugs: The Current Armamentarium and Development of New Agents. AB - Invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. The fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus collectively contribute to over 1 million human deaths annually. Hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for drug development remains limited. Only three classes of molecules are currently approved for the treatment of invasive mycoses. The efficacy of these agents is compromised by host toxicity, fungistatic activity, or the emergence of drug resistance in pathogen populations. Here we describe our current arsenal of antifungals and highlight current strategies that are being employed to improve the therapeutic safety and efficacy of these drugs. We discuss state-of-the-art approaches to discover novel chemical matter with antifungal activity and highlight some of the most promising new targets for antifungal drug development. We feature the benefits of combination therapy as a strategy to expand our current repertoire of antifungals and discuss the antifungal combinations that have shown the greatest potential for clinical development. Despite the paucity of new classes of antifungals that have come to market in recent years, it is clear that by leveraging innovative approaches to drug discovery and cultivating collaborations between academia and industry, there is great potential to bolster the antifungal armamentarium. PMID- 27763260 TI - Host-Microsporidia Interactions in Caenorhabditis elegans, a Model Nematode Host. AB - Microsporidia comprise a phylum of obligate intracellular pathogens related to fungi that infect virtually all animals. Recently, the nematode Caenorhabditis elegans has been developed as a convenient model for studying microsporidia infection in a whole-animal host through the identification and characterization of a natural microsporidian pathogen of this commonly studied laboratory organism. The C. elegans natural microsporidian pathogen is named Nematocida parisii, and it causes a lethal intestinal infection in C. elegans. Comparison of the genomes of N. parisii and its closely related species Nematocida sp. 1, together with the genomes of other microsporidian species, has provided insight into the evolutionary events that led to the emergence of the large, specialized microsporidia phylum. Cell biology studies of N. parisii infection in C. elegans have shown how N. parisii restructures host intestinal cells and, in particular, how it hijacks host exocytosis for nonlytic exit to facilitate transmission. Recent results also show how the host responds to infection with ubiquitin mediated responses, and how a natural variant of C. elegans is able to clear N. parisii infection, but only during early life. Altogether, these studies provide insight into the mechanisms of microsporidia pathogenesis using a whole-animal host. PMID- 27763261 TI - Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays. AB - The identification of individuals with latent tuberculosis infection (LTBI) is useful for both fundamental understanding of the pathogenesis of disease and for clinical and public health interventions (i.e., to prevent progression to disease). Basic research suggests there is a pathogenetic continuum from exposure to infection to disease, and individuals may advance or reverse positions within the spectrum, depending on changes in the host immunity. Unfortunately, there is no diagnostic test that resolves the various stages within the spectrum of Mycobacterium tuberculosis infection. Two main immune-based approaches are currently used for identification of LTBI: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). TST can use either the conventional purified protein derivative or more specific antigens. Extensive research suggests that both TST and IGRA represent indirect markers of M. tuberculosis exposure and indicates a cellular immune response to M. tuberculosis. The imperfect concordance between these two tests suggests that neither test is perfect, presumably due to both technical and biological reasons. Neither test can accurately differentiate between LTBI and active TB. Both IGRA and TST have low sensitivity in a variety of immunocompromised populations. Cohort studies have shown that both TST and IGRA have low predictive value for progression from infection to active TB. For fundamental applications, basic research is necessary to identify those at highest risk of disease with a positive TST and/or IGRA. For clinical applications, the identification of such biomarkers can help prioritize efforts to interrupt progression to disease through preventive therapy. PMID- 27763262 TI - Correction: Cortex commands the performance of skilled movement. PMID- 27763264 TI - Invited commentary. PMID- 27763263 TI - Endothelial cell-derived CD95 ligand serves as a chemokine in induction of neutrophil slow rolling and adhesion. AB - Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells. In myeloid cells, CD95 triggers activation of Syk-Btk/PLCgamma2/Rap1 signaling that ultimately leads to integrin activation. Excitingly, CD95-deficient myeloid cells exhibit impaired bacterial clearance in an animal model of sepsis induced by cecal ligation and puncture (CLP). Our data identify the cellular and molecular mechanisms underlying the chemoattractant effect of endothelial cell-derived CD95L in induction of neutrophil recruitment and support the use of therapeutic inhibition of CD95's activity in inflammatory diseases. PMID- 27763265 TI - Percutaneous common femoral artery interventions using angioplasty, atherectomy, and stenting. AB - BACKGROUND: This study evaluated the feasibility, safety, and effectiveness of endovascular interventions for common femoral artery (CFA) occlusive disease. METHODS: Using a prospectively maintained multicenter database, we analyzed outcomes in 167 consecutive patients who underwent percutaneous CFA interventions for Rutherford class 3 to class 6 (R3-R6) disease. The standardized treatment approach included primary percutaneous transluminal angioplasty (PTA) only, atherectomy + PTA, and provisional stenting. Outcomes included technical failure rate, recurrence, complications, and major or minor amputation rate. Data were analyzed using multivariate regression analysis. RESULTS: During a 7-year period, 167 patients with R3 (n = 91 [54.5%]) and R4 to R6 (n = 76 [45.5%]) disease underwent CFA interventions that included PTA only (n = 114 [68.2%]), atherectomy +/- PTA (n = 38 [22.8%]), and provisional stenting (n = 15 [9.0%]) for failed atherectomy +/- PTA. Procedure-related complications included pseudoaneurysm (n = 1 [0.6%]), thrombosis (n = 1 [0.6%]), distal embolization (n = 1 [0.6%]), and death (R6, n = 1 [0.06%]). CFA restenosis was observed in 34 (20.4%) patents; these underwent further percutaneous (n = 18 [10.8%]) or surgical (n = 17 [10.2%]) revascularization that included CFA endarterectomy +/- femoral distal bypass. Major or minor amputations were observed in none of the R3 patients and in only three (3.9%) and five (6.5%) of the R4 to R6 patients, respectively. Compared with the atherectomy + PTA group, patients in the PTA-only group had a significantly lower patency. Furthermore, during long-term mean follow-up of 42.5 months, the CFA provisional stent group had a 100% primary patency, which was significantly better than the primary patency in the CFA nonstent groups combined (77.0%; P = .0424). CONCLUSIONS: Data from this study to date would suggest that percutaneous CFA interventions in select patients are relatively safe and effective. In the long term, CFA stenting has significantly better primary patency than CFA atherectomy and PTA combined. CFA atherectomy + PTA has significantly better primary patency than CFA PTA-only at midterm, especially in patients with claudication. Future randomized controlled trials are warranted. PMID- 27763255 TI - Cytokines and Chemokines in Mycobacterium tuberculosis Infection. AB - Chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into Mycobacterium tuberculosis-infected lungs. Correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the "goldilocks" (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease. PMID- 27763267 TI - Invited commentary. PMID- 27763266 TI - Predictive factors for better bypass patency and limb salvage after prosthetic above-knee bypass reconstruction. AB - BACKGROUND: Peripheral arterial disease (PAD) is one of the most underestimated diseases because of its high prevalence and unfavorable prognosis. Many PAD patients without suitable autologous veins or options for endovascular treatment receive prosthetic above-knee femoropopliteal bypass (PAKB). Until now predictors of prosthetic bypass failure and of increased amputation risk remain indistinct. This study aimed to identify predictive factors associated with better bypass patency and limb salvage to achieve a more favorable outcome after PAKB reconstruction. METHODS: Pre-, intra-, and postoperative data of 244 PAKB procedures performed at a German university medical center were collected and analyzed using univariate and multivariate methods. To our knowledge this 12-year experience is the largest retrospective study to identify predictors for patency and limb salvage after PAKB reconstruction. RESULTS: Of the PAD patients 94% (229/244) were followed for an average of 34.9 months. Patient cohorts characteristics were: mean age, 66.1 years, 181 men (74%), claudication (64%), rest pain (16%), ischemic lesions (20%), arterial hypertension (92%), smoking (79%), hyperlipidemia (65%) and type 2 diabetes (43%). Cumulative primary 1- and 3-year graft patency rates were 60.8% and 50.7%, respectively, and cumulative 1- and 3-year limb salvage rates were 89.3% and 86.1%, respectively. One hundred seven bypasses (43.9%) failed, 26 patients (10.7%) required a major and seven patients (2.9%) required a minor amputation. Overall survival rates of PAD patients after 1- and 3-years were 94.4% and 82.9%, respectively. Subjective symptom improvement was found to be the most important prognostic follow-up factor for graft patency and limb salvage. Patients with recurrent symptoms in the follow-up had an increased risk of emerging bypass failure compared with patients with subjective symptom improvement (patency at 1 year: 40.8% vs 100% and at 3 years: 26% vs 100%; P < .001). No patient with subjective improvement in symptoms during follow-up underwent an amputation (limb salvage at 1 year: 100% vs 79% and at 3 years: 100% vs 72.8%; P < .001). Therefore, subjective symptom improvement should be the decisive criterion to determine follow-up intervals of PAD patients. In univariate analysis further significant factors associated with better graft patency and limb salvage rates were: claudication compared with critical ischemia, larger graft diameter (>6 mm), pre- and postoperative antiplatelet therapy, statin therapy independent from lipid values after PAKB revascularization, and an experienced vascular surgeon. CONCLUSIONS: In our study, we determined the subjective improvement in symptoms as the most important prognostic factor for bypass function and limb salvage after PAKB. Furthermore, disease stage of critical ischemia, graft diameter, preoperative aspirin use, and postoperative statin medication were independent predictive factors. Therefore, PAD patients should be treated with aspirin pre- and postoperatively as well as with a statin postoperatively. In case of PAKB reconstruction only prostheses with a large diameter (>6 mm) should be used and the procedure should be performed by an experienced surgeon. Considering these results with regard to the predictive factors for better graft patency and limb salvage rates a significant more favorable outcome during the follow-up and an increased 5-year patency rate for PAKB reconstructions can be expected. PMID- 27763269 TI - Collateral flow-related superior mesenteric artery aneurysm in chronic juxtarenal aortic occlusion. PMID- 27763268 TI - Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia. AB - BACKGROUND: Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia. METHODS: Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV. RESULTS: FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture. CONCLUSIONS: Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV. PMID- 27763270 TI - Release of tracheal compression by innominate artery aneurysm. PMID- 27763271 TI - Composite sequential bypass using profunda vein hitchhike. AB - Patients with long-segment occlusions of the iliac and femoral arteries often undergo sequential bypass procedures. There exists a subgroup of patients who have no suitable vessels in the groin. We report our experience with a new technique of using the profunda vein as a hitchhike point in our series of seven patients (eight limbs) with critical ischemia and occlusion at the iliac or aortic level with reformation of infrageniculate arteries and no reformation in the groin. The proximal graft was anastomosed to the profunda vein, which was ligated proximal to the anastomosis. The saphenous vein graft was taken from the distal end of the polytetrafluoroethylene graft and anastomosed to the appropriate tibial arteries. The procedure was technically successful in all the patients. The median follow-up was 8 months (range, 0-30). The profunda vein as a hitchhike point gives an excellent outcome in the short and medium term in this uncommon group of patients. PMID- 27763321 TI - Regarding "A new metric for centralization of ruptured abdominal aortic aneurysm repair in large territories". PMID- 27763322 TI - Reply. PMID- 27763323 TI - Correction. PMID- 27763327 TI - Role of diffusion-weighted imaging for detecting bone marrow infiltration in skull in children with acute lymphoblastic leukemia. AB - PURPOSE: We aimed to determine whether diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) measurement can detect skull bone marrow infiltration in newly diagnosed acute lymphoblastic leukemia (ALL) children before therapy and normalization in complete remission after treatment. METHODS: Fifty-one newly diagnosed acute lymphoblastic leukemia (ALL) patients and 30 healthy age-matched subjects were included. Cranial magnetic resonance imaging (MRI) scans were reviewed, and skull marrow ADC values were compared before treatment and in complete remission after therapy. RESULTS: Skull marrow infiltration, manifested with abnormal DWI signals, was present in 37 patients (72.5%) before treatment. Of these, 23 (62.2%) showed scattered signal abnormalities and 14 (37.8%) showed a uniform abnormal signal pattern. Compared with the control group, ADC was significantly decreased in patients with ALL. DWI signal intensity and ADC normalized in patients with complete remission. CONCLUSION: DWI is a useful and noninvasive tool for detecting skull infiltration in ALL children before treatment and normalization at complete remission after therapy, and it is superior to conventional MRI in terms of conspicuity of these lesions. DWI could be used as an MRI biomarker for evaluation of treatment in ALL children. PMID- 27763328 TI - It takes two T to shape immunity: emerging role for T-type calcium channels in immune cells. PMID- 27763329 TI - Apoptotic mechanisms of N1-acetylacetone, N4-4-methoxy-salicylidene thiosemicarbazide chelating with Nickel(II) on HL60 leukemia cells. AB - Thiosemicarbozone complexes that have a broad spectrum of biological activity are formed as a result of condensation reaction between thiosemicarbazide [H2N(C=S) NH-NH2] and carbonyl-containing compounds. A new Nickel(II) complexes with N1 acetylacetone, N4-4-methoxy-salicylidene-thiosemicarbazidato ligand was synthesized and characterized. We studied the antileukemic activity of the Ni(II) thiosemicarbazone compound and assessed their potential for drug development. Specifically, the effects of this Ni(II) thiosemicarbazone compound on intracellular signal nodes and apoptotic pathways were investigated. According to our results, the Ni(II) thiosemicarbazone compound has apoptotic activity against HL60 cells. Moreover, while Ni(II) thiosemicarbazone compound significantly increased levels of p53 and cleaved caspase-3 proteins, it decreased level of Phospho-Akt1 protein in HL60 cells. The Ni(II) thiosemicarbazone compound could induce HL60 cell apoptosis through inhibiting of PI3K/Akt pathway. These results showed that Ni(II) thiosemicarbozone compound might be an antileukemic agent. PMID- 27763330 TI - The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin. AB - In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides. PMID- 27763331 TI - COD removal efficiency and mechanism of HMBR in high volumetric loading for ship domestic sewage treatment. AB - The hybrid membrane bioreactor (HMBR) has been applied in ship domestic sewage treatment under high volumetric loading for ship space saving. The mechanism and influence factors on the efficiency, including hydraulic retention time (HRT), dissolved oxygen (DO) of chemical oxygen demand (COD) removal were investigated. The HMBR's average COD removal rate was up to 95.13% on volumetric loading of 2.4 kgCOD/(m3*d) and the COD concentration in the effluent was 48.5 mg/L, far below the International Maritime Organization (IMO) discharge standard of 125 mg/L. DO had a more remarkable effect on the COD removal efficiency than HRT. In addition, HMBR revealed an excellent capability of resisting organics loading impact. Within the range of volumetric loading of 0.72 to 4.8 kg COD/(m3*d), the effluent COD concentration satisfied the discharge requirement of IMO. It was found that the organics degradation in the aeration tank followed the first-order reaction, with obtained kinetic parameters of vmax (2.79 d-1) and Ks (395 mg/L). The original finding of this study had shown the effectiveness of HMBR in organic contaminant degradation at high substrate concentration, which can be used as guidance in the full scale of the design, operation and maintenance of ship domestic sewage treatment devices. PMID- 27763332 TI - Innovation results of IAM planning in urban water services. AB - The requirement to provide urban water services continuously while infrastructures are ageing, imposes the need for increasingly sustainable infrastructure asset management (IAM). To achieve and maintain adequate levels of service, the AWARE-P IAM methodology has been applied in collaborative projects launched by the National Civil Engineering Laboratory, in partnership with IST (Technical University of Lisbon), Addition (software company) and several water utilities. The objective of these projects is to support urban water utilities in the development, implementation and maintenance of IAM plans. To guarantee the success of IAM planning, following the AWARE-P IAM methodology, utilities are required to: consider that the infrastructure has system behaviour and lifespan is indefinite and guarantee the full-alignment of IAM planning with organisation objectives. By analysing the strategic and tactical plans of participating utilities, the proposed methodology principles are discussed and supported. The main innovation results from the implementation of IAM planning are also presented and discussed, including the challenges of setting up an IAM process, together with the major benefits and drawbacks that come up when developing IAM plans. The results were demonstrated by the effective implementation of 16 strategic and 14 tactical IAM plans by the participating utilities. PMID- 27763333 TI - Phosphate treatment by onsite wastewater systems in nutrient-sensitive watersheds of North Carolina's Piedmont. AB - The goal of this study was to gain a better understanding of the PO4-P treatment efficiency of onsite wastewater systems (OWS) installed in nutrient-sensitive watersheds of the North Carolina Piedmont. Four OWS including two conventional and two single-pass sand filter (SF) systems were evaluated at sites with clay rich soils. Piezometers were installed near all of the OWS, and down-gradient from the conventional OWS for groundwater collection and characterization. Septic tanks, groundwater, SF effluent, and surface waters were sampled each season during 2015 (five times) and analyzed for PO4-P and Cl concentrations and for various environmental parameters. The conventional and SF OWS reduced PO4-P concentrations by an average of 99% and 90%, respectively, before discharge to surface waters. Mass-load reductions of PO4-P were also greater for the conventional OWS (mean 95%), relative to SF (83%) systems. The effluents discharged by SF OWS were influencing surface water quality. Additional treatment of the effluent from single-pass SF with reactive media is suggested, along with monitoring of the final effluent for PO4-P concentrations. This research provides important information that is absent from the published literature concerning PO4 P contributions to water resources from OWS in clay soils. PMID- 27763334 TI - A decision classifier to classify rivers for river management based on their structure in China: an example from the Yongding river. AB - River classification is a very useful tool for river management yet still a difficult task. This paper proposed a new decision classifier (DCF) to classify rivers for Chinese river management based on existing classification systems. Aimed at river function management, the DCF with the five-layers frame was developed on reach level in a spatially nested pattern that from top to bottom are natural province, basin, valley, reach, habitat and microhabitat. Five indexes (artificial degree, closeness, sinuosity, bed material texture, geomorphic units (GUs)) were selected and organized into the DCF according to the importance of the influence on river structure from macro to micro, large to small and top to bottom, because they represent main aspects of river structures and are easy to obtain. In addition, the closeness index is another good connector between valley level and reach level, and the GUs index links reach level to habitat level. The overall procedure to use DCF includes primary indoor classification and field validation. Remote sensing, geographical information system and global positioning system technologies were adopted in the process to dramatically reduce workload, especially fieldwork. Finally, the approach was applied to the Yongding river as a good example, and 17 river styles were identified. PMID- 27763335 TI - The ecological filter system for treatment of decentralized wastewater. AB - A vertical flow constructed wetland was combined with a biological aerated filter to develop an ecological filter, and to obtain the optimal operating parameters: The hydraulic loading was 1.55 m3/(m2.d), carbon-nitrogen ratio was 10, and gas water ratio was 6. The experimental results demonstrated considerable removal efficiency of chemical oxygen demand (COD), ammonia nitrogen (NH4+-N), total nitrogen (TN), and total phosphorus (TP) in wastewater by the ecological filter, with average removal rates of 83.79%, 93.10%, 52.90%, and 79.07%, respectively. Concentration of NH4+-N after treatment met the level-A discharge standard of GB18918-2002. Compared with non-plant filter, the ecological filter improved average removal efficiency of COD, NH4+-N, TN, and TP by 13.03%, 25.30%, 14.80%, and 2.32%, respectively: thus, plants significantly contribute to the removal of organic pollutants and nitrogen. Through microporous aeration and O2 secretion of plants, the ecological filter formed an aerobic-anaerobic-aerobic alternating environment; thus aerobic and anaerobic microbes were active and effectively removed organic pollutants. Meanwhile, nitrogen and phosphorus were directly assimilated by plants and as nutrients of microorganisms. Meanwhile, pollutants were removed through nitrification, denitrification, filtration, adsorption, and interception by the filler. High removal rates of pollutants on the ecological filter proved that it is an effective wastewater-treatment technology for decentralized wastewater of mountainous towns. PMID- 27763336 TI - A realistic dynamic blower energy consumption model for wastewater applications. AB - At wastewater treatment plants (WWTPs) aeration is the largest energy consumer. This high energy consumption requires an accurate assessment in view of plant optimization. Despite the ever increasing detail in process models, models for energy production still lack detail to enable a global optimization of WWTPs. A new dynamic model for a more accurate prediction of aeration energy costs in activated sludge systems, equipped with submerged air distributing diffusers (producing coarse or fine bubbles) connected via piping to blowers, has been developed and demonstrated. This paper addresses the model structure, its calibration and application to the WWTP of Mekolalde (Spain). The new model proved to give an accurate prediction of the real energy consumption by the blowers and captures the trends better than the constant average power consumption models currently being used. This enhanced prediction of energy peak demand, which dominates the price setting of energy, illustrates that the dynamic model is preferably used in multi-criteria optimization exercises for minimizing the energy consumption. PMID- 27763337 TI - Effective removal of lead (II) ions by dead calcareous skeletons: sorption performance and influencing factors. AB - Dead calcareous skeletons (CSs) as low-cost adsorbents were studied to remove lead ions (Pb (II)) in an aqueous solution. Factors influencing the efficiency of CSs were evaluated by adsorbent size, contact time, initial concentration, dosage concentration and pH. The optimum CS size for removal of Pb (II) was 710 MUm at an equilibrium time of 720 min. The best dosage of CS was 10 g/L for a 99% removal efficiency without pH adjustment. Pb (II) ions were effectively removed in the initial pH of the metal solution. CS was able to remove a high concentration (100 mg/L) of Pb (II) at a removal efficiency of 99.92% and at an adsorption capacity of 13.06 mg/g. Our results demonstrated the potential of CS as a metal adsorbent in the aqueous phase with a high-removal efficiency and distinct physical characteristics. PMID- 27763338 TI - Calcium-alginate/carbon nanotubes/TiO2 composite beads for removal of bisphenol A. AB - In this study, composite calcium-alginate/carbon nanotubes/TiO2 beads were prepared and tested for their potential in the removal of bisphenol A (BPA) from aqueous solutions. The removal traits were inspected using a fixed-bed sorption column. By varying parameters such as bed height (15-20 cm), flow rate (2.0-6.0 mL.min-1) and inlet BPA concentration (10-30 mg.L-1) we assessed the removal capacity of these composites. The highest sorption capacity of 5.46 mg.g-1 was achieved at 10 mg.L-1 BPA concentration, 2.0 mL.min-1 flow rate and 20 cm bed height at saturation. Adams-Bohart, Yoon-Nelson and Dose-Response isotherm models were applied to evaluate the performance of the column at different inlet concentrations. The experimental data satisfactorily fit the Dose-Response model with high correlation (r2 > 0.97) across the breakthrough curve. Regeneration of the used adsorbent beads were performed by immersion in the desorption solvent followed by light irradiation. It was postulated that inclusion of TiO2 facilitates the desorbed pollutant degradation from the used adsorbent beads. PMID- 27763339 TI - Evaluation of unclogging aspects in horizontal subsurface flow constructed wetlands. AB - In horizontal subsurface flow constructed wetlands (HSSF-CWs), the main operational problem is clogging of the porous medium. In this study, the unclogging of HSSF-CWs was evaluated, at rest, by adding a nitrogen-based nutrient solution to the influent. For this, six HSSF-CWs were used, consisting of two uncultivated (CW-C), two cultivated with Tifton 85-grass (Cynodon spp.) (CW-T) and two cultivated with alligator weed (Alternanthera philoxeroides) (CW A), which were fully clogged after being used for the treatment of swine wastewater. The results indicated that passage of the nutrient solution for 55 days through the bed of the HSSF-CWs resulted in reductions of 11 and 33%, respectively, in the total volatile solids (TVS) concentration of fine clogging material in the CW-T and CW-A. With regard to the TVS content of the coarse clogging material, the reduction was even greater, being 33% for CW-T and 62% for CW-A. Measurements of K0 made along the beds (thirds 1, 2 and 3) before and after passage of the nutrient solution in the CWs indicated respective increases of 7, 13 and 0.1% in CW-C; 21, 11 and 7% in CW-T; and 52%, 6% and -6% (decrease) in CW A. Runoff of the nutrient solution decreased gradually over time, presenting at the beginning of the experiment 26, 35 and 150 cm, and at the end (after 55 days of application) 0, 0 and 50 cm in the flow direction of the CW-C and CW-T and CW A, respectively. PMID- 27763340 TI - Comparison of wastewater treatment processes on the removal efficiency of organophosphate esters. AB - Organophosphate esters (OPs), widely used as flame retardants and plasticizers, are regarded as a class of emerging pollutants. The effluent of municipal wastewater treatment plants is generally considered to be the main contributor of OP pollution to the surface water. In this study, anoxic-oxic (AO) and University of Capetown (UCT) processes were selected to investigate the removal efficiency of OPs. The results indicated that the UCT process showed better removal efficiency than that of the AO process. For the chlorinated OPs, approximately 12.3% of tri(2-chloroethyl)phosphate and 11.8% of tri(chloropropyl)phosphate can be removed in the UCT process, which was 12% and 7.8% higher than that of the AO process. In contrast, non-chlorinated OPs, including tris(2 butoxyethyal)phosphate, triphenyl phosphate, and tributyl phosphate, were able to be removed in both processes, with the removal rate of 85.1%, 74.9%, and 29.1% in the AO process, and 88.4%, 63.6%, and 25.2% in the UCT process. Furthermore, linear correlation between the removal rate and logKow of OPs (r2 = 0.539) was observed in the AO process, indicating that OPs with high Kow value (e.g. tri(dichloropropyl)phosphate and triphenyl phosphate) are prone to be removed by adsorption on the residual activated sludge. PMID- 27763341 TI - Short-term temperature impact on simultaneous biological nitrogen-sulphur treatment in EGSB reactor. AB - Sulphides are present in many wastewater streams; their removal is important due to corrosiveness, toxicity and unpleasant odour, and can be carried out by anaerobic biological treatment. This study focuses on the temperature effect (25 10 degrees C) on an expanded granular sludge bed (EGSB) reactor for sulphide removal using nitrate as electron acceptor. The reactor was run at a NO3-/HS- molar ratio of 0.35 and pH of 8.5-9.0. Samples were analysed by ion chromatography (NO3-, SO42- and S2O32-), spectrophotometry (S2-) and by scanning electron microscopy (SEM). S2- and NO3- removal was 99.74 +/- 0.04 and 99.5 +/- 2.9%, respectively. Sulphur (S0) was found on the outer granule surface and struvite inside the granule, by SEM. Sulphide conversion to sulphur was up to 76%. Temperature transitions and levels influenced S2O32- and SO42- concentrations. PMID- 27763342 TI - Effects of DMSO and glycerol additives on the property of polyamide reverse osmosis membrane. AB - The polyamide reverse osmosis (RO) membranes were prepared through interfacial polymerization of m-phenylenediamine (MPD) and trimesoyl chloride (TMC). The use of dimethyl sulfoxide (DMSO) and glycerol as additives for the formation of thin film composite (TFC) was investigated. We studied the effect of DMSO and glycerol addition on membrane property and RO performance. Microscopic morphology was examined by atomic force microscopy and scanning electron microscopy. The surface hydrophilicity was characterized on the basis of water contact angle and surface solid-liquid interfacial free energy (-DeltaGSL). Water flux and salt rejection ability of the membranes prepared with or without the additives were evaluated by cross-flow RO tests. The results reveal that the addition of DMSO and glycerol strongly influences the property of the TFC RO membrane. Compared to the MPD/TMC membrane fabricated without DMSO and glycerol, the MPD/TMC/DMSO/glycerol membrane has a rougher surface and is more hydrophilic, showing smaller water contact angle and larger -DeltaGSL value. Without decrease in salt rejection ability, the MPD/TMC/DMSO/glycerol membrane shows water flux significantly larger than that of the MPD/TMC membrane. The unique property of the MPD/TMC/DMSO/glycerol membrane is attributed to the cooperative effect of DMSO and glycerol on membrane structure during the interfacial polymerization process. PMID- 27763343 TI - Post-denitrification using alginate beads containing organic carbon and activated sludge microorganisms. AB - Nitrate concentration in the final effluent is a key issue in pre-denitrification biological treatment systems. This study investigated post-denitrification with alginate beads containing immobilized activated sludge microorganisms and organic carbon source. A batch study was first performed to identify suitable carbon sources among acetate, glucose, calcium tartrate, starch and canola oil on the basis of nitrate removal and bead stability. Canola oil and starch beads exhibited significantly higher denitrification rates, greater bead stability and lower nitrite accumulation (6 mg/L and 10 mg/L, respectively). Glucose and acetate beads showed longer acclimation phases and degraded faster whereas tartrate beads had higher nitrite build-up (39 mg/L) and degraded due to brittleness. Post-denitrification with canola oil and starch beads was investigated in the final clarifier of a coupled upflow bioreactor and aerobic system treating synthetic dairy farm wastewater, and showed a denitrification efficiency of >90%. Beads faded in 12 days due to alginate degradation. Therefore, enhancement in bead strength or use of more stable nontoxic gel would be required to further prolong the treatment. Moreover, this study was conducted at laboratory scale and further research is needed for application in real systems. PMID- 27763344 TI - Coagulation behavior and floc characteristics of a novel composite poly-ferric aluminum chloride-polydimethyl diallylammonium chloride coagulant with different OH/(Fe3+ + Al3+) molar ratios. AB - In this paper, flocculating performance and mechanisms of a new composite coagulant, poly-ferric aluminum chloride-polydimethyl diallylammonium chloride (PFAC-PD) with different OH-/(Fe3+ + Al3+) molar ratios, were investigated for humic acid (HA)-kaolin synthetic wastewater treatment. The impact of OH-/(Fe3+ + Al3+) molar ratios on the removal efficiencies of turbidity and dissolved organic carbon, specific UV absorbance, coagulation mechanisms and dynamics was explored during the coagulation process using composite coagulants. The coagulation experimental results revealed that the composite coagulants with lower OH-/(Fe3+ + Al3+) molar ratio exhibited better coagulation efficiency. When OH-/(Fe3+ + Al3+) molar ratio of the composite coagulant was 1.5, adsorption-bridging played a dominant role in coagulating HA-kaolin synthetic wastewater. The floc growth rate and floc size, increased with increasing OH-/(Fe3+ + Al3+) molar ratio and the highest peak height of the size distribution was obtained by PFAC-PD with OH /(Fe3+ + Al3+) = 1.5. Also, the composite coagulants with higher OH-/(Fe3+ + Al3+) molar ratio formed more compact flocs, as reflected by the higher fractal dimension value. The flocs coagulated by PFAC-PD with basicity value of 1.0 gave strong strength and good recoverability. PMID- 27763345 TI - Adsorption of heavy metals from aqueous solutions by Mg-Al-Zn mingled oxides adsorbent. AB - In our study, Mg-Al-Zn mingled oxides were prepared by the co-precipitation method. The structure, composition, morphology and thermal stability of the synthesized Mg-Al-Zn mingled oxides were analyzed by powder X-ray diffraction, Fourier transform infrared spectrometry, N2 physisorption, scanning electron microscopy, differential scanning calorimetry and thermogravimetry. Batch experiments were performed to study the adsorption behavior of cobalt(II) and nickel(II) as a function of pH, contact time, initial metal ion concentration, and adsorbent dose. The maximum adsorption capacity of Mg-Al-Zn mingled oxides for cobalt and nickel metal ions was 116.7 mg g-1, and 70.4 mg g-1, respectively. The experimental data were analyzed using pseudo-first- and pseudo-second-order kinetic models in linear and nonlinear regression analysis. The kinetic studies showed that the adsorption process could be described by the pseudo-second-order kinetic model. Experimental equilibrium data were well represented by Langmuir and Freundlich isotherm models. Also, the maximum monolayer capacity, qmax, obtained was 113.8 mg g-1, and 79.4 mg g-1 for Co(II), and Ni(II), respectively. Our results showed that Mg-Al-Zn mingled oxides can be used as an efficient adsorbent material for removal of heavy metals from industrial wastewater samples. PMID- 27763346 TI - Photocatalytic removal of doxycycline from aqueous solution using ZnO nano particles: a comparison between UV-C and visible light. AB - Zinc oxide nano-particles were synthesized, characterized and used for photocatalytic degradation of doxycycline using UV-C and visible light. Effects of several operational factors including initial pH of antibiotic solution, initial antibiotic concentration and ZnO nano-particles loading amount were investigated. Comparing photocatalytic degradation and mineralization of doxycycline under UV-C and visible light showed successful application of the method under both light sources. However, reaction rate was higher under UV-C irradiation, which degraded doxycycline almost completely in 5 hours, and 68% mineralization was achieved. Synthesized ZnO nano-particles were successfully applied for photocatalytic degradation of doxycycline in a pharmaceutical wastewater sample. The process was fitted to the pseudo first order kinetic model with rate constants in the range of 6-22(*10-3) mg L-1 min-1 with respect to initial concentration of doxycycline under UV-C irradiation. The Langmuir Hinshelwood model was also employed for describing the photocatalytic reaction with surface reaction kinetic constant kc and equilibrium adsorption constant KLH values calculated as 0.12 mg L-1 min-1 and 2.2 L mg-1, respectively. Degradation of doxycycline was followed by UV-visible spectroscopy and a validated stability indicating high-performance liquid chromatography method that was developed using stressed samples of doxycycline and could selectively determine doxycycline in the presence of its degradation products. Mass spectrometry was used for determining final degradation products. PMID- 27763347 TI - Nutrient load concept-reservoir vs. bay impacts: a case study from a semi-arid watershed. AB - Large flow-through reservoirs and lakes possess environmental gradients and monitoring programs are mostly adapted for cost and time effectiveness. Bay areas are often more isolated from the main water body and are likely to have unobserved different environmental processes and impacts. This study was performed at the Itaparica Reservoir, Sao Francisco River, located in semi-arid Northeast Brazil, with dendritic form. Water residence time in the Ico-Mandantes Bay was estimated by hydrodynamic flow and transport simulations. The P chlorophyll a relationship was used to develop the P use efficiency coefficient for critical P load estimation of 25 MUg P L-1. Phosphorus sources and input rates into a bay and the respective reservoir were calculated and compared regarding their different origins for the period after flooding (1988) and for 2013. After impoundment, the P load highly exceeded the carrying capacity because of leaching and mineralization processes. In 2013, P inputs were still above this threshold, whereas inflow and sub-basin P export during the rainy season were crucial. But eutrophication processes have increased in the bay relative to the main water body. Hence, water in hydraulic isolated parts is prone to eutrophication processes, thus, bays have to be specially considered in water resource management. PMID- 27763348 TI - Immobilization of PDMS-SiO2-TiO2 composite for the photocatalytic degradation of dye AO-7. AB - Crack-free PDMS-SiO2-TiO2 composite as photocatalyst was prepared for degrading dyes by using thin-film fixed bed reactor. The hydrophobic surface of the photocatalyst loaded with PDMS-SiO2-TiO2 composite could be considered as an extractant for organic pollutants. The effect of different supports including pumice stone, medicinal stone, and fiberglass for photocatalytic efficiency were compared. Under the same condition, it was found that the photocatalytic degradation effect of dyes was best when PDMS-SiO2-TiO2 composite was fixed on pumice stone rather than medicinal stone or fiberglass. Furthermore, when pumice stone was used as the support for PDMS-SiO2-TiO2 composite, the photocatalytic degradation effect of dyes hardly decreased after five cycles. PMID- 27763349 TI - Enhancement of photocatalytic degradation of furfural and acetophenone in water media using nano-TiO2-SiO2 deposited on cementitious materials. AB - In the present study, silicon dioxide (SiO2) nanoparticles were loaded to titanium dioxide (TiO2) nano-particles by sol-gel method to make a high porosity photocatalyst nano-hybrid. These photocatalysts were synthesized using titanium tetrachloride and tetraethyl orthosilicate as titanium and silicon sources, respectively, and characterized by X-ray powder diffraction (XRD) and scanning electron microscope methods. Subsequently, the optimizations of the component and operation conditions were investigated. Then, nano-sized TiO2 and TiO2-SiO2 were supported on concrete bricks by the dip coating process. The photocatalytic activity of nano photocatalysts under UV irradiation was examined by studying the decomposition of aqueous solutions of furfural and acetophenone (10 mg/L) as model of organic pollutants to CO2 and H2O at room temperature. A decrease in the concentration of these pollutants was assayed by using UV-visible absorption, gas chromatography technique, and chemical oxygen demand. The removal of these pollutants from water using the concrete-supported photocatalysts under UV irradiation was performed with a greater efficiency, which does not require an additional separation stage to recover the catalyst. Therefore, it would be applicable to use in industrial wastewater treatment at room temperature and atmospheric pressure within the optimized pH range. PMID- 27763350 TI - Wastewater containing Cr(VI) treatment using solar tubular reactor. AB - The hexavalent chromium, Cr(VI), which is generated in the electroplating process, is toxic to most organisms and potentially harmful to human health. The method generally used for remediation of wastewater containing Cr(VI) employs chemicals with high toxicity. This work proposes an alternative technology for the treatment of these wastewaters, based on photochemical reduction of Cr(VI) by alcohols under radiation, which is environmentally sustainable and economically viable. Initially, a batch reactor in laboratory scale was used to determine the best experimental conditions and its specific reaction rate was calculated. Based on these results, a tubular reactor (artificial radiation and sunlight) was designed and built in semi-pilot scale. Tests were carried out with real wastewater from an electroplating industry containing Cr(VI). Tests conducted under sunlight showed a higher total Cr(VI) reduction than the tests with artificial radiation. The remediation of Cr(VI) from wastewater was 86.7% after 6 h of reaction under sunlight, indicating the high efficiency of the developed process. PMID- 27763351 TI - Magnetically modified biochar for organic xenobiotics removal. AB - Large amounts of biochar are produced worldwide for potential agricultural applications. However, this material can also be used as an efficient biosorbent for xenobiotics removal. In this work, biochar was magnetically modified using microwave-synthesized magnetic iron oxide particles. This new type of a magnetically responsive biocomposite material can be easily separated by means of strong permanent magnets. Magnetic biochar has been used as an inexpensive magnetic adsorbent for the removal of water-soluble dyes. Five dyes (malachite green, methyl green, Bismarck brown Y, acridine orange and Nile blue A) were used to study the adsorption process. The dyes adsorption could be usually described with the Langmuir isotherm. The maximum adsorption capacities reached the value 137 mg of dye per g of dried magnetically modified biochar for Bismarck brown Y. The adsorption processes followed the pseudo-second-order kinetic model and the thermodynamic studies indicated spontaneous and endothermic adsorption. Extremely simple magnetic modification of biochar resulted in the formation of a new, promising adsorbent suggested for selected xenobiotics removal. PMID- 27763353 TI - Spatial and seasonal variation of organic pollutants in surface water using multivariate statistical techniques. AB - In this study, analysis of variance (ANOVA), cluster analysis (CA) and principal component analysis (PCA) were employed in order to evaluate the concentration profile of organic contaminants found in three main river from central Transylvania, Romania. Samples were collected from nine sampling stations, in two different sampling campaigns (wet season and dry season). Water samples were extracted using solid-phase extraction and analyzed using gas chromatography coupled with mass spectrometry (GC/MS). Twelve organic pollutants belonging to different classes were used for further interpretations. ANOVA highlighted compounds which distinguished Olt River from Mures River, and compounds that are influenced by increased river flow from the wet season. CA was applied to group the sampling stations. Three clusters were obtained, according to their organic load. PCA extracted five principal components explaining 87.330% from data set variability. Based on these results, a future monitoring study may be optimized by reducing the sampling points and compounds to those that are representative for each river, thereby reducing costs, without any information loss. PMID- 27763352 TI - Characterization and biodegradability of sludge from a high rate A-stage contact tank and B-stage membrane bioreactor of a pilot-scale AB system treating municipal wastewaters. AB - In light of global warming mitigation efforts, increasing sludge disposal costs, and need for reduction in the carbon footprint of wastewater treatment plants, innovation in treatment technology has been tailored towards energy self sufficiency. The AB process is a promising technology for achieving maximal energy recovery from wastewaters with minimum energy expenditure and therefore inherently reducing excess sludge production. Characterization of this novel sludge and its comparison with the more conventional B-stage sludge are necessary for a deeper understanding of AB treatment process design. This paper presents a case study of a pilot-scale AB system treating municipal wastewaters as well as a bio- (biochemical methane potential and adenosine tri-phosphate analysis) and physico-chemical properties (chemical oxygen demand, sludge volume index, dewaterability, calorific value, zeta potential and particle size distribution) comparison of the organic-rich A-stage against the B-stage activated sludge. Compared to the B-sludge, the A-sludge yielded 1.4 to 4.9 times more methane throughout the 62-week operation. PMID- 27763354 TI - Promotion of nitrifiers through side-stream bioaugmentation: a full-scale study. AB - Bioaugmentation of nitrifiers from a side-stream treatment is an efficient method for boosting the mainstream process at a wastewater treatment plant (WWTP). Although this technology has been known for several years, the number of full scale applications for it is limited. For a WWTP approaching its critical nitrogen load capacity, the benefits are doubled if the introduced side-stream treatment for digester supernatant is combined with bioaugmentation. Not only is the nitrogen load to the mainstream process decreased by 10-25%, but the mainstream process is also boosted with nitrifiers, increasing the nitrifying capacity. In this full-scale study, the increment of the nitrification rate is examined in the mainstream process at different temperatures and at different flow rates of returned activated sludge to the side-stream treatment. Our results show that the nitrification rate in the mainstream process was increased by 41% during the coldest period of the study, implying that the examined WWTP could treat considerably higher nitrogen loads if bioaugmentation were permanently installed. PMID- 27763355 TI - Adsorption characteristics of Bisphenol-A on tailored activated carbon in aqueous solutions. AB - The adsorption behavior of pharmaceuticals and personal care product, Bisphenol-A (BPA), according to four coal-based and four wood-based granular activated carbons modified using outgassing treatment, acidic treatment or alkaline treatment was studied. The adsorption isotherm results indicated that carbon surface acidity played a very important role in the adsorption of BPA. It was found that increasing surface acidity would increase the hydrogen bonding effects and increase adsorption of BPA on activated carbon. The acidic modified sample (F600-A and OLC-A) represented the best adsorption capacity, and the equilibrium adsorption amounts reached 346.42 and 338.55 mg/g, respectively. Further, effects of surface charge and surface basicity were examined. It was found that the adsorbed amount of BPA decreased with the increase of surface charge. Finally, there appeared to be a significant oligomerization phenomenon with BPA molecules onto the surface of activated carbon. OLC and OLC-OG, which have higher micropore percentages, are very effective in hampering the oligomerization of BPA under oxic conditions. PMID- 27763356 TI - Introduction: Pain, Trauma, and Philia in Middle English Literature. PMID- 27763357 TI - Cultural Trauma and Christian Identity in the Late Medieval Heroic Epic, The Siege of Jerusalem. AB - This essay examines scenes of violence in the late medieval poem The Siege of Jerusalem in order to reveal the ways in which trauma is used as the grounds upon which Christian/Jewish difference is established. In particular, I argue that this poem serves as an example of a widespread element in Christian chivalric identity, namely the need to manage the repetitive invocation of Christ's crucifixion (ritually repeated through liturgical and poetic invocation) as a means of asserting both the bodily and psychic integrity of the Christian subject in contrast to the violently abjected figure of the Jewish body. The failure of The Siege protagonist, Wespasian, to navigate the cultural trauma of the crucifixion is contrasted to the successful management of trauma by the martial hero, Tancred, in Tasso's epic, Gerusalemme Liberata, illustrating the range of imaginative possibilities for understanding trauma in pre-modern war literature. PMID- 27763358 TI - Lydgate's Danse Macabre and the Trauma of the Hundred Years War. AB - This essay argues that the foundational traumatic lacuna behind John Lydgate's Danse Macabre is the social agon between those who wage the Hundred Years War and those who fight in it. Drawing from the insights of trauma theory to discuss the poem's form, the essay uncovers Lydgate's persistent concern with the damage caused by the war and the concomitant political unrest it causes. It argues further that Lydgate theorized this agon using the emergent genre of tragedy, which is beginning to be practiced anew in late-medieval England. Tragic discourse is riven by concerns about the efficacy of human action and the radical contingency of fortune, creating a crisis of agency that can be used as a form of political critique. Ultimately, Lydgate blends the genre of tragedy with the mirror for princes and estates satire genres to argue that, while everyone must eventually dance with death, during war some estates lead the dance. PMID- 27763359 TI - Dismemberment and the Attempt at Re-membering in R. D. Laing's The Bird of Paradise. AB - Despite renewed interest in the radical psychiatrist R. D. Laing (1927-1989), his The Bird of Paradise (1967), published in a single volume with The Politics of Experience, has received scant scholarly attention. Characterized largely as odd, it has even been read as a sign that Laing, deeply sympathetic to the mad, had himself gone crazy. Eschewing biographical criticism, I focus rather on the problem of assigning Bird to a genre (and the significance of this difficulty). Finding the capacious prose poem genre the most appropriate category, I take Bird seriously as a complex literary text, offer an overview of it, relate it to Politics and 1960s counterculture, and attend to Laing's ambivalent attitude towards writing. Bird, I argue, represents an attempt-albeit an ultimately unsuccessful one-at overcoming what Laing understands as alienated self-division ("dismemberment") through a reaching towards wholeness (a "re-membering" of the self). PMID- 27763361 TI - Designs and Dreams: Questions of Technology in Hayao Miyazaki's The Wind Rises. PMID- 27763362 TI - From Cabling the Atlantic to Wiring the World: A Review Essay on the 150th Anniversary of the Atlantic Telegraph Cable of 1866. AB - The year 2016 witnesses the 150th anniversary of laying the first successful transatlantic telegraph cables. This review essay offers a critical rereading of existing scholarship while simultaneously suggesting new perspectives for research. Telegraphy = globalization, the history of wiring the world commencing with the Atlantic cable of 1866 seems to suggest. At the same time, this essay argues, this equation should make scholars uneasy and cautious of a possible technological determinism retracing its steps back into the middle of scholarly debates on globalization. More attention needs to be paid to whose globalization we are talking about, what the globalization of politics, markets, and media means in connection to communication, and whether the cables really started something radically new. 150 years after laying the "first" Atlantic cable, there is still room for research. New spaces, theories, and methodologies, as well as alternate user groups including women and subalterns, offer avenues to test established scholarship on global communications. PMID- 27763363 TI - Technological Innovation: On the Origins and Development of an Inclusive Concept. AB - Over the last several decades, many students of technology have tried to make sense of the concept of technology and its origins. However, nothing similar exists in the literature on "technological innovation," a phrase that emerged after World War II. This paper suggests that technological innovation is a counter-concept to science-and more particularly to basic research-as a dominant cultural value of the twentieth century. Technological innovation emerged as a phrase or concept because in discourse, action, and policy, it was useful to include in understandings of economic growth a larger number of people than just scientists and more activities than just science or basic research. Technological innovation is a total process. "It integrates what would otherwise be separate activities and inquiries in order to redraw the intellectual world that society adopts" (Roy Harris, The Semantics of Science, [p. xi]). PMID- 27763364 TI - Standard Cocoa: Transnational Networks and Technoscientific Regimes in West African Plantations. AB - In the early 1900s, an obscure Portuguese colony in the equatorial Atlantic rose as the world's leading cocoa producer. Cocoa from the island of Sao Tome was grown on large plantations with indentured labor and high technological inputs. This technoscientific system, to control both plants and people, became the model for making an industry-suited cocoa, and the material evidence of the moral and economic virtues of the colonial plantation. Experts played a crucial role in building and putting into circulation such a system. Sao Tome's cocoa expertise, along with its labor and racial relations, landscape patterns, and imperial imaginaries, contributed to the colonization of other African territories, namely the German Cameroons. This article agues that commodities and their technological histories can help bring to light the transnational and transcolonial features that are embedded at the core of empire building. PMID- 27763365 TI - Seeing the Forest and the Trees: Western Forestry Systems and Soviet Engineers, 1955-1964. AB - This article examines the transfer of technology from Finnish enterprises to Soviet industry during the USSR's period of technological modernization between 1955 and 1964. It centers on the forestry sector, which was a particular focus of modernization programs and a key area for the transfer of foreign techniques and expertise. The aim of the article is to investigate the role of trips made by Soviet specialists to foreign (primarily Finnish) enterprises in order to illustrate the nontechnological influences that occurred during the transfer of technologies across the cold war border. To do so, the article is divided into two parts: the first presents a general analysis of technology transfer from a micro-level perspective, while the second investigates the cultural influences behind technological transfer in the Soviet-Finnish case. This study contends that although the Soviet government expected its specialists to import advanced foreign technical experience, they brought not only the technologies and expertise needed for modernizing the industry, but also a changed view on Soviet workplace management and everyday practices. PMID- 27763366 TI - Domestic Appliances and Industrial Design: The Italian White-Goods Industry during the 1950s and 1960s. AB - The white-goods sector was one of the industries that led economic development in Italy following World War II and featured companies that achieved notable results in foreign markets. According to the literature on the subject, price competitiveness generated mainly by the lower cost of labor was the key to this success. This article explores the as-yet unstudied role played by industrial design, and not only for its ability to significantly facilitate the reduction of production costs. It shows how industrial design played a wider and more decisive role in reinventing Italian white goods by differentiating the products of Italian producers from those of their main foreign competitors. Therefore the article contributes to understanding how and why certain products and technologies are reworked, assimilated, and diffused in the ways they are. PMID- 27763367 TI - Epic Audiovisual History of Technology Course by a Historian of Innovation: W. Bernard Carlson, "Understanding the Inventions that Changed the World". PMID- 27763368 TI - To the Editor. PMID- 27763369 TI - Response to Mark. PMID- 27763370 TI - 2013 Arthur O. Lovejoy Lecture: A Cognitive History of Divination in Ancient Greece. AB - Ancient Greeks drew advice from oracles, dreams, entrails, the movements of birds, sneezes, and myriad other sources for divination. Classicists typically study such phenomena as examples of occult religion, or for their use as a social mechanism for managing dissent and forging consensus. Ancient philosophical accounts by contrast go a longer way toward considering them seriously, on their own terms. They take them as an invitation into developing speculative accounts of non-standard epistemological schemes. Plato is examined as a case study of a more general Greek philosophical tendency to treat divination as something akin to what we might call intuition. PMID- 27763371 TI - President Edwards and the Sage of Highgate: Determinism, Depravity, and the Supernatural Will. AB - Scarce attention has been given to Samuel Taylor Coleridge's engagement with the philosophical theology of Jonathan Edwards, and yet a clear understanding of each thinker's position on determinism and Original Sin is of vital importance if we are understand the lasting significance of their disagreements. There have been a number of studies to take up Coleridge's influence on the American Romantics, but there is no scholarship that has taken into account how the reception of this influence was inflected both by the legacy of Edwards and by the critical response that his theology elicited from Coleridge. PMID- 27763372 TI - Formulating an Anarchist Sociology: Peter Kropotkin's Reading of Herbert Spencer. AB - The work of Herbert Spencer was a crucial influence on the development of Peter Kropotkin's historical sociology. However, scholars have underestimated this relationship; either overlooking it entirely, or minimizing Kropotkin's attachment to Spencer with the aim of maintaining the utility of his political thought in the present. This article contests these interpretations by analyzing Kropotkin's reading of Spencer's epistemological, biological, and political ideas. It argues that Kropotkin was engaged in a critical dialogue with Spencer, incorporating many Spencerian principles in his own system, but also using this reading to articulate a distinctive anarchist politics. PMID- 27763373 TI - Facing Asymmetry: Nordic Intellectuals and Center-Periphery Dynamics in European Cultural Space. AB - This article addresses the role of asymmetry in the interaction between intellectual fields in Europe in the late nineteenth and early twentieth centuries. By focusing on the spatial and temporal hierarchies implicit in the ways intellectuals from the Nordic countries perceived and made use of marginality and backwardness, the article brings a peripheral perspective to the discussion of transnational intellectual history. This is important as the discussion on transnational history tends to stress notions like reciprocity and hybridity, which reproduce the ideal of a borderless and equal republic of letters, and paints a too harmonious picture of global cultural space. PMID- 27763374 TI - Symposium on J. G. A. Pocock's Barbarism and Religion: Introduction. AB - The sixth and final volume of J. G. A. Pocock's Barbarism and Religion appeared in 2015; Wolin designates this work an exemplar of "total history" and of "philosophical historiography," in Momigliano's term. The symposium to follow comprising this introduction by Richard Wolin, essays by Helena Rosenblatt, Jonathan Israel, and Pierre Force, and a concluding response by Pocock constitutes one of the first critical examinations of Pocock's late work, and arises out of a conference hosted at the CUNY Graduate Center in 2010. PMID- 27763375 TI - J. G. A. Pocock and the "Language of Enlightenment" in His Barbarism and Religion. AB - In Barbarism and Religion, his six-volume work on the "Enlightenments" of Edward Gibbon, J. G. A. Pocock argues for a "family of enlightenments," disputing accounts, particularly Venturi's and Gay's, of it as a unified phenomenon. This article asserts, however, that Pocock's reconfiguration of different national contexts to emphasize the diversity of strands of the Enlightenment underestimates their commonality and the degree to which they fall into the recognizable currents of radical and moderate. Ultimately, Pocock's attention to the ecclesiastical and theological dimensions of the Enlightenment undermines rather than supports his argument for its pluralism. PMID- 27763376 TI - The "Exasperating Predecessor": Pocock on Gibbon and Voltaire. AB - This article offers a critical discussion of Pocock's analysis of the relationship between Gibbon and Voltaire, and particularly the extent to which Decline and Fall was inspired by Voltaire's Essai sur les moeurs. It shows that "Momigliano's hypothesis" about the divorce of philosophy and erudition and their reconciliation in Gibbon was initially a commentary by Momigliano on Voltaire's historical work. It argues that the "Momiglianian model" plays a central role in Pocock's argument in Barbarism and Religion. In that sense, understanding Gibbon's highly ambiguous appraisal of Voltaire helps us understand the overall purpose of Decline and Fall. PMID- 27763377 TI - On Context and Meaning in Pocock's Barbarism and Religion, and on Gibbon's "Protestantism" in His Chapters on Religion. AB - Rosenblatt questions whether Pocock's Barbarism and Religion, though enormously learned and rich, in fact accomplishes Pocock's stated aims. In other words, does the context presented help to explain the intended meaning and significance of Gibbon's Decline and Fall? She asks whether Pocock's methodology, indebted to the Cambridge School, is consistent and serviceable and challenges his claim that Gibbon should be seen as a member of the "Protestant Enlightenment." PMID- 27763378 TI - Response and Commentary. AB - Barbarism and Religion, the first half of J. G. A. Pocock's study of Gibbon's Decline and Fall, was designed to set Gibbon's work in context, using a method developed in Cambridge, by juxtaposing his narrative to many others-to some but not all of which he explicitly referred. Helena Rosenblatt has misunderstood Pocock's intent, which was to show that Gibbon's work took much of its inspiration for its treatment of Christianity from a world of ecclesiastical scholarship. Though Pierre Force shows that Voltaire's erudition was richer than has been thought, he and Gibbon pursued very different forms of learning. And though Pocock agrees with Jonathan Israel that many thinkers challenged traditional Christian theology, their efforts were far more varied than Israel holds. Brief studies of Jean LeClerc and Ralph call Israel's vision of radical Enlightenment into question. PMID- 27763381 TI - She Never Met a Stranger-Death is No Stranger. PMID- 27763382 TI - Mom's VSED Journey. PMID- 27763383 TI - Hunger Games. PMID- 27763384 TI - Editors' Note. PMID- 27763385 TI - Introduction: Voluntarily Stopping Eating and Drinking. AB - This symposium includes twelve personal narratives from those who have personally participated in voluntarily stopping eating and drinking (VSED). This issue also includes three commentaries on these narratives by experts in philosophy, palliative care, and hospice medicine. The successes, challenges, and observations described by these narrative and commentary authors will not only inform the academic debate about the legitimacy of VSED but will also inform much needed practical guidance for patients, clinicians, and family members on how they can best implement and support VSED. PMID- 27763386 TI - My Life-My Death. PMID- 27763387 TI - Narrative Symposium: Patient, Family, and Clinician Experiences with Voluntarily Stopping Eating and Drinking (VSED). PMID- 27763388 TI - The Less, the Better: One Patient's Journey with VSED. PMID- 27763389 TI - Kept Alive-The Enduring Tragedy of Margot Bentley. PMID- 27763391 TI - Voluntary Stopping of Eating and Drinking: A Patient's Right to Choose or an Act of Suicide? PMID- 27763390 TI - VSED at Home with Hospice: The experiences of a Husband and Daughter. PMID- 27763392 TI - 'I'd Like to Choose my Own Way:' VSED in the Non-Terminal Patient. PMID- 27763393 TI - Sam's Final Story. PMID- 27763394 TI - Not Here by Choice: My Husband's Choice About How and When to Die. PMID- 27763395 TI - Life and Death on Her Own Terms. PMID- 27763396 TI - Sarah's Second Attempt to Stop Eating and Drinking: Success at Last. PMID- 27763397 TI - To Live Long Enough to Warm the Hearts of Others: Reflections on Informing my Patient about a Peaceful Way to Die. PMID- 27763398 TI - The Deacon's Mom Wants to Die. PMID- 27763399 TI - VSED: Death With Dignity or Without? AB - Conceivably, in an ideal world, all patients with a life-limiting illness would receive optimal hospice and palliative care so that no one would ever wish to hasten their own death. The reality, however, is that despite provision of optimal hospice and palliative care, individuals with terminal illness experience suffering, loss of meaning, or deterioration in quality of life to the extent where they express the desire to expedite the dying process. While there has been extensive discussion surrounding physician-assisted death (PAD), there has been less attention paid to the practice of voluntary stopping eating and drinking (VSED) near the end of life. These twelve compelling narratives represent a dramatic groundswell of attention to the practice of VSED. Through my review of these narratives, numerous statements of significance emerged along with common ethical themes which bring to light matters that might otherwise remain idle. As such, integrity and autonomy become paramount while, unfortunately, logical fallacies like that of the slippery slope argument are asserted. Ultimately, the suffering that leads people to embrace VSED is compelling and must not be minimized. Therefore, this paper, while not comprehensive, is an attempt to dissect these major themes and offer recommendations for addressing concerns regarding end-of-life care that have surfaced during the VSED debate. It is through this endeavor that I will hopefully challenge prevailing assumptions and misconceptions that can only exist in an ideal world. PMID- 27763400 TI - VSED Narratives: Exploring Complexity. AB - In this article three palliative care physicians review narratives about the complicated experience of voluntarily stopping eating and drinking (VSED). Despite consensus about its legality, the decision to end life by VSED is emotionally and ethically challenging for patients, family members and clinicians. Each VSED story is unique, and the individual perspectives within a single story may diverge, conflict, and evolve over time. The narratives differ substantially in the range of suffering described, from acute, graphic, physical symptoms to primarily anticipatory and psychological distress. The narrators' conclusions about the meaning of VSED also vary, some perceiving it to be an irrational act of suicide, others describing it as an affirmation of personal autonomy, and most with a mixture of sometimes conflicting reactions in between these edges. The authors conclude with observations drawn from the narratives about the potential in VSED for benefit, harm and conflict for all involved. PMID- 27763401 TI - Merits, Demands, and Challenges of VSED. AB - VSED demands willful determination from those who do it. The requisite willfulness is an ethical strength, providing greater assurance of voluntariness. Dying by VSED has another major merit: its pace provides time for the person and loved ones to embrace death in a shared appreciation of life. Support from professional caregivers is important in making dying by VSED comfortable. If acknowledged by its providers, this need for professional support has ancillary benefits: accurate information is more likely to be communicated to patients, and professional caregivers help normalize VSED and minimize abuses. VSED faces a moral challenge when it is categorized as suicide. In an obvious sense, VSED is suicide: the person's intention is to die, and the means employed assuredly causes death. Being a form of suicide does not imply that VSED is morally impermissible. Pursued to hasten death in a last stage of life, it is a response to "terminal" situations. This contributes greatly to VSED's moral acceptability when perceived as suicide. PMID- 27763402 TI - A Qualitative Study of US Clinical Ethics Services: Objectives and Outcomes. AB - The quality of clinical ethics services in health care organizations is increasingly seen as an important aspect of the overall quality of care. But measuring this quality is difficult because there is a lack of clarity and consensus regarding the objectives of clinical ethics and the best outcome domains to measure. The aim of this qualitative study is to explore the views of experts about the objectives and outcomes of clinical ethics services in the US. We interviewed 19 experts in clinical ethics, focusing on the appropriate objectives and outcomes of a clinical ethics service (CES). Participants were selected using a purposive snowball sampling strategy. The development of the interview protocol was informed by the clinical ethics literature as well as by research and theories that inform clinical ethics practice. Interviews were conducted by phone, recorded, and transcribed for individual analysis. Analysis proceeded through the development of a codebook of categories using QDA Miner software. Our experts identified 12 objectives and nine outcomes. Some of these identifications were familiar (e.g., mediation and satisfaction) and some were novel (e.g., be of service and transformation). We found that experts are divided in their emphasis on the kinds of objectives that are most important. In terms of outcomes, our experts were concerned with the appropriateness of different proxy and direct measures. This study provides the perspectives of a select group of experts on the objectives and outcomes appropriate for a CES in the United States. The themes identified will be used in future research to inform a Delphi study to refine and obtain expert consensus. PMID- 27763403 TI - Ethical Challenges in the Care of the Inpatient with Morbid Obesity. AB - OBJECTIVE: To provide a thorough analysis of the range of ethical concerns that may present in relation to the care of the morbidly obese inpatient over the course of several years of care. METHODS: A narrative of the patient's complex medical care is given, with particular attention to the recommendations of three separate ethics committee consultations that were sought by his health care providers. An ethical analysis of the relevant issues is given within the Principles of Biomedical Ethics framework, highlighting the principles of autonomy, beneficence, non-maleficence, and justice. RESULTS: The case study presents a patient with morbid obesity, obesity hypoventilation syndrome, and numerous ICU admissions. The first ethics consultation was requested regarding the permissibility of forcing bariatric surgery on him against his will. The second consultation was regarding a request by nursing staff to no longer attempt to mobilize him. The third was regarding the patient's refusal to be discharged. CONCLUSIONS AND RECOMMENDATIONS: The care of inpatients with morbid obesity presents a unique set of practical and ethical challenges to health care personnel. A disciplined approach to ethical analysis using the Principles of Biomedical Ethics framework may be helpful in dealing with these challenges. Recommendations for improvement are made for the individual and local settings, as well as nationally. PMID- 27763404 TI - Walter Odington's De etate mundi and the Pursuit of a Scientific Chronology in Medieval England. AB - This article deals with a forgotten treatise on the age of the world, written between 1308 and 1316 by Walter Odington, a monk of Evesham Abbey, otherwise known for his writings on alchemy and music theory. By tracing the sources and rationale behind Odington's arguments and comparing them with those of other medieval authors, the article attempts to shed new light on the state of chronological scholarship in England in the eleventh to fourteenth centuries, when astronomical and astrological methods were freely used to supplement or replace scriptural interpretation, yielding creative and unexpected results. PMID- 27763405 TI - Land and Nation: The Ancient Modernity of National Geography (Piedmont, 1750 1800). AB - This paper focuses on the shift that occurred in the spatial representation of states in the eighteenth century. This shift will be considered as a combination of institutional reforms and of a new social awareness of space. A consideration of the case of the Italian Piedmont will demonstrate how "national" space was created through antiquarian research and how a larger political confrontation took place in the guise of a learned debate. The diverse accounts of Piedmontese history under examination all employed methods derived from previous ages, relying upon a concept of space as historically continuous, embedded in time immemorial. PMID- 27763406 TI - John Adams's Montesquieuean Moment: Enlightened Historicism in the Discourses on Davila. AB - At the outset of the French Revolution John Adams penned a series of Discourses of Davila, philosophical ruminations on the sixteenth-century French Wars of Religion. Recent historians have read these Discourses in terms of Adams's Machiavellianism-his conviction that men's passions lead to violence, if unrestrained. But this reading overlooks the extent to which Adams intended his Discourses as a particular investigation into the French nation's character, and into whether the revolutionaries could lay claim to a native, French tradition of mixed constitutional government. Situating the Discourses vis-a-vis Adams's contemporaneous reading of Montesquieu, this article argues for an underappreciated historicist dimension to his thought. PMID- 27763407 TI - Empiricism and Rationalism in Nineteenth-Century Histories of Philosophy. AB - This paper traces the ancestry of a familiar historiographical narrative, according to which early modern philosophy was marked by the development of empiricism, rationalism, and their synthesis by Kant. It is often claimed that this narrative became standard in the nineteenth century because of the influence of Thomas Reid, Kant and his disciples, or German and British idealists. I argue that the narrative became standard at the turn of the twentieth century. Among the factors that allowed it to become standard are its aptness to be adopted by philosophers of the most diverse persuasions, its simplicity and suitability for teaching. PMID- 27763408 TI - A Contingent Affinity: Max Weber, Carl Schmitt, and the Challenge of Modern Politics. AB - The thesis that the theory of charismatic-plebiscitary democracy developed by Max Weber in the wake of the Weimar Republic was developed to its ultimate consequences by Carl Schmitt in the final crisis of Weimar has been hotly debated since it was first advanced in the 1950s. This paper proposes a fresh look at the controversy. By comparing both authors' concepts of politics in their relation to the problem of modernity, it argues that the Weber-Schmitt affair is neither a baseless legend nor a case of natural continuity. Instead, it should rather be understood in terms of a contingent affinity. PMID- 27763409 TI - Big is a Thing of the Past: Climate Change and Methodology in the History of Ideas. AB - The climate crisis has raised questions about the proper scale of historical analysis in the Anthropocene. After explaining how this methodological crisis differs from an earlier stand-off between proponents of microhistory and total history, this paper suggests a role for intellectual history in moving us beyond the current debate. What is needed is a history of "scaling"; that is, we need to historicize the process of mediating between different frameworks of measurement, even those that might at first appear incommensurable. Historical examples are explored in which such a process of commensuration has allowed for a pluralism of perceptions of space and time. PMID- 27763410 TI - Dialogue, Eurocentrism, and Comparative Political Theory: A View from Cross Cultural Intellectual History. AB - Comparative political theory is an emerging sub-field of political theory; it is a response to the dissatisfaction with the prevalent Eurocentric mode of political theorizing in the age of globalization. A methodological characteristic of comparative political theory is cross-cultural engagement through dialogue with foreign political ideas. The present paper argues that the dialogical mode of cross-cultural engagement is distinctively European. While the dialogical engagement with foreign worldviews constitutes a mainstream of the European literary tradition, it is largely absent, for example, from the Japanese counterpart. Despite its anti-Eurocentric motivations, comparative political theory is methodologically rooted in the European tradition. PMID- 27763413 TI - Searching beyond the Medical Heritage Library: An Analytic Bibliography of On Line Neo-Latin Texts http://www.philological.bham.ac. k/. PMID- 27763414 TI - Website Review: Nursing Clio http://nursingclio.org/. PMID- 27763418 TI - Narrative Symposium: Political Influence on Bioethical Deliberation. PMID- 27763421 TI - Nonegalitarian Social Responsibility for Health: A Confucian Perspective on Article 14 of the UNESCO Declaration on Bioethics and Human Rights. AB - This essay offers a Confucian evaluation of Article 14 of the UNESCO Declaration on Bioethics and Human Rights, with a focus given to its statement that "the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being." It indicates that "a right to health" contained in the statement is open to two different interpretations, one radically egalitarian, another a decent minimum. It shows that Confucianism has strong moral considerations to reject the radical egalitarian interpretation, and argues that a Confucian nonegalitarian health distribution ethics of differentiated and graded love and obligation can reasonably be supported with a right to the decent minimum of health at the international level. PMID- 27763424 TI - Editorial Special Issue Journal of Health Care for Poor and Underserved, Indigenous Oral Health. PMID- 27763425 TI - American Indian and Alaska Native Access to Oral Health Care: A Potential Solution. AB - : American Indians and Alaska Natives (AI/AN) experience significant health disparities relative to the general U.S. POPULATION: In particular, oral diseases affect the majority of the AI/AN population and their prevalence is significantly greater than observed in other demographic sectors of the U.S. POPULATION: The reasons for these disparities are multiple but lack of access to dental care is clearly a contributing factor. The dentist-to-population ratio in many AI/AN communities is less than half the U.S. average. A solution has been developed in Alaska by AI/AN leaders: dental therapists, i.e., local people trained for two years to provide basic dental services. This solution is being fought by organized dentistry that sees the approach as an economic threat, but AI/AN organizations are committed to implementing this Native solution to their access problem. The Alaska experience indicates that access to oral health services can be improved through the addition of dental therapists to the dental team. PMID- 27763426 TI - Historical Consequences of Colonialism, Disempowerment, and Reactionary Government Decisions in Relation to Imprisonment Rates in Australia's Northern Territory: A Potential Solution. AB - The Northern Territory (N.T.) of Australia has the highest imprisonment rate per capita in the country. The vast majority of prisoners (86%) are Indigenous Australian despite only 30% of the N.T. population identifying as Indigenous. This paper investigates factors influencing this over-representation. The most common reason for imprisonment concerns violence. Alcohol is consumed in high quantities, particularly in Central Australia and is thought to affect incarceration rates. Recent strategies to control alcohol abuse in the N.T. have been ineffective in comparison with other states of Australia. Notwithstanding that crimes committed are serious enough to warrant arrest, the cumulative effects of past and recent history have resulted in poor educational outcomes for Indigenous Australian children which influence employment opportunities. Solutions to reduce imprisonment must address the nexus between education, meaningful employment and community-led alcohol management strategies. Failure to adopt this approach may perpetuate ever-increasing imprisonment of Indigenous Australians. PMID- 27763427 TI - Historical Factors, Discrimination and Oral Health among Aboriginal Australians. AB - Discrimination is a very real facet of Australian Aboriginal and Torres Strait Islander (ATSI) life. Paradies has detailed the strong links between racism and chronic stress and the influence this may have on general health, confounding the pre-supposed notion that ATSI populations are more genetically predisposed to chronic diseases. For example a genetic predisposition promoting central adipose storage in populations with recent (in evolutionary terms) changes to hunter gatherer dietary patterns is thought to contribute to the higher rates of diabetes seen in ATSI and other Native populations. This relationship, however, is far from causal in any straight-forward way. In support of the work by Paradies, research from the U.S. also shows that racism, both explicit and subtle, contributes to chronic disease and suffering among ethnic minorities. While the exploration of the perceived or self-reported racial discrimination is recent, this concept has increasing evidence to support its relationship to poor health outcomes. PMID- 27763428 TI - Developing a Sustainable Model of Oral Health Care for Disadvantaged Aboriginal People Living in Rural and Remote Communities in NSW, Using Collective Impact Methodology. AB - A sustainable model of oral health care for disadvantaged Aboriginal people living in rural and remote communities in New South Wales was developed using collective impact methodology. Collective impact is a structured process which draws together organizations to develop a shared agenda and design solutions which are jointly resourced, measured and reported upon. PMID- 27763429 TI - Quality Improvement: Indigenous Influence in Oral Health Policy, Process, and Practice. AB - A Quality Improvement Group for Maori oral health providers [Indigenous New Zealand oral health services] has been an effective and necessary mechanism for engaging Indigenous oral health expertise in decision-making for Indigenous oral health policy and sector developments to reduce oral health inequalities and improve Indigenous oral health outcomes. PMID- 27763430 TI - Nganampa Health Council Dental Program: Remote Dentistry in the Australian Desert Partnership or Perish. AB - The Nganampa Health Council (literally "Our Health Council") is an Aboriginal community-controlled Primary Health Care service established in 1983. It was born out of the political struggle for Aboriginal Land Rights in South Australia which culminated in The Anangu Pitjantjatjara Yankunytjatjara (APY) Land Rights Act, 1981, a milestone in Indigenous Land Rights both in Australia and internationally. PMID- 27763432 TI - Income as a Protective Factor for Dental Caries among Indigenous People from Central Brazil. AB - The objective of this paper was to evaluate the association between eligibility for a conditional cash transfer program, based on household income, and dental caries in 12-year-old children from three Indigenous ethnic groups living in Mato Grosso do Sul state, Central Brazil. A population-based cross-sectional study was performed in three ethnic groups: Kaiwoa, Guarani, and Terena. The study population was drawn by stratified sampling according to each ethnic group with a probability proportional to the village size. The number of untreated decayed permanent teeth as a count variable was the outcome measure. Ethnic group and eligibility for the conditional cash transfer program showed significant association with untreated caries. Children from Guarani and Terena presented respectively two-fold and 2.8-fold higher caries rate (p<.001) compared with Kaiwoa in the adjusted model, while children from no eligible cash transfer program households had a 40% lower caries rate (p=.034). PMID- 27763431 TI - Factors Associated with Routine Dental Attendance among Aboriginal Australians. AB - OBJECTIVES: To determine factors associated with routine dental attendance in Aboriginal Australians. METHODS: Data of 271 Aboriginal adults residing in Australia's Northern Territory were used. Routine dental attendance was defined as last visiting a dentist less than one year ago or visiting a dentist for a check-up. Both bivariate and multivariable analytical techniques were used. RESULTS: While 27% visited a dentist in the past year, 29% of these visited for a check-up. In bivariate analysis, being female, low psychological distress, and low clinical attachment loss (CAL) were associated with visiting a dentist within last year. Being aged younger than 39 years, male, no oral health impairment, being caries-free, low CAL, and low apolipoprotein B were associated with visiting for a check-up. Clinical attachment loss remained associated with visiting a dentist less than one year ago while being younger than 39 years and having no oral health impairment remained associated with usually visiting for a check-up in multivariable analysis. CONCLUSIONS: Younger age, no oral health impairment, and low CAL were associated with routine dental attendance among Indigenous Australians. PMID- 27763433 TI - Service Use and Perceived Need among an Aboriginal Population in Western Australia. AB - : Limited information is available about dental service use, perceived need and perceived oral health status among Aboriginal populations in Western Australia. This study collected information from a convenience sample of people attending the opening ceremony of the 2014 National Aborigines and Islanders Day Observance Committee celebrations in Perth, Western Australia. METHODS: People who visited the Dental Health Services display stall at the event completed a questionnaire on dental service use, perceived need and self-rated oral health domains. RESULTS: Participants provided 145 usable questionnaires; 75% of the sample identified themselves as Aboriginal/Torres Strait Islander of whom 45% had a dental visit less than 12 months ago; 33% had a check-up visit and 25% rated their oral health as fair or poor. CONCLUSIONS: More Aboriginal respondents reported lower frequency of service use and asymptomatic visiting compared with non-Aboriginal respondents. PMID- 27763434 TI - Tikanga Maori (Maori Customary Practices) in Oral Health Research. AB - : Early childhood caries is a global health issue for Indigenous populations. The study, "Reducing disease burden and health inequalities arising from chronic dental disease among Indigenous children: an early childhood caries intervention," is being conducted in Australia, Canada, and Aotearoa/New Zealand. OBJECTIVE: To conduct the research in New Zealand using a kaupapa Maori (Maori philosophy) approach. METHODS: This is a mixed-method study incorporating quantitative and qualitative data whilst acknowledging Maori cultural practices by the utilization of Te Whare Tapa Wha, a model for Maori health and well-being. RESULTS: This paper describes the application of the four dimensions of this model, (spiritual, mental, physical and family dimensions) within the research activity. CONCLUSION: Health research projects that are undertaken with Indigenous populations must ensure that the research process embraces Indigenous cultural practices. In Aotearoa/New Zealand Maori leadership over the research process ensures meaningful and beneficial outcomes for the Maori Indigenous population. PMID- 27763435 TI - Changes in Area-level Socioeconomic Status and Oral Health of Indigenous Australian Children. AB - OBJECTIVE: Dental diseases have shown to be influenced by area-level socioeconomic status. This study aims to assess the effects of change in area level SES on the oral health of Australian Indigenous children. METHODS: Data were collected from a national surveillance survey for children's dental health at two points of time (2000-2002/2007-2010). The study examines caries experienced by area-level SES and whether changes in area-level SES (stable-high, upwardly-mobile, downwardly-mobile and stable low) affects caries experience. RESULTS: Dental caries in both the deciduous and permanent dentition increased significantly among Indigenous children during the study period. In stable low SES areas, the experience of decayed, missing and overall dmft/DMFT in both dentitions was highest compared with other groups at both Time 1(2.15 vs 1.61, 1.77, 1.87 and 0.86 vs 0.55, 0.67, 0.70 respectively) and Time 2 (3.23 vs 2.08, 2.17, 2.02 and 1.49 vs 1.18, 1.21 respectively). CONCLUSION: A change in area level SES was associated with experience of dental disease among Indigenous Australian children. PMID- 27763436 TI - Fidelity of Motivational Interviewing in an Early Childhood Caries Intervention Involving Indigenous Australian Mothers. AB - OBJECTIVES: This paper assessed the fidelity of an early childhood caries MI intervention among Aboriginal mothers in South Australia. METHODS: Four MI trained staff delivered the intervention and all interviews were recorded. A randomly selected subset (n = 164, 41.2%) were tested for MI fidelity using the Motivational Interviewing Treatment Integrity (MITI) code 3.1.1. A further randomly selected 20 taped sessions were additionally scored by an external expert to assess external reliability. RESULTS: Mean scores for evocation, collaboration, autonomy/support, direction and empathy ranged from 3.5 (95% CI 3.4-3.7) to 4.1 (95% CI 4.0-4.2). The mean global score was 3.8 (95% 3.7-3.9). The Reflection:Question ratio was 0.9 (95% CI 0.8-1.0), % Open-ended Questions was 54.9 (95% CI 50.0-59.8), % Complex Reflections was 54.0 (95% CI 50.5-57.5) and % MI-adherent statements was 95.0 (95% CI 92.0-98.0). Inter-assessor reliability was high. CONCLUSIONS: Beginner to expert competency in fidelity to the MI model was observed. PMID- 27763437 TI - Oral Health Status of the Veddas-Sri Lankan Indigenous People. AB - Sri Lanka's Veddas/Vanniya-laeto, are a small Indigenous group today with little information on their oral health status. This report is to provide an overview on oral health status of Veddas. Oral health status was recorded by the principal investigator after obtaining consent, using World Health Organization criteria, at an initial screening point before sending the person for any necessary treatment. Total participants were 194: 78% were males>35 years. Mean decayed, missing, filled teeth was 0.9 and 3% had pockets <3.5mm. Three had oral potentially malignant disorders (OPMDs), while three were treated for oral cancer. While the prevalence of dental caries and periodontal conditions was low, oral cancer and OPMDs is a serious concern. The Veddas have a culturally specific health system based on herbal medicinal knowledge. Thus, it is challenging to introduce and implement a preventive and curative oral health care system that would be culturally acceptable to this community. PMID- 27763438 TI - Factors Relating to Access to Dental Care for Indigenous South Australians. AB - OBJECTIVE: To explore and document self-reported factors contributing to Indigenous Australians' attendance and non-attendance at South Australian public dental clinics. METHODS: Semi-structured interviews were conducted with people (18 males and 26 females) referred for oral care through the Aboriginal Liaison Program of the South Australian Dental Service. Thematic analysis was performed on 44 transcribed conversations and a conceptual model developed. RESULTS: Persons completing all recommended treatment reported high self-efficacy, health literacy, social cohesion and previous use of dental services and presence of a health advocate. Those completing some recommended treatment reported achieving desired oral health outcome of relief of pain or system-level barriers to completion. Those reporting accessing no dental treatment in contrast reported varied and complex barriers to dental care. CONCLUSION AND IMPLICATIONS: Differences in both individual and health service-related factors were evident. Individual-level factors related to health literacy, self-efficacy, and social control. Service factors related to availability of an advocate, service delivery, and culture. Practical service-level changes may alleviate the effects of individual-level factors. PMID- 27763439 TI - Inequalities in Tooth Decay in Australian Children by Neighbourhood Characteristics and Indigenous Status. AB - OBJECTIVE: Tooth decay is related to poverty, measured at individual and neighbourhood levels. It is however uncertain if living in an advantaged neighbourhood reduces tooth decay similarly in Australian Indigenous and non Indigenous children. METHODS: This study describes tooth decay by neighbourhood characteristics and Indigenous status, and examines inequalities by Indigenous status. RESULTS: In deciduous dentition the percentage of children with tooth decay and untreated decay decreased on average 26% and 20% respectively in the non-Indigenous sample from poor to affluent neighbourhoods. In Indigenous children tooth decay and untreated decay decreased on average 6% and 8%, respectively, from poor to affluent neighbourhoods. CONCLUSION: While all children from affluent areas had less tooth decay, the gap between non-Indigenous and Indigenous children remained significant across neighbourhood characteristics. This suggests that both universal and targeted prevention programs should be considered for all Indigenous children irrespective of where they live. PMID- 27763441 TI - Oral Health Impact among Rural-dwelling Indigenous Adults in South Australia. AB - AIMS: The aim of this study was to describe the impact of oral health conditions among a convenience sample of Indigenous Australian adults and compare findings with nationally representative data. METHODS: Data were obtained from the Indigenous Oral Health Literacy Project (IOHLP) based in South Australia. Nationally representative data were obtained from the National Survey of Adult Oral Health (NSAOH). The impact of oral disease was measured using the shortened form of the oral health impact profile, OHIP-14. All data were standardised by age group and sex utilising Census data. RESULTS: For each OHIP-14 measure the impact was greater for IOHLP participants. There was considerable variation in the degree of difference between IOHLP and NSAOH participants for individual OHIP 14 items. CONCLUSION: High levels of effects of oral health conditions were reported by rural-dwelling Indigenous adults. This may exacerbate the health and social disadvantage experienced by this marginalised group. PMID- 27763440 TI - Racism and Oral Health Outcomes among Pregnant Canadian Aboriginal Women. AB - This study assessed links between racism and oral health outcomes among pregnant Canadian Aboriginal women. Baseline data were analyzed for 541 First Nations (94.6%) and Metis (5.4%) women in an early childhood caries preventive trial conducted in urban and on-reserve communities in Ontario and Manitoba. One-third of participants experienced racism in the past year determined by the Measure of Indigenous Racism Experience. In logistic regressions, outcomes significantly associated with incidents of racism included: wearing dentures, off-reserve dental care, asked to pay for dental services, perceived need for preventive care, flossing more than once daily, having fewer than 21 natural teeth, fear of going to dentist, never received orthodontic treatment and perceived impact of oral conditions on quality of life. In the context of dental care, racism experienced by Aboriginal women can be a barrier to accessing services. Programs and policies should address racism's insidious effects on both mothers' and children's oral health outcomes. PMID- 27763442 TI - This Issue: Something for Almost Everybody. PMID- 27763443 TI - Annual Index 2015-2016. PMID- 27763444 TI - Partnership with the Confederated Salish and Kootenai Tribes: Establishing an Advisory Committee for Pharmacogenetic Research. PMID- 27763453 TI - Erratum. PMID- 27763454 TI - Note from the Editor. PMID- 27763455 TI - Dr. Virgilio Licona-A Crusader for Health and Social Justice. PMID- 27763456 TI - Integration of Clinical Pharmacist Services into an Underserved Primary Care Clinic Utilizing an Interprofessional Collaborative Practice Model. AB - This report describes the role of a clinical pharmacist serving onsite in an interprofessional collaborative practice care model at an urban underserved primary care clinic. It also overviews current health care legislative policy as it relates to expanding pharmacists roles as an integrated team member in medically underserved, vulnerable populations. PMID- 27763457 TI - Implementing Community Engagement as a Mission at the David Geffen School of Medicine at the University of California, Los Angeles. AB - This manuscript describes the development and implementation of community engagement as a mission at UCLA's David Geffen School of Medicine (DGSOM) and UCLA Health System, and summarizes survey results documenting existing community engaged projects and interest between 2010 to 2013. PMID- 27763458 TI - Reducing Medical School Admissions Disparities in an Era of Legal Restrictions: Adjusting for Applicant Socioeconomic Disadvantage. AB - A diverse physician workforce is needed to increase access to care for underserved populations, particularly as the Affordable Care Act expands insurance coverage. Yet legal restrictions constrain the extent to which medical schools may use race/ethnicity in admissions decisions. We conducted simulations using academic metrics and socioeconomic data from applicants to a California public medical school from 2011 to 2013. The simulations systematically adjusted medical school applicants' academic metrics for socioeconomic disadvantage. We found that socioeconomic and under-represented minority disparities in admissions could be eliminated while maintaining academic readiness. Adjusting applicant academic metrics using socioeconomic information on medical school applications may be a race-neutral means of increasing the socioeconomic and racial/ethnic diversity of the physician workforce. PMID- 27763459 TI - A Community-Based Participatory Research on Smoking Cessation Intervention for Urban Communities. AB - : Smoking disproportionally affects minority and underserved populations but only a handful of interventions tailored to these populations have demonstrated effectiveness in real-life situations. We use community-based participatory research (CBPR) to test two interventions delivered by a community-based health care center. METHODS: Participants randomly assigned to individual or group-based intervention for smoking cessation (N= 400). Both included cessation counseling and health education, a contingency behavioral program, Nicotine Replacement Therapy, and health care for other comorbidities. Smoking cessation was verified by expired carbon monoxide at the end of the program. RESULTS: No differences were observed between the two treatment modalities (8.9% and 8.6%, respectively). Those with greater attendance had 1.4 times better odds of cessation per additional session. Retention and follow up proved to be challenging with this population. PMID- 27763460 TI - Barriers to Cancer Care among American Indians and Alaska Natives. AB - INTRODUCTION: Cancer is among the leading causes of death in American Indians and Alaska Natives (AI/ANs), with rates increasing over the last two decades. Barriers in accessing cancer screening and treatment likely contribute to this situation. METHODS: We administered structured clinical interviews and conducted descriptive and multiple linear regression analyses of demographic, health, spiritual, and treatment factors associated with self-reported barriers to cancer care among 143 adult AI/AN oncology patients. RESULTS: High levels of satisfaction with cancer care, older age, positive mental health quality of life, and positive physical health quality of life were all significantly associated with lower scores for cancer care barriers, explaining 27% of the total model variance. CONCLUSION: Addressing barriers to cancer care might help to reduce health disparities among AI/AN oncology patients. Future research should determine whether reducing barriers improves engagement with cancer treatment and overall health outcomes. PMID- 27763461 TI - Institutional Alliances to Reduce Cancer Disparities in Chicago. AB - A partnership formed between Northeastern Illinois University (NEIU) and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University sought to address well-documented cancer health disparities in Chicago by developing a collaborative research, training, and educational infrastructure between a minority-serving institution and a National Cancer Institute designated comprehensive cancer center. With a critical examination of partnership documentation and outputs, we describe the partnership's community-engaged approaches, challenges, and lessons learned. Northeastern Illinois University and the Lurie Cancer Center engaged in a yearlong partnership-building phase, identified interdisciplinary research teams, formed a governance structure, and identified collective aims. Partnership outcomes included funded inter institutional research projects, new curriculum, and an annual research trainee program. Significant challenges faced included uncertain fiscal climate, widespread turnover, and dissimilar institutional demands. Lessons learned from this minority serving institution and comprehensive cancer center partnership may be useful for bridging distinct academic communities in the pursuit of ameliorating health disparities. PMID- 27763463 TI - Ideological vs. Instrumental Barriers to Accessing Formal Mental Health care in the Developing World: Focus on South-eastern Nigeria. AB - The striking gaps in formal mental health care in the developing world are largely traceable to Instrumental and Ideological Barriers. Focusing on south eastern Nigeria, the study aimed to establish the relative weight, significance and determinants of these barriers for prioritised policy interventions. Multistage sampling method was used to select participants (n = 706) to whom questionnaires were administered. Ideological Barriers (cultural and mental health literacy constraints) were more significantly perceived (84.8%) than Instrumental Barriers (systemic and financial impediments) (56.6%). The study demonstrated the primacy of improved knowledge in plugging the gap in conventional mental health care in a region ironically defined more by systemic and material poverty. This is instructive for prioritised policy interventions with an indication that even if facilities and socio-economic status improve, services will likely be underused without greater improvement in people's conceptualisation of mental illness. It equally underscored the need for cultural competence in mental health service provision. PMID- 27763464 TI - The Social Context of Substance Use and Perceived Risk among Rhode Island Urban Minority Adolescents. AB - Our qualitative study examined how stresses of daily life affected substance use and perceived risk among Black and Hispanic adolescents. We conducted 11 focus groups with students aged 13-25 in public and alternative schools in Providence, Rhode Island, using Bourdieu's Social Practice theoretical approach to guide questioning and data analysis. Despite participants' frequent marijuana use, they perceived the emphasis society places on substance use as misguided, obfuscating the persistence of more critical problems such as stress and reduced opportunity resulting from neighborhood violence, poor schools, financial difficulties, and home troubles. Drug use appeared not to be a catalyst but a response. Our findings underscore the need for prevention strategies to address systemic racism and structural conditions limiting opportunities in young people's lives. Planners should explore adolescents' pragmatic decision-making contexts and ways that social, health, and community resources can together contribute to conditions where adolescents have opportunities to make healthful choices. PMID- 27763462 TI - Black Americans and Incarceration: A Neglected Public Health Opportunity for HIV Risk Reduction. AB - Black Americans are incarcerated at disproportionate rates, largely due to racial differences in the application of drug laws. Human immunodeficiency virus (HIV) prevalence rates among Black Americans are also disproportionately high. Moreover, availability of and access to HIV prevention services in correctional settings are limited. Recognizing that Blacks are at an elevated risk of contracting HIV, and that incarceration worsens health outcomes, this paper addresses the importance of implementing comprehensive prison-based HIV programs and prevention interventions to improve the health of this vulnerable population. In the absence of a vaccine, prevention interventions can serve as an effective method of systematically addressing HIV-related health disparities. Prevention strategies offered within correctional settings provide a unique opportunity to engage a high-risk population when its members may be receptive to behavior modification. PMID- 27763465 TI - Utility of Respondent Driven Sampling to Reach Disadvantaged Emerging Adults for Assessment of Substance Use, Weight, and Sexual Behaviors. AB - Emerging adulthood often entails heightened risk-taking with potential life-long consequences, and research on risk behaviors is needed to guide prevention programming, particularly in under-served and difficult to reach populations. This study evaluated the utility of Respondent Driven Sampling (RDS), a peer driven methodology that corrects limitations of snowball sampling, to reach at risk African American emerging adults from disadvantaged urban communities. Initial "seed" participants from the target group recruited peers, who then recruited their peers in an iterative process (110 males, 234 females; M age = 18.86 years). Structured field interviews assessed common health risk factors, including substance use, overweight/obesity, and sexual behaviors. Established gender-and age-related associations with risk factors were replicated, and sample risk profiles and prevalence estimates compared favorably with matched samples from representative U.S. national surveys. Findings supported the use of RDS as a sampling method and grassroots platform for research and prevention with community-dwelling risk groups. PMID- 27763466 TI - Toward Eliminating Hospice Enrollment Disparities among African Americans: A Qualitative Study. AB - Over the past decade, scholars and practitioners have called for efforts to reduce disparities in the cost and quality of end-of-life care; a key contributor to these disparities is the underuse of hospice care by African American patients. While previous studies have often relied on interviewing minority individuals who may or may not have been terminally ill, among them only few who were using hospice care services, this essay reports the findings of a grounded theory analysis of interviews with 26 African American hospice patients (n = 10) and lay caregivers (n = 16). Participants identified several barriers to hospice enrollment and reported how they were able to overcome these barriers by reframing/prioritizing cultural values and practices, creating alternative goals for hospice care, and relying on information obtained outside the formal health system. Finally, participants offered suggestions for eliminating barriers and providing salient information about hospice care to other African Americans. PMID- 27763467 TI - Hip and Knee Replacement in Safety-net Hospitals: Recognizing the Challenges. AB - Factors endemic in safety-net hospitals may breed poor outcomes in hip and knee arthroplasty. This review highlights these challenges and discusses strategies to reduce operative risk and promote better surgical outcomes. Sub-optimally managed medical co-morbidities, poverty, and substance abuse are examples of challenges common in safety-net hospital populations and are associated with poor surgical outcomes. Patient management strategies that positively affect surgical outcomes may be nonexistent, underfunded, or underused. Surgical complications frequently lead to reoperations, particularly revision arthroplasty. Revision procedures are costly, in terms of patient morbidity and financial expenditure. Safety-net institutions can ill afford the burden of caring for preventable complications following arthroplasty procedures. Prospective studies are needed to define the status of arthroplasty care and patient outcomes in U.S. safety-net hospitals. Best practices that have been shown in non-safety-net hospitals to improve outcomes may prove beneficial in safety-net hospitals. PMID- 27763468 TI - Cultural Health Assets of Somali and Oromo Refugees and Immigrants in Minnesota: Findings from a Community-Based Participatory Research Project. AB - This community-based participatory research study sought to identify the cultural health assets of the Somali and Oromo communities in one Minnesota neighborhood that could be mobilized to develop culturally appropriate health interventions. Community asset mappers conducted 76 interviews with Somali and Oromo refugees in in Minnesota regarding the cultural assets of their community. A community university data analysis team coded data for major themes. Key cultural health assets of the Somali and Oromo refugee communities revealed in this study include religion and religious beliefs, religious and cultural practices, a strong culture of sharing, interconnectedness, the prominence of oral traditions, traditional healthy eating and healthy lifestyles, traditional foods and medicine, and a strong cultural value placed on health. These cultural health assets can be used as building blocks for culturally relevant health interventions. PMID- 27763469 TI - Predictors of Adherence to Post-Polypectomy Surveillance Colonoscopy. AB - OBJECTIVE: To identify predictors of adherence with surveillance colonoscopy at a safety-net hospital. METHODS: We evaluated average-risk patients aged 50-75 with adenomas diagnosed at screening colonoscopy between 1/1/05-12/31/07. The primary outcome was on-time follow-up defined as attendance at surveillance colonoscopy within 5.5 years of screening colonoscopy. RESULTS: Among 881 patients, of whom 38% were English-speaking non-Hispanic Blacks, 38.3% attended on-time surveillance colonoscopy. In unadjusted analyses, >=3 PCP visits after baseline colonoscopy (OR 3.6 [2.5-5.0]), "adenoma" on the EMR problem list (OR 2.2 [1.6 2.9]), and Charlson Index >=1 (OR 1.4 [1.0-1.8]) were associated with adherence. "Adenoma" on the EMR problem list remained significant in multivariable analyses (aOR 1.8 [1.3-2.5]). A significant interaction was observed between ethnicity/language and PCP visits (p=.003). CONCLUSION: Many adenoma-bearing patients fail to attend surveillance colonoscopy in a safety-net setting. Adding "adenomas" to the EMR problem list improved attendance, suggesting that system level interventions can increase adherence. PMID- 27763471 TI - Fostering a Commitment to Quality: Best Practices in Safety-net Hospitals. AB - In 2007, the Martin Luther King, Jr.-Harbor Hospital (MLK-Harbor), which served a large safety-net population in South Los Angeles, closed due to quality challenges. Shortly thereafter, an agreement was made to establish a new hospital, Martin Luther King, Jr. Community Hospital (MLKCH), to serve the unmet needs of the community. To assist the newly appointed MLKCH Board of Directors in building a culture of quality, we conducted a series of interviews with five high performing hospital systems. In this report, we describe our findings. The hospitals we interviewed achieved a culture of quality by: 1) developing guiding principles that foster quality; 2) hiring and retaining personnel who are stewards of quality; 3) promoting efficient resource utilization; 4) developing a well-organized quality improvement infrastructure; and 5) cultivating integrated, patient-centric care. The institutions highlighted in this report provide important lessons for MLKCH and other safety-net institutions. PMID- 27763472 TI - Estimates of Mental Health Problems in a Vulnerable Population within a Primary Care Setting. AB - We examined the prevalence of mental disorders in a primary care setting affiliated with a large academic medical center. We also examined whether there were racial differences in mental health disorders. Patients were seeking medical care in an outpatient medical clinic; mental health data were available for them via medical records (n=767). Overall, 45% of patients had a diagnosed mental health problem; the most commonly reported form of mental disorder was depression. African Americans (OR= 1.88; CI: 1.21-2.91) were more likely than Whites to have a diagnosed mental health problem. These results suggest a strong mental health treatment need among patients seeking primary care in urban settings. The evidence garnered from this study underscores the need to detect and treat mental health problems systematically within outpatient primary care clinics that serve similarly vulnerable populations. PMID- 27763470 TI - Maintaining High Level of Care at Satellite Sickle Cell Clinics. AB - Traveling to and from university-based clinics is a major health care barrier for children with sickle cell disease in Alabama. To reduce this barrier, the University of Alabama at Birmingham (UAB) developed satellite clinics. This study seeks to determine if these satellite clinics provide a similar level of comprehensive care when compared with the university-based clinic using four surrogate markers: 1) attendance rates, 2) percentage of patients on hydroxyurea, 3) percentage of screening MRIs obtained, and 4) percentage of transcranial dopplers (TCD) completed. A retrospective review of sickle cell visits from June 1, 2012 to May 31, 2013 demonstrated that satellite clinics can provide levels of medical care for children with sickle cell disease similar to those provided by university-based clinics. PMID- 27763473 TI - Issues and Solutions for Collecting Biological Specimen in Longitudinal Studies: Experience from the Community Child Health Network Research Network. AB - The inclusion of biomarkers in studies of stress and health outcomes is of growing interest, including for community-based participatory research (CBPR) studies. Yet the perspectives of participants and communities have been infrequently consulted to inform the biomarker collection process. The objective of this paper is to describe the process and outcomes of using CBPR in framing biomarker collection in a study of allostatic load in a maternal and child health population. Through analysis of focus group data, we identify aspects of CBPR that facilitate increased community trust and endorsement related to collecting biological samples, and also provide a community perspective that is often overlooked in the literature. We found that a CBPR approach facilitated greater understanding among community members about the importance of biomarkers, while simultaneously informing the design of a biomarker data collection protocol that was responsive to the desired scope and data collection procedures that reflected community priorities. PMID- 27763474 TI - Engaging Patients and Caregivers to Design Transitional Care Management Services at a Minority Serving Institution. AB - Limited socioeconomic resources contribute to high readmission rates at minority serving institutions (MSIs). A better understanding of patient-level factors and need for patient navigators could inform approaches to enhance care transitions tailored to these vulnerable patient populations. We sought to understand the perspectives of patients and their caregivers about hospital to home transitions from an MSI, as well as their attitudes about patient navigators to facilitate care transitions. We conducted qualitative research using focus groups (FGs)-five disease-specific patient FGs and two caregiver FGs, including 23 patients and 10 caregivers. Findings support the need for additional services to address: (1) gaps in the hospital discharge; (2) socioeconomic resources; (3) access to post discharge care; (4) patient's health care seeking behaviors; (5) patient anxiety; (6) self-management education; and (7) social supports for patients and caregivers. While caregivers uniformly expressed interest in patient navigators, support for navigators among patients was more variable. PMID- 27763476 TI - Quality research in Indian medical colleges and teaching institutions: The need of the hour. PMID- 27763477 TI - Temporal variability of readmission determinants in postoperative vascular surgery patients. AB - INTRODUCTION: Clinical information continues to be limited regarding changes in the temporal risk profile for readmissions during the initial postoperative year in vascular surgery patients. We set out to describe the associations between demographics, clinical outcomes, comorbidity indices, and hospital readmissions in a sample of patients undergoing common extremity revascularization or dialysis access (ERDA) procedures. We hypothesized that factors independently associated with readmission will evolve from "short-term" to "long-term" determinants at 30 , 180-, and 360-day postoperative cutoff points. METHODS: Following IRB approval, medical records of patients who underwent ERDA at two institutions were retrospectively reviewed between 2008 and 2014. Abstracted data included patient demographics, procedural characteristics, the American Society of Anesthesiologists score, Goldman Criteria for perioperative cardiac assessment, the Charlson comorbidity index, morbidity, mortality, and readmission (at 30-, 180-, and 360-days). Univariate analyses were performed for readmissions at each specified time point. Variables reaching statistical significance of P< 0.20 were included in multivariate analyses for factors independently associated with readmission. RESULTS: A total of 450 of 744 patients who underwent ERDA with complete medical records were included. Patients underwent either an extremity revascularization (e.g. bypass or endarterectomy, 406/450) or a noncatheter dialysis access procedure (44/450). Sample characteristics included 262 (58.2%) females, mean age 61.4 +/- 12.9 years, 63 (14%) emergent procedures, and median operative time 164 min. Median hospital length of stay (index admission) was 4 days. Cumulative readmission rates at 30-, 180-, and 360-day were 12%, 27%, and 35%, respectively. Corresponding mortality rates were 3%, 7%, and 9%. Key factors independently associated with 30-, 180-, and 360-day readmissions evolved over the study period from comorbidity and morbidity-related issues in the short-term to cardiovascular and graft patency issues in the long-term. Any earlier readmission elevated the risk of subsequent readmission. CONCLUSIONS: We noted important patterns in the temporal behavior of hospital readmission risk in patients undergoing ERDA. Although factors independently associated with readmission were not surprising (e.g. comorbidity profile, cardiovascular status, and graft patency), the knowledge of temporal trends described in this study may help determine clinical risk profiles for individual patients and guide readmission reduction strategies. These considerations will be increasingly important in the evolving paradigm of value-based healthcare. PMID- 27763478 TI - A case-control study of epidemiological factors associated with leptospirosis in South Gujarat region. AB - BACKGROUND: The current study was planned to identify the epidemiological factors associated with leptospirosis in South Gujarat region using neighborhood controls. METHODS: A total of 100 cases of leptospirosis occurred in South Gujarat region during the year 2012 were selected using simple random sampling. Three neighbors of the selected cases formed the controls (n = 300). A pretested structured questionnaire was used for data collection and data were analyzed using Epi Info 2007. RESULTS: There was significant association of illiteracy (odds ratio [OR] =1.82, 95% confidence interval [CI] =1.14-2.89), working in waterlogged fields during the reference season (OR = 4.6, 95% CI = 1.6-17.9), swimming/bathing in canals, open air defecation practices, storage of cow dung in or surrounding house, residence in the house made up of cow dung walls, households with access of food to rodents, injuries over hands/foot during the endemic season (OR = 3, 95% CI = 1.8-4.8), and history of skin disease during the endemic season (OR = 4.2, 95% CI = 2-8.5), with leptospirosis. Only 10% of individuals had gumboots for protection. A total of 83 (83%) cases and 240 (80%) controls had taken oral doxycycline chemoprophylaxis (P > 0.05). Cases had taken chemoprophylaxis for a median 4 weeks (range: 1-8) while controls had taken the same for median 8 weeks (range = 1-8) (P < 0.002). CONCLUSIONS: Although the commonly established factors appear to be associated with leptospirosis, the role of host factors seems to play a more important role in determining susceptibility to leptospirosis in exposed individuals. PMID- 27763479 TI - An appropriately performed conventional blood culture can facilitate choice of therapy in resource-constrained settings-comparison with BACTEC 9050. AB - AIMS: Comparison of conventional blood culture with BACTEC 9050 for rate and time to detection of microorganisms. SETTINGS AND DESIGN: A prospective study was carried out in a multispecialty tertiary care teaching hospital. SUBJECTS AND METHODS: A total of 835 paired specimens (797 blood and 38 nonblood specimens) were collected and processed according to standard microbiological procedures by both conventional method as well as by BACTEC 9050 automated culture system. Clinical details of patients were recorded. Data were analyzed for time to detection and isolation rate by the two systems and compared. RESULTS: Overall culture positivity for BACTEC 9050 and the conventional system was 32% and 19.88%, respectively. Eighty-five demonstrated concordant growth, 136 specimens were culture positive by BACTEC only, and 38 specimens were culture positive by conventional only. Twelve contaminants in BACTEC and nine contaminants in conventional system were detected. Using BACTEC 9050, higher isolation was observed for Acinetobacter spp., coagulase negative Staphylococcus spp., Streptococcus spp., and Candida spp. A total of 410 patients were on antimicrobial treatment and culture positivity was significantly higher with BACTEC 9050 (P < 0.0001). There was a significant difference in the mean time to detection with BACTEC 9050 recovering 86.8% of isolates within 48 h (P < 0.0001). CONCLUSIONS: Although BACTEC 9050 demonstrated a significantly higher recovery of microorganisms from blood, an appropriately performed conventional blood culture can facilitate the choice of therapy. PMID- 27763480 TI - Chest radiographic manifestations of scrub typhus. AB - BACKGROUND AND RATIONALE: Respiratory system involvement in scrub typhus is seen in 20-72% of patients. In endemic areas, good understanding and familiarity with the various radiologic findings of scrub typhus are essential in identifying pulmonary complications. MATERIALS AND METHODS: Patients admitted to a tertiary care center with scrub typhus between October 2012 and September 2013 and had a chest X ray done were included in the analysis. Details and radiographic findings were noted and factors associated with abnormal X-rays were analyzed. RESULTS: The study cohort contained 398 patients. Common presenting complaints included fever (100%), generalized myalgia (83%), headache (65%), dyspnea (54%), cough (24.3%), and altered sensorium (14%). Almost half of the patients (49.4%) had normal chest radiographs. Common radiological pulmonary abnormalities included pleural effusion (14.6%), acute respiratory distress syndrome (14%), airspace opacity (10.5%), reticulonodular opacities (10.3%), peribronchial thickening (5.8%), and pulmonary edema (2%). Cardiomegaly was noted in 3.5% of patients. Breathlessness, presence of an eschar, platelet counts of <20,000 cells/cumm, and total serum bilirubin >2 mg/dL had the highest odds of having an abnormal chest radiograph. Patients with an abnormal chest X-ray had a higher requirement of noninvasive ventilation (odds ratio [OR]: 13.98; 95% confidence interval CI: 5.89 33.16), invasive ventilation (OR: 18.07; 95% CI: 6.42-50.88), inotropes (OR: 8.76; 95% CI: 4.35-17.62), higher involvement of other organ systems, longer duration of hospital stay (3.18 +/- 3 vs. 7.27 +/- 5.58 days; P< 0.001), and higher mortality (OR: 4.63; 95% CI: 1.54-13.85). CONCLUSION: Almost half of the patients with scrub typhus have abnormal chest radiographs. Chest radiography should be included as part of basic evaluation at presentation in patients with scrub typhus, especially in those with breathlessness, eschar, jaundice, and severe thrombocytopenia. PMID- 27763481 TI - Utility and limitations of multiplex ligation-dependent probe amplification technique in the detection of cytogenetic abnormalities in products of conception. AB - : Background and Introduction: Chromosomal abnormality is found in about half of first-trimester abortions. Karyotype is the gold standard to detect chromosomal abnormalities. Multiplex ligation-dependent probe amplification (MLPA) offers advantage over karyotype in terms of lower failure rate, faster turnaround time, and much higher resolution than conventional karyotyping and found to be 98% concordant with conventional karyotype. AIM: We performed this study to look for the utility of MLPA in diagnosing chromosomal abnormalities in first-trimester abortions. MATERIALS AND METHODS: MLPA using subtelomeric SALSA probe sets (P036 and P070) was used to detect cytogenetic abnormalities in products of conception in missed/spontaneous abortions. RESULTS: A total of ninety abortus samples were analyzed by MLPA. Successful results were provided in (67) 74.4% of the cases while no conclusion could be drawn in 25.6% (23) of the cases. Fifty-five (82.1%) cases were cytogenetically normal and 17.9% (12) had some abnormality. Aneuploidy was detected in 8 (66.7%) cases, 3 (25%) had double-segment imbalance, and one (8.3%) had partial aneuploidy. CONCLUSION: We suggest that MLPA is a good substitute to traditional karyotype. PMID- 27763482 TI - Can angiotensin-converting enzyme inhibitors impact cognitive decline in early stages of Alzheimer's disease? An overview of research evidence in the elderly patient population. AB - Alzheimer's disease (AD) is a neurodegenerative disease, in which an accumulation of toxic amyloid beta in the brain precedes the emergence of clinical symptoms. AD spectrum consists of presymptomatic, early symptomatic, and symptomatic phase of dementia. At present, no pharmacotherapy exists to modify or reverse a course of AD, and only symptomatic treatments are available. Many elderly patients, diagnosed with multiple medical conditions (such as cardiovascular diseases, Type 2 diabetes mellitus, and cerebrovascular diseases) are at increased risk of the development of mild cognitive impairment (MCI), AD, and vascular dementia. Studies have revealed reduced rates of cognitive decline, in elderly patients, who were treated with centrally active angiotensin-converting enzyme inhibitors (ACE-Is) (that have an ability to cross the blood-brain barrier). This article reviews recently published literature, focused on possible protective influence of the centrally active ACE-Is, in the elderly population, at risk for cognitive decline. PMID- 27763484 TI - Evolution of medical education in India: The impact of colonialism. AB - The cross-cultural exchanges between the people of India and their colonial rulers provides a fascinating insight into how these encounters shaped medicine and medical education in India. This article traces the history of how Indian medicine was transformed in the backdrop of colonialism and hegemony. It goes on to show how six decades after independence, we have have still been unable to convincingly shrug off the colonial yoke. India needs to work out a national medical curriculum which caters to our country's needs. A symbiotic relationship needs to be developed between the indigenous and allopathic systems of medicine. PMID- 27763483 TI - The mysterious Zika virus: Adding to the tropical flavivirus mayhem. AB - Until now, known as the demure cousin of dengue virus (DENV) inhabiting Africa, Zika virus (ZIKV) has reinvented itself to cause explosive epidemics captivating the Western hemisphere. The outbreak causing potential for ZIKV was realized when it made its way from Africa to Yap Island Micronesia in 2007, and in French Polynesia in 2013. From there, it moved on to Brazil in 2015. Now ZIKV has infected people in more than 33 countries in Central and South America and the Caribbean. Moreover the epidemiological and subsequent virological association with microcephaly cases in Brazil has prompted the World Health Organization to declare a public health emergency of International Concern. ZIKV shares not only its vector Aedes aegypti with dengue and chikungunya but also the geographic distribution and clinical features, which makes the laboratory confirmation mandatory for definitive diagnosis. The serological cross-reactivity with other Flavivirus, particularly with DENV makes laboratory confirmation challenging and will place additional burden on health systems to establish molecular diagnostic facilities. The evidence of additional nonvector modes of transmission, such as perinatal, sexual as well as transfusion has made preventative strategies more difficult. As ZIKV disease continues to mystify us with several unanswered questions, it calls for coordinated effort of global scientific community to address the ever growing arboviral threat to mankind. PMID- 27763485 TI - Wernicke's encephalopathy due to hyperemesis gravidarum: Clinical and magnetic resonance imaging characteristics. AB - Hyperemesis gravidarum-induced Wernicke's encephalopathy (WE) is an underestimated condition. The purpose of this study is to improve its awareness and early diagnosis. We report five cases of WE secondary to hyperemesis gravidarum. Classic triad of encephalopathy, ataxia, and ocular signs was seen in four out of five patients. Two unusual features noted in this series were papilledema in one patient and severe sensory-motor peripheral neuropathy in one patient. Magnetic resonance imaging (MRI) was abnormal in all the five patients, and high signal in medial thalamus and surrounding the aqueduct was the most common abnormality (5/5). Involvement of caudate nucleus was seen in two patients with severe psychosis, and two patients had bilateral cerebellar peduncle involvement. Median time delay between onset of neurological symptoms and diagnosis was 7 days. All patients improved with thiamine, but minor sequelae were seen in four patients at 12 months follow-up. One patient had a fetal demise. Hyperemesis gravidarum-induced WE is a common cause of maternal morbidity. Typical MRI findings of symmetric medial thalamic and periaqueductal signal changes may permit a specific diagnosis. A delay in diagnosis, therefore treatment, leads to worse prognosis. PMID- 27763487 TI - Obturator hernia: An uncommon cause of small bowel obstruction. AB - A 70 year old lady presented to surgery emergency with small bowel obstruction without any obvious etiology. On exploration she was found to have an obstructed obturator hernia, which is a rare pelvic hernia with an incidence of 0.07-1.4% of all intra-abdominal hernias. Diagnosis is often delayed until laparotomy for bowel obstruction. Strangulation is frequent and mortality remains high (25%). Early diagnosis and surgical treatment contributes greatly to reduce the mortality and morbidity rates. A variety of techniques have been described, however surgical repair has not been standardized. It is an important diagnosis to be considered in elderly patients with intestinal obstruction. PMID- 27763486 TI - Stroke mimic: Perfusion magnetic resonance imaging of a patient with ictal paralysis. AB - We present an uncommon case of clinically diagnosed window period stroke subsequently recognised on diffusion - perfusion MRI as ictal paralysis due to focal inhibitory seizures or negative motor seizures. This case highlights the importance of MRI with perfusion imaging in establishing the diagnosis of stroke mimics and avoiding unnecessary thrombolysis. PMID- 27763488 TI - Relapsing-remitting chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids syndrome in association with P/Q-type voltage gated calcium channel antibody. PMID- 27763489 TI - Maternal infection, malnutrition, and low birth weight. PMID- 27763490 TI - Prevalence of burnout and its correlates among residents in a tertiary medical center in Kerala, India: A cross-sectional study. PMID- 27763492 TI - Synthesis of Polymer-Lipid Nanoparticles by Microfluidic Focusing for siRNA Delivery. AB - Polyethylenimine (PEI) as a cationic polymer is commonly used as a carrier for gene delivery. PEI-800 is less toxic than PEI-25K but it is also less efficient. A novel nanocarrier was developed by combining PEI-800 with a pH-sensitive lipid to form polymer-lipid hybrid nanoparticles (P/LNPs). They were synthesized by microfluidic focusing (MF). Two microfluidic devices were used to synthesize P/LNPs loaded with VEGF siRNA. A series of P/LNPs with different particle sizes and distributions were obtained by altering the flow rate and geometry of microfluidic chips, and introducing sonication. Furthermore, the P/LNPs can be loaded with VEGF siRNA efficiently and were stable in serum for 12 h. Finally, P/LNPs produced by the microfluidic chip showed greater cellular uptake as well as down-regulation of VEGF protein level in both A549 and MCF-7 with reduced cellular toxicity. All in all, the P/LNPs produced by MF method were shown to be a safe and efficient carrier for VEGF siRNA, with potential application for siRNA therapeutics. PMID- 27763493 TI - Use of Distributed Temperature Sensing Technology to Characterize Fire Behavior. AB - We evaluated the potential of a fiber optic cable connected to distributed temperature sensing (DTS) technology to withstand wildland fire conditions and quantify fire behavior parameters. We used a custom-made 'fire cable' consisting of three optical fibers coated with three different materials-acrylate, copper and polyimide. The 150-m cable was deployed in grasslands and burned in three prescribed fires. The DTS system recorded fire cable output every three seconds and integrated temperatures every 50.6 cm. Results indicated the fire cable was physically capable of withstanding repeated rugged use. Fiber coating materials withstood temperatures up to 422 degrees C. Changes in fiber attenuation following fire were near zero (-0.81 to 0.12 dB/km) indicating essentially no change in light gain or loss as a function of distance or fire intensity over the length of the fire cable. Results indicated fire cable and DTS technology have potential to quantify fire environment parameters such as heat duration and rate of spread but additional experimentation and analysis are required to determine efficacy and response times. This study adds understanding of DTS and fire cable technology as a potential new method for characterizing fire behavior parameters at greater temporal and spatial scales. PMID- 27763494 TI - Fabrication of All-SiC Fiber-Optic Pressure Sensors for High-Temperature Applications. AB - Single-crystal silicon carbide (SiC)-based pressure sensors can be used in harsh environments, as they exhibit stable mechanical and electrical properties at elevated temperatures. A fiber-optic pressure sensor with an all-SiC sensor head was fabricated and is herein proposed. SiC sensor diaphragms were fabricated via an ultrasonic vibration mill-grinding (UVMG) method, which resulted in a small grinding force and low surface roughness. The sensor head was formed by hermetically bonding two layers of SiC using a nickel diffusion bonding method. The pressure sensor illustrated a good linearity in the range of 0.1-0.9 MPa, with a resolution of 0.27% F.S. (full scale) at room temperature. PMID- 27763496 TI - Association between Vitamin D Status and Coronary Heart Disease among Adults in Saudi Arabia: A Case-Control Study. AB - Recent evidence has pointed out an association between vitamin D deficiency and coronary heart disease (CHD). Due to the growing epidemic of CHD and vitamin D deficiency in Saudi Arabia, exploring the role of vitamin D in the prevention of CHD is crucial. The aim of this study was to examine the association between vitamin D status and CHD in Saudi Arabian adults. This case-control study included 130 CHD cases and 195 age-sex matched controls. Study subjects were recruited from three hospitals in the western region of Saudi Arabia. Study participants were interviewed face-to-face to collect data on their socio demographic characteristics and family history of CHD. Fasting blood samples were collected, and serum levels of vitamin D, glucose, and total cholesterol were measured. Body weight, height, and blood pressure measurements were also recorded. Severe vitamin D deficiency (25(OH)D < 10 ng/mL) was much more prevalent in CHD cases than in controls (46% and 3%, respectively). The results of multivariate logistic regression showed that vitamin D deficiency (25(OH)D < 20 ng/mL) was associated with CHD, with an odds ratio of 6.5 (95% CI: 2.7-15, p < 0.001). The current study revealed that vitamin D deficiency is independently associated with CHD, suggesting an important predictor of CHD among Saudi adults. PMID- 27763495 TI - Auraptene and Other Prenyloxyphenylpropanoids Suppress Microglial Activation and Dopaminergic Neuronal Cell Death in a Lipopolysaccharide-Induced Model of Parkinson's Disease. AB - In patients with Parkinson's disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7 IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4'-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD. PMID- 27763498 TI - The Disturbing Effect of the Stray Magnetic Fields on Magnetoimpedance Sensors. AB - The disturbing effect of the stray magnetic fields of Fe-based amorphous ribbons on the giant magnetoimpedance (GMI) sensor has been investigated systematically in this paper. Two simple methods were used for examining the disturbing effect of the stray magnetic fields of ribbons on the GMI sensor. In order to study the influence of the stray magnetic fields on the GMI effect, the square-shaped amorphous ribbons were tested in front, at the back, on the left and on the top of a meander-line GMI sensor made up of soft ferromagnetic films, respectively. Experimental results show that the presence of ribbons in front or at the back of GMI sensor shifts the GMI curve to a lower external magnetic field. On the contrary, the presence of ribbons on the left or on the top of the GMI sensor shifts the GMI curve to a higher external magnetic field, which is related to the coupling effect of the external magnetic field and the stray magnetic fields. The influence of the area and angle of ribbons on GMI was also studied in this work. The GMI sensor exhibits high linearity for detection of the stray magnetic fields, which has made it feasible to construct a sensitive magnetometer for detecting the typical stray magnetic fields of general soft ferromagnetic materials. PMID- 27763497 TI - Regulatory Roles of MicroRNAs in Diabetes. AB - MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological processes. Disruption of miRNA levels correlates with many diseases, including diabetes mellitus, a complex multifactorial metabolic disorder affecting >400 million people worldwide. miRNAs are involved in the pathogenesis of diabetes mellitus by affecting pancreatic beta-cell functions, insulin resistance, or both. In this review, we summarize the investigations of the regulatory roles of important miRNAs in diabetes, as well as the potential of circulating miRNAs as diagnostic markers for diabetes mellitus. PMID- 27763500 TI - Estimating Shape and Micro-Motion Parameter of Rotationally Symmetric Space Objects from the Infrared Signature. AB - Shape serves as an important additional feature for space target classification, which is complementary to those made available. Since different shapes lead to different projection functions, the projection property can be regarded as one kind of shape feature. In this work, the problem of estimating the projection function from the infrared signature of the object is addressed. We show that the projection function of any rotationally symmetric object can be approximately represented as a linear combination of some base functions. Based on this fact, the signal model of the emissivity-area product sequence is constructed, which is a particular mathematical function of the linear coefficients and micro-motion parameters. Then, the least square estimator is proposed to estimate the projection function and micro-motion parameters jointly. Experiments validate the effectiveness of the proposed method. PMID- 27763499 TI - A New Dioic Acid from a wbl Gene Mutant of Deepsea-Derived Streptomyces somaliensis SCSIO ZH66. AB - The wblAso gene functions as a global regulatory gene in a negative manner in deepsea-derived Streptomyces somaliensis SCSIO ZH66. A new dioic acid (1) as well as two known butenolides (2 and 3) were isolated from the DeltawblAso mutant strain of S. somaliensis SCSIO ZH66. The structure of 1 was elucidated by a combination of spectroscopic analyses, including MS and NMR techniques. In the cell growth inhibitory evaluation, compound 3 exhibited moderate activity against the human hepatic carcinoma cell line (Huh7.5) with an IC50 value of 19.4 MUg/mL, while compounds 1 and 2 showed null activity up to 100 MUg/mL. PMID- 27763501 TI - Generic Dynamic Environment Perception Using Smart Mobile Devices. AB - The driving environment is complex and dynamic, and the attention of the driver is continuously challenged, therefore computer based assistance achieved by processing image and sensor data may increase traffic safety. While active sensors and stereovision have the advantage of obtaining 3D data directly, monocular vision is easy to set up, and can benefit from the increasing computational power of smart mobile devices, and from the fact that almost all of them come with an embedded camera. Several driving assistance application are available for mobile devices, but they are mostly targeted for simple scenarios and a limited range of obstacle shapes and poses. This paper presents a technique for generic, shape independent real-time obstacle detection for mobile devices, based on a dynamic, free form 3D representation of the environment: the particle based occupancy grid. Images acquired in real time from the smart mobile device's camera are processed by removing the perspective effect and segmenting the resulted bird-eye view image to identify candidate obstacle areas, which are then used to update the occupancy grid. The occupancy grid tracked cells are grouped into obstacles depicted as cuboids having position, size, orientation and speed. The easy to set up system is able to reliably detect most obstacles in urban traffic, and its measurement accuracy is comparable to a stereovision system. PMID- 27763502 TI - Purification of Antioxidant Peptides by High Resolution Mass Spectrometry from Simulated Gastrointestinal Digestion Hydrolysates of Alaska Pollock (Theragra chalcogramma) Skin Collagen. AB - In this study, the stable collagen hydrolysate was prepared by alcalase hydrolysis and twice simulated gastrointestinal digestion from Alaska pollock skin. The characteristics of hydrolysates and antioxidant activities in vitro, including 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS*+) scavenging activity, ferric-reducing antioxidant power (FRAP) and hydroxyl radical (OH.) scavenging activity, were determined. After twice simulated gastrointestinal digestion of skin collagen (SGI-2), the degree of hydrolysis (DH) reached 26.17%. The main molecular weight fractions of SGI-2 were 1026.26 and 640.53 Da, accounting for 59.49% and 18.34%, respectively. Amino acid composition analysis showed that SGI-2 had high content of total hydrophobic amino acid (307.98/1000). With the simulated gastrointestinal digestion progressing, the antioxidant activities increased significantly (p < 0.05). SGI-2 was further purified by gel filtration chromatography, ion exchange chromatography and high performance liquid chromatography, and the A1a3c-p fraction with high hydroxyl radical scavenging activity (IC50 = 7.63 MUg/mL) was obtained. The molecular weights and amino acid sequences of key peptides of A1a3c p were analyzed using high resolution mass spectrometry (LC-ESI-LTQ-Orbitrap-MS) combined with de novo software and UniProt of MaxQuant software. Four peptides were identified from A1a3c-p, including YGCC (444.1137 Da) and DSSCSG (554.1642 Da) identified by de novo software and NNAEYYK (900.3978 Da) and PAGNVR (612.3344 Da) identified by UniProt of MaxQuant software. The molecular weights and amino acid sequences of four peptides were in accordance with the features of antioxidant peptides. The results indicated that different peptides were identified by different data analysis software according to spectrometry mass data. Considering the complexity of LC-ESI-LTQ-Orbitrap-MS, it was necessary to use the different methods to identify the key peptides from protein hydrolysates. PMID- 27763503 TI - Debris Evaluation after Root Canal Shaping with Rotating and Reciprocating Single File Systems. AB - This study evaluated the root canal dentine surface by scanning electron microscope (SEM) after shaping with two reciprocating single-file NiTi systems and two rotating single-file NiTi systems, in order to verify the presence/absence of the smear layer and the presence/absence of open tubules along the walls of each sample; Forty-eight single-rooted teeth were divided into four groups and shaped with OneShape (OS), F6 SkyTaper (F6), WaveOne (WO) and Reciproc and irrigated using 5.25% NaOCl and 17% EDTA. Root canal walls were analyzed by SEM at a standard magnification of 2500*. The presence/absence of the smear layer and the presence/absence of open tubules at the coronal, middle, and apical third of each canal were estimated using a five-step scale for scores. Numeric data were analyzed using Kruskal-Wallis and Mann-Whitney U statistical tests and significance was predetermined at P < 0.05; The Kruskal-Wallis ANOVA for debris score showed significant differences among the NiTi systems (P < 0.05). The Mann-Whitney test confirmed that reciprocating systems presented significantly higher score values than rotating files. The same results were assessed considering the smear layer scores. ANOVA confirmed that the apical third of the canal maintained a higher quantity of debris and smear layer after preparation of all the samples; Single-use NiTi systems used in continuous rotation appeared to be more effective than reciprocating instruments in leaving clean walls. The reciprocating systems produced more debris and smear layer than rotating instruments. PMID- 27763507 TI - Transmit Power Allocation for Physical Layer Security in Cooperative Multi-Hop Full-Duplex Relay Networks. AB - In this paper, we consider a transmit power allocation problem for secure transmission in multi-hop decode-and-forward (DF) full-duplex relay (FDR) networks, where multiple FDRs are located at each hop and perform cooperative beamforming to null out the signal at multiple eavesdroppers. For a perfect self interference cancellation (PSIC) case, where the self-interference signal at each FDR is completely canceled, we derive an optimal power allocation (OPA) strategy using the Karush-Kuhn-Tucker (KKT) conditions to maximize the achievable secrecy rate under an overall transmit power constraint. In the case where residual self interferences exist owing to imperfect self-interference cancellation (ISIC), we also propose a transmit power allocation scheme using the geometric programming (GP) method. Numerical results are presented to verify the secrecy rate performance of the proposed power allocation schemes. PMID- 27763504 TI - Neuroprotective Effect of the Marine-Derived Compound 11-Dehydrosinulariolide through DJ-1-Related Pathway in In Vitro and In Vivo Models of Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and gait impairment. In a previous study, we found that the marine-derived compound 11-dehydrosinulariolide (11-de) upregulates the Akt/PI3K pathway to protect cells against 6-hydroxydopamine (6-OHDA)-mediated damage. In the present study, SH-SY5Y, zebrafish and rats were used to examine the therapeutic effect of 11-de. The results revealed the mechanism by which 11 de exerts its therapeutic effect: the compound increases cytosolic or mitochondrial DJ-1 expression, and then activates the downstream Akt/PI3K, p CREB, and Nrf2/HO-1 pathways. Additionally, we found that 11-de could reverse the 6-OHDA-induced downregulation of total swimming distance in a zebrafish model of PD. Using a rat model of PD, we showed that a 6-OHDA-induced increase in the number of turns, and increased time spent by rats on the beam, could be reversed by 11-de treatment. Lastly, we showed that 6-OHDA-induced attenuation in tyrosine hydroxylase (TH), a dopaminergic neuronal marker, in zebrafish and rat models of PD could also be reversed by treatment with 11-de. Moreover, the patterns of DJ-1 expression observed in this study in the zebrafish and rat models of PD corroborated the trend noted in previous in vitro studies. PMID- 27763505 TI - Identification of a Pro-Angiogenic Potential and Cellular Uptake Mechanism of a LMW Highly Sulfated Fraction of Fucoidan from Ascophyllum nodosum. AB - Herein we investigate the structure/function relationships of fucoidans from Ascophyllum nodosum to analyze their pro-angiogenic effect and cellular uptake in native and glycosaminoglycan-free (GAG-free) human endothelial cells (HUVECs). Fucoidans are marine sulfated polysaccharides, which act as glycosaminoglycans mimetics. We hypothesized that the size and sulfation rate of fucoidans influence their ability to induce pro-angiogenic processes independently of GAGs. We collected two fractions of fucoidans, Low and Medium Molecular Weight Fucoidan (LMWF and MMWF, respectively) by size exclusion chromatography and characterized their composition (sulfate, fucose and uronic acid) by colorimetric measurement and Raman and FT-IR spectroscopy. The high affinities of fractionated fucoidans to heparin binding proteins were confirmed by Surface Plasmon Resonance. We evidenced that LMWF has a higher pro-angiogenic (2D-angiogenesis on Matrigel) and pro-migratory (Boyden chamber) potential on HUVECs, compared to MMWF. Interestingly, in a GAG-free HUVECs model, LMWF kept a pro-angiogenic potential. Finally, to evaluate the association of LMWF-induced biological effects and its cellular uptake, we analyzed by confocal microscopy the GAGs involvement in the internalization of a fluorescent LMWF. The fluorescent LMWF was mainly internalized through HUVEC clathrin-dependent endocytosis in which GAGs were partially involved. In conclusion, a better characterization of the relationships between the fucoidan structure and its pro-angiogenic potential in GAG-free endothelial cells was required to identify an adapted fucoidan to enhance vascular repair in ischemia. PMID- 27763506 TI - Improvement of the Pharmacological Properties of Maize RIP by Cysteine-Specific PEGylation. AB - To improve the pharmacological properties of maize ribosome-inactivating protein (maize RIP) for targeting HIV-infected cells, the previously engineered TAT-fused active form of maize RIP (MOD) was further engineered for cysteine-directed PEGylation. In this work, two potential antigenic sites, namely Lys-78 and Lys 264, were identified. They were mutated to cysteine residue and conjugated with PEG5k or PEG20k. The resultant PEG derivatives of MOD variants were examined for ribosome-inactivating activity, circulating half-life and immunogenicity. Our results showed that MOD-PEG conjugates had two- to five-fold lower biological activity compared to the wild-type. Mutation of the two sites respectively did not decrease the anti-MOD IgG and IgE level in mice, but the conjugation of PEG did dramatically reduce the antigenicity. Furthermore, pharmacokinetics studies demonstrated that attachment of PEG20k prolonged the plasma half-life by five fold for MOD-K78C and 17-fold for MOD-K264C, respectively. The site-specific mutation together with PEGylation therefore generated MOD derivatives with improved pharmacological properties. PMID- 27763508 TI - A Robust Method for Ego-Motion Estimation in Urban Environment Using Stereo Camera. AB - Visual odometry estimates the ego-motion of an agent (e.g., vehicle and robot) using image information and is a key component for autonomous vehicles and robotics. This paper proposes a robust and precise method for estimating the 6 DoF ego-motion, using a stereo rig with optical flow analysis. An objective function fitted with a set of feature points is created by establishing the mathematical relationship between optical flow, depth and camera ego-motion parameters through the camera's 3-dimensional motion and planar imaging model. Accordingly, the six motion parameters are computed by minimizing the objective function, using the iterative Levenberg-Marquard method. One of key points for visual odometry is that the feature points selected for the computation should contain inliers as much as possible. In this work, the feature points and their optical flows are initially detected by using the Kanade-Lucas-Tomasi (KLT) algorithm. A circle matching is followed to remove the outliers caused by the mismatching of the KLT algorithm. A space position constraint is imposed to filter out the moving points from the point set detected by the KLT algorithm. The Random Sample Consensus (RANSAC) algorithm is employed to further refine the feature point set, i.e., to eliminate the effects of outliers. The remaining points are tracked to estimate the ego-motion parameters in the subsequent frames. The approach presented here is tested on real traffic videos and the results prove the robustness and precision of the method. PMID- 27763509 TI - Electrochemical Selective and Simultaneous Detection of Diclofenac and Ibuprofen in Aqueous Solution Using HKUST-1 Metal-Organic Framework-Carbon Nanofiber Composite Electrode. AB - In this study, the detection protocols for the individual, selective, and simultaneous determination of ibuprofen (IBP) and diclofenac (DCF) in aqueous solutions have been developed using HKUST-1 metal-organic framework-carbon nanofiber composite (HKUST-CNF) electrode. The morphological and electrical characterization of modified composite electrode prepared by film casting was studied by scanning electronic microscopy and four-point-probe methods. The electrochemical characterization of the electrode by cyclic voltammetry (CV) was considered the reference basis for the optimization of the operating conditions for chronoamperometry (CA) and multiple-pulsed amperometry (MPA). This electrode exhibited the possibility to selectively detect IBP and DCF by simple switching the detection potential using CA. However, the MPA operated under optimum working conditions of four potential levels selected based on CV shape in relation to the potential value, pulse time, and potential level number, and order allowed the selective/simultaneous detection of IBP and DCF characterized by the enhanced detection performance. For this application, the HKUST-CNF electrode exhibited a good stability and reproducibility of the results was achieved. PMID- 27763511 TI - Hierarchical Sparse Learning with Spectral-Spatial Information for Hyperspectral Imagery Denoising. AB - During the acquisition process hyperspectral images (HSI) are inevitably corrupted by various noises, which greatly influence their visual impression and subsequent applications. In this paper, a novel Bayesian approach integrating hierarchical sparse learning and spectral-spatial information is proposed for HSI denoising. Based on the structure correlations, spectral bands with similar and continuous features are segmented into the same band-subset. To exploit local similarity, each subset is then divided into overlapping cubic patches. All patches can be regarded as consisting of clean image component, Gaussian noise component and sparse noise component. The first term is depicted by a linear combination of dictionary elements, where Gaussian process with Gamma distribution is applied to impose spatial consistency on dictionary. The last two terms are utilized to fully depict the noise characteristics. Furthermore, the sparseness of the model is adaptively manifested through Beta-Bernoulli process. Calculated by Gibbs sampler, the proposed model can directly predict the noise and dictionary without priori information of the degraded HSI. The experimental results on both synthetic and real HSI demonstrate that the proposed approach can better suppress the existing various noises and preserve the structure/spectral spatial information than the compared state-of-art approaches. PMID- 27763510 TI - Effect of Degradation of Zearalenone-Contaminated Feed by Bacillus licheniformis CK1 on Postweaning Female Piglets. AB - Zearalenone (ZEA), an estrogenic mycotoxin, is mainly produced by Fusarium fungi. In this study, Bacillus licheniformis CK1 isolated from soil with the capability of degrading ZEA was evaluated for its efficacy in reducing the adverse effects of ZEA in piglets. The gilts were fed one of the following three diets for 14 days: a basic diet for the control group; the basic diet supplemented with ZEA contaminated basic diet for the treatment 1 (T1) group; and the basic diet supplemented with fermented ZEA-contaminated basic diet by CK1 for the treatment 2 (T2) group. The actual ZEA contents (analyzed) were 0, 1.20 +/- 0.11, 0.47 +/- 0.22 mg/kg for the control, T1, and T2 diets, respectively. The results showed that the T1 group had significantly increased the size of vulva and the relative weight of reproductive organs compared to the control group at the end of the trial. The T1 group significantly decreased the concentration of the luteinizing hormone (LH) compared with the control and T2 groups. Expression of ERbeta was significantly up-regulated in the T2 group compared with the control. In addition, expression of ERbeta was not different between the control and the T1 group. In summary, our results suggest that Bacillus licheniformis CK1 could detoxify ZEA in feed and reduce the adverse effects of ZEA in the gilts. PMID- 27763512 TI - Synthesis, Properties and Stereochemistry of 2-Halo-1,2lambda5-oxaphosphetanes. AB - Results of research into four-membered 2-halo-1,2lambda5-oxaphosphetane phosphorus(V)-heterocycles are presented. The preparation of 2-halo-1,2lambda5 oxaphosphetanes by reaction of P-haloylides with carbonyl compounds is described. The mechanism of asynchronous [2+2]-sycloaddition of ylides to aldehydes was proposed on the base of low-temperature NMR investigations. 2-Halo-1,2lambda5 oxaphosphetanes were isolated as individual compounds and their structures were confirmed by 1N-, 13C-, 19F- and 31R-NMR spectra. These compounds are convenient reagents for preparing of various organic and organophosphorus compounds hardly available by other methods. Chemical and physical properties of the 2-halo 1,2lambda5-oxaphosphetanes are reviewed. The 2-chloro-1,2lambda5-oxaphosphetanes, rearrange with formation of 2-chloroalkyl-phosphonates or convert into trans phosphorylated alkenes depending on the substituents at the alpha-carbon atom. Prospective synthetic applications of 2-halo-1,2lambda5-oxaphosphetanes are analyzed. The 2-halo-1,2lambda5-oxaphosphetanes may be easily converted to various alkenylphosphonates: allyl- or vinylphosphonates, phosphorus ketenes, thioketenes, ketenimines. PMID- 27763515 TI - Analysis of the Effects of Thermal Environment on Optical Systems for Navigation Guidance and Control in Supersonic Aircraft Based on Empirical Equations. AB - The thermal environment is an important factor in the design of optical systems. This study investigated the thermal analysis technology of optical systems for navigation guidance and control in supersonic aircraft by developing empirical equations for the front temperature gradient and rear thermal diffusion distance, and for basic factors such as flying parameters and the structure of the optical system. Finite element analysis (FEA) was used to study the relationship between flying and front dome parameters and the system temperature field. Systematic deduction was then conducted based on the effects of the temperature field on the physical geometry and ray tracing performance of the front dome and rear optical lenses, by deriving the relational expressions between the system temperature field and the spot size and positioning precision of the rear optical lens. The optical systems used for navigation guidance and control in supersonic aircraft when the flight speed is in the range of 1-5 Ma were analysed using the derived equations. Using this new method it was possible to control the precision within 10% when considering the light spot received by the four-quadrant detector, and computation time was reduced compared with the traditional method of separately analysing the temperature field of the front dome and rear optical lens using FEA. Thus, the method can effectively increase the efficiency of parameter analysis and computation in an airborne optical system, facilitating the systematic, effective and integrated thermal analysis of airborne optical systems for navigation guidance and control. PMID- 27763514 TI - Gene Regulation and Quality Control in Murine Polyomavirus Infection. AB - Murine polyomavirus (MPyV) infects mouse cells and is highly oncogenic in immunocompromised hosts and in other rodents. Its genome is a small, circular DNA molecule of just over 5000 base pairs and it encodes only seven polypeptides. While seemingly simply organized, this virus has adopted an unusual genome structure and some unusual uses of cellular quality control pathways that, together, allow an amazingly complex and varied pattern of gene regulation. In this review we discuss how MPyV leverages these various pathways to control its life cycle. PMID- 27763513 TI - A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives. AB - Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several measures of risk estimation were developed for predicting clinical course in MS, but none is specific for the PMS forms. Personalized medicine is a therapeutic approach, based on identifying what might be the best therapy for an individual patient, taking into account the risk profile. We need to achieve more accurate estimates of useful predictors in PMS, including unconventional and qualitative markers which are not yet currently available or practicable routine diagnostics. The evaluation of an individual patient is based on the profile of disease activity.Within the neurology field, PMS is one of the fastest-moving going into the future. PMID- 27763516 TI - Transcriptome Profile Reveals that Pu-Erh Tea Represses the Expression of Vitellogenin Family to Reduce Fat Accumulation in Caenorhabditis elegans. AB - Due to misbalanced energy surplus and expenditure, obesity has become a common chronic disorder that is highly associated with many metabolic diseases. Pu-erh tea, a traditional Chinese beverage, has been believed to have numerous health benefits, such as anti-obesity. However, the underlying mechanisms of its anti obesity effect are yet to be understood. Here, we take the advantages of transcriptional profile by RNA sequencing (RNA-Seq) to view the global gene expression of Pu-erh tea. The model organism Caenorhabditis elegans was treated with different concentrations of Pu-erh tea water extract (PTE, 0 g/mL, 0.025 g/mL, and 0.05 g/mL). Compared with the control, PTE indeed decreases lipid droplets size and fat accumulation. The high-throughput RNA-Sequence technique detected 18073 and 18105 genes expressed in 0.025 g/mL and 0.05 g/mL PTE treated groups, respectively. Interestingly, the expression of the vitellogenin family (vit-1, vit-2, vit-3, vit-4 and vit-5) was significantly decreased by PTE, which was validated by qPCR analysis. Furthermore, vit-1(ok2616), vit-3(ok2348) and vit 5(ok3239) mutants are insensitive to PTE triggered fat reduction. In conclusion, our transcriptional profile by RNA-Sequence suggests that Pu-erh tea lowers the fat accumulation primarily through repression of the expression of vit(vitellogenin) family, in addition to our previously reported (sterol regulatory element binding protein) SREBP-SCD (stearoyl-CoA desaturase) axis. PMID- 27763517 TI - Practical Recommendations for Diagnosis and Management of Respiratory Muscle Weakness in Late-Onset Pompe Disease. AB - Pompe disease is an autosomal-recessive lysosomal storage disorder characterized by progressive myopathy with proximal muscle weakness, respiratory muscle dysfunction, and cardiomyopathy (in infants only). In patients with juvenile or adult disease onset, respiratory muscle weakness may decline more rapidly than overall neurological disability. Sleep-disordered breathing, daytime hypercapnia, and the need for nocturnal ventilation eventually evolve in most patients. Additionally, respiratory muscle weakness leads to decreased cough and impaired airway clearance, increasing the risk of acute respiratory illness. Progressive respiratory muscle weakness is a major cause of morbidity and mortality in late onset Pompe disease even if enzyme replacement therapy has been established. Practical knowledge of how to detect, monitor and manage respiratory muscle involvement is crucial for optimal patient care. A multidisciplinary approach combining the expertise of neurologists, pulmonologists, and intensive care specialists is needed. Based on the authors' own experience in over 200 patients, this article conveys expert recommendations for the diagnosis and management of respiratory muscle weakness and its sequelae in late-onset Pompe disease. PMID- 27763519 TI - Segmental Aging Underlies the Development of a Parkinson Phenotype in the AS/AGU Rat. AB - There is a paucity of information on the molecular biology of aging processes in the brain. We have used biomarkers of aging (SA beta-Gal, p16Ink4a, Sirt5, Sirt6, and Sirt7) to demonstrate the presence of an accelerated aging phenotype across different brain regions in the AS/AGU rat, a spontaneous Parkinsonian mutant of PKCgamma derived from a parental AS strain. P16INK4a expression was significantly higher in AS/AGU animals compared to age-matched AS controls (p < 0.001) and displayed segmental expression across various brain regions. The age-related expression of sirtuins similarly showed differences between strains and between brain regions. Our data clearly show segmental aging processes within the rat brain, and that these are accelerated in the AS/AGU mutant. The accelerated aging, Parkinsonian phenotype, and disruption to dopamine signalling in the basal ganglia in AS/AGU rats, suggests that this rat strain represents a useful model for studies of development and progression of Parkinson's disease in the context of biological aging and may offer unique mechanistic insights into the biology of aging. PMID- 27763520 TI - Design, Synthesis and Antifungal Activity of Coumarin Ring-Opening Derivatives. AB - Based on our initial design, we synthesized two series of coumarin ring-opening derivatives by the reactions of hydrolysis and methylation. Results of antifungal screening in vitro showed that the target compounds exhibited potent activity against the six common pathogenic fungi. Compounds 6b, 6e, 6g, 6i, 7b and 7c were identified as the most active ones, and the EC50 values of these active compounds were further tested. Compared to the commonly used fungicide Azoxystrobin (0.0884 uM), compounds 6b (0.0544 uM) and 6e (0.0823 uM) displayed improved activity against Botrytis cinerea. PMID- 27763521 TI - Deep Eutectic Solvent-Based Microwave-Assisted Method for Extraction of Hydrophilic and Hydrophobic Components from Radix Salviae miltiorrhizae. AB - Deep eutectic solvents (DESs) have attracted significant attention as a promising green media. In this work, twenty-five kinds of benign choline chloride-based DESs with microwave-assisted methods were applied to quickly extract active components from Radix Salviae miltiorrhizae. The extraction factors, including temperature, time, power of microwave, and solid/liquid ratio, were investigated systematically by response surface methodology. The hydrophilic and hydrophobic ingredients were extracted simultaneously under the optimized conditions: 20 vol% of water in choline chloride/1,2-propanediol (1:1, molar ratio) as solvent, microwave power of 800 W, temperature at 70 degrees C, time at 11.11 min, and solid/liquid ratio of 0.007 g.mL-1. The extraction yield was comparable to, or even better than, conventional methods with organic solvents. The microstructure alteration of samples before and after extraction was also investigated. The method validation was tested as the linearity of analytes (r2 > 0.9997 over two orders of magnitude), precision (intra-day relative standard deviation (RSD) < 2.49 and inter-day RSD < 2.96), and accuracy (recoveries ranging from 95.04% to 99.93%). The proposed DESs combined with the microwave-assisted method provided a prominent advantage for fast and efficient extraction of active components, and DESs could be extended as solvents to extract and analyze complex environmental and pharmaceutical samples. PMID- 27763522 TI - Effectiveness Testing of a Piezoelectric Energy Harvester for an Automobile Wheel Using Stochastic Resonance. AB - The collection of clean power from ambient vibrations is considered a promising method for energy harvesting. For the case of wheel rotation, the present study investigates the effectiveness of a piezoelectric energy harvester, with the application of stochastic resonance to optimize the efficiency of energy harvesting. It is hypothesized that when the wheel rotates at variable speeds, the energy harvester is subjected to on-road noise as ambient excitations and a tangentially acting gravity force as a periodic modulation force, which can stimulate stochastic resonance. The energy harvester was miniaturized with a bistable cantilever structure, and the on-road noise was measured for the implementation of a vibrator in an experimental setting. A validation experiment revealed that the harvesting system was optimized to capture power that was approximately 12 times that captured under only on-road noise excitation and 50 times that captured under only the periodic gravity force. Moreover, the investigation of up-sweep excitations with increasing rotational frequency confirmed that stochastic resonance is effective in optimizing the performance of the energy harvester, with a certain bandwidth of vehicle speeds. An actual vehicle experiment validates that the prototype harvester using stochastic resonance is capable of improving power generation performance for practical tire application. PMID- 27763523 TI - A Novel Tetrahydrocannabinol Electrochemical Nano Immunosensor Based on Horseradish Peroxidase and Double-Layer Gold Nanoparticles. AB - In the current study, a novel double-layer gold nanoparticles-electrochemical immunosensor electrode immobilized with tetrahydrocannabinol (THC) antibody derived from Balb/c mice was developed. To increase the fixed quantity of antibodies and electrochemical signals, an electrochemical biosensing signal amplification system was utilized with gold nanoparticles-thionine-chitosan absorbing horseradish peroxidase (HRP). In addition, a transmission electron microscope (TEM) was used to characterize the nanogold solution. To evaluate the quality of the immunosensor, the amperometric I-t curve method was applied to determine the THC in PBS. The results showed that the response current had a good linear correlation with the THC concentration range from 0.01~103 ng/mL with a correlation coefficient of 0.9986. The lowest detection limit for THC was 3.3 pg/mL (S/N = 3). Moreover, it was validated with high sensitivity and reproducibility. Apparently, the immunosensor may be a very useful tool for monitoring the THC. PMID- 27763518 TI - The Eighth Central European Conference "Chemistry towards Biology": Snapshot. AB - The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on August 28-September 1, 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting. PMID- 27763524 TI - Characterization, in Vivo and in Vitro Evaluation of Solid Dispersion of Curcumin Containing d-alpha-Tocopheryl Polyethylene Glycol 1000 Succinate and Mannitol. AB - The aim of this study was to prepare a solid dispersion formulation of curcumin to enhance its solubility, dissolution rate, and oral bioavailability. The formulation was prepared with d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and mannitol using solvent evaporation and freeze-drying methods, which yielded a solid dispersion composed of curcumin, TPGS, and mannitol at a ratio of 1:10:15 (w/w/w). The solubility and dissolution rate of the curcumin solid dispersion markedly improved compared with those of curcumin powder and a physical mixture of curcumin, TPGS, and mannitol. About 90% of the curcumin was released from the solid dispersion formulation within 10 min. After administering the formulation orally to rats, higher plasma concentrations of curcumin were observed, with increases in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of 86- and 65-fold, respectively, compared with those of curcumin powder. The solid dispersion formulation effectively increased intestinal permeability and inhibited P-gp function. These effects increased the anti-proliferative effect of curcumin in MDA-MB-231 breast cancer cells. Moreover, 2 h incubation with curcumin powder, solid dispersion formulation, and its physical mixture resulted in differential cytotoxic effect of paclitaxel in P-gp overexpressed LLC-PK1-P-gp and MDA-MB-231 cells through the inhibition of P-gp-mediated paclitaxel efflux. In conclusion, compared with curcumin, a solid dispersion formulation of curcumin with TPGS and mannitol could be a promising option for enhancing the oral bioavailability and efficacy of curcumin through increased solubility, dissolution rate, cell permeability, and P-gp modulation. PMID- 27763525 TI - The Need for a Definition of Big Data for Nursing Science: A Case Study of Disaster Preparedness. AB - The rapid development of technology has made enormous volumes of data available and achievable anytime and anywhere around the world. Data scientists call this change a data era and have introduced the term "Big Data", which has drawn the attention of nursing scholars. Nevertheless, the concept of Big Data is quite fuzzy and there is no agreement on its definition among researchers of different disciplines. Without a clear consensus on this issue, nursing scholars who are relatively new to the concept may consider Big Data to be merely a dataset of a bigger size. Having a suitable definition for nurse researchers in their context of research and practice is essential for the advancement of nursing research. In view of the need for a better understanding on what Big Data is, the aim in this paper is to explore and discuss the concept. Furthermore, an example of a Big Data research study on disaster nursing preparedness involving six million patient records is used for discussion. The example demonstrates that a Big Data analysis can be conducted from many more perspectives than would be possible in traditional sampling, and is superior to traditional sampling. Experience gained from the process of using Big Data in this study will shed light on future opportunities for conducting evidence-based nursing research to achieve competence in disaster nursing. PMID- 27763526 TI - Analytical Enantio-Separation of Linagliptin in Linagliptin and Metformin HCl Dosage Forms by Applying Two-Level Factorial Design. AB - A novel, stability indicating, reverse phase high-performance liquid chromatography (RP-HPLC) method was developed to determine the S-isomer of linagliptin (LGP) in linagliptin and metformin hydrochloride (MET HCl) tablets (LGP-MET HCl) by implementing design of experiment (DoE), i.e., two-level, full factorial design (23 + 3 centre points = 11 experiments) to understand the critical method parameters (CMP) and its relation with the critical method attribute (CMA), and to ensure robustness of the method. The separation of the S isomer, LGP and MET HCl in the presence of their impurities was achieved on Chiralpak(r) IA-3 (Amylose tris (3, 5-dimethylphenylcarbamate), immobilized on 3 um silica gel) stationary phase (250 * 4.6 mm, 3 um) using isocratic elution and detector wavelength at 225 nm with a flow rate of 0.5 mL.min-1, an injection volume of 10 uL with a sample cooler (5 degrees C) and column oven temperature of 25 degrees C. Ethanol:Methanol:Monoethanolamine (EtOH:MeOH:MEA) in the ratio of 60:40:0.2 v/v/v was used as a mobile phase. The developed method was validated in accordance with international council for harmonisation (ICH) guidelines and was applied for the estimation of the S-isomer of LGP in LGP-MET HCl tablets. The same method also can be extended for the estimation of the S-isomer in LGP dosage forms. PMID- 27763527 TI - Simultaneous Saccharification and Fermentation of Sugar Beet Pulp with Mixed Bacterial Cultures for Lactic Acid and Propylene Glycol Production. AB - Research into fermentative production of lactic acid from agricultural by products has recently concentrated on the direct conversion of biomass, whereby pure sugars are replaced with inexpensive feedstock in the process of lactic acid production. In our studies, for the first time, the source of carbon used is sugar beet pulp, generated as a by-product of industrial sugar production. In this paper, we focus on the simultaneous saccharification of lignocellulosic biomass and fermentation of lactic acid, using mixed cultures with complementary assimilation profiles. Lactic acid is one of the primary platform chemicals, and can be used to synthesize a wide variety of useful products, including green propylene glycol. A series of controlled batch fermentations was conducted under various conditions, including pretreatment with enzymatic hydrolysis. Inoculation was performed in two sequential stages, to avoid carbon catabolite repression. Biologically-synthesized lactic acid was catalytically reduced to propylene glycol over 5% Ru/C. The highest lactic acid yield was obtained with mixed cultures. The yield of propylene glycol from the biological lactic acid was similar to that obtained with a water solution of pure lactic acid. Our results show that simultaneous saccharification and fermentation enables generation of lactic acid, suitable for further chemical transformations, from agricultural residues. PMID- 27763529 TI - Polymorphism of the XRCC1 Gene Is Associated with Susceptibility and Short-Term Recovery of Ischemic Stroke. AB - Background: Base excision repair (BER) is the primary DNA repair system with the ability to fix base lesions caused by oxidative damage. Genetic variants influencing the BER pathway may affect the susceptibility and the outcomes of ischemic stroke. Here, we examined how single nucleotide polymorphisms (SNPs) associated with BER impact susceptibility and short-term recovery of ischemic stroke. Methods: We selected 320 ischemic stroke patients and 303 controls. Then we genotyped SNPs of NEIL1 rs4462560, NEIL3 rs12645561 and XRCC1 rs25487 in both groups. Results: Polymorphism in XRCC1 rs25487 was significantly associated with reduced ischemic stroke (IS) risk (dominant model: OR = 0.53, 95% CI = 0.36-0.79, p = 0.002), a milder initial stroke (dominant model: OR = 0.57, 95% CI = 0.33 0.98, p = 0.043), and also a better short-term recovery (dominant model: OR = 0.57, 95% CI = 0.35-0.92, p = 0.022). No association was observed in the other two SNPs. Conclusions: Our study suggests that the genetic variant of XRCC1 rs25487 may contribute to the etiology of ischemic stroke. PMID- 27763530 TI - New Sesquiterpenoids and Anti-Platelet Aggregation Constituents from the Rhizomes of Curcuma zedoaria. AB - Two new sesquiterpenoids-13-hydroxycurzerenone (1) and 1-oxocurzerenone (2)-have been isolated from the rhizomes of Curcuma zedoaria, together with 13 known compounds (3-15). The structures of two new compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, 13 hydroxycurzerenone (1), 1-oxocurzerenone (2), curzerenone (3), germacrone (4), curcolone (5), procurcumenol (6), ermanin (7), curcumin (8), and a mixture of stigmast-4-en-3,6-dione (12) and stigmasta-4,22-dien-3,6-dione (13) exhibited inhibition (with inhibition % in the range of 21.28%-67.58%) against collagen induced platelet aggregation at 100 MUM. Compounds 1, 5, 7, 8, and the mixture of 12 and 13 inhibited arachidonic acid (AA)-induced platelet aggregation at 100 MUM with inhibition % in the range of 23.44%-95.36%. PMID- 27763528 TI - Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation. AB - It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6) is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG) and control mice were continuously provided doxycycline from postnatal day (PN) 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS) via a nose only inhalation system from PN30-90 and compared to room air (RA) controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E) staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C) or Club Cell Secretory Protein (CCSP), respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-alpha and IL-1beta. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal captivating information suggesting a role for Cldn6 in lungs exposed to tobacco smoke. Further research is critically necessary in order to fully explain roles for tight junctional components such as Cldn6 and other related molecules in lungs coping with exposure. PMID- 27763531 TI - The Determination of Food Dyes in Vitamins by RP-HPLC. AB - Reversed-phase high performance liquid chromatography (RP-HPLC) for the determination of five synthetic food dyes (Quinoline Yellow E104, Sunset Yellow E110, Ponceau 4R E124, Tartrazine E102 and Carmine E120) in vitamins was used. The dyes were analyzed within 10 min using a column with stationary phase C 18 (250 mm * 4.6 mm, 5 MUm) at 40 degrees C with isocratic elution, and the mobile phase contained acetonitrile and a mixture of CH3COONa:CH3OH (85:15, v/v) in a ratio of 10:90 (v/v) for yellow-colored capsules and 20:80 (v/v) for red-colored capsules, respectively. A diode-array detector was used to monitor the dyes between 190 and 800 nm. It was established that the analyzed samples contained synthetic dyes in a concentration range from 79.5 +/- 0.01 MUg/capsule of Ponceau 4R, E124 to 524 +/- 0.01 MUg/capsule of Tartrazine, E102. The obtained results were compared with existing acceptable daily intakes (ADIs) for individual dyes. This paper provides information about the content of dyes in samples of vitamins. This information is not generally available to consumers. PMID- 27763532 TI - High Vaccination Coverage among Children during Influenza A(H1N1)pdm09 as a Potential Factor of Herd Immunity. AB - The objective of this study was to identify factors related to the expansion of infection and prevention of influenza A(H1N1)pdm09. A retrospective non randomized cohort study (from June 2009 to May 2010) on influenza A(H1N1)pdm09 was conducted in a sample of residents from Hiroshima Prefecture, Japan. The cumulative incidence of the influenza A(H1N1)pdm09 and the pandemic vaccine effectiveness (VE) were estimated. The response rate was 53.5% (178,669/333,892). Overall, the odds ratio of non-vaccinated group to vaccinated group for cumulative incidence of influenza A(H1N1)pdm09 was 2.18 (95% confidence interval (CI): 2.13-2.23) and the VE was 43.9% (CI: 42.8-44.9). The expansion of infection, indicating the power of transmission from infected person to susceptible person, was high in the 7-15 years age groups in each area. In conclusion, results from this survey suggested that schoolchildren-based vaccination rate participates in determining the level of herd immunity to influenza and children might be the drivers of influenza transmission. For future pandemic preparedness, vaccination of schoolchildren may help to prevent disease transmission during influenza outbreak. PMID- 27763533 TI - Non-Enzymatic Glucose Sensing Using Carbon Quantum Dots Decorated with Copper Oxide Nanoparticles. AB - Perturbations in glucose homeostasis is critical for human health, as hyperglycemia (defining diabetes) leads to premature death caused by macrovascular and microvascular complications. However, the simple and accurate detection of glucose in the blood at low cost remains a challenging task, although it is of great importance for the diagnosis and therapy of diabetic patients. In this work, carbon quantum dots decorated with copper oxide nanostructures (CQDs/Cu2O) are prepared by a simple hydrothermal approach, and their potential for electrochemical non-enzymatic glucose sensing is evaluated. The proposed sensor exhibits excellent electrocatalytic activity towards glucose oxidation in alkaline solutions. The glucose sensor is characterized by a wide concentration range from 6 uM to 6 mM, a sensitivity of 2.9 +/- 0.2 uA.uM-1.cm-2, and a detection limit of 6 uM at a signal-to-noise ratio S/N = 3. The sensors are successfully applied for glucose determination in human serum samples, demonstrating that the CQDs/Cu2O-based glucose sensor satisfies the requirements of complex sample detection with adapted potential for therapeutic diagnostics. PMID- 27763534 TI - Proteomic Characterization and Comparison of Malaysian Tropidolaemus wagleri and Cryptelytrops purpureomaculatus Venom Using Shotgun-Proteomics. AB - Tropidolaemus wagleri and Cryptelytrops purpureomaculatus are venomous pit viper species commonly found in Malaysia. Tandem mass spectrometry analysis of the crude venoms has detected different proteins in T. wagleri and C. purpureomaculatus. They were classified into 13 venom protein families consisting of enzymatic and nonenzymatic proteins. Enzymatic families detected in T. wagleri and C. purpureomaculatus venom were snake venom metalloproteinase, phospholipase A2, L-amino acid oxidase, serine proteases, 5'-nucleotidase, phosphodiesterase, and phospholipase B. In addition, glutaminyl cyclotransferase was detected in C. purpureomaculatus. C-type lectin-like proteins were common nonenzymatic components in both species. Waglerin was present and unique to T. wagleri-it was not in C. purpureomaculatus venom. In contrast, cysteine-rich secretory protein, bradykinin-potentiating peptide, and C-type natriuretic peptide were present in C. purpureomaculatus venom. Composition of the venom proteome of T. wagleri and C. purpureomaculatus provides useful information to guide production of effective antivenom and identification of proteins with potential therapeutic applications. PMID- 27763535 TI - Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-beta-Cyclodextrin (DEN-HPbetaCD). AB - Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPbetaCD (hydroxypropyl-beta-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPbetaCD complex leads to cell growth inhibition as determined by MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPbetaCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA) based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPbetaCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPbetaCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future. PMID- 27763536 TI - Fluid Biomarkers of Traumatic Brain Injury and Intended Context of Use. AB - Traumatic brain injury (TBI) is one of the leading causes of death and disability around the world. The lack of validated biomarkers for TBI is a major impediment to developing effective therapies and improving clinical practice, as well as stimulating much work in this area. In this review, we focus on different settings of TBI management where blood or cerebrospinal fluid (CSF) biomarkers could be utilized for predicting clinically-relevant consequences and guiding management decisions. Requirements that the biomarker must fulfill differ based on the intended context of use (CoU). Specifically, we focus on fluid biomarkers in order to: (1) identify patients who may require acute neuroimaging (cranial computerized tomography (CT) or magnetic resonance imaging (MRI); (2) select patients at risk for secondary brain injury processes; (3) aid in counseling patients about their symptoms at discharge; (4) identify patients at risk for developing postconcussive syndrome (PCS), posttraumatic epilepsy (PTE) or chronic traumatic encephalopathy (CTE); (5) predict outcomes with respect to poor or good recovery; (6) inform counseling as to return to work (RTW) or to play. Despite significant advances already made from biomarker-based studies of TBI, there is an immediate need for further large-scale studies focused on identifying and innovating sensitive and reliable TBI biomarkers. These studies should be designed with the intended CoU in mind. PMID- 27763537 TI - The Effect of Vegan Protein-Based Diets on Metabolic Parameters, Expressions of Adiponectin and Its Receptors in Wistar Rats. AB - Vegan protein-based diet has attracted increasing interest in the prevention of metabolic syndrome (MetS). Meanwhile, adiponectin has become a highly potential molecular target in the prevention of MetS. Our study will identify a potential vegan protein diet for the prevention of MetS using rat models. Thirty-six Wistar rats were randomly assigned into three groups and given diets containing one of the following proteins for 12 weeks: casein (CAS, control diet), soy protein (SOY), and gluten-soy mixed protein (GSM). Changes in metabolic parameters as well as the expressions of adiponectin and its receptors were identified. Compared to CAS diet, both SOY and GSM diets led to decreases in blood total cholesterol and triglycerides, but only GSM diet led to an increase in HDL cholesterol; no marked difference was observed in blood glucose in all three groups; HOMA-IR was found lower only in SOY group. Among groups, the order of serum adiponectin level was found as GSM > SOY > CAS. Similar order pattern was also observed in expression of adiponectin in adipose tissue and AdipoR1 mRNA in skeletal muscle. Our results suggested for the first time that, besides SOY diet, GSM diet could also be a possible substitute of animal protein to prevent MetS. PMID- 27763538 TI - An Effective Correction Method for Seriously Oblique Remote Sensing Images Based on Multi-View Simulation and a Piecewise Model. AB - Conventional correction approaches are unsuitable for effectively correcting remote sensing images acquired in the seriously oblique condition which has severe distortions and resolution disparity. Considering that the extraction of control points (CPs) and the parameter estimation of the correction model play important roles in correction accuracy, this paper introduces an effective correction method for large angle (LA) images. Firstly, a new CP extraction algorithm is proposed based on multi-view simulation (MVS) to ensure the effective matching of CP pairs between the reference image and the LA image. Then, a new piecewise correction algorithm is advanced with the optimized CPs, where a concept of distribution measurement (DM) is introduced to quantify the CPs distribution. The whole image is partitioned into contiguous subparts which are corrected by different correction formulae to guarantee the accuracy of each subpart. The extensive experimental results demonstrate that the proposed method significantly outperforms conventional approaches. PMID- 27763539 TI - High Quality Plasmonic Sensors Based on Fano Resonances Created through Cascading Double Asymmetric Cavities. AB - In this paper, a type of compact nanosensor based on a metal-insulator-metal structure is proposed and investigated through cascading double asymmetric cavities, in which their metal cores shift along different axis directions. The cascaded asymmetric structure exhibits high transmission and sharp Fano resonance peaks via strengthening the mutual coupling of the cavities. The research results show that with the increase of the symmetry breaking in the structure, the number of Fano resonances increase accordingly. Furthermore, by modulating the geometrical parameters appropriately, Fano resonances with high sensitivities to the changes in refractive index can be realized. A maximum figure of merit (FoM) value of 74.3 is obtained. Considerable applications for this work can be found in bio/chemical sensors with excellent performance and other nanophotonic integrated circuit devices such as optical filters, switches and modulators. PMID- 27763540 TI - A Vision-Based Approach for Building Telecare and Telerehabilitation Services. AB - In the last few years, telerehabilitation and telecare have become important topics in healthcare since they enable people to remain independent in their own homes by providing person-centered technologies to support the individual. These technologies allows elderly people to be assisted in their home, instead of traveling to a clinic, providing them wellbeing and personalized health care. The literature shows a great number of interesting proposals to address telerehabilitation and telecare scenarios, which may be mainly categorized into two broad groups, namely wearable devices and context-aware systems. However, we believe that these apparently different scenarios may be addressed by a single context-aware approach, concretely a vision-based system that can operate automatically in a non-intrusive way for the elderly, and this is the goal of this paper. We present a general approach based on 3D cameras and neural network algorithms that offers an efficient solution for two different scenarios of telerehabilitation and telecare for elderly people. Our empirical analysis reveals the effectiveness and accuracy of the algorithms presented in our approach and provides more than promising results when the neural network parameters are properly adjusted. PMID- 27763542 TI - Green Extraction from Pomegranate Marcs for the Production of Functional Foods and Cosmetics. AB - The aim of this study was to investigate the potential of retrieving polyphenolic antioxidants directly from wet pomegranate marcs: the fresh by-products obtained after pomegranate juice processing. These by-products mainly consist of internal membranes (endocarp) and aril residues. Even if they are still edible, they are usually discharged during juice production and, thus, they represent a great challenge in an eco-sustainable industrial context. Green technologies, such as ultrasound assisted extraction (UAE) and microwave assisted extraction (MAE), have been employed to convert these organic residues into recycled products with high added value. UAE and MAE were used both in parallel and in series in order to make a comparison and to ensure exhaustive extractions, respectively. Water, as an environmentally friendly extraction solvent, has been employed. The results were compared with those ones coming from a conventional extraction. The most promising extract, in terms of total polyphenol yield and radical scavenging activity, has been tested both as a potential natural additive and as a functional ingredient after its incorporation in a real food model and in a real cosmetic matrix, respectively. This study represents a proposal to the agro alimentary sector given the general need of environmental "responsible care". PMID- 27763541 TI - Properties of Gluten Intolerance: Gluten Structure, Evolution, Pathogenicity and Detoxification Capabilities. AB - Theterm gluten intolerance may refer to three types of human disorders: autoimmune celiac disease (CD), allergy to wheat and non-celiac gluten sensitivity (NCGS). Gluten is a mixture of prolamin proteins present mostly in wheat, but also in barley, rye and oat. Gluten can be subdivided into three major groups: S-rich, S-poor and high molecular weight proteins. Prolamins within the groups possess similar structures and properties. All gluten proteins are evolutionarily connected and share the same ancestral origin. Gluten proteins are highly resistant to hydrolysis mediated by proteases of the human gastrointestinal tract. It results in emergence of pathogenic peptides, which cause CD and allergy in genetically predisposed people. There is a hierarchy of peptide toxicity and peptide recognition by T cells. Nowadays, there are several ways to detoxify gluten peptides: the most common is gluten-free diet (GFD), which has proved its effectiveness; prevention programs, enzymatic therapy, correction of gluten pathogenicity pathways and genetically modified grains with reduced immunotoxicity. A deep understanding of gluten intolerance underlying mechanisms and detailed knowledge of gluten properties may lead to the emergence of novel effective approaches for treatment of gluten-related disorders. PMID- 27763543 TI - Cross-Neutralisation of In Vitro Neurotoxicity of Asian and Australian Snake Neurotoxins and Venoms by Different Antivenoms. AB - There is limited information on the cross-neutralisation of neurotoxic venoms with antivenoms. Cross-neutralisation of the in vitro neurotoxicity of four Asian and four Australian snake venoms, four post-synaptic neurotoxins (alpha bungarotoxin, alpha-elapitoxin-Nk2a, alpha-elapitoxin-Ppr1 and alpha-scutoxin; 100 nM) and one pre-synaptic neurotoxin (taipoxin; 100 nM) was studied with five antivenoms: Thai cobra antivenom (TCAV), death adder antivenom (DAAV), Thai neuro polyvalent antivenom (TNPAV), Indian Polyvalent antivenom (IPAV) and Australian polyvalent antivenom (APAV). The chick biventer cervicis nerve-muscle preparation was used for this study. Antivenom was added to the organ bath 20 min prior to venom. Pre- and post-synaptic neurotoxicity of Bungarus caeruleus and Bungarus fasciatus venoms was neutralised by all antivenoms except TCAV, which did not neutralise pre-synaptic activity. Post-synaptic neurotoxicity of Ophiophagus hannah was neutralised by all antivenoms, and Naja kaouthia by all antivenoms except IPAV. Pre- and post-synaptic neurotoxicity of Notechis scutatus was neutralised by all antivenoms, except TCAV, which only partially neutralised pre synaptic activity. Pre- and post-synaptic neurotoxicity of Oxyuranus scutellatus was neutralised by TNPAV and APAV, but TCAV and IPAV only neutralised post synaptic neurotoxicity. Post-synaptic neurotoxicity of Acanthophis antarcticus was neutralised by all antivenoms except IPAV. Pseudonaja textillis post-synaptic neurotoxicity was only neutralised by APAV. The alpha-neurotoxins were neutralised by TNPAV and APAV, and taipoxin by all antivenoms except IPAV. Antivenoms raised against venoms with post-synaptic neurotoxic activity (TCAV) cross-neutralised the post-synaptic activity of multiple snake venoms. Antivenoms raised against pre- and post-synaptic neurotoxic venoms (TNPAV, IPAV, APAV) cross neutralised both activities of Asian and Australian venoms. While acknowledging the limitations of adding antivenom prior to venom in an in vitro preparation, cross-neutralization of neurotoxicity means that antivenoms from one region may be effective in other regions which do not have effective antivenoms. TCAV only neutralized post-synaptic neurotoxicity and is potentially useful in distinguishing pre-synaptic and post-synaptic effects in the chick biventer cervicis preparation. PMID- 27763544 TI - Dissecting Candida albicans Infection from the Perspective of C. albicans Virulence and Omics Approaches on Host-Pathogen Interaction: A Review. AB - Candida bloodstream infections remain the most frequent life-threatening fungal disease, with Candida albicans accounting for 70% to 80% of the Candida isolates recovered from infected patients. In nature, Candida species are part of the normal commensal flora in mammalian hosts. However, they can transform into pathogens once the host immune system is weakened or breached. More recently, mortality attributed to Candida infections has continued to increase due to both inherent and acquired drug resistance in Candida, the inefficacy of the available antifungal drugs, tedious diagnostic procedures, and a rising number of immunocompromised patients. Adoption of animal models, viz. minihosts, mice, and zebrafish, has brought us closer to unraveling the pathogenesis and complexity of Candida infection in human hosts, leading towards the discovery of biomarkers and identification of potential therapeutic agents. In addition, the advancement of omics technologies offers a holistic view of the Candida-host interaction in a non-targeted and non-biased manner. Hence, in this review, we seek to summarize past and present milestone findings on C. albicans virulence, adoption of animal models in the study of C. albicans infection, and the application of omics technologies in the study of Candida-host interaction. A profound understanding of the interaction between host defense and pathogenesis is imperative for better design of novel immunotherapeutic strategies in future. PMID- 27763545 TI - MDN-0170, a New Napyradiomycin from Streptomyces sp. Strain CA-271078. AB - A new napyradiomycin, MDN-0170 (1), was isolated from the culture broth of the marine-derived actinomycete strain CA-271078, together with three known related compounds identified as 4-dehydro-4a-dechloronapyradiomycin A1 (2), napyradiomycin A1 (3) and 3-chloro-6,8-dihydroxy-8-alpha-lapachone (4). The structure of the new compound was determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). The relative configuration of compound 1, which contains two independent stereoclusters, has been established by molecular modelling in combination with nOe and coupling constant analyses. Biosynthetic arguments also allowed us to propose its absolute stereochemistry. The antimicrobial properties of the compounds isolated were evaluated against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Aspergillus fumigatus, and Candida albicans. The potent bioactivity previously reported for compounds 2 and 3 against methicillin-sensitive S. aureus has been extended to methicillin-resistant strains in this report. PMID- 27763547 TI - Higher Fusarium Toxin Accumulation in Grain of Winter Triticale Lines Inoculated with Fusarium culmorum as Compared with Wheat. AB - Resistance to Fusarium head blight in 32 winter triticale and 34 winter wheat accessions was evaluated. Triticale and wheat were sown in field experiments in two locations. At the time of flowering, heads were inoculated with three Fusarium culmorum isolates. Fusarium head blight index was scored and after the harvest percentage of Fusarium damaged kernels was assessed. Grain was analysed for type B trichothecenes (deoxynivalenol and derivatives, nivalenol) and zearalenone (ZEN) content. The average Fusarium head blight indexes were 28.0% for wheat and 19.2% for triticale accessions. The percentage of Fusarium damaged kernels was also higher for wheat and came to 55.6%, while for triticale this figure was 40.2%. The average content of deoxynivalenol (DON) for wheat amounted to 11.65 mg/kg and was lower than the result for triticale which was 14.12 mg/kg. The average contents of nivalenol were similar in both cereals: 4.13 mg/kg and 5.19 mg/kg for wheat and triticale respectively. Considerable amounts of DON derivatives in the cereals were also detected. The ZEN content in the grain was 0.60 mg/kg for wheat and 0.66 mg/kg for triticale. Relationships between Fusarium head blight index, Fusarium damaged kernels and mycotoxin contents were statistically significant for wheat and mostly insignificant for triticale. Triticale proved to have less infected heads and kernels than wheat. However, the content of type B trichothecenes was higher in triticale grain than in wheat grain. PMID- 27763548 TI - The Interacting Axes of Environmental, Health, and Social Justice Cumulative Impacts: A Case Study of the Blueberry River First Nations. AB - We consider the case of intensive resource extractive projects in the Blueberry River First Nations in Northern British Columbia, Canada, as a case study. Drawing on the parallels between concepts of cumulative environmental and cumulative health impacts, we highlight three axes along which to gauge the effects of intensive extraction projects. These are environmental, health, and social justice axes. Using an intersectional analysis highlights the way in which using individual indicators to measure impact, rather than considering cumulative effects, hides the full extent by which the affected First Nations communities are impacted by intensive extraction projects. We use the case study to contemplate several mechanisms at the intersection of these axes whereby the negative effects of each not only add but also amplify through their interactions. For example, direct impact along the environmental axis indirectly amplifies other health and social justice impacts separately from the direct impacts on those axes. We conclude there is significant work still to be done to use cumulative indicators to study the impacts of extractive industry projects like liquefied natural gas-on peoples, environments, and health. PMID- 27763546 TI - Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics. AB - Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance. PMID- 27763550 TI - Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer's Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET. AB - Alzheimer's disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer's cognition after cognitive decline, at least in animals. PMID- 27763549 TI - Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification. AB - Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring. PMID- 27763551 TI - The Snake with the Scorpion's Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus). AB - Millions of years of evolution have fine-tuned the ability of venom peptides to rapidly incapacitate both prey and potential predators. Toxicofera reptiles are characterized by serous-secreting mandibular or maxillary glands with heightened levels of protein expression. These glands are the core anatomical components of the toxicoferan venom system, which exists in myriad points along an evolutionary continuum. Neofunctionalisation of toxins is facilitated by positive selection at functional hotspots on the ancestral protein and venom proteins have undergone dynamic diversification in helodermatid and varanid lizards as well as advanced snakes. A spectacular point on the venom system continuum is the long-glanded blue coral snake (Calliophis bivirgatus), a specialist feeder that preys on fast moving, venomous snakes which have both a high likelihood of prey escape but also represent significant danger to the predator itself. The maxillary venom glands of C. bivirgatus extend one quarter of the snake's body length and nestle within the rib cavity. Despite the snake's notoriety its venom has remained largely unstudied. Here we show that the venom uniquely produces spastic paralysis, in contrast to the flaccid paralysis typically produced by neurotoxic snake venoms. The toxin responsible, which we have called calliotoxin (delta-elapitoxin-Cb1a), is a three-finger toxin (3FTx). Calliotoxin shifts the voltage-dependence of NaV1.4 activation to more hyperpolarised potentials, inhibits inactivation, and produces large ramp currents, consistent with its profound effects on contractile force in an isolated skeletal muscle preparation. Voltage-gated sodium channels (NaV) are a particularly attractive pharmacological target as they are involved in almost all physiological processes including action potential generation and conduction. Accordingly, venom peptides that interfere with NaV function provide a key defensive and predatory advantage to a range of invertebrate venomous species including cone snails, scorpions, spiders, and anemones. Enhanced activation or delayed inactivation of sodium channels by toxins is associated with the extremely rapid onset of tetanic/excitatory paralysis in envenomed prey animals. A strong selection pressure exists for the evolution of such toxins where there is a high chance of prey escape. However, despite their prevalence in other venomous species, toxins causing delay of sodium channel inhibition have never previously been described in vertebrate venoms. Here we show that NaV modulators, convergent with those of invertebrates, have evolved in the venom of the long-glanded coral snake. Calliotoxin represents a functionally novel class of 3FTx and a structurally novel class of NaV toxins that will provide significant insights into the pharmacology and physiology of NaV. The toxin represents a remarkable case of functional convergence between invertebrate and vertebrate venom systems in response to similar selection pressures. These results underscore the dynamic evolution of the Toxicofera reptile system and reinforces the value of using evolution as a roadmap for biodiscovery. PMID- 27763552 TI - Maporal Hantavirus Causes Mild Pathology in Deer Mice (Peromyscus maniculatus). AB - Rodent-borne hantaviruses can cause two human diseases with many pathological similarities: hantavirus cardiopulmonary syndrome (HCPS) in the western hemisphere and hemorrhagic fever with renal syndrome in the eastern hemisphere. Each virus is hosted by specific reservoir species without conspicuous disease. HCPS-causing hantaviruses require animal biosafety level-4 (ABSL-4) containment, which substantially limits experimental research of interactions between the viruses and their reservoir hosts. Maporal virus (MAPV) is a South American hantavirus not known to cause disease in humans, thus it can be manipulated under ABSL-3 conditions. The aim of this study was to develop an ABSL-3 hantavirus infection model using the deer mouse (Peromyscus maniculatus), the natural reservoir host of Sin Nombre virus (SNV), and a virus that is pathogenic in another animal model to examine immune response of a reservoir host species. Deer mice were inoculated with MAPV, and viral RNA was detected in several organs of all deer mice during the 56 day experiment. Infected animals generated both nucleocapsid-specific and neutralizing antibodies. Histopathological lesions were minimal to mild with the peak of the lesions detected at 7-14 days postinfection, mainly in the lungs, heart, and liver. Low to modest levels of cytokine gene expression were detected in spleens and lungs of infected deer mice, and deer mouse primary pulmonary cells generated with endothelial cell growth factors were susceptible to MAPV with viral RNA accumulating in the cellular fraction compared to infected Vero cells. Most features resembled that of SNV infection of deer mice, suggesting this model may be an ABSL-3 surrogate for studying the host response of a New World hantavirus reservoir. PMID- 27763553 TI - 4EBP-Dependent Signaling Supports West Nile Virus Growth and Protein Expression. AB - West Nile virus (WNV) is a (+) sense, single-stranded RNA virus in the Flavivirus genus. WNV RNA possesses an m7GpppNm 5' cap with 2'-O-methylation that mimics host mRNAs preventing innate immune detection and allowing the virus to translate its RNA genome through the utilization of cap-dependent translation initiation effectors in a wide variety of host species. Our prior work established the requirement of the host mammalian target of rapamycin complex 1 (mTORC1) for optimal WNV growth and protein expression; yet, the roles of the downstream effectors of mTORC1 in WNV translation are unknown. In this study, we utilize gene deletion mutants in the ribosomal protein kinase called S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4EBP) pathways downstream of mTORC1 to define the role of mTOR-dependent translation initiation signals in WNV gene expression and growth. We now show that WNV growth and protein expression are dependent on mTORC1 mediated-regulation of the eukaryotic translation initiation factor 4E-binding protein/eukaryotic translation initiation factor 4E-binding protein (4EBP/eIF4E) interaction and eukaryotic initiation factor 4F (eIF4F) complex formation to support viral growth and viral protein expression. We also show that the canonical signals of mTORC1 activation including ribosomal protein s6 (rpS6) and S6K phosphorylation are not required for WNV growth in these same conditions. Our data suggest that the mTORC1/4EBP/eIF4E signaling axis is activated to support the translation of the WNV genome. PMID- 27763554 TI - Development of Bt Rice and Bt Maize in China and Their Efficacy in Target Pest Control. AB - Rice and maize are important cereal crops that serve as staple foods, feed, and industrial material in China. Multiple factors constrain the production of both crops, among which insect pests are an important one. Lepidopteran pests cause enormous yield losses for the crops annually. In order to control these pests, China plays an active role in development and application of genetic engineering (GE) to crops, and dozens of GE rice and GE maize lines expressing insecticidal proteins from the soil bacterium Bacillus thuringiensis (Bt) have been developed. Many lines have entered environmental release, field testing, and preproduction testing, and laboratory and field experiments have shown that most of the Bt rice and Bt maize lines developed in China exhibited effective control of major target lepidopteran pests on rice (Chilo suppressalis, Scirpophaga incertulas, and Cnaphalocrocismedinalis) and maize (Ostrinia furnacalis), demonstrating bright prospects for application. However, none of these Bt lines has yet been commercially planted through this writing in 2016. Challenges and perspectives for development and application of Bt rice and maize in China are discussed. This article provides a general context for colleagues to learn about research and development of Bt crops in China, and may shed light on future work in this field. PMID- 27763555 TI - CCD-Based Skinning Injury Recognition on Potato Tubers (Solanum tuberosum L.): A Comparison between Visible and Biospeckle Imaging. AB - Skinning injury on potato tubers is a kind of superficial wound that is generally inflicted by mechanical forces during harvest and postharvest handling operations. Though skinning injury is pervasive and obstructive, its detection is very limited. This study attempted to identify injured skin using two CCD (Charge Coupled Device) sensor-based machine vision technologies, i.e., visible imaging and biospeckle imaging. The identification of skinning injury was realized via exploiting features extracted from varied ROIs (Region of Interests). The features extracted from visible images were pixel-wise color and texture features, while region-wise BA (Biospeckle Activity) was calculated from biospeckle imaging. In addition, the calculation of BA using varied numbers of speckle patterns were compared. Finally, extracted features were implemented into classifiers of LS-SVM (Least Square Support Vector Machine) and BLR (Binary Logistic Regression), respectively. Results showed that color features performed better than texture features in classifying sound skin and injured skin, especially for injured skin stored no less than 1 day, with the average classification accuracy of 90%. Image capturing and processing efficiency can be speeded up in biospeckle imaging, with captured 512 frames reduced to 125 frames. Classification results obtained based on the feature of BA were acceptable for early skinning injury stored within 1 day, with the accuracy of 88.10%. It is concluded that skinning injury can be recognized by visible and biospeckle imaging during different stages. Visible imaging has the aptitude in recognizing stale skinning injury, while fresh injury can be discriminated by biospeckle imaging. PMID- 27763556 TI - Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes. AB - The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface areas in selected homodimers vary with respect to their contribution to share as well as individual (domain-specific) hydrophobic cores. The basic definition of a protein domain, i.e., a structural unit characterized by tighter packing than its immediate environment, is extended in order to acknowledge the role of a structured hydrophobic core, which includes the interface area. The hydrophobic properties of interfaces vary depending on the status of interacting domains-In this context we can distinguish: (1) Shared hydrophobic cores (spanning the whole dimer); (2) Individual hydrophobic cores present in each monomer irrespective of whether the dimer contains a shared core. Analysis of interfaces in dystrophin and utrophin indicates the presence of an additional quasi-domain with a prominent hydrophobic core, consisting of fragments contributed by both monomers. In addition, we have also attempted to determine the relationship between the type of interface (as categorized above) and the biological function of each complex. This analysis is entirely based on the fuzzy oil drop model. PMID- 27763557 TI - Decrystallization of Crystals Using Gold "Nano-Bullets" and the Metal-Assisted and Microwave-Accelerated Decrystallization Technique. AB - Gout is caused by the overproduction of uric acid and the inefficient metabolism of dietary purines in humans. Current treatments of gout, which include anti inflammatory drugs, cyclooxygenase-2 inhibitors, and systemic glucocorticoids, have harmful side-effects. Our research laboratory has recently introduced an innovative approach for the decrystallization of biological and chemical crystals using the Metal-Assisted and Microwave-Accelerated Evaporative Decrystallization (MAMAD) technique. In the MAMAD technique, microwave energy is used to heat and activate gold nanoparticles that behave as "nano-bullets" to rapidly disrupt the crystal structure of biological crystals placed on planar surfaces. In this study, crystals of various sizes and compositions were studied as models for tophaceous gout at different stages (i.e., uric acid as small crystals (~10-100 MUm) and l-alanine as medium (~300 MUm) and large crystals (~4400 MUm). Our results showed that the use of the MAMAD technique resulted in the reduction of the size and number of uric acid and l-alanine crystals up to >40% when exposed to intermittent microwave heating (up to 20 W power at 8 GHz) in the presence of 20 nm gold nanoparticles up to 120 s. This study demonstrates that the MAMAD technique can be potentially used as an alternative therapeutic method for the treatment of gout by effective decrystallization of large crystals, similar in size to those that often occur in gout. PMID- 27763559 TI - In-Situ Measurement of High-Temperature Proton Exchange Membrane Fuel Cell Stack Using Flexible Five-in-One Micro-Sensor. AB - In the chemical reaction that proceeds in a high-temperature proton exchange membrane fuel cell stack (HT-PEMFC stack), the internal local temperature, voltage, pressure, flow and current nonuniformity may cause poor membrane material durability and nonuniform fuel distribution, thus influencing the performance and lifetime of the fuel cell stack. In this paper micro-electro mechanical systems (MEMS) are utilized to develop a high-temperature electrochemical environment-resistant five-in-one micro-sensor embedded in the cathode channel plate of an HT-PEMFC stack, and materials and process parameters are appropriately selected to protect the micro-sensor against failure or destruction during long-term operation. In-situ measurement of the local temperature, voltage, pressure, flow and current distributions in the HT-PEMFC stack is carried out. This integrated micro-sensor has five functions, and is favorably characterized by small size, good acid resistance and temperature resistance, quick response, real-time measurement, and the goal is being able to be put in any place for measurement without affecting the performance of the battery. PMID- 27763558 TI - Involvement of JNK/NFkappaB Signaling Pathways in the Lipopolysaccharide-Induced Modulation of Aquaglyceroporin Expression in 3T3-L1 Cells Differentiated into Adipocytes. AB - Aquaglyceroporins, belonging to the family of aquaporins (AQPs), are integral plasma membrane proteins permeable to water and glycerol that have emerged as key players in obesity. The aim of this study was to investigate the expression profile of AQPs in undifferentiated and differentiated 3T3-L1 cells and to investigate the changes in expression of aquaglyceroporins in 3T3-L1 cells differentiated into adipocytes and subjected to lipopolysaccharide (LPS) mimicking inflammation occurring during obesity. Furthermore, the study aimed at identifying the signaling cascade involved in the regulation of aquaglyceroporins expression upon LPS stimulation. 3T3-L1 cells were grown as undifferentiated cells (UDC; preadipocytes) or cells differentiated into adipocytes (DC, adipocytes). DC were incubated in the presence or absence of LPS with or without inhibitors of various protein kinases. AQPs mRNA expression levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). AQP1, AQP2, AQP3, AQP9 and AQP11 mRNA were expressed in both UDC and DC, whereas AQP4, AQP7 and AQP8 mRNA were expressed only in DC. In DC, LPS up-regulated AQP3 mRNA levels (p < 0.05) compared to control; these effects were inhibited by CLI095, SP600125 and BAY11-7082 (p < 0.05). LPS decreased both AQP7 and AQP11 mRNA levels (p < 0.01) in DC as compared to control; this decrease was inhibited by CLI095 and BAY11 7082 (p < 0.05) and additionally by SP00125 for AQP7 (p < 0.05). SB203580 had no effect on LPS-induced AQP3, AQP7 and AQP11 mRNA levels modulations. In conclusion, our results clearly show that many AQPs are expressed in murine 3T3 L1 adipocytes. Moreover, in DCs, LPS led to decreased AQP7 and AQP11 mRNA levels but to increased AQP3 mRNA levels, resulting from the Toll-like receptor 4 (TLR4) induced activation of JNK and/or NFkappaB pathway. PMID- 27763560 TI - Renal Protective Effects of 17beta-Estradiol on Mice with Acute Aristolochic Acid Nephropathy. AB - Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by a Chinese herb containing aristolochic acid. Excessive death of renal tubular epithelial cells (RTECs) characterized the acute phase of AAN. Therapies for acute AAN were limited, such as steroids and angiotensin-receptor blockers (ARBs)/angiotensin-converting enzyme inhibitors (ACEIs). It was interesting that, in acute AAN, female patients showed relative slower progression to renal failure than males. In a previous study, female hormone 17beta-estradiol (E2) was found to attenuate renal ischemia-reperfusion injury. Thus, the aim of this study was to investigate the potential protective role of E2 in acute AAN. Compared with male C57BL/6 mice of acute AAN, lower serum creatinine (SCr) and less renal injury, together with RTEC apoptosis in females, were found. Treatment with E2 in male AAN mice reduced SCr levels and attenuated renal tubular injury and RTEC apoptosis. In the mice kidney tissue and human renal proximal tubule cells (HK-2 cells), E2 both attenuated AA-induced cell apoptosis and downregulated the expression of phosphor-p53 (Ser15), p53, and cleaved-caspase-3. This study highlights that E2 exhibited protective effects on the renal injury of acute AAN in male mice by reducing RTEC apoptosis, which might be related to inhibiting the p53 signaling pathway. PMID- 27763561 TI - Towards Water Soluble Mitochondria-Targeting Theranostic Osmium(II) Triazole Based Complexes. AB - The complex [Os(btzpy)2][PF6]2 (1, btzpy = 2,6-bis(1-phenyl-1,2,3-triazol-4 yl)pyridine) has been prepared and characterised. Complex 1 exhibits phosphorescence (lambdaem = 595 nm, tau = 937 ns, phiem = 9.3% in degassed acetonitrile) in contrast to its known ruthenium(II) analogue, which is non emissive at room temperature. The complex undergoes significant oxygen-dependent quenching of emission with a 43-fold reduction in luminescence intensity between degassed and aerated acetonitrile solutions, indicating its potential to act as a singlet oxygen sensitiser. Complex 1 underwent counterion metathesis to yield [Os(btzpy)2]Cl2 (1Cl), which shows near identical optical absorption and emission spectra to those of 1. Direct measurement of the yield of singlet oxygen sensitised by 1Cl was carried out (phi (1O2) = 57%) for air equilibrated acetonitrile solutions. On the basis of these photophysical properties, preliminary cellular uptake and luminescence microscopy imaging studies were conducted. Complex 1Cl readily entered the cancer cell lines HeLa and U2OS with mitochondrial staining seen and intense emission allowing for imaging at concentrations as low as 1 MUM. Long-term toxicity results indicate low toxicity in HeLa cells with LD50 >100 MUM. Osmium(II) complexes based on 1 therefore present an excellent platform for the development of novel theranostic agents for anticancer activity. PMID- 27763562 TI - Adsorption of Wine Constituents on Functionalized Surfaces. AB - The adsorption of macromolecules on solid surfaces is of great importance in the field of nanotechnology, biomaterials, biotechnological, and food processes. In the field of oenology adsorption of wine macromolecules such as polyphenols, polysaccharides, and proteins is much less desirable on membrane materials because of fouling and reduced filtering performance. On the other hand, adsorption of these molecules on processing aids is very beneficial for achieving wine clarity and stability. In this article, the effect of surface chemical functionalities on the adsorption of white, rose, and red wine constituents was evaluated. Allylamine, acrylic acid, and ethanol were selected as precursors for plasma polymerization in order to generate coatings rich in amine, carboxyl, and hydroxyl chemical groups, respectively. The surface chemical functionalities were characterized by X-ray photoelectron spectroscopy (XPS) and the ability of different surface chemical functionalities to adsorb wine constituents were characterized by quartz crystal microbalance with dissipation (QCM-D) and atomic force microscopy (AFM). The results demonstrated that the amine and carboxyl modified surfaces encourage adsorption of constituents from white wine. The hydroxyl modified surfaces have the ability to preferentially adsorb rose wine constituents, whereas red wine adsorbed to the highest extent on acrylic acid surface. PMID- 27763563 TI - Cloning and Expression of Ecdysone Receptor and Retinoid X Receptor from Procambarus clarkii: Induction by Eyestalk Ablation. AB - Ecdysone receptor and retinoid X receptor are key regulators in molting. Here, full length ecdysone receptor (PcEcR) and retinoid X receptor (PcRXR) cDNAs from Procambarus clarkii were cloned. Full length cDNA of PcEcR has 2500 bp, encoding 576 amino acid proteins, and full length cDNA of PcRXR has 2593 bp, in which a 15 bp and a 204 bp insert/deletion splice variant regions in DNA binding domain and hinge domain were identified. The two splice variant regions in PcRXR result four isoforms: PcRXR1-4, encoding 525, 520, 457 and 452 amino acids respectively. PcEcR was highly expressed in the hepatopancreas and eyestalk and PcRXR was highly expressed in the eyestalk among eight examined tissues. Both PcEcR and PcRXR had induced expression after eyestalk ablation (ESA) in the three examined tissues. In muscle, PcEcR and PcRXR were upregulated after ESA, PcEcR reached the highest level on day 3 after ESA and increased 33.5-fold relative to day 0, and PcRXR reached highest the level on day 1 after ESA and increased 2.7-fold relative to day 0. In the hepatopancreas, PcEcR and PcRXR dEcReased continuously after ESA, and the expression levels of PcEcR and PcRXR were only 0.7% and 1.7% on day 7 after ESA relative to day 0, respectively. In the ovaries, PcEcR was upregulated after ESA, reached the highest level on day 3 after ESA, increased 3.0-fold relative to day 0, and the expression level of PcRXR changed insignificantly after ESA (p > 0.05). The different responses of PcEcR and PcRXR after ESA indicates that different tissues play different roles (and coordinates their functions) in molting. PMID- 27763564 TI - alpha6beta4 Integrin Genetic Variations (A380T and R1281W) and Breast Cancer Risk in an Argentinian Population. AB - The alpha6beta4 integrin is composed of the alpha6 and beta4 subunits that are encoded by the ITGalpha6 and the ITGbeta4 genes, respectively. The alpha6beta4 main function is to intervene in lamination and epithelia integrity maintenance by cell-matrix interactions. This integrin appears to have importance in breast cancer malignancy, as well as other epithelial carcinomas. The aim of this work was to investigate the potential role of ITGalpha6 (A380T) and ITGbeta4 (R1281W) genetic variations in breast cancer susceptibility, in a female population from the northeast region of Argentina (Misiones). We performed a case-control study of 85 breast cancer patients and 113 cancer-free controls. Genotyping was performed by RFLP-PCR. For ITGalpha6 (A380T) single nucleotide polymorphism, a high frequency of heterozygous genotype GA in cases compared to controls was observed, achieving values of 48% and 49%, respectively. No association between the A380T SNP and breast cancer development was found (Odds Ratio = 0.92; 95% Confidence Interval = 0.52-1.63; p = 0.884). In conclusion, we did not find evidence of an association between A380T (ITGalpha6) and the risk of developing breast cancer. The results represent the first report of these genetic variations in breast cancer; therefore, they are an important contribution to the literature. PMID- 27763566 TI - Correction: Pennisi, R., et al. Hsp90: A New Player in DNA Repair? Biomolecules 2015, 5, 2589-2618. AB - n/a. PMID- 27763565 TI - The Rural-Urban Difference in BMI and Anemia among Children and Adolescents. AB - There is growing concern over the double burden of over- and under-nutrition in individuals, especially in children and adolescents, which could dwarf their growth and development. This study aims to explore the rural-urban difference in BMI and anemia among children and adolescents. A stratified cluster sampling technique was employed. Dietary data were collected through interviews, and anthropometric values were measured. There were 1534 children and adolescents who participated in this study, including 775 male and 759 female participants. The prevalence of obesity among children living in a city, township and rural area was 10.3%, 8.5% and 5.5%, and that among adolescents was 1.4%, 2.9% and 2.8%. The prevalence of anemia among children and living in a city, township and rural area was 4.3%, 2.5% and 4.5%, while that among adolescents was 6.1%, 3.7% and 11.3%, respectively, with significant difference (chi2 = 10.824, p = 0.004). The prevalence of being overweight, obesity and anemia was significant when comparing children with adolescents (chi2 = 37.861, p = 0.000; chi2 = 19.832, p = 0.000; chi2 = 8.611, p = 0.003). Findings of this study indicate the double burden of malnutrition in Zhejiang province, characterized by a high prevalence of being overweight, obesity and anemia among children and a high prevalence of anemia among adolescents living in townships. PMID- 27763567 TI - Associations between Body Mass Index and Visual Impairment of School Students in Central China. AB - Body Mass Index (BMI) is a risk indicator for some eye diseases. However, the association between BMI and Visual Impairment (VI) was not quite certain in Chinese students. Our aim was to assess the relationship between BMI and VI with a cross-sectional study. A total of 3771 students aged 6-21 years, including 729 with VI, were sampled from 24 schools in Huangpi District of central China to participate in the study. A multistage stratified cluster random sampling was adopted. Each of the students answered a questionnaire and had physical and eye examinations. The association between BMI and VI was examined with logistic regression and threshold effect analysis. The prevalence of VI was 19.33% (729/3771). Compared to normal and underweight, overweight/obese students showed a stronger relation with VI in age- and sex-adjusted (Odds Ratio (OR) = 16.16, 95% Confidence Interval (CI): 12.37-21.09, p < 0.001) and multivariable models (OR = 8.32, 95% CI: 6.13-11.30, p < 0.001). There was a nonlinear dose-response relation between levels of BMI and the prevalence of VI (p < 0.001). A high level of BMI (>=19.81 kg/m2) was associated with a higher VI prevalence (adjusted OR = 1.20, 95% CI: 1.15-1.25, p < 0.001). In conclusion, the study demonstrated BMI levels were significantly associated with the prevalence of VI. PMID- 27763568 TI - Overexpression of RACK1 Promotes Metastasis by Enhancing Epithelial-Mesenchymal Transition and Predicts Poor Prognosis in Human Glioma. AB - Emerging studies show that dysregulation of the receptor of activated protein kinase C1 (RACK1) plays a crucial role in tumorigenesis and progression of various cancers. However, the biological function and underlying mechanism of RACK1 in glioma remains poorly defined. Here, we found that RACK1 was significantly up-regulated in glioma tissues compared with normal brain tissues, being closely related to clinical stage of glioma both in mRNA and protein levels. Moreover, Kaplan-Meier analysis demonstrated that patients with high RACK1 expression had a poor prognosis (p = 0.0062, HR = 1.898, 95% CI: 1.225 3.203). In vitro functional assays indicated that silencing of RACK1 could dramatically promote apoptosis and inhibit cell proliferation, migration, and invasion of glioma cells. More importantly, knockdown of RACK1 led to a vast accumulation of cells in G0/G1 phase and their reduced proportions at the S phase by suppressing the expression of G1/S transition key regulators Cyclin D1 and CDK6. Additionally, this forced down-regulation of RACK1 significantly suppressed migration and invasion via inhibiting the epithelial-mesenchymal transition (EMT) markers, such as MMP2, MMP9, ZEB1, N-Cadherin, and Integrin-beta1. Collectively, our study revealed that RACK1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma. PMID- 27763569 TI - The Association between LIPC rs493258 Polymorphism and the Susceptibility to Age Related Macular Degeneration. AB - The purpose of this study was to evaluate the association of the hepatic lipase (LIPC) rs493258 polymorphism and susceptibility to age-related macular degeneration (AMD). A systematic search in PubMed, EMBASE, and ISI web of science databases was performed to identify eligible published studies without language restrictions up to April 2016. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) in different stages of AMD were estimated under different genetic models using meta-analytic methods. Seven studies comprising 20,559 cases and 17,200 controls met the inclusion criteria and were included in the meta analysis. The LIPC rs493258 polymorphism showed a significant association with a lower risk of AMD under the allelic model (OR = 0.87, 95% CI = 0.84-0.90). Significant relationships between the variant and AMD were also observed in other genetic models (OR ranging from 0.71 to 0.86, all p < 0.05). Stratified analysis based on ethnicity found that LIPC rs493258 polymorphism had a significant association with the decreased risk of the disease in the Caucasian population, but not in the Asian population. For late AMD, significant associations of the rs493258 polymorphism with a lower risk of this disease were also observed in the allelic genetic model (OR = 0.87, 95% CI = 0.83-0.90). This meta-analysis demonstrates that the T allele in the LIPC rs493258 polymorphism was significantly associated with the risk of any and late AMD. The associations of the locus with early and late AMD risk in various populations need further exploration. PMID- 27763571 TI - International Medical Collaboration: Lessons from Cuba. AB - Over 50,000 Cuban health professionals are currently working overseas in 67 different countries. They work in conjunction with local health professionals. The majority work in primary care in deprived areas. The aim is to reduce morbidity and mortality but also improve health in the long term by training local health professionals, and building both institutions and a structure to deliver health care alongside educating the local population. Cuba is a small, middle-income country. It has, however, made a significant international contribution in relation to medical collaboration. Cuba's international collaboration is based on the principles of social justice and equity for all. It has set an example for other countries to emulate. PMID- 27763572 TI - Destabilization Mechanism of Ionic Surfactant on Curcumin Nanocrystal against Electrolytes. AB - We have successfully developed curcumin nanosuspension intended for oral delivery. The main purpose is to improve bioavailability through enhancing its solubility. The nanoparticles were stabilized using various stabilizers, including polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), sodium carboxymethylcellulose (Na-CMC), d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), and sodium dodecyl sulfate (SDS). The average diameter of particles, microscopic appearance, and sedimentation of each preparation was observed and compared. Each stabilizer demonstrated a different degree of inhibition of particle aggregation under electrolyte-containing simulated gastrointestinal (GIT) fluid. Non-ionic stabilizers (PVA, PVP, and TPGS) were shown to preserve the nanosuspension stability against electrolytes. In contrast, strong ionic surfactants such as SDS were found to be very sensitive to electrolytes. The results can provide useful information for the formulators to choose the most suitable stabilizers by considering the nature of stabilizers and physiological characteristics of the target site of the drug. PMID- 27763573 TI - Effect of Cyclodextrin Types and Co-Solvent on Solubility of a Poorly Water Soluble Drug. AB - The aim of the study was to investigate the solubility of piroxicam (Prx) depending on the inclusion complexation with various cyclodextrins (CDs) and on ethanol as a co-solvent. The phase-solubility method was applied to determine drug solubility in binary and ternary systems. The results showed that in systems consisting of the drug dissolved in ethanol-water mixtures, the drug solubility increased exponentially with a rising concentration of ethanol. The phase solubility measurements of the drug in aqueous solutions of CDs, beta-CD and gamma-CD exhibited diagrams of AL-type, whereas 2,6-dimethyl-beta-CD revealed AP type. The destabilizing effect of ethanol as a co-solvent was observed for all complexes regardless of the CD type, as a consequence of it the lowering of the complex formation constants. In systems with a higher concentration of ethanol, the drug solubility was increased in opposition to the decreasing complex formation constants. According to this study, the type of CDs played a more important role on the solubility of Prx, and the use of ethanol as a co-solvent exhibited no synergistic effect on the improvement of Prx solubility. The Prx solubility was increased again due to the better solubility in ethanol. PMID- 27763570 TI - Vitamin D Status and Its Consequences for Health in South Africa. AB - In this review, reports were retrieved in which vitamin D status, as assessed by serum 25-hydroxyvitamin D [25(OH)D] levels, was measured in South African population groups with varied skin colours and ethnicities. Healthy children and adults were generally vitamin D-sufficient [25(OH)D level >50 nmol/L] but the majority of those aged above 65 years were deficient. A major role for exposure to solar ultraviolet radiation (UVR) in determining 25(OH)D levels was apparent, with the dietary contribution being minor. Limited data exist regarding the impact of recent changes in lifestyles on vitamin D status, such as urbanisation. With regard to disease susceptibility, 11 of 22 relevant publications indicated association between low 25(OH)D levels and disease, with deficiency most notably found in individuals with tuberculosis and HIV-1. Information on the relationship between vitamin D receptor variants and ethnicity, disease or treatment response in the South African population groups demonstrated complex interactions between genetics, epigenetics and the environment. Whether vitamin D plays an important role in protection against the range of diseases that currently constitute a large burden on the health services in South Africa requires further investigation. Only then can accurate advice be given about personal sun exposure or dietary vitamin D supplementation. PMID- 27763574 TI - The effect of prediabetes on hepatocellular carcinoma risk: a systematic review and meta-analysis. AB - INTRODUCTION: Some studies suggested an increased risk of hepatocellular carcinoma (HCC) risk in subjects with prediabetes, whereas other studies have reported negative results. Therefore, we did this meta-analysis to assess the role of prediabetes on HCC risk. EVIDENCE ACQUISITION: We searched studies from PubMed, Embase, and Web of Science databases. The strength of association between prediabetes and HCC risk was assessed by calculating hazard ratio (HR) with 95% CI. EVIDENCE SYNTHESIS: A total of 8 cohort studies and 1 case-control study with 1384594 individuals were included. Patients with prediabetes showed an increased HCC risk (HR=1.21; 95% CI, 1.13-1.30; P<0.00001). Subgroup analyses were performed according to race and gender. The results showed that both Asians with prediabetes (HR=1.19; 95% CI, 1.11-1.28; P<0.00001) and Caucasians with prediabetes (HR=2.12; 95% CI, 1.36-3.31; P=0.001 were significantly associated with increased risk of HCC, respectively. In the subgroup analysis by gender, both male patients with prediabetes (HR=1.49; 95% CI, 1.03-2.15; P=0.03) and female patients with prediabetes (HR=1.24; 95% CI, 1.01-1.52; P=0.04) showed increased risk of HCC, respectively. CONCLUSIONS: In conclusion, this meta analysis demonstrated that prediabetes might be a risk factor of HCC. PMID- 27763575 TI - Optimal treatment of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome associated with decompensated liver disease. The spectrum of disease ranges from trivial abnormalities in complex decision-making and prolonged reaction time to coma in its most severe form. The very initial stages, recently termed covert hepatic encephalopathy, can only be diagnosed with the help of neuropsychiatric testing, while the later and more severe forms, termed overt hepatic encephalopathy, can be diagnosed clinically. Management of HE is very critical as it can dramatically increase morbidity and mortality. This leads to financial hardships, which tend to make matters worse. Timely management of HE will help diminish the disease burden and thus decrease morbidity and mortality. It is thus crucial that liver cirrhosis and HE are managed aggressively to try and lower the need for transplantation and other aggressive treatment measures. PMID- 27763576 TI - The Prevention of Respiratory Insufficiency after Surgical Management (PRISM) Trial. Report of the protocol for a pragmatic randomized controlled trial of CPAP to prevent respiratory complications and improve survival following major abdominal surgery. AB - BACKGROUND: Over 300 million patients undergo surgery worldwide each year. Postoperative morbidity - particularly respiratory complications - are most frequent and severe among high-risk patients undergoing major abdominal surgery. However, standard treatments, like physiotherapy or supplemental oxygen, often fail to prevent these. Preliminary research suggests that prophylactic continuous positive airways pressure (CPAP) can reduce the risk of postoperative respiratory complications. However, without evidence from a large clinical effectiveness trial, CPAP has not become routine care. This trial aims to determine whether early postoperative CPAP reduces the incidence of respiratory complications and improves one-year survival following major intra-peritoneal surgery. METHODS: This is an international multicenter randomized controlled trial with open study group allocation. The participants are aged 50 years and over undergoing major elective intra-peritoneal surgery. The intervention is CPAP for at least four hours, started within four hours of the end of surgery. RESULTS: The primary outcome is a composite of pneumonia, re-intubation, or death within 30 days of randomization. All participants with a recorded outcome will be analyzed on an intention-to-treat basis. The primary analysis will use a mixed-effects logistic regression model, which includes center as a random-intercept, and will be adjusted for the minimization factors and other pre-specified covariates. Trial Registration: ISRCTN 56012545. CONCLUSIONS: This is the first proposed clinical effectiveness trial of postoperative CPAP to prevent respiratory complications of which we are aware. The large sample size and multicenter international design will make the result generalizable to a variety of healthcare settings. PMID- 27763577 TI - Residual neuromuscular blockade: in the beginning there was chaos, but light has not been made yet. PMID- 27763578 TI - Injury-induced immunosuppression: we are finally on the right track? PMID- 27763579 TI - Effects of physical training for people with HIV-associated lipodystrophy syndrome: a systematic review. AB - INTRODUCTION: Human immunodeficiency virus-associated lipodystrophy syndrome (HALS) is a major problem among people living with HIV/aids. The exercise training has been used for its treatment; however, the knowledge about benefits and safety still is emerging. The aim was systematically review the literature for physiological, metabolic, immunologic, and morphologic adaptations to aerobic, resistance, and concurrent training in people living with HALS. EVIDENCE ACQUISITION: A search of the Medline, Embase, Cinahl, Lilacs, Scielo, Web of Science, the Cochrane Controlled Trials Register Library and PEDro was performed. The study selection was performed by two blinded researchers follow screening of titles, abstracts, and full-text articles. Therefore, only randomised clinical trials, which investigated the effects of physical training in people with HALS, were included in the present review. The risk of bias was assessed using a Jadad's scale. EVIDENCE SYNTHESIS: From the electronic and manual searches, 332 studies were selected by title, 139 abstracts were read and 95 were excluded, leaving 44 studies, which were read in full. After full text examination only five studies were included in the qualitative analyses. The limitations were: heterogeneity in training prescription, nutritional recommendations, and diagnosis of lipodystrophy, small sample size, utilization of methods with questionable validity for assessments. CONCLUSIONS: There is no effect of physical training on CD4 cell count. In addition, aerobic and concurrent training improve VO2max, likewise resistance and concurrent training improve muscular strength. PMID- 27763580 TI - Impact of rotator cuff surgery on postoperative sporting activity. AB - INTRODUCTION: The aim of this study was to systematically review the literature for the impact of rotator cuff tear (RCT) surgery on postoperative sporting activity in professional and recreational athletes. EVIDENCE ACQUISITION: To identify any published clinical study on return to sports data for athletes following rotator cuff surgery, a systematic search in literature was conducted. Inclusion criteria were partial and full-thickness rotator cuff tears and any open or arthroscopic RCT surgery in sports participating people. E-published and print journal articles with a Level of Evidence I, II, III and IV were acceptable. The review was based on using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Guidelines. Included studies were assessed for reporting quality by using the Coleman Methodology Score (CMS). EVIDENCE SYNTHESIS: Twelve studies including 314 athletes met the inclusion criteria. From the 12 identified studies there were 10 studies with Level IV evidence with an average CMS of 45.2 (poor rating) and 2 studies with Level III evidence with an average CMS of 47 (poor rating). The mean time for returning to sports participation following RCT surgery was 8.3 months (4.8-10.7 months), 79% of all athletes returned to sports participation, therefrom 60.5% were able to return to their pre-injury level of competition. Forty-eight percent of the professional overhead athletes had reached their pre-injury level after RCT surgery. 20.3% participated at a lower level. Amongst professional overhead athletes, 54.5% were treated using arthroscopic debridement and 32.5% were treated using an arthroscopic repair technique. RTS rate to prior level of competition for arthroscopic debridement was 53.7% and 47.5% for arthroscopic repair. For recreational athletes RCT repair was reported for 62%. RTS rate to prior level of competition was 69.4% in this group of athletes. 38% were treated with an arthroscopic RCT repair. RTS rate to same level was 76% in this group. In contact athletes arthroscopic repair resulted in RTS rate of 91% to prior level of competition. CONCLUSIONS: Approximately 50% of professional overhead athletes return to their prior level of competition after arthroscopic RCT surgery. Professional athletes underwent arthroscopic surgery more often compared to recreational athletes with a comparable RTS rate after either arthroscopic debridement or repair. Open repair of RCT is mainly used for recreational athletes and results in a RTS rate of 70% to same level of competition. Although there is a lack of high quality studies in recent literature regarding this topic this study shows that RCT surgery has a crucial impact on postoperative level of competition in professional and recreational athletes. The present study enables the sports physician to better understand and discuss the consequences of rotator cuff surgery with athletes in daily clinical practice. PMID- 27763581 TI - Match analysis of an elite beach soccer team. AB - BACKGROUND: The aim of this study was to investigate the physiological demands and technical-tactical performances of field players in Italian elite beach soccer team. METHODS: Three official matches of the Italian First Division beach soccer tournament were analyzed to evaluate the heart rate (HR) and time-motion analysis considering: standing, walking, jogging, running and sprinting, and technical-tactical aspects. Repeated-measures ANOVAs were used to determine the effects of time on the physiological measures and time motion analysis. RESULTS: The mean heart rate (HR) was 161+/-20 b.min-1 corresponding to an overall mean of 84.3+/-10.5% of maximum heart rate (HRmax). Beach soccer players spent 52.5% of the time exercising at HR>85% of their HRmax. The time motion analysis results showed that for 50% of the match the players performed very low intensity activities. The notational analysis showed that during the 52.8% of the offensive actions 2 players were involved and the 42.6% of the offensive actions was performed by one pass. CONCLUSIONS: These findings demonstrate that the beach soccer is an intermittent high intensity sport with a significant involvement of anaerobic metabolism. The results of time motion analysis and notational analysis underscored that the sand does not support the movements of players overall high intensity running. Team work is difficult to implement due to irregular rebounds and it does not consent precise passes. Furthermore this study suggests that it is important to include an intermittent training with high intensity and short recovery to improve the athlete's performance. PMID- 27763582 TI - Assessment of the impact of regular judo practice on body posture, balance, and lower limbs mechanical output in six-year-old boys. AB - BACKGROUND: Physical activity is beneficial for young children. The aim of this study was to monitor the changes in body posture and balance, as well as in the level of lower limbs mechanical output in six-year-old boys practicing judo (JU) and in a group not practicing that sport (NT). METHODS: In 12 matched pairs of boys (JU+NT) body mass and height were measured and Body Mass Index (BMI) was calculated at three time points (baseline, three months, six months). Body posture was evaluated with the use of Moire method (TT, DTK, MR, LALBC-F, DALBS). The balance was examined by means of the UPST Test with the eyes open (EOA) and closed (ECA). Ground reaction and relative power were assessed in standing vertical jump on the dynamometric platform. In the subsequent calculations, the MANOVA with the GLM procedure using 10 dependent above variables (excluding BMI and Pr indices), and next Factorial Repeated Measures ANOVA were used. RESULTS: In MANOVA a significant interaction of the time, and group, factor was ascertained. Next, the series of univariate ANOVAs yielded following results: for MR the difference between groups was significant after three months (with JU having better results than NT group), but not at the baseline or after six months. For UPST EOA, JU group had higher results after three months than those of NT group. For impulse (J), the interaction and time positive trend were significant. CONCLUSIONS: A six-month practice of judo results in a significant improvement in the quality of body posture, balance, and lower limbs muscle strength impulse. PMID- 27763583 TI - Altered gas-exchange at peak exercise in obese adolescents: implications for verification of effort during cardiopulmonary exercise testing. AB - BACKGROUND: Cardiopulmonary exercise testing is advised ahead of exercise intervention in obese adolescents to assess medical safety of exercise and physical fitness. Optimal validity and reliability of test results are required to identify maximal exercise effort. As fat oxidation during exercise is disturbed in obese individuals, it remains an unresolved methodological issue whether the respiratory gas exchange ratio (RER) is a valid marker for maximal effort during exercise testing in this population. METHODS: RER during maximal exercise testing (RERpeak), and RER trajectories, was compared between obese and lean adolescents and relationships between RERpeak, RER slope and subject characteristics (age, gender, Body Mass Index [BMI], Tanner stage, physical activity level) were explored. Thirty-four obese (BMI: 35.1+/-5.1 kg/m2) and 18 lean (BMI: 18.8+/-1.9 kg/m2) adolescents (aged 12-18 years) performed a maximal cardiopulmonary exercise test on bike, with comparison of oxygen uptake (VO2), heart rate (HR), expiratory volume (VE), carbon dioxide output (VCO2), and cycling power output (W). RESULTS: RERpeak (1.09+/-0.06 vs. 1.14+/-0.06 in obese vs. lean adolescents, respectively) and RER slope (0.03+/-0.01 vs. 0.05+/-0.01 per 10% increase in VO2, in obese vs. lean adolescents, respectively) was significantly lower in obese adolescents, and independently related to BMI (P<0.05). Adjusted for HRpeak and VEpeak, RERpeak and RER slope remained significantly lower in obese adolescents (P<0.05). RER trajectories (in relation to %VO2peak and %Wpeak) were significantly different between groups (P<0.001). CONCLUSIONS: RERpeak is significantly lowered in obese adolescents. This may have important methodological implications for cardiopulmonary exercise testing in this population. PMID- 27763584 TI - [Forensic medical characteristic of the causes behind sudden death in the young subjects]. AB - The objective of the present study was to analyze the causes of sudden death in the general population and in the fraction of the young subjects (below 39 years of age). The results of the original retrospective study were obtained in the course of forensic medical autopsies of the subjects aged below 39 years that had been carried out during a period of 10 years. It was shown that one of the causes behind sudden death among the young subjects is cardiovascular disorders associated with the pre-existing pathological condition in the form of connective tissue dysplasia. The principal mechanism underlying sudden death among the young subjects has an arrhythmogenic nature. The development of terminal symptoms is promoted by a number of provocative factors including sporting activities, physical loading, psychoemotional stress, and alcohol consumption. PMID- 27763585 TI - [The expert assessment of kidney damage morphology for the elucidation of the mechanism, intravitality, and duration of the injury]. AB - The objective of the present study was the expert assessment of the morphological signs of renal lesions depending on the type of deformation associated with a blunt trauma. The authors proposed the algorithm for the description of a kidney damage taking into consideration the specific morphological features associated with a blunt trauma. The pathomorphological changes in the kidney tissue under the normal hemodynamic conditions and in the case of hemorrhagic shock at different times after the injury taking into account its organ specificity make it possible to reliably predict the duration of the post-traumatic period. PMID- 27763586 TI - [Forensic medical implications of the traumas and traces of biological deposits in the context of comprehensive expertises of the injuries inflicted inside the passenger compartment of the car]. AB - The results of analysis of forensic medical expertises carried out by different state institutions of forensic medical expertise of this country are presented. It was shown that the practice of standardized expertises of the injuries inflicted inside the passenger compartment of the car remains to be established. The comprehensive approach to the solution of the problem of the circumstances of the road traffic accident and the positions of its participants in the passenger compartment of the car is possible based only on the multi-faceted investigation. The definitive combined study including the analysis and comparison of the results of the autotechnical expertise, forensic medical examination of the corpses and the survivors inside the passenger car compartment, forensic biological (molecular genetic) expertises, and medico-criminalistic investigations of the traces of biological deposits and microparticles retained on the components of the passenger compartments and the clothes of the victims makes it possible to determine, with a high degree of accuracy, the position of the participants of the traffic accident inside the passenger compartment of the car at the moment of collision. PMID- 27763587 TI - [Forensic medical characteristics of the damages to the human clothes caused by blowgun shots of various types of darts]. AB - The objective of the present experimental study was to determine certain regular features of the damages to the human clothes caused by blowgun shots of various types of darts and to elucidate the mechanisms underlying the formation of the damages. The study revealed the objective morphological features of the damages inflicted by various types of darts shot from the blowguns of two calibers. PMID- 27763588 TI - [The morphological features of the testicles under conditions of experimental acute and chronic alcohol intoxication]. AB - This paper is designed to report the results of the comparative analysis of the structural alterations in the testicles under conditions of experimental acute and chronic alcohol intoxication in the laboratory rats. It was shown that experimental acute alcohol intoxication causes only such changes that suggest the non-specific gonadal response to alcohol poisoning and represent characteristic manifestations of the general organ reactions. The chronic exposure of the experimental animals to alcohol results in more pronounced changes in the testicles the severity of which depends on the duration of alcohol consumption. PMID- 27763589 TI - [The interpopulation differences between nucleotide sequence polymorphisms in alleles of the STR-loci of human chromosomal DNA]. AB - The objective of the present work was to study the phenomenon of nucleotide sequence polymorphism in alleles of the STR-loci of human chromosomal DNA and to estimate its interpopulation differences with a view to the search for the molecular-genetic markers to be used as an efficient tool for the determination of belonging of the subjects of interest to a given population. We undertook the comprehensive analysis of amplified DNA fragment sequence polymorphism (AFSP) and amplified DNA fragment length polymorphism (AFLP) with the use of the PLEX-ID-TM analytical mass-spectrometry platform (Abbott Molecular, USA). The interpopulation differences were estimated in terms of the presence or the absence of single nucleotide replacements (SNP) in the STR markers based on a few population samples. Some of the loci of interest were found to have allelic variants the occurrence of which was significantly different in individual samples. Such alleles are of importance for the further investigation since they can be regarded as potential ethno-geographical markers. Their application opens up the new promising prospects for the expert detection of the ethnic affiliation of individual subjects. PMID- 27763590 TI - [The use of the spectral analysis techniques for the medico-criminalistic identification of the speaker]. AB - The objective of the present article is to discuss the theoretical foundations and the methodological basis for the use of the apparatus of spectral analysis for the purpose of medico-criminalistic personality identification from the characteristics of the subject's voice and sounding speech. The article is based on the review of the literature sources and the methodological approaches developed by the author. PMID- 27763591 TI - [The development and validation of the methods for the quantitative determination of sibutramine derivatives in dietary supplements]. AB - The objective of the present study was the development and validation of sibutramine demethylated derivatives, desmethyl sibutramine and didesmethyl sibutramine. Gas-liquid chromatography with the flame ionization detector was used for the quantitative determination of the above substances in dietary supplements. The conditions for the chromatographic determination of the analytes in the presence of the reference standard, methyl stearate, were proposed allowing to achieve the efficient separation. The method has the necessary sensitivity, specificity, linearity, accuracy, and precision (on the intra-day and inter-day basis) which suggests its good validation characteristics. The proposed method can be employed in the analytical laboratories for the quantitative determination of sibutramine derivatives in biologically active dietary supplements. PMID- 27763592 TI - [The peculiarities of determination of 2-chloro-1,4-dihydrooxybenzene in the biological material]. AB - The objective of the present study was to elucidate the peculiarities of the determination of 2-chloro-1,4-dihydrooxybenzene in the tissues of different organs and blood. The analytical methods used in the study included TLC, GC-MS, and UF-spectrophotometry. The study has demonstrated the usefulness of using acetone as an insulating solvent for the extraction of 2-chloro-1,4 dihydrooxybenzene from the biological materials. It was shown that the compound being analyzed can be separated from the endogenous substances contained in the biological matrices on the "Silasorb C-18" columns, 30 mcm. The method for the identification of 2-chloro-1,4-dihydrooxybenzene in the blood and organ tissues (such as normal and putrefied renal tissues) was developed. The method permits to determine 0.26 mg and 0.30 mg of the substance of interest in 100 g of the normal and putrefied renal tissues respectively; in addition, it measures 0.22 mg of 2 chloro-1,4-dihydrooxybenzene in the blood. PMID- 27763593 TI - [The new technique for the identification of aluminium on the study objects by the contact-diffusion method]. AB - This article was designed to discuss the possibility of discovering the trace deposits of a metal (aluminium) sedimented on various objects with the use of the indicator alizarin S in order to determine the distance of the shot and identify the concrete traumatic weapons of the "Osa", "Strazhnik" type used for the purpose. PMID- 27763594 TI - [The forensic medical implications of the determination of the species composition of necrophilic dipterans]. AB - The objective of the present work was to study the species composition of necrophilic dipterans and their participation in corpse decomposition. The material for the study was collected from the swine corpses weighing from 50 to 70 kg and from the dead human bodies in Karelia during the period from 2014 to 2015. It was shown that 8 dipteran species belonging to 5 families contribute to corpse decomposition in the European part of Russia. They are dominated by Protophormia terraenovae and Calliphora vicina. The quantitative composition of the necrophilic dipterans developing in human and animal corpses differ depending on the local environmental conditions. PMID- 27763595 TI - [The interstitial disease of the lungs revealed by a histological study]. AB - The authors report a case of the interstitial disease of the lungs revealed by a histological study that demonstrated intravital diagnostic faults in the patient in question. Moreover, a postmortem diagnostic error occurred; namely, the macroscopic study of the thoracic organs had shown the 0.5 cm long linear rupture of the adhesion in the right lung root region that was considered to be the cause of hemothorax and anemia of the internal organs which supposedly resulted in the patient's death. The definitive diagnosis of interstitial disease of the lungs was established based on the results of the histological study. The histological picture of the process is illustrated. PMID- 27763596 TI - Predictors for mortality due to acute exacerbation of COPD in primary care: protocol for the derivation of a clinical prediction rule. PMID- 27763597 TI - Hollywood raising awareness of smoking-related diseases: can it proactively counteract the impact of smoking in movies?-the final mission of Star Trek's Mr Spock. PMID- 27763598 TI - New Australian sauropods shed light on Cretaceous dinosaur palaeobiogeography. AB - Australian dinosaurs have played a rare but controversial role in the debate surrounding the effect of Gondwanan break-up on Cretaceous dinosaur distribution. Major spatiotemporal gaps in the Gondwanan Cretaceous fossil record, coupled with taxon incompleteness, have hindered research on this effect, especially in Australia. Here we report on two new sauropod specimens from the early Late Cretaceous of Queensland, Australia, that have important implications for Cretaceous dinosaur palaeobiogeography. Savannasaurus elliottorum gen. et sp. nov. comprises one of the most complete Cretaceous sauropod skeletons ever found in Australia, whereas a new specimen of Diamantinasaurus matildae includes the first ever cranial remains of an Australian sauropod. The results of a new phylogenetic analysis, in which both Savannasaurus and Diamantinasaurus are recovered within Titanosauria, were used as the basis for a quantitative palaeobiogeographical analysis of macronarian sauropods. Titanosaurs achieved a worldwide distribution by at least 125 million years ago, suggesting that mid Cretaceous Australian sauropods represent remnants of clades which were widespread during the Early Cretaceous. These lineages would have entered Australasia via dispersal from South America, presumably across Antarctica. High latitude sauropod dispersal might have been facilitated by Albian-Turonian warming that lifted a palaeoclimatic dispersal barrier between Antarctica and South America. PMID- 27763600 TI - Three cheers for the three-spined stickleback. PMID- 27763601 TI - Anticoagulation therapy in animal research. PMID- 27763599 TI - Effect of cannabis smoking on lung function and respiratory symptoms: a structured literature review. AB - As cannabis use increases, physicians need to be familiar with the effects of both cannabis and tobacco on the lungs. However, there have been very few long term studies of cannabis smoking, mostly due to legality issues and the confounding effects of tobacco. It was previously thought that cannabis and tobacco had similar long-term effects as both cause chronic bronchitis. However, recent large studies have shown that, instead of reducing forced expiratory volume in 1 s and forced vital capacity (FVC), marijuana smoking is associated with increased FVC. The cause of this is unclear, but acute bronchodilator and anti-inflammatory effects of cannabis may be relevant. Bullous lung disease, barotrauma and cannabis smoking have been recognised in case reports and small series. More work is needed to address the effects of cannabis on lung function, imaging and histological changes. PMID- 27763605 TI - Compliance training within an institution, but not for direct users. PMID- 27763606 TI - Response to Protocol Review Scenario: Call me maybe. PMID- 27763607 TI - RFID: untangling mutant phenotypes. AB - Improvements to RFID technology are making it an increasingly flexible tool for tracking genetically modified rodents, characterizing their natural behaviors, and improving data integrity. PMID- 27763610 TI - State-of-the-art equipment for sterilization and biocontainment since 1925. PMID- 27763611 TI - PulseCMC(r)-Monitoring and protecting your critical research. PMID- 27763613 TI - Response to Protocol Review Scenario: Know your role and options. PMID- 27763615 TI - Response to Protocol Review Scenario: A Word from OLAW. PMID- 27763617 TI - Ferrets that help fight the flu. PMID- 27763618 TI - Who should decide when and how to contact OLAW? PMID- 27763619 TI - An overview of laboratory animal science in the nation of Georgia. PMID- 27763620 TI - Response to Protocol Review Scenario: Taking too many liberties can affect trust. PMID- 27763621 TI - Use of the Phadebas amylase test to assess the presence of rodent saliva. PMID- 27763622 TI - Measurement characteristics of the childhood Asthma-Control Test and a shortened, child-only version. AB - The childhood Asthma-Control Test (C-ACT) is validated for assessing asthma control in paediatric asthma. Among children aged 4-11 years, the C-ACT requires the simultaneous presence of both parent and child. There is an unmet need for a tool that can be used to assess asthma control in children when parents or caregivers are not present such as in the school setting. We assessed the psychometric properties and estimated the minimally important difference (MID) of the C-ACT and a modified version, comprising only the child responses (C-ACTc). Asthma patients aged 6-11 years (n=161) from a previously completed multicenter randomised trial were included. Demographic information, spirometry and questionnaire scores were obtained at baseline and during follow-up. Participants or their guardians kept a daily asthma diary. Internal consistency reliabilities of the C-ACT and C-ACTc were 0.76 and 0.67 (Cronbach's alpha), respectively. Test retest reliabilities of the C-ACT and C-ACTc were 0.72 and 0.66 (intra-class correlation), respectively. Significant correlations were noted between C-ACT scores and ACQ scores (Spearman's correlation r=-0.56, 95% CI (-0.66, -0.44), P<0.001). The strength of the correlation between C-ACTc scores and ACQ scores was weaker (Spearman's correlation r=-0.46, 95% CI (-0.58, -0.33), P<0.001). We estimated the MID for the C-ACT and C-ACTc to be 2 points and 1 point, respectively. Among asthma patients aged 6-11 years, the C-ACT had good psychometric properties. The psychometric properties of a shortened child-only version (C-ACTc), although acceptable, are not as strong. PMID- 27763623 TI - Change in health status in COPD: a seven-year follow-up cohort study. AB - Health status is a prognostic factor included in the assessment of chronic obstructive pulmonary disease (COPD). The aim of our study was to examine the associations of clinical factors with change in health status over a 7-year follow-up period. In 2005, 970 randomly selected primary and secondary care patients with a COPD diagnosis completed questionnaires including the Clinical COPD Questionnaire (CCQ); and in 2012, 413 completed the CCQ questionnaire again. Linear regression used difference in mean total CCQ score between 2005 and 2012 as the dependent variable. Independent variables were CCQ score at baseline 2005, sex, age, educational level, body mass index (BMI), smoking status, heart disease, diabetes, depression, number of exacerbations in the previous 6 months, dyspnoea (modified Medical Research Council (mMRC)). Health status worsened from mean total CCQ (s.d.) 2.03 (1.26) in 2005 to 2.16 (1.37) in 2012 (P=0.011). In linear regression with adjustment for baseline CCQ; older age, lower education, higher mMRC and BMI below 25 kg/m2 at baseline were associated with worsened health status in 2012. When sex, age and all statistically significant measures were included simultaneously in the analysis of the main study group, higher mMRC and BMI below 25 kg/m2 were were associated with deteriorated health status (P<0.0001). A higher level of dyspnoea and lower weight were associated with worse health status in COPD. Strategies for decreasing dyspnoea and awareness of the possible increased risk of worsening disease in under- and normal-weight COPD patients are clinically important. PMID- 27763624 TI - Preparation of plasmonic vesicles from amphiphilic gold nanocrystals grafted with polymer brushes. AB - Gold nanovesicles contain multiple nanocrystals within a polymeric coating. The strong plasmonic coupling between adjacent nanoparticles in their vesicular shell makes ultrasensitive biosensing and bioimaging possible. In our laboratory, multifunctional plasmonic vesicles are assembled from amphiphilic gold nanocrystals (such as gold nanoparticles and gold nanorods) coated with mixed hydrophilic and hydrophobic polymer brushes or amphiphilic diblock co-polymer brushes. To fulfill the different requirements of biomedical applications, different polymers that are either pH=responsive, photoactive or biodegradable can be used to form the hydrophobic brush, while the hydrophilicity is maintained by polyethylene glycol (PEG). This protocol covers the preparation, surface functionalization and self-assembly of amphiphilic gold nanocrystals grafted covalently with polymer brushes. The protocol can be completed within 2 d. The preparation of amphiphilic gold nanocrystals, coated with amphiphilic diblock polymer brushes using a 'grafting to' method or mixed hydrophilic and hydrophobic polymer brushes using tandem 'grafting to' and 'grafting from' methods, is described. We also provide detailed procedures for the preparation and characterization of pH-responsive plasmonic gold nanovesicles from amphiphilic gold nanocrystals using a film-rehydration method that can be completed within ~3 d. PMID- 27763625 TI - Identification and propagation of haploid human pluripotent stem cells. AB - Haploid human pluripotent stem cells (PSCs) integrate haploidy and pluripotency, providing a novel system for functional genomics and developmental research in humans. We have recently derived haploid human embryonic stem cells (ESCs) by parthenogenesis and demonstrated their wide differentiation potential and applicability for genetic screening. Because haploid cells can spontaneously become diploid, their enrichment at an early passage is key for successful derivation. In this protocol, we describe two methodologies, namely metaphase spread analysis and cell sorting, for the identification of haploid human cells within parthenogenetic ESC lines. The cell sorting approach also enables the isolation of haploid cells at low percentages, as well as the maintenance of highly enriched haploid ESC lines throughout passaging. The isolation of essentially pure populations of haploid human ESCs by this protocol requires basic PSC culture expertise and can be achieved within 4-6 weeks. PMID- 27763626 TI - Assembly of multienzyme complexes on DNA nanostructures. AB - In nature, the catalytic efficiency of multienzyme complexes highly depends on their spatial organization. The positions and orientations of the composite enzymes are often precisely controlled to facilitate substrate transport between them. Self-assembled DNA nanostructures hold great promise for organizing biomolecules at the nanoscale. Here, we present detailed protocols for exploiting DNA nanostructures as assembly scaffolds that organize the spatial arrangements of multienzyme cascades with control over their relative distance, compartmentalization and substrate diffusion paths. The protocol describes the preparation and purification of DNA-conjugated enzymes and cofactors, along with the assembly of these prepared complexes on DNA nanostructures. The architecture of assembled enzyme complexes is then readily characterized using a broad selection of techniques from routine gel electrophoresis to advanced single molecule imaging. We also describe methods of purifying these nano-assemblies and testing them with functional assays based on either bulk or single-molecule fluorescence measurements. The entire assembly and characterization of a multienzyme complex can be completed within 1-2 weeks. PMID- 27763628 TI - Reliability of transcutaneous bilirubinometry from shielded skin in neonates receiving phototherapy: a prospective cohort study. AB - OBJECTIVE: To determine the agreement between transcutaneous bilirubin (TcB) measured from shielded skin and serum total bilirubin (STB) in infants (34 to 41 weeks of gestation) with hyperbilirubinemia receiving phototherapy (PT). STUDY DESIGN: In this prospective cohort study, we shielded a small area of skin on sternum using a commercial photo-opaque patch (BilEclipseTM, Philips Respironics, Murrysville, PA, USA). The TcB from the shielded skin (TcBs) and STB were measured at four time points-before initiation, 12 and 24 h during and once after (12 h) cessation of PT. TcB was measured using multiwavelength transcutaneous bilirubinometer (BiliChek, Philips Children's Medical Ventures, Monroeville, PA, USA). The STB was measured in triplicate by spectrophotometry (Apel BR 5100, APEL, Japan). Bland and Altman plots were drawn to determine agreement between the TcBs and STB. RESULTS: The gestation and birth weight of enrolled neonates were 37.0 (1.0) weeks and 2750 (458) g, respectively. The age at initiation and duration of PT were 75 (27 to 312) and 25.3 (4.4) h, respectively. Bland and Altman plot showed poor agreement between TcBs and STB at all time points. The gradient (median, range) between TcBs and STB at 0, 12, 24 h and 12 h after cessation of PT were -0.2 (-4.9 to 3.5), 1.4 (-4.7 to 4.0), 1.5 (-3.8 to 9.4) and 2 (-2.9 to 5.8) mg dl-1. The proportions of TcBs values outside +/-1.5 mg dl-1 of STB ranged from 47 to 64% at four time points. CONCLUSION: TcBs does not appear to be reliable for estimating serum bilirubin in late preterm and term neonates receiving PT. PMID- 27763627 TI - Human Intestinal Barrier Function in Health and Disease. AB - The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed. PMID- 27763629 TI - Risk factors for persistent disability in children with obstetric brachial plexus palsy. AB - OBJECTIVE: Obstetric brachial plexus palsy (OBPP) at birth, is a serious neurologic injury that may lead to a long lasting disability. We aimed to examine the occurrence and risk factors associated with disability lasting >1 year. STUDY DESIGN: A retrospective cohort study conducted between 1993 and 2012 included individuals with diagnosis of OBPP at birth. Affected individual's motor function was evaluated by a direct physical exam based on a muscle grading system of the limb, shoulder, elbow and hand. When not feasible a telephone questionnaire was used. Participants reported on activities of daily living, disability duration and any type of intervention. Stepwise logistic regression model was used to identify demographic and obstetric risk factors for disability lasting >1 year. RESULTS: Of all 83 806 deliveries during this period, 144 OBPP cases were identified (1.7/1000). Of the 91 (63.2%) individuals located 42 (46.2%) were evaluated by a physical exam and 49 (53.8%) answered a telephone questionnaire. In 12 (13.2%) disability lasted >1 year. Significant predictors for disability lasting >1 year included birthweight >4 kg (P=0.02; odds ratio (OR) 6.17; 95% confidence interval (CI) 1.33-28.65) and younger maternal age (P=0.02; OR 0.84; 95% CI: 0.73-0.97). OBPP decreased 16% per 1 year increase in maternal age. CONCLUSIONS: OBPP is a transient injury in most cases. Birthweight over 4 kg and younger maternal age maybe associated with disability lasting >1 year. PMID- 27763630 TI - Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants. AB - OBJECTIVE: To determine the effect of concomitant administration of prophylactic indomethacin and early enteral feeds on the risk of spontaneous intestinal perforation (SIP) in extremely low-birth-weight (ELBW) infants, and to describe the variation in prophylactic indomethacin use in Canada. STUDY DESIGN: A retrospective cohort study of 4268 ELBW infants born at <30 weeks' gestation admitted to Canadian neonatal units between 2010 and 2014 was conducted. Prophylactic indomethacin (I+ or I-, administered within 24 h) and early feeding (E+ or E-, initiated in the first 2 days) exposures were studied concurrently and independently. The primary outcomes were SIP and death before discharge. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Compared with the I-/E+ reference group (n=1829), infants in I+/E+ (n=285; aOR 2.92, 95% CI 1.41 to 6.08) and I+/E- (n=213; aOR 2.84, 95% CI 1.35 to 5.98) groups had higher odds of SIP, whereas those in the I-/E- group had similar odds (n=1941; aOR 1.37, 95% CI 0.88 to 2.14). Odds of SIP were higher in the indomethacin exposed group (I+) compared with the unexposed (I-) group when controlled for early feeding (aOR 2.43, 95% CI 1.41 to 4.19), but not in the early feeding group when controlled for indomethacin. The use of prophylactic indomethacin ranged from 0% usage in 13 sites to 78% use in one site. CONCLUSION: Prophylactic indomethacin was associated with increased odds of SIP independently from early feeding in this cohort; however, early enteral feeding was not associated with SIP. Marked variation in the use of prophylactic indomethacin was identified. PMID- 27763632 TI - Managing sickle cell carrier results generated through newborn screening in Ontario: a precedent-setting policy story. PMID- 27763631 TI - Enhancing sensory experiences for very preterm infants in the NICU: an integrative review. AB - OBJECTIVE: Very preterm infants hospitalized in the neonatal intensive care unit (NICU) experience alterations in sensory experiences. Defining types, timing and frequency of sensory-based interventions that optimize outcomes can inform environmental modifications. The objective of this study was to conduct an integrative review on sensory-based interventions used with very preterm infants in the NICU to improve infant and parent outcomes. STUDY DESIGN: The data sources include MEDLINE, CINAHL, Cochrane Library and Google Scholar. Studies were identified that used sensory-based interventions in the NICU with preterm infants born ?32 weeks gestation, were published in a peer-reviewed journal between 1995 and 2015, and measured outcomes related to infant and parent outcomes. Studies were extracted from electronic databases and hand-searched from identified reference lists. RESULTS: Eighty-eight articles were identified (31 tactile, 12 auditory, 3 visual, 2 kinesthetic, 2 gustatory/olfactory and 37 multimodal). There was evidence to support the use of kangaroo care, music and language exposure, and multimodal interventions starting at 25 to 28 weeks postmenstrual age. These interventions were related to better infant development and lower maternal stress, but not all findings were consistent. Limitations included lack of consistent outcome measures, study quality and gaps in the literature. CONCLUSIONS: Most research identified interventions that were done for short periods of time. It is unclear what the potential is for improving outcomes if positive sensory exposures occur consistently throughout NICU hospitalization. Until more research defines appropriate sensory-based interventions to use with infants born very preterm in the NICU, information from this review can be combined with expert opinion and parent/family values to determine best practice. PMID- 27763633 TI - Engagement and communication among participants in the ClinSeq Genomic Sequencing Study. AB - PURPOSE: As clinical genome sequencing expand its reach, understanding how individuals engage with this process are of critical importance. In this study, we aimed to describe internal engagement and its correlates among a ClinSeq cohort of adults consented to genome sequencing and receipt of results. METHODS: This study was framed using the precaution adoption process model (PAPM), in which knowledge predicts engagement and engagement predicts subsequent behaviors. Prior to receipt of sequencing results, 630 participants in the study completed a baseline survey. Engagement was assessed as the frequency with which participants thought about their participation in ClinSeq since enrollment. RESULTS: Results were consistent with the PAPM: those with higher genomics knowledge reported higher engagement (r = 0.13, P = 0.001) and those who were more engaged reported more frequent communication with their physicians (r = 0.28, P < 0.001) and family members (r = 0.35, P < 0.001) about ClinSeq. Characteristics of those with higher engagement included poorer overall health (r = -0.13, P = 0.002), greater seeking of health information (r = 0.16, P < 0.001), and more recent study enrollment (r = -0.21, P < 0.001). CONCLUSION: These data support the importance of internal engagement in communication related to genomic sequencing.Genet Med 19 1, 98-103. PMID- 27763634 TI - Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing. AB - INTRODUCTION: RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. MATERIALS AND METHODS: The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children's Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies. RESULTS: Twenty-four patients had pathogenic variants on the RASopathy panel, for a diagnostic yield of 19%. Reported features of pulmonic stenosis and ptosis were significantly correlated with a positive test result; no reported features were significantly correlated with a negative test result. We identified 27 different alternative diagnoses for patients originally suspected of having RASopathies. DISCUSSION: This study provides information that can assist in guiding differential diagnosis and genetic testing for patients suspected of having a RASopathy disorder.Genet Med advance online publication 20 October 2016. PMID- 27763635 TI - Genetics/genomics education for nongenetic health professionals: a systematic literature review. AB - PURPOSE: The completion of the Human Genome Project has enhanced avenues for disease prevention, diagnosis, and management. Owing to the shortage of genetic professionals, genetics/genomics training has been provided to nongenetic health professionals for years to establish their genomic competencies. We conducted a systematic literature review to summarize and evaluate the existing genetics/genomics education programs for nongenetic health professionals. METHODS: Five electronic databases were searched from January 1990 to June 2016. RESULTS: Forty-four studies met our inclusion criteria. There was a growing publication trend. Program participants were mainly physicians and nurses. The curricula, which were most commonly provided face to face, included basic genetics; applied genetics/genomics; ethical, legal, and social implications of genetics/genomics; and/or genomic competencies/recommendations in particular professional fields. Only one-third of the curricula were theory-based. The majority of studies adopted a pre-/post-test design and lacked follow-up data collection. Nearly all studies reported participants' improvements in one or more of the following areas: knowledge, attitudes, skills, intention, self-efficacy, comfort level, and practice. However, most studies did not report participants' age, ethnicity, years of clinical practice, data validity, and data reliability. CONCLUSION: Many genetics/genomics education programs for nongenetic health professionals exist. Nevertheless, enhancement in methodological quality is needed to strengthen education initiatives.Genet Med advance online publication 20 October 2016. PMID- 27763636 TI - ZNF32 contributes to the induction of multidrug resistance by regulating TGF-beta receptor 2 signaling in lung adenocarcinoma. AB - Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells. In this study, we found that ZNF32 is upregulated by Sp1 (specificity protein 1) in response to drug treatment and that ZNF32 promotes drug resistance and protects AC cells against cisplatin or gefitinib treatment. ZNF32 overexpression in AC cells conferred resistance to EGFR (epidermal growth factor receptor) inhibitors by enhancing MEK/ERK activation. Moreover, ZNF32 was found to directly bind to the TGF-betaR2 (transforming growth factor-beta receptor 2) promoter to promote its expression, and ZNF32-induced resistance was mediated by enhancing TGF-betaR2 expression and activating the TGF-betaR2/SMAD2 pathway. In both a mouse model and ex vivo cultured patient samples, a high level of ZNF32 expression was closely associated with worse overall survival and cisplatin resistance. ZNF32 appears to be a potential inducer of drug resistance that could increase the expression of the drug resistance-associated gene TGF-betaR2 and subsequently facilitate the induction of drug resistance during both conventional chemotherapy and novel target therapy. Thus, ZNF32-associated target therapy is a potential novel adjuvant therapy that might effectively prevent the occurrence of multidrug resistance (MDR) during chemotherapy and improve the survival of patients with AC. PMID- 27763637 TI - Nogo-C regulates cardiomyocyte apoptosis during mouse myocardial infarction. AB - Myocardial infarction is caused by insufficient coronary blood supply, which leads to myocardial damage and eventually the heart failure. Molecular mechanisms associated with the loss of cardiomyocytes during myocardial infarction (MI) and ischemia-related cardiac diseases are not yet fully understood. Nogo-C is an endoplasmic reticulum protein ubiquitously expressed in tissues including in the heart, however, the cardiac function of Nogo-C is still unknown. In the present study, we found that Nogo-C was upregulated in mouse hearts after MI, and hypoxic treatments also increased Nogo-C protein level in cardiomyocytes. Adenovirus mediated overexpression of Nogo-C led to cardiomyocyte apoptosis, whereas knockdown of Nogo-c by shRNA protected cardiomyocytes from hypoxia-induced cell apoptosis. Importantly, Nogo-C knockout mice displayed improved cardiac function, smaller infarct area, and less apoptotic cells after MI. Moreover, we found that miR-182 negatively regulated Nogo-C expression and was downregulated during MI, expressing miR-182 in cardiomyocytes protected hypoxia- and Nogo-C-mediated cell apoptosis. Our results indicate that increased cardiac Nogo-C expression is both sufficient and necessary for ischemia-induced cardiomyocyte apoptosis and cardiac dysfunction, suggesting that deregulation of Nogo-C by miRNA may be a potential therapeutic target for ischemia-related heart diseases. PMID- 27763638 TI - 1, 25-dihydroxy-vitamin D3 with tumor necrosis factor-alpha protects against rheumatoid arthritis by promoting p53 acetylation-mediated apoptosis via Sirt1 in synoviocytes. AB - Impaired apoptosis of fibroblast-like synoviocytes (FLSs) causes synovial hyperplasia, facilitating destruction of cartilage and bone in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)-alpha, a dominant inflammatory mediator in RA pathogenesis, promotes progression of RA symptoms. Prevalence of 1, 25-dihydroxy-vitamin D3 (hereafter termed VD) deficiency is 30-63% in patients with RA. Whether VD leads to apoptosis or enhances TNF-alpha-mediated apoptosis in FLSs to ameliorate RA is unclear. To determine this, 10-week-old CYP27B1 deficient (CYP27B1-/-) mice with collagen-induced arthritis (CIA) were intraperitoneally treated with 1 MUg/kg VD every other day for 9 weeks. RA phenotypes were compared between vehicle-treated CYP27B1-/- and wild-type CIA mice. Human rheumatoid FLS-MH7A cells were treated with Dulbecco's modified Eagle's medium (DMEM) without fetal bovine serum (FBS) for 24 h, then with different concentrations of VD and TNF-alpha, human vitamin D receptor (VDR) siRNA or the p53 pro-apoptotic inhibitor pifithrin-alpha. Apoptosis and p53 pro apoptotic signaling were analyzed. The 19-week-old vehicle-treated CYP27B1-/- CIA mice had increased cumulative arthritis scores and levels of serous rheumatoid factors and C-reactive protein. They had exacerbated articular cartilage and bone destruction, joint space narrowing, joint stiffness, deformity and dysfunction, synovitis and TNF-alpha secretion, FLS hyperplasia with increased proliferation and decreased apoptosis compared to CIA mice. These RA phenotypes that were aggravated in CIA mice by CYP27B1 deficiency were largely rescued by VD treatment. In vitro, VD with TNF-alpha treatment upregulated p53 acetylation mediated apoptosis in MH7A cells by promoting Sirt1 translocation from the nucleus to the cytoplasm. These findings indicated that VD with TNF-alpha protected against RA by promoting apoptosis of FLSs. The results indicated that clinical administration of VD could be a specific therapy to promote FLS apoptosis and prevent RA progression. PMID- 27763639 TI - Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts. AB - Myoblasts are mononucleated precursors of myofibers; they persist in mature skeletal muscles for growth and regeneration post injury. During myotonic dystrophy type 1 (DM1), a complex autosomal-dominant neuromuscular disease, the differentiation of skeletal myoblasts into functional myotubes is impaired, resulting in muscle wasting and weakness. The mechanisms leading to this altered differentiation are not fully understood. Here, we demonstrate that the calcium- and voltage-dependent potassium channel, KCa1.1 (BK, Slo1, KCNMA1), regulates myoblast proliferation, migration, and fusion. We also show a loss of plasma membrane expression of the pore-forming alpha subunit of KCa1.1 in DM1 myoblasts. Inhibiting the function of KCa1.1 in healthy myoblasts induced an increase in cytosolic calcium levels and altered nuclear factor kappa B (NFkappaB) levels without affecting cell survival. In these normal cells, KCa1.1 block resulted in enhanced proliferation and decreased matrix metalloproteinase secretion, migration, and myotube fusion, phenotypes all observed in DM1 myoblasts and associated with disease pathogenesis. In contrast, introducing functional KCa1.1 alpha-subunits into DM1 myoblasts normalized their proliferation and rescued expression of the late myogenic marker Mef2. Our results identify KCa1.1 channels as crucial regulators of skeletal myogenesis and suggest these channels as novel therapeutic targets in DM1. PMID- 27763640 TI - Methamphetamine potentiates HIV-1 gp120-mediated autophagy via Beclin-1 and Atg5/7 as a pro-survival response in astrocytes. AB - Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity. We found that METH and gp120 IIIb caused an increase in LC3II level in astrocytes in a dose- and time dependent manner, and the level of LC3II was further increased when the cells were treated with METH and gp120 IIIb in combination. Next, we sought to explore the mechanism by which METH and gp120 induce the autophagic response. We found that METH induces autophagy via opioid and metabotropic glutamate receptor type 5 (mGluR5) receptors. Other than that, signaling proteins Akt, mammalian target of rapamycin (mTOR), Beclin-1, Atg5 and Atg7 were involved in METH and gp120 mediated autophagy. In addition, long-term treatment of METH and gp120 IIIb resulted in cell death, which was exacerbated by inhibition of autophagy. This suggests that autophagy functions as a protective response against apoptosis caused by METH and gp120. This study is novel and clinically relevant because METH abuse among HIV-infected populations is highly prevalent and is known to cause exacerbated neuroAIDS. PMID- 27763641 TI - PKN2 and Cdo interact to activate AKT and promote myoblast differentiation. AB - Skeletal myogenesis is coordinated by multiple signaling pathways that control cell adhesion/migration, survival and differentiation accompanied by muscle specific gene expression. A cell surface protein Cdo is involved in cell contact mediated promyogenic signals through activation of p38MAPK and AKT. Protein kinase C-related kinase 2 (PKN2/PRK2) is implicated in regulation of various biological processes, including cell migration, adhesion and death. It has been shown to interact with and inhibit AKT thereby inducing cell death. This led us to investigate the role of PKN2 in skeletal myogenesis and the crosstalk between PKN2 and Cdo. Like Cdo, PKN2 was upregulated in C2C12 myoblasts during differentiation and decreased in cells with Cdo depletion caused by shRNA or cultured on integrin-independent substratum. This decline of PKN2 levels resulted in diminished AKT activation during myoblast differentiation. Consistently, PKN2 overexpression-enhanced C2C12 myoblast differentiation, whereas PKN2-depletion impaired it, without affecting cell survival. PKN2 formed complexes with Cdo, APPL1 and AKT via its C-terminal region and this interaction appeared to be important for induction of AKT activity as well as myoblast differentiation. Furthermore, PKN2-enhanced MyoD-responsive reporter activities by mediating the recruitment of BAF60c and MyoD to the myogenin promoter. Taken together, PKN2 has a critical role in cell adhesion-mediated AKT activation during myoblast differentiation. PMID- 27763642 TI - Bcl-2 proteins bid and bax form a network to permeabilize the mitochondria at the onset of apoptosis. AB - The most critical step in the initiation of apoptosis is the activation of the Bcl-2 family of proteins to oligomerize and permeabilize the outer-mitochondrial membrane (OMM). As this step results in the irreversible release of factors that enhance cellular degradation, it is the point of no return in programmed cell death and would be an ideal therapeutic target. However, the arrangement of the Bcl-2 proteins in the OMM during permeabilization still remains unknown. It is also unclear whether the Bcl-2 protein, Bid, directly participates in the formation of the oligomers in live cells, even though it is cleaved and translocates to the OMM at the initiation of apoptosis. Therefore, we utilized confocal microscopy to measure Forster resonance energy transfer (FRET) efficiencies in live cells to determine the conformation(s) and intermolecular contacts of Bid within these Bcl-2 oligomers. We found that Bid adopts an extended conformation, which appears to be critical for its association with the mitochondrial membrane. This conformation is also important for intermolecular contacts within the Bid oligomer. More importantly for the first time, direct intermolecular contacts between Bid and Bax were observed, thereby, confirming Bid as a key component of these oligomers. Furthermore, the observed FRET efficiencies allowed us to propose an oligomeric arrangement of Bid, Bax, and possibly other members of the Bcl-2 family of proteins that form a self propagating network that permeabilizes the OMM. PMID- 27763643 TI - Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration. AB - The renin-angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the 'classical' humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in which local RAS play a key role in degenerative and aging-related diseases. The local brain RAS plays a major role in brain function and neurodegeneration. It is normally assumed that the effects are mediated by the cell-surface-specific G-protein-coupled angiotensin type 1 and 2 receptors (AT1 and AT2). A combination of in vivo (rats, wild-type mice and knockout mice) and in vitro (primary mesencephalic cultures, dopaminergic neuron cell line cultures) experimental approaches (confocal microscopy, electron microscopy, laser capture microdissection, transfection of fluorescent-tagged receptors, treatments with fluorescent angiotensin, western blot, polymerase chain reaction, HPLC, mitochondrial respirometry and other functional assays) were used in the present study. We report the discovery of AT1 and AT2 receptors in brain mitochondria, particularly mitochondria of dopaminergic neurons. Activation of AT1 receptors in mitochondria regulates superoxide production, via Nox4, and increases respiration. Mitochondrial AT2 receptors are much more abundant and increase after treatment of cells with oxidative stress inducers, and produce, via nitric oxide, a decrease in mitochondrial respiration. Mitochondria from the nigral region of aged rats displayed altered expression of AT1 and AT2 receptors. AT2-mediated regulation of mitochondrial respiration represents an unrecognized primary line of defence against oxidative stress, which may be particularly important in neurons with increased levels of oxidative stress such as dopaminergic neurons. Altered expression of AT1 and AT2 receptors with aging may induce mitochondrial dysfunction, the main risk factor for neurodegeneration. PMID- 27763646 TI - Green-to-red primed conversion of Dendra2 using blue and red lasers. AB - Recently, an unusual phenomenon of primed conversion of fluorescent protein Dendra2 by combined action of blue (488 nm) and near-infrared (700-780 nm) lasers was discovered. Here we demonstrate that primed conversion can be induced by red lasers (630-650 nm) common for most confocal and single molecule detection microscopes. PMID- 27763644 TI - miR-125b modulates megakaryocyte maturation by targeting the cell-cycle inhibitor p19INK4D. AB - A better understanding of the mechanisms involved in megakaryocyte maturation will facilitate the generation of platelets in vitro and their clinical applications. A microRNA, miR-125b, has been suggested to have important roles in the self-renewal of megakaryocyte-erythroid progenitors and in platelet generation. However, miR-125b is also critical for hematopoietic stem cell self renewal. Thus, the function of miR-125b and the complex signaling pathways regulating megakaryopoiesis remain to be elucidated. In this study, an attentive examination of the endogenous expression of miR-125b during megakaryocyte differentiation was performed. Accordingly, the differentiation of hematopoietic stem cells requires the downregulation of miR-125b, whereas megakaryocyte determination and maturation synchronize with miR-125b accumulation. The overexpression of miR-125b improves megakaryocytic differentiation of K562 and UT 7 cells. Furthermore, stage-specific overexpression of miR-125b in primary cells demonstrates that miR-125b mediates an enhancement of megakaryocytic differentiation after megakaryocyte determination, the stage at which megakaryocytes are negative for the expression of the hematopoietic progenitor marker CD34. The identification of miR-125b targets during megakaryopoiesis was focused on negative regulators of cell cycle because the transition of the G1/S phase has been associated with megakaryocyte polyploidization. Real-time PCR, western blot and luciferase reporter assay reveal that p19INK4D is a direct target of miR-125b. P19INK4D knockdown using small interfering RNA (siRNA) in megakaryocyte-induced K562 cells, UT-7 cells and CD61+ promegakaryocytes results in S-phase progression and increased polyploidy, as well as improved megakaryocyte differentiation, similarly to the effects of miR-125b overexpression. P19INK4D overexpression reverses these effects, as indicated by reduced expression of megakaryocyte markers, G1-phase arrest and polyploidy decrease. P19INK4D knockdown in miR-125b downregulated cells or p19INK4D overexpression in miR-125b upregulated cells rescued the effect of miR-125b. Taken together, these findings suggest that miR-125b expression positively regulates megakaryocyte development since the initial phases of megakaryocyte determination, and p19INK4D is one of the key mediators of miR-125b activity during the onset of megakaryocyte polyploidization. PMID- 27763645 TI - The prosurvival protein BAG3: a new participant in vascular homeostasis. AB - Bcl2-associated athanogene 3 (BAG3), is constitutively expressed in a few normal cell types, including myocytes, peripheral nerves and in the brain, and is also expressed in certain tumors. To date, the main studies about the role of BAG3 are focused on its pro-survival effect in tumors through various mechanisms that vary according to cellular type. Recently, elevated concentrations of a soluble form of BAG3 were described in patients affected by advanced stage of heart failure (HF), identifying BAG3 as a potentially useful biomarker in monitoring HF progression. Despite the finding of high levels of BAG3 in the sera of HF patients, there are no data on its possible role on the modulation of vascular tone and blood pressure levels. The aim of this study was to investigate the possible hemodynamic effects of BAG3 performing both in vitro and in vivo experiments. Through vascular reactivity studies, we demonstrate that BAG3 is capable of evoking dose-dependent vasorelaxation. Of note, BAG3 exerts its vasorelaxant effect on resistance vessels, typically involved in the blood pressure regulation. Our data further show that the molecular mechanism through which BAG3 exerts this effect is the activation of the PI3K/Akt signalling pathway leading to nitric oxide release by endothelial cells. Finally, we show that in vivo BAG3 administration is capable of regulating blood pressure and that this is dependent on eNOS regulation since this ability is lost in eNOS KO animals. PMID- 27763647 TI - Carbohydrates as efficient catalysts for the hydration of alpha-amino nitriles. AB - Directed hydration of alpha-amino nitriles was achieved under mild conditions using simple carbohydrates as catalysts exploiting temporary intramolecularity. A broadly applicable procedure using both formaldehyde and NaOH as catalysts efficiently hydrated a variety of primary and secondary susbtrates, and allowed the hydration of enantiopure substrates to proceed without racemization. This work also provides a rare comparison of the catalytic activity of carbohydrates, and shows that the simple aldehydes at the basis of chemical evolution are efficient organocatalysts mimicking the function of hydratase enzymes. Optimal catalytic efficiency was observed with destabilized aldehydes, and with difficult substrates only simple carbohydrates such as formaldehyde and glycolaldehyde proved reliable. PMID- 27763648 TI - The effect of surface capping on the diffusion of adatoms in the synthesis of Pd@Au core-shell nanocrystals. AB - We offer new insights into the roles played by surface capping in controlling the pattern of growth involving Pd cubic seeds and a HAuCl4 precursor. The final products can take different surface structures (concave vs. flat side faces) depending on the presence or absence of surface capping. PMID- 27763649 TI - Palladium-catalyzed direct intermolecular silylation of remote unactivated C(sp3) H bonds. AB - An efficient and convenient method has been developed to achieve direct silylation of unactivated remote primary or secondary C(sp3)-H bonds to form C-Si bonds with hexamethyldisilane (HMDS). This method highlights the emerging strategy to transform unactivated methyl or methylene into versatile functional groups in organic synthesis and provides a new method to construct functionalized C-Si bonds for synthetic chemistry. PMID- 27763651 TI - All-solid state, flexible, high-energy integrated hybrid micro-supercapacitors based on 3D LSG/CoNi2S4 nanosheets. AB - 3D LSG/CoNi2S4//LSG interdigitated microelectrodes have been firstly developed by a facile, scalable and low cost process for all-solid-state, flexible integrated asymmetric micro-supercapacitors. These devices can achieve energy densities of up to 49 W h l-1 which is comparable to those of lead acid batteries. PMID- 27763650 TI - Cu-Sn-S plasmonic semiconductor nanocrystals for ultrafast photonics. AB - Here, we show that solution-processed Cu-Sn-S semiconductor nanocrystals (NCs) demonstrate a tunable localized surface plasmon resonance band in the near infrared region, where strong saturable absorption occurs. A saturable absorber based on these plasmonic NCs enables the construction of a stable mode-locked femtosecond fiber laser operating at the telecommunication band. PMID- 27763652 TI - Magnesium hydridotriphenylborate [Mg(thf)6][HBPh3]2: a versatile hydroboration catalyst. AB - Magnesium bis(hydridotriphenylborate), isolated as a solvent-separated ion pair [Mg(thf)6][HBPh3]2, effectively catalyzed the hydroboration of several unsaturated substrates including CO2. PMID- 27763654 TI - A theoretical study of the Duff reaction: insights into its selectivity. AB - The Duff reaction is one of the most employed methods for the ortho-formylation of phenols; however, not much is truly known about its mechanism. Using DFT calculations, we disclose the first theoretical study regarding the selectivity determining step of the reaction. We have found that this stage is governed by a hydrogen bond, that gives rise to a cyclohexa-2,4-dienone intermediate and establishes the position where the formylation will take place. These findings were evaluated by analysis of the reaction outcome of several non-symmetrically substituted phenols. PMID- 27763653 TI - Three-dimensional conductive networks based on stacked SiO2@graphene frameworks for enhanced gas sensing. AB - Graphene is an ideal candidate for gas sensing due to its excellent conductivity and large specific surface areas. However, it usually suffers from sheet stacking, which seriously debilitates its sensing performance. Herein, we demonstrate a three-dimensional conductive network based on stacked SiO2@graphene core-shell hybrid frameworks for enhanced gas sensing. SiO2 spheres are uniformly encapsulated by graphene oxide (GO) through an electrostatic self-assembly approach to form SiO2@GO core-shell hybrid frameworks, which are reduced through thermal annealing to establish three-dimensional (3D) conductive sensing networks. The SiO2 supported 3D conductive graphene frameworks reveal superior sensing performance to bare reduced graphene oxide (RGO) films, which can be attributed to their less agglomeration and larger surface area. The response value of the 3D framework based sensor for 50 ppm NH3 and 50 ppm NO2 increased 8 times and 5 times, respectively. Additionally, the sensing performance degradation caused by the stacking of the sensing materials is significantly suppressed because the graphene layers are separated by the SiO2 spheres. The sensing performance decays by 92% for the bare RGO films when the concentration of the sensing material increases 8 times, while there is only a decay of 25% for that of the SiO2@graphene core-shell hybrid frameworks. This work provides an insight into 3D frameworks of hybrid materials for effectively improving gas sensing performance. PMID- 27763655 TI - Periodontal ligament cells as alternative source for cell-based therapy of tendon injuries: in vivo study of full-size Achilles tendon defect in a rat model. AB - Tendon's natural healing potential is extremely low and inefficient, with significant dysfunction and disability due to hypocellularity and hypovascularity of tendon tissues. The application of stem cells can aid in significantly enhanced repair of tendon rupture; therefore, the main aim of this study is to assess the potential of using periodontal ligament cells (PDL), usually obtained from patients undergoing orthodontic treatment, as a novel cell source for cell based therapy for tendon injuries in a clinically relevant rat full-size Achilles tendon defect. In addition, the study compares the differences between the healing effects of Achilles tendon-derived cells (AT) versus PDL and, hence, comprises of four experimental groups, native tendon (NT), empty defect (ED), PDL and human AT (hAT). The tendon healing in each group was assessed in the late remodelling phase at 16 weeks after surgery using a combination of methods, including evaluation of gross morphological appearance; various histological and immunohistological stainings; and detailed analyses of cell morphometry. Based on these outcome measures, PDL cell-implanted tendons exhibited not only advanced tissue maturation, less ectopic fibrocartilage formation, more organised collagen fibres, tendon matrix expression corresponding to the final healing stage, and better cell-morphometry parameters when compared with the ED group, but were also very similar to the tendons treated with hAT-derived cells. Taken together, our study clearly demonstrates the feasibility of using PDL cells as a novel cell source for tendon repair and strongly recommends this cell type for the future development of innovative regenerative applications for treatment of different tendon or ligament pathologies. PMID- 27763657 TI - Renal recruitment of B lymphocytes exacerbates tubulointerstitial fibrosis by promoting monocyte mobilization and infiltration after unilateral ureteral obstruction. AB - Renal fibrosis is a significant threat to public health globally. Diverse primary aetiologies eventually result in chronic kidney disease (CKD) and immune cells influence this process. The roles of monocytes/macrophages, T cells, and mast cells have been carefully examined, whilst only a few studies have focused on the effect of B cells. We investigated B-cell function in tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO), using genetic B-cell-deficient MUMT mice or CD20 antibody-mediated B-cell-depleted mice. Obstructed kidneys of MUMT and anti-CD20-treated mice showed lower levels of monocyte/macrophage infiltration and collagen deposition compared to wild-type mice. Mechanistically, anti-CD20 attenuated UUO-induced alterations of renal tumour necrosis factor alpha (TNF-alpha), vascular cell adhesion molecule 1 (VCAM-1) pro-inflammatory genes, and CC chemokine ligand-2 (CCL2) essential for monocyte recruitment; B cells were one of the main sources of CCL2 in post-UUO kidneys. Neutralization of CCL2 reduced monocyte/macrophage influx and fibrotic changes in obstructed kidneys. Therefore, early-stage accumulation of B cells in the kidney accelerated monocyte/macrophage mobilization and infiltration, aggravating the fibrosis resulting from acutely induced kidney nephropathy. (c) 2016 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 27763656 TI - CD4+ and CD8+ T-cell immunity to Dengue - lessons for the study of Zika virus. AB - Dengue virus (DENV) and Zika virus (ZIKV) are rapidly emerging mosquito-borne flaviviruses that represent a public health concern. Understanding host protective immunity to these viruses is critical for the design of optimal vaccines. Over a decade of research has highlighted a significant contribution of the T-cell response to both protection and/or disease enhancement during DENV infection, the latter being mainly associated with sub-optimal cross-reactive T cell responses during secondary infections. Phase IIb/III clinical trials of the first licensed tetravalent dengue vaccine highlight increased vaccine efficacy in dengue-immune as opposed to dengue-naive vaccinees, suggesting a possible immunoprotective role of pre-existing DENV-specific T cells that are boosted upon vaccination. No vaccine is available for ZIKV and little is known about the T cell response to this virus. ZIKV and DENV are closely related viruses with a sequence identity ranging from 44% and 56% for the structural proteins capsid and envelope to 68% for the more conserved non-structural proteins NS3/NS5, which represent the main targets of the CD4+ and CD8+ T-cell response to DENV, respectively. In this review we discuss our current knowledge of T-cell immunity to DENV and what it can teach us for the study of ZIKV. The extent of T-cell cross-reactivity towards ZIKV of pre-existing DENV-specific memory T cells and its potential impact on protective immunity and/or immunopathology will also be discussed. PMID- 27763658 TI - Multiplex pyrosequencing of InDel markers for forensic DNA analysis. AB - The capillary electrophoresis (CE) technology is commonly used for fragment length separation of markers in forensic DNA analysis. In this study, pyrosequencing technology was used as an alternative and rapid tool for the analysis of biallelic InDel (insertion/deletion) markers for individual identification. The DNA typing is based on a subset of the InDel markers that are included in the Investigator(r) DIPplex Kit, which are sequenced in a multiplex pyrosequencing analysis. To facilitate the analysis of degraded DNA, the polymerase chain reaction (PCR) fragments were kept short in the primer design. Samples from individuals of Swedish origin were genotyped using the pyrosequencing strategy and analysis of the Investigator(r) DIPplex markers with CE. A comparison between the pyrosequencing and CE data revealed concordant results demonstrating a robust and correct genotyping by pyrosequencing. Using optimal marker combination and a directed dispensation strategy, five markers could be multiplexed and analyzed simultaneously. In this proof-of-principle study, we demonstrate that multiplex InDel pyrosequencing analysis is possible. However, further studies on degraded samples, lower DNA quantities, and mixtures will be required to fully optimize InDel analysis by pyrosequencing for forensic applications. Overall, although CE analysis is implemented in most forensic laboratories, multiplex InDel pyrosequencing offers a cost-effective alternative for some applications. PMID- 27763659 TI - Transgenic expression of ephrinB2 in periodontal ligament stem cells (PDLSCs) modulates osteogenic differentiation via signaling crosstalk between ephrinB2 and EphB4 in PDLSCs and between PDLSCs and pre-osteoblasts within co-culture. AB - BACKGROUND AND OBJECTIVE: The goal of periodontal therapy is to regenerate/reconstruct the damaged supporting tissues of diseased teeth and to facilitate recovery of their physiological functions. Combination of stem cell transplantation and gene therapy offers a viable method for accelerating periodontal repair and regeneration. In this study, the role of the ephrinB2/EphB4 signaling pathway in regulating osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and crosstalk between PDLSCs and pre osteoblasts within co-culture was investigated through ephrinB2 transgenic expression in PDLSCs. MATERIAL AND METHODS: PDLSCs isolated from premolar teeth of teenage patients undergoing orthodontic treatment were transfected with transgenic (hEfnB2-GFP-Bsd) vector or empty vector (GFP-Bsd). Vector-PDLSCs, EfnB2-PDLSCs, MC3T3-E1 and co-cultures of vector-PDLSCs with MC3T3-E1, and EfnB2 PDLSCs with MC3T3-E1 were subjected to osteogenic induction. The osteogenic differentiation of EfnB2-PDLSCs, vector-PDLSCs and co-cultures were assessed by reverse transcription-polymerase chain reaction, alkaline phosphatase (ALP) assay and Alizarin-red S staining. Protein expression levels of ephrinB2, EphB4, phosphorylated ephrinB2 and EphB4 were analyzed by western blot, immunoprecipitation and co-immunoprecipitation assays. RESULTS: ALP assay and Alizarin-red S staining demonstrated higher ALP activity and increased mineralization with EfnB2-PDLSCs vs. vector-PDLSCs and with co-culture of EfnB2 PDLSCs and MC3T3-E1 vs. vector-PDLSCs and MC3T3-E1. Reverse transcription polymerase chain reaction revealed that the expression of human odonto/osteogenic markers were significantly enhanced in EfnB2-PDLSCs compared to vector-PDLSCs, and that the expression of mouse odonto/osteogenic markers were significantly higher in co-culture of EfnB2-PDLSCs with MC3T3-E1 vs. vector-PDLSCs with MC3T3 E1. The EphB4 receptor was activated through phosphorylation during osteogenic differentiation. CONCLUSION: Our data indicate that transgenic expression of ephrinB2 in PDLSCs could promote osteogenic differentiation via stimulation of the phosphorylation of ephrinB2 and EphB4, which regulates cell communication between PDLSCs and between PDLSCs and pre-osteoblasts within co-culture. PMID- 27763660 TI - Minimum number of myosin motors accounting for shortening velocity under zero load in skeletal muscle. AB - KEY POINTS: Myosin filament mechanosensing determines the efficiency of the contraction by adapting the number of switched ON motors to the load. Accordingly, the unloaded shortening velocity (V0 ) is already set at the end of latency relaxation (LR), ~10 ms after the start of stimulation, when the myosin filament is still in the OFF state. Here the number of actin-attached motors per half-myosin filament (n) during V0 shortening imposed either at the end of LR or at the plateau of the isometric contraction is estimated from the relation between half-sarcomere compliance and force during the force redevelopment after shortening. The value of n decreases progressively with shortening and, during V0 shortening starting at the end of LR, is 1-4. Reduction of n is accounted for by a constant duty ratio of 0.05 and a parallel switching OFF of motors, explaining the very low rate of ATP utilization found during unloaded shortening. ABSTRACT: The maximum velocity at which a skeletal muscle can shorten (i.e. the velocity of sliding between the myosin filament and the actin filament under zero load, V0 ) is already set at the end of the latency relaxation (LR) preceding isometric force generation, ~10 ms after the start of electrical stimulation in frog muscle fibres at 4 degrees C. At this time, Ca2+ -induced activation of the actin filament is maximal, while the myosin filament is in the OFF state characterized by most of the myosin motors lying on helical tracks on the filament surface, making them unavailable for actin binding and ATP hydrolysis. Here, the number of actin-attached motors per half-thick filament during V0 shortening (n) is estimated by imposing, on tetanized single fibres from Rana esculenta (at 4 degrees C and sarcomere length 2.15 MUm), small 4 kHz oscillations and determining the relation between half-sarcomere (hs) compliance and force during the force development following V0 shortening. When V0 shortening is superimposed on the maximum isometric force T0 , n decreases progressively with the increase of shortening (range 30-80 nm per hs) and, when V0 shortening is imposed at the end of LR, n can be as low as 1-4. Reduction of n is accounted for by a constant duty ratio of the myosin motor of ~0.05 and a parallel switching OFF of the thick filament, providing an explanation for the very low rate of ATP utilization during extended V0 shortening. PMID- 27763663 TI - The Journal of Analytical Psychology. PMID- 27763661 TI - A Strange Fire: an exploration of psycho-spiritual development aided by Jungian analysis and Vedanta. AB - This paper explores the process of psychological and spiritual development through a series of active imaginations arising from the author's 'psycho spiritual quest', a process of transformation in which the individual progressively frees themselves from the ego's identifications and may be afforded a vision of the 'self as consciousness', as described by Vedanta. The author describes how this quest was facilitated by the disciplines of Transcendental Meditation, Jungian analysis and Vedanta, and how these three disciplines can work together to foster psycho-spiritual development. The paper aims to de mystify the actual experiences that can accompany these practices. The records of these active imaginations, tracing some key stages in this process, are then presented, with a commentary by Marcus West, linking them to Jung's concepts of ego and Self and recent understandings of consciousness and ego development. There is a discussion of Jung's conceptualizations of the ego and the Self and his rejection of the Vedantic understanding of the Self as consciousness. These views are then explored and a reconciliation is suggested through the understanding of the process of disidentification where the difference between Jung's view of the Self and that of Vedanta is understood to be due to the extent of disidentification from the contents of consciousness. PMID- 27763666 TI - XIV International Conference : Dissociation: Trauma and the Self 20th - 23rd April 2017. The Roosevelt Hotel, New York City. PMID- 27763664 TI - Cultural unconscious in research: integrating multicultural and depth paradigms in qualitative research. AB - Culturally focused research has gained momentum in many disciplines, including psychology. However, much of this research fails to pay attention to the unconscious dynamics that underlie the study of culture and culturally influenced human beings. Such dynamics may be especially significant when issues of marginalization and oppression are present. Therefore, this paper seeks to contribute a framework for understanding cultural dynamics, especially unconscious cultural dynamics, within depth psychological qualitative research influenced by Jungian and post-Jungian scholarship. Inquiry that is approached with a commitment to making the unconscious conscious seeks to empower and liberate not only the subject/object studied but also the researchers themselves. Following a brief review of multiculturalism in the context of analytically informed psychology, this paper offers several case examples that focus on researchers' integration of awareness of the cultural unconscious in their study of cultural beings and topics. PMID- 27763667 TI - Falling into language life: a montage of pre-faces in search of a text-ual body. AB - Clinical work, as all of consciousness, is steeped in and emerges out of language. Language is the medium of our knowing, and knowing the medium of our relating. Language has us; words dream us. For the mythical Navajo as for John of the New Testament, in the Beginning was the Word. Before any kind of distinction of thought, feeling, sensation or intuition comes language - language, not as 'just words', but as image. Words are images, and images as encompassing worlds present themselves as and through language. As a determinant of identity, language undermines all cues as to individual subjectivity, Yahweh's 'I am here' rendering time and place relative, and subjectivity co-constituted. This paper is a meditation on language for clinicians in the form that language presents itself, as a meandering flow of consciousness with associations and signposts leading onward. PMID- 27763669 TI - Waltz with Bashir. PMID- 27763668 TI - Nina Coltart and the border of Bethlehem. AB - Nina Coltart's freedom in addressing delicate areas such as spirituality and Buddhism within a psychoanalytic framework has opened borders between different psychoanalytic communities. This paper sets out to identify a deep-rooted philosophical tension that runs through several aspects of Coltart's work starting from her 'Slouching towards Bethlehem ... or, thinking the unthinkable in psychoanalysis'. In exploring this central topic in depth psychology, of the distinction between thinkable and unthinkable contents, the author argues that it is not a fundamental distinction in Coltart's work but is rather a particular example of a more fundamental structural dichotomy which pervades her approach and which manifests in several different guises. It is the breadth and sincerity of Coltart's writings which make this a useful exercise, not only for understanding the structure of her work but also in illuminating some structural tensions which permeate depth-psychological pursuits in general. PMID- 27763670 TI - A response to George Bright. PMID- 27763671 TI - The lives of Mary Foote: painter and Jungian. AB - Mary Foote (1872-1968) was a successful early twentieth century American artist who suddenly closed her New York studio in 1926 to go to Zurich to study with Jung. There she joined his 'Interpretation of Visions' seminars (1930-1934), which she recorded and edited. This work won Jung's praise and his friendship, but all too often Foote was seen merely as a secretary or background figure. Deirdre Bair's biography of Jung suggested that Foote's life and work deserved fuller study, if only to rebalance our view of Jung's early women followers. This paper takes up that work to ask how Foote's early life and career led to her important work in preserving and describing Jung's earliest attempts to apply his theories to clinical practice. PMID- 27763672 TI - David Bowie: integrating the alien. PMID- 27763673 TI - Jung's psychoid concept and Bion's proto-mental concept: a comparison. AB - Jung and Bion both developed theoretical concepts propounding a deeply unknowable area of the psyche in which body and mind are undifferentiated and the individual has no distinct identity, from which a differentiated consciousness arises. In Jung's case, this is enshrined in his psychoid concept and the associated notion of synchronicity and, in Bion's case, in his proto-mental concept and his ideas on group dynamics. It is by means of these two concepts that Jung and Bion approach and locate a combined body-mind, a monism, in which body and mind are seen as different aspects of the same thing. This paper reviews the claim that although the two concepts are associated clinically with very different situations, their commonality may arise from a similar intellectual basis: both men appear to have been influenced by the same source of vitalist ideas in philosophy including Henri Bergson, and Jung's ideas also exerted a direct influence on Bion. PMID- 27763675 TI - The Journal of Analytical Psychology Index to Volume 61, 2016. PMID- 27763674 TI - Comment on A Strange Fire. PMID- 27763676 TI - Film and culture: art works. PMID- 27763677 TI - Editorial. PMID- 27763678 TI - Factors associated with utilization of dental services in a long-term care facility: a descriptive cross-sectional study. AB - PURPOSE: To describe factors associated with the utilization of dental services in a long-term care facility (LTCF) in Western New York. METHODS AND MATERIALS: A descriptive cross-sectional study reviewed the dental and medical records of residents of an LTCF discharged between January 1, 2008 and December 30, 2012. Information on demographic and health variables at admission was extracted from electronic health records. Information on oral health variables was extracted from patient charts. RESULTS: A total of 2,516 residents were discharged between 2008 and 2012. From those, 259 (10.3%) utilized dental services at least once during their stay. Those who utilized dental services were significantly older at admission (78.5 vs. 82.0 years, p < 0.001), stayed longer (1.6 vs. 3.9 years, p < 0.001), more likely to be female (63.6 vs. 75.6%, p = 0.008), and less likely to be married (37.7 vs. 14.0%, p = < 0.001) compared to those who did not. Patients with endocrine, nutritional, metabolic, and immunity disorders, mental disorders, and circulatory system diseases were more likely to receive dental services. CONCLUSIONS: Dental services appear to be underutilized by residents of LTCF. Significant differences exist in demographic and health variables between residents who utilize these services compared to those who do not. PMID- 27763680 TI - Humoral and Cellular Responses to a Single Dose of Fendrix in Renal Transplant Recipients with Non-response to Previous Hepatitis B Vaccination. AB - Approximately 70% of kidney transplant recipients are non-responders to conventional hepatitis B virus (HBV) vaccines. We examined whether FendrixTM, an HBV vaccine containing 3-O-desacyl-4'-monophosphoryl lipid A (MPL) as adjuvant, could induce HBV immunity in these patients and compared their vaccination efficacy with healthy controls tested previously by the same assays. We selected 35 kidney transplant recipients who had been vaccinated at least thrice against HBV but had never displayed anti-HBs antibodies. We re-assessed their anti-HBs antibody titres and further determined cellular HBV immunity by proliferation assay and interferon (IFN)-gamma ELISpot. Seventeen recipients did neither display humoral nor cellular immunity and could be tested prior to and at month 1 after vaccination. Of note, HLA antigens associated with non-response to HBV vaccination (HLA-DRB1*03 and HLA-DQB1*02) were over-represented in these 17 recipients. At month 1 after a single vaccination with FendrixTM, we observed a significant increase in anti-HBs antibodies (P = 0.02). In seven of 17 recipients, we detected anti-HBs antibodies >=10 IU/l (10-264), in four HBV specific lymphocyte proliferation (stimulation index of 2.6-8.7) and in one specific IFN-gamma responses (12 spots increment). The vaccination response to FendrixTM was significantly higher (P = 0.035) than the response to HBVaxProTM in young healthy controls. In summary, the results show that a single vaccination with FendrixTM could already induce HBV-specific humoral and/or cellular responses in ten of 17 kidney transplant patients. Thus, FendrixTM appears as an efficient vaccine in this patient cohort. PMID- 27763679 TI - Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients. AB - AIMS: The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks. RESULTS: Warfarin PK was described using a one compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax PD model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin. CONCLUSION: A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo. PMID- 27763681 TI - Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management. AB - Selective immunoglobulin A deficiency (SIgAD) is the most common primary antibody deficiency. Although more patients with SIgAD are asymptomatic, selected patients suffer from different clinical complications such as pulmonary infections, allergies, autoimmune diseases, gastrointestinal disorders and malignancy. Pathogenesis of SIgAD is still unknown; however, a defective terminal differentiation of B cells and defect in switching to IgA-producing plasma cells are presumed to be responsible. Furthermore, some cytogenic defects and monogenic mutations are associated with SIgAD. There is no specific treatment for patients with symptomatic IgA deficiency, although prophylactic antibiotic therapy along with circumstantial immunoglobulin replacement with justification and supportive care (using a product that contains minimal IgA) could be helpful for patients with a severe phenotype. The epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis, management and treatment in patients with SIgAD have been reviewed. PMID- 27763682 TI - Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics. AB - AIMS: To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. METHODS: Two randomized, double blind, sex-balanced, placebo controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once-daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LB was administered. RESULTS: All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose-dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (Emax ) and extent (AUEC) of the catechol-O-methyltransferase activity in relation to placebo. The tolerability profile was favourable. CONCLUSION: Opicapone, as once-daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long-lasting and sustained catechol-O-methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo. PMID- 27763683 TI - Testing interaction between treatment and high-dimensional covariates in randomized clinical trials. AB - In this paper, we considered different methods to test the interaction between treatment and a potentially large number (p) of covariates in randomized clinical trials. The simplest approach was to fit univariate (marginal) models and to combine the univariate statistics or p-values (e.g., minimum p-value). Another possibility was to reduce the dimension of the covariates using the principal components (PCs) and to test the interaction between treatment and PCs. Finally, we considered the Goeman global test applied to the high-dimensional interaction matrix, adjusted for the main (treatment and covariates) effects. These tests can be used for personalized medicine to test if a large set of biomarkers can be useful to identify a subset of patients who may be more responsive to treatment. We evaluated the performance of these methods on simulated data and we applied them on data from two early phases oncology clinical trials. PMID- 27763684 TI - Incidence, risk factors and clinical implications of chyle leak after pancreatic surgery. AB - BACKGROUND: Chyle leak is a well known but poorly characterized complication after pancreatic surgery. Available data on incidence, risk factors and clinical significance of chyle leak are highly heterogeneous. METHODS: For this cohort study all patients who underwent pancreatic surgery between January 2008 and December 2012 were identified from a prospective database. Chyle leak was defined as any drainage output with triglyceride content of 110 mg/dl or more. Risk factors for chyle leak were assessed by univariable and multivariable analyses. The clinical relevance of chyle leak was evaluated using hospital stay and resolution by 14 days for short-term outcome and overall survival for long-term outcome. RESULTS: Chyle leak developed in 346 (10.4 per cent) of 3324 patients. Pre-existing diabetes, resection for malignancy, distal pancreatectomy, duration of surgery 180 min or longer, and concomitant pancreatic fistula or abscess were independent risk factors for chyle leak. Both isolated chyle leak and coincidental chyle leak (with other intra-abdominal complications) were associated with prolonged hospital stay. Some 178 (87.7 per cent) of 203 isolated chyle leaks and 90 (70.3 per cent) of 128 coincidental chyle leaks resolved with conservative management within 14 days. Initial and maximum drainage volumes were associated with duration of hospital stay and success of therapy by 14 days. Impact on survival was restricted to chyle leaks that persisted at 14 days in patients with cancer undergoing palliative surgery. CONCLUSION: Chyle leak is a relevant complication, with an incidence of more than 10 per cent after pancreatic surgery, and has a major impact on hospital stay. Drainage volume is associated with hospital stay and success of therapy. PMID- 27763686 TI - Melatonin and the pathologies of weakened or dysregulated circadian oscillators. AB - Dynamic aspects of melatonin's actions merit increasing future attention. This concerns particularly entirely different effects in senescent, weakened oscillators and in dysregulated oscillators of cancer cells that may be epigenetically blocked. This is especially obvious in the case of sirtuin 1, which is upregulated by melatonin in aged tissues, but strongly downregulated in several cancer cells. These findings are not at all controversial, but are explained on the basis of divergent changes in weakened and dysregulated oscillators. Similar findings can be expected to occur in other accessory oscillator components that are modulated by melatonin, among them several transcription factors and metabolic sensors. Another cause of opposite effects concerns differences between nocturnally active laboratory rodents and the diurnally active human. This should be more thoroughly considered in the field of metabolic syndrome and related pathologies, especially with regard to type 2 diabetes and other aspects of insulin resistance. Melatonin was reported to impair glucose tolerance in humans, especially in carriers of the risk allele of the MT2 receptor gene, MTNR1B, that contains the SNP rs10830963. These findings contrast with numerous reports on improvements of glucose tolerance in preclinical studies. However, the relationship between melatonin and insulin may be more complex, as indicated by loss-of-function mutants of the MT2 receptor that are also prodiabetic, by the age-dependent time course of risk allele overexpression, by progressive reduction in circadian amplitudes and melatonin secretion, which are aggravated in diabetes. By supporting high-amplitude rhythms, melatonin may be beneficial in preventing or delaying diabetes. PMID- 27763685 TI - Long-term outcomes of a randomized clinical trial of supervised exercise, percutaneous transluminal angioplasty or combined treatment for patients with intermittent claudication due to femoropopliteal disease. AB - BACKGROUND: The aim was to compare the long-term outcomes of percutaneous transluminal angioplasty (PTA), a supervised exercise programme (SEP) and combined treatment (PTA + SEP) in patients with intermittent claudication owing to femoropopliteal disease. METHODS: Patients recruited to an RCT comparing these treatments were invited for long-term follow-up from 2010 to 2011. Indicators of limb ischaemia were recorded (ankle : brachial pressure index (ABPI) and treadmill walking distances). Duplex ultrasound imaging was also done. Patients completed Short Form 36 and VascuQol quality-of-life (QoL) questionnaires. RESULTS: Of 178 patients initially recruited to the trial, 139 were alive at the time of follow-up (PTA 46, SEP 47, PTA + SEP 46). Assessments were completed for 111 patients. Median time to follow-up was 5.2 (i.q.r. 3.8-7.4) years. Sixty-nine patients (62.2 per cent) were symptomatic; 18 (16.2 per cent) had experienced a major cardiovascular event since their last follow-up visit. Improvement was observed in ABPI in all groups. QoL outcomes were inconsistent across individual groups. PTA and PTA + SEP groups had a significantly higher ABPI than the SEP group. No significant difference was observed in treadmill walking distances, QoL outcomes, restenosis rates, and new ipsilateral and contralateral lesions on duplex imaging. Patients in all groups required reinterventions (PTA 14, SEP 10, PTA + SEP 6). The total number of reinterventions was higher after PTA (29) compared with SEP (17) and PTA + SEP (9), but failed to reach statistical significance. CONCLUSION: PTA, SEP and combined treatment were equally effective long-term treatment options for patients with claudication owing to femoropopliteal disease. The addition of a SEP to PTA can reduce the rate of symptomatic restenosis and reintervention. Registration number: NCT00798850 (http://www.clinicaltrials.gov). PMID- 27763687 TI - Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study. AB - BACKGROUND: In previous work, a single administration of anticarcinoembryonic antigen (anti-CEA) 131 I-labetuzumab radioimmunotherapy (RIT) after complete resection of colorectal liver metastases was well tolerated and significantly improved survival compared with controls. In the current phase 2 trial, the authors studied repeated RIT in the same setting, examining safety, feasibility, and efficacy. METHODS: Sixty-three patients (median age, 64.5 years) received RIT at 40 to 50 millicuries/m2 per dose. Before the receipt of RIT, restaging was performed with computed tomography/magnetic resonance imaging and 18 F fluorodeoxyglucose-positron emission to confirm that patients were "truly adjuvant." Patients who had elevated serum CEA levels or radiographically inconclusive new lesions were classified as "possibly nonadjuvant," but they also received RIT. Time to progression (TTP), overall survival (OS), and cause specific survival (CSS) were calculated. The median follow-up was 54 months. RESULTS: After the first course of RIT, 14 of 63 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity; 19 patients did not receive the second course of RIT because of impaired performance status (N = 5) or relapse (N = 14). After the second course of RIT, 9 of 44 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity. Five patients developed myelodysplastic syndrome (MDS) from 22 to 55 months after their last RIT. The median TTP, OS, and CSS for all patients were 16, 55, and 60 months, respectively. The "truly adjuvant" patients (N = 39) had an improved median TTP (not reached vs 6.1 months; hazard ratio, 0.12; P < .001), OS (75.6 vs 33.4 months; hazard ratio, 0.44; P = .014), and CSS (not reached vs 41.4 months; hazard ratio,0.42; P = .014) compared with "possibly nonadjuvant" patients (N = 24). CONCLUSIONS: Repeated RIT with 131 I-labetuzumab is feasible but is associated with hematotoxicity. Survival is very encouraging, especially for "truly adjuvant" patients. However, the maximum safe dose of 131 I labetuzumab is a single administration of 50 millicuries/m2 . Cancer 2017;123:638 649. (c) 2016 American Cancer Society. PMID- 27763688 TI - The experience of treatment barriers and their influence on quality of life in American Indian/Alaska Native breast cancer survivors. AB - BACKGROUND: American Indian and Alaska Native (AI/AN) breast cancer survivors experience disparities in breast cancer incidence and age-adjusted mortality compared with non-Hispanic white (NHW) breast cancer survivors. In addition, mortality-to-incidence rates indicate that AI/ANs continue to have the poorest survival from breast cancer compared with other racial groups. "Native American Cancer Education for Survivors" (NACES) is a cultural education and support intervention for AI/AN patients with cancer that collects data from voluntary participants through the NACES quality-of-life (QOL) survey regarding their cancer experience and survivor journey. METHODS: Data from the NACES QOL survey were analyzed to determine whether barriers accessing and during initial cancer treatment impacted QOL domains for AI/AN cancer survivors. Exploratory analyses of selected variables were conducted and were followed by Kruskal-Wallis tests to determine whether these barriers influenced survivorship QOL for AI/AN breast cancer survivors. RESULTS: AI/AN breast cancer survivors' social QOL was significantly affected by barriers to accessing cancer treatment. Many respondents experienced barriers, including a lack of cancer care at local clinics and the distance traveled to receive cancer care. During treatment, too much paperwork and having to wait too long in the clinic for cancer care were the most frequently reported barriers. CONCLUSIONS: Treatment barriers influence AI/AN breast cancer survivors' social QOL. Mediating these barriers is crucial to ameliorating AI/AN survivors' disparities when accessing and completing cancer treatment and improving survivorship QOL. Cancer 2017;123:861-68. (c) 2016 American Cancer Society. PMID- 27763689 TI - Dynamic optical contrast imaging as a novel modality for rapidly distinguishing head and neck squamous cell carcinoma from surrounding normal tissue. AB - BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are debilitating diseases for which a patient's prognosis depends heavily on complete tumor resection. Currently, the surgeon's fingers determine the location of tissue margins. This study evaluated the diagnostic utility of a novel imaging modality, dynamic optical contrast imaging (DOCI), in the detection of HNSCC. This system generates contrast by illuminating the tissue with pulsed light and detecting variations in endogenous fluorophore lifetimes. METHODS: A total of 47 fresh ex vivo samples from 15 patients were imaged with the DOCI system immediately after surgical resection. DOCI maps were analyzed to determine the statistical significance of contrast between tumors and adjacent nonmalignant tissue. Pilot intraoperative clinical data were also acquired. RESULTS: Statistical significance (P < .05) between muscle and tumor was established for 10 of 10 emission wavelengths, between collagen and tumor for 8 of 10 emission wavelengths, and between fat and tumor for 2 of 10 wavelengths. The system extracted relative fluorescence decay information in a surgically relevant field of view in <2 minutes. CONCLUSIONS: This study demonstrates the feasibility of using DOCI to rapidly and accurately distinguish HNSCC from surrounding normal tissue. An analysis of DOCI images revealed microscopic characterization sufficient for tissue-type identification consistent with histology. Such an intraoperative tool would be transformative by allowing the rapid delineation of tumor tissue from nontumor tissue and thus maximizing the efficacy of resection and improving patient outcomes. Cancer 2017;123:879-86. (c) 2016 American Cancer Society. PMID- 27763691 TI - Pregabalin for essential tremor. AB - BACKGROUND: Essential tremor is one of the most common movement disorders. Treatment primarily consists of pharmacological agents. While primidone and propranolol are well-established treatments in clinical practice, they may be ineffective in 25% to 55% of patients and can produce serious adverse events in a large percentage of them. For these reasons, it is worth evaluating the treatment alternatives for essential tremor. Some specialists have suggested that pregabalin could be a potentially useful agent, but there is uncertainty about its efficacy and safety. OBJECTIVES: To assess the effects of pregabalin versus placebo or other treatment for essential tremor in adults. SEARCH METHODS: We performed a systematic search without language restrictions to identify all relevant trials up to December 2015. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, NICE, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We handsearched grey literature and examined the reference lists of identified studies and reviews. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of pregabalin versus placebo or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in patients presenting secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently collected and extracted data using a data collection form. We assessed the risk of bias of the body of evidence, and we used inverse variance methods to analyse continuous outcomes and measurement scales. We compared the mean difference between treatment groups, and we combined results for dichotomous outcomes using Mantel-Haenszel methods and risk differences We used Review Manager software for data management and analysis. MAIN RESULTS: We only found one study eligible for this review (22 participants). We assessed the risk of bias for most domains as unclear. We graded the overall quality of evidence as very low. Compared to placebo, patients treated with pregabalin showed no significant improvement of motor tasks on the 36-point subscale of the Fahn Tolosa-Marin Tremor Rating Scale (TRS) (MD -2.15 points; 95% CI -9.16 to 4.86) or on the 32-point functional abilities subscale of the TRS (MD -0.66 points; 95% CI -2.90 to 1.58).The limited evidence showed no difference in study withdrawal (Mantel-Haenszel RD -0.09; 95% CI -0.48 to 0.30) and presentation of adverse events between pregabalin and placebo (Mantel-Haenszel RD 0.18; 95% CI -0.13 to 0.50). AUTHORS' CONCLUSIONS: The effects of pregabalin for treating essential tremor are uncertain because the quality of the evidence is very low. One small study did not highlight any effect of this treatment; however, the high risk of bias and the lack of other studies on this topic limit further conclusion. PMID- 27763692 TI - Accelerated mapping of magnetic susceptibility using 3D planes-on-a-paddlewheel (POP) EPI at ultra-high field strength. AB - With the advent of ultra-high field MRI scanners in clinical research, susceptibility based MRI has recently gained increasing interest because of its potential to assess subtle tissue changes underlying neurological pathologies/disorders. Conventional, but rather slow, three-dimensional (3D) spoiled gradient-echo (GRE) sequences are typically employed to assess the susceptibility of tissue. 3D echo-planar imaging (EPI) represents a fast alternative but generally comes with echo-time restrictions, geometrical distortions and signal dropouts that can become severe at ultra-high fields. In this work we assess quantitative susceptibility mapping (QSM) at 7 T using non Cartesian 3D EPI with a planes-on-a-paddlewheel (POP) trajectory, which is created by rotating a standard EPI readout train around its own phase encoding axis. We show that the threefold accelerated non-Cartesian 3D POP EPI sequence enables very fast, whole brain susceptibility mapping at an isotropic resolution of 1 mm and that the high image quality has sufficient signal-to-noise ratio in the phase data for reliable QSM processing. The susceptibility maps obtained were comparable with regard to QSM values and geometric distortions to those calculated from a conventional 4 min 3D GRE scan using the same QSM processing pipeline. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27763693 TI - Progesterone analogue protects stressed photoreceptors via bFGF-mediated calcium influx. AB - Retinitis pigmentosa (RP) is a degenerative retinal disease leading to photoreceptor cell loss. In 2011, our group identified the synthetic progesterone 'Norgestrel' as a potential treatment for RP. Subsequent research showed Norgestrel to work through progesterone receptor membrane component 1 (PGRMC1) activation and upregulation of neuroprotective basic fibroblast growth factor (bFGF). Using trophic factor deprivation of 661W photoreceptor-like cells, we aimed to further elucidate the mechanism leading to Norgestrel-induced neuroprotection. In the present manuscript, we show by flow cytometry and live cell immunofluorescence that Norgestrel induces an increase in cytosolic calcium in both healthy and stressed 661Ws over 24 h. Specific PGRMC1 inhibition by AG205 (1 MUm) showed this rise to be PGRMC1-dependent, primarily utilizing calcium from extracellular sources, for blockade of L-type calcium channels by verapamil (50 MUm) prevented a Norgestrel-induced calcium influx in stressed cells. Calcium influx was also shown to be bFGF-dependent, for siRNA knock down of bFGF prevented Norgestrel-PGRMC1 induced changes in cytosolic calcium. Notably, we demonstrate PGRMC1-activation is necessary for Norgestrel-induced bFGF upregulation. We propose that Norgestrel protects through the following pathway: binding to and activating PGRMC1 expressed on the surface of photoreceptor cells, PGRMC1 activation drives bFGF upregulation and subsequent calcium influx. Importantly, raised intracellular calcium is critical to Norgestrel's protective efficacy, for extracellular calcium chelation by EGTA abrogates the protective effects of Norgestrel on stressed 661W cells in vitro. PMID- 27763694 TI - Feasibility of Defibrillation and Pacing Without Transvenous Leads in a Combined MICRA and S-ICD System Following Lead Extraction. PMID- 27763690 TI - Chronic myeloid leukemia among patients with a history of prior malignancies: A tale of dual survivorship. AB - BACKGROUND: Some patients with chronic myeloid leukemia (CML) have a history of previous malignancies. To the authors' knowledge, outcomes for CML diagnosed in these patients have not been well described. The current study was conducted to determine the outcome of patients with CML and a history of prior malignancies. METHODS: The current study included patients who were enrolled in clinical trials of tyrosine kinase inhibitors as initial therapy for CML in chronic phase from July 2000 to January 2014. RESULTS: Of the 630 patients with CML who were treated with frontline tyrosine kinase inhibitors, 626 had a known prior malignancy status. Of these, 45 patients (7%) had a prior malignancy other than nonmelanoma skin cancer whereas 17 patients (3%) had a history of nonmelanoma skin cancers alone. Characteristics of CML were similar between the patients with no prior malignancy, those with a prior malignancy, and those with nonmelanoma skin cancer. Patients with a prior malignancy were found to have an older median age compared with the other 2 groups. The most common prior malignancies were nonmelanoma skin cancer in 20 patients, breast cancer in 11 patients, melanoma in 7 patients, prostate cancer in 6 patients, and colorectal cancer in 5 patients. With regard to CML, the event-free survival, transformation-free survival, and failure-free survival rates were found to be similar between the groups. There was a statistically significantly decreased survival in the group with a prior malignancy versus the group with no prior malignancy versus the group with nonmelanoma skin cancer. In a multivariate analysis, advanced age and an elevated creatinine level were found to be associated with worse survival after a diagnosis of CML. CONCLUSIONS: Patients with CML with a history of prior malignancies appear to have the same excellent outcome as patients with no prior malignancies. In the few instances in which concomitant therapy for other malignancies was required during therapy with tyrosine kinase inhibitors, this was able to be accomplished without significant toxicity. Cancer 2017;123:609 616. (c) 2016 American Cancer Society. PMID- 27763695 TI - Use of New Imaging CARTO(r) Segmentation Module Software to Facilitate Ablation of Ventricular Arrhythmias. AB - INTRODUCTION: A new imaging software (CARTO(r) Segmentation Module, Biosense Webster) allows preprocedural 3-D reconstruction of all heart chambers based on cardiac CT. We describe our initial experience with the new module during ablation of ventricular arrhythmias. METHODS AND RESULTS: Eighteen consecutive patients with idiopathic ventricular arrhythmias or ischemic ventricular tachycardia (VT) were studied. In the latter group, a combined endocardial and epicardial ablation was performed. Of the 14 patients with idiopathic arrhythmias, 12 were ablated in the outflow tract (OT), 1 in the midseptal left ventricle, and 1 at the left posterior fascicular area; acute successful ablation was achieved in 11 (78.6%) patients. The procedure was discontinued due to close proximity of the arrhythmia origin to the coronary arteries (CA) in 2 patients. Acute successful uncomplicated ablation was achieved in all 4 patients with ischemic VT. During ablation in the coronary cusps commissures, the CARTO(r) Segmentation Module accurately defined the cusps anatomy. The precise anatomic location provided by the module assisted in successfully ablating when information from activation mapping was not optimal, by ablating at the opposite side of the cusps. In addition, by demonstrating the precise location of the CA, it allowed safe ablation of arrhythmias that originated in close proximity to the CA both in the OT area and the epicardium, eliminating the need for repeat angiography. CONCLUSIONS: The CARTO(r) Segmentation Module is useful for accurate definition of the exact anatomic location of ventricular arrhythmias and for safely ablating them especially in close proximity to the CA. PMID- 27763696 TI - Nanoscale MnII -Coordination Polymers for Cell Imaging and Heterogeneous Catalysis. AB - A mixed ligand approach was exploited to synthesize a new series of MnII -based coordination polymers (CPs), namely, CP1 {[Mn(MU-dpa)(MU-4,4'-bp)]?MeOH}infinity , CP2 {[Mn3 (MU-dpa)3 (2,2'-bp)2 ]}infinity , CP3 {[Mn3 (MU-dpa)3 (1,10-phen)2 ]?2 H2 O}infinity , CP4 {[Mn(MU-dpa)(MU-4,4'-bpe)1.5 ]?H2 O}infinity , CP5 {[Mn2 (MU-dpa)2 (MU-4,4'-bpe)2 ]?1/2 DEF}infinity , and CP6 {[Mn(MU-dpa)(MU-4,4' bpe)1.5 ]?1/2 DMA}infinity (dpa=3,5-dicarboxyphenyl azide, 2,2'-bp=2,2' bipyridine, 1,10-phen=1,10-phenanthroline, 4,4'-bpe=1,2-bis(4-pyridyl)ethylene, 4,4'-bp=4,4'-bipyridine, DEF=N,N-diethylformamide, DMA=N,N-dimethylacetamide), to develop multifunctional CPs. Various techniques, such as single-crystal X-ray diffraction (SXRD), FTIR spectroscopy, elemental analysis, and thermogravimetric analysis, were employed to fully characterize these CPs. The majority of the CPs displayed a four-connected sql topology, whereas CP4 and CP6 exhibited a two dimensional SnS network architecture, which was further entangled in a polycatenation mode. Compound CP1 displayed an open framework structure. The CPs were scaled down to the nanoregime in a ball mill for cell imaging studies. Whereas CP2 and CP4 were employed for cell imaging with RAW264.7 cells, CP1 was exploited for both cell imaging and heterogeneous catalysis in a cyanosilylation reaction. PMID- 27763698 TI - Multispecies genetic structure and hybridization in the Betula genus across Eurasia. AB - Boreal and cool temperate forests are the major land cover of northern Eurasia, and information about continental-scale genetic structure and past demographic history of forest species is important from an evolutionary perspective and has conservation implications. However, although many population genetic studies of forest tree species have been conducted in Europe or Eastern Asia, continental scale genetic structure and past demographic history remain poorly known. Here, we focus on the birch genus Betula, which is commonly distributed in boreal and cool temperate forests, and examine 129 populations of two tetraploid and four diploid species collected from Iceland to Japan. All individuals were genotyped at seven to 18 nuclear simple sequence repeats (nSSRs). Pairwise FST' among the six species ranged from 0.285 to 0.903, and genetic differentiation among them was clear. structure analysis suggested that Betula pubescens is an allotetraploid and one of the parental species was Betula pendula. In both species pairs of B. pendula and B. plathyphylla, and B. pubescens and B. ermanii, genetic diversity was highest in central Siberia. A hybrid zone was detected around Lake Baikal for eastern and western species pairs regardless of ploidy level. Approximate Bayesian computation suggested that the divergence of B. pendula and B. platyphylla occurred around the beginning of the last ice age (36 300 years BP, 95% CI: 15 330-92 700) and hybridization between them was inferred to have occurred after the last glacial maximum (1614 years BP, 95% CI: 561 4710), with B. pendula providing a higher contribution to hybrids. PMID- 27763697 TI - Changes in cardiovascular responses to chemoreflex activation of rats recovered from protein restriction are not related to AT1 receptors. AB - NEW FINDINGS: What is the central question of this study? In this study, we sought to investigate whether cardiovascular responses to peripheral chemoreflex activation of rats recovered from protein restriction are related to activation of AT1 receptors. What is the main finding and its importance? This study highlights the fact that angiotensinergic mechanisms activated by AT1 receptors do not support increased responses to peripheral chemoreflex activation by KCN in rats recovered from protein restriction. Also, we found that protein restriction led to increased resting ventilation in adult rats, even after recovery. The effects of a low-protein diet followed by recovery on cardiorespiratory responses to peripheral chemoreflex activation were tested before and after systemic angiotensin II type 1 (AT1 ) receptor antagonism. Male Fischer rats were divided into control and recovered (R-PR) groups after weaning. The R-PR rats were fed a low-protein (8%) diet for 35 days and recovered with a normal protein (20%) diet for 70 days. Control rats received a normal protein diet for 105 days (CG105 ). After cannulation surgery, mean arterial pressure, heart rate, respiratory frequency, tidal volume and minute ventilation were acquired using a digital recording system in freely moving rats. The role of angintensin II was evaluated by systemic antagonism of AT1 receptors with losartan (20 mg kg-1 i.v.). The peripheral chemoreflex was elicited by increasing doses of KCN (20-160 MUg kg min 1 , i.v.). At baseline, R-PR rats presented increased heart rate and minute ventilation (372 +/- 34 beats min-1 and 1.274 +/- 377 ml kg-1 min-1 ) compared with CG105 animals (332 +/- 22 beats min-1 and 856 +/- 112 ml kg-1 min-1 ). Mean arterial pressure was not different between the groups. Pressor and bradycardic responses evoked by KCN (60 MUg kg-1 ) were increased in R-PR (+45 +/- 13 mmHg and -77 +/- 47 beats min-1 ) compared with CG105 rats (+25 +/- 17 mmHg and -27 +/ 28 beats min-1 ), but no difference was found in the tachypnoeic response. These differences were preserved after losartan. The data suggest that angiotensin II acting on AT1 receptors may not be associated with the increased heart rate, increased minute ventilation and acute cardiovascular responses to peripheral chemoreflex activation in rats that underwent postweaning protein restriction followed by recovery. PMID- 27763699 TI - Saltmarsh plant responses to eutrophication. AB - In saltmarsh plant communities, bottom-up pressure from nutrient enrichment is predicted to increase productivity, alter community structure, decrease biodiversity, and alter ecosystem functioning. Previous work supporting these predictions has been based largely on short-term, plot-level (e.g., 1-300 m2 ) studies, which may miss landscape-level phenomena that drive ecosystem-level responses. We implemented an ecosystem-scale, nine-year nutrient experiment to examine how saltmarsh plants respond to simulated conditions of coastal eutrophication. Our study differed from previous saltmarsh enrichment studies in that we applied realistic concentrations of nitrate (70-100 MUM NO3- ), the most common form of coastal nutrient enrichment, via tidal water at the ecosystem scale (~60,000 m2 creeksheds). Our enrichments added a total of 1,700 kg N.creek 1 .yr-1 , which increased N loading 10-fold vs. reference creeks (low-marsh, 171 g N.m-2 .yr-1 ; high-marsh, 19 g N.m-2 .yr-1 ). Nutrients increased the shoot mass and height of low marsh, tall Spartina alterniflora; however, declines in stem density resulted in no consistent increase in aboveground biomass. High marsh plants S. patens and stunted S. alterniflora did not respond consistently to enrichment. Nutrient enrichment did not shift community structure, contrary to the prediction of nutrient-driven dominance of S. alterniflora and Distichlis spicata over S. patens. Our mild responses may differ from the results of previous studies for a number of reasons. First, the limited response of the high marsh may be explained by loading rates orders of magnitude lower than previous work. Low loading rates in the high marsh reflect infrequent inundation, arguing that inundation patterns must be considered when predicting responses to estuarine eutrophication. Additionally, we applied nitrate instead of the typically used ammonium, which is energetically favored over nitrate for plant uptake. Thus, the form of nitrogen enrichment used, not just N-load, may be important in predicting plant responses. Overall, our results suggest that when coastal eutrophication is dominated by nitrate and delivered via flooding tidal water, aboveground saltmarsh plant responses may be limited despite moderate-to high water-column N concentrations. Furthermore, we argue that the methodological limitations of nutrient studies must be considered when using results to inform management decisions about wetlands. PMID- 27763700 TI - Early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on learned helplessness behaviours and alter gene expression within neural circuits important for stress resistance. AB - Manipulating gut microbes may improve mental health. Prebiotics are indigestible compounds that increase the growth and activity of health-promoting microorganisms, yet few studies have examined how prebiotics affect CNS function. Using an acute inescapable stressor known to produce learned helplessness behaviours such as failure to escape and exaggerated fear, we tested whether early life supplementation of a blend of two prebiotics, galactooligosaccharide (GOS) and polydextrose (PDX), and the glycoprotein lactoferrin (LAC) would attenuate behavioural and biological responses to stress later in life. Juvenile, male F344 rats were fed diets containing either GOS and PDX alone, LAC alone, or GOS, PDX and LAC. All diets altered gut bacteria, while diets containing GOS and PDX increased Lactobacillus spp. After 4 weeks, rats were exposed to inescapable stress, and either immediately killed for blood and tissues, or assessed for learned helplessness 24 h later. Diets did not attenuate stress effects on spleen weight, corticosterone and blood glucose; however, all diets differentially attenuated stress-induced learned helplessness. Notably, in situ hybridization revealed that all diets reduced stress-evoked cfos mRNA in the dorsal raphe nucleus (DRN), a structure important for learned helplessness behaviours. In addition, GOS, PDX and LAC diet attenuated stress-evoked decreases in mRNA for the 5-HT1A autoreceptor in the DRN and increased basal BDNF mRNA within the prefrontal cortex. These data suggest early life diets containing prebiotics and/or LAC promote behavioural stress resistance and uniquely modulate gene expression in corresponding circuits. PMID- 27763701 TI - Alternative methods of lung isolation in cases of pediatric bilateral thoracoscopic surgery. AB - We compare airway management and lung isolation methods in two pediatric cases of congenital central hypoventilation syndrome undergoing bilateral throacoscopic phrenic-nerve-stimulator surgery. One child received lung isolation using a 7Fr bronchial blocker in conjunction with a 6.0 cuffed endotracheal tube; and the second received a technique of endobronchial intubation using a 3.5 microcuffed tube via the tracheostomy stoma in conjunction with 5.0 cuffed endotracheal intubation; a technique previously undescribed in pediatric patients. PMID- 27763702 TI - Cooperative Catalysis and Activation with N-Heterocyclic Carbenes. AB - N-Heterocyclic carbene (NHC) catalysis has emerged as a powerful stratagem in organic synthesis to construct complex molecules primarily by polarity reversal (umpolung) approaches. These unique Lewis bases have been used to generate acyl anions, enolates, and homoenolates in catalytic fashion. Recently, a new strategy has emerged that dramatically expands the synthetic utility of carbene catalysis by leveraging additional activation modes: cooperative catalysis. The careful selection and balance of cocatalysts have led to enhanced reactivity, increased yields, and improved stereoselectivity. In certain cases, these catalytic additives have changed the regioselectivity or diastereoselectivity. This Minireview highlights new advances in NHC cooperative catalysis and surveys the evolution of this field. PMID- 27763703 TI - Performance Measures of Diagnostic Codes for Detecting Opioid Overdose in the Emergency Department. AB - OBJECTIVES: Opioid overdose mortality has tripled in the United States since 2000 and opioids are responsible for more than half of all drug overdose deaths, which reached an all-time high in 2014. Opioid overdoses resulting in death, however, represent only a small fraction of all opioid overdose events and efforts to improve surveillance of this public health problem should include tracking nonfatal overdose events. International Classification of Disease (ICD) diagnosis codes, increasingly used for the surveillance of nonfatal drug overdose events, have not been rigorously assessed for validity in capturing overdose events. The present study aimed to validate the use of ICD, 9th revision, Clinical Modification (ICD-9-CM) codes in identifying opioid overdose events in the emergency department (ED) by examining multiple performance measures, including sensitivity and specificity. METHODS: Data on ED visits from January 1, 2012, to December 31, 2014, including clinical determination of whether the visit constituted an opioid overdose event, were abstracted from electronic medical records for patients prescribed long-term opioids for pain from any of six safety net primary care clinics in San Francisco, California. Combinations of ICD-9-CM codes were validated in the detection of overdose events as determined by medical chart review. Both sensitivity and specificity of different combinations of ICD-9 CM codes were calculated. Unadjusted logistic regression models with robust standard errors and accounting for clustering by patient were used to explore whether overdose ED visits with certain characteristics were more or less likely to be assigned an opioid poisoning ICD-9-CM code by the documenting physician. RESULTS: Forty-four (1.4%) of 3,203 ED visits among 804 patients were determined to be opioid overdose events. Opioid-poisoning ICD-9-CM codes (E850.2-E850.2, 965.00-965.09) identified overdose ED visits with a sensitivity of 25.0% (95% confidence interval [CI] = 13.6% to 37.8%) and specificity of 99.9% (95% CI = 99.8% to 100.0%). Expanding the ICD-9-CM codes to include both nonspecified and general (i.e., without a decimal modifier) drug poisoning and drug abuse codes identified overdose ED visits with a sensitivity of 56.8% (95% CI = 43.6%-72.7%) and specificity of 96.2% (95% CI = 94.8%-97.2%). Additional ICD-9-CM codes not explicitly relevant to opioid overdose were necessary to further enhance sensitivity. Among the 44 overdose ED visits, neither naloxone administration during the visit, whether the patient responded to the naloxone, nor the specific opioids involved were associated with the assignment of an opioid poisoning ICD-9 CM code (p >= 0.05). CONCLUSIONS: Tracking opioid overdose ED visits by diagnostic coding is fairly specific but insensitive, and coding was not influenced by administration of naloxone or the specific opioids involved. The reason for the high rate of missed cases is uncertain, although these results suggest that a more clearly defined case definition for overdose may be necessary to ensure effective opioid overdose surveillance. Changes in coding practices under ICD-10 might help to address these deficiencies. PMID- 27763704 TI - The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database. AB - Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype-phenotype correlation studies and pharmacogenetic approaches. PMID- 27763705 TI - In vitro cell culture system optimization of keratinocytes from oral lichen planus (OLP) patients. AB - OBJECTIVES: The aim of this study was to optimize the culture system of keratinocytes obtained from patients with oral lichen planus (OLP) and verify whether this model could simulate the local inflammatory environment of OLP. MATERIALS AND METHODS: Keratinocytes were isolated from 48 patients with OLP and cultured in vitro. The ultrastructure of OLP keratinocytes was observed via electron microscopy. The expression of pancytokeratin and vimentin was determined by immunohistochemistry, and the proliferation of OLP keratinocytes was measured by CCK-8 assay. Immunofluorescence staining was used to detect TLR4 and NF-kappaB p65 expression, and the levels of IL-1beta, IL-6, and TNF-alpha in the supernatant were measured by ELISA. RESULTS: When seeded in plates precoated with recombinant human type-1 collagen, keratinocytes isolated from patients who received systemic antifungal treatment and were younger than 40 years were more successful to be cultured in vitro. Characteristic pancytokeratin was expressed in almost all OLP keratinocytes. Compared with normal oral keratinocytes, OLP keratinocytes demonstrated higher levels of TLR4/NF-kappaB p65 and inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha. CONCLUSIONS: We successfully optimized the culture system of OLP keratinocytes,which mimicked the local inflammatory environment of OLP and may be used as a cell model of OLP. PMID- 27763706 TI - Noncovalent Functionalization of Black Phosphorus. AB - Black phosphorus (BP) was functionalized with organic moieties on the basis of liquid exfoliation. The treatment of BP with electron-withdrawing 7,7,8,8 tetracyano-p-quinodimethane (TCNQ) led to electron transfer from BP to the organic dopant. On the other hand, the noncovalent interaction of BP with a perylene diimide was mainly due to van der Waals interactions but also led to considerable stabilization of the BP flakes against oxygen degradation. PMID- 27763710 TI - Synthesis of Chemically Asymmetric Silica Nanobottles and Their Application for Cargo Loading and as Nanoreactors and Nanomotors. AB - We report the synthesis of chemically asymmetric silica nanobottles (NBs) with a hydrophobic exterior surface (capped with 3-chloropropyl groups) and a hydrophilic interior surface for spatially selective cargo loading, and for application as nanoreactors and nanomotors. The silica NBs, which have a "flask bottle" shape with an average diameter of 350 nm and an opening of ca. 100 nm, are prepared by anisotropic sol-gel growth in a water/n-pentanol emulsion. Due to their chemically asymmetric properties, nanoparticles (NPs) with hydrophilic or hydrophobic surface properties can be selectively loaded inside the NBs or on the outside of the NBs, respectively. A high-performance nanomotor is constructed by selectively loading catalytically active hydrophilic Pt NPs inside the NBs. It is also demonstrated that these NBs can be used as vessels for various reactions, such as the in situ synthesis of Au NPs, and using Au NP-loaded NBs as nanoreactors for catalytic reactions. PMID- 27763709 TI - Triggering Emission with the Helical Turn in Thiadiazole-Helicenes. AB - Introduction of heterocycles into the helical skeleton of helicenes allows modulation of their redox, chiroptical, and photophysical properties. This paper describes the straightforward preparation and structural characterization by single-crystal X-ray diffraction of thiadiazole-[7]helicene, which was resolved into M and P enantiomers by chiral HPLC, together with its S-shaped double [4]helicene isomer, as well as the smaller congeners thiadiazole-[5]helicene and benzothiadiazole-anthracene. A copper(II) complex with two thiadiazole [5]helicene ligands was structurally characterized, and it shows the presence of both M and P isomers coordinated to the metal center. The emission properties of the heterohelicenes are highly dependent on the helical turn, as the [7]- and [5]helicene are poorly emissive, whereas their isomers, that is, the S-shaped double [4]helicene and thiadiazole-benzanthracene, are luminescent, with quantum efficiencies of 5.4 and 6.5 %, respectively. DFT calculations suggest quenching of the luminescence of enantiopure [7]helicenes through an intersystem-crossing mechanism arising from the relaxed excited S1 state. PMID- 27763711 TI - Near-Ultraviolet Fluorescent "ON-OFF-ON" Switching Sensors Based on Nitrogen Enriched Dual-Color Single-Functional Polymer Carbon Nanosheets. AB - Graphene quantum-dot-like structures of highly enriched N-based dual-color single functional polymer carbon nanosheets (GLNPCNs) with an average diameter as large as 170 nm (ca. five layers) are prepared through a facile hydrothermal method. Intermolecular C5 H5 N5 ???C5 H5 N5 and/or C2 H5 OH chemical polymerization interactions in the liquid state of the peripheral crown-ether-like "hole" decorated compound GLNPCNs lead to a fascinating 2 D supramolecular polymer architecture, which exhibits near-ultraviolet (NUV) fluorescence, ultrahigh brightness, a narrow full-width at half-maximum, and excellent potential for practical applications. The unique NUV fluorescence of the GLNPCNs might be attributed to the "self-passivated" crown-ether-like layer on their surface; the GLNPCNs exhibit properties independent of the excitation wavelength, which is unexpected in the NUV region. Moreover, these GLNPCNs show highly selective and sensitive detection of hazardous and toxic silver (Ag+ ) ions, and discriminate other metal ions or anions in the range 1.5 nm to 50 MUm through a fluorescence quenching response. The high sensing selectivity toward Ag+ ions could be attributable to the restricted rigid conformation of the peripheral crown-ether like "hole", which binds exclusively to the Ag+ ion. In addition to Ag+ ion sensing, the GLNPCNs quenched by Ag+ ions exhibit high selectivity and sensitivity for cysteine (Cys) in the range 2.0 nm to 50 MUm through a fluorescence recovery process, which could be attributed to the effective coordination/chelation interactions between Ag+ ions and the plentiful mercapto and amino groups of Cys. Our results suggest that the facile preparation, biocompatibility, outstanding photoluminescence, and physicochemical properties of these GLNPCNs make them potentially useful in numerous applications such as bioimaging, optical and electrochemical sensors, and energy devices. PMID- 27763708 TI - Increasing the Chemical-Shift Dispersion of Unstructured Proteins with a Covalent Lanthanide Shift Reagent. AB - The study of intrinsically disordered proteins (IDPs) by NMR often suffers from highly overlapped resonances that prevent unambiguous chemical-shift assignments, and data analysis that relies on well-separated resonances. We present a covalent paramagnetic lanthanide-binding tag (LBT) for increasing the chemical-shift dispersion and facilitating the chemical-shift assignment of challenging, repeat containing IDPs. Linkage of the DOTA-based LBT to a cysteine residue induces pseudo-contact shifts (PCS) for resonances more than 20 residues from the spin labeling site. This leads to increased chemical-shift dispersion and decreased signal overlap, thereby greatly facilitating chemical-shift assignment. This approach is applicable to IDPs of varying sizes and complexity, and is particularly helpful for repeat-containing IDPs and low-complexity regions. This results in improved efficiency for IDP analysis and binding studies. PMID- 27763707 TI - IL-17: overview and role in oral immunity and microbiome. AB - Interleukin-17 (IL-17) is a multifaceted cytokine with diverse roles in both immune protection and also immunopathology. IL-17 has a well-recognized role in immune surveillance at mucosal and barrier surfaces, but also has been increasingly implicated as a driver of immunopathology in settings of autoimmunity and chronic inflammation. The current review introduces basic aspects of IL-17 biology and examines the protective and pathogenic roles of IL 17 with a focus on oral mucosal immunity and inflammation. Specific emphasis is given to the role of the IL-17 response as a catalyst in 'shaping the microbiome at the oral barrier'. PMID- 27763713 TI - Mechanochemically Induced Conversion of Crystalline Benzamide Polymorphs by Seeding. AB - Benzamide has been known for its polymorphism for almost 200 years. Three polymorphic forms are described. To date, it was only possible to crystallize a metastable form in a mixture together with the thermodynamically most stable form I. A complete transformation of form I into the metastable form III by mechanochemical treatment has been achieved. Catalytic amounts of nicotinamide seeds were used to activate the conversion by mechanochemical seeding. NMR experiments indicated that the nicotinamide molecules were incorporated statistically in the crystal lattice of benzamide form III during the conversion. The transformation pathway was evaluated using in situ powder X-ray diffraction. PMID- 27763712 TI - Conservation implications of a lack of relationship between baseline glucocorticoids and fitness in a wild passerine. AB - The application of physiological measures to conservation monitoring has been gaining momentum and, while a suite of physiological traits are available to ascertain disturbance and condition in wildlife populations, glucocorticoids (i.e., GCs; cortisol and corticosterone) are the most heavily employed. The interpretation of GC levels as sensitive indicators of population change necessitates that GCs and metrics of population persistence are linked. However, the relationship between GCs and fitness may be highly context-dependent, changing direction, or significance, depending on the GC measure, fitness metric, life history stage, or other intrinsic and extrinsic contexts considered. We examined the relationship between baseline plasma corticosterone (CORT) levels measured at two periods of the breeding season and three metrics of fitness (offspring quality, reproductive output, and adult survival) in female Tree Swallows (Tachycineta bicolor). Specifically, we investigated whether (1) a relationship between baseline CORT metrics and fitness exists in our population, (2) whether the inclusion of energetic contexts, such as food availability, reproductive investment, or body mass, could alter or improve the strength of the relationship between CORT and fitness, and (3) whether energetic contexts could better predict fitness compared to CORT metrics. Importantly, we investigated these relationships in both natural conditions and under an experimental manipulation of foraging profitability (feather clipping) to determine the influence of an environmental constraint on GC-fitness relationships. We found a lack of relationship between baseline CORT and both short- and long-term metrics of fitness in control and clipped birds. In contrast, loss in body mass over reproduction positively predicted reproductive output (number of chicks leaving the nest) in control birds; however, the relationship was characterized by a low R2 (5%), limiting the predictive capacity, and therefore the application potential, of such a measure in a conservation setting. Our results stress the importance of ground-truthing GC-fitness relationships and indicate that baseline GCs will likely not be easily employed as conservation biomarkers across some species and life history stages. Given the accumulating evidence of temporally dynamic, inconsistent, and context-dependent GC-fitness relationships, placing effort towards directly measuring fitness traits, rather than plasma GC levels, will likely be more worthwhile for many conservation endeavours. PMID- 27763714 TI - Bifunctional Ammonium Salt Catalyzed Asymmetric alpha-Hydroxylation of beta Ketoesters by Simultaneous Resolution of Oxaziridines. AB - Chiral bifunctional urea-containing ammonium salts were found to be very efficient catalysts for asymmetric alpha-hydroxylation reactions of beta ketoesters with oxaziridines under base-free conditions. The reaction is accompanied by a simultaneous kinetic resolution of the oxaziridine and a plausible and so far unprecedented bifunctional transition-state model has been obtained by means of DFT calculations. PMID- 27763715 TI - Insight into Oxide-Bridged Heterobimetallic Al/Zr Olefin Polymerization Catalysts. AB - Reaction of (TBBP)AlMe?THF with [Cp*2 Zr(Me)OH] gave [(TBBP)Al(THF)-O-Zr(Me)Cp*2 ] (TBBP=3,3',5,5'-tetra-tBu-2,2'-biphenolato). Reaction of [DIPPnacnacAl(Me)-O Zr(Me)Cp2 ] with [PhMe2 NH]+ [B(C6 F5 )4 ]- gave a cationic Al/Zr complex that could be structurally characterized as its THF adduct [(DIPPnacnac)Al(Me)-O Zr(THF)Cp2 ]+ [B(C6 F5 )4 ]- (DIPPnacnac=HC[(Me)C=N(2,6-iPr2 -C6 H3 )]2 ). The first complex polymerizes ethene in the presence of an alkylaluminum scavenger but in the absence of methylalumoxane (MAO). The adduct cation is inactive under these conditions. Theoretical calculations show very high energy barriers (DeltaG=40-47 kcal mol-1 ) for ethene insertion with a bridged AlOZr catalyst. This is due to an unfavorable six-membered-ring transition state, in which the methyl group bridges the metal and ethene with an obtuse metal-Me-C angle that prevents synchronized bond-breaking and making. A more-likely pathway is dissociation of the Al-O-Zr complex into an aluminate and the active polymerization catalyst [Cp*2 ZrMe]+ . PMID- 27763716 TI - Catalytic Conversion of Renewable Resources into Bulk and Fine Chemicals. AB - Several strategies can be chosen to convert renewable resources into chemicals. In this account, I exemplify the route that starts with so-called platform chemicals; these are relatively simple chemicals that can be produced in high yield, directly from renewable resources, either via fermentation or via chemical routes. They can be converted into the existing bulk chemicals in a very efficient manner using multistep catalytic conversions. Two examples are given of the conversion of sugars into nylon intermediates. 5-Hydroxymethylfurfural (HMF) can be prepared in good yield from fructose. Two hydrogenation steps convert HMF into 1,6-hexanediol. Oppenauer oxidation converts this product into caprolactone, which in the past, has been converted into caprolactam in a large-scale industrial process by reaction with ammonia. An even more interesting platform chemical is levulinic acid (LA), which can be obtained directly from lignocellulose in good yield by treatment with dilute sulfuric acid at 200 degrees C. Hydrogenation converts LA into gamma-valerolactone, which is ring opened and esterified in a gas-phase process to a mixture of isomeric methyl pentenoates in excellent selectivity. In a remarkable selective palladium catalysed isomerising methoxycarbonylation, this mixture is converted in to dimethyl adipate, which is finally hydrolysed to adipic acid. Overall selectivities of both processes are extremely high. The conversion of lignin into chemicals is a much more complicated task in view of the complex nature of lignin. It was discovered that breakage of the most prevalent beta-O-4 bond in lignin occurs not only via the well-documented C3 pathway, but also via a C2 pathway, leading to the formation of highly reactive phenylacetaldehydes. These compounds went largely unnoticed as they immediately recondense on lignin. We have now found that it is possible to prevent this by converting these aldehydes in a tandem reaction, as they are formed. For this purpose, we have used three different methods: acetalisation, hydrogenation, and decarbonylation. These reactions were first established in the tandem reactions of model compounds, but subsequently, we were able to show that this works equally well on organosolv lignin and even on lignocellulose. PMID- 27763718 TI - Proteomic and N-glycoproteomic quantification reveal aberrant changes in the human saliva of oral ulcer patients. AB - Human whole saliva is a vital body fluid for studying the physiology and pathology of the oral cavity. As a powerful technique for biomarker discovery, MS based proteomic strategies have been introduced for saliva analysis and identified hundreds of proteins and N-glycosylation sites. However, there is still a lack of quantitative analysis, which is necessary for biomarker screening and biological research. In this study, we establish an integrated workflow by the combination of stable isotope dimethyl labeling, HILIC enrichment, and high resolution MS for both quantification of the global proteome and N-glycoproteome of human saliva from oral ulcer patients. With the help of advanced bioinformatics, we comprehensively studied oral ulcers at both protein and glycoprotein scales. Bioinformatics analyses revealed that starch digestion and protein degradation activities are inhibited while the immune response is promoted in oral ulcer saliva. PMID- 27763717 TI - Additive effects of the Rho kinase inhibitor Y-27632 and vardenafil on relaxation of the corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure. AB - OBJECTIVES: To evaluate the expression of the Rho/Rho-associated protein kinase (ROCK) pathway in the corpus cavernosum of patients with severe erectile dysfunction (ED) compared with healthy human corpus cavernosum, and to test the functional effects of two Rho kinase inhibitors (RKIs) on erectile tissue of patients with severe ED, which did not respond to phosphodiesterase type 5 inhibitors (PDE5Is). PATIENTS AND METHODS: Human corpus cavernosum samples were obtained after consent from men undergoing penile prosthesis implantation (n = 7 for organ bath experiments, n = 17 for quantitative PCR [qPCR]). Potent control subjects (n = 5) underwent penile needle biopsy. qPCR was performed for the expression of RhoA and ROCK subtypes 1 and 2. Immunohistochemistry staining against ROCK and alpha smooth muscle actin (alphaSMA) was performed on the corpus cavernosum of patients with ED. Tissue strips were precontracted with phenylephrine and incubated with 1 MUm of the PDE5I vardenafil or with DMSO (control). Subsequently, increasing concentrations of the RKIs azaindole or Y 27632 were added, and relaxation of tissue was quantified. RESULTS: The expression of ROCK1 was unchanged (P > 0.05), while ROCK2 (P < 0.05) was significantly upregulated in patients with ED compared with controls. ROCK1 and ROCK2 protein colocalized with alphaSMA, confirming the presence of this kinase in cavernous smooth muscle cells and/or myofibroblasts. After incubation with DMSO, 10 MUm azaindole and 10 MUm Y-27632 relaxed precontracted tissues with 49.5 +/- 7.42% (P = 0.1470 when compared with vehicle) and 85.9 +/- 10.3% (P = 0.0016 when compared with vehicle), respectively. Additive effects on relaxation of human corpus cavernosum were seen after preincubation with 1 MUm vardenafil. CONCLUSION: The RKI Y-27632 causes a significant relaxation of corpus cavernosum in tissue strips of patients with severe ED. The additive effect of vardenafil and Y-27632 shows that a combined inhibition of Rho-kinase and phosphodiesterase type 5 could be a promising orally administered treatment for severe ED. PMID- 27763719 TI - Stable isotope metabolic labeling suggests differential turnover of the DPYSL protein family. AB - PURPOSE: In this work, we discuss how in vivo 15 N metabolic labeling in combination with MS simultaneously provides information on protein expression and protein turnover. EXPERIMENTAL DESIGN: We metabolically labeled mice with the stable nitrogen isotope 15 N using a 15 N-enriched diet and analyzed unlabeled (14 N) versus 15 N-labeled brain tissue with LC-MS/MS. We then compared the 14 N versus 15 N peptide isotopologue clusters of 14 N and 15 N-labeled dihydropyrimidinase-related (DPYSL) proteins. RESULTS: We present a workflow assessing protein expression and turnover at different time points of mouse brain development. Our data demonstrate distinct protein turnover patterns of DPYSL3 and DPYSL5 compared to other quantified proteins. We report the presence of two DPYSL3 and DPYSL5 populations with different 15 N incorporation rates, indicating altered protein turnover during development. CONCLUSIONS AND CLINICAL RELEVANCE: In vivo 15 N metabolic labeling allows the simultaneous investigation of protein expression and turnover, enabling detailed protein dynamics studies. We report for the first time protein turnover data for the DPYSL2, DPYSL3, and DPYSL5 protein family members. As DPYSL proteins have important functions for nervous system maturation, our data provide useful information on their molecular fate during brain development. PMID- 27763720 TI - Diabetes News. PMID- 27763721 TI - Redox proteomics screening cellular factors associated with oxidative stress in hepatocarcinogenesis. AB - Liver cancer is a major global health problem being the sixth most common cancer and the third cause of cancer-related death, with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Mounting evidence suggests that, compared with their normal counterparts, many types of cancer cell have increased levels of ROS. Therefore, cancer cells need to combat high levels of ROS, especially at early stages of tumor development. Recent studies have revealed that ROS-mediated regulation of redox-sensitive proteins (redox sensors) is involved in the pathogenesis and/or progression of many human diseases, including cancer. Unraveling the altered functions of redox sensors and the underlying mechanisms in hepatocarcinogenesis is critical for the development of novel cancer therapeutics. For this reason, redox proteomics has been developed for the high-throughput screening of redox sensors, which will benefit the development of novel therapeutic strategies for the treatment of HCC. In this review, we will briefly introduce several novel redox proteomics techniques that are currently available to study various oxidative modifications in hepatocarcinogenesis and summarize the most important discoveries in the study of redox processes related to the development and progression of HCC. PMID- 27763722 TI - Methoprene does not affect juvenile hormone titers in honey bee (Apis mellifera) workers. AB - Methoprene, a juvenile hormone (JH) analog, is a widely used insecticide that also accelerates behavioral development in honey bees (Apis mellifera). JH regulates the transition from nursing to foraging in adult worker bees, and treatment with JH or methoprene have both been shown to induce precocious foraging. To determine how methoprene changes honey bee behavior, we compared JH titers of methoprene-treated and untreated bees. Behavioral observations confirmed that methoprene treatment significantly increased the number of precocious foragers in 3 out of 4 colonies. In only 1 out of 4 colonies, however, was there a significant difference in JH titers between the methoprene-treated and control bees. Further, in all 4 colonies, there was no significant differences in JH titers between precocious and normal-aged foragers. These results suggest that methoprene did not directly affect the endogenous JH secreted by corpora allata. Because methoprene caused early foraging without changing workers' JH titers, we conclude that methoprene most likely acts directly on the JH receptors as a substitute for JH. PMID- 27763723 TI - Don't Forget Product Recovery in Catalysis Research-Check the Distillation Resistance. AB - When investigating a new catalytic reaction, scientists may wonder if the crude reaction product can be easily separated and purified. We present here a new concept-distillation resistance-to assess the potential of distillation as a purification technique and to guide catalyst formulation or operation at the very early stage of the research. Distillation resistance, which has been developed from the analysis of 15 industrial distillation trains, can be quickly calculated with knowledge of only the product composition and atmospheric boiling points of the components. It can be directly converted into a preliminary distillation cost that considers investment and energy cost. Its application and its potential guidance in catalysis research are illustrated through a few cases studies derived from biorefinery processes. PMID- 27763724 TI - A Minimal, Unstrained S-Allyl Handle for Pre-Targeting Diels-Alder Bioorthogonal Labeling in Live Cells. AB - The unstrained S-allyl cysteine amino acid was site-specifically installed on apoptosis protein biomarkers and was further used as a chemical handle and ligation partner for 1,2,4,5-tetrazines by means of an inverse-electron-demand Diels-Alder reaction. We demonstrate the utility of this minimal handle for the efficient labeling of apoptotic cells using a fluorogenic tetrazine dye in a pre targeting approach. The small size, easy chemical installation, and selective reactivity of the S-allyl handle towards tetrazines should be readily extendable to other proteins and biomolecules, which could facilitate their labeling within live cells. PMID- 27763725 TI - Targeting EphA2-Sam and Its Interactome: Design and Evaluation of Helical Peptides Enriched in Charged Residues. AB - The EphA2 receptor controls diverse physiological and pathological conditions and its levels are often upregulated in cancer. Targeting receptor overexpression, through modulation of endocytosis and consequent degradation, appears to be an appealing strategy for attacking tumor malignancy. In this scenario, the Sam domain of EphA2 plays a pivotal role because it is the site where protein regulators of endocytosis and stability are recruited by means of heterotypic Sam Sam interactions. Because EphA2-Sam heterotypic complexes are largely based on electrostatic contacts, we have investigated the possibility of attacking these interactions with helical peptides enriched in charged residues. Several peptide sequences with high predicted helical propensities were designed, and detailed conformational analyses were conducted by diverse techniques including NMR, CD, and molecular dynamics (MD) simulations. Interaction studies were also performed by NMR, surface plasmon resonance (SPR), and microscale thermophoresis (MST) and led to the identification of two peptides capable of binding to the first Sam domain of Odin. These molecules represent early candidates for the generation of efficient Sam domain binders and antagonists of Sam-Sam interactions involving EphA2. PMID- 27763726 TI - Suspension Electrodes Combining Slurries and Upflow Fluidized Beds. AB - Carbon-based suspension electrodes are currently intensively investigated for emerging electrochemical systems, such as flow batteries, flow capacitors, and capacitive deionization cells. The main limitation of such electrodes is their low electric conductivity, which is typically orders of magnitude lower than that of traditional static carbon electrodes. Two main categories of suspension electrodes exist: 1) slurry electrodes where particles are not significantly affected by gravity, and 2) fluidized bed electrodes where particles are affected by gravity. We introduce a novel category that we term "combined" suspension electrodes, which combine dilute slurries and dense fluidized beds. We present experimental measurements of the electrochemical impedance and electric conductivity of two combined electrodes. For one set of materials, the measured electric conductivity of the combined electrode is at least an order of magnitude above the fluidized bed and slurry components alone, demonstrating that a synergetic effect can be achieved when adding dilute slurry to dense fluidized bed. For a second set of materials, results show that the combined electrode conductivity is lower than the slurry component alone, a counter-intuitive result, demonstrating that increasing electrode carbon loading does not always enhance the electric conductivity. PMID- 27763727 TI - Genesis of the Nanomachines: The 2016 Nobel Prize in Chemistry. AB - In the beginning...: The Nobel Prize in Chemistry 2016 goes to three of the pioneers of the field of synthetic molecular machines, Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Ben L. Feringa. Their work has led from the reliable synthesis of rotaxanes and catenanes to molecular rotary motors, shuttles, muscles, and other devices. PMID- 27763728 TI - Ni-Cu Hydrotalcite-Derived Mixed Oxides as Highly Selective and Stable Catalysts for the Synthesis of beta-Branched Bioalcohols by the Guerbet Reaction. AB - A series of Ni-Cu hydrotalcite-derived mixed oxides have been synthesized and evaluated as heterogeneous catalysts for the dimerization of linear aliphatic alcohols to afford beta-branched Guerbet alcohols. The use of the hydrotalcite structured catalyst precursor highly favors the catalyst stability. This Cu/Ni catalyst has an enhanced reducibility of Ni2+ species under reaction conditions, favoring the hydrogen transfer and hydrogenation capacity of the catalyst system. Catalytic results are reported for C8 , mixed C8 /C10 , and C18 alcohol feeds, with full conversions and Guerbet product purities of 72.5-96 %. PMID- 27763729 TI - Metal-Cluster-Based Colloidal Excimer Superstructures. AB - Luminescent network: Colloidal excimer superstructures with unique optical and electronic properties have recently been described. Ground-state gold cluster cores were held together by the hydrogen-bonding network formed by their capping ligands, which enabled excimer formation. PMID- 27763730 TI - Donor-Stabilized 1,3-Disila-2,4-diazacyclobutadiene with a Nonbonded Si???Si Distance Compressed to a Si=Si Double Bond Length. AB - A donor-stabilized 1,3-disila-2,4-diazacyclobutadiene presents an exceptionally short nonbonded Si???Si distance (2.23 A), which is as short as that of Si=Si bonds (2.15-2.23 A). Theoretical investigations indicate that there is no bond between the two silicon atoms, and that the unusual geometry can be related to a significant coulomb repulsion between the two ring nitrogen atoms. This chemical pressure phenomenon could provide an alternative and superior way of squeezing out van der Waals space in highly strained structures, as compared to the classical physical methods. PMID- 27763731 TI - Development of a Photoactivatable Phosphine Probe for Induction of Intracellular Reductive Stress with Single-Cell Precision. AB - Photoactivatable phosphines that induce intracellular reductive stress are reported. The design of these probes takes advantage of the conjugate addition of trialkylphosphines to carbocyanine dyes, which can be reverted photochemically to produce the trialkylphosphine and a fluorescent reporter. The photochemical release depends on the efficiency of photoinduced electron transfer from the indolenine arm of the probe to the coumarin acceptor. These probes readily permeate the mammalian plasma membrane and can be photoactivated in live cells. Upon irradiation of the probe, the released trialkylphosphine induces intracellular reductive stress, which ultimately leads to formation of thioflavin positive intracellular protein aggregates. These effects could be induced in individual cells within a monolayer, with minimal disturbance of neighboring cells. PMID- 27763732 TI - Antibiotics for ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a significant cause of morbidity and mortality, complicating the medical course of approximately 10% of mechanically-ventilated patients, with an estimated attributable mortality of 13%. To treat VAP empirically, the American Thoracic Society currently recommends antibiotic therapy based on the patients' risk of colonisation by an organism with multidrug resistance. The selection of initial antibiotic therapy in VAP is important, as inappropriate initial antimicrobial treatment is associated with higher mortality and longer hospital stay in intensive care unit (ICU) patients.While guidelines exist for the antibiotic treatment of hospital-acquired pneumonia (HAP) from the American Thoracic Society and the British Society for Antimicrobial Chemotherapy, there are many limitations in the quality of available evidence. This systematic review aimed to summarise the results of all randomised controlled trials (RCTs) that compare empirical antibiotic regimens for VAP. OBJECTIVES: The primary objective of this review was to assess the effect of different empirical antimicrobial therapies on the survival and clinical cure of adult patients with ventilator-associated pneumonia (VAP). Secondary objectives included reporting the incidence of adverse events, new superinfections, length of hospital stay, and length of intensive care unit (ICU) stay associated with these therapies. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CINAHL and Web of Science to December 2015; we searched ClinicalTrials.gov to September 2016. SELECTION CRITERIA: Two review authors independently assessed RCTs comparing empirical antibiotic treatments of VAP in adult patients, where VAP was defined as new-onset pneumonia that developed more than 48 hours after endotracheal intubation. Physicians and researchers were not required to be blinded for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. We pooled studies and analysed them in two ways. We examined monotherapy, or a single experimental antimicrobial drug, versus combination therapy, or multiple experimental antimicrobial drugs. We also examined carbapenem therapy versus non-carbapenem therapy. MAIN RESULTS: We included 12 studies with 3571 participants. All included studies examined the empiric use of one antimicrobial regimen versus another for the treatment of adults with VAP, but the particular drug regimens examined by each study varied. There was potential for bias because some studies did not report outcomes for all participants. All but one study reported sources of funding or author affiliations with pharmaceutical companies.We found no statistical difference in all-cause mortality between monotherapy and combination therapy (N = 4; odds ratio (OR) monotherapy versus combination 0.97, 95% confidence interval (CI) 0.73 to 1.30), clinical cure (N = 2; OR monotherapy versus combination 0.88, 95% CI 0.56 to 1.36), length of stay in ICU (mean difference (MD) 0.65, 95% CI 0.07 to 1.23) or adverse events (N = 2; OR monotherapy versus combination 0.93, 95% CI 0.68 to 1.26). We downgraded the quality of evidence for all-cause mortality, adverse events, and length of ICU stay to moderate for this comparison. We determined clinical cure for this comparison to be of very low-quality evidence.For our second comparison of combination therapy with optional adjunctives only one meta-analysis could be performed due to a lack of trials comparing the same antibiotic regimens. Two studies compared tigecycline versus imipenem-cilastatin for clinical cure in the clinically evaluable population and there was a statistically significant increase in clinical cure for imipenem cilastatin (N = 2; OR tigecycline versus imipenem-cilastatin 0.44, 95% CI 0.23 to 0.84). Of importance, this effect was due to a single study.We found no statistical difference in all-cause mortality between carbapenem and non carbapenem therapies (N = 1; OR carbapenem versus non-carbapenem 0.59, 95% CI 0.30 to 1.19) or adverse events (N = 3; OR carbapenem versus non-carbapenem 0.78, 95% CI 0.56 to 1.09), but we found that carbapenems are associated with a statistically significant increase in the clinical cure (N = 3; OR carbapenem versus non-carbapenem 1.53, 95% CI 1.11 to 2.12 for intention-to-treat (ITT) analysis and N = 2; OR carbapenem versus non-carbapenem 2.29, 95% CI 1.19 to 4.43 for clinically evaluable patients analysis). For this comparison we downgraded the quality of evidence for mortality, and clinical cure (ITT and clinically evaluable populations) to moderate. We determined the quality of evidence for adverse events to be low. AUTHORS' CONCLUSIONS: We did not find a difference between monotherapy and combination therapy for the treatment of people with VAP. Since studies did not identify patients with increased risk for multidrug resistant bacteria, these data may not be generalisable to all patient groups. However, this is the largest meta-analysis comparing monotherapy to multiple antibiotic therapies for VAP and contributes further evidence to the safety of using effective monotherapy for the empiric treatment of VAP.Due to lack of studies, we could not evaluate the best antibiotic choice for VAP, but carbapenems as a class may result in better clinical cure than other tested antibiotics. PMID- 27763733 TI - Comparison of formula-fed infants with and without colic revealed significant differences in total bacteria, Enterobacteriaceae and faecal ammonia. AB - AIM: This study compared the faecal microbial composition of formula-fed infants who did and did not have colic. METHODS: Faecal samples from formula-fed infants under 16 weeks of age with (n = 38) and without (n = 39) colic were collected at Department of Pediatrics in Turin, Italy, between February 2014 and October 2015. The pH and faecal ammonia were determined and total bacteria, bifidobacteria, lactic acid bacteria and coliforms were quantified by fluorescent in situ hybridisation (FISH). RESULTS: Faecal ammonia was significantly higher in the colicky infants than in the controls (483 vs. 216 MUg/g, p < 0.05). The FISH counts of total bacteria were lower in colicky infants (1.8E10 +/- 1.5E10) than in the controls (3.4E10 +/- 3.0E10) (p < 0.05). The relative abundance of coliform bacteria was significantly higher in colicky infants (p < 0.05). No differences were observed for the bifidobacteria and lactic acid bacteria counts between the two groups. CONCLUSION: Our comparison of formula-fed infants with and without colic revealed significant differences in total bacteria, Enterobacteriaceae and faecal ammonia. This study provides the stimulus for further studies of the gut microbiome, using new methods of analysis such as 16S metagenomics sequencing in order to lead to more tailored dietary approaches. PMID- 27763734 TI - Low occurrence of extended spectrum beta-lactamases in urinary tract infections is reassuring given limited treatment options. PMID- 27763735 TI - A Thermally Populated, Perpendicularly Twisted Alkene Triplet Diradical. AB - Variable-temperature NMR and ESR spectroscopic studies reveal that bis(dibenzo[a,i]fluorenylidene) 1 possesses a singlet ground state, 1(S0 ), while the 90 degrees twisted triplet 1(T1 ) is populated to a small extent already at room temperature. Analysis of the increasing amount of paramagnetic 1(T1 ) at temperatures between 300 and 500 K yields the exchange interaction Jex /h c=3351 cm-1 and a singlet-triplet energy splitting of 9.6 kcal mol-1 , which is in excellent agreement with calculations (9.3 kcal mol-1 at the UKS BP86/B3LYP/revPBE level of theory). In contrast, the zero-field splitting parameter D is very small (calculated value -0.018 cm-1 ) and unmeasurable. PMID- 27763736 TI - Reversible Stannylenoid Formation from the Corresponding Stannylene and Cesium Fluoride. AB - A fluorostannylenoid (Cs+ [R2 SnF]- (9), R2 =(TMS)2 CCH2 CH2 C(TMS)2 ) was prepared by reacting a stable dialkylstannylene (R2 Sn (8), R2 =(TMS)2 CCH2 CH2 C(TMS)2 ) with cesium fluoride at room temperature in THF. While 9 is stable in THF and DME, removal of the solvent leads to the regeneration of stannylene 8. No reaction occurred when 8 was treated with CsF in a hydrocarbon solvent. Addition of dibenzo-21-crown-7 ether to the THF solution of stannylenoid 9 followed by usual workup affords the corresponding crystalline stannylenoid crown ether complex, the X-ray structural analysis of which revealed a fluorine-bridged contact ion-pair structure. The reaction of 9 with excess phenylacetylene gives the corresponding di(phenylethynyl)stannane. PMID- 27763737 TI - Bifunctional Ionic Liquids Derived from Biorenewable Sources as Sustainable Catalysts for Fixation of Carbon Dioxide. AB - A series of highly efficient, bifunctional ionic liquids containing a quaternary alkyl ammonium cation and an amine anion were prepared from choline and amino acids, respectively. Nine ILs were synthesized, characterized, and applied as organocatalysts for the chemical fixation of carbon dioxide to form cyclic carbonates and quinazoline-2,4(1 H,3 H)-diones. A binary mixture of an IL and a co-catalysts generates deep eutectic solvents (DESs) and accelerates the rate of the cycloaddition reaction at atmospheric pressure and low temperature (70 degrees C). The presence of the hydroxyl functional group of choline and the free amine group of the amino acids in the ILs has a synergistic effect on the activation of the epoxide and carbon dioxide towards the cycloaddition reactions. These ILs are biodegradable and are synthesized from easily available biorenewable sources. Additionally, this catalytic method demonstrates ultimate environmental benignity because of the mild metal- and solvent-free conditions as well as the recyclability of the catalyst and co-catalyst. PMID- 27763738 TI - Robotic Ureteroureterostomy for Treatment of a Proximal Ureteric Stricture. PMID- 27763739 TI - Editorial Comment: Robotic Ureteroureterostomy for Treat ment of a Proximal Ureteric Stricture. PMID- 27763740 TI - Off-clamp robotic-assisted partial nephrectomy. PMID- 27763741 TI - Editorial Comment: Off-clamp robotic-assisted partial nephrectomy. PMID- 27763743 TI - Editorial Comment: Laparoscopic single port cystolithotomy using pneumovesicum. PMID- 27763742 TI - Laparoscopic single port cystolithotomy using pneumovesicum. PMID- 27763762 TI - Molecular Scissoring: Facile 3D to 2D Conversion of Lanthanide Metal Organic Frameworks Via Solvent Exfoliation. AB - Five lanthanide MOFs with pcu topology have been exfoliated into nanoplatelets of two-dimensional structures via sonication in the dimethylacetamide solvent. These nanosheets are fluorescent under two-photon excitation dominated by the ligand, indicating energy upconversion ability. PMID- 27763763 TI - Establishment of 2D Crystal Heterostructures by Sulfurization of Sequential Transition Metal Depositions: Preparation, Characterization, and Selective Growth. AB - A nine-layer WS2/MoS2 heterostructure is established on a sapphire substrate after sequential growth of large-area and uniform five- and four-layer MoS2 and WS2 films by using sulfurization of predeposited 1.0 nm molybdenum (Mo) and tungsten (W), respectively. By using the results obtained from the ultraviolet photoelectron spectroscopy and the absorption spectrum measurements of the standalone MoS2 and WS2 samples, a type-II band alignment is predicated for the WS2/MoS2 heterostructure. Increasing drain currents and enhanced field-effect mobility value of the transistor fabricated on the heterostructure suggested that a channel with higher electron concentration compared with the standalone MoS2 transistor channel is obtained with electron injection from WS2 to MoS2 under thermal equilibrium. Selective 2D crystal growth with (I) blank sapphire substrate, (II) standalone MoS2, (III) WS2/MoS2 heterostructure, and (IV) standalone WS2 was demonstrated on a single sapphire substrate. The results have revealed the potential of this growth technique for practical applications. PMID- 27763764 TI - Extraordinary Off-Stoichiometric Bismuth Telluride for Enhanced n-Type Thermoelectric Power Factor. AB - Thermoelectrics directly converts waste heat into electricity and is considered a promising means of sustainable energy generation. While most of the recent advances in the enhancement of the thermoelectric figure of merit (ZT) resulted from a decrease in lattice thermal conductivity by nanostructuring, there have been very few attempts to enhance electrical transport properties, i.e., the power factor. Here we use nanochemistry to stabilize bulk bismuth telluride (Bi2Te3) that violates phase equilibrium, namely, phase-pure n-type K0.06Bi2Te3.18. Incorporated potassium and tellurium in Bi2Te3 far exceed their solubility limit, inducing simultaneous increase in the electrical conductivity and the Seebeck coefficient along with decrease in the thermal conductivity. Consequently, a high power factor of ~43 MUW cm-1 K-2 and a high ZT > 1.1 at 323 K are achieved. Our current synthetic method can be used to produce a new family of materials with novel physical and chemical characteristics for various applications. PMID- 27763765 TI - Hydrophobic Cobalt-Ethylimidazolate Frameworks: Phase-Pure Syntheses and Possible Application in Cleaning of Contaminated Water. AB - Two highly porous Co-based metal-azolate frameworks (MAFs), MAF-5(Co) and MAF 6(Co), which are isostructural with MAF-5(Zn) and MAF-6(Zn), respectively, were first synthesized in high yield and purity at room temperature. The syntheses compared two mixing methods, slow and fast, using cobalt acetate as the metal ion (Co2+) source and 2-ethylimidazole as the ligand. Triethylamine was applied as an additive/promoter in aqueous/ethanol solutions, and benzene and cyclohexane were used as hydrophobic templates. Phase-pure MAF-5(Co) and MAF-6(Co) were obtained in high yield by optimizing the mixing speed, reactant composition, and solvent/template ratio. It was found that fast mixing of the reactant mixtures was effective for synthesizing MAF(Co) materials. MAF-5(Co) and MAF-6(Co) were found to be very hydrophobic, similar to the MAFs composed of Zn, suggesting possible applications in water purification. MAF-5(Co) and MAF-6(Co) were then applied to adsorb n-octane as a model oil and nonpolar adsorbate from water, and the obtained results were compared to those of related materials, i.e., MAF-4(Co and Zn), MAF-5(Zn), and MAF-6(Zn), as well as with Cu-BTC (Cu benzenetricarboxylate) and a conventional adsorbent, activated carbon. Surprisingly, despite having low porosity, MAF-5(Co) showed remarkable competitiveness among the typical porous materials for n-octane removal. The results suggest that the framework structure such as cavity and aperture sizes rather than surface area plays a significant role in n-octane removal. Moreover, MAF-5(Co) can easily be regenerated by simple evacuation and reused, and thus it was found to be a potential adsorbent for the removal of spilled oil from water. Additionally, MAFs were applied in the adsorption of diclofenac sodium from water, showing the competitiveness of MAFs in water purification probably because of hydrophobicity. PMID- 27763766 TI - Carbon Nanotube Macroelectronics for Active Matrix Polymer-Dispersed Liquid Crystal Displays. AB - Active matrix liquid crystal display (AMLCD) is the most widely used display technology nowadays. Transparent display is one of the emerging technologies to provide people with more features such as displaying images on transparent substrates and simultaneously enabling people to see the scenery behind the panel. Polymer-dispersed liquid crystal (PDLC) is a possible active matrix transparent display technology due to its high transparency, good visibility, and low power consumption. Carbon nanotubes (CNTs) with excellent mobility, high transparency, and room-temperature processing compatibility are ideal materials for the driver circuit of the PDLC display. Here, we report the monolithic integration of CNT thin-film transistor driver circuit with PDLC pixels. We studied the transmission properties of the PDLC pixels and characterized the performance of CNT thin-film transistors. Furthermore, we successfully demonstrated active matrix seven-segment PDLC displays using CNT driver transistors. Our achievements open up opportunities for future nanotube-based, flexible thin-film transparent display electronics. PMID- 27763767 TI - Drug Burden Index and change in cognition over time in community-dwelling older men: the CHAMP study. AB - OBJECTIVE: Anticholinergic and sedative medications are associated with acute cognitive impairment, but the long-term impact on change in cognition is unclear. This study investigated the effect of anticholinergic and sedative medications, quantified using the Drug Burden Index (DBI), on change in cognition over time in community-dwelling older men. METHODS: This was a prospective cohort study of men aged >=70 years in Sydney, Australia. DBI was assessed at baseline, 2, and 5 years. Cognitive performance was assessed using the Mini-Mental State Exam (MMSE) at each wave. Logistic quantile mixed-effects modelling was used to assess the adjusted effect of DBI on the median MMSE-time profile. Analyses were restricted to men with English-speaking backgrounds (n = 1059, 862, and 611 at baseline, 2, and 5 years). RESULTS: Overall, 292 (27.7%), 258 (29.9%), and 189 (31.3%) men used anticholinergic or sedative medications at baseline, 2, and 5 years. There was a concave relationship between MMSE and time, where higher DBI corresponded to lower MMSE scores (coefficient: -0.161; 95% CI: -0.250 to -0.071) but not acceleration of declining MMSE over time. CONCLUSIONS: Exposure to anticholinergic and sedative medications is associated with a small impairment in cognitive performance but not decline in cognition over time. KEY MESSAGES Exposure to anticholinergic and sedative medications, quantified using the Drug Burden Index, is associated with small cross-sectional impairments in cognitive performance. There was no evidence that exposure to anticholinergic and sedative medications is associated with accelerating decline in cognitive performance over a 5-year follow-up. Older people taking anticholinergic and sedative medications may derive immediate but small benefits in cognitive performance from clinical medication reviews to minimize or cease prescribing of these medications. PMID- 27763768 TI - How and Where Parents of Infants and Young Children Want to Receive Nutrition Information. AB - PURPOSE: To understand how and where parents of infants and young children (children <=5 years old) prefer to receive nutrition information. METHODS: A 1 page survey was developed and pilot tested at 2 community agencies. The final survey was distributed at 18 community health centres (CHCs) in Calgary and surrounding rural areas. Any parent attending a well-child visit (child <=5 years old) was able to participate. RESULTS: Five hundred and twenty-nine surveys were completed. The majority of respondents at every CHC identified online reading (79.2%) in their home (86.0%) as the preferred method and location to receive nutrition information. Almost all (99.4%) participants had internet access. Handouts (38.6%) were the second most popular way to receive nutrition information. In-person and online classes were only a preferred method by a small percentage of respondents, 10.6% and 8.1%, respectively. CONCLUSIONS: Appropriate, evidence-based nutrition websites should be promoted to parents with young children. Health professionals should be aware that parents likely access nutrition information online, and they need to provide an opportunity for parents to discuss what they found. Future research is needed to understand which websites parents access for online nutrition information and how they discern whether it is credible. PMID- 27763769 TI - Standing on the Shoulders of Stem Cell Gene Therapists: History, Hyperbole, and Hope for the Future. AB - A new type of medicine approved in Europe at the end of May represents the culmination of the successful convergence of two fields of science: stem cell transplantation and gene therapy. Strimvelis, a patient-specific gene-modified stem cell medicine for ADA-SCID (adenosine deaminase deficiency leading to severe combined immunodeficiency; a fatal immunometabolic disorder similar to the bubble boy disease), was developed by scientists at the San Raffaele Telethon Institute for Gene Therapy (TIGET) in Milan, Italy, which then later partnered with GlaxoSmithKline (GSK, Brentford, UK). The journey took more than 25 years of dedicated work by many groups and involved a pivotal trial with 12 children and their brave families. I was fortunate to be involved on the GSK side of the TIGET alliance from 2010 to 2015, building on my previous experiences with gene modified stem cells during a postdoctoral fellowship in the mid-1990s and at Chiron, which had acquired Viagene, an early gene therapy biotech firm. I thought it was timely to pick out a couple of observations from the development of Strimvelis, to see how these might apply to the future of stem cell gene therapy and perhaps act like shoulders for the related chimeric antigen receptor T-cell (CAR-T) and gene-editing technologies to stand on. PMID- 27763772 TI - Estimates of functional cerebral hemispheric differences in monolingual and bilingual people who stutter: Visual hemifield paradigm. AB - The relationship between stuttering and bilingualism to functional cerebral hemispheric processing was examined using a visual hemifield paradigm. Eighty native German speakers, half of whom were also proficient speakers of English as a second language (L2), were recruited. The participants were organised into four different groups according to speech status and language ability: 20 monolinguals who stutter, 20 bilinguals who stutter, 20 monolinguals who do not stutter, and 20 bilinguals who do not stutter. All participants completed a task involving selective identification of common objects simultaneously presented to both visual fields. Overall, an LVF advantage was observed across all groups with no significant group differences in regard to hemispheric asymmetry. However, both bilingual groups showed faster reaction times and fewer identification errors than the two monolingual groups. A prevailing finding was that bilingualism seems to offset deficits in executive functioning associated with stuttering. Hence, the results lend support to previous findings implicating the benefits of bilingualism. PMID- 27763773 TI - High Concentrations of Ozone Air Pollution on Mount Everest: Health Implications for Sherpa Communities and Mountaineers. AB - : Semple, John L., G.W. Kent Moore, Petros Koutrakis, Jack M. Wolfson, Paolo Cristofanelli, and Paolo Bonasoni. High concentrations of ozone air pollution on Mount Everest: health implications for Sherpa communities and mountaineers. High Alt Med Biol. 17:365-369, 2016.-Introduction: Populations in remote mountain regions are increasingly vulnerable to multiple climate mechanisms that influence levels of air pollution. Few studies have reported on climate-sensitive health outcomes unique to high altitude ecosystems. In this study, we report on the discovery of high-surface ozone concentrations and the potential impact on health outcomes on Mount Everest and the high Himalaya. MATERIALS AND METHODS: Surface ozone measurements were collected during ascending transects in the Mount Everest region of Nepal with passive nitrite-coated Ogawa filter samplers to obtain 8 hour personal exposures (2860-5364 m asl). In addition, the Nepal Climate Observatory-Pyramid, a GAW-WMO Global Station sited in the Khumbu Valley (5079 m asl), collected ozone mixing ratios with photometric gas analyzer. RESULTS: Surface ozone measurements increased with altitude with concentrations that exceed 100 ppb (8-hour exposure). Highest values were during the spring season and the result of diverse contributions: hemispheric background values, the descent of ozone-rich stratospheric air, and the transport of tropospheric pollutants occurring at different spatial scales. DISCUSSION: Multiple climate factors, including descending stratospheric ozone and imported anthropogenic air masses from the Indo-Gangetic Plain, contribute to ambient ozone exposure levels in the vicinity of Mount Everest that are similar to if not higher than those reported in industrialized cities. PMID- 27763774 TI - Modeling faults among e-bike-related fatal crashes in China. AB - OBJECTIVES: This article aims to model fault in e-bike fatal crashes in a county level city in China. METHOD: Three-year crash data are retrieved from the crash reports (2012-2014) from the Taixing Police Department. A mixed logit model is introduced to explore significant factors associated with fault assignment, as well as accounting for similarity among fault assignment and heterogeneity within unobserved variables. RESULTS: The modeling results indicate some interesting new findings. First, precrash behaviors of both drivers and e-bike riders are found to be significant to fault assignment. Second, bike lane and median type are significantly associated with e-bike rider fault commitment. Third, specific groups of e-bike riders (low-educated and older) and drivers (heavy good vehicles) are more likely to be at fault in e-bike crashes. Last, crash location and the built environment have significant correlations with faulty behaviors of e-bike riders. CONCLUSIONS: Safety countermeasures are proposed including (1) the deployment of traffic design and control elements including physically separated bike lanes, medians, video surveillance systems for e-bike riders, and left turning treatments for nonmotorists (e.g., a 2-step e-bike left turning); (2) the amendment of the current traffic regulations on drunk e-bike riders and child e bike passengers; (3) the development of a license system for specific e-bike rider groups (older and low-educated) and a safety campaign for drivers (to increase safety awareness when parking on-street or driving heavy good vehicles). Some interesting future research topics are also suggested: e-bike riders' behaviors at unsignalized intersections and mid-block openings, e-bike safety in suburban areas, and an in-depth study of the effect of the built environment on e bike safety. PMID- 27763775 TI - Reliability of Haemophilus influenzae biofilm measurement via static method, and determinants of in vitro biofilm production. AB - Information is lacking regarding the precision of microtitre plate (MTP) assays used to measure biofilm. This study investigated the precision of an MTP assay to measure biofilm production by nontypeable Haemophilus influenzae (NTHi) and the effects of frozen storage and inoculation technique on biofilm production. The density of bacterial final growth was determined by absorbance after 18-20 h incubation, and biofilm production was then measured by absorbance after crystal violet staining. Biofilm formation was categorised as high and low for each strain. For the high biofilm producing strains of NTHi, interday reproducibility of NTHi biofilm formation measured using the MTP assay was excellent and met the acceptance criteria, but higher variability was observed in low biofilm producers. Method of inoculum preparation was a determinant of biofilm formation with inoculum prepared directly from solid media showing increased biofilm production for at least one of the high producing strains. In general, storage of NTHi cultures at -80 degrees C for up to 48 weeks did not have any major effect on their ability to produce biofilm. PMID- 27763776 TI - Can variations in visual behavior measures be good predictors of driver sleepiness? A real driving test study. AB - OBJECTIVE: The primary purpose of this study was to examine the association between variations in visual behavior measures and subjective sleepiness levels across age groups over time to determine a quantitative method of measuring drivers' sleepiness levels. METHOD: A total of 128 volunteer drivers in 4 age groups were asked to finish 2-, 3-, and 4-h continuous driving tasks on expressways, during which the driver's fixation, saccade, and blink measures were recorded by an eye-tracking system and the subjective sleepiness level was measured through the Stanford Sleepiness Scale. Two-way repeated measures analysis of variance was then used to examine the change in visual behavior measures across age groups over time and compare the interactive effects of these 2 factors on the dependent visual measures. RESULTS: Drivers' visual behavior measures and subjective sleepiness levels vary significantly over time but not across age groups. A statistically significant interaction between age group and driving duration was found in drivers' pupil diameter, deviation of search angle, saccade amplitude, blink frequency, blink duration, and closure duration. Additionally, change in a driver's subjective sleepiness level is positively or negatively associated with variation in visual behavior measures, and such relationships can be expressed in regression models for different period of driving duration. CONCLUSIONS: Driving duration affects drivers' sleepiness significantly, so the amount of continuous driving time should be strictly controlled. Moreover, driving sleepiness can be quantified through the change rate of drivers' visual behavior measures to alert drivers of sleepiness risk and to encourage rest periods. These results provide insight into potential strategies for reducing and preventing traffic accidents and injuries. PMID- 27763778 TI - Correlation of Prenatal Diagnosis and Pathology Findings Following Dilation and Evacuation for Fetal Anomalies. AB - CONTEXT: -Despite increased use of dilation and evacuation in the setting of fetuses with developmental anomalies, the pathology examination of fragmented specimens obtained by this technique has been understudied. OBJECTIVES: -To correlate pathologic findings in second-trimester fetal dilation and evacuation specimens with prenatal diagnoses established through ultrasound and/or chromosome studies to determine the value of pathology examination for supplementing or correcting clinical diagnoses. DESIGN: -In this retrospective study, clinical and pathology findings were correlated in 448 dilation and evacuation specimens performed for second-trimester termination of pregnancy for fetal anomalies discovered on ultrasound examination (278 cases) or chromosome analysis (170 cases). RESULTS: -In 109 of the 170 cases with chromosomal abnormalities (64%), pathologists identified at least 1 congenital defect associated with the respective karyotype. In 278 cases with ultrasound-detected anomalies, pathologists confirmed the major congenital defect in 116 fetal specimens (42%). Evaluating for congenital central nervous system and body wall/diaphragm pathologic findings proved challenging owing to tissue disruption. However, taking all categories into account, pathology studies corrected ultrasound diagnoses in 152 of 413 cases (37%) and yielded additional diagnostic findings in 137 cases (33%). CONCLUSIONS: -In a substantial number of cases, examination of fragmented fetuses corrected or refined prenatal diagnoses, demonstrating a role for detailed pathology examination of dilation and evacuation specimens in quality control of prenatal imaging studies and for potentially aiding subsequent genetic counseling. PMID- 27763777 TI - Complementary Roles of Estrogen-Related Receptors in Brown Adipocyte Thermogenic Function. AB - Brown adipose tissue (BAT) thermogenesis relies on a high abundance of mitochondria and the unique expression of the mitochondrial Uncoupling Protein 1 (UCP1), which uncouples substrate oxidation from ATP synthesis. Adrenergic stimulation of brown adipocytes activates UCP1-mediated thermogenesis; it also induces the expression of Ucp1 and other genes important for thermogenesis, thereby endowing adipocytes with higher oxidative and uncoupling capacities. Adipocyte mitochondrial biogenesis and oxidative capacity are controlled by multiple transcription factors, including the estrogen-related receptor (ERR)alpha. Whole-body ERRalpha knockout mice show decreased BAT mitochondrial content and oxidative function but normal induction of Ucp1 in response to cold. In addition to ERRalpha, brown adipocytes express ERRbeta and ERRgamma, 2 nuclear receptors that are highly similar to ERRalpha and whose function in adipocytes is largely unknown. To gain insights into the roles of all 3 ERRs, we assessed mitochondrial function and adrenergic responses in primary brown adipocytes lacking combinations of ERRs. We show that adipocytes lacking just ERRalpha, the most abundant ERR, show only mild mitochondrial defects. Adipocytes lacking ERRbeta and ERRgamma also show just mild defects. In contrast, adipocytes lacking all 3 ERRs have severe reductions in mitochondrial content and oxidative capacity. Moreover, adipocytes lacking all 3 ERRs have defects in the transcriptional and metabolic response to adrenergic stimulation, suggesting a wider role of ERRs in BAT function than previously appreciated. Our study shows that ERRs have a great capacity to compensate for each other in protecting mitochondrial function and the metabolic response to adrenergic signaling, processes vital to BAT function. PMID- 27763779 TI - Prevalence of Traditional and Reverse-Algorithm Syphilis Screening in Laboratory Practice: A Survey of Participants in the College of American Pathologists Syphilis Serology Proficiency Testing Program. AB - CONTEXT: -Syphilis serology screening in laboratory practice is evolving. Traditionally, the syphilis screening algorithm begins with a nontreponemal immunoassay, which is manually performed by a laboratory technologist. In contrast, the reverse algorithm begins with a treponemal immunoassay, which can be automated. The Centers for Disease Control and Prevention has recognized both approaches, but little is known about the current state of laboratory practice, which could impact test utilization and interpretation. OBJECTIVE: -To assess the current state of laboratory practice for syphilis serologic screening. DESIGN: In August 2015, a voluntary questionnaire was sent to the 2360 laboratories that subscribe to the College of American Pathologists syphilis serology proficiency survey. RESULTS: -Of the laboratories surveyed, 98% (2316 of 2360) returned the questionnaire, and about 83% (1911 of 2316) responded to at least some questions. Twenty-eight percent (378 of 1364) reported revision of their syphilis screening algorithm within the past 2 years, and 9% (170 of 1905) of laboratories anticipated changing their screening algorithm in the coming year. Sixty-three percent (1205 of 1911) reported using the traditional algorithm, 16% (304 of 1911) reported using the reverse algorithm, and 2.5% (47 of 1911) reported using both algorithms, whereas 9% (169 of 1911) reported not performing a reflex confirmation test. Of those performing the reverse algorithm, 74% (282 of 380) implemented a new testing platform when introducing the new algorithm. CONCLUSION: -The majority of laboratories still perform the traditional algorithm, but a significant minority have implemented the reverse-screening algorithm. Although the nontreponemal immunologic response typically wanes after cure and becomes undetectable, treponemal immunoassays typically remain positive for life, and it is important for laboratorians and clinicians to consider these assay differences when implementing, using, and interpreting serologic syphilis screening algorithms. PMID- 27763780 TI - Systemic effects of controlled exposure to diesel exhaust: a meta-analysis from randomized controlled trials. AB - INTRODUCTION: Ambient air pollution is associated with adverse cardiovascular events. This meta-analysis aimed to investigate the short-term association between air pollution and cardiovascular effects on healthy volunteers. METHODS: We searched databases to identify randomized trials with controlled human exposures to either of two models for studying ambient particulate matter: diesel exhaust or concentrated ambient particles. Estimates of size effect were performed using standardized mean difference (SMD). Heterogeneity was assessed with I2 statistics. Outcomes were vascular function estimated by forearm blood flow (FBF), blood pressure, heart rate, and blood analysis. RESULTS: Database searches yielded 17 articles (n = 342) with sufficient information for meta analyses. High levels of heterogeneity for the some outcomes were analyzed using random-effects model. The pooled effect estimate showed that short-term exposure to air pollution impaired FBF response from 2.7 to 2.5 mL/100 mL tissue/min (SMD 0.404; p = .006). There was an increase in 5000 platelet/mm3 following pollution exposure (SMD 0.390; p = .050) but no significant differences for other outcomes. CONCLUSION: Controlled human exposures to air pollution are associated with the surrogates of vascular dysfunction and increase in platelet count, which might be related to adverse cardiovascular events. Given the worldwide prevalence of exposure to air pollution, these findings are relevant for public health. KEY MESSAGES Controlled exposure to air pollution impairs vasomotor response, which is a surrogate for adverse cardiovascular events. This is the first meta-analysis from randomized clinical trials showing short-term association between air pollution and cardiovascular effects on healthy volunteers. Given the worldwide prevalence of exposure to air pollution, this finding is important for public health. PMID- 27763781 TI - Markers of atherosclerosis in patients with Cushing's syndrome: a meta-analysis of literature studies. AB - BACKGROUND: Several studies reported an increased cardiovascular (CV) risk in Cushing's syndrome (CS). We performed a meta-analysis on the impact of CS on major markers of atherosclerosis. METHODS: Studies on intima-media thickness (IMT), carotid plaques prevalence, and flow-mediated dilation (FMD) in CS patients and controls were searched in the PubMed, Web of Science, Scopus, and EMBASE. Differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95%CI) for continuous variables, and as Odds Ratio (OR) with 95%CI for dichotomous variables. RESULTS: Fourteen studies (332 CS, 462 controls) were included. Compared with controls, CS patients showed higher IMT (MD: 0.20 mm; 95% CI: 0.12, 0.28; p < .001), increased prevalence of carotid plaques (OR: 8.85, 95%CI: 4.09, 19.14; p < .001), and lower FMD (MD: 2.65%; 95% CI: -3.65, -1.65; p < .001). Difference in IMT and in the prevalence of carotid plaques was confirmed also in patients with CS remission (MD: 0.24 mm; 95% CI: 0.07, 0.40; p = .005 and OR: 9.88, 95%CI: 2.69, 36.3; p < 0.001, respectively). Regression models showed that age, diabetes, obesity, ACTH dependent CS, serum and urinary cortisol levels impacted on the observed difference in IMT. CONCLUSIONS: CS is significantly associated with markers of subclinical atherosclerosis and CV risk. These findings could help establish more specific CV prevention strategies in this clinical setting. Key messages A series of studies reported an increased cardiovascular risk in patients with Cushing's syndrome (CS). In the present meta-analysis we demonstrated that CS is associated with an increased intima-media thickness, higher prevalence of carotid plaques, and lower flow-mediated dilation as compared with controls. These data consistently suggest the need for a strict monitoring of early signs of subclinical atherosclerosis in CS patients. PMID- 27763784 TI - Assessing the Efficacy of a Group Mediated Nutritional Knowledge Intervention for Individuals with Obesity. AB - PURPOSE: This study reports on the effect of a group-based nutrition and physical activity intervention program on nutrition knowledge and eating habits in a cohort of people with obesity. METHODS: A quasi-experimental design with pre- and post-test measures. The intervention consisted of physical activity led by certified exercise physiologists and a nutritional education component led by registered dietitians over a 6-month period followed by 6 months of self management. Participants' nutrition knowledge and eating habits were assessed using the modified Nutrition Assessment, the Nutrition Knowledge Survey, and the Food Choice Questionnaires at baseline, after the 6-month intervention, and after 6 months of self-management. RESULTS: Complete data were available for 59 (40%) of participants after 12 months because of attrition. Nutritional knowledge and behaviours improved. Participants reported increasing their consumption of healthy foods during the active intervention and maintained these changes through the self-management phase. Knowledge of healthy foods was improved and a greater likelihood of choosing food for weight control and health properties was reported. CONCLUSIONS: Knowledge and reported consumption of healthier nutrition improved during the active intervention and was maintained during the self management period for individuals who completed the program. Registered dietitians can play an important role in managing patients with obesity in group settings. PMID- 27763785 TI - Aromatherapy Improves Work Performance Through Balancing the Autonomic Nervous System. AB - OBJECTIVE: This study analyzed the efficacy of aromatherapy in improving work performance and reducing workplace stress. SUBJECTS: The initial sample comprised 42 administrative university workers (Mage = 42.21 years, standard deviation = 7.12; 10 male). INTERVENTION: All sessions were performed in a university computer classroom. The participants were randomly assigned into an aromatherapy group (AG) and a control group (CG), and they were invited to participate in a specific session only once. They were seated in front of a computer. During the intervention period, some oil diffusers were switched on and were in operation throughout the session with petitgrain essential oil for AG sessions and a neutral oil (almond) for CG sessions. At the same time, participants completed a computer task on a specific Web site typing on their keyboard until they had finished it. The single times were different for all participants and were recorded on the Web site as "performance time." OUTCOME MEASURES: Before and after the intervention, participants completed anxiety and mood state questionnaires (the Stait-Trait Anxiety Inventory [STAI] and the Profile of Mood States [POMS]). Heart-rate variability (HRV) was measured before (PRE), during (20-25 min), and after (POS) the intervention to analyze autonomic nervous system regulation. RESULTS: The AG performed the Web site task 2.28 min faster than the CG (p = 0.05). The two groups showed differences in the following HRV parameters: low frequency (p = 0.05), high frequency (p = 0.02), standard deviation of all RR intervals (p = 0.05), and root mean square of differences (p = 0.02). All participants in all groups showed a decrease from PRE to POST for STAI (p < 0.001), Tension-POMS (p < 0.001), and Vigour-POMS (p = 0.01) scales. CONCLUSIONS: Aromatherapy (inhaling petitgrain essential oil) can improve performance in the workplace. These results could be explained by an autonomic balance on the sympathetic/parasympathetic system through a combined action of the petitgrain main components (linalyl acetate, linalool, and myrcene). The final effect could be an improvement of the mental and emotional condition by a combination of reducing the stress level and increasing the arousal level of the participants in terms of attentiveness and alertness. PMID- 27763786 TI - Application of Droplet Digital PCR for Estimating Vector Copy Number States in Stem Cell Gene Therapy. AB - Stable gene transfer into target cell populations via integrating viral vectors is widely used in stem cell gene therapy (SCGT). Accurate vector copy number (VCN) estimation has become increasingly important. However, existing methods of estimation such as real-time quantitative PCR are more restricted in practicality, especially during clinical trials, given the limited availability of sample materials from patients. This study demonstrates the application of an emerging technology called droplet digital PCR (ddPCR) in estimating VCN states in the context of SCGT. Induced pluripotent stem cells (iPSCs) derived from a patient with X-linked chronic granulomatous disease were used as clonable target cells for transduction with alpharetroviral vectors harboring codon-optimized CYBB cDNA. Precise primer-probe design followed by multiplex analysis conferred assay specificity. Accurate estimation of per-cell VCN values was possible without reliance on a reference standard curve. Sensitivity was high and the dynamic range of detection was wide. Assay reliability was validated by observation of consistent, reproducible, and distinct VCN clustering patterns for clones of transduced iPSCs with varying numbers of transgene copies. Taken together, use of ddPCR appears to offer a practical and robust approach to VCN estimation with a wide range of clinical and research applications. PMID- 27763787 TI - Laboratory Diagnosis of Zika Virus Infection. AB - CONTEXT: -The rapid and accurate diagnosis of Zika virus infection is an international priority. OBJECTIVE: -To review current recommendations, methods, limitations, and priorities for Zika virus testing. DATA SOURCES: -Sources include published literature, public health recommendations, laboratory procedures, and testing experience. CONCLUSIONS: -Until recently, the laboratory diagnosis of Zika infection was confined to public health or research laboratories that prepared their own reagents, and test capacity has been limited. Furthermore, Zika cross-reacts serologically with other flaviviruses, such as dengue, West Nile, and yellow fever. Current or past infection, or even vaccination with another flavivirus, will often cause false-positive or uninterpretable Zika serology results. Detection of viral RNA during acute infection using nucleic acid amplification tests provides more specific results, and a number of commercial nucleic acid amplification tests have received emergency use authorization. In addition to serum, testing of whole blood and urine is recommended because of the higher vial loads and longer duration of shedding. However, nucleic acid amplification testing has limited utility because many patients are asymptomatic or present for testing after the brief period of Zika shedding has passed. Thus, the greatest need and most difficult challenge is development of accurate antibody tests for the diagnosis of recent Zika infection. Research is urgently needed to identify Zika virus epitopes that do not cross-react with other flavivirus antigens. New information is emerging at a rapid pace and, with ongoing public-private and international collaborations and government support, it is hoped that rapid progress will be made in developing robust and widely applicable diagnostic tools. PMID- 27763788 TI - Professionalism in Pathology: A Case-Based Approach as a Potential Educational Tool. AB - CONTEXT: -Professionalism issues in residency training can be difficult to assess and manage. Generational or role-based differences may also exist between faculty and residents as to what constitutes unprofessional behavior and how to manage it. OBJECTIVE: -To examine and compare how faculty and residents would approach the same 5 case scenarios detailing various aspects of unprofessional behavior. DESIGN: -Five case scenarios highlighting various unprofessional behaviors were presented in a workshop at an annual meeting of pathology department chairs, residency program directors, and undergraduate pathology medical educators (ie, pathologists involved in medical student pathology education). The same cases were presented to a cohort of pathology residents currently in training. A standard set of responses were offered to the participants, polling results were collected electronically, and results were compared. RESULTS: -Faculty and residents were fairly consistent within their respective groups. In a subset of cases, faculty were more likely to favor working with the individual in the scenario, whereas resident respondents were more likely to favor either no response or a severe response. Generational or role-based differences were also potentially evident. CONCLUSIONS: -Assessing expectations and differences around professionalism for both faculty and residents should be considered as part of any educational and management approach for professionalism. Although a level of generational differences appears to be evident in this study regarding the recognition and management of unprofessional behavior, there was also agreement in some cases. Further exploration into the discrepant responses between faculty and residents may prove useful in developing educational, assessment, and remediation resources. PMID- 27763789 TI - Facebook Discussion Groups Provide a Robust Worldwide Platform for Free Pathology Education. AB - CONTEXT: - Facebook (Menlo Park, California) is one of many online sites that provide potential educational tools for pathologists. We have each founded Facebook groups dedicated to anatomic pathology, in which members can share cases, ask questions, and contribute to discussions. OBJECTIVES: - To report our experiences in founding and maintaining these Facebook groups and to characterize the contributed content. DESIGN: - We circulated a survey among the group founders, then compiled and analyzed the responses. RESULTS: - The groups varied in membership and in the quality of member contribution. Most posts were of pathology cases, although other topics (such as research articles) were also shared. All groups remained active and received posts from users all over the world, although all groups had many noncontributing members and received unwanted messages (which were screened and removed). Most founders were glad they had founded the groups because they provided an opportunity to both teach and learn. CONCLUSIONS: - Each analyzed Facebook group had a different character, and some downsides exist, but the groups all provided a no-cost way for pathologists and others across the world to interact online with many colleagues. PMID- 27763782 TI - Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures. AB - Circadian (~24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important. PMID- 27763790 TI - Improving Adequacy of Small Biopsy and Fine-Needle Aspiration Specimens for Molecular Testing by Next-Generation Sequencing in Patients With Lung Cancer: A Quality Improvement Study at Dartmouth-Hitchcock Medical Center. AB - CONTEXT: - At our medical center, cytopathologists perform rapid on-site evaluation for specimen adequacy of fine-needle aspiration and touch imprint of needle core biopsy lung cancer samples. Two years ago the molecular diagnostics laboratory at our institution changed to next-generation sequencing using the Ion Torrent PGM and the 50-gene AmpliSeq Cancer Hotspot Panel v2 for analyzing mutations in a 50-gene cancer hot spot panel. This was associated with a dramatic fall in adequacy rate (68%). OBJECTIVE: - To improve the adequacy rate to at least 90% for molecular testing using next-generation sequencing for all specimens collected by rapid on-site evaluation by the cytology laboratory. DESIGN: - After baseline data on adequacy rate of cytology specimens with rapid on-site evaluation for molecular testing had been collected, 2 changes were implemented. Change 1 concentrated all the material in one block but did not produce desired results; change 2, in addition, faced the block only once with unstained slides cut up front for molecular testing. Data were collected in an Excel spreadsheet and adequacy rate was assessed. RESULTS: - Following process changes 1 and 2 we reached our goal of at least 90% adequacy rate for molecular testing by next-generation sequencing on samples collected by rapid on-site evaluation including computed tomography-guided needle core biopsies (94%; 17 of 18) and fine-needle aspiration samples (94%; 30 of 32). CONCLUSION: - This study focused on factors that are controllable in a pathology department and on maximizing use of scant tissue. Optimizing the adequacy of the specimen available for molecular tests avoids the need for a second procedure to obtain additional tissue. PMID- 27763791 TI - Challenges of Frozen Section in Thoracic Pathology: Lepidic Lesions, Limited Resections, and Margins. AB - CONTEXT: - The use of frozen section in thoracic pathology includes assessment of peripheral lung lesions with lepidic pattern, with greater emphasis on evaluating lung-sparing resections and margin assessment. OBJECTIVE: - To review pitfalls of frozen section in thoracic pathology; in this setting, reduction of false positive and false-negative diagnosis in lesion identification and margin assessment is critical. DATA SOURCES: - PubMed search of frozen section lung pathology yielded specific references related to the use of frozen section in the identification of lepidic lesions and the clinical recommendation for margin distance. CONCLUSIONS: - Frozen section diagnosis is overall accurate in assessment of lepidic lesions. Pitfalls include rare benign mimickers and more common reactive lesions. Standard approaches to gross assessment and margin measurement require further research with increasing use of lung-sparing resections. PMID- 27763792 TI - CDH17 Is a More Sensitive Marker for Gastric Adenocarcinoma Than CK20 and CDX2. AB - CONTEXT: -CDH17, which is expressed in the intestinal epithelium, is a novel oncogene involved in tumor invasion and metastasis. A panel consisting of cytokeratin (CK) 7, CD20, and CDX2 antibodies is typically used to diagnose gastrointestinal adenocarcinomas. However, studies have shown that CDH17 is a highly specific marker for gastrointestinal adenocarcinoma and may be important in clinical diagnosis. OBJECTIVE: -To evaluate the sensitivity and specificity of CDH17, CK20, and CDX2 antibodies in neoplastic tissues, with emphasis on colon, stomach, and esophageal gastrointestinal lineage. DESIGN: -Immunohistochemistry was performed with CDH17, CK20, and CDX2 antibodies on formalin-fixed, paraffin embedded tissue microarrays from normal (n = 26) and neoplastic (n = 884) tissues. RESULTS: -CDH17 immunostaining was positive in 97.3% (145 of 149) of colon adenocarcinomas, whereas CK20 and CDX2 stained positively in 88.6% (132 of 149) and 93.3% (139 of 149), respectively. In metastatic colon cancers, CDH17, CK20, and CDX2 positive staining was observed in 90.6% (29 of 32), 59.4% (19 of 32), and 81.3% (26 of 32) of cases, respectively. In stomach adenocarcinomas, CDH17 positively stained 64.0% (112 of 175) of tissues, compared to CK20 and CDX2, where staining was observed in only 24.6% (43 of 175) and 46.9% (82 of 175), respectively. In esophageal adenocarcinomas, CDH17, CK20, and CDX2 stained 38.7% (12 of 31), 25.8% (8 of 31), and 29% (9 of 31) of specimens, respectively. Low or no expression was observed in other neoplastic tissues, except pancreatic cancers, where CDH17 displayed higher expression than CK20 and CDX2. CONCLUSIONS: -CDH17 is a specific and more sensitive marker in the gastrointestinal tract than CK20 and CDX2. CDH17 may be especially valuable when gastrointestinal tumors are suspected in cancers of unknown primary. PMID- 27763793 TI - The Origins and Emergence of Zika Virus, the Newest TORCH Infection: What's Old Is New Again. PMID- 27763794 TI - Evaluation of the Vulvar Cancer Histology Code Reported by Central Cancer Registries: Importance in Epidemiology. AB - CONTEXT: -Knowing the subtype of vulvar cancer histology is important for estimating human papillomavirus-related cancer etiology. Surveillance of human papillomavirus-related vulvar cancers informs public health decisions related to vaccination against human papillomavirus. OBJECTIVE: -To assess the accuracy of registry classifications of vulvar cancer and determine the histologic classification of cases reported as not otherwise specified. DESIGN: -Pathology specimens were collected from Florida, Iowa, and Hawaii cancer registries. Registry diagnosis was compared with the pathology report from the medical record and a single expert study histology review of a representative histologic section from each case. RESULTS: -The study included 60 invasive vulvar squamous cell carcinoma (SCC) cases, 6 Paget disease cases, 2 basal cell carcinoma cases, and 53 in situ cases. Comparing subtypes of invasive vulvar SCC, the registry agreed with the pathology report classification in 49 of 60 cases (81.7%). Study histology review identified the same SCC subtype as the registry in 9 of 60 cases (15.0%) and the same SCC subtype as the pathology report in 11 of 60 cases (18.3%). Whereas the registry and pathology reports classified 37 and 34 cases, respectively, as being SCC not otherwise specified, the study histology review identified a more specific subtype in all cases. CONCLUSIONS: -Subtypes of vulvar cancer were frequently recorded as not otherwise specified in the cancer registry primarily because the pathology report often did not specify the histologic subtype. Vulvar cancer registry data are useful for tracking broad diagnostic categories, but are less reliable for vulvar cancer subtypes. PMID- 27763795 TI - Zika Virus: The Agent and Its Biology, With Relevance to Pathology. AB - Once obscure, Zika virus (ZIKV) has attracted significant medical and scientific attention in the past year because of large outbreaks associated with the recent introduction of this virus into the Western hemisphere. In particular, the occurrence of severe congenital infections and cases of Guillain-Barre syndrome has placed this virus squarely in the eyes of clinical and anatomic pathologists. This review article provides a basic introduction to ZIKV, its genetics, its structural characteristics, and its biology. A multidisciplinary effort will be essential to establish clinicopathologic correlations of the basic virology of ZIKV in order to advance development of diagnostics, therapeutics, and vaccines. PMID- 27763796 TI - Medication Use Among Mount Everest Climbers: Practice and Attitudes. AB - Luks, Andrew M., Colin Grissom, Luanne Freer, and Peter Hackett. Medication use among mount Everest climbers: practice and attitudes. High Alt Med Biol. 17:315 322, 2016.-The lay public, media, and medical experts have expressed concern about the ethics of climbers using medications to improve performance and increase the odds of summit success while climbing at high altitude, but the true incidence of this practice remains unclear. We conducted an anonymous survey of climbers who have attempted to climb Mt. Everest to gather information about medication use and attitudes toward medication and supplemental oxygen use while climbing the mountain. One hundred eighty-seven individuals completed the survey, providing information about medication and oxygen use for 262 expeditions to Mt. Everest between 1963 and 2015, the majority of which occurred after the year 2000. The majority of respondents were male (82%) and from English-speaking countries (75%). Medications were used on 43% of climbs, with acetazolamide being the most commonly used medication. Reported use of dexamethasone, nifedipine, sildenafil, or tadalafil was uncommon as was use of multiple medications at the same time. The majority of respondents indicated that it was acceptable for climbers to use medications and supplemental oxygen to prevent altitude illness while climbing Mt. Everest. Opinions were more mixed regarding whether summiting without the use of medications or oxygen carried the same value as reaching the summit using those interventions. Our data suggest that less than one-half of Mt. Everest climbers use medications during their expedition, with the primary medication used being acetazolamide, for prevention of altitude illness. Given the limitations of the study design and preliminary nature of these data, further research is warranted to further clarify these issues. PMID- 27763797 TI - Expression of TRAIL and Fas in Primary Hyperparathyroidism. AB - AIM: Differentiating between parathyroid lesions is still difficult and ambiguous. In cases of primary hyperparathyroidism, appropriate and prompt diagnosis is of great importance for effective treatment and follow-up. A great amount of mechanisms contribute to the pathogenesis of primary hyperparathyroidism, such as disturbance in balance between pro- and anti apoptotic factors. Therefore, we examined whether immunohistochemical expression of apoptotic factors, TNF-related apoptosis-inducing ligand (TRAIL) and Fas, could have clinical utility as a marker of proliferative lesions of parathyroid gland. MATERIALS AND METHODS: Parathyroid specimens of 58 consecutive patients who had undertaken surgery due to primary hyperparathyroidism were incubated with purified mouse monoclonal antihuman antibodies: anti-TRAIL and anti-Fas. Staining was considered positive when at least 5% of the cells showed immunoreactivity. RESULTS: The percentage of cells which were positively stained for TRAIL in parathyroid hyperplasia was 9.65%, in parathyroid adenoma 8.31%, and in normal controls 2.24%. Immunoreactivity for TRAIL was detected in 91.89% of parathyroid hyperplasias, 85.71% of parathyroid adenomas, and none in healthy glands. The percentage of cells with a positive reaction to Fas in parathyroid hyperplasia was 8.92%, in parathyroid adenoma 8.09%, and in normal tissue 1.9%. The expression of Fas was found in 94.59% of parathyroid hyperplasias, 90.48% of parathyroid adenomas, and none in healthy glands. CONCLUSIONS: In our study, hyperplasias demonstrated the highest expression of TRAIL and Fas, whereas in adenomas it was increased compared to normal tissue, but lower than in hyperplasias. These factors could be an additive tool in the differential diagnosis of parathyroid lesions. PMID- 27763798 TI - A negative view of menopause: does the type of symptom matter? AB - OBJECTIVES: To assess the association between the type of symptom and women's self-reported view of menopause. METHODS: The study was conducted at Mayo Clinic, Rochester MN, between January 2006 and October 2014. Women aged 40-64 were included. Data from 1420 women were analyzed in a cross-sectional design. The Menopause Health Questionnaire was used for symptom assessment. Odds ratios (ORs) and population attributable risk (PAR) (OR * percent frequency) were calculated for each symptom. Logistic regression analyses were performed with the view of menopause as the dependent variable. RESULTS: Anxiety (2.34), depressed mood (2.24), irritability (2.22), vaginal itching (2.27), crying spells (2.1) and breast tenderness (2.08) were associated with highest odds of having a negative view of menopause. Highest PAR (population impact) symptoms were anxiety (22.27), weight gain (20.66), fatigue (20.28) and irritability (19.41). Hot flushes and night sweats, although common, were not associated with a negative view of menopause (OR 1.3 and 1.16; PAR 3.85 and 4.42, respectively). CONCLUSION: Mood symptoms, vaginal itching, weight gain, breast tenderness and fatigue, although less common than hot flushes, were noted to have greater association with a negative view of menopause. Specifically addressing these symptoms during menopausal consultation may improve patient satisfaction and outcomes. PMID- 27763800 TI - The Utility of Decision Trees in Oncofertility Care in Japan. AB - PURPOSE: To identify the utility and issues associated with the use of decision trees in oncofertility patient care in Japan. METHODS: A total of 35 women who had been diagnosed with cancer, but had not begun anticancer treatment, were enrolled. We applied the oncofertility decision tree for women published by Gardino et al. to counsel a consecutive series of women on fertility preservation (FP) options following cancer diagnosis. Percentage of women who decided to undergo oocyte retrieval for embryo cryopreservation and the expected live-birth rate for these patients were calculated using the following equation: expected live-birth rate = pregnancy rate at each age per embryo transfer * (1 - miscarriage rate) * No. of cryopreserved embryos. RESULTS: Oocyte retrieval was performed for 17 patients (48.6%; mean +/- standard deviation [SD] age, 36.35 +/- 3.82 years). The mean +/- SD number of cryopreserved embryos was 5.29 +/- 4.63. The expected live-birth rate was 0.66. CONCLUSIONS: The expected live-birth rate with FP indicated that one in three oncofertility patients would not expect to have a live birth following oocyte retrieval and embryo cryopreservation. While the decision trees were useful as decision-making tools for women contemplating FP, in the context of the current restrictions on oocyte donation and the extremely small number of adoptions in Japan, the remaining options for fertility after cancer are limited. In order for cancer survivors to feel secure in their decisions, the decision tree may need to be adapted simultaneously with improvements to the social environment, such as greater support for adoption. PMID- 27763799 TI - Creating conditional dual fluorescence labeled transgenic animals for studying function of small noncoding RNAs. AB - Because the function of most noncoding (nc) RNAs is unknown, Cre-lox transgenic mice are useful tools to determine their functions in a tissue or developmental stage-specific manner. However, the technology faces challenges because expression of ncRNA-transgene lacks protein product. No antibody or peptide-tag can be used to trace ncRNA expression in mouse tissues in real time. Furthermore, transgene integration at different locus or orientations in the genome may result in recombination of genomic fragments in the Cre-lox system. Establishing a reliable method that can be used to determine the precise copy number and orientation of the transgene is critical to the field. We developed a fast and straightforward method to determine ncRNA-transgene copy number, orientation, and insertion site in the genome. Furthermore, upon tissue-specific expression of ncRNA, a Cre-loxP-mediated dual-fluorescence expression system facilitates fluorescence signal switching from green to red, which enables real-time monitoring of ncRNA expression by fluorescence signals. As proof of concept, we demonstrate that after microRNA (miRNA)-Flox mice crossed with Col2a1-Cre mice, miRNA transgene expression could be detected successfully by red fluorescence signals in various cartilaginous tissues. This method of creating small ncRNA transgenic mice facilitates both tissue-specific ncRNA expression and real-time visualization of its expression. It is particularly suitable for in vivo studies of the functional roles and lineage tracing of small ncRNA. PMID- 27763801 TI - The prevalence of symptomatic pelvic floor disorders in women in Bangladesh. AB - OBJECTIVE: To investigate the prevalence of, and risk factors for, pelvic floor disorders (PFDs) in women in Bangladesh. METHODS: A nationally representative sample of 1590 Bangladeshi women, aged 30-59 years, was recruited using a multistage cluster sampling technique, between September 2013 and March 2014. Urinary incontinence (UI), fecal incontinence (FI) and pelvic organ prolapse (POP) were assessed using validated questionnaires. The weighted prevalence and the factors associated with each PFD were investigated using multivariable weighted logistic regression. RESULTS: The weighted prevalence of UI was 23.7% (95% confidence interval (CI) 21.3-26.0%), FI 5.3% (95% CI 4.0-6.6%), POP 16.2% (95% CI 14.2-18.2%), and having at least one PFD 35.3% (95% CI 32.6-37.9%). Women were more likely to have at least one PFD if aged 40-49 years (adjusted odds ratio (AOR) 1.46, 95% CI 1.02-2.08; p = 0.040) or 50-59 years (AOR 2.39, 95% CI 1.59-3.58; p < 0.0001), compared with women aged 30-39 years. Having at least one PFD was positively associated with having three or more versus fewer children (AOR 1.61, 95% CI 1.14-2.27; p = 0.007), being in the middle (AOR 3.05, 95% CI 1.72-5.41; p < 0.0001), second lowest (AOR 2.49, 95% CI 1.39-4.47; p = 0.002) or lowest (AOR 3.13, 95% CI 1.68-5.86; p < 0.0001) wealth quintile compared with the highest, and self-reporting diabetes (AOR 2.55, 95% CI 1.54-4.23; p < 0.0001). CONCLUSIONS: One-third of Bangladeshi women aged 30-59 years had at least one symptomatic PFD. Risk factors included greater age, higher parity, lower wealth status and self-reported diabetes. The diagnosis, treatment, and prevention of PFDs in Bangladesh need greater attention, as the prevalence of these disabling conditions is likely to increase with the aging of the population. PMID- 27763802 TI - A randomized, double-blind, placebo-controlled trial of Schisandra chinensis for menopausal symptoms. AB - OBJECTIVES: The purpose of this clinical trial was to evaluate the effectiveness of a natural extract from Schisandra chinensis for relief of various menopausal symptoms. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from January 1, 2014 until January 13, 2015. We recruited women between the ages of 40 and 70 years who complained of menopausal symptoms measured by the Kupperman Index (KI). Patients were randomly assigned to treatment with either an extract from Schisandra chinensis (BMO-30) or placebo. They received the treatment for 6 weeks and were followed for 12 weeks. The primary endpoint was the mean interval change in KI score from baseline to week 12. Secondary measures included laboratory studies and the Menopause Rating Scale (MRS) score for sexual and bladder problems. RESULTS: Forty-one patients were considered eligible for enrolment, and 36 completed the study. After screening and randomization, patients were categorized into the placebo group (n = 18) and the BMO-30 group (n = 18). Total KI scores were significantly lower in the BMO-30 group than in the placebo group when evaluated with respect to group and time (p = 0.042). CONCLUSIONS: BMO-30 from Schisandra chinensis can be a safe and effective complementary medicine for menopausal symptoms, especially for hot flushes, sweating, and heart palpitations. PMID- 27763803 TI - Role of Arabidopsis sterol 4alpha-methyl oxidase2 family in embryo and postembryonic development. AB - Sterols play important roles in plant growth, including embryogenesis, cell expansion, vascular differentiation, male fertility, and endocytosis. Sterols become functional only after removal of the 2 methyl groups at C-4. There are 2 distinct sterol C-4-methyl oxidase (SMO) families in higher plants, SMO1 and SMO2, which contain 3 and 2 isoforms, respectively, involving in the removal of the first and second C4 methyl groups during sterols biosynthesis. In a recent study we showed that single smo2-1 and smo2-2 mutants displayed no significant phenotype, while smo2-1 smo2-2 double mutant was embryonic lethal. smo2-1/+ smo2 2 and smo2-1 smo2-2/+ mutants showed defect in abnormal embryo patterning and smo2-1 smo2-2/+ mutant displayed dwarf phenotype. In this mini-review, we summarize the functions and regulatory mechanisms of SMO2-1 and SMO2-2 in embryo and postembryonic development. PMID- 27763804 TI - Defense priming by non-jasmonate producing fatty acids in maize (Zea mays). AB - Previously, we described a priming effect of alpha-linolenic acid (LnA) on anti herbivore defense response in maize seedlings. 1 We showed that exogenous application of LnA stimulated higher jasmonic acid (JA) accumulation and herbivore-induced plant volatile (HIPV) emission after treatment with insect elicitor (IE). To further investigate the specificity of LnA's priming effect, we incubated maize seedlings in palmitoleic acid (PeicA), gamma-linolenic acid (gamma LnA) and stearic acid (StA) solutions, and analyzed HIPV emission in response to IE. Seedlings incubated in PeicA and gamma LnA had 3 and 1.8 times higher HIPV release when compared to controls. In contrast, treatment with StA did not up-regulate HIPV release. We propose that the elevated level and/or the presence of unsaturated fatty acids sensitize the defense signaling system, which in turn augments the defense response of maize when under insect herbivore attack. PMID- 27763805 TI - Role of non-coding RNA transcription around gene regulatory elements in transcription factor recruitment. AB - Eukaryotic cells produce a variety of non-coding RNAs (ncRNAs), many of which have been shown to play pivotal roles in biological processes such as differentiation, maintenance of pluripotency of stem cells, and cellular response to various stresses. Genome-wide analyses have revealed that many ncRNAs are transcribed around regulatory DNA elements located proximal or distal to gene promoters, but their biological functions are largely unknown. Recently, it has been demonstrated in yeast and mouse that ncRNA transcription around gene promoters and enhancers facilitates DNA binding of transcription factors to their target sites. These results suggest universal roles of promoter/enhancer associated ncRNAs in the recruitment of transcription factors to their binding sites. PMID- 27763806 TI - RNAseq reveals hypervirulence-specific host responses to M. tuberculosis infection. AB - The distinguishing factors that characterize the host response to infection with virulent Mycobacterium tuberculosis (M.tb) are largely confounding. We present an infection study with 2 genetically closely related M.tb strains that have vastly different pathogenic characteristics. The early host response to infection with these detergent-free cultured strains was analyzed through RNAseq in an attempt to provide information on the subtleties which may ultimately contribute to the virulent phenotype. Murine bone marrow derived macrophages (BMDMs) were infected with either a hyper- (R5527) or hypovirulent (R1507) Beijing M. tuberculosis clinical isolate. RNAseq revealed 69 differentially expressed host genes in BMDMs during comparison of these 2 transcriptomes. Pathway analysis revealed activation of the stress-induced and growth inhibitory Gadd45 signaling pathway in hypervirulent infected BMDMs. Upstream regulators of interferon activation such as and IRF3 and IRF7 were predicted to be upregulated in hypovirulent-infected BMDMs. Additional analysis of the host immune response through ELISA and qPCR included the use of human THP-1 macrophages where a robust proinflammatory response was observed after infection with the hypervirulent strain. RNAseq revealed 2 early-response genes (ier3 and saa3) and 2 host-defense genes (oasl1 and slpi) that were significantly upregulated by the hypervirulent strain. The role of these genes under M.tb infection conditions are largely unknown but here we provide validation of their presence with use of qPCR and Western blot. Further analysis into their biological role during infection with virulent M.tb is required. PMID- 27763807 TI - Culture at low glucose up-regulates mitochondrial function in pancreatic beta cells with accompanying effects on viability. AB - We tested whether exposure of beta cells at reduced glucose leads to mitochondrial adaptions and whether such adaptions modulate effects of hypoxia. Rat islets, human islets and INS-1 832/13 cells were pre-cultured short term at half standard glucose concentrations (5.5 mM for rat islets and cells, 2.75 mM for human islets) without overtly negative effects on subsequently measured function (insulin secretion and cellular insulin contents) or on viability. Culture at half standard glucose upregulated complex I and tended to upregulate complex II in islets and INS-1 cells alike. An increased release of lactate dehydrogenase that followed exposure to hypoxia was attenuated in rat islets which had been pre-cultured at half standard glucose. In INS-1 cells exposure to half standard glucose attenuated hypoxia-induced effects on several viability parameters (MTT, cell number and incremental apoptotic DNA). Thus culture at reduced glucose of pancreatic islets and clonal beta cells leads to mitochondrial adaptions which possibly lessen the negative impact of hypoxia on beta cell viability. These findings appear relevant in the search for optimization of pre transplant conditions in a clinical setting. PMID- 27763808 TI - Complete genome sequence of Vibrio mimicus strain SCCF01 with potential application in fish vaccine development. PMID- 27763809 TI - Do Australian immunoglobulin products meet international measles antibody titer standards? AB - The effectiveness of passive immunisation post-exposure to measles appears subject to a dose-response effect. New Zealand and the United Kingdom have increased the recommended dose of polyclonal human immunoglobulin for post exposure prophylaxis within the last decade in response to concerns about decreasing levels of measles antibodies in these products. This study used the plaque-reduction neutralization test (PRNT) to measure the titer of measles specific antibodies in Australian immunoglobulin products for post-exposure prophylaxis and compared the utility of an enzyme-linked immunosorbent assay (ELISA) to the PRNT in available Australian and international samples: Australian intramuscular (n = 10), Australian intravenous (n = 28), New Zealand intramuscular (n = 2), Hizentra (subcutaneous)(USA) (n = 3), and Privigen (intravenous)(USA) (n = 2). Measles titres in Australian IM and IV immunoglobulins ranged from 51 to 76 IU/mL and 6 to 24 IU/mL respectively, as measured by PRNT calibrated to the WHO 3rd international standard. ELISA titres were variable but higher than PRNT titres in all tested samples. Measles antibody titres in Australian immunoglobulin products meet consensus-prescribed international thresholds. Development of a convenient, standardized, readily accessible assay for determination of measles titres in immunoglobulin products would be useful for future studies and facilitate international comparisons. PMID- 27763810 TI - Economic evaluation of routine infant rotavirus immunisation program in Japan. AB - Two rotavirus vaccines are currently available in Japan. We estimated the incremental cost-effectiveness ratio (ICER) of routine infant rotavirus immunisation program without defining which vaccine to be evaluated, which reflects the current deliberation at the Health Science Council in charge of Immunisation and Vaccine established by the Ministry of Health, Labor and Welfare of Japan. Three ICERs were estimated, one from payers' perspective and 2 from societal perspective depending on the scenarios to uptake vaccines. The health statuses following the birth cohort were as follows: not infected by rotavirus, asymptomatic infection, outpatients after infection, hospitalised after infection, developing encephalitis/encephalopathy followed by recovery, sequelae, and death. Costs of per course of vaccination was Y30,000 (US$283; US$1 = Y106). The model runs for 60 months with one month cycle. From payers' perspective, estimated ICERs were Y6,877,000 (US$64,877) per QALY. From societal perspective, immunisation program turns out to be cost-saving for 75% simultaneous vaccination scenario, while it is at Y337,000 (US$3,179) per QALY gained with vaccine alone scenario. The probability of rotavirus immunisation program to be under Y5,000,000 (US$47,170) per QALY was at 19.8%, 40.7%, and 75.6% when costs per course of vaccination were set at Y30,000 (US$283), Y25,000 (US$236), and Y20,000 (US$189), respectively. Rotavirus immunisation program has a potential to be cost effective from payers' perspective and even cost-saving from societal perspective in Japan, however, caution should be taken with regard to the interpretation of the results as cost-effectiveness is critically dependent on vaccination costs. PMID- 27763811 TI - Small GTPase proteins in macroautophagy. AB - Macroautophagy, a highly conserved process in eukaryotic cells, is initiated in response to stress, especially nutrient starvation. Macroautophagy helps cells survive by engulfing proteins and organelles into an unusual double-membraned structure called the autophagosome, which then fuses with the lysosome. Upon degradation of the engulfed contents, the building blocks are recycled for synthesis of new macromolecules. Recent work has demonstrated that construction of the autophagosome requires a variety of small GTPases in variations of their normal roles in membrane traffic. In this Commentary, we review our own recent findings with respect to 2 different GTPases, Arl1, a member of the Arf/Arl/Sar family, and Ypt6, a member of the Rab family, in the yeast S. cerevisiae in light of other information from the literature and discuss future directions for further discerning the roles of small GTPases in autophagy. PMID- 27763812 TI - Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments. AB - PURPOSE: Since all prostanoid receptors affect intraocular pressure (IOP) and endogenous prostanoids are found in ocular tissues, the pressor effects of prostanoid antagonists were comprehensively evaluated. The absence of effects of most of these antagonists was not entirely anticipated. To ensure no false negative results, ocular biodisposition studies were conducted. METHODS: Monkeys with laser-induced ocular hypertension were used to study antagonist effects on IOP. Ocular biodisposition of each antagonist was assessed in rabbits, with LC/MS/MS analyses of tissue extracts and blood. RESULTS: EP1, EP2, EP3, EP4, FP, IP, and TP prostanoid receptor antagonists did not affect IOP, even at a high 1% dose. These studies were followed by ocular biodisposition studies. Striking differences in ocular tissue bioavailability were observed, which were independent of solubility. Only the EP1 antagonist SC-51322 failed to penetrate sufficiently to be bioavailable in the aqueous humor and ciliary body/iris. This obliged testing an alternative EP1 antagonist, namely ONO-8713, to reliably conclude that an EP1 antagonist does not alter IOP. CONCLUSIONS: These antagonist studies provided no evidence for individual endogenous prostanoids exerting a meaningful role in regulating IOP. They do reaffirm the critical importance of studying ocular bioavailability for confirming negative data. Large differences among the antagonists in anterior segment and even ocular surface tissue biodisposition were observed in rabbits. It appears from these monkey studies, supported by rabbit ocular bioavailability data, that an absence of drug effect in the eye cannot be adequately substantiated without determination of ocular pharmacokinetics. PMID- 27763813 TI - Trojan horse L-selectin monocytes: A portal of Burkholderia pseudomallei entry into the brain. PMID- 27763814 TI - The RNA-binding landscape of RBM10 and its role in alternative splicing regulation in models of mouse early development. AB - Mutations in the RNA-binding protein, RBM10, result in a human syndromic form of cleft palate, termed TARP syndrome. A role for RBM10 in alternative splicing regulation has been previously demonstrated in human cell lines. To uncover the cellular functions of RBM10 in a cell line that is relevant to the phenotype observed in TARP syndrome, we used iCLIP to identify its endogenous RNA targets in a mouse embryonic mandibular cell line. We observed that RBM10 binds to pre mRNAs with significant enrichment in intronic regions, in agreement with a role for this protein in pre-mRNA splicing. In addition to protein-coding transcripts, RBM10 also binds to a variety of cellular RNAs, including non-coding RNAs, such as spliceosomal small nuclear RNAs, U2 and U12. RNA-seq was used to investigate changes in gene expression and alternative splicing in RBM10 KO mouse mandibular cells and also in mouse ES cells. We uncovered a role for RBM10 in the regulation of alternative splicing of common transcripts in both cell lines but also identified cell-type specific events. Importantly, those pre-mRNAs that display changes in alternative splicing also contain RBM10 iCLIP tags, suggesting a direct role of RBM10 in these events. Finally, we show that depletion of RBM10 in mouse ES cells leads to proliferation defects and to gross alterations in their differentiation potential. These results demonstrate a role for RBM10 in the regulation of alternative splicing in two cell models of mouse early development and suggests that mutations in RBM10 could lead to splicing changes that affect normal palate development and cause human disease. PMID- 27763815 TI - Diverted recycling-Shigella subversion of Rabs. AB - Small GTPases of the Rab protein family control intracellular vesicular trafficking to allow their communication and maintenance. It is a common strategy for intracellular bacteria to exploit these pathways to shape their respective niches for survival. The subversion of Rabs for the generation of an intracellular environment favoring the pathogen has been described almost exclusively for intracellular bacteria that reside within bacterial containing vacuoles (BCVs). However, less is known about Rab subversion for bacteria that rupture the BCV to reach the host cytoplasm. Here, we provide recent examples of Rab targeting by both groups of intracellular bacteria with a special focus on Shigella, the causative agent of bacillary dysentery. Shigella recruits Rab11, the hallmark of the perinuclear recycling compartment to in situ formed macropinosomes at the entry foci via the bacterial effector IpgD. This leads to efficient BCV rupture and cytosolic escape. We discuss the concept of diverted recycling through host Rab GTPases that emerges as a novel pathogen strategy. PMID- 27763818 TI - Parents who refuse or delay HPV vaccine: Differences in vaccination behavior, beliefs, and clinical communication preferences. AB - BACKGROUND: We sought to estimate the national prevalence of HPV vaccine refusal and delay in a nationally-representative sample of parents of adolescents. We also compared parents who refused versus delayed HPV vaccine in terms of their vaccination beliefs and clinical communication preferences. METHODS: In 2014 to 2015, we conducted an online survey of 1,484 US parents who reported on an 11- to 17-year-old child in their household. We used weighted multinomial logistic regression to assess correlates of HPV vaccine refusal and delay. RESULTS: Overall, 28% of parents reported that they had ever "refused or decided not to get" HPV vaccine for their child, and an additional 8% of parents reported that they had "delayed or put off getting" HPV vaccine. Compared to no refusal/delay, refusal was associated with lower confidence in adolescent vaccination (relative risk ratio [RRR] = 0.66, 95% confidence interval [CI], 0.48-0.91), lower perceived HPV vaccine effectiveness (RRR = 0.68, 95% CI, 0.50-0.91), and higher perceived harms (RRR = 3.49, 95% CI, 2.65-4.60). In contrast, delay was associated with needing more information (RRR = 1.76, 95% CI, 1.08-2.85). Most parents rated physicians and information sheets as helpful for making decisions about HPV vaccination, although parents who reported refusal endorsed these resources less often. CONCLUSIONS: Our findings suggest that HPV vaccine refusal is common among parents of adolescents and may have increased relative to previous estimates. Because the vaccination beliefs and communication preferences of parents who refuse appear to differ from those who delay, targeted communication strategies may be needed to effectively address HPV vaccine hesitancy. PMID- 27763816 TI - Uptake and impact of natural diet-derived small RNA in invertebrates: Implications for ecology and agriculture. AB - The putative transfer and gene regulatory activities of diet-derived small RNAs (sRNAs) in ingesting animals are still debated. The existence of natural uptake of diet-derived sRNA by invertebrate species could have significant implication for our understanding of ecological relationships and could synergize with efforts to use RNA interference (RNAi) technology in agriculture. Here, we synthesize information gathered from studies in invertebrates using natural or artificial dietary delivery of sRNA and from studies of sRNA in vertebrate animals and plants to review our current understanding of uptake and impact of natural diet-derived sRNA on invertebrates. Our understanding has been influenced and sometimes confounded by the diversity of invertebrates and ingested plants studied, our limited insights into how gene expression may be modulated by dietary sRNAs at the mechanistic level, and the paucity of studies focusing directly on natural uptake of sRNA. As such, we suggest 2 strategies to investigate this phenomenon more comprehensively and thus facilitate the realization of its potentially broad impact on ecology and agriculture in the future. PMID- 27763819 TI - Metabolomic comparative analysis of the phloem sap of curry leaf tree (Bergera koenegii), orange jasmine (Murraya paniculata), and Valencia sweet orange (Citrus sinensis) supports their differential responses to Huanglongbing. AB - Orange jasmine, Murraya paniculata and curry leaf tree, Bergera koenegii are alternative hosts for Diaphorina citri, the vector of Candidatus Liberibacter asiaticus (CLas), the pathogen of huanglongbing (HLB) in citrus. D. citri feeds on the phloem sap where CLas grows. It has been shown that orange jasmine was a better host than curry leaf tree to D. citri. In addition, CLas can infect orange jasmine but not curry leaf tree. Here, we compared the phloem sap composition of these 2 plants to the main host, Valencia sweet orange, Citrus sinensis. Phloem sap was analyzed by gas chromatography-mass spectrometry after trimethylsilyl derivatization. Orange jasmine was the highest in proteinogenic, non proteinogenic amino acids, organic acids, as well as total metabolites. Valencia was the highest in mono- and disaccharides, and sugar alcohols. Curry leaf tree was the lowest in most of the metabolites as well as total metabolites. Interestingly, malic acid was high in Valencia and orange jasmine but was not detected in the curry leaf. On the other hand, tartaric acid which can prevent the formation of malic acid in Krebs cycle was high in curry leaf. The nutrient inadequacy of the phloem sap in curry leaf tree, especially the amino acids could be the reason behind the longer life cycle and the low survival of D. citri and the limitation of CLas growth on this host. Information obtained from this study may help in cultivation of CLas and development of artificial diet for rearing of D. citri. PMID- 27763817 TI - Transcription of highly repetitive tandemly organized DNA in amphibians and birds: A historical overview and modern concepts. AB - Tandemly organized highly repetitive DNA sequences are crucial structural and functional elements of eukaryotic genomes. Despite extensive evidence, satellite DNA remains an enigmatic part of the eukaryotic genome, with biological role and significance of tandem repeat transcripts remaining rather obscure. Data on tandem repeats transcription in amphibian and avian model organisms is fragmentary despite their genomes being thoroughly characterized. Review systematically covers historical and modern data on transcription of amphibian and avian satellite DNA in somatic cells and during meiosis when chromosomes acquire special lampbrush form. We highlight how transcription of tandemly repetitive DNA sequences is organized in interphase nucleus and on lampbrush chromosomes. We offer LTR-activation hypotheses of widespread satellite DNA transcription initiation during oogenesis. Recent explanations are provided for the significance of high-yield production of non-coding RNA derived from tandemly organized highly repetitive DNA. In many cases the data on the transcription of satellite DNA can be extrapolated from lampbrush chromosomes to interphase chromosomes. Lampbrush chromosomes with applied novel technical approaches such as superresolution imaging, chromosome microdissection followed by high throughput sequencing, dynamic observation in life-like conditions provide amazing opportunities for investigation mechanisms of the satellite DNA transcription. PMID- 27763820 TI - Is There Hope? Is She There? How Families and Clinicians Experience Severe Acute Brain Injury. AB - BACKGROUND: Patients with severe acute brain injury (SABI) raise important palliative care considerations associated with sudden devastating injury and uncertain prognosis. OBJECTIVE: The goal of this study was to explore how family members, nurses, and physicians experience the palliative and supportive care needs of patients with SABI receiving care in the neuroscience intensive care unit (neuro-ICU). DESIGN: Semistructured interviews were audiotaped, transcribed, and analyzed using thematic analysis. SETTING/SUBJECTS: Thirty-bed neuro-ICU in a regional comprehensive stroke and level-one trauma center in the United States. We completed 47 interviews regarding 15 patients with family members (n = 16), nurses (n = 15), and physicians (n = 16). RESULTS: Two themes were identified: (1) hope and (2) personhood. (1) Families linked prognostic uncertainty to a need for hope and expressed a desire for physicians to acknowledge this relationship. The language of hope varied depending on the participant: clinicians used hope as an object that can be given or taken away, generally in the process of conveying prognosis, while families expressed hope as an action that supported coping with their loved one's acute illness and its prognostic uncertainty. (2) Participants described the loss of personhood through brain injury, the need to recognize and treat the brain-injured patient as a person, and the importance of relatedness and connection, including personal support of families by clinicians. CONCLUSIONS: Support for hope and preservation of personhood challenge care in the neuro-ICU as identified by families and clinicians of patients with SABI. Specific practical approaches can address these challenges and improve the palliative care provided to patients and families in the neuro-ICU. PMID- 27763822 TI - Prevalence and Diversity of Cryptosporidium and Giardia Identified Among Feral Pigs in Texas. AB - The population size and geographic range of feral pigs in the United States are rapidly expanding. Nevertheless, the role of this invasive species in the ecology and transmission of zoonotic enteric pathogens is poorly understood. Our objectives were to describe the prevalence and diversity of Cryptosporidium and Giardia shedding among feral pigs throughout Texas and to identify risk factors for infection. Fecal samples were collected from feral pigs in Texas from February 2014 through May 2015. Cryptosporidium oocysts and Giardia cysts were detected using a direct immunofluorescence assay, and genotyping of positive samples was performed. The prevalence of Cryptosporidium shedding was 1.6% (6/370), and C. scrofarum and C. suis were identified. The prevalence of Giardia shedding was 4.3% (16/370), and assemblages A and E were identified. Cryptosporidium shedding was significantly more common among juvenile and subadult pigs than among adult pigs, but age group was not associated with Giardia shedding status. Feral pigs may serve as a source of Cryptosporidium and Giardia transmission to humans and livestock. PMID- 27763821 TI - Coxiella Detection in Ticks from Wildlife and Livestock in Malaysia. AB - Recent studies have shown that ticks harbor Coxiella-like bacteria, which are potentially tick-specific endosymbionts. We recently described the detection of Coxiella-like bacteria and possibly Coxiella burnetii in ticks found from rural areas in Malaysia. In the present study, we collected ticks, including Haemaphysalis bispinosa, Haemaphysalis hystricis, Dermacentor compactus, Dermacentor steini, and Amblyomma sp. from wildlife and domesticated goats from four different locations in Malaysia. Coxiella 16s rRNA genomic sequences were detected by PCR in 89% of ticks tested. Similarity analysis and phylogenetic analyses of the 16s rRNA and rpoB partial sequences were performed for 10 representative samples selected based on the tick species, sex, and location. The findings here suggested the presence of C. burnetii in two samples, each from D. steini and H. hystricis. The sequences of both samples clustered with published C. burnetii sequences. The remaining eight tick samples were shown to harbor 16s rRNA sequences of Coxiella-like bacteria, which clustered phylogenetically according to the respective tick host species. The findings presented here added to the growing evidence of the association between Coxiella-like bacteria and ticks across species and geographical boundaries. The importance of C. burnetii found in ticks in Malaysia warrants further investigation. PMID- 27763825 TI - In Vitro Dose Studies on Chitosan Nanoplexes for microRNA Delivery in Breast Cancer Cells. AB - Changes in microRNA (miRNA) expression levels that play important roles in regulation lead to many pathological events such as cancer. The miR-200 family is an important target in cancer therapy. The aim of this study is to equilibrate endogenous levels between cancer and noncancerous cells to prevent serious side effects of miR-200c- and miR-141-like metastatic colonization. For the first time, the characterization of miR-200c and miR-141 cluster containing chitosan nanoplexes was shown, and the optimization of miRNA expression levels by conducting dose studies in breast cancer cell lines was made. The mean diameter of chitosan/miR-141 and chitosan/miR-200c nanoplexes ranged from 296 to 355 nm and from 294 to 380 nm depending on the N/P ratio, respectively. The surface charge of nanoplexes was positive with zeta potential of +12 to +26 mV. While naked miRNA was degraded after 0 min in a 10% serum-containing medium, chitosan/miRNA nanoplexes were protected for 72 h. During the in vitro cellular uptake study, nanoplexes were observed to be accumulating in the cytoplasm or nucleus. After using different doses for miR-200c, the determined doses are 750, 100, and 750 ng in the MCF-7, MDA-MB-231, and MDA-MB-435 cell lines, respectively. Doses were determined as 100 ng for MDA-MB-231 and 150 ng for MDA MB-435 to reach endogenous miR-141 levels of MCF-10A. Our results suggest that chitosan nanoplexes for miR-200c and miR-141 are an efficient delivery system in terms of formulation and transfection. As a conclusion, dose studies are important to provide effective treatment with miRNAs. PMID- 27763824 TI - Blue light treatment of Pseudomonas aeruginosa: Strong bactericidal activity, synergism with antibiotics and inactivation of virulence factors. AB - Pseudomonas aeruginosa is among the most common pathogens responsible for both acute and chronic infections of high incidence and severity. Additionally, P. aeruginosa resistance to conventional antimicrobials has increased rapidly over the past decade. Therefore, it is crucial to explore new therapeutic options, particularly options that specifically target the pathogenic mechanisms of this microbe. The ability of a pathogenic bacterium to cause disease is dependent upon the production of agents termed 'virulence factors', and approaches to mitigate these agents have gained increasing attention as new antibacterial strategies. Although blue light irradiation is a promising alternative approach, only limited and preliminary studies have described its effect on virulence factors. The current study aimed to investigate the effects of lethal and sub-lethal doses of blue light treatment (BLT) on P. aeruginosa virulence factors. We analyzed the inhibitory effects of blue light irradiation on the production/activity of several virulence factors. Lethal BLT inhibited the activity of pyocyanin, staphylolysin, pseudolysin and other proteases, but sub-lethal BLT did not affect the production/expression of proteases, phospholipases, and flagella- or type IV pili-associated motility. Moreover, a eukaryotic cytotoxicity test confirmed the decreased toxicity of blue light-treated extracellular P. aeruginosa fractions. Finally, the increased antimicrobial susceptibility of P. aeruginosa treated with sequential doses of sub-lethal BLT was demonstrated with a checkerboard test. Thus, this work provides evidence-based proof of the susceptibility of drug resistant P. aeruginosa to BLT-mediated killing, accompanied by virulence factor reduction, and describes the synergy between antibiotics and sub-lethal BLT. PMID- 27763826 TI - Anti-HIV Activities of Intramolecular G4 and Non-G4 Oligonucleotides. AB - New natural and chemically modified DNA aptamers that inhibit HIV-1 activity at submicromolar concentrations (presumably via preventing viral entry into target cells) are reported. The new DNA aptamers were developed based on known intramolecular G-quadruplexes (G4s) that were functionally unrelated to HIV inhibition [the thrombin-binding aptamer and the fragment of the human oncogene promoter (Bcl2)]. The majority of previously described DNA inhibitors of HIV infection adopt intermolecular structures, and thus their folding variability represents an obvious disadvantage. Intramolecular architectures refold correctly after denaturation and are generally easier to handle. However, whether the G4 topology or other factors account for the anti-HIV activity of our aptamers is unknown. The impact of chemical modification (thiophosphoryl internucleotide linkages) on aptamer activity is discussed. The exact secondary structures of the active compounds and further elucidation of their mechanisms of action hopefully will be the subjects of future studies. PMID- 27763827 TI - Serosurvey for Selected Viral Pathogens among Sympatric Species of the African Large Predator Guild in Northern Botswana. AB - The recent increase in the creation of transboundary protected areas and wildlife corridors between them lends importance to information on pathogen prevalence and transmission among wildlife species that will become connected. One such initiative is the Kavango Zambezi Transfrontier Conservation Area of which Botswana's Okavango Delta constitutes a major contribution for wildlife and ecosystems. Between 2008 and 2011, we collected serum samples from 14 lions ( Panthera leo ), four leopards ( Panthera pardus ), 19 spotted hyenas ( Crocuta crocuta ), and six cheetahs ( Acinonyx jubatus ) in the Okavango. Samples were tested for antibodies against canine distemper virus (CDV), feline panleukopenia virus, enteric coronavirus, feline calicivirus, feline herpesvirus (FHV-1), and feline immunodeficiency virus (FIV). Evidence of exposure to all of these pathogens was found, to varying degrees, in at least one of the species sampled. High antibody prevalence (>90%) was only found to FHV-1 and FIV in lions. Only hyenas (26%, 5/19) were positive for CDV antibody. Except for one case, all individuals displayed physical conditions consistent with normal health for >=12 mo following sampling. Our results emphasize the need for a comprehensive, multispecies approach to disease monitoring and the development of coordinated management strategies for subpopulations likely to be connected in transboundary initiatives. PMID- 27763828 TI - Mortality of Western Burrowing Owls ( Athene cunicularia hypugaea) Associated with Brodifacoum Exposure. AB - Western Burrowing Owls ( Athene cunicularia hypugaea) frequently occupy periurban areas, where they may be exposed to pest control agents. This short communication describes necropsy findings and detected brodifacoum rodenticide levels for four Western Burrowing Owls in Lake Havasu City, Arizona, US, 2013-15. Levels detected ranged from 0.077 mg/kg to 0.497 mg/kg. Brodifacoum, one of several second generation anticoagulant rodenticides recently removed from the general consumer market, is still available for use by licensed pesticide applicators. Despite recent regulatory actions, second-generation anticoagulant pesticides continue to threaten predatory species in periurban areas. PMID- 27763829 TI - PREVALENCE AND DISTRIBUTION OF WELLFLEET BAY VIRUS EXPOSURE IN THE COMMON EIDER (SOMATERIA MOLLISSIMA). AB - Between 1998 and 2014, recurrent mortality events were reported in the Dresser's subspecies of the Common Eider ( Somateria mollissima dresseri) on Cape Cod, Massachusetts, US near Wellfleet Harbor. The early die-offs were attributed to parasitism and emaciation, but beginning in 2006 a suite of distinct lesions was observed concomitant with the isolation of a previously unknown RNA virus. This novel pathogen was identified as an orthomyxovirus in the genus Quaranjavirus and was named Wellfleet Bay virus (WFBV). To assess evidence of exposure to this virus in Common Eiders, we conducted a longitudinal study of the prevalence of WFBV antibodies at multiple locations from 2004-14; we collected 2,258 serum samples from six locations and analyzed each using a microneutralization assay. Results corroborate the emergence of WFBV in 2006 based on the first detection of antibodies in that year. Significantly higher prevalence was detected in Common Eiders sampled in Massachusetts compared to those in Maine, Nova Scotia, and Quebec. For birds breeding and wintering in Massachusetss, viral exposure varied by age, sex, and season of sampling, and prevalence by season and sex were highly interrelated with greater numbers of antibody-positive males in the autumn and females in the spring. No evidence of viral exposure was detected in the Northern subspecies ( Somateria mollissima borealis). Among the locations sampled, Massachusetts appears to be the epicenter of Common Eider exposure to WFBV. Further research is warranted to understand the factors controlling the epidemiology of WFBV in Massachussetts, including those that may be limiting geographic expansion of this virus. PMID- 27763830 TI - Health, Secondhand Smoke Exposure, and Smoking Behavior Impacts of No-Smoking Policies in Public Housing, Colorado, 2014-2015. AB - INTRODUCTION: Exposure to secondhand smoke is problematic for residents living in multiunit housing, as the smoke migrates through shared ventilation systems, unsealed cracks, and door spaces. The objective of our research was to assess resident exposure to secondhand smoke, support for no-smoking policies, and the health impacts of no-smoking policies in multiunit housing. METHODS: Surveys of 312 heads of households who resided in 1 of 3 multiunit buildings managed by a Colorado public housing authority were administered before and after implementation of a no-smoking policy that prohibited smoking in all resident apartments and all indoor common areas. A matched-pairs analysis of initial surveys and 15-month post-policy implementation surveys for 115 respondents was conducted. RESULTS: Decreases were found in the number and percentage of smokers who smoked every day and the number of cigarettes smoked per day, and 30% had quit smoking 15 months after policy implementation. The percentage of residents who smelled secondhand smoke indoors declined significantly. A significant decrease in breathing problems was found after policy implementation. Although decreases were found in the incidence of asthma attacks, emphysema/chronic obstructive pulmonary disease, eye irritation, colds, nasal congestion, and ear/sinus infections, these decreases were not significant. CONCLUSION: Consistent findings across nearly all variables tested suggest that no-smoking policies reduce resident exposure to secondhand smoke, lower the incidence of secondhand smoke-associated breathing problems, decrease daily smoking and cigarette consumption, encourage smoking cessation, and increase quit attempts. If implemented in all multiunit housing, these policies could reduce exposure to secondhand smoke and health problems associated with secondhand smoke, promote smoking cessation, and reduce cigarette consumption. PMID- 27763831 TI - Factors Affecting Implementation of the California Childhood Obesity Research Demonstration (CA-CORD) Project, 2013. AB - INTRODUCTION: Ecological approaches to health behavior change require effective engagement from and coordination of activities among diverse community stakeholders. We identified facilitators of and barriers to implementation experienced by project leaders and key stakeholders involved in the Imperial County, California, Childhood Obesity Research Demonstration project, a multilevel, multisector intervention to prevent and control childhood obesity. METHODS: A total of 74 semistructured interviews were conducted with project leaders (n = 6) and key stakeholders (n = 68) representing multiple levels of influence in the health care, early care and education, and school sectors. Interviews, informed by the Multilevel Implementation Framework, were conducted in 2013, approximately 12 months after year-one project implementation, and were transcribed, coded, and summarized. RESULTS: Respondents emphasized the importance of engaging parents and of ensuring support from senior leaders of participating organizations. In schools, obtaining teacher buy-in was described as particularly important, given lower perceived compatibility of the intervention with organizational priorities. From a program planning perspective, key facilitators of implementation in all 3 sectors included taking a participatory approach to the development of program materials, gradually introducing intervention activities, and minimizing staff burden. Barriers to implementation were staff turnover, limited local control over food provided by external vendors or school district policies, and limited availability of supportive resources within the broader community. CONCLUSION: Project leaders and stakeholders in all sectors reported similar facilitators of and barriers to implementation, suggesting the possibility for synergy in intervention planning efforts. PMID- 27763833 TI - Innovations in Policy and Practice: A work in progress. AB - No abstract available. PMID- 27763832 TI - Accelerometer-Derived Total Activity Counts, Bouted Minutes of Moderate to Vigorous Activity, and Insulin Resistance: NHANES 2003-2006. AB - INTRODUCTION: The objective of this study was to compare the associations of accelerometer-derived total activity counts per day and minutes of bouted moderate to vigorous physical activity (MVPA) with insulin resistance. METHODS: The sample included 2,394 adults (aged >=20 y) from the 2003-2006 National Health and Nutrition Examination Survey. Time spent in MVPA, measured by using 2 cutpoints (>=2,020 counts/min [MVPA2,020] and >=760 counts/min [MVPA760]), was calculated for bouts of at least 8 to 10 minutes. Total activity counts per day reflects the total amount of activity across all intensities. Insulin resistance was measured via the homeostatic model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). Two nested regression models regressed HOMA-IR and QUICKI, respectively, on minutes of bouted MVPA and total activity counts per day. We used an adjusted Wald F statistic to illustrate strength of association. RESULTS: After adjustment for covariates, total activity counts per day was more strongly associated with both HOMA-IR (adjusted Wald F = 36.83 , P < .001) and QUICKI (adjusted Wald F = 29.44, P < .001) compared with MVPA2,020 (HOMA-IR, adjusted Wald F = 4.00, P = .06; QUICKI, adjusted Wald F = 1.08, P = .31).Total activity counts per day was more strongly associated with both HOMA-IR (adjusted Wald F = 13.64, P < .001) and QUICKI (adjusted Wald F = 12.10, P < .001) compared with MVPA760 (HOMA-IR, adjusted Wald F = 1.13, P = .30; QUICKI, adjusted Wald F = 0.97, P = .33). CONCLUSION: Our study indicated that total activity counts per day has stronger associations with insulin resistance compared with minutes of bouted MVPA. The most likely explanation is that total activity counts per day captures data on light physical activity and intermittent MVPA, both of which influence insulin resistance. PMID- 27763834 TI - Profiling a one-health model for priority populations. AB - No abstract available. PMID- 27763835 TI - Process evaluation of the Prevent Overdose in Toronto (POINT) program. AB - SETTING: A harm reduction program at a public health unit in Toronto, Ontario, between August 31, 2011 and August 31, 2013. INTERVENTION: We conducted a process evaluation of the first two years of an opioid overdose prevention and response program, Prevent Overdose in Toronto (POINT), including analysis of data from program documentation forms, as well as qualitative interviews with program staff, representatives from partner agencies, and program clients. OUTCOMES: In the first two years of the program, 662 individuals (52.4% male; mean age 38.3 years) were trained in opioid overdose prevention and given a naloxone kit. Among clients currently using opioids, the most frequently reported opioids were oxycodone (40.4%) and heroin (34.4%). Clients reported 98 administrations of naloxone, primarily to friends and acquaintances. Nearly all naloxone recipients reportedly survived; one did not survive, and one had an unknown outcome.Staff and partner agencies feel the program reaches the target population and that POINT training meets clients' needs. Clients would like to see the training offered more widely. Overall, staff, partner agencies and clients were pleased with the POINT program, and they offered suggestions on program recruitment and delivery. IMPLICATIONS: Individuals at risk of opioid overdose have participated in overdose prevention and response training, and reported using naloxone in overdose events. Results of this initial program evaluation are being used to improve the delivery of the POINT program and can inform broader public health practice in opioid overdose prevention. PMID- 27763836 TI - Trends and demographic characteristics of physical fighting and fighting-related injuries among Canadian youth, 1993-2010. AB - OBJECTIVES: Physical fighting is a behaviour of concern that puts adolescents at increased risk for injury. The study objectives were to: 1) describe current patterns of physical fighting and fighting-related injury among Canadian adolescents, and 2) investigate potential trends in fighting and fighting-related injuries during the period 1993-2010. METHODS: Canadian data from cycles 2-6 (1993-2010) of the Health Behaviour in School-aged Children (HBSC) study were used, giving cross-sections for 61,465 grade 6-10 students. Prevalence estimates for physical fighting and fighting-related injury were calculated and described by sex, grade and subjective social status. A trend analysis was conducted across time cycles overall and within subgroups. RESULTS: A significant increase over time for physical fights was observed overall (ptrend = 0.015) and within female, grade 7-8, and high status subgroups, although further time points are necessary to determine this pattern with certainty. There was a significant trend increase over time for fighting-related injury overall and within all subgroups (ptrend < 0.001). Males were twice as likely as females to report a physical fight (p < 0.001) and fighting-related injury (p < 0.044). There was a significant decreased likelihood of physical fight involvement from lower to higher grades (p < 0.001), and an increased probability of fighting-related injury with increasing grades for three of five HBSC cycles. Subjective lower status was significantly associated with a higher likelihood of reporting a physical fight at all time points (p < 0.001) and fighting-related injury in three of five HBSC cycles. CONCLUSION: Specific subgroups are more likely to report physical fight participation and sustaining a fighting injury. Understanding the context and trends of these outcomes is informative for public health interventions. PMID- 27763837 TI - Homicide mortality rates in Canada, 2000-2009: Youth at increased risk. AB - OBJECTIVES: To estimate and compare Canadian homicide mortality rates (HMRs) and trends in HMRs across age groups, with a focus on trends for youth. METHODS: Data for the period of 2000 to 2009 were collected from Statistics Canada's CANSIM (Canadian Statistical Information Management) Table 102-0540 with the following ICD-10-CA coded external causes of death: X85 to Y09 (assault) and Y87.1 (sequelae of assault). Annual population counts from 2000 to 2009 were obtained from Statistics Canada's CANSIM Table 051-0001. Both death and population counts were organized into five-year age groups. A random effects negative binomial regression analysis was conducted to estimate age group-specific rates, rate ratios, and trends in homicide mortality. RESULTS: There were 9,878 homicide deaths in Canada during the study period. The increase in the overall homicide mortality rate (HMR) of 0.3% per year was not statistically significant (95% CI: 1.1% to +1.8%). Canadians aged 15-19 years and 20-24 years had the highest HMRs during the study period, and experienced statistically significant annual increases in their HMRs of 3% and 4% respectively (p < 0.05). A general, though not statistically significant, decrease in the HMR was observed for all age groups 50+ years. A fixed effects negative binomial regression model showed that the HMR for males was higher than for females over the study period [RRfemale/male = 0.473 (95% CI: 0.361, 0.621)], but no significant difference in sex-specific trends in the HMR was found. CONCLUSION: An increasing risk of homicide mortality was identified among Canadian youth, ages 15-24, over the 10 year study period. Research that seeks to understand the reasons for the increased homicide risk facing Canada's youth, and public policy responses to reduce this risk, are warranted. PMID- 27763838 TI - Supportive neighbourhood built characteristics and dog-walking in Canadian adults. AB - OBJECTIVES: Our study objectives were to: 1) estimate differences in perceptions of the neighbourhood built environment among non-dog-owners, owners who walk their dogs (dog-walkers) and owners who do not walk their dogs (non-dog-walkers), and 2) estimate associations between perceptions of the neighbourhood built environment and dog-walking frequency. METHOD: A random cross-section of Calgary adults completed telephone interviews during August-October 2007 (n = 2,199, response rate = 33.6%) or January-April 2008 (n = 2,223, response rate = 36.7%). Telephone interviews and a follow-up questionnaire captured physical activity, health and sociodemographic characteristics, dog-ownership, and perceived built environment characteristics. Using ANOVA, we compared the perceived built environment among non-dog-owners, non-dog-walkers and dog-walkers. For dog-owners only, logistic regression estimated associations (odds ratios: OR) between dog walking participation and perceived built environment. Among dog-walkers, logistic regression estimated associations between dog-walking >=4 times/week and perceived built environment. Furthermore, among dog-walkers, linear regression estimated associations (unstandardized beta) between dog-walking frequency and perceived built environment. RESULTS: Compared with dog-walkers, non-dog-owners reported more positive perceptions of neighbourhood street connectivity, pedestrian infrastructure, and walkability (p < 0.05). Among dog-walkers, aesthetics was positively associated (p < 0.05) with the likelihood of walking the dog >=4 times in a usual week (covariate-adjusted-OR = 1.67) and dog-walking frequency (covariate-adjusted-beta = 0.15). Among dog-walkers, walkability was also positively associated (p < 0.05) with dog-walking >=4 times in a usual week (covariate-adjusted-OR = 1.03) and dog-walking frequency (covariate-adjusted-beta = 0.05). CONCLUSION: Perceptions of the neighbourhood built environment appear to differ between non-dog-owners and dog-owners. While built environment improvements may not encourage owners to initiate dog-walking, creating attractive and walkable neighbourhoods may support regular dog-walking among owners already walking their dogs. PMID- 27763839 TI - Individual- and community-level determinants of Inuit youth mental wellness. AB - OBJECTIVES: Following the onset of intensive colonial intervention and rapid social change in the lives of Inuit people, youth in Nunavik have experienced high rates of mental health problems and suicide. Inuit people describe a broad range of contextual influences on mental wellness based on lived experience, but most epidemiological studies have focused on individual risk factors and pathologies. This study aimed to assess the influence of multiple determinants of mental wellness among Inuit youth in Nunavik, including culturally meaningful activities, housing and community social characteristics. METHODS: Mental wellness was measured in the form of two primary outcomes: self-esteem and suicidal ideation. Using cross-sectional data from the 2004 Nunavik Inuit Health Survey and multilevel regression modelling, we estimated associations between these two outcomes and various independent individual- and community-level explanatory factors among Inuit youth. All variables were selected to reflect Inuit perspectives on determinants of mental wellness. The study design and interpretation of results were validated with Inuit community representatives. RESULTS: Pride in Inuit identity, traditional activities, community-level social support and community-level socio-economic status were found to be protective. Barriers to participating in traditional activities, household crowding and high community rates of violence were risk factors. CONCLUSION: These findings support Inuit perspectives, expand the scope of epidemiological analysis of Inuit mental wellness and reinforce the need for locally informed, community-wide approaches to mental wellness promotion for Inuit youth. PMID- 27763840 TI - Risk and protective factors for heat-related events among older adults of Southern Quebec (Canada): The NuAge study. AB - OBJECTIVES: Extreme heat is known to increase heat-related health outcomes (HRHO). Incidence and predictors of HRHO were examined among older adults living in Quebec (Canada). METHOD: This prospective five-year study used data from the first follow-up of community-dwelling older adults from the NuAge cohort (2005 2006), located in three health regions of Southern Quebec. Medical, social and environmental factors, identified in Health Canada guidelines (2011), were used to develop the Older Adult Health Vulnerability Index (OAHVI). HRHO, obtained from a medico-administrative database, were defined as events occurring on a hot day (maximal temperature >=30 degrees C) between 2006 and 2010. Two outcomes were examined: heat-related 1) emergency department presentations (EDPs) and 2) health events (i.e., EDP, hospitalizations or deaths). Multivariate logistic regressions were performed to assess the associations between risk and protective factors, including OAHVI, and both outcomes. RESULTS: EDP and hospitalizations were, respectively, 2.6 (95% CI: 2.0-3.5) and 1.7 (95% CI: 1.1-2.6) times more frequent on hot days compared to normal summer days. Low household income and disability increased risk of heat-related EDP (AOR = 3.20; 95% CI: 1.16-8.81 and AOR = 2.66; 95% CI: 1.15-6.14 respectively) and health events (AOR = 2.84; 95% CI: 1.06-7.64 and AOR = 2.51; 95% CI: 1.13-5.61 respectively). High social participation was a protective factor of heat-related EDP (AOR = 0.05; 95% CI: 0.01-0.20) and health events (AOR = 0.04; 95% CI: 0.01-0.18). Older adults presenting >=6 OAHVI factors out of 9 were 7-8 times more at risk of heat-related EDP (OR = 7.40; 95% CI: 1.51 36.19) and health events (OR = 7.77; 95% CI: 1.63-37.20) compared to participants having 0-1 factor. CONCLUSION: Social participation, reduced autonomy and low income were predictors of HRHO. The OAHVI, also a strong predictor, should help clinicians identify high-risk elderly patients. PMID- 27763841 TI - Unmet health care needs among sex workers in five census metropolitan areas of Canada. AB - OBJECTIVES: This paper examines unmet health care needs in one of Canada's most hard-to-reach populations, adult sex workers, and investigates whether their reasons for not accessing health care are different from those of other Canadians. METHODS: Data gathered in 2012-2013 from sex workers aged 19 and over (n = 209) in five Canadian census metropolitan areas (CMAs) were analyzed to estimate the perceived health, health care access and level of unmet health care needs of sex workers, and their principal reasons for not accessing health care. These data were collected using questions identical to those of the Canadian Community Health Survey (CCHS) Cycle 2.1, 2003. The results were compared with those of residents aged 19 and over in the same CMAs who had participated in the CCHS. RESULTS: Sex workers reported notably worse perceived mental health, poorer social determinants of health (with the exception of income) and nearly triple the prevalence of unmet health care needs (40.4% vs. 14.9%). Those with the greatest unmet health care needs in both groups were younger, unmarried or single and in poorer health, and reported lower income and a weaker sense of community belonging. Even without these within-group risk factors, sex workers were more likely to report unmet health care needs compared with CCHS respondents. Sex workers were also more likely to identify "didn't get around to it", "too busy", "cost", "transportation problems" and "dislike doctors/afraid" as reasons for eschewing care. CONCLUSION: Equity policies that reduce cost and transportation barriers may go some way in helping sex workers access needed health care. Qualitative research is needed to better understand the realities of sex workers' personal and work lives, including the degree of freedom they have in accessing health care when they need it, but also their experiences when they do manage to engage with the health care system. PMID- 27763842 TI - Correlates and preferences of resistance training among older adults in Alberta, Canada. AB - OBJECTIVE: The prevalence of resistance training among older adults in Alberta, Canada, has never been measured. Hence, there is no clear understanding of the demographic and health-related factors associated with resistance training, or older adults' resistance training programming preferences. The purpose of this study was to gain a better understanding of resistance training behaviours among older adults in Alberta. METHODS: Older adults (>55 years) from across Alberta were invited to participate in this study. Participants completed self-reported measures of resistance training behaviours, demographics, health-related information, and resistance training program interest and preferences. RESULTS: A total of 358 (of 393) participants returned a completed survey, for a response rate of 91.1%. Overall, 53.1% met Canadian resistance training guidelines. On average, participants engaged in resistance training on 1.8 (SD = 1.9) days per week for an average of 1.6 hours (SD = 1.3). Preferences included resistance training in a fitness club (45.7%) and morning training times (51.7%). Indicating an ability to participate in a resistance training program for older adults was associated with being age 65 years or older (OR = 2.4; 95% CI, 0.69 to 8.0, p = 0.017) and being male (OR = 2.2; 95% CI, 0.73 to 6.69, p = 0.016). Those meeting resistance training guidelines were significantly less likely to have a chronic disease (OR = 0.60; 95% CI, 0.39 to 0.95, p = 0.03). CONCLUSION: Older adults had unique preferences for receiving resistance training counseling and programming. These preferences were associated with specific demographic and health-related variables. PMID- 27763843 TI - Black-White health inequalities in Canada at the intersection of gender and immigration. AB - OBJECTIVES: Intersectionality theory proposes that each combination of social categories derived from gender, race and nationality, such as immigrant White man or native-born Black woman, is associated with unique social experiences. We tested the potential of intersectionality theory for explicating racial inequalities in Canada by investigating whether Black-White health inequalities are conditioned by gender and immigrant status in a synergistic way. METHODS: Our dataset comprised 10 cycles (2001-2013) of the Canadian Community Health Survey. We used binary logistic regression to model Black- White inequalities in hypertension, diabetes, self-rated health, self-rated mental health and asthma separately for native-born women, native-born men, immigrant women and immigrant men. RESULTS: After controlling for potentially confounding factors we found that immigrant Black women had significantly higher odds of hypertension, diabetes and fair/poor self-rated health than immigrant White women. Native-born Black women and immigrant Black men had higher odds of hypertension and diabetes than native born White women and immigrant White men respectively, and native-born White women were more likely than native-born Black women to report asthma. There were no statistically significant health differences between native-born Black and White men. Socio-economic status, smoking, physical activity and body mass index were implicated in some but not all of these racial health inequalities. None of the three-way interactions between racial identity, gender and immigration status was statistically significant. CONCLUSION: We found relatively high risks of ill health for Black Canadians in three of the four samples. Overall, however, we found little support for the intersectional hypothesis that Black-White health inequalities in Canada are conditioned by gender and immigrant status in a synergistic way. PMID- 27763844 TI - Examination of a prenatal syphilis screening program, Alberta, Canada: 2010-2011. AB - OBJECTIVES: In 2009, due to increasing congenital syphilis rates, prenatal syphilis tests (PST) at both mid-gestation and delivery were added to first trimester prenatal screening in the province of Alberta. We sought to determine the proportion of mothers who had all three recommended PSTs during this period and to identify factors associated with incomplete PST. METHODS: A cohort of all pregnancies resulting in a live or stillborn infant in Alberta for 2010 and 2011 was developed from Vital Statistics and linked with prenatal screening data to determine the number and timing of PSTs for pregnant women. The proportion of women who had PSTs at the three recommended time points in pregnancy and associated correlates were identified using basic statistics and logistic regressions. RESULTS: Of 99,609 pregnancies, 20.7% had all three PSTs at the recommended time points. Overall, 98.5% (98,162) had at least one PST, 1.5% only had PST at delivery and 1.5% had no PST performed. Independent risk factors for not having the three recommended PSTs included First Nations status (adjusted odds ratio [AOR]: 1.78 [95% CI: 1.62-1.96]), rural remote residence (AOR 3.61 [95% CI: 3.10-4.20]) and sole use of a midwife for prenatal care (AOR 13.70 [95% CI: 9.20-20.39]). CONCLUSIONS: Nearly all pregnant women in Alberta received a PST at least once during their pregnancy, however far fewer received PSTs at the recommended time points. Interventions that target those who are less likely to be prenatally screened may help to ensure that pregnant women get early and appropriate care for syphilis during pregnancy. PMID- 27763845 TI - Prevalence of HIV infection and acceptability of point-of-care testing in a Canadian inner-city emergency department. AB - OBJECTIVES: The objective of this study was to estimate the seroprevalence of HIV infection and the acceptability of point-of-care HIV testing in an innercity Canadian emergency department. METHODS: We conducted a prospective cohort study in an urban tertiary care emergency department between August 2009 and January 2011. Randomly selected patients were enrolled using probabilistic sampling based on patient volumes. Inclusion criteria were age 19-75 years and ability to provide informed consent. Patients who were intoxicated or in extremis were excluded. After informed consent and brief pre-test counselling, participants' HIV status was obtained using the INSTI HIV-1/HIV-2 Antibody Test. Participants completed a questionnaire on HIV risk behaviours and satisfaction with emergency department HIV testing. Participants with a positive result or those having other blood tests received confirmatory Western blot testing. HIV-positive participants were offered immediate referral to an HIV specialty clinic. RESULTS: A total of 2,077 patients were approached, and 1,402 (67.5%) agreed to participate. Participants' mean age was 43.3 years, and 58.4% of participants were male. The HIV antibody seroprevalence based on the point-of-care test was 65/1,402 (4.6%; 95% confidence interval: 3.5%-5.8%). No new diagnoses of HIV were identified in our cohort. Patient satisfaction with point-of-care HIV testing was high (mean satisfaction score 9.6/10). CONCLUSION: On the basis of a rapid, point-of-care HIV antibody test, the seroprevalence rate of HIV in an inner city emergency department was 4.6%. Point-of-care testing in the emergency department is acceptable, and patients' satisfaction with the testing procedure was high. PMID- 27763846 TI - The efficacy of calorie labelling formats on pre-packaged foods: An experimental study among adolescents and young adults in Canada. AB - OBJECTIVES: Several countries have proposed changes to calorie labelling on nutrition facts tables (NFTs) on pre-packaged foods. As most research to date has examined general use of NFTs, there is a lack of evidence to guide specific design changes to calorie information on labels. This study examined the efficacy of various calorie labelling formats on recall, comprehension, and consumer preferences for calorie information. METHODS: Experiments were conducted as part of an online survey with a national sample of 2,008 Canadians aged 16-24. In Task 1, participants were shown one of six labelling formats (e.g., %DV, Traffic Light) with calories in either small or large font, and asked to recall the amount of calories. Task 2 examined comprehension of calories in the context of recommended daily intake (RDI), using the same NFT as in Task 1. Task 3 identified participants' preferences for labelling formats. RESULTS: NFTs with calories in large font enhanced calorie recall (p < 0.001). When small font was displayed, the Traffic Light format performed best at improving recall (p < 0.01). With large font, the highest recall was in the Current, RDI and Traffic Light formats (all p < 0.05). Comprehension of servings per RDI was highest in the Infographic format, with no difference by font size (p < 0.001). Respondents preferred the large font calorie condition and the Infographic format (p < 0.001). CONCLUSIONS: Enhancements in visibility and design can improve the efficacy of calorie labelling on pre-packaged foods. The findings have direct implication for proposed changes to calorie labelling on NFTs in Canada and the United States. PMID- 27763847 TI - Impact of a mass media mental health campaign on psychiatric emergency department visits. AB - OBJECTIVE: Despite the high prevalence of mental illnesses and addictions, treatment rates remain low. In April 2010, a regional mass media campaign was implemented to increase awareness of mental health services in central Toronto, Canada. We studied the impact of this campaign on rates of psychiatric emergency department (PED) visits among all hospital emergency departments (EDs) located in Toronto. DESIGN: Monthly PED visit totals were obtained for all Toronto EDs from April 1, 2007 to March 31, 2012 (n = 148,704). The campaign's impact on visit rates was measured using interrupted time series analysis and a difference-in difference estimator. We conducted pre- and post-campaign analyses to examine whether volume increases were explained by specific diagnostic categories and/or new presentations (new patients with no prior PED visits), and to examine geographic trends. RESULTS: The campaign was associated with an increased volume of PED visits at downtown hospitals (Centre for Addiction and Mental Health, an increase of 7.6 visits/month [p < 0.0001]; University Health Network, 5.8 visits/month [p < 0.0001]; St. Michael's Hospital, 4.2 visits/month [p < 0.0001]; and Mount Sinai Hospital, 3.2 visits/month [p < 0.0001]) but not in hospitals located outside of the downtown area. Neither new patient visits nor specific diagnostic categories disproportionately accounted for the overall observed increases. Following the campaign, patients travelled greater distances to receive ED services. CONCLUSIONS: Mass media campaigns promoting mental health and psychiatric services can affect health care-seeking behaviour and utilization. Our findings have implications for system-level service planning, which should anticipate volume increases when public mental health campaigns are being considered. PMID- 27763848 TI - Healthy Start - Depart Sante: A pilot study of a multilevel intervention to increase physical activity, fundamental movement skills and healthy eating in rural childcare centres. AB - OBJECTIVES: In order to improve healthy behaviours among rural children in their early years, a physical activity and healthy eating intervention (Healthy Start - Depart Sante) was implemented in rural childcare centres throughout Saskatchewan. The objective of the current study was to evaluate the impact of a multimodal physical activity and healthy eating intervention on educators' provision of opportunities for children to improve their physical activity levels, fundamental movement skills and healthy eating behaviours. SETTINGS: Six childcare centres (three Francophone and three Anglophone) located in five different rural and semi rural communities in Saskatchewan participated in this intervention. PARTICIPANTS: A total of 69 children with a mean age of 4 years 9 months, and 19 female early childhood educators. INTERVENTION: Guided by an ecological framework, we implemented a population health controlled intervention, using a wait list control design (48 weeks delayed intervention), and evaluated its impact in rural childcare centres. Mixed methods were employed to determine the effectiveness of the intervention. OUTCOMES: Overall, educators felt that the intervention supported the provision of physical activity and healthy eating opportunities for children. Increases in children's physical activity levels were reported following the intervention. CONCLUSION: The lessons learned in this study can be used to improve the Healthy Start - Depart Sante intervention so that its implementation can be effectively expanded to childcare centres within and outside Saskatchewan, in turn, supporting the healthy development of early years (0-5) children in the province and beyond. PMID- 27763849 TI - Implementation of a radon measurement protocol and its communication plan by child care centre managers in Quebec. AB - OBJECTIVES: To invite and support managers of child care centres to measure radon concentrations in their buildings. Their ability to carry out a measurement protocol and communication plan was also evaluated as well as the intention of parents and educators to test for radon at home. PARTICIPANTS: Managers, parents and educators of child care centres. SETTING: 36 child care centres located in two priority investigation areas in Quebec. INTERVENTION: A kit containing radon detectors with installation and recovery instructions was shipped by mail in addition to factsheets intended for parents and educators. Site visits and phone calls were also conducted with a sample of child care centres and participants. OUTCOMES: The instructions related to detector installation were generally well respected. Afterward, more than half (18) of the 34 parents and educators interviewed said that they had been directly informed of this radon testing by managers or other educators, and not by the factsheet provided. This radon measurement intervention was considered very relevant by 91% of them and a quarter (26%) expressed their intention to test for radon at home, while 6% had already done so. Two child care centres (5.5%) had at least one measurement above the Canadian guideline level of 200 Bq/m3. CONCLUSION: This intervention has demonstrated the ability of child care centre managers to carry out this type of autonomous procedure, which can be centralized to minimize costs. This type of intervention may influence parents to become more familiar with this contaminant and measure their family's exposure at home. PMID- 27763850 TI - Public health systems under attack in Canada: Evidence on public health system performance challenges arbitrary reform. AB - Public health is currently being weakened in several Canadian jurisdictions. Unprecedented and arbitrary cuts to the public health budget in Quebec in 2015 were a striking example of this. In order to support public health leaders and citizens in their capacity to advocate for evidence-informed public health reforms, we propose a knowledge synthesis of elements of public health systems that are significantly associated with improved performance. Research consistently and significantly associates four elements of public health systems with improved productivity: 1) increased financial resources, 2) increased staffing per capita, 3) population size between 50,000 and 500,000, and 4) specific evidence-based organizational and administrative features. Furthermore, increased financial resources and increased staffing per capita are significantly associated with improved population health outcomes. We contend that any effort at optimization of public health systems should at least be guided by these four evidence-informed factors. Canada already has existing capacity in carrying out public health systems and services research. Further advancement of our academic and professional expertise on public health systems will allow Canadian public health jurisdictions to be inspired by the best public health models and become stronger advocates for public health's resources, interventions and outcomes when they need to be celebrated or defended. PMID- 27763851 TI - Towards a shared understanding: Perspectives from Toronto's first media forum for suicide prevention. AB - Media reporting on suicide may have harmful and/or protective effects on deaths by suicide, depending on the nature of the coverage. Canada's first forum on this important issue was held in Toronto on November 6, 2015. Participating in the forum were public health policy-makers, mental health and suicide prevention experts and senior media representatives. This commentary summarizes the content of the forum and highlights the need for ongoing collaboration between suicide prevention experts and media professionals aimed at safe and respectful reporting that maintains the public's need to be informed. PMID- 27763852 TI - Delayed parenthood on the rise: A call for upstream preconception health promotion in Canada. AB - The trend toward delayed parenthood is on the rise across Canada. Societal emphasis on attaining higher education, career advancement and financial security may be some reasons why individuals delay becoming a parent; whatever the reason, this trend is linked to significant health and economic impacts. Many Canadians are unaware of the impact this may have on their fertility and potential birth outcomes. It is important that health care professionals apprise individuals in their reproductive years about these issues and the steps they can take to mitigate these risks. Implementing a health equity and broader determinants of health approach through social policy development may also prove beneficial. Such upstream approaches could enhance maternal and child health outcomes, and also help ensure that people of reproductive age are making an informed decision about delaying parenthood. This article calls for developing a comprehensive preconception health promotion and care strategy encompassing individual, community and population level approaches. PMID- 27763853 TI - Population attributable risk of smoking during pregnancy on obesity in offspring. AB - No abstract available. PMID- 27763854 TI - Vaporizing cannabis through e-cigarettes: Prevalence and socio-demographic correlates among Ontario high school students. AB - No abstract available. PMID- 27763855 TI - Hypersensitivity Reactions to Implanted Metal Devices: Facts and Fictions. AB - The use of metals in the medical field has become increasingly prevalent over the past few decades. Patients find themselves being exposed to metals in a variety of ways, ranging from external exposure to instruments such as the stainless steel in surgical blades to internal exposure via medical devices being implanted in their bodies. There has been growing interest in the possibility of developing hypersensitivity reactions to constituent metals in medical implant devices, both in cutaneous and systemic forms. Hypersensitivity reactions to metals are uncommon, but they are reported and require appropriate evaluation and management, particularly if they are symptomatic. In view of the lack of consensus in the field on the appropriate steps to evaluate and manage patients with suspected metal hypersensitivity reactions, this review aims to analyze current evidence on hypersensitivity reactions to metallic implants in orthopedic surgery, endovascular surgery, obstetrics and gynecology, and dental surgery. PMID- 27763856 TI - Relevance of Allergenic Sensitization to Cynodon dactylon and Phragmites communis: Cross-reactivity With Pooideae Grasses. AB - BACKGROUND AND OBJECTIVES: The homologous group of sweet grasses belongs to the Pooideae subfamily, but grass pollen species from other subfamilies can also cause allergy, such as Cynodon dactylon (Chloridoideae) and Phragmites communis (Arundinoideae). C dactylon and P communis have not been included in the sweet grasses homologous group because of their low cross-reactivity with other grasses. The aims of this study were to investigate the profile of sensitization to C dactylon and P communis in patients sensitized to grasses and to analyze cross-reactivity between these 2 species and temperate grasses. METHODS: Patients were skin prick tested with a grass mixture (GM). Specific IgE to GM, C dactylon, P communis, Cyn d 1, and Phl p 1 was measured by ImmunoCAP. A pool of sera was used for the immunoblot assays. Cross-reactivity was studied by ELISA and immunoblot inhibition. RESULTS: Thirty patients had sIgE to GM. Twenty-four (80%) had positive results for C dactylon, 27 (90%) for P communis, 22 (73.3%) for nCyn d 1, and 92.9% for rPhl p 1. Bands were detected in the 3 extracts by immunoblot. Inhibition of GM was not observed with C dactylon or P communis by immunoblot or ELISA inhibition. When C dactylon or P communis were used in the solid phase, GM produced almost complete inhibition. CONCLUSIONS: Eighty percent of patients sensitized to grasses were also sensitized to C dactylon and 90% were sensitized to P communis. Sensitization to these species seems to be induced by allergens different to those in sweet grasses. PMID- 27763857 TI - Detection of Low-Molecular-Weight Mast Cell-Activating Factors in Serum From Patients With Chronic Spontaneous Urticaria. AB - BACKGROUND AND OBJECTIVES: Functionally active autoantibodies to IgE and to the high-affinity IgE receptor (FcepsilonRI) can be detected in serum in about 40% of patients with chronic spontaneous urticaria (CSU). Recent studies showed that serum from patients with CSU can induce activation of mast cells, irrespective of whether they carry high-affinity IgE receptors. To evaluate mast cell activation induced by factors in the serum of CSU patients with a molecular weight lower than that of autoantibodies. METHODS: Eight CSU patients and 5 healthy controls were evaluated. Whole serum and serum fractionated at 100, 50, and 30 kDa were used to stimulate in vitro LAD2 mast cells. The enzymatic activity of beta hexosaminidase was evaluated in supernatants and cell pellets as a measure of mast cell degranulation. RESULTS: Mean (SEM) release of mast cell beta hexosaminidase induced by whole serum from CSU patients was higher than that induced by serum from the healthy controls (14.4 [2.7%] vs 5.1 [2.4%]; P=.027). In addition, serum fractions below 100 kDa and below 50 kDa from CSU patients induced mast cell degranulation that was significantly higher than that induced by the corresponding fractions in sera from healthy controls (10.2% [1.4%] vs 3.8% [1.9%] [P=.024] and 10.1% [1.2%] vs 3.9% [1.7%] [P=.012], respectively). In 4 CSU patients, we evaluated serum fractions <30 kDa, which retained their capacity to activate mast cells (11.0% [0.7%]). CONCLUSIONS: This study shows that sera from CSU patients may contain low-molecular-weight mast cell-activating factors other than autoantibodies. These factors could be an additional mechanism contributing to the pathogenesis of CSU. PMID- 27763858 TI - Successful Desensitization to Irinotecan After Severe Hypersensitivity Reaction. PMID- 27763859 TI - Hypersensitivity to Quail Egg Proteins: What About Hen Egg? PMID- 27763860 TI - Is Vitamin D Deficiency a Marker of Severity of Wheezing in Children? A Cross sectional Study. PMID- 27763861 TI - Psychometric Validation of the Spanish Version of the DHRQoL Questionnaire. PMID- 27763862 TI - A Protocol for Induction of Tolerance to Apomorphine in Patients With Parkinson Disease and Hypersensitivity to Apomorphine. PMID- 27763863 TI - Aquagenic Urticaria: Report of a Case in an Adolescent Girl. PMID- 27763864 TI - Yogurt in the Treatment of beta-Lactoglobulin-Induced Gastrointestinal Cow's Milk Allergy. PMID- 27763865 TI - Cross-reactivity in AED-Induced Severe Cutaneous Adverse Reaction: A Case Report. PMID- 27763866 TI - Vitiligo Induced by Specific Immunotherapy With Grass Pollen: The Koebner Phenomenon. PMID- 27763867 TI - Resolution of Common Variable Immunodeficiency After HIV Infection. PMID- 27763868 TI - Kounis Syndrome After Levofloxacin Intake: A Clinical Report and Cross-reactivity Study. PMID- 27763869 TI - Therapeutic Potential of Zoledronate-Activated Autologous gammadeltaT Cells in Atopic Dermatitis. PMID- 27763870 TI - Evaluation of Tolerance in Patients With Type-1 Hypersensitivity Reaction to Wheat After Oral Immunotherapy. PMID- 27763871 TI - Induction of Tolerance by Oral Immunotherapy in Patients With Cow's Milk Allergy. PMID- 27763872 TI - Regional gas transport in the heterogeneous lung during oscillatory ventilation. AB - Regional ventilation in the injured lung is heterogeneous and frequency dependent, making it difficult to predict how an oscillatory flow waveform at a specified frequency will be distributed throughout the periphery. To predict the impact of mechanical heterogeneity on regional ventilation distribution and gas transport, we developed a computational model of distributed gas flow and CO2 elimination during oscillatory ventilation from 0.1 to 30 Hz. The model consists of a three-dimensional airway network of a canine lung, with heterogeneous parenchymal tissues to mimic effects of gravity and injury. Model CO2 elimination during single frequency oscillation was validated against previously published experimental data (Venegas JG, Hales CA, Strieder DJ, J Appl Physiol 60: 1025 1030, 1986). Simulations of gas transport demonstrated a critical transition in flow distribution at the resonant frequency, where the reactive components of mechanical impedance due to airway inertia and parenchymal elastance were equal. For frequencies above resonance, the distribution of ventilation became spatially clustered and frequency dependent. These results highlight the importance of oscillatory frequency in managing the regional distribution of ventilation and gas exchange in the heterogeneous lung. PMID- 27763873 TI - Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans. AB - The effects of whole body heat stress on sympathetic and cardiovascular responses to stimulation of muscle metaboreceptors and mechanoreceptors remains unclear. We examined the muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate in 14 young healthy subjects during fatiguing isometric handgrip exercise, postexercise circulatory occlusion (PECO), and passive muscle stretch during PECO. The protocol was performed under normothermic and whole body heat stress (increase internal temperature ~0.6 degrees C via a heating suit) conditions. Heat stress increased the resting MSNA and heart rate. Heat stress did not alter the mean blood pressure (MAP), heart rate, and MSNA responses (i.e., changes) to fatiguing exercise. During PECO, whole body heat stress accentuated the heart rate response [change (Delta) of 5.8 +/- 1.5 to Delta10.0 +/- 2.1 beats/min, P = 0.03], did not alter the MSNA response (Delta16.4 +/- 2.8 to Delta17.3 +/- 3.8 bursts/min, P = 0.74), and lowered the MAP response (Delta20 +/- 2 to Delta12 +/- 1 mmHg, P < 0.001). Under normothermic conditions, passive stretch during PECO evoked significant increases in MAP and MSNA (both P < 0.001). Of note, heat stress prevented the MAP and MSNA responses to stretch during PECO (both P > 0.05). These data suggest that whole body heat stress attenuates the pressor response due to metaboreceptor stimulation, and the sympathetic nerve response due to mechanoreceptor stimulation. PMID- 27763874 TI - Effects of body position on exercise capacity and pulmonary vascular pressure flow relationships. AB - There has been revival of interest in exercise testing of the pulmonary circulation for the diagnosis of pulmonary vascular disease, but there still is uncertainty about body position and the most relevant measurements. Doppler echocardiography pulmonary hemodynamic measurements were performed at progressively increased workloads in 26 healthy adult volunteers in supine, semirecumbent, and upright positions that were randomly assigned at 24-h intervals. Mean pulmonary artery pressure (mPAP) was estimated from the maximum tricuspid regurgitation jet velocity. Cardiac output was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility alpha-index, the percent change of vessel diameter per millimeter mercury of mPAP, was calculated from multipoint mPAP-cardiac output plots. Body position did not affect maximum oxygen uptake (Vo2max), maximum respiratory exchange ratio, ventilatory equivalent for carbon dioxide, or slope of mPAP-cardiac output relationships, which was on average of 1.5 +/- 0.4 mmHg.l-1.min-1 Maximum mPAP, cardiac output, and total pulmonary vascular resistance were, respectively, 34 +/ 4 mmHg, 18 +/- 3 l/min, and 1.9 +/- 0.3 Wood units. However, the semirecumbent position was associated with a 10% decrease in maximum workload. Furthermore, cardiac output-workload or cardiac output-Vo2 relationships were nonlinear and variable. These results suggest that body position does not affect maximum exercise testing of the pulmonary circulation when results are expressed as mPAP cardiac output or maximum total pulmonary vascular resistance. Maximum workload is decreased in semirecumbent compared with upright exercise. Workload or Vo2 cannot reliably be used as surrogates for cardiac output. PMID- 27763875 TI - Modulation of respiratory output by cervical epidural stimulation in the anesthetized mouse. AB - Respiration is produced and controlled by well-characterized brain stem nuclei, but the contributions of spinal circuits to respiratory control and modulation remain under investigation. Many respiratory studies are conducted in in vitro preparations (e.g., brain stem slice) obtained from neonatal rodents. While informative, these studies do not fully recapitulate the complex afferent and efferent neural circuits that are likely to be involved in eupnea (i.e., quiet breathing). To begin to investigate spinal contributions to respiration, we electrically stimulated the cervical spinal cord during unassisted respiration in anesthetized, intact mice. Specifically, we used epidermal electrical stimulation at 20 Hz and varied current intensity to map changes in respiration. Stimulating at 1.5 mA at cervical level 3 (C3) consistently caused a significant increase in respiratory frequency compared with prestimulation baseline and when compared with sham stimulations. The increase in respiratory frequency persisted for several minutes after epidural stimulation ceased. There was no change in tidal volume, and the estimated minute ventilation was increased as a consequence of the increase in respiratory frequency. Sigh frequency also increased during epidural stimulation at C3. Neither the increase in respiratory frequency nor the increase in sighing were observed after stimulation at other dorsal cervical levels. These findings suggest that the spinal circuits involved in the modulation of eupnea and sighing may be preferentially activated by specific endogenous inputs. Moreover, the cervical spinal cord may play a role in respiratory modulation that affects both eupneic respiration and sigh production in intact, adult mice. PMID- 27763876 TI - The effect of body mass and sex on the accuracy of respiratory magnetometers for measurement of end-expiratory lung volumes. AB - Respiratory magnetometers are increasingly being used in sleep studies to measure changes in end-expiratory lung volume (EELV), including in obese obstructive sleep apnea patients. Despite this, the accuracy of magnetometers has not been confirmed in obese patients nor compared between sexes. Thus we compared spirometer-measured and magnetometer-estimated lung volume and tidal volume changes during voluntary end-expiratory lung volume changes of 1.5, 1, and 0.5 l above and 0.5 l below functional respiratory capacity in supine normal-weight [body mass index (BMI) < 25 kg/m] and healthy obese (BMI > 30 kg/m) men and women. Two different magnetometer calibration techniques proposed by Banzett et al. [Banzett RB, Mahan ST, Garner DM, Brughera A, Loring SH. J Appl Physiol (1985) 79: 2169-2176, 1995] and Sackner et al. [Sackner MA, Watson H, Belsito AS, Feinerman D, Suarez M, Gonzalez G, Bizousky F, Krieger B. J Appl Physiol (1985) 66: 410-420, 1989] were assessed. Across all groups and target volumes, magnetometers overestimated spirometer-measured EELV by ~65 ml (<0.001) with no difference between techniques (0.07). The Banzett method overestimated the spirometer EELV change in normal-weight women for all target volumes except +0.5 l, whereas no differences between mass or sex groups were observed for the Sackner technique. The variability of breath-to-breath measures of EELV was significantly higher for obese compared with nonobese subjects and was higher for the Sackner than Banzett technique. On the other hand, for tidal volume, both calibration techniques underestimated spirometer measurements (<0.001), with the underestimation being more marked for the Banzett than Sackner technique (0.03), in obese than normal weight (<0.001) and in men than in women (0.003). These results indicate that both body mass and sex affect the accuracy of respiratory magnetometers in measuring EELV and tidal volume. PMID- 27763877 TI - Green tea extract does not affect exogenous glucose appearance but reduces insulinemia with glucose ingestion in exercise recovery. AB - We reported that supplementation with green tea extract (GTE) lowered the glycemic response to an oral glucose load following exercise, but via an unknown mechanism (Martin BJ, MacInnis MJ, Gillen JB, Skelly LE, Gibala MJ. Appl Physiol Nutr Metab 41: 1057-1063, 2016. Here we examined the effect of supplementation with GTE on plasma glucose kinetics on ingestion of a glucose beverage during exercise recovery. Eleven healthy, sedentary men (21 +/- 2 yr old; body mass index = 23 +/- 4 kg/m2, peak O2 uptake = 38 +/- 7 ml.kg-1.min-1; means +/- SD) ingested GTE (350 mg) or placebo (PLA) thrice daily for 7 days in a double-blind, crossover design. In the fasted state, a primed constant infusion of [U 13C6]glucose was started, and 1 h later, subjects performed a graded exercise test (25 W/3 min) on a cycle ergometer. Immediately postexercise, subjects ingested a 75-g glucose beverage containing 2 g of [6,6-2H2]glucose, and blood samples were collected every 10 min for 3 h of recovery. The rate of carbohydrate oxidation was lower during exercise after GTE vs. PLA (1.26 +/- 0.34 vs. 1.48 +/- 0.51 g/min, P = 0.04). Glucose area under the curve (AUC) was not different between treatments after drink ingestion (GTE = 1,067 +/- 133 vs. PLA = 1,052 +/- 91 mM/180 min, P = 0.91). Insulin AUC was lower after GTE vs. PLA (5,673 +/- 2,153 vs. 7,039 +/- 2,588 uIU/180 min, P = 0.05), despite similar rates of glucose appearance (GTE = 0.42 +/- 0.16 vs. PLA = 0.43 +/- 0.13 g/min, P = 0.74) and disappearance (GTE = 0.43 +/- 0.14 vs. PLA = 0.44 +/- 0.14 g/min, P = 0.57). We conclude that short-term GTE supplementation did not affect glucose kinetics following ingestion of an oral glucose load postexercise; however, GTE was associated with attenuated insulinemia. These findings suggest GTE lowers the insulin required for a given glucose load during postexercise recovery, which warrants further mechanistic studies in humans. PMID- 27763878 TI - The effect of endothelin A and B receptor blockade on cutaneous vascular and sweating responses in young men during and following exercise in the heat. AB - During exercise, cutaneous vasodilation and sweating responses occur, whereas these responses rapidly decrease during postexercise recovery. We hypothesized that the activation of endothelin A (ETA) receptors, but not endothelin B (ETB) receptors, attenuate cutaneous vasodilation during high-intensity exercise and contribute to the subsequent postexercise suppression of cutaneous vasodilation. We also hypothesized that both receptors increase sweating during and following high-intensity exercise. Eleven men (24 +/- 4 yr) performed an intermittent cycling protocol consisting of two 30-min bouts of moderate- (40% Vo2peak) and high-intensity (75% Vo2peak) exercise in the heat (35 degrees C), each separated by a 20- and 40-min recovery period, respectively. Cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal microdialysis skin sites: 1) lactated Ringer (control), 2) 500 nM BQ123 (a selective ETA receptor blocker), 3) 300 nM BQ788 (a selective ETB receptor blocker), or 4) a combination of BQ123 + BQ788. There were no between-site differences in CVC during each exercise bout (all P > 0.05); however, CVC following high-intensity exercise was greater at BQ123 (56 +/- 9%max) and BQ123 + BQ788 (55 +/- 14%max) sites relative to the control site (43 +/- 12%max) (all P <= 0.05). Sweat rate did not differ between sites throughout the protocol (all P > 0.05). We show that neither ETA nor ETB receptors modulate cutaneous vasodilation and sweating responses during and following moderate- and high-intensity exercise in the heat, with the exception that ETA receptors may partly contribute to the suppression of cutaneous vasodilation following high-intensity exercise. PMID- 27763879 TI - A Prospective, Descriptive Study to Assess the Effect of Dietary and Pharmacological Strategies to Manage Constipation in Patients with a Stoma. AB - The term constipation with regard to patients with a stoma is defined as impaired bowel movements associated with increased stool consistency or long periods without bowel movements that lead to discomfort, flatulence, and abdominal pain. Information about constipation in patients with a stoma is limited. A prospective, descriptive study was conducted among patients attending ostomy and proctology outpatient clinics in Poznan, Poland between January 2011 and December 2014 to assess the role of dietary and pharmacological strategies in the management of constipation in patients with a stoma. Patients were included if they experienced a 3-day period without bowel movements leading to abdominal discomfort and bloating. Patients who were terminally ill from neoplastic disease or could not provide informed consent for study participation were not eligible to participate. Patients underwent 3 evaluations 3 months apart: the first assessed problems with passing stool through the stoma, at which time patients were told to increase fiber and fluid intake. During the next 2 visits, patients were asked if their symptoms had improved. If dietary changes were not successful, first-line pharmacological interventions were suggested (laxatives, osmotic agents, and probiotics). If no improvement was reported during the third assessment, second line pharmacologic therapy (eg, stimulant laxatives) were prescribed. Of the 405 patients initially assessed for participation, 331 met the initial screening criteria and were scheduled for followup. Of those, 93 (28%) had constipation; 50 (15%) required a surgical referral for morphological stoma changes and 43 (12.9%) met the study inclusion criteria for dietary recommendations. Almost all (42) had a colostomy and most (28) had a history of stoma creation due to diverticular disease. Twenty-five (25) men and 18 women (average age 55.9 +/- 9.3 years) received dietary recommendations during the first visit. Diet modifications were effective and sufficient to resolve the problem with constipation in more than half (24) of the patients. Among the remaining 19 patients, only 2 did not improve after using first-line or second line pharmacological management strategies. One patient required emergency surgery due to complicated colonic diverticulosis (perforation). The results of this study suggest constipation among patients with a stoma can be associated with morphological stoma changes and in the absence of morphologic changes the majority of patients respond well to a change in diet. Additional studies are needed to increase understanding about the incidence and optimal management strategies of constipation in persons with a stoma. PMID- 27763880 TI - A Retrospective Study to Evaluate Use of Negative Pressure Wound Therapy in Patients Undergoing Bilateral Internal Thoracic Artery Grafting. AB - Bilateral internal thoracic artery (BITA) grafting may be associated with a higher risk of postoperative deep sternal wound infection than monolateral internal thoracic artery grafting due to a limited blood supply to the thoracic chest wall. Because preliminary studies suggest negative pressure wound therapy (NPWT) may reduce the risk of infection, a retrospective chart review of 129 patients who underwent BITA between February 2003 and October 2014 was conducted. Of those, 21 patients received NPWT for 5 days immediately following surgery and the incisions of 108 patients were covered with a conventional gauze dressing. Patient demographic and history variables as well as surgical procedure and outcome variables were abstracted. Outcome variables assessed included infection, need for transfusion, and length of hospital stay. The NPWT group was significantly younger (average age 55.9 +/- 7.6 versus 60 +/- 10.5 years, P = 0.049), had fewer urgent/emergent surgeries (4 [19%] versus 36 [33.3%], P = 0.247), and had significantly lower surgical risk scores (2.0 +/- 2.3 versus 3.8 +/- 2.8, P = 0.010). The rate of deep sternal wound infections was lower in the NPWT than in the control group, but the difference was not statistically significant (0% versus 5.6%, P = 0.336). Sternal instability was noted in 4 control patients, requiring wound re-exploration versus 0 in the NPWT group (3.7% versus 0%, P = 0.487). One (1) patient in the NPWT group had postoperative bleeding that required removal of the device. The rates of re-thoracotomy due to bleeding were 9.3% in the control compared to 4.8% in the NPWT group (P = 0.435), which translated into a greater need for blood transfusions (1.77 +/- 3.4 units versus 0.3 3+/- 0.7 units, P = 0.056) and larger chest drainage volume (997.8 +/- 710 mL versus 591.2 +/- 346 mL, P = 0.012) in the control group. Hospital stay was longer in the control group, but the difference was not statistically significant (12 +/- 8.8 days versus 9.4 +/- 4.2 days, P = 0.184). These preliminary results are encouraging, and prospective, randomized, controlled clinical studies to compare the efficacy, effectiveness, and costeffectiveness of NPWT to other wound management modalities following cardiac surgery are warranted. PMID- 27763881 TI - Neuropathic Ulcers Among Children With Neural Tube Defects: A Review of Literature. AB - A trophic ulcer is a pressure ulcer caused by external trauma to a part of the body that is compromised due to disease, vascular insufficiency, or loss of afferent nerve fibers. Spinal dysraphism (ie, neural tube defects [NTD]) such as meningomyelocele is a risk factor for developing these ulcers in adults and pediatric patients. Information regarding the occurrence of trophic ulcers in pediatric patients with NTD is lacking. A review of the English-language literature on skin/neuropathic ulcers in patients with NTDs, irrespective of study design, published between 1975 and 2014, was undertaken using the PubMed database. Search terms included trophic ulcer, neuropathic ulcer, NTDs, and meningomyelocele. From among the more than 200 papers related to skin care in neonates and pediatric patients, 11 addressed skin ulcers in patients of NTD - 1 in French (a review article), 1 in German (a case report), and 9 in English (7 cohort studies and 2 reviewing surgical techniques). Typically, ulcers in patients with NTD are neuropathic (ie, related to nerve pathology). The most common type is meningomyelocele. Patients with NTD present with a spectrum of functional and sensory deficits that impair mobility; other causative factors that may contribute to the occurrence of ulcers include stress to the tissue, the length of time the stress occurs, muscle spasticity, infection, moisture, and nutritional status of the patient. Awareness of ulcer risk and preventive measures, such as maintaining foot flexibility or careful handling bony prominences such as kyphosis, is important. Once an ulcer occurs, management is challenging and involves collaboration of multiple medical, surgical, nutrition, and other specialists. If an ulcer develops and NTD has not been previously treated surgically or the MRI shows evidence of retethering, surgical treatment is needed. More research is needed to help guide ulcer prevention and treatment strategies in pediatric patients with NTD. PMID- 27763882 TI - Matrix metalloproteinases: an emerging role in regulation of actin microfilament system. AB - Matrix metalloproteinases (MMPs) are implicated in many physiological and pathological processes, including contraction, migration, differentiation, and proliferation. These processes all involve cell phenotype changes, known to be accompanied by reorganization of actin cytoskeleton. Growing evidence indicates a correlation between MMP activity and the dynamics of actin system, suggesting their mutual regulation. Here, data on the influence of MMPs on the actin microfilament system, on the one hand, and the dependence of MMP expression and activation on the organization of actin structures, on the other hand, are reviewed. The different mechanisms of putative actin-MMP regulation are discussed. PMID- 27763884 TI - Cerebral Air Embolism: A Clinical, Radiologic and Histopathologic Correlation. AB - Cerebral air embolism is a recognized life-threatening complication, sometimes iatrogenic. Its timely diagnosis is essential because it can result in neurologic deficits or death. We report a case of a 58-year-old man who died from cerebral air embolism diagnosed by nonenhanced computed tomography scan of the head after a cardiac bypass surgery with Biventricular Assist Device and multiple vascular line placements. Autopsy revealed extensive subcutaneous emphysema, intravascular and perivascular air bubbles in the central nervous system and associated cerebral and cerebellar hemorrhagic infarction. The autopsy was helpful in documenting the extent of the air embolism and its appearance in soft tissue and central nervous system. PMID- 27763885 TI - Duration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate. AB - Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT>=13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC>=28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5 year overall survival was 74 vs. 50%; P=0.14). The duration of response to first line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data. PMID- 27763883 TI - Clinical chorioamnionitis at term VII: the amniotic fluid cellular immune response. AB - OBJECTIVES: 1) To characterize the cellular composition of the amniotic fluid of patients diagnosed with clinical chorioamnionitis at term, as a function of the presence or absence of microorganisms determined by cultivation techniques, and 2) to characterize the cytokine production by white blood cells present in the amniotic fluid using flow cytometry-based techniques. MATERIALS AND METHODS: Amniotic fluid samples from 20 women who had the diagnosis of clinical chorioamnionitis at term were analyzed using cultivation techniques (for aerobic and anaerobic bacteria as well as genital Mycoplasmas). Amniotic fluid IL-6 concentrations were determined by an enzyme-linked immunosorbent assay. Amniotic fluid leukocytes were visualized by using hematoxylin and eosin staining and immunofluorescence. Immunophenotyping of surface markers and cytokines was performed in amniotic fluid leukocytes using flow cytometry. RESULTS: 1) Neutrophils (CD45+CD15+ cells) were the most common leukocyte subset found in the amniotic fluid, followed by monocytes (CD45+CD14+ cells); other white blood cells (such as lymphocytes and natural killer cells) were scarce in the amniotic fluid; 2) the absolute counts of neutrophils and monocytes were significantly higher in patients with microorganisms found in the amniotic fluid than in those without detectable microorganisms, using cultivation techniques; 3) there was a significant correlation between the absolute counts of neutrophils and monocytes determined by flow cytometry (Spearman's correlation=0.97; P<0.001); 4) there was a significant correlation between the absolute white blood cell count determined with a hemocytometer chamber and by flow cytometric analysis (Spearman's correlation=0.88; P<0.001); and 5) the profile of cytokine expression differed between monocytes and neutrophils; while neutrophils predominantly produced TNF alpha and MIP-1beta, monocytes expressed higher levels of IL-1beta and IL-1alpha. CONCLUSION: Flow cytometry analysis of the amniotic fluid of patients with intra amniotic infection and clinical chorioamnionitis at term demonstrated that neutrophils and monocytes are the most common cells participating in the inflammatory process. We have characterized, for the first time, the differential cytokine expression by these cells in this important complication of pregnancy. PMID- 27763886 TI - CYP2B6*6 or Not CYP2B6*6-That Remains a Question for Precision Medicine and Ketamine! PMID- 27763887 TI - Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance. AB - BACKGROUND: At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B6*6 allele would have decreased clinical ketamine metabolism and clearance. METHODS: Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects' self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration-time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances. RESULTS: There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects. CONCLUSIONS: These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations. PMID- 27763888 TI - Very Severe Aplastic Anemia During Treatment With Doxycycline. PMID- 27763889 TI - Effectiveness of Anakinra in Acute Gout: A Retrospective Review of Initial and Refractory Therapy. PMID- 27763890 TI - Enoxaparin-Induced Spontaneous Rupture of Spleen Leading to Life Threatening Hypotensive Shock. PMID- 27763891 TI - Skin advanced glycation end products in HIV infection are increased and predictive of development of cardiovascular events. AB - OBJECTIVE: HIV-1 infection is associated with an increased cardiovascular disease (CVD) risk. Advanced glycation end products are formed as stable markers of glycaemic and oxidative stress. Skin autofluorescence (SAF) as marker of accumulated advanced glycation end products is increased and predictive of CVD events in diabetes mellitus, chronic kidney disease (CKD), and preexisting CVD. We determined SAF levels in HIV-1 infected patients, testing the hypothesis that SAF predicts CVD events in HIV infection. DESIGN: Single-centre prospective cohort study. METHODS: In 2010-2011, SAF was measured in 91 patients. Development of CVD events was monitored during a median follow-up of 4.8 years. SAF values of the patients were expressed as a ratio (rSAF) to expected SAF levels in age matched healthy volunteers. RESULTS: Seventy-nine men and 12 women were included, mean age 47 years; 81 patients were on combination antiretroviral therapy. With a mean rSAF of 1.155, SAF levels in patients were 15.5% higher than predicted for their age (95% confidence interval, 10.0-20.0; P < 0.001). In multivariate regression analysis, rSAF was associated with nadir CD4 cell count less than 200 cells/MUl (beta -0.274; P = 0.01), smoking (beta 0.240; P = 0.03), and men who have sex with men (MSM) (beta 0.202; P = 0.07). CVD events occurred in six patients (7%). In Cox regression analysis including age, SAF, smoking, diabetes, hypertension and CKD, SAF (P = 0.01), and (Wet Medisch-wetenschappelijk Onderzoek met mensen; WMO) CKD (P = 0.03) remained as independent predictors of CVD events. CONCLUSION: SAF is increased in HIV-infected patients, and related with smoking, low nadir CD4 cell count, and MSM. Larger studies are needed to confirm whether SAF is an independent predictor of CVD events. PMID- 27763892 TI - Neuroinflammatory response to experimental stroke is inhibited by boldine. AB - Inflammation plays a pivotal role in the development of ischemic brain damage. Astrocyte activation promotes the production of several proinflammatory mediators, such as TNF-alpha and iNOS. Eventually, neuronal death occurs, leading to the development of motor and memory deficits in patients. Boldine is the main alkaloid in the leaves and bark of the Peumus boldus Molina, and has anti inflammatory and antioxidant properties. The aim of this work was to investigate the neuroprotective effect of boldine on neuroinflammation and memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) in mice. Thirty minutes before pMCAO and during the next 5 days, animals received vehicle (0.025 umol/l HCl) or boldine (8, 16 and 25 mg/kg, intraperitoneally). The extension of the infarct area, neurological scores, and myeloperoxidase activity were evaluated 24 h after pMCAO. Locomotor activity, working, and aversive memory were evaluated 72 h after pMCAO, object recognition memory was tested 96 h after pMCAO, and spatial memory was tested 120 h after pMCAO. Cresyl violet, Fluoro Jade C staining, and immunohistochemical for GFAP, TNF-alpha, and iNOS were also carried out. The treatment with boldine significantly decreased the infarct area, improved the neurological scores, and increased cell viability. The vertical exploratory activity and aversive, spatial, object recognition, and working memory deficits induced by pMCAO were prevented by boldine. Moreover, myeloperoxidase activity and GFAP, TNF-alpha, and iNOS immunoreactivity were decreased significantly by boldine. Although various mechanisms such as its antioxidant activity should be considered, these results suggest that the neuroprotective effect of boldine might be related in part to its anti inflammatory properties. PMID- 27763893 TI - Implications of frailty screening in clinical practice. AB - PURPOSE OF REVIEW: Many frailty screening instruments have been proposed due to the lack of consensus on a unified operational definition of frailty. This review reports on recent frailty screening tools in addition to revisiting the frailty concept. RECENT FINDINGS: Although there are two representative frailty models, both have issues that prevent them from being implemented in clinical settings despite their remarkable advantages. Due to their different characteristics, these models are thought to be complementary rather than substitutive. The recent introduction of frailty identification into primary care and specific clinical settings has led to both a focus on its importance and the development of new screening methods. SUMMARY: The phenotype model is rather faithfully based on biological change with aging, while the deficit model comprehensively captures risk of disability. Most of the current frailty screening tools are based on these models. Screening tools based on the former model primarily capture declines in physical functions, whereas screening tools based on the latter model involve questionnaires that examine functional impairments in multiple domains. Implementation of a model in a clinical setting depends on both the model characteristics and the clinical settings. PMID- 27763894 TI - Histological features of pituitary adenomas and sellar region masses. AB - PURPOSE OF REVIEW: Most pituitary region masses are pituitary adenomas; however, when other sellar region masses are encountered by clinicians or pathologists, the differential diagnosis can be broad. This review will focus on updates for pituitary adenomas, as well as briefly discuss some of these other entities: Rathke cleft cyst, hypophysitis, craniopharyngioma, pituicytoma, and spindle cell oncocytoma. RECENT FINDINGS: The use of new immunohistochemical (IHC) tools for assessing transcription factors, pituitary transcription factor-1, steroidogenic factor-1, and the not-yet-widely available Tpit IHC have provided insights into origin particularly of clinically silent and even hormone-negative pituitary adenomas. IHC for keratins coupled with use of E-cadherin IHC can serve to easily identify sparsely granulated growth hormone adenomas that behave more aggressively and may not respond well to some therapies. Thyroid transcription factor-1 IHC has shown common embryological lineage of pituicytoma, spindle cell oncocytoma, and granular cell tumor of neurohypophysis. SUMMARY: IHC supplements classification of pituitary adenoma subtypes for clinicians and can confirm diagnosis of nonpituitary adenoma sellar region masses. PMID- 27763896 TI - Reply to: The Letter to the Editor "Randomized Controlled Trial of Pancreaticojejunostomy versus Stapler Closure of the Pancreatic Stump During Distal Pancreatectomy to Reduce Pancreatic Fistula". PMID- 27763895 TI - Low Versus Standard Urine Output Targets in Patients Undergoing Major Abdominal Surgery: A Randomized Noninferiority Trial. AB - OBJECTIVE: To determine whether a low perioperative minimum urine output target is safe and fluid sparing when compared with the standard target. BACKGROUND: A minimum hourly urine output of 0.5 mL/kg is a key target guiding perioperative fluid therapy. Few data support this standard practice, which may contribute to perioperative fluid overloading. METHODS: We randomized patients without significant risk factors for acute kidney injury undergoing elective colectomy to a minimum urine output target of 0.2 mL/kg/h (low group) or 0.5 mL/kg/h (standard group) from induction of anesthesia until 8 AM 2 days after surgery. Maintenance fluids were standardized and additional fluids administered to achieve the targets. Primary outcome was noninferiority for urine neutrophil gelatinase associated lipocalin on the day after surgery. RESULTS: Between November 21, 2011 and July 11, 2013, 40 participants completed the study. The low group received 3170 mL (95% confidence interval 2380-3960) intravenous fluids versus 5490 mL (95% confidence interval 4570-6410) in the standard group (P = 0.0004), and was noninferior for neutrophil gelatinase-associated lipocalin [14.7 MUg/L (interquartile range 7.60-28.9) vs 18.4 MUg/L (interquartile range 8.30-21.2); Pnoninferiority = 0.0011], serum cystatin C (Pnoninferiority < 0.0001), serum creatinine (Pnoninferiority = 0.0004), and measured glomerular filtration (Pnoninferiority = 0.0003). Effective renal plasma flow increased in both groups after surgery, and more in the standard group (Pnoninferiority = 0.125). CONCLUSIONS: A perioperative urine output target of 0.2 mL/kg/h is noninferior to the standard target of 0.5 mL/kg/h and results in a large intravenous fluid sparing. This target should be adopted in surgical patients without significant kidney injury risk factors. PMID- 27763897 TI - The Tumor Burden Score: A New "Metro-ticket" Prognostic Tool For Colorectal Liver Metastases Based on Tumor Size and Number of Tumors. AB - OBJECTIVE: To apply the principles of the Metro-ticket paradigm to develop a prognostic model for patients undergoing hepatic resection of colorectal liver metastasis (CRLM). BACKGROUND: Whereas the hepatocellular "Metro-ticket" prognostic tool utilizes a continuum of tumor size and number, a similar concept of a CRLM Metro-ticket paradigm has not been investigated. METHODS: Tumor Burden Score (TBS) was defined using distance from the origin on a Cartesian plane incorporating maximum tumor size (x-axis) and number of lesions (y-axis). The discriminatory power [area under the curve (AUC)] and goodness-of-fit (Akaike information criteria) of the TBS model versus standard tumor morphology categorization were assessed. The TBS model was validated using 2 external cohorts from Asia and Europe. RESULTS: TBS (AUC 0.669) out-performed both maximum tumor size (AUC 0.619) and number of tumors (AUC 0.595) in predicting overall survival (OS) (P < 0.05). As TBS increased, survival incrementally worsened (5 year OS: zone 1, zone 2, and zone 3-68.9%, 49.4%, and 25.5%; P < 0.05). The stratification of survival based on traditional tumor size and number cut-off criteria was poor. Specifically, 5-year survival for patients in category 1, category 2, and category 3 was 58.3%, 45.5%, and 50.6%, respectively (P > 0.05). The corrected Akaike score information criteria value of the TBS model (2865) was lower than the traditional tumor morphologic categorization model (2905). Survival analysis revealed excellent prognostic discrimination for the TBS model among patients in both external cohorts (P< 0.05). CONCLUSIONS: An externally validated "Metro-ticket" TBS model had excellent prognostic discriminatory power. TBS may be an accurate tool to account for the impact of tumor morphology on long term survival among patients undergoing resection of CRLM. PMID- 27763898 TI - The Critical View of Safety: Why It Is Not the Only Method of Ductal Identification Within the Standard of Care in Laparoscopic Cholecystectomy. PMID- 27763899 TI - A Letter to the Editor. PMID- 27763900 TI - Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer. AB - OBJECTIVE: This study was aimed to investigate the prognostic value of tumor infiltrating neutrophils (TINs) and to generate a predictive model to refine postoperative risk stratification system for patients with gastric cancer. BACKGROUND: TIN presents in various malignant tumors, but its clinical significance in gastric cancer remains obscure. METHODS: The study enrolled 3 independent sets of patients with gastric cancer from 2 institutional medical centers of China. TIN was estimated by immunohistochemical staining of CD66b, and its relationship with clinicopathological features and clinical outcomes were evaluated. Prognostic accuracies were evaluated by C-index and Akaike information criterion. RESULTS: TINs in gastric cancer tissues ranged from 0 to 192 cells/high magnification filed (HPF), 0 to 117 cells/HPF, and 0 to 142 cells/HPF in the training, testing, and validation sets, respectively. TINs were negatively correlated with lymph node classification (P = 0.007, P = 0.041, and P = 0.032, respectively) and tumor stage (P = 0.019, P = 0.013, and P = 0.025, respectively) in the 3 sets. Moreover, multivariate analysis identified TINs and tumor node metastasis (TNM) stage as 2 independent prognostic factors for overall survival. Incorporation of TINs into well-established TNM system generated a predictive model that shows better predictive accuracy for overall survival. More importantly, patients with higher TINs were prone to overall survival benefit from postoperative adjuvant chemotherapy. These results were validated in the independent testing and validation sets. CONCLUSIONS: TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer. PMID- 27763901 TI - Extraocular Sebaceous Carcinoma-A Clinicopathologic Reassessment. AB - Sebaceous carcinoma is an aggressive adnexal neoplasm with sebaceous differentiation. Few reports have described the histopathologic characteristics of the sebaceous carcinoma occurring extraocularly. Seventy-two cases of extraocular sebaceous carcinoma were identified from the database of a Dermatopathology Laboratory from January 1, 2007 to May 31, 2013. More cases occurred in men (60%), with a mean age at diagnosis of 65.8 years (range 39-99 years). Neoplasms were histopathologically classified as well-differentiated (22%), moderately differentiated (67%), and poorly differentiated (11%). Sixty seven percent (67%) of cases demonstrated a squamoid growth pattern and thirty three percent (33%) demonstrated a basaloid growth pattern. A majority of the neoplasms histopathologically classified as well-differentiated (94%) and moderately differentiated (65%) demonstrated a squamoid growth pattern. Ten percent (10%) of cases exhibited cystic histopathologic changes. The histopathological features reported in this study aid in the understanding of extraocular sebaceous carcinoma and its eventual diagnosis and classification. PMID- 27763902 TI - Erythematous Nodular Lesion on the Upper Back. PMID- 27763903 TI - Periarticular Swelling and Skin Thickening Involving the Proximal Interphalangeal Joints. PMID- 27763904 TI - Primary Cutaneous Mammary Analog Secretory Carcinoma With ETV6-NTRK3 Translocation. AB - Mammary analog secretory carcinoma (MASC) is a recently described tumor of the salivary glands named for its morphological and molecular similarity to secretory carcinoma of the breast. Many primary carcinomas arising from the adnexal glands also share similar morphology to those arising from the breast. Brandt et al first described primary cutaneous MASC in 2009 and since then only 2 other cases have been reported. Herein, we describe a long-standing mass on the arm of an otherwise healthy 40-year-old female. Histologic examination revealed a circumscribed but unencapsulated, nodular tumor composed of bland epithelial cells arranged in solid and microcystic growth patterns. The cells showed vacuolated cytoplasm and round to oval nuclei with vesicular chromatin. Intraluminal homogenous eosinophilic secretions were present. Mitotic figures were not identified. The tumor cells stained positive for CK8/18, CK7, and S100 but were negative for other markers performed, including estrogen receptor, progesterone receptor, HER2/neu, paired box 8 (PAX8), and thyroid transcription factor 1 (TTF1). As the patient clinically had no other masses or known carcinomas, a diagnosis of primary cutaneous MASC was rendered. The ETV6-NTRK3 fusion transcript was subsequently detected by reverse transcriptase polymerase chain reaction amplification, further supporting the diagnosis. We present this case to review the histologic features of MASC and highlight the importance of recognizing this lesion not only as a possible cutaneous metastasis but also as a primary cutaneous tumor. PMID- 27763905 TI - Erythematous Nodular Lesion on the Upper Back. PMID- 27763906 TI - Periarticular Swelling and Skin Thickening Involving the Proximal Interphalangeal Joints. PMID- 27763907 TI - Electromyographic Activities of the Rotator Cuff Muscles During Walking, Eating, and Washing. AB - OBJECTIVE: The aim of this study was to evaluate the activity of rotator cuff (RC) muscles during activities of daily living. DESIGN: Motion analysis was conducted with 14 volunteers. Activation of RC (subscapularis, supraspinatus, and infraspinatus) was assessed using electromyography (EMG). Walking was performed with or without a shoulder immobilizer. Eating was conducted with or without the support of the elbow with the contralateral hand. Washing the hair was simulated while standing or leaning forward; washing the body was simulated while standing or holding the elbow; and washing the face was simulated using both hands while leaning forward. RESULTS: During walking, RC's peak EMG activities remained below 7% maximum voluntary isometric contraction at all times, regardless of the use of immobilizers. Eating caused mild EMG activities (14%-32%), whereas eating with elbow support resulted in significantly lower EMG activities in the supraspinatus and infraspinatus. Washing the hair standing moderately activated RC (23%-57%), whereas leaning forward decreased it to 6% to 36%. Washing the body while holding the elbow decreased infraspinatus activation to 4% from 10% when standing. Washing the face with both hands and leaning forward resulted in high-peak EMG activities in the upper subscapularis (37%). CONCLUSIONS: There was no difference in RC activity level between walking with or without immobilizers. From the point of muscle contraction, an immobilizer is not mandatory. Holding the elbow with the contralateral hand while eating or washing can help decrease the load in the supraspinatus and infraspinatus. PMID- 27763908 TI - Ultrasonographic and Surgical Findings of Acute Radial Neuropathy Following Blunt Trauma. AB - Ultrasonographic study is useful for decision making of treatment for focal neuropathy with unusual electrodiagnostic findings. We present a patient with severe acute radial neuropathy with sensory sparing around the distal arm secondary to twisting of the radial nerve following blunt trauma. A 24-year-old man with a 2-week history of left wrist drop and severe pain around the left elbow presented after hitting the left distal arm on the doorknob. The left wrist and finger extensions were grade 0, but elbow extension could not be tested because of severe pain during this action. The left superficial radial sensory territory was intact. Electrodiagnostic findings suggested severe left radial neuropathy around the distal arm with sensory sparing. Ultrasonographic study demonstrated 2 stenotic lesions around the distal arm and absence of the left superficial radial sensory nerve. Surgical exploration revealed 2 stenotic lesions with twisting of the nerve, concordant with ultrasonographic study. End to-end anastomosis was performed in the proximal lesion. Sixteen months later, wrist and finger extension was grade 3, and reinnervation signs in the radial innervated muscles except extensor indicis muscle were observed. The complementary relationship between electrophysiologic and ultrasonographic examinations is very important for precise lesion location and decision making for treatment of peripheral nerve injury. PMID- 27763909 TI - Neonatal Nurses NICU Quality Improvement: Embracing EBP Recommendations to Provide Parent Psychosocial Support. AB - BACKGROUND: The neonatal intensive care unit (NICU) can be a stressful environment for infants, their families, and the healthcare team. There is an immediate need for neonatal nurses to embrace and translate the new National Perinatal Association recommendations for psychosocial support of NICU parents into clinical practice to demonstrate best practices for infants, their families, and the whole team. PURPOSE: To summarize the current evidence-based practice recommendations and to provide suggestions for team members to develop strategies to adopt and implement them through quality improvement (QI) projects. METHODS: Literature reviews were conducted by the original 6 National Perinatal Association workgroup teams and covered all levels of available evidence (eg, qualitative, quantitative, and clinical research, guidelines, and clinical and parental expertise). Evidence was synthesized to formulate this set of recommendations published in December 2015. We describe their applicability to the vital role of neonatal nurses, while elucidating QI projects that track measurements of change to translate these recommendations into practice. RESULTS: Neonatal nurses are in an ideal position to transform systems of support for NICU parents through the adoption of these recommendations at the bedside, and further to identify areas for QI to enhance implementation. IMPLICATIONS FOR PRACTICE: Neonatal nurses are integral to problem solving and identifying QI strategies for translating these recommendations into NICU clinical practice to improve parent psychosocial support. IMPLICATIONS FOR RESEARCH: This article disseminates evidence and encourages scientific investigation into various methods of supporting emotional health of NICU parents to create better health outcomes. PMID- 27763910 TI - Short-Term and Long-Term Changes in Corneal Power Are Not Correlated With Axial Elongation of the Eye Induced by Orthokeratology in Children. AB - PURPOSE: To assess the relationship between short-term and long-term changes in power at different corneal locations relative to the change in central corneal power and the 2-year change in axial elongation relative to baseline in children fitted with orthokeratology contact lenses (OK). METHODS: Thirty-one white European subjects 6 to 12 years of age and with myopia -0.75 to -4.00 DS and astigmatism <=1.00 DC were fitted with OK. Differences in refractive power 3 and 24 months post-OK in comparison with baseline and relative to the change in central corneal power were determined from corneal topography data in eight different corneal regions (i.e., N[nasal]1, N2, T[temporal]1, T2, I[inferior]1, I2, S[superior]1, S2), and correlated with OK-induced axial length changes at two years relative to baseline. RESULTS: After 2 years of OK lens wear, axial length increased by 0.48+/-0.18 mm (P<0.001), which corresponded to an increase of 1.94+/-0.74% ([2-years change in axial length/baseline axial length]*100). However, the change in axial elongation in comparison with baseline was not significantly correlated with changes in corneal power induced by OK relative to baseline for any of the corneal regions assessed (all P>0.05). CONCLUSION: The reduction in central corneal power and relative increase in paracentral and pericentral power induced by OK over 2 years were not significantly correlated with concurrent changes in axial length of white European children. PMID- 27763911 TI - Accounting for Ethnicity-Related Differences in Ocular Surface Integrity as a Step Toward Understanding Contact Lens Discomfort. AB - Contact lens discomfort is a common problem that can lead to unsuccessful or limited contact lens wear. Although many factors may contribute to contact lens discomfort, limited research has explored the influence of ethnicity-related differences in the anatomy and physiology of the ocular surface. Therefore, we performed a search of the literature in PubMed using key words related to "ocular surface" paired with the terms "race" and "ethnicity." The goal of this review was to determine potential areas of research regarding ethnicity differences, particularly between Asian and non-Asian eyes, in ocular surface integrity to advance our understanding of contact lens discomfort. PMID- 27763912 TI - Metrics of Arterial Hyperoxia and Associated Outcomes in Critical Care. AB - OBJECTIVE: Emerging evidence has shown the potential risks of arterial hyperoxia, but the lack of a clinical definition and methodologic limitations hamper the interpretation and clinical relevance of previous studies. Our purpose was to evaluate previously used and newly constructed metrics of arterial hyperoxia and systematically assess their association with clinical outcomes in different subgroups in the ICU. DESIGN: Observational cohort study. SETTING: Three large tertiary care ICUs in the Netherlands. PATIENTS: A total of 14,441 eligible ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 295,079 arterial blood gas analyses, including the PaO2, between July 2011 and July 2014 were extracted from the patient data management system database. Data from all admissions with more than one PaO2 measurement were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation registry. Mild hyperoxia was defined as PaO2 between 120 and 200 mm Hg; severe hyperoxia as PaO2 greater than 200 mm Hg. Characteristics of existing and newly constructed metrics for arterial hyperoxia were examined, and the associations with hospital mortality (primary outcome), ICU mortality, and ventilator-free days and alive at day 28 were retrospectively analyzed using regression models in different subgroups of patients. Severe hyperoxia was associated with higher mortality rates and fewer ventilator-free days in comparison to both mild hyperoxia and normoxia for all metrics except for the worst PaO2. Adjusted effect estimates for conditional mortality were larger for severe hyperoxia than for mild hyperoxia. This association was found both within and beyond the first 24 hours of admission and was consistent for large subgroups. The largest point estimates were found for the exposure identified by the average PaO2, closely followed by the median PaO2, and these estimates differed substantially between subsets. Time spent in hyperoxia showed a linear and positive relationship with hospital mortality. CONCLUSIONS: Our results suggest that we should limit the PaO2 levels of critically ill patients within a safe range, as we do with other physiologic variables. Analytical metrics of arterial hyperoxia should be judiciously considered when interpreting and comparing study results and future studies are needed to validate our findings in a randomized fashion design. PMID- 27763913 TI - The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome. AB - OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome. DESIGN: Experimental study. SETTING: Animal research laboratory. SUBJECTS: Ten pigs, 35 +/- 5.2 kg. INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves. MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 +/- 94 to 444 +/- 115 dyn.s.cm and from 0.27 +/- 0.14 to 0.62 +/- 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 +/- 0.86 to 1.48 +/- 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 +/- 0.07 vs 0.14 +/- 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 +/- 83 vs 378 +/- 79 dyn.s.cm, p = 0.033, and vs 450 +/- 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 +/- 0.08 vs 0.50 +/- 0.15 mm Hg/mL, p = 0.04, and vs 0.61 +/- 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 +/- 0.17 vs 0.48 +/- 0.10, p = 0.024, and vs 0.53 +/- 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively. CONCLUSIONS: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings. PMID- 27763914 TI - Clinical and scientific challenges in HIV-associated malignancies. PMID- 27763915 TI - Towards Understanding Mechanisms of Anesthesia. PMID- 27763917 TI - Supine Position, Sleep, Wet Airways, and Wet Lungs. PMID- 27763916 TI - Hemodynamic Instability Following Airway Spray Cryotherapy. AB - BACKGROUND: Spray cryotherapy (SCT) of airway lesions is used to effectively palliate respiratory symptoms related to airway obstruction, but significant intraoperative hemodynamic complications have been noted. We reviewed the experience at a single institution using SCT for the treatment of obstructive airway tumors. METHODS: A retrospective review of a single institution experience with intraoperative and postoperative hemodynamic complications associated with SCT was performed. Descriptive statistics were performed. RESULTS: Between June 2009 and April 2010, 34 treatment sessions were performed on 28 patients. Median age was 60 years (range, 15-88 years). Tumor characteristics were as follows: 13 primary lung cancers (43%), 11 pulmonary metastases (50%), 1 direct extension of an esophageal cancer (3%), and 2 benign pulmonary lesions (7%). Twenty-one tumors (75%) were distal to the carina; 14 (50%) were >95% occlusive. Median procedure length was 78 minutes (range, 15-176 minutes). Eleven sessions (31%) led to severe hypotension and/or bradycardia, with 2 patients requiring cardiopulmonary resuscitation. One patient died intraoperatively after cardiac arrest; a second patient was stable intraoperatively but died within 24 hours of SCT. Four patients required reintubation and short-term mechanical ventilation. CONCLUSIONS: Unpredictable life-threatening hemodynamic instability can follow endobronchial SCT. We propose that the most likely cause is pulmonary venous gaseous emboli entering the right heart, the coronary arteries, and the systemic circulation. Although SCT may offer advantages over airway laser therapy (such as no risk of fire and rapid hemostasis), further study is needed to delineate the relative likelihood of therapeutic benefit versus catastrophic complications. PMID- 27763918 TI - Verification of Nasopharyngeal Temperature Probes-They Are Not Always Where You Think They Are! PMID- 27763919 TI - In Dialogue. PMID- 27763920 TI - In Response. PMID- 27763922 TI - Why are patients still getting and dying from acute kidney injury? AB - PURPOSE OF REVIEW: Acute kidney injury is common and is associated with increased morbidity and mortality. Rates of acute kidney injury in most settings remain high and in some settings are increasing. Moreover, outcomes associated with acute kidney injury remain relatively poor. This review focuses on recent advances in understanding of acute kidney injury and discusses possible interventions based on these advances. RECENT FINDINGS: Acute kidney injury is not a disease with a single etiology and clinical course but rather a loose collection of syndromes whose unifying phenotype is an acute loss of glomerular filtration. Traditional taxonomy based on anatomic locations (pre, intra, and post) in reference to the kidney is overly simplistic and has given way to specific 'endotypes' including hepatorenal, cardiorenal, nephrotoxic, and sepsis associated and these syndromes all have unique pathophysiologies and treatments. Our tendency to lump all of these clinical syndromes into a single disease and seek a single treatment has led to the profound lack of progress observed in terms of improving outcomes. The hope is that this is about to change. SUMMARY: Understanding the epidemiology, pathogenesis, and pathophysiology of acute kidney injury is critical to achieving improved outcomes for the millions of patients who develop this loose constellation of syndromes. PMID- 27763923 TI - The multidisciplinary nature of trauma care: also in the intensive care unit. PMID- 27763924 TI - The Impact of Microbiota on Health and Illness. PMID- 27763925 TI - Suffering of Traumatic Amputees in Spain: Meaning, Spirituality, and Biomedicine. AB - Amputation is a traumatic incident that entails a chain of psychological, physical, and social events. The objectives of the study are to describe the beliefs and the philosophies of life related to the experience of suffering of traumatic amputees, analyze the importance of biomedical care, and describe other forms of care used. PMID- 27763926 TI - Exploring Spirituality Among African American Women: Implications for Promoting Breast Health Behaviors. AB - The purpose of this qualitative study was to gain understanding of the definition, meaning, and function of spirituality to African American women. Four categories emerged that add insight for nurses to develop innovative spiritual based strategies to promote African American women's positive health behaviors. Implications for promoting breast health behaviors are described. PMID- 27763927 TI - The Effect of Spiritual Care on Mental Health in Mothers of Children With Cancer. AB - This study measured the effect of spiritual care on mental health in mothers of children with cancer. The present quasi-experimental study was with one group pretest posttest design. The findings show that implementation of spiritual care in mothers of children with cancer can improve their mental health. PMID- 27763928 TI - Nurses' Knowledge, Perceived Barriers, and Practices Regarding Complementary and Alternative Medicine in South Korea. AB - Complementary and alternative medicine (CAM) is widely used by patients across the world. As nurses play a key role in patient care, describing nurses' knowledge, perceived barriers, and practices regarding CAM would be essential. A descriptive design was applied with 170 Korean nurses to measure the nurses' knowledge, perceived barriers, and practice experience regarding CAM. Nurses in Korea reported a lack of knowledge regarding CAM, moderate to high levels of perceived barriers to using CAM, and low levels of CAM practice in nursing. CAM practice in nursing was highly correlated with and affected by the participants' knowledge and clinical experience. This research should motivate all nursing disciplines to reflect upon how to improve CAM knowledge, overcome perceived barriers, and achieve the best nursing practice possible. PMID- 27763929 TI - Relatedness Matters. AB - Today, nurses are confronted with much more in their day-to-day activities than 40 years ago. Not only are nurses caring for more patients during their shifts, patients are acute and complex and have shorter hospital stays. The nurse-patient relationship has been a focus of nursing since the profession began. Nurses today engage with vulnerable individuals in intimate and highly technical environments. Not only do nurses care for people using highly technical skills, but also nurses educate and support individuals toward healing by listening, and encouraging people toward improved health. The relationship between nurse and patient remains relevant today and important for patient outcomes. This publication introduces a theoretical approach that exemplifies the importance of relatedness in maintaining the nurse-patient relationship. PMID- 27763930 TI - Effects of Reflexology on Pain in Patients With Fibromyalgia. AB - The aim of this study was to investigate the effect of reflexology on pain intensity in patients with fibromyalgia, using an experimental repeated-measures design, and a convenience sample of 30 fibromyalgia inpatients. Thirty patients aged 18 to 70 years with fibromyalgia and hospitalized in the algology clinic were taken as a convenience sample. Patients received a total of 12 60-minute sessions of reflexology over a period of 6 consecutive weeks. Reflexology was carried out bilaterally on the hands and feet of patients at the reflex points relating to their pain at a suitable intensity and angle. Subjects had pain scores taken immediately before the intervention (0 minute), and at the 60th minute of the intervention. Data were collected over a 10-month period in 2012. The patients' mean pain intensity scores were reduced by reflexology, and this decrease improved progressively in the first and sixth weeks of the intervention, indicating a cumulative dose effect. The results of this study implied that the inclusion of reflexology in the routine care of patients with fibromyalgia could provide nurses with an effective practice for reducing pain intensity in these patients. PMID- 27763931 TI - Mantram Repetition With Homeless Women: A Pilot Study. AB - Women and families are the fastest growing segment of the homeless population. Negative attitudes of nurses toward homeless women are a major barrier to homeless women seeking health care. This cross-sectional, mixed-methods pilot study, conducted primarily by nurses, tested the Mantram Repetition Program for the first time with 29 homeless women. The Mantram Repetition Program is a spiritually based skills training that teaches mantram (sacred word) repetition as a cost-effective, personalized, portable, and focused strategy for reducing stress and improving well-being. For the cross-sectional, pretest-posttest design portion of the study, the hypothesis that at least half of the homeless women would repeat their mantram at least once a day was supported with 88% of the women repeating their mantram 1 week later. The qualitative portion of this study using phenomenology explored the women's thoughts on mantram week 2. Themes of mantram repetition, mantram benefits, and being cared for emerged. This groundbreaking, interventional, mixed-methods pilot study fills a gap in interventional homeless research. PMID- 27763933 TI - The Miracle of Henry the Hospice Cat. PMID- 27763932 TI - Effects of Reiki on Pain and Vital Signs When Applied to the Incision Area of the Body After Cesarean Section Surgery: A Single-Blinded, Randomized, Double Controlled Study. AB - This study was conducted to determine the effects of Reiki on pain and vital signs when applied for 15 minutes to the incision area of the body after cesarean section surgery. The study was single-blinded, randomized, and double-controlled (Reiki, sham Reiki, and control groups). Forty-five patients, equalized by age and number of births, were randomly assigned to the Reiki, sham Reiki, and control groups. The treatment, which was applied to the patients in these 3 groups, was applied for 15 minutes to the incision area of body in the first 24 and 48 hours after the operation within 4 to 8 hours of the application of standard analgesics. The study data were collected using a patient follow-up form and a visual analog scale. Mean visual analog scale measurement values were significantly different from each other according to groups and times (P < .05). A reduction in pain of 76.06% was determined in the Reiki group patients between day 1 pre-tx and after application on the second day (day 2 post-tx) measurements. Mean breathing rate and systolic blood pressure measurement values were significantly different from each other according to groups (P < .05). The Reiki group was observed to use fewer analgesics throughout the study and to need them after a longer time than the sham Reiki and control groups (P < .05). It was concluded that Reiki applied for 15 minutes to the incision area after a cesarean operation had the expected effects on pain and the need for the use of analgesics, but it had no effect on vital signs. PMID- 27763934 TI - Omega-3 Fatty Acids: Clinical Applications in the Treatment of Depression. PMID- 27763935 TI - Oral Health: A Critical Influence on the Health of the Whole. PMID- 27763937 TI - Foreword. PMID- 27763940 TI - Myocardial T2 Mapping in Patients With Hypertrophic Cardiomyopathy. AB - OBJECTIVE: The aim of this study was to evaluate the usefulness of T2 mapping for detecting myocardial injuries in patients with hypertrophic cardiomyopathy (HCM). METHODS: Twenty-one HCM patients and 7 healthy volunteers were examined. The T2 values were measured at hyperintense areas (high-T2 areas) identified with T2 mapping, at late gadolinium enhancement (LGE) areas, and in nullified myocardium of the HCM patients. The associations between T2 values and laboratory data or LGE areas were assessed. RESULTS: High-T2 areas had significantly greater T2 values than LGE areas (P < 0.05) and nullified areas (P < 0.01) of HCM and normal myocardium (P < 0.01). The presence of high-T2 areas was associated with an increase in troponin T levels (P = 0.02), and T2 values correlated with the levels of brain natriuretic peptide (P = 0.036, r = 0.86). CONCLUSIONS: T2 mapping identified myocardial injuries suggested by the laboratory data in HCM. PMID- 27763942 TI - Medical treatment in multivessels coronary disease. PMID- 27763941 TI - Analysis of Patient-reported Outcomes of Quality of Life and Functioning Before and After Treatment of Major Depressive Disorder Comorbid With Alcohol Use Disorders. AB - OBJECTIVE: Alcohol use disorders (AUDs) are common among persons with major depressive disorder (MDD) and have an adverse impact on course of illness and patient outcomes. The aim of this study was to examine whether AUD adversely impacted patient-centered outcomes in a sample of research subjects evaluated as part of a large clinical trial for depression. The outcomes of interest to this post hoc analysis are quality of life (QOL), functioning, and depressive symptom severity. METHODS: We analyzed 2280 adult MDD outpatient research subjects using data from the Sequenced Treatment Alternatives to Relieve Depression trial. We compared entry and post-selective serotonin reuptake inhibitors (SSRI) treatment QOL, functioning, and depressive symptom severity scores between 121comorbid MDD with AUD (MDD + AUD) subjects and 2159 MDD-no-AUD subjects, and also differences between subjects categorized as remitters versus nonremitters within each group at exit. RESULTS: At entry, MDD + AUD subjects reported similar QOL, functioning, and depressive symptom severity compared with the MDD-no-AUD subjects. After treatment with citalopram, both groups showed significant improvements throughout treatment; however, 36% to 55% of subjects still suffered from severely impaired QOL and functioning at exit. CONCLUSIONS: The overall study population demonstrated a significant response to treatment with large effect sizes in depressive symptom reduction, but to a lesser extent in QOL and functioning. Findings suggest that subjects with MDD + AUD benefited equally as MDD-no-AUD from treatment with selective serotonin reuptake inhibitors (SSRI) medication, yet both groups continue to experience reduced QOL and functioning after treatment. Monitoring QOL and functioning is critical to determine whether interventions that improve clinical outcomes also impact patient-centered outcomes, and our analysis suggests that there is a pressing need for innovative interventions that effectively improve these outcomes. PMID- 27763943 TI - How important are triglycerides as risk factors? PMID- 27763945 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY ASSOCIATED WITH RETINAL ARTERY OCCLUSION AFTER COSMETIC FILLER INJECTION. AB - PURPOSE: To report a single case of paracentral acute middle maculopathy in association with retinal artery occlusion in the setting of ipsilateral facial cosmetic filler injection. METHODS: Case report. PATIENT: A 35-year-old woman presenting with sudden vision loss to finger count vision immediately after left nasal fat pad cosmetic filler injection. RESULTS: Dilated funduscopic examination revealed a swollen optic disc with multiple branch arterial occlusions with visible embolic material. Fluorescein angiography confirmed multiple branch arterial occlusions in addition to a focal choroidal infarction in the macula. Spectral-domain optical coherence tomography revealed middle retinal hyperreflectivity in the superotemporal macula consistent with paracentral acute middle maculopathy. En face optical coherence tomography demonstrated a superotemporal area of whitening at the level of the deep capillary plexus corresponding to the paracentral acute middle maculopathy lesion seen on spectral domain optical coherence tomography. On twelve-month follow-up, final visual acuity was 20/100 due to optic neuropathy. CONCLUSION: Emboli from cosmetic facial filler injections may rarely result in ipsilateral arterial occlusions and now have a novel association with paracentral acute middle maculopathy likely due to deep capillary plexus feeder vessel occlusion. PMID- 27763944 TI - MULTIMODALITY IMAGING OF TORPEDO MACULOPATHY WITH SWEPT-SOURCE, EN FACE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: Multimodality image analysis of two cases of torpedo maculopathy. METHODS: Imaging with fundus photography, autofluorescence (AF), swept-source optical coherence tomography (OCT), en face OCT, and OCT angiography. RESULTS: The basal diameter of the torpedo lesions was 1 mm * 2 mm. One case had a satellite lesion. Autofluorescence indicated variable loss of signal. Swept source OCT and en face OCT demonstrated fundus excavation, attenuation of nuclear layers and disruption of the outer plexiform layer, loss of photoreceptors and a subretinal cleft. In one case, Sattler layer appeared extended at the cleft. Optical coherence tomography angiography indicated loss of flow in deep retinal vessels and increased flow in choroidal vessels surrounding the cleft. CONCLUSION: Multimodal imaging findings of torpedo maculopathy include disruption of the deep retinal capillary network, expansion of Sattler layer, and increased signal around the subretinal cleft. PMID- 27763946 TI - Surgical Reconstruction of Lower Face Degloving. AB - One of the most impressive soft tissue injuries is the facial degloving, normally associated with industrial machines and traffic accidents. This injury is characterized by the separation of the skin and cartilage from the bones, compromising the soft tissues correlated in the trauma area, nerves, and blood vessels. A 28-year-old patient, male, was referred to Aracatuba's Santa Casa Hospital, after a motorcycle accident, hitting his face on the sidewalk. The patient was conscious, oriented, denying fainting and unconsciousness during the accident, and complaining of pain in the nasal region of the face. The suture of wounds was performed using 5-0 absorbable sutures for muscle planes, and reconstruction of the septum and nasal cartilages. The skin was sutured with interrupted stitches using 6-0 nylon. After reducing the edema, a slight increase in alar base was observed. Subsequently, the alar base cinch suture was performed aiming to bring the alar bases to a measure of 34.0 mm in diameter. As a conclusion, the knowledge of the anatomy of the region involved, the healing of tissues, and suture techniques for the facial region process were critical to the successful treatment. The evaluation of the alar base in degloving cases can involve aesthetic features. PMID- 27763947 TI - Prosthetic Rehabilitation After Fibular Free Flap Surgery of Mandibular Defects in a Patient With Oral Squamous Cell Carcinoma. AB - OBJECTIVE: This report is to present the treatment procedure and clinical considerations of prosthodontic management of a patient who had undergone a partial mandibulectomy and fibular free flap surgery. DESIGN: A 59-year-old man with a squamous cell carcinoma received a partial mandibular resection. Microsurgical reconstruction with a fibular free flap surgery and implant supported zirconia-fixed prosthesis produced by computer-aided manufacturing led to successful results for the oral rehabilitation of mandibular defects. CONCLUSIONS: The implant-supported zirconia-fixed prosthesis can be recommended for use in patients with mandibulectomy and fibular free flaps. Close cooperation between the surgeon and the prosthodontist is mandatory for the satisfaction of the patient. PMID- 27763948 TI - Comparison of the Efficacy of Reoperation, Percutaneous Radiofrequency Thermocoagulation When Microvascular Decompression of Trigeminal Neuralgia Is Invalid. AB - OBJECTIVE: To compare the curative effect of reoperation in short-term and percutaneous radiofrequency thermocoagulation (PRT) when trigeminal neuralgia patient after microvascular decompression (MVD) is invalid. METHODS: Follow-up of 54 patients (30 patients with reoperation in the short term, 24 patients with PRT of primitive trigeminal neuralgia) when MVD is invalid between January 2008 and December 2014. To evaluate the degree of pain relief and facial numbness of patients after the treatment in short-term (1 month), in long-term (1 year). RESULT: One month after surgery, the authors compared the reoperation group with PRT group. The ratio of cure rate P = 0.02, the ratio of effective rate P = 0.04, the ratio of facial numbness P = 0.01; 1 year after surgery, the authors compared the reoperation group with PRT group. The ratio of cure rate P = 0.004, the ratio of effective rate P = 0.006, the ratio of facial numbness P = 0.02, the ratio of recurrence P = 0.04. The short-term and long-term clinical efficacy in reoperation group was better than PRT group (P < 0.05). CONCLUSION: For the patients of trigeminal neuralgia when first MVD is invalid, reoperation is better than PRT, and a significantly lower incidence of facial numbness and recurrence than PRT. PMID- 27763949 TI - After a Decade of Human Papillomavirus Vaccination, How to Bend the Vaccination Uptake Curve Upward. PMID- 27763950 TI - Toward an Algorithm for the Diagnosis and Management of CMV in Patients with Colitis. AB - INTRODUCTION: Concurrent cytomegalovirus (CMV) in inflammatory bowel disease related colitis is an important yet complex clinical scenario associated with high rates of colectomy and other morbidity. This review aimed to examine the literature to produce a comprehensive diagnostic and treatment algorithm for the management of CMV in patients with colitis. METHODS: A systematic literature review was conducted via PubMed/Medline databases until August 31, 2015, using multiple keywords in English language and where original data only presented. RESULTS: This review discusses the concept of CMV reactivation which frequently occurs in inflammatory bowel disease-related colitis, most commonly in those presenting with steroid-refractory colitis. In this context, although signifying a poorer prognosis, in most cases, the virus is nonpathogenic and thus antiviral treatment is unhelpful. However, when reactivation gives rise to true CMV disease (colitis) as best discriminated by histology with immunohistochemistry (and the density of such) in colonic biopsy tissue, the patient does benefit from antivirals. CONCLUSION: Diagnostic-based patient selection and treatment is integral to optimal outcomes in CMV, and therefore we propose an algorithm based on these concepts that now requires prospective evaluation. PMID- 27763952 TI - Factors Predicting Testing and Treatment of Iron Deficiency in a Nationwide Cohort of Anemic UC Patients. AB - BACKGROUND: Iron deficiency anemia (IDA) is an often unrecognized and undertreated complication of ulcerative colitis (UC). We conducted the first nationwide study in the United States to evaluate the prevalence of testing for iron deficiency (ID) in anemic UC patients and determine the frequency of treatment with iron supplementation in patients with IDA. METHODS: Nationwide cohort of patients with newly diagnosed UC in the Veterans Affairs health care system was identified. Primary outcome was to evaluate if anemic UC patients were tested for ID and subsequently treated with iron replacement therapy if IDA is confirmed. Candidate parameters included factors that can impact testing and treatment of anemia including patients' demographics, severity of anemia, and endoscopic findings. RESULTS: Of 836 newly diagnosed patients with UC, 585 patients (70%) developed anemia over the course of median 8 years of follow-up. Of 585 patients, 401 patients (68.6%) had iron study evaluation. Two hundred fifty-one patients (62.6%) were diagnosed with IDA, and among them, 191 patients (76.1%) were treated with oral iron therapy. None of the patient received intravenous iron therapy. In multivariate analysis, patients with mild/moderate anemia and patients from Midwest and South region were independent predictors of iron study evaluation in patients with anemia. CONCLUSIONS: More than a third of anemic UC patients were not tested for ID. Once tested, almost a quarter of the patients with IDA were not treated with iron replacement therapy. Testing for ID and subsequent treatment with iron replacement therapy should be considered among the quality process indicators in UC. PMID- 27763953 TI - Incremental value of single-photon emission computed tomography/computed tomography in the diagnosis of active condylar hyperplasia. AB - OBJECTIVE: To evaluate the incremental value of technetium-99m methylene diphosphonate (Tc-MDP) single-photon emission computed tomography/computed tomography (SPECT/CT) over planar bone scintigraphy (BS) and SPECT for the diagnosis of active condylar hyperplasia (CH). PATIENTS AND METHODS: Data of 21 patients (mean age: 21.9+/-5.3 years, 10 males, 11 females) who underwent Tc-MDP BS along with regional SPECT/CT for the diagnosis of active CH were retrospectively evaluated. Planar BS, SPECT, and SPECT/CT images were evaluated by two nuclear medicine physician in consensus. Radioactive counts were measured per region of interest and the respective ratios were calculated. A percentage of condylar uptake 55% or higher, generating differences of 10% or more between condyles, was considered to be indicative of active unilateral condylar hyperactivity. Sensitivity, specificity, and positive and negative predictive values were calculated separately for planar BS, SPECT, and SPECT/CT. Clinical/imaging follow-up and histopathology was considered the reference standard. RESULTS: Planar BS, SPECT, and SPECT-CT of 21 patients with suspected CH were retrospectively evaluated. Planar BS was positive in eight patients, of whom six had active CH as the final diagnosis. SPECT was positive in 14 patients, of whom 12 patients had CH. Out of 14 patients who were positive in SPECT, two patients were considered negative in SPECT-CT. The diagnostic accuracy was the lowest for planar BS (47.6%) and the highest for SPECT/CT (85.8%). SPECT/CT and SPECT had similar sensitivity (80%), whereas SPECT-CT had the highest specificity (100%). CONCLUSION: SPECT/CT is superior to planar BS and SPECT for the diagnosis of active CH. PMID- 27763954 TI - Can Residents Assess Other Providers' Infant Lumbar Puncture Skills?: Validity Evidence for a Global Rating Scale and Subcomponent Skills Checklist. AB - OBJECTIVES: The aims of this study were to provide validity evidence for infant lumbar puncture (ILP) checklist and global rating scale (GRS) instruments when used by residents to assess simulated ILP performances and to compare these metrics to previously obtained attending rater data. METHODS: In 2009, the International Network for Simulation-based Pediatric Innovation, Research, and Education (INSPIRE) developed checklist and GRS scoring instruments, which were previously validated among attending raters when used to assess simulated ILP performances. Video recordings of 60 subjects performing an LP on an infant simulator were collected; 20 performed by subjects in 3 categories (beginner, intermediate, and expert). Six blinded pediatric residents independently scored each performance (3 via the GRS, 3 via the checklist). Four of the 5 domains of validity evidence were collected: content, response process, internal structure (reliability and discriminant validity), and relations to other variables. RESULTS: Evidence for content and response process validity is presented. When used by residents, the checklist performed similarly to what was found for attending raters demonstrating good internal consistency (Cronbach alpha = 0.77) and moderate interrater agreement (intraclass correlation coefficient = 0.47). Residents successfully discerned beginners (P < 0.01, effect size = 2.1) but failed to discriminate between expert and intermediate subjects (P = 0.68, effect size = 0.34). Residents, however, gave significantly higher GRS scores than attending raters across all subject groups (P < 0.001). Moderate correlation was found between GRS and total checklist scores (P = 0.49, P < 0.01). CONCLUSIONS: This study provides validity evidence for the checklist instrument when used by pediatric residents to assess ILP performances. Compared with attending raters, residents appeared to over-score subjects on the GRS instrument. PMID- 27763951 TI - New Biomarkers for Diagnosing Inflammatory Bowel Disease and Assessing Treatment Outcomes. AB - Despite advances in our understanding of the pathophysiology underlying inflammatory bowel disease, there remains a significant need for biomarkers that can differentiate between Crohn's disease and ulcerative colitis with high sensitivity and specificity, in a cost-efficient manner. As the focus on personalized approaches to the delivery of medical treatment increases, new biomarkers are being developed to predict an individual's response to therapy and their overall disease course. In this review, we will outline many of the existing and recently developed biomarkers, detailing their role in the assessment of patients with inflammatory bowel disease. We will identify opportunities for improvement in our biomarkers, including better differentiation between the subtypes of inflammatory bowel disease. We will also discuss new targets and strategies in biomarker development, including combining modalities to create biomarker signatures to improve the ability to predict disease courses and response to therapy among individual patients. PMID- 27763955 TI - Effectiveness of a High-Fidelity Simulation-Based Training Program in Managing Cardiac Arrhythmias in Children: A Randomized Pilot Study. AB - OBJECTIVES: Pediatric cardiac arrest is a rare event. Its management requires technical (TSs) and nontechnical skills (NTSs). We assessed the effectiveness of a simulation-based training to improve these skills in managing life-threatening pediatric cardiac arrhythmias. METHODS: Four teams, each composed of 1 pediatric resident, 1 emergency medicine resident, and 2 pediatric nurses, were randomly assigned to the experimental group (EG) participating in 5 video-recorded simulation sessions with debriefing or to the control group (CG) assessed 2 times with video-recorded simulation sessions without debriefing at a 2-week interval. Questionnaires assessed self-reported changes in self-efficacy, stress, and satisfaction about skills. Blinded evaluators assessed changes in leaders' TSs and NTSs during the simulations and the time to initiate cardiopulmonary resuscitation. RESULTS: After training, stress decreased and satisfaction about skills increased in the EG, whereas it remained the same in the CG (P = 0.014 and P < 0.001, respectively). There was no significant change in self-efficacy. Analyses of video-recorded skills showed significant improvements in TSs and NTSs of the EG leaders after training, but not of the CG leaders (P = 0.026, P = 0.038, respectively). The comparison of the evolution of the 2 groups concerning time to initiate cardiopulmonary resuscitation was not significantly different between the first and last simulation sessions. CONCLUSIONS: A simulation-based training with debriefing had positive effects on stress and satisfaction about skills of pediatric residents and nurses and on observed TSs and NTSs of the leaders during simulation sessions. A future study should assess the effectiveness of this training in a larger sample and its impact on skills during actual emergencies. PMID- 27763956 TI - Concentration of D-dimers in Bile-a Novel Marker of Pancreatic Cancer Enhancing Accuracy of Standard CA19-9 Measurement: Dual Test Hypothesis. PMID- 27763957 TI - Limited Blood Transfusions Are Safe in Orthopaedic Trauma Patients. AB - OBJECTIVES: Controversy exists over association of blood transfusions with complications. The purpose was to assess effects of limited transfusions on complication rates and hospital course. SETTING: Level 1 trauma center. PATIENTS AND METHODS: Three hundred seventy-one consecutive patients with Injury Severity Score >=16 underwent fixation of fractures of spine (n = 111), pelvis (n = 72), acetabulum (n = 57), and/or femur (n = 179). Those receiving >3 units of packed red blood cell were excluded. MAIN OUTCOME MEASUREMENTS: Fracture type, associated injuries, treatment details, ventilation time, complications, and hospital stay were prospectively recorded. RESULTS: Ninety-eight patients with 107 fractures received limited transfusion, and 119 patients with 123 fractures were not transfused. The groups did not differ in age, fracture types, time to fixation, or associated injuries. Lowest hematocrit was lower in the transfused group (22.8 vs. 30.0, P < 0.0001). Surgical duration (3:23 vs. 2:28) and estimated blood loss (462 vs. 211 mL) were higher in transfused patients (all P < 0.003). Pulmonary complications occurred in 12% of transfused and 4% of nontransfused, (P = 0.10). Mean days of mechanical ventilation (2.51 vs. 0.45), intensive care unit days (4.5 vs. 1.5) and total hospital stay (8.8 vs. 5.7) were higher in transfused patients (all P <= 0.006). After multivariate analysis, limited transfusion was associated with increased hospital and intensive care unit stays and mechanical ventilation time, but not with complications. CONCLUSIONS: Patients receiving <=3 units of packed red blood cell had lower hematocrit and greater surgical burden, but no difference in complications versus the nontransfused group. Limited blood transfusions are likely safe, excepting a possible association with longer mechanical ventilation times and hospital stays. LEVEL OF EVIDENCE: Therapeutic level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27763958 TI - A Multicenter Randomized Control Trial Comparing a Novel Intramedullary Device (InterTAN) Versus Conventional Treatment (Sliding Hip Screw) of Geriatric Hip Fractures. AB - OBJECTIVES: To compare outcomes in elderly patients with intertrochanteric hip fractures treated with either the sliding hip screw (SHS) or InterTAN intramedullary device (IT). DESIGN: Prospective, randomized, multicenter clinical trial. SETTING: Five level 1 trauma centers. PATIENTS: Two hundred forty-nine patients 55 years of age or older with AO/OTA 31A1 (43) and OA/OTA 31A2 (206) fractures were prospectively enrolled and followed for 12 months. INTERVENTION: Computer generated randomization to either IT (n = 123) or SHS (n = 126). MAIN OUTCOME MEASUREMENTS: The Functional Independence Measure (FIM) and the Timed Up and Go test (TUG) were used to measure function and motor performance. Secondary outcome measures included femoral shortening, complications, and mortality. RESULTS: Demographics, comorbidities, preinjury FIM scores and TUG scores were similar between groups. Patients (17.2%) who received an IT had limb shortening greater than 2 cm compared with 42.9% who received an SHS (P < 0.001). To determine the importance of preinjury function and fracture stability, we analyzed the subgroup of patients with the ability to walk 150 m independently preinjury and an OA/OTA 31A-2 fracture (n = 70). In this subgroup, patients treated with SHS had greater shortening and demonstrated poorer FIM and TUG scores compared with patients treated with an IT. CONCLUSIONS: Overall, most patients with intertrochanteric femur fractures can expect similar functional results whether treated with an intramedullary or extramedullary device. However, active, functional patients have an improved outcome when the InterTAN is used to treat their unstable intertrochanteric fracture. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 27763960 TI - Does a Staged Posterior Approach Have a Negative Effect on OTA 43C Fracture Outcomes? AB - OBJECTIVE: To determine whether multiple approaches pose an increased risk to fracture healing when compared with a standard single approach in the treatment of pilon (OTA 43C) fractures. DESIGN: Retrospective review of a prospective database. SETTING: Level I academic trauma center and level II community trauma center. METHODS: From January 1, 2005 to December 31, 2011, all records of patients treated for OTA 43C fractures of the distal tibia were reviewed. Patients were grouped according to multiple (posterior-anterior) and single (anterior-alone) approaches. Medical charts and surgical documentation were reviewed and postoperative computed tomography (CT) scans were examined for residual articular displacement and quantified. Ultimate union rate was correlated with approach strategy. Articular reduction was subdivided into 3 groups (<1, 1-2, and >2 mm). RESULTS: A total of 116 patients were identified as having had 43C fractures treated surgically with postoperative CT scans completed. Twenty-six fractures presented as an open injury. Of these 116 patients, 35 underwent staged fixation of the posterior malleolar component at an average of 2 days postinjury, followed by delayed anterior fixation at an average of 14 days postinjury. The remaining 81 patients underwent anterior fixation alone, on average 17 days postinjury. Twenty-one patients were lost to follow-up before 12 months. Of the 95 patients with sufficient follow-up (>=12 months), there were 24 nonunions. There was a statistically significant association of nonunion with staged posterior approach (40% vs. 19%, P = 0.015). CT reduction for staged posterior versus anterior-alone approach was not significantly different for any of the 3 categories (63% vs. 57% <1 mm, 31% vs. 26% 1-2 mm, and 6% vs. 17% >2 mm). CONCLUSIONS: In this series, there was no statistically proven benefit to combined surgical approaches to tibial pilon fractures with regard to the quality of articular reduction. It appears from this investigation that there may be a significantly higher risk of nonunion associated with the addition of the staged posterior approach. Although articular reduction is of paramount importance, multiple approaches for direct reduction and fixation of all fragments may lead to further complications. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27763959 TI - Mortality Following Surgical Management of Vancouver B Periprosthetic Fractures. AB - OBJECTIVES: The goals of this study are to evaluate mortality after Vancouver B periprosthetic fractures and determine predictors of mortality; compare mortality among patients with loose femoral stems treated with revision arthroplasty versus fixation alone; compare mortality among patients with radiographically "indeterminate" fractures treated with revision or fixation; and evaluate the rate of return to surgery for patients who underwent revision compared with fixation. DESIGN: Retrospective study. SETTING: Three academic level 1 trauma centers. PATIENTS/PARTICIPANTS: Two hundred three patients treated for Vancouver B periprosthetic fractures. INTERVENTION: N/A. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was mortality. The secondary outcome measure was reoperation because of infection, failure of fixation, dislocation, or other mechanical failure. RESULTS: Overall 1-year survival was 87% and 5-year survival was 54%. Among patients with loose femoral stems, there was no significant difference with regard to survival between patients treated with fracture fixation or revision arthroplasty (1-year survival 83% vs. 85%, 5-year survival 41% vs. 58%). Among patients whose radiographs were classified as indeterminate, there was no significant difference between patients treated with fracture fixation alone or revision arthroplasty. There was no significant difference between total reoperation rates between the two groups (11% vs. 16%). CONCLUSION: This study suggests that there is no discernible survival benefit to treating patients with periprosthetic fractures with either revision arthroplasty or fixation alone. Therefore, from a mortality perspective, when faced with Vancouver B periprosthetic fractures, the orthopaedic surgeon should feel comfortable performing the type of intervention he/she is most proficient to perform. LEVEL OF EVIDENCE: Prognostic level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27763961 TI - No Incidence of Postoperative Knee Sepsis With Suprapatellar Nailing of Open Tibia Fractures. AB - OBJECTIVE: To evaluate the incidence of knee sepsis after suprapatellar (SP) nailing of open tibia fractures. DESIGN: Retrospective; Setting: ACS level 1 trauma center. PATIENTS/PARTICIPANTS: We reviewed 139 open tibia fractures that underwent SP nailing as definitive treatment over a 5-year period (January 1, 2011 to January 1, 2016). Most patients (90%, n = 126) underwent intramedullary nailing at the time of their initial surgery. We defined knee sepsis as intra articular infection requiring operative debridement, either open or arthroscopically, within 1 month's time. INTERVENTION: Open tibia fractures treated with an SP tibial nail. MAIN OUTCOME MEASUREMENTS: Demographic data, fracture characteristics, Gustilo and Anderson classification of open fractures, and occurrence of knee sepsis. RESULTS: In 139 open tibia fractures, there were no cases of knee sepsis in the 30 days after treatment with an SP intramedullary nail. Eighty-seven percent of our cohort had Gustilo and Anderson type II (41%) or type III (46%) open fractures. Most open fractures (83%) underwent primary wound closure during the index procedures. Twenty-five limbs (18%) had evidence of infection at the open fracture site of their open fracture necessitating operative intervention and/or antibiotics: none, however, developed knee sepsis. CONCLUSIONS: Although the SP approach carries intra-articular risks, we found a low risk of knee sepsis using this technique in the treatment of open tibia fractures. Our data suggest that there is no greater risk of intra-articular infection using an SP portal as compared with an infrapatellar one. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27763962 TI - The Role of Radiographs and Office Visits in the Follow-Up of Healed Intertrochanteric Hip Fractures: An Economic Analysis. AB - OBJECTIVES: The purpose of this study was to evaluate the role and the necessity of radiographs and office visits obtained during follow-up of intertrochanteric hip injuries. DESIGN: Retrospective study. SETTING: Two level I trauma centers. PATIENTS: Four hundred sixty-five elderly patients who were surgically treated for an intertrochanteric fracture of the femur at 2 level I trauma centers between January 2009 and August 2014 were retrospectively identified from orthopaedic trauma databases. INTERVENTION: Analysis of all healed intertrochanteric hip fractures, including demographic characteristics, quality of reduction, time of healing, number of office visits, number of radiographs obtained, and each radiograph for fracture alignment, implant position or any pathological changes. RESULTS: The surgical fixation of 465 fractures included 155 short nails (33%), 232 long nails (50%), 69 sliding hip screw devices (15%), 7 trochanteric stabilizing plates (1.5%), and 2 proximal femur locking plates (0.5%). The average fracture healing time was 12.8 weeks and the average follow up was 81.2 weeks. Radiographs of any patient obtained after the fracture had healed did not reveal any changes, including fracture alignment or implant position and hardware failure. In 9 patients, pathological changes, including arthritis (3), avascular necrosis (3), and ectopic ossification (3) were noted. The average number of elective office visits and radiographs obtained after the fracture had healed were 2.8 (range: 1-8) and 2.6 (range: 1-8), respectively. According to Medicare payments to the institution, these radiographs and office visits account for a direct cost of $360.81 and $192, respectively, per patient. CONCLUSION: The current study strongly suggests that there is a negligible role for radiographs and office visits during the follow-up of a well-healed hip fracture when there is documented evidence of radiographic and clinical healing with acceptable fracture alignment and implant position. Implementation of this simple measure will help in reducing the cost of care and inconvenience to elderly patients. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27763964 TI - Can EEG Differentiate Among Syndromes in Genetic Generalized Epilepsy? AB - PURPOSE: To evaluate EEG differences among syndromes in genetic generalized epilepsy based on quantified data. METHODS: Twenty-four-hour ambulatory EEGs were recorded in consecutive patients diagnosed with genetic generalized epilepsy. All epileptiform EEG abnormalities were quantified into density scores (total duration of epileptiform discharges per hour). One-way analysis of variance was conducted to find out differences in EEG density scores among the syndromes. Generalized linear mixed models were also fitted to explore the association between the proportion of "pure" generalized spike-wave paroxysms and fragments (without intervening polyspikes/polyspike-waves) and the syndromes. RESULTS: In total, 6,923 epileptiform discharges were analyzed from 105 abnormal EEGs. In the analysis of variance, six EEG variables were significantly different among syndromes: total spike density (P = 0.001), total polyspike and polyspike-wave density (P = 0.049), generalized spike-wave-only density (P < 0.001), generalized paroxysm density (P < 0.001), generalized paroxysm duration mean (P = 0.018), and generalized paroxysm duration maximum (P = 0.009). The density of epileptiform discharges and the paroxysm durations were the highest in juvenile absence epilepsy followed by juvenile myoclonic epilepsy, childhood absence epilepsy, and generalized epilepsy with tonic-clonic seizures only. Generalized linear mixed models revealed that "pure" generalized spike-wave discharges (without intervening polyspikes/polyspike waves) tended to be more frequent in absence epilepsies, although the difference was not statistically significant (P = 0.21). CONCLUSIONS: The findings of this study suggest that the density and duration of epileptiform discharges can help differentiate among genetic generalized epilepsy syndromes. PMID- 27763965 TI - Evaluation of Cognitive Function When Hearing One's Own Name in Patients With Brain Injuries in Early Developmental Stages. AB - PURPOSE: The level of residual cognitive function in patients with early brain injury is a key factor limiting rehabilitation and the quality of life. Although understanding residual function is necessary for appropriate rehabilitation, the extent of its effects on cognitive improvement remains unknown. This study evaluated cognitive function in patients with severe motor and intellectual disabilities after early brain injuries due to cerebral hemorrhage or periventricular leukomalacia. We focused on neural responses to hearing the subject's own name (SON). According to previous studies, differences in response to SON are associated with several types of cognitive dysfunction. METHODS: We examined healthy subjects (aged 21.4 +/- 1.10 years; control) and patients with a previous brain injury (aged 13-27 years at the time of our analysis) resulting in periventricular leukomalacia or a cerebral hemorrhage during the perinatal period or childhood. We recorded EEG responses to the SON and to other Japanese words, obtaining EEG-evoked potentials with wavelet transformations. RESULTS: Compared with healthy controls, beta power (not alpha power) revealed differences in response to SON by patients with brain injury, especially those with cerebral hemorrhage. CONCLUSIONS: We suggest that alpha and beta power differences reflect different cognitive functions and that the SON response reveals more than one process. Beta powers may reflect the intellectual disability of cognitive function in response to self-relevant stimuli, especially in patients with cerebral hemorrhage. Meanwhile, alpha powers did not differ from those of the healthy controls, suggesting that the patients perhaps paid attention to their own names. PMID- 27763967 TI - Functional MRI Correlates of Resting-State Temporal Theta and Delta EEG Rhythms. AB - PURPOSE: The EEG rhythms demonstrate changes in frequency and power with spontaneous changes in behavioral state that do not have well-understood metabolic correlates within the brain. To investigate this question and compare the temporal lobe theta and delta rhythms, resting-state functional MRI was obtained with simultaneous EEG. METHODS: Simultaneous EEG-functional MRI was recorded from 14 healthy sleep-deprived subjects in awake and drowsy states. Scalp electrodes corresponding to bilateral temporal lobes were used to calculate delta and theta band power. The resulting time series was used as input in a general linear model, and the final power curves were convolved with the standard hemodynamic response function. Resulting images were thresholded at Z > 2.0. RESULTS: Positive and negative correlations for unilateral theta and delta rhythms were present bilaterally in different structures and with differing correlation signs. Theta rhythm positive correlation was present in hindbrain, peri-opercular, and frontoparietal regions and subcortical gray structures, whereas negative correlation was present in parietooccipital cortex. Delta rhythm positive correlation was present in parietooccipital cortex, and negative correlation roughly resembled positive correlations for the theta rhythm. CONCLUSIONS: Temporal lobe theta and delta rhythms are correlated with functional MRI signal in an almost mutually exclusive distribution. The different distributions indicate different corresponding networks. These normal findings supplement the understanding of theta and delta rhythm significance. PMID- 27763968 TI - Effects of Marijuana on Ictal and Interictal EEG Activities in Idiopathic Generalized Epilepsy. AB - Marijuana-based treatment for refractory epilepsy shows promise in surveys, case series, and clinical trials. However, literature on their EEG effects is sparse. Our objective is to analyze the effect of marijuana on EEG in a 24-year-old patient with idiopathic generalized epilepsy treated with cannabis. We blindly reviewed 3 long-term EEGs-a 24-hour study while only on antiepileptic drugs, a 72 hour EEG with Cannabis indica smoked on days 1 and 3 in addition to antiepileptic drugs, and a 48-hour EEG with combination C indica/sativa smoked on day 1 plus antiepileptic drugs. Generalized spike-wave discharges and diffuse paroxysmal fast activity were categorized as interictal and ictal, based on duration of less than 10 seconds or greater, respectively. Data from three studies concatenated into contiguous time series, with usage of marijuana modeled as time-dependent discrete variable while interictal and ictal events constituted dependent variables. Analysis of variance as initial test for significance followed by time series analysis using Generalized Autoregressive Conditional Heteroscedasticity model was performed. Statistical significance for lower interictal events (analysis of variance P = 0.001) was seen during C indica use, but not for C indica/sativa mixture (P = 0.629) or ictal events (P = 0.087). However, time series analysis revealed a significant inverse correlation between marijuana use, with interictal (P < 0.0004) and ictal (P = 0.002) event rates. Using a novel approach to EEG data, we demonstrate a decrease in interictal and ictal electrographic events during marijuana use. Larger samples of patients and EEG, with standardized cannabinoid formulation and dosing, are needed to validate our findings. PMID- 27763969 TI - Orbital Expansion for Congenital Anophthalmia May Be Achievable in Infancy But Not in Childhood. AB - BACKGROUND: Congenital anophthalmia is a rare anomaly that results in micro orbitism and craniofacial microsomia. Treatment with static conformers is labor intensive and provides minimal stimulation for orbital growth that requires eventual reconstruction with orbital osteotomies after skeletal maturity. METHODS: A protocol for the treatment of congenital anophthalmia is presented. Patients underwent a preoperative low-dose radiation computed tomography (CT) scan of the facial bones to assess orbital volume. An intraorbital expander was placed and was filled on a monthly basis. Quantitative changes in the affected and unaffected orbits were assessed by a repeat CT scan obtained 1 year postoperatively. RESULTS: Two patients with left unilateral congenital anophthalmia were prospectively followed. In a 4-month-old, the affected orbital width and height increased by 171.6% and 116.7% respectively compared with the unaffected orbit. In a 4-year-old, the affected orbital width increased by 36.1% but the height decreased by 35.3% compared with the unaffected orbit. At 18 months follow-up, no complications, ruptures, infections, or extrusions have been observed. CONCLUSIONS: Our results support that accelerated expansion can be achieved in a 4-month-old orbit reversing the effects of anophthalmia. However, in a 4-year-old, minimal growth was observed. The lack of accelerated growth in this study may be explained by synostosis of the orbital sutures. As such, expansion should be initiated at the earliest age possible. Further longitudinal study is ongoing to determine if sustained catch-up growth will obviate or reduce the complexity of a secondary correction. PMID- 27763970 TI - Evaluation of the Biocompatibility of New Fiber-Reinforced Composite Materials for Craniofacial Bone Reconstruction. AB - This study aims to assess the biocompatibility of new advanced fiber-reinforced composites (FRC) to be used for custom-made cranial implants. Four new formulations of FRC were obtained using polymeric matrices (combinations of monomers bisphenol A glycidylmethacrylate [bis-GMA], urethane dimethacrylate [UDMA], triethylene glycol dimethacrylate [TEGDMA], hydroxyethyl methacrylate [HEMA]) and E-glass fibers (300 g/mp). Every FRC contains 65% E-glass and 35% polymeric matrix. Composition of polymeric matrices are: bis-GMA (21%), TEGDMA (14%) for FRC1; bis-GMA (21%), HEMA (14%) for FRC2; bis-GMA (3.5%), UDMA (21%), TEGDMA (10.5%) for FRC3, and bis-GMA (3.5%), UDMA (21%), HEMA (10.5%) for FRC4. Cytotoxicity test was performed on both human dental pulp stem cells and dermal fibroblasts. Viability was assessed by tetrazolium dye colorimetric assay. Subcutaneous implantation test was carried out on 40 male Wistar rats, randomly divided into 4 groups, according to the FRC tested. Each group received subcutaneous dorsal implants. After 30 days, intensity of the inflammatory reaction, tissue repair status, and presence of the capsule were the main criteria assessed. Both cell populations showed no signs of cytotoxicity following the FRC exposures. In terms of cytotoxicity, the best results were obtained by FRC3 followed by FRC2, FRC4, and FRC1. FRC3 showed also the mildest inflammatory reaction and this correlated both with the noncytotoxic behavior and the presence of a well-organized capsule. The composite biomaterials developed may constitute an optimized alternative of the similar materials used for the reconstruction of craniofacial bone defects. According to authors' studies, the authors conclude that FRC3 is the best formulation regarding the biological behavior. PMID- 27763971 TI - Noses of the Middle East: Variety of Phenotypes and Surgical Approaches. AB - BACKGROUND: The Middle East (ME) proper, a vast area between the East coast of the Mediterranean Sea and Afghanistan, is populated by many nations and tribes. Several nose phenotypes are prevalent throughout the region, but there is no published study encompassing and exploring nose phenotypes encountered in the various countries and subregions of the ME. METHODS: The current study was based on the analysis of compiled data from 1207 patients of ME origin (53% of my total rhinoplasty patient cohort) operated by the author during the years 1985 to 2015. Among them 1046 (86.5%) underwent primary rhinoplasty and 161 (13.5%) were previously operated elsewhere, almost all in the ME. RESULTS: The following nose subtypes were defined according to the data gathered during the duration of this study in the computerized medical charts and photo archives: Egyptian, Levantine, Turkish (Anatolian), oriental Turkish (Goturks of Central Asian origin), Iraqi, Kurdish, and Persian. From 1985 to 1994, 30% of my patients were of ME origin, from 2001 to 2013 60% and since 2014 65%. Prevalence of various ethnic origins among the patients seeking for rhinoplasty in Sweden was studied. Most frequently represented ethnic groups were quoted in the order of largest prevalence: Assyrians, Iraqis, Kurds, and Iranians. Technical peculiarities concerning surgery on the various ethnic groups were described. CONCLUSION: Noses of Middle Eastern populations exhibit some similarities, but also broad phenotypic variation. Consequently, there is no single typical Middle Eastern nose, although large size, prominent arched dorsum, and a naso-labial angle <=90 degrees are common. PMID- 27763972 TI - Dermal Matrix for Intraoral Lining Following Composite Mandibular Defect Reconstruction With Chimeric Fibular Osseocutaneous Flap. AB - BACKGROUND: This report aims to first present Integra as an adjunct to complex mandibular reconstruction for intraoral lining resurfacing, and to review the literature on the use of dermal matrices for mucosal resurfacing of the floor of the mouth. CLINICAL REPORT: A 62-year-old female patient with previous ablation surgery for squamous cell carcinoma of the floor of the mouth, presented with extrusion of the mandibular plate through the chin skin and serious tongue tethering. The patient was managed with a chimeric osseocutaneous free fibula flap to restore the mandibular bone and chin skin defect, followed by a second stage reconstruction of the intraoral defect with bilayer Integra. Complete release of tongue tethering was achieved enabling normal speech and deglutition and allowing for dental rehabilitation. CONCLUSIONS: Integra was safely used as an alternative for intraoral lining, in composite mandibular reconstruction, downgrading reconstructive demands and offering optimal functional results. PMID- 27763973 TI - Barriers to Cleft Lip and Palate Repair Around the World. AB - BACKGROUND: Cleft lip and/or palate (CLP) is estimated to occur in 1 out of every 700 births, but for many people residing in low- and middle-income countries this deformity may be repaired late in life or not at all. This study aims to analyze worldwide provider-perceived barriers to the surgical repair of CLP in low- and middle-income countries. METHODS: From 2011 to 2014, Smile Train distributed a multiple-choice, voluntary survey to healthcare providers to identify areas of need in CLP care worldwide. Data on provider-reported barriers to care were aggregated by year, country, and larger world regions. RESULTS: A total of 1997 surveys were completed by surgeons and healthcare providers (60.7% response rate). The most commonly reported barriers were "patient travel costs" (60.7%), "lack of patient awareness" (54.1%), and "lack of financial support" (52.8%). "Patient travel costs" was the most commonly reported barrier in sub-Saharan Africa, the Middle East and North Africa, and South and Southeast Asia. "Lack of financial support" was the most commonly reported barrier in the Americas, Eastern Europe, and East Asia. CONCLUSIONS: This is the largest intercontinental study on healthcare provider-identified barriers to care, representing the limitations experienced by healthcare professionals in providing corrective surgery for CLP around the world. Financial risk protection from hidden costs, such as patient travel costs, is essential. Community health workers and nurses are critical for communication and linking CLP care to the rest of the community. Recognition of these barriers can inform future policy decisions, targeted by region, for surgical systems delivering care for patients with CLP worldwide. PMID- 27763974 TI - Superiorly Based Pharyngeal Flap for the Surgical Treatment of Velopharyngeal Insufficiency and Speech Outcomes. AB - A retrospective chart review comparing pre and postoperative speech in 19 patients who underwent pharyngeal flap surgery for the diagnosis of velopharyngeal insufficiency. Eighteen of the patients had a history of cleft palate. Patients were assigned a speech grade between 1 and 5 based on the objective and subjective quality of their speech. Comparison of pre and postoperative speech showed significant improvement in speech quality from a mean grade of 3.37 to 2.00 (P < 0.001). This study demonstrates that a wide, superiorly based pharyngeal flap did lead to significant improvement in speech outcomes in this group of patients independent of gender or age. PMID- 27763975 TI - Effect of Platelet-Rich Fibrin on Peripheral Nerve Regeneration. AB - PURPOSE: This study aimed to evaluate the effect of platelet-rich fibrin (PRF) on peripheral nerve regeneration on the sciatic nerve of rats by using functional, histopathologic, and electrophysiologic analyses. MATERIALS AND METHODS: Thirty female Wistar rats were divided randomly into 3 experimental groups. In group 1 (G1), which was the control group, the sciatic nerve was transected and sutured (n = 10). In group 2 (G2), the sciatic nerve was transected, sutured, and then covered with PRF as a membrane (n = 10). In group 3 (G3), the sciatic nerve was transected, sutured by leaving a 5-mm gap, and then covered by PRF as a nerve guide (n = 10). Functional, histopathologic, and electrophysiologic analyses were performed. RESULTS: The total histopathologic semiquantitative score was significantly higher in G1 compared to G2 and G3 (P < 0.05). Myelin thickness and capillaries were significantly lower in G3 compared to G1 (P < 0.05). There was no statistically significant difference between the groups with regard to the functional and electrophysiologic results. CONCLUSION: The study results suggest that PRF decreases functional recovery in sciatic nerve injury. Further studies are required to determine the efficacy of PRF on peripheral nerve regeneration. PMID- 27763976 TI - Transseptal Subperichondrial Endoscopic Hypophysectomy With Preservation of Vital Nasal Structures. AB - INTRODUCTION: Pituitary surgery involving different techniques is often applied to the excision of benign adenomas. Operative interventions involved various approaches and techniques. Endoscopic transsphenoidal approach is the less traumatic route to the sella turcica, avoiding brain retraction, and also permitting good visualization, with lower rates of morbidity and mortality. Although mortality of pituitary surgery decreased by advances in surgical techniques morbidities such as synechiae formation, anosmia, bleeding, nasal septal perforations, drying, and incrustation due to traumatization of the nasal structures such as septum, nasal mucosa, and middle concha are the current problems in pituitary surgery. Here, the authors described an endoscopic transseptal subpericondrial hypophysectomy with minimal damage to normal anatomy and physiology and discussed advantages of this technique. METHODS: The authors performed endoscopic transseptal subpericondrial hypophysectomy to 2 patients and evaluated intraoperative and postoperative results. RESULTS: No complication was noted during surgery or postoperative period with endoscopic transseptal subpericondrial hypophysectomy technique. CONCLUSIONS: Endoscopic transseptal subpericondrial hypophysectomy is a safe technique and, requires only a short surgery time and does not require the removal of any physiological tissue or cause any bleeding. PMID- 27763977 TI - The Origins of Deltopectoral Flaps and the Pectoralis Major Myocutaneous Flap. AB - The aim of this paper was to review the origins and history of deltopectoral flaps and the pectoralis major myocutaneous flap.The first published paper on the deltopectoral flap was written by Aymard in 1917. He described raising a medially based fasciocutaneous flap from the shoulder skin, which was then tubed and used for staged nasal reconstruction. Conley introduced the laterally based deltopectoral flap, which was supplied by the lateral thoracic and thoracocranial branches. Bakamjian used a medially based deltopectoral flap for pharyngoesophageal reconstruction; this was an axial flap based medially on the intercostal perforating vessels of the internal mammary artery. Krizek reviewed the literature and stated that Aymard flap was the keystone to the conception and execution of Bakamjian flap. Hueston was the first to combine a skin flap and pectoralis major muscle for repair of the large defects of the chest wall. The pectoralis major myocutaneous flaps described by Ariyan and Baek are a hybrid of Conley's laterally based deltopectoral flap and Hueston's inclusion of the pectoralis major muscle in the skin flap.When the authors develop what appears to be a new surgical technique, the authors are prone to be excited. However, at such a moment the authors must perform a literature review. In most patients, the authors will realize that the previous authors have already developed a given concept. The authors must not commit plagiarism due to their ignorance or laziness in conducting a literature review. PMID- 27763978 TI - Evaluation of the Transverse Craniofacial Morphology of Adolescents With Repaired Unilateral Cleft Lip and Palate Using Cone-Beam Computed Tomography. AB - AIM: The aim of the study was to evaluate the transverse craniofacial morphology of the adolescent patients affected by unilateral cleft lip and palate (UCLP) and to compare the findings with age- and sex-matched control group without any cleft using their cone-beam computed tomography (CBCT) images. METHODS: The study sample (n = 56 patients; mean age: 14.35 +/- 3.06 years) consisted of 26 UCLP (n = 26 patients; 10 women and 16 men; mean age: 13.70 +/- 2.94 years) and 30 control (n = 30 patients; 19 women and 11 men; mean age: 14.90 +/- 3.10 years) subjects. Twenty-five conventional skeletal and dental tissue landmarks were identified. Twenty widely used frontal cephalometric variables (14 linear distances, 3 angles, and 3 ratios) were measured. The data were analyzed using the independent t-test between the groups. RESULTS: Patients affected by UCLP had statistically significantly smaller interorbital width (89.83 +/- 4.16 mm), maxillary width (58.02 +/- 5.77 mm), maxillary intermolar width (52.83 +/- 4.83 mm), and upper face height (57.64 +/- 4.57 mm) (P < 0.05) compared with the control group. Conversely, ANS-isf distance was significantly greater in the UCLP group (29.62 +/- 5.19 mm) than in the control group (26.74 +/- 3.99 mm) (P = 0.023). Moreover, alveolar cleft width had significant effect on Cr-ANS (r = 0.446, P = 0.022) and the ANS-isf (r = 0.459, P = 0.018) measurements. CONCLUSION: The UCLP group showed statistically significantly smaller values for interorbital width, maxillary width, maxillary intermolar width, and upper face height than the noncleft controls. PMID- 27763979 TI - Is More Cortical Bone Decortication Effective on Guided Bone Augmentation? AB - This study aims to evaluate the possible effect of more cortical bone decortication (CBD) on guided bone augmentation. A total of 16 New Zealand rabbits and 32 titanium domes were used. No cortical bone decortication was applied to the control group and in the study groups, the cortical bones were decorticated with a round burr (Group A: 1 hole with bleeding, Group B: 5 holes with bleeding, Group C: a thin layer of compact bone was completely removed with no bleeding). Then 2 titanium domes were placed on the calvarium of each rabbit with hydroxyapatite/beta-tricalcium phosphate. After 3 months, the animals were sacrificed and specimens were sent for histological and histomorphometric analysis. Histological and histomorphometric analysis showed that bone decortication with burr significantly increased new bone regeneration in all the experimental groups compared with the control group (P <0.05). No statistically significant difference was determined between the study groups. In conclusion, CBD, which has no negative impact on surgery, has a positive effect on guided bone augmentation. However, a greater amount of CBD does not have a greater effect. PMID- 27763981 TI - A Different Approach for Usage of the Implant Materials: The Composite Graft Prefabrication. AB - With all implanted materials, a certain sequence of biological events occurs following the implantation. This process is destructive to the implant and peri implant tissues. The aforementioned sequence of biological events may be responsible for the complications. In this study, the natural biologic process following implantation was completed in an area other than the final implantation area. The aim was to keep the peri-implant tissues in the final implantation area away from the process. In the control group, the porous polyethylene discs were implanted to subcutaneous area on the frontal bone of the rats. A month after the implantation, macroscopic and microscopic examinations were performed. In the study group, the discs were implanted primarily above the rectus abdominis muscle of the rats. It was named as "the composite graft prefabrication." Twenty-one days after the first implantation, the discs were removed from the rectus muscle and implanted to subcutaneous area on the frontal bone of the rats. A month after the final implantation, macroscopic and microscopic examinations were performed. In macroscopic examination, all possible complications were evaluated. In microscopic examination, apoptosis, fibrosis, inflammation, and fibrovascular in growing were evaluated. In the control group, implant exposure was observed in 3 of the rats. In the study group, no complications were observed. Although there was no statistical difference between 2 groups in the microscopic findings, at first glance, the inflammation seemed to be the factor responsible for the complication in the control group. According to the macroscopic results, the composite graft prefabrication seemed to be effective in preventing complications. PMID- 27763980 TI - Three-Dimensional Anthropometric Database of Attractive Caucasian Women: Standards and Comparisons. AB - The aim of this paper is to develop a database to determine a new biomorphometric standard of attractiveness. Sampling was carried out using noninvasive three dimensional relief methods to measure the soft tissues of the face. These anthropometric measurements were analyzed to verify the existence of any canons with respect to shape, size, and measurement proportions which proved to be significant with regard to the aesthetics of the face. Finally, the anthropometric parameters obtained were compared with findings described in the international literature.The study sample was made up competitors in the Miss Italy 2010 and 2009 beauty contest. The three-dimensional (3D) scanning of soft tissue surfaces allowed 3D digital models of the faces and the spatial 3D coordinates of 25 anthropometric landmarks to be obtained and used to calculate linear and angular measurements. A paired Student t test for the analysis of the means allowed 3 key questions in the study of biomorphometric parameters of the face to be addressed through comparison with the data available in the literature.The question of statistical evidence for the samples analyzed being members of the populations samples reported in literature was also addressed.The critical analysis of the data helped to identify the anthropometric measurements of the upper, middle, and lower thirds of the face, variations in which have a major influence on the attractiveness of the face. These changes involve facial width, height, and depth. Changes in measurements of length, angles, and proportions found in the sample considered were also analyzed. PMID- 27763983 TI - Plasma Fibrinogen in Patients With Bell Palsy. AB - OBJECTIVE: To determine the plasma fibrinogen level in patients with Bell palsy and explore the significances of it in Bell palsy. METHODS: One hundred five consecutive patients with facial paralysis were divided into 3 groups: group I (Bell palsy), group II (temporal bone fractures), and group III (facial nerve schwannoma). In addition, 22 volunteers were defined as control group. Two milliliters fasting venous blood from elbow was collected, and was evaluated by CA-7000 Full-Automatic Coagulation Analyzer. RESULTS: The plasma fibrinogen concentration was significantly higher in the group of patients with Bell palsy (HB IV-VI) than that in the control group (P <0.05). There was no significant difference between group II and control group (P >0.05); similarly, there was also no marked difference between group III and control group (P >0.05). In group I, the plasma fibrinogen levels became higher with the HB grading increase. The plasma fibrinogen level of HB-VI was highest. CONCLUSIONS: Plasma fibrinogen has an important clinical meaning in Bell palsy, which should be used as routine examination items. Defibrinogen in treatment for patients with high plasma fibrinogen content also should be suggested. PMID- 27763984 TI - Relation of Lower Last Molar Teeth With Mandibular Fractures. AB - OBJECTIVES: The objectives of this study were to study and investigate the relation between the state of the lower last molar teeth eruption and the site of the mandibular fractures. METHODS: Adult patients with traumatic mandibular fractures were included in this study. Panorama and computed tomography was performed for all patients. The relation between the state of the lower last molar eruption and criteria of the fracture was analyzed. RESULTS: In 106 patients who had 168 mandibular fractures, impacted lower third molar teeth were found to significantly increase the incidence of mandibular angle fracture while they had nonsignificant effect on incidence of other sites of mandibular fractures. CONCLUSION: Impacted lower third molar teeth significantly increase the incidence of mandibular angle fracture but did not have the same effect on other sites of mandibular fractures. PMID- 27763985 TI - Early-Life Experiences and Telomere Length in Adult Rhesus Monkeys: An Exploratory Study. AB - OBJECTIVE: Child-rearing environments have been associated with morbidity in adult rhesus monkeys. We examine whether such links are also seen with leukocyte telomere length. METHODS: To determine telomere length in leukocytes, blood was collected from 11 adult female monkeys aged 7 to 10 years who had been exposed to different rearing environments between birth and 7 months. Four had been reared with their mothers in typical social groups composed of other female monkeys, their offspring, and 1 to 2 adult male monkeys. The other 7 had been reared in either small groups of peers or individual cages with extensive peer interaction daily. After 7 months, all shared a common environment. RESULTS: Telomere lengths were longer for those adults who had been reared with their mothers in social groups (median = 16.0 kb, interquartile range = 16.5-15.4) than for those who were reared without their mothers (median = 14.0 kb, interquartile range = 14.3 12.7; 2.2 kb/telomere difference, p < .027). CONCLUSIONS: This observation adds to emerging knowledge about early adverse child-rearing conditions and their potential for influencing later morbidity. Because newborns were randomly assigned to the mother or other rearing conditions, the findings are not confounded by other conditions that co-occur with adverse child-rearing environments in humans (e.g., prenatal stress, nutrition and health as well as postnatal nutrition and negative life experiences over and above rearing conditions). PMID- 27763986 TI - Prenatal Major Depressive Disorder, Placenta Glucocorticoid and Serotonergic Signaling, and Infant Cortisol Response. AB - OBJECTIVES: Extending prior studies of prenatal adversity and depressive symptoms, we tested associations between maternal prenatal major depressive disorder (MDD) and infant cortisol regulation. Based on prior findings by our group, we also tested placenta glucocorticoid (HSD11B2 methylation) and serotonin (SLC6A4 gene expression) signaling as moderators of links between prenatal MDD and infant cortisol. METHODS: Participants were 153 mother-infant pairs from a low-income, diverse sample (M [SD] age = 26 [6] years). Repeated structured diagnostic interviews were used to identify mothers with (a) prenatal MDD, (b) preconception-only MDD, and (c) controls. Placenta samples were assayed for HSD11B2 methylation and SLC6A4 gene expression. Infant salivary cortisol response to a neurobehavioral examination was assessed at 1 month. RESULTS: Daughters of prenatal MDD mothers had 51% higher baseline (ratio = 1.51; 95% confidence interval [CI] = 1.01-2.27; p = .045) and 64% higher stress responsive cortisol (ratio = 1.64; 95% CI = 1.05-2.56; p = .03) than daughters of controls and 75% higher stress-responsive cortisol (ratio = 1.75; 95% CI = 1.04-2.94; p = .04) than daughters of preconception-only MDD mothers. HSD11B2 methylation moderated links between prenatal MDD and baseline cortisol (p = .02), with 1% methylation decreases associated with 9% increased baseline cortisol in infants of prenatal MDD mothers (ratio = 1.09; 95% CI = 1.01-1.16). SLC6A4 expression moderated links between prenatal MDD and cortisol response among boys alone (p = .007), with 10 fold increases in expression associated with threefold increases in stress responsive cortisol (ratio = 2.87; 95% CI = 1.39-5.93) in sons of control mothers. CONCLUSIONS: Results highlight specificity of associations between prenatal versus preconception MDD and cortisol regulation and the importance and complexity of placenta glucocorticoid and serotonergic pathways underlying the intergenerational transmission of risk from maternal adversity. PMID- 27763987 TI - Insomnia and the Risk of Breast Cancer: The HUNT Study. AB - OBJECTIVE: The association of insomnia with subsequent breast cancer risk is largely unknown. Therefore, we assessed whether different symptoms of insomnia and their combination are associated with incident breast cancer in a large population-based study. METHODS: In a prospective cohort study, 33,332 women were followed to monitor the occurrence of their first invasive breast cancer identified by the Cancer Registry of Norway. Insomnia symptoms including () nonrestorative sleep and () difficulty initiating and () maintaining sleep were self-reported using a study specific measure reflecting the current Diagnostic and Statistical Manual of Mental Disorders criteria. Hazard ratios and 95% confidence intervals were calculated using multiadjusted Cox proportional hazards models. RESULTS: A total of 862 incident breast cancer cases occurred during a mean follow-up of 14.7 years. No consistent association was observed between the individual insomnia symptoms and breast cancer risk. However, compared to women reporting no insomnia complaints, those who reported having all three aspects of insomnia simultaneously were at increased risk (hazard ratio, 2.38; 95% confidence interval = 1.11-5.09). CONCLUSION: Our results suggest that having only some aspects of insomnia may not predispose someone to breast cancer. In contrast, experiencing all insomnia symptoms simultaneously might confer considerable excess risk. PMID- 27763988 TI - Child Abuse and Neglect and Subclinical Cardiovascular Disease Among Midlife Women. AB - OBJECTIVE: A childhood history of abuse or neglect may be associated with elevated adult cardiovascular disease (CVD) risk. No studies have examined associations between child abuse/neglect and subclinical CVD using a validated measure of abuse and neglect. We hypothesized that midlife women with a history of childhood abuse or neglect would have increased subclinical CVD beyond standard CVD risk factors. We tested moderation of associations by sleep, hot flashes, and race/ethnicity. METHODS: Two hundred ninety-five midlife women completed the Child Trauma Questionnaire, physiologic hot flash and actigraphic sleep monitoring, blood draw, and carotid ultrasound (intima media thickness [IMT]; plaque). Relations between abuse/neglect and outcomes were tested in linear regression models adjusting for demographic, psychosocial, and CVD risk factors. Interactions with sleep, hot flashes, and race/ethnicity were tested. RESULTS: Forty-five percent of women reported a history of child abuse or neglect. Women with any child abuse or neglect had higher IMT [b(SE) = .039 (.011), p = .001] and carotid plaque [odds ratio (95% [CI] = 1.95 [1.15-3.33]); p = .014] than nonabused/neglected women. Furthermore, physical abuse, emotional abuse, and emotional neglect were associated with higher subclinical CVD. Sexual abuse was associated with higher IMT among nonwhite women. Interactions with sleep time and sleep hot flashes (p values < .05) indicated that higher subclinical CVD with an abuse/neglect history was observed primarily among women sleeping less than 6 hours/night or with sleep hot flashes. CONCLUSIONS: A history of child abuse or neglect is associated with higher subclinical CVD in women, particularly when paired with short sleep or hot flashes. Findings underscore the importance of childhood adversity in midlife women's CVD risk. PMID- 27763989 TI - Childhood Psychological Distress as a Mediator in the Relationship Between Early Life Social Disadvantage and Adult Cardiometabolic Risk: Evidence From the 1958 British Birth Cohort. AB - OBJECTIVES: Prior research on the relationship between early adversity and adult chronic disease has often relied on retrospective reports of a limited range of exposures and has not considered childhood psychological distress as a mediator. We investigate whether distress in childhood is one pathway by which early social disadvantage leads to greater cardiometabolic risk in middle adulthood. METHODS: Data are from the 1958 British Birth Cohort study (sample n = 6027). We created an early social disadvantage index based on 16 exposures related to family and socioeconomic hardship from birth to age 7. Childhood psychological distress was ascertained from internalizing and externalizing symptoms at ages 7, 11, and 16 years. Cardiometabolic risk was assessed with a Z-standardized score derived from 9 immune, cardiovascular, and metabolic biomarkers measured at age 45. We used linear regression models and formal tests of mediation to assess relationships between disadvantage, distress, and subsequent cardiometabolic risk. RESULTS: Higher social disadvantage predicted increased adult cardiometabolic risk (beta = 0.05; 95% CI = 0.03-0.07). Mediation analyses revealed a significant direct (path c'; beta = 0.03; 95% CI = 0.01-0.05) and indirect (path ab; beta = 0.02; 95% CI = 0.01-0.02) effect of social disadvantage on cardiometabolic risk, adjusting for potential confounders. Child psychological distress accounted for 37% (95% CI = 34-46%) of the observed association. CONCLUSIONS: Results suggest childhood distress may be one factor on the pathway linking early disadvantage to higher risk of developing cardiometabolic diseases. Such results may point to the importance of blocking the translation of psychosocial to biological risk during a potentially sensitive developmental window. PMID- 27763990 TI - Maternal History of Childhood Abuse and Risk of Asthma and Allergy in 2-Year-Old Children. AB - OBJECTIVES: Exposure to child abuse (CA) is associated with an increased risk of developing asthma and allergies; it is unknown if that risk is present across generations. This study investigated if 2-year-old children born to mothers with a history of CA were at an increased risk of receiving a diagnosis of asthma or allergies. METHODS: Data from 1,551 participants were collected as part of the All Our Babies (AOB) study, a prospective pregnancy cohort. During pregnancy, each woman provided information about her own history of CA, and at 24 months postpartum, she provided information about her child's medical diagnoses. Symptoms of maternal depression and anxiety were assessed during pregnancy and at 24 months postpartum. RESULTS: Unadjusted models showed that compared to children born to mothers without a history of CA, 2-year-old children born to mothers with a history of CA were more likely to have had a diagnosis of asthma (7.4% vs 4.2%, p = .016) or allergy (15.6% vs 9.2%, p < .001). Maternal symptoms of depression assessed in late pregnancy and symptoms of depression and anxiety at 24 months postpartum were significant mediators of the relationship between maternal CA and 2-year-old asthma diagnosis. Maternal symptoms of depression and anxiety assessed in late pregnancy were also significant mediators of the relationship between maternal CA and 2-year-old allergy diagnosis. CONCLUSIONS: The results indicate that maternal exposure to CA is associated with increased risk of asthma and allergy in their 2-year-old children; symptoms of maternal depression and anxiety were identified as pathways linking the variables. PMID- 27763991 TI - Mechanisms Underlying the Association Between Early-Life Adversity and Physical Health: Charting a Course for the Future. AB - Early-life adversities (ELA) are associated with subsequent pervasive alterations across a wide range of neurobiological systems and psychosocial factors that contribute to accelerated onset of health problems and diseases. In this article, we provide an integrated perspective on recent developments in research on ELA, based on the articles published in this Special Issue of Psychosomatic Medicine. We focus on the following: 1) the distinction between specific versus general aspects of ELA with regard to the nature of exposure (e.g., physical and sexual abuse, emotional abuse or neglect, relative socioeconomic deprivation), biological and behavioral correlates of ELA, and differences across diseases; 2) the importance of timing in the critical phases of exposure to ELA; and 3) adaptive versus dysfunctional responses to ELA and their consequences for biological and behavioral risk factors for adverse health outcomes. This article concludes with outlining important new targets for research in this area, including the neurobiology of affect as a mechanism linking ELA to adverse health outcomes, and the need for large-scale longitudinal investigations of multisystem processes relevant to ELA in diverse samples, starting prenatally, continuing to late adolescence, and with long-term follow-up assessments that enable evaluation of incident disease outcomes. PMID- 27763993 TI - Heritability of arterial stiffness in a Brazilian population: Baependi Heart Study. AB - BACKGROUND: Increased arterial stiffness is an important determinant of cardiovascular disease risk. In addition, it has been recognized that arterial stiffness has familial aggregation; however, there are no studies involving Brazilian families. Thus, the aim of this study was to evaluate the heritability of arterial stiffness in a Brazilian population. METHODS: In this study, 1675 eligible individuals (both sexes and aged 18-102 years) were distributed in 125 families resident in the municipality of Baependi, a city located in the southeast of Brazil. Carotid-femoral pulse wave velocity (PWV) was measured with a noninvasive automatic device (Complior; Artech Medical, Pantin, France). Variance component approaches, implemented in the SOLAR computer package (San Antonio, Texas, USA), were applied to estimate the heritability of the studied phenotype under different statistical models. RESULTS: Heritability estimates for carotid-femoral PWV stratified by age ranging from 11 to 35% (higher in individuals aged <=45 years and lower in individuals aged 18-102 years). Age and hypertension showed significant effects on the PWV trait and significantly affect heritability estimates in all models. CONCLUSION: We conclude that the heritability of carotid-femoral PWV in a Brazilian population is intermediate, and therefore genetic studies evolving arterial stiffness phenotypes should be encouraged. PMID- 27763994 TI - Invasive validation of a novel brachial cuff-based oscillometric device (SphygmoCor XCEL) for measuring central blood pressure. AB - BACKGROUND: Studies have established the prognostic value of central SBP and pulse pressure (PP). The SphygmoCor XCEL (AtCor Medical, Sydney, Australia) device provides practical central blood pressure (BP) measurement for daily clinical use with its easy-to-use, operator-independent procedure. However, this device has not been validated against invasive measurement. METHOD: Simultaneous oscillometric and high-fidelity invasive measurements of central SBP and PP were compared for 36 patients who underwent coronary arteriography. Invasive measurement of brachial BP was also performed. Oscillometrically measured brachial SBP and DBP were used for calibration. RESULTS: The differences between the invasive and the oscillometric measurements were -4.6 +/- 9.9 mmHg for central SBP and -18.5 +/- 10.6 mmHg for central PP (mean +/- SD). We found strong correlation between the invasive and oscillometric measurements (central SBP and central PP, respectively: r = 0.91 and 0.89; slope, 1.28 and 1.38; both P < 0.001). Although the large slopes of the regression lines indicated a systemic bias toward lower values when measuring in high pressure ranges, the bias was mainly due to calibration error rather than device-specific error because errors of the central measurements correlated well with those of brachial measurements (SBP and PP, respectively: r = 0.80 and 0.77; both P < 0.001). CONCLUSION: The impaired accuracy of central BP measurement was mainly due to calibration derived, but not device-dependent, bias. Strong correlation between oscillometric and invasive measurements indicates that SphygmoCor XCEL warrants future investigations to determine the clinical validity of this device. PMID- 27763992 TI - Introduction to the Special Issue of Psychosomatic Medicine: Mechanisms Linking Early-Life Adversity to Physical Health. PMID- 27763995 TI - Impact of Health Insurance, ADAP, and Income on HIV Viral Suppression Among US Women in the Women's Interagency HIV Study, 2006-2009. AB - BACKGROUND: Implementation of the Affordable Care Act motivates assessment of health insurance and supplementary programs, such as the AIDS Drug Assistance Program (ADAP) on health outcomes of HIV-infected people in the United States. We assessed the effects of health insurance, ADAP, and income on HIV viral load suppression. METHODS: We used existing cohort data from the HIV-infected participants of the Women's Interagency HIV Study. Cox proportional hazards models were used to estimate the time from 2006 to unsuppressed HIV viral load (>200 copies/mL) among those with Medicaid, private, Medicare, or other public insurance, and no insurance, stratified by the use of ADAP. RESULTS: In 2006, 65% of women had Medicaid, 18% had private insurance, 3% had Medicare or other public insurance, and 14% reported no health insurance. ADAP coverage was reported by 284 women (20%); 56% of uninsured participants reported ADAP coverage. After accounting for study site, age, race, lowest observed CD4, and previous health insurance, the hazard ratio (HR) for unsuppressed viral load among those privately insured without ADAP, compared with those on Medicaid without ADAP (referent group), was 0.61 (95% CI: 0.48 to 0.77). Among the uninsured, those with ADAP had a lower relative hazard of unsuppressed viral load compared with the referent group (HR, 95% CI: 0.49, 0.28 to 0.85) than those without ADAP (HR, 95% CI: 1.00, 0.63 to 1.57). CONCLUSIONS: Although women with private insurance are most likely to be virally suppressed, ADAP also contributes to viral load suppression. Continued support of this program may be especially critical for states that have not expanded Medicaid. PMID- 27763997 TI - Closing the Gap in Antiretroviral Initiation and Viral Suppression: Time Trends and Racial Disparities. AB - BACKGROUND: In the current antiretroviral (ART) era, the evolution of HIV guidelines and emergence of new ART agents might be expected to impact the times to ART initiation and HIV virologic suppression. We sought to determine if times to AI and virologic suppression decreased and if disparities exist by age, race/ethnicity, and HIV risk. METHODS: We performed a retrospective cohort study of data from 12 sites of the HIV Research Network, a consortium of US clinics caring for HIV-infected patients. HIV-infected adults (>=18 year old) newly presenting for care between 2003 and 2013 were included in this study. Times to AI and virologic suppression were defined as time from enrollment to AI and HIV RNA <400 copies per milliliter, respectively. We conducted time-to-event analyses using competing risk regression in the HIV Research Network cohort from 2003 to 2012 in 2-year intervals, with follow-up through 2013. RESULTS: Among 15,272 participants, 76.9% were male, 48.4% black, and 10.9% were injection drug use with median age of 38 years (interquartile range: 29-46 years). The adjusted subdistribution hazards ratios (SHRs) for AI and virologic suppression each increased for years 2007-2008 [SHR 1.23 (1.16-1.30), and SHR 1.25 (1.17-1.34), respectively], 2009-2010 [1.55 (1.46-1.64), and 1.54 (1.43-1.65), respectively], and 2011-2012 [1.94 (1.83-2.07), and 1.73 (1.61-1.86), respectively] compared with 2003-2004. Blacks had a lower probability of AI than whites and Hispanics. CONCLUSIONS: Since 2007, times from enrollment to AI and virologic suppression have decreased significantly compared with 2003-2004, but persisting disparities should be addressed. PMID- 27763998 TI - New York City Achieves the UNAIDS 90-90-90 Targets for HIV-Infected Whites but Not Latinos/Hispanics and Blacks. PMID- 27763996 TI - County-Level Vulnerability Assessment for Rapid Dissemination of HIV or HCV Infections Among Persons Who Inject Drugs, United States. AB - OBJECTIVE: A recent HIV outbreak in a rural network of persons who inject drugs (PWID) underscored the intersection of the expanding epidemics of opioid abuse, unsterile injection drug use (IDU), and associated increases in hepatitis C virus (HCV) infections. We sought to identify US communities potentially vulnerable to rapid spread of HIV, if introduced, and new or continuing high rates of HCV infections among PWID. DESIGN: We conducted a multistep analysis to identify indicator variables highly associated with IDU. We then used these indicator values to calculate vulnerability scores for each county to identify which were most vulnerable. METHODS: We used confirmed cases of acute HCV infection reported to the National Notifiable Disease Surveillance System, 2012-2013, as a proxy outcome for IDU, and 15 county-level indicators available nationally in Poisson regression models to identify indicators associated with higher county acute HCV infection rates. Using these indicators, we calculated composite index scores to rank each county's vulnerability. RESULTS: A parsimonious set of 6 indicators were associated with acute HCV infection rates (proxy for IDU): drug-overdose deaths, prescription opioid sales, per capita income, white, non-Hispanic race/ethnicity, unemployment, and buprenorphine prescribing potential by waiver. Based on these indicators, we identified 220 counties in 26 states within the 95th percentile of most vulnerable. CONCLUSIONS: Our analysis highlights US counties potentially vulnerable to HIV and HCV infections among PWID in the context of the national opioid epidemic. State and local health departments will need to further explore vulnerability and target interventions to prevent transmission. PMID- 27763999 TI - Electronic health (e-Health): emerging role in asthma. AB - PURPOSE OF REVIEW: Asthma is the most prevalent chronic respiratory disease and represents a relevant socioeconomic burden. e-Health has the potential to improve disease control and adherence to treatment in asthmatic patients. Available data are, however, scarce and inconsistent limiting the use of e-health in clinical practice. This article aims to provide a systematic review of the literature published in the last year regarding the real place and impact of e-health in the management of asthma. RECENT FINDINGS: Despite few conflicting results, collected findings support a beneficial effect of e-health on asthma management and control, as well as positive patients' acceptance and satisfaction. Included studies mainly assessed m-health, telemedicine, electronic health record and digital app interventions, in both adults and children. Existing evidence appears however to be only of moderate quality and high heterogeneity was found in the study endpoints and designs. SUMMARY: There is the need to establish widely adopted standards for conducting trials and reporting results in e-health. These should include minimal clinical difference assessment and prevent potential pitfalls such as patient privacy protection, data fishing and lack of compliance of interventions with evidence-based medicine, guideline recommendations and regulatory board statements. PMID- 27764000 TI - Pharmacogenetics of asthma: toward precision medicine. AB - PURPOSE OF REVIEW: Although currently available drugs to treat asthma are effective in most patients, a proportion of patients do not respond or experience side-effects; which is partly genetically determined. Pharmacogenetics is the study of how genetic variations influence drug response. In this review, we summarize prior results and recent studies in pharmacogenetics to determine if we can use genetic profiles for personalized treatment of asthma. RECENT FINDINGS: The field of pharmacogenetics has moved from candidate gene studies in single populations toward genome-wide association studies and meta-analysis of multiple studies. New technologies have been used to enrich results, and an expanding number of genetic loci have been associated with therapeutic responses to asthma drugs. Prospective, genotype-stratified treatment studies have been conducted for beta2-agonists, showing attenuated response in children carrying the Arg16 variant in the beta2-adrenoreceptor gene. SUMMARY: Although there has been much progress, many findings have not been replicated and currently known genetic loci only account for a fraction of variability in drug response. More research is necessary to translate into clinical practice. A polygenic predictive approach integrated in complex networks with other 'omics' technologies could aid to achieve this goal. Finally, to change clinical practice, studies that compare precision medicine with traditional medicine are needed. PMID- 27764002 TI - Smartphone-Based Hearing Screening at Primary Health Care Clinics. AB - OBJECTIVE: To evaluate the performance of smartphone-based hearing screening with the hearScreen application in terms of sensitivity, specificity, referral rates, and time efficiency at two primary health care clinics. DESIGN: Nonprobability purposive sampling was used at both clinics. A total of 1236 participants (mean age: 37.8 +/- SD 17.9 and range 3 to 97 years; 71.3% female) were included in the final analysis. Participants were screened using the hearScreen application following a two-step screening protocol and diagnostic pure-tone audiometry to confirm hearing status. RESULTS: Sensitivity and specificity for smartphone screening was 81.7 and 83.1%, respectively, with a positive and negative predictive value of 87.6 and 75.6%, respectively. Sex [chi(1, N = 126) = 0.304, p > 0.05] and race [chi(1, N = 126) = 0.169, p > 0.05)] had no significant effect on screening outcome for children while for adults age (p < 0.01; beta = 0.04) and sex (p = 0.02; beta = -0.53) had a significant effect on screening outcomes with males more likely to fail. Overall referral rate across clinics was 17.5%. Initial screening test times were less than a minute (48.8 seconds +/- 20.8 SD) for adults and slightly more than a minute for children (73.9 seconds +/- 44.5 SD). CONCLUSIONS: The hearScreen smartphone application provides time-efficient identification of hearing loss with adequate sensitivity and specificity for accurate testing at primary health care settings. PMID- 27764003 TI - Epidemiology and Statistical Pearls for Interventional Pulmonologists: Combining the Tools of the Mind With the Tools of the Trade. PMID- 27764004 TI - The When, the How and the Why of Metallic Stent Removal. PMID- 27764001 TI - Visual Temporal Acuity Is Related to Auditory Speech Perception Abilities in Cochlear Implant Users. AB - OBJECTIVES: Despite significant improvements in speech perception abilities following cochlear implantation, many prelingually deafened cochlear implant (CI) recipients continue to rely heavily on visual information to develop speech and language. Increased reliance on visual cues for understanding spoken language could lead to the development of unique audiovisual integration and visual-only processing abilities in these individuals. Brain imaging studies have demonstrated that good CI performers, as indexed by auditory-only speech perception abilities, have different patterns of visual cortex activation in response to visual and auditory stimuli as compared with poor CI performers. However, no studies have examined whether speech perception performance is related to any type of visual processing abilities following cochlear implantation. The purpose of the present study was to provide a preliminary examination of the relationship between clinical, auditory-only speech perception tests, and visual temporal acuity in prelingually deafened adult CI users. It was hypothesized that prelingually deafened CI users, who exhibit better (i.e., more acute) visual temporal processing abilities would demonstrate better auditory only speech perception performance than those with poorer visual temporal acuity. DESIGN: Ten prelingually deafened adult CI users were recruited for this study. Participants completed a visual temporal order judgment task to quantify visual temporal acuity. To assess auditory-only speech perception abilities, participants completed the consonant-nucleus-consonant word recognition test and the AzBio sentence recognition test. Results were analyzed using two-tailed partial Pearson correlations, Spearman's rho correlations, and independent samples t tests. RESULTS: Visual temporal acuity was significantly correlated with auditory-only word and sentence recognition abilities. In addition, proficient CI users, as assessed via auditory-only speech perception performance, demonstrated significantly better visual temporal acuity than nonproficient CI users. CONCLUSIONS: These findings provide the first behavioral evidence that visual temporal acuity is related to post implantation CI proficiency as indexed by auditory-only speech perception performance. These preliminary data bring to light the possible future role of visual temporal acuity in predicting CI outcomes before implantation, as well as the possible utility of visual training methods in improving CI outcomes. PMID- 27764005 TI - Randomization in Diagnostic and Therapeutic Interventional Pulmonary Trials. PMID- 27764006 TI - Removal of Self-Expanding Metallic Stents. AB - BACKGROUND: Despite their safety profile, self-expanding metallic stents (SEMS) have been difficult to remove. We aim to describe our experience in removal of SEMS at Henry Ford Hospital with a specific emphasis on safety. METHODS: We reviewed the charts of all patients who underwent removal of a SEMS at Henry Ford Hospital between 2003 and 2013. We recorded demographic information, indication for initial stent placement, indication for stent removal, time to stent removal, procedure of removal, and any complications. RESULTS: In all, 19 stents were removed in 16 separate procedures in 14 patients. The median age was 62 years, and 50% of the patients were female. Stents were removed at a median of 35 days (range, 2 to 595 d). No complications occurred in 10/16 (62.5%) procedures. In the remaining 5 patients, complications were not directly related to the stent removal, and serious complications were mostly related to severity of underlying lung disease. Of the 10 procedures done as outpatients, 70% were discharged immediately after the procedure. CONCLUSIONS: Removal of SEMS can be done safely. Routine postoperative ventilation and intensive care unit monitoring is not required. In the absence of severe underlying lung disease, patients can safely be discharged if there are no immediate postprocedure complications. PMID- 27764007 TI - Teflon Injection into the Trachea Causes Predictable Fibroblastic Response and Collagen Deposition: A Pilot Study. AB - BACKGROUND: Expiratory central airway collapse is an increasingly recognized abnormality of the central airways and may be present in as many as 22% of patients evaluated for chronic obstructive pulmonary disease and/or asthma. Many current treatment options require invasive procedures that have been shown to cause significant morbidity and mortality. To test the hypothesis that Teflon injection will induce sufficient fibroblast proliferation and collagen deposition, we evaluated the time course on the effect of Teflon injection in the posterior membranous trachea on the histopathology of the tracheobronchial tree. METHODS: Six Yucatan Pigs were assigned to undergo general anesthesia and injection of 0.3 to 0.5 mL of sterile Teflon paste in 50% glycerin into the posterior membranous tracheal wall. A control pig received an equivalent volume of glycerin. Animals were euthanized in predefined intervals and tracheas were excised and examined under light microscopy for identifying fibroblast proliferation and collagen deposition. RESULTS: Compared with the control pig, the Teflon injection site showed tissue reaction of fibrohistiocytic proliferation and subsequent collagen deposition in all animals. Furthermore, the increased fibroblast proliferation and collagen deposition were time dependent (P<0.01). CONCLUSION: This pilot study demonstrates histopathologic changes in the trachea after Teflon injection, comprised of increased fibroblast activity and collagen deposition that could be of potential use in creating greater airway rigidity in patients with sever diffuse excessive dynamic airway collapse. PMID- 27764008 TI - Primary Laryngotracheal Amyloidosis With Bilateral Vocal Cord Involvement and Associated Bronchiectasis. AB - Localized tracheobronchial amyloidosis is a rare disease that results from submucosal deposition of insoluble amyloid proteins in the large airways. Amyloidosis affecting the larynx and subglottic space typically results in unilateral, nodular vocal cord infiltration. It rarely can present with bilateral vocal cord involvement and can progress to lifethreatening respiratory failure due to upper airway obstruction. In these patients, typical treatment modalities such as CO2 laser ablation are often ineffectual. Bronchiectasis is a predisposing risk factor associated with the secondary (AA) form of disease. We present a patient with the primary (AL) form of localized laryngotracheal amyloidosis with pre-existing bronchiectasis, and also review the existing literature on this disease. PMID- 27764009 TI - Dislodgement of Radial EBUS-Guide Sheath Radiopaque Cuff: A Rare Complication. PMID- 27764010 TI - Endobronchial Silicosis and Tuberculosis Presenting as the Right Middle Lobe Syndrome. PMID- 27764012 TI - Glue in Hemoptysis. PMID- 27764011 TI - Formation of Obstructive Fibrinous Pseudomembrane Following Self-Expanding Metallic Airway Stent Placement. PMID- 27764013 TI - Bite Block for Interventional Pulmonology: Novelty at No Cost. PMID- 27764014 TI - Spontaneous Pneumothorax Complicating Chronic Hepatic Hydrothorax: Successful Treatment by Small Bore Chest Tube. PMID- 27764015 TI - Progesterone as a tocolytic agent for preterm labor: a systematic review. AB - PURPOSE OF REVIEW: Tocolytic agents have been used for over 60 years in the fight against preterm labor, which ultimately can lead to preterm birth. Currently, clinicians can choose from a variety of drug classes to achieve the primary goal of delaying delivery by 48 h, thereby allowing time for administration of corticosteroids for fetal lung maturity, and if appropriate, starting magnesium sulfate for fetal neuroprotection. However, there are currently no known therapies to maintain the tocolytic effect beyond those initial 48 h. RECENT FINDINGS: Progesterone, which has been used in the prevention of preterm birth for over 10 years, has long been known to have the effect of uterine quiescence. It was first studied as a tocolytic agent in the 1960s. In the last several years, more studies have been done that suggest a potential use for maintenance tocolysis after the successful arrest of preterm labor. Although the studies are conflicting, the meta-analyses on progesterone show some promise in different outcomes of delayed delivery, reduced incidence of preterm birth, and reduced neonatal morbidity. SUMMARY: Progesterone is currently the most promising agent for maintenance tocolysis. Although further trials are certainly needed, this is an exciting advancement in the realm of tocolysis. PMID- 27764016 TI - Current status of robotic-assisted surgery for the treatment of vesicoureteral reflux in children. AB - PURPOSE OF REVIEW: Although open ureteral reimplantation remains the gold standard for surgical correction of vesicoureteral reflux (VUR), robotic-assisted laparoscopic ureteral reimplantation (RALUR) holds promise and is becoming more widely utilized. The present article outlines primary operative techniques for RALUR, summarizes the current literature with respect to surgical outcomes and costs, and discusses early applications of RALUR to complex and reoperative cases. RECENT FINDINGS: Intravesical and extravesical techniques for RALUR have been described. Published outcomes vary with respect to operational definitions of surgical success and reporting of complications. Several studies have directly compared RALUR and open reimplant, suggesting equivalent efficacy and safety. Recent noncomparative studies have reported lower VUR resolution rates and higher complication rates for RALUR, particularly in bilateral cases. The application of RALUR to reoperative surgery and cases requiring tapering and dismemberment is under very early investigation. RALUR is consistently associated with lower postoperative analgesic requirements and decreased hospital stay, but longer operative times and higher costs compared to open reimplant. SUMMARY: Published outcomes after RALUR show mixed results that, on average, may be inferior to open reimplant. Future investigations should seek to identify patient-related and intraoperative factors associated with successful and unsuccessful outcomes. PMID- 27764017 TI - The insomnia with short sleep duration phenotype: an update on it's importance for health and prevention. AB - PURPOSE OF REVIEW: It was first proposed in the late 1990s that objective markers of sleep disturbance could serve as an index of the biological severity of insomnia. In 2013, a heuristic model of two insomnia phenotypes based on objective sleep duration was proposed. Herein, we review the studies conducted in the past 3 years on the insomnia with short sleep duration phenotype and its implications for a clinical research agenda. RECENT FINDINGS: Studies have shown that insomnia with objective short sleep duration is associated with physiologic hyperarousal and cardiometabolic and neurocognitive morbidity, whereas insomnia with normal sleep duration is not. Both insomnia phenotypes are associated with psychiatric morbidity albeit through different psychobiological mechanisms. Novel recent studies have included occupational outcomes, developmental approaches, at home objective sleep testing, diagnostic accuracy measures, and response to cognitive-behavioral treatment. SUMMARY: Accumulating evidence in the past years has continued to support that insomnia with short sleep duration is a more severe phenotype of the disorder associated with physiologic changes, significant morbidity and mortality and, potentially, a differential response to treatment. PMID- 27764018 TI - Preparing Residents Effectively in Emergency Skills Training With a Serious Game. AB - INTRODUCTION: Training emergency care skills is critical for patient safety but cost intensive. Serious games have been proposed as an engaging self-directed learning tool for complex skills. The objective of this study was to compare the cognitive skills and motivation of medical residents who only used a course manual as preparation for classroom training on emergency care with residents who used an additional serious game. METHODS: This was a quasi-experimental study with residents preparing for a rotation in the emergency department. The "reading" group received a course manual before classroom training; the "reading and game" group received this manual plus the game as preparation for the same training. Emergency skills were assessed before training (with residents who agreed to participate in an extra pretraining assessment), using validated competency scales and a global performance scale. We also measured motivation. RESULTS: All groups had comparable important characteristics (eg, experience with acute care). Before training, the reading and game group felt motivated to play the game and spent more self-study time (+2.5 hours) than the reading group. Game playing residents showed higher scores on objectively measured and self-assessed clinical competencies but equal scores on the global performance scale and were equally motivated for training, compared with the reading group. After the 2-week training, no differences between groups existed. CONCLUSIONS: After preparing training with an additional serious game, residents showed improved clinical competencies, compared with residents who only studied course material. After a 2 week training, this advantage disappeared. Future research should study the retention of game effects in blended designs. PMID- 27764019 TI - FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY. AB - PURPOSE: To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). METHODS: Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. RESULTS: Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8-6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6-72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1-10). The median gain in visual acuity was greater in the treated versus the observed group-0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P < 0.05 Mann-Whitney U test). Although a significant reduction in central macular thickness was evident in both groups, 150 MUm (treated) and 104 MUm (observed), active treatment was not associated with greater thinning than observation (P > 0.05 Mann-Whitney U test). CONCLUSION: There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone. PMID- 27764021 TI - Descemet membrane detachment during cataract surgery: etiology and management. AB - PURPOSE OF REVIEW: The review updates the mechanisms, clinical presentations, diagnoses, and managements of Descemet membrane detachment during cataract surgery. RECENT FINDINGS: The advent of new imaging techniques such as anterior segment optical coherence tomography and better comprehension of the clinical and pathological aspects of detachment have improved the diagnosis and treatment of this complication to the extent that the first algorithms and protocols have been proposed. SUMMARY: Though infrequent, Descemet membrane detachment is a complication of intraocular surgery, including cataract surgery and phacoemulsification. Since the first systematic description and classification in the literature by Samuels in 1928 and its characterization as a potential sight threatening condition by Scheie in 1964, plenty of retrospective and anecdotal evidence contribute to uncertainty and debate. The main controversy still lies in the choice between conservative treatment in hopes of spontaneaous reattachment and surgical treatment in a timely manner to maximize visual recovery. PMID- 27764022 TI - Central corneal thickness in glaucoma. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the role of central corneal thickness (CCT) in the clinical management of a glaucoma patient. RECENT FINDINGS: The prognostic value of CCT is well recognized in patients with ocular hypertension. However, its predictive value in other glaucoma suspects and patients with established glaucoma is less certain. Tonometry artefacts can result from variations in CCT. However, an adequately validated correction algorithm for Goldmann applanation tonometry measurements does not exist. Newer methods of tonometry are potentially less influenced by CCT but are limited in their clinical use. There may also be biological and genetic associations between corneal thickness and glaucoma. Demographics, environmental factors, glaucoma treatment and the measurement device used have a significant influence on CCT, and should be considered when interpreting the effect of cornea thickness in patients with glaucoma. New measurements of the biomechanical properties of the cornea are likely to be better approximations of the globe biomechanics than CCT, but these require further evaluation. SUMMARY: The clinical significance of CCT is well recognized in the context of glaucoma diagnosis and management, though the extent of its importance remains debatable. Corneal biomechanical properties may be more significantly associated with glaucoma than CCT. PMID- 27764023 TI - Sustained drug delivery for glaucoma: current data and future trends. AB - PURPOSE OF REVIEW: Sustained drug delivery has been recognized as a need for patients with ocular hypertension or glaucomatous optic neuropathy. Several sustained drug delivery systems and devices are currently on the horizon. This review aims to summarize initial results with these platforms, as reported in the literature, and also provide insight into their possible role in the glaucoma treatment paradigm. RECENT FINDINGS: Sustained drug delivery systems currently on the horizon include the topical bimatoprost ocular insert, travoprost and latanoprost punctal plugs, latanoprost-eluting contact lenses, bimatoprost and travoprost intraocular implants, as well as several other therapies in earlier stages of development. Delivery strategies differ with respect to ocular site of implantation, ocular hypotensive agent, and duration of efficacy. Efficacy and safety outcomes with these devices are favorable thus far. SUMMARY: The glaucoma treatment paradigm is currently in a state of flux as sustained drug delivery systems bring promise to individuals suffering from ocular hypertension or glaucoma. Several options will likely become available in the near future to ease the burden of daily administration of chronic therapy with intraocular pressure lowering agents. PMID- 27764024 TI - Clinical investigation of new glaucoma procedures. AB - PURPOSE OF REVIEW: This article reviews recent studies evaluating the efficacy and complication profiles of novel glaucoma procedures promoting aqueous outflow. RECENT FINDINGS: Literature from the 2015 to 2016 review period includes abundant data regarding new and emerging glaucoma procedures. Notable findings from recent randomized clinical trials include titratability of intraocular pressure with multiple trabecular microbypass stents (iStent; Glaukos, Laguna Hills, California, USA) and greater reduction in intraocular pressure and medication usage following intracanalicular scaffolding (Hydrus Microstent; Ivantis Inc., Irvine, California, USA) combined with phacoemulsification vs. phacoemulsification alone. A supraciliary microstent (CyPass Micro-Stent; Transcend Medical, Inc., Menlo Park, California, USA) received approval from the Food and Drug Administration after a pivotal trial demonstrated its efficacy and safety. Early studies of investigational subconjunctival filtering devices (XEN Gel Stent; AqueSys, Inc., Aliso Viejo, California, USA and InnFocus MicroShunt; InnFocus Inc., Miami, Florida, USA) offer promising evidence, but late complications are as yet unknown. SUMMARY: Newer glaucoma procedures targeting different aqueous outflow pathways have improved the safety profile of glaucoma surgery while preserving modest efficacy. Most can be combined with phacoemulsification, allowing for simultaneous treatment of comorbid cataract and glaucoma. Well-designed randomized clinical trials with extended follow-up remain necessary to evaluate the long-term efficacy and late complications of these novel procedures. PMID- 27764026 TI - Suitability of the DRI Hydrocodone/Hydromorphone Immunoassay in the Clinical Environment at a Lower Cutoff: Validation With LC-MS/MS Analysis. AB - BACKGROUND: We evaluated the analytical performance of the DRI hydrocodone/hydromorphone assay by comparing semiquantitative values obtained by this assay with values obtained by a liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method. We also evaluated the possibility of lowering the cutoff of the DRI assay from 300 to 100 ng/mL. METHODS: We compared semiquantitative values obtained by the DRI assay in 97 specimens with values obtained by the LC-MS/MS method including 10 specimens containing hydrocodone and/or hydromorphone concentrations between 105.0 and 145.0 ng/mL (determined by LC-MS/MS) to determine the sensitivity at 100 ng/mL. In addition, several opioids at a concentration of 5000 ng/mL were also analyzed by the DRI assay to determine its specificity. RESULTS: We observed no false-negative result using the DRI immunoassay in 96 specimens that showed semiquantitative values at 100 ng/mL or higher. However, one specimen containing 110 ng/mL of hydrocodone was false negative with the DRI assay (semiquantitative value 88 ng/mL, below 100 ng/mL cutoff). The semiquantitative values produced by DRI showed poor correlation with values determined by the LC-MS/MS method. The sensitivity of the DRI assay at 100 ng/mL was 90%, and the assay was very specific showing minimal cross-reactivity only with oxycodone and oxymorphone. CONCLUSIONS: DRI immunoassay for hydrocodone/hydromorphone is a cost-effective method of screening urine specimens in the clinical environment at a lower cutoff of 100 ng/mL. PMID- 27764027 TI - Quantitative Method for Simultaneous Analysis of a 5-Probe Cocktail for Cytochrome P450 Enzymes. AB - BACKGROUND: The metabolic activity of P450 enzymes in vivo can be determined using selective probe drugs. The simultaneous administration of multiple CYP specific probe drugs is commonly known as the "cocktail approach." Disadvantages of a cocktail are large volumes of samples required for analysis and time consuming analyses. The aim of this study was to develop and validate a simplified but sensitive method for the simultaneous quantification of 5 probe drugs [caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19), and S-warfarin (CYP2C9)] in a previously validated cocktail using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. METHODS: The method entailed a single method for sample preparation that enables quick processing of the samples containing all 5 probe drugs in a small volume of blood (>=10 MUL) followed by a chiral and nonchiral LC-MS/MS method. The method was validated for selectivity, specificity, resolution of racemic warfarin, linearity, accuracy, imprecision, recovery, process efficiency, ionization efficiency, and carryover effect. RESULTS: The method showed good selectivity without matrix interferences and differentiated S- and R-warfarin enantiomers with adequate resolution (Rs = 1.55). For all analytes, the mean process efficiency was >95%, and the mean ionization efficiency was >97%. Furthermore, the accuracy was between 94.9% and 108% for all analytes, and the within- and between-run imprecision were <11.7% for the lower limit of quantification and <12.6% for the middle level and upper limit of quantification. CONCLUSIONS: The method presented here enables the simultaneous quantification of the 5 probes in a very small blood volume (>=10 MUL). Furthermore, it is less time consuming than previously reported methods because it requires only 1 simple method for sample preparation followed by a nonchiral and chiral LC-MS/MS method that can be performed sequentially. PMID- 27764025 TI - Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine. AB - BACKGROUND: Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. METHODS: Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. RESULTS: For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1 compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. CONCLUSIONS: This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration response relationships. PMID- 27764028 TI - A simple high-performance liquid chromatography for determining lapatinib and erlotinib in human plasma. AB - BACKGROUND: Lapatinib and erlotinib are used for cancer treatment, showing large interindividual variability. Therapeutic drug monitoring may be useful for assessing the clinical outcomes and adverse events. A simple high-performance liquid chromatography ultraviolet method was developed for the determination of lapatinib and erlotinib in human plasma. METHODS: An aliquot of plasma sample spiked with IS was treated with acetonitrile to precipitate the proteins. Lapatinib and erlotinib were separated on an octadecylsilyl silica-gel column using a mobile phase consisting of acetonitrile, methanol, water, and trifluoroacetic acid (26:26:48:0.1) pumped at a flow rate of 1.0 mL/min. The detection wavelength was set at 316 nm. RESULTS: The calibration curves for lapatinib and erlotinib were linear (r = 0.9999) in the range of 0.125-8.00 ug/mL. The extraction recoveries for both lapatinib and erlotinib at the plasma concentration of 0.125-8.00 ug/mL were higher than 89.9% with coefficients of variation (CVs) less than 3.5%. The CVs for intraday and interday assays of lapatinib and erlotinib were less than 5.1% and 6.1%, respectively. CONCLUSIONS: The present method can be used for blood concentration monitoring for lapatinib or erlotinib in exactly the same conditions. PMID- 27764030 TI - Family Over Rules? An Ethical Analysis of Allowing Families to Overrule Donation Intentions. AB - Millions of people want to donate their organs after they die for transplantation, and many of them have registered their wish to do so or told their family and friends about their decision. For most of them, however, this wish is unlikely to be fulfilled, as only a small number of deaths (1% in the United Kingdom) occur in circumstances where the opportunity to donate organs is possible. Even for those who do die in the "right" way and have recorded their wishes or live in a jurisdiction with a "presumed consent" system, donation often does not go ahead because of another issue: their families refuse to allow donation to proceed. In some jurisdictions, the rate of "family overrule" is over 10%. In this article, we provide a systematic ethical analysis of the family overrule of donation of solid organs by deceased patients, and examine arguments both in favor of and against allowing relatives to "veto" the potential donor's intentions. First, we provide a brief review of the different consent systems in various European countries, and the ramifications for family overrule. Next, we describe and discuss the arguments in favor of permitting donation intentions to be overruled, and then the arguments against doing so. The "pro" arguments are: overrule minimises family distress and staff stress; families need to cooperate for donation to take place; families might have evidence regarding refusal; and failure to permit overrules could weaken trust in the donation system. The "con" arguments are: overrule violates the patient's wishes; the family is too distressed and will regret the decision; overruling harms other patients; and regulations prohibit overrule. We conclude with a general discussion and recommendations for dealing with families who wish to overrule donation. Overall, overrule should only rarely be permitted. PMID- 27764031 TI - Diagnosing the Decades-Long Rise in the Deceased Donor Kidney Discard Rate in the United States. AB - BACKGROUND: The proportion of deceased donor kidneys recovered for transplant but discarded increased steadily in the United States over 2 decades, from 5.1% in 1988 to 19.2% by 2009. Over 100 000 patients are waiting for a kidney transplant, yet 3159 kidneys were discarded in 2015. METHODS: We evaluated trends in donor characteristics, discard reasons, and Organ Procurement Organization-specific discard rates. Multivariable regression and propensity analysis were used to estimate the proportion of the discard rate rise in the 2000s attributable to changes in donor factors and decisions to biopsy and pump kidneys. RESULTS: This study found that at least 80% of the discard rate rise can be explained by the recovery of kidneys from an expanding donor pool and changes in biopsy and pumping practices. However, a residual discard rate increase could not be explained by changes in these factors. From 1987 to 2009, median donor age rose from 26 to 43 years; median Kidney Donor Risk Index increased from 1.1 in 1994 to 1.3 in 2009. Our findings suggest that the increase from 10% to 30% in the proportion of kidneys pumped during the 2000s served as a buffer, keeping the discard rate from rising even higher than it did. CONCLUSIONS: The majority of the kidney discard rate rise can be explained by the broadening donor pool. However, the presence of an unexplained, residual increase suggests behavioral factors (eg, increased risk aversion) and/or allocation inefficiencies may have played a role. Reducing risk aversion, improving allocation, and more often pumping less-than-ideal, yet potentially transplantable kidneys, may help reverse the trend. PMID- 27764032 TI - The Addition of Low-Dose Total Body Irradiation to Fludarabine and Melphalan Conditioning in Haplocord Transplantation for High-Risk Hematological Malignancies. AB - BACKGROUND: Preliminary evidence indicates that the addition of low-dose total body irradiation (TBI) (2-4 Gy) to reduced intensity conditioning may reduce the rate of relapse in allogeneic stem cell transplants. In very high-risk patients receiving combination haploidentical single-unit cord blood transplants, we have added 4 Gy TBI to the widely used fludarabine, melphalan conditioning regimen, in hopes of reducing relapse and decreasing graft rejection. METHODS: We retrospectively reviewed the posttransplant outcomes of patients who underwent haplocord stem cell transplant between May 2013 and March 2015 and who received fludarabine 30 mg/m day (D)-7 to -3, melphalan 140 mg/m D-2, and 2 Gy TBI D-4 and -3. RESULTS: All 25 patients achieved primary neutrophil engraftment after a median of 12 days. The median time to platelet engraftment was 27 days. The cumulative incidence of nonrelapse mortality was 16% by D+100 and 33% by 1 year. The cumulative incidence of grade III to IV acute graft-versus-host disease was 36% by D+100. The CIR was 13% by D+100 and 29% by 1 year. The estimated 1-year overall survival and progression-free survival were 40% and 37%, respectively. In a subgroup analysis, we compared the outcome of 13 acute myeloid leukemia patients receiving this conditioning regimen with age and disease risk index matched acute myeloid leukemia patients receiving fludarabine-melphalan without TBI. The TBI group had lower incidence of relapse at 1 year (15% vs 54%, P = 0.05). CONCLUSIONS: Overall, combination fludarabine-melphalan with low-dose TBI after haplocord stem cell transplant assures good engraftment and leads to acceptable toxicity and disease control in the setting of high risk, heavily pretreated patients. These findings warrant further investigation at a larger scale, prospective level. PMID- 27764034 TI - Triple Fracture of the Intra-Articular Second Metacarpal Head, Intra-Articular Fourth Metacarpal Base, and Ulnar Styloid of An Ice Hockey Player: A Case Report. AB - We present a case of simultaneous ipsilateral fractures at the intra-articular second metacarpal head, intra-articular fourth metacarpal base, and ulnar styloid. These fractures were caused by the peculiar condition of a blow to the fist during an ice hockey game; the hand was struck while it was gripping a stick. The specific combination of these fractures has not been previously reported in the literature. In this incident, axial compression force was transmitted from the second and fourth metacarpal heads while skipping the third metacarpal head to the ulnar side of the wrist via the carpometacarpal joints and carpal bones. Because each fracture exhibited only slight displacement, we used conservative treatment with good outcomes. PMID- 27764033 TI - Underlying Mechanisms of Protection Involved in Immunocloak. AB - BACKGROUND: We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic immunosuppressive drugs. This novel therapy is a nanobarrier membrane called ImmunoCloak, consisting of a matrix of laminin, proteoglycans, fibronectin, and collagens. The membrane "immunocloaks" the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the recipient's immune cells, without adversely affecting renal function. The resulting nonthrombogenic and nonimmunogenic apical surface significantly delays the onset of rejection fivefold over untreated controls. Currently, our focus is to elucidate the mechanisms of protection provided by placement of the membrane. METHODS: The mechanisms underlying the protective effect of the ImmunoCloak treatment was evaluated using human peripheral blood mononuclear cells and by testing for antigen presentation by cytokine/chemokine analysis using the Luminex platform, T cell allogeneic responses were measured by flow cytometry, and diapedesis was assessed using transwell plates. RESULTS: We now report that ImmunoCloak interrupts antigen presentation thereby preventing early T cell activation and interferes with diapedesis. There was significant inhibition in the synthesis of proinflammatory cytokines with a concordant blockade of T cell-mediated responses. The placement of the ImmunoCloak also significantly reduced leukocyte migration through the endothelial cell layer by 93%. CONCLUSIONS: Eliminating the need for nephrotoxic immunosuppressive drugs during the early posttransplant period could help to ameliorate the severity of delayed graft function and could provide a path to using more ischemically damaged renal allografts. PMID- 27764035 TI - The persistence of the effects of acupuncture after a course of treatment: a meta analysis of patients with chronic pain. AB - There is uncertainty regarding how long the effects of acupuncture treatment persist after a course of treatment. We aimed to determine the trajectory of pain scores over time after acupuncture, using a large individual patient data set from high-quality randomized trials of acupuncture for chronic pain. The available individual patient data set included 29 trials and 17,922 patients. The chronic pain conditions included musculoskeletal pain (low back, neck, and shoulder), osteoarthritis of the knee, and headache/migraine. We used meta analytic techniques to determine the trajectory of posttreatment pain scores. Data on longer term follow-up were available for 20 trials, including 6376 patients. In trials comparing acupuncture to no acupuncture control (wait-list, usual care, etc), effect sizes diminished by a nonsignificant 0.011 SD per 3 months (95% confidence interval: -0.014 to 0.037, P = 0.4) after treatment ended. The central estimate suggests that approximately 90% of the benefit of acupuncture relative to controls would be sustained at 12 months. For trials comparing acupuncture to sham, we observed a reduction in effect size of 0.025 SD per 3 months (95% confidence interval: 0.000-0.050, P = 0.050), suggesting approximately a 50% diminution at 12 months. The effects of a course of acupuncture treatment for patients with chronic pain do not seem to decrease importantly over 12 months. Patients can generally be reassured that treatment effects persist. Studies of the cost-effectiveness of acupuncture should take our findings into account when considering the time horizon of acupuncture effects. Further research should measure longer term outcomes of acupuncture. PMID- 27764036 TI - Psychiatric disorders as predictors of long-term opioid therapy and the need for treating chronic pain correctly in patients with prior opioid substance use disorder: a commentary. PMID- 27764037 TI - Disentangling mood and pain: a commentary on 2 manuscripts. PMID- 27764038 TI - Quality and Safety in Health Care, Part XVIII: Improving Outcomes in Colorectal Surgery. AB - An important way to improve outcomes after colorectal surgery is to follow the recommendations of the enhanced recovery pathway after surgery (ERAS). The ERAS guidelines are recommendations that address certain aspects of what should be done before surgery, in the operating room, and following surgery. There is a substantial fall in complications and a decrease in the length of stay for the patient if the recommendations are followed. Elements of the ERAS program are now being adopted for other surgical procedures besides colorectal surgery. PMID- 27764039 TI - Increased 18F-2-Fluorodeoxysorbitol (18F-FDS) Activity in a Pituitary Spindle Cell Carcinoma. AB - A 33-year-old woman presented with progressive visual loss. An MRI examination revealed a pituitary lesion which was suspicious of abscess. FDG and F-2 fluorodeoxysorbitol (F-FDS) PET were performed to differentiate malignancy from inflammation. FDS is a new tracer with potential in differentiating inflammatory tissues based on results from animal studies. However, intense tracer uptake was found in the pituitary in both PET studies. The lesion was proved to be spindle cell carcinoma following biopsy. PMID- 27764040 TI - 123I-FP-CIT and 99mTc-HMPAO in Pathologically Confirmed Progressive Supranuclear Palsy. AB - Molecular brain imaging I-FP-CIT SPECT is an important tool in evaluation of patients with parkinsonism. However, various neurodegenerative etiologies cannot be differentiated by I-FP-CIT SPECT alone. We present a case of progressive supranuclear palsy with abnormal I-FP-CIT SPECT and abnormal Tc-HMPAO SPECT depicted by quantitative analyses but unremarkable MRI 16 months after the onset of symptoms. Brain autopsy demonstrated presence of neuronal and glial tau pathology in both cortical and subcortical regions confirming the diagnosis of progressive supranuclear palsy. This case illustrates potential values of multimodal molecular brain imaging in conjunction with quantitative analysis in the evaluation of movement disorders. PMID- 27764041 TI - Intraductal Papillary Mucinous Neoplasm of the Pancreas With High Malignant Potential on FDG PET/MRI. AB - A 57-year-old man underwent FDG PET/CT to evaluate a mass in the head of the pancreas. The imaged revealed mildly, nonuniformly increased activity in the mass, but the exact location of the activity could not be determined on the low dose noncontrast CT portion of the study. On subsequent PET/MRI images acquired 60 minutes after the FDG PET/CT study, the increased activity was clearly localized on the cystic wall. The pathological examination showed that the lesion was intraductal papillary mucinous neoplasm of the pancreas with high degree of dysplasia. PMID- 27764042 TI - IgG4-Related Renal Lesions Detected by Delayed 18F-FDG PET/CT Scan. AB - Multiple renal lesions, which showed clearly demarcated low densities on contrast enhanced CT, were revealed in a 56-year-old woman. The F-FDG avidity of the renal lesions was equal to or mildly higher than that of the renal cortex on the routine PET/CT scan, but significantly higher on the delayed scan. IgG4-related disease with renal involvement was confirmed subsequently by the measurement of serous IgG4 and the pathology of renal lesion. PMID- 27764043 TI - 18F-Choline Uptake in Acute Ischemic Stroke. AB - A 75-year-old man with a history of prostate cancer was referred to our department to perform F-choline (FCH) PET/CT. FCH PET/CT showed a markedly increased uptake in the right temporoparietal junction brain. Three weeks earlier, acute ischemic stroke was diagnosed in the right temporoparietal junction brain on diffusion-weighted sequence and thrombosis in a distal branch of the right middle cerebral artery on MR angiography. Choline precursors promote repair and growth of cell membranes in neurologic diseases, so FCH PET/CT uptake could be explained by repair processes during early outcome of acute ischemic stroke. PMID- 27764044 TI - Serous Cystadenoma of the Pancreas Showing Uptake on 68Ga PSMA PET/CT. AB - Ga prostate-specific membrane antigen (PSMA) PET/CT is increasingly used to evaluate extent of disease in prostate carcinoma. Several other benign and malignant pathologies have also been reported to demonstrate PSMA avidity. We present a case of serous cystadenoma of the pancreas showing focal uptake on PSMA PET/CT. PMID- 27764045 TI - Evaluation of Prognostic Factors Associated With Differentiated Thyroid Carcinoma With Pulmonary Metastasis. AB - BACKGROUND: Because one of the major sites for metastasis of thyroid cancers is the lung, studying the pattern of pulmonary metastasis may provide useful information for the effective treatment of these patients. In this study, by assessing the metastasis pattern, we aimed to identify the factors that may affect prognosis and response to treatment in patients with differentiated thyroid carcinoma (DTC) with pulmonary metastasis. METHODS: This retrospective study included 75 patients with DTC with pulmonary metastasis who were referred to our nuclear medicine section over a period of 10 years. The data obtained were analyzed with regard to response to treatment to assess the effects of the included factors on prognosis. RESULTS: Of the 1746 patients referred to our section, 75 (4.3%) had pulmonary metastasis. According to the pattern of pulmonary metastasis, they were divided into 4 groups: nodular, diffuse, combined, and other. The mean age of the patients was 43.8 +/- 18.5 years. After the follow-up, 58 patients survived, 14 of whom responded to the treatment. The mean number of radioiodine therapy sessions that the patients received was 3.2 +/ 2, and the mean cumulative dose was 554.7 +/- 387.8 mCi. Statistical analysis of the data revealed that there was no significant difference in the response to treatment between patients with different patterns of pulmonary metastasis (P > 0.3). However, significant differences were reported in the response to treatment between patients with papillary thyroid carcinoma and those with follicular thyroid carcinoma (P < 0.03). The 1-, 5-, and 9-year survival rates were reported as 98%, 76%, and 51%, respectively. CONCLUSIONS: Patients with DTC with pulmonary metastasis have a relatively favorable prognosis and response rate, as well as longer survival. The type of DTC is the only factor that affects the response to treatment. PMID- 27764047 TI - The future of postoperative quality of recovery assessment: multidimensional, dichotomous, and directed to individualize care to patients after surgery. AB - PURPOSE OF REVIEW: Recovery after surgery is a complex interplay of the patient, the surgery, and the perioperative anaesthesia management. Assessment of recovery should address the needs of multiple stakeholders, including the institutions and healthcare providers, but primarily should be focused on the patients and their perception of quality of recovery and return to normalcy. This review will summarize the development of assessment of recovery to a multidimensional dichotomous construct that requires a real-time assessment tool validated for repeat measures and containing cognitive assessment. RECENT FINDINGS: Recovery is neither defined by a single composite number nor is it quantified at a single time point, but rather it is a continuum occurring in multiple domains and over periods of time from hours, to days to weeks or months after surgery. Recovery is often incomplete which may persist long term, leading to patient suffering, loss of work, and increased demands on family and healthcare providers long after apparently successful surgery. The important correlation between poor recovery, cognitive decline, institutional placement, and increased short and long-term mortality has been hampered by the heterogeneity of definitions and tools used and their assessment of recovery as a continuous vs. dichotomous score and at the group vs. individual level. Most research has been aimed at audit or group comparison rather than attempting to identify incomplete recovery at an early time period after surgery in specific patients and individualization of care based on the domain where recovery has failed. SUMMARY: Recovery is best defined as a multidimensional dichotomous construct encompassing nociceptive, emotive, functional, and cognitive domains. Its assessment tool should provide both real time and restrospective recovery data, thus enabling clinical and research applications, and be validated for repeat measures over a breadth of multiple clinically relevant postoperative time points. PMID- 27764046 TI - 68Ga-DOTATOC and 68Ga-PSMA PET/CT Unmasked a Case of Prostate Cancer With Neuroendocrine Differentiation. AB - A bedridden 90-year-old man with fever and elevated prostate-specific antigen (PSA) (49 ng/mL) was referred for differentiation between infection and tumor. F FDG PET/CT was negative for infection, but Ga-PSMA PET/CT showed multiple lesions in prostate gland with infiltration to bladder wall and seminal vesicle, consistent with locally advanced prostate cancer. The lesion with the highest Ga PSMA uptake was strongly avid for Ga-DOTATOC, suggesting neuroendocrine tumor differentiation. After hormonal therapy, PSA normalized, but chromogranin-A increased (from 251 to 398 ng/mL), inferring progression of neuroendocrine tumor differentiation. Advanced prostate cancer may require investigation for pathological neuroendocrine transformation, although PSA may suggest improvement. PMID- 27764048 TI - Anesthesiology mentoring. AB - PURPOSE OF REVIEW: Mentoring is fundamentally valuable and important to students considering a path into our specialty, as well as to colleagues already in it and with ambition to advance. General principles and personal experiences are collected and described to help inform future mentors and to reinforce the value of having a mentor and the satisfaction (and work) that is associated with such a role. RECENT FINDINGS: Detecting a latent talent among medical students or residents may be challenging but is worth the effort to develop personal careers and the specialty itself. Upon agreeing to jointly move a certain project, a professional plan is needed to improve chances of success and decrease the likelihood of frustration. Various challenges always have to be detected and solved, with the ultimate goal to guide a medical student to residency, subsequently into faculty status and preferably to lifelong collaboration. SUMMARY: Access to a mentor is an often-cited key to choosing a specialty and the success of junior colleagues and thus the entire department. Mentoring is fundamentally valuable in providing role modeling and also in protecting the mentee from the inefficiency of learning lessons the hard way. PMID- 27764049 TI - Current trends in anesthesia for esophagectomy. AB - PURPOSE OF REVIEW: Despite marked improvements in perioperative outcomes, esophagectomy continues to be a high-risk operation associated with significant morbidity and mortality. Progress has been achieved through evidence-based changes in preoperative optimization, intraoperative ventilation strategies, fluid therapy, and analgesia, as well as expedited postoperative recovery pathways. This review will summarize the recent literature on the anesthetic management of patients undergoing esophageal resection. RECENT FINDINGS: The current focus in publications on the perioperative management of esophagectomy patients can be summarized under the umbrella term of enhanced recovery pathways, focusing on ventilation, fluid therapy, analgesia and minimally invasive surgical approaches. Lung protective ventilation reduces pulmonary complications in cases requiring one-lung ventilation. Excess fluid administration contributes to morbidity while restrictive approaches have not resulted in an increased risk of acute kidney injury. Goal-directed fluid therapy remains intuitive yet unproven. Thoracic epidural analgesia reduces the systemic inflammatory response, pulmonary complications, and enhances postoperative pain control, yet if causing perioperative hypotension may be associated with anastomotic leaks. Enhanced recovery pathways have facilitated low morbidity and mortality rates in a high risk population but are heterogeneous and limited by a weak evidence base. Minimally invasive surgical approaches are increasingly popular and appear to have at least equivalent outcomes to open procedures. SUMMARY: The morbidity and mortality after esophagectomy remains high despite significant improvements over the last decades. Enhanced recovery pathways appear promising in achieving further marginal gains but at present are lacking large scale, prospective, multicenter evidence. PMID- 27764050 TI - A Pilot Study of Randomized, Head-to-Head of Metformin Versus Topiramate in Obese People With Schizophrenia. AB - OBJECTIVES: A number of research studies support the weight loss effects of metformin and topiramate for obese people with schizophrenia. However, only a few studies have addressed the sustainability of the body weight reduction after discontinuation of these drugs. Moreover, head-to-head studies are still lacking. The study aims to evaluate and compare the efficacy of metformin and topiramate in weight reduction and weight maintenance after discontinuation of these drugs in obese people with schizophrenia. METHODS: Twenty-two obese inpatients with schizophrenia were recruited and randomized into the metformin group (n = 11; daily dose, 1000 mg) and the topiramate group (n = 11; daily dose, 100 mg). A head-to-head, fixed-dose, and single-blinded design was used. Ten obese patients with schizophrenia of similar sex as that of the treated group were included as the control group. RESULTS: After a 4-month treatment, the metformin group showed a body weight reduction of 3.8 kg, and the topiramate group showed a reduction of 2.7 kg. However, the reduction could be sustained only in the metformin group at 3 and 9 months after metformin discontinuation. Interestingly, 3 months after treatment discontinuation, leptin levels showed a reduction in both metformin (baseline, 25.3 +/- 14.7, week 7: 5.7 +/- 3.7 ng/mL) and topiramate (baseline: 28.4 +/- 16.1, week 7: 9.2 +/- 15.5 ng/mL) groups. CONCLUSIONS: The trend of weight changes supports the superiority of metformin at 1000 mg/d over topiramate at 100 mg/d in weight reduction and weight maintenance. PMID- 27764052 TI - A Case of Resistant Schizophrenia Successfully Treated With Clozapine/Long-acting Injectable Aripiprazole Combination. AB - BACKGROUND: Treatment-resistant schizophrenia (TRS) is a condition characterized by intense symptom severity and poor response to different antipsychotic agents. The first therapeutic option in TRS is clozapine, but often high/medium doses are not tolerated. Adding an oral antipsychotic to low doses of clozapine is a promising strategy in the management of TRS. On the contrary, there are few data on combined clozapine/long-acting injectable (LAI) medications, and none on clozapine/LAI-aripiprazole. CASE: A 21-year-old male schizophrenic patient, resistant to several oral and LAI medications, partially improved after clozapine 300 mg/d treatment. Unfortunately, he also reported excessive sedation and an episode of myoclonus, so clozapine was reduced to 150 mg/d, but no additional benefits were observed. Subsequently, LAI-aripiprazole (first 200 mg/mo, then 400 mg/mo) was added, and the patient's conditions dramatically improved over time. After 1 year of observation, symptoms reduction was 50% or greater, without significant adverse events. CONCLUSIONS: Clozapine use in TRS is often reduced or delayed due to the fear of serious adverse effects. Adding LAI-aripiprazole to low doses of clozapine may be a useful therapeutic option to obtain a good efficacy/tolerability balance. PMID- 27764051 TI - Quality of Life and Functioning in Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder After Treatment With Citalopram Monotherapy. AB - OBJECTIVES: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) often have high comorbidity, consequently influencing patient-reported outcomes of depressive symptom severity, quality of life (QOL), and functioning. We hypothesized that the combined effects of concurrent PTSD and MDD would result in worse treatment outcomes, whereas individuals who achieved MDD remission would have better treatment outcomes. METHODS: We analyzed 2280 adult participants who received level 1 treatment (citalopram monotherapy) in the Sequenced Treatment Alternatives to Relieve Depression study, including 2158 participants with MDD without comorbid PTSD and 122 participants with MDD with comorbid PTSD (MDD + PTSD). Post hoc analysis examined the proportion of participants whose scores were within normal or severely impaired for functioning and QOL. Remission status at exit from MDD was also determined. RESULTS: At entry, participants with MDD + PTSD experienced significantly worse QOL, functioning, and depressive symptom severity compared with participants with MDD without comorbid PTSD. Although both groups had significant improvements in functioning and QOL posttreatment, the participants with MDD + PTSD were less likely to achieve remission from MDD. CONCLUSIONS: Findings suggested that participants with MDD + PTSD are at a greater risk for severe impairment across all domains and less likely to achieve remission from MDD after treatment with citalopram monotherapy. As such, the use of patient-reported measures of QOL and functioning may inform practicing clinicians' and clinical trial researchers' abilities to develop appropriate interventions and monitor treatment efficacy. More importantly, we encourage clinicians and health care providers to routinely screen for PTSD in patients with MDD because this at-risk group requires tailored and specific pharmacotherapy and psychotherapy interventions beyond traditionally standard treatments for depression. PMID- 27764053 TI - Escitalopram-Associated Acute Urinary Retention in Elderly Men With Known or Latent Benign Prostatic Hyperplasia: A Case Series. AB - Lower urinary tract outflow dysfunction is frequent in older men and a potential cause of serious complications such as acute urinary retention (AUR). Drug induced AUR has only rarely been reported with selective serotonin reuptake inhibitors including escitalopram; reported cases had no history of urinary outflow dysfunction. We herein report the development of AUR after the introduction of escitalopram at a standard dose in 3 male patients with previously diagnosed or unknown/latent and nonsymptomatic benign prostatic hyperplasia. Urinary retention receded after escitalopram discontinuation in 2 cases but led to emergent prostatectomy in the third. This case series highlights escitalopram's potential association with AUR in elderly men with known or latent benign prostatic hyperplasia. Further studies are warranted to investigate whether compromised or marginal urinary outflow should be considered a contraindication for treatment with escitalopram. PMID- 27764054 TI - Impact of Glycemic Control on Morbidity and Mortality in Adult Idiopathic Scoliosis Patients Undergoing Spinal Fusion. AB - STUDY DESIGN: This is a retrospective analysis of administrative database. OBJECTIVE: To elucidate the effect of glycemic control on surgical outcomes of middle-aged and elderly idiopathic scoliosis patients undergoing spinal fusion surgery. SUMMARY OF BACKGROUND DATA: Diabetes mellitus (DM) is a condition thought to adversely affect outcomes of spine surgery. However, no study has stratified glycemic control levels and their impact on outcome for idiopathic scoliosis patients receiving a spinal fusion surgery. Previous studies may have reported higher than true rates of complications for controlled diabetic patients, who are the majority of diabetic patients. MATERIALS AND METHODS: The Nationwide Inpatient Sample was queried from years 2002 to 2011. We extracted idiopathic scoliosis patients older than 45 years of age that received spinal fusion and analyzed complications and outcomes variables among 3 cohorts: nondiabetic patients, controlled diabetics, and uncontrolled diabetics. Multivariate analyses were used to assess whether glycemic control was a risk factor for adverse postoperative outcomes. RESULTS: Controlled diabetics had significantly increased rates of acute renal failure (ARF), while uncontrolled diabetics had significantly increased rates of acute postoperative hemorrhage. In multivariate analyses controlling for patient factors and comorbidities, controlled DM was found to be an independent predictor of ARF [odds ratio (OR), 1.863; 95% confidence interval (CI), 1.346-2.579; P=0.0002), and uncontrolled DM was found to be a significant risk factor for acute postoperative hemorrhage (OR, 2.182; 95% CI, 1.192-3.997; P=0.0115), ARF (OR, 4.839; 95% CI, 1.748-13.392; P=0.0024), deep vein thrombosis (OR, 5.825; 95% CI, 1.329-25.522, P=0.0194) and in-patient mortality (OR, 8.889; 95% CI, 1.001-78.945; P=0.0499). CONCLUSIONS: Controlled DM was found to be a risk factor for ARF in adult idiopathic scoliosis patients undergoing spinal fusion surgery, while uncontrolled DM was shown to be a risk factor for postoperative hemorrhage, ARF, deep vein thrombosis, and mortality. The present study provides valuable data for better informed consent for patients with diabetes considering surgery for idiopathic scoliosis. LEVEL OF EVIDENCE: Level III. PMID- 27764055 TI - Patient Satisfaction is Not Associated With Self-reported Disability in a Spine Patient Population. AB - STUDY DESIGN: This is a retrospective review. OBJECTIVE: To evaluate the relationship between patient functional status and self-assessment of disability as measured by 3 commonly used clinical assessment instruments-the Oswestry Disability Index (ODI), the Neck Disability Index (NDI), and the EuroQol (EQ)-5D and patient satisfaction scores in a spine surgery clinic population. SUMMARY OF BACKGROUND DATA: Patient satisfaction surveys, which measure the "patient experience of care" are becoming an increasingly important measure of the quality of medical care. Despite the widespread use of patient satisfaction surveys, little is known about the relationship between patient satisfaction and patient functional status or self-assessed level of disability. MATERIALS AND METHODS: We retrospectively reviewed records of 231 consecutive patients presenting to a single academic spine surgery center between February 2011 and October 2013 who completed both a patient satisfaction survey as well as one or more patient reported outcome questionnaires (NDI, ODI, and/or EQ-5D) for a single clinical encounter. Statistical analysis was performed to determine if an association exists between the overall patient satisfaction score and each patient-reported outcome score. RESULTS: Spearman correlation coefficients demonstrated no correlation between any patient-reported outcome score and the patient satisfaction score [NDI=-0.113 (-0.409 to 0.207) P=0.489] [ODI=-0.008 (-0.149 to 0.133) P=0.912] [EQ-5D=0.011 (-0.119 to 0.140) P=0.872] for a single clinical encounter. CONCLUSIONS: These results provide evidence against an association between patient-reported functional status or self-assessed level of disability and patient satisfaction in a spine patient population. PMID- 27764056 TI - Predictive Factors of the Effectiveness of Caudal Epidural Steroid Injections in Managing Patients With Chronic Low Back Pain and Radiculopathy. AB - STUDY DESIGN: Retrospective clinical outcome analysis. OBJECTIVE: To evaluate and determine whether demographic, comorbid factors, or physical examination findings may predict the outcome of caudal epidural steroid injections in managing patients with chronic low back pain and radiculopathy SUMMARY OF BACKGROUND DATA:: The caudal epidural approach is commonly utilized with patients who are on anticoagulation or who have had prior lumbar surgery to treat L5 or S1 radiculopathies. METHODS: A retrospective review of 136 patients undergoing an initial caudal epidural steroid injection for radiculopathy from January 1, 2006 to August 30, 2013. The patients were assessed before their injections for their pain levels: visual analog scale, presence of lumbar paraspinal and sciatic notch sensitivity, pain with provocative maneuvers, motor weakness, and sensory loss. The patients were then reassessed following their injection for their visual analog scale pain levels, percentage improvement, and duration of pain relief. RESULTS: Stepwise regression was used to determine whether demographic, comorbid factors, or physical examination signs were predictive of percentage improvement or length of relief following an injection. Among these variables, duration of symptoms was found to be negatively significantly related with a P-value of 0.032 for percentage of improvement. For each week of the duration of symptoms, the percentage of improvement decreased by 0.07%. Regarding physical examination findings, presence of pain with lumbar extension was negatively and significantly related to length of relief duration with a P-value of 0.0124. The mean length of relief duration is 38.37 weeks for individuals without painful lumbar extension and 14.68 weeks for individuals with painful lumbar extension CONCLUSIONS:: The mean length of relief following a caudal injection is reduced by 62% in patients who exhibit pain with lumbar extension. PMID- 27764057 TI - Can an Anchored Cage be Substituted for an Anterior Cervical Plate and Screw for Single-Level Anterior Cervical Fusion Surgery?: Prediction of Poor Candidates Through a Review of Early Clinical and Radiologic Outcomes. AB - STUDY DESIGN: This is a case series of device failure patients. OBJECTIVE: To identify poor candidates for anterior cervical discectomy and fusion (ACDF) using an anchored cage. SUMMARY OF BACKGROUND DATA: An anchored cage has been used as an alternative implant for ACDF surgery because of ease of use, relatively acceptable fusion rate, and lower risk of plate-related complications, including dysphagia. MATERIALS AND METHODS: We retrospectively reviewed the outcomes of 36 patients who underwent ACDF using an anchored cage between January 2012 and December 2013. The initial diagnoses included 8 traumatic soft disk herniations without posterior ligamentous complex injury, 25 degenerative soft disk herniations, 1 degenerative foraminal stenosis, 1 traumatic soft disk herniation after reducing a unilaterally dislocated facet joint, and 1 subluxation of a previously implanted cervical artificial disk. We encountered 5 cases with poor outcomes and performed 3 revisions on the index level. We reviewed the clinical and radiologic data for 31 patients with reasonable outcomes and reviewed the failed 5 cases separately. RESULTS: Among the 31 patients with reasonable outcomes, all the clinical parameters improved. For the radiologic outcomes, 10 cases of cage subsidence occurred and no patient experienced instability.Among the 5 patients with poor outcomes, 1 patient had traumatic soft disk herniation and a reduced unilaterally dislocated facet joint, 1 patient had subluxation of a previously implanted cervical artificial disk, and 3 patients had degenerative soft disk herniation and poor bone quality. Although 3 patients required revision surgeries, 2 patients showed only radiologic failures without revision. CONCLUSIONS: We analyzed the short-term outcomes of ACDF using an anchored cage and observed 5 patients with poor outcomes among 36 patients. We recommend the use of a single anchored cage for patients with definite evidence of posterior column stability and healthy bone. LEVEL OF EVIDENCE: Level 3. PMID- 27764058 TI - Prospective Cohort Study of Performance Status and Activities of Daily Living After Surgery for Spinal Metastasis. AB - STUDY DESIGN: A prospective cohort study of performance status (PS) and activities of daily living (ADL) in patients with spinal metastasis. OBJECTIVE: To identify the effect of spinal surgery on PS and ADL in patients with spinal metastasis. SUMMARY OF BACKGROUND DATA: Spinal metastasis causes severe neurological deficits, resulting in drastic loss of patients' PS and ADL. However, the effect of spine surgery on PS and ADL is not well known. MATERIALS AND METHODS: Seventy patients with spinal metastasis were enrolled in this study. Forty-six patients desired and underwent spine surgery ("surgery" group) and 24 patients did not desire surgery ("nonsurgery" group). Both groups received optimal treatments, including radiation, chemotherapy, and palliative care services. Evaluation was performed at 1, 3, and 6 months after study enrollment using the Eastern Cooperative Oncology Group PS, the Barthel index (BI) for ADL, and Frankel classification for neurological status. RESULTS: There was no significant difference in baseline PS, the BI, or Frankel classification between the groups. The surgery group showed significant improvement in PS, maintaining grade 2 or less throughout the duration of the study, as well as in ADL, exceeding 70 points of the BI, compared with the nonsurgery group (P<0.05). Significantly improved neurological condition was also observed in the surgery group over the following 6 months. More than 95% of patients who underwent surgery improved their PS, the BI, and neurological status. Furthermore, >80% of these patients maintained improvement in PS, the BI, and neurological status for at least 6 months. In contrast, PS, the BI, and neurological status of patients in the "nonsurgery" group deteriorated throughout the study period. CONCLUSIONS: Spine surgery improves PS, ADL, and neurological status in patients with spinal metastasis for a minimum 6 months. This indicates that these patients can acquire an independent daily life. PMID- 27764059 TI - Measurement of Spinopelvic Parameters on Standing Lateral Lumbar Radiographs: Validity and Reliability. AB - STUDY DESIGN: This was a radiographic validity and reliability study. OBJECTIVE: We assessed the validity and reliability of measurements made on standing lateral lumbar radiographs, compared with lateral whole-spine radiographs, for evaluating spinopelvic parameters and lumbar lordosis (LL). SUMMARY OF BACKGROUND DATA: A lateral whole-spine radiograph is the gold standard image for measurement of spinopelvic parameters. However, little evidence is available on the reliability of measurements made on such radiograph. A standing lateral lumbar radiograph is routinely obtained from patients with back pain and/or a disability. This image can include upper end plate of L1 vertebra, sacral dome and both femoral heads. Thus, this radiograph can be used for evaluation of spinopelvic parameters. MATERIALS AND METHODS: We randomly selected 50 sets of digital radiographs (standing lateral lumbar and lateral whole-spine radiographs) from our database. Three experienced spinal surgeons independently measured LL, pelvic incidence, pelvic tilt, and sacral slope on all images. A paired t test and Pearson correlation was used to analyze the validity of the lateral lumbar radiograph. Interobserver and intraobserver reliabilities were assessed by intraclass correlation coefficient. RESULTS: Thee spinopelvic parameters and LL measured on lateral lumbar radiographs were similar to those measured on lateral whole-spine radiographs (All P-values >0.05, Pearson correlation coefficients, 0.807-0.969). The intraobserver and interobserver reproducibilities of both measurement types were good-to-excellent. CONCLUSIONS: Spinopelvic parameters and LL values measured on lateral lumbar radiographs were reproducibly similar to those measured on lateral whole-spine radiographs. Use of a standing lateral lumbar radiograph is reasonable when spinopelvic parameters and LL are to be measured. PMID- 27764060 TI - Adjuvant external beam radiotherapy after therapeutic groin lymphadenectomy for patients with melanoma: a dosimetric comparison of three-dimensional conformal and intensity-modulated radiotherapy techniques. AB - Radiotherapy after lymph node dissection is recommended in high-risk melanoma cases. The aim of this study is to assess whether intensity-modulated radiotherapy (IMRT) offers advantages over three-dimensional conformal radiotherapy (3DCRT) in the groin nodal basin. Fifteen consecutively treated patients (5 3DCRT and 10 IMRT) were selected. Optimized theoretical plans using the other modality were created - enabling direct comparisons of 3DCRT and IMRT. Target volume and organs at risk constraints were assessed as achieved or as having minor (<=5%) or major (>5%) deviations. The Wilcoxon signed-rank test was used to compare the dose received from each patient plan (3DCRT vs. IMRT), whereas the Mann-Whitney U-test was used to compare clinical plans with theoretical plans. Fisher's exact test was used to compare categorical data. Target coverage was achievable in most patients (major deviations - 1 IMRT and 3 3DCRT). Conformity index improved with IMRT - median 0.65, range 0.48-0.81, versus median 0.44, range 0.29-0.60 for 3DCRT; P value less than 0.001. All 3DCRT plans had major deviations for femoral head/neck constraints. Twelve and 13 IMRT plans achieved the high (V42<5%) and low (V36<35%) constraints; P value less than 0.001. IMRT delivered statistically significant lower doses to small bowel volumes up to 40 ml. There were no differences in beam numbers used nor dosimetric endpoints measured when clinical plans were compared with theoretical plans. IMRT appears to allow superior conformity of dose to the target volume while relatively sparing the adjacent the bowel and femoral head/neck. This may reduce toxicity while maintaining control rates. PMID- 27764062 TI - Recreating healthcare: The next generation. PMID- 27764061 TI - Inflammatory regulation of stem-like cells in melanoma. AB - The link between inflammation, immunity and cancer is well established. In the last decade, there has been considerable excitement over cancer stem cells, believed to be a subset of tumour cells responsible for their initiation, propagation and resistance to conventional chemoradiotherapy. In this review, we discuss the characterization of cancer stem cells and describe their modulation by inflammation with a focus on melanoma. PMID- 27764064 TI - The Veterans Health Administration's proposal for APRN full-practice authority. AB - The Veterans Health Administration (VHA) is proposing full-practice authority for advanced practice registered nurses (APRNs) to improve access, care delivery, and patient choice, as well as reduce costs. The authors performed a mixed-methods assessment to obtain the perspectives of administrators and APRNs on the characterization of the APRN workforce and their present practice in the VHA. PMID- 27764066 TI - A multidisciplinary response to commercial sexual exploitation of children. PMID- 27764065 TI - Herbal supplements used to treat common chronic conditions. AB - This is part 2 of a three-part series designed to provide clinicians with a working knowledge of the use of herbal supplements for health and disease states. Part 2 of the series focuses on the efficacy of herbal supplements used in the treatment of common chronic conditions. PMID- 27764067 TI - Evidence-based treatment of chronic kidney disease. PMID- 27764068 TI - Managing behavioral disturbances in a patient with dementia. AB - A 92-year-old patient with Parkinson disease and dementia provides an opportunity for the advanced practice registered nurse to shift thinking about behavioral disturbances in dementia, away from controlling behavior with pharmacologic approaches, such as antipsychotics, toward understanding behavior by applying the nonpharmacologic Describe, Investigate, Create, and Evaluate method. PMID- 27764070 TI - Evaluation and treatment of vitamin D deficiency. AB - Although evidence is inconsistent regarding the relationship between vitamin D deficiency and the causality of many chronic disease processes, the functions of vitamin D impact more than just bone health. By understanding basic vitamin D concepts and varied recommendations, nurse practitioners can provide safe, individualized, effective evaluation and treatment of each patient's vitamin D status to promote positive health outcomes. PMID- 27764071 TI - Recognizing and treating vasospastic angina. PMID- 27764072 TI - National League for Nursing Commission for Nursing Education Accreditation. PMID- 27764073 TI - Use of Quick Response Code for Teaching in Nursing. PMID- 27764075 TI - Vital Signs: Dental Sealant Use and Untreated Tooth Decay Among U.S. School-Aged Children. AB - BACKGROUND: Tooth decay is one of the greatest unmet treatment needs among children. Pain and suffering associated with untreated dental disease can lead to problems with eating, speaking, and learning. School-based dental sealant programs (SBSP) deliver a highly effective intervention to prevent tooth decay in children who might not receive regular dental care. SBSPs benefits exceed their costs when they target children at high risk for tooth decay. METHODS: CDC used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 to estimate current prevalences of sealant use and untreated tooth decay among low-income (<=185% of federal poverty level) and higher-income children aged 6-11 years and compared these estimates with 1999-2004 NHANES data. The mean number of decayed and filled first molars (DFFM) was estimated for children with and without sealants. Averted tooth decay resulting from increasing sealant use prevalence was also estimated. All reported differences are significant at p<0.05. RESULTS: From 1999-2004 to 2011-2014, among low- and higher-income children, sealant use prevalence increased by 16.2 and 8.8 percentage points to 38.7% and 47.8%, respectively. Among low-income children aged 7-11 years, the mean DFFM was almost three times higher among children without sealants (0.82) than among children with sealants. Approximately 6.5 million low-income children could potentially benefit from the delivery of sealants through SBSP. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: The prevalence of dental sealant use has increased; however, most children have not received sealants. Increasing sealant use prevalence could substantially reduce untreated decay, associated problems, and dental treatment costs. PMID- 27764074 TI - Intensive Care Unit (ICU) - Managed Elderly Hospitalizations with Dementia in Texas, 2001-2010: A Population-Level Analysis. AB - BACKGROUNDThe demand for critical care services among elderly with dementia outpaces that of their non-dementia elderly counterparts. However, there are scarce data on the corresponding attributes among ICU-managed patients with dementia.MATERIAL AND METHODSWe used the Texas Inpatient Public Use Data File to examine temporal trends of the demographics, burden of comorbidities, measures of severity of illness, use of healthcare resources, and short-term outcomes among hospitalizations aged 65 years or older with a reported diagnosis of dementia, who were admitted to ICU (D-ICU hospitalizations) between 2001 and 2010. Average annual percent changes (AAPC) were derived.RESULTSD-ICU hospitalizations (n=276,056) had increasing mean (SD) Charlson comorbidity index [1.7 (1.5) vs. 2.6 (1.9)], with reported organ failure (OF) nearly doubling from 25% to 48.5%, between 2001-2001 and 2009-2010, respectively. Use of life support interventions was infrequent, but rose in parallel with corresponding changes in respiratory and renal failure. Median total hospital charges increased from $26,442 to $36,380 between 2001-2002 and 2009-2010. Routine home discharge declined ( 5.2%/year [-6.2%- -4.1%]) with corresponding rising use of home health services (+7.2%/year [4.4-10%]). Rates of discharge to another hospital or a nursing facility remained unchanged, together accounting for 60.4% of discharges of hospital survivors in 2010. Transfers to a long-term acute care hospital increased 9.2%/year (6.9-11.5%). Hospital mortality (7.5%) remained unchanged.CONCLUSIONSElderly D-ICU hospitalizations have increasing comorbidity burden, with rising severity of illness, and increasing use of health care resources. Though the majority survived hospitalization, most D-ICU hospitalizations were discharged to another facility. PMID- 27764077 TI - Errata: Vol. 65, No. 36. PMID- 27764076 TI - Notes from the Field: Outbreak of Zika Virus Disease - American Samoa, 2016. AB - During December 2015-January 2016, the American Samoa Department of Health (ASDoH) detected through surveillance an increase in the number of cases of acute febrile rash illness. Concurrently, a case of laboratory-confirmed Zika virus infection, a mosquito-borne flavivirus infection documented to cause microcephaly and other severe brain defects in some infants born to women infected during pregnancy (1,2) was reported in a traveler returning to New Zealand from American Samoa. In the absence of local laboratory capacity to test for Zika virus, ASDoH initiated arboviral disease control measures, including public education and vector source reduction campaigns. On February 1, CDC staff members were deployed to American Samoa to assist ASDoH with testing and surveillance efforts. PMID- 27764078 TI - Notes from the Field: Pediatric Emergency Department Visits for Buprenorphine/Naloxone Ingestion - United States, 2008-2015. AB - Expanding access to office-based medication-assisted treatment with buprenorphine/naloxone for opioid dependence is a key part of the national strategy to address the opioid abuse epidemic (1). However, as buprenorphine/naloxone prescribing increased, emergency department (ED) visits and hospitalizations for unsupervised ingestions by young children began to increase, with buprenorphine/naloxone ingestions becoming the most common cause of hospitalization for medication ingestions by young children during 2010-2011 (2). Buprenorphine ingestions might be asymptomatic or can cause drowsiness, vomiting, or respiratory depression, which if untreated can result in death (3). Buprenorphine/naloxone was available only as tablets in multidose child-resistant bottles (Suboxone) until late 2010, when film strips packaged in unit-dose, child resistant pouches were introduced. In 2013, tablets became available in unit-dose packaging (Zubsolv). Because unit-dose, child-resistant packaging encloses each dose until opened, it might limit unintended ingestions by young children compared with traditional child-resistant bottles that must be resecured after every use (4). This study compared ED visits for pediatric buprenorphine/naloxone ingestions before and after these product packaging/formulation changes. PMID- 27764080 TI - QuickStats: Cancer Death Rates* for Children and Teens Aged 1-19 Years - United States, 1999, 2006, and 2014?. PMID- 27764079 TI - Notes from the Field: Chlorination Strategies for Drinking Water During a Cholera Epidemic - Tanzania, 2016. AB - Since August 2015, the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC) of Tanzania has been leading the response to a widespread cholera outbreak. As of June 9, 2016, cholera had affected 23 of 25 regions in Tanzania, with 21,750 cumulative cases and 341 deaths reported (Ally Nyanga, MoHCDGEC Emergency Operations Center, personal communication, June 2016). Approximately one fourth of all cases occurred in the Dar es Salaam region on the east coast. Regions surrounding Lake Victoria, in the north, also reported high case counts, including Mwanza with 9% (Ally Nyanga, MoHCDGEC Emergency Operations Center, personal communication, June 2016). Since the start of the outbreak, MoHCDGEC and the Ministry of Water (MOW) have collaborated with the Tanzania Red Cross Society, United Nations Children's Fund (UNICEF), World Health Organization (WHO), and CDC to enhance the water, sanitation, and hygiene (WASH) response to prevent the further spread of cholera. PMID- 27764081 TI - National Progress Toward Hepatitis C Elimination - Georgia, 2015-2016. AB - The country of Georgia has a high prevalence of hepatitis C virus (HCV) infection, associated with exposures to HCV in health care settings with inadequate infection control and unsafe injections among persons who inject drugs (1). In April 2015, in collaboration with CDC and other partners, Georgia embarked on a program to eliminate HCV infection, subsequently defined as achieving a 90% reduction in prevalence by 2020. The initial phase of the program focused on providing HCV treatment to infected persons with advanced liver disease and at highest risk for HCV-associated morbidity and mortality. By April 27, 2016, a total of 27,392 HCV-infected persons registered for the program, 8,448 (30.8%) started treatment, and 5,850 patients (69.2%) completed HCV treatment. Among patients completing treatment who were eligible for posttreatment testing, 2,398 received polymerase chain reaction (PCR) testing for HCV at least 12 weeks after completion of treatment; 1,980 (82.6%) had no detectable virus, indicative of a sustained virologic response* (i.e., cure). Major challenges to achieving elimination remain, including the need to increase access to care and treatment services and implement a comprehensive approach to prevention and control of HCV infection. As a global leader in this effort, the Georgia HCV Elimination Program can help pave the way for other countries experiencing high rates of HCV infection to undertake similar initiatives. PMID- 27764082 TI - Declines in Opioid Prescribing After a Private Insurer Policy Change - Massachusetts, 2011-2015. AB - Overdose deaths involving opioid pain medications are epidemic in the United States, in part because of high opioid prescribing rates and associated abuse of these drugs (1). In 2014, nearly 2 million U.S. residents either abused or were dependent on prescription opioids (2). In Massachusetts, unintentional opioid related overdose deaths, including deaths involving heroin, increased 45% from 2012 to 2013.* In 2014, the rate of these deaths reached 20.0 per 100,000, nearly 2.5 times higher than the U.S. rate overall (3,4). On July 1, 2012, Blue Cross Blue Shield of Massachusetts (BCBSMA), the largest insurer in the state with approximately 2.8 million members,? implemented a comprehensive opioid utilization program after learning that many of its members were receiving new prescriptions with a >30-day supply of opioids. The 2016 CDC Guideline for Prescribing Opioids for Chronic Pain recommends avoiding opioids as a first-line therapy for chronic pain and limiting quantities when initiating opioids for acute pain (5). CDC analyzed BCBSMA prescription claims data for the period 2011 2015 to assess the effect of the new utilization program on opioid prescribing rates. During the first 3 years after policy implementation, the average monthly prescribing rate for opioids decreased almost 15%, from 34 per 1,000 members to 29. The percentage of BCBSMA members per month with current opioid prescriptions also declined. The temporal association between implementation of the program and statistically significant declines in both prescribing rates and proportion of members using opioids suggests that the BCBSMA initiative played a role in reducing the use of prescription opioids among its members. Public and private insurers in the United States could benefit from developing their own best practices for prescription opioid utilization that ensure accessible pain care, while reducing the risk for dependence and abuse associated with these drugs. PMID- 27764083 TI - Status of New Vaccine Introduction - Worldwide, September 2016. AB - Since the global Expanded Program on Immunization (EPI) was launched in 1974, vaccination against six diseases (tuberculosis, polio, diphtheria, tetanus, pertussis, and measles) has prevented millions of deaths and disabilities (1). Significant advances have been made in the development and introduction of vaccines, and licensed vaccines are now available to prevent 25 diseases (2,3). Historically, new vaccines only became available in low-income and middle-income countries decades after being introduced in high-income countries. However, with the support of global partners, including the World Health Organization (WHO) and the United Nations Children's Fund, which assist with vaccine prequalification and procurement, as well as Gavi, the Vaccine Alliance (Gavi) (4), which provides funding and shapes vaccine markets through forecasting and assurances of demand in low-income countries in exchange for lower vaccine prices, vaccines are now introduced more rapidly. Based on data compiled in the WHO Immunization Vaccines and Biologicals Database* (5), this report describes the current status of introduction of Haemophilus influenzae type b (Hib), hepatitis B, pneumococcal conjugate, rotavirus, human papillomavirus, and rubella vaccines, and the second dose of measles vaccine. As of September 2016, a total of 191 (99%) of 194 WHO member countries had introduced Hib vaccine, 190 (98%) had introduced hepatitis B vaccine, 132 (68%) had introduced pneumococcal conjugate vaccine (PCV), and 86 (44%) had introduced rotavirus vaccine into infant vaccination schedules. Human papillomavirus vaccine (HPV) had been introduced in 67 (35%) countries, primarily targeted for routine use in adolescent girls. A second dose of measles-containing vaccine (MCV2) had been introduced in 161 (83%) countries, and rubella vaccine had been introduced in 149 (77%). These efforts support the commitment outlined in the Global Vaccine Action Plan (GVAP), 2011-2020 (2), endorsed by the World Health Assembly in 2012, to extend the full benefits of immunization to all persons. PMID- 27764084 TI - Novel Nuclear Factor-KappaB Targeting Peptide Suppresses beta-Amyloid Induced Inflammatory and Apoptotic Responses in Neuronal Cells. AB - In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-kappabeta) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-kappaBeta dimers. In Alzheimer's disease (AD), beta-amyloid (Abeta) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration. Hence selective targeting of activated p65 is an attractive therapeutic strategy for AD. Here we report the design, structural and functional characterization of peptide analogs of a p65 interacting protein, the glucocorticoid induced leucine zipper (GILZ). By virtue of binding the transactivation domain of p65 exposed after release from the inhibitory IkappaBeta proteins in activated cells, the GILZ analogs can act as highly selective inhibitors of activated p65 with minimal potential for off-target effects. PMID- 27764085 TI - Use of Household Cluster Investigations to Identify Factors Associated with Chikungunya Virus Infection and Frequency of Case Reporting in Puerto Rico. AB - BACKGROUND: Chikungunya virus (CHIKV) is transmitted by Aedes species mosquitoes and is the cause of an acute febrile illness characterized by potentially debilitating arthralgia. After emerging in the Caribbean in late 2013, the first locally-acquired case reported to public health authorities in Puerto Rico occurred in May 2014. During June-August 2014, household-based cluster investigations were conducted to identify factors associated with infection, development of disease, and case reporting. METHODOLOGY/PRINCIPAL FINDINGS: Residents of households within a 50-meter radius of the residence of laboratory positive chikungunya cases that had been reported to Puerto Rico Department of Health (PRDH) were offered participation in the investigation. Participants provided a serum specimen and answered a questionnaire that collected information on demographic factors, household characteristics, recent illnesses, healthcare seeking behaviors, and clinical diagnoses. Current CHIKV infection was identified by rRT-PCR, and recent CHIKV infection was defined by detection of either anti CHIKV IgM or IgG antibody. Among 250 participants, 74 (30%) had evidence of CHIKV infection, including 12 (5%) with current and 62 (25%) with recent CHIKV infection. All specimens from patients with CHIKV infection that were collected within four days, two weeks, and three weeks of illness onset were positive by RT PCR, IgM ELISA, and IgG ELISA, respectively. Reporting an acute illness in the prior three months was strongly associated with CHIKV infection (adjusted odds ratio [aOR] = 21.6, 95% confidence interval [CI]: 9.24-50.3). Use of air conditioning (aOR = 0.50, 95% CI = 0.3-0.9) and citronella candles (aOR = 0.4, 95% CI = 0.1-0.9) were associated with protection from CHIKV infection. Multivariable analysis indicated that arthralgia (aOR = 51.8, 95% CI = 3.8-700.8) and skin rash (aOR = 14.2, 95% CI = 2.4-84.7) were strongly associated with CHIKV infection. Hierarchical cluster analysis of signs and symptoms reported by CHIKV infected participants demonstrated that fever, arthralgia, myalgia, headache, and chills tended to occur simultaneously. Rate of symptomatic CHIKV infection (defined by arthralgia with fever or skin rash) was 62.5%. Excluding index case patients, 22 (63%) participants with symptomatic CHIKV infection sought medical care, of which 5 (23%) were diagnosed with chikungunya and 2 (9%) were reported to PRDH. CONCLUSIONS/SIGNIFICANCE: This investigation revealed high rates of CHIKV infection among household members and neighbors of chikungunya patients, and that behavioral interventions such as use of air conditioning were associated with prevention of CHIKV infection. Nearly two-thirds of patients with symptomatic CHIKV infection sought medical care, of which less than one-quarter were reportedly diagnosed with chikungunya and one-in-ten were reported to public health authorities. These findings emphasize the need for point-of-care rapid diagnostic tests to optimize identification and reporting of chikungunya patients. PMID- 27764087 TI - Optimized Treatment Schedules for Chronic Myeloid Leukemia. AB - Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib) have been developed to treat Chronic Myeloid Leukemia (CML). Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies. However, the design of such combination therapies (timing, sequence, etc.) remains an open challenge. In this work we mathematically model the dynamics of CML response to combination therapy and analyze the impact of combination treatment schedules on treatment efficacy in patients with preexisting resistance. We then propose an optimization problem to find the best schedule of multiple therapies based on the evolution of CML according to our ordinary differential equation model. This resulting optimization problem is nontrivial due to the presence of ordinary different equation constraints and integer variables. Our model also incorporates drug toxicity constraints by tracking the dynamics of patient neutrophil counts in response to therapy. We determine optimal combination strategies that maximize time until treatment failure on hypothetical patients, using parameters estimated from clinical data in the literature. PMID- 27764086 TI - Number of People Blind or Visually Impaired by Glaucoma Worldwide and in World Regions 1990 - 2010: A Meta-Analysis. AB - OBJECTIVE: To assess the number of individuals visually impaired or blind due to glaucoma and to examine regional differences and temporal changes in this parameter for the period from 1990 to 2012. METHODS: As part of the Global Burden of Diseases (GBD) Study 2010, we performed a systematic literature review for the period from 1980 to 2012. We primarily identified 14,908 relevant manuscripts, out of which 243 high-quality, population-based studies remained after review by an expert panel that involved application of selection criteria that dwelt on population representativeness and clarity of visual acuity methods used. Sixty six specified the proportion attributable to glaucoma. The software tool DisMod MR (Disease Modeling-Metaregression) of the GBD was used to calculate fraction of vision impairment due to glaucoma. RESULTS: In 2010, 2.1 million (95% Uncertainty Interval (UI):1.9,2.6) people were blind, and 4.2 (95% UI:3.7,5.8) million were visually impaired due to glaucoma. Glaucoma caused worldwide 6.6% (95% UI:5.9,7.9) of all blindness in 2010 and 2.2% (95% UI:2.0,2.8) of all moderate and severe visual impairment (MSVI). These figures were lower in regions with younger populations (<5% in South Asia) than in high-income regions with relatively old populations (>10%). From 1990 to 2010, the number of blind or visually impaired due to glaucoma increased by 0.8 million (95%UI:0.7, 1.1) or 62% and by 2.3 million (95%UI:2.1,3.5) or 83%, respectively. Percentage of global blindness caused by glaucoma increased between 1990 and 2010 from 4.4% (4.0,5.1) to 6.6%. Age-standardized prevalence of glaucoma related blindness and MSVI did not differ markedly between world regions nor between women. SIGNIFICANCE: By 2010, one out of 15 blind people was blind due to glaucoma, and one of 45 visually impaired people was visually impaired, highlighting the increasing global burden of glaucoma. PMID- 27764089 TI - Ten Simple Rules for Developing a MOOC. PMID- 27764088 TI - Ten Simple Rules for Digital Data Storage. PMID- 27764090 TI - Chronic Kidney Disease Is Positively and Diabetes Mellitus Is Negatively Associated with Abdominal Aortic Aneurysm. AB - BACKGROUND AND AIMS: Chronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. The purpose of this study was to clarify the relationship of CKD and DM with the presence of abdominal aortic aneurysm (AAA). METHODS: We enrolled 261 patients with AAA (AAA+) and age and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, in order to investigate the prevalence of AAA in each group, we enrolled 1126 patients with CKD and 400 patients with DM. RESULTS: The presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA- (AAA+; 65%, AAA-; 52%, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA- (AAA+; 17%, AAA-; 35%, P < 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was a negatively independent determinant, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1%, whereas, that in patients with DM 65 years old and above was only 0.6%. CONCLUSION: CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA in Japanese population. PMID- 27764092 TI - Epidemiology of HPV Genotypes among HIV Positive Women in Kenya: A Systematic Review and Meta-Analysis. AB - BACKGROUND: There is a scarcity of data on the distribution of human papillomavirus (HPV) genotypes in the HIV positive population and in invasive cervical cancer (ICC) in Kenya. This may be different from genotypes found in abnormal cytology. Yet, with the advent of preventive HPV vaccines that target HPV 16 and 18, and the nonavalent vaccine targeting 90% of all ICC cases, such HPV genotype distribution data are indispensable for predicting the impact of vaccination and HPV screening on prevention. Even with a successful vaccination program, vaccinated women will still require screening to detect those who will develop ICC from other High risk (HR) HPV genotypes not prevented by current vaccines. The aim of this review is to report on the prevalence of pHR/HR HPV types and multiple pHR/HR HPV genotypes in Kenya among HIV positive women with normal, abnormal cytology and ICC. METHODS: PUBMED, EMBASE, SCOPUS, and PROQUEST were searched for articles on HPV infection up to August 2nd 2016. Search terms were HIV, HPV, Cervical Cancer, Incidence or Prevalence, and Kenya. RESULTS: The 13 studies included yielded a total of 2116 HIV-infected women, of which 89 had ICC. The overall prevalence of pHR/HR HPV genotypes among HIV-infected women was 64% (95%CI: 50%-77%). There was a borderline significant difference in the prevalence of pHR/HR HPV genotypes between Female Sex workers (FSW) compared to non-FSW in women with both normal and abnormal cytology. Multiple pHR/HR HPV genotypes were highly prominent in both normal cytology/HSIL and ICC. The most prevalent HR HPV genotypes in women with abnormal cytology were HPV 16 with 26%, (95%CI: 23.0%-30.0%) followed by HPV 35 and 52, with 21% (95%CI: 18%-25%) and 18% (95%CI: 15%-21%), respectively. In women with ICC, the most prevalent HPV genotypes were HPV 16 (37%; 95%CI: 28%-47%) and HPV 18 (24%; 95%CI: 16%-33%). CONCLUSION: HPV 16/18 gains prominence as the severity of cervical disease increases, with HPV 16/18 accounting for 61% (95%CI: 50.0%-70.0%) of all ICC cases. A secondary prevention program will be necessary as this population harbors multiple pHR/HR HPV co-infections, which may not be covered by current vaccines. A triage based on FSW as an indicator may be warranted. PMID- 27764091 TI - Pomegranate Supplementation Accelerates Recovery of Muscle Damage and Soreness and Inflammatory Markers after a Weightlifting Training Session. AB - PURPOSE: The aim of this study was to investigate the effect of natural Pomegranate juice supplementation on performance and acute and delayed responses of muscle soreness and biomarkers of muscle damage after a weightlifting training session. METHODS: Nine elite weightlifters (21+/-0.5 years) performed two Olympic Weightlifting-sessions after either placebo (PLA) or natural pomegranate juice (POMj) supplementations. Heart rate, blood pressure and blood samples (hematological parameters, muscle damage and C-reactive protein (CRP)) were collected at rest, 3min and 48h after each session. Weightlifting performance, RPE, and DOMS were also assessed after each training session. RESULTS: T-test showed higher performance (+8.30%) and lower RPE values (-4.37%) using POMj supplementation (p<0.05) in comparison with PLA. For the DOMS values, a significant improvement (13.4%) was shown only for the knee extensors (p<0.01) using the POMj. Compared to PLA condition, POMj attenuated the acute (i.e., 3min) increase of systolic blood pressure (SBP), HR, CK and LDH (p<0.05; -4.46%, 1.81%, -8.75%, -1.64%, respectively) and blunted the significant increase of ASAT, PAL and CRP (p>0.05). Additionally, during the 48h following the training session, POMj improved the recovery kinetic of SBP (p<0.01, 7.97%), CK (p<0.001, 11.34%), LDH (p<0.05, 7.30%) and ASAT (p<0.05, 6.77%). Indeed, the present study showed that 48h of recovery associated to natural POMj supplementation was sufficient to reach the resting values of the selected muscle damage markers after intensive training session. CONCLUSION: Natural POMj seems to ameliorate the capacity to adhere to an intensive training program. Therefore, elite weightlifters are advised to use natural POMj during intensive training program and competition to accelerate muscle recovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT02697903. PMID- 27764093 TI - High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting. AB - In the present study we have investigated whether Caveolin-1 expression in non malignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients managed by watchful waiting. Caveolin-1 was measured in prostate tissues obtained through transurethral resection of the prostate from 395 patients diagnosed with prostate cancer. The majority of the patients (n = 298) were followed by watchful waiting after diagnosis. Tissue microarrays constructed from malignant and non-malignant prostate tissue were stained with an antibody against Caveolin-1. The staining pattern was scored and related to clinicopathologic parameters and outcome. Microdissection and qRT-PCR analysis of Cav-1 was done of the prostate stroma from non-malignant tissue and stroma from Gleason 3 and 4 tumors. Cav-1 RNA expression was highest in non malignant tissue and decreased during cancer progression. High expression of Caveolin-1 in tumor stroma was associated with significantly longer cancer specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were combined with Caveolin 1 in a Cox regression model. High stromal Caveolin-1 immunoreactivity in prostate tumors is associated with a favourable prognosis in prostate cancer patients managed by watchful waiting. Caveolin-1 could possibly become a useful prognostic marker for prostate cancer patients that are potential candidates for active surveillance. PMID- 27764094 TI - Long-Term Outcomes on Antiretroviral Therapy in a Large Scale-Up Program in Nigeria. AB - BACKGROUND: While there has been a rapid global scale-up of antiretroviral therapy programs over the past decade, there are limited data on long-term outcomes from large cohorts in resource-constrained settings. Our objective in this evaluation was to measure multiple outcomes during first-line antiretroviral therapy in a large treatment program in Nigeria. METHODS: We conducted a retrospective multi-site program evaluation of adult patients (age >=15 years) initiating antiretroviral therapy between June 2004 and February 2012 in Nigeria. The baseline characteristics of patients were described and longitudinal analyses using primary endpoints of immunologic recovery, virologic rebound, treatment failure and long-term adherence patterns were conducted. RESULTS: Of 70,002 patients, 65.2% were female and median age was 35 (IQR: 29-41) years; 54.7% were started on a zidovudine-containing and 40% on a tenofovir-containing first-line regimen. Median CD4+ cell counts for the cohort started at 149 cells/mm3 (IQR: 78 220) and increased over duration of ART. Of the 70,002 patients, 1.8% were reported as having died, 30.1% were lost to follow-up, and 0.1% withdrew from treatment. Overall, of those patients retained and with viral load data, 85.4% achieved viral suppression, with 69.3% achieving suppression by month 6. Of 30,792 patients evaluated for virologic failure, 24.4% met criteria for failure and of 45,130 evaluated for immunologic failure, 34.0% met criteria for immunologic failure, with immunologic criteria poorly predicting virologic failure. In adjusted analyses, older age, ART regimen, lower CD4+ cell count, higher viral load, and inadequate adherence were all predictors of virologic failure. Predictors of immunologic failure differed slightly, with age no longer predictive, but female sex as protective; additionally, higher baseline CD4+ cell count was also predictive of failure. Evaluation of long-term adherence patterns revealed that the majority of patients retained through 84 months maintained >=95% adherence. CONCLUSION: While improved access to HIV care and treatment remains a challenge in Nigeria, our study shows that a high quality of care was achieved as evidenced by strong long-term clinical, immunologic and virologic outcomes. PMID- 27764095 TI - Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections. AB - The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) of an antibiotic as a function of the initial size of a microbial population. The IE has been observed in a wide range of bacteria, implying that antibiotic efficacy may depend on population density. Such density dependence could have dramatic effects on bacterial population dynamics and potential treatment strategies, but explicit measures of per capita growth as a function of density are generally not available. Instead, the IE measures MIC as a function of initial population size, and population density changes by many orders of magnitude on the timescale of the experiment. Therefore, the functional relationship between population density and antibiotic inhibition is generally not known, leaving many questions about the impact of the IE on different treatment strategies unanswered. To address these questions, here we directly measured real-time per capita growth of Enterococcus faecalis populations exposed to antibiotic at fixed population densities using multiplexed computer-automated culture devices. We show that density-dependent growth inhibition is pervasive for commonly used antibiotics, with some drugs showing increased inhibition and others decreased inhibition at high densities. For several drugs, the density dependence is mediated by changes in extracellular pH, a community-level phenomenon not previously linked with the IE. Using a simple mathematical model, we demonstrate how this density dependence can modulate population dynamics in constant drug environments. Then, we illustrate how time-dependent dosing strategies can mitigate the negative effects of density-dependence. Finally, we show that these density effects lead to bistable treatment outcomes for a wide range of antibiotic concentrations in a pharmacological model of antibiotic treatment. As a result, infections exceeding a critical density often survive otherwise effective treatments. PMID- 27764096 TI - A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records. AB - Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10 11), 52Kb 3' of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI. PMID- 27764098 TI - The Spatial Dynamics of Predators and the Benefits and Costs of Sharing Information. AB - Predators of all kinds, be they lions hunting in the Serengeti or fishermen searching for their catch, display various collective strategies. A common strategy is to share information about the location of prey. However, depending on the spatial characteristics and mobility of predators and prey, information sharing can either improve or hinder individual success. Here, our goal is to investigate the interacting effects of space and information sharing on predation efficiency, represented by the expected rate at which prey are found and consumed. We derive a feeding functional response that accounts for both spatio temporal heterogeneity and communication, and validate this mathematical analysis with a computational agent-based model. This agent-based model has an explicit yet minimal representation of space, as well as information sharing about the location of prey. The analytical model simplifies predator behavior into a few discrete states and one essential trade-off, between the individual benefit of acquiring information and the cost of creating spatial and temporal correlation between predators. Despite the absence of an explicit spatial dimension in these equations, they quantitatively predict the predator consumption rates measured in the agent-based simulations across the explored parameter space. Together, the mathematical analysis and agent-based simulations identify the conditions for when there is a benefit to sharing information, and also when there is a cost. PMID- 27764097 TI - Dynamic Nucleosome Movement Provides Structural Information of Topological Chromatin Domains in Living Human Cells. AB - The mammalian genome is organized into submegabase-sized chromatin domains (CDs) including topologically associating domains, which have been identified using chromosome conformation capture-based methods. Single-nucleosome imaging in living mammalian cells has revealed subdiffusively dynamic nucleosome movement. It is unclear how single nucleosomes within CDs fluctuate and how the CD structure reflects the nucleosome movement. Here, we present a polymer model wherein CDs are characterized by fractal dimensions and the nucleosome fibers fluctuate in a viscoelastic medium with memory. We analytically show that the mean-squared displacement (MSD) of nucleosome fluctuations within CDs is subdiffusive. The diffusion coefficient and the subdiffusive exponent depend on the structural information of CDs. This analytical result enabled us to extract information from the single-nucleosome imaging data for HeLa cells. Our observation that the MSD is lower at the nuclear periphery region than the interior region indicates that CDs in the heterochromatin-rich nuclear periphery region are more compact than those in the euchromatin-rich interior region with respect to the fractal dimensions as well as the size. Finally, we evaluated that the average size of CDs is in the range of 100-500 nm and that the relaxation time of nucleosome movement within CDs is a few seconds. Our results provide physical and dynamic insights into the genome architecture in living cells. PMID- 27764099 TI - Liquid Organic Fertilizers for Sustainable Agriculture: Nutrient Uptake of Organic versus Mineral Fertilizers in Citrus Trees. AB - The main objective of this study was to compare the performance of two liquid organic fertilizers, an animal and a plant-based fertilizer, with mineral fertilization on citrus trees. The source of the fertilizer (mineral or organic) had significant effect in the nutritional status of the organic and conventionally managed mandarins. Nutrient uptake, vegetative growth, carbohydrate synthesis and soil characteristics were analyzed. Results showed that plants fertilized with animal based liquid fertilizers exhibited higher total biomass with a more profuse development of new developing organs (leaves and fibrous roots). Liquid organic fertilization resulted in an increased uptake of macro and micronutrients compared to mineral fertilized trees. Moreover, organic fertilization positively affected the carbohydrate content (fructose, glucose and sucrose) mainly in summer flush leaves. Liquid organic fertilization also resulted in an increase of soil organic matter content. Animal-based fertilizer, due to intrinsic composition, increased total tree biomass and carbohydrate leaves content, and led to lower soil nitrate concentration and higher P and Mg exchangeable in soil extract compared to vegetal-based fertilizer. Therefore, liquid organic fertilizers could be used as an alternative to traditional mineral fertilization in drip irrigated citrus trees. PMID- 27764100 TI - High Serum Tumor Necrosis Factor-Alpha Levels in Women with Polycystic Ovary Syndrome: A Meta-Analysis. AB - The objective of the study is to assess the TNF-alpha levels in PCOS patients and healthy controls. A comprehensive electronic search in Medline, Embase, and the Cochrane Library database was conducted up to July 2016. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs). Twenty-nine studies with a total of 1960 participants (1046 PCOS patients and 914 controls) were included in this meta-analysis. The TNF-alpha levels in PCOS patients were significantly higher than those in controls (random effects, SMD = 0.60, 95% CI = 0.28-0.92, P<0.001). With regard to the subgroup analyses stratified by ethnicity, study quality, methods, and BMI, significantly high TNF-alpha levels were found in patients with PCOS in almost all of these subgroups. In the subgroup stratified by HOMA-IR ratio and T ratio, significant differences were only observed in the subgroups with HOMA-IR ratio of >1.72(SMD = 0.967, 95% CI = 0.103-1.831, P = 0.028, I2 = 93.5%) and T ratio>2.10 (SMD = 1.420, 95% CI = 0.429-2.411, P = 0.005, I2 = 96.1%). By meta-regression it was suggested that ethnicity might contribute little to the heterogeneity between the included studies. Through cumulative meta-analysis and sensitivity analysis it was supposed that the higher TNF-alpha levels of PCOS patients compared to healthy controls was stable and reliable. This meta-analysis suggests that the circulating TNF-alpha levels in women with PCOS are significantly higher than those in healthy controls. It may be involved in promoting insulin resistance and androgen excess of PCOS. PMID- 27764103 TI - Determining the Stationarity Distance via a Reversible Stochastic Process. AB - The problem of controlling stationarity involves an important aspect of forecasting, in which a time series is analyzed in terms of levels or differences. In the literature, non-parametric stationary tests, such as the Kwiatkowski-Phillips-Schmidt-Shin (KPSS) tests, have been shown to be very important; however, they are affected by problems with the reliability of lag and sample size selection. To date, no theoretical criterion has been proposed for the lag-length selection for tests of the null hypothesis of stationarity. Their use should be avoided, even for the purpose of so-called 'confirmation'. The aim of this study is to introduce a new method that measures the distance by obtaining each numerical series from its own time-reversed series. This distance is based on a novel stationary ergodic process, in which the stationary series has reversible symmetric features, and is calculated using the Dynamic Time warping (DTW) algorithm in a self-correlation procedure. Furthermore, to establish a stronger statistical foundation for this method, the F-test is used as a statistical control and is a suggestion for future statistical research on resolving the problem of a sample of limited size being introduced. Finally, as described in the theoretical and experimental documentation, this distance indicates the degree of non-stationarity of the times series. PMID- 27764102 TI - Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial. AB - BACKGROUND: It is recommended that children aged 3 months to five years of age living in areas of seasonal transmission in the sub-Sahel should receive Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) during the malaria transmission season. The purpose of this study was to evaluate the safety of SMC with SPAQ in children when delivered by community health workers in three districts in Senegal where SMC was introduced over three years, in children from 3 months of age to five years of age in the first year, then in children up to 10 years of age. METHODS: A surveillance system was established to record all deaths and all malaria cases diagnosed at health facilities and a pharmacovigilance system was established to detect adverse drug reactions. Health posts were randomized to introduce SMC in a stepped wedge design. SMC with SPAQ was administered once per month from September to November, by nine health-posts in 2008, by 27 in 2009 and by 45 in 2010. RESULTS: After three years, 780,000 documented courses of SMC had been administered. High coverage was achieved. No serious adverse events attributable to the intervention were detected, despite a high level of surveillance. CONCLUSIONS: SMC is being implemented in countries of the sub-Sahel for children under 5 years of age, but in some areas the age distribution of cases of malaria may justify extending this age limit, as has been done in Senegal. Our results show that SMC is well tolerated in children under five and in older children. However, pharmacovigilance should be maintained where SMC is implemented and provision for strengthening national pharmacovigilance systems should be included in plans for SMC implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00712374. PMID- 27764104 TI - Measuring Concurrency Attitudes: Development and Validation of a Vignette-Based Scale. AB - BACKGROUND: Concurrent sexual partnerships (partnerships that overlap in time) may contribute to higher rates of HIV transmission in African Americans. Attitudes toward a behavior constitute an important component of most models of health-related behavior and behavioral change. We have developed a scale, employing realistic vignettes that appear to reliably measure attitudes about concurrency in young African American adults. METHODS: Vignette-based items to assess attitudes about concurrency were developed following focus groups and cognitive testing of items adapted from existing scales assessing psychosocial constructs surrounding related sexual behaviors. The new items were included in a telephone survey of African American adults (18-34 years old) in Eastern North Carolina immediately before and after a radio campaign designed to discourage concurrency. We performed an exploratory factor analysis on each sample (pre- and post-campaign) to cross-validate results. We retained factors with a primary loading of >=0.50 and no secondary loading >0.30. Cronbach's coefficient alpha was used to evaluate internal reliability. Associations in the predicted direction between the mean responses to items on the final factor and known correlates of concurrency validated the scale. RESULTS: Factor analysis in a random pre-campaign subsample yielded a one-factor 6-item scale with acceptable internal consistency (Cronbach's alpha = 0.79). As expected, the attitude factor was positively associated with participation in concurrent partnerships, whether assessed by self-report (r = 0.298, p<0.0001) or deduced from dates of recent sexual partnerships (r = 0.298, p<0.0001). The factor was also positively associated with alcohol (r = 0.216, p<0.0001) and drug use (r = 0.225, p<0.0001) and negatively associated with increasing age (r = -0.088, p- = 0.02) and female gender (r = -0.232, p<0.0001). Factor analyses repeated in the second random pre campaign subsample and post-campaign sample confirmed these results. CONCLUSION: A vignette-based scale may be an effective measure of key attitudes related to concurrency and potentially a useful tool to evaluate interventions addressing this network pattern. PMID- 27764101 TI - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. AB - We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade. PMID- 27764106 TI - Provenancing Archaeological Wool Textiles from Medieval Northern Europe by Light Stable Isotope Analysis (delta13C, delta15N, delta2H). AB - We investigate the origin of archaeological wool textiles preserved by anoxic waterlogging from seven medieval archaeological deposits in north-western Europe (c. 700-1600 AD), using geospatial patterning in carbon (delta13C), nitrogen (delta15N) and non-exchangeable hydrogen (delta2H) composition of modern and ancient sheep proteins. delta13C, delta15N and delta2H values from archaeological wool keratin (n = 83) and bone collagen (n = 59) from four sites were interpreted with reference to the composition of modern sheep wool from the same regions. The isotopic composition of wool and bone collagen samples clustered strongly by settlement; inter-regional relationships were largely parallel in modern and ancient samples, though landscape change was also significant. Degradation in archaeological wool samples, examined by elemental and amino acid composition, was greater in samples from Iceland (Reykholt) than in samples from north-east England (York, Newcastle) or northern Germany (Hessens). A nominal assignment approach was used to classify textiles into local/non-local at each site, based on maximal estimates of isotopic variability in modern sheep wool. Light element stable isotope analysis provided new insights into the origins of wool textiles, and demonstrates that isotopic provenancing of keratin preserved in anoxic waterlogged contexts is feasible. We also demonstrate the utility of delta2H analysis to understand the location of origin of archaeological protein samples. PMID- 27764105 TI - Genome-Wide Meta-Analysis of Sciatica in Finnish Population. AB - Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate. PMID- 27764107 TI - Development of a Web-Based Clinical Decision Support System for Drug Prescription: Non-Interventional Naturalistic Description of the Antipsychotic Prescription Patterns in 4345 Outpatients and Future Applications. AB - PURPOSE: The emergence of electronic prescribing devices with clinical decision support systems (CDSS) is able to significantly improve management pharmacological treatments. We developed a web application available on smartphones in order to help clinicians monitor prescription and further propose CDSS. METHOD: A web application (www.MEmind.net) was developed to assess patients and collect data regarding gender, age, diagnosis and treatment. We analyzed antipsychotic prescriptions in 4345 patients attended in five Psychiatric Community Mental Health Centers from June 2014 to October 2014. The web application reported average daily dose prescribed for antipsychotics, prescribed daily dose (PDD), and the PDD to defined daily dose (DDD) ratio. RESULTS: The MEmind web-application reported that antipsychotics were used in 1116 patients out of the total sample, mostly in 486 (44%) patients with schizophrenia related disorders but also in other diagnoses. Second generation antipsychotics (quetiapine, aripiprazole and long-acting paliperidone) were preferably employed. Low doses were more frequently used than high doses. Long acting paliperidone and ziprasidone however, were the only two antipsychotics used at excessive dosing. Antipsychotic polypharmacy was used in 287 (26%) patients with classic depot drugs, clotiapine, amisulpride and clozapine. CONCLUSIONS: In this study we describe the first step of the development of a web application that is able to make polypharmacy, high dose usage and off label usage of antipsychotics visible to clinicians. Current development of the MEmind web application may help to improve prescription security via momentary feedback of prescription and clinical decision support system. PMID- 27764109 TI - When Significant Others Suffer: German Validation of the Burden Assessment Scale (BAS). AB - There is a need of an economical, reliable, and valid instrument in the German speaking countries to measure the burden of relatives who care for mentally ill persons. We translated the Burden Assessment Scale (BAS) and conducted a study investigating factor structure, psychometric quality and predictive validity. We used confirmative factor analyses (CFA, maximum-likelihood method) to examine the dimensionality of the German BAS in a sample of 215 relatives (72% women; M = 32 years, SD = 14, range: 18 to 77; 39% employed) of mentally ill persons (50% (ex )partner or (best) friend; M = 32 years, SD = 13, range 8 to 64; main complaints were depression and/or anxiety). Cronbach's alpha determined the internal consistency. We examined predictive validity using regression analyses including the BAS and validated scales of social systems functioning (Experience In Social Systems Questionnaire, EXIS.pers, EXIS.org) and psychopathology (Brief Symptom Inventory, BSI). Variables that might have influenced the dependent variables (e.g. age, gender, education, employment and civil status) were controlled by their introduction in the first step, and the BAS in the second step of the regression analyses. A model with four correlated factors (Disrupted Activities, Personal Distress, Time Perspective, Guilt) showed the best fit. With respect to the number of items included, the internal consistency was very good. The modified German BAS predicted relatives' social systems functioning and psychopathology. The economical design makes the 19-item BAS promising for practice-oriented research, and for studies under time constraints. Strength, limitations and future directions are discussed. PMID- 27764108 TI - Identification and Characterization of VNI/VNII and Novel VNII/VNIV Hybrids and Impact of Hybridization on Virulence and Antifungal Susceptibility Within the C. neoformans/C. gattii Species Complex. AB - Cryptococcus neoformans and C. gattii are pathogenic basidiomycetous yeasts and the commonest cause of fungal infection of the central nervous system. Cryptococci are typically haploid but several inter-species, inter-varietal and intra-varietal hybrids have been reported. It has a bipolar mating system with sexual reproduction occurring normally between two individuals with opposite mating types, alpha and a. This study set out to characterize hybrid isolates within the C. neoformans/C. gattii species complex: seven unisexual mating intra varietal VNI/VNII (alphaAAalpha) and six novel inter-varietal VNII/VNIV (aADalpha). The URA5-RFLP pattern for VNII/VNIV (aADalpha) differs from the VNIII (alphaADa) hybrids. Analysis of the allelic patterns of selected genes for AD hybrids showed 79% or more heterozygosis for the studied loci except for CBS132 (VNIII), which showed 50% of heterozygosity. MALDI-TOF MS was applied to hybrids belonging to different sero/mating type allelic patterns. All hybrid isolates were identified as belonging to the same hybrid group with identification scores ranging between 2.101 to 2.634. All hybrids were virulent when tested in the Galleria mellonella (wax moth) model, except for VNII/VNIV (aADalpha) hybrids. VNI/VGII hybrids were the most virulent hybrids. Hybrids recovered from larvae manifested a significant increase in capsule and total cell size and produced a low proportion (5-10%) of giant cells compared with the haploid control strains. All strains expressed the major virulence factors-capsule, melanin and phospholipase B-and grew well at 37 degrees C. The minimal inhibitory concentration of nine drugs was measured by micro-broth dilution and compared with published data on haploid strains. MICs were similar amongst hybrids and haploid parental strains. This is the first study reporting natural same sex alphaAAalpha intra-varietal VNI/VNII hybrids and aADalpha inter-varietal VNII/VNIV hybrids. PMID- 27764110 TI - Inferring Muscle-Tendon Unit Power from Ankle Joint Power during the Push-Off Phase of Human Walking: Insights from a Multiarticular EMG-Driven Model. AB - INTRODUCTION: Inverse dynamics joint kinetics are often used to infer contributions from underlying groups of muscle-tendon units (MTUs). However, such interpretations are confounded by multiarticular (multi-joint) musculature, which can cause inverse dynamics to over- or under-estimate net MTU power. Misestimation of MTU power could lead to incorrect scientific conclusions, or to empirical estimates that misguide musculoskeletal simulations, assistive device designs, or clinical interventions. The objective of this study was to investigate the degree to which ankle joint power overestimates net plantarflexor MTU power during the Push-off phase of walking, due to the behavior of the flexor digitorum and hallucis longus (FDHL)-multiarticular MTUs crossing the ankle and metatarsophalangeal (toe) joints. METHODS: We performed a gait analysis study on six healthy participants, recording ground reaction forces, kinematics, and electromyography (EMG). Empirical data were input into an EMG-driven musculoskeletal model to estimate ankle power. This model enabled us to parse contributions from mono- and multi-articular MTUs, and required only one scaling and one time delay factor for each subject and speed, which were solved for based on empirical data. Net plantarflexing MTU power was computed by the model and quantitatively compared to inverse dynamics ankle power. RESULTS: The EMG-driven model was able to reproduce inverse dynamics ankle power across a range of gait speeds (R2 >= 0.97), while also providing MTU-specific power estimates. We found that FDHL dynamics caused ankle power to slightly overestimate net plantarflexor MTU power, but only by ~2-7%. CONCLUSIONS: During Push-off, FDHL MTU dynamics do not substantially confound the inference of net plantarflexor MTU power from inverse dynamics ankle power. However, other methodological limitations may cause inverse dynamics to overestimate net MTU power; for instance, due to rigid-body foot assumptions. Moving forward, the EMG-driven modeling approach presented could be applied to understand other tasks or larger multiarticular MTUs. PMID- 27764111 TI - The QTL GNP1 Encodes GA20ox1, Which Increases Grain Number and Yield by Increasing Cytokinin Activity in Rice Panicle Meristems. AB - Cytokinins and gibberellins (GAs) play antagonistic roles in regulating reproductive meristem activity. Cytokinins have positive effects on meristem activity and maintenance. During inflorescence meristem development, cytokinin biosynthesis is activated via a KNOX-mediated pathway. Increased cytokinin activity leads to higher grain number, whereas GAs negatively affect meristem activity. The GA biosynthesis genes GA20oxs are negatively regulated by KNOX proteins. KNOX proteins function as modulators, balancing cytokinin and GA activity in the meristem. However, little is known about the crosstalk among cytokinin and GA regulators together with KNOX proteins and how KNOX-mediated dynamic balancing of hormonal activity functions. Through map-based cloning of QTLs, we cloned a GA biosynthesis gene, Grain Number per Panicle1 (GNP1), which encodes rice GA20ox1. The grain number and yield of NIL-GNP1TQ were significantly higher than those of isogenic control (Lemont). Sequence variations in its promoter region increased the levels of GNP1 transcripts, which were enriched in the apical regions of inflorescence meristems in NIL-GNP1TQ. We propose that cytokinin activity increased due to a KNOX-mediated transcriptional feedback loop resulting from the higher GNP1 transcript levels, in turn leading to increased expression of the GA catabolism genes GA2oxs and reduced GA1 and GA3 accumulation. This rebalancing process increased cytokinin activity, thereby increasing grain number and grain yield in rice. These findings uncover important, novel roles of GAs in rice florescence meristem development and provide new insights into the crosstalk between cytokinin and GA underlying development process. PMID- 27764112 TI - The NIH-NIAID Schistosomiasis Resource Center at the Biomedical Research Institute: Molecular Redux. AB - Schistosomiasis remains a health burden in many parts of the world. The complex life cycle of Schistosoma parasites and the economic and societal conditions present in endemic areas make the prospect of eradication unlikely in the foreseeable future. Continued and vigorous research efforts must therefore be directed at this disease, particularly since only a single World Health Organization (WHO)-approved drug is available for treatment. The National Institutes of Health (NIH)-National Institute of Allergy and Infectious Diseases (NIAID) Schistosomiasis Resource Center (SRC) at the Biomedical Research Institute provides investigators with the critical raw materials needed to carry out this important research. The SRC makes available, free of charge (including international shipping costs), not only infected host organisms but also a wide array of molecular reagents derived from all life stages of each of the three main human schistosome parasites. As the field of schistosomiasis research rapidly advances, it is likely to become increasingly reliant on omics, transgenics, epigenetics, and microbiome-related research approaches. The SRC has and will continue to monitor and contribute to advances in the field in order to support these research efforts with an expanding array of molecular reagents. In addition to providing investigators with source materials, the SRC has expanded its educational mission by offering a molecular techniques training course and has recently organized an international schistosomiasis-focused meeting. This review provides an overview of the materials and services that are available at the SRC for schistosomiasis researchers, with a focus on updates that have occurred since the original overview in 2008. PMID- 27764113 TI - Genetic Analysis of Collective Motility of Paenibacillus sp. NAIST15-1. AB - Bacteria have developed various motility mechanisms to adapt to a variety of solid surfaces. A rhizosphere isolate, Paenibacillus sp. NAIST15-1, exhibited unusual motility behavior. When spotted onto 1.5% agar media, Paenibacillus sp. formed many colonies, each of which moved around actively at a speed of 3.6 MUm/sec. As their density increased, each moving colony began to spiral, finally forming a static round colony. Despite its unusual motility behavior, draft genome sequencing revealed that both the composition and organization of flagellar genes in Paenibacillus sp. were very similar to those in Bacillus subtilis. Disruption of flagellar genes and flagellar stator operons resulted in loss of motility. Paenibacillus sp. showed increased transcription of flagellar genes and hyperflagellation on hard agar media. Thus, increased flagella and their rotation drive Paenibacillus sp. motility. We also identified a large extracellular protein, CmoA, which is conserved only in several Paenibacillus and related species. A cmoA mutant could neither form moving colonies nor move on hard agar media; however, motility was restored by exogenous CmoA. CmoA was located around cells and enveloped cell clusters. Comparison of cellular behavior between the wild type and cmoA mutant indicated that extracellular CmoA is involved in drawing water out of agar media and/or smoothing the cell surface interface. This function of CmoA probably enables Paenibacillus sp. to move on hard agar media. PMID- 27764115 TI - OpenZika: An IBM World Community Grid Project to Accelerate Zika Virus Drug Discovery. AB - The Zika virus outbreak in the Americas has caused global concern. To help accelerate this fight against Zika, we launched the OpenZika project. OpenZika is an IBM World Community Grid Project that uses distributed computing on millions of computers and Android devices to run docking experiments, in order to dock tens of millions of drug-like compounds against crystal structures and homology models of Zika proteins (and other related flavivirus targets). This will enable the identification of new candidates that can then be tested in vitro, to advance the discovery and development of new antiviral drugs against the Zika virus. The docking data is being made openly accessible so that all members of the global research community can use it to further advance drug discovery studies against Zika and other related flaviviruses. PMID- 27764114 TI - Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype Specific Neutralizing Antibody Responses. AB - Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year. Dengue vaccine development is challenging because of the need to induce simultaneous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial efficacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been precisely molded using Particle Replication in Non-wetting Template (PRINT) technology. Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE), purified and adsorbed to poly (lactic-co-glycolic acid) (PLGA) nanoparticles of different sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika. PMID- 27764116 TI - My Body Looks Like That Girl's: Body Mass Index Modulates Brain Activity during Body Image Self-Reflection among Young Women. AB - Body image distress or body dissatisfaction is one of the most common consequences of obesity and overweight. We investigated the neural bases of body image processing in overweight and average weight young women to understand whether brain regions that were previously found to be involved in processing self-reflective, perspective and affective components of body image would show different activation between two groups. Thirteen overweight (O-W group, age = 20.31+/-1.70 years) and thirteen average weight (A-W group, age = 20.15+/-1.62 years) young women underwent functional magnetic resonance imaging while performing a body image self-reflection task. Among both groups, whole-brain analysis revealed activations of a brain network related to perceptive and affective components of body image processing. ROI analysis showed a main effect of group in ACC as well as a group by condition interaction within bilateral EBA, bilateral FBA, right IPL, bilateral DLPFC, left amygdala and left MPFC. For the A W group, simple effect analysis revealed stronger activations in Thin-Control compared to Fat-Control condition within regions related to perceptive (including bilateral EBA, bilateral FBA, right IPL) and affective components of body image processing (including bilateral DLPFC, left amygdala), as well as self-reference (left MPFC). The O-W group only showed stronger activations in Fat-Control than in Thin-Control condition within regions related to the perceptive component of body image processing (including left EBA and left FBA). Path analysis showed that in the Fat-Thin contrast, body dissatisfaction completely mediated the group difference in brain response in left amygdala across the whole sample. Our data are the first to demonstrate differences in brain response to body pictures between average weight and overweight young females involved in a body image self reflection task. These results provide insights for understanding the vulnerability to body image distress among overweight or obese young females. PMID- 27764117 TI - Effects of Non-Symbolic Approximate Number Practice on Symbolic Numerical Abilities in Pakistani Children. AB - Current theories of numerical cognition posit that uniquely human symbolic number abilities connect to an early developing cognitive system for representing approximate numerical magnitudes, the approximate number system (ANS). In support of this proposal, recent laboratory-based training experiments with U.S. children show enhanced performance on symbolic addition after brief practice comparing or adding arrays of dots without counting: tasks that engage the ANS. Here we explore the nature and generality of this effect through two brief training experiments. In Experiment 1, elementary school children in Pakistan practiced either a non-symbolic numerical addition task or a line-length addition task with no numerical content, and then were tested on symbolic addition. After training, children in the numerical training group completed the symbolic addition test faster than children in the line length training group, suggesting a causal role of brief, non-symbolic numerical training on exact, symbolic addition. These findings replicate and extend the core findings of a recent U.S. laboratory-based study to non-Western children tested in a school setting, attesting to the robustness and generalizability of the observed training effects. Experiment 2 tested whether ANS training would also enhance the consistency of performance on a symbolic number line task. Over several analyses of the data there was some evidence that approximate number training enhanced symbolic number line placements relative to control conditions. Together, the findings suggest that engagement of the ANS through brief training procedures enhances children's immediate attention to number and engagement with symbolic number tasks. PMID- 27764118 TI - Whole-Genome Resequencing of a Cucumber Chromosome Segment Substitution Line and Its Recurrent Parent to Identify Candidate Genes Governing Powdery Mildew Resistance. AB - Cucumber is an economically important vegetable crop worldwide. Powdery mildew (PM) is one of the most severe diseases that can affect cucumber crops. There have been several research efforts to isolate PM resistance genes for breeding PM resistant cucumber. In the present study, we used a chromosome segment substitution line, SSL508-28, which carried PM resistance genes from the donor parent, JIN5-508, through twelve generations of backcrossing with a PM susceptible inbred line, D8. We performed whole-genome resequencing of SSL508-28 and D8 to identify single nucleotide polymorphisms (SNPs), and insertions and deletions (indels). When compared against the reference genome of the inbred cucumber line 9930, a total of 468,616 SNPs and 67,259 indels were identified in SSL508-28, and 537,352 SNPs and 91,698 indels were identified in D8. Of these, 3,014 non-synonymous SNPs and 226 frameshift indels in SSL508-28, and 3,104 non synonymous SNPs and 251 frameshift indels in D8, were identified. Bioinformatics analysis of these variations revealed a total of 15,682 SNPs and 6,262 indels between SSL508-28 and D8, among which 120 non-synonymous SNPs and 30 frameshift indels in 94 genes were detected between SSL508-28 and D8. Finally, out of these 94 genes, five resistance genes with nucleotide-binding sites and leucine-rich repeat domains were selected for qRT-PCR analysis. This revealed an upregulation of two transcripts, Csa2M435460.1 and Csa5M579560.1, in SSL508-28. Furthermore, the results of qRT-PCR analysis of these two genes in ten PM resistant and ten PM susceptible cucumber lines showed that when exposed to PM, Csa2M435460.1 and Csa5M579560.1 exhibited a higher expression level of resistant lines than susceptible lines. This indicates that Csa2M435460.1 and Csa5M579560.1 are candidate genes for PM resistance in cucumber. In addition, the non-synonymous SNPs in Csa2M435460.1 and Csa5M579560.1, identified in SSL508-28 and D8, might be the key to high PM-resistance in SSL508-28. PMID- 27764119 TI - Contrast Gain Control in Plaid Pattern Detection. AB - A plaid is a combination of two gratings whose orientations are orthogonal to each other with the same or similar contrasts. We used plaid patterns as stimuli to investigate the mechanisms underlying the detection of a plaid to understand how the visual system combines information from orientation-selective channels. We used a masking paradigm in which an observer was required to detect a target (either a spiral or a plaid) superimposed on a pedestal. We measured the target threshold versus pedestal contrast (TvC) functions at 7 pedestal contrasts for various target-pedestal combinations with a temporal 2AFC paradigm and a staircase procedure. All TvC functions, except the one with an orthogonal spiral pedestal, showed a dipper shape, although the position of the dip and the slope varied across conditions. The result can be explained by a multiple-mechanism divisive inhibition model, which contains several orientation-selective mechanisms. The response of each mechanism is the excitation of a linear filter divided by a broadband inhibitory input. The threshold is determined by a nonlinear combination of the responses of those mechanisms. Alternative models with mechanism(s) specific for plaid did not provide a better description of the data. Thus, a plaid pattern is mediated by a combination of orientation-selective mechanisms. An early plaid-specific mechanism is not necessary for plaid detection. PMID- 27764120 TI - Exploring the Use of Non-Image-Based Ultrasound to Detect the Position of the Residual Femur within a Stump. AB - A satisfactorily fitted socket interacts dynamically with the stump in order to support body weight, transmit load effectively, enhance dynamic stability, and enable the control and stabilization of the residual limb. The internal dynamics occurring within a socket is important in determining optimal fit. Many measurement and imaging techniques, such as X-rays, have been utilized to investigate the movement of the residual femur within the stump during gait. However, due to associated health risks and costs, none of the current techniques have been extended to clinical prosthetics. The use of B-mode ultrasound has been suggested as a safe and cheap alternative, and has been utilized in previous studies to monitor the motion of the femur. However, the need to create a duplicate socket and time-consuming analysis of the images were obstacles to the system being applied clinically. This study aims to gauge the effectiveness of a non-image based ultrasound system. Here, we determined errors expected from the measurements. Accuracy errors of 2.9 mm to 8.4 mm and reproducibility measurements within a standard deviation of 3.9 mm are reported. We also estimated errors up to 14.4 mm in in-vivo measurements. We think there is potential in developing this technique, and we hope to reduce some technical difficulties such that it can, one day, be easily incorporated into prosthetic fitting. PMID- 27764121 TI - Urinary Analysis of Fluid Retention in the General Population: A Cross-Sectional Study. AB - OBJECTIVE: Renal conservation (retention) of fluid might affect the outcome of hospital care and can be indicated by increased urinary concentrations of metabolic waste products. We obtained a reference material for further studies by exploring the prevalence of fluid retention in a healthy population. METHODS: Spot urine sampling was performed in 300 healthy hospital workers. A previously validated algorithm summarized the urine-specific gravity, osmolality, creatinine, and color to a fluid retention index (FRI), where 4.0 is the cut-off for fluid retention consistent with dehydration. In 50 of the volunteers, we also studied the relationships between FRI, plasma osmolality, and water-retaining hormones. RESULTS: The cut-off for fluid retention (FRI >= 4.0) was reached by 38% of the population. No correlation was found between the FRI and the time of the day of urine sample collection, and the FRI was only marginally correlated with the time period spent without fluid intake. Volunteers with fluid retention were younger, generally men, and more often had albuminuria (88% vs. 34%, P < 0.001). Plasma osmolality and plasma sodium were somewhat higher in those with a high FRI (mean 294.8 vs. 293.4 mosmol/kg and 140.3 vs. 139.9 mmol/l). Plasma vasopressin was consistently below the limit of detection, and the plasma cortisol, aldosterone, and renin concentrations were similar in subjects with a high or low FRI. The very highest FRI values (>= 5.0, N = 61) were always accompanied by albuminuria. CONCLUSION: Fluid retention consistent with moderate dehydration is common in healthy staff working in a Swedish hospital. PMID- 27764122 TI - Blood Plasma-Derived Anti-Glycan Antibodies to Sialylated and Sulfated Glycans Identify Ovarian Cancer Patients. AB - Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined. Results were compared to CA125, the commonly used ovarian cancer biomarker. AGA to seven glycans that significantly (P<0.05) differentiated between HGSOC and control were identified: AGA to top candidates SiaTn and 6-OSulfo-TF (both IgM) differentiated comparably to CA125. The area under the curve (AUC) of a panel of AGA to 5 glycans (SiaTn, 6-OSulfo-TF, 6 OSulfo-LN, SiaLea, and GM2) (0.878) was comparable to CA125 (0.864), but it markedly increased (0.985) when combined with CA125. AGA to SiaTn and 6-OSulfo-TF were also valuable predictors for HGSOC when CA125 values appeared inconclusive, i.e. were below a certain threshold. AGA-glycan binding was in some cases isotype dependent and sensitive to glycosidic linkage switch (alpha2-6 vs. alpha2-3), to sialylation, and to sulfation of the glycans. In conclusion, plasma-derived AGA to sialylated and sulfated glycans including SiaTn and 6-OSulfo-TF detected by SGA present a valuable alternative to CA125 for differentiating controls from HGSOC patients and for predicting the likelihood of HGSOC, and may be potential HGSOC tumor markers. PMID- 27764123 TI - The Importance of Medical Students' Attitudes Regarding Cognitive Competence for Teaching Applied Statistics: Multi-Site Study and Meta-Analysis. AB - BACKGROUND: The scientific community increasingly is recognizing the need to bolster standards of data analysis given the widespread concern that basic mistakes in data analysis are contributing to the irreproducibility of many published research findings. The aim of this study was to investigate students' attitudes towards statistics within a multi-site medical educational context, monitor their changes and impact on student achievement. In addition, we performed a systematic review to better support our future pedagogical decisions in teaching applied statistics to medical students. METHODS: A validated Serbian Survey of Attitudes Towards Statistics (SATS-36) questionnaire was administered to medical students attending obligatory introductory courses in biostatistics from three medical universities in the Western Balkans. A systematic review of peer-reviewed publications was performed through searches of Scopus, Web of Science, Science Direct, Medline, and APA databases through 1994. A meta-analysis was performed for the correlation coefficients between SATS component scores and statistics achievement. Pooled estimates were calculated using random effects models. RESULTS: SATS-36 was completed by 461 medical students. Most of the students held positive attitudes towards statistics. Ability in mathematics and grade point average were associated in a multivariate regression model with the Cognitive Competence score, after adjusting for age, gender and computer ability. The results of 90 paired data showed that Affect, Cognitive Competence, and Effort scores demonstrated significant positive changes. The Cognitive Competence score showed the largest increase (M = 0.48, SD = 0.95). The positive correlation found between the Cognitive Competence score and students' achievement (r = 0.41; p<0.001), was also shown in the meta-analysis (r = 0.37; 95% CI 0.32-0.41). CONCLUSION: Students' subjective attitudes regarding Cognitive Competence at the beginning of the biostatistics course, which were directly linked to mathematical knowledge, affected their attitudes at the end of the course that, in turn, influenced students' performance. This indicates the importance of positively changing not only students' cognitive competency, but also their perceptions of gained competency during the biostatistics course. PMID- 27764125 TI - Comparing Eye Tracking with Electrooculography for Measuring Individual Sentence Comprehension Duration. AB - The aim of this study was to validate a procedure for performing the audio-visual paradigm introduced by Wendt et al. (2015) with reduced practical challenges. The original paradigm records eye fixations using an eye tracker and calculates the duration of sentence comprehension based on a bootstrap procedure. In order to reduce practical challenges, we first reduced the measurement time by evaluating a smaller measurement set with fewer trials. The results of 16 listeners showed effects comparable to those obtained when testing the original full measurement set on a different collective of listeners. Secondly, we introduced electrooculography as an alternative technique for recording eye movements. The correlation between the results of the two recording techniques (eye tracker and electrooculography) was r = 0.97, indicating that both methods are suitable for estimating the processing duration of individual participants. Similar changes in processing duration arising from sentence complexity were found using the eye tracker and the electrooculography procedure. Thirdly, the time course of eye fixations was estimated with an alternative procedure, growth curve analysis, which is more commonly used in recent studies analyzing eye tracking data. The results of the growth curve analysis were compared with the results of the bootstrap procedure. Both analysis methods show similar processing durations. PMID- 27764124 TI - Influence of Temporal Expectations on Response Priming by Subliminal Faces. AB - Unconscious processes are often assumed immune from attention influence. Recent behavioral studies suggest however that the processing of subliminal information can be influenced by temporal attention. To examine the neural mechanisms underlying these effects, we used a stringent masking paradigm together with fMRI to investigate how temporal attention modulates the processing of unseen (masked) faces. Participants performed a gender decision task on a visible neutral target face, preceded by a masked prime face that could vary in gender (same or different than target) and emotion expression (neutral or fearful). We manipulated temporal attention by instructing participants to expect targets to appear either early or late during the stimulus sequence. Orienting temporal attention to subliminal primes influenced response priming by masked faces, even when gender was incongruent. In addition, gender-congruent primes facilitated responses regardless of attention while gender-incongruent primes reduced accuracy when attended. Emotion produced no differential effects. At the neural level, incongruent and temporally unexpected primes increased brain response in regions of the fronto-parietal attention network, reflecting greater recruitment of executive control and reorienting processes. Congruent and expected primes produced higher activations in fusiform cortex, presumably reflecting facilitation of perceptual processing. These results indicate that temporal attention can influence subliminal processing of face features, and thus facilitate information integration according to task-relevance regardless of conscious awareness. They also suggest that task-congruent information between prime and target may facilitate response priming even when temporal attention is not selectively oriented to the prime onset time. PMID- 27764126 TI - Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes. AB - INTRODUCTION: Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors should be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors. METHODS: 28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array. RESULTS: Increased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes, and their regulators. CONCLUSION: Our data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies. PMID- 27764128 TI - "They just come, pick and go." The Acceptability of Integrated Medication Adherence Clubs for HIV and Non Communicable Disease (NCD) Patients in Kibera, Kenya. AB - INTRODUCTION: The number of people on antiretroviral therapy (ART) for the long term management of HIV in low- and middle-income countries (LMICs) is continuing to increase, along with the prevalence of Non-Communicable Diseases (NCDs). The need to provide large volumes of HIV patients with ART has led to significant adaptations in how medication is delivered, but access to NCD care remains limited in many contexts. Medication Adherence Clubs (MACs) were established in Kibera, Kenya to address the large numbers of patients requiring chronic HIV and/or NCD care. Stable NCD and HIV patients can now collect their chronic medication every three months through a club, rather than through individual clinic appointments. METHODOLOGY: We conducted a qualitative research study to assess patient and health-care worker perceptions and experiences of MACs in the urban informal settlement of Kibera, Kenya. A total of 106 patients (with HIV and/or other NCDs) and health-care workers were purposively sampled and included in the study. Ten focus groups and 19 in-depth interviews were conducted and 15 sessions of participant observation were carried out at the clinic where the MACs took place. Thematic data analysis was conducted using NVivo software, and coding focussed on people's experiences of MACs, the challenges they faced and their perceptions about models of care for chronic conditions. RESULTS: MACs were considered acceptable to patients and health-care workers because they saved time, prevented unnecessary queues in the clinic and provided people with health education and group support whilst they collected their medication. Some patients and health-care workers felt that MACs reduced stigma for HIV positive patients by treating HIV as any other chronic condition. Staff and patients reported challenges recruiting patients into MACs, including patients not fully understanding the eligibility criteria for the clubs. There were also some practical challenges during the implementation of the clubs, but MACs have shown that it is possible to learn from ART provision and enable stable HIV and NCD patients to collect chronic medication together in a group. CONCLUSIONS: Extending models of care previously only offered to HIV-positive cohorts to NCD patients can help to de-stigmatise HIV, allow for the efficient clinical management of co-morbidities and enable patients to benefit from peer support. Through MACs, we have demonstrated that an integrated approach to providing medication for chronic diseases including HIV can be implemented in resource-poor settings and could thus be rolled out in other similar contexts. PMID- 27764127 TI - De Novo Sequencing and Assembly Analysis of the Pseudostellaria heterophylla Transcriptome. AB - Pseudostellaria heterophylla (Miq.) Pax is a mild tonic herb widely cultivated in the Southern part of China. The tuberous roots of P. heterophylla accumulate high levels of secondary metabolism products of medicinal value such as saponins, flavonoids, and isoquinoline alkaloids. Despite numerous studies on the pharmacological importance and purification of these compounds in P. heterophylla, their biosynthesis is not well understood. In the present study, we used Illumina HiSeq 4000 sequencing platform to sequence the RNA from flowers, leaves, stem, root cortex and xylem tissues of P. heterophylla. We obtained 616,413,316 clean reads that we assembled into 127, 334 unique sequences with an N50 length of 951 bp. Among these unigenes, 53,184 unigenes (41.76%) were annotated in a public database and 39, 795 unigenes were assigned to 356 KEGG pathways; 23,714 unigenes (8.82%) had high homology with the genes from Beta vulgaris. We discovered 32, 095 DEGs in different tissues and performed GO and KEGG enrichment analysis. The most enriched KEGG pathway of secondary metabolism showed up-regulated expression in tuberous roots as compared with the ground parts of P. heterophylla. Moreover, we identified 72 candidate genes involved in triterpenoids saponins biosynthesis in P. heterophylla. The expression profiles of 11 candidate unigenes were analyzed by quantitative real-time PCR (RT-qPCR). Our study established a global transcriptome database of P. heterophylla for gene identification and regulation. We also identified the candidate unigenes involved in triterpenoids saponins biosynthesis. Our results provide an invaluable resource for the secondary metabolites and physiological processes in different tissues of P. heterophylla. PMID- 27764129 TI - The Phylogeographic and Spatiotemporal Spread of HCV in Pakistani Population. AB - Hepatitis C Virus (HCV) is the most prevalent human pathogen in Pakistan and is the major cause of liver cirrhosis and hepatocellular carcinoma in infected patients. It has shifted from being hypo-endemic to being hyper-endemic. There was no information about the origin and evolution of the local variants. Here we use newly developed phyloinformatic methods of sequence analysis to conduct the first comprehensive investigation of the evolutionary and biogeographic history in unprecedented detail and breadth. Considering evolutionary rate and molecular clock hypothesis in context, we reconstructed the spatiotemporal spread of HCV in the whole territory of its circulation using a combination of Bayesian MCMC methods utilizing all sequences available in GenBank. Comparative analysis were performed and were addressed. Whole genome and individual gene analysis have shown that sub-types 1a, 1b and 3a are recognized as epidemic strains and are distributed globally. Here we confirm that the origin of HCV 3a genotypes is in South Asia and HCV has evolved in the region to become stably adapted to the host environment. PMID- 27764130 TI - First Results in the Use of Bovine Ear Notch Tag for Bovine Viral Diarrhoea Virus Detection and Genetic Analysis. AB - BACKGROUND: Infection due to bovine viral diarrhoea virus (BVDV) is endemic in most cattle-producing countries throughout the world. The key elements of a BVDV control programme are biosecurity, elimination of persistently infected animals and surveillance. Bovine viral diarrhoea (BVD) is a notifiable disease in Belgium and an official eradication programme started from January 2015, based on testing ear notches sampled during the official identification and registration of calves at birth. An antigen-capture ELISA test based on the detection of BVDV Erns protein is used. Ear notch sample may also be used to characterize the genotype of the calf when appropriate elution/dilution buffer is added. Both BVDV antigen ELISA analysis and animal traceability could be performed. METHODOLOGY: With regards to the reference protocol used in the preparation of ear notch samples, alternative procedures were tested in terms of BVDV analytic sensitivity, diagnostic sensitivity and specificity, as well as quality and purity of animal DNA. PRINCIPAL FINDINGS/SIGNIFICANCE: The Allflex DNA Buffer D showed promising results in BVDV diagnosis and genome analyses, opening new perspectives for the livestock industry by the exploitation of the animal genome. Due to the high number of cattle involved in the Belgian official BVDV eradication programme based on ear notch tags sample, a large database on both BVDV status of newborn calves and cattle genome could be created for subsequent different uses (e.g. traceability, determination of parentage, genetic signatures throughout the genome associated with particular traits) evolving through a more integrated animal health. PMID- 27764132 TI - Can We Spare the Pancreas and Other Abdominal Organs at Risk? A Comparison of Conformal Radiotherapy, Helical Tomotherapy and Proton Beam Therapy in Pediatric Irradiation. AB - OBJECTIVES: Late abdominal irradiation toxicity during childhood included renal damage, hepatic toxicity and secondary diabetes mellitus. We compared the potential of conformal radiotherapy (CRT), helical tomotherapy (HT) and proton beam therapy (PBT) to spare the abdominal organs at risk (pancreas, kidneys and liver- OAR) in children undergoing abdominal irradiation. METHODS: We selected children with abdominal tumors who received more than 10 Gy to the abdomen. Treatment plans were calculated in order to keep the dose to abdominal OAR as low as possible while maintaining the same planned target volume (PTV) coverage. Dosimetric values were compared using the Wilcoxon signed-rank test. RESULTS: The dose distribution of 20 clinical cases with a median age of 8 years (range 1-14) were calculated with different doses to the PTV: 5 medulloblastomas (36 Gy), 3 left-sided and 2 right-sided nephroblastomas (14.4 Gy to the tumor + 10.8 Gy boost to para-aortic lymphnodes), 1 left-sided and 4 right-sided or midline neuroblastomas (21 Gy) and 5 Hodgkin lymphomas (19.8 Gy to the para-aortic lymphnodes and spleen). HT significantly reduced the mean dose to the whole pancreas (WP), the pancreatic tail (PT) and to the ipsilateral kidney compared to CRT. PBT reduced the mean dose to the WP and PT compared to both CRT and HT especially in midline and right-sided tumors. PBT decreased the mean dose to the ispilateral kidney but also to the contralateral kidney and the liver compared to CRT. Low dose to normal tissue was similar or increased with HT whereas integral dose and the volume of normal tissue receiving at least 5 and 10 Gy were reduced with PBT compared to CRT and HT. CONCLUSION: In children undergoing abdominal irradiation therapy, proton beam therapy reduces the dose to abdominal OAR while sparing normal tissue by limiting low dose irradiation. PMID- 27764131 TI - Generating Rho-0 Cells Using Mesenchymal Stem Cell Lines. AB - INTRODUCTION: The generation of Rho-0 cells requires the use of an immortalization process, or tumor cell selection, followed by culture in the presence of ethidium bromide (EtBr), incurring the drawbacks its use entails. The purpose of this work was to generate Rho-0 cells using human mesenchymal stem cells (hMSCs) with reagents having the ability to remove mitochondrial DNA (mtDNA) more safely than by using EtBr. METHODOLOGY: Two immortalized hMSC lines (3a6 and KP) were used; 143B.TK-Rho-0 cells were used as reference control. For generation of Rho-0 hMSCs, cells were cultured in medium supplemented with each tested reagent. Total DNA was isolated and mtDNA content was measured by real time polymerase chain reaction (PCR). Phenotypic characterization and gene expression assays were performed to determine whether 3a6 Rho-0 hMSCs maintain the same stem properties as untreated 3a6 hMSCs. To evaluate whether 3a6 Rho-0 hMSCs had a phenotype similar to that of 143B.TK-Rho-0 cells, in terms of reactive oxygen species (ROS) production, apoptotic levels and mitochondrial membrane potential (Deltapsim) were measured by flow cytometry and mitochondrial respiration was evaluated using a SeaHorse XFp Extracellular Flux Analyzer. The differentiation capacity of 3a6 and 3a6 Rho-0 hMSCs was evaluated using real-time PCR, comparing the relative expression of genes involved in osteogenesis, adipogenesis and chondrogenesis. RESULTS: The results showed the capacity of the 3a6 cell line to deplete its mtDNA and to survive in culture with uridine. Of all tested drugs, Stavudine (dt4) was the most effective in producing 3a6-Rho cells. The data indicate that hMSC Rho-0 cells continue to express the characteristic MSC cell surface receptor pattern. Phenotypic characterization showed that 3a6 Rho-0 cells resembled 143B.TK-Rho-0 cells, indicating that hMSC Rho-0 cells are Rho-0 cells. While the adipogenic capability was higher in 3a6 Rho-0 cells than in 3a6 cells, the osteogenic and chondrogenic capacities were lower. CONCLUSION: Among the drugs and conditions tested, the use of d4t was the best option for producing Rho-0 cells from hMSCs. Rho-0 cells are useful for studying the role of mitochondria in hMSC differentiation. PMID- 27764133 TI - Intra- and Interspecific Interactions as Proximate Determinants of Sexual Dimorphism and Allometric Trajectories in the Bottlenose Dolphin Tursiops truncatus (Cetacea, Odontoceti, Delphinidae). AB - Feeding adaptation, social behaviour, and interspecific interactions related to sexual dimorphism and allometric growth are particularly challenging to be investigated in the high sexual monomorphic Delphinidae. We used geometric morphometrics to extensively explore sexual dimorphism and ontogenetic allometry of different projections of the skull and the mandible of the bottlenose dolphin Tursiops truncatus. Two-dimensional landmarks were recorded on the dorsal, ventral, lateral, and occipital views of the skull, and on the lateral view of the left and the right mandible of 104 specimens from the Mediterranean and the North Seas, differing environmental condition and degree of interspecific associations. Landmark configurations were transformed, standardized and superimposed through a Generalized Procrustes Analysis. Size and shape differences between adult males and females were respectively evaluated through ANOVA on centroid size, Procrustes ANOVA on Procrustes distances, and MANOVA on Procrustes coordinates. Ontogenetic allometry was investigated by multivariate regression of shape coordinates on centroid size in the largest homogenous sample from the North Sea. Results evidenced sexual dimorphic asymmetric traits only detected in the adults of the North Sea bottlenose dolphins living in monospecific associations, with females bearing a marked incision of the cavity hosting the left tympanic bulla. These differences were related to a more refined echolocalization system that likely enhances the exploitation of local resources by philopatric females. Distinct shape in immature versus mature stages and asymmetric changes in postnatal allometry of dorsal and occipital traits, suggest that differences between males and females are established early during growth. Allometric growth trajectories differed between males and females for the ventral view of the skull. Allometric trajectories differed among projections of skull and mandible, and were related to dietary shifts experienced by subadults and adults. PMID- 27764134 TI - Calcium Sensitive Fluorescent Dyes Fluo-4 and Fura Red under Pressure: Behaviour of Fluorescence and Buffer Properties under Hydrostatic Pressures up to 200 MPa. AB - The fluorescent Ca2+ sensitive dyes Fura Red (ratiometric) and Fluo-4 (non ratiometric) are widely utilized for the optical assessment of Ca2+ fluctuations in vitro as well as in situ. The fluorescent behavior of these dyes is strongly depends on temperature, pH, ionic strength and pressure. It is crucial to understand the response of these dyes to pressure when applying calcium imaging technologies in the field of high pressure bioscience. Therefore, we use an optically accessible pressure vessel to pressurize physiological Ca2+-buffered solutions at different fixed concentrations of free Ca2+ (1 nM to 25.6 MUM) and a specified dye concentration (12 MUM) to pressures of 200 MPa, and record dye fluorescence intensity. Our results show that Fluo-4 fluorescence intensity is reduced by 31% per 100 MPa, the intensity of Fura Red is reduced by 10% per 100 MPa. The mean reaction volume for the dissociation of calcium from the dye molecules [Formula: see text] is determined to -17.8 ml mol-1 for Fluo-4 and 21.3 ml mol-1 for Fura Red. Additionally, a model is presented that is used to correct for pressure-dependent changes in pH and binding affinity of Ca2+ to EGTA, as well as to determine the influence of these changes on dye fluorescence. PMID- 27764135 TI - Linking Data for Mothers and Babies in De-Identified Electronic Health Data. AB - OBJECTIVE: Linkage of longitudinal administrative data for mothers and babies supports research and service evaluation in several populations around the world. We established a linked mother-baby cohort using pseudonymised, population-level data for England. DESIGN AND SETTING: Retrospective linkage study using electronic hospital records of mothers and babies admitted to NHS hospitals in England, captured in Hospital Episode Statistics between April 2001 and March 2013. RESULTS: Of 672,955 baby records in 2012/13, 280,470 (42%) linked deterministically to a maternal record using hospital, GP practice, maternal age, birthweight, gestation, birth order and sex. A further 380,164 (56%) records linked using probabilistic methods incorporating additional variables that could differ between mother/baby records (admission dates, ethnicity, 3/4-character postcode district) or that include missing values (delivery variables). The false match rate was estimated at 0.15% using synthetic data. Data quality improved over time: for 2001/02, 91% of baby records were linked (holding the estimated false-match rate at 0.15%). The linked cohort was representative of national distributions of gender, gestation, birth weight and maternal age, and captured approximately 97% of births in England. CONCLUSION: Probabilistic linkage of maternal and baby healthcare characteristics offers an efficient way to enrich maternity data, improve data quality, and create longitudinal cohorts for research and service evaluation. This approach could be extended to linkage of other datasets that have non-disclosive characteristics in common. PMID- 27764136 TI - Immunohistochemistry Successfully Uncovers Intratumoral Heterogeneity and Widespread Co-Losses of Chromatin Regulators in Clear Cell Renal Cell Carcinoma. AB - Recent studies have shown that intratumoral heterogeneity (ITH) is prevalent in clear cell renal cell carcinoma (ccRCC), based on DNA sequencing and chromosome aberration analysis of multiple regions from the same tumor. VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal). ITH has been studied mostly by DNA sequencing in limited numbers of samples, either by whole genome sequencing or by targeted sequencing. It is not known whether immunohistochemistry (IHC) can be used as a tool to study ITH. To address this question, we examined the protein expression of PBRM1, and PBRM1-related proteins such as ARID1A, SETD2, BRG1, and BRM. Altogether, 160 ccRCC (40 per stage) were used to generate a tissue microarray (TMA), with four foci from each tumor included. Loss of expression was defined as 0-5% of tumor cells with positive nuclear staining in an individual focus. We found that 49/160 (31%), 81/160 (51%), 23/160 (14%), 24/160 (15%), and 61/160 (38%) of ccRCC showed loss of expression of PBRM1, ARID1A, SETD2, BRG1, and BRM, respectively, and that IHC could successfully detect a high prevalence of ITH. Phylogenetic trees were constructed that reflected the ITH. Striking co-losses among proteins were also observed. For instance, ARID1A loss almost always accompanied PBRM1 loss, whereas BRM loss accompanied loss of BRG1, PBRM1 or ARID1A. SETD2 loss frequently occurred with loss of one or more of the other four proteins. Finally, in order to learn the impact of combined losses, we compared the tumor growth after cells acquired losses of ARID1A, PBRM1, or both in a xenograft model. The results suggest that ARID1A loss has a greater tumor promoting effect than PBRM1 loss, indicating that xenograft analysis is a useful tool to investigate how these losses impact on tumor behavior, either alone or in combination. PMID- 27764137 TI - Role of TEFFECTOR/MEMORY Cells, TBX21 Gene Expression and T-Cell Homing Receptor on Type 1 Reaction in Borderline Lepromatous Leprosy Patients. AB - In spite of hyporesponsivity to Mycobacterium leprae, borderline lepromatous (BL) patients show clinical and immunological instability, and undergo frequent acute inflammatory episodes such as type 1 reaction (T1R), which may cause nerve damages. This work focused on the participation of T cell subsets from blood and skin at T1R onset. We observed a significantly increased ex vivo frequency of both effector and memory CD4+ and CD8+ T cells in T1R group. Besides, ex vivo frequency of T cell homing receptor, the Cutaneous Leukocyte-associated Antigen (CLA) was significantly increased in T cells from T1R patients. M. leprae induced a higher frequency of CD4+ TEM and CD8+ TEF cells, as well as of CD8+/TEMRA (terminally differentiated effector T cells) subset, which expressed high CD69+. The presence of IFN-gamma-producing-CD4+ TEF and naive and effector CD8+ T lymphocytes was significant in T1R. TBX21 expression was significantly higher in T1R, while BL showed increased GATA3 and FOXP3 expression. In T1R, TBX21 expression was strongly correlated with CD8+/IFN-gamma- T cells frequency. The number of double positive CD8+/CLA+ and CD45RA+/CLA+ cells was significantly higher in skin lesions from T1R, in comparison with non-reactional BL group. The observed increase of ex vivo T cells at T1R onset suggests intravascular activation at the beginning of reactional episodes. The antigen-specific response in T1R group confirmed the higher number of CD8+/CLA+ and CD45RA+/CLA+ cells in T1R lesions suggests possible migration of these cells activated by M. leprae components inside the vascular compartment to skin and participation in T1R physiopathology. PMID- 27764138 TI - IGSA: Individual Gene Sets Analysis, including Enrichment and Clustering. AB - Analysis of gene sets has been widely applied in various high-throughput biological studies. One weakness in the traditional methods is that they neglect the heterogeneity of genes expressions in samples which may lead to the omission of some specific and important gene sets. It is also difficult for them to reflect the severities of disease and provide expression profiles of gene sets for individuals. We developed an application software called IGSA that leverages a powerful analytical capacity in gene sets enrichment and samples clustering. IGSA calculates gene sets expression scores for each sample and takes an accumulating clustering strategy to let the samples gather into the set according to the progress of disease from mild to severe. We focus on gastric, pancreatic and ovarian cancer data sets for the performance of IGSA. We also compared the results of IGSA in KEGG pathways enrichment with David, GSEA, SPIA, ssGSEA and analyzed the results of IGSA clustering and different similarity measurement methods. Notably, IGSA is proved to be more sensitive and specific in finding significant pathways, and can indicate related changes in pathways with the severity of disease. In addition, IGSA provides with significant gene sets profile for each sample. PMID- 27764140 TI - Variation in Lateral Plate Quality in Threespine Stickleback from Fresh, Brackish and Marine Water: A Micro-Computed Tomography Study. AB - INTRODUCTION: It is important to understand the drivers leading to adaptive phenotypic diversity within and among species. The threespine stickleback (Gasterosteus aculeatus) has become a model system for investigating the genetic and phenotypic responses during repeated colonization of fresh waters from the original marine habitat. During the freshwater colonization process there has been a recurrent and parallel reduction in the number of lateral bone plates, making it a suitable system for studying adaptability and parallel evolution. OBJECTIVE: The aim of this study was to investigate an alternative evolutionary path of lateral plate reduction, where lateral plates are reduced in size rather than number. MATERIALS AND METHODS: A total of 72 threespine stickleback individuals from freshwater (n = 54), brackish water (n = 27) and marine water (n = 9) were analysed using microcomputed tomography (MUCT) to determine variation in size, thickness and structure of the lateral plates. Furthermore, whole-body bone volume, and bone volume, bone surface and porosity of lateral plate number 4 were quantified in all specimens from each environment. RESULTS: The results showed a significant difference in plate size (area and volume) among populations, where threespine stickleback from polymorphic freshwater and brackish water populations displayed lateral plates reduced in size (area and volume) compared to marine stickleback. CONCLUSIONS: Reduction of lateral plates in threespine stickleback in fresh and brackish water occurs by both plate loss and reduction in plate size (area and volume). PMID- 27764139 TI - Prevalence of Glomerulopathies in Canine Mammary Carcinoma. AB - The incidence and prevalence of paraneoplastic glomerulopathy, especially associated with carcinoma, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. The aim of this study was to evaluate renal biopsies of selected bitches with spontaneous mammary gland carcinoma. We hypothesized that dogs with mammary carcinomas would show histologic evidence of glomerular pathology. A prospective study was performed in dogs with naturally occurring mammary carcinoma that were undergoing tumor resection and ovariohysterectomy. We evaluated renal biopsies of 32 bitches with spontaneous mammary gland carcinoma and 11 control dogs without mammary gland neoplasia. Samples were obtained from the left kidney and the biopsy material was divided for light microscopy (LM), immunofluorescence (IF) and transmission electron microscopy (TEM). Light microscopy abnormalities were identified in 78.1% of dogs with mammary carcinoma (n = 25) and in none of the dogs in the control group. Focal glomerular mesangial matrix expansion was the most common alteration (n = 15, 60.0%), but mesangial cell proliferation (n = 9, 36.0%) and focal segmental glomerulosclerosis (n = 9, 36.0%), synechiae (n = 7, 28.0%), and globally sclerotic glomeruli (n = 6, 24.0%) were also frequent in dogs with malignancy. Immunofluorescence microscopy revealed strong IgM staining was demonstrated in 64.3% (n = 18) of carcinoma dogs. Transmission electron microscopy from dogs with carcinoma revealed slight changes, the most frequent of which was faint sub-endothelial and mesangial deposits of electron-dense material (78%). Mesangial cell interpositioning and segmental effacement of podocyte foot processes were identified in some specimens (45%). Changes in the glomerulus and proteinuria are common in dogs with naturally occurring mammary carcinoma and this condition appears to provide an excellent large animal model for cancer associated glomerulopathy in humans. PMID- 27764141 TI - Memory Elicited by Courtship Conditioning Requires Mushroom Body Neuronal Subsets Similar to Those Utilized in Appetitive Memory. AB - An animal's ability to learn and to form memories is essential for its survival. The fruit fly has proven to be a valuable model system for studies of learning and memory. One learned behavior in fruit flies is courtship conditioning. In Drosophila courtship conditioning, male flies learn not to court females during training with an unreceptive female. He retains a memory of this training and for several hours decreases courtship when subsequently paired with any female. Courtship conditioning is a unique learning paradigm; it uses a positive-valence stimulus, a female fly, to teach a male to decrease an innate behavior, courtship of the female. As such, courtship conditioning is not clearly categorized as either appetitive or aversive conditioning. The mushroom body (MB) region in the fruit fly brain is important for several types of memory; however, the precise subsets of intrinsic and extrinsic MB neurons necessary for courtship conditioning are unknown. Here, we disrupted synaptic signaling by driving a shibirets effector in precise subsets of MB neurons, defined by a collection of split-GAL4 drivers. Out of 75 lines tested, 32 showed defects in courtship conditioning memory. Surprisingly, we did not have any hits in the gamma lobe Kenyon cells, a region previously implicated in courtship conditioning memory. We did find that several gamma lobe extrinsic neurons were necessary for courtship conditioning memory. Overall, our memory hits in the dopaminergic neurons (DANs) and the mushroom body output neurons were more consistent with results from appetitive memory assays than aversive memory assays. For example, protocerebral anterior medial DANs were necessary for courtship memory, similar to appetitive memory, while protocerebral posterior lateral 1 (PPL1) DANs, important for aversive memory, were not needed. Overall, our results indicate that the MB circuits necessary for courtship conditioning memory coincide with circuits necessary for appetitive memory. PMID- 27764142 TI - Hypoalgesia Induced by Reward Devaluation in Rats. AB - Reduced sensitivity to physical pain (hypoalgesia) has been reported after events involving reward devaluation. Reward devaluation was implemented in a consummatory successive negative contrast (cSNC) task. Food-deprived Wistar rats had access to 32% sucrose during 16 sessions followed by access to 4% sucrose during 3 additional sessions. An unshifted control group had access to 4% sucrose throughout the 19 sessions. Pain sensitivity was measured using von Frey filaments (Experiment 1) and Hargreaves thermal stimuli (Experiment 2) in pretraining baseline, 5 min, and 300 min after either the first (session 17) or second (session 18) devaluation session in the cSNC situation. Sucrose consumption was lower in downshifted groups relative to unshifted groups during postshift sessions-the cSNC effect. Hypoalgesia was observed in downshifted groups relative to unshifted controls when pain sensitivity was assessed 5 min after either the first or second devaluation session, regardless of the pain sensitivity test used. Both pain sensitivity tests yielded evidence of hypoalgesia 300 min after the second downshift session, but not 300 min after the first devaluation session. Whereas hypoalgesia was previously shown only after the second devaluation session, here we report evidence of hypoalgesia after both the first and second devaluation sessions using mechanical and thermal nociceptive stimuli. Moreover, the hypoalgesia observed 300 min after the second devaluation session in both experiments provides unique evidence of the effects of reward loss on sensitivity to physical pain 5 hours after the loss episode. The underlying neurobehavioral mechanisms remain to be identified. PMID- 27764144 TI - Does a Pre-Training Program Influence Colonoscopy Proficiency during Fellowship? AB - OBJECTIVES: The objective of this study was to determine whether a pre-training program influences the entire learning process and overall proficiency of colonoscopy during fellowship. METHODS: From March 2011 to February 2013, a total of 28 first-year gastrointestinal fellows were trained in colonoscopy at a single tertiary center. Before entering their fellowship training, all fellows were board certified in internal medicine, but had no experience performing a full colonoscopy. Endoscopic quality indices were prospectively measured throughout the first training year and were compared between two groups, "pre-trained" fellows (n = 14), who had more than 100 cases of upper endoscopy experience and colonoscopy observation before starting their fellowship, and the "not pre trained" group (n = 14), who had less experience. RESULTS: A total of 15,494 colonoscopies were evaluated and 5,411 were screening colonoscopies. There were no significant differences in the overall quality index between the pre-trained and not pre-trained groups. However, the improvement in the adenoma detection rate (ADR) from the first half of the year to the latter half was significantly higher for the pre-trained group compared to the not pre-trained group (28.6% to 34.5% vs. 36.7% to 28.3%, respectively, P = 0.007). Multivariate analysis showed that pre-training before learning colonoscopy was the only significant factor for high ADR in the second half of the year (11.666 +/- 4.251 [B+/-SE], P = 0.012). CONCLUSION: Sufficient observation of colonoscopy and experience of upper endoscopy before colonoscopy training might facilitate improvement of fellows' manual and cognitive colonoscopic skills during the learning period. PMID- 27764143 TI - Outcomes in Critically Ill Patients with Cancer-Related Complications. AB - INTRODUCTION: Cancer patients are at risk for severe complications related to the underlying malignancy or its treatment and, therefore, usually require admission to intensive care units (ICU). Here, we evaluated the clinical characteristics and outcomes in this subgroup of patients. MATERIALS AND METHODS: Secondary analysis of two prospective cohorts of cancer patients admitted to ICUs. We used multivariable logistic regression to identify variables associated with hospital mortality. RESULTS: Out of 2,028 patients, 456 (23%) had cancer-related complications. Compared to those without cancer-related complications, they more frequently had worse performance status (PS) (57% vs 36% with PS>=2), active malignancy (95% vs 58%), need for vasopressors (45% vs 34%), mechanical ventilation (70% vs 51%) and dialysis (12% vs 8%) (P<0.001 for all analyses). ICU (47% vs. 27%) and hospital (63% vs. 38%) mortality rates were also higher in patients with cancer-related complications (P<0.001). Chemo/radiation therapy induced toxicity (6%), venous thromboembolism (5%), respiratory failure (4%), gastrointestinal involvement (3%) and vena cava syndrome (VCS) (2%) were the most frequent cancer-related complications. In multivariable analysis, the presence of cancer-related complications per se was not associated with mortality [odds ratio (OR) = 1.25 (95% confidence interval, 0.94-1.66), P = 0.131]. However, among the individual cancer-related complications, VCS [OR = 3.79 (1.11-12.92), P = 0.033], gastrointestinal involvement [OR = 3.05 (1.57-5.91), P = <0.001] and respiratory failure [OR = 1.96(1.04-3.71), P = 0.038] were independently associated with in hospital mortality. CONCLUSIONS: The prognostic impact of cancer-related complications was variable. Although some complications were associated with worse outcomes, the presence of an acute cancer-related complication per se should not guide decisions to admit a patient to ICU. PMID- 27764145 TI - The Relationship between Parkinson Disease and Brain Tumor: A Meta-Analysis. AB - OBJECTIVE: Epidemiological studies have investigated the association between Parkinson disease (PD) occurrence and the risk of brain tumors, while the results remain controversial. We performed a meta-analysis to clarify the exact relationship between PD and brain tumors. METHODS: A systematic literature search was conducted using PubMed, Embase, ScienceDirect and CBM (China Biology Medicine Disc) before February 2016. Eligible studies were those that reported risk estimates of brain tumors among patients with PD or vice versa. A random-effects model was used to calculate the pooled odds ratio (OR) of the outcomes. Subgroup analyses and sensitivity analysis were conducted to explore the potential sources of heterogeneity. RESULTS: In total, eight studies involving 329,276 participants met our inclusion criteria. The pooled OR was 1.51 (95%CI 1.21-1.89), indicating that PD carried a higher risk of brain tumor. Analyses by temporal relationship found that the occurrence of brain tumor was significantly higher after the diagnosis of PD (OR 1.55, 95% CI 1.18-2.05), but not statistically significant before PD diagnosis (OR 1.21, 95%CI 0.93-1.58). Subgroup analysis showed that gender differences, ethnicity differences and the characteristic of the tumor (benign or malignant) did not make much change in the association between brain tumor and PD. CONCLUSIONS: Our meta-analysis collecting epidemiological studies suggested a positive association of PD with brain tumors, while the influence of anti-parkinson drugs and ascertainment bias could not be excluded. Further studies with larger sample size and more strict inclusion criteria should be conducted in the future. PMID- 27764146 TI - Noninvasive Recognition and Biomarkers of Early Allergic Asthma in Cats Using Multivariate Statistical Analysis of NMR Spectra of Exhaled Breath Condensate. AB - Asthma is prevalent in children and cats, and needs means of noninvasive diagnosis. We sought to distinguish noninvasively the differences in 53 cats before and soon after induction of allergic asthma, using NMR spectra of exhaled breath condensate (EBC). Statistical pattern recognition was improved considerably by preprocessing the spectra with probabilistic quotient normalization and glog transformation. Classification of the 106 preprocessed spectra by principal component analysis and partial least squares with discriminant analysis (PLS-DA) appears to be impaired by variances unrelated to eosinophilic asthma. By filtering out confounding variances, orthogonal signal correction (OSC) PLS-DA greatly improved the separation of the healthy and early asthmatic states, attaining 94% specificity and 94% sensitivity in predictions. OSC enhancement of multi-level PLS-DA boosted the specificity of the prediction to 100%. OSC-PLS-DA of the normalized spectra suggest the most promising biomarkers of allergic asthma in cats to include increased acetone, metabolite(s) with overlapped NMR peaks near 5.8 ppm, and a hydroxyphenyl-containing metabolite, as well as decreased phthalate. Acetone is elevated in the EBC of 74% of the cats with early asthma. The noninvasive detection of early experimental asthma, biomarkers in EBC, and metabolic perturbation invite further investigation of the diagnostic potential in humans. PMID- 27764148 TI - Century-Old DNA Barcodes Reveal Phylogenetic Placement of the Extinct Jamaican Sunset Moth, Urania sloanus Cramer (Lepidoptera: Uraniidae). AB - Analysis of the DNA barcode region of the cytochrome c oxidase 1 gene from a specimen of the extinct Jamaican sunset moth, Urania sloanus, places this species as a sister to the Central American U. fulgens. We found that all Urania F. species were closely related (<2.8% maximum divergence at COI), with the Cuban endemic U. boisduvalii appearing as sister to the rest. The low divergence in DNA barcodes and genitalic structures indicate that the Cuban U. poeyi and eastern Brazilian U. brasiliensis are geographic segregates of U. fulgens and U. leilus respectively, so the former two taxa are accordingly recognized as subspecies. PMID- 27764147 TI - Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia. AB - INTRODUCTION: Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies. METHOD AND RESULTS: We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 MUM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05). CONCLUSIONS: We recapitulated the electrophysiological features of CPVT derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs. PMID- 27764149 TI - miRNA Expression Profiles of HPV-Infected Patients with Cervical Cancer in the Uyghur Population in China. AB - The study aimed to investigate the state of human papillomavirus (HPV) infection in patients with cervical cancer in the Uyghur population in China and to identify miRNA as biomarker for cervical cancer and HPV infection. We also performed genotyping to determine the variation in the types of HPV. Using microRNA (miRNA) microarray technology, differential miRNA expression between HPV infected cervical cancer and uninfected normal cervical tissues was determined; the microarray results were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) using 20 samples of both the tissues. The infection rate of HPV in patients with cervical cancer was 96.7% (29 of 30), and the main subtype identified was HPV16 (29 of 29). HPV16 integration assay demonstrated that the majority of infectious cases were of the integrated form (26 of 29). Analysis of 140 miRNAs demonstrated greater than two-fold change in miRNA expression in HPV-infected cervical cancer tissue as compared to that in uninfected cervical tissue. The qRT-PCR analysis verified that the expression of miR-15a-5p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-96, miR-106b-5p, and miR-3653 was higher, while the expression of miR-497-5p was lower in cancer tissues than in normal tissues. The results demonstrate significant changes in miRNA expression in cervical cancer tissues associated with HPV infection as compared to that in normal tissues. These molecular markers may be useful for an early diagnosis and prognosis of cervical cancer in specific human populations. PMID- 27764150 TI - Stability Characterization of a Vaccine Antigen Based on the Respiratory Syncytial Virus Fusion Glycoprotein. AB - Infection with Respiratory Syncytial Virus (RSV) causes both upper and lower respiratory tract disease in humans, leading to significant morbidity and mortality in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. During the infection process, the type I viral fusion (F) glycoprotein on the surface of the RSV particle rearranges from a metastable prefusion conformation to a highly stable postfusion form. In people naturally infected with RSV, most potent neutralizing antibodies are directed to the prefusion form of the F protein. Therefore, an engineered RSV F protein stabilized in the prefusion conformation (DS-Cav1) is an attractive vaccine candidate. Long-term stability at 4 degrees C or higher is a desirable attribute for a commercial subunit vaccine antigen. To assess the stability of DS-Cav1, we developed assays using D25, an antibody which recognizes the prefusion F-specific antigenic site O, and a novel antibody 4D7, which was found to bind antigenic site I on the postfusion form of RSV F. Biophysical analysis indicated that, upon long-term storage at 4 degrees C, DS Cav1 undergoes a conformational change, adopting alternate structures that concomitantly lose the site O epitope and gain the ability to bind 4D7. PMID- 27764151 TI - The Effectiveness of Daily Mindful Breathing Practices on Test Anxiety of Students. AB - The present study examined the effectiveness of daily mindful breathing practices on test anxiety of university students. A total of 36 participants were randomly assigned to one of three conditions: a training mindful breathing condition (n = 12), a training cognitive reappraisal condition (contrast group, n = 12), and a non-training condition (control group, n = 12). Each of the participants trained by themselves for 6 days after they had taken one session of education for mindful or cognitive reappraisal practices. They wrote their experiences on daily worksheets and sent it by mobile with taking pictures that were confirmed by the researcher. Before and after training, each of the participants completed a questionnaire to assess: test anxiety, positive thought, and positive affect. The results of the study showed that both mindful breathing practice and cognitive reappraisal practice yielded large effect sizes in reducing test anxiety. In addition, the mindful breathing condition scored significantly higher on positive thoughts than the cognitive reappraisal and control conditions. The findings of this study suggest that both daily mindful breathing and cognitive reappraisal practices were effective in reducing test anxiety; however, mindful breathing increased positive automatic thoughts to a greater extent than cognitive reappraisal. PMID- 27764153 TI - Immunomodulatory Effects of Different Lactic Acid Bacteria on Allergic Response and Its Relationship with In Vitro Properties. AB - Some studies reported that probiotic could relieve allergy-induced damage to the host, but how to get a useful probiotic is still a challenge. In this study, the protective effects of three lactic acid bacteria (La, Lp and Lc) were evaluated in a mouse model, and its relationship with the in vitro properties was analyzed. The in vitro results indicated that La with the capacity to inhibit IL-4 production could have a better anti-allergy effect in vivo than two others. However, the animal trials showed that all LAB strains could alleviate allergen induced airway inflammation. Among them, LAB strain Lp had a better effect in inhibiting allergic response through a modulation of Th1/Th2 balance and an increase of regulatory T cells. This difference could be explained by that different LAB strains have a strain-specific effect on gut microbiota closely associated with host immune responses. Finally, this study did not only obtain an effective anti-allergy probiotic strain via animal study, but also indicate that probiotic-induced effect on intestinal microbiota should be considered as an important screening index, apart from its inherent characteristics. PMID- 27764152 TI - Multiple Evolutionary Origins of Ubiquitous Cu2+ and Zn2+ Binding in the S100 Protein Family. AB - The S100 proteins are a large family of signaling proteins that play critical roles in biology and disease. Many S100 proteins bind Zn2+, Cu2+, and/or Mn2+ as part of their biological functions; however, the evolutionary origins of binding remain obscure. One key question is whether divalent transition metal binding is ancestral, or instead arose independently on multiple lineages. To tackle this question, we combined phylogenetics with biophysical characterization of modern S100 proteins. We demonstrate an earlier origin for established S100 subfamilies than previously believed, and reveal that transition metal binding is widely distributed across the tree. Using isothermal titration calorimetry, we found that Cu2+ and Zn2+ binding are common features of the family: the full breadth of human S100 paralogs-as well as two early-branching S100 proteins found in the tunicate Oikopleura dioica-bind these metals with MUM affinity and stoichiometries ranging from 1:1 to 3:1 (metal:protein). While binding is consistent across the tree, structural responses to binding are quite variable. Further, mutational analysis and structural modeling revealed that transition metal binding occurs at different sites in different S100 proteins. This is consistent with multiple origins of transition metal binding over the evolution of this protein family. Our work reveals an evolutionary pattern in which the overall phenotype of binding is a constant feature of S100 proteins, even while the site and mechanism of binding is evolutionarily labile. PMID- 27764154 TI - A Low-Cost HPV Immunochromatographic Assay to Detect High-Grade Cervical Intraepithelial Neoplasia. AB - OBJECTIVE: To evaluate the reproducibility and accuracy of the HPV16/18-E6 test. METHODS: The study population was comprised of 448 women with a previously abnormal Pap who were referred to the Barretos Cancer Hospital (Brazil) for diagnosis and treatment. Two cervical samples were collected immediately before colposcopy, one for the hr-HPV-DNA test and cytology and the other for the HPV16/18-E6 test using high-affinity monoclonal antibodies (mAb). Women with a histologic diagnosis of cervical intraepithelial neoplasia grade 2 or 3 were considered to be positive cases. Different strategies using a combination of screening methods (HPV-DNA) and triage tests (cytology and HPV16/18-E6) were also examined and compared. RESULTS: The HPV16/18-E6 test exhibited a lower positivity rate compared with the HPV-DNA test (19.0% vs. 29.3%, p<0.001) and a moderate/high agreement (kappa = 0.68, 95%CI: 0.60-0.75). It also exhibited a significantly lower sensitivity for CIN2+ and CIN3+ detection compared to the HPV DNA test and a significantly higher specificity. The HPV16/18-E6 test was no different from cytology in terms of sensitivity, but it exhibited a significantly higher specificity in comparison to ASCH+. A triage test after HPV-DNA detection using the HPV16/18-E6 test exhibited a significantly higher specificity compared with a triage test of ASCH+ to CIN2+ (91.8% vs. 87.4%, p = 0.04) and CIN3+ (88.6% vs. 84.0%, p = 0.05). CONCLUSION: The HPV16/18-E6 test exhibited moderate/high agreement with the HPV-DNA test but lower sensitivity and higher specificity for the detection of CIN2+ and CIN3+. In addition, its performance was quite similar to cytology, but because of the structural design addressed for the detection of HPV16/18-E6 protein, the test can miss some CIN2/3+ lesions caused by other high risk HPV types. PMID- 27764155 TI - Maltreatment and Mental Health Outcomes among Ultra-Poor Children in Burkina Faso: A Latent Class Analysis. AB - OBJECTIVES: Research about the mental health of children in Francophone West Africa is scarce. This paper examines the relationships between adverse childhood experiences, including exposure to violence and exploitation, and mental health outcomes among children living in ultra-poverty in rural Burkina Faso. METHODS: This paper utilizes baseline data collected from 360 children ages 10-15 and 360 of their mothers recruited from twelve impoverished villages in the Nord Region of Burkina, located near the Sahel Desert and affected by extreme food insecurity. We used a Latent Class Analysis to identify underlying patterns of maltreatment. Further, the relationships between latent classes and mental health outcomes were tested using mixed effected regression models adjusted for clustering within villages. RESULTS: About 15% of the children in the study scored above the clinical cut-off for depression, 17.8% for posttraumatic stress disorder (PTSD), and 6.4% for low self-esteem. The study identified five distinct sub-groups (or classes) of children based on their exposure to adverse childhood experiences. Children with the highest exposure to violence at home, at work and in the community (Abused and Exploited class) and children not attending school and working for other households, often away from their families (External Laborer class), demonstrated highest symptoms of depression and trauma. Despite living in adverse conditions and working to assist families, the study also identified a class of children who were not exposed to any violence at home or at work (Healthy and Non-abused class). Children in this class demonstrated significantly higher self-esteem (b = 0.92, SE = 0.45, p<0.05) and lower symptoms of trauma (b = -3.90, SE = 1.52, p<0.05). CONCLUSIONS: This study offers insight into the psychological well-being of children in the context of ultra-poverty in Burkina Faso and associated context-specific adverse childhood experiences. Identifying specific sub-groups of children with increased exposure to life stressors has implications for program developers. Study findings indicate a further need to explore the mental health consequences of traumatic experiences within the context of ultra-poverty and to develop integrated economic and psychosocial interventions that prevent or mitigate childhood adversities linked with the family-level poverty and violence in the family. PMID- 27764158 TI - Postural Stability Margins as a Function of Support Surface Slopes. AB - This investigation examined the effects of slope of the surface of support (35 degrees , 30 degrees , 20 degrees , 10 degrees Facing(Toe) Down, 0 degrees Flat and 10 degrees , 20 degrees , 25 degrees Facing (Toe) Up) and postural orientation on the margins of postural stability in quiet standing of young adults. The findings showed that the center of pressure-CoP (displacement, area and length) had least motion at the baseline (0 degrees Flat) platform condition that progressively increased as a function of platform angle in both facing up and down directions. The virtual time to collision (VTC) dynamics revealed that the spatio-temporal margins to the functional stability boundary were progressively smaller and the VTC time series also more regular (SampEn-Sample Entropy) as slope angle increased. Surface slope induces a restricted stability region with lower dimension VTC dynamics that is more constrained when postural orientation is facing down the slope. These findings provide further evidence that VTC acts as a control variable in standing posture that is influenced by the emergent dynamics of the individual-environment-task interaction. PMID- 27764156 TI - Nemo-Like Kinase (NLK) Is a Pathological Signaling Effector in the Mouse Heart. AB - Nemo-like kinase (NLK) is an evolutionary conserved serine/threonine protein kinase implicated in development, proliferation and apoptosis regulation. Here we identified NLK as a gene product induced in the hearts of mice subjected to pressure overload or myocardial infarction injury, suggesting a potential regulatory role with pathological stimulation to this organ. To examine the potential functional consequences of increased NLK levels, cardiac-specific transgenic mice with inducible expression of this gene product were generated, as well as cardiac-specific Nlk gene-deleted mice. NLK transgenic mice demonstrated baseline cardiac hypertrophy, dilation, interstitial fibrosis, apoptosis and progression towards heart failure in response to two surgery-induced cardiac disease models. In contrast, cardiac-specific deletion of Nlk from the heart, achieved by crossing a Nlk-loxP allele containing mouse with either a mouse containing a beta-myosin heavy chain promoter driven Cre transgene or a tamoxifen inducible alpha-myosin heavy chain promoter containing transgene driving a MerCreMer cDNA, protected the mice from cardiac dysfunction following pathological stimuli. Mechanistically, NLK interacted with multiple proteins including the transcription factor Stat1, which was significantly increased in the hearts of NLK transgenic mice. These results indicate that NLK is a pathological effector in the heart. PMID- 27764157 TI - Long-Term Outcome of Combined (Percutaneous Intramyocardial and Intracoronary) Application of Autologous Bone Marrow Mononuclear Cells Post Myocardial Infarction: The 5-Year MYSTAR Study. AB - OBJECTIVE: The long-term (5-year) outcome of early (3-6 weeks after acute myocardial infarction [AMI], BM-MNC Early group) and late (3-4 months after AMI, BM-MNC Late group) combined (percutaneous intramyocardial and intracoronary) delivery of autologous bone marrow mononuclear cells (BM-MNCs) was evaluated in patients with ejection fractions (EF) between 30-45% post-AMI. METHODS: Major adverse cardiac and cerebrovascular events (MACCE) and hospitalization were recorded. Left (LV) and right (RV) ventricular function were measured by transthoracic echocardiography. Cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography was performed in a subgroup of patients. Pre-cell therapy myocardial voltage values of treated areas (assessed by NOGA mapping) were correlated with clinical outcome. RESULTS: Five year MACCE incidences (7.4%. vs 24.1%) and the composite of all adverse events (11.1% vs 27.6%) were not different between the Early and Late treatment groups. The significant LV-EF increase at 1-year follow-up was preserved at the 5-year control (from baseline to 5-year: 5.3%, 95% CI:0.5-10.1, and 5.7%, 95% CI:1.7 9.6, p<0.05 in the Early and Late groups, respectively), with no significant changes between 1- and 5-year follow-ups. Similarly, RVEF increased significantly from baseline to the 5-year follow-up (Early group: 5.4%, 95% CI:1.0-9.6; and Late group: 8.4%, 95% CI:4.5-12.3). Lower baseline levels of myocardial viability of the treated cardiac area (6.3+/-2.4 vs 8.2+/-3.0 mV, p<0.05) were associated with incidence of MACCE. CONCLUSIONS: Percutaneous combined delivery of autologous BM-MNCs is feasible and safe after 5 years, and may result in sustained improvement of cardiac function at 5 years in patients with low EF post AMI (Clinicaltrials.gov NCT01395212). PMID- 27764159 TI - Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease. AB - INTRODUCTION: White Blood Cell (WBC) count, %HbF, and serum creatinine (Cr), have been identified as markers for increased mortality in sickle cell anemia (SCA) but no studies have examined the significance of longitudinal rate of change in these or other biomarkers for SCA individuals. METHODS: Clinical, demographic and laboratory data from SCA patients seen in 2002 by our hospital system were obtained. Those who were still followed in 2012 (survival cohort) were compared to those who had died in the interim (mortality cohort). Patients lost to follow up were excluded. Age adjusted multivariable Cox proportional hazards models were constructed to assess hazard ratios of mortality risk associated with the direction and degree of change for each variable. RESULTS: 359 SCA patients were identified. Baseline higher levels of WBC, serum creatinine and hospital admissions were associated with increased mortality, as were alkaline phosphatase and aspartate aminotransaminase levels. Lower baseline levels of %HbF were also associated with increased mortality. When longitudinal rates of change for individuals were assessed, increases in Hb or WBC over patient baseline values were associated with greater mortality risk (HR 1.54, p = 0.02 and HR 1.16, p = 0.01 with negative predictive values of 87.8 and 94.4 respectively), while increasing ED use was associated with decreased mortality (HR 0.84, p = 0.01). We did not detect any increased mortality risk for longitudinal changes in annual clinic visits or admissions, creatinine or %HbF. CONCLUSIONS: Although initial steady state observations can help predict survival in SCA, the longitudinal course of a patient may give additional prognostic information. PMID- 27764160 TI - CSF Biomarkers and Its Associations with 18F-AV133 Cerebral VMAT2 Binding in Parkinson's Disease-A Preliminary Report. AB - OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers, such as alpha-synuclein (alpha syn), amyloid beta peptide 1-42 (Abeta1-42), phosphorylated tau (181P) (p-tau), and total tau (t-tau), have long been associated with the development of Parkinson disease (PD) and other neurodegenerative diseases. In this investigation, we reported the assessment of CSF biomarkers and their correlations with vesicular monoamine transporter 2 (VMAT2) bindings measured with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV133) that is being developed as a biomarker for PD. We test the hypothesis that monoaminergic degeneration was correlated with CSF biomarker levels in untreated PD patients. METHODS: The available online data from the Parkinson's Progression Markers Initiative study (PPMI) project were collected and analyzed, which include demographic information, clinical evaluations, CSF biomarkers (alpha-syn, Abeta1 42, p-tau, and t-tau), 18F-AV133 brain PET, and T1 weighted MRIs. Region of interest (ROI) and voxel-wise Pearson correlation between standardized uptake value ratio (SUVR) and CSF biomarkers were calculated. RESULTS: Our major findings are: 1) Compared with controls, CSF alpha-syn and tau levels decreased significantly in PD; 2) alpha-syn was closely correlated with Abeta1-42 and tau in PD, especially in early-onset patients; and 3) hypothesis-driven ROI analysis found a significant negative correlation between CSF Abeta1-42 levels and VMAT2 densities in post cingulate, left caudate, left anterior putamen, and left ventral striatum in PDs. CSF t-tau and p-tau levels were significantly negatively related to VMAT2 SUVRs in substantia nigra and left ventral striatum, respectively. Voxel-wise analysis showed that left caudate, parahippocampal gyrus, insula and temporal lobe were negatively correlated with Abeta1-42. In addition, superior frontal gyrus and transverse temporal gyrus were negatively correlated with CSF p-tau levels. CONCLUSION: These results suggest that monoaminergic degeneration in PD is correlated with CSF biomarkers associated with cognitive impairment in neurodegenerative diseases including Alzheimer's disease. The association between loss of dopamine synaptic function and pathologic protein accumulations in PD indicates an important role of CSF biomarkers in PD development. PMID- 27764161 TI - Polycomb Protein OsFIE2 Affects Plant Height and Grain Yield in Rice. AB - Polycomb group (PcG) proteins have been shown to affect growth and development in plants. To further elucidate their role in these processes in rice, we isolated and characterized a rice mutant which exhibits dwarfism, reduced seed setting rate, defective floral organ, and small grains. Map-based cloning revealed that abnormal phenotypes were attributed to a mutation of the Fertilization Independent Endosperm 2 (OsFIE2) protein, which belongs to the PcG protein family. So we named the mutant as osfie2-1. Histological analysis revealed that the number of longitudinal cells in the internodes decreased in osfie2-1, and that lateral cell layer of the internodes was markedly thinner than wild-type. In addition, compared to wild-type, the number of large and small vascular bundles decreased in osfie2-1, as well as cell number and cell size in spikelet hulls. OsFIE2 is expressed in most tissues and the coded protein localizes in both nucleus and cytoplasm. Yeast two-hybrid and bimolecular fluorescence complementation assays demonstrated that OsFIE2 interacts with OsiEZ1 which encodes an enhancer of zeste protein previously identified as a histone methylation enzyme. RNA sequencing-based transcriptome profiling and qRT-PCR analysis revealed that some homeotic genes and genes involved in endosperm starch synthesis, cell division/expansion and hormone synthesis and signaling are differentially expressed between osfie2-1 and wild-type. In addition, the contents of IAA, GA3, ABA, JA and SA in osfie2-1 are significantly different from those in wild-type. Taken together, these results indicate that OsFIE2 plays an important role in the regulation of plant height and grain yield in rice. PMID- 27764162 TI - Novel Strategy to Control Transgene Expression Mediated by a Sendai Virus-Based Vector Using a Nonstructural C Protein and Endogenous MicroRNAs. AB - Tissue-specific control of gene expression is an invaluable tool for studying various biological processes and medical applications. Efficient regulatory systems have been utilized to control transgene expression in various types of DNA viral or integrating viral vectors. However, existing regulatory systems are difficult to transfer into negative-strand RNA virus vector platforms because of significant differences in their transcriptional machineries. In this study, we developed a novel strategy for regulating transgene expression mediated by a cytoplasmic RNA vector based on a replication-defective and persistent Sendai virus (SeVdp). Because of the capacity of Sendai virus (SeV) nonstructural C proteins to specifically inhibit viral RNA synthesis, overexpression of C protein significantly reduced transgene expression mediated by SeVdp vectors. We found that SeV C overexpression concomitantly reduced SeVdp mRNA levels and genomic RNA synthesis. To control C expression, target sequences for an endogenous microRNA were incorporated into the 3' untranslated region of the C genes. Incorporation of target sequences for miR-21 into the SeVdp vector restored transgene expression in HeLa cells by decreasing C expression. Furthermore, the SeVdp vector containing target sequences for let-7a enabled cell-specific control of transgene expression in human fibroblasts and induced pluripotent stem cells. Our findings demonstrate that SeV C can be used as an effective regulator for controlling transgene expression. This strategy will contribute to efficient and less toxic SeVdp-mediated gene transfer in various biological applications. PMID- 27764164 TI - Optimising Land-Sea Management for Inshore Coral Reefs. AB - Management authorities seldom have the capacity to comprehensively address the full suite of anthropogenic stressors, particularly in the coastal zone where numerous threats can act simultaneously to impact reefs and other ecosystems. This situation requires tools to prioritise management interventions that result in optimum ecological outcomes under a set of constraints. Here we develop one such tool, introducing a Bayesian Belief Network to model the ecological condition of inshore coral reefs in Moreton Bay (Australia) under a range of management actions. Empirical field data was used to model a suite of possible ecological responses of coral reef assemblages to five key management actions both in the sea (e.g. expansion of reserves, mangrove & seagrass restoration, fishing restrictions) and on land (e.g. lower inputs of sediment and sewage from treatment plants). Models show that expanding marine reserves (a 'marine action') and reducing sediment inputs from the catchments (a 'land action') were the most effective investments to achieve a better status of reefs in the Bay, with both having been included in >58% of scenarios with positive outcomes, and >98% of the most effective (5th percentile) scenarios. Heightened fishing restrictions, restoring habitats, and reducing nutrient discharges from wastewater treatment plants have additional, albeit smaller effects. There was no evidence that combining individual management actions would consistently produce sizeable synergistic until after maximum investment on both marine reserves (i.e. increasing reserve extent from 31 to 62% of reefs) and sediments (i.e. rehabilitating 6350 km of waterways within catchments to reduce sediment loads by 50%) were implemented. The method presented here provides a useful tool to prioritize environmental actions in situations where multiple competing management interventions exist for coral reefs and in other systems subjected to multiple stressor from the land and the sea. PMID- 27764163 TI - Targeting Epithelial-Mesenchymal Transition for Identification of Inhibitors for Pancreatic Cancer Cell Invasion and Tumor Spheres Formation. AB - BACKGROUND: Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition. METHODS: An immunofluorescent assay was established and optimized for HTS to identify compounds that enhance E-cadherin expression, as a hallmark of inhibition of EMT. Four chemical libraries containing 41,472 compounds were screened in PANC-1 pancreatic cancer cell line. Positive hits were validated for EMT and CSC inhibition in vitro using sphere formation assay, western blotting, immune fluorescence, and scratch assay. RESULTS: Initial hits were refined to 73 compounds with a secondary screening, among which 17 exhibited concentration dependent induction of E-cadherin expression. Six compounds were selected for further study which belonged to 2 different chemical structural clusters. A novel compound 1-(benzylsulfonyl) indoline (BSI, Compound #38) significantly inhibited pancreatic cancer cell migration and invasion. BSI inhibited histone deacetylase, increased histone 4 acetylation preferably, resulting in E-cadherin up-regulation. BSI effectively inhibited tumor spheres formation. Six more analogues of BSI were tested for anti migration and anti-CSC activities. CONCLUSION: This study demonstrated a feasible approach for discovery of agents targeting EMT and CSCs using HTS, and identified a class of novel chemicals that could be developed as anti-EMT and anti-CSC drug leads. PMID- 27764165 TI - Detection of Acute and Early HIV-1 Infections in an HIV Hyper-Endemic Area with Limited Resources. AB - BACKGROUND: Two thirds of the world's new HIV infections are in sub-Saharan Africa. Acute HIV infection (AHI) is the time of virus acquisition until the appearance of HIV antibodies. Early HIV infection, which includes AHI, is the interval between virus acquisition and establishment of viral load set-point. This study aimed to detect acute and early HIV infections in a hyper-endemic setting. METHODS: This was a cross-sectional diagnostic study that enrolled individuals who had negative rapid HIV results in five clinics in South Africa. Pooled nucleic acid amplification testing (NAAT) was performed, followed by individual sample testing in positive pools. NAAT-positive participants were recalled to the clinics for confirmatory testing and appropriate management. HIV antibody, p24 antigen, Western Blot and avidity tests were performed for characterization of NAAT-positive samples. RESULTS: The study enrolled 6910 individuals with negative rapid HIV results. Median age was 27 years (interquartile range {IQR}: 23-31). NAAT was positive in 55 samples, resulting in 0.8% newly diagnosed HIV-infected individuals (95% confidence interval {CI}: 0.6 1.0). The negative predictive value for rapid HIV testing was 99.2% (95% CI: 99.0 99.4). Characterization of NAAT-positive samples revealed that 0.04% (95% CI: 0.000-0.001) had AHI, 0.3% (95% CI: 0.1-0.4) had early HIV infection, and 0.5% (95% CI: 0.5-0.7) had chronic HIV infection. Forty-seven (86%) of NAAT-positive participants returned for follow-up at a median of 4 weeks (IQR: 2-8). Follow-up rapid tests were positive in 96% of these participants. CONCLUSIONS: NAAT demonstrated that a substantial number of HIV-infected individuals are misdiagnosed at South African points-of-care. Follow-up rapid tests done within a 4 week interval detected early and chronic HIV infections initially missed by rapid HIV testing. This may be a practical and affordable strategy for earlier detection of these infections in resource-constrained settings. Newer molecular tests that can be used at the points-of-care should be evaluated for routine diagnosis of HIV in hyper-endemic settings. PMID- 27764166 TI - Asymmetry Analysis of Macular Inner Retinal Layers for Glaucoma Diagnosis: Swept Source Optical Coherence Tomography Study. AB - PURPOSE: To report an asymmetry analysis of macular inner retinal layers using swept-source optical coherence tomography (OCT) and to evaluate the utility for glaucoma diagnosis. DESIGN: Observational, cross-sectional study. PARTICIPANTS: Seventy normal healthy subjects and 62 glaucoma patients. METHODS: Three dimensional scans were acquired from 70 normal subjects and 62 open angle glaucoma patients by swept-source OCT. The thickness of the retinal nerve fiber layer, ganglion cell-inner plexiform layer (GCIPL), ganglion cell complex, and total retina were calculated within a 6.2*6.2 mm macular area divided into a 31*31 grid of 200*200 MUm superpixels. For each of the corresponding superpixels, the thickness differences between the subject eyes and contra-lateral eyes and between the upper and lower macula halves of the subject eyes were determined. The negative differences were displayed on a gray-scale asymmetry map. Black superpixels were defined as thickness decreases over the cut-off values. RESULTS: The negative inter-ocular and inter-hemisphere differences in GCIPL thickness (mean +/- standard deviation) were -2.78 +/- 0.97 MUm and -3.43 +/- 0.71 MUm in the normal group and -4.26 +/- 2.23 MUm and -4.88 +/- 1.46 MUm in the glaucoma group. The overall extent of the four layers' thickness decrease was larger in the glaucoma group than in the normal group (all Ps<0.05). The numbers of black superpixels on all of the asymmetry maps were larger in the glaucoma group than in the normal group (all Ps<0.05). The area under receiver operating characteristic curves of average negative thickness differences in macular inner layers for glaucoma diagnosis ranged from 0.748 to 0.894. CONCLUSIONS: The asymmetry analysis of macular inner retinal layers showed significant differences between the normal and glaucoma groups. The diagnostic performance of the asymmetry analysis was comparable to that of previous methods. These findings suggest that the asymmetry analysis can be a potential ancillary diagnostic tool. PMID- 27764167 TI - One in the Dance: Musical Correlates of Group Synchrony in a Real-World Club Environment. AB - Previous research on interpersonal synchrony has mainly investigated small groups in isolated laboratory settings, which may not fully reflect the complex and dynamic interactions of real-life social situations. The present study expands on this by examining group synchrony across a large number of individuals in a naturalistic environment. Smartphone acceleration measures were recorded from participants during a music set in a dance club and assessed to identify how group movement synchrony covaried with various features of the music. In an evaluation of different preprocessing and analysis methods, giving more weight to front-back movement provided the most sensitive and reliable measure of group synchrony. During the club music set, group synchrony of torso movement was most strongly associated with pulsations that approximate walking rhythm (100-150 beats per minute). Songs with higher real-world play counts were also correlated with greater group synchrony. Group synchrony thus appears to be constrained by familiarity of the movement (walking action and rhythm) and of the music (song popularity). These findings from a real-world, large-scale social and musical setting can guide the development of methods for capturing and examining collective experiences in the laboratory and for effectively linking them to synchrony across people in daily life. PMID- 27764168 TI - Effects of Secondary Hyperparathyroidism Treatment on Improvement in Anemia: Results from the MBD-5D Study. AB - OBJECTIVES: Anemia is an important prognostic factor in hemodialysis patients. It has been reported that parathyroidectomy ameliorates anemia and reduces the requirement of postoperative erythropoiesis-stimulating agents. The objective of this study was to assess the effect of cinacalcet, which is considered as a pharmacological parathyroidectomy, on anemia in hemodialysis patients. METHODS: We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism; the criteria were: intact parathyroid hormone concentrations >= 180 pg/mL or use of an intravenous or oral vitamin D receptor activator. All patients were cinacalcet-naive at study enrollment. The main outcome measure was achievement of the target hemoglobin level (>=10.0 g/dL), which was measured repeatedly every 6 months. Cinacalcet exposure was defined as cumulative time since initiation. Both conventional longitudinal models and marginal structural models were adjusted for confounding factors. RESULTS: Among 3,201 cinacalcet-naive individuals at baseline, cinacalcet was initiated in 1,337 individuals during the follow up. Cinacalcet users were slightly younger; included more patients with chronic glomerulonephritis and fewer with diabetes; were more likely to have a history of parathyroidectomy; and were more often on activated vitamin D agents, phosphate binders, and iron supplements. After adjusting for both time-invariant and time-varying potential confounders, including demographics, comorbidities, comedications, and laboratory values, each additional 6-month duration on cinacalcet was associated with a 1.1-fold increase in the odds of achieving the target hemoglobin level. CONCLUSIONS: Cinacalcet may improve anemia in chronic hemodialysis patients with secondary hyperparathyroidism, possibly through pathways both within and outside the parathyroid hormone pathways. Further investigations are warranted to delineate the roles of cinacalcet not only in the management of chronic kidney disease mineral and bone disorder but also in anemia control. PMID- 27764169 TI - Maternal Vitamin D Status at Week 30 of Gestation and Offspring Cardio-Metabolic Health at 20 Years: A Prospective Cohort Study over Two Decades. AB - BACKGROUND/OBJECTIVES: Vitamin D deficiency is common among pregnant women and since the fetus relies exclusively on maternal supply, deficiency could potentially interfere with fetal development. Vitamin D blood concentrations during pregnancy have been associated with offspring cardio-metabolic health in a few previous studies but the evidence is still inconsistent and only one previous study has followed the offspring into adulthood. The aim of the present study was to investigate the association between maternal serum concentration of vitamin D (25(OH)D) in week 30 of gestation and offspring cardio-metabolic risk factors at 20 years. SUBJECTS/METHODS: A follow up study of a Danish birth cohort from 1988 89 (n = 965) was conducted. A blood sample was drawn from the women in week 30 of gestation. In 2008-2009, 95% of the original mother and child dyads could be identified in the central registration registry and were alive and living in Denmark. The offspring were followed up with self-reported anthropometrics (N = 629, 69%) and a clinical examination (N = 410, 45%). Multiple linear regression was used to estimate the association between maternal 25(OH)D and offspring cardio-metabolic risk factors adjusting for potential confounders. RESULTS: No overall association was observed between maternal 25(OH)D in week 30 of gestation and offspring cardio-metabolic risk factors. However, the analyses did suggest a possible inverse association with blood pressure in females. CONCLUSIONS: No clear association between maternal 25(OH)D concentration in week 30 of gestation and cardio-metabolic risk factors in the 20 year old offspring was found. PMID- 27764170 TI - Clinical Implications of FADD Gene Amplification and Protein Overexpression in Taiwanese Oral Cavity Squamous Cell Carcinomas. AB - Amplification of 11q13.3 is a frequent event in human cancers, including head and neck squamous cell carcinoma. This chromosome region contains several genes that are potentially cancer drivers, including FADD (Fas associated via death domain), an apoptotic effector that was previously identified as a novel oncogene in laryngeal/pharyngeal cancer. This study was designed to explore the role of FADD in oral squamous cell carcinomas (OSCCs) samples from Taiwanese patients, by assessing copy number variations (CNVs) and protein expression and the clinical implications of these factors in 339 male OSCCs. The intensity of FADD protein expression, as determined by immunohistochemistry, was strongly correlated with gene copy number amplification, as analyzed using a TaqMan CNV assay. Both FADD gene copy number amplification and high protein expression were significantly associated with lymph node metastasis (P < 0.001). Patients with both FADD copy number amplification and high protein expression had the shortest disease-free survival (DFS; P = 0.074 and P = 0.002) and overall survival (OS; P = 0.011 and P = 0.027). After adjusting for primary tumor status, tumor differentiation, lymph node metastasis and age at diagnosis, DFS was still significantly lower in patients with either copy number amplification or high protein expression (hazard ratio [H.R.] = 1.483; 95% confidence interval [C.I.], 1.044-2.106). In conclusion, our data reveal that FADD gene copy number and protein expression can be considered potential prognostic markers and are closely associated with lymph node metastasis in patients with OSCC in Taiwan. PMID- 27764171 TI - The Association of Helicobacter pylori Eradication with the Occurrences of Chronic Kidney Diseases in Patients with Peptic Ulcer Diseases. AB - The association of Helicobacter pylori eradication with the occurrence of renal dysfunction in patients with peptic ulcer diseases is still unclear. This study aimed to clarify the relevance of H. pylori eradication to the occurrence of chronic kidney diseases in patients with peptic ulcer diseases. Data that were available from 2000-2011 were extracted from the National Health Insurance Research Database in Taiwan, and all patients with peptic ulcer diseases (n = 208 196) were screened for eligibility. We divided randomly selected patients into an H. pylori eradication cohort (cohort A, n = 3593) and matched them by age and sex to a without H. pylori eradication cohort (cohort B, n = 3593). Subgroup analysis was further performed for H. pylori eradication within <= 90 days of the diagnosis date (early eradication, n = 2837) and within 91-365 days (non-early eradication, n = 756). Cox proportional hazards regression analysis was used to estimate the association of H. pylori eradication with the risk of developing chronic kidney diseases and mortality. We observed that there were more patients suffering from chronic kidney disease in cohort B than in the early eradication subgroup of cohort A (8.49% vs. 6.70%, respectively, p = 0.0075); the mortality rate was also higher in cohort B (4.76% vs. 3.70%, respectively, p = 0.0376). Old age, pulmonary disease, connective tissue disorders, and diabetes were risk factors for chronic kidney diseases but early H. pylori eradication was a protective factor against chronic kidney diseases (hazard ratio: 0.68, 95% confidence interval: 0.52-0.88, p = 0.0030), and death (hazard ratio: 0.69, 95% confidence interval: 0.49-0.96, p = 0.0297). In conclusion, our findings have important implications suggesting that early H. pylori eradication is mandatory since it is associated with a protective role against the occurrence of chronic kidney diseases. PMID- 27764172 TI - Developmental Changes in Hippocampal CA1 Single Neuron Firing and Theta Activity during Associative Learning. AB - Hippocampal development is thought to play a crucial role in the emergence of many forms of learning and memory, but ontogenetic changes in hippocampal activity during learning have not been examined thoroughly. We examined the ontogeny of hippocampal function by recording theta and single neuron activity from the dorsal hippocampal CA1 area while rat pups were trained in associative learning. Three different age groups [postnatal days (P)17-19, P21-23, and P24 26] were trained over six sessions using a tone conditioned stimulus (CS) and a periorbital stimulation unconditioned stimulus (US). Learning increased as a function of age, with the P21-23 and P24-26 groups learning faster than the P17 19 group. Age- and learning-related changes in both theta and single neuron activity were observed. CA1 pyramidal cells in the older age groups showed greater task-related activity than the P17-19 group during CS-US paired sessions. The proportion of trials with a significant theta (4-10 Hz) power change, the theta/delta ratio, and theta peak frequency also increased in an age-dependent manner. Finally, spike/theta phase-locking during the CS showed an age-related increase. The findings indicate substantial developmental changes in dorsal hippocampal function that may play a role in the ontogeny of learning and memory. PMID- 27764174 TI - Redundant Design in Interdependent Networks. AB - Modern infrastructure networks are often coupled together and thus could be modeled as interdependent networks. Overload and interdependent effect make interdependent networks more fragile when suffering from attacks. Existing research has primarily concentrated on the cascading failure process of interdependent networks without load, or the robustness of isolated network with load. Only limited research has been done on the cascading failure process caused by overload in interdependent networks. Redundant design is a primary approach to enhance the reliability and robustness of the system. In this paper, we propose two redundant methods, node back-up and dependency redundancy, and the experiment results indicate that two measures are effective and costless. Two detailed models about redundant design are introduced based on the non-linear load capacity model. Based on the attributes and historical failure distribution of nodes, we introduce three static selecting strategies-Random-based, Degree-based, Initial load-based and a dynamic strategy-HFD (historical failure distribution) to identify which nodes could have a back-up with priority. In addition, we consider the cost and efficiency of different redundant proportions to determine the best proportion with maximal enhancement and minimal cost. Experiments on interdependent networks demonstrate that the combination of HFD and dependency redundancy is an effective and preferred measure to implement redundant design on interdependent networks. The results suggest that the redundant design proposed in this paper can permit construction of highly robust interactive networked systems. PMID- 27764173 TI - Longitudinal Visuomotor Development in a Malaria Endemic Area: Cerebral Malaria and Beyond. AB - Paediatric cerebral malaria is the most serious complication of Plasmodium falciparum infection. While the majority recover, long-term cognitive impairment has been highlighted as a significant and neglected problem. Persistent or serious deficits in processes such as attention or behavioural inhibition should be manifest in changes to performance on oculomotor tasks. Therefore we investigated the impact of cerebral malaria on the development of reflexive pro saccades and antisaccades. In a longitudinal study, 47 children previously admitted with retinopathy-confirmed cerebral malaria (mean age at admission 54 months), were compared with 37 local healthy controls (mean ages at first study visit 117 and 110 months respectively). In each of three or four test sessions, over a period of up to 32 months, participants completed 100 prosaccade tasks and 100 antisaccade tasks. Eye movements were recorded using infrared reflectance oculography; prosaccade, correct antisaccade and error prosaccade latency, and antisaccade directional error rate were calculated. Hierarchical linear modelling was used to investigate the effect of age and the influence of cerebral malaria on these parameters. Data were also collected from an independent, older group (mean age 183 months) of 37 local healthy participants in a separate cross sectional study. Longitudinal data exhibited the expected decrease in latency with age for all saccade types, and a decrease in the antisaccade directional error rate. Hierarchical linear modelling confirmed that age had a statistically significant effect on all parameters (p< = 0.001). However, there were no statistically significant differences between the cerebral malaria and control groups. Combining groups, comparison with the literature demonstrated that antisaccade directional error rate for the Malawi sample was significantly higher than expected, while latencies for all saccade types were indistinguishable from published. The high directional error rate was also confirmed in the older, healthy Malawian participants from the cross sectional study. Our observation of similar oculomotor performance in cerebral malaria and control groups at long follow-up periods suggests that cerebral malaria survivors are not at a generally increased risk of persistent cognitive deficits. Our data raise questions about the prevailing hypothesis that cerebral malaria has gross impacts on the development of processes such as attention and behavioural inhibition. More importantly, our novel finding of a clear difference in antisaccade performance between all of the Malawi participants and published data suggests that the Malawian paediatric population as a whole faces serious challenges to cognitive development beyond cerebral malaria. PMID- 27764175 TI - Analysis of Arbovirus Isolates from Australia Identifies Novel Bunyaviruses Including a Mapputta Group Virus from Western Australia That Links Gan Gan and Maprik Viruses. AB - The Mapputta group comprises antigenically related viruses indigenous to Australia and Papua New Guinea that are included in the family Bunyaviridae but not currently assigned to a specific genus. We determined and analyzed the genome sequences of five Australian viruses isolated from mosquitoes collected during routine arbovirus surveillance in Western Australia (K10441, SW27571, K13190, and K42904) and New South Wales (12005). Based on matching sequences of all three genome segments to prototype MRM3630 of Trubanaman virus (TRUV), NB6057 of Gan Gan virus (GGV), and MK7532 of Maprik virus (MPKV), isolates K13190 and SW27571 were identified as TRUV, 12005 as GGV, and K42904 as a Mapputta group virus from Western Australia linking GGV and MPKV. The results confirmed serum neutralization data that had linked SW27571 to TRUV. The fifth virus, K10441 from Willare, was most closely related to Batai orthobunyavirus, presumably representing an Australian variant of the virus. Phylogenetic analysis also confirmed the close relationship of our TRUV and GGV isolates to two other recently described Australian viruses, Murrumbidgee virus and Salt Ash virus, respectively. Our findings indicate that TRUV has a wide circulation throughout the Australian continent, demonstrating for the first time its presence in Western Australia. Similarly, the presence of a virus related to GGV, which had been linked to human disease and previously known only from the Australian southeast, was demonstrated in Western Australia. Finally, a Batai virus isolate was identified in Western Australia. The expanding availability of genomic sequence for novel Australian bunyavirus variants supports the identification of suitably conserved or diverse primer-binding target regions to establish group wide as well as virus-specific nucleic acid tests in support of specific diagnostic and surveillance efforts throughout Australasia. PMID- 27764176 TI - A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti Diabetic Agen. AB - Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent. PMID- 27764177 TI - Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource Restricted and Large Population Study Settings. AB - HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4 item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study-HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman's Rho), and inter-tester concordance > 0.93 (Spearman's Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4 interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain. PMID- 27764178 TI - Multi-Country Evaluation of Safety of Dihydroartemisinin/Piperaquine Post Licensure in African Public Hospitals with Electrocardiograms. AB - The antimalarial drug piperaquine is associated with delayed ventricular depolarization, causing prolonged QT interval (time taken for ventricular de polarisation and re-polarisation). There is a lack of safety data regarding dihydroartemisinin/piperaquine (DHA/PPQ) for the treatment of uncomplicated malaria, which has limited its use. We created a platform where electrocardiograms (ECG) were performed in public hospitals for the safety assessment of DHA/PPQ, at baseline before the use of dihydroartemisinin/piperaquine (Eurartesim(r)), and on day 3 (before and after administration of the final dose) and day 7 post-administration. Laboratory analyses included haematology and clinical chemistry. The main objective of the ECG assessment in this study was to evaluate the effect of administration of DHA/PPQ on QTc intervals and the association of QTc intervals with changes in blood biochemistry, full and differential blood count over time after the DHA/PPQ administration. A total of 1315 patients gave consent and were enrolled of which 1147 (87%) had complete information for analyses. Of the enrolled patients 488 (42%), 323 (28%), 213 (19%) and 123 (11%) were from Ghana, Burkina Faso, Tanzania and Mozambique, respectively. Median (lower-upper quartile) age was 8 (5-14) years and a quarter of the patients were children under five years of age (n = 287). Changes in blood biochemistry, full and differential blood count were temporal which remained within clinical thresholds and did not require any intervention. The mean QTcF values were significantly higher than on day 1 when measured on day 3 before and after administration of the treatment as well as on day 7, four days after completion of treatment (12, 22 and 4 higher, p < 0.001). In all age groups the values of QT, QTcF and QTcB were highest on day 3 after drug intake. The mean extreme QTcF prolongation from baseline was lowest on day 3 before drug intake (33 ms, SD = 19) and highest on day 3 after the last dose (60 ms, SD = 31). There were 79 (7%) events of extreme mean QTcF prolongation which were not clinically significant. Nearly a half of them (n = 37) were grade 3 and mainly among males (33/37). Patients in Burkina Faso, Mozambique and Tanzania had significantly lower mean QTcF than patients in Ghana by an average of 3, 4 and 11 ms, respectively. We found no evidence that Eurartesim(r) administered in therapeutic doses in patients with uncomplicated malaria and no predisposing cardiac conditions in Africa was associated with adverse clinically significant QTc prolongation. PMID- 27764179 TI - Exogenous gamma-Aminobutyric Acid Improves the Structure and Function of Photosystem II in Muskmelon Seedlings Exposed to Salinity-Alkalinity Stress. AB - Gamma-aminobutyric acid (GABA) is important in plant responses to environmental stresses. We wished to clarify the role of GABA in maintenance of photosynthesis in muskmelon seedlings (Cucumis melo L., cv. Yipintianxia) during saline-alkaline stress. To this end, we assessed the effect of GABA on the structure and function of the photosynthetic apparatus in muskmelon seedlings grown under saline alkaline stress. These stresses in combination reduced net photosynthetic rate, gas-exchange, and inhibited photosystem II (PSII) electron transport as measured by the JIP-test. They also reduced the activity of chloroplast ATPases and disrupted the internal lamellar system of the thylakoids. Exogenous GABA alleviated the stress-induced reduction of net photosynthesis, the activity of chloroplast ATPases, and overcame some of the damaging effects of stress on the chloroplast structure. Based on interpretation of the JIP-test, we conclude that exogenous GABA alleviated stress-related damage on the acceptor side of PSII. It also restored energy distribution, the reaction center status, and enhanced the ability of PSII to repair reaction centers in stressed seedlings. GABA may play a crucial role in protecting the chloroplast structure and function of PSII against the deleterious effects of salinity-alkalinity stress. PMID- 27764180 TI - Biodistribution of Idursulfase Formulated for Intrathecal Use (Idursulfase-IT) in Cynomolgus Monkeys after Intrathecal Lumbar Administration. AB - Enzyme replacement therapy with intravenous idursulfase (recombinant iduronate-2 sulfatase) is approved for the treatment of Hunter syndrome. Intravenous administration does not, however, treat the neurological manifestations, due to its low central nervous system bioavailability. Using intrathecal-lumbar administration, iduronate-2-sulfatase is delivered directly to the central nervous system. This study investigates the central nervous system biodistribution of intrathecal-lumbar administered iduronate-2-sulfatase in cynomolgus monkeys. Twelve monkeys were administered iduronate-2-sulfatase in one 30 mg intrathecal-lumbar injection. Brain, spinal cord, liver, and kidneys were collected for iduronate-2-sulfatase concentration (measured by an enzyme linked immunosorbent assay) and enzyme activity measurement (via a method utilizing 4 methylumbelliferyl-alpha-iduronate-2-sulfate) at 1, 2, 5, 12, 24, and 48 hours following administration. The tissue enzyme linked immunosorbent assay confirmed iduronate-2-sulfatase uptake to the brain, spinal cord, kidneys, and liver in a time-dependent manner. In spinal cord and brain, iduronate-2-sulfatase appeared as early as 1 hour following administration, and peak concentrations were observed at ~2 and ~5 hours. Iduronate-2-sulfatase appeared in liver and kidneys 1 hour post intrathecal-lumbar dose with peak concentrations between 5 and 24 hours. Liver iduronate-2-sulfatase concentration was approximately 10-fold higher than kidney. The iduronate-2-sulfatase localization and enzyme activity in the central nervous system, following intrathecal administration, demonstrates that intrathecal-lumbar treatment with iduronate-2-sulfatase may be considered for further investigation as a treatment for Hunter syndrome patients with neurocognitive impairment. PMID- 27764181 TI - Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer. AB - Enhancer of zeste homology 2 (EZH2) is the methyltransferase component of the polycomb repressive complex (PRC2) which represses gene transcription via histone H3 trimethylation at lysine 23 (H3K27me3). EZH2 activity has been linked with oncogenesis where it is thought to block expression of certain tumor suppressors. Relative to a role in cancer, EZH2 functions to promote self-renewal and has been shown to be important for the tumor-initiating cell (TIC) phenotype in breast cancer. Recently a non-canonical role for EZH2 has been identified where it promotes transcriptional activation of certain genes. Here we show that EZH2, through a methyltransferase-independent mechanism, promotes the transcriptional activation of the non-canonical NF-kappaB subunit RelB to drive self-renewal and the TIC phenotype of triple-negative breast cancer cells. PMID- 27764182 TI - Characterization of In-Body to On-Body Wireless Radio Frequency Link for Upper Limb Prostheses. AB - Wireless implanted devices can be used to interface patients with disabilities with the aim of restoring impaired motor functions. Implanted devices that record and transmit electromyographic (EMG) signals have been applied for the control of active prostheses. This simulation study investigates the propagation losses and the absorption rate of a wireless radio frequency link for in-to-on body communication in the medical implant communication service (MICS) frequency band to control myoelectric upper limb prostheses. The implanted antenna is selected and a suitable external antenna is designed. The characterization of both antennas is done by numerical simulations. A heterogeneous 3D body model and a 3D electromagnetic solver have been used to model the path loss and to characterize the specific absorption rate (SAR). The path loss parameters were extracted and the SAR was characterized, verifying the compliance with the guideline limits. The path loss model has been also used for a preliminary link budget analysis to determine the feasibility of such system compliant with the IEEE 802.15.6 standard. The resulting link margin of 11 dB confirms the feasibility of the system proposed. PMID- 27764184 TI - Comparison of the Inverted Internal Limiting Membrane Flap Technique and the Internal Limiting Membrane Peeling for Macular Hole with Retinal Detachment. AB - PURPOSE: To evaluate the efficacy of the inverted internal limiting membrane (ILM) flap technique in vitrectomy for macular hole (MH) with retinal detachment (RD) compared with vitrectomy using ILM peeling. METHODS: A retrospective case series study was performed. Twenty-two eyes of 22 patients who underwent vitrectomy for MH with RD and followed-up more than 12 months after the surgery were included in this study. We retrospectively reviewed the medical records of patients who underwent vitrectomy with inverted ILM flap technique or vitrectomy with ILM peeling. Ten patients who had been treated vitrectomy with inverted ILM flap technique, and 12 patients who had been treated vitrectomy with ILM peeling were analyzed. We evaluated changes in best-corrected visual acuity (BCVA) before and after surgery, closing rates of MH, and retinal reattachment rates and compared between both groups. RESULTS: MH was closed and RD was reattached postoperatively in 9 eyes (90%) in the inverted ILM flap group. In the ILM peeling group, the MH was closed in 4 eyes (33.3%) and the retinas were reattached in 6 eyes (50%) after surgery. Significant improvement in BCVA after surgery (P = 0.0017) was only found in the inverted ILM flap group. CONCLUSIONS: Higher rates of closed MH and retinal reattachment, and small but significant improvement in BCVA were found in the inverted ILM flap group. Based on our data, the inverted ILM flap technique may be useful in vitrectomy for MH with RD. PMID- 27764183 TI - Morphological and Molecular Characterization of Human Dermal Lymphatic Collectors. AB - Millions of patients suffer from lymphedema worldwide. Supporting the contractility of lymphatic collectors is an attractive target for pharmacological therapy of lymphedema. However, lymphatics have mostly been studied in animals, while the cellular and molecular characteristics of human lymphatic collectors are largely unknown. We studied epifascial lymphatic collectors of the thigh, which were isolated for autologous transplantations. Our immunohistological studies identify additional markers for LECs (vimentin, CCBE1). We show and confirm differences between initial and collecting lymphatics concerning the markers ESAM1, D2-40 and LYVE-1. Our transmission electron microscopic studies reveal two types of smooth muscle cells (SMCs) in the media of the collectors with dark and light cytoplasm. We observed vasa vasorum in the media of the largest collectors, as well as interstitial Cajal-like cells, which are highly ramified cells with long processes, caveolae, and lacking a basal lamina. They are in close contact with SMCs, which possess multiple caveolae at the contact sites. Immunohistologically we identified such cells with antibodies against vimentin and PDGFRalpha, but not CD34 and cKIT. With Next Generation Sequencing we searched for highly expressed genes in the media of lymphatic collectors, and found therapeutic targets, suitable for acceleration of lymphatic contractility, such as neuropeptide Y receptors 1, and 5; tachykinin receptors 1, and 2; purinergic receptors P2RX1, and 6, P2RY12, 13, and 14; 5-hydroxytryptamine receptors HTR2B, and 3C; and adrenoceptors alpha2A,B,C. Our studies represent the first comprehensive characterization of human epifascial lymphatic collectors, as a prerequisite for diagnosis and therapy. PMID- 27764185 TI - Atrial Substrate Modification in Atrial Fibrillation: Targeting GP or CFAE? Evidence from Meta-Analysis of Clinical Trials. AB - Several clinically relevant outcomes post atrial substrate modification in patients with atrial fibrillation (AF) have not been systematically analyzed among published studies on adjunctive cardiac ganglionated plexi (GP) or complex fractionated atrial electograms (CFAE) ablation vs. pulmonary vein isolation (PVI) alone. Out of 176 reports identified, the present meta-analysis included 14 randomized and non-randomized controlled trials (1613 patients) meeting inclusion criteria. Addition of GP ablation to PVI significantly increased freedom from atrial tachyarrhythmia in short- (OR: 1.72; P = 0.003) and long-term (OR: 2.0, P = 0.0006) follow-up, while adjunctive CFAE ablation did not after one or repeat procedure (P<0.05). The percentage of atrial tachycardia or atrial flutter (AT/AFL) after one procedure was higher for CFAE than GP ablation. In sub analysis of non-paroxysmal AF, relative to PVI alone, adjunctive GP but not CFAE ablation significantly increased sinus rhythm maintenance (OR: 1.88, P = 0.01; and OR:1.24, P = 0.18, respectively). Meta regression analysis of the 14 studies indicated that sample size was significant source of heterogeneity either in outcomes after one or repeat procedure. In conclusion, in patients with AF, adjunctive GP but not CFAE ablation appeared to significantly add to the beneficial effects on sinus rhythm maintenance of PVI ablation alone; and CFAE ablation was associated with higher incidence of subsequent AT/AFL. PMID- 27764186 TI - Drivers of Tree Growth, Mortality and Harvest Preferences in Species-Rich Plantations for Smallholders and Communities in the Tropics. AB - There is growing interest in multi-species tropical plantations but little information exists to guide their design and silviculture. The Rainforestation Farming system is the oldest tropical polyculture planting system in the Philippines and provides a unique opportunity to understand the underlying processes affecting tree performance within diverse plantings. Data collected from 85 plots distributed across the 18 mixed-species plantations in the Philippines was used to identify the factors influencing growth, probability of harvest, and death of trees in these complex plantings. The 18 sites (aged from 6 to 11 years at time of first measurement) were measured on three occasions over a 6-year period. We used data from the first period of data collection to develop models predicting harvesting probability and growth of trees in the second period. We found little evidence that tree species diversity had an effect on tree growth and tree loss at the community level, although a negative effect was found on tree growth of specific species such as Parashorea plicata and Swietenia macrophylla. While tree density of stands at age 10+ years (more than 1000 trees/ha with diameter > 5cm) did not have an impact on growth, growth rates were decreasing in stands with a high basal area. Tree size in the first period of measure was a good predictor for both tree growth and tree status in the next period, with larger trees tending to grow faster and having a greater chance of being harvested, and a lower possibility of mortality than smaller trees. Shade intolerant trees were both more likely to be harvested, and had a higher probability of death, than shade-tolerant individuals. Native species and exotic species were equally likely to have been lost from the plots between measurement periods. However, shade-tolerant native trees were likely to grow faster than the others at age 10+ years. Our findings suggest that species traits (e.g. shade tolerance) could play an important role in optimizing species composition for this type of plantation. Shade-intolerant species with rapid early growth could contribute early income for farmers in mixed plantings where some products may take years to realize. We also suggest selective harvesting or thinning (for small shade-intolerant trees) applied at age 10+ years could reduce the competition for resources between individuals. PMID- 27764187 TI - Diagnosing the Dynamics of Observed and Simulated Ecosystem Gross Primary Productivity with Time Causal Information Theory Quantifiers. AB - Data analysis and model-data comparisons in the environmental sciences require diagnostic measures that quantify time series dynamics and structure, and are robust to noise in observational data. This paper investigates the temporal dynamics of environmental time series using measures quantifying their information content and complexity. The measures are used to classify natural processes on one hand, and to compare models with observations on the other. The present analysis focuses on the global carbon cycle as an area of research in which model-data integration and comparisons are key to improving our understanding of natural phenomena. We investigate the dynamics of observed and simulated time series of Gross Primary Productivity (GPP), a key variable in terrestrial ecosystems that quantifies ecosystem carbon uptake. However, the dynamics, patterns and magnitudes of GPP time series, both observed and simulated, vary substantially on different temporal and spatial scales. We demonstrate here that information content and complexity, or Information Theory Quantifiers (ITQ) for short, serve as robust and efficient data-analytical and model benchmarking tools for evaluating the temporal structure and dynamical properties of simulated or observed time series at various spatial scales. At continental scale, we compare GPP time series simulated with two models and an observations-based product. This analysis reveals qualitative differences between model evaluation based on ITQ compared to traditional model performance metrics, indicating that good model performance in terms of absolute or relative error does not imply that the dynamics of the observations is captured well. Furthermore, we show, using an ensemble of site-scale measurements obtained from the FLUXNET archive in the Mediterranean, that model-data or model-model mismatches as indicated by ITQ can be attributed to and interpreted as differences in the temporal structure of the respective ecological time series. At global scale, our understanding of C fluxes relies on the use of consistently applied land models. Here, we use ITQ to evaluate model structure: The measures are largely insensitive to climatic scenarios, land use and atmospheric gas concentrations used to drive them, but clearly separate the structure of 13 different land models taken from the CMIP5 archive and an observations-based product. In conclusion, diagnostic measures of this kind provide data-analytical tools that distinguish different types of natural processes based solely on their dynamics, and are thus highly suitable for environmental science applications such as model structural diagnostics. PMID- 27764188 TI - Running Opposes the Effects of Social Isolation on Synaptic Plasticity and Transmission in a Rat Model of Depression. AB - Stress, such as social isolation, is a well-known risk factor for depression, most probably in combination with predisposing genetic factors. Physical exercise on the other hand, is depicted as a wonder-treatment that makes you healthier, happier and live longer. However, the published results on the effects of exercise are ambiguous, especially when it comes to neuropsychiatric disorders. Here we combine a paradigm of social isolation with a genetic rat model of depression, the Flinders Sensitive Line (FSL), already known to have glutamatergic synaptic alterations. Compared to group-housed FSL rats, we found that social isolation further affects synaptic plasticity and increases basal synaptic transmission in hippocampal CA1 pyramidal neurons. These functional synaptic alterations co-exist with changes in hippocampal protein expression levels: social isolation in FSL rats reduce expression of the glial glutamate transporter GLT-1, and increase expression of the GluA2 AMPA-receptor subunit. We further show that physical exercise in form of voluntary running prevents the stress-induced synaptic effects but do not restore the endogenous mechanisms of depression already present in the FSL rat. PMID- 27764189 TI - Human Serum Albumin (HSA) Suppresses the Effects of Glycerol Monolaurate (GML) on Human T Cell Activation and Function. AB - Glycerol monolaurate (GML) is a monoglyceride with well characterized anti microbial properties. Because of these properties, GML is widely used in food, cosmetics, and personal care products and currently being tested as a therapeutic for menstrual associated toxic shock syndrome, superficial wound infections, and HIV transmission. Recently, we have described that GML potently suppresses select T cell receptor (TCR)-induced signaling events, leading to reduced human T cell effector functions. However, how soluble host factors present in the blood and at sites of infection affect GML-mediated human T cell suppression is unknown. In this study, we have characterized how human serum albumin (HSA) affects GML induced inhibition of human T cells. We found that HSA and other serum albumins bind to 12 carbon acyl side chain of GML at low micromolar affinities and restores the TCR-induced formation of LAT, PLC-gamma1, and AKT microclusters at the plasma membrane. Additionally, HSA reverses GML mediated inhibition of AKT phosphorylation and partially restores cytokine production in GML treated cells. Our data reveal that HSA, one of the most abundant proteins in the human serum and at sites of infections, potently reverses the suppression of human T cells by GML. This suggests that GML-driven human T cell suppression depends upon the local tissue environment, with albumin concentration being a major determinant of GML function. PMID- 27764191 TI - Validated LC-MS/MS Method for the Quantification of Ponatinib in Plasma: Application to Metabolic Stability. AB - In the current work, a rapid, specific, sensitive and validated liquid chromatography tandem mass-spectrometric method was developed for the quantification of ponatinib (PNT) in human plasma and rat liver microsomes (RLMs) with its application to metabolic stability. Chromatographic separation of PNT and vandetanib (IS) were accomplished on Agilent eclipse plus C18 analytical column (50 mm * 2.1 mm, 1.8 MUm particle size) maintained at 21+/-2 degrees C. Flow rate was 0.25 mLmin-1 with run time of 4 min. Mobile phase consisted of solvent A (10 mM ammonium formate, pH adjusted to 4.1 with formic acid) and solvent B (acetonitrile). Ions were generated by electrospray (ESI) and multiple reaction monitoring (MRM) was used as basis for quantification. The results revealed a linear calibration curve in the range of 5-400 ngmL-1 (r2 >= 0.9998) with lower limit of quantification (LOQ) and lower limit of detection (LOD) of 4.66 and 1.53 ngmL-1 in plasma, 4.19 and 1.38 ngmL-1 in RLMs. The intra- and inter-day precision and accuracy in plasma ranged from1.06 to 2.54% and -1.48 to 0.17, respectively. Whereas in RLMs ranged from 0.97 to 2.31% and -1.65 to -0.3%. The developed procedure was applied for quantification of PNT in human plasma and RLMs for study metabolic stability of PNT. PNT disappeared rapidly in the 1st 10 minutes of RLM incubation and the disappearance plateaued out for the rest of the incubation. In vitro half-life (t1/2) was 6.26 min and intrinsic clearance (CLin) was 15.182+/- 0.477. PMID- 27764190 TI - Substance P Promotes the Proliferation, but Inhibits Differentiation and Mineralization of Osteoblasts from Rats with Spinal Cord Injury via RANKL/OPG System. AB - Spinal cord injury (SCI) causes a significant amount of bone loss, which results in osteoporosis (OP). The neuropeptide substance P (SP) and SP receptors may play important roles in the pathogenesis of OP after SCI. To identify the roles of SP in the bone marrow mesenchymal stem cell derived osteoblasts (BMSC-OB) in SCI rats, we investigated the expression of neurokinin-1 receptors (NK1R) in BMSC-OB and the effects of SP on bone formation by development of BMSC-OB cultures. Sixty young male Sprague-Dawley rats were randomized into two groups: SHAM and SCI. The expression of NK1R protein in BMSC-OB was observed using immunohistochemistry and Western blot analysis. The dose- and time-dependent effects of SP on the proliferation, differentiation and mineralization of BMSC-OB and the expression of osteoblastic markers by in vitro experiments. The expression of NK1R in BMSC OB was observed on plasma membranes and in cytoplasm. One week after osteogenic differentiation, the expression of NK1R was significantly increased after SCI at mRNA and protein levels. However, this difference was gradually attenuated at 2 or 3 weeks later. SP have the function to enhance cell proliferation, inhibite cell differentiation and mineralization at a proper concentration and incubation time, and this effect would be inhibited by adding SP or NK1R antagonist. The expression of RANKL/OPG was significantly increased in tibiae after SCI. Similarly, the RANKL/OPG expression in SCI rats was significantly increased when treating with 10-8 M SP. SP plays a very important role in the pathogenesis of OP after SCI. The direct effect of SP may lead to increased bone resorption through the RANKL/OPG axis after SCI. In addition, high expression of SP also results in the suppression of osteogenesis in SCI rats. Then, the balance between bone resorption and bone formation was broken and finally osteoporosis occurred. PMID- 27764192 TI - Incidence of Exposure of Patients in the United States to Multiple Drugs for Which Pharmacogenomic Guidelines Are Available. AB - Pre-emptive pharmacogenomic (PGx) testing of a panel of genes may be easier to implement and more cost-effective than reactive pharmacogenomic testing if a sufficient number of medications are covered by a single test and future medication exposure can be anticipated. We analysed the incidence of exposure of individual patients in the United States to multiple drugs for which pharmacogenomic guidelines are available (PGx drugs) within a selected four-year period (2009-2012) in order to identify and quantify the incidence of pharmacotherapy in a nation-wide patient population that could be impacted by pre emptive PGx testing based on currently available clinical guidelines. In total, 73 024 095 patient records from private insurance, Medicare Supplemental and Medicaid were included. Patients enrolled in Medicare Supplemental age > = 65 or Medicaid age 40-64 had the highest incidence of PGx drug use, with approximately half of the patients receiving at least one PGx drug during the 4 year period and one fourth to one third of patients receiving two or more PGx drugs. These data suggest that exposure to multiple PGx drugs is common and that it may be beneficial to implement wide-scale pre-emptive genomic testing. Future work should therefore concentrate on investigating the cost-effectiveness of multiplexed pre-emptive testing strategies. PMID- 27764193 TI - Anterior Gradient 2 (AGR2) Induced Epidermal Growth Factor Receptor (EGFR) Signaling Is Essential for Murine Pancreatitis-Associated Tissue Regeneration. AB - A recently published study identified Anterior Gradient 2 (AGR2) as a regulator of EGFR signaling by promoting receptor presentation from the endoplasmic reticulum to the cell surface. AGR2 also promotes tissue regeneration in amphibians and fish. Whether AGR2-induced EGFR signaling is essential for tissue regeneration in higher vertebrates was evaluated using a well-characterized murine model for pancreatitis. The impact of AGR2 expression and EGFR signaling on tissue regeneration was evaluated using the caerulein-induced pancreatitis mouse model. EGFR signaling and cell proliferation were examined in the context of the AGR2-/- null mouse or with the EGFR-specific tyrosine kinase inhibitor, AG1478. In addition, the Hippo signaling coactivator YAP1 was evaluated in the context of AGR2 expression during pancreatitis. Pancreatitis-induced AGR2 expression enabled EGFR translocation to the plasma membrane, the initiation of cell signaling, and cell proliferation. EGFR signaling and tissue regeneration were partially inhibited by the tyrosine kinase inhibitor AG1478, but absent in the AGR2-/- null mouse. AG1478-treated and AGR2-/- null mice with pancreatitis died whereas all wild-type controls recovered. YAP1 activation was also dependent on pancreatitis-induced AGR2 expression. AGR2-induced EGFR signaling was essential for tissue regeneration and recovery from pancreatitis. The results establish tissue regeneration as a major function of AGR2-induced EGFR signaling in adult higher vertebrates. Enhanced AGR2 expression and EGFR signaling are also universally present in human pancreatic cancer, which support a linkage between tissue injury, regeneration, and cancer pathogenesis. PMID- 27764194 TI - Vitamin D Deficiency Increases the Risk of Adverse Neonatal Outcomes in Gestational Diabetes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) and vitamin D deficiency have been associated with increased risk of adverse perinatal outcomes but the consequences of both conditions simultaneously present in pregnancy have not yet been evaluated. Our objective was to study the influence of vitamin D deficiency in neonatal outcomes of pregnancies with GDM. METHODS: 184 pregnant women with GDM referred to specialized prenatal monitoring were included in this cohort and had blood sampled for 25-hydroxyvitamin D measurement. Vitamin D was measured by chemiluminescence and deficiency was defined as < 20 ng/mL. Participants were followed until puerperium and adverse neonatal outcomes were evaluated. RESULTS: Newborns of women with vitamin D deficiency had higher incidences of hospitalization in intensive care units (ICU) (32 vs 19%, P = 0.048), of hypoglycemia (any, 17.3 vs 7.1%, P = 0.039requiring ICU, 15.3 vs 3.6%, P = 0.008), and were more frequently small for gestational age (SGA) (17.3 vs 5.9%, P = 0.017). After adjustment, relative risk (RR) for hypoglycemia requiring ICU was 3.63 (95%CI 1.09-12.11) and for SGA was 4.32 (95%CI 1.75-10.66). The incidence of prematurity, jaundice and shoulder dystocia was no statistically different between groups. CONCLUSIONS: In this cohort of pregnant women with GDM, vitamin D deficiency was associated with a major increase in the incidence of adverse neonatal outcomes such as SGA newborns and neonatal hypoglycemia. PMID- 27764196 TI - Patent Network Analysis and Quadratic Assignment Procedures to Identify the Convergence of Robot Technologies. AB - Because of the remarkable developments in robotics in recent years, technological convergence has been active in this area. We focused on finding patterns of convergence within robot technology using network analysis of patents in both the USPTO and KIPO. To identify the variables that affect convergence, we used quadratic assignment procedures (QAP). From our analysis, we observed the patent network ecology related to convergence and found technologies that have great potential to converge with other robotics technologies. The results of our study are expected to contribute to setting up convergence based R&D policies for robotics, which can lead new innovation. PMID- 27764195 TI - Discriminative Prediction of A-To-I RNA Editing Events from DNA Sequence. AB - RNA editing is a post-transcriptional alteration of RNA sequences that, via insertions, deletions or base substitutions, can affect protein structure as well as RNA and protein expression. Recently, it has been suggested that RNA editing may be more frequent than previously thought. A great impediment, however, to a deeper understanding of this process is the paramount sequencing effort that needs to be undertaken to identify RNA editing events. Here, we describe an in silico approach, based on machine learning, that ameliorates this problem. Using 41 nucleotide long DNA sequences, we show that novel A-to-I RNA editing events can be predicted from known A-to-I RNA editing events intra- and interspecies. The validity of the proposed method was verified in an independent experimental dataset. Using our approach, 203 202 putative A-to-I RNA editing events were predicted in the whole human genome. Out of these, 9% were previously reported. The remaining sites require further validation, e.g., by targeted deep sequencing. In conclusion, the approach described here is a useful tool to identify potential A-to-I RNA editing events without the requirement of extensive RNA sequencing. PMID- 27764199 TI - Power-Law Modeling of Cancer Cell Fates Driven by Signaling Data to Reveal Drug Effects. AB - Extracellular signals are captured and transmitted by signaling proteins inside a cell. An important type of cellular responses to the signals is the cell fate decision, e.g., apoptosis. However, the underlying mechanisms of cell fate regulation are still unclear, thus comprehensive and detailed kinetic models are not yet available. Alternatively, data-driven models are promising to bridge signaling data with the phenotypic measurements of cell fates. The traditional linear model for data-driven modeling of signaling pathways has its limitations because it assumes that the a cell fate is proportional to the activities of signaling proteins, which is unlikely in the complex biological systems. Therefore, we propose a power-law model to relate the activities of all the measured signaling proteins to the probabilities of cell fates. In our experiments, we compared our nonlinear power-law model with the linear model on three cancer datasets with phosphoproteomics and cell fate measurements, which demonstrated that the nonlinear model has superior performance on cell fates prediction. By in silico simulation of virtual protein knock-down, the proposed model is able to reveal drug effects which can complement traditional approaches such as binding affinity analysis. Moreover, our model is able to capture cell line specific information to distinguish one cell line from another in cell fate prediction. Our results show that the power-law data-driven model is able to perform better in cell fate prediction and provide more insights into the signaling pathways for cancer cell fates than the linear model. PMID- 27764197 TI - RAP2.4a Is Transported through the Phloem to Regulate Cold and Heat Tolerance in Papaya Tree (Carica papaya cv. Maradol): Implications for Protection Against Abiotic Stress. AB - Plants respond to stress through metabolic and morphological changes that increase their ability to survive and grow. To this end, several transcription factor families are responsible for transmitting the signals that are required for these changes. Here, we studied the transcription factor superfamily AP2/ERF, particularly, RAP2.4 from Carica papaya cv. Maradol. We isolated four genes (CpRap2.4a, CpRAap2.4b, CpRap2.1 and CpRap2.10), and an in silico analysis showed that the four genes encode proteins that contain a conserved APETALA2 (AP2) domain located within group I and II transcription factors of the AP2/ERF superfamily. Semiquantitative PCR experiments indicated that each CpRap2 gene is differentially expressed under stress conditions, such as extreme temperatures. Moreover, genetic transformants of tobacco plants overexpressing CpRap2.4a and CpRap2.4b genes show a high level of tolerance to cold and heat stress compared to non-transformed plants. Confocal microscopy analysis of tobacco transgenic plants showed that CpRAP2.4a and CpRAP2.4b proteins were mainly localized to the nuclei of cells from the leaves and roots and also in the sieve elements. Moreover, the movement of CpRap2.4a RNA in tobacco grafting was analyzed. Our results indicate that CpRap2.4a and CpRap2.4b RNA in the papaya tree have a functional role in the response to stress conditions such as exposure to extreme temperatures via direct translation outside the parental RNA cell. PMID- 27764200 TI - Remote Cameras Reveal Experimental Artifact in a Study of Seed Predation in a Semi-Arid Shrubland. AB - Granivorous animals may prefer to predate or cache seed of certain plant species over others. Multiple studies have documented preference for larger, non-native seed by granivores. To accomplish this, researchers have traditionally used indirect inference by relating patterns of seed removal to the species composition of the granivorous animal community. To measure seed removal, researchers present seed to granivorous animals in the field using equipment intended to exclude certain animal taxa while permitting access to others. This approach allows researchers to differentiate patterns of seed removal among various taxa (e.g., birds, small mammals, and insects); however, it is unclear whether the animals of interest are freely using the exclusion devices, which may be a hindrance to discovering the seed dishes. We used video observation to perform a study of seed predation using a custom-built, infrared digital camera and recording system. We presented native and non-native seed mixtures in partitioned Petri dishes both within and outside of exclusion cages. The exclusion cages were intended to allow entrance by rodent taxa while preventing entrance by rabbits and birds. We documented all seed removal visits by granivorous animals, which we identified to the genus level. Genera exhibited varying seed removal patterns based on seed type (native vs. non-native) and dish type (open vs. enclosed). We documented avoidance of the enclosed dishes by all but one rodent taxa, even though these dishes were intended to be used freely by rodents. This suggests that preference for non-native seed occurs differentially among granivorous animals in this system; however, interpretation of these nuanced results would be difficult without the benefit of video observation. When feasible, video observation should accompany studies using in situ equipment to ensure incorrect assumptions do not lead to inappropriate interpretation of results. PMID- 27764198 TI - Comparative Analysis of Membrane Vesicles from Three Piscirickettsia salmonis Isolates Reveals Differences in Vesicle Characteristics. AB - Membrane vesicles (MVs) are spherical particles naturally released from the membrane of Gram-negative bacteria. Bacterial MV production is associated with a range of phenotypes including biofilm formation, horizontal gene transfer, toxin delivery, modulation of host immune responses and virulence. This study reports comparative profiling of MVs from bacterial strains isolated from three widely disperse geographical areas. Mass spectrometry identified 119, 159 and 142 proteins in MVs from three different strains of Piscirickettsia salmonis isolated from salmonids in Chile (LF-89), Norway (NVI 5692) and Canada (NVI 5892), respectively. MV comparison revealed several strain-specific differences related to higher virulence capability for LF-89 MVs, both in vivo and in vitro, and stronger similarities between the NVI 5692 and NVI 5892 MV proteome. The MVs were similar in size and appearance as analyzed by electron microscopy and dynamic light scattering. The MVs from all three strains were internalized by both commercial and primary immune cell cultures, which suggest a potential role of the MVs in the bacterium's utilization of leukocytes. When MVs were injected into an adult zebrafish infection model, an upregulation of several pro-inflammatory genes were observed in spleen and kidney, indicating a modulating effect on the immune system. The present study is the first comparative analysis of P. salmonis derived MVs, highlighting strain-specific vesicle characteristics. The results further illustrate that the MV proteome from one bacterial strain is not representative of all bacterial strains within one species. PMID- 27764201 TI - Improving the Thermostability of Acidic Pullulanase from Bacillus naganoensis by Rational Design. AB - Pullulanase (EC 3.2.1.41) plays an important role in the specific hydrolysis of branch points in amylopectin. Enhancing its thermostability is required for its industrial application. In this study, rational protein design was used to improve the thermostability of PulB from Bacillus naganoensis (AB231790.1), which has strong enzymatic properties. Three positive single-site mutants (PulB-D328H, PulB-N387D, and PulB-A414P) were selected from six mutants. After incubation at 65 degrees C for 5 min, the residual activities of PulB-D328H, PulB-N387D, and PulB-A414P were 4.5-, 1.7-, and 1.47-fold higher than PulB-WT, and their Tm values (the temperature at which half protein molecule denature) were 1.8 degrees C, 0.4 degrees C, and 0.9 degrees C higher than PulB-WT, respectively. Then the final combined mutant PulB-328/387/414 was constructed. The t1/2 of it was 12.9 fold longer than that of PulB-WT at 65 degrees C and the total increase in Tm of it (5.0 degrees C) was almost 60% greater than the sum of individual increases (3.1 degrees C). In addition, kinetic studies revealed that the kcat and the kcat/Km of PulB-328/387/414 increased by 38.8% and 12.9%. The remarkable improvement in thermostability and the high catalytic efficiency of PulB 328/387/414 make it suitable for industrial applications. PMID- 27764202 TI - Spatially Explicit Modelling of the Belgian Major Endurance Event 'The 100 km Dodentocht'. AB - 'The 100 km Dodentocht', which takes place annually and has its start in Bornem, Belgium, is a long distance march where participants have to cover a 100 km trail in at most 24 hours. The approximately 11 000 marchers per edition are tracked by making use of passive radio-frequency-identification (RFID). These tracking data were analyzed to build a spatially explicit marching model that gives insights into the dynamics of the event and allows to evaluate the effect of changes in the starting procedure of the event. For building the model, the empirical distribution functions (edf) of the marching speeds at every section of the trail in between two consecutive checkpoints and of the checkpoints where marchers retire, are determined, taking into account age, gender, and marching speeds at previous sections. These distribution functions are then used to sample the consecutive speeds and retirement, and as such to simulate the times when individual marchers pass by the consecutive checkpoints. We concluded that the data-driven model simulates the event reliably. Furthermore, we tested three scenarios to reduce the crowdiness along the first part of the trail and in this way were able to conclude that either the start should be moved to a location outside the town center where the streets are at least 25% wider, or that the marchers should start in two groups at two different locations, and that these groups should ideally merge at about 20 km after the start. The crowdiness at the start might also be reduced by installing a bottleneck at the start in order to limit the number of marchers that can pass per unit of time. Consequently, the operating hours of the consecutive checkpoints would be longer. The developed framework can likewise be used to analyze and improve the operation of other endurance events if sufficient tracking data are available. PMID- 27764203 TI - The Impact of Rainfall on Soil Moisture Dynamics in a Foggy Desert. AB - Soil moisture is a key variable in dryland ecosystems since it determines the occurrence and duration of vegetation water stress and affects the development of weather patterns including rainfall. However, the lack of ground observations of soil moisture and rainfall dynamics in many drylands has long been a major obstacle in understanding ecohydrological processes in these ecosystems. It is also uncertain to what extent rainfall controls soil moisture dynamics in fog dominated dryland systems. To this end, in this study, twelve to nineteen months' continuous daily records of rainfall and soil moisture (from January 2014 to August 2015) obtained from three sites (one sand dune site and two gravel plain sites) in the Namib Desert are reported. A process-based model simulating the stochastic soil moisture dynamics in water-limited systems was used to study the relationships between soil moisture and rainfall dynamics. Model sensitivity in response to different soil and vegetation parameters under diverse soil textures was also investigated. Our field observations showed that surface soil moisture dynamics generally follow rainfall patterns at the two gravel plain sites, whereas soil moisture dynamics in the sand dune site did not show a significant relationship with rainfall pattern. The modeling results suggested that most of the soil moisture dynamics can be simulated except the daily fluctuations, which may require a modification of the model structure to include non-rainfall components. Sensitivity analyses suggested that soil hygroscopic point (sh) and field capacity (sfc) were two main parameters controlling soil moisture output, though permanent wilting point (sw) was also very sensitive under the parameter setting of sand dune (Gobabeb) and gravel plain (Kleinberg). Overall, the modeling results were not sensitive to the parameters in non-bounded group (e.g., soil hydraulic conductivity (Ks) and soil porosity (n)). Field observations, stochastic modeling results as well as sensitivity analyses provide soil moisture baseline information for future monitoring and the prediction of soil moisture patterns in the Namib Desert. PMID- 27764204 TI - Correction: Improving the Secretory Expression of an alpha-Galactosidase from Aspergillus niger in Pichia pastoris. AB - [This corrects the article DOI: 10.1371/journal.pone.0161529.]. PMID- 27764205 TI - ADAMTS-1 Is Found in the Nuclei of Normal and Tumoral Breast Cells. AB - Proteins secreted in the extracellular matrix microenvironment (ECM) by tumor cells are involved in cell adhesion, motility, intercellular communication and invasion. The tumor microenvironment is expansively modified and remodeled by proteases, resulting in important changes in both cell-cell and cell-ECM interactions and in the generation of new signals from the cell surface. Metalloproteinases belonging to the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family have been implicated in tissue remodeling events observed in cancer development, growth and progression. Here we investigated the subcellular localization of ADAMTS-1 in normal-like (MCF10-A) and tumoral (MCF7 and MDA-MB-231) human breast cells. ADAMTS-1 is a secreted protease found in the extracellular matrix. However, in this study we show for the first time that ADAMTS-1 is also present in the nuclei and nucleoli of the three mammary cell lines studied here. Our findings indicate that ADAMTS-1 has proteolytic functions in the nucleus through its interaction with aggrecan substrate. PMID- 27764206 TI - Molecular Characterization of a Novel Bovine Viral Diarrhea Virus Isolate SD-15. AB - As one of the major pathogens, bovine viral diarrhea virus caused a significant economic loss to the livestock industry worldwide. Although BVDV infections have increasingly been reported in China in recent years, the molecular aspects of those BVDV strains were barely characterized. In this study, we reported the identification and characterization of a novel BVDV isolate designated as SD-15 from cattle, which is associated with an outbreak characterized by severe hemorrhagic and mucous diarrhea with high morbidity and mortality in Shandong, China. SD-15 was revealed to be a noncytopathic BVDV, and has a complete genomic sequence of 12,285 nucleotides that contains a large open reading frame encoding 3900 amino acids. Alignment analysis showed that SD-15 has 93.8% nucleotide sequence identity with BVDV ZM-95 isolate, a previous BVDV strain isolated from pigs manifesting clinical signs and lesions resembling to classical swine fever. Phylogenetic analysis clustered SD-15 to a BVDV-1m subgenotype. Analysis of the deduced amino acid sequence of glycoproteins revealed that E2 has several highly conserved and variable regions within BVDV-1 genotypes. An additional N glycosylation site (240NTT) was revealed exclusively in SD-15-encoded E2 in addition to four potential glycosylation sites (Asn-X-Ser/Thr) shared by all BVDV 1 genotypes. Furthermore, unique amino acid and linear epitope mutations were revealed in SD-15-encoded Erns glycoprotein compared with known BVDV-1 genotype. In conclusion, we have isolated a noncytopathic BVDV-1m strain that is associated with a disease characterized by high morbidity and mortality, revealed the complete genome sequence of the first BVDV-1m virus originated from cattle, and found a unique glycosylation site in E2 and a linear epitope mutation in Erns encoded by SD-15 strain. Those results will broaden the current understanding of BVDV infection and lay a basis for future investigation on SD-15-related pathogenesis. PMID- 27764207 TI - Step-Wise Increase in Tigecycline Resistance in Klebsiella pneumoniae Associated with Mutations in ramR, lon and rpsJ. AB - Klebsiella pneumoniae is a gram-negative bacterium that causes numerous diseases, including pneumonia and urinary tract infections. An increase in multidrug resistance has complicated the treatment of these bacterial infections, and although tigecycline shows activity against a broad spectrum of bacteria, resistant strains have emerged. In this study, the whole genomes of two clinical and six laboratory-evolved strains were sequenced to identify putative mutations related to tigecycline resistance. Of seven tigecycline-resistant strains, seven (100%) had ramR mutations, five (71.4%) had lon mutations, one (14.2%) had a ramA mutation, and one (14.2%) had an rpsJ mutation. A higher fitness cost was observed in the laboratory-evolved strains but not in the clinical strains. A transcriptome analysis demonstrated high expression of the ramR operon and acrA in all tigecycline-resistant strains. Genes involved in nitrogen metabolism were induced in the laboratory-evolved strains compared with the wild-type and clinical strains, and this difference in nitrogen metabolism reflected the variation between the laboratory-evolved and the clinical strains. Complementation experiments showed that both the wild-type ramR and the lon genes could partially restore the tigecycline sensitivity of K. pneumoniae. We believe that this manuscript describes the first construct of a lon mutant in K. pneumoniae, which allowed confirmation of its association with tigecycline resistance. Our findings illustrate the importance of the ramR operon and the lon and rpsJ genes in K. pneumoniae resistance to tigecycline. PMID- 27764208 TI - Is Endotoxemia in Stable Hemodialysis Patients an Artefact? Limitations of the Limulus Amebocyte Lysate Assay and Role of (1->3)-beta-D Glucan. AB - BACKGROUND: Elevated blood endotoxin levels are frequently reported in the dialysis population and are strongly linked with inflammation, a major predictor of mortality. Virtually all studies have employed the Limulus Amoebocyte Lysate (LAL) assay to detect endotoxin. However this assay is not endotoxin-specific and can be activated by (1->3)-beta-glucan (BG), a component of fungal cell walls leading to false positive signals. Very few studies have taken account of this. We examined the influence of BG-based activation of the LAL assay on the detection of endotoxemia in this setting. METHOD: We measured plasma endotoxin levels in 50 hemodialysis patients with and without the use of BG-blocking buffers. These buffers inhibit BG activation of the LAL assay to ensure that any signal detected is endotoxin-specific. Blood samples were measured for BG, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-alpha) to examine the association between endotoxin signals, BG and inflammation. RESULTS: Endotoxin signals were detected in 50% of patients. On repeat measurement with a BG blocking buffer, all detected endotoxin signals were extinguished. No patient had detectable endotoxemia. Plasma BG levels were significantly elevated in 58% of patients and were higher in those with detectable endotoxin signals using the LAL assay without BG-blocking buffers (78vs.54pg/mL;p<0.001). Endotoxin signal and BG levels did not correlate with levels of TNF-alpha or IL-6. CONCLUSION: Use of the LAL assay for blood endotoxin detection in dialysis patients has its limitations due to high blood BG. Endotoxemia frequently reported in non-infected hemodialysis patients may be artefactual due to BG interference. PMID- 27764209 TI - Impacts of Cropping Systems on Aggregates Associated Organic Carbon and Nitrogen in a Semiarid Highland Agroecosystem. AB - The effect of cropping system on the distribution of organic carbon (OC) and nitrogen (N) in soil aggregates has not been well addressed, which is important for understanding the sequestration of OC and N in agricultural soils. We analyzed the distribution of OC and N associated with soil aggregates in three unfertilized cropping systems in a 27-year field experiment: continuously cropped alfalfa, continuously cropped wheat and a legume-grain rotation. The objectives were to understand the effect of cropping system on the distribution of OC and N in aggregates and to examine the relationships between the changes in OC and N stocks in total soils and in aggregates. The cropping systems increased the stocks of OC and N in total soils (0-40 cm) at mean rates of 15.6 g OC m-2 yr-1 and 1.2 g N m-2 yr-1 relative to a fallow control. The continuous cropping of alfalfa produced the largest increases at the 0-20 cm depth. The OC and N stocks in total soils were significantly correlated with the changes in the >0.053 mm aggregates. 27-year of cropping increased OC stocks in the >0.053 mm size class of aggregates and N stocks in the >0.25 mm size class but decreased OC stocks in the <0.053 mm size class and N stocks in the <0.25 mm size class. The increases in OC and N stocks in these aggregates accounted for 99.5 and 98.7% of the total increases, respectively, in the continuous alfalfa system. The increases in the OC and N stocks associated with the >0.25 mm aggregate size class accounted for more than 97% of the total increases in the continuous wheat and the legume-grain rotation systems. These results suggested that long-term cropping has the potential to sequester OC and N in soils and that the increases in soil OC and N stocks were mainly due to increases associated with aggregates >0.053 mm. PMID- 27764210 TI - Shoulder Arthroplasty Trials Are Infrequently Registered: A Systematic Review of Trials. AB - INTRODUCTION: With the intent of improving transparency in clinical research, the International Committee of Medical Journal Editors (ICMJE) established guidelines in 2005 regarding prospective clinical trial registration. This action worked to address bias related to selective outcome reporting in the medical literature. The objective of this study was to assess and characterize the quality of registration of clinical trials appearing in shoulder arthroplasty-related medical journals. METHODS: All randomized trials involving human subjects, pertaining to shoulder arthroplasty, published between July 1, 2005 and December 31, 2015, and indexed in either PubMed or SportDISCUS were analyzed. We assessed the prevalence of registration, the timing of registration relative to patient enrollment periods, and the variable rates of orthopedic journal compliance with ICMJE and Food and Drug Administration clinical registration standards for our study. RESULTS: Of the 382 articles identified, 345 (90.3%) were excluded due to failure to meet inclusion criteria. From the remaining 37, only 12 (32.4%) studies were found to be registered in a trial registry. Ten (10/12, 83.3%) of these provided their registration information within the body of the article. None of the included studies from ICMJE-recognized journals were registered. From 34 included studies from non-ICMJE recognized journals, 12 (35.3%) were registered. CONCLUSION: The level of compliance with clinical trial registration guidelines in the decade since their release among shoulder arthroplasty trials in orthopedic journals is poor. Given the importance of the issue, the prevalence of the problem, and the fact that many other medical specialties have already made efforts to improve ICMJE compliance, further work on the part of orthopedic surgery journal authors and editors is needed to ensure the publication of unbiased results. TRIAL REGISTRATION: UMIN000022487. PMID- 27764211 TI - Metagenomic-Based Screening and Molecular Characterization of Cowpea-Infecting Viruses in Burkina Faso. AB - Cowpea, (Vigna unguiculata L. (Walp)) is an annual tropical grain legume. Often referred to as "poor man's meat", cowpea is one of the most important subsistence legumes cultivated in West Africa due to the high protein content of its seeds. However, African cowpea production can be seriously constrained by viral diseases that reduce yields. While twelve cowpea-infecting viruses have been reported from Africa, only three of these have so-far been reported from Burkina Faso. Here we use a virion-associated nucleic acids (VANA)-based metagenomics method to screen for the presence of cowpea viruses from plants collected from the three agro climatic zones of Burkina Faso. Besides the three cowpea-infecting virus species which have previously been reported from Burkina Faso (Cowpea aphid borne mosaic virus [Family Potyviridae], the Blackeye cowpea mosaic virus-a strain of Bean common mosaic virus-[Family Potyviridae] and Cowpea mottle virus [Family Tombusviridae]) five additional viruses were identified: Southern cowpea mosaic virus (Sobemovirus genus), two previously uncharacterised polerovirus-like species (Family Luteoviridae), a previously uncharacterised tombusvirus-like species (Family Tombusviridae) and a previously uncharacterised mycotymovirus like species (Family Tymoviridae). Overall, potyviruses were the most prevalent cowpea viruses (detected in 65.5% of samples) and the Southern Sudan zone of Burkina Faso was found to harbour the greatest degrees of viral diversity and viral prevalence. Partial genome sequences of the two novel polerovirus-like and tombusvirus-like species were determined and RT-PCR primers were designed for use in Burkina Faso to routinely detect all of these cowpea-associated viruses. PMID- 27764212 TI - Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes. AB - Cystatin superfamily is a large group of evolutionarily related proteins involved in numerous physiological activities through their inhibitory activity towards cysteine proteases. Despite sharing the same cystatin fold, and inhibiting cysteine proteases through the same tripartite edge involving highly conserved N terminal region, L1 and L2 loop; cystatins differ widely in their inhibitory affinity towards C1 family of cysteine proteases and molecular details of these interactions are still elusive. In this study, inhibitory interactions of human family 1 & 2 cystatins with cathepsin L1 are predicted and their stability and viability are verified through protein docking & comparative molecular dynamics. An overall stabilization effect is observed in all cystatins on complex formation. Complexes are mostly dominated by van der Waals interaction but the relative participation of the conserved regions varied extensively. While van der Waals contacts prevail in L1 and L2 loop, N-terminal segment chiefly acts as electrostatic interaction site. In fact the comparative dynamics study points towards the instrumental role of L1 loop in directing the total interaction profile of the complex either towards electrostatic or van der Waals contacts. The key amino acid residues surfaced via interaction energy, hydrogen bonding and solvent accessible surface area analysis for each cystatin-cathepsin L1 complex influence the mode of binding and thus control the diverse inhibitory affinity of cystatins towards cysteine proteases. PMID- 27764213 TI - A New Feedback-Based Method for Parameter Adaptation in Image Processing Routines. AB - The parametrization of automatic image processing routines is time-consuming if a lot of image processing parameters are involved. An expert can tune parameters sequentially to get desired results. This may not be productive for applications with difficult image analysis tasks, e.g. when high noise and shading levels in an image are present or images vary in their characteristics due to different acquisition conditions. Parameters are required to be tuned simultaneously. We propose a framework to improve standard image segmentation methods by using feedback-based automatic parameter adaptation. Moreover, we compare algorithms by implementing them in a feedforward fashion and then adapting their parameters. This comparison is proposed to be evaluated by a benchmark data set that contains challenging image distortions in an increasing fashion. This promptly enables us to compare different standard image segmentation algorithms in a feedback vs. feedforward implementation by evaluating their segmentation quality and robustness. We also propose an efficient way of performing automatic image analysis when only abstract ground truth is present. Such a framework evaluates robustness of different image processing pipelines using a graded data set. This is useful for both end-users and experts. PMID- 27764216 TI - Consequences of Hatch Phenology on Stages of Fish Recruitment. AB - Little is known about how hatch phenology (e.g., the start, peak, and duration of hatching) could influence subsequent recruitment of freshwater fishes into a population. We used two commonly sympatric fish species that exhibit different hatching phenologies to examine recruitment across multiple life stages. Nine yellow perch (Perca flavescens) and bluegill (Lepomis macrochirus) annual cohorts were sampled from 2004 through 2013 across larval, age-0, age-1, and age-2 life stages in a Nebraska (U.S.A.) Sandhill lake. Yellow perch hatched earlier in the season and displayed a more truncated hatch duration compared to bluegill. The timing of hatch influenced recruitment dynamics for both species but important hatching metrics were not similar between species across life stages. A longer hatch duration resulted in greater larval yellow perch abundance but greater age 1 bluegill abundance. In contrast, bluegill larval and age-0 abundances were greater during years when hatching duration was shorter and commenced earlier, whereas age-0 yellow perch abundance was greater when hatching occurred earlier. As a result of hatch phenology, yellow perch recruitment variability was minimized sooner (age-0 life stage) than bluegill (age-1 life stage). Collectively, hatch phenology influenced recruitment dynamics across multiple life stages but was unique for each species. Understanding the complexities of when progeny enter an environment and how this influences eventual recruitment into a population will be critical in the face of ongoing climate change. PMID- 27764215 TI - Experimental Evidence of Classical Conditioning and Microscopic Engrams in an Electroconductive Material. AB - Synthetic experimental substrates are indispensable tools which can allow researchers to model biological processes non-invasively in three-dimensional space. In this study, we investigated the capacities of an electroconductive material whose properties converge upon those of the brain. An electrically conductive material composed of carbohydrates, proteins, fats, ions, water, and trace amounts of other organic compounds and minerals was classically conditioned as inferred by electrophysiological measurements. Spectral densities evoked during the display of a conditioned stimulus (CS) probe were strongly congruent with those displayed during the conditioned-unconditioned stimulus pairing (CS UCS). The neutral stimulus consisted of the pulsed light from a LED. The unconditioned stimulus was an alternating current. Interstimulus intervals >130 ms did not result in conditioned responses. Microscopic analysis of the chemically-fixed substratum revealed 10-200 MUm wide 'vessel structures' within samples exposed to a stimulus. Greater complexity (increased fractal dimensions) was clearly discernable by light microscopy for stained sections of fixed samples that had been conditioned compared to various controls. The denser pixels indicated greater concentration of stain and increased canalization. Implications for learning and memory formation are discussed. PMID- 27764214 TI - Evidence that Illness-Compatible Cues Are Rewarding in Women Recovered from Anorexia Nervosa: A Study of the Effects of Dopamine Depletion on Eye-Blink Startle Responses. AB - In anorexia nervosa (AN), motivational salience is attributed to illness compatible cues (e.g., underweight and active female bodies) and this is hypothesised to involve dopaminergic reward circuitry. We investigated the effects of reducing dopamine (DA) transmission on the motivational processing of AN-compatible cues in women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15). This involved the acute phenylalanine and tyrosine depletion (APTD) procedure and a startle eye-blink modulation (SEM) task. In a balanced amino acid state, AN REC showed an increased appetitive response (decreased startle potentiation) to illness-compatible cues (underweight and active female body pictures (relative to neutral and non-active cues, respectively)). The HC had an aversive response (increased startle potentiation) to the same illness-compatible stimuli (relative to neutral cues). Importantly, these effects, which may be taken to resemble symptoms observed in the acute stage of illness and healthy behaviour respectively, were not present when DA was depleted. Thus, AN REC implicitly appraised underweight and exercise cues as more rewarding than did HC and the process may, in part, be DA-dependent. It is proposed that the positive motivational salience attributed to cues of emaciation and physical activity is, in part, mediated by dopaminergic reward processes and this contributes to illness pathology. These observations are consistent with the proposal that, in AN, aberrant reward-based learning contributes to the development of habituation of AN-compatible behaviours. PMID- 27764217 TI - Cardiosphere-Derived Cells Facilitate Heart Repair by Modulating M1/M2 Macrophage Polarization and Neutrophil Recruitment. AB - Cardiosphere-derived cells (CDCs), one of the promising stem cell sources for myocardial repair, have been tested in clinical trials and resulted in beneficial effects; however, the relevant mechanisms are not fully understood. In this study, we examined the hypothesis that CDCs favor heart repair by switching the macrophages from a pro-inflammatory phenotype (M1) into a regulatory anti inflammatory phenotype (M2). Macrophages from mice were cultured with CDCs conditioned medium or with fibroblasts-conditioned medium as a control. Immunostaining showed that CDCs-conditioned medium significantly enhanced the expression of CD206 (a marker for M2 macrophages), but decreased the expression of CD86 (a marker for M1 macrophages) 3 days after culture. For animal studies, we used an acute myocardial infarction model of mice. We injected CDCs, fibroblasts, or saline only into the border zone of infarction. Then we collected the heart tissues for histological analysis 5 and 14 days after treatment. Compared with control animals, CDCs treatment significantly decreased M1 macrophages and neutrophils but increased M2 macrophages in the infarcted heart. Furthermore, CDCs-treated mice had reduced infarct size and fewer apoptotic cells compared to the controls. Our data suggest that CDCs facilitate heart repair by modulating M1/M2 macrophage polarization and neutrophil recruitment, which may provide a new insight into the mechanisms of stem cell-based myocardial repair. PMID- 27764218 TI - Model Based Analysis of Clonal Developments Allows for Early Detection of Monoclonal Conversion and Leukemia. AB - The availability of several methods to unambiguously mark individual cells has strongly fostered the understanding of clonal developments in hematopoiesis and other stem cell driven regenerative tissues. While cellular barcoding is the method of choice for experimental studies, patients that underwent gene therapy carry a unique insertional mark within the transplanted cells originating from the integration of the retroviral vector. Close monitoring of such patients allows accessing their clonal dynamics, however, the early detection of events that predict monoclonal conversion and potentially the onset of leukemia are beneficial for treatment. We developed a simple mathematical model of a self stabilizing hematopoietic stem cell population to generate a wide range of possible clonal developments, reproducing typical, experimentally and clinically observed scenarios. We use the resulting model scenarios to suggest and test a set of statistical measures that should allow for an interpretation and classification of relevant clonal dynamics. Apart from the assessment of several established diversity indices we suggest a measure that quantifies the extension to which the increase in the size of one clone is attributed to the total loss in the size of all other clones. By evaluating the change in relative clone sizes between consecutive measurements, the suggested measure, referred to as maximum relative clonal expansion (mRCE), proves to be highly sensitive in the detection of rapidly expanding cell clones prior to their dominant manifestation. This predictive potential places the mRCE as a suitable means for the early recognition of leukemogenesis especially in gene therapy patients that are closely monitored. Our model based approach illustrates how simulation studies can actively support the design and evaluation of preclinical strategies for the analysis and risk evaluation of clonal developments. PMID- 27764219 TI - Study on the Cytotoxic, Genotoxic and Clastogenic Potential of Attalea phalerata Mart. ex Spreng. Oil Pulp In Vitro and In Vivo Experimental Models. AB - Attalea phalerata Mart. ex Spreng. (Arecaceae), popularly known as "bacuri", is used in Brazilian folk medicine. Its oil is used orally to relieve pulmonary congestion and joint pain. In topical applications, it is applied as an effective hair tonic and anti-dandruff. The in natura pulp and its nuts are used as food because of its nutritional value. Despite its use in folk medicine, there is a lack of data regarding its in vivo/in vitro cytotoxic/genotoxic and clastogenic effects. Therefore, in this study, we evaluated the cytotoxic, genotoxic and clastogenic effects of Attalea phalerata Mart. ex Spreng. oil (APMO) in vitro and in vivo. For the analysis of cytotoxic potential, the Artemia salina and MTT (3 (4,5-dimethizzol-zyl)-2,5-diphenyltetrazolium bromide) assays were performed. Possible cytotoxic, genotoxic and clastogenic effects of APMO intake were determined by performing the comet and micronucleus assays. Male and female Wistar rats were orally treated with doses of 125, 250, 500 or 1000 mg.kg-1 of the APMO daily for 28 consecutive days (four weeks). The results showed that the APMO did not induce cell death in the experiments of Artemia salina and MTT, indicating that it has no cytotoxicity. The APMO did not cause significant damage to the DNA of the rats in the four doses used when compared to the negative control group (saline + Tween(r) 80). The APMO did not present any significant increase in micronucleated polychromatic erythrocytes (MNPCEs) for the four tested doses. When compared to the positive control group, all groups (comet and micronucleus tests) were statistically different. These data suggest that the administration of Attalea phalerata Mart oil. ex Spreng does not cause cytotoxicity, genotoxicity and clastogenicity in experimental models in vitro and in vivo following oral administration in this study. PMID- 27764220 TI - Epidemiology and Clinical Presentations of Respiratory Syncytial Virus Subgroups A and B Detected with Multiplex Real-Time PCR. AB - Respiratory syncytial virus (RSV) is one of the most important pathogenic infections of children and requires in-depth research worldwide, and especially in developing countries. We used a novel multiplex real-time PCR to test 5483 patients (<= 14 years old) hospitalized with respiratory illness in Guangzhou, China, over a 3-year period. Of these patients, 729 were positive for RSV-A (51.2%, 373/729) or RSV-B (48.8%, 356/729), but none was infected with both viruses. Two seasonal peaks in total RSV were detected at the changes from winter to spring and from summer to autumn. RSV-B was dominant in 2013 and RSV-A in 2015, whereas RSV-A and RSV-B cocirculated in 2014. The clinical presentations of 645 RSV-positive patients were analyzed. Bronchiolitis, dyspnea, coryza, vomiting, poor appetite, and diarrhea occurred more frequently in RSV-A-positive than RSV-B-positive patients, whereas chill, headache, myalgia, debility, and rash etc. were more frequent in RSV-B-positive than RSV-A-positive patients, suggesting specific clinical characteristics for RSV-A and RSV-B. Coinfectons with other pathogens were common and diverse. Bronchiolitis, fever (>= 38 degrees C), and poor appetite were more frequent in patients with single RSV infections than in coinfected patients, suggesting the key pathogenic activity of RSV. Analysis of the relationships between the comparative viral load and clinical presentations showed significant differences in bronchiolitis, fever (>= 38 degrees C), and rash etc. among patients with different viral loads. This study provides a novel rapid method for detecting RSV subgroups, and provides new insights into the epidemiology and clinical implications of RSV. PMID- 27764221 TI - Transfer in Rule-Based Category Learning Depends on the Training Task. AB - While learning is often highly specific to the exact stimuli and tasks used during training, there are cases where training results in learning that generalizes more broadly. It has been previously argued that the degree of specificity can be predicted based upon the learning solution(s) dictated by the particular demands of the training task. Here we applied this logic in the domain of rule-based categorization learning. Participants were presented with stimuli corresponding to four different categories and were asked to perform either a category discrimination task (which permits learning specific rule to discriminate two categories) or a category identification task (which does not permit learning a specific discrimination rule). In a subsequent transfer stage, all participants were asked to discriminate stimuli belonging to two of the categories which they had seen, but had never directly discriminated before (i.e., this particular discrimination was omitted from training). As predicted, learning in the category-discrimination tasks tended to be specific, while the category-identification task produced learning that transferred to the transfer discrimination task. These results suggest that the discrimination and identification tasks fostered the acquisition of different category representations which were more or less generalizable. PMID- 27764222 TI - EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar 4. AB - Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture with a high mortality rate. Although eicosapentaenoic acid (EPA) has been reported to prevent AAA formation, the mechanism by which EPA works on vascular smooth muscle cells is unknown. This study aimed to investigate the mechanism by which orally-administered EPA prevents the formation of severe AAAs that develop in Osteoprotegerin (Opg) knockout (KO) mice. In the CaCl2-induced AAA model, EPA attenuated the enhanced progression of AAAs in Opg-KO mice, including the increase in aortic diameter with destruction of elastic fibers in the media. Immunohistochemical analyses showed that EPA reduced the phosphorylation of transforming growth factor beta activated kinase-1/Map3k7 (Tak-1) and c-Jun NH2-terminal kinase (JNK), as well as the expression of Matrix metalloproteinase-9 (Mmp-9) in the media of the aorta. In smooth muscle cell cultures, rh-TRAIL-induced activation of the Tak-1-JNK pathway and increase in Mmp-9 expression were inhibited by EPA. Moreover, GW9508, a specific ligand for G-protein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4, mimicked the effects of EPA. The effects of EPA were abrogated by knockdown of the Gpr-120/Ffar-4 receptor gene. Our data demonstrate that the Trail-Tak-1-JNK-Mmp-9 pathway is responsible for the enhancement of AAAs in Opg KO mice, and that EPA inhibits the Tak-1-JNK pathway by activating Gpr-120/Ffar 4, which results in the attenuation of AAA development. PMID- 27764223 TI - Academic Outcomes in High-School Students after a Concussion: A Retrospective Population-Based Analysis. AB - BACKGROUND: Many concussion symptoms, such as headaches, vision problems, or difficulty remembering or concentrating may deleteriously affect school functioning. Our objective was to determine if academic performance was lower in the academic calendar year that students sustain a concussion compared to the previous year when they did not sustain a concussion. METHODS: Using Manitoba Health and Manitoba Education data, we conducted a population-based, controlled before-after study from 2005-2006 to 2010-2011 academic years. Grade 9-12 students with an ICD9/10 code for concussion were matched to non-concussed controls. Overall changes in grade point average (GPA) were compared for the academic year prior to the concussion to the academic year the concussion occurred (or could have occurred among non-concussed matched students). RESULTS: Overall, 8240 students (1709 concussed, 6531 non-concussed students) were included. Both concussed and non-concussed students exhibited a lower overall GPA from one year to the next. Having sustained a concussion resulted in a -0.90% (95% CI: -1.88, 0.08) reduction in GPA. Over the same period, non-concussed matched students' GPA reduced by -0.57% (95% CI: -1.32, 0.19). Students who sustained a concussion during high school were just as likely to graduate within four years as their non-concussed peers (ORadj: 0.84; 95% CI: 0.73, 1.02). CONCLUSIONS: We found that, at a population level, a concussion had minimal long term effects on academic performance during high school. While academic accommodations and Return-to-Learn programs are an important component of pediatric concussion management, research is needed to identify risk factors for poor academic performance after a concussion and who should receive these programs. PMID- 27764225 TI - Correction: Factors Affecting the Radiosensitivity of Hexaploid Wheat to gamma Irradiation: Radiosensitivity of Hexaploid Wheat (Triticum aestivum L.). AB - [This corrects the article DOI: 10.1371/journal.pone.0161700.]. PMID- 27764226 TI - Crowd-Sourced Amputee Gait Data: A Feasibility Study Using YouTube Videos of Unilateral Trans-Femoral Gait. AB - Collecting large datasets of amputee gait data is notoriously difficult. Additionally, collecting data on less prevalent amputations or on gait activities other than level walking and running on hard surfaces is rarely attempted. However, with the wealth of user-generated content on the Internet, the scope for collecting amputee gait data from alternative sources other than traditional gait labs is intriguing. Here we investigate the potential of YouTube videos to provide gait data on amputee walking. We use an example dataset of trans-femoral amputees level walking at self-selected speeds to collect temporal gait parameters and calculate gait asymmetry. We compare our YouTube data with typical literature values, and show that our methodology produces results that are highly comparable to data collected in a traditional manner. The similarity between the results of our novel methodology and literature values lends confidence to our technique. Nevertheless, clear challenges with the collection and interpretation of crowd-sourced gait data remain, including long term access to datasets, and a lack of validity and reliability studies in this area. PMID- 27764224 TI - The CORM ALF-186 Mediates Anti-Apoptotic Signaling via an Activation of the p38 MAPK after Ischemia and Reperfusion Injury in Retinal Ganglion Cells. AB - PURPOSE: Ischemia and reperfusion injury may induce apoptosis and lead to sustained tissue damage and loss of function, especially in neuronal organs. While carbon monoxide is known to exert protective effects after various harmful events, the mechanism of carbon monoxide releasing molecules in neuronal tissue has not been investigated yet. We hypothesize that the carbon monoxide releasing molecule (CORM) ALF-186, administered after neuronal ischemia-reperfusion injury (IRI), counteracts retinal apoptosis and its involved signaling pathways and consecutively reduces neuronal tissue damage. METHODS: IRI was performed in rat's retinae for 1 hour. The water-soluble CORM ALF-186 (10 mg/kg) was administered intravenously via a tail vein after reperfusion. After 24 and 48 hours, retinal tissue was harvested to analyze mRNA and protein expression of Bcl-2, Bax, Caspase-3, ERK1/2, p38 and JNK. Densities of fluorogold pre-labeled retinal ganglion cells (RGC) were analyzed 7 days after IRI. Immunohistochemistry was performed on retinal cross sections. RESULTS: ALF-186 significantly reduced IRI mediated loss of RGC. ALF-186 treatment differentially affected mitogen-activated protein kinases (MAPK) phosphorylation: ALF-186 activated p38 and suppressed ERK1/2 phosphorylation, while JNK remained unchanged. Furthermore, ALF-186 treatment affected mitochondrial apoptosis, decreasing pro-apoptotic Bax and Caspase-3-cleavage, but increasing anti-apoptotic Bcl-2. Inhibition of p38-MAPK using SB203580 reduced ALF-186 mediated anti-apoptotic effects. CONCLUSION: In this study, ALF-186 mediated substantial neuroprotection, affecting intracellular apoptotic signaling, mainly via MAPK p38. CORMs may thus represent a promising therapeutic alternative treating neuronal IRI. PMID- 27764227 TI - Association between Myopia, Biometry and Occludable Angle: The Jiangning Eye Study. AB - BACKGROUND: Myopia subjects usually have long axial lengths and are predisposed to deep anterior chamber depths and open angles. Jiangning eye study is a randomized, population based study in Shanghai to determine whether myopia has an effect on the prevalence of occludable angles. METHODS: A total of 2478 residents aged 50 years and over were randomly selected, and 2044 (82.5%) individuals of them participated in ophthalmic examinations between November 2012 and February 2013. Eye examinations included autorefraction, noncontact tonometry, measurement of axial length, anterior chamber depth, lens thickness and spectral domain optical coherence tomography. RESULTS: The crude prevalences of iris trabecular meshwork contact in Jiangning Chinese individuals with myopia, emmetropia, and hyperopia are 1.25%, 6.44%, and 7.43%, respectively. There is also iris trabecular meshwork contact and shallow anterior chamber depth in myopia subjects even with long axial lengths. CONCLUSIONS: The prevalence of iris trabecular meshwork contact in myopia subjects is lower than their emmetropia or hyperopia counterparts. Axial length is an important factor associate with occludable angle. PMID- 27764228 TI - Survivin Overexpression Is Associated with Aggressive Clinicopathological Features in Cervical Carcinoma: A Meta-Analysis. AB - OBJECTIVE: Overexpression of survivin has been reported in many human tumors. However, the clinicopathological features associated with survivin overexpression in cervical carcinoma remain controversial. Thus, the current meta-analysis was performed to assess the clinicopathological significance of survivin in cervical carcinoma. METHODS: PubMed, EMBASE, and Web of Science databases were searched for relevant studies published through November 1, 2015. A meta-analysis was performed to evaluate the association between survivin expression and clinicopathological outcome in cervical carcinoma. RESULTS: Eleven eligible studies with a total of 865 patients were included. Survivin overexpression was closely related to lymph node metastasis (odds ratio [OR] = 0.679, 95% confidence interval [CI]: 0.509-0.905, P = 0.008) but was not significantly associated with tumor FIGO stage (I+II vs. III+IV) (OR = 0.843, 95% CI: 0.626-1.137, P = 0.264), tumor grade (G1+G2 vs. G3) (OR = 0.913, 95% CI: 0.689-1.210, P = 0.527), tumor size (>4 vs. <=4 cm) (OR = 0.825, 95% CI: 0.434-1.570, P = 0.559), or stromal involvement (OR = 0.820, 95% CI: 0.545-1.233, P = 0.340). The correlation between survivin expression and overall survival was evaluated among a total of 238 patients from three eligible studies. The pooled HR was 1.129 (95% CI: 0.597 1.661; P = 0.000), indicating that survivin expression was significantly associated with poor survival in cervical carcinoma. CONCLUSIONS: Based on the current meta-analysis, survivin is strongly associated with lymph node metastasis and poor prognosis. Additionally, survivin is a novel clinicopathological marker of cervical carcinoma and thus may be a therapeutic target for cervical carcinoma. PMID- 27764230 TI - A New Model for Temperature Jump at a Fluid-Solid Interface. AB - The problem presented involves the development of a new analytical model for the general fluid-solid temperature jump. To the best of our knowledge, there are no analytical models that provide the accurate predictions of the temperature jump for both gas and liquid systems. In this paper, a unified model for the fluid solid temperature jump has been developed based on our adsorption model of the interfacial interactions. Results obtained from this model are validated with available results from the literature. PMID- 27764231 TI - Regression Model-Based Walking Speed Estimation Using Wrist-Worn Inertial Sensor. AB - Walking speed is widely used to study human health status. Wearable inertial measurement units (IMU) are promising tools for the ambulatory measurement of walking speed. Among wearable inertial sensors, the ones worn on the wrist, such as a watch or band, have relatively higher potential to be easily incorporated into daily lifestyle. Using the arm swing motion in walking, this paper proposes a regression model-based method for longitudinal walking speed estimation using a wrist-worn IMU. A novel kinematic variable is proposed, which finds the wrist acceleration in the principal axis (i.e. the direction of the arm swing). This variable (called pca-acc) is obtained by applying sensor fusion on IMU data to find the orientation followed by the use of principal component analysis. An experimental evaluation was performed on 15 healthy young subjects during free walking trials. The experimental results show that the use of the proposed pca acc variable can significantly improve the walking speed estimation accuracy when compared to the use of raw acceleration information (p<0.01). When Gaussian process regression is used, the resulting walking speed estimation accuracy and precision is about 5.9% and 4.7%, respectively. PMID- 27764229 TI - Oral Administration of Linoleic Acid Induces New Vessel Formation and Improves Skin Wound Healing in Diabetic Rats. AB - INTRODUCTION: Impaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals. OBJECTIVES: We investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats. METHODS: Dorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process. RESULTS: LA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2alphabeta), tumor necrosis factor-alpha (TNF-alpha) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2). CONCLUSIONS: Oral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis. PMID- 27764232 TI - Modelling Neonatal Care Pathways for Babies Born Preterm: An Application of Multistate Modelling. AB - Modelling length of stay in neonatal care is vital to inform service planning and the counselling of parents. Preterm babies, at the highest risk of mortality, can have long stays in neonatal care and require high resource use. Previous work has incorporated babies that die into length of stay estimates, but this still overlooks the levels of care required during their stay. This work incorporates all babies, and the levels of care they require, into length of stay estimates. Data were obtained from the National Neonatal Research Database for singleton babies born at 24-31 weeks gestational age discharged from a neonatal unit in England from 2011 to 2014. A Cox multistate model, adjusted for gestational age, was used to consider a baby's two competing outcomes: death or discharge from neonatal care, whilst also considering the different levels of care required: intensive care; high dependency care and special care. The probabilities of receiving each of the levels of care, or having died or been discharged from neonatal care are presented graphically overall and adjusted for gestational age. Stacked predicted probabilities produced for each week of gestational age provide a useful tool for clinicians when counselling parents about length of stay and for commissioners when considering allocation of resources. Multistate modelling provides a useful method for describing the entire neonatal care pathway, where rates of in-unit mortality can be high. For a healthcare service focussed on costs, it is important to consider all babies that contribute towards workload, and the levels of care they require. PMID- 27764233 TI - ESCRT-I Protein Tsg101 Plays a Role in the Post-macropinocytic Trafficking and Infection of Endothelial Cells by Kaposi's Sarcoma-Associated Herpesvirus. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) binding to the endothelial cell surface heparan sulfate is followed by sequential interactions with alpha3beta1, alphaVbeta3 and alphaVbeta5 integrins and Ephrin A2 receptor tyrosine kinase (EphA2R). These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells. The Endosomal Sorting Complexes Required for Transport (ESCRT) proteins, ESCRT-0, -I, -II, and-III, play a central role in clathrin-mediated internalized ubiquitinated receptor endosomal trafficking and sorting. ESCRT proteins have also been shown to play roles in viral egress. We have recently shown that ESCRT-0 component Hrs protein associates with the plasma membrane during macropinocytosis and mediates KSHV entry via ROCK1 mediated phosphorylation of NHE1 and local membrane pH change. Here, we demonstrate that the ESCRT-I complex Tsg101 protein also participates in the macropinocytosis of KSHV and plays a role in KSHV trafficking. Knockdown of Tsg101 did not affect virus entry in HMVEC-d and human umbilical vein endothelial (HUVEC) cells but significantly inhibited the KSHV genome entry into the nucleus and consequently viral gene expression in these cells. Double and triple immunofluorescence, proximity ligation immunofluorescence and co immuoprecipitation studies revealed the association of Tsg101 with the KSHV containing macropinosomes, and increased levels of Tsg101 association/interactions with EphA2R, c-Cbl, p130Cas and Crk signal molecules, as well as with upstream and downstream ESCRT components such as Hrs (ESCRT-0), EAP45 (ESCRT-II), CHMP6 (ESCRT-III) and CHMP5 (ESCRT-III) in the KSHV infected cells. Tsg101 was also associated with early (Rab5) and late endosomal (Rab7) stages of KSHV intracellular trafficking, and CHMP5 (ESCRT-III) was also associated with Rab 5 and Rab 7. Knockdown of Tsg101 significantly inhibited the transition of virus from early to late endosomes. Collectively, our studies reveal that Tsg101 plays a role in the trafficking of macropinocytosed KSHV in the endothelial cells which is essential for the successful viral genome delivery into the nucleus, viral gene expression and infection. Thus, ESCRT molecules could serve as therapeutic targets to combat KSHV infection. PMID- 27764234 TI - Uncovering the Complex Transcriptome Response of Mytilus chilensis against Saxitoxin: Implications of Harmful Algal Blooms on Mussel Populations. AB - Saxitoxin (STX), a principal phycotoxin contributing to paralytic shellfish poisoning, is largely produced by marine microalgae of the genus Alexandrium. This toxin affects a wide range of species, inducing massive deaths in fish and other marine species. However, marine bivalves can resist and accumulate paralytic shellfish poisons. Despite numerous studies on the impact of STX in marine bivalves, knowledge regarding STX recognition at molecular level by benthic species remains scarce. Therefore, the aim of this study was to identify novel genes that interact with STX in the Chilean mussel Mytilus chilensis. For this, RNA-seq and RT-qPCR approaches were used to evaluate the transcriptomic response of M. chilensis to a purified STX as well as in vivo Alexandrium catenella exposure. Approximately 800 million reads were assembled, generating 138,883 contigs that were blasted against the UniProt Mollusca database. Pattern Recognition Receptors (PRRs) involved in mussel immunity, such as Toll-like receptors, tumor necrosis factor receptors, and scavenger-like receptors were found to be strongly upregulated at 8 and 16 h post-STX injection. These results suggest an involvement of PRRs in the response to STX, as well as identifying potential, novel STX-interacting receptors in this Chilean mussel. This study is the first transcriptomic overview of the STX-response in the edible species M. chilensis. However, the most significant contribution of this work is the identification of immune receptors and pathways potentially involved in the recognition and defense against STX's toxicity and its impact of harmful algae blooms on wild and cultivated mussel populations. PMID- 27764235 TI - Investigating CD99 Expression in Leukemia Propagating Cells in Childhood T Cell Acute Lymphoblastic Leukemia. AB - A significant number of children with T-lineage acute lymphoblastic leukemia (T ALL) fail to respond to therapy and experience early relapse. CD99 has been shown to be overexpressed on T-ALL cells and is considered to be a reliable detector of the disease. However, the relevance of CD99 overexpression in ALL has not been investigated in a functional context. The aim of this study was to investigate the functional capacity of CD99+ cells in childhood ALL and determine the suitability of CD99 as a therapeutic target. Flow cytometric analyses confirmed higher expression of CD99 in ALL blasts (81.5+/-22.7%) compared to normal hemopoietic stem cells (27.5+/-21.9%) and T cells (3.1+/-5.2%, P<=0.004). When ALL cells were sorted and assessed in functional assays, all 4 subpopulations (CD34+/CD99+, CD34+/CD99-, CD34-/CD99+ and CD34-/CD99-) could proliferate in vitro and establish leukemia in NSG mice. Leukemia propagating cell frequencies ranged from 1 in 300 to 1 in 7.4x104 but were highest in the CD34+/CD99- subpopulation. In addition, all four subpopulations had self-renewal ability in secondary NSG mice. Cells in each subpopulation contained patient specific TCR rearrangements and karyotypic changes that were preserved with passage through serial NSG transplants. Despite high levels of CD99 antigen on the majority of blast cells, leukemia initiating capacity in vivo was not restricted to cells that express this protein. Consequently, targeting CD99 alone would not eliminate all T-ALL cells with the ability to maintain the disease. The challenge remains to develop therapeutic strategies that can eliminate all leukemia cells with self renewal capacity in vivo. PMID- 27764236 TI - Phenotype and Function of CD209+ Bovine Blood Dendritic Cells, Monocyte-Derived Dendritic Cells and Monocyte-Derived Macrophages. AB - Phylogenic comparisons of the mononuclear phagocyte system (MPS) of humans and mice demonstrate phenotypic divergence of dendritic cell (DC) subsets that play similar roles in innate and adaptive immunity. Although differing in phenotype, DC can be classified into four groups according to ontogeny and function: conventional DC (cDC1 and cDC2), plasmacytoid DC (pDC), and monocyte derived DC (MoDC). DC of Artiodactyla (pigs and ruminants) can also be sub-classified using this system, allowing direct functional and phenotypic comparison of MoDC and other DC subsets trafficking in blood (bDC). Because of the high volume of blood collections required to study DC, cattle offer the best opportunity to further our understanding of bDC and MoDC function in an outbred large animal species. As reported here, phenotyping DC using a monoclonal antibody (mAb) to CD209 revealed CD209 is expressed on the major myeloid population of DC present in blood and MoDC, providing a phenotypic link between these two subsets. Additionally, the present study demonstrates that CD209 is also expressed on monocyte derived macrophages (MoPhi). Functional analysis revealed each of these populations can take up and process antigens (Ags), present them to CD4 and CD8 T cells, and elicit a T-cell recall response. Thus, bDC, MoDC, and MoPhi pulsed with pathogens or candidate vaccine antigens can be used to study factors that modulate DC driven T-cell priming and differentiation ex vivo. PMID- 27764238 TI - Distribution of DI*A and DI*B Allele Frequencies and Comparisons among Central Thai and Other Populations. AB - Alloantibodies to the Diego (DI) blood group system, anti-Dia and anti-Dib are clinically significant in causing hemolytic transfusion reactions (HTRs) and hemolytic disease of the fetus and newborn (HDFN), especially in Asian populations with Mongolian ancestry. This study aimed to report the frequency of the DI*A and DI*B alleles in a Central Thai population and to compare them with those of other populations previously published. Altogether, 1,011 blood samples from unrelated healthy blood donors at the National Blood Centre, Thai Red Cross Society, Bangkok were included. Only 391 samples were tested with anti-Dia by conventional tube technique. All samples were genotyped for DI*A and DI*B alleles using an in-house polymerase chain reaction with sequence-specific primer (PCR SSP) technique. The DI phenotyping and genotyping results were in 100% concordance. The DI*A and DI*B allele frequencies among 1,011 Central Thais were 0.0183 (37/2,022) and 0.9817 (1,985/2,022), respectively. Allele frequencies were compared between Central Thai and other populations. Our data shows that DI*A and DI*B allele frequencies are similar to Southeast Asian, Brazilian, Southern Brazilian and American Native populations; whereas, these frequencies significantly differ from those reported in East Asian, Italian, Alaska Native/Aleut, Hawaiian/Pacific Islander and Filipino populations (P<0.05), corresponding to the results of a matrix of geometric genetic distances. This study confirms that the prevalence of DI*A and DI*B alleles among Central Thais is similar to Southeast Asians and different to others populations of the world. A PCR-based identification of DI genotyping should overcome some of the serological limitations in transfusion medicine and provides a complementary tool for further population-genetic studies. PMID- 27764237 TI - Dietary Interventions in Multiple Sclerosis: Development and Pilot-Testing of an Evidence Based Patient Education Program. AB - BACKGROUND: Dietary factors have been discussed to influence risk or disease course of multiple sclerosis (MS). Specific diets are widely used among patients with MS. OBJECTIVE: To design and pilot-test an evidence based patient education program on dietary factors in MS. METHODS: We performed a systematic literature search on the effectiveness of dietary interventions in MS. A web-based survey among 337 patients with MS and 136 healthy controls assessed knowledge, dietary habits and information needs. An interactive group education program was developed and pilot-tested. RESULTS: Fifteen randomised-controlled trials (RCTs) were included in the systematic review. Quality of evidence was low and no clear benefit could be seen. Patients with MS significantly more often adhered to a 'Mediterranean Diet'(29.7% versus 14.0%, p<0.001) compared to controls. 143 (42%) of the patients with MS had tried special MS diets. Important information needs addressed effectiveness of MS diets (44%) and relation between nutrition and MS (43%). A pilot test of our newly developed patient education program with 13 participants showed excellent comprehensibility and the MS-specific content was judged as very important. However, the poor evidence base for dietary approaches in MS was perceived disappointing. CONCLUSIONS: Development and pilot-testing of an evidence-based patient education program on nutrition and MS is feasible. Patient satisfaction with the program suffers from the lack of evidence. Further research should focus on generating evidence for the potential influence of lifestyle habits (diet, physical activity) on MS disease course thus meeting the needs of patients with MS. PMID- 27764239 TI - Association between Knee Osteoarthritis, Cardiovascular Risk Factors, and the Framingham Risk Score in South Koreans: A Cross-Sectional Study. AB - BACKGROUND: Osteoarthritis is a significant burden on personal health and for social cost, and its prevalence is rising. Recent research has revealed an association between osteoarthritis and cardiovascular disease, and this study uses the Framingham risk score (FRS), which is widely used as a composite index of cardiovascular risk factors, to investigate the association between osteoarthritis and various cardiovascular risk factors. METHODS: A total 9,514 participants aged 50 years or older who received knee X-ray diagnosis of the 5th Korean National Health and Nutrition Examination Survey (total surveyees = 24,173) released by the Korean Centers for Disease Control and Prevention was included for analysis. Knee osteoarthritis patients were defined as participants with K-L grade >=2 on knee X-ray regardless of knee pain. The association between major cardiovascular risk factors (blood pressure, diabetes, cholesterol, and smoking habits), FRS, and knee osteoarthritis was analyzed, adjusting for various covariates. RESULTS: Prevalence of knee osteoarthritis in Koreans aged >=50 years was 36.6%, and higher in women (men: 24.9%, women: 45.4%). Prevalence of knee osteoarthritis in participants with hypertension was significantly higher than those without hypertension (fully adjusted odds ratio (OR) 1.26; 95% confidence interval (CI) 1.08-1.48). Knee osteoarthritis prevalence was also higher in participants with impaired fasting glucose or diabetes than those without (age, sex adjusted OR 1.19; 95% CI 1.00-1.41). Also, OR values increased statistically significantly with FRS as a continuous variable (fully adjusted OR 1.007; 95% CI 1.00-1.01). CONCLUSIONS: Prevalence of knee osteoarthritis was associated with hypertension and diabetes, which are major cardiovascular risk factors, and the FRS. Further studies on FRS pertaining to its relationship with osteoarthritis are warranted. PMID- 27764240 TI - Feasibility of In-Vivo Simulation of Acute Hemodynamics in Human Atrial Fibrillation. AB - This study evaluated hemodynamic feasibility and reproducibility of a new method for in vivo simulation of human atrial fibrillation (AF). The method was tested during sinus rhythm in 10 patients undergoing catheter ablation for AF. A simple electronic device was assembled that allowed triggering a cardiac stimulator by predefined series of RR intervals. Irregular RR interval sequences with a mean heart rate of 90/min and 130/min were obtained from ECG recordings of another patients with AF. Simultaneous atrioventricular pacing was delivered by catheters placed inside the coronary sinus and at the His bundle region. Hemodynamic effect of the simulated AF was assessed by invasive measurement of the left ventricular (LV) pressure, dP/dt, and Tau. Compared to regular pacing at the same mean heart rate, the simulated AF significantly impaired the LV both systolic and diastolic function. Repeated AF pacing in the same patients generated similar LV hemodynamics. The proposed method provides a realistic and reproducible in-vivo model of AF. It can be exploited for investigation of the hemodynamic consequences of AF in various patient populations. PMID- 27764241 TI - Campomanesia adamantium Peel Extract in Antidiarrheal Activity: The Ability of Inhibition of Heat-Stable Enterotoxin by Polyphenols. AB - Campomanesia adamantium (Myrtaceae) is a medicinal plant distributed in Brazilian Cerrado. Different parts of this plant are used in popular medicine for treatment of several diseases like fever, diarrhea, hypercholesterolemia and rheumatism. The aim of this work was to evaluate the inhibition of heat-stable enterotoxin type A (STa) by gallic acid present in the peel of C. adamantium fruit and assays to assess the antidiarrheal activity, anti-inflammatory and cytotoxic properties of peel extract using the T84 cell line model. The possible inhibition exerted by the gallic acid of the peel extract on the STa peptide was inferred by molecular dynamics simulations. The antidiarrheal effects were investigated measuring cGMP accumulation in cells after stimulation by STa toxin and antibacterial activity was assessed. The anti-inflammatory activity was assessed by inhibition of COX-1 and COX-2. MTT and LDH assays were used to evaluate any possible cytotoxic action while the CyQUANT test was used to investigate the effect on cell proliferation. A representation showing how the possible interactions between STa and the gallic acid of the extract might reduce the action of the enterotoxin is presented. C. adamantium peel extract significantly decreased the levels of cGMP in T84 cells. However, no effect on the species of microorganisms was observed. The extract also inhibited COX-1 (IC50 255.70 +/- 0.04 ng/mL) and COX-2 (IC50 569.50 +/- 0.11 ng/mL) enzymes. Cytotoxicity assay have shown significant changes in cells treated with the extract, which inhibited the cell proliferation until 72 hours of treatment. Direct interactions of phenolic compounds present in the extract with the STa toxin may limit its activity. Curative effect in the diarrhea treatment and its anti-inflammatory action is based on the pharmacological properties, mechanism of action of the C. adamantium peel extract, and no toxic effects of the peel extract presented on this work. PMID- 27764243 TI - Correction: Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein. AB - [This corrects the article DOI: 10.1371/journal.pone.0159449.]. PMID- 27764242 TI - Secreted Alpha-N-Arabinofuranosidase B Protein Is Required for the Full Virulence of Magnaporthe oryzae and Triggers Host Defences. AB - Rice blast disease caused by Magnaporthe oryzae is one of the most devastating fungal diseases of rice and results in a huge loss of rice productivity worldwide. During the infection process, M. oryzae secretes a large number of glycosyl hydrolase proteins into the host apoplast to digest the cell wall and facilitate fungal ingression into host tissues. In this study, we identified a novel arabinofuranosidase-B (MoAbfB) protein that is secreted by M. oryzae during fungal infection. Deletion of MoAbfB from M. oryzae resulted in reduced disease severity in rice. Biochemical assays revealed that the MoAbfB protein exhibited arabinofuranosidase activity and caused degradation of rice cell wall components. Interestingly, pre-treatment of rice with the MoAbfB protein inhibited fungal infection by priming defence gene expression. Our findings suggest that MoAbfB secretion affects M. oryzae pathogenicity by breaking down the host cell wall, releasing oligosaccharides that may be recognized by the host to trigger innate immune responses. PMID- 27764244 TI - Correction: Caffeine Ingestion Increases Estimated Glycolytic Metabolism during Taekwondo Combat Simulation but Does Not Improve Performance or Parasympathetic Reactivation. AB - [This corrects the article DOI: 10.1371/journal.pone.0142078.]. PMID- 27764245 TI - An Epigenetic Compound Library Screen Identifies BET Inhibitors That Promote HSV 1 and -2 Replication by Bridging P-TEFb to Viral Gene Promoters through BRD4. AB - The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection. BRD4 regulates HSV replication through complex formation involving CDK9 and RNAP II; whereas, JQ1 promotes HSV-1 infection by allocating the complex to HSV gene promoters. Therefore, suppression of BRD4 expression or inhibition of CDK9 activity impeded HSV infection. Our data support a model that JQ1 enhances HSV infection by switching BRD4 to transcription regulation of viral gene expression from chromatin targeting since transient expression of BRD4 BD1 or BD1/2 domain had similar effect to that by JQ1 treatment. In addition to the identification that BRD4 is a modulator for JQ1 action on HSV infection, this study demonstrates BRD4 has an essential role in HSV infection. PMID- 27764246 TI - Interrelationships in the Variability of Root Canal Anatomy among the Permanent Teeth: A Full-Mouth Approach by Cone-Beam CT. AB - OBJECTIVES: In endodontic practice, clinicians should be aware of possible root canal anatomic variations. The aim of this study was to assess using CBCT acquisitions regarding whether one root canal anatomy of a tooth is associated with a specific anatomy of another tooth. METHODS: A total of 106 CBCT acquisitions were obtained using a CBCT scanner with 200MUm voxel size. Numbers of roots and canals of the entire dentition were described. Bivariate analyses and logistic regressions were conducted to explore root canal anatomy on one tooth according to age, gender, jaw, side and the others teeth. Multiple correspondence analysis (MCA) was performed to correlate the different numbers of canals profiles. RESULTS: A total of 2424 teeth were analyzed. Independently from the other variables, the presence of an additional root canal on a mandibular incisor increases the risk of having an additional root canal on a mandibular premolar (OR [95%] 3.7 [1.0;13.2]). The mandibular molar variability increases in women compared to men (OR [95%] 0.4 [0.1; 0.9]). MCA showed correspondence between 2-canals maxillary incisor and canines and 5-canals maxillary molars, and some correlation between additional canal on maxillary and mandibular premolars. CONCLUSIONS: Although CBCT examinations are conducted in the first intention of making a diagnosis or prognostic evaluation, medium FOV acquisitions could be used as an initial database thus furnishing preliminary evaluations and information. In endodontic practice, clinicians should be aware of possible root canal anatomic variations. The visualization of all canals is considered essential in endodontic therapy. The use of multi-correspondence analysis for statistics in endodontic research is a new approach as a prognostic tool. PMID- 27764248 TI - Correction: Characterization of Three Novel Fatty Acid- and Retinoid-Binding Protein Genes (Ha-far-1, Ha-far-2 and Hf-far-1) from the Cereal Cyst Nematodes Heterodera avenae and H. filipjevi. AB - [This corrects the article DOI: 10.1371/journal.pone.0160003.]. PMID- 27764247 TI - SIRT1-PGC1alpha-NFkappaB Pathway of Oxidative and Inflammatory Stress during Trypanosoma cruzi Infection: Benefits of SIRT1-Targeted Therapy in Improving Heart Function in Chagas Disease. AB - Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease. The 3-weeks SRT1720 therapy provided significant benefits in restoring the left ventricular (LV) function (stroke volume, cardiac output, ejection fraction etc.) in chagasic mice, though cardiac hypertrophy presented by increased thickness of the interventricular septum and LV posterior wall, increased LV mass, and disproportionate synthesis of collagens was not controlled. SRT1720 treatment preserved the myocardial SIRT1 activity and PGC1alpha deacetylation (active-form) that were decreased by 53% and 9-fold respectively, in chagasic mice. Yet, SIRT1/PGC1alpha-dependent mitochondrial biogenesis (i.e., mitochondrial DNA content, and expression of subunits of the respiratory complexes and mtDNA replication machinery) was not improved in chronically-infected/SRT1720-treated mice. Instead, SRT1720 therapy resulted in 2 10-fold inhibition of Tc-induced oxidative (H2O2 and advanced oxidation protein products), nitrosative (inducible nitric oxide synthase, 4-hydroxynonenal, 3 nitrotyrosine), and inflammatory (IFNgamma, IL1beta, IL6 and TNFalpha) stress and inflammatory infiltrate in chagasic myocardium. These benefits were delivered through SIRT1-dependent inhibition of NFkappaB transcriptional activity. We conclude that Tc inhibition of SIRT1/PGC1alpha activity was not a key mechanism in mitochondrial biogenesis defects during Chagas disease. SRT1720-dependent SIRT1 activation led to suppression of NFkappaB transcriptional activity, and subsequently, oxidative/nitrosative and inflammatory pathology were subdued, and antioxidant status and LV function were enhanced in chronic chagasic cardiomyopathy. PMID- 27764249 TI - Correction: Morphological and Molecular Phylogenetic Data Reveal a New Species of Primula (Primulaceae) from Hunan, China. AB - [This corrects the article DOI: 10.1371/journal.pone.0161172.]. PMID- 27764250 TI - Histone H2B-IFI16 Recognition of Nuclear Herpesviral Genome Induces Cytoplasmic Interferon-beta Responses. AB - IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1beta and antiviral type-1 interferon-beta (IFN-beta) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1beta generation. Acetylated IFI16 also interacted with cytoplasmic STING and induced IFN-beta. However, the identity of IFI16 associated nuclear proteins involved in STING activation and the mechanism is not known. Mass spectrometry of proteins precipitated by anti-IFI16 antibodies from uninfected endothelial cell nuclear lysate revealed that histone H2B interacts with IFI16. Single and double proximity ligation microscopy, immunoprecipitation, EdU-genome labeled virus infection, and chromatin immunoprecipitation studies demonstrated that H2B is associated with IFI16 and BRCA1 in the nucleus in physiological conditions. De novo KSHV and HSV-1 infection as well as latent KSHV and EBV infection induces the cytoplasmic distribution of H2B-IFI16, H2B-BRCA1 and IFI16-ASC complexes. Vaccinia virus (dsDNA) cytoplasmic replication didn't induce the redistribution of nuclear H2B-IFI16 or H2B into the cytoplasm. H2B is critical in KSHV and HSV-1 genome recognition by IFI16 during de novo infection. Viral genome sensing by IFI16-H2B-BRCA1 leads to BRCA1 dependent recruitment of p300, and acetylation of H2B and IFI16. BRCA1 knockdown or inhibition of p300 abrogated the acetylation of H2B-IFI16 or H2B. Ran-GTP protein mediated the translocation of acetylated H2B and IFI16 to the cytoplasm along with BRCA1 that is independent of IFI16-ASC inflammasome. ASC knockdown didn't affect the acetylation of H2B, its cytoplasmic transportation, and the association of STING with IFI16 and H2B during KSHV infection. Absence of H2B didn't affect IFI16-ASC association and cytoplasmic distribution and thus demonstrating that IFI16-H2B complex is independent of IFI16-ASC-procaspase-1-inflammasome complex formed during infection. The H2B-IFI16-BRCA1 complex interacted with cGAS and STING in the cytoplasm leading to TBK1 and IRF3 phosphorylation, nuclear translocation of pIRF3 and IFN-beta production. Silencing of H2B, cGAS and STING inhibited IFN beta induction but not IL-1beta secretion, and cGAMP activity is significantly reduced by H2B and IFI16 knockdown during infection. Silencing of ASC inhibited IL-1beta secretion but not IFN-beta secretion during de novo KSHV and HSV-1 infection. These studies identify H2B as an innate nuclear sensor mediating a novel extra chromosomal function, and reveal that two IFI16 complexes mediate KSHV and HSV-1 genome recognition responses, with recognition by the IFI16-BRCA1 H2B complex resulting in IFN-beta responses and recognition by IFI16-BRCA1 resulting in inflammasome responses. PMID- 27764251 TI - Heterologous Expression and Delivery of Biologically Active Exendin-4 by Lactobacillus paracasei L14. AB - Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, is an excellent therapeutic peptide drug for type 2 diabetes due to longer lasting biological activity compared to GLP-1. This study explored the feasibility of using probiotic Lactobacillus paracasei as an oral vector for recombinant exendin-4 peptide delivery, an alternative to costly chemical synthesis and inconvenient administration by injection. L. paracasei transformed with a plasmid encoding the exendin-4 gene (L. paracasei L14/pMG76e-exendin-4) with a constitutive promotor was successfully constructed and showed efficient secretion of exendin-4. The secreted exendin-4 significantly enhanced insulin secretion of INS-1 beta-cells, along with an increment in their proliferation and inhibition of their apoptosis, corresponding to the effect of GLP-1 on these cells. The transcription level of the pancreatic duodenal homeobox-1 gene (PDX-1), a key transcription factor for cellular insulin synthesis and secretion, was upregulated by the treatment with secreted exendin-4, paralleling the upregulation of insulin gene expression. Caco 2 cell monolayer permeability assay showed a 34-fold increase in the transport of exendin-4 delivered by L. paracasei vs. that of free exendin-4 (control), suggesting effective facilitation of exendin-4 transport across the intestinal barrier by this delivery system. This study demonstrates that the probiotic Lactobacillus can be engineered to secrete bioactive exendin-4 and facilitate its transport through the intestinal barrier, providing a novel strategy for oral exendin-4 delivery using this lactic acid bacterium. PMID- 27764252 TI - The Chloroplast Genome of Utricularia reniformis Sheds Light on the Evolution of the ndh Gene Complex of Terrestrial Carnivorous Plants from the Lentibulariaceae Family. AB - Lentibulariaceae is the richest family of carnivorous plants spanning three genera including Pinguicula, Genlisea, and Utricularia. Utricularia is globally distributed, and, unlike Pinguicula and Genlisea, has both aquatic and terrestrial forms. In this study we present the analysis of the chloroplast (cp) genome of the terrestrial Utricularia reniformis. U. reniformis has a standard cp genome of 139,725bp, encoding a gene repertoire similar to essentially all photosynthetic organisms. However, an exclusive combination of losses and pseudogenization of the plastid NAD(P)H-dehydrogenase (ndh) gene complex were observed. Comparisons among aquatic and terrestrial forms of Pinguicula, Genlisea, and Utricularia indicate that, whereas the aquatic forms retained functional copies of the eleven ndh genes, these have been lost or truncated in terrestrial forms, suggesting that the ndh function may be dispensable in terrestrial Lentibulariaceae. Phylogenetic scenarios of the ndh gene loss and recovery among Pinguicula, Genlisea, and Utricularia to the ancestral Lentibulariaceae cladeare proposed. Interestingly, RNAseq analysis evidenced that U. reniformis cp genes are transcribed, including the truncated ndh genes, suggesting that these are not completely inactivated. In addition, potential novel RNA-editing sites were identified in at least six U. reniformis cp genes, while none were identified in the truncated ndh genes. Moreover, phylogenomic analyses support that Lentibulariaceae is monophyletic, belonging to the higher core Lamiales clade, corroborating the hypothesis that the first Utricularia lineage emerged in terrestrial habitats and then evolved to epiphytic and aquatic forms. Furthermore, several truncated cp genes were found interspersed with U. reniformis mitochondrial and nuclear genome scaffolds, indicating that as observed in other smaller plant genomes, such as Arabidopsis thaliana, and the related and carnivorous Genlisea nigrocaulis and G. hispidula, the endosymbiotic gene transfer may also shape the U. reniformis genome in a similar fashion. Overall the comparative analysis of the U. reniformis cp genome provides new insight into the ndh genes and cp genome evolution of carnivorous plants from Lentibulariaceae family. PMID- 27764253 TI - Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment. AB - Discovery of somatic mutations in the calreticulin gene (CALR) has identified a subgroup of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) with separate haematological characteristics and prognosis. CALR mutations serve as novel markers both of diagnostic value and as targets for monitoring molecular responses during therapy. Interferon-alpha (IFN) selectively targets the malignant clone in a subset of MPN patients and can induce both haematological and molecular remissions in CALR mutated essential thrombocythemia (ET) patients. We investigated the response to IFN in a cohort of 21 CALR mutated MPN patients including ET, prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF) with a median follow-up of 31 months. For evaluation of a molecular response, we developed highly sensitive quantitative PCR (qPCR) assays for monitoring the mutant allele burden of the two most prevalent CALR mutations (type 1 and type 2). Thirteen patients (62%) experienced a decrease in the mutant allele burden with a median decline of 29% from baseline. However, only four patients, including patients with ET, pre-PMF, and PMF diagnosis, achieved molecular responder (MR) status with >50% reduction in mutant allele burden according to European LeukemiaNet (ELN) guidelines. MR patients displayed significant differences in the dynamics of the CALR mutant load with regard to time to response and dynamics in mutant allele burden after discontinuation of IFN treatment. Furthermore, we highlight the prognostic value of the CALR mutant allele burden by showing a close association with leucocyte- and platelet counts, hemoglobin concentration, in addition to plasma lactate dehydrogenase (LDH) irrespective of molecular response and treatment status. PMID- 27764255 TI - Correction: LMethyR-SVM: Predict Human Enhancers Using Low Methylated Regions based on Weighted Support Vector Machines. AB - [This corrects the article DOI: 10.1371/journal.pone.0163491.]. PMID- 27764254 TI - Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals. AB - Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population. PMID- 27764256 TI - Entamoeba Encystation: New Targets to Prevent the Transmission of Amebiasis. AB - Amebiasis is caused by Entamoeba histolytica infection and can produce a broad range of clinical signs, from asymptomatic cases to patients with obvious symptoms. The current epidemiological and clinical statuses of amebiasis make it a serious public health problem worldwide. The Entamoeba life cycle consists of the trophozoite, the causative agent for amebiasis, and the cyst, the form responsible for transmission. These two stages are connected by "encystation" and "excystation." Hence, developing novel strategies to control encystation and excystation will potentially lead to new measures to block the transmission of amebiasis by interrupting the life cycle of the causative agent. Here, we highlight studies investigating encystation using inhibitory chemicals and categorize them based on the molecules inhibited. We also present a perspective on new strategies to prevent the transmission of amebiasis. PMID- 27764258 TI - Correction: Prevalence of Gestational Diabetes Mellitus in Korea: A National Health Insurance Database Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0153107.]. PMID- 27764257 TI - HIV-1 Integrates Widely throughout the Genome of the Human Blood Fluke Schistosoma mansoni. AB - Schistosomiasis is the most important helminthic disease of humanity in terms of morbidity and mortality. Facile manipulation of schistosomes using lentiviruses would enable advances in functional genomics in these and related neglected tropical diseases pathogens including tapeworms, and including their non-dividing cells. Such approaches have hitherto been unavailable. Blood stream forms of the human blood fluke, Schistosoma mansoni, the causative agent of the hepatointestinal schistosomiasis, were infected with the human HIV-1 isolate NL4 3 pseudotyped with vesicular stomatitis virus glycoprotein. The appearance of strong stop and positive strand cDNAs indicated that virions fused to schistosome cells, the nucleocapsid internalized and the RNA genome reverse transcribed. Anchored PCR analysis, sequencing HIV-1-specific anchored Illumina libraries and Whole Genome Sequencing (WGS) of schistosomes confirmed chromosomal integration; >8,000 integrations were mapped, distributed throughout the eight pairs of chromosomes including the sex chromosomes. The rate of integrations in the genome exceeded five per 1,000 kb and HIV-1 integrated into protein-encoding loci and elsewhere with integration bias dissimilar to that of human T cells. We estimated ~ 2,100 integrations per schistosomulum based on WGS, i.e. about two or three events per cell, comparable to integration rates in human cells. Accomplishment in schistosomes of post-entry processes essential for HIV-1replication, including integrase-catalyzed integration, was remarkable given the phylogenetic distance between schistosomes and primates, the natural hosts of the genus Lentivirus. These enigmatic findings revealed that HIV-1 was active within cells of S. mansoni, and provided the first demonstration that HIV-1 can integrate into the genome of an invertebrate. PMID- 27764260 TI - The Missing Link between Candida albicans Hyphal Morphogenesis and Host Cell Damage. PMID- 27764259 TI - Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI. AB - INTRODUCTION: Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIalpha), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIalpha, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIalpha by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. METHODS AND RESULTS: Purified soluble SCP was prepared by size fractionation of sodium polyphosphate. TFPIalpha proteolysis was analyzed by western blot. TFPIalpha activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIalpha by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIalpha by FXIa. TFPIalpha activity was not affected by SCP in recalcified FXI-depleted plasma. CONCLUSIONS: Our data suggest that SCP is a cofactor for TFPIalpha inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP. PMID- 27764262 TI - Procedures for Counting and Charting A Target Phoneme. PMID- 27764261 TI - ERRATUM: Sex Trafficking Assessment and Resources (STAR) for Pediatric Attendings in Rhode Island. AB - BACKGROUND: Domestic minor sex trafficking (DMST) victims have unique medical and mental health needs and present frequently for medical attention. Little is known about the reported training, screening, comfort and knowledge of DMST among pediatricians in Rhode Island who likely encounter these patient victims without knowing. METHODS: An anonymous electronic survey sent to Rhode Island Hospital staff physicians from November 2014 through January 2015. RESULTS: Of the 109 participants, the majority reported no training, screened no patients for DMST in the past year, did not know any resources available and had limited knowledge and comfort with this pediatric patient population. CONCLUSIONS: Rhode Island pediatricians of various specialties do not feel adequately prepared to identify and respond to a DMST patient population. These findings inform the need for increased training and education on DMST in our medical community. [Full article available at http://rimed.org/rimedicaljournal-2016-09.asp, free with no login]. PMID- 27764263 TI - Selection of Achievement Test Level for Hearing-Impaired Children. PMID- 27764265 TI - A Structured Program for Modifying /r/ Misarticulations. PMID- 27764264 TI - Effect of Frequencies on Speech Therapy On Several Measures of Articulatory Proficiency. PMID- 27764266 TI - A Preschool Program for Children Who Have Communication Problems. PMID- 27764267 TI - Organic Impairments: A Need for Emphasis in Schools. PMID- 27764268 TI - Written Versus Oral Contact with Classroom Teachers. PMID- 27764269 TI - Language Intervention: Ten Techniques. PMID- 27764270 TI - The Voice-Disordered Child: A Descriptive Approach. PMID- 27764271 TI - An Educational-Diagnostic Approach To Language Problems. PMID- 27764272 TI - Auditory Perception-Implications for Language Development. PMID- 27764274 TI - From the Editor... PMID- 27764273 TI - Evaluating the Velopharyngeal Mechanism In Hypernasal Speakers. PMID- 27764275 TI - Language Testing in Adolescents With Brain Injury: A Consideration of the CELF-3. AB - The validity of the Clinical Evaluation of Language Fundamentals-Third Edition (CELF-3, Semel, Wiig, & Secord, 1995) for the identification and description of language disorders following traumatic brain injury (TBI) was considered in 11 adolescents with TBI. In general, the CELF-3 identified only the individuals who had previously been diagnosed as language impaired, not the individuals with verbal information processing impairments but no diagnosis of language impairment. The test did not permit the identification of strengths and weaknesses. Intercorrelations among subtest standard scores were as high in the TBI group as in the standardization sample, which is consistent with the CELF-3 being a one-factor test. Test performance may have been influenced by the interaction of the subjects' memory abilities and the subtests' memory demands, although this relationship was not statistically significant in the present data. PMID- 27764276 TI - Effects of Familiarity on Idiom Comprehension in African American and European American Fifth Graders. AB - In order to test the language experience hypothesis, the comprehension of high-, moderate-, and low-familiarity idioms was examined in African American (N=24) and European American (N= 24) fifth-grade students in the Mid-South. This study was designed to augment the existing literature on cross-cultural idiom comprehension, of which there is a paucity of research, and provide a look from a culturally diverse perspective at idiom comprehension in youth. Results indicate a significant effect of group on idioms rated as low-familiarity, whereas idioms rated as high- and moderate-familiarity did not distinguish the groups. Additionally, the current results indicate a pattern of comprehension that is different from that found in previous studies, based on levels of familiarity (Nippold & Rudzinski, 1993) that were established in a different U.S. geographic location. The influences of social and regional culture on idiom comprehension and familiarity is discussed, and a preliminary hypothesis is proposed to explain these influences. PMID- 27764277 TI - Assessment of Complex Sentence Production in a Narrative Context. AB - This study focused on eliciting and assessing complex sentence structure in a meaningful discourse context. The effect of clinician support (modeling of specific structures and practice with the structures) on the subsequent use of complex sentence structures in story retelling was studied. Experiment 1 was conducted with students demonstrating language abilities within normal limits. Because these initial results were promising, Experiment 2 was conducted with students demonstrating language impairments. The results of these experiments indicated, first, that amount of exposure to the stimulus is a critical variable affecting length and syntactic complexity in story retelling. Evidence further supported the use of modeling and practice of specific structures when assessing students' syntactic skills. The assessment protocol used in these experiments was found to be useful for eliciting a large number and variety of complex syntactic structures in a meaningful context from children with and without language impairments. PMID- 27764278 TI - The Hearing Aid Effect in African American and Caucasian Males as Perceived by Female Judges of the Same Race. AB - Prior studies have proven the existence of the "hearing aid effect" when photographs of Caucasian males and females wearing a body aid, a post-auricular aid (behind-the-ear), or no hearing aid were judged by lay persons and professionals. This study was performed to determine if African American and Caucasian males, judged by female members of their own race, were likely to be judged in a similar manner on the basis of appearance, personality, assertiveness, and achievement. Sixty female undergraduate education majors (30 African American; 30 Caucasian) used a semantic differential scale to rate slides of preteen African American and Caucasian males, with and without hearing aids. The results of this study showed that female African American and Caucasian judges rated males of their respective races differently. The hearing aid effect was predominant among the Caucasian judges across the dimensions of appearance, personality, assertiveness, and achievement. In contrast, the African American judges only exhibited a hearing aid effect on the appearance dimension. PMID- 27764279 TI - The Effectiveness of Audiologists' Information Sources for Classroom Teachers. AB - This study investigated how well 273 teachers in Georgia understood the needs of mainstreamed children who were hard of hearing who were in their classrooms. A survey was sent to 273 teachers of students with hearing loss who were not receiving special education services. The survey sought information regarding the teachers' awareness of their students' hearing loss and what they knew about the loss. Teachers were also asked how they received information about the hearing loss and how they preferred to receive it. Deficiencies were found in the teachers' level of awareness and knowledge regarding their students' hearing loss across all grade levels. Teachers generally preferred the information sources with which they were most familiar. Recommendations are offered to improve communication with classroom teachers regarding students' hearing loss. PMID- 27764280 TI - Withdrawn and Sociable Behavior of Children With Language Impairment. AB - This study examined the dimensions of withdrawal and sociability in children with language impairment (LI) and their typically developing chronological age-matched peers. Classroom teachers rated the withdrawn and sociable behaviors of 41 children with LI and 41 typically developing peers using the Teacher Behavioral Rating Scale (TBRS, Hart & Robinson, 1996). Children were sampled from the age ranges of 5 to 8 years and 10 to 13 years. Subtypes of both withdrawn (solitary passive withdrawal, solitary-active withdrawal, reticence) and sociable (impulse control/likability, prosocial) behavior were examined. Teachers rated children with LI as displaying higher levels of reticent behavior than typically developing children. Teachers also rated boys with LI as displaying significantly higher levels of solitary-active withdrawal than girls with LI or typically developing children of either gender. The groups did not differ on solitary passive withdrawal, although boys were rated higher than girls. In the dimension of sociable behavior, children with LI were rated significantly below typical peers on subtypes of impulse control/likability and prosocial behavior. The relationship between language impairment and withdrawn and sociable behavior is complex. Although language impairment is an important factor in social difficulty, the current results suggest that language impairment is not the sole factor leading to social problems in children with LI. Assessment and intervention procedures for children with language and social problems should take the complex nature of this relationship into account. PMID- 27764281 TI - The Diagnostic Accuracy of Four Vocabulary Tests Administered to Preschool-Age Children. AB - This study examined the empirical evidence for using four vocabulary tests (Peabody Picture Vocabulary Test-III [Dunn & Dunn, 1997], Receptive One-Word Vocabulary Test [Gardner, 1985], Expressive Vocabulary Test [Williams, 1997], Expressive One-Word Vocabulary Test-Revised [Gardner, 1990]) to screen or identify specific language impairment (SLI) in preschool-age children. Tests were administered to 31 4- and 5-year-old children with SLI and 31 age-matched controls with normal language (NL). All children spoke General American English. Despite moderate to strong inter-test correlations, no test was a strong identifier of SLI. The group with SLI scored lower than the NL group on each test; however, the individual scores of children with SLI typically fell within the normal range. Vocabulary tests are frequently administered to determine whether a child's language skills require further evaluation (screening), as a method of identifying SLI in children, or simply to describe aspects of language functioning. These purposes for administering a vocabulary test require various forms of empirical evidence in support of their use. Our data support construct validity for the four vocabulary tests examined, but do not support their use for identification purposes. Clinicians must apply a degree of sophistication in evaluating the evidence presented for test validity relative to the purposes for which the test will be administered. Unfortunately, although many test manuals offer inter-test correlations or statistically significant group differences as evidence of construct validity, they often omit data that would support common clinical uses, such as screening or identification. PMID- 27764282 TI - Oral Language Development in a Child With Floating-Harbor Syndrome. AB - This clinical exchange presents a 3-year case study of oral language skill development in a child with Floating-Harbor syndrome (FHS). FHS is a rare condition that is characterized by short stature, expressive language delay, and triangular facies. Oral language skills were developed in the context of a naturalistic language intervention approach, within an early childhood schoolbased program. Initial presenting speech and language characteristics, as well as long-term needs, are discussed. PMID- 27764283 TI - Listen and Learn? A Software Review of Earobics(r). AB - The evaluation of software in the treatment of a language-learning disability requires analysis of both the technical and conceptual aspects of software development. The Earobics(r) program is reviewed with this dual purpose. The Earobics(r) program, as reported by the publisher, is an auditory development and phonics software program that is designed to provide auditory processing and phonemic awareness training. Considered first are the technical aspects of the program, including the program description, hardware requirements, and user friendliness. Next, the conceptual framework motivating the software development is assessed through an analysis of the six games that make up the program. These six games appear to be premised on a combination of auditory processing and phonological awareness principles, which are not necessarily compatible. Finally, the strengths and limitations of the program are examined for the developmental sequence presented in its games and utility of the game sequence in the reading acquisition process. PMID- 27764284 TI - A Format for Identifying Interactions Among Measures of Communication Skills: A Case Study. AB - A format for longitudinally tracking interactions among measures representing different domains of communication was developed in response to calls for integrative approaches to language assessment. This longitudinal case study examined measures of segmental phonology, nonsegmental phonology, and syntax/ morphology in a child with language impairment in order to illustrate the effectiveness of this format in identifying interactions. The format detected trade-offs and co-occurrences, which changed during the 6 1/2 yearsof study. The results support Crystal's (1987) "bucket" theory of language and the value of integrative approaches to assessment. PMID- 27764285 TI - Unilateral Hearing Loss in Children: An Update for the 1990s. AB - In the 1980s, two studies found that children with unilateral hearing impairment were 10 times more likely to repeat a grade compared to the general school-age population. Since the publication of those reports, grade retention has been found to be an ineffective strategy for achieving long-term academic success, and is no longer widely recommended. This survey describeshow children with unilateral hearing loss are presently supported given this change in educational practices. Reports on 406 children indicated that 54% received individualized special education services, in addition to some level of audiologic support, and that 24% were functioning below average relative to their peers. Other information regarding demographics, use of amplification, and additional educational concerns are also reported. PMID- 27764286 TI - From the Editor... PMID- 27764287 TI - Importance of Selected Communication Skills for Talking With Peers and Teachers: Adolescents' Opinions. AB - This research explored normally achieving 10th-grade adolescents' opinions concerning the relative importance of 14 communication skills for their own communication when talking with their teachers and when talking with their peers. It also investigated if the adolescents' gender influenced their opinions. Results indicated that the adolescents tended to perceive skillsassociated with characteristics of empathy and considered to be addressee-focused as relatively more important for their communication with their peers. When the adolescents considered their communication with teachers, communication skills related to discoursemanagement strategies assumed relatively more importance. Although gender appeared to influence the types of communication skills considered to be more important than others, gender-based differences in the relative importance of the communication skills were less apparent when gender and communication partnerdifferences were considered together. Future research directions and clinical implications are discussed. PMID- 27764288 TI - Dimensions of Multiskilling: Considerations for Educational Audiology. AB - Educational audiologists often must delegate certain tasks to other educational personnel who function as support personnel and need training in order to perform assigned tasks. Support personnel are people who, after appropriate training, perform tasks that are prescribed, directed, and supervised by a professional such as a certified and licensed audiologist. The training of support personnel to perform tasks that are typically performed by those in other disciplines is calledmultiskilling. This article discusses multiskilling and the use of support personnel in educational audiology in reference to the following principles: guidelines, models of multiskilling, components of successful multiskilling, and "dos and don'ts" for multiskilling. These principles are illustrated through the use of multiskilling in the establishment of a hearing aid monitoring program. Successful multiskilling and the use of support personnel by educational audiologists can improve service delivery to school-age children with hearing loss. PMID- 27764289 TI - Phonological Awareness and Production: Changes During Intervention. AB - Changes in feature awareness and production during phonological intervention were examined separatelyin four preschool-aged children with severe phonological impairment. Each received intervention that incorporated attention to the features of three error patterns and provided opportunities to practice productions for those patterns. Awareness skills and productionperformance were assessed repeatedly in the context of a multiple-probe design. Relationships between the two variables were then observed. Results indicated that the rate and degree of change in awareness did not always parallel production performance. The findings suggest that both feature awareness and production should be considered when planning intervention. PMID- 27764290 TI - The Influence of Language/Cognitive Profile on Discourse Intervention Outcome. AB - Children with communication needs are often allocated intervention services as a result of the relationship between their cognitive ability and language performance. Children with higher cognitive skills relative to language skills are considered promising candidates for language services. In contrast, children who are delayed in both cognitive and language abilities are considered poor candidates for intervention and are often excluded from services, or given a lower priority for services. This study examines the effects of intervention on one aspect of pragmatic development (discourse skills) following intervention for two groups of young children with delayed language development: one group with measured cognitive performance above language performance, and the other group with similar delays in both language and cognitive performance. Repeated measures analyses of variance indicated significant differences between groups for two of 15 measures derived from language samples. Both favored the children with equivalent delays in language and cognition. These findings do not support the notion that children with equivalent delays in cognition and language development are poor candidates for language intervention. Service delivery and policy implications are discussed. PMID- 27764291 TI - Computer-Based Language Assessment Software: The Effects of Presentation and Response Format. AB - Nonstandard presentation and response formats are often employed by speech language pathologists when clients are unable to perform the pointing response required of many standardized tests. However, any adaptation to test administration potentially compromises the norming standards of that test. The present study investigated the effects of computerized presentation of the Peabody Picture Vocabulary Test-Revised (PPVT-R, Dunn & Dunn, 1981) Form M, using two computer-based response formats. Seventy-two normally developing children between the ages of 4:0 (years:months) and 8:11 participated in this study. Subjects were randomly assigned to one of three response conditions: (1) standard presentation -direct pointing, (2) computer presentation-trackball, and (3) computer presentation-automated scanning. Statistical analyses revealed that there were no differences in performance across the response conditions, which is consistent with the hypothesis that computerized testforms are equivalent to standard forms. Age was strongly related to increased accuracy regardless of condition. Thus, the adapted response formats of the computerized version constitute statistically equivalent forms of the PPVT-R and can be used with the published norms for this test. PMID- 27764292 TI - Performances of At-Risk, African American Preschoolers on the Peabody Picture Vocabulary Test-III. AB - This study examined the performance of 59 at-risk, African American preschoolers on the Peabody Picture Vocabulary Test-III (PPVT-III, Dunn & Dunn, 1997). The subjects were considered at-risk based on low-income status and/or social status variables such as family density and teenage parents. A mean standard score of 91 and a standard deviation of 11 were achieved by these children. Although these scores are below those reported for the PPVT-III standardization sample, the performance spread resulted in a normal distribution of scores. Differences in performance based on gender and income were not apparent, but level of education of the primary caregiver significantly influenced performance. The findings indicate that unlike the Peabody Picture Vocabulary Test-Revised (PPVT-R, Dunn & Dunn, 1981) the PPVT-III is a culturally fair instrument that is appropriate for use with this population. PMID- 27764293 TI - Classroom-Based Assessment of a Collaborative Intervention Program With Kindergarten and First-Grade Students. AB - The Maximizing Academic Growth by Improving Communication (MAGIC) comprehensive classroom teacher and speech-language pathologist collaborative intervention program was developed and initially implemented in 12 kindergarten and first grade classes to determine whether children receiving this language-enriched program performed significantly better than control peers on a curriculum-based test and on teacher reports of classroom communication. Results indicated that weekly classroom intervention resulted in significantly higher scores on the subtests of listening and writing for the children involved in the MAGIC program. Students in the treatment groups demonstrated significantly higher abilities in understanding vocabulary and cognitive-linguistic concepts in addition to increased writing skill development for producing relevant sentences with correct mechanics and spelling. PMID- 27764294 TI - To Use or Not to Use: Factors That Influence the Selection of New Treatment Approaches. AB - Clinicians are often faced with decisions concerning whether to use a new or different treatment approach. What factors influence these decisions? Are clinicians more influenced by treatment efficacy studies or their own theoretical biases? What role do parents and families play in influencing these decisions? Why are scientists so skeptical of new treatment approaches? When should a clinician try out a new or different treatment approach? Should clinicians be trusted to use the best treatment approaches? These are the central questions addressed in this article. PMID- 27764295 TI - Checks and Balances: Keeping the Science in Our Profession. AB - Kamhi (1999) suggests that clinicians may choose to use an intervention approach "because it works" rather than relying on their theory of language learning. This suggestion spawned a number of concerns, including who the scientists in our field are, whether our professional definition of language is used in our language theories and intervention approaches, and what we say the "best" intervention is. In this article, these issues are discussed as discrepancies, along with some suggestions for addressing these gaps, in order to integrate science into all of our professional endeavors. PMID- 27764296 TI - The Relationship Between Multiple Birth Children's Early Phonological Skills and Later Literacy. AB - Previous studies have shown that multiple birth children (MBC) are prone to early phonological difficulties and later literacy problems. However, to date, there has been no systematic long-term follow-up of MBC with phonological difficulties in the preschool years to determine whether these difficulties predict later literacy problems. In this study, 20 MBC whose early speech and language skills had been previously documented were compared to normative data and 20 singleton controls on tasks assessing phonological processing and literacy. The major findings indicated that MBC performed significantly more poorly on some tasks of phonological processing than singleton controls did. Further, the early phonological skills of MBC (i.e., the number of inappropriate phonological processes used) were correlated with poor performance on visual rhyme recognition, word repetition, and phoneme detection tasks 5 years later. There was no significant relationship between early biological factors (birth weight and gestation period) and performance on the phonological processing and literacy related subtests. These results support the hypothesis that MBC's early speech and language difficulties are not merely a transient phase of development, but a real disorder, with consequences for later academic achievement. PMID- 27764297 TI - Parents Working With Speech-Language Pathologists to Foster Partnerships in Education. AB - This article outlines a parent involvement program that was developed and implemented by speech-language pathologists as part of a comprehensive program to improve academic achievement and literacy by focusing on communication skills. The basis of the program was to help parents become active participants in their child's educational and learning experiences. The organization and content of the parent program are explained and information needed to replicate the program is provided. Results of descriptive evaluations of the sessions and feedback from school personnel indicate a need for continued parent-focused educational programs. PMID- 27764298 TI - Guidelines for Using Portfolios in Assessment and Evaluation. AB - In selecting assessment tools and procedures, school-based speech-language pathologists are frequently faced with the dilemma of meeting stringent district, state, and federal regulations while trying to evaluate the language and communication of learners in ways that are holistic and educationally relevant. The purpose of this article is to provide guidelines for the use of portfolios for conducting various types of speech-language evaluations and assessments in school settings. Emphasis will be placed on the use of portfolios as a tool for functional assessment. PMID- 27764299 TI - Trying to Make Sense of Developmental Language Disorders. AB - In this article, I share my thoughts concerning what children with developmental language disorders should be called, how they should be defined, and how we might differentiate children with specific language impairment (SLI) from other children with developmental language disorders. Among other things, I attempt to show why a lack of congruence between clinical and research constructs should be expected. Researchers and clinicians use different identification criterion and procedures because clinical and educational objectives are different from research objectives. While recognizing these differences, I suggest several possible ways to differentiate a subgroup of children with SLI from the general population of children with developmental language disorders without using nonverbal IQ. Even if researchers are able to identify this unique group of children, clinicians may never embrace the SLI construct. In the best of all possible worlds, clinicians would be familiar with how researchers define SLI and appreciate the value of research that attempts to identify distinct subgroups of children with developmental language disorders. Researchers, in this ideal world, would recognize and acknowledge the lack of congruence between the research populations of SLI and the larger clinical population of children with developmental language disorders. PMID- 27764300 TI - An Audiological Fear Reduction Program for a Child. AB - This article presents a program for reducing the fear of audiological procedures in a 6-year-old female student who is deaf. Developed by a school audiologist and the school counselor, this eight-session program involved several interventions. These included familiarizing the subject with the procedures and providing reassurance, hands-on activities, graded exposure to the procedures, peer modeling, and reinforcement for cooperation with the procedures. A significant reduction in anxiety and an increase in cooperation with audiological procedures at the school was noted. At 8-month follow-up, the client was cooperative when earmolds were made for her at the school. In addition, some generalization to another audiological setting was reported. PMID- 27764301 TI - Ears On, Voice On, Hands On-Right On! Workshop Activities. AB - Workshops are an opportunity to promote collaboration for the benefit of students. This clinical exchange describes five participatory workshop activities that may be used when offering a communication workshop. The activities include: second/foreign language simulation, speech reading, language/learning disabilities simulation, and one that's even butter. Together with other approaches, these activities can help ensure understanding, retention, and application of the ideas and information presented at workshops. PMID- 27764303 TI - From the Editor... PMID- 27764302 TI - Using Photography to Enhance Language and Learning: A Picture Can Encourage a Thousand Words. AB - Speech-language pathologists often face the challenge of engaging children with language and learning disabilities in active conversation that allows opportunities to develop more elaborate linguistic and discourse abilities. School-based speech-language pathologists often search for tools that will aid them in creating meaningful and effective techniques in their work with an emphasis on: developing therapy plans that reflect more natural language environments; collaboration with classroom teachers on curriculum and communication skills objectives; and involvement of parents in the treatment program. PMID- 27764304 TI - An Introduction to Assessment and Intervention With Older Students With Language Learning Impairments: Bridges From Research to Clinical Practice. PMID- 27764305 TI - Second Chances: Improving Decoding Skills in the Older Student. AB - The case of a 29-year-old university student is used to discuss impairments in decoding skills in older students. Factors are reviewed that contribute to decoding unfamiliar words, such as phonological awareness skills, quality of visual orthographic images, type of decoding strategy used, and morphological awareness skills. The assessment and intervention procedures used with this student highlight the application of current literature when developing assessment and intervention programs for students from middle school and high school to the university level. Additionally, the need is emphasized to recognize and work with the special emotional needs of older students with reading impairments. PMID- 27764306 TI - Learning to Spell: Implications for Assessment and Intervention. AB - Background information regarding spelling development and factors that influence spelling performance are presented. The use of this information in assessment and intervention activities with a student who had deficits in spelling is illustrated. After 6 weeks of treatment, the student showed improvements in both formal and informal measures of spelling performance. Implications for optimal assessment and intervention methods, as well as directions for future research, are discussed. PMID- 27764307 TI - Assessment and Intervention in Overcoming Writing Difficulties: An Illustration From the Self-Regulated Strategy Development Model. AB - The progress of a 12-year-old boy with learning disabilities and severe writing difficulties is followed from initial assessment through instruction in strategies for planning, revising, and managing the composing process. A validated instructional model, Self-Regulated Strategy Development (SRSD), was used to teach these processes. With SRSD, writing strategies are explicitly taught in combination with procedures for regulating the use of these strategies, the writing process, and any undesirable behaviors that may impede performance. Recommendations are offered to speech-language pathologists for applying the SRSD model to children experiencing writing difficulties. PMID- 27764308 TI - What Are Executive Functions and Self-Regulation and What Do They Have to Do With Language-Learning Disorders? AB - In this article, executive functions and selfregulation are defined and the reciprocal influence of these factors on the performance of students with language-learning disorders (LLD) is explored. A case study demonstrates the integration of executive functions, self-regulation, and language processes within speech and language assessment and intervention. Clinicians are urged to consider the interactive effects of executive function, self-regulatory, and language processes when addressing the needs of students with LLD. PMID- 27764309 TI - When "Emily Dickinson" Met "Steven Spielberg": Assessing Social Information Processing in Literacy Contexts. AB - Current research and theory on social information processing is used to frame the peer interactions of "Emily Dickinson," a 16-year-old girl with a long history of oral language problems and social isolation, but strong interests in literacy. In ongoing assessment that prioritized authentic and ecologically valid data collected in classroom settings, the Crick and Dodge (1994) model was used to guide an analysis of Emily's social-cognitive abilities and disabilities during peer interaction. These observations revealed that Emily had evolved a social schema that strategically recruited her strong literacy interests and skills to initiate and mediate social interaction with peers. This suggests that literacy curricula may be a valuable site for assessing and scaffolding social/communication problem-solving in students with language disabilities. PMID- 27764310 TI - Mediating Literacy Skills in Spanish-Speaking Children With Special Needs. AB - The purpose of this article is to: (a) describe sources of variability in reading and spelling performance of children learning English as a second language, with a specific emphasis on Spanish-speaking children; (b) encourage teachers and clinicians to consider these differences when developing intervention plans; and (c) suggest specific intervention procedures that might facilitate development of reading and spelling skills of Spanish-speaking children with language difficulties and limited English proficiency. An integrated approach to intervention is highlighted that addresses reading and spelling as reciprocal processes. Implementation of this approach is presented using various contexts for learning and strategies specific to developing second-language reading and writing skills. PMID- 27764311 TI - Moving Ahead. PMID- 27764312 TI - Altered Auditory Input and Language Webs to Improve Language Processing Skills. AB - A method of altering auditory input and a structured set of listening tasks are described. The parameters of rate, prosody, and pattern of pausing are modified in the Altered Auditory Input (AAI) technique to make language input easier for the child with language delays to process. This technique is used during play activities, reading to the child, language activities, faceto-face conversation, and structured listening tasks called Language Webs. The Language Webs are a set of highly redundant, hierarchical picture identification listening tasks. The goal of these approaches is to improve language processing in children with language difficulties so that they can both access their current language knowledge and learn new language. PMID- 27764313 TI - Comments on "To Use or Not to Use Factors that Influence the Selection of New Treatment Approaches" by Kamhi (1999). PMID- 27764315 TI - From the Editor... PMID- 27764314 TI - To Use or Not to Use: Factors that Influence the Selection of New Treatment Approaches: Response to Leonard (1999). PMID- 27764316 TI - Prologue: What Child Language Research May Contribute to the Understanding and Treatment of Stuttering. PMID- 27764317 TI - Epilogue: What Child Language Research May Contribute to the Understanding and Treatment of Stuttering. PMID- 27764318 TI - From the Editor... PMID- 27764319 TI - Prologue: Autism Spectrum Disorder: The Context of Speech-Language Pathologist Intervention. AB - As the need for services for children with autism and related disorders has increased, so has the need for information about communication assessment and intervention for these children. Each of the articles in this forum considers essential knowledge for meeting the social, behavioral, and communication challenges presented by this population, as well as considerations for the individual variation noted within this population. It is hoped that the knowledge contained in this forum will provide interdisciplinary insight into the challenges of autism and related disorders and a research-based framework for making assessment and intervention decisions. PMID- 27764320 TI - Early Identification of and Intervention for Infants and Toddlers Who Are at Risk for Autism Spectrum Disorder. AB - Providing intensive early intervention is critical to maximizing outcomes for children with autism spectrum disorder (ASD), and evidence suggests that the earlier intervention can begin, the better the outcome. The first purpose of this article is to review the earliest indicators of ASD in very young children-social and communication impairments-which have important implications for early identification. The second purpose is to review evidence-based intervention practices for children with ASD and to develop a set of guiding principles for providing intervention for infants and toddlers who are at risk for ASD. Issues that are delineated include providing intervention in natural environments, supporting families in early intervention, and embedding intervention in daily routines. PMID- 27764321 TI - Interdisciplinary Assessment of Young Children With Autism Spectrum Disorder. AB - This paper describes an interdisciplinary model for the assessment of children with autism spectrum disorder (ASD) that includes families as active participants and collaborators in the process. Family-centered care, cultural competence, and a strengths perspective provide the theoretical foundation for the assessment model. Steps in the assessment process include assignment of an assessment coordinator, intake, preassessment planning, community-based assessment, postassessment planning, report writing, community follow-up, and resource notebook development. Preliminary research examining the effectiveness of the assessment model reveals the positive impact of family-centered, culturally competent, and strengths-based service provision (Beatson & Prelock, 2002). The model has implications for school-based practitioners in increasing the role of families in the assessment of children with ASD. PMID- 27764322 TI - Toward Functional Augmentative and Alternative Communication for Students With Autism: Manual Signs, Graphic Symbols, and Voice Output Communication Aids. AB - Many individuals with autism are candidates for augmentative and alternative communication (AAC) systems, either to supplement (i.e., augment) their existing speech or to act as their primary (i.e., alternative) method of expressive communication. The purpose of this article is to summarize research and directions for future research with regard to two questions related to the delivery of AAC supports to these individuals: (a) What AAC modality is preferable to use? and (b) What do we know about the use of voice output communication aids with people with autism? PMID- 27764323 TI - Understanding and Intervening With the Challenging Behavior of Young Children With Autism Spectrum Disorder. AB - Young children with autism and behavioral challenges are at great risk for lives that are characterized by social isolation and segregated placements. These restrictive placements often occur when the child's challenging behavior interferes with successful adaptation in educational, therapeutic, and community environments. In this article, positive behavior support is described as a process that may be used to understand and intervene effectively with the challenging behavior of young children with autism. The article describes the history, empirical support, and implementation steps of positive behavior support. A case study is provided to illustrate successful application of the process. PMID- 27764324 TI - Priming as a Method of Coordinating Educational Services for Students With Autism. AB - PURPOSE: The importance of coordination of educational services has been well documented in the literature. For students with disabilities, coordinated programs result in more rapid acquisition of targeted behaviors and the increased likelihood of long-term maintenance of gains. The purpose of this study was to assess whether "priming" or exposing students with autism and disruptive behaviors to school assignments before their presentation in class would affect academic performance and problem behaviors. METHOD: Two students diagnosed with autism who attended general education classrooms, both of whom exhibited numerous disruptive behaviors and low academic performance, participated in this study. A repeated reversals design was used to monitor student progress. RESULTS: The results demonstrated decreases in problem behavior and increases in academic responding when priming sessions occurred. CLINICAL IMPLICATIONS: Application is discussed in terms of a mechanism for speech-language pathologists to assist classroom teachers with a systematic educational coordination plan that can quickly produce improved school performance. PMID- 27764326 TI - Epilogue: Autism Spectrum Disorder: The Context of Speech-Language Pathologist Intervention. PMID- 27764325 TI - A New Look at Performance on Theory-of-Mind Tasks by Adolescents With Autism Spectrum Disorder. AB - PURPOSE: A hallmark of autistic spectrum disorder (ASD) is disruption in theory of-mind development, including the understanding of false beliefs. Previous studies have typically assessed the development of first- and second-order false belief concepts in ASD, with tasks primarily emphasizing physical causality and logical inferencing. The present study investigated how preadolescents and adolescents with ASD performed on false belief tasks that included social inferencing of psychological states as well as logical inferencing of physical states. METHOD: Two categories of tasks were administered: four traditional logical inferencing tasks and four social inferencing tasks specifically developed for this study. In addition, a prompt hierarchy was included to ascertain if performance on both task types improved. Participants were 45 children and adolescents primarily selected from three urban school districts: 15 adolescents with a previous diagnosis of ASD (ASD group); 15 typically developing children matched for age, gender, and ethnicity (CA group); and 15 typically developing children matched for language age, gender, and ethnicity (LA group). RESULTS: Three findings were pertinent. First, the CA group performed at higher levels than did the LA group and the ASD group on both task sets. Second, although the CA and the LA groups performed equally well on both the logical and the social inferencing tasks, the ASD group performed better on the social inferencing tasks. Finally, the prompt hierarchy significantly improved overall task performance for the ASD and LA groups. CLINICAL IMPLICATIONS: These findings indicate that task type, variations in vocabulary ability, and the provision of support influenced performance on the false belief tasks. PMID- 27764327 TI - Working With Educational Interpreters. AB - Increasing numbers of students who are deaf or hard of hearing are being educated in their local schools. Accommodations frequently made for these students include the provision of educational interpreting services. Educational interpreters serve to equalize the source language or source communication mode (usually spoken English) with a target language or target mode (either sign language, cued speech, or oral transliterating). Educational interpreters' expertise in sign language or cued speech will likely exceed that of speech-language pathologists, whose expertise in speech and language development and in discourse demands of the classroom will likely exceed that of the educational interpreters. This article addresses the mutual needs of speech-language pathologists and educational interpreters in providing services to their students. Guidelines supported by recent research reports and survey data collected from interpreters are offered to speech-language pathologists as ways to improve the working relationships with educational interpreters in three areas: (a) evaluating a student's communication skills, (b) establishing treatment goals and intervening to meet those goals, and PMID- 27764328 TI - Prologue: Identification and Management of Dysphagia in the Public Schools. PMID- 27764329 TI - Evaluation of Children With Feeding and Swallowing Problems. AB - Speech-language pathologists in schools are increasingly being presented with children who have feeding and swallowing problems. These speech-language pathologists are in strategic positions to identify the problems, carry out an evaluation of feeding and swallowing skills, and determine the needs for medical team referral. Evaluation of children with feeding and swallowing problems is best carried out by speech-language pathologists in the context of a school-based team with links to a medically based team. This article focuses on guidelines for obtaining a history, carrying out a physical examination, and observing a typical meal. Team members in school settings make important contributions to considerations for instrumental assessments that are needed when making management decisions for children with suspected pharyngeal phase deficits. PMID- 27764330 TI - From the Editor... PMID- 27764331 TI - Family-Responsive Individualized Family Service Plans for Speech-Language Pathologists. AB - Speech-language pathologists are the most frequent providers of services to infants and toddlers who have disabilities and their families. Because of this role, they are often involved with the family in the development of the individualized family service plan (IFSP). The Division for Early Childhood of the Council for Exceptional Children has developed a set of recommended practices for the development of the IFSP that reflects family-centered practices. This article describes those recommended practices and provides a summary of recent research examining their use in Kansas as an example of how they can be used as a component of program review. The authors also provide suggestions of how speech language pathologists can apply recommended practices in developing family centered IFSPs for young children with speech and/or language disabilities. PMID- 27764332 TI - The Role of the School-Based Speech-Language Pathologist Serving Preschool Children With Dysphagia: A Personal Perspective. AB - Increasing numbers of medically complex children are being referred to preschool programs managed by the public school systems. Public school speech-language pathologists have the responsibility of evaluation and intervention in the area of dysphagia. Although the American Speech-Language-Hearing Association's Scope of Practice includes dysphagia, there is some controversy about whether this more traditional medical intervention belongs in the educational model. In the educational setting, information and techniques must be accurately and safely transmitted to the entire team working with the child. Ongoing communication between the medical community and the school staff is crucial. The increased responsibility of the speechlanguage pathologist brings with it a variety of concerns. These include safety, mandatory cardiopulmonary resuscitation training, awareness of dangerous mealtime practices, specific education in pediatric dysphagia intervention, liability, and financial support. PMID- 27764333 TI - Therapy for Children With Swallowing Disorders in the Educational Setting. AB - Many children of all ages with swallowing disorders now receive at least part of their swallowing therapy in the public schools. This article presents the various types of swallowing therapy available, including postural changes, sensory enhancements, changes in feeding processes, and exercise programs. Other therapy issues discussed include the relationship of the feeding process to swallowing therapy, the schedule of therapy, and maintenance programs as compared to therapy. Clinicians are also provided with a number of references for additional reading on therapy procedures. PMID- 27764334 TI - Legal, Ethical, and Financial Aspects of Providing Services to Children With Swallowing Disorders in the Public Schools. AB - The public schools must follow laws that deal with services for children who meet the legal requirements for having a disability. Children who have swallowing disorders that require the services of a speech-language pathologist typically meet the definition of a child with a disability. This article addresses the importance of the speech-language pathologist being aware of legal requirements for the provision of services as well as liability, ethical, and risk management issues related to the provision of such services. Financial considerations relating to service provision are also described. PMID- 27764335 TI - Development of an Interdisciplinary Dysphagia Team in the Public Schools. AB - This article describes the development of a school-based dysphagia team (swallowing action team [SWAT]) within the St. Tammany Parish School System located in Covington, Louisiana. The team's vision was to ensure safe nutrition and hydration for students at risk for swallowing dysfunction during school hours. This article addresses how the team was initially formed, the process of identifying students who were exhibiting a swallowing disorder, steps taken for staff development, and problems encountered in seeking administrative approval. The current status of the dysphagia program, as well as future plans for further implementation, are also presented. PMID- 27764336 TI - Serving Students With Dysphagia in the Schools? Educational Preparation Is Essential! AB - Speech-language pathologists employed in public schools are increasingly being faced with serving students with dysphagia because schools are serving students who may have previously been served in health care or institutional facilities. Students with significant health problems, severe disabilities, or orthopedic impairments may require the services of a school team-a team that may not include any person with adequate training in swallowing evaluation and treatment. Speechlanguage pathologists should not provide services to students with dysphagia without pursuing continuing education to acquire the necessary knowledge and skills. To do so would compromise the speech-language pathologist's ethical standards, jeopardize the student's health, and create undue liability for the school division. PMID- 27764337 TI - Epilogue: Identification and Management of Dysphagia in the Public Schools. PMID- 27764339 TI - From the Editor... PMID- 27764338 TI - Language Sample Analysis in Spanish-Speaking Children: Methodological Considerations. AB - The purposes of this article are (a) to discuss issues related to the selection and development of language assessment procedures for children who speak Spanish and English based on spontaneous language samples and (b) to show how available procedures can be applied to research and clinical aims with these children. Sociolinguistic influences in the language performance of Spanish-speaking children, including patterns of language shift, differences in the amount of exposure to each of a bilingual's languages, and contextual effects of different language-learning environments, are discussed. Methodological issues and effects of codeswitching and dialect are examined concerning use of the Developmental Assessment of Spanish Grammar (DASG), mean length of response in words (MLR-w), mean length of terminable unit (MLTU), and mean length of utterance in morphemes (MLU-m). Measures of Spanish grammar with diagnostic potential are proposed. Clinical suggestions for the language assessment of Spanish-speaking children with different levels of English proficiency and research implications are discussed. PMID- 27764340 TI - Teaching the Conditional Use of Communicative Requests to Two School-Age Children With Severe Developmental Disabilities. AB - PURPOSE: Two boys with severe developmental disabilities were taught to conditionally use requests to obtain desired snack items. METHOD: When items were in the possession of another person (teacher, peer) or proximally distant, learners were taught to emit communicative requests. When items were proximally near, learners engaged in a self-selecting response. RESULTS: Results suggest that the conditional discriminations were established quickly. Both learners generalized their conditional discriminations to other contexts within the classroom. CLINICAL IMPLICATIONS: This study demonstrates the importance of attending to conditional discriminations when teaching communication requests. PMID- 27764341 TI - Prologue: Evaluating Language Intervention Approaches: Contrasting Perspectives. PMID- 27764342 TI - Clinical Issues in Central Auditory Processing Disorders. AB - Speech-language pathologists are often faced with the need to assess and treat the suspected auditory processing problems of children with language and learning difficulties. This article discusses central auditory processing disorders (CAPDs). Included are a discussion of background information, a current definition of CAPDs, a general discussion of test battery approaches following suggestions made by the American Speech-Language- Hearing Association (ASHA) Task Force on Central Auditory Processing Consensus Development (1996), and various approaches to intervention with persons identified as having a CAPD. Finally, there is brief discussion of remaining questions to be answered. The article attempts to examine various controversies related to all aspects of CAPDs and increase the reader's awareness of current issues concerning this disorder. PMID- 27764343 TI - Clinical Decision-Making in the Assessment and Intervention of Central Auditory Processing Disorders. AB - Central auditory processing disorders (CAPDs) are fraught with problems arising from confusion concerning the clinical evidence of the disorder. A major controversy revolves around characterizing the disorder as a unique cluster of behaviors reflecting impairment in some underlying mechanism(s) or as a disorder defined on the basis of performance on a set of tests. This article reviews some recent developments in auditory processing research and considers the role of the speech-language pathologist in evaluating and treating children with suspected auditory processing problems. Particular attention is given to clinical criteria, including characteristics of the population, assessment, and intervention considerations. Areas for clinical caution are highlighted. PMID- 27764344 TI - Targeting Temporal Processing Deficits Through Fast ForWord(r): Language Therapy With a New Twist. AB - In the past 3 years, new computer-based language intervention models have been introduced into the communication sciences arena. The most prominent of these, the FastForWord(r) program (Scientific Learning Corporation, 1998), is an outgrowth of research that characterizes the relationship between language learning impairment and temporal processing abilities. This article highlights the research history leading up to this innovation, describes the therapeutic protocol and client selection processes, discusses the pros and cons of clinical applications, and suggests future research directions relative to this new brand of language therapy. PMID- 27764345 TI - Computer-Assisted Language Intervention Using Fast ForWord(r): Theoretical and Empirical Considerations for Clinical Decision-Making. AB - A computer-assisted language intervention program called Fast ForWord(r) (Scientific Learning Corporation, 1998) has received a great deal of attention at professional meetings and in the popular media. Newspaper and magazine articles about this program contain statements like, "On average, after only 6 to 7 weeks of training, language-learning impaired children ages 4 to 12 showed improvement of more than one and a half years in speech processing and language ability." (Scientific Learning Corporation, 1997). Are the claims that are being made about this intervention approach just a matter of product promotion, or is this really a scientifically proven remedy for language-learning impairments? This article critiques the theoretical basis of Fast ForWord(r), the documented treatment outcomes, and the clinical methods associated with the procedure. Fifteen cautionary statements are provided that clinicians may want to consider before they recommend Fast ForWord(r) intervention for the children they serve. PMID- 27764346 TI - Auditory Integration Training: One Clinician's View. AB - Auditory integration training (AIT) is a developing treatment for auditory disorders that include sensitivity to sound, auditory attention problems, and auditory processing disorders. Although there is limited published research, a growing body of anecdotal and clinical data is being reported at professional meetings. This article discusses some of the issues related to AIT and presents preliminary data indicating that word recognition scores in the presence of competing noise improves for children with a variety of disorders who have been treated with AIT. PMID- 27764347 TI - Auditory Integration Training: The Magical Mystery Cure. AB - Since its introduction in this country at the beginning of the decade, auditory integration training (AIT) has generated enthusiasm in parents and some clinicians, and harsh criticism by others. AIT has been promoted as a non invasive treatment for auditory disorders that are believed to lead to attention and behavior problems. It has been particularly popular as a treatment for autism. Although parents cite numerous anecdotal reports of treatment success, many professionals frown on AIT's widespread practice prior to undergoing scientific scrutiny. The reasons for cautious evaluation of AIT prior to implementation in clinical practice are reviewed, along with a brief summary of current research findings. PMID- 27764348 TI - Issues and Applications of Sensory Integration Theory and Treatment With Children With Language Disorders. AB - Sensory integration (SI) intervention is used with children with a wide range of learning and developmental challenges. Research both supports and questions the constructs of SI and the efficacy of SI intervention. Therefore, the purpose of this article is to facilitate an understanding of SI theory and intervention; delineate strategies that can enhance language, learning, and academic success for students; and provide suggestions for ways to contribute to our knowledge through further research in school settings. PMID- 27764349 TI - Is Sensory Integration Effective for Children With Language-Learning Disorders?: A Critical Review of the Evidence. AB - Sensory integration therapy has become widely accepted as an intervention for enhancing language-learning disorders and academic difficulties in hildren. However, much controversy surrounds this approach because of the small amount of empirical evidence to support its application to this clinical population. The purpose of this article is threefold: review the relevant research pertaining to treatment efficacy studies involving sensory integration conducted over the last three decades, discuss the perspectives from which various researchers and clinicians view language disorders in children, and discuss parameters for evaluating efficacy studies and the clinical use of sensory integration, suggesting directions for future research. PMID- 27764350 TI - Views of Facilitated Communication: What's the Point? AB - Facilitated communication (FC) has generated considerable debate, with the main concern being whether the facilitators (often speech-language pathologists) are physically influencing what is being expressed by the communicator. FC has placed speech-language pathologists in an ethical bind, having to weigh the risks of denying their client the right to effective and efficient communication against the risk of using an approach that has not held up under the rigors of controlled scientific studies. The dilemma is further complicated by the different ways FC has been described. Those who describe it in social participation terms are more positive concerning its potential than those who see it in terms of information processing. In this article, views of FC are outlined. A way out of the dilemma is suggested through the development of clinical practice guidelines. Such guidelines should include protections of both clients and clinicians and should be built on both social participation and information processing views of FC. PMID- 27764352 TI - Epilogue: Evaluating Language Intervention Approaches: Contrasting Perspectives. PMID- 27764351 TI - Look Who's Pointing Now: Cautions Related to the Clinical Use of Facilitated Communication. AB - This article focuses on three factors related to the use of facilitated communication (FC), all of which constitute possible reasons for caution by speech-language pathologists who are considering this technique for individuals with severe communication impairments. First, problems with the theoretical bases of FC are discussed, especially those attributing the success of this method to its ability to target individuals' underlying difficulties with apraxia, word finding, and social-emotional challenges. A case is made that there is insufficient evidence to support claims that FC overrides such problems. The notion of the method unlocking communication and related skills from otherwise competent individuals is also questioned. Next, the subject of candidacy is discussed. Special attention is called to the absence of criteria for initiating, maintaining, modifying, and terminating this approach. Finally, outcomes of the method are summarized. Discrepancies between qualitative and experimental investigations are summarized, along with some possible explanations for these differences. Suggested parameters for evaluating individuals' uses of FC are discussed, along with the continuing need for speech-language pathologists to make informed decisions concerning the role FC will play in their interventions with individuals who exhibit severe communication impairments. PMID- 27764353 TI - Narrative Discourse in Bilingual Children: Language and Task Effects. AB - PURPOSE: This study investigated the effect of language on Spanish-English bilingual children's production of narrative samples elicited in two ways. METHOD: Twelve bilingual (Spanish-English-speaking) children ranging in age from 4;0 (years;months) to 6;11 who were fluent speakers of English as a second language produced two narratives-one elicited by using a wordless picture book and another by using a static picture. The children produced stories for each task in each language, for a total of four stories. For the book task, the story complexities were compared across both languages. Stories were scored for complexity of story grammar and the inclusion of specific narrative elements. Both stories in each language were further analyzed for productivity (total words, number of C-units, and mean length of C-unit). The grammaticality (proportion of grammatically acceptable C-units) and the proportion of utterances influenced by the nontarget language was compared across each language and story task. RESULTS: Children produced narratives of equal complexity for the book task regardless of language. However, children used more attempts and initiating events in Spanish, while producing more consequences in English. The picture task yielded mixed results, and these were not compared quantitatively. There were differences in the two task conditions with respect to the children's use of Spanish influenced English and English-influenced Spanish. Although children were equally productive in both languages, they used proportionally more Spanish influenced utterances in the book task. CLINICAL IMPLICATIONS: The results demonstrate the importance of considering the test language when eliciting narratives from bilingual children and the type of the narrative task for eliciting a productive and complex narrative. PMID- 27764354 TI - Social Behaviors of Children With Language Impairment on the Playground: A Pilot Study. AB - PURPOSE: This pilot study examined the social behaviors of children with language impairment (LI) and their typical peers on the playground. METHOD: Eight children with LI and their age-matched peers were videotape recorded for 45 minutes during morning and lunch recesses. Samples were divided into 5-second segments and coded according to the child's behavior occurring during the segment. The behavior displayed during each interval was then coded into one of 37 subcategories. These subcategories were grouped into six general categories of (a) peer interaction, (b) adult interaction, (c) withdrawal, (d) aggression, (e) victimization, and (f) other. RESULTS: Significant differences were observed in the categories of peer interaction and withdrawal. Typical children spent significantly more time interacting with peers than did children with LI. Conversely, children with LI demonstrated significantly more withdrawn behaviors than did their typical peers. Analyses of effect size using omega2 indicated that group membership accounted for approximately 30% of the variability in both of these types of playground behavior. No other significant differences were observed. These findings support the conclusions of researchers using teacher interview procedures, indicating that children with LI are more withdrawn than their typical peers at school. CLINICAL IMPLICATIONS: Specific intervention targeting social language skills in playground contexts may be warranted to include children with LI in social interactions at recess. PMID- 27764356 TI - From the Editor... PMID- 27764355 TI - Literate Language Features in Spoken Narratives of Children With Typical Language and Children With Language Impairments. AB - PURPOSE: This study focused on literate language features in spoken narratives of school-age children with typical language development and school-age children with language impairments (LI). METHOD: The spoken narrative retellings from male and female children aged 7 to 10 years were analyzed. The samples yielded scores for the literate language features of conjunctions, elaborated noun phrases, mental and linguistic verbs, and adverbs. A general language performance measure (number of different words) also was studied. RESULTS: Group membership main effects were statistically significant for conjunctions and elaborated noun phrases, with effect sizes ranging from small to moderate. No statistically significant differences were obtained for age level or gender. Correlations between scores for number of different words and scores for the literate language features were low to moderate. CLINICAL IMPLICATIONS: The measures of conjunctions and elaborated noun phrases differentiated children with LI from those with typical language. When the number of different words was normalized for sample length, support for its use as a general language performance measure was not obtained. PMID- 27764357 TI - Concomitant Disorders in School-Age Children Who Stutter. AB - PURPOSE: The purposes of this survey study were to (a) determine the number of children who stutter with verified concomitant phonological and language disorders, (b) determine the number of children who stutter with suspected concomitant phonological and language disorders, and (c) determine the type of treatment clinicians use with these children. METHOD: A systematic sampling plan was used to obtain survey responses from 241 American Speech-Language-Hearing Association (ASHA)-certified, school-based speech-language pathologists from 10 states that were considered to have similar state verification criteria for fluency, articulation/phonology, and language disorders. Respondents were asked to provide information concerning verified and suspected concomitant disorders in children who stutter. They also were asked to select one of four types of intervention approaches suggested by Bernstein Ratner (1995) in treating concomitant disorders in stuttering (i.e., blended, cyclic, sequential, and concurrent). RESULTS: The speech-language pathologists reported on 467 children who stuttered. Of that total, 262 (56%) children had a fluency disorder only and 205 (44%) had a verified concomitant phonological and/or language disorder. A subgroup of children with verified fluency-only disorders were suspected of having a concomitant disorder. When treating a fluency and a concomitant phonological and/or language disorder, the majority of clinicians used a blended approach. CLINICAL IMPLICATIONS: Using similar state verification guidelines, this survey showed that a large percentage of preschool through high school students possessed a verified fluency disorder and a phonological and/or language disorder. Thus, clinicians need to be aware of the strong possibility that school age children who stutter might have a phonological disorder and/or a language disorder. Additionally, because the majority of respondents used a blended treatment approach when treating children with a fluency and a verified concomitant phonological and/or language disorder, it appears that many school based clinicians believe it is best to address both problems simultaneously. PMID- 27764358 TI - Grammatical Deviations in the Spoken and Written Language of Hebrew-Speaking Children With Hearing Impairments. AB - PURPOSE: The present study reports a detailed analysis of written and spoken language samples of Hebrew-speaking children aged 11-13 years who are deaf. It focuses on the description of various grammatical deviations in the two modalities. METHOD: Participants were 13 students with hearing impairments (HI) attending special classrooms integrated into two elementary schools in Tel Aviv, Israel, and 9 students with normal hearing (NH) in regular classes in these same schools. Spoken and written language samples were collected from all participants using the same five preplanned elicitation probes. RESULTS: Students with HI were found to display significantly more grammatical deviations than their NH peers in both their spoken and written language samples. Most importantly, between modality differences were noted. The participants with HI exhibited significantly more grammatical deviations in their written language samples than in their spoken samples. However, the distribution of grammatical deviations across categories was similar in the two modalities. The most common grammatical deviations in order of their frequency were failure to supply obligatory morphological markers, failure to mark grammatical agreement, and the omission of a major syntactic constituent in a sentence. Word order violations were rarely recorded in the Hebrew samples. CLINICAL IMPLICATIONS: Performance differences in the two modalities encourage clinicians and teachers to facilitate target linguistic forms in diverse communication contexts. Furthermore, the identification of linguistic targets for intervention must be based on the unique grammatical structure of the target language. PMID- 27764360 TI - From the Editor... PMID- 27764359 TI - Proverb Comprehension as a Function of Reading Proficiency in Preadolescents. AB - PURPOSE: Proverb comprehension through reading was examined in 42 preadolescents (mean age=12:2 [years:months]) attending a rural public middle school. The study was designed to learn about individual differences with respect to reading, word knowledge, and analogical reasoning skills. METHOD: The 42 students were assigned to subgroups of proficient and less proficient readers based on their scores on a school-administered achievement test. Reading tasks were presented to examine their comprehension of unfamiliar concrete (e.g., every bird must hatch its own eggs) and abstract (e.g., gratitude is a heavy burden) proverbs, and their knowledge of nouns contained in the expressions. A nonverbal analogical reasoning task also was administered. RESULTS: Proverb comprehension was found to be associated with reading proficiency, word knowledge, and analogical reasoning. Although all students were considered by their school to be typical achievers, they demonstrated wide individual differences in their ability to interpret unfamiliar concrete and abstract proverbs. Proficient readers outperformed less proficient readers on comprehension of both types of proverbs, knowledge of abstract nouns contained in proverbs, and analogical reasoning. They did not differ, however, on knowledge of concrete nouns, with both subgroups having mastered those words. Educational Implications: The results support the view that reading is an important language modality in older children, significantly related to their understanding of words and figurative expressions. Implications for instruction in proverb comprehension as part of a language arts curriculum are offered for speech-language pathologists working collaboratively with classroom teachers. These guidelines reflect the view that multiple factors (i.e., reading, word knowledge, analogical reasoning) promote proverb comprehension in youth. PMID- 27764361 TI - Description of a Program for Social Language Intervention: If You Can Have a Conversation, You Can Have a Relationship. AB - Adolescents with impaired language comprehension and formulation skills often experience difficulty keeping up with the linguistic and social demands of peer interaction. This clinical exchange describes an individualized treatment program designed to increase the conversational skill of an adolescent male with language impairment. Treatment focused on increasing awareness of the listener's needs and on balancing the exchange of conversational turns. Clinical performance, parent report, and client report were used to assess outcomes. PMID- 27764362 TI - Task Familiarity: Effects on the Test Performance of Puerto Rican and African American Children. AB - Two studies compared the performance of Puerto Rican and African American Head Start children on presumably familiar (description) and unfamiliar (one-word labeling) test tasks. Results indicated that children performed significantly better on the familiar test task, and that the familiar task was more sensitive in differentiating children who were typically developing from those with low language ability. Implications for the use of standardized tests, local norms, and dynamic assessment with culturally/linguistically diverse children are discussed. PMID- 27764364 TI - Introduction to Clinical Forum. AB - The issues presented in this forum concerning the development of communication and literacy abilities in school-age children who are deaf or hard of hearing are introduced in this article. The author organized this forum in an effort to renew conversation on the topics of teacher talk, the contemporary assessment of communication, best practices in the mainstream, interpersonal and school discourse as organizers for intervention, choosing sign language and sign systems, and working with marginal/at-risk students who are deaf or hard of hearing. The benefits of qualitative research to clinicians and teachers who seek local answers regarding these topics is stressed in the conclusion. PMID- 27764363 TI - Invented Spelling: Developmental Patterns in Kindergarten Children and Guidelines for Early Literacy Intervention. AB - Types and distributions of spelling patterns were identified in the invented spelling samples of 100 children in the second semester of their kindergarten year. Invented spellings were studied because they provide a valid measure of children's phonemic awareness in print-a skill that is highly correlated with reading success in the early stages of literacy acquisition. The subjects' spelling errors were used to develop a taxonomy of 10 invented spelling patterns and 21 response types that characterized the children's most frequently occurring spellings of graphemes targeted for analysis in 12 words. The acquisition of spelling patterns was examined by dividing the children into three groups based on the phonemic accuracy of their spellings on a pre-readirng instrument. A developmental ordering of spelling patterns is presented and relationships among phonological awareness, spelling, and reading are discussed as they are relevant to speech-language pathologists treating children who are at risk for reading disabilities. PMID- 27764365 TI - Communicating With Children Who Are Deaf: Pitfalls and Possibilities. AB - Adults vary in how far they control what is talked about in interactions with children who are deaf. The evidence discussed in this article involves teachers and students in classrooms, but the same principles apply to interactions between children and parents, speech clinicians, or other clinicians. We analyze teacher communication in terms of four dimensions: power, repair, pace, and linguistic complexity. These features of teacher discourse are associated in that teachers who exert the most power (e.g., who ask frequent questions) also spend more time repairing students' communication and exhibit a relatively rapid turn rate in discourse. Their language also exhibits fewer complex grammatical features. Students in communication with these teachers produce shorter utterances, ask fewer questions, offer less frequent contributions, communicate less often with peers, and show more signs of confusion and misunder-standing than they do with teachers who exert less power. We also discuss evidence that demonstrates that adults can change the way in which they manage conversations with children who are deaf in order to bring about more productive interactions. The implications of these findings for the development of linguistic competence in children who are deaf are explored. PMID- 27764366 TI - Intervention for Children With Hearing Impairment in General Education Settings. AB - Students with hearing impairments who are educated in classes with normally hearings peers represent the majority of children with hearing impairment. With hearing losses ranging from mild to profound, they require services to optimize their use of residual hearing and reduce the secondary effects of hearing loss, such as communication deficits and academic delays. For most of these students, the speech-language pathologist will be the on-site specialist in hearing responsible for designing a collaborative rehabilitation/education plan that addresses all deficit areas and for assisting in its implementation in the classroom. PMID- 27764367 TI - The Challenge of Assessing Language in Children With Hearing Loss. AB - This article challenges current practices in language evaluation for school-aged children with significant hearing loss. In light of recent theoretical beliefs, arguments supporting an interactional approach to assessment are presented, along with specific recommendations for the interpretation of test results. Application of current connectionist and competition theories of language acquisition promotes the concept of differential weighting of aspects of language (semantics, syntax, pragmatics, and phonology) at various stages of development. PMID- 27764368 TI - Issues in the Development of School and Interpersonal Discourse for Children Who Have Hearing Loss. AB - English instruction for children with haring loss has traditionally focused on teaching about language conventions, with much less attention to learning language, or to learning through language-especially its discourse features. The author argues that language intervention, through the collaborative efforts of speech-language pathologists and teachers, should promote communication interactions that emphasize English discourse that facilitates interpersonal and school language learning. Particular focus in this article is on issues of teacher talk, talk around print, self-talk in problem-solving, and the uses of narrative and descriptive discourse in interpersonal and school contexts. PMID- 27764369 TI - The Use of Sign Language and Sign Systems in Facilitating the Language Acquisition and Communication of Deaf Students. AB - With a historical context as a foundation, the current trends, practices, and perspectives regarding the manual component of educating deaf children is examined, including Manually Coded English systems and American Sign Language. As decisions are considered regarding various approaches to sign communication, it is necessary to investigate issues that support and also question the appropriateness of any given language/system. In addition to the sign language/systems, an equally important aspect is the instructional strategy that supports sign usage, such as Total Communication, Simultaneous Communication, and Bilingual Education. Issues affecting the selection and use of sign language/systems conclude this article. PMID- 27764371 TI - From the Editor... PMID- 27764370 TI - Educational Considerations for At-Risk/Marginal Students Who Are Deaf or Hard of Hearing. AB - The teaching of children who are at risk, marginally deaf, or hard of hearing is considered in this article, primarily from the framework provided by Ogbu (1990), Sinclair and Ghory (1990), Cromer (1993), and the contemporary writings of others working with multiethnic populations of children who are hearing and hearing impaired. Emphasis is put on the social constructive nature of this complex phenomenon, the heterogeneity (both inter- and intraculturally) of the populations involved, and some of the processes that students go through in becoming marginalized. Finally, consideration is given to how one might address some of the problems of educating these children. Descriptions and examples of some successful intervention projects are presented. PMID- 27764372 TI - Stickwriting Stories: A Quick and Easy Narrative Representation Strategy. AB - Narrative is an important target of language intervention. However, oral narratives are difficult to remember, review, and revise because of their length and complexity. Writing is an option, but is often frustrating for both student and clinician. This article introduces a notational system called pictography that can be useful for temporarily preserving story content. Children represent the characters, settings, and sequences of actions with simple, chronologically or episodically organized stick-figure drawings. As a quick and easy representational strategy, pictography is applicable to both individual language intervention and inclusive classroom settings. This article describes benefits observed in narrative intervention, including facilitation of a time sequence, increased length and quality, and a greater focus on narrative content rather than on the mechanics of writing. PMID- 27764373 TI - Syntactic Skills of Spanish-Speaking Children With Low School Achievement. AB - This study compared the syntactic skills of Spanish-speaking children with low and average school achievement from kindergarten to fifth grade using oral narratives that were elicited with book and film retelling tasks. Both narrative tasks required the child to provide information that was presumably unknown to the listener and that could not be derived from the visual context. Results indicated that children who were performing below grade expectations (according to curriculum-based assessments) exhibited limited use of complex syntax and greater formulation difficulties in their narratives than their peers. There were no significant task differences in the use of complex language. The analysis of children's syntactic performance in narratives provided information regarding language skills that appeared related to school achievement. PMID- 27764374 TI - Metaphor Performance in Children With Hearing Impairment. AB - Metaphor comprehension and use were evaluated in children with hearing impairment (HI) who performed within normal age limits on norm-referenced measures of language. Participants were 13 children with mild-to-moderate sensorineural hearing loss and 12 children with normal hearing and normal development (10:0 to 15:7 years:months). Three verbal metaphor tasks (comprehension, preference, and completion) and one visual metaphor task, the Metaphor Triads Task (MTT), were administered. No significant group differences were found on any of the tasks. Both groups exhibited the same metaphor competence and response patterns on the four tasks. These findings add to a growing body of literature showing that a significant number of children with mild-to-moderate HI have age-appropriate language abilities. PMID- 27764375 TI - Meeting the Critical Shortage of Speech-Language Pathologists to Serve the Public Schools-Collaborative Rewards. AB - This article presents a collaborative approach to providing graduate education to speech-language pathologists who are employed in public school districts. A partnership called the Central Florida Speech-Language Consortium was established among the University of Central Florida, 10 Central Florida school districts, and community agencies to address the issue of the critical shortage of speech language pathologists in the public schools. The consortium program provided bachelor-level speech-language pathologists in the public schools the opportunity to obtain a master's degree while they continued to work in the schools. Key innovations of the program included: (a) additional graduate slots for public school employees; (b) modifications in the location and time of university courses, as well as practica opportunities in the schools; and (c) the participation and support of public school administrators in facilitating supervision and practicum experiences for the consortium participants. The consortium program resulted in an increase in the number of master's level and culturally and linguistically diverse speech-language pathologists available for employment in the public schools of Central Florida. Recommendations for facilitating future endeavors are discussed. PMID- 27764376 TI - Treatment Outcomes and Efficacy in the Schools. PMID- 27764377 TI - Policy, Politics, and the Power of Information: The Critical Need for Outcomes and Clinical Trials Data in Policy-Making in the Schools. PMID- 27764378 TI - Overview, Definitions, and Goals for ASHA's Treatment Outcomes and Clinical Trials Activities (What Difference Do Outcome Data Make to You?). AB - This article examines differences between efficacy and effectiveness, describes two research designs related to measuring efficacy and effectiveness, and describes the American Speech-Language-Hearing Association's (ASHA's) efforts relative to these research designs, with examples presented for how each of these designs can be used in the school setting. Outcomes studies and clinical trials research are the particular focus of the article. The characteristics of each type of research are described and related to the school setting. PMID- 27764379 TI - Collecting Outcomes Data in Schools: Needs and Challenges. AB - The definition of treatment outcomes, its interpretive limitations, and the need for this type of information are discussed. The activities of the American Speech Language-Hearing Association's (ASHA's) Task Force on Treatment Outcomes and Cost Effectiveness and the development of the National Outcomes Measurement System for Speech-Language Pathology and Audiology (NOMS) are reviewed, with an emphasis on the NOMS: K-12 (Education) component. How outcomes data can be used and the challenges its collection presents in school settings are also discussed. PMID- 27764380 TI - Conducting Clinical Trials in the Public Schools. AB - This manuscript explores the general whys and hows clinicians in the public school can and should be involved in clinical trials research and describes the Communication Sciences and Disorders Research Group (CSDRG). The CSDRG is a group of clinicians, clinical investigators, basic scientists, epidemiologists, and statisticians in communication sciences and disorders (funded by the National Institutes of Health) who came together to design and implement clinical trials examining the effectiveness of interventions with speech, hearing, language, balance, and voice/swallowing disorders. Clinical trials are a very specific type of treatment research requiring the randomization of children to several different treatment arms. Because of the required characteristics of clinical trials, conducting them in the school setting poses unique challenges and logistic issues that are described, along with potential solutions. PMID- 27764381 TI - Impact of Managed Care in the Schools. AB - This article examines the effect of managed care on the types of children and services offered in the schools. The role of cost containment in service delivery in the schools relative to managed care is described. Skills that the speech language pathologist must develop and maintain in the school systems in this era of managed care are outlined. Case management skills, definition of critical outcomes of service, and building and maintaining team approaches to communication problems are also emphasized. PMID- 27764383 TI - From the Editor... PMID- 27764382 TI - Speech-Language Hearing Interventions in the Schools: A Public Health Perspective on Measuring Their Short-Term and Long-Term Impact. AB - Prevalence of studies of speech, language, and hearing disorders do not yet adequately define the frequency of specific communication disorders in children. Such data are needed to provide a strong rationale for funding of research on the effectiveness of our interventions. Establishing the effectiveness of our treatments is critical to continued support of our services. This article emphasizes the importance of collecting prevalence data and of measuring both the short-term and long-term impact of our interventions in the schools. PMID- 27764384 TI - The Effect of Examiner's Race on the Performance of African American Children on the SCAN. AB - PURPOSE: With African American children, processingdependent central auditory nervous system (CANS) tests, such as the Screening Test for Auditory Processing Disorders (SCAN) (Keith, 1986), may be less culturally biased than traditional knowledge-dependent standardized language measures. Keith found that African American children received lower scores on the SCAN than did Anglo American children. The primary purpose of this study was to determine whether middle-class African American children might improve their SCAN performance when tested by an African American versus an Anglo American examiner. METHOD: The SCAN was administered twice to 47 African American children, ages 5-10 years. Half of the participants were tested by an African American examiner first and then by an Anglo American examiner, with the order of testing counterbalanced for the remaining half of the participants. Data were also analyzed by grade level. RESULTS: A 2 (examiner race) x 3 (grade level) analysis of variance did not reveal a significant effect for examiner race, but did show a main effect for grade level on certain SCAN subtests; however, effect size results revealed that the magnitude of differences between mean scores on the Competing Words subtest and the composite score were large enough to be potentially significant. Results also indicated a significant learning effect. CLINICAL IMPLICATIONS: Although examiner race did not appear to influence SCAN performance for this group of children, the possibility of a race effect needs further investigation with a larger sample, as does the clinical utility of the SCAN as a processing-dependent measure. The significant learning effect also suggests potential problems with the test-retest reliability of the SCAN. PMID- 27764385 TI - The Efficacy of Phonological Awareness Intervention for Children With Spoken Language Impairment. AB - PURPOSE: This study investigated the efficacy of an integrated phonological awareness intervention approach for children with spoken language impairment (SLI) who demonstrated early reading delay. Ninety-one, 5- to 7-year-old New Zealand children participated in this study: 61 children with SLI and 30 children with typically developing speech and language skills. All of the children with language impairment exhibited expressive phonological difficulties and some also had delayed semantic and syntactic development. METHOD: The children with SLI participated in either: (a) an integrated phonological awareness program, (b) a more traditional speech-language intervention control program that focused on improving articulation and language skills, or (c) a minimal intervention control program over a 4 1/2-month time period. RESULTS: Effects of the interventions on phonological awareness ability, reading performance, and speech production were examined. The children who received phonological awareness intervention made significantly more gains in their phonological awareness ability and reading development than the children receiving the other types of speech and language intervention. Despite significant delays in phonological awareness prior to training, children who received the phonological awareness intervention reached levels of performance similar to children with typically developing speech and language skills at post-test assessment. The phonological awareness intervention also improved the children's speech articulation. CLINICAL IMPLICATIONS: The findings suggest that integrated phonological awareness intervention may be an efficient method to improve phonological awareness, speech production, and reading development of children with SLI. Findings are discussed with reference to a speech-literacy link model. PMID- 27764386 TI - A Preliminary Investigation of Dynamic Assessment With Native American Kindergartners. AB - PURPOSE: This study examined dynamic assessment as a lessbiased evaluation procedure for assessing the languagelearning ability of Native American children. METHOD: Twenty-three Arapahoe/Shoshone kindergartners were identified as stronger (n = 15) or weaker (n = 8) language learners through teacher report and examiner classroom observation. Through a test-teach-test protocol, participants were briefly taught the principles of categorization. Participant responses to learning were measured in terms of an index of modifiability and post-test categorization scores. The modifiability index, determined during the teaching phase, was a combined score reflecting the child's learning strategies, such as ability to attend, plan, and self-regulate, and the child's responses to the learning situation. Post-test scores consisted of performance on expressive and receptive subtests from a standardized categorization test after partialling out pretest score differences. Effect sizes and confidence intervals were also determined. RESULTS: Group and individual results indicated that modifiability and post-test scores were significantly greater for stronger than for weaker language learners. The response to modifiability components was a better discriminator than was the learner strategies components. CLINICAL IMPLICATIONS: These results provide support for the further development of dynamic assessment as a valid measure of language learning ability in minority children. PMID- 27764387 TI - Patterns of Adult-Child Linguistic Interaction in Integrated Day Care Groups. AB - PURPOSE: This study investigated the language input of eight childcare providers to children with developmental disabilities, including language delay, who were integrated into community day care centers. METHOD: Structural and discourse features of the adults' language input was compared across two groups (integrated, typical) and two naturalistic day care contexts (book reading, play dough activity). The eight children with developmental disabilities and language delay were between 33-50 months of age; 32 normally developing peers ranged in age from 32-53 months of age. Adult-child interactions were transcribed and coded to yield estimates of structural indices (number of utterances, rate, mean length of utterances, ratio of different words to total words used (TTR) and discourse features (directive, interactive, language-modelling) of their language input. RESULTS: The language input addressed to the children with developmental disabilities was directive and not finely tuned to their expressive language levels. In turn, these children interacted infrequently with the adult or with the other children. Contextual comparisons indicated that the play dough activity promoted adult-child interaction that was less directive and more interaction promoting than book reading, and that children interacted more frequently in the play-dough activity. CLINICAL IMPLICATIONS: Implications for speech-language pathologists include the need for collaborative consultation in integrated settings, modification of adult-child play contexts to promote interaction, and training childcare providers to use language input that promotes communication development. PMID- 27764388 TI - Part I: Speech Characteristics of the Disorder. AB - Practicing speech-language pathologists frequently ask about the existence of information regarding developmental apraxia of speech (DAS) that they can share with the parents of their clients and patients. Hoping to fill a need, a series of letters, addressed to the parent(s) of a child with DAS, has been written. These letters discuss such issues as the nature and causes of DAS, other problems often associated with the disorder, and the treatment of DAS. This initial letter discusses the characteristics involved in the disorder. Included with this letter is an appendix of publications that may be helpful for both parents and speech language pathologists. PMID- 27764389 TI - Part II: The Nature and Causes of DAS. AB - In a previous letter to the parent(s) of children with developmental apraxia of speech (DAS), the speech characteristics often exhibited as part of the disorder were described. In this second letter, the issues involved in current thinking about the nature of the disorder are explored. Also shared is information concerning what is thought to be known about the causes of the disorder. An appendix of publications exploring these issues appears at the end of the letter. PMID- 27764390 TI - Part III: Other Problems Often Associated With the Disorder. AB - Two previous letters written to the parent(s) of children with developmental apraxia of speech (DAS) shared information regarding the speech characteristics and the current thinking concerning the nature and causes of the disorder. A future letter will discuss treatment of DAS. However, children with DAS often seem to have problems in addition to those involving their speech production. This third letter discusses several of the problems that may co-occur with DAS, and includes an appendix of publications that can provide additional information concerning other problems that may be present with DAS. PMID- 27764391 TI - Part IV: Treatment of DAS. AB - Three previous letters written to the parent(s) of children with developmental apraxia of speech (DAS) described the speech characteristics of DAS, the nature and causes of the disorder, and problems that often co-occur with DAS. This final letter discusses the treatment of DAS and includes an appendix of publications for a more complete review of this aspect of the problem. PMID- 27764392 TI - Practice Makes Perfect: The Incompatibility of Practicing Speech and Meaningful Communication. AB - In this article, the possibility is raised that some children may implicitly view the therapy situation as one in which new sounds and language forms are learned and practiced. In contrast, the primary purpose of talking outside of therapy is meaningful communication. Inherent in this view of therapy and non-therapy is the incompatibility or inconsistency between practicing speech and communicating effectively. What led me to recognize this inconsistency and consider its potential clinical implications was the way in which my daughter Franne dealt with her phonological disorder. PMID- 27764393 TI - Does It Matter What Your Client Thinks? The Role of Theory in Intervention: Response to Kamhi. AB - Kamhi (2000) presents a case study of a child with a phonological impairment whose view of the intervention process led her to refuse to work on her goals with anyone other than her clinician. In this response, the potential clinical impact of discrepant views among the participants in a clinical intervention is discussed. In particular, it is argued that subjectivity is inherent in all interactions, but that different theories place differing emphasis on the importance of the subjective states of interactional participants. Three prominent theories of intervention are discussed: social interactionist, behaviorist, and information processing. It is argued that discrepancies between a clinician's and a client's view of what is happening during clinical interactions may complicate intervention. It is further argued that theoretical eclecticism may have a particularly negative impact, as it will increase the likelihood of misunderstandings. A conclusion is that, when clashes in perspectives arise, they force the clinician to make explicit what he or she believes-what causes disorders, what processes work to remediate them, and why. PMID- 27764394 TI - From the Editor.... PMID- 27764395 TI - Challenges in Optimizing Oral Communication in Children With Cochlear Implants. AB - As the number of children with cochlear implants increases, more speech and hearing professionals will be called on to take leadership roles in developing specialized intervention and educational programs. Because of their graduate level training in speech, language, and hearing disorders, speech-language pathologists and audiologists will increasingly find themselves viewed as "local experts" on cochlear implant issues. The articles in this forum support that role by addressing topics that are critical for serving children who have cochlear implants. Although cochlear implant technology clearly has impressive potential for improving the lives of deaf children, the actualization of those improvements requires informed and concerted effort from highly skilled professionals. It is hoped that the information in this clinical forum will enable readers to expand their knowledge base and clinical skills to meet the challenges of serving children who have cochlear implants. PMID- 27764396 TI - An Introduction to Cochlear Implant Technology, Activation, and Programming. AB - Over the last decade, cochlear implantation has become an increasingly viable alternative for the treatment of profound sensorineural hearing loss in children. Although speech and hearing professionals play an important role in the communicative, social, and academic development of children with cochlear implants, many may be unfamiliar with recent advances in implant technology. This article provides an overview of the components of cochlear implant systems and the speech processing strategies that are currently being used by toddlers, preschoolers, and school-age children. A brief description of cochlear implant surgery and the procedures for programming these devices are also included. Finally, information regarding the use of assistive listening technology in the classroom is presented. PMID- 27764397 TI - School-Based Services for Children With Cochlear Implants. AB - School-based speech, language, and hearing professionals are instrumental in the provision of rehabilitative, consultative, and support services for children with cochlear implants. This article reviews current candidacy requirements as well as factors that are considered when a child is evaluated for a cochlear implant. Following implantation, school professionals play a pivotal role in providing an appropriate educational program that should include auditory training and the integration of listening into the child's daily routine. The article presents procedures for maintaining and troubleshooting the device, and suggestions for establishing routines for device use and for improving the listening environment for children in classrooms. PMID- 27764398 TI - Factors Affecting the Development of Speech, Language, and Literacy in Children With Early Cochlear Implantation. AB - PURPOSE: This study investigated factors contributing to auditory, speech, language, and reading outcomes in children with prelingual deafness after 4-6 years of multichannel cochlear implant use. The analysis controlled for the effects of child, family, and implant characteristics so that educational factors most conducive to maximum implant benefit could be identified. METHOD: The sample included 136 8- and 9-year-old children from across the United States and Canada who were implanted by age 5 with the Nucleus 22-channel implant. Type and amount of educational intervention since implantation constituted the independent variables. The dependent variable was performance on a battery of tests of speech perception, speech production, language, and reading administered 4-6 years postimplant. Characteristics of the child, the family, and the implant itself constituted intervening variables. A series of multiple regression analyses determined the amount of variance in each outcome accounted for by the intervening variables and the amount of additional variance attributable to independent variables. RESULTS: Characteristics of the child and the family (primarily nonverbal IQ) accounted for approximately 20% of the variance in postimplant outcome. An additional 24% was accounted for by implant characteristics and 12% by educational variables, particularly oral communication mode. CLINICAL IMPLICATIONS: Auditory, speech, language, and reading skills achieved 4-6 years after cochlear implantation were most strongly associated with nonverbal IQ, implant functioning, and use of an oral communication mode. PMID- 27764399 TI - Vocal Development in Young Children With Cochlear Implants: Profiles and Implications for Intervention. AB - PURPOSE: This article describes prelinguistic vocal development in 2 prelingually deaf children who received multichannel cochlear implants at 10 and 28 months of age, respectively. METHODS: Vocalizations were recorded in half-hour mother- child interactions before and after implantation and then classified into three levels of development: precanonical, canonical, and postcanonical. RESULTS: One child made rapid progress in vocal development after her implant was activated. The other child showed slower progress with continued dominance of precanonical vocalizations throughout the first year of implant experience. Increases in vowel, diphthong, and consonant diversity; the establishment of canonical vocalizations; and the emergence of postcanonical forms were found to be indicators of progress in vocal development. CLINICAL IMPLICATIONS: Observed differences in the rate and completeness of vocal development between the 2 children suggest that some young implant recipients may need specialized intervention strategies to stimulate speech development. The rationale and procedures for implementing Short Periods of Prelinguistic Input (SPPI), a potentially useful approach for stimulating vocal development, are presented. PMID- 27764400 TI - Introducing Young Children Who Are Deaf or Hard of Hearing to Spoken Language: Child'sVoice, an Oral School. AB - This article provides an overview of the workings of an oral school for children who are deaf or hard of hearing. The key features of the school include low student-teacher ratios, teachers who are trained as oral educators of deaf children, ongoing staff and parent education, specialized curricula, and a strong emphasis on listening and speaking throughout the day. Approximately 75% of the students at the school use cochlear implants; the remainder wear hearing aids. The graduates of this program have shown that an oral school can help many children who are deaf or hard of hearing achieve success as oral communicators and students in mainstream classrooms. PMID- 27764401 TI - Communication Intervention for Children With Cochlear Implants: Two Case Studies. AB - This article describes the intervention programs attended and progress made by 2 children who exhibited considerable differences in benefit from their cochlear implants. The children differed in many ways, including age at onset of deafness, preimplantation communications skills, age at implantation, the amount and types of intervention services received, and the rate at which they developed oral communication skills. Their intervention programs employed both analytical and synthetic auditory training and emphasized the development of speech production and language skills. These case studies help to illustrate the range of outcomes among cochlear implant recipients and the adaptability needed to design and implement individualized intervention programs. PMID- 27764403 TI - From the Editor.... PMID- 27764402 TI - Technological Innovations and Intervention Practices for Children With Cochlear Implants. AB - This clinical forum has addressed many of the challenges associated with serving children who have cochlear implants. These include determining who may be a candidate for implantation; optimizing parent-child interactions for oral communication; developing comprehensive preschool programs; assessing and maximizing opportunities to communicate and learn in regular classrooms; making choices in communication modalities; providing effective intervention; and serving as a liaison for parents, school personnel, and medical professionals. In response to these challenges, the forum has provided the technical information needed to understand how a cochlear implant works, important research findings regarding choices in communication modalities, and ideas for assessing and serving children with implants. This information can provide speech, language, and hearing professionals with a base for developing their skills in the role of "local experts" for children who have cochlear implants. Filling this role also requires continuing education to keep up with innovations in technology and advancements in clinical practice. It is hoped that this forum has provided an impetus for further learning in a rapidly emerging and fascinating area of our profession. PMID- 27764404 TI - A Framework for Managing Controversial Practices. AB - Every day, speech-language pathologists working in schools make difficult, life impacting decisions regarding which assessment and intervention approaches to use with their clients. These decisions can become even more difficult when the approaches being considered for use are controversial. The risks involved in making choices about controversial practices are likely to have increased significance simply because the approach being considered is not widely accepted. The increased professional risk may cause decisions to be made based on risk avoidance rather than on a careful consideration of the pros and cons of the approach itself. This article offers a clinical practice framework for gathering information about controversial approaches and for implementing and monitoring their use. The framework will be illustrated using facilitated communication as an example of a controversial practice. PMID- 27764405 TI - Listeners' Perceptions of Language Use in Children. AB - Past research suggests that when children's communication skills do not match others' expectations, children are likely to be perceived negatively and may consequently experience less academic and social success. This project focused on listeners' perceptions of three children, one with specific language impairment (SLI) and two typically developing peers. The listeners consisted of teachers, speech-language pathologists, undergraduate students, and sixth-grade students. All four listener groups consistently perceived the child with SLI more negatively than the typically developing youngsters, thereby illuminating the need for clinicians to (a) increase their awareness of personal biases, (b) educate parents and teachers regarding the nature of SLI, PMID- 27764406 TI - Prologue: Developing Evidence-Based Practices and Research Collaborations in School Settings. PMID- 27764407 TI - An Initial Investigation of Phonological Patterns in Typically Developing 4-Year Old Spanish-English Bilingual Children. AB - PURPOSE: This collaborative study investigated phonological patterns in 12 typically developing 4-year-old bilingual (Spanish-English) children. METHOD: A single-word phonological assessment with separate versions for English and Spanish was administered to each child. Analyses consisted of a phonetic inventory; percentage of consonants correct; percentage of consonants correct for voicing, place of articulation, and manner of articulation; and the percentage of occurrence for phonological processes. RESULTS: The results indicated that there were no significant differences between the two languages on percentage of consonants correct; percentage of consonants correct for voicing, place of articulation, and manner of articulation; or percentage of occurrence for phonological processes. However, the children exhibited different patterns of production across the two languages and showed different patterns compared to monolingual children of either language. CLINICAL IMPLICATIONS: The preliminary findings suggest that the phonological system of bilingual (Spanish-English) children is both similar to and different from that of monolingual speakers of either language. Compared to monolingual speakers, bilingual children should be expected to exhibit different types of errors and different substitution patterns for target sounds. PMID- 27764408 TI - Collaborating to Obtain Phonological Acquisition Data for Local Schools. AB - PURPOSE: Twelve school-based speech-language practitioners enlisted the assistance of a university clinical phonologist to help them implement a collaborative research project for their school system in order to investigate phonological acquisition. METHOD: The school practitioners transcribed speech samples of 520 typically developing children between the ages of 2:6 and 8:0 (years:months). Responses were coded for syllable/word structures (e.g., final consonant deletion) and phoneme classes (e.g., velar deficiencies). RESULTS: The 3-year-olds in this sample had acquired all major phoneme classes except liquids. For the older participants, /l/ was acquired between 4 and 5 years of age and /r/ between 5 and 6 years of age. Although the strident phoneme class had reached the criterion for acquisition by age 3 years, sibilant lisps were still common until the age of 7 years. Another finding was the rare occurrence of omissions. CLINICAL IMPLICATIONS: The practitioners resolved that when determining whether a preschooler would be eligible to receive treatment services as a part of their caseloads, consistent speech sound omissions appeared to be a critical indicator and should be considered a higher priority than substitutions and/or distortions. CONCLUSION: The collaborative effort between the university clinical phonologist and the school-based speech-language practitioners was considered to be a valuable experience and a model for future collaborative partnerships. PMID- 27764409 TI - Spelling Development and Disability: The Importance of Linguistic Factors. AB - This article reviews the literature on normal and impaired spelling development in English. Once children begin to learn that the function of alphabetic writing is to represent the sounds of language, they go through the process of learning sound-spelling correspondences in increasingly fine detail. Continued experience with print allows children to learn about orthographic and morphological conventions of the language. Within this general framework, the authors describe research that underscores the importance of fine-grained linguistic analyses of spelling performance. It is concluded that such an approach holds a great deal of promise for theory and practice. PMID- 27764410 TI - Theory-Guided Spelling Assessment and Intervention: A Case Study. AB - PURPOSE: Current research and theory in spelling development and best practices for literacy instruction were reviewed to develop a set of theoretically guided assessment and intervention procedures. These procedures were applied to the case of a 13-year-old student with spelling difficulties. METHOD: The student was involved in an intensive group intervention program that focused on increasing foundational skills for spelling and on oral word-level reading. Assessment results led to an intervention program targeting phonemic and morphological awareness skills and orthographic knowledge. RESULTS: The student demonstrated clinically significant growth in phonemic and morphological awareness, orthographic knowledge, spelling, and word-level reading. CONCLUSION: Results of the case study suggest that assessment and intervention procedures guided by theory and research can lead speech-language pathologists to effective participation in aspects of spelling remediation. Additionally, the case study may serve as a model for clinical services and evidence-based practice within clinical settings. PMID- 27764411 TI - Epilogue: Developing Evidence-Based Practices and Research Collaborations in School Settings. PMID- 27764412 TI - The Lexicon and Phonology: Interactions in Language Acquisition. AB - The purpose of this paper is to underscore the importance of the link between lexical and phonological acquisition by considering learning by children beyond the 50-word stage and by applying cognitive models of spoken word processing to development. Lexical and phonological variables that have been shown to influence perception and production across the lifespan are considered relative to their potential role in learning by preschool children. The effect of these lexical and phonological variables on perception, production, and learning are discussed in the context of a two-representation connectionist model of spoken word processing. The model appears to offer insights into the complex interaction between the lexicon and phonology and may be useful for clinical diagnosis and treatment of children with language delays. PMID- 27764413 TI - From the Editor.... PMID- 27764414 TI - Aspects of Stop Consonant Production by Pediatric Users of Cochlear Implants. AB - PURPOSE: Data and analyses are reported for stop consonant production by 12 children who have used cochlear implants for at least 5 years, focusing on variation within and between individual phonological systems. METHOD: Participants were 6 oral communication users and 6 total communication users. Productions of single words were analyzed for stop inventories, phonotactic constraints, and morphophonemic alternations. Variation was further analyzed within optimality theory. RESULTS: Children's inventories differed from English mainly in having additional, non-English stops. Total communication users had fewer ambient stops and more nonambient ones than did oral communication users. Control over English allophonic and neutralization rules varied among children. Phonological variation could be accounted for by positing unique underlying representations and different constraint rankings within optimality theory. CLINICAL IMPLICATIONS: Atypical speech by children with cochlear implants involves both articulation and phonological organization. Although children vary considerably, characteristic patterns emerge. An understanding of these patterns is useful for identifying areas of difficulty and formulating intervention programs. PMID- 27764415 TI - Prologue: Recent Advances in Phonological Theory and Treatment: Part II. AB - Each of the articles in this forum considers how phonology interacts with other aspects of language and language learning. The contributors show that this interaction plays a major role in a child's learning of language, whether through typical routes, as evidenced by the normally developing child, or through clinical intervention. These interactions are apparent in both typical and atypical language learning, with the development of the lexicon being closely tied to the development of phonological representations (or URs). The correctness of these URs, as determined from morphophonemic alternations, plays a major role in accounting for children's production patterns and determining what a child "knows" about the target sound system. Finally, the interaction between morphosyntax and phonology can be observed in language learning even when it occurs as a result of clinical intervention. It is hoped that this clinical forum will be informative and enlightening for researchers and clinical professionals. PMID- 27764417 TI - Epilogue: Recent Advances in Phonological Theory and Treatment: Part II. PMID- 27764416 TI - Efficacy and Cross-Domain Effects of a Morphosyntax and a Phonology Intervention. AB - PURPOSE: The purpose of this study was three-fold: (a) to determine the efficacy of a morphosyntax and a phonology intervention against a no-treatment control group, (b) to assess the effects of those interventions on the non-targeted domain, and (c) to evaluate sequence effects when children receive both interventions. METHOD: Twenty preschoolers with impairments in both morphosyntax and phonology were assigned randomly to an intervention of two 12-week blocks beginning with either a block of phonology first (n = 10) or a block of morphosyntax first (n = 10). Data were collected at pretreatment, after the first intervention block, and posttreatment. For a control group of 7 children, data were collected at the beginning and end of a time period equivalent to one intervention block. Changes in a finite morpheme composite and target/generalization phoneme composite were assessed. RESULTS: In comparison to the control group, both interventions were effective at a statistically significant level in facilitating improvement in the target domain after 12 weeks. The morphosyntax intervention led to cross-domain change in phonology that was similar to that achieved by the phonology intervention. The morphosyntax first sequence also led to slightly better overall morphosyntactic performance. CLINICAL IMPLICATIONS: Clinically, results suggest targeting morphosyntax first, followed by phonology, if using a block intervention sequence for children with concomitant morphosyntactic and phonological impairments. PMID- 27764419 TI - From the Editor... PMID- 27764420 TI - Language Sampling Protocols for Eliciting Text-Level Discourse. AB - The identification of linguistic vulnerability in school-age students is likely to require collecting and analyzing samples of text-level discourse. Text-level discourse produced as part of narrative and expository tasks is more likely to reveal school-age children's most advanced language abilities and to evoke more communication breakdowns and production errors. This article briefly reviews the research literature establishing the need to sample text-level discourse and identifies several issues for clinicians to consider when constructing their own language sampling protocols. The article concludes with the description of two different protocols that could be used in school- and clinic-based settings, along with examples of how these protocols have been administered and analyzed for clinical purposes. PMID- 27764418 TI - Whole-Word Phonology and Templates: Trap, Bootstrap, or Some of Each? AB - Advances in psycholinguistics have identified cognitive mechanisms that may account for the phenomena of whole-word phonology and phonological templates in normally developing children. Deficits in these same mechanisms may also account for certain types of disordered phonologies. In this paper, these cognitive mechanisms are described, strategies for identifying whole-word phonological patterns in normal and disordered phonologies are proposed, and intervention strategies that draw on these same mechanisms as a way to overcome their inappropriate persistence are recommended. PMID- 27764421 TI - Task Variability Effects on the Language Test Performance of Southern Lower Socioeconomic Class African American and Caucasian Five-Year-Olds. AB - Twelve African American and twelve Caucasian preschool children were administered items from the Preschool Language Assessment Instrument (PLAI) under standard conditions and in thematic interactions (PLAI-T) to determine if task variability had an effect on language test scores. The African American group earned significantly higher test scores when the items were administered in the thematic mode as compared to the standardized test format, with the major score increases tending to occur on the more complex and difficult items. Clinical implications of considering task effects and dynamic assessment in multicultural assessment are discussed. PMID- 27764422 TI - A Comparison of the Oral Narrative Abilities of Underachieving and High-Achieving Gifted Adolescents: A Preliminary Investigation. AB - Few researchers have examined the narrative abilities of underachieving gifted students. This study investigated the ability of eighth-grade underachieving gifted adolescents to spontaneously produce oral narratives by comparing their stories to those that were produced by achieving gifted peers. It was hypothesized that evidence of difficulty generating the stories relative to the macrostructure (organization of ideas across sentences) and the microstructure (organization of ideas within sentences) would be exhibited by the underachieving gifted subjects. Twenty 13-year-old eighth-graders served as subjects in the present investigation. All were identified as gifted by their local school system and were enrolled in the gifted program at the time of their participation in the study. Ten of the subjects met criteria for the underachieving gifted group and ten met criteria for the achieving gifted group. The stories produced by the underachieving gifted subjects were compared to those produced by their achieving gifted peers for differences in 13 dependent measures of story length, episodic integrity, story grammar components, and sentence complexity. Differences in the mean number of occurrences of each of the 13 variables were found. The result of the MANOVA revealed that when the 13 dependent variables were considered in combination, the stories told by the underachieving gifted subjects differed significantly from those produced by the achieving gifted subjects at the p < .05 level of significance. Results of the univariate analyses indicated that these differences were not accounted for by any one element of story macrostructure or microstructure, but rather that the stories differed across multiple dimensions, each of which contributed to the overall difference. The results of this study suggest that the language of underachieving gifted children may differ from that of gifted peers when narrative language is examined. Results are discussed relative to the limitations of the study and implications for future research. PMID- 27764423 TI - Culture-Based Considerations in Programming for Stuttering Intervention With African American Clients and Their Families. AB - This article describes a clinical framework that may be used with African American children who stutter and their families. It includes discussion of the clinical importance of culture-based factors such as myths, oral presentation styles, narrative discourse styles, and cognitive learning styles, as well as rules for interaction and turn-taking. These factors are considered relative to the various clinical stages in the evaluation and treatment of stuttering in African Americans. PMID- 27764424 TI - Sensitivity and Specificity of Keith's Auditory Continuous Performance Test. AB - The Auditory Continuous Performance Test (ACPT) was evaluated on one group of subjects who had been diagnosed as having attention deficit-hyperactivity disorder (ADHD) and another group for whom ADHD had been ruled out. Although the specificity of the ACPT was acceptably high for a screening test, the sensitivity was very low. The conclusions drawn from these results are limited because of small sample size (n=23). However, until reports based on large study samples are forthcoming, the use of the ACPT as a screening test for ADHD appears questionable. PMID- 27764425 TI - Phonological Awareness Screening to Identify At-Risk Readers: Implications for Practitioners. AB - The purpose of this study was to investigate informal phonological awareness measures as predictors of first-grade broad reading ability. Subjects were 91 former Head Start students who were administered standardized assessments of cognitive ability and receptive vocabulary, and informal phonological awareness measures during kindergarten and early first grade. Regression analyses indicated that three phonological awareness tasks, Invented Spelling, Categorization, and Blending, were the most predictive of standardized reading measures obtained at the end of first grade. Discriminant analyses indicated that these three phonological awareness tasks correctly identified at-risk students with 92% accuracy. Clinical use of a cutoff score for these measures is suggested, along with general intervention guidelines for practicing clinicians. PMID- 27764426 TI - Comments on "The Use of SCAN to Identify Children at Risk for CAPD" by Emerson et al. (1997). PMID- 27764427 TI - The Use of SCAN to Identify Children at Risk for CAPD: Response to Keith (1998). PMID- 27764428 TI - Constructivist Strategies in Phonological Intervention: Facilitating Self Regulation for Carryover. AB - This tutorial describes an instructional approach for school-age children who have difficulty achieving phonological carryover. Behavioral, cognitive, and constructivist instructional strategies are examined in regard to their usefulness during the establishment, transfer, and carryover phases of phonological intervention. The advantages of using constructivist strategies to facilitate carryover are presented. A model of self-regulated learning is then applied to constructivist carryover activities (performances) so that children who have difficulty attaining carryover might develop metacognitive abilities similar to those of children who easily achieve carryover. Ideas for implementing a constructivist approach to facilitating self-regulated carryover are presented and examples are provided. PMID- 27764429 TI - A Clinical Synthesis of the "Late Talker" Literature: Implications for Service Delivery. AB - "Late talkers" are most often differentiated from their normally developing peers by their limited expressive lexicons. In the majority of the studies conducted on late talkers, these children are described as producing fewer than 50 words and/or producing limited word combinations by 24 months of age. The expressive language of some of the late talkers will eventually resemble their same-age peers; however, a substantial number of these children will continue to evidence difficulties with their expressive language acquisition. This article provides a review of the literature on late talkers in order to assist speech-language pathologists as they tackle those issues that are specific to service provision with this population of children. PMID- 27764430 TI - Efficacy of Expansions and Cloze Procedures in the Development of Interpretations by Preschool Children Exhibiting Delayed Language Development. AB - Recent intervention studies have demonstrated that adult-provided expansions of child utterances during storybook reading can result in preschool children's development of two-word utterances that describe characters and their actions as well as grammatical morphemes that are targeted for development via expansions. The present study used an alternating-treatments experimental design to compare the effects of two styles of storybook reading on the production of interpretations by two preschool children experiencing delayed language development. One reading style used a combination of expansions and cloze procedures; the other provided questions followed by modeling of appropriate answers. The children produced more answers to questions regarding the storybook, more interpretations, and syntactically more complex utterances in the condition using expansions and cloze procedures. Results are discussed with respect to the use of these techniques in naturalistic intervention and the relationship between their use and the discourse context of the intervention sessions. PMID- 27764431 TI - Difference Versus Deficit in Child African American English. AB - We propose that shared features (noncontrastive) between African American English (AAE) and Standard American English (SAE) may be more diagnostically salient than features not shared (contrastive) when identifying children of AAE language backgrounds with language disorders. The syntax of child speakers of AAE with language disorders (LD) and child speakers of AAE without language disorders (NLD) were compared. Syntactic features were transcribed from conversational language samples of seven LD and seven NLD children, and these features were classified according to their overlapping relationship with SAE. Shared features between AAE and SAE were designated as "noncontrastive" and features not shared as "contrastive". The production of several noncontrastive linguistic features were significantly different between groups, whereas group differences were nonsignificant for all contrastive features, with the exception of the past tense /ed/ morpheme. PMID- 27764432 TI - Beyond the Basics I: The Need for Strategic Sampling for In-Depth Phonological Analysis. AB - One of the challenges in the assessment of children with phonological disorders is the collection of a valid and reliable speech sample. Whichever framework is used, the sample can bias the analysis, sometimes in a way that fails to elucidate key phonological patterns. This article discusses sampling in terms of a current framework, nonlinear phonological analysis. It provides an overview of the theory and relevant sampling criteria and gives suggestions for elicitation. Nonlinear analyses examine multiple aspects or levels of a child's phonological system, providing a comprehensive basis for identifying strengths and needs. Whether or not nonlinear analyses are used, the principles and suggestions included provide general guidance for adequate sample elicitation. PMID- 27764434 TI - From the Editor... PMID- 27764433 TI - Beyond the Basics II: Supplemental Sampling for In-Depth Phonological Analysis. AB - Sometimes, a phonological sample is insufficient for describing patterns and determining goals for treatment. This article discusses how to evaluate a given word list in terms of a set of criteria for a detailed phonological analysis. In addition, suggestions are provided for sample supplementation for two frequent areas of difficulty in phonological development: CVC and CCV(C) word shapes and place sequences. PMID- 27764435 TI - Estimating the Risk of Future Reading Difficulties in Kindergarten Children: A Research-Based Model and Its Clinical Implementation. AB - PURPOSE: Speech-language pathologists have the skills and knowledge needed to play an important role in the early identification of children who are at risk for reading difficulties. Whereas research has identified language and other factors that may be predictive of future reading problems, studies have not provided the statistical models and classification data needed for the implementation of early identification programs. In this paper, we report the results of a longitudinal study that examined kindergarten predictors of second grade reading outcome. METHOD: Six hundred and four children were given a battery of language, early literacy, and nonverbal cognitive measures in kindergarten as part of an epidemiologic study of language impairments in children. Follow-up testing of reading achievement was completed in second grade. Participants were divided into those children with and without reading difficulties. RESULTS: Findings indicated that five kindergarten variables (letter identification, sentence imitation, phonological awareness, rapid naming, and mother's education) uniquely predicted reading outcome in second grade. CLINICAL IMPLICATIONS: A logistic regression formula and classification data based on these results are provided. Suggestions are offered concerning how this information could be used in an early identification and intervention program for children who are at risk for reading difficulties. PMID- 27764436 TI - Current Policies and New Directions for Speech-Language Pathology Assistants. AB - This article provides an overview of current American Speech-Language-Hearing Association (ASHA) policies for the appropriate use and supervision of speech language pathology assistants with an emphasis on the need to preserve the role of fully qualified speech-language pathologists in the service delivery system. Seven challenging issues surrounding the appropriate use of speech-language pathology assistants are considered. These include registering assistants and approving training programs; membership in ASHA; discrepancies between state requirements and ASHA policies; preparation for serving diverse multicultural, bilingual, and international populations; supervision considerations; funding and reimbursement for assistants; and perspectives on career-ladder/bachelor-level personnel. The formation of a National Leadership Council is proposed to develop a coordinated strategic plan for addressing these controversial and potentially divisive issues related to speech-language pathology assistants. This council would implement strategies for future development in the areas of professional education pertaining to assistant-level supervision, instruction of assistants, communication networks, policy development, research, and the dissemination/promotion of information regarding assistants. PMID- 27764438 TI - From the Editor... PMID- 27764437 TI - Professional Skills for Serving Students Who Use AAC in General Education Classrooms: A Team Perspective. AB - The roles of school-based professionals serving students with augmentative and alternative communication (AAC) needs are changing in light of the inclusion movement. Focus group research methodology was used to investigate professional skills regarded by educational team members as necessary to support students who used AAC in general education classrooms. Educational teams consisted of speech language pathologists, classroom teachers, inclusion support teachers, instructional assistants, and parents. All valued the ability to work collaboratively, provide access to the core curriculum, cultivate social supports, maintain and operate the AAC system, and create classroom structures to educate heterogeneous groups of students. Implications are discussed for AAC service delivery and the professional preparation of speech-language pathologists serving as members of AAC teams in inclusive classrooms. PMID- 27764439 TI - Multiple Perspectives for Determining the Roles of Speech-Language Pathologists in Inclusionary Classrooms. AB - Most likely, readers will be left with more questions than answers in reflecting on the six perspectives presented in the clinical forum. Despite the different points of view and approaches of the contributors, their message is clear. One aspect of this message is that a theoretical and empirical foundation has been laid for the use, and potential misuse, of collaborative, inclusionary models of service delivery and their related practices. The second aspect of the contributors' message is equally important. Regardless of variations in conceptual frameworks, we all share a common goal-to meet more effectively the needs of students with LLI who are being educated in inclusion programs. PMID- 27764440 TI - Maintaining a Therapeutic Focus and Sharing Responsibility for Student Success: Keys to In-Classroom Speech-Language Services. AB - Although speech-language pathologists in the schools are being encouraged to provide services more inclusively, they often express concern that they are becoming like classroom teachers and are "watering down" the therapy they should be providing to students on their caseloads. This article explores these concerns and offers solutions to the role confusion and dissatisfaction of many speech language pathologists who provide in-classroom speech-language services. Two key principles are offered to preserve the speech-language pathologist's role identity and the integrity of services provided: maintaining a therapeutic focus and sharing the responsibility for student success. PMID- 27764441 TI - Related Services Research for Students With Low-Incidence Disabilities: Implications for Speech-Language Pathologists in Inclusive Classrooms. AB - When speech-language pathologists provide educationally related services for students with lowincidence disabilities who are placed in inclusive classrooms, they are asked to work with a variety of other adults. The ways in which these adults make decisions about individualizing a student's educational program, determine related services, and coordinate their activities have an impact on educational outcomes for students as well as on interprofessional interactions. This article summarizes a team process for making related services decisions called VISTA (Vermont Interdependent Services Team Approach) and a series of nine research studies pertaining to the use and impact of VISTA. It also addresses related topics, such as team size, consumer perspectives, and paraprofessional supports. Five major implications from these studies are offered concerning (a) developing a disposition of being an ongoing learner, (b) developing a shared framework among team members, PMID- 27764442 TI - Investigating the Engagement and Learning of Students With Learning Disabilities in Guided Inquiry Science Teaching. AB - Contemporary reform efforts pose numerous challenges for students and their teachers, especially in the context of inclusion classrooms that serve students with diverse academic and social profiles. The research reported in this article was conducted for the purpose of closely studying the engagement and learning of students who have learning disabilities as they participate in a particular approach to guided inquiry called Guided Inquiry supporting Multiple Literacies (GIsML). Questions guiding the research included (a) What are the opportunities and challenges that GIsML instruction presents students with special needs? (b) How do students with special needs respond to these opportunities and challenges? and (c) What hypotheses emerge from the data that will usefully guide subsequent research investigating the means of mediating these students' participation in GIsML for the purpose of enhancing their engagement and learning? The research was conducted using an array of ethnographic methods. The findings were summarized in a set of claims concerning the engagement and learning of these students. Finally, cases of individual students were constructed to illustrate these claims. The article concludes with the case of one fourth-grade student as he engaged in a program of study investigating why objects float and sink. The case revealed (a) the ways in which, in the context of guided inquiry, the student achieved a number of positive outcomes; (b) how his learning problems, principally with regard to print literacy, revealed themselves in his activity; and PMID- 27764443 TI - Children With Language Impairment in Cooperative Work Groups: A Pilot Study. AB - PURPOSE: This pilot study examined the manner in which the individual social behavioral profiles of children with language impairment (LI) influenced their ability to work within cooperative groups. METHOD: Six children with LI each participated in four different cooperative work groups. In each of these groups, the child with LI interacted with two typically developing children (for a total of 48 different typical children). Groups were structured to make it possible for the child with LI to play a meaningful role in the interactions (e.g., assignment of specific roles). The success of each of these interactions was evaluated to determine the extent to which all of the children participated and worked together toward a joint goal. Social profiles of each of the children with LI were obtained using the Teacher Behavioral Rating Scale (TBRS, Hart & Robinson, 1996). The success of the collaborative work of each triad was then considered in light of the child's social profile. RESULTS: The success of the individual interactions was highly variable from child to child. However, the social profile of the child with LI appeared to be a good predictor of the child's ability to work with other members of the triad toward a joint goal. CLINICAL IMPLICATIONS: In facilitating cooperative groups, teachers and speech-language pathologists need to consider the social profiles, as well as the language levels, of children with LI who participate. Children who show withdrawn behaviors may need support to help them become more responsive to their partners. Children with LI who show withdrawn as well as aggressive behaviors may need a variety of accommodations, including specific intervention designed to help them understand the value of working with others. PMID- 27764444 TI - Scaffolds for Learning to Read in an Inclusion Classroom. AB - PURPOSE: This article describes a study on the scaffolding of learning to read in a primary-level, continuous-progress, inclusion classroom that stressed a critical thinking curriculum and employed a collaborative teaching model. Two emergent reading groups were the focus of study-one group that was taught by a general educator and the other by a special educator. The primary purposes were to discern the teachers' discourse patterns in order to define whether scaffolding sequences were more directive or more supportive and the degree to which these sequences represented differentiated instruction for children with a language learning disability (LLD). METHOD: Two students with an LLD and two younger, typically developing peers were videotaped in their emergent reading groups during an 8-week period. The distribution, types, and functions of teacher scaffolding sequences were examined. RESULTS: Both team members primarily used directive scaffolding sequences, suggesting that the assistance provided to children emphasized only direct instruction (skill learning) and not analytical thinking concerning phonemegrapheme relationships (strategy learning). Distribution of scaffolding sequence types directed to the four students indicated that the two children with an LLD were receiving reading instruction that was undifferentiated from the two typically developing, younger children. CLINICAL IMPLICATIONS: In order for children with an LLD to benefit from inclusion, explicit, systematic, and intensive instruction in phonological awareness and spelling-sound relationships should be implemented within the context of multilevel instruction that balances skill- and strategy-based learning. PMID- 27764446 TI - An Intervention Focus for Inclusionary Practice. PMID- 27764445 TI - Facilitating Language Development for Inner-City Children: Experimental Evaluation of a Collaborative, Classroom-Based Intervention. AB - PURPOSE: This study explores the effectiveness of a collaborative, classroom based model in enhancing the development of vocabulary and phonological awareness skills for kindergarten and first-grade children in an inner-city school district. METHOD: Four regular education teachers from the neighborhood school were randomly selected for participation. Children were randomly assigned to classrooms following usual school procedures. Two classrooms served as standard practice controls. In the other two classrooms, a collaborative service delivery model was implemented. One certified speech-language pathologist taught in each experimental classroom 2 1/2 days per week. The speech-language pathologist and the regular education teachers engaged in joint curriculum planning on a weekly basis. Vocabulary and phonological awareness instruction was embedded into ongoing curricular activities. Additionally, explicit instruction in phonological awareness was planned for a 25-minute small-group activity center weekly. RESULTS: Following the 6-month intervention, superior gains were noted in receptive vocabulary, expressive vocabulary, beginning sound awareness, and letter-sound associations for children in the experimental classrooms as compared to children in the standard practice control classrooms. The children in the experimental classrooms also showed greater improvement on a deletion task in comparison to the children in the standard practice classrooms. Importantly, this task was never used as an instructional activity, and thus demonstrated generalization to a novel phonological awareness task. CLINICAL IMPLICATIONS: The results are discussed with regard to the positive benefits of collaboration in facilitating the language abilities of inner-city children who are at risk for academic difficulties in the early elementary grades. PMID- 27764447 TI - From the Editor.... PMID- 27764448 TI - Dynamic Assessment of Diverse Children: A Tutorial. AB - Dynamic assessment (DA) has been advocated as an alternative and/or supplemental approach to traditional standardized testing with children who are culturally and linguistically diverse (CLD). However, there is great variability across DA methods and applications, as well as limited information concerning which methods and procedures may be best suited to differentiate language disorder from difference. In this tutorial, DA methods are compared with respect to their assessment applications. Next, an assessment protocol recommended for the identification of language disorder versus difference is described. Finally, examples of two Spanish-English bilingual children are used to show how the protocol may be useful to assess children's language-learning potential and to minimize misdiagnosis. PMID- 27764449 TI - Prologue: Recent Advances in Phonological Theory and Treatment. AB - With the introduction, development, and application of new theoretical frameworks, both assessment and treatment methods for phonological disorders may continue to be evaluated and improved on. It is hoped that this clinical forum will be of practical use to researchers and professionals alike in shaping their understanding of how phonological systems work generally, and in guiding the development of treatment programs. PMID- 27764450 TI - Complexity in Phonological Treatment: Clinical Factors. AB - The construct of complexity has been advanced recently as a potentially contributing variable in the efficacy of treatment for children with functional phonological disorders. Thus far, complexity has been defined in terms of linguistic and psycholinguistic structure, articulatory phonetic variables, and conventional clinical factors. The focus of this paper is on clinical complexity as it influences the selection of target sounds for treatment, with three clinical factors reviewed: consistency of the error, normative age of acquisition, and number of errors to be treated. The collective findings suggest that treatment of seemingly more complex targets results in greater phonological gains. These results are integrated with converging evidence from other populations and language and learning domains. PMID- 27764451 TI - Case Study: Optimality Theory and the Assessment and Treatment of Phonological Disorders. AB - Recently, the development of the constraint-based framework of optimality theory has been adopted and applied to the assessment and treatment of children with phonological disorders. This paper provides a demonstration of the application of optimality theory to the assessment and treatment of a single child with a phonological disorder. First, a tutorial of the theory is provided. Then, several prototypical error patterns evident in the child's productions are analyzed within the framework. These errors are accounted for by assuming that constraints against marked structure are ranked over constraints that require faithfulness to input forms within the child's grammar. Following that, a demonstration of how optimality theory accounts for different types of variation in the child's productions is provided. These different types of variation are revealing of the true nature of certain error patterns, particularly an apparent pattern of cluster reduction. Finally, the results of the analysis lead to suggestions for treatment that focus on the demotion of markedness constraints below faithfulness constraints. PMID- 27764452 TI - Implicationally Related Error Patterns and the Selection of Treatment Targets. AB - This paper compares some of the different claims that have been made concerning acquisition by traditional rule-based derivational theories and the more recent framework of optimality theory. Case studies of children with phonological delays are examined with special attention given to two seemingly independent error patterns, namely, place harmony and spirantization. Contrary to the expectations of derivational theories, these (and other) error patterns are argued to be implicationally related. Optimality theory is shown to offer a principled explanation for the facts with novel implications for clinical treatment. PMID- 27764453 TI - A Whole-Word Approach to Phonological Analysis and Intervention. AB - This paper introduces a whole-word approach to phonological analysis and then demonstrates the use of the approach by conducting an analysis and outlining treatment recommendations for a child with a phonological disability. Rationale for using a whole-word approach and also for defining phonological typologies are presented using the view that children are word oriented and use different patterns to acquire their phonological systems. New measures for word complexity and target proximity are explained, and four components of a phonological analysis are outlined and subsequently demonstrated. PMID- 27764454 TI - Prosodic Patterns in Children's Multisyllabic Word Productions. AB - This paper reviews results from a series of studies that examined the influence of metrical and segmental effects on English-speaking children's multisyllabic word productions. Three different approaches (prosodic structure, trochaic template, and perceptual salience) that have been proposed in the literature to account for children's prosodic patterns are presented and evaluated. An analysis of children's truncation or syllable deletion patterns revealed the following robust findings: (a) Stressed and word-final unstressed syllables are preserved more frequently than nonfinal unstressed syllables, (b) word-internal unstressed syllables with obstruent onsets are preserved more frequently than word-internal syllables with sonorant onsets, (c) unstressed syllables with non-reduced vowels are preserved more frequently than unstressed syllables with reduced vowels, and (d) right-sided stressed syllables are preserved more frequently than left-sided stressed syllables. An analysis of children's stress patterns revealed that children made greater numbers of stress errors in target words with irregular stress. Clinical implications of these findings are presented and additional studies that have applied a metrical approach to clinical populations are described. PMID- 27764455 TI - Epilogue: Recent Advances in Phonological Theory and Treatment. PMID- 27764456 TI - From the Editor... PMID- 27764457 TI - Evidence-Based Practice in Schools: Evaluating Research and Reducing Barriers. AB - This article examines the clinician/researcher relationship, suggests directions for improving the relationship, and discusses avenues for transferring information from research to clinical practice. An eight-step model for transferring research studies to practice is adopted, and three of the eight steps are targeted for discussion and illustration. To illustrate the use and interpretation of effect size measures for practical significance, as well as the transfer of research results to practice (evidence-based practice [EBP]), a case study from the contemporary literature is presented. Speech-language pathologists in schools and other work settings were surveyed to evaluate barriers to EBP. The survey suggested several possible barriers to EBP. For example, the speech language pathologists surveyed agreed that there is not enough time on the job for research and other EBP activities. Collaborations between clinicians and researchers are recommended as a good avenue for applied research. The methods illustrated for critically evaluating research are useful for engaging EBPs. Further, clinicians in schools are encouraged to adopt EBPs with active involvement in research collaboration whenever possible. PMID- 27764458 TI - "What Isn't Language?": A Qualitative Study of the Role of the School Speech Language Pathologist. AB - PURPOSE: This study examined how speech-language pathologists (SLPs) carry out their roles in the schools. The focus was on language as a domain of specialization and roles relative to other remedial educators. METHOD: The study was a qualitative constant-comparative design. Five Wyoming school SLPs and 15 teachers from their five schools participated. RESULTS: Results showed that language was difficult to define and delimit. Language was present throughout the curriculum and all of the educators taught it. The SLPs and resource teachers demonstrated similar types of language instruction. Oral language and speech were clearly specialty domains of the SLPs. The SLPs were also distinctive in terms of the instructional framework and service delivery structure. IMPLICATIONS: The findings contribute to understanding the role of SLPs in the schools and how these roles complement and overlap with other remedial educators. PMID- 27764459 TI - Frameworks of Education: Perspectives of Southeast Asian Parents and Head Start Staff. AB - PURPOSE: Interviews with Southeast Asian families and Head Start staff, participant observation of family and staff conferences, observations of teacher child and parent-child interactions, and a review of all written Head Start information given to parents were used to gain information regarding how Southeast Asian parents, children, and Head Start staff make sense of early childhood education, their roles in child learning, and the identification of disabilities or learning problems. METHODS: Nine Southeast Asian families and 10 children were participants. One Vietnamese and 3 EuroAmerican Head Start staff members participated in a series of two or three semistructured individual interviews. Additionally, 3 families were observed during scheduled conferences with Head Start staff. Each child was observed at Head Start during meals, center time, and outdoor play time. All literature routinely given to parents was analyzed. Ethnomethodology (the study of how participants make sense of their world) was used in collection and analysis of the data. The constructs of organizational culture (Schein, 1987, 1992), independence/interdependence, and power/distance relationships were used to help to make sense of the data themes. CLINICAL IMPLICATIONS: Both families and staff were unaware of differences in their beliefs and values in the areas of education, parenting, child learning, and disability, which led to confusion and misunderstanding. All early childhood staff need to be aware of their underlying assumptions and how these may affect their interactions with children and families who may have different assumptions and expectations. PMID- 27764460 TI - Early Intervention Practices and Communication Intervention Strategies for Young Males With Fragile X Syndrome. AB - PURPOSE: This study describes speech-language pathologists' impressions of the communication difficulties of young males with fragile X syndrome (FXS) and the need for both syndrome-specific and individualized interventions. The findings of a regional study that identified speech-language pathologists' impressions of the speech, language, and behavioral difficulties experienced by males with FXS and an array of interventions used by speech-language pathologists to improve communication skills for these children are reported. METHODS: Fifty-one speech language pathologists providing intervention for males with FXS ranging in age from 2 to 9 years (mean age=6;3 [years;months]) were interviewed. RESULTS: The majority of the speech-language pathologists reported that boys with FXS exhibit a visually based, experiential or wholistic learning preference. They emphasized the necessity of making environmental accommodations for limited attention span, difficulties with topic and activity transitions, sensory deficits, and low threshold for anxiety. They reported that speech goals focused on slowing rate and increasing precision for verbal children and both low and high levels of assistive technology for nonverbal or minimally verbal children. Language goals focused on listening, auditory comprehension, and narrative/conversation skills. Pragmatic goals emphasized social dialogue, role playing, and topic maintenance. CLINICAL IMPLICATIONS: This study suggests that young males with FXS present the clinician with a constellation of behaviors and communication impairments that are both syndrome specific and symptom familiar. The specific communication strengths and deficits described by clinicians working with these children are common to many children with speech and language impairments compounded by cognitive deficits. Intervention programs for young boys with FXS should also attend closely to the specific behavioral (e.g., increased anxiety, attention deficits) and sensory "overload" problems they often exhibit before designing a tailored intervention program. PMID- 27764461 TI - Measures of Language Development in Fictional Narratives of Latino Children. AB - PURPOSE: This preliminary study was designed to determine whether commonly used measures of language productivity, sentence organization, and story structure were sensitive to developmental differences in narratives produced by Latino preschool children from a low-socioeconomic status (SES) community. METHOD: Twenty-four children, divided equally into younger and older groups, produced oral narratives that corresponded with the wordless picture book, Frog, Where Are You? (Mayer, 1969). Their narratives were analyzed for productivity (total number of words, total number of different words), sentence organization (number of utterances, mean length of C unit in words, and percentage of grammatically acceptable utterances), and story structure (complete and incomplete narrative episodes). RESULTS: The length of children's narratives did not differ significantly by age. However, older Latino children produced stories that contained longer sentences, a higher proportion of grammatically acceptable sentences, and more complete episodes than did younger children. CLINICAL IMPLICATIONS: These results suggest that measures of language productivity (such as total number of words and number of different words) that reflect developmental differences in monolingual mainstream preschoolers may not be sensitive indicators of narrative language development in young Latino children from low-SES environments. However, measures of syntactic accuracy and episodic structure are likely to be valid indicators of developmental changes in these children's narrative abilities. PMID- 27764462 TI - The Relative Importance of Selected Communication Skills for Adolescents' Interactions With Their Teachers: High School Teachers' Opinions. AB - PURPOSE: This study investigated the opinions of high school teachers regarding the relative importance of selected communication skills for their students' communication with them and explored if the content areas in which the teachers taught or the amount of high school teaching experience they had were associated with their opinions. METHOD: Teachers ranked 14 communication skills according to perceived order of importance for Grade 10 adolescents' communication with them as teachers. RESULTS: Teachers tended to perceive skills associated with discourse management strategies as relatively more important than other skills. The two communication skills that were associated with metalinguistic/figurative language aspects of communication were ranked as least important. Inexperienced and experienced high school teachers tended to rank the importance of the communication skills similarly, as did sciences and humanities teachers, except for the communication skill of turn taking, which sciences teachers ranked higher than humanities teachers. CLINICAL IMPLICATIONS: The results provide guidelines for developing intervention approaches that can facilitate successful communicative interactions in high school environments and target goals that teachers of adolescents with language and/or learning disabilities perceive as more important for teacher-adolescent interactions. PMID- 27764463 TI - Emotion Regulation in Children With Specific Language Impairment. AB - PURPOSE: The purpose of this preliminary study was to determine if emotion regulation warrants investigation as a factor influencing social outcomes in children with specific language impairment (SLI). Emotion regulation was evaluated in children with SLI and their typically developing peers. METHOD: Teachers were asked to rate the emotion regulation behaviors of 41 children with SLI and 41 typical peers using the "Emotion Regulation Checklist" (ERC, Shields & Cicchetti, 1997; 1998). Children were sampled from two age levels (6-9 years and 10-13 years). At each age level, equal numbers of boys and girls were sampled. RESULTS: As a group, children with SLI received significantly lower ratings than typical children. In addition, girls produced higher scores than boys. None of the other interactions was significant. Scores on the two subscales of the ERC, labeled as lability/negativity and emotion regulation, were then examined to further delineate performance. Boys with SLI had notably lower ratings than all the other groups on the emotion regulation subscale. CLINICAL IMPLICATIONS: Emotion regulation warrants further research to determine if it is associated with specific social outcomes in children with SLI. PMID- 27764464 TI - The Use of Repair Strategies by Children With and Without Hearing Impairment. AB - PURPOSE: This study examined how students with hearing impairments, having different levels of speech intelligibility, responded to a communication breakdown as compared to students with normal hearing. METHOD: Participants included 16 students with profound hearing impairment who were assessed as having ageappropriate expressive language (8 with good speech intelligibility and 8 with poor speech intelligibility) and 10 students with normal hearing, ages 11-18 years. The students' task was to describe pictures and to respond to a series of three clarification requests ("Huh?," "What?," and "I didn't understand") presented by the examiner. RESULTS: Repetition was the most frequently used strategy by all groups. However, significant differences emerged in the use of other repair strategies among the three groups. The group's choice of strategies across the three requests also differed significantly. CLINICAL IMPLICATIONS: Although the groups evidenced similar levels of age-appropriate expressive language, they appeared to differ in its pragmatic use. It was suggested that strategy training programs should consider the speech intelligibility of the speaker and be tailored according to individual needs. PMID- 27764465 TI - A Case Management Model for School-Age Children With Multiple Needs. AB - Although the American Speech-Language-Hearing Association (ASHA) includes case management among the responsibilities for school-based speech-language pathologists, there is limited information in the speech-language pathology literature describing models of, or best practice for, case management in the schools. Recent amendments to the Individuals With Disabilities Education Act (1997) focusing on enhancing students with disabilities involvement and progress in the general curriculum and participation in state- and district-wide assessment suggest that the speech-language pathologist serving as case manager should effectively coordinate appropriate accommodations and adaptations. The authors describe a case management model for speech-language pathologists working with school-age children who have multiple needs. The skills necessary for effective case management are outlined and functional outcomes are demonstrated with a child and family story. PMID- 27764466 TI - The Transition Process in the Early Years: Enhancing Speech-Language Pathologists' Perspectives. AB - The purpose of this clinical exchange is to provide speech-language pathologists with the basic information needed to participate as active, informed, and effective members of transition teams. A speech-language pathologist's role of bridging language and curriculum across the grades creates a unique opportunity to bring meaningful contributions to the transition process. Typical speech language pathology preparation does not focus on the specifics of the transition process. This article provides speech-language pathologists, as well as families and other professionals, with information pertaining to transitions in the early years, particularly between preschool settings and kindergarten. Expertise in the transition process is necessary for effective participation and implementation. This article will highlight challenges in transition and delineate specific components of transition planning. The article will conclude with a set of best practices that can provide the foundation of a model for early transitions. PMID- 27764467 TI - From the Editor.... PMID- 27764468 TI - Designing and Implementing an Early Literacy Screening Protocol: Suggestions for the Speech-Language Pathologist. AB - The American Speech-Language-Hearing Association (2001) recently asserted that speech-language pathologists can and should play an important role in promoting literacy for young children with communicative impairments. Early literacy screening provides a valuable tool for speech-language pathologists to use for the timely detection of difficulties in literacy achievement. In addition, results of early literacy screening can be used to guide intervention and instruction. This article provides a rationale for incorporating early literacy screening into service delivery. It also makes recommendations for determining which children and what areas of literacy should be targeted in screening activities. Suggestions for interpreting findings are also provided, as are strategies for using screening to guide early literacy intervention. PMID- 27764469 TI - From the Editor.... PMID- 27764470 TI - The Benefits of Sound Field Amplification in Classrooms of Inuit Students of Nunavik: A Pilot Project. AB - PURPOSE: This pilot study investigated the potential benefits of sound field amplification for Inuit first and second language learners in a remote community of Nunavik, Northern Quebec. Hearing screening results showed that 26% of students attending the local school had hearing loss due to otitis media. The study used speech intelligibility and attending behavior measures, as well as interviews, to examine the appropriateness of sound field amplification in the multilingual and multilevel instructional contexts found in the classrooms of Nunavik. METHOD: Sound field amplification systems were installed in three representative classrooms for a period of 3 months. Speech intelligibility of Inuttitut syllables was compared in amplified versus non-amplified conditions for 10 students with hearing loss and 10 age-matched normal hearing peers. Observations of four categories of attending behaviors for a separate set of seven students were carried out prior to the installation of the systems and with the systems in place. Teacher and student comments were collected during the study and after the study was completed. RESULTS: Results showed significant improvements in speech intelligibility scores for students with hearing impairment and normal hearing in the amplified condition. Total scores for on task behavior improved for six of the seven students observed; all students demonstrated improvement in at least one category of attending behavior. Teacher and student comments identified numerous advantages of the amplification systems. IMPLICATIONS: Results point to the potential benefits of sound field amplification for multicultural populations that are similarly challenged by high rates of hearing loss, as well as for second language learners. PMID- 27764471 TI - From Old to New: Examining Score Increases on the Peabody Picture Vocabulary Test III. AB - The Peabody Picture Vocabulary Test-III (PPVT-III, Dunn & Dunn, 1997) is a relatively recent revision of the old standby, the Peabody Picture Vocabulary Test-Revised (PPVT-R, Dunn & Dunn, 1981). Although the new vocabulary test appears to be improved in several aspects, there is one change that warrants serious attention. Data indicate that children from 4 to 10 years of age are scoring, on average, 10 standard score points higher on the PPVT-III than on the PPVT-R (Williams, 1998). This article investigates possible reasons for this change and discusses implications for clinical practice. PMID- 27764472 TI - The New Peabody Picture Vocabulary Test-III: An Illusion of Unbiased Assessment? AB - This article examines whether changes in the ethnic minority composition of the standardization sample for the latest edition of the Peabody Picture Vocabulary Test (PPVT-III, Dunn & Dunn, 1997) can be used as the sole explanation for children's better test scores when compared to an earlier edition, the Peabody Picture Vocabulary Test-Revised (PPVT-R, Dunn & Dunn, 1981). Results from a comparative analysis of these two test editions suggest that other factors may explain improved performances. Among these factors are the number of words and age levels sampled, the types of words and pictures used, and characteristics of the standardization sample other than its ethnic minority composition. This analysis also raises questions regarding the usefulness of converting scores from one edition to the other and the type of criteria that could be used to evaluate whether the PPVT-III is an unbiased test of vocabulary for children from diverse cultural and linguistic backgrounds. PMID- 27764473 TI - Improving Acoustics in American Schools. PMID- 27764474 TI - Acoustical Barriers to Learning: Children at Risk in Every Classroom. AB - There are surprisingly large numbers of children with various auditory disorders in the schools. Their classrooms are often noisy, reverberant, and active places of learning. For these children, their auditory problems plus the poor classroom acoustics cause significant learning problems. Poor listening conditions can affect all children, but they affect those with auditory disorders more. Improving classroom acoustics can significantly reduce the negative educational impact of auditory disorders. This article reviews relevant literature on acoustical barriers to successful learning and provides guidance for school personnel making decisions regarding classroom facilities. PMID- 27764475 TI - Classroom Acoustics for Children With Normal Hearing and With Hearing Impairment. AB - Past investigations demonstrate that the acoustical environment of a classroom is a critical factor in the academic, psychoeducational, and psychosocial achievement of children with normal hearing and with hearing impairment. This article examines several acoustical variables, such as noise, reverberation, and speaker-listener distance, which can deleteriously affect speech perception in classrooms. Moreover, the discussion examines the effects of these variables on the speech perception abilities of both children with normal hearing and children with hearing loss. Finally, appropriate acoustical criteria are suggested for children in educational settings. PMID- 27764476 TI - Classroom Amplification Technology: Theory and Practice. AB - Many children are struggling to listen and learn in noisy and reverberant classrooms. Some of these children have hearing loss; others have essentially normal hearing but are at risk for accurate speech perception. Hearing aid fitting protocols and technology can be effective for children with hearing loss, but the aids must be selected and adjusted for classroom environments. For many children, personal amplification may not provide enough benefit for listening and learning to occur. For children who require more than a hearing aid and for at risk children who have difficulty separating the teacher's message from background noise, technology that is specifically designed to improve the classroom signal-to-noise ratio (SNR) may be required. In addition to the use of technology, children must learn to listen effectively in order for a meaningful signal to be received and used. PMID- 27764477 TI - Ten Ways to Provide a High-Quality Acoustical Environment in Schools. AB - The purpose of this article is to describe the use of impulse response measures and observations in Florida classrooms. As a result of measures and observations in "healthy" and poor acoustical environments, 10 practical recommendations are proposed for improving the acoustical environment in schools. The primary research for these recommendations consisted of recording acoustical measurements of reverberation time and background noise, as well as newer acoustical measurements based on impulse response techniques, in 56 actual classrooms. Observations of classroom situations occurred in a subset of these schools. Computer and physical models of eight classrooms were constructed and tested with varying room finish materials and background noise levels to study the comeverberation bined effects of these architectural items on speech perception in the model rooms. The primary recommendations all relate to school design and planning. These include air-conditioning system selection and noise control techniques to minimize interference with listening, interior classroom acoustical design principles for maximizing speech perception, and the documentation of teaching methods and classroom arrangements that result in improving speech intelligibility and other factors affecting speech perception. PMID- 27764479 TI - Improving Acoustics in American Schools. PMID- 27764478 TI - The Classroom Acoustical Environment and the Americans With Disabilities Act. AB - Audiologists and acoustical engineers have urged that acoustics be considered in the design of classrooms for more than 30 years. Research has demonstrated that children with hearing loss have great difficulty understanding speech in noisy, reverberant environments. However, there has never been a legal mechanism to require local educational systems to address acoustics in the design and construction of schools. An effort by a broad-based coalition of engineers, audiologists, parents, architects, and educators is now underway to develop a standard for acoustics that would then be referenced in the Americans with Disabilities Act (ADA). Although the legal mechanism for this action is to address the needs of children with disabilities as the ADA requires (most notably, children with hearing impairments, but also those with central auditory disorders, attention deficit disorders, and vision impairments), the impact will be more far-reaching. All children-whether or not they have a disability-will benefit from a favorable acoustical environment. PMID- 27764480 TI - Improving Acoustics in American Schools: Working Draft of Standard "Acoustics in School Classrooms and Other Learning Spaces". PMID- 27764481 TI - From the Editor... PMID- 27764482 TI - Prologue: Toward an Understanding of Literacy Issues in Multicultural School-Age Populations. PMID- 27764483 TI - Home Literacy Experiences and Their Relationship to Bilingual Preschoolers' Developing English Literacy Abilities: An Initial Investigation. AB - PURPOSE: This study investigated the relationship between home literacy experiences and bilingual preschoolers' early literacy outcomes. METHOD: Forty three Puerto Rican mother-child dyads recruited from Head Start programs in central Pennsylvania participated in this study of home literacy experiences and emerging English literacy abilities. The dyads were grouped according to whether the children had learned Spanish and English from birth (simultaneously; n=28) or Spanish from birth and English in Head Start (sequentially; n=15). Mothers of simultaneous and sequential learners were compared on the value they placed on literacy, press for achievement, the number of reading materials that were available in the home, and how often they read to their child. The children were compared on their scores on the Test of Early Reading Ability-2 (Reid, Hresko, & Hammill, 1991), which was given during the first and second years of their Head Start program. RESULTS: Mothers of simultaneous and sequential learners differed with regard to mothers' press for achievement. No differences were found between the two groups with respect to the other measures. When the early literacy abilities of the two groups of children were assessed, all learners had comparable mean emergent reading scores. The mean literacy scores of the entire group of children were significantly lower at Year 2 as compared to Year 1. CLINICAL IMPLICATIONS: Although the children experienced literacy activities at home and in Head Start, it appears that children's literacy development would benefit from increased exposure to literacy materials and literacy events during the preschool years. PMID- 27764484 TI - From the Editor.... PMID- 27764485 TI - Early Positive Predictors of Later Reading Comprehension for African American Students: A Preliminary Investigation. AB - PURPOSE: This investigation examined the performance of 50 African American children on a reading comprehension test. METHOD: Longitudinal data were compared for two groups of students who were preschoolers or kindergartners at Time 1 and elementary-grade students at Time 2. Outcomes were examined for positive predictive relationships based on their oral language and cognitive skills as preschoolers and kindergartners at Time 1. The Time 1 preschoolers were all from low-income homes, whereas the Time 1 kindergartners were all from middle-income homes. All students were urban dwellers and speakers of African American English. RESULTS: Two measures predicted later reading comprehension levels for the Time 1 preschoolers: use of complex syntax and shape matching. The Time 1 preschoolers and kindergartners showed no significant differences in reading comprehension at the end of first grade, but the preschoolers were significantly ahead of the kindergartners in reading by third grade. CLINICAL IMPLICATIONS: The potential of preschools that emphasize early language and literacy for improving the reading outcomes of African American students is discussed. PMID- 27764486 TI - Alternative Assessment of Language and Literacy in Culturally and Linguistically Diverse Populations. AB - Over- and underdiagnosis of language and literacy problems are common with low socioeconomic status ethnically and racially diverse children. In recent years, a number of alternative assessment procedures have been developed that reduce some of the biases inherent in norm-referenced standardized tests. Problems and recent solutions to the use of norm-referenced testing will be discussed, with a focus on processing-dependent and dynamic assessment procedures. PMID- 27764487 TI - Comparison of Spanish, English, and Bilingual Children's Performance Across Semantic Tasks. AB - PURPOSE: This study investigated predominantly Spanish-speaking, predominantly English-speaking, and Spanish-English bilingual children's performance on a battery of semantic tasks. METHOD: Six semantic tasks (associations, characteristic properties, categorization, functions, linguistic concepts, and similarities and differences) were developed in Spanish and English. The tasks contained comparable items but were not direct translations of each other. Each task consisted of expressive and receptive items. Predominantly Spanish-speaking children completed the tasks in Spanish, predominantly English-speaking children completed the tasks in English, and bilingual children completed the tasks in Spanish and English. RESULTS: Children in all three groups achieved similar average levels of performance on the assessment battery. However, there were differences in the patterns of performance for English and Spanish, as well as group performance differences when compared in the same language. CLINICAL IMPLICATIONS: These findings highlight the importance of testing bilingual children in both of their languages and across a variety of semantic tasks in order to gain insight into bilingual children's semantic knowledge. PMID- 27764488 TI - Cultural Knowledge in African American Children. AB - PURPOSE: This study sought to determine whether typically developing African American children's culturally based mainstream and ethnocultural knowledge increased between grades four and six. Because a lack of mainstream cultural knowledge has been implicated in reduced reading comprehension among many African American children, this study also investigated the degree to which ethnocultural and mainstream cultural knowledge differed. METHOD: Fifty-eight African American children in grades four, five, and six responded to the Test of Core Knowledge (Bradford & Harris, 2000), a divergent task that required free associations about topics drawn from both mainstream and African American history, arts, and news events. Responses were audiotape-recorded, orthographically transcribed, and analyzed for accuracy and quantity of information. RESULTS: Participants' knowledge of both mainstream and African American cultural items increased significantly between grades four and five and their knowledge of history, news events, and African American arts increased significantly between grades four and six. Additionally, significant differences were found between grades five and six for mainstream and African American news events. CLINICAL IMPLICATIONS: This sample of African American children demonstrated mainstream cultural knowledge that often surpassed ethnocultural knowledge. Such broadbased mainstream cultural knowledge meets academic expectations and can be used to facilitate further development of language and reading comprehension skills. However, this finding also suggests the need for future investigations of the relationship between mainstream cultural knowledge and literacy, bicultural knowledge in African American children from lower socioeconomic status and/or more ethnocentric backgrounds, and bicultural knowledge in those children who have language and reading comprehension deficits. PMID- 27764489 TI - Contextual Variation, Familiarity, Academic Literacy, and Rural Adolescents' Idiom Knowledge. AB - PURPOSE: The paucity of data on idiom development in adolescents, particularly rural adolescents, limits the ability of speech-language pathologists and educators to test and teach idioms appropriately in this population. This study was designed to delineate the interrelationships between context, familiarity, and academic literacy relative to rural adolescents' idiom knowledge. METHOD: Ninety-five rural eighth graders (M age=13.4 years) were quasi-randomly assigned to complete the Idiom Comprehension Test (Qualls & Harris, 1999) in one of three contexts: idioms in a short story (n=25), idioms in isolation (n=32), and idioms in a verification task (n=38). For all conditions, the identical 24 idioms-8 each of high, moderate, and low familiarity (Nippold & Rudzinski, 1993)-were presented. For a subset (N=54) of the students, reading and language arts scores from the California Achievement Tests (5th ed., 1993), a standardized achievement test, were correlated with performance on the idiom test. RESULTS: Performance in the story condition and on high-familiarity idioms showed the greatest accuracy. For the isolation and verification conditions, context interacted with familiarity. Associations existed between idiom performance and reading ability and idiom performance and language literacy, but only for the story and verification conditions. High-proficiency readers showed the greatest idiom accuracy. CLINICAL IMPLICATIONS: The results support the notion that context facilitates idiom comprehension for rural adolescents, and that idiom testing should consider not only context, but idiom familiarity as well. Thus, local norms should be established. Findings also confirm that good readers are better at comprehending idioms, likely resulting from enriched vocabulary obtained through reading. These normative data indicate what might be expected when testing idiom knowledge in adolescents with language impairments. PMID- 27764490 TI - Epilogue: Toward an Understanding of Literacy Issues in Multicultural School-Age Populations. PMID- 27764491 TI - Comparison of Three Approaches to Supplementary Reading Instruction for Low Achieving Second-Grade Readers. AB - PURPOSE: This research evaluated the relative effectiveness of three instructional approaches to supplementing the regular reading program for second graders with low word reading and/or pseudoword reading skills. METHOD: In the instructional experiment, 96 second graders with low reading achievement were randomly assigned to one of four conditions: (a) explicit and reflective word recognition, (b) explicit and reflective reading comprehension, (c) combined explicit word recognition and explicit reading comprehension, or (d) treated control that only practiced reading skills without any instruction. In the extension study, these conditions were compared to an untreated control group of 29 second graders. RESULTS: In the instructional experiment, combined word recognition and reading comprehension treatment increased phonological decoding (pronouncing pseudowords) significantly more than the treated control or word recognition only treatment and had the highest effect size. The comprehension only treatment was not significantly different from the treated control. In the extension study, (a) the treated children receiving supplemental instruction improved significantly more in phonological decoding and reading real words than did those in the regular program, and (b) the combined word recognition and reading comprehension treatment, which was explicit, had the highest effect sizes for both pseudoword and real-word reading. CLINICAL IMPLICATIONS: The most effective supplemental instruction for increasing phonological decoding was combining explicit word recognition and explicit reading comprehension training. PMID- 27764492 TI - Interactive Behaviors in Adolescent Conversation Dyads. AB - PURPOSE: Verbal and nonverbal conversational behaviors often are the target of intervention for adolescents with social communication disorders. There are, however, few sources of data on the interactive conversational behaviors of typically developing adolescents that can be used as guidelines when working with clinical populations. The purpose of this study was to collect behavioral data from conversations of adolescents so as to provide comparison data for adolescents with communication disorders. METHOD: Conversational behaviors were measured in 50 typically developing African American and Caucasian adolescents (24 females, 26 males) from the Midwest United States who engaged in extemporaneous, 3-minute conversations in dyads with peers. The effects of age, race, and sex of the participant were assessed. RESULTS: Behaviors occurring at relatively high frequencies included directing gaze at the partner, particularly during listening; nodding and showing neutral and positive facial expressions; using back-channel responses; and giving contingent responses. Participants rarely showed negative emotions, turned away from each other, asked for clarification, or failed to answer questions. Overall, there were few effects of race and sex of the speaker and greater variability within than between groups. CLINICAL IMPLICATIONS: The data may serve as a source of information for clinicians serving individuals with communication disorders, with the caveat that the conversations included here represent a subset of typical adolescent interactive conversational behaviors. PMID- 27764493 TI - Young Children's Letter-Sound Knowledge. AB - PURPOSE: This study compares three essential skills in early literacy: letter sound recognition, letter-sound recall, and letter reproduction. Previous research comparing these aspects of letter-sound knowledge is limited. METHOD: Eighty-three normally developing children between the ages of 4:11 (years:months) and 6:4 were asked to recognize (i.e., point to the appropriate letter when the letter's sound is given), recall (i.e., say the letter's sound), and reproduce (i.e., write the letter when the letter's sound is given) 32 letter sounds. RESULTS: The children performed better in letter-sound recognition than in letter sound recall, and better in letter-sound recall than in letter reproduction. Girls performed no differently from boys. Younger children performed as well as older children. Socioeconomic status had significant influence on the level of development for all tasks. CLINICAL IMPLICATIONS: Clinicians and educators need to be aware of the different aspects of letter-sound knowledge development and how it can be assessed so that intervention can follow the normal developmental sequence of acquisition. PMID- 27764494 TI - A Prospective Longitudinal Study of Phonological Development in Late Talkers. AB - PURPOSE: This study involved prospective longitudinal data on 5 late talkers to provide information about the course of phonological development in order to identify possible predictors of delayed versus deviant development. METHOD: Five children (3 boys, 2 girls) were identified as late talkers and divided into a younger group and an older group. Each child was followed monthly for 10 to 12 months (22-33 months for the younger group and 30-42 months for the older group). Two types of monthly language samples (free play and elicited) were obtained to describe the individual courses of phonological development for each child. Independent and relational analyses were completed at each age to describe word initial and word-final phonetic inventories, syllable structure, syllable diversity, percentage of consonants correct (PCC), sound variability, and error patterns. RESULTS: The results indicated that 3 of the children resolved their late onset of speech by 33 to 35 months of age. In addition to quantitative factors, (e.g., limited phonetic inventory, lower PCC, and more sound errors), qualitative variables (e.g., atypical error patterns, greater sound variability, and slower rate of resolution) also were identified as potential markers of long term phonological delay. CLINICAL IMPLICATIONS: This study provides information to clinicians so they can identify those children who are less likely to resolve their late onset of phonological development without direct intervention. Procedures are described for assessing early linguistic behaviors that incorporate independent and relational analyses on more extensive speech samples (elicited and free play). From these analyses, clinicians can examine quantitative and qualitative variables to differentiate phonological delay from deviance. PMID- 27764495 TI - Facilitating Peer-Group Entry in Kindergartners With Impairments in Social Communication. AB - PURPOSE: This series of case studies examined the efficacy of intervention designed to teach peer-group entry skills to kindergartners with social interaction and communication deficits. METHOD: The participants were 3 kindergartners at the University of Washington Experimental Educational Unit (EEU) who were selected because of difficulty with peer-group entry and cooperative play as compared to other children in the classroom. The intervention program included direct treatment of the children by the primary researcher and teachers in the classroom. The intervention was modeled on research describing a sequential peer-entry hierarchy that incorporated the children moving from low risk strategies to high-risk strategies. Specifically, the treatment focused on teaching the children to use props to facilitate the production of high-risk verbal statements. RESULTS: Results demonstrated increases in (a) children's use of props and verbal statements to enter peer groups, (b) cooperative play, and (c) time spent interacting with peers. Results also indicated that following treatment, the children's behaviors more closely resembled those of their comparison peers. CLINICAL IMPLICATIONS: Results are encouraging for suggesting strategies for working with kindergartners who exhibit social communication interaction problems. The data indicate that a combined speech-language pathologist/teacher intervention using modeling and prompting with visual stimuli may be successful in teaching children to use props and specific verbal statements as a means of entering peer groups and engaging in cooperative play. PMID- 27764496 TI - From the Editor.... PMID- 27764497 TI - From the Editor.... PMID- 27764498 TI - From Ear to Cortex: A Perspective on What Clinicians Need to Understand About Speech Perception and Language Processing. AB - Phoneme-sized phonetic segments are often defined as the most basic unit of language organization. Two common inferences made from this description are that there are clear correlates to phonetic segments in the acoustic speech stream, and that humans have access to these segments from birth. In fact, well replicated studies have shown that the acoustic signal of speech lacks invariant physical correlates to phonetic segments, and that the ability to recognize segmental structure is not present from the start of language learning. Instead, the young child must learn how to process the complex, generally continuous acoustic speech signal so that phonetic structure can be derived. This paper describes and reviews experiments that have revealed developmental changes in speech perception that accompany improvements in access to phonetic structure. In addition, this paper explains how these perceptual changes appear to be related to other aspects of language development, such as syntactic abilities and reading. Finally, evidence is provided that these critical developmental changes result from adequate language experience in naturalistic contexts, and accordingly suggests that intervention strategies for children with language learning problems should focus on enhancing language experience in natural contexts. PMID- 27764499 TI - Partner Influences on the Social Pretend Play of Children With Language Impairments. AB - PURPOSE: This study examined the social pretend play and conversational behaviors of children with language impairment (LI) in dyadic interactions with peers. METHOD: The participants (aged 4;3 [years;months] to 6;2) were 3 boys with LI and 4 with typical language development (LN). In this multiple embedded case study, hypotheses regarding the sophistication of verbal interaction and social pretend play were developed and tested with respect to two cases. Each case consisted of five interactions-four involving a child with LI in dyadic play with peers (2 LI, 2 LN), and the last involving the 2 LN peers. The dyad types for each case were LI, mixed, and LN. Within each case, LI dyads were expected to perform less well than mixed dyads, who were, in turn, expected to perform less well than the LN dyad on measures of verbal interaction and social pretend play. Also, greater conversational success was expected in social pretend play than in other forms of play for all dyads. RESULTS: For both cases, the results for verbal sophistication generally conformed to expectations for the dyad types. In contrast, social pretend play behaviors were inconsistent with expectations across dyads and cases. In all dyads, social pretend play yielded greater conversational success than other forms of play. The quality of play varied as a function of partner characteristics, such as responsiveness, theme knowledge, verbal skill, and adaptability. CLINICAL IMPLICATIONS: Clinicians are cautioned to ensure that evaluations of play in children with LI encompass multiple aspects of both play and conversation, as well as observation of children with multiple partners. Likewise, in planning interventions, it may be important to address both play and verbal behaviors and to incorporate opportunities for interaction with multiple partners. PMID- 27764500 TI - Responsiveness of Child Care Providers in Interactions With Toddlers and Preschoolers. AB - PURPOSE: This exploratory study investigated the responsive language input of 26 child care providers to young children enrolled in community child care centers. METHOD: Three subtypes of responsive interaction strategies were rated and compared across two age groups (toddlers, preschoolers) and two naturalistic contexts (book reading, play dough activity). The toddlers were between 17 and 33 months of age and the preschoolers were between 30 and 53 months of age. Caregiver-child interactions were rated using the Teacher Interaction and Language Rating Scale (Girolametto, Weitzman, & Greenberg, 2000) to provide information about the frequency of responsive language strategies. RESULTS: Caregivers used similar levels of child-centered and interaction-promoting strategies with both age groups, but used more labelling with toddlers and more topic extensions with preschoolers. The context of the interaction exerted a systematic influence on the caregivers' use of responsive strategies, with the play dough activity providing the most responsive input overall. There was a strong positive relationship between all three subtypes of caregivers' responsiveness and variation in the preschoolers' language productivity. In contrast, only interaction-promoting strategies were positively related to measures of the toddlers' language productivity. CLINICAL IMPLICATIONS: The results of this study suggest that caregivers' responsiveness in group interactions is highly dependent on the context of the interaction and, to a lesser extent, on the language abilities of the children. Future research is required to determine if inservice training can enhance levels of responsiveness and accelerate language learning in young children in group care. PMID- 27764501 TI - Predicting Job Satisfaction Among Speech-Language Pathologists Working in Public Schools. AB - PURPOSE: The aims of the present study were (a) to compare the job satisfaction ratings of speech-language pathologists (SLPs) working in schools with other workers on a standardized index and (b) to examine whether geographic setting (i.e., rural, suburban, and urban), specific demographic variables (i.e., gender, ethnicity, age, and education), and practice-related variables (i.e., years in current position and caseload size) explain/predict job satisfaction among SLPs working in public schools. METHOD: A mail survey methodology was employed. Two thousand practicing SLPs, members of the American Speech-Language-Hearing Association (ASHA), residing in the United States were randomly selected from the national membership list. Usable responses were obtained from 1,207 SLPs, representing a 60.4% response rate. Participants completed the Job Satisfaction Survey (Spector, 1996), demographic and practice-related questions, and information regarding their geographic work setting. RESULTS: These results suggest that the majority of SLPs are generally satisfied (42.2%) or highly satisfied (34.1%) with their jobs. Results of the regression analyses revealed that the age of participants (i.e., older were more satisfied), years at current job (i.e., SLPs with greater number of years were more satisfied), and caseload size (i.e., SLPs with smaller caseloads were more satisfied) were predictive of job satisfaction in SLPs working in the schools. CLINICAL IMPLICATIONS: The findings provide additional assurance for SLPs concerning overall group satisfaction. The information could also assist educational training programs with data concerning SLPs' satisfaction. Smaller caseload size is predictive of job satisfaction. There were no differences among rural, suburban, and urban SLPs in their overall job satisfaction. This information could be useful for personnel directors in recruiting and retaining SLPs. PMID- 27764502 TI - Translucency and Complexity: Effects on Blissymbol Learning Using Computer and Teacher Presentations. AB - PURPOSE: A single-subject alternating treatment design was used to (a) evaluate the influence of translucency (i.e., the guessability of the symbol when the referent is known) and complexity (i.e., the number of lines or strokes that compose the symbol) on Blissymbol acquisition and (b) compare the effectiveness of computer-based instruction (CBI) and traditional teacher-based instruction (TBI) on students' accuracy in identifying Blissymbols. METHOD: Three students with communication disorders were taught to identify 40 Blissymbols using the two instructional formats. RESULTS: Findings revealed that high translucency Blissymbols were learned significantly faster than low translucency Blissymbols for all participants. High complexity assisted learning when translucency was high, but hindered learning when translucency was low. These results were evident in both interventions. CLINICAL IMPLICATIONS: Both interventions were found to be effective instructional methods for teaching Blissymbols. PMID- 27764503 TI - From the Editor.... PMID- 27764504 TI - Conceptual Versus Monolingual Scoring: When Does It Make a Difference? AB - PURPOSE: This study evaluates the extent to which bilingual children produce the same or overlapping responses on tasks assessing semantic skills in each of their languages and whether classification analysis based on monolingual or conceptual scoring can accurately classify the semantic development of typically developing (TD) bilingual children. METHOD: In Study 1, 55 TD children (ages 4;0 [years;months] to 7;11) from bilingual backgrounds named characteristic properties of familiar items. The extent to which children produced overlapping responses in each of their languages and their errors were examined. In Study 2, 40 TD children (ages 5;0 to 6;1), group matched for age and bilingual language exposure, responded to the Phase 2 version of the Bilingual English Spanish Assessment (BESA; E. D. Pena, V. Gutierrez-Clellen, A. Iglesias, B. A. Goldstein, & L. M. Bedore, in development). Conceptual and monolingual scores were compared to determine the extent to which these were comparable for groups of children. RESULTS: The results of Study 1 indicated that TD children from bilingual backgrounds are more likely to produce unique than overlapping responses when they respond to test items. Children were more likely to code switch when tested in Spanish than in English, but they were more likely to produce errors in English. In Study 2, monolingual and bilingual children achieved comparable conceptual scores. For Spanish-speaking bilingual children, the conceptual score was more likely to be in the average range of the monolingual children than was their monolingual score. For testing in English, monolingual and conceptual scores were similar. CLINICAL IMPLICATIONS: Bilingual children will benefit from conceptual scoring, especially when they are tested in Spanish. PMID- 27764506 TI - From the Editor.... PMID- 27764507 TI - Response to "Clinicians Deserve Better: Observations on a Clinical Forum Titled 'What Child Language Research May Contribute to the Understanding and Treatment of Stuttering'" by Ingham (2005). PMID- 27764505 TI - English Language Narratives of Filipino Children. AB - Purpose: The current study focuses on describing the English language narrative skills of children who have been exposed to the Filipino language. Method: Eight children between the ages of 6;0 (years;months) and 7;7 who spoke primarily English but who were exposed to the Filipino language at home participated. Each child produced three narrative samples based on wordless picture books. Samples were analyzed for narrative complexity as well as measures of productivity and grammaticality. Results: The complexity of children's narratives was comparable to that reported in the literature for monolingual English-speaking children. Grammaticality measures show use of an average of 16.55% Filipino-influenced English forms across three stories. The observed patterns of Filipino-influenced English were predictable based on the comparison of English and Filipino structures. Variability in maze use was related to the amount of exposure to Filipino. Clinical Implications: Care should be taken to evaluate grammaticality with respect to nonstandard English forms predicted by the rules of the language in contact with English. Further, maze use may be related to level of exposure to another language and should be further explored when using such information in language evaluation. PMID- 27764508 TI - Response to Ingham (2005). PMID- 27764510 TI - From the Editor.... PMID- 27764509 TI - From the Editor... PMID- 27764511 TI - From the Editor... PMID- 27764512 TI - Childhood Voice Disorders: Tell Me Something I Don't Know. PMID- 27764513 TI - Heterogeneity of histopathological presentation of pilocytic astrocytoma - diagnostic pitfalls. A review. AB - Pilocytic astrocytomas (PAs) are the most frequent primary astroglial tumours affecting children and adolescents. They occur sporadically or in association with a genetically determined syndrome - neurofibromatosis type 1. Classic PA usually manifests as a well-circumscribed, often cystic, slowly growing tumour, which corresponds to WHO grade I. The majority of pilocytic tumours arise along the neuraxis, predominantly in the cerebellum. They are associated with favourable long-term outcome or spontaneous regression, even after incomplete resection. However, the behaviour and prognosis might also be related to tumour histology and location. Pilomyxoid astrocytoma (PMA) represents a variant of classical PA with more invasive growth and increased risk of recurrences and dissemination. Typically, PAs exhibit distinct histology with biphasic architecture of loose, microcystic and compact, fibrillary areas. However, some tumours arise in an uncommon location and display heterogeneous histopathological appearance. The morphological pattern of PA can mimic some other glial neoplasms, including oligodendroglioma, pleomorphic xanthoastrocytoma, ependymoma or diffuse astrocytoma. Not infrequently, the advanced degenerative changes, including vascular fibrosis, and recent and old haemorrhages, may mimic vascular pathology. Sometimes, the neoplastic piloid tissue can resemble reactive gliosis, related to long-standing non neoplastic lesions. Not infrequently, PA exhibits histological features typical for anaplasia, including necrosis, mitoses and glomeruloid vascular proliferation that can suggest a diffuse high-grade glioma. However, even those PAs that lack distinct histological features of anaplasia can behave unpredictably, in a more aggressive manner, with leptomeningeal spreading. Genetic alterations resulting in aberrant signalling of the mitogen-activated protein kinase (MAPK) pathway have been considered to underlie the development of PAs. The most commonly identified KIAA1549-BRAF fusion is important for appropriate tumour molecular diagnosis. In this paper we summarize the clinicopathological presentation of PAs, with emphasis on their heterogeneous morphology, based on our own experience in the field of surgical neuropathology and the literature data. Diagnosis of pilocytic tumours requires careful analysis of clinical, histopathological and molecular features to avoid misinterpretation of these benign neoplastic lesions. PMID- 27764514 TI - Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases. AB - Sirtuins (SIRT1 to -7) are unique histone deacetylases (HDACs) whose activity depends on NAD+, thus making them capable of sensing the cellular metabolic status. Sirtuins orchestrate the stress response and damage repair, and are able to modulate the course of ageing and neurodegenerative diseases. Despite their classification as HDACs, sirtuins deacetylate a vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-?B, and DNA-PK (DNA dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADP- ribose) polymerases (PARPs), a crucial and widespread class of NAD+ consuming post-translational protein modifiers. PARPs share a significant number of roles with sirtuins: these enzymes modulate DNA repair, gene expression, and the activities of signalling pathways. We focus on the expanding cross-talk between sirtuins, transcription factors and PARPs, which is a highly promising therapeutic target in a number of age-related neurodegenerative disorders, including the most devastating: Alzheimer's and Parkinson's diseases. PMID- 27764515 TI - 5-Aminolevulinic acid-mediated sonosensitization of rat RG2 glioma cells in vitro. AB - Sonodynamic therapy (SDT) is a promising technique based on the ability of certain substances, called sonosensitizers, to sensitize cancer cells to non thermal effects of low-energy ultrasound waves, allowing their destruction. Sonosensitization is thought to induce cell death by direct physical effects such as cavitation and acoustical streaming as well as by complementary chemical reactions generating oxygen free radicals. One of the promising sonosensitizers is 5-aminolevulinic acid (ALA) which upon selective uptake by cancer cells is metabolized and accumulated as protoporphyrin IX. The objective of the study was to describe ALA-mediated sonodynamic effects in vitro on a rat RG2 glioma cell line. Glioma cells, seeded at the bottom of 96-well plates and incubated with ALA (10 ug/ml) for 6 h, were exposed to the sinusoidal US pulses with a resonance frequency of 1 MHz, 1000 us duration, 0.4 duty-cycle, and average acoustic power varying from 2 W to 6 W. Ultrasound waves were generated by a flat circular piezoelectric transducer with a diameter of 25 mm. Cell viability was determined by MTT assay. Structural cellular changes were visualized with a fluorescence microscope. Signs of cytotoxicity such as a decrease in cell viability, chromatin condensation and apoptosis were found. ALA-mediated SDT evokes cytotoxic effects of low intensity US on rat RG2 glioma cells in vitro. This cell line is indicated for further preclinical assessment of SDT in in vivo conditions. PMID- 27764516 TI - Characteristics of the expression of KAI1/CD82 and PDGFRbeta and their impact on glioma progression. AB - The biological features of glioma cells may define their clinical outcome. Little is known about the interactions between KAI1/CD82 metastatic suppressor protein and PDGFR? in gliomas. The aim of the study was to examine KAI1/CD82 and PDGFR? expression in gliomas in order to find the impact of these proteins on progression of the tumors. PDGFR?, KAI1/CD82 protein expression and mRNA of genes were evaluated on eighty four paraffin-embedded tissue of gliomas using immunohistochemical staining and RT-PCR analysis. The PDGFR? expression was higher in IV/III than in I/II glioma grades (p = 0.0004). The level of mRNA PDGFR? was associated with the degree of PDGFR? immunoreactivity. Downregulation of KAI1/CD82 was associated with tumor malignancy (p = 0.007). The increased level of KAI1/CD82 gene expression (3-4-fold) was found in gliomas with strong KAI1/CD82 immunoreactivity. The parallel KAI1/CD82 and PDGFR? expression was more significantly associated with cases in a group graded as III and IV than in a group graded as I/II (p = 0.002). We found that a loss of KAI1/CD82 and an increase in PDGFR? expression in gliomas relate to a progressive tumor growth. The correlation between PDGFR? and KAI1 expression in high grade gliomas suggests that a direct or indirect interaction between these proteins might have an impact on cell motility and invasive behavior of the tumor. PMID- 27764517 TI - Effect of recombinant Lactococcus lactis producing myelin peptides on neuroimmunological changes in rats with experimental allergic encephalomyelitis. AB - Multiple sclerosis (MS) is a human autoimmune neurodegenerative disease with an unknown etiology. Despite various therapies, there is no effective cure for MS. Since the mechanism of the disease is based on autoreactive T-cell responses directed against myelin antigens, oral tolerance is a promising approach for the MS treatment. Here, the experiments were performed to assess the impact of oral administration of recombinant Lactococcus lactis producing encephalogenic fragments of three myelin proteins: myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein, on neuroimmunological changes in rats with experimental allergic encephalomyelitis (EAE) - an animal model of MS. Lactococcus lactis whole-cell lysates were administered intragastrically at two doses (103 and 106 colony forming units) in a twenty-fold feeding regimen to Lewis rats with EAE. Spinal cord slices were subjected to histopathological analysis and morphometric evaluation, and serum levels of cytokines (IL-1b, IL 10, TNF-alpha and IFN-gamma) were measured. Results showed that administration of the L. lactis preparations at the tested doses to rats with EAE, diminished the histopathological changes observed in EAE rats and reduced the levels of serum IL 1b, IL-10 and TNF-alpha, previously increased by evoking EAE. This suggests that oral delivery of L. lactis producing myelin peptide fragments could be an alternative strategy to induce oral tolerance for the treatment of MS. PMID- 27764518 TI - Administration of vitamin D3 induces CNPase and myelin oligodendrocyte glycoprotein expression in the cerebral cortex of the murine model of cuprizone induced demyelination. AB - In the central nervous system (CNS) the main proteins of myelin are proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and CNPase. Myelin oligodendrocyte glycoprotein is a minor component of the myelin sheath, but is an important autoantigen linked to the pathogenesis of multiple sclerosis (MS). CNPase is expressed exclusively by oligodendrocytes in the CNS, and the appearance of CNPase seems to be one of the earliest events of oligodendrocyte differentiation and myelination. In this study the effects of vitamin D on total protein concentration, CNPase and MOG expression in the cerebral cortex of the murine model of cuprizone-induced demyelination was investigated. The mice were treated by cuprizone for five weeks in order to induce demyelination. The mice were then divided into 3 groups. The first group was injected intraperitoneally (IP) with vitamin D diluted in olive oil in the amount of 5 ug/kg/daily body weight. The second group (SHAM) was injected IP with olive oil and the third group was left without any injection as the control group (n = 11 for each group). After five weeks the mice were killed and the cerebral cortex was collected and the expression of CNPase and MOG was studied by Western blot. Total protein concentration in the vitamin D injected, SHAM and control groups were 0.918 +/- 0.003, 0917 +/- 0.004 and 0.916 +/- 0.004 g/l, respectively (p > 0.05). However, a significant increase in the MOG and CNPase expression was seen in vitamin D injected group as compared to SHAM and control groups. It is concluded that vitamin D plays a role in the process of remyelination by increasing MOG and CNPase expression in the cortex. PMID- 27764519 TI - Protective effects of peel and seed extracts of Citrus aurantium on glutamate induced cytotoxicity in PC12 cell line. AB - Oxidative stress and apoptosis contribute to neuronal degeneration in many neurodegenerative diseases such as Alzheimer's disease. Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and is considered responsible for the pathogenesis of many neurological disorders. Reactive oxygen species (ROS) production is thought to be involved in glutamate-induced apoptosis process. In this study, the neuroprotective effects of Citrus aurantium in the glutamate-induced rat's adrenal pheochromocytoma cell line (PC12 cells) were investigated. The cell viability and apoptotic cell death were measured using MTT and propidium iodine (PI)-staining methods, respectively. In addition, intracellular ROS and malondialdehyde (MDA) levels were determined by fluorometric methods. The results showed that glutamate cytotoxicity in PC12 cells was accompanied by an increment of MDA content, ROS generation, and apoptotic induction. However, pretreatment with peel and seed extracts of C. aurantium significantly reduced MDA content, ROS generation, and apoptotic cells. All these findings indicated that C. aurantium protected PC12 cells against glutamate-induced apoptosis by inhibiting ROS production. Therefore, the present study supports that C. aurantium extracts possess neuroprotective effects against glutamate-induced toxicity in PC12 cell line. The protective effect of C. aurantium might be attributed to its antioxidant properties. PMID- 27764520 TI - Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy. AB - The Warburg micro syndrome (WARBM) is a genetically heterogeneous syndrome linked to at least 4 loci. At the clinical level, WARBM is characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, severe mental retardation, and hypogonadism. In some families additional clinical features have been reported. The presence of uncommon clinical features (peripheral neuropathy, cardiomyopathy) may result in misdirected molecular diagnostics. Using the next generation sequencing approach (NGS), we were able to diagnose WARBM1 syndrome by detection of a new mutation within the RAB3GAP1 gene. We have detected some DNA variants which may be responsible for cardiomyopathy. We did not find any obvious pathogenic mutation within a set of genes known to be responsible for hereditary motor and sensory neuropathy (HMSN). We conclude that: (i) in clinically delineated syndromes, a classical single-gene oriented approach may be not conclusive especially in the presence of rare clinical features, (ii) peripheral neuropathy and cardiomyopathy are rare additional symptoms coexisting with WARBM1, (iii) a pleiotropic effect of a single point mutation is sufficient to be causative for WARBM1 and (iv) more WARBM-affected patients should be reported to delineate a complete phenotype. PMID- 27764521 TI - Fahr's syndrome and clinical correlation: a case series and literature review. AB - INTRODUCTION: Fahr's disease is characterized by bilateral calcium deposition within the basal ganglia, cerebellar dentate nucleus and subcortical brain white matter. The main clinical manifestations are rigid or hyperkinetic syndrome, mood disorders and cognitive impairment. The correlation between neurological impairment and symmetrical basal ganglia calcification is not so frequent. Aim of the study was to report the results of neurological assessment of three sporadic cases of Fahr's disease highlighting a correlation between the clinical syndrome and neuroimaging. CASE REPORTS: Three adults of aged 32, 55 and 70, were studied. They all showed a heterogeneous clinical spectrum. One case developed neuropsychiatric symptoms, whereas the others complained of the tremorigen syndrome. Brain computed tomography scans revealed several calcifications in basal ganglia, cerebellar white matter and dentate nuclei. CONCLUSIONS: The pathogenesis of Fahr's disease is probably secondary to the dysfunction of cortico-basal connections and their interhemispheric relations. No significant correlation between calcifications and neurological symptoms is proved. PMID- 27764522 TI - Combination of acid phosphatase positivity and rimmed vacuoles as useful markers in the diagnosis of adult-onset Pompe disease lacking specific clinical and pathological features. AB - INTRODUCTION: The clinical and histological presentations of the adult form of Pompe disease may be atypical. In such cases, identifying histological signs that point to the diagnosis would be crucial to avoid a delay in care. The aim of our study was to investigate the presence of rimmed vacuoles and acid phosphatase positivity in muscle biopsies of patients with late-onset Pompe disease. MATERIAL AND METHODS: We retrospectively studied muscle biopsies of all cases of the adult form of Pompe disease diagnosed at the University Hospital of Caen. Three of these four cases showed atypical clinical signs, and diagnosis was established tardily based on family history or systematic analysis of acid maltase activity. RESULTS: All biopsies showed some rimmed vacuoles. The acid phosphatase reaction showed positive inclusions and labelled vacuoles in biopsies of all patients. CONCLUSIONS: The presence of rimmed vacuoles and acid phosphatase positivity in muscle biopsy should suggest the diagnosis of the adult form of Pompe disease, this is decisive since effective therapy is available. PMID- 27764523 TI - Benzodiazepines for the relief of breathlessness in advanced malignant and non malignant diseases in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2010, on 'Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults'. Breathlessness is one of the most common symptoms experienced in the advanced stages of malignant and non-malignant disease. Benzodiazepines are widely used for the relief of breathlessness in advanced diseases and are regularly recommended in the literature. At the time of the previously published Cochrane review, there was no evidence for a beneficial effect of benzodiazepines for the relief of breathlessness in people with advanced cancer and chronic obstructive pulmonary disease (COPD). OBJECTIVES: The primary objective of this review was to determine the efficacy of benzodiazepines for the relief of breathlessness in people with advanced disease. Secondary objectives were to determine the efficacy of different benzodiazepines, different doses of benzodiazepines, different routes of application, adverse effects of benzodiazepines, and the efficacy in different disease groups. SEARCH METHODS: This is an update of a review published in 2010. We searched 14 electronic databases up to September 2009 for the original review. We checked the reference lists of all relevant studies, key textbooks, reviews, and websites. For the update, we searched CENTRAL, MEDLINE, and EMBASE and registers of clinical trials for further ongoing or unpublished studies, up to August 2016. We contacted study investigators and experts in the field of palliative care asking for further studies, unpublished data, or study details when necessary. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effect of benzodiazepines compared with placebo or active control in relieving breathlessness in people with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neurone disease (MND), and idiopathic pulmonary fibrosis (IPF). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three review authors independently performed assessment of all potentially relevant studies (full text), data extraction, and assessment of methodological quality. We carried out meta-analysis where appropriate. MAIN RESULTS: Overall, we identified eight studies for inclusion: seven in the previous review and an additional study for this update. We also identified two studies awaiting classification in this update. The studies were small (a maximum number of 101 participants) and comprised data from a total of 214 participants with advanced cancer or COPD, which we analysed. There was only one study of low risk of bias. Most of the studies had an unclear risk of bias due to lack of information on random sequence generation, concealment, and attrition. Analysis of all studies did not show a beneficial effect of benzodiazepines for the relief of breathlessness (the primary outcome) in people with advanced cancer and COPD (8 studies, 214 participants) compared to placebo, midazolam, morphine, or promethazine. Furthermore, we observed no statistically significant effect in the prevention of episodic breathlessness (breakthrough dyspnoea) in people with cancer (after 48 hours: risk ratio of 0.76 (95% CI 0.53 to 1.09; 2 studies, 108 participants)) compared to morphine. Sensitivity analyses demonstrated no statistically significant differences regarding type of benzodiazepine, dose, route and frequency of delivery, duration of treatment, or type of control. Benzodiazepines caused statistically significantly more adverse events, particularly drowsiness and somnolence, when compared to placebo (risk difference 0.74 (95% CI 0.37, 1.11); 3 studies, 38 participants). In contrast, two studies reported that morphine caused more adverse events than midazolam (RD -0.18 (95% CI -0.31, -0.04); 194 participants). AUTHORS' CONCLUSIONS: Since the last version of this review, we have identified one new study for inclusion, but the conclusions remain unchanged. There is no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. Benzodiazepines may be considered as a second- or third-line treatment, when opioids and non-pharmacological measures have failed to control breathlessness. There is a need for well-conducted and adequately powered studies. PMID- 27764524 TI - Impact of chronic disease on emotional distress in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. AB - BACKGROUND: The current study was performed to examine associations between childhood cancer therapies, chronic health conditions, and symptoms of emotional distress in adult survivors of childhood cancer. METHODS: Participants included 5021 adult survivors of childhood cancer (mean age, 32.0 years [standard deviation, 7.6 years] with a time since diagnosis of 23.2 years [standard deviation, 4.5 years]) who completed measures assessing symptoms of anxiety, depression, and posttraumatic stress. Cardiac, pulmonary, and endocrine conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03; grades 1-4). Structural equation modeling was used to examine hypothesized pathways between cancer treatment exposures, chronic health conditions, and symptoms of emotional distress. Multivariable models were used to estimate relative risks (RRs) for associations between chronic health conditions and distress. RESULTS: Survivors with cardiovascular, endocrine, or pulmonary conditions were found to have a significantly higher prevalence of emotional distress symptoms. In path analyses and multivariable models, significant effects were observed between endocrine (beta = .12 [P = .002] and RR, 1.3 [95% confidence interval (95% CI), 1.1-1.6]) and pulmonary (beta = .13 [P<.001] and RR, 1.4 [95% CI, 1.1-1.7]) conditions and depression, and between cardiac (beta = .13 [P = .001] and RR, 1.5 [95% CI, 1.2 1.8]) and pulmonary (beta = .15 [P<.001] and RR, 1.6 [95% CI, 1.3-2.0]) conditions and anxiety. All treatment-related chronic health conditions were found to be associated with posttraumatic stress symptoms (cardiac: beta = .09 [P = .004] and RR, 1.3 [95% CI, 1.2-1.5]; endocrine: beta = .12 [P<.001] and RR, 1.3 [95% CI, 1.2-1.5]; and pulmonary: beta = .13 [P<.001] and RR, 1.4 [95% CI, 1.2 1.6]). CONCLUSIONS: Chronic health conditions resulting from childhood cancer therapies contribute to emotional distress in adult survivors. Targeted mental health screening efforts in this at-risk population appear warranted. Therapeutic approaches should consider the complex interplay between chronic health conditions and symptoms of emotional distress. Cancer 2017;123:521-528. (c) 2016 American Cancer Society. PMID- 27764526 TI - An in vitro investigation to assess procedure parameters for injecting therapeutic hydrogels into the myocardium. AB - Localized delivery of stem cells is potentially a promising therapeutic strategy for regenerating damaged myocardium. Many studies focus on limiting the biologic component of cell loss, but few address the contribution of mechanical factors. This study investigates optimal parameters for retaining the largest volume of cell loaded hydrogels post intramyocardial injection, without compromising cell viability. In vitro, hydrogel was injected into porcine hearts using various needle designs. Hydrogel retention and distribution pattern was then determined. The two most promising needles were then investigated to understand the effect of needle geometry on stem cell viability. The needle to best impact cell viability was then used to investigate the effect of differing hydrogels on retention and distribution. Three-dimensional experimental modeling revealed needles with smaller diameter's to have greater poloxamer 407 hydrogel retention. No difference in retention existed among various needle designs of similar gauge, despite differences in bolus geometries. When hMSC's, embedded in fibrin hydrogel, were injected through helical and 26G bevel needles no difference in the percent of live cells was seen at 48 h. However, the helical group had almost half the metabolic activity of the 26G bevel group at both time points, and had a significant decline in the percent of live cells from 24 to 48 h. Varying gel type resulted in significantly more alginate being retained in the tissue in comparison to fibrin or poloxamer hydrogels. In conclusion, mechanical properties of injected hydrogels, and the diameter of the needle used, highly influences the volume of hydrogel retained. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2618-2629, 2017. PMID- 27764525 TI - Celastrol prevents cadmium-induced neuronal cell death by blocking reactive oxygen species-mediated mammalian target of rapamycin pathway. AB - BACKGROUND AND PURPOSE: Increasing evidence has suggested cadmium (Cd), as an inducer of ROS, is a potential pathogenic factor in human neurodegenerative diseases. Thus, it is important to find effective interventions for Cd-induced oxidative stress in the CNS. Here, we have studied the effects of celastrol, a plant-derived triterpene, on ROS production and cell death in neuronal cells, induced by Cd. EXPERIMENTAL APPROACH: PC12, SH-SY5Y cells and primary murine neurons were used to study celastrol neuroprotection against Cd-poisoning. Cd induced changes in cell viability, apoptosis, ROS and AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the cells were analysed by Trypan blue exclusion, DAPI and TUNEL staining, ROS imaging, immunofluorescence staining and Western blotting. Pharmacological and genetic approaches were employed to investigate the mechanisms underlying Cd neurotoxicity. RESULTS: Celastrol attenuated Cd-induced apoptosis by suppressing Cd activation of mTOR, which was attributed to preventing Cd inactivation of AMPK. Inhibition of AMPK with compound C or expression of dominant negative AMPKalpha prevented celastrol from hindering Cd-induced dephosphorylation of AMPKalpha, activation of mTOR and apoptosis. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated prevention by celastrol, of Cd-induced phosphorylation of p70 S6 kinase 1/eukaryotic initiation factor 4E binding protein 1 and apoptosis. Celastrol attenuated Cd-induced cell death by suppressing induction of mitochondrial ROS. CONCLUSIONS AND IMPLICATIONS: Celastrol prevented the inactivation of AMPK by mitochondrial ROS, thus attenuating Cd-induced mTOR activation and neuronal apoptosis. Celastrol may be a promising agent for prevention of Cd-induced oxidative stress and neurodegenerative diseases. PMID- 27764527 TI - Which Homeless Veterans Benefit From a Peer Mentor and How? AB - OBJECTIVE: Veterans Affairs (VA) is expanding peer support. Research is limited on Veterans' perspective on benefits from peer services. We describe homeless Veteran perceptions of value and examine characteristics associated with benefit. METHOD: From a sample of Veterans in a multisite randomized control trial, we studied addition of peers in VA Primary Care and homeless-oriented primary care clinics. We used qualitative methods to study the perceptions of peer services among a subsample of homeless Veterans. Quantitative methods were used to validate findings in both samples. RESULTS: Sixty-five percent of the subsample and 83% of the full sample benefited from a peer mentor. Participants who benefited had more peer visits and minutes of intervention (p<.05), were more likely to be minority, and were less likely to have posttraumatic stress disorder. CONCLUSION: The majority of Veteran participants in this study benefited from receiving peer mentor intervention. African American Veterans were more likely to benefit and Veterans with PTSD were less likely to benefit. Client endorsement of the peer's role influenced outcomes. PMID- 27764528 TI - Sluggish Cognitive Tempo is Associated With Poorer Study Skills, More Executive Functioning Deficits, and Greater Impairment in College Students. AB - OBJECTIVES: Few studies have examined sluggish cognitive tempo (SCT) in college students even though extant research suggests a higher prevalence rate of SCT symptoms in this population compared to general adult or youth samples. The current study examined SCT symptoms in relation to two domains related to college student's academic success, study skills and daily life executive functioning (EF), as well as specific domains of functional impairment. METHOD: 158 undergraduate students (Mage = 19.05 years; 64% female) completed measures of psychopathology symptoms, study skills, daily life EF, and functional impairment. RESULTS: After controlling for demographics and symptoms of attention deficit/hyperactivity disorder (ADHD), anxiety, and depression, SCT remained significantly associated with poorer study skills, greater daily life EF deficits, and global impairment and with greater functional impairment in the specific domains of educational activities, work, money/finances, managing chores and household tasks, community activities, and social situations with strangers and friends. In many instances, ADHD inattentive symptoms were no longer significantly associated with study skills or impairment after SCT symptoms were added to the model. CONCLUSION: SCT is associated with poorer college student functioning. Findings highlight the need for increased specificity in studies examining the relation between SCT and adjustment. PMID- 27764529 TI - T-lymphocyte and glycemic status after vitamin D treatment in type 1 diabetes: A randomized controlled trial with sequential crossover. AB - BACKGROUND: Type 1 diabetes mellitus (T1D) is mediated by autoaggressive T effector cells with an underlying regulatory T-cell (Treg) defect. Vitamin D deficiency is highly prevalent in T1D, which can aggravate immune dysfunction. High-dose vitamin D treatment may enhance Tregs and improve metabolism in T1D patients. METHODS: In a randomized double-blind placebo-controlled trial with crossover design, patients received either for 3 months cholecalciferol 4000 IU/d followed by 3 months placebo or the sequential alternative. Thirty-nine T1D patients (19 women and 20 men) completed the trial. RESULTS: Primary outcome was a change of Tregs, secondary HbA1C, and insulin demand. Effects were evaluated based on intra-individual changes between treatment and placebo periods for outcome measures. Exploratory analyses included vitamin D system variant genotyping and C-peptide measurements. Median 25(OH)D3 increased to 38.8 ng/ml with males showing a significantly stronger increase (p = .003). T-lymphocyte profiles did not change significantly (p > 2); however, the intra-individual change of Tregs between males and females was different with a significantly stronger increase in men (p = .017), as well as between genotypes of the vitamin D receptor (Apa, Taq, and Bsm: genotypes aa, TT, and bb; p = .004-0.015). Insulin demands declined significantly (p = .003-.039) and HbA1C improved (p < .001). Random C-peptide levels were low but rising (median, 0.125 ng/ml; range, 0.02 0.3) in 6 patients. No toxicity was observed. CONCLUSION: A daily vitamin D dose of 4000 IU for 3 months was well tolerated and enhanced Tregs in males. Glucometabolic control improved in all. Subsequent larger trials need to address beta-cell function and genotyping for individualized vitamin D doses. PMID- 27764530 TI - 6-TIPS-beta-Cyclodextrin-Modified Fe3 O4 for Facile Enantioseparation of 1-(1 Naphthyl)ethylamine. AB - A new type of chiral magnetic nanoparticle was prepared from covalently linked magnetic nanoparticles (Fe3 O4 ) and heptakis-(6-O-triisopropylsilyl)-beta cyclodextrin (6-TIPS-beta-CD). The resulting selectors (TIPS-beta-CD-MNPs) combined the good magnetic properties Fe3 O4 and efficient chiral recognition ability of 6-TIPS-beta-CD. The enantioselectivity of TIPS-beta-CD-MNPs towards 1 (1-naphthyl)ethylamine was six times higher than that of the parent beta-CD modified Fe3 O4 particles. PMID- 27764531 TI - The effect of image quality, repeated study, and assessment method on anatomy learning. AB - The use of two-dimensional (2D) images is consistently used to prepare anatomy students for handling real specimen. This study examined whether the quality of 2D images is a critical component in anatomy learning. The visual clarity and consistency of 2D anatomical images was systematically manipulated to produce low quality and high-quality images of the human hand and human eye. On day 0, participants learned about each anatomical specimen from paper booklets using either low-quality or high-quality images, and then completed a comprehension test using either 2D images or three-dimensional (3D) cadaveric specimens. On day 1, participants relearned each booklet, and on day 2 participants completed a final comprehension test using either 2D images or 3D cadaveric specimens. The effect of image quality on learning varied according to anatomical content, with high-quality images having a greater effect on improving learning of hand anatomy than eye anatomy (high-quality vs. low-quality for hand anatomy P = 0.018; high quality vs. low-quality for eye anatomy P = 0.247). Also, the benefit of high quality images on hand anatomy learning was restricted to performance on short answer (SA) questions immediately after learning (high-quality vs. low-quality on SA questions P = 0.018), but did not apply to performance on multiple-choice (MC) questions (high-quality vs. low-quality on MC questions P = 0.109) or after participants had an additional learning opportunity (24 hours later) with anatomy content (high vs. low on SA questions P = 0.643). This study underscores the limited impact of image quality on anatomy learning, and questions whether investment in enhancing image quality of learning aids significantly promotes knowledge development. Anat Sci Educ 10: 249-261. (c) 2016 American Association of Anatomists. PMID- 27764532 TI - Disaster Mental Health and Positive Psychology-Considering the Context of Natural and Technological Disasters: An Introduction to the Special Issue. AB - This article serves as an introduction to the Journal of Clinical Psychology's special issue on disaster mental health and positive psychology. The special issue comprises two sections. The first section presents a series of data-driven articles and research-informed reviews examining meaning and resilience in the context of natural and technological disasters. The second section presents key topics in the area of disaster mental health, with particular relevance for positive psychology and related frameworks. The special issue is intended to bridge the gap between these two areas of applied science, with the audience being experienced clinicians or clinicians in training. PMID- 27764533 TI - Signaling events associated with gonadotropin releasing hormone-agonist-induced hormonal castration and its reversal in canines. AB - A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c-Raf-Erk1/2-p53 signaling cascade that triggers growth arrest or apoptosis. GnRH-A also suppressed the anti-apoptotic protein Bcl-xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down-regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH-A treatment, levels of ZIP9, a membrane-bound Zn2+ transporter that mediates non-classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant-dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 83: 1092-1101, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27764534 TI - What is your diagnosis? Nasal cavity imprint from a dog. PMID- 27764535 TI - Evaluation of species difference in peripheral lymphocyte reduction effect of CS 0777, a sphingosine 1-phosphate receptor modulator, based on a pharmacokinetic/pharmacodynamic model analysis. AB - Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS-0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS-0777, M1, is a selective sphingosine 1-phosphate receptor-1 modulator. A linear one- and two-compartment model with a reversible metabolism process characterized the time courses of CS 0777 and M1 concentrations in rats and monkeys, respectively. The relationship between lymphocyte counts and M1 concentrations in blood was well described by an indirect response model in all animals examined. An Imax of 0.815 and an IC50 of 6.58 nM in healthy rats, an Imax of 0.807 and an IC50 of 5.09 nM in the EAE rats, an Imax of 0.789 and an IC50 of 0.484 nM in monkeys were estimated by the indirect PD model. Since the IC50 values calculated in terms of the unbound plasma concentration in rats and monkeys were within a similar range, after correction of the IC50 in blood described above with the blood to plasma concentration ratio and the plasma free fraction of M1, it was revealed that there is no species difference in the essential activity of M1 against lymphocyte reduction. The sensitivity of the lymphocytes to M1 was not affected by the EAE status. Comparison of the simulated lymphocyte reduction in EAE rats after multiple dosing with CS-0777 and the actual EAE clinical scores implies that the significant suppressive effect on EAE did not require the elimination of all lymphocytes from the blood. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27764536 TI - Circulating CD14+ HLA-DR-/low myeloid-derived suppressor cells predicted early recurrence of hepatocellular carcinoma after surgery. AB - AIM: Myeloid-derived suppressor cells (MDSCs) play an important role in tumor progression. The aim of the present study was to investigate the prognostic value of MDSCs for early recurrence of hepatocellular carcinoma (HCC) in patients undergoing curative resection. METHODS: Myeloid-derived suppressor cells were measured by flow cytometry. The correlation between MDSCs and tumor recurrence was analyzed using a cohort of 183 patients who underwent curative resection between February 2014 and July 2015. Prognostic significance was further assessed using Kaplan-Meier survival estimates and log-rank tests. RESULTS: In vivo, CD14+ HLA-DR-/low MDSCs inhibit T cell proliferation and secretion. The frequency of CD14+ HLA-DR-/low MDSCs was significantly higher in HCC patients (3.7 +/- 5.3%, n = 183) than in chronic hepatitis patients (1.4 +/- 0.6%, n = 25) and healthy controls (1.1 +/- 0.5%, n = 50). High frequency of MDSCs was significantly correlated with recurrence (time to recurrence) (P < 0.001) and overall survival (P = 0.034). Patients with HCC in the high MDSC group were prone to more vascular invasion (P = 0.018) and high systemic immune-inflammation index (SII) (P = 0.009) than those in the low MDSC group. Scatter-plot analyses revealed a significant positive correlation between the SII level and the frequency of MDSCs (r = 0.188, P = 0.011). Patients with HCC with a high MDSC frequency and high SII level had significantly shorter time to recurrence (P < 0.001) and overall survival (P = 0.028) than those with a low MDSC frequency and low SII. CONCLUSIONS: An increased frequency of MDSCs was correlated with early recurrence and predicted the prognosis of patients with HCC undergoing curative resection. The HCC patients with high frequency of MDSCs should be provided more advanced management and frequent monitoring. PMID- 27764537 TI - Increasing the spatial resolution and sensitivity of magnetic resonance elastography by correcting for subject motion and susceptibility-induced image distortions. AB - PURPOSE: To improve the resolution of elasticity maps by adapting motion and distortion correction methods for phase-based magnetic resonance imaging (MRI) contrasts such as magnetic resonance elastography (MRE), a technique for measuring mechanical tissue properties in vivo. MATERIALS AND METHODS: MRE data of the brain were acquired with echo-planar imaging (EPI) at 3T (n = 14) and 7T (n = 18). Motion and distortion correction parameters were estimated using the magnitude images. The real and imaginary part of the complex MRE data were corrected separately and recombined. The width of the point-spread function (PSF) and the position variability were calculated. The images were normalized to the Montreal Neurological Institute (MNI) anatomical template. The gray-to-white matter separability of the elasticity maps was tested. RESULTS: Motion correction sharpened the |G*| maps as demonstrated by a narrowing of the PSF by 0.78 +/- 0.51 mm at 7T and 0.52 +/- 0.63 mm at 3T. The amount of individual head motion during MRE acquisition correlated with the decrease in the width of the PSF at 7T (r = 0.53, P = 0.025) and at 3T (r = 0.69, P = 0.006) and with the increase of gray-to-white matter separability after motion correction at 7T (r = 0.64, P = 0.0039) and at 3T (r = 0.57, P = 0.0319). Improved spatial accuracy after distortion correction results in a significant increase in separability of gray and white matter stiffness (P = 0.0067), especially in inferior parts of the brain suffering from strong B0 inhomogeneities. CONCLUSION: We demonstrate that our method leads to sharper images and higher spatial accuracy, raising the prospect of the investigation of smaller brain areas with increased sensitivity in studies using MRE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:134-141. PMID- 27764538 TI - Comparative evaluation of chemical profiles of three representative 'snow lotus' herbs by UPLC-DAD-QTOF-MS combined with principal component and hierarchical cluster analyses. AB - Herbal healthcare products are used worldwide as relatively safe and effective alternatives to allopathic drugs. Saussurea laniceps Hand.-Mazz. (SL), S. medusa Maxim. (SM) and S. involucrata (Kar. et Kir.) Sch.Bip. (SI) are three sources of the renowned 'snow lotus', Chinese materia medica for treating inflammatory diseases. The three species have different therapeutic effects, among which SL has been proved to be the most potent, but they are frequently confused on the market and in the academic community. An ultra-high performance liquid chromatography-diode array detector-quadrupole time of flight-mass spectrometry (UPLC-DAD-QTOF-MS) method was developed and used to analyze 49 herbal samples for species analysis and overall quality evaluation. With 25 simultaneously identified constituents, of which 12 were quantified, the three herbs showed different chemical profiles. Four-dimensional principle component analysis (4D PCA) and orthogonal hierarchical cluster analysis (2D-HCA) results illustrated that SL should be grouped away from SM and SI, contradicting the botanical record in Flora of China. The present chemical determination and pattern recognition results directly explain the therapeutic potency of SL and distinguish the three confused snow lotus herbs. Furthermore, the findings suggest a possible extensive quality evaluation model for multi-origin medicinal plants and help monitor falsification of snow lotus herbal products on the market, contributing to a more regulated pharmaceutical industry. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27764539 TI - Different anti-remodeling effect of nilotinib and fluticasone in a chronic asthma model. AB - BACKGROUND/AIMS: Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling. METHODS: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated with fluticasone and/or nilotinib intranasally during the OVA challenge. RESULTS: Mice chronically exposed to OVA developed eosinophilic airway inflammation and showed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Both fluticasone and nilotinib attenuated airway smooth muscle thickening. However, only nilotinib suppressed fibrotic changes, demonstrating inhibition of collagen deposition. Fluticasone reduced pro inflammatory cells, such as eosinophils, and several cytokines, such as interleukin 4 (IL-4), IL-5, and IL-13, induced by repeated OVA challenges. On the other hand, nilotinib reduced transforming growth factor beta1 levels in bronchoalveolar lavage fluid and inhibited fibroblast proliferation significantly. CONCLUSIONS: These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti inflammatory and anti-fibrotic pathways, respectively. PMID- 27764540 TI - Clinical significance of the presence of anti-human leukocyte antigen-donor specific antibody in kidney transplant recipients with allograft dysfunction. AB - BACKGROUND/AIMS: This study investigated the clinical significance of detecting anti-human leukocyte antigen-donor specific antibody (HLA-DSA) in kidney transplant recipients (KTRs) requiring indication biopsy owing to allograft dysfunction. METHODS: We analyzed the presence of HLA-DSA in 210 KTRs who took indication biopsy. We divided these cases into two groups, HLA-DSA (+) (n = 52) and HLA-DSA (-) (n = 158) group, and compared the clinical characteristics, pathological findings, and clinical outcomes of the two groups. RESULTS: The rates of retransplant, pretransplant sensitization, and HLA-mismatch were significantly higher in HLA-DSA (+) group than in HLA-DSA (-) group (p < 0.05 for each comparison). In histologic finding, all types of rejections were more frequent in the former group. Besides, scores of both the T-cell injury markers such as tubulitis, interstitial inf lammation, and vasculitis and antibody mediated injury markers such as peritubular C4d deposition and microvascular inflammation (glomerulitis plus peritubular capillaritis) were higher in HLA-DSA (+) group (p < 0.05 for each). Notably, allograft outcomes were worse in HLA-DSA (+) group. Further, multivariate analysis showed that presence of HLA-DSA, advanced interstitial fibrosis/tubular atrophy (interstitial fibrosis plus tubular atrophy >= 2), and allograft rejection in biopsy were independent risk factors for allograft failure. CONCLUSIONS: The results of this study showed that presence of HLA-DSA in a case of allograft dysfunction adversely influences allograft outcome, and its detection, irrespective of the result of the allograft biopsy, necessitates intensive monitoring and treatment. PMID- 27764542 TI - Optic cup segmentation from fundus images for glaucoma diagnosis. AB - Glaucoma is a serious disease that can cause complete, permanent blindness, and its early diagnosis is very difficult. In recent years, computer-aided screening and diagnosis of glaucoma has made considerable progress. The optic cup segmentation from fundus images is an extremely important part for the computer aided screening and diagnosis of glaucoma. This paper presented an automatic optic cup segmentation method that used both color difference information and vessel bends information from fundus images to determine the optic cup boundary. During the implementation of this algorithm, not only were the locations of the 2 types of information points used, but also the confidences of the information points were evaluated. In this way, the information points with higher confidence levels contributed more to the determination of the final cup boundary. The proposed method was evaluated using a public database for fundus images. The experimental results demonstrated that the cup boundaries obtained by the proposed method were more consistent than existing methods with the results obtained by ophthalmologists. PMID- 27764541 TI - Human Atg8-cardiolipin interactions in mitophagy: Specific properties of LC3B, GABARAPL2 and GABARAP. AB - The phospholipid cardiolipin (CL) has been proposed to play a role in selective mitochondrial autophagy, or mitophagy. CL externalization to the outer mitochondrial membrane would act as a signal for the human Atg8 ortholog subfamily, MAP1LC3 (LC3). The latter would mediate both mitochondrial recognition and autophagosome formation, ultimately leading to removal of damaged mitochondria. We have applied quantitative biophysical techniques to the study of CL interaction with various Atg8 human orthologs, namely LC3B, GABARAPL2 and GABARAP. We have found that LC3B interacts preferentially with CL over other di anionic lipids, that CL-LC3B binding occurs with positive cooperativity, and that the CL-LC3B interaction relies only partially on electrostatic forces. CL-induced increased membrane fluidity appears also as an important factor helping LC3B to bind CL. The LC3B C terminus remains exposed to the hydrophilic environment after protein binding to CL-enriched membranes. In intact U87MG human glioblastoma cells rotenone-induced autophagy leads to LC3B translocation to mitochondria and subsequent delivery of mitochondria to lysosomes. We have also observed that GABARAP, but not GABARAPL2, interacts with CL in vitro. However neither GABARAP nor GABARAPL2 were translocated to mitochondria in rotenone-treated U87MG cells. Thus the various human Atg8 orthologs might play specific roles in different autophagic processes. PMID- 27764543 TI - Many roles for Pax7. PMID- 27764544 TI - Association of plasma 25-hydroxyvitamin D with physical performance in physically active children. AB - Vitamin D is thought to regulate skeletal muscle function and boost physical performance. The aim of this study was to assess the relationship between vitamin D and physical performance in physically active children. This cross-sectional study included 125 children who practice football as a leisure activity. Plasma 25-hydroxyvitamin D (25-OHD) was assessed using a chemiluminescence immunoassay method. Vitamin D inadequacy was defined as 25-OHD < 20 ng/mL. Physical performance testing included measurements of muscle strength (maximal isometric contraction), jumping ability (vertical jump, standing broad jump, triple hop test), linear sprint (10 m and 20 m), and agility (9 * 4-m shuttle run). Plasma 25-OHD concentrations were positively correlated with muscle strength (r = 0.539; p < 0.001), vertical jump (r = 0.528; p < 0.001), and standing broad jump (r = 0.492; p < 0.001) but inversely correlated with sprint performance (r = -0.539; p < 0.001). In multivariate analysis models, plasma 25-OHD concentrations were associated with each physical performance parameter independently of age, maturity status, body mass index, fat mass, and protein and calcium intakes. In conclusion, a low plasma 25-OHD level was associated with decreased muscle strength, agility, and jumping and sprinting abilities in physically active children. Vitamin D inadequacy may limit exercise performance. Further research should verify whether correction of vitamin D deficiency enhances physical performance. PMID- 27764545 TI - Collagen gel protects L929 cells from TNFalpha-induced death by activating NF kappaB. AB - PURPOSE: Type I collagen is one of the most abundant components of extracellular matrix. We previously illustrated that murine fibrosarcoma L929 cells grew well on type I collagen gel and escaped from TNFalpha-induced cell death. In this study, we investigated the mechanism underlying the protective effect of collagen gel. MATERIAL AND METHODS: We used western blot, confocal microscopy, MTT assay and flow cytometry by introducing fluorescence staining to determine the expression levels of nuclear factor kappa B (NF-kappaB), inhibitory ratio and autophagy. RESULTS: L929 cells on collagen gel showed higher expression of NF kappaB in the nucleus. Inhibition of NF-kappaB with pyrrolidine dithiocarbamate hydrochloride (PDTC) or knockdown by NF-kappaB-siRNA canceled the protective effect of collagen gel on L929 cells from TNFalpha-induced death, suggesting for the role of NF-kappaB in the protection from cell death. We found a new aspect of the effect of PDTC on L929 cells cultured on collagen gel. PDTC alone without TNFalpha induced apoptosis in the L929 cells cultured on collagen gel but not the cells on plastic dish. The apoptosis induction of the L929 cells cultured on collagen gel with PDTC was repressed by inhibiting autophagy with chloroquine, an autophagy inhibitor, suggesting that autophagy contributes to the death induced by the treatment with PDTC. Possible underlying mechanism of this finding is discussed. CONCLUSION: NF-kappaB played an important role in protecting the L929 cells cultured on collagen gel from TNFalpha-induced death. PMID- 27764546 TI - The psychological impact of traffic injuries sustained in a road crash by bicyclists: A prospective study. AB - OBJECTIVE: The objective of this study was to investigate the psychological impact of traffic injuries in bicyclists (cyclists) in comparison to car occupants who also sustained traffic injuries. Factors predictive of elevated psychological distress were also investigated. METHODS: An inception cohort prospective design was used. Participants included cyclists aged >=17 years (mean age 41.7 years) who sustained a physical injury (n = 238) assessed within 28 days of the crash, following medical examination by a registered health care practitioner. Injury included musculoskeletal and soft tissue injuries and minor/moderate traumatic brain injury (TBI), excluding severe TBI, spinal cord injury, and severe multiple fractures. Assessment also occurred 6 months postinjury. Telephone-administered interviews assessed a suite of measures including sociodemographic, preinjury health and injury factors. Psychological impact was measured by pain catastrophization, trauma-related distress, and general psychological distress. The psychological health of the cyclists was compared to that of the car occupants (n = 234; mean age 43.1 years). A mixed model repeated measures analysis, adjusted for confounding factors, was used to determine differences between groups and regression analyses were used to determine contributors to psychological health in the cyclists 6 months postinjury. RESULTS: Cyclists had significantly better psychological health (e.g., lower pain catastrophizing, lower rates of probable posttraumatic stress disorder [PTSD], and lower general distress levels) compared to car occupants at baseline and 6 months postinjury. Factors predictive of cyclists' psychological distress included younger age, greater perceived danger of death, poorer preinjury health, and greater amount of time in hospital after the injury. CONCLUSIONS: These data provide insight into how cyclists perceive and adjust to their traffic injuries compared to drivers and passengers who sustain traffic injuries, as well as direction for preventing the development of severe psychological injury. Future research should examine the utility of predictors of psychological health to improve recovery. PMID- 27764547 TI - Unmasking PTEN's nuclear functions. PMID- 27764549 TI - NOTCH and the 2 SASPs of senescence. PMID- 27764548 TI - Resistance to ALK inhibitors: Pharmacokinetics, mutations or bypass signaling? PMID- 27764550 TI - Paclitaxel-induced aberrant mitosis and mitotic slippage efficiently lead to proliferative death irrespective of canonical apoptosis and p53. AB - Spindle poisons elicit various cellular responses following metaphase arrest, but how they relate to long-term clonogenicity has remained unclear. We prepared several HeLa lines in which the canonical apoptosis pathway was attenuated, and compared their acute responses to paclitaxel, as well as long-term fate, with the parental line. Three-nanomolar paclitaxel induced brief metaphase arrest (<5 h) often followed by aberrant mitosis, and about 90% of the cells of each line had lost their clonogenicity after 48 h of the treatment. A combination of the same concentration of paclitaxel with the kinesin-5 inhibitor, S-trityl-L-cysteine (STLC), at 1 uM led to much longer arrest (~20 h) and predominance of subsequent line-specific responses: mitochondrial outer membrane permeabilization (MOMP) in the apoptosis-prone line, or mitotic slippage without obvious MOMP in the apoptosis-reluctant lines. In spite of this, combination with STLC did not lead to a marked difference in clonogenicity between the apoptosis-prone and reluctant lines, and intriguingly resulted in slightly better clonogenicity than that of cells treated with 3 nM paclitaxel alone. This indicates that changes in the short-term response within 3 possible scenarios - acute MOMP, mitotic slippage or aberrant mitosis - has only a weak impact on clonogenicity. Our results suggest that once cells have committed to slippage or aberrant mitosis they eventually undergo proliferative death irrespective of canonical apoptosis or p53 function. Consistent with this, cells with irregular DNA contents originating from mitotic slippage or aberrant mitosis were mostly eliminated from the population within several rounds of division after the drug treatment. PMID- 27764551 TI - Klp10A modulates the localization of centriole-associated proteins during Drosophila male gametogenesis. AB - Mutations in Klp10A, a microtubule-depolymerising Kinesin-13, lead to overly long centrioles in Drosophila male germ cells. We demonstrated that the loss of Klp10A modifies the distribution of typical proteins involved in centriole assembly and function. In the absence of Klp10A the distribution of Drosophila pericentrin like protein (Dplp), Sas-4 and Sak/Plk4 that are restricted in control testes to the proximal end of the centriole increase along the centriole length. Remarkably, the cartwheel is lacking or it appears abnormal in mutant centrioles, suggesting that this structure may spatially delimit protein localization. Moreover, the parent centrioles that in control cells have the same dimensions grow at different rates in mutant testes with the mother centrioles longer than the daughters. Daughter centrioles have often an ectopic position with respect to the proximal end of the mothers and failed to recruit Dplp. PMID- 27764571 TI - Technical Feasibility of Enterotomy Closure with Knotless Barbed Suture Material (V-Loc 180) in Esophagojejunostomy Using Linear Stapler during Totally Laparoscopic Total Gastrectomy for Gastric Cancer. AB - PURPOSE: Intra-corporeal esophagojejunostomy (EJ) using a linear stapler creates a stapler entry hole that requires secure closure during the totally laparoscopic total gastrectomy (TLTG) procedure for gastric cancer. Since a standard method has not been established yet, the feasibility of using V-loc 180 (Covidien, Mansfield, MA, USA) suture material was evaluated in this study. MATERIALS AND METHODS: During January 2012 to March 2015, 25 patients who underwent linear stapling EJ and V-loc 180 closure of remaining enterotomy were included in this study. Basic clinico-pathological characteristics, surgical outcomes, and short term complications were analyzed. RESULTS: The mean patient age was 60.4 +/- 8.5 years. Nineteen males and six females were included in this study. The mean body mass index was 25.3 +/- 2.3 kg/m2. There were 22 stage-I, 2 stage-II, and 1 stage III gastric cancer patients. The mean operation time was 240.5 +/- 44.6 min, and the time for anastomosis was 38.8 +/- 11.2 min. The procedures were successfully performed in all cases without any intra-operative complications. There was one case of EJ leakage that occurred at the corner of EJ staple line and not at the enterotomy closure site. CONCLUSIONS: The closure of the remaining enterotomy site using V-loc 180 suture following linear stapler EJ is technically feasible and safe during the TLTG procedure. However, further experience and results from other surgeons are necessary to generalize this procedure. PMID- 27764552 TI - Molecular and functional characterization of cry1Ac transgenic pea lines. AB - Transgenic pea lines transformed with the cry1Ac gene were characterized at molecular (PCR, RT-PCR, qRT-PCR and immunostrip assay) and functional levels (leaf paint and insect feeding bioassays). The results showed the presence, expression, inheritance and functionality of the introduced transgene at different progeny levels. Variation in the expression of the cry1Ac gene was observed among the different transgenic lines. In the insect bioassay studies using the larvae of Heliothis virescens, both larval survival and plant damage were highly affected on the different transgenic plants. Up to 100 % larval mortality was observed on the transgenic plants compared to 17.42 % on control plants. Most of the challenged transgenic plants showed very negligible to substantially reduced feeding damage indicating the insect resistance of the developed transgenic lines. Further analysis under field condition will be required to select promising lines for future uses. PMID- 27764560 TI - Ebola vaccines in clinical trial: The promising candidates. AB - Ebola virus disease (EVD) has become a great threat to humans across the world in recent years. The 2014 Ebola epidemic in West Africa caused numerous deaths and attracted worldwide attentions. Since no specific drugs and treatments against EVD was available, vaccination was considered as the most promising and effective method of controlling this epidemic. So far, 7 vaccine candidates had been developed and evaluated through clinical trials. Among them, the recombinant vesicular stomatitis virus-based vaccine (rVSV-EBOV) is the most promising candidate, which demonstrated a significant protection against EVD in phase III clinical trial. However, several concerns were still associated with the Ebola vaccine candidates, including the safety profile in some particular populations, the immunization schedule for emergency vaccination, and the persistence of the protection. We retrospectively reviewed the current development of Ebola vaccines and discussed issues and challenges remaining to be investigated in the future. PMID- 27764572 TI - Subchronic Exposure to Fenthion Induces Hematological Changes in Liver Tissue of African Catfish Clarias gariepinus. AB - In this study, African Catfish (also known as Sharptooth Catfish) Clarias gariepinus were exposed to sublethal concentrations of fenthion of 2.0, 4.0, and 8.0 mg/L for 21 d and allowed to recover for 7 d to investigate the potential for hematological changes. Whole blood was sampled on days 1, 7, 14, and 21 postexposure and after a 7-d recovery period. During exposure, fenthion caused a reduction in red blood cell counts, hemoglobin concentration, and packed cell volume. There was an increase in white blood cell counts but no significant difference in mean corpuscular hemoglobin concentration, mean corpuscular volume, and mean corpuscular hemoglobin. Both increases and decreases were observed in white blood cell differentials. After the 7-d recovery period, both increases and decreases were observed in the hematological parameters. These results reveal that sublethal concentrations of fenthion can cause hematological alterations in African Catfish and that the substance should be used with caution. Received October 20, 2015; accepted May 4, 2016. PMID- 27764574 TI - Mice continue to be a good model for preliminary assessment of tuberculosis vaccine candidates. PMID- 27764573 TI - MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2. AB - Autophagy is an important antimicrobial effector process that defends against Mycobacterium tuberculosis (Mtb), the human pathogen causing tuberculosis (TB). MicroRNAs (miRNAs), endogenous noncoding RNAs, are involved in various biological functions and act as post-transcriptional regulators to target mRNAs. The process by which miRNAs affect antibacterial autophagy and host defense mechanisms against Mtb infections in human monocytes and macrophages is largely uncharacterized. In this study, we show that Mtb significantly induces the expression of MIR144*/hsa-miR-144-5p, which targets the 3'-untranslated region of DRAM2 (DNA damage regulated autophagy modulator 2) in human monocytes and macrophages. Mtb infection downregulated, whereas the autophagy activators upregulated, DRAM2 expression in human monocytes and macrophages by activating AMP-activated protein kinase. In addition, overexpression of MIR144* decreased DRAM2 expression and formation of autophagosomes in human monocytes, whereas inhibition of MIR144* had the opposite effect. Moreover, the levels of MIR144* were elevated, whereas DRAM2 levels were reduced, in human peripheral blood cells and tissues in TB patients, indicating the clinical significance of MIR144* and DRAM2 in human TB. Notably, DRAM2 interacted with BECN1 and UVRAG, essential components of the autophagic machinery, leading to displacement of RUBCN from the BECN1 complex and enhancement of Ptdlns3K activity. Furthermore, MIR144* and DRAM2 were critically involved in phagosomal maturation and enhanced antimicrobial effects against Mtb. Our findings identify a previously unrecognized role of human MIR144* in the inhibition of antibacterial autophagy and the innate host immune response to Mtb. Additionally, these data reveal that DRAM2 is a key coordinator of autophagy activation that enhances antimicrobial activity against Mtb. PMID- 27764576 TI - Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective. AB - INTRODUCTION: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed. Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concentration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy. PMID- 27764575 TI - More than meets the dimer: What is the quaternary structure of the glucocorticoid receptor? AB - It is widely accepted that the glucocorticoid receptor (GR), a ligand-regulated transcription factor that triggers anti-inflammatory responses, binds specific response elements as a homodimer. Here, we will discuss the original primary data that established this model and contrast it with a recent report characterizing the GR-DNA complex as a tetramer. PMID- 27764578 TI - Timeless insights into prevention of acetaldehyde genotoxicity? PMID- 27764577 TI - Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-kappaB) signaling during cell proliferation. AB - Guanine nucleotide binding protein-like 3-like (GNL3L) is an evolutionarily conserved putative nucleolar GTPase belonging to the HSR1-MMR1 family. In the present study, using protein-protein interaction assays, we show that Leucine Zipper Down-regulated in Cancer-1 (LDOC1) is a novel interacting partner of GNL3L. Furthermore, our results reveal that ectopic expression of LDOC1 destabilizes endogenous GNL3L levels and down modulates GNL3L-induced cell proliferation, in contrast, the knockdown of LDOC1 potentiates cell proliferation upon GNL3L expression. Interestingly, GNL3L upregulates NF-kappaB dependent transcriptional activity by modulating the expression of NF-kappaB subunit p65, which is reversed upon co-expression of LDOC1 with GNL3L. GNL3L also potentiates TNF-alpha mediated NF-kappaB activity. In addition, anti-apoptotic function of GNL3L is impaired upon p65 knockdown, suggesting its critical role in GNL3L mediated cell proliferation/survival. An inverse correlation of GNL3L and LDOC1 expression profiles in various tumor tissues from BioXpress database indicate their critical role in cancer. Collectively, our data provides evidence that GNL3L-LDOC1 interplay regulates cell proliferation through the modulation of NF kappaB pathway during tumorigenesis. PMID- 27764579 TI - Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR). AB - The broadly expressed volume-sensitive outwardly rectifying anion channel (VSOR, also called VRAC) plays essential roles in cell survival and death. Recent findings have suggested that LRRC8A is a core component of VSOR in human cells. In the present study, VSOR currents were found to be largely reduced by siRNA against LRRC8A in mouse C127 cells as well. In contrast, LRRC8A knockdown never affected activities of 4 other types of anion channel activated by acid, Ca2+, patch excision or cAMP. While cisplatin-resistant KCP-4 cells poorly expressed endogenous VSOR activity, molecular expression levels of LRRC8A, LRRC8D and LRRC8E were indistinguishable between VSOR-deficient KCP-4 cells and the parental VSOR-rich KB cells. Furthermore, overexpression of LRRC8A alone or together with LRRC8D or LRRC8E in KCP-4 cells failed to restore VSOR activity. These results show that deficiency of VSOR currents in KCP-4 cells is not due to insufficient expression of the LRRC8A/D/E gene, suggesting an essential involvement of some other factor(s), and indicate that further study is required to better understand the complexities of the molecular determinants of VSOR, including the precise role of LRRC8 proteins. PMID- 27764580 TI - Acceptance by laypersons and medical professionals of the personalized eHealth platform, eHealthMonitor. AB - INTRODUCTION AND BACKGROUND: Often, eHealth services are not accepted because of factors such as eHealth literacy or trust. Within this study, eHealthMonitor was evaluated in three European countries (Germany, Greece, and Poland) by medical professionals and laypersons with respect to numerous acceptance factors. METHODS: Questionnaires were created on the basis of factors from literature and with the help of scales which have already been validated. A qualitative survey was conducted in Germany, Poland, and Greece. RESULTS: The eHealth literacy of all participants was medium/high. Laypersons mostly agreed that they could easily become skillful with eHealthMonitor and that other people thought that they should use eHealthMonitor. Amongst medical professionals, a large number were afraid that eHealthMonitor could violate their privacy or the privacy of their patients. Overall, the participants thought that eHealthMonitor was a good concept and that they would use it. DISCUSSION AND CONCLUSION: The main hindrances to the use of eHealthMonitor were found in trust issues including data privacy. In the future, more research on the linkage of all measured factors is needed, for example, to address the question of whether highly educated people tend to mistrust eHealth information more than people with lower levels of education. PMID- 27764581 TI - Liver alterations in Oreochromis niloticus (Pisces) induced by insecticide imidacloprid: Histopathology and heat shock protein in situ localization. AB - Liver is very sensitive to environmental contaminants such as pesticides, it being the first target of toxicity of a substance. The objective of this study was to investigate the possible effects of the insecticide imidacloprid (IMI) on the liver of Oreochromis niloticus according concentrations used for growing sugarcane. A semi-quantitative analysis of histopathological alterations of IMI on liver was performed by light microscopy and cellular labeling of heat shock proteins (HSP70) by immunohistochemistry. The most common changes in liver at all concentrations of IMI were hydropic degeneration, pyknotic nuclei, and loss of cell limits. Steatosis and increased levels of HSP70 were detected in hepatocytes with the highest concentration of IMI. In conclusion, the tested concentrations of IMI induced histopathological changes in the liver of O. niloticus and active defence mechanisms to maintain the morphophysiological integrity of the liver. This insecticide has a toxicity potential for these fish, which is a non-target organism of its action. PMID- 27764589 TI - A Combinatorial Model for Dentate Gyrus Sparse Coding. AB - The dentate gyrus forms a critical link between the entorhinal cortex and CA3 by providing a sparse version of the signal. Concurrent with this increase in sparsity, a widely accepted theory suggests the dentate gyrus performs pattern separation-similar inputs yield decorrelated outputs. Although an active region of study and theory, few logically rigorous arguments detail the dentate gyrus's (DG) coding. We suggest a theoretically tractable, combinatorial model for this action. The model provides formal methods for a highly redundant, arbitrarily sparse, and decorrelated output signal.To explore the value of this model framework, we assess how suitable it is for two notable aspects of DG coding: how it can handle the highly structured grid cell representation in the input entorhinal cortex region and the presence of adult neurogenesis, which has been proposed to produce a heterogeneous code in the DG. We find tailoring the model to grid cell input yields expansion parameters consistent with the literature. In addition, the heterogeneous coding reflects activity gradation observed experimentally. Finally, we connect this approach with more conventional binary threshold neural circuit models via a formal embedding. PMID- 27764590 TI - Online Reinforcement Learning Using a Probability Density Estimation. AB - Function approximation in online, incremental, reinforcement learning needs to deal with two fundamental problems: biased sampling and nonstationarity. In this kind of task, biased sampling occurs because samples are obtained from specific trajectories dictated by the dynamics of the environment and are usually concentrated in particular convergence regions, which in the long term tend to dominate the approximation in the less sampled regions. The nonstationarity comes from the recursive nature of the estimations typical of temporal difference methods. This nonstationarity has a local profile, varying not only along the learning process but also along different regions of the state space. We propose to deal with these problems using an estimation of the probability density of samples represented with a gaussian mixture model. To deal with the nonstationarity problem, we use the common approach of introducing a forgetting factor in the updating formula. However, instead of using the same forgetting factor for the whole domain, we make it dependent on the local density of samples, which we use to estimate the nonstationarity of the function at any given input point. To address the biased sampling problem, the forgetting factor applied to each mixture component is modulated according to the new information provided in the updating, rather than forgetting depending only on time, thus avoiding undesired distortions of the approximation in less sampled regions. PMID- 27764591 TI - Improving the Incoherence of a Learned Dictionary via Rank Shrinkage. AB - This letter considers the problem of dictionary learning for sparse signal representation whose atoms have low mutual coherence. To learn such dictionaries, at each step, we first update the dictionary using the method of optimal directions (MOD) and then apply a dictionary rank shrinkage step to decrease its mutual coherence. In the rank shrinkage step, we first compute a rank 1 decomposition of the column-normalized least squares estimate of the dictionary obtained from the MOD step. We then shrink the rank of this learned dictionary by transforming the problem of reducing the rank to a nonnegative garrotte estimation problem and solving it using a path-wise coordinate descent approach. We establish theoretical results that show that the rank shrinkage step included will reduce the coherence of the dictionary, which is further validated by experimental results. Numerical experiments illustrating the performance of the proposed algorithm in comparison to various other well-known dictionary learning algorithms are also presented. PMID- 27764592 TI - Selective Interareal Synchronization through Gamma Frequency Differences and Slower-Rhythm Gamma Phase Reset. AB - The communication-through-coherence (CTC) hypothesis states that a sending group of neurons will have a particularly strong effect on a receiving group if both groups oscillate in a phase-locked ("coherent") manner (Fries, 2005 , 2015 ). Here, we consider a situation with two visual stimuli, one in the focus of attention and the other distracting, resulting in two sites of excitation at an early cortical area that project to a common site in a next area. Taking a modeler's perspective, we confirm the workings of a mechanism that was proposed by Bosman et al. ( 2012 ) in the context of providing experimental evidence for the CTC hypothesis: a slightly higher gamma frequency of the attended sending site compared to the distracting site may cause selective interareal synchronization with the receiving site if combined with a slow-rhythm gamma phase reset. We also demonstrate the relevance of a slightly lower intrinsic frequency of the receiving site for this scenario. Moreover, we discuss conditions for a transition from bottom-up to top-down driven phase locking. PMID- 27764582 TI - Autophagy and its implication in human oral diseases. AB - Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression. In particular, activated autophagy functions as a cytoprotective mechanism under environmental stress conditions, which regulates tumor growth and mediates resistance to anticancer treatment in established tumors. During infections and inflammation, activated autophagy selectively delivers microbial antigens to the immune systems, and is therefore connected to the elimination of intracellular pathogens. Impaired autophagy contributes to oxidative stress, genomic instability, chronic tissue damage, inflammation and tumorigenesis, and is involved in aberrant bacterial clearance and immune priming. Hence, substantial progress in the study of autophagy provides new insights into the pathogenesis of oral diseases. This review outlines the mechanisms of autophagy, and highlights the emerging roles of this process in oral cancer, periapical lesions, periodontal diseases, and oral candidiasis. PMID- 27764593 TI - On the Mathematical Consequences of Binning Spike Trains. AB - We initiate a mathematical analysis of hidden effects induced by binning spike trains of neurons. Assuming that the original spike train has been generated by a discrete Markov process, we show that binning generates a stochastic process that is no longer Markov but is instead a variable-length Markov chain (VLMC) with unbounded memory. We also show that the law of the binned raster is a Gibbs measure in the DLR (Dobrushin-Lanford-Ruelle) sense coined in mathematical statistical mechanics. This allows the derivation of several important consequences on statistical properties of binned spike trains. In particular, we introduce the DLR framework as a natural setting to mathematically formalize anticipation, that is, to tell "how good" our nervous system is at making predictions. In a probabilistic sense, this corresponds to condition a process by its future, and we discuss how binning may affect our conclusions on this ability. We finally comment on the possible consequences of binning in the detection of spurious phase transitions or in the detection of incorrect evidence of criticality. PMID- 27764594 TI - Fast, Accurate Localization of Epileptic Seizure Onset Zones Based on Detection of High-Frequency Oscillations Using Improved Wavelet Transform and Matching Pursuit Methods. AB - This letter describes the improvement of two methods of detecting high-frequency oscillations (HFOs) and their use to localize epileptic seizure onset zones (SOZs). The wavelet transform (WT) method was improved by combining the complex Morlet WT with Shannon entropy to enhance the temporal-frequency resolution during HFO detection. And the matching pursuit (MP) method was improved by combining it with an adaptive genetic algorithm to improve the speed and accuracy of the calculations for HFO detection. The HFOs detected by these two methods were used to localize SOZs in five patients. A comparison shows that the improved WT method provides high specificity and quick localization and that the improved MP method provides high sensitivity. PMID- 27764595 TI - Efficient Neural Codes That Minimize Lp Reconstruction Error. AB - The efficient coding hypothesis assumes that biological sensory systems use neural codes that are optimized to best possibly represent the stimuli that occur in their environment. Most common models use information-theoretic measures, whereas alternative formulations propose incorporating downstream decoding performance. Here we provide a systematic evaluation of different optimality criteria using a parametric formulation of the efficient coding problem based on the [Formula: see text] reconstruction error of the maximum likelihood decoder. This parametric family includes both the information maximization criterion and squared decoding error as special cases. We analytically derived the optimal tuning curve of a single neuron encoding a one-dimensional stimulus with an arbitrary input distribution. We show how the result can be generalized to a class of neural populations by introducing the concept of a meta-tuning curve. The predictions of our framework are tested against previously measured characteristics of some early visual systems found in biology. We find solutions that correspond to low values of [Formula: see text], suggesting that across different animal models, neural representations in the early visual pathways optimize similar criteria about natural stimuli that are relatively close to the information maximization criterion. PMID- 27764596 TI - LSV-Based Tail Inequalities for Sums of Random Matrices. AB - The techniques of random matrices have played an important role in many machine learning models. In this letter, we present a new method to study the tail inequalities for sums of random matrices. Different from other work (Ahlswede & Winter, 2002 ; Tropp, 2012 ; Hsu, Kakade, & Zhang, 2012 ), our tail results are based on the largest singular value (LSV) and independent of the matrix dimension. Since the LSV operation and the expectation are noncommutative, we introduce a diagonalization method to convert the LSV operation into the trace operation of an infinitely dimensional diagonal matrix. In this way, we obtain another version of Laplace-transform bounds and then achieve the LSV-based tail inequalities for sums of random matrices. PMID- 27764597 TI - On Decoding Grid Cell Population Codes Using Approximate Belief Propagation. AB - Neural systems are inherently noisy. One well-studied example of a noise reduction mechanism in the brain is the population code, where representing a variable with multiple neurons allows the encoded variable to be recovered with fewer errors. Studies have assumed ideal observer models for decoding population codes, and the manner in which information in the neural population can be retrieved remains elusive. This letter addresses a mechanism by which realistic neural circuits can recover encoded variables. Specifically, the decoding problem of recovering a spatial location from populations of grid cells is studied using belief propagation. We extend the belief propagation decoding algorithm in two aspects. First, beliefs are approximated rather than being calculated exactly. Second, decoding noises are introduced into the decoding circuits. Numerical simulations demonstrate that beliefs can be effectively approximated by combining polynomial nonlinearities with divisive normalization. This approximate belief propagation algorithm is tolerant to decoding noises. Thus, this letter presents a realistic model for decoding neural population codes and investigates fault tolerant information retrieval mechanisms in the brain. PMID- 27764598 TI - Derivation of Human Chromatic Discrimination Ability from an Information Theoretical Notion of Distance in Color Space. AB - The accuracy with which humans detect chromatic differences varies throughout color space. For example, we are far more precise when discriminating two similar orange stimuli than two similar green stimuli. In order for two colors to be perceived as different, the neurons representing chromatic information must respond differently, and the difference must be larger than the trial-to-trial variability of the response to each separate color. Photoreceptors constitute the first stage in the processing of color information; many more stages are required before humans can consciously report whether two stimuli are perceived as chromatically distinguishable. Therefore, although photoreceptor absorption curves are expected to influence the accuracy of conscious discriminability, there is no reason to believe that they should suffice to explain it. Here we develop information-theoretical tools based on the Fisher metric that demonstrate that photoreceptor absorption properties explain about 87% of the variance of human color discrimination ability, as tested by previous behavioral experiments. In the context of this theory, the bottleneck in chromatic information processing is determined by photoreceptor absorption characteristics. Subsequent encoding stages modify only marginally the chromatic discriminability at the photoreceptor level. PMID- 27764599 TI - Multiple Diffusion Models to Compare Saccadic and Manual Responses for Inhibition of Return. AB - Cuing a location in space produces a short-lived advantage in reaction time to targets at that location. This early advantage, however, switches to a reaction time cost and has been termed inhibition of return (IOR). IOR behaves differently for different response modalities, suggesting that it may not be a unified effect. This letter presents new data from two experiments testing the gradient of IOR with random, continuous cue-target Euclidean distance and cue-target onset asynchrony. These data were then used to train multiple diffusion models of saccadic and manual reaction time for these cuing experiments. Diffusion models can generate accurate distributions of reaction time data by modeling a response as a buildup of evidence toward a response threshold. If saccadic and attentional IOR are based on similar processes, then differences in distribution will be best explained by adjusting parameter values such as signal and noise within the same model structure. Although experimental data show differences in the timing of IOR across modality, best-fit models are shown to have similar model parameters for the gradient of IOR, suggesting similar underlying mechanisms for saccadic and manual IOR. PMID- 27764646 TI - Responses by hospital complaints managers to recommendations for systemic reforms by health complaints commissions. AB - Objective This paper explores how hospital complaints managers react to recommendations for systemic quality reforms by health complaints commissions in response to complaints by patients in Queensland and New South Wales. Methods Semi-structured qualitative interviews were conducted with complaints managers in 17 hospitals. Interview transcripts were then thematically analysed and data on responses to health complaint commissions was organised in relation to Valerie Braithwaite's typology of motivational postures. Results Respondents supported involvement by an independent authority where patients had serious complaints about the services they received in hospital, but wanted more negotiation with commissions on service improvement recommendations. Conclusions Hospital complaints managers mostly responded as virtuous or rational actors to the symbolic power of complaints commissions. This may be context dependent because Australian health commissions operate within a pro-reform context as a result of recent publicity around health system failures. What is known about the topic? Little is known about regulatory relationships between complaints commissions and hospitals. There has been no Australian research considering how complaints managers respond to commission recommendations for quality improvements and reforms to hospital services. What does the paper add? The paper uses a novel theoretical framework based on regulatory theory to understand and describe the reactions of complaints managers to commission recommendations. What are the implications for practitioners? Commissions should seek commentary from complaints managers through open dialogue before making final recommendations. This will ease the progress of reforms and make recommendations more acceptable and 'genuine' in the specific context of the hospital. PMID- 27764647 TI - Capturing religious identity during hospital admission: a valid practice in our increasingly secular society? AB - Objective Most major Victorian hospitals include religious identity in routine admission demographic questions. However, approximately 20% of admissions do not have their religious identity recorded. At the Royal Melbourne Hospital this missing 20% was surveyed throughout 2014-15 for two reasons: (1) to enable patient care; and (2) to provide an insight into the significance of religious identity for patients. There is scarce literature on this subject, so the present mixed-methods study, including a qualitative component, will start to bridge the gap. Methods Mixed methods, cross-sectional survey. Results The quantitative component of the study found that religious identity was important for a significant proportion of our diverse population and that, in general, demographics were congruent with Australian Bureau of Statistics (ABS) census figures. The qualitative component also revealed significant complexity behind religious identity labels, which the census is unable to capture, providing an insight into the requirements of our growing multicultural population. Conclusions This study illustrates that religious identity is important for a majority of Royal Melbourne's culturally diverse inpatients. This data would seem to give the practice of collecting religious identity data on admission new credence, especially as our culturally and linguistically diverse populations increase. In order to understand these nuances and provide appropriate care, skilled spiritual screening and assessment would appear to be not optional, but rather necessary in our increasingly complex healthcare future. What is known about the topic? A search of the literature using related terms (religious, religion, spiritual identity, care) revealed that there is scarce literature on the subject of religious identity and its importance and meaning to patients. What does this paper add? This mixed methods study approaches the issue of the importance of religious identity from the patient perspective via a spiritual screening survey that included a qualitative component, so will begin to bridge a gap in knowledge. What are the implications for practitioners? Improved understanding of the complexity of the spiritual needs of our Victorian multicultural population and commensurate emphasis on the need for individual spiritual screening and assessment. PMID- 27764648 TI - Preliminary evidence of HIV seroconversion among HIV-negative men who have sex with men taking non-prescribed antiretroviral medication for HIV prevention in Miami, Florida, USA. AB - : Background Limited information suggests that men who have sex with men (MSM) are informally obtaining antiretroviral medication (ARVs) and using them for HIV pre-exposure prophylaxis (PrEP). METHODS: Data are drawn from an on-going study examining the use of non-prescribed ARVs for PrEP. To date, 24 qualitative interviews have been conducted with HIV-negative, substance-using MSM living in Miami, Florida, USA. Data are presented from two participants who reported HIV seroconversion while using non-prescribed ARVs for PrEP. RESULTS: Preliminary data indicate that some young MSM: (i) lack awareness of and accurate information about the efficacious use of PrEP; (ii) obtain non-prescribed ARVs from HIV positive sex partners and use these medications for PrEP in a way that does not provide adequate protection against HIV infection or cohere with established guidelines; and (iii) engage in multiple HIV transmission risk behaviours, including condomless anal sex and injection drug use. CONCLUSIONS: The informal, non-prescribed and non-medically supervised use of ARVs for HIV prevention has the potential to undermine the protective benefits of PrEP and leave men unprotected against HIV transmission and at risk for ARV resistance. PMID- 27764649 TI - Uptake and trends in ordering of funded hepatitis B immunisation for priority populations in Victoria, Australia, 2013-2014. AB - : Background The Department of Health and Human Services in Victoria provides funded hepatitis B vaccine to many priority groups at risk of acquiring infection. We aimed to determine the uptake of vaccine ordering for at-risk groups over time, to assess any trends and identify any gaps in prevention of hepatitis B for those at risk. METHODS: Routinely collected administrative data regarding the indication for vaccine ordered by practitioners were analysed for the period June 2013 to December 2014. Number of doses and courses distributed was determined and compared with the estimated size of the priority populations. RESULTS: During the 18-month period assessed, 20498 doses of funded hepatitis B vaccine were ordered, equating to ~5700 complete courses, with the overall number of orders per quarter increasing between 2013 and 2014. The most common indication was being a household or sexual contact of people living with hepatitis B (2803 courses, 49.2% of the total), equating to approximately one course per new chronic hepatitis B notification. The remaining doses were largely distributed to people living with HIV (648 courses, 11.4%), people living with hepatitis C (621 courses, 10.9%), and people who inject drugs (594 courses, 10.4%). CONCLUSIONS: This analysis demonstrates that access to hepatitis B immunisation among priority populations appears to have increased in Victoria during 2013-14, however it could still be improved. Continued assessment of these data over time will be important to measure the impact of interventions on increasing the reach of the funded vaccine program. PMID- 27764650 TI - High chlamydia and gonorrhoea repeat positivity in remote Aboriginal communities 2009-2011: longitudinal analysis of testing for re-infection at 3 months suggests the need for more frequent screening. AB - : Background Extremely high rates of diagnosis of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) have been recorded in remote communities across northern and central Australia. Re-testing at 3 months, after treatment administered, of CT or NG is recommended to detect repeat infections and prevent morbidity and ongoing transmission. METHODS: Baseline CT and NG laboratory data (2009-2010) from 65 remote health services participating in a cluster randomised trial was used to calculate the proportion of individuals re-tested after an initial CT or NG diagnosis at <2 months (not recommended), 2-4 months (recommended) and 5-12 months and the proportion with repeat positivity on re test. To assess if there were difference in re-testing and repeat positivity by age group and sex, t-tests were used. RESULTS: There was a total of 2054 people diagnosed with CT and/or NG in the study period; 14.9% were re-tested at 2-4 months, 26.9% at 5-12 months, a total of 41.8% overall. Re-testing was higher in females than in males in both the 2-4-month (16.9% v. 11.5%, P<0.01) and 5-12 month (28.9% v. 23.5%, P=0.01) periods. Women aged 25-29 years had a significantly higher level of re-testing 5-12 months post-diagnosis than females aged 16-19 years (39.8% v. 25.4%, P<0.01). There was a total of 858 people re tested at 2-12 months and repeat positivity was 26.7%. There was higher repeat NG positivity than repeat CT positivity (28.8% v. 18.1%, P<0.01). CONCLUSIONS: Just under half the individuals diagnosed with CT or NG were re-tested at 2-12 months post-diagnosis; however, only 15% were re-tested in the recommended time period of 2-4 months. The higher NG repeat positivity compared with CT is important, as repeat NG infections have been associated with higher risk of pelvic inflammatory disease-related hospitalisation. Findings have implications for clinical practice in remote community settings and will inform ongoing sexual health quality improvement programs in remote community clinics. PMID- 27764651 TI - Finite element modeling of nonlinear acoustics/ultrasonics for the detection of closed delaminations in composites. AB - Linear ultrasonics methods based on the principle of reflection, transmission, dissipation of sound waves have been traditionally used to detect delaminations in composite structures. However, when the delamination is in very early stages such that it is almost closed, or closed due to a compressive load, the linear methods may fail to detect such cases of delaminations. Nonlinear acoustics/ultrasonics have shown potential to identify damages in composite structures which are difficult to detect using conventional linear ultrasonic methods. The nonlinear method involves exciting the structure with a sinusoidal signal of certain (or multiple) frequency and observing the vibrations of the structure. The vibrations of the damage region differ significantly from intact regions and can be used to identify the damage. However due to the complex and varying nature of the nonlinear phenomena created by the interaction between the exciting signal and the damage, there are many variables at play which can lead to success or failure of the method. While experiments lead to the establishment of the method to be used as a damage detection technique, numerical simulations can help to explain the various phenomena associated with nonlinearity. This work presents a quick approach to model the nonlinear behavior caused by closed delaminations. The model is validated with a previously available approach for nonlinear vibrations modeling and a comparison is made between the two. The local nature of the nonlinearity enables to map out the area of damage in the structure. Additionally, a few parametric studies are performed to study the effect of various parameters related to the nonlinear phenomenon. PMID- 27764652 TI - Formation, dissolution and properties of surface nanobubbles. AB - Surface nanobubbles are stable gaseous phases in liquids that form on solid substrates. While their existence has been confirmed, there are many open questions related to their formation and dissolution processes along with their structures and properties, which are difficult to investigate experimentally. To address these issues, we carried out molecular dynamics simulations based on atomistic force fields for systems comprised of water, air (N2 and O2), and a Highly Oriented Pyrolytic Graphite (HOPG) substrate. Our results provide insights into the formation/dissolution mechanisms of nanobubbles and estimates for their density, contact angle, and surface tension. We found that the formation of nanobubbles is driven by an initial nucleation process of air molecules and the subsequent coalescence of the formed air clusters. The clusters form favorably on the substrate, which provides an enhanced stability to the clusters. In contrast, nanobubbles formed in the bulk either move randomly to the substrate and spread or move to the water-air surface and pop immediately. Moreover, nanobubbles consist of a condensed gaseous phase with a surface tension smaller than that of an equivalent system under atmospheric conditions, and contact angles larger than those in the equivalent nanodroplet case. We anticipate that this study will provide useful insights into the physics of nanobubbles and will stimulate further research in the field by using all-atom simulations. PMID- 27764653 TI - Kinetic discrimination of DNA single-base mutations by localized surface plasmon resonance. AB - Clinical application of DNA microarrays used for screening of single nucleotide polymorphisms (SNPs) are very important for diagnosis of diseases and appropriate treatment of patients. In this paper localized surface plasmon resonance (LSPR) technique has been used to study the DNA hybridization process for binary solutions of respectively perfectly matching (PM) and single base mismatching (MM) 93-mer ssDNA from KRAS codon 12. 5'-thiol modified 35-mer ssDNA has been linked to the Au nanodisks array as probe with a surface coverage of 2.8+/ 0.1*1012/cm2. Probe's binding properties was investigated in details, obtaining a sensitivity down to 10nMand 13nM, respectively for PM and MM, showing that the hybridization process occurs at a lower rate for MM with respect to PM target. The competitive hybridization is accounted for by an inhibition model, where the non-complementary sequences kinetically hinder the hybridization of the perfect matching sequences, owing to their above mentioned affinity constant differences for the same probe. Accordingly, the single nucleotide polymorphisms can therefore be revealed in a single step and label free mode with high sensitivity and specificity by LSPR measurements. PMID- 27764655 TI - The Quality and Outcomes Framework: Body commodification in UK general practice. AB - The UK's Quality and Outcomes Framework (QOF) is the largest pay-for-performance scheme in the world. This ethnographic study explored how QOF's monetary logic influences the approach to healthcare in UK general practice. From August 2013 to April 2014, we researched two UK general practice surgeries and one general practice training programme. These environments provided the opportunity for studying various spaces such as QOF meetings, consultation rooms, QOF recoding sessions, and the collection of computer-screen images depicting how patients' biomarkers are evaluated and costed through software systems. QOF as a biomedical technology has led to the commodification of patients and their bodies. This complex phenomenon breaks down into three main themes: commodification of patients, QOF as currency, and valuing commodities. Despite the ostensible aim of QOF being to improve healthcare in general practice, it is accompanied by a body commodification process. The interface between patients and care providers has been commodified, with QOF's pricing mechanism and fragmentation of care provision performing an important role in animating the UK economy. PMID- 27764654 TI - The role of socioeconomic factors in Black-White health inequities across the life course: Point-in-time measures, long-term exposures, and differential health returns. AB - Research links Black-White health disparities to racial differences in socioeconomic status (SES), but understanding of the role of SES in racial health gaps has been restricted by reliance on static measures of health and socioeconomic well-being that mask the dynamic quality of these processes and ignore the racialized nature of the SES-health connection. Utilizing twenty-three years of longitudinal data from the Panel Study of Income Dynamics (1984-2007), this study uses multilevel growth curve models to examine how multiple dimensions of socioeconomic well-being-including long-term economic history and differential returns to SES-contribute to the life course patterning of Black-White health disparities across two critical markers of well-being: body mass index (N = 9057) and self-rated health (N = 11,329). Findings indicate that long-term SES exerts a significant influence on both body mass index and self-rated health, net of point in-time measures, and that Black-White health gaps are smallest in models that adjust for both long-term and current SES. I also find that Blacks and Whites receive differential health returns to increases in SES, which suggests that other factors-such as neighborhood segregation and exposure racial discrimination may restrict Blacks from converting increases in SES into health improvements in the same way as Whites. Together, these processes contribute to the life course patterning of Black-White health gaps and raise concerns about previous misestimation of the role of SES in racial health disparities. PMID- 27764656 TI - Tau Phosphorylation-Much More than a Biomarker. AB - Lasagna-Reeves et al. (2016) demonstrate that preventing the kinase Nuak1 from phosphorylating the microtubule-associated protein tau reduces the level of potentially pathogenic tau species in brain, a novel therapeutic strategy that could help counteract Alzheimer's disease and several other neurological disorders. PMID- 27764657 TI - Synaptic Suppression of Axon Regeneration. AB - In this issue of Neuron, Tedeschi et al. (2016) describe the voltage-gated calcium channel subunit alpha2delta2 as a developmental switch from axon elongation to synapse formation and transmission that doubles as a suppressor of axon regeneration, providing a molecular clue for the synaptic stabilization hypothesis of CNS regeneration failure. PMID- 27764658 TI - Presynaptic Plasticity Found in Translation. AB - In this issue of Neuron, Younts et al. (2016) demonstrate that activation of presynaptic CB1 receptors by retrograde endocannabinoid signaling stimulates protein synthesis in axon terminals to induce long-term depression of hippocampal inhibitory transmission. PMID- 27764659 TI - Laminar Differences in Associative Memory Signals in Monkey Perirhinal Cortex. AB - New research published in Neuron describes assignment of cortical layer to single neurons recorded in awake monkeys. Applying the procedure to perirhinal cortex, Koyano et al. (2016) found marked and unsuspected differences among layers in the coding of associative memory signals. PMID- 27764660 TI - Probability by Time. AB - In this issue of Neuron, Orban et al. (2016) test whether the brain represents probabilities by sampling: do neurons interpret the world by generating causal explanations of sense data and quickly sample different interpretations over time? Orban et al. (2016) find agreement between this model's predictions and neural data. PMID- 27764661 TI - Integrated Brain Network Architecture Supports Cognitive Task Performance. AB - Spontaneous fluctuations in neural activity and connectivity are thought to support cognition and behavior. In this issue of Neuron, Shine et al. (2016) describe a possible mechanism responsible for fluctuations in the human brain's network architecture that are related to rapid shifts in cognitive state. PMID- 27764662 TI - Grid Cells for Conceptual Spaces? AB - "Grid cells" encode an animal's location and direction of movement in 2D physical environments via regularly repeating receptive fields. Constantinescu et al. (2016) report the first evidence of grid cells for 2D conceptual spaces. The work has exciting implications for mental representation and shows how detailed neural coding hypotheses can be tested with bulk population-activity measures. PMID- 27764663 TI - Re-energizing the Development of Pain Therapeutics in Light of the Opioid Epidemic. AB - Limited options for treating moderate-severe pain led to an overreliance on opioids and the current opioid epidemic. Addressing the factors contributing to a dearth of effective alternatives and re-energizing the development of pain therapeutics is necessary to quell this epidemic. PMID- 27764665 TI - Non-canonical Signaling, the Hidden Life of Ligand-Gated Ion Channels. AB - Neurotransmitter receptors are responsible for the transfer of information across the synapse. While ionotropic receptors form ion channels and mediate rapid membrane depolarization, so-called metabotropic receptors exert their action though slower, less direct intracellular signaling pathways. Glutamate, GABA, and acetylcholine can activate both ionotropic and metabotropic receptors, yet the distinction between these "canonical" signaling systems has become less clear since ionotropic receptors were proposed to also activate second messenger systems, defining a "non-canonical" signaling pathway. How these alternative pathways affect neuronal circuit activity is not well understood, and their influence could be more significant than previously anticipated. In this review, we examine the evidence available that supports the existence of parallel and unsuspected signaling pathways used by ionotropic neurotransmitter receptors. PMID- 27764666 TI - Editorial Note to:Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. PMID- 27764668 TI - Publicly Available Data Provide Evidence against NR1H3 R415Q Causing Multiple Sclerosis. AB - It has recently been reported that an NR1H3 missense variant, R415Q, causes a novel familial form of multiple sclerosis (Wang et al., 2016a). This claim is at odds with publicly available data from the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). The allele frequency of R415Q is not significantly higher in cases (0.024%-0.049%) than in ExAC population controls (0.031%), whereas if R415Q conferred even 50% lifetime risk of developing MS, it would be hundreds of times more common in cases than in controls. The upper bound of the 95% confidence interval of penetrance for R415Q can be estimated at 2.2% for women and 1.2% for men, indicating that even if this variant is disease associated, individuals harboring the variant would have a lifetime risk of developing MS no higher than a few percent. ExAC data should be considered when evaluating claims of variant pathogenicity. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by The International Multiple Sclerosis Genetics Consortium (2016) and the response by Wang et al. (2016b), published in this issue. PMID- 27764664 TI - Rapid Sensory Adaptation Redux: A Circuit Perspective. AB - Adaptation is fundamental to life. All organisms adapt over timescales that span from evolution to generations and lifetimes to moment-by-moment interactions. The nervous system is particularly adept at rapidly adapting to change, and this in fact may be one of its fundamental principles of organization and function. Rapid forms of sensory adaptation have been well documented across all sensory modalities in a wide range of organisms, yet we do not have a comprehensive understanding of the adaptive cellular mechanisms that ultimately give rise to the corresponding percepts, due in part to the complexity of the circuitry. In this Perspective, we aim to build links between adaptation at multiple scales of neural circuitry by investigating the differential adaptation across brain regions and sub-regions and across specific cell types, for which the explosion of modern tools has just begun to enable. This investigation points to a set of challenges for the field to link functional observations to adaptive properties of the neural circuit that ultimately underlie percepts. PMID- 27764667 TI - NR1H3 p.Arg415Gln Is Not Associated to Multiple Sclerosis Risk. AB - A recent study by Wang et al. (2016a) claims that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause multiple sclerosis in certain individuals and determines a patient's likelihood of primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al. (2016a), but we find no evidence that this variant is associated with either MS or disease subtype. Wang et al. (2016a) also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS-of which no examples exist-can therefore not be substantiated by data. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by Minikel and MacArthur (2016) and the response by Wang et al. (2016b), published in this issue. PMID- 27764669 TI - Case-Control Studies Are Not Familial Studies. AB - Identifying rare genetic variants that drive the onset of disease is challenging, even before considering the additional genetic and environmental influences that likely exist in complex diseases. We recently published a study proposing a rare variant in the NR1H3 gene (p.R415Q, rs61731956) as responsible for the onset of multiple sclerosis (MS) in two multi-incident families (Wang et al., 2016). This publication has generated much discussion, and fortunately the possibility to validate a finding or prove it spurious can occur rapidly in genetic studies. All novel discoveries must be replicated, and best efforts should be made to ensure that these replications use the appropriate samples and approach, and provide the correct interpretation of the results. This Matters Arising Response paper addresses the Minikel and MacArthur (2016) and The International Multiple Sclerosis Genetics Consortium (2016) Matters Arising papers, published concurrently in Neuron. PMID- 27764670 TI - In Situ Transcription Profiling of Single Cells Reveals Spatial Organization of Cells in the Mouse Hippocampus. AB - Identifying the spatial organization of tissues at cellular resolution from single-cell gene expression profiles is essential to understanding biological systems. Using an in situ 3D multiplexed imaging method, seqFISH, we identify unique transcriptional states by quantifying and clustering up to 249 genes in 16,958 cells to examine whether the hippocampus is organized into transcriptionally distinct subregions. We identified distinct layers in the dentate gyrus corresponding to the granule cell layer and the subgranular zone and, contrary to previous reports, discovered that distinct subregions within the CA1 and CA3 are composed of unique combinations of cells in different transcriptional states. In addition, we found that the dorsal CA1 is relatively homogeneous at the single cell level, while ventral CA1 is highly heterogeneous. These structures and patterns are observed using different mice and different sets of genes. Together, these results demonstrate the power of seqFISH in transcriptional profiling of complex tissues. PMID- 27764671 TI - Nascent Proteome Remodeling following Homeostatic Scaling at Hippocampal Synapses. AB - Homeostatic scaling adjusts the strength of synaptic connections up or down in response to large changes in input. To identify the landscape of proteomic changes that contribute to opposing forms of homeostatic plasticity, we examined the plasticity-induced changes in the newly synthesized proteome. Cultured rat hippocampal neurons underwent homeostatic up-scaling or down-scaling. We used BONCAT (bio-orthogonal non-canonical amino acid tagging) to metabolically label, capture, and identify newly synthesized proteins, detecting and analyzing 5,940 newly synthesized proteins using mass spectrometry and label-free quantitation. Neither up- nor down-scaling produced changes in the number of different proteins translated. Rather, up- and down-scaling elicited opposing translational regulation of several molecular pathways, producing targeted adjustments in the proteome. We discovered ~300 differentially regulated proteins involved in neurite outgrowth, axon guidance, filopodia assembly, excitatory synapses, and glutamate receptor complexes. We also identified differentially regulated proteins that are associated with multiple diseases, including schizophrenia, epilepsy, and Parkinson's disease. PMID- 27764675 TI - Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. PMID- 27764672 TI - Microtubule Organization Determines Axonal Transport Dynamics. AB - Axonal microtubule (MT) arrays are the major cytoskeleton substrate for cargo transport. How MT organization, i.e., polymer length, number, and minus-end spacing, is regulated and how it impinges on axonal transport are unclear. We describe a method for analyzing neuronal MT organization using light microscopy. This method circumvents the need for electron microscopy reconstructions and is compatible with live imaging of cargo transport and MT dynamics. Examination of a C. elegans motor neuron revealed how age, MT-associated proteins, and signaling pathways control MT length, minus-end spacing, and coverage. In turn, MT organization determines axonal transport progression: cargoes pause at polymer termini, suggesting that switching MT tracks is rate limiting for efficient transport. Cargo run length is set by MT length, and higher MT coverage correlates with shorter pauses. These results uncover the principles and mechanisms of neuronal MT organization and its regulation of axonal cargo transport. PMID- 27764676 TI - Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex. PMID- 27764674 TI - Neural Variability and Sampling-Based Probabilistic Representations in the Visual Cortex. AB - Neural responses in the visual cortex are variable, and there is now an abundance of data characterizing how the magnitude and structure of this variability depends on the stimulus. Current theories of cortical computation fail to account for these data; they either ignore variability altogether or only model its unstructured Poisson-like aspects. We develop a theory in which the cortex performs probabilistic inference such that population activity patterns represent statistical samples from the inferred probability distribution. Our main prediction is that perceptual uncertainty is directly encoded by the variability, rather than the average, of cortical responses. Through direct comparisons to previously published data as well as original data analyses, we show that a sampling-based probabilistic representation accounts for the structure of noise, signal, and spontaneous response variability and correlations in the primary visual cortex. These results suggest a novel role for neural variability in cortical dynamics and computations. PMID- 27764677 TI - The temporal stability of the bifactor model of comorbidity: An examination of moderated continuity pathways. AB - BACKGROUND: Structural models of psychopathology indicate that common mental disorder comorbidity reflects latent transdiagnostic factors. Multiple studies have replicated transdiagnostic internalizing (mood and anxiety disorders) and externalizing (substance use, antisociality-, and impulsivity-related disorders) factors; other studies support distress and fear sub-factors of internalizing. These factors show a high degree of temporal stability. Recently, a bifactor conceptualization of multivariate comorbidity has emerged, positing the existence of an orthogonal general psychopathology factor that saturates all diagnoses in addition to internalizing/distress/fear and externalizing, although no studies have examined the temporal stability of the factors in this competing model over time among adults. METHOD: In a large, two-wave nationally representative sample (N=43,093), we investigated the structure of the bifactor model and examined all potential within- and between-factor stability pathways in a structural equation modeling framework. RESULTS: In general, within-domain stability (e.g., Wave 1 general factor predicting Wave 2 general factor) was high, while between-domain pathways (e.g., Wave 1 general factor predicting the Wave 2 externalizing factor) did not differ significantly from zero. We then tested possible age and gender moderation of factor stability, finding that the stability for all factors, except fear, significantly differed across demographic sub-groups. However, these differences were not clinically meaningful. CONCLUSIONS: Results indicated that bifactor model factors show varying degrees of temporal stability, with lowest comorbidity continuity over time reflecting distress stability. Findings are discussed with regard to recent evidence that the general factor may, to some extent, represent the negative emotionality captured by internalizing/distress in correlated two- and three-factor solutions. PMID- 27764673 TI - Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release. AB - Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remain unclear. Here, using paired whole cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type 1 cannabinoid receptor (CB1)-expressing axons. This long-term depression of inhibitory transmission (iLTD) involves cap-dependent protein synthesis in presynaptic interneuron axons, but not somata. Translation is required during the induction, but not maintenance, of iLTD. Mechanistically, CB1 activation enhances protein synthesis via the mTOR pathway. Furthermore, using super-resolution STORM microscopy, we revealed eukaryotic ribosomes in CB1 expressing axon terminals. These findings suggest that presynaptic local protein synthesis controls neurotransmitter release during long-term plasticity in the mature mammalian brain. PMID- 27764678 TI - Time-resolved record of 236U and 239,240Pu isotopes from a coral growing during the nuclear testing program at Enewetak Atoll (Marshall Islands). AB - A comprehensive series of nuclear tests were carried out by the United States at Enewetak Atoll in the Marshall Islands, especially between 1952 and 1958. A Porites Lutea coral that was growing in the Enewetak lagoon within a few km of all of the high-yield tests contains a continuous record of isotopes, which are of interest (e.g. 14C, 236U, 239,240Pu) through the testing period. Prior to the present work, 14C measurements at ~2-month resolution had shown pronounced peaks in the Delta14C data that coincided with the times at which tests were conducted. Here we report measurements of 236U and 239,240Pu on the same coral using accelerator mass spectrometry, and again find prominent peaks in the concentrations of these isotopes that closely follow those in 14C. Consistent with the 14C data, the magnitudes of these peaks do not, however, correlate well with the explosive yields of the corresponding tests, indicating that smaller tests probably contributed disproportionately to the debris that fell in the lagoon. Additional information about the different tests can also be obtained from the 236U/239Pu and 240Pu/239Pu ratios, which are found to vary dramatically over the testing period. In particular, the first thermonuclear test, Ivy-Mike, has characteristic 236U/239Pu and 240Pu/239Pu signatures which are diagnostic of the first arrival of nuclear test material in various archives. PMID- 27764679 TI - Clotrimazole and econazole inhibit Streptococcus mutans biofilm and virulence in vitro. AB - OBJECTIVE: The aim of this study was to determine the inhibitory effect of eight antifungal drugs on S. mutans growth, biofilm formation and virulence factors. METHODS: The actions of antifungal drugs on S. mutans were determined by recovery plates and survival kinetic curves. Biofilms were observed by scanning electron microscopy and the viable cells were recovered on BHI plates, meanwhile biofilms were stained by BacLight live/dead kit to investigate the biofilm viability. Bacteria/extracellular polysaccharides staining assays were performed to determine the EPS production of S. mutans biofilms. Acidogenicity and acidurity of S. mutans were determined using pH drop and acid tolerance assays, and the expression of ldh gene was evaluated using qPCR. RESULTS: We found that clotrimazole (CTR) and econazole (ECO) showed antibacterial activities on S. mutans UA159 and S. mutans clinical isolates at 12.5 and 25mg/L, respectively. CTR and ECO could also inhibit S. mutans biofilm formation and reduce the viability of preformed biofilm. CTR and ECO affected the live/dead ratio and the EPS/bacteria ratio of S. mutans biofilms. CTR and ECO also inhibited the pH drop, lactate acid production, and acid tolerance. The abilities of CTR and ECO to inhibit S. mutans ldh expression were also confirmed. CONCLUSIONS: We found that two antifungal azoles, CTR and ECO, had the abilities to inhibit the growth and biofilm formation of S. mutans and more importantly, they could also inhibit the virulence factors of S. mutans. PMID- 27764681 TI - Cyclic-stretch induces apoptosis in human periodontal ligament cells by activation of caspase-5. AB - BACKGROUND AND OBJECTIVE: As caspase-5 plays a role in apoptosis, the present study aimed to identify the expression and activation of caspase-5 in human periodontal ligament cells in response to cyclic stretch and the role of caspase 5 in stretch-induced apoptosis. METHODS: Human PDL cells were exposed to 10% or 20% stretch strain for 6 or 24h, and the mRNA and protein expressions of caspase 5 were analyzed with real-time PCR and Western blot, respectively. The caspase-5 activation was detected by colorimetric assay. Then the influence of the inhibition of caspase-5 on the stretch-induced apoptosis and caspase-3 activation were analyzed with flow cytometry and colorimetric assay, respectively. RESULTS: Both 6 and 24h stretches increased mRNA, protein expression and activation of caspase-5 in human PDL cells. Inhibition of caspase-5 inhibited the stretch induced apoptosis and caspase-3 activation in human PDL cells. CONCLUSION: This study for the first time identified the expression and activation of caspase-5 in cyclic stretched human PDL cells and found that the stretch-induced apoptosis and caspase-3 activation were caspase-5 dependent. PMID- 27764680 TI - Human dental follicle cells express embryonic, mesenchymal and neural stem cells markers. AB - OBJECTIVE: This study was conducted to identify and characterize dental follicle stem cells (DFSCs) by analyzing expression of embryonic, mesenchymal and neural stem cells surface markers. Design Dental follicle cells (DFCs) were evaluated by immunocytochemistry using embryonic stem cells markers (OCT4 and SOX2), mesenchmal stem cells (MSCs) markers (Notch1, active Notch1, STRO, CD44, HLA-ABC, CD90), neural stem cells markers (Nestin and beta-III-tubulin), neural crest stem cells (NCSCs) markers (p75 and HNK1) and a glial cells marker (GFAP). RT-PCR was performed to identify the expression of OCT4 and NANOG in DFCs and dental follicle tissue. RESULTS: Immunocytochemistry and RT-PCR analysis revealed that a significant proportion of the DFCs evaluated expressed human embryonic stem cells marker OCT4 (75%) whereas NANOG was weakly expressed. A considerable amount of MSCs (90%) expressed Notch1, STRO, CD44 and HLA-ABC. However, they were weakly positive for CD90. Moreover, it was possible to demonstrate that dental follicle contains a significant proportion of neural stem/progenitors cells, expressing beta-III-tubulin (90%) and nestin (70%). Interestingly, immunocytochemistry showed DFCs positive for p75 (50%), HNK1 (<10%) and a small proportion (<20%) of GFAP-positive cells. This is the first study reporting the presence of NCSCs and glial-like cells in the dental follicle. CONCLUSIONS: The results of the present study suggest the occurrence of heterogeneous populations of stem cells, particularly neural stem/progenitor cells, in the dental follicle, Therefore, the human dental follicle might be a promising source of adult stem cells for regenerative purposes. PMID- 27764682 TI - Frequency of intake and amount of fluoride in milk for remineralisation of artificial caries on enamel and dentine: Ex vivo/in situ study. AB - OBJECTIVES: This study analysed the effect of frequency of intake and amount of fluoride in milk on the remineralisation of artificial enamel and dentine caries lesions ex vivo/in situ. MATERIALS AND METHODS: Pre-demineralised bovine enamel and dentine slabs were randomly allocated into 5 groups and fixed in removable appliances used by subjects for 7days in each phase. Each treatment comprised milk containing 2.5ppm fluoride daily (T1), or every other day (T2), 5.0ppm F daily (T3), or every other day (T4) or no treatment (T5). RESULTS: Enamel alterations were quantified by surface hardness recovery (%SHR) and transversal microradiography (TMR), and in dentine by TMR only. Data were analysed by ANOVA and Tukey's test (p<0.05). For enamel, the highest %SHR was found for T1 and T3 compared to control, without significant differences between them. All groups showed positive values of DeltaDeltaZ - T1 (247.3+/-198.5); T2 (110.9+/-303.2); T3 (226.0+/-299.2); T5 (5.0+/-288.0), except T4 (-274.5+/-407.3). For dentine, the only group that presented remineralisation was T2 (350.0+/-657.5). CONCLUSIONS: Fluoridated milk daily seems to have higher remineralising effect on enamel than its use every other day. Dentine, does not seem to benefit from daily use of fluoridated milk. PMID- 27764683 TI - Assessing the midwifery workforce demand: Utilising Birthrate Plus in China. AB - OBJECTIVE: To assess the ability of the Birthrate Plus Workforce Planning Methodology (BR+) to forecast midwifery workforce demand in Chinese settings. DESIGN: A retrospective analysis of medical records. SETTING: ten hospitals in Beijing District. METHODS: Hospitals were selected using stratified sampling methods. The client category and midwife hours in each hospital were analysed over 1 month in consecutive three years (2013, 2014, and 2015). FINDINGS: Client category allocation varied between different hospital levels; Clients in higher category tended to need longer midwife hours; Mean birthrate of the ten hospitals was 154.30 (SD=40.700). Seven out of the ten hospitals were in need of more midwives. CONCLUSIONS: Birthrate Plus was proved to be effective and efficient in Chinese settings; Gaps between available and needed midwives were large and prevalent in Chinese hospitals. PMID- 27764684 TI - Mutual coordination strengthens the sense of joint agency in cooperative joint action. AB - Philosophers have proposed that when people coordinate their actions with others they may experience a sense of joint agency, or shared control over actions and their effects. However, little empirical work has investigated the sense of joint agency. In the current study, pairs coordinated their actions to produce tone sequences and then rated their sense of joint agency on a scale ranging from shared to independent control. People felt more shared than independent control overall, confirming that people experience joint agency during joint action. Furthermore, people felt stronger joint agency when they (a) produced sequences that required mutual coordination compared to sequences in which only one partner had to coordinate with the other, (b) held the role of follower compared to leader, and (c) were better coordinated with their partner. Thus, the strength of joint agency is influenced by the degree to which people mutually coordinate with each other's actions. PMID- 27764685 TI - Assessing the impact of geogenic chromium uptake by carrots (Daucus carota) grown in Asopos river basin. AB - A methodology was developed to assess the impact of geogenic origin hexavalent chromium uptake by carrots, and the risk of human consumption of carrots grown in Asopos River basin in Greece. A field scale experiment was conducted with carrots cultivated in treatment plots, with and without compost amendment, in order to assess the impact of carbon in the mobility and uptake of chromium by plants. The results suggested that there is a trend for chromium mobilization and uptake in the surface and the leaves of the carrots cultivated in the treatment plot with the higher carbon addition, but not in the core of the carrots. Limited mobility of hexavalent chromium in the soil-plant-water system is presented due to the affinity of chromium to be retained in the solid phase and be uptaken by plants. Hexavalent chromium tolerant bacterial strains were isolated from the carrots. These endophytic bacteria, present in all parts of the plant, were able to reduce hexavalent chromium to trivalent form to levels below the detection limit. Finally, a site-specific risk assessment analysis suggested no adverse effects to human health due to the consumption of carrots. These findings are of particular importance since they confirm that carrots grown in soils with geogenic origin chromium does not pose any adverse risk for human consumption, but could also have the beneficial effect of the micronutrient trivalent chromium. PMID- 27764687 TI - Nanomechanical properties of composite protein networks of erythroid membranes at lipid surfaces. AB - Erythrocyte membranes have been particularly useful as a model for studies of membrane structure and mechanics. Native erythroid membranes can be electroformed as giant unilamellar vesicles (eGUVs). In the presence of ATP, the erythroid membrane proteins of eGUVs rearrange into protein networks at the microscale. Here, we present a detailed nanomechanical study of individual protein microfilaments forming the protein networks of eGUVs when spread on supporting surfaces. Using Peak Force tapping Atomic Force Microscopy (PF-AFM) in liquid environment we have obtained the mechanical maps of the composite lipid-protein networks supported on solid surface. In the absence of ATP, the protein pool was characterized by a Young's Modulus Epool~5-15MPa whereas the complex filaments were found softer after protein supramolecular rearrangement; Efil~0.4MPa. The observed protein softening and reassembling could be relevant for understanding the mechanisms of cytoskeleton reorganization found in pathological erythrocytes or erythrocytes that are affected by biological agents. PMID- 27764688 TI - Application of chitosan/poly(vinyl alcohol)/CuO (CS/PVA/CuO) beads as an adsorbent material for the removal of Pb(II) from aqueous environment. AB - The utilization of CS/PVA/CuO as a novel adsorbent for the removal of Pb(II) from aqueous solution has been examined in a batch adsorption process with several experimental conditions including initial solution pH, dose, contact time, initial metal ion concentration, and temperature. The new and novel material was characterized by structural (XRD), spectral (FTIR), morphological with elemental (SEM with EDS), and size of the nanoparticles (TEM) analyses. The pseudo-first order, pseudo-second-order and intraparticle diffusion kinetics equations were used to analyze the kinetic data of the adsorption process and the data was fitted well with the pseudo-second-order kinetic model with R2 values (close to the unity). Equilibrium isotherms for the adsorption of Pb(II) were analyzed by the Langmuir, Freundlich, and D-R isotherm models. The best interpretation for the equilibrium data was given by Langmuir isotherm, and the maximum adsorption capacity was 116.84mg/g at pH 5, and adsorbent dose of 100mg at 323K. Different thermodynamic parameters namely, Gibbs free energy change (-8.436, -9.167 and 9.723kJ/mol for 303, 313 and 323K respectively), enthalpy change (11.61, 11.52 and 11.62kJ/mol), and entropy change (0.0661J/mol k), were also evaluated from the temperature dependence, and the results suggest that the adsorption reaction is spontaneous and endothermic in nature. PMID- 27764686 TI - Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. AB - PURPOSE: To assess preliminary safety and efficacy results of the anti-programmed cell death ligand-1 (anti-PD-L1) durvalumab in combination with radiotherapy (RT) in an expansion cohort of patients included in a phase 1/2 trial at our institution. PATIENTS AND METHODS: Data from patients who received concurrent palliative RT with durvalumab (10 mg/kg every 2 weeks via intravenous infusion) were analysed in terms of safety (CTCAE v4.0) and efficacy (RECIST v1.1 and tumour growth rate [TGR]). RESULTS: Between 02/2014 and 04/2016, 10 patients received palliative local irradiation of 15 isolated lesions. Most patients (90%) had received one or more prior lines of systemic therapy for advanced disease. The median duration of exposure to durvalumab was 5.2 months with a median delivery of 11 cycles (range, 4-38 cycles). RT (conformal 3D RT, 79% and intracranial stereotactic RT, 21%) was delivered at a median biologically effective dose of 28 Gy (range, 6-92), in a median number of five fractions (range, 1-10) and over a median duration of 6 d (range, 1-14). Five patients (50%) reported an irradiation-related adverse event (AE) grade (G) 1 or 2 and one patient had two G2 AEs. The most frequently reported AE (3/6) was G2 mucositis. There was no G3 or more RT-related AEs. All AEs were transient, lasted less than one week, and were manageable by standard guidelines. There was no unexpected AE. On 10/15 in-field (IF) evaluable lesions, the objective response (OR) rate was 60% (complete response, 2/10 and partial response, 4/10) and 4/10 stable disease (SD). All evaluated IF lesions had a TGR decrease resulting in a significant decrease in the TGR between the two periods (before versus after RT; p < 0.01). Outfields disease evaluation retrieved 10/14 SD and 4/14 progressive disease (PD). There was no out-field OR, no abscopal effect and no out-field difference between the two periods according to TGR (p = 0.09). CONCLUSION: In this small data set of patients, concurrent palliative RT with the anti-PD-L1 durvalumab was well tolerated. ClinicalTrials.gov number: NCT01693562; EudraCT number: 2012 002206-52. PMID- 27764689 TI - Factors affecting interactions between sulphonate-terminated dendrimers and proteins: A three case study. AB - This work proposes a deep study on the interactions between sulphonate-terminated carbosilane dendrimers and proteins. Three different proteins with different molecular weights and isoelectric points were employed and different pHs, dendrimer concentrations and generations were tested. Variations in fluorescence intensity and emission wavelength were used as protein-dendrimer interaction probes. Interaction between dendrimers and proteins greatly depended on the protein itself and pH. Other important issues were the dendrimer concentration and generation. Protein-dendrimer interactions were favored under acidic working conditions when proteins were positively charged. Moreover, in general, high dendrimer generations promoted these interactions. Modeling of protein-dendrimer interactions allowed to understand the different behaviors observed for every protein. PMID- 27764690 TI - Predicting expressway crash frequency using a random effect negative binomial model: A case study in China. AB - To investigate the relationship between crash frequency and potential influence factors, the accident data for events occurring on a 50km long expressway in China, including 567 crash records (2006-2008), were collected and analyzed. Both the fixed-length and the homogeneous longitudinal grade methods were applied to divide the study expressway section into segments. A negative binomial (NB) model and a random effect negative binomial (RENB) model were developed to predict crash frequency. The parameters of both models were determined using the maximum likelihood (ML) method, and the mixed stepwise procedure was applied to examine the significance of explanatory variables. Three explanatory variables, including longitudinal grade, road width, and ratio of longitudinal grade and curve radius (RGR), were found as significantly affecting crash frequency. The marginal effects of significant explanatory variables to the crash frequency were analyzed. The model performance was determined by the relative prediction error and the cumulative standardized residual. The results show that the RENB model outperforms the NB model. It was also found that the model performance with the fixed-length segment method is superior to that with the homogeneous longitudinal grade segment method. PMID- 27764691 TI - Object individuation is invariant to attentional diffusion: Changes in the size of the attended region do not interact with object-substitution masking. AB - When the human brain is confronted with complex and dynamic visual scenes, two pivotal processes are at play: visual attention (the process of selecting certain aspects of the scene for privileged processing) and object individuation (determining what information belongs to a continuing object over time versus what represents two or more distinct objects). Here we examined whether these processes are independent or whether they interact. Object-substitution masking (OSM) has been used as a tool to examine such questions, however, there is controversy surrounding whether OSM reflects object individuation versus substitution processes. The object-individuation account is agnostic regarding the role of attention, whereas object-substitution theory stipulates a pivotal role for attention. There have been attempts to investigate the role of attention in OSM, but they have been subject to alternative explanations. Here, therefore, we manipulated the size of the attended region, a pure and uncontaminated attentional manipulation, and examined the impact on OSM. Across three experiments, there was no interaction. This refutes the object-substitution theory of OSM. This, in turn, tell us that object-individuation is invariant the distribution of attention. PMID- 27764692 TI - Memory performance predicts recurrence of mania in bipolar disorder following psychotherapy: A preliminary study. AB - OBJECTIVE: Cognitive complaints are common features of bipolar disorder (BD). Not much is, however, known about the potential moderator effects of these factors on the outcome of talking therapies. The goal of our study was to explore whether learning and memory abilities predict risk of recurrence of mood episodes or interact with a psychological intervention. METHOD: We analyzed data collected as part of a clinical trial evaluating relapse rates following Cognitive Behavioral Therapy (CBT) and Supportive Therapy (ST) (Meyer and Hautzinger, 2012). We included cognitive (Auditive Verbal Learning Test, general intelligence - Leistungsprufsystem) and clinical measures from 76 euthymic patients with BD randomly assigned to either 9 months of CBT or ST and followed up for 2 years. RESULTS: Survival analyses including treatment condition, AVLT measures, and general intelligence revealed that recurrence of mania was predicted by verbal free recall. The significant interaction between therapy condition and free recall indicated that while in CBT recurrence of mania was unrelated to free recall performance, in ST patients with a better free recall were more likely to remain euthymic, and those with a poorer free recall were less likely to remain mania-free. CONCLUSIONS: These findings constitute first evidence that, when considering treatment outcome in BD, differences in verbal free recall might interact with the kind of psychotherapy provided. More research is needed to determine what other areas of cognitive functioning are related to outcome in psychological interventions. PMID- 27764693 TI - Familial aggregation of schizotypy in schizophrenia-spectrum disorders and its relation to clinical and neurodevelopmental characteristics. AB - INTRODUCTION: This study explored schizotypy as a familial liability marker for schizophrenia-spectrum disorders (SSD) by examining: 1) the aggregation of schizotypy in families with a SSD patient, 2) whether familial resemblance of schizotypy is associated with ridge dissociations (RD), another SSD liability marker, 3) whether schizotypy aggregation patterns influence patients' psychopathology. METHODS: The sample comprised 30 SSD patients and 82 healthy first-degree relatives. Schizotypy was assessed using the Structured Interview for Schizotypy-Revised (SIS-R). Patients' psychopathology was evaluated using the Comprehensive Assessment of Symptoms and History (CASH). RD were identified as anomalies of the dermal ridge junction. Familiality of SIS-R was investigated using a linear mixed model (LMM) and its strength was assessed using an intraclass correlation coefficient (ICC). Another LMM using the absolute differences in SIS-R scores between all possible pairs of relatives as the dependent variable was fitted to obtain an intra-family resemblance score, a family-specific indicator of resemblance of SIS-R scores within each family. RESULTS: 1) Schizotypy was familial (ICC = 0.30); families with high resemblance displayed low schizotypy, whereas families with low resemblance included at least one healthy relative with high schizotypy (p < 0.001). 2) Relatives with RD had higher SIS-R scores (p = 0.018) and belonged to families with discordant schizotypy scores among members (p < 0.001). 3) Patients from high schizotypy families showed more severe disorganized symptoms at the psychotic episode (p = 0.035) and 1 year later (p = 0.011). CONCLUSIONS: Schizotypy is a marker of vulnerability for SSD that runs within a subgroup of families. The schizotypy familial aggregation pattern correlates with RD in relatives and with patients' psychopathology. PMID- 27764694 TI - Toxicity and genotoxicity assessment in sediments from the Matanza-Riachuelo river basin (Argentina) under the influence of heavy metals and organic contaminants. AB - The aim of this study was to investigate the parameters of chemical extraction associated with the detection of toxicity and genotoxicity in sediment sample extracts. Quantitative analysis of metals and polycyclic aromatic hydrocarbons (PAHs), together with a battery of four bioassays, was performed in order to evaluate the extraction efficiency of inorganic and organic toxicants. The extracts were carried out using two inorganic solvents, two organic solvents and two extraction methodologies, making a total of five extracts. Two toxicity tests, the algal growth inhibition of Pseudokirchneriella subcapitata and the root elongation inhibition of Lactuca sativa, and two genotoxicity tests, the analysis of revertants of Salmonella typhimurium and the analysis of micronuclei and chromosomal aberrations in Allium cepa, were performed. According to the chemical analysis, the acidic solution extracted more heavy metal concentrations than distilled water, and dichloromethane extracted more but fewer concentrations of PAH compounds than methanol. Shaker extracts with distilled water were non toxic to P. subcapitata, but were toxic to L. sativa. The acidic extracts were more toxic to P. subcapitata than to L. sativa. The methanolic organic extracts were more toxic to the alga than those obtained with dichloromethane. None of these extracts resulted toxic to L. sativa. Mutagenic effects were only detected in the organic dichloromethane extracts in the presence of metabolic activation. All the inorganic and organic extracts were genotoxic to A. cepa. This study showed that the implementation of different extraction methods together with a battery of bioassays could be suitable tools for detecting toxicity and genotoxicity in sediment samples. PMID- 27764695 TI - Biodegradation, ecotoxicity and UV254/H2O2 treatment of imidazole, 1-methyl imidazole and N,N'-alkyl-imidazolium chlorides in water. AB - Imidazole-based compounds are used as reagents for the manufacturing of other compounds including imidazolium-based ionic liquids, which have been recently proposed as a green alternative to conventional solvents. Since some imidazole based compounds have been demonstrated to be harmful to aquatic organisms, the removal of imidazole, 1-methylimidazole, 1-ethyl-3-methyl-imidazolium chloride and 1-butyl-3-methyl-imidazolium chloride from aqueous solutions was attempted by biological oxidation, direct UV254 photolysis, and UV254/H2O2 process at pH 5.5 and 8.5. Results showed that UV254/H2O2 treatment is an effective tool for the removal of the selected compounds at both pHs. In fact, the kinetic constants of the reaction between the photogenerated HO radicals and the four target compounds, estimated by means of both numerical and competition kinetic method, range between 2.32.109 M-1 s-1 and 5.52 .109 M-1 s-1. Moreover, an ecotoxicity assessment of the contaminated water before and after initial treatment without further processing was assessed by using two living aquatic organisms: Raphidocelis subcapitata and Daphnia magna. The results of this assessment not only corresponded closely to previous findings (in terms of EC50 values) reported in the literature, but also indicated that, in some cases, UV254/H2O2 oxidation by-products could be even more toxic than parent compounds. PMID- 27764696 TI - Temporospatial evolution and removal mechanisms of As(V) and Se(VI) in ZVI column with H2O2 as corrosion accelerator. AB - Enhanced removal of As(V) and Se(VI) by zero valent iron (ZVI) has been recently revealed by using H2O2 as the corrosion accelerator, however, the detailed performance of such enhanced removal in ZVI column as well as the underlying mechanism is still unclear. In this study, the temporospatial evolution of As(V) and Se(VI) along a self-designed ZVI/H2O2 column in down-flow mode was systematically investigated. The variations of concerned aqueous parameters (pH, ORP, H2O2, Fe2+, As, and Se) were monitored at different positions along the column throughout the experiments. Results showed the corrosion degree of ZVI decreased with the depth of the column, as confirmed by SEM and XRD analyses of the solid samples from different layers. The retention of As and Se also decreased along the column, suggesting the uptake of As(V) and Se(VI) was highly dependent upon the ZVI corrosion evolution. In the initial stage, the influent H2O2 was mostly consumed by ZVI in the top layer. With the continuous corrosion of ZVI, the breakthrough of H2O2 would activate the ZVI at lower positions, resulting in the reactive zone continuously shifting downward along the column. The reduction of As(V) and Se(VI) to aqueous As(III) and Se(IV) was significantly inhibited at the positions in the presence of H2O2, whereas favorably enhanced in the presence of abundant Fe2+. The retention of As(III) in the lower part of the column was observed while that of Se(IV) was negligible, as related to the different effects of pH on the adsorption of As(III) and Se(IV). In addition, the evolution of different oxidation states of As and Se retained in the column were identified by XPS, further demonstrating the comprehensive mechanisms of As(V)/Se(VI) removal involving reduction and adsorption in the ZVI/H2O2 column. PMID- 27764697 TI - Prognostic Impact of HER2 and ER Status of Circulating Tumor Cells in Metastatic Breast Cancer Patients with a HER2-Negative Primary Tumor. AB - BACKGROUND: Preclinical and clinical studies have reported that human epidermal growth factor receptor 2 (HER2) overexpression yields resistance to endocrine therapies. Here the prevalence and prognostic impact of HER2-positive circulating tumor cells (CTCs) were investigated retrospectively in metastatic breast cancer (MBC) patients with a HER2-negative primary tumor receiving endocrine therapy. Additionally, the prevalence and prognostic significance of HER2-positive CTCs were explored in a chemotherapy cohort, as well as the prognostic impact of the estrogen receptor (ER) CTC status in both cohorts. METHODS: Included were MBC patients with a HER2-negative primary tumor, with >=1 detectable CTC, starting a new line of treatment. CTCs were enumerated using the CellSearch system, characterized for HER2 with the CellSearch anti-HER2 phenotyping reagent, and characterized for ER mRNA expression. Primary end point was progression-free rate after 6 months (PFR6months) of endocrine treatment in HER2-positive versus HER2 negative CTC patients. RESULTS: HER2-positive CTCs were present in 29% of all patients. In the endocrine cohort (n=72), the PFR6months was 53% for HER2 positive versus 68% for HER2-negative CTC patients (P=.23). In the chemotherapy cohort (n=82), no prognostic value of HER2-positive CTCs on PFR6months was observed either. Discordances in ER status between the primary tumor and CTCs occurred in 25% of all patients but had no prognostic value in exploratory survival analyses. CONCLUSION: Discordances regarding HER2 status and ER status between CTCs and the primary tumor occurred frequently but had no prognostic impact in our MBC patient cohorts. PMID- 27764698 TI - Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase. AB - A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS. PMID- 27764699 TI - Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation. AB - Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-KrasG12D;Fbxw7fl/fl (KFCfl/fl) compound mice. We found that KFCfl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFCfl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFCfl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of KrasG12D-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap. PMID- 27764701 TI - Prenatal Paraquat exposure induces neurobehavioral and cognitive changes in mice offspring. AB - In the present work, we investigated developmental toxicity of Paraquat (PQ), from the 1st or 6th day of mating and throughout the gestation period. We have examined several parameters, including toxicity indices, reproductive performance, sensorimotor development, as well as anxiety and cognitive performance of the offspring. Our results showed that exposure to 20mg/kg of Paraquat during the first days of pregnancy completely prevents pregnancy in treated mice, but from the 6th day of pregnancy, an alteration in fertility and reproductive parameters was observed. In offspring, the PQ was responsible for an overall delay of innate reflexes and a deficit in motor development. All exposed animals showed a decrease in the level of locomotor activity, increased levels of anxiety-like behavior and pronounced cognitive impairment in adulthood. These results demonstrated that Paraquat led to the onset of many behavioral changes that stem from the impairment of neuronal developmental processes in prenatally exposed mice. PMID- 27764702 TI - Contribution of the nitric oxide donor molsidomine and the antiparkinsonian drug l-DOPA to the modulation of the blood pressure in unilaterally 6-OHDA-lesioned rats. AB - BACKGROUND: Interaction between dopaminergic and nitrergic neurotransmission in the brain plays a crucial role in the control of motor function and in the regulation of blood pressure (BP). In Parkinson's disease (PD), dopaminergic denervation of the striatum leads to disturbances in the nitrergic system in the basal ganglia. Recently, it has been demonstrated that addition of a low dose of the nitric oxide donor molsidomine to l-DOPA therapy improves dopaminergic neurotransmission in the denervated nigrostriatal system and weakens dyskinesias in rodent models of the disease. METHODS: The aim of the present study was to examine the impact of chronic administration of molsidomine (2mg/kg) and l-DOPA (25mg/kg), alone and in combination, on systolic (SBP) and diastolic (DBP) blood pressure in the anesthetized, unilaterally 6-OHDA-lesioned rats. The measurement of SBP and DBP was performed 24h after the penultimate and immediately after the last drug doses. RESULTS: In 6-OHDA-lesioned rats receiving saline, spontaneous, small decreases in SBP and DBP were observed during the measurements lasting 60min. Administration of molsidomine alone or in combination with l-DOPA distinctly decreased the BP in 6-OHDA-lesioned rats already after 10min compared to those treated with saline or l-DOPA alone, respectively. In both groups, the molsidomine-mediated declines in BP persisted till the end of measurement but they disappeared after 24h. CONCLUSIONS: Our results indicate that in this PD model molsidomine evokes a short-lasting decrease in BP in contrast to conventional antihypertensive drugs that maintain long-term effect and worsen orthostatic hypotension in parkinsonian patients. PMID- 27764700 TI - Current Evidence and Future Perspectives on HuR and Breast Cancer Development, Prognosis, and Treatment. AB - Hu-antigen R (HuR) is an RNA-binding posttranscriptional regulator that belongs to the Hu/ELAV family. HuR expression levels are modulated by a variety of proteins, microRNAs, chemical compounds, or the microenvironment, and in turn, HuR affects mRNA stability and translation of various genes implicated in breast cancer formation, progression, metastasis, and treatment. The aim of the present review is to critically summarize the role of HuR in breast cancer development and its potential as a prognosticator and a therapeutic target. In this aspect, all the existing English literature concerning HuR expression and function in breast cancer cell lines, in vivo animal models, and clinical studies is critically presented and summarized. HuR modulates many genes implicated in biological processes crucial for breast cancer formation, growth, and metastasis, whereas the link between HuR and these processes has been demonstrated directly in vitro and in vivo. Additionally, clinical studies reveal that HuR is associated with more aggressive forms of breast cancer and is a putative prognosticator for patients' survival. All the above indicate HuR as a promising drug target for cancer therapy; nevertheless, additional studies are required to fully understand its potential and determine against which types of breast cancer and at which stage of the disease a therapeutic agent targeting HuR would be more effective. PMID- 27764703 TI - Molecular dynamics simulations reveal the allosteric effect of F1174C resistance mutation to ceritinib in ALK-associated lung cancer. AB - Anaplastic lymphoma kinase (ALK) has become as an important target for the treatment of various human cancers, especially non-small-cell lung cancer. A mutation, F1174C, suited in the C-terminal helix alphaC of ALK and distal from the small-molecule inhibitor ceritinib bound to the ATP-binding site, causes the emergence of drug resistance to ceritinib. However, the detailed mechanism for the allosteric effect of F1174C resistance mutation to ceritinib remains unclear. Here, molecular dynamics (MD) simulations and binding free energy calculations [Molecular Mechanics/Generalized Born Surface Area (MM/GBSA)] were carried out to explore the advent of drug resistance mutation in ALK. MD simulations observed that the exquisite aromatic-aromatic network formed by residues F1098, F1174, F1245, and F1271 in the wild-type ALK-ceritinib complex was disrupted by the F1174C mutation. The resulting mutation allosterically affected the conformational dynamic of P-loop and caused the upward movement of the P-loop from the ATP-binding site, thereby weakening the interaction between ceritinib and the P-loop. The subsequent MM/GBSA binding free energy calculations and decomposition analysis of binding free energy validated this prediction. This study provides mechanistic insight into the allosteric effect of F1174C resistance mutation to ceritinib in ALK and is expected to contribute to design the next-generation of ALK inhibitors. PMID- 27764704 TI - Buthionine sulfoximine, a glutathione depletor, attenuates endotoxic fever and reduces IL-1beta and IL-6 level in rats. AB - PURPOSE: The aim of our study was to investigate the effect of buthionine sulfoximine (BSO) - a glutathione depletor - on a course of endotoxic fever and IL-1beta and IL-6 production. MATERIAL AND METHODS: Male Wistar rats were subjected to intraperitoneal injection of lipopolysaccharide (LPS) from E. coli (50MUg/kg, ip) to provoke fever. The level of spleen glutathione, plasma interleukin (IL)-1beta, IL-6, and deep body temperature (Tb) were measured. RESULTS: The LPS administration provoked fever (the average Tb was 38.14+/-0.05 degrees C in NaCl/LPS-treated rats vs 37.10+/-0.03 degrees C in control, not treated rats; p<0.001). We observed that LPS injection induced a decrease in spleen glutathione level (7.67+/-0.92nM/g vs 13.27+/-0.47nM/g in not-treated rats; p<0.001). Furthermore, the injection of LPS provoked an elevation of plasma IL-1beta and IL-6 concentration (from values below the lowest detectable standard in not-treated animals to 199.99+/-34.89pg/mL and 7500+/-542.21pg/mL, respectively; p<0.001). Pretreatment with BSO enhanced glutathione decrease in LPS-treated rats (5.05+/-0.49nM/g), and significantly affected fever (maximal Tb was 37.81+/-0.07 degrees C in BSO/LPS-treated rats vs 38.76+/-0.11 degrees C in NaCl/LPS-treated rats). BSO 4h after LPS injection decreased IL-1beta and IL-6 gene expression (about 1.5 fold, and 2 fold, respectively). In a consequence we observed a decrease in plasma IL-6 concentration (4h after LPS injection plasma IL-6 was 4167.17+/-956.54pg/mL in BSO/LPS-treated rats vs 7500+/-542.21pg/mL in NaCl/LPS-treated rats; p<0.001), and later IL-1beta (7h after LPS injection the IL-1beta concentration was not detected). CONCLUSION: Based on these data, we conclude that BSO, in addition to well-known application as an inhibitor of glutathione synthesis, is an antipyretic agent which reduces both IL-1beta and IL 6 concentration. PMID- 27764705 TI - IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy. AB - PURPOSE: This study aimed to investigate the potential association between IDH mutation and O6-methyl-guanine methyl transferase (MGMT) gene promoter methylation and pseudoprogression disease (psPD) in glioblastoma multiforme (GBM) patients after concurrent temozolomide (TMZ)-based chemoradiotherapy. METHODS: A total of 157 GBM patients who received concurrent TMZ-based chemoradiotherapy were included in this retrospective study. The association between psPD and a number of demographic and genetic factors, including IDH mutation and MGMT promoter methylation, were analyzed based on logistic regression, Cox regression, and multivariate analysis. RESULTS: Of the 157 GBM patients, 145 (92.36%) patients, including 38 patients with psPD, 38 patients with early progression (ePD), and 69 patients with non-progression (non-PD), were followed up for six to 56 months. We identified a higher rate of MGMT promoter methylation and IDH1 mutation in psPD patients compared with ePD patients (P=0.002). In addition, MGMT promoter methylation and IDH1 mutation predicted a high probability of psPD development in GBM patients (P=0.001 and P<0.001, respectively). MGMT promoter methylation, IDH1 mutation, Karnofsky performance score (KPS) >=70, and psPD were associated with a significantly longer overall survival of GBM patients (P=0.001, 0.001, 0.002, and P<0.001, respectively). Both of MGMT promoter methylation and IDH mutation had a cumulative effect on the OS of GBM patients. GBM patients with psPD (39.2+/-2.1months, P<0.001) had a longer median survival (MS) than GBM patients with ePD (11.9+/-1.1months) or with non-PD (24.4+/-2.4months). CONCLUSION: MGMT promoter methylation and IDH1 mutation were associated with PsPD and predicted a longer median survival in GBM patients after TMZ-based chemoradiotherapy. Genetic analyses of the MGMT promoter and IDH1 may allow us to effectively treat GBM patients. PMID- 27764706 TI - Management of postoperative pain after Lumbar surgery-pregabalin for one day and 14 days-a randomized, triple-blinded, placebo-controlled study. AB - OBJECTIVES: Despite the progress in understanding acute pain physiology during recent decade, eighty percent of patients still suffer from post-operative discomfort. Pregabalin is an anticonvulsant agent that is approved for painful neuropathies in diabetic patients and post herpetic neuralgia. The main objective of the present study was to compare the improvement in post-operative pain management and patient lifestyle in 3 groups, as first group received placebo, second who received Pregabalin for one day and the last group those who received it for 14 days. METHODS: This was a prospective single center, randomized, triple blind, 3-arm, parallel group study. In this triple-blind study, patients were randomized to 1 of 3 groups using computer-generated random number table. 1) The first group received placebo for 14 days, the second group received Pregabalin 300mg 8h preoperatively and 150mg 12 and 24h postoperatively and for the rest of 13days received placebo and the third group received Pregabalin 300mg eight hours preoperatively and 15mg every 12h postoperatively for 14 days. Name, age, gender, height, weight, education, duration of pain, past medical history, drug history,total morphine requirement at the time of discharge and MRI findings of all the patients were recorded, also they Numerical scale system (NRS) and Oswestry low back pain disability index (ODI) questionnaire were completed for them. All the patients were operated based on standard surgery techniques, bilateral foramenotomy and interlaminar discectomy. RESULTS: Of the 105 patients who entered the run-in period, 47 patients (44.8%) were female and 58 (55.2%) were male. The Patients radicular pain mean score based on NRS estimated before surgery was 7.22+/-1.95 in pregabalin14, 7.71+/-1.84 in pregabalin1 and 7.45+/ 1.9 in control group. There were no statically significant differences between three groups (P-Value>0.05). The Patients back pain mean score based on NRS was 5.2+/-2.87 in pregabalin14, 5.11+/-3.23 in pregabalin1 and 6.4+/-3.06 in control group. This means that there were no significant differences in the overall score among those three groups (P-Value>0.05). In comparison to their preoperative pain, the average radicular pain in each group of patients improved significantly 4, 8, 12 and 24h after the operation (P-Value<0.001), but there were no significant differences in radicular pain improvements comparing three groups. CONCLUSION: The results of this study indicate that 1day and 2 weeks post operative 300mg pregabalin administration may not improve acute pain, morphine consumption and quality of life of patients after surgery. It seems that the diseases cause chronic pain that requires long-term treatment with higher doses. PMID- 27764707 TI - New copper(I) complexes bearing lomefloxacin motif: Spectroscopic properties, in vitro cytotoxicity and interactions with DNA and human serum albumin. AB - In this paper we present lomefloxacin's (HLm, 2nd generation fluoroquinolone antibiotic agent) organic and inorganic derivatives: aminomethyl(diphenyl)phosphine (PLm), its oxide as well as new copper(I) iodide or copper(I) thiocyanate complexes with PLm and 2,9-dimethyl-1,10-phenanthroline (dmp) or 2,2'-biquinoline (bq) as the auxiliary ligands. The synthesized compounds were fully characterised by NMR, UV-Vis and luminescence spectroscopies. Selected structures were analysed by theoretical DFT (density functional theory) methods. High stability of the complexes in aqueous solutions in the presence of atmosferic oxygen was proven. Cytotoxic activity of all compounds was tested towards three cancer cell lines (CT26 - mouse colon carcinoma, A549 - human lung adenocarcinoma, and MCF7 - human breast adenocarcinoma). All complexes are characterised by cytotoxic activity higher than the activity of the parent drug and its organic derivatives as well as cisplatin. Studied derivatives as well as parent drug do not intercalate to DNA, except Cu(I) complexes with bq ligand. All studied complexes caused single stranded cleavage of the sugar-phosphate backbone of plasmid DNA. The addition of H2O2 caused distinct changes in the plasmid structure and led to single- and/or double-strain plasmid cleavage. Studied compounds interact with human serum albumin without affecting its secondary structure. PMID- 27764708 TI - Coordination ability and biological activity of a naringenin thiosemicarbazone. PMID- 27764709 TI - Ictal EEG source imaging in presurgical evaluation: High agreement between analysis methods. AB - PURPOSE: To determine the agreement between five different methods of ictal EEG source imaging, and to assess their accuracy in presurgical evaluation of patients with focal epilepsy. It was hypothesized that high agreement between methods was associated with higher localization-accuracy. METHODS: EEGs were recorded with a 64-electrode array. Thirty-eight seizures from 22 patients were analyzed using five different methods phase mapping, dipole fitting, CLARA, cortical-CLARA and minimum norm. Localization accuracy was determined at sub lobar level. Reference standard was the final decision of the multidisciplinary epilepsy surgery team, and, for the operated patients, outcome one year after surgery. RESULTS: Agreement between all methods was obtained in 13 patients (59%) and between all but one methods in additional six patients (27%). There was a trend for minimum norm being less accurate than phase mapping, but none of the comparisons reached significance. Source imaging in cases with agreement between all methods was not more accurate than in the other cases. Ictal source imaging achieved an accuracy of 73% (for operated patients: 86%). CONCLUSION: There was good agreement between different methods of ictal source imaging. However, good inter-method agreement did not necessarily imply accurate source localization, since all methods faced the limitations of the inverse solution. PMID- 27764710 TI - Prolonged survival effects induced by immature dendritic cells and regulatory T cells in a rat liver transplantation model. AB - BACKGROUND: Dendritic cells (DCs) and regulatory T (Treg) cells are crucial for inducing immune tolerance. However, the suppressive function of infused Treg cells and immature DCs (imDCs) following solid organ transplantation remains unclear. METHODS: ImDCs derived from DA-donor rats and Treg cells isolated from spleens of Lewis rats were prepared. A heterotopic liver transplantation model was established to examine the immune tolerance effects of infusion of Treg imDCs, imDCs and Treg cells individually. Th1/Th2 cytokines and TRAL were detected by ELISA. The overall rejection grade was assessed and the rejection activity index (RAI) was calculated. TUNEL-positive lymphocytes were detected in the portal area in liver sections. RESULTS: The infusion of Treg-imDCs was more effective than imDCs or Treg cells individually. Moreover, the expression of IL 10 and TGF-beta1 was significantly up-regulated, and IL-12 expression was significantly down-regulated, especially in the Treg-imDCs group. The percentage of TUNEL-positive cells was significantly higher in the Treg cells and imDCs groups. The RAI values in Treg-imDCs group on days 3 and 7 were lower than control, imDCs and Treg cells groups individually (p<0.05). Both TBIL and ALT levels in the Treg-imDCs and imDCs groups were significantly lower than those of the control and Treg cells groups, and serum TRAL levels increased significantly 10days after transplantation in the imDC and Treg-imDC groups compared with the control and Treg cells groups (P<0.001). CONCLUSION: These data demonstrated that infusion of Treg cells and/or imDCs induces alloantigen tolerance and prolongs liver allograft survival. The infusion of Treg-imDCs was more effective than imDCs or Treg cells individually. ImDCs synergize with Treg cells in inducing and maintaining the feedback loop between imDCs and Treg cells in vivo. PMID- 27764711 TI - Comparative assessment of lipid based nano-carrier systems for dendritic cell based targeting of tumor re-initiating cells in gynecological cancers. AB - We aimed to identify an optimum nano-carrier system to deliver tumor antigen to dendritic cells (DCs) for efficient targeting of tumor reinitiating cells (TRICs) in gynecological malignancies. Different lipid based nano-carrier systems i.e. liposomes, ethosomes and solid lipid nanoparticles (SLNPs) were examined for their ability to activate DCs in allogeneic settings. Out of these three, the most optimized formulation was subjected for cationic and mannosylated surface modification and pulsed with DCs for specific targeting of tumor cells. In both allogeneic and autologous trials, SLNPs showed a strong ability to activate DCs and orchestrate specific immune responses for targeting TRICs in gynecological malignancies. Our findings suggest that the mannosylated form of SLNPs is a suitable molecular vector for DC based therapeutics. DCs pulsed with mannosylated SLNPs may be utilized as adjuvant therapy for specific removal of TRICs to benefit patients from tumor recurrence. PMID- 27764712 TI - Detection probability models for bacteria, and how to obtain them from heterogeneous spiking data. An application to Bacillus anthracis. AB - Efficient and correct evaluation of sampling results with respect to hypotheses about the concentration or distribution of bacteria generally requires knowledge about the performance of the detection method. To assess the sensitivity of the detection method an experiment is usually performed where the target matrix is spiked (i.e. artificially contaminated) with different concentrations of the bacteria, followed by analyses of the samples using the pre-enrichment method and the analytical detection method of interest. For safety reasons or because of economic or time limits it is not always possible to perform exactly such an experiment, with the desired number of samples. In this paper, we show how heterogeneous data from diverse sources may be combined within a single model to obtain not only estimates of detection probabilities, but also, crucially, uncertainty estimates. We indicate how such results can then be used to obtain optimal conclusions about presence of bacteria, and illustrate how strongly the sampling results speak in favour of or against contamination. In our example, we consider the case when B. cereus is used as surrogate for B. anthracis, for safety reasons. The statistical modelling of the detection probabilities and of the growth characteristics of the bacteria types is based on data from four experiments where different matrices of food were spiked with B. anthracis or B. cereus and analysed using plate counts and qPCR. We show how flexible and complex Bayesian models, together with inference tools such as OpenBUGS, can be used to merge information about detection probability curves. Two different modelling approaches, differing in whether the pre-enrichment step and the PCR detection step are modelled separately or together, are applied. The relative importance on the detection curves for various existing data sets are evaluated and illustrated. PMID- 27764713 TI - An AFLP based method for the detection and identification of indigenous yeast in complex must samples without a microbiological culture. AB - Ribera de Duero Spanish wines are appreciated worldwide for their organoleptic characteristics; however, the wine market is very competitive, and the demand for high quality natural wines has been increasing in recent years. The microbiology of the process, specifically the yeasts involved in the alcoholic fermentation, constitutes an essential element directly related to the complexity and quality of the wine. Our work has focused on the development of a procedure to identify the indigenous wine yeasts present in complex samples of must and wine, without requiring colony isolation or a microbiological culture. The procedure is based on the use of AFLP molecular markers. The AFLP allele profiles obtained from complex samples are compared with the species-specific ones previously determined and included in a database using a sorting algorithm. The system allows a fast and efficient identification of yeast species and strains present in complex must and wine samples. This information can then be used by the enologists during the fermentation process in order to obtain signed wines. PMID- 27764714 TI - Propulsion strategy in the gait of primary school children; the effect of age and speed. AB - The strategy used to generate power for forward propulsion in walking and running has recently been highlighted as a marker of gait maturation and elastic energy recycling. This study investigated ankle and hip power generation as a propulsion strategy (PS) during the late stance/early swing phases of walking and running in typically developing (TD) children (15: six to nine years; 17: nine to 13years) using three-dimensional gait analysis. Peak ankle power generation at push-off (peakA2), peak hip power generation in early swing (peakH3) and propulsion strategy (PS) [peakA2/(peakA2+peakH3)] were calculated to provide the relative contribution of ankle power to total propulsion. Mean PS values decreased as speed increased for comfortable walking (p<0.001), fast walking (p<0.001) and fast running (p<0.001), and less consistently during jogging (p=0.054). PS varied with age (p<0.001) only during fast walking. At any speed of fast walking, older children generated more peakA2 (p=0.001) and less peakH3 (p=0.001) than younger children. While the kinetics of running propulsion appear to be developed by age six years, the skills of fast walking appeared to require additional neuromuscular maturity. These findings support the concept that running is a skill that matures early for TD children. PMID- 27764716 TI - Mobile clinics in Haiti, part 2: Lessons learned through service. AB - Learning from experience is a positive approach when preparing for mobile clinic service in a developing country. Mobile clinics provide healthcare services to people in hard to reach areas around the world, but preparation for their use needs to be done in collaboration with local leaders and healthcare providers. For over 16 years, Azusa Pacific University School of Nursing has sponsored mobile clinics to rural northern Haiti with the aim to provide culturally sensitive healthcare in collaboration with Haitian leaders. Past Haiti mobile clinic experiences have informed the APU-SON approach on best practices in study abroad, service-learning, and mission trips providing healthcare services. Hopefully, lessons learned from these experiences with mobile clinic service learning opportunities in Haiti will benefit others who seek to plan study abroad service-learning trips for students in healthcare majors who desire to serve the underserved around the world. PMID- 27764715 TI - Understanding mechanisms of autoimmunity through translational research in vitiligo. AB - Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells. Once the autoimmune T cell response is established, the IFN-gamma-STAT1-CXCL10 signaling axis becomes the primary inflammatory pathway driving both progression and maintenance of vitiligo. This pathway is a tempting target for both existing and developing pharmaceuticals, but further detailing how melanocytes signal their own demise may also lead to new therapeutic targets. Research in vitiligo may be the future key to understand the pathogenesis of organ-specific autoimmunity, as vitiligo is common, reversible, progresses over the life of the individual, has been relatively well-defined, and is quite easy to study using translational and clinical approaches. What is revealed in these studies can lead to innovative treatments and also help elucidate the principles that underlie similar organ-specific autoimmune diseases, especially in cases where the target organ is less accessible. PMID- 27764717 TI - CAFE-Map: Context Aware Feature Mapping for mining high dimensional biomedical data. AB - : Feature selection and ranking is of great importance in the analysis of biomedical data. In addition to reducing the number of features used in classification or other machine learning tasks, it allows us to extract meaningful biological and medical information from a machine learning model. Most existing approaches in this domain do not directly model the fact that the relative importance of features can be different in different regions of the feature space. In this work, we present a context aware feature ranking algorithm called CAFE-Map. CAFE-Map is a locally linear feature ranking framework that allows recognition of important features in any given region of the feature space or for any individual example. This allows for simultaneous classification and feature ranking in an interpretable manner. We have benchmarked CAFE-Map on a number of toy and real world biomedical data sets. Our comparative study with a number of published methods shows that CAFE-Map achieves better accuracies on these data sets. The top ranking features obtained through CAFE-Map in a gene profiling study correlate very well with the importance of different genes reported in the literature. Furthermore, CAFE-Map provides a more in-depth analysis of feature ranking at the level of individual examples. AVAILABILITY: CAFE-Map Python code is available at: http://faculty.pieas.edu.pk/fayyaz/software.html#cafemap . The CAFE-Map package supports parallelization and sparse data and provides example scripts for classification. This code can be used to reconstruct the results given in this paper. PMID- 27764718 TI - Beyond the greater trochanter: a pictorial review of the pelvic bursae. AB - PURPOSE: Review the MRI appearance of different bursae located throughout the pelvis, including the pertinent osseous and musculotendinous anatomy. MATERIALS AND METHODS: Bursae are potential spaces that reduce friction between opposed moving components which can become inflamed, clinically mimicking internal derangement. RESULTS: This series illustrates the most common as well as lesser known pelvic bursae. Common causes of bursitis including overuse, trauma, and infection are presented. CONCLUSION: Multiple bursae are located throughout the pelvis. It is important for radiologists to recognize bursitis as a potential etiology of pain and be familiar with their anatomical locations in order to guide appropriate management. PMID- 27764719 TI - Leptomeningeal metastasis from gynecologic cancers diagnosed by brain MRI. AB - Leptomeningeal metastasis (LM) is rarely observed in gynecologic cancers. As gadolinium-enhanced magnetic resonance imaging (Gd-MRI) is highly effective for diagnosing LM, the aim of this study is to describe the clinical behaviors and outcomes of LM patients who were diagnosed by Gd-MRI. After securing institutional review board approvals, we retrospectively reviewed patient records. Eight patients were found to have LM from gynecological malignancies. Primary tumors included three ovarian cancers, one tubal cancer, one peritoneal cancer, two endometrial cancers, and one cervical cancer. Gd-MRI of the brain and the spine is indicated as the high-priority inspection for the diagnosis of this devastating complication. PMID- 27764720 TI - High serum oxytocin is associated with metabolic syndrome in older men - The MINOS study. AB - AIM: Oxytocin regulates food intake, carbohydrate and lipid metabolism, and urinary sodium excretion. We assessed the association between serum oxytocin levels and presence of metabolic syndrome (MetS) in older men. METHODS: Cross sectional study was performed in 540 volunteer men aged 50-85yrs from the MINOS cohort. Oxytocin was measured in fasting serum by radioimmunoassay (Oxytocin RIA, Phoenix Pharmaceuticals). MetS was diagnosed using the harmonized definition. RESULTS: Serum oxytocin was higher in 166 men with MetS vs. controls (p<0.005). After adjustment for confounders including leptin, higher oxytocin was associated with higher odds of MetS (OR=1.38 per SD, 95%CI: 1.10-1.71, p<0.005). Men with serum oxytocin >0.74pg/mL (median) had higher odds of MetS vs. men with oxytocin ?0.74pg/mL (OR=2.06, 95%CI: 1.33-3.18, p<0.005). Higher oxytocin levels and low testosterone levels (total or free) were significantly associated with higher odds of MetS jointly and independently of each other. Men having oxytocin >0.74pg/mL and total testosterone <300ng/dL (<10.4nmol/L) had higher odds of MetS vs. men without these characteristics (OR=3.95, 95%CI: 1.65-9.46, p<0.005). Men having 25-hydroxycholecalciferol levels <30ng/mL and oxytocin >0.74pg/mL had higher odds of MetS vs. men without these characteristics (OR=2.86, 95%CI: 1.47 5.58, p<0.01). Men having oxytocin >0.74pg/mL and osteocalcin levels <14.6ng/mL (lowest quartile) had higher odds of MetS vs. men without these characteristics (OR=4.12, 95%CI: 2.07-8.20, p<0.001). CONCLUSION: In older men, higher serum oxytocin levels are associated with higher odds of MetS regardless of potential confounders. PMID- 27764722 TI - Integration of military and veteran health in a psychiatric mental health BSN curriculum: A mindful analysis. AB - The military and veteran populations in the U. S. state of Hawaii have a strong presence in the local communities. It was this substantial presence that provided the impetus to integrate military and veteran health into a Bachelor's of Science in Nursing (BSN) curriculum. This exploratory study investigated the relationship between the integration of military and veteran health into a psychiatric mental health BSN curriculum and nursing students' understanding of the many facets of military veterans' health. The concepts related to military and veterans' health was infused in didactic, seminar, simulation and clinical instruction. Examples of approaches to teaching include guest speakers from military clinical partners, inclusion of military/military families in simulation, the reading of evidence based articles focusing on the military and veteran population, use of identification of problem based learning and clinical placements in hospital(s) and community agencies specific to servicing military and veterans and their families. Students were encouraged to record their reflections which provided some insight on the value of integration of this important segment into the curriculum. Classroom discussions and reflections were analyzed using an exploratory method of inquiry by categorizing themes which revealed some biases about the military and veteran population and how working with this population helped students to understand their health needs. Although the data is limited, it an important foundation for further exploration into the significance of the integration of military and veterans' health in a psychiatric mental health BSN nursing curriculum. The recommendation is to further include military and veterans' health across the curriculum in order to help future nursing graduates understand and evaluate their role in working with this distinctive population, recognize challenges and opportunities in working with this population and identify available evidence-based resources to inform their practice. PMID- 27764721 TI - Type 1 diabetes in older adults: Comparing treatments and chronic complications in the United States T1D Exchange and the German/Austrian DPV registries. AB - AIMS: Compare characteristics, therapies and clinical outcomes in older adults with type 1 diabetes in the United States T1D Exchange (T1DX) and German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registries. METHODS: Cross sectional study of adults >=60years old with type 1 diabetes seen in 2011-2012 in the T1DX (n=1283) and DPV (n=2014) registries. Wilcoxon rank-sum test was used for continuous variables and chi-square test for categorical variables. Adjusted analyses used generalized linear models. RESULTS: Individuals in both registries were similar in body mass index (mean 27kg/m2), percent with obesity (25%) and gender (48% male). In T1DX there was longer diabetes duration (32.3 vs. 28.8years), greater use of antihypertensive medications (including ACE-I and ARBs; 85% vs. 62%), statins (68% vs. 40%), aspirin (77% vs. 21%), insulin pumps (58% vs. 18%), and less smoking (7% vs. 10%); lower adjusted mean LDL-cholesterol (84 vs. 109mg/dL), and lower adjusted mean systolic and diastolic blood pressures (128 vs. 136 and 68 vs. 74mmHg); fewer myocardial infarctions (6% vs. 9% [99% CI of difference, 1% to 5%]), strokes (2% vs. 8% [3% to 7%]), microvascular complications including microalbuminuria (17% vs. 44% [22% to 32%]) but increased depression (16.1% vs. 8.7%). Adjusted mean HbA1c levels were similar (7.5%, 58mmol/mol). CONCLUSIONS: Differences between the registries included greater use of antihypertensives, statins and insulin pumps, and fewer chronic complications in the T1DX. Further research is needed to better understand the role of intensive therapy in improving outcomes in older adults with type 1 diabetes. PMID- 27764723 TI - Efficacy and safety of long-term treatment with statins for coronary heart disease: A Bayesian network meta-analysis. AB - BACKGROUND AND AIMS: Our study aims to evaluate the efficacy and safety of long term treatment of statins for coronary heart disease (CHD). METHODS: Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE). Bayesian network meta-analysis was used to compare the direct and indirect effects between different statins. RESULTS: The systematic review showed that levels of blood lipids decreased during statin treatment. High dose of atorvastatin was the most obvious treatment for the reduction of blood lipids. Network meta-analysis showed that statins were significantly more effective than the control in reducing the risk of CHD mortality (Odds Ratio (OR) 0.69, 95% CI 0.61-0.77) and all-cause mortality (OR 0.84, 95% CI 0.80-0.87). In terms of reducing the risk of CHD morality, fluvastatin (77.3%), atorvastatin (72.3%) and lovastatin (68.4%) had higher cumulative probability than other statins, which were more effective treatments for the reduction of CHD morality. In terms of reducing all-cause mortality, atorvastatin (78.6%), fluvastatin (77.1%) and pitavastatin (74.1%) had higher cumulative probability than other statins, which were more effective treatment for reducing the all-cause mortality. Compared with placebo, statins increased the incidence risk of muscle disease (OR 1.05, 95% CI 1.00-1.10) and kidney disease (OR 1.11, 95% CI 1.05-1.72). CONCLUSIONS: Statins significantly reduced levels of blood lipids, with a high dose of atorvastatin being the most effective in blood-lipid level modification. Statins reduced the risk of CHD mortality and all-cause mortality, with atorvastatin and fluvastatin being the most effective in reducing the risk of CHD mortality and all-cause mortality. Statins increased the risk of muscle disease and kidney damage. PMID- 27764724 TI - Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. AB - BACKGROUND AND AIMS: We have recently reported that monocytes can undergo functional and transcriptional reprogramming towards a long-term pro-inflammatory phenotype after brief in vitro exposure to atherogenic stimuli such as oxidized LDL. This process is termed 'trained immunity', and is mediated by epigenetic remodeling and a metabolic switch towards increased aerobic glycolysis. We hypothesize that trained immunity contributes to atherogenesis. Therefore, we investigated the inflammatory phenotype and epigenetic remodeling of monocytes from patients with and without established atherosclerosis. METHODS: Monocytes were isolated from 20 patients with severe symptomatic coronary atherosclerosis (total plaque score >4 on coronary computed tomography angiography) and 17 patients with asymptomatic carotid atherosclerosis and matched controls for both groups. Ex vivo stimulation, RNA analysis and chromatin immunoprecipitation were performed. RESULTS: Monocytes from patients with symptomatic atherosclerosis have a higher production of pro-inflammatory cytokines upon LPS stimulation than healthy controls (TNFalpha 499 +/- 102 vs. 267 +/- 45 pg/ml, p = 0.01). This was associated with lower histone 3 lysine 4 trimethylation (H3K4me3) (19% vs. 33%, p = 0.002), and lower H3K27me3 (0.005% vs. 0.8%, p < 0.0001) on the TNFalpha promoter. Furthermore, relative mRNA expression of the glycolytic rate limiting enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 was higher in patients (0.7 +/- 0.2 vs. 0.3 +/- 0.1 resp. 1.7 +/- 0.2 vs. 1.0 +/- 0.1, p = 0.007 resp. 0.003) compared to control individuals. Interestingly, this pro-inflammatory phenotype was only present in patients with symptomatic atherosclerosis, and not in patients with asymptomatic carotid atherosclerosis. CONCLUSIONS: Circulating monocytes of patients with symptomatic, but not asymptomatic, atherosclerosis have a pro-inflammatory phenotype and increased expression of glycolytic enzymes, associated with epigenetic remodeling at the level of histone methylation. PMID- 27764725 TI - Drinks containing anthocyanin-rich blackcurrant extract decrease postprandial blood glucose, insulin and incretin concentrations. AB - Blackcurrants are rich in polyphenolic glycosides called anthocyanins, which may inhibit postprandial glycemia. The aim was to determine the dose-dependent effects of blackcurrant extract on postprandial glycemia. Men and postmenopausal women (14M, 9W, mean age 46 years, S.D.=14) were enrolled into a randomized, double-blind, crossover trial. Low sugar fruit drinks containing blackcurrant extract providing 150-mg (L-BE), 300-mg (M-BE) and 600-mg (H-BE) total anthocyanins or no blackcurrant extract (CON) were administered immediately before a high-carbohydrate meal. Plasma glucose, insulin and incretins (GIP and GLP-1) were measured 0-120min, and plasma 8-isoprostane F2alpha, together with arterial stiffness by digital volume pulse (DVP) was measured at 0 and 120min. Early plasma glucose response was significantly reduced following H-BE (n=22), relative to CON, with a mean difference (95% CI) in area over baseline (AOB) 0 30min of -0.34mmol/l.h (-0.56, -0.11, P<.005); there were no differences between the intermediate doses and placebo. Plasma insulin concentrations (AOB 0-30min) were similarly reduced. Plasma GIP concentrations (AOB 0-120min) were significantly reduced following H-BE, with a mean difference of -46.6ng/l.h ( 66.7, -26.5, P<.0001) compared to CON. Plasma GLP-1 concentrations were reduced following H-BE at 90min. There were no effects on 8-isoprostane F2alpha or vascular function. Consumption of blackcurrant extract in amounts roughly equivalent to 100-g blackcurrants reduced postprandial glycemia, insulinemia and incretin secretion, which suggests that inclusion of blackcurrant polyphenols in foods may provide cardio-metabolic health benefits. This trial was registered at clinicaltrials.gov as NCT01706653. PMID- 27764726 TI - Are resistance and aerobic exercise training equally effective at improving knee muscle strength and balance in older women? AB - This study aimed to compare the magnitude of knee muscle strength and static and dynamic balance change in response to 8 months of progressive RE and AE training in healthy community-dwelling older women. A secondary aim was to assess the relationship between muscle strength and balance changes (up and go test (UGT), one-leg stance test, and center of pressure measures). This study was a secondary analysis of longitudinal data from a randomized controlled trial, a three-arm intervention study in older women (n=71, mean age 69.0y). The results suggest that both interventions elicited likely to almost certain improvements (using magnitude-based inference) in balance performance. Leg strength was improved after RE whereas it was unclear following AE. Improvements in strength were almost certainly moderate after RE and possibly trivial after AE, with very likely greater improvements following RE compared to AE. A large and significant negative correlation (r=-0.5; CI 90%: -0.7 to -0.2) was found between DeltaUGT and change in both knee extension and knee flexion strength after 8-month RE. In conclusion, our results showed that both types of training improve balance, but RE was also effective at improving leg strength. In addition, improvements in both knee extension and flexion strength after RE appear to make an important contribution to meaningful improvements in static and dynamic balance. PMID- 27764727 TI - The safety and effectiveness of liver resection for breast cancer liver metastases: A systematic review. AB - Breast cancer liver metastases have traditionally been considered incurable and any treatment given therefore palliative. Liver resections for breast cancer metastases are being performed, despite there being no robust evidence for which patients benefit. This review aims to determine the safety and effectiveness of liver resection for breast cancer metastases. A systematic literature review was performed and resulted in 33 papers being assembled for analysis. All papers were case series and data extracted was heterogeneous so a meta-analysis was not possible. Safety outcomes were mortality and morbidity (in hospital and 30-day). Effectiveness outcomes were local recurrence, re-hepatectomy, survival (months), 1-, 2-, 3-, 5- year overall survival rate (%), disease free survival (months) and 1-, 2-, 3-, 5- year disease free survival rate (%). Overall median figures were calculated using unweighted median data given in each paper. Results demonstrated that mortality was low across all studies with a median of 0% and a maximum of 5.9%. The median morbidity rate was 15%. Overall survival was a median of 35.1 months and a median 1-, 2-, 3- and 5-year survival of 84.55%, 71.4%, 52.85% and 33% respectively. Median disease free survival was 21.5 months with a 3- and 5 year median disease free survival of 36% and 18%. Whilst the results demonstrate seemingly satisfactory levels of overall survival and disease free survival, the data are of poor quality with multiple confounding variables and small study populations. Recommendations are for extensive pilot and feasibility work with the ultimate aim of conducting a large pragmatic randomised control trial to accurately determine which patients benefit from liver resection for breast cancer liver metastases. PMID- 27764730 TI - Effect of rivaroxaban on prothrombin fragment 1+2 compared with warfarin in patients with acute cardioembolic stroke: Insight from its serial measurement. AB - INTRODUCTION: Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. MATERIALS AND METHODS: In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured. RESULTS: Median plasma F1+2 was 276 (IQR, 195-454) pmol/L before starting rivaroxaban, and significantly decreased to 196 (141-267) and 192 (151 248) on 7 and 28days after rivaroxaban, respectively (both p<0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6h after taking rivaroxaban showed a positive correlation (R2=0.69, p<0.01). PT at 4h after rivaroxaban was significantly prolonged compared with trough (16.6 versus 11.5s, p<0.0001). F1+2 at 4h was also decreased compared with trough (160 (123 245.5) versus 196 (141-266.5), p=0.04), but no patients showed F1+2 below the normal range at 4h. In other 34 patients with warfarin treatment (77years), median PT-INR and F1+2 were 2.06 (1.75-2.50) and 75 (48-111) (p<0.0001 versus 4h after rivaroxaban). Notably, of those with PT-INR>=2.0 (18/34), 12 (12/18, 67%) showed F1+2 below the normal range. CONCLUSIONS: Rivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events. PMID- 27764729 TI - Risk stratifying emergency department patients with acute pulmonary embolism: Does the simplified Pulmonary Embolism Severity Index perform as well as the original? AB - INTRODUCTION: The Pulmonary Embolism Severity Index (PESI) is a validated prognostic score to estimate the 30-day mortality of emergency department (ED) patients with acute pulmonary embolism (PE). A simplified version (sPESI) was derived but has not been as well studied in the U.S. We sought to validate both indices in a community hospital setting in the U.S. and compare their performance in predicting 30-day all-cause mortality and classification of cases into low risk and higher-risk categories. MATERIALS AND METHODS: This retrospective cohort study included adults with acute objectively confirmed PE from 1/2013 to 4/2015 across 21 community EDs. We evaluated the misclassification rate of the sPESI compared with the PESI. We assessed accuracy of both indices with regard to 30 day mortality. RESULTS: Among 3006 cases of acute PE, the 30-day all-cause mortality rate was 4.4%. The sPESI performed as well as the PESI in identifying low-risk patients: both had similar sensitivities, negative predictive values, and negative likelihood ratios. The sPESI, however, classified a smaller proportion of patients as low risk than the PESI (27.5% vs. 41.0%), but with similar low-risk mortality rates (<1%). Compared with the PESI, the sPESI overclassified 443 low-risk patients (14.7%) as higher risk, yet their 30-day mortality was 0.7%. The sPESI underclassified 100 higher-risk patients (3.3%) as low risk who also had a low mortality rate (1.0%). CONCLUSIONS: Both indices identified patients with PE who were at low risk for 30-day mortality. The sPESI, however, misclassified a significant number of low-mortality patients as higher risk, which could lead to unnecessary hospitalizations. PMID- 27764728 TI - HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes. AB - Productive replication of human papillomaviruses (HPV) is restricted to the uppermost layers of the differentiating epithelia. How HPV ensures an adequate supply of cellular substrates for viral DNA synthesis in a differentiating environment is unclear. Here, we demonstrate that HPV31 positive cells exhibit increased dNTP pools and levels of RRM2, a component of the ribonucleotide reductase (RNR) complex, which is required for de novo synthesis of dNTPs. RRM2 depletion blocks productive replication, suggesting RRM2 provides dNTPs for viral DNA synthesis in differentiating cells. We demonstrate that HPV31 regulates RRM2 levels through expression of E7 and activation of the ATR-Chk1-E2F1 DNA damage response, which is essential to combat replication stress upon entry into S phase, as well as for productive replication. Our findings suggest a novel way in which viral DNA synthesis is regulated through activation of ATR and Chk1 and highlight an intriguing new virus/host interaction utilized for viral replication. PMID- 27764732 TI - Major depressive episode, cognition, and epilepsy. AB - PURPOSE: In patients with epilepsy (PWE), relationships between depression, epilepsy characteristics, and cognitive aspects are complex. This study aimed to assess the occurrence of possible major depressive episode in PWE and to verify whether it is associated with the clinical aspects of the disease and cognition. METHODS: Two hundred consecutive PWE with a mean age and standard deviation of 47.6 (+/-15.1) years were included in the study. We determined whether their Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) scores were associated with their clinical, cognitive, and QOLIE-31 aspects using a significance level of 5% (p<0.05). RESULTS: Twenty-six patients (13%) had an NDDI E score >15, suggestive of major depressive episode. Logistic regression showed that NDDI-E >15 was associated with seizure frequency (p=0.022) and worse performance in the category fluency test (p=0.003). An NDDI-E >15 was also correlated with lower quality of life (p<0.001). CONCLUSION: The present findings suggest that possible major depressive episode is associated not only with epilepsy characteristics but also with cognitive aspects, such as category fluency, and quality of life. PMID- 27764733 TI - Social support for people with epilepsy in China. AB - The aim of this study was to better understand social support in adult people with epilepsy (PWE) in China and to explore the factors related to weaker or stronger social support in PWE when compared with a group of matching healthy controls. Consecutively, we recruited PWE from the epilepsy outpatient clinic of the West China Hospital and healthy controls from nearby urban and rural areas. People with epilepsy and healthy controls were gender- and age-matched. Each participant was interviewed and completed the following instruments: the Social Support Rating Scale (SSRS) and the Hospital Anxiety and Depression Scale (HADS). In addition, we measured quality of life (QoL) in PWE using the Quality of Life in Epilepsy Inventory (QOLIE-31). We compared the SSRS scores between PWE and healthy controls and searched for relevant factors using correlation and regression analyses. The results showed that PWE scored lower on the SSRS than healthy controls. For PWE, early onset and depression were related to weaker social support. In healthy controls, being married and being psychiatrically healthy (i.e., scored lower on the HADS) were related to stronger support. Family members, especially parents and spouses, were the most powerful supporters for PWE and healthy people, but PWE relied on their families to a greater extent. Early intervention and psychiatric treatment are important to address and improve social support for PWE. PMID- 27764731 TI - My Cousin, My Enemy: quasispecies suppression of drug resistance. AB - If a freshly minted genome contains a mutation that confers drug resistance, will it be selected in the presence of the drug? Not necessarily. During viral infections, newly synthesized viral genomes occupy the same cells as parent and other progeny genomes. If the antiviral target is chosen so that the drug resistant progeny's growth is dominantly inhibited by the drug-susceptible members of its intracellular family, its outgrowth can be suppressed. Precedent for 'dominant drug targeting' as a deliberate approach to suppress the outgrowth of inhibitor-resistant viruses has been established for envelope variants of vesicular stomatitis virus and for capsid variants of poliovirus and dengue virus. Small molecules that stabilize oligomeric assemblages are a promising means to an unfit family to destroy the effectiveness of a newborn drug-resistant relative due to the co-assembly of drug-susceptible and drug-resistant monomers. PMID- 27764734 TI - Risk of seizure relapse after antiepileptic drug withdrawal in adult patients with focal epilepsy. AB - OBJECTIVE: The objective of this study was to estimate the risk of a seizure relapse and the high-risk period of recurrence after antiepileptic drug (AED) withdrawal and to determine the predictive factors for a seizure relapse in adult patients with focal epilepsy who were seizure-free for more than 2years. METHODS: Using the Wenzhou Epilepsy Follow-Up Registry Database, 200 adult patients with focal epilepsy were recruited, who were undergoing follow-up, met the inclusion criteria of this study, were seizure-free for more than 2years, began withdrawing between June 2003 and June 2014, and were followed up prospectively for at least 1year or until a seizure relapse. The risk of recurrence and the time to seizure relapse were analyzed by the Kaplan-Meier method, and the predictive factors were identified by the Cox proportional hazard regression model. RESULT: A total of 99 patients had an unprovoked relapse during the follow-up period. The relapse rate was 49.5%, and each year, the recurrence probability of 12, 24, 36, 48, 60, 72, and 84months after AED withdrawal was 24.0%, 20.4%, 8.3%, 2.7%, 4.6%, 0.97%, and 0.98%, respectively. The two independent risk factors for recurrence after withdrawal in adult patients with focal epilepsy were a longer duration of active epilepsy and a shorter seizure-free period before withdrawal. CONCLUSION: The high-risk period of a seizure relapse in adult patients with focal epilepsy is the first 2years after withdrawal, and beyond 5years after withdrawal, seizures rarely relapse (relapse rate<1%). A seizure-free period for less than 4years before withdrawal is a predictive factor of risk for seizure recurrence after AED withdrawal in adult patients with focal epilepsy. PMID- 27764735 TI - Diagnosing infantile spasms: Accuracy of the internet. AB - Infantile spasms, one of the catastrophic epilepsies, can be a diagnostic challenge since the clinical manifestations may be subtle and may mimic benign conditions. Because of the rarity of the condition, primary care physicians and pediatricians may never see a case of infantile spasms during their career and may be unfamiliar with the seizure semiology. This is a serious issue since there is evidence that early diagnosis and treatment may improve outcome. Patients and families are increasingly using the internet more than their physician as a source of medical information about epilepsy. The reliance on using the internet for diagnostic information raises concerns about the accuracy of posted material that has not undergone professional review. To assess the quality of information being obtained about infantile spasms, we reviewed written and video content addressing infantile spasms on the internet. A total of 135 websites and 156 videos were reviewed for accuracy. Using the search terms Infantile Spasms and West Syndrome, we report that the majority of the written and video information provided was accurate and provided important and pertinent information. We conclude that internet searches provide accurate and pragmatic information about infantile spasms that has the potential for reducing the delay between the onset of the spasms and medical intervention. PMID- 27764736 TI - Selective functional activity measurement of a PEGylated protein with a modification-dependent activity assay. AB - BAX 855 (ADYNOVATE) is a PEGylated recombinant factor VIII (rFVIII) that showed prolonged circulatory half-life compared to unmodified rFVIII in hemophilic patients. Here, the development and validation of a novel assay is described that selectively measures the activity of BAX 855 as cofactor for the serine protease factor IX, which actives factor X. This method type, termed modification dependent activity assay, is based on PEG-specific capture of BAX 855 by an anti PEG IgG preparation, followed by a chromogenic FVIII activity assay. The assay principle enabled sensitive measurement of the FVIII cofactor activity of BAX 855 down to the pM-range without interference by non-PEGylated FVIII. The selectivity of the capture step, shown by competition studies to primarily target the terminal methoxy group of PEG, also allowed assessment of the intactness of the attached PEG chains. Altogether, the modification-dependent activity not only enriches, but complements the group of methods to selectively, accurately, and precisely measure a PEGylated drug in complex biological matrices. In contrast to all other methods described so far, it allows measurement of the biological activity of the PEGylated protein. Data obtained demonstrate that this new method principle can be extended to protein modifications other than PEGylation and to a variety of functional activity assays. PMID- 27764737 TI - Is emotional dysregulation a risk indicator for auto-aggression behaviors in adolescents with oppositional defiant disorder? AB - BACKGROUND: The Child Behavior Checklist Dysregulation Profile (CBCL-DP), (high scores in Anxious/Depressed, Attention Problems, and Aggressive Behavior subscales), has been related to poor emotional and behavioral self-regulation in children and adolescents. Our aim is to evaluate if it may be associated with auto-aggression in youth with oppositional defiant disorder (ODD). Method In 72 consecutively referred youths with ODD, emotional dysregulation was assessed with the CBCL-DP, auto-aggression and physical aggression against other persons with the Modified Overt Aggression Scale. RESULTS: Regression analysis showed that greater higher CBCL-DP scores were associated to higher levels of auto aggression, even when controlling for the levels of physical aggression against others and CBCL Total score. LIMITATIONS: The small sample size, the cross sectional design, and the lack of a control group limit the generalization of our findings. CONCLUSIONS: Referred ODD youths with higher scores of CBCL-DP are more likely to present auto-aggression, besides aggression against others. The CBCL could improve the screening and detection of these high-risk patients. PMID- 27764738 TI - Factors associated with relapse after a response to electroconvulsive therapy in unipolar versus bipolar depression. AB - BACKGROUND: While electroconvulsive therapy (ECT) treatment for depression is highly effective, the high rate of relapse is a critical problem. The current study investigated factors associated with the risk of relapse in mood disorders in patients in which ECT was initially effective. METHOD: The records of 100 patients with mood disorders (61 unipolar depression, 39 bipolar depression) who received and responded to an acute ECT course were retrospectively reviewed. Associations between clinical variables and relapse after responding to acute ECT were analyzed. The Ethics Committee of NHO Kure Medical Center approved the study protocol. RESULTS: After one year, the percentage of relapse-free patients was 48.7%. There was no significant difference between patients with either unipolar or bipolar depression who were relapse-free (unipolar: 51.1%, bipolar: 45.5%, P=0.603). Valproate maintenance pharmacotherapy in unipolar depression patients was associated with a lower risk of relapse compared to patients without valproate treatment (multivariate analysis, hazard ratio: 0.091; P=0.022). Lithium treatment, reportedly effective for unipolar depression following a course of ECT, tended to lower the risk of relapse (hazard ratio: 0.378; P=0.060). For bipolar depression, no treatment significantly reduced the risk of relapse. LIMITATIONS: The current findings were retrospective and based on a limited sample size. CONCLUSIONS: The relapse-free rate was similar between unipolar and bipolar depression. Valproate could have potential for unipolar depression patients as a maintenance therapeutic in preventing relapse after ECT. PMID- 27764739 TI - Performance, kinetics behaviors and microbial community of internal circulation anaerobic reactor treating wastewater with high organic loading rate: Role of external hydraulic circulation. AB - Performance of internal circulation anaerobic reactor (IC) treating wastewater at high organic loading rate (OLR) and role of external hydraulic circulation were evaluated. When the OLR was increased from 2.50 to 18.94kgCOD/m3/d, COD removal decreased to 85% slightly and methane production increased to 4.49L/L/d with the upflow velocity of 1.0m/h resulted from the additional hydraulic circulation. Withdrawal of external hydraulic circulation led to decrease of COD removal to lower than 60% drastically and methane production by 81%. Accumulation of volatile fatty acids caused decline of pH to below 6.0 and the shift of substrate metabolic pathway to the hybrid fermentation. In addition, both maximum methane production rate and maximum substrate degradation rate obtained from mathematical models decreased significantly. Hydrogenotrophic methanogens including Methanobacterium and Methanocorpusculum predominated in the anaerobic sludge and the shift of microbial community was also observed. PMID- 27764740 TI - Modeling three-dimensional surface morphology of biocake layer in a membrane bioreactor based on fractal geometry. AB - While the adsorptive fouling in membrane bioreactors (MBRs) is highly dependent of the surface morphology, little progress has been made on modeling biocake layer surface morphology. In this study, a novel method, which combined static light scattering method for fractal dimension (Df) measurement with fractal method represented by the modified two-variable Weierstrass-Mandelbrot function, was proposed to model biocake layer surface in a MBR. Characterization by atomic force microscopy showed that the biocake surface was stochastic, disorder, self similarity, and with non-integer dimension, illustrating obvious fractal features. Fractal dimension (Df) of sludge suspension experienced a significant change with operation of the MBR. The constructed biocake layer surface by the proposed method was quite close to the real surface, showing the feasibility of the proposed method. It was found that Df was the critical factor affecting surface morphology, while other factors exerted moderate or minor effects on the roughness of biocake layer. PMID- 27764741 TI - Elevated levels of Insulin-like Growth Factor-1 (IGF-1) in drug-naive patients with psychosis. AB - Insulin-like growth factor 1 (IGF-1) plays an important role in neurogenesis and synaptogenesis and may be implicated in schizophrenia, although data so far have been inconclusive. The aim of our study was to compare levels of IGF-1 in drug naive patients with a first episode of schizophrenia and related disorders with matched healthy controls. Forty drug naive first-episode patients with schizophrenia and related disorders and forty healthy subjects matched for age, gender, body mass index (BMI) and smoking status were enrolled in the study. Serum levels of IGF-1 for each sample were measured in duplicate by the enzyme linked immunosorbent assay (ELISA) method using human IGF-1. The median IGF-1 levels were significantly higher in drug-naive patients with psychosis compared to healthy controls (109.66ng/ml vs. 86.96ng/ml, respectively p=0.039). Multiple regression analysis revealed that differences in serum IGF-1 values were independent of glucose metabolism (fasting glucose, fasting insulin, insulin resistance) and cortisol. These results show that IGF-1 may be implicated in the pathophysiology of psychosis but confirmation is needed from other studies. PMID- 27764742 TI - Hyperin inhibits nuclear factor kappa B and activates nuclear factor E2-related factor-2 signaling pathways in cisplatin-induced acute kidney injury in mice. AB - Hyperin, a flavonoid compound found in Ericaceae, Guttiferae, and Celastraceae, has been reported to have anti-inflammatory effects. In the present study, we investigated the effects of hyperin on cisplatin-induced acute kidney injury (AKI) in mice. The renal tissue damage induced by cisplatin was detected by H&E staining. Blood urea nitrogen (BUN), creatinine, reactive oxygen species (ROS), and malondialdehyde (MDA) were also detected. Further, the effects of hyperin on cisplatin-induced TNF-alpha, IL-1beta and IL-6 were detected by ELISA. In addition, the phosphorylation of nuclear factor kappa B (NF-kappaB) and the expression of nuclear factor E2-related factor-2 (Nrf2) and HO-1 were detected by western blot analysis. The results showed that hyperin attenuated histological changes of kidney induced by cisplatin. The levels of BUN, creatinine, ROS, MDA, TNF-alpha, IL-1beta and IL-6 induced by cisplatin were also inhibited by hyperin. Cisplatin-induced NF-kappaB activation was inhibited by hyperin. Additionally, hyperin was found to up regulate the expression of Nrf2 and HO-1. In conclusion, the results suggest that hyperin protects against cisplatin-induced AKI by inhibiting inflammatory and oxidant response. PMID- 27764743 TI - Oroxylin A attenuates cigarette smoke-induced lung inflammation by activating Nrf2. AB - Oroxylin A, a natural flavonoid isolated from the medicinal herb Scutellaria baicalensis Georgi, has been reported to have anti-inflammatory and antioxidant properties. However, the effect of oroxylin A on cigarette smoke (CS)-induced lung inflammation remains unclear. In this study, the ability of oroxylin A to protect against CS-induced lung inflammation was detected in vivo and in vitro. Oroxylin A was administered intraperitoneally to mice 2h prior CS exposure every day for five consecutive days. BEAS-2B bronchial epithelial cells and RAW264.7 cells were used to investigate the molecular mechanism of oroxylin A in vitro. In vivo, the results showed that oroxylin A dose-dependently attenuated CS-induced lung histopathologic changes, expression of cytokines TNF-alpha, IL-1beta, and MCP-1, and levels of oxidative biomarkers 3-nitrotyrosine and 8-isoprostane. Meanwhile, oroxylin A up-regulated GSH level and glutathione reductase (GR) activity in lung tissues. In vitro, oroxylin A significantly up-regulated Nrf2 expression and total cellular glutathione level in cigarette smoke extract (CSE) stimulated cells. In addition, oroxylin A promoted Nrf2 binding to antioxidant response element (ARE) and up-regulated ARE-regulated gene such as heme oxygenase 1 (HO-1), GPx, and GR in CSE-stimulated cells. Oroxylin A could protect both epithelial cells and macrophages from damage by cigarette smoke in vitro. Taken together, these data indicated that oroxylin A attenuated oxidative stress and lung inflammation induced by CS via activating Nrf2 signaling pathway. Oroxylin A may be a protective agent against CS-induced lung inflammation and chronic obstructive pulmonary disease. PMID- 27764744 TI - Effective removal of contaminants in landfill leachate membrane concentrates by coagulation. AB - Leachate membrane concentrates containing high concentrations of organics and trace toxic compounds pose a major threat to the environment, and their treatment is an urgent issue. In this work, various coagulants were used to treat leachate membrane concentrates. Appropriate pH values for treatments with FeCl2, FeSO4, polyaluminum chloride, and FeCl3 were 3, 5, 5, and 4, respectively. FeCl3 achieved the highest total organic carbon (TOC) removal efficiency. The effect of the various anions in ferric coagulants [FeCl3, Fe2(SO4)3, and Fe(NO3)3] on the TOC removal efficiency was negligible. The main organics remaining in the leachate membrane concentrates after coagulation were humic and fulvic acids. The conditions for coagulation with FeCl3 were optimized using the response surface method (RSM). The highest TOC, chemical oxygen demand (COD), and chromaticity reduction efficiencies, 81%, 82%, and 97%, respectively, were achieved at pH 4 using FeCl3 (5 g L-1) and polyacrylamide (PAM; 0.07 g L-1). The COD of leachate membrane concentrates was reduced from 4000 to 718 mg L-1. The mole ratio of removed COD and Fe(III) (2.4 mol) at 5 g L-1 FeCl3 (pH 4, PAM 0.07 g L-1) was lower than that (3.8 mol) at 3 g L-1 FeCl3 (pH 4, PAM 0.07 g L-1); based on the cost and COD removal efficiency, the latter conditions were the best choice. Our work provides guidelines for the treatment of leachate membrane concentrates in engineering. PMID- 27764745 TI - Toxicogenetic evaluation of dichlorophene in peripheral blood and in the cells of the immune system using molecular and flow cytometric approaches. AB - Dichlorophene; a halogenated phenolic compound with wide applications as a fungicide, bactericide and antiprotozoan. Dichlorophene spray also has therapeutic use in the disease digital dermatitis. In guinea pigs, a few studies obtained mixed results in dicholorophene sensitization tests. In consideration of the fact, that the mechanism of its genotoxicity has not been adequately elucidated lead to present study assessing the acute in vivo toxicological impact in Rattus norvegicus. A systematic research has been made encompassing the use of molecular and flow cytometric approaches. The study was designed on blood cells for comet assay which revealed dichlorophene induced DNA damage in all exposures understandable in time dependent manner. The feasibility of this assay was also established as an effective, fast and accurate method with a great potential in biomonitoring. Contemporary molecular techniques were further engaged using leukocytes for the cell apoptosis/cycle and mitochondrial membrane potential employing propidium iodide staining and rhodamine 123 respectively. The effect on cell cycle phases and mitochondrial membrane permeability was analyzed through flow cytometry. These indicators exposed that dichlorophene decreased the mitochondrial membrane potential, altered the cell cycle and confirmed the DNA damage leading to apoptosis of the cells of the immune system accountable for immunotoxic effects of dichlorophene on rat leukocytes. PMID- 27764746 TI - How incense and joss paper burning during the worship activities influences ambient mercury concentrations in indoor and outdoor environments of an Asian temple? AB - This study firstly investigated the species, concentration variation, and emission factors of mercury emitted from the burning of incenses and joss papers in an Asian temple. Both indoor and outdoor speciated mercury (GEM, GOM, and PHg) were sampled by manual samplers, while ambient GEM at an indoor site was in-situ monitored by a continuous GEM monitor. Field measurement results showed that the total atmospheric mercury (TAM) concentrations in indoor and outdoor environments were in the range of 8.03-35.72 and 6.03-31.35 ng/m3, respectively. The indoor and outdoor ratios (I/O) of TAM in the daytime and at nighttime were in the range of 0.64-0.90 and 1.50-2.04, respectively. The concentrations of GEM, GOM, and PHg during the holiday periods were approximately 1-4 times higher than those during the non-holiday periods. GEM was the dominant mercury species in the indoor and outdoor environments and accounted for 63-81% of TAM, while the oxidized mercury accounted for 19-37% of TAM. Burning incenses and joss papers in a combustion chamber showed that the concentration of GEM from joss paper burning ranged from 4.07 to 11.62 MUg/m3, or about 13.97 times higher than that of incense burning, while the concentration of PHg from incense burning ranged from 95.91 to 135.07 ng/m3, or about 3.29 times higher than that of joss paper burning. The emission factors of incense burning were 10.39 ng/g of GEM and 1.40 ng/g of PHg, while those of joss paper burning were 12.65 ng/g of GEM and 1.27 ng/g of PHg, respectively. This study revealed that speciated mercury emitted from worship activities had significant influence on the indoor and outdoor mercury concentrations in an Asian temple. Higher intensity of worship activities during holidays resulted in a higher concentration of speciated mercury in indoor and outdoor air, which might cause health threats to worshipers, staffs, and surrounding inhabitants through long-term exposure. PMID- 27764747 TI - Stochastic hyperelastic constitutive laws and identification procedure for soft biological tissues with intrinsic variability. AB - In this work, we address the constitutive modeling, in a probabilistic framework, of the hyperelastic response of soft biological tissues. The aim is on the one hand to mimic the mean behavior and variability that are typically encountered in the experimental characterization of such materials, and on the other hand to derive mathematical models that are almost surely consistent with the theory of nonlinear elasticity. Towards this goal, we invoke information theory and discuss a stochastic model relying on a low-dimensional parametrization. We subsequently propose a two-step methodology allowing for the calibration of the model using standard data, such as mean and standard deviation values along a given loading path. The framework is finally applied and benchmarked on three experimental databases proposed elsewhere in the literature. It is shown that the stochastic model allows experiments to be accurately reproduced, regardless of the tissue under consideration. PMID- 27764748 TI - Parameter identification of hyperelastic material properties of the heel pad based on an analytical contact mechanics model of a spherical indentation. AB - Accurate identification of the material properties of the plantar soft tissue is important for computer-aided analysis of foot pathologies and design of therapeutic footwear interventions based on subject-specific models of the foot. However, parameter identification of the hyperelastic material properties of plantar soft tissues usually requires an inverse finite element analysis due to the lack of a practical contact model of the indentation test. In the present study, we derive an analytical contact model of a spherical indentation test in order to directly estimate the material properties of the plantar soft tissue. Force-displacement curves of the heel pads are obtained through an indentation experiment. The experimental data are fit to the analytical stress-strain solution of the spherical indentation in order to obtain the parameters. A spherical indentation approach successfully predicted the non-linear material properties of the heel pad without iterative finite element calculation. The force-displacement curve obtained in the present study was found to be situated lower than those identified in previous studies. The proposed framework for identifying the hyperelastic material parameters may facilitate the development of subject-specific FE modeling of the foot for possible clinical and ergonomic applications. PMID- 27764749 TI - Position of the major curve influences asymmetrical trunk kinematics during gait in adolescent idiopathic scoliosis. AB - BACKGROUND AND PURPOSE: Adolescent idiopathic scoliosis (AIS) is a structural, lateral curvature with rotation of the spine that develops around puberty. The influence of this spinal deformity on three-dimensional trunk movements during gait has not yet been elucidated. The aim of this study was to determine the influence of spinal curve pattern (single thoracic curve vs. single lumbar curve) on trunk kinematics during gait. METHODS: Twenty-two patients with a single thoracic curve (Lenke type 1) and 17 patients with a single lumbar curve (Lenke type 5) were included in this study. Trunk symmetry in the sagittal, coronal, and transverse planes during gait was evaluated using an optoelectronic motion capture system. RESULTS: In the type 1 group, the trunk was significantly rotated towards the concave side in the transverse plane during gait (mean difference of transverse rotation angle between concave side load and the convex side load, 8.8+/-0.6 degrees , p<0.01). In the type 5 group, the trunk was significantly rotated towards the convex side in the coronal plane throughout the stance phase of gait (mean difference of coronal inclination angle, 1.9+/-0.3 degrees , p<0.05). CONCLUSIONS: The AIS patients with a single thoracic curve showed asymmetrical trunk movement in the transverse plane, and patients with a single lumbar curve showed asymmetrical trunk movement in the coronal plane. These results indicate that the spinal curve pattern influenced trunk kinematics, and suggest that the global postural control strategy of patients with AIS differs according to the curve pattern. PMID- 27764750 TI - Changes of posture and muscle activities in the trunk and legs during walking in patients with lumbar spinal stenosis after decompression surgery. A preliminary report. AB - Neurogenic intermittent claudication is a main symptom in lumbar spinal stenosis (LSS), and postural change is often observed during walking. This study aimed to identify the changes in posture and muscle activity in the trunk and legs during walking in patients with LSS by examining 6 patients who had undergone decompression surgery. None of them had significant paralysis. Gait analysis using Vicon motion capture system(r) with electromyographic recordings of the paravertebral muscles (PVM) and vastus lateralis muscle (VL) was performed preoperatively and 2 weeks postoperatively. Results showed that the thorax angle indicating the degree of trunk flexion after walking decreased significantly and the pelvic angle tended to decrease after surgery. However, there were no difference in the spine angle, which is a measure of the motion of the thoraco lumbar spine among the evaluations. The knee angle increased significantly after surgery both at the beginning and at the end of walking, but the angles of the hip and ankle did not change significantly after surgery. Knee torques increased significantly after surgery both at the beginning and at the end of walking. The activity of the PVM decreased and that of the VL increased after surgery. The results indicate that patients with LSS walk in a forward-bending position without flexing the spine, which can be one of the neurologic symptoms. Increases in knee torque and VL activity seemed to reflect the increase of walking speed, and the decrease of PVM activity appeared to be caused by postural improvement after surgery. PMID- 27764751 TI - Forensic examination after exhumation: Contribution and difficulties after more than thirty years of burial. AB - We report a case of a Tunisian footballer who was found dead abroad under suspicious circumstances. The cause of death was, originally, attributed to a lightning strike. The corpse was buried without/autopsy. Over thirty years later, the family requested the exhumation to verify the identity and the cause of death. The exhumation was performed in 2011. DNA profiling from teeth and femur bone samples confirmed the identity of the deceased. The dry bone study revealed defects in the skull and the pelvis evoking firearm injuries. Post-mortem CT with three-dimensional (3-D) reconstruction allowed to confirm the characteristics of firearms injuries and to speculate about the number and the trajectories of potential shots. Nevertheless, the vitality of these injuries as well as the eventual fatal shot and the shooting distance could not be determined. Likewise, the type of the eventual weapon could not be clarified as there were no bullets or any metallic projectile fragments. Despite all doubts, the forensic explorations have allowed to verify the identity of the deceased, to evoke firearms injuries and, mainly, to deny the proposed cause of death after more than thirty years of burial. Moreover, the loss of soft tissues and bone fragility were the major obstacles. PMID- 27764752 TI - Anticancer effects of morin-7-sulphate sodium, a flavonoid derivative, in mouse melanoma cells. AB - BACKGROUND: Increasing evidence supports the anticancer effects of morin in vitro and in vivo. However, the role of morin-7-sulphate sodium (NaMoS), a water soluble flavonoid derivative synthesized from morin remains unclear. The present study investigated the tumor suppression by NaMoS in mouse melanoma cells. MATERIALS AND METHODS: We synthesized the flavonoid derivative morin-7-sulphate sodium according to the method described for quercetin-sulphate derivative, and further isolated, purified and identified the compound. Cell proliferation in vitro was assessed using a CCK-8 assay. The wound healing assay was performed to evaluate cell motility, and flow cytometry was used to detect cellular apoptosis. Protein levels of vimentin, matrix metalloproteinase 9 (MMP9), phosphorylation of Akt1/2/3 (p-Akt1/2/3), extracellular signal-regulated kinase 1/2 (p-ERK1/2) and Caspase3 in B16F10 cells were detected by immunohistochemistry and Western blot. RESULTS: The results suggest that cell proliferation was markedly decreased in NaMoS-treated groups (1, 10, 25, 50, 100, 500, 1000MUM) in a dose-dependent manner compared with the Control group and the IC50 was 221.67MUM at 48h. NaMoS at 200MUM concentration significantly inhibited the invasion and promoted apoptosis of B16F10 cells. Moreover, protein level of Caspase3 increased significantly in B16F10 cells treated by NaMoS. Immunohistochemistry and Western blot further confirmed that NaMoS decreased the expression of vimentin, MMP9, p Akt1/2/3 and p-ERK1/2 in B16F10 cells. CONCLUSIONS: This study provides robust evidence that NaMoS, a water-soluble flavonoid, manifests anticancer properties and may act as a signal transduction inhibitor in melanoma cells. PMID- 27764753 TI - Inactivation of transforming growth factor-beta-activated kinase 1 promotes taxol efficacy in ovarian cancer cells. AB - Resistance to taxol represents a major obstacle for long-term remission in ovarian cancer. Transforming Growth Factor-beta-Activated Kinase 1 (TAK1) is a critical component in immune response pathway. However, the role of TAK1 in the development of chemoresistance in ovarian cancer remains unknown. Here, we showed that in vitro, taxol-resistant cells expressed higher TAK1, and the ratio of p TAK1/TAK1 positively associated with taxol resistance in ovarian cancer cells. Inactivation of TAK1 by inhibitor 5Z-7-oxozeaenol or gene knockdown sensitized taxol cytotoxicity in vitro, promoting cell apoptosis and mitosis arrest. Moreover, resistant cells were much more sensitive to the combined TAK1 inhibitor and taxol treatment than their parental counterparts. Using xenograft mouse model, we found that 5Z-7-oxozeaenol significantly enhanced taxol efficacy in vivo. Thus, targeting TAK1 pathway is a promising strategy to enhance taxol response in ovarian cancer treatment. PMID- 27764754 TI - Tetrandrine protects against oxygen-glucose-serum deprivation/reoxygenation induced injury via PI3K/AKT/NF-kappaB signaling pathway in rat spinal cord astrocytes. AB - Tetrandrine (TET) is a bis-benzylisoquinoline alkaloid, which is isolated from a Chinese medicinal herb with antioxidant and anti-inflammatory activities. In this study, we investigated the effects of TET on oxygen-glucose-serum deprivation/reoxygenation (OGSD/R)-induced injury in rat spinal cord astrocytes, which mimics hypoxic/ischemic conditions in vivo. MTT and LDH assays indicated that cell viability was distinctly reduced and LDH leakage was elevated after OGSD/R exposure, which were dose-dependently reversed by pretreatment with TET (0.1, 1, 10, 20MUM). Western blot analysis showed that OGSD/R exposure resulted in an enhanced expression of Bax and Caspase-3 proteins, and Bcl-2 reduction; whereas these effects were dose-dependently restored by TET pretreatment. TET pretreatment also dose-dependently inhibited the elevated Caspase-3 activity in OGSD/R-treated astrocytes. The oxidative stress status was evaluated using commercial kits, and the results demonstrated that OGSD/R exposure induced obvious oxidative stress, accompanied by elevated levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced superoxide dismutase (SOD) activity, which were dose-dependently restored by TET pretreatment. In addition, TET pretreatment diminished the accumulation of tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) induced by OGSD/R. Moreover, TET pretreatment dose-dependently suppressed Akt phosphorylation and nuclear factor-kappaB (NF-kappaB) activity augmented by OGSD/R. Similarly, both PI3K inhibitor LY294002 and NF-kappaB inhibitor PDTC notably attenuated OGSD/R induced Akt phosphorylation, NF-kappaB activation, ROS generation, and TNF-alpha secretion. Taken together, these data demonstrated that TET protected against OGSD/R-induced injury in rat spinal cord astrocytes, which may be attributed to its antioxidant and anti-inflammatory activities via PI3K/AKT/NF-kappaB signaling pathway. PMID- 27764755 TI - Icariin promotes osteogenic differentiation of rat bone marrow stromal cells by activating the ERalpha-Wnt/beta-catenin signaling pathway. AB - Icariin, the main effective component of Herba Epimedii, has been identified to regulate the osteogenic differentiation of rat bone marrow stromal cells (rBMSCs) and have potential application in preventing bone loss and promoting bone regeneration. However, the underlying signaling pathway of its osteogenic effect remains unclear. Here, we investigated whether icariin could promote osteogenesis of rBMSCs through modulating the estrogen receptor alpha (ERalpha) and Wnt/beta catenin signaling pathways, which implicated in rBMSCs osteogenesis. rBMSCs were cultured in osteogenic induction medium and treated with icariin or together with ICI 182780 or DKK1, the effects on the expression of osteogenic genes and Wnt/beta-catenin signaling were detected. Results indicated that icariin (0.1MUM) markedly enhanced the proliferation of rBMSCs and alkaline phosphatase (ALP) activity. Additionally, icariin (0.1MUM) significantly up-regulated the expression of osteogenic genes (Runx2, osteopotin, DLX5, osteocalcin, collagen type I, and ERalpha) and Wnt signal members (beta-catenin, Lef1, TCF7, c-jun, c myc, and cyclin D). Furthermore, icariin stimulated the activation of beta catenin as evidenced by increased total beta-catenin protein and nuclear translocation. These osteogenesis-potentiating effects of icariin were blocked by ICI 182780 or DKK1. Taken together, these results suggest that the osteogenic effects of icariin on rBMSCs involves the ERalpha-Wnt/beta-catenin signaling pathway. PMID- 27764756 TI - KLF5 overexpression attenuates cardiomyocyte inflammation induced by oxygen glucose deprivation/reperfusion through the PPARgamma/PGC-1alpha/TNF-alpha signaling pathway. AB - The primary physiological function of Kruppel-like zinc-finger transcription factor (KLF5) is the regulation of cardiovascular remodeling. Vascular remodeling is closely related to the amelioration of various ischemic diseases. However, the underlying correlation of KLF5 and ischemia is not clear. In this study, we aim to investigate the role of KLF5 in myocardial ischemia reperfusion (IR) injury and the potential mechanisms involved. Cultured H9C2 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/Rep) to mimic myocardial IR injury in vivo. Expressions of KLF5 and PPARgamma were distinctly inhibited, and PGC-1alpha expression was activated at 24h after myocardial OGD/Rep injury. After myocardial OGD/Rep injury, we found that KLF5 overexpression down-regulated levels of TNF alpha, IL-1beta, IL-6 and IL-8. Through the analysis of lactate dehydrogenase (LDH) release, we demonstrate that KLF5 overexpression reduced the release of OGD/Rep-induced LDH. KLF5 overexpression significantly enhanced cell activity and decreased cell apoptosis during OGD/Rep injury. Compared with the OGD/Rep group, cells overexpressing KLF5 showed anti-apoptotic effects, such as decreased expression of Bax and cleaved caspase-3 as well as increased Bcl-2 expression. KLF5 overexpression activated PPARgamma, a protein involved in OGD/Rep injury, and increased levels of PGC-1alpha, while TNF-alpha expression was remarkably inhibited. In addition, GW9662, a PPARgamma receptor antagonist, reversed the expression of PPARgamma/PGC-1alpha/TNF-alpha and cell activity induced by KLF5 overexpression. The effects of KLF5 overexpression on PPARgamma/PGC-1alpha/TNF alpha and cell activity were abolished by co-treatment with GW9662. Taken together, these results suggest that KLF5 can efficiently alleviate OGD/Rep induced myocardial injury, perhaps through regulation of the PPARgamma/PGC 1alpha/TNF-alpha pathway. PMID- 27764757 TI - miR-10b promotes invasion by targeting KLF4 in osteosarcoma cells. AB - OBJECTIVE: Osteosarcoma is a common malignancy with high rate of metastasis. miR 10b has been reported to be expressed in many types of tumors abnormally and be associated with cancer carcinogenesis and progression. But the function of miR 10b in osteosarcoma is still unknown. So this study was aimed to investigate the role of miR-10b in osteosarcoma development. METHODS: miR-10b expression in osteosarcoma tissues and osteosarcoma cells were detected using real time PCR. The effects of miR-10b on osteosarcoma cells proliferation, apoptosis, migration and invasion were detected using CCK-8 assay, flow cytometry, wound-healing assay and transwell assay, respectively. The relationship between miR-10b and KLF4 was evaluated using dual-luciferase assay, correlation analysis. RESULTS: miR-10b was highly expressed in osteosarcoma tissues and osteosarcoma cells. Furthermore, inhibition of miR-10b in osteosarcoma cells depressed the cells proliferation, migration and invasion but promoted cells apoptosis. In addition, KLF4 was down regulated by miR-10b and miR-10b expression was negatively related to KLF4 expression in osteosarcoma tissue, miR-10b participated in the process of osteosarcoma cells invasion by regulating KLF4 expression. CONCLUSION: miR-10b is overexpressed in osteosarcoma and KLF4 is the direct target gene of miR-10b. Furthermore, miR-10b promotes osteosarcoma cells progression by downregulating KLF4 expression. These results suggest that miR-10b functions as an oncomiR and play an important role in osteosarcoma cellular processes at least partially through regulating KLF4; miR-10b may be a therapeutic target for osteosarcoma treatment. PMID- 27764758 TI - TAT modified and lipid - PEI hybrid nanoparticles for co-delivery of docetaxel and pDNA. AB - BACKGROUND: Co-delivery of anticancer drugs and gene is promising to generate synergistic anticancer effects. Surface modification of nanocarriers with specific ligands could further assist in targeting and internalization of the nanocarriers into specific cell populations, such as cancers and disease organs. PURPOSE: The aim of the study reported here is to develop Cell-penetrating peptides (CPPs) modified lipid - PEI hybrid nanoparticles (LPNs) for effective co delivery of docetaxel (DTX) and plasmid DNA (pDNA) for combination chemotherapy. METHODS: RKKRRQRRR peptide (TAT) modified, DTX and pDNA loaded LPNs (TAT-DTX/pDNA LPNs) were prepared and evaluated in PC3 cancer cells (in vitro) and in a murine prostate cancer model (in vivo). RESULTS: The results illustrated that the in vitro anticancer effect, in vitro transfection efficiency, in vivo antitumor and gene delivery efficacy of TAT-DTX/pDNA LPNs have advantages over other formulation tested. CONCLUSION: The results demonstrated that TAT-DTX/pDNA LPNs could be a promising co-delivery nano-system to achieve therapeutic efficacy for treatment of cancer. PMID- 27764759 TI - 6-Methoxyflavanone attenuates mechanical allodynia and vulvodynia in the streptozotocin-induced diabetic neuropathic pain. AB - BACKGROUND: Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities. OBJECTIVE: Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain. METHODS: 6-MeOF was evaluated for analgesic effect in the hot plate test and streptozotocin induced diabetic neuropathic pain in female rats using von Frey hairs. The possible involvement of opioidergic and GABAergic mechanisms was investigated using naloxone and pentylenetetrazole (PTZ) antagonists, respectively. The biodistribution of 6-MeOF in plasma and CNS was examined using a validated HPLC/UV analytical method. The binding affinity of 6-MeOF with opioid and GABA receptors was studied using molecular docking simulation approach. RESULTS: 6 MeOF (10 and 30mg/kg) attenuated the acute phasic thermal nociception in the hot plate test while in the case of streptozotocin-induced diabetic neuropathy model, 6-MeOF (10 and 30mg/kg) produced static/dynamic anti-allodynic (increased paw withdrawal threshold and latency) as well as static/dynamic anti-vulvodynic effects (increased flinching response threshold and latency), when compared to the vehicle and standard gabapentin (75mg/kg). In silico studies depicted the preference of 6-MeOF for the delta- and kappa-opioid and GABAA receptors. Moreover, the pharmacokinetic profile revealed a quick appearance of 6-MeOF in the systemic circulation and brain areas with maximum concentration observed after 30min in the amygdala, brain stem and cerebral cortex. CONCLUSION: 6-MeOF readily crosses the blood brain barrier and may be effective in attenuating the diabetes-induced allodynia as well as vulvodynia, probably through interactions with the GABAergic and opioidergic systems. PMID- 27764760 TI - Artesunate restores spatial learning of rats with hepatic encephalopathy by inhibiting ammonia-induced oxidative damage in neurons and dysfunction of glutamate signaling in astroglial cells. AB - BACKGROUND: Artesunate (ART) is an antimalarial drug with potential anti inflammatory effect. This study aimed to explore the potential protective role of ART in hepatic encephalopathy (HE), involving its function against ammonia toxicity. METHODS: HE rats were induced by the administration of thioacetamide (TAA, 300mg/kg/day). Spatial learning ability was tested in both Morris water and eight-arm radial maze. Rat cerebellar granule neurons (CGNs) were prepared for ammonia treatment in vitro, in line with SH-SY5Y and C6 cells. ART was administrated at 50 or 100mg/kg/day in vivo or added at 50 or 100MUM in vitro. Oxidative damages were evaluated by the changes of cell viability, reactive oxygen species (ROS) levels and glutathione (GSH) content, while glutamate uptake and release, and the activities of glutamine synthetase (GS) and Na+K+-ATPase were measured to indicate the dysfunction of glutamate signaling. RESULTS: Decreased escape latency and increased numbers of working errors were observed in TAA-induced HE rats, which could be significantly restored by ART at a dosage dependent manner. Decreased cell viability and GSH content and increased ROS accumulation were detected in ammonia-treated SH-SY5Y and CGNs, while ammonia treated C6 cells showed reduced glutamate uptake, increased glutamate release, and decrease of GSH content, GS and Na+K+-ATPase activity. In contrast, ART, especially at 100MUM, strongly reversed all changes induced by ammonia, showing a similar dosage-dependent manner in vitro. CONCLUSION: This study revealed a new neuroprotective role of ART in the pathogenesis of HE, by protecting neurons and astroglial cells from ammonia-induced damages and dysfunctions. PMID- 27764761 TI - Human platelet lysate versus minoxidil stimulates hair growth by activating anagen promoting signaling pathways. AB - Minoxidil and human platelet lysate (HPL) are commonly used to treat patients with hair loss. However, the roles of HPL versus minoxidil in hair follicle biology largely remain unknown. Here, we hypothesized that bulge and dermal papilla (DP) cells may express specific genes, including Kras, Erk, Akt, Shh and beta-catenin after exposure to minoxidil or HPL. The mouse hair follicles were isolated on day 10 after depilation and bulge or DP regions were dissected. The bulge and DP cells were cultured for 14days in DMEM/F12 medium. Then, the cells were treated with 100MUM minoxidil and 10% HPL for 10 days. Nuclear morphology was identified using DAPi staining. Reverse transcriptase and real-time polymerase chain reaction (PCR) analysis were also performed to examine the expression of Kras, Erk, Akt, Shh and beta-catenin mRNA levels in the treated bulge and DP regions after organ culture. Here, we found that minoxidil influences bulge and DP cell survival (P<0.05). Apoptosis in DP cells was also meaningfully decreased by HPL treatment (P=0.014). In addition, Kras, Akt, Erk, Shh and beta-catenin mRNA levels were changed in response to minoxidil treatment in both bulge and DP cells. HPL mediated Erk upregulation in both bulge and DP cells (P<0.05), but Kras and Akt mRNA levels were not considerably different in the HPL-treated cells. beta-catenin mRNA level was also significantly increased in the bulge region by HPL. We also found that Shh mRNA level was considerably higher in HPL-treated bulge cells than in minoxidil-treated bulge cells. In contrast, the expression of beta-cateinin and Shh in the DP cells was not meaningfully increased after treatment with HPL. Our results suggest that minoxidil and HPL can promote hair growth by activating the main anagen inducing signaling pathways. PMID- 27764763 TI - Lifestyle and DNA base composition in polychaetes. AB - A comparative analysis of polychaete species, classified as motile and low-motile forms, highlighted that the former were characterized not only by a higher metabolic rate (MR), but also by a higher genomic GC content. The fluctuation of both variables was not affected by the phylogenetic relationship of the species. Thus, present results further support that a very active lifestyle affects MR and GC at the same time, showing an unexpected similarity between invertebrates and vertebrates. In teleosts, indeed, a similar pattern has been also observed in comparisons of migratory and nonmigratory species. A cause-effect link between MR and GC has not yet been proved, but the fact that the two variables are significantly linked in all the organisms so far analyzed is, most probably, of relevant biological and evolutionary meaning. The present results fit very well within the frame of the metabolic rate hypothesis proposed to explain the DNA base composition variability among organisms. On the contrary, the thermostability hypothesis was not supported. At present, no data about the recombination rate in polychaetes were available to test the biased gene conversion (BGC hypothesis). PMID- 27764762 TI - Therapeutic outcomes of autologous CIK cells as a maintenance therapy in the treatment of lung cancer patients: A retrospective study. AB - OBJECTIVE: Few clinical studies have confirmed the role of cytokine-induced killer cells (CIKs) in the maintenance therapy of advanced lung cancer patients. We investigate effectiveness and tolerability of CIKs as a maintenance therapy in the treatment of advanced lung cancer patients. METHODS: 70 patients with advanced lung cancer (stage IIIB to IV) admitted to the First Affiliated Hospital of Third Military Medical University in Chongqing from Nov. 2011 to Jan. 2015 and treated with CIKs were enrolled as a CIKs group (T group), and another 70 advanced lung cancer patients treated with optimal supportive care during the same period were enrolled as a control group(C group). The changes of immune system, response rate, disease control rate, overall survival, and side effects were compared between the two groups. Furthermore, the factors that might influence the efficacy of CIKs therapy were evaluated. RESULTS: Compared with the healthy people, the ratios of CD3+, CD4+ and CD8+ T cells significantly decreased (P<0.05) in lung cancer patients. After CIKs treatment, the ratios of CD3+ and CD4+ T cells and CD4+/CD8+ significantly increased (P<0.05). The response rate (RR) and disease control rate (DCR) were 34.3% and 80.0% in the CIKs group, which were significantly higher than those in the control group (11.4% and 54.3%, both P<0.05). Besides, the median PFS was significantly improved in the CIKs group than that in control group (6 months vs. 4 months, P<0.05). Although median OS was 28 months in CIKs group while 22 months in control group, no significant difference was observed (P>0.05). However, The 2-year, 3-year survival rates were 56.8% and 21.6% in the CIK group, respectively, which were significantly improved compared to that in the control group (both P<0.05). KPS score significantly increased in the CIKs group (P=0.001). 6 patients suffered from transient fever or chills in the process of CIKs transfusion, and no other side effect was observed. Furthermore, we also found that TNM stage, tumor size, metastasis in vital organs and KPS score were all factors associated with efficacy of CIKs treatment. CONCLUSION: CIKs treatment, as a maintenance therapy, is safe and effective for advanced lung cancer patients, and can also improve the immune imbalance, RR, DCR, PFS, OS and quality of life of the lung cancer patients. PMID- 27764764 TI - Transcriptomic differences in intra-abdominal adipose tissue in extremely obese adolescents with different stages of NAFLD. AB - Mechanisms responsible for progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain poorly defined. To examine the potential contribution of adipose tissue to NAFLD progression, we performed a complete transcriptomic analysis using RNA sequencing (RNA-Seq) on intra-abdominal adipose tissue (IAT) from severely obese adolescents [Mage 16.9 +/- 0.4 yr, body mass index (BMI) z-score 2.7 +/- 0.1] undergoing bariatric surgery and liver biopsy categorized into three groups: no steatosis (normal, n = 8), steatosis only (n = 13), or NASH (n = 10) by liver histology. Age, body weight, and BMI did not differ among groups, but subjects with NASH were more insulin resistant (increased homeostatic model assessment/insulin resistance, P < 0.05 vs. other groups). RNA-Seq revealed 175 up- and 492 downregulated mRNA transcripts (>=+/ 1.5-fold, false discovery rate <0.10) in IAT between NASH vs. Normal, with "mitochondrial dysfunction, P = 4.19E-7" being the top regulated canonical pathway identified by Ingenuity Pathway Analysis; only 19 mRNA transcripts were up- and 148 downregulated when comparing Steatosis vs. Normal, with suppression of "EIF2 signaling, P = 1.79E-27" being the top regulated pathway indicating increased cellular stress. A comparison of IAT between NASH vs. Steatosis found 515 up- and 175 downregulated genes, with "antigen presentation, P = 6.03E-18" being the top regulated canonical pathway and "inflammatory response" the top diseases and disorders function. Unique transcriptomic differences exist in IAT from severely obese adolescents with distinct stages of NAFLD, providing an important resource for identifying potential novel therapeutic targets for childhood NASH. PMID- 27764765 TI - Strain survey and genetic analysis of vasoreactivity in mouse aorta. AB - Understanding the genetic influence on vascular reactivity is important for identifying genes underlying impaired vascular function. The purpose of this study was to characterize the genetic contribution to intrinsic vascular function and to identify loci associated with phenotypic variation in vascular reactivity in mice. Concentration response curves to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh), and sodium nitroprusside (SNP) were generated in aortic rings from male mice (12 wk old) from 27 inbred mouse strains. Significant strain-dependent differences were found for both maximal responses and sensitivity for each agent, except for SNP Max (%). Strain differences for maximal responses to ACh, PE, and KCl varied by two- to fivefold. On the basis of these large strain differences, we performed genome-wide association mapping (GWAS) to identify loci associated with variation in responses to these agents. GWAS for responses to ACh identified four significant and 19 suggestive loci. Several suggestive loci for responses to SNP, PE, and KCl (including one significant locus for KCl EC50) were also identified. These results demonstrate that intrinsic endothelial function, and more generally vascular function, is genetically determined and associated with multiple genomic loci. Furthermore, these results are supported by the finding that several genes residing in significant and suggestive loci for responses to ACh were previously identified in rat and/or human quantitative trait loci/GWAS for cardiovascular disease. This study represents the first step toward the unbiased comprehensive discovery of genetic determinants that regulate intrinsic vascular function, particularly endothelial function. PMID- 27764766 TI - Reactive oxygen species and bacterial biofilms in diabetic wound healing. AB - Chronic wounds are a common and debilitating complication for the diabetic population. It is challenging to study the development of chronic wounds in human patients; by the time it is clear that a wound is chronic, the early phases of wound healing have passed and can no longer be studied. Because of this limitation, mouse models have been employed to better understand the early phases of chronic wound formation. In the past few years, a series of reports have highlighted the importance of reactive oxygen species and bacterial biofilms in the development of chronic wounds in diabetics. We review these recent findings and discuss mouse models that are being utilized to enhance our understanding of these potentially important contributors to chronic wound formation in diabetic patients. PMID- 27764767 TI - Muscle dysfunction in a zebrafish model of Duchenne muscular dystrophy. AB - Sapje zebrafish lack the protein dystrophin and are the smallest vertebrate model of Duchenne muscular dystrophy (DMD). Their small size makes them ideal for large scale drug discovery screens. However, the extent that sapje mimic the muscle dysfunction of higher vertebrate models of DMD is unclear. We used an optical birefringence assay to differentiate affected dystrophic sapje larvae from their unaffected siblings and then studied trunk muscle contractility at 4-7 days postfertilization. Preparation cross-sectional area (CSA) was similar for affected and unaffected larvae, yet tetanic forces of affected preparations were only 30-60% of normal. ANCOVA indicated that the linear relationship observed between tetanic force and CSA for unaffected preparations was absent in the affected population. Consequently, the average force/CSA of affected larvae was depressed 30-70%. Disproportionate reductions in twitch vs. tetanic force, and a slowing of twitch tension development and relaxation, indicated that the myofibrillar disorganization evident in the birefringence assay could not explain the entire force loss. Single eccentric contractions, in which activated preparations were lengthened 5-10%, resulted in tetanic force deficits in both groups of larvae. However, deficits of affected preparations were three- to fivefold greater at all strains and ages, even after accounting for any recovery. Based on these functional assessments, we conclude that the sapje mutant zebrafish is a phenotypically severe model of DMD. The severe contractile deficits of sapje larvae represent novel physiological endpoints for therapeutic drug screening. PMID- 27764768 TI - Peptide affinity analysis of proteins that bind to an unstructured region containing the transactivating domain of the osmoprotective transcription factor NFAT5. AB - NFAT5 is a transcription factor originally identified because it is activated by hypertonicity and that activation increases expression of genes that protect against the adverse effects of the hypertonicity. However, its targets also include genes not obviously related to tonicity. The transactivating domain of NFAT5 is contained in its COOH-terminal region, which is predicted to be unstructured. Unstructured regions are common in transcription factors particularly in transactivating domains where they can bind co-regulatory proteins essential to their function. To identify potential binding partners of NFAT5 from either cytoplasmic or nuclear HEK293 cell extracts, we used peptide affinity chromatography followed by mass spectrometry. Peptide aptamer-baits consisted of overlapping 20 amino acid peptides within the predicted COOH terminal unstructured region of NFAT5. We identify a total of 351 unique protein preys that associate with at least one COOH-terminal peptide bait from NFAT5 in either cytoplasmic or nuclear extracts from cells incubated at various tonicities (NaCl varied). In addition to finding many proteins already known to associate with NFAT5, we found many new ones whose function suggest novel aspects of NFAT5 regulation, interaction, and function. Relatively few of the proteins pulled down by peptide baits from NFAT5 are generally involved in transcription, and most, therefore, are likely to be specifically related to the regulation of NFAT5 or its function. The novel associated proteins are involved with cancer, effects of hypertonicity on chromatin, development, splicing of mRNA, transcription, and vesicle trafficking. PMID- 27764769 TI - Establishing the involvement of the novel gene AGBL5 in retinitis pigmentosa by whole genome sequencing. AB - While more than 250 genes are known to cause inherited retinal degenerations (IRD), nearly 40-50% of families have the genetic basis for their disease unknown. In this study we sought to identify the underlying cause of IRD in a family by whole genome sequence (WGS) analysis. Clinical characterization including standard ophthalmic examination, fundus photography, visual field testing, electroretinography, and review of medical and family history was performed. WGS was performed on affected and unaffected family members using Illumina HiSeq X10. Sequence reads were aligned to hg19 using BWA-MEM and variant calling was performed with Genome Analysis Toolkit. The called variants were annotated with SnpEff v4.11, PolyPhen v2.2.2, and CADD v1.3. Copy number variations were called using Genome STRiP (svtoolkit 2.00.1611) and SpeedSeq software. Variants were filtered to detect rare potentially deleterious variants segregating with disease. Candidate variants were validated by dideoxy sequencing. Clinical evaluation revealed typical adolescent-onset recessive retinitis pigmentosa (arRP) in affected members. WGS identified about 4 million variants in each individual. Two rare and potentially deleterious compound heterozygous variants p.Arg281Cys and p.Arg487* were identified in the gene ATP/GTP binding protein like 5 (AGBL5) as likely causal variants. No additional variants in IRD genes that segregated with disease were identified. Mutation analysis confirmed the segregation of these variants with the IRD in the pedigree. Homology models indicated destabilization of AGBL5 due to the p.Arg281Cys change. Our findings establish the involvement of mutations in AGBL5 in RP and validate the WGS variant filtering pipeline we designed. PMID- 27764770 TI - Visualization of early prostatic adenocarcinoma as a stem cell disease. AB - Prostate Cancer represents the second leading cause of cancer death among men in the United States, and the third leading cause of cancer death among men in Europe. We have previously shown that cells possessing Cancer Stem Cell (CSC) characteristics can be grown from human PrCa tissue harvested at the time of prostatectomy. However, the cellular origin of these CSCs was not previously known. In most cases, simple hematoxylin and eosin (H&E) stained sections are sufficient to make a definitive diagnosis of prostatic adenocarcinoma (PrCa) in needle biopsy samples. We utilized six different antibodies specific for stem cell antigens to examine paraffin sections of PrCa taken at the time of needle biopsy diagnosis. These antisera were specific for CD44, CD133, ALDH7A1, LGR-5, Oct-4 and NANOG. We demonstrate specific staining of tumor cells with all six antisera specific for stem cell antigens. Some of these antibodies also react with cells of hyperplastic glands, but the patterns of reactivity differ from those of malignant glands. These findings demonstrate that at the time of diagnosis, PrCa consists of cells exhibiting properties of CSCs and consistent with the possibility that PrCa is a stem cell disease. PMID- 27764771 TI - Epigenetic silencing of miR-137 contributes to early colorectal carcinogenesis by impaired Aurora-A inhibition. AB - MicorRNA-137 is silenced in human colorectal cancer tissues and colon polyps. Our study showed that the decreased expression of miR-137 is significantly different in various types of polyp which maintain different potentials to lead to CRC development. The expression of miR-137 gradually decreases during the process of colorectal carcinogenesis. Receiver operating characteristic curve (ROC) analysis indicates that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the predisposition of colorectal carcinogenesis. By cell model and xenograft animal model, the enforced expression of miR-137 in colorectal cancer cells can inhibit cell proliferation and tumor formation, induce G2/M arrest, and lead to apoptosis. The expression pattern of miR-137 and Aurora-A or PTGS2 is negatively correlated in human colorectal cancer tissues and colon polyps. Those effects induced by overexpressed miR-137 can be rescued by the overexpression of Aurora-A. In summary, our study suggests that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the tendency toward to CRC formation through the impaired inhibitory effect of Aurora A. The investigation of the regulatory mechanism of miR-137-mediated Aurora-A inhibition may shed new light on the early prognosis of cancer therapy for CRC in the future. PMID- 27764772 TI - Gene-environment interaction for polymorphisms in ataxia telangiectasia-mutated gene and radiation exposure in carcinogenesis: results from two literature-based meta-analyses of 27120 participants. AB - PURPOSE: We conducted two meta-analyses of ATM genetic polymorphisms and cancer risk in individuals with or without radiation exposure to determine whether there was a joint effect between the ATM gene and radiation exposure in carcinogenesis. RESULTS: rs1801516, which was the only ATM polymorphism investigated by more than 3 studies of radiation exposure, was eligible for the present study. The meta analysis of 23333 individuals without radiation exposure from 24 studies showed no association between the rs1801516 polymorphism and cancer risk, without heterogeneity across studies. The meta-analysis of 3787 individuals with radiation exposure from 6 studies showed a significant association between the rs1801516 polymorphism and a decreased cancer risk, with heterogeneity across studies. There was a borderline-significant difference between the ORs of the two meta-analyses (P = 0.066), and the difference was significant when only Caucasians were included (P = 0.011). MATERIALS AND METHODS: Publications were identified by searching PubMed, EMBASE, Web of Science, and CNKI databases. Odds ratios (ORs) were calculated to estimate the association between ATM genetic polymorphisms and cancer risk. Tests of interaction were used to compare differences between the ORs of the two meta-analyses. CONCLUSIONS: Our meta analyses confirmed the presence of a gene-environment interaction between the rs1801516 polymorphism and radiation exposure in carcinogenesis, whereas no association was found between the rs1801516 polymorphism and cancer risk for individuals without radiation exposure. The heterogeneity observed in the meta analysis of individuals with radiation exposure might be due to gene-ethnicity or gene-gene interactions. Further studies are needed to elucidate sources of the heterogeneity. PMID- 27764774 TI - Correlation between anti-PD-L1 tumor concentrations and tumor-specific and nonspecific biomarkers in a melanoma mouse model. AB - Blockade of PD-L1 with specific monoclonal antibodies (anti-PD-L1) represents a therapeutic strategy to increase the capability of the immune system to modulate the tumor immune-resistance. The relationship between anti-PD-L1 tumor exposition and anti-tumor effect represents a challenge that has been addressed in this work through the identification of certain biomarkers implicated in the antibody's mechanism of action, using a syngeneic melanoma mouse model. The development of an in-vitro/in-vivo platform has allowed us to investigate the PD-L1 behavior after its blockage with anti-PD-L1 at cellular level and in animals. In-vitro studies showed that the complex PD-L1/anti-PD-L1 was retained mainly at the cell surface. The antibody concentration and time exposure affected directly the recycling or ligand turnover. In-vivo studies showed that anti-PD-L1 was therapeutically active at all stage of the disease, with a rapid onset, a low but durable efficacy and non-relevant toxic effect. This efficacy measured as tumor shrinkage correlated with tumor-specific infiltrating lymphocytes (TILs), which increased as antibody tumor concentrations increased. Both, TILS and antibody concentrations followed similar kinetic patterns, justifying the observed anti-PD L1 rapid onset. Interestingly, peripheral lymphocytes (PBLs) behave as infiltrating lymphocytes, suggesting that these PBLs might be considered as a possible biomarker for antibody activity. PMID- 27764775 TI - Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer. AB - Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer. PMID- 27764776 TI - IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process. AB - Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor 1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers.We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment.In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments. PMID- 27764777 TI - Prognostic significance of serum beta-2 microglobulin in patients with diffuse large B-cell lymphoma in the rituximab era. AB - The prognostic value of serum beta-2 microglobulin for diffuse large B-cell lymphoma (DLBCL) is not well known in the rituximab era. A retrospective registry data analysis of 833 patients with de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was conducted to establish the prognostic significance of serum beta-2 microglobulin at a >=2.5 mg/L cutoff. Five-year progression-free survival (PFS, 76.1% vs. 41.0%; p < 0.001) and overall survival (OS, 83.8% vs. 49.2%; p < 0.001) were significantly worse in patients with elevated serum beta-2 microglobulin (n = 290, 34.8%). Furthermore, the five parameters of the International Prognostic Index, accompanying B symptoms, bone marrow involvement and impaired renal function were associated with worse PFS and OS. In multivariate analysis, elevated beta-2 microglobulin was a significant poor prognostic factor for PFS (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.29-2.24; p < 0.001) and OS (HR, 2.0; 95% CI, 1.47-2.75; p < 0.001). In an independent validation cohort of 258 R-CHOP treated patients with de novo DLBCL, elevated beta-2 microglobulin levels remained a significant poor prognostic factor for PFS (HR, 2.03; 95% CI, 1.23 3.32; p = 0.005) and exhibited a strong trend of association with worse OS (HR, 1.64; 95% CI, 0.98-2.75; p = 0.062). The significance of serum beta-2 microglobulin levels as an independent prognostic factor for patients with DLBCL receiving R-CHOP is confirmed. PMID- 27764778 TI - Intensity-modulated radiation therapy achieves better local control compared to three-dimensional conformal radiation therapy for T4-stage nasopharyngeal carcinoma. AB - PURPOSE: To examine the survival outcomes and late toxicity profiles of three dimensional conformal radiation therapy (3DCRT) vs. intensity-modulated radiation therapy (IMRT) for patients with nasopharyngeal carcinoma (NPC). METHODS: Three hundred and seventy-four patients with newly diagnosed, non-metastatic, NPC who were curatively treated with 3DCRT between 2004 and 2006 and 481 patients treated with IMRT between 2007 and 2009 were analyzed. Patients were categorized as having advanced-stage disease (stage III, IVA, and IVB disease; n = 709) or early stage disease (stage I and II; n = 146). The median follow-up time was 90.3 months for patients treated with 3DCRT and 86.3 months for patients treated with IMRT. RESULTS: For early-stage patients, the outcomes of IMRT vs. 3DCRT were similar considering locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). For advanced-stage patients, IMRT was associated with better LRC compared with 3DCRT (5-year LRC rate: 85.6% vs. 76.6%, respectively; p = 0.035) and OS (5-year OS rate: 82.3% vs. 71.8%, respectively; p = 0.002), whereas DMFS was similar for both treatments (5-year DMFS rate: 80.9% vs. 79.0%, respectively; p = 0.324). Furthermore, the IMRT technique was more beneficial for patients with T4 disease. Late toxicities occurred more frequently in patients treated with 3DCRT than in those treated with IMRT (grade >=3 neck fibrosis: 6.7% vs. 3.7%, respectively, p = 0.036; radiographic temporal lobe necrosis: 10.2% vs. 4.4%, respectively, p < 0.001). CONCLUSIONS: Compared with 3DCRT, IMRT offered better LRC in patients with advanced-stage non-metastatic NPC, which corresponded with better OS. PMID- 27764780 TI - The concept of immune surveillance against tumors. The first theories. AB - The immune system plays a major role in the surveillance against tumors. To avoid attack from the immune system, tumor cells develop different strategies to escape immune surveillance. Evidence of immune surveillance comes from both animal models and clinical observations. Mice with a wide variety of immunodeficiencies have a high rate of tumor incidence and are more susceptible to transplanted or chemical carcinogen-induced tumors. Immunosuppressed patients have a high incidence of tumors. However, many patients develop cancer even in the presence of an apparently normal immune system. This indicates that tumor cells are able to escape immune surveillance. The aim of this review article is to summarize the literature concerning the development of the theory of immune surveillance against tumors; to discuss the evidence for and against this theory, and to discuss the concept of immunoediting. Finally, the current approaches in anti tumor immunotherapy will be analyzed. PMID- 27764779 TI - Mesenchymal stem cells overexpressing Sirt1 inhibit prostate cancer growth by recruiting natural killer cells and macrophages. AB - Prostate cancer (PCa) has become the second leading cause of male cancer-related mortality in the United States. Mesenchymal stem cells (MSCs) are able to migrate to tumor tissues, and are thus considered to be novel antitumor carriers. However, due to their immunosuppressive nature, the application of MSCs in PCa therapy remains limited. In this study, we investigated the effect of MSCs overexpressing an NAD-dependent deacetylase sirtuin 1 (MSCs-Sirt1) on prostate tumor growth, and we analyzed the underlying mechanisms. Our results show that MSCs accelerate prostate tumor growth, whereas MSCs-Sirt1 significantly suppresses tumor growth. Natural killer (NK) cells and macrophages are the prominent antitumor effectors of the MSCs-Sirt1-induced antitumor activity. IFN gamma and C-X-C motif chemokine ligand 10 (CXCL10) are highly expressed in MSCs Sirt1 mice. The antitumor effect of MSCs-Sirt1 is weakened when CXCL10 and IFN gamma are inhibited. These results show that MSCs-Sirt1 can effectively inhibit prostate cancer growthrecruiting NK cells and macrophages in a tumor inflammatory microenvironment. PMID- 27764781 TI - A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non small cell lung cancer. AB - BACKGROUND: Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer. PATIENTS AND METHODS: This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status. RESULTS: Due to a low accrual rate in this study, the sample size (n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events related deaths during the chemotherapy period (pulmonary embolism (n = 1) and sudden death after the administration of the 3rd course of chemotherapy (n = 1)). CONCLUSION: The benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC. PMID- 27764782 TI - LncRNA profile study reveals four-lncRNA signature associated with the prognosis of patients with anaplastic gliomas. AB - Anaplastic glioma is Grade III and the median overall survival is about 37.6 months. However, there are still other factors that affect the prognosis for anaplastic glioma patients due to variable overall survival. So we screened four lncRNA signature (AGAP2-AS1, TPT1-AS1, LINC01198 and MIR155HG) from the lncRNA expression profile from the GSE16011, CGGA and REMBRANDT datasets. The patients in low risk group had longer overall survival than high risk group (median OS 2208.25 vs. 591.30 days; P < 0.0001). Moreover, patients in the low risk group showed similar overall survival to Grade II patients (P = 0.1669), while the high risk group showed significant different to Grade IV (P = 0.0005) with similar trend. So based on the four-lncRNA, the anaplastic gliomas could be divided into grade II-like and grade IV-like groups. On the multivariate analysis, it showed the signature was an independent prognostic factor (P = 0.000). The expression of four lncRNAs in different grades showed that AGAP2-AS1, LINC01198 and MIR155HG were increased with tumor grade, while TPT1-AS1 was decreased. Knockdown of AGAP2 AS1 can inhibit the cell proliferation, migration and invasion, while increase the apoptosis cell rates in vitro. In conclusion, our results showed that the four-lncRNA signature has prognostic value for anaplastic glioma. Moreover, clinicians should conduct corresponding therapies to achieve best treatment with less side effects for two groups patients. PMID- 27764784 TI - DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer. AB - This work investigated the role of paired box 2 (PAX2) in endometrial cancer and its epigenetic regulation mechanism. Endometrial cancer tissues and cell lines exhibited increased PAX2 expression compared with hyperplasia, normal endometrium and endometrial epithelial cells. Knock-down of PAX2 resulted in reduced cell viability, invasion and migration, and PAX2 overexpression caused the opposite effects. Increased methylation of the PAX2 promoter was observed in both cancer tissues and cell lines and was positively correlated with PAX2 expression. After 5-Aza-CdR treatment, PAX2 mRNA and protein were down-regulated, and PAX2 methylation was decreased. Deletion analysis confirmed that a repressive transcriptional regulatory region of the PAX2 promoter coincided with the hypermethylated region identified in MassARRAY analysis. Binding sites of myeloid zinc finger 1 (MZF1) are predicted in the defined region. Knock-down of MZF1 up regulated the transcriptional activity and protein level of PAX2 after 5-Aza-CdR treatment, which indicated that MZF1 may act as a repressive transcription factor when the PAX2 promoter is unmethylated. In conclusion, PAX2 is involved in the carcinogenesis of endometrial cancer by stimulating cell growth and promoting cell motility. The overexpression of PAX2 in endometrial cancer is regulated by promoter hypermethylation and the transcription factor MZF1. PMID- 27764785 TI - Overexpression of ZNF703 facilitates tumorigenesis and predicts unfavorable prognosis in patients with cholangiocarcinoma. AB - BACKGROUND: NET (NocA/Nlz, Elbow, Tlp-1) family members have recently emerged as important players in the development of human cancers. Zinc finger protein 703 (ZNF703), locating on chromosome 8 (8p11.23), a member of the NET/Nlz family of zinc finger transcription factors, had been demonstrated to be a much novel oncogene of several malignancies. This study aimed to investigate the expression of ZNF703 in cholangiocarcinoma (CCA) and attempted to elucidate its biological effects in CCA progression. METHODS: The correlation between ZNF703 expression and clinicopathological characteristics of CCA was evaluated through analyzing 85 cases. The biological effects of ZNF703 were investigated both in vitro and in vivo in which proliferation, migration, and invasive potential were mainly explored. Statistical software SPSS 16.0 was used for statistical analyses. RESULTS: ZNF703 was overexpressed in CCA tissues with subcellular localizations mainly in the nucleus and partly in the cytoplasm or membrane. High expression of ZNF703 was related to tumor location (P=0.002), pathological grading (P=0.024), depth of invasion (P=0.002), distant metastasis (P=0. 011) and AJCC stage (P=0.008). Both in vitro and in vivo studies demonstrated that ZNF703 could potently promote proliferation, migration and invasion throughout the progression of CCA. CONCLUSION: ZNF703 can potently facilitate tumor growth and metastasis in many respects throughout the progression of CCA, which may act as an oncogene in CCA and can be considered as a novel potential therapeutic target. PMID- 27764783 TI - The role of transcriptional coactivator TAZ in gliomas. AB - The transcriptional coactivator with PDZ-binding motif (TAZ) is one of the important downstream effectors of Hippo pathway. In this study, the potential implication of TAZ in gliomagenesis was explored. TAZ expression was identified to be upregulated in glioma specimens and positively correlated with tumor grade. Meanwhile, its expression in nucleus was increased more significantly with the ascending order of tumor grade. Knocking down TAZ inhibited glioma cell proliferation, invasion and promoted apoptosis. Conversely, enforced upregulation of TAZ promoted proliferation, invasion of glioma cells, and suppressed apoptosis in vitro. When orthotopic glioblastoma mouse model implanted with TAZ knocked down cells, glioma growth was inhibited and survival period was prolonged. Expression of Ki67, MMP-9, Cyclin D1, Bcl-2 and C-myc was varied in accordance with the level of TAZ in glioma cell. The biomarkers of EMT (epithelial mesenchymal transition), vimentin and N-cadherin, were downregulated when TAZ was suppressed. Using Co-immunoprecipitation TAZ was identified to bind to TEAD4. Therefore, our findings indicate that TAZ is overexpressed in glioma and translocated more into nucleus in high grade glioma. TAZ is involved in gliomagenesis by promoting glioma growth and may benefit to EMT progression. This result suggests that TAZ serves as a potential target for the treatment of glioma. PMID- 27764786 TI - Assessment of combined expression of B7-H3 and B7-H4 as prognostic marker in esophageal cancer patients. AB - The co-stimulatory ligands of B7-family have been confirmed to play an important role in negatively regulating the T-cell mediated anti-tumor immunity. In addition, these inhibitory molecules are also aberrantly expressed on various human cancers tissues, and significantly associated with cancer progression and patients' poor prognoses. We have previously reported that B7-H3 and B7-H4 ligands are highly expressed in human esophageal cancer tissues. Herein, we tried to further analyze the value of their combined expression on prognostic prediction for esophageal cancer patients. We found that the combined expression of both B7-H3 and B7-H4 could be used as a valuable risk factor for predicting the prognosis of esophageal cancer patients (P=0.003). Moreover the status of these patients with high expression of both B7-H3 and B7-H4, was positively and significantly associated with the tumor invasion depth (P=0.0414) and TNM stage (P=0.0414). The Cox multivariate proportional hazards regression analysis revealed that the tumor size (P=0.007), the TNM stage (P=0.024) and the status of both B7-H3 and B7-H4 high expression (P=0.011), could be used as an independent risk factor for predicting patients' postoperative prognosis, respectively. In conclusion, our data indicated that the combined application of B7-H3 and B7-H4 expression can be effectively used as a prognostic marker in esophageal cancer patients. PMID- 27764787 TI - PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omics approach. AB - Melanoma is the most aggressive skin-cancer, showing high mortality at advanced stages. Platelet Derived Growth Factor Receptor-alpha (PDGFR-alpha) potently inhibits melanoma- and endothelium-proliferation and its expression is significantly reduced in melanoma-biopsies, suggesting that melanoma progression eliminates cells expressing PDGFR-alpha. In the present study transient overexpression of PDGFR-alpha in endothelial (HUVEC) and melanoma (SKMel-28, A375, Preyer) human-cells shows strong anti-proliferative effects, with profound transcriptome and miRNome deregulation. PDGFR-alpha overexpression strongly affects expression of 82 genes in HUVEC (41 up-, 41 down-regulated), and 52 genes in SKMel-28 (43 up-, 9 down-regulated). CXCL10/IP-10 transcript showed up to 20 fold-increase, with similar changes detectable at the protein level. miRNA expression profiling in cells overexpressing PDGFR-alpha identified 14 miRNAs up- and 40 down-regulated, with miR-503 being the most down-regulated (6.4 fold reduction). miR-503, miR-630 and miR-424 deregulation was confirmed by qRT-PCR. Interestingly, the most upregulated transcript (i.e., CXCL10/IP-10) was a validated miR-503 target and CXCL10/IP-10 neutralization significantly reverted the anti-proliferative action of PDGFR-alpha, and PDGFR-alpha inhibition by Dasatinb totally reverted the CXCL10/IP10 induction, further supporting a functional interplay of these factors. Finally, integration of transcriptomics and miRNomics data highlighted several pathways affected by PDGFR-alpha.This study demonstrates for the first time that PDGFR-alpha strongly inhibits endothelial and melanoma cells proliferation in a CXCL10/IP-10 dependent way, via miR-503 down-regulation. PMID- 27764788 TI - Proximal and distal regulation of the HYAL1 gene cluster by the estrogen receptor alpha in breast cancer cells. AB - Chromosomal and genome abnormalities at the 3p21.3 locus are frequent events linked to epithelial cancers, including ovarian and breast cancers. Genes encoded in the 3p21.3 cluster include HYAL1, HYAL2 and HYAL3 members of hyaluronidases involved in the breakdown of hyaluronan, an abundant component of the vertebrate extracellular matrix. However, the transcriptional regulation of HYAL genes is poorly defined. Here, we identified the estrogen receptor ERalpha as a negative regulator of HYAL1 expression in breast cancer cells. Integrative data mining using METABRIC dataset revealed a significant inverse correlation between ERalpha and HYAL1 gene expression in human breast tumors. ChIP-Seq analysis identified several ERalpha binding sites within the 3p21.3 locus, supporting the role of estrogen as an upstream signal that diversely regulates the expression of 3p21.3 genes at both proximal and distal locations. Of these, HYAL1 was repressed by estrogen through ERalpha binding to a consensus estrogen response element (ERE) located in the proximal promoter of HYAL1 and flanked by an Sp1 binding site, required to achieve optimal estrogen repression. The repressive chromatin mark H3K27me3 was increased at the proximal HYAL1 ERE but not at other EREs contained in the cluster, providing a mechanism to selectively downregulate HYAL1. The HYAL1 repression was also specific to ERalpha and not to ERbeta, whose expression did not correlate with HYAL1 in human breast tumors. This study identifies HYAL1 as an ERalpha target gene and provides a functional framework for the direct effect of estrogen on 3p21.3 genes in breast cancer cells. PMID- 27764789 TI - Proteomic analysis reveals diverse proline hydroxylation-mediated oxygen-sensing cellular pathways in cancer cells. AB - Proline hydroxylation is a critical cellular mechanism regulating oxygen-response pathways in tumor initiation and progression. Yet, its substrate diversity and functions remain largely unknown. Here, we report a system-wide analysis to characterize proline hydroxylation substrates in cancer cells using an immunoaffinity-purification assisted proteomics strategy. We identified 562 sites from 272 proteins in HeLa cells. Bioinformatic analysis revealed that proline hydroxylation substrates are significantly enriched with mRNA processing and stress-response cellular pathways with canonical and diverse flanking sequence motifs. Structural analysis indicates a significant enrichment of proline hydroxylation participating in the secondary structure of substrate proteins. Our study identified and validated Brd4, a key transcription factor, as a novel proline hydroxylation substrate. Functional analysis showed that the inhibition of proline hydroxylation pathway significantly reduced the proline hydroxylation abundance on Brd4 and affected Brd4-mediated transcriptional activity as well as cell proliferation in AML leukemia cells. Taken together, our study identified a broad regulatory role of proline hydroxylation in cellular oxygen-sensing pathways and revealed potentially new targets that dynamically respond to hypoxia microenvironment in tumor cells. PMID- 27764790 TI - Is ovarian cancer a targetable disease? A systematic review and meta-analysis and genomic data investigation. AB - OBJECTIVES: The current gold-standard for the first-line treatment in IIIb/IV stages of epithelial ovarian cancer (EOC) is the combination of carboplatin and paclitaxel plus bevacizumab in some countries. In the era of personalized medicine, there is still uncertainty on the impact of several molecularly targeted agents, which have been investigated for the management of this disease. To shed light on the actual role of targeted therapy in EOC, a systematic review and meta-analysis was performed. METHODS: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings within the time-frame of January 2004-June 2015. The endpoints were survival outcome and response rate (RR). Hazard ratios (HRs) of survival outcomes, with confidence intervals and odds-ratios (ORs) of RR, were extracted from retrieved studies and used for current analysis. Meta-analysis was carried out by random effect model. RESULTS: 30 randomized trials for a total of 10,530 patients were selected and included in the final analysis. A benefit in terms of OS (pooled HR 0.915; 95%CI 0.840-0.997; p=0.043), particularly for anti-angiogenetic agents (HR 0.872; 95%CI 0.761-1.000; p=0.049), has been demonstrated for targeted therapy. Moreover, a significant advantage in platinum-resistant subgroup in term of PFS (HR 0.755; 95%CI 0.624-0.912; p=0.004) was found. CONCLUSIONS: This systematic review and meta-analysis provide the first evidence that targeted therapy is potentially able to translate into improved survival of EOC patients, with a major role played by anti-angiogenetic drugs. The role of target therapy is underlined in the platinum-resistant setting that represents the "pain in the neck" in EOC management. PMID- 27764792 TI - AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer. AB - The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer. PMID- 27764793 TI - DcR3 induces epithelial-mesenchymal transition through activation of the TGF beta3/SMAD signaling pathway in CRC. AB - Decoy receptor 3 (DcR3), a novel member of the tumor necrosis factor receptor (TNFR) family, was recently reported to be associated with tumorigenesis and metastasis. However, the role of DcR3 in human colorectal cancer (CRC) has not been fully elucidated. In this study, we found that DcR3 expression was significantly higher in human colorectal cancer tissues than in paired normal tissues, and that DcR3 expression was strongly correlated with tumor invasion, lymph node metastases and poor prognoses. Moreover, DcR3 overexpression significantly enhanced CRC cell proliferation and migration in vitro and tumorigenesis in vivo. Conversely, DcR3 knockdown significantly repressed CRC cell proliferation and migration in vitro, and DcR3 deficiency also attenuated CRC tumorigenesis and metastasis in vivo. Functionally, DcR3 was essential for TGF-beta3/SMAD-mediated epithelial-mesenchymal transition (EMT) of CRC cells. Importantly, cooperation between DcR3 and TGF-beta3/SMAD-EMT signaling-related protein expression was correlated with survival and survival time in CRC patients. In conclusion, our results demonstrate that DcR3 may be a prognostic biomarker for CRC and that this receptor facilitates CRC development and metastasis by participating in TGF-beta3/SMAD-mediated EMT of CRC cells. PMID- 27764791 TI - Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma. AB - Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common childhood extracranial malignant tumor. In NB, somatic mutations of the tumor suppressor, p53, are exceedingly rare. Unlike in adult tumors, the majority of p53 downstream functions are still intact in NB cells with wild-type p53. Thus, restoring p53 function by blocking its interaction with p53 suppressors such as MDM2 is a viable therapeutic strategy for NB treatment. Herein, we show that MDM2 inhibitor SAR405838 is a potent therapeutic drug for NB. SAR405838 caused significantly decreased cell viability of p53 wild-type NB cells and induced p53-mediated apoptosis, as well as augmenting the cytotoxic effects of doxorubicin (Dox). In an in vivo orthotopic NB mouse model, SAR405838 induced apoptosis in NB tumor cells. In summary, our data strongly suggest that MDM2-specific inhibitors like SAR405838 may serve not only as a stand-alone therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact MDM2-p53 axis. PMID- 27764795 TI - A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications. AB - Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM. PMID- 27764794 TI - The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs. AB - BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2. Treatment with JQ1 blocked the recruitment of Nrf2 to the antioxidant responsive elements at Nrf2 target gene promoters, and JQ1 exerted synergistic anticancer effects with nanaomycin by blocking the Nrf2 antioxidant signaling pathway. JQ1 and vincristine synergistically induced neuroblastoma cell cycle arrest at the G2/M phase, aberrant mitotic spindle assembly formation and apoptosis, but showed no effect on cell survival in normal non-malignant cells. Importantly, co-treatment with JQ1 and vincristine synergistically suppressed tumor progression in neuroblastoma-bearing mice. These results strongly suggest that patients treated with BET bromodomain inhibitors in clinical trials should be co-treated with vincristine. PMID- 27764798 TI - Safety and efficacy of vismodegib in patients aged >=65 years with advanced basal cell carcinoma. AB - Because many patients with unresectable basal cell carcinoma (BCC) are aged >=65 years, this study explores the efficacy and safety of vismodegib in these patients with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC) in the ERIVANCE BCC trial and the expanded access study (EAS).We compared patients aged >=65 years to patients aged <65 years taking vismodegib 150 mg/day, using descriptive statistics for response and safety. Patients aged >=65 years (laBCC/mBCC) were enrolled in ERIVANCE BCC (33/14) and EAS (27/26). Investigator assessed best overall response rate in patients >=65 and <65 years was 46.7%/35.7% and 72.7%/52.6% (laBCC/mBCC), respectively, in ERIVANCE BCC and 45.8%/33.3% and 46.9%/28.6%, respectively, in EAS. These differences were not clinically meaningful. Safety was similar in both groups, although those aged >=65 years had a higher percentage of grade 3-5 adverse events than those aged <65 years. Vismodegib demonstrated similar clinical activity and adverse events regardless of age. PMID- 27764799 TI - Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model. AB - We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2. Pharmacokinetics, tumor response, toxicities were evaluated. Preclinical result revealed the more potent cytotoxic effect of PNP DTX than docetaxel (DTX). However, there was no difference between PNP-DTX and DTX in subcutaneous model. Tubulin polymerization assay showed that PNP-DTX preserved original mode of action of DTX. For phase I clinical trial, 18 patients were analyzed. The dose of 75 mg/m2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The Cmax of 60 mg/m2 PNP-DTX and AUClast of 45 mg/m2 PNP-DTX were measured to be comparable to those of 75 mg/m2 DTX. Partial remission (PR) was achieved in 4 (22%) patients. The potency of PNP-DTX was revealed especially in orthotopic mouse model. The MTD of PNP-DTX could not be confirmed, but 75 mg/m2 was tentatively determined. The PNP-DTX of 45 mg/m2 had the same pharmacokinetic profile with that of 75 mg/m2 DTX. PMID- 27764796 TI - Pharmacological interventions for melanoma: Comparative analysis using bayesian meta-analysis. AB - We conducted a network meta-analysis in order to compare different strategies for managing melanoma patients. Electronic databases were searched for eligible randomized trials that compared different strategies in efficacy and tolerability. Five interventions were associated with a significant improvement in PFS over chemotherapy (all HR < 1): Ipilimumab, Tremelimumab, Nivolumab, Pembrolizumab 2 mg/kg and Ipilimumab + Nivolumab. Three interventions exhibited significantly improved OS results over chemotherapy (all HR < 1): Ipilimumab, Nivolumab and Ipilimumab + Chemotherapy. Four interventions were superior to chemotherapy in CR and PR (all OR > 1): Nivolumab, Pembrolizumab 10 mg/kg, Pembrolizumab 2 mg/kg and Ipilimumab + Nivolumab. However, the other seven interventions were associated with an increased risk of pruritus compared to chemotherapy (all OR > 1). Ipilimumab, Tremelimumab, Ipilimumab + Nivolumab and Ipilimumab + Chemotherapy might result in a higher risk of diarrhea compared to chemotherapy (all OR > 1). Immune checkpoint therapy or combined interventions might be more effective than chemotherapy for managing melanoma patients. However, chemotherapy appears to be more tolerable than these combined strategies with respect to adverse events. PMID- 27764800 TI - GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients. AB - Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46*10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16*10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors. PMID- 27764801 TI - FOXM1 and STAT3 interaction confers radioresistance in glioblastoma cells. AB - Glioblastoma multiforme (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. Adjuvant chemo-radiotherapy remains the standard of care following surgical resection. In this study, using reverse phase protein arrays (RPPAs), we assessed the biological effects of radiation on signaling pathways to identify potential radiosensitizing molecular targets. We identified subsets of proteins with clearly concordant/discordant behavior between irradiated and non-irradiated GBM cells in vitro and in vivo. Moreover, we observed high expression of Forkhead box protein M1 (FOXM1) in irradiated GBM cells both in vitro and in vivo. Recent evidence of FOXM1 as a master regulator of metastasis and its important role in maintaining neural, progenitor, and GBM stem cells, intrigued us to validate it as a radiosensitizing target. Here we show that FOXM1 inhibition radiosensitizes GBM cells by abrogating genes associated with cell cycle progression and DNA repair, suggesting its role in cellular response to radiation. Further, we demonstrate that radiation induced stimulation of FOXM1 expression is dependent on STAT3 activation. Co immunoprecipitation and co-localization assays revealed physical interaction of FOXM1 with phosphorylated STAT3 under radiation treatment. In conclusion, we hypothesize that FOXM1 regulates radioresistance via STAT3 in GBM cells. We also, show GBM patients with high FOXM1 expression have poor prognosis. Collectively our observations might open novel opportunities for targeting FOXM1 for effective GBM therapy. PMID- 27764802 TI - MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells. AB - We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification. ASCL1, a transcription factor shown to play a role in SCLC, was also expressed in 11/14 cell lines. All SCLC cell lines were sensitive to JQ1 with GI50 values <=1.23 MUM, with six of them showing GI50 values <0.1 MUM. Expression of MYCL as well as MYCN, ASCL1 and other driver oncogenes including CDK6 was reduced by JQ1 treatment, in particular in the cell lines with high expression of the respective genes; however, no association was observed between the sensitivity to JQ1 and the levels of MYCL, MYCN and ASCL1 expression. In contrast, levels of CDK6 expression and its reduction rates by JQ1 were associated with JQ1 sensitivity. Therefore, we concluded that CDK6 is a novel target of JQ1 and predictive marker for JQ1 sensitivity in SCLC cells. PMID- 27764803 TI - CD133+CD54+CD44+ circulating tumor cells as a biomarker of treatment selection and liver metastasis in patients with colorectal cancer. AB - INTRODUCTION: Liver is the most common site of distant metastasis in colorectal cancer (CRC). Early diagnosis and appropriate treatment selection decides overall prognosis of patients. However, current diagnostic measures were basically imaging but not functional. Circulating tumor cells (CTCs) known as hold the key to understand the biology of metastatic mechanism provide a novel and auxiliary diagnostic strategy for CRC with liver metastasis (CRC-LM). RESULTS: The expression of CD133+ and CD133+CD54+CD44+ cellular subpopulations were higher in the peripheral blood of CRC-LM patients when compared with those without metastasis (P<0.001). Multivariate analysis proved the association between the expression of CD133+CD44+CD54+ cellular subpopulation and the existence of CRC-LM (P<0.001). The combination of abdominal CT/MRI, CEA and the CD133+CD44+CD54+ cellular subpopulation showed increased detection and discrimination rate for liver metastasis, with a sensitivity of 88.2% and a specificity of 92.4%. Meanwhile, it also show accurate predictive value for liver metastasis (OR=2.898, 95% C.I.1.374-6.110). MATERIALS AND METHODS: Flow cytometry and multivariate analysis was performed to detect the expression of cancer initiating cells the correlation between cellular subpopulations and liver metastasis in patients with CRC. The receiver operating characteristic curves combined with the area under the curve were generated to compare the predictive ability of the cellular subpopulation for liver metastasis with current CT and MRI images. CONCLUSIONS: The identification, expression and application of CTC subpopulations will provide an ideal cellular predictive marker for CRC liver metastasis and a potential marker for further investigation. PMID- 27764804 TI - A combined gene expression and functional study reveals the crosstalk between N Myc and differentiation-inducing microRNAs in neuroblastoma cells. AB - MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical role in neuroblastoma tumorigenesis. MYCN regulates neuroblastoma cell differentiation, which is one of the mechanisms underlying its oncogenic function. We recently identified a group of differentiation-inducing microRNAs. Given the demonstrated inter-regulation between MYCN and microRNAs, we speculated that MYCN and the differentiation-inducing microRNAs might form an interaction network to control the differentiation of neuroblastoma cells. In this study, we found that eight of the thirteen differentiation-inducing microRNAs, miR-506-3p, miR-124-3p, miR-449a, miR-34a-5p, miR-449b-5p, miR-103a 3p, miR-2110 and miR-34b-5p, inhibit N-Myc expression by either directly targeting the MYCN 3'UTR or through indirect regulations. Further investigation showed that both MYCN-dependent and MYCN-independent pathways play roles in mediating the differentiation-inducing function of miR-506-3p and miR-449a, two microRNAs that dramatically down-regulate MYCN expression. On the other hand, we found that N-Myc inhibits the expression of multiple differentiation-inducing microRNAs, suggesting that these miRNAs play a role in mediating the function of MYCN. In examining the published dataset collected from clinical neuroblastoma specimens, we found that expressions of two miRNAs, miR-137 and miR-2110, were significantly anti-correlated with MYCN mRNA levels, suggesting their interactions with MYCN play a clinically-relevant role in maintaining the MYCN and miRNA expression levels in neuroblastoma. Our findings altogether suggest that MYCN and differentiation-inducing miRNAs form an interaction network that play an important role in neuroblastoma tumorigenesis through regulating cell differentiation. PMID- 27764805 TI - Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. AB - BACKGROUND: An anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice. METHODS: We retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks. RESULTS: As for pretreatment prognostic factors, ECOG performance status (PS) >=1, maximum tumor diameters of >=30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) >= 1000/MUl (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/MUl (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS. CONCLUSION: ALC>=1000/MUl and ANC<4000/MUl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden. PMID- 27764806 TI - Resistance to neoplastic transformation of ex-vivo expanded human mesenchymal stromal cells after exposure to supramaximal physical and chemical stress. AB - The risk of malignant transformation of ex-vivo expanded human mesenchymal stromal cells (huMSCs) has been debated in the last years; however, the biosafety of these cells after exposure to supramaximal physical and chemical stress has never been systematically investigated.We established an experimental in vitro model to induce supramaximal physical (ionizing radiation, IR) and chemical (starvation) stress on ex-vivo expanded bone marrow (BM)-derived huMSCs and investigated their propensity to undergo malignant transformation. To this aim, we examined MSC morphology, proliferative capacity, immune-phenotype, differentiation potential, immunomodulatory properties and genetic profile before and after stressor exposure. Furthermore, we investigated the cellular mechanisms underlying MSC response to stress. MSCs were isolated from 20 healthy BM donors and expanded in culture medium supplemented with 5% platelet lysate (PL) up to passage 2 (P2). At this stage, MSCs were exposed first to escalating doses of IR (30, 100, 200 Gy) and then to starvation culture conditions (1% PL).With escalating doses of radiation, MSCs lost their typical spindle-shaped morphology, their growth rate markedly decreased and eventually stopped (at P4-P6) by reaching early senescence. Irradiated and starved MSCs maintained their typical immune-phenotype, ability to differentiate into adipocytes/osteoblasts and to inhibit mitogen-induced T-cell proliferation. The study of the genetic profile of irradiated/starved MSCs did not show any alteration. While the induction of supramaximal stress triggered production of ROS and activation of DNA damage response pathway via multiple mechanisms, our data indicate that irradiated/starved MSCs, although presenting altered morphology/growth rate, do not display increased propensity for malignant transformation. PMID- 27764807 TI - c-Myc suppresses miR-451?YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia. AB - Aberrant activation of c-Myc plays an important oncogenic role via regulating a series of coding and non-coding genes in acute myeloid leukemia (AML). Histone deacetylases (HDACs) can remove acetyl group from histone and regulate gene expression via changing chromatin structure. Here, we found miR-451 is abnormally down-regulated in AML patient samples; c-Myc recruits HDAC3 to form a transcriptional suppressor complex, co-localizes on the miR-451 promoter, epigenetically inhibits its transcription and finally induces its downregulation in AML. Furthermore, our in vitro and in vivo results suggest that miR-451 functions as a tumor suppressor via promoting apoptosis and suppressing malignant cell proliferation. The mechanistic study demonstrated that miR-451 directly targets YWHAZ mRNA and suppresses YWHAZ/AKT signaling in AML. Knockdown of c-Myc results in restoration of miR-451 and inhibition of YWHAZ/AKT signaling. In AML patients, low level of miR-451 is negatively correlated with high levels of c-Myc and YWHAZ, while c-Myc level is positively related to YWHAZ expression. These results suggested that c-Myc?miR-451?YWHAZ/AKT cascade might play a crucial role during leukemogenesis, and reintroduction of miR-451 could be as a potential strategy for AML therapy. PMID- 27764808 TI - The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma. AB - Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (-87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets ( PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis. PMID- 27764809 TI - Mitochondrial Lon is over-expressed in high-grade gliomas, and mediates hypoxic adaptation: potential role of Lon as a therapeutic target in glioma. AB - Mitochondrial dysfunction is a hallmark of cancer biology. Tumor mitochondrial metabolism is characterized by an abnormal ability to function in scarce oxygen conditions through glycolysis (the Warburg effect), and accumulation of mitochondrial DNA defects are present in both hereditary neoplasia and sporadic cancers. Mitochondrial Lon is a major regulator of mitochondrial metabolism and the mitochondrial response to free radical damage, and plays an essential role in the maintenance and repair of mitochondrial DNA. Despite these critical cellular functions of Lon, very little has been reported regarding its role in glioma. Lon expression in gliomas and its relevance with patient survival was examined using published databases and human tissue sections. The effect of Lon in glioma biology was investigated through siRNA targeting Lon. We also tested the in vitro antitumor activity of Lon inhibitor, CC4, in the glioma cell lines D-54 and U 251. High Lon expression was associated with high glioma tumor grade and poor patient survival. While Lon expression was elevated in response to a variety of stimuli, Lon knockdown in glioma cell lines decreased cell viability under normal conditions, and dramatically impaired glioma cell survival under hypoxic conditions. Furthermore, the Lon inhibitor, CC4, efficiently prohibited glioma cell proliferation and synergistically enhanced the therapeutic efficacy of the chemotherapeutic agents, temozolomide (TMZ) and cisplatin. We demonstrate that Lon plays a key role in glioma cell hypoxic survival and mitochondrial respiration, and propose Lon as a promising therapeutic target in the treatment of malignant gliomas. PMID- 27764810 TI - Epithelial-to-mesenchymal transition leads to disease-stage differences in circulating tumor cell detection and metastasis in pre-clinical models of prostate cancer. AB - Metastasis is the cause of most prostate cancer (PCa) deaths and has been associated with circulating tumor cells (CTCs). The presence of >=5 CTCs/7.5mL of blood is a poor prognosis indicator in metastatic PCa when assessed by the CellSearch(r) system, the "gold standard" clinical platform. However, ~35% of metastatic PCa patients assessed by CellSearch(r) have undetectable CTCs. We hypothesize that this is due to epithelial-to-mesenchymal transition (EMT) and subsequent loss of necessary CTC detection markers, with important implications for PCa metastasis. Two pre-clinical assays were developed to assess human CTCs in xenograft models; one comparable to CellSearch(r) (EpCAM-based) and one detecting CTCs semi-independent of EMT status via combined staining with EpCAM/HLA (human leukocyte antigen). In vivo differences in CTC generation, kinetics, metastasis and EMT status were determined using 4 PCa models with progressive epithelial (LNCaP, LNCaP-C42B) to mesenchymal (PC-3, PC-3M) phenotypes. Assay validation demonstrated that the CellSearch(r)-based assay failed to detect a significant number (~40-50%) of mesenchymal CTCs. In vivo, PCa with an increasingly mesenchymal phenotype shed greater numbers of CTCs more quickly and with greater metastatic capacity than PCa with an epithelial phenotype. Notably, the CellSearch(r)-based assay captured the majority of CTCs shed during early-stage disease in vivo, and only after establishment of metastases were a significant number of undetectable CTCs present. This study provides important insight into the influence of EMT on CTC generation and subsequent metastasis, and highlights that novel technologies aimed at capturing mesenchymal CTCs may only be useful in the setting of advanced metastatic disease. PMID- 27764812 TI - MicroRNA-7 inhibits cell proliferation, migration and invasion in human non-small cell lung cancer cells by targeting FAK through ERK/MAPK signaling pathway. AB - OBJECTIVE: To investigate the effects of microRNA-7 (miR-7) on the proliferation, migration and invasion of non-small cell lung cancer NSCLC) cells by targeting FAK through ERK/MAPK signaling pathway. METHODS: NSCLC tissues and adjacent normal tissues were obtained from 160 NSCLC patients after operation. NSCLC cell lines (A549, H1299 and H1355) and a normal human fetal lung fibroblast cell line (MRC-5) were obtained. NSCLC cells were assigned into miR-7 inhibitors, miR-7 mimics, blank, miR-7 mimics control, miR-7 inhibitors control, FAK siRNA and miR 7 inhibitors + FAK siRNA groups. The expressions of miR-7 and FAK mRNA in tissues and cell lines were detected by qRT-PCR and Western-Blotting. Cell proliferation, migration and invasion were detected by MTT assay, wound scratch assay and Transwell assay. RESULTS: Compared with adjacent normal tissues, miR-7 expression was down-regulated, but the mRNA and protein expressions of FAK, ERK and MAPK were up-regulated. Compared with the blank and mimics control groups, miR-7 significantly increased but FAK, ERK and MAPK expressions decreased in miR-7 mimics and FAK siRNA groups. Cell proliferation, migration and invasion were inhibited in the miR-7 mimics and FAK siRNA groups, while opposite regarding miR 7 inhibitors group. CONCLUSION: The miR-7 can inhibit the activation of ERK/MAPK signaling pathway by down-regulating FAK expression, thereby suppressing the proliferation, migration and invasion of NSCLC cells. The miR-7 and its target gene FAK may be novel targets for the diagnosis and treatment of NSCLC. PMID- 27764811 TI - Altered RECQL5 expression in urothelial bladder carcinoma increases cellular proliferation and makes RECQL5 helicase activity a novel target for chemotherapy. AB - RECQ helicases are a family of enzymes with both over lapping and unique functions. Functional autosomal recessive loss of three members of the family BLM, WRN and RECQL4, results in hereditary human syndromes characterized by cancer predisposition and premature aging, but despite the finding that RECQL5 deficient mice are cancer prone, no such link has been made to human RECQL5. Here we demonstrate that human urothelial carcinoma of the bladder (UCC) has increased expression of RECQL5 compared to normal bladder tissue and that increasing RECQL5 expression can drive proliferation of normal bladder cells and is associated with poor prognosis. Further, by expressing a helicase dead RECQL5 and by depleting bladder cancer cells of RECQL5 we show that inhibition of RECQL5 activity has potential as a new target for treatment of UCC. PMID- 27764813 TI - Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation. AB - In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3betaHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC. PMID- 27764814 TI - Downregulation of osteoprotegerin expression in metastatic colorectal carcinoma predicts recurrent metastasis and poor prognosis. AB - We recently reported the downregulation of osteoprotegerin expression in primary colorectal carcinoma and its significant association with aggressive oncogenic behavior, which suggest that this process contributes to colorectal carcinoma development and progression. In this study, we used immunohistochemical staining to evaluate osteoprotegerin expression in 81 colorectal liver metastasis tissue samples and investigated its possible association with the clinicopathological characteristics and outcomes of patients with colorectal liver metastasis. These tissues exhibited significantly reduced expression of osteoprotegerin compared to primary colorectal carcinomas and normal colorectal mucosa. This reduced expression was significantly associated with the extent of colorectal liver metastasis, including multiplicity of metastatic tumors, involvement of the bilateral hepatic lobes, and higher histological grade. In addition, reduced osteoprotegerin expression was an independent significant predictor of recurrent liver metastasis and prognostic factor for reduced patient survival. These findings suggest that osteoprotegerin expression may be a novel predictor of recurrent liver metastasis and a prognostic biomarker in patients with colorectal liver metastasis. Patients harboring colorectal liver metastasis with reduced osteoprotegerin expression should be carefully monitored after hepatic resection for colorectal liver metastasis to enable early detection of potentially resectable metastatic recurrences. PMID- 27764815 TI - Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity. AB - NEK2 is a conserved mitotic regulator critical for cell cycle progression. Aberrant expression of NEK2 has been found in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. In the present study, we have identified a novel compound MBM-5, which was found to bind to NEK2 with high affinity by docking simulations study. MBM-5 potently inhibited NEK2 kinase activity in vitro in a concentration dependent manner. MBM-5 also suppressed cellular NEK2 kinase activity, as evidenced by the decreased phosphorylation of its substrate Hec1 on S165 in a concentration- and time-dependent manner. This inhibition impeded mitotic progression by inducing chromosome segregation defects and cytokinesis failure; therefore leading to accumulation of cells with >=4N DNA content, which finally underwent apoptosis. More importantly, MBM-5 treatment effectively suppressed the tumor growth of human gastric and colorectal cancer cells xenografts. Taken together, we demonstrated that MBM-5 effectively inhibited the kinase activity of NEK2 and showed a potential application in anti-cancer treatment regimens. PMID- 27764816 TI - DNMT3B in vitro knocking-down is able to reverse embryonal rhabdomyosarcoma cell phenotype through inhibition of proliferation and induction of myogenic differentiation. AB - Aberrant DNA methylation has been frequently observed in many human cancers, including rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children. To date, the expression and function of the de novo DNA methyltransferase (DNMT) 3B in RMS have not yet been investigated. Our study show for the first time a significant up-regulation of DNMT3B levels in 14 RMS tumour samples and 4 RMS cell lines in comparison to normal skeletal muscle. Transfection of RD and TE671 cells, two in vitro models of embryonal RMS (ERMS), with a synthetic DNMT3B siRNA decreased cell proliferation by arresting cell cycle at G1 phase, as demonstrated by the reduced expression of Cyclin B1, Cyclin D1 and Cyclin E2, and by the concomitant up-regulation of the checkpoint regulators p21 and p27. DNMT3B depletion also impaired RB phosphorylation status and decreased migratory capacity and clonogenic potential. Interestingly, DNMT3B knock-down was able to commit ERMS cells towards myogenic terminal differentiation, as confirmed by the acquisition of a myogenic-like phenotype and by the increased expression of the myogenic markers MYOD1, Myogenin and MyHC. Finally, inhibition of MEK/ERK signalling by U0126 resulted in a reduction of DNMT3B protein, giving evidence that DNMT3B is a down-stream molecule of this oncogenic pathway.Taken together, our data indicate that altered expression of DNMT3B plays a key role in ERMS development since its silencing is able to reverse cell cancer phenotype by rescuing myogenic program. Epigenetic therapy, by targeting the DNA methylation machinery, may represent a novel therapeutic strategy against RMS. PMID- 27764817 TI - Intravoxel incoherent motion (IVIM) in diffusion-weighted imaging (DWI) for Hepatocellular carcinoma: correlation with histologic grade. AB - PURPOSE: To assess the correlation between DWI diffusion parameters obtained using Intravoxel Incoherent Motion Method (IVIM) and histological grade of Hepatocellular carcinoma (HCC). RESULTS: According to Edmondson-Steiner grade lesions were classified with grade 1 (14), grade 2 (30), grade 3 (18), and grade 4 (0). Apparent Diffusion Coefficient (ADC), perfusion fraction (fp), tissue diffusion coefficient (Dt) median values were statistically different in HCC groups with 1, 2, 3 histological grade (p<0.001). A significant correlation was reported between ADC, fp, Dt and histologic grade respectively of 0.687, 0.737 and 0.674. Receiver operating characteristic (ROC) analysis demonstrated that an ADC of 2.11x10-3 mm2/sec, an fp of 47.33% and an Dt of 0.94x10-3 mm2/sec were the optimal cutoff values to differentiate high histological grade (3) versus low histological grade (1-2), with a sensitivity and specificity for ADC of 100% and 100%, for fp of 100% and 89%, for Dt of 100% and 74%, respectively. MATERIALS AND METHODS: A retrospective approved study was performed including 34 patients with 62 HCCs. IVIM was performed to obtain ADC, fp, pseudo-diffusion coefficient (Dp), Dt coefficients. Kruskal Wallis, Spearman Correlation Coefficient, ROC analysis were performed. CONCLUSIONS: ADC and IVIM-derived fp showed significantly better diagnostic performance in differentiating high-grade from low-grade HCC, and significant correlation was observed between ADC, fp, Dt and histological grade. PMID- 27764819 TI - Expression of CK19 is an independent predictor of negative outcome for patients with squamous cell carcinoma of the tongue. AB - OBJECTIVES: To explore the prognostic role of CK19 expression in squamous cell carcinomas within a well-defined cohort of oral tongue cancer patients. METHODS: In our retrospective study, we investigated 129 patients with tongue cancer that had suitable material for inclusion in a tissue microarray (TMA). Where possible, samples were taken from central and peripheral regions of the tumor to generate a representative sample of the tumor. The expression level of CK19 was assessed by immunohistochemical staining. RESULTS: Expression of CK19 in squamous cell carcinoma of the tongue was identified as a negative predictor for overall survival (OS; p<0.000) and disease specific survival (DSS; p=0.001). No significant difference could be shown for disease free survival (DFS) between patients with positive and negative CK19 staining (p=.094). CONCLUSION: This is the first description of the highly significant role of CK19 in a selective, organ specific head and neck cancer cohort. Our results are of special importance against the background that CK19 positive carcinomas revealed a significantly poorer prognosis and therefore emphasize its prognostic and possible diagnostic role in tongue cancer. PMID- 27764818 TI - 14-3-3zeta/TGFbetaR1 promotes tumor metastasis in lung squamous cell carcinoma. AB - 14-3-3zeta is involved in tumor cell growth and apoptosis. However, the mechanism of 14-3-3zeta in lung squamous cell carcinoma (SCC) metastasis has not been illuminated. In our studies, we found that the expression of 14-3-3zeta was highly expressed in lung SCC compared to normal lung tissues. High expression of 14-3-3zeta was associated with pTNM stage (p<0.05) and lymph node metastasis (p<0.05). Furthermore, the expression of 14-3-3zeta protein was associated with high levels of TGFbetaR1 protein (p=0.005), and pSMAD3 (p=0.033). Lung SCC patients with high 14-3-3zeta expression have significantly shorter OS and DFS compared to patients with low 14-3-3zeta expression. Additionally, 14-3-3zeta knockdown inhibited cell proliferation, migratory and invasive properties of human lung SCC cells. TGFbetaR1 was involved in 14-3-3zeta-mediated cell proliferation and metastasis of lung SCC cells. Additionally, sh-14-3-3zeta can suppress tumor growth and metastasis in vivo. Thus, these data provide the evidence that 14-3-3zeta promote tumor metastasis and might be a prognostic biomarker and target for therapeutic strategy in lung SCC. PMID- 27764821 TI - Sesquicentennial Tribute to Emil Redlich (1866-1930), The 'Embodied Conscience of Neurology'. AB - Professor Emil Redlich (1866-1930) of the University of Vienna was born 150 years ago. Raised in a humble environment, he became an eminent researcher and neurology scholar, and succeeded in laying some of the key foundations of neuroanatomy and neuropathology. His name is linked to medical eponyms that define the dorsal root entry zone into the spinal cord, epidemic disseminated encephalomyelitis, narcolepsy, senile plaques and dementia. As its first director, he managed to organize the Maria-Theresien-Schlossel into a first-class neuropsychiatric hospital. The one attribute that his colleagues constantly recognized was his inexorable scientific demeanor, always insisting on a critical checking of the facts before formulating any hypothesis. PMID- 27764820 TI - ON 01910.Na (rigosertib) inhibits PI3K/Akt pathway and activates oxidative stress signals in head and neck cancer cell lines. AB - Squamous cell carcinoma of the head and neck (HNSCC) is characterized by high morbidity and mortality. Treatment failure, drug resistance and chemoradiation toxicity have necessitated the development of alternative treatment strategies. Styryl benzyl sulfones, a family of novel small molecule inhibitors, are being evaluated as anti-neoplastic agents in multiple clinical trials. The activity of these compounds has been well characterized in several preclinical tumor studies, but their activity has yet to be fully examined in HNSCC. We tested ON 01910.Na (rigosertib), a styryl benzyl sulfone in late-stage development, in HNSCC preclinical models. Rigosertib induced cytotoxicity in both HPV(+) and HPV(-) HNSCC cells in a dose-dependent manner. Characterization of the underlying molecular mechanism indicated that rigosertib induced inhibition of the PI3K/Akt/mTOR pathway, induced oxidative stress resulting in increased generation of reactive oxygen species (ROS), and activated extracellular signal-regulated kinases (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Increased phosphorylation and cytoplasmic translocation of ATF-2 were also observed following rigosertib treatment. These changes in cell signaling led us to consider combining rigosertib with HNSCC standard-of-care therapies, such as cisplatin and radiation. Our study highlights the promising preclinical activity of rigosertib in HNSCC irrespective of HPV status and provides a molecular basis for rigosertib in combination with standard of care agents for HNSCC. PMID- 27764822 TI - Discordance between Lifestyle-Related Health Practices and Beliefs of People Living in Kuwait: A Community-Based Study. AB - OBJECTIVE: To examine the concordance between lifestyle practices and beliefs of people living in Kuwait, and between their lifestyle practices and established evidence-informed recommendations for health. SUBJECTS AND METHODS: A cross sectional interview questionnaire study was conducted using a convenience sample of 100 adults living in Kuwait (age range 19-75 years). The interview included sections on demographics, and lifestyle-related practices and beliefs related to smoking, diet/nutrition, physical activity/exercise, sleep, and stress. Diet/nutrition and physical activity/exercise benchmarks were based on international standards. Analyses included descriptive statistics and the chi2 test. RESULTS: Beliefs about the importance of nutrition in lifestyle-related conditions were limited, and this was apparent in participants' dietary habits, e.g., low consumption of fruit/vegetables and multigrains: 16 (16%) and 9 (9%) met the recommended guidelines, respectively. Ninety-nine (99%) believed physical activity/exercise affects health overall, and 44 (44%) exercised regularly. Of the sample of 100, 20 (20%) exercised in accordance with evidence-based recommendations for maximal health. Compared with beliefs about other lifestyle related behaviors/attributes, respondents believed nutrition contributed more than stress to heart disease, cancer, and stroke, and stress contributed more than nutrition to hypertension and diabetes. CONCLUSION: In this study, our findings showed a discrepancy between lifestyle-related practices and beliefs, and between each of these and evidence-based recommendations for maximal health, i.e., not smoking, several servings of fruit and vegetables and whole-grain foods daily, healthy weight, restorative sleep, and low-to-moderate stress levels. PMID- 27764823 TI - Immunological Microenvironment of Hepatocellular Carcinoma and Its Clinical Implication. AB - Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with advanced stage of disease remains unfavorable. Several immune therapies have been applied to HCC, and their responses have not been satisfactory. The immune response to cancer is determined by the balance between the antigenicity of the tumor and the microenvironment of cancer tissues. Generally, accumulated genetic mutations are observed in HCC, which may lead to increased neoantigens on cancer cells with high antigenicity. However, cancer cells may evade the immune system because of alterations in molecules and cellular pathways involved in antigen processing and presentation. In addition, hypoxia in tissue induces several cytokines, chemokines, and immunosuppressive molecules from HCC cells and stromal cells. These cells also produce cytokines that attract regulatory T cells infiltrating tumor tissues and contribute to establishing an immunosuppressive microenvironment. Some cancers show a good response to immune checkpoint therapy. However, prolonged stabilization of disease for this treatment is reportedly 12-41% in patients with advanced cancer. Therefore, immunosuppressive forces in the microenvironment of HCC may cause resistance to immune therapy, and modification of the tumor microenvironment may restore normal anticancer immunity. In this review, we focus on the immunological microenvironment of HCC tissues and discuss how the immunosuppressive environment of HCC should be modulated to achieve a favorable response to immune therapy, such as immune checkpoint therapy, in HCC. PMID- 27764824 TI - Intra- and Inter-Rater Agreement of Anterior Lamina Cribrosa Depth Measurements Using Enhanced-Depth Imaging Optical Coherence Tomography. AB - PURPOSE: To determine intra- and inter-rater agreement of anterior lamina cribrosa depth (ALCD) manual measurements using enhanced-depth imaging optical coherence tomography (EDI-OCT). METHODS: Observational study. EDI-OCT of the optic nerve head was performed in healthy subjects. ALCD was defined as the perpendicular distance between the line connecting both edges of Bruch's membrane opening and the anterior border of the lamina cribrosa (LC), at the maximum depth point. Two experienced operators performed manual ALCD measurements of the LC independently, and one of the observers performed the same measurements twice. Intra- and inter-rater agreement was evaluated using intraclass correlation coefficients (ICC) and concordance correlation coefficients (CCC) for the right eye vertical (REV) and horizontal (REH) scans and left eye vertical (LEV) and horizontal (LEH) scans. RESULTS: 120 eyes of 61 subjects, with a mean age of 62.1 +/- 15.0 years. The mean REV, REH, LEV and LEH ALCD were 456.2 +/- 84.3, 444.5 +/ 92.2, 436.7 +/- 81.6, 427.6 +/- 82.7 MUm, respectively. ALCD intra- and inter rater ICC and intra- and inter-rater CCC varied between 0.85-0.95, 0.84-0.93, 0.85-0.95 and 0.84-0.93, respectively. CONCLUSIONS: ALCD manual intra- and inter rater measurements with EDI-OCT showed high agreement. EDI-OCT is a reliable tool for ALCD measurement, which can provide potentially useful information for integrated glaucoma management. PMID- 27764826 TI - Normal Range of Fetal Nasal Bone Length during the Second Trimester in an Afro Caribbean Population and Likelihood Ratio for Trisomy 21 of Absent or Hypoplastic Nasal Bone. AB - OBJECTIVE: To establish the normal reference range of fetal nasal bone length (NBL) during the second trimester in an Afro-Caribbean population and the likelihood ratio (LR) for fetal trisomy 21. METHODS: Prenatal records of euploid, non-malformed singleton fetuses who underwent second-trimester ultrasonographic scans at 20-24 weeks of gestation were retrospectively analyzed for NBL and gestational age (GA). Only Afro-Caribbean couples were selected. The relationship between fetal NBL and GA was determined. The data of all fetuses with Down syndrome were provided by the French West Indies Register of Congenital Malformations (REMALAN). RESULTS: There was a significant linear association between fetal NBL and GA (R2 = 0. 354). The 50th percentile for NBL increased from 5.0 to 7.0 mm from week 20 to 24 of gestation. The nasal bone (NB) was absent or hypoplastic in 8.6% of the euploid fetuses and in 69.2% of the trisomy 21 fetuses. The LR for trisomy 21 of absent or hypoplastic NB in an Afro Caribbean population was 8.02, but only 2.32 when this sign was isolated. CONCLUSION: The reference range for fetal NBL at 20-24 weeks of gestation in an Afro-Caribbean population and the LR for trisomy 21 of absent or hypoplastic NB differed from the other populations. PMID- 27764825 TI - The Bethesda System for Reporting Thyroid Cytopathology: Proposed Modifications and Updates for the Second Edition from an International Panel. AB - The Bethesda System for Reporting Thyroid Cytology (TBSRTC) was proposed in 2007 at the National Cancer Institute Thyroid Fine Needle Aspiration State of the Art and Science Conference held in Bethesda, Maryland. The aim was to address the inconsistent and sometimes confusing reporting terminologies used for thyroid FNA throughout the world. The TBSRTC consists of 6 diagnostic categories, each associated with an implied risk of malignancy that translates directly into a clinical management algorithm. Since the publication of the TBSRTC cytology Atlas in January 2010, considerable experience has been gained regarding its application in cytology practice, clinical impact, and limitations. In conjunction with the International Academy of Cytology (IAC), an international panel composed of sixteen cytopathologists and an endocrinologist with special interest in thyroid cytology, including several co-authors of the 2010 TBSRTC Atlas, was created to: (1) analyze the current worldwide impact of TBSRTC, (2) report on the current state of TBSRTC based upon a review of the published literature, and (3) provide possible recommendations for a future update of TBSRTC. Herein, we summarize the panel's deliberations and key recommendations that our panel hopes will be useful during the preparation of the second edition of TBSRTC. PMID- 27764827 TI - Glomerular Filtration Rate in Healthy Living Potential Kidney Donors: A Meta Analysis Supporting the Construction of the Full Age Spectrum Equation. AB - BACKGROUND: Normal kidney function or, more specifically, normal glomerular filtration rate (GFR) in men and women and its decline with age is still much debated today. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has gender (and race) multiplication factors, accounts for a decline that starts at very young age and assumes that the mean GFR is as high as 120-130 ml/min/1.73 m2 from a young age. The full age spectrum (FAS) estimated mean GFR is about 107 ml/min/1.73 m2 at a young age and remains constant until the age of 40 years and then starts to decline both in men and women. The aim of this research study was to give more insight into 'normal' GFR levels and the physiological decrease of kidney function with age and to use a meta-analysis to evaluate the mathematical construction of the FAS and the CKD-EPI equation. METHODS: We conducted a meta-analysis of published GFR measurements in healthy Caucasian living potential kidney donors (n = 5,482, 46.8% men). Only publications dating from 2000 were selected to avoid the possible influence of body surface area changes in the last decades on the indexed GFR, expressed in ml/min/1.73 m2. RESULTS: We found that the mean GFR ~ 107 ml/min/1.73 m2 up to the age of 40 years, but renal decline begins beyond 40 years. No evidence could be found for any difference between men and women in the separate age groups. CONCLUSIONS: The current meta-analysis supports the mathematical form of the FAS equation, which matches the age/sex dependency of measured GFR for healthy potential living kidney donors. PMID- 27764828 TI - Driving Characteristics of Older Drivers and Their Relationship to the Useful Field of View Test. AB - BACKGROUND: To maintain the mobility of older people in later life, it is essential to sustain their autonomy; however, driving is a complex task, requiring a large range of visual, psychomotor and cognitive abilities. Subsequently, a key issue is to measure and evaluate the fitness to drive of older drivers. Several methods have been proposed, among them the useful field of view (UFOV) test. OBJECTIVE: The present study aimed to identify driving characteristics in older drivers and the relationship between the UFOV test and the on-road driving results. METHOD: A total of 80 drivers aged 70 years or older performed both the UFOV test and the on-road driving assessment. The 'B On-Road' (Behaviour On-Road) protocol was used for the fitness-to-drive assessment. RESULTS: 'Driving too fast' was the item reported most often during the on-road assessment, followed by problems with the manual gearbox and 'attention to signs, road lines and traffic lights'. Overall, the results showed that the older the driver, the more errors were reported during the on-road driving assessment, as well as the slower the performance on the UFOV test. A significant relationship between the total number of on-road errors, as measured by the B On-Road protocol, and the UFOV 3, which stresses the capacity of selective attention, was found. CONCLUSION: The recommendation is still to use on-road driving assessment to fully assess fitness to drive for older drivers whose ability to drive requires assessment. However, to supplement this, the UFOV test, in particular the UFOV 3, is a valuable complement in selecting those drivers requiring to be assessed. PMID- 27764829 TI - Determination of the Mutant Prevention Concentration and the Mutant Selection Window of Topical Antimicrobial Agents against Propionibacterium acnes. AB - Determination of the mutant prevention concentration (MPC) and the mutant selection window (MSW) of antimicrobial agents used to treat pathogenic bacteria is important in order to apply effective antimicrobial therapies. Here, we determined the MPCs of the major topical antimicrobial agents against Propionibacterium acnes and Staphylococcus aureus which cause skin infections and compared their MSWs. Among the MPCs of nadifloxacin and clindamycin, the clindamycin MPC was determined to be the lowest against P. acnes. In contrast, the nadifloxacin MPC was the lowest against S. aureus. Calculations based on the minimum inhibitory concentrations and MPCs showed that clindamycin has the lowest MSW against both P. acnes and S. aureus. Nadifloxacin MSWs were 4-fold higher against P. acnes than against S. aureus. It is more likely for P. acnes to acquire resistance to fluoroquinolones than S. aureus. Therefore, topical application of clindamycin contributes very little to the emergence of resistant P. acnes and S. aureus strains. PMID- 27764831 TI - Mixed-Up Sex Chromosomes: Identification of Sex Chromosomes in the X1X1X2X2/X1X2Y System of the Legless Lizards of the Genus Lialis (Squamata: Gekkota: Pygopodidae). AB - Geckos in general show extensive variability in sex determining systems, but only male heterogamety has been demonstrated in the members of their legless family Pygopodidae. In the pioneering study published more than 45 years ago, multiple sex chromosomes of the type X1X1X2X2/X1X2Y were described in Burton's legless lizard (Lialisburtonis) based on conventional cytogenetic techniques. We conducted cytogenetic analyses including comparative genomic hybridization and fluorescence in situ hybridization (FISH) with selected cytogenetic markers in this species and the previously cytogenetically unstudied Papua snake lizard (Lialis jicari) to better understand the nature of these sex chromosomes and their differentiation. Both species possess male heterogamety with an X1X1X2X2/X1X2Y sex chromosome system; however, the Y and one of the X chromosomes are not small chromosomes as previously reported in L. burtonis, but the largest macrochromosomal pair in the karyotype. The Y chromosomes in both species have large heterochromatic blocks with extensive accumulations of GATA and AC microsatellite motifs. FISH with telomeric probe revealed an exclusively terminal position of telomeric sequences in L. jicari (2n = 42 chromosomes in females), but extensive interstitial signals, potentially remnants of chromosomal fusions, in L.burtonis (2n = 34 in females). Our study shows that even largely differentiated and heteromorphic sex chromosomes might be misidentified by conventional cytogenetic analyses and that the application of more sensitive cytogenetic techniques for the identification of sex chromosomes is beneficial even in the classical examples of multiple sex chromosomes. PMID- 27764830 TI - Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1 CREB1 Fusion. AB - Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S 100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen. PMID- 27764832 TI - Attenuation of Renal Functional Decline Following Angioplasty and Stenting in Atherosclerotic Renovascular Disease. AB - BACKGROUND: To date, renal revascularization has not been shown to be advantageous when compared to optimized medical treatment in patients with atheromatous renovascular disease (ARVD). This study aims to investigate the effect of revascularization in patients with pre-intervention worsening renal function and in those with stable renal function. PATIENTS AND METHODS: In this single-centre observational study, patients who were diagnosed with at least 60% angiographic stenosis unilaterally or bilaterally between January 1996 and October 2008 and who were followed-up until February 2011 were retrospectively analysed. Evolution of renal function was determined from the slope of reciprocal of serum creatinine (RCr-slope) before and after diagnostic angiography or revascularization; this required 5 or more creatinine measurements before and at least another 5 measurements post-procedure. Patients were divided into 2 groups: one comprising patients with negative RCr-slope before the procedure and a second group of patients with prior positive RCr-slope. A stepwise, adjusted logistic regression was used to determine the OR of revascularization on attenuation of RCr-slope. RESULTS: Data for 52 patients were analysed. Median age was 64 (58-72) and median follow-up was 15 (8-34) months. Only patients with a negative RCr slope (-0.0078 (95% CI -0.0174, -0.0033) dl/mg/month) who underwent revascularization manifested an improved RCr-slope during follow-up (+0.0013 (95% CI -0.0002, 0.0039) dl/mg/month, p < 0.001). This finding remained statistically significant even after the adjustment for proteinuria and bilateral arterial disease. CONCLUSION: Revascularization may be indicated for patients with ARVD and progressively worsening renal function. This patient subgroup should ideally be evaluated in future randomized controlled trials. PMID- 27764833 TI - Effects of the Sympathetic Nervous System on Regulatory T Cell and T Helper 1 Chemokine Expression in Patients with Acute Coronary Syndrome. AB - OBJECTIVE: To observe the effects of sympathetic overactivity on the immune system involved in the imbalance of T helper (Th) lymphocytes, we investigated the correlation between autonomic dysregulation and the generation of regulatory T (Treg) and Th1 chemokines in patients with acute coronary syndrome (ACS). METHODS: Blood samples obtained from patients with coronary artery disease and controls were analyzed for levels of Th1 and Treg cells and their associated cytokines by flow cytometry. In addition, the activity of the cyclic adenosine monophosphate (cAMP), the levels of norepinephrine (NE), epinephrine (EPI) and serum cytokines, and the activity of protein kinase A (PKA) were analyzed by Western blot, radioimmunoassay, high-performance liquid chromatography and enzyme linked immunoassay, respectively. All subjects were evaluated for heart rate variability (HRV). RESULTS: Levels of Th1 cells and T-bet (a T-box transcription factor), NE, EPI, cAMP and PKA significantly increased (all p < 0.01) whereas HRV and levels of Treg cells and STAT5 decreased (all p < 0.01) in ACS patients compared to patients with stable angina and controls. The disorder of Th1 and Treg cells is closely related to the activation of cAMP-PKA induced by hyperactivity of the sympathetic system. CONCLUSIONS: This study showed that the abnormalities in specific subsets of CD4+ T cells are associated with sympathetic hyperactivity in ACS patients. It may provide surprising insights into the pathogenesis of arteriosclerosis, involving the regulation of the sympathetic nervous system on immune inflammation. PMID- 27764834 TI - Increased Heme Oxygenase-1 and Nuclear Factor Erythroid 2-Related Factor-2 in the Placenta Have a Cooperative Action on Preeclampsia. AB - BACKGROUND: Previous studies have shown that oxidative stress is an important factor in preeclampsia (PE). Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor-2 (Nrf2) are protective proteins that are involved in combating oxidative stress in the body. Nrf2 is also an essential upstream transcription factor regulating HO-1. This study was aimed at exploring the physiological roles of HO-1 and Nrf2 in PE. METHODS: Serum and placenta were collected from 30 patients who presented with severe PE and 30 healthy pregnant females. HO-1 and Nrf2 levels in placenta were measured. Following stimulation of the HTR-8/SVneo cell line with tert-butylhydroquinone (tBHQ), an Nrf2 activator, nuclear Nrf2 protein and HO-1 mRNA levels were determined. RESULTS: Compared with the healthy pregnancy group, HO-1 protein and mRNA levels were increased in placental samples obtained from the severe PE group (p < 0.01, p < 0.05). Similar increases were also observed for Nrf2 protein levels (p < 0.01). Nuclear Nrf2 protein and HO-1 mRNA levels were both increased in the HTR-8/SVneo cell line following stimulation with tBHQ (p < 0.05). CONCLUSION: Patients with severe PE may be protected against oxidative injury following an elevation in HO-1 and Nrf2 levels. Nrf2 is likely to have a synergistic effect on HO-1 in PE. PMID- 27764835 TI - Effect of Verbal Empathy and Touch on Anxiety Relief in Patients Undergoing Flexible Bronchoscopy: Can Empathy Reduce Patients' Anxiety? AB - BACKGROUND: Patients undergoing flexible bronchoscopy usually experience anxiety before and during the procedure. OBJECTIVES: We performed this study to investigate whether verbal empathy and intentional touch from a bronchoscopist could reduce anxiety in patients undergoing flexible bronchoscopy. METHODS: We conducted a prospective randomized trial in a university-affiliated hospital. Participants were randomly assigned to one of the following groups: a control group, a verbal empathy group, or a verbal empathy and touch group. The staff pulmonologist performing bronchoscopy expressed verbal empathy and used touch by speaking to the patient (using predefined short statements) and making eye contact, and by laying his/her left hand on the patient's right shoulder. We assessed the level of patient anxiety with a visual analog scale before and after the intervention. RESULTS: Participants were 267 patients with a median age of 65 years; 62.2% were men. Although there were no differences in changes in anxiety between the three groups, subgroup analysis of the visual analog scale including participants with higher baseline anxiety (empathy and touch group participants with anxiety >=60 mm; empathy group and empathy and touch group participants with anxiety >=70 mm) showed a larger reduction in anxiety than the control group. CONCLUSIONS: Verbal empathy and touch given by a bronchoscopist before bronchoscopy reduced anxiety in patients with high baseline anxiety levels. PMID- 27764836 TI - Lysosome Inhibitors Enhance the Chemotherapeutic Activity of Doxorubicin in HepG2 Cells. AB - The lysosome inhibitors bafilomycin A1 and chloroquine have both lysosomotropic properties and autophagy inhibition ability, and are promising clinical agents to be used in combination with anticancer drugs. In order to investigate this combination effect, HepG2 cells were treated with bafilomycin A1, chloroquine, or/and doxorubicin, and their proliferative ability, induction of apoptosis, and the changes of lysosomal membrane permeabilization and mitochondrial membrane potential were studied. The results demonstrate that treatment with bafilomycin A1 or chloroquine alone at a relatively low concentration promotes the inhibitory effect of doxorubicin on cell growth and apoptosis. Further studies reveal that bafilomycin A1 and chloroquine promote lysosomal membrane permeabilization and the reduction of mitochondrial membrane potential induced by doxorubicin. Our findings suggest that bafilomycin A1 and chloroquine potentiate the anticancer effect of doxorubicin in hepatic cancer cells and that supplementation of conventional chemotherapy with lysosome inhibitors may provide a more efficient anticancer therapy. PMID- 27764837 TI - Effect of Age on Transcranial Doppler Velocities in Patients with Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: It is not well understood whether age impacts transcranial Doppler (TCD) mean flow velocities (MFVs) in patients with aneurysmal subarachnoid hemorrhage (SAH) with or without delayed cerebral ischemia (DCI). The aim of our study was to analyze the behavior of TCD MFV during the first 7 days after SAH in patients of different ages and correlate them with the occurrence of DCI. METHODS: This study is a databank analysis of patients with SAH admitted between 2010 and 2012 in a single center. We analyzed mean MFV of bilateral middle cerebral arteries (MCAs) in all patients enrolled in the study on days 1, 3 and 7. The correlation between age and TCD MFV was analyzed using a univariate linear regression model. RESULTS: Fifty-five patients were studied. Starting on the third day after the bleeding, increasing age was associated with slower MFVs. This trend was not affected by the interrogation of the right or left MCA. After correction to include only patients who developed DCI, the same findings persisted on days 3 and 7. CONCLUSION: Older age was correlated with a significant decrease on TCD velocities in patients with SAH, even after correction for patients who developed DCI. PMID- 27764838 TI - NCCN-IPI score-independent prognostic potential of pretreatment uric acid levels for clinical outcome of diffuse large B-cell lymphoma patients. AB - BACKGROUND: Blood-based parameters are gaining increasing interest as potential prognostic biomarkers in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this study was to comprehensively evaluate the prognostic significance of pretreatment plasma uric acid levels in patients with newly diagnosed DLBCL. METHODS: The clinical course of 539 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian high-volume centres with rituximab-based immunochemotherapy was evaluated retrospectively. The prognostic influence of uric acid on overall survival (OS) and progression-free survival (PFS) were studied including multi-state modelling, and analysis of conditional survival. RESULTS: Five-year OS and PFS were 50.4% (95% CI: 39.2-60.6) and 44.0% (33.4 54.0) in patients with uric acid levels above the 75th percentile of the uric acid distribution (Q3, cut-off: 6.8 mg dl-1), and 66.2% (60.4-71.5) and 59.6% (53.7-65.0%) in patients with lower levels (log-rank P=0.002 and P=0.0045, respectively). In univariable time-to-event analysis, elevated uric acid levels were associated with a worse PFS (hazard ratio (HR) per 1 log increase in uric acid 1.47, 95% CI: 1.10-1.97, P=0.009) and a worse OS (HR=1.60, 95% CI: 1.16 2.19, P=0.004). These associations prevailed upon multivariable adjustment for the NCCN-IPI score. Uric acid levels significantly improved the predictive performance of the R-IPI and NCCN-IPI scores, and in multi-state analysis, it emerged as a highly significant predictor of an increased risk of death without developing recurrence (transition-HR=4.47, 95% CI: 2.17-9.23, P<0.0001). CONCLUSIONS: We demonstrate that elevated uric acid levels predict poor long-term outcomes in DLBCL patients beyond the NCCN-IPI risk index. PMID- 27764839 TI - Impact of tumour RAS/BRAF status in a first-line study of panitumumab + FOLFIRI in patients with metastatic colorectal cancer. AB - BACKGROUND: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). METHODS: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. RESULTS: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression. CONCLUSIONS: First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated. PMID- 27764840 TI - Risk factors cannot explain the higher prevalence rates of precancerous colorectal lesions in men. AB - BACKGROUND: Prevalence of (pre)cancerous colorectal lesions are higher in men than in women, although transition rates from advanced lesions to cancer is similar in both sexes. Our aim was to investigate whether the sex-specific difference in incidence of premalignant colorectal lesions might be explained by the impact of risk factors. METHODS: A cross-sectional study analysing health check-up examinations and screening colonoscopies performed within a national quality assurance program. RESULTS: A total of 25 409 patients were included in this study, 50.8% were women. Median age for both sexes was 60 years (interquartile range (IQR) 54-67). A multivariable model showed that risk factors mediated only 0.6 of the 10.4% gender gap in adenoma and 0.47 of the 3.2% gender gap in advanced adenoma detection rate. Smoking was the only independent risk factor with a varying sex-specific effect (men OR 1.46, CI 1.29, 1.64, women OR 1.76, CI 1.53, 2.06) and advanced adenomas (men OR 1.06, CI 0.80-1.42; women OR 2.08, CI 1.52-2.83). Independent risk factors for adenomas were BMI (OR 1.35 per IQR, CI 1.25-1.47) and triglyceride level (OR 1.03 per IQR, CI 1.00-1.06); for advanced adenomas physical activity (none vs regular: OR 1.54, CI 1.18-2.00, occasional vs regular: OR 1.17, CI 1.00-1.38), cholesterol level (OR 1.13 per IQR, CI 1.02-1.25), blood glucose level (OR 1.05 per IQR, CI 1.01-1.09) and alcohol score (OR 1.09 per IQR, CI 1.01-1.18). CONCLUSIONS: Risk factors cannot explain higher prevalence rates in men. Results of this study strongly underline the need for sex-specific screening recommendations. PMID- 27764842 TI - Patients' and clinicians' preferences for adjuvant chemotherapy in endometrial cancer: an ANZGOG substudy of the PORTEC-3 intergroup randomised trial. AB - BACKGROUND: To determine the minimum survival benefits that patients, and their clinicians, judged sufficient to make adjuvant chemotherapy (ACT) worthwhile, in addition to pelvic radiotherapy, for women with high risk and advanced stage endometrial cancer. METHODS: Eighty-three participants in the PORTEC-3 trial completed a time trade-off questionnaire before and after adjuvant therapy; 44 of their clinicians completed it once only. The questionnaire used four hypothetical scenarios including baseline survival times without ACT of 5 and 8 years, and baseline survival rates at 5 years without ACT of 50 and 65%. RESULTS: Over 50% of patients judged an extra 1 year of survival time or an extra 5% in survival rate sufficient to make ACT worthwhile. Over 50% of clinicians judged an extra 1 year of survival time, or an extra 10% in survival rate, sufficient to make ACT worthwhile. Compared with patients, clinicians required similar survival time benefits (medians both 1 year, P=0.4), but larger survival rate benefits (medians 8.5% vs 5%, P=0.03), and clinicians' preferences varied less (IQR 0.5-1.5 years vs 0.4-2 years, P=0.0007; 5-10% vs 1-13%, P=0.004). Patients' preferences changed over time for the survival rate scenarios depending on whether they had ACT or not (change in median benefit - 3 months vs 2.5 months respectively, P=0.028). There were no strong predictors of patients' or clinicians' preferences. CONCLUSIONS: Patients and clinicians judged moderate survival benefits sufficient to make ACT worthwhile after pelvic radiotherapy for endometrial cancer. These benefits are larger than those judged sufficient by patients with breast or colon cancers, but similar to those judged sufficient by patients with lung or ovarian cancers. PMID- 27764843 TI - Surgeon volume and 30 day mortality for brain tumours in England. AB - BACKGROUND: There is evidence that surgeons who perform more operations have better outcomes. However, in patients with brain tumours, all of the evidence comes from the USA. METHODS: We examined all English patients with an intracranial neoplasm who had an intracranial resection in 2008-2010. We included surgeons who performed at least six operations over 3 years, and at least one operation in the first and last 6 months of the period. RESULTS: The analysis data set comprised 9194 operations, 163 consultant neurosurgeons and 30 centres. Individual surgeon volumes varied widely (7-272; median=46). 72% of operations were on the brain, and 30 day mortality was 3%. A doubling of surgeon load was associated with a 20% relative reduction in mortality. Thirty day mortality varied between centres (0.95-8.62%) but was not related to centre workload. CONCLUSIONS: Individual surgeon volumes correlated with patient 30 day mortality. Centres and surgeons in England are busier than surgeons and centres in the USA. There is no relationship between centre volume and 30 day mortality in England. Services in the UK appear to be adequately arranged at a centre level, but would benefit from further surgeon sub-specialisation. PMID- 27764841 TI - Main nutrient patterns and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition study. AB - BACKGROUND: Much of the current literature on diet-colorectal cancer (CRC) associations focused on studies of single foods/nutrients, whereas less is known about nutrient patterns. We investigated the association between major nutrient patterns and CRC risk in participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: Among 477 312 participants, intakes of 23 nutrients were estimated from validated dietary questionnaires. Using results from a previous principal component (PC) analysis, four major nutrient patterns were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed for the association of each of the four patterns and CRC incidence using multivariate Cox proportional hazards models with adjustment for established CRC risk factors. RESULTS: During an average of 11 years of follow-up, 4517 incident cases of CRC were documented. A nutrient pattern characterised by high intakes of vitamins and minerals was inversely associated with CRC (HR per 1 s.d.=0.94, 95% CI: 0.92-0.98) as was a pattern characterised by total protein, riboflavin, phosphorus and calcium (HR (1 s.d.)=0.96, 95% CI: 0.93-0.99). The remaining two patterns were not significantly associated with CRC risk. CONCLUSIONS: Analysing nutrient patterns may improve our understanding of how groups of nutrients relate to CRC. PMID- 27764845 TI - Comment on 'Molecular evidence of viral DNA in non-small cell lung cancer and non neoplastic lung'. PMID- 27764847 TI - [Pediatric Ophthalmology and Eye Muscle Surgery]. PMID- 27764844 TI - In the Wnt-er of life: Wnt signalling in melanoma and ageing. AB - Although the clinical landscape of melanoma is improving rapidly, metastatic melanoma remains a deadly disease. Age remains one of the greatest risk factors for melanoma, and patients older than 55 have a much poorer prognosis than younger individuals, even when the data are controlled for grade and stage. The reasons for this disparity have not been fully uncovered, but there is some recent evidence that Wnt signalling may have a role. Wnt signalling is known to have roles both in cancer progression as well as in organismal ageing. In melanoma, the interplay of Wnt signalling pathways is complex, with different members of the Wnt family guiding different aspects of invasion and proliferation. Here, we will briefly review the current literature addressing the roles of different Wnt pathways in melanoma pathogenesis, provide an overview of Wnt signalling during ageing, and discuss the intersection between melanoma and ageing in terms of Wnt signalling. PMID- 27764846 TI - Reply to: Comment on 'Molecular evidence of viral DNA in non-small cell lung cancer and non-neoplastic lung'. PMID- 27764848 TI - ? PMID- 27764849 TI - [Editor's Comment]. PMID- 27764850 TI - ? PMID- 27764852 TI - ? PMID- 27764851 TI - ? PMID- 27764853 TI - ? PMID- 27764854 TI - [Head and Neck Cancer in Pregnancy - Recommendations for Diagnosis and Therapy With Case Report]. AB - Objective: The diagnosis of cancer in pregnancy is rare, but might become more relevant even for head and neck cancer patients due to a shift of age of primipara towards the last third of reproductive years. Unsureness exists about the risk and benefit of diagnostic and therapeutic cancer modalities for the unborn and established recommendations are still missing. But, according to recent data, even multimodal therapeutic approaches (e. g. surgery, radiation, chemotherapy) seem possible in face of pregnancy and should be traded against the risk of prematurity. Material and Methods: Our findings are discussed on the basis of a case report of a pregnant woman with advanced carcinoma of the outer ear canal and therapy options are formulated. Results: Sufficient performed diagnostic modalities do not reach imperilling uterus dosages. A growing number of case reports und studies did not detect any developmental disadvantage of children of prenatal exposed mothers by radiation or chemotherapy, whereas long term impairments of premature infants are proven. Conclusion: In cancer in pregnancy, an immediate start of well-established therapy modalities like surgery and/or cisplatin-based chemoradiation seems to be possible without unjustifiable risks for the unborn. PMID- 27764855 TI - [Broader Authority for Ward Physicians - Innovations on Discharge Management Provide Flexible Subsequent Care]. PMID- 27764856 TI - [Surgery in Salivary Gland Diseases]. AB - Salivary gland surgery is a common procedure in otorhinolaryngology. Parotidectomy and submandibulectomy represent the treatment of choice in benign and malignant tumors of the salivary glands. However, as to this point there are no guidelines are concerning diagnostic and therapeutic approaches of benign and malignant tumors of the salivary gland. Since the introduction of sialendoscopy there are new diagnostic and therapeutic procedures available in treating obstructive sialadenitis. The present article provides an overview of anatomical principles, diagnostic approaches and the most important salivary gland surgeries for future otorhinolaryngologists under specialist training. PMID- 27764857 TI - ? PMID- 27764859 TI - ? PMID- 27764858 TI - ? PMID- 27764860 TI - ? PMID- 27764861 TI - ? PMID- 27764862 TI - ? PMID- 27764863 TI - ? PMID- 27764864 TI - ? PMID- 27764865 TI - ? PMID- 27764866 TI - [Remote Ischaemic Conditioning - an overview]. AB - The strategy of Remote Ischaemic Conditionings (RIC) is easy to apply, cost effective, low in side effects and belongs to the most potent cardioprotective strategies evaluated within recent years. Its practical application is carried out by simple use of a blood pressure cuff, more precise by 4 repetitive cycles of inflating the cuff above 200 mmHg for 5 minutes followed by an equal long break between the cycles. First experimental and clinical data repetitively demonstrated a significant reduction in myocardial injury following ischemia/reperfusion. Nevertheless, given the neutral results of two recent clinical multicentre trials, the clinical significance and benefits of RIC in cardiac surgery patients remains uncertain. The combination of co-medication and narcotic agents is thought to be responsible for the failed transfer into the clinical practice. PMID- 27764867 TI - ? PMID- 27764868 TI - ? PMID- 27764869 TI - [Hemodynamic monitoring - Basic monitoring]. AB - Basic haemodynamic monitoring is an essential part of the anaesthesia work place. This includes Monitoring of ECG, blood pressure and pulse oximetry. For early assessement of perioperative complications every patient should have a basic haemodynamic monitoring, independant of current health status or the type of anaesthesia applied. Knowledge of function, principles and limitations ais necessary for proper interpretation of the measured values. Here, we describe the function and application of ECG, non - invasive intermittent blood pressure and pulse oximetry in the perioperative setting. PMID- 27764870 TI - [Invasive and minimally invasive hemodynamic monitoring]. AB - Advanced hemodynamic monitoring is necessary for adequate management of high-risk patients or patients with derangement of circulation. Studies demonstrate a benefit of early goal directed therapy in unstable cardiopulmonary situations. In these days we have different possibilities of minimally invasive or invasive hemodynamic monitoring. Minimally invasive measurements like pulse conture analysis or pulse wave analysis being less accurate under some circumstances, however only an artery catheter is needed for cardiac output monitoring. Pulmonary artery, transpulmonary thermodilution and lithium dilution technology have acceptable accuracy in cardiac output measurement. For therapy of unstable circulation there are additionally parameters to obtain. The pulmonary artery catheter is the device with the largest rate of complications, used by a trained crew and with a correct indication, his use is unchained justified. PMID- 27764871 TI - [Hemodynamic monitoring - imaging procedures / cardiac ultrasound]. AB - Echocardiography as an imaging method in anaesthesia and intensive care medicine has enabled a new dimension of hemodynamic monitoring: the direct visualization of the cardiac function and its disruptions. Preconditions for a broad application in this area was the development of mobile, high-definition ultrasonic devices and the origination of focused examination techniques. A successful application of this method requires the respective know-how of the examiner, in order to take relevant decisions and avoid misdiagnoses. The following article shows the advantages and limitations of echocardiography in the diagnosis of hemodynamic instability. For TTE and TEE focused examination techniques are illustrated and evaluated with regards to their applicability to hemodynamic monitoring. Furthermore, the requirements on devices and education of the examiner are discussed. PMID- 27764873 TI - ? PMID- 27764872 TI - [Crawford Williamson Long - The true discoverer of anesthesia?] AB - October 16, 1846 is regarded as the birth of anaesthesia at the Massachusetts General Hospital in Boston. However, was this really the first anaesthesia with sulphuric ether? In the priority dispute that started already in 1846 there were more participants: WTG Morton, CT Jackson and H Wells. Not involved was CW Long, who has already administered ether anaesthesia in 1842. He has published his results only 1849 and therefore he gained no glory. PMID- 27764874 TI - ? PMID- 27764875 TI - ? PMID- 27764876 TI - ? PMID- 27764877 TI - Venous Thromboembolism in Patients Undergoing Craniotomy for Brain Tumors: A U.S. Nationwide Analysis. AB - Background Patients who undergo craniotomy for brain tumor have an increased risk of developing venous thromboembolism (VTE). Using the National Surgical Quality Improvement Program (NSQIP) registry, patients undergoing craniotomy for brain tumor from 2006 and 2014 were analyzed to identify risk factors for postoperative VTE. Methods The study population, identified by Current Procedural Terminology codes, included all NSQIP-reported patients who underwent a craniotomy for brain tumor resection. Results There were 629 instances of VTE among 19,409 craniotomies for brain tumor (3.2%) recorded in NSQIP. Occurrence of VTE was associated with other postoperative complications on univariate analysis, including pneumonia, respiratory failure, stroke, and sepsis (all p < 0.001). On multivariate analysis, independent predictors of VTE included age 46 to 57 years (odds ratio [OR], 1.432; p = 0.006), 57 to 66 years (OR, 1.550; p = 0.001), or over 66 years (OR, 2.493; p < 0.001), body mass index (BMI) over 32.1 kg/m2 (OR, 1.835; p < 0.001), functional dependence (OR, 1.657; p < 0.001), ventilator dependence (OR, 2.516; p < 0.001), steroid use (OR, 1.661; p < 0.001), prior sepsis (OR, 1.845; p < 0.001), and total operative time 183 to 271 minutes (OR, 1.462; p = 0.032) and longer than 271 minutes (OR, 1.945; p < 0.001). Conclusions VTE occurs in approximately 3% of patients undergoing craniotomy for brain tumor resection. Independent predictors for developing VTE include older age, higher BMI, recent steroid use, and total operative time. PMID- 27764879 TI - State-of-the-Art Imaging in Pulmonary Embolism: Ventilation/Perfusion Single Photon Emission Computed Tomography versus Computed Tomography Angiography - Controversies, Results, and Recommendations from a Systematic Review. AB - Pulmonary embolism (PE) is a common, ubiquitous, and potentially lethal disease. As symptoms and clinical findings are notoriously nonspecific, diagnostic imaging is essential to avoid undertreatment as well as overtreatment. Controversies remain regarding first-line imaging in suspected PE. The two main contemporary contenders are ventilation/perfusion scintigraphy with single-photon emission computed tomography (V/Q SPECT) with or without additional low-dose CT (SPECT/CT) and CT angiography (CTA). We present our results from a systematic review and meta-analysis of the diagnostic performances of these modalities: V/Q SPECT, V/Q SPECT/CT, and CTA are all viable options, but we consider V/Q SPECT/CT to be superior in most clinical settings with better overall diagnostic performance, that is, pooled sensitivities (97.6 vs. 82.0%), specificities (95.9 vs. 94.9%), positive predictive values (93.0 vs. 93.8%), negative predictive values (98.6 vs. 84.7%), and accuracies (96.5 vs. 88.6%). We further address some of the ongoing controversies regarding the various modalities, that is, radiation exposure, the issues of subsegmental PE, nondiagnostic studies, and various challenges in specific patient populations. PMID- 27764880 TI - Extensive Computed Tomography versus Limited Screening for Detection of Occult Cancer in Unprovoked Venous Thromboembolism: A Multicenter, Controlled, Randomized Clinical Trial. AB - Patients with unprovoked venous thromboembolism (VTE) may harbor occult cancer. Whether an extensive diagnostic work-up for cancer has additional value over a more limited screening for detection of underlying malignancy in these patients is controversial. We performed a randomized multicenter trial to assess if in patients with unprovoked VTE, a computed tomography (CT)-based diagnostic strategy including thoracic, abdominal, and pelvic CT in combination with fecal occult blood test yields a higher cancer detection rate than a nonstandardized testing approach based on physicians' clinical judgment and patients' preferences. Cancer-free patients were followed up for up to 24 months. Of the 195 consecutive patients with unprovoked VTE who were eligible for this investigation, an occult cancer was identified in 10 of the 98 patients (10.2%) randomized to the CT-based strategy, and in 8 of the 97 (8.2%) allocated to the personalized strategy (absolute difference, 2.0%; 95% confidence interval, -7.2 11.1; p = 0.81). During follow-up, cancer was identified in an additional 2 patients in each group. Overall, 7 (7.1%) patients of the CT-based strategy died, as compared with 11 (11.3%) of the personalized strategy, with 2 and 4, respectively, due to cancer. In conclusion, a CT-based strategy in combination with fecal occult blood test does not provide a clinically significant benefit over more limited cancer screening for detecting occult cancer in patients with unprovoked VTE. (ClinicalTrials.gov number, NCT00361647). PMID- 27764881 TI - Update on the Treatment of Venous Thromboembolism. AB - During the past 7 years, results from phase III trials comparing nonvitamin antagonist K oral anticoagulants (NOACs) with vitamin K antagonists (VKAs) or with placebo, including 34,900 patients, have been published. Recent guidelines have been updated and now suggest treatment with NOACs rather than with VKA. Other updates in the guidelines concern the initial thrombolytic treatment for selected patients with deep vein thrombosis or pulmonary embolism as well as the possibility of withholding anticoagulation for minimal venous thromboembolism. The optimal duration of anticoagulation after an unprovoked event is still debatable, depending on values and preferences assigned to recurrent thromboembolism versus bleeding complications. The choice is essentially between a short duration of 3 or perhaps 6 months for extensive thromboembolism and indefinite duration. Several clinical prediction rules have been developed to aid in this choice but they all address only the risk of recurrent thrombosis without weighing in the risk of bleeding. This review provides an update on recent systematic reviews, meta-analyses, and guidelines on the treatment of venous thromboembolism. PMID- 27764882 TI - The Outpatient Treatment of Venous Thromboembolism: Operational Impact and the Role of Novel Anticoagulants. AB - Pulmonary embolism (PE) and venous thromboembolism (VTE) are common diagnoses in the emergency department (ED), with significant potential morbidity and mortality. As a result, historically nearly all patients with PE have been admitted to the hospital for observation and treatment. In recent years, the ability to rapidly and accurately risk stratify patients with VTE according to their risk of short-term clinical deterioration has supported outpatient treatment, and non-vitamin K antagonist oral anticoagulants (NOACs) have further facilitated this approach. This review details the historical context and operational impact of managing VTE in the outpatient setting, describes a model for outpatient management of VTE, and suggests potential areas of further inquiry. PMID- 27764878 TI - Environmental and Genetic Risk Factors Associated with Venous Thromboembolism. AB - Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism, and a combination of environmental and genetic risk factors contributes to VTE risk. Within environmental risk factors, some are provoking (e.g., cancer, surgery, trauma or fracture, immobilization, pregnancy and the postpartum period, long-distance travel, hospitalization, catheterization, and acute infection) and others are nonprovoking (e.g., age, sex, race/ethnicity, body mass index and obesity, oral contraceptive or hormone therapy use, corticosteroid use, statin use, diet, physical activity, sedentary time, and air pollution). Additionally, VTE has a strong genetic basis, with approximately 50 to 60% of the variance in VTE incidence attributed to genetic effects. Some genetic susceptibility variants that contribute to risk have been identified in candidate genes, mostly related to the clotting system and responsible for inherited hypercoagulable states (e.g., factor V Leiden, prothrombin, fibrinogen gamma, or blood group non-O). Other susceptibility single-nucleotide polymorphisms have been identified from genome-wide association studies, such as the two new loci in TSPAN15 (rs78707713) and SCL44A2 (rs2288904) genes. Risk factors are not always associated with VTE in isolation; however, and an understanding of how environmental and genetic factors interact may provide insight into the pathophysiology of VTE, possibly identifying opportunities for targeted prevention and treatment. PMID- 27764883 TI - Epidemiology of Familial Aggregation of Venous Thromboembolism. AB - Familial aggregation (clustering) of venous thromboembolism (VTE) is the clustering of VTE within a family. Though several genes, such as antithrombin, protein C, protein S, factor V, and prothrombin are associated with the familial clustering of VTE, these loci only partially explain the familial aggregation of VTE. The epidemiology of the familial aggregation of VTE exhibits typical characteristics of complex traits. The family history of VTE in first-degree relatives is associated with a two to three times increased familial relative risk (FRR). The FRR of VTE is higher in younger individuals, increases with a number of affected relatives, decreases as the familial relationship becomes more distant, increases with severity (unprovoked), and exhibits slightly stronger male transmission (Carter effect). High FRR is observed in individuals with two or more affected siblings (FRR > 50). Because familial aggregation represents the sum of shared family environmental and genetic factors, one should not assume that evidence of familial aggregation implies genetic effects. However, studies in twins, extended families, adoptees, and spouses indicate a weak involvement of shared environmental factors to the familial aggregation of VTE. Moreover, familial aggregation of VTE fulfills the Hill's criteria for causation. In conclusion, familial aggregation of VTE signals a clinically relevant inherent predisposition for VTE. PMID- 27764884 TI - ? PMID- 27764885 TI - ? PMID- 27764886 TI - [Female Preterm Monozygotic Twins Discordant for Fetal Megacystis due to Cloacal Dysgenesis After Conception by Intracytoplasmatic Sperm Injection - Case Report and Review of Literature]. AB - Monozygotic twins were previously regarded as "identical". By now an increasing number of case reports of monozygotic but discordant twins have been reported, and therefore discordance between monozygotic twins is being investigated intensively. We report a case of female preterm monozygotic twins who were discordant for fetal megacystis due to cloacal dysgenesis. Pregnancy was achieved after intracytoplasmatic sperm injection and transfer of 2 embryos. By the first trimester fetal megacystis with consecutive oligohydramnios and hypoplasia of the lungs was diagnosed. Both foetuses had normal karyotypes. After delivery at 25+3 weeks of gestation due to premature labour, the affected child was treated palliatively and died within 2 hours. In the postmortem physical examination, a cloacal dysgenesis was detected. In the male foetus, megacystis is typically caused by obstructive uropathy. In the rarely affected female foetus, it usually results from complex urogenital malformations like cloacal dysgenesis which originates from disruption during gastrulation. We identified 10 case series of mono- or dizygotic twins who were discordant either for fetal megacystis or for cloacal dysgenesis. Issues like conception, zygosity, sex, karyotype and aetiology of fetal megacystis were not reported in all cases. Discordance between monozygotic twins for structural birth defects is closely linked to the twinning process itself. Assisted reproduction is said to generate a higher rate of monozygotic twin pregnancies and to be responsible for a higher prevalence of chromosomal aberrations or congenital malformations. With regard to conception, zygosity, sex, karyotype and combination of malformations, our case is unique. PMID- 27764888 TI - Riparian spiders as sentinels of polychlorinated biphenyl contamination across heterogeneous aquatic ecosystems. AB - Riparian spiders are being used increasingly to track spatial patterns of contaminants in and fluxing from aquatic ecosystems. However, our understanding of the circumstances under which spiders are effective sentinels of aquatic pollution is limited. The present study tests the hypothesis that riparian spiders may be effectively used to track spatial patterns of sediment pollution by polychlorinated biphenyls (PCBs) in aquatic ecosystems with high habitat heterogeneity. The spatial pattern of SigmaPCB concentrations in 2 common families of riparian spiders sampled in 2011 to 2013 generally tracked spatial variation in sediment SigmaPCBs across all sites within the Manistique River Great Lakes Area of Concern (AOC), a rivermouth ecosystem located on the south shore of the Upper Peninsula, Manistique (MI, USA) that includes harbor, river, backwater, and lake habitats. Sediment SigmaPCB concentrations normalized for total organic carbon explained 41% of the variation in lipid-normalized spider SigmaPCB concentrations across 11 sites. Furthermore, 2 common riparian spider taxa (Araneidae and Tetragnathidae) were highly correlated (r2 > 0.78) and had similar mean SigmaPCB concentrations when averaged across all years. The results indicate that riparian spiders may be useful sentinels of relative PCB availability to aquatic and riparian food webs in heterogeneous aquatic ecosystems like rivermouths where habitat and contaminant variability may make the use of aquatic taxa less effective. Furthermore, the present approach appears robust to heterogeneity in shoreline development and riparian vegetation that support different families of large web-building spiders. Environ Toxicol Chem 2017;36:1278-1286. Published 2016 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 27764887 TI - Uptake Pathways of Guandinylated Disulfide Containing Polymers as Nonviral Gene Carrier Delivering DNA to Cells. AB - Polymers of guanidinylated disulfide containing poly(amido amine)s (Gua-SS-PAAs), have shown high transfection efficiency and low cytotoxicity. Previously, we synthesized two Gua-SS-PAA polymers, using guanidino containing monomers (i.e., arginine and agmatine, denoted as ARG and AGM, respectively) and N,N' cystaminebisacrylamide (CBA). In this study, these two polymers, AGM-CBA and ARG CBA were complexed with plasmid DNA, and their uptake pathway was investigated. Complexes distribution in MCF-7 cells, and changes on cell endosomes/lysosomes and membrane after the cells were exposed to complexes were tested. In addition, how the transfection efficiency changed with the cell cycle status as well as endocytosis inhibitors were studied. The polymers of AGM-CBA and ARG-CBA can avoid endosomal/lysosomal trap, therefore, greatly delivering plasmid DNA (pDNA) to the cell nucleoli. It is the guanidine groups in the polymers that enhanced complexes' permeation through cell membrane with slight membrane damage, and targeting to the nucleoli. J. Cell. Biochem. 118: 903-913, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27764889 TI - Circumferentially oversewn inverted stapled anastomosis. AB - BACKGROUND: Leak rates of over 5% following anastomoses between the ileum and colon continue to be reported in large series and are associated with substantial morbidity and with mortality rates of 10-20%. In 1994, we began performing circumferentially oversewn inverted stapled anastomoses in patients undergoing ileo-colic anastomoses or ileostomy closure. It has become increasingly apparent that this method is associated with a low risk of leakage, which we should report. METHODS: The anastomotic technique described was used in all patients undergoing ileo-colic anastomosis or closure of ileostomy by surgeon 1 (1994 2015) and in all ileo-colic anastomoses by surgeon 2 (2007-2015). All patients had a widely patent anastomosis constructed by two firings of a linear cutting stapler, as previously described. Additionally, the entire staple line was carefully oversewn with interrupted, inverting 4/0 polydioxanone sutures. Anastomotic leak was defined as a patient requiring re-operation or radiological drainage. RESULTS: One thousand and twelve patients underwent ileo-colic anastomosis and 685 patients underwent closure of ileostomy by surgeon 1, and 165 patients underwent ileo-colic anastomosis by surgeon 2. None of the 1862 patients required re-operation or radiological drainage for a leak (event rate 0%, 95% confidence interval 0-0.2%). However, there were three possible contained leaks treated successfully conservatively. The time taken to perform the actual anastomosis was measured in the last 30 ileo-colic resections. The median time was 42 min. CONCLUSION: While this method may well be too slow to gain widespread adoption, we hope this report encourages increased research into finding techniques with similar low leak rates. PMID- 27764890 TI - Developmental dysplasia of the hip: A computational biomechanical model of the path of least energy for closed reduction. AB - This study utilized a computational biomechanical model and applied the least energy path principle to investigate two pathways for closed reduction of high grade infantile hip dislocation. The principle of least energy when applied to moving the femoral head from an initial to a final position considers all possible paths that connect them and identifies the path of least resistance. Clinical reports of severe hip dysplasia have concluded that reduction of the femoral head into the acetabulum may occur by a direct pathway over the posterior rim of the acetabulum when using the Pavlik harness, or by an indirect pathway with reduction through the acetabular notch when using the modified Hoffman Daimler method. This computational study also compared the energy requirements for both pathways. The anatomical and muscular aspects of the model were derived using a combination of MRI and OpenSim data. Results of this study indicate that the path of least energy closely approximates the indirect pathway of the modified Hoffman-Daimler method. The direct pathway over the posterior rim of the acetabulum required more energy for reduction. This biomechanical analysis confirms the clinical observations of the two pathways for closed reduction of severe hip dysplasia. The path of least energy closely approximated the modified Hoffman-Daimler method. Further study of the modified Hoffman-Daimler method for reduction of severe hip dysplasia may be warranted based on this computational biomechanical analysis. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1799-1805, 2017. PMID- 27764891 TI - Hepatic resection for post-operative solitary liver metastasis from oesophageal squamous cell carcinoma. AB - BACKGROUND: Liver metastasis is common in patients with oesophageal cancer. The effect of operative intervention for post-operative solitary liver metastasis from oesophageal squamous cell carcinoma (ESCC) has not previously been examined. This research was to compare the effect of surgery and non-surgical therapy in patients with post-operative solitary liver metastasis from ESCC. METHODS: We retrospectively analysed the clinical data of 69 consecutive patients with solitary hepatic metastasis who had undergone oesophagectomy for ESCC and were subsequently referred to the First Affiliated Hospital of Zhengzhou University from January 2005 to December 2013. The survival rates of the surgical and non surgical groups were compared. RESULTS: There were 26 patients in the surgical group and 43 patients in the non-surgical group. There was no operative death in the surgical group. Post-operative complications were observed in six patients, and all of these patients recovered after additional treatments. Patients in the surgical group had 1- and 2-year cumulative survival rates of 50.8 and 21.2%, respectively, which were significantly higher than the 31.0 and 7.1% survival rates of patients in the non-surgical group (P < 0.05). In each group, the patients with a disease-free interval (DFI) lasting >12 months had a better survival rate than those with a DFI lasting <=12 months (all P < 0.05). CONCLUSIONS: Operative intervention is a better treatment choice for patients with post-operative solitary liver metastasis from ESCC, especially for patients with a DFI lasting >12 months. Patients selected for hepatic resection should be considered on an individual basis through a multidisciplinary team of specialists. PMID- 27764892 TI - Association between plasminogen activator inhibitor-1 and severity of liver injury and cardiovascular risk in children with non-alcoholic fatty liver disease. AB - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of the endogenous fibrinolytic system and is known to be increased in obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD). We previously demonstrated that PAI-1 levels were closely related to the amount of hepatic steatosis in children. OBJECTIVES: The aim of this study was to characterize plasma PAI-1 in relationship to severity of inflammation and fibrosis, as well as to plasma lipids in children with NAFLD. METHODS: In 44 children with NAFLD, plasma PAI-1 levels and lipids were measured at the time of a liver biopsy. Hepatic histological features were systematically scored. Trend analysis was applied to determine the correlation of plasma PAI-1 levels with lipid markers for cardiovascular disease and with the staging of histological features in the liver. RESULTS: We found that plasma PAI-1 levels were significantly increased in children with increased severity of steatosis, lobular inflammation, ballooning and fibrosis. Furthermore, PAI-1 was strongly correlated with plasma lipids and insulin resistance indices. CONCLUSIONS: PAI-1 appears to be tightly related to both histologic severity of NAFLD as well as systemic features of the disease including insulin resistance and dyslipidemia. PAI-1 may be a mediator of disease progression and future cardiovascular complications in children with NAFLD. PMID- 27764894 TI - Predicting stomatal responses to the environment from the optimization of photosynthetic gain and hydraulic cost. AB - Stomatal regulation presumably evolved to optimize CO2 for H2 O exchange in response to changing conditions. If the optimization criterion can be readily measured or calculated, then stomatal responses can be efficiently modelled without recourse to empirical models or underlying mechanism. Previous efforts have been challenged by the lack of a transparent index for the cost of losing water. Yet it is accepted that stomata control water loss to avoid excessive loss of hydraulic conductance from cavitation and soil drying. Proximity to hydraulic failure and desiccation can represent the cost of water loss. If at any given instant, the stomatal aperture adjusts to maximize the instantaneous difference between photosynthetic gain and hydraulic cost, then a model can predict the trajectory of stomatal responses to changes in environment across time. Results of this optimization model are consistent with the widely used Ball-Berry-Leuning empirical model (r2 > 0.99) across a wide range of vapour pressure deficits and ambient CO2 concentrations for wet soil. The advantage of the optimization approach is the absence of empirical coefficients, applicability to dry as well as wet soil and prediction of plant hydraulic status along with gas exchange. PMID- 27764895 TI - Cessation of oil exposure in harlequin ducks after the Exxon Valdez oil spill: Cytochrome P4501A biomarker evidence. AB - The authors quantified hepatic hydrocarbon-inducible cytochrome P4501A (CYP1A) expression, as ethoxyresorufin-O-deethylase (EROD) activity, in wintering harlequin ducks (Histrionicus histrionicus) captured in Prince William Sound, Alaska (USA), during 2011, 2013, and 2014 (22-25 yr following the 1989 Exxon Valdez oil spill). Average EROD activity was compared between birds from areas oiled by the spill and those from nearby unoiled areas. The present study replicated studies conducted from 1998 to 2009 demonstrating that harlequin ducks using areas oiled in 1989 had elevated EROD activity, indicative of oil exposure, up to 2 decades post spill. In the present study, it was found that average EROD activity during March 2011 was significantly higher in wintering harlequin ducks captured in oiled areas relative to unoiled areas, which the authors interpret to indicate that harlequin ducks continued to be exposed to residual Exxon Valdez oil up to 22 yr after the original spill. However, the 2011 results also indicated reductions in exposure relative to previous years. Average EROD activity in birds from oiled areas was approximately 2 times that in birds from unoiled areas in 2011, compared with observations from 2005 to 2009, in which EROD activity was 3 to 5 times higher in oiled areas. It was also found that average EROD activity during March 2013 and March 2014 was not elevated in wintering harlequin ducks from oiled areas. The authors interpret these findings to indicate that exposure of harlequin ducks to residual Exxon Valdez oil abated within 24 yr after the original spill. The present study finalizes a timeline of exposure, extending over 2 decades, for a bird species thought to be particularly vulnerable to oil contamination in marine environments. Environ Toxicol Chem 2017;36:1294-1300. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 27764893 TI - Post-traumatic osteoarthritis of the ankle: A distinct clinical entity requiring new research approaches. AB - The diagnosis of ankle osteoarthritis (OA) is increasing as a result of advancements in non-invasive imaging modalities such as magnetic resonance imaging, improved arthroscopic surgical technology and heightened awareness among clinicians. Unlike OA of the knee, primary or age-related ankle OA is rare, with the majority of ankle OA classified as post-traumatic (PTOA). Ankle trauma, more specifically ankle sprain, is the single most common athletic injury, and no effective therapies are available to prevent or slow progression of PTOA. Despite the high incidence of ankle trauma and OA, ankle-related OA research is sparse, with the majority of clinical and basic studies pertaining to the knee joint. Fundamental differences exist between joints including their structure and molecular composition, response to trauma, susceptibility to OA, clinical manifestations of disease, and response to treatment. Considerable evidence suggests that research findings from knee should not be extrapolated to the ankle, however few ankle-specific preclinical models of PTOA are currently available. The objective of this article is to review the current state of ankle OA investigation, highlighting important differences between the ankle and knee that may limit the extent to which research findings from knee models are applicable to the ankle joint. Considerations for the development of new ankle specific, clinically relevant animal models are discussed. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:440-453, 2017. PMID- 27764896 TI - New Potential Biomarker Proteins for Alcoholic Liver Disease Identified by a Comparative Proteomics Approach. AB - Chronic alcohol consumption causes hepatic steatosis, which is characterized by a considerable increase in free fatty acid (FFA) and triglyceride levels. To identify the possible proteins involved in the progression to alcoholic hepatosteatosis, we performed proteomic analysis on livers of mice exposed to alcohol. 2D-based proteomic analysis revealed that EtOH exposure in mice changed the expression of 43 proteins compared with that in mice fed a normal diet (ND). The most notable protein changes were proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in alcohol exposed animals. Although non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) seem to share the same molecular processes, the difference between these conditions is still unclear. To address this question, we explored the features of alcoholic hepatosteatosis that were different compared with those of methionine and choline deficient (MCD) diet-induced mice with nonalcoholic liver damage. Although most of the differentially expressed proteins associated with ALD did not significantly differ from those of NAFLD, nine proteins showed considerably different patterns. Of these, ornithine aminotransferase, vitamin D binding protein, and phosphatidylethanolamine-binding protein were considerably upregulated in ALD mice, compared to that in NAFLD and ND mice. However, other proteins including inorganic pyrophosphatase were differentially regulated in MCD mice; however, they did not differ significantly between the alcoholic model and ND control mice. These results suggested that the identified proteins might be useful candidate markers to differentiate ALD from NAFLD. J. Cell. Biochem. 118: 1189-1200, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27764897 TI - The barriers and enablers of healthy eating among young adults: a missing piece of the obesity puzzle: A scoping review. AB - Young adults in Western countries are gaining weight faster than their parents and are more likely to gain weight than any other age cohort. Despite this, investigation into the complex young adults' food choice motives, which enable and prevent healthy eating, has not been widely investigated. A scoping review was conducted involving an extensive literature search of four major electronic databases: Medline, Embase, PsychInfo and CINAHL. Data were collected from 34 articles: study descriptions numerically analysed and key findings thematically analysed. The key barriers found included: male apathy towards diet; unhealthy diet of friends and family; expected consumption of unhealthy foods in certain situations; relative low cost of unhealthy foods; lack of time to plan, shop, prepare and cook healthy foods; lack of facilities to prepare, cook and store healthy foods; widespread presence of unhealthy foods; lack of knowledge and skills to plan, shop, prepare and cook healthy foods; lack of motivation to eat healthily (including risk-taking behaviour). The key enablers found included: female interest in a healthy diet; healthy diet of friends and family; support/encouragement of friends and family to eat healthy; desire for improved health; desire for weight management; desire for improved self-esteem; desire for attractiveness to potential partners and others; possessing autonomous motivation to eat healthy and existence and use of self-regulatory skills. This research provides evidence that can be used to tailor interventions for healthy eating and overweight and obesity in this population. However, government intervention in addressing food access, affordability, marketing and taxation remains essential to any significant change. PMID- 27764898 TI - Prophylactic abdominal drainage for pancreatic surgery. AB - BACKGROUND: The use of surgical drains has been considered mandatory after pancreatic surgery. The role of prophylactic abdominal drainage to reduce postoperative complications after pancreatic surgery is controversial. OBJECTIVES: To assess the benefits and harms of routine abdominal drainage after pancreatic surgery, compare the effects of different types of surgical drains, and evaluate the optimal time for drain removal. SEARCH METHODS: For the initial version of this review, we searched the Cochrane Library (2015, Issue 3), MEDLINE (1946 to 9 April 2015), Embase (1980 to 9 April 2015), Science Citation Index Expanded (1900 to 9 April 2015), and Chinese Biomedical Literature Database (CBM) (1978 to 9 April 2015). For this updated review, we searched the Cochrane Library, MEDLINE, Embase, Science Citation Index Expanded, and CBM from 2015 to 28 August 2016. SELECTION CRITERIA: We included all randomized controlled trials that compared abdominal drainage versus no drainage in people undergoing pancreatic surgery. We also included randomized controlled trials that compared different types of drains and different schedules for drain removal in people undergoing pancreatic surgery. DATA COLLECTION AND ANALYSIS: We identified five trials (of 985 participants) which met our inclusion criteria. Two review authors independently identified the trials for inclusion, collected the data, and assessed the risk of bias. We performed the meta-analyses using Review Manager 5. We calculated the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). For all analyses, we employed the random-effects model. MAIN RESULTS: Drain use versus no drain useWe included three trials involving 711 participants who were randomized to the drainage group (N = 358) and the no drainage group (N = 353) after pancreatic surgery. There was inadequate evidence to establish the effect of drains on mortality at 30 days (2.2% with drains versus 3.4% no drains; RR 0.78, 95% CI 0.31 to 1.99; three studies; low-quality evidence), mortality at 90 days (2.9% versus 11.6%; RR 0.24, 95% CI 0.05 to 1.10; one study; low-quality evidence), intra-abdominal infection (7.3% versus 8.5%; RR 0.89, 95% CI 0.36 to 2.20; three studies; very low-quality evidence), wound infection (12.3% versus 13.3%; RR 0.92, 95% CI 0.63 to 1.36; three studies; low-quality evidence), morbidity (64.8% versus 62.0%; RR 1.04, 95% CI 0.93 to 1.16; three studies; moderate-quality evidence), length of hospital stay (MD -0.66 days, 95% CI -1.60 to 0.29; three studies; moderate-quality evidence), or additional open procedures for postoperative complications (11.5% versus 9.1%; RR 1.18, 95% CI 0.55 to 2.52; three studies). There was one drain-related complication in the drainage group (0.6%). Type of drainWe included one trial involving 160 participants who were randomized to the active drain group (N = 82) and the passive drain group (N = 78) after pancreatic surgery. There was no evidence of differences between the two groups in mortality at 30 days (1.2% with active drain versus 0% with passive drain), intra-abdominal infection (0% versus 2.6%), wound infection (6.1% versus 9.0%; RR 0.68, 95% CI 0.23 to 2.05), morbidity (22.0% versus 32.1%; RR 0.68, 95% CI 0.41 to 1.15), or additional open procedures for postoperative complications (1.2% versus 7.7%; RR 0.16, 95% CI 0.02 to 1.29). The active drain group was associated with shorter length of hospital stay (MD -1.90 days, 95% CI -3.67 to 0.13; 14.1% decrease of an 'average' length of hospital stay) than in the passive drain group. The quality of evidence was low, or very low. Early versus late drain removalWe included one trial involving 114 participants with a low risk of postoperative pancreatic fistula who were randomized to the early drain removal group (N = 57) and the late drain removal group (N = 57) after pancreatic surgery. There was no evidence of differences between the two groups in mortality at 30 days (0% for both groups) or additional open procedures for postoperative complications (0% with early drain removal versus 1.8% with late drain removal; RR 0.33, 95% CI 0.01 to 8.01). The early drain removal group was associated with lower rates of postoperative complications (38.5% versus 61.4%; RR 0.63, 95% CI 0.43 to 0.93), shorter length of hospital stay (MD -2.10 days, 95% CI -4.17 to 0.03; 21.5% decrease of an 'average' length of hospital stay), and hospital costs (17.0% decrease of 'average' hospital costs) than in the late drain removal group. The quality of evidence for each of the outcomes was low. AUTHORS' CONCLUSIONS: It is unclear whether routine abdominal drainage has any effect on the reduction of mortality and postoperative complications after pancreatic surgery. In case of drain insertion, low-quality evidence suggests that active drainage may reduce hospital stay after pancreatic surgery, and early removal may be superior to late removal for people with low risk of postoperative pancreatic fistula. PMID- 27764899 TI - Bioaccumulation of methylmercury in a marine copepod. AB - Methylmercury (MeHg) is known to biomagnify in marine food chains, resulting in higher concentrations in upper trophic level animals than their prey. To better understand how marine copepods, an important intermediate between phytoplankton and forage fish at the bottom of the food chain, assimilate and release MeHg, the authors performed a series of laboratory experiments using the gamma-emitting radiotracer 203 Hg2+ and Me203 Hg with the calanoid copepod Acartia tonsa. Assimilation efficiencies of Hg2+ and MeHg ranged from 25% to 31% and 58% to 79%, respectively, depending on algal diets. Assimilation efficiencies were positively related to the fraction of Hg in the cytoplasm of the algal cells that comprised their diet. Efflux rates of Hg2+ (0.29/d) and MeHg (0.21/d) following aqueous uptake were similar, but efflux rates following dietary uptake were significantly lower for MeHg (0.11-0.22/d) than Hg2+ (0.47-0.66/d). The calculated trophic transfer factors in copepods were >1 for MeHg and consistently low (<=0.2) for Hg2+ . The authors used the parameters measured to quantitatively model the relative importance of MeHg sources (water or diet) for copepods and to predict the overall MeHg concentrations in copepods in different marine environments. In general, MeHg uptake from the diet accounted for most of the body burden in copepods (>50%). For an algal diet with a MeHg dry weight bioconcentration factor >=106 , >90% of a copepod's MeHg body burden can be shown to derive from the diet. The model-predicted MeHg concentrations in the copepods were comparable to independent measurements for copepods in coastal and open-ocean regions, implying that the measured parameters and model are applicable to natural waters. Environ Toxicol Chem 2017;36:1287-1293. (c) 2016 SETAC. PMID- 27764900 TI - Evaluation of long-term neurodevelopment in twin-twin transfusion syndrome after laser therapy. AB - OBJECTIVE: The primary objective of our study was to evaluate the long-term neurodevelopment outcome after laser surgery for twin-twin transfusion syndrome (TTTS). The secondary objective was to identify perinatal prognostic factors associated with neurodevelopmental impairment. METHOD: This was a single-center cohort prospective study carried out in pregnancies complicated by TTTS and treated by laser. Neurodevleopmental assesment included the administration of Ages and Stages Questionnaires(r) (ASQ), for the infants between 2 and 5 years of age. RESULTS: A total of 187 patients underwent a laser for TTTS between 2004 and 2013. Significant brain lesions were detected in eight (2.9%) cases by ultrasound and/or magnetic resonance imaging including intraventricular hemorrhage, periventricular leukomalacia, and porencephaly. Questionnaires were administered to 126 children (50.4%) at 24 months or older at the moment of testing. There were 13.5% of those infants who had an abnormal ASQ (established as one area or more scoring < 2 SD) at 3.6 years +/-1.3 follow-up. There was a higher rate of abnormal ASQ among the infants with a birth weight below the fifth percentile (p = 0.036). CONCLUSION: Twin-twin transfusion syndrome is associated with a risk of abnormal neurological development, even in case of laser surgery. Further studies are necessary to identify the risk factors for neurological impairment. (c) 2016 John Wiley & Sons, Ltd. PMID- 27764901 TI - Dermal-Epidermal Cross-Talk: Differential Interactions With Microvascular Endothelial Cells. AB - The biological importance of circulatory blood supply and angiogenesis for hair growth is now well recognized, but the their regulatory mechanisms require more mechanistic investigation. In vitro cocultures and tricultures can be successfully employed to greatly improve our knowledge on paracrine crosstalk between cell types that populate the dermal-epidermal interface and cutaneous vasculature. Here we report that human dermal fibroblasts (NHDF) promote viability and proliferation of microvascular endothelial cells (HMVEC), while HMVEC are not mitogenic for NHDF. In triculture setup, conditioned media (CM) obtained by cocultures (HMVEC/NHDF or HMVEC/follicle fibroblasts) differently modulate growth and proliferation of keratinocytes and alter the expression of metabolic and pro-inflammatory markers. In conclusion, tricultures were successfully employed to characterize in vitro dermal-epithelial and endothelial interactions and could integrate ex vivo and in vivo approaches by the use of high-throughput and standardized protocols in controlled conditions. J. Cell. Physiol. 232: 897-903, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27764902 TI - Urinary N-acetyl-beta-glucosaminidase and estimated Glomerular filtration rate may identify patients to be treated with immuno-suppression at diagnosis in idiopathic membranous nephropathy. AB - AIM: The clinical course of idiopathic membranous nephropathy (IMN) varies from spontaneous remission of nephrotic syndrome (NS) to end-stage renal disease (ESRD). The aim of the study was baseline identification of patients with high risk of progression for which immunosuppressive therapy is mandatory. METHODS: Eighty-six IMN subjects were followed for a median of 69 months (range 6-253). Receiver operating characteristic curve and Cox proportional hazards model were used to evaluate prognostic factors for progression, defined as ESRD or estimated glomerular filtration rate (eGFR) reduction >=50% of baseline. RESULTS: Among all, 24 subjects had progression. Area under the ROC curve of N-acetyl-beta glucosaminidase/creatinine ratio (NAG/C) were significantly higher than proteinuria/24 h (0.770 and 0.637 respectively, P = 0.018). In Cox proportional hazards regression analysis, NAG/C and eGFR were independent predictors of progression. Compared to lowest tertile of NAG/C (<9.4 UI/gC) or highest tertile of eGFR (>=88 mL/min per 1.73m2 ), the multivariable-adjusted hazard ratio of highest tertile of NAG/C (>=19.2) was 18.97 (95%CI, 1.70-211.86) and lowest tertile of eGFR (<59) was 11.58 (95%CI, 2.02-66.29). Subjects with high NAG/C or low eGFR (high-risk, n = 43) had greater progression rate compared to moderate to low NAG/C and high eGFR (low-risk, n = 43) with or without NS at baseline (Log rank test P = 0.001 and 0.006, respectively). In NS subjects (n = 65), high-risk group progression rate was significantly higher (91% vs. 29%, P = 0.003) and remission rate significantly lower (0% vs. 42%, p < 0.001) in non immunosuppressed compared to steroids and cyclophosphamide treated patients; no significant differences were observed in low-risk group. CONCLUSION: Idiopathic membranous nephropathy subjects with high NAG/C and low eGFR have greater risk of progression, and immunosuppressive treatment is suggested at diagnosis. PMID- 27764903 TI - Quality and clarity in systematic review abstracts: an empirical study. AB - BACKGROUND: Systematic review (SR) abstracts are important for disseminating evidence syntheses to inform medical decision making. We assess reporting quality in SR abstracts using PRISMA for Abstracts (PRISMA-A), Cochrane Handbook, and Agency for Healthcare Research & Quality guidance. METHODS: We evaluated a random sample of 200 SR abstracts (from 2014) comparing interventions in the general medical literature. We assessed adherence to PRISMA-A criteria, problematic wording in conclusions, and whether "positive" studies described clinical significance. RESULTS: On average, abstracts reported 60% of PRISMA-A checklist items (mean 8.9 +/- 1.7, range 4 to 12). Eighty percent of meta-analyses reported quantitative measures with a confidence interval. Only 49% described effects in terms meaningful to patients and clinicians (e.g., absolute measures), and only 43% mentioned strengths/limitations of the evidence base. Average abstract word count was 274 (SD 89). Word count explained only 13% of score variability. PRISMA A scores did not differ between Cochrane and non-Cochrane abstracts (mean difference 0.08, 95% confidence interval -1.16 to 1.00). Of 275 primary outcomes, 48% were statistically significant, 32% were not statistically significant, and 19% did not report significance or results. Only one abstract described clinical significance for positive findings. For "negative" outcomes, we identified problematic simple restatements (20%), vague "no evidence of effect" wording (9%), and wishful wording (8%). CONCLUSIONS: Improved SR abstract reporting is needed, particularly reporting of quantitative measures (for meta-analysis), easily interpretable units, strengths/limitations of evidence, clinical significance, and clarifying whether negative results reflect true equivalence between treatments. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27764904 TI - Incorporating Risk Factors to Identify the Indication of Post-mastectomy Radiotherapy in N1 Breast Cancer Treated with Optimal Systemic Therapy: A Multicenter Analysis in Korea (KROG 14-23). AB - PURPOSE: In a recent meta-analysis, post-mastectomy radiotherapy (PMRT) reduced any first recurrence (AFR) and improved survival in N1 and N2 patients. We investigated risk factors for AFR in N1 after optimal systemic therapy without PMRT, to define a subgroup of patients who may benefit from PMRT. MATERIALS AND METHODS: One thousand three hundred eighty-two pT1-2N1M0 breast cancer patients treated with mastectomy without PMRT between 2005 and 2010 were retrospectively analyzed. Only 0.6% had no systemic therapy. RESULTS: After a median follow-up of 5.9 years, there were 173 AFR (53 loco-regional recurrence [LRR] without distant metastases [DM], 38 LRR with DM, and 82 DM without LRR). The 5-year LRR and AFR rates were 6.1% and 12.0%, respectively. Multivariate analysis revealed that close resection margin (p=0.001) was the only independent risk factor for LRR. Multivariate analysis for AFR revealed that age < 35 years (p=0.025), T2 stage (p=0.004), high tumor grade (p=0.032), close resection margin (p=0.035), and triple-negative biological subtype (p=0.031) were independent risk factors. Two or three positive lymph nodes (p=0.078) were considered a marginally significant factor. When stratified by these six factors, the 5-year LRR rates were 3.6% with 0-1 (n=606), 7.5% with 2-3 (n=655), and 12.7% with 4-6 (n=93) risk factors. The 5 year AFR rates were 7.1% with 0-1, 15.0% with 2-3, and 24.5% with 4-6 risk factors. CONCLUSION: Patients with pT1-2N1M0 breast cancer who underwent mastectomy and optimal systemic therapy showed excellent loco-regional control and disease control. The patients with four or more risk factors may benefit from PMRT, and those with two or three risk factors merit consideration of PMRT. PMID- 27764905 TI - Development of a Community-Based Palliative Care Model for Advance Cancer Patients in Public Health Centers in Busan, Korea. AB - PURPOSE: A feasible palliative care model for advance cancer patients is needed in Korea with its rapidly aging population and corresponding increase in cancer prevalence. This study describes the process involved in the development of a community-based palliative care (CBPC) model implemented originally in a Busan pilot project. MATERIALS AND METHODS: The model development included steps I and II of the pilot project, identification of the service types, a survey exploring the community demand for palliative care, construction of an operational infrastructure, and the establishment of a service delivery system. Public health centers (including Busan regional cancer centers, palliative care centers, and social welfare centers) served as the regional hubs in the development of a palliative care model. RESULTS: The palliative care project included the provision of palliative care, establishment of a support system for the operations, improvement of personnel capacity, development of an educational and promotional program, and the establishment of an assessment system to improve quality. The operational infrastructure included a service management team, provision teams, and a support team. The Busan Metropolitan City CBPC model was based on the principles of palliative care as well as the characteristics of public health centers that implemented the community health projects. CONCLUSION: The potential use of the Busan CBPC model in Korea should be explored further through service evaluations. PMID- 27764906 TI - A Multicenter Randomized Phase II Study of Docetaxel vs. Docetaxel Plus Cisplatin vs. Docetaxel Plus S-1 as Second-Line Chemotherapy in Metastatic Gastric Cancer Patients Who Had Progressed after Cisplatin Plus Either S-1 or Capecitabine. AB - PURPOSE: This study evaluated the re-challenge of S-1 or cisplatin in combination with docetaxel in metastatic gastric cancer (MGC) that had progressed on a cisplatin plus either S-1 or capecitabine regimen. MATERIALS AND METHODS: Patients with progressive disease after first-line cisplatin plus S-1 or capecitabine were randomized to receive 3-week cycles of docetaxel 75 mg/m2 intravenously (IV) on D1 (D), docetaxel 60 mg/m2 IV plus cisplatin 60 mg/m2 IV on D1 (DC), or docetaxel 60 mg/m2 IV D1 plus oral S-1 30 mg/m2 twice a day on D1-14 (DS). RESULTS: Seventy-two patients were randomized to the D (n=23), DC (n=24), or DS (n=25) group. The confirmed response rate was 4.3% (95% confidence interval [CI], 0% to 12.6%), 4.3% (95% CI, 0% to 12.6%), and 8.7% (95% CI, 0% to 20.2%) for the D, DC, and DS groups, respectively. Compared to the D arm, the DS arm had a better progression-free survival (2.7 months vs. 1.3 months, p=0.034) without any deterioration in safety or quality of life, whereas the DC arm had a similar progression-free survival (1.8 months vs. 1.3 months, p=0.804) and poorer overall survival (5.6 months vs. 10.0 months, p=0.035). CONCLUSION: A re-challenge with S 1, but not cisplatin, in combination with docetaxel has potential anticancer benefits over docetaxel alone in MGC with progression after prior cisplatin plus S-1 or capecitabine. PMID- 27764907 TI - Assessment of the Asian Neurogastroenterology and Motility Association Chronic Constipation Criteria: An Asian Multicenter Cross-sectional Study. AB - Background/Aims: There is a need for a simple and practical tool adapted for the diagnosis of chronic constipation (CC) in the Asian population. This study compared the Asian Neurogastroenterology and Motility Association (ANMA) CC tool and Rome III criteria for the diagnosis of CC in Asian subjects. Methods: This multicenter, cross-sectional study included subjects presenting at outpatient gastrointestinal clinics across Asia. Subjects with CC alert symptoms completed a combination Diagnosis Questionnaire to obtain a diagnosis based on 4 different diagnostic methods: self-defined, investigator's judgment, ANMA CC tool, and Rome III criteria. The primary endpoint was the level of agreement/disagreement between the ANMA CC diagnostic tool and Rome III criteria for the diagnosis of CC. Results: The primary analysis comprised of 449 subjects, 414 of whom had a positive diagnosis according to the ANMA CC tool. Rome III positive/ANMA positive and Rome III negative/ANMA negative diagnoses were reported in 76.8% and 7.8% of subjects, respectively, resulting in an overall percentage agreement of 84.6% between the 2 diagnostic methods. The overall percentage disagreement between these 2 diagnostic methods was 15.4%. A higher level of agreement was seen between the ANMA CC tool and self-defined (374 subjects [90.3%]) or investigator's judgment criteria (388 subjects [93.7%]) compared with the Rome III criteria. Conclusion: This study demonstrates that the ANMA CC tool can be a useful for Asian patients with CC. PMID- 27764908 TI - Which supplementary imaging modality should be used for breast ultrasonography? Comparison of the diagnostic performance of elastography and computer-aided diagnosis. AB - PURPOSE: The aim of this study was to evaluate and compare the diagnostic performance of grayscale ultrasonography (US), US elastography, and US computer aided diagnosis (US-CAD) in the differential diagnosis of breast masses. METHODS: A total of 193 breast masses in 175 consecutive women (mean age, 46.4 years) from June to August 2015 were included. US and elastography images were obtained and recorded. A US-CAD system was applied to the grayscale sonograms, which were automatically analyzed and visualized in order to generate a final assessment. The final assessments of breast masses were based on the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories, while elasticity scores were assigned using a 5-point scoring system. The diagnostic performance of grayscale US, elastography, and US-CAD was calculated and compared. RESULTS: Of the 193 breast masses, 120 (62.2%) were benign and 73 (37.8%) were malignant. Breast masses had significantly higher rates of malignancy in BI-RADS categories 4c and 5, elastography patterns 4 and 5, and when the US-CAD assessment was possibly malignant (all P<0.001). Elastography had higher specificity (40.8%, P=0.042) than grayscale US. US-CAD showed the highest specificity (67.5%), positive predictive value (PPV) (61.4%), accuracy (74.1%), and area under the curve (AUC) (0.762, all P<0.05) among the three diagnostic tools. CONCLUSION: US-CAD had higher values for specificity, PPV, accuracy, and AUC than grayscale US or elastography. Computer-based analysis based on the morphologic features of US may be very useful in improving the diagnostic performance of breast US. PMID- 27764909 TI - Value of sagittal color Doppler ultrasonography as a supplementary tool in the differential diagnosis of fetal cleft lip and palate. AB - PURPOSE: The purpose of this study was to evaluate the feasibility and usefulness of sagittal color Doppler ultrasonography (CDUS) for the diagnosis of fetal cleft lip (CL) and cleft palate (CP). METHODS: We performed targeted ultrasonography on 25 fetuses with CL and CP, taking coronal and axial images of the upper lip and maxillary alveolar arch in each case. The existence of defects in and malalignment of the alveolus on the axial image, hard palate defects on the midsagittal image, and flow-through defects on CDUS taken during fetal breathing or swallowing were assessed. We compared the ultrasonography findings with postnatal findings in all fetuses. RESULTS: Alveolar defects were detected in 16 out of 17 cases with CP and four out of eight cases with CL. Alveolar malalignment and hard palate defects were detected in 11 out of 17 cases and 14 out of 17 cases with CP, respectively, but not detected in any cases with CL. Communicating flow through the palate defect was detected in 11 out of 17 cases of CL with CP. The accuracy of detection in axial scans of an alveolar defect and malalignment was 80% and 76%, respectively. Accuracy of detection of in mid sagittal images of hard palate defect and flow was 80% and 86%, respectively. The overall diagnostic accuracy of combined axial and sagittal images with sagittal CDUS was 92%. CONCLUSION: Sagittal CDUS of the fetal hard palate is a feasible method to directly reveal hard palate bony defects and flow through defects, which may have additional value in the differential diagnosis of fetal CL and CP. PMID- 27764910 TI - Magnetic resonance imaging and pathological characteristics of pure mucinous carcinoma in the breast according to echogenicity on ultrasonography. AB - PURPOSE: The aim of this study was to explore the clinical and pathological characteristics of pure mucinous breast carcinoma (PMBC) according to internal echogenicity on ultrasonography (US). METHODS: Thirty-three patients with PMBC diagnosed at surgery were included in this study. Cases of PMBC were classified according to internal echogenicity on US. The imaging features on magnetic resonance (MR) imaging and clinicohistopathological characteristics were compared between the hypoechogenic and the isoechogenic to hyperechogenic groups. RESULTS: Eleven cases of PMBC (33.3%) exhibited hypoechogenicity on US, while 22 cases (66.7%) exhibited isoechogenicity or hyperechogenicity. Of the isoechogenic to hyperechogenic PMBCs, 95.5% showed a high signal on T2-weighted images, which was a significantly greater percentage than was observed for the hypoechogenic group (54.5%) (P=0.010). Of the hypoechogenic PMBCs, 63.6% showed a washout pattern in the delayed phase, which was substantially more than the result of 23.8% observed for the isoechogenic to hyperechogenic PMBCs (P=0.053). CONCLUSION: PMBCs with isoechogenicity or hyperechogenicity were more likely to show a high signal intensity on T2-weighted images than hypoechogenic PMBCs. However, other MR imaging and clinicohistopathological characteristics were not significantly different between the two groups. PMID- 27764911 TI - Ultrasonographic measurement of the axillary recess thickness in an asymptomatic shoulder. AB - PURPOSE: The purpose of this study was to measure the axillary recess (AR) thickness in an asymptomatic shoulder by using ultrasonography (US) and to analyze the factors affecting it. METHODS: We recruited 141 patients (52 males; 89 females; age, 57.7+/-9.9 years) with unilateral shoulder pain and performed US on the unaffected shoulder. Two physiatrists measured the AR thickness of the unaffected shoulder independently. All patients were examined in an upright sitting position with 90 degrees shoulder abduction. The ultrasonographic transducer was placed longitudinally on the mid-axillary line and along the long axis of the humeral shaft. The factors affecting the AR thickness values were analyzed, and intra-class correlation coefficients were used for assessing the reproducibility of each measurement. RESULTS: The intrarater reliability values for the two physiatrists were 0.98 and 0.96, respectively. The inter-rater reliability of the mean AR thickness measurements was 0.91. The mean AR thickness in all subjects, males, and females was 2.8+/-0.6 mm, 3.1+/-0.6 mm, and 2.6+/-0.5 mm (P<0.01), respectively. No difference between the left and the right sides (males, P=0.086; females, P=0.535) or between the dominant and the non-dominant sides (males, P=0.173; female, P=0.244) was found. The AR thickness correlated positively with the height (r=0.313, P<0.01) and the weight (r=0.319, P<0.01). However, it did not correlate with the body mass index (r=0.152, P=0.077) or the age (r=-0.056, P=0.515). CONCLUSION: US measurements of the AR thickness in asymptomatic shoulders demonstrated excellent intrarater and inter-rater reliabilities. The AR thickness showed anatomical variation with sex, height, and weight. PMID- 27764912 TI - Efficient transgene expression system using a cumate-inducible promoter and Cre loxP recombination in avian cells. AB - OBJECTIVE: Transgenic technology is widely used for industrial applications and basic research. Systems that allow for genetic modification play a crucial role in biotechnology for a number of purposes, including the functional analysis of specific genes and the production of exogenous proteins. In this study, we examined and verified the cumate-inducible transgene expression system in chicken DF1 and quail QM7 cells, as well as loxP element-mediated transgene recombination using Cre recombinase in DF1 cells. METHODS: After stable transfer of the transgene with piggyBac transposon and transposase, transgene expression was induced by an appropriate concentration of cumate. Additionally, we showed that the transgene can be replaced with additional transgenes by co-transfection with the Cre recombinase expression vector. RESULTS: In the cumate-GFP DF1 and QM7 cells, green fluorescent protein (GFP) expression was repressed in the off state in the absence of cumate, and the GFP transgene expression was successfully induced in the presence of cumate. In the cumate-MyoD DF1 cells, MyoD transgene expression was induced by cumate, and the genes controlled by MyoD were upregulated according to the number of days in culture. Additionally, for the translocation experiments, a stable enhanced green fluorescent protein (eGFP) expressing DF1 cell line transfected with the loxP66-eGFP-loxP71 vector was established, and DsRed-positive and eGFP-negative cells were observed after 14 days of co-transfection with the DsRed transgene and Cre recombinase indicating that the eGFP transgene was excised, and the DsRed transgene was replaced by Cre recombination. CONCLUSION: Transgene induction or replacement cassette systems in avian cells can be applied in functional genomics studies of specific genes and adapted further for efficient generation of transgenic poultry to modulate target gene expression. PMID- 27764913 TI - Influences of somatic donor cell sex on in vitro and in vivo embryo development following somatic cell nuclear transfer in pigs. AB - OBJECTIVE: The present study investigates pre- and post-implantation developmental competence of nuclear-transferred porcine embryos derived from male and female fetal fibroblasts. METHODS: Male and female fetal fibroblasts were transferred to in vitro-matured enucleated oocytes and in vitro and in vivo developmental competence of reconstructed embryos was investigated. And, a total of 6,789 female fibroblast nuclear-transferred embryos were surgically transferred into 41 surrogate gilts and 4,746 male fibroblast nuclear-transferred embryos were surgically transferred into 25 surrogate gilts. RESULTS: The competence to develop into blastocysts was not significantly different between the sexes. The mean cell number of female and male cloned blastocysts obtained by in vivo culture (143.8+/-10.5 to 159.2+/-14.8) was higher than that of in vitro culture of somatic cell nuclear transfer (SCNT) groups (31.4+/-8.3 to 33.4+/ 11.1). After embryo transfer, 5 pregnant gilts from each treatment delivered 15 female and 22 male piglets. The average birth weight of the cloned piglets, gestation length, and the postnatal survival rates were not significantly different (p<0.05) between sexes. CONCLUSION: The present study found that the sex difference of the nuclear donor does not affect the developmental rate of porcine SCNT embryos. Furthermore, postnatal survivability of the cloned piglets was not affected by the sex of the donor cell. PMID- 27764914 TI - The effects of high-fat diets composed of different animal and vegetable fat sources on the health status and tissue lipid profiles of male Japanese quail (Coturnix coturnix japonica). AB - OBJECTIVE: The current study aimed to investigate the impact of high-fat diets composed of different animal and vegetable fat sources on serum metabolic health markers in Japanese quail, as well as the overall lipid content and fatty acid profiles of the edible bird tissues following significantly increased dietary lipid supplementation. METHODS: Fifty seven male quail were divided into six groups and fed either a standard diet or a diet enriched with one of five different fats (22% coconut oil, lard, palm oil, soybean oil, or sunflower oil) for 12 weeks. The birds were subjected to an oral glucose tolerance test following the feeding period, after which they were euthanized and blood, liver, breast, and thigh muscle samples collected. Total fat content and fatty acid profiles of the tissue samples, as well as serum uric acid, triglyceride, cholesterol, total protein, albumin, aspartate transaminase, and total bilirubin concentrations were assessed. RESULTS: High-fat diet feeding had no significant effects on the glucose tolerance of the birds. Dietary fatty acid profiles of the added fats were reflected in the lipid profiles of both the liver and breast and thigh muscle tissues, indicating successful transfer of dietary fatty acids to the edible bird tissues. The significantly increased level of lipid inclusion in the diets of the quail used in the present study was unsuccessful in increasing the overall lipid content of the edible bird tissues. Serum metabolic health markers in birds on the high-fat diets were not significantly different from those observed in birds on the standard diet. CONCLUSION: Thus, despite the various high-fat diets modifying the fatty acid profile of the birds' tissues, unlike in most mammals, the birds maintained a normal health status following consumption of the various high-fat diets. PMID- 27764915 TI - Characteristics of isolated lactic acid bacteria and their effects on the silage quality. AB - OBJECTIVE: Four lactic acid bacteria (LAB) strains isolated from common vetch, tall fescue and perennial ryegrass on the Tibetan Plateau were characterized, and their effects on the fermentation quality of Italian ryegrass (Lolium multiflorum Lam.) silage were studied. METHODS: The four isolated strains and one commercial inoculant (G, Lactobacillus plantarum MTD-1) were evaluated using the acid production ability test, morphological observation, Gram staining, physiological, biochemical and acid tolerance tests. The five LAB strains were added to Italian ryegrass for ensiling at three different temperatures (10 degrees C, 15 degrees C, and 25 degrees C). RESULTS: All isolated strains (LCG3, LTG7, I5, and LI3) could grow at 5 degrees C to 20 degrees C, pH 3.0 to 8.0 and NaCl (3.0%, 6.5%). Strains LCG3, LTG7, I5, and LI3 were identified as Lactobacillus plantarum, Pediococcus acidilactici, Lactobacillus paraplantarum, and Lactobacillus casei by sequencing 16S rDNA, respectively. All LAB inoculants significantly (p<0.05) increased lactic acid (LA) contents and ratios of lactic acid to acetic acid, and reduced pH and ammonia nitrogen/total nitrogen (AN/TN) compared with uninoculated silages at various temperatures (10 degrees C, 15 degrees C, and 25 degrees C). Compared to the commercial inoculant G, I5, and LI3 showed similar effects on improving the silage quality of Italian ryegrass at 10 degrees C and 15 degrees C, indicated by similar pH, LA content and AN/TN. CONCLUSION: All inoculants could improve the silage fermentation quality at various temperatures (10 degrees C, 15 degrees C, and 25 degrees C). At the temperature of 10 degrees C and 15 degrees C, strain I5 and LI3 had similar effects with the commercial inoculant G on improving the silage quality of Italian ryegrass. PMID- 27764916 TI - Myostatin gene knockout mediated by Cas9-D10A nickase in chicken DF1 cells without off-target effect. AB - OBJECTIVE: Based on rapid advancement of genetic modification techniques, genomic editing is expected to become the most efficient tool for improvement of economic traits in livestock as well as poultry. In this study, we examined and verified the nickase of mutated CRISPR-associated protein 9 (Cas9) to modulate the specific target gene in chicken DF1 cells. METHODS: Chicken myostatin which inhibits muscle cell growth and differentiation during myogenesis was targeted to be deleted and mutated by the Cas9-D10A nickase. After co-transfection of the nickase expression vector with green fluorescent gene (GFP) gene and targeted multiplex guide RNAs (gRNAs), the GFP-positive cells were sorted out by fluorescence-activated cell sorting procedure. RESULTS: Through the genotyping analysis of the knockout cells, the mutant induction efficiency was 100% in the targeted site. Number of the deleted nucleotides ranged from 2 to 39 nucleotide deletion. There was no phenotypic difference between regular cells and knockout cells. However, myostatin protein was not apparently detected in the knockout cells by Western blotting. Additionally, six off-target sites were predicted and analyzed but any non-specific mutation in the off-target sites was not observed. CONCLUSION: The knockout technical platform with the nickase and multiplex gRNAs can be efficiently and stablely applied to functional genomics study in poultry and finally adapted to generate the knockout poultry for agribio industry. PMID- 27764917 TI - Expression and regulation of prostaglandin transporters, ATP-binding cassette, subfamily C, member 1 and 9, and solute carrier organic anion transporter family, member 2A1 and 5A1 in the uterine endometrium during the estrous cycle and pregnancy in pigs. AB - OBJECTIVE: Prostaglandins (PGs) function in various reproductive processes, including luteolysis, maternal pregnancy recognition, conceptus development, and parturition. Our earlier study has shown that PG transporters ATP-binding cassette, subfamily C, member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) are expressed in the uterine endometrium in pigs. Since several other PG transporters such as ABCC1, ABCC9, SLCO4C1, and SLCO5A1 are known to be present in the uterine endometrium, this study investigated the expression of these PG transporters in the porcine uterine endometrium and placenta. METHODS: Uterine endometrial tissues were obtained from gilts on day (D) 12 and D15 of the estrous cycle and days 12, 15, 30, 60, 90, and 114 of pregnancy. RESULTS: ABCC1, ABCC9, SLCO4C1, and SLCO5A1 mRNAs were expressed in the uterine endometrium, and levels of expression changed during the estrous cycle and pregnancy. Expression of ABCC1 and ABCC9 mRNAs was localized mainly to luminal and glandular epithelial cells in the uterine endometrium, and chorionic epithelial cells during pregnancy. Conceptuses during early pregnancy and chorioallantoic tissues from mid to late pregnancy also expressed these PG transporters. Estradiol-17beta increased the expression of ABCC1 and SLCO5A1, but not ABCC9 and SLCO4C1 mRNAs and increasing doses of interleukin-1beta induced the expression of ABCC9, SLCO4C1, and SLCO5A1 mRNAs in endometrial explant tissues. CONCLUSION: These data showed that several PG transporters such as ABCC1, ABCC9, SLCO4C1, and SLCO5A1 were expressed at the maternal-conceptus interface, suggesting that these PG transporters may play an important role in the establishment and maintenance of pregnancy by regulating PG transport in the uterine endometrium and placenta in pigs. PMID- 27764918 TI - Estimation of the net energy requirement for maintenance in broilers. AB - OBJECTIVE: The net energy requirement for the maintenance (NEm) of broilers was determined using regression models by the indirect calorimetry method (ICM) or the comparative slaughter method (CSM). METHODS: A 2*4 factorial arrangement of treatments including the evaluation method (ICM or CSM) and feed intake (25%, 50%, 75%, or 100% of ad libitum recommended) was employed in this experiment. In the ICM, 96 male Arbor Acres (AA) birds aged d 15 were used with 4 birds per replicate and 6 replicates in each treatment. In the CSM, 116 male AA birds aged d 15 were used. Among these 116 birds, 20 were selected as for initial data and 96 were assigned to 4 treatments with 6 replicate cages and 4 birds each. The linear regression between retained energy (RE) and metabolizable energy intake (MEI) or the logarithmic regression between heat production (HP) and MEI were used to calculate the metabolizable or net energy requirement for maintenance (MEm) or NEm, respectively. RESULTS: The evaluation method did not detect any differences in the metabolizable energy (ME), net energy (NE), and NE:ME of diet, and in the MEI, HP, and RE of broilers. The MEI, HP, and RE of broilers decreased (p<0.01) as the feed intake decreased. No evaluation method* feed intake interaction was observed on these parameters. The MEm and NEm estimated from the linear relationship were 594 and 386 kJ/kg of body weight (BW)0.75/d in the ICM, and 618 and 404 kJ/kg of BW0.75/d in the CSM, respectively. The MEm and NEm estimated by logarithmic regression were 607 and 448 kJ/kg of BW0.75/d in the ICM, and were 619 and 462 kJ/kg of BW0.75/d in the CSM, respectively. CONCLUSION: The NEm values obtained in this study provide references for estimating the NE values of broiler diets. PMID- 27764919 TI - [Health expenditure for prevention in Italy (2006-2013): descriptive analysis, regional trends and international comparisons]. AB - Il dato dell'Organizzazione per la cooperazione e lo sviluppo economico (OCSE) del 2012, che indicava l'Italia come il Paese con la piu bassa spesa in prevenzione sanitaria, ha dato lo spunto per una raccolta sistematica e un'analisi critica dei flussi disponibili sulla spesa per le attivita di prevenzione in Italia. Le statistiche correnti di spesa sanitaria sono raccolte centralmente dall'Agenzia nazionale per i servizi sanitari regionali (Agenas) attraverso i modelli di rilevazione dei costi dei livelli essenziali di assistenza (LEA) delle aziende USL. Le tre macroaree dei LEA sono: assistenza distrettuale, assistenza ospedaliera e assistenza sanitaria collettiva in ambiente di vita e di lavoro. Le spese per la prevenzione rientrano in quest'ultima e sono ripartite nelle seguenti voci: attivita di prevenzione rivolte alle persone, igiene degli alimenti e della nutrizione, igiene e sanita pubblica, prevenzione e sicurezza negli ambienti di lavoro, sanita pubblica veterinaria, attivita medico-legale per finalita pubblica. Tra il 2006 e il 2013, ultimo dato disponibile, la spesa per le attivita di prevenzione del Servizio sanitario nazionale (SSN) e rimasta costante in rapporto alla spesa sanitaria totale (4,2%), pari a 4,9 miliardi nel 2013. Nel periodo di studio considerato (2006-2013) appaiono in aumento le spese per le attivita rivolte alle persone (+8,7%), attribuibili soprattutto a vaccinazioni e screening, e in diminuzione le attivita di igiene pubblica (-5,7%) e quelle della sanita pubblica veterinaria ( 3,8%). I confronti internazionali indicano una spesa per la prevenzione del 2,9% rispetto alla spesa sanitaria totale, costante negli anni e nella media dei Paesi OCSE. Per la prevenzione, l'Italia spende tanto quanto i Paesi che non possiedono un servizio sanitario pubblico; il dato risulta inferiore del 5% rispetto alla programmazione nazionale, con poche eccezioni e molta variabilita regionale all'interno delle componenti delle voci di spesa. In questo contesto si sottolinea l'importanza di investire maggiori risorse nella pianificazione e nell'implementazione di interventi preventivi di provata efficacia e costo efficacia. PMID- 27764920 TI - [An Italian example of misuse of scientific evidence]. PMID- 27764921 TI - [Epidemiological evidence and misclassification]. PMID- 27764922 TI - [The Congress for the 40 years of the Italian Epidemiological Association]. PMID- 27764923 TI - [The experience of the "Life+ HIA21" project in Arezzo (Tuscany Region, Central Italy) within a participatory health impact assessment]. PMID- 27764924 TI - [Does local knowledge help epidemiology?] PMID- 27764925 TI - [Ecological study on the mortality of residents in Manfredonia (Apulia Region, Southern Italy) from 1970 to 2013]. AB - OBIETTIVI: valutare lo stato di salute della popolazione residente nel comune di Manfredonia dal 1970 al 2013. DISEGNO: analisi descrittiva dell'andamento temporale della mortalita generale, per gruppi di cause, dal 1970 al 2013. SETTING E PARTECIPANTI: i dati di mortalita e le popolazioni residenti sono di fonte Istat. Sono state esaminate 55 cause di decesso. Le analisi sono disaggregate per sesso e periodo. PRINCIPALI MISURE DI OUTCOME: sono stati elaborati i rapporti standardizzati di mortalita (SMR%), con i rispettivi intervalli di confidenza al 90% (IC90%), e i tassi di mortalita standardizzati col metodo diretto (TSD ). RISULTATI: lo stato di salute misurato dal tasso di mortalita per tutte le cause migliora nel tempo: i TSD passano da 92 x10.000 negli anni 1970-1974 a 52 x10.000 nel biennio 2012-2013 negli uomini, da 70 x10.000 a 39 x10.000 nelle donne. Tuttavia, rispetto alla media regionale Manfredonia perde progressivamente il suo vantaggio, passando da -20% a -10% negli uomini, e da -20% a +1,5% nelle donne. Questo andamento e molto evidente per il complesso delle cause cardiovascolari, mentre i tumori maligni sono in generale nella media regionale. Nell'ultimo periodo disponibile per causa di decesso (2006-2011), la mortalita per infarto miocardico e stata piu alta della media regionale (uomini: +35%; donne: +54%). I rapporti standardizzati di mortalita (SMR) mostrano tra gli uomini valori in crescita, in particolar modo rispetto al riferimento provinciale, con un eccesso a cominciare dal periodo 2006 2011 (22 decessi/anno e 19 attesi; SMR%: 117,2; IC90% 101,1-135,2; riferimento: provincia di Foggia). Anche tra le donne gli SMR% superano i riferimenti provinciali negli ultimi periodi esaminati (nel 2012-2013: 7 decessi/ anno e 4,2 attesi; SMR%: 116,4; IC90% 97,0-260,7; riferimento: provincia di Foggia). CONCLUSIONI: la mortalita a Manfredonia e diminuita in misura minore rispetto a quella osservata nei riferimenti provinciali e regionali. Il vantaggio che si osservava negli anni Sessanta si e, infatti, ridotto nel tempo, fino ad annullarsi negli ultimi anni. Dal 1970, Manfredonia ha progressivamente perso il vantaggio che aveva. Dagli anni Duemila, la mortalita per infarto del miocardio e in eccesso sulla media regionale e provinciale. Da casi documentati in letteratura si osserva che le popolazioni che sperimentano catastrofi di origine naturale o antropica possono fronteggiare un aumento di patologie cardiovascolari. La mortalita per tumore polmonare mostra un eccesso sulla media regionale, in particolare provinciale, a cominciare dal 2000, coerentemente con i tempi di latenza legati all'esposizione ad arsenico negli anni Settanta. PMID- 27764926 TI - [Atmospheric non-methane hydrocarbons near plants of crude oil first treatment]. AB - La continua espansione delle attivita di perforazione ai fini dell'estrazione petrolifera in prossimita di aree abitate ha fatto si che negli ultimi anni l'attenzione si focalizzasse sull'impatto di questo processo fortemente industrializzato sulla salute pubblica. Le comunita che vivono nei dintorni di impianti di questo tipo devono, infatti, fronteggiare diversi problemi, quali l'inquinamento atmosferico e acustico, la contaminazione del suolo e delle acque sotterranee, il traffico dei camion da e verso il sito, incidenti e malfunzionamenti all'interno dell'impianto. In questo contesto, la valutazione del rischio per la salute e ostacolata dal fatto che l'esposizione alle sostanze chimiche presenti non puo essere valutata in via definitiva, poiche non sempre si e a conoscenza di tutti i composti immessi nell'ambiente ne delle loro concentrazioni, per non parlare del problema delle coesposizioni ad altri inquinanti. Nonostante l'oramai conclamato e vasto interesse generato da questo argomento, ad oggi esistono pochi studi basati su popolazioni riguardanti gli effetti sulla salute delle comunita che vivono in prossimita dei siti di perforazione ed estrazione; cio genera la necessita di condurre campagne di monitoraggio mirate e studi epidemiologici che verifichino l'eventuale esistenza e natura di pattern di malattie associati a tali attivita. La presente rassegna bibliografica individua, quindi, i principali inquinanti atmosferici presenti in prossimita di un impianto di primo trattamento del greggio e cerca di fornire un quadro generale delle loro potenziali sorgenti e caratteristiche. PMID- 27764927 TI - [Evaluation of mercury exposure in populations living near the industrial Augusta Bay (Sicily Region, Southern Italy)]. AB - : OBIETTIVI: valutare e quantificare l'esposizione umana al mercurio (Hg) ed esplorare i fattori chiave che influenzano la contaminazione nelle popolazioni residenti in prossimita della Rada di Augusta, un'area a elevato rischio ambientale a causa degli effetti degli sversamenti incontrollati di Hg da parte di uno dei piu grandi impianti cloro-soda d'Europa. DISEGNO: un campione di residenti nei comuni di Augusta, Priolo e Melilli (Sicilia orientale) e stato selezionato per lo studio di biomonitoraggio umano. Un questionario dettagliato e stato somministrato a ogni partecipante per raccogliere informazioni anagrafiche sulle abitudini di vita e alimentari. I livelli di Hg in sangue e capelli, usati come traccianti di esposizione a metilmercurio, sono stati messi in relazione al consumo di pesce locale. Il contenuto di Hg nelle urine e stato utilizzato per esplorare eventuali esposizioni atmosferiche a Hg inorganico. Una regressione lineare multivariata e stata applicata con l'obiettivo di esplorare i fattori che influenzano l'esposizione umana al Hg. L'approccio tossicocinetico e stato impiegato al fine di calcolare la dose settimanale provvisoria tollerabile ( provisional tolerable weekly intake, PTWI) e di predire le concentrazioni di Hg attese nel sangue degli individui con una dieta alimentare basata esclusivamente su pesce locale. SETTING E PARTECIPANTI: 224 individui residenti nei comuni di Augusta, Melilli e Priolo. RISULTATI: eccessi di Hg sono stati misurati nel sangue e nei capelli del campione considerato. I piu alti livelli sono stati rilevati ad Augusta, dove anche il consumo di pesce locale risulta maggiore. I valori di dose settimanale tollerabile provvisoria (PTWI) calcolati eccedono, nella maggior parte dei casi, le raccomandazioni internazionali, specialmente nei residenti ad Augusta. CONCLUSIONI: gli elevati livelli di Hg registrati nei campioni di sangue e capelli derivano, con ogni probabilita, dal consumo di pesce locale. Rispetto ad Augusta, gli individui di Priolo e Melilli subiscono un impatto piu limitato. L'esposizione a Hg inorganico puo essere considerata trascurabile. PMID- 27764928 TI - [Levels of trace elements in the fruits and vegetables from the so-called Land of fires in Campania Region (Southern Italy)]. AB - INTRODUZIONE: una vasta area compresa tra le province di Napoli e Caserta nella regione Campania ha negli ultimi anni attirato l'attenzione dei mass media a causa degli interramenti illeciti di rifiuti di varia origine nei campi o del loro abbandono lungo le strade. A tali pratiche illecite si aggiunge il fenomeno dei roghi incontrollati di questo materiale, motivo per il quale la zona e stata soprannominata "Terra dei fuochi". OBIETTIVI: ricerca di elementi in tracce presenti nei prodotti alimentari di origine vegetale prodotti nella Terra dei fuochi. DISEGNO E SETTING: piano di monitoraggio per il rilevamento dei livelli di alcuni metalli tossici ed essenziali nei vegetali coltivati in Campania nella Terra dei fuochi. La determinazione dei microelementi e stata effettuata dopo mineralizzazione della sostanza organica mediante microonde, utilizzando la spettrometria di massa a plasma induttivamente accoppiato (ICP-MS). RISULTATI: durante l'attivita di monitoraggio sono stati raccolti 65 campioni di ortaggi e 49 campioni di frutta in 43 comuni rientranti nella Terra dei fuochi. Il contenuto medio di metalli tossici, cadmio e piombo nei prodotti ortofrutticoli e risultato ben lontano dai limiti massimi fissati dalla normativa europea. I valori delle concentrazioni sono significativamente inferiori rispetto a quanto riscontrato in zone ad alto impatto ambientale a causa della presenza di impianti industriali. CONCLUSIONI: la presenza di elementi tossici o potenzialmente tali nei campioni vegetali prodotti nella Terra dei fuochi e attribuibile a una varieta di fattori ambientali rilevanti (caratteristiche geologiche dell'area, inquinamento del suolo, dell'atmosfera e delle acque di irrigazione, pratiche illecite di smaltimento dei rifiuti industriali); non sembra, tuttavia, sussistere un rischio per la salute dei consumatori. Resta comunque l'allerta per la loro presenza nell'ambiente e la necessita che le attivita di monitoraggio continuino. PMID- 27764929 TI - [Mortality from respiratory diseases in the provinces of Apulia Region (Southern Italy) from 1933 to 2010]. AB - OBIETTIVI: valutare l'andamento temporale della mortalita per patologie respiratorie nelle province pugliesi utilizzando dati omogenei per fonte e metodologia di calcolo. DISEGNO: analisi ecologica storica degli andamenti temporali di mortalita per tumori e patologie dell'apparato respiratorio nelle province pugliesi, in Puglia e nelle ripartizioni geografiche italiane dal 1933 al 2010. SETTING E PARTECIPANTI: i dati di mortalita e le popolazioni residenti sono di fonte Istat. Sono state esaminate tutte le cause di decesso, il tumore della laringe, il tumore del polmone, l'insieme dei tumori respiratori, la bronchite, la polmonite e la broncopolmonite considerate congiuntamente, e l'insieme delle patologie respiratorie. Le analisi sono disaggregate per sesso dal 1969. PRINCIPALI MISURE DI OUTCOME: rapporti standardizzati di mortalita (SMR%) in riferimento all'Italia, con intervalli di confidenza al 95%, e tassi di mortalita standardizzati col metodo diretto (TSD ) in riferimento alla popolazione standard europea. RISULTATI: dal 1933 al 2010, i TSD per tumori respiratori e per bronchiti diminuiscono in tutte le aree analizzate. Tuttavia, nelle province di Taranto, Brindisi e Lecce, l'SMR% per tumori respiratori, inferiore al riferimento nazionale fino agli anni Sessanta, si allinea (a Brindisi) e supera (a Lecce e Taranto) il riferimento negli anni successivi. Nelle province di Foggia e Bari il numero dei decessi per tumore del polmone e costantemente inferiore all'atteso. CONCLUSIONI: la ricostruzione storica e l'analisi dei trend temporali di mortalita dal 1933 al 2010 mostrano alcune criticita sanitarie in periodi specifici. L'elaborazione dei dati di mortalita per un arco temporale di circa 80 anni ha messo in evidenza la maggiore rilevanza di queste criticita con l'avvio dello sviluppo industriale. PMID- 27764930 TI - [National epidemiological surveillance systems of mesothelioma cases]. AB - : INTRODUZIONE: sebbene la relazione causale tra esposizione ad amianto e malattie neoplastiche sia ben nota, in molti Paesi il consumo del materiale e ancora rilevante e crescente. A causa della lunga latenza, nei Paesi dove e stato bandito (come in Italia) e oggi in corso un'epidemia di malattie correlate ad amianto. OBIETTIVI: descrivere i sistemi di sorveglianza dei mesoteliomi attivi nel mondo mediante un'analisi comparativa. METODI: e stata condotta una revisione bibliografica della letteratura disponibile sui sistemi di sorveglianza epidemiologica dei mesoteliomi attivi nel mondo, comparando metodi e risultati disponibili. RISULTATI: sistemi di ricerca dei casi incidenti e di analisi anamnestica dei soggetti ammalati sono attivi solo in Italia, Francia e Corea del Sud. I Paesi presso i quali sono attivi sistemi di rilevazione e controllo dei casi incidenti di mesotelioma sono quelli in cui vige il bando dell'amianto e che hanno sperimentato consumi rilevanti in passato. Non sono stati istituiti sistemi epidemiologici di sorveglianza in molti Paesi dove il consumo di amianto e ancora importante (inclusi Russia, Cina, India e Brasile). CONCLUSIONI: si conferma l'importanza dei sistemi di sorveglianza epidemiologica dei mesoteliomi per la sanita pubblica, il sostegno alle politiche di welfare e la prevenzione dei rischi. Lo sviluppo di progetti per tendere a una maggiore uniformita nei metodi di ricerca dei casi, di classificazione delle diagnosi e dell'esposizione e nelle tecniche di analisi dei dati potrebbe consentire una maggiore fruibilita dei dati aggregati. La disponibilita di dati internazionali confrontabili puo essere di stimolo all'adozione di provvedimenti di bando internazionale. PMID- 27764931 TI - [Assessment of a project for integrated management of care given to patients with type-2 diabetes in the Local Health Authority 21 of Legnago (Veneto Region, Northern Italy) in the period 2010-2012]. AB - OBIETTIVI: descrivere, nella ASL 21 di Legnago (VR), l'andamento di alcuni indicatori sanitari tra il 2009, anno precedente all'avvio di un progetto triennale per la gestione integrata dell'assistenza al paziente con diabete mellito di tipo 2, e il 2012, ultimo anno del progetto. DISEGNO: studio longitudinale trasversale ripetuto. SETTING E PARTECIPANTI: tutti i pazienti diabetici di tipo 2 della ASL 21, identificati nei database aziendali (in base a esenzioni per patologia, accessi al servizio diabetologico, consumo di farmaci antidiabetici e strisce per la determinazione della glicemia) e nelle cartelle cliniche dei medici di famiglia. PRINCIPALI MISURE DI OUTCOME: numero di test diagnostici e di follow-up erogati, consumo di farmaci, prestazioni specialistiche, accessi al pronto soccorso, ricoveri e mortalita. RISULTATI: nonostante un calo generalizzato (-3,1%) nei test erogati dalla ASL 21 ai suoi assistititi nel periodo 2009-2012, l'analisi ha documentato un marcato aumento per gli esami previsti nella gestione del diabete, quali curve da carico glicemico (+104,3%), emoglobina glicata (+19,0%) e microalbuminuria (+296,1%). I soggetti identificati come diabetici sono aumentati da 8.084 nel 2009 (5,2%) a 9.221 nel 2012 (5,9%). Sono stati osservati aumenti nella prevalenza di pazienti visitati presso un servizio diabetologico (dal 22,6% al 39,0%), nonche negli utilizzatori di metformina (dal 28,0% al 37,5%), insuline (dal 13,5% al 18,3%) e incretine (dall'1,4% al 9,0%). Il consumo di sulfaniluree e, invece, calato (dal 49,9% al 40,8%), come anche l'erogazione di alcune prestazioni specialistiche, gli accessi al pronto soccorso e i ricoveri, mentre il tasso di mortalita e rimasto stabile (29,6 decessi x1.000/anno). CONCLUSIONE: durante il periodo di implementazione del progetto sembra essersi verificato un aumento della sensibilita diagnostica e una maggiore presa in carico del paziente diabetico. Anche se la natura osservazionale dello studio non consente di dimostrare una relazione causa-effetto, i risultati sembrano supportare l'ipotesi che la gestione integrata della patologia migliori l'appropriatezza dell'assistenza. PMID- 27764932 TI - [Analysis of factors predicting early unplanned readmissions]. AB - : OBIETTIVI: determinare i fattori associati ai ricoveri ripetuti per identificare i pazienti a rischio di riospedalizzazione entro i 30 giorni dalla dimissione. DISEGNO: analisi retrospettiva delle dimissioni nell'anno 2013 attraverso le schede di dimissione ospedaliera (SDO). SETTING E PARTECIPANTI: 3.900 pazienti ricoverati presso il presidio ospedaliero "Fabrizio Spaziani" di Frosinone. PRINCIPALI MISURE DI OUTCOME: analisi bivariata per l'analisi dell'associazione tra variabili. La regressione logistica e stata utilizzata per identificare i fattori di rischio associati al ricovero ripetuto. RISULTATI: tra i 3.900 pazienti considerati, il 12,8% ha avuto una riammissione non programmata entro un mese dalla dimissione precedente per le stesse categorie diagnostiche principali (MCD). Sono state rilevate differenze statisticamente significative tra i pazienti con e senza ricovero ripetuto per eta, durata della degenza, titolo di studio, condizione occupazionale e diagnosi. I fattori che aumentano la probabilita di una riospedalizzazione sono il vivere da solo, la condizione di pensionato o casalinga, una degenza piu lunga e alcune diagnosi, fra cui malattie dell'apparato respiratorio, del sistema nervoso e dell'apparato urinario. CONCLUSIONE: alcune caratteristiche sociodemografiche e la diagnosi dei pazienti ospedalizzati sono associate al rischio di riospedalizzazione entro 30 giorni dalla dimissione. I dati disponibili nell'archivio delle SDO possono essere utilizzati per un'identificazione dei pazienti a rischio sui quali definire specifici piani di dimissione. PMID- 27764933 TI - [Effectiveness of school-based interventions to prevent traffic accidents: an overview of secondary literature]. AB - INTRODUZIONE: gli incidenti stradali sono l'ottava causa di morte al mondo e la prima tra i giovani di 15-29 anni. In Italia il Piano nazionale sicurezza stradale raccomanda l'educazione scolastica per la prevenzione degli incidenti stradali; ad oggi non esistono documenti che raccolgano evidenze di efficacia sugli interventi educativi stradali e le rapportino al contesto italiano. OBIETTIVI: riassumere e discutere cio che e noto in letteratura riguardo agli interventi scolastici per la prevenzione degli incidenti stradali. METODI: sono state ricercate linee guida e revisioni sistematiche usando i seguenti criteri di inclusione: popolazione di eta inferiore ai 25 anni di entrambi i sessi; interventi scolastici di educazione stradale; effetti su indicatori primari di esito come riduzione degli incidenti stradali, astinenza dalla guida sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol; effetti su indicatori secondari di esito come conoscenze e competenze sui comportamenti di guida sicura. RISULTATI: sono state identificate due revisioni sistematiche. L'educazione stradale nelle scuole non mostra evidenza di efficacia (rischio relativo 1,03; IC95% 0,98-1,08) nel ridurre gli incidenti. Programmi scolastici piu specifici mostrano risultati solo in parte convincenti per l'adozione di comportamenti sicuri come l'astinenza dal guidare sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol. DISCUSSIONE: le revisioni incluse non hanno trovato programmi efficaci nella riduzione degli incidenti stradali o dei fattori che possano determinarli. Nell'attesa di studi piu recenti, appare opportuno promuovere l'implementazione di interventi misti, scolastici e di comunita, che hanno mostrato maggiori prove di efficacia. PMID- 27764934 TI - [Population health surveillance of the general population living near Turin (Northern Italy) incinerator (SPoTT): methodology of the study]. AB - Si intende qui descrivere il sistema di sorveglianza sugli effetti sulla salute (SpoTT) dell'inquinamento ambientale nelle aree circostanti l'inceneritore di Torino. SPoTT ha 3 linee di attivita: 1. monitoraggio epidemiologico degli effetti a breve termine attraverso analisi temporali e misura della correlazione tra livelli giornalieri di emissioni dell'impianto e andamento degli eventi individuati dagli archivi dei dimessi (SDO), di pronto soccorso e di mortalita; sono coinvolti coloro che nel 2013-2018 risiedevano nell'area di ricaduta delle emissioni; 2. sorveglianza epidemiologica degli effetti a lungo termine, stimando tassi standardizzati di mortalita e morbosita; a ogni soggetto e attribuito il valore stimato di esposizione cumulato nel tempo caratteristico della residenza anagrafica; le informazioni sulla salute sono reperite dagli archivi SDO, di mortalita e dai certificati di assistenza al parto; sono studiati due decenni pre post l'avvio dell'impianto: 2003-2012 e 2013-2022; 3. monitoraggio biologico con misurazione pre-post di metalli, PCDD/F, PCB, OH-IPA; sono coinvolti 196 residenti esposti e 196 di controllo di 35-69 anni, campionati a caso dalle anagrafi comunali; sono effettuate misure di funzionalita endocrina e respiratoria, pressione arteriosa, rischio cardiovascolare; l'esposizione cumulativa sara stimata per ciascuna persona campionata integrando l'indirizzo di residenza, il tempo di permanenza in ciascun indirizzo e i dati ricavati dai modelli di ricaduta; sara costituita una biobanca per future indagini di laboratorio; sono coinvolti anche 20 allevatori e i lavoratori dell'impianto. Una quarta linea di attivita, non descritta in questo articolo, riguarda il monitoraggio della salute dei lavoratori addetti all'impianto. SPoTT e il primo studio in Italia su inceneritori e salute che adotta un disegno di studio longitudinale di adeguata potenza sia per i residenti sia per i lavoratori. I primi risultati sono attesi nel corso del 2016. PMID- 27764935 TI - [Educational level influences the use of hysterectomy in Italy (data from PASSI survey, 2008-2015)]. PMID- 27764937 TI - [Life entwined with work: uplifting stories]. PMID- 27764936 TI - [Hodgkin lymphoma in Italian children and adolescents]. PMID- 27764938 TI - 1,2,4-Triazolidine-3-thiones Have Specific Activity against Acinetobacter baumannii among Common Nosocomial Pathogens. AB - Acinetobacter baumannii are Gram-negative bacilli that pose a constant threat to susceptible patients because of increased resistance to multiple antibiotics and persistence in the hospital environment. After genome analysis, we discovered that A. baumannii harbors genes that share homology to an enzymatic pathway that elongates long-chain fatty acids (LCFA) in fungi. Previously, 1,2,4-triazolidine 3-thiones (T-3-Ts) were shown to inhibit hyphae production in fungi, and this same LCFA elongation pathway was implicated as the possible target. Therefore, we investigated if T-3-Ts also have activity against multidrug-resistant A. baumannii. Surprisingly, all of the clinical isolates of A. baumannii that were tested have susceptibility to ECC145 and ECC188 with MIC90 values of 8.0 MUg/mL. In contrast, reference strains and clinical isolates of other common nosocomial bacteria that lack the LCFA pathway also lacked susceptibility. Time-kill experiments revealed that both ECC145 and ECC188 have a bacteriostatic effect against A. baumannii. Mass spectrometry analysis suggested that exposure to T-3 Ts resulted in less LCFA production. Supplementation of media with either 0.02% w/v oleic or linoleic acid abrogated the bacteriostatic effect of the compounds, which again implicated LCFA elongation as the target. Our results suggest these molecules could be a promising start to further exploit what appears to be an important aspect of A. baumannii membrane function and integrity. PMID- 27764939 TI - Nrf2 Knockdown Disrupts the Protective Effect of Curcumin on Alcohol-Induced Hepatocyte Necroptosis. AB - It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alcohol-caused liver injury might be attributed to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), whereas the role of curcumin in regulating necroptosis and the underlying mechanism remain to be determined. We first found that chronic alcohol consumption triggered obvious hepatocyte necroptosis, leading to increased expression of receptor-interacting protein 1, receptor-interacting protein 3, high-mobility group box 1, and phosphorylated mixed lineage kinase domain-like in murine livers. Curcumin dose-dependently ameliorated hepatocyte necroptosis and alleviated alcohol-caused decrease in hepatic Nrf2 expression in alcoholic mice. Then Nrf2 shRNA lentivirus was introduced to generate Nrf2-knockdown mice. Our results indicated that Nrf2 knockdown aggravated the effects of alcohol on liver injury and necroptosis and even abrogated the inhibitory effect of curcumin on necroptosis. Further, activated Nrf2 by curcumin inhibited p53 expression in both livers and cultured hepatocytes under alcohol stimulation. The next in vitro experiments, similar to in vivo ones, revealed that although Nrf2 knockdown abolished the suppression of curcumin on necroptosis of hepatocytes exposed to ethanol, p53 siRNA could clearly rescued the relative effect of curcumin. In summary, for the first time, we concluded that curcumin attenuated alcohol induced hepatocyte necroptosis in a Nrf2/p53-dependent mechanism. These findings make curcumin an excellent candidate for ALD treatment and advance the understanding of ALD mechanisms associated with hepatocyte necroptosis. PMID- 27764940 TI - Secretomic Analysis of Host-Pathogen Interactions Reveals That Elongation Factor Tu Is a Potential Adherence Factor of Helicobacter pylori during Pathogenesis. AB - The secreted proteins of bacteria are usually accompanied by virulence factors, which can cause inflammation and damage host cells. Identifying the secretomes arising from the interactions of bacteria and host cells could therefore increase understanding of the mechanisms during initial pathogenesis. The present study used a host-pathogen coculture system of Helicobacter pylori and monocytes (THP-1 cells) to investigate the secreted proteins associated with initial H. pylori pathogenesis. The secreted proteins from the conditioned media from H. pylori, THP-1 cells, and the coculture were collected and analyzed using SDS-PAGE and LC MS/MS. Results indicated the presence of 15 overexpressed bands in the coculture. Thirty-one proteins were identified-11 were derived from THP-1 cells and 20 were derived from H. pylori. A potential adherence factor from H. pylori, elongation factor-Tu (EF-Tu), was selected for investigation of its biological function. Results from confocal microscopic and flow cytometric analyses indicated the contribution of EF-Tu to the binding ability of H. pylori in THP-1. The data demonstrated that fluorescence of EF-Tu on THP-1 cells increased after the addition of the H. pylori-conditioned medium. This study reports a novel secretory adherence factor in H. pylori, EF-Tu, and further elucidates mechanisms of H. pylori adaptation for host-pathogen interaction during pathogenesis. PMID- 27764941 TI - Ethenesulfonyl Fluoride (ESF): An On-Water Procedure for the Kilogram-Scale Preparation. AB - A two-step, on-water procedure for the synthesis of ethenesulfonyl fluoride (ESF) is described. 2-Chloroethanesulfonyl fluoride is made via a neat reaction with an aqueous, nearly saturated potassium bifluoride solution from readily available 2 chloroethanesulfonyl chloride. The subsequent dehydrochlorination of 2 chloroethanesulfonyl fluoride proceeds neatly with magnesium oxide as the base in an aqueous suspension to give ESF. This recipe allows the preparation of ESF in 98% yield on a kilogram scale. PMID- 27764942 TI - First-Principles Prediction of Thermodynamically Stable Two-Dimensional Electrides. AB - Two-dimensional (2D) electrides, emerging as a new type of layered material whose electrons are confined in interlayer spaces instead of at atomic proximities, are receiving interest for their high performance in various (opto)electronics and catalytic applications. Experimentally, however, 2D electrides have been only found in a couple of layered nitrides and carbides. Here, we report new thermodynamically stable alkaline-earth based 2D electrides by using a first principles global structure optimization method, phonon spectrum analysis, and molecular dynamics simulation. The method was applied to binary compounds consisting of alkaline-earth elements as cations and group VA, VIA, or VIIA nonmetal elements as anions. We revealed that the stability of a layered 2D electride structure is closely related to the cation/anion size ratio; stable 2D electrides possess a sufficiently large cation/anion size ratio to minimize electrostatic energy among cations, anions, and anionic electrons. Our work demonstrates a new avenue to the discovery of thermodynamically stable 2D electrides beyond experimental material databases and provides new insight into the principles of electride design. PMID- 27764943 TI - Controlling Selectivity by Controlling Energy Partitioning in a Thermal Reaction in Solution. AB - The comparison of experimental and predicted kinetic isotope effects in the alpha cleavage of alkoxy radicals is used here to judge the applicability of statistical rate theories. It is found that the governing rate theory and the statistical versus nonstatistical nature of the cleavage depend on the cleavage barrier and how much energy is imparted to the radical. The latter can then be controlled by changing the size of substituents in the system. With a large alkyl group substituent, the vibrational energy of the alkoxy radical is increased, but this energy is not statistically distributed, leading to a lower isotope effect than predicted by statistical theories. The observed isotope effect can be approximately rationalized using a semistatistical localized RRKM model. PMID- 27764945 TI - Synthetic Biology in Europe. PMID- 27764950 TI - Experiences of vision impairment in Papua New Guinea: implications for blindness prevention programs. AB - INTRODUCTION: A person's capability to access services and achieve good eye health is influenced by their behaviours, perceptions, beliefs and experiences. As evidence from Papua New Guinea (PNG) about people's lived experience with vision impairment is limited, the purpose of the present study was to better understand the beliefs, perceptions and emotional responses to vision impairment in PNG. METHODS: A qualitative study, using both purposive and convenience sampling, was undertaken to explore common beliefs and perceptions about vision impairment, as well as the emotional responses to vision impairment. In-depth interviews were undertaken with 51 adults from five provinces representing culturally and geographically diverse regions of PNG. Grounded theory was used to elicit key themes from interview data. RESULTS: Participants described activities of everyday life impacted by vision impairment and the related worry, sadness and social exclusion. Common beliefs about the causes of vision impairment were environmental stressors (sun, dust, dirt and smoke), ageing and sorcery. CONCLUSIONS: Findings provide insight into the unique social context in PNG and identify a number of programmatic and policy implications, such as the need for preventative eye health information and services, addressing persisting beliefs in sorcery when developing health information packages, and the importance of coordinating with counselling and well-being services for people experiencing vision impairment. PMID- 27764951 TI - Unintentional injury prevention and the role of occupational therapy in the Solomon Islands: an integrative review. AB - INTRODUCTION: Unintentional injuries (injuries for which there is no evidence of a predetermined intent) are one of the leading causes of death worldwide, particularly in low- and middle-income countries (LMICs). Although evidence demonstrates unintentional injuries are preventable it is a public health challenge for many LMICs such as the Solomon Islands. Occupational therapists are well placed to contribute to injury prevention, as they have specialised skills to analyse the accessibility and safety of the environments within which people conduct their daily occupations. While the role of occupational therapy in unintentional injury prevention is well known in high-income countries, it is unfamiliar in LMICs, especially in the Solomon Islands. This integrative review aimed to explore the incidence of common unintentional injuries, and the burden in the Solomon Islands; and explore the potential role of occupational therapy in unintentional injury prevention in the Solomon Islands, based on current activities in LMICs. METHOD: Articles were reviewed from six databases (Medline, CINAHL, OTDBase, OT Seeker, Scopus and PsychInfo). Five articles met the inclusion criteria for the first objective and 15 articles met the inclusion criteria for the second objective. These articles were thematically analysed where themes and codes associated with the research objectives were extracted and analysed. RESULTS: Unintentional injuries in the Solomon Islands reported in the literature included ocular trauma, falls from fruit trees and coconut palms, and road traffic crashes. Burden of injury reported was mostly associated with loss of productivity. Occupational therapists undertook rehabilitative, biomechanical, neurodevelopmental and educational roles in LMIC, focusing on tertiary and secondary injury prevention. CONCLUSIONS: This integrative review suggests that there is limited information regarding injury in the Solomon Islands. However, evidence is available in LMICs to suggest that occupational therapy services can play a potential significant role in unintentional injury prevention, demonstrating a need for establishing injury prevention within the occupational therapy role in the Solomon Islands. PMID- 27764952 TI - Young people and snowmobiling in northern Norway: accidents, injury prevention and safety strategies. AB - INTRODUCTION: Snowmobiling among young people in Scandinavia frequently leads to accidents and injuries. Systematic studies of accidents exist, but few studies have addressed young drivers' experiences. The aim of this article is to reveal how young people experience and interpret accidents, and to outline a prevention strategy. METHODS: Thirty-one girls and 50 boys aged 16-23 years from secondary schools in Northern Norway and on Svalbard, a Norwegian archipelago in the Arctic Ocean, participated in 17 focus groups segregated by gender. A content analysis identified themes addressing the research questions. RESULTS: Participants described risk as being inherent to snowmobiling, and claimed that accidents followed from poor risk assessment, careless driving or mishaps. Evaluation of accidents and recommendations for preventive measures varied. Girls acknowledged the risks and wanted knowledge about outdoor life, navigation and external risks. Boys underestimated or downplayed the risks, and wanted knowledge about safety precautions while freeriding. Both genders were aware of how and why accidents occurred, and took precautions. Boys tended to challenge norms in ways that contradict the promotion of safe driving behaviour. Stories of internal justice regarding driving under the influence of alcohol occurred. CONCLUSIONS: Adolescents are aware of how accidents occur and how to avoid them. Injury prevention strategies should include a general population strategy and a high risk strategy targeted at extreme risk-seekers. Drivers, snowmobilers' organisations and the community should share local knowledge in an effort to define problem areas, set priorities and develop and implement preventive measures. Risk prevention should include preparation of safe tracks and focus on safety equipment and safe driving behaviour, but should also pay increased attention to the potential of strengthening normative regulation within peer groups regarding driving behaviour and mutual responsibility for preventing accidents. PMID- 27764953 TI - Informal interpreting in general practice: the migrant patient's voice. AB - OBJECTIVE: To explore the perspective of Turkish-Dutch general practitioner (GP) patients on informal interpreting from an integrated theory base, focusing on interpreters' roles, trust and power. DESIGN: Semi-structured in depth interviews were conducted with 21 first-generation Turkish-Dutch migrant patients who made use of informal interpreters to communicate with their GPs. An interview guide was designed based on the theoretical framework of interpreter's roles, trust and power, covering questions about interpreters' role, trust in informal/professional interpreters and power division in the medical consultation. The interviews were transcribed verbatim and analyzed according to the constant comparative method. RESULTS: Besides providing linguistic translation, informal interpreters were expected to perform the roles of advocates and caregivers of the patients. Informal interpreters were trusted more than professional interpreters, mainly for fidelity reasons, that is, because the patients assumed that informal interpreters would act in their best interests. Although informal interpreters were often perceived as the primary interlocutor, the patients did not feel dominated by them, but rather empowered by their presence. CONCLUSION: Our findings indicate a connection between the role of the advocate, the fidelity dimension of trust and the perceived empowerment of the patients. By linking interpreters' role to trust and power, this study contributes to theory building in the field of informal interpreting, which is needed to design evidence-based interventions to improve health care delivery to patients with insufficient language ability and thus to advance health care delivery to migrant patients, which is currently lagging behind. PMID- 27764954 TI - Are immigrants and descendants with ill health more prone to unemployment? Evidence from 18 European countries. AB - OBJECTIVE: Previous research has established that both ill health and minority status are associated with unemployment. Less is known, however, about the interplay between having ill health and being from minority background. The present study examines whether immigrants and descendants with ill health are particularly prone to unemployment during an economic downturn in Europe. DESIGN: The European Union Statistics on Income and Living Conditions (EU-SILC) cross sectional data material is utilized, and linear probability models are estimated. The analysis is run for countries in which the two minority samples are acceptably large (N >= 100), resulting in 18 included European countries. The year 2011 is chosen because it is possible to identify both immigrants and descendants in EU-SILC due to a module on intergenerational transfer of disadvantages. RESULTS: The results indicate - as expected - that both ill health and minority status are independently related to higher unemployment likelihood. Immigrants and descendants with ill health, however, are not particularly likely to be unemployed. This finding is robust to a number of sensitivity tests, and the empirical pattern is very similar across the 18 included countries. CONCLUSION: Both minority status and ill health are associated with high unemployment probability in Europe. However, there does not seem to exist a 'double disadvantage' for immigrants and descendants with ill health, which is in line with a human capital perspective on how employers evaluate potential employees. Both a non-native-sounding name and bad health status are interpreted as a risk factor, but there is no reason to expect ill health to lower the productivity level more if the applicant is a descendant or immigrant. PMID- 27764955 TI - Recruitment and retention challenges and successes. AB - OBJECTIVE: Addressing health disparities requires well designed, culturally adapted research. However, recruiting/retaining minority participants has often been challenging. We present strategies used to successfully recruit and retain rural Hispanic women during a breastfeeding education intervention. DESIGN: This study involved a two-group repeated measures quasi-experimental design with assessments at seven intervals between enrollment and 6 months postpartum. Participants (Hispanic women >= 15 years old) were recruited through a regional hospital. RESULTS: We successfully met our recruitment goals, most women contacted were enrolled (46 of 58), and 100% completed the study. DISCUSSION: Research staff with ties within the community helped establish trust. Using bilingual study materials, simple language, and an interpreter addressed language/literacy concerns. Phone assessments facilitated participation as transportation was an issue. Accommodating requests to deliver or mail study materials and providing incentives were important. Extra effort was needed to maintain contact when phone service was disrupted or participants moved. Keys to success were persistence, flexibility, and alleviating barriers to participation. PMID- 27764956 TI - Aid, growth and poverty. PMID- 27764957 TI - Care transitions among Latino diabetics: barriers to study enrollment and transition care. AB - OBJECTIVE: Latinos are disproportionately affected by diabetes and people with diabetes experience frequent hospital admissions and readmissions. Care transition interventions can help reduce rates of readmission; however, there are many barriers to recruiting Latinos for participation in intervention research. Exploring reasons for study refusal furthers understanding of low research participation rates to help researchers address barriers. DESIGN: This study presents a cross-sectional, descriptive analysis of reasons for study refusal and attrition drawing from data collected as part of a randomized controlled trial conducted to test the effectiveness of a transitions intervention for diabetic Latino discharged from the hospital to home. Reasons for refusal were elicited from participants, transcribed, and coded. Descriptive statistics and bivariate analyses were used to compare those who completed the study and those who did not complete the study. RESULTS: Reasons for study enrollment refusal and loss to follow-up ranged from difficulty locating the patient to homelessness to patient reluctance to having providers in the home. Study completers were more likely than non-completers to reside with family members (p = .03) and have a spouse as a primary caregiver (p = .08). CONCLUSIONS: Inner city, monolingual Latinos may be difficult to enroll and engage in home-based interventions. Although not representative of all Latino populations, barriers encountered highlight the need for targeted research to improve transitional care among Latinos. Researchers and clinicians should take into consideration the unique barriers that Latinos face in participating in research and intervention studies. PMID- 27764958 TI - Insecticidal Constituents from Buddlej aalbiflora Hemsl. AB - Eleven known compounds, deoxymikanolide (1), 1,3-dihydroxyxanthone (2), kumatakenin (3), apigenin (4), chrysin (5), kaempferol (6), Iso-kaempferol (7), luteolin (8), luteolin-3',4'-dimethylether-7-O-beta-glucoside (9), luteolin-7-O beta-glucoside (10) and quercetin (11) were identified in MeOH extract of Buddleja albiflora Hemsl (Oleaceae). These compounds (each, 1, 0.5 and 0.25 mg mL 1) were tested for insecticidal activity against 3rd and 4th-instar larvae of Plutella xylostella, 3rd-instar larvae of Mythimna separata and 3rd-instar larvae of Macrosiphoniella sanborni. The lowest 50% anti-feedant concentration (AFC50) against P. xylostella and 50% lethal concentration (LC50) against P. xylostella and M. sanborni were observed as 0.0058, 0.0046 and 3.4048 mg L-1, respectively. PMID- 27764959 TI - 'Love and trust, you can be blinded': HIV risk within relationships among Latina women in Miami, Florida. AB - OBJECTIVES: Latina women are disproportionately affected by HIV in the US, and account for 30% of all HIV infections in Miami-Dade County, Florida. The main risk for Latina women is heterosexual contact. Little is known about the relational and cultural factors that may impact women's HIV risk perception. This study aims to describe Latina women's perception of their HIV risk within a relational, cultural, and linguistic context. DESIGN: Eight focus groups of Latina women (n = 28), four English speaking groups and four Spanish speaking groups, were conducted between December 2013 and May 2014. Women were recruited from a diversion program for criminal justice clients and by word of mouth. Eligibility criteria included the following: self-identify as Hispanic/Latino, 18 49 years of age, and self-identify as heterosexual. A two-level open coding analytic approach was conducted to identify themes across groups. RESULTS: Most participants were foreign-born (61%) and represented the following countries: Cuba (47%), Honduras (17.5%), Mexico (12%), as well as Nicaragua, Puerto Rico, Colombia, and Venezuela (15%). Participant ages ranged between 18 and 49, with a mean age of 32 years. Relationship factors were important in perceiving HIV risk including male infidelity, women's trust in their male partners, relationship type, and getting caught up in the heat of the moment. For women in the English speaking groups, drug use and trading sex for drugs were also reasons cited for putting them at risk for HIV. English speaking women also reported that women should take more responsibility regarding condom use. CONCLUSION: Findings emphasize the importance of taking relational and cultural context into account when developing HIV prevention programs for Latina women. Interventions targeting English speaking Latina women should focus on women being more proactive in their sexual health; interventions focused on Spanish speaking women might target their prevention messages to either men or couples. PMID- 27764960 TI - Use of alcohol, tobacco and illicit drugs among ethnic Norwegian and ethnic minority adolescents in Hordaland county, Norway: the youth@hordaland-survey. AB - OBJECTIVE: To describe potential differences in unhealthy behaviours among ethnic Norwegian adolescents and minority adolescents from countries within the European Union, European Economic Area or US (EU/EEA countries) and adolescents from non EU/EEA countries. Specifically, we aimed to investigate ethnic differences in use of alcohol, tobacco and illicit drugs, and potential confounding due to socio demographic characteristics. DESIGN: Cross-sectional population-based study of adolescents aged 16-19 (N = 10,122), with self-reported ethnicity as grouping variable, and self-reported use of alcohol, tobacco and illicit drugs as dependent variables. RESULTS: We found that minority adolescents from EU/EEA and non-EU/EEA countries differed from ethnic Norwegian adolescents on important indicators of unhealthy behaviours. Compared to Norwegian adolescents, adolescents from EU/EEA were more likely to report having tried to smoke, to be a daily smoker and to ever having tried an illicit drug (adjusted odds ratio (OR) ranging from 2.01 to 3.74). They were, however, less likely to have tried snus (a form of smokeless tobacco; adjusted OR 0.64; confidence interval (CI) 95% 0.43 0.97) and to report daily snus use (adjusted OR 0.31; CI95% 0.15-0.67). There were no differences in having tried alcohol. Non-EU/EEA adolescents were less likely to have ever tried alcohol (OR 0.24; CI95% 0.18-0.31), snus (OR 0.47; CI95% 0.34-0.65) and to smoke (0.68; CI95% 0.52-0.91), and less likely to report daily snus use (OR 0.36; CI95% 0.21-0.62) compared to Norwegian adolescents. There were no differences with regard to having tried illicit drugs and reporting being a daily smoker. All differences observed were robust to adjustment for age, gender and family socio-economic status. CONCLUSION: The presents study identified important differences in unhealthy behaviours across different ethnic groups in Norway. The differences in the prevalence of unhealthy behaviours among ethnic minorities are still relevant in a public health perspective, and potential mechanisms should be investigated further. PMID- 27764961 TI - Exploring reasons for ethnic disparities in diet- and lifestyle-related chronic disease for Asian sub-groups in New Zealand: a scoping exercise. AB - OBJECTIVES: The current study aimed to explore if the impact of various risk factors for chronic disease differed for people of Chinese, Indian and New Zealand European and Other (NZEO) ethnicities. DESIGN: Data analysed for this paper was extracted from the 2003-04 and the 2006-07 NZ Health surveys for adults aged 25-70 which used a cross-sectional survey design. Data from both the survey waves were combined and all statistical analysis was done using SAS version 9.2 or 9.3. Ethnicity of participants was coded using a priority-based classification system as (1) Indian, (2) Chinese, (3) Other Asian, (4) NZEO, (5) Maori and (6) Pacific. Only data for Indians, Chinese and NZEO were used for the current study. Prevalence estimates and 95% confidence intervals for chronic disease and the associated risk factors were generated to describe the sample. Logistic regression analysis was used to examine whether the difference in the change in risk of chronic disease with different exposures was different according to ethnicity. RESULTS: Higher deprivation resulted in increased risk of chronic disease in Indian and Chinese males but not in NZEO males (p = .03). There was a weak evidence for a differing effect of physical activity (p = .10) on chronic disease with the protective effect not seen in Indian or Chinese participants. CONCLUSION: The results of the current study indicate that some factors such as socio-economic deprivation and physical activity may impact differently on the prevalence of chronic disease according to ethnicity. The authors recommend further investigation of these factors using improved and innovative methodology and high-quality ethnicity data to better understand the factors underpinning ethnic disparities in disease prevalence among Asian sub-groups. PMID- 27764962 TI - Willingness to use mental health counseling and antidepressants in older Korean Americans: the role of beliefs and stigma about depression. AB - OBJECTIVES: Despite a high prevalence of mental health problems, racial/ethnic minorities are often reluctant to seek mental health services. Their reluctance may be shaped by cultural beliefs and stigma about mental health. The present study examined how beliefs and stigma about depression (e.g. disbelief in depression as a health-related condition, perception of depression as a normal part of aging, and/or depression as a sign of personal weakness/family shame) pose barriers to older Korean Americans' willingness to use mental health counseling and antidepressants. METHOD: Data were drawn from surveys with 420 Korean American older adults (Mage= 71.6, SD = 7.6) living in the New York City metropolitan area in 2010. Using a separate logistic regression model, the role of beliefs and stigma about depression in predicting participants' willingness to receive mental health counseling and to take antidepressants was tested. Based on Andersen's behavioral health service use model, the analysis was conducted in consideration of predisposing characteristics (age, gender, marital status, education, and acculturation), mental health needs (anxiety, depressive symptoms, and self-rated mental health), and enabling/hindering factors (beliefs and stigma). RESULTS: Similar proportions of the sample (69-70%) indicated their willingness to use mental health counseling or antidepressants. Willingness was more likely among participants who had beliefs about depression as a health related concern (OR = 1.94, 95% CI = 1.15-3.27 for mental health counseling; OR = 4.47, 95% CI = 2.59-7.70 for antidepressants) and less likely among those who associated depression with family shame (OR = .55, 95% CI = 0.33-0.91 for mental health counseling; OR = .56, 95% CI = 0.33-0.95 for antidepressants). CONCLUSION: In addressing mental health problems and promoting the use of mental health services, cultural beliefs and stigma shared within an ethnic community should be considered. Given that disbelief in the medical model of depression and family shame reduced willingness to use mental health counseling and antidepressants, promoting mental health literacy for older immigrants could be beneficial. PMID- 27764963 TI - The relationship between osteoporosis and body composition in pre- and postmenopausal women from different ethnic groups in China. AB - OBJECTIVE: To investigate the ethnic differences in osteoporosis (OP) and body composition (BC) and their relationship in the Maonan, Mulam, Hmong, and Yao minorities in China. DESIGN: A total of 860 Maonan, Mulam, Hmong, and Yao women were included in this cross-sectional study. Demographic, health history, and lifestyle information was collected using questionnaires. BC was measured through bioelectrical impedance analysis, and bone mineral density (BMD) was assessed via calcaneal quantitative ultrasound. RESULTS: Compared with premenopausal women, postmenopausal women exhibited a lower fat-free mass (FFM), muscle mass (MM), limb muscle mass, and T-score but a higher waist-to-hip ratio and prevalence of OP in each minority (p < .05). After adjustment for age, Hmong women displayed the highest body mass index, fat mass, percentage of body fat, visceral fat, and subcutaneous fat contents, while Yao women presented the highest T-scores and lowest prevalence of OP among the four minorities (p < .05). Having a greater number of children and an older age were significant risk factors for OP in all ethnic groups (p < .05, OR > 1). In addition, our results revealed that FFM and MM exhibited exactly the same weak positive relationship with the T-score (r = 0.081, p < .05) after adjusting for menopausal status and age in all of the participants. Furthermore, significant ethnic differences in the relationship between BC and the T-score existed in the four minorities studied here. CONCLUSIONS: BC and OP prevalence varied by menopausal status and ethnic group, and ethnic-specific relationships between BC and BMD were present in the four minorities. More research is needed to further investigate the ethnic differences in BC, OP, and risk factors for lower BMD to develop targeted prevention strategies to reduce the burden of OP across different ethnic groups in China. PMID- 27764964 TI - Human dignity and autonomy in the care for patients with dementia: differences among formal caretakers from various cultural backgrounds. AB - OBJECTIVES: To explore whether gaps exist between caretakers from different ethno cultural groups (Israeli-born Jews [Sabras], Israeli Arabs [Arabs], and migrants from Russia [Russians]) regarding their perceptions of autonomy and human dignity of patients with dementia. DESIGN: A mixed-methods research scheme was used, comprised of qualitative and quantitative methods, utilizing semi-structured interviews and self-reported questionnaires. Twenty formal caretakers participated in the qualitative portion, and approximately 200 caretakers were included in the quantitative portion. All participants were recruited from three nursing homes and one hospital in the Galilee region (Israel). RESULTS: The qualitative portion of the study yielded eight themes encapsulated in the concept of autonomy and ten themes entailed within human dignity, in the context of care for patients with dementia. By utilizing these themes in the quantitative portion, substantial differences in nursing homes were found in the attitudes to autonomy and dignity of patients with dementia between Russian and Arab as well as Sabra caretakers (index score for autonomy: 2.97, 4.07, and 4, respectively; index score for dignity: 3.17, 4.1, and 4.07). A multi-variable regression, focusing on caretakers from nursing homes, showed the most significant influencing variables on the indexes of autonomy and dignity were ethno-culture Arab/Russian (0.84, 0.62) and the patient's family (0.29, 0.30). Regarding the autonomy index, being a female caretaker also had a significant influence (0.24). In the hospital, no influence emerged for the ethno-culture variables, and neither type of institution showed any influence of religion or religiousness as well as societal or community norms. CONCLUSIONS: Contrary to past research, in nursing homes, significant differences were found between certain ethno-cultural groups (Arabs and Russians) regarding their stance toward the dignity and autonomy of patients with dementia. Arab caretakers' fostering of more encompassing conceptions of dignity and autonomy, irrespective of institutional setting, provides better grounds for person-centered care. PMID- 27764965 TI - Safety of video-assisted thoracic surgery lobectomy for non-small-cell lung cancer in a low-volume unit. AB - Several studies have demonstrated that for complex surgical procedures, surgeons who treat more patients have better outcomes than their lower-volume counterparts. The aim of this paper is to review the experience with video assisted thoracic surgery (VATS) lobectomies in our small thoracic unit (group A), to understand whether our short-term results were different to the outcomes obtained by the same surgeon previously working in a high-volume unit (group B). 37 patients underwent VATS lobectomy. Hospital stay was on average 4.5 days (group A) versus 4.1 days (group B). Operative time and the number of 'frozen sections' were higher in group A. Hospital mortality was 0. VATS lobectomies are a safe approach in a low-volume unit formed by a single surgeon with a previous high-volume experience. PMID- 27764966 TI - The impact of comorbidity on the relationship between life stress and health related quality of life for Chinese- and Korean-American breast cancer survivors. AB - OBJECTIVE: The current study aimed to (1) identify the occurrence of comorbidities among Chinese- and Korean-American breast cancer survivors (BCS), (2) examine whether health-related quality of life (HRQOL) scores varied with the occurrence of specific comorbidities, and (3) investigate the mediating effect of comorbidities on the relationship between life stress and HRQOL. DESIGN: Data were drawn from the parent study, a cross-sectional study investigating HRQOL in 86 Chinese- and 71 Korean-American BCS in Southern California. Two comorbidity related variables, the occurrence of the specific comorbidity and the total number of comorbidities, were used to comprehensively reflect the characteristics of comorbidity. RESULTS: Approximately 60% of participants had at least one comorbid disease, and osteoporosis was the most prevalent comorbidity. HRQOL differences based on the occurrence of a specific comorbidity were evident for arthritis, eye/vision problems, dental and gum problems, lymphedema, and psychological difficulties. Structural equation modeling demonstrated that the nature of the outcome variable, either physical or mental HRQOL, influenced the overall patterns of the findings. For example, life stress was significantly associated with the total number of comorbidities and in turn influenced physical HRQOL. In terms of mental HRQOL, arthritis, dental and gum problems, chronic pain, heart disease, lymphedema, and psychological difficulties mediated the relationship between life stress and mental HRQOL. CONCLUSION: The current study adds to the existing literature by examining the mediating effects of comorbidity on the relationship between life stress and HRQOL. The findings support the need for health care professionals to clearly assess physical and psychological comorbidities when providing survivorship care for cancer survivors. PMID- 27764967 TI - Cardiovascular fitness in young males and risk of unprovoked venous thromboembolism in adulthood. AB - BACKGROUND: Whether high cardiovascular fitness is associated with reduced risk of venous thromboembolism (VTE) is unknown. The present study aims to determine whether high cardiovascular fitness reduces the risk of VTE. METHODS: A Swedish cohort of male conscripts (n = 773,925) born in 1954-1970 with no history of previous VTE were followed from enlistment (1972-1990) until 2010. Data on cardiovascular fitness using a cycle ergonometric test (maximal aerobic workload in Watt [Wmax]) at conscription were linked with national hospital register data and the Multi-Generation Register. We identified all full-siblings and first cousin pairs discordant for maximal aerobic workload. This co-relative design allows for adjustment for familial resemblance. RESULTS: In total, 3005 (0.39%) males were affected by VTE. Cardiovascular fitness estimated with Wmax was not associated with VTE risk when adjusted for body mass index (BMI). However, cardiovascular fitness estimated with Wmax/kg and adjusted for BMI was associated with reduced risk for VTE (Hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.78-0.85 per standard deviation compared with mean Wmax/kg). The association was weaker over time and also when examining discordant first cousins and full sibling pairs. CONCLUSIONS: These results suggest that there is a relationship between cardiovascular fitness and weight that is important for future VTE risk. Key messages Whether high cardiovascular fitness is associated with reduced risk of venous thromboembolism (VTE) is unknown. A Swedish cohort of male conscripts (n = 773,925) tested with a cycle ergometric test with no history of previous VTE were followed from enlistment (1972-1990) until 2010. Cardiovascular fitness estimated with Wmax/kg and adjusted for BMI was associated with reduced risk for VTE (HR 0.81, 95% CI 0.78-0.85). These results suggest that there is a relationship between cardiovascular fitness and weight that is important for future VTE risk. PMID- 27764969 TI - 'Yarning up with Koori kids' - hearing the voices of Australian urban Indigenous children about their health and well-being. AB - OBJECTIVE: Australian Indigenous children experience some of the most substantial health inequalities globally. In this context, research regarding their health and well-being has overemphasised physical illnesses with limited exploration of a diverse range of dimensions and determinants, particularly those based on Indigenous holistic understandings of health and well-being. This deficit-based approach has thus missed many strengths and assets of Indigenous children. This research aimed to gain insight into the perspectives of Indigenous children about their health and well-being in an urban setting in Australia. It joins a limited international literature examining views and experiences of non-majority children. DESIGN: Participatory and qualitative child-friendly research methods were utilised. The project was developed in partnership with Indigenous community organisations and members. Photo-elicitation activities and focus groups were conducted with 31 Indigenous children aged 8-12 years. Qualitative data were analysed thematically, combining focus group and interview data. RESULTS: It was evident an urban Indigenous child perspective of health and well-being includes rich understandings of the interconnectedness of physical, social-emotional and cultural dimensions of holism, as well as the integral importance of family and community relationships. The study also found that specific worries regarding loss of loved ones and racism were highly salient in Indigenous children's lives. CONCLUSION: The overwhelming conclusion to be drawn from this research is that Indigenous children in urban areas need ongoing recognition of both their agency and resilience in the face of adversity, within a wider context of historical and contemporary racialisation and racism. PMID- 27764968 TI - The relationship between anthropometry and body composition from computed tomography: The Mediators of Atherosclerosis in South Asians Living in America Study. AB - OBJECTIVE: Few studies examine the relationships between anthropometry and the body composition measures they approximate, or whether they differ by sex, and no studies have examined these relationships in South Asians living in the US. DESIGN: We conducted a cross-sectional study of 871 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study who had BMI < 40 kg/m2 and underwent abdominal CT scans for measurement of visceral and subcutaneous fat. Linear regression was used to model the associations between anthropometric measures and naturally log-transformed body composition measures. RESULTS: All measures of anthropometry, except height, were significantly associated with visceral fat and had a significant non-linear component (p < .05). The only associations for visceral fat that exhibited significant heterogeneity by sex were waist circumference (% difference in visceral fat slope: women 1.92, men 2.74, p = .007 for interaction) and waist-to-hip ratio (women 25.9, men 717.4, p < .001). Except for height, all measures of anthropometry were significantly associated with subcutaneous fat, had a significant quadratic component, and significant heterogeneity by sex (weight (kg): 2.74 for women, 4.08 for men; BMI (kg/m2): 10.3, 14.0; waist circumference (cm): 1.51, 3.36; hip circumference (cm): 2.53, 4.50) with p < .001 for each. CONCLUSIONS: In MASALA participants, the relationships of anthropometric measures with visceral and subcutaneous fat appear similar to other race/ethnic groups, but with weaker non-linearity and heterogeneity by sex. Given these results, researchers should consider separate models by sex for US South Asians when approximating subcutaneous fat or when using waist circumference to approximate visceral fat. PMID- 27764970 TI - Combination of Microbubbles and Diagnostic Ultrasound at a High Mechanical Index for the Synergistic Microwave Ablation of Tumours. AB - OBJECTIVES: To determine whether combining microbubbles (MBs) with diagnostic ultrasound (US) at a high mechanical index (MI) could enhance the microwave (MW) ablation of tumours. MATERIALS AND METHODS: Five therapeutic MW adjuvant protocols were studied: MW, MW + US, MW + US + MB, MW + US + NS (saline), and MW + MB. In 30 normal rabbit livers, the synergistic effects were evaluated via temperature, necrosis volume and histology. In 90 VX2 rabbit hepatic tumours, residual cells in the peripheral ablated tumours were examined via immunohistochemical assay and tumour growth. Additional 40 VX2 hepatic tumours were evaluated for ablation safety via blood assay and weight and for survival to 105 days. Results were compared using analysis of variance. RESULTS: Compared with the other protocols, the ablation volumes in normal rabbit livers were significantly larger using the MW + US + MB protocol (P < .001). The histological examination was consistent with more efficient ablation in that protocol. In detecting residual cells, the apoptotic index was higher, the proliferating index was lower (P < .05), tumour growth was significantly smaller (P < .001), and the rabbits of the MW + US + MB T-Group survived longer (P < .05) than those of, the other groups. Additionally, no damage to the liver function or blood cells was found in any of the protocols after ablation (P < .05). CONCLUSIONS: MBs in combination with diagnostic US at a high MI showed potential synergy in the MW ablation of tumours in rabbits. PMID- 27764971 TI - Effect of electrical stimulation as an adjunct to botulinum toxin type A in the treatment of adult spasticity: a systematic review. AB - OBJECTIVE: To investigate whether electrical stimulation (ES) as an adjunct to BTX-A boosts botulinum activity and whether the combined therapeutic procedure is more effective than BTX-A alone in reducing spasticity in adult subjects. DATA SOURCES: A search was conducted in PubMed, EMBASE, Cochrane Central Register, and CINAHL from January 1966 to January 2016. STUDY SELECTION: Only randomized controlled studies (RCT) involving the combination of BTX-A and ES were considered. RCTs were excluded if BTX plus ES was investigated in animals or healthy subjects; certain techniques were used as an adjunct to BTX-A, but ES was not used; BTX-A or ES were compared but were not used in combination. ES was divided into neuromuscular stimulation (NMS), functional electrical stimulation (FES), and transcutaneous electrical nerve stimulation (TENS). Two authors independently screened all search results and reviewed study characteristics using the Physiotherapy Evidence Database (PEDro) scale. RESULTS: Fifteen RCTs were pinpointed and nine studies were included. Trials varied in methodological quality, size, and outcome measures used. ES was used in the form of NMS and FES in seven and two studies, respectively. No study investigating BTX-A plus TENS was found. BTX-A plus ES produced significant reduction in spasticity on the Ashworth Scale (AS) and on the modified AS in seven studies, but only four showed high quality on the PEDro scale. Significant reduction in compound muscular action potential (CMAP) amplitude was detected after BTX-A plus ES in two studies. CONCLUSIONS: ES as an adjunctive therapy to BTX-A may boost BTX-A action in reducing adult spasticity, but ES variability makes it difficult to recommend the combined therapy in clinical practice. Implications for rehabilitation Electrical stimulation (ES) as adjunct to botulinum toxin type A (BTX-A) injections may boost neurotoxin action in treating adult spasticity. Given the variability of ES characteristics and the paucity of high-quality trials, it is difficult to support definitively the use of BTX-A plus ES to potentiate BTX-A effect in clinical practice. A vast array of rehabilitation interventions combined with BTX-A have been provided in reducing spasticity, but the present evidence is not sufficient to recommend any combined therapeutic strategy. PMID- 27764972 TI - The dermatologic intimacy scale: quantitatively measuring the impact of skin disease on intimacy. AB - INTRODUCTION: Patient-reported outcome measures are increasingly utilized in dermatology to assess the impact of skin disease on quality of life. Despite recognition of the influence of skin disease on intimate relationships, an instrument to assess intimacy has not been developed. The objective of this study was to create the dermatologic intimacy scale (DIS) and administer the prototype to a patient population. METHODS: A group of healthcare providers at the University of California San Francisco created the DIS prototype. A total of 1676 psoriasis patients of an online community were invited to complete a cross sectional survey including demographic information, DIS, body surface area (BSA) and anatomical involvement. RESULTS: A total of 1109 patients completed the survey in its entirety. Patients with moderate-to-severe psoriasis (BSA >=3%) had a higher DIS score overall and for each individual question than patients with mild disease (BSA < 3%; p < .001). Patients with genitalia, nails, face, neck and scalp involvement had higher scores compared to patients without involvement (p < .001). CONCLUSIONS: Patients with more extensive disease and specific anatomical involvement experience a greater impact on intimacy. Interpretation is limited by patient response rate, as patients with or without intimacy issues may be more or less likely to respond. Further analysis is necessary for validation and interpretation. PMID- 27764973 TI - Predictors of cardiorespiratory fitness in female and male adults with different body mass index: National Health and Nutrition Examination Survey 1999-2004 dataset. AB - BACKGROUND: The aim of this study was to explore factors affecting cardiorespiratory fitness in males and females with different body mass index (BMI). METHODS: The National Health and Nutrition Examination Survey 1999-2004 data were used for this retrospective study. Estimated maximal oxygen uptake (VO2max) is surrogate for cardiorespiratory fitness (CRF). Univariate and multivariate linear regression analyses were performed to explore whether study variables were associated with estimated VO2max stratified by gender and BMI categories. RESULTS: A total of 3292 subjects 20-49 years of age were included in the analysis. CRF significantly decreased as BMI increased in both females and males. Ethnic difference was found in normal BMI in both genders and obese females; homocysteine was significantly negatively associated with estimated VO2max, as was total cholesterol. Obese male subjects with diabetes had a lower estimated VO2max than those without diabetes, and C-reactive protein (CRP) level and vitamin B12 level were significantly negatively associated with CRF. Female subjects with diabetes had higher estimated VO2max than those without diabetes. Folate was significantly positively correlated with estimated VO2max, whereas CRP was negatively correlated in obese female. CONCLUSIONS: There are different predictors of CRF in males and females, and in individuals with different BMI. Key messages Different BMI classes are associated with different predictors of cardiorespiratory fitness. Indicators of cardiorespiratory fitness differ between sexes. PMID- 27764974 TI - Physical activity and cognitive function in adults with multiple sclerosis: an integrative review. AB - PURPOSE: To identify and synthesize the research evidence concerning (1) the relationship between physical activity and cognitive performance in persons with multiple sclerosis (MS) and (2) to review the reported effects of physical activity interventions on neurocognitive performance conducted in this population. METHODS: Relevant peer-reviewed journal articles were identified by searching PubMed, PsychINFO, and SPORTDiscus through May 2016. Full-text articles meeting the inclusion criteria were evaluated for quality using tools developed by the National Institutes of Health. Studies deemed to be of poor quality were excluded from the review. RESULTS: Nineteen studies meeting the inclusion/exclusion criteria were analyzed. Nine studies reported significant relationships between higher levels of physical activity or cardiorespiratory fitness and measures of cognitive function. Data extracted from 10 physical activity intervention studies reported mixed results on the effectiveness of physical activity to improve selected domains of cognitive function in persons with MS. CONCLUSION: Although correlational studies provide evidence to support a linkage between physical activity and cognitive function in persons with MS, this linkage is confounded by factors that may have influenced the studies' results. Evidence derived from intervention studies that could support a positive effect of physical activity on cognition in persons with MS is equivocal. Implications for Rehabilitation Physical activity has numerous benefits for persons with multiple sclerosis (MS) including improvements in balance, ambulation, depression, fatigue, and quality of life. Structured physical activity programs may contribute to cognitive function stability or improvement in persons with MS. PMID- 27764975 TI - Early patient experiences with montelukast orally disintegrating tablets in Japan: a cross-sectional survey of treatment satisfaction in patients with asthma and/or allergic rhinitis. AB - OBJECTIVE: Orally disintegrating tablets (ODTs) offer a valuable treatment option, particularly when swallowing solid tablets with water is difficult or inconvenient. Montelukast is an effective treatment for asthma and allergic rhinitis (AR), and an ODT formulation became available in Japan in 2015. This study investigated levels of satisfaction with this new formulation among adults with asthma and/or AR in Japan. METHODS: Patients aged 20 years or older who were refilling a prescription for montelukast ODT in pharmacies across Japan completed questions on satisfaction with key features of montelukast ODT and the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). Study variables were analyzed descriptively. Factors associated with TSQM-9 global satisfaction and convenience domain scores were examined using analysis of covariance. RESULTS: Of the 201 patients who participated, 89.6% reported overall satisfaction with montelukast ODT. Overall satisfaction was highest in patients with AR only (94.7% satisfied) or with asthma and AR (90.2% satisfied), and in patients with treatment duration <4 weeks (98.5% satisfied). Mean TSQM-9 global satisfaction and convenience domain scores were 58.9 and 66.7, respectively; scores were higher for patients with both asthma and AR and for those with longer disease duration. Overall ease of taking and dissolving speed were most closely associated with TSQM-9 global satisfaction scores, and ability to take without water and taste were most closely associated with TSQM-9 convenience scores. LIMITATIONS: The generalizability of the findings was limited by the convenience sample and the descriptive, single-arm study design. The study was limited to adults with asthma and/or AR. CONCLUSION: Montelukast ODT may be an acceptable dosage formulation for adults with mild-to-moderate asthma and/or AR in Japan. Satisfaction was high, particularly with respect to tablet size, dissolving speed, taste, and ease of taking. PMID- 27764976 TI - Clinical usefulness of the Oxford classification in determining immunosuppressive treatment in IgA nephropathy. AB - BACKGROUND: The Oxford classification has been widely used in IgA nephropathy. However, its clinical usefulness of determining immunosuppression is unknown. AIM: Whether the Oxford classification could predict the development of proteinuria >=1 g/g Cr and worsening kidney function, as well as the clinical efficacy of corticosteroid treatment according to each histologic variable of the Oxford-MEST. METHODS: We included 377 patients with early-stage IgA nephropathy. The study endpoints were the development of a heavy proteinuria and a decline renal function. RESULTS: The results showed that among the Oxford-MEST lesions, only M1 predicted the risk of the development of proteinuria >=1.0 g/g Cr compared to other lesions in a time-varying Cox model adjusted for multiple confounding factors. In addition, the risk of reaching a 30% decline in eGFR was significantly higher in patients with M1 than in those with M0. Furthermore, patients with M1 had a greater decline of eGFR than patients with M0. However, steroid treatment in M1 lesion was not associated with improving clinical outcomes in the unmatched and propensity score matched cohort. CONCLUSIONS: This finding may provide a rationale for using the Oxford classification as a guidance to initiate immunosuppression in the early stages of IgA nephropathy. KEY MESSAGES M1 has independently predictive role among the Oxford lesions in IgA nephropathy. Oxford classification should be defined during pathologic approach. Decision of starting immunosuppression according to the Oxford lesions. PMID- 27764977 TI - Optimizing engagement in goal pursuit with youth with physical disabilities attending life skills and transition programs: an exploratory study. AB - PURPOSE: Identify strategies youth perceive will optimize their engagement in goal pursuit in life skills and transition programs using an engagement framework involving affective, cognitive, and behavioral components. METHODS: A qualitative descriptive design was used. Two semi-structured interviews were conducted with seven youth. The first was informed by a prior observation session, and the second occurred after the program ended and explored youths' perceptions of whether and how their engagement changed. Data were analyzed using thematic analysis. RESULTS: The analysis generated eight strategies youth considered effective. These were categorized under the three components of engagement. Affective strategies: (1) building a relationship on familiarity and reciprocity; and (2) guiding the program using youths' preferences and strengths. Cognitive strategies: (3) assisting youth to envision meaningful change; (4) utilizing youths' learning styles; and (5) promoting awareness of goal progress. Behavioral strategies: (6) ensuring youth access to a resource network; (7) providing youth multiple decision opportunities; and (8) enabling youth to showcase capabilities. CONCLUSIONS: Service providers together with youth are encouraged to consider the role of context and self-determination needs in order to optimize youth engagement in goal pursuit. Systematic approaches to studying engagement are necessary to learn how to maximize rehabilitation potential. Implications for Rehabilitation Service providers are encouraged to be aware of the nature of engagement strategies identified by youth. Comprehensive frameworks of engagement are essential to generate knowledge on the range of strategies service providers can use to engage clients in rehabilitation services. Strategies perceived by youth to optimize their engagement in goal pursuit in life skills and transition programs have subtle yet significant differences with strategies used in other rehabilitation settings like mental health and adult healthcare services. Self determination theory shows potential in guiding further research on exploring the role of engagement in maximizing rehabilitation outcomes. PMID- 27764978 TI - The prevalence of sacroiliitis in patients with acne vulgaris using isotretinoin. AB - BACKGROUND/OBJECTIVE: Acne vulgaris is a chronic inflammatory disease affecting the pilosebaceous unit in the skin. Isotretinoin is a synthetic vitamin A derivative regarded as the most effective agent in the treatment of acne. There have recently been increasing reports of adverse effects of isotretinoin on the skeletal system. Our aim in this study was to evaluate the rheumatic side-effects triggered by this drug, and particularly the prevalence of sacroiliitis. MATERIALS AND METHODS: A total of 73 patients receiving isotretinoin due to moderate or severe acne vulgaris were included. All patients were questioned about inflammatory low back pain and musculoskeletal pains during the treatment process. Inflammatory low back pain was evaluated using Assessment of Spondyloarthritis International Society (ASAS) criteria. Patients meeting ASAS criteria were evaluated with radiography and when necessary with sacroiliac magnetic resonance. RESULTS: The dose range for isotretinoin was between 0.4 and 0.8 mg/kg/day (mean 0.53 mg/kg/day). Treatment lasted for 6-8 months (mean 6.8 months). Lethargy was determined in 37 (50.7%) patients, myalgia in 31 (42.5%) and low back pain in 36 (49.3%). Mechanical low back pain symptoms were present in 20 of the patients describing low back pain and inflammatory low back pain in 16. Acute sacroiliitis was determined in six patients (8.2%) following a sacroiliac magnetic resonance imaging (MRI). Five (83.3%) of the patients with sacroiliitis were female and one (16.7%) was male. No statistically significant difference was determined between male and female patients in terms of prevalence of sacroiliitis (p = 0.392). CONCLUSION: The incidence of sacroiliitis in patients using isotretinoin is quite high. Patients using isotretinoin must be questioned about sacroiliitis findings and must be subjected to advanced assessment when necessary. Further studies regarding the development of sacroiliitis under isotretinoin therapy are now needed. PMID- 27764979 TI - Budget impact of treating commercially insured type 1 and type 2 diabetes patients in the United States with insulin degludec compared to insulin glargine. AB - OBJECTIVE: To quantify the annual budget impact if all US commercially insured type 1 diabetes mellitus patients on basal-bolus therapy (T1DMBBT), type 2 diabetes mellitus patients on basal-oral therapy (T2DMBOT), and type 2 diabetes mellitus patients on basal-bolus therapy (T2DMBBT) switched from insulin glargine (IGlar) to insulin degludec (IDeg). METHODS: A short-term (1 year) budget impact model was developed to evaluate the costs of IDeg vs. IGlar in three treatment groups (T1DMBBT, insulin-naive T2DMBOT, and T2DMBBT) through a simulation for a potential US health plan population of 35 million. The analysis captured direct medical costs associated with insulin treatment (insulin, needles, and self monitored glucose testing) and costs related to managing hypoglycemic episodes. There were a total of 59,780 T1DMBBT patients, 383,145 T2DMBOT patients, and 171,325 T2DMBBT patients expected to be using long-acting insulin. A sensitivity analysis on the entire US population was also conducted. RESULTS: Among T1DMBBT patients, IDeg was associated with an annual cost savings of -$357.13 per patient per year (PPPY), driven primarily by reduced insulin utilization. IDeg was also found to be cost saving among T2DMBOT patients (-$1206.61 PPPY), driven primarily by reductions in the cost of treating severe hypoglycemic episodes. Among T2DMBBT patients, IDeg was associated with an additional cost to the plan of $1420.04 PPPY; however, this result was driven by a higher insulin dose for IDeg compared to IGlar. Overall, IDeg demonstrated cost savings of $240 million per year, which accounted for total cost savings of 3.5% vs. IGlar. CONCLUSIONS: The results of this analysis suggest that the reduced insulin utilization and fewer hypoglycemic episodes associated with IDeg may translate into reduced costs for payers. The model is limited by simplification of a complex disease state and assumptions surrounding disease state, treatment patterns, and costs. Therefore, results may not accurately reflect actual health plans or real-world practice patterns. PMID- 27764980 TI - Which echocardiographic parameter is a better marker of volume status in hemodialysis patients? AB - AIM: Bio-impedance analysis (BIA) is a preferred method for estimating the volume status. However, it cannot be utilized in daily practice. Since the assessment of the volume status is important and challenging for hemodialysis (HD) patients, the aim of study was to determine the volume status in chronic HD patients using echocardiographic parameters and assess its correlation with BIA. METHODS: In this cross-sectional analysis, echocardiography and BIA were performed on 30 chronic HD patients 30 min before and 30 min after dialysis. All the cases of dialysis were performed in the middle of the week. This study also assessed the correlation between echocardiographic parameters and BIA parameters. RESULTS: There were significant differences between ECW, TBW, and TBW% (TBW/W) before and after HD. Significant differences were observed between echocardiographic parameters of IVCD, IVCDimin, IVCDimax before and after the HD. LVEDD, LVESD, LA area, mitral valve inflow, E/E', and IVRT, were improved after dialysis, too. There was a significant correlation between IVCDimin as an index of volume status, ECW% and TBW% before HD and IVCDimin change after dialysis had a significant correlation with %ECW change after dialysis. Comparison between hypertensive and non-hypertensive groups indicated IVCDimin was significantly lower in non-hypertensive group after dialysis. CONCLUSION: Our results showed a correlation between IVCDimin and BIA parameters before HD. So, it seems that IVCDimin can be a good parameter for determining the volume status of HD patients. However, further studies, with larger sample size and with a prospective study design, are required to confirm these results. PMID- 27764981 TI - Luteolin ameliorates colistin-induced nephrotoxicity in the rat models. AB - INTRODUCTION AND AIM: To study the protective, preventive effect of luteolin from colistin-induced nephrotoxicity. MATERIAL AND METHOD: Four different treatment options were tested on rats: colistin, luteolin, and a combination of colistin and luteolin, intraperitoneally as two doses a day, for seven days. Another group of rats were used as the control and treated with sterile saline. Serum creatinine levels were measured before and after treatment. Histological changes and colistin-induced apoptosis (Insitu BrdU-red DNA Fragmentation Assay Kit) of the renal tissues were examined after the scarification procedure. RESULTS: In the Colistin Group, post-treatment creatinine levels were statistically higher than the pretreatment levels (p = .001). In the remaining groups, no significant changes were observed. Cells that undergo apoptosis were counted and it was shown that all groups except the colistin-treated group had a similar number of apoptotic cells, whereas the colistin-treated group had statistically higher number of apoptotic cells compared to other groups (p = .0001). Renal histological damage was also measured and the score of the colistin treated group was higher as compared to other groups. CONCLUSION: The results obtained from this study demonstrated us that luteolin was capable of preventing colistin induced nephrotoxicity and that this effect was significant at histopathological level. PMID- 27764982 TI - Development of nanosponges from erythrocyte ghosts for removal of streptolysin-O from mammalian blood. AB - AIM: To produce mammalian biomimetic nanosponges from mammalian erythrocyte ghosts. Biomimetic nanosponges were studied in vitro as treatment platforms against exotoxin-related sepsis. METHODS: Ovine blood was treated with hypotonic buffer to create erythrocyte ghosts and then subjected to sonication to produce erythrocyte vesicles of nonuniform size. Vesicles were then serially extruded through 400-nm and 100-nm polycarbonate membranes. Nanosponges were prepared by fusing poly(d,l-lactic-co-glycolic acid) cores with ovine erythrocyte vesicles. RESULTS: Ovine erythrocytes were the most susceptible to streptolysin-O lysis, making it a model to study sepsis treatment. Ovine nanosponges adsorbed streptolysin-O at 37 and 40 degrees C. CONCLUSION: These results identify ovine nanosponges as novel therapeutic model to test adsorption of cholesterol binding toxins such as streptolysin-O. PMID- 27764983 TI - Familial juvenile hyperuricemic nephropathy as rare cause of dialysis-dependent chronic kidney disease-a series of cases in two families. AB - Hyperuricemia is a common symptom in adult population. It usually accompanies the chronic kidney disease. Less frequently, it is a primary phenomenon causing later serious clinical consequences. Familial juvenile hyperuricemic nephropathy (FJHN) is one of the hereditary conditions associated with high levels of serum uric acid and leading to dialysis in young adult age. It results from mutation in the UMOD gene, encoding the uromodulin protein, that is, Tamm-Horsfall protein. The aim of this paper was to present two families (7 affected members) with FJHN, in whom standard nephrological diagnostics did not provide clear cause of dialysis dependent chronic kidney disease, until genetic testing was performed. PMID- 27764984 TI - End-stage renal disease adherence questionnaire: translation and validation to the portuguese language. AB - Non-adherence to medical plans is recognized as an important problem in dialysis patients, since it has been associated with increased morbidity and mortality, resulting in disproportionately high costs of care. The success of renal replacement therapy depends on the adherence of patients to the different aspects of the therapeutic strategy, which includes a complex drug regimen involving a wide variety of drugs and doses, several prescribed dialysis sessions with different durations, dietetic recommendations and restriction of fluid intake. In this work, we aimed to translate and validate a previously described self reported end-stage renal disease questionnaire (ESRD-AQ) to the Portuguese language (PESRD-AQ). After ESRD-AQ translation, a validation was performed by experts and by using a cohort of 185 Portuguese dialysis patients. PESRD-AQ reliability analysis showed strong test-retest stability across all items, with an intra-class correlation of 0.931. The average of the item-level content validity index by experts for the 46 items was 0.98, ranging from 0.94 to 1. Moreover, we found that PESRD-AQ scores indicative of non-adherence were associated with alterations in some biological and biochemical markers of non adherence, including interdialytic weight gain. In conclusion, our results showed that PESRD-AQ, which presented an acceptable reliability and validity, is a valid tool to be used for adherence evaluation by Portuguese-speaking dialysis patients. PMID- 27764992 TI - Toward an Interdisciplinary Psychology of Appearances. PMID- 27764985 TI - Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with chronic kidney disease (CKD) including kidney transplant recipients (KTR). Secondary lipid metabolism disorders, endothelial dysfunction, and inflammation enhance the risk of CVD development in these patients. The aim of the present study was to investigate the lipid profile, adiponectin, leptin, nitric oxide (NO), and high sensitivity C-reactive protein (hs-CRP) levels in KTR and to compare these parameters with those of the patients with chronic renal failure (CRF), hemodialysis (HD) patients, and healthy controls. METHODS: Serum adiponectin and leptin levels were measured by radioimmunoassay; hs-CRP was determined immunoturbidimetrically. Determination of NO was based on the Griess reaction. RESULTS: Compared with the control group, serum NO and adiponectin levels were significantly higher in the KTR, CRF, and HD groups; hs-CRP levels were significantly higher in the KTR and HD groups; leptin levels were significantly higher in the KTR. In addition, serum NO level was significantly higher in the KTR compared to CRF cases. Adiponectin correlated positively with high density lipoprotein-cholesterol in the control and patient groups. A positive correlation was observed between hs-CRP and NO in the KTR and the patients with CRF. Serum adiponectin levels were inversely correlated with hs CRP and leptin in the HD group. CONCLUSION: KTR suffer from inflammation and accompanying changes in levels of adipocytokines and NO which contribute to the increased risk of CVD in these patients. PMID- 27764994 TI - A Study of Former Mental Patients Who Returned to Visit the Ward on Which They Were Hospitalized. PMID- 27764996 TI - Announcement: The Judith Baskin Offer Prize. PMID- 27764997 TI - Scan posture definition and hip girth measurement: the impact on clothing design and body scanning. AB - Ergonomic measurement is central to product design and development; especially for body worn products and clothing. However, there is a large variation in measurement definitions, complicated by new body scanning technology that captures measurements in a posture different to traditional manual methods. Investigations of hip measurement definitions in current clothing measurement practices supports analysis of the effect of scan posture and hip measurement definition on the circumferences of the hip. Here, the hip girth is a key clothing measurement that is not defined in current body scanning measurement standards. Sixty-four participants were scanned in the standard scan posture of a [TC]2 body scanner, and also in a natural posture similar to that of traditional manual measurement collection. Results indicate that scan posture affects hip girth circumferences, and that some current clothing measurement practices may not define the largest lower body circumference. Recommendations are made concerning how the hip is defined in measurement practice and within body scanning for clothing product development. Practitioner Summary: The hip girth is an important measurement in garment design, yet its measurement protocol is not currently defined. We demonstrate that body posture during body scanning affects hip circumferences, and that current clothing measurement practices may not define the largest lower body circumference. This paper also provides future measurement practice recommendations. PMID- 27764998 TI - Helicobacter pylori participates in the pathogenesis of IgA nephropathy. AB - Increasing evidences have shown that Helicobacter pylori (Hp) is a pathogen closely related to extra-gastric disorders. Our previous in vitro studies had demonstrated that Hp infection, at least via cytotoxin-associated gene A protein (CagA), might play an important role in the pathogenesis of IgA nephropathy (IgAN) by stimulating proliferation and ectopic synthesis of aberrantly glycosylated IgA1 of B cells. However, the relevant clinical evidence of IgAN resulted from Hp infection remain to be elucidated. This study aimed to investigate the risk incidence of IgAN caused by Hp infection. 22 primary IgAN, 20 non-IgA nephropathy (n-IgAN), and 30 healthy controls were included in this study. We found that the rate of IgG anti-Hp seropositivity was significantly improved in IgAN, but the current Hp infection was similar in all groups. The production and underglycosylation of IgA1 tended to increase in IgAN patients with IgG anti-Hp seropositivity. A tendency toward increased the risk of clinical prognosis was seen in IgAN with Hp infection. Hp antigen and CagA were only deposited in renal tubules, and enhanced antigen deposition in response to Hp was observed in IgAN. Our study suggested that Hp infection might have a pathogenic role in IgAN through giving rise to strongly mucosal immune response, and based on damage of renal tubular. PMID- 27765000 TI - How to treat a fulminant erysipelas and sepsis caused by Myroides odoratimimus: case report and literature review. AB - We report a case of a 77-year old male who developed a fulminant erysipelas and sepsis, caused by Myroides odoratimimus. Selecting the optimal antibiotic therapy for the treatment of infections with M. odoratimimus is challenging due to limited clinical experience with this micro-organism and its reported multidrug resistance. Review of previous studies concerning in vitro antibacterial susceptibility and clinical experience with M. odoratimimus resulted in six case reports describing bacteremia, soft tissue and bone infections, pneumonia and urinary tract infections. In vitro susceptibility to aminoglycosides, fluoroquinolones and trimethoprim/sulfamethoxazole is variable. Treatment of M. odoratimimus infections should be based on antimicrobial susceptibility testing results. In a majority of the case reports, including the present one, treatment with fluoroquinolones proved to be a good therapeutic option. PMID- 27764999 TI - A fatal case of transplantation-mediated alloimmune thrombocytopenia following liver transplantation. AB - OBJECTIVE AND IMPORTANCE: Transplantation-mediated alloimmune thrombocytopenia (TMAT) occurs when leukocytes transferred in a donor organ from a patient with immune thrombocytopenia (ITP), mount a response against recipient platelets. We present the first fatal case of TMAT following liver transplantation and review its aetiology and treatment. CLINICAL PRESENTATION: The liver donor had ITP and died from an intracranial haemorrhage. The recipient platelet count fell to 2 * 109/l on post-operative day 2. Treatment refractory thrombocytopenia resulted in pulmonary haemorrhage and death. TMAT did not occur in a kidney recipient from the same ITP donor. INTERVENTION: Extramedullary haematopoiesis was identified in the donor liver biopsy. Antibodies against platelet GPIb/IX were demonstrated in both donor and recipient. The thrombocytopenia was refractory to platelet transfusions, intravenous immunoglobulin, methylprednisolone, rituximab, romiplostim, plasmapheresis, vincristine and splenic artery embolization. On review of the literature, severe thrombocytopenia (<10 * 109/l) has started within 3 days of transplantation in all reported TMAT cases. Serious non-fatal bleeding was observed in 3/5 previously reported cases. The optimal treatment is unclear. TMAT should resolve as donor lymphocytes are eliminated but re transplantation may be required in severe refractory cases. TMAT has been reported in recipients of a liver but not kidney or heart transplant from ITP donors, probably because of the greater burden of co-transplanted lymphoid tissue. CONCLUSION: Before using the liver of an ITP donor, the recipient's fully informed consent is required. However, the risk of TMAT from an ITP donor is currently unknown and systematic review of donor registries is needed. PMID- 27765001 TI - A conformal hydrogel nanocomposite for local delivery of paclitaxel. AB - Conventional surgical methods can not completely remove the tumor cells, and an inevitable recurrence always results in death. In this study, we prepared a conformal hydrogel nanocomposite with potential to inhibit the recurrence of glioma. Based on the MRI of a patient's brain tumor cavity (BTC), we 3D-printed a mould for preparing the customized implants that could match the resection cavity. The obtained macroporous hydrogel, containing Paclitaxel (PTX) nanoparticles, could sustained release PTX. From the confocal microscopy image, we could detect that the hydrogel nanocomposite combined with nanoparticles uniformly. The nanoparticles were fabricated through a self-assembled process with PTX. Moreover, the in vitro studies showed that nanoparticles could release PTX slowly and efficiently inhibited the proliferation of tumor cells. This work prepared a conformal hydrogel nanocomposite for local delivery of paclitaxel, which could inspire the development of future protocols for precision therapy of residual glioma after surgical resection. PMID- 27765002 TI - Prevalence of restless legs syndrome in chronic kidney disease: a systematic review and meta-analysis of observational studies. AB - INTRODUCTION: Nowadays prevalence of restless legs syndrome (RLS) in chronic kidney disease (CKD) patients was reported in many studies, while the results varied. The aim of our study was to investigate the prevalence of RLS in this population, considering different data collecting measures and diagnostic criteria. METHODS: MEDLINE, Embase, PsycINFO, and Scopus databases were searched for relevant studies. We limited the analyses to studies using clinical interview or questionnaire for diagnosis. Univariate meta-regression analysis was preformed to assess the effects of the disease-related covariates on prevalence estimates. Comprehensive Meta-Analysis 2.0 was used to perform the meta-analysis. RESULTS: Fifty-one studies were included in the analysis. Prevalence of RLS was varied by renal function and diagnostic methods. Overall prevalence in CKD populations was 24.2% (95%CI, 20.1-28.7). Pooled prevalence of RLS was higher in patients diagnosed by questionnaire than by clinical interview [26.2% (95%CI, 17.9-36.5) vs. 23.6% (95%CI, 19.6-28.1)]. When grouped by CKD setting, the prevalence was 28.4% (95%CI, 24.6-32.6) in dialysis patients, followed by early stages patients [9.9% (95%CI, 5.4-17.5)], and kidney transplant recipients [6.7% (95%CI, 5.6 7.8)]. CONCLUSIONS: Our meta-analysis suggested that more than one-quarter of CKD sufferers, especially those who were on dialysis, were plagued by RLS. Higher sensitivity of diagnostic criteria in interview may be valuable for timely treatment. PMID- 27765003 TI - Determinants in the number of staff in hospitals' maintenance departments: a multivariate regression analysis approach. AB - To date, there are no broadly accepted or accurate models to determine appropriate staffing [levels] for clinical engineering departments (CEDs). The purpose of this study is to determine what the determinants of the staffing levels are (total number of full time equivalents (FTEs)) in CEDs in healthcare organisations. In doing so, we used a cross-sectional exploratory approach by using a multivariate regression model over a secondary source of data information from the AAMI Benchmarking Solutions-Healthcare Technology Management database. Two hundred and one healthcare organisations were included in our study. Our study revealed that on average, there are almost 14 biomedical technicians (BMETs) per clinical engineer and one FTE per 1083.72 devices (SD 545.69). The results of this study also revealed that the total number of devices and the total technology management hours devoted to these devices positively affects the number of FTEs in a CED, whereas the hospital complexity, measured by healthcare organisation patient discharges matters inversely. The most important factor that matters in the number of FTEs in CEDs was the total technology management hours devoted to devices. A value of explained variance (i.e. R2) of 85% was obtained, indicating the strong power of the prediction accuracy of our multivariate regression model. PMID- 27765004 TI - The effect of hyperbaric oxygen therapy on rhabdomyolysis-induced myoglobinuric acute renal failure in rats. AB - Myoglobinuric acute renal failure (MARF) may develop after severe muscle injury. Heme oxygenase-1 (HO-1), a stress-response protein, has been implicated as a protective agent against MARF. We hypothesized that hyperbaric oxygen therapy (HBOT) may alleviate MARF by inducing renal HO-1 expression. Wistar-Albino rats were randomly assigned into three groups: Control (n = 4), MARF (n = 8), MARF + HBO (n = 8). MARF was induced by intramuscular glycerol (50%, 8 mL/kg) injection. Saline (8 mL/kg) was injected into the hind limb of the animals in the control group. Animals in the MARF + HBO group received two sessions of HBO therapy (90 min at 2.5 atm) 2 and 18 h after glycerol injection. Serum and tissue samples were taken at 24 h. Serum urea and creatinine levels increased in the MARF and MARF + HBO groups confirming the development of MARF. But, serum urea and creatinine levels were similar in MARF and MARF + HBO groups. Oxidative stress parameters were similar among all groups. Histological renal injury score was similar in MARF and MARF + HBO groups. HO-1 level, determined by immunohistochemistry, was significantly higher in MARF and MARF + HBO groups, compared to the control group. Although HO-1 level in MARF + HBO group was higher than MARF group, it was not statistically significant. We found that HBOT did not reduce renal injury in experimental MARF model. HBOT is used to reduce the muscle damage after crush injury, which may be accompanied by MARF. Therefore, more studies are needed to understand the effects of HBO treatment on renal functions after MARF. PMID- 27765005 TI - Beneficial Effect of the Nutritional Support in Children Who Underwent Hematopoietic Stem Cell Transplant. AB - OBJECTIVES: The aim of this study was to evaluate nutritional status in children who underwent hematopoietic stem cell transplant compared with a healthy control group. A secondary aim was to utilize mid-upper arm circumference as a measure of nutritional status in these groups of children. MATERIALS AND METHODS: Our study group included 40 children (18 girls, 22 boys) with mean age of 9.2 +/- 4.6 years (range, 2-17 y) who underwent hematopoietic stem cell transplant. Our control group consisted of 20 healthy children (9 girls, 11 boys). The children were evaluated at admission to the hospital and followed regularly 3, 6, 9, and 12 months after discharge from the hospital. RESULTS: In the study group, 27 of 40 patients (67.5%) received nutritional support during hematopoietic stem cell transplant, with 15 patients (56%) receiving enteral nutrition, 6 (22%) receiving total parenteral nutrition, and 6 (22%) receiving enteral and total parenteral nutrition. Chronic malnutrition rate in the study group was 47.5% on admission to the hospital, with the control group having a rate of 20%. One year after transplant, the rate decreased to 20% in the study group and 5% in the control group. The mid-upper arm circumference was lower in children in the study group versus the control group at the beginning of the study (P < .05). However, there were no significant differences in mid-upper arm circumference measurements between groups at follow-up examinations (P > .05). During follow-up, all anthropometric measurements increased significantly in both groups. CONCLUSIONS: Monitoring nutritional status and initiating appropriate nutritional support improved the success of hematopoietic stem cell transplant and provided a more comfortable process during the transplant period. Furthermore, mid-upper arm circumference is a more sensitive, useful, and safer parameter that can be used to measure nutritional status of children who undergo hematopoietic stem cell transplant. PMID- 27765006 TI - Rigler Sign in a Child With Posttransplant Lymphoproliferative Disease: A Sign That Should Not Be Missed. AB - Rigler sign is a double wall sign suggesting pneumoperitoneum and intestinal perforation, and it needs emergency surgical treatment. Early diagnosis of intestinal perforation by clinical symptoms, presence of Rigler sign in abdominal radiography, and then early surgical treatment can reduce mortality. Here, we report a patient with Crigler-Najjar syndrome who underwent liver transplant and then developed posttransplant lymphoproliferative disease and received chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. She was referred to the emergency department due to abdominal distension with positive Rigler sign in abdominal radiography; intraoperative findings revealed intestinal perforation. Pediatricians and surgeons should be aware of Rigler sign so that it is diagnosed early and emergency surgical treatment can be performed. PMID- 27765007 TI - Outcome of Kidney Transplant in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. AB - OBJECTIVES: Kidney transplant outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis are comparable with outcomes in patients transplanted for other causes. Here, we report our single center experience of kidney transplant in patients with this condition and a pooled analysis of published studies. MATERIALS AND METHODS: This retrospective study included all patients with end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis who received a kidney transplant between 1987 and 2013 in the East of Scotland. We examined patient and graft survival and disease recurrence after transplant. We also performed a pooled analysis of published literature. RESULTS: We identified 24 patients who received a total of 31 kidney allografts. Median age at first transplant was 45.5 years (range, 18-68 y), and median follow-up after transplant was 60 months (range, 0.5 226 mo). All patients were positive for antineutrophil cytoplasmic antibody (71% by proteinase 3 and 29% by myeloperoxidase) at diagnosis. Patient survival at 1 and 5 years was 92% and 88%, with corresponding death-censored allograft survival of 93% and 71%. Overall patient and allograft relapse rates were 0.022 and 0.016 relapse/patient-years. The pooled analysis comprised 20 studies (1169 patients). Patient/graft survival ranged from 64% to 80%/77% to 100% at 5 years and from 60% to 100%/59% to 84% at 10 years. Relapse rate was significantly higher in patients with positive antineutrophil cytoplasmic antibody at transplant (14% vs 5%; P = .042). CONCLUSIONS: Our experience shows that kidney transplant remains a safe option for patients with end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis. Disease relapse posttransplant is uncommon and associated with pretransplant relapse. Pooled analyses suggest that relapse rate is higher in patients with positive antineutrophil cytoplasmic antibody at transplant. Multicenter registry data are needed to define renal outcome predictors in antineutrophil cytoplasmic antibody-associated vasculitis. PMID- 27765008 TI - SGLT2 Inhibitors in Diabetes Mellitus Treatment. AB - Type 2 Diabetes Mellitus (T2DM) is a chronic illness with high prevalence in Mexico, Latin- America, and the world and is associated to high morbidity, disability, and mortality rate, especially in developing countries. T2DM physiopathology is very complex; insulin resistance in the muscle, liver, and adipose tissue, a reduction in the production of incretins (mainly GLP-1) in the intestine, increased glucagon synthesis, an insufficient response of insulin generation, and increased glucose reabsorption in the kidney lead all together to an hyperglycemic state, which has been closely associated with the development of micro and macrovascular complications. Sodium Glucose Linked Transporter 2 inhibitors (SGLT2i) are the most recent therapeutic class available for treating T2DM. SGLT2i central effect is a glycosuric action, and they can reverse the deleterious effect of tubular reabsorption of glucose in the diabetic patient resulting in greater hyperglycemia. Because their mechanism of action is completely different to current drugs, they can be considered as monotherapy or in combination with any other oral or parenteral medication, including different types of insulin or its analogues. This therapeutic synergy accomplishes a greater percentage of patients achieving glycemic control goals. PMID- 27765009 TI - The differential diagnosis of tiredness: a systematic review. AB - BACKGROUND: Tiredness is one of the most frequent complaints in primary care. Although often self-limiting and frequently associated with psychosocial stress, patients but also their physicians are often uncertain regarding a serious cause and appropriate diagnostic work-up. We conducted a systematic review and meta analysis of studies reporting on differential diagnosis of fatigue in primary care. METHODS: MEDLINE, EMBASE and conference abstracts were searched for primary care based studies of patients presenting with tiredness. Twenty-six studies were included. We report on anaemia, malignancy, serious organic disease, depression and the chronic fatigue syndrome (CFS) as causes of tiredness as presenting complaint. RESULTS: We found considerable heterogeneity of estimates which was reduced by limiting our analysis to high quality studies. Prevalences were as follows-anaemia: 2.8 % (CI (confidence interval) 1.6-4.8 %); malignancy: 0.6 % (CI 0.3-1.3 %); serious somatic disease: 4.3 % (CI 2.7-6.7 %); depression 18.5 % (CI 16.2-21.0 %). Pooling was not appropriate for CFS. In studies with control groups of patients without the symptom of tiredness, prevalence of somatic disease was identical to those complaining of tiredness. Depression, however, was more frequent among those with tiredness. CONCLUSIONS: Serious somatic disease is rare in patients complaining of tiredness. Since prevalence is similar in patients without tiredness, the association may not be causal. Extensive investigations are only warranted in case of specific findings from the history or clinical examination. Instead, attention should focus on depression and psychosocial problems. PMID- 27765010 TI - Dexamethasone does not diminish sugammadex reversal of neuromuscular block - clinical study in surgical patients undergoing general anesthesia. AB - BACKGROUND: Sugammadex reverses neuromuscular block (NMB) through binding aminosteroid neuromuscular blocking agents. Although sugammadex appears to be highly selective, it can interact with other drugs, like corticosteroids. A prospective single-blinded randomized clinical trial was designed to explore the significance of interactions between dexamethasone and sugammadex. METHODS: Sixty five patients who were anesthetized for elective abdominal or urological surgery were included. NMB was assessed using train-of-four stimulation (TOF), with rocuronium used to maintain the desired NMB depth. NMB reversal at the end of anaesthesia was achieved using sugammadex. According to their received antiemetics, the patients were randomized to either the granisetron or dexamethasone group. Blood samples were taken before and after NMB reversal, for plasma dexamethasone and rocuronium determination. Primary endpoint was time from sugammadex administration to NMB reversal. Secondary endpoints included the ratios of the dexamethasone and rocuronium concentrations after NMB reversal versus before sugammadex administration. RESULTS: There were no differences for time to NMB reversal between the control (mean 121 +/- 61 s) and the dexamethasone group (mean 125 +/- 57 s; P = 0.760). Time to NMB reversal to a TOF ratio >=0.9 was significantly longer in patients with lower TOF prior to sugammadex administration (Beta = -0.268; P = 0.038). The ratio between the rocuronium concentrations after NMB reversal versus before sugammadex administration was significantly affected by sugammadex dose (Beta = -0.375; P = 0.004), as was rocuronium dose per hour of operation (Beta = -0.366; p = 0.007), while it was not affected by NMB depth before administration of sugammadex (Beta = -0.089; p = 0.483) and dexamethasone (Beta = -0.186; p = 0.131). There was significant drop in plasma dexamethasone after sugammadex administration and NMB reversal (p < 0.001). CONCLUSIONS: Administration of dexamethasone to anesthetized patients did not delay NMB reversal by sugammadex. TRIAL REGISTRATION: The trial was retrospectively registered with The Australian New Zealand Clinical Trials Registry (ANZCTR) on February 28th 2012 (enrollment of the first patient on February 2nd 2012) and was given a trial ID number ACTRN12612000245897 and universal trial number U1111-1128-5104. PMID- 27765011 TI - Physical, social, psychological and existential trajectories of loss and adaptation towards the end of life for older people living with frailty: a serial interview study. AB - BACKGROUND: The experiences of people with cancer and organ disease have been described across different dimensions of need as they approach death. Such information is lacking for frail older people approaching death, but could highlight how a palliative approach might be relevant for this population. METHODS: Cognitively intact, community dwelling adults considered to be moderately or severely frail were recruited from a medical day hospital. Those recruited nominated an informal carer and case-linked professional. Qualitative in-depth serial interviews with older people and their informal carers were conducted over an 18 month period, and single interviews with case-linked healthcare professionals. Interviews were recorded, transcribed and narrative analytical techniques were used to compile case studies. RESULTS: Thirty-four participants (13 patients, 13 informal carers and 8 healthcare professionals) completed 40 individual, 14 joint and 8 professional interviews. Five patients died during the study. The analysis highlighted a dynamic balance between losses and adaptations. Three typical patterns of multi-dimensional change emerged. 1) Maintenance of psychological and existential well-being with a gradual social decline mirroring the physical deterioration. 2) a gradual reduction in both psychological and existential well-being. 3) a marked downturn in social, psychological and existential well-being before death. Frail older people sustained their well-being through maintaining a sense-of-self, garnering support from carers and community structures, and focusing on living from day to day. Their well-being lessened when they lost their sense-of-self, feeling alienated from the world, and confused over the cause of their circumstances. Death remained distant and 'undiagnosed'. Social and community frameworks were essential for supporting their well-being. CONCLUSIONS: Multidimensional end-of life trajectories for frail older people differed from those with other conditions. Alleviating psychological, social and existential distress should be a priority of care as frail older people reach the end of life. The current palliative care model is problematic for this group. Care should address future concerns and not necessarily involve a focus on death or place of death. PMID- 27765012 TI - Erratum to: 'Consensus pan-genome assembly of the specialised wine bacterium Oenococcus oeni'. PMID- 27765013 TI - A genome-wide assessment of genetic diversity and population structure of Korean native cattle breeds. AB - BACKGROUND: The native cattle breeds are an important genetic resource for meat and milk production throughout Asia. In Asia cattle were domesticated around 10,000 years ago and in Korea cattle are being raised since 2000 B.C. There are three native breeds of cattle in Korea viz. Brown Hanwoo, Brindle Hanwoo and Jeju Black. While one of these breeds, Brown Hanwoo, is a part of a Food and Agricultural Organization and national genetic evaluation plans, others get little attention. This study is an effort to understand and provide a detailed insight into the population structure and genetic variability of the Korean cattle breeds along with other Asian breeds using various methods. In this study we report the genetic variation and structure of the Korean cattle breeds and their comparison with five other Asian cattle breeds along with a panel of animals from European taurine, African taurine and indicine cattle breeds. RESULTS: Asian cattle were found to be least differentiated which reflects their recent history. Amongst the Asian breeds Hainan, which is an indicine breed, had the lowest gene diversity while Yanbian had the highest followed by Mongolian and Korean cattle. Amongst the Korean breeds Brown Hanwoo had the highest diversity followed by Brindle Hanwoo and Jeju Black. The genetic diversity in Asian cattle breeds was found comparable to the European taurines and more than the African taurines and Zebu cattle. Korean cattle breed, Brown Hanwoo was consistently found to be closer to Yanbian, a Chinese cattle breed. We found low divergence and moderate levels of genetic diversity among the native Korean breeds. Indicine introgression from Hainan was seen in other Asian breeds. From Europe, Limousin, Holstein and Hereford introgression was found in Asian breeds. CONCLUSIONS: In this study we provide a genome-wide insight into the genetic history of the native cattle breeds of Korea. The outcomes of this study will help in prioritization and designing of the conservation plans. PMID- 27765014 TI - Distinct transcriptome responses to water limitation in isohydric and anisohydric grapevine cultivars. AB - BACKGROUND: Grapevine (Vitis vinifera L.) is an economically important crop with a wide geographical distribution, reflecting its ability to grow successfully in a range of climates. However, many vineyards are located in regions with seasonal drought, and these are often predicted to be global climate change hotspots. Climate change affects the entire physiology of grapevine, with strong effects on yield, wine quality and typicity, making it difficult to produce berries of optimal enological quality and consistent stability over the forthcoming decades. RESULTS: Here we investigated the reactions of two grapevine cultivars to water stress, the isohydric variety Montepulciano and the anisohydric variety Sangiovese, by examining physiological and molecular perturbations in the leaf and berry. A multidisciplinary approach was used to characterize the distinct stomatal behavior of the two cultivars and its impact on leaf and berry gene expression. Positive associations were found among the photosynthetic, physiological and transcriptional modifications, and candidate genes encoding master regulators of the water stress response were identified using an integrated approach based on the analysis of topological co-expression network properties. In particular, the genome-wide transcriptional study indicated that the isohydric behavior relies upon the following responses: i) faster transcriptome response after stress imposition; ii) faster abscisic acid-related gene modulation; iii) more rapid expression of heat shock protein (HSP) genes and iv) reversion of gene-expression profile at rewatering. Conversely, that reactive oxygen species (ROS)-scavenging enzymes, molecular chaperones and abiotic stress related genes were induced earlier and more strongly in the anisohydric cultivar. CONCLUSIONS: Overall, the present work found original evidence of a molecular basis for the proposed classification between isohydric and anisohydric grapevine genotypes. PMID- 27765015 TI - Recent horizontal transfer, functional adaptation and dissemination of a bacterial group II intron. AB - BACKGROUND: Group II introns are catalytically active RNA and mobile retroelements present in certain eukaryotic organelles, bacteria and archaea. These ribozymes self-splice from the pre-mRNA of interrupted genes and reinsert within target DNA sequences by retrohoming and retrotransposition. Evolutionary hypotheses place these retromobile elements at the origin of over half the human genome. Nevertheless, the evolution and dissemination of group II introns was found to be quite difficult to infer. RESULTS: We characterized the functional and evolutionary relationship between the model group II intron from Lactococcus lactis, Ll.LtrB, and Ef.PcfG, a newly discovered intron from a clinical strain of Enterococcus faecalis. Ef.PcfG was found to be homologous to Ll.LtrB and to splice and mobilize in its native environment as well as in L. lactis. Interestingly, Ef.PcfG was shown to splice at the same level as Ll.LtrB but to be significantly less efficient to invade the Ll.LtrB recognition site. We also demonstrated that specific point mutations between the IEPs of both introns correspond to functional adaptations which developed in L. lactis as a response to selective pressure on mobility efficiency independently of splicing. The sequence of all the homologous full-length variants of Ll.LtrB were compared and shown to share a conserved pattern of mutation acquisition. CONCLUSIONS: This work shows that Ll.LtrB and Ef.PcfG are homologous and have a common origin resulting from a recent lateral transfer event followed by further adaptation to the new target site and/or host environment. We hypothesize that Ef.PcfG is the ancestor of Ll.LtrB and was initially acquired by L. lactis, most probably by conjugation, via a single event of horizontal transfer. Strong selective pressure on homing site invasion efficiency then led to the emergence of beneficial point mutations in the IEP, enabling the successful establishment and survival of the group II intron in its novel lactococcal environment. The current colonization state of Ll.LtrB in L. lactis was probably later achieved through recurring episodes of conjugation-based horizontal transfer as well as independent intron mobility events. Overall, our data provide the first evidence of functional adaptation of a group II intron upon invading a new host, offering strong experimental support to the theory that bacterial group II introns, in sharp contrast to their organellar counterparts, behave mostly as mobile elements. PMID- 27765016 TI - The addition of S100B to guidelines for management of mild head injury is potentially cost saving. AB - BACKGROUND: Mild traumatic brain injury (TBI) is associated with substantial costs due to over-triage of patients to computed tomography (CT) scanning, despite validated decision rules. Serum biomarker S100B has shown promise for safely omitting CT scans but the economic impact from clinical use has never been reported. In 2007, S100B was adapted into the existing Scandinavian management guidelines in Halmstad, Sweden, in an attempt to reduce CT scans and save costs. METHODS: Consecutive adult patients with mild TBI (GCS 14-15, loss of consciousness and/or amnesia), managed with the aid of S100B, were prospectively included in this study. Patients were followed up after 3 months with a standardized questionnaire. Theoretical and actual cost differences were calculated. RESULTS: Seven hundred twenty-six patients were included and 29 (4.7 %) showed traumatic abnormalities on CT. No further significant intracranial complications were discovered on follow-up. Two hundred twenty-nine patients (27 %) had normal S100B levels and 497 patients (73 %) showed elevated S100B levels. Over-triage occurred in 73 patients (32 %) and under-triage occurred in 39 patients (7 %). No significant intracranial complications were missed. The introduction of S100B could save 71 ? per patient if guidelines were strictly followed. As compliance to the guidelines was not perfect, the actual cost saving was 39 ? per patient. CONCLUSION: Adding S100B to existing guidelines for mild TBI seems to reduce CT usage and costs, especially if guideline compliance could be increased. PMID- 27765017 TI - High third-generation cephalosporin resistant Enterobacteriaceae prevalence rate among neonatal infections in Dakar, Senegal. AB - BACKGROUND: Neonatal infection constitutes one of Senegal's most important public health problems, with a mortality rate of 41 deaths per 1,000 live births. METHODS: Between January 2007 and March 2008, 242 neonates with suspected infection were recruited at three neonatal intensive care units in three major tertiary care centers in Dakar, the capital of Senegal. Neonatal infections were confirmed by positive bacterial blood or cerebrospinal fluid culture. The microbiological pattern of neonatal infections and the antibiotic susceptibility of the isolates were characterized. In addition, the genetic basis for antibiotic resistance and the genetic background of third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae were studied. RESULTS: A bacteriological infection was confirmed in 36.4 % (88/242) of neonates: 22.7 % (30/132) during the early-onset and 52.7 % (58/110) during the late-onset periods (p > 0.20). Group B streptococci accounted for 6.8 % of the 88 collected bacterial isolates, while most of them were Enterobacteriaceae (n = 69, 78.4 %). Of these, 55/69 (79.7 %) were 3GC-R. The bla CTX-M-15 allele, the bla SHV and the bla TEM were highly prevalent (63.5, 65.4 and 53.8 %, respectively), usually associated with qnr genes (65.4 %). Clonally related strains of 3GC-R Klebsiella pneumoniae and 3GC-R Enterobacter cloacae, the two most commonly recovered 3GC-R Enterobacteriaceae (48/55), were detected at the three hospitals, underlining the role of cross transmission in their spread. The overall case fatality rate was 18.6 %. CONCLUSIONS: Measures should be taken to prevent nosocomial infections and the selection of resistant bacteria. PMID- 27765018 TI - Arthropathy-related pain in a patient with congenital impairment of pain sensation due to hereditary sensory and autonomic neuropathy type II with a rare mutation in the WNK1/HSN2 gene: a case report. AB - BACKGROUND: Hereditary sensory and autonomic neuropathy (HSAN) type II with WNK1/HSN2 gene mutation is a rare disease characterized by early-onset demyelination sensory loss and skin ulceration. To the best of our knowledge, no cases of an autonomic disorder have been reported clearly in a patient with WNK/HSN2 gene mutation and only one case of a Japanese patient with the WNK/HSN2 gene mutation of HSAN type II was previously reported. CASE PRESENTATION: Here we describe a 54-year-old woman who had an early childhood onset of insensitivity to pain; superficial, vibration, and proprioception sensation disturbances; and several symptoms of autonomic failure (e.g., orthostatic hypotension, fluctuation in body temperature, and lack of urge to defecate). Genetic analyses revealed compound homozygous mutations in the WNK1/HSN2 gene (c.3237_3238insT; p.Asp1080fsX1). The patient demonstrated sensory loss in the "stocking and glove distribution" but could perceive visceral pain, such as menstrual or gastroenteritis pain. She experienced frequent fainting episodes. She had undergone exenteration of the left metatarsal because of metatarsal osteomyelitis at 18 years. Sural nerve biopsy revealed a severe loss of myelinated and unmyelinated nerves. She complained of severe pain in multiple joints, even on having pain impairment. Although non-steroidal anti-inflammatory drugs are generally more effective than acetaminophen for arthritis, in our case, they were ineffective and acetaminophen (2400 mg/day) adequately controlled her pain and improved quality of life. Over 3 months, the numerical rating scale, pain interference scale of the Brief Pain Inventory, and the Pain Catastrophizing Scale decreased from 6/10 to 3/10, from 52/70 to 20/70, and from 22/52 to 3/52 points, respectively. CONCLUSIONS: This is the second reported case of a Japanese patient with WNK/HSN2 gene mutation of HSAN type II and the first reported case of an autonomic disorder in a patient with the WNK/HSN2 gene mutation. Acetaminophen adequately controlled arthropathy related pain in a patient with congenital impairment of pain sensation. PMID- 27765019 TI - Impact of RNA degradation on fusion detection by RNA-seq. AB - BACKGROUND: RNA-seq is a well-established method for studying the transcriptome. Popular methods for library preparation in RNA-seq such as Illumina TruSeq(r) RNA v2 kit use a poly-A pulldown strategy. Such methods can cause loss of coverage at the 5' end of genes, impacting the ability to detect fusions when used on degraded samples. The goal of this study was to quantify the effects RNA degradation has on fusion detection when using poly-A selected mRNA and to identify the variables involved in this process. RESULTS: Using both artificially and naturally degraded samples, we found that there is a reduced ability to detect fusions as the distance of the breakpoint from the 3' end of the gene increases. The median transcript coverage decreases exponentially as a function of the distance from the 3' end and there is a linear relationship between the coverage decay rate and the RNA integrity number (RIN). Based on these findings we developed plots that show the probability of detecting a gene fusion ("sensitivity") as a function of the distance of the fusion breakpoint from the 3' end. CONCLUSIONS: This study developed a strategy to assess the impact that RNA degradation has on the ability to detect gene fusions by RNA-seq. PMID- 27765020 TI - Demographic and mortality analysis of hospitalized children at a referral hospital in Addis Ababa, Ethiopia. AB - BACKGROUND: Global childhood mortality rates remain high. Millennium Development Goal 4 focused efforts on reducing rates by two-thirds between 1990 and 2015. In Ethiopia, child mortality rates dropped 71 % from 1990 to 2015, however it is estimated that 184,000 Ethiopian children die each year. There is limited information about pediatric hospital admissions in Ethiopia. Our aims were to examine the temporal relationship of mortality to admission, describe the demographics, and identify cause mortality of children admitted to the Zewditu Memorial Hospital (ZMH). METHODS: A four-year retrospective review of pediatric admissions was conducted at the pediatric emergency room and pediatric hospital ward at ZMH in Addis Ababa, Ethiopia. Admission entries from 2011-2014 of children age 29 days-14 years were reviewed. Age, gender, admission date, disease classification, discharge status and date were obtained. Patient gender was compared using Chi-square analysis. A descriptive analysis was used for age and cause mortality. RESULTS: A total of 6866 patient entries were reviewed. The proportion of admissions younger than age 5 was 0.747 (95 % CI 0.736-0.757). Overall mortality was 0.042 (95 % CI, 0.037-0.047). The proportion of recorded deaths occurring within 2 days of admission was 0.437 (95 % CI 0.380-0.494). The proportion of male admissions was significantly higher than female admissions in all age groups (male 0.575, p < 0.0001, 95 % CI 0.562-0.586). The main causes of mortality were pneumonia (0.253, 95 % CI, 0.203-0.303), severe acute malnutrition (0.222, 95 % CI 0.174-0.27), HIV/AIDS-related complications (0.056, 95 % CI 0.029 0.083), spina bifida (0.049, 95 % CI 0.024-0.074), and hydrocephalus (0.045, 95 % CI 0.021-0.069). CONCLUSIONS: Our study revealed a lower mortality rate than previously reported in Ethiopia. Despite this, 44 % of pediatric hospital mortality occurred early during hospitalization, higher than reported at other Ethiopian hospitals. This adds further evidence that systematic efforts should be dedicated to improve pediatric emergency care. Admissions included 58 % male patients, similar to other reports in Ethiopia implying that this may be a nation wide phenomenon. The observed disparity may be due to societal factors regarding care-seeking behaviors or male predilection for respiratory illness warranting further investigation. Cause mortality patterns were similar to reports in analogous settings. PMID- 27765021 TI - HIV epidemiology and responses among men who have sex with men and transgender individuals in China: a scoping review. AB - BACKGROUND: Despite global efforts to control HIV among key populations, new infections among men who have sex with men (MSM) and transgender (TG) individuals are still increasing. The increasing HIV epidemic among MSM/TG in China indicates that more effective services are urgently needed. However, policymakers and program managers must have a clear understanding of MSM/TG sexual health in China to improve service delivery. To meet this need, we undertook a scoping review to summarize HIV epidemiology and responses among MSM and TG individuals in China. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library for recent studies on MSM/TG HIV epidemiology and responses. We also included supplemental articles, grey literature, government reports, policy documents, and best practice guidelines. RESULTS: Overall, HIV prevalence among Chinese MSM was approximately 8 % in 2015 with a higher prevalence observed in Southwest China. TG are not captured in national HIV, STD, or other sexual health surveillance systems. There is limited data sharing between the public health authorities and community-based organizations (CBOs). Like other low and middle income countries, China is challenged by low rates of HIV testing, linkage, and retention. Several pilot interventions have been shown to be effective to increase HIV testing among MSM and TG individuals, but have not been widely scaled up. Data from two randomized controlled trials suggests that crowdsourcing contests can increase HIV testing, creating demand for services while engaging communities. CONCLUSION: Improving HIV surveillance and expanding HIV interventions for Chinese MSM and TG individuals are essential. Further implementation research is needed to ensure high-quality HIV services for MSM and TG individuals in China. PMID- 27765022 TI - Modifying effects of education on the association between lifestyle behaviors and the risk of obesity: evidence from South Korea. AB - BACKGROUND: No previous study has explored the interactions between education and lifestyle in relation to obesity. This study hypothesized that education may be obesogenic through its interplay with lifestyle behaviors. METHODS: Data for a nationally representative sample (6937 men and 9333 women) from the Korea National Health and Nutrition Examination Survey (2010-2012) were analyzed. Multivariate logistic regressions were performed for three education levels and six lifestyle behaviors, each of which comprised two groups. RESULTS: Interactions between education and lifestyle behaviors in relation to obesity were observed for all lifestyle behaviors in women (p for interaction <0.001) and for three lifestyle behaviors in men. Education appeared obesogenic for three groups of lifestyle behaviors in men (p for trend <0.05), but was protective against obesity for 11 groups in women. Each one-unit increase in education level in men increased the odds of obesity by 1.29-fold among under-reported energy intake groups (95 % confidence interval: 1.16, 1.44). CONCLUSIONS: Education may be a risk factor for obesity through its interplay with lifestyle behaviors. Further research is required to examine these findings in different socio cultural settings. PMID- 27765024 TI - Lumbar disc degeneration is associated with modic change and high paraspinal fat content - a 3.0T magnetic resonance imaging study. AB - BACKGROUND: Degenerative disc disease of the lumbar spine is common, with severe disease increasing the risk for chronic low back pain. This cross-sectional study examined whether disc degeneration is representative of a 'whole-organ' pathology, by examining its association with bone (vertebral endplate) and soft tissue (paraspinal muscle fat) abnormalities. METHODS: Seventy-two community based individuals unselected for low back pain, had Magnetic Resonance Imaging (MRI). Lumbosacral disc degeneration was determined via the Pfirrmann grading system, a validated method to assess the intervertebral disc, distinguishing the nucleus and annulus, the signal intensity and the height of the intervertebral disc. Modic change and high paraspinal muscle fat content was also measured from MRI. RESULTS: Severe disc degeneration was associated, or tended to be associated with type 2 Modic change from L2 to L5 (OR range 3.5 to 25.3, p <= 0.06). Moreover, severe disc degeneration at all intervertebral levels was associated with or tended to be associated with high fat content of the paraspinal muscles (OR range 3.7 to 14.3, p <= 0.09). CONCLUSION: These data demonstrate that disc degeneration of the lumbar spine is commonly accompanied by Modic change and high fat content of paraspinal muscles, thus representing a 'whole-organ' pathology. Longitudinal studies are required to determine the temporal relationship between these structural abnormalities. Understanding this may have the potential to identify novel targets for the treatment and prevention of lumbosacral disc degeneration. PMID- 27765023 TI - School-based intervention to prevent overweight and disordered eating in secondary school Malaysian adolescents: a study protocol. AB - BACKGROUND: Obesity, eating disorders and unhealthy weight-loss practices have been associated with diminished growth in adolescents worldwide. Interventions that address relevant behavioural dimensions have been lacking in Malaysia. This paper describes the protocol of an integrated health education intervention namely 'Eat Right, Be Positive About Your Body and Live Actively' (EPaL), a primary prevention which aimed to promote healthy lifestyle in preventing overweight and disordered eating among secondary school adolescents aged 13-14 years old. METHODS/DESIGN: Following quasi-experimental design, the intervention is conducted in two secondary schools located in the district of Hulu Langat, Selangor, Malaysia. Adolescents aged 13-14 years will be included in the study. A peer-education strategy is adopted to convey knowledge and teach skills relevant to achieving a healthy lifestyle. The intervention mainly promoted: healthy eating, positive body image and active lifestyle. The following parameters will be assessed: body weight, disordered eating status, stages of change (for healthy diet, breakfast, food portion size, screen viewing and physical activity), body image, health-related quality of life, self-esteem, eating and physical activity behaviours; and knowledge, attitude and practice towards a healthy lifestyle. Assessment will be conducted at three time points: baseline, post-intervention and 3-month follow-up. DISCUSSION: It is hypothesized that EPaL intervention will contribute in preventing overweight and disordered eating by giving the positive effects on body weight status, healthy lifestyle behaviour, as well as health related quality of life of peer educators and participants. It may serve as a model for similar future interventions designed for the Malaysian community, specifically adolescents. TRIAL REGISTRATION: UMIN Clinical Trial Registration UMIN000024349 (Date of registration: 11th. October 2016, retrospectively registered). PMID- 27765025 TI - Staphylococcus aureus bacteremia with iliac artery endarteritis in a patient receiving ustekinumab. AB - BACKGROUND: Ustekinumab (Stelara(r)), a human monoclonal antibody targeting the p40-subunit of interleukin (IL)-12 and IL-23, is indicated for moderate to severe plaque psoriasis and psoriatic arthritis. In large multicenter, prospective trials assessing efficacy and safety of ustekinumab increased rates of severe infections have not been observed so far. CASE PRESENTATION: Here, we report the case of a 64-year old woman presenting with chills, pain and swelling of her right foot with dark maculae at the sole, and elevated inflammatory markers. She had received a third dose of ustekinumab due to psoriatic arthritis three days before admission. Blood cultures revealed growth of Staphylococcus aureus and imaging showed a thickening of the aortic wall ventral the bifurcation above the right internal iliac artery, resembling an acute bacterial endarteritis. Without the evidence of aneurysms and in absence of foreign bodies, the decision for conservative management was made. The patient received four weeks of antibiotic therapy with intravenous flucloxacillin, followed by an oral regime with levofloxacin and rifampicin for an additional four weeks. Inflammatory markers resolved promptly and the patient was discharged in good health. CONCLUSION: To our knowledge, this is the first report of a severe S. aureus infection in a patient receiving ustekinumab. Albeit ustekinumab is generally regarded as a safe drug, severe bacterial infections should always be included in the differential diagnosis of elevated inflammatory markers in patients receiving biologicals as these might present with nonspecific symptoms and fever might be absent. Any effort to detect deep-seated or metastatic infections should be made to prevent complications and to secure appropriate treatment. Although other risk factors for an invasive staphylococcal infection like psoriasis, recent corticosteroid injection, or prior hospitalisations were present, and therefore a directive causative link between the S. aureus bacteraemia and ustekinumab can not be drawn, we considered the reporting of this case worthwhile to alert clinicians as we believe that ongoing pharmacovigilance to detect increased risks for rare but severe infections beyond phase II and phase III trials in patients treated with biologicals is essential. PMID- 27765026 TI - Increasing incidence associated with herpes zoster infection in British Columbia, Canada. AB - BACKGROUND: Recent studies have shown an increasing incidence of herpes zoster (HZ) infection, which may be related to the introduction of varicella vaccination programs in children. We examined the epidemiology and treatment costs of HZ and post-herpetic neuralgia (PHN) over time in British Columbia, Canada. METHODS: The cohort consisted of all cases with HZ infection from January 1, 1997 and December 31, 2012. Incident zoster was defined as a case (ICD-9 053 or ICD-10 B02) without a previous episode of HZ or PHN in the previous 12 months. We determined the incidence for HZ and PHN and the age-sex standardized rate for the overall population. We determined the association between the varicella vaccination program and increased HZ rates by evaluating the rate ratios in the publicly funded varicella vaccine period compared to the non-publicly funded period in a regression model. We evaluated the hospitalization rates, treatment by GPs and their associated yearly costs for HZ and PHN. RESULTS: HZ incidence increased for the entire study period from 3.2 per 1000 population in 1997 to 4.5 in 2012. HZ rates were higher for females than males and all age groups had an increased incidence rate, except the 0-9 year olds, where the rate decreased. Crude and age sex standardized incidence rates of PHN demonstrated very similar patterns to HZ incidence. Based on the regression model, rates of HZ were higher in the older individuals. No significant increase with HZ incidence was seen during the publically funded varicella vaccination program compared to the non-publicly funded period. From 1997 to 2012, the annual HZ-related costs associated with hospitalizations and GP visits were over $CDN4.9 million and $CDN537,286, respectively; treatment costs for hospitalizations have increased significantly over time. Majority of PHN-related cases are managed by GPs, with a steady increase over time in number of cases and associated annual costs. CONCLUSIONS: The incidence of zoster and PHN is increasing with time, particularly in the elderly population and the risk is greater in the over 65 year olds. Treatment costs for both HZ and PHN represent a significant burden on the Canadian healthcare system. PMID- 27765028 TI - A qualitative study of gestational weight gain goal setting. AB - BACKGROUND: Gestational weight gain (GWG) is an important predictor of short and long-term pregnancy outcomes for both mother and child, and women who set a GWG goal are more likely to gain within recommended ranges. Little information is available regarding potentially modifiable factors that underlie a woman's GWG goals. Our aims were to explore women's perceptions regarding factors that affect GWG, their understanding of appropriate GWG, their goal-setting experiences including patient-health care provider (HCP) conversations, and supportive interventions they would most like to help them achieve the recommended GWG. METHODS: We conducted nine in-depth interviews and seven focus groups with a total of 33 Boston, Massachusetts (MA) area women who were pregnant and had delivered within the prior 6 months. We recorded and transcribed all interviews. Two investigators independently coded resulting transcripts. We managed data using MAXQDA2 and conducted a content analysis. RESULTS: Perceived factors that contributed to GWG goal-setting included the mother's weight control behaviors concerning exercise and diet-including a "new way of eating for two" and "semblance of control", experiences during prior pregnancies, conversations with HCPs, and influence from various information sources. Women focused on behaviors with consistent messaging across multiple sources of information, but mainly trusted their HCP, valued one-to-one conversations with them about GWG, preferred that the HCP initiate the conversation about GWG goals, and would be open to have the conversation started based on visual aid based on their own GWG progression. CONCLUSIONS: Pregnant women highly value discussions with their HCP to set GWG goals. Pregnant women view their clinicians as the most reliable source of information and believe that clinicians should open weight-related discussions throughout pregnancy. PMID- 27765029 TI - A randomized trial of an intervention to improve resident-fellow teaching interactions on the wards. AB - BACKGROUND: Subspecialty fellows can serve as a tremendous educational resource to residents; however, there are multiple barriers to an effective resident fellow teaching interaction in the setting of inpatient consultation. We designed and evaluated a resident-directed intervention to enhance communication and teaching during consultation on the general medicine wards. METHODS: Five medical teams were randomized to receive the intervention over a 3 month period (3 control, 2 intervention teams). The intervention was evaluated with pre and post intervention surveys. RESULTS: Fifty-nine of 112 interns completed the pre intervention survey, and 58 completed the post-intervention survey (53 % response rate). At baseline, 83 % of the interns noted that they had in-person interactions with fellows less than 50 % of the time. 81 % responded that they received teaching from fellows in less than 50 % of consultations. Following the intervention, the percentage of interns who had an in-person interaction with fellows greater than 50 % of the time increased in the intervention group (9 % control versus 30 % intervention, p = 0.05). Additionally, interns in the intervention group reported receiving teaching in more than 50 % of their interactions more frequently (19 % control versus 42 % intervention, p = 0.05). There were no differences in other measures of teaching and communication. CONCLUSIONS: We demonstrate that a time-efficient intervention increased perceptions of in-person communication and the number of teaching interactions between interns and fellows. Further studies are warranted to determine whether such an approach can impact resident learning and improve patient care. PMID- 27765027 TI - Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone sensitive breast cancer. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERalpha) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option. METHODS: Using hormone sensitive breast cancer cells stably transfected with the aromatase gene (MCF 7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; "MK-0646"; anti-IGF-1R antibody), ridaforolimus (RIDA; "MK-8669"; mTORC1 small molecule inhibitor) and letrozole ("LET", aromatase inhibitor). RESULTS: With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK 0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach. CONCLUSION: These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK 8669 as an efficacious anti-tumor strategy for ER-positive breast tumors. PMID- 27765030 TI - A century of morphological variation in Cyprinidae fishes. AB - BACKGROUND: Aquatic habitats have been altered over the past century due to a variety of anthropogenic influences. Ecomorphology is an area of aquatic ecology that can both directly and indirectly assess the effects of habitat alterations on organisms. However, few studies have explored long term trends in morphological variation. Long term changes in morphology can potentially impact niche and ultimately contribute to organismal success and the ecosystem. Therefore, in this study we assessed long term morphological variation with body size, sex, time, and hydrology using museum collections of five species of Cyprinidae (Minnows) from lentic and lotic systems over the past 100 years to gain insight into long term patterns in morphology. RESULTS: Variation in Cyprinidae morphology tended to relate to: body size-indicating strong allometric growth patterns with robustness of larger individuals; sex-indicating a level of fecundity selection for deeper bodies in females compared with males; and year indirectly suggesting responses to habitat changes over the past century. In lotic ecosystems, Cyprinidae morphology tended to be more fusiform in conjunction with lower mean annual discharge or higher variation in discharge. In lentic ecosystems, change in morphology was observed but no historic habitat variables were available to discern potential mechanisms. Interestingly, not all species responded in the same magnitude or directionality. CONCLUSIONS: Long term changes in morphological variation provide a link to exploring functional relationships between taxa and their environment and have implications for understanding ecosystem attributes, community assembly patterns, and conservation. PMID- 27765031 TI - Effect of the new rural cooperative medical system on farmers' medical service needs and utilization in Ningbo, China. AB - BACKGROUND: Many countries are developing health mechanisms to pursue the goal of universal coverage. In China, a rural health insurance system entitled New Cooperative Medical System (NCMS) has being developed since 2003. This paper aims to explore the changes in the health service needs and utilization among rural residents in Ningbo, China after the implementation of the new rural cooperative medical system (NCMS), and provide evidence to further improve the strategies of NCMS in China. METHODS: Stratified multistage cluster sampling was used to randomly select 10 villages from 5 townships in Yuyao and Fenghua counties of Ningbo Municipality. Eighty families were selected from each village, and face-to face interviews were conducted by trained investigators to collect data using questionnaires. RESULTS: The two-week visiting rate and prevalence of chronic diseases among the farmers included in the study was 25.40 and 22.50 %, respectively, which were higher than the levels in 2003 and 2008. The rate of not visiting the healthcare facility amongst those with illness, and the rate of non- hospitalization amongst those who required it were 32.36 and 0.60 %, respectively, which was lower than the levels in 2003 and 2008. Most of the outpatient visits were to the village clinics, while the hospitalizations were mainly to county hospitals. CONCLUSION: NCMS greatly affected the utilization of healthcare services from outpatient clinics and improved the hospitalization rate in county hospitals. Financial difficulties are not the major causes of non hospitalization and non-visiting any longer. These findings suggest that the NCMS policies alleviated the medical burdens of farmers in a certain degree. PMID- 27765032 TI - Association between olfactory identification and cognitive function in community dwelling elderly: the Shanghai aging study. AB - BACKGROUND: The smell sense reduction was considered to represent the potentially warning of early stage of neurodegenerative disorders. The Shanghai Aging Study provided us a unique opportunity to explore the association between olfactory identification (OI) and cognitive function among community-dwelling elderly in China. METHODS: OI of each participant was measured by the 12-item identification tests from Sniffin' Sticks Screening test (SSST-12). Participants with mild cognitive impairment (MCI) were diagnosed by Petersen criteria. We used the logistic regression analysis to explore the association between OI scores and cognitive function by adjusting potential confounders. RESULTS: Among 1782 non demented participants, 345 (19.4 %) participants were diagnosed as MCI. The mean OI score for participants with MCI [7.1 (SD 2.3)] was significantly lower than that for those with normal cognition [8.2 (SD 2.0), P < 0.0001]. After adjusted for age, gender, education, lifestyles, medical history, Apolipoprotein E genotype, lower OI score was found to be an independent influence factor related to MCI (OR 1.19, 95 % CI 1.11-1.27). CONCLUSIONS: Our study suggests that poor OI may be associated with MCI in elderly population. Further prospective studies may confirm the OI as a reliable and early marker predicting the decline of cognitive function. PMID- 27765033 TI - Psychotic relapse and associated factors among patients attending health services in Southwest Ethiopia: a cross-sectional study. AB - BACKGROUND: Psychotic relapse leads to repeated hospitalization and negatively affects the clinical prognosis of the patients. Information on prevalence of relapse among patients with psychotic disorders in Ethiopian setting is scarce. This study aimed to assess the prevalence of relapse among patients with psychotic disorders attending services in Jimma University Specialized Hospital (JUSH). METHODS: Data were collected using interviewer administered questionnaire. We used medication adherence rating scale (MARS) to assess compliance to medication and abnormal involuntary movement scale (AIMS) to detect medication side effects. Logistic regression analysis was used to identify independent predictors of psychotic relapse. All variables with P-value <0.25 in the bivariate analyses were entered into multivariate logistic regression and variables with P-value < 0.05 in the final model were declared to be significantly associated with the outcome variable. RESULTS: The prevalence of relapse among patients with psychotic disorder was 24.6 % (n = 95). Of this, 25.4 and 22.4 % were males and females respectively. The odds of developing psychotic relapse among patients living with family was 72 % lower than that of patients living alone (aOR = 0.28, 95 % CI = 0.08, 0.93). The odds of developing psychotic relapse among patients compliant to medication was 69 % lower than that of patients who were not compliant to medications (aOR = 0.31, 95 % CI = 0.12, 0.80). The odds of developing psychotic relapse among patients having high score on social support score was 48 % lower than that of patients who were compliant to medications (aOR = 0.52, 95 % CI = 0.28, 0.95). The odds of developing psychotic relapse among patients reporting to have sought religious support was 45 % lower than that of patients who have not sought religious support (aOR = 0.55, 95 % CI = 0.31, 0.96). On the other hand, the odds of developing psychotic relapse among participants who have experienced medication side effects was 1.83 times higher when compared to those who have never experienced medication side effects (aOR = 1.83, 95 % CI = 1.01, 3.31). CONCLUSIONS: The high prevalence of relapse among patients with psychotic disorder needs special attention. Clinicians need to pay attention to medication side effects the patient faces. Intervening noncompliance to medication and appropriately managing medication side effects may help in preventing psychotic relapse that may result because of non-compliance. The provision of counseling, psycho education, psycho social support may help patients in improving compliance to medication and reducing psychotic relapse. Developing and strengthening community based rehabilitation services should be emphasized as part of mental healthcare services. PMID- 27765034 TI - Use of structured musculoskeletal examination routines in undergraduate medical education and postgraduate clinical practice - a UK survey. AB - BACKGROUND: Structured examination routines have been developed as educational resources for musculoskeletal clinical skills teaching, including Gait-Arms-Legs Spine (GALS), Regional Examination of the Musculoskeletal System (REMS) and paediatric GALS (pGALS). In this study, we aimed to assess the awareness and use of these examination routines in undergraduate medical teaching in UK medical schools and UK postgraduate clinical practice. METHODS: Electronic questionnaires were distributed to adult and paediatric musculoskeletal teaching leads at UK medical schools and current UK doctors in training. RESULTS: Responses were received from 67 tutors representing teaching at 22/33 [67 %] of all UK medical schools, and 70 trainee doctors across a range of postgraduate training specialities. There was widespread adoption, at responding medical schools, of the adult examination routines within musculoskeletal teaching (GALS: 14/16 [88 %]; REMS: 12/16 [75 %]) and assessment (GALS: 13/16 [81 %]; REMS: 12/16 [75 %]). More trainees were aware of GALS (64/70 [91 %]) than REMS (14/67 [21 %]). Of the 39 trainees who used GALS in their clinical practice, 35/39 [90 %] reported that it had improved their confidence in musculoskeletal examination. Of the 17/22 responding medical schools that included paediatric musculoskeletal examination within their curricula, 15/17 [88 %] used the pGALS approach and this was included within student assessment at 4 medical schools. CONCLUSIONS: We demonstrate the widespread adoption of these examination routines in undergraduate education and significant uptake in postgraduate clinical practice. Further study is required to understand their impact upon clinical performance. PMID- 27765035 TI - BioVeL: a virtual laboratory for data analysis and modelling in biodiversity science and ecology. AB - BACKGROUND: Making forecasts about biodiversity and giving support to policy relies increasingly on large collections of data held electronically, and on substantial computational capability and capacity to analyse, model, simulate and predict using such data. However, the physically distributed nature of data resources and of expertise in advanced analytical tools creates many challenges for the modern scientist. Across the wider biological sciences, presenting such capabilities on the Internet (as "Web services") and using scientific workflow systems to compose them for particular tasks is a practical way to carry out robust "in silico" science. However, use of this approach in biodiversity science and ecology has thus far been quite limited. RESULTS: BioVeL is a virtual laboratory for data analysis and modelling in biodiversity science and ecology, freely accessible via the Internet. BioVeL includes functions for accessing and analysing data through curated Web services; for performing complex in silico analysis through exposure of R programs, workflows, and batch processing functions; for on-line collaboration through sharing of workflows and workflow runs; for experiment documentation through reproducibility and repeatability; and for computational support via seamless connections to supporting computing infrastructures. We developed and improved more than 60 Web services with significant potential in many different kinds of data analysis and modelling tasks. We composed reusable workflows using these Web services, also incorporating R programs. Deploying these tools into an easy-to-use and accessible 'virtual laboratory', free via the Internet, we applied the workflows in several diverse case studies. We opened the virtual laboratory for public use and through a programme of external engagement we actively encouraged scientists and third party application and tool developers to try out the services and contribute to the activity. CONCLUSIONS: Our work shows we can deliver an operational, scalable and flexible Internet-based virtual laboratory to meet new demands for data processing and analysis in biodiversity science and ecology. In particular, we have successfully integrated existing and popular tools and practices from different scientific disciplines to be used in biodiversity and ecological research. PMID- 27765037 TI - A method for extracting electronic patient record data from practice management software systems used in veterinary practice. AB - BACKGROUND: Data extracted from electronic patient records (EPRs) within practice management software systems are increasingly used in veterinary research. The use of real patient data gives the potential to generate research that can readily be applied to clinical practice. The use of veterinary EPRs for research in the United Kingdom is hindered by the number of different Practice Management System (PMS) providers used by practices, as obtaining and combining data from different systems electronically can be problematic. The use of extensible mark up language (XML) to extract clinical data for research would potentially resolve the compatibility issues between systems. The aim of this study was to establish and validate a method for the extraction of small animal patient records from a veterinary PMS that could potentially be used across multiple systems. An XML schema was designed to extract clinical information from EPRs. The schema was tested and validated in a test system, and was then tested in a real small animal practice where data was extracted for 16 weeks. A 10 % sample of the extracted records was then compared to paper copies provided by the practice. RESULTS: All 21 fields encoded by the XML schema, from all of the records in the test system, were extracted with 100 % accuracy. Over the 18 week data collection period 4946 records, from 1279 patients, were extracted from the small animal practice. The 10 % printed records checked and compared with the XML extracted records demonstrated all required data was present. No unrequired, sensitive information e.g. costs or services/products or personal client information was extracted. CONCLUSIONS: This is the first time a method for data extraction from EPRs in veterinary practice using an XML schema has been reported in the United Kingdom. This is an efficient and accurate way of extracting data which could be applied to all PMSs nationally and internationally. PMID- 27765036 TI - Short-term markers of DNA damage among roofers who work with hot asphalt. AB - BACKGROUND: Roofers are at increased risk for various malignancies and their occupational exposures to polycyclic aromatic hydrocarbons (PAHs) have been considered as important risk factors. The overall goal of this project was to investigate the usefulness of phosphorylated histone H2AX (gammaH2AX) as a short term biomarker of DNA damage among roofers. METHODS: Blood, urine, and dermal wipe samples were collected from 20 roofers who work with hot asphalt before and after 6 h of work on Monday and Thursday of the same week (4 sampling periods). Particle-bound and gas-phase PAHs were collected using personal monitors during work hours. gammaH2AX was quantified in peripheral lymphocytes using flow cytometry and 8-hydroxy-2-deoxyguanosine (8-OHdG) was assessed in urine using ELISA. General linear mixed models were used to evaluate associations between DNA damage and possible predictors (such as sampling period, exposure levels, work- and life-style factors). Differences in mean biomarker and DNA damage levels were tested via ANOVA contrasts. RESULTS: Exposure measurements did not show an association with any of the urinary biomarkers or the measures of DNA damage. Naphthalene was the most abundant PAH in gas-phase, while benzo(e)pyrene was the most abundant particle-bound PAH. Post-shift levels of gammaH2AX and 8-OHdG were higher on both study days, when compared to pre-shift levels. Cigarette smoking was a predictor of gammaH2AX and urinary creatinine was a predictor of urinary 8 OHdG. Between-subject variance to total variance ratio was 35.3 % for gammaH2ax and 4.8 % for 8-OHdG. CONCLUSION: gammaH2AX is a promising biomarker of DNA damage in occupational epidemiology studies. It has a lower within-subject variation than urinary 8-OHdG and can easily be detected in large scale groups. Future studies that explore the kinetics of H2AX phosphorylation in relation to chemical exposures may reveal the transient and persistent nature of this sensitive biomarker of early DNA damage. PMID- 27765038 TI - T cells suppress memory-dependent rapid mucous cell metaplasia in mouse airways. AB - BACKGROUND: Airway epithelial cells (AECs) are crucial for mucosal and adaptive immunity but whether these cells respond in a memory-dependent manner is poorly studied. Previously, we have reported that LPS intratracheal instillation in rodents causes extensive neutrophilic inflammation and airway epithelial cell hyperplasia accompanied by mucous cell metaplasia (MCM). And the resolution process required a period of 40 d for the inflammation to subside and the lung epithelia to resemble the non-exposed condition. Therefore, the present study investigated the memory-dependent response of airway epithelial cells to a secondary LPS challenge after the initial inflammation was resolved. METHODS: Airway epithelial and mucous cells were assessed in response to a secondary LPS challenge in F344/N rats, and in C57BL/6 wild-type (Foxn1WT) and T cell-deficient athymic (Foxn1nu) mice that were instilled with LPS or saline 40 d earlier. Epithelial expression of TLR4, EGFR, and phosphorylated-ERK1/2 (pERK) were also analyzed. RESULTS: LPS-pretreated F344/N rats responded with elevated numbers of AECs after saline challenge and with 3-4-fold increased MCM following the LPS challenge in LPS- compared with saline-pretreated rats. LPS-pretreated rats showed 5-fold higher number of AECs expressing TLR4 apically than saline pretreated rats. Also, the expression of EGFR was increased in LPS-pretreated rats along with the number of AECs with active or nuclear pERK, and the levels were further increased upon LPS challenge. LPS-pretreated Foxn1nu compared with Foxn1WT mice showed increased MCM and elevated levels of TLR4, EGFR, and nuclear pERK at 40 d after LPS instillation. LPS challenge further augmented MCM rapidly in Foxn1nu compared with Foxn1WT mice. CONCLUSION: Together, these data suggest that AECs preserve an 'innate memory' that drives a rapid mucous phenotype via spatiotemporal regulation of TLR4 and EGFR. Further, T cells may suppress the sustained elevated expression of TLR4 and EGFR and thereby the hyperactive epithelial response. PMID- 27765039 TI - Dairy products intake and cancer mortality risk: a meta-analysis of 11 population based cohort studies. AB - BACKGROUND: Dairy products are major components of daily diet and the association between consumption of dairy products and public health issues has captured great attention. In this study, we conducted a meta-analysis to investigate the association between dairy products intake and cancer mortality risk. METHODS: After a literature search in PubMed and EMBASE, 11 population-based cohort studies involving 778,929 individuals were considered eligible and included in the analyses. Data were extracted and the association between dairy products intake and cancer mortality risk was estimated by calculating pooled relative risks (RRs) and corresponding 95 % confidence intervals (CIs). Sensitivity analyses and subgroup analyses based on regions, genders and dairy types were performed as well. Potential dose-response relationship was further explored by adopting the generalized least squares (GLST) method. RESULTS: Total dairy products intake was not associated with all cancer mortality risk, with the pooled RR of 0.99 (95 % CI 0.92-1.07, p = 0.893). Subgroup analyses showed that the pooled RRs were 0.97 (95 % CI 0.92-1.03, p = 0.314) for milk, 0.88 (95 % CI 0.71-1.10, p = 0.271) for yogurt, 1.23 (95 % CI 0.94-1.61, p = 0.127) for cheese and 1.13 (95 % CI 0.89-1.44, p = 0.317) for butter in male and female, however the pooled RR was 1.50 (95 % CI 1.03-2.17, p = 0.032) for whole milk in male, which was limited to prostate cancer. Further dose-response analyses were performed and we found that increase of whole milk (serving/day) induced elevated prostate cancer mortality risk significantly, with the RR of 1.43 (95 % CI 1.13 1.81, p = 0.003). CONCLUSIONS: Total dairy products intake have no significant impact on increased all cancer mortality risk, while low total dairy intake even reduced relative risk based on the non-linear model. However, whole milk intake in men contributed to elevated prostate cancer mortality risk significantly. Furthermore, a linear dose-response relationship existed between increase of whole milk intake and increase of prostate cancer mortality risk. PMID- 27765040 TI - Attractor landscape analysis of colorectal tumorigenesis and its reversion. AB - BACKGROUND: Colorectal cancer arises from the accumulation of genetic mutations that induce dysfunction of intracellular signaling. However, the underlying mechanism of colorectal tumorigenesis driven by genetic mutations remains yet to be elucidated. RESULTS: To investigate colorectal tumorigenesis at a system level, we have reconstructed a large-scale Boolean network model of the human signaling network by integrating previous experimental results on canonical signaling pathways related to proliferation, metastasis, and apoptosis. Throughout an extensive simulation analysis of the attractor landscape of the signaling network model, we found that the attractor landscape changes its shape by expanding the basin of attractors for abnormal proliferation and metastasis along with the accumulation of driver mutations. A further hypothetical study shows that restoration of a normal phenotype might be possible by reversely controlling the attractor landscape. Interestingly, the targets of approved anti cancer drugs were highly enriched in the identified molecular targets for the reverse control. CONCLUSIONS: Our results show that the dynamical analysis of a signaling network based on attractor landscape is useful in acquiring a system level understanding of tumorigenesis and developing a new therapeutic strategy. PMID- 27765041 TI - Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer. AB - BACKGROUND: ErbB2 Receptor Tyrosine Kinase 2 (ErbB2, HER2/Neu) is amplified in breast cancer and associated with poor prognosis. Growing evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling. For example, ErbB2 inhibitors can block IGF-induced signaling while, conversely, IGF1R inhibitors can inhibit ErbB2 action. ErbB receptors can bind and phosphorylate insulin receptor substrates (IRS) and this may be critical for ErbB mediated anti-estrogen resistance in breast cancer. Herein, we examined crosstalk between ErbB2 and IRSs using cancer cell lines and transgenic mouse models. METHODS: MMTV-ErbB2 and MMTV-IRS2 transgenic mice were crossed to create hemizygous MMTV-ErbB2/MMTV-IRS2 bigenic mice. Signaling crosstalk between ErbB2 and IRSs was examined in vitro by knockdown or overexpression followed by western blot analysis for downstream signaling intermediates and growth assays. RESULTS: A cross between MMTV-ErbB2 and MMTV-IRS2 mice demonstrated no enhancement of ErbB2 mediated mammary tumorigenesis or metastasis by elevated IRS2. Substantiating this, overexpression or knockdown of IRS1 or IRS2 in MMTV-ErbB2 mammary cancer cell lines had little effect upon ErbB2 signaling. Similar results were obtained in human mammary epithelial cells (MCF10A) and breast cancer cell lines. CONCLUSION: Despite previous evidence suggesting that ErbB receptors can bind and activate IRSs, our findings indicate that ErbB2 does not cooperate with the IRS pathway in these models to promote mammary tumorigenesis. PMID- 27765042 TI - Circulating microparticles in severe pulmonary arterial hypertension increase intercellular adhesion molecule-1 expression selectively in pulmonary artery endothelium. AB - BACKGROUND: Microparticles (MPs) stimulate inflammatory adhesion molecule expression in systemic vascular diseases, however it is unknown whether circulating MPs stimulate localized ICAM-1 expression in the heterogeneically distinct pulmonary endothelium during pulmonary arterial hypertension (PAH). Pulmonary vascular lesions with infiltrating inflammatory cells in PAH form in the pulmonary arteries and arterioles, but not the microcirculation. Therefore, we sought to determine whether circulating MPs from PAH stimulate pulmonary artery endothelial cell-selective ICAM-1 expression. RESULTS: Pulmonary artery endothelial cells (PAECs) were exposed to MPs isolated from the circulation of a rat model of severe PAH. During late-stage (8-weeks) PAH, but not early-stage (3 weeks), an increase in ICAM-1 was observed. To determine whether PAH MP-induced ICAM-1 was selective for a specific segment of the pulmonary circulation, pulmonary microvascular endothelial cells (PMVECs) were exposed to late-stage PAH MPs and no increase in ICAM-1 was detected. A select population of circulating MPs, the late-stage endoglin + MPs, were used to assess their ability to stimulate ICAM-1 and it was determined that the endoglin + MPs were sufficient to promote ICAM-1 increases in the whole cell, but not surface only expression. CONCLUSIONS: Late-stage, but not early-stage, MPs in a model of severe PAH selectively induce ICAM-1 in pulmonary artery endothelium, but not pulmonary microcirculation. Further, the selected endoglin + PAH MPs, but not endoglin + MPs from control, are sufficient to promote whole cell ICAM-1 in PAECs. The implications of this work are that MPs in late-stage PAH are capable of inducing ICAM-1 expression selectively in the pulmonary artery. ICAM-1 likely plays a significant role in the observed inflammatory cell recruitment, specifically to vascular lesions in the pulmonary artery and not the pulmonary microcirculation. PMID- 27765045 TI - Individual predictors of frequent emergency department use: a scoping review. AB - BACKGROUND: A small proportion of patients use an excessively large amount of emergency care resources which often results in emergency department (ED) overcrowding, decreased quality of care and efficiency. There is a need to better identify these patients in order to target those who will benefit most from interventions adapted to their specific needs. We aimed to identify the predictive factors of short-term frequent use of ED (over a 1-year period) and chronic frequent use of ED (over a multiple-year period) and to highlight recurring characteristics in patients. METHODS: A scoping review was performed of all relevant articles found in Medline published between 1979 and 2015 (Ovid). This scoping review included a total of 20 studies, of these, 16 articles focussed on frequent ED users and four others on chronic frequent ED users. RESULTS: A majority of articles confirm that patients who frequently visit the ED are persons of low socioeconomic status. Both frequent and chronic frequent ED users show high levels of health care use (other than the ED) and suffer from multiple physical and mental conditions. CONCLUSIONS: This research highlights which individual factors predict frequent emergency department use. Further research is needed to better characterize and understand chronic frequent users as well as the health issues and unmet medical needs that lead to chronic frequent ED use. PMID- 27765043 TI - The impact of user fees on health services utilization and infectious disease diagnoses in Neno District, Malawi: a longitudinal, quasi-experimental study. AB - BACKGROUND: User fees have generally fallen out of favor across Africa, and they have been associated with reductions in access to healthcare. We examined the effects of the introduction and removal of user fees on outpatient attendances and new diagnoses of HIV, malaria, and tuberculosis in Neno District, Malawi where user fees were re-instated at three of 13 health centres in 2013 and subsequently removed at one of these in 2015. METHODS: We conducted two analyses. Firstly, an unadjusted comparison of outpatient visits and new diagnoses over three periods between July 2012 and October 2015: during the period with no user fees, at the re-introduction of user fees at four centres, and after the removal of user fees at one centre. Secondly, we estimated a linear model of the effect of user fees on the outcome of interest that controlled for unobserved health centre effects, monthly effects, and a linear time trend. RESULTS: The introduction of user fees was associated with a change in total attendances of 68 % [95 % CI: -89 %, -12 %], similar reductions were observed for new malaria and HIV diagnoses. The removal of user fees was associated with an increase in total attendances of 352 % [213 %, 554 %] with similar increases for malaria diagnoses. The results were not sensitive to control group or model specification. CONCLUSIONS: User fees for outpatient healthcare services present a barrier to patients accessing healthcare and reduce detection of serious infectious diseases. PMID- 27765044 TI - Bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review. AB - BACKGROUND: Sarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2-0.6 % of all histological bladder tumor subtypes. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen. CASE PRESENTATION: We report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 ureter cancer of the contralateral upper urinary tract. From the 4th year of follow-up after nephroureterectomy, multiple recurrent bladder tumors staged as Ta transitional cell carcinoma developed, and six transurethral resections of the bladder (TURB) with multiple intravesical instillations were performed without any evidence of metastases and upper tract recurrences. In 2015, a right partial distal ureterectomy and an additional TURB were performed due to a papillary mass at the right contralateral ureterovesical junction of the bladder, which was confirmed as a high-grade pT1 transitional cell carcinoma. After a further 2 years of follow-up, total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 transitional cell carcinoma and chondrosarcoma. Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule was detected on chest CT. The patient was scheduled for adjuvant gemcitabine-cisplatin chemotherapy. CONCLUSIONS: The present case was interesting because we cannot be sure if the SUC chondrosarcoma originated from the 12-year-ago proximal ureter tumor, the 2 year-ago contralateral distal ureter tumor, or a new primary bladder tumor. Genetic profiling might have been useful to determine the origin of the SUC chondrosarcoma. PMID- 27765046 TI - Asna1/TRC40 that mediates membrane insertion of tail-anchored proteins is required for efficient release of Herpes simplex virus 1 virions. AB - BACKGROUND: Herpes simplex virus type 1 (HSV1), a member of the alphaherpesvirinae, can cause recurrent facial lesions and encephalitis. Two membrane envelopment processes, one at the inner nuclear membrane and a second at cytoplasmic membranes are crucial for a productive viral infection. Depending on the subfamily, herpesviruses encode more than 11 different transmembrane proteins including members of the tail-anchored protein family. HSV1 encodes three tail anchored proteins pUL34, pUL56 and pUS9 characterized by a single hydrophobic region positioned at their C-terminal end that needs to be released from the ribosome prior to posttranslational membrane insertion. Asna1/TRC40 is an ATPase that targets tail-anchored proteins to the endoplasmic reticulum in a receptor dependent manner. Cell biological data point to a critical and general role of Asna1/TRC40 in tail-anchored protein biogenesis. With this study, we aimed to determine the importance of the tail-anchored insertion machinery for HSV1 infection. METHODS: To determine protein-protein interactions, the yeast-two hybrid system was applied. Asna1/TRC40 was depleted using RNA interference. Transient transfection and virus infection experiments followed by indirect immunofluorescence analysis were applied to analyse the localization of viral proteins as well as the impact of Asna1/TRC40 depletion on virus infection. RESULTS: All HSV1 tail-anchored proteins specifically bound to Asna1/TRC40 but independently localized to their target membranes. While non-essential for cell viability, Asna1/TRC40 is required for efficient HSV1 replication. We show that early events of the replication cycle like virion entry and overall viral gene expression were unaffected by depletion of Asna1/TRC40. Furthermore, equal amounts of infectious virions were formed and remained cell-associated. This indicated that both nuclear egress of capsids that requires the essential tail anchored protein pUL34, and secondary envelopment to form infectious virions were successfully completed. Despite large part of the virus life cycle proceeding normally, viral propagation was more than 10 fold reduced. We show that depletion of Asna1/TRC40 specifically affected a step late in infection during release of infectious virions to the extracellular milieu. CONCLUSIONS: Asna1/TRC40 is required at a late step of herpesviral infection for efficient release of mature virions to the extracellular milieu. This study reveals novel tools to decipher exocytosis of newly formed virions as well as hitherto unknown cellular targets for antiviral therapy. PMID- 27765047 TI - Used protocols for isolation and propagation of ovarian stem cells, different cells with different traits. AB - Although existence of ovarian stem cells (OSCs) in mammalian postnatal ovary is still under controversy, however, it has been almost accepted that OSCs are contributing actively to folliculogenesis and neo-oogenesis. Recently, various methods with different efficacies have been employed for OSCs isolation from ovarian tissue, which these methods could be chosen depends on aim of isolation and accessible equipments and materials in lab. Although isolated OSCs from different methods have various traits and characterizations, which might become from their different nature and origin, however these stem cells are promising source for woman infertility treatment or source of energy for women with a history of repeat IVF failure in near future. This review has brought together and summarized currently used protocols for isolation and propagation of OSCs in vitro. PMID- 27765048 TI - Correlation between health-related quality of life in the physical domain and heart rate variability in asymptomatic adults. AB - BACKGROUND: Reduced health-related quality of life in the physical domain (HRQOLphysical) has been reported to increase risks for cardiovascular disease (CVD); however, the mechanism underlying this phenomenon is still unclear. The autonomic nervous system (ANS) that connects the body and mind is a biologically plausible candidate to investigate this mechanism. The aim of our study is to examine whether the HRQOLphysical independently contributes to heart rate variability (HRV), which reflects ANS activity. METHODS: We recruited 329 physically and mentally healthy adults. All participants completed Beck Anxiety Inventory, Beck Depression Inventory and World Health Organization Questionnaire on Quality of Life: Short Form-Taiwanese version (WHOQOL-BREF). They were divided into groups of individuals having high or low scores of HRQOLphysical as discriminated by the quartile value of WHOQOL-BREF. We obtained the time and frequency-domain indices of HRV, namely variance (total HRV), the low-frequency power (LF; 0.05-0.15 Hz), which may reflect baroreflex function, the high frequency power (HF; 0.15-0.40 Hz), which reflects cardiac parasympathetic activity, and the LF/HF ratio. RESULTS: There was an independent contribution of HRQOLphysical to explaining the variance in HRV after excluding potential confounding factors (gender, age, physical activity, alcohol use, depression and anxiety). Compared with the participants with high levels of HRQOLphysical, those with low levels of HRQOLphysical displayed significant reductions in variance and LF. CONCLUSIONS: This study highlights the independent role of low HRQOLphysical in contributing to the reduced HRV in healthy adults and points to a potential underlying mechanism for HRQOLphysical to confer increased risks for CVD. PMID- 27765049 TI - Development and psychometric evaluation of a context-based parental self-efficacy instrument for healthy dietary and physical activity behaviors in preschool children. AB - BACKGROUND: Parental self-efficacy (PSE) refers to beliefs of parents to effectively engage in behaviors that result in desired outcomes for their children. There are several instruments of PSE for promoting healthy dietary or physical activity (PA) behaviors in children. These measures typically assess PSE in relation to some quantity or frequency of behavior, for example, number of servings or times per week. However, measuring PSE in relation to contextual circumstances, for example, psychological states and situational demands, may be a more informative approach. The purpose of the present study was to develop and psychometrically evaluate a context-based PSE instrument. METHODS: Swedish mothers of five-year-old children (n = 698) responded to the Parental Self Efficacy for Healthy Dietary and Physical Activity Behaviors in Preschoolers Scale (PDAP) and a questionnaire on dietary and PA behaviors in children. Interviews were conducted to explore participant perceptions of the quality of the PDAP items. Psychometric evaluation was conducted using exploratory and confirmatory factor analyses. Spearman correlations between PSE and child behaviors were examined. RESULTS: Twenty-seven interviews were conducted with participants, who perceived the items as highly comprehensible, relevant and acceptable. A four-factor model of a revised 21-item version of the PDAP fitted the data, with different factors of PSE for promoting healthy dietary or PA behaviors in children depending on whether circumstances were facilitating or impeding successful performance. Internal consistency was excellent for total scale (Cronbach's alpha = .94), and good for factors (alpha = .84-.88). Correlations were in the expected direction: positive correlations between PSE and healthy behaviors, and negative correlations between PSE and unhealthy behaviors (all r ss <= .32). CONCLUSIONS: Psychometric evaluation of the PDAP provided preliminary support of construct validity and internal consistency. PMID- 27765050 TI - Identification of internalin-A-like virulent proteins in Leishmania donovani. AB - BACKGROUND: An active immune surveillance and a range of barriers to infection allow the host to effectively eliminate microbial pathogens. However, pathogens may use diverse strategies to subdue such host defences. For instance, one such mechanism is the use of leucine-rich repeat (LRR) proteins by pathogens (microbial) to cause infection. In this study, we aimed at identifying novel virulence factor(s) in Leishmania donovani, based on the possibility of lateral gene transfers of bacterial virulence factor(s) to L. donovani. METHODS: Rigorous homology searching protocols including Hidden Markov Model (HMM) and BLASTp based searches were employed to detect remote but significant similarities between L. donovani proteins and bacterial virulence factors. RESULTS: We found that some L. donovani proteins are similar to internalin-A (Inl-A) protein of Listeria monocytogenes, a surface LRR protein that helps mediate host cell invasion by interacting with E-cadherin on the cell membrane. However, to date, no such invasion mechanism has been reported in Leishmania donovani, the causative agent of visceral leishmaniasis. Moreover, a comparative LRR motif analysis of L. donovani Inl-A-like proteins against the Inl-A protein of L. monocytogenes revealed existence of characteristic consensus LRR regions, suggesting a reliable evolutionary relationship between them. Further, through rigorous three dimensional (3D) modeling of L. donovani Inl-A-like proteins and subsequent molecular docking studies we suggest the probability of human E-cadherin binding with the L. donovani Inl-A-like proteins. CONCLUSIONS: We have identified three potential candidates (UniProt ID: E9B7L9, E9BMT7 and E9BUL5) of Inl-A-like LRR containing proteins in L. donovani with the help of systematic whole genome sequence analysis. Thus, herein we propose the existence of a novel class of Inl A-like virulence factor proteins in L. donovani and other Leishmania species based on sequence similarity, phylogenetic analysis and molecular modelling studies in L. donovani. PMID- 27765051 TI - Wild food plants and minor crops in the Ripolles district (Catalonia, Iberian Peninsula): potentialities for developing a local production, consumption and exchange program. AB - BACKGROUND: Wild food plants (WFP) have always been consumed by humans, first as the main basis of their food and, since the origins of agriculture, as ingredients of normal diets or as an alternative during situations of scarcity. In contemporary industrialized societies their use is for the most part being abandoned, but they may still play an important role. With the purpose of advancing in the ethnobotanical knowledge of one region of the Catalan Pyrenees, the present study reports the findings of a research project conducted in the Ripolles district (Catalonia, Iberian Peninsula), concerning ethnobotanical knowledge and use of wild and semi-wild vascular plants as foods, along with minor crops. METHODS: From August 2004 to July 2014, we performed 104 interviews (93 of which yielded data on food plants) with 163 informants, using the method of semi-structured ethnobotanical interview. We identified the plants quoted and kept herbarium vouchers. RESULTS: We detected 967 use reports for 80 wild or naturalized taxa, which are or have been consumed in the Ripolles district, the most cited being Taraxacum dissectum, Cynara cardunculus and Origanum vulgare. Certain frequently reported species such as Molopospermum peloponnesiacum and Taraxacum dissectum have only been rarely cited previously or indicated as food plant in very restricted geographical areas. Most cited families included Asteraceae and Lamiaceae, followed by Rosaceae and Apiaceae. Preferred consumed plant parts included leaves, followed by aerial parts, along with fruits and infructescences, while most wild food plants are eaten raw or used as condiments. Demographic factors such as age and locality of informants seem to be more relevant to wild food plant knowledge than gender. Middle-aged people and inhabitants from the Higher Freser River Valley seem to have a greater knowledge of WFP, both in relation to the number of species elicited, as well as the diversity of uses and preparations. To a lesser degree, women seem to have a slightly higher WFP knowledge than men. The consumption of these resources is still fairly alive amongst the populace, yet changes affecting younger generations-in most cases abandonment-have been reported by various participants. CONCLUSION: The information provided by this kind of research permits the detection of those traditional species that could constitute the basis for the future development and management of wild edible plant resources along with minor crops. It also helps to determine the factors affecting their use, as well as the distinct target groups that such programmes could be addressed to. PMID- 27765052 TI - Distinct functional enrichment of transcriptional signatures in pigs with high and low IFN-gamma responses after vaccination with a porcine reproductive and respiratory syndrome virus (PRRSV). AB - Little is known about the host factor in the response to PRRSV vaccination. For this purpose, piglets were immunized with a commercial PRRSV-live vaccine and classified as high responders (HR) or low responders (LR) as regards to the frequencies of virus-specific IFN-gamma-secreting cells. Six weeks post vaccination, PBMCs isolated from three individuals with the most extreme responses in each HR and LR groups and 3 unvaccinated controls, were either stimulated with phytohaemagglutinin, challenged with the vaccine or mock treated for 24 h, prior conducting transcriptional studies, gene ontology and pathway analyses. The LR group had very low neutralizing antibody levels and showed a higher number of down-regulated transcripts compared with the HR group (FDR < 0.2, P < 0.001). Down-regulated genes encoded chemoattractants, proinflammatory cytokines and the interferon-inducible GBP family, and showed enrichment in wounding (FDR < 3.6E-13), inflammation (FDR < 8E-12), defence (FDR < 8.7E-09) and immunity (FDR < 7.6E-08), suggesting immune response impairment. In the HR group, down-regulated genes were involved in protein transport (FDR < 4.77E-03), locomotory behavior (FDR < 5.47E-3), regulation of protein localization (FDR < 1.02E-02), and regulation of TNF superfamily member 15 and miR181. In contrast, the HR group presented up-regulated transcripts associated with wounding (FDR < 4.95). Moreover, IFN-gamma was predicted to be an inhibited upstream regulator since IFN-gamma pathways were associated with higher number of down-regulated genes in the LR (n = 40) than the HR (n = 10). Divergent responses to PRRSV vaccination may be the result of the genetic background of the host. PMID- 27765053 TI - Impact of recent guideline changes on aspirin prescribing after knee arthroplasty. AB - BACKGROUND: Prior to 2012, the American Academy of Orthopaedic Surgeons (AAOS) and American College of Chest Physicians (ACCP) differed in their recommendations for postoperative pharmacologic venous thromboembolism prophylaxis (VTEP) after total joint arthroplasty. More specifically, aspirin (ASA) monotherapy was not endorsed by the ACCP as an acceptable prophylaxis. In 2012, the ACCP supported ASA monotherapy compared with no prophylaxis. Our aim was to investigate the impact of the convergence of ACCP and AAOS recommendations on surgeon prescribing patterns after knee arthroplasty (KA). METHODS: This is a retrospective chart review. We collected data to assess preoperative VTE risk and examined VTEP prescriptions on postoperative day 1 (POD1) and at discharge (D/C) from 7/2008 to 12/2011 (pre-period) and 1/2012 to 7/2014 (post-period). Adult patients undergoing primary and revision KA were identified by ICD-9 procedure codes. Patients on preoperative full-dose anticoagulation and with hypercoagulability disorders were excluded. RESULTS: Of 368 records reviewed, 329 were included in the analysis. There were no differences between the two period groups for age, sex, BMI, estrogen therapy, malignancy, smoking status, prior VTE, bilateral procedures, or surgery within 3 months. On POD1, in the pre-period, 4.6 % were prescribed ASA monotherapy versus 44.4 % in the post-period (p < 0.001). On D/C, in the pre-period, 13.9 % were prescribed ASA versus 55.6 % in the post-period (p < 0.001). CONCLUSIONS: Our results indicate a statistically significant change in orthopedist prescribing patterns after guideline convergence. Furthermore, there was no apparent change in VTE risk between the two study groups when excluding patients necessitating full anticoagulation. Prior literature has shown that the divergence in guidelines influenced physicians away from ASA and toward more potent anticoagulants in order to avoid potential litigation. Once its role in VTEP was supported by the ACCP, it appears that ASA monotherapy was readily and rapidly incorporated into clinical practice. ASA may be favored over other VTEP agents for its lower bleeding risk profile and cost. This study highlights the profound impact clinical practice guidelines have on clinician prescribing patterns. Although prospective randomized trials are needed to compare the efficacy of ASA with other VTEP agents, ASA is now a predominant part of the VTEP armamentarium after KA. PMID- 27765054 TI - Regulation of blood flow and volume exchange across the microcirculation. AB - Oxygen delivery to cells is the basic prerequisite of life. Within the human body, an ingenious oxygen delivery system, comprising steps of convection and diffusion from the upper airways via the lungs and the cardiovascular system to the microvascular area, bridges the gap between oxygen in the outside airspace and the interstitial space around the cells. However, the complexity of this evolutionary development makes us prone to pathophysiological problems. While those problems related to respiration and macrohemodynamics have already been successfully addressed by modern medicine, the pathophysiology of the microcirculation is still often a closed book in daily practice. Nevertheless, here as well, profound physiological understanding is the only key to rational therapeutic decisions. The prime guarantor of tissue oxygenation is tissue blood flow. Therefore, on the premise of intact macrohemodynamics, the microcirculation has three major responsibilities: 1) providing access for oxygenated blood to the tissues and appropriate return of volume; 2) maintaining global tissue flood flow, even in the face of changes in central blood pressure; and 3) linking local blood flow to local metabolic needs. It is an intriguing concept of nature to do this mainly by local regulatory mechanisms, impacting primarily on flow resistance, be this via endothelial or direct smooth muscle actions. The final goal of microvascular blood flow per unit of time is to ensure the needed exchange of substances between tissue and blood compartments. The two principle means of accomplishing this are diffusion and filtration. While simple diffusion is the quantitatively most important form of capillary exchange activity for the respiratory gases, water flux across the blood-brain barrier is facilitated via preformed specialized channels, the aquaporines. Beyond that, the vascular barrier is practically nowhere completely tight for water, with paracellular filtration giving rise to generally low but permanent fluid flux outwards into the interstitial space at the microvascular high pressure segment. At the more leaky venular aspect, both filtration and diffusion allow for bidirectional passage of water, nutrients, and waste products. We are just beginning to appreciate that a major factor for maintaining tissue fluid homeostasis appears to be the integrity of the endothelial glycocalyx. PMID- 27765055 TI - Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft versus-host disease development. AB - BACKGROUND: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. METHODS: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. RESULTS: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naive T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. CONCLUSIONS: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis. PMID- 27765057 TI - New classification of lunate fossa fractures of the distal radius. AB - BACKGROUND: A die-punch fracture is a depression fracture of the lunate fossa of the distal radius. We propose a morphological classification of die-punch fractures that includes five types: center depression fractures, vertical depression fractures, volar depression fractures, dorsal depression fractures, and double die-punch fractures. METHODS: The radiographs of 112 die-punch fractures treated between January 2005 and January 2015 were retrospectively reviewed. The clinical images were examined independently for two rounds by six orthopedists with different clinical experiences: two residents, two attending physicians, and two consultants. A category-specific kappa score and a kappa score for more than two observers were analyzed. We used Cohen's kappa to test intraobserver variation. RESULTS: The kappa score for interobserver reliability was 0.69 for the first round and 0.70 for the second round. The intraclass correlations were 0.65 and 0.63, respectively. Intraobserver reproducibility using Cohen's kappa test was satisfactory. All of the results indicated a kappa value >0.4, suggesting good agreement within, as well as between, observers. CONCLUSIONS: The outcome was assessed using kappa statistics, which showed good interobserver reliability and intraobserver reproducibility. PMID- 27765056 TI - Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G. AB - BACKGROUND: Neuromyelitis optica (NMO), an autoimmune inflammatory disease of the central nervous system, is often associated with retinal abnormalities including thinning of the retinal nerve fiber layer and microcystic changes. Here, we demonstrate that passive transfer of an anti-aquaporin-4 autoantibody (AQP4-IgG) produces primary retinal pathology. METHODS: AQP4-IgG was delivered to adult rat retinas by intravitreal injection. Rat retinas and retinal explant cultures were assessed by immunofluorescence. RESULTS: Immunofluorescence showed AQP4-IgG deposition on retinal Muller cells, with greatly reduced AQP4 expression and increased glial fibrillary acidic protein by 5 days. There was mild retinal inflammation with microglial activation but little leukocyte infiltration and loss of retinal ganglion cells by 30 days with thinning of the ganglion cell complex. Interestingly, the loss of AQP4 was complement independent as seen in cobra venom factor-treated rats and in normal rats administered a mutated AQP4 IgG lacking complement effector function. Exposure of ex vivo retinal cultures to AQP4-IgG produced a marked reduction in AQP4 expression by 24 h, which was largely prevented by inhibitors of endocytosis or lysosomal acidification. CONCLUSIONS: Passive transfer of AQP4-IgG results in primary, complement independent retinal pathology, which might contribute to retinal abnormalities seen in NMO patients. PMID- 27765058 TI - Medicine in spine exercise (MiSpEx) for nonspecific low back pain patients: study protocol for a multicentre, single-blind randomized controlled trial. AB - BACKGROUND: Arising from the relevance of sensorimotor training in the therapy of nonspecific low back pain patients and from the value of individualized therapy, the present trial aims to test the feasibility and efficacy of individualized sensorimotor training interventions in patients suffering from nonspecific low back pain. METHODS AND STUDY DESIGN: A multicentre, single-blind two-armed randomized controlled trial to evaluate the effects of a 12-week (3 weeks supervised centre-based and 9 weeks home-based) individualized sensorimotor exercise program is performed. The control group stays inactive during this period. Outcomes are pain, and pain-associated function as well as motor function in adults with nonspecific low back pain. Each participant is scheduled to five measurement dates: baseline (M1), following centre-based training (M2), following home-based training (M3) and at two follow-up time points 6 months (M4) and 12 months (M5) after M1. All investigations and the assessment of the primary and secondary outcomes are performed in a standardized order: questionnaires - clinical examination - biomechanics (motor function). Subsequent statistical procedures are executed after the examination of underlying assumptions for parametric or rather non-parametric testing. DISCUSSION: The results and practical relevance of the study will be of clinical and practical relevance not only for researchers and policy makers but also for the general population suffering from nonspecific low back pain. TRIAL REGISTRATION: Identification number DRKS00010129. German Clinical Trial registered on 3 March 2016. PMID- 27765059 TI - Localization of neonatal Fc receptor for IgG in aggregated lymphoid nodules area in abomasum of Bactrian camels (Camelus bactrianus) of different ages. AB - BACKGROUND: The neonatal Fc receptor (FcRn) plays a crucial role in transporting IgG and associated antigens across polarized epithelial barriers in mucosal immunity. However, it was not clear that FcRn expression in aggregated lymphoid nodules area (ALNA) in abomasum, a unique and important mucosal immune structure discovered only in Bactrian camels. In the present study, 27 Alashan Bactrian camels were divided into the following five age groups: fetus (10-13 months of gestation), young (1-2 years), pubertal (3-5 years), middle-aged (6-16 years) and old (17-20 years). The FcRn expressions were observed and analyzed in detail with histology, immunohistochemistry, micro-image analysis and statistical methods. RESULTS: The results showed that the FcRn was expressed in mucosal epithelial cells of ALNA from the fetus to the old group, although the expression level rapidly declined in old group; moreover, after the ALNA maturated, the FcRn expression level in the non-follicle-associated epithelium (non-FAE) was significantly higher than that in FAE (P < 0.05). In addition, the FcRn was also expressed in the vessel endothelium, smooth muscle tissue, and macrophages and dendritic cells (DCs) of secondary lymphoid follicles (sLFs). CONCLUSIONS: It was demonstrated that FcRn was mainly expressed in non-FAE, the effector sites, although which was expressed in FAE, the inductive sites for mucosal immunity. And it was also expressed in DCs and macrophages in sLFs of all ages of Bactrian camels. The results provided a powerful evidence that IgG (including HCAb) could participate in mucosal immune response and tolerance in ALNA of Bactrian camels through FcRn transmembrane transport. PMID- 27765060 TI - Side effect profile similarities shared between antidepressants and immune modulators reveal potential novel targets for treating major depressive disorders. AB - BACKGROUND: Side effects, or the adverse effects of drugs, contain important clinical phenotypic information that may be useful in predicting novel or unknown targets of a drug. It has been suggested that drugs with similar side-effect profiles may share common targets. The diagnostic class, Major Depressive Disorder, is increasingly viewed as being comprised of multiple depression subtypes with different biological root causes. One 'type' of depression generating substantial interest today focuses on patients with high levels of inflammatory burden, indicated by elevated levels of C-reactive proteins (CRP) and pro-inflammatory cytokines such as interleukin 6 (IL-6). It has been suggested that drugs targeting the immune system may have beneficial effect on this subtype of depressed patients, and several studies are underway to test this hypothesis directly. However, patients have been treated with both anti inflammatory and antidepressant compounds for decades. It may be possible to exploit similarities in clinical readouts to better understand the antidepressant effects of immune-related drugs. METHODS: Here we explore the space of approved drugs by comparing the drug side effect profiles of known antidepressants and drugs targeting the immune system, and further examine the findings by comparing the human cell line expression profiles induced by them with those induced by antidepressants. RESULTS: We found 7 immune-modulators and 14 anti-inflammatory drugs sharing significant side effect profile similarities with antidepressants. Five of the 7 immune modulators share most similar side effect profiles with antidepressants that modulate dopamine release and/or uptake. In addition, the immunosuppressant rapamycin and the glucocorticoid alclometasone induces transcriptional changes similar to multiple antidepressants. CONCLUSIONS: These findings suggest that some antidepressants and some immune-related drugs may affect common molecular pathways. Our findings support the idea that certain medications aimed at the immune system may be helpful in relieving depressive symptoms, and suggest that it may be of value to test immune-modulators for antidepressant-like activity in future proof-of-concept studies. PMID- 27765061 TI - Cardiovascular magnetic resonance patterns of biopsy proven cardiac involvement in systemic sclerosis. AB - BACKGROUND: To determine morphological and functional cardiovascular magnetic resonance (CMR) patterns in histopathologically confirmed myocardial involvement in patients with systemic sclerosis (SSc). METHODS: Twenty patients (6 females; mean age 41 +/- 11 years) with histopathologically proven cardiac involvement in SSc in the years 2008-2016 were retrospectively evaluated. Morphological, functional and late gadolinium enhancement (LGE) images were acquired in standard angulations at 1.5 T CMR. Pathologies were categorized: 1) Pericardial effusion; 2) pathologic left (LV) or right ventricular (RV) contractility (hypokinesia, dyssynchrony, and diastolic restriction); 3) reduced left (LV-EF) and right ventricular ejection fraction (RV-EF); 4) fibrosis and/or inflammation (positive LGE); 5) RV dilatation. 95 % confidence intervals (CI) were calculated for appearance of pathologic EF and RV dilatation. RESULTS: Seven patients (35 %) had positive CMR findings in three categories, 9 patients (45 %) in four categories and 4 patients (20 %) in five categories. The distribution of pathologic findings was: minimal pericardial effusion in 7 patients (35 %), moderate pericardial effusion >5 mm in nine patients (45 %); abnormal LV or RV contractility in 19 patients (95 %), reduced LV or RV function in 14 patients (70 %; 95 % CI: 51-88 %), pathologic LGE in all patients, RV dilatation in 6 patients (30 %; 95 % CI: 15-54 %). CONCLUSIONS: CMR diagnosis of myocardial involvement in SSc requires increased attention to subtle findings. Pathologic findings in at least three of five categories indicate myocardial involvement in SSc. PMID- 27765062 TI - The 60S ribosomal protein L13 is the most preferable reference gene to investigate gene expression in selected organs from turkeys and chickens, in context of different infection models. AB - Evaluation of reference genes for expression studies in chickens and turkeys is very much limited and unavailable for various infectious models. In this study, eight candidate reference genes HMBS, HPRT1, TBP, VIM, TFRC, RPLP0, RPL13 and RPS7 were evaluated by five different algorithms (GeNorm, NormFinder, BestKeeper(c), delta CT, RefFinder) to assess their stability. In order to analyze a broad variation of tissues, spleen, liver, caecum and caecal tonsil of different aged specific pathogen free (SPF) layer chickens and commercial turkeys, uninfected or infected with the extracellular pathogen Histomonas meleagridis, were included. For tissue samples from SPF chickens RPL13 and TBP were found to be the most stable reference genes. Further testing of RPL13 and TBP in the same organs of uninfected and infected SPF broiler chickens with the intracellular pathogen fowl aviadenovirus confirmed this finding. In tissue samples from turkeys, a stable expression of RPL13 and TFRC genes was noticed. Overall, the determined reference genes should be considered whenever gene expression studies in spleen, liver, caecum and caecal tonsil of chickens and turkeys are performed. PMID- 27765063 TI - Responses to altered oxygen tension are distinct between human stem cells of high and low chondrogenic capacity. AB - BACKGROUND: Lowering oxygen from atmospheric level (hyperoxia) to the physiological level (physioxia) of articular cartilage promotes mesenchymal stem cell (MSC) chondrogenesis. However, the literature is equivocal regarding the benefits of physioxic culture on preventing hypertrophy of MSC-derived chondrocytes. Articular cartilage progenitors (ACPs) undergo chondrogenic differentiation with reduced hypertrophy marker expression in hyperoxia but have not been studied in physioxia. This study sought to delineate the effects of physioxic culture on both cell types undergoing chondrogenesis. METHODS: MSCs were isolated from human bone marrow aspirates and ACP clones were isolated from healthy human cartilage. Cells were differentiated in pellet culture in physioxia (2 % oxygen) or hyperoxia (20 % oxygen) over 14 days. Chondrogenesis was characterized by biochemical assays and gene and protein expression analysis. RESULTS: MSC preparations and ACP clones of high intrinsic chondrogenicity (termed high-GAG) produced abundant matrix in hyperoxia and physioxia. Poorly chondrogenic cells (low-GAG) demonstrated a significant fold-change matrix increase in physioxia. Both high-GAG and low-GAG groups of MSCs and ACPs significantly upregulated chondrogenic genes; however, only high-GAG groups had a concomitant decrease in hypertrophy-related genes. High-GAG MSCs upregulated many common hypoxia-responsive genes in physioxia while low-GAG cells downregulated most of these genes. In physioxia, high-GAG MSCs and ACPs produced comparable type II collagen but less type I collagen than those in hyperoxia. Type X collagen was detectable in some ACP pellets in hyperoxia but reduced or absent in physioxia. In contrast, type X collagen was detectable in all MSC preparations in hyperoxia and physioxia. CONCLUSIONS: MSC preparations and ACP clones had a wide range of chondrogenicity between donors. Physioxia significantly enhanced the chondrogenic potential of both ACPs and MSCs compared with hyperoxia, but the magnitude of response was inversely related to intrinsic chondrogenic potential. Discrepancies in the literature regarding MSC hypertrophy in physioxia can be explained by the use of low numbers of preparations of variable chondrogenicity. Physioxic differentiation of MSC preparations of high chondrogenicity significantly decreased hypertrophy-related genes but still produced type X collagen protein. Highly chondrogenic ACP clones had significantly lower hypertrophic gene levels, and there was little to no type X collagen protein in physioxia, emphasizing the potential advantage of these cells. PMID- 27765064 TI - Distinct immune responses and virus shedding in pigs following aerosol, intra nasal and contact infection with pandemic swine influenza A virus, A(H1N1)09. AB - Influenza virus infection in pigs is a major farming problem, causing considerable economic loss and posing a zoonotic threat. In addition the pig is an excellent model for understanding immunity to influenza viruses as this is a natural host pathogen system. Experimentally, influenza virus is delivered to pigs intra-nasally, by intra-tracheal instillation or by aerosol, but there is little data comparing the outcome of different methods. We evaluated the shedding pattern, cytokine responses in nasal swabs and immune responses following delivery of low or high dose swine influenza pdmH1N1 virus to the respiratory tract of pigs intra-nasally or by aerosol and compared them to those induced in naturally infected contact pigs. Our data shows that natural infection by contact induces remarkably high innate and adaptive immune response, although the animals were exposed to a very low virus dose. In contacts, the kinetics of virus shedding were slow and prolonged and more similar to the low dose directly infected animals. In contrast the cytokine profile in nasal swabs, antibody and cellular immune responses of contacts more closely resemble immune responses in high dose directly inoculated animals. Consideration of these differences is important for studies of disease pathogenesis and assessment of vaccine protective efficacy. PMID- 27765067 TI - Rheumatoid arthritis antigens homocitrulline and citrulline are generated by local myeloperoxidase and peptidyl arginine deiminases 2, 3 and 4 in rheumatoid nodule and synovial tissue. AB - BACKGROUND: Seropositive rheumatoid arthritis (RA) is characterized by autoantibodies binding to citrullinated and homocitrullinated proteins. We wanted to study the expression patterns of these disease-associated protein forms and if the rheumatoid nodule and synovial tissue itself contain biologically active levels of citrullinating peptidyl arginine deiminases 2, 3 and 4 and homocitrullination-facilitating neutrophil enzyme myeloperoxidase. METHOD: Total of 195 synovial samples from metatarsal joints from five ACPA/RF-positive RA patients (n = 77), synovial samples from knees of eight seropositive RA (n = 60), seven seronegative RA (n = 33) and five osteoarthritis (n = 25) patients were analyzed for citrulline and homocitrulline contents using HPLC. The location of citrulline- and homocitrulline-containing proteins, PAD 2, 3, 4 and myeloperoxidase were shown by immunostaining. Myeloperoxidase and citrulline- or homocitrulline-containing proteins were stained on Western blot. RESULTS: Overall, necrosis was frequent in metatarsals of seropositive RA and absent in seronegative RA and osteoarthritis patients. In histological analysis, there was a significant local patterning and variation in the citrulline and homocitrulline content and it was highest in metatarsal synovial tissues of seropositive RA patients. We found peptidyl arginine deiminase 2, 3 and 4 in the lining and sublining layers of intact synovial tissue. Myeloperoxidase was found locally around necrotic areas. The tissues with necrosis contained the highest levels of citrulline and homocitrulline. CONCLUSIONS: Rheumatoid nodules and synovia contain significant amount of PAD2, 3 and 4 and myeloperoxidase enzymes. These enzymes could explain the levels of citrulline and homocitrulline in seropositive RA synovial and rheumatoid nodule tissues especially around necrotic tissue. PMID- 27765066 TI - Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. AB - We introduce the Microenvironment Cell Populations-counter (MCP-counter) method, which allows the robust quantification of the absolute abundance of eight immune and two stromal cell populations in heterogeneous tissues from transcriptomic data. We present in vitro mRNA mixture and ex vivo immunohistochemical data that quantitatively support the validity of our method's estimates. Additionally, we demonstrate that MCP-counter overcomes several limitations or weaknesses of previously proposed computational approaches. MCP-counter is applied to draw a global picture of immune infiltrates across human healthy tissues and non hematopoietic human tumors and recapitulates microenvironment-based patient stratifications associated with overall survival in lung adenocarcinoma and colorectal and breast cancer. PMID- 27765068 TI - Genome-wide methylation profiling of ovarian cancer patient-derived xenografts treated with the demethylating agent decitabine identifies novel epigenetically regulated genes and pathways. AB - BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far. Aims of this study were to explore how representative HGSOC PDXs are of their corresponding patient tumor methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. METHODS: Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450 K methylation arrays. Furthermore, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the prognostic value of the identified genes. RESULTS: Only 0.6-1.0 % of all analyzed CpGs (388,696 CpGs) changed significantly (p < 0.01) during propagation, showing that HGSOC PDXs were epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6 % of CpG sites in comparison to untreated PDXs (p < 0.01, false discovery rate <10 %). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g., the Src family kinase pathway). In particular, the C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p < 0.05) with improved progression-free survival and overall survival in HGSOC patients. CONCLUSIONS: HGSOC PDXs resemble the global epigenome of patients over many generations and can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our observations encourage future application of PDXs for cancer epigenome studies. PMID- 27765069 TI - Genetic loci of Mycoplasma agalactiae involved in systemic spreading during experimental intramammary infection of sheep. AB - Mycoplasmas are amongst the most successful pathogens of both humans and animals yet the molecular basis of mycoplasma pathogenesis is poorly understood. This is partly due to the lack of classical virulence factors and little similarity to common bacterial pathogenic determinants. Using Mycoplasma agalactiae as a model we initiated research in this direction by screening a transposon mutant library in the natural sheep host using a negative selection method. Having successfully identified putative factors involved in the colonization of local infection and lymphogenic sites, the current study assessed mutants unable to spread systemically in sheep after experimental intramammary infection. Analysis of distant body sites for complete absence of mutants via SSM PCR revealed that additional set of genes, such as pdhB, oppC, oppB, gtsB, MAG1890, MAG5520 and MAG3650 are required for systemic spreading apart from those that were necessary for initial colonization. Additional in vitro studies with the mutants absent at these systemic sites confirmed the potential role of some of the respective gene products concerning their interaction with host cells. Mutants of pdhB, oppC and MAG4460 exhibited significantly slower growth in the presence of HeLa cells in MEM medium. This first attempt to identify genes exclusively required for systemic spreading provides a basis for further in-depth research to understand the exact mechanism of chronicity and persistence of M. agalactiae. PMID- 27765070 TI - Discrepancy between short-term and long-term effects of bone marrow-derived cell therapy in acute myocardial infarction: a systematic review and meta-analysis. AB - BACKGROUND: Bone marrow-derived cell therapy has been used to treat acute myocardial infarction. However, the therapeutic efficacy of this approach remains controversial. Here, we performed a systematic review and meta-analysis to evaluate short-term and long-term effectiveness of bone marrow-derived therapy. METHODS: We searched eight databases (Ovid-Medline, Ovid-EMBASE, Cochrane Library, KoreaMed, KMBASE, KISS, RISS, and KisTi) up to December 2014. Demographic characteristics, clinical outcomes, and adverse events were analyzed. We identified 5534 potentially relevant studies; 405 were subjected to a full text review. Forty-three studies with 2635 patients were included in this review. RESULTS: No safety issues related to cell injection were reported during follow up. At 6 months, cell-injected patients showed modest improvements in left ventricular ejection fraction (LVEF) compared with the control group. However, there were no differences between groups at other time points. In the cardiac MRI analysis, there were no significant differences in infarct size reduction between groups. Interestingly, mortality tended to be reduced at the 3-year follow-up, and at the 5-year follow-up, cell injection significantly decreased all-cause mortality. CONCLUSIONS: This meta-analysis demonstrated discrepancies between short-term LV functional improvement and long-term all-cause mortality. Future clinical trials should include long-term follow-up outcomes to validate the therapeutic efficacy of cell therapy. PMID- 27765071 TI - Circadian rhythms have significant effects on leaf-to-canopy scale gas exchange under field conditions. AB - BACKGROUND: Molecular clocks drive oscillations in leaf photosynthesis, stomatal conductance, and other cell and leaf-level processes over ~24 h under controlled laboratory conditions. The influence of such circadian regulation over whole canopy fluxes remains uncertain; diurnal CO2 and H2O vapor flux dynamics in the field are currently interpreted as resulting almost exclusively from direct physiological responses to variations in light, temperature and other environmental factors. We tested whether circadian regulation would affect plant and canopy gas exchange at the Montpellier European Ecotron. Canopy and leaf level fluxes were constantly monitored under field-like environmental conditions, and under constant environmental conditions (no variation in temperature, radiation, or other environmental cues). RESULTS: We show direct experimental evidence at canopy scales of the circadian regulation of daytime gas exchange: 20 79 % of the daily variation range in CO2 and H2O fluxes occurred under circadian entrainment in canopies of an annual herb (bean) and of a perennial shrub (cotton). We also observed that considering circadian regulation improved performance by 8-17 % in commonly used stomatal conductance models. CONCLUSIONS: Our results show that circadian controls affect diurnal CO2 and H2O flux patterns in entire canopies in field-like conditions, and its consideration significantly improves model performance. Circadian controls act as a 'memory' of the past conditions experienced by the plant, which synchronizes metabolism across entire plant canopies. PMID- 27765073 TI - Anaplasma marginale and A. phagocytophilum in cattle in Tunisia. AB - BACKGROUND: Tick-borne diseases caused by Anaplasma species put serious constraints on the health and production of domestic cattle in tropical and sub tropical regions. After recovering from a primary infection, cattle typically become persistent carriers of pathogens and play a critical role in the epidemiology of the disease, acting as reservoirs of the Anaplasma spp. METHODS: In this study a duplex PCR assay was used for the simultaneous detection of Anaplasma marginale and Anaplasma phagocytophilum in cattle using two primer pairs targeting msp4 and msp2 genes, respectively. We used this method to analyze DNA preparations derived from 328 blood cattle samples that were collected from 80 farms distributed among Tunisia's four bioclimatic zones. RESULTS: The prevalence of the A. marginale infection (24.7 %) was significantly higher and more widespread (in all bioclimatic areas) than that of A. phagocytophilum (0.6 %), which was found in a mixed infection with A. marginale. CONCLUSIONS: The duplex PCR assay used proved to be a rapid, specific and inexpensive mean for the simultaneous detection of Anaplasma marginale and Anaplasma phagocytophilum in cattle blood. It allowed us to report the identification of A. phagocytophilum for the first time in cattle in Tunisia and confirm the presence of A. marginale in cattle from several geographical areas of the country. Further epidemiological studies undertaken using this assay will help improve the surveillance of the associated diseases in the regions where they are endemic. PMID- 27765072 TI - Bioavailable estradiol concentrations are elevated and predict mortality in septic patients: a prospective cohort study. AB - BACKGROUND: Experimental studies demonstrate beneficial immunological and hemodynamic effects of estradiol in animal models of sepsis. This raises the question whether estradiol contributes to sex differences in the incidence and outcomes of sepsis in humans. Yet, total estradiol levels are elevated in sepsis patients, particularly nonsurvivors. Bioavailable estradiol concentrations have not previously been reported in septic patients. The bioavailable estradiol concentration accounts for aberrations in estradiol carrier protein concentrations that could produce discrepancies between total and bioavailable estradiol levels. We hypothesized that bioavailable estradiol levels are low in septic patients and sepsis nonsurvivors. METHODS: We conducted a combined case control and prospective cohort study. Venous blood samples were obtained from 131 critically ill septic patients in the medical and surgical intensive care units at the University of Rochester Medical Center and 51 control subjects without acute illness. Serum bioavailable estradiol concentrations were calculated using measurements of total estradiol, sex hormone-binding globulin, and albumin. Comparisons were made between patients with severe sepsis and control subjects and between hospital survivors and nonsurvivors. Multivariable logistic regression analysis was also performed. RESULTS: Bioavailable estradiol concentrations were significantly higher in sepsis patients than in control subjects (211 [78-675] pM vs. 100 [78-142] pM, p < 0.01) and in sepsis nonsurvivors than in survivors (312 [164-918] pM vs. 167 [70-566] pM, p = 0.04). After adjustment for age and comorbidities, patients with bioavailable estradiol levels above the median value had significantly higher risk of hospital mortality (OR 4.27, 95 % CI 1.65-11.06, p = 0.003). Bioavailable estradiol levels were directly correlated with severity of illness and did not differ between men and women. CONCLUSIONS: Contrary to our hypothesis, bioavailable estradiol levels were elevated in sepsis patients, particularly nonsurvivors, and were independently associated with mortality. Whether estradiol's effects are harmful, beneficial, or neutral in septic patients remains unknown, but our findings raise caution about estradiol's therapeutic potential in this setting. Our findings do not provide an explanation for sex-based differences in sepsis incidence and outcomes. PMID- 27765074 TI - Multicentric lymphoma in buffaloes in the Amazon region, Brazil. AB - BACKGROUND: The presence of lymphoma in buffaloes was first reported in India in the 1960s. The disease is similar to Enzootic Bovine Leucosis (EBL) caused by Bovine leukemia virus (BLV) in cattle; however, according to our results and those of other studies, the etiology of these lymphomas in buffalo do not appear to be associated with BLV. The objectives of this study are to describe four cases of the disease in buffaloes belonging to the same herd in the Amazon region of Brazil and to perform a clinical-anatomopathological, immunohistochemical, and etiological study of the lymphomas. RESULTS: Over a period of ten years, four buffaloes were observed presenting progressive weight loss, swelling of peripheral lymph nodes, and nodules in the subcutaneous tissue. Upon necropsy, whitish-colored tumor masses were observed in the form of nodules in the subcutaneous tissue, along with miliary nodules on the serosal surfaces of abdominal and thoracic organs and tumors in lymph nodes and other organs. Neoplastic lymphocyte proliferation was observed through histopathology. An immunohistochemical study revealed that the neoplasias were formed by proliferation of predominantly B lymphocytes. The presence of BLV genome was not detected in the lymphomas when using the real-time PCR technique, nor was it detected through immunohistochemical staining using monoclonal antibodies against two viral proteins. Bovine herpesvirus 6 was not detected in the tumors. However, Bovine immunodeficiency virus (BIV) was detected in samples of lymphoma and in the lymph nodes and kidneys of one of the animals. CONCLUSIONS: The occurrence of lymphoma in buffaloes is reported for the first time in Brazil and is characterized by B-cell multicentric lymphoma. The etiology of the disease does not appear to be associated with BLV; however, the detection of BIV in samples of lymphoma from one sick animal deserves further study, considering the oncogenic potential of this virus. PMID- 27765076 TI - Interspecific interactions between two Tuta absoluta (Lepidoptera: Gelechiidae) larval parasitoids with contrasting life histories. AB - Interspecific interactions between two larval parasitoids of Tuta absoluta (Meyrick) with partially overlapping host niches were studied: the idiobiont ectoparasitoid Dineulophus phthorimaeae De Santis, and the koinobiont endoparasitoid Pseudapanteles dignus (Muesebeck). T. absoluta is an important pest of tomato crops worldwide, and its management could be improved by understanding the competitive interactions and potential coexistence between these two parasitoids. Firstly, a 15-min fixed time laboratory test evaluated the host-searching ability of adult D. phthorimaeae and P. dignus wasps on T. absoluta larvae. Secondly, D. phthorimaeae host discrimination against endoparasitized and non-endoparasitized hosts by P. dignus, at different adult female ages, was experimentally examined. D. phthorimaeae wasps spent significantly more time in general searching in the presence of its competitor than in its absence, but, parasitism was only effective by P. dignus. Older D. phthorimaeae wasps discriminated significantly less than young wasps between T. absoluta larvae parasitized and unparasitized by P. dignus, and an interaction took place by non-concurrent host-feeding. Intra-guild predation of P. dignus larvae by D. phthorimaeae female feeding behaviour might have a minor effect in this system. Results are discussed in the context of literature supporting diverse evidence of coexistence in other parasitoid-host systems, with implications for T. absoluta biological control. PMID- 27765075 TI - Ex-vivo expansion of nonhuman primate CD34+ cells by stem cell factor Sall4B. AB - BACKGROUND: Hematopoietic CD34+ stem cells are widely used in the clinical therapy of complicated blood diseases. Stem cell factor Sall4B is a zinc finger transcription factor that plays a vital role in hematopoietic stem cell expansion. The purpose of our current study is to further evaluate how Sall4B might affect the expansion of CD34+ cells derived from nonhuman primates. METHODS: Sall4B was overexpressed in nonhuman primate bone marrow-derived CD34+ cells via a lentiviral transduction system. The granulocyte-erythrocyte macrophage-megakaryocyte colony-forming unit (CFU) assay evaluated the differentiation potential of primate CD34+ cells that were expanded with Sall4B. Furthermore, an in-vivo murine system was employed to evaluate the hematopoietic potential of primate Sall4B-expanded CD34+ cells. RESULTS: Overexpression of Sall4B promoted ex-vivo nonhuman primate CD34+ cell expansion by 9.21 +/- 1.94 fold on day 9, whereas lentiviral transduction without Sall4B expanded cells by only 2.95 +/- 0.77-fold. Sall4B maintained a significant percentage of CD34+ cells as well. The CFU assay showed that the Sall4B-expanded CD34+ cells still possessed multilineage differentiation potential. A study using nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice in vivo revealed that Sall4B led to an increase in the number of repopulating cells and the 9-day-old Sall4B-transduced CD34+ cells still possess self-renewal and multilineage differentiation capacity in vivo, which are similar stemness characteristics to those in freshly isolated primate bone marrow-derived CD34+ cells. CONCLUSIONS: We investigated the expansion of nonhuman primate bone marrow-derived CD34+ cells using the Sall4B lentiviral overexpression approach; our findings provide a new perspective on mechanisms of rapid stem cell proliferation. The utilization of Sall4B to expand CD34+ cells on a large scale through use of suitable model systems would prove helpful towards preclinical trials of autologous transplantation. PMID- 27765077 TI - Geographic distribution, large-scale spatial structure and diversity of parasitoids of the seed-feeding beetle Acanthoscelides macrophthalmus. AB - Bruchine beetles are highly host-specific seed feeders during the larval stage. Although some specific parasitoid families have been recorded attacking bruchine beetles, most studies have been done at small spatial scales. Therefore, the current knowledge about the diversity and the geographic distribution of parasitoid species parasitizing bruchines is scarce, especially at a wide geographic area that extends over large distances through a latitudinal cline (i.e. large-scale spatial structure). The present study determined the species richness and evenness of parasitoids attacking the bruchine beetle Acanthoscelides macrophthalmus feeding on Leucaena leucocephala seeds, examined their geographic distribution, and characterized the large-scale spatial structure in parasitoid species composition. A total of 1420 parasitoids (all Hymenoptera) belonging to four families, five subfamilies and eight species were collected (genera: Horismenus, Paracrias, Urosigalphus, Stenocorse, Chryseida, Eupelmus). Most parasitoid species showed wide spatial distribution, high evenness in species abundance and the species richness estimators were close to stabilization (approximately eight species). Overall, greater similarity was observed in the species composition of plant populations near to each other than those farther apart, revealing a large-scale spatial structure in parasitoid species composition. PMID- 27765078 TI - Whole-blood fatty acids are associated with executive function in Tanzanian children aged 4-6 years: a cross-sectional study. AB - Essential fatty acids (EFA) are PUFA that are metabolised to long-chain PUFA and are important for brain development and cognitive function. The objective of this study was to determine the association between whole-blood EFA and cognitive function in Tanzanian children. A total of 325 2-6-year-old children attempted the dimensional change card sort (DCCS) tasks to assess executive function. Blood samples were collected for fatty acid (FA) analysis by GC. Associations between executive function and FA levels were assessed by regression. Among the 130 4-6 year-old children who attempted the DCCS tasks, whole-blood levels of linoleic acid were positively associated with executive function, whereas whole-blood levels of alpha-linolenic acid and nervonic acid were inversely associated with executive function. A full model including all twenty-five FA explained 38 % of the variation in executive function, whereas a reduced model including only the EFA (alpha-linolenic acid and linoleic acid), DHA and EPA explained 25 % of the variation in executive function. Children who had sufficient whole-blood levels of EFA were 3.8 times more likely to successfully complete all DCCS tasks compared with children with insufficient EFA. These results suggest that whole blood FA levels are associated with cognitive abilities. Intervention trials that include assessment of whole-blood FA levels are required to determine the relationships between intake, blood levels and executive function in Tanzanian children. PMID- 27765079 TI - Effect of dietary lysine on performance and expression of electron transport chain genes in the pectoralis major muscle of broilers. AB - The aim of this study was to evaluate the effect of dietary lysine on performance, protein deposition and respiratory chain gene expression in male broilers. A total of 252 Cobb 500 broilers were distributed, in a completely randomized design, into four treatments with seven replicates of nine birds per experimental unit. Experimental treatments consisted of diets based on corn and soybean meal, with four levels of digestible lysine: 1.016%, 1.099%, 1.182% and 1.265%. The increase in the level of digestible lysine in the diet provided higher weight gains, feed efficiency and body protein deposition. Birds fed the lowest level of dietary lysine (1.016%) showed a lower expression of genes such as NADH dehydrogenase subunit I (ND1), cytochrome b (CYTB) and cytochrome c oxidase subunits I (COX I), II (COX II) and III (COX III), displaying the worst performance and body protein deposition. This demonstrates the relationship existing between the expression of the evaluated genes and the performance responses. In conclusion, results indicate that broilers fed diets with higher levels of digestible lysine have increased messenger RNA expression of some genes coded in the mitochondrial electron transport chain (ND1, CYTB, COX I, COX II and COX III). It may be stated that diets with proper levels of digestible lysine, within the 'ideal protein' concept, promote the expression of genes, which increases the mitochondrial energy, thereby fostering body protein deposition and the performance of broilers in the starter phase. PMID- 27765080 TI - Survey of Thai Commercial Food Products That Have Been Reported to Contain No Wheat, Rye, Barley, or Gluten According to Their Labels. AB - Celiac disease (CD) and gluten-related disorders are significant health and social issues in Western countries, and CD individuals need to exclude gluten from their diets. The adverse health impacts of CD have extended to Asian countries in which CD was not a problem previously. Thai commercial food products that do not contain wheat, rye, barley, or gluten on their labels were surveyed as to whether they were suitable for CD individuals by examining the absence of gluten or the presence of gluten <20 ppm. In Thailand, ELISA tested for gluten content in 129 commercial food products that contained neither wheat, rye, barley, nor gluten on their labels. One hundred nineteen of these 129 products included <20 ppm gluten, and 10 products contained >20 ppm gluten. Surprisingly, four products showed gluten levels >1%. In these 10 products, wheat presence was confirmed by PCR analysis. Our survey suggests that CD individuals can consume most of the examined Thai food products, and the survey showed the potential of these Thai products as new diets for CD patients so as to expand the limited food choices from different food cultures, and ultimately to improve the quality of life for all CD individuals globally. The appropriate gluten management strategies need to be implemented by Thai food manufacturers to ensure accurate labeling and to protect the safety of consumers with CD. PMID- 27765081 TI - Development of a Multiplex PCR System for the Simultaneous Detection of the Shrimp Species Fenneropenaeus chinensis, Litopenaeus vannamei, and Penaeus monodon. AB - Due to mixed use of shrimp in foodstuffs, it is important to distinguish Fenneropenaeus chinensis from other shrimp species, such as Litopenaeus vannamei and Penaeus monodon. For this purpose, we have developed a multiplex PCR method to detect the simultaneous presence of all three species. Universal primers specific to the 16S ribosomal RNA subunit were used to sequence and ascertain the species in the samples. In this study, specific primers were designed to result in a unique PCR product size (143, 260, and 348 bp for L. vannamei, F. chinensis and P. monodon, respectively). In addition, duplex and triplex PCR protocols were developed to concurrently and rapidly detect these three shrimp species without nonspecific gene amplification. This multiplex PCR system is expected to be widely used to distinguish shrimp species that should be monitored to prevent their mixed use in food. PMID- 27765082 TI - Investigation of the Virulence Factors and Molecular Characterization of the Clonal Relations of Multidrug-Resistant Acinetobacter baumannii Isolates. AB - Multidrug-resistant (MDR) Acinetobacter baumannii infections are a great public health concern and demand continuous surveillance and antibiotic stewardship. Virulence traits and the pathogenicity of Acinetobacter are less studied compared with the molecular epidemiological and antibiotic resistance profile of this organism. In our present study, we investigated the primary characteristics contributing to the virulence of MDR A. baumannii isolates and compared them with avirulent isolates. A total of 32 well-characterized MDR A. baumannii clinical isolates and 22 avirulent isolates from a healthy individual were subjected to multilocus sequence typing and polymerase chain reaction (PCR) for a variety of biofilm-associated genes. Additionally, a number of in vitro tests were performed to determine virulence properties. Isolates were found to relate to six sequence types (STs) in which the dominant sequence was ST557 in clinical isolates, followed by ST195 and ST208. However, ST557 and ST222 were absent in avirulent isolates. All STs belonged to clonal complex 2 and clonal lineage 2, which is considered to be a universal clone. PCR analysis showed that most clinical isolates were positive for biofilm-forming genes, such as csu and bap, and also carried pga and ompA genes, which were less common in avirulent isolates. Biofilm formation, phospholipase C production, hemolytic activity, and acinetobactin production occurred significantly more frequently in clinical isolates compared with avirulent isolates. Though A. baumannii clonal lineages showed common virulence traits, they differed in virulent phenotype expression. These findings further support previous studies indicating that A. baumannii is a versatile pathogen with an ability to acquire iron and survive in iron-limiting conditions, highlighting the acinetobactin-mediated iron acquisition mechanisms involved in the pathogenesis of A. baumannii infections. PMID- 27765083 TI - Determination of Diphenylether Herbicides in Water Samples Using Dispersive Liquid-Liquid Microextraction Combined with High-Performance Liquid Chromatography. AB - Shaker-assisted dispersive liquid-liquid microextraction (SA-DLLME) and surfactant dispersive liquid-liquid microextraction (SDLLME) have been developed to determine five diphenylether herbicides in water samples using high performance liquid chromatography with photodiode array detection (HPLC-PDA). For SA-DLLME, an up-and-down shaker-assisted emulsification was used. Extraction was complete in 3 min. Only 30 MUL of decyl acetate was required, without a dispersive solvent. The linear range was from 2 to 1000 MUg L-1, the coefficient of determination (r2) was better than 0.9992, and the limit of detection (LOD) was from 0.62 to 1.74 MUg L-1. The relative recovery (RR) ranged from 90 to 102% for river water, 88 to 104% for lake water, and 93 to 102% for irrigating water. In SDLLME, a microsyringe was used to withdraw and discharge a mixture consisting of an extraction solvent and 1 mg L-1 Tween 60 as a surfactant four times within 10 s to form an emulsified solution. The linear range for the target compounds was from 2 to 1000 MUg L-1. The LODs were between 0.72 and 1.38 MUg L-1. The RR ranged from 95 to 108% for river water, 96 to 109% for lake water, and 86 to 114% for irrigating water. PMID- 27765084 TI - Multiresidue Analysis of Five Neonicotinoid Insecticides and Their Primary Metabolite in Cucumbers and Soil Using High-Performance Liquid Chromatography with Diode-Array Detection. AB - A sensitive, selective, and validated HPLC-diode-array detection method was developed for the simultaneous determination of five neonicotinoid insecticides acetamiprid, imidacloprid, nitenpyram, flonicamid, and thiacloprid-and their primary metabolite, 6-chloronicotinic acid, in cucumbers and soil based on the quick, easy, cheap, effective, rugged, and safe (QuEChERS) technique as a pretreatment procedure. In the QuEChERS procedure, cucumber samples were extracted with acetonitrile and cleaned using C18, whereas soil samples were extracted with an acetonitrile-dichloromethane mixture (1 + 2). The HPLC conditions were optimized by separating neonicotinoids using an acetonitrile water mixture (25 + 75) and a Synergi Hydro RP C18 column. Matrix-matched calibration standards were prepared in cucumber and soil to eliminate any matrix interference. RSDs were <=9% in all recovery tests. LODs and LOQs for the five neonicotinoids were in the ranges of 0.006-0.122 and 0.018-0.366 MUg/g, respectively. This method was successfully applied to determine residues, the rate of disappearance of the five neonicotinoids from cucumber and soil, and the half-lives of the neonicotinoids. PMID- 27765086 TI - [Treatment of patients with refractory wounds]. AB - Experienced over twenty years of theoretical accumulation and ten years of clinical exploration, wound repair speciality in our country is in the phase of enhancing comprehensive ability. Our wound healing experts team has successfully carried out treatment of suspected bacterial weapon related chronic wounds, which lasted up to more than 70 years, through multilateral cooperation. We summarized the surgical program of wound fibrous tissue removal and scalp as donor sites for long-term non-healing wounds in the elderly. At the same time, we explored the operating mode of internet-based technology to extend diagnosis and treatment of chronic wounds in remote areas, which was with efficiency and convenience. PMID- 27765085 TI - Differential Expression of MicroRNAs in Hepatitis C Virus-Mediated Liver Disease Between African Americans and Caucasians: Implications for Racial Health Disparities. AB - African Americans (AAs) have higher hepatocellular carcinoma (HCC) mortality rates than Caucasian Americans (CAs). Chronic hepatitis C virus (HCV) infection leads to cirrhosis and HCC. HCV infection is highly prevalent in the AA population compared to other racial groups. AAs are also less likely to naturally clear HCV, potentially contributing to higher prevalence of HCV. However, the explanation for this disparity is currently unknown. Circulating microRNAs (miRNAs) in the blood are emerging as biomarkers for pathological conditions. Expression analysis of miRNAs in major racial groups would be important for optimizing personalized treatment strategies. Here we assessed the differential expression of circulatory miRNAs from HCV-infected AA and CA patients. We identified increased expression of miR-146a, miR-150, and miR-155 in HCV-infected AA patient sera compared to that of CA. Further analysis demonstrated that these miRNAs were significantly elevated in AA patients diagnosed with HCV-mediated HCC. Higher expression of miR-150 was also noted in cirrhosis and HCC in AA patients, which may serve as a predictor of liver disease progression in this population. The differential expression of miRNAs suggests that these miRNAs and their target genes could be useful to gain further mechanistic insight of racial disparity associated with HCV-mediated pathogenesis. PMID- 27765087 TI - [Wound healing is still a game of " blind men and an elephant"]. AB - The wound healing includes non-healing and overhealing of the wounds. The results of wound healing are well known by people such as non-healing of the diabetic ulcer or hypertrophic scar after deep burn. In this issue, three papers involve in wound healing, one about autologous adipose-derived mesenchymal stem cells injected into wound or scar of rabbit ear, one about severe hypoxia and hypoalbuminemia inducing human hypertrophic scar derived fibroblast apoptosis in vitro, and another about the dysfunction of protein kinase B/mammalian target of rapamycin signaling pathway contributing to the pathophysiological characteristics of diabetic skin and non-healing wound. The basic problem of hypertrophic scar study is lacking an ideal animal model. Although rabbit ear model or red Duroc pig model has been used widely for study on hypertrophic scar, they can not fully represent human dermal fibrosis after deep trauma on the skin. I recommend A novel nude mouse model of hypertrophic scarring using scratched full thickness human skin grafts recently published in Advances in Wound Care to the readers. The author emphasizes that the wound healing study is still in the situation like the game of " blind men and an elephant" . PMID- 27765088 TI - [Effects of local transplantation of autologous adipose-derived mesenchymal stem cells on the formation of hyperplastic scar on rabbit ears]. AB - Objective: To investigate the effects of local transplantation of autologous adipose-derived mesenchymal stem cells (ADSCs) on the formation of hyperplastic scar on rabbit ears. Methods: ADSCs were isolated from inguinal fat of six New Zealand rabbits and then sub-cultured. ADSCs of the third passage of each rabbit were used in the following experiments. Six full-thickness skin defect wounds with diameter of 6 mm on the ventral surface of every rabbit ear were made. Wound healing and local-tissue proliferation were observed, and complete epithelization time of wounds and formation time of hyperplastic scar were recorded. The wounds on left ears were selected as group ADSCs, and the wounds on right ears were selected as control group, with 36 wounds in each group. After the complete epithelization of wounds (post injury day 25), 0.2 mL bromodeoxyuridine (BrdU) labeled autologous ADSCs with the concentration of 5*106 per milliliter were injected into each wound of the rabbit of group ADSCs, while the same amount of phosphate buffer solution was injected into each wound of the rabbit of control group. The frequency of injection was once every 5 days, totally for 3 times, and the latter 2 times were injected into scars generated from healed wound. Hyperplastic scars of rabbits of two groups were harvested on the fifth day after the third injection, then the morphology was observed by HE staining, and the arrangement of collagen in hyperplastic scar was observed by VG staining. The distribution of BrdU-labeled ADSCs in the hyperplastic scar was observed with fluorescence microscope. The protein content of type I collagen, type III collagen, transforming growth factor beta1 (TGF-beta1), and decorin in hyperplastic scar were detected by enzyme-linked immunosorbent assay, and the mRNA expression of decorin and TGF-beta1 in hyperplastic scar were tested by real time fluorescent quantitative reverse transcription-polymerase chain reaction. Data were processed with paired t test. Results: (1) The complete epithelization time of wounds of rabbits' ears was (20.0+/-2.0) d post injury, and hyperplastic scars were formed on post injury day 35.0+/-2.2. On post injury day 40, hyperplastic scars of rabbits of control group were still obvious, while those of group ADSCs became smaller, flat, soft, and light colored. (2) Compared with those in control group, epithelial cell layers and the number of nucleated cells in corium layer of hyperplastic scars of rabbits of group ADSCs were increased, and epithelium foot like and dermal papilla like structures were observed. The collagen density of hyperplastic scars of rabbits of control group was tight and arranged disorderly, while that of group ADSCs were decreased significantly and arranged regularly as compared with that of control group. (3) On post injury day 40, BrdU-labeled ADSCs were still observed in the hyperplastic scars of rabbits of group ADSCs. (4) The protein content of type I collagen, type III collagen, TGF-beta1, and decorin in hyperplastic scars of rabbits of group ADSCs were respectively (1.40+/-0.04) and (8.18+/-0.23) MUg/L, (25.1+/-0.7) ng/L, and (4.872+/-0.101) ng/mL, and those in hyperplastic scars of rabbits of control group were respectively (2.29+/-0.05) and (12.20+/-0.38) MUg/L, (37.2+/-1.1) ng/L, and (4.143+/-0.024) ng/mL. Compared with those in control group, the protein content of type I collagen, type III collagen, and TGF-beta1 in hyperplastic scars of rabbit of group ADSCs were significantly decreased (with t values from -33.66 to -22.84, P values below 0.001), while the protein content of decorin were significantly increased (t=10.41, P<0.001). (5) Compared with those in control group, the mRNA expression of TGF-beta1 in hyperplastic scars of rabbits of group ADSCs was significantly decreased (t=4.45, P<0.01), while the mRNA expression of decorin was significantly increased (t=5.61, P<0.01). Conclusions: Autologous transplantation of ADSCs into scar of rabbit at the early stage can inhibit the formation of hyperplastic scar, promote the quality of wound healing, and the mechanism may relate to the down-regulation of TGF-beta1, type I collagen, and type III collagen and the up-regulation of decorin induced by ADSCs. PMID- 27765089 TI - [Expressions of the key proteins of the protein kinase B/mammalian target of rapamycin signaling pathway in skin tissue and wound tissue of diabetic rats]. AB - Objective: To explore the changes in the expressions of key proteins of the protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling pathway in skin tissue and wound tissue of diabetic rats, and to elucidate the associated mechanisms. Methods: Seventy-eight SD rats aged from 7 to 8 weeks were divided into diabetes group and non-diabetes group according to the random number table, with 39 rats in each group. Rats in diabetes group were intraperitoneally injected with 20 mg/mL streptozotocin fluid in the dose of 65 mg/kg (dissolved in citrate buffer solution) for once to establish the model of diabetes mellitus. Rats in non-diabetes group were injected with the equivalent volume of citrate buffer solution in the same way. Three rats of each group were respectively selected in each week from post injection week (PIW) 1 to 8 for collection of full-thickness skin samples on the back with area approximately of 1.0 cm*1.0 cm to determine epidermal thickness with HE staining. Fifteen rats of each group were inflicted with full-thickness skin defect by resection of skin as above in PIW 1. Three rats of each group were respectively sacrificed immediately after injury and on post injury day (PID) 1, 3, 5 and 7. One piece of skin tissue around the wound edge in each rat was cut off immediately after injury, and wound tissue in each rat was cut off from PID 1 to 7. One part of the tissue was used for determination of protein expression levels of Akt, phosphorylated Akt, mTOR, and phosphorylated mTOR in skin tissue and wound tissue with Western blotting. Surplus tissue was used for observation of expressions of phosphorylated Akt and vimentin in skin tissue and wound tissue with immunofluorescent staining. Data were processed with analysis of variance of factorial design and multiple t test. Results: (1) The epidermal thicknesses in rats between the two groups were similar in PIW 1 and 2 (with t values respectively 0.25 and 1.33, P values above 0.05). From PIW 3 on, the epidermal thicknesses were significantly thinned in rats of diabetes group as compared with those of non-diabetes group (with t values from 4.44 to 9.71, P<0.05 or P<0.01). (2) Compared with those in skin tissue immediately after injury, the protein expression levels of Akt, phosphorylated Akt, mTOR, and phosphorylated mTOR in wound tissue of rats in non diabetes group were increased remarkably from PID 1 to 7 (except for mTOR on PID 3, with t values from 3.75 to 21.44, P<0.05 or P<0.01). Compared with those in skin tissue immediately after injury, the protein expression levels of Akt and mTOR in wound tissue of rats in diabetes group were not significantly changed from PID 1 to 7 (except for mTOR on PID 1, with t values from 0.03 to 2.32, P values above 0.05), but the protein expression levels of phosphorylated Akt and phosphorylated mTOR in wound tissue were increased remarkably from PID 1 to 7 (except for phosphorylated Akt on PID 1, with t values from 3.79 to 8.11, P<0.05 or P<0.01). The protein expression levels of Akt in skin tissue of rats between the two groups were similar immediately after injury (t=0.66, P>0.05). However, the protein expression level of phosphorylated Akt in skin tissue of rats in diabetes group immediately after injury (0.310+/-0.035) was significantly decreased as compared with that in non-diabetes group (0.790+/-0.032, t=6.20, P< 0.05). Compared with those in non-diabetes group, the protein expression levels of mTOR and phosphorylated mTOR in skin tissue of rats in diabetes group immediately after injury and the protein expression levels of Akt, phosphorylated Akt, mTOR, and phosphorylated mTOR in wound tissue from PID 1 to 7 were all significantly decreased (with t values from 3.52 to 13.44, P<0.05 or P<0.01). (3) Compared with those in skin tissue immediately after injury, the expressions of phosphorylated Akt and vimentin in wound tissue of rats in the two groups from PID 1 to 7 presented a gradually increased tendency, however, the expressions of these indexes in skin tissue and wound tissue of rats in diabetes group were significantly weaker than those in non-diabetes group. Conclusions: Trauma can stimulate activation of Akt/mTOR signaling pathway, and upregulate the expression of key proteins. The attenuation of this signaling pathway in skin tissue and wound tissue of diabetes mellitus may be the key mechanism for causing impaired healing of wound. PMID- 27765090 TI - [Effects of severe hypoxia and low concentration of serum protein on the function of human hypertrophic scar fibroblasts]. AB - Objective: To simulate the environmental factors during the process of formation and evolution of hypertrophic scar, so as to explore the effects of moderate and severe hypoxia and low concentration of serum protein on the function of human hypertrophic scar fibroblasts (HSFs). Methods: Human HSFs were routinely cultured. Cells of the 3rd to the 6th passage were divided into 10.0% oxygen+ 10.0% fetal calf serum (FCS), 5.0% oxygen+ 5.0% FCS, and 0.5% oxygen+ 0.5% FCS groups according to the random number table. After being cultured with DMEM nutrient solution with no FCS for 24 h, the cells were cultured with the corresponding volume fraction of oxygen and FCS. Cell proliferation activity was determined with methyl-thiazole-tetrazolium assay (denoted as actual cell number). Content of total collagen was detected with Sirius red staining method (denoted as absorbance value). Protein expression levels of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), transforming growth factor beta1 (TGF-beta1), B-cell lymphoma 2 (Bcl-2), and P53 were determined with Western blotting (denoted as ratio of gray value). Cell apoptosis rate was detected by in situ end labeling method. The sample numbers of each group in the above experiments were all 3. Data were processed with Kruskal Wallis test and Dunnett test. Results: (1) Compared with 11 000+/-1 306 in 10.0% oxygen+ 10.0% FCS group, the cell proliferation activity was higher in 5.0% oxygen+ 5.0% FCS group (13 290+/-1 500, P<0.05), but lower in 0.5% oxygen+ 0.5% FCS group (6 999+/-765, P<0.05). (2) Compared with 0.039 6+/-0.004 2 in 10.0% oxygen+ 10.0% FCS group, the content of total collagen of cells was higher in 5.0% oxygen+ 5.0% FCS group (0.051 6+/-0.005 1, P<0.05), but lower in 0.5% oxygen+ 0.5% FCS group (0.015 6+/-0.002 4, P<0.05). (3) Compared with those in 10.0% oxygen+ 10.0% FCS group, the protein expression levels of HIF-1alpha, VEGF, TGF-beta1, and Bcl-2 were increased (with P values below 0.05), with no obvious difference in protein expression level of P53 in 5.0% oxygen+ 5.0% FCS group (P>0.05), whereas the protein expression levels of HIF-1alpha, VEGF, TGF-beta1, and Bcl-2 were decreased (with P values below 0.05), while the protein expression level of P53 was increased in 0.5% oxygen+ 0.5% FCS group (P<0.05). (4) Compared with (1.2+/-0.9)% in 10.0% oxygen+ 10.0% FCS group, the cell apoptosis rate in 5.0% oxygen+ 5.0% FCS group showed no significant difference [(2.6+/-0.9)%, P>0.05], while it was significantly increased in 0.5% oxygen+ 0.5% FCS group [(13.3+/-4.1)%, P<0.05]. Conclusions: Severe hypoxia and low concentration of serum protein can inhibit proliferation activity and production of total collagen of human HSFs and induce their apoptosis. PMID- 27765091 TI - [Multicenter epidemiological investigation of hospitalized children with severe burn]. AB - Objective: To analyze the epidemiological characteristics of hospitalized children with severe burn from several regions in China during 3 years, so as to provide evidence for prevention of burns in children. Methods: Relying on the entry system of epidemiology data and biological sample of severe burn from multicenter in clinic, medical records of children with severe burn, aged 18 and under, hospitalized in 6 burn wards from February 2012 to February 2015 were collected. The children were divided into 5 age brackets: less than or equal to 1 year old, more than 1 year old and less than or equal to 3 years old, more than 3 years old and less than or equal to 6 years old, more than 6 years old and less than or equal to 12 years old, more than 12 years old and less than or equal to 18 years old. Meanwhile the children were divided into rural and urban children according to their residences. Data of gender and residence of children in the 5 age brackets, cause of injury, location of injury, total burn area, wound site, inhalation injury and combined injury, and source of hospitalization expenses of children in the 5 age brackets and two types of residence, and outcome and length of hospital stay of the children were analyzed. The cause of injury of children in different location of injury was analyzed. In addition, they were divided into 2 age brackets: less than or equal to 6 years old and more than 6 years old and less than or equal to 18 years old, and then incidences of hand and foot burn injury were compared. Data were processed with chi-square test, and the correlation between age and total burn area was processed with Spearman correlation analysis. Results: Four hundred and forty out of 1 106 inpatients with severe burn were children, accounting for 39.8% who were included in the system. (1) The majority of children were male (270, 61.4%). The number of children more than 1 year old and less than or equal to 3 years old ranked the first (222, 50.5%) in the 5 age brackets. The ratio of children from rural areas to that from urban areas was 2.9?1.0. There were no statistically significant differences in both gender and residence of children among the 5 age brackets (with chi2 values respectively 7.649 and 9.399, P values above 0.05). (2) Scald was the most common cause of burn. There was statistically significant difference in injury cause of children among the 5 age brackets (chi2=136.307, P<0.001). There was no statistically significant difference in injury cause of children among the two types of residence (chi2=5.164, P>0.05). (3) Private house was the most common location of injury. There was statistically significant difference in location of injury of children among the 5 age brackets (chi2=124.930, P<0.001). There was no statistically significant difference in location of injury of children among the two types of residence (chi2=3.364, P>0.05). There was statistically significant difference in injury cause of children in different location of injury (chi2=118.284, P<0.001). (4) Most of children were with total burn areas from 10% to 39% total body surface area. There was statistically significant difference in total burn area of children among the 5 age brackets (chi2=103.568, P<0.001). There was positive correlation between age and total burn area (r=0.177, P<0.001). There was no statistically significant difference in total burn area of children among the two types of residence (chi2=16.213, P>0.05). (5) Trunk, lower extremity, and upper extremity were the most common wound sites, respectively. There was statistically significant difference in wound site of children among the 5 age brackets (chi2=45.674, P=0.019). There was statistically significant difference in incidence of hand and foot burn between children less than or equal to 6 years old and children more than 6 years old and less than or equal to 18 years old (with chi2 values respectively 29.188 and 14.612, P values below 0.01). There was no statistically significant difference in wound site of children among the two types of residence (chi2=8.515, P>0.05). (6) Twenty-seven children suffered inhalation injury. The main age bracket was more than 12 years old and less than or equal to 18 years old (8 children). The main residence was rural area (18 children). The main cause of inhalation injury was flame burn (23 children). Nine children suffered combined injury, among which the children more than 12 years old and less than or equal to 18 years old accounted for the highest ratio (5 children), and the urban children accounted for higher ratio (5 children). (7) Among the 437 children, most of their hospitalization expenses were at their own expense. There was statistically significant difference in the source of hospitalization expenses of children among the 5 age brackets (chi2=17.917, P=0.001). There was no statistically significant difference in the source of hospitalization expenses of children among the two types of residence (chi2=0.749, P>0.05). (8) Among the 437 children, 34 children abandoned treatment and were discharged from hospital, attributed to lack of funding. Seventy-eight children were discharged with a better health condition and 347 were cured. The condition of 6 children worsened and 6 children died. Mean length of hospital stay was 28.6 days for all the children, and 8.8 days for the deteriorated and dead children. Conclusions: Children were the major group of patients with severe burn in China. Male children less than or equal to 6 years old were common with scald as the major cause of injury, private house as the major location of injury, and trunk, lower and upper extremity as the most common wound sites, their own expenses as the major source of hospitalization expenses. There were statistically significant differences in cause of injury, location of injury, total burn area, wound site, and hospitalization expenses source of children among the 5 age brackets. PMID- 27765092 TI - [Acute toxicity and bio-distribution of silver nitrate and nano-silver with different particle diameters in rats]. AB - Objective: To explore the acute toxic effect and the cumulative target organ of silver nitrate and nano-silver with two different particle diameters in rats. Methods: Thirty-six adult SD rats were divided into small particle size nano silver group (SNS), large particle size nano-silver group (LNS), silver nitrate group (SN), and control group (C) according to the random number table, with 9 rats in each group. The rats of the four groups were respectively injected with 10 mg/mL nano-silver solution (particle diameter of 20 nm, prepared by saline) in silver dose of 30 mg/kg by tail vein for once, 10 mg/mL nano-silver solution (particle diameter of 100 nm, prepared by saline) in silver dose of 30 mg/kg, 1.67 mg/mL silver nitrate solution (prepared by glucose solution) in silver dose of 3 mg/kg, and 30 mg/mL polyvinylpyrrolidone solution (prepared by saline) in dose of 90 mg/kg. (1) Toxicity test. The general observation was performed within 14 days after injection, and the deviation between value of body mass before injection and each of that on post injection day (PID) 1, 7, and 14 were respectively recorded. On PID 1, 7, and 14, 3 rats of each group were harvested for determination of serum content of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, and albumin by fully automatic biochemical analyzer. Then the rats were sacrificed immediately, and heart tissue, liver tissue, spleen tissue, lung tissue, kidney tissue, and brain tissue were collected to calculate the organ coefficient. Organ samples with obvious changes in organ coefficient were collected for histopathological observation by HE staining, with 3 samples in each group at each time point. (2) Bio-distribution. The specimens of heart, liver, spleen, lung, and kidney of rats from groups SNS, LNS, and SN were collected for detection of silver content by inductively coupled plasma mass spectrometry, with 3 samples in each group at each time point. Data were processed with analysis of variance of factorial design, LSD test, and Dunnett's T3 test. Results: (1) The general condition of rats in groups C and SN after injection were normal. The state of rats of groups SNS and LNS was poor with black secretion in the eye and other phenomena on PID 1, which recovered from PID 3 on. (2) The deviations between values of body mass before injection and that on PID 14 in rats of groups LNS and SN were significantly decreased as compared with deviation of group C (with P values below 0.01), but deviation of group SNS was not significantly changed (P>0.05). The deviations between values of body mass before injection and each of that on PID 1 and 7 in rats in the other three groups were similar to those in group C (with P values above 0.05). (3) Compared with those in group C, the serum content of total protein of rats in group SN on PID 1 was significantly decreased, and liver coefficient was significantly increased (with P values below 0.05). On PID 1, the serum content of ALT of rats in group LNS was (61.0+/-8.7) U/L, which was significantly higher than that in group C [(40.0+/-4.6) U/L, P<0.01]. Compared with those in group C [(126.0+/-3.5) U/L and 4.05+/-0.23], the serum content of AST of rats in groups SNS and LNS on PID 1[(249.7+/-107.2) and (237.0+/-38.3) U/L] was significantly increased, and liver coefficients (3.50+/-0.38 and 3.31+/-0.07) were significantly decreased, with P values below 0.05. Compared with those in group C [(69.2+/-4.8) U/L and 4.32+/-0.39], the serum content of AST of rats in groups SNS and LNS on PID 7 [(181.0+/-51.5) and (167.7+/-16.5) U/L] was also significantly increased, and liver coefficients (3.55+/-0.18 and 3.62+/-0.21) were also significantly decreased, P<0.05 or P<0.01. On PID 14, the four liver biochemical indexes in serum and all organ coefficients of rats in the other three groups were similar to those in group C (with P values above 0.05). (4) The liver of rats in group SN had slight degeneration on PID 1, the liver cells around the central vein of liver of rats in group SNS had slight degeneration on PID 7, and the liver cells got severely eosinophilic degeneration in liver of rats in group LNS on PID 7. There was no significant pathological change in the liver of rats in each group at the rest time points. (5) The silver content of lung and kidney in rats of group SNS on PID 1, that of spleen and kidney in rats of group LNS on PID 1, and that of heart and kidney in rats of groups LNS and SNS on PID 7 was significantly less than that of group SN (with P values below 0.05). The silver content of liver and spleen in rats of group SNS on PID 14 was significantly more than that of group SN (with P values below 0.05). Compared with that of group SN, the silver content of lung on PID 1 and liver on PID 7 in rats of group LNS was significantly increased (with P values below 0.05). On PID 14, there was no significant change in the silver content of all organs of rats between group SN and group LNS (with P values above 0.05). The silver content of heart, lung, and kidney on PID 1 and heart on PID 7 in rats of group LNS was significantly more than that of group SNS (with P values below 0.05). On PID 14, the silver content of each organ of rats in group SNS was close to that in group LNS (with P values above 0.05). Conclusions: Silver nitrate and nano-silver with two different particle diameters have a short acute toxic effect on the liver of rats, and the liver has certain ability of self-healing. Nano-silver is mainly accumulated in the liver. The distribution of nano-silver with large particle diameter in organs is more widely than that of nano-silver with small particle diameter. PMID- 27765093 TI - [Effects of microporous polysaccharide on foreign body reaction induced by subcutaneously imbedding expanded polytetrafluoroethylene in mice]. AB - Objective: To observe the effects of early applying of microporous polysaccharide on foreign body reaction induced by subcutaneously imbedding expanded polytetrafluoroethylene (e-PTFE) in mice. Methods: Ten wide type adult C57BL/6J mice were collected and made a full-thickness skin incision on both sides of their back. The two incisions on the back of each mouse were divided into two groups according the random number table, with 10 incisions in each group. A tube shaped e-PTFE was imbedded into each incision in microporous polysaccharide group, and then 0.03 g microporous polysaccharide was evenly sprayed in the cavity. Whereas, a tube-shaped e-PTFE was imbedded into each incision in control group without other treatment. The incisions in two groups were performed with conventional full-thickness suture. On post operation day (POD) 14, the e-PTFE surrounded with fibrous capsule in each incision of two groups was taken out, and then fibrous capsule tissue was harvested. The thickness of fibrous capsule was observed and measured with HE staining. Collagen fiber distribution in fibrous capsule tissue was observed with Masson staining to calculate the collagen fiber index. Neovascularization and macrophage infiltration in fibrous capsule tissue were observed respectively with immunohistochemical staining, and the numbers of new vessels and macrophages were counted. Data were processed with t test. Results: On POD 14, the thickness of fibrous capsule surrounding e-PTFE imbedded into the incision of microporous polysaccharide group was (127+/-19) MUm, which was significantly thinner than that of control group [(250+/-35) MUm, t=4.13, P<0.05]. On POD 14, the collagen fiber index of fibrous capsule tissue surrounding e-PTFE imbedded into the incision of microporous polysaccharide group was 0.500+/-0.003, which was significantly higher than that of control group (0.488+/-0.004, t=5.00, P<0.05). On POD 14, the number of new vessels in fibrous capsule tissue surrounding e-PTFE imbedded into the incision of microporous polysaccharide group was 19+/-3 per 400 fold visual field, which was significantly more than that of control group (11+/-3 per 400 fold visual field, t=2.05, P<0.05). On POD 14, the number of macrophages in fibrous capsule tissue surrounding e-PTFE imbedded into the incision of microporous polysaccharide group was 64+/-5 per 400 fold visual field, which was close to that of control group (66+/-7 per 400 fold visual field, t=0.78, P>0.05). Conclusions: Topically applying microporous polysaccharide can reduce the formation of fibrous capsule after subcutaneous imbedding of e-PTFE in mice, and it can improve the collagen deposition and angiogenesis but not impact on macrophage infiltration. PMID- 27765094 TI - [Advances in the research of nutrition therapy in patients with severe burn]. AB - Patients with severe burn are characterized by strong oxidative stress and intense inflammatory response, which will cause metabolic disorder. Therefore, nutrition therapy is very important for severe burn. Nutrition therapy includes enteral nutrition (EN) and parenteral nutrition, and EN has the unique advantages. In recent years, more and more researchers focused on the EN for severe burn injuries, but there were still some confusing problems needing to solve. This article reviews the recent research about nutrition therapy for severe burn, including the route of feeding, energy requirements, and supplements of protein, carbohydrates, and microelements, and so on, so as to clarify some confusing questions about nutrition therapy for severe burn in clinical practice. PMID- 27765096 TI - [Advances in the research of promotion effect of Aloe vera on wound healing and its clinical use]. AB - Aloe vera has been widely investigated and used as folk medicine since ancient time. Biologically active substances in its gel include polysaccharides, glycoprotein, enzymes, anthraquinones or phenolic compounds, vitamins, minerals, and so on, which play important roles in anti-inflammatory response, antimicrobial, antiviral, antioxidant activity, immunoregulation effects, and especially in wound healing. In this paper, we review the advances in the mechanism and clinical application of Aloe vera and its extract on wound healing, so as to provide new ideas for the treatment of various kinds of wounds. PMID- 27765095 TI - [Antimicrobial applications and toxicity of nano-silver in the medical field]. AB - With the rapid development of modern science and technology, the application of nanomaterial is ubiquitous in our daily life and medical field, in which the application related to nano-silver is more extensive. On one hand, it can make positive effects, such as anti-bacteria, anti-virus, anti-fungi, anti-parasitic infection and anti-tumor. In particular, its anti-bacterial activity in some acute or chronic treatment of infected wounds is more prominent. The application in diseases of gynecology, orthopedics, cardiovascular system, oral cavity, and ophthalmology is increasing. On the other hand, it can induce negative impacts and potential toxicity. It can be harmful to skin, gastrointestinal tract, respiratory tract, cardiovascular system, and so on. This article summarizes the antimicrobial application of nano-silver on treatment of diseases, its potential toxic effects on some organs or systems, and the possible toxic mechanism, as well as makes prospects of the research trends of nano-silver in future. PMID- 27765097 TI - [Advances in the research of application of collagen in three-dimensional bioprinting]. AB - As a new industrial technology with characteristics of high precision and accuracy, the application of three-dimensional bioprinting technology is increasingly wide in the field of medical research. Collagen is one of the most common ingredients in tissue, and it has good biological material properties. There are many reports of using collagen as main composition of " ink" of three dimensional bioprinting technology. However, the applied collagen is mainly from heterogeneous sources, which may cause some problems in application. Recombinant human source collagen can be obtained from microorganism fermentation by transgenic technology, but more research should be done to confirm its property. This article reviews the advances in the research of collagen and its biological application in three-dimensional bioprinting. PMID- 27765098 TI - [CT study on the development of facial nerve canal in children]. AB - Objective: To assess the characteristics of facial nerve canal between normal anatomy and dysplasia of children in different ages. Methods: A total of 492 health ears were divided into six groups, neonatal group (<1 m , n=42), infancy group(1 m-1 y, n=106), toddler group(1-3 y, n=102), preschool group (3-6 y, n=100), school group(6-10 y, n=60)and adolescent group (10-14 y, n=82). The length and diameter of facial nerve canal and that angles of first and second genu were measured with CT in each group. Results: 1The lengths of facial nerve canal in neonatal and infancy group were shorter than other four groups, especially in the mastoid segments of facial nerve canal. The lengths of mastoid segments in neonatal, infancy, toddler, preschool, school and adolescent groups were 5.03+/-0.84, 6.25+/-1.40, 8.34+/-1.38, 9.70+/-1.34, 10.84+/-1.41 and 12.17+/ 1.83 mm, with P<0.05, respectively. After school age, the lengths of labyrinthine and tympanic segment grew slowly or developed completely (P>0.05). 2 The diameter of labyrinth and tympanic segment in neonatal group were narrower than other five groups (P<0.05), but no significant difference among them in other groups (P>0.05). 3The dysplasia of facial nerve canal were occurred on 978 locations. Among them, the percentage of dehiscence, aberrance, partially expanding and bifurcation were 72.9%(713/978), 5.1%(50/978), 18.9%(185/978) and 3.1%(30/978) respectively. The percentage of dehiscence in geniculate fossa segment was decreased significantly with age (neonatal group 85.7%(36/42), infancy group 59.4%(63/106), toddler group 39.2%(40/102), preschool group 33%(33/100), school group 30%(18/60)and adolescent group 26.8%(22/82), with P<0.05). Except the dehiscence of geniculate fossa and mastoid segment, there was no significant difference in the occurrence rate of the other variants (P>O.05). Conclusions: The growth of length and dehiscence in labyrinth segment of facial nerve canal are significant in difference ages. The changes of diameter and angles of first and second genu in facial nerve canal, and the rate of other dysplasia are individual. PMID- 27765099 TI - [Exclusive endoscopic transsuprameatal approach for the pure intracanalicular acoustic neuroma]. PMID- 27765100 TI - [Therapy of adult-onset laryngeal papilloma: integrallty submucosal dissection of the tumor by CO2 laser]. AB - Objective: To evaluate the feasibility and efficacy of the integrallty submucosal resection of adult-onset laryngeal papilloma by CO2 laser. Methods: A group of 64 cases (36 males and 28 females, multipe lesions 54 cases and single lesion 10 cases, aged 18-75 years, mean age 43.13 years) with adult-onset laryngeal papilloma encountered in the first affliated hospital of Sun Yatsen university from 2009 to 2015 was retrospectively analyzed. All cases were treated with integrallty submucosal dissection of the tumor by CO2 laser, and observed the changes of tumor integral scope, inter-operative, operative processes, postoperative voice quality, postoperative scarring, and the tracheotomy conditions, which were analysed and evaluated. Results: A total of 64 patients were followed up from 1 year to 5 years. Preoperative tumor integral scope of these patients averaged of 7.00. A total of 62 cases kept 0 score of the tumor integral scope for at least one year, which lead to a clinical cure rate of 96.9%. The inter-operative averaged of 25.7 months. The total operative processes of these patients were 87 times (mean time 1.36). Four cases resulted in postoperative scarring. However these was a good result in postoperative voice quality with a mean score 4.25. As to the changes of tumor integral scope, all cases got a declining score (mean score 6.72), which resulted in a remission rate of 100%. Conclusion: The integrallty submucosal dissection of adult-onset 1aryngeal papilloma by CO2 laser was an effective way to reduce the tumor integral scope; lengthen their inter-operative; decrease the operative processes, avoid the occurrence of tracheotomy; and improve the postoperative voice quality. Most of the patients could even be cured ultimately. PMID- 27765101 TI - [Nasopharyngeal changes in 8-13 years old healthy children in China: a longitudinal study]. AB - Objective: Nasopharynx is an important compartment of the upper airway. It is closely associated with the characteristic craniofacial skeletal pattern related to sleep breathing. The present study aimed to investigate the growth pattern of the nasopharynx during rapid puberty growth period. Methods: Thirty non-snoring children (aged 8 to 11 years old) were selected by means of questionnaires and clinical examination. Periodic yearly follow up using MRI, lateral cephalogram, and polysomnograph (PSG) was done in these children. Fifty-one final mixed longitudinal samples were consisted of 23 children completed three consecutive follow-up, and 5 children completed two consecutive follow-up. The yearly changes of the nasopharynx and craniofacial structures were measured. ANOVA was used to evaluate the yearly growth of the nasopharynx. Correlated analysis was used to explore the potential influencing factors of craniofacial structures. Results: The rapid growth period of the nasopharynx located in the age range of 8-10 years old, during which the transverse dimension of the nasopharynx developed rapidly, while the rapid development of the sagittal dimension of the nasopharynx was around 12-13 years old. The growth of the nasopharynx was continuous. The changes in the cross-sectional area of the nasopharynx (?CSA) was positively correlated with the changes in distance between mandible of glossopharyngeus (?M), distance of hyoid to cervical anterior surface (?H-CVP), and anterior pharyngeal distance of glossopharyngeus (?AD) (r=0.363, 0.363, 0.323, respectively, all P<0.05). The changes in the volume of the nasopharynx (?V) was positively correlated with the changes in upper facial height (?N-ANS), ?M, and ?AD (r=0.336, 0.413, 0.478, respectively, all P<0.05). The changes in the sagittal dimension of the nasopharynx (?S) was negatively correlated with angulation in supramental and anatomical horizontal line (?SNB) (r=-0.322, P=0.045). The changes in the transverse dimension of the nasopharynx (?T) was negatively correlated with the changes in adenoid (?A) (r=-0.411, P=0.009). Conclusions: The growth and development of the nasopharynx was early and continuous, which could be affected by the development of either maxilla or mandible. PMID- 27765103 TI - [A case of bilateral vocal cord carcinoma in situ involving anterior commissure]. PMID- 27765102 TI - [Gastric pull-up reconstruction after pharyngoesphagectomy for advanced hypopharyngeal or cervical esophageal squamous cell carcinoma]. AB - Objective: To analyze the clinical results of gastric pull-up reconstruction following total pharyngoesophagectomy. Methods: A total of 90 patients with hypopharyngeal or cervical esophageal cancinoma who underwent gatric pull-up reconstruction after pharyngoesophagectomy between June 2006 and June 2015 were reviewed retrospectively. Clinical data were analyzed. Rates of survival, recurrence and complicates were calculated with SPSS software. Results: Of 90 patients, 8 patients had hypopharyngeal cancinoma invading cervical esophagus, 51 patients had cervical esophageal carcinoma, and 31 patients had hypophageal and esophageal multiple parimary carcinomas. Forty patients were treated with surgery alone, 29 patients with planned surgery, and 21 patients with salvage surgery. After follow up of 6-104 months with a median of 22 months, 54 patients died and the total 3-year survival rate was 36.3%. Seventeen patients developed local recurrences and 10 patients cervical or mediastinal lymph node metastasis (LNM). The 3-year survival rates of patients with and without recurrence or LNM were respectively 5.9%, and 45.7% (chi2=11.564, P=0.001). Twenty-three patients developed distant metastasis. The 3-year survival rate of patients with and without distant metastasis were respectively 22.9% and 41.8% (chi2=4.534, P=0.033). Multivariate analysis showed local recurrence and distant metastasis as predictors for poor survival. The rates of perioperative mortality and anastomotic fistula were 3.3% (3/90) and 13.3%(12/90), respectively. Conclusions: Gastric pull-up reconstruction is a relatively safe and effective method for esophageal reconstruction after removal of hypopharyngeal or cervical esophageal carcinoma. Some patients could achieve good survival with low mortality and acceptable morbidity after multidisciplinary treatments. PMID- 27765104 TI - [Mutant Rad50 enhances killing effects of radiation on nasopharyngeal carcinoma cell line CNE1]. AB - Objective: To investigate the killing effects of radiation and mutant Rad50 transfection on human nasopharyngeal carcinoma cell line CNE1. Methods: The experimental groups included: control group, Ad-Rad50-GFP group, Ad-EGFP group, irradiation group, Ad-Rad50-GFP combined with irradiation group, and Ad-EGFP combined with irradiation group. CNE1 cells were transfected with recombinant adenoviral vector Ad-Rad50-GFP carrying mutant Rad50 gene. The expressions of Mre11, Rad50, Nbs1, and relevant constituents composing MRN complex were detected by Western Blot. Neutral comet assay was used to detect the effect of mutant Rad50 on restoration process of DNA damage. Cell growth curve was used to evaluate the growth inhibition of CNE1 by mutant Rad50 and radiation. Results: Expressions of Mre11, Rad50, and Nbs1 in cells of Ad-Rad50-GFP group were less significantly than those in control group when irradiation was completed (0.48 vs 0.62, 0.42 vs 0.5, and 0.53 vs 0.69, respectively, P<0.05) and 24 hours after irradiation (0.41 vs 0.69, 0.46 vs 0.58, and 0.34 vs 0.78, respectively, P<0.05). The mean tail moment (MTM) in Ad-Rad50-GFP plus irradiation group was higher than that in irradiation group when irradiation was completed (16.06 vs 14.8, P<0.05), 24 hours after irradiation (58.23 vs 15.89, P<0.05) and 48 hours after irradiation: (45.12 vs 11.42, P<0.05). Seven days after irradiation, the cells in Ad-Rad50-GFP plus irradiation group was less than those in control group or irradiation group (both P<0.05). Conclusion: Mutant Rad50 enhances killing effects of radiation on nasopharyngeal carcinoma cell line CNE1. PMID- 27765105 TI - [Analysis of microRNA regulatory network in cochlear hair cells with oxidative stress injury]. AB - Objective: To analysis the important genes and functions of cochlear hair cells with oxidative stress injury, by the construction of gene regulatory network which based on different miRNA in cochlear hair cells in vitro with oxidative stress injury, and to explore the molecular mechanisms of deafness based on oxidative stress injury. Method: The oxidative stress damage cochlear hair cell model was induced by 200 MUmol/L t-BHP exposure in vitro. Small RNA deep sequencing analyzed the difference expression of miRNA and contructed gene regulatory network by 6 most significant difference miRNA. The important interaction genes in regulatory network were screened and important genes function were annotated by GeneCards. Result: There were 24 different miRNAs in cochlear hair cells with oxidative stress injury by sRNA deep sequencing.Six most significant difference miRNA were: mir-1934 (logFC=2.367 947, P=2.35*10-7), mir 411 (logFC=2.093 687, P=3.13*10-6), mir-717 (logFC=1.927 67, P=3.24*10-5), mir 503 (logFC=-2.021 45, P=3.07*10-6), mir-467e (logFC=-1.953 28, P=0.000 137), and mir-699o (logFC=-1.950 06, P=0.000 517). Eleven important genes in miRNA regulatory network were: Akt1, Src, Ctnnb1, Creb1, Ccnd1, Egfr, Gsk3b, Pten, Cdh1, Fras1, and Ccnd2. Their main functions were to regulate hair cells apoptosis and proliferation by different intracellular signaling pathways. Conclusion: There are many signaling pathways (PI3K-AKT/PKB signaling pathway, AKT/PKB signaling pathway, Wnt signaling pathway, ERK signaling pathway, and Ras signaling pathway) involved in the regulation of apoptosis and proliferation in cochlear hair cells with oxidative stress injury and these signaling pathways are linked to each other to form a network. PI3K-AKT/PKB signaling pathway seems to be the most active in cochlear hair cells with oxidative stress injury. PMID- 27765106 TI - [Construction of ear tissue engineered epithelial patch]. AB - Objective: To construct tissue engineered-epithelial patches with human adipose derived mesenchymal stem cells (hADSC) and extracellular matrix scaffold (ECM), and to observe their morphological characteristics and biological behaviors. Methods: The cultured and purified hADSC were co-cultured with the ECM. The adhesion of hADSC formed sheet on the ECM were observed by the scanning electron microscopy. The activity and apoptosis of hADSC cultured on the ECM were observed by laser scanning confocal microscope. The autocrine function of hADSC were determined by qPCR(hepatoeyte growth factor, transforming growth factor-beta, epidermal growth factor). Results: hADSC proliferated actively when cultured on the ECM. The scanning electron microscopy demonstrated that the bottom of the ECM possessed smooth, with uneven thickness, widely interconnected collagen bundles. Meanwhile, it showed that hADSC had good adhesion with ECM surface and grew overlapped. The immunofluorescence revealed that hADSC proliferated stably, did not appear a large number of apoptosis when cultured on the ECM. qPCR results indicated that the autocrine function of hADSC cultured on the ECM were significantly higher than those in non-scaffold group(P<0.05). Conclusion: hADSC has good biocompatibility with ECM scaffold. hADSC grows well in the environment of ECM and has active secretion function. PMID- 27765107 TI - [Expression of mTOR/autophagy pathway in the hippocampus following cerebral ischemia/reperfusion injure in intermittent hypoxia rats]. AB - Objective: To compare the changes in the expression of mTOR and beclin1 in the hippocampus of normal rats and intermittent hypoxia rats with cerebral ischemia/reperfusion, so as to explore the roles of mTOR/autophagy pathway in global cerebral ischemia/reperfusion injure aggravated by intermittent hypoxia. Methods: One hundred healthy male Wistar rats were randomly divided into: sham operation group(SO group, n=20), intermittent hypoxia group(IH group, n=20), merely ischemia/reperfusion group(I/R group, n=20), intermittent hypoxia ischemia/reperfusion group(IH+ I/R group, n=20), intermittent hypoxia ischemia/reperfusion+ mTOR inhibitor group(Inhibitor group, n=20). IH group, IH+ I/R group and inhibitor group were respectively given intermittent hypoxia for 21 days before ischemia/reperfusion. Ischemia animals were prepared cerebral ischemia-reperfusion model by improved pulsinelli four vessels block (4-VO), the morphological changes of hippocampus nerve cells of rat brain were detected with HE respectively 6, 24 h after ischemia, and the expressions of mTOR protein and beclin1 protein in hippocampus of rat brain was detected with immunohistochemistry and RT-PCR respectively 6, 24 h after ischemia.SPSS 17.0 software was used to analyze the data. Results: Compared with the SO group, the IH group increased the never cells morphology damages and the empression of mTOR and beclin1 (q value was 32.94, 47.31, 63.68, 78.45, all P<0.05); the I/R group increased the never cells morphology damages and the empression of mTOR and beclin1 (mTOR in I/R group: 22.38+/-0.46, 24.16+/-0.60; mTOR in SO group: 14.65+/ 0.48, 15.40+/-0.58; beclin1 in I/R group: 8.58+/-0.58, 10.58+/-0.49; beclin1 in SO group: 2.06+/-0.23, 2.10+/-0.30; the differences were significant, q value was 90.59, 106.83, 95.88, 119.44, all P<0.05). Compared with the IH group, IH+ I/R group increased the never cells morphology damages and the empression of mTOR and beclin1 (q value was 152.23, 165.61, 135.01, 156.48, all P<0.05). Compared with the I/R group, IH+ I/R group increased the never cells morphology damages and the empression of mTOR and beclin1(q value was 94.35, 106.99, 102.79, 115.49, all P<0.05). Compared with the IH+ I/R group, the inhibitor group decreased the never cells morphology damages and the expression of mTOR, increased the expression of beclin1(mTOR in IH+ I/R group: 30.40+/-0.43, 32.86+/-0.50; mTOR in inhibitor group: 26.60+/-0.37, 28.51+/-0.52; beclin1 in IH+ I/R group: 15.57+/-0.57, 18.78+/-0.43; beclin1 in inhibitor group: 21.74+/-0.51, 24.32+/-0.49; the differences were significant, q value was 44.71, 53.05, 90.74, 78.03, all P<0.05). Conclusion: Intermittent hypoxia can aggravate the damage on nerve cells by activating mTOR/autophagy pathway after ischemia. PMID- 27765108 TI - [Effect of extent of glottal incompetence on phonation in excised canine larynx models]. AB - Objective: To compare the acoustic signal, mucosal wave and aerodynamic parameter (phonation threshold pressure, PTP) under different sub-glottal pressure (SGP) on the excised canine models with different extent of glottal incompetence. Methods: Perturbation measures and nonlinear dynamic measures were applied to analyze the acoustic signal (jitter, shimmer), mucosal wave [frequency(F), amplitude(A), phase(P)] and PTP from our study including 11 excised canine larynges with different extent of glottal incompetence (0 mm, 1 mm, 2 mm, 3 mm, n=11, respectively) under 1-4 kPa sub-glottal pressure. Results: There were significant differences between different groups in jitter, shimmer, amplitude, frequency and PTP under various SGPs and extent of glottal incompetence (all P<0.05), inversely, there was no significant difference in P between groups (P>0.05). Jitter and shimmer changed obviously when the SGP increased to 3 kPa in the control group and GI 1 mm group. Jitter and shimmer changed obviously when the SGP increased to 2 kPa in the GI 2 mm and 3 mm groups. The F and A of mucosal wave increased with increasing SGP, decreased with increasing GI, and the P changed irregularly. There was statistically significant difference of PTP between different GI groups. Conclusions: The SGP and the extent of GI had obvious affection on the the acoustic signal, mucosal wave and aerodynamic parameters. PMID- 27765109 TI - [A retrospective analysis on occult neck lymphatic metastasis in early tongue cancer]. AB - Objective: To investigate the number and level of occult neck lymphatic metastasis for squamous cell carcinoma of tongue in clinical stage I/II, and the relationship between cell differentiation and occult neck lymphatic metastasis. Methods: A total of 101 cases diagnosed preoperatively as having squamous cell carcinoma of tongue in clinical stage I/II (cT1/T2N0M0) between January 2005 and April 2015 were analysed retrospectively. Whether presence of occult neck lymphatic metastasis in these cases was studied. Results: Occult neck lymphatic metastases were found in 22 (21.78%) of 101 cases, 10 men and 12 women, with an age range of 22 to 83 years. There was not statistically significant association between tumor size or cell differentiation and occult neck lymphatic metastasis (P>0.05). The metastasis occurred most commonly in level II, followed by levelsI, III and IV. There was no lymph node metastasis in Level V. There were total 20 cases with occult neck lymphatic metastasis in at least one of levelI, II, III(90.9%), One of these case was skipping metastasis in level III(4.6%). Conclusion: The early tongue cancer has a high rate of occult lymph metastasis, which occurs commonly in levels II, I and III, but there is not significant association between the metastasis and tumor size or cell differentiation. PMID- 27765110 TI - [Fourth branchial cleft deformity with skin orifice: a series of 10 cases]. AB - Objective: To report rare cases of congenital neck cutaneous sinus with an orifice near the sternoclavicular joint and to investigate their origins and managements. Methods: A total of ten patients with congenital neck cutaneous sinus having an orifice near the sternoclavicular joint treated in the Guangdong General Hospital from January 2010 to June 2015 were retrospectively analyzed. Results: There four boys and six girls, aging from 11 months to 96 months with an average of 33.4 months, and they had a common feature showing a congenital cutaneous sinus with an orifice near sternoclavicular joint. Discharge of pus from the orifice or abscess formation was commonly seen soon after infection. With bacteriological study, staphylococcus aureus was positive in five cases and klebsiella pneumonia in a case. Another orifice of fistula/sinus was not depicted in pyriform with barium swallow X-ray in five cases Ultrasound studies of three cases demonstrated anechoic (i.e., nearly black) and solid-cystic lesion near sternoclavicular joint with posterior acoustic enhancement. Magnetic resonance imaging (MRI) showed isointensity of the lesion on T1 and T2 weighted images with heterogeneous enhancement and a close relationship with sternoclavicular joint. All patients underwent laryngoscopic examination, which showed no orifice of sinus in pyriform at same side. Surgical resection of fistula/sinus was performed in all cases. The lengths of the fistula varied from 5 mm to 22 mm with an average of 11 mm. Postoperative pathological examination showed all specimens were accordance with fistula. No complications were noticed. Recurrence was not observed in the cases by following-up of 6 months to 70 months (median: 33 months). Conclusion: Congenital neck cutaneous sinus with orifice near the sternoclavicular joint maybe a special clinical phenotype of the fourth branchial cleft sinus with skin orifice in cervicothoracic junction. Differential diagnoses between low cervical diseases are required. The curative treatment is a complete excision during inflammatory quiescent period. PMID- 27765111 TI - [Reconstruct the complex defects of mandible individually by computer-aided design and manufacturing technology: a case report]. PMID- 27765112 TI - [Hypokalemic paralysis induced by methylprednisolone in patient with sudden deafness: one case report]. PMID- 27765113 TI - [Implication study of angled handed cutter with suction system in endoscopic frontal recess surgery]. PMID- 27765114 TI - [Throat small angle nodule fungal disease: a case report]. PMID- 27765115 TI - [Pathological changes of temporal bone after cochlear implantation and the countermeasures]. AB - Cochlear implant (CI) is an artificial electronic device which can provide a sense of sound to a patient with severe or profound hearing loss. Pathological changes have been observed after CI surgery, which might influence the effectiveness of the CI procedure. In this review, we divided the postoperative pathological changes of the temporal bone into two categories according to different stages: immediate trauma and delayed side effects. Immediate trauma might arise from traumatic insertion of the electrode during CI surgery, which included trauma at cochleostomy site, lateral wall trauma, basilar membrane injury, osseous lamina fracture and modiolar injury. Delayed side effects arised from the host response against the inserted electrode, which involved a tissue reaction consisting of fibrotic and osseous changes in the cochlea, intracochlear inflammatory response to the electrode, changes in spiral ganglion cells number, pathological changes outside the cochlea and pathological changes after reimplantation. Published data suggested that the effectiveness of the surgery would be affected in many ways by postoperative pathological changes, and individuals with these changes would have an increased risk of the surgical failure. Therefore, subsequent countermeasures need to be taken to reduce the damages. PMID- 27765116 TI - [Present situation and analysis of murine allergic rhinitis model]. AB - There have been 20 years of history in the study of allergic rhinitis(AR) using a mice model. At present, the AR mice model still exists some problems in the selection of mice strains, allergens and adjuvant types, molding cycle, allergen dose, model judgment, and so on, which affects the authenticity and comparability of the research results. By gradually solving the problems existing in the mice AR model, it is of great significance to realize the standardization of AR model, and the depth of the AR research. PMID- 27765117 TI - [Research progress of suppressor gene PTEN]. AB - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase that functions as a tumor suppressor. PTEN regulates the multiple biological processes such as cell proliferation, invasion, metastasis, apoptosis and stem cell self-renewal through the phosphatidylinositol 3-kinase/ protein kinase B signaling pathway. PTEN activity can be modulated by mutations, epigenetic silencing, transcriptional repression, post-transcriptional contral and post-translational modifications. PMID- 27765118 TI - [Association between serum albumin and cognitive performance in elderly Chinese]. AB - Objective: To explore association between serum albumin level and cognitive performance in elderly Chinese. Methods: All the subjects aged >=65 years in the 8 longevity areas in Chinese longitudinal health longevity survey (CLHLS) were invited to participate the biomedical indepth CLHLS study, information about subjects' demographic characteristics, lifestyle, prevalence of diseases and health status was collected through household-interview. The cognitive performance was assessed with Mini Mental State Evaluation (MMSE) scale. Health examination was conducted by medical personnel and fasting venous blood samples were collected to detect the levels of triglycerides, total cholesterol, fasting glucose, creatine and blood albumin. MMSE score was compared and the trend was analyzed with generalized linear model. Association between albumin concentration and cognitive impairment was analyzed by logistic regression model. Results: Generalized linear model showed that adjusted MMSE score increased from 23.22 in the lowest quartile group to 25.07 in the highest quartile group (P for linear trend <0.001). Logistic regression analysis results showed that the higher albumin level was associated with the lower risk of cognitive impairment (P< 0.001), the OR decreased linearly with the increasing level of albumin (P<0.01), with the OR (95%CI) for the lower, higher and highest quartile groups was 0.64(0.45-0.91), 0.60(0.40-0.89) and 0.43(0.27-0.69), respectively, compared with the lowest quartile group. Conclusion: High level of serum albumin was associated with low risk of cognitive impairment. PMID- 27765119 TI - [A survey of deployment of sidewalks in central urban areas of 12 cities, China]. AB - Objective: To explore the deployment of sidewalks and the possible relationship with local GDP, population density and prosperity of streets in 12 cities selected in China. Methods: For all the streets in 333 blocks of 12 cities surveyed (Beijing, Tianjin, Shanghai, Qingdao, Hangzhou, Shaoxing, Suzhou, Nantong, Zhenjiang, Chengdu, Xining and Harbin), the deployment and management of sidewalks were observed. And we collected the GDP data of the 12 cities, the population data of 333 blocks, and the numbers of stores and restaurants along the streets. Results: A total of 4 255 streets were included in the study. In the 12 cities, 71.1% of the streets had sidewalks. The deployment rates of sidewalks was high in Qingdao (91.9%) and Harbin (90.6%), and low in Suzhou (48.6%) and Shaoxing (52.6%), the differences were significant. The higher GDP of city was, the more sidewalks were deployed. But on the other hand there were more parking cars and obstacles on the sidewalks. The higher the population density was, the worse the condition of sidewalks was. Conclusions: The survey of sidewalks in the 12 cities indicated that efforts could be made to improve the condition of sidewalks. Attention should be paid not only to the deployment of sidewalks, but also the management of sidewalks. Reasonable deployment of sidewalks should be considered according to the local population density and traffic flow. PMID- 27765120 TI - [Association between body mass index and its change and type 2 diabetes mellitus risk in a prospective study]. AB - Objective: To investigate the influence of body mass index (BMI) and its change on the incidence of type 2 diabetes mellitus (T2DM) in an adult cohort. Methods: A total of 3 043 subjects randomly selected among those without T2DM at baseline survey from the Rural Deqing Health Cohort Study were included into this study and follow up was conducted for 1 867 of them from July to November 2015. The subjects were divided into 3 groups according to their baseline BMI, normal group (BMI<24.0), overweight group (BMI: 24.0-27.9) and obese group (BMI>=28.0) and the subjects with stable weight (BMI change of-0.05 to + 0.05 per year) were used as the referent category. Cox proportional model was used to estimate associations between BMI, its changes and T2DM. Results: With an average of (8.68+/-1.25) person years, 213 new T2DM cases, including 125 females were detected, and incidence density was 13.14 per 1 000 person years. After adjusted for other covariates, the risk for incidence of T2DM was significantly higher in subjects with baseline BMI>=28.0 kg/m2 than those with baseline BMI<24.0 kg/m2 (aHR=2.12, 95% CI: 1.22-3.68), and weight gains were strongly associated with the incidence of T2DM in those with baseline BMI< 24.0 kg/m2 (aHR=2.21, 95%CI:1.17-4.17). Conclusion: Both BMI and its change were significantly associated with incidence of T2DM, especially in the population with BMI<24.0 kg/m2 at baseline. PMID- 27765121 TI - [Association between gestational weight gain per trimester/total gestational weight gain and gestational diabetes mellitus]. AB - Objective: To understand the association between gestational weight gain (GWG) per trimester/total (GWG) and gestational diabetes mellitus (GDM). Methods: A prospective cohort study was conducted among 829 healthy pregnant women from Chengdu who delivered a singleton during March-September 2013. Basic information about pre-pregnancy was collected at the first time, exercise information per trimester, dietary intake information per trimester and gestational age at delivery were obtained by questionnaire. Weight at the (12 +/- 1)th, (28 +/- 1)th, (36 +/- 1)th and last week before delivery were measured. GDM was diagnosed according to the National Diabetes and Pregnancy Prevention Guidelines (2014). At last, a total of 682 pregnant women were analyzed. After controlling the potential confounders, multiple logistic regression models were used to test the associations between GWG per trimester/total GWG and GDM. Results: After adjusting for age at delivery, pre-pregnancy body mass index, family histories of type 2 diabetes and hypertension, exercise in the first trimester, parity and energy intake in trimester and other potential confounders. Compared with adequate GWG in the first trimester, insufficient and excessive GWG in the first trimester were associated with increased risk of GDM (OR=1.23, 95%CI: 0.63-2.38, and OR=2.20, 95%CI: 1.12-4.35). Compared with adequate GWG in the second trimester, insufficient and excessive GWG in the second trimester were associated with decreased risk of GDM (OR=0.47, 95%CI: 0.18-1.19, and OR=0.78, 95% CI: 0.43 1.42). Compared with adequate GWG in the third trimester, insufficient GWG in the third trimester was associated with increased risk of GDM (OR=1.48, 95%CI: 0.77 2.84), excessive GWG in the third trimester was associated with decreased risk of GDM (OR= 0.53, 95% CI: 0.28-0.99). Compared with adequate total GWG in pregnancy, insufficient GWG in pregnancy was associated with increased risk of GDM (OR=2.16, 95% CI: 1.04-4.46), excessive GWG in pregnancy was associated with decreased risk of GDM (OR=0.74, 95% CI: 0.38-1.46). Conclusions: Insufficient and excessive GWG in the first trimester were associated with increased risk of GDM, the first trimester may represent a critical period for risk of GDM. The effects of GWG in the second and third trimester on GDM need further study. PMID- 27765122 TI - [Correlation between body fat percentage and general obesity indexes in middle aged and old people in Guangzhou]. AB - Objective: To examine the correlation between body fat percentage (BFP) and general obesity indexes, including body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHR) and calculate the corresponding BFP cutoff values in the middle aged and old people in Guangzhou. The corresponding cut point of optimal body fat percentage for Guangzhou older population. Methods: Based on the Guangzhou Biobank Cohort Study (GBCS), 3 490 relatively healthy Guangzhou residents aged >=50 years were selected and were randomly divided into 2 groups. The equations between BFP and BMI, WC, WHR were set up with Curve fitting analysis in one group. The multiple regression analysis was undertaken to establish predictive equations between BFP and BMI, WC, WHR with stepwise model for adding gender, age, physical activity, drinking and smoking. Then, the optimal cut-points of BFP corresponding to BMI, WC and WHR to reflect the degree of obesity were calculated. The equations were then validated with another group. Results: BFP increased with the increase of WHR, WC and BMI. BMI was a better predictor of body fat percentage than WC and WHR. The final regression equation was BFP=(-23.47 -8.87*sex) +2.94* (BMI) - 0.024 * (BMI)2,the coefficient of determination was 0.805. Based on the equation, the BFP corresponding to overweight/obesity (24 kg/m2<=BMI<28 kg/m2) were 24.3% <=BFP<31.1% in men and 33.2%<=BFP<40.0% in women, respectively. BMI had a better consistency with BFP in identify obesity compared with WC and WHR, obtained the area of ROC 0.909 in men and 0.919 in women respectively. The sensitivity and specificity were 70.3% and 85.5% in men; and 75.2% and 93.0% in women respectively. Conclusion: BFP has a better correlation with BMI. The study results indicated that BFP for middle aged and old males and females in Guangzhou corresponding to overweight/obesity (BMI>=24 kg/m2) were <24.0% and <33.0% respectively. PMID- 27765123 TI - [Follow-up study on efficacy of blocking mother-to-infant transmission of HBV and its influence factors in Jiangsu province, 2010-2015]. AB - Objective: To evaluate the effects of blocking transmission of HBV from mother to infant in Jiangsu, and discuss influencing factors related to development of chronic HBV infection in children of HBsAg positive mother. Methods: HBsAg positive mothers delivered during 2010-2015 in three counties of Jiangsu (Zhangjiagang, Danyang and Taixing) and their neonates were included in the study. The neonates were vaccinated with hepatitis B vaccine (10 MUg) and hepatitis B immunoglobin (100 units) within 24 hours after birth. Blood samples were collected from the infants 7 months later, and serum HBsAg, anti-HBs and anti-HBc were detected by Abbott particles chemiluminescence. Results: A total of 2 099 children aged 7-52 months were surveyed, of whom 34 (1.62%) developed chronic HBV infection. Logistic regression analysis showed that mother HBeAg positivity (RR=4.997, 95% CI: 2.408-10.370) was the independent risk factors of mother-to-infant transmission of HBV, while elder delivery age (RR=0.264, 95% CI: 0.101-0.691) was independent protective factors of HBV transmission. Among the other 2 065 uninfected children, 9.7% had anti-HBs level less than 10 mIU/ml, 35.4% between 10 and 100 mIU/ml, and 54.9% higher than 100 mIU/ml. The anti-HBs positive rate was 90.3% and the anti-HBc positive rate was 13.7%. The positive rate and geometric mean titers (GMT) of anti-HBs reached the peaks at 7-12 months after birth, and decreased with the age. Conclusions: The current immunological strategy of Jiangsu has good protective efficacy for the interruption of perinatal transmission of HBV. Mother HBeAg positivity is the major risk factor for perinatal blocking failure. Children with effective immunization still need to be monitored for anti-HBs and revaccinated if necessary. PMID- 27765124 TI - [Study of epidemiological characteristics and viral sources of dengue fever outbreak in Guangxi Zhuang Autonomous Region, 2014]. AB - Objective: To understand the epidemiological characteristics and viral sources of dengue fever outbreak in Guangxi Zhuang Autonomous Region (Guangxi) in 2014. Methods: A combined analysis of epidemiological characteristics and genetic characteristics were performed in this study. The time, population and area distributions of the cases were analyzed. Serum samples were collected from dengue fever cases to detect NS1 antigen by using commercial ELISA kits according to the guideline of the manufacture. RT-PCR assay was conducted to detect dengue virus in NS1 positive samples. Phylogenetic tree based on E gene sequence of dengue virus were further analyzed. Results: During September-December 2014, an outbreak of dengue fever caused by dengue virus type 1 and 2 occurred in Guangxi, a total of 854 cases were reported without death, including 712 laboratory confirmed cases and 142 clinical diagnosed cases, in which 79.63% (680/854) occurred during 22 September-21 October 2014. All the cases had typical dengue fever symptoms. Most cases occurred in Nanning and Wuzhou, in which 83.61% (714/854) were in age group 15-59 years; 46.60% (398/854) were staff or people engaged in commercial service. A total 526 serum samples were tested for dengue virus serotype by RT-PCR assay. Among 414 positive samples, 345 were positive for dengue virus type 1 (DENV-1) and 69 were positive for dengue virus type 2 (DENV 2), no DENV-3 and DENV-4 were detected. The results of phylogenetic analysis of E gene sequence indicated that the sequences of 99.12%(113/114) of DENV-1 strains in Nanning in China shared 100.00% homology with the isolate (SG EHI D1/529Y13) from Singapore in 2013, which belonged to the genotype I; All the DENV-2 isolates from Wuzhou shared 99.80% homology with the isolate (D14005) from Guangdong province, which belonged to genotype Cosmopolitan. Conclusions: The outbreak was caused by DENV-1 from Singapore and DENV-2 from Guangdong province in China. It is necessary to strengthen the surveillance and early warning for imported dengue fever, conduct vector control and improve the diagnosis of suspected dengue fever cases for the effective control of dengue fever outbreak. PMID- 27765125 TI - [Willingness for HIV test and associated factors among 535 college students who had sex in Zhejiang province]. AB - Objective: To understand the willingness of HIV test uptake and associated factors among sexual active college students. Methods: A cross-sectional study were conducted among college students from 11 cities in Zhejiang province, and those who had sexual behaviors were included in this study. Results: A total of 9 615 students completed the questionnaire, and 6.5% (619/9 468) of them had sexual behaviors. A total of 535 students were recruited in this study. And 77.2% of them were willing to receive HIV test. Hospitals and CDC were commonly accepted testing sites. Being sophomore and junior (aOR=2.618, 95%CI: 1.511-4.536), being aware of rapid growing HIV epidemic among students who are men who have sex with men (MSM) (aOR=1.879, 95%CI: 1.153-3.060) and being aware of HIV infection risk (aOR=1.701, 95% CI: 1.041-2.780) were associated with HIV test willingness. Conclusions: Future effort should be made to increase the awareness of HIV infection, including the severity of AIDS epidemic in college students and infection source, in order to increase their willingness to receive HIV test. School-based HIV counsel and test sites should be set up to provide convenient and private HIV test service. PMID- 27765126 TI - [Association and interaction between age at menarche and risk of diabetes in adult women]. AB - Objective: To explore the associations between age at menarche and diabetes in adult women. Methods: We analyzed the baseline data of 32 364 female participants who were aged 30-79 years and had been enrolled into China Kadoorie Biobank (CKB) study from Tongxiang, Zhejiang province. Multiple logistic regression analysis were used to investigate the putative associations after adjusting for potential confounders. Variables of menarche age and others were added to the logistic regression model to evaluate the multiplicative interaction, respectively. Results: The mean age of female participants was (51.42 +/- 9.63) years. And 3.73% and 24.17% of them reported their menarche age, <=12 years, >=17 years, respectively. The prevalence of diabetes among them was 5.75%. Compared with those with menarche age <=12 years, the OR(95%CI) of 15-16, 13-14 and <=12 years group were 1.13(1.00-1.27), 1.29(1.12-1.49) and 1.68(1.31-2.15) after adjusting for age, socioeconomic status, family history, health behaviors, menopause status, BMI and waist circumference. No significant differences were found in multiplicative interaction on diabetes between menarche age and smoking, alcohol consumption, physical activity, obesity, etc. (P>0.05). Conclusions: Menarche age is associated with higher risk of diabetes in female adults. The earlier menarche age is the higher risk of diabetes. There are no multiplicative interaction on diabetes between menarche age and other adults factors. PMID- 27765127 TI - [Changes on patterns of sleep duration: findings from China Health and Nutrition Survey in population in 9 provinces]. AB - Objective: To understand the changes on patterns of sleep duration of the China Health and Nutrition Survey (CHNS) cohort in 9 provinces from 2004 to 2011. Methods: Four rounds of CHNS data were used. Urban/rural, age and gender specific insufficient sleeping rates and excessive sleeping rates were analyzed. Results: In 2004, 2006, 2009 and 2011, a total of 274, 281, 329 and 304 children aged 3-5 years; 874, 806, 768 and 742 children aged 6-12 years; 789, 529, 426 and 367 children aged 13-17 years; 9 568, 9 530, 9 942 and 9 609 adults aged >=18 years were surveyed respectively. The lowest insufficient sleeping rate was 53.9% (200/371) in 3-17 years old children in rural area in 2006, the highest insufficient sleeping rate was 77.2% (44/57) in 3-5 years old children in urban area in 2004. The insufficient sleeping rate increased in rural 3-5 years old children from 2004 to 2011. For the adults aged >=18 years, the insufficient sleeping rate ranged from 4.2% (82/1 954) in females aged 18-44 years in 2004 and 2009 to 20.8% (211/1 015) in urban residents aged > 60 years in 2011. The insufficient sleeping rate in age-groups 44-59 years and >=60 years increased in both males and females and in both urban area and rural area from 2004 to 2011. The gender specific excessive sleeping rate in 3-17 years old children was very low in both urban area and rural area and no difference was found in different rounds of survey. The excessive sleeping rate in adults ranged from 18.4% (569/3 093) in urban population in 2011 to 32.5% (1 617/4 969) in females in 2004. The excessive sleeping rate of adult decreased from 2004 to 2011. Conclusion: We should pay attention to the fact that the insufficient sleeping rate in adolescents is high and in increase in rural 3-5 years old children and adults aged >=45 years. PMID- 27765128 TI - [Preliminary influence of 2015 cigarette excise tax up-regulation on cigarette retail price]. AB - Objective: To evaluate the impact of cigarette excise tax up-regulation on the retail price of cigarettes in 2015. Methods: Nominal and real price of selected cigarette varieties were calculated with data from Tobacco Retail Price Monitoring Project, which was conducted in 10 cities of China from 2013 to 2015. The trend of the cigarette prices changing was analyzed with annual data. Results: A total of 352 varieties of cigarettes were surveyed during the three years. The nominal price of these cigarettes did not change significantly from 2013 to 2014. Compared with nominal price of 2014, the price of 286 varieties increased and the price of 10 most popular varieties increased from 0.6% to 7.4% after cigarette excise tax increased, but the actual prices had both rise and fall compared with 2013. Conclusions: Cigarette excise tax raise in 2015 had influence on the retail price of cigarettes. But the increase in retail price was very limited, if factors including inflation and purchasing power are taken into consideration. Therefore, the influence of 2015 cigarette excise tax raise on tobacco control needs further evaluation. PMID- 27765129 TI - [Active etiological surveillance for foodborne diseases in Guangdong province, 2013-2014]. AB - Objective: To study the infection status, serotypes, drug resistance and molecular characteristics of Salmonella, Shigella, Vibrio parahemolyticus, enterotoxigenic Escherichia (E.) coli (ETEC), pathogenic E. coli (EPEC), Shiga Toxin producing E. coli (STEC) and Enteroinvasive E. coli (EIEC) collected from diarrhea patients in Guangdong. Methods: The strains of Salmonella, Shigella, V. parahemolyticus and 4 kinds of E. coli isolated from foodborne diseases surveillance during 2013-2014 were collected to conduct serotyping, drug resistance test and pulsed-field gel electrophoresis (PFGE). Results: A total of 3 372 stains of pathogens were isolated from 57 834 stool samples during 2013 2014, the overall positive rate was 5.83% and the positive rate of Salmonella was highest, followed by that of V. parahemolyticus, 4 kinds of E. coli and Shigella. And 3 213 strains of Salmonella were divided into 143 serotypes. The most prevalent serotypes were Salmonella typhimurium, 4, 5, 12: i:-, Enteritidis, Stanley and Derby. Salmonella was sensitive to cephalosporin and fluoroquinolones, and showed significant differences in drug resistance rate among different serotypes. In top 10 common serotypes, S. enteritidis and S. derby were most resistant to cephalosporin and ciprofloxacin respectively. PFGE was performed for 2 289 strains of Salmonella, showing distribution diversity and significant fingerprint polymorphisms. The 85 strains of V. parahemolyticus were divided into 10 serotypes, O3?K6 (61.18%) was the most common serotype, followed by O4?K8. The results showed that the carrying rate of virulence genes tdh (81.18%) was high, while the carrying rate of trh was low (7.06%), and there were 10 strains carrying no the two kinds of virulence genes. The sensitive rate of V. parahemolyticus to imipenem, nalidixic acid, SMZ-TMP, chloramphenicol and tetracycline were more than 95%. Thirteen strains of Shigella were detected, including 9 strains of Shigella sonnei, 3 strains of Shigella flexneri and 1 strains of Shigella bogdii. The strains all showed sensitivity to ceftazidime, ciprofloxacin and chloramphenicol (76.92%). There were 86 strains of E. coli detected, including 29 strains of ETEC (33.72%), 27 strains of EPEC (31.39%), 27 strains of STEC (31.39%) and 3 strains of EIEC (3.48%). Conclusions: In the active etiological surveillance for foodborne diseases in Guangdong during 2013 2014, the detection rate of Salmonella was highest (5.57% ), followed by that of V. parahemolyticus, 4 kinds of E. coli and Shigella. Salmonella, V. parahemolyticus and Shigella were sensitive to cephalosporin and fluoroquinolones. Clustered cases of Salmonella infection were found in the surveillance, but no outbreaks occurred. PMID- 27765130 TI - [Epidemiological study on adverse pregnancy outcomes in Shaanxi province]. AB - Objective: To understand the incidence and epidemiological characteristics of adverse pregnancy outcome in Shaanxi province. Methods: General information of the study was derived from the prevalence and risk factors of birth defects in Shaanxi province in 2010-2013. Descriptive epidemiological method was used to analyze the data of adverse pregnancy outcome. Results: The overall incidence of adverse pregnancy outcome was 25.45% during 2010-2013 (26.84% in 2010, 26.11% in 2011, 24.96% in 2012 and 24.80% in 2013, respectively). Fetal macrosomia and low birth weight accounted for 31.91% and 23.42%, spontaneous abortion and premature delivery accounted for 18.94% and 16.65%, while birth defects and embryo death in the palace accounted for 7.38% and 1.70%, respectively. There were significant differences in distribution of adverse pregnancy outcome among different age groups (P<0.001) and different years (P<0.05). Age was positively associated with risk on adverse pregnancy outcomes (P<0.001). The incidence of adverse pregnancy outcome were high in Liquan (37.49%), Wugong (35.50%) and Qianxian counties (35.13%). Conclusions: The overall incidence of adverse pregnancy outcome was 25.45% in Shaanxi. Fetal macrosomia, low birth weight and spontaneous abortion were the three major types of adverse pregnancy outcome, while age and area were related factors. Targeted strategies should be taken to reduce the incidence of adverse pregnancy outcome in Shaanxi. PMID- 27765131 TI - [Surveillance for HIV infection in MSM selected through respondent driven sampling in Beijing, 2005-2012]. AB - Objective: To understand the HIV prevalence among men who have sex with men (MSM) and discuss the feasibility of respondent driven sampling (RDS) as a tool to conduct long term HIV surveillance in MSM in Beijing. Methods: From 2005 to 2012 RDS was used to recruit MSM for face-to-face interview with structured questionnaire to collect their demographic characteristics and HIV risk-related behavior. Blood samples were collected from them for HIV test. Results: A total of 427, 540, 607, 614, 616, 602, 579 and 600 MSM were surveyed, respectively, from 2005 to 2012. The HIV infection prevalence increased from 4.2%(95%CI: 1.9 7.0) in 2005 to 10.1% (95%CI: 7.2-13.2) in 2012 (P=0.02). Meanwhile, HIV prevalence substantially increased among MSM aged >25 years, in floating population and with lower education level (<=high school), from 6.4%(95%CI: 2.2 9.5), 3.3%(95%CI: 1.8-5.4) and 5.5% (95%CI: 2.2-8.9) in 2005 to 7.6% (95%CI: 5.4 10.3, P=0.04), 10.7% (95% CI: 7.8-14.6, P=0.04) and 10.4% (95% CI:7.2-14.3, P=0.04) in 2012, respectively. Moreover, the HIV infection prevalence in MSM aged <=25 years old and with higher education level (>high school) increased from 1.7%(95%CI: 0.4-3.1) in 2009 and 1.1%(95%CI: 0.2-1.7) in 2007 to 13.7%(95%CI: 7.2 20.4) and 9.1%(95%CI: 4.7-13.8) in 2012, respectively, the differences were not significant. Furthermore, the HIV infection prevalence in MSM who had 2-9 male sex partners in the last six months increased from 4.0% (95% CI: 1.0-8.0) in 2005 to 12.6% (95% CI: 8.7-16.7) in 2012 (P=0.02). Conclusions: Studies have shown that RDS is an effective and feasible sampling method for long term HIV surveillance in MSM. The HIV infection prevalence in MSM in Beijing increased from 2005 to 2012, especially among those with older age, in floating population and with lower educational level. More attention should be paid to MSM with younger age and with higher educational level. PMID- 27765133 TI - [Genomic diversity and population structure of Helicobacter pylori isolates in China]. AB - Objective: To learn about the overall genomic characteristics and population structure of Helicobacter pylori isolated in China. Methods: In this study, we used 10 public available genome sequences of H. pylori strains isolated in China, combined with other H. pylori sequences from GenBank, to analyzed the overall genomic characteristics of H. pylori isolated in China. Core genes and strain specific genes were determined for a further function definition. Results: A total of 1 203 core genes were found among all sequenced China H. pylori isolates. The number of strain specific genes ranged from 19 to 32. These genes mainly encodes hypothetical proteins which might play an important role in adaption to different hosts. Genomic variation regions were mainly in genes encoding type four secretion systems and restriction modification systems. All the China isolates belong to hpEastAsia group, hspEAsia subgroup. Prophages sequences were found in three China H. pylori strains, carrying key elements required for phage assembly. Conclusion: China H. pylori isolates belong to hpEastAsia group, hspEAsia subgroup, and some isolates contain prophages. PMID- 27765132 TI - [Surveillance for viral diarrhea in sentinel hospitals in Henan province, 2013 2015]. AB - Objective: To investigate the infection status of human rotavirus, calicivirus, astrovirus and enteric adenovirus in children aged <5 years in disease surveillance areas in Henan province from 2013 to 2015. Methods: A total of 880 stool samples were collected from four sentinel hospitals and group A rotavirus was detected by ELISA and group A rotavirus G/P genotyping was performed with nested multiplex RT-PCR, while rotavirus (group B, C), calicivirus and astrovirus were detected by two-step multiplex RT-PCR and adenovirus were detected by PCR. The epidemiological data of positive cases were statistically analyzed. Results: A total of 594 positive samples were detected, including 24 mixed infection samples, 370 rotavirus positive samples (42.0%); 162 calicivirus positive samples (18.4%); 69 astrovirus positive samples (7.8%) and 17 enteric adenovirus positive samples (1.9%). The overall positive rate of four viruses was significantly higher in urban area than in rural area, but the positive rate of rotavirus was higher in males than in females and in younger age group than in older age group. G9P [8] was the major genotype of group A rotavirus, there were two seasonal infection peaks in autumn and spring. Norovirus II was the predominant type of calicivirus and the infection peak was in spring. Viral diarrhea cases were distributed in different age groups, mainly in age groups 0-12 months (rotavirus) and 3-5 years (calicivirus). The main clinical symptoms included fever, diarrhea and vomiting. The etiological characteristics differed with gender and area. Conclusions: The infection rate of diarrheal viruses was higher in young children <5 years old in disease surveillance areas. The epidemiological and clinical features varied with the type of pathogen. PMID- 27765134 TI - [Distribution and molecular type of Salmonella from external environment in Henan province]. AB - Objective: To understand the distribution of Salmonella in external environment in Henan province, and explore the distribution of different serotypes of the Salmonella and their homology. Methods: A total of 4 488 samples were collected form animal dung, meat products and kitchen utensils, and identified by biochemical tests and serotyped by serum agglutination reaction. The predominant serotypes were further typed by PFGE. Results: A total of 324 Salmonella strains were detected in these samples, the detection rate was 7.21%. The 324 Salmonella isolates belonged to 39 serotypes, S. enteritidis (24.07%, 78/324) and S. derby (20.37%, 66/324) were predominant. Forty six strains of S. enteritidis and 30 strains of S. derby were divided into 12 and 17 molecular patterns by digestion with Xba I, while chicken and swine were the predominant animal hosts. Conclusions: Serotyping of external environment Salmonella were phenotypically diverse and the serotype of Salmonella from different sources were different. The same clone was prevalent in same area. It is necessary to strengthen supervision and surveillance to ensure food safety. PMID- 27765135 TI - [Comparison of gender specific structure profiles of immunoglobulin G N-glycans]. AB - Objective: To analyze and compare the gender specific structure profiles of immunoglobulin G(IgG) N-glycans and provide evidence to understand the distribution of the structure of IgG N-glycans in general population. Methods: A cluster sampling was conducted to randomly select 669 participants from Beijing Xuanwu Hospital during January-June 2012. Venous blood sample (5 ml) was collected from each participant with vacuum negative pressure tube containing EDTA. Plasma IgG N-glycome was determined using ultra-performance liquid chromatography (UPLC) on Waters BEH Glycan chromatography column and mass spectrometry after the separation, purification and labeling. Finally, we got 24 chromatographic peaks. Each peak represented a different carbohydrate structure. Independent sample t-test or nonparametric test were used to compare the gender specific difference, P<0.05 was regarded as significant. Results: A total of 669 healthy participants were included, including 235 men (35.13%) and 434 women (64.87%). The average age of the participants was (44.23+/-9.82) years. The core fucosylation level and the galactosylation level of females were higher than those of males [Fn(Z=-2.192, P=0.028), G0n(Z=-7.898, P<0.001), G1n (Z=-2.343, P=0.019), G2n (Z=-8.414, P<0.001)], but FtotalS1/FtotalS2(Z=-5.049, P<0.001) and FS1/FS2 (Z=-3.336, P=0.001) of females were higher than those of males, indicating a higher saliva acidification level in males than in females. Conclusion: IgG N-glycosylation levels might be gender dependent. PMID- 27765136 TI - [Association between parental exposure to environmental risk factors and the risk of childhood acute lymphoblastic leukemia]. AB - Objective: To investigate the association between parental environmental risk factors exposure and the risk for childhood acute lymphoblastic leukemia (ALL). Methods: A total of 179 ALL children cases were selected in Tianjin Blood Disease Hospital and 136 healthy children matched by age, gender and living place were selected in 2015 for a case control study. The data were analyzed with univariate and multivariate non conditional logistic regression models. Results: The results of multivariate logistic regression analysis indicated that sex, history of abortion, exposure in a smoking environment during pregnancy, catching a cold, taking antipyretic analgesics, maternal exposure to air purifying agent, father' s occupational exposure to petroleum products and home decoration during pregnancy were associated with the risk of childhood ALL (P<0.05) and the results of multivariate logistic regression analysis indicated that sex, history of abortion, catching a cold, father's occupational exposure to petroleum products and home decoration during pregnancy were associated with the risk of childhood ALL (P<0.05). Conclusion: The five factors including sex, history of abortion, catching a cold, father' s occupational exposure to petroleum products and home decoration during pregnancy were risk factors for childhood ALL. PMID- 27765137 TI - [Meta-analysis on partial risk factors of full-term infants with low birth weight]. AB - Objective: To evaluate the risk factors of full-term infants with low birth weight. Methods: All related Chinese and English literatures published from 1980 to February 25, 2016 were collected from CBM, CNKI, Wang Fang Data, Medline and Embase databases, and screened with inclusion and exclusion criteria and Stata13.0 software was used in this Meta-analysis. Results: Twenty three studies were included and there were 278 020 subjects. Female infants (pooled OR=1.60, 95%CI: 1.49-1.72), less antenatal care visits (pooled OR=1.81, 95%CI: 1.54-2.11), maternal passive smoking (pooled OR=1.49, 95% CI: 1.08-2.06), pregnancy-induced hypertension (pooled OR=2.96, 95% CI: 1.85-4.74) and hypamnion (pooled OR=2.71, 95%CI: 1.87-3.93) were the risk factors for full-term infants with low birth weight. Conclusion: Departments of maternal and health care should encourage pregnant women to have antenatal care visits to find and treat their pregnancy complications, and avoid passive smoking actively through health education for the purpose to prompt the birth quality of infants. PMID- 27765138 TI - [A review of pension status quo in China and domestic and overseas pension models]. AB - With the aging of population and progressive decline of traditional pension model, the problems in the aged supporting have caused serious social concern in China. Since 1980' s, different opinions about pension models have been suggested in many research papers. This paper summarizes the characteristics of different pension model used in both China and abroad in terms of the financial sources of the aged supporting, life style and the combination with medical service, suggesting to establish a pension model with Chinese characteristics to provide multiple and personalized services on the basis of China' s national situation and successful experiences of other countries. PMID- 27765139 TI - [Progress in research of mobile health intervention]. AB - With the rapid development of mobile communication technology and the growing popularity of smartphones worldwide, mobile health has become an extension of e Health and Tele-Health, and is of value in the research and practice of public health. In this paper, we systematically assessed research literature of mobile health' s application on disease prevention and control as well as health promotion. Based on the characteristics of current literature, this paper focused on the application of mobile health in maternal health promotion, chronic disease management, and communicable disease prevention and control to provide reference for the mobile health intervention research in China. PMID- 27765140 TI - [Progress in research of tick-borne encephalitis]. AB - Tick-borne encephalitis, also called forest encephalitis, is caused by tick-borne encephalitis virus. Central nervous system lesion is the major clinical symptom of tick-borne encephalitis, as an acute infectious disease, the case fatality rate is as high as 10%-20%. Virology experts consider it as a key and difficult point in recent years. This paper summarizes the progress in research of epidemiological characteristics, pathogenesis, clinical manifestations, outcome, diagnosis and treatment of tick-borne encephalitis to provide evidence for the prevention and treatment of tick-borne encephalitis. PMID- 27765141 TI - Stuck in limbo: illicit drug users' experiences with opioid maintenance treatment and the relation to recovery. AB - OBJECTIVE: The objective of this article is to gain insight into how individuals who frequent open illicit drug scenes experience opioid maintenance treatment (OMT) and investigate how this appears to affect their recovery processes. METHOD: By means of the ethnographic method, one of the researchers spent time in an open illicit drug scene over a 1-year span, and gathered data on individuals who frequent the scene on a regular basis, and their experiences with OMT. The data are based on field notes and audiotaped interviews. FINDINGS: Four themes emerged as relevant for the participants' experiences with OMT: 1) the loss of hope, 2) trapped in OMT, 3) substitution treatment is not enough, and 4) stigmatization of identity. CONCLUSION: The participants found the OMT to be overruling and degrading. Several of the individuals from the illicit drug scene are part of the OMT programme, but as the treatment does not remove painful emotions, they supplement OMT with illegal substances, violate the OMT regulations, and run the risk of being excluded from the programme. In fear of losing the replacement opioid, they conceal parts of the addiction they seek treatment for and end up lying and cheating instead of exploring strategies for reducing and managing the addiction. The patients' relation to the OMT personnel is negatively affected by the need to hide a large portion of their issues. The result is a feeling of hopelessness, increased stigmatization, lack of control and being trapped between two worlds-in limbo, an intermediate state which interferes with the recovery process. PMID- 27765142 TI - Affordability of adult HIV/AIDS treatment in developing countries: modelling price determinants for a better insight of the market functioning. AB - INTRODUCTION: This study aims to provide a landscape of the global antiretroviral (ARV) market by analyzing the transactional data on donor-funded ARV procurement between 2003 and 2015, and the ARV price determinants. DESIGN: The data were obtained from the Global Price Reporting Mechanism (GPRM) managed by the AIDS Medicines and Diagnostics Service of the WHO, and it consists of information that covers approximately 80% of the total donor-funded adult ARV transactions procurement. METHODS: ExWorks prices and procured quantities were standardized according to the guidelines in terms of yearly doses. Descriptive statistics on quantities and prices show the main trends of the ARV market. Ordinary least squares estimation was carried out for the whole sample, then stratified according to the type of supplier (originator and generic) and controlled for time and geographical fixed-effects. Given that analyses were carried out on a public dataset on ARV transactional prices from the GPRM, ethics are respected and consent was not necessary. RESULTS: Originator medicines are on average the least expensive in the sub-Saharan Africa region, where at the same time, generic medicines are on average the most expensive. By contrast, originator medicines are the most expensive in Europe and Central Asia, and generic medicines are the least expensive. In fact, the data suggest mixed strategies by ARV suppliers to exploit opportunities for profit maximization and to adapt to the specific conditions of market competition in each region. Our results also suggest that the expiration of patents is not sufficient to boost additional developments in generic competition (at least in the ARV market) and that formal or informal agreements between generic firms may de facto slow down or even reverse long-term trends towards price decreases. CONCLUSIONS: Our findings provide an improved understanding of the ARV market that can help countries strengthen policy measures to increase their bargaining power in price negotiations and the use of TRIPS flexibilities, with a special emphasis on negotiations with generic manufacturers. PMID- 27765143 TI - In vivo protein quality of selected cereal-based staple foods enriched with soybean proteins. AB - BACKGROUND: One way to diminish protein malnutrition in children is by enriching cereal-based flours for the manufacturing of maize tortillas, wheat flour tortillas, and yeast-leavened breads, which are widely consumed among low socio economic groups. OBJECTIVE: The aim was to determine and compare the essential amino acid (EAA) scores, protein digestibility corrected amino acid scores (PDCAAS), and in vivo protein quality (protein digestibility, protein efficiency ratio (PER), biological values (BV), and net protein utilization (NPU) values) of regular versus soybean-fortified maize tortillas, yeast-leavened bread, and wheat flour tortillas. DESIGN: To comparatively assess differences in protein quality among maize tortillas, wheat flour tortillas, and yeast-leavened breads, EAA compositions and in vivo studies with weanling rats were performed. The experimental diets based on regular or soybean-fortified food products were compared with a casein-based diet. Food intake, weight gains, PER, dry matter and protein digestibility, BV, NPU, and PDCAAS were assessed. The soybean-fortified tortillas contained 6% of defatted soybean flour, whereas the yeast-leavened bread flour contained 4.5% of soybean concentrate. RESULTS: The soybean-fortified tortillas and bread contained higher amounts of lysine and tryptophan, which improved their EAA scores and PDCAAS. Rats fed diets based on soybean-fortified maize or wheat tortillas gained considerably more weight and had better BV and NPU values compared with counterparts fed with respective regular products. As a result, fortified maize tortillas and wheat flour tortillas improved PER from 0.73 to 1.64 and 0.69 to 1.77, respectively. The PER improvement was not as evident in rats fed the enriched yeast-leavened bread because the formulation contained sugar that decreased lysine availability possibly to Maillard reactions. CONCLUSIONS: The proposed enrichment of cereal-based foods with soybean proteins greatly improved PDCAAS, animal growth, nitrogen retention, and PER primarily in both maize and wheat flour tortillas. Therefore, these foods can help to diminish protein malnutrition among children who greatly depend on cereals as the main protein dietary source. PMID- 27765144 TI - Meals based on vegetable protein sources (beans and peas) are more satiating than meals based on animal protein sources (veal and pork) - a randomized cross-over meal test study. AB - BACKGROUND: Recent nutrition recommendations advocate a reduction in protein from animal sources (pork, beef) because of environmental concerns. Instead, protein from vegetable sources (beans, peas) should be increased. However, little is known about the effect of these vegetable protein sources on appetite regulation. OBJECTIVE: To examine whether meals based on vegetable protein sources (beans/peas) are comparable to meals based on animal protein sources (veal/pork) regarding meal-induced appetite sensations. DESIGN: In total, 43 healthy, normal weight, young men completed this randomized, double-blind, placebo-controlled, three-way, cross-over meal test. The meals (all 3.5 MJ, 28 energy-% (E%) fat) were either high protein based on veal and pork meat, HP-Meat (19 E% protein, 53 E% carbohydrate, 6 g fiber/100 g); high protein based on legumes (beans and peas), HP-Legume (19 E% protein, 53 E% carbohydrate, 25 g fiber/100 g); or low protein based on legumes, LP-Legume (9 E% protein, 62 E% carbohydrate, 10 g fiber/100 g). Subjective appetite sensations were recorded at baseline and every half hour using visual analog scales until the ad libitum meal 3 h after the test meal. Repeated measurements analyses and summary analyses were performed using ANCOVA (SAS). RESULTS: HP-Legume induced lower composite appetite score, hunger, prospective food consumption, and higher fullness compared to HP-Meat and LP Legume (p<0.05). Furthermore, satiety was higher after HP-Legume than HP-Meat (p<0.05). When adjusting for palatability, HP-Legume still resulted in lower composite appetite scores, hunger, prospective consumption, and higher fullness compared to HP-Meat (p<0.05). Furthermore, HP-Legume induced higher fullness than LP-Legume (p<0.05). A 12% and 13% lower energy intake, respectively, was seen after HP-Legume compared to HP-Meat or LP-Legume (p<0.01). CONCLUSION: Vegetable based meals (beans/peas) influenced appetite sensations favorably compared to animal-based meals (pork/veal) with similar energy and protein content, but lower fiber content. Interestingly, a vegetable-based meal with low protein content was as satiating and palatable as an animal-based meal with high protein content. PMID- 27765145 TI - New early Pleistocene hominin teeth from the Swartkrans Formation, South Africa. AB - We describe 14 hominin teeth and tooth fragments excavated recently from Swartkrans Cave (South Africa). The fossils derive from Members 1 (Lower Bank) and 3, from the Member 2/3 interface and from two deposits not yet assigned to member (the "Talus Cone Deposit" and the "Underground North Excavation" [UNE]) of the Swartkrans Formation, and include the first hominin fossil from the UNE, the two smallest Paranthropus robustus deciduous maxillary second molars in the entire hominin fossil record, and one of the smallest P. robustus permanent maxillary second molars from Swartkrans. The small permanent molar is accompanied by another tooth from a different individual but from the same stratigraphic level of the Swartkrans Formation; this second tooth is among, if not, the largest P. robustus permanent maxillary first molars known from anywhere-lending credence to assertions that degrees of body size sexual dimorphism previously ascribed to this species may be underestimated. It is more equivocal whether this evidence also supports hypotheses proposing that P. robustus assemblages from Swartkrans (as well as those from other South African cave sites) formed through the taphonomically biasing actions of large carnivores. PMID- 27765146 TI - Stem members of Platyrrhini are distinct from catarrhines in at least one derived cranial feature. AB - The pterion, on the lateral aspect of the cranium, is where the zygomatic, frontal, sphenoid, squamosal, and parietal bones approach and contact. The configuration of these bones distinguishes New and Old World anthropoids: most extant platyrrhines exhibit contact between the parietal and zygomatic bones, while all known catarrhines exhibit frontal-alisphenoid contact. However, it is thought that early stem-platyrrhines retained the apparently primitive catarrhine condition. Here we re-evaluate the condition of key fossil taxa using MUCT (micro computed tomography) imaging. The single known specimen of Tremacebus and an adult cranium of Antillothrix exhibit the typical platyrrhine condition of parietal-zygomatic contact. The same is true of one specimen of Homunculus, while a second specimen has the 'catarrhine' condition. When these new data are incorporated into an ancestral state reconstruction, they support the conclusion that pterion frontal-alisphenoid contact characterized the last common ancestor of crown anthropoids and that contact between the parietal and zygomatic is a synapomorphy of Platyrrhini. PMID- 27765147 TI - Being fat and smart: A comparative analysis of the fat-brain trade-off in mammals. AB - Humans stand out among non-aquatic mammals by having both an extremely large brain and a relatively large amount of body fat. To understand the evolution of this human peculiarity we report a phylogenetic comparative study of 120 mammalian species, including 30 primates, using seasonal variation in adult body mass as a proxy of the tendency to store fat. Species that rely on storing fat to survive lean periods are expected to be less active because of higher costs of locomotion and have increased predation risk due to reduced agility. Because a fat-storage strategy reduces the net cognitive benefit of a large brain without reducing its cost, such species should be less likely to evolve a larger brain than non-fat-storing species. We therefore predict that the two strategies to buffer food shortages (storing body fat and cognitive flexibility) are compensatory, and therefore predict negative co-evolution between relative brain size and seasonal variation in body mass. This trade-off is expected to be stronger in predominantly arboreal species than in more terrestrial ones, as the cost of transporting additional adipose depots is higher for climbing than for horizontal locomotion. We did, indeed, find a significant negative correlation between brain size and coefficient of variation (CV) in body mass in both sexes for the subsample of arboreal species, both in all mammals and within primates. In predominantly terrestrial species, in contrast, this correlation was not significant. We therefore suggest that the adoption of habitually terrestrial locomotor habits, accompanied by a reduced reliance on climbing, has allowed for a primate of our body size the unique human combination of unusually large brains and unusually large adipose depots. PMID- 27765148 TI - Dentognathic remains of Australopithecus afarensis from Nefuraytu (Woranso-Mille, Ethiopia): Comparative description, geology, and paleoecological context. AB - Australopithecus afarensis is the best-known and most dimorphic species in the early hominin fossil record. Here, we present a comparative description of new fossil specimens of Au. afarensis from Nefuraytu, a 3.330-3.207 million-years-old fossil collection area in the Woranso-Mille study area, central Afar, Ethiopia. These specimens include NFR-VP-1/29, one of the most complete mandibles assigned to the species thus far and among the largest mandibles attributed to Au. afarensis, likely representing a male individual. NFR-VP-1/29 retains almost all of the distinctive archaic features documented for Au. afarensis. These features include a posteriorly sloping symphysis, a low and rounded basally set inferior transverse torus, anterosuperiorly opening mental foramen, a lateral corpus hollow bound anteriorly by the C/P3 jugae and posteriorly by the lateral prominence, and the ascending ramus arising high on the corpus. Dental morphology and metrics of the Nefuraytu specimens also falls within the range of Au. afarensis. The presence of this species at Woranso-Mille between 3.330 and 3.207 million years ago confirms the existence of this species in the area in close spatial and temporal proximity to other middle Pliocene hominin taxa such as the one represented by the Burtele foot (BRT-VP-2/73) and the recently named species Australopithecus deyiremeda. This has important implications for our understanding of middle Pliocene hominin diversity. PMID- 27765149 TI - Mandibular ramus shape of Australopithecus sediba suggests a single variable species. AB - The fossils from Malapa cave, South Africa, attributed to Australopithecus sediba, include two partial skeletons-MH1, a subadult, and MH2, an adult. Previous research noted differences in the mandibular rami of these individuals. This study tests three hypotheses that could explain these differences. The first two state that the differences are due to ontogenetic variation and sexual dimorphism, respectively. The third hypothesis, which is relevant to arguments suggesting that MH1 belongs in the genus Australopithecus and MH2 in Homo, is that the differences are due to the two individuals representing more than one taxon. To test these hypotheses, we digitized two-dimensional sliding semilandmarks in samples of Gorilla, Pan, Pongo, and Homo, as well as MH1 and MH2. We document large amounts of shape variation within all extant species, which is related neither to ontogeny nor sexual dimorphism. Extant species nevertheless form clusters in shape space, albeit with some overlap. The shape differences in extant taxa between individuals in the relevant age categories are minimal, indicating that it is unlikely that ontogeny explains the differences between MH1 and MH2. Similarly, the pattern of differences between MH1 and MH2 is inconsistent with those found between males and females in the extant sample, suggesting that it is unlikely that sexual dimorphism explains these differences. While the difference between MH1 and MH2 is large relative to within-species comparisons, it does not generally fall outside of the confidence intervals for extant intraspecific variation. However, the MH1-MH2 distance also does not plot outside and below the between-species confidence intervals. Based on these results, as well as the contextual and depositional evidence, we conclude that MH1 and MH2 represent a single species and that the relatively large degree of variation in this species is due to neither ontogeny nor sexual dimorphism. PMID- 27765150 TI - OH-65: The earliest evidence for right-handedness in the fossil record. AB - Labial striations on the anterior teeth have been documented in numerous European pre-Neandertal and Neandertal fossils and serve as evidence for handedness. OH 65, dated at 1.8 mya, shows a concentration of oblique striations on, especially, the left I1 and right I1, I2 and C1, which signal that it was right-handed. From these patterns we contend that OH-65 was habitually using the right hand, over the left, in manipulating objects during some kind of oral processing. In living humans right-handedness is generally correlated with brain lateralization, although the strength of the association is questioned by some. We propose that as more specimens are found, right-handedness, as seen in living Homo, will most probably be typical of these early hominins. PMID- 27765151 TI - Comparative biomechanics of Australopithecus sediba mandibles. AB - Fossils attributed to Australopithecus sediba are described as having phylogenetic affinities with early Homo to the exclusion of other South African australopiths. With respect to functional anatomy of mastication, one implication of this hypothesis is that A. sediba mandibles should exhibit absolutely and relatively reduced stiffness and strength in comparison to Australopithecus africanus and Paranthropus robustus jaws. Examination of cortical bone distribution in the MH 1 and MH 2 mandibles of A. sediba (evaluated against samples of Pan, early and modern Homo as well as A. africanus and P. robustus) indicate that the A. sediba mandibular corpus was geometrically similar to other South African australopiths. In particular, enhanced torsional rigidity is characteristic of all South African australopiths including A. sediba. These findings are consistent with a hypothesis that masticatory mechanics may have been similar to other australopiths (and distinct from exemplars of early Homo), and as such suggest that A. sediba's mandibles were functionally suited to consume hard and tough objects. Recent mechanical modeling of the A. sediba cranium, however, has been interpreted as indicating that this species was relatively poorly adapted to produce large bite forces and likely experienced relatively modest strains in its facial skeleton. This paradox - that the cranium signals a departure from the australopith morphotype whereas the mandibles conform to a hypodigm of australopith grade - can be resolved, in part, if it is acknowledged that mechanical performance variables offer imperfect insight into what constitutes feeding adaptations. PMID- 27765152 TI - Corrigendum to "Children's involvement in care order decision-making: A cross country analysis" [Child Abuse & Neglect 49 (2015) 128-141]. PMID- 27765153 TI - Preface on application of omics technologies in cancer biology and therapy. PMID- 27765154 TI - Recurring themes in the legacy of Jens Rasmussen. PMID- 27765155 TI - Commentary: Analysis, investigation and judgement: The post-hoc application of human factors analyses to incidents. PMID- 27765156 TI - The Complicated Relationship of Stress and Prefrontal Cortex. PMID- 27765157 TI - Feeding the Developing Brain: The Persistent Epigenetic Effects of Early Life Malnutrition. PMID- 27765158 TI - Brain Connectivity Reflects Mental and Physical States in Generalized Anxiety Disorder. PMID- 27765160 TI - Foreword. PMID- 27765159 TI - Sex Differences and Personalized Psychiatric Care. PMID- 27765162 TI - Surgical treatment of gastrointestinal motility disorders. PMID- 27765163 TI - Isotretinoin-Induced Elkonyxis. PMID- 27765164 TI - Drug Survival Analysis Is Not a Good Method for Assessing the Safety or Effectiveness of Systemic Therapies in Psoriasis. PMID- 27765165 TI - A Case Series of Patients With Psoriasis Exposed to Biologic Therapy During Pregnancy: The BIOBADADERM Register and a Review of the Literature. PMID- 27765166 TI - Reply. PMID- 27765167 TI - Outcomes of Same-Size Host and Donor Trephine in Deep Anterior Lamellar Keratoplasty for Keratoconus. PMID- 27765169 TI - Biomechanics of Failed Pulmonary Autografts Compared to Native Aortic Roots. AB - BACKGROUND: Progressive autograft dilatation after a Ross operation suggests that remodeling does not effectively reproduce native aortic root biomechanics. In the first of this two-part series, we compared mechanical properties of explanted autografts to pulmonary roots at pulmonary pressures. The goal of this study was to compare mechanical properties of explanted autografts to native aortic roots at systemic pressures. METHODS: Autograft specimens were obtained from patients undergoing reoperation after Ross operation. For comparison, native aortic roots were obtained from unused donor hearts. Biaxial stretch testing was performed to determine tissue mechanical properties. Tissue stiffness was determined at patient-specific physiologic stresses corresponding to systemic pressures (80 and 120 mm Hg) and hypertensive state (200 mm Hg). RESULTS: Nonlinear stress-strain curves were present for both failed autografts and native aortic roots. Explanted autografts were significantly more compliant than native aortic roots at 80 mm Hg (1.53 +/- 0.68 versus 2.99 +/- 1.34 MPa; p = 0.011), 120 mm Hg (2.54 +/- 1.18 versus 4.93 +/- 2.21 MPa; p = 0.013), and 200 mm Hg (4.79 +/- 2.30 versus 9.21 +/ 4.16 MPa; p = 0.015). Autograft tissue stiffness at 80, 120, and 200 mm Hg was not correlated with age at the time of Ross operation (p = 0.666, p = 0.639, and p = 0.616, respectively) or time in the systemic circulation (p = 0.635, p = 0.637, and p = 0.647, respectively). CONCLUSIONS: Failed pulmonary autografts retained a nonlinear response to mechanical loading typical of healthy arterial tissue. Despite similar wall thickness between autografts and aorta, autograft stiffness in this patient population was significantly reduced compared with native aortic roots. We demonstrated that biomechanical remodeling was inadequate in these specimens to achieve native aortic mechanical properties, which may have resulted in progressive autograft root dilatation. PMID- 27765168 TI - Radiation to the Gastric Fundus Increases the Risk of Anastomotic Leakage After Esophagectomy. AB - BACKGROUND: Concerns have been raised regarding the toxicity of neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer that could contribute to an increased risk of postoperative complications. The aim of this study was to determine the influence of the radiation dose to the gastric fundus on the risk of postoperative anastomotic leakage in patients undergoing nCRT followed by transthoracic esophagectomy. METHODS: Between January 2012 and July 2015, 97 consecutive patients who underwent nCRT followed by transthoracic esophagectomy were included in this single-center cohort study. The gastric fundus was contoured on the pretreatment planning computed tomography. Within this contour, dose-volume histogram variables were calculated, and logistic regression analysis was used to determine their influence on the risk of anastomotic leakage. RESULTS: In 25 of 97 patients (26%) anastomotic leakage occurred. The mean radiation dose to the gastric fundus was significantly higher in patients with than without leakage (median 35.6 Gy versus 24.9 Gy, respectively, p = 0.047). A mean dose more than versus less than 31.4 Gy was associated with leakage rates of 43% versus 15%, respectively. Adjusted for tumor location, clinical T stage, and radiation method, the mean radiation dose to the gastric fundus remained significantly and independently associated with an increased risk of anastomotic leakage (adjusted odds ratio 1.05 per 1-Gy increase, 95% confidence interval: 1.002 to 1.10, p = 0.043). CONCLUSIONS: Efforts should be made to minimize the radiation dose to the gastric fundus when planning nCRT for esophageal cancer, because higher dose levels to the gastric fundus are associated with an increased risk of anastomotic leakage after subsequent transthoracic esophagectomy and cervical anastomosis. PMID- 27765170 TI - Amount of Epithelioid Differentiation Is a Predictor of Survival in Malignant Pleural Mesothelioma. AB - BACKGROUND: Macroscopic complete surgical resection with adjuvant chemotherapy can provide a survival advantage in patients with malignant pleural mesothelioma (MPM). Patients with nonepithelioid histology are largely excluded from such radical operations even though they might benefit. The degree of epithelioid differentiation varies in biphasic histology. We report the outcomes of pleurectomy and decortication and the effect of epithelioid differentiation on overall survival of patients with MPM. METHODS: This report is based on the outcomes of 144 patients who underwent pleurectomy and decortication at a single institution between 2008 and 2015. The variables assessed were age, gender, histology, and pathologic T and N stage. No patients with pure sarcomatoid histology were included. Two independent pathologists estimated the percentage of epithelioid histology. A Cox regression model was used to identify significant predictors of survival. The Kaplan-Meier method was used to summarize overall and subgroup survival. RESULTS: Included were 116 men and 28 women with a median age of 69 years (range, 43 to 88 years). The 2-year survival from pleurectomy and decortication was 20%. Median survival overall was 13.34 months and was 20.1 months for the 100% epithelioid subgroup (n = 77), 11.8 months for the 51% to 99% epithelioid subgroup (n = 39), and 6.62 months for the less than 50% epithelioid subgroup (n = 28). The amount of epithelioid differentiation was a significant predictor of survival (p < 0.001). Differences in survival based on the T, but N stage, were not statistically significant. CONCLUSIONS: The percentage of epithelioid differentiation is an independent predictor of survival in MPM and should be taken into careful consideration when recommending surgical treatment for patients with biphasic MPM. PMID- 27765171 TI - Concomitant Interstitial Lung Disease Is a Risk Factor for Pleural Invasion in Lung Cancer. AB - BACKGROUND: Lung carcinoma is often associated with interstitial lung disease (ILD), and the prognosis of lung cancer accompanied by ILD is unfavorable. In this study, cases of patients with primary lung cancer with or without ILD were reviewed to analyze surgical outcome, with special interest in the conformity of clinical and pathologic stages, pathologic findings of pleural invasion, malignant pleurisy first detected at the time of thoracotomy, and survival. METHODS: Retrospective chart review was performed for 1,264 primary lung cancer patients who underwent surgery from 2004 to 2015. Concomitant ILD was diagnosed by pathological examination or preoperative chest computed tomography findings. RESULTS: ILD was found in 104 patients (8.2%) with primary lung cancer. Conformity of clinical and pathological stages in the ILD-positive patients was poor, with a lower kappa value than that for the 1,160 ILD-negative patients (0.34 versus 0.51). The ILD group had significantly higher incidences of pleural invasion and unexpected malignant pleurisy than did the non-ILD group (for pleural invasion, 49.0% versus 24.5%, p < 0.0001; for malignant pleurisy, 7.69% versus 1.47%, p < 0.0001). The 5-year overall survival rates of the ILD group showed significantly lower than those of the non-ILD group (45.2% versus 70.1%; p = 0.0014) after propensity score matching. CONCLUSIONS: In lung cancer, the concomitant existence of ILD is a risk factor for pleural invasion. Concomitant ILD might cause underestimation of clinical staging, increase the chance of unexpected malignant pleurisy during surgery, and shorten survival time. PMID- 27765172 TI - A Series of Transbronchial Removal of Intracavitary Pulmonary Aspergilloma. AB - BACKGROUND: Intracavitary pulmonary aspergilloma is a chronic, debilitating fungal infection. Without definitive therapy, death can occur from massive hemoptysis, cachexia, or secondary infection. Although surgical resection is the standard therapy, it is not possible for many patients owing to poor pulmonary function or medical comorbidities. Aspergilloma removal through bronchoscopy is an important alternative therapy that may be available in select cases. METHODS: We retrospectively reviewed all cases referred to the University of Calgary Interventional Pulmonary Service for transbronchial removal of intracavitary aspergilloma from January 1, 2009, to January 1, 2014. RESULTS: Ten patients with intracavitary pulmonary aspergilloma were identified. In 3 patients, the aspergilloma cavity was not accessible by bronchoscopy. Successful removal of the aspergilloma with symptom improvement or resolution was achieved in 6 of 7 cases. One of the patients was lost to follow-up. Minor hypoxia lasting 12 to 72 hours was observed in 5 cases. Severe sepsis requiring an extended critical care unit stay occurred in 1 case. Follow-up ranged from 9 months to 5 years. CONCLUSIONS: Although not without risk of minor hypoxia and possible sepsis, for carefully selected patients, bronchoscopic removal of symptomatic intracavitary pulmonary aspergilloma may be an alternative therapy to surgical resection for this life threatening disease. PMID- 27765174 TI - Implant Failure: STRATOS System for Pectus Repair. AB - BACKGROUND: Three European centers have recently reported dramatic failures of the STRATOS titanium system, approved in Europe and the United States since 2007 and meant for pectus repair, without detailed exploration of its causes. METHODS: Failed implants (fractures or loosened crimp connectors) were surgically explanted from 12 patients and biopsies taken from surrounding discolored tissue. Detailed failure analysis was performed to find the cause of failures. Inductively coupled mass spectroscopy, scanning electron microscopy, and energy dispersive radiograph spectroscopy was used to determine titanium and to visualize titanium wear debris in histologic sections. RESULTS: Implants failed in all patients by fracture of connecting bar, fracture of lateral bar at reduced cross-section, loosening of crimp connector, or different combinations of these. All fracture surfaces were clean and smooth without any signs of plastic deformation. Failure already started at 10 months after implantation and continued for 2.5 years. Biopsy of discolored tissue around the failures showed 0.4 mg to 105 mg titanium per gram tissue, and close observation showed titanium wear debris. CONCLUSIONS: Combined tensile, compressive, bending, and torsional loading on the implant during each breathing cycle caused loosening and fatigue fractures, which led to failure. Excessive rubbing at the fracture and loosening site caused the release of large amounts of titanium in the surrounding tissue, which may lead to metallosis. Long and sharp pieces of failed implant in the cardiothoracic region is a grave danger to vital organs. All patients should be closely followed, and in our opinion, all implants should be removed. Serious reconsideration for clinical use of this implant is necessary. PMID- 27765173 TI - Clinical Safety and Effectiveness of Endoaortic as Compared to Transthoracic Clamp for Small Thoracotomy Mitral Valve Surgery: Meta-Analysis of Observational Studies. AB - Controversies remain on the increased rate of neurological events after small thoracotomy mitral valve surgery attributed to endoaortic balloon occlusion (EABO). Systematic literature search of databases identified 17 studies enrolling 6,643 patients comparing safety and effectiveness of EABO versus transthoracic clamp. In a meta-analysis, there was no difference in occurrence of cerebrovascular events, all-cause mortality, and kidney injury. EABO was associated with a significantly higher risk of iatrogenic aortic dissection (0.93% versus 0.13%; risk ratio, 4.67; 95% confidence interval, 1.62 to 13.49; p = 0.004) and a trend toward longer operative times. The data is limited to observational studies. PMID- 27765175 TI - Learning Alternative Access Approaches for Transcatheter Aortic Valve Replacement: Implications for New Transcatheter Aortic Valve Replacement Centers. AB - BACKGROUND: Smaller transcatheter aortic valve replacement (TAVR) delivery systems have increased the number of patients eligible for transfemoral procedures while decreasing the need for transaortic (TAo) or transapical (TA) access. As a result, newer TAVR centers are likely to have less exposure to these alternative access techniques, making it harder to achieve proficiency. The purpose of this study was to evaluate the learning curve for TAVR approaches and compare perioperative outcomes. METHODS: From January 2008 to December 2014, 400 patients underwent TAVR (transfemoral, n = 179; TA, n = 120; and TAo, n = 101)). Learning curves were constructed using metrics of contrast utilization, procedural, and fluoroscopy times. Outcomes during the learning curve were compared with after proficiency was achieved. RESULTS: Depending on the metric, learning curves for all three routes differed slightly but all demonstrated proficiency by the 50th case. There were no significant differences in procedural times whereas improvements in contrast use were most notable for TA (69 +/- 40 mL versus 50 +/- 23 mL, p = 0.002). For both TA and TAo, fewer patients received transfusions once proficiency was reached (62% versus 34%, p = 0.003, and 42% versus 14%, p = 0.002, respectively). No differences in 30-day or 1-year mortality were seen before or after proficiency was reached for any approach. CONCLUSIONS: The learning curves for TA and TAo are distinct but technical proficiency begins to develop by 25 cases and becomes complete by 50 cases for both approaches. Given the relatively low volume of alternative access, achieving technical proficiency may take significant time. However, technical proficiency had no effect on 30-day or 1-year mortality for any access approach. PMID- 27765176 TI - Evaluation of a New Ultrasound Thoracoscope for Localization of Lung Nodules in Ex Vivo Human Lungs. AB - BACKGROUND: Localization of small, nonvisible and nonpalpable nodules is challenging during video-assisted thoracoscopic surgery. We evaluated the feasibility of using a new ultrasound thoracoscope to localize nodules in resected ex vivo human lungs. METHODS: The tumor was localized and measured in its greatest dimension with a prototype ultrasound thoracoscope (XLTF-UC180; Olympus Corporation, Tokyo, Japan) at different frequencies (5.0 to 12.0 MHz) and different lung specimen states (deflated, semiinflated). Measured tumor size and depth from lung surface were compared and correlated to the true diameter and depth from lung surface acquired from pathologic morphology. RESULTS: Ex vivo evaluation was performed on 16 solid nodules and nine part solid ground-glass nodules. All tumors were successfully localized in the deflated lung specimens (average size, 13.7 +/- 5.2 mm). The tumor boundaries were best evaluated with an ultrasound frequency of 10 MHz. Solid nodules were more easily visualized than ground-glass nodules. Part solid ground-glass nodules were not easily detected in the semiinflated specimen owing to peritumoral air surrounding the tumor. Tumor boundaries were also difficult to identify in deeply situated tumors and in lungs with underlying disease. A strong positive correlation existed between the ultrasound measurement and true measurement of tumor size (R2 = 0.89, p < 0.001). CONCLUSIONS: The ultrasound thoracoscope can be used to localize nodules in resected human lungs. The clarity of the tumor boundaries is influenced by the tumor type and depth and the underlying pulmonary disease. Complete lung deflation and the use of 10 MHz ultrasound frequency optimize the visualization of target tumors. PMID- 27765177 TI - Survival After Orthotopic Heart Transplantation in Patients Undergoing Bridge to Transplantation With the HeartWare HVAD Versus the Heartmate II. AB - BACKGROUND: Our objective was to determine whether the choice of a HeartWare HVAD as opposed to a Heartmate II left ventricular assist device (HMII LVAD), impacts survival after heart transplantation after controlling for patient, donor, and center characteristics. METHODS: We queried the United Network for Organ Sharing (UNOS) database, which has recently made pretransplantation device duration available, for all adult patients undergoing bridge to transplantation (BTT) between January 2011 and March 2016. Recipient, donor, and transplant-specific characteristics were compared between patients receiving either device. Unadjusted survival was estimated with the Kaplan-Meier method. Risk-adjusted Cox proportional hazard models were constructed to determine the independent impact of device selection on mortality. RESULTS: Three thousand three hundred fifty-six patients who received the HMII and 1,051 patients who received the HVAD met inclusion criteria. Patients who received the HMII had a longer mean duration of VAD support (HMII, 429 days versus HVAD, 314 days; p < 0.001) but spent shorter periods on the waiting list (median, 190 days versus 232 days; p < 0.001). Patients who received the HMII had worse pre-LVAD renal function than did those who received the HVAD (glomerular filtration rate [GFR], 57 mL/min versus 62 mL/min, respectively; p = 0.001), but there was no difference in postoperative new-onset dialysis after transplantation (11.6% versus 10.5%, respectively; p = 0.14). There was no difference in unadjusted posttransplantation 30-day (95.5% versus 96.7%, respectively; log-rank p = 0.09), 6-month (91.8% versus 92.6%, respectively; p = 0.35), or 1-year (89.7% versus 90.9%, respectively; p = 0.22) survival between the 2 groups. After risk adjustment with Cox modeling, device selection did not predict mortality at any time point. CONCLUSIONS: Among patients who received a BTT LVAD and then received a heart transplant, no survival differences were seen between patients initially implanted with an HVAD versus an HMII. PMID- 27765178 TI - Surgical outcomes and failure-to-rescue events after colectomy in teaching hospitals: a nationwide analysis. AB - BACKGROUND: The relationship between failure-to-rescue (FTR) after colectomy is not well understood, particularly in teaching institutions. We sought to examine this relationship using a large national database. METHODS: Patients undergoing colectomy from 2010 to 2012 were identified in the Nationwide Inpatient Sample database. FTR events were defined as deaths following deep vein thrombosis or pulmonary embolism, sepsis, gastrointestinal bleed, acute myocardial infarction, acute kidney injury, pneumonia, respiratory failure, shock. We compared outcomes between teaching hospitals (TH) and nonteaching hospitals (NTH). RESULTS: A total of 220,369 patients underwent colectomy; 50.2% were performed at TH. Overall mortality was 3.7% with 96% of deaths attributed to at least one FTR event. More complications occurred in NTH, but there was no difference in mortality or FTR rates. However, TH had higher incidences of deep vein thrombosis or pulmonary embolism and sepsis leading to postoperative mortality, whereas NTH had higher rates of acute myocardial infarction and gastrointestinal bleed. CONCLUSIONS: A substantial proportion of mortality is attributed to FTR events after colectomy in both TH and NTH. Further investigation targeting specific complications is warranted. PMID- 27765179 TI - From the laboratory bench to the operating room: the role of the surgeon in cancer prevention. AB - BACKGROUND: The last 200 years have seen remarkable achievements in the art and clinical practice of surgery. These advances include the introduction of antisepsis, anesthesia, vascular anastomosis, antimicrobials, organ transplantation, and the widespread application of minimally invasive operative procedures. Very recently, a surgical procedure has been shown to cure diabetes, representing the most effective treatment of a metabolic disorder by surgeons. METHODS: The author reviewed the major surgical milestones in the modern surgical era and prepared this monograph for presentation as the Claude H. Organ, Jr. Memorial Lecture at the 68th Annual Meeting of the Southwestern Surgical Congress. RESULTS/CONCLUSIONS: This address summarizes the story of medullary thyroid carcinoma and multiple endocrine neoplasia type 2, an archetype for a surgical procedure to prevent cancer development. PMID- 27765180 TI - Individualized care in patients undergoing laparoscopic cholecystectomy. PMID- 27765181 TI - Intraoperative questioning to advance higher-order thinking. AB - BACKGROUND: The type of question asked elicits a particular response. The purpose of this study was to determine what types and levels of questions were asked in the operating room. These insights are important for understanding how questions are used to advance learners. METHODS: 12 laparoscopic cholecystectomy operations were observed and recorded at a single institution. Intraoperative questions asked by faculty were transcribed for all cases. Using revised Bloom's taxonomy, questions were classified into one of 5 levels: (1) remembering, (2) understanding, (3) applying, (4) analyzing, (5) evaluating. RESULTS: 141 questions were asked by faculty and ranged from 0 to 34 questions per case. Classification of questions showed there were 43 remembering, 29 understanding, 47 applying, 13 analyzing, and 8 evaluating questions asked. CONCLUSIONS: Questioning was predominately classified at lower-order and mid-level thinking skills (120/141). Integrating intraoperative questions at higher-order levels has the potential to guide trainees into progressively complex thinking and decision making. PMID- 27765182 TI - Setting goals, not just roles: Improving teamwork through goal-focused debriefing. AB - INTRODUCTION: The role of goal setting within post-simulation debriefing is not well known. This study sought to examine how inclusion of group-level goals, individual-level goals, or no goals in the debriefing process impacts teamwork. METHODS: Students participated in two high-fidelity team training scenarios. Between scenarios, teams were assigned to one of three debriefing groups: jointly creating five teamwork goals for the group to achieve (group-level goals); independently creating five teamwork goals for each individual to attain (individual-level goals); or no goals. Paired-samples t tests and one-way ANOVA with post-hoc Tukey tests were used to examine performance improvements and differences between groups. RESULTS: 86 MS3s participated in the training program across 22 groups. Percentage of items achieved on the teamwork tool from first to second scenario were 61.7+/-20.4 to 60.2+/-8.8 (no goals; ns), 59.8+/-14.0 to 76.8+/-7.0 (individual goals; p<0.01), and 62.5+/-9.5 to 67.0+/-10.0 (group goals; ns). Performance improvement in the individual goals group was significantly higher than the no goals group (p<0.05). CONCLUSIONS: Debriefing facilitators should encourage learners to focus on creating and achieving personal goals contributing to teamwork. PMID- 27765183 TI - Experimental comparison of abdominal drainage systems. AB - BACKGROUND: In an experimental study the performance of different closed abdominal drainage systems was tested. METHODS: A vacuum bottle designed for Redon Drainage, a flexible plastic bulb designed for Jackson-Pratt drains and a V.A.C.(r) Negative Pressure Wound Therapy System were used. In a porcine cadaveric study mimicking the abdominal cavity the intrinsic pressure (IP) at one and three minutes (T0, T3) and the amount of evacuated fluid were measured. RESULTS: The Redon and Jackson drainage displayed a rapid decline to IP values of almost zero comparing T0 and T3. Only the V.A.C.(r) system was able to preserve constant values of negative IP values measured at both time points. Only the V.A.C.(r) system was able to remove almost the whole amount of inserted fluid. CONCLUSIONS: In an experimental setting the V.A.C.(r) system was superior to the other two tested systems in delivering constant negative IP and the amount of evacuated fluid. PMID- 27765184 TI - Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction. AB - BACKGROUND: Impaired functional capacity is a hallmark of patients with heart failure with preserved ejection fraction (HFpEF). Despite the association of HFpEF with reduced myocardial compliance attributed to fibrosis, spironolactone has not been shown to alter outcomes-perhaps reflecting the heterogeneity of underlying pathological mechanisms. OBJECTIVES: The authors sought to identify improvement in exercise capacity with spironolactone in the subset of patients with HFpEF with exercise-induced increase in ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') reflecting elevation of left ventricular (LV) filling pressure. METHODS: In this randomized, blinded, parallel-group, placebo-controlled trial, 150 subjects (age 67 +/- 9 years) with exertional dyspnea (New York Heart Association functional class II to III, left ventricular ejection fraction >50%, diastolic dysfunction, and exertional E/e' >13), excluding those with ischemic heart disease, were recruited in a tertiary cardiology center. Patients were randomized to 6 months of oral spironolactone 25 mg/day or matching placebo. Primary outcomes were improvements in peak oxygen uptake (VO2) and exertional E/e' ratio, and secondary outcomes were improvements in exercise blood pressure response and global LV longitudinal strain. RESULTS: At follow-up, 131 patients completed therapy-64 taking spironolactone and 67 placebo. At baseline, subjects had substantial exercise limitation (peak VO2 64 +/- 17% predicted). The spironolactone group showed improvement in exercise capacity (increment in peak VO2 [2.9 ml/min/kg (95% confidence interval [CI]: 1.9 to 3.9 ml/min/kg) vs. 0.3 ml/min/kg (95% CI: -0.5 to 1.1 ml/min/kg); p < 0.001], anaerobic threshold [2.0 ml/min/kg (95% CI: 0.9 to 3.2 ml/min/kg) vs. -0.9 ml/min/kg (95% CI: -3.4 to 1.6 ml/min/kg); p = 0.03], and O2 uptake efficiency [0.19 (95% CI: 0.06 to 0.31) vs. -0.07 (95% CI: -0.17 to 0.04); p = 0.002]), with reduction in exercise-induced increase in E/e' (-3.0 [95% CI: -3.9 to -2.0] vs. 0.5 [95% CI: -0.6 to 1.6]; p < 0.001). There was a significant interaction of spironolactone and change in E/e' on VO2 (p = 0.039). CONCLUSIONS: In patients with HFpEF and abnormal diastolic response to exertion, improvement in exercise E/e' mediates the beneficial effect of spironolactone on exercise capacity. Identification of exercise-induced increase in LV filling pressure in patients with HFpEF may define a subgroup with warranting trial of spironolactone. PMID- 27765185 TI - If Exercise Is the Best Medicine, Should Medicine Be More Focused on Exercise in HFpEF? PMID- 27765186 TI - Valve-Sparing Root Replacement Compared With Composite Valve Graft Procedures in Patients With Aortic Root Dilation. AB - BACKGROUND: Although aortic valve-sparing (AVS) operations are established alternatives to composite valve graft (CVG) procedures for patients with aortic root aneurysms, comparative long-term outcomes are lacking. OBJECTIVES: This study sought to compare the results of patients undergoing AVS procedures with those undergoing CVG operations. METHODS: From 1990 to 2010, a total of 616 patients age <70 years and without aortic stenosis underwent elective aortic root surgery (AVS, n = 253; CVG with a bioprosthesis [bio-CVG], n = 180; CVG with a mechanical prosthesis [m-CVG], n = 183). A propensity score was used as a covariate to adjust for unbalanced variables in group comparisons. Mean age was 46 +/- 14 years, 83.3% were male, and mean follow-up was 9.8 +/- 5.3 years. RESULTS: Patients undergoing AVS had higher rates of Marfan syndrome and lower rates of bicuspid aortic valve than those undergoing bio-CVG or m-CVG procedures. In-hospital mortality (0.3%) and stroke rate (1.3%) were similar among groups. After adjusting for clinical covariates, both bio-CVG and m-CVG procedures were associated with increased long-term major adverse valve-related events compared with patients undergoing AVS (hazard ratio [HR]: 3.4, p = 0.005; and HR: 5.2, p < 0.001, respectively). They were also associated with increased cardiac mortality (HR: 7.0, p = 0.001; and HR: 6.4, p = 0.003). Furthermore, bio-CVG procedures were associated with increased risk of reoperations (HR: 6.9; p = 0.003), and m CVG procedures were associated with increased risk of anticoagulant-related hemorrhage (HR: 5.6; p = 0.008) compared with AVS procedures. CONCLUSIONS: This comparative study showed that AVS procedures were associated with reduced cardiac mortality and valve-related complications when compared with bio-CVG and m-CVG. AVS is the treatment of choice for young patients with aortic root aneurysm and normal or near-normal aortic cusps. PMID- 27765187 TI - Aortic Valve-Sparing Surgery: Yes, But Not for Every Patient and Select the Center Very Carefully. PMID- 27765188 TI - Selecting the Duration of Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Complex Decision or Not? PMID- 27765190 TI - What We Are Learning From Transcatheter Aortic Valve Replacement Risk Prediction Models. PMID- 27765189 TI - Prediction of Poor Outcome After Transcatheter Aortic Valve Replacement. AB - BACKGROUND: A series of models have been developed to identify patients at high risk for poor outcomes after transcatheter aortic valve replacement (TAVR) to help guide treatment choices, offer patients realistic expectations of long-term outcomes, and support decision making. OBJECTIVES: This study examined the performance of the previously developed TAVR Poor Outcome risk models in an external dataset and explored the incremental contribution of geriatric domains to model performance. METHODS: Poor outcome after TAVR was defined as death, poor quality of life (QOL), or decline in QOL, as assessed using the Kansas City Cardiomyopathy Questionnaire. We tested 4 TAVR Poor Outcome risk models: 6-month and 1-year full and clinical (reduced) models. We examined each model's discrimination and calibration in the CoreValve trial dataset, and then tested the incremental contribution of frailty and disability markers to the model's discrimination using the incremental discrimination index. RESULTS: Among 2,830 patients who underwent TAVR in the CoreValve US Pivotal Extreme and High Risk trials and associated continued access registries, 31.2% experienced a poor outcome at 6 months following TAVR (death, 17.6%; very poor QOL, 11.6%; QOL decline, 2.0%) and 50.8% experienced a poor outcome at 1 year (death, 30.2%; poor QOL, 19.6%; QOL, decline 1.0%). The models demonstrated similar discrimination as in the Placement of Aortic Transcatheter Valves Trial cohorts (c-indexes, 0.637 to 0.665) and excellent calibration. Adding frailty as a syndrome increased the c indexes by 0.000 to 0.004 (incremental discrimination index, p < 0.01 for all except the 1-year clinical model), with the most important individual components being disability and unintentional weight loss. CONCLUSIONS: Although discrimination of the TAVR Poor Outcome risk models was generally moderate, calibration was excellent among patients with different risk profiles and treated with a different TAVR device. These findings demonstrated the value of these models for individualizing outcome predictions in high-risk patients undergoing TAVR. PMID- 27765192 TI - Toward Translation of Genomic Discovery to Clinical Efficacy in Atrial Fibrillation. PMID- 27765191 TI - PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers. AB - BACKGROUND: Antiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Recent data suggested that paired like homeodomain-2 transcription factor (PITX2) might play an important role in regulating gene expression and electrical function of the adult left atrium (LA). OBJECTIVES: After determining LA PITX2 expression in AF patients requiring rhythm control therapy, the authors assessed the effects of Pitx2c on LA electrophysiology and the effect of antiarrhythmic drugs. METHODS: LA PITX2 messenger ribonucleic acid (mRNA) levels were measured in 95 patients undergoing thoracoscopic AF ablation. The effects of flecainide, a sodium (Na+)-channel blocker, and d,l-sotalol, a potassium channel blocker, were studied in littermate mice with normal and reduced Pitx2c mRNA by electrophysiological study, optical mapping, and patch clamp studies. PITX2 dependent mechanisms of antiarrhythmic drug action were studied in human embryonic kidney (HEK) cells expressing human Na channels and by modeling human action potentials. RESULTS: Flecainide 1 MUmol/l was more effective in suppressing atrial arrhythmias in atria with reduced Pitx2c mRNA levels (Pitx2c+/ ). Resting membrane potential was more depolarized in Pitx2c+/- atria, and TWIK related acid-sensitive K+ channel 2 (TASK-2) gene and protein expression were decreased. This resulted in enhanced post-repolarization refractoriness and more effective Na-channel inhibition. Defined holding potentials eliminated differences in flecainide's effects between wild-type and Pitx2c+/- atrial cardiomyocytes. More positive holding potentials replicated the increased effectiveness of flecainide in blocking human Nav1.5 channels in HEK293 cells. Computer modeling reproduced an enhanced effectiveness of Na-channel block when resting membrane potential was slightly depolarized. CONCLUSIONS: PITX2 mRNA modulates atrial resting membrane potential and thereby alters the effectiveness of Na-channel blockers. PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF. PMID- 27765193 TI - The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease. AB - Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial. PMID- 27765194 TI - Overcoming the Challenges of Conducting Early Feasibility Studies of Medical Devices in the United States. AB - Initial clinical studies of new medical technologies involve a complex balance of research participant benefits versus risks and costs of uncertainty when novel concepts are tested. The Food and Drug Administration Center for Devices and Radiological Health has recently introduced the Early Feasibility Study (EFS) Program for facilitating the conduct of these studies under the Investigational Device Exemption regulations. However, a systematic approach is needed to successfully implement this program while affording appropriate preservation of the rights and interests of patients. For this to succeed, a holistic reform of the clinical studies ecosystem for performing early-stage clinical research in the United States is necessary. The authors review the current landscape of the U.S. EFS and make recommendations for developing an efficient EFS process to meet the goal of improving access to early-stage, potentially beneficial medical devices in the United States. PMID- 27765195 TI - Managing Pregnancy as an Interventional Cardiologist Fellow-in-Training: My Experience With a Simulator. PMID- 27765196 TI - Single Antiplatelet Therapy Following Left Atrial Appendage Closure in Patients With Contraindication to Anticoagulation. PMID- 27765197 TI - Cardio-Oncology: The Carney Complex Type I. PMID- 27765198 TI - T1 and T2 Mapping in Nonischemic Cardiomyopathies and Agreement With Endomyocardial Biopsy. PMID- 27765199 TI - Early Surgery for Mixed Aortic Valve Disease: A Precocious or Premature Proposition? PMID- 27765200 TI - Reply: T1 and T2 Mapping in Nonischemic Cardiomyopathies and Agreement With Endomyocardial Biopsy. PMID- 27765201 TI - Reply: Early Surgery for Mixed Aortic Valve Disease: A Precocious or Premature Proposition? PMID- 27765202 TI - A Comprehensive Plan to Prevent Bullying. PMID- 27765203 TI - Tracking thermal degradation on passion fruit juice through Nuclear Magnetic Resonance and chemometrics. AB - Thermal food processing mainly aims to control microorganism in order to extend its shelf life. However, it may induce chemical and nutritional changes in foodstuff. The Nuclear Magnetic Resonance (NMR) coupled to multivariate analysis was used to evaluate the effect of different thermal processing conditions (85 and 140 degrees C for 4; 15; 30; and 60s) on the passion fruit juice using an Armfield pasteurizer. Through this approach it was possible to identify the changes in the juice composition. The temperature and the time lead to a hydrolysis of the sucrose to glucose and fructose. Additionally, juice submitted to 140 degrees C for 60s results in the degradation of the sucrose and the formation of 5-(hydroxymethyl)-2-furfural (HMF). Despite no novel chemical marker has been identified, the 1H NMR chemometrics approach may contribute in the choice of the temperature and time to be employed in the juice processing. PMID- 27765204 TI - Inorganic selenium speciation analysis in Allium and Brassica vegetables by ionic liquid assisted liquid-liquid microextraction with multivariate optimization. AB - A highly sensitive vortex assisted liquid-liquid microextraction (VA-LLME) method was developed for inorganic Se [Se(IV) and Se(VI)] speciation analysis in Allium and Brassica vegetables. Trihexyl(tetradecyl)phosphonium decanoate phosphonium ionic liquid (IL) was applied for the extraction of Se(IV)-ammonium pyrrolidine dithiocarbamate (APDC) complex followed by Se determination with electrothermal atomic absorption spectrometry. A complete optimization of the graphite furnace temperature program was developed for accurate determination of Se in the IL enriched extracts and multivariate statistical optimization was performed to define the conditions for the highest extraction efficiency. Significant factors of IL-VA-LLME method were sample volume, extraction pH, extraction time and APDC concentration. High extraction efficiency (90%), a 100-fold preconcentration factor and a detection limit of 5.0ng/L were achieved. The high sensitivity obtained with preconcentration and the non-chromatographic separation of inorganic Se species in complex matrix samples such as garlic, onion, leek, broccoli and cauliflower, are the main advantages of IL-VA-LLME. PMID- 27765205 TI - Infrared drying of strawberry. AB - The effects of different drying conditions, such as infrared power, drying air temperature and velocity, on quality of strawberry were evaluated. Drying time decreased with increased infrared power, air temperature and velocity. An increase in power from 100W to 300W, temperature from 60 to 80 degrees C and velocity from 1.0m.s-1 to 2.0m.s-1 decreased fruit color quality index. For total phenol and anthocyanin content, 300W, 60 degrees C, and 1.0m.s-1 were superior to the other experimental conditions. The drying processes increased N, P and K and decreased Ca, Mg, Fe, Mn, Zn and Cu contents. The optimal conditions to preserve nutrients in infrared drying of strawberry were 200W, 100 degrees C and 1.5m.s-1. PMID- 27765206 TI - Characterisation of aged infant formulas and physicochemical changes. AB - Three different infant formulas (P1, P2 and P3) were characterised, and changes in their physicochemical properties under three different ageing conditions (i.e. 25 degrees C, 45 degrees C and 60 degrees C) were established. At 60 degrees C, all of the three powders exhibited increased moisture content, which was consistent with an increase in water activity. The GAB sorption model fitted for P1 while P2 and P3 did not follow the same sorption isotherm pattern. The glass transition temperature (Tg) for all of the powders significantly decreased at 45 degrees C and 60 degrees C. Confocal analysis revealed that all three powders had different concentrations of surface fat, and fat globules migrated from within the powders to the powder surface during storage under the conditions described. XRD analysis of the aged powders showed no occurrence of lactose crystallisation. PMID- 27765207 TI - Effects of temperature and NaCl on the formation of 3-MCPD esters and glycidyl esters in refined, bleached and deodorized palm olein during deep-fat frying of potato chips. AB - The effects of frying duration, frying temperature and concentration of sodium chloride on the formation of 3-monochloropropane-1,2-diol (3-MCPD) esters and glycidyl esters (GEs) of refined, bleached and deodorized (RBD) palm olein during deep-fat frying (at 160 degrees C and 180 degrees C) of potato chips (0%, 1%, 3% and 5% NaCl) for 100min/d for five consecutive days in eight systems were compared in this study. All oil samples collected after each frying cycle were analyzed for 3-MCPD esters, GEs, free fatty acid (FFA) contents, specific extinction at 232 and 268 nm (K232 and K268), p-anisidine value (pAV), and fatty acid composition. The 3-MCPD ester trend was decreasing when the frying duration increased, whereas the trend was increasing when frying temperature and concentration of NaCl increased. The GEs trend was increasing when the frying temperature, frying duration and concentration of NaCl increased. All of the oil qualities were within the safety limit. PMID- 27765208 TI - Studies on the volatile fraction composition of three native Amazonian-Brazilian fruits: Murici (Byrsonima crassifolia L., Malpighiaceae), bacuri (Platonia insignis M., Clusiaceae), and sapodilla (Manilkara sapota L., Sapotaceae). AB - The volatile fraction of murici, bacuri and sapodilla are here studied because of their increasing interest for consumers, abundance of production in Brazil, and the general demand for new flavors and aromas. Their volatile profiles were studied by two High Concentration Capacity Headspace techniques (HCC-HS), Headspace Solid Phase Microextraction (HS-SPME) and Headspace Sorptive Extraction (HSSE), in combination with GC-MS. Murici volatile fraction mainly contains esters (38%), carboxylic acids (19%), aldehydes (11%), alcohols (14%), others (13%) and sulfur compounds; bacuri is characterized by terpenes (41%), non terpenic alcohols (24%), esters (15%), aldehydes (6%), and others (12%); sapodilla consists of esters (33%), alcohols (27%), terpenes (18%) and others (21%). The GC-MS component co-elution was overcome by GC*GC-qMS. The adoption of modern analysis technologies afforded to achieve a better knowledge of the volatile fraction composition of these fruit pulps by increasing substantially the number of compounds identified. PMID- 27765209 TI - Cultivar classification of Apulian olive oils: Use of artificial neural networks for comparing NMR, NIR and merceological data. AB - The development of an efficient and accurate method for extra-virgin olive oils cultivar and origin authentication is complicated by the broad range of variables (e.g., multiplicity of varieties, pedo-climatic aspects, production and storage conditions) influencing their properties. In this study, artificial neural networks (ANNs) were applied on several analytical datasets, namely standard merceological parameters, near-infra red data and 1H nuclear magnetic resonance (NMR) fingerprints, obtained on mono-cultivar olive oils of four representative Apulian varieties (Coratina, Ogliarola, Cima di Mola, Peranzana). We analyzed 888 samples produced at a laboratory-scale during two crop years from 444 plants, whose variety was genetically ascertained, and on 17 industrially produced samples. ANN models based on NMR data showed the highest capability to classify cultivars (in some cases, accuracy>99%), independently on the olive oil production process and year; hence, the NMR data resulted to be the most informative variables about the cultivars. PMID- 27765210 TI - NMR metabolomics demonstrates phenotypic plasticity of sea buckthorn (Hippophae rhamnoides) berries with respect to growth conditions in Finland and Canada. AB - The berries of sea buckthorn (Hippophae rhamnoides ssp. rhamnoides) cultivars 'Terhi' and 'Tytti' were studied with respect to their growth location, 60 degrees and 68 degrees N latitude in Finland and 46 degrees N in Canada, using 1H NMR metabolomics. The berries of 'Terhi' were characterised by stronger signals of quinic acid, while 'Tytti' had higher levels of O-ethyl beta-d glucopyranoside. The metabolic profile of the northernmost berries was distinctly different from those grown in southern Finland or Canada. Berries from northern Finland had relatively higher levels of quinic acid, glucose, l-quebrachitol and ascorbic acid. Ethyl glucoside was shown to accumulate by several fold at the late stage of maturation in the south as it correlated with degree days (r=0.63) and global radiation (r=0.59), but not in the north. The variance in the composition of the sea buckthorn berries demonstrates plasticity in the acclimatisation to growth environments. PMID- 27765211 TI - New isobaric lignans from Refined Olive Oils as quality markers for Virgin Olive Oils. AB - Herein we describe the influence of olive oil refining processes on the lignan profile. The detection of new isobaric lignans is suggested to reveal frauds in commercial extra-Virgin Olive Oils. We analyzed five commercial olive oils by HPLC-DAD-TOF/MS to evaluate their lignan content and detected, for the first time, some isobaric forms of natural (+)-pinoresinol and (+)-1 acetoxypinoresinol. Then we analyzed partially and fully-refined oils from Italy, Tunisia and Spain. The isobaric forms occur only during the bleaching step of the refining process and remain unaltered after the final deodorizing step. Molecular dynamic simulation helped to identify the most probable chemical structures corresponding to these new isobars with data in agreement with the chromatographic findings. The total lignan amounts in commercial olive oils was close to 2mg/L. Detection of these new lignans can be used as marker of undeclared refining procedures in commercial extra-virgin and/or Virgin Olive Oils. PMID- 27765212 TI - Structural and oxidative stabilization of spray dried fish oil microencapsulates with gum arabic and sage polyphenols: Characterization and release kinetics. AB - The synergistic efficacy of gum arabic and sage polyphenols in stabilising capsule wall and protecting fish oil encapsulates from heat induced disruption and oxidative deterioration during spray drying was assessed. The emulsions prepared with sodium caseinate as wall polymer, gum arabic as wall co-polymer and sage extract as wall stabiliser was spray dried using a single fluid nozzle. Fish oil encapsulates stabilised with gum arabic and sage extract (SOE) exhibited significantly higher encapsulation efficiency compared to encapsulates containing gum arabic alone (FOE). Scanning electron microscopic and atomic force microscopic images revealed uniform encapsulates with good sphericity and smooth surface for SOE, compared to FOE powder. In vitro oil release of microencapsulates indicated negligible oil release in buffered saline whereas more than 80% of the oil loaded in encapsulates were released in simulated GI fluids. The encapsulates containing sage extract showed a lower rate of lipid oxidation during storage. PMID- 27765213 TI - Influence of pH on viscoelastic properties of heat-induced gels obtained with a beta-Lactoglobulin fraction isolated from bovine milk whey hydrolysates. AB - A beta-Lactoglobulin fraction (r-betaLg) was isolated from whey hydrolysates produced with cardosins from Cynara cardunculus. The impact of the hydrolysis process on the r-betaLg structure and the rheological properties of heat-induced gels obtained thereafter were studied at different pH values. Differences were observed between r-betaLg and commercial beta-Lg used as control. Higher values for the fluorescence emission intensity and red shifts of the emission wavelength of r-betaLg suggested changes in its tertiary structure and more solvent-exposed tryptophan residues. Circular dichroism spectra also supported these evidences indicating that hydrolysis yielded an intermediate (non-native) beta-Lg state. The thermal history of r-betaLg through the new adopted conformation improved the microstructure of the gels at acidic pH. So, a new microstructure with better rheological characteristics (higher conformational flexibility and lower rigidity) and greater water holding ability was founded for r-betaLg gel. These results were reflected in the microstructural analysis by scanning electron microscopy. PMID- 27765215 TI - Investigation of CO2 precursors in roasted coffee. AB - Two CO2 formation pathways (chlorogenic acid (CGA) degradation and Maillard reaction) during coffee roasting were investigated. CGA is shown not a major contributor to CO2 formation, as heating of this compound under typical roasting conditions did not release a large quantity of CO2. However, heating of a CGA moiety, caffeic acid, resulted in high yield of CO2 (>98%), suggesting that CGA hydrolysis could be the rate limiting step for CO2 formation from CGA. A large amount of CO2 was detected from glycine-sucrose model system under coffee roasting conditions, implying the importance of Maillard reactions in CO2 formation. Further studies on the heating of various components isolated from green coffee beans showed that CO2 was generated from various green coffee components, including water insoluble proteins and polysaccharides. Around 50% of CO2 was formed from thermal reactions of lower molecular weight compounds that represent ~25% by weight in green coffee. PMID- 27765214 TI - Selenium delays tomato fruit ripening by inhibiting ethylene biosynthesis and enhancing the antioxidant defense system. AB - The antioxidant activity of selenium (Se) detoxifies reactive oxygen species (ROS) in plants and animals. In the present study, we elucidated the mechanism underlying Se induced fruit development and ripening. Our study showed that foliar pretreatment with 1mgL-1 sodium selenate effectively delayed fruit ripening and maintained fruit quality. Gene expression studies revealed that the repression of ethylene biosynthetic genes 1-aminocyclopropane-1-carboxylic acid (ACC) synthase and ACC oxidase decreased ethylene production and respiration rate. Moreover, Se treatment probably boosted the antioxidant defense system to reduce ROS generation and membrane damage. The enhanced antioxidative effect was attributed to higher glutathione content and increased activity of enzymes such as glutathione peroxidase and glutathione reductase. The upregulation of respiratory burst oxidase homologue genes in tomato fruit may also contribute to the enhanced antioxidative effect. Selenium treatment represents a promising strategy for delaying ripening and extending the shelf life of tomato fruit. PMID- 27765216 TI - The use of capillary electrophoresis with contactless conductivity detection for sensitive determination of stevioside and rebaudioside A in foods and beverages. AB - Two electrophoretic methods with contactless conductivity detection have been developed for determination of the content of rebaudioside A and stevioside in samples of sweeteners and beverages prepared from extracts of the plant Stevia rebaudiana Bertoni. The total content of rebaudioside A and stevioside can be determined in a fused silica capillary with an inner diameter of 10MUm and total length of 31.5cm in optimised background electrolyte with the composition 170mM H3BO3/LiOH (pH 9.0). The combined peak of the two glucosides is characterised by a migration time of 54s, which completely separates it from EOF. INST coating solution in an amount of 0.5% v/v, which effectively suppresses the electroosmotic flow, was added to the background electrolyte for mutual separation of rebaudioside A and stevioside. The CE method with suppression of EOF is characterised by complete separation of rebaudioside A and stevioside, LOD is 0.3mg/L (0.1MUM). PMID- 27765217 TI - Lutein ester profile in wheat and tritordeum can be modulated by temperature: Evidences for regioselectivity and fatty acid preferential of enzymes encoded by genes on chromosomes 7D and 7Hch. AB - The increase of lutein retention through the food chain is desirable for wheat breeding. Lutein esters are more stable than free lutein during post-harvest storage and two loci on chromosomes 7D and 7Hch are important for esterification. We investigated the effect of temperature during grain filling on carotenoid accumulation and lutein ester profile including fatty acid selectivity (palmitic vs. linoleic) and regioselectivity (esterification at positions 3 vs. 3'). Three different temperature regimes were assayed (controlled, semi-controlled and non controlled). Lutein esters were more stable than free carotenoids in vivo and the enzymes encoded by chromosomes 7Hch and 7D are complementary. Indeed, they show differential preferences for the fatty acid (palmitic and linoleic, respectively) and regioselectivity (3 and 3', respectively). Besides, H. chilense has additional genes for esterification. Finally, the increase of temperature favoured the accumulation of lutein esters with linoleic acid and the synthesis of regioisomers at position 3'. PMID- 27765218 TI - Properties of adsorption of vitamin B12 on nanoclay as a versatile carrier. AB - In this study properties of adsorption of vitamin B12 onto nanoclay were investigated. Results of kinetics of adsorption were used to investigate the structural formation and nature of interaction of vitamin B12 onto montmorillonite as a carrier. The results showed that at the early stages of adsorption with migration of interlayer cations of montmorillonite (Ca2+and Na+) to the edges a cationic bridge was formed and the vitamin biomolecules were adsorbed at the edges of montmorillonite. By increasing the adsorption duration, vitamin B12 molecules gradually diffused in between montmorillonite layers. Such diffusion was facilitated when enough interaction existed between montmorillonite surface charges and vitamin biomolecules. The results of this study provided information about controlling the adsorption properties of biomolecules to the montmorillonite for preparation of nano-engineered nano/biomaterials for food and pharmaceutical applications. PMID- 27765219 TI - Effect of transglutaminase-catalyzed glycosylation on the allergenicity and conformational structure of shrimp (Metapenaeus ensis) tropomyosin. AB - Tropomyosin (TM), a myofibrillar protein, is a major allergen in shrimp. The aim of this study was to evaluate the effect of transglutaminase (TGase)-catalyzed glycosylation on the potential allergenicity and conformational structure of TM in Metapenaeus ensis. Results showed that glycosylation of TM induced unfolding of the primary protein structure followed by loss of the secondary structure. Cleavage of certain free amino groups was observed during TGase-catalyzed glycosylation. The glycosylation rate correlated with reaction temperature. Western blotting and indirect ELISA with TM-specific polyclonal antibodies from rabbit and sera from patients allergic to shrimp demonstrated that antigenicity and potential allergenicity of TM decreased, which correlated well with the conformational changes in its structure. Considering TGase is widely utilized in the food industry, these results indicate that TGase-catalyzed glycosylation has the potential to serve as a mild method for reducing the allergenicity of shrimp products. PMID- 27765221 TI - Optimization of the ultrasound-assisted extraction of anthocyanins and total phenolic compounds in mulberry (Morus nigra) pulp. AB - New ultrasound-assisted extraction methods for the determination of anthocyanins and total phenolic compounds present in mulberries have been developed. Several extraction variables, including methanol composition (50-100%), temperature (10 70 degrees C), ultrasound amplitude (30-70%), cycle (0.2-0.7s), solvent pH (3-7) and solvent-solid ratio (10:1.5-20:1.5) were optimized. A Box-Behnken design in conjunction with a response surface methodology was employed to optimize the conditions for the maximum response based on 54 different experiments. Two response variables were considered: total anthocyanins and total phenolic compounds. Extraction temperature and solvent composition were found to be the most influential parameters for anthocyanins (48 degrees C and 76%) and phenolic compounds (64 degrees C and 61%). The developed methods showed high reproducibility and repeatability (RSD<5%). Finally, the new methods were successfully applied to real samples in order to investigate the presence of anthocyanins and total phenolic compounds in several mulberry jams. PMID- 27765220 TI - Comparative proteomic analysis of two clam species: Chamelea gallina and Tapes philippinarum. AB - Clams have long been a fisheries and aquaculture sector of great importance in Italy, the main resource of fisheries is the Chamelea gallina of indigenous origin, whereas clams breeding is supported almost entirely by the Tapes philippinarum, a species of Indo-Pacific origin. Bivalve molluscs quality depends mainly on the water quality, and then by a series of factors such as water temperature and salinity, gametogenic cycle, food availability, and environmental conditions, that affect the Condition Index. In this work crude extracts obtained from the edible part of Chamelea gallina and Tapes philippinarum were analyzed by a proteomic approach based on a two-dimensional gel electrophoresis followed by liquid chromatography-tandem mass spectrometry, in order to detect biomarkers useful for identification of the two kinds of clams and to assess their nutritional characteristics. As a result, four differentially expressed spots were found and identified, namely enolase, cyclophilin-A, ribosomal protein L13 and actin-1. PMID- 27765222 TI - Rationale behind the near-ideal catalysis of Candida antarctica lipase A (CAL-A) for highly concentrating omega-3 polyunsaturated fatty acids into monoacylglycerols. AB - Dramatic decline in the quality and quantity of omega-3 PUFAs from marine resource demands new environmental-friendly technology to produce high quality omega-3 PUFAs concentrates in a better bioavailable form. Accordingly this work demonstrated an exceptionally highly efficient non-aqueous approach that non regiospecific and non omega-3 PUFAs preferential Candida antarctica lipase A (CAL A), functioning as a near-ideal biocatalyst, is capable to directly concentrate omega-3 PUFAs from 20% to 30% in oils to up to >90% in monoacylglycerols form through one step reaction. The rationale behind the experimental observation is justified and the catalytic property and specificity of an ideal enzyme tackling this task are defined. High selectivity and efficiency, excellent reusability of biocatalyst, general applicability for concentrating omega-3 PUFAs from both fish and microalgae oils, simple process for product recovery (e.g. by short path distillation), make this novel approach a highly industrially relevant and with potential application in food and drug industries. PMID- 27765224 TI - Determination of volatile marker compounds in raw ham using headspace-trap gas chromatography. AB - A simple, reliable and automated method was developed and optimized for qualification and quantification of aroma-relevant volatile marker compounds of North European raw ham using a headspace (HS)-Trap gas chromatography-mass spectrometry (GC-MS) and GC-flame ionization detector (FID) analysis. A total of 38 volatile compounds were detected with this HS-Trap GC-MS method amongst which the largest groups were ketones (12), alcohols (8), hydrocarbons (7), aldehydes (6) and esters (3). The HS-Trap GC-FID method was optimized for the parameters: thermostatting time and temperature, vial and desorption pressure, number of extraction cycles and salt addition. A validation for 13 volatile marker compounds with limits of detection in ng/g was carried out. The optimized method can serve as alternative to conventional headspace and solid phase micro extraction methods and allows users to determine volatile compounds in raw hams making it of interest to industrial and academic meat scientists. PMID- 27765223 TI - Mechanically fractionated flour isolated from green bananas (M. cavendishii var. nanica) as a tool to increase the dietary fiber and phytochemical bioactivity of layer and sponge cakes. AB - This article describes the effect of mechanically fractionated flours from green bananas on the nutritional, physical and sensory attributes of two types of cakes (sponge and layer). A plausible 30% replacement of banana flour in the formulation of layer cakes is demonstrated, finding only a small decline in the sensory perception. On the contrary, sponge cakes were noticeable worsened with the use of banana flours (lower specific volume, worse sensory attributes and higher hardness), which was minimized when using fine flour. Both layer and sponge cakes exhibited an enhancement of the resistant starch and dietary fiber content with the replacement of green banana flour (up to a fivefold improvement in RS performance). Moreover, sponge cakes yielded more polyphenols and antioxidant capacity with banana flours, especially with the coarse fraction. Therefore, results showed that a mechanical fractionation allowed a feasible nutritional enhancement of cakes with the use of banana flours. PMID- 27765225 TI - Starch digestibility and molecular weight distribution of proteins in rice grains subjected to heat-moisture treatment. AB - The objective of this study was to evaluate the effects of the heat-moisture treatment (HMT) applied to paddy rice grains on the physicochemical properties, in vitro starch digestibility, and molecular weight distribution of proteins in rice flour. The paddy rice grains were adjusted to 13%, 16%, and 18% moisture and autoclaved at 121 degrees C for 30 and 60min. The HMT promoted a reduction of the amylose content, the swelling power, and the solubility of the rice flour. Changes in the relative crystallinity and molecular weight of the proteins extracted with a sodium phosphate buffer containing 2.0% sodium dodecyl sulfate (SDDS) were observed in HMT samples. The different methods for the quantification of resistant starch resulted in distinct resistant starch contents. The HMT (18% 60min) promoted an increase in resistant starch content and the HMT (16%-60min) caused an increase in the slowly digestible starch in the rice flour. PMID- 27765226 TI - Octyl gallate: An antioxidant demonstrating selective and sensitive fluorescent property. AB - Octyl gallate (OG) is an internationally recognized antioxidant that demonstrates selective and sensitive fluorescent property. The fluorescence of OG can be selectively enhanced in the presence of human serum albumin (HSA) and bovine serum albumin (BSA). The specific structures of HSA and BSA provided the basic conditions for fluorescence enhancement. OG yielded approximately 49- and 11-fold increments in emission intensity in the presence of HSA and BSA at a molar ratio of 1:1, respectively. The lifetimes of HSA and BSA correspondingly decreased. A Forster resonance energy transfer phenomenon occurred during interaction between OG and HSA or BSA. Our in-depth investigation of OG-HSA interaction showed that formation of a stable complex was an important prerequisite to efficiently enhance the fluorescence of OG. The selective and sensitive fluorescent property of OG can possibly be used to determine OG concentration via the standard addition method, which must be performed under certain conditions. PMID- 27765227 TI - Impact of blanching, sweating and drying operations on pungency, aroma and color of Piper borbonense. AB - Low pungency, high aromatic potential and red color, give to Piper borbonense its originality when compared to Piper nigrum. Effects of blanching, sweating and drying on these characteristics were assessed. The three operations had no impact on the concentration of piperine and essential oil but affected the composition of essential oil slightly and considerably affected the color of the pepper. The "wet process", including blanching, sweating and drying, had the largest impact on the composition of aroma, increasing para-cymene content by 89% and reducing safrole content by 33% in dried pepper compared to fresh. Blanching increased the drying rate thus reducing drying time. Drying had a major impact on color, which changed from red to brown. The biggest differences observed led to reductions of 2.2, 7.9 and 8.4units in L*, a* and b* values, when chromatic values measured in fresh pepper were compared to those of dried pepper. PMID- 27765228 TI - Great diversity among commercial inactive dry-yeast based products. AB - Commercial inactive dry-yeast based (IDYB) products have been shown to impact positively in different ways on the winemaking process, including sensory enhancement. Despite their relevance little information about physicochemical characteristics of individual IDYB products is available. This study aimed to physicochemically characterize a group of ten commercial IDYB products. Organic, protein and carbohydrate contents by spectrophotometric methods, protein diffusion on cellulose membranes and electrophoretic protein profiles were assessed. Interaction of a IDYB product (CP10) with either salivary protein or a proanthocyanidin-rich extract (binary mixtures) or with both of them (ternary mixtures) was also assessed. Marked physicochemical differences were observed among all ten products. CP10 was found to interact with seed extract and salivary protein. Also, as part of CP10-SE complexes, CP10 interacted with the salivary protein to form ternary complexes. Due to their huge diversity, physicochemical characterization of IDYB products before use in winemaking is recommended. PMID- 27765229 TI - Effects of high hydrostatic pressure on the structure and potential allergenicity of the major allergen bovine beta-lactoglobulin. AB - Bovine beta-lactoglobulin (beta-Lg) is recognized as a significant milk allergen in several countries. In this study, beta-Lg was isolated and treated with high hydrostatic pressure (HHP) at 100, 200, 300, 400, and 500MPa. The allergenic properties of the HHP-treated beta-Lg were characterized by indirect competitive enzyme-linked immunosorbent assay with anti-beta-Lg rabbit antibody and the sera of patients allergic to cows' milk. The conformation of the HHP-treated beta-Lg was examined with ultraviolet absorption spectroscopy, endogenous fluorescence spectroscopy, exogenous fluorescence spectroscopy, and circular dichroism spectroscopy analyses. The results indicated that IgG binding increased with treatment pressure, and IgE binding was lowest at 200MPa and highest at 400MPa. The tertiary structure of beta-Lg changed significantly after HHP, whereas the primary and secondary structures remained stable. Overall, this study suggests that the conformational changes in HHP-treated beta-Lg contribute to its altered allergenicity. PMID- 27765230 TI - Fluorescence imaging of spatial location of lipids and proteins during digestion of protein-stabilized oil-in-water emulsions: A simulated gastrointestinal tract study. AB - A whey protein isolate-rhodamine B conjugate (WPI-RB) was synthesized to visualize changes in the location of a protein emulsifier in oil-in-water emulsions during digestion. An oil-soluble dye (Nile Red) was used to visualize changes in the lipid phase during digestion. Protein-labeled and lipid-labeled emulsions were passed through a simulated gastrointestinal tract consisting of mouth, stomach, and intestinal phases, and changes in protein and lipid location and morphology were monitored using confocal laser scanning microscopy. The proteins remained attached to the lipid droplet surfaces in the mouth and stomach, but formed large aggregates in the small intestine. The lipid droplets were highly flocculated in the mouth, highly coalesced in the stomach, and fully digested in the small intestine. Our results show that conjugation of fluorescence dyes to protein emulsifiers is useful for direct visualization of their location, as well as for understanding the behavior of food emulsions within the gastrointestinal tract. PMID- 27765231 TI - Effects of protein phosphorylation on color stability of ground meat. AB - The influence of protein phosphorylation on meat color stability was investigated in this study. Phosphatase and protein kinase inhibitors were added to minced ovine Longissimus thoracis et lumborum (LTL) muscle to manipulate the global phosphorylation of sarcoplasmic proteins. The data obtained show that the rate and extent of pH decline, along with lactate accumulation in postmortem muscle, were related to protein phosphorylation. Analysis of meat color and the relative content of myoglobin redox forms revealed that meat color stability was inversely related to the phosphorylation of sarcoplasmic proteins. Thus, this study suggests that protein phosphorylation may be involved in meat color development by regulating glycolysis and the redox stability of myoglobin. PMID- 27765232 TI - Identification of novel peptides from 3 to 10kDa pine nut (Pinus koraiensis) meal protein, with an exploration of the relationship between their antioxidant activities and secondary structure. AB - In the present study, two novel peptides Lys-Trp-Phe-Cys-Thr (KWFCT) and Gln-Trp Phe-Cys-Thr (QWFCT) were purified and identified from 3 to 10kDa pine nut (Pinus koraiensis) meal protein. Their cytotoxicity and antioxidant activities in vitro were determined. Additionally, pulsed electric field technology, antioxidant activities, and circular dichroism were used together to investigate the relationship between antioxidant activities and secondary structure. The results showed that neither peptide demonstrated cytotoxicity in HepG2 cells. KWFCT had higher values for 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition (67.43%+/ 1.33%) and ferric-reducing antioxidant power (67.86+/-1.03mM Fe2+/mg), and Ac QWFCT had higher values for 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) inhibition (74.9%+/-1.19%) and cellular antioxidant activity (916.32MUmol of QE/100g) (P<0.05). The antioxidant activities reached their highest values when parameters of PEF were 5kV/cm and 2400Hz. An increase in antioxidant activities of Ac-QWFCT was correlated with a decrease in random coil content. PMID- 27765233 TI - Fetal bovine serum influences the stability and bioactivity of resveratrol analogues: A polyphenol-protein interaction approach. AB - Fetal bovine serum (FBS) is a universal growth supplement of cell and tissue culture media. Herein, the influences of FBS on the stability and antioxidant activity of 21 resveratrol analogues were investigated using a polyphenol-protein interaction approach. The structure-stability relationships of resveratrol analogues in FBS showed a clear decrease in the stability of hydroxylated resveratrol analogues in the order: resorcinol-type>pyrogallol-type>catechol type. The glycosylation and methoxylation of resveratrol analogues enhanced their stability. A linear relationship between the stability of resveratrol analogues in FBS and the affinity of resveratrol analogues-FBS interaction was found. The oxidation process is not the only factor governing the stability of resveratrol analogues in FBS. These results facilitated the insightful investigation of the role of polyphenol-protein interactions in serum, thereby providing some fundamental clues for future clinical research and pharmacological studies on natural small molecules. PMID- 27765234 TI - Characterization of Stevia leaves by LC-QTOF MS/MS analysis of polar and non polar extracts. AB - Stevia is currently a well-known plant thanks to its sweeting power. Numerous studies that elucidate its composition were exclusively focused on determination of steviol and its glycosides. Untargeted analysis was applied to obtain a profile of main compounds present in extracts from Stevia (Stevia rebaudiana Bertoni) leaves using LC-MS in high resolution mode with a quadrupole-time of flight analyzer. Eighty-nine compounds were tentatively identified and classified into different families: flavonoids; quinic and caffeic acids and derivatives; diterpenoids (including steviol and glycosides); sesquiterpenoids; amino acids and derivatives; fatty amides and derivatives; fatty acids and derivatives; oligosaccharides; glycerolipids; purines; and retinoids. New steviol glycosides were tentatively identified and their possible structures proposed. Other compounds were tentatively identified in Stevia for the first time, such as fatty acid amides. These results reveal the wide range of compounds present in Stevia, which could be responsible for the nutraceutical effects ascribed to their leaves. PMID- 27765235 TI - Ethyl esters versus fermentative organoleptic defects in virgin olive oil. AB - The quality and genuineness of extra-virgin olive oils (EVOOs) were assessed following the methods and parameters of EU Commission Regulation N degrees 2568/91/EEC and subsequent modifications, which also set specific limits for fatty-acid ethyl esters (FAEEs). This study included a subset of EVOOs from among 399 samples analysed as part of a monitoring study for FAEEs in EVOOs. The subset was subjected to statistical evaluation to quantify the relationships between FAEE content and sensory defects associated with fermentation: fusty/muddy sediment, musty/humid/earthy, and winey/vinegary. The use of multiple regression analysis demonstrates that FAEE content can be inferred as a function of the intensity of organoleptic defects for samples with high alkyl esters content. The intensity of the rancid defect negatively influences the accuracy of this model, because of underestimation of the fermentation defects that are also present. PMID- 27765236 TI - Influence of pH on the antioxidant phenols solubilised from hydrothermally treated olive oil by-product (alperujo). AB - The application of a novel industrial process based on the hydrothermal treatment of olive oil waste (alperujo) led to a final liquid phase that contained a high concentration of simple phenolic compounds. In this study the effect of pH on phenol extraction with ethyl acetate from the aqueous phase of hydrothermally treated alperujo at 160 degrees C/60min (without modification, pH 4.5, and adjusted to pH 2.5) was evaluated, beside the increase of hydroxytyrosol during the storage. The variation of the concentration of phenolic compounds in each extract was analyzed by HPLC. The phenolic extract obtained at pH 4.5 presented a higher proportion of total and individual phenols and better antioxidant capacity in vitro than the extract obtained at pH 2.5. The use of lower pH values enhances the concentration of hydroxytyrosol in the liquid diminishing the storage times. PMID- 27765237 TI - 'Fortified' wines volatile composition: Effect of different postharvest dehydration conditions of wine grapes cv. Malvasia moscata (Vitis vinifera L.). AB - The impact of postharvest dehydration on the volatile composition of Malvasia moscata grapes and fortified wines produced from them was assessed. The ripeness effect of fresh grapes on volatile compounds of dehydrated grapes was evaluated for the first time in this study. Fresh grape berries were densimetrically sorted, and more represented density classes were selected. Dehydration of riper berries (20.5 degrees Brix) led to volatile profiles richer in terpenes, particularly linalool and geraniol. The effect of dehydration rate on the volatile composition of dehydrated grapes and fortified wines was also evaluated. Fast dehydration grapes were richer in total free terpenes, and the resulting wines contained greater amounts of volatile compounds. The predominant compounds were free esters, but linalool, rose oxide, citronellol and geraniol can also contribute to wine aroma, particularly for fast dehydration. beta-Damascenone can be an active odorant, although its contribution was greater in wines made from slow dehydrated grapes. PMID- 27765238 TI - Effect of heat treatment and storage conditions on mead composition. AB - The effects of heat treatment and storage conditions on the composition of pure mead (honey wine) made from only honey and water were investigated. Heat treatment experiments were performed at 7 different temperatures ranging from 40 degrees C to100 degrees C with 10 degrees C increments for 60min. Storage condition experiments were performed at room temperature (20-25 degrees C) in daylight without direct sunlight and in darkness in a refrigerator at 4 degrees C for 1, 2, 4 and 12weeks. The parameters evaluated were phenolic compounds, peak area of unidentified compounds, 5-hydroxymethylfurfural content and antioxidant capacity. Significant changes in compound content were observed in the case of 6 identified compounds and 9 unidentified compounds. However, the antioxidant activity was not affected by the heat treatments or storage at room temperature. PMID- 27765239 TI - Evaluation of the antioxidant capacity, furan compounds and cytoprotective/cytotoxic effects upon Caco-2 cells of commercial Colombian coffee. AB - Antioxidant capacity (AC), total phenolics (TPs), furan compounds (HMF and furfural F) and cytoprotective/cytotoxic effects upon Caco-2 cells (MTT, cell cycle and reactive oxygen species (ROS)) were evaluated in Colombian coffee (2 ground and 4 soluble samples). The AC (ABTS and FRAP), TPs and HMF ranged between 124-722, 95-802MUmoles Trolox/g, 21-100mg gallic acid/g and 69-2900mg/kg, respectively. Pretreatment of cells for 24h with lyophilized coffee infusions at the highest dose without cytotoxic effects (500MUg/mL) significantly prevented the decrease in cell viability compared to control stress with H2O2 (5mM/2h), recovering viability to values between 34% and 45% and restoring the control values without stress induction in the G1 phase of cell cycle. After exposure to stress, four extracts decreased ROS values significantly to 22.5-24.9%. The coffee samples exerted a cytoprotective effect against oxidative stress, with improvement in cell viability and a reduction of intracellular ROS. PMID- 27765240 TI - Degradation studies of cholecalciferol (vitamin D3) using HPLC-DAD, UHPLC-MS/MS and chemical derivatization. AB - In any food fortification program, the stability of added micronutrients is an important factor. Cholecalciferol or vitamin D3 is known to isomerise under various conditions, thereby making its analysis challenging. In the current study, the effects of different parameters, such as temperature, iodine, acidic conditions, and oxidation, on the isomerisation of vitamin D3 were studied using HPLC-DAD and UHPLC-MS/MS. Vitamin D3 thermally and reversibly transforms to pre vitamin D3 type isomers. In the presence of iodine, cis/trans isomerisation of both cholecalciferol and pre-vitamin D3 takes place to form trans-vitamin D3 and tachysterol, respectively. Another isomer, isotachysterol, was formed under acidic conditions. The different rates of reaction of these products with a dienophile through the Diels-Alder reaction confirmed the formation of vitamin D3 isomerisation products. The derivatization enhanced the ionisation efficiency of vitamin D3 and its isomers in UHPLC-MS/MS and improved the separation and fragmentation enabling sensitive detection. PMID- 27765241 TI - Peptide profile of Coalho cheese: A contribution for Protected Designation of Origin (PDO). AB - Coalho cheese of Ceara and the Jaguaribe region of Brazil has been studied to determine its peptide profile. Peptides generated by the action of peptidases upon cheese proteins were separated by reverse-phase HPLC to give 28 fractions. Peptide sequencing after MS/MS fragmentation enabled the identification of 116 different peptides; 74 of them originated from beta-casein, 4 from betaA2-casein, 4 from betaA3-casein, 25 from alphaS1-casein, 5 from alphaS2-casein, and 4 from kappa-casein. Phosphorylated peptides were identified, one from alphaS1-casein and 17 from beta-casein. Other reports on the bioactivity of casein-derived peptides have shown that the beta-casein peptide (193-209) exhibits immunomodulatory, antimicrobial and antihypertensive activity. The peptides beta casein (58-72), beta-casein (193-202), alphas1-casein (85-91), alphas1-casein (1 9), as well as alphas2-casein (189-197) have antihypertensive activity. The fragment alphaS1-casein (1-23) is an immunomodulatory and antimicrobial peptide. These results can be a marker to determine the authenticity of this Brazilian cheese. PMID- 27765243 TI - Preparative high-speed counter-current chromatography separation of grape seed proanthocyanidins according to degree of polymerization. AB - Separation of plant proanthocyanidins remains a major challenge for scientists due to the structural diversity and complexity. In this work, a new and effective method was developed for preparative separation of grape seed proanthocyanidins (GSPs) according to degree of polymerization (DP) by high-speed counter-current chromatography (HSCCC). Under the optimized HSCCC conditions, GSPs could be separated into seven distinct fractions (F1-F7) with mean degree of polymerization in increasing order, from 1.44 to 6.95. High yields for these fractions (53.7, 12.2, 29.5, 30.2, 11.2, 50.8 and 169.8mg, respectively) were achieved by only one-step HSCCC of 400mg of GSPs. Further, seventeen individual proanthocyanidins, most of which are commercially not available, were efficiently isolated by re-chromatography on HSCCC or prep-HPLC; each of the isolated compounds presented high yields (7.1-78.9mg) and high purity (70.0-95.7%). The positive correlation was observed between DP and antioxidant activity of proanthocyanidins. PMID- 27765244 TI - A novel isoflavone profiling method based on UPLC-PDA-ESI-MS. AB - A novel non-targeted isoflavone profiling method was developed using the diagnostic fragment-ion-based extension strategy, based on ultra-high performance liquid chromatography coupled with photo-diode array detector and electrospray ionization-mass spectrometry (UPLC-PDA-ESI-MS). 16 types of isoflavones were obtained in positive mode, but only 12 were obtained in negative mode due to the absence of precursor ions. Malonyldaidzin and malonylgenistin glycosylated at the 4'-O position or malonylated at the 4"-O position of glucose were indicated by their retention behavior and fragmentation pattern. Three possible quantification methods in one run based on UPLC-PDA and UPLC-ESI-MS were validated and compared, suggesting that methods based on UPLC-ESI-MS possess remarkable selectivity and sensitivity. Impermissible quantitative deviations induced by the linearity calibration with 400-fold dynamic range was observed for the first time and was recalibrated with a 20-fold dynamic range. These results suggest that isoflavones and their stereoisomers can be simultaneously determined by positive-ion UPLC-ESI MS in soymilk. PMID- 27765242 TI - Protection mechanism of Se-containing protein hydrolysates from Se-enriched rice on Pb2+-induced apoptosis in PC12 and RAW264.7 cells. AB - This study aimed to investigate the protection mechanism of Se-containing protein hydrolysates (SPH) from Se-enriched rice on Pb2+-induced apoptosis in PC12 and RAW264.7 cells. Results showed that SPHs could alleviate Pb2+-induced morphological changes of apoptosis and the loss of mitochondrial transmembrane potential in both cell types. Besides this, SPHs could significantly reduce the activation of caspase-3, -8, -9 induced by Pb2+, reverse the Pb2+-induced upregulation of Bax and release of cytochrome C, and downregulate Bcl-2 in cells. HPLC-ICP-MS and SEC-HPLC assays showed that SPHs were low molecular weight peptides (229.4-534.9Da), and the major Se species found in SPHs was SeMet. Taken together, these findings suggested that SPHs could possibly protect the cells against Pb2+-induced apoptosis via a caspase-dependent mitochondrial pathway, and the primary effective constituents in SPHs were SeMet and Se-containing peptides, suggesting that SPHs might be a novel potential candidate to improve the health of people with Se deficiency or in Pb-contaminated areas. PMID- 27765245 TI - Geographical identification of saffron (Crocus sativus L.) by linear discriminant analysis applied to the UV-visible spectra of aqueous extracts. AB - We attempted geographical classification of saffron using UV-visible spectroscopy, conventionally adopted for quality grading according to the ISO Normative 3632. We investigated 81 saffron samples produced in L'Aquila, Citta della Pieve, Cascia, and Sardinia (Italy) and commercial products purchased in various supermarkets. Exploratory principal component analysis applied to the UV vis spectra of saffron aqueous extracts revealed a clear differentiation of the samples belonging to different quality categories, but a poor separation according to the geographical origin of the spices. On the other hand, linear discriminant analysis based on 8 selected absorbance values, concentrated near 279, 305 and 328nm, allowed a good distinction of the spices coming from different sites. Under severe validation conditions (30% and 50% of saffron samples in the evaluation set), correct predictions were 85 and 83%, respectively. PMID- 27765246 TI - Investigation by response surface methodology of the combined effect of pH and composition of water-methanol mixtures on the stability of curcuminoids. AB - Response surface methodology, coupled to a full factorial three-level experimental design, was applied to investigate the combined influence of pH (between 7.0 and 8.6) and composition of methanol-water mixtures (between 30 and 70% v/v of methanol content) on the stability of curcumin and its analogues demethoxycurcumin and bisdemethoxycurcumin. The response plots revealed that addition of methanol noticeably improved the stability of curcuminoids, this effect being both pH- and structure-dependent. In the central point of the experimental domain, half-life times of curcumin, demethoxycurcumin and bisdemethoxycurcumin were 3.8+/-0.2, 27+/-2 and 251+/-17h, respectively. Stability of curcuminoids increased at lower pH and higher methanol content and decreased in the opposite vertex of the experimental domain. These results can be interpreted by assuming that addition of methanol to water produces a different variation of pH of the medium and apparent pKa values of the ionisable groups of curcuminoids. PMID- 27765247 TI - Characterization of glycerophospholipid molecular species in six species of edible clams by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. AB - The molecular species of glycerophosphocholine (GPCho), glycerophosphoethanolamine (GPEtn), glycerophosphoserine (GPSer), lysoglycerophosphocholine (LGPCho) and lysoglycerophosphoethanolamine (LGPEtn) from six species of edible clams were characterized by using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. At least 435, 453, 468, 443, 427 and 444 glycerophospholipid (GP) molecular species were characterized, respectively, from Cyclina sinensis, Mactra chinensis Philippi, Mactra veneriformis Reeve, Meretrix meretrix, Ruditapes philippinarum and Saxidomus purpurata. Most of the predominant GP molecular species in clam contained polyunsaturated fatty acids (PUFA), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), indicating that clam is a potential resource of GP enriched PUFA. According to the amount of the major molecular species containing EPA and DHA, Cyclina sinensis was the best fit species for GPCho, Mactra veneriformis Reeve was the best fit species for GPEtn, Mactra chinensis Philippi was the best fit species for GPSer and LGPEtn, and Saxidomus purpurata was the best fit species for LGPCho. PMID- 27765248 TI - Desalted duck egg white peptides promote calcium uptake by counteracting the adverse effects of phytic acid. AB - The structure of the desalted duck egg white peptides-calcium chelate was characterized by fluorescence spectroscopy, fourier transform infrared spectroscopy, and dynamic light scattering. Characterization results showed structural folding and aggregation of amino acids or oligopeptides during the chelation process. Desalted duck egg white peptides enhanced the calcium uptake in the presence of oxalate, phosphate and zinc ions in Caco-2 monolayers. Animal model indicated that desalted duck egg white peptides effectively enhanced the mineral absorption and counteracted the deleterious effects of phytic acid. These findings suggested that desalted duck egg white peptides might promote calcium uptake in three pathways: 1) desalted duck egg white peptides bind with calcium to form soluble chelate and avoid precipitate; 2) the chelate is absorbed as small peptides by enterocyte; and 3) desalted duck egg white peptides regulate the proliferation and differentiation of enterocytes through the interaction with transient receptor potential vanilloid 6 calcium channel. PMID- 27765249 TI - Composition and morphology of cuticular wax in blueberry (Vaccinium spp.) fruits. AB - The chemical composition and morphology of cuticular wax in mature fruit of nine blueberry cultivars were investigated using gas chromatography-mass spectrometry (GC-MS) and scanning electron microscope (SEM). Triterpenoids and beta-diketones were the most prominent compounds, accounting for on average 64.2% and 16.4% of the total wax, respectively. Ursolic or oleanolic acid was identified as the most abundant triterpenoids differing in cultivars. Two beta-diketones, hentriacontan 10,12-dione and tritriacontan-12,14-dione, were detected in cuticular wax of blueberry fruits for the first time. Notably, hentriacontan-10,12-dione and tritriacontan-12,14-dione were only detected in highbush (V. corymbosum) and rabbiteye (V. ashei) blueberries, respectively. The results of SEM showed that a large amount of tubular wax deposited on the surface of blueberry fruits. There was no apparent difference in wax morphology among the nine cultivars. PMID- 27765250 TI - Determination of volatile organic compounds, catechins, caffeine and theanine in Jukro tea at three growth stages by chromatographic and spectrometric methods. AB - Tea contains characteristic volatile organic compounds, polyphenols, caffeine and catechins, and is therefore among the most widely consumed beverages all over the world. In this study, fresh Jukro tea leaves collected from Damyang-gun (Jeollanam-do) at 40, 60 and 90day growth stages, were semi-fermented. The volatile organic compounds (VOCs) were extracted by simultaneous distillation solvent extraction (SDE) and analyzed by gas chromatography/mass spectrometry (GC/MS). Catechins, caffeine and theanine were analyzed by high performance liquid chromatography (HPLC). A total of 159 VOCs were identified in the analyzed Jukro tea leaves. Comparatively, the increase in the concentrations of VOCs was high in 60day leaves. The content of catechins increased along the three growth stages, whereas caffeine, compared to 90day leaves, was higher for 40 and 60day leaves. Based on the results, the 60day leaves were found to be the most suitable and useful for making semi-fermented Jukro tea. PMID- 27765251 TI - Determination of cadmium in herbs by SFODME with ETAAS detection. AB - A method for the determination of cadmium in herb samples based on solidified floating organic drop microextraction (SFODME) using 1-(2-Pyridylazo)-2-naphthol (PAN) as a chelating reagent and detection by electrothermal atomic absorption spectrometry (ETAAS) was developed in the present work. The effects of pH, extraction solvent, extraction time, stirring rate, and extraction temperature were investigated. Under the optimized conditions, the calibration graph was linear in the range of 0.017-3.0MUgL-1, with a detection limit (LOD) of 0.0052MUgL-1. The relative standard deviation (%RSD) for 6 replicate measurements of 1.0MUgL-1 cadmium was +/-2.67%. The method was applied to the analysis of 10 types of Thai herb samples. Percentage recoveries were in the range 94.5-110.2%. It was found that cadmium concentrations in all Thai herb samples were less than the maximum residue level. PMID- 27765252 TI - Newly discovered ergot alkaloids in Sorghum ergot Claviceps africana occurring for the first time in Israel. AB - Sorghum ergot is a disease caused commonly by C. africana. In 2015, ergot was identified for the first time in sorghum fields in Israel, leading to measures of eradication and quarantine. The aims of the study were to identify the ergot species by molecular and ergot alkaloid profile analysis, to determine the ergot alkaloid profile in pure honeydew and in infected sorghum silages and to estimate the safety of sorghum silages as a feed source. C. africana was rapidly and reliably identified by microscopical and molecular analysis. Dihydroergosine was identified as the major ergot alkaloid. Dihydrolysergol and dihydroergotamine were identified for the first time as significant ergot alkaloid components within the C. africana sclerotia, thereby providing for the first time a proof for the natural occurrence of dihydroergotamine. The sorghum silages were found to be safe for feed consumption, since the ergot alkaloids and the regulated mycotoxins were below their regulated limits. PMID- 27765253 TI - The preparation of Fe-glycine complexes by a novel method (pulsed electric fields). AB - A novel method for synthesizing Fe-glycine complex by pulsed electric fields (PEFs) was developed, and the physiochemical properties of Fe-glycine complexes were evaluated in this study. Results showed that the highest yield (81.2%) of Fe glycine complexes was obtained by PEF treatment with 4.0kV/cm for 15min at 25 degrees C, which was higher than thermal treatment of 79.5% at 60 degrees C for 30min. Moreover, the highest Fe-chelating capacity was obtained at 107.13mg/L after PEF treatment with 4.0kV/cm for 15min. Results from Fourier transform infrared (FT-IR), X-ray diffraction (XRD) and thermal gravimetric (TG) analysis indicated that the structure of the ferrous ion-glycine complexes prepared by PEF and thermal treatment was similar. It was implied that the PEF treatment can be used as a novel and efficient method for synthesis of metal ion-amino acid complexes under moderate condition such as 25 degrees C and pH 6.0. PMID- 27765254 TI - Dairy products and the Maillard reaction: A promising future for extensive food characterization by integrated proteomics studies. AB - Heating of milk and dairy products is done using various technological processes with the aim of preserving microbiological safety and extending shelf-life. These treatments result in chemical modifications in milk proteins, mainly generated as a result of the Maillard reaction. Recently, different bottom-up proteomic methods have been applied to characterize the nature of these structural changes and the modified amino acids in model protein systems and/or isolated components from thermally-treated milk samples. On the other hand, different gel-based and shotgun proteomic methods have been utilized to assign glycation, oxidation and glycoxidation protein targets in diverse heated milks. These data are essential to rationalize eventual, different nutritional, antimicrobial, cell stimulative and antigenic properties of milk products, because humans ingest large quantities of corresponding thermally modified proteins on a daily basis and these molecules also occur in pharmaceuticals and cosmetics. This review provides an updated picture of the procedures developed for the proteomic characterization of variably-heated milk products, highlighting their limits as result of concomitant factors, such as the multiplicity and the different concentration of the compounds to be detected. PMID- 27765255 TI - Structural characterization and physicochemical properties of protein extracted from soybean meal assisted by steam flash-explosion with dilute acid soaking. AB - The aim of this work was to analyze the influence of steam flash-explosion (SFE) with dilute acid soaking pretreatment on the structural characteristics and physiochemical properties of protein from soybean meal (SBM). The pretreatment led to depolymerisation of soy protein isolate (SPI) and formation of new protein aggregation through non-disulfide covalent bonds, which resulted in broader MW distribution of SPI. The analysis of CD spectroscopy showed that the SFE treatment induced minor changes in secondary structure, however, the intrinsic tryptophan fluorescence revealed that acid soaking and SFE treatment pronouncedly altered the tertiary structure of SPI. The protein zeta potential was shown to be increased after SFE treatment attributed to the changes in protein structure and the covalent coupling between carbohydrate and protein. These results contribute to clarifying the mechanisms of the effect of pretreatment on SPI structure, thus moving further toward implementing SFE in the processing chain of SPI. PMID- 27765256 TI - Polyphenol profile and antioxidant activity of the fruit and leaf of Vaccinium glaucoalbum from the Tibetan Himalayas. AB - Vaccinium glaucoalbum, a perennial evergreen shrub, is naturally distributed in high-altitude areas. In this study, the composition and content of polyphenolic compounds in the fruit and leaf of V. glaucoalbum were characterized. In total, 24 chemical compounds were detected and identified by HPLC-DAD and HPLC-ESI-MS2. Among all the compounds determined, 15 were anthocyanins and detected in fruit, 5 were flavonols and monitored in leaf, and 4 were chlorogenic acids and found in both fruit and leaf. The total anthocyanin content (TAC) of fruit (682mg/100gFW) was the highest among wild Vaccinium berries in China which have been investigated for now, and the total flavonol content of leaf was 2764mg/100gFW. The antioxidant activity of both fruit and leaf was assessed by DPPH and FRAP assays. Given its high TAC and strong antioxidant activity, the fruit of V. glaucoalbum has great potential in functional food. PMID- 27765257 TI - Composition, distribution and risk of total fluorine, extractable organofluorine and perfluorinated compounds in Chinese teas. AB - To explore the residual characteristics of fluorine and perfluorinated compounds (PFCs) in tea, the total fluorine (TF), extractable organofluorine (EOF) and PFCs in 19 Chinese commercial teas of five categories were measured using cyclic neutron activation analysis combined with HPLC-MS/MS. The results showed that fluorine mainly existed as inorganic fluorine in teas, and identified fluorine (?PFCs quantified as F) only accounted for 0.023-0.41% of EOF, indicating that most EOF in tea were still unknown. 50-99% of ?PFCs in tea were short-chain (C?6), while perfluorooctanoic acid was the typical PFCs residual species. Less fermented teas contained significantly higher PFCs (mean, 20ng/g) than more fermented teas (3.0ng/g, p<0.01), suggesting that microbe may degrade PFCs during fermentation. The highest TF content was discovered in Hubei brick tea, which poses risk of fluorosis, whereas PFCs residues in teas caused no immediate harm. PMID- 27765258 TI - Pork detection in binary meat mixtures and some commercial food products using conventional and real-time PCR techniques. AB - Pork DNA was detected in meat mixtures using both conventional PCR and real-time PCR (RT-PCR). Thirty meat mixtures containing beef, chicken, camel, rabbit, goat and sheep with varying percentage of pork (0%, 1%, 5%, 10%, and 20%) and 75 commercial food products, were analyzed using conventional and RT-PCR to determine the presence of pork DNA. Pork DNA standard curves and cycle threshold (Ct) values were used for quantification. The detection limits for pork DNA in the mixtures were 0.22, 0.047, 0.048, 0.0000037, 0.015ng/MUl respectively. Unlike conventional PCR, RT-PCR detected pork DNA in nine processed food samples [chicken sausages (2), chicken luncheon (2), turkey meat loaf, milk chocolate with soft nougat, jelly, cake, and candies] at pork DNA concentrations of 0.0001ng/MUl or less. PMID- 27765259 TI - Influence of serving temperature on flavour perception and release of Bourbon Caturra coffee. AB - The present study aimed to investigate coffee flavour perception and release as function of serving temperature to support standardisation in the specialty coffee branch. The coffee cultivar Bourbon Caturra was evaluated at six serving temperatures ranging from 31 degrees C to 62 degrees C. Coffee samples were analysed by dynamic headspace sampling gas chromatography-mass spectrometry and descriptive analyses using sip-and-spit tasting. The release of volatiles followed mostly the van't Hoff principle and was exuberated at temperatures above 40 degrees C. Aliphatic ketones, alkylpyrazines, some furans and pyridines increased most notably at temperatures ?50 degrees C. The changes in volatile release profiles could explain some of the sensory differences observed. The flavour notes of 'sour', 'tobacco' and 'sweet' were mostly associated with the coffees served at 31-44 degrees C, whereas coffees served between 50 degrees C and 62 degrees C exhibited stronger 'overall intensity', 'roasted' flavour and 'bitter' notes. PMID- 27765260 TI - Determination of essential elements in beverages, herbal infusions and dietary supplements using a new straightforward sequential approach based on flame atomic absorption spectrometry. AB - A simple method based on FAAS was developed for the sequential multi-element determination of Cu, Zn, Mn, Mg and Si in beverages and food supplements with successful results. The main absorption lines for Cu, Zn and Si and secondary lines for Mn and Mg were selected to carry out the measurements. The sample introduction was performed using a flow injection system. Using the choice of the absorption line wings, the upper limit of the linear range increased up to 110mgL 1 for Mg, 200mgL-1 for Si and 13mgL-1 for Zn. The determination of the five elements was carried out, in triplicate, without the need of additional sample dilutions and/or re-measurements, using less than 3.5mL of sample to perform the complete analysis. The LODs were 0.008mgL-1 for Cu, 0.017mgL-1 for Zn, 0.011mgL-1 for Mn, 0.16mgL-1 for Si and 0.11mgL-1 for Mg. PMID- 27765261 TI - Combination of micelle collapse and field-amplified sample stacking in capillary electrophoresis for determination of trimethoprim and sulfamethoxazole in animal originated foodstuffs. AB - An on-line preconcentration method combining micelle to solvent stacking (MSS) with field-amplified sample stacking (FASS) was employed for the analysis of trimethoprim (TMP) and sulfamethoxazole (SMZ) by capillary zone electrophoresis (CZE). The optimized experimental conditions were as followings: (1) sample matrix, 10.0mM SDS-5% (v/v) methanol; (2) trapping solution (TS), 35mM H3PO4-60% acetonitrile (CH3CN); (3) running buffer, 30mM Na2HPO4 (pH=7.3); (4) sample solution volume, 168nL; TS volume, 168nL; and (5) 9kV voltage, 214nm UV detection. Under the optimized conditions, the limits of detection (LODs) for SMZ and TMP were 7.7 and 8.5ng/mL, and they were 301 and 329 times better compared to a typical injection, respectively. The contents of TMP and SMZ in animal foodstuffs such as dairy products, eggs and honey were analyzed, too. Recoveries of 80-104% were acquired with relative standard deviations of 0.5-5.4%. PMID- 27765262 TI - Low-temperature conditioning induces chilling tolerance in stored mango fruit. AB - In this study, mango fruit were pre-treated with low-temperature conditioning (LTC) at 12 degrees C for 24h, followed by refrigeration at 5 degrees C for 25days before removal to ambient temperature (25 degrees C) to investigate the effects and possible mechanisms of LTC on chilling injury (CI). The results showed that LTC effectively suppressed the development of CI in mango fruit, accelerated softening, and increased the soluble solids and proline content. Furthermore, LTC reduced electrolyte leakage, and levels of malondialdehyde, O2- and H2O2, maintaining membrane integrity. To reveal the molecular regulation of LTC on chilling tolerance in mango fruit, a C-repeat/dehydration-responsive element binding factor (CBF) gene, MiCBF1, was identified and its expression in response to LTC was examined using RT-qPCR. LTC resulted in a higher MiCBF1 expression. These findings suggest that LTC enhances chilling tolerance in mango fruit by inducing a series of physiological and molecular responses. PMID- 27765263 TI - Rapid screening test for detection of oxytetracycline residues in milk using lateral flow assay. AB - A rapid, semi-quantitative lateral flow assay (LFA) was developed to screen the oxytetracycline (OTC) antibiotics residues in milk samples. In this study a competitive immuno-assay format was established. Colloidal gold nano-particles (GNP) were prepared and used as labelling material in LFA. Polyclonal antibodies were generated against OTC molecule (anti-OTC), purified and the quality was assessed by enzyme linked immuno sorbet assay. For the first time membrane components required for LFA in milk system was optimized. GNP and anti-OTC stable conjugate preparation method was standardized, and then these components were placed over the conjugate pad. OTC coupled with carrier protein was placed on test line; species specific secondary antibodies were placed on the control line of the membrane matrix. Assay was validated by spiking OTC to antibiotic free milk samples and results could be accomplished within 5min. without need of any equipment. The visual detection limit was 30ppb. PMID- 27765264 TI - Physicochemical properties and micro-structural characteristics in starch from kudzu root as affected by cross-linking. AB - Kudzu starch was cross-linked with sodium trimetaphosphate (STMP) at different temperatures, time and of STMP concentrations in this work. The cross-linked starches (CLSs) were fractionated further into cross-linked amylose and amylopectin in order to compare the effect of cross-linking on the microstructure. According to scanning electron microscope (SEM), CLSs displayed the resemble appearance of spherical and polygonal shapes like NS. X-ray diffraction (XRD) revealed that amylose of native starch (A), NS and CLS displayed a combination of A-type and B-type structure, while that was not found in amylose of cross-linked starch (CLA). The deconvoluted fourier transform infrared (FT-IR) indicated that crystal structure of kudzu starch was losing with the proceeding of cross-linking reaction. The CLSs exhibited a higher retrogradation and freeze-thaw stability than NS. This was accompanied by a significant decrease in sedimentation, transparency, swelling power and solubility. PMID- 27765265 TI - On the shoulders of Hubrecht: From embryos to stem cells. AB - One hundred years of the Hubrecht Institute were celebrated in May 2016 with the organization of a one-day symposium "From embryos to stem cells" on the Uithof Campus, Utrecht, the Netherlands. Nine distinguished speakers were invited. They all represent a research branch originating from the passion of Institute founder, Ambrosius Hubrecht, for embryology:, regulation of gene expression, genome structure and function, embryonic and adult stem cells, nuclear reprogramming, and understanding cancer and other diseases using model organisms. The centennial symposium not only retraced the history of the Institute and of modern developmental biology, but was also a tribute to basic research. From there, avenues to therapeutics are being developed and implemented. The symposium was organized, introduced and chaired by Jeroen den Hertog and Alexander van Oudenaarden, the present Directors of the Institute, who also stand on Hubrecht's shoulders. PMID- 27765266 TI - Mechanics of cutaneous wound rupture. AB - A cutaneous wound may rupture during healing as a result of stretching in the skin and incompatibility at the wound-skin interface, among other factors. By treating both wound and skin as hyperelastic membranes, and using a biomechanical framework of interfacial growth, we study rupturing as a problem of cavitation in nonlinear elastic materials. We obtain analytical solutions for deformation and residual stress field in the skin-wound configuration while emphasizing the coupling between wound rupture and wrinkling in the skin. The solutions are analyzed in detail for variations in stretching environment, healing condition, and membrane stiffness. PMID- 27765267 TI - Redo pull-through surgery in Hirschsprung disease: Short-term clinical outcome. AB - INTRODUCTION: Although surgery is effective in most patients with Hirschsprung disease (HD), some have persistent obstructive symptoms. Additional medical treatment is generally sufficient, but a small fraction of these patients needs secondary surgery. Series on redo surgery are scarce. Aim of this study is to evaluate complications and clinical outcome of patients in need of redo surgery for HD. MATERIALS AND METHODS: Sixteen patients underwent redo endorectal pull through surgery in our center between 2007 and 2015. Medical records were reviewed and demographics, indication for redo surgery, surgical procedures, complications, and clinical outcome were scored. RESULTS: The median age at the time of redo was 4.6years (range: 2months-21years). Median follow-up after redo was 3years (range: 9months-7years). Before redo surgery, all patients (100%) had obstructive symptoms, one patient had recurrent enterocolitis, and four patients were fecally incontinent despite adequate attempts of bowel management. Surgical procedure consisted of a transanal endorectal pull-through (TERPT) in all patients, with additional laparotomy in 7 (44%) and protective stoma in 8 patients (50%). Complications within 30days after redo surgery were anastomotic dehiscence (3; 19%), wound abscess (2; 13%), rectovaginal fistula (1; 7%) or enterocutaneous fistula (1; 7%). During follow-up, nine patients needed additional surgery, mainly to close the stoma. At final follow-up there were no patients with stenosis, obstructive symptoms, remaining rectovaginal fistula, or small bowel obstruction. Only one patient experienced enterocolitis. Six patients (43%) reported soiling or fecal incontinence. CONCLUSION: TERPT for redo surgery for HD is effective in resolving sustained severe obstructive symptoms after primary surgery, but the outcome is complicated by a relatively high rate of soiling and fecal incontinence. PMID- 27765269 TI - Can Naloxone Be Used to Treat Synthetic Cannabinoid Overdose? PMID- 27765270 TI - Ex vivo gene therapy in France. PMID- 27765268 TI - An Examination of Polygenic Score Risk Prediction in Individuals With First Episode Psychosis. AB - BACKGROUND: Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses. METHODS: The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis. RESULTS: PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p < 10-6), but lower in individuals of African ancestry (R2 = 1.1%, p = .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R2 = 9.2%, p = .002). CONCLUSIONS: PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP. PMID- 27765271 TI - Down-regulation of tumor suppressor PDCD4 expression in endometrium of adenomyosis patients. AB - OBJECTIVE: Adenomyosis is a common benign gynecological disease which has some malignant behaviors. Programmed cell death 4 (PDCD4) is a newly identified tumor suppressor gene which lowly expresses in various cancers. However, the expression status of PDCD4 in endometrium of adenomyosis patients has not been investigated. The aim of this study is to assess the expression levels of PDCD4 in endometrium of normal controls and adenomyosis patients. METHODS: The expression of PDCD4 in endometrium of normal controls and eutopic or ectopic endometrium of patients with adenomyosis was evaluated with quantitative real-time PCR, western blot and immunohistochemistry. In addition, the levels of serum estradiol and progesterone in normal controls and adenomyosis patients were detected using electrochemiluminescence immunoassay. RESULTS: The results showed that PDCD4 mainly expressed in the cytoplasma of glandular epithelium of control endometrium and varied during the cycle changes of endometrium, which may be regulated by changing concentrations of progesterone in the menstrual cycle. Compared with the proliferative phase of control endometrium, PDCD4 expression was down-regulated in proliferative phase of eutopic endometrium or ectopic endometrium, and there was no cyclic variation of PDCD4 expression in eutopic endometrium of adenomyosis patients due to progesterone resistance. CONCLUSION: These results suggest that PDCD4 may be involved in the pathogenesis of adenomyosis, which will provide a novel strategy for the early diagnosis and new therapeutic target of adenomyosis. PMID- 27765272 TI - Major bleeding complications in patients treated with direct oral anticoagulants: One-year observational study in a Paris Hospital. AB - Direct oral anticoagulants (DAOC) are indicated for the treatment of venous thromboembolism and the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. Given their advantages and friendly use for patient, the prescription of long term DOAC therapy has rapidly increased both as first line treatment while initiating anticoagulation and as a substitute to vitamins K antagonist (VKA) in poorly controlled patients. However, DOAC therapy can also be associated with significant bleeding complications, and in the absence of specific antidote at disposal, treatment of serious hemorrhagic complications under DOAC remains complex. We report and discuss herein five cases of major hemorrhagic complications under DOAC, which were reported to the pharmacological surveillance department over one year at Saint-Louis University Hospital (Paris, France). We further discuss the need for careful assessment of the risk/benefit ratio at time of starting DOAC therapy in daily clinical practice. PMID- 27765273 TI - Distinctive roles of PKC delta isozyme in platelet function. AB - Platelet activation is a complex balance of positive and negative signaling pathways. Several protein kinase C (PKC) isoforms are expressed in human platelets. They are a major regulator of platelet granule secretion, activation and aggregation activity. One of those isoforms is the PKCdelta isozyme, it has a central yet complex role in platelets such as opposite signaling functions depending on the nature of the agonist, it concentration and pathway. In fact, it has been shown that PKCdelta has an overall negative influence on platelet function in response to collagen, while, following PAR stimulation, PKCdelta has a positive effect on platelet function. Understanding the crucial role of PKCdelta in platelet functions is recently emerging in the literature, therefore, further investigations should shed light into its specific role in hemostasis. In this review, we focus on the different roles of PKCdelta in platelet activation, aggregation and thrombus formation. PMID- 27765274 TI - 18F-FDG labelling of hematopoietic stem cells: Dynamic study of bone marrow homing by PET-CT imaging and impact on cell functionality. AB - PURPOSE OF THE STUDY: After transplantation, cord blood (CB) hematopoietic stem and progenitor cells (HSPCs) are able to home to the bone marrow niche and to reconstitute the hematopoietic system. PET-CT imaging may be a useful method to monitor this parameter in different conditions. The aim of our study was to set up an efficient method for HSPC radiolabelling with [18F] fluorodeoxyglucose (18F FDG) and to follow early HSPC homing through PET-CT in mice. MATERIALS AND METHODS: Purified CB HSPCs were radiolabelled with 18F-FDG at 37 degrees C with various conditions of cell concentration, incubation time and radioactivity concentration in order to define the in vitro condition that allows both sufficient 18F-FDG uptake to get high quality PET imaging, and preservation of HSPC viability and functional properties during 3h after radiolabelling. Then, 24h after 2.25Gy irradiation, eight NOD-scid/gammac-/- mice were injected with 18F-FDG-labelled HSPCs, the biodistribution of which was followed using micro-PET CT. RESULTS: The optimal incubation time was 45min with a stability of 48.3%+/ 12.8% after 180min. The radio-uptake rate we obtained was 7.2%+/-1.7% with an activity of 5.6+/-2.1 MBq. Three hours after radiolabelling, viability was 96.7%+/-3.4%. Fifteen hours after radiolabelling, cell viability was 64.0%+/ 2.3%, migration ability diminished from 51.0%+/-23.6% to 12.0%+/-9.1%, clonogenic capacity was null, and long-term engraftment in NSG mice also decreased compared to unlabelled cells. Micro-PET-CT experiments showed an accumulation of radiolabelled HSPCs for 2.5h after injection in the bone marrow and a slight elution of 18F-FDG. CONCLUSION: The activity of the obtained 18F-FDG-labelled HSPCs was sufficient to perform the micro-PET-CT imaging. Although the radiolabelling had a significant toxicity on HSPCs 15h after labelling, this technique allowed monitoring the beginning of HSPC homing into the bone marrow. PMID- 27765275 TI - Quantitative study on morphology of calcified cartilage zone in OARSI 0~4 cartilage from osteoarthritic knees. AB - OBJECTIVE: To observe the morphological feature of calcified cartilage zone (CCZ) in mild to moderate degeneration of cartilages from patients with knee osteoarthritis (OA), revealing the pattern of CCZ during OA progression and its correlation to the surrounding structures. METHODS: Osteochondral specimens were collected from the center of the lateral tibial plateau of 42 OA patients undergoing total knee replacement. Sections were stained with hematoxylin-eosin and Safranin-O/Fast green. Morphological parameters (thickness of CCZ, hyaline cartilage, and subchondral bone, roughness of tidemark and cement line, number of tidemarks and chondrocytes in CCZ, area and number of vascular channels in CCZ) of OARSI grades 0~4 cartilages were measured. RESULTS: The thickness of CCZ increased with grading except in grade 2. This changing trend of CCZ was in accordance with chondrocyte number and area of vascular channel. The roughness of cement lines increased with the grading, and was correlated with the thickness of subchondral bone. The roughness of tidemarks was associated with thickness of hyaline cartilage in grade 0 to grade 3. CONCLUSIONS: In mild OA, the thickness of CCZ was increased at first and then decreased, the roughness of tidemark and cement line was nearly unchanged, which suggests that the pathological change of CCZ is reversible. However, in moderate OA, the thickness of CCZ, the roughness of tidemark and cement line were progressively increased, which suggests that the pathological change of CCZ is irreversible. PMID- 27765276 TI - The role of Toll-like receptor 9 in gynecologic cancer. AB - Toll-like receptor 9 (TLR9) plays a major role in the fight against DNA viruses infections. Despite its antitumor properties, inappropriate activation of TLR9 during chronic inflammation may cause the activation of transcription factors inducing pro-cancerous activities. Thus, the relationship between TLR9 and cancer remains highly confrontational especially in gynecological cancers and cervical cancer induced by viruses. In this review, we focus on the beneficial and detrimental role of TLR9 in gynecological carcinogenesis. TLR9 contributes to tumor regression by inducing cytotoxic T cell response (CTL), reducing the numbers of myeloid-derived suppressor cells (MDSCs), the tumor-associated macrophages (TAMs) and the regulatory T cells (T regs). It can however, also promote tumor progression and invasiveness of cervical tissue. Therefore, the dichotomous role of TLR9 needs to be carefully investigated in the setting of neoplastic disease. PMID- 27765277 TI - Ovarian cancer presenting as an axillary mass: Case series and literature review. AB - AIM: Ovarian cancer is a common cause of death in women worldwide. The purpose of this article was to report a case series and draw physicians' attention to the benefits of histpathologic techniques in determining uncommon metastatic diseases. METHODS: In this study, we report a case series of axillary involvement of ovarian cancer in 6 patients. The data were collected between 2006 and 2015 by analyzing patient's characteristics, and biochemical and immunohistochemical features. No pathologic lesions were detected in breasts. Specific immunohistochemical methods such as GCDFP-15, CA12-5, WT-1, and PAX-8 supported evidence of metastasis from ovarian cancer to axillary lymph nodes. RESULTS: Biochemical tests showed increased levels of CA12-5 in all patients. In 5 patients, GCDFP-15 was negative and WT-1 was positive with specific immunohistochemical staining. PAX-8 was positive in 3 of 5 patients. CONCLUSIONS: Physicians need to be aware that histopathologic and immunohistochemical results can make a significant contribution in determining the true primary tissue of metastatic adenocarcinoma, even in the absence of typical clinical findings. PMID- 27765278 TI - Oxygen, a regulator of viral gene expression? PMID- 27765279 TI - Diabetes mellitus and takotsubo syndrome: Dissecting the paradox. PMID- 27765280 TI - The design of long term care insurance contracts. AB - This paper studies the design of long term care (LTC) insurance contracts in the presence of ex post moral hazard. While this problem bears some similarity with the study of health insurance (Blomqvist, 1997) the significance of informal LTC affects the problem in several crucial ways. It introduces the potential crowding out of informal care by market care financed through insurance coverage. Furthermore, the information structure becomes more intricate. Informal care is not publicly observable and, unlike the insurer, caregivers know the true needs of their relatives. We determine the optimal second-best contract and show that the optimal reimbursement rate can be written as an A-B-C expression a la Diamond (1998). These terms respectively reflect the efficiency loss as measured by the inverse of the demand elasticity, the distribution of needs and the preferences for risk sharing. Interestingly, informal care directly affects only the first term. More precisely the first term decreases with the presence and significance of informal care. Roughly speaking this means that an efficient LTC insurance contract should offer lower (marginal) reimbursement rates than its counterpart in a health insurance context. PMID- 27765282 TI - Fibrous dysplasia. Clinical review and therapeutic management. AB - Fibrous dysplasia is a skeletal disorder that is associated with a wide spectrum of clinical manifestations, including localized asymptomatic forms and extensive severe forms with severe bone deformities and endocrinological alterations, depending on age, location, extent and associated processes. Although the treatment of choice is based on bisphosphonates, the therapeutic efficacy of these agents in the control of disease activity remains uncertain. This article reviews the current data available on the treatment of this disease as well as the preliminary data on new therapeutic approaches. PMID- 27765281 TI - Junior research track faculty in U.S. schools of nursing: Resources and expectations. AB - BACKGROUND: Concerns about U.S. nursing research workforce preparation and success in the research arena require information about support mechanisms and readiness because the first research position is key to researcher retention and success. PURPOSE: The purpose was to describe the state of junior nursing research faculty recruitment terms, nursing programs' support during the first 2 years of employment, and administrators' views about strengths and weaknesses of the junior nursing research faculty pool and adequacy of the support provided. METHODS: Survey administrators in all U.S. nursing programs offering research doctorates (n = 125; response rate: 52%). DISCUSSION: Resource availability varied widely across institutions. Most respondents reported resources were adequate regardless of the actual level provided. Administrators' teaching and research expectations of these faculty also varied widely. Administrators identified readiness to perform as an issue of concern. CONCLUSION: As consumers of nursing research program graduates and as administrators responsible for the nursing research enterprise, deans need to take collective as well as individual actions. PMID- 27765283 TI - Disease, conflict, and the challenge of elimination in the Americas. PMID- 27765284 TI - New strategies for cholera control. PMID- 27765285 TI - Cause-specific mortality findings from the Global Burden of Disease project and the INDEPTH Network. PMID- 27765286 TI - Disadvantages of having an adolescent mother. PMID- 27765288 TI - Chloroquine-resistant Plasmodium vivax in Pakistan: an emerging threat. PMID- 27765287 TI - Combating antimicrobial resistance: quality standards for prescribing for respiratory infections in Vietnam. PMID- 27765289 TI - Medical journals and Wikipedia: a global health matter. PMID- 27765290 TI - Health beyond health to bridge the global health gap. PMID- 27765291 TI - Correction to Lancet Glob Health 2016; 4: e736-43. PMID- 27765292 TI - Correction to Lancet Glob Health 2016; 4: e568-78. PMID- 27765293 TI - Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study. AB - BACKGROUND: Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2-4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Medecins Sans Frontieres, and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine effectiveness study in conjunction with this large public health intervention. METHODS: We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). FINDINGS: Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classified as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine effectiveness was 80.2% (95% CI 61.5-100.0) and after adjusting for potential confounders was 87.3% (70.2-100.0). INTERPRETATION: One dose of Shanchol was effective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings. FUNDING: Medecins Sans Frontieres. PMID- 27765294 TI - Response to R. Colebunders: Helminth infections in Nodding syndrome. PMID- 27765295 TI - Acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in contacts of patients newly identified as colonized or infected with MRSA in the immediate postexposure and postdischarge periods. AB - The acquisition of methicillin-resistant Staphylococcus aureus (MRSA) after exposure to patients colonized or infected with MRSA was assessed. Among contacts with complete surveillance screening, the rate of acquisition was 5.7% and was lower in those identified postdischarge (17/683, 2.5%) compared with those tested in the immediate postexposure period (62/706, 8.8%). PMID- 27765296 TI - Predictors of mortality in bloodstream infections caused by multidrug-resistant gram-negative bacteria: 4 years of collection. AB - The study was undertaken to describe the profile of patients and the characteristics of all multidrug-resistant gram-negative bacteria (MDR-GNB) and to assess mortality. We examined 138 patients with bloodstream infections (BSIs) caused by MDR-GNB. Clinical characteristics, antibiotic therapy, and in-hospital mortality were analyzed. Survivor and nonsurvivor subgroups were compared to identify predictors of mortality. The in-hospital mortality rate was 25.4%. Univariate analysis revealed that comorbidities and inadequate initial antimicrobial treatment could increase risk of death. In Cox regression analysis, mortality was independently associated with the age (P = .034), hospitalization in an intensive care unit (ICU) (P = .04), invasive procedures (P < .001), and Acute Physiology and Chronic Health Evaluation II scores (P < .001), whereas combination therapy or monotherapy was not associated with mortality (P = .829). Postantibiogram therapy was associated with hospitalization in an ICU (P = .006), Charlson comorbidity index score (P = .003), and inadequate initial antimicrobial treatment (P < .001). MDR-GNB strains and antimicrobial regimens were not the major risk factors of mortality. Inadequate initial antimicrobial treatment, invasive procedures, high Acute Physiology And Chronic Health Evaluation II scores, hospitalization in an ICU, and comorbidities were the important factors responsible for mortality. Although there was no difference between combination therapy and monotherapy in mortality, combined treatment may be more effective than monotherapy for patients in an ICU, with a Charlson comorbidity index score < 4, or inadequate initial antimicrobial treatment. PMID- 27765297 TI - Follicular wave emergence in Santa Ines ewes subjected to long-term, progesterone based estrous synchronization protocols at different times of the year. AB - This study was conducted to document the pattern of antral follicular wave emergence throughout the 14-day, progesterone (P4)-based estrous synchronization protocol in ewes that were maintained in subtropical conditions, during the period of increasing day lengths (ID), decreasing day lengths (DD), and the transitional period (TP). In addition, the influence of ovarian status (i.e., size of ovarian antral follicles and the presence of corpora lutea) at the outset of P4 treatment on ensuing ovarian follicular wave development was examined. Sexually mature Santa Ines ewes (n=70) were subjected to one of the two estrous synchronization protocols in the three seasons. On Day 0, the ewes received an i.m. injection of prostaglandin F2alpha and an intravaginal P4-releasing device that remained in place for 14days (G-1CIDR) or was replaced on Day 7 (G-2CIDR). Daily ultrasonography of ovaries was conducted from Days 0 to 15. Mean (+/-SEM) numbers of follicular waves per ewe were 3.7+/-0.1 and 3.6+/-0.1 for G-1CIDR and G-2CIDR (P>0.05). The number of emerging follicular waves was greater (P<0.05) during the ID period than during the TP and DD periods (4.0+/-0.1, 3.4+/-0.1 and 3.6+/-0.1, respectively). The presence of medium-sized antral follicles (4.0 to 5.75mm) in the absence of corpora lutea at the time of CIDR insertion tended to advance follicular wave emergence. Although the long-term P4 treatment was not originally designed to synchronize follicular waves, there was a distinctive pattern of follicular wave dynamics during the period of application of CIDRs that was affected mainly by the number of emerging follicular waves and ovarian status at CIDR insertion. PMID- 27765298 TI - Fulminant sepsis caused by Clostridium perfringens. PMID- 27765300 TI - Climate and health: joining up the pieces, scaling up the action. PMID- 27765299 TI - Prognostic Value of Coronary Artery Calcium Score in Acute Chest Pain Patients Without Known Coronary Artery Disease: Systematic Review and Meta-analysis. AB - STUDY OBJECTIVE: Coronary artery calcium score (CACS) is a well-established test for risk stratifying asymptomatic patients. Recent studies also indicate that CACS may accurately risk stratify stable patients presenting to the emergency department (ED) with acute chest pain; however, many were underpowered. The purpose of this systematic review and meta-analysis is to evaluate the prognostic value and accuracy of a zero (normal) CACS for identifying patients at acceptable low risk for future cardiovascular events who might be safely discharged home from the ED. METHODS: We searched multiple databases for longitudinal studies of CACS in symptomatic patients without known coronary artery disease that reported major adverse cardiovascular events (MACEs), including death and myocardial infarction. Pooled risk ratios, sensitivity, specificity, and likelihood ratios were analyzed. RESULTS: Eight studies evaluated 3,556 patients, with a median follow-up of 10.5 months. Pooled prevalence of zero CACS was 60%. Patients with CACS=0 had a significantly lower risk of cardiovascular events compared with those with CACS greater than 0 (MACEs: relative risk 0.06, 95% confidence interval 0.04 to 0.11, I2=0%; death/myocardial infarction: relative risk 0.19; 95% confidence interval 0.08 to 0.47, I2=0%). The pooled event rates for CACS=0 (MACEs 0.8%/year; death/myocardial infarction 0.5%/year) were significantly lower than for CACS greater than 0 (MACEs 14.6%/year; death/myocardial infarction 3.5%/year). Analysis of summary testing parameters showed a sensitivity of 96%, specificity of 60%, positive likelihood ratio of 2.36, and negative likelihood ratio of 0.07. CONCLUSION: Acute chest pain patients without history of coronary artery disease, ischemic ECG changes, or increased cardiac enzyme levels commonly have a CACS of zero, with a very low subsequent risk of MACEs or death or myocardial infarction. This meta-analysis proffers the potential role of initial CACS testing for avoiding unnecessary hospitalization and further cardiac testing in acute chest pain patients with a CACS of zero. PMID- 27765301 TI - Implications of Public Reporting of Risk-Adjusted Mortality Following Percutaneous Coronary Intervention: Misperceptions and Potential Consequences for High-Risk Patients Including Nonsurgical Patients. AB - Assessment of clinical outcomes such as 30-day mortality following coronary revascularization procedures has historically been used to spur quality improvement programs. Public reporting of risk-adjusted outcomes is already mandated in several states, and proposals to further expand public reporting have been put forward as a means of increasing transparency and potentially incentivizing high quality care. However, for public reporting of outcomes to be considered a useful surrogate of procedural quality of care, several prerequisites must be met. First, the reporting measure must be truly representative of the quality of the procedure itself, rather than be dominated by other underlying factors, such as the overall level of illness of a patient. Second, to foster comparisons among physicians and institutions, the metric requires accurate ascertainment of and adjustment for differences in patient risk profiles. This is particularly relevant for high-risk clinical patient scenarios. Finally, the potential deleterious consequences of public reporting of a quality metric should be considered prior to expanding the use of public reporting more broadly. In this viewpoint, the authors review in particular the characterization of high-risk patients currently treated by percutaneous coronary interventional procedures, assessing the adequacy of clinical risk models used in this population. They then expand upon the limitations of 30-day mortality as a quality metric for percutaneous coronary intervention, addressing the strengths and limitations of this metric, as well as offering suggestions to enhance its future use in public reporting. PMID- 27765302 TI - Impact of Operator Experience and Volume on Outcomes After Left Main Coronary Artery Percutaneous Coronary Intervention. AB - OBJECTIVES: The aim of this study was to assess the impact of operator experience on prognosis after left main coronary artery (LM) percutaneous coronary intervention (PCI). BACKGROUND: LM PCI can be technically challenging and potentially risky considering the amount of supplied myocardium. METHODS: Consecutive patients who underwent unprotected LM PCI at a single institution were included and compared according to whether the primary operator was an experienced, high-volume LM operator (defined as an operator who performed at least 15 LM PCIs per year for at least 3 consecutive years) or not. Kaplan-Meier estimates and Cox proportional hazards models are presented. RESULTS: From January 2004 to December 2011, a total of 1,948 patients underwent unprotected LM PCI by 25 operators. Of these, 7 operators (28%) were considered experienced, and 18 (72%) were considered less experienced, with an overall mean experience of 12.0 +/- 11.5 LM PCIs per year. LM PCI was performed in 1,422 patients (73%) by experienced operators and in 526 patients (27%) by less experienced operators. Patients treated by experienced operators had more complex and extensive coronary artery disease. Unadjusted and adjusted risks for cardiac death were lower for patients who were treated by experienced operators, both at 30-day (unadjusted hazard ratio [HR]: 0.23; 95% confidence interval [CI]: 0.09 to 0.60; p = 0.003; adjusted HR: 0.22; 95% CI: 0.09 to 0.59; p = 0.003) and 3-year (unadjusted HR: 0.53; 95% CI: 0.32 to 0.89, p = 0.02; adjusted HR: 0.49; 95% CI: 0.29 to 0.84; p = 0.009) follow-up. Discrimination improved when operator experience was added to Cox proportional hazards models containing the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score (integrated discriminatory index = 0.004, p = 0.03) or SYNTAX score II (integrated discriminatory index = 0.007, p = 0.02). No significant interaction was detected between operator experience and distal bifurcation LM lesion, 2-stent bifurcation stenting, and intravascular ultrasound use (p > 0.10 for all). CONCLUSIONS: Patients who underwent LM PCI by high-volume and experienced operators had better short- and long-term prognoses. Operator experience is an important factor in a complex intervention such as LM PCI. PMID- 27765303 TI - The Volume-Outcome Relationship Revisited: Does It Matter for High-Risk PCI? PMID- 27765304 TI - Transcarotid Transcatheter Aortic Valve Replacement: General or Local Anesthesia. AB - OBJECTIVES: The study sought to assess the safety and efficacy of a minimally invasive strategy (MIS) (local anesthesia and conscious sedation) compared to general anesthesia (GA) among the largest published cohort of patients undergoing transcarotid transcatheter aortic valve replacement (TAVR). BACKGROUND: Transcarotid TAVR has been shown to be feasible and safe. There is, however, no information pertaining to the mode anesthesia in these procedures. METHODS: Between 2009 and 2014, 174 patients underwent transcarotid TAVR at 2 French centers. All patients were unsuitable for transfemoral TAVR due to severe peripheral vascular disease. An MIS was undertaken in 29.8% (n = 52) and GA in 70.1% (n = 122). One-year clinical outcomes were available in all patients and were described according to the Valve Academic Research Consortium-2 consensus. RESULTS: Transcarotid vascular access and transcatheter valve deployment was successful in all cases. Thirty-day mortality was 7.4% (n = 13) and 1-year all cause and cardiovascular mortality were 12.6% (n = 22) and 8.0% (n = 14), respectively. According to the type of anesthesia, there was no between group difference in 30-day mortality (GA 7.3% vs. MIS 7.6%; p = 0.94), 1-year mortality (GA 13.9% vs. MIS 9.6%; p = 0.43), 1-month clinical efficacy (GA 85.2% vs. MIS 94.2%; p = 0.09), and early safety (GA 77.8% vs. MIS 86.5%; p = 0.18). There were 10 (5.7%) periprocedural cerebrovascular events: 4 strokes (2.2%) and 6 transient ischemic attacks (3.4%) among those treated with GA. There was neither stroke nor transient ischemic attack in the MIS group (p < 0.001). CONCLUSIONS: The transcarotid approach for TAVR is feasible using general or local anesthesia. A higher rate of perioperative strokes was observed with GA. PMID- 27765305 TI - Transcarotid Transcatheter Aortic Valve Replacement: Not Just a Pain in the Neck. PMID- 27765306 TI - Neurological Outcomes With Embolic Protection Devices in Patients Undergoing Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: The aim of this study was to investigate the efficacy and safety of intraprocedural embolic protection (EP) during transcatheter aortic valve replacement (TAVR). BACKGROUND: Randomized controlled trials (RCTs) investigating the efficacy of EP devices during TAVR were relatively underpowered. METHODS: A systematic review and study-level meta-analysis was performed of randomized controlled trials that tested the efficacy and safety of EP during TAVR. Trials using any type of EP and TAVR vascular access were included. Primary imaging efficacy endpoints were total lesion volume and number of new ischemic lesions. Primary clinical efficacy endpoints were any deterioration in National Institutes of Health Stroke Scale and Montreal Cognitive Assessment scores at hospital discharge. Primary analyses were performed using the intention-to-treat approach. RESULTS: Four randomized clinical trials (total n = 252) were included. Use of EP was associated with lower total lesion volume (standardized mean difference 0.65; 95% confidence interval [CI]: -1.06 to -0.25; p = 0.002) and smaller number of new ischemic lesions (standardized mean difference -1.27; 95% CI: -2.45 to 0.09; p = 0.03). EP was associated with a trend toward lower risk for deterioration in National Institutes of Health Stroke Scale score at discharge (risk ratio: 0.55; 95% CI: 0.27 to 1.09; p = 0.09) and higher Montreal Cognitive Assessment score (standardized mean difference 0.40; 95% CI: 0.04 to 0.76; p = 0.03). Risk for overt stroke and all-cause mortality were nonsignificantly lower in the EP group. CONCLUSIONS: Use of EP seems to be associated with reductions in imaging markers of cerebral infarction and early clinical neurological effectiveness in patients undergoing TAVR. PMID- 27765307 TI - The Pros and Cons of Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement. PMID- 27765309 TI - Is There a Place for Surgical Aortic Valve Replacement in Patients With Aortic Stenosis and Previous Coronary Bypass Grafting? PMID- 27765308 TI - Transcatheter Aortic Valve Replacement: The New Standard in Patients With Previous Coronary Bypass Grafting? AB - OBJECTIVES: The aim of this study was to assess how the introduction of transcatheter aortic valve replacement (TAVR) has changed clinical practice and outcome in patients who have previously undergone coronary artery bypass grafting (CABG). BACKGROUND: A significant proportion of patients admitted for aortic valve replacement have previously undergone CABG and are therefore at increased operative risk in case of redo surgery. METHODS: In-hospital outcome data were analyzed from patients with or without previous CABG undergoing isolated surgical aortic valve replacement or TAVR in Germany from 2007 to 2013. RESULTS: In total, 32,581 TAVR and 55,992 surgical aortic valve replacement procedures were performed in patients with (n = 6,221) or without (n = 82,352) previous CABG. TAVR increased markedly in patients with previous CABG, from 18 procedures in 2007 to 1,191 in 2013, while surgical aortic valve replacement decreased in these patients from 471 to 179 procedures. In 2013, TAVR was the preferred therapy in almost 90% of patients with previous CABG. In-hospital mortality was increased in patients with previous CABG compared with those without (7.6% vs. 6.3% for TAVR and 7.2% vs. 2.6% for surgical aortic valve replacement). Bleeding and stroke rates were also increased with redo surgical aortic valve replacement procedures (with vs. without previous CABG: stroke, 3.2% vs. 1.8%; relevant bleeding, 29.6% vs. 13.4%; acute kidney injury, 4.2% vs. 2.9%), whereas this was not the case with TAVR (stroke, 2.1% vs. 2.6%; relevant bleeding, 7.3% vs. 8.3%; acute kidney injury, 6.3% vs. 5.4% respectively). A similar influence was seen in resource utilization (discharge destination home: TAVR after CABG, 51%; surgical aortic valve replacement after CABG, 31%). CONCLUSIONS: Since its introduction in 2007, TAVR has been increasingly used in Germany in patients with previous CABG, and in hospital outcome data support the trend away from redo surgery. PMID- 27765310 TI - Local Ultrasound to Enhance Paclitaxel Delivery After Femoral-Popliteal Treatment in Critical Limb Ischemia: The PACUS Trial. AB - OBJECTIVES: The aim of this study was to evaluate the safety and efficacy of percutaneous catheter-delivered ultrasound energy to improve local paclitaxel delivery effects in patients with critical limb ischemia (CLI) treated for femoral-popliteal arterial disease. BACKGROUND: Treatment of patients with CLI continues to be the greatest challenge in peripheral artery disease; in particular, treatment of femoral-popliteal chronic total occlusion is characterized by poor primary patency. METHODS: This single-center, single-blind, randomized trial included 56 patients with CLI randomly assigned to treatment in 2 groups: 28 patients (the control group) were treated with drug-eluting balloons, and 28 patients (the study group) were treated with intravascular ultrasound using the CardioProlific Genesis System followed by local administration of a liquid mixture of iopromide 370 and paclitaxel 1.0 MUg/mm3. In the study group, mean lesion length was 168.8 mm, and 21 patients had calcifications. In the control group, mean lesion length was 164 mm, and 23 patients had calcifications. RESULTS: No adverse procedural events were observed; all 56 patients tolerated the procedure well. At 6-month follow-up, no myocardial infarction, deaths, or amputations were observed in either group. In the study group, the rate of restenosis at 6 months was 3.6% (1 of 28), and the rate of target lesion revascularization (TLR) was 0% (0 of 28); at 12 months, the rate of TLR was 3.8% (1 of 26), and the rate of amputation was 0% (0 of 26). In the control group, the rate of restenosis at 6 months was 21.4% (6 of 28), and the rate of TLR was 10.7% (3 of 28); at 12 months, the rate of TLR was 36% (9 of 25), and the rate of amputation was 16% (4 of 25). CONCLUSIONS: This study demonstrates encouraging results at 6- and 12-month follow-up in patients treated with ultrasound and paclitaxel compared with drug-eluting balloons. Larger multicenter studies are required to validate this approach. PMID- 27765311 TI - Ultrasound Plus Paclitaxel Trumps Drug-Coated Balloon: Progress in the Periphery? PMID- 27765312 TI - Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2 degrees P-TIMI 50 Trial. AB - OBJECTIVES: The aim of this study was to determine whether the reduction in peripheral revascularization with vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. BACKGROUND: The protease-activated receptor-1 antagonist vorapaxar reduces peripheral revascularization in patients with PAD. METHODS: The TRA 2 degrees P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of vorapaxar was consistent across indication and type of procedure. RESULTS: Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. CONCLUSIONS: Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2 degrees P - TIMI 50] [P04737]; NCT00526474). PMID- 27765313 TI - Appropriate Use of Vorapaxar in Patients With Peripheral Artery Disease. PMID- 27765314 TI - Patent Foramen Ovale Combined With Pulmonary Arteriovenous Malformation. PMID- 27765315 TI - Index of Microvascular Resistance and Microvascular Obstruction in Patients With Acute Myocardial Infarction. PMID- 27765316 TI - "Do We Know What We Are Adding?" PMID- 27765317 TI - Antithrombotic Therapy and Vascular Access Site: Comparing Effect Sizes, Not Only p Values. PMID- 27765318 TI - Reply: Antithrombotic Therapy and Vascular Access Site: Comparing Effect Sizes, Not Only p Values. PMID- 27765319 TI - Complicated and Impractical Classification of LAA Morphologies: How to Relate to LAA Closure Procedures? PMID- 27765320 TI - Reply: Complicated and Impractical Classification of LAA Morphologies: How to Relate to LAA Closure Procedures? PMID- 27765321 TI - Should All Roads Lead to Rome? PMID- 27765322 TI - Correction. PMID- 27765323 TI - Correction. PMID- 27765324 TI - Total synthesis and stereochemical determination of yoshinone A. AB - In 2014, the gamma-pyrone-containing polyketide, yoshinone A, was isolated from the marine cyanobacterium Leptolyngbya sp. and its structure was determined. Yoshinone A inhibited differentiation of 3T3-L1 cells into adipocytes, with an EC50 value of 420 nM without any cytotoxicity, and therefore is expected to be a lead compound for obesity drugs. To establish its absolute configuration, and to provide sufficient amounts for further research, the total synthesis of yoshinone A was achieved through synthesis of its two possible diastereomers. PMID- 27765325 TI - An opportunity to reflect. PMID- 27765326 TI - AAOM Clinical Practice Statement: Subject: Dental Evaluation Before Head and Neck Radiotherapy. PMID- 27765327 TI - Comparison of mean radiation dose and dosimetric distribution to tooth-bearing regions of the mandible associated with proton beam radiation therapy and intensity-modulated radiation therapy for ipsilateral head and neck tumor. AB - OBJECTIVE: The purpose of this study was to compare the dosimetric distribution of ipsilateral proton beam radiation therapy (PBRT) with intensity-modulated radiation therapy (IMRT) in the tooth-bearing region of the mandible in patients with head and neck cancer (HNC). STUDY DESIGN: The mandibular dosimetric distribution in patients with head and neck cancer treated with >=60 Gy relative biologic equivalent PBRT was evaluated. The mean radiation doses were calculated in 5 regions: ipsilateral molar, ipsilateral premolar, anterior, contralateral premolar, and contralateral molar (CM) regions. CM was used as the reference region for comparative analysis. The mandibular dosimetric distribution in patients treated with PBRT was compared with that in IMRT patients with similar tumor sites and planning target volumes. RESULTS: The mean radiation dose to the contralateral regions was lower in patients treated with PBRT compared with those treated with IMRT. The average mean radiation doses to the reference region (CM) in patients treated with PBRT (relative biologic equivalent) versus IMRT were oropharynx (2.2 Gy vs 23.2 Gy; P < .00002), parotid (0 Gy vs 11.8 Gy; P = .01), and oral cavity (0.4 Gy vs 15.6 Gy; P = .006). CONCLUSIONS: This study revealed the effective tissue-sparing capability of PBRT compared with IMRT. Utilization of PBRT could translate to less radiation-related toxicity. PMID- 27765328 TI - Diagnostic validity of clinical protocols to assess temporomandibular disk displacement disorders: a meta-analysis. AB - OBJECTIVE: To evaluate the diagnostic validity of clinical examination protocols compared with magnetic resonance imaging (MRI) in adults with temporomandibular joint disk displacement disorders. STUDY DESIGN: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was undertaken using a selection process in 2 phases; 283 different references were identified, and 10 articles were included for qualitative analysis and 7 for meta-analysis. Temporomandibular joint disorders were assessed through clinical diagnosis protocols with the aid of Research Diagnostic Criteria for Temporomandibular Disorders, Diagnostic Criteria for Temporomandibular Disorders, or Clinical Diagnostic Criteria for Temporomandibular Disorders. The authors searched the following electronic databases: Cochrane, LILACS, PubMed, Science Direct, SCOPUS, and Web of Science. Additional search of gray literature was performed. Selected studies were evaluated by using the Quality Assessment Tool for Diagnostic Accuracy Studies-2. Two subgroups were analyzed: Disk displacement with reduction (DDwR) and disk displacement without reduction (DDwoR). RESULTS: The validity of clinical protocols compared with MRI performed in studies evaluating only DDwR presented sensitivity of 44% (39%-49%) and specificity 51% (46%-57%). In studies evaluating only DDwoR, sensitivity was 22% (16%-30%) and specificity 93% (85%-98%). The area under the curve value for validity of clinical protocols in all studies was 0.63, 0.56 for studies evaluating DDwR and 0.64 for studies evaluating DDwoR. Area under the curve values were considered poor. CONCLUSIONS: Clinical examination protocols have poor validity to diagnose DDwR and DDwoR compared with MRI. MRI should be used to increase the diagnostic accuracy when the information provided can influence clinical decisions. PMID- 27765329 TI - Effect of G-CSF on oral mucositis and traumatic ulcers produced in the tongue of rats undergoing radiotherapy: clinical and histologic evaluation. AB - OBJECTIVE: To investigate the effect of granulocyte colony-stimulating factor (G CSF) on oral mucositis (OM) and on the healing of traumatic ulcers produced in the tongue of rats undergoing radiotherapy (RT). STUDY DESIGN: Twenty-seven Wistar rats were assigned to four groups: (1) RT + traumatic ulcer + filgrastim (G-CSF analog; n = 7); (2) RT + traumatic ulcer + saline (n = 7); (3) no RT + traumatic ulcer + filgrastim (n = 7); and (4) no RT + traumatic ulcer (n = 6). The radiation dose was 30 Gy, and medication was filgrastim (10 MUg/kg) for 7 days. RESULTS: Clinically, groups differed in the presence (Fisher's exact test: P = .008) and size of traumatic ulcers after irradiation (Kruskal-Wallis test: P = .032) and in the severity of OM (Fisher's exact test: P = .005 between the irradiated groups). Histologically, there was an increased inflammatory response in the nonirradiated groups (Fisher's exact test: P = .001). CONCLUSIONS: Filgrastim reduced manifestations and the severity of trauma-induced ulcers and radiation-induced OM. Significant differences were not observed histologically between the study drug and respective control groups. PMID- 27765330 TI - Low prevalence of transcriptionally active human papilloma virus in Indian patients with HNSCC and leukoplakia. AB - OBJECTIVES: In the present study, we comprehensively analyzed the prevalence of transcriptionally active human papilloma virus (HPV) in tissue samples of Indian patients with leukoplakia, predominantly hyperplastic lesions and head and neck squamous cell carcinoma (HNSCC). In addition, saliva samples from patients with HNSCC were screened for HPV detection. STUDY DESIGN: P16 overexpression was analyzed by immunohistochemistry. Tissue samples of leukoplakia (n = 121) and HNSCC (n = 427) and saliva from patients with HNSCC (n = 215) were tested for HPV using nested polymerase chain reaction. Positive samples were sequenced for subtyping. The presence of HPV E6/E7 mRNA was confirmed by RNA in situ hybridization. RESULTS: P16 expression and HPV DNA were not detected in any of the leukoplakia specimens. Of the 427 HNSCC tumors, 9 showed p16 overexpression and 7/427 cases were positive for HPV16 DNA, in saliva or tissue. E6/E7 mRNA positivity was observed in 8 HNSCC samples, primarily from patients with no habit of tobacco consumption. The prevalence of high-risk HPV was restricted to oropharynx and larynx, with very little concordance between p16 overexpression and HPV positivity. All patients with HPV-positive saliva samples had transcriptionally active HPV present in their tumors. CONCLUSION: The presence of HPV DNA does not necessarily reflect transcriptionally active virus in tumors; hence, it is important to consider this fact while categorizing HPV-associated tumors. PMID- 27765331 TI - Altered expression of interleukin-17A and its targeting microRNAs in oral lichen planus: a pilot study. AB - OBJECTIVE: To investigate the potential role of interleukin (IL)-17A and its targeting microRNAs (miRNAs) in oral lichen planus (OLP). STUDY DESIGN: We compared the IL-17A expression levels in biopsies from patients with OLP (n = 50) against normal controls (n = 19) by using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analyses, identified the targeting miRNAs of IL-17A, and examined the miRNA expression levels in OLP. RESULTS: IL-17A expression was significantly increased in patients with OLP compared with controls. The dual-luciferase reporter assay system demonstrated that miR-635 and miR-578 were the target miRNAs of IL-17A in human embryonic kidney 293 cells, which was consistent with predictions from bioinformatics software analyses. In contrast with IL-17A, the expression levels of miR-635 and miR-578 in OLP were significantly decreased compared with controls. CONCLUSIONS: This pilot study found that low levels of miR-635 and miR-578 expression were associated with high expression of IL-17A, suggesting that IL-17A and its targeting miRNAs contribute to the pathogenesis of OLP. PMID- 27765332 TI - Keratinizing odontogenic cysts with a spectrum of verrucoid morphology: investigation of a potential role of human papillomavirus. AB - OBJECTIVE: The role of human papillomavirus (HPV) in keratinizing odontogenic cysts (OC) has only rarely been studied. We describe the clinicopathologic findings in a series of OCs that had unusual keratinization patterns and were investigated for a possible HPV etiology. STUDY DESIGN: Tissue samples from 29 patients with keratinizing OCs were studied for light microscopic features suggestive of HPV infection and by an HPV DNA polymerase chain reaction assay. RESULTS: The mean age at presentation was 31.1 years; 79.3% of the OCs occurred in the mandible and 46.4% were associated with an impacted tooth. The phenotypic characteristics koilocytes, hypergranulosis, and a verrucous pattern of the cyst lining epithelium were observed in 69%, 62.1%, and 17.2% of cases, respectively. These histomorphologic features did not, however, correlate with HPV infection. CONCLUSIONS: HPV does not appear to play a role in keratinizing OCs and is not responsible for the wart-like histomorphologic features that may be seen in these lesions. PMID- 27765333 TI - Influence of voxel size and scan field of view on fracture-like artifacts from gutta-percha obturated endodontically treated teeth on cone-beam computed tomography images. AB - OBJECTIVE: To determine the optimal scan settings (scan mode and position of field of view [FOV]) for cone beam computed tomography to reduce root fracture like artifacts that are often observed in teeth filled with gutta-percha cones (GPCs). STUDY DESIGN: Fracture-like artifacts that appeared on cone beam computed tomography images of 9 extracted human mandibular premolars filled with GPCs were analyzed using I-mode (FOV, 102 mm; voxel size, 0.2 mm) and D-mode (FOV, 51 mm; voxel size, 0.1 mm) settings. RESULTS: The artificial lines were more obvious in I-mode than in D-mode. Increased distance between the center of the FOV and the GPCs produced stronger artificial lines in both I-mode and D-mode. CONCLUSION: To reduce fracture-like artifacts, it is critical to use a mode with small voxel size and to place the target tooth in the center of the FOV. PMID- 27765334 TI - MRI alone versus MRI-CBCT registered images to evaluate temporomandibular joint internal derangement. AB - OBJECTIVE: To evaluate the effect of magnetic resonance imaging-cone beam computed tomography (MRI-CBCT) image registration on inter- and intraexaminer consistency when evaluating temporomandibular joint (TMJ) internal derangement compared to MRI alone. METHODS: MRI and CBCT images of 25 patients (50 TMJs) were obtained and coregistered using mutual-information rigid image registration via Mirada XD software. Two experienced radiologists independently and blindly evaluated two types of images (MRI alone and MRI-CBCT registered images) at two different times (T1 and T2) for TMJ internal derangement, based on sagittal and coronal articular disc position in relation to the head of the condyle and the posterior slope of the articular eminence. RESULTS: The intraexaminer consistency with MRI alone (examiner 1 = 0.85 [0.74-0.92]; examiner 2 = 0.91 [0.84-0.95]) was lower than for the MRI-CBCT registered images (examiner 1 = 0.95 [0.91-0.97]; examiner 2 = 0.97 [0.96-0.99]). The interexaminer consistency of evaluating internal derangement with MRI alone (0.52 [0.18-0.73] at T1; 0.71 [0.45-0.84] at T2) was lower than for the MRI-CBCT registered images (0.97 [0.95-0.98] at T1; 0.98 [0.96-0.99] at T2). When disc position classification was dichotomized to normal versus anteriorly displaced, intraexaminer agreement for the two examiners was 0.52 and 0.63 for MRI alone, but was 0.91 and 0.92 for MRI-CBCT registered images. Interexaminer agreement for MRI alone was 0.29 at T1 and 0.42 at T2, but was 0.96 at both examination times for MRI-CBCT registered images. CONCLUSION: The MRI-CBCT registered images improved intra- and interexaminer consistency in the evaluation of internal derangement of TMJ. PMID- 27765335 TI - The effect of milliamperage, number of basis images, and export slice thickness on contrast-to-noise ratio and detection of mandibular canal on cone beam computed tomography scans: an in vitro study. AB - OBJECTIVES: The aim of this study was to evaluate the effect of milliamperage, number of basis images, and export slice thickness on contrast-to-noise ratio (CNR) and confidence in detecting mandibular canal. STUDY DESIGN: Two phantoms were used. Each phantom consisted of a dry mandible with an epoxy resin bone tissue substitute block and a water-equivalent block, submerged in water. Each mandible was scanned with a Morita 3D Accuitomo cone beam computed tomography (CBCT) machine (Morita, Kyoto, Japan). Scans were made with 180-degree and 360 degree rotations, at 4, 6, and 8 mA. Each scan was exported in Digital Imaging and Communications in Medicine (DICOM) format at slice thicknesses of 0.125 mm, 0.25 mm, 0.75 mm, and 1.0 mm, resulting in 24 image sets for each phantom. The CNR was calculated. Variables were analyzed using factorial analysis of variance. The scans were also evaluated by five observers who were asked to state their confidence in detecting the mandibular canal on a four-point confidence scale. RESULTS: Increasing the number of basis images, milliamperage, or export slice thickness significantly increased the CNR. Reducing the export slice thickness improved observers' confidence in detecting the mandibular canal. CONCLUSIONS: The CBCT acquisition settings should be carefully chosen, depending on specific diagnostic tasks. The lowest slice thickness equal to the voxel size should always be used for exporting CBCT data despite the higher noise. PMID- 27765336 TI - How accurate is information about the diagnosis and management of temporomandibular disorders on dentist websites?-a commentary. PMID- 27765337 TI - Differences in the risk of osteoporotic femur fractures among Japanese and white women as predicted by carotid artery calcification visualized on panoramic images. PMID- 27765338 TI - Response to Letter to the Editor: Re: Differences in the risk of osteoporotic femur fractures among Japanese and white women as predicted by carotid artery calcification visualized on panoramic images. PMID- 27765339 TI - Erratum to "Microvascular stent anastomosis using N-fibroin stents: feasibility, ischemia time, and complications" [Oral Surg Oral Med Oral Pathol Oral Radiol 2016;121:e97-e103]. PMID- 27765340 TI - Erratum to "Overexpression of ErbB4 is an independent marker for lymph node metastasis in Japanese patients with oral squamous cell carcinoma" [Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:313-321]. PMID- 27765341 TI - Unusual presentation of squamous cell carcinoma of the maxilla in an 8-year-old child. AB - Oral squamous cell carcinoma (OSCC) is extremely rare in patients younger than 20 years of age. We present here a case of OSCC of the maxillary alveolar ridge in an otherwise healthy 8-year-old patient. The clinicohistologic presentation was not typical for mucosal SCC, and the possibility of an intrabony origin from the odontogenic epithelium was considered. The patient was treated with surgical resection, and treatment decisions were made with consideration of the need for eradication of tumor as well as tissue preservation to allow normal growth and development. A review of the literature indicated a preponderance of gingival alveolar ridge as the site of OSCC in children with no known genetic predisposition to cancer. More studies of this rare subset of OSCC will help understand the underlying biology and guide treatment decisions. PMID- 27765342 TI - Systematic review and meta-analyses of the effect of lipid emulsion on microbial growth in parenteral nutrition. AB - BACKGROUND: As lipid in parenteral nutrition (PN) purportedly enhances microbial growth, recommendations limit infusion of lipid PN (or lipid emulsion) from a single container to 24h (48h for lipid-free PN). However, the associated evidence base is ambiguous. AIM: To examine factors affecting microbial growth in PN. METHODS: A systematic review with meta-analyses examined effects of nutrients on microbial growth in PN infusates over a 48-h period using the growth ratio {GR=log10[colony-forming units (cfu)/mL at 48h/cfu/mL at time zero]}. FINDINGS: Factors influencing GR in PN included glucose, microbial species, temperature, osmolarity, presence of vitamins, trace elements and lipid, and amino acid profile. Using unmatched datasets (N=306), a general linear model found that lipid inclusion in PN represented 3.3% of the variability, which was less than that due to glucose concentration (5.8%), microbial species (35.3%) and microbe infusate interaction (4.4%). Using matched datasets (N=38 pairs), lipid inclusion in PN represented 5.4% of the variability (P=0.076), which was less than that due to glucose concentration (8.5%; P=0.025), microbial species (75.5%; P<0.001) and microbe-infusate interaction (13.3%; P=0.382). Using meta-analyses of matched datasets, the presence of lipid in PN at fixed glucose concentrations did not significantly increase GR of Candida albicans, Escherichia coli or Staphylococcus epidermidis (P=0.352, P=0.025 and P=0.494, respectively; overall P=0.175). CONCLUSION: Lipid inclusion in PN is only one of several factors that may influence microbial growth in PN. Any recommendations about the duration of PN infusion from a single container should account for all these factors, and should be weighted according to microbial species likely to contaminate PN. PMID- 27765345 TI - Re: Re: Management of a mucocoele of the submandibular gland without removal of the gland: a case report. PMID- 27765344 TI - Measures of disease status in systemic sclerosis: A systematic review. AB - OBJECTIVES: To identify and appraise measures of disease status in systemic sclerosis (SSc). METHODS: A systematic review of Medline (1966-2015), EMBASE (1974-2015), and Cochrane Library (inception-2015) was undertaken to identify indices of disease status in SSc. We focused on objective measures and excluded non-English articles. Measures were reviewed for content, whether they measured activity, damage and/or severity and whether they were validated according to the OMERACT filter. RESULTS: Of the 4558 articles retrieved through the search, we identified 58 articles for review. We found a further 44 articles through a search of the bibliography of relevant articles. We identified the following 10 "composite" (multi-organ) indices: two disease activity indices, six disease severity scales, and two combined response indices. There was no disease damage index for SSc. CONCLUSIONS: We identified a number of composite and organ specific indices in SSc, incorporating mostly objective measures, developed to quantify disease activity, severity, and response in clinical trials. However, none of the indices was developed to exclusively quantify organ damage. Most of the existing indices require further validation according to the OMERACT filter. There is a need to develop and validate a disease damage index in SSc. PMID- 27765347 TI - Neurohormetic responses of quercetin and rutin in a cell line over-expressing the amyloid precursor protein (APPswe cells). AB - BACKGROUND: Plant secondary metabolites may induce adaptive cellular stress responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids such as quercetin or rutin, may involve cell responses driven by modulation of signaling pathways which are responsible for its neuroprotective effects. PURPOSE: We attempt to explore the molecular mechanisms involved in the neurohormetic responses to quercetin and rutin exposure, in a SH-SY5Y cell line which stably overexpresses the amyloid precursor protein (APP) Swedish mutation, based on a biphasic concentration-response relationship for cell viability. METHODS: We examined the impact of both natural compounds, at concentrations in its hormetic range on the following cell parameters: chymotrypsin-like activity of the proteasome system; PARP-1 protein levels and expression and caspase activation; APP processing; and the main endogenous antioxidant enzymes. RESULTS: Proteasome activities following quercetin or rutin treatment were significantly augmented in comparison with non-treated cells. Activity of caspase-3 was significantly attenuated by treatment with quercetin or rutin. Modest increased levels of PARP 1 protein and mRNA transcripts were observed in relation to the mild increase of proteasome activity. Significant reductions of the full-length APP and sAPP protein and APP mRNA levels were related to significant enhancements of alpha secretase ADAM-10 protein and mRNA transcripts and significant increases of BACE processing in cells exposed to rutin. Furthermore, quercetin or rutin treatment displayed an overall increase of the four antioxidant enzymes. CONCLUSIONS: The upregulation of the proteasome activity observed upon quercetin or rutin treatment could be afforded by a mild increased of PARP-1. Consequently, targeting the proteasome by quercetin or rutin to enhance its activity in a mild manner could avoid caspase activation. Moreover, it is likely that APP processing of cells upon rutin treatment is mostly driven by the non-amyloidogenic pathway leading to a putative reduction of betaA production. Overall induction of endogenous antioxidant enzymes under quercetin or rutin treatments of APPswe cells might modulate its proteasome activity. We might conclude that quercetin and rutin might exert a neurohormetic cell response affecting various signaling pathways and molecular networks associated with modulation of proteasome function. PMID- 27765346 TI - Dietary Foeniculum vulgare Mill extract attenuated UVB irradiation-induced skin photoaging by activating of Nrf2 and inhibiting MAPK pathways. AB - BACKGROUND: Foeniculum vulgare Mill (FV) has long been prescribed in traditional medicine due to its antioxidant anti-inflammatory properties. However, little research has been done on the use of FV to alleviate changes in UVB-induced photoaging PURPOSE: This study was to investigate the photoprotective effects and mechanism of FV in vitro and in vivo. METHODS: The anti-photoaging effect of FV was assessed in normal human dermal fibroblasts (NHDFs) in vitro. The secretion of reactive oxygen species (ROS), lactate dehydrogenase (LDH), GSH, matrix metalloproteinases (MMPs), procollagen type I, IL-6 and transforming growth factor-beta1 (TGF-beta1) were measured by kits. Additionally, the level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), p-ERK and p38 were evaluated by western blotting. In vivo, H&E and Masson's trichrome staining were employed. The expression of MMP-1, procollagen type I, TGF-beta1 and elastin were measured by western blot. RESULTS: FV significantly increased the production of collagen, elastin and TGF-beta1 levels, while blocked matrix metalloproteinases (MMPs) production in UVB irradiation induced hairless mice, which were consistent with the result in NHDFs. Furthermore, FV dose-dependently decreased the production of ROS and LDH by promoting the nuclear amount of Nrf2 and enhancing the expression of cytoprotective antioxidants such as GSH. FV also significantly quenched UVB induced phosphorylation of ERK and p38 in NHDFs. CONCLUSION: Our results indicate that FV is a potential botanical agent for the treatment of skin damage induced by UV irradiation. PMID- 27765348 TI - Ginkgo biloba extract in combination with sorafenib is clinically safe and tolerable in advanced hepatocellular carcinoma patients. AB - BACKGROUND: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). However, the clinical efficacy of sorafenib is limited. Combination therapy targeting multiple signaling pathways may improve outcomes. Ginkgo biloba extract (GBE) has exhibited antitumor activity in multiple human cancers. HYPOTHESIS/PURPOSE: This study was designed to evaluate the tolerability and effectiveness of GBE combined with sorafenib in patients with advanced HCC. STUDY DESIGN: Patients with advanced HCC were treated with increasing doses of GBE in combination with sorafenib. METHODS: We first determined the maximum tolerated dose (MTD) of GBE, then the patients were treated with GBE at the MTD to evaluate its safety and efficacy. 27 patients were enrolled in the first part of our study and treated with sorafenib 400mg twice daily (BID) and increasing doses (cohort 1: 60mg, cohort 2: 120mg, cohort 3: 240mg, cohort 4: 360mg) of GBE once daily (QD). An additional group of 32 new patients next to the 27 described before were accrued for the second part of our study, and all these 32 patients were eligible for the evaluation of toxicity and efficacy. RESULTS: No patient in cohort 1 and 2 experienced a dose-limiting toxicity (DLT). One of the ten patients in cohort 3 experienced a DLT. DLT occurred in two of the three initial patients in cohort 4. Cohort 3 (GBE 240mg QD plus sorafenib 400mg BID) was considered to be the MTD. Three patients had a partial response, 21 had stable disease, and 8 had progressive disease. The median times to progression and overall survival were 2.5 and 11.6 months, respectively. Compared with previous study, the toxicities of the combination therapy were similar with those observed in sorafenib monotherapy, GBE in combination with sorafenib slightly improved OS. CONCLUSIONS: The combination of GBE (240mg QD) and standard dose sorafenib (400mg BID) is safe and tolerable among patients with advanced HCC. Early signs of antitumor activity may warrant further development of this combination. PMID- 27765349 TI - Target molecules in 3T3-L1 adipocytes differentiation are regulated by maslinic acid, a natural triterpene from Olea europaea. AB - BACKGROUND: Metabolic syndrome is a set of pathologies among which stand out the obesity, which is related to the lipid droplet accumulation and changes to cellular morphology regulated by several molecules and transcription factors. Maslinic acid (MA) is a natural product with demonstrated pharmacological functions including anti-inflammation, anti-tumor and anti-oxidation, among others. PURPOSE: Here we report the effects of MA on the adipogenesis process in 3T3-L1 cells. METHODS: Cell viability, glucose uptake, cytoplasmic triglyceride droplets, triglycerides quantification, gene transcription factors such as peroxisome proliferator-activated receptor gamma (PPARgamma) and adipocyte fatty acid-binding protein (aP2) and intracellular Ca2+ levels were determined in pre adipocytes and adipocytes of 3T3-L1 cells. RESULTS: MA increased glucose uptake. MA also decreased lipid droplets and triglyceride levels, which is in concordance with the down-regulation of PPARgamma and aP2. Finally, MA increased the intracellular Ca2+ concentration, which could also be involved in the demonstrated antiadipogenic effect of this triterpene. CONCLUSION: MA has been demonstrated as potential antiadipogenic compound in 3T3-L1 cells. PMID- 27765350 TI - Isolation and characterization of bioactive metabolites from Xylaria psidii, an endophytic fungus of the medicinal plant Aegle marmelos and their role in mitochondrial dependent apoptosis against pancreatic cancer cells. AB - BACKGROUND: The genus Xylaria has been reported as a rich source of biologically active secondary metabolites. In the present study, an endophytic fungus Xylaria psidii has been isolated from the leaf sample of Aegle marmelos (L.) Corr., characterized on the basis of its morphological features and sequence data for the ITS region (KU291350) of the nuclear ribosomal DNA. Biological screening of ethyl acetate extract of Xylaria psidii displayed a potential therapeutic effect on pancreatic cancer cells. HYPOTHESIS: This study was designed systematically to explore Xylaria psidii, an endophytic fungus for the identification of biologically active secondary metabolites against pancreatic cancer cells. METHODS: While exploring the bioactive secondary metabolites, a sensitive and reliable LC-MS based dereplication approach was applied to identify four compounds A-D from fungal extract. Further bioactivity guided isolation of fungal extract yielded two major metabolites 1 and 2. The structures of 1 and 2 have been determined by detailed spectroscopic analysis including MS, NMR, IR and UV data and similarity with published data. Xylarione A (1) is new whereas (-) 5 methylmellein (2) is reported for the first time from X. psidii. Both the isolated compounds were screened for their effect on the viability and proliferation against a panel of cancer cell lines (MCF-7, MIA-Pa-Ca-2, NCI-H226, HepG2 and DU145) of different tissue origin. RESULTS: Compounds 1 and 2 exhibited cytotoxicity against pancreatic cancer (MIA-Pa-Ca-2) cells with IC50 values of 16.0 and 19.0 um, respectively. The cell cycle distribution in MIA-Pa-Ca-2 cells, confirmed a cell cycle arrest at the sub-G1 phase. Cell death induced by 1 and 2 displayed features characteristic of apoptosis. Flow cytometry based analysis of 1 and 2 using Rhodamine-123 displayed substantial loss of mitochondrial membrane potential in a concentration dependent manner by both the compounds. CONCLUSION: Results conclude that the isolated compounds 1 and 2 are responsible for the activity shown by crude ethyl acetate extract and may act as potential leads for medicinal chemists for designing more potent analogs. PMID- 27765351 TI - The anthraquinones rubiadin and its 1-methyl ether isolated from Heterophyllaea pustulata reduces Candida tropicalis biofilms formation. AB - BACKGROUND: Candida tropicalis is increasingly becoming among the most commonly isolated pathogens causing fungal infections with an important biofilm-forming capacity. PURPOSE: This study addresses the antifungal effect of rubiadin (AQ1) and rubiadin 1-methyl ether (AQ2), two photosensitizing anthraquinones (AQs) isolated from Heterophyllaea pustulata, against C. tropicalis biofilms, by studying the cellular stress and antioxidant response in two experimental conditions: darkness and irradiation. The combination with Amphotericin B (AmB) was assayed to evaluate the synergic effect. STUDY DESIGN/METHODS: Biofilms of clinical isolates and reference strain of Candida tropicalis were treated with AQs (AQ1 or AQ2) and/or AmB, and the biofilms depletion was studied by crystal violet and confocal scanning laser microscopy (CSLM). The oxidant metabolites production and the response of antioxidant defense system were also evaluated under dark and irradiation conditions, being the light a trigger for photo activation of the AQs. The Reactive Oxygen Species (ROS) were detected by the reduction of Nitro Blue Tetrazolium test, and Reactive Nitrogen Intermediates (RNI) by the Griess assay. ROS accumulation was also detected inside biofilms by using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe, which was visualized by CSLM. Superoxide dismutase (SOD) activity and the total antioxidant capacity of biofilms were measured by spectrophotometric methods. The minimun inhibitory concentration for sessile cells (SMIC) was determined for each AQs and AmB. The fractional inhibitory concentration index (FICI) was calculated for the combinations of each AQ with AmB by the checkerboard microdilution method. RESULTS: Biofilm reduction of both strains was more effective with AQ1 than with AQ2. The antifungal effect was mediated by an oxidative and nitrosative stress under irradiation, with a significant accumulation of endogenous ROS detected by CSLM and an increase in the SOD activity. Thus, the prooxidant-antioxidant balance was altered especially by AQ1. The best synergic combination with AmB was also obtained with AQ1 (80.5%) (FICI=0.74). CONCLUSION: Under irradiation, the oxidative stress was the predominant effect, altering the prooxidant-antioxidant balance, which may be the cause of the irreversible cell injury in the biofilm. Our results showed synergism of these natural AQs with AmB. Therefore, the photosensitizing AQ1 could be an alternative for the Candida infections treatment, which deserves further investigation. PMID- 27765352 TI - Dioscin suppresses hepatocellular carcinoma tumor growth by inducing apoptosis and regulation of TP53, BAX, BCL2 and cleaved CASP3. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver, occurs frequently in the setting of chronic liver injury. Although multiple therapeutic approaches are available, the prognosis of patients with HCC remains poor. Dioscin is a natural steroid saponin that presents in various plants. The anti-cancer and anti-fibrotic effects have been extensively reported. However, the effect of dioscin on HCC remains unclear. We aimed to investigate the anti-HCC properties of dioscin in vitro and in vivo. METHODS: MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl-tetrazolium bromide) assay was used to analyze the growth inhibition activity of Dioscin in human cell lines, Bel-7402, HepG2, Lovo, and EAhy926. Antitumor activity through induction of apoptosis was evaluated by flow cytometry using Annexin-V and propidium iodide (PI) staining, laser scanning confocal microscopy (LSCM) analysis with Hochest33342 and PI labeling, and DNA fragmentation analysis. The expression of apoptosis-related proteins tumor protein p53 (TP53), BCL2-associated X protein (BAX), B-Cell CLL/Lymphoma 2 (BCL2) and Caspase 3 (CASP3) was measured by Western blot. Nude mice bearing Bel-7402 were administered intraperitoneally at different doses of dioscin and 5-FU (5-Fluorouracil) treatment was used as a control. Tumor volume and tumor weight of each mouse were then measured. RESULTS: We demonstrated that Dioscin inhibited proliferation of HCC cell lines in a dose dependent manner. Dioscin also significantly induced morphological changes during death by apoptosis and increased DNA damage of Bel-7402 cells. Moreover, we demonstrated that Dioscin displayed anticancer activity via up-regulating expression of TP53, BAX and CASP3 protein, as well as down-regulating BCL2 in Bel 7402 cells. Notably, the in vivo anticancer activity of Dioscin was further assessed and achieved greater inhibition efficiency at the concentration increased to 24mg/kg/day than 5-FU at dose of 10mg/kg/day in nude mice bearing Bel-7402 cells. CONCLUSIONS: Dioscin inhibited tumor growth via inducing apoptosis, which was accompanied by altered expression of apoptotic pathway proteins, such as TP53, BAX, BCL2 and CASP3. Our findings indicate that further evaluation of dioscin as a novel therapeutic approach for HCC is warranted. PMID- 27765353 TI - Carnosic acid acts synergistically with gentamicin in killing methicillin resistant Staphylococcus aureus clinical isolates. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to different commonly used antibiotics, stressing the need for further strategies to treat this human pathogen with worldwide prevalence. The use of phytochemicals within the current pharmacology is a promising approach to enhance the antimicrobial activity of common antibiotics in the battle against these bacteria. PURPOSE: The purpose of this study was to determine the antimicrobial effectiveness of carnosic acid, the major constituent of Rosmarinus officinalis L. leaves, in combination with gentamicin against multi-drug resistant MRSA clinical isolates obtained from pediatric patients with bacteremia. MATERIALS AND METHODS: Anti-MRSA activity was studied using the broth microdilution assay and time-kill method. Combinations of subinhibitory concentrations of carnosic acid and gentamicin were examined using the checkerboard method. RESULTS: Carnosic acid exhibited a good antibacterial activity against all multidrug-resistant MRSA clinical isolates tested, which are resistant to four up to nine antibiotics. In addition, the combination of carnosic acid with gentamicin not only decreased the minimal inhibitory concentration (MIC) of both by 4- to 5-fold, but also improved the bactericidal potency of the common antibiotic by 32- to 40-fold against both gentamicin-susceptible and gentamicin-resistant MRSA clinical isolates. A clear bactericidal synergistic activity between carnosic acid and gentamicin in killing multidrug-resistant MRSA clinical isolates with a fractional bactericidal concentration index (FBCI) of 0.28-0.35 was demonstrated. CONCLUSIONS: Our findings show the potential use of carnosic acid in combination with gentamicin as a promising alternative for the control of healthcare-associated infections caused by multidrug-resistant MRSA. PMID- 27765354 TI - Anti-cancer effect of (-)-epigallocatechin-3-gallate (EGCG) in head and neck cancer through repression of transactivation and enhanced degradation of beta catenin. AB - BACKGROUND AND PURPOSE: Aberrant expression of beta-catenin is highly associated with progression of various cancers including head and neck cancer (HNC). Green tea is most commonly used beverage in the world and one of the more bioactive compounds is the antioxidant epigallocatechin gallate (EGCG). This study was performed to investigate the mechanism by which EGCG inhibits the growth of HNC, focusing on the modulation of the expression and activity of beta-catenin. METHODS: In vitro effects of EGCG on the transcription, translation, or degradation of beta-catenin were investigated. Antitumor effects of EGCG in vivo were evaluated in a syngeneic mouse model and beta-catenin expression was checked in HNC patients' samples. RESULTS: beta-catenin expression was elevated in tumor samples of HNC patients. EGCG induced apoptosis in KB and FaDu cells through the suppression of beta-catenin signaling. Knockdown of beta-catenin using siRNA enhanced the proapoptotic activities of EGCG. EGCG decreased mRNA and transcriptional activity of beta-catenin in p53 wild-type KB cells. EGCG also enhanced the ubiquitination and proteasomal degradation of beta-catenin. The suppression of beta-catenin and consequent apoptosis were observed in response to EGCG treatment in a syngeneic mouse model. In conclusion, we report that EGCG inhibits beta-catenin expression through multiple mechanisms including decreased transcription and increased ubiquitin-mediated 26S proteasomal degradation. CONCLUSION: This study proposes a novel molecular rationale for antitumor activities of green tea in HNCs. PMID- 27765355 TI - Ginkgo biloba L. extract protects against chronic cerebral hypoperfusion by modulating neuroinflammation and the cholinergic system. AB - BACKGROUND: Ginkgo biloba extract (GBE)-a widely used nutraceutical-is reported to have diverse functions, including positive effects on memory and vasodilatory properties. Although numerous studies have assessed the neuroprotective properties of GBE in ischemia, only a few studies have investigated the neuro pharmacological mechanisms of action of GBE in chronic cerebral hypoperfusion (CCH). PURPOSE: In the present study, we sought to determine the effects of GBE on CCH-induced neuroinflammation and cholinergic dysfunction in a rat model of bilateral common carotid artery occlusion (BCCAo). METHODS: Chronic BCCAo was induced in adult male Wistar rats to reflect the CCH conditions. On day 21 after BCCAo, the animals were treated orally with saline or GBE (5, 10, 20, and 40mg/kg) daily for 42 days. After the final treatment, brain tissues were isolated for the immunohistochemical analysis of glial markers and choline acetyltransferase (ChAT), as well as for the western blot analysis of proinflammatory cytokines, toll-like receptor (TLR)-related pathway, receptor for advanced glycation end products (RAGE), angiotensin-II (Ang-II), and phosphorylated mitogen-activated protein kinases (MAPKs). RESULTS: BCCAo increased glial proliferation in the hippocampus and white matter, whereas proliferation was significantly attenuated by GBE treatment. GBE also attenuated the BCCAo-related increases in the hippocampal expression of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), TLR4, myeloid differentiation primary response gene 88, RAGE, Ang-II, and phosphorylated MAPKs (ERK, p38, and JNK). Furthermore, GBE treatment restored the ChAT expression in the basal forebrain following BCCAo. CONCLUSIONS: These findings suggest that GBE has specific neuroprotective effects that may be useful for the treatment of CCH. The pharmacological mechanism of GBE partly involves the modulation of inflammatory mediators and the cholinergic system. PMID- 27765356 TI - Anti-stress effects of drinking green tea with lowered caffeine and enriched theanine, epigallocatechin and arginine on psychosocial stress induced adrenal hypertrophy in mice. AB - BACKGROUND: Theanine, an amino acid in tea, has significant anti-stress effects on animals and humans. However, the anti-stress effects of drinking green tea have not yet been elucidated. HYPOTHESIS/PURPOSE: The present study aimed to explore anti-stress effects of green tea and roles of tea components in a mouse model of psychosocial stress. STUDY DESIGN: We examined anti-stress effects of three types of green teas, theanine-rich "Gyokuro", standard "Sencha", and Sencha with lowered caffeine (low-caffeine green tea). Furthermore, the roles of tea components such as caffeine, catechins, and other amino acids in anti-stress effects were examined. METHODS: To prepare low-caffeine green tea, plucked new tea leaves were treated with a hot-water spray. Mice were psychosocially stressed from a conflict among male mice under confrontational housing. Mice consumed each tea that was eluted with room temperature water ad libitum. As a marker for the stress response, adrenal hypertrophy was compared with mice that ingested water. RESULTS: Caffeine was significantly lowered by spraying hot-water on tea leaves. While epigallocatechin gallate (EGCG) is the main catechin in tea leaves, epigallocatechin (EGC) was mainly infused into water at room temperature. Adrenal hypertrophy was significantly suppressed in mice that ingested theanine-rich and low-caffeine green tea that were eluted with water at room temperature. Caffeine and EGCG suppressed the anti-stress effects of theanine while EGC and arginine (Arg) retained these effects. CONCLUSION: These results suggest that drinking green tea exhibits anti-stress effects, where theanine, EGC and Arg cooperatively abolish the counter-effect of caffeine and EGCG on psychosocial stress induced adrenal hypertrophy in mice. PMID- 27765357 TI - A single-dose, randomized, cross-over, two-way, open-label study for comparing the absorption of boswellic acids and its lecithin formulation. AB - BACKGROUND: The oral administration of the gum resin extracts of Indian frankincense (Boswellia serrata Roxb. ex Colebr) results in very low plasma concentrations of boswellic acids (BAs), being far below the pharmacologically active concentrations required in vitro for anti-inflammatory activity. For that reason the use of Indian frankincense in clinical practice and pharmaceutical development has substantially lagged behind. Recently the application of new formulation technologies resulted in a formulation of frankincense extract with lecithin, which revealed improved absorption and tissue penetration of BAs in a rodent study, leading for the first time to plasma concentrations of BAs in the range of their anti-inflammatory activity. PURPOSE: In order to verify these encouraging results in humans, the absorption of a standardized Boswellia serrata extract (BE) and its lecithin formulation (CSP) was comparatively investigated in healthy volunteers. STUDY DESIGN: According to a randomized cross-over design with two treatments, two sequences and two periods, 12 volunteers alternatively received the lecithin-formulated Boswellia extract (CSP) or the non-formulated Boswellia extract (BE) at a dosage of 2*250mg capsules. METHODS: The plasma concentrations of the six major BAs (KBA, AKBA, betaBA, alphaBA, AbetaBA, AalphaBA) were determined using LC/MS. RESULTS: With the exception of KBA, a significantly higher (both in terms of weight-to-weight and molar comparison) and quicker absorption of BAs from the lecithin formulation was observed, leading to Cmax in the range required for the interaction with their molecular targets. CONCLUSION: These findings pave the way to further studies evaluating the clinical potential of BAs, and verify the beneficial effect of lecithin formulation to improve the absorption of poorly soluble phytochemicals. PMID- 27765358 TI - Sennoside A, derived from the traditional chinese medicine plant Rheum L., is a new dual HIV-1 inhibitor effective on HIV-1 replication. AB - BACKGROUND: Despite the availability of effective antiretroviral therapies, drugs for HIV-1 treatment with new mode of action are still needed. An innovative approach is aimed to identify dual HIV-1 inhibitors, small molecules that can inhibit two viral functions at the same time. Rhubarb, originated from Rheum palmatum L. and Rheum officinale Baill., is one of the earliest and most commonly used medicinal plants in Traditional Chinese Medicine (TCM) practice. We wanted to explore TCM for the identification of new chemical scaffolds with dual action abilities against HIV-1. METHODS: R. palmatum L. and R. officinale Baill. extracts along with their main single isolated constituents anthraquinone derivatives were tested on both HIV-1 Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities in biochemical assays. Active compounds were then assayed for their effects on HIV-1 mutated RTs, integrase (IN) and viral replication. RESULTS: Both R. palmatum L. and R. officinale Baill. extracts inhibited the HIV-1 RT-associated RNase H activity. Among the isolated constituents, Sennoside A and B were effective on both RDDP and RNase H RT-associated functions in biochemical assays. Sennoside A was less potent when tested on K103N, Y181C, Y188L, N474A and Q475A mutated RTs, suggesting the involvement of two RT binding sites for its antiviral activity. Sennoside A affected also HIV-1 IN activity in vitro and HIV-1 replication in cell-based assays. Viral DNA production and time of addition studies showed that Sennoside A targets the HIV-1 reverse transcription process. CONCLUSION: Sennoside A is a new scaffold for the development of HIV-1 dual RT inhibitors. PMID- 27765359 TI - Cardioprotective actions of curcumin on the pathogenic NFAT/COX-2/prostaglandin E2 pathway induced during Trypanosoma cruzi infection. AB - BACKGROUND: Diverse cardiovascular signaling routes have been considered critical for Chagas cardiomyopathy caused by the protozoan parasite Trypanosoma cruzi. Along this line, T. cruzi infection and endothelin-1 (ET-1) have been shown to cooperatively activate the Ca2+/NFAT cascade in cardiomyocytes, leading to cyclooxygenase type 2 (COX-2) induction and increased release of prostanoids and prohypertrophic peptides. PURPOSE: To determine whether the well-known cardioprotective and anti-inflammatory effects of curcumin (Cur) could be helpful to interfere with this key machinery for pathogenesis of Chagas myocarditis. STUDY DESIGN: Cur treatment was evaluated through in vivo studies using a murine model of acute T. cruzi infection and in vitro experiments using ET-1-stimulated and parasite-infected mouse cardiomyocytes. METHODS: Cur-treated and untreated infected mice were followed-up to estimate survival postinfection and heart tissues from both groups were analyzed for inflammatory infiltration by histopathology, whereas parasite load, induction of arachidonic acid pathway and natriuretic peptide expression were determined by real-time PCR. Molecular analysis of Cur myocardial targets included intracellular calcium measurement, NFAT and COX-2 induction in transfected cells, and assessment of NFAT, COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) levels by immunoblotting, prostaglandin E2 (PGE2) by ELISA, b-type natriuretic peptide (BNP) by real-time PCR, and PGE2/EP4 receptor/BNP interaction by transwell experiments. RESULTS: Cur treatment of acute Chagas mice enhanced survival and proved to hinder relevant inflammatory processes in the heart, including leukocyte recruitment, activation of the eicosanoid pathway and BNP overexpression, without modifying parasite burden in the organ. Cur was capable of blocking Ca2+-dependent NFATc1 transcriptional activity, COX-2 and mPGES-1 induction, and subsequent PGE2 production in ET-1-stimulated and parasite-infected cardiomyocytes. Furthermore, the decline of cardiomyocyte-derived prostaglandin levels achieved upon Cur treatment impaired effective PGE2/EP4 receptor interaction, resulting in attenuated expression of BNP, a strong indicator of cardiac pathogenesis in Chagas disease, in both infected and uninfected cells. CONCLUSION: Our current study shows a putative mechanism of action of Cur involving inhibition of the Ca2+/NFAT-dependent, pathogenic COX-2/mPGES-1/PGE2 pathway in T. cruzi-infected myocytes, underlying cardioprotection achieved in Cur-treated infected mice. With a view to the limited therapeutic possibilities available, Cur represents a promising approach for the treatment of Chagas heart disease. PMID- 27765360 TI - Kampeferol protects against oxidative stress and apoptotic damage in experimental model of isoproterenol-induced cardiac toxicity in rats. AB - BACKGROUND: Myocardial infarction (MI) continues to be associated with high morbidity and mortality worldwide despite the availability of current therapeutic modalities. Kaempferol (KMP), a dietary flavonoid, possesses good antioxidant, immunomodulatory and anti-apoptotic properties and has been evaluated in the present study for its role in mitigating myocardial injury following MI. PURPOSE: In this study, the ability of KMP to protect heart against isoproterenol (ISO) induced oxidative stress and myocardial infarction was evaluated. MATERIAL AND METHODS: Male Wistar rats (n=48) were administered KMP (5, 10 & 20mg/kg/day, i.p.) or vehicle for 15 days with ISO, 85mg/kg, subcutaneously, for 2 consecutive days was also administered at 24h interval on the 13th and 14th days. On the 15th day, rats were anaesthetized and right coronary artery was cannulated to record hemodynamic parameters. Later on blood sample was collected and heart was removed to estimate biochemical, histopathological, ultrastructural and immuohistochemical studies respectively. RESULTS: ISO-treated rats showed a significant reduction in arterial pressure, maximum rate of development of left ventricular pressure and increase in left ventricular end-diastolic pressure. Also, there was a significant decrease in antioxidant enzyme levels such as superoxide dismutase, catalase and glutathione and increase in the level of malondialdehyde and serum TNF-alpha and IL-6 levels. In addition, the cardiac injury markers such as creatine kinase-MB and lactate dehydrogenase were increased in the serum. Furthermore, immunohistochemistry revealed an increased Bax/Bcl-2 ratio in the myocardium. KMP (5, 10 and 20mg/kg) dose dependently restored hemodynamic, left ventricular functions, decreased cardiac injury marker enzymes in serum, increased antioxidant levels, reduced lipid peroxidation and TNF-alpha level and apoptosis. Histopathological and ultrastructural studies support the protective effect of KMP in ISO-induced myocardial infarcted rats. CONCLUSION: Thus, the present study revealed that KMP mitigates myocardial damage in ISO-induced cardiac injury by maintaining hemodynamic and biochemical parameters and reducing inflammation owing to its anti-apoptotic, anti inflammatory and antioxidant activities. It may be concluded that a diet containing KMP may be beneficial in those who are at the risk of myocardial injury. PMID- 27765361 TI - Aralia elata var. mandshurica (Rupr. & Maxim.) J.Wen: An overview of pharmacological studies. AB - PURPOSE: Aralia elata var. mandshurica (Rupr. & Maxim.) J.Wen syn. A. mandshurica Rupr. & Maxim is evaluated for its medicinal application. The aim of this study is to analyze pharmacological studies on A. elata var. mandshurica published until December 2015. METHODS: The information regarding the chemistry, safety, effectiveness, and pharmacological and clinical effects of A. elata was systematically collected from the scientific literature through library catalogs; online services such as E-library.ru, Medline/PubMed, Scopus, Web of Science, and Google Scholar. RESULTS: A. elata is often considered an example of a medicinal plant used in Chinese, Korean, and Japanese traditional medicine. However, the contemporary applications of Aralia in officinal medicine result primarily from a large number of pharmacological and clinical investigations carried out in the former USSR in the mid-20th century. Since the 1950s, medicinal preparations from radices of A. elata and radices of A. mandshurica have secured an established position within Russian/USSR medicine as evidenced by the inclusion of the drug in recent editions of the National Pharmacopoeia of the USSR and in the Register of Medicinal Preparations of Russia. Pharmacological studies on animals have shown that Aralia increases physical working capacity and affords a stress protective effect against a broad spectrum of harmful factors including cold stress, immobilization, UV irradiation, and low air pressure. The phytoadaptogen exerts an effect on the central nervous, reproductive, immune, respiratory, and gastrointestinal systems; the metabolic syndrome including hypolipidemic and antidiabetic effects; and blood coagulation. Together with general properties of adaptogens, Aralia has its own specificity, which manifests in cardioprotective and antiarrhythmic activities. Studies on isolated organs, cells, and enzymes have revealed that Aralia preparations exhibit antioxidant activities and enhance sarcoplasmic reticulum Ca2+-ATPase activity, inhibit endoplasmic reticulum stress associated apoptosis markers (GRP78, CHOP, Caspase-12, and JNK), and increase phosphorylation of STAT3 and Bcl2/Bax ratio; they also show cytotoxic activities against some tumor cell lines; affect NF-kappaB and PPARs activities; and regulate biosynthesis of pro-inflammatory cytokines and inflammation-related protein expression, tissue respiration, and oxygen consumption. In healthy subjects, Aralia increases mental performance, working capacity, and endurance of movement. Numerous clinical trials have shown the efficiency of Aralia preparations in patients with traumatic brain injury (accompanied with asthenic syndrome and neurotic reactions, depression, neurasthenia, and psychasthenia), neurological diseases (accompanied with astheno-depressive and astheno hypochondriasis syndromes), myasthenia syndrome (accompanied with chronic post influenza arachnoiditis), and arterial hypotension. Aralia tincture and "Saparal" are useful as antiviral remedies. Radioprotective properties of Aralia have been reported in pregnant women. Synergistic antiobesity effect was reported for the combination of A. mandshurica and Engelhardtia chrysolepis extracts and antidiabetic effect for the combination of Aralia and glipizide. Promising stress relieving effects of Aralia are reported for professionals whose work requires a high level of attention. Its proposed ability to moderate stress-induced damage and dysfunction in the cardiovascular tissue might make Aralia the adaptogen of choice among patients with higher risk for cardiovascular diseases. Because Aralia extract administration appears to affect plasma glucose level and hepatic lipid accumulation and ameliorate hyperinsulinemia, it might also provide benefits and be the adaptogen of choice for patients with obesity and diabetes. CONCLUSION: This review describes the considerable diversity of pharmacological effects of A. elata reported in numerous studies carried out in the former USSR and other countries, which have been confirmed over >47 years of use of the plant as an official medicinal remedy. The knowledge discussed in this review can be applied to the expansion of the use of this high-value plant in the pharmacotherapy of European and other countries and for the further discovery of new drugs based on the secondary metabolites of this plant. Modern approaches in mechanisms of action, including a study of gene expression profiling, suggest the most up-to-date challenges for the future research of Aralia. PMID- 27765362 TI - Medicinal herbs Oenanthe javanica (Blume) DC., Casuarina equisetifolia L. and Sorghum bicolor (L.) Moench protect human cells from MPP+ damage via inducing FBXO7 expression. AB - BACKGROUND: The F-box protein 7 (FBXO7) mutations have been identified in families with early-onset parkinsonism and pyramidal tract signs, and designated as PARK15. In addition, FBXO7 mutations were found in typical and young onset Parkinson's disease (PD). Evidence has also shown that FBXO7 plays an important role in the development of dopaminergic neurons and increased stability and overexpression of FBXO7 may be beneficial to PD. PURPOSE: We screened extracts of medicinal herbs to enhance FBXO7 expression for neuroprotection in MPP+-treated cells. METHODS: Promoter reporter assay in HEK-293 cells was used to examine the cis/trans elements controlling FBXO7 expression and to screen extracts of medicinal herbs enhancing FBXO7 expression. MTT assay was performed to assess cell viability of MPP+-treated HEK-293/SH-SY5Y cells. In addition, proteasome activity, mitochondrial membrane potential and FBXO7/TRAF2/GATA2 protein expression were evaluated. RESULTS: We demonstrated that -202--57 region of the FBXO7 promoter is likely to contain sequences that are bound by positive trans protein factors to activate FBXO7 expression and GATA2 is the main trans protein factor enhancing FBXO7 expression. Extracts of medicinal herbs Oenanthe javanica (Blume) DC. (Umbelliferae), Casuarina equisetifolia L. (Casuarinaceae), and Sorghum bicolor (L.) Moench (Gramineae) improved cell viability of both MPP+ treated HEK-293 and SH-SY5Y cells, rescued proteasome activity in MPP+-treated HEK-293 cells, and restored mitochondrial membrane potential in MPP+-treated SH SY5Y cells. These protection effects of herbal extracts are acting through enhancing FBXO7 and decreasing TRAF2 expression, which is probably mediated by GATA2 induction. CONCLUSION: Collectively, our study provides new targets, FBXO7 and its regulator GATA2, for the development of potential treatments of PD. PMID- 27765364 TI - Phyllanthin from Phyllanthus amarus inhibits cellular and humoral immune responses in Balb/C mice. AB - BACKGROUND: Phyllanthin found in many Phyllanthus species has various biochemical and pharmacological properties especially on its hepatoprotective effects. However, its effect on the immune system has not been well documented. PURPOSE: In the present study, phyllanthin isolated from Phyllanthus amarus was investigated for its immunosuppressive effects on various cellular and humoral immune responses in Balb/C mice. METHODS: Male mice were treated daily at 20, 40 and 100mg/kg of phyllanthin for 14 days by oral gavage. The effects of phyllanthin on cellular immune responses in treated /non treated mice were determined by measuring CD 11b/CD 18 integrin expression, phagocytosis, nitric oxide (NO) production, myeloperoxidase activity (MPO), T and B cells proliferation, lymphocyte phenotyping, serum cytokines production by activated T cells and delayed type hypersensitivity (DTH). Its effects on humoral immune responses were evaluated by determining the serum levels of lysozyme and ceruloplasmin, and immunoglobulins (IgG and IgM). RESULTS: Phyllanthin dose dependently inhibited CD11b/CD18 adhesion, the engulfment of E. coli by peritoneal macrophages molecules, NO and MPO release in treated mice. Phyllanthin caused significant and dose-dependent inhibition of T and B lymphocytes proliferation and down-regulation of the Th1 (IL-2 and IFN-gamma) and Th2 (IL-4) cytokines. Phyllanthin at 100mg/kg caused a significant reduction in the percentage expression of CD4+ and CD8+ in splenocytes and the inhibition was comparable to that of cyclosporin A at 50mg/kg. At 100mg/kg, phyllanthin also dose-dependently exhibited strong inhibition on the sheep red blood cell (sRBC) induced swelling rate of mice paw in DTH. Significant inhibition of serum levels of ceruloplasmin and lysozyme were observed in mice fed with higher doses (40 and 100mg/kg) of phyllanthin. Anti-sRBC immunoglobulins (IgM and IgG) antibody titer was down-regulated in immunized and phyllanthin-treated mice in a dose-dependent manner with maximum inhibition being observed at 100mg/kg. CONCLUSION: The strong inhibitory effects of phyllanthin on the cellular and humoral immune responses suggest that phyllanthin may be a good candidate for development into an effective immunosuppressive agent. PMID- 27765363 TI - Coadministration of a Gloriosa superba extract improves the in vivo antitumoural activity of gemcitabine in a murine pancreatic tumour model. AB - BACKGROUND: Gloriosa superba L. (glory lily, Colchicaceae) contains colchicine, and related alkaloids such as 3-O-demethylcolchicine and its glycoside colchicoside. Previously the in vivo efficacy of a crude extract and a colchicine poor / colchicoside-rich extract of G. superba seeds was shown in a murine model of pancreatic adenocarcinoma. HYPOTHESIS/PURPOSE: The efficacy can be improved without obvious signs of toxicity by increasing the treatment dose; the efficacy of gemcitabine can be improved by coadministration of a Gloriosa superba extract. STUDY DESIGN: A survival experiment was carried out in a murine model of pancreatic adenocarcinoma and the semi-long-term toxicity of both G. superba extracts was determined; a combination therapy with gemcitabine was evaluated. METHODS: A crude ethanolic extract (GS) and a colchicine-poor / colchicoside-rich extract (GS2B) were prepared, containing 3.22% colchicine, 2.52% colchicoside and 1.52% 3-O-demethylcolchicine (GS), and 0.07%, 2.26% and 0.46% (m/m) (GS2B). They were evaluated in a murine model of pancreatic adenocarcinoma at a dose of 4.5mg/kg (p.o., daily) total content of colchicine and derivatives during 3 weeks, or at 3.0mg/kg (p.o., daily) combined with gemcitabine (60mg/kg, i.p., 3x/week) during 54 days. RESULTS: A significant effect in tumour growth over time was observed for gemcitabine and the combination therapy compared to the control group. No significant difference was observed for the groups treated with colchicine and both extracts. However, combination therapy was significantly better than the monotherapy with gemcitabine. Moreover, survival analysis showed a significant prolongation of the survival of the groups treated with gemcitabine and the combination therapy. A slight difference in survival was observed between gemcitabine and the combination therapy, the latter one being slightly better. No significant prolongation of survival was observed for the extracts and colchicine compared to the control group. CONCLUSION: Although a relevant tumour growth inhibition and a difference of relative tumour volume compared to the control group were observed on day 11, and a slightly longer survival was noticed for GS2B, the most important conclusion from this study is that the crude G. superba extract (GS) might have an added value combined with gemcitabine in the treatment of pancreatic tumours. PMID- 27765365 TI - Effects of low molecular weight procyanidin rich extract from french maritime pine bark on cardiovascular disease risk factors in stage-1 hypertensive subjects: Randomized, double-blind, crossover, placebo-controlled intervention trial. AB - BACKGROUND: Oligopin? (OP) is a quantified extract from French Maritime Pine bark (FMPB) with low molecular weight procyanidins. The cardioprotective effects of OP need to be tested in human clinical intervention trials with an appropriate design. PURPOSE: The aim of the present study was to assess the effect of subchronic consumption of OP on cardiovascular disease risk factors such as lipid profile, systolic blood pressure (BP) and oxidized-Low Density Lipoprotein (ox LDL) in stage-1-hypertensive subjects. METHODS: Between February 14 and May 31, 2014, eligible subjects were recruited from the outpatient clinics of Hospital Universitari Sant Joan (Reus, Spain). A total of 24 participants (mean age +/- DS; 57.36 +/- 11.25; 17 men) with stage-1-hypertension who were not receiving BP lowering medication and LDL cholesterol < 4.88 mmol/l were randomized in a double blind, placebo-controlled, crossover study. The subjects received 2 capsules/day with 75 mg of OP or placebo for 5-weeks. RESULTS: At 5-weeks, compared to the placebo, OP raised High Density Lipoprotein-cholesterol (HDL-c) by 14.06% (p = 0.012) and apolipoprotein A-1 by 8.12% (p = 0.038) and reduced the ratio of apolipoprotein B-100/A-1 by 10.26% (p = 0.046). Moreover, at 5-weeks, compared to the baseline, OP reduced the systolic BP by 6.36 mmHg (p = 0.014), and decreased ox-LDL concentrations by 31.72 U/l (p = 0.015). CONCLUSION: At 5-weeks, the consumption of 150 mg/day of OP improve lipid cardiovascular profile and represents one of the scarce ways to increase HDL-c in stage-1-hypertensive subjects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02063477. PMID- 27765366 TI - Cytotoxic effects of kazinol A derived from Broussonetia papyrifera on human bladder cancer cells, T24 and T24R2. AB - BACKGROUND: Broussonetia papyrifera (B. papyrifera), also known as paper mulberry, has been used as a traditional medicine for the treatment of several diseases, including ophthalmic disorders and impotency. However, the biological activity of kazinol A (1) among flavonols isolated from B. papyrifera has not been identified. PURPOSE: We identified a candidate metabolite for anti-human bladder cancer treatment from B. papyrifera and investigated the possible molecular mechanisms underlying its cytotoxic effects in T24 and cisplatin resistant T24R2 human bladder cancer cells. METHODS: T24 and T24R2 cells were treated with five flavonols from B. papyrifera and their cytotoxic effects were determined using MTT assay, cell cycle analysis, mitochondrial membrane potential, and propidium iodide staining. Autophagy rate was calculated by counting LC3-GFP dots in the cells. All related protein expressions were analyzed by immunoblotting. RESULTS: Compound 1 showed relatively higher cytotoxicity in the human bladder cancer cells, T24 and T24R2, rather than other tissues originated cancer cells. Compound 1 significantly attenuated cell growth through G0/1 arrest mediated by a decrease in cyclin D1 and an increase of p21. Apoptosis and autophagy induced by compound 1 treatment was accompanied by a modulation of the AKT-BAD pathway and AMPK-mTOR pathway, respectively. CONCLUSIONS: Our results suggest that compound 1 induces cytotoxic effects in human bladder cancer cells, including the cisplatin-resistant T24R2. Compound 1 may be a candidate for the development of effective anti-cancer drug on human urinary bladder cancer. PMID- 27765367 TI - Herbalog: A tool for target-based identification of herbal drug efficacy through molecular docking. AB - BACKGROUND: Traditionally, molecular docking is primarily employed to screen pure compounds; the top-ranking chemicals are subsequently selected for experimental validation. Unlike synthetic chemicals, most natural products are commercially unavailable. The isolation and purification of each natural product is extremely time-consuming, which has restricted the screening of lead compounds from natural products. PURPOSE: We developed a protocol, Herbalog, to facilitate the identification of bioactive phytochemicals through molecular docking. METHODS: We wrote a script using Python and Autodock Vina for docking; ligand displacement and adipolysis assays were used to determine the anti-fatty acid binding protein (FABP) 4 activity of bioactive extracts. An ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry system was applied for identifying major peaks of bioactive extracts. RESULTS: Herbalog, a natural product database, contains 5,112 phytochemicals from 197 common herbs and a script that counts the number of hits from docking in each herb and calculates the hit rate of herbs. Herbalog prioritizes herbs according to their hit rates, and top-ranking herb candidates contain a large repertoire of hits. We used Herbalog as a screening tool and identified labdane diterpenoids from Andrographis paniculata as leading candidates of FABP4 inhibitors. CONCLUSION: Herbalog facilitates the discovery of herbs that possess the highest number of inhibitors or activators against target proteins, which reduces the sample preparation time for preliminary validation. PMID- 27765368 TI - The chloroform extract of Cyclocarya paliurus attenuates high-fat diet induced non-alcoholic hepatic steatosis in Sprague Dawley rats. AB - BACKGROUND: Hepatic steatosis (HS) is the early stage of nonalcoholic fatty liver disease which is caused by impaired hepatic lipid homeostasis. Cyclocarya paliurus, an herbal tea consumed in China, has been demonstrated to ameliorate abnormal lipid metabolism for the treatment of metabolic diseases. PURPOSE: We aimed to investigate the regulative effect of chloroform extract from Cyclocarya paliurus (ChE) on treatment of HS, as well as key factors involved in hepatic lipid metabolism. STUDY DESIGN: Sprague Dawley rats were fed with high-fat diet (HFD) for 6 weeks to induce HS and treated with or without ChE by gavage for 4 weeks. METHODS: The body weight, relative liver weight and liver fat content were measured. Serum and liver total cholesterol, triglyceride and non-esterified fatty acids, as well as hepatic malonaldehyde levels were accessed by biochemical methods. Serum and liver TNF-alpha levels were quantified by ELISA kit. Histologic analysis and 1H-MRS study were performed to evaluate HS level. RT-PCR and Western blot were also applied to observe the expression changes of key factors involved in hepatic lipid intake, synthesis, utilization and export. RESULTS: ChE significantly decreased the rats' body weight, serum lipid and TNF alpha level. ChE also reduced their relative liver weight, liver fat content, hepatic oxidative products and TNF-alpha level. Hepatic steatosis in HFD-fed rats was effectively regressed after 2-weeks administration of ChE. Moreover, ChE treatment remarkably reduced HFD-induced high expression level of fatty acid synthesis genes (including sterol-regulatory element-binding protein 1, acetyl CoA carboxylase 1 and fatty acid synthase). However, it had no effect on mRNA expression of some genes involved in lipid uptake, beta-oxidation and lipid outflow. CONCLUSION: ChE exerted a promising regression effect on HS due to a reduced level of serum non-esterified fatty acids which might lead to a decrease in the amount of lipid taken in by the liver, as well as owing to the inhibition of hepatic lipid de novo synthesis to reduce liver lipid production. PMID- 27765369 TI - Eremophila maculata-Isolation of a rare naturally-occurring lignan glycoside and the hepatoprotective activity of the leaf extract. AB - BACKGROUND: The Australian plant Eremophila maculata F. Muell (Scrophulariaceae) is cultivated worldwide as an ornamental plant. PURPOSE: This study was designed to assess the antioxidant and hepatoprotective activities of a methanol extract from E. maculata leaves (EMM) both in vitro and in vivo (rats) experiments. Detailed phytochemical study was done on the extract followed by molecular docking experiments on TNF-alpha ascertain the efficacy of the isolated compounds. METHODS: The antiproliferative activity was evaluated in the human cancer cell lines A-495, PC3 and HepG2 cells using the SRB method. The antioxidant activitywas evaluated in vitro using the DPPH* assay while the hepatoprotective properties were investigated by determining the amelioration of CCl4-induced cytotoxicity and oxidative stress in HepG2 cells. The activity was confirmed in vivo by studying tamoxifen-induced hepatotoxicity in rats. An in depth phytochemical investigation of a methanol extract was performed using 1D and 2D NMR experiments. In silico molecular modeling studies of the isolated compounds on TNF-alpha (PDB ID 2AZ5) were carried out using Discovery Studio 2.5 software applying C-Docker protocol. RESULTS: The IC50 values of EMM were >500ug/ml for both PC3 and HepG2 cells indicating its safety. Similar to the standard drug silymarin, EMM could restore AST, ALT values; replenish GSH level, SOD activity and TAC in vitro. The hepatoprotective activity was confirmed in vivo in which the extract (20mg/kg body weight) decreased ALT and AST levels by 45.23 and 45.79%, respectively as compared to the tamoxifen treated groups. Oxidative stress was reduced by lowering of thiobarbituric acid reactive substances by 28.57%. Additionally, hepatocyte inflammation was improved by reducing the pro-inflammatory mediator TNF-alpha by 54.29%. Phytochemical investigation resulted in the isolation of a rare naturally-occurring lignan glycoside, namely pinoresinol-4-O-[6"-O-(E)-feruloyl]-beta-D-glucopyranoside for the first time from the Scrophulariaceae in addition to 12 known compounds.Pinoresinol-4-O-[6''-O-(E)-feruloyl]-beta-D-glucopyranoside was the strongest inhibitor of TNF-alpha as evidenced from its higher fitting scores comparable to lead compound. CONCLUSIONS: These findings highlighted for the first time that EMM could be an interesting candidate as a safe, natural liver supplement for relieving of various hepatic disorders and counteracting the effect of many xenobiotics. PMID- 27765370 TI - Resveratrol, piperine and apigenin differ in their NADPH-oxidase inhibitory and reactive oxygen species-scavenging properties. AB - BACKGROUND: Many plant-derived chemicals have been studied for their potential benefits in ailments including inflammation, cancer, neurodegeneration, and cardiovascular disease. The health benefits of phytochemicals are often attributed to the targeting of reactive oxygen species (ROS). However, it is not always clear whether these agents act directly as antioxidants to remove ROS, or whether they act indirectly by blocking ROS production by enzymes such as NADPH oxidase (NOX) enzymes, or by influencing the expression of cellular pro- and anti oxidants. HYPOTHESIS/PURPOSE: Here we evaluate the pro- and anti-oxidant and NOX inhibiting qualities of four phytochemicals: celastrol, resveratrol, apigenin, and piperine. STUDY DESIGN: This work was done using the H661 cell line expressing little or no NOX, modified H661 cells expressing NOX1 and its subunits, and an EBV-transformed B-lymphoblastoid cell line expressing endogenous NOX2. ROS were measured using Amplex Red and nitroblue tetrazolium assays. In addition, direct ROS scavenging of hydrogen peroxide or superoxide generated were measured using Amplex Red and methyl cypridina luciferin analog (MCLA). RESULTS: Of the four plant-derived compounds evaluated, only celastrol displayed NOX inhibitory activities, while celastrol and resveratrol both displayed ROS scavenging activity. Very little impact on ROS was observed with apigenin, or piperine. CONCLUSION: The results of this study reveal the differences that exist between cell-free and intracellular pro-oxidant and antioxidant activities of several plant-derived compounds. PMID- 27765371 TI - Protodioscin ameliorates fructose-induced renal injury via inhibition of the mitogen activated protein kinase pathway. AB - BACKGROUND: High dietary fructose can cause metabolic syndrome and renal injury. PURPOSE: The effects of protodioscin on metabolic syndrome and renal injury were investigated in mice receiving high-dose fructose. METHODS: Mice received 30% (w/v) fructose in water and standard chow for 6 weeks to induce metabolic syndrome and were divided into four groups to receive carboxymethylcellulose sodium, allopurinol (5 mg/kg) and protodioscin (5 and 10 mg/kg) continuously for 6 weeks, respectively. The glucose intolerance, serum uric acid (UA), blood urea nitrogen (BUN), creatinine (Cr), total cholesterol (TC), triglyceride (TG), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were determined. RESULTS: Protodioscin significantly improved glucose intolerance and reduced the levels of serum UA, BUN, Cr, TC and TG. Histological examinations showed that protodioscin ameliorated glomerular and tubular pathological changes. Protodioscin significantly reduced renal concentrations of IL-1beta, IL-6 and TNF-alpha by inhibiting the activation of nuclear factor-kappaB, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. In addition, the effect of protodioscin on the mitogen activated protein kinases (MAPK) pathway was examined. CONCLUSION: Taken together, protodioscin is a potential drug candidate for high dietary fructose-induced metabolic syndrome and renal injury. PMID- 27765372 TI - Gastrodia elata and epilepsy: Rationale and therapeutic potential. AB - BACKGROUND: Gastrodia elata Blume (G. elata) is a traditional Chinese herb used for centuries in folk medicine. Due to the claimed anticonvulsant properties of G. elata, it is expected that this herb continues to be a target of research, aiming to deepen the available knowledge on its biological activity and safety. PURPOSE: The current review aims to discuss the most recent advances on the elucidation of the phytochemical composition and anticonvulsant potential of G. elata. METHODS: Available literature was reviewed from PubMed, ISI Web of Knowledge and Science Direct, using combinations of the following keywords: Gastrodia elata, tianma, epilepsy, anticonvulsant and pharmacokinetics. Abstracts and full texts were evaluated for their clarity and scientific merit. RESULTS: G. elata rhizome, as well as specific phenolic compounds isolated from this herb, have demonstrated anticonvulsant potential in a variety of in vitro and in vivo models. The pharmacological mechanisms potentially involved in the anticonvulsant activity have been extensively studied, being similar to the known mechanisms claimed for the available antiepileptic drugs. In addition, the pharmacokinetics of the main bioactive component of G. elata (gastrodin) has also been studied. CONCLUSION: Due to its recognised therapeutic properties, G. elata has gained an increasing interest within the scientific community and, therefore, new medicinal preparations containing G. elata rhizome itself or its bioactive components are expected to be developed in the coming years. Moreover, specific phytochemical constituents isolated from G. elata may also be considered to integrate programs of discovery and development of new anticonvulsant drug candidates. PMID- 27765373 TI - Lichen-derived compounds show potential for central nervous system therapeutics. AB - BACKGROUND: Natural products from lichens are widely investigated for their biological properties, yet their potential as central nervous system (CNS) therapeutic agents is less explored. PURPOSE: The present study investigated the neuroactive properties of selected lichen compounds (atranorin, perlatolic acid, physodic acid and usnic acid), for their neurotrophic, neurogenic and acetylcholine esterase (AChE) activities. METHODS: Neurotrophic activity (neurite outgrowth) was determined using murine neuroblastoma Neuro2A cells. A MTT assay was performed to assess the cytotoxicity of compounds at optimum neurotrophic activity. Neuro2A cells treated with neurotrophic lichen compounds were used for RT-PCR to evaluate the induction of genes that code for the neurotrophic markers BDNF and NGF. Immunoblotting was used to assess acetyl H3 and H4 levels, the epigenetic markers associated with neurotrophic and/or neurogenic activity. The neurogenic property of the compounds was determined using murine hippocampal primary cultures. AChE inhibition activity was performed using a modified Ellman's esterase method. RESULTS: Lichen compounds atranorin, perlatolic acid, physodic acid and (+)-usnic acid showed neurotrophic activity in a preliminary cell-based screening based on Neuro2A neurite outgrowth. Except for usnic acid, no cytotoxic effects were observed for the two depsides (atranorin and perlatolic acid) and the alkyl depsidone (physodic acid). Perlatolic acid appears to be promising, as it also exhibited AChE inhibition activity and potent proneurogenic activity. The neurotrophic lichen compounds (atranorin, perlatolic acid, physodic acid) modulated the gene expression of BDNF and NGF. In addition, perlatolic acid showed increased protein levels of acetyl H3 and H4 in Neuro2A cells. CONCLUSION: These lichen depsides and depsidones showed neuroactive properties in vitro (Neuro2A cells) and ex vivo (primary neural stem or progenitor cells), suggesting their potential to treat CNS disorders. PMID- 27765374 TI - Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells. AB - BACKGROUND: Oral cancer is the sixth most common cancer worldwide and 90% of oral malignancies are caused by oral squamous cell carcinoma (OSCC). Curcumin, a phytocompound derived from turmeric (Curcuma longa) was observed to have anti cancer activity which can be developed as an alternative treatment option for OSCC. However, OSCC cells with various clinical-pathological features respond differentially to curcumin treatment. HYPOTHESIS: Intracellular copper levels have been reported to correlate with tumor pathogenesis and affect the sensitivity of cancer cells to cytotoxic chemotherapy. We hypothesized that intracellular copper levels may affect the sensitivity of oral cancer cells to curcumin. METHODS: We analysed the correlation between intracellular copper levels and response to curcumin treatment in a panel of OSCC cell lines derived from oral cancer patients. Exogenous copper was supplemented in curcumin insensitive cell lines to observe the effect of copper on curcumin-mediated inhibition of cell viability and migration, as well as induction of oxidative stress and apoptosis. Protein markers of cell migration and oxidative stress were also analysed using Western blotting. RESULTS: Concentrations of curcumin which inhibited 50% OSCC cell viability (IC50) was reduced up to 5 times in the presence of 250 uM copper. Increased copper level in curcumin-treated OSCC cells was accompanied by the induction of intracellular ROS and increased level of Nrf2 which regulates oxidative stress responses in cells. Supplemental copper also inhibited migration of curcumin-treated cells with enhanced level of E-cadherin and decreased vimentin, indications of suppressed epithelial-mesenchymal transition. Early apoptosis was observed in combined treatment but not in treatment with curcumin or copper alone. CONCLUSION: Supplement of copper significantly enhanced the inhibitory effect of curcumin treatment on migration and viability of oral cancer cells. Together, these findings provide molecular insight into the role of copper in overcoming insensitivity of oral cancer cells to curcumin treatment, suggesting a new strategy for cancer therapy. PMID- 27765375 TI - Perspectives on the feasibility of using microalgae for industrial wastewater treatment. AB - Although microalgae can serve as an appropriate alternative feedstock for biofuel production, the high microalgal cultivation cost has been a major obstacle for commercializing such attempts. One of the feasible solution for cost reduction is to couple microalgal biofuel production system with wastewater treatment, as microalgae are known to effectively eliminate a variety of nutrients/pollutants in wastewater, such as nitrogen/phosphate, organic carbons, VFAs, pharmaceutical compounds, textile dye compounds, and heavy metals. This review aims to critically discuss the feasibility of microalgae-based wastewater treatment, including the strategies for strain selection, the effect of wastewater types, photobioreactor design, economic feasibility assessment, and other key issues that influence the treatment performance. The potential of microalgae-bacteria consortium for treatment of industrial wastewaters is also discussed. This review provides useful information for developing an integrated wastewater treatment with microalgal biomass and biofuel production facilities and establishing efficient co-cultivation for microalgae and bacteria in such systems. PMID- 27765377 TI - The information needs of adult cancer survivors across the cancer continuum: A scoping review. AB - OBJECTIVE: To provide an updated synthesis of the literature that investigates the self-reported information needs of people diagnosed with cancer across the cancer continuum. METHODS: We conducted a scoping review of the literature published from August 2003 to June 2015 and expanded an existing typology summarizing the information needs of people diagnosed with cancer. RESULTS: The majority of the included studies (n=104) focused on questions relevant to the diagnosis/active treatment phase of the cancer continuum (52.9%) and thus the most frequently identified information needs related to this phase (33.4%). Information needs varied across the continuum and the results highlight the importance of recognising this fact. CONCLUSION: People diagnosed with cancer experience discrete information needs at different points from diagnosis to survival. Much of the research conducted in this area has focused on their information needs during the diagnosis and treatment of cancer, and literature relating to information needs following completion of treatment is sparse. PRACTICE IMPLICATIONS: Further research is needed to discern the specific nature of the treatment concerns and identify the information needs that survivors experience during recurrence of cancer, metastasis or changes in diagnosis, and the end of life phase of the cancer continuum. PMID- 27765378 TI - A systematic review of effectiveness of decision aids to assist older patients at the end of life. AB - OBJECTIVE: To describe the range of decision aids (DAs) available to enable informed choice for older patients at the end of life and assess their effectiveness or acceptability. METHODS: Search strategy covered PubMed, Scopus, Ovid MEDLINE, EMBASE, EBM Reviews, CINAHL and PsycInfo between 1995 and 2015. The quality criteria framework endorsed by the International Patient Decision Aids Standards (IPDAS) was used to assess usefulness. RESULTS: Seventeen DA interventions for patients, their surrogates or health professionals were included. Half the DAs were designed for self-administration and few described use of facilitators for decision-making. TREATMENT: options and associated harms and benefits, and patient preferences were most commonly included. Patient values, treatment goals, numeric disease-specific prognostic information and financial implications of decisions were generally not covered. DAs at the end of life are generally acceptable by users, and appear to increase knowledge and reduce decisional conflict but this effectiveness is mainly based on low-level evidence. CONCLUSIONS: Continuing evaluation of DAs in routine practice to support advance care planning is worth exploring further. In particular, this would be useful for conditions such as cancer, or situations such as major surgery where prognostic data is known, or in dementia where concordance on primary goals of care between surrogates and the treating team can be improved. PRACTICE IMPLICATIONS: Given the sensitivities of end-of-life, self-administered DAs are inappropriate in this context and genuine informed decision-making cannot happen while those gaps in the instruments remain. PMID- 27765380 TI - Optimising glycemic index in diets for older people. PMID- 27765379 TI - Impact of pharmacists as immunizers on vaccination rates: A systematic review and meta-analysis. AB - BACKGROUND: Underutilization of vaccination programs remains a significant public health concern. Pharmacists serve as educators, facilitators, and in some jurisdictions, as administrators of vaccines. Though pharmacists have been involved with immunizations in various ways for many years, there has yet to be a systematic review assessing the impact of pharmacists as immunizers in these three roles. OBJECTIVE: To complete a systematic review of the literature on the impact of pharmacists as educators, facilitators, and administrators of vaccines on immunization rates. METHODS: We identified 2825 articles searching the following databases from inception until October 2015: PubMed, EMBASE, Cochrane Libraries, Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts, Google Scholar. Grey literature was identified through use of the Canadian Agency for Drugs and Technology in Health "Grey Matters" search tool. Content from relevant journals and references of included studies were also searched. Inclusion criteria were clinical or epidemiologic studies in which pharmacists were involved in the immunization process. Studies were excluded if no comparator was reported. Two reviewers independently completed data extraction and bias assessments using standardized forms. RESULTS: Thirty-six studies were included in the review, 22 assessed the role of pharmacists as educators and/or facilitators and 14 assessed their role as administrators of vaccines. All studies reviewed found an increase in vaccine coverage when pharmacists were involved in the immunization process, regardless of role (educator, facilitator, administrator) or vaccine administered (e.g., influenza, pneumococcal), when compared to vaccine provision by traditional providers without pharmacist involvement. Limitations of the results include the large number of non-randomized trials and the heterogeneity between study designs. CONCLUSIONS: Pharmacist involvement in immunization, whether as educators, facilitators, or administrators of vaccines, resulted in increased uptake of immunizations. PROSPERO Registration: CRD42013005067. PMID- 27765381 TI - Surgical resection of complicated pericardial cyst. PMID- 27765382 TI - Automated endoscope reprocessors. PMID- 27765383 TI - Panitumumab-Induced Immune Complex Glomerulonephritis. PMID- 27765385 TI - Highly cited articles in "Zeitschrift fur Medizinische Physik". PMID- 27765386 TI - Optimization of a Pixel-to-Pixel Curve-Fitting Method for Poroelastography Imaging. AB - Ultrasound poroelastography is an imaging modality used to characterize the temporal behavior of soft tissue that can be modeled as a solid permeated by interconnected pores filled with liquid (poroelastic medium). It could be useful in the stage classification of lymphedema. Generally, time-constant models are applied to strain images, and precision of the fitting process, computational cost and versatility in response to changes in tissues properties are crucial aspects of clinical applications. In the work described here, we performed creep experiments on poroelastic phantoms and used rheologic models to visualize the changes in viscoelastic response associated with fluid mobility. We used the Levenberg-Marquardt algorithm as a fitting tool and performed parametric studies to improve its performance. On the basis of these studies, we proposed an optimization schema for the pixel-to-pixel curve-fitting process. We determined that the bimodal Kelvin-Voigt model describes efficiently the temporal evolution of the strain images in heterogeneous phantoms. PMID- 27765384 TI - Acute Kidney Injury Secondary to Trauma-Induced Hemolysis: The Need for Increased Awareness and a Preventative Strategy. PMID- 27765387 TI - T wave alternans: An ominous marker for malignant cardiac arrhythmias. PMID- 27765388 TI - Long delay to onset of ACE inhibitors-induced cough: Reason of difficult diagnosis in primary care? PMID- 27765389 TI - A 77-year-old man with fever and night sweats. PMID- 27765390 TI - Relationship between retention forces and stress at the distal border in maxillary complete dentures: Measurement of retention forces and finite-element analysis in individual participants. AB - STATEMENT OF PROBLEM: Although the retention force of maxillary complete dentures has been measured in numerous studies with different devices, the biomechanical mechanism associated with the generation of this retention force cannot be determined. PURPOSE: The purpose of this clinical study was to investigate whether 3-dimensional finite-element analysis can be used to estimate the retention force of maxillary complete dentures. MATERIAL AND METHODS: The study included 12 participants (6 men and 6 women, mean 77.5 years of age). Replicas of the maxillary complete dentures of all the participants were made using scanning resin. The denture replicas were scanned using cone-beam computed tomography (CBCT), and 3-dimensional finite-element models were constructed (dentures, mucosa, and jig). The tensile site was located 5 mm anterior from the central point of the denture's posterior border, and the loading site was located at the central point of the central incisor edge and the right first premolar buccal cusp. The load was 10 N and perpendicular to the occlusal plane. One-way ANOVA was calculated to determine any differences in the maximum principal stress value among the 3 sites. The Games-Howell test for multiple comparisons was applied to determine which sites were different. A Spearman rank correlation coefficient was used to determine any correlation between the retention force and maximum principal stress at measurement posterior site, and a Pearson correlation coefficient was used at the central incisor edge and premolar buccal cusp (all alpha=.05). Comparative investigations of the association between the maximum principal stress generated and the denture retention force were carried out. RESULTS: The stress distribution of the maximum principal stress at each measurement point was similar for each participant. The maximum principal stress at the posterior site measurement was significantly higher than measurements at the incisor edge and posterior buccal cusp (P<.01). The maximum principal stress the posterior and incisor edge sites were found to be correlated (P<.05). CONCLUSIONS: This study results suggest that although more factors need to be considered, a 3-dimensional finite-element analysis may be used to estimate the retention force of maxillary complete dentures. PMID- 27765391 TI - Fabrication of postsurgical auricle separator stent in reconstruction of the ear. AB - A natural appearing ear with appropriate projection from the head remains a great challenge in the reconstruction of the ear. Surgical and prosthetic means have been addressed in the management of patients with microtia, with each carrying its own merits and demerits. Lack of adequate projection of the ear and adhesion of tissues are some common complications of reconstructive surgery that can adversely affect the treatment outcome. This article describes a technique for the fabrication of a postsurgical stent to prevent adhesion of the surgically reconstructed ear to the underlying tissues. This also enhances the projection of the ear from the head. PMID- 27765392 TI - Effect of locator abutment height on the retentive values of pink locator attachments: An in vitro study. AB - STATEMENT OF PROBLEM: Currently, no guidelines exist to help in the selection of Locator abutments for implants at different heights. PURPOSE: The purpose of this in vitro study was to evaluate the effect of the differential heights of pairs of Locator abutments on the retention of overdentures after 6 months of simulated function. MATERIAL AND METHODS: In vitro testing was performed with 4 sets of average-sized edentulous mandible analogs with 2 implants placed in the canine positions. There were 10 specimens in each of the 4 groups, with a total sample size of 40. Four groups of 2 implant-retained overdentures were fabricated, with Locator attachments at different vertical levels with differences of 0, 2, 4, and 6 mm. The overdentures were subjected to simulated function for a period corresponding to 6 months of clinical service and then tested with a universal testing machine for changes in peak load-to-dislodgement. The data were analyzed using 1-way ANOVA followed by the Tukey honest significant differences test (alpha=.05). RESULTS: Varying the heights of Locator abutments had a statistically significant effect on the retentive values of the pink Locator attachments after 6 months of simulated function (F=7.342, P=.001). The peak load to-dislodgement ranged from 32.3 N (95% confidence interval [CI]: 26.0 to 38.6) for group 0 mm to 53.6 N (95% CI: 46.3 to 60.8) for group 6 mm. When the difference in Locator abutment heights was 2 and 4 mm, the peak load was 37.1 N (95% CI: 32.3 to 42.0) and 41.9 N (95% CI: 31.2 to 52.7). Statistical analysis revealed that the retention of group 0 mm and group 2 mm was significantly lower than group 6 mm. The retention of group 4 mm was not significantly different from groups 0 mm, 2 mm, or 6 mm. CONCLUSIONS: Although significant differences were found among the groups, these differences were small and may not be clinically detectable. PMID- 27765394 TI - Effect of brand and shade of resin cements on the final color of lithium disilicate ceramic. AB - STATEMENT OF PROBLEM: Resin cements are available in various shades from different manufacturers. However, there is no standard for the optical properties of these cements, which may result in differences in the color of translucent ceramic restorations. PURPOSE: The purpose of this in vitro study was to evaluate the effects of different shades and brands of resin cements on the color of a lithium disilicate ceramic. MATERIALS AND METHODS: Ten ceramic disks (11*1.5 mm, shade A2) were fabricated from lithium disilicate high-translucency blocks. Eighty cement disks (11*0.2 mm) were fabricated from 4 brands (Maxcem; Variolink; Clearfil; and RelyX) of resin cements in translucent and universal (shade A2) shades. Color measurements of ceramic specimens were made without (control) and with each brand/shade of resin cement material (test) with a spectrophotometer, and International Commission on Illumination Lab (CIELab) color coordinates were recorded. Color differences (DeltaE00) between the control and test groups were calculated. DeltaE00 results were analyzed by 2-way ANOVA and subsequent pairwise testing. Comparisons were performed using the Student t test, and then all P values were corrected with the step-down Bonferroni procedure (alpha=.05). RESULTS: The effect on the DeltaE00 values (P<.001) of the brand and shade of resin cement materials was significant. Both shades of RelyX cement groups had significantly lower and Variolink_translucent cement group had significantly higher DeltaE00 results than other brands (P<.05). Only RelyX_translucent and RelyX_universal were significantly different from each other for comparisons within brands (P<.05). The effect of RelyX_universal cement on the ceramic was not visually perceptible (DeltaE00<=1.30). Clinically unacceptable results (DeltaE00>2.25) were observed only for Variolink_translucent cement (2.36). CONCLUSIONS: Same-shade resin cements from different manufacturers had different effects on the color of lithium disilicate ceramic. The effects of different shades of resin cements from the same manufacturer on the color of lithium disilicate ceramic were statistically different for only RelyX, which may also be considered clinically different based on clinical acceptability thresholds for color difference values (DeltaE00). Accordingly, this effect may be considered clinically different for Variolink but not clinically different for Maxcem and Clearfil. PMID- 27765393 TI - Effect of polyvinyl siloxane impression material on the polymerization of composite resin. AB - STATEMENT OF PROBLEM: Polyvinyl siloxane impression material has been widely used as a lingual matrix for rebuilding missing tooth structure with composite resin. The composite resin is light polymerized in contact with the polyvinyl siloxane impression material. However, polyvinyl siloxane impression material has been shown to interact with other dental materials. PURPOSE: The purpose of this study was to assess the effect of polyvinyl siloxane impression materials on the polymerization of composite resins by assessing the Vickers microhardness and degree of conversion of polyvinyl siloxane. MATERIAL AND METHODS: The composite resins were light polymerized in contact with 3 polyvinyl siloxane impression materials (Flexitime Easy Putty; President Light Body; Xantopren L Blue) (n=8) and in contact with a matrix strip as the control group (n=8). Vickers microhardness and degree of conversion on contact surfaces were measured to evaluate the polymerization of composite resins. The depth of the effect was assessed by Vickers microhardness on section surfaces and observed with scanning electron microscopy. The results were analyzed by 1-way analysis of variance and the post hoc Tukey honest significant differences test (alpha=.05). RESULTS: The Vickers microhardness and degree of conversion values on the contact surfaces of the experiment groups were significantly lower than those of the control group (P<.05); the Vickers microhardness values on the section surfaces indicated that there was no significant difference at the same depth of different groups (P>.05). The scanning electron microscope observation showed that an approximately 10-MUm deep unpolymerized layer was found in the experimental group. CONCLUSIONS: Polyvinyl siloxane impression materials have an inhibitory effect on the polymerization of the composite resins, but just limited to within approximately 10 MUm from the surface in contact with the impression material. PMID- 27765395 TI - Impact of oral rehabilitation on patients with head and neck cancer: A study using the Liverpool Oral Rehabilitation Questionnaire and the Oral Health Impact Profile-14. AB - STATEMENT OF PROBLEM: The treatment of oral cancers affects oral functions and quality of life (QOL). Dental rehabilitation is a major step toward enhancing quality of life after controlling the disease. The effects of the disease, treatment, and rehabilitation need to be evaluated to assess oral health-related QOL. The Liverpool Oral Rehabilitation Questionnaire version 3 (LORQv3) and Oral Health Impact Profile-14 (OHIP-14) are specific assessment questionnaires of oral rehabilitation. PURPOSE: The purpose of this study was to assess the impact of oral rehabilitation on patients with head and neck cancer by using the LORQv3 and OHIP-14 questionnaires and to discover and document specific patient-derived problems related to the issues of oral rehabilitation. MATERIAL AND METHODS: The LORQv3 and OHIP-14 questionnaires were administered to 60 participants with oral cancer, who were in need of oral rehabilitation. They were asked to rate their dental problems on a Likert scale before fabrication of their prostheses (baseline) and at the 3-month follow-up visit after prosthetic rehabilitation. Paired comparison was done using the Wilcoxon signed rank test according to the distribution, and Cronbach alpha was used to assess internal consistency. Subscale scores were determined by mean value (alpha=.05). RESULTS: For the LORQv3 questionnaire, a 10% to 27% improvement was found in the domain of oral function, and a 20% improvement in orofacial appearance, with improvement in patient satisfaction with the prosthesis. Using the OHIP-14 questionnaire, a 45% to 67% improvement was generally seen in all domains. CONCLUSIONS: After assessment using the LORQv3 and OHIP-14 questionnaires, prosthetic rehabilitation was seen to contribute to the betterment of patients with head and neck cancer. PMID- 27765396 TI - Prospective cohort clinical study assessing the 5-year survival and success of anterior maxillary zirconia-based crowns with customized zirconia copings. AB - STATEMENT OF PROBLEM: Studies evaluating anterior zirconia-based crowns are limited. PURPOSE: The purpose of this prospective cohort clinical study was to assess the efficacy of zirconia-based anterior maxillary crowns with 0.3-mm customized copings at the cervical third and anatomical design elsewhere for up to 5 years of service. MATERIAL AND METHODS: Eighteen participants who required an anterior maxillary crown (n=20) and who had signed a consent form approved by the University of Washington Health Sciences Center Human Subjects Division were enrolled. All preparations were standardized and prepared with an occlusal reduction of 1.5 to 2 mm and an axial reduction of 1 to 1.5 mm with 10 degrees of convergence angle. All finish lines were located on the sound tooth structure. Zirconia copings (Lava; 3M ESPE) were custom designed and milled to a 0.3-mm thickness at the cervical third and with selective thickness elsewhere to support the veneering porcelain. All restorations were luted with self-etching self adhesive composite resin cement. Recall appointments were at 2 weeks, 6 months, and 12 months, and annually thereafter for 5 years. Modified Ryge criteria were used to assess the clinical fracture measurements, esthetics, marginal discoloration, marginal adaptation, radiographic proximal recurrent caries, and periapical pathoses. Descriptive statistics and 95% confidence intervals were used to describe the number and rate of complications and self-reported satisfaction with the crowns. RESULTS: Twenty crowns with a mean follow-up of 58.7 months were evaluated. All crowns were rated as Alfa for fracture measurements (smooth surface, no fracture/chipping). Twelve crowns were rated esthetically as Romeo (no mismatch in color and shade) and 8 as Sierra (mismatch in color and shade within normal range). Twelve crowns were rated as Alfa (no visible evidence of crevice) and 8 as Bravo (visible evidence of crevice, no penetration of explorer) for marginal integrity. Nineteen were rated as Alfa (no discoloration) and 1 as Bravo (superficial discoloration) for marginal discoloration. No proximal caries or periapical pathoses were detected in 5 years. Participants were highly satisfied with their crowns after 5 years (mean +/-SD: 9.8 +/-0.4 on 0 to 10 scale). CONCLUSIONS: Zirconia-based anterior maxillary crowns with customized copings with 0.3-mm thickness at the cervical third and zirconia margins performed well after 5 years of service. PMID- 27765397 TI - Compatible CAD-CAM titanium abutments for posterior single-implant tooth replacement: A retrospective case series. AB - STATEMENT OF PROBLEM: In addition to the original abutments provided by implant companies, compatible computer-aided design and computer-aided manufacturing (CAD CAM) abutments are also available from different manufacturers. However, the combination of abutments and implant systems from different manufacturers may lead to mechanical problems between components. Little has been reported on the clinical performance of this treatment option. PURPOSE: The purpose of this retrospective case series was to evaluate the outcome of compatible CAD-CAM titanium abutments (TiAs) for posterior single-implant tooth replacement (PSITR) up to 6 years after insertion. MATERIAL AND METHODS: Eighty-one patients (34 men, 47 women) who received PSITR restored with compatible CAD-CAM TiAs and had a final recall examination between May 2014 and April 2015 were included in this study. Clinical and radiographic examinations were documented. Retrospective evaluation of the patient records was also performed. Correlations between bone level changes and variables were calculated using the Spearman correlation. RESULTS: Implant and prosthesis survival rates were 100%. Twenty technical complications were observed, including 9 decementations of the crown, 6 screw loosenings, and 5 ceramic fractures. Periimplant mucositis was diagnosed in 36 patients (44.4%) and periimplantitis in 6 patients (7.4%). Correlation analysis showed a significant effect of the extent of periodontal bone loss of the remaining teeth on the marginal bone-level changes around implants (r=0.548, P<.001). CONCLUSIONS: Compatible CAD-CAM TiAs provide a viable treatment option for PSITR. However, in light of relatively high screw-loosening and decementation rates, choosing appropriate cements and abutment manufacturers is essential to improve the clinical performance of this treatment option. PMID- 27765398 TI - A survey to determine agreement regarding the definition of centric relation. AB - STATEMENT OF PROBLEM: The definition of centric relation (CR) has been both controversial and divisive, with little consensus. PURPOSE: The purpose of this study was to determine whether agreement can be reached on a definition for CR among the Fellows of the Academy of Prosthodontics, the organization that writes the Glossary of Prosthodontic Terms. MATERIAL AND METHODS: A survey of the Fellows of the Academy of Prosthodontics was conducted at the organization's annual business meeting. RESULTS: Of the 83 eligible Fellows in attendance, 72 responded to the survey, a response rate of 86%. Of those, the 5 responders who did not indicate a preferred definition and the 2 that chose 2 definitions were censored, yielding an analyzable sample of 65 for the definitions. The most common definition received 19 votes, the next 16, and the third 13, with the other 6 definitions receiving from 2 to 5 votes. Some of the variability in definition depended on the era of training. CONCLUSIONS: Disagreement and confusion continues regarding the definition of centric relation. Some of this disagreement can be explained by training era. PMID- 27765399 TI - Comparison of retention between maxillary milled and conventional denture bases: A clinical study. AB - STATEMENT OF PROBLEM: Clinical studies comparing the retention values of milled denture bases with those of conventionally processed denture bases are lacking. PURPOSE: The purpose of this clinical study was to compare the retention values of conventional heat-polymerized denture bases with those of digitally milled maxillary denture bases. MATERIAL AND METHODS: Twenty individuals with completely edentulous maxillary arches participated in this study. Definitive polyvinyl siloxane impressions were scanned (iSeries; Dental Wings), and the standard tessellation language files were sent to Global Dental Science for the fabrication of a computer-aided design and computer-aided manufacturing (CAD-CAM) milled denture base (group MB) (AvaDent). The impression was then poured to obtain a definitive cast that was used to fabricate a heat-polymerized acrylic resin denture base resin (group HB). A custom-designed testing device was used to measure denture retention (N). Each denture base was subjected to a vertical pulling force by using an advanced digital force gauge 3 times at 10-minute intervals. The average retention of the 2 fabrication methods was compared using repeated ANOVA (alpha=.05). RESULTS: Significantly increased retention was observed for the milled denture bases compared with that of the conventional heat polymerized denture bases (P<.001). CONCLUSIONS: The retention offered by milled complete denture bases from prepolymerized poly(methyl methacrylate) resin was significantly higher than that offered by conventional heat- polymerized denture bases. PMID- 27765400 TI - Failure rate of single-unit restorations on posterior vital teeth: A systematic review. AB - STATEMENT OF PROBLEM: No knowledge synthesis exists concerning when to use a direct restoration versus a complete-coverage indirect restoration in posterior vital teeth. PURPOSE: The purpose of this systematic review was to identify the failure rate of conventional single-unit tooth-supported restorations in posterior permanent vital teeth as a function of remaining tooth structure. MATERIAL AND METHODS: Four databases were searched electronically, and 8 selected journals were searched manually up to February 2015. Clinical studies of tooth supported single-unit restorative treatments with a mean follow-up period of at least 3 years were selected. The outcome measured was the restorations' clinical or radiological failure. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, the Cochrane Collaboration procedures for randomized control trials, the Strengthening the Reporting of Observational Studies in Epidemiology criteria for observational studies, 2 reviewers independently applied eligibility criteria, extracted data, and assessed the quality of the evidence of the included studies using the American Association of Critical Care Nurses' system. The weighted-mean group 5-year failure rates of the restorations were reported according to the type of treatment and remaining tooth structure. A metaregression model was used to assess the correlation between the number of remaining tooth walls and the weighted-mean 5-year failure rates. RESULTS: Five randomized controlled trials and 9 observational studies were included and their quality ranged from low to moderate. These studies included a total of 358 crowns, 4804 composite resins, and 303582 amalgams. Data obtained from the randomized controlled trials showed that, regardless of the amount of remaining tooth structure, amalgams presented better outcomes than composite resins. Furthermore, in teeth with fewer than 2 remaining walls, high-quality observational studies demonstrated that crowns were better than amalgams. A clear inverse correlation was found between the amount of remaining tooth structure and restoration failure. CONCLUSIONS: Insufficient high-quality data are available to support one restorative treatment or material over another for the restoration of vital posterior teeth. However, the current evidence suggests that the failure rates of treatments may depend on the amount of remaining tooth structure and types of treatment. PMID- 27765401 TI - Effects of chlorine-based and quaternary ammonium-based disinfectants on the wettability of a polyvinyl siloxane impression material. AB - STATEMENT OF PROBLEM: Polyvinyl siloxane (PVS) impression materials must be cold disinfected before cast pouring to prevent cross-contamination among personnel and patients. However, disinfection may affect the ability of PVS impression materials to provide bubble-free stone surfaces because of the removal of surfactants. PURPOSE: The purpose of this in vitro study was to compare the water contact angles of a PVS impression material treated with either a quaternary ammonium-based (QAB) (DisCide Ultra) or a chlorine-based (CLB) (Dispatch) disinfectant for various exposure times. No disinfection and acetone-immersed (total surfactant removal) specimens were used as positive and negative controls. An additional purpose was to measure changes in the contact angles of the disinfected PVS impression material after applying a topical wetting agent. MATERIAL AND METHODS: Flat and disk-shaped PVS specimens (n=5/test condition) were fabricated and subsequently exposed to disinfectants for different times (1 minute, 5 minutes, 30 minutes, 6 hours, and 24 hours). After disinfection, the contact angle with distilled water was determined over a 3-minute period using dynamic contact analysis. The same contact angle measurements were repeated after a wetting agent was applied to the previously disinfected specimens. Contact angles were statistically compared using 2-way ANOVA. The Sidak post hoc test was used to perform pairwise simple contrast and effect comparisons (alpha=.05). RESULTS: The contact angle increased directly with disinfectant contact time. For the CLB product, the contact angle after 30-minute disinfection was not significantly different from that of 1 minute disinfection (P>.05). For the QAB product, exceeding 5-minutes of disinfection resulted in a significantly greater contact angle (P<.001). The application of a wetting agent made the disinfected PVS specimens less hydrophobic. CONCLUSIONS: A QAB disinfectant product is more effective at removing surfactant than a CLB disinfectant product. Therefore, a CLB disinfectant provides more working time and control. A wetting agent can reduce the hydrophobicity of a disinfected impression material if the duration of cold disinfection is less than 6 hours. PMID- 27765402 TI - Type 2 diabetes and gender differences in liver cancer by considering different confounding factors: a meta-analysis of cohort studies. AB - PURPOSE: Questions remain uncertainty regarding the gender differences in the relationship between type 2 diabetes (T2DM) and liver cancer risk. By considering several confounding factors, we aimed to identify this issue according to a meta analysis of cohort studies. METHODS: We searched EMBASE and MEDLINE for studies on the association between T2DM and risk of liver cancer up to November 30, 2014. A random-effects model was performed to calculate summary relative risks (SRRs) with corresponding 95% confidence intervals (CIs). RESULTS: A total of 24 cohort studies (including more than 20,000 liver cancer cases) were recruited. T2DM was associated with an elevated liver cancer incidence in both men (SRR = 2.16; 95% CI, 1.74-2.69) and women (SRR = 1.85; 95% CI, 1.40-2.44). Stratified analyses showed that the risk associations were significantly stronger in non-Asian than those in Asian for both men and women. Both tobacco smoking and body mass index were significant confounding factors for the T2DM-liver cancer association in men, whereas alcohol use was not the case. The SRR estimates of liver cancer mortality with T2DM were statistically significant in both men and women (men: SRR = 2.26; 95% CI, 1.60-3.19 and women: SRR = 2.01; 95% CI, 1.45-2.74). CONCLUSIONS: Results of this meta-analysis indicate that the T2DM-liver cancer correlation is confounded by smoking and body mass index in both men and women. Results also suggest a significantly stronger T2DM-liver cancer correlation in non-Asian than that in Asian for both men and women. PMID- 27765403 TI - Renal amyloidosis. PMID- 27765404 TI - A study of oxidative stress induced by two polybrominated diphenyl ethers in the rotifer Brachionus plicatilis. AB - Polybrominated diphenyl ethers (PBDEs) are widely dispersed persistent organic pollutants in the marine ecosystem. However, their toxic mechanisms in marine organisms, especially invertebrates, remain poorly understood. Two common congeners of PBDEs, tetrabrominated diphenyl ether-47 (BDE-47) and decabrominated diphenyl ether-209 (BDE-209), were investigated. Their toxic mechanisms, with a focus on oxidative stress, were examined in rotifer Brachionus plicatilis. Overproduction of reactive oxygen species (ROS) was induced by two PBDEs. The expression of superoxide dismutase (SOD) mRNA was increased, suggesting SOD play a main role in ROS-scavenging. The intercellular concentrations of calcium ([Ca2+]in) and the expression of calmodulin (CaM) mRNA were increased. This indicates the calcium ion (Ca2+) signaling channel is involved in PBDEs stress. Further analysis showed that the reproductive system might be the target site for toxicity of PBDEs. Moreover, high value of detection indexes in BDE-47 experimental groups suggested BDE-47 might cause higher oxidative damage than BDE 209 in rotifers. PMID- 27765405 TI - The behaviour of 137Cs in the North Atlantic Ocean assessed from numerical modelling: Releases from nuclear fuel reprocessing factories, redissolution from contaminated sediments and leakage from dumped nuclear wastes. AB - A Lagrangian model which simulates the dispersion of 137Cs in the North Atlantic has been developed. The model includes water/sediment interactions. It has been tested comparing calculated and measured 137Cs concentrations in water and sediments of the European Shelf resulting after the releases from the nuclear fuel reprocessing plants of Sellafield and La Hague. Some additional numerical experiments have been carried out. First, the redissolution of 137Cs from contaminated sediments after the reduction in releases from the reprocessing plants has been studied. This allowed to calculate effective half-lives of 137Cs in several sub-basins. Later, potential leakage of 137Cs from dumped nuclear wastes in several locations of the Atlantic has been investigated. Even in worst case scenarios, these leakages should not lead to any radiological implications. PMID- 27765406 TI - Underwater noise in an impacted environment can affect Guiana dolphin communication. AB - This study focused on whistles produced by Guiana dolphin under different noise conditions in Guanabara Bay, southeastern Brazil. Recording sessions were performed with a fully calibrated recording system. Whistles and underwater noise levels registered during two behavioral states were compared separately between two areas. Noise levels differed between the two areas across all frequencies. Whistle duration differed between areas and was negatively correlated with noise levels. Whistling rate was positively correlated with noise levels, showing that whistling rate was higher in noisier conditions. Results demonstrated that underwater noise influenced Guiana dolphin acoustic behavior. PMID- 27765407 TI - Heavy metals in fish tissues/stomach contents in four marine wild commercially valuable fish species from the western continental shelf of South China Sea. AB - The concentrations of heavy metals (Cd, Pb, Cr, Ni, Cu and Zn) were determined in four commercially valuable fish species (Thunnus obesus, Decapterus lajang, Cubiceps squamiceps and Priacanthus macracanthus), collected in the western continental shelf of the South China Sea. Concentrations of Cd, Pb, Cr, Ni, Cu, and Zn in fish muscles were 0.006-0.050, 0.13-0.68, 0.18-0.85, 0.11-0.25, 0.12 0.77, and 2.41-4.73MUg/g, wet weight, respectively. Concentrations of heavy metals in all species were below their acceptable daily upper limit, suggesting human consumption of these wild fish species may be safe, with health risk assessment based on the target hazard quotients (THQ) and total THQ, indicating no significant adverse health effects with consumption. The average concentrations of Zn were higher in gills than in stomach contents, backbones or muscle, while conversely, the other heavy metals had higher concentrations in stomach contents than in other tissues. PMID- 27765408 TI - Design, synthesis and biological evaluation of novel non-covalent piperidine containing peptidyl proteasome inhibitors. AB - A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4+/-0.1nM) and cytotoxicities with IC50 values at 13.9+/-1.8nM and 9.5+/-0.5nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27-29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs. PMID- 27765409 TI - Synthesis of N-aryl and N-arylcarbamoylamino derivatives of 1,3-diazinane-5 carboxamide and their activity against glioblastoma LN-229 cell line. AB - Six structural motifs based on the initial (lead) structure of merbarone were designed, prepared, and tested against the glioblastoma LN-229 cell line. Three different structural moieties were modified in the search for optimal glioblastoma activity: the 1,3-diazinane moiety, the aryl moiety, and the heteroatom linker. Calculated molecular descriptors such as lipophilicity (ClogP), acidic strength (calculated pKa), and polar surface area (PSA) were used to design a diverse structural library of these compounds. From six different structural motifs and 136 compounds, a handful of examples with moderate (100MUg/ml), good (10MUg/ml) and excellent (1MUg/ml) glioblastoma activity were elucidated. PMID- 27765410 TI - Adaptive support ventilation of cardiac surgical patients: A component of a complex intervention. PMID- 27765411 TI - Effect of 5alpha-reductase inhibitors on sexual function: New contributions. PMID- 27765413 TI - Personality dimensions and substance use in individuals with mild to borderline intellectual disabilities. AB - AIMS: The aim of this study was to examine the role of the personality dimensions anxiety sensitivity, negative thinking, impulsivity and sensation seeking (as assessed by the revised version of the Substance Use Risk Profile Scale; SURPS) in substance use in individuals with mild to borderline intellectual disabilities (MBID). METHOD: We tested the relationship between level of ID and SURPS personality dimensions and the relationship between SURPS personality dimensions and severity of alcohol and drug use. Participants were 118 persons (mean age 20.5 years) with a mean IQ of 71.1 admitted to care facilities for persons with MBID and severe behavioral problems. RESULTS: We found no significant relationship between level of ID and the four personality dimensions. In addition, findings showed that individuals with lower levels of anxiety sensitivity, higher levels of negative thinking, impulsivity and sensation seeking showed more severe alcohol use. Individuals with higher levels of negative thinking and sensation seeking had more severe drug use. CONCLUSIONS AND IMPLICATIONS: The SURPS personality dimensions identify persons at increased risk for substance use disorders and might be useful in developing selective substance use interventions for individuals with MBID. PMID- 27765412 TI - Characterisation of fosfomycin resistance mechanisms and molecular epidemiology in extended-spectrum beta-lactamase-producing Klebsiella pneumoniae isolates. AB - Although fosfomycin is a treatment option for infections caused by extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, fosfomycin resistance has been documented. To our knowledge, fosfomycin resistance mechanisms in Klebsiella pneumoniae have not been systematically investigated. A total of 108 ESBL-producing K. pneumoniae isolates collected from Kaohsiung Medical University Hospital, Taiwan, from August 2012 to May 2013 were analysed in this study. Pulsed-field gel electrophoresis (PFGE) revealed 64 pulsotypes and six non-typeable isolates, indicating high genetic diversity. Moreover, pulsotypes V (n = 6), VII (n = 11) and LI (n = 4) belonging to ST11 were major types. Among 30 (27.8%) fosfomycin-non-susceptible isolates, 21 (70%) had a MurA amino acid substitution, and seven new variations increased the fosfomycin minimum inhibitory concentration (MIC) by 8- to 16-fold compared with wild-type MurA in Escherichia coli DH5alpha.strain. Functionless transporters (GlpT and UhpT) with various mutations were found in 29 isolates (97%). No known fosfomycin modifying enzymes were detected in this study. The major resistance mechanisms to fosfomycin in K. pneumoniae were amino acid variations in the drug target and transporters. PMID- 27765414 TI - [Eruptive epidermoid cysts during topical imiquimod treatment]. AB - BACKGROUND: Imiquimod is a local immune-response modifier that works by stimulating innate and acquired immunity. It is frequently used to treat superficial basal cell carcinoma, the most common form of skin cancer. Marked local inflammatory reaction is common during treatment. We report a case of the rare condition, multiple eruptive milia, during topical imiquimod therapy. PATIENTS AND METHODS: A 67-year-old male patient presented infiltrating basal cell carcinoma above the left eyebrow. The patient underwent surgery and skin grafting. He presented superficial relapse at the periphery of the graft and was initially treated with Aldara(r). Fifteen days after initiation, Aldara(r) was withdrawn due to a critical inflammatory reaction. A few weeks after complete healing, an erythematous annular plaque of milia, excluding the graft zone, appeared. This element was confirmed by histopathology. DISCUSSION: The most common local side effects reported with Aldara(r) are erythema, irritation and crusting. Reports of eruptive milia following Aldara(r) therapy are rare and they are never mentioned in the summary of product characteristics. Application of imiquimod in fact induces local inflammatory reaction due to stimulation of local cytokines, which can result in marked reaction in the infundibular epithelium of hair follicles and thus in the production of abnormal keratin that can cause pilosebaceous duct obstruction and thus the formation of epidermoid cysts. This pathological mechanism explains the absence of lesions on the skin graft of the inner arm. CONCLUSION: The occurrence of eruptive milia during treatment with Aldara(r) is rarely described. The timing of occurrence of these eruptive milia as well as the mechanism of action of the drug made such a reaction highly probable in our patient. PMID- 27765415 TI - [Infrapatellar hypertrichosis in adult dermatomyositis]. PMID- 27765416 TI - [Sporadic progressive mucinous histiocytosis]. AB - BACKGROUND: Progressive mucinous histiocytosis is a very rare, benign, non Langerhans' cell histiocytosis limited to the skin. This disorder has been observed solely in women, with the exception of three cases in male patients, and most cases are hereditary. The hereditary forms begin in childhood, with sporadic cases occurring later, and it is characterized by numerous papules of slow progression. The aetiology and mode of genetic transmission remain unclear. We report one sporadic case of progressive mucinous histiocytosis. PATIENTS AND METHODS: A 33-year-old woman presented with a 15-year history of multiple small purplish asymptomatic papules on the outside of both legs. There was no history of similar cases in her family. The dermatologists she consulted suggested a diagnosis of lichen planus. A punch biopsy was performed and revealed dermal accumulation of histiocytes with abundant mucin deposition. DISCUSSION: Seventeen hereditary cases in seven families, all of which concerned women except for three males, and five sporadic cases have been described to date. The clinical and histological presentation is typical. Histopathology shows dermal accumulation of histiocytes with abundant mucin deposition. The ultrastructural aspect (intracytoplasmic phospholipid deposits) and progressive extension suggest a disorder similar to that observed in lysosomal diseases. However, primary proliferation of macrophages in response to an unknown stimulus cannot be ruled out. At present, there is no treatment. PMID- 27765417 TI - Electrodeposition of self-assembled poly(3,4-ethylenedioxythiophene) @gold nanoparticles on stainless steel wires for the headspace solid-phase microextraction and gas chromatographic determination of several polycyclic aromatic hydrocarbons. AB - In this work, a novel poly(3,4-ethylenedioxythiophene)@Au nanoparticles (PEDOT@AuNPs) hybrid coating was prepared and characterized. Firstly, the monomer 3,4-ethylenedioxythiophene was self-assembled on AuNPs, and then electropolymerization was performed on a stainless steel wire by cyclic voltammetry. The obtained PEDOT@AuNPs coating was rough and showed cauliflower like micro-structure with thickness of ~40MUm. It displayed high thermal stability (up to 330 degrees C) and mechanical stability and could be used for at least 160 times of solid phase microextraction (SPME) without decrease of extraction performance. The coating exhibited high extraction capacity for some environmental pollutants (e.g. naphthalene, 2-methylnaphthalene, acenaphthene, fluorene and phenathrene) due to the hydrophobic interaction between the analytes and PEDOT and the additional physicochemical affinity between polycyclic aromatic hydrocarbons and AuNPs. Through coupling with GC detection, good linearity (correlation coefficients higher than 0.9894), wide linear range (0.01-100MUgL 1), low limits of detection (2.5-25ngL-1) were achieved for these analytes. The reproducibility (defined as RSD) was 1.1-4.0% and 5.8-9.9% for single fiber (n=5) and fiber-to-fiber (n=5), respectively. The SPME-GC method was successfully applied for the determination of three real samples, and the recoveries for standards added were 89.9-106% for lake water, 95.7-112% for rain water and 93.2 109% for soil saturated water, respectively. PMID- 27765418 TI - Validation of molecularly imprinted polymers for side chain selective phosphopeptide enrichment. AB - Selective enrichment techniques are essential for mapping of protein posttranslational modifications (PTMs). Phosphorylation is one of the PTMs which continues to be associated with significant analytical challenges. Particularly problematic are tyrosine-phosphorylated peptides (pY-peptides) resulting from tryptic digestion which commonly escape current chemo- or immuno- affinity enrichments and hence remain undetected. We here report on significant improvements in this regard using pY selective molecularly imprinted polymers (pY MIPs). The pY-MIP was compared with titanium dioxide (TiO2) affinity based enrichment and immunoprecipitation (IP) with respect to selective enrichment from a mixture of 13 standard peptides at different sample loads. At a low sample load (1pmol of each peptide), IP resulted in enrichment of only a triply phosphorylated peptide whereas TiO2 enriched phosphopeptides irrespective of the amino acid side chain. However, with increased sample complexity, TiO2 failed to enrich the doubly phosphorylated peptides. This contrasted with the pY-MIP showing enrichment of all four tyrosine phosphorylated peptides at 1pmol sample load of each peptide with a few other peptides binding unselectively. At an increased sample complexity consisting of the standard peptides spiked into mouse brain digest, the MIP showed clear enrichment of all four pY- peptides. PMID- 27765419 TI - Nano-liquid chromatography applied to enantiomers separation. AB - This paper presents the state of the art concerning the separation of chiral compounds by means of nano-liquid chromatography (nano-LC). The enantiomers' separation and determination are a subject of fundamental importance in various application fields such as pharmaceutical industry, biomedicine, food, agrochemical etc. Nano-LC is a miniaturized chromatographic technique offering some advantages over conventional ones such as low consumption of mobile phase, sample volume and amount of chiral stationary phase, reduced costs etc. This is reported in the first part of the paper illustrating the features of the nano-LC. In addition, chiral resolution methods are briefly illustrated. Some chiral selectors, used in high-performance liquid chromatography have also been applied in nano-LC including cyclodextrins, glycopeptide antibiotics, modified polysaccharides etc. This is discussed in the second part of the review. Finally some examples of the applications available in literature are reported. PMID- 27765420 TI - Simultaneous quantification of propranolol and sulfamethoxazole and major human metabolite conjugates 4-hydroxy-propranolol sulfate and sulfamethoxazole-beta glucuronide in municipal wastewater-A framework for multiple classes of drugs and conjugates. AB - Recent data suggests there are non-trivial amounts of human pharmaceutical conjugates potentially entering environmental surface waters. These compounds could contribute to eliciting toxic effects on aquatic biota either directly or indirectly, via de-conjugation. The need for developing a single method for quantifying both parents and conjugates is necessary. Propranolol (PRO), sulfamethoxazole (SMX), and their respective major conjugates 4-OH-propranolol sulfate (PRO-Sul) and sulfamethoxazole-beta-glucuronide (SMX-Glc) were successfully simultaneously extracted through weak anion exchange solid phase extraction cartridges from primary and secondary clarification wastewaters from the North End Winnipeg Water Pollution Treatment Plant in Winnipeg, Canada. Subsequent separation and quantification were achieved by reversed-phase C18 chromatography coupled to positive electrospray ionisation tandem mass spectrometry. Linearity for all compounds throughout the 7-point calibration range was >0.99. Recovery RSD ranges across all matrices for PRO, SMX, PRO-Sul, and SMX-Glc were 2.1-13.2%, 2.3-10.2%, 9.8-19.2%, and 2.0-10.3% respectively. Primary and secondary filtrates respectively showed a significant increase of PRO from 0.039 to 0.045MUg/L; a significant decrease for SMX from 1.56 to 0.58MUg/L; significant decrease of PRO-Sul from 0.050 to 0.020MUg/L; and a significant decrease of SMX-Glc from 0.41 to 0.019MUg/L. These observations indicate that there was removal of all compounds, except for PRO, from the aqueous phase occurring at some point between the stages of treatment. To our knowledge, this is first study that simultaneously separated and quantified two different classes of parent compounds and two different kinds of human metabolite conjugates (glucuronide and sulfate) from a major urban wastewater treatment plant. PMID- 27765421 TI - Development of a high speed counter-current chromatography system with Cu(II) chiral ionic liquid complexes and hydroxypropyl-beta-cyclodextrin as dual chiral selectors for enantioseparation of naringenin. AB - Cu(II) complexed amino acid ionic liquid, Cu(II)-[1-butyl-3-methylimidazolium][L Pro] (Cu(II)-[BMIm][L-Pro]), was successfully adopted as chiral ligand to improve the enantioseparation efficiency in high speed counter-current chromatography (HSCCC). For the enantioseparation of intractable naringenin (NRG) racemic mixtures, Cu(II)-[BMIm][L-Pro] coupled with hydroxypropyl-beta-cyclodextrin (HP beta-CD) was successfully applied as dual chiral selectors in HSCCC. The influence of important parameters, including the concentration of the chiral selectors, the pH value, and the temperature were investigated. Under optimal conditions, 4.5mg of (+)-NRG and 4.1mg of (-)-NRG were successfully separated from 10mg NRG racemic mixtures with the purity of 98%. The chiral recognition mechanism of dual chiral selectors was illuminated by the UV-vis and NMR spectra, suggesting that the enantioseparation was upon the difference of the thermodynamic stability of the quaternary complexes of Cu(II), [BMIm][L-Pro], HP beta-CD, and NRG. The results illustrated that the developed HSCCC system, based on the synergistic mechanism of Cu(II)-[BMIm][L-Pro] and HP-beta-CD, exhibited better performance on enantioseparation and had great application potential in preparative chiral separation of natural products. PMID- 27765422 TI - Preparation and characterization of monodisperse large-porous silica microspheres as the matrix for protein separation. AB - High performance liquid chromatography (HPLC) is a kind of efficient separation technology and has been used widely in many fields. Micro-sized porous silica microspheres as the most popular matrix have been used for fast separation and analysis in HPLC. In this paper, the monodisperse large-porous silica microspheres with controllable size and structure were successfully synthesized with polymer microspheres as the templates and characterized. First, the poly(glycidyl methacrylate-co-ethyleneglycol dimethacrylate) microspheres (PGMA EDMA) were functionalized with tetraethylenepentamine (TEPA) to generate amino groups which act as a catalyst in hydrolysis of tetraethyl orthosilicate (TEOS) to form Si-containing low molecular weight species. Then the low molecular weight species diffused into the functionalized PGMA-EDMA microspheres by induction force of the amino groups to form polymer/silica hybrid microspheres. Finally, the organic polymer templates were removed by calcination, and the large-porous silica microspheres were obtained. The compositions, morphology, size distribution, specific surface area and pore size distribution of the porous silica microspheres were characterized by infrared analyzer, scanning-electron microscopy, dynamic laser scattering, the mercury intrusion method and thermal gravimetric analysis, respectively. The results show that the agglomeration of the hybrid microspheres can be overcome when the templates were functionalized with TEPA as amination reagent, and the yield of 95.7% of the monodisperse large porous silica microspheres can be achieved with high concentration of polymer templates. The resulting large-porous silica microspheres were modified with octadecyltrichlorosilane (ODS) and the chromatographic evaluation was performed by separating the proteins and the digest of BSA. The baseline separation of seven kinds of protein standards was achieved, and the column delivered a better performance when separating BSA digests comparing with the commercial one currently available. The high column efficiency and good reproducibility present that the large-porous silica microspheres obtained can be used as a matrix for peptide and protein separation. PMID- 27765424 TI - Filling the gap: Calibration of the low molar-mass range of cellulose in size exclusion chromatography with cello-oligomers. AB - Degraded celluloses are becoming increasingly important as part of product streams coming from various biorefinery scenarios. Analysis of the molar mass distribution of such fractions is a challenge, since neither established methods for mono- or disaccharides nor common methods for polysaccharide characterization cover the intermediate oligomer range appropriately. Size exclusion chromatography (SEC) with multi-angle laser light scattering (MALLS), the standard approach for celluloses, suffers from decreased scattering intensities in the lower-molar mass range. The limitation in the low-molecular range can, in principle, be overcome by calibration, but calibration standards for such "short" celluloses are either not readily available or structurally remote and thus questionable. In this paper, we present the calibration of a SEC system- for the first time - with monodisperse cellooligomer standards up to about 3400gmol-1. These cellooligomers are "short-chain celluloses" and can be seen as the "true" standard compounds, by contrast to commonly used standards that are chemically different from cellulose, such as pullulan, dextran, polystyrene, or poly(methyl methacrylate). The calibration is compared against those commercial standards and correction factors are calculated. Calibrations with non-cellulose standards can now be adjusted to yield better fitting results, and data already available can be corrected retrospectively. PMID- 27765423 TI - An approach for extraction of kernel oil from Pinus pumila using homogenate circulating ultrasound in combination with an aqueous enzymatic process and evaluation of its antioxidant activity. AB - In this study, a novel approach involving homogenate-circulating ultrasound in combination with aqueous enzymatic extraction (H-CUAEE) was developed for extraction of kernel oil from Pinus pumila. Following comparison of enzyme types and concentrations, an enzyme mixture consisting of cellulase, pectinase and hemicellulase (1:1:1, w/w/w) at a concentration of 2.5% was selected and applied for effective oil extraction and release. Several variables potentially influencing extraction yields, namely, homogenization time, incubation temperature, incubation time, mark-space ratio of ultrasound irradiation, ultrasound irradiation power, liquid-solid ratio, pH and stirring rate, were optimized by Plackett-Burman design. Among the eight variables, incubation temperature, incubation time and liquid-solid ratio were statistically significant and were further optimized by Box-Behnken design to predict optimum extraction conditions and ascertain operability ranges for maximum extraction yield. Under optimum operating conditions, extraction yields of P. pumila kernel oil were 31.89+/-1.12% with a Delta5-unsaturated polymethylene interrupted fatty acid content of 20.07% and an unsaturated fatty acid content of 93.47%. Our study results indicate that the proposed H-CUAEE process has enormous potential for efficient and environmentally friendly extraction of edible oils. PMID- 27765425 TI - Modeling of preparative closed-loop recycling liquid-liquid chromatography with specified duration of sample loading. AB - The closed-loop recycling counter-current chromatography (CLR CCC) is performed in several consecutive separation stages. First, the loop is opened, and within a specified time the solution of solutes in the mobile phase is continuously fed to the column. After the solutes loading is finished, the loop is closed, and the first separation stage starts. After a certain number of cycles the first fraction of solutes is eluted, the loop is closed, and the second separation stage starts, and so on. In this study, simple equations are presented allowing the simulation of such separation processes. These equations can help to select a suitable compromise between the productivity and the resolution in the preparative and production CLR CCC separations. It is shown that the sample loading time about 20%-30% of the mean residence time is quite acceptable from the practical point of view: proper selection of the loading time and the recycling line length can allow increasing the productivity by an order of magnitude ensuring, a desirable separation. PMID- 27765426 TI - Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature. AB - Parkinson's disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings. PMID- 27765428 TI - The 14th International Conference on Trichinellosis. PMID- 27765427 TI - Maxillary sinus lift surgery-with or without graft material? A systematic review. AB - The purpose of this systematic review was to perform a comparative analysis of the use or not of graft material in maxillary sinus lift surgery. Relevant studies published in the last 10 years were identified through a search of the PubMed/MEDLINE, ScienceDirect, and Cochrane Library databases and were assessed against the study inclusion and exclusion criteria. The initial search resulted in 1037 articles. After applying the inclusion and exclusion criteria, 16 articles remained. Four hundred and thirty-six patients were followed up over a postoperative period ranging from 6 months to 11 years. In total, 868 implants were installed in 397 maxillary sinuses. The implant survival rate was 96.00% for surgeries performed without graft material and 99.60% for those in which biomaterial was used, within a follow-up period of 48 to 60 months. In conclusion, maxillary sinus lift surgery, with or without graft material, is a safe procedure with a low complication rate and predictable results. PMID- 27765429 TI - [Information to patients in endometriosis: We must stop the frightening machine!] PMID- 27765430 TI - [Obstetrical prognosis of patients after a previous caesarean section performed before 32 weeks of amenorrhea]. AB - OBJECTIVE: To assess delivery mode, maternal morbidity including uterine rupture and scar dehiscence and neonatal outcome, during a pregnancy after a previous caesarean delivery before 32 weeks of amenorrhea. METHODS: A retrospective descriptive study was carried out at the Besancon University Hospital during an 8 year period. We identified 292 consecutive patients presenting a singleton pregnancy delivery before 32 weeks of amenorrhea. We analysed the next pregnancy. Patients presenting more than one caesarean section were excluded from this study. RESULTS: Out of the 292 patients, 62 met inclusion criteria. The average gestational age of the first caesarean section was 29 weeks and 3 days. Among these patients, 17 (27.4%) had a planned caesarean delivery after caesarean (CDAC) and 45 (72.6%) had a trial of vaginal delivery (TVD) with a success rate of 71.1%, that is a total of 51.6% of vaginal delivery after a previous early caesarean section. In case of a failed TVD, arterial pH (P<0.005), Apgar score at one minute (P<0.05) and at 10minutes (P<0.05) were significantly lower compared to the CDAC group. Regarding perinatal outcome, there was no significant difference (P=0.31) between the groups in intention to treat. The only uterine rupture (1.6%) was noticed during a caesarean section at 26 weeks and 3 days, in a patient initially included in the TVD group. Five uterine scar-dehiscences (8.1%) were discovered including 80% during caesarean section, at an average term of 32 weeks and 2 days of amenorrhea. CONCLUSION: After an early caesarean section, trial of vaginal delivery can be implemented if local conditions are favorable. There is no difference in maternal morbidity, success of labour and neonatal outcome if previous caesarean section was performed before 32 weeks or at term. It appears however that uterine rupture rate (complete or incomplete) is slightly higher in comparison to a previous caesarean at term, which might occur prematurely and before labour. PMID- 27765431 TI - The Effect of Surface Hydration on Teachers' Voice Quality: An Intervention Study. AB - PURPOSE: This study aimed to investigate the effects of surface hydration on teachers' voice quality. STUDY DESIGN: This is an examiner-blinded, pretest and posttest intervention study with a single group of subjects. METHOD: Subjects were 27 teachers from a public-sector state school in Salvador, Bahia, Brazil. Pre- and post-intervention voice recordings were obtained. Voice samples collected underwent computerized acoustic analysis (VoxMetria) and perceptual analysis via the Consensus Auditory-Perceptual Evaluation of Voice. Intervention was conducted daily before teaching for a 4-week period, consisting of 5 minutes of nebulization with saline solution (NaCl 0.9%), after 10 minutes of dehydration breathing through the mouth. RESULTS: A reduction in the overall level of voice alteration was observed in the Consensus Auditory-Perceptual Evaluation of Voice, but with no statistical significance. The following were observed: an increase in the mean fundamental frequency of the vowel /a:/ (P = 0.036); a statistically significant reduction in the minimum intensity of connected speech (P = 0.028), in the median intensity of connected speech (P = 0.014), and in the maximum intensity of connected speech (P = 0.007). There was also a statistically significant reduction in the minimum (P = 0.001) and mean intensities of spontaneous speech (P = 0.011). CONCLUSION: Surface hydration with saline solution led to an improvement in teachers' voice quality. PMID- 27765432 TI - Characteristics of Euphony in Direct and Indirect Mucosal Wave Imaging Techniques. AB - OBJECTIVES: There is a necessity to include objective methods to the study protocol of voice. Such procedure will help not only in diagnosing and monitoring the course of treatment, but also in comparing the results of studies between research centers. METHODS: Vocal fold mucosal wave characteristics of 70 healthy people were made using videostrobokymographic open quotient (VSKOQ) and electroglottographic quasi-open quotient (EGGQOQ). RESULTS: Statistically significant differences were achieved regarding gender for the averaged values of VSKOQ as well as for values calculated from the posterior part of the vocal folds. A statistically significant correlation between the value of VSKOQ and age was observed for the posterior part of the glottis. Differences between gender and the value of EGGQOQ were observed. No statistically significant correlation between EGGQOQ and age was obtained. CONCLUSIONS: VSKOQ and EGGQOQ are parameters characterizing glottal function in a coherent manner. These parameters can be included easily in phoniatric examination and help to objectify glottal function. PMID- 27765434 TI - The contribution of dermoscopy to early excision of basal cell carcinoma: A study on the tumor sizes acquired between 1998 and 2013 at a university hospital in Japan. PMID- 27765433 TI - Residential, soil and water radon surveys in north-western part of Romania. AB - The exposure to radon and radon decay products in homes and at workplaces represents the greatest risk from natural ionizing radiation. The present study brings forward the residential, soil and water radon surveys in 5 counties of Romania. Indoor radon measurements were performed by using CR-39 track detectors exposed for 3 months on ground-floor level of dwellings, according to the NRPB Measurements Protocol. Radon concentrations in soil and water were measured using the LUK3C device. The indoor radon concentrations ranged from 5 to 2592 Bq?m-3 with an updated preliminary arithmetic mean of 133 Bq?m-3, and a geometric mean of 90 Bq?m-3. In about 6% of the investigated grid cells the indoor radon concentrations exceed the threshold of 300 Bq?m-3. The soil gas radon concentration varies from 0.8 to 169 kBq?m-3, with a geometric mean of 28.4 kBq?m 3. For water samples, the results show radon concentrations within the range of 0.3-352 kBq?m-3 with a geometric mean of 7.7 Bq?L-1. The indoor radon map was plotted on a reference grid developed by JRC with the resolution 10 * 10 km2. PMID- 27765435 TI - Alopecia areata: What's new in epidemiology, pathogenesis, diagnosis, and therapeutic options? AB - Alopecia areata (AA) is a common and stressful disorder that results in hair loss, and resistant to treatment in some cases. Experimental and clinical evidence suggests that AA is caused by autoimmune attack against the hair follicles. The precise pathomechanism, however, remains unknown. Here, we focus on the recent progress in multidisciplinary approaches to the epidemiology, pathogenesis, and new treatments of AA in 996 publications from January 2010 to July 2016, and provide an overview of the current understanding in clinical management and research directions. PMID- 27765436 TI - Calcific Tendonitis of the Longus Colli: An Uncommon but Benign Cause of Throat Pain that Closely Mimics Retropharyngeal Abscess. PMID- 27765437 TI - Pyogenic Liver Abscess: A Retrospective Study of 105 Cases in an Emergency Department from East China. AB - BACKGROUND: Pyogenic liver abscesses have become common in emergency departments (EDs) in recent years in Shanghai, China due to a variety of risk factors contributory to the disease. OBJECTIVE: To review our experience in managing pyogenic liver abscesses to aid in the current management of this complex condition. METHODS: This retrospective study was conducted to collect and analyze information from adult patients diagnosed with liver hepatic abscesses who were admitted to Ren Ji Hospital during the period from January 1, 2010 to December 31, 2015. The demographic data, etiology, underlying diseases, clinical presentation, imaging features, laboratory examinations, microbiological tests, treatment, and clinical outcomes were analyzed. RESULTS: The data of a total 105 patients were retrospectively analyzed. The mean age of the patients was 62.0 +/- 13.5 years. The etiology was predominantly hepatobiliary disease (43/105, 40.1%) or diabetes mellitus (42/105, 40.0%). During hospitalization, 12 patients (11.4%) with septic shock required intensive care. One patient died, yielding a 0.9% fatality rate. In addition to empiric antimicrobial therapy, 66/105 (62.9%) patients underwent ultrasound-guided percutaneous drainage of the liver abscess at diagnosis. Only 3 patients required surgical intervention. Bacterial culture of pyogenic fluids revealed 25 positive results of 66 cases (37.9%). Among them, Klebsiella pneumoniae was the primary pathogen detected in 15 cases (60.0%). CONCLUSIONS: Pyogenic liver abscesses have become common in EDs in Shanghai, China. The early recognition of the disease, prompt use of empirical antimicrobial therapy, initiation of drainage in the appropriate patients, and controlling the underlying conditions were crucial for preventing severe sepsis and improving the outcome. PMID- 27765438 TI - Power Injection Through Ultrasound-Guided Intravenous Lines: Safety and Efficacy Under an Institutional Protocol. AB - BACKGROUND: After an index case of contrast-associated compartment syndrome, an urban hospital instituted a protocol limiting high-speed injection to intravenous (IV) lines started proximal to the forearm and testing those lines before contrast injection. OBJECTIVE: In this article, we estimate the safety and efficacy of high-speed injection using this protocol in patients with IV lines inserted under ultrasound guidance. METHODS: In an ambispective study, we enrolled prospective cohorts of ED patients requiring high-speed radiographic contrast media injection (>=3.5 mL/sec) into two groups: those with IV lines placed under ultrasound guidance and those with IV lines placed using traditional inspection and palpation. We also performed a retrospective review involving those groups. In addition, we reviewed hospital records for all patients with compartment syndrome between January 2010 and December 2011. We calculated 95% confidence intervals using normal approximation or exact calculation. RESULTS: Between November 2013 and August 2014, the ED referred 32 patients to the Department of Radiology for computed tomography angiography involving high-speed contrast injection through ultrasound-guided IV lines. Of these, 25 of 32 (78%) had successful injection (7 failed in the Department of Radiology) vs. 26 of 27 (96%) with catheters inserted using traditional methods (risk difference 0.18 [95% confidence interval -0.01 to 0.38]). Based on retrospective records, we estimated 79 additional cases. We found no cases of compartment syndrome during either period, for an incidence estimate of 0 per 100 cases (95% confidence interval 0-3). CONCLUSION: A hospital policy for high-speed contrast injection through ultrasound-guided IV lines has a safe record. However, 22% of patients with ultrasound-guided IV lines were refused for CT. PMID- 27765439 TI - Might Interspecific Interactions between Pathogens Drive Host Evolution? The Case of Plasmodium Species and Duffy-Negativity in Human Populations. AB - Malarial infections have long been recognized as a driver of human evolution, as demonstrated by the influence of Plasmodium falciparum on sickle-cell anemia persistence. Duffy-negativity is another blood disorder thought to have been selected because it confers nearly complete resistance against Plasmodium vivax infection. Recent evidence suggests that the benefits of being Duffy-negative cannot be expected to play a strong selective pressure on humans, whereas its costs cannot be considered as negligible. Here, we suggest that the cross-talk between P. falciparum and P. vivax in coinfected children could represent the most parsimonious explanation of the frequency of Duffy-negativity. We discuss how this new hypothesis could be tested and call for a reconsideration of the evolution of the Duffy-negative group. PMID- 27765440 TI - Can Lymphatic Filariasis Be Eliminated by 2020? AB - Interventions against neglected tropical diseases (NTD), including lymphatic filariasis (LF), scaled up dramatically after the signing of the London Declaration (LD) in 2012. LF is targeted for elimination by 2020, but some countries are considered not on track to meet the 2020 target using the recommended preventive chemotherapy and morbidity management strategies. In this Opinion article we review the prospects for achieving LF elimination by 2020 in the light of the renewed global action against NTDs and the global efforts to achieve the sustainable development goals (SDGs) by 2030. We conclude that LF can be eliminated by 2020 using cross-sectoral and integrated approaches because of the compound effect of the other SDG activities related to poverty reduction and water and sanitation. PMID- 27765441 TI - Health conditions and role limitation in three European Regions: a public-health perspective. AB - OBJECTIVE: To describe the distribution of role limitation in the European population aged 18-64 years and to examine the contribution of health conditions to role limitation using a public-health approach. METHODS: Representative samples of the adult general population (n=13,666) aged 18-64 years from 10 European countries of the World Mental Health (WMH) Surveys Initiative, grouped into three regions: Central-Western, Southern and Central-Eastern. The Composite International Diagnostic Interview (CIDI 3.0) was used to assess six mental disorders and standard checklists for seven physical conditions. Days with full and with partial role limitation in the month previous to the interview were reported (WMH-WHODAS). Population Attributable Fraction (PAFs) of full and partial role limitation were estimated. RESULTS: Health conditions explained a large proportion of full role limitation (PAF=62.6%) and somewhat less of partial role limitation (46.6%). Chronic pain was the single condition that consistently contributed to explain both disability measures in all European Regions. Mental disorders were the most important contributors to full and partial role limitation in Central-Western and Southern Europe. In Central-Eastern Europe, where mental disorders were less prevalent, physical conditions, especially cardiovascular diseases, were the highest contributors to disability. CONCLUSION: The contribution of health conditions to role limitation in the three European regions studied is high. Mental disorders are associated with the largest impact in most of the regions. There is a need for mainstreaming disability in the public health agenda to reduce the role limitation associated with health conditions. The cross-regional differences found require further investigation. PMID- 27765443 TI - [Physical activity patterns during pregnancy in women in Aragon (Spain)]. PMID- 27765442 TI - [Liability for loss of chance in neurological conditions in the Spanish public healthcare system]. AB - OBJECTIVE: To analyse the sentences due to loss of chance that were passed by the Contentious-Administrative Court (i.e., in public medicine), in which both the origin of the disease to be treated and the damages were neurological. METHODS: We analysed the 90 sentences concerning neurological conditions that referred to the concept of loss of chance that were passed in Spain from 2003 (year of the first sentence) until May 2014. FINDINGS: Of the 90 sentences, 52 (57.8%) were passed due to diagnostic error and 30 (33.3%), due to inadequate treatment. 72 (80.0%) of the sentences were passed from 2009 onwards, which equates to more than a 300% increase with respect to the 18 (20.0%) issued in the first six years of the study (from 2003 to 2008). Most of the patients (66.7%) were men, and a 61.1% presented sequelae. Hypoxic-ischaemic encephalopathy (14.4%) and spinal cord disorders (14.4%) were the most common conditions to lead to sentencing. CONCLUSIONS: The litigant activity due to loss of chance in neurological disease in the Spanish public healthcare system has significantly increased in the last few years. The sentences were mainly passed because of diagnostic error or inadequate treatment. PMID- 27765444 TI - [Retinopathy associated with strokes at the Sylvanus Olympio Teaching Hospital in Lome, Togo]. PMID- 27765446 TI - [Ocular syphilis: 9 cases]. AB - Syphilis is a disease with ocular involvement may be opening and cover all ocular structures. The objective of the study was to retrospectively identify and describe all cases of ocular syphilis diagnosed in the ophthalmology department of Besancon University Hospital from March 2004 to April 2014. Between March 2004 and April 2014, we diagnosed and monitored 9 male patients (13 eyes) with ocular syphilis (1 interstitial keratitis, chorioretinitis associated with a 1 hyalite, 3 panuveites, 1 chorioretinitis after placoid, 3 bilateral papillary edema). Patients had a mean age of 52.6 years (32-77 years) at diagnosis and the inaugural symptoms were in 100% of cases decreased visual acuity. The follow-up period ranged from 1 month to 5 years. The curative treatment included intravenous antibiotics penicillin G for 3 weeks. All patients had an improvement in their AV (AV initial range "counting fingers" and 0.6 versus AV final between 0.5 and 1 in decimal scale). Syphilis is a disease currently on the rise. It must be systematically sought before any inflammatory disease of the eye or papilledema. PMID- 27765445 TI - [Pathological profiles of retinoblastoma in Senegal]. AB - OBJECTIVES: Describe the macroscopic and microscopic profiles of retinoblastoma (RB) in Senegal and correlate histological criteria with progression to establish severity factors. METHODOLOGY: We realized a retrospective study over 10 years (January 2005-December 2014). Only patients (n=67) who underwent histological analysis of the enucleation specimen (n=68) were followed until the end of the study. RESULTS: The tumor measured an average of 3.8cm (2/4.5). Endophytic tumor development was observed in 55 cases (80.8%), exophytic in 6 cases (8.9%) and mixed in 7 cases (10.3%). Retinal detachment was present in 13 cases (19.2%). The RB was well differentiated in 11 cases (16.2%), moderately differentiated in 31 cases (45.6%) and undifferentiated in 26 cases. Optic nerve (ON) invasion was present in 18 cases (26.5%). The tumor was extraretinal in 37 cases (54.4%). The anterior chamber was invaded in 6 cases (8.8%). The global survival at 2 years was 84% and 70% at 5 years. On multivariate analysis, well differentiated tumors and stage pT1 were associated with remission. Retrolaminar ON invasion, massive choroidal invasion and stage pT3 were risk factors for recurrence. Poor tumor differentiation, invasion of the ON resection margin, tumor invasion through the sclera, and stage pT4 were predictive of death. CONCLUSION: The pathologist is a principal actor in the management of RB because his account guide the post surgical management strategy. PMID- 27765447 TI - [Epidemiological and clinical aspects of tropical endemic limbo-conjunctivitis in students in Yaounde]. AB - INTRODUCTION: TELC, tropical endemic limbo-conjunctivitis, is a keratoconjunctivitis seen more frequently in dry intertropical settings than humid ones. We aim to determine the epidemiologic and clinical profile of this condition in a city with a humid equatorial climate. PATIENTS AND METHODS: During first third of 2014, we conducted a cross-sectional descriptive study in schools. Included were children aged 3-15 years who received parental consent. The selection was conducted in two steps. After an initial examination of children within the schools, the diagnosis was then confirmed by a complete ophthalmologic examination carried out in the hospital. For ethical clearance, the study received all necessary authorizations. The data were analyzed using the CSPro version 4.0 software in French and the comparison test used was chi2 with a confidence limit of 95 %. RESULTS: Out of 353 students examined, 129 were referred to the Yaounde central hospital, among which 82 (23.2 %) were confirmed with TELC. The median age of the children diagnosed with TELC was 8.24+0.6 years. Boys (57.3 %) were affected more than girls. The age range of 6-12 years (64.6 %) was the most represented. A recrudescence of the attacks was observed during the dry season (93 %) of cases. Dust (49 %) and sun exposure (43 %) were aggravating factors. CONCLUSION: The prevalence of TELC observed in school in this study is significant. PMID- 27765448 TI - Cyclic esotropia and impaired vision after strabismus surgery. PMID- 27765450 TI - [Post-traumatic hypotony maculopathy]. PMID- 27765449 TI - [Unusual association of trisomy 21 and Behcet disease]. PMID- 27765451 TI - [Glaucoma and mucopolysaccharidosis type I: Report of two children]. PMID- 27765452 TI - [Refractive changes after retinal detachment surgery: Retrospective study of 45 eyes]. PMID- 27765453 TI - [Strabismus and reading: Effect of strabismus on reading tests in children from 8 to 11 years]. AB - PURPOSE: We try to show a relationship between strabismus and changes in reading skills. MATERIAL AND METHODS: We have carried out a prospective study including 135 children from 8 to 11 years (French level CE2 to CM2). They were given an ophthalmologic and orthoptic examination and then divided into 4 groups: strabismus with vertical deviation without binocular vision, accommodative strabismus with binocular vision, accommodative strabismus without binocular vision and control group (children without strabismus). Each child took 4 validated reading tests: reading fluency, uncommon words reading, comparison of letters sequences without signification, searching "verbal index". RESULTS: Results are significantly lower in children with accommodative strabismus without binocular vision for two tests (reading fluency and uncommon words reading). In contrast, results for the two other tests do not differ significantly between the 4 groups. CONCLUSION: Our study demonstrated lowered reading skills in tests of reading fluency in children with accommodative strabismus without binocular vision. PMID- 27765454 TI - Identification and characterization of miRNAs transcriptome in the South African abalone, Haliotis midae. AB - Aquatic animal diseases are one of the most important limitations to the growth of aquaculture. miRNAs represent an important class of small ncRNAs able to modulate host immune and stress responses. In Mollusca, a large phylum of invertebrates, miRNAs have been identified in several species. The current preliminary study identified known miRNAs from the South African abalone, Haliotis midae. The economic and ecological importance of abalone makes this species a suitable model for studying and understanding stress response in marine gastropods. Furthermore, the identification of miRNA, represents an alternative and powerful tool to combat infectious disease. PMID- 27765455 TI - Evaluating the Effect of Comorbidities on the Success, Risk, and Cost of Digital Replantation. AB - PURPOSE: The clinical decision to replant an amputated digit is driven primarily by surgical indication. However, the extent to which patient comorbidity should play into this decision is less well defined. This study was designed to determine the effect of patient comorbidities on the success, risk, and cost of digital replantation. METHODS: All amputation injuries and digital replantation procedures captured by the National Inpatient Sample during 2001 to 2012 were identified. A successful replantation procedure was defined as one in which a replantation occurred without a subsequent revision amputation. Patient comorbidities were tested for association with failure of replantation, risk of postoperative complications, and overall hospital costs. RESULTS: We identified 11,788 digital replantation procedures. A total of 3,604 patients (30.6%) experienced revascularization failure associated with replantation. The risk for replant failure was highest among patients with psychotic disorders, peripheral vascular disease, and electrolyte imbalances. The risk for postoperative complications was highest among patients with electrolyte imbalances, drug abuse, or chronic obstructive pulmonary disease. Hospital costs were greatest among patients with deficiency anemias, electrolyte imbalances, or psychotic disorders. Patients with more than 3 comorbidities experienced significantly higher failure, risk of postoperative complications, and cost of digital replantation. CONCLUSIONS: These data suggest that even when surgical indications are met, patients with more than 3 comorbidities and those who have a history of alcohol abuse, deficiency anemias, electrolyte imbalances, obesity, peripheral vascular disease, or psychotic disorders are at increased risk of replantation failure and associated postoperative complications. Assessment of this risk should have a role in decision making regarding whether a digit should be replanted. Patients at high risk should be carefully counseled regarding the difficult perioperative course before undergoing digital replantation. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 27765456 TI - [Pneumococcal disease in adults: Risk levels and vaccine recommendations]. AB - There are currently two anti-pneumococcal vaccines available for use in adults: the classical 23-valent polysaccharide pneumococcal vaccine (PPV23) and the new 13-valent pneumococcal conjugate vaccine (PCV13). The main advantage of the PCV13 is the potentially better immunogenicity, with its major disadvantages being the higher cost and the lower serotype-coverage than the PPV23. The currently available scientific evidence supports the following basic recommendations: (i)among adults with greatest risk (basically asplenia and immunocompromised), a dual vaccination (PCV13+PPV23) is recommended; (ii)among adults with increased risk (basically persons >65years-old and patients 15-64years with chronic pulmonary or heart disease, diabetes and/or alcoholism), a single vaccination with PPV23 is recommended (single dose in primo-vaccinated >65years; re vaccination at 5-10years in those primo-vaccinated <65years-old); and (iii) in the rest of adults (risk normal/low) vaccination is not recommended. PMID- 27765457 TI - A machine learning tool for re-planning and adaptive RT: A multicenter cohort investigation. AB - PURPOSE: To predict patients who would benefit from adaptive radiotherapy (ART) and re-planning intervention based on machine learning from anatomical and dosimetric variations in a retrospective dataset. MATERIALS AND METHODS: 90 patients (pts) treated for head-neck cancer (H&N) formed a multicenter data-set. 41 H&N pts (45.6%) were considered for learning; 49 pts (54.4%) were used to test the tool. A homemade machine-learning classifier was developed to analyze volume and dose variations of parotid glands (PG). Using deformable image registration (DIR) and GPU, patients' conditions were analyzed automatically. Support Vector Machines (SVM) was used for time-series evaluation. "Inadequate" class identified patients that might benefit from replanning. Double-blind evaluation by two radiation oncologists (ROs) was carried out to validate day/week selected for re planning by the classifier. RESULTS: The cohort was affected by PG mean reduction of 23.7+/-8.8%. During the first 3weeks, 86.7% cases show PG deformation aligned with predefined tolerance, thus not requiring re-planning. From 4th week, an increased number of pts would potentially benefit from re-planning: a mean of 58% of cases, with an inter-center variability of 8.3%, showed "inadequate" conditions. 11% of cases showed "bias" due to DIR and script failure; 6% showed "warning" output due to potential positioning issues. Comparing re-planning suggested by tool with recommended by ROs, the 4th week seems the most favorable time in 70% cases. CONCLUSIONS: SVM and decision-making tool was applied to overcome ART challenges. Pts would benefit from ART and ideal time for re planning intervention was identified in this retrospective analysis. PMID- 27765458 TI - Initial and accidental reactions are managed inadequately in children with sesame allergy. PMID- 27765459 TI - Carboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation. PMID- 27765460 TI - Allergy profile should be updated after uneventful administration of a penicillin or penicillin-related antibiotic to a patient with penicillin allergy. PMID- 27765462 TI - Respiratory allergy buzz on the Internet. PMID- 27765461 TI - Anaphylaxis Conundrum: A Trojan Horse Phenomenon. AB - Anaphylaxis is a serious and potentially life-threatening allergic reaction that may follow the ingestion of foods. Although these reactions usually follow a common clinical pattern and often demonstrate IgE sensitization to the antigen in question, both the clinical presentation and causative allergen may be atypical, surprising, and difficult to identify. Failure to identify the actual cause of the reaction can compromise treatment and complicate long-term care. Here, we present a patient who had symptoms of anaphylaxis after eating salmon, but confirmation of the causative allergen was not readily apparent. This particular case serves as an insightful lesson for patients undergoing evaluation for anaphylaxis and also provides a framework for navigating through a case involving identification of an underlying allergen. PMID- 27765463 TI - Age-specific incidence of new asthma diagnoses in Finland. PMID- 27765464 TI - Cigarette smoking represses expression of cytokine IL-12 and its regulator miR-21 An observational study in patients with coronary artery disease. AB - RATIONALE: The heterodimer IL-12 is an inducer of Th1 responses and stimulates INFy production. Micro-RNA-21 (miR-21) is described as a key regulator of the pro inflammatory response and has IL-12p35 mRNA as one of its main targets. The IL 12p40 1188A/C genetic variant located in 3'untranslated region (UTR), thus environmentally exposed, has further been reported to modify IL-12 levels. We have previously reported on the lowering effect of cigarette smoke on circulating IL-12 in patients with coronary artery disease (CAD). OBJECTIVES: To explore if cigarette smoking affects IL-12p35, IL-12p40, INFy and miR-21 gene-expression and further modulates any effect of the IL-12p40 polymorphism on circulating IL-12 levels. METHODS AND RESULTS: The IL-12p40 1188A/C polymorphism was analyzed in 1001 stable CAD patients, of which 330 subjects were included for IL-12p35, IL 12p40 and INFy gene-expression analyses in circulating leukocytes and 200 were further selected for plasma miR-21 analysis. Smoking associated with lower expression of miR-21 and its target IL-12p35 mRNA (adjusted p<0.05, both) whereas the influence on INFy expression tended to be high-dose reliant (p = 0.057). The IL-12p40 CC genotype associated with elevated circulating IL-12 levels, however, when stratified according to smoking, only in the non-smoking group (adjusted p < 0.05). Although the markers were mainly downregulated in current smokers, their inter-correlations were potentiated. CONCLUSION: Smoking associated with reduced miR-21 gene-repression and the results can therefore not explain the previously observed reduction in circulating IL-12. Smoking attenuated the IL-12 pro inflammatory axis in which the investigated IL-12p40 genetic variant may have different clinical impact in smokers vs non-smokers. PMID- 27765465 TI - [Do STOP-IgAN results mean STOP-steroids in IgA nephropathy?] PMID- 27765466 TI - [Wasting in chronic kidney disease: Refeeding techniques and artificial nutrition practices]. AB - Protein energy wasting (PEW) is an independent factor associated with morbi mortality in chronic kidney disease. Wasting is particularly common in chronic diseases of organs such as kidney disease with a major impact at the stage of dialysis. It covers 20 to 70% of patients diagnosed with chronic kidney disease according to the degree of evolution of the disease and the diagnostic method used patients. Mechanisms of PEW are based mainly on anorexia and metabolic abnormalities caused by kidney disease. Nutritional treatment differs depending on the stage of the kidney disease acute or chronic treated whether or not by dialysis. Nutritional monitoring should be regular, individualized and collaborative to detect a risk of PEW or treat installed PEW. Refeeding techniques should allow all the nutritional needs. Their indications depend on the clinic, biochemical assessment and nutrient intake. PMID- 27765468 TI - Memory consolidation in sleep disorders. AB - In recent years sleep-related memory consolidation has become a central topic in the sleep research field. Several studies have shown that in healthy individuals sleep promotes memory consolidation. Notwithstanding this, the consequences of sleep disorders on offline memory consolidation remain poorly investigated. Research studies indicate that patients with insomnia, obstructive sleep apnea, and narcolepsy often exhibit sleep-related impairment in the consolidation of declarative and procedural information. On the other hand, patients with parasomnias, such as sleep-walking, night terrors and rapid eye movement (REM) behavior disorder, do not present any memory impairment. These studies suggest that only sleep disorders characterized by increased post-learning arousal and disrupted sleep architecture seem to be associated with offline memory consolidation issues. Such impairments, arising already in childhood, may potentially affect the development and maintenance of an individual's cognitive abilities, reducing their quality of life and increasing the risk of accidents. However, promising findings suggest that successfully treating sleep symptoms can result in the restoration of memory functions and marked reduction of direct and indirect societal costs of sleep disorders. PMID- 27765469 TI - Patellar dislocation: Not the bees knees. AB - BACKGROUND: Patellar dislocations are common, particularly in the adolescent polulation. Registered Advanced Nurse Practitioners are healthcare professionals who can appropriately manage these injuries to minimise the risk of chronicity. METHODS: This is a case study which uses a clinical examplar from the authors practice focusing on the assessment, diagnosis and managment of patellar dislocations. Particular reference is made of the significance of the MPFL. RESULTS: This paper highlights the importance of recognition of appropriate management of patellar dislocations in the ED setting. Discussion points include the role of the MDT and the role of exercise prescription in the injury management. CONCLUSION: The diagnosis of patellar dislocation is heavily dependant on eliciting a comprehensive history and conducting an appropriate clinical exam. Patient outcomes may be optimised by adopting an MDT approach. PMID- 27765467 TI - Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking. AB - Cocaine self-administration induces dysfunctional neuroadaptations in the prefrontal cortex that underlie relapse to cocaine-seeking. Cocaine self administration disturbs glutamatergic transmission in the nucleus accumbens that is prevented by infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic area of the prefrontal cortex. Intra-prelimbic infusion of BDNF decreases cocaine-seeking in a TrkB-ERK MAP kinase-dependent manner. Neuronal activity triggers an interaction between TrkB receptors and NMDA receptors, leading to ERK activation. In the present study, infusion of the GluN2A containing NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the prelimbic cortex of rats blocked the suppressive effect of BDNF on cocaine-seeking. During early withdrawal from cocaine self-administration, tyrosine phosphorylation of ERK, GluN2A, and GluN2B in the prelimbic cortex was reduced and this reduction of phospho-proteins was prevented by intra-prelimbic BDNF infusion. TCN-201 infusion into the prelimbic cortex inhibited the BDNF-mediated increase in pERK and pGluN2A whereas Ro-25 6981 infusion into the prelimbic cortex blocked BDNF-induced elevation of pERK and pGluN2B, indicating that both GluN2A- and GluN2B-containing NMDA receptors underlie BDNF-induced ERK activation. These data demonstrate that BDNF-mediated activation of GluN2A- and GluN2B-containing NMDA receptors underlies ERK activation in the prelimbic cortex during early withdrawal, preventing subsequent relapse to cocaine-seeking. PMID- 27765471 TI - Cerebral Proliferative Angiopathy. PMID- 27765470 TI - Implementation of the Hammersmith Infant Neurological Examination in a High-Risk Infant Follow-Up Program. AB - BACKGROUND: High-risk infant follow-up programs provide early identification and referral for treatment of neurodevelopmental delays and impairments. In these programs, a standardized neurological examination is a critical component of evaluation for clinical and research purposes. METHODS: To address primary challenges of provider educational diversity and standardized documentation, we designed an approach to training and implementation of the Hammersmith Infant Neurological Examination with precourse materials, a workshop model, and adaptation of the electronic medical record. CONCLUSIONS: Provider completion and documentation of a neurological examination were evaluated before and after Hammersmith Infant Neurological Examination training. Standardized training and implementation of the Hammersmith Infant Neurological Examination in a large high risk infant follow-up is feasible and effective and allows for quantitative evaluation of neurological findings and developmental trajectories. PMID- 27765472 TI - Treatment of post-traumatic elbow deformities in children with the Ilizarov distraction osteogenesis technique. AB - OBJECTIVE: The present study assessed functional and radiographic outcomes of distraction osteogenesis treatment of post-traumatic elbow deformities in children. METHODS: Eight children were treated between 2008 and 2013 for post traumatic elbow deformities using distraction osteogenesis. Mean age at time of operation was 10.9 years. Six patients had varus and 2 had valgus deformity. Magnitude of correction, fixator index, complications, carrying angle, and elbow range of motion were assessed. Functional results were graded according to protocol of Bellemore et al. RESULTS: Mean follow-up was 43 months. Mean preoperative varus deformity in 6 patients was 29.2 degrees and valgus deformity in 2 patients was 28.5 degrees . Preoperative flexion and extension of elbow were 123.8 degrees and -10.6 degrees , respectively. Mean carrying angle was 9 degrees valgus at last follow-up. Mean flexion and extension were 134.4 degrees and -6.0 degrees , respectively. Change in carrying angle was statistically significant (p = 0.002). There were 2 grade 1 pin tract infections and 1 diaphyseal fracture of humerus. Functional outcome was rated excellent in 7 patients and good in 1 patient. CONCLUSION: Ilizarov distraction osteogenesis is a valuable alternative in treatment of elbow deformities in children. The surgical technique is simple and correction is adjustable. Gradual correction prevents possible neurovascular complications and minimally invasive surgery produces less scarring. Compliance of patient and family is key factor in the success of the outcome. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 27765473 TI - Utility of a Validated Rating Scale for Self-Assessment in Microsurgical Training. AB - OBJECTIVE: The purpose of this study is to determine the utility of self assessment in microsurgical training using a previously validated rating scale. DESIGN: A prospective study of surgical residents taking a hands-on 5-day microsurgical training course. Learners completed multiple self-assessments of their technical skills using the University of Western Ontario Microsurgical Acquisition/Assessment instrument. Simultaneously, preceptors assessed the learners using the same scale. Self-assessment and preceptor scores were compared using the Pearson correlation coefficient (PCC). RESULTS: There was a significant agreement noted between the 32 preceptor assessments and 36 self-assessments that were completed. Correlation between scores for the knot-tying (PCC = 0.62) and anastomosis modules (PCC = 0.77) was good and excellent, respectively. Preceptor scores and self-scores improved over the duration of the course: for preceptors, knot-tying scores increased from 58% on day 1 to 78% on day 5 (p = 0.02) and anastomosis scores improved from 56% to 82% (p = 0.004); for self-scores, knot tying scores increased from 44% to 81% (p = 0.001) and anastomosis scores from 49% to 84% (p = 0.001). Learners with greater experience (higher postgraduate year level) tended to have higher self as well as preceptor ratings, albeit not statistically significant. CONCLUSION: Self-assessment using the University of Western Ontario Microsurgical Acquisition/Assessment instrument has good to excellent agreement with preceptor-assessment scores suggesting good interrater reliability. Self-assessment using such tools may, therefore, be used along with preceptor supervision and assessment to potentially improve self-directed learning during these courses. PMID- 27765474 TI - Amoxicillin-clavulanic acid prescriptions at the Greater Paris University Hospitals (AP-HP). AB - OBJECTIVE: We aimed to document amoxicillin-clavulanic acid prescription to improve the proper use of antibiotics in hospital settings. We used three criteria: quality of medical charts, adequacy of indications, and adequacy of treatment duration. METHOD: This study was designed as a one-day point prevalence survey carried out by antibiotic lead specialists. RESULTS: We included 387 prescriptions from 32 hospitals. Immunodeficiency was recorded as a risk factor in 30% of patients. Computerized prescriptions were observed in 79% of cases. The indication was mentioned in 73% of cases and a 48/78-hour re-assessment of the antibiotic therapy was performed in 54% of cases. The antibiotic indication was primarily for pneumonia and was deemed appropriate in 75% of patients. Adult mean treatment duration was 11.1 days. Use of dual combination therapy and/or treatment duration exceeding two weeks accounted for the main reasons for an inappropriate use of antibiotics. Prescriptions recorded as having been made by senior physicians were of the shortest treatment duration (P=0.0163). CONCLUSION: Medical charts should be better filled in. Reinforcing the role of senior physicians in supervising antibiotic prescriptions is likely to result in a better control of treatment duration and ultimately in a reduced antibiotic consumption. By reinforcing the collaboration between pharmacists and antibiotic lead specialists, the improvement of computerized prescriptions at hospital level should help better detect the "at risk" prescriptions, namely those exceeding seven days or those combining antibiotics. PMID- 27765475 TI - Characteristics of HPV infection in women at risk in Western Algeria. AB - OBJECTIVES: We aimed to characterize HPV infections and cervical lesions in Western Algeria. PATIENTS AND METHODS: A total of 96 cervical samples obtained from women at risk of HPV infection (HIV-1-infected or presenting with a gynecological disease) were analyzed to characterize this infection and search for cytological abnormalities. RESULTS: A total of 60% of women at risk had an HPV infection. The rate of high-risk HPV (HR-HPV) infection among these women was 84.5% and that of intraepithelial lesions was 29.3%. The frequency of HPV infection was significantly higher among HIV-1-infected patients. An association between the presence of HR-HPV and the polygamy of the partner was observed. An association between cytological abnormalities and the use of oral contraceptives was observed among HIV-1-infected women. CONCLUSION: Given the high frequency of HPV infection in this at risk population, close monitoring and regular gynecological screening are essential. PMID- 27765476 TI - Lactobacillus bacteremia: Pathogen or prognostic marker? AB - OBJECTIVE: Lactobacillus bacteremia is a rare event and its epidemiology is poorly known. Whether Lactobacillus bacteremia is a contaminant, a risk factor, or a risk marker of death remains an open question. PATIENTS AND METHODS: We conducted a retrospective study of patients presenting with Lactobacillus bacteremia (LB), between January 2005 and December 2014, at the Grenoble University Hospital. RESULTS: LB was observed in 38 patients (0.34% of all positive blood cultures). Cancer (40%), immunosuppression (37%), and use of central venous devices (29%) were frequently associated with LB. We observed a significant increase with time in the number of Lactobacillus positive blood cultures among all blood cultures performed (P=0.04). LBs were divided into two clinical-biological presentations: secondary bacteremia with a known portal of entry (n=30) and isolated bacteremia (n=8). Case fatality was 31% at D28, 55.2% at 1 year in the secondary bacteremia group, and 12.5% (both at D28 and 1 year) in the isolated bacteremia group. Secondary bacteremia with a known portal of entry was significantly associated with case fatality after adjustment for age, co-infection, cancer, immunosuppression, diabetes, and sex (OR 14.9 [1.04-216] P=0.047) for fatality at one year, but not for D28 fatality (P=0.14). CONCLUSION: Lactobacillus bacteremia may be an important marker of disease severity rather than a pathogen, suggesting comorbidities. It should not be considered a contaminant, but should lead physicians to screen for associated infections and underlying diseases. PMID- 27765477 TI - Haemophilus parainfluenzae endocarditis in young adults. PMID- 27765478 TI - Mitral valve aneurysm: A serious complication of aortic valve endocarditis. AB - Mitral valve aneurysms are rare and occur most commonly in association with aortic valve endocarditis. Transesophageal echocardiography is the most sensitive imaging modality for the diagnosis of this entity and its potential complications, such as leaflet rupture and mitral regurgitation, which mandate prompt surgical intervention. We present the case of a 70-year-old male patient with aortic valve endocarditis complicated with a ruptured aneurysm of the anterior mitral valve leaflet and associated severe mitral regurgitation, diagnosed by transesophageal echocardiography, with impressive images. We hypothesized that the aneurysm developed through direct extension of infection from the aortic valve or from a prolapsing aortic vegetation, with abscess formation and subsequent rupture and drainage. This case highlights the importance of appropriate imaging for early detection and timely surgical intervention (repair or replacement) to prevent fatal outcomes. PMID- 27765479 TI - Etiologies and delirium rates of elderly ED patients with acutely altered mental status: a multicenter prospective study. AB - OBJECTIVES: Altered mental status (AMS) is a challenging diagnosis in older patients and has a large range of etiologies. The aim of this study was to investigate the nature of such etiologies for physicians to be better aware of AMS backgrounds and hence improve outcomes and mortality rates. METHODS: This prospective observational study was conducted at 4 emergency departments. Patients 65 years and older who presented to the emergency department with acute AMS (<=1 week), with symptoms ranging from comas and combativeness, were eligible for inclusion in this study. The outcomes, etiologies, Richmond Agitation and Sedation Scale scores, and the presence of delirium were recorded. RESULTS: Among 822 older patients with AMS, infection (39.5%) and neurological diseases (36.5%) were the most common etiologies. The hospital admission and mortality rates were 73.7% (n = 606) and 24.7% (n = 203), respectively. The mortality rate rose if AMS persisted for more than 3 days. Delirium was observed in 55.7% of the patients; these individuals had higher durations of AMS than those without delirium (median, 24 hours; interquartile range, 3-48 hours; median 6 hours, interquartile range, 3-48 hours, respectively; P = .010). Notably, delirium was observed in more than two-thirds of neurological patients. CONCLUSIONS: The most common causes of AMS were infection and neurological diseases. Delirium was associated with AMS in nearly half the patients. Moreover, the rates of hospitalization and mortality remained high. PMID- 27765480 TI - Avoiding disaster in the management of dislocated hip hemiarthroplasties: case presentation, diagnosis, and management. PMID- 27765482 TI - Bacteremia in nonneutropenic pediatric oncology patients with central venous catheters in the ED. AB - OBJECTIVE: To examine clinical characteristics associated with bacteremia in febrile nonneutropenic pediatric oncology patients with central venous catheters (CVCs) in the emergency department (ED). BACKGROUND: Fever is the primary reason pediatric oncology patients present to the ED. The literature states that 0.9% to 39% of febrile nonneutropenic oncology patients are bacteremic, yet few studies have investigated infectious risk factors in this population. METHODS: This was a retrospective cohort study in a pediatric ED, reviewing medical records from 2002 to 2014. Inclusion criteria were patients with cancer, temperature at least 38 degrees C, presence of a CVC, absolute neutrophil count greater than 500 cells/MUL, and age less than 22 years. Exclusion criteria were repeat ED visits within 72 hours, bloodwork results not reported by the laboratory, and patients without oncologic history documented at the study hospital. The primary outcome measure is a positive blood culture (+BC). Other variables include age, sex, CVC type, cancer diagnosis, absolute neutrophil count, vital signs, upper respiratory infection (URI) symptoms, and amount of intravenous (IV) normal saline (NS) administered in the ED. Data were analyzed using descriptive statistics and a multiple logistic regression model. RESULTS: A total of 1322 ED visits were sampled, with 534 enrolled, and 39 visits had +BC (7.3%). Variables associated with an increased risk of +BC included the following: absence of URI symptoms (odds ratio [OR], 2.30; 95% CI, 1.13-4.69), neuroblastoma (OR, 3.65; 95% CI, 1.47 9.09), "other" cancer diagnosis (OR, 4.56; 95% CI, 1.93-10.76), tunneled externalized CVC (OR, 5.04; 95% CI, 2.25-11.28), and receiving at least 20 mL/kg IV NS (OR, 2.34; 95% CI, 1.2-4.55). The results of a multiple logistic regression model also showed these variables to be associated with +BC. CONCLUSION: The absence of URI symptoms, presence of an externalized CVC, neuroblastoma or other cancer diagnosis, and receiving at least 20 mL/kg IV NS in the ED are associated with increased risk of bacteremia in nonneutropenic pediatric oncology patients with a CVC. PMID- 27765481 TI - Cost analysis of the History, ECG, Age, Risk factors, and initial Troponin (HEART) Pathway randomized control trial. AB - INTRODUCTION: The HEART Pathway is a diagnostic protocol designed to identify low risk patients presenting to the emergency department with chest pain that are safe for early discharge. This protocol has been shown to significantly decrease health care resource utilization compared with usual care. However, the impact of the HEART Pathway on the cost of care has yet to be reported. METHODS AND RESULTS: We performed a cost analysis of patients enrolled in the HEART Pathway trial, which randomized participants to either usual care or the HEART Pathway protocol. For low-risk patients, the HEART Pathway recommended early discharge from the emergency department without further testing. We compared index visit cost, cost at 30 days, and cardiac-related health care cost at 30 days between the 2 treatment arms. Costs for each patient included facility and professional costs. Cost at 30 days included total inpatient and outpatient costs, including the index encounter, regardless of etiology. Cardiac-related health care cost at 30 days included the index encounter and costs adjudicated to be cardiac-related within that period. Two hundred seventy of the 282 patients enrolled in the trial had cost data available for analysis. There was a significant reduction in cost for the HEART Pathway group at 30 days (median cost savings of $216 per individual), which was most evident in low-risk (Thrombolysis In Myocardial Infarction score of 0-1) patients (median savings of $253 per patient) and driven primarily by lower cardiac diagnostic costs in the HEART Pathway group. CONCLUSIONS: Using the HEART Pathway as a decision aid for patients with undifferentiated chest pain resulted in significant cost savings. PMID- 27765483 TI - Endovascular treatment of TransAtlantic Inter-Society Consensus D aortoiliac occlusive disease using unibody bifurcated endografts. AB - OBJECTIVE: Aortobifemoral bypass has been the gold standard treatment for extensive aortoiliac occlusive disease. Endovascular therapy and stenting of aortic and iliac occlusive lesions has proven to be efficacious, especially when dealing with short segment lesions. Endovascular treatment of TransAtlantic Inter Society Consensus II (TASC) D aortoiliac occlusive lesions remains a challenge, but a valuable treatment option in poor surgical candidates. We present our operative technique and midterm results in treating TASC D aortoiliac occlusive disease using unibody bifurcated endografts. METHODS: We performed a retrospective review of patients with TASC D aortoiliac occlusive disease who underwent transfemoral endovascular revascularization with the Endologix Powerlink unibody bifurcated endograft (Endologix, Irvine, Calif). Demographic data, operative details, and outcomes were collected. Paired t-tests were performed to compare preoperative and postoperative ankle brachial indexes. RESULTS: Between March 2009 and July 2011, 10 high-risk patients (8 male and 2 female) for a traditional aortobifemoral bypass were treated using this endovascular technique. The mean age was 59 +/- 6 years (range, 50-69 years). All patients presented with rest pain, and four with tissue loss. Technical success was 100%, with two patients requiring brachial access and eight patients requiring additional stent placement. Postoperatively, all patients reported clinical improvement with resolution of ischemic symptoms. Mean improvement ankle brachial index was 0.50 +/- 0.08 (P = .028) and 0.50 +/- 0.01 (P = .034) in the left and right legs, respectively. Mean follow-up time was 40 +/- 24 months (range, 4-81 months). The primary and secondary patency rates were 80% and 100%, respectively. Complications requiring early reintervention occurred in two patients and included one expanding hematoma from the percutaneous access site and one acute iliac artery thrombosis. Additionally, one patient underwent repeat angioplasty/stenting for threatened endograft limbs at 4 months. One patient expired during follow-up from an unrelated cardiac cause 19 weeks postoperatively. CONCLUSIONS: This series demonstrates that endovascular repair using a unibody bifurcated endograft for TASC D aortoiliac occlusive disease is feasible, effective, and has excellent midterm patency. It should be considered an effective treatment option when the disease process involves the aorta, in particular if the patient is surgically unfit for a traditional aortobifemoral bypass. The unibody configuration preserves the anatomic aortic bifurcation, which is particularly important in patients with peripheral occlusive disease who are deemed to undergo subsequent endovascular interventions. PMID- 27765485 TI - Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps. AB - The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health. The efficiency of antimicrobial treatment is determined by both pharmacokinetics and pharmacodynamics. In spite of their selective toxicity, antibiotics still cause severe, life-threatening adverse reactions in host body mostly due to defective drug metabolism or excessive dosing regimen. The present article aims at updating current knowledge on pharmacokinetics/pharmacodynamics concepts and models, toxicity of antibiotics as well as antibiotic resistance mechanisms, resistome analyses and search for novel antibiotic resistance determinants with special emphasis given to the-state-of-the-art regarding multidrug efflux pumps and their additional physiological functions in stress adaptation and virulence of bacteria. All these issues are highly linked to each other and not only important for most efficient and prolonged use of current antibiotics, but also for discovery and development of new antibiotics and novel inhibitors of antibiotic resistance determinants of pathogens. PMID- 27765486 TI - Tauroursodeoxycholic acid improves pre-implantation development of porcine SCNT embryo by endoplasmic reticulum stress inhibition. AB - The aim of this study is to investigate whether endoplasmic reticulum (ER) stress attenuation could improve porcine somatic cell nuclear transfer (SCNT) embryo developmental competence. We treated porcine SCNT embryos with TUDCA (tauroursodeoxycholic acid, an inhibitor of ER stress) and/or TM (tunicamycin, an ER stress inducer), and examined embryonic developmental potential, embryo quality, the levels of ER stress markers (XBP1 protein and mRNA) and apoptosis related-genes (BAX and BCL2 mRNA). Immunostaining detected X-box-binding protein (XBP1), a key gene regulator during ER stress, at all stages of SCNT embryo development. Embryo development analysis revealed that TUDCA treatment markedly increased (p<0.05) blastocyst formation rate, total cell number and inner cell mass (ICM) cell number compared to untreated control group. The TUDCA and TM groups showed significant alterations in XBP1 protein and XBP1-s mRNA levels compared to controls (lower and higher, respectively; p<0.05). Also, TUDCA treatment reduced oxidative stress by up-regulation of the antioxidant, GSH. TUNEL assay showed that TUDCA treatment significantly reduced apoptosis in porcine SCNT blastocysts confirmed by decreased pro-apoptotic BAX and increased anti-apoptotic BCL2 mRNA levels. Collectively, our results indicated that TUDCA can enhance the developmental potential of porcine SCNT embryos by attenuating ER stress and reducing apoptosis. PMID- 27765487 TI - Simultaneous removing of Pb2+ ions and alizarin red S dye after their complexation by ultrasonic waves coupled adsorption process: Spectrophotometry detection and optimization study. AB - Funthenalized chitosan (CS) was composited with mesoprous SBA-15 and characterized via. different techniques such as FT-IR and FE-SEM. Subsequently, this new material was applied for simulations ultrasound-assisted adsorption of Pb2+ ion and alizarin red S (ARS) dye after their complexation. Efficient conventional variables in adsorption process such as initial ARS and Pb2+ concentration, adsorbent mass and sonication time were studied by small central composite design (CCD) and optimized with desirability function approach. Lack of fit testes and model summary statistics for linear, 2FI, quadratic and cubic models were investigated and according to the insignificant lack of fit and maximizing the R-squared (R2), adjusted R-squared and the predicted R-squared quadratic model was selected for other step analysis for removal of ARS dye, while, for Pb2+ ions 2FI model was selected as best model. Quadratic model ANOVA for ARS dye removal shows the F-value parameter (683.91), very low p-value model (<0.0001) and p-value lack of fit (0.0568) that implied this model was highly significant. Also, 2FI model ANOVA for Pb2+ ions removal shows the F-value parameter (282.51), very low p-value model (<0.0001) and p-value lack of fit (2.05). According to desirability function approach maximum removal percentage of ARS (87.61%) and Pb2+ ions (83.54%) was shown at optimum of condition that were set as at: 25 and 25mgL-1, 0.028g and 11.8min for initial ARS and Pb2+ ions concentration, adsorbent mass and sonication time, respectively. Finally, it was found that the equilibrium and kinetic of adsorption process follow the Langmuir isotherm and pseudo-second-order kinetic model, respectively. From the Langmuir isotherm, maximum monolayer capacity (qmax) was obtained 50.25 and 57.14mgg-1 for ARS and Pb2+ ions removal, respectively. PMID- 27765484 TI - Sequencing and comparative analyses of Aegilops tauschii chromosome arm 3DS reveal rapid evolution of Triticeae genomes. AB - Bread wheat (Triticum aestivum, AABBDD) is an allohexaploid species derived from two rounds of interspecific hybridizations. A high-quality genome sequence assembly of diploid Aegilops tauschii, the donor of the wheat D genome, will provide a useful platform to study polyploid wheat evolution. A combined approach of BAC pooling and next-generation sequencing technology was employed to sequence the minimum tiling path (MTP) of 3176 BAC clones from the short arm of Ae. tauschii chromosome 3 (At3DS). The final assembly of 135 super-scaffolds with an N50 of 4.2 Mb was used to build a 247-Mb pseudomolecule with a total of 2222 predicted protein-coding genes. Compared with the orthologous regions of rice, Brachypodium, and sorghum, At3DS contains 38.67% more genes. In comparison to At3DS, the short arm sequence of wheat chromosome 3B (Ta3BS) is 95-Mb large in size, which is primarily due to the expansion of the non-centromeric region, suggesting that transposable element (TE) bursts in Ta3B likely occurred there. Also, the size increase is accompanied by a proportional increase in gene number in Ta3BS. We found that in the sequence of short arm of wheat chromosome 3D (Ta3DS), there was only less than 0.27% gene loss compared to At3DS. Our study reveals divergent evolution of grass genomes and provides new insights into sequence changes in the polyploid wheat genome. PMID- 27765488 TI - The leaching kinetics of K-feldspar in sulfuric acid with the aid of ultrasound. AB - The leaching kinetics of K-feldspar in H2SO4-CaF2 system with the assistant of ultrasound was investigated. The effects of various factors, such as sulfuric acid concentration, liquid-to-solid ratio, CaF2 dosage and leaching temperature were comprehensively studied. The dissolution fraction of potassium can reach more than 83% under the optimum operation conditions with ultrasound. Because of the cavitation effect, the intensified effect with ultrasound has more obvious at lower temperature than higher temperature. The leaching kinetics of K-feldspar with and without ultrasound was successfully modeled by a classic shrinking core model with the product layer diffusion as the rate-controlling step. The activation energies over the temperature range from 60 to 90 degrees C with and without ultrasound were found to be 55.67kJmol-1 and 72.33kJmol-1, respectively. It was found that the rate constant increases greatly in the presence of ultrasound due to the decreased apparent activation energy, resulting in the improved dissolution fraction of potassium. PMID- 27765489 TI - Bariatric surgery results in patients with type 1 diabetes mellitus on continuous subcutaneous insulin infusion therapy. PMID- 27765490 TI - Impact of diabetes education on type 1 diabetes mellitus control in children. AB - INTRODUCTION: Diabetes education is an essential tool to achieve treatment objectives in type1 diabetes mellitus (T1DM). The aim of this study was to determine if understanding of diabetes by caregivers/patients or sociodemographic factors affect blood glucose control in children and adolescents with T1DM. PATIENTS AND METHODS: The level of knowledge of 105 caregivers of children and adolescents with T1DM was assessed using a survey adapted to the type of treatment used (multiple dose insulin [MDI] or continuous subcutaneous insulin infusion [CSII]). Mean HbA1c levels in the previous year was considered as metabolic control marker. RESULTS: Mean HbA1c levels were similar in both treatment groups, with slightly higher values in children over 12years of age. Patients on CSII had a longer time since disease onset and had poorer results, maybe because the items were more difficult due to the higher level of knowledge required for this treatment modality (P=.005). Caregivers with lower educational levels achieved poorer scores in the survey, but mean HbA1c levels of their children were lower, probably because of their greater involvement in disease care. CONCLUSIONS: The level of knowledge of caregivers and/or patients with T1DM was high, and this was associated to good metabolic control. Studies to assess the impact of caregiver knowledge on metabolic control of children are needed. PMID- 27765491 TI - A novel fuzzy set based multifactor dimensionality reduction method for detecting gene-gene interaction. AB - BACKGROUND: Gene-gene interaction (GGI) is one of the most popular approaches for finding the missing heritability of common complex traits in genetic association studies. The multifactor dimensionality reduction (MDR) method has been widely studied for detecting GGIs. In order to identify the best interaction model associated with disease susceptibility, MDR compares all possible genotype combinations in terms of their predictability of disease status from a simple binary high(H) and low(L) risk classification. However, this simple binary classification does not reflect the uncertainty of H/L classification. METHODS: We regard classifying H/L as equivalent to defining the degree of membership of two risk groups H/L. By adopting the fuzzy set theory, we propose Fuzzy MDR which takes into account the uncertainty of H/L classification. Fuzzy MDR allows the possibility of partial membership of H/L through a membership function which transforms the degree of uncertainty into a [0,1] scale. The best genotype combinations can be selected which maximizes a new fuzzy set based accuracy measure. RESULTS: Two simulation studies are conducted to compare the power of the proposed Fuzzy MDR with that of MDR. Our results show that Fuzzy MDR has higher power than MDR. We illustrate the proposed Fuzzy MDR by analysing bipolar disorder (BD) trait of the WTCCC dataset to detect GGI associated with BD. CONCLUSIONS: We propose a novel Fuzzy MDR method to detect gene-gene interaction by taking into account the uncertainly of H/L classification and show that it has higher power than MDR. Fuzzy MDR can be easily extended to handle continuous phenotypes as well. The program written in R for the proposed Fuzzy MDR is available at https://statgen.snu.ac.kr/software/FuzzyMDR. PMID- 27765492 TI - Optimization of micronutrient supplement for enhancing biogas production from food waste in two-phase thermophilic anaerobic digestion. AB - The aim of this study was to enhance the biogas productivity of two-phase thermophilic anaerobic digestion (AD) using food waste (FW) as the primary substrate. The influence of adding four trace metals (Ca, Mg, Co, and Ni) as micronutrient supplement in the methanogenic phase of the thermophilic system was investigated. Initially, Response Surface Methodology (RSM) was applied to determine the optimal concentration of micronutrients in batch experiments. The results showed that optimal concentrations of 303, 777, 7 and 3mg/L of Ca, Mg, Co and Ni, respectively, increased the biogas productivity as much as 50% and significantly reduced the processing time. The formulated supplement was tested in continuous two-phase thermophilic AD system with regard to process stability and productivity. It was found that a destabilized thermophilic AD process encountering high VFA accumulation recovered in less than two weeks, while the biogas production was improved by 40% yielding 0.46L CH4/gVSadded/day. There was also a major increase in soluble COD utilization upon the addition of micronutrient supplement. The results of this study indicate that a micronutrient supplement containing Ca, Mg, Co and Ni could probably remedy any type of thermophilic AD process. PMID- 27765493 TI - Concrete drill core characterization finalized to optimal dismantling and aggregates recovery. AB - An innovative strategy, based on micro X-ray fluorescence and HyperSpectralImaging in the short wave infrared range (1000-2500nm), was developed in order to characterize drill core samples collected from End-of-Life concrete. Micro X-ray fluorescence maps were realized to check the drill cores chemical composition, to develop the best approach for HSI analyses and to verify the correctness of the obtained HSI results. HSI analysis was carried out in order to recognize and classify aggregates and mortar paste in concrete. A morphological and morphometrical analysis of aggregates was also carried out on the prediction maps. Results showed as the proposed approach can be profitably applied to analyze and characterize demolition waste materials before dismantling. Starting from an efficient in-situ characterization of the objects to dismantle, demolition actions can be optimized in order to maximize the EOL concrete derived materials, minimizing the final waste. PMID- 27765494 TI - Vitrification of incinerated tannery sludge in silicate matrices for chromium stabilization. AB - The vitrification process was applied for the stabilization and solidification of a rich in chromium ash that was the by-product of incineration of tannery sludge. Six different batch compositions were produced, based on silica as the glass former and sodium and calcium oxides as flux agents. As-vitrified products (monoliths) were either composed of silicate matrices with separated from the melt Eskolaite (Cr2O3) crystallites or were homogeneous glasses (in one case). All as-vitrified products were thermally treated in order to transform them to partially crystallized, i.e. devitrified products. Devitrification is an important part of the work since studying the transformation of the initial as vitrified products into glass-ceramics with better properties could result to stabilized products with potential added value. The devitrified products were diversified by the effective crystallization mode and separated crystal phase composition. These variations originated from differences in: (a) batch composition of the initial as-vitrified products and (b) thermal treatment conditions. In devitrified products crystallization led to the separation of Devitrite (Na2Ca3Si6O16), Combeite (Na4Ca4Si6O18) and Wollastonite (CaSiO3) crystalline phases, while Eskolaite crystallites were not affected by thermal treatment. Leaching test results revealed that chromium was successfully stabilized inside the as-vitrified monoliths. Devitrification impairs chromium stabilization, only in the case where the initial as-vitrified product was a homogeneous glass. In all other cases, devitrification did not affect successful chromium stabilization. PMID- 27765495 TI - Long-term performance of anaerobic digestion for crop residues containing heavy metals and response of microbial communities. AB - In order to investigate the long-term stability on the performance of the anaerobic digestion process, a laboratory-scale continuous stirred-tank reactor (CSTR) was operated for 1100 days with sunflower harvested in a heavy metal contaminated site. Changes of microbial communities during digestion were identified using pyrosequencing. According to the results, soluble heavy metal concentrations were lower than the reported inhibitory level and the reactor performance remained stable up to OLR of 2.0g-VS/L/day at HRT of 20days. Microbial communities commonly found in anaerobic digestion for cellulosic biomass were observed and stably established with respect to the substrate. Thus, the balance of microbial metabolism was maintained appropriately and anaerobic digestion seems to be feasible for disposal of heavy metal-containing crop residues from phytoremediation sites. PMID- 27765496 TI - Emerging Mechanisms in Initiating and Terminating Autophagy. AB - Autophagy is a major degradative process activated in a rapid and transient manner to cope with stress conditions. Whether autophagy is beneficial or detrimental depends upon the rate of induction and the appropriateness of the duration. Alterations in both autophagy initiation and termination predispose the cell to death, and affect the execution of other inducible processes such as inflammation. In this review we discuss how stress signaling pathways dynamically control the activity of the autophagy machinery by mediating post-translational modifications and regulatory protein interactions. In particular, we highlight the emerging role of TRIM and CULLIN families of ubiquitin ligases which play opposite roles in the autophagy response by promoting or inhibiting, respectively, the activity of the autophagy initiation complex. PMID- 27765497 TI - Editorial commentary: On the evaluation of patients with chest pain: Who are the risk takers? PMID- 27765498 TI - Myokines and adipokines: Involvement in the crosstalk between skeletal muscle and adipose tissue. AB - Skeletal muscle and adipose tissue are the two largest organs in the body. Skeletal muscle is an effector organ, and adipose tissue is an organ that stores energy; in addition, they are endocrine organs that secrete cytokines, namely myokines and adipokines, respectively. Myokines consist of myostatin, interleukin (IL)-8, IL-15, irisin, fibroblast growth factor 21, and myonectin; adipokines include leptin, adiponectin, resistin, chemerin, and visfatin. Furthermore, certain cytokines, such as IL-6 and tumor necrosis factor-alpha, are released by both skeletal muscle and adipose tissue and exhibit a bioactive effect; thus, they are called adipo-myokines. Recently, novel myokines or adipokines were identified through the secretomic technique, which has expanded our knowledge on the previously unknown functions of skeletal muscle and adipose tissue and provide a new avenue of investigation for obesity treatment or animal production. This review focuses on the roles of and crosstalk between myokines and adipokines in skeletal muscle and adipose tissue that modulate the molecular events in the metabolic homeostasis of the whole body. PMID- 27765500 TI - Loss of reduction and complications of coracoclavicular ligament reconstruction with autogenous tendon graft in acute acromioclavicular dislocations. AB - BACKGROUND: This study was conducted to report loss of reduction and complications after single-tunnel coracoclavicular (CC) ligament reconstruction with autogenous semitendinosus tendon graft for acute acromioclavicular (AC) joint dislocations. METHODS: This retrospective study included patients with acute, unstable AC dislocations (surgery within 6 weeks after trauma). We excluded patients with chronic injury and distal clavicle fractures with CC ligaments disruption. We measured the CC distance on anteroposterior radiographs of both clavicles, preoperatively, immediately postoperatively, and at the final follow-up visit. We evaluated clinical outcomes using the American Shoulder and Elbow Surgeons Shoulder Assessment and the University of California, Los Angeles Shoulder Rating Scale scores and perioperative complications. RESULTS: There were 30 patients (27 men and 3 women) with mean age of 41 years (range, 19-70 years). The mean follow-up period was 31 months (range, 12-186 months). Mean CC distance was 15.5 +/- 3.7 mm (84% +/- 14% of the contralateral shoulder) preoperatively, 8.9 +/- 2.6 mm (9% +/- 40%) immediately postoperatively (P < .001), and 10.6 +/- 3.3 mm (24% +/- 39%) at the final assessment (P < .001), showing an increase of the CC distance during the follow-up. Loss of reduction (defined as >25% increase of CC distance) developed in 14 patients (47%), and complications occurred in 6 patients (20%), including 3 distal clavicle fractures through the tunnel. Final clinical scores were significantly lower in patients with complications (27 vs. 33 of the University of California, Los Angeles assessment [P < .001] and 81 vs. 95 of the American Shoulder and Elbow Surgeons Shoulder assessment [P < .001]). CONCLUSION: In acute AC joint dislocation, single-tunnel CC ligament reconstruction using autogenous tendon graft resulted in loss of reduction rate of 47% and a complication rate of 20%. The development of complications adversely affected clinical outcomes. PMID- 27765501 TI - Magnetic resonance imaging is comparable to computed tomography for determination of glenoid version but does not accurately distinguish between Walch B2 and C classifications. AB - BACKGROUND: Computed tomography (CT) scan is the standard for the preoperative assessment of glenoid version and morphology before total shoulder arthroplasty. However, the capacity of magnetic resonance imaging (MRI) to visualize bone morphology has improved with advancing technology. The purpose of this study was to compare the accuracy of MRI to CT for assessment of glenoid version and Walch classification. METHODS: Three fellowship-trained shoulder surgeons assessed glenoid version and Walch classification of 30 patients with primary shoulder osteoarthritis who received both CT and MRI scans before total shoulder arthroplasty. Version measurements, Walch classification, and observer agreement were compared. RESULTS: Mean glenoid version was -15.5 degrees and -18.6 degrees by CT and MRI, respectively (P = .17). Interobserver reliability coefficients were good for both imaging modalities (CT, 0.73; MRI, 0.62). Intraobserver coefficients were good to excellent for CT (range, 0.76-0.87) and good for MRI (range, 0.75-0.79). For Walch classification, interobserver reliability for both modalities was merely fair, whereas intraobserver reliability was moderate to good. Although identification of type A1, A2, and B1 was nearly identical between CT and MRI, there was observer disagreement on type B2 (P = .001) and C glenoids (P = .03). Specifically, MRI underidentified type B2 and overidentified type C compared with CT. CONCLUSIONS: MRI is largely comparable to CT scan for evaluation of the glenoid, with similar measurements of version and identification of less extreme Walch glenoids. However, MRI is less accurate at distinguishing between type B2 and C glenoids. PMID- 27765499 TI - Neuroendocrine-immune circuits, phenotypes, and interactions. AB - Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions. PMID- 27765502 TI - Generic targeting guides place revision glenoid components in more anatomic version than traditional techniques. AB - BACKGROUND: Glenoid component positioning in revision shoulder arthroplasty is difficult because of distorted anatomic landmarks and scarring in and around the glenoid vault. This study compared glenoid component version in revision total shoulder arthroplasty (TSA) and reverse TSA (RTSA) using traditional instrumentation vs. a generic glenoid targeting guide. METHODS: Radiographs of 50 shoulders undergoing revision arthroplasty were reviewed by an independent reviewer. Twenty-one components were placed using traditional instrumentation and 29 with a generic targeting guide. Glenoid component version was measured on axillary lateral radiographs, and absolute deviation from anatomic version was calculated. RESULTS: The average deviation in version from anatomic was 8 degrees (range, 0 degrees -21 degrees ) with the traditional technique and 5 degrees (range, 0 degrees -18 degrees ) with the targeting guide (P = .03). In revision to TSA, the average deviation was 10 degrees with the traditional technique and 3 degrees with the targeting guide (P = .01). There was no significant difference in revision to RTSA (average deviation was 8 degrees with traditional technique and 6 degrees with the targeting guide). Glenoid components in obese patients (body mass index >30 kg/m2) had less deviation (5 degrees ) with the targeting guide technique than with the traditional technique (9 degrees , P = .04). No significant differences were found between techniques in glenoids with more than 15 degrees of preoperative retroversion, TSA conversion to RSTA, or arthroplasty after proximal humeral fixation. CONCLUSIONS: For revision arthroplasty, glenoid components placed with the generic targeting guide were significantly more accurate in version than with traditional instrumentation, particularly with revision to anatomic TSA. The targeting guide was useful in obese patients. PMID- 27765503 TI - Valgus extension overload syndrome in adolescent baseball players: clinical characteristics and surgical outcomes. AB - BACKGROUND: Little is known about the clinical characteristics and surgical outcomes of valgus extension overload syndrome (VEOS) in adolescent athletes. We evaluated posteromedial compartment pathology, including combined lesions, and reported the surgical outcomes in adolescent baseball players. METHODS: We retrospectively reviewed the medical records of 13 male adolescent baseball players (mean age, 15.4 years) who underwent arthroscopic olecranon tip resection (n = 9) or staged operations (arthroscopic olecranon tip resection, followed by medial collateral ligament reconstruction 2 weeks later; n = 4). The shape of the tip fragment was used to classify the olecranon into 2 types: type 1, dot-like fragment (n = 3); type 2, triangular-shape fragment (n = 10). Four outcome measures were analyzed: range of motion, visual analog scale (VAS) pain score, rate of return to play, and Conway scale score. RESULTS: At a mean follow-up of 3.3 years (range, 2-6 years), the mean VAS pain score decreased from 4.1 preoperatively to 1.1 postoperatively (P < .05). Preoperative mean extension and supination were 4.2 degrees and 70.0 degrees , which improved to 1 degrees (P < .05) and 76.2 degrees (P < .05), respectively. The overall rate of return to play was 85% (11 of 13). On the Conway scale, 8 of 13 patients (62%) were classified as excellent. Patients who underwent isolated arthroscopic surgery reported less pain postoperatively and achieved a higher grade on the Conway scale than patients who underwent staged operations. CONCLUSIONS: Arthroscopic resection of olecranon tip yielded favorable outcomes at a minimum of 2 years of follow-up. Patients with concomitant ulnar collateral ligament insufficiency had less optimal outcomes than those with isolated posteromedial impingement. PMID- 27765504 TI - Cochlearoids F-K: Phenolic meroterpenoids from the fungus Ganoderma cochlear and their renoprotective activity. AB - Ganoderma mushrooms are of great nutritious and medicinal values. This study was designed to characterize compounds from the fruiting bodies of Ganoderma cochlear and investigate their protective effects against kidney disorders. Six novel meroterpenoids cochlearoids F-K (1-6) were isolated by utilizing phytochemical approaches. Their structures were identified on the basis of extensive spectroscopic data and calculation methods. Biological evaluation shows that compounds 1-4 and 6 exhibit potent inhibitory activity on fibronectin overproduction in TGF-beta1-induced HKC-8 cells. PMID- 27765505 TI - C-H activation reactions as useful tools for medicinal chemists. AB - In recent years, there has been an exponential rise in the number of reports describing synthetic methods that utilize catalytic sp3 and sp2 C-H bond activation. Many have emerged as powerful synthetic tools for accessing biologically active motifs. Indeed, application to C-C and C-heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C-H activation processes that exemplify the utility of these transformations in medicinal chemistry. PMID- 27765506 TI - Synthesis and biological evaluation of crown ether acyl derivatives. AB - A set of crown ethyl acyl derivatives based on 18-crown-6 moiety was synthesized and evaluated for biological activity. In vitro antiproliferative profiling demonstrated significant activities against HBL-100, HeLa, SW1573 and WiDr human cell lines. The most active compound exhibited GI50 values in the range of 3.7 5.6MUM. Antimicrobial evaluation showed that three polyaromatic compounds were active against Staphylococcus aureus (MIC90 values from 8.3MUM to 50MUM), whereas a (decyloxy)benzene substitution exhibited moderate activity against Candida albicans (MIC90 values 36MUM). According to SAR evaluation, the size of the crown ether and the acyl side chain had a significant effect on the bioactivity. Aromatic moieties close to the acyl group led to improved bioactivity as exemplified by some of the tested compounds. These results provide further evidence on the potential of crown ethyl structure as a scaffold for developing new biological probes and lead candidates for drug development. PMID- 27765507 TI - 5-Alkyloxytryptamines are membrane-targeting, broad-spectrum antibiotics. AB - Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6-12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6-10 carbons increased the membrane permeability of Gram-positive and Gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)-where mammalian cell toxicity is low-these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs. PMID- 27765508 TI - Antioxidant and anti-inflammatory neolignans from the seeds of hawthorn. AB - Seven new neolignans (1-2, 7-11) and five known compounds (3-6, 12) were isolated from the 70% EtOH extract of hawthorn seeds. Their structures were determined by spectroscopic analyses. The antioxidant and anti-inflammatory activities of all the isolates were investigated. Most of the isolates showed moderate radical scavenging activity in the DPPH assay and significant activities in the ABTS and FRAP assays. Furthermore, compounds 7-12 exhibited marked nitric oxide (NO) inhibition and compounds 1-4 had a potent necrosis factor-alpha (TNF-alpha) inhibitory effect. The results we obtained showed that hawthorn seeds can be regarded as a potential new and cheap source of antioxidants and inflammation inhibitors. PMID- 27765509 TI - 2-Phenylbenzo[b]furans: Synthesis and promoting activity on estrogen biosynthesis. AB - Estrogen biosynthesis is pivotal to many physiological processes of human. Aberrant estrogen level is closely related to a variety of diseases, including breast cancer and osteoporosis. Previously we found that 2-phenylbenzo[b]furan glycosides could promote estrogen biosynthesis. To find high active 2 phenylbenzo[b]furans, fifty-four 2-phenylbenzo[b]furans were prepared via four strategies according to corresponding substrate scopes. Biological evaluation in HEK293A cells showed that some compounds exhibited promotive activity on estrogen biosynthesis. 2-(4-Chlorophenyl)-7-methoxybenzo[b]furan possessed the highest activity with EC50 value of 14.68MUM. Furthermore, these compounds did not affect aromatase expression in HEK292A cells, indicating that these 2 phenylbenzo[b]furans might enhance estrogen biosynthesis via directly allosteric regulation of aromatase or indirectly via posttranslational modification. PMID- 27765510 TI - Synthesis of linear and angular aryl-morpholino-naphth-oxazines, their DNA-PK, PI3K, PDE3A and antiplatelet activity. AB - To continue our study of 2-morpholino-benzoxazine based compounds, which show useful activity against PI3K family enzymes or antiplatelet activity, we designed and synthesized a series of linear 6.7-fused, 5,6-angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines. The compounds were prepared from substituted 2-hydroxynaphthoic acid to give the corresponding thioxo analogues 8, 9, 15 and 19. The thioxo products were then converted to the morpholino substituted analogue. The aryl group was introduced by Suzuki coupling of bromo precursors. The products were evaluated for activity at PI3K family enzymes and as platelet aggregation inhibitors and compared to reported unsubstituted analogues. The linear 6.7-fused product 13a and 13b were moderated potent but selective PI3Kdelta isoform inhibitors (IC50=7.7 and 5.61MUM). Good antiplatelet activity was noticed for the angular 7,8-fused compounds 22a, b, k and l with IC50=3.0,14.0, 2.0 and 5.0MUM respectively. The antiplatelet activity is independent of PDE3. PMID- 27765511 TI - Design, synthesis and structure-activity relationships of novel phenylalanine based amino acids as kainate receptors ligands. AB - A new series of carboxyaryl-substituted phenylalanines was designed, synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors as well as at cloned homomeric kainate receptors GluK1-GluK3. Among them, six compounds bound to GluK1 receptor subtypes with reasonable affinity (Ki values in the range of 4.9-7.5MUM). A structure-activity relationship (SAR) for the obtained series, focused mainly on the pharmacological effect of structural modifications in the 4- and 5-position of the phenylalanine ring, was established. To illustrate the results, molecular docking of the synthesized series to the X-ray structure of GluK1 ligand binding core was performed. The influence of individual substituents at the phenylalanine ring for both the affinity and selectivity at AMPA, GluK1 and GluK3 receptors was analyzed, giving directions for future studies. PMID- 27765512 TI - High-viscosity glass-ionomer cements for direct posterior tooth restorations in permanent teeth: The evidence in brief. AB - OBJECTIVES: To provide a brief overview of the current evidence-base for direct posterior tooth restorations in permanent teeth placed using high-viscosity glass ionomer cement (HVGIC). METHODS: The evidence sources: laboratory trials, uncontrolled clinical trials, controlled clinical trials with HVGIC restorations placed after conventional cavity preparation by drill and controlled clinical trials with HVGIC restorations placed following the atraumatic restorative treatment (ART) approach, were assessed based on systematic reviews and meta analyses, as well as methodological studies. RESULTS: The precision and validity of evidence from laboratory trials, uncontrolled clinical trials and non-ART controlled clinical trials are insufficient for clinical guidance. Clinical evidence for HVGIC restorations placed using ART, comprises of 38 controlled clinical trials including over 10 000 tooth restorations. Systematic review results of these trials indicate no statistically significant differences (p>0.05) in the failure rates between HVGIC and amalgam restorations in single- and multiple surface tooth cavities after up to six years. Although, many of these trials suffered from too low sample sizes, their results could be pooled in three meta-analyses. The bias risk in all trials was judged to be high. CONCLUSION: Controlled clinical trials with HVGIC restorations placed using ART provide the bulk of the available evidence that suggest that the failure rate of direct posterior HVGIC restorations in permanent teeth are comparable to that of dental amalgam restorations. PMID- 27765514 TI - Uniform and diffuse fatty replacement of the pancreas revealing cystic fibrosis in a 48-year-old man: CT findings. PMID- 27765515 TI - Rapid percutaneous nephrostomy catheter placement in neonates with the trocar technique. AB - PURPOSE: The purpose of this study was to assess the efficacy of a modified percutaneous nephrostomy procedure for grade III-IV hydronephrosis in neonates. MATERIAL AND METHODS: Eleven neonates (five girls, six boys) with a mean age of 13.7days+/-9.9 (SD) (range, 4-28days) with pronounced hydronephrosis had percutaneous nephrostomy using a modified procedure. In all patients, percutaneous nephrostomy was performed with a trocar catheter under ultrasound guidance and then the catheter was placed into the collecting system without prior dilatation. RESULTS: Technical success was achieved in all patients. There were no major procedure-related complications. There was no perirenal hematoma on control ultrasound examinations and no hematuria was observed after the procedure. The median drainage time was 75days (range: 42-120days). Two children had urinary tract infection, which was controlled by using antibiotics. CONCLUSION: The trocar nephrostomy is a practical and feasible method, which can be used for neonates with grade III-IV hydronephrosis. PMID- 27765513 TI - Microtubule Motors Drive Hedgehog Signaling in Primary Cilia. AB - The mammalian Hedgehog (Hh) signaling pathway is required for development and for maintenance of adult stem cells, and overactivation of the pathway can cause tumorigenesis. All responses to Hh family ligands in mammals require the primary cilium, an ancient microtubule-based organelle that extends from the cell surface. Genetic studies in mice and humans have defined specific functions for cilium-associated microtubule motor proteins: they act in the construction and disassembly of the primary cilium, they control ciliary length and stability, and some have direct roles in mammalian Hh signal transduction. These studies highlight how integrated genetic and cell biological studies can define the molecular mechanisms that underlie cilium-associated health and disease. PMID- 27765517 TI - Does Consciousness Disappear in Dreamless Sleep? AB - Consciousness is often said to disappear in deep, dreamless sleep. We argue that this assumption is oversimplified. Unless dreamless sleep is defined as unconscious from the outset there are good empirical and theoretical reasons for saying that a range of different types of sleep experience, some of which are distinct from dreaming, can occur in all stages of sleep. We introduce a novel taxonomy for describing different kinds of dreamless sleep experiences and suggest research methods for their investigation. Future studies should focus on three areas: memory consolidation, sleep disorders, and sleep state (mis)perception. Our proposal suggests new directions for sleep and dream science, as well as for the neuroscience of consciousness, and can also inform the diagnosis and treatment of sleep disorders. PMID- 27765516 TI - Effects of gintonin-enriched fraction on hippocampal cell proliferation in wild type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease. AB - We previously showed that gintonin, an exogenous lysophosphatidic acid (LPA) receptor ligand, attenuated beta-amyloid plaque formation in the cortex and hippocampus, and restored beta-amyloid-induced memory dysfunction. Both endogenous LPA and LPA receptors play a key role in embryonic brain development. However, little is known about whether gintonin can induce hippocampal cell proliferation in adult wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease (AD). In the present study, we examined the effects of gintonin on the proliferation of hippocampal neural progenitor cells (NPCs) in vitro and its effects on the hippocampal cell proliferation in wild-type mice and a transgenic AD mouse model. Gintonin treatment increased 5-bromo-2'-deoxyuridine (BrdU) incorporation in hippocampal NPCs in a dose- and time-dependent manner. Gintonin (0.3 MUg/ml) increased the immunostaining of glial fibrillary acidic protein, NeuN, and LPA1 receptor in hippocampal NPCs. However, the gintonin induced increase in BrdU incorporation and immunostaining of biomarkers was blocked by an LPA1/3 receptor antagonist and Ca2+ chelator. Oral administration of the gintonin-enriched fraction (50 and 100 mg/kg) increased hippocampal BrdU incorporation and LPA1/3 receptor expression in adult wild-type and transgenic AD mice. The present study showed that gintonin could increase the number of hippocampal neurons in adult wild-type mice and a transgenic AD mouse model. Our results indicate that gintonin-mediated hippocampal cell proliferation contributes to the gintonin-mediated restorative effect against beta-amyloid induced hippocampal dysfunction. These results support the use of gintonin for the prevention or treatment of neurodegenerative diseases such as AD via promotion of hippocampal neurogenesis. PMID- 27765519 TI - The new approach to classification of focal epilepsies: Epileptic discharge and disconnectivity in relation to cognition. AB - The new classification of epilepsy stratifies the disease into an acute level, based on seizures, and an overarching chronic level of epileptic syndromes (Berg et al., 2010). In this new approach, seizures are considered either to originate and evolve in unilateral networks or to rapidly encompass both hemispheres. This concept extends the former vision of focal and generalized epilepsies to a genuine pathology of underlying networks. These key aspects of the new classification can be linked to the concept of cognitive curtailing in focal epilepsy. The present review will discuss the conceptual implications for acute and chronic cognitive deficits with special emphasis on transient and structural disconnectivity. Acute transient disruption of brain function is the hallmark of focal seizures. Beyond seizures, however, interictal epileptic discharges (IEDs) are increasingly recognized to interfere with physiological brain circuitry. Both concomitant EEG and high-precision neuropsychological testing are necessary to detect these subtle effects, which may concern task-specific or default-mode networks. More recent data suggest that longstanding IEDs may affect brain maturation and eventually be considered as a biomarker of pathological wiring. This brings us to the overarching level of chronic cognitive and behavioral comorbidity. We will discuss alterations in structural connectivity measured with diffusion-weighted imaging and tractography. Among focal epilepsies, much of our current insights are derived from temporal lobe epilepsy and its impact on neuropsychological and psychiatric functioning. Structural disconnectivity is maximal in the temporal lobe but also concerns widespread language circuitry. Eventually, pathological wiring may contribute to the clinical picture of cognitive dysfunction. We conclude with the extrapolation of these concepts to current research topics and to the necessity of establishing individual patient profiles of network pathology with EEG, high-precision neuropsychological testing, and state-of-the-art neuroimaging. This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy". PMID- 27765518 TI - Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer. AB - BACKGROUND: This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: A total of 62 patients received MLN2704 at ascending doses on 4 schedules: weekly (60, 84, 118, and 165mg/m2; 12 patients); every 2 weeks (120, 168, 236, and 330mg/m2; 15 patients); every 3 weeks (330 and 426mg/m2; 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330mg/m2; 17 patients). The primary efficacy endpoint was a sustained >=50% decline from baseline prostate-specific antigen (PSA) without evidence of disease progression. Toxicity, pharmacokinetics, immunogenicity, and antitumor activity were assessed. RESULTS: Neurotoxicity was dose-limiting. Overall, 44 patients (71%) exhibited peripheral neuropathy: 6 (10%) had grade 3/4. Neurotoxicity rates remained high despite increasing the dosing interval to 3 (13 of 14; one grade 3) and 6 weeks (16 of 17; three grade 3). MLN2704 pharmacokinetics were dose-linear. Rapid deconjugation of DM1 from the conjugated antibody was seen. In all, 5 patients (8%) experienced >=50% decline in PSA; 5 (8%) had PSA stabilization lasting>=90 days. Only 2 of 35 patients on the 3- and 6-week schedules achieved a PSA decline of >50%. CONCLUSIONS: MLN2704 has limited activity in metastatic castration resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window. PMID- 27765521 TI - Clinical and neuropsychological features of violence in schizophrenia: A prospective cohort study. AB - The increased risk of violence in schizophrenia has been linked to several environmental, clinical and neuropsychological factors, including executive dysfunction. However, data about the nature of these effects are mixed and controversial. The main aim of this study was to investigate the relationship between clinical and neuropsychological factors with violence risk in patients with schizophrenia, taking into account current psychopathology and lifetime alcohol use. We compared a sample of patients living in Residential Facilities (RFs) with schizophrenia and a past history of interpersonal violence (vSZ, N=50) to patients with schizophrenia matched on age, gender and alcohol abuse/dependence but with no violence history (nvSZ, N=37). We then established the association between the clinical and neuropsychological factors that predicted violence over a 1year follow-up period. The results revealed that vSZ patients living in RFs were characterized by greater compulsory hospital admissions, higher anger and less negative symptoms as compared to nvSZ patients. vSZ patients performed better on executive and motor tasks than nvSZ; however, these differences appeared to be explained by the lower negative psychotic symptom in the vSZ group. Both groups were involved in episodes of violence during the follow-up period; among the two, the vSZ patients were more likely to be violent. Negative symptoms predicted less verbal aggression at 1year follow up. Overall, these findings support a key role of negative rather than positive symptoms in driving violence risk among SZ patients living in RFs, in a manner that negative symptoms are linked to a lower risk of violence. PMID- 27765520 TI - Initial treatment of congenital idiopathic clubfoot: Prognostic factors. AB - BACKGROUND: The initial treatment of congenital idiopathic clubfoot (CIC) is nonoperative. Either the French physiotherapy method or the Ponseti casting method may be used. Whether either method is superior over the other remains unclear. However, the method used initially is not the only determinant of the final outcome. OBJECTIVE: The primary objective was to identify determinants of the final outcome as evaluated based on the need for surgical treatment and on the Ghanem-Seringe score. HYPOTHESIS: Factors associated with the final outcome can be identified. METHODS: Between 2004 and 2011, 100 CICs in 79 patients were treated in two centres, 47 using the French method and 53 the Ponseti method. The Dimeglio grade was determined at baseline and the Ghanem-Seringe score at last follow-up. Surgical procedures (if any), splinting duration, and rehabilitation therapy duration were recorded. The two groups showed no statistically significant differences for Dimeglio grade distribution, time from birth to treatment initiation, or mean follow-up. RESULTS: Factors significantly associated with a poor outcome by univariate analysis were use of the Ponseti method (P=0.0027), older age at last follow-up (P=3*10-4), initial Dimeglio grade (P=7*10-5), and need for surgery (P=10-5); no significant effect was found for splinting duration, rehabilitation duration, bilateral involvement, or antenatal diagnosis. By multivariate analysis, factors independently associated with a poor prognosis were older age at last follow-up, Dimeglio grade, and need for surgery. CONCLUSION: This study confirms the major prognostic significance of initial severity (Dimeglio grade) on the final outcome. The data do not firmly establish that one method is superior over the other. Nevertheless, the need for percutaneous Achilles tenotomy with the Ponseti method leads us to prefer the French physiotherapy method. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 27765522 TI - Deficits in the identification of pleasant odors predict the transition of an at risk mental state to psychosis. AB - OBJECTIVE: Existing knowledge of the relationship between olfactory identification (OI) ability and clinical risk of psychosis is inconsistent. To address this inconsistency, the aim of the present study was to identify the relationship between OI ability, with regard to the hedonic attributes of odors, and the risk of transition to psychosis in individuals with an ARMS. METHODS: A group of 81 individuals meeting the ARMS criteria according to the Comprehensive Assessment of At Risk Mental State were at baseline administered with the University of Pennsylvania Smell Identification Test. The hedonic attributes of odorants were normatively established. Participants were followed up for transition to psychosis for a mean period of 36.1months (SD:27.5months). RESULTS: The presence of deficits in the identification of pleasant odors was found to be a risk factor for conversion from an ARMS to schizophrenia. The hazard ratio for each point in deficit scores in the Cox regression model was 1.455 (95% CI: 1.211 1.747), p<0.0001. Significant deficits in the identification of pleasant odors were associated with a risk for conversion at both early and late time points from baseline. CONCLUSIONS: The findings imply that the impaired identification of pleasant odorants may be a risk factor for the transition of an ARMS into a psychotic disorder, and highlights the need for further research of OI in "at risk" cohorts, taking into account the hedonic attributes of odors. PMID- 27765523 TI - Bacterial selection for biological control of plant disease: criterion determination and validation. AB - This study aimed to evaluate the biocontrol potential of bacteria isolated from different plant species and soils. The production of compounds related to phytopathogen biocontrol and/or promotion of plant growth in bacterial isolates was evaluated by measuring the production of antimicrobial compounds (ammonia and antibiosis) and hydrolytic enzymes (amylases, lipases, proteases, and chitinases) and phosphate solubilization. Of the 1219 bacterial isolates, 92% produced one or more of the eight compounds evaluated, but only 1% of the isolates produced all the compounds. Proteolytic activity was most frequently observed among the bacterial isolates. Among the compounds which often determine the success of biocontrol, 43% produced compounds which inhibit mycelial growth of Monilinia fructicola, but only 11% hydrolyzed chitin. Bacteria from different plant species (rhizosphere or phylloplane) exhibited differences in the ability to produce the compounds evaluated. Most bacterial isolates with biocontrol potential were isolated from rhizospheric soil. The most efficient bacteria (producing at least five compounds related to phytopathogen biocontrol and/or plant growth), 86 in total, were evaluated for their biocontrol potential by observing their ability to kill juvenile Mesocriconema xenoplax. Thus, we clearly observed that bacteria that produced more compounds related to phytopathogen biocontrol and/or plant growth had a higher efficacy for nematode biocontrol, which validated the selection strategy used. PMID- 27765524 TI - Costs of hospital malnutrition. AB - BACKGROUND & AIMS: Hospital malnutrition has been established as a critical, prevalent, and costly problem in many countries. Many cost studies are limited due to study population or cost data used. The aims of this study were to determine: the relationship between malnutrition and hospital costs; the influence of confounders on, and the drivers (medical or surgical patients or degree of malnutrition) of the relationship; and whether hospital reported cost data provide similar information to administrative data. To our knowledge, the last two goals have not been studied elsewhere. METHODS: Univariate and multivariate analyses were performed on data from the Canadian Malnutrition Task Force prospective cohort study combined with administrative data from the Canadian Institute for Health Information. Subjective Global Assessment was used to assess the relationship between nutritional status and length of stay and hospital costs, controlling for health and demographic characteristics, for 956 patients admitted to medical and surgical wards in 18 hospitals across Canada. RESULTS: After controlling for patient and hospital characteristics, moderately malnourished patients' (34% of surveyed patients) hospital stays were 18% (p = 0.014) longer on average than well-nourished patients. Medical stays increased by 23% (p = 0.014), and surgical stays by 32% (p = 0.015). Costs were, on average, between 31% and 34% (p-values < 0.05) higher than for well-nourished patients with similar characteristics. Severely malnourished patients (11% of surveyed patients) stayed 34% (p = 0.000) longer and had 38% (p = 0.003) higher total costs than well-nourished patients. They stayed 53% (p = 0.001) longer in medical beds and had 55% (p = 0.003) higher medical costs, on average. Trends were similar no matter the type of costing data used. CONCLUSIONS: Over 40% of patients were found to be malnourished (1/3 moderately and 1/10 severely). Malnourished patients had longer hospital stays and as a result cost more than well-nourished patients. PMID- 27765525 TI - The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes. AB - BACKGROUND & AIMS: Patients admitted to intensive care units (ICUs) often need enteral nutrition (EN) support. For patients with type 2 diabetes (T2D), standard EN formulas may not provide ideal nutrients. The purpose was to investigate whether use of a diabetes-specific formula (DSF) could provide clinical and health economic benefits (compared to standard formulas) in critically ill patients with T2D. METHODS: This study was a retrospective analysis of medical records and expenditure data covering a 5-year period (2009-2013) from the hospitalization database of the National Taiwan University Hospital. Records of ICU patients who had T2D and were receiving enteral feeding with either the DSF or non-diabetes-specific formula (non-DSF) for at least 5 days were included in the analysis. Mortality, ICU length of stay (LOS), diabetes-related medications, and total costs of care (including all costs covered by the National Health Insurance and private expenses) were considered as the primary outcomes. RESULTS: A total of 158 patient records were analyzed in the DSF group and 794 in the non DSF group. The baseline demographics including age, gender, weight, body mass index (BMI), and comorbidity patterns were mostly comparable between the groups. Compared to those receiving non-DSF, patients with T2D receiving DSF were found to have significantly decreased mortality (5.1% vs. 12.3%, P = 0.0118) and reduced need for insulin prescription (29.1% vs. 38.4%, P = 0.0269). ICU LOS was shorter for DSF patients, but no statistical difference was found (13.0 days vs. 15.1 days, P = 0.1843). However, significantly lower total ICU costs were reported for DSF patients (6700 USD vs. 9200 USD, P < 0.0001). CONCLUSIONS: The use of DSF in ICU patients with T2D is correlated with significant reduction in mortality and improved health economic outcomes. PMID- 27765526 TI - Response to "Letter to the editor: Robot training for hand motor recovery in subacute stroke patients: A randomized controlled trial". PMID- 27765527 TI - Effects of health literacy on treatment outcome and satisfaction in patients with mallet finger injury. AB - STUDY DESIGN: Prospective cohort. INTRODUCTION: Patient comprehension of their injury, its treatment, and health care provider's instructions plays an important role in health management and recovery from trauma. PURPOSE OF THE STUDY: This study investigates the effects of health literacy (the ability to obtain, process, and understand health information needed to make appropriate health decisions) on treatment outcomes and satisfaction in patients with mallet finger injuries. METHODS: A total of 72 patients who had been treated with an orthosis for an acute mallet finger injury were enrolled in this prospective study. Health literacy was measured according to the newest vital sign during the initial visit, and adherence according to the treatment protocol was rated at week 7 when orthotic intervention was ceased. At 6 months, a follow-up visit was conducted to assess the extensor lag, treatment satisfaction, and disability (through the Quick Disabilities of the Arm, Shoulder, and Hand score). Bivariate and multivariable analyses were performed to determine whether patient demographics, injury characteristics, and health literacy factors accounted for following outcomes: extensor lag, satisfaction, and disability. RESULTS: The newest vital sign scores were moderately correlated with patient adherence and age. Extensor lag was associated with an increase in age, poor adherence, and low health literacy, and these 3 factors accounted for 28% of the variation in the extensor lag. A greater disability was associated with poor adherence, which accounted for 12% of the variance in disability. Lower treatment satisfaction was associated with low health literacy and poor adherence, and these 2 factors accounted for 21% of the variation in treatment satisfaction. DISCUSSION AND CONCLUSIONS: Limited health literacy was associated with poor adherence in orthosis care for mallet finger injuries and led to poorer treatment outcomes in terms of extensor lag and treatment satisfaction. LEVEL OF EVIDENCE: 2B. PMID- 27765528 TI - The dual role of autoimmune regulator in maintaining normal expression level of tissue-restricted autoantigen in the thymus: A modeling investigation. AB - The expression level of tissue-restricted autoantigens (TSA) in the thymus is crucial for the negative selection of autoreactive T cells during central tolerance. The autoimmune regulator factor (AIRE) plays an important role in the positive regulation of these TSA in medullary thymic epithelial cells and, consequently, in the negative selection of high-avidity autoreactive T cells. Recent studies, however, revealed that thymic islet cell autoantigen (ICA69) expression level in non-obese diabetic (NOD) mice, prone to developing type 1 diabetes (T1D), is reduced due to an increase in the binding affinity of AIRE to the Ica1-promoter region, which regulates ICA69 protein synthesis. This seemed to suggest that AIRE acts as a transcriptional repressor of Ica1 gene in the thymus, causing down regulation in the expression level of ICA69. To investigate this hypothesis and the apparent dual role of AIRE in negative selection, we develop a series of mathematical models of increasing complexity describing the temporal dynamics of self-reactive T cells, AIRE-mRNA and AIRE-(in)dependent thymic TSA associated genes. The goal is to understand how changing the binding affinity of AIRE to Ica1-promoter affects both T-cell tolerance and the dual role of the transcription factor. Using stability analysis and numerical computations, we show that the model possesses a bistable switch, consisting of healthy and autoimmune states, in the expression level of Ica1 gene with respect to AIRE binding affinity, and that it can capture the experimentally observed dual role of AIRE. We also show that the model must contain a positive feedback loop exerted by T cells on AIRE expression (e.g., via lymphotoxin released by T cells) to produce bistability. Our results suggest that the expression-level of AIRE mRNA in the healthy state is lower than that of the autoimmune state, and that negative selection is very sensitive to parameter perturbations in T-cell avidity. PMID- 27765529 TI - Identification of key genes involved in nasopharyngeal carcinoma. AB - INTRODUCTION: Nasopharyngeal carcinoma is the most common cancer originating from the nasopharynx. OBJECTIVE: To study the mechanisms of nasopharyngeal carcinoma, we analyzed GSE12452 microarray data. METHODS: GSE12452 was downloaded from the Gene Expression Omnibus database and included 31 nasopharyngeal carcinoma samples and 10 normal nasopharyngeal tissue samples. The differentially expressed genes were screened by ANOVA in the PGS package. Using the BiNGO plugin in Cytoscape and pathway enrichment analysis in the PGS package, functional and pathway enrichment analyses were performed separately to predict potential functions of the differentially expressed genes. Furthermore, Transcription factor differentially expressed gene pairs were searched, and then the transcription factor-differentially expressed gene regulatory network was visualized using Cytoscape software. RESULTS: A total of 487 genes were screened as differentially expressed genes between the nasopharyngeal carcinoma samples and the normal nasopharyngeal tissue samples. Enrichment analysis indicated that PTGS2 was involved in the regulation of biological process and small cell lung cancer. ZIC2 and OVOL1 may function in nasopharyngeal carcinoma through targeting significantly up-regulated genes (such as PTGS2, FN1, CXCL9 and CXCL10) in the Transcription factor-differentially expressed gene regulatory network (e.g., ZIC2 >PTGS2 and OVOL1->CXCL10). CONCLUSION: PTGS2, FN1, CXCL9, CXCL10, ZIC2 and OVOL1 might play roles in nasopharyngeal carcinoma. PMID- 27765530 TI - Free Field Word recognition test in the presence of noise in normal hearing adults. AB - INTRODUCTION: In ideal listening situations, subjects with normal hearing can easily understand speech, as can many subjects who have a hearing loss. OBJECTIVE: To present the validation of the Word Recognition Test in a Free Field in the Presence of Noise in normal-hearing adults. METHODS: Sample consisted of 100 healthy adults over 18 years of age with normal hearing. After pure tone audiometry, a speech recognition test was applied in free field condition with monosyllables and disyllables, with standardized material in three listening situations: optimal listening condition (no noise), with a signal to noise ratio of 0dB and a signal to noise ratio of -10dB. For these tests, an environment in calibrated free field was arranged where speech was presented to the subject being tested from two speakers located at 45 degrees , and noise from a third speaker, located at 180 degrees . RESULTS: All participants had speech audiometry results in the free field between 88% and 100% in the three listening situations. CONCLUSION: Word Recognition Test in Free Field in the Presence of Noise proved to be easy to be organized and applied. The results of the test validation suggest that individuals with normal hearing should get between 88% and 100% of the stimuli correct. The test can be an important tool in measuring noise interference on the speech perception abilities. PMID- 27765531 TI - Steroid therapy ameliorated cataplexy in three children with recent-onset of narcolepsy. PMID- 27765532 TI - An approach to expand description of the pump and co-transporter steady-state current. AB - The membrane transporters (pumps and co-transporters) are the main players in maintaining the cell homeostasis. Models of various types, each with their own drawbacks, describe transporter behavior. The aim of this study is to find the link between the biophysically based and empirical models to face and solve their specific problems. Instead of decreasing the number of states and using few complex rate constants as is usually done, we use the number of states as great as possible. Then, each transition in the cycle can represent an elementary process and we can apply the mass action law, according to which if rate constants depend on concentrations the dependence is linear. Thus, the expression for the steady state transporter current can be transformed from a function of rate constants into a function of concentrations. When transporter states form a single cycle, it can be characterized by two modes of action - forward and backward ones. Specific mode is realized depending on the available free energy. Each mode of action is characterized by a set of transporter affinities together with a parameter that describes the maximal turning rate. Except standard affinities corresponding to the substances that are binding to the transporter, affinities for the substances that are released are also defined. Such scheme provides great possibilities to construct approximations as each individual affinity could be estimated from experiments as precisely as possible. The approximations may be used for not only description and study of the transporter current but also in cellular models that attempt to describe wide variety of processes in excitable cells. PMID- 27765533 TI - A novel comprehensive set of fungal Real time PCR assays (fuPCR) for the detection of fungi in immunocompromised haematological patients-A pilot study. AB - Fungal infections are recognized in an increasing number of patients with immunological deficits and are associated with high rates of mortality (Brown et al., 2012a). In this pilot-study, a rapid Real time PCR (fuPCR) was designed for the detection and differentiation of fungal pathogens in clinical specimens of haematological patients. The fuPCR, targeting the internal transcribed spacer region 2 (ITS2) of rDNA region, is comprised of seven multiplex reactions, which were shown to be specific and sensitive for a comprehensive spectrum of clinically relevant fungal species. This was validated by testing respective fungal DNAs in each fuPCR reaction and 28 respiratory samples of fungal pneumonia proven patients. Clinical sample sets of throat swab, EDTA-blood and blood sera from 50 patients with severe haematological malignancies, including haematopoietic stem cell transfer (HSCT), and samples from 30 healthy individuals were then analysed. In a first step, 198 samples of immunosuppressed patients were solely examined by fuPCR; and 50.8% (33/65) respiratory swabs, 4.8% (3/63) EDTA blood samples and 1.4% (1/70) blood serum samples were tested positive. In a second step, 56 respiratory samples of immunosuppressed patients and 30 of healthy individuals were simultaneously analysed by fuPCR and standard cultivation techniques. By both methods 30.4% (17/56) swabs of the immunocompromised patients were tested positive, 37.5% (21/56) were tested negative and 32.1% (18/56) were tested fuPCR positive and culture negative. In analysing the blood samples of the immunocompromised patients 5.4% (3/56) EDTA blood samples and 16.1% (9/56) sera samples were tested fuPCR-positive, whereas all samples of 30 healthy individuals with no signs of immunological deficits were tested negative by fuPCR. 38.9% (14/36) of the fungi detected in respiratory samples of the immunosuppressed patients, belonged to Candida spp., 47.2% (17/36) to Saccharomyces spp., 5.6% (2/36) to Cladosporium spp. and 8.3% (3/36) to Alternaria spp., whereas cultivation only identified Candida spp. (10/17) and Saccharomyces spp. (7/17). In this pilot study a novel fuPCR assay was developed and validated for the simultaneous and comprehensive detection of fungal pathogens in clinical respiratory specimens of haematological patients. Future work will focus on the validation of the blood-stream detected fungi in pathogenicity of these patients. PMID- 27765534 TI - Diabetic nephropathy and endothelial dysfunction: Current and future therapies, and emerging of vascular imaging for preclinical renal-kinetic study. AB - An explosion in global epidemic of type 2 diabetes mellitus poses major rise in cases with vascular endothelial dysfunction ranging from micro- (retinopathy, nephropathy and neuropathy) to macro-vascular (atherosclerosis and cardiomyopathy) conditions. Functional destruction of endothelium is regarded as an early event that lays the groundwork for the development of renal microangiopathy and subsequent clinical manifestation of nephropathic symptoms. Recent research has shed some light on the molecular mechanisms of type 2 diabetes-associated comorbidity of endothelial dysfunction and nephropathy. Stemming from currently proposed endothelium-centered therapeutic strategies for diabetic nephropathy, this review highlighted some most exploited pathways that involve the intricate coordination of vasodilators, vasoconstrictors and vaso modulatory molecules in the pathogenesis of diabetic nephropathy. We also emphasized the emerging roles of oxidative and epigenetic modifications of microvasculature as our prospective therapeutics for diabetic renal diseases. Finally, this review in particular addressed the potential use of multispectral optoacoustic tomography in real-time, minimally-invasive vascular imaging of small experimental animals for preclinical renal-kinetic drug trials. PMID- 27765535 TI - Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. AB - INTRODUCTION: We performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC. METHODS: Randomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation-defined subgroups. We used the fixed-effects inverse variance-weighted method to pool estimates of treatment efficacy. Statistical tests were two sided. RESULTS: In the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p = 0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients. PMID- 27765536 TI - 75SeHCAT scan in bile acid malabsorption in chronic diarrhoea. AB - Chronic diarrhoea is a common entity in daily clinical practice and it leads to a loss in these patients quality of life. It may be the main symptom of multiple ethiologies including bile acid malabsorption (BAM) which has a comparable prevalence to celiac disease. The BAM results from imbalances in the homeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease or ileal dysfunction (BAM type i), it can be considered idiopathic or primary (BAM type ii) or associated with other gastrointestinal entities (BAM type iii). Among the different diagnostic methods available, 75SeHCAT study is the primary current method due to its sensitivity, specificity, safety and low cost. The main disadvantage is that it's not available in all countries, so other diagnostic methods have appeared, such as serum measurement of FGF19 and C4, however they are significantly more complex and costly. The first-line treatment of bile acid diarrhoea is bile acid sequestrant, such as cholestyramine, which can be difficult to administer due to its poor tolerability and gastrointestinal side effects. These are less prominent with newer agents such as colesevelam. In summary, the BAM is a common entity underdiagnosed and undertreated, so it is essential to establish a diagnosis algorithm of chronic diarrhoea in which the 75SeHCAT study would be first or second line in the differential diagnosis of these patients. PMID- 27765538 TI - [Management of renal cystic masses]. AB - Cystic renal masses are a specific renal entity with a different management from solid lesions. Renal cysts are present in over 50% of patients after 50 years. Radiological diagnostic enables to rank their suspect nature of malignancy through the Bosniak classification. Type III and IV lesions are at high risk of malignancy, and are usually treated by partial nephrectomy. PMID- 27765537 TI - Aspirin, stroke and drug-drug interactions. AB - Low-dose aspirin, alone or in combination, is recommended for the secondary prevention of acute non-cardioembolic ischemic stroke and transient ischemic attack, starting soon after the acute event. Clinically-relevant drug-drug interactions (DDIs) are a major concern of regulatory agencies and practicing physicians. Drug's pharmacodynamics and/or pharmacokinetics account for clinically-relevant DDIs that modify efficacy and/or safety of one or more of the co-administered drugs. Some non-steroidal anti-inflammatory drugs interact with aspirin pharmacodynamics by competing on the drug target, i.e. the platelet's cyclooxygenase-1 protein. Although the molecular mechanism(s) of this DDI and its effect on the degree of platelet inhibition in vitro and ex vivo are well unraveled, nevertheless, the extent to which this DDI impacts on long-term antithrombotic efficacy of aspirin in secondary prevention remains unclear. Aspirin pharmacokinetics does not involve critical cytochrome P450 enzymes nor efflux transporters, therefore clinically-relevant DDIs competing on pharmacokinetic pathways seem unlikely. The co-administration of antiplatelet drugs with serotonin storage reuptake inhibitors can create a synergistic effect with antiplatelet agents on platelet inhibition. Low-dose aspirin, alone or in combination with other antiplatelet agents, remains a cornerstone in treating cerebrovascular disorders. The relatively straightforward pharmacokinetics of aspirin limits DDIs, giving it a unique advantage over most antiplatelet drugs. PMID- 27765539 TI - Chinese Version of the Healthy Lifestyle Beliefs Scale for Taiwanese Adolescents: A Psychometric Study. AB - BACKGROUND: Taiwanese adolescents' unhealthy lifestyles (e.g., unhealthy eating and sedentary behavior) are associated with excess weight and obesity, which affect their physical and mental health (e.g., depression). Because adolescents' beliefs about healthy lifestyles predict their actual lifestyles, a valid and reliable tool to measure their beliefs about healthy lifestyles is needed. METHODS: The Healthy Lifestyle Behavior Scale (HLBS) was translated into Chinese based on recommended guidelines. A convenience sample of 186 Taiwanese adolescents completed the Chinese version Healthy Lifestyle Behavior Scale (CHLBS) anonymously. We used Cronbach's alpha to determine the internal consistency of the CHLBS and exploratory and confirmatory factor analyses to examine the factor structure. RESULTS: The Cronbach's alpha for the CHLBS was .94. Exploratory analysis suggested that there were two factors and explained 57% of the total variance. The confirmatory factor analysis indicated an acceptable fit. CONCLUSION: The CHLBS is a reliable and valid scale. It can be used to gather information about Taiwanese adolescents' beliefs about healthy lifestyles, which will assist in developing culturally and developmentally relevant interventions. PMID- 27765540 TI - The economic legacy of endocrine-disrupting chemicals. PMID- 27765541 TI - Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. AB - BACKGROUND: Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison. METHODS: We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (?1=$1.33). FINDINGS: The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2.33% of GDP] vs $217 billion [1.28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12.6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion). INTERPRETATION: EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention. FUNDING: Endocrine Society, Ralph S French Charitable Foundation, and Broad Reach Foundation. PMID- 27765542 TI - Dosimetric comparison of helical tomotherapy, intensity-modulated radiation therapy, volumetric-modulated arc therapy, and 3-dimensional conformal therapy for the treatment of T1N0 glottic cancer. AB - Various radiotherapy planning methods for T1N0 laryngeal cancer have been proposed to decrease normal tissue toxicity. We compare helical tomotherapy (HT), linac-based intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), and 3-D conformal radiotherapy (3D-CRT) techniques for T1N0 laryngeal cancer. Overall, 10 patients with T1N0 laryngeal cancer were selected and evaluated. Furthermore, 10 radiotherapy treatment plans have been created for all 10 patients, including HT, IMRT, VMAT, and 3D-CRT. IMRT, VMAT, and HT plans vs 3D-CRT plans consistently provided superior planning target volume (PTV) coverage. Similar target coverage was observed between the 3 IMRT modalities. Compared with 3D-CRT, IMRT, HT, and VMAT significantly reduced the mean dose to the carotid arteries. VMAT resulted in the lowest mean dose to the submandibular and thyroid glands. Compared with 3D-CRT, IMRT, HT, and VMAT significantly increased the maximum dose to the spinal cord It was observed that the 3 IMRT modalities studied showed superior target coverage with less variation between each plan in comparison with 3D-CRT. The 3D-CRT plans performed better at the Dmax of the spinal cord. Clinical investigation is warranted to determine if these treatment approaches would translate into a reduction in radiation therapy induced toxicities. PMID- 27765543 TI - The Ratio Between Visceral and Subcutaneous Abdominal Fat Assessed by Computed Tomography Is an Independent Predictor of Mortality and Cardiac Events. AB - INTRODUCTION AND OBJECTIVES: Obesity is an important cardiovascular risk factor and the location of fat deposits seems to be an important determinant of its metabolic impact. Visceral adipose tissue (VAT) exerts a harmful effect on metabolic homeostasis, but few longitudinal studies have evaluated the prognostic impact of the ratio of VAT to subcutaneous adipose tissue (SAT). This study aimed to evaluate whether the VAT/SAT ratio was associated with all-cause mortality and cardiac events. METHODS: Registry-based retrospective cohort study. Eligible patients consisted of those without known heart disease referred to cardiac computed tomography (CT) angiography to evaluate suspected coronary artery disease (CAD). We included all patients with available information on VAT and SAT areas and coronary artery calcium (CAC) score. We assessed the combined endpoint of all-cause mortality, myocardial infarction or revascularization procedure at least 1 month after cardiac CT. RESULTS: The final population consisted of 713 participants (61% male; mean age, 57.7+/-10.2 years) followed up for a median of 1.3 years. The combined endpoint occurred in 66 patients; these patients showed a higher VAT/SAT ratio (1.06+/-0.74 vs 0.80+/-0.52, P=.0001). The VAT/SAT ratio was an independent predictor of death and cardiac events (HR = 1.43; 95%CI, 1.03 1.99), irrespective of cardiovascular risk factors, CAC, and the presence of CAD. CONCLUSIONS: The ratio between abdominal VAT/SAT was an independent predictor of death and coronary events, irrespective of cardiovascular risk factors, CAC, and the presence of CAD. This ratio is a CT-derived metric that may help to better identify patients with increased risk of death or cardiac events. PMID- 27765544 TI - Maximal Oxygen Consumption and Composite Indices of Femoral Neck Strength in a Group of Young Overweight and Obese Men. PMID- 27765545 TI - Multiscale molecular dynamics simulation approaches to the structure and dynamics of viruses. AB - Viral pathogens are a significant source of human morbidity and mortality, and have a major impact on societies and economies around the world. One of the challenges inherent in targeting these pathogens with drugs is the tight integration of the viral life cycle with the host's cellular machinery. However, the reliance of the virus on the host cell replication machinery is also an opportunity for therapeutic targeting, as successful entry- and exit-inhibitors have demonstrated. An understanding of the extracellular and intracellular structure and dynamics of the virion - as well as of the entry and exit pathways in host and vector cells - is therefore crucial to the advancement of novel antivirals. In recent years, advances in computing architecture and algorithms have begun to allow us to use simulations to study the structure and dynamics of viral ultrastructures at various stages of their life cycle in atomistic or near atomistic detail. In this review, we outline specific challenges and solutions that have emerged to allow for structurally detailed modelling of viruses in silico. We focus on the history and state of the art of atomistic and coarse grained approaches to simulate the dynamics of the large, macromolecular structures associated with viral infection, and on their usefulness in explaining and expanding upon experimental data. We discuss the types of interactions that need to be modeled to describe major components of the virus particle and advances in modelling techniques that allow for the treatment of these systems, highlighting recent key simulation studies. PMID- 27765546 TI - Intravascular Fibrolipoma of the Femoral Vein. AB - Lipoma of the lower leg vein is rare, and the histopathological variant, fibrolipoma, is even rarer. Here, we report an intravascular fibrolipoma located at the junction of the deep femoral vein and the femoral vein in a 50-year-old male patient. Tumor resection and venous reconstruction with a prosthetic graft were performed. Eight months later, the patient was asymptomatic and did not exhibit swelling. To our knowledge, this is the first case report of an intravascular fibrolipoma in the literature. Lower vein venography, computed tomography venography, ultrasonography, and histologic images are presented, along with a description of the procedures employed for tumor resection and venous reconstruction. PMID- 27765547 TI - Does Psychological Profile Influence Third Molar Extraction and Postoperative Pain? AB - PURPOSE: Our purposes were to determine the influence of psychological profile on hemodynamic changes in patients who undergo surgical removal of the third molars under intravenous sedation and to evaluate the effect on patients' anxiety and postoperative recovery. PATIENTS AND METHODS: We performed a prospective study of 100 patients (American Society of Anesthesiologists classes I and II; aged >=18 years) seen in the CIMIVClinic (Department of Oral Surgery, Casa de Salud University Hospital, Valencia, Spain) who underwent extractions of all third molars under intravenous sedation. All patients were administered the Symptom Checklist 90 Revised (SCL-90-R). The following parameters were monitored at different times during the surgical interventions: systolic blood pressure, diastolic blood pressure, oxygen saturation, and heart rate. Position and depth of impaction of the tooth (Pell and Gregory classification and Winter classification), surgery duration, and surgical technique also were recorded. Finally, the degree of pain experienced the week after the surgical intervention was measured using a visual analog scale. RESULTS: Patients' anxiety levels preoperatively were significantly higher in patients with psychological distress (P = .023). Postoperative pain significantly decreased from the first day to the seventh day in healthy patients but not in patients with altered psychological conditions (P < .05). Nevertheless, the hemodynamic changes were not correlated with the psychological impairment. CONCLUSIONS: Intravenous sedation enables the control of hemodynamic changes in all patients independently of their psychological profile. Patients with psychological distress present with higher levels of dental anxiety and postoperative pain. Future studies are needed to further clarify this interaction. PMID- 27765548 TI - Metastasis of Mammary Gland Malignant Phyllodes Tumor to the Mandibular Region: A Case Report and Review of the Literature. AB - Phyllodes tumor is a rare breast tumor described by Muller (1938) as a lesion comprising leaflike stromal fibrous components and narrow cysts. The frequency of distant metastasis from this entity is reportedly approximately 20%, and no effective therapy has been established, so the prognosis is poor. This report describes the case of a 60-year-old woman with a history of left lung resection who showed metastasis of a mammary gland malignant phyllodes tumor to the oral cavity. Intraoral examination showed an elastic, hard mass measuring 28 * 27 mm in the gingiva around the left mandibular second molar. Biopsy examination showed growth of giant cells and roughly circular cells showing positivity for S-100, p63, and vimentin on immunohistochemical staining. The authors diagnosed metastasis of the mammary gland malignant phyllodes tumor to the left mandible and performed cyber knife irradiation (44 Gy in 5 fractions) of the left mandible. The mass in the oral cavity disappeared after cyber knife irradiation, but the patient died of direct invasion to the spine. PMID- 27765549 TI - Factors Influencing Postoperative Complications in Reconstructive Microsurgery for Head and Neck Cancer. AB - PURPOSE: The present study aimed to analyze multiple variables and to determine the factors influencing postoperative complications in reconstructive microsurgeries for head and neck cancer. MATERIALS AND METHODS: This was a retrospective review of the medical records of patients with head and neck cancer who underwent free flap reconstruction after ablation surgery at the Cathay General Hospital (Taipei, Taiwan) from January 2010 to December 2014. Clinical and surgical procedure-related factors were retrieved from a database and analyzed. Major complications included flap failure and life-threatening events. Minor complications were defined as requiring only routine wound care or conservative treatments. To evaluate group differences, the chi2 test was applied for categorical variables and the Mann-Whitney U test was used for continuous variables. RESULTS: In total, 158 patients (145 men [91.8%], 13 women [8.2%]) were included in this study. The mean age of the study population was 52.4 years (range, 34 to 84 yr). The mean body mass index (BMI) was 23.71 kg/m2. Most patients (93.7%) had a history of cigarette smoking. Some patients had diabetes (20.3%) and hypertension (31.6%). The percentage of patients who underwent radiotherapy before surgery was 19.6%. The percentage whose flap required a salvage operation was 8.9%. The success rate of the microvascular surgeries was 95.6%. The major complication rate was 6.3% and the minor complication rate was 27.8%. No surgical mortality was noted. CONCLUSION: In these patients, poor nutrition status, indicated by low BMI and low albumin level, was associated with a greater tendency to develop postoperative complications. Patients who had diabetes or who had received radiotherapy before surgery had a high risk for major complications. A large skin paddle seemed to be an influencing factor for minor complications, such as wound dehiscence and superficial loss of flaps. PMID- 27765550 TI - Lingual Nerve Microsurgery Outcomes Using 2 Different Conduits: A Retrospective Cohort Study. AB - PURPOSE: This study compared a type 1 collagen conduit (NeuraGen) with a porcine small intestinal submucosa conduit (AxoGuard) when used in lingual nerve microsurgery and any differences in achieving functional sensory recovery (FSR). PATIENTS AND METHODS: All patients who underwent lingual nerve microsurgery performed by 1 surgeon (V.B.Z.) from 2007 to 2014 had their surgical information obtained by a retrospective review of hospital records and office charts after institutional review board approval. Those patients whose surgery included the use of a nerve conduit were included in the study. Subjective neurosensory recovery was determined by neurosensory testing, including responses to hot, cold, wisp, brush, and pinprick. Objective recovery was determined by testing 2 point discrimination and fine touch threshold with von Frey fibers. The objective findings were correlated to a Medical Research Council System score, with grades S3, S3+, and S4 indicating FSR. RESULTS: The conduits were compared using a Student t test with a 2-tailed hypothesis. The von Frey fiber test had a preoperative mean of 6.29 (standard deviation [SD], 0.95), which improved to 3.97 (SD, 0.67) for the NeuraGen and 4.17 (SD, 0.56) for the AxoGuard. Two-point discrimination improved from a mean higher than 19.42 to 9.32 mm (SD, 2.96 mm) for the NeuraGen and 9.67 mm (SD, 2.13 mm) for the AxoGuard. The mean FSR was S3+. CONCLUSIONS: There were no meaningful differences in outcomes between the 2 conduits studied, and all patients achieved FSR according to the Medical Research Council Scale. PMID- 27765551 TI - Facial bone reconstruction with prefabricated vascularized calvarium flaps in children and young adults: Advantages and long-term results. AB - INTRODUCTION: Reconstruction of facial bone defects in children is challenging. The use of well-vascularized bone is mandatory to obtain stable lasting results. This study reports our experience of facial bone reconstruction using prefabricated vascularized calvarium flaps. METHODS: Retrospective case series of 50 patients who underwent 52 maxillary, malar, and mandibular reconstructions between 1988 and 2014 using prefabricated vascularized calvarium flaps. Forty nine patients suffered from noma sequels; one patient had craniofacial cleft Tessier 3-11. Surgery consisted of a two-step procedure beginning with flap delay and prelamination with skin grafting on the galea. Flap harvest followed at least 2 weeks later (range, 2-16 weeks), including a full-thickness calvarium fragment, which was set into the facial defect. RESULTS: Early complications concerned wound healing and infections requiring surgical revision in six patients at the recipient and six at the donor site. There was one flap loss. Clinical long-term assessment at 15-year median follow-up (range, 1-27 years) showed good results, assuring facial height and contour. Radiological long-term results demonstrated excellent integration of the flap to the adjacent facial skeleton of the growing child. CONCLUSIONS: Prefabricated vascularized calvarium flaps are an effective, safe and lasting method for reconstruction of facial bone defects in children. PMID- 27765552 TI - A retrospective analysis of preoperative staging modalities for oral squamous cell carcinoma. AB - BACKGROUND: An accurate preoperative assessment of cervical lymph node status is a prerequisite for individually tailored cancer therapies in patients with oral squamous cell carcinoma. The detection of malignant spread and its treatment crucially influence the prognosis. The aim of the present study was to analyze the different staging modalities used among patients with a diagnosis of primary oral squamous cell carcinoma between 2008 and 2015. MATERIAL AND METHODS: An analysis of preoperative staging findings, collected by clinical palpation, ultrasound, and computed tomography (CT), was performed. The results obtained were compared with the results of the final histopathological findings of the neck dissection specimens. A statistical analysis using McNemar's test was performed. RESULTS: The sensitivity of CT for the detection of malignant cervical tumor spread was 74.5%. The ultrasound obtained a sensitivity of 60.8%. Both CT and ultrasound demonstrated significantly enhanced sensitivity compared to the clinical palpation with a sensitivity of 37.1%. No significant difference was observed between CT and ultrasound. A combination of different staging modalities increased the sensitivity significantly compared with ultrasound staging alone. No significant difference in sensitivity was found between the combined use of different staging modalities and CT staging alone. The highest sensitivity, of 80.0%, was obtained by a combination of all three staging modalities: clinical palpation, ultrasound and CT. CONCLUSIONS: The present study indicates that CT has an essential role in the preoperative staging of patients with oral squamous cell carcinoma. Its use not only significantly increases the sensitivity of cervical lymph node metastasis detection but also offers a preoperative assessment of local tumor spread and resection borders. An additional non invasive cervical lymph node examination increases the sensitivity of the tumor staging process and reduces the risk of occult metastasis. PMID- 27765553 TI - Implant survival and patient satisfaction of reduced diameter implants made from a titanium-zirconium alloy: A retrospective cohort study with 550 implants in 311 patients. AB - The aim of the study was to evaluate implant survival of reduced-diameter implants compared to regular-diameter implants. A retrospective evaluation of 154 Straumann Bone Level Roxolid(r) implants (diameter 3.3 mm) with SLActive(r) surface in 107 patients, which were inserted between 2009 and 2010 in private practice, was performed. The mean observation period was 22.4 +/- 8.2 months. 396 Straumann SLActive(r) implants (4.1 mm and 4.8 mm) in 204 patients, with an observation period of 28.4 +/- 10.1 months served as control group. Implant survival rate, resonance frequency analysis and patient satisfaction were evaluated. The implant survival rate was 97.4% in the test vs. 98.5% in the control group. Resonance frequency analysis showed statistically significant lower values for the reduced-diameter implants. Patient satisfaction showed no significant difference between the test and the control group. Reduced-diameter implants displayed high survival rates during the period investigated and represent a convincing treatment alternative. Long-term follow-up investigations confirmed the high implant survival rates of 96.8% (after 69.7 +/- 12.3 months) in the test group and 98.5% (after 76.0 +/- 13.6 months) in the control group. PMID- 27765554 TI - Environmental Tobacco Smoke Exposure and Risk of Stroke in Never Smokers: An Updated Review with Meta-Analysis. AB - OBJECTIVES: The study aimed to review the epidemiological evidence relating environmental tobacco smoke exposure to stroke in never smokers. METHODS: The study is similar to our review in 2006, with searches extended to March 2016. RESULTS: Twelve further studies were identified. A total of 28 studies varied considerably in design, exposure indices used, and disease definition. Based on 39 sex-specific estimates and the exposure index current spousal exposure (or nearest equivalent), the meta-analysis gave an overall fixed-effect relative risk estimate of 1.23 (95% confidence interval: 1.16-1.31), with significant (P < .05) heterogeneity. There was no significant heterogeneity by sex, continent, fatality, disease end point, or degree of adjustment for potential confounding factors. Relative risks were less elevated in prospective studies (1.15, 1.06 1.24) than in case-control studies (1.44, 1.22-1.60) or cross-sectional studies (1.40, 1.21-1.61). They also varied by publication year, but with no trend. A significant increase was not seen in studies that excluded smokers of any tobacco (1.07, .97-1.17), but was seen for studies that included pipe- or cigar-only smokers, occasional smokers, or long-term former smokers. No elevation was seen for hemorrhagic stroke. Relative risk estimates were similar using ever rather than current exposure, or total rather than spousal exposure. Eleven studies provided dose-response estimates, the combined relative risk for the highest exposure level being 1.56 (1.37-1.79). Many studies have evident weaknesses, recall bias, and particularly publication bias being major concerns. CONCLUSIONS: Although other reviewers inferred a causal relationship, we consider the evidence does not conclusively demonstrate this. We repeat our call for publication of data from existing large prospective studies. PMID- 27765555 TI - Magnetic Resonance Imaging-Based Assessment of Carotid Atheroma: a Comparative Study of Patients with and without Coronary Artery Disease. AB - BACKGROUND: Functional magnetic resonance (MR) imaging of atheroma using contrast media enables assessment of the systemic severity of atherosclerosis in different arterial beds. Whether black-blood imaging has similar ability remains widely unexplored. In this study, we evaluate whether black-blood imaging can differentiate carotid plaques of patients with and without coronary artery disease (CAD) in terms of morphological and biomechanical features of plaque vulnerability, thereby allowing assessment of the systemic severity nature of atherosclerosis in different arterial beds. METHODS: Forty-one patients with CAD and 59 patients without CAD underwent carotid black-blood MR imaging. Plaque components were segmented to identify large lipid core (LC), ruptured fibrous cap (FC), and plaque hemorrhage (PH). These segmented contours of plaque components were used to quantify maximum structural biomechanical stress. RESULTS: Patients with CAD and without CAD had comparable demographics and comorbidities. Both groups had comparable prevalence of morphological features of plaque vulnerability (FC rupture, 44% versus 41%, P = .90; PH, 58% versus 47%, P = .78; large LC, 32% versus 47%, P = .17), respectively. The maximum biomechanical stress was not significantly different for both groups (241versus 278 kPa, P = .14) respectively. CONCLUSIONS: Black-blood imaging does not appear to have the ability to differentiate between the morphological and biomechanical features of plaque vulnerability when comparing patients with and without symptomatic atherosclerotic disease in a distant arterial territory such as coronary artery. PMID- 27765556 TI - Impact of the New American Heart Association/American Stroke Association Definition of Stroke on the Results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial. AB - BACKGROUND: An American Heart Association/American Stroke Association (AHA/ASA) writing committee has recently recommended that tissue evidence of cerebral infarction associated with temporary symptoms (CITS) lasting <24 hours should be considered a stroke. We analyzed the impact of considering CITS as equivalent to stroke on the results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. METHODS: We compared outcomes in the medical (n = 227) and stenting (n = 224) groups in SAMMPRIS using the following primary end point (new components in bold): any stroke, CITS, or death within 30 days after enrollment or within 30 days after a revascularization procedure for the qualifying lesion during follow-up; or ischemic stroke or CITS in the territory of the qualifying artery beyond 30 days. We also compared the use of brain magnetic resonance imaging (MRI) after transient ischemic attacks (TIAs) in both treatment groups. RESULTS: By considering CITS as equivalent to stroke, the number of primary end points increased from 34 to 43 in the medical group and from 52 to 66 in the stenting group of SAMMPRIS. The Kaplan-Meier curves for the primary end points in the 2 groups were significantly different (P = .009). The percentage of patients with reported TIAs who underwent brain MRI was 69% in the medical group and 61% in the stenting group (P = .40). CONCLUSION: Using the AHA/ASA definition of stroke resulted in a substantially higher primary end point rate in both treatment groups and an even higher benefit from medical therapy over stenting than originally shown in SAMMPRIS. The higher rate of CITS in the stenting group was not due to ascertainment bias. PMID- 27765557 TI - Effects of Talocrural Mobilization with Movement on Ankle Strength, Mobility, and Weight-Bearing Ability in Hemiplegic Patients with Chronic Stroke: A Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVE: In general, adequate movement of the ankle joint is known to play an important role in functional activities. Stroke survivors frequently have limited range of motion of the ankle, leading to dysfunctional weight transfer toward the paretic lower limb during standing or gait. The purpose of this study was to investigate the effects of talocrural mobilization with movement (MWM) on ankle strength, dorsiflexion passive range of motion (DF PROM), and weight-bearing ability on the paretic limb during standing or gait in stroke patients with limited ankle dorsiflexion. METHODS: Twenty-six participants with chronic hemiplegia (>6 months post stroke) were divided into 2 groups: MWM group (n = 13) and control group (n = 13). Both groups attended conventional physiotherapy sessions 3 times a week for 5 weeks. Additionally, the MWM group underwent talocrural MWM 3 times a week for 5 weeks. Isokinetic ankle strength, DF-PROM, and weight-bearing ability measures included the limit of stability (LOS); gait parameters were evaluated before and after interventions. RESULTS: Plantarflexors peak torque and DF-PROM significantly increased in the MWM group. In addition, forward and forward-paretic direction LOS significantly increased in the MWM group. Paretic direction LOS, single-limb support phase of the paretic limb significantly increased and double limb support phase significantly decreased within the MWM group. CONCLUSIONS: This study demonstrates that talocrural MWM has an augmented effect on ankle strength, mobility, and weight bearing ability in chronic stroke patients with limited ankle motion when added to conventional therapy. PMID- 27765558 TI - Juvenile myoclonic epilepsy may be a disorder of cortex rather than thalamus: An effective connectivity analysis. AB - Although juvenile myoclonic epilepsy has been considered as a disorder of thalamo cortical circuit, it is not determined the causality relationship between thalamus and cortex. The aim of this study was to evaluate whether juvenile myoclonic epilepsy is a disorder of thalamus or cortex. Twenty-nine patients with juvenile myoclonic epilepsy and 20 normal controls were enrolled in this study. In addition, we included 10 patients with childhood absence epilepsy as a disease control group. Using whole-brain T1-weighted MRIs, we analyzed the volumes of the structures, including hippocampus, thalamus, and total cortex, with FreeSurfer 5.1. We also investigated the effective connectivity among these structures using SPSS Amos 21 based on these volumetric measures. The structural volumes in juvenile myoclonic epilepsy were not different from those in normal controls. There was a statistically significant effective connectivity from the total cortex to the thalamus in the patients with juvenile myoclonic epilepsy. In addition, a significant effective connectivity from the hippocampus to the ipsilateral thalamus was revealed. Unlike the patients with juvenile myoclonic epilepsy, neither the patients with childhood absence epilepsy nor normal controls had a significant effective connectivity from the total cortex to the thalamus or from the thalamus to the cortex. The connectivity of brain in patients with juvenile myoclonic epilepsy could be different from that in patients with childhood absence epilepsy, and the cortex rather than the thalamus might play a critical role in the pathogenesis of juvenile myoclonic epilepsy. PMID- 27765559 TI - The use of isoflurane and desflurane as inhalational agents for glioblastoma surgery. A survival analysis. AB - BACKGROUND: Several studies have examined the impact of anesthetics on cancer recurrence. Isoflurane but not desflurane has protumoral effects. We hypothesize the use of isoflurane but not desflurane during surgery for primary GBM is an independent predictor of disease progression and mortality. METHODS: 378 adult patients were included in the study. The progression free survival (PFS) and overall survival (OS) rates at 1 and 5years were compared in patients who had either desflurane or isoflurane alone or in combination with propofol infusion. Multivariate analyses were conducted to test the association between preoperative, intraoperative and postoperative hyperglycemia with PFS and OS. RESULTS: Kaplan-Meier curves demonstrated similar survival in patients who had either desflurane or isoflurane. The use of a propofol infusion during surgery did not affect survival. Univariate analysis demonstrated that age, body mass index and the adjusted Charlson comorbidity score were associated with reduced survival. The multivariate analysis confirmed that age and BMI but not the type volatile anesthetic use were independent prognostic factors for PFS (HR, 95%CI: 1.07, 0.85-1.37, 9=0.531) and OS (HR, 95%CI: 1.13, 0.86-1.48, p=0.531). CONCLUSION: The use of isoflurane or desflurane during GBM surgery is not associated with reduced PFS or OS. PMID- 27765560 TI - The incidence of adjacent segment disease after lumbar discectomy: A study of 751 patients. AB - INTRODUCTION: The objective of this study is to determine the incidence and prognostic factors of adjacent segment disease (ASD) following first-time lumbar discectomy (LD). METHODS: We retrospectively reviewed all neurosurgical patients who underwent first-time LD for degenerative lumbar disease from 1990 to 2012. ASD was defined as a clinical and radiographic progression of degenerative spinal disease that required surgical decompression (with or without fusion) at the level above or below the index discectomy. Adjusted odds ratios were calculated from multivariable logistical regression controlling for sex and age, as well as postoperative sensory deficit, motor deficit, back pain, neurogenic claudication, and radiculopathy. RESULTS: Of the 751 patients who underwent single-level LD, the cumulative reoperation rate for degenerative spinal disease was 10.79%. The incidence of ASD requiring reoperation was 4% over 3.11years. More specifically, the incidence of adjacent level discectomy was 1.86% over 3.45years. The annualized reoperation rate for ASD was 1.35% (1.35 ASD reoperations per 100 person-years). The 63.33% incidence of cranial ASD requiring reoperation was statistically significantly higher than the 40.00% incidence of caudal ASD requiring reoperation. Following multivariable logistical regression, the strongest (and only) statistically significant predictor of ASD requiring reoperation was lower extremity radiculopathy after the index discectomy operation (OR=14.23, p<0.001). CONCLUSIONS: In the first series on ASD following first-time LD without fusion, the rate of reoperation for ASD was 4% and the cumulative reoperation rate 10.79%. Rostral ASD is more common than caudal ASD and lower extremity radiculopathy is the strongest predictor of ASD. PMID- 27765561 TI - Impact of Parkinson's disease on perioperative complications and hospital cost in multilevel spine fusion: A population-based analysis. AB - Parkinson's disease (PD) is a neurodegenerative disorder manifesting over time to result in reduced mobility. The impact of PD on spinal fusion has yet to be addressed on a nationwide level. The Nationwide Inpatient Sample (NIS) from 2001 to 2012 was used for analysis. Admissions with spinal fusion of two or more vertebrae (ICD-9 codes=81.62, 81.63 and 81.64) were included and then stratified based on the presence or absence of PD (ICD-9 code=332.0); patients with cancer (ICD-9 codes=140-239) or trauma (ICD-9 codes=805.0-806.9) were excluded. Propensity score matching adjusted for potential confounding effects introduced by patient age, race, sex, and primary payer for care. 570,858 patients receiving spinal fusion of two or three vertebrae (1-2 levels) were identified, 2648 (0.5%) of whom had PD. Analysis revealed that PD was independently predictive for increased in-hospital mortality, durotomy, paraplegia, postoperative infection, venous thrombotic events, inferior vena cava filter placement, red blood cell transfusion, pulmonary embolism, total hospital charge >$200,000, length of stay >1week, non-routine discharge disposition, acute respiratory distress syndrome, acute posthemorrhagic anemia, multisystem complications (nervous system, cardiac, respiratory, urinary), and device-related complications (all P<0.001). In conclusion, these findings from a nationwide analysis comprising a 12-year period indicate that PD is significantly associated with increased in-hospital morbidity, mortality, and cost following spine fusion of 1-2 levels when compared with the general population. These findings point to the need for risk stratification and adjustment of quality metrics for this growing patient population, and should be integrated into operative decision-making and patient counseling. PMID- 27765562 TI - Extreme lateral interbody fusion (XLIF): A single-center clinical and radiological follow-up study of 20 patients. AB - Extreme lateral interbody fusion (XLIF) is an alternative to standard posterior approaches for achieving fusion in the lumbar spine. It allows exposure of the lateral aspect of the lumbar disc through a lateral approach with the possibility to insert a wide footprint interbody cage as a stand-alone procedure or associated with a uni- or bilateral percutaneous fixation. This is a retrospective series of 20 consecutive patients operated with a XLIF procedure from 2014 to 2015. N=10 women and N=10 men with a mean age of 67.5years (range 37.9-81.2) were included in the study. N=18 patients have been operated at one level, while N=2 patients underwent a double-level XLIF. The index levels were: L2-L3 in 2, L3-L4 in 7, L4-L5 in 9 and L3-L5 in 2 patients, respectively. The mean clinico-radiological follow-up was 9.8months (range 2.5-16.6). The clinical outcome was assessed with the Oswestry Disability Index (ODI), Euro-Qol (EQ)-5D, visual analogue scale (VAS) and EQ-5D index scores. Preoperative, postoperative and follow-up sagittal balance was assessed by EOS full spine X-ray. Furthermore, presence or absence of fusion was assessed by thin cuts CT scan at the end of the follow-up. The analysis highlighted a clear clinical improvement for the study collective. The mean ODI improved from 41.6 preoperatively to 23.5 at the last follow-up (p<0.0036). EQ-5D VAS and EQ-5D index improved from 45.5 to 71.8 (p<0.0001) and from 0.454 to 0.693 (p<0.0002), respectively. Analysis of the sagittal balance revealed an increase of the total lumbar lordosis, however not in a statistically significant manner (p=0.164). Furthermore, an increase of 55.7% in mean disc height (from 7.0mm to 10.9mm) has been observed (p<0.0001). Surprisingly, the right foramen height was increased in a statistically significant manner compared to the left one, but both of them increased in absolute values. However, foraminal area on both sides did not significantly increase. The mean canal area was 115.7mm2 preoperatively and 136.5mm2 at follow up (p=0.1325). Radiological fusion was observed in every case at the end of the follow-up period. The XLIF procedure accomplishes a secure and effective interbody fusion. This approach allows for an indirect decompression of neural structures by restoring foramen dimensions and disc space height, leading to an improvement of symptoms. Furthermore, XLIF seems to improve segmental sagittal balance. PMID- 27765564 TI - Evaluation of the LDBIO point of care test for the combined detection of toxoplasmic IgG and IgM. AB - The toxoplasma ICT IgG-IgM rapid diagnostic test for the simultaneous detection of specific toxoplasmic immunoglobulin (Ig) G and IgM was compared with the Architect fully automated chemiluminescence test. Four hundred sera were included, among which 248 scored negative in Architect. The cassettes were easily read with the naked eye. Diagnostic sensitivity and specificity were 97% and 96%, respectively. The test scored 8 false-positive IgG and yielded negative results in 3 sera displaying unspecific IgM in Architect. The LDBIO appears to be a reliable first line test, although the false-positive results for IgG deserve further investigation. Such an easily performed test could be used advantageously for screening for toxoplasmosis in pregnant women. PMID- 27765563 TI - Predictors of aggressive clinical phenotype among immunohistochemically confirmed atypical adenomas. AB - Despite formal pathological criteria, not all atypical pituitary adenomas display clinically aggressive behavior. We set out to determine which factors predict a clinically aggressive phenotype among a cohort of atypical pituitary adenomas. Medical records were retrospectively reviewed from April 2008 to July 2015. Of 569 pituitary adenomas, 47 (8.3%) patients were surgically treated for atypical adenomas as defined by the WHO criteria. Clinically aggressive adenomas were defined as occurring in those patients who necessitated additional therapeutic intervention after the index (first) surgery, including additional surgery, medical therapy, or radiosurgery. Forty-seven patients with histopathological and immunohistochemical confirmation of atypical adenomas were identified and of these, 23 were noted to have a clinically aggressive course. Among the remaining 24 patients, the disease remained quiescent after the index surgery. On univariate analysis, clinically aggressive lesions were more likely to have a larger axial diameter on MRI (2.9+/-1.9cm vs. 1.9+/-0.7cm, p=0.02), greater incidence of cavernous sinus invasion (65.2% vs. 20.8%, p<0.01), and greater incidence of clival extension (60.9% vs. 0, p<0.01) on preoperative imaging. The two groups were equivalent with regard to immunohistochemical staining for ACTH, HGH, LH, FSH, PRL, and TSH. Clinically aggressive lesions, however, trended towards a greater average MIB-1 proliferative index (7.5%+/-4.9 vs. 6.0%+/-3.6, p=0.03). On multivariate analysis, the MIB-1 proliferative index trended towards statistical significance (p=0.06) as an independent predictor of clinical aggressiveness. Atypical pituitary adenomas are defined by a rigid set of immunohistochemical markers, but not all necessarily demonstrate an aggressive clinical phenotype. PMID- 27765565 TI - [Real-time safety audits in a neonatal unit]. AB - BACKGROUND: Random audits are a safety tool to help in the prevention of adverse events, but they have not been widely used in hospitals. The aim of the study was to determine, through random safety audits, whether the information and material required for resuscitation were available for each patient in a neonatal intensive care unit and determine if factors related to the patient, time or location affect the implementation of the recommendations. MATERIAL AND METHODS: Prospective observational study conducted in a level III-C neonatal intensive care unit during the year 2012. The evaluation of written information on the endotracheal tube, mask and ambu bag prepared of each patient and laryngoscopes of the emergency trolley were included within a broader audit of technological resources and study procedures. The technological resources and procedures were randomly selected twice a week for audit. Appropriate overall use was defined when all evaluated variables were correctly programmed in the same procedure. RESULTS: A total of 296 audits were performed. The kappa coefficient of inter observer agreement was 0.93. The rate of appropriate overall use of written information and material required for resuscitation was 62.50% (185/296). Mask and ambu bag prepared for each patient was the variable with better compliance (97.3%, P=.001). Significant differences were found with improved usage during weekends versus working-day (73.97 vs. 58.74%, P=.01), and the rest of the year versus 3rd quarter (66.06 vs. 52%, P=.02). CONCLUSIONS: Only in 62.5% of cases was the information and the material necessary to attend to a critical situation urgently easily available. Opportunities for improvement were identified through the audits. PMID- 27765566 TI - Improvement of thermostability and halostability of beta-1,3-1,4-glucanase by substituting hydrophobic residue for Lys48. AB - The aim of this study was to improve the stability of beta-1,3-1,4-glucanase by substituting hydrophobic residue for specific amino acid. The results indicated that the catalytic efficiency, thermostability and halostability were enhanced simultaneously by replacement of Lys48 with Ala (K48A) or Leu (K48L). Comparison of kinetic parameters revealed that catalytic efficiency of mutants is enhanced as a result of the increase in substrate affinity. A great improvement in thermostability and halostability was observed. The half-lives of mutants significantly increased (up to ~7-fold) at 60-70 degrees C. Moreover, relative enzymatic activities of mutants were observed more than 80% even in the presence of 30% NaCl, and half-lives were increased to 3-fold that of wild-type. Based on above results, when applied to ionic liquid, mutants were more active and stable compared to wild-type. These were the results from improvement of protein functions by the substitution of hydrophobic single residue in adjacent with forming carbohydrate binding cavity. Therefore, this report could be helpful for improvement of the enzyme property and for biotechnological application as well. PMID- 27765567 TI - Hypermethylation of 28S ribosomal RNA in beta-thalassemia trait carriers. AB - Ribosome biogenesis is the process of synthesis of the cellular ribosomes which mediate protein translation. Integral with the ribosomes are four cytoplasmic ribosomal RNAs (rRNAs) which show extensive post-transcriptional modifications including 2'-O-methylation and pseudouridylation. Several hereditary hematologic diseases including Diamond-Blackfan anemia have been shown to be associated with defects in ribosome biogenesis. Thalassemia is the most important hematologic inherited genetic disease worldwide, and this study examined the post transcriptional ribose methylation status of three specific active sites of the 28S rRNA molecule at positions 1858, 4197 and 4506 of beta-thalassemia trait carriers and normal controls. Samples from whole blood and cultured erythroid cells were examined. Results showed that site 4506 was hypermethylated in beta thalassemia trait carriers in both cohorts. Expression of fibrillarin, the ribosomal RNA methyltransferase as well as snoRNAs were additionally quantified by RT-qPCR and evidence of dysregulation was seen. Hemoglobin E trait carriers also showed evidence of dysregulation. These results provide the first evidence that ribosome biogenesis is dysregulated in beta-thalassemia trait carriers. PMID- 27765568 TI - Biochemical characterization of an extremely stable pH-versatile laccase from Sporothrix carnis CPF-05. AB - Functionality of enzymes within narrow pH range and temperature is a major challenge which limits their industrial applications, hence, there is need to search for thermostable pH-versatile enzymes. Here, a novel thermostable pH versatile laccase from Sporothrix carnis CPF-05 was purified by ion-exchange and gel filtration chromatography. Single protein band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) confirmed homogeneity of the enzyme with molecular weight of 56kDa. Enzyme yield was 3.9% and purification fold was 2.84. Purified laccase exhibited optimum activity at 50 degrees C and retained 56% of its initial activity at 80 degrees C after 180min of incubation with 2,2' azino-di-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) as substrate. The enzyme had optimum pH of 7.0 and was stable over pH range of 3.0 to 11.0. Laccase activity was enhanced by Cu2+ and Mn2+ ions but inhibited by Ca2+, Mg2+, Ba2+and Hg2+ ions. Purified laccase was mildly inhibited by urea, sodium azide and surfactants while exhibiting tolerance to organic solvents. The enzyme demonstrated broad substrate specificity. Kinetic parameters, Km and Vmax of the purified laccase for ABTS were 0.0316mM and 7.940mM/min, respectively. Thermostability, pH-versatility and other characteristics of laccase from S. carnis CPF-05 indicate its suitability for variety of industrial processes. PMID- 27765569 TI - beta-(1->3,1->6)-d-glucans produced by Diaporthe sp. endophytes: Purification, chemical characterization and antiproliferative activity against MCF-7 and HepG2 C3A cells. AB - This study reports the characterization and antiproliferative activity of exopolysaccharides (EPS) produced by submerged cultures of the endophytes Diaporthe sp. JF766998 and Diaporthe sp. JF767007 isolated from the medicinal plant Piper hispidum Sw. Both strains secreted a crude EPS that, upon size exclusion chromatography, showed to contain a heteropolysaccharide (galactose, glucose and mannose) and a high-molecular weight glucan. Data from methylation analysis, FTIR and NMR spectroscopy (1H, COSY, TOCSY and HSQC-DEPT) indicated that the purified glucan consisted of a main chain of glucopyranosyl beta-(1->3) linkages substituted at O-6 by glucosyl residues. According to MTT assay, some treatments of both beta-glucans have antiproliferative activity against human breast carcinoma (MCF-7) and hepatocellular carcinoma (HepG2-C3A) cells after 24 and 48h of treatment, exhibiting a degree of inhibition ratio that reached the highest values at 400MUg/mL: 58.0% (24h) and 74.6% (48h) for MCF-7 cells, and 61.0% (24h) and 83.3% (48h) for HepG2-C3A cells. These results represent the first reports on the characterization and antiproliferative effect of beta glucans from Diaporthe species and also expand the knowledge about bioactive polysaccharides from endophytic sources. PMID- 27765571 TI - Important amino acid residues involved in folding and binding of protein-protein complexes. AB - Protein-protein interactions perform diverse functions in living organism. The integrative analysis of binding and stabilizing residues will provide insights on the functions of protein-protein complexes. In this work, we constructed a non redundant dataset of 261 protein-protein complexes and identified binding site residues, stabilizing residues and common to both binding and stabilizing, termed as "key residues". We found that 6.1% of residues are involved in binding and 6.8% of residues are important for folding and stability. Among them, only 2% are involved in both folding and binding, which shows the importance and specific roles played by these residues. The key residues have been analyzed based on protein function, binding affinity, rigid and flexible complexes, amino acid preference and structure based parameters. We found that high affinity complexes have more key residues than low affinity complexes. In addition, key residues are enriched with the combination of specific hydrophobic and charged/polar residues. Atomic contacts between interacting proteins have distinct preferences of polar polar, nonpolar-nonpolar and polar-nonpolar contacts in different functional classes of protein-protein complexes. Further, the influence of sequence and structural parameters such as surrounding hydrophobicity, solvent accessibility, secondary structure, long-range order and conservation score has been discussed. The analysis can be used to comprehend the interplay between stability and binding in protein-protein complexes. PMID- 27765570 TI - Alkaline proteases from a newly isolated Micromonospora chaiyaphumensis S103: Characterization and application as a detergent additive and for chitin extraction from shrimp shell waste. AB - The present study was undertaken to characterize the extracellular thermostable serine alkaline proteases from newly actinomycete strain Micromonospora chaiyaphumensis S103 and to describe their evaluation in commercial detergents and shrimp waste deproteinization. This proteolytic crude extract was active and stable in alkaline solution. It was extremely stable in the pH range of 5.0-12.0. The optimum pH and temperature were 8.0 and 70 degrees C, respectively, using casein as a substrate. The thermoactivity and thermostability of proteases were enhanced by the addition of 5mM Ca2+. Proteases from S103 were also used for shrimp wastes deproteinization in the process of chitin preparation. The percent of protein removal after 3h hydrolysis at 45 degrees C with an enzyme/substrate ratio of 20U/mg had reached 93%. Furthermore, S103 crude enzyme was stable towards several organic solvents and retained 100% of its original activity after 90days of incubation in the presence of methanol, hexane, acetone, and DMSO. These properties make S103 proteases an ideal choice for application in detergent formulations, chitin production, and enzymatic peptide synthesis. PMID- 27765572 TI - Mouse eosinophil associated ribonucleases: Mechanism of cytotoxic, antibacterial and antiparasitic activities. AB - Ribonuclease A family is a group of proteins having similar structures and catalytic mechanism but different functions. Human eosinophil granules contain two ribonucleases belonging to the RNase A family, eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN). In mouse, 15 orthologs of EDN and ECP, called mouse eosinophil associated ribonucleases (mEARs) have been reported which are expressed under different pathophysiological conditions. In this study, we have characterized mEAR2, mEAR5, mEAR7 and mEAR11, and compared them with ECP for their catalytic, cytotoxic, antibacterial and antiparasitic activities. All four mEARs had cytotoxic, antibacterial and antiparasitic activities. Generally, mEAR5 and mEAR2 were more cytotoxic than mEAR7, mEAR11 and ECP. The antimicrobial activities of mEAR7 and mEAR5 were higher than those of mEAR11 and mEAR2. The cytotoxic activity appeared to be associated with the basicity and RNase activity of mEARs, whereas no such correlation was observed for antimicrobial activities. The differential selective expression of mEARs under various pathophysiological conditions may be associated with the different biological activities of various mEARs. PMID- 27765573 TI - A polysaccharide from Sargassum thunbergii inhibits angiogenesis via downregulating MMP-2 activity and VEGF/HIF-1alpha signaling. AB - A water-soluble polysaccharide (STPC2) was isolated from the boiling-water extract of Sargassum thunbergii, purified by CaCl2 precipitation and chromatography on DEAE-cellulose and Sephacryl S-300 column. It was found that STPC2, with a molecular weight of 57kD, was composed of fucose, xylose, galactose and glucuronic acid, in a ratio of 8.1: 3.8: 2.1: 1.0. Additionally, we found that STPC2 significantly inhibited endothelial cell migration and tube formation without toxicity. Moreover, STPC2 significantly inhibited lung cancer cell A549 migration and proliferation. It was found that STPC2 treatment suppressed MMP-2 gene expression at transcriptional level and enzymatic activity. Furthermore, STPC2 reduced the mRNA and protein expression of vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor (HIF)-1 alpha in the endothelial cells. Taken together, our findings indicated that STPC2 was a potent bioactive polysaccharide with distinct anti-angiogenesis activity against tumor migration via down-regulation of MMP-2 activity and VEGF/HIF-1alpha signaling pathway. PMID- 27765574 TI - An investigation into corneal enzymatic resistance following epithelium-off and epithelium-on corneal cross-linking protocols. AB - The aim of this study was to investigate corneal enzymatic resistance following epithelium off and on riboflavin/UVA cross-linking (CXL). One hundred and fourteen porcine eyes were divided into four non-irradiated control groups and seven CXL groups. The latter comprised; (i) epithelium-off, 0.1% iso-osmolar riboflavin, 9 mW UVA irradiation for 10 min, (ii) disrupted epithelium, 0.1% hypo osmolar riboflavin, 9 mW UVA for 10 min, (iii) epithelium-on, 0.25% hypo-osmolar riboflavin with 0.01% benzylalkonium chloride (BACS), 9 mW UVA for 10 min, (iv) epithelium-on, 5 min iontophoresis at 0.1 mA for 5 min with 0.1% riboflavin solution, 9 mW UVA for 10 min or (v) 12.5 min, (vi) epithelium-on, prolonged iontophoresis protocol of 25 min with 1.0 mA for 5 min and 0.5 mA for 5 min with 0.25% riboflavin with 0.01% BACS, 9 mW UVA for 10 min or (vii) 12.5 min. Enzymatic resistance was assessed by daily measurement of a corneal button placed in pepsin solution and measurement of corneal button dry weight after 11 days of digestion. This study revealed that the enzymatic resistance was greater in CXL corneas than non-irradiated corneas (p < 0.0001). Epithelium-off CXL showed the greatest enzymatic resistance (p < 0.0001). The prolonged iontophoresis protocol was found to be superior to all other trans-epithelial protocols (p < 0.0001). A 25% increase in UVA radiance significantly increased corneal enzymatic resistance (p < 0.0001). In conclusion, although epithelium-on CXL appears to be inferior to epithelium-off CXL in terms of enzymatic resistance to pepsin digestion, the outcome of epithelium-on CXL may be significantly improved through the use of higher concentrations of riboflavin solution, a longer duration of iontophoresis and an increase in UVA radiance. PMID- 27765576 TI - Small and diminutive polyps: No cancer, no risk! PMID- 27765575 TI - Exercise interventions for the improvement of falls-related outcomes among older adults with diabetes mellitus: A systematic review and meta-analyses. AB - INTRODUCTION: Falls as a complication of diabetes mellitus (DM) can have a major impact on the health of older adults. Previous reviews have demonstrated that certain exercise interventions are effective at reducing falls in older people; however, no studies have quantified the effectiveness of exercise interventions on falls-related outcomes among older adults with DM. METHODS: A systematic search for all years to September 2015 identified available literature. Eligibility criteria included: appropriate exercise intervention/s; assessed falls-related outcomes; older adults with DM. Effect sizes were pooled using a random effects model. Positive effect sizes favoured the intervention. RESULTS: Ten RCTs were eligible for the meta-analyses. Exercise interventions were more effective than the control condition for static balance (0.53, 95% CI: 0.13 to 0.93), lower-limb strength (0.63, 95% CI: 0.09 to 1.18), and gait (0.59, 95% CI: 0.22 to 0.96). No RCTs assessed falls-risk; one RCT reported 12month falls-rate, with no differential treatment effect observed. CONCLUSION: Exercise interventions can improve certain falls-related outcomes among older adults with DM. Substantial heterogeneity and limited numbers of studies should be considered when interpreting results. Among older adults, where DM burden is increasing, exercise interventions may provide promising approaches to assist the improvement of falls-related outcomes. PMID- 27765577 TI - Increased rate of abdominal surgery both before and after diagnosis of celiac disease. AB - BACKGROUND: The detection of celiac disease (CD) is suboptimal. AIMS: We hypothesized that misdiagnosis is leading to diagnostic delays, and examine this assertion by determining if patients have increased risk of abdominal surgery before CD diagnosis. METHODS: Through biopsy reports from Sweden's 28 pathology departments we identified all individuals with CD (Marsh stage 3; n=29,096). Using hospital-based data on inpatient and outpatient surgery recorded in the Swedish Patient Register, we compared abdominal surgery (appendectomy, laparotomy, biliary tract surgery, and uterine surgery) with that in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression estimated odds ratios (ORs). RESULTS: 4064 (14.0%) individuals with CD and 15,760 (10.9%) controls had a record of earlier abdominal surgery (OR=1.36, 95% CI=1.31-1.42). Risk estimates were highest in the first year after surgery (OR=2.00; 95% CI=1.79-2.22). Appendectomy, laparotomy, biliary tract surgery, and uterine surgery were all associated with having a later CD diagnosis. Of note, abdominal surgery was also more common after CD diagnosis (hazard ratio=1.34; 95% CI=1.29-1.39). CONCLUSIONS: There is an increased risk of abdominal surgery both before and after CD diagnosis. Surgical complications associated with CD may best explain these outcomes. Medical nihilism and lack of CD awareness may be contributing to outcomes. PMID- 27765578 TI - Late treatment with choline alfoscerate (l-alpha glycerylphosphorylcholine, alpha GPC) increases hippocampal neurogenesis and provides protection against seizure induced neuronal death and cognitive impairment. AB - Choline alfoscerate (alpha-GPC) is a common choline compound and acetylcholine precursor in the brain, which has been shown to be effective in the treatment of Alzheimer's disease and dementia. alpha-GPC has been shown to enhance memory and cognitive function in stroke and Alzheimer's patients but currently remains untested in patients suffering from epilepsy. This study aimed to evaluate whether alpha-GPC treatment after seizure can ameliorate seizure-induced cognitive impairment and neuronal injury. The potential therapeutic effects of alpha-GPC on seizure-induced cognitive impairment were tested in an animal model of pilocarpine-induced seizure. Seizures were induced by intraperitoneal injection of pilocarpine (25mg/kg) in male rats. alpha-GPC (250mg/kg) was injected into the intramuscular space once daily for one or three weeks from immediately after seizure, or from 3 weeks after the seizure onset for 3 weeks. Here we found that immediate 1-week treatment of alpha-GPC showed no neuroprotective effects and neurogenesis. Immediate 3-week treatment of alpha-GPC showed neuroprotective effect but no effect on neurogenesis. To evaluate the effect of late treatment of alpha-GPC on cognitive impairment following seizure, rats were injected alpha-GPC from 3 weeks after seizure for 3 weeks and subjected to a water maze test. In the present study, we found that administration of alpha GPC starting at 3 weeks after seizure improved cognitive function through reduced neuronal death and BBB disruption, and increased neurogenesis. Therefore, alpha GPC injection may serve as a beneficial treatment for improvement of cognitive function in epilepsy patients. PMID- 27765579 TI - Antisera against Neisseria gonorrhoeae cross-react with specific brain proteins of the common marmoset monkey and other nonhuman primate species. AB - Prenatal maternal infections with Neisseria gonorrhoeae (NG) correlate with an increased lifetime probability for the offspring to develop psychosis. We could previously demonstrate that in human choroid plexus papilloma cells, anti-NG antibodies (alpha-NG) bind to mitochondrial proteins HSP60 and ATPB, and interfere with cellular energy metabolism. To assess the in vivo relevance for this, especially during prenatal neural development, we investigated here interactions of NG-specific antisera (alpha-NG1, alpha-NG2) with brain, choroid plexus and other non-neural tissues in pre- and perinatal samples of the nonhuman primate (NHP) Callithrix jacchus (CJ), a NHP model for preclinical research. In histological sections at embryonic day E75, immunohistochemistry revealed alpha NG1 and -2-staining in choroid plexus, ganglionic hill, optic cup, heart, and liver. Within the cells, organelle-like structures were labeled, which could be identified by immunohistochemical double-labeling as mitochondria. Both one- and two-dimensional Western blot analysis revealed tissue specific patterns of alpha NG1 immunoreactive bands and spots, respectively, which were subsequently characterized by mass spectrometry. Thereby we could confirm the interactions of alpha-NG1 with human HSP60 and ATPB also in CJ choroid plexus and liver. Even more important, in the CJ brain, several new targets, including NCAM1, CRMP2, and SYT1, were identified, which by unrelated studies have been previously suggested to correlate with an increased schizophrenia risk. These findings support the idea that the marmoset monkey is a useful NHP model to investigate the role of maternal bacterial infections during prenatal brain development, and thereby might improve the understanding of this important aspect of schizophrenia pathology. PMID- 27765580 TI - Comparison of different antibiotic protocols for asymptomatic bacteriuria in patients with neurogenic bladder treated with botulinum toxin A. AB - Intravesical botulinum toxin A (BoNTA) injection has been widely used for the treatment of detrusor overactivity in patients with neurogenic bladder due to spinal cord injury who do not respond to conventional treatment. There is no consensus about antibiotic prophylaxis for this procedure. We conducted a retrospective analysis of medical records of adult patients with spinal cord injury who underwent detrusor BoNTA injection between January of 2007 and December of 2013 in a rehabilitation hospital. Occurrence of symptomatic urinary tract infection (UTI) was assessed in 3 groups in accordance with their use of antibiotics (prophylactic dosage, 3 days, more than 3 days) for the treatment of asymptomatic bacteriuria. All patients were performing self or assisted clean intermittent bladder catheterization and underwent a rigid cystoscopy, under general or regional anesthesia with sedation, and the drug used was Botox(r). A total of 616 procedures were performed during the study period. There were 11 identified cases of UTI (1.8%) with a trend to a higher rate in the group that used antibiotics for longer time. This report shows that a single dose of antibiotics before the detrusor BoNTA injection is enough to prevent UTI. Randomized clinical trial should be conducted for definitive conclusions. PMID- 27765581 TI - Anogenital infection by Chlamydia trachomatis and Neisseria gonorrhoeae in HIV infected men and women in Salvador, Brazil. AB - BACKGROUND: Infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae are the most common bacterial sexually transmitted infections throughout the world. These sexually transmitted infections are a growing problem in people living with HIV/AIDS. However, the presence of these agents in extra genital sites, remains poorly studied in our country. The objective of this study was to estimate the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae anal and genital infection in people living with HIV/AIDS followed in a reference center in Salvador, Brazil. METHODS: Cross-sectional study, from June 2013 to June 2015. Proven HIV-infected people attending this reference center were invited. Clinical and epidemiological data were obtained through interview with standardized form. Chlamydia trachomatis and Neisseria gonorrhoeae screening was performed using qPCR (COBAS 4800(r) Roche). RESULTS: The frequency of positive cases of Chlamydia trachomatis and Neisseria gonorrhoeae was 12.3% in total, 9.2% cases amongst women and 17.1% amongst men. We found 14.0% of positive cases in anus and 3.1% in genital region in men, while 5.6% and 3.6%, in women, respectively. Among men, anal infection was associated with age <29 years (p=0.033), report of anal intercourse (p=0.029), pain during anal intercourse (p=0.028). On the other hand, no association between genital infection and other variables were detected in bivariate analysis. Among women, we detected an association between Chlamydia trachomatis genital infection and age <29 years (p<0.001), younger age at first sexual intercourse (p=0.048), pregnancy (p<0.001), viral load >50copies/mL (p=0.020), and no antiretroviral use (p=0.008). Anal infection in women was associated with age <29 years old (p<0.001) and pregnancy (p=0.023), and was not associated with report of anal intercourse (p=0.485). CONCLUSION: Missed opportunities for diagnosis in extra genital sites could impact on HIV transmission. The extra genital sites need to be considered to break the HIV and bacterial sexually transmitted infections chain-of-transmission. PMID- 27765582 TI - Major liver resection, systemic fibrinolytic activity, and the impact of tranexamic acid. AB - BACKGROUND: Hyperfibrinolysis may occur due to systemic inflammation or hepatic injury that occurs during liver resection. Tranexamic acid (TXA) is an antifibrinolytic agent that decreases bleeding in various settings, but has not been well studied in patients undergoing liver resection. METHODS: In this prospective, phase II trial, 18 patients undergoing major liver resection were sequentially assigned to one of three cohorts: (i) Control (no TXA); (ii) TXA Dose I - 1 g bolus followed by 1 g infusion over 8 h; (iii) TXA Dose II - 1 g bolus followed by 10 mg/kg/hr until the end of surgery. Serial blood samples were collected for thromboelastography (TEG), coagulation components and TXA concentration. RESULTS: No abnormalities in hemostatic function were identified on TEG. PAP complex levels increased to peak at 1106 MUg/L (normal 0-512 MUg/L) following parenchymal transection, then decreased to baseline by the morning following surgery. TXA reached stable, therapeutic concentrations early in both dosing regimens. There were no differences between patients based on TXA. CONCLUSIONS: There is no thromboelastographic evidence of hyperfibrinolysis in patients undergoing major liver resection. TXA does not influence the change in systemic fibrinolysis; it may reduce bleeding through a different mechanism of action. Registered with ClinicalTrials.gov: NCT01651182. PMID- 27765583 TI - Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve. AB - Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function. Larvae treated with 10MUg/ml cisplatin had normal survival with deficiencies in righting and heat sensing behavior. Behavior was abrogated by, the pan caspase inhibitor, p35. However, active caspase 3 was not detected by immunostaining. There was a 27% decrease in mitochondrial membrane potential and a 42% increase in reactive oxygen species (ROS) in mitochondria along the axon. Examination of mitochondrial axonal trafficking showed no changes in velocity, flux or mitochondrial length. However, cisplatin treatment resulted in a greater number of stationary organelles caused by extended pausing during axonal motility. These results demonstrate that cisplatin induces behavior deficiencies in Drosophila larvae, decreased mitochondrial activity, increased ROS production and mitochondrial pausing without killing the larvae. Thus, we identified particular aspects of mitochondrial dynamics and function that are affected in cisplatin-induced peripheral neuropathy and may represent key therapeutic targets. PMID- 27765584 TI - Long-term Bladder and Upper Urinary Tract Follow-up Recurrence and Progression Rates of G1-2 Non-muscle-invasive Urothelial Carcinoma of the Bladder. AB - OBJECTIVE: To evaluate the risk of long-term tumor recurrence and progression in patients with low- and intermediate-risk non-muscle-invasive bladder cancers, which could facilitate optimization in the follow-up schedules. MATERIALS AND METHODS: A single-institution, retrospective analysis of 704 patients with primary TaG1, TaG2, T1G1, and T1G2 urothelial carcinomas of the bladder without concomitant carcinoma in situ, treated with transurethral resection, was performed. Response was determined and monitored by routine periodic urine cytology, cystoscopy, and upper tract imaging. RESULTS: The median follow-up was 64.9 months (maximum, 120 months). Among all of the tumors, 59.3% did not relapse, 36.6% recurred in the bladder during the first 5 years of surveillance, and only 3.6% recurred after 5 years of follow-up. Eight urothelial bladder cancers (1.1%) progressed in stage, and 87.5% of the progressions occurred during the first 5 years of surveillance. An upper urinary tract recurrence was detected in 2.4% of the patients; 94.1% were diagnosed within the upper urinary tract during the first 5 years of follow-up and 5.9% occurred after 5 years of surveillance. CONCLUSION: G1-2 urothelial bladder cancers recur and progress uncommonly in the long-term period. Although limited by its retrospective nature, the present study provides potential grounds for re-examination of the follow-up schedule for patients with primary non-muscle-invasive bladder cancer G1-2 tumors who remain asymptomatic and disease-free for at least 5 years. PMID- 27765585 TI - Comparison of Laparoscopic Approaches for Dismembered Pyeloplasty in Children With Ureteropelvic Junction Obstruction: Critical Analysis of 11-Year Experiences in a Single Surgeon. AB - OBJECTIVE: The choice of different laparoscopic approaches of laparoscopic pyeloplasty (LP) in children remains controversial. We present a comparison of different approaches of LP in children and a critical analysis of 11-year experiences in a single surgeon. MATERIALS AND METHODS: There were 1750 patients (1889 sides) who underwent LP between 2003 and 2014 reviewed. The diagnosis and outcomes of ureteropelvic junction obstruction (UPJO) were reviewed based on clinical and imaging data. Retroperitoneal laparoscopic pyeloplasty (RPLP) were performed in 451 cases (RPLP group), conventional transperitoneal laparoscopic pyeloplasty (CTLP) were performed in 311 cases (CTLP group), transumbilical single-site laparoscopic pyeloplasty (TSLP) were performed in 322 cases (TSLP group), and transumbilical multiport laparoscopic pyeloplasty (TMLP) were performed in 805 cases (TMLP group). We assessed preoperative clinical data and outcomes, and analyzed the transition experience. Data are expressed as medians for continuous variables. RESULTS: The start of oral feeding, hospital stay, and the operative time of RPLP group were 1.10 +/- 0.10 days, 5.22 +/- 1.32 days, and 138.2 +/- 20.1 minutes, respectively. Compared with the other 3 groups, the start of oral feeding was the soonest, hospital stay was the shortest, and the operative time was the longest in the RPLP group (P < .01 or .05). The cosmetic result of the TMLP group was 7.07 +/- 1.20 scores, and there are significant differences in cosmetic results between the TMLP group and the other 3 groups (P < .05). CONCLUSION: Although the 4 laparoscopic approaches for LP in children with UPJO are safe and efficient procedures with equivalent success rates, we recommend RPLP or TMLP as a treatment option for children with UPJO. PMID- 27765586 TI - A Case of Chromosomal Disorders of Sex Development with Transverse Testicular Ectopia Mimicking Mixed Gonadal Dysgenesis. AB - Transverse testicular ectopia (TTE) is a rare form of ectopic testis observed in boys with a normal 46, XY karyotype. TTE can be associated with persistent Mullerian duct syndrome or other genital anomalies such as hypospadias. However, TTE concomitant with both persistent Mullerian duct remnants and hypospadias has never been reported in the literature. A case of chromosomal disorders of sex development with TTE and persistent Mullerian duct remnants, which was initially presumed to represent mixed gonadal dysgenesis, is presented. PMID- 27765587 TI - Outcomes Following First-line Endourologic Management of Ureteroenteric Anastomotic Strictures After Urinary Diversion: A Single-center Study. AB - OBJECTIVE: To assess the outcomes of patients following a first-line systematic endourologic procedure used to treat ureteroenteric anastomotic strictures (UEAS). MATERIALS AND METHODS: All data from patients treated using a first-line endourologic approach for UEAS between 2010 and 2015 were reviewed retrospectively. The following data were analyzed: age, type of urinary diversion, initial symptoms, surgical endoscopic approach (antegrade or retrograde), pre- and postoperative creatinine levels, and postoperative complications and outcomes. Follow-up visits occurred at 6 weeks, 3 months, and 6 months postoperatively, and at least annually thereafter. RESULTS: A total of 27 patients (median age: 62.5 years) were included. Overall, 28 UEAS were treated endoscopically (ileal conduit: n = 25; neobladder: n = 3). Most UEAS developed following radical cystectomy for bladder cancer (n = 19). Overall, the endoscopic approach was successful in 20 cases (71.4%). The UEAS length was >1 cm in 21 cases (75%). All UEAS of <1 cm were treated successfully (n = 7). There were three grade II and five grade III complications. The median follow-up period was 25 months. The median creatinine levels before surgery and at last follow-up were 1.3 mg/dL and 0.9 mg/dL, respectively. CONCLUSION: An endourologic procedure is a reasonable option for first-line treatment for UEAS and has promising functional outcomes and limited morbidity. PMID- 27765588 TI - Increased Use of Cystectomy in Patients 75 and Older: A Contemporary Analysis of Survival and Perioperative Outcomes From the National Cancer Database. AB - OBJECTIVE: To assess national utilization patterns for cystectomy and nonsurgical treatments for elderly patients with muscle-invasive bladder cancer. METHODS: From the National Cancer Database, we identified patients >=75 years old with T2 T4, non-metastatic urothelial carcinoma between 2003 and 2012. Patients were grouped by treatment: cystectomy, chemoradiation, or nonstandard treatment. Cochran-Armitage trend test was used to evaluate time trends for treatments and perioperative outcomes. Kaplan-Meier and Cox regression tests were used for overall survival analyses. RESULTS: Of 18,945 patients with muscle-invasive bladder cancer, 3898 (21%) underwent cystectomy. Cystectomy use increased from 14% in 2003 to 24% in 2012 (P <.01 for overall trend). Inpatient length of stay after cystectomy decreased over time (P = .02), whereas 30-day readmission and mortality rates remained stable (P = .86 and P = .73, respectively). Median overall survival (95% confidence interval [CI]) was 26.5 (23.1-28.9) months for cystectomy, 22.1 (20.1-24.2) months for chemoradiation, and 12.0 (11.3-12.7) months for nonstandard treatment (P <.01). The survival benefit of cystectomy compared with nonstandard treatment was seen regardless of comorbidity burden. In the Cox analysis, the hazard of death was 0.69 (95% CI 0.63-0.75, P <.01) for cystectomy and 0.75 (95% CI 0.70-0.82, P <.01) for chemoradiation, compared with nonstandard treatment. CONCLUSION: Cystectomy use is increasing in elderly patients, with stable or improved perioperative outcomes and improved survival compared with nonstandard treatment. These findings support continued use of cystectomy in appropriately selected elderly patients. PMID- 27765589 TI - Surgical Management of the Adult Symptomatic Retractile Testicle. AB - OBJECTIVE: To assess the efficacy and safety of circumferential cremasteric lysis in the treatment of adult symptomatic retractile testicles. MATERIALS AND METHODS: This is a retrospective chart review of all patients who had undergone circumferential cremasteric lysis at a single institution performed by a single surgeon between January 2010 and December 2011. We evaluated the etiology, pre- and postoperative pain intensity, postoperative pain alleviation, and any surgical complications. We used the Wilcoxon signed-rank test to compare pain levels before and at last follow-up after surgery. RESULTS: Eight patients (mean age, 31.5 +/- 10.60; range, 22-51 years) underwent circumferential cremasteric lysis. The procedure resulted in a clinically meaningful and statistically significant difference in postoperative pain intensity. The mean pain levels decreased from 5.6 (preoperatively) to 1.5 (at last follow-up) (5.6 vs 1.5, P < .01, Wilcoxon signed-rank test). The mean follow-up was 21.63 +/- 13.70 months (range, 9-50 months). Four patients (50%) reported complete resolution and four (50%) reported partial resolution of their testicular pain at last follow-up. CONCLUSION: In this limited retrospective study, we demonstrated that circumferential lysis of the cremasteric muscle through a small subinguinal incision is a safe and effective minimally invasive procedure for physical activity-precipitated painful retractile testicular pain. PMID- 27765590 TI - Patient-perceived Causes of Prostate Cancer: Result of an Internet-based Survey. AB - OBJECTIVE: To assess patients' perceived causes of prostate cancer (PCa) and relation to treatment satisfaction, an Internet-based survey study was designed. PCa is a profoundly personal disease, considering the location and common sequelae of treatment. Deeply held patient self-perceptions regarding the etiology of a patient's PCa may generate lasting beliefs that impact satisfaction with treatment selection. MATERIALS AND METHODS: Third-party web-based surveys were sent to patients receiving radical prostatectomy for clinically localized PCa. Patients were queried regarding demographic characteristics, family history, socioeconomic status, sexual function, urinary control, and factors believed to cause their PCa. RESULTS: Among respondents (293 of 524, 55.9%), 237 (81.5%) provided primary causes for PCa. Evidence-based answers were provided by 128 (53.5%) patients, whereas a wide range of non-evidence-based responses were provided by 49 (20.5%) patients. Forty patients (16.7%) were undecided, and 20 (8.3%) offered belief-based responses. Evidence-based responses were more common in patients with a family history of PCa (P <.01); however, no significant differences were seen among race, educational level, or income. Patients providing an evidence-based cause of PCa were more likely to be potent (P <.01). Providing a non-evidence-based cause for PCa was associated with considering surgery as a wrong decision in treatment selection. CONCLUSION: Among men with localized PCa, there is a wide spectrum of patient beliefs regarding the etiology of their disease that may reflect background and information sources. Further research is warranted to determine whether patient counseling should incorporate these considerations. PMID- 27765592 TI - Ureteral Stone in the Distal Blind-ending Branch of a Bifid Ureter. AB - A bifid ureter with a distal blind-ending branch is a rare congenital anomaly. Most patients are asymptomatic; only patients with complications, such as infection, vesicoureteral reflux, or stone formation, present symptoms. We describe the case of a patient with urinary stone located in the distal blind ending branch of a bifid ureter diagnosed during transurethral lithotripsy. Preoperative noncontrast-enhanced computed tomography did not reveal a stone in the distal blind-ending branch of the bifid ureter, but a rigid ureteroscope did; however, it could not reach the stone. Therefore, the stone was extracted using a basket catheter under a flexible ureteroscope. PMID- 27765593 TI - Metastatic Prostate Cancer Presenting as Lower Extremity Soft Tissue Mass: A Rare Case Presentation. AB - A 69-year-old homeless African American male with prostate cancer diagnosed 2 years prior presents a large mass in the right thigh. An evaluation of the patient revealed a prostate-specific antigen of 9362 ng/mL. Biopsy of the leg mass was performed and final pathology indicated metastatic adenocarcinoma of the prostate. Although metastatic prostate cancer presents most commonly in bone, lymph nodes, lungs, and liver, metastatic disease presenting as a soft tissue mass is extremely rare (Bubendorf et al, 2000; Molenaar et al, 1996; Ward and Bourken, 1984). The advent of screening with prostate-specific antigen has led to earlier diagnosis of lower-grade disease, yet underserved populations continue to present with aggressive and morbid disease (Winer et al, 2014). PMID- 27765591 TI - Functional and Morphological Outcomes of Pyeloplasty at Different Ages in Prenatally Diagnosed Society of Fetal Urology Grades 3-4 Ureteropelvic Junction Obstruction: Is It Safe to Wait? AB - OBJECTIVE: To evaluate changes in functional and morphological outcomes in children with prenatally diagnosed Society of Fetal Urology (SFU) grades 3-4 ureteropelvic junction obstruction (UPJO) who underwent pyeloplasty at different ages. We also examined the effect of surgical wait time on recovery of renal function. MATERIALS AND METHODS: All patients (aged 0-12 months) with prenatally diagnosed SFU grades 3-4 UPJO who underwent pyeloplasty in a single center between January 2013 and December 2015 were reviewed. One hundred thirty-three children were enrolled in this study. The children were divided into 2 groups according to their age at the time of surgery (group I: 0-3 months, group II: 3 12 months). We evaluated changes in parenchymal thickness, anteroposterior diameter (APD), and differential renal function (DRF) using ultrasound and diuretic renography. Functional and morphological outcomes were compared using Student t test. RESULTS: A total of 133 patients were included in the study. We found a significant difference in the change of DRF (difference between before and after pyeloplasty) between the 2 groups (P < .05). There were no significant differences in changes in parenchymal thickness and APD. Patients who waited 1-2 months had a significantly lower functional improvement compared with those who waited less than 1 month. CONCLUSION: Early surgery leads to a significant improvement in DRF. Wait times greater than 1 month can decrease functional improvement. For patients with prenatally diagnosed SFU grades 3-4 UPJO, early pyeloplasty is recommended in those with increasing renal pelvic APD and an obstructed renogram with differential renal function <40%. PMID- 27765594 TI - Testicular Hypoplasia Is Driven by Defective Vascular Formation. AB - OBJECTIVE: To determine if vanishing testis could result from a fault in embryological development as a result of an arrest in endothelial cell migration rather than secondary to just a random physical torsion/twist. A testicular nubbin or vanishing testis is considered to be secondary to a neonatal torsion and is usually associated with a hemosiderin deposit. MATERIALS AND METHODS: Cases of vanishing testis excision were compared with age-matched controls from cadaveric testes without known genitourinary pathology. To assess the testis microvasculature, we performed immunohistochemistry using an automated staining platform with controlled and standardized conditions and positive and negative controls. We used cluster of differentiation (CD) 34 to stain blood vessel endothelium, stem cells, and interstitium; CD31 (all endothelium); and D2-40 for lymphatic endothelium. Morphometric analysis was carried out, % of the total tissue with CD31 and CD34 positive stain was assessed, and the number of the lymphatic vessels (D2-40) per mm2 was counted. RESULTS: Of the 10 cases, 7 had evidence of hemosiderin deposit and calcification. The % distribution of CD34 in controls was higher, 13.4 +/- 3.1 (mean +/- standard deviation), compared to nubbin cases, 4.5 +/- 2.9 (P <= .001). The % distribution of CD31 was 2.8 +/- 0.83 in controls compared to 1.31 +/- 0.60 in cases (P <= .001). The lymphatic distribution was similar in both groups, cases (6.4 +/- 4.3 n/mm2) and controls (6.4 +/- 1.7 n/mm2) (P = .99) CONCLUSION: This histopathological study suggests that disturbances in endothelial development may be a contributing factor leading to testicular hypoplasia and a resultant nubbin testis, independent of a physical torsion event. PMID- 27765595 TI - Delayed Partial Nephrectomy for Hydronephrosis After Renal Trauma. AB - Delayed sequelae following conservative management of renal trauma in the pediatric population are uncommon. Reports of delayed operations to manage these sequelae are even less common. Here we present the case of a 16-year-old male patient who had delayed development of upper urinary tract obstruction with recurrent infections following high-grade renal trauma managed conservatively. Ultimately, he required a robotic-assisted partial nephrectomy 2 years after initial nonoperative management. This is unique as no prior studies to our knowledge have described delayed hydronephrosis and delayed partial nephrectomy over a year following renal trauma. PMID- 27765596 TI - A New Contrast Enhancement Protocol for Subtraction Coronary Computed Tomography Requiring a Short Breath-Holding Time. AB - RATIONALE AND OBJECTIVES: We have developed a new contrast enhancement protocol for subtraction coronary computed tomography (SCCTA) requiring a short breath holding time. In the protocol, test and main boluses were sequentially and automatically injected, and correct timings for pre-contrast and contrast enhanced scans for main bolus were automatically determined only by the test bolus tracking. Combined with a fixed short main bolus injection for 7 seconds, the breath-holding time was shortened as possible. The purpose of this study was to evaluate whether use of this new protocol produced adequate quality images, taking into account calcified lesions and in-stent lumens. MATERIALS AND METHODS: Patients (n = 127) with calcium scores of >400 Agatston units or a history of stent placement were enrolled. Breath-holding times were recorded, and image quality was visually evaluated by two observers. RESULTS: The mean +/- standard deviation breath-holding time was 13.2 +/- 0.6 seconds. The mean +/- SD computed tomography (CT) number of coronary arteries for the pre-contrast scan was sufficiently low [99.2 +/- 32.2 Hounsfield units (HU)] and, simultaneously, that for SCCTA was 367.0 +/- 77.2 HU. The rate of segments evaluated as unreadable was sufficiently low (3.8%). CONCLUSIONS: Use of the SCCTA protocol was efficient and allowed for a shorter breath-holding time and adequate diagnostic accuracy of SCCTA images, including images of calcified and stent implantation segments. PMID- 27765597 TI - Contrast-enhanced Spectral Mammography: Modality-Specific Artifacts and Other Factors Which May Interfere with Image Quality. AB - RATIONALE AND OBJECTIVES: Contrast-enhanced spectral mammography (CESM) uses full field digital mammography with the added benefit of intravenous contrast administration to significantly reduce false-positive and false-negative results and improve specificity while maintaining high sensitivity. For CESM to fulfill its purpose, one should be aware of possible artifacts and other factors which may interfere with image quality, and attention should be taken to minimize these factors. MATERIALS AND METHODS: This pictorial demonstration will depict types of artifacts detected and other factors that interfere with image acquisition in our practice since CESM implementation. RESULTS: Many of the artifacts and other factors we have encountered while using CESM have simple solutions to resolve them. CONCLUSION: The illustrated artifacts and other factors interfering with image quality will serve as a useful reference to anyone using CESM. PMID- 27765598 TI - Diagnostic Value of ARFI (Acoustic Radiation Force Impulse) in Differentiating Benign From Malignant Breast Lesions. AB - RATIONALE AND OBJECTIVES: The aim of this study was to correlate acoustic radiation force impulse (ARFI) imaging velocities with the pathology results and to evaluate the ability of ARFI in distinguishing benign from malignant breast lesions. MATERIALS AND METHODS: B-mode ultrasonography (US) and ARFI were performed in patients with previously diagnosed and selected breast lesions for biopsy. Shear wave velocity (SWV) was measured inside lesions and in the surrounding parenchyma (m/s). SWV measurements as well as lesion-to-parenchyma ratio (LPR) were compared between benign and malignant lesions, and receiver operating characteristic (ROC) curves were plotted. Two blinded readers independently classified the lesions as benign or malignant in two separate reading sessions, one using B-mode US alone and the other using a combined set of B-mode US and ARFI. RESULTS: Eighty-one patients with a total of 92 breast lesions were included (57 benign and 35 malignant nodules). SWV inside lesions were significantly higher for malignant neoplasms compared to benign (medians of 9.1 m/s vs 3.5 m/s; P < 0.001). LPR was also significantly higher for malignant lesions (3.0 vs 1.4; P < 0.001). Parenchyma SWV had no differences between groups (P = 0.071). ROC curves showed a significant discriminative power for lesion SWV (area under the curve [AUC] = 0.980; P < 0.001) and LPR (AUC = 0.954; P < 0.001). For lesion measures, a cutoff of 6.593 m/s was obtained, with sensitivity and specificity of 88.6% and 96.5%, respectively. CONCLUSIONS: ARFI provides quantitative elasticity measurements, adding valuable complementary information to B-mode ultrasound, that can potentially help in breast lesion characterization and assisting the decision for biopsy recommendations. PMID- 27765599 TI - Should Radiologists Adapt to a New Audience? PMID- 27765600 TI - Fixed-points in random Boolean networks: The impact of parallelism in the Barabasi-Albert scale-free topology case. AB - Fixed points are fundamental states in any dynamical system. In the case of gene regulatory networks (GRNs) they correspond to stable genes profiles associated to the various cell types. We use Kauffman's approach to model GRNs with random Boolean networks (RBNs). In this paper we explore how the topology affects the distribution of the number of fixed points in randomly generated networks. We also study the size of the basins of attraction of these fixed points if we assume the alpha-asynchronous dynamics (where every node is updated independently with probability 0<=alpha<=1). It is well-known that asynchrony avoids the cyclic attractors into which parallel dynamics tends to fall. We observe the remarkable property that, in all our simulations, if for a given RBN with Barabasi-Albert topology and alpha-asynchronous dynamics an initial configuration reaches a fixed point, then every configuration also reaches a fixed point. By contrast, in the parallel regime, the percentage of initial configurations reaching a fixed point (for the same networks) is dramatically smaller. We contrast the results of the simulations on Barabasi-Albert networks with the classical Erdos-Renyi model of random networks. Everything indicates that Barabasi-Albert networks are extremely robust. Finally, we study the mean and maximum time/work needed to reach a fixed point when starting from randomly chosen initial configurations. PMID- 27765601 TI - Mesenchymal stromal/stem cells in drug therapy: New perspective. AB - Mesenchymal stromal/stem cells (MSC) have emerged as a class of cells suitable for cellular delivery of nanoparticles, drugs and micro-RNA cargo for targeted treatments such as tumor and other protective mechanisms. The special properties of MSC underscore the current use for various clinical applications. Examples of applications include but are not limited to regenerative medicine, immune disorders and anti-cancer therapies. In recent years, there has been intense research in modifying MSC to achieve targeted and efficient clinical outcomes. This review discusses effects of MSC in an inflammatory microenvironment and then explains how these properties could be important to the overall application of MSC in cell therapy. The article also advises caution in the application of these cells because of their role in tumorigenesis. The review stresses the use of MSC as vehicles for drug delivery and discusses the accompanying challenges, based on the influence of the microenvironment on MSC. PMID- 27765602 TI - Spatial and temporal structure of the clinical research based on mesenchymal stromal cells: A network analysis. AB - BACKGROUND AIMS: Using innovative tools derived from social network analysis, the aims of this study were (i) to decipher the spatial and temporal structure of the research centers network dedicated to the therapeutic uses of mesenchymal stromal cells (MSCs) and (ii) to measure the influence of fields of applications, cellular sources and industry funding on network topography. METHODS: From each trial using MSCs reported on ClinicalTrials.gov, all research centers were extracted. Networks were generated using Cytoscape 3.2.2, where each center was assimilated to a node, and one trial to an edge connecting two nodes. RESULTS: The analysis included 563 studies. An independent segregation was obvious between continents. Asian, South American and African centers were significantly more isolated than other centers. Isolated centers had fewer advanced phases (P <0.001), completed studies (P = 0.01) and industry-supported studies (P <0.001). Various thematic priorities among continents were identified: the cardiovascular, digestive and nervous system diseases were strongly studied by North America, Europe and Asia, respectively. The choice of cellular sources also affected the network topography; North America was primarily involved in bone-marrow-derived MSC research, whereas Europe and Asia dominated the use of adipose-derived MSCs. Industrial funding was the highest for North American centers (90.5%). CONCLUSIONS: Strengthening of international standards and statements with institutional, federal and industrial partners is necessary. More connections would facilitate the transfer of knowledge, sharing of resources, mobility of researchers and advancement of trials. Developing partnerships between industry and academic centers seems beneficial to the advancement of trials across different phases and would facilitate the translation of research discoveries. PMID- 27765603 TI - Different microRNA alterations contribute to diverse outcomes following EV71 and CA16 infections: Insights from high-throughput sequencing in rhesus monkey peripheral blood mononuclear cells. AB - Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) are the predominant pathogens of hand, foot, and mouth disease (HFMD). Although these viruses exhibit genetic homology, the clinical manifestations caused by the two viruses have some discrepancies. In addition, the underlying mechanisms leading to these differences remain unclear. microRNAs (miRNAs) participate in numerous biological or pathological processes, including host responses to viral infections. Here, we focused on differences in miRNA expression patterns in rhesus monkey peripheral blood mononuclear cells (PBMCs) infected with EV71 and CA16 at various time points using high-throughput sequencing. The results demonstrated that 106 known and 13 novel miRNAs exhibited significant differences, and 32 key miRNAs among them for target prediction presented opposite trends in the EV71- and CA16 infected samples. GO and pathway analysis of the predicted targets showed enrichment in 14 biological processes, 10 molecular functions, 8 cellular components and 104 pathways. Subsequently, regulatory networks of miRNA transcription factors, miRNA-predicted targets, miRNA-GOs and miRNA-pathways were constructed to reveal the complex regulatory mechanisms of miRNAs during the infection phase. Ultimately, we analysed hierarchical GO categories of the predicted targets involved in immune system processes, which indicated that the innate and adaptive immunity following EV71 and CA16 infections may be remarkably distinct. In conclusion, this report is the first describing miRNA expression profiles in PBMCs with EV71 and CA16 infections using high-throughput sequencing. Our findings could provide a valuable basis for further studies on the regulatory roles of miRNAs related to the different immune responses caused by EV71 and CA16 infections. PMID- 27765604 TI - Functional characterization of Vitellogenin_N domain, domain of unknown function 1943, and von Willebrand factor type D domain in vitellogenin of the non bilaterian coral Euphyllia ancora: Implications for emergence of immune activity of vitellogenin in basal metazoan. AB - Our understanding of the function of vitellogenin (Vg) in reproduction has undergone a transformation over the past decade in parallel with new insights into the role of Vg in immunity. However, the time when Vg was endowed with immunological activities during animal evolution remains elusive. Here we demonstrate for the first time that the recombinant proteins rVitellogenin_N, rDUF1943, and rVWD from Vg of the basal metazoan coral Euphyllia ancora not only interact with Gram-positive and negative bacteria as well as their conserved surface components LTA and LPS but also enhance phagocytosis of bacteria by macrophages. Moreover, challenge with LPS results in a marked up-regulation of vg in the coral E. ancora. These data suggest that E. ancora Vg, like that described in the bilaterian oviparous animals fish and amphioxus, is a molecule related to antibacterial defense, indicating that the timing of the emergence of immune role of Vg predates the divergence of the cnidarian (non-bilaterian) and bilaterian lineages. PMID- 27765605 TI - Identification, annotation and expression analysis of 29 Rho GTPase genes from channel catfish (Ictalurus punctatus) after bacterial infections. AB - The Rho family GTPases are a group of small monomeric G proteins, which are molecular switches in signaling pathways. They have been known to regulate a diverse range of cellular processes including actin cytoskeleton rearrangement and microtubule dynamics. In particular, their participations in immune responses are also significant. However, little information of the Rho GTPases is available in teleost including channel catfish, an economically important species and one of the best teleost models forimmunological research. In this study, Rho GTPase genes were identified from channel catfish and well annotated by phylogenetic and syntenic analyses. Their expression profiles were determined in channel catfish healthy tissues and infected tissues. Altogether seven Rho GTPase genes were significantly regulated after bacterial infection, with six genes in the gill after Flavobacterium columnare challenge and two genes in the intestine in response to Edwardsiella ictaluri. All the differentially expressed genes were up regulated soon after bacterial infection. Different expression patterns between the two experiments were observed, which may be attributed to tissue-specific regulation or pathogen-specific regulation. These results suggested that Rho GTPases play important roles in immune responses to bacterial pathogens, setting a foundation for future investigation on Rho GTPases. PMID- 27765606 TI - Effect of Lippia alba and Cymbopogon citratus essential oils on biofilms of Streptococcus mutans and cytotoxicity in CHO cells. AB - BACKGROUND: Caries is a public health problem, given that it prevails in 60 to 90% of the school-age global population. Multiple factors interact in its etiology, among them dental plaque is necessary to have lactic acid producing microorganisms like Streptococcus from he Mutans group. Existing prevention and treatment measures are not totally effective and generate adverse effects, which is why it is necessary to search for complementary strategies for their management. AIM: The study sought to evaluate the eradication capacity of Streptococcus mutans biofilms and the toxicity on eukaryotic cells of Lippia alba and Cymbopogon citratus essential oils. METHODOLOGY: Essential oils were extracted from plant material through steam distillation and then its chemical composition was determined. The MBEC-high-throughput (MBEC-HTP) (Innovotech, Edmonton, Alberta, Canada) assay used to determine the eradication concentration of S. mutans ATCC 35668 strain biofilms. Cytotoxicity was evaluated on CHO cells through the MTT cell proliferation assay. RESULTS: The major components in both oils were Geraniol and Citral; in L. alba 18.9% and 15.9%, respectively, and in C. citratus 31.3% and 26.7%. The L. alba essential oils presented eradication activity against S. mutans biofilms of 95.8% in 0.01mg/dL concentration and C. citratus essential oils showed said eradication activity of 95.4% at 0.1, 0.01mg/dL concentrations and of 93.1% in the 0.001mg/dL concentration; none of the concentrations of both essential oils showed toxicity on CHO cells during 24h. CONCLUSION: The L. alba and C. citratus essential oils showed eradication activity against S. mutans biofilms and null cytotoxicity, evidencing the need to conduct further studies that can identify their active components and in order to guide a safe use in treating and preventing dental caries. PMID- 27765607 TI - Gastroprotective activity of the rhizome ethanol extract of Zingiber simaoense Y. Y. Qian in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zingiber simaoense Y. Y. Qian belongs to the Zingiberaceae family. Its rhizome has been used in Thai folk medicine to relieve gastric disorders; however, scientific evidence of its pharmacological activities has not yet been revealed. AIM OF THE STUDY: This study was designed to validate the gastroprotective activity and to identify possible mechanisms of gastroprotection of Z. simaoense rhizome ethanol extract (ZSE) in rats. MATERIALS AND METHODS: The gastroprotective effect of ZSE was tested using models of gastric ulcers induced by acidified ethanol, indomethacin, and restraint water immersion stress. Models for determination of gastric wall mucus secretion and plasma malondialdehyde levels as well as pylorus ligation were used to explore the mechanisms of action. RESULTS: After oral administration by intragastric gavage, ZSE 7.5, 15, and 30mg/kg or cimetidine 100mg/kg significantly inhibited the formation of gastric ulcer in all gastric ulcer models. The gastric wall mucus amount was significantly higher than that of the ulcer control group, plasma malondialdehyde levels were normalized, and gastric secretion was partly inhibited by pretreatment with ZSE. CONCLUSIONS: This study demonstrates the gastroprotective activity of ZSE in rats. The mechanisms of action of ZSE may depend on its ability to maintain the integrity of gastric wall mucus through the protection of gastric mucus, and/or by increasing the gastric mucus synthesis and secretion through prostaglandin synthesis. Moreover, the antioxidant activity of ZSE may also contribute to its mechanism of gastroprotection. PMID- 27765608 TI - Influence of geography, seasons and pedology on chemical composition and anti inflammatory activities of essential oils from Lippia multiflora Mold leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lippia multiflora is a plant with nutritional and pharmaco-therapeutic properties that is native to central and occidental Africa. The potential effects of plants on health are associated with their chemical composition. Therefore, the present study aimed to identify chemical variations in essential oils of Lippia multiflora as a function of geographic origin and time of annual harvest to determine optimal chemical profiles for ethno pharmacotherapeutic applications. MATERIALS AND METHODS: Experimental plants were cultivated at Abidjan (LPA), Toumodi (LPT) and Bondoukou (LPB). Natural Lippia multiflora seeds were sourced to produce standardized plants over a period of six months. Standard plants (n=40) were re-introduced into natural plots, cultivated for 12 months and leaves were sampled monthly in a standardized fashion. Essentials oils (n=36) were then extracted from these samples by hydro distillation according to the European Pharmacopoeia and qualitatively and quantitatively analyzed using GC/FID and GC/MS. These data were then analyzed using Principal Component Analysis (PCA). Anti-inflammatory properties were also assessed against activated macrophages in vitro. RESULTS: The results indicated that chemical profiles and essential oil yields vary according to the location where the plants were cultivated. One essential oil chemotype corresponded to the LPA and LPT sites and one corresponded to the LPB site. Statistical analysis of the chemical profiles and monthly evolution of the three sites over a period of one year allowed assessment of variations in composition and the subsequent choice of the optimal harvest time for ethnopharmacological applications. Anti inflammatory activity apparently correlated with chemical profiles of essential oils and the geographic origins of the plants. CONCLUSION: The optimal harvest time was associated with the maximum yield of pharmacological compounds with the most potential interest for health. PMID- 27765609 TI - Anti-inflammatory effect of volatile oil from Schizonepeta tenuifolia on carrageenin-induced pleurisy in rats and its application to study of appropriate harvesting time coupled with multi-attribute comprehensive index method. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schizonepeta tenuifolia Briq. (ST) herbs have been used as a Traditional Chinese Medicine (TCM) for treating colds for thousands of years. The volatile oil is considered as the main material basis responsible for the efficacy of ST and has attracted lots of attention on its anti-inflammatory effect recently. AIM OF STUDY: This paper investigated the anti inflammatory effects of the distilled volatile oils from Schizonepeta tenuifolia (STVO) that were collected at different harvesting times on carrageenin-induced pleurisy in rats. Based on the anti-inflammatory effects, instead of contents of marker components, we aim to evaluate the quality and determine the appropriate harvesting time of ST. MATERIALS AND METHODS: There were eleven groups with eight male rats in each randomly. They were model group, control group, positive group (dexamethasone) and eight groups treated with eight STVOs at different harvesting times. All treatments were performed by gavage and administered once a day on four consecutive days. One hour after the last treatments, except the rats in control group, those in other groups were treated with carrageenin to induce the pleurisy. Four hours later, all the rats were sacrificed and their pleurisy exudates and lung tissues were collected for further analysis. To evaluate the comprehensive anti-inflammatory effect of the eight STVOs, multi-attribute comprehensive index method (MACIM) was used to obtain the integration of various effects. RESULTS: All the eight STVOs could decrease the seven indicators relating to pleurisy, which were exudate volume, leukocytes, protein level, myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF alpha) and interleukine-1beta (IL-1beta). Majority of these decreases were significant (P<0.01, P<0.05). As far as each indicator was concerned, each STVO showed different effect from others. With MACIM, it was found that STVO in Group 6 was the most effective one with the highest Vs and appropriate harvesting time of ST was in late September. CONCLUSIONS: The study may provide scientific basis to further understanding of the mechanism of STVO in anti-inflammatory effect of carrageenin-induced pleurisy. Meanwhile, this study also provides a new access to determining the appropriate harvesting time of TCM and even evaluating the quality of TCM. PMID- 27765610 TI - Neural signature of tDCS, tPCS and their combination: Comparing the effects on neural plasticity. AB - Transcranial pulsed current stimulation (tPCS) and transcranial direct current stimulation (tDCS) are two noninvasive neuromodulatory brain stimulation techniques whose effects on human brain and behavior have been studied individually. In the present study we aimed to quantify the effects of tDCS and tPCS, individually and in combination, on cortical activity, sensitivity and pain related assessments in healthy individuals in order to understand their neurophysiological mechanisms and potential applications in clinical populations. A total of 48 healthy individuals participated in this randomized double blind sham controlled study. Participants were randomized to receive a single stimulation session of either: active or sham tPCS and active or sham tDCS. Quantitative electroencephalography (qEEG), sensitivity and pain assessments were used before and after each stimulation session. We observed that tPCS had a higher effect on power, as compared to tDCS, in several bandwidths on various cortical regions: the theta band in the parietal region (p=0.021), the alpha band in the temporal (p=0.009), parietal (p=0.0063), and occipital (p<0.0001) regions. We found that the combination of tPCS and tDCS significantly decreased power in the low beta bandwidth of the frontal (p=0.0006), central (p=0.0001), and occipital (p=0.0003) regions, when compared to sham stimulation. Additionally, tDCS significantly increased power in high beta over the temporal (p=0.0015) and parietal (p=0.0007) regions, as compared to sham. We found no effect on sensitivity or pain-related assessments. We concluded that tPCS and tDCS have different neurophysiological mechanisms, elicit distinct signatures, and that the combination of the two leads to no effect or a decrease on qEEG power. Further studies are required to examine the effects of these techniques on clinical populations in which EEG signatures have been found altered. PMID- 27765611 TI - Manual segmentation of the fornix, fimbria, and alveus on high-resolution 3T MRI: Application via fully-automated mapping of the human memory circuit white and grey matter in healthy and pathological aging. AB - Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter- and intra-rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimer's disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all p's<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required. PMID- 27765612 TI - Preoperative Albumin Is Predictive of Early Postoperative Morbidity and Mortality in Common Urologic Oncologic Surgeries. AB - INTRODUCTION: Multiple studies have linked preoperative nutrition status to postoperative outcomes. This relationship has been little studied in urology. We used a standardized, national, risk-adjusted surgical database to evaluate 30-day outcomes of patients undergoing common urologic oncologic procedures as they related to preoperative albumin. METHODS: The American College of Surgeons National Surgical Quality Improvement Program is a risk-adjusted dataset analyzing preoperative risk factors, demographics, and 30-day outcomes. From 2005 through 2012, we identified a total of 17,805 patients who underwent prostatectomy, nephrectomy, partial nephrectomy, cystectomy, or transurethral resection of bladder tumor (TURBT). Hypoalbuminemic patients were compared with those with normal preoperative albumin, and 30-day outcomes were evaluated. Logistic regression analyses were used to estimate odds ratios for mortality and complication rates. RESULTS: Evaluation of the cohort noted significantly increased overall morbidity, serious morbidity, and mortality in the hypoalbuminemic group (P < .01 for all procedures). Hypoalbuminemia was associated with a significantly higher 30-day mortality in major procedures such as cystectomy, and in smaller procedures such as TURBT (P < .01). Hypoalbuminemia was associated with a 6.4% 30-day mortality in the TURBT group compared with 0.6% in those with normal albumin (P < .0001). These findings remained significant after adjustment for other risk factors. CONCLUSIONS: The large sample size, standardized data definitions, and quality control measures of the American College of Surgeons National Surgical Quality Improvement Program database allow for in-depth analysis of subtle but significant differences in outcomes between groups. Serum albumin is a strong predictor of short-term postoperative complications in the urologic oncology patient. PMID- 27765615 TI - Everolimus restrains the IL-17A-dependent osteoclast-like transdifferentiation of dendritic cells in multiple myeloma. AB - Interleukin-17A (IL-17A) promotes the osteoclast (OC)-like differentiation of dendritic cells (DCs) in multiple myeloma (MM) and contributes to the pathogenesis of myeloma bone disease (MBD). In our study, everolimus (EVR) abrogated the in vitro OC-like activity of DCs from 12 MM patients significantly. Exploring the EVR effects, we found that the inhibition of the osteoerosive activity of OC-DCs was mostly due to the blockade of signals driven by the IL-17A receptor toward the CCAAT/enhancer-binding protein beta/musculoaponeurotic fibrosarcoma oncogene homolog B axis Therefore, MM patients with MBD would probably benefit from mammalian target of rapamycin inhibition. PMID- 27765613 TI - The Use of Neoadjuvant Chemotherapy in Patients With Urothelial Carcinoma of the Bladder: Current Practice Among Clinicians. AB - INTRODUCTION: Guidelines recommend neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in patients with urothelial carcinoma of the bladder in clinical stages T2-T4a, cN0M0. We examined the frequency and current practice of NAC and sought to identify predictors for the use of NAC in a prospective contemporary cohort. MATERIALS AND METHODS: We analyzed prospective data from 679 patients in the PROMETRICS (PROspective MulticEnTer RadIcal Cystectomy Series 2011) database. All patients underwent RC in 2011. Uni- and multivariable regression analyses identified predictors of NAC application. Furthermore, a questionnaire was used to evaluate the practice patterns of NAC at the PROMETRICS centers. RESULTS: A total of 235 patients (35%) were included in the analysis. Only 15 patients (2.2%) received NAC before RC. Younger age (< 70 years; P = .035), lower case volume of the center (< 30 RC/year; P < .001), and advanced tumor stage (>= cT3; P = .038) were identified as predictors for NAC. Of the 200 urologists who replied to the questionnaire, 69% (n = 125) declared tumor stage cT3-4 a/o N1M0 to be the best indication for NAC application, although 45% of the urologists stated that they would not perform NAC despite recommendations. The decision for NAC was made by the individual urologist in 69% of cases, and only 29% reported that all cases were discussed in an interdisciplinary tumor board. CONCLUSION: NAC was rarely applied in the present cohort. We observed a discrepancy between guideline recommendations and practice patterns, despite medical indication and pre-therapeutic interdisciplinary discussion. The potential benefit of NAC within a multimodal approach seems to be neglected by many urologists. PMID- 27765614 TI - Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy. AB - Natural killer (NK) cells play a significant role in reducing relapse in patients with hematological malignancies after allogeneic stem cell transplantation, but NK cell number and naturally occurring inhibitory signals limit their capability. Interleukin-15 (IL-15) and 4-1BBL are important modulators of NK expansion and functional activation. To overcome these limitations, cord blood mononuclear cells (CB MNCs) were ex vivo expanded for 7 days with genetically modified K562 mbIL15-41BBL (MODK562) or wild-type K562 (WTK562). NK cell expansion; expression of lysosome-associated membrane protein-1 (LAMP-1), granzyme B, and perforin; and in vitro and in vivo cytotoxicity against B-cell non-Hodgkin lymphoma (B-NHL) were evaluated. In vivo tumor growth in B-NHL-xenografted nonobese diabetic severe combined immune deficient (NOD-scid) gamma (NSG) mice was monitored by tumor volume, cell number, and survival. CB MNCs cultured with MODK562 compared with WTK562 demonstrated significantly increased NK expansion (thirty-fivefold, p < 0.05); LAMP-1 (p < 0.05), granzyme B, and perforin expression (p < 0.001); and in vitro cytotoxicity against B-NHL (p < 0.01). Xenografted mice treated with MODK562 CB experienced significantly decreased B-NHL tumor volume (p = 0.0086) and B-NHL cell numbers (p < 0.01) at 5 weeks and significantly increased survival (p < 0.001) at 10 weeks compared with WTK562. In summary, MODK562 significantly enhanced CB NK expansion and cytotoxicity, enhanced survival in a human Burkitt's lymphoma xenograft NSG model, and could be used in the future as adoptive cellular immunotherapy after umbilical CB transplantation. Future directions include expanding anti-CD20 chimeric receptor-modified CB NK cells to enhance B NHL targeting in vitro and in vivo. PMID- 27765616 TI - Chronic intrathecal infusion of T-type calcium channel blockers attenuates CaV3.2 upregulation in nerve-ligated rats. AB - OBJECTIVE: T-type channel (TCC) CaV3.2 plays a pivotal role in pain transmission. In this study, we examined the effects of intrathecal TCC blockers on CaV3.2 expression in a L5/6 spinal nerve ligation (SNL) pain model. The neurotoxicity of TCC blockers were also evaluated. METHODS: Male Sprague-Dawley rats (200-250 g) were used for right L5/6 SNL to induce neuropathic pain. Intrathecal infusion of saline or TCC blockers [mibefradil (0.7 MUg/h) or ethosuximide (60 MUg/h)] was started after surgery for 7 days. Fluorescent immunohistochemistry and Western blotting were used to determine the expression pattern and protein level of CaV3.2. Hematoxylin-eosin and toluidine blue staining were used to evaluate the neurotoxicity of tested agents. RESULTS: Seven days after SNL, CaV3.2 protein levels were upregulated in ipsi-lateral L5/6 spinal cord and dorsal root ganglia (DRG) in immunofluorescence and Western blotting studies. Compared with the saline-treated group, rats receiving mibefradil or ethosuximide showed significant lower CaV3.2 expression in the spinal cord and DRG. No obvious histopathologic change in hematoxylin-eosin and toluidine blue staining were observed in all tested groups. CONCLUSION: In this study, we demonstrate that SNL induced CaV3.2 upregulation in the spinal cord and DRG was attenuated by intrathecal infusion of mibefradil or ethosuximide. No obvious neurotoxicity effects were observed in all the tested groups. Our data suggest that continuous intrathecal infusion of TCC blockers may be considered as a promising alternative for the treatment of nerve injury-induced pain. PMID- 27765617 TI - A rapid, highly sensitive and culture-free detection of pathogens from blood by positive enrichment. AB - Molecular diagnostics is a promising alternative to culture based methods for the detection of bloodstream infections, notably due to its overall lower turnaround time when starting directly from patient samples. Whole blood is usually the starting diagnostic sample in suspected bloodstream infections. The detection of low concentrations of pathogens in blood using a molecular assay necessitates a fairly high starting volume of blood sample in the range of 5-10mL. This large volume of blood sample has a substantial accompanying human genomic content that interferes with pathogen detection. In this study, we have established a workflow using magnetic beads coated with Apolipoprotein H that makes it possible to concentrate pathogens from a 5.0mL whole blood sample, thereby enriching pathogens from whole blood background and also reducing the sample volume to ~200MUL or less. We have also demonstrated that this method of enrichment allows detection of 1CFU/mL of Escherichia coli, Enterococcus gallinarum and Candida tropicalis from 5mL blood using quantitative PCR; a detection limit that is not possible in unenriched samples. The enrichment method demonstrated here took 30min to complete and can be easily integrated with various downstream molecular and microbiological techniques. PMID- 27765619 TI - Mycobacterium tuberculosis Rv0431 expressed in Mycobacterium smegmatis, a potentially mannosylated protein, mediated the immune evasion of RAW 264.7 macrophages. AB - Tuberculosis remains a global major problem. The immune responses of host against Mycobacterium tuberculosis (M. tuberculosis) are complicated. M. tuberculosis lives mainly within host cells, usually macrophages which constitute the first line of host defense. Mycobacterial proteins, especially cell wall-associated proteins, interact with macrophages of host to regulate the functions and cytokine production. Recent studies indicate that glycoproteins are involved in this process. Here, we investigated the function of Rv0431, a cell wall associated protein in the M. tuberculosis H37Rv strain. Rv0431 protein was heterologously overexpressed in the fast-growing and nonpathogenic Mycobacterium smegmatis (M. smegmatis). Binding assay to concanavalin A (ConA) lectin was performed and the result indicated that Rv0431 protein was a potentially mannosylated protein. M. smegmatis MSMEG_5447 gene encoding a polyprenol phosphate-mannose-protein mannosyl-transferase (PMT) which catalyzes the O mannosylation of protein was knocked out. The Rv0431 protein overexpressed in MSMEG_5447 gene knockout stain, DeltaM5447, lost its reactivity to ConA, providing evidence that Rv0431 was likely O-mannosylated. M. smegmatis overexpressed Rv0431 evaded the killing of RAW264.7 macrophages and altered the cytokine production of macrophages compared to M. smegmatis carrying empty vector. These results suggested that Rv0431, a probably mannosylated protein might promote the evasion of immune responses during mycobacterial infection. PMID- 27765618 TI - Optimization of PAR-CLIP for transcriptome-wide identification of binding sites of RNA-binding proteins. AB - Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) in combination with next-generation sequencing is a powerful method for identifying endogenous targets of RNA-binding proteins (RBPs). Depending on the characteristics of each RBP, key steps in the PAR-CLIP procedure must be optimized. Here we present a comprehensive step-by-step PAR-CLIP protocol with detailed explanations of the critical steps. Furthermore, we report the application of a new PAR-CLIP data analysis pipeline to three distinct RBPs targeting different annotation categories of cellular RNAs. PMID- 27765620 TI - Multiple-locus variable-number tandem repeat analysis (MLVA) for genotyping of Salmonella enterica subspecies enterica serotype Infantis isolated from human sources. AB - Salmonella is an important cause of food-borne infection worldwide. Detection of outbreaks caused by Salmonella spp. relies on suitable and robust methods for genotyping. Little is known about the genetic diversity of the Salmonella enterica subspecies enterica serotype Infantis strains isolated from human sources in Iran. In this study, 40 isolates of S. Infantis, which were previously recovered from patients with gastroenteritis or diarrhea in Tehran between years 2007 and 2009, were subjected to multiple-locus variable-number of tandem repeat (VNTR) analysis (MLVA), pulsed-field gel electrophoresis (PFGE), and ERIC-PCR. Using MLVA method, 31 types were identified. The MLVA clustering of the isolates by the unweighted pair group method with arithmetic mean (UPGMA) revealed the presence of two major clusters. The discriminatory power of MLVA was superior to that of PFGE and ERIC-PCR. Overall, our data showed that MLVA assay could effectively differentiate closely related strains. It is technically simple and inexpensive to perform. Furthermore, MLVA can be used as a helpful method for epidemiological investigations. PMID- 27765621 TI - Green synthesis of silver, gold and silver/gold bimetallic nanoparticles using the Gloriosa superba leaf extract and their antibacterial and antibiofilm activities. AB - The green fabrication of metal nanoparticles using botanical extracts is gaining increasing research attention in nanotechnology, since it does not require high energy inputs or the production of highly toxic chemical byproducts. Here, silver (Ag), gold (Au) and their bimetallic (Ag/Au) nanoparticles (NPs) were green synthesized using the Gloriosa superba aqueous leaf extract. Metal NPs were studied by spectroscopic (UV-visible spectroscopy, fluorescence spectroscopy, FT IR spectroscopy, XRD and EDX) and microscopic (AFM and TEM) analysis. AFM and TEM showed that Ag and Au NPs had triangular and spherical morphologies, with an average size of 20 nm. Bimetallic Ag/Au NPs showed spherical shapes with an average size of 10 nm. Ag and Ag/Au bimetallic NPs showed high antibacterial and antibiofilm activities towards Gram-positive and Gram-negative bacteria. Overall, the proposed synthesis route of Ag, Au and Ag/Au bimetallic NPs can be exploited by the pharmaceutical industry to develop drugs effective in the fight against microbic infections. PMID- 27765624 TI - Does cold activate the Drosophila melanogaster immune system? AB - Cold exposure appears to activate aspects of the insect immune system; however, the functional significance of the relationship between cold and immunity is unclear. Insect success at low temperatures is shaped in part by interactions with biotic stressors, such as pathogens, thus it is important to understand how and why immunity might be activated by cold. Here we explore which components of the immune system are activated, and whether those components differ among different kinds of cold exposure. We exposed Drosophila melanogaster to both acute (2h, -2 degrees C) and sustained (10h, -0.5 degrees C) cold, and measured potential (antimicrobial peptide expression, phenoloxidase activity, haemocyte counts) and realised (survival of fungal infection, wound-induced melanisation, bacterial clearance) immunity following recovery. Acute cold increased circulating haemocyte concentration and the expression of Turandot-A and diptericin, but elicited a short-term decrease in the clearance of gram-positive bacteria. Sustained cold increased the expression of Turandot-A, with no effect on other measures of potential or realised immunity. We show that measures of potential immunity were up-regulated by cold, whereas realised immunity was either unaffected or down-regulated. Thus, we hypothesize that cold-activation of potential immunity in Drosophila may be a compensatory mechanism to maintain stable immune function during or after low temperature exposure. PMID- 27765622 TI - Guidelines of the French Society of Otorhinolaryngology (SFORL). Second-line treatment of epistaxis in adults. AB - OBJECTIVES: The authors present the guidelines of the French Oto-Rhino Laryngology - Head and Neck Surgery Society (Societe Francaise d'Oto-Rhino Laryngologie et de Chirurgie de la Face et du Cou: SFORL) on second-line treatment of epistaxis in adults, after failure of anterior and/or anterior posterior nasal packing. METHODS: A multidisciplinary work group was entrusted with a review of the scientific literature on the above topic. Guidelines were drawn up, based on the articles retrieved and the group members' individual experience. They were then read over by an editorial group independent of the work group. The final version was established in a coordination meeting. The guidelines were graded as A, B, C or expert opinion, by decreasing level of evidence. RESULTS: Arterial embolization should be performed by an experienced interventional neuroradiologist with adequate technical facilities, to reduce the risk of complications. Cerebral and supra-aortic vessel CT angiography should be performed in case of post-traumatic epistaxis with suspected internal carotid injury. In case of persistent bleeding despite endoscopic hemostasis of the sphenopalatine artery, anterior ethmoidal artery hemostasis should be performed via a medial canthal incision, with endoscopic assistance as needed. In case of persistent epistaxis despite the usual surgical and neuroradiological procedures, surgical exploration of the sinonasal cavities should be performed, with elective coagulation in case of bleeding from secondary branches, and/or ethmoidectomy in case of diffuse bleeding. A decision-tree was drawn up for the management of second-line treatment of epistaxis. PMID- 27765623 TI - Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA. AB - Gene therapy is aimed at selectively knocking up or knocking down the target genes involved in the development of diseases. In many human diseases, dysregulation of disease-associated genes is occurred concurrently: some genes are abnormally turned up and some are turned down. In the field of non-viral gene therapy, plasmid DNA (pDNA) and small interfering RNA (siRNA) are suggested as representative regulation tools for activating and silencing the expression of genes of interest, representatively. Herein, we simultaneously loaded both siRNA (Src homology region 2 domain-containing tyrosine phosphatase-1 siRNA, siSHP-1) for anti-apoptosis and pDNA (hypoxia-inducible vascular endothelial growth factor expression vector, pHI-VEGF) for angiogenesis in a single polymeric nanocarrier and used to synergistically attenuate ischemia-reperfusion (IR)-induced myocardial infarction, which is mainly caused by dysregulating of cardiac apoptosis and angiogenesis. For dual-modality cardiac gene delivery, siSHP-1 and pHI-VEGF were sequentially incorporated into a stable nanocomplex by using deoxycholic acid-modified polyethylenimine (DA-PEI). The resulting DA-PEI/siSHP 1/pHI-VEGF complexes exhibited the high structural stability against polyanion competition and the improved resistance to digestion by nucleases. The cardiac administration of DA-PEI/siSHP-1/pHI-VEGF reduced cardiomyocyte apoptosis and enhanced cardiac microvessel formation, thereby reducing infarct size in rat ischemia-reperfusion model. The simultaneous anti-apoptotic and angiogenic gene therapies synergized the cardioprotective effects of each strategy; thus our dual modal single-carrier gene delivery system can be considered as a promising candidate for treating ischemic heart diseases. PMID- 27765625 TI - Cold tolerance of third-instar Drosophila suzukii larvae. AB - Drosophila suzukii is an emerging global pest of soft fruit; although it likely overwinters as an adult, larval cold tolerance is important both for determining performance during spring and autumn, and for the development of temperature based control methods aimed at larvae. We examined the low temperature biology of third instar feeding and wandering larvae in and out of food. We induced phenotypic plasticity of thermal biology by rearing under short days and fluctuating temperatures (5.5-19 degrees C). Rearing under fluctuating temperatures led to much slower development (42.1days egg-adult) compared to control conditions (constant 21.5 degrees C; 15.7days), and yielded larger adults of both sexes. D. suzukii larvae were chill-susceptible, being killed by low temperatures not associated with freezing, and freezing survival was not improved when ice formation was inoculated externally via food or silver iodide. Feeding larvae were more cold tolerant than wandering larvae, especially after rearing under fluctuating temperatures, and rearing under fluctuating temperatures improved survival of prolonged cold (0 degrees C) to beyond 72h in both larval stages. There was no evidence that acute cold tolerance could be improved by rapid cold-hardening. We conclude that D. suzukii has the capacity to develop at low temperatures under fluctuating temperatures, but that they have limited cold tolerance. However, phenotypic plasticity of prolonged cold tolerance must be taken into account when developing low temperature treatments for sanitation of this species. PMID- 27765627 TI - Nucleotide dependence of the dimerization of ATP binding cassette nucleotide binding domains. AB - ATP-binding cassette proteins are ubiquitously present throughout all known genomes. Their basic functional unit possesses two transmembrane domains and two nucleotide-binding domains. The nucleotide-binding domains are responsible for ATP binding and hydrolysis, and their 3-dimensional structure is conserved across ATP-binding cassette proteins. Binding of ATP produces nucleotide-binding domain dimerization, a step necessary for hydrolysis. However, the possibility that nucleotide-binding domains bind and/or hydrolyze nucleotide triphosphates different from ATP has not been explored in detail. Here, we studied that possibility using M. jannaschii MJ0796, a prototypical ATP-binding cassette nucleotide-binding domain. We found that nucleotide-binding domain dimerization occurs as a result of binding to the natural nucleotide triphosphates ATP, GTP, CTP and UTP, and also to the analog ATP-gamma-S. All the natural nucleotide triphosphates are hydrolyzed at similar rates, whereas ATP-gamma-S is not hydrolyzed. We also found that the non-hydrolyzable ATP analog AMP-PNP, frequently assumed to produce the nucleotide-bound conformation, failed to elicit nucleotide-binding domain dimerization. Our results raise the possibility that not all the nucleotide binding sites of nucleotide-binding domains are occupied by ATP under physiological conditions, and that ATP is not always the nucleotide hydrolyzed to dissociate the nucleotide-binding domain dimers. PMID- 27765628 TI - Long non-coding RNA CCAT1 promotes glioma cell proliferation via inhibiting microRNA-410. AB - BACKGROUND AND AIM: Long non-coding RNAs have been confirmed to play a critical role in various cancers. In the present study, the effect of long non-coding RNA (lncRNA) CCAT1 on glioma cell proliferation and its potential mechanism were investigated. METHODS AND RESULTS: Real-time PCR results showed that lncRNA-CCAT1 expression was significantly upregulated in glioma cancer tissues and cell lines compared with controls. After inhibiting CCAT1 expression in glioma cell line U251 with siRNA-CCAT1 (si-CCAT1), the cell viability and cell colony formation were decreased, the cell cycle was arrested in G1 phase, and the cell apoptosis was increased. As reported in bioinformatics software starbase2.0, a total of 22 microRNAs were potentially targeted by CCAT1. It was confirmed that miR-410 was altered most by si-CCAT1. After up-regulating CCAT1 expression in U251 cells, miR 410 level was decreased. Luciferase reporter assay confirmed that CCAT1 targeted miR-410. Correlation analysis showed that CCAT1 expression was negatively related to miR-410 expression in glioma cancer tissues. In addition, down-regulation of miR-410 reversed the inhibitory effect of si-CCAT1 on glioma proliferation. CONCLUSION: These data demonstrated that lncRNA-CCAT1 promoted glioma cell proliferation via inhibiting miR-410, providing a new insight about the pathogenesis of glioma proliferation. PMID- 27765626 TI - The effect of sazetidine-A and other nicotinic ligands on nicotine controlled goal-tracking in female and male rats. AB - Nicotine is the primary addictive component of tobacco products and its complex stimulus effects are readily discriminated by human and non-human animals. Previous research with rodents directly investigating the nature of the nicotine stimulus has been limited to males. The current study began to address this significant gap in the literature by training female and male rats to discriminate 0.4 mg/kg nicotine from saline in the discriminated goal-tracking task. In this task, access to sucrose was intermittently available on nicotine session. On interspersed saline session, sucrose was not available. Both sexes acquired the discrimination as evidenced by increased head entries into sucrose receptacle (goal-tracking) evoked by nicotine; the nicotine generalization curves were also similar between females and males. The pharmacological profile of the nicotine stimulus was assessed using substitution and targeted combination tests with the following ligands: sazetidine-A, PHA-543613, PNU-120596, bupropion, nornicotine, and cytisine. For females and males, nornicotine fully substituted for the nicotine stimulus, whereas sazetidine-A, bupropion, and cytisine all evoked partial substitution. Female and male rats responded in a similar manner to interaction tests where a combination of 1 mg/kg of sazetidine-A plus nicotine or nornicotine shifted the nicotine dose-effect curve to the left. The combination of sazetidine-A plus bupropion or cytisine failed to do so. These findings begin to fill a significant gap the in scientific literature by studying the nature of the nicotine stimulus and response to therapeutically interesting combinations using a model that includes both sexes. PMID- 27765629 TI - Identification of THY1 as a novel thyrotrope marker and THY1 antibody-mediated thyrotrope isolation in the rat anterior pituitary gland. AB - Contact-dependent (juxtacrine) signaling is important for local cell-to-cell interaction and has received attention in recent years regarding its role in pituitary function, differentiation, and development. This study investigated one of the juxtacrine-related molecules, thymocyte differentiation antigen 1 (THY1), in the anterior lobe of the rat pituitary gland. Western blot analysis revealed expression of the THY1 protein in the adult rat anterior lobe. We also found that the THY1 ligand, integrin-beta2 (ITGB2), is also expressed in the pituitary gland. In situ hybridization and immunohistochemical analyses showed that both THY1 mRNA and protein were present in almost, if not all, thyroid-stimulating hormone (TSH)-immunopositive cells (thyrotropes) and that ITGB2 was co-expressed in these cells. As THY1 appeared to represent a novel marker for thyrotropes, we then attempted to isolate these cells from various anterior lobe cells by the use of a THY1 antibody and a pluriBead-cascade cell isolation system. This technology allowed the isolation of thyrotropes with 83% purity at about 17-fold enrichment. Furthermore, the isolated THY1-immunopositive cells had higher Tsh mRNA levels compared with THY1-immunonegative cells and released TSH in response to thyrotropin-releasing hormone. These findings indicated that THY1 represents a potent thyrotrope marker and that the thyrotrope isolation method using the THY1 antibody may serve as a powerful tool to analyze their function including juxtacrine regulation through THY1/ITGB2 interaction. PMID- 27765630 TI - Long non-coding RNA linc-cdh4-2 inhibits the migration and invasion of HCC cells by targeting R-cadherin pathway. AB - Long non-coding RNAs (LncRNAs) have played very important roles in the malignancy behaviors of hepatocellular carcinoma (HCC). Linc-cdh4-2 (TCONS_00027978) is a novel LncRNA that has been identified in HCC tissues from our previous study. Overexpression of linc-cdh4-2 in HCC cell lines (SK-Hep-1 and Huh7) significantly decreases the migration and invasion abilities of these cells, while knockdown the expression of linc-cdh4-2 significantly increases the migration and invasion abilities. Interestingly, neither the over expression nor the knock down of linc cdh4-2 could affect the viability and proliferation of HCC cells. Mechanistically, the linc-cdh4-2 could up-regulate the protein level of R cadherin through direct binding that might improve the protein stability. Over expression of linc-cdh4-2 could significantly increase the protein levels of R cadherin and decrease the protein levels of small GTPase RAC1, and vice-versa. Further knockdown R-cadherin in linc-cdh4-2 stably overexpressed cells, could significantly upregulate the protein levels of RAC1 and improve the cell migration and invasion abilities. Taken together, the novel linc-cdh4-2 may negatively regulate the motility of the HCC cells through targeting R-cadherin RAC1 signaling pathway. PMID- 27765631 TI - Fluorescent 6-amino-6-deoxyglycoconjugates for glucose transporter mediated bioimaging. AB - Two novel fluorescent bioprobes, namely, 6N-Gly-Cy3 and 6N-Gly-Cy5, were designed and synthesized for real-time glucose transport imaging as well as potentially useful tracer for galactokinase metabolism. The structure of the bioprobes was fully characterized by 1H NMR, 13C NMR, IR, and HRMS. The fluorescence properties, glucose transporter (GLUT) specificity, and the quenching and safety profiles were studied. The cellular uptake of both bioprobes was competitively diminished by d-glucose, 2-deoxy-d-glucose and GLUT specific inhibitor in a dose dependent manner in human colon cancer cells (HT29). Comparison study results revealed that the 6N-derived bioprobes are more useful for real-time imaging of cell-based glucose uptake than the structurally similar fluorescent tracer 6-NBDG which was not applicable under physiological conditions. The up to 96 h long lasting quenching property of 6N-Gly-Cy5 in HT29 suggested the potential applcability of the probe for cell labeling in xenograft transplantation as well as in vivo animal imaging studies. PMID- 27765632 TI - A six-gene phylogeny provides new insights into choanoflagellate evolution. AB - Recent studies have shown that molecular phylogenies of the choanoflagellates (Class Choanoflagellatea) are in disagreement with their traditional taxonomy, based on morphology, and that Choanoflagellatea requires considerable taxonomic revision. Furthermore, phylogenies suggest that the morphological and ecological evolution of the group is more complex than has previously been recognized. Here we address the taxonomy of the major choanoflagellate order Craspedida, by erecting four new genera. The new genera are shown to be morphologically, ecologically and phylogenetically distinct from other choanoflagellate taxa. Furthermore, we name five novel craspedid species, as well as formally describe ten species that have been shown to be either misidentified or require taxonomic revision. Our revised phylogeny, including 18 new species and sequence data for two additional genes, provides insights into the morphological and ecological evolution of the choanoflagellates. We examine the distribution within choanoflagellates of these two additional genes, EF-1A and EFL, closely related translation GTPases which are required for protein synthesis. Mapping the presence and absence of these genes onto the phylogeny highlights multiple events of gene loss within the choanoflagellates. PMID- 27765633 TI - Transcriptomics analysis and human preimplantation development. AB - : The study of oocyte and preimplantation embryo biology has been regarded with great curiosity throughout scientific history, but it is not until the development of robust methods for in vitro observation and manipulation of animal gametes that developmental biology has flourished as a discipline. By far the biggest technical challenge in studying transcription in oocytes and early embryo has been the necessity of developing techniques that retain a high level of accuracy when starting from small amount of material. The objective of this narrative review is to summarize the knowledge gained about the embryonic preimplantation period in the human species from transcriptomics experiments, and to discuss technical limitations and solutions to the study of transcriptomics in these samples. SIGNIFICANCE: In this review we identify key critical issues in performing transcriptomics experiments during the human preimplantation period, and identifying possible ways to overcome them. This, combined with a description of clinical perspectives and the definition of future avenues for research will provide useful for future research. PMID- 27765634 TI - Transcriptomic and proteomic analyses of leaves from Clematis terniflora DC. under high level of ultraviolet-B irradiation followed by dark treatment. AB - : High level of UV-B irradiation followed by dark treatment (HUV-B+D) causes accumulation of secondary metabolites in Clematis terniflora DC. To investigate the response mechanism under HUV-B+D, transcriptomic and proteomic analyses were performed in leaves of C. terniflora. The number of genes related to tetrapyrrole synthesis, amino acid metabolism, tricarboxylic acid cycle, and mitochondrial electron transport chains was hierarchically changed in leaves of C. terniflora under HUV-B+D. Data from RNA-sequencing transcriptomics and gel-free/label-free proteomics were integrated. The genes related to biosynthesis of lignins and flavonoids/isoflavonoids were significantly upregulated. Luteolin 7-O-beta-D glucosiduronic acid, rutin, and kaempferol 3-O-rutinose were accumulated. The number of differentially expressed genes (DEGs) and differentially abundant proteins (DAPs) related to protein metabolism were largely changed in posttranslational modification, ubiquitin proteasome, and ribosomal protein. The expression of NADP-dependent malic enzyme and the abundance of NADP-malate dehydrogenase were upregulated and increased, respectively. The activities of these two enzymes were also enhanced. These results suggest that the secondary metabolism pathway and tricarboxylic acid cycle might be activated in leaves of C. terniflora in response to HUV-B+D. BIOLOGICAL SIGNIFICANCE: This study reported response mechanism in leaves of Clematis terniflora DC. under high level of UV-B irradiation followed by dark treatment using transcriptomic and proteomic techniques. Transcriptomic analysis revealed that the number of genes related to secondary metabolism was increased by >2 times. Phenylalanine ammonia-lyase, 4 Coumarate: CoA ligase, chalcone synthase, isoflavone reductase homolog, and cinnamoyl-CoA reductase were significantly upregulated, which suggests that the secondary metabolism pathway related to lignins and flavonoids/isoflavonoids might be activated. Genes and proteins related to protein metabolism were largely changed in postranslational modification, ubiquitin proteasome, and ribosomal protein. NADP-dependent malic enzyme and NADP-malate dehydrogenase were activated in tricarboxylic acid cycle, which suggests that tricarboxylic acid cycle might be enhanced in leaf of C. terniflora in response to HUV-B+D. PMID- 27765635 TI - Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and alpha-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor. AB - Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the alpha-T catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of alpha-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged alpha-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of alpha-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors. PMID- 27765637 TI - The wing venation patterns to identify single tsetse flies. AB - This is the first study to explore the potential of various geometric morphometrics methods to help the morphological diagnostic of tsetse species, vectors of human and animal trypanosomiases in sub-Saharan Africa. We compared landmarks, semilandmarks and outlines techniques on male and female samples of species, and suggested adapted strategies according to the countries and their own Glossina fauna. We could compare up to 7 taxa belonging to the three main subgenera of the Glossina genus: Nemorhina (5 species), Glossina (1 species) and Austenina (1 species). Our sample included the major vectors of sleeping sickness: G. palpalis palpalis, G. p. gambiensis, G. fuscipes fuscipes and G. f. quanzensis, as well as two important vectors of African animal trypanosomoses: G. tachinoides and Glossina morsitans submorsitans. The average level of correct species recognition by the wing shape was satisfactory, and slightly higher for females than for males. The best scores of correct assignment, in both sexes, were obtained by the contour technique (96% of correct attribution in females, 92% in males), slightly higher than for semilandmarks (95% and 91%) or landmarks (94% and 89%) techniques. We made our images of wings freely available to be used as reference images (http://mome-clic.com), and we describe the conditions and the analytical steps to be followed to identify unknown specimens using external reference images. Under adequate conditions, such use of reference images obtained from a free access server could help species identification of new samples anywhere in Africa. PMID- 27765636 TI - Cigarette Smoke Mediates Nuclear to Cytoplasmic Trafficking of Transcriptional Inhibitor Kaiso through MUC1 and P120-Catenin. AB - Lung cancer is the leading cause of cancer-related death, and 87% of these deaths are directly attributable to smoking. Using three-dimensional cultures of primary human bronchial epithelial cells, we demonstrated that loss of adherens junction protein, epithelial cadherin, and the aberrant interaction of its adherens junction binding partner, p120-catenin (p120ctn), with the cytoplasmic tail of apical mucin-1 (MUC1-CT) represent initiating steps in the epithelial-to mesenchymal transition. Smoke provoked the rapid nuclear entry of p120ctn in complex with MUC1-CT that was inhibited using the MUC1-CT inhibitory peptides, PMIP and GO-201. Nuclear entry of p120ctn promoted its interaction with transcriptional repressor kaiso and the rapid shuttling of kaiso to the cytoplasm. Nuclear exit of kaiso permitted the up-regulation of oncogenic transcription factors Fos/phospho-Ser32 Fos, FosB, Fra1/phospho-Ser265 Fra1, which was inhibited through suppression of p120ctn's nuclear export using leptomycin-B. These data indicated that smoke-induced nuclear-to-cytoplasmic translocation of kaiso depends on the nuclear import of p120ctn in complex with MUC1-CT and the nuclear export of kaiso in complex with p120ctn. The presence of MUC1-CT/p120ctn and p120ctn/kaiso complexes in lung squamous cell carcinoma and adenocarcinoma specimens from human patients confirms the clinical relevance of these events. Thus, enhancing kaiso's suppressor role of protumor genes by sequestering kaiso in the nucleus of a smoker's airway epithelium may represent a novel approach of treating lung cancer. PMID- 27765638 TI - Assessment of nuclear and mitochondrial genes in precise identification and analysis of genetic polymorphisms for the evaluation of Leishmania parasites. AB - The polymorphism and genetic diversity of Leishmania genus has status under discussion depending on many items such as nuclear and/or mitochondrial genes, molecular tools, Leishmania species, geographical origin, condition of micro environment of Leishmania parasites and isolation of Leishmania from clinical samples, reservoir host and vectors. The genetic variation of Leishmania species (L. major, L. tropica, L. tarentolae, L. mexicana, L. infantum) were analyzed and compared using mitochondrial (COII and Cyt b) and nuclear (nagt, ITS-rDNA and HSP70) genes. The role of each enzymatic (COII, Cyt b and nagt) or housekeeping (ITS-rDNA, HSP70) gene was employed for accurate identification of Leishmania parasites. After DNA extractions and amplifying of native, natural and reference strains of Leishmania parasites, polymerase chain reaction (PCR) products were sequenced and evaluation of genetic proximity and phylogenetic analysis were performed using MEGA6 and DnaSP5 software. Among the 72 sequences of the five genes, the number of polymorphic sites was significantly lower as compared to the monomorphic sites. Of the 72 sequences, 54 new haplotypes (five genes) of Leishmania species were submitted in GenBank (Access number: KU680818 - KU680871). Four genes had a remarkable number of informative sites (P=0.00), except HSP70 maybe because of its microsatellite regions. The non-synonymous (dN) variants of nagt gene were more than that of other expression genes (47.4%). The synonymous (dS)/dN ratio in three expression genes showed a significant variation between five Leishmania species (P=0.001). The highest and lowest levels of haplotype diversity were observed in L. tropica (81.35%) and L. major (28.38%) populations, respectively. Tajima's D index analyses showed that Cyt b gene in L. tropica species was significantly negative (Tajima's D=-2.2, P<0.01), while COII and nagt genes were produced through evolutionary processes for both L. tropica and L. major (Tajima's D=2.85 & 2.91, P<0.01). More different clinical lesions with extensive phylogenetic and evolutionary analyses should be employed to avoid confusion in the diagnosis of leishmaniasis and development of vaccines for eradicating Leishmania parasites. PMID- 27765639 TI - ZIKV Strains' Different Phenotypes in Human Neural Cells Could be a Hint for the Emergence of the New Clinical Neurological Outcomes. PMID- 27765640 TI - Beyond Undetectable Viral Load: Effect of Nucleotides on Inflammation. PMID- 27765641 TI - Targeting Bacterial Abscess Formation. PMID- 27765642 TI - Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI). AB - BACKGROUND: We recently reported that six alleles from class II genes of the Human Leukocyte Antigen (HLA) confer protection from Gulf War Illness (GWI) (Georgopoulos et al., 2015). The most significant effect is exerted on Neurological-Cognitive-Mood (NCM), Pain, and Fatigue symptoms, such that higher number of copies of the protective alleles are associated with lower symptom severity. Here we tested the hypothesis that this effect is exerted by modulating the strength of neural synchronicity. METHODS: Eighty-one Gulf War veterans (65 with GWI and 16 healthy controls) underwent a magnetoencephalography (MEG) scan to assess the strength of brain synchronicity by computing zero-lag crosscorrelations (and their Fisher z transforms) between prewhitened MEG time series. A high-resolution HLA genotyping determined the number of copies, k, of the 6 protective alleles above in each participant. We tested the hypothesis above by regressing NCM, Pain and Fatigue symptom severity against the interaction term, k*z (HLA-related effect), while including z (non-HLA-related effect), gender and age as covariates. The k*z and z terms assessed HLA- and non HLA-related effects, respectively, of neural synchronicity on symptom severity. The distributions of these effects in sensor space were visualized using statistical heatmaps. FINDINGS: We found significant, graded HLA- and non-HLA related effects: (a) NCM>Pain>Fatigue for HLA-related effects, (b) NCM>Fatigue>Pain for non-HLA-related effects, and (c) HLA-related>non-HLA-related effects for all symptoms. These effects had widespread but distinct distributions in sensor space that allowed the orderly separation of the 6 terms (3 symptom domains*2 HLA factors) in a multidimensional plot, where one dimension separated the symptoms and the other the HLA relation. INTERPRETATION: These findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural influences on NCM, Pain and Fatigue symptom severity in GWI. FUNDING: U.S. Department of Veterans Affairs and University of Minnesota. PMID- 27765644 TI - Binge-like intake of HFD attenuates alcohol intake in rats. AB - Binge eating and binge alcohol intake are behavioral manifestations of pathological feeding and alcohol use disorder (AUD), respectively. Binge-feeding and AUD have high comorbidity with other psychiatric disorders such as depression, which could have important implications for the management of these conditions. Importantly, these behaviors share many common features suggesting a singular etiology. However, the nature by which binge-feeding affects the development or maintenance of AUD is unclear. The present study examined the impact of a binge-feeding from a nutritionally complete high-fat diet (HFD) on initiation and maintenance of alcohol intake, anxiolytic behavior and central genetic changes in brain regions that control alcohol-reinforced behaviors. To do this, male Long-Evans rats received chow (controls) or HFD every three days (HFD 3D) or every day (HFD-ED) for 5weeks. Rodent chow and water were available ad libitum to all groups throughout the experiment. Following 5weeks of HFD cycling, 20.0% ethanol or 2.0% sucrose intake was evaluated. In addition, anxiety-like behavior was measured using a light-dark box apparatus. Both HFD-3D and -ED groups of rats consumed significantly large amount of food during 2h HFD access sessions and reduced their chow intake in the next 22h. Surprisingly, binge-fed rats displayed attenuated acquisition of alcohol intake whereas sucrose consumption was unaffected. Rats exposed to HFD spent more time in the light side compared to chow controls, indicating that binge-feeding induced anxiolytic effects. In addition, alterations in the brain neurotensin system were observed following HFD exposure. These data indicate that binge-feeding behavior induces behavioral and genetic changes that help explain how alcohol intake is influenced by co-morbid eating disorders. PMID- 27765645 TI - Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior. AB - Gestational infection is increasingly being recognized for its involvement as causative mechanism in severe developmental brain abnormalities and its contribution to the pathogenesis of psychopathologies later in life. First observations in the widely accepted maternal immune activation (MIA) model based upon the systemic administration of the viral mimetic Polyinosinic:polycytidylic acid (poly(I:C)) have recently suggested a transmission of behavioral and transcriptional traits across generations. Although maternal care behavior (MCB) is known as essential mediator of the transgenerational effects of environmental challenges on offspring brain function and behavior, the possible propagation of alterations of MCB resulting from MIA to following generations has not yet been examined. Here we show that poly(I:C) stimulation at embryonic day 12.5 (E12.5) leads to aberrant MCB and that this effect is transmitted to the female F1 offspring. The transgenerational effects on MCB are paralleled by enhanced depression-like behavior in the second generation F2 offspring with contributions of both maternal and paternal heritages. Examination of offspring hippocampal expression of genes known as targets of MCB and relevant for ensuing non-genetic transmission of altered brain function and behavior revealed transgenerationally conserved and modified expressional patterns in the F1 and F2 generation. Collectively these data firstly demonstrate the transgenerational transmission of the impact of gestational immune activation on the reproductive care behavior of the mother. Behavioral and molecular characteristics of first and second generation offspring suggest transgenerationally imprinted consequences of gestational infection on psychopathological traits related to mood disorders which remain to be examined in future cross-fostering experiments. PMID- 27765643 TI - Identifying Treatment Effect Modifiers in the STarT Back Trial: A Secondary Analysis. AB - : Identification of patient characteristics influencing treatment outcomes is a top low back pain (LBP) research priority. Results from the STarT Back trial support the effectiveness of prognostic stratified care for LBP compared with current best care, however, patient characteristics associated with treatment response have not yet been explored. The purpose of this secondary analysis was to identify treatment effect modifiers within the STarT Back trial at 4-month follow-up (n = 688). Treatment response was dichotomized using back-specific physical disability measured using the Roland-Morris Disability Questionnaire (>=7). Candidate modifiers were identified using previous literature and evaluated using logistic regression with statistical interaction terms to provide preliminary evidence of treatment effect modification. Socioeconomic status (SES) was identified as an effect modifier for disability outcomes (odds ratio [OR] = 1.71, P = .028). High SES patients receiving prognostic stratified care were 2.5 times less likely to have a poor outcome compared with low SES patients receiving best current care (OR = .40, P = .006). Education level (OR = 1.33, P = .109) and number of pain medications (OR = .64, P = .140) met our criteria for effect modification with weaker evidence (.20 > P >= .05). These findings provide preliminary evidence for SES, education, and number of pain medications as treatment effect modifiers of prognostic stratified care delivered in the STarT Back Trial. PERSPECTIVE: This analysis provides preliminary exploratory findings about the characteristics of patients who might least likely benefit from targeted treatment using prognostic stratified care for LBP. PMID- 27765646 TI - Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: An epigenetic link. AB - African American men (AAM) who are exposed to trauma and adversity during their early life are at greater risk for poor health over their lifespan. Exposure to adversity during critical developmental windows may embed an epigenetic signature that alters expression of genes that regulate stress response systems, including those genes that regulate the inflammatory response to stress. Such an epigenetic signature may increase risk for diseases exacerbated by inflammation, and may contribute to health disparity. The purpose of this study was to evaluate the extent to which exposure to early life adversity influences the psychological, cortisol, and proinflammatory response to acute stress (Trier Social Stress Test TSST) in emerging adult AAM, ages 18-25years (N=34). Hierarchical linear modeling was used to examine the cortisol and IL-6 pattern of response to the TSST with respect to childhood adversity factors and DNA methylation of the IL-6 promoter. Findings revealed that in response to the TSST, greater levels of childhood trauma and indirect exposure to neighborhood violence were associated with a greater TSST-induced IL-6 response, and a blunted cortisol response. Reduced methylation of the IL6 promoter was related to increased exposure to childhood trauma and greater TSST-induced IL-6 levels. These results support the concept that exposure to childhood adversity amplifies the adult proinflammatory response to stress, which is related to epigenetic signature. PMID- 27765648 TI - Immunomodulatory effect of G-CSF on the CNS infiltrating monocytes in ischemic stroke. PMID- 27765647 TI - Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study. AB - OBJECTIVE: Elevated inflammation has been repeatedly observed in posttraumatic stress disorder (PTSD), and it may drive the development of both psychiatric symptoms and physical comorbidities. However, it is not clear if elevated inflammation is a feature of both remitted and current PTSD, and little is known about relationships between specific clusters of PTSD symptoms and inflammation. Exaggerated threat sensitivity, as indexed by threat reactivity and avoidance of perceived threats, may be particularly closely associated with inflammation. METHODS: We assessed PTSD symptoms and threat sensitivity using the Clinician Administered PTSD Scale in 735 Veterans Affairs patients (35% current PTSD; 16% remitted PTSD) who participated in the Mind Your Heart Study (mean age=59+/-11; 94% male). High sensitivity C-reactive protein (hsCRP), white blood cell count (WBC), and fibrinogen were used as indices of inflammation. Analysis of covariance models with planned contrasts were used to examine differences in inflammation by PTSD status, adjusting for age, sex, race, kidney function and socioeconomic status. RESULTS: Individuals with current PTSD had significantly higher hsCRP and WBC than patients with no history of PTSD, but there were no significant differences in inflammatory markers between those with remitted versus no history of PTSD. Within patients with current PTSD, higher threat reactivity was independently associated with higher hsCRP (beta=0.16, p=0.01) and WBC count (beta=0.24, <0.001), and higher effortful avoidance was associated with higher fibrinogen (beta=0.13, p=0.04). CONCLUSION: Our data indicate that elevated inflammation may be a feature of current, but not remitted, PTSD. Within patients with PTSD, higher threat reactivity was also associated with elevated inflammation. A better understanding of the relationship between threat sensitivity and inflammation may inform interventions for patients with PTSD. PMID- 27765650 TI - A PCR-based protocol to accurately size C9orf72 intermediate-length alleles. AB - Although large expansions of the non-coding GGGGCC repeat in C9orf72 gene are clearly defined as pathogenic for Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), intermediate-length expansions have also been associated with those and other neurodegenerative diseases. Intermediate-length allele sizing is complicated by intrinsic properties of current PCR-based methodologies, in that somatic mosaicism could be suspected. We designed a protocol that allows the exact sizing of intermediate-length alleles, as well as the identification of large expansions. PMID- 27765649 TI - Consecutive emamectin benzoate and deltamethrin treatments affect the expressions and activities of detoxification enzymes in the rainbow trout (Oncorhynchus mykiss). AB - Rainbow trout (Oncorhynchus mykiss) subjected to three consecutive, alternating treatments with emamectin benzoate (EMB) and deltamethrin (DM) during outbreaks of Caligus rogercresseyi in a farm located in southern Chile (Hornopiren, Chiloe), were studied to determine the effects of these treatments on the protein and enzymatic activity levels of cytochrome P450 1A (CYP1A), flavin-containing monooxygenase (FMO) and glutathione S-transferase (GST) in different tissues. Consecutive and alternating EMB/DM treatments resulted in a 10-fold increase and 3-fold decrease of CYP1A protein levels in the intestine and gills, respectively. Notably, CYP1A activity levels decreased in most of the analyzed tissues. FMO protein and activity levels markedly increased in the kidney and the intestine. GST was up-regulated in all tissues, either as protein or enzyme activity. When comparing consecutive EMB/DM treatments against previous studies of EMB treatment alone, CYP1A activity levels were similarly diminished, except in muscle. Likewise, FMO activity levels were increased in most of the analyzed tissues, particularly in the muscle, kidney, and intestine. The increases observed for GST were essentially unchanged between consecutive EMB/DM and EMB only treatments. These results indicate that consecutive EMB/DM treatments in rainbow trout induce the expression and activity of FMO and GST enzymes and decrease CYP1A activity. These altered activities of detoxification enzymes could generate imbalances in metabolic processes, synthesis, degradation of hormones and complications associated with drug interactions. It is especially important when analyzing possible effects of consecutive antiparasitic treatments on withholding periods and salmon farming yields. PMID- 27765652 TI - Antibody-drug conjugate directed against the guanylyl cyclase antigen for the treatment of gastrointestinal malignancies. AB - Antibody-directed cancer chemotherapy in the form of antibody-drug conjugates (ADCs) may improve the therapeutic index with the potential to enhance efficacy and decrease systemic toxicity. ADCs consist of three key components including an antibody that specifically binds to the target, a toxic agent and a linker which releases the toxic agent inside tumor cells. A novel ADC, MLN0264 (TAK-264) was recently investigated in patients with gastrointestinal (GI) malignancies. TAK 264 is an anti- guanylyl cyclase C (GCC) antibody conjugated via a protease cleavable linker to the potent anti-microtubule agent monomethyl auristatin E (MMAE) (linker and toxin licensed from Seattle Genetics). Following binding to GCC, the ADC is internalized and transported to lysosomes where MMAE is released to bind to tubulin, leading to cell cycle arrest and apoptosis. This GCC targeting ADC has been evaluated in clinical studies in patients with advanced gastrointestinal malignancies. The early findings from Phase 1 study have shown preliminary activity signals in gastric, gastroesophageal, and pancreatic cancer. Results from two phase II studies in pancreatic and gastoesophageal adenocarcinoma showed only limited activity. Antibody-drug-conjugates offer a promising therapeutic modality aimed at providing target-directed cancer chemotherapy. Herein we discuss the GCC target and gastrointestinal malignancies where GCC based targeted therapies could further evolve and offer a significant clinical benefit. PMID- 27765653 TI - Latin American Clinical Epidemiology Network Series - Paper 9: The Kangaroo Mother Care Method: from scientific evidence generated in Colombia to worldwide practice. AB - Kangaroo Mother Care (KMC) is a human-based care intervention devised to complement neonatal care for low birth weight and premature infants. Kangaroo position (skin-to-skin contact on the mother's chest) offers thermal regulation, physiological stability, appropriate stimulation, and enhances bonding and breastfeeding. Kangaroo nutrition is based on breastfeeding, and kangaroo discharge policy relies on family empowerment and early discharge in kangaroo position with close ambulatory follow-up. We describe how the evidence has been developed and how it has been put into practice by means of direct preterm infants care and dissemination of the method, including training of KMC excellence centers in many countries not only in Latin America but worldwide. PMID- 27765654 TI - Latin American Clinical Epidemiology Network Series - Paper 7: Central obesity measurements better identified risk factors for coronary heart disease risk in the Chilean National Health Survey (2009-2010). AB - OBJECTIVES: Obesity is an important determinant of cardiovascular risk. However, the optimal measure and cutoffs in Latin America are not defined. We sought to assess the relationship between body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) with risk factor prevalence and estimated coronary heart disease (CHD) risk and to assess if recommended cutoffs apply to the Chilean population. STUDY DESIGN AND SETTING: Data from 2,200 men and 3,216 women from the Chilean Health Survey 2009-2010 were analyzed. Receiver operator characteristic (ROC) curves were used to compare discrimination and estimate optimal cutoffs. Sensitivity, specificity, and net reclassification improvement (NRI) for these cutoffs were compared with values obtained applying international recommendations. RESULTS: WHtR and WC have a higher ROC area for risk factors and CHD risk. BMI and WC optimal cutoffs did not improve net reclassification when compared with international recommendations. A WHtR of 0.55 in men improves NRI compared with proposed values (P < 0.01). A WHtR of 0.6 in women improves NRI when compared with BMI (P > 0.01) but not when compared with WC. CONCLUSION: Central obesity measurements demonstrated the strongest associations with CV risk factors and estimated risk. Optimal cutoffs were similar to those recommended internationally with the exception of WHtR. PMID- 27765651 TI - Metamorphosis of the Drosophila visceral musculature and its role in intestinal morphogenesis and stem cell formation. AB - The visceral musculature of the Drosophila intestine plays important roles in digestion as well as development. Detailed studies investigating the embryonic development of the visceral muscle exist; comparatively little is known about postembryonic development and metamorphosis of this tissue. In this study we have combined the use of specific markers with electron microscopy to follow the formation of the adult visceral musculature and its involvement in gut development during metamorphosis. Unlike the adult somatic musculature, which is derived from a pool of undifferentiated myoblasts, the visceral musculature of the adult is a direct descendant of the larval fibers, as shown by activating a lineage tracing construct in the larval muscle and obtaining labeled visceral fibers in the adult. However, visceral muscles undergo a phase of remodeling that coincides with the metamorphosis of the intestinal epithelium. During the first day following puparium formation, both circular and longitudinal syncytial fibers dedifferentiate, losing their myofibrils and extracellular matrix, and dissociating into mononuclear cells ("secondary myoblasts"). Towards the end of the second day, this process is reversed, and between 48 and 72h after puparium formation, a structurally fully differentiated adult muscle layer has formed. We could not obtain evidence that cells apart from the dedifferentiated larval visceral muscle contributed to the adult muscle, nor does it appear that the number of adult fibers (or nuclei per fiber) is increased over that of the larva by proliferation. In contrast to the musculature, the intestinal epithelium is completely renewed during metamorphosis. The adult midgut epithelium rapidly expands over the larval layer during the first few hours after puparium formation; in case of the hindgut, replacement takes longer, and proceeds by the gradual caudad extension of a proliferating growth zone, the hindgut proliferation zone (HPZ). The subsequent elongation of the hindgut and midgut, as well as the establishment of a population of intestinal stem cells active in the adult midgut and hindgut, requires the presence of the visceral muscle layer, based on the finding that ablation of this layer causes a severe disruption of both processes. PMID- 27765655 TI - Threading: A novel insilico indagation method for genetic characterization of some diplostomoid metacercariae (Digenea:Diplostomidae Poirier, 1886). AB - The protein encoding zone of Mitochondrial DNA region (inherited from single lineage) seems most suitable and effective for taxonomic, systematic, ecological, evolutionary, DNA barcoding, cryptic species and population studies, exploiting nucleotide/amino acid datasets (1D/2D/3D conformational level). Nowadays, expeditious computerized methods are in trend for analyzing genetic material to demonstrate variations at various levels of protein structures. Structural proteomics have implemented here for genetic identification, differentiation and relationship of species from information rich data of mt COI gene of the family Diplostomidae with inclusion of molecular tools. Various aspects have been utilized herein for re-validation and infallible discrimination of Trematode diplostomoid metacercariae (Tetracotyle lucknowensis Pandey, 1971; T. xenentodoni Chakrabarti, 1970; T. fausti Rai and Pande, 1969; T. muscularius Chakrabarti, 1970 and Diplostomulum minutum Pandey, 1968), the infective stage in the life cycle, causing severe damage to fish host, whose adults are found mainly in fish eating birds and mammals. PMID- 27765657 TI - Intraperitoneal exposure of whitefish to microcystin-LR induces rapid liver injury followed by regeneration and resilience to subsequent exposures. AB - To date, there has been no systematic approach comprehensively describing the sequence of pathological changes in fish during prolonged exposure to microcystin LR (MC-LR). Towards this aim, juvenile whitefish individuals received an intraperitoneal injection with pure MC-LR, and the injection was repeated every week to maintain continuous exposure for 28days. During the exposure period, growth and condition of the fish were assessed based on biometric measurements. Additionally, selected biochemical markers were analysed in the fishes' blood, and their livers were carefully examined for morphological, ultrastructural, and molecular changes. The higher dose of MC-LR (100MUg.kg-1) caused severe liver injury at the beginning of the exposure period, whereas the lower dose (10MUg.kg 1) caused less, probably reversible injury, and its effects began to be observed later in the exposure period. These marked changes were accompanied by substantial MC-LR uptake by the liver. However, starting on the 7th day of exposure, cell debris began to be removed by phagocytes, then by 14th day, proliferation of liver cells had markedly increased, which led to reconstruction of the liver parenchyma at the end of the treatment. Surprisingly, despite weekly repeated intraperitoneal injections, MC-LR did not accumulate over time of exposure which suggests its limited uptake in the later phase of exposure. In support, mRNA expression of the membrane transport protein oatp1d was decreased at the same time as the regenerative processes were observed. Our study shows that closing of active membrane transport may serve as one defence mechanism against further MC-LR intoxication. PMID- 27765656 TI - Dynamic changes in the main regulatory genes of mitochondrial permeability transition pore in Eimeria tenella host cells. AB - The purpose of the present study was to investigate the dynamic changes in the main regulatory genes of the mitochondrial permeability transition pore in E. tenella host cells. Primary chick embryo cecum epithelial cell culture techniques, spectrophotometer technology, Hoechst-Annexin V-PI apoptosis staining and ELISA were used to detect the apoptosis rate and dynamic changes of Bcl-2, Bcl-xl, Bax, Bak, Bid, Bad, HK-II, and ATP content in E. tenella host cells at 4, 24, 48, 72, 96, and 120 h. The rates of early apoptosis, late apoptosis, and necrosis of group T0 were significantly lower (P < 0.05) or highly significantly lower (P < 0.01) than those of group C at 4 h, but higher (P < 0.05 or P < 0.01) at varying degrees than those of the same group at 24-120 h. Compared to group C, the amount of Bcl-2, ATP, Bax and Bad in group T0 were visibly lower (P < 0.05 or P < 0.01) at 4 h, whereas Bcl-xl/Bax was highly significantly higher (P < 0.01) at 4 h. In addition, group T0 had less ATP at 24-120 h than group C, whereas the amount of Bcl-2, Bcl-xl, Bax, Bak, Bid, Bad and HK-II in group T0 inversely increased in varying degrees at 24-120 h compared with group C. Moreover, Bcl 2/Bax was lower (P < 0.01) at 24, 48, and 96 h, and Bcl-xl/Bax was lower (P < 0.05) at 48 h in group T0 than in group C, respectively. Taken together, these observations indicate that in the early developmental stages of E. tenella, the host-cell apoptosis rate decreased; although the amount of anti- and pro apoptotic genes in host cells decreased, the ratios of anti-apoptotic to pro apoptotic bcl-2 gene-family members increased. In the middle and later developmental stages of E. tenella, the host-cell apoptosis rate increased; the amount of anti- and pro-apoptotic genes increased, while the ratios of anti apoptotic to pro-apoptotic bcl-2 gene-family members decreased. In addition, ATP decreased at all developmental stages of E. tenella. PMID- 27765659 TI - Are lower levels of cardiorespiratory fitness associated with incident depression? A systematic review of prospective cohort studies. AB - Physical activity (PA) is protective from future depression, however, the potential impact of cardiorespiratory fitness (CRF) on the development of depression is less clear. We aimed to investigate if lower levels of CRF are associated with a higher risk for depression onset. Major electronic databases were searched, from inception to January 2016 for prospective cohort studies evaluating the association between CRF and incident depression. Pooled hazard ratio (HR) with 95% confidence intervals (CIs) were calculated. Methodological quality was evaluated using the Newcastle-Ottawa scale (NOS). Three prospective studies were identified and data from two studies were pooled. Our data provide preliminary evidence found that people with low CRF and medium CRF were at increased risk of developing depression (n=1,128,290, HR=1.76, 95% CI 1.61-1.91, p<0.001, I2=11.88, and HR=1.23, 95% CI 1.20-1.38, p<0.001, I2=0, respectively). Considered alongside the wider benefits of higher levels of CRF, these findings further support the rationale for interventions specifically targeting fitness, in order to reduce the significant burden associated with depression. PMID- 27765658 TI - Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome. AB - BACKGROUND: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. METHODS: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS2 analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. RESULTS: 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. CONCLUSIONS: Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity. PMID- 27765660 TI - The role of area-level deprivation and gender in participation in population based faecal immunochemical test (FIT) colorectal cancer screening. AB - This study aimed to investigate the effects of sex and deprivation on participation in a population-based faecal immunochemical test (FIT) colorectal cancer screening programme. The study population included 9785 individuals invited to participate in two rounds of a population-based biennial FIT-based screening programme, in a relatively deprived area of Dublin, Ireland. Explanatory variables included in the analysis were sex, deprivation category of area of residence and age (at end of screening). The primary outcome variable modelled was participation status in both rounds combined (with "participation" defined as having taken part in either or both rounds of screening). Poisson regression with a log link and robust error variance was used to estimate relative risks (RR) for participation. As a sensitivity analysis, data were stratified by screening round. In both the univariable and multivariable models deprivation was strongly associated with participation. Increasing affluence was associated with higher participation; participation was 26% higher in people resident in the most affluent compared to the most deprived areas (multivariable RR=1.26: 95% CI 1.21-1.30). Participation was significantly lower in males (multivariable RR=0.96: 95%CI 0.95-0.97) and generally increased with increasing age (trend per age group, multivariable RR=1.02: 95%CI, 1.01-1.02). No significant interactions between the explanatory variables were found. The effects of deprivation and sex were similar by screening round. Deprivation and male gender are independently associated with lower uptake of population-based FIT colorectal cancer screening, even in a relatively deprived setting. Development of evidence-based interventions to increase uptake in these disadvantaged groups is urgently required. PMID- 27765661 TI - The complete genome of Dietzia timorensis ID05-A0528T revealed the genetic basis for its saline-alkali tolerance. AB - The type strain Dietzia timorensis ID05-A0528T, was reported to be able to survive in the highly saline and alkaline environments with diverse carbon sources. In order to more pertinently understand the genetic mechanisms of its environmental tolerance and crude oil emulsification, we reported the complete genome sequence of the strain in the study. The genome contains only one circular chromosome, with the total size of 3,607,892 bps, and the G+C content of this strain is 65.58%, much lower than other type strains of this genus. It was found that strain ID05-A0528T contains genes involved in transportation and biosynthesis of compatible solutes, as well as genes encoding monovalent cation/proton antiporters, which could explain its abilities to tolerate high salinity and alkalinity. Various central metabolic routes and complete alkane hydroxylation pathway were also identified in the genome of strain ID05-A0528T, which is in accordance with its ability to use a wide spectrum of carbon sources and to degrade n-alkanes. PMID- 27765662 TI - Bactericidal effect of gamma-radiation with 137Cesium in platelet concentrates. AB - INTRODUCTION: gamma-radiation is a method that was originally designed for inactivation of T lymphocytes in blood and blood components in order to prevent transfusion associated-graft versus host disease (TA-GVHD). Klebsiella pneumoniae, Escherichia coli, Enterococcus faecium and Staphylococcus epidermidis strains are important pathogens in blood banks since they have been related to post-transfusional sepsis. This study was conducted to demonstrate that gamma radiation is effective in reducing the viability of bacteria in platelet concentrates (PC). MATERIAL AND METHODS: Klebsiella pneumoniae, E. coli, E. faecium and S. epidermidis strains were adjusted at 101 to 106 CFU/ml and used in artificial contamination assays in PC. Contaminated platelet concentrates were subjected to gamma-radiation with doses of 2500 cGy in a 137Cesium irradiator. The average of surviving bacteria at different bacterial concentrations, logarithmic reduction values (LRV) and bacterial death after gamma-radiation percentage was calculated. RESULTS: Escherichia coli and K. pneumoniae were eliminated in 101 to 103 CFU; in contrast with 104 to 106 CFU, the LRV were 2.4, 2.6 and 2.6 for E. coli and 3.3, 2.7 and 3.0 for K. pneumoniae strains at 104, 105 and 106 CFU respectively. For Gram-positive strains, 101 CFU in PC, the inactivation post gamma-radiation was not completed. Logarithmic reduction values post gamma-radiation were 0.8 to 1.2 for E. faecium and S. epidermidis strains respectively. CONCLUSION: gamma-radiation cannot be an alternative for the inactivation of pathogens in PC, because of the bacterial concentration and pathogen nature - being resistant to gamma-radiation, the Gram-positive bacteria. PMID- 27765663 TI - Comprehensive technical and patient-care optimization in the management of pediatric apheresis for peripheral blood stem cell harvesting. AB - BACKGROUND: Pediatric apheresis for peripheral blood stem cell transplantation should be carried out with due concern for low corporeal blood volume and vulnerability to hypocalcemia-related complications, hypovolemic shock, and hypervolemic cardiac overload. STUDY DESIGN AND METHODS: We retrospectively investigated a total of 267 apheresis procedures from 1990 to 2013 on 93 children between 0 and 10 years old, including 89 patients and 4 healthy donors, with body weights of 6.3 to 44.0 kg. RESULTS: The median CD34+ cell yield per apheresis procedure was 2.3 * 106 CD34+ cells/kg (0.2-77.9 * 106 CD34+ cells/kg). Adverse events occurred in 11.6% of procedures (n = 31), including mild perivascular pain (n = 12), emesis (n = 9), hypotension (n = 3), urticaria (n = 2), numbness (n = 2), chest pain (n = 1), facial flush (n = 1), and abdominal pain (n = 1). Among hypotensive events, shock in a 9.6 kg one-year-old boy required emergency treatment in 1996. Thereafter, we adopted continuous injection of calcium gluconate, ionized calcium monitoring, central venous catheter access and circuit priming with albumin in addition to concentrated red cells. Since then we have had fewer complications: 16.4% per apheresis during 1990-1997 versus 5.8% during 1998-2013. No healthy pediatric donors suffered from any late-onset complications related to apheresis or G-CSF administration. CONCLUSION: By employing appropriate measures, peripheral blood stem cell apheresis for small children can have an improved safety profile, even for children weighing <10 kg. PMID- 27765664 TI - Differentiation of pernicious anemia from thrombotic thrombocytopenic purpura: The clinical value of subtle pathologic findings. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia that requires emergent treatment with plasma exchange and is one of the most important conditions for which apheresis service professionals are consulted. Careful interpretation of initial laboratory values and the peripheral blood smear is a critical first step to determining the need for plasma exchange because other conditions can show deceptively similar red cell morphology, and ADAMTS13 levels are often not rapidly available. CASE REPORT: We report a case of a patient who was initially diagnosed with TTP and treated with plasma exchange based on preliminary laboratory data and a peripheral blood smear that contained bizarre microcytic red blood cells presumed to be schistocytes. The peripheral blood smear was later interpreted by the hematopathologist to be inconsistent with TTP, and further workup led to a diagnosis of severe vitamin B12 deficiency secondary to pernicious anemia. RESULTS AND CONCLUSION: This case highlights the diagnostic complexity of thrombotic microangiopathies and the importance of a critical evaluation of the blood smear and presenting laboratory data when there is a concern for TTP. PMID- 27765665 TI - Improved labelling of antiretrovirals for paediatric use. PMID- 27765666 TI - Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment naive, HIV-infected adolescents: a single-arm, open-label trial. AB - BACKGROUND: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents. METHODS: We did a 48 week, single arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per MUL, and estimated glomerular filtration rate of at least 90 mL/min per 1.73 m2 by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS: Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUCtau for elvitegravir was 23 840 ng * h per mL (coefficient of variation [CV] 25.5%), and the mean AUClast for tenofovir alafenamide was 189 ng * h per mL (CV 55.8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults. INTERPRETATION: The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV infected adolescents and its timely assessment in younger children. FUNDING: Gilead Sciences. PMID- 27765667 TI - Einstein, the Blind Men, and the Elephant: Making Sense of Heart Failure With Preserved Ejection Fraction. PMID- 27765668 TI - Heart Failure Care: More Than Just Heart Failure. PMID- 27765669 TI - Cardiac Resynchronization Therapy in Older Patients: Age Is Just a Number, and Yet .... PMID- 27765670 TI - Ventricular Assist Device Therapy in Older Patients With Heart Failure: Characteristics and Outcomes. AB - BACKGROUND: Limited data exist on outcomes in patients >=70 years of age supported with the use of continuous-flow left ventricular assist devices (LVADs). METHODS: Data on 1149 continuous-flow LVAD recipients was queried from the Mechanical Circulatory Support Research Network. Groups were assigned based on age: >=70 years ("older patients") and <70 years. The primary outcome was survival at one-year based on age grouping. RESULTS: Compared with younger patients (54.3 +/- 11.2 y; n = 986), older patients (73.4 +/- 3.0 y) constituted only 14% of LVAD implants. Older patients had similar rates of device thrombosis (P = .47) and stroke (P = .44), but survival-free of gastrointestinal bleeding (GIB) at 1 year was lower compared with younger patients (58% vs 69%; P < .01). Unadjusted survival at 1 year in older patients was 75% compared with 84% in younger patients, and at 2 years 65% versus 73% (P = .18). Age >=70 years was not associated with increased mortality (adjusted hazard ratio [aHR] 0.94, 95% confidence interval [CI] 0.70-1.26; P = .67). Preoperative creatinine (aHR 1.57, 95% CI: 1.30-1.89, P < .0001), bilirubin (aHR 1.22, 95% CI 1.05-1.42; P = .010), and ischemic cardiomyopathy (aHR 1.43, 95% CI 1.11-1.84; P = .005) portended increased risk of death. In older patients, the only predictor of mortality was creatinine (HR 2.1, 95% CI 1.2-3.4; P = .007). Creatinine >=1.4 mg/dL was associated with a 1-year survival of 65%, compared with 84% when the creatinine was <1.4 mg/dL (P = .009). CONCLUSION: Age >70 years is an important consideration when assessing LVAD risk, but other correlates may be more predictive of LVAD survival. Older patients without renal dysfunction have survival similar to younger patients. Older patients should be counseled about age-correlated risks, including higher rates of GIB. PMID- 27765671 TI - The oncoprotein HBXIP up-regulates YAP through activation of transcription factor c-Myb to promote growth of liver cancer. AB - The oncoprotein Yes-associated protein (YAP) in Hippo pathway plays crucial roles in the development of cancer. However, the mechanism of YAP regulation in cancer remains poorly understood. Here, we supposed that the oncoprotein hepatitis B X interacting protein (HBXIP) might be involved in the modulation of YAP in liver cancer. Interestingly, our data showed that the expression levels of HBXIP were positively associated with those of YAP in clinical hepatocellular carcinoma (HCC) samples by immunohistochemistry (IHC) staining and real-time PCR assays. HBXIP was able to up-regulate YAP in hepatoma cells at the levels of promoter, mRNA and protein. Mechanistically, we identified that HBXIP up-regulated YAP through co-activating the transcription factor c-Myb in hepatoma cells. Functionally, silencing YAP abolished the proliferation of hepatoma cells mediated by HBXIP in vitro. Moreover, knockdown of YAP strongly blocked the HBXIP enhanced tumor growth in mice. Thus, we conclude that HBXIP up-regulates YAP expression via activating transcription factor c-Myb to facilitate the growth of hepatoma cells. Our finding provides new insights into the mechanism of YAP regulation. Therapeutically, the oncoprotein HBXIP and YAP might serve as targets in liver cancer. PMID- 27765672 TI - Aged dominant negative p38alpha MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning. AB - A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age related senescence of self-renewal occurs simultaneously with chronic up regulation of the p38MAPKalpha (p38alpha) signaling pathway, we used the dominant negative mouse model for attenuated p38alpha activity (DN-p38alphaAF/+) in which Thr180 and Tyr182 are mutated (T->A/Y->F) to prevent phosphorylation activation (DN-p38alphaAF/+) and kinase activity. As a result, aged DN-p38alphaAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38alphaAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38alpha mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38alphaAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38alphaAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN p38alphaAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38alphaAF/+ mice compared to wildtype littermates. Our findings support the notion that p38alpha inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. PMID- 27765673 TI - Bone marrow stromal cells promote neuroplasticity of cerebral ischemic rats via a phosphorylated CRMP2-mediated mechanism. AB - Collapsin response mediator protein 2 (CRMP2), an important protein involved in axonal growth and the maintenance of neuronal membrane integrity, has proved to be altered in nervous system diseases. This study was aimed to investigate the role of CRMP2 in bone marrow stromal cells (BMSCs) treating rats with cerebral ischemia. BMSCs were isolated from shaft of the femurs, tibiae, and humeri and were intra-carotid administrated immediately after middle cerebral artery occlusion (MCAO). Modified Neurological Severity Scores (mNSS) was conducted at 3, 7, 14dpo and the electrophysiologic evaluation was evaluated at 14dpo. Then all rats were sacrificed and brain tissues were harvested for RT-PCR, Western blot and Immunohistochemistry analysis. We found BMSCs treatment significantly improved the neurobehavioral performance impaired by ischemic brain injury, accompanied with the notably increasing levels of Synaptophysin (SYP) and Growth associated protein 43 (GAP43). We also found the protein level of phosphorylated CRMP2 (p-CRMP2) and phosphorylation-mediated protein including Glycogen synthase kinase 3 Beta (GSK3beta), Cyclin-dependent kinase 5 (CDK5) were dramatically downregulated in ischemic rats following BMSCs transplant. Furthermore, the GSK3beta-mediated factors including neurotrophic and signaling factors were all significantly upregulated in BMSCs-treated group. On the basis of these findings, we suggest that the neuroplasticity effect of BMSCs on cerebral ischemia may be associated with the phosphorylated modulation of CRMP2. PMID- 27765674 TI - Both cholestatic and steatotic drugs trigger extensive alterations in the mRNA level of biliary transporters in rat hepatocytes: Application to develop new predictive biomarkers for early drug development. AB - Disruption of the vectorial bile acid transport in the liver is a key feature of cholestatic drugs, although many causal and mechanistic aspects are still unknown. The aim of the present study was to explore if cholestatic drugs can repress or induce the expression of hepatic transporters. To this end, sandwich cultured rat hepatocytes were treated with cholestatic and non-cholestatic (steatotic, non-hepatotoxic, etc.) drugs and the mRNA expression of 10 uptake and efflux biliary transporters was measured. Results evidenced that all cholestatic drugs cause extensive alterations in the mRNA expression of most biliary transporters. Surprisingly, nearly all steatotic drugs also affected the expression of these genes. The most frequent alterations triggered by both types of drugs were the repression of OATP1A1, NTCP and BSEP, and the induction of MRP2/3/4, MDR2 and ABCG5/8. The majority of these alterations were also observed in vivo, in the livers of treated rats. The common signature of cholestatic and steatotic drugs was the repression of OATP1A1. Indeed, ROC curve analysis indicated that OATP1A1 mRNA is a very sensitive marker to identify drugs with cholestatic or steatotic potential, with a maximal sensitivity and specificity of 0.917 and 0.941, respectively. We conclude that alteration of expression of hepatobiliary transporters is a hallmark of both cholestatic and steatotic drugs, lending support to a connection between these two mechanisms of hepatotoxicity. Moreover, OATP1A1 mRNA is proposed as a very simple and useful screening biomarker for the prediction of new cholestatic or steatotic drugs in early drug development. PMID- 27765675 TI - A novel classification of musculocutaneous nerve variations: The relationship between the communicating branch and transposed innervation of the brachial flexors to the median nerve. AB - The musculocutaneous nerve innervates the brachial flexors; i.e., the coracobrachialis, biceps brachii, and brachialis. The musculocutaneous and median nerve sometimes share a communicating branch and also muscular branches to brachial flexors are sometimes transposed to median nerve. Because these variations constitute a potentially important clinical and surgical issue, we evaluated 130 upper limbs of 65 cadavers and 184 cases of musculocutaneous and median nerve variations in the literature and devised a novel system of classification that covers each pattern of variation. Our proposed classification was applicable in all of our cases and those previously reported. In addition, transposed innervation of the brachial flexors from the musculocutaneous nerve to the communicating branches was observed in one limb in our case series. In this case and all previously reported cases of transposed innervation of the brachial flexors, communicating branches between the musculocutaneous and median nerve were found and no brachial flexor branch arose from the musculocutaneous nerve distal to the communicating branches. Consequently, we established that, as per our novel classification, all patterns of communicating branches could be classified into five types and the patterns of transposed innervation of the brachial flexors into three types. PMID- 27765677 TI - Blood collection tubes as medical devices: The potential to affect assays and proposed verification and validation processes for the clinical laboratory. AB - Blood collection tubes (BCTs) are an often under-recognized variable in the preanalytical phase of clinical laboratory testing. Unfortunately, even the best designed and manufactured BCTs may not work well in all clinical settings. Clinical laboratories, in collaboration with healthcare providers, should carefully evaluate BCTs prior to putting them into clinical use to determine their limitations and ensure that patients are not placed at risk because of inaccuracies due to poor tube performance. Selection of the best BCTs can be achieved through comparing advertising materials, reviewing the literature, observing the device at a scientific meeting, receiving a demonstration, evaluating the device under simulated conditions, or testing the device with patient samples. Although many publications have discussed method validations, few detail how to perform experiments for tube verification and validation. This article highlights the most common and impactful variables related to BCTs and discusses the validation studies that a typical clinical laboratory should perform when selecting BCTs. We also present a brief review of how in vitro diagnostic devices, particularly BCTs, are regulated in the United States, the European Union, and Canada. The verification and validation of BCTs will help to avoid the economic and human costs associated with incorrect test results, including poor patient care, unnecessary testing, and delays in test results. We urge laboratorians, tube manufacturers, diagnostic companies, and other researchers to take all the necessary steps to protect against the adverse effects of BCT components and their additives on clinical assays. PMID- 27765676 TI - Disability stage and receipt of recommended care among elderly medicare beneficiaries. AB - BACKGROUND: Receipt of recommended care among older adults is generally low. Findings regarding service use among persons with disabilities supports the notion of disparities but provides inconsistent evidence of underuse of recommended care. OBJECTIVE: To examine the extent to which receipt of recommended care among older Medicare beneficiaries varies by disability status, using a newly developed staging method to classify individuals according to disability. METHODS: In a cohort study, we included community-dwelling Medicare beneficiaries aged 65 and older who participated in the Medicare Current Beneficiary Survey between 2001 and 2008. Logistic regression modeling assessed the association of receiving recommended care on 38 indicators across different activity limitation stages. RESULTS: Nearly one out of every three elderly Medicare beneficiaries did not receive overall recommended care. Adjusted odds ratios (ORs) revealed a decrease in use of recommended care with increasing activity limitation stage. For instance, ORs (95% CIs) across mild, moderate, severe and complete limitation stages (stages I-IV) compared to no limitation (stage 0) in ADLs were 0.99 (0.94-1.05), 0.89 (0.83-0.95), 0.81 (0.75-0.89) and 0.56 (0.46-0.68). Disparities in receipt of recommended care by disability stage were most marked for care related to post-hospitalization follow-up and, to a lesser degree, care of chronic conditions and preventive care. CONCLUSIONS: Elderly beneficiaries at higher activity limitation stages experienced substantial disparities in receipt of recommended care. Tailored interventions may be needed to reduce disparities in receipt of recommended medical care in this population. PMID- 27765679 TI - Coating of Quantum Dots strongly defines their effect on lysosomal health and autophagy. AB - : In the last decade the interest in autophagy got an incredible boost and the phenomenon quickly turned into an extensive research field. Interestingly, dysfunction of this cytoplasmic clearance system has been proposed to lie at the root of multiple diseases including cancer. We therefore consider it crucial from a toxicological point of view to investigate if nanomaterials that are developed for biomedical applications interfere with this cellular process. Here, we study the highly promising 'gradient alloyed' Quantum Dots (QDs) that differ from conventional ones by their gradient core composition which allows for better fluorescent properties. We carefully examined the toxicity of two identical gradient alloyed QDs, differing only in their surface coatings, namely 3 mercaptopropionic (MPA) acid and polyethylene glycol (PEG). Next to more conventional toxicological endpoints like cytotoxicity and oxidative stress, we examined the influence of these QDs on the autophagy pathway. Our study shows that the cellular effects induced by QDs on HeLa cells were strongly dictated by the surface coat of the otherwise identical particles. MPA-coated QDs proved to be highly biocompatible as a result of lysosomal activation and ROS reduction, two cellular responses that help the cell to cope with nanomaterial-induced stress. In contrast, PEGylated QDs were significantly more toxic due to increased ROS production and lysosomal impairment. This impairment next results in autophagy dysfunction which likely adds to their toxic effects. Taken together, our study shows that coating QDs with MPA is a better strategy than PEGylation for long term cell tracking with minimal cytotoxicity. STATEMENT OF SIGNIFICANCE: Gradient alloyed Quantum Dots (GA-QDs) are highly promising nanomaterials for biomedical imaging seeing they exhibit supremely fluorescent properties over conventional QDs. The translation of these novel QDs to the clinic requires a detailed toxicological examination, though the data on this is very limited. We therefore applied a systematic approach to examine the toxicity of GA-QDs coated with two commonly applied surface ligands, this while focusing on the autophagy pathway. The impact of QDs on this pathway is of importance since it has been connected with various diseases, including cancer. Our data accentuates that the coating defines the impact on autophagy and therefore the toxicity induced by QDs on cells: while MPA coated QDs were highly biocompatible, PEGylated QDs were toxic. PMID- 27765680 TI - Investigation of relationship between 2,3-butanediol toxicity and production during growth of Paenibacillus polymyxa. AB - Understanding the capacity of Paenibacillus polymyxa DSM 365 to tolerate increasing concentrations of 2,3-butanediol (2,3-BD) is critical to engineering a 2,3-BD-overproducing strain. Hence, we investigated the response of P. polymyxa to high 2,3-BD concentrations. In fed-batch cultures (6-L bioreactor) 2,3-BD was accumulated to a maximum concentration of 47g/L despite the presence of residual 13g/L glucose in the medium. Concomitantly, accumulation of acetoin, the precursor of 2,3-BD increased after maximum 2,3-BD concentration was reached, suggesting that 2,3-BD was reconverted to acetoin after the concentration tolerance threshold of 2,3-BD was exceeded. Cultures of P. polymyxa were then challenged with levo-2,3-BD (20, 40 and 60g/L) at 0h in a glucose medium, and a concentration dependent growth inhibition response to levo-2,3-BD was observed. The growth of P. polymyxa was completely inhibited by 60g/L levo-2,3-BD. Furthermore, P. polymyxa was challenged with incremental 2,3-BD concentrations (20, 40 and 60g/L at 12, 24 and 36h, respectively) to mimic 2,3-BD accumulation during fermentation. Interestingly, 2,3-BD was reconverted to acetoin when its concentration reached 60g/L, possibly to alleviate 2,3-BD toxicity. Collectively, our findings indicate that 2,3-BD-mediated toxicity is a major metabolic impediment to 2,3-BD overproduction, thus, making it an important metabolic engineering target towards rational design of a 2,3-BD-overproducing strain. PMID- 27765678 TI - Effect of anticoagulants on the protein corona-induced reduced drug carrier adhesion efficiency in human blood flow. AB - : Plasma proteins rapidly coat the surfaces of particulate drug carriers to form a protein corona upon their injection into the bloodstream. The high presence of immunoglobulins in the corona formed on poly(lactic-co-glycolic acid) (PLGA) vascular-targeted carrier (VTC) surfaces was recently shown to negatively impact their adhesion to activated endothelial cells (aECs) in vitro. Here, we characterized the influence of anticoagulants, or their absence, on the binding efficiency of VTCs of various materials via modulation of their protein corona. Specifically, we evaluated the adhesion of PLGA, poly(lactic acid) (PLA), polycaprolactone (PCL), silica, and polystyrene VTCs to aECs in heparinized, citrated, and non-anticoagulated (serum and whole) blood flows relative to buffer control. Particle adhesion is substantially reduced in non-anticoagulated blood flows regardless of the material type while only moderate to minimal reduction is observed for VTCs in anticoagulant-containing blood flow depending on the anticoagulant and material type. The substantial reduction in VTC adhesion in blood flows was linked to a high presence of immunoglobulin-sized proteins in the VTC corona via SDS-PAGE analysis. Of all the materials evaluated, PLGA was the most sensitive to plasma protein effects while PCL was the most resistant, suggesting particle hydrophobicity is a critical component of the observed negative plasma protein effects. Overall, this work demonstrates that anticoagulant positively alters the effect of plasma proteins in prescribing VTC adhesion to aECs in human blood flow, which has implication in the use of in vitro blood flow assays for functional evaluation of VTCs for in vivo use. STATEMENT OF SIGNIFICANCE: This study addresses the impact of anticoagulant on altering the extent of the previously observed protein corona-induced adhesion reduction of vascular-targeted drug carriers in human blood flows. Specifically, serum blood flow (no anticoagulant) magnifies the negative effect of the plasma protein corona on drug carrier adhesion relative to citrated or heparinized blood flows. Overall, the results from this work suggest that serum better predicts targeted drug carrier adhesion efficiency in vivo compared to anticoagulant containing plasma. Furthermore, this study offers critical insight into the importance of how the choice of anticoagulant can greatly affect drug delivery related processes in vitro. PMID- 27765681 TI - Novel morphological and molecular data for Corynosoma hannae Zdzitowiecki, 1984 (Acanthocephala: Polymorphidae) from teleosts, fish-eating birds and pinnipeds from New Zealand. AB - The polymorphid acanthocephalan, Corynosoma hannae Zdzitowiecki, 1984 is characterised on the basis of newly collected material from a New Zealand sea lion, Phocarctos hookeri (Gray), and long-nosed fur seal, Arctophoca forsteri (Lesson) (definitive hosts), and from Stewart Island shags, Leucocarbo chalconotus (Gray), spotted shags, Phalacrocorax punctatus (Sparrman) and yellow eyed penguins, Megadyptes antipodes (Hombron & Jacquinot) (non-definitive hosts) from New Zealand. Specimens are described in detail and scanning electron micrographs for C. hannae are provided. Additionally, cystacanths of C. hannae are reported and described for the first time from the body cavity and mesenteries of New Zealand brill, Colistium guntheri (Hutton) and from New Zealand sole, Peltorhamphus novaezeelandiae Gunther from Kaka Point, Otago in New Zealand. Partial sequence data for the mitochondrial cytochrome c oxidase 1 gene (cox1) for adults, immature specimens and cystacanths of C. hannae were obtained. Phylogenetic analyses of the newly-generated sequences and for available cox1 sequences of Corynosoma spp. revealed a close relationship between C. hannae and C. australe Johnston, 1937, both species infecting pinnipeds in the Southern Hemisphere. However, a morphological comparison of the species suggests that C. hannae mostly closely resembles C. evae Zdzitowiecki, 1984 and C. semerme (Forssell, 1904), the latter of which occurs in pinnipeds in the Northern Hemisphere. PMID- 27765682 TI - Recent advances on the stimulatory effects of metals in breast cancer. AB - Certain environmental chemicals may accumulate in human serum and tissues eliciting estrogenic and/or carcinogenic effects. Therefore, there is heightened interest in determining whether environmental chemicals may increase the risk for endocrine-related tumors like breast cancer. For instance, metals as cadmium, zinc, copper, iron, nickel and aluminum have been shown to mimic estrogen action. Moreover, the exposure to these chemicals has been reported to stimulate diverse malignancies including breast cancer, which is the most common tumor in women worldwide. In this review, we summarize the epidemiologic and experimental evidence regarding the association between the exposure to some trace elements and breast cancer risk. We also address recent insights on the molecular mechanisms involved by metals in breast tumorigenesis. PMID- 27765683 TI - Persistent transcriptional responses show the involvement of feed-forward control in a repeated dose toxicity study. AB - Chemical carcinogenesis, albeit complex, often relies on modulation of transcription through activation or repression of key transcription factors. While analyzing extensive networks may hinder the biological interpretation, one may focus on dynamic network motifs, among which persistent feed-forward loops (FFLs) are known to chronically influence transcriptional programming. Here, to investigate the relevance a FFL-oriented approach in depth, we have focused on aflatoxin B1-induced transcriptomic alterations during distinct states of exposure (daily administration during 5days followed by a non-exposed period) of human hepatocytes, by exploring known interactions in human transcription. Several TF-coding genes were persistently deregulated after washout of AFB1. Oncogene MYC was identified as the prominent regulator and driver of many FFLs, among which a FFL comprising MYC/HIF1A was the most recurrent. The MYC/HIF1A FFL was also identified and validated in an independent set as the master regulator of metabolic alterations linked to initiation and progression of carcinogenesis, i.e. the Warburg effect, possibly as result of persistent intracellular alterations arising from AFB1 exposure (nuclear and mitochondrial DNA damage, oxidative stress, transcriptional activation by secondary messengers). In summary, our analysis shows the involvement of FFLs as modulators of gene expression suggestive of a carcinogenic potential even after termination of exposure. PMID- 27765684 TI - Acephate exposure during a perinatal life program to type 2 diabetes. AB - Acephate has been used extensively as an insecticide in agriculture. Its downstream sequelae are associated with hyperglycemia, lipid metabolism dysfunction, DNA damage, and cancer, which are rapidly growing epidemics and which lead to increased morbidity and mortality rates and soaring health-care costs. Developing interventions will require a comprehensive understanding of which excess insecticides during perinatal life can cause insulin resistance and type 2 diabetes. A Wistar rat animal model suggests that acephate exposure during pregnancy and lactation causes alterations in maternal glucose metabolism and programs the offspring to be susceptible to type 2 diabetes at adulthood. Therapeutic approaches based on preventive actions to food contaminated with insecticides during pregnancy and lactation could prevent new cases of type 2 diabetes. PMID- 27765685 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) role in hematopoiesis and in hematologic diseases: A critical review. AB - Dioxin exposure and its effect on hematopoiesis and cancer have been largely investigated in both human and non-human settings. Here we systematically reviewed literature to address the question of what we know about TCDD biology and exposure. Most effects are due to TCDD interaction with a receptor of xenobiotics called AHR, which is ubiquitously represented and also works on hematopoietic myeloid and lymphoid stem cells, inducing proliferation and stem cell release from bone marrow to peripheral circulation. Epidemiologic studies on TCDD exposure demonstrated an association with onco-hematologic diseases, particularly with non Hodgkin lymphomas and multiple myeloma, and non hematologic cancers, such as sarcomas, although these relationships are affected by multiple confounding factors. PMID- 27765686 TI - Efficacy of 10% sucralfate ointment after anal fistulotomy: A prospective, double blind, randomized, placebo-controlled trial. AB - INTRODUCTION: The most frequent problems after anal fistulotomy are pain, bleeding, and delayed or impaired wound healing. Topical Sucralfate preparation has been used to treat a wide variety of wounds. In this study, we investigate effects of 10% sucralfate ointment on wound healing and postoperative pain after fistulotomy. METHODS AND MATERIALS: A total of 41 patients undergoing anorectal fistulotomy were included in this randomized, blinded, controlled trial and were randomly allocated to either sucralfate ointment (every 12 h) or placebo. The patients were visited weekly for up to 5 weeks. The intensity of pain and the wound healing were assessed. RESULTS: The sucralfate group had significantly less pain at rest (1.92 +/- 0.88 vs 2.96 +/- 0.98; P = 0.002) and on defecation (1.68 +/- 0.92 vs 3.08 +/- 1.12; p < 0.001) than the placebo group from 1st to 5th post operative visits. Complete wound healing was achieved after 8.15 +/- 1 weeks in placebo group versus 5.9 +/- 0.8 weeks in sucralfate group (p < 0.001). There were no significant differences in the frequencies of postoperative complications between the two groups. CONCLUSION: Compared with placebo, sucralfate ointment reduced postoperative pain at rest and on defecation and improves wound healing in patients undergoing fistulotomy. PMID- 27765687 TI - Changing Paradigms in Detection of Dysplasia and Management of Patients With Inflammatory Bowel Disease: Is Colectomy Still Necessary? AB - This review chronicles the evolution of dysplasia detection and management in inflammatory bowel disease since 1925, the year the first case report of colitis related colorectal cancer was published. We conclude that colorectal cancer prevention and dysplasia management for patients with inflammatory bowel disease has changed since this first case report, from somewhat hopeless to hopeful. PMID- 27765688 TI - Drug-Induced Liver Injury in Patients With Preexisting Chronic Liver Disease in Drug Development: How to Identify and Manage? PMID- 27765689 TI - How to Create and Deliver an Effective Presentation. PMID- 27765691 TI - Hepatitis C Virus: From Obscurity to the Lasker. PMID- 27765690 TI - Isocaloric Diets High in Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2 Diabetes. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with increased risk of hepatic, cardiovascular, and metabolic diseases. High-protein diets, rich in methionine and branched chain amino acids (BCAAs), apparently reduce liver fat, but can induce insulin resistance. We investigated the effects of diets high in animal protein (AP) vs plant protein (PP), which differ in levels of methionine and BCAAs, in patients with type 2 diabetes and NAFLD. We examined levels of liver fat, lipogenic indices, markers of inflammation, serum levels of fibroblast growth factor 21 (FGF21), and activation of signaling pathways in adipose tissue. METHODS: We performed a prospective study of individuals with type 2 diabetes and NAFLD at a tertiary medical center in Germany from June 2013 through March 2015. We analyzed data from 37 subjects placed on a diet high in AP (rich in meat and dairy foods; n = 18) or PP (mainly legume protein; n = 19) without calorie restriction for 6 weeks. The diets were isocaloric with the same macronutrient composition (30% protein, 40% carbohydrates, and 30% fat). Participants were examined at the start of the study and after the 6-week diet period for body mass index, body composition, hip circumference, resting energy expenditure, and respiratory quotient. Body fat and intrahepatic fat were detected by magnetic resonance imaging and spectroscopy, respectively. Levels of glucose, insulin, liver enzymes, and inflammation markers, as well as individual free fatty acids and free amino acids, were measured in collected blood samples. Hyperinsulinemic euglycemic clamps were performed to determine whole-body insulin sensitivity. Subcutaneous adipose tissue samples were collected and analyzed for gene expression patterns and phosphorylation of signaling proteins. RESULTS: Postprandial levels of BCAAs and methionine were significantly higher in subjects on the AP vs the PP diet. The AP and PP diets each reduced liver fat by 36%-48% within 6 weeks (for AP diet P = .0002; for PP diet P = .001). These reductions were unrelated to change in body weight, but correlated with down-regulation of lipolysis and lipogenic indices. Serum level of FGF21 decreased by 50% in each group (for AP diet P < .0002; for PP diet P < .0002); decrease in FGF21 correlated with loss of hepatic fat. In gene expression analyses of adipose tissue, expression of the FGF21 receptor cofactor beta-klotho was associated with reduced expression of genes encoding lipolytic and lipogenic proteins. In patients on each diet, levels of hepatic enzymes and markers of inflammation decreased, insulin sensitivity increased, and serum level of keratin 18 decreased. CONCLUSIONS: In a prospective study of patients with type 2 diabetes, we found diets high in protein (either animal or plant) significantly reduced liver fat independently of body weight, and reduced markers of insulin resistance and hepatic necroinflammation. The diets appear to mediate these changes via lipolytic and lipogenic pathways in adipose tissue. Negative effects of BCAA or methionine were not detectable. FGF21 level appears to be a marker of metabolic improvement. ClinicalTrials.gov ID NCT02402985. PMID- 27765692 TI - How to Improve Your Adenoma Detection Rate During Colonoscopy. PMID- 27765694 TI - Postoperative Outcome of Cystic Renal Cell Carcinoma Defined on Preoperative Imaging: A Retrospective Study. AB - PURPOSE: We evaluated the postoperative outcome of cystic renal cell carcinoma defined on preoperative computerized tomography. We also sought to find the optimal cutoff of the cystic proportion in association with patient prognosis. MATERIAL AND METHODS: In this institutional review board approved study with waiver of informed consent, 1,315 patients were enrolled who underwent surgery for a single renal cell carcinoma with preoperative computerized tomography. The cystic proportion of renal cell carcinoma was determined on computerized tomography. The optimal cutoff of the cystic proportion was explored regarding cancer specific survival. Renal cell carcinomas were categorized as cystic or noncystic renal cell carcinoma according to a conventional cutoff (ie cystic proportion 75% or greater) and an optimal cutoff. Postoperative outcomes were then compared between the 2 groups. Multivariate Cox regression analysis was performed to determine the independent predictor of cancer specific survival. RESULTS: Of the 1,315 lesions 107 (8.1%) were identified as cystic renal cell carcinoma according to a conventional cutoff. The postoperative outcome of cystic renal cell carcinoma was significantly better than that of noncystic renal cell carcinoma (p <0.001). Neither metastasis nor recurrence developed after surgery in patients with cystic renal cell carcinoma. In association with the cancer specific survival rate, the optimal cutoff of the cystic proportion was 45% and 197 cases (15.0%) were accordingly defined as cystic renal cell carcinoma. On Cox regression analysis, a cystic proportion of 45% or greater of the renal cell carcinoma was an independent predictor of a favorable outcome regarding cancer specific survival (HR 0.34, p = 0.03). CONCLUSIONS: Cystic renal cell carcinoma defined on preoperative computerized tomography is associated with low metastatic potential and favorable outcomes after surgery. Particularly, a cystic proportion of 45% or greater is an independent prognostic factor for favorable survival. PMID- 27765693 TI - A pilot study to evaluate multi-dimensional effects of dance for people with Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease associated with deficits in motor, cognitive, and emotion/quality of life (QOL) domains, yet most pharmacologic and behavioral interventions focus only on motor function. Our goal was to perform a pilot study of Dance for Parkinson's-a community-based program that is growing in popularity-in order to compare effect sizes across multiple outcomes and to inform selection of primary and secondary outcomes for a larger trial. Study participants were people with PD who self-enrolled in either Dance for Parkinson's classes (intervention group, N=8) or PD support groups (control group, N=7). Assessments of motor function (Timed-Up-and-Go, Gait Speed, Standing Balance Test), cognitive function (Test of Everyday Attention, Verbal Fluency, Alternate Uses, Digit Span Forward and Backward), and emotion/QOL (Geriatric Depression Scale, Falls Efficacy Scale-International, Parkinson's Disease Questionnaire-39 (total score and Activities of Daily Living subscale)) were performed in both groups at baseline and follow-up. Standardized effect sizes were calculated within each group and between groups for all 12 measures. Effect sizes were positive (suggesting improvement) for all 12 measures within the intervention group and 7 of 12 measures within the control group. The largest between-group differences were observed for the Test of Everyday Attention (a measure of cognitive switching), gait speed and falls efficacy. Our findings suggest that dance has potential to improve multiple outcomes in people with PD. Future trials should consider co-primary outcomes given potential benefits in motor, cognitive and emotion/QOL domains. PMID- 27765695 TI - Vitamin D Repletion in Kidney Stone Formers: A Randomized Controlled Trial. AB - PURPOSE: Vitamin D deficiency is often detected during metabolic evaluation in the nephrolithiasis population. Multiple vitamin D repletion protocols exist, although their differing impact on urinary stone formation risk factors is unclear. MATERIALS AND METHODS: Patients with a history of calcium stones and vitamin D deficiency (less than 30 ng/ml) were randomized to receive either 1,000 IU daily or 50,000 IU weekly of vitamin D supplementation for 6 weeks. Patients completed a pretreatment and posttreatment serum vitamin D level evaluation and 24-hour urine collections to assess the response and any changes in urine stone formation risk parameters. RESULTS: A total of 21 patients completed the study, including 8 who received 1,000 IU daily and 13 who received 50,000 IU weekly. The 50,000 IU weekly group showed a significant increase in median serum vitamin D levels of 23 ng/ml (135%, p <0.01), while the 1,000 IU daily group showed a nonsignificant median increase of 9 ng/ml (49%, p = 0.12). Post-repletion 24-hour urine analysis demonstrated no significant change in urine calcium between the groups, including a median change of -11 mg (IQR -143-29) in patients receiving 1,000 IU and -16 mg (IQR -42-66) in those receiving 50,000 IU. Between the groups there was no significant difference in the supersaturation of calcium oxalate or calcium phosphate. CONCLUSIONS: High dose and low dose vitamin D repletion had no effect on urine calcium excretion or the supersaturation of calcium salts in known stone formers. The higher dosing regimen, which had superior repletion, may be the optimal protocol in patients with vitamin D deficiency. PMID- 27765696 TI - Laparoscopic vs Open Pyeloplasty in Children: Results of a Randomized, Prospective, Controlled Trial. AB - PURPOSE: Open dismembered pyeloplasty is the preferred repair for ureteropelvic junction obstruction. Minimally invasive techniques have been applied to the original open approach but no clear advantage has been demonstrated for these technological advances. We evaluate outcomes between transperitoneal laparoscopic and open pyeloplasty in children. MATERIALS AND METHODS: All children 1 to 18 years old with ureteropelvic junction obstruction requiring operative repair were offered enrollment in the study. Patients were prospectively randomized to either laparoscopic or open pyeloplasty through a flank incision. RESULTS: A total of 50 patients in the laparoscopic group and 48 in the open group were enrolled from 2005 to 2014. Mean followup was similar between the groups (13.7 months in the laparoscopic group vs 12.3 months in the open group, p = 0.54). The only significantly different outcomes were for mean operative time, which was 139.5 minutes (range 94 to 213) in the laparoscopic group and 122.5 minutes (83 to 239) in the open group (p <0.01), and mean length of stay, which was 25.9 hours (18 to 143) in the laparoscopic group and 28.2 hours (16 to 73) in the open group (p = 0.02). Analgesic usage, success rate, total charges and all parameters in children older than 11 years were similar between the groups. CONCLUSIONS: Open and laparoscopic dismembered pyeloplasty are comparable and effective methods for repair of ureteropelvic junction obstruction. Although operative time was statistically shorter in the open group and length of stay was shorter in the laparoscopic group, the clinical significance of these variables is questionable. The approach to repair may best be based on family preference for incision aesthetics and surgeon comfort with either approach, rather than more classically objective outcome measures. PMID- 27765697 TI - Comparative study of two single CRD C-type lectins, CgCLec-4 and CgCLec-5, from pacific oyster Crassostrea gigas. AB - C-type lectins (CTLs), a superfamily of Ca2+-dependent carbohydrate-recognition proteins, are involved in nonself-recognition and pathogen elimination, and play crucial roles in the innate immunity. In the present study, two single CRD C-type lectins, CgCLec-4 and CgCLec-5, were identified from oyster Crassostrea gigas. The open reading frame (ORF) of CgCLec-4 and CgCLec-5 encoded polypeptides of 152 and 150 amino acids, respectively. Both CgCLec-4 and CgCLec-5 contained one CRD with six conserved cysteines to form three disulfide bridges. The motif in Ca2+ binding site 2 of CgCLec-4 was QPE, while it was QYE, a non-a typical motif in CgCLec-5. CgCLec-4 was a secreted lectin with a signal peptide which was highly expressed in hepatopancreas, mantle and hemocytes. CgCLec-5 was an intracellular lectin which was mostly expressed in hemocytes. The lipopolysaccharide stimulation could induce the expressions of CgCLec-4 and CgCLec-5. The recombinant proteins of CgCLec-4 and CgCLec-5 (rCgCLec-4 and rCgCLec-5) could bind to various PAMPs including LPS, PGN, GLU and mannan, while the binding affinity of rCgCLec-5 was stronger than that of rCgCLec-4. Meanwhile, rCgCLec-4 and rCgCLec-5 could bind to different kinds of microorganisms, including Staphylococcus aureus, Escherichia coli and Vibro anguillarum and Yarrowia lipolytica, and the microbial agglutinating ability of rCgCLec-4 was stronger than that of CgCLec-5. Moreover, rCgCLec-4 exhibited anti-microbial activity against bacteria and fungi, but anti-microbial activity of CgCLec-5 was not obvious. All these results suggested that CgCLec-4 and CgCLec-5 could function as an important PRR involved in immune defense against invading pathogen in oyster, and the diversity and complexity of motifs in Ca2+ binding site 2 in CRDs determined their comprehensive recognition spectrum and multiple immune functions. PMID- 27765698 TI - Mitogen-activated protein kinase 1 from disk abalone (Haliotis discus discus): Roles in early development and immunity-related transcriptional responses. AB - Mitogen-activated protein kinase (MAPK) is involved in the regulation of cellular events by mediating signal transduction pathways. MAPK1 is a member of the extracellular-signal regulated kinases (ERKs), playing roles in cell proliferation, differentiation, and development. This is mainly in response to growth factors, mitogens, and many environmental stresses. In the current study, we have characterized the structural features of a homolog of MAPK1 from disk abalone (AbMAPK1). Further, we have unraveled its expressional kinetics against different experimental pathogenic infections or related chemical stimulants. AbMAPK1 harbors a 5' untranslated region (UTR) of 23 bps, a coding sequence of 1104 bps, and a 3' UTR of 448 bp. The putative peptide comprises a predicted molecular mass of 42.2 kDa, with a theoretical pI of 6.28. Based on the in silico analysis, AbMAPK1 possesses two N-glycosylation sites, one S_TK catalytic domain, and a conserved His-Arg-Asp domain (HRD). In addition, a conservative glycine rich ATP-phosphate-binding loop and a threonine-x-tyrosine motif (TEY) important for the autophosphorylation were also identified in the protein. Homology assessment of AbMAPK1 showed several conserved regions, and ark clam (Aplysia californica) showed the highest sequence identity (87.9%). The phylogenetic analysis supported close evolutionary kinship with molluscan orthologs. Constitutive expression of AbMAPK1 was observed in six different tissues of disk abalone, with the highest expression in the digestive tract, followed by the gills and hemocytes. Highest AbMAPK1 mRNA expression level was detected at the trochophore developmental stage, suggesting its role in abalone cell differentiation and proliferation. Significant modulation of AbMAPK1 expression under pathogenic stress suggested its putative involvement in the immune defense mechanism. PMID- 27765699 TI - The protection effect of LEAP-2 on the mudskipper (Boleophthalmus pectinirostris) against Edwardsiella tarda infection is associated with its immunomodulatory activity on monocytes/macrophages. AB - Liver-expressed antimicrobial peptide 2 (LEAP-2) is a cationic peptide that plays an important role in the host's innate immune system. However, the mechanism by which LEAP-2 modulates/regulates the host defense against pathogens remains largely unknown. In this study, we identified a cDNA sequence encoding LEAP-2 homolog (BpLEAP-2) in the mudskipper, Boleophthalmus pectinirostris. Sequence analysis revealed that BpLEAP-2 belonged to the fish LEAP-2A cluster and that it was closely related to ayu LEAP-2. BpLEAP-2 mRNA was detected in a wide range of tissues, with the highest level of transcripts found in the liver. Upon infection with Edwardsiella tarda, BpLEAP-2 mRNA expression was significantly increased in the liver, kidney, spleen, and gill, but decreased in the intestine. Chemically synthesized BpLEAP-2 mature peptide did not exhibit antibacterial activity against E. tarda in vitro. Intraperitoneal injection of BpLEAP-2 (1.0 or 10.0 MUg/g) resulted in significantly improved survival rate and reduced tissue bacterial load in E. tarda-infected mudskippers. In E. tarda-infected fish, BpLEAP-2 (0.1, 1.0, or 10.0 MUg/g) eliminated E. tarda-induced tissue mRNA expression of BpTNF-alpha and BpIL-1beta. In monocytes/macrophages (MO/MF), BpLEAP-2 (1.0 or 10.0 MUg/ml) induced chemotaxis, enhanced respiratory burst, and inhibited E. tarda-induced mRNA expression of BpTNF-alpha and BpIL-1beta. At a concentration of 10.0 MUg/ml, BpLEAP-2 also significantly enhanced the bacterial killing efficiency of MO/MF. No significant effect was seen in the phagocytic activity of MO/MF upon treatment with BpLEAP-2. Our study provides evidence, for the first time, that LEAP-2 exhibited immunomodulatory effects on immune cells, and protected the host from pathogenic infections independent of direct bacterial killing function. PMID- 27765700 TI - Design and evaluation of an Edwardsiella tarda DNA vaccine co-encoding antigenic and adjuvant peptide. AB - Edwardsiella tarda is associated with edwardsiellosis in cultured fish, resulting in heavy losses in aquaculture. So far, different types of vaccine have been attempted against E. tarda. In this study, an optimized eukaryotic expression plasmid was developed and an optimized DNA vaccine co-encoding antigenic and adjuvant peptide using a bicistronic expression system was designed. As a result, a modified plasmid harbored cytomegalovirus (CMV) promoter attached with R region of long terminal repeat from human T-cell leukemia virus type 1 (CMV/R) and woodchuck hepatitis virus post-transcriptional response element (WPRE) component showed an increased antigenic gene expression compared with unmodified plasmid. Moreover, the designed system based on bicistronic system exhibited a stronger ability to express antigenic gene and the RPS achieved 87.3% compared with plasmid encoding antigentic gene. Finally, immunological analysis showed that the DNA vaccine induced both innate and adaptive immune responses. These results suggest that co-encoding antigenic and adjuvant proteins might be an efficient strategy to develop DNA vaccines in aquaculture in the future. PMID- 27765701 TI - Analysis of liver and gill miRNAs of Larimichthys crocea against Cryptocryon irritans challenge. AB - The white-spot disease caused by marine ciliate Cryptocryon irritans hindered the sustainable development of large yellow croaker Larimichthys crocea industry. Better understandings about the parasite-host interactions in the molecular level will facilitate the prevention of mass mortality of the L. crocea caused by white spot disease. MicroRNAs (miRNAs) are a class of small RNA molecules about 20-22 nucleotides which post-transcriptionally regulated many protein-coding genes and involved in many biological processes, especially in host-pathogen responses. In this study, we identified known and novel miRNAs in the gill and liver of L. crocea challenged by C. irritans by high throughput sequencing using Solexa technology. The data were further studied to screen differentially expressed miRNAs, and predict their target genes. The differential expression (p < 0.05) between libraries was observed in 103 miRNAs in liver tissue, among which 65 and 38 were conserved and novel miRNAs, 67 and 36 were up- and down-regulated miRNAs. While in gill tissue, 122 significant differentially expressed miRNAs were identified, among which 83 and 39 were conserved and novel miRNAs, 79 and 43 were up- and down-regulated miRNAs. In addition, these differentially expressed miRNAs target a series of genes which involved in many important biological processes including immune response. Here via deep sequencing, we for the first time characterize L. crocea miRNAs in response to C. irritans challenge, the results should help for better understandings about the immune response of the L. crocea under C. irritans challenge. PMID- 27765702 TI - Editorial Comment. PMID- 27765704 TI - Reply by Authors. PMID- 27765703 TI - Re: Limitations of Elastography Based Prostate Biopsy: J. Schiffmann, M. Grindei, Z. Tian, D.-J. Yassin, T. Steinwender, S.-R. Leyh-Bannurah, M. Randazzo, M. Kwiatkowski, P. I. Karakiewicz, P. Hammerer and L. Manka J Urol 2016;195:1731 1736. PMID- 27765705 TI - Reply by Authors. PMID- 27765706 TI - Estimating the Global Need for Palliative Care for Children: A Cross-sectional Analysis. AB - CONTEXT: The need for children's palliative care (CPC) globally is unknown. To understand the scope of the need and to advocate to meet it, more accurate estimates are needed. OBJECTIVES: The objective of this study was to create an accurate global estimate of the worldwide need for CPC based on a representative sample of countries from all regions of the world and all World Bank income groups. METHODS: This work builds on previously published methods developed by the International Children's Palliative Care Network, United Nations Children's Fund, and World Health Organization and tested in three African countries. The study used a cross-sectional design with quantitative data obtained from primary and secondary data sources. Estimation of the need used prevalence data from the Institute for Health Metrics and Evaluation, mortality data from the World Health Organization for the specific diseases known to require CPC, and Joint United Nations Programme on HIV/AIDS (UNAIDS) data on HIV prevalence. Representative data were analyzed for 23 countries representing 59.5% of the world's population. RESULTS: The findings show estimated need for CPC ranged from almost 120 per 10,000 children in Zimbabwe to slightly more than 20 per 10,000 in the United Kingdom. Overall, among the over 21 million with conditions that will benefit annually from a palliative care approach, more than eight million need specialized CPC worldwide. CONCLUSION: The estimation of need for CPC is a critical step in meeting the needs of children with life-threatening conditions and provides a sound platform to advocate for closure of the unacceptably wide gaps in coverage. PMID- 27765707 TI - Subsequent health-care utilization associated with early physical therapy for new episodes of low back pain in older adults. AB - BACKGROUND: The association between early physical therapy (PT) and subsequent health-care utilization following a new visit for low back pain is not clear, particularly in the setting of acute low back pain. PURPOSE: This study aimed to estimate the association between initiating early PT following a new visit for an episode of low back pain and subsequent back pain-specific health-care utilization in older adults. DESIGN/SETTING: This is a prospective cohort study. Data were collected at three integrated health-care systems in the United States through the Back Pain Outcomes using Longitudinal Data (BOLD) registry. PATIENT SAMPLE: We recruited 4,723 adults, aged 65 and older, presenting to a primary care setting with a new episode of low back pain. OUTCOME MEASURES: Primary outcome was total back pain-specific relative value units (RVUs), from days 29 to 365. Secondary outcomes included overall RVUs for all health care and use of specific health-care services including imaging (x-ray and magnetic resonance imaging [MRI] or computed tomography [CT]), emergency department visits, physician visits, PT, spinal injections, spinal surgeries, and opioid use. METHODS: We compared patients who had early PT (initiated within 28 days of the index visit) with those not initiating early PT using appropriate, generalized linear models to adjust for potential confounding variables. RESULTS: Adjusted analysis found no statistically significant difference in total spine RVUs between the two groups (ratio of means 1.19, 95% CI of 0.72-1.96, p=.49). For secondary outcomes, only the difference between total spine imaging RVUs and total PT RVUs was statistically significant. The early PT group had greater PT RVUs; the ratio of means was 2.56 (95% CI of 2.17-3.03, p<.001). The early PT group had greater imaging RVUs; the ratio of means was 1.37 (95% CI of 1.09-1.71, p=.01.) CONCLUSIONS: We found that in a group of older adults presenting for a new episode of low back pain, the use of early PT is not associated with any statistically significant difference in subsequent back pain-specific health-care utilization compared with patients not receiving early PT. PMID- 27765708 TI - Slump sitting X-ray of the lumbar spine is superior to the conventional flexion view in assessing lumbar spine instability. AB - BACKGROUND CONTEXT: Flexion radiographs have been used to identify cases of spinal instability. However, current methods are not standardized and are not sufficiently sensitive or specific to identify instability. PURPOSE: This study aimed to introduce a new slump sitting method for performing lumbar spine flexion radiographs and comparison of the angular range of motions (ROMs) and displacements between the conventional method and this new method. STUDY DESIGN: This study used is a prospective study on radiological evaluation of the lumbar spine flexion ROMs and displacements using dynamic radiographs. PATIENT SAMPLE: Sixty patients were recruited from a single spine tertiary center. OUTCOME MEASURE: Angular and displacement measurements of lumbar spine flexion were carried out. METHOD: Participants were randomly allocated into two groups: those who did the new method first, followed by the conventional method versus those who did the conventional method first, followed by the new method. A comparison of the angular and displacement measurements of lumbar spine flexion between the conventional method and the new method was performed and tested for superiority and non-inferiority. RESULTS: The measurements of global lumbar angular ROM were, on average, 17.3 degrees larger (p<.0001) using the new slump sitting method compared with the conventional method. They were most significant at the levels of L3-L4, L4-L5, and L5-S1 (p<.0001, p<.0001 and p=.001, respectively). There was no significant difference between both methods when measuring lumbar displacements (p=.814). CONCLUSION: The new method of slump sitting dynamic radiograph was shown to be superior to the conventional method in measuring the angular ROM and non-inferior to the conventional method in the measurement of displacement. PMID- 27765709 TI - Preoperative estimation of disc herniation recurrence after microdiscectomy: predictive value of a multivariate model based on radiographic parameters. AB - BACKGROUND CONTEXT: Recurrence of lumbar disc herniation (rLDH) is one of the unfavorable outcomes after microdiscectomy. Prediction of the patient population with increased risk of rLDH is important because patients may benefit from preventive measures or other surgical options. PURPOSE: The study assessed preoperative factors associated with rLDH after microdiscectomy and created a mathematical model for estimation of chances for rLDH. STUDY DESIGN/SETTING: This is a retrospective case-control study. PATIENT SAMPLE: The study includes patients who underwent microdiscectomy for LDH. OUTCOME MEASURES: Lumbar disc herniation recurrence was determined using magnetic resonance imaging. METHODS: The study included 350 patients with LDH and a minimum of 3 years of follow-up. Patients underwent microdiscectomy for LDH at the L4-L5 and L5-S1 levels from 2008 to 2012. Patients were divided into two groups to identify predictors of recurrence: those who developed rLDH (n=50) within 3 years and those who did not develop rLDH (n=300) within the same follow-up period. Multivariate analysis was performed using patient baseline clinical and radiography data. Non-linear, multivariate, logistic regression analysis was used to build a predictive model. RESULTS: Recurrence of LDH occurred within 1 to 48 months after microdiscectomy. Preoperatively, patients who developed rLDH were smokers (70% vs. 27%, p<.01; odds ratio [OR]=6.31, 95% confidence interval [CI]: 3.27-12.16) and had higher body mass index (29.0+/-6.1 vs. 27.0+/-4.3, p=.03; OR=1.09 per 0.01 unit change). Radiological parameters that were associated with rLDH were higher disc height index (0.35+/-0.007 vs. 0.26+/-0.002, p<.001), higher segmental range of motion (9.8+/-0.28 degrees vs. 7.6+/-0.11 degrees , p<.001; OR=0.53 per 0.01 unit change), and lower central angle of lumbar lordosis (33.4+/-0.81 degrees vs. 47.1+/-0.47 degrees , p<.001; OR=0.53 per 0.01 unit change). Additionally, Pfirrmann grade 3 (OR=16.62, 95% CI: 8.10-34.11), protrusion type of LDH (OR=5.90, 95% CI: 3.06-11.36), and Grogan sclerosis grades 3 and 4 (OR=4.81, 95% CI: 2.50-9.22) were also associated with rLDH. Multivariate non-linear modeling allowed for more accurate prediction of rLDH (90% correct prediction of rLDH; 99% correct prediction of no rLDH) than other univariate logit models. CONCLUSIONS: Preoperative radiographic parameters in patients with LDH can be used to assess the risk of recurrence after microdiscectomy. The multifactorial non-linear model provided more accurate rLDH probability estimation than the univariate analyses. The software developed from this model may be implemented during patient counseling or decision making when choosing the type of primary surgery for LDH. PMID- 27765710 TI - Rates and risk factors associated with unplanned hospital readmission after fusion for pediatric spinal deformity. AB - BACKGROUND CONTEXT: Short-term readmission rates are becoming widely used as a quality and performance metric for hospitals. Data on unplanned short-term readmission after spine fusion for deformity in pediatric patients are limited. PURPOSE: To characterize the rate and risk factors for short-term readmission after spine fusion for deformity in pediatric patients. STUDY DESIGN: This is a retrospective cohort study. PATIENT SAMPLE: Data were obtained from the State Inpatient Database from New York, Utah, Nebraska, Florida, North Carolina (years 2006-2010), and California (years 2006-2011). OUTCOME MEASURES: Outcome measures included 30- and 90-day readmission rates. MATERIALS AND METHODS: Inclusion criteria were patients aged 0-21 years, a primary diagnosis of spine deformity, and a primary 3+-level lumbar or thoracic fusion. Exclusion criteria included revision surgery at index admission and cervical fusion. Readmission rates were calculated and logistic analyses were used to identify independent predictors of readmission. RESULTS: There were a total of 13,287 patients with a median age of 14 years. Sixty-seven percent were girls. The overall 30- and 90-day readmission rates were 4.7% and 6.1%. The most common reasons for readmission were infection (38% at 30 days and 33% at 90 days), wound dehiscence (19% and 17%), and pulmonary complications (12% and 13%). On multivariate analysis, predictors of 30 day readmission included male sex (p=.008), neuromuscular (p<.0001) or congenital scoliosis (p=.006), Scheuermann kyphosis (p=.003), Medicaid insurance (p<.0001), length of stay of <=3 days or >=6 days (p<.0001), and surgery at a teaching hospital (p=.011). Surgery at a hospital performing >80 operations/year was associated with a 34% reduced risk of 30-day readmission (95% confidence interval 12%-50%, p=.005) compared with hospitals performing <20 operations/year. CONCLUSIONS: The short-term readmission rate for pediatric spine deformity surgery is driven by patient-related factors, as well as several risk factors that may be modified to reduce this rate. PMID- 27765711 TI - A multicenter cohort study of spinal osteoid osteomas: results of surgical treatment and analysis of local recurrence. AB - BACKGROUND CONTEXT: Spinal osteoid osteomas are benign primary tumors arising predominantly from the posterior column of the spine. These "osteoblastic" lesions have traditionally been treated with intralesional excision. PURPOSE: The purpose of the present study was to review the treatment and local recurrence rates for symptomatic spinal osteoid osteomas. STUDY DESIGN/SETTING: Multicenter ambispective cross-sectional observational cohort study. PATIENT SAMPLE: During the study period, a total of 84 patients (65 males, 19 females) were diagnosed with a spinal osteoid osteoma and received surgical treatment. The mean age at surgery was 21.8 +/- 9.0 years (range: 6.7-52.4 years) and the mean follow-up was 2.7 years (13 days-14.5 years). OUTCOME MEASURES: Local recurrence, perioperative morbidity, and cross-sectional survival. METHODS: Using the AOSpine Knowledge Forum Tumor multicenter ambispective database, surgically treated osteoid osteoma cases were identified. Patient demographic, clinical and diagnostic, treatment, local recurrence, perioperative morbidity, and cross-sectional survival data were collected and retrieved. Descriptive statistics were summarized using mean/standard deviation or frequency/percentage. RESULTS: In our study, most of the tumors were localized in the mobile spine (81 of 84 [96%]); all patients reported pain as a symptom. According to the postoperative assessment, 10 (12%) patients received an en bloc resection with marginal or wide margins, whereas two (2%) patients received en bloc resections with intralesional margins, 69 (82%) patients were treated by piecemeal "intralesional" resection, and three (4%) patients were not assessed. A total of six patients (7%) experienced a local recurrence, all of which occurred in patients who had received an intralesional resection. CONCLUSIONS: Benign bone-forming tumors of the spine are uncommon. Most patients in our series underwent a piecemeal resection with intralesional margins. This remains safe with a low local recurrence rate. En bloc excision may provide more chance of complete excision of the nidus but is not mandatory. The importance of complete excision of the nidus cannot be overemphasized. PMID- 27765712 TI - Walking balance and compensatory gait mechanisms in surgically treated patients with adult spinal deformity. AB - BACKGROUND CONTEXT: Gait patterns and their relationship to demographic and radiographic data in patients with adult spinal deformity (ASD) have not been fully documented. PURPOSE: This study aimed to assess gait pattern in patients with ASD and the effect of corrective spinal surgery on gait. DESIGN/SETTING: This is a prospective case series. PATIENT SAMPLE: The gait patterns of 33 consecutive women with ASD (age 67.1 years; body mass index [BMI] 22.5+/-2.5 kg/m2, Cobb angle 46.8+/-18.2 degrees , coronal vertical axis [CVA] 1.5+/-3.7 cm, C7 sagittal vertical axis [SVA] 9.1+/-6.4 cm, pelvic incidence minus lumbar lordosis [PI-LL] 38.2+/-22.1 degrees , and lean volume of the lower leg, 5.5+/ 0.6 kg) before and after corrective surgery were compared with those of 33 age- and gender-matched healthy volunteers. OUTCOME MEASURES: Scoliosis Research Society Patient Questionnaire (SRS22r), Oswestry Disability Index (ODI), and forceplate analysis. METHODS: All subjects underwent gait analysis on a custom built forceplate using optical markers placed on all joints and spinal processes. Dual X-ray absorptiometry scores were used to calculate the lean composition of the lower legs. Subjects with ASD were followed for at least 2 years post operation. RESULTS: Preop mean values showed that patients with ASD had a significantly worse gait velocity (54+/-10 m/min vs. 70.7+/-12.9 m/min, p<.01) and stride (97.8+/-13.4 cm vs. 115.3+/-15.1 cm, p<.01), but no difference was observed in the stance-to-swing ratio. The right and left ground reaction force vectors were also discordant in the ASD group (vertical direction; r=0.84 vs. r=.97, p=.01). The hip range of motion (ROM) was also significantly decreased in ASD. Correlation coefficient showed moderate correlations between the preoperative gait velocity and the gravity line (GL), PI, ROM of the lower extremity joints, and lean volume, and between the stride and the lean volume, GL, and PI-LL. Gait pattern, stride, and velocity all improved significantly in the patients with ASD after surgery, but were still not as good as in healthy volunteers. The SRS22r satisfaction domain correlated moderately with postoperative gait velocity (r=0.34). CONCLUSIONS: The patients with ASD had an asymmetric gait pattern and impaired gait ability compared with healthy volunteers. Gait ability correlated significantly with the GL, spinopelvic alignment, lower extremity joint ROM, and lean volume. The surgical correction of spinopelvic alignment and exercises to build muscle strength may improve the gait pattern and ability in patients with ASD. PMID- 27765714 TI - Individualized functional restoration as an adjunct to advice for lumbar disc herniation with associated radiculopathy. A preplanned subgroup analysis of a randomized controlled trial. AB - BACKGROUND CONTEXT: Physical therapy is commonly sought by people with lumbar disc herniation and associated radiculopathy. It is unclear whether physical therapy is effective for this population. PURPOSE: To determine the effectiveness of physical therapist-delivered individualized functional restoration as an adjunct to guideline-based advice in people with lumbar disc herniation and associated radiculopathy. STUDY DESIGN: This is a preplanned subgroup analysis of a multicenter parallel group randomized controlled trial. PATIENT SAMPLE: The study included 54 participants with clinical features of radiculopathy (6-week to 6-month duration) and imaging showing a lumbar disc herniation. OUTCOME MEASURES: Primary outcomes were activity limitation (Oswestry Disability Index) and separate 0-10 numerical pain rating scales for leg pain and back pain. Measures were taken at baseline and at 5, 10, 26, and 52 weeks. METHODS: The participants were randomly allocated to receive either individualized functional restoration incorporating advice (10 sessions) or guideline-based advice alone (2 sessions) over a 10-week period. Treatment was administered by 11 physical therapists at private clinics in Melbourne, Australia. RESULTS: Between-group differences for activity limitation favored the addition of individualized functional restoration to advice alone at 10 weeks (7.7, 95% confidence interval [CI] 0.3-15.1) and 52 weeks (8.2, 95% CI 0.7-15.6), as well as back pain at 10 weeks (1.4, 95% CI 0.2 2.7). There were no significant differences between groups for leg pain at any follow-up. Several secondary outcomes also favored individualized functional restoration over advice. CONCLUSIONS: In participants with lumbar disc herniation and associated radiculopathy, an individualized functional restoration program incorporating advice led to greater reduction in activity limitation at 10- and 52-week follow-ups compared with guideline-based advice alone. Although back pain was significantly reduced at 10 weeks with individualized functional restoration, this effect was not maintained at later timepoints, and there were no significant effects on leg pain, relative to guideline-based advice. PMID- 27765713 TI - Association between insurance status and patient safety in the lumbar spine fusion population. AB - BACKGROUND CONTEXT: Lumbar fusion is a common and costly procedure in the United States. Reimbursement for surgical procedures is increasingly tied to care quality and patient safety as part of value-based reimbursement programs. The incidence of adverse quality events among lumbar fusion patients is unknown using the definition of care quality (patient safety indicators [PSI]) used by the Centers for Medicare and Medicaid Services (CMS). The association between insurance status and the incidence of PSI is similarly unknown in lumbar fusion patients. PURPOSE: This study sought to determine the incidence of PSI in patients undergoing inpatient lumbar fusion and to quantify the association between primary payer status and PSI in this population. STUDY DESIGN: A retrospective cohort study was carried out. PATIENT SAMPLE: The sample comprised all adult patients aged 18 years and older who were included in the Nationwide Inpatient Sample (NIS) that underwent lumbar fusion from 1998 to 2011. OUTCOME MEASURE: The incidence of one or more PSI, a validated and widely used metric of inpatient health-care quality and patient safety, was the primary outcome variable. METHODS: The NIS data were examined for all cases of inpatient lumbar fusion from 1998 to 2011. The incidence of adverse patient safety events (PSI) was determined using publicly available lists of the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Logistic regression models were used to determine the association between primary payer status (Medicaid and self-pay relative to private insurance) and the incidence of PSI. RESULTS: A total of 539,172 adult lumbar fusion procedures were recorded in the NIS from 1998 to 2011. Patients were excluded from the secondary analysis if "other" or "missing" was listed for primary insurance status. The national incidence of PSI was calculated to be 2,445 per 100,000 patient years of observation, or approximately 2.5%. In a secondary analysis, after adjusting for patient demographics and hospital characteristics, Medicaid and self-pay patients had significantly greater odds of experiencing one or more PSI during the inpatient episode relative to privately insured patients (odds ratio 1.16, 95% confidence interval 1.07-1.27). CONCLUSIONS: Among patients undergoing inpatient lumbar fusion, insurance status is associated with the adverse health-care quality events used to determine hospital reimbursement by the CMS. The source of this disparity must be studied to improve the quality of care delivered to vulnerable patient populations. PMID- 27765715 TI - An allograft generated from adult stem cells and their secreted products efficiently fuses vertebrae in immunocompromised athymic rats and inhibits local immune responses. AB - BACKGROUND CONTEXT: Spine pain and the disability associated with it are epidemic in the United States. According to the National Center for Health Statistics, more than 650,000 spinal fusion surgeries are performed annually in the United States, and yet there is a failure rate of 15%-40% when standard methods employing current commercial bone substitutes are used. Autologous bone graft is the gold standard in terms of fusion success, but the morbidity associated with the procedure and the limitations in the availability of sufficient material have limited its use in the majority of cases. A freely available and immunologically compatible bone mimetic with the properties of live tissue is likely to substantially improve the outcome of spine fusion procedures without the disadvantages of autologous bone graft. PURPOSE: This study aimed to compare a live human bone tissue analog with autologous bone grafting in an immunocompromised rat model of posterolateral fusion. DESIGN/SETTING: This is an in vitro and in vivo preclinical study of a novel human stem cell-derived construct for efficacy in posterolateral lumbar spine fusion. METHODS: Osteogenically enhanced human mesenchymal stem cells (OEhMSCs) were generated by exposure to conditions that activate the early stages of osteogenesis. Immunologic characteristics of OEhMSCs were evaluated in vitro. The secreted extracellular matrix from OEhMSCs was deposited on a clinical-grade gelatin sponge, resulting in bioconditioned gelatin sponge (BGS). Bioconditioned gelatin sponge was used alone, with live OEhMSCs (BGS+OEhMSCs), or with whole human bone marrow (BGS+hBM). Efficacy for spine fusion was determined by an institutionally approved animal model using 53 nude rats. RESULTS: Bioconditioned gelatin sponge with live OEhMSCs did not cause cytotoxicity when incubated with immunologically mismatched lymphocytes, and OEhMSCs inhibited lymphocyte expansion in mixed lymphocyte assays. Bioconditioned gelatin sponge with live OEhMSC and BGS+hBM constructs induced profound bone growth at fusion sites in vivo, with a comparable rate of fusion with syngeneic bone graft (negative [0 of 10], BGS alone [0 of 10], bone graft [7 of 10], BGS+OEhMSC [10 of 15], and BGS+hBM [8 of 8]). CONCLUSIONS: Collectively, these studies demonstrate that BGS+OEhMSC constructs possess low immunogenicity and drive vertebral fusion with efficiency matching syngeneic bone graft in rodents. We also demonstrate that BGS serves as a promising scaffold for spine fusion when combined with hBM. PMID- 27765716 TI - GHS additivity formula: A true replacement method for acute systemic toxicity testing of agrochemical formulations. AB - Acute systemic (oral, dermal, inhalation) toxicity testing of agrochemical formulations (end-use products) is mainly needed for Classification and Labelling (C&L) and definition of personal protection equipment (PPE). A retrospective analysis of 225 formulations with available in vivo data showed that: A) LD50/LC50 values were above limit doses in <20.2% via oral route but only in <1% and <2.4% of cases via dermal and inhalation route, respectively; B) for each formulation the acute oral toxicity is always equal or greater than the Acute Toxicity Estimate (ATE) via the other two routes; C) the GHS (Global Harmonised System) computational method based on ATE, currently of limited acceptance, has very high accuracy and specificity for prediction of agrochemical mixture toxicity according to the internationally established classification thresholds. By integrating this evidence, an exposure- and data-based waiving strategy is proposed to determine classification and adequate PPE and to ensure only triggered animal testing is used. Safety characterisation above 2000 mg/kg body weight or 1.0 mg/L air should not be recommended, based on the agrochemical exposure scenarios. The global implementation of these tools would allow a remarkable reduction (up to 95%) in in vivo testing, often inducing lethality and/or severe toxicity, for agrochemical formulations. PMID- 27765717 TI - Comparison of in vivo immunomodulatory effects of 5-hydroxymethylfurfural and 5, 5'-oxydimethylenebis (2-furfural). AB - The standard of 5-Hydroxymethylfurfural (5-HMF) existed in dextrose injection as an inevitable by-product during high-temperature setrilization has been included in pharmacopoeias considering its hazardous effects on human health. We found that the concentrations of 5-HMF in some traditional Chinese medicine injections (TCMIs) far exceeded its limit in dextrose injection. Besides, we detected 5, 5' Oxydimethylenebis (2-furfural) (OMBF) in those TCMIs containing high concentrations of 5-HMF. We investigated the in vivo immunomodulatory effects of 5-HMF and OMBF at three dose levels using the reporter antigen popliteal lymph node assay (RA-PLNA), which allows the straightforward examination and mechanistic study of immunotoxicity of low molecular weight compounds. We found that 5-HMF increased the production of IgG2a and IFN-gamma when co-injected with TNP-OVA, indicating its capability of providing a co-stimulatory signal to evoke a typical type-1 immune response. Compared with the 5-HMF, OMBF elevated the production of IgG1, IgG2, IL-4 and IFN-gamma in response to both reporter antigens, suggesting that OMBF can act as a neo-antigen or neo-epitope to elicit a mixed type-1 and type-2 immune response. It indicates that both 5-HMF and OMBF have immunosensitizing potential with different mechanisms, and exposure to 5-HMF and OMBF may represent a safety concern for humans. PMID- 27765718 TI - Weight-of-evidence evaluation of associations between particulate matter exposure and biomarkers of lung cancer. AB - Research suggests that exposure to ambient particulate matter (PM) may be associated with lung cancer; however, no mode of action (MoA) for this has been established. We applied a weight-of-evidence (WoE) approach to evaluate recent evidence from four realms of research (controlled human exposure, epidemiology, animal, and in vitro) to determine whether the overall evidence supports one or more MoAs by which PM could cause lung cancer. We evaluated three general MoAs: DNA damage and repair; other genotoxic effects, including mutagenicity and clastogenicity; and gene expression, protein expression, and DNA methylation. After assessing individual study quality, we evaluated the strength of the evidence within as well as across disciplines using a modified set of Bradford Hill considerations. We conclude that the overall WoE indicates it is plausible that PM of various size fractions may cause direct DNA damage, but the evidence is insufficient regarding the alternative MoAs we evaluated. More research is needed to determine whether DNA damage can lead to downstream events and, ultimately, lung cancer. PMID- 27765719 TI - Accidental Intrathecal Injection of Ionic Contrast: Case Report and Review of the Literature. AB - BACKGROUND: Ionic contrast, if accidentally injected into the intrathecal space during routine imaging studies or interventional procedures, may significantly interfere with neuronal activity, potentially causing ascending tonic-clonic seizure syndrome and even death. As a result, ionic contrast is strictly contraindicated for intrathecal use. Rapid recognition of the condition followed by prompt management, typically involving aggressive cerebrospinal fluid (CSF) drainage, is critical to improving patient outcome. Lumbar drain has previously been well described as a management strategy. CASE DESCRIPTION: We present a case of accidental intrathecal injection of an ionic contrast agent, iothalamate meglumine, in a patient undergoing cervical epidural steroid injection. This patient was managed successfully with drainage of CSF using an external ventricular drain alone. CONCLUSION: Our literature review and analysis of the previously published cases demonstrate that aggressive CSF drainage is essential to improve outcomes, and in some cases an external ventricular drain alone may be effectively used. PMID- 27765720 TI - Magnetic Resonance-Guided Laser Ablation for the Treatment of Recurrent Dural Based Lesions: A Series of Five Cases. AB - BACKGROUND AND OBJECTIVE: Magnetic resonance-guided laser-induced thermotherapy (MR-LITT) is a minimally invasive technique that shows promise in neuro-oncology because of its superiority in delivering precise minimally invasive thermal energy with minimal collateral damage. In this analysis, we investigate initial data on the effect of MR-LITT on dural-based lesions. METHODS: Five patients were identified with dural-based lesions (4 meningiomas, 1 solitary fibrous tumor) with clear evidence of radiologic progression. In all 5 cases, the tumors were localized to the lateral convexity or paramedian locations in the supratentorial space. All patients received MR-LITT and then a follow-up magnetic resonance imaging scan at 24 hours after treatment, at 1 month, and at each subsequent follow-up visit. Local control of the ablated tumor was evaluated with radiographic follow-up and symptomatic progression-free survival was recorded. RESULTS: Five LITT treatments were performed on 5 patients with an average age of 65.2 years. The average tumor volume was 29.7 cm3 and ablation dosage was 12.4 W. On average, 80% of the pretreatment lesion volume was ablated. The mean follow-up time was 59.3 weeks. In total, 2 patients (1 with an anaplastic meningioma and 1 with a solitary fibrous tumor) had radiographic evidence of disease progression. In the observed time of the 3 patients with no progression, there was a 52% reduction in tumor volume. There were no major perioperative complications. CONCLUSIONS: MR-LITT is a promising technology for dural-based lesion treatment. This initial study demonstrates that MR-LITT is safe and offers several advantages over open surgical treatment. Randomized studies are needed to evaluate its role as a treatment adjunct. PMID- 27765721 TI - Neuronavigated Fiber Dissection with Pial Preservation: Laboratory Model to Simulate Opercular Approaches to Insular Tumors. AB - BACKGROUND: Advances in the oncologic and functional results of insular surgery have been reported recently. Such successes have been made possible by the advent of the transopercular approach under awake monitoring and by improved anatomic and functional knowledge of white matter pathways surrounding the insula. Nonetheless, given the rarity of insular tumors, it is difficult to get familiar with the complex 3-dimensional anatomy of the different neuronal and vascular structures encountered during a transopercular insular resection. We thus propose to develop a laboratory model allowing to train transopercular approaches of the insula. METHODS: Two hemispheres prepared with Klinger's technique were dissected under light microscope, preserving all pial membranes. The different steps of the dissection were video recorded. RESULTS: Preservation of pial membranes enabled us to simulate subpial resection, both during operculum removal and during insular cortex resection. The medial wall of the resection was defined by the inferior-fronto-occipital fasciculus, protecting from the lenticulostriate arteries. CONCLUSION: In this paper, we show that Klinger dissection with preservation of pial membranes provides a realistic model of insular surgery, allowing surgeons to learn and train on this highly specialized surgery. PMID- 27765723 TI - Integration of organohalide-respiring bacteria and nanoscale zero-valent iron (Bio-nZVI-RD): A perfect marriage for the remediation of organohalide pollutants? AB - Due to massive production and improper handling, organohalide compounds are widely distributed in subsurface environments, primarily in anoxic groundwater, soil and sediment. Compared to traditional pump-and-treat or dredging-and disposal treatments, in situ remediation employing abiotic or biotic reductive dehalogenation represents a sustainable and economic solution for the removal of organohalide pollutants. Both nanoscale zero-valent iron (nZVI) and organohalide respiring bacteria remove halogens through reductive dehalogenation and have been extensively studied and successfully applied for the in situ remediation of chloroethenes and other organohalide pollutants. nZVI and microbial reductive dehalogenation (Bio-RD) complement each other to boost reductive dehalogenation efficiency, suggesting that the integration of nZVI with Bio-RD (Bio-nZVI-RD) may constitute an even more promising strategy for the in situ remediation of organohalide pollutants. In this review, we first provide an overview of the current literature pertaining to nZVI- and organohalide-respiring bacteria mediated reductive dehalogenation of organohalide pollutants and compare the pros and cons of individual treatment methods. We then highlight recent studies investigating the implementation of Bio-nZVI-RD to achieve rapid and complete dehalogenation and discuss the halogen removal mechanism of Bio-nZVI-RD and its prospects for future remediation applications. In summary, the use of Bio-nZVI-RD facilitates opportunities for the effective in situ remediation of a wide range of organohalide pollutants. PMID- 27765722 TI - Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes. AB - Bacteria that reside on the skin can influence the behavior of the cutaneous immune system, but the mechanisms responsible for these effects are incompletely understood. Colonization of the skin by Staphylococcus aureus (S. aureus) is increased in atopic dermatitis and can result in increased severity of the disease. In this study, we show that S. aureus stimulates human keratinocytes to increase their endogenous protease activity, including specific increases in trypsin activity. This increased protease activity coincided with increased expression of mRNA for kallikreins (KLKs), with KLK6, 13, and 14 showing the greatest induction after exposure to S. aureus. Suppression of mRNA for these KLKs in keratinocytes by targeted small interfering RNA silencing before S. aureus exposure blocked the increase in protease activity. Keratinocytes exposed to S. aureus showed enhanced degradation of desmoglein-1 and filaggrin, whereas small interfering RNA for KLK6, KLK13, and KLK14 partially blocked this degradation. These data illustrate how S. aureus directly influences the skin barrier integrity by stimulating endogenous proteolytic activity and defines a previously unknown mechanism by which S. aureus may influence skin diseases. PMID- 27765724 TI - Systemic delivery of small interfering RNA targeting nuclear factor kappaB in mice with collagen-induced arthritis using arginine-histidine-cysteine based oligopeptide-modified polymer nanomicelles. AB - This study aimed to build an innovative system to deliver a systemic small interfering RNA (siRNA) treatment for rheumatoid arthritis. We combined arginine histidine-cysteine based oligopeptide-modified polymer micelles with siRNA targeting the nuclear factor kappaB subunit, RelA (siRelA). This is a key molecule in the control of inflammation. We tested the cellular uptake of siRNA and its effects on inflammatory cytokine levels in vitro using synoviocytes, and siRNA distribution and therapeutic effects in vivo in mice with collagen-induced arthritis (CIA). These studies showed that arginine-histidine based oligopeptide modified micelles produced effective cellular siRNA uptake and suppressed inflammatory cytokine levels in synoviocytes. In vivo, these micelles produced marked accumulation of siRNAs in arthritic paws in CIA mice, with much less accumulation in healthy mice. The siRelA-polymer micelle complexes also produced more effective suppression of RelA mRNA expression and inflammatory cytokine levels in the arthritic paws of CIA mice and reduced their clinical symptom scores and paw thickness. PMID- 27765725 TI - Oral sustained-release suspension based on a lauryl sulfate salt/complex. AB - The objective of this study was to evaluate the feasibility of lauryl sulfate (LS) salt/complex as a novel carrier in oral sustained-release suspensions. Mirabegron, which has a pH-dependent solubility, was selected as the model drug. Sodium lauryl sulfate (SLS) was bound to mirabegron in a stoichiometric manner to form an LS salt/complex. LS salt/complex formulation significantly reduced the solubility of mirabegron and helped mirabegron achieve sustained-release over a wide range of pH conditions. Microparticles containing the LS salt/complex were prepared by spray drying with the aqueous dispersion of ethylcellulose (Aquacoat(r) ECD). The diameter of the microparticles was less than 200MUm, which will help avoid a gritty taste. In vitro results indicated the microparticles had slower dissolution profiles than the LS salt/complex. The dissolution rate could be controlled flexibly by changing the amount of Aquacoat(r) ECD. The microparticle suspension retained the desired sustained-release property and dissolution profile after being stored for 30days at 40 degrees C. In addition, the suspension displayed sustained-release behavior in dogs without a pronounced Cmax peak, which will help prevent side effects. These results suggest that microparticles containing LS salt/complex may be useful as a novel sustained release suspension for oral delivery. PMID- 27765727 TI - Aspirin Use Is Associated With Reduced Risk of Occlusion of Metallic Biliary Stents. AB - BACKGROUND & AIMS: Biliary self-expandable metallic stents (SEMSs) are widely used to treat malignant and benign conditions of bile duct. Despite their lower rate of occlusion and longer patency than plastic stents, SEMSs still have significant rates of occlusion. We aimed to identify factors associated with occlusion of biliary SEMS. METHODS: We performed a retrospective study of consecutive patients who underwent endoscopic retrograde cholangiopancreatography with biliary SEMS placement at the Cleveland Clinic Foundation from March 2011 to April 2016. We collected clinical, endoscopic, radiographic, and surgical data from medical records and performed multivariable analysis to identify factors associated with SEMS patency. Subjects that received minimal daily dose of 81 mg at the time of stent placement until the end of follow-up were assigned to the aspirin exposure group (n = 157) and compared with subjects with no aspirin exposure (n = 436). Patients were followed for a median 81 days. The primary outcome was hazard ratio for SEMS occlusion requiring an interventional maneuver for biliary drainage. RESULTS: We analyzed data from patients receiving a total of 593 biliary SEMS for treatment of malignant and benign conditions of bile duct. Stent occlusion was observed in 126 cases. Multivariable analysis showed that daily use of aspirin (81 mg or more) was associated with 51% lower risk of stent occlusion than in patients without daily use of aspirin (hazard ratio, 0.49; 95% confidence interval, 0.32-0.75). Furthermore, SEMSs had a longer duration of stent patency in patients in the aspirin exposure group (434.4 days) versus the no aspirin exposure group (339.9 days) (P < .001). Stricture location limited to distal bile duct (in comparison with strictures involving proximal extrahepatic duct) was associated with lower risk of stent occlusion (hazard ratio, 0.39; 95% CI, 0.22-0.71). CONCLUSIONS: In an analysis of a large cohort of subjects with metallic biliary stent placement for malignant and benign conditions of bile duct, we associated daily use of aspirin (81 mg or more) with lower risk of SEMS occlusion and longer stent patency duration. PMID- 27765726 TI - Trospium chloride is absorbed from two intestinal "absorption windows" with different permeability in healthy subjects. AB - Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30mg/250ml=[I]2) for 6h and after swallowing 30mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ~10h) after gastric infusion involving two processes with different input rates, peaking at about 3h and 7h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two "windows" located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1. PMID- 27765730 TI - A Rare Benign Gastrointestinal Lesion Identified as a Calcifying Fibrous Tumor. PMID- 27765728 TI - Major Gastrointestinal Bleeding Often Is Caused by Occult Malignancy in Patients Receiving Warfarin or Dabigatran to Prevent Stroke and Systemic Embolism From Atrial Fibrillation. AB - BACKGROUND & AIMS: Gastrointestinal (GI) bleeding in patients receiving anticoagulation agents can be caused by occult malignancies. We investigated the proportions and features of major GI bleeding (MGIB) events related to occult GI cancers in patients receiving anticoagulation therapy. METHODS: We analyzed data from the Randomized Evaluation of Long Term Anticoagulant Therapy study (conducted between December 2005 and March 2009 in 951 clinical centers in 44 countries worldwide), which compared the abilities of dabigatran vs warfarin to prevent stroke and systemic embolism in 18,113 patients with atrial fibrillation. Two blinded gastroenterologists independently reviewed source documents of MGIB events (n = 595) that occurred during the study period. We collected data on MGIB events caused by previously unidentified GI malignancies, and compared characteristics of MGIB events in patients who received dabigatran vs warfarin (primary end point), and in patients with bleeding from cancer, vs patients bleeding from a nonmalignant or unidentified source. RESULTS: Of 546 unique MGIB events, 44 (8.1%) were found to be from GI cancers (34 of 398 MGIB events in dabigatran users and 10 of 148 MGIB events in warfarin users; P = .60). Colorectal cancer accounted for 35 of 44 of all cancers identified. There were more colorectal cancer-associated MGIB events in the dabigatran group (30 of 34) than in the warfarin group (5 of 10) (P = .02), but more gastric cancer associated MGIB events in the warfarin group (5 of 10) than in the dabigatran group (1 of 34) (P = .001). There were no differences in the short-term outcomes of cancer-related MGIB events in the dabigatran vs the warfarin group, but 75% of all cancer-related MGIB events required at least 1 blood transfusion and the mean hospital stay was 10.1 days. Compared with MGIB events from a nonmalignant or unidentified source, MGIB from cancer occurred sooner (343.0 vs 223.1 d; P = .003), but the bleeding was more likely to be chronic (for >7 d) (27.3% vs 63.6%; P < .001). CONCLUSIONS: In evaluating data from a study of the effects of anticoagulation therapy, we found approximately 1 of every 12 MGIB events to be related to an occult cancer. Approximately two thirds of cancer-related MGIB presents with chronic bleeding, and morbidity, and resource utilization is high. PMID- 27765731 TI - Evaluating Google, Twitter, and Wikipedia as Tools for Influenza Surveillance Using Bayesian Change Point Analysis: A Comparative Analysis. AB - BACKGROUND: Traditional influenza surveillance relies on influenza-like illness (ILI) syndrome that is reported by health care providers. It primarily captures individuals who seek medical care and misses those who do not. Recently, Web based data sources have been studied for application to public health surveillance, as there is a growing number of people who search, post, and tweet about their illnesses before seeking medical care. Existing research has shown some promise of using data from Google, Twitter, and Wikipedia to complement traditional surveillance for ILI. However, past studies have evaluated these Web based sources individually or dually without comparing all 3 of them, and it would be beneficial to know which of the Web-based sources performs best in order to be considered to complement traditional methods. OBJECTIVE: The objective of this study is to comparatively analyze Google, Twitter, and Wikipedia by examining which best corresponds with Centers for Disease Control and Prevention (CDC) ILI data. It was hypothesized that Wikipedia will best correspond with CDC ILI data as previous research found it to be least influenced by high media coverage in comparison with Google and Twitter. METHODS: Publicly available, deidentified data were collected from the CDC, Google Flu Trends, HealthTweets, and Wikipedia for the 2012-2015 influenza seasons. Bayesian change point analysis was used to detect seasonal changes, or change points, in each of the data sources. Change points in Google, Twitter, and Wikipedia that occurred during the exact week, 1 preceding week, or 1 week after the CDC's change points were compared with the CDC data as the gold standard. All analyses were conducted using the R package "bcp" version 4.0.0 in RStudio version 0.99.484 (RStudio Inc). In addition, sensitivity and positive predictive values (PPV) were calculated for Google, Twitter, and Wikipedia. RESULTS: During the 2012-2015 influenza seasons, a high sensitivity of 92% was found for Google, whereas the PPV for Google was 85%. A low sensitivity of 50% was calculated for Twitter; a low PPV of 43% was found for Twitter also. Wikipedia had the lowest sensitivity of 33% and lowest PPV of 40%. CONCLUSIONS: Of the 3 Web-based sources, Google had the best combination of sensitivity and PPV in detecting Bayesian change points in influenza-related data streams. Findings demonstrated that change points in Google, Twitter, and Wikipedia data occasionally aligned well with change points captured in CDC ILI data, yet these sources did not detect all changes in CDC data and should be further studied and developed. PMID- 27765729 TI - Infection With Hepatitis C Virus Genotype 3 Is an Independent Risk Factor for End Stage Liver Disease, Hepatocellular Carcinoma, and Liver-Related Death. AB - BACKGROUND & AIMS: Few studies have examined factors associated with disease progression in hepatitis C virus (HCV) infection. We examined the association of 11 risk factors with adverse outcomes in a population-based prospective cohort observational study of Alaska Native/American Indian persons with chronic HCV infection. METHODS: We collected data from a population-based cohort study of liver-related adverse outcomes of infection in American Indian/Alaska Native persons with chronic HCV living in Alaska, recruited from 1995 through 2012. We calculated adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for end-stage liver disease (ESLD; presence of ascites, esophageal varices, hepatic encephalopathy, or coagulopathy), hepatocellular carcinoma (HCC), and liver related death using a Cox proportional hazards model. RESULTS: We enrolled 1080 participants followed up for 11,171 person-years (mean, 10.3 person-years); 66%, 19%, and 14% were infected with HCV genotypes 1, 2, and 3, respectively. On multivariate analysis, persons infected with HCV genotype 3 had a significantly increased risk of developing all 3 adverse outcomes. Their aHR for ESLD was 2.1 (95% CI, 1.5-3.0), their aHR for HCC was 3.1 (95% CI, 1.4-6.6), and their aHR for liver-related death was 2.4 (95% CI, 1.5-4.0) compared with genotype 1. Heavy alcohol use was an age-adjusted risk factor for ESLD (aHR, 2.2; 95% CI, 1.6-3.2), and liver-related death (aHR, 2.9; 95% CI, 1.8-4.6). Obesity was a risk factor for ESLD (aHR, 1.4; 95% CI, 1.0-1.9), and diabetes was a risk factor for ESLD (aHR, 1.5; 95% CI, 1.1-2.2). Male sex was a risk factor for HCC (aHR, 3.6; 95% CI, 1.6-8.2). CONCLUSIONS: In a population-based cohort study of American Indian/Alaska Native persons with chronic HCV infection, we found those infected with HCV genotype 3 to be at high risk for ESLD, HCC, and liver-related death. PMID- 27765733 TI - Preoperative Outcome Scores Are Predictive of Achieving the Minimal Clinically Important Difference After Arthroscopic Treatment of Femoroacetabular Impingement. AB - BACKGROUND: There is increasing interest in defining meaningful improvement in patient-reported outcomes. Knowledge of the thresholds and determinants for successful femoroacetabular impingement (FAI) outcomes is evolving. PURPOSE: To define preoperative outcome score thresholds and determine clinical/demographic patient factors predictive for achieving the minimal clinically important difference (MCID) after arthroscopic FAI surgery. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A prospective institutional hip preservation registry was reviewed to identify patients undergoing arthroscopic FAI surgery. The modified Harris Hip Score (mHHS), the Hip Outcome Score (HOS), and the international Hip Outcome Tool (iHOT-33) were administered at baseline and 1 year postoperatively. The MCID was calculated using a distribution-based method. Receiver operating characteristic (ROC) analysis was used to calculate cohort-based threshold values predictive of achieving the MCID. The area under the curve (AUC) was used to define predictive ability, with AUC >0.7 considered acceptably predictive. Multivariable analysis identified patient factors associated with achieving the MCID. Sensitivity analysis was performed to derive the MCID by an alternative anchor-based method. RESULTS: There were 364 patients (mean [+/-SD] age, 32.5 +/- 10.3 years), and 57.1% were female. The MCID for the mHHS, HOS-Activities of Daily Living (HOS-ADL), HOS-Sports, and iHOT-33 was 8.2, 8.3, 14.5, and 12.1, respectively. ROC analysis findings (threshold, percentage achieving the MCID, and strength of association) for these tools were as follows: mHHS (60.5, 77.2%, and 0.68, respectively), HOS-ADL (83.3, 68.1%, and 0.85, respectively), HOS-Sports (58.3, 65.9%, and 0.76, respectively), and iHOT-33 (53.9, 81.9%, and 0.65, respectively). The likelihood for achieving the MCID significantly declined above these thresholds. In multivariable analysis, a higher sagittal center-edge angle (CEA) (odds ratio [OR], 1.04; 95% CI, 1.01 1.08) was a positive predictor of achieving the MCID on the iHOT-33, while a higher Outerbridge grade for the acetabulum was a negative predictor (OR, 0.56; 95% CI, 0.32-0.99) on the mHHS. Sensitivity analysis confirmed these variables and identified relative femoral retroversion as another negative predictor (OR, 0.40; 95% CI, 0.17-0.94). CONCLUSION: The HOS had excellent predictive ability for identifying patient thresholds of achieving the MCID; patients with preoperative scores below identified thresholds were most likely to achieve the MCID. Additionally, anterior acetabular undercoverage, chondral injuries, and relative femoral retroversion were clinically significant negative modifiers of outcomes. These findings have implications for managing preoperative expectations of FAI surgery. PMID- 27765732 TI - Text Message-Based Intervention Targeting Alcohol Consumption Among University Students: Findings From a Formative Development Study. AB - BACKGROUND: Drinking of alcohol among university students is a global phenomenon; heavy episodic drinking is accepted despite several potential negative consequences. There is emerging evidence that short message service (SMS) text messaging interventions are effective to promote behavior change among students. However, it is still unclear how effectiveness can be optimized through intervention design or how user interest and adherence can be maximized. OBJECTIVE: The objective of this study was to develop an SMS text message-based intervention targeting alcohol drinking among university students using formative research. METHODS: A formative research design was used including an iterative revision process based on input from end users and experts. Data were collected via seven focus groups with students and a panel evaluation involving students (n=15) and experts (n=5). Student participants were recruited from five universities in Sweden. A semistructured interview guide was used in the focus groups and included questions on alcohol culture, message content, and intervention format. The panel evaluation asked participants to rate to what degree preliminary messages were understandable, usable, and had a good tone on a scale from 1 (very low degree) to 4 (very high degree). Participants could also write their own comments for each message. Qualitative data were analyzed using qualitative descriptive analysis. Quantitative data were analyzed using descriptive statistics. The SMS text messages and the intervention format were revised continuously in parallel with data collection. A behavior change technique (BCT) analysis was conducted on the final version of the program. RESULTS: Overall, students were positive toward the SMS text message intervention. Messages that were neutral, motivated, clear, and tangible engaged students. Students expressed that they preferred short, concise messages and confirmed that a 6-week intervention was an appropriate duration. However, there was limited consensus regarding SMS text message frequency, personalization of messages, and timing. Overall, messages scored high on understanding (mean 3.86, SD 0.43), usability (mean 3.70, SD 0.61), and tone (mean 3.78, SD 0.53). Participants added comments to 67 of 70 messages, including suggestions for change in wording, order of messages, and feedback on why a message was unclear or needed major revision. Comments also included positive feedback that confirmed the value of the messages. Twenty-three BCTs aimed at addressing self-regulatory skills, for example, were identified in the final program. CONCLUSIONS: The formative research design was valuable and resulted in significant changes to the intervention. All the original SMS text messages were changed and new messages were added. Overall, the findings showed that students were positive toward receiving support through SMS text message and that neutral, motivated, clear, and tangible messages promoted engagement. However, limited consensus was found on the timing, frequency, and tailoring of messages. PMID- 27765734 TI - Current Public Knowledge Pertaining to Traumatic Brain Injury: Influence of Demographic Factors, Social Trends, and Sport Concussion Experience on the Understanding of Traumatic Brain Injury Sequelae. AB - Objective: The current study aimed to assess current broad traumatic brain injury (TBI)-related knowledge in the general public, as well as understanding regarding specific TBI-related conditions including post-concussive syndrome (PCS) and chronic traumatic encephalopathy (CTE). Methods: Data were collected from 307 domestic and 73 international individuals via online researcher-developed survey instrumentation utilizing the Amazon Mechanical Turk marketplace, a recently developed website that allows for a streamlined process of survey-based participant recruitment and data collection. Participants completed background demographics questions, a 31-item true/false questionnaire pertaining to TBI related knowledge, and an inquiry related to willingness to allow (future) child(ren) to participate in several popular U.S. sports. Results: The overall accuracy rate of our U.S. sample was 61%. No accuracy differences were present for gender or geographic region (p's > .05). Participants who self-reported a prior concussion diagnosis, who reported receiving formal concussion training, and who endorsed participation in collegiate, semi-professional, or professional athletic competition, all exhibited lower accuracy rates than the respective comparison groups (p's < .001). Finally, individual item analysis revealed the presence of significant misconceptions pertaining to PCS and CTE. Conclusions: Misconceptions regarding TBI remain highly prevalent within the general public and may be explained, to some extent, by inefficiencies in current TBI-education practices. Moreover, misconceptions regarding PCS and CTE are also prevalent and likely reflect inconsistencies in the scientific literature, coupled with misleading media reports. To combat these trends, greater emphasis must be placed on construct definition within the field and streamlined, efficient communication with the general public. PMID- 27765735 TI - A process evaluation of the WHiTE Two trial comparing total hip arthroplasty with and without dual mobility component in the treatment of displaced intracapsular fractures of the proximal femur: Can a trial investigating total hip arthroplasty for hip fracture be delivered in the NHS? AB - OBJECTIVES: The annual incidence of hip fracture is 620 000 in the European Union. The cost of this clinical problem has been estimated at 1.75 million disability-adjusted life years lost, equating to 1.4% of the total healthcare burden in established market economies. Recent guidance from The National Institute for Health and Clinical Excellence (NICE) states that research into the clinical and cost effectiveness of total hip arthroplasty (THA) as a treatment for hip fracture is a priority. We asked the question: can a trial investigating THA for hip fracture currently be delivered in the NHS? METHODS: We performed a contemporaneous process evaluation that provides a context for the interpretation of the findings of WHiTE Two - a randomised study of THA for hip fracture. We developed a mixed methods approach to situate the trial centre within the context of wider United Kingdom clinical practice. We focused on fidelity, implementation, acceptability and feasibility of both the trial processes and interventions to stakeholder groups, such as healthcare providers and patients. RESULTS: We have shown that patients are willing to participate in this type of research and that surgeons value being part of a team that has a strong research ethos. However, surgical practice does not currently reflect NICE guidance. Current models of service delivery for hip fractures are unlikely to be able to provide timely total hip arthroplasty for suitable patients. CONCLUSIONS: Further observational research should be conducted to define the population of interest before future interventional studies are performed.Cite this article: C. Huxley, J. Achten, M. L. Costa, F. Griffiths, X. L. Griffin. A process evaluation of the WHiTE Two trial comparing total hip artroplasty with and without dual mobility component in the treatment of displaced intracapsular fractures of the proximal femur: Can a trial investigating total hip arthroplasty for hip fracture be delivered in the NHS? Bone Joint Res 2016;5:444-452. DOI: 10.1302/2046 3758.510.BJR-2015-0008.R1. PMID- 27765736 TI - Collateral Assessment by CT Angiography as a Predictor of Outcome in Symptomatic Cervical Internal Carotid Artery Occlusion. AB - BACKGROUND AND PURPOSE: Cervical internal carotid artery occlusion can present with varied clinical manifestations such as transient ischemic attack, stroke, and chronic ocular ischemia, or can be asymptomatic. The outcome in these patients is considerably influenced by cerebral hemodynamic compensatory adaptation of the intracranial collateral pathways. Our aim was to study whether collateral circulation as assessed by CT angiography can predict 3-month outcome and initial stroke severity in patients with symptomatic cervical ICA occlusion. MATERIALS AND METHODS: This was a retrospective study of 65 patients with symptomatic cervical ICA occlusion from January 2011 to December 2013. The collateral vessels (anterior and posterior communicating arteries, ophthalmic artery, and leptomeningeal arteries) were assessed by CTA. The outcome at 3 months was defined as poor if the modified Rankin Scale score was >=3. RESULTS: The mean age of subjects was 57 +/- 11.6 years (range, 32-80 years), and 92% were men. Thirty-three (50.8%) patients had poor outcome. Absence of the ipsilateral ophthalmic artery, poor leptomeningeal collaterals, and <2 collaterals were predictors of stroke severity at onset and poor 3-month outcome in univariate analysis. In the multiple logistic regression analysis, inadequate flow through the secondary collaterals (ipsilateral ophthalmic artery or leptomeningeal collaterals; OR, 4.5; 95% CI, 1.4-14.9; P = .01) and higher NIHSS score at stroke onset (OR, 19.2; 95% CI, 2.2-166.2; P = .007) independently predicted poor outcome at 3 months. CONCLUSIONS: Assessment of collateral circulation with CTA can be a useful predictor of 3-month outcome in patients with symptomatic cervical ICA occlusion. PMID- 27765737 TI - Quantifying the Cerebral Hemodynamics of Dural Arteriovenous Fistula in Transverse Sigmoid Sinus Complicated by Sinus Stenosis: A Retrospective Cohort Study. AB - BACKGROUND AND PURPOSE: Sinus stenosis occasionally occurs in dural arteriovenous fistulas. Sinus stenosis impedes venous outflow and aggravates intracranial hypertension by reversing cortical venous drainage. This study aimed to analyze the likelihood of sinus stenosis and its impact on cerebral hemodynamics of various types of dural arteriovenous fistulas. MATERIALS AND METHODS: Forty-three cases of dural arteriovenous fistula in the transverse-sigmoid sinus were reviewed and divided into 3 groups: Cognard type I, type IIa, and types with cortical venous drainage. Sinus stenosis and the double peak sign (occurrence of 2 peaks in the time-density curve of the ipsilateral drainage of the internal jugular vein) in dural arteriovenous fistula were evaluated. "TTP" was defined as the time at which a selected angiographic point reached maximum concentration. TTP of the vein of Labbe, TTP of the ipsilateral normal transverse sinus, trans fistula time, and trans-stenotic time were compared across the 3 groups. RESULTS: Thirty-six percent of type I, 100% of type IIa, and 84% of types with cortical venous drainage had sinus stenosis. All sinus stenosis cases demonstrated loss of the double peak sign that occurs in dural arteriovenous fistula. Trans-fistula time (2.09 seconds) and trans-stenotic time (0.67 seconds) in types with cortical venous drainage were the most prolonged, followed by those in type IIa and type I. TTP of the vein of Labbe was significantly shorter in types with cortical venous drainage. Six patients with types with cortical venous drainage underwent venoplasty and stent placement, and 4 were downgraded to type IIa. CONCLUSIONS: Sinus stenosis indicated dysfunction of venous drainage and is more often encountered in dural arteriovenous fistula with more aggressive types. Venoplasty ameliorates cortical venous drainage in dural arteriovenous fistulas and serves as a bridge treatment to stereotactic radiosurgery in most cases. PMID- 27765738 TI - Flow Diverters in the Treatment of Pediatric Cerebrovascular Diseases. AB - BACKGROUND AND PURPOSE: There is very limited data concerning utilization of flow diverters in children. Our aim is to report results for the treatment of complex intracranial aneurysms and carotid cavernous fistulas by using flow diverters in children. MATERIALS AND METHODS: Retrospective review of children (17 years of age or younger) treated with flow diverters between May 2011 and July 2014 was performed. Clinical and laboratory data and angiographic findings were extracted. Seven patients (6 males, 1 female; mean age, 12.7 years; range, 3-16 years) were included. Two presented with posttraumatic fistulas. The remaining patients presented with traumatic aneurysms of the cavernous carotid artery or fusiform aneurysms of the distal vertebral artery, M1, or A2 segments. All patients were premedicated with clopidogrel (75 mg daily for patients with body weights of >45 kg, 37.5 mg daily for 1 small child with a body weight of <45 kg) and aspirin (300 mg daily for >=45 kg, 100 mg daily for smaller children). RESULTS: VerifyNow and Multiplate Analyzer values were higher than expected. No clinical complications were noted. Imaging performed at 7-52 months after the procedure (mean/median, 22.3/14 months) revealed occlusions of all aneurysms and fistulas. One patient had an asymptomatic occlusion of the parent artery; otherwise, no hemodynamically significant parent artery restenosis was observed. There were no clinically significant neurologic events during follow-up. CONCLUSIONS: Although flow-diverter placement appears to be safe and effective on midterm follow-up in children, longer follow-up is critical. The current sizes of flow diverter devices and delivery systems cover the pediatric size range, obviating developing flow diverters specific to children. PMID- 27765739 TI - Limited Dorsal Myeloschisis and Congenital Dermal Sinus: Comparison of Clinical and MR Imaging Features. AB - BACKGROUND AND PURPOSE: While limited dorsal myeloschisis is a distinctive form of spinal dysraphism, it may be confused with congenital dermal sinus. The aim of this study was to describe clinical and MR imaging findings of limited dorsal myeloschisis that can distinguish it from congenital dermal sinus. MATERIALS AND METHODS: We retrospectively reviewed the clinical and MR imaging findings of 12 patients with limited dorsal myeloschisis and 10 patients with congenital dermal sinus. Skin abnormalities, neurologic deficits, and infectious complication were evaluated on the basis of clinical information. We evaluated the following MR imaging features: visibility of the tract along the intrathecal course, attachment site of the tract, level of the conus medullaris, shape of the spinal cord, and presence of intradural lesions such as dermoid/epidermoid tumors. RESULTS: A crater covered with pale epithelium was the most common skin lesion in limited dorsal myeloschisis (10/12, 83%). Infectious complications were common in congenital dermal sinus (6/10, 60%), whereas none were found in limited dorsal myeloschisis (P = .003). The following MR imaging findings were significantly different between the 2 groups (P < .05): 1) higher visibility of the intrathecal tract in limited dorsal myeloschisis (10/12, 83%) versus in congenital dermal sinus (1/10, 10%), 2) the tract attached to the cord in limited dorsal myeloschisis (12/12, 100%) versus various tract attachments in congenital dermal sinus, 3) dorsal tenting of the cord in limited dorsal myeloschisis (10/12, 83%) versus in congenital dermal sinus (1/10, 10%), and 4) the presence of dermoid/epidermoid tumors in congenital dermal sinus (6/10, 60%) versus none in limited dorsal myeloschisis. CONCLUSIONS: Limited dorsal myeloschisis has distinct MR imaging features: a visible intrathecal tract with dorsal tenting of the cord at the tract-cord union. Limited dorsal myeloschisis was not associated with infection and dermoid/epidermoid tumors. PMID- 27765740 TI - Endovascular Therapy of M2 Occlusion in IMS III: Role of M2 Segment Definition and Location on Clinical and Revascularization Outcomes. AB - BACKGROUND AND PURPOSE: Uncertainty persists regarding the safety and efficacy of endovascular therapy of M2 occlusions following IV tPA. We reviewed the impact of revascularization on clinical outcomes in 83 patients with M2 occlusions in the Interventional Management of Stroke III trial according to specific M1-M2 segment anatomic features. MATERIALS AND METHODS: Perfusion of any M2 branch distinguished M2-versus-M1 occlusion. Prespecified modified TICI and arterial occlusive lesion revascularization and clinical mRS 0-2 end points at 90 days for endovascular therapy-treated M2 occlusions were analyzed. Post hoc analyses of the relationship of outcomes to multiple baseline angiographic M2 and M1 subgroup characteristics were performed. RESULTS: Of 83 participants with M2 occlusion who underwent endovascular therapy, 41.0% achieved mRS 0-2 at 90 days, including 46.6% with modified TICI 2-3 reperfusion compared with 26.1% with modified TICI 0 1 reperfusion (risk difference, 20.6%; 95% CI, -1.4%-42.5%). mRS 0-2 outcome was associated with reperfusion for M2 trunk (n = 9) or M2 division (n = 42) occlusions, but not for M2 branch occlusions (n = 28). Of participants with trunk and division occlusions, 63.2% with modified TICI 2a and 42.9% with modified TICI 2b reperfusion achieved mRS 0-2 outcomes; mRS 0-2 outcomes for M2 trunk occlusions (33%) did not differ from distal (38.2%) and proximal (26.9%) M1 occlusions. CONCLUSIONS: mRS 0-2 at 90 days was dependent on reperfusion for M2 trunk but not for M2 branch occlusions. For M2 division occlusions, good outcome with modified TICI 2b reperfusion did not differ from that in modified TICI 2a. M2 segment definition and occlusion location may contribute to differences in revascularization and good outcome between Interventional Management of Stroke III and other endovascular therapy studies. PMID- 27765741 TI - MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis. AB - BACKGROUND AND PURPOSE: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. MATERIALS AND METHODS: Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions. PMID- 27765742 TI - Reply. PMID- 27765743 TI - Regarding "Neurovascular Manifestations of Hereditary Hemorrhagic Telangiectasia: A Consecutive Series of 376 Patients during 15 Years". PMID- 27765744 TI - Ion channel mechanisms of rat tail artery contraction-relaxation by menthol involving, respectively, TRPM8 activation and L-type Ca2+ channel inhibition. AB - Transient receptor potential melastatin 8 (TRPM8) is the principal cold and menthol receptor channel. Characterized primarily for its cold-sensing role in sensory neurons, it is expressed and functional in several nonneuronal tissues, including vasculature. We previously demonstrated that menthol causes variable mechanical responses (vasoconstriction, vasodilatation, or biphasic reactions) in isolated arteries, depending on vascular tone. Here we aimed to dissect the specific ion channel mechanisms and corresponding Ca2+ signaling pathways underlying such complex responses to menthol and other TRPM8 ligands in rat tail artery myocytes using patch-clamp electrophysiology, confocal Ca2+ imaging, and ratiometric Ca2+ recording. Menthol (300 MUM, a concentration typically used to induce TRPM8 currents) strongly inhibited L-type Ca2+ channel current (L-ICa) in isolated myocytes, especially its sustained component, most relevant for depolarization-induced vasoconstriction. In contraction studies, with nifedipine present (10 MUM) to abolish L-ICa contribution to phenylephrine (PE)-induced vasoconstrictions of vascular rings, a marked increase in tone was observed with menthol, similar to resting (i.e., without alpha-adrenoceptor stimulation by PE) conditions, when L-type channels were mostly deactivated. Menthol-induced increases in PE-induced vasoconstrictions could be inhibited both by the TRPM8 antagonist AMTB (thus confirming the specific role of TRPM8) and by cyclopiazonic acid treatment to deplete Ca2+ stores, pointing to a major contribution of Ca2+ release from the sarcoplasmic reticulum in these contractile responses. Immunocytochemical analysis has indeed revealed colocalization of TRPM8 and InsP3 receptors. Moreover, menthol Ca2+ responses, which were somewhat reduced under Ca2+-free conditions, were strongly reduced by cyclopiazonic acid treatment to deplete Ca2+ store, whereas caffeine-induced Ca2+ responses were blunted in the presence of menthol. Finally, two other common TRPM8 agonists, WS-12 and icilin, also inhibited L-ICa With respect to L-ICa inhibition, WS-12 is the most selective agonist. It augmented PE-induced contractions, whereas any secondary phase of vasorelaxation (as with menthol) was completely lacking. Thus TRPM8 channels are functionally active in rat tail artery myocytes and play a distinct direct stimulatory role in control of vascular tone. However, indirect effects of TRPM8 agonists, which are unrelated to TRPM8, are mediated by inhibition of L type Ca2+ channels and largely obscure TRPM8-mediated vasoconstriction. These findings will promote our understanding of the vascular TRPM8 role, especially the well-known hypotensive effect of menthol, and may also have certain translational implications (e.g., in cardiovascular surgery, organ storage, transplantation, and Raynaud's phenomenon). PMID- 27765746 TI - Heart-lung interaction in a model of COPD: importance of lung volume and direct ventricular interaction. AB - Chronic obstructive pulmonary disease (COPD) is associated with dynamic lung hyperinflation (DH), increased pulmonary vascular resistance (PVR), and large increases in negative intrathoracic pressure (nITP). The individual and interactive effect of these stressors on left ventricular (LV) filling, emptying, and geometry and the role of direct ventricular interaction (DVI) in mediating these interactions have not been fully elucidated. Twenty healthy subjects were exposed to the following stressors alone and in combination: 1) inspiratory resistive loading of -20 cmH2O (nITP), 2) expiratory resistive loading to cause dynamic hyperinflation (DH), and 3) normobaric-hypoxia to increase PVR (hPVR). LV volumes and geometry were assessed using triplane echocardiography. LV stroke volume (LVSV) was reduced during nITP by 7 +/- 7% (mean +/- SD; P < 0.001) through a 4 +/- 5% reduction in LV end-diastolic volume (LVEDV) (P = 0.002), while DH reduced LVSV by 12 +/- 13% (P = 0.001) due to a 9 +/- 10% reduction in LVEDV (P < 0.001). The combination of nITP and DH (nITP+DH) caused larger reductions in LVSV (16 +/- 16%, P < 0.001) and LVEDV (12 +/- 10%, P < 0.001) than nITP alone (P < 0.05). The addition of hPVR to nITP+DH did not further reduce LV volumes. Significant septal flattening (indicating DVI) occurred in all conditions, with a significantly greater leftward septal shift occurring with nITP+DH than either condition alone (P < 0.05). In summary, the interaction of nITP and DH reduces LV filling through DVI. However, DH may be more detrimental to LV hemodynamics than nITP, likely due to mediastinal constraint of the heart amplifying DVI. PMID- 27765745 TI - Influence of menopause status and age on integrated central and peripheral hemodynamic responses to subsystolic cuffing during submaximal exercise. AB - Although pathophysiological links between postmenopause and healthy aging remain unclear, both factors are associated with increased blood pressure and sympathetic nerve activity (SNA) in women. Activation of polymodal musculoskeletal neural afferents originating within adventia of venules modulates SNA and blood pressure control during exercise in healthy adults. We hypothesized transient subsystolic regional circulatory occlusion (RCO) during exercise sensitizes these afferents leading to augmented systemic vascular resistance (SVR)-mediated increased mean arterial pressure (MAP) in postmenopause vs. premenopause. Normotensive women in premenopause or postmenopause (n = 14 and 14; ages: 30 +/- 9 and 55 +/- 7 yr, respectively; P < 0.01) performed: 1) peak exercise testing and 2) fixed-load cycling at 30% peak workload (48 +/- 11 and 38 +/- 6 W, respectively; P < 0.01), whereby the initial 3 min were control exercise without RCO (CTL), thereafter including 2 min of bilateral-thigh RCO to 20, 40, 60, 80, or 100 mmHg (randomized), with 2 min deflation between RCO. Both MAP (17 +/- 4 vs. 4 +/- 4%, P = 0.02) and SVR (16 +/- 8 vs. -3 +/- 8%, P = 0.04) increased at 80 mmHg from CTL in postmenopause vs. premenopause, respectively. However, cardiac index was similar in postmenopause vs. premenopause at 80 mmHg from CTL (1 +/- 6 vs. 7 +/- 6%, respectively; P = 0.15). There was no continuous effect of aging in MAP (P = 0.12), SVR (P = 0.07), or cardiac index (P = 0.18) models. These data suggest transient locomotor subsystolic RCO sensitizes musculoskeletal afferents, which provoke increased SVR to generate augmented MAP during exercise in postmenopause. These observations provide a novel approach for understanding the age-independent variability in exercise blood pressure control across the normotensive adult pre- to postmenopause spectrum. PMID- 27765748 TI - Limitations of skeletal muscle oxygen delivery and utilization during moderate intensity exercise in moderately impaired patients with chronic heart failure. AB - The extent and speed of transient skeletal muscle deoxygenation during exercise onset in patients with chronic heart failure (CHF) are related to impairments of local O2 delivery and utilization. This study examined the physiological background of submaximal exercise performance in 19 moderately impaired patients with CHF (Weber class A, B, and C) compared with 19 matched healthy control (HC) subjects by measuring skeletal muscle oxygenation (SmO2) changes during cycling exercise. All subjects performed two subsequent moderate-intensity 6-min exercise tests (bouts 1 and 2) with measurements of pulmonary oxygen uptake kinetics and SmO2 using near-infrared spatially resolved spectroscopy at the vastus lateralis for determination of absolute oxygenation values, amplitudes, kinetics (mean response time for onset), and deoxygenation overshoot characteristics. In CHF, deoxygenation kinetics were slower compared with HC (21.3 +/- 5.3 s vs. 16.7 +/- 4.4 s, P < 0.05, respectively). After priming exercise (i.e., during bout 2), deoxygenation kinetics were accelerated in CHF to values no longer different from HC (16.9 +/- 4.6 s vs. 15.4 +/- 4.2 s, P = 0.35). However, priming did not speed deoxygenation kinetics in CHF subjects with a deoxygenation overshoot, whereas it did reduce the incidence of the overshoot in this specific group (P < 0.05). These results provide evidence for heterogeneity with respect to limitations of O2 delivery and utilization during moderate-intensity exercise in patients with CHF, with slowed deoxygenation kinetics indicating a predominant O2 utilization impairment and the presence of a deoxygenation overshoot, with a reduction after priming in a subgroup, indicating an initial O2 delivery to utilization mismatch. PMID- 27765747 TI - Hydrogen sulfide-induced vasodilation mediated by endothelial TRPV4 channels. AB - Hydrogen sulfide (H2S) is a recently described gaseous vasodilator produced within the vasculature by the enzymes cystathionine gamma-lyase and 3 mercaptopyruvate sulfurtransferase. Previous data demonstrate that endothelial cells (EC) are the source of endogenous H2S production and are required for H2S induced dilation. However, the signal transduction pathway activated by H2S within EC has not been elucidated. TRPV4 and large-conductance Ca2+-activated K channels (BK channels) are expressed in EC. H2S-induced dilation is inhibited by luminal administration of iberiotoxin and disruption of the endothelium. Calcium influx through TRPV4 may activate these endothelial BK channels (eBK). We hypothesized that H2S-mediated vasodilation involves activation of TRPV4 within the endothelium. In pressurized, phenylephrine-constricted mesenteric arteries, H2S elicited a dose-dependent vasodilation blocked by inhibition of TRPV4 channels (GSK2193874A, 300 nM). H2S (1 MUM) increased TRPV4-dependent (1.8-fold) localized calcium events in EC of pressurized arteries loaded with fluo-4 and Oregon Green. In pressurized EC tubes, H2S (1 MUM) and the TRPV4 activator, GSK101679A (30 nM), increased calcium events 1.8- and 1.5-fold, respectively. H2S induced an iberiotoxin-sensitive outward current measured using whole cell patch clamp techniques in freshly dispersed EC. H2S increased K+ currents from 10 to 30 pA/pF at +150 mV. Treatment with Na2S increased the level of sulfhydration of TRPV4 channels in aortic ECs. These results demonstrate that H2S-mediated vasodilation involves activation of TRPV4-dependent Ca2+ influx and BK channel activation within EC. Activation of TRPV4 channels appears to cause calcium events that result in the opening of eBK channels, endothelial hyperpolarization, and subsequent vasodilation. PMID- 27765752 TI - Important Recall and Correction Notice. PMID- 27765751 TI - Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators. AB - Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-gamma-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension. PMID- 27765753 TI - Multiple-band melanonychia striata. PMID- 27765750 TI - Ebselen does not improve oxidative stress and vascular function in patients with diabetes: a randomized, crossover trial. AB - Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione peroxidase mimetic. A single-site, randomized, double masked, placebo-controlled, crossover trial was carried out in 26 patients with type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg po twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 wk duration, with a 4 wk washout between treatments. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced to oxidized glutathione. Vascular ultrasound of the brachial artery and plethysmographic measurement of blood flow were used to assess flow-mediated and methacholine induced endothelium-dependent vasodilation of conduit and resistance vessels, respectively. Ebselen administration did not affect parameters of oxidative stress or conduit artery or forearm arteriolar vascular function compared with placebo treatment. There was no difference in outcome by diabetes type. Ebselen, at the dose and duration evaluated, does not improve the oxidative stress profile, nor does it affect endothelium-dependent vasodilation in patients with diabetes mellitus. PMID- 27765749 TI - Spontaneous initiation of premature ventricular complexes and arrhythmias in type 2 long QT syndrome. AB - The occurrence of early afterdepolarizations (EADs) and increased dispersion of repolarization are two known factors for arrhythmogenesis in long QT syndrome. However, increased dispersion of repolarization tends to suppress EADs due to the source-sink effect, and thus how the two competing factors cause initiation of arrhythmias remains incompletely understood. Here we used optical mapping and computer simulation to investigate the mechanisms underlying spontaneous initiation of arrhythmias in type 2 long QT (LQT2) syndrome. In optical mapping experiments of transgenic LQT2 rabbit hearts under isoproterenol, premature ventricular complexes (PVCs) were observed to originate from the steep spatial repolarization gradient (RG) regions and propagated unidirectionally. The same PVC behaviors were demonstrated in computer simulations of tissue models of rabbits. Depending on the heterogeneities, these PVCs could lead to either repetitive focal excitations or reentry without requiring an additional vulnerable substrate. Systematic simulations showed that cellular phase 2 EADs were either suppressed or confined to the long action potential region due to the source-sink effect. Tissue-scale phase 3 EADs and PVCs occurred due to tissue scale dynamical instabilities caused by RG and enhanced L-type calcium current (ICa,L), occurring under both large and small RG. Presence of cellular EADs was not required but potentiated PVCs when RG was small. We also investigated how other factors affect the dynamical instabilities causing PVCs. Our main conclusion is that tissue-scale dynamical instabilities caused by RG and enhanced ICa,L give rise to both the trigger and the vulnerable substrate simultaneously for spontaneous initiation of arrhythmias in LQT2 syndrome. PMID- 27765754 TI - Fever in a child with cerebrospinal fluid access device or shunt: a pragmatic approach to management. AB - Children with shunts commonly present with fever, and often the focus of infection will be unrelated to their shunt. However, as shunt infections may present with few or even no specific symptoms, evaluation of a child with a shunt presenting with fever should be careful and comprehensive to ensure shunt infections are not missed. Treatment of an infected shunt involves removal of the shunt followed by a long course of antibiotics; missing or partially treating shunt infections can result in significant morbidity and potentially even mortality. Our experience of managing children with shunts presenting with fever is that many non-specialist clinicians have little experience in this area so initial management may not always be appropriate. Those children who are most at risk of shunt infection are those who within the preceding 8 weeks have had insertion, revision or access of their shunt or chemotherapy device, or have had abdominal surgery in the presence of a ventriculoperitoneal shunt. We have chosen 8 weeks as a pragmatic time point, as in our experience the vast majority of children who have had shunt infections have presented within this period. The caveat is that this should not be used as an absolute cut-off where there is strong suspicion of shunt infection or no clear focus at a later time point. PMID- 27765755 TI - Environment-dependent prey capture in the Atlantic mudskipper (Periophthalmus barbarus). AB - Few vertebrates capture prey in both the aquatic and the terrestrial environment due to the conflicting biophysical demands of feeding in water versus air. The Atlantic mudskipper (Periophthalmus barbarus) is known to be proficient at feeding in the terrestrial environment and feeds predominately in this environment. Given the considerable forward flow of water observed during the mouth-opening phase to assist with feeding on land, the mudskipper must alter the function of its feeding system to feed successfully in water. Here, we quantify the aquatic prey-capture kinematics of the mudskipper and compare this with the previously described pattern of terrestrial feeding. Prior to feeding in the aquatic environment, the gill slits open, allowing water to be expelled through the gill slits. The opposite happens in terrestrial feeding during which the gill slits remain closed at this point. In water, the expansive movements of the head are larger, amounting to a larger volume increase and are initiated slightly later than in the terrestrial environment. This implies the generation of strong suction flows when feeding in water. Consequently, the kinematic patterns of the hydrodynamic tongue during terrestrial feeding and aquatic suction feeding are similar, except for the amplitude of the volume increase and the active closing of the gill slits early during the terrestrial feeding strike. The mudskipper thus exhibits the capacity to change the kinematics of its feeding apparatus to enable successful prey capture in two disparate environments. PMID- 27765758 TI - Arterial hypertension as an uninvited player in hepatic stiffness? PMID- 27765756 TI - Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study. AB - BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD 1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071. PMID- 27765757 TI - Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. AB - BACKGROUND: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). PATIENTS AND METHODS: Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided alpha = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken. RESULTS: Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade >=3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS. CONCLUSION: The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. CLINICALTRIALSGOV IDENTIFIER: NCT01246960. PMID- 27765759 TI - Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy. AB - There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters. In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with reductions in levels of alanine aminotransferase and Pro-C3, as well as improved insulin sensitivity and lipid profile. Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis, and it can potentially identify patients most likely to benefit from antimetabolic and antifibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up antifibrotic drug development and validation. PMID- 27765760 TI - Advanced spatiotemporal mapping methods give new insights into the coordination of contractile activity in the stomach of the rat. AB - We used spatiotemporal mapping of strain rate to determine the direction of propagation and amplitudes of the longitudinal and circumferential components of antrocorporal (AC) contractions and fundal contractions in the rat stomach maintained ex vivo and containing a volume of fluid that was within its normal functional capacity. In the region of the greater curvature the longitudinal and circular components of AC contractions propagated synchronously at right angles to the arciform geometric axis of the stomach. However, the configuration of AC contractions was U shaped, neither the circular nor the longitudinal component of contractions being evident in the upper proximal corpus. Similarly, in the distal upper antrum of some preparations, circumferential components propagated more rapidly than longitudinal components. Ongoing "high-frequency, low-amplitude myogenic contractions" were identified in the upper proximal gastric corpus and on the anterior and posterior wall of the fundus. The amplitudes of these contractions were modulated in the occluded stomach by low-frequency pressure waves that occurred spontaneously. Hence the characteristics of phasic contractions vary regionally in the antrum and corpus and a previously undescribed high-frequency contractile component was identified in the proximal corpus and fundus, the latter being modulated in synchrony with cyclic variation in intrafundal pressure in the occluded fundus. PMID- 27765762 TI - MicroRNA-29c regulates apoptosis sensitivity via modulation of the cell-surface death receptor, Fas, in lung fibroblasts. AB - MicroRNAs play an important role in the development and progression of various diseases, such as idiopathic pulmonary fibrosis (IPF). Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in IPF lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in IPF lungs and is also known as a regulator of extracellular matrix (ECM), in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex leading to extrinsic apoptosis. The representative profibrotic transforming growth factor (TGF)-beta downregulated the expression of miR-29c as well as Fas receptor and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-beta-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in IPF lungs may be associated with the apoptosis-resistant phenotype of IPF lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in IPF lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of IPF. PMID- 27765761 TI - Nur77 attenuates endothelin-1 expression via downregulation of NF-kappaB and p38 MAPK in A549 cells and in an ARDS rat model. AB - Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF kappaB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-kappaB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-kappaB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats. PMID- 27765763 TI - Rac1 modulates mammalian lung branching morphogenesis in part through canonical Wnt signaling. AB - Lung branching morphogenesis relies on a number of factors, including proper epithelial cell proliferation and differentiation, cell polarity, and migration. Rac1, a small Rho GTPase, orchestrates a number of these cellular processes, including cell proliferation and differentiation, cellular alignment, and polarization. Furthermore, Rac1 modulates both noncanonical and canonical Wnt signaling, important pathways in lung branching morphogenesis. Culture of embryonic mouse lung explants in the presence of the Rac1 inhibitor (NSC23766) resulted in a dose-dependent decrease in branching. Increased cell death and BrdU uptake were notably seen in the mesenchyme, while no direct effect on the epithelium was observed. Moreover, vasculogenesis was impaired following Rac1 inhibition as shown by decreased Vegfa expression and impaired LacZ staining in Flk1-Lacz reporter mice. Rac1 inhibition decreased Fgf10 expression in conjunction with many of its associated factors. Moreover, using the reporter lines TOPGAL and Axin2-LacZ, there was an evident decrease in canonical Wnt signaling in the explants treated with the Rac1 inhibitor. Activation of canonical Wnt pathway using WNT3a or WNT7b only partially rescued the branching inhibition. Moreover, these results were validated on human explants, where Rac1 inhibition resulted in impaired branching and decreased AXIN2 and FGFR2b expression. We therefore conclude that Rac1 regulates lung branching morphogenesis, in part through canonical Wnt signaling. However, the exact mechanisms by which Rac1 interacts with canonical Wnt in human and mouse lung requires further investigation. PMID- 27765765 TI - Circulating Ceramides Predict Cardiovascular Outcomes in the Population-Based FINRISK 2002 Cohort. AB - OBJECTIVE: Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals. APPROACH AND RESULTS: FINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatography-tandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21-1.41), which remained significant at 1.21 (95% confidence interval, 1.11-1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% (P=6.9*10-5) for Cer(d18:1/18:0). CONCLUSIONS: Distinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk. PMID- 27765764 TI - Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. AB - OBJECTIVE: Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic. APPROACH AND RESULTS: We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL). CONCLUSIONS: In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores. PMID- 27765766 TI - TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcgammaRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice. AB - OBJECTIVE: The objective of this study is to investigate the role of T-cell ubiquitin ligand-2 (TULA-2) in the platelet Fc receptor for IgG IIA (FcgammaRIIA) pathway and in the pathogenesis of heparin-induced thrombocytopenia (HIT). APPROACH AND RESULTS: HIT is a life-threatening thrombotic disease in which IgG antibodies against the heparin-platelet factor 4 complex activate platelets via FcgammaRIIA. We reported previously differential expression of TULA-2 in human population was linked to FcgammaRIIA responsiveness. In this study, we investigated the role of TULA-2, a protein phosphatase, in the FcgammaRIIA pathway and HIT pathogenesis by crossing TULA-2-/- mice with transgenic FcgammaRIIA +/+ mice. Ablation of TULA-2 resulted in hyperphosphorylation of spleen tyrosine kinase, linker for the activation of T cells, and phospholipase Cgamma2 in platelets via FcgammaRIIA activation. Platelet integrin activation, granule secretion, phosphatidylserine exposure, and aggregation were also enhanced in TULA-2-/- murine platelets. Compared with wild-type mice, TULA-2-/- mice showed aggravated antibody-mediated thrombocytopenia, augmented thrombin generation, and shortened tail bleeding time. In contrast, there was no significant difference between TULA-2-/- and TULA-2+/+ platelets in platelet spreading and clot retraction. Of note, heterozygous TULA-2+/- mice, whose platelets contained 50% as much protein as the TULA-2+/+ platelets, showed significantly increased platelet reactivity and more severe thrombocytopenia in vivo compared with TULA-2+/+ mice. CONCLUSIONS: Together, the data demonstrate that not only the absence of TULA-2 but also the relative level of TULA-2 expression modulates FcgammaRIIA-mediated platelet reactivity and HIT in vivo. TULA-2 expression could be a valuable marker for HIT and inhibiting TULA-2 may serve as a potential therapy to reverse the bleeding adverse effect of anticoagulants. PMID- 27765767 TI - UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses. AB - OBJECTIVE: UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. APPROACH AND RESULTS: Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4+ forkhead box P3+ regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB dependent induction of CD4+ forkhead box P3+ regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. CONCLUSIONS: Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis. PMID- 27765768 TI - Monocyte Conversion During Inflammation and Injury. AB - Monocytes are circulating leukocytes important in both innate and adaptive immunity, primarily functioning in immune defense, inflammation, and tissue remodeling. There are 2 subsets of monocytes in mice (3 subsets in humans) that are mobilized from the bone marrow and recruited to sites of inflammation, where they carry out their respective functions in promoting inflammation or facilitating tissue repair. Our understanding of the fate of these monocyte subsets at the site of inflammation is constantly evolving. This brief review highlights the plasticity of monocyte subsets and their conversion during inflammation and injury. PMID- 27765770 TI - Pim-1L Protects Cell Surface-Resident ABCA1 From Lysosomal Degradation in Hepatocytes and Thereby Regulates Plasma High-Density Lipoprotein Level. AB - OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) exerts an atheroprotective action through the biogenesis of high-density lipoprotein in hepatocytes and prevents the formation of foam cells from macrophages. Controlling ABCA1 is a rational approach to improving atherosclerotic cardiovascular disease. Although much is known about the regulatory mechanism of ABCA1 synthesis, the molecular mechanism underpinning its degradation remains to be clearly described. APPROACH AND RESULTS: ABCA1 possesses potential sites of phosphorylation by serine/threonine-protein kinase Pim-1 (Pim-1). Pim-1 depletion decreased the expression of cell surface-resident ABCA1 (csABCA1) and apolipoprotein A-I mediated [3H]cholesterol efflux in the human hepatoma cell line HepG2, but not in peritoneal macrophages from mice. In vitro kinase assay, immunoprecipitation, and immunocytochemistry suggested phosphorylation of csABCA1 by the long form of Pim 1 (Pim-1L). Cell surface biotinylation indicated that Pim-1L inhibited lysosomal degradation of csABCA1 involving the liver X receptor beta, which interacts with csABCA1 and thereby protects it from ubiquitination and subsequent lysosomal degradation. Cell surface coimmunoprecipitation with COS-1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that Pim-1L-mediated phosphorylation of csABCA1 facilitated the interaction between csABCA1 and liver X receptor beta and thereby stabilized the csABCA1-Pim-1L complex. Mice deficient in Pim-1 kinase activity showed lower expression of ABCA1 in liver plasma membranes and lower plasma high-density lipoprotein levels than control mice. CONCLUSIONS: Pim-1L protects hepatic csABCA1 from lysosomal degradation by facilitating the physical interaction between csABCA1 and liver X receptor beta and subsequent stabilization of the csABCA1-Pim-1L complex and thereby regulates the circulating level of high-density lipoprotein. Our findings may aid the development of high-density lipoprotein-targeted therapy. PMID- 27765771 TI - Estimating the Population Impact of Lp(a) Lowering on the Incidence of Myocardial Infarction and Aortic Stenosis-Brief Report. AB - OBJECTIVE: High lipoprotein(a) (Lp[a]) is the most common genetic dyslipidemia and is a causal factor for myocardial infarction (MI) and aortic stenosis (AS). We sought to estimate the population impact of Lp(a) lowering that could be achieved in primary prevention using the therapies in development. APPROACH AND RESULTS: We used published data from 2 prospective cohorts. High Lp(a) was defined as >=50 mg/dL (~20th percentile). Relative risk, attributable risk, the attributable risk percentage, population attributable risk, and the population attributable risk percentage were calculated as measures of the population impact. For MI, the event rate was 4.0% versus 2.8% for high versus low Lp(a) (relative risk, 1.46; 95% confidence interval [CI], 1.45-1.46). The attributable risk was 1.26% (95% CI, 1.24-1.27), corresponding to 31.3% (95% CI, 31.0-31.7) of the excess MI risk in those with high Lp(a). The population attributable risk was 0.21%, representing a population attributable risk percentage of 7.13%. For AS, the event rate was 1.51% versus 0.78% for high versus low Lp(a) (relative risk, 1.95; 95% CI, 1.94-1.97). The attributable risk was 0.74% (95% CI, 0.73-0.75), corresponding to 48.8% (95% CI, 48.3-49.3) of the excess AS risk in those with high Lp(a). The population attributable risk was 0.13%, representing a population attributable risk percentage of 13.9%. In sensitivity analyses targeting the top 10% of Lp(a), the population attributable risk percentage was 5.2% for MI and 7.8% for AS. CONCLUSIONS: Lp(a) lowering among the top 20% of the population distribution for Lp(a) could prevent 1 in 14 cases of MI and 1 in 7 cases of AS, suggesting a major impact on reducing the burden of cardiovascular disease. Targeting the top 10% could prevent 1 in 20 MI cases and 1 in 12 AS cases. PMID- 27765769 TI - Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase: Influence of Exercise Training. AB - OBJECTIVE: The objectives of this study were to determine the impact of in vivo reactive oxygen species (ROS) on microvascular endothelial function in obese human subjects and the efficacy of an aerobic exercise intervention on alleviating obesity-associated dysfunctionality. APPROACH AND RESULTS: Young, sedentary men and women were divided into lean (body mass index 18-25; n=14), intermediate (body mass index 28-32.5; n=13), and obese (body mass index 33-40; n=15) groups. A novel microdialysis technique was utilized to detect elevated interstitial hydrogen peroxide (H2O2) and superoxide levels in the vastus lateralis of obese compared with both lean and intermediate subjects. Nutritive blood flow was monitored in the vastus lateralis via the microdialysis-ethanol technique. A decrement in acetylcholine-stimulated blood flow revealed impaired microvascular endothelial function in the obese subjects. Perfusion of apocynin, an NADPH oxidase inhibitor, lowered (normalized) H2O2 and superoxide levels, and reversed microvascular endothelial dysfunction in obese subjects. After 8 weeks of exercise, H2O2 levels were decreased in the obese subjects and microvascular endothelial function in these subjects was restored to levels similar to lean subjects. Skeletal muscle protein expression of the NADPH oxidase subunits p22phox, p47phox, and p67phox was increased in obese relative to lean subjects, where p22phox and p67phox expression was attenuated by exercise training in obese subjects. CONCLUSIONS: This study implicates NADPH oxidase as a source of excessive ROS production in skeletal muscle of obese individuals and links excessive NADPH oxidase-derived ROS to microvascular endothelial dysfunction in obesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these maladies. PMID- 27765773 TI - Comparing young people's experience of technology-delivered v. face-to-face mindfulness and relaxation: two-armed qualitative focus group study. AB - BackgroundThe current popularity of mindfulness-based practices has coincided with the increase in access to mobile technology. This has led to many mindfulness apps and programs becoming available, some specifically for children. However, little is known about the experience of engaging with mindfulness through these mediums.AimsTo explore children's experience of mindfulness delivered both face-to-face and through a computer game to highlight any differences or similarities.MethodA two-armed qualitative focus groups design was used to explore children's experiences. The first arm offered mindfulness exercises in a traditional face-to-face setting with guided meditations. The second arm offered mindfulness exercises through a computer game avatar.ResultsThemes of relaxation, engagement, awareness, thinking, practice and directing attention emerged from both arms of focus groups. Subthematic codes highlight key differences as well as similarities in the experience of mindfulness.ConclusionsThese results indicate that mindfulness delivered via technology can offer a rich experience. PMID- 27765772 TI - Heritable temperament pathways to early callous-unemotional behaviour. AB - BACKGROUND: Early callous-unemotional behaviours identify children at risk for antisocial behaviour. Recent work suggests that the high heritability of callous unemotional behaviours is qualified by interactions with positive parenting. AIMS: To examine whether heritable temperament dimensions of fearlessness and low affiliative behaviour are associated with early callous-unemotional behaviours and whether parenting moderates these associations. METHOD: Using an adoption sample (n = 561), we examined pathways from biological mother self-reported fearlessness and affiliative behaviour to child callous-unemotional behaviours via observed child fearlessness and affiliative behaviour, and whether adoptive parent observed positive parenting moderated pathways. RESULTS: Biological mother fearlessness predicted child callous-unemotional behaviours via earlier child fearlessness. Biological mother low affiliative behaviour predicted child callous unemotional behaviours, although not via child affiliative behaviours. Adoptive mother positive parenting moderated the fearlessness to callous-unemotional behaviour pathway. CONCLUSIONS: Heritable fearlessness and low interpersonal affiliation traits contribute to the development of callous-unemotional behaviours. Positive parenting can buffer these risky pathways. PMID- 27765774 TI - Extremism, religion and psychiatric morbidity in a population-based sample of young men. AB - BACKGROUND: There is growing risk from terrorism following radicalisation of young men. It is unclear whether psychopathology is associated. AIMS: To investigate the population distribution of extremist views among UK men. METHOD: Cross-sectional study of 3679 men, 18-34 years, in Great Britain. Multivariate analyses of attitudes, psychiatric morbidity, ethnicity and religion. RESULTS: Pro-British men were more likely to be White, UK born, not religious; anti British were Muslim, religious, of Pakistani origin, from deprived areas. Pro- and anti-British views were linearly associated with violence (adjusted odds ratio (OR) = 1.51, 95% CI 1.38-1.64, P<0.001, adjusted OR = 1.33, 95% CI 1.13 1.58, P<0.001, respectively) and negatively with depression (adjusted OR = 0.72, 95% CI 0.61-0.85, P<0.001, adjusted OR = 0.64, 95% CI 0.48-0.86, P = 0.003, respectively). CONCLUSIONS: Men at risk of depression may experience protection from strong cultural or religious identity. Antisocial behaviour increases with extremism. Religion is protective but may determine targets of violence following radicalisation. PMID- 27765776 TI - Geographic variation in resistance to nectar robbing and consequences for pollination. AB - PREMISE OF THE STUDY: Floral evolution is frequently ascribed to selection by pollinators, but may also be shaped by antagonists. However, remarkably few studies have examined geographic mosaics in resistance to floral antagonists or the consequences for other floral interactions. METHODS: Gelsemium sempervirens experiences frequent nectar robbing in northern Georgia, but rarely in southern Georgia. We conducted common-garden experiments in both locations using genotypes from each region and measured robbing, pollinator attraction, floral attractive and defensive traits, and plant reproduction. KEY RESULTS: Nectar robbing was more than four times higher in the north vs. south, and pollinator visits did not differ between gardens. Across both gardens, northern genotypes were half as likely to be nectar-robbed but received half as many pollinator visits as southern genotypes, suggesting evolution of resistance to robbing at a cost of reduced pollinator attraction. Plant-level traits, such as height and number of flowers, were more closely associated with resistance to robbing than floral size, shape, or chemistry. Northern genotypes had lower female and estimated male reproduction compared to southern genotypes at both locations, which could be due to costs of resistance to nectar robbing, or costs of adaptations to other biotic or abiotic differences between regions. CONCLUSIONS: Our study indicates that geographic variation can play a strong role structuring interactions with floral antagonists and mutualists and provides evidence consistent with the hypothesis that local resistance to nectar robbing imposes costs in terms of decreased pollinator attraction and reproduction. PMID- 27765777 TI - Prezygotic resource-allocation dynamics and reproductive trade-offs in Calymperaceae (Bryophyta). AB - PREMISE OF THE STUDY: Resource allocation is difficult to characterize in plants because of the challenges of quantifying gametes and propagules. We surveyed six sympatric, unisexual species in the family Calymperaceae (Bryophyta) to test for trade-offs in prezygotic sexual and asexual expression and density-dependent survivorship of female gametangia. METHODS: We tallied gametangial and asexual propagule output for 1820 shoots from 17 populations of six species at monthly intervals during one year (2010-2011) in a central Amazonian forest. Generalized linear mixed models were used to test for trade-offs in sexual and asexual expression and density-dependent senescence probability of gametangia. Precipitation and microsite variables were also included in the model. KEY RESULTS: For all species, sexual and asexual expression were positively correlated with mean monthly precipitation. Asexually expressing shoots produced significantly fewer gametangia than nonexpressing ones, and the probability of senescence increased with shoot density. Archegonium density per shoot was also consistently lower than the modeled optimum to maximize the number of receptive archegonia. CONCLUSIONS: Trade-offs among reproductive strategies and positive density-dependent senescence of female gametangia suggest that prezygotic sexual and asexual expression come at a tangible investment. However, the apparently inefficient resource-allocation dynamics in the production of female gametangia makes the possible advantages of squandering such investments unclear. One possibility is that the study populations, like those of many dioicous mosses, are skewed toward expressing females with low sporophyte production, which would suggest that asexual reproduction predominates and upstages efficient resource allocation in prezygotic investment. PMID- 27765779 TI - Twin problems of climate change and air pollution. PMID- 27765775 TI - Diversification and coevolution in brood pollination mutualisms: Windows into the role of biotic interactions in generating biological diversity. AB - Brood pollination mutualisms-interactions in which specialized insects are both the pollinators (as adults) and seed predators (as larvae) of their host plants have been influential study systems for coevolutionary biology. These mutualisms include those between figs and fig wasps, yuccas and yucca moths, leafflowers and leafflower moths, globeflowers and globeflower flies, Silene plants and Hadena and Perizoma moths, saxifrages and Greya moths, and senita cacti and senita moths. The high reciprocal diversity and species-specificity of some of these mutualisms have been cited as evidence that coevolution between plants and pollinators drives their mutual diversification. However, the mechanisms by which these mutualisms diversify have received less attention. In this paper, we review key hypotheses about how these mutualisms diversify and what role coevolution between plants and pollinators may play in this process. We find that most species-rich brood pollination mutualisms show significant phylogenetic congruence at high taxonomic scales, but there is limited evidence for the processes of both cospeciation and duplication, and there are no unambiguous examples known of strict-sense contemporaneous cospeciation. Allopatric speciation appears important across multiple systems, particularly in the insects. Host-shifts appear to be common, and widespread host-shifts by pollinators may displace other pollinator lineages. There is relatively little evidence for a "coevolution through cospeciation" model or that coevolution promotes speciation in these systems. Although we have made great progress in understanding the mechanisms by which brood pollination mutualisms diversify, many opportunities remain to use these intriguing symbioses to understand the role of biotic interactions in generating biological diversity. PMID- 27765780 TI - Taskforce to help integrate health and social care is scrapped. PMID- 27765781 TI - Birth complications are more common within two years of bariatric surgery, study finds. PMID- 27765782 TI - Sixty seconds on . . . symptom checkers. PMID- 27765783 TI - Australia backs down over jail terms for doctors who speak out about abuse of asylum seekers. PMID- 27765784 TI - Study casts more doubt on weekend effect. PMID- 27765785 TI - GP is struck off for a string of hurried and wrong diagnoses. PMID- 27765787 TI - NICE calls for wider use of blood tests to diagnose coeliac disease. PMID- 27765786 TI - Psychophysical Evaluation of Sweetness Functions Across Multiple Sweeteners. AB - Sweetness is one of the 5 prototypical tastes and is activated by sugars and non nutritive sweeteners (NNS). The aim of this study was to investigate measures of sweet taste function [detection threshold (DT), recognition threshold (RT), and suprathreshold intensity ratings] across multiple sweeteners. Sixty participants, 18-52 years of age (mean age in years = 26, SD = +/-7.8), were recruited to participate in the study. DT and RT were collected for caloric sweeteners (glucose, fructose, sucrose, erythritol) and NNS (sucralose, rebaudioside A). Sweetness intensity for all sweeteners was measured using a general Labeled Magnitude Scale. There were strong correlations between DT and RT of all 4 caloric sweeteners across people (r = 0.62-0.90, P < 0.001), and moderate correlations between DT and RT for both of the NNS (r = 0.39-0.48, P < 0.05); however, weaker correlations were observed between the DT or RT of the caloric sweeteners and NNS (r = 0.26-0.48, P < 0.05). The DT and RT of glucose and fructose were not correlated with DT or RT of sucralose (P > 0.05). In contrast, there were strong correlations between the sweetness intensity ratings of all sweeteners (r = 0.70-0.96, P < 0.001). This suggests those caloric sweeteners and NNS access at least partially independent mechanisms with respect to DT and RT measures. At suprathreshold level, however, the strong correlation between caloric sweeteners and NNS through weak, moderate, and strong intensity indicates a commonality in sweet taste mechanism for the perceived intensity range. PMID- 27765788 TI - Assessing flow limitation in patients with stable coronary artery disease. PMID- 27765789 TI - Commissioning groups' performance on cancer care in England. PMID- 27765790 TI - A view to a plan? PMID- 27765791 TI - Nearly 300 general practices to get premises and IT upgrades. PMID- 27765792 TI - Driving and dementia: a clinical update for mental health professionals. AB - Most people with mild dementia can continue to drive, but dementia is progressive and many patients and clinicians will be faced with questions about driving safety in the course of their illness. Determining when this happens is a complex decision, with risks of personal and public safety needing to be weighed against individual patient benefits of driving in terms of autonomy, independence and well-being. Decisions need to make reference to cognitive abilities, as well as other factors including physical comorbidity, vision, mobility, insight and history of driving errors and accidents. Deciding to stop driving, or being required to stop driving is often difficult for patients to accept and can be a particularly problematic consequence of a dementia diagnosis. Legal frameworks help in decision-making but may not provide sufficient detail to advise individual patients. We review the current guidelines and evidence relating to driving and dementia to help clinicians answer questions about driving safety and to consider the full range of assessment tools available. PMID- 27765793 TI - A Precision Medicine Approach to the Rescue of Function on Malignant Calmodulinopathic Long-QT Syndrome. AB - RATIONALE: Calmodulinopathies comprise a new category of potentially life threatening genetic arrhythmia syndromes capable of producing severe long-QT syndrome (LQTS) with mutations involving CALM1, CALM2, or CALM3. The underlying basis of this form of LQTS is a disruption of Ca2+/calmodulin (CaM)-dependent inactivation of L-type Ca2+ channels. OBJECTIVE: To gain insight into the mechanistic underpinnings of calmodulinopathies and devise new therapeutic strategies for the treatment of this form of LQTS. METHODS AND RESULTS: We generated and characterized the functional properties of induced pluripotent stem cell-derived cardiomyocytes from a patient with D130G-CALM2-mediated LQTS, thus creating a platform with which to devise and test novel therapeutic strategies. The patient-derived induced pluripotent stem cell-derived cardiomyocytes display (1) significantly prolonged action potentials, (2) disrupted Ca2+ cycling properties, and (3) diminished Ca2+/CaM-dependent inactivation of L-type Ca2+ channels. Next, taking advantage of the fact that calmodulinopathy patients harbor a mutation in only 1 of 6 redundant CaM-encoding alleles, we devised a strategy using CRISPR interference to selectively suppress the mutant gene while sparing the wild-type counterparts. Indeed, suppression of CALM2 expression produced a functional rescue in induced pluripotent stem cell-derived cardiomyocytes with D130G-CALM2, as shown by the normalization of action potential duration and Ca2+/CaM-dependent inactivation after treatment. Moreover, CRISPR interference can be designed to achieve selective knockdown of any of the 3 CALM genes, making it a generalizable therapeutic strategy for any calmodulinopathy. CONCLUSIONS: Overall, this therapeutic strategy holds great promise for calmodulinopathy patients as it represents a generalizable intervention capable of specifically altering CaM expression and potentially attenuating LQTS-triggered cardiac events, thus initiating a path toward precision medicine. PMID- 27765794 TI - Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo. AB - BACKGROUND: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. METHODS: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. RESULTS: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. CONCLUSIONS: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases. PMID- 27765795 TI - Disseminated infections with antibiotic-resistant non-typhoidal Salmonella strains: contributions of host and pathogen factors. AB - Non-typhoidal Salmonella enterica serovars (NTS) are generally associated with gastroenteritis; however, the very young and elderly, as well as individuals with compromised immunity, are at risk of developing disseminated infection that can manifest as bacteremia or focal infections at systemic sites. Disseminated NTS infections can be fatal and are responsible for over 600 000 deaths annually. Most of these deaths are in sub-Saharan Africa, where multidrug-resistant NTS clones are currently circulating in a population with a high proportion of individuals that are susceptible to disseminated disease. This review considers how genome degradation observed in African NTS isolates has resulted in phenotypic differences in traits related to environmental persistence and host pathogen interactions. Further, it discusses host mechanisms promoting susceptibility to invasive infection with NTS in individuals with immunocompromising conditions. We conclude that mechanistic knowledge of how risk factors compromise immunity to disseminated NTS infection will be important for the design of interventions to protect against systemic disease. PMID- 27765796 TI - Early Life Residence, Fish Consumption, and Risk of Breast Cancer. AB - Background: Little is known about fish intake throughout the life course and the risk of breast cancer.Methods: We used data on the first residence of 9,340 women born 1908 to 1935 in the Reykjavik Study as well as food frequency data for different periods of life from a subgroup of the cohort entering the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (n = 2,882).Results: During a mean follow-up of 27.3 years, 744 women were diagnosed with breast cancer in the Reykjavik Study. An inverse association of breast cancer was observed among women who lived through the puberty period in coastal villages, compared with women residing in the capital area [HR, 0.78; 95% confidence interval (CI), 0.61-0.99]. In the subgroup analysis of this Icelandic population, generally characterized by high fish intake, we found an indication of lower risk of breast cancer among women with high fish consumption (more than 4 portions per week) in adolescence (HR, 0.71; 95% CI, 0.44-1.13) and midlife (HR, 0.46; 95% CI, 0.22-0.97), compared with low consumers (2 portions per week or less). No association was found for fish liver oil consumption in any time period, which could be due to lack of a reference group with low omega-3 fatty acids intake in the study group.Conclusions: Our findings suggest that very high fish consumption in early to midlife may be associated with a reduced risk of breast cancer.Impact: Very high fish consumption in early adulthood to midlife may be associated with decreased risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 26(3); 346-54. (c)2016 AACR. PMID- 27765797 TI - Exploring Differences in the Aspirin-Colorectal Cancer Association by Sex and Race/Ethnicity: The Multiethnic Cohort Study. AB - BACKGROUND: Evidence has accumulated that long-term use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protects against colorectal cancer. We tested whether the inverse associations between NSAIDs and colorectal cancer is similarly observed across sexes and five racial/ethnic groups (Japanese, Latino, African American, Native Hawaiian, and white) in the Multiethnic Cohort (MEC) Study. METHODS: During a mean follow-up of 16.1 years, we identified 4,882 invasive incident colorectal cancer cases among 183,199 eligible participants. Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI). RESULTS: Use of aspirin and other NSAIDs was associated with a lower incidence of colorectal cancer in men (HR = 0.77; 95% CI, 0.69-0.86 for current vs. never users of aspirin) but not in women (Pinteraction = 0.005). Among male current users, a reduced risk was observed with >=6 years of aspirin or total NSAID use. The inverse association with current NSAID use in men was observed in all racial/ethnic groups, except for Native Hawaiians, and was stronger in whites. CONCLUSIONS: Our findings suggest that the benefit of NSAIDs for colorectal cancer may be strongest for white men and generalizes to African American, Japanese, and Latino, but not to Native Hawaiian men. The lack of inverse association observed in women and Native Hawaiian men in the MEC should be interpreted with caution. IMPACT: As only very few ethnic/racial groups are likely to be represented in trials of NSAIDs and colorectal cancer, it is important to conduct prospective observational studies in various populations to test the generalizability of their results. Cancer Epidemiol Biomarkers Prev; 26(2); 162-9. (c)2016 AACR. PMID- 27765798 TI - Environmental Tobacco Smoke Exposure and Survival Following Breast Cancer. AB - BACKGROUND: Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association. METHODS: A population-based cohort of women (N = 1,508) diagnosed with first primary invasive or in situ breast cancer in 1996 to 1997 was interviewed shortly after diagnosis and again approximately 5 years later to assess ETS exposure, and women were followed for more than 18 years using the National Death Index; 597 deaths (237 associated with breast cancer) were identified. Multivariable Cox regression was used to estimate adjusted HRs and 95% confidence intervals (CI) for mortality among women with breast cancer as related to at-diagnosis and at-/postdiagnosis changes in ETS exposure. RESULTS: There was little or no association between at-diagnosis ETS exposure and all cause (HR = 1.04; 95% CI, 0.78-1.40) or breast cancer-specific (HR = 0.98; 95% CI, 0.63-1.52) mortality. Mortality was elevated among women who reported cessation in postdiagnosis ETS exposure up to 1 year before the follow-up assessment, for all-cause (HR = 1.81; 95% CI, 0.87-3.74) and breast cancer mortality (HR = 1.89; 95% CI, 0.68-5.24); however, estimates were imprecise. CONCLUSIONS: We found little evidence of an association between at-diagnosis ETS exposure and mortality after breast cancer. Postdiagnosis cessation of ETS exposure was positively associated with mortality, although we could not rule out chance and reverse causation as possible explanations. IMPACT: Exposure to ETS does not appear to influence mortality after breast cancer. Cancer Epidemiol Biomarkers Prev; 26(2); 278-80. (c)2016 AACR. PMID- 27765799 TI - ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy. AB - Approximately 15-20% of breast cancers (BC) show either membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbBs family of receptor tyrosine kinases, or ERBB2 gene amplification. Until the development of MErbB-2-targeted therapies, this BC subtype, called ErbB-2-positive, was associated with increased metastatic potential and poor prognosis. Although these therapies have significantly improved overall survival and cure rates, resistance to available drugs is still a major clinical issue. In its classical mechanism, MErbB-2 activates downstream signaling cascades, which transduce its effects in BC. The fact that ErbB-2 is also present in the nucleus of BC cells was discovered over twenty years ago. Also, compelling evidence revealed a non-canonical function of nuclear ErbB-2 as a transcriptional regulator. As a deeper understanding of nuclear ErbB-2 actions would be crucial to the disclosure of its role as a biomarker and a target of therapy in BC, we will here review its function in BC, in particular, its role in growth, metastatic spreading and response to currently available MErbB-2-positive BC therapies. PMID- 27765801 TI - Targeting PP2A to overcome enzalutamide resistance in AR+ breast tumors. PMID- 27765800 TI - Sex-Specific Associations between One-Carbon Metabolism Indices and Posttranslational Histone Modifications in Arsenic-Exposed Bangladeshi Adults. AB - BACKGROUND: Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation. METHODS: We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMC) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults. Sex specific associations between several blood OCM indices (folate, vitamin B12, choline, betaine, homocysteine) and PTHMs were examined at baseline using regression models, adjusted for multiple tests by controlling for the false discovery rate (PFDR). We also evaluated the effects of folic acid supplementation (400 MUg/d for 12 weeks), compared with placebo, on PTHMs. RESULTS: Associations between choline and H3K36me2 and between vitamin B12 and H3K79me2 differed significantly by sex (Pdiff < 0.01 and <0.05, respectively). Among men, plasma choline was positively associated with H3K36me2 (PFDR < 0.05), and among women, plasma vitamin B12 was positively associated with H3K79me2 (PFDR < 0.01). Folic acid supplementation did not alter any of the PTHMs examined (PFDR = 0.80). CONCLUSIONS: OCM indices may influence PTHMs in a sex-dependent manner, and folic acid supplementation, at this dose and duration, does not alter PTHMs in PBMCs. IMPACT: This is the first study to examine the influences of OCM indices on PTHMs in a population that may have increased susceptibility to cancer development due to widespread exposure to arsenic-contaminated drinking water and a high prevalence of hyperhomocysteinemia. Cancer Epidemiol Biomarkers Prev; 26(2); 261-9. (c)2016 AACR. PMID- 27765803 TI - Catheter-Based Therapy for Inoperable Chronic Thromboembolic Pulmonary Hypertension. PMID- 27765802 TI - Procedural and Long-Term Outcomes of Bioresorbable Scaffolds Versus Drug-Eluting Stents in Chronic Total Occlusions: The BONITO Registry (Bioresorbable Scaffolds Versus Drug-Eluting Stents in Chronic Total Occlusions). AB - BACKGROUND: There is little evidence regarding the efficacy and safety of bioresorbable scaffolds (BRS) for the percutaneous treatment of chronic total occlusions. METHODS AND RESULTS: We performed a multicenter registry of consecutive chronic total occlusion patients treated with BRS (Absorb; Abbott Vascular) and second-generation drug-eluting stents (DES) at 5 institutions. Long term target-vessel failure (a composite of cardiac death, target-vessel myocardial infarction, and ischemia-driven target-lesion revascularization) was the primary end point. Inverse probability of treatment weight-adjusted Cox regression was used to account for pretreatment differences between the 2 groups. A total of 537 patients (n=153 BRS; n=384 DES) were included. BRS patients were younger and had lower prevalence of comorbidities. Overall mean Japan-Chronic Total Occlusion (J-CTO) score was 1.43+/-1.16, with no differences between groups. Procedural success was achieved in 99.3% and 96.6% of BRS- and DES treated patients, respectively (P=0.07). At a median follow-up of 703 days, there were no differences in target-vessel failure between BRS and DES (4.6% versus 7.7%; P=0.21). By adjusted Cox regression analysis, there were still no significant differences between BRS and DES (hazard ratio, 1.54; 95% confidence interval, 0.69-3.72; P=0.34). However, secondary analyses suggested a signal toward higher ischemia-driven target-lesion revascularization with BRS. CONCLUSIONS: Implantation of BRS versus second-generation DES in chronic total occlusion was associated with similar risk of target-vessel failure at long-term follow-up. However, a signal toward increased ischemia-driven target-lesion revascularization with BRS was observed. Large randomized studies should confirm these findings. PMID- 27765804 TI - Cerebral metastases from Merkel cell carcinoma: long-term survival. AB - Merkel cell carcinoma is a rare primary cutaneous neuroendocrine tumour that is locally aggressive. In most cases the primary treatment is local surgical excision; however, there is a high incidence recurrence both local and distant. Cerebral metastases from Merkel cell carcinoma are extremely uncommon with only 12 cases published in the literature. This case is particularly unusual in that, not only was no established primary lesion identified, but also the patient has survived for 10 years following initial diagnosis and for 9 years following excision of a single brain metastasis. PMID- 27765805 TI - Total colectomy for colon perforation after kayexalate administration: a case report and literature review of a rare complication. AB - Kayexalate is an ion exchange resin that is commonly used to acutely treat patients with hyperkalemia. Bowel ulceration and necrosis is a rare and uncommonly recognized complication of kayexalate administration. More often, concomitant administration with sorbitol is reported to damage the bowel; however, there are reports of kayexalate administration causing bowel necrosis without sorbitol. We present a case of a critically ill patient who underwent total colectomy for colonic necrosis secondary to oral kayexalate administration that was not recognized until late in the pathologic process. We also review the literature to further investigate this progression. PMID- 27765806 TI - Perforated jejunal diverticulum: a rare case of acute abdomen. AB - Jejunal pseudo-diverticulosis is a rare acquired herniation of the mucosa and submucosa through weakened areas of the muscularis mucosa of the mesenteric aspect of the bowel. They are asymptomatic in the majority of cases; however, they can present with a wide spectrum of non-specific symptoms such as chronic abdominal discomfort, postprandial flatulence, diarrhoea, malabsorption and steattorhoea. In up to 15% of cases, more serious acute complications may arise such as the development of intestinal obstruction, haemorrhage or as in our case, localized peritonitis secondary to perforation. Perforation carries an overall mortality rate of up to 40% and exploratory laparotomy followed by copious lavage with segmental resection and primary anastomosis remains the mainstay of managing such sequalae of jejunal pseudo-diverticulosis. Our case report highlights the importance of maintaining a high clinical suspicion of a perforated jejunal diverticulum in an elderly patient presenting with an acute abdomen. PMID- 27765807 TI - Recombineering and I-SceI-mediated Pseudomonas putida KT2440 scarless gene deletion. AB - Pseudomonas putida KT2440 is a saprophytic, generally recognized as safe microorganism that plays important roles in the biodegradation and production of value-added chemicals. Chromosomal gene deletion of P. putida KT2440 usually involves time-consuming gene coning, conjugal transfer and counterselection. Recently, we developed a P. putida KT2440 markerless gene deletion method based on recombineering and Cre/loxP site-specific recombination. PCR-based lambda Red recombineering circumvents the tedious cloning steps and is more amenable to high throughput manipulation. Herein we report an improved scarless gene deletion strategy based on recombineering and I-SceI-mediated double-strand break repair. Sixteen drug exporter gene(s) were deleted and the minimal inhibition concentrations of the mutants to a variety of antibiotics were determined. The robustness of the procedure was also demonstrated by sequential deletion of five large genomic regions. Up to 59% recombination efficiency was achieved for 54.8 kb deletion, and the efficiency of RecA mediated double-strand break repair, which was boosted by lambda Red recombinase, was nearly 100%. The strain with a 3.76% genome reduction showed an improved growth rate and transformation efficiency. The straightforward, time-saving and highly efficient scarless deletion approach has the potential to facilitate the genetic study and biotechnological and environmental applications of P. putida KT2440. PMID- 27765808 TI - Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine. AB - Background: Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression. Methods: We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor, TrkB, phospho-TrkB, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1), postsynaptic density protein 95, and dendritic spine density in selected brain regions were measured. Results: In the tail suspension and forced swimming tests, both MGS0039 and ketamine significantly attenuated the increased immobility time observed in susceptible mice, compared with vehicle treated animals, 1 or 2 days after a single dose of drug. In the sucrose preference test, both compounds significantly improved the reduced preference typically seen in susceptible mice at 3 to 7 days after a single dose of drug. Western-blot analyses showed that similar to ketamine, MGS0039 significantly attenuated the reduced brain-derived neurotrophic factor, phospho-TrkB/TrkB ratio, GluA1 and postsynaptic density protein 95 seen in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from susceptible mice, 8 days after a single dose. Again, in a similar manner to ketamine, MGS0039 significantly attenuated the reduction of spine density in the prelimbic regions of the medial prefrontal cortex, dentate gyrus, and CA3 of the hippocampus, but not infralimbic regions of the medial prefrontal cortex and CA1, in susceptible mice 8 days after a single dose. In contrast, neither drug elicited an effect on altered brain derived neurotrophic factor-TrkB signaling, GluA1, and postsynaptic density protein 95 levels and did not increase spine density observed in the nucleus accumbens of susceptible mice. Conclusions: Similar to ketamine, MGS0039 shows rapid and sustained antidepressant effects in the social defeat stress model. Long-lasting synaptogenesis in the prelimbic regions of medial prefrontal cortex, dentate gyrus, and CA3 might be implicated in this sustained antidepressant effect. PMID- 27765809 TI - Discovering Single Nucleotide Polymorphisms Regulating Human Gene Expression Using Allele Specific Expression from RNA-seq Data. AB - The study of the genetics of gene expression is of considerable importance to understanding the nature of common, complex diseases. The most widely applied approach to identifying relationships between genetic variation and gene expression is the expression quantitative trait loci (eQTL) approach. Here, we increased the computational power of eQTL with an alternative and complementary approach based on analyzing allele specific expression (ASE). We designed a novel analytical method to identify cis-acting regulatory variants based on genome sequencing and measurements of ASE from RNA-sequencing (RNA-seq) data. We evaluated the power and resolution of our method using simulated data. We then applied the method to map regulatory variants affecting gene expression in lymphoblastoid cell lines (LCLs) from 77 unrelated northern and western European individuals (CEU), which were part of the HapMap project. A total of 2309 SNPs were identified as being associated with ASE patterns. The SNPs associated with ASE were enriched within promoter regions and were significantly more likely to signal strong evidence for a regulatory role. Finally, among the candidate regulatory SNPs, we identified 108 SNPs that were previously associated with human immune diseases. With further improvements in quantifying ASE from RNA-seq, the application of our method to other datasets is expected to accelerate our understanding of the biological basis of common diseases. PMID- 27765810 TI - Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers. AB - Wild-derived mouse inbred strains are becoming increasingly popular for complex traits analysis, evolutionary studies, and systems genetics. Here, we report the whole-genome sequencing of two wild-derived mouse inbred strains, LEWES/EiJ and ZALENDE/EiJ, of Mus musculus domesticus origin. These two inbred strains were selected based on their geographic origin, karyotype, and use in ongoing research. We generated 14* and 18* coverage sequence, respectively, and discovered over 1.1 million novel variants, most of which are private to one of these strains. This report expands the number of wild-derived inbred genomes in the Mus genus from six to eight. The sequence variation can be accessed via an online query tool; variant calls (VCF format) and alignments (BAM format) are available for download from a dedicated ftp site. Finally, the sequencing data have also been stored in a lossless, compressed, and indexed format using the multi-string Burrows-Wheeler transform. All data can be used without restriction. PMID- 27765812 TI - Direct Thrombin Inhibitor for LVAD Thrombosis: A Closer Look. AB - Available options for the treatment of advanced heart failure have expanded to include the use of mechanical circulatory assist devices to improve quality of life in those both eligible and ineligible for heart transplant. Although there have been significant advancements in device technologies, anticoagulation protocols, and multidisciplinary team management, bleeding and thrombosis are the most common adverse effects. Management strategies for pump thrombosis and their outcomes vary considerably among mechanical circulatory support centers and include intensification of antithrombotic therapy (medical) and device exchange (surgical). We describe a successful case of medical therapy for pump thrombosis with bivalirudin monotherapy. PMID- 27765813 TI - Limited resection for early-stage non-small cell lung cancer as function preserving radical surgery: a review. AB - Since 'radical lobectomy' was reported by Cahan in 1960, the standard surgical care for lung cancer has been lobectomy, in which units of the lobe are excised with their specific regional hilar and mediastinal lymphatics. However, pulmonary function-preserving limited resection for lung cancer has gradually become more prevalent in the late 20th century. In 1995, Ginsberg et al. conducted a randomized controlled trial in which limited resection (segmentectomy and wide wedge resection) and lobectomy for stage I lung cancer were compared and reported that limited resection should not be applied to healthy patients with clinical stage IA lung cancer. The detection of small-sized and early-stage lung cancers has improved with advancement in diagnostic technology. Ground-glass opacity of lung nodules, as recognized on thin-slice computed tomography, has also been widely recognized as being correlated with less-invasive pathological findings of alveolar epithelial cell replacement of cancer cells. The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group conducted a cohort study of early peripheral lung cancer and investigated the validity thin-slice computed tomography criteria to diagnose non-invasive lung adenocarcinoma for the preoperative prediction of pathological non-invasive cancer. Following this observational study, the on-going JCOG0802/WJOG4607L, JCOG0804/WJOG4507L and JCOG1211 trials were initiated to confirm the validity of limited resection for stage I lung cancer patients stratified according to preoperative thin-slice computed tomography findings; these trials will clarify whether limited resection for lung cancer is not function-preserving but also only curative surgery. PMID- 27765811 TI - Genomic analyses of multidrug resistant Pseudomonas aeruginosa PA1 resequenced by single-molecule real-time sequencing. AB - As a third-generation sequencing (TGS) method, single-molecule real-time (SMRT) technology provides long read length, and it is well suited for resequencing projects and de novo assembly. In the present study, Pseudomonas aeruginosa PA1 was characterized and resequenced using SMRT technology. PA1 was also subjected to genomic, comparative and pan-genomic analyses. The multidrug resistant strain PA1 possesses a 6,498,072 bp genome and a sequence type of ST-782. The genome of PA1 was also visualized, and the results revealed the details of general genome annotations, virulence factors, regulatory proteins (RPs), secretion system proteins, type II toxin-antitoxin (T-A) pairs and genomic islands. Whole genome comparison analysis suggested that PA1 exhibits similarity to other P. aeruginosa strains but differs in terms of horizontal gene transfer (HGT) regions, such as prophages and genomic islands. Phylogenetic analyses based on 16S rRNA sequences demonstrated that PA1 is closely related to PAO1, and P. aeruginosa strains can be divided into two main groups. The pan-genome of P. aeruginosa consists of a core genome of approximately 4,000 genes and an accessory genome of at least 6,600 genes. The present study presented a detailed, visualized and comparative analysis of the PA1 genome, to enhance our understanding of this notorious pathogen. PMID- 27765815 TI - Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-beta/delta Modulation of SP1 Promoter Occupancy. AB - Alcoholic liver disease is a pathological condition caused by overconsumption of alcohol. Because of the high morbidity and mortality associated with this disease, there remains a need to elucidate the molecular mechanisms underlying its etiology and to develop new treatments. Because peroxisome proliferator activated receptor-beta/delta (PPARbeta/delta) modulates ethanol-induced hepatic effects, the present study examined alterations in gene expression that may contribute to this disease. Chronic ethanol treatment causes increased hepatic CYP2B10 expression inPparbeta/delta+/+ mice but not in Pparbeta/delta-/- mice. Nuclear and cytosolic localization of the constitutive androstane receptor (CAR), a transcription factor known to regulate Cyp2b10 expression, was not different between genotypes. PPARgamma co-activator 1alpha, a co-activator of both CAR and PPARbeta/delta, was up-regulated in Pparbeta/delta+/+ liver following ethanol exposure, but not in Pparbeta/delta-/- liver. Functional mapping of the Cyp2b10 promoter and ChIP assays revealed that PPARbeta/delta-dependent modulation of SP1 promoter occupancy up-regulated Cyp2b10 expression in response to ethanol. These results suggest that PPARbeta/delta regulates Cyp2b10 expression indirectly by modulating SP1 and PPARgamma co-activator 1alpha expression and/or activity independent of CAR activity. Ligand activation of PPARbeta/delta attenuates ethanol-induced Cyp2b10 expression in Pparbeta/delta+/+ liver but not in Pparbeta/delta-/- liver. Strikingly, Cyp2b10 suppression by ligand activation of PPARbeta/delta following ethanol treatment occurred in hepatocytes and was mediated by paracrine signaling from Kupffer cells. Combined, results from the present study demonstrate a novel regulatory role of PPARbeta/delta in modulating CYP2B10 that may contribute to the etiology of alcoholic liver disease. PMID- 27765816 TI - Four-and-a-half LIM Domains 1 (FHL1) Protein Interacts with the Rho Guanine Nucleotide Exchange Factor PLEKHG2/FLJ00018 and Regulates Cell Morphogenesis. AB - PLEKHG2/FLJ00018 is a Gbetagamma-dependent guanine nucleotide exchange factor for the small GTPases Rac and Cdc42 and has been shown to mediate the signaling pathways leading to actin cytoskeleton reorganization. Here we showed that the zinc finger domain-containing protein four-and-a-half LIM domains 1 (FHL1) acts as a novel interaction partner of PLEKHG2 by the yeast two-hybrid system. Among the isoforms of FHL1 (i.e. FHL1A, FHL1B, and FHL1C), FHL1A and FHL1B interacted with PLEKHG2. We found that there was an FHL1-binding region at amino acids 58 150 of PLEKHG2. The overexpression of FHL1A but not FHL1B enhanced the PLEKHG2 induced serum response element-dependent gene transcription. The co-expression of FHL1A and Gbetagamma synergistically enhanced the PLEKHG2-induced serum response element-dependent gene transcription. Increased transcription activity was decreased by FHL1A knock-out with the CRISPR/Cas9 system. Compared with PLEKHG2 expressing cells, the number and length of finger-like protrusions were increased in PLEKHG2-, Gbetagamma-, and FHL1A-expressing cells. Our results provide evidence that FHL1A interacts with PLEKHG2 and regulates cell morphological change through the activity of PLEKHG2. PMID- 27765820 TI - New Cochrane protocols and reviews of relevance to health promotion and public health, published in January 2016-July 2016 of The Cochrane Library. PMID- 27765818 TI - Time-resolved Analysis of Proteome Dynamics by Tandem Mass Tags and Stable Isotope Labeling in Cell Culture (TMT-SILAC) Hyperplexing. AB - Recent advances in mass spectrometry have enabled system-wide analyses of protein turnover. By globally quantifying the kinetics of protein clearance and synthesis, these methodologies can provide important insights into the regulation of the proteome under varying cellular and environmental conditions. To facilitate such analyses, we have employed a methodology that combines metabolic isotopic labeling (Stable Isotope Labeling in Cell Culture - SILAC) with isobaric tagging (Tandem Mass Tags - TMT) for analysis of multiplexed samples. The fractional labeling of multiple time-points can be measured in a single mass spectrometry run, providing temporally resolved measurements of protein turnover kinetics. To demonstrate the feasibility of the approach, we simultaneously measured the kinetics of protein clearance and accumulation for more than 3000 proteins in dividing and quiescent human fibroblasts and verified the accuracy of the measurements by comparison to established non-multiplexed approaches. The results indicate that upon reaching quiescence, fibroblasts compensate for lack of cellular growth by globally downregulating protein synthesis and upregulating protein degradation. The described methodology significantly reduces the cost and complexity of temporally-resolved dynamic proteomic experiments and improves the precision of proteome-wide turnover data. PMID- 27765817 TI - Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex. AB - Exosomes, 40-150-nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. Although exosomes are known to originate from maturation of endosomes into multivesicular endosomes (also known as multivesicular bodies) with subsequent fusion of the multivesicular endosomes with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes. The L-type lectin LMAN2 (also known as VIP36) appears to be specifically required for the accumulation of GPRC5B in the Golgi complex and restriction of GPRC5B transport along the exosomal pathway. This may occur due to interference with the adaptor protein GGA1-mediated trans Golgi network-to endosome transport of GPRC5B. The adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum. Our data thus reveal a Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively. PMID- 27765819 TI - Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1). AB - Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4+ T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-gamma-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B. abortus is able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated that B. abortus infection inhibits the IFN-gamma-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as B. abortus infection. IL-6 contributes to these down-regulatory phenomena. In addition, B. abortus and its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-gamma signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection. PMID- 27765822 TI - Dizziness caused by meningocele-associated intracranial hypotension in neurofibromatosis type 1. PMID- 27765821 TI - Mechanistic insights into the manganese-dependent phosphodiesterase activity of yeast Dbr1 with bis-p-nitrophenylphosphate and branched RNA substrates. AB - Saccharomyces cerevisiae Dbr1 is a manganese-dependent RNA debranching enzyme that cleaves the 2'-5' phosphodiester bond of the lariat introns formed during pre-mRNA splicing. Dbr1 is a member of the binuclear metallophosphoesterase enzyme superfamily. We showed previously via alanine scanning that RNA debranching in vivo and in vitro depends on conserved active site residues His13, Asp40, Asn85, His86, His179, His231, and His233. Here, by extending the alanine scan, we added Cys11 to the ensemble of essential active site components. We report that Dbr1 has a vigorous manganese-dependent phosphodiesterase activity with the non-RNA substrate bis-p-nitrophenylphosphate. Whereas RNA debranching requires His86, bis-p-nitrophenylphosphatase activity does not. We interpret these and other structure-activity relations reported here in light of the crystal structures of Entamoeba Dbr1 and other homologous binuclear metallophosphodiesterases. Our results suggest that (i) Dbr1 adheres to the two metal mechanism of the enzyme superfamily, but is distinguished by its reliance on a Cys11-Xaa-His13 motif to engage one of the catalytic metals instead of the Asp-Xaa-His element typical of other clades within the superfamily; (ii) His86 is a general acid catalyst that protonates the O2' leaving group of the RNA 2'-5' phosphodiester; and (iii) the favorable pKa of p-nitrophenol elides the strict need for a general acid during hydrolysis of bis-p-nitrophenylphosphate. The Dbr1 bis-p-nitrophenylphosphatase activity is well suited for high-throughput screening for inhibitors of debranching. PMID- 27765824 TI - Standardized EEG interpretation accurately predicts prognosis after cardiac arrest. PMID- 27765823 TI - Not only bright tongue sign in Pompe disease. PMID- 27765825 TI - Depression in ALS in a large self-reporting cohort. PMID- 27765826 TI - Clinical Reasoning: A 20-year-old man with headache and double vision. PMID- 27765827 TI - Clinical Reasoning: A benign but potentially life-threatening headache. PMID- 27765828 TI - Pearls & Oy-sters: An unusual cause of hypokalemic paralysis. PMID- 27765829 TI - Teaching NeuroImages: One-and-a-half Brown-Sequard syndrome: When spinal neuroanatomy helps localize the lesion. PMID- 27765830 TI - Superior Labral Anterior-Posterior (SLAP) Tears in the Military. AB - CONTEXT: Given the notable physical demands placed on active members of the military, comprehension of recent trends in management and outcomes of superior labral anterior-posterior (SLAP) tears in this patient population is critical for successful treatment. EVIDENCE ACQUISITION: Electronic databases, including PubMed, MEDLINE, and Embase, were reviewed for the years 1985 through 2016. STUDY DESIGN: Database review. LEVEL OF EVIDENCE: Level 5. RESULTS: Active members of the military are at increased risk of sustaining shoulder injuries, particularly SLAP tears. Recent trends in management of SLAP lesions have shifted toward operative intervention. In the correct patient population, repairs of superior labrum tears demonstrate improved function and pain. Surgical repair of SLAP tears, especially in young and active military personnel, is supported. CONCLUSION: Military personnel are at greater risk of suffering a SLAP tear in comparison with their civilian counterparts. Surgical repair of these lesions is advocated in this subpopulation when the patient is younger than approximately 36 years of age, and if older, biceps tenodesis is likely superior. PMID- 27765831 TI - Effect of X-ray High-voltage Variations on the Conversion Coefficients. AB - Conversion coefficients (CCs) are an essential vehicle in radiation protection for the determination of the dose (rate) of a given radiation field. According to the current draft of the revision of international standard ISO 4037, an X-ray field is a reference field if the CCs of the field match the tabulated ISO values within 2%. Deviations of the high-voltage (HV) tube-potential from its nominal value influence the resulting spectra and change the corresponding CCs. This work investigates the maximum allowable deviation of the HV from its nominal value such that the requirements of ISO 4037 remain fulfilled. This is achieved using both synthetic spectra created by a software simulation program and spectra measured at one of the X-ray facilities of the Physikalisch-Technische Bundesanstalt. The results are summarised in form of a new proposal for upper limit values which are suggested to be used in the next version of ISO 4037. PMID- 27765832 TI - IMAGING DOSE OF HUMAN ORGANS FROM kV-CBCT IN IMAGE-GUIDED RADIATION THERAPY. AB - This study investigates dose distribution due to kV cone-beam computed tomography (CBCT) for the patients undergoing CBCT-based image-guided radiation therapy (IGRT). The kV-CBCT provides an efficient image-guidance tool for acquiring the latest volumetric image of a patient's anatomy, and has been being routinely used in clinics for an accurate treatment setup. Imaging radiation doses resulting from six different acquisition protocols of the on-board imager (OBI) were calculated using a Geant4 Application for Tomographic Emission (GATE) Monte Carlo simulation toolkit, and the absorbed doses by various organs were analyzed for the adult and pediatric numerical XCAT phantoms in this study. The calculated organ doses range from 0.1 to 24.1 mGy in the adult phantom, and from 0.1 to 36.8 mGy in the pediatric one. The imaging organ doses to the pediatric phantom turn out to be consistently higher than those to the adult phantom. It is believed that our results would provide reliable data to the clinicians for their making better decisions on CBCT scanning options and would also provide a platform for developing a new kV-CBCT scanning protocol in conjunction with a low-dose capability. PMID- 27765833 TI - OCULAR ORGAN DOSE ASSESSMENT OF NUCLEAR MEDICINE WORKERS HANDLING DIAGNOSTIC RADIONUCLIDES. AB - The dose distribution in the ocular organs of nuclear medicine workers during the handling of diagnostic radionuclides was assessed via simulation in virtual space. The cornea and lenses received the highest dose, and the dose distribution tended to be proportional to the gamma-ray energy emitted from the radiation source being handled. Moreover, calculations on the dose-reduction effects of eyewear protectors for the eyes of the workers showed that the effects were inversely proportional to the emitted gamma-ray energy, with the dose-reduction effect decreasing in the order of 201Tl, 123I, 99mTc, 67Ga, 111In and 18F. Among the considered sources, the dose-reduction effect was significant for sources that emit relatively less energy, namely 123I, 201Tl and 99mTc, while it was lower for the remaining sources, namely 18F, 111In and 67Ga. PMID- 27765834 TI - Density and distribution of feline conjunctival goblet cells. AB - Objectives The objective of this study was to examine the density and distribution of goblet cells (GCs) in the feline conjunctiva and to investigate a potential effect of age and sex on GC density (GCD). Methods Thirty-nine eyes of 21 cats euthanased for reasons unrelated to this study were used. Fixed upper and lower eyelid and bulbar conjunctiva were divided into nasal and temporal regions. The third eyelid was excised and investigated separately. Samples were embedded in paraffin wax; sections were stained with periodic acid-Schiff reaction and analysed with light microscopy. To determine the topographic distribution of GCs, each region was subdivided into the marginal, palpebral and bulbar zone. In each zone 200 epithelial cells, including GCs, were counted. Goblet cell index was defined as a percentage of the epithelial cells. Results The palpebral zone of both eyelids contained significantly ( P <0.001) more GCs (27.5-32.0%) than the marginal or bulbar areas. The highest GCD was found in the nasal palpebral zone of the upper eyelid (32.0%). Marginal and bulbar sites contained fewer numbers of GCs (2.6-10.0%). The lowest GCD was detected in the nasal bulbar zone of the lower eyelid (2.6%). Overall the nasal region contained significantly ( P = 0.036) more GCs than the temporal region, but there was no significant difference in GCD between the upper and lower eyelids. Correlation analysis did not show any effect of age or sex on GC counts. Conclusions and relevance GCD in the palpebral zones and on the anterior surface of the third eyelid was highest; the lowest density was found in the bulbar zones of the lower eyelid and in the marginal zones of both eyelids. Overall, higher GCD was found in the cat than in other species. Age and sex have no effect on GCD. PMID- 27765835 TI - Immune modulatory nanoparticle therapeutics for intracerebral glioma. AB - Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects. Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable. Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies. PMID- 27765836 TI - Glioma resection and tumor recurrence: back to Semmelweis. PMID- 27765837 TI - Response to "Glioma resection and tumor recurrence: back to Semmelweis". PMID- 27765838 TI - Mental health care for Indigenous young people: moving culture from the margins to the centre. AB - OBJECTIVE: Recently, Indigenous academics have evolved an Indigenist discourse that centralises Indigenous 'ways of knowing, being and doing'. Through this dialogue, Indigenous 'ways of knowing and being' augment Western biopsychosocial treatments. METHODS: This paper outlines the authors' clinical encounters with young people from the Koori community and ongoing consultation with Koori community Elders in Victoria that led to engaging young people and their families in an Indigenist dialogue. RESULTS: The Indigenist dialogue facilitates deeper engagement in the therapeutic process, opportunities to mirror and reflect on young people's experiences, and drawing parallels between Western health interventions and Aboriginal cultural ways of doing health and being healthy. CONCLUSIONS: The young people and their families evince greater faith in the management process and a deeper focus, centred awareness and knowledge of their Cultural rights and responsibilities. Future developments should include a systematic database with qualitative and quantitative data to support its evaluation and iterative development and improved community engagement to ensure holistic health gains are maintained. PMID- 27765841 TI - Ghosts of Company. PMID- 27765840 TI - Evaluating complex medical treatment options: a case report. AB - OBJECTIVE: Complex treatment decisions can be suboptimal due to lack of a reliable decision-making model, a need this paper aims to meet. METHOD: A model for making complex treatment decisions is introduced. RESULTS: The utility of the proposed method is demonstrated by making a complex treatment decision involving evaluation of clozapine treatment in a treatment-resistant patient. CONCLUSION: The proposed method implemented as a software tool can provide a framework for shared decision-making involving the patient. PMID- 27765842 TI - Adrenodemedullation activates the Ca2+-dependent proteolysis in soleus muscles from rats exposed to cold. AB - Previous studies have shown that catecholamines in vivo and in vitro inhibit the activity of Ca2+-dependent proteolysis in skeletal muscles under basal conditions. In the present study we sought to investigate the role of catecholamines in regulating the Ca2+-dependent proteolysis in soleus and extensor digitorum longus (EDL) muscles from rats acutely exposed to cold. Overall proteolysis, the activity of proteolytic systems, protein levels and gene expression of different components of the calpain system were investigated in rats submitted to adrenodemedullation (ADMX) and exposed to cold for 24 h. ADMX drastically reduced plasma epinephrine and promoted an additional increase in the overall proteolysis, which was already increased by cold exposure. The rise in the rate of protein degradation in soleus muscles from adrenodemedullated cold exposed rats was caused by the high activity of the Ca2+-dependent proteolysis, which was associated with the generation of a 145-kDa cleaved alpha-fodrin fragment, a typical calpain substrate, and lower protein levels and mRNA expression of calpastatin, the endogenous calpain inhibitor. Unlike that observed for soleus muscles, the cold-induced muscle proteolysis in EDL was not affected by ADMX. In isolated soleus muscle, clenbuterol, a selective beta2-adrenoceptor agonist, reduced the basal Ca2+-dependent proteolysis and completely abolished the activation of this pathway by the cholinergic agonist carbachol. These data suggest that catecholamines released from the adrenal medulla inhibit cold induced protein breakdown in soleus, and this antiproteolytic effect on the Ca2+ dependent proteolytic system is apparently mediated through expression of calpastatin, which leads to suppression of calpain activation.NEW & NOTEWORTHY Although many effects of the sympathetic nervous system on muscle physiology are known, the role of catecholamines in skeletal muscle protein metabolism has been scarcely studied. We suggest that catecholamines released from adrenal medulla may be of particular importance for restraining the activation of the Ca2+ dependent proteolysis in soleus muscles during acute cold exposure. This finding helps us to understand the adaptive changes that occur in skeletal muscle protein metabolism during cold stress. PMID- 27765843 TI - Blood pressure reduction after gastric bypass surgery is explained by a decrease in cardiac output. AB - : Blood pressure (BP) decreases in the first weeks after Roux-and-Y gastric bypass surgery. Yet the pathophysiology of the BP-lowering effects observed after gastric bypass surgery is incompletely understood. We evaluated BP, systemic hemodynamics, and baroreflex sensitivity in 15 obese women[mean age 42 +/- 7 standard deviation (SD) yr, body mass index 45 +/- 6 kg/m2] 2 wk before and 6 wk following Roux-and-Y gastric bypass surgery. Six weeks after gastric bypass surgery, mean body weight decreased by 13 +/- 5 kg (10%, P < 0.001). Office BP decreased from 137 +/- 10/86 +/- 6 to 128 +/- 12/81 +/- 9 mmHg (P < 0.001, P < 0.01), while daytime ambulatory BP decreased from 128 +/- 14/80 +/- 9 to 114 +/- 10/73 +/- 6 mmHg (P = 0.01, P = 0.05), whereas nighttime BP decreased from 111 +/ 13/66 +/- 7 to 102 +/- 9/62 +/- 7 mmHg (P = 0.04, P < 0.01). The decrease in BP was associated with a 1.6 +/- 1.2 l/min (20%, P < 0.01) decrease in cardiac output (CO), while systemic vascular resistance increased (153 +/- 189 dyn.s.cm 5, 15%, P < 0.01). The maximal ascending slope in systolic blood pressure decreased (192 mmHg/s, 19%, P = 0.01), suggesting a reduction in left ventricular contractility. Baroreflex sensitivity increased from 9.0 [6.4-14.3] to 13.8 [8.5 19.0] ms/mmHg (median [interquartile range]; P < 0.01) and was inversely correlated with the reductions in heart rate (R = -0.64, P = 0.02) and CO (R = 0.61, P = 0.03). In contrast, changes in body weight were not correlated with changes in either BP or CO. The BP reduction following Roux-and-Y gastric bypass surgery is correlated with a decrease in CO independent of changes in body weight. The contribution of heart rate to the reduction in CO together with enhanced baroreflex sensitivity suggests a shift toward increased parasympathetic cardiovascular control. NEW & NOTEWORTHY: The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patients. PMID- 27765844 TI - Intermittent hypobaric hypoxia combined with aerobic exercise improves muscle morphofunctional recovery after eccentric exercise to exhaustion in trained rats. AB - Unaccustomed eccentric exercise leads to muscle morphological and functional alterations, including microvasculature damage, the repair of which is modulated by hypoxia. We present the effects of intermittent hypobaric hypoxia and exercise on recovery from eccentric exercise-induced muscle damage (EEIMD). Soleus muscles from trained rats were excised before (CTRL) and 1, 3, 7, and 14 days after a double session of EEIMD protocol. A recovery treatment consisting of one of the following protocols was applied 1 day after the EEIMD: passive normobaric recovery (PNR), a 4-h daily exposure to passive hypobaric hypoxia at 4,000 m (PHR), or hypobaric hypoxia exposure followed by aerobic exercise (AHR). EEIMD produced an increase in the percentage of abnormal fibers compared with CTRL, and it affected the microvasculature by decreasing capillary density (CD, capillaries per mm2) and the capillary-to-fiber ratio (CF). After 14 days, AHR exhibited CD and CF values similar to those of CTRL animals (789 and 3.30 vs. 746 and 3.06) and significantly higher than PNR (575 and 2.62) and PHR (630 and 2.92). Furthermore, VEGF expression showed a significant 43% increase in AHR when compared with PNR. Moreover, after 14 days, the muscle fibers in AHR had a more oxidative phenotype than the other groups, with significantly smaller cross sectional areas (AHR, 3,745; PNR, 4,502; and PHR, 4,790 um2), higher citrate synthase activity (AHR, 14.8; PNR, 13.1; and PHR, 12 umol.min-1.mg-1) and a significant 27% increment in PGC-1alpha levels compared with PNR. Our data show that hypoxia combined with exercise attenuates or reverses the morphofunctional alterations induced by EEIMD.NEW & NOTEWORTHY Our study provides new insights into the use of intermittent hypobaric hypoxia combined with exercise as a strategy to recover muscle damage induced by eccentric exercise. We analyzed the effects of hypobaric exposure combined with aerobic exercise on histopathological features of muscle damage, fiber morphofunctionality, capillarization, angiogenesis, and the oxidative capacity of damaged soleus muscle. Most of these parameters were improved after a 2-wk protocol of intermittent hypobaric hypoxia combined with aerobic exercise. PMID- 27765845 TI - The reservoir-wave approach to characterize pulmonary vascular-right ventricular interactions in humans. AB - Using the reservoir-wave approach (RWA) we previously characterized pulmonary vasculature mechanics in a normal canine model. We found reflected backward traveling waves that decrease pressure and increase flow in the proximal pulmonary artery (PA). These waves decrease right ventricular (RV) afterload and facilitate RV ejection. With pathological alterations to the pulmonary vasculature, these waves may change and impact RV performance. Our objective in this study was to characterize PA wave reflection and the alterations in RV performance in cardiac patients, using the RWA. PA pressure, Doppler-flow velocity, and pulmonary arterial wedge pressure were measured in 11 patients with exertional dyspnea. The RWA was employed to analyze PA pressure and flow; wave intensity analysis characterized PA waves. Wave-related pressure was partitioned into two components: pressures due to forward-traveling and to backward-traveling waves. RV performance was assessed by examining the work done in raising reservoir pressure and that associated with the wave components of systolic PA pressure. Wave-related work, the mostly nonrecoverable energy expended by the RV to eject blood, tended to vary directly with mean PA pressure. Where PA pressures were lower, there were pressure-decreasing/flow-increasing backward waves that aided RV ejection. Where PA pressures were higher, there were pressure increasing/flow-decreasing backward waves that impeded RV ejection. Pressure increasing/flow-decreasing backward waves were responsible for systolic notches in the Doppler flow velocity profiles in patients with the highest PA pressure. Pulmonary hypertension is characterized by reflected waves that impede RV ejection and an increase in wave-related work. The RWA may facilitate the development of therapeutic strategies. PMID- 27765846 TI - Noninvasive assessment of cardiac output by brachial occlusion-cuff technique: comparison with the open-circuit acetylene washin method. AB - Cardiac output (CO) assessment as a basic hemodynamic parameter has been of interest in exercise physiology, cardiology, and anesthesiology. Noninvasive techniques available are technically challenging, and thus difficult to use outside of a clinical or laboratory setting. We propose a novel method of noninvasive CO assessment using a single, upper-arm cuff. The method uses the arterial pressure pulse wave signal acquired from the brachial artery during 20-s intervals of suprasystolic occlusion. This method was evaluated in a cohort of 12 healthy individuals (age, 27.7 +/- 5.4 yr, 50% men) and compared with an established method for noninvasive CO assessment, the open-circuit acetylene method (OpCirc) at rest, and during low- to moderate-intensity exercise. CO increased from rest to exercise (rest, 7.4 +/- 0.8 vs. 7.2 +/- 0.8; low, 9.8 +/- 1.8 vs. 9.9 +/- 2.0; moderate, 14.1 +/- 2.8 vs. 14.8 +/- 3.2 l/min) as assessed by the cuff-occlusion and OpCirc techniques, respectively. The average error of experimental technique compared with OpCirc was -0.25 +/- 1.02 l/min, Pearson's correlation coefficient of 0.96 (rest + exercise), and 0.21 +/- 0.42 l/min with Pearson's correlation coefficient of 0.87 (rest only). Bland-Altman analysis demonstrated good agreement between methods (within 95% boundaries); the reproducibility coefficient (RPC) = 0.84 l/min with R2 = 0.75 at rest and RPC = 2 l/min with R2 = 0.92 at rest and during exercise, respectively. In comparison with an established method to quantify CO, the cuff-occlusion method provides similar measures at rest and with light to moderate exercise. Thus, we believe this method has the potential to be used as a new, noninvasive method for assessing CO during exercise. PMID- 27765848 TI - Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer. AB - Pancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells three to four orders of magnitude more efficiently than found for the parental compound. Respiration assessment documented CI as the molecular target for MitoMet, which was corroborated by molecular modeling. MitoMet also efficiently suppressed pancreatic tumors in three mouse models. We propose that the novel mitochondrially targeted agent is clinically highly intriguing, and it has a potential to greatly improve the bleak prospects of patients with pancreatic cancer. Mol Cancer Ther; 15(12); 2875-86. (c)2016 AACR. PMID- 27765847 TI - Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress induced HIF Signaling in the Recurrent GBM Model. AB - Increasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme. CSCs are highly tumorigenic, capable of self renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. To elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft glioblastoma recurrent models induced by anti glioma chemotherapy, temozolomide. In this model, we observed a significant phenotypic shift towards an undifferentiated population. We confirmed these findings in vitro as sorted CD133-negative populations cultured in differentiation-forcing media were found to acquire CD133 expression following chemotherapy treatment. To investigate this phenotypic switch at the single-cell level, glioma stem cell (GSC)-specific promoter-based reporter systems were engineered to track changes in the GSC population in real time. We observed the active phenotypic and functional switch of single non-stem glioma cells to a stem like state and that temozolomide therapy significantly increased the rate of single-cell conversions. Importantly, we showed the therapy-induced hypoxia inducible factors (HIF) 1alpha and HIF2alpha play key roles in allowing non-stem glioma cells to acquire stem-like traits, as the expression of both HIFs increase upon temozolomide therapy and knockdown of HIFs expression inhibits the interconversion between non-stem glioma cells and GSCs post-therapy. On the basis of our results, we propose that anti-glioma chemotherapy promotes the accumulation of HIFs in the glioblastoma multiforme cells that induces the formation of therapy-resistant GSCs responsible for recurrence. Mol Cancer Ther; 15(12); 3064-76. (c)2016 AACR. PMID- 27765849 TI - Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer. AB - Oncogenic BRAFV600E mutations activate MAPK signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer. In BRAFV600E-mutant colorectal cancers, treatment failure may be related to BRAFV600E-mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using colorectal cancer cell lines isogenic for BRAF BRAFV600E-induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1Thr163) and stabilize MCL-1. Upregulation of MCL-1 was mediated by MEK/ERK shown by the ability of ERK siRNA to suppress MCL-1. Stabilization of MCL-1 by phosphorylation was shown by a phosphorylation-mimicking mutant and an unphosphorylated MCL-1 mutant that decreased or increased MCL-1 protein turnover, respectively. MEK/ERK inhibition by cobimetinib suppressed MCL-1 expression/phosphorylation and induced proapoptotic BIM to a greater extent than did vemurafenib in BRAFV600E cell lines. MCL-1 knockdown versus control shRNA significantly enhanced cobimetinib induced apoptosis in vitro and in HT29 colon cancer xenografts. The small molecule MCL-1 inhibitor, A-1210477, also enhanced cobimetinib-induced apoptosis in vitro that was due to disruption of the interaction of MCL-1 with proapoptotic BAK and BIM. Knockdown of BIM attenuated BAX, but not BAK, activation by cobimetinib plus A-1210477. In summary, BRAFV600E-mediated MEK/ERK activation can upregulate MCL-1 by phosphorylation/stabilization to confer apoptosis resistance that can be reversed by MCL-1 antagonism combined with cobimetinib, suggesting a novel therapeutic strategy against BRAFV600E-mutant CRCs. Mol Cancer Ther; 15(12); 3015-27. (c)2016 AACR. PMID- 27765850 TI - Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine Resistant Breast Cancer. AB - Endocrine therapy has been highly effective for the treatment of estrogen receptor-positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine-resistant breast cancer, we have evaluated a potent and specific MDM2-p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models. Both WHIM9 and WHIM18 PDX models exhibit estradiol independent tumor growth and are resistant to fulvestrant, a highly effective and selective estrogen receptor degrader (SERD). MI-77301 activates wild-type p53 in WHIM9 and WHIM18 cells in vitro and in xenograft tumor tissues in vivo, and it effectively induces upregulation of p21 and cell-cycle arrest in vitro in both models. Although fulvestrant fails to inhibit tumor growth in either of the xenograft models, MI-77301 is highly effective in inhibition of tumor growth at a well-tolerated dose schedule. This study provides a preclinical rationale for evaluation of MI-77301 or other MDM2 inhibitors as a new therapeutic strategy for the treatment of endocrine-resistant breast cancer retaining wild-type p53. Mol Cancer Ther; 15(12); 2887-93. (c)2016 AACR. PMID- 27765851 TI - The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate-Lactate Exchange in BRAF-Mutant Human Melanoma Cells. AB - Understanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity, and potential as noninvasive imaging response biomarkers. 1H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF-mutant (WM266.4 and SKMEL28) but not BRAFWT (CHL-1 and D04) human melanoma cells. In WM266.4 cells, this was associated with increased acetate, glycine, and myo-inositol levels and decreased fatty acyl signals, while the bioenergetic status was maintained. 13C NMR metabolic flux analysis of treated WM266.4 cells revealed inhibition of de novo lactate synthesis and glucose utilization, associated with increased oxidative and anaplerotic pyruvate carboxylase mitochondrial metabolism and decreased lipid synthesis. This metabolic shift was associated with depletion of hexokinase 2, acyl-CoA dehydrogenase 9, 3-phosphoglycerate dehydrogenase, and monocarboxylate transporters (MCT) 1 and 4 in BRAF-mutant but not BRAFWT cells and, interestingly, decreased BRAF-mutant cell dependency on glucose and glutamine for growth. Further, the reduction in MCT1 expression observed led to inhibition of hyperpolarized 13C-pyruvate-lactate exchange, a parameter that is translatable to in vivo imaging studies, in live WM266.4 cells. In conclusion, our data provide new insights into the molecular and metabolic consequences of BRAF inhibition in BRAF-driven human melanoma cells that may have potential for combinatorial therapeutic targeting as well as noninvasive imaging of response. Mol Cancer Ther; 15(12); 2987-99. (c)2016 AACR. PMID- 27765852 TI - Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation. AB - The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment of advanced prostate cancer. However, due to the development of drug resistance and tumor cell survival, a majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC. Here, we explore the functional activity of this site by using an advanced BF3-specific small molecule (VPC-13566) that was previously reported to effectively inhibit AR transcriptional activity and to displace the BAG1L peptide from the BF3 pocket. We show that VPC-13566 inhibits the growth of various prostate cancer cell lines, including an enzalutamide resistant cell line, and reduces the growth of AR-dependent prostate cancer xenograft tumors in mice. Importantly, we have used this AR-BF3 binder as a chemical probe and identified a co-chaperone, small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA), as an important AR-BF3 interacting partner. Furthermore, we used this AR-BF3-directed small molecule to demonstrate that inhibition of AR activity through the BF3 functionality can block translocation of the receptor into the nucleus. These findings suggest that targeting the BF3 site has potential clinical importance, especially in the treatment of CRPC and provide novel insights on the functional role of the BF3 pocket. Mol Cancer Ther; 15(12); 2936-45. (c)2016 AACR. PMID- 27765853 TI - Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma. AB - Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. Mol Cancer Ther; 15(12); 2966-76. (c)2016 AACR. PMID- 27765855 TI - Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma. AB - Predictive tools for guiding therapy in children with brain tumors are urgently needed. In this first molecular drug imaging study in children, we investigated whether bevacizumab can reach tumors in children with diffuse intrinsic pontine glioma (DIPG) by measuring the tumor uptake of 89Zr-labeled bevacizumab by PET. In addition, we evaluated the safety of the procedure in children and determined the optimal time for imaging. Methods: Patients received 89Zr-bevacizumab (0.1 mg/kg; 0.9 MBq/kg) at least 2 wk after completing radiotherapy. Whole-body PET/CT scans were obtained 1, 72, and 144 h after injection. All patients underwent contrast (gadolinium)-enhanced MRI. The biodistribution of 89Zr-bevacizumab was quantified as SUVs. Results: Seven DIPG patients (4 boys; 6-17 y old) were scanned without anesthesia. No adverse events occurred. Five of 7 primary tumors showed focal 89Zr-bevacizumab uptake (SUVs at 144 h after injection were 1.0 6.7), whereas no significant uptake was seen in the healthy brain. In 1 patient, multiple metastases all showed positive PET results. We observed inter- and intratumoral heterogeneity of uptake, and 89Zr-bevacizumab uptake was present predominantly (in 4/5 patients) within MRI contrast-enhanced areas, although 89Zr bevacizumab uptake in these areas was variable. Tumor targeting results were quantitatively similar at 72 and 144 h after injection, but tumor-to-blood-pool SUV ratios increased with time after injection (P = 0.045). The mean effective dose per patient was 0.9 mSv/MBq (SD, 0.3 mSv/MBq). Conclusion:89Zr-bevacizumab PET studies are feasible in children with DIPG. The data suggest considerable heterogeneity in drug delivery among patients and within DIPG tumors and a positive, but not 1:1, correlation between MRI contrast enhancement and 89Zr bevacizumab uptake. The optimal time for scanning is 144 h after injection. Tumor 89Zr-bevacizumab accumulation assessed by PET scanning may help in the selection of patients with the greatest chance of benefit from bevacizumab treatment. PMID- 27765854 TI - Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells. AB - Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 MUmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rnu1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863-74. (c)2016 AACR. PMID- 27765856 TI - Reliability of PET/CT Shape and Heterogeneity Features in Functional and Morphologic Components of Non-Small Cell Lung Cancer Tumors: A Repeatability Analysis in a Prospective Multicenter Cohort. AB - The main purpose of this study was to assess the reliability of shape and heterogeneity features in both the PET and the low-dose CT components of PET/CT. A secondary objective was to investigate the impact of image quantization. Methods: A Health Insurance Portability and Accountability Act-compliant secondary analysis of deidentified prospectively acquired PET/CT test-retest datasets of 74 patients from multicenter Merck and American College of Radiology Imaging Network trials was performed. Metabolically active volumes were automatically delineated on PET with a fuzzy locally adaptive bayesian algorithm. Software was used to semiautomatically delineate the anatomic volumes on the low dose CT component. Two quantization methods were considered: a quantization into a set number of bins (quantization B) and an alternative quantization with bins of fixed width (quantization W). Four shape descriptors, 10 first-order metrics, and 26 textural features were evaluated. Bland-Altman analysis was used to quantify repeatability. Features were subsequently categorized as very reliable, reliable, moderately reliable, or poorly reliable with respect to the corresponding volume variability. Results: Repeatability was highly variable among features. Numerous metrics were identified as poorly or moderately reliable. Others were reliable or very reliable in both modalities and in all categories (shape and first-, second-, and third-order metrics). Image quantization played a major role in feature repeatability. Features were more reliable in PET with quantization B, whereas quantization W showed better results in CT. Conclusion: The test-retest repeatability of shape and heterogeneity features in PET and low-dose CT varied greatly among metrics. The level of repeatability also depended strongly on the quantization step, with different optimal choices for each modality. The repeatability of PET and low-dose CT features should be carefully considered when selecting metrics to build multiparametric models. PMID- 27765859 TI - Modeling Strategies for Quantification of In Vivo 18F-AV-1451 Binding in Patients with Tau Pathology. AB - Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer disease (AD). In vivo imaging with PET may offer important insights into pathophysiologic mechanisms, diagnosis, and disease progression. We describe different strategies for quantification of 18F-AV-1451 (T807) tau binding, including models with blood sampling and noninvasive alternatives. Methods: Fifteen subjects (4 controls, 6 AD, 3 progressive supranuclear palsy, 2 cortico basal syndrome) underwent 180-min PET with 18F-AV-1451 and arterial blood sampling. Modeling with arterial input functions included 1-, 2-, and 3-tissue-compartment models and the Logan plot. Using the cerebellum as reference region, we applied the simplified reference tissue model 2 and Logan reference plot. Finally, simplified outcome measures were calculated as ratio, with reference to cerebellar concentrations (SUV ratio [SUVR]) and SUVs. Results: Tissue compartment models were not able to describe the kinetics of 18F-AV-1451, with poor fits in 33%-53% of cortical regions and 80% in subcortical areas. In contrast, the Logan plot showed excellent fits and parameter variance (total volume of distribution SE < 5%). Compared with the 180 min arterial-based Logan model, strong agreement was obtained for the Logan reference plot also for a reduced scan time of 100 min (R2 = 0.91) and SUVR 100 120 min (R2 = 0.94), with 80-100 min already representing a reasonable compromise between duration and accuracy (R2 = 0.93). Time-activity curves and kinetic parameters were equal for cortical regions and the cerebellum in control subjects but different in the putamen. Cerebellar total volumes of distribution were higher in controls than patients. For these methods, increased cortical binding was observed for AD patients and to some extent for cortico basal syndrome, but not progressive supranuclear palsy. Conclusion: The Logan plot provided the best estimate of tau binding using arterial input functions. Assuming that the cerebellum is a valid reference region, simplified methods seem to provide robust alternatives for quantification, such as the Logan reference plot with 100-min scan time. Furthermore, SUVRs between target and cerebellar activities obtained from an 80- to 100-min static scan offer promising potential for clinical routine application. PMID- 27765857 TI - Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l Tryptophan and alpha-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts. AB - : Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. alpha-11C methyl-l-tryptophan (11C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18F-fluoroethyl)-l-tryptophan (18F FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18F-FETrp in patient-derived xenograft mouse models and compared them with 11C-AMT uptake. METHODS: Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18F-FETrp and 11C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared. RESULTS: 18F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18F-FETrp showed higher tumoral SUV than 11C-AMT in all 3 tumor types tested. The radiation dosimetry for 18F FETrp determined from the mouse data compared favorably with the clinical 18F-FDG PET tracer. CONCLUSION: 18F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors. PMID- 27765858 TI - Metabolic Evaluation of Non-Small Cell Lung Cancer Patient-Derived Xenograft Models Using 18F-FDG PET: A Potential Tool for Early Therapy Response. AB - : Lung cancer heterogeneity makes response to therapy extremely hard to predict. Patient-derived xenografts (PDXs) are a reliable preclinical model that closely recapitulates the main characteristics of the parental tumors and may represent a useful asset for testing new therapies. Here, using PET imaging, we investigated whether lung cancer PDXs reproduce the metabolic characteristics of the corresponding parental tumors. METHODS: We performed longitudinal 18F-FDG PET studies on 9 different PDX groups obtained by implanting primary-cancer fragments harvested from patients into mice. The SUVmax of each PDX was calculated and compared with the SUVmax of the corresponding parental tumor. RESULTS: Tumor growth rate and uptake varied among the different PDXs and confirmed the preservation of individual characteristics. The intragroup reproducibility of PET measurements was good. Furthermore, PDXs from tumors with a higher metabolic rate displayed a rank order of uptake similar to that of the parental tumors. CONCLUSION: PDXs reproduced the glucose metabolism of the parental tumors and therefore represent a promising preclinical model for the early assessment of therapy efficacy. PMID- 27765860 TI - Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Nonthyroid Tissues. AB - : Targeted alpha-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation, resulting in a certain percentage of free radionuclide in the body. The radiohalogen 211At accumulates in various tissues, with specifically high uptake in the thyroid. When normal thyroid function is disturbed because of ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiologic function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from 211At. Here, we present supportive evidence on systemic effects after 211At administration. METHODS: Expression microarray data from the kidney cortex and medulla, liver, lungs, and spleen were used from previous studies in which mice were intravenously injected with 0.064-42 kBq of 211At and killed after 24 h or injected with 1.7 kBq of 211At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. RESULTS: Responses in IR- or TH-associated gene signatures were tissue-specific and varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least an extent similar to the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream regulators with differences in incidence and strength of regulation depending on tissue type. CONCLUSION: These findings indicate that transcriptional regulation in various nonthyroid tissues was-in part-induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures. PMID- 27765861 TI - Brain 18F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis. AB - The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18F-FDG. Methods:18F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean +/- SD], 45.9 +/- 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 +/- 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment (n = 42), those with frontal subcortical (FSC) dysfunction (n = 29), those with Papez circuit dysfunction (n = 22), and those with callosal disconnection (n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism (P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction. PMID- 27765862 TI - German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. AB - : 177Lu-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of 177Lu-PSMA-617 in a large cohort of patients. METHODS: One hundred forty-five patients (median age, 73 y; range, 43-88 y) with mCRPC were treated with 177Lu PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1-4 therapy cycles and an activity range of 2-8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician's report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline >= 50% from baseline to at least 2 wk after the start of RLT. RESULTS: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2-30 wk). Nineteen patients died during the observation period. Grade 3-4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. CONCLUSION: The present retrospective multicenter study of 177Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC. PMID- 27765864 TI - Effect of aphasia on acute stroke outcomes. AB - OBJECTIVE: To determine the independent effects of aphasia on outcomes during acute stroke admission, controlling for total NIH Stroke Scale (NIHSS) scores and loss of consciousness. METHODS: Data from the Tulane Stroke Registry were used from July 2008 to December 2014 for patient demographics, NIHSS scores, length of stay (LOS), complications (sepsis, deep vein thrombosis), and discharge modified Rankin Scale (mRS) score. Aphasia was defined as a score >1 on question 9 on the NIHSS on admission and hemiparesis as >1 on questions 5 or 6. RESULTS: Among 1,847 patients, 866 (46%) had aphasia on admission. Adjusting for NIHSS score and inpatient complications, those with aphasia had a 1.22 day longer LOS than those without aphasia, whereas those with hemiparesis (n = 1,225) did not have any increased LOS compared to those without hemiparesis. Those with aphasia had greater odds of having a complication (odds ratio [OR] 1.44, confidence interval [CI] 1.07-1.93, p = 0.0174) than those without aphasia, which was equivalent to those having hemiparesis (OR 1.47, CI 1.09-1.99, p = 0.0137). Controlling for NIHSS scores, aphasia patients had higher odds of discharge mRS 3-6 (OR 1.42 vs 1.15). CONCLUSION: Aphasia is independently associated with increased LOS and complications during the acute stroke admission, adding $2.16 billion annually to US acute stroke care. The presence of aphasia was more likely to produce a poor functional outcome than hemiparesis. These data suggest that further research is necessary to determine whether establishing adaptive communication skills can mitigate its consequences in the acute stroke setting. PMID- 27765865 TI - Treatment of unstable proximal interphalangeal joint fractures with hemi-hamate osteochondral autografts. AB - : The primary aim of this study was to assess the clinical and radiological results after hemi-hamate resurfacing arthroplasty in patients with acute or chronic unstable fractures of the base of the middle phalanx and to describe technical features that can facilitate the surgical procedure. Hemi-hamate arthroplasties were done in 19 patients (mean age 39 years) with an isolated fracture at the base of the middle phalanx that involved more than 40% of the articular surface. We assessed ten chronic cases (treated >6 weeks after fracture) and nine acute ones (<6 weeks) at a mean of 24 months. Pain scores, QuickDASH scores, grip strengths, range of motion and radiological findings were recorded at follow-up. At follow-up, the mean active flexion at the proximal interphalangeal joint was to 83 degrees with a mean fixed flexion of 17 degrees (active range of motion 66 degrees ). The mean active distal interphalangeal motion was 41 degrees . The mean visual analogue scale score was 1.1. The mean QuickDASH score was 11. The mean pinch strength was 82% of the opposite side. Radiographs revealed one partial graft lysis. LEVEL OF EVIDENCE: IV. PMID- 27765863 TI - Characterization of 11C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation. AB - The purinergic receptor subtype 7 (P2X7R) represents a novel molecular target for imaging neuroinflammation via PET. GSK1482160, a potent P2X7R antagonist, has high receptor affinity, high blood-brain barrier penetration, and the ability to be radiolabeled with 11C. We report the initial physical and biologic characterization of this novel ligand. Methods:11C-GSK1482160 was synthesized according to published methods. Cell density studies were performed on human embryonic kidney cell lines expressing human P2X7R (HEK293-hP2X7R) and underwent Western blotting, an immunofluorescence assay, and radioimmunohistochemistry analysis using P2X7R polyclonal antibodies. Receptor density and binding potential were determined by saturation and association-disassociation kinetics, respectively. Peak immune response to lipopolysaccharide treatment in mice was determined in time course studies and analyzed via Iba1 and P2X7R Western blotting and Iba1 immunohistochemistry. Whole-animal biodistribution studies were performed on saline- or lipopolysaccharide-treated mice at 15, 30, and 60 min after radiotracer administration. Dynamic in vivo PET/CT was performed on the mice at 72 h after administration of saline, lipopolysaccharide, or lipopolysaccharide + blocking, and 2-compartment, 5-parameter tracer kinetic modeling of brain regions was performed. Results: P2X7R changed linearly with concentrations or cell numbers. For high-specific-activity 11C-GSK1482160, receptor density and Kd were 1.15 +/- 0.12 nM and 3.03 +/- 0.10 pmol/mg, respectively, in HEK293-hP2X7R membranes. Association constant kon, dissociation constant koff, and binding potential (kon/koff) in HEK293-hP2X7R cells were 0.2312 +/- 0.01542 min-1?nM-1, 0.2547 +/- 0.0155 min-1, and 1.0277 +/- 0.207, respectively. Whole-brain Iba1 expression in lipopolysaccharide-treated mice peaked by 72 h on immunohistochemistry, and Western blot analysis of P2X7R for saline- and lipopolysaccharide-treated brain sections showed a respective 1.8- and 1.7-fold increase in signal enhancement at 72 h. Biodistribution of 11C GSK1482160 in saline- and lipopolysaccharide-treated mice at 72 h was statistically significant across all tissues studied. In vivo dynamic 11C GSK1482160 PET/CT of mice at 72 h after administration of saline, lipopolysaccharide, or lipopolysaccharide + blocking showed a 3.2-fold increase and 97% blocking by 30 min. The total distribution volumes for multiple cortical regions and the hippocampus showed statistically significant increases and were blocked by an excess of authentic standard GSK1482160. Conclusion: The current study provides compelling data that support the suitability of 11C-GSK1482160 as a radioligand targeting P2X7R, a biomarker of neuroinflammation. PMID- 27765867 TI - Risk of Cognitive Decline Associated With Paroxetine Use in Elderly Nursing Home Patients With Depression. AB - OBJECTIVE: This study evaluated the risk of cognitive decline associated with paroxetine use in elderly nursing home patients with depression. METHODS: A retrospective cohort study was conducted using the 2007 to 2010 Medicare Part D claims and minimum data set (MDS) data involving new users of paroxetine and other selective serotonin reuptake inhibitors (SSRIs). The primary outcome was MDS Cognition Scale. The repeated-measures mixed model was used to examine the effect of paroxetine on cognition after controlling for other factors. RESULTS: The baseline MDS Cognition Scale measures for paroxetine (n = 63) and other SSRI users (n =1018) were 2.02 (+/-1.85) and 2.50 (+/-2.39), respectively. The repeated-measures mixed model did not find statistically significant difference in cognition with the use of paroxetine (beta = 0.02, 95% CI: -0.16 to 0.21]) when compared to other SSRIs. CONCLUSIONS: There was no differential effect of paroxetine on cognition when compared to other SSRIs. PMID- 27765866 TI - Unexpected complications with head and neck hydrogel microsphere particle embolization: A case series and a technical note. AB - Endovascular particle embolization is a common procedure with a relatively safe profile. We report here four cases in which cranial nerves, skin and mucosal ischemic complications occurred with the use of hydrogel microspheres (250-500 um in size). Given the compressibility and higher penetration potential of microsphere particles compared with polyvinyl alcohol particles of similar size, we suggest oversizing hydrogel microsphere particles for head and neck embolizations. PMID- 27765868 TI - An Anatomic Study of the Percutaneous Endoscopically Assisted Calcaneal Osteotomy Technique to Correct Hindfoot Malalignment. AB - BACKGROUND: Open calcaneal osteotomy using traditional methods is associated with complications such as sural nerve injury and potential wound healing problems. We hypothesized that by using novel minimally invasive techniques, these potential risks could be mitigated. This anatomic cadaveric study serves to assess the safety of percutaneous endoscopically assisted calcaneal osteotomy (PECO) compared to a traditional open osteotomy technique. METHODS: Anatomic safety of PECO was assessed using 8 fresh-frozen cadaver below-knee specimens. Lateral calcaneal nerve (LCN) damage was primarily noted and then secondly compared to a potential open surgical incision approach. RESULTS: Only 1 of 11 LCN branches (n = 8 limbs) was transected using PECO, compared to up to 8 of 10 LCN branches (n = 6 limbs) that potentially would have been injured during open surgery. CONCLUSIONS: Percutaneous endoscopically assisted calcaneal osteotomy is a minimally invasive technique that had fewer nerve injuries in this cadaveric model than traditional open surgery. CLINICAL RELEVANCE: Percutaneous endoscopically assisted calcaneal osteotomy due to its less invasive nature may result in fewer neurovascular injuries relative to an open procedure. PMID- 27765869 TI - Mid- to Long-term Results of Supramalleolar Osteotomy. AB - BACKGROUND: Good clinical and radiographic short-term results have been reported for patients who underwent realignment surgery of the hindfoot for treatment of early- and mid-stage ankle osteoarthrosis (OA). However, no mid- to long-term results have been reported. The aim of this study was to gain a better insight into the indications and contraindications for realignment surgery. METHODS: Two hundred ninety-four patients (298 ankles) underwent realignment surgery between December 1999 and June 2013. Kaplan-Meier survival analysis was performed with total ankle replacement and arthrodesis of the ankle joint as endpoints. A Cox proportional hazards model was performed to identify risk factors for failure. The mean time to follow-up was 5.0 +/- 3.7 years. RESULTS: The overall 5-year survival rate was 88%. Thirty-eight patients (12.9%) underwent either secondary total ankle replacement or ankle arthrodesis (30 total ankle replacements, 8 ankle arthrodesis). Risk factors for failure following realignment surgery were age at the time of surgery and a Takakura score of 3b preoperatively. CONCLUSION: Realignment surgery of the hindfoot was an excellent treatment option for young and physically active patients with early to mid-stage ankle OA. LEVEL OF EVIDENCE: Level IV, prospective observational study. PMID- 27765870 TI - Acute Achilles Tendon Rupture Treated by Double Side-Locking Loop Suture Technique With Early Rehabilitation. AB - BACKGROUND: Although early accelerated rehabilitation is recommended for the treatment of acute Achilles tendon rupture, most traditional rehabilitation techniques require some type of brace. METHODS: We retrospectively analyzed 44 feet of 44 patients (25 male and 19 female) with a mean age of 31.8 years who had an acute Achilles tendon rupture related to athletic activity. Patients had been treated by a double side-locking loop suture (SLLS) technique using double antislip knots between stumps and had undergone early accelerated rehabilitation, including active and passive range of motion exercises on the day following the operation and full weight-bearing at 4 weeks. No brace was applied postoperatively. The evaluation criteria included the American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale (AOFAS) score; active plantar flexion and dorsiflexion angles; and the intervals between surgery and the time when patients could walk normally without any support, perform double-leg heel raises, and perform 20 continuous single-leg heel raises of the operated foot. RESULTS: Despite postoperative early accelerated rehabilitation, the AOFAS score and active dorsiflexion angles improved over time (6, 12, and 24 weeks and 2 years). A mean of 4.3 +/- 0.6 weeks was required for patients to be able to walk normally without any support. The mean period to perform double-leg heel raises and 20 continuous single-leg heel raises of the injured foot was 8.0 +/- 1.3 weeks and 10.9 +/- 2.1 weeks, respectively. All patients, except one who was engaged in classical ballet, could return to their preinjury level of athletic activities, and the interval between operation and return to athletic activities was 17.1 +/- 3.7 weeks. CONCLUSION: The double SLLS technique with double antislip knots between stumps adjusted the tension of the sutured Achilles tendon at the ideal ankle position and provided good clinical outcomes following accelerated rehabilitation after surgery without the use of a brace. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 27765871 TI - Charcot Arthropathy of the Foot and Ankle. PMID- 27765873 TI - Active packaging of chicken meats with modified atmosphere including oxygen scavengers. AB - The effects of modified atmosphere packaging (MAP-70% CO2/30%N2) and iron-based oxygen scavengers (OS) with various absorption capacities (Ageless(r) ss100, ss300, and ss500) as an active packaging system on microbiological and oxidative changes in chicken thigh meats were evaluated during refrigerated storage (4 degrees C) for 19 d at 3-day intervals. Total aerobic mesophilic bacteria counts exceeded the acceptability limit at d 7 in the control group without MAP (AIR), and at d 19 in MAP and OS containing samples. OS utilization resulted in around 1.5 and 1.0 log unit reductions in Pseudomonas spp. counts at d 7 and d 10 of storage, respectively, as compared with AIR and MAP groups (P < 0.05). MAP and OS groups had fewer (P < 0.05) coliform counts than did the AIR group, with an approximately 1.0 log reduction observed at d 10. Although in some cases OS utilization resulted in lower TBARS values and carbonyl and sulphydryl contents, particularly during later stages of refrigerated storage as compared to AIR and MAP groups, in general, these effects were not always apparent. The results of this study suggested that MAP suppressed microbiological growth and retarded lipid and protein oxidation in chicken thigh meats, with a 9-day shelf-life extention with insignificant effects of OS. PMID- 27765872 TI - Discovery of an expanded set of avian leucosis subgroup E proviruses in chickens using Vermillion, a novel sequence capture and analysis pipeline. PMID- 27765874 TI - Effect of whole flax seed and carbohydrase enzymes on gastrointestinal morphology, muscle fatty acids, and production performance in broiler chickens. AB - Flax seed is a rich source of alpha-linolenic acid (18:3 n-3). Feeding broiler birds flax seed can increase n-3 fatty acids in meat tissues. However, non-starch polysaccharides in flax seed decrease nutrient digestibility and can have a negative impact on bird performance and muscle fatty acid content. Addition of carbohydrase enzymes to flax-based broiler diets can decrease the anti-nutritive effects of non-starch polysaccharides. An experiment was conducted to investigate on the effect of flax seed and carbohydrase enzyme foregut morphology, muscle tissue, fatty acids, and bird performance. A total of 112 five-day-old broiler chicks were assigned to one of four treatments: Flax10 (corn-soybean meal basal diet adjusted for 10% flax), Flax15 (basal diet adjusted for 15% flax), Flax10E (Flax10 + 0.05% enzyme), and Flax15E (Flax 15 + 0.05% enzyme). Addition of enzyme led to large increases in villi height and villi width in the jejunum of birds fed Flax10 and increases in crypt depth in the jejunum of birds fed Flax15 (P < 0.05). The ratio of villi height to crypt depth was larger in the duodenum and jejunum of birds fed Flax10E when compared to Flax10 (P < 0.05). Feeding the Flax15 diet led to a significant decrease in total lipids in breast muscle compared to Flax10 (P < 0.05). The effect of level of flax or enzyme supplementation was minimal on the fatty acids measured in breast muscle except for total n-6 fatty acids which was higher (P < 0.05) in Flax15 when compared to Flax10. In thigh muscle, stearic acid, arachidonic acid, and total n-6 fatty acids were higher in birds fed Flax15 vs. Flax10. Feeding Flax15 led to a reduction in dry matter of excreta when compared to Flax10 (P < 0.05). There were no differences in BW, average daily gain, or feed consumption during the starter or grower phase due to flax level or enzyme addition (P > 0.05). PMID- 27765875 TI - Hemiarch: The Real Operation for Ascending Aortic Aneurysm. AB - The extent and technique of resection for ascending aortopathies remains debated. The 2 main camps are divided into those who believe in the hemiarch resection utilizing hypothermic circulatory arrest and those who feel that the same goal can be accomplished with just an ascending aortic resection with an aortic cross clamp. While this debate continues to happen within groups and in some cases even in the same hospital, it certainly has not happened in the literature. There are no studies directly comparing the safety and efficacy of these 2 ideologies. The aim of this review is to present the little data that do exist and to ultimately show that the hemiarch technique is superior after careful deliberation. PMID- 27765876 TI - Home Gardening and the Health and Well-Being of Adolescents. AB - BACKGROUND: The current article explores the associations between home gardening and dietary behaviors, physical activity, mental health, and social relationships among secondary school students in New Zealand. METHOD: Data were drawn from a national youth health and well-being survey, conducted in 2012. In total, 8,500 randomly selected students from 91 randomly selected secondary schools completed the survey. RESULTS: Two thirds of students had a vegetable garden at home and one quarter of all students participated in home gardening. Students participating in gardening were most likely to be male, of a Pacific Island ethnicity, of younger age, and living in a rural area. Gardening was positively associated with healthy dietary habits among students, such as greater fruit and vegetable consumption. Gardening was also positively associated with physical activity and improved mental health and well-being. Students who participate in gardening report slightly lower levels of depressive symptoms and enhanced emotional well-being and experience higher family connection than students who do not participate in gardening. CONCLUSIONS: Gardening may make a difference for health and nutrition behaviors and may contribute to adolescents' health and well being in a positive manner. Health promoters should be encouraged to include gardening in future interventions for young people. PMID- 27765877 TI - Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. AB - BACKGROUND: Stable disease course may prompt consideration of disease-modifying treatment (DMT) discontinuation in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To investigate the clinical outcome after DMT discontinuation and to identify predictive factors supporting decision-making. METHODS: We included 221 RRMS patients, who discontinued DMT after ?12 months and had documented follow-up ?2 years after discontinuation. Hazard ratios (HRs) with 95% confidence intervals (CIs) regarding relapse and disability progression after DMT discontinuation were calculated from Cox regression models. RESULTS: Age >45 years at discontinuation (HR = 0.47, CI = 0.23-0.95, p = 0.038), absence of relapses for ?4 years on DMT before discontinuation (HR = 0.29, CI = 0.10-0.82, p = 0.020) and absence of contrast enhancing lesions (HR = 0.46, CI = 0.28-0.78, p = 0.004) were independent predictors of absence of relapse after discontinuation. Age >45 years and absence of relapses ?4 years on DMT combined had an HR of 0.06 (CI = 0.01 0.44, p < 0.001). Higher Expanded Disability Status Scale (EDSS) at discontinuation, age >45 years and longer disease duration were significantly associated with disability progression after discontinuation. CONCLUSION: While freedom from further disease activity is generally unpredictable, there is a subset of patients (age ?45 years, DMT intake ?4 years without evidence of clinical or radiological disease activity) having a high likelihood of remaining relapse-free after DMT discontinuation. However, close clinical monitoring for recurrent disease activity is mandatory after discontinuing treatment. PMID- 27765878 TI - Diagnosing Pediatric Malnutrition. AB - The publication of the landmark paper "Defining Pediatric Malnutrition: A Paradigm Shift Toward Etiology-Related Definitions" launched a new era in diagnosing pediatric malnutrition. This work introduced the paradigm shift of etiology-related definitions-nonillness and illness related-and the use of anthropometric z scores to help identify and describe children with malnutrition (undernutrition) in the developed world. Putting the new definition into practice resulted in some interesting observations: (1) Etiology-related definitions result in etiology-related interventions. (2) Illness-related malnutrition cannot always be immediately "fixed." (3) Using z scores in clinical practice often puts the burden of proof on the clinician to show that a child is not malnourished, rather than the other way around. (4) Children with growth failure severe enough to be admitted with "failure to thrive" should always be assessed for malnutrition, and when they meet the criteria, malnutrition should be documented and coded. The publication of the consensus statement came next, announcing the evidence-informed, consensus-derived pediatric malnutrition indicators. Since the indicators are a work in progress, clinicians are encouraged to use them and give feedback through an iterative process. This review attempts to respond to the consensus statement's call to action by thoughtfully appraising the indicators and making recommendations for future review. Coming together as a healthcare community to identify pediatric malnutrition will ensure that this vulnerable population is not overlooked. Outcomes research will validate the indicators and result in new discoveries of effective ways to prevent and treat pediatric malnutrition. PMID- 27765879 TI - Identifying Key Elements to Inform the Development of an HIV Health Behavior Maintenance Intervention. AB - PURPOSE: To collect information that will inform the development of an intervention to support the maintenance of HIV-related health-promoting behaviors. DESIGN: Focused, in-depth individual and group interviews. SETTING: The New York City (NYC) Department of Health and Mental Hygiene (DOHMH) and DOHMH funded community-based organizations that primarily serve low-income people living with HIV within the five boroughs of NYC. PARTICIPANTS: A total of 42 individuals who had participated in The Positive Life Workshop-an HIV self management intervention adapted and implemented by the NYC DOHMH. METHOD: Purposive sampling was used to recruit study participants. Five 60- to 90-minute focus groups (n = 38) and 4 individual interviews were conducted to assess motivations for and barriers to maintaining HIV-related health-promoting behaviors and to elicit feedback on the content and format for the proposed maintenance intervention. Thematic analysis was used to summarize the data. RESULTS: Participants reported that relationships with family, a responsibility to protect others from HIV, and faith/spirituality supported the maintenance of health-promoting behaviors. Barriers to behavior maintenance included substance use and mental health issues. Meeting in small groups was also highlighted as a motivator to sustaining health behaviors, particularly in decreasing isolation and receiving affirmation from others. CONCLUSION: Participants identified several factors that could be incorporated into an intervention to support HIV related health-promoting behavior maintenance that could supplement existing HIV self-management interventions. PMID- 27765880 TI - Evaluating the Potential of Routine Blood Tests to Identify the Risk of Deep Vein Thrombosis: A 1-Year Monocenter Cohort Study. AB - Study on 295 consecutive medical patients to evaluate the potential of routine blood tests to identify the risk of deep vein thrombosis (DVT). The tests included in a DVT risk stratification model system were erythrocyte sedimentation rate, antithrombin III, C-reactive protein, D-dimer, and N-terminal pro-brain natriuretic peptide. The DVT risk stratification system was moderately prognostic (area under the curve: 0.838; 95% confidence interval: 0.771-0.904; P < .001), whereas its performance was as follows-sensitivity, 100%; specificity, 20%; positive predictive value, 21%; and negative predictive value, 100%. The prevalence of DVT and DVT + superficial thrombophlebitis was 7.5% and 3.1%, respectively. These routine blood tests may prove helpful to stratify the DVT risk in medical patients. PMID- 27765881 TI - Oral Toxicity of 2,4-Dinitroanisole in Rats. AB - Subacute and subchronic studies were conducted to assess the toxicity of 2,4 dinitroanisole (DNAN) and to provide information important for protecting the health of military and civilian personnel. In the subchronic study, male and female Sprague-Dawley rats were dosed with DNAN via oral gavage at 0, 1.25, 5, 20, and 80 mg/kg/d. Likely owing to its conversion to 2,4-dinitrophenol, an inhibitor of energy homeostasis, DNAN caused an apparent increase in metabolism, leading to reduced feed efficiency ratios and body mass gains in males. Anemia, splenic enlargement, hemosiderosis, and extramedullary hematopoiesis indicated blood as a target organ, with females more sensitive than males. The DNAN was a testicular toxicant, causing decreased mass of testes and epididymides, as well as degeneration and atrophy of testicular seminiferous tubules and epididymal aspermia. Stereotypical behavior in males, gait irregularities, and cerebellar lesions indicated that DNAN is neurotoxic. Splenic enlargement, anemia, testicular toxicity, and neurotoxicity occurred only at or near lethal doses in the subchronic study. PMID- 27765882 TI - Testosterone downregulates angiotensin II type-2 receptor via androgen receptor mediated ERK1/2 MAP kinase pathway in rat aorta. AB - INTRODUCTION: Blood pressure is lower in females than males. Angiotensin II type 2 receptor (AT2R) induces vasodilation. This study determined whether sex differences in vascular AT2R expression occur and if androgens exert control on AT2R expression in the vasculature. METHODS: AT2Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. RESULTS: AT2R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT2R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT2R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT2R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT2R downregulation in isolated aorta was blocked by an androgen receptor antagonist. Furthermore, blockade of ERK1/2 but not p38 MAP kinase or TGFbeta signaling with specific inhibitors abolished dihydrotestosterone-induced AT2R downregulation. CONCLUSION: Androgens downregulate AT2R expression levels in aorta, in vivo and ex vivo. The androgen receptor-mediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT2R expression, implicating androgens' contributing role to gender differences in vascular AT2R expression. PMID- 27765884 TI - Consideration of food wastage along the supply chain in lifecycle assessments: A mini-review based on the case of tomatoes. AB - In recent years, increased light has been shed on the large amounts of food wasted along the food supply chain (FSC). As lifecycle assessments (LCAs) are commonly used for estimations of environmental impacts from food production, it is relevant to investigate and discuss how such wastage is reflected in foodstuff LCAs. The objective of the present paper is to review a larger set of LCAs of foodstuff in order to (1) investigate if and how wastage along the FSC is addressed and (2) explore the importance of including wastage accumulated along the FSC in terms of environmental impacts. Twenty-eight LCA case studies and two review papers, focusing on tomatoes, were reviewed and greenhouse gas (GHG) emissions chosen as indicator for the second objective. Only one third of the studies consider wastage at some part of the supply chain, in many cases in an inconsistent manner, and only in nine cases were GHG emissions from wastage included in overall systems GHG emissions. In these, wastage accounts for between 2 and 33% of total contribution to climate change. Omitting wastage when conducting LCA of foodstuff could result in underestimations of environmental impacts. Occurrence of wastage along all phases of the supply chain should be acknowledged in order to estimate environmental benefits from prevention and to identify areas where strategies with the aim of reducing wastage could be most efficient. PMID- 27765883 TI - Inhibitory effects of telmisartan on culture and proliferation of and Kv1.3 potassium channel expression in peripheral blood CD4+ T lymphocytes from Xinjiang Kazakh patients with hypertension. AB - INTRODUCTION: Activation of T lymphocytes, for which potassium channels are essential, is involved in the development of hypertension. In this study, we explored the inhibitory effects of telmisartan on the culture and proliferation of and Kv1.3 potassium channel expression in peripheral blood CD4+ T lymphocytes derived from Xinjiang Kazakh patients with hypertension. METHODS: CD4+ T-cell samples from hypertensive Kazakh patients and healthy Kazakh people were divided into healthy control, case control, telmisartan, and 4-aminopytidine groups. Changes in the expression levels of interleukin (IL)-6 and IL-17 in the blood of the healthy control and case control subjects were detected by enzyme-linked immunosorbent assay. Peripheral blood CD4+ T lymphocytes were first activated and proliferated in vitro and then incubated for 0, 24, and 48 h under various treatment conditions. Thereafter, changes in CD4+ T-lymphocytic proliferation were determined using Cell Counting Kit-8 and microscope photography. Changes in messenger RNA (mRNA) and protein expression of the Kv1.3 potassium channel in CD4+ T lymphocytes were detected using real-time quantitative polymerase chain reaction and Western blots, respectively. RESULTS: The IL-6 and IL-17 expression levels were significantly higher in the blood of the hypertensive Kazakh patients than in the healthy Kazakh people. Telmisartan inhibited T-lymphocytic proliferation, as well as the mRNA and protein expression of the Kv1.3 potassium channel in CD4+ T lymphocytes, and the inhibitory effects were time-dependent, with the strongest inhibition observed after 48 h and significantly weaker inhibition observed after 24 h of treatment. CONCLUSIONS: Telmisartan may potentially regulate hypertensive inflammatory responses by inhibiting T lymphocytic proliferation and Kv1.3 potassium channel expression in CD4+ T lymphocytes. PMID- 27765885 TI - Novel oral anticoagulants for acute coronary syndrome. AB - Acute coronary syndrome (ACS) is a cardiovascular condition with a multifactorial pathophysiology that includes atherosclerotic plaques, platelet activation and thrombin production, among others. Thrombin production and the prothrombotic state of ACS patients have provided a role for anticoagulants to treat patients during the acute event and has led to subsequent research for the post-acute state. Warfarin has an indication for ACS, however, it is restricted to specific patients and many factors limit its use. Therefore, novel oral anticoagulants (NOACs) are being explored for ACS. Limitations for the use of NOACs in ACS are centered on the increased risk of bleeding that occurs when these agents are added to the current standard of care with dual antiplatelet therapy. Rivaroxaban is the only NOAC that has achieved approval in Europe for this indication with none of the NOAC currently approved in the US for use in ACS. Ongoing studies for rivaroxaban and apixaban may provide evidence to further clarify the place in therapy for NOAC agents in ACS management. PMID- 27765886 TI - A Factor Analytic Investigation of the Person-in-Recovery and Provider Versions of the Revised Recovery Self-Assessment (RSA-R). AB - Recovery is understood as living a life with hope, purpose, autonomy, productivity, and community engagement despite a mental illness. The aim of this study was to provide further information on the psychometric properties of the Person-in-Recovery and Provider versions of the Revised Recovery Self-Assessment (RSA-R), a widely used measure of recovery orientation. Data from 654 individuals were analyzed, 519 of whom were treatment providers (63.6% female), while 135 were inpatients (10.4% female) of a Canadian tertiary-level psychiatric hospital. Confirmatory and exploratory techniques were used to investigate the factor structure of both versions of the instrument. Results of the confirmatory factor analyses showed that none of the four theoretically plausible models fit the data well. Principal component analyses could not replicate the structure obtained by the scale developers either and instead resulted in a five-component solution for the Provider and a four-component solution for the Person-in-Recovery version. When considering the results of a parallel analysis, the number of components to retain dropped to two for the Provider version and one for the Person-in-Recovery version. We can conclude that the RSA-R requires further revision to become a psychometrically sound instrument for assessing recovery-oriented practices in an inpatient mental health-care setting. PMID- 27765887 TI - Total Aortic Arch Replacement: Advantages of Varied Techniques. AB - We review the operative techniques of aortic arch replacement. Aortic arch replacement presents several formidable challenges, as it requires arresting the circulation to the body and replacement of the brachiocephalic vessels with special consideration for protecting the central nervous system. Perfusion strategies, selective antegrade cerebral perfusion, and operative graft selection are key elements in aortic arch replacement surgery. Standard approaches include the island technique, the branched graft technique, and the "Spielvogel" trifurcated graft technique-each having its own advantages. In addition, thoracic aortic aneurysms involving the arch and descending aorta pose a substantial surgical challenge and often require hybrid or nonclamp technique with staged operative interventions. Hybrid and endovascular (thoracic endovascular aortic repair) techniques for the descending aorta are evolving and require consideration in operative planning. Areas of controversy include management of the subclavian artery, extent of distal arch replacement, elephant trunk and hybrid frozen elephant trunk techniques, and use and timing of staged approaches. Aortic arch replacement remains a complex, potentially difficult procedure. Better understanding of the potential open approaches to arch replacement will optimize the potential outcomes for patients. Aortic arch pathology is best served by tailoring the procedure to the patient-specific anatomy and pathology. PMID- 27765888 TI - Neonatal Sepsis in Haiti. AB - Infections (including sepsis, meningitis, pneumonia and tetanus) stand as a major contributor to neonatal mortality in Haiti (22%). Infants acquire bacteria that cause neonatal sepsis directly from the mother's blood, skin or vaginal tract either before or during delivery. Nosocomial and environmental pathogens introduce further risk after delivery. The absence of cohesive medical systems and methods for collecting information limits the available data in countries such as Haiti. This study seeks to add more information on the burden of severe bacterial infections and their etiology in neonates of Haiti. Researchers conducted a secondary retrospective analysis of a de-identified database from the Neonatal Intensive Care Unit (NICU) at Nos Petit Freres et Soeurs-St. Damien Hospital (NPFS-SDH). Records from 1292 neonates admitted to the NICU at NPFS-SDH in Port-au-Prince Haiti from 2013 to 2015 were reviewed. Sepsis accounted for 708 of 1292 (54.8%) of all admissions to the NICU. Infants admitted for sepsis had a mortality rate of 23% (163 of 708 infants admitted for sepsis). The most common organism cultured was Streptococcus agalactiae, followed by Klebsiella pneumoniae, Pseudomonas aeroginusa, Enterobacter aerogenes, Staphylococcus aureus and Proteus mirabillis Failure to order or obtain a culture was associated with an increased fatality (odds ratio 2.4) for infants with sepsis. Resistance should be a concern when treating empirically. PMID- 27765890 TI - BETA DOSE EVALUATION ALGORITHM FOR CaSO4:Dy BYSED TLD BADGE USED IN COUNTRYWIDE PERSONNEL MONITORING PROGRAMME IN INDIA. AB - The prevalent algorithm for the estimation of beta dose, which in turn is used for estimation of skin dose for exposures involving beta radiations was observed to significantly overestimate the dose in individual monitoring based on CaSO4:Dy TLD badge in India. A new algorithm has been developed by estimating the correction factor from the response of dosemeter to different beta sources at various angles of incidence. The correction factor was observed to vary linearly with the ratio of the responses of dosemeter element without filter (D3) and dosemeter element under Perspex filter (D2). The correction factor determined using the ratio of D3 and D2 was applied to the response (D3) of dosemeter element without filter for estimation of beta dose. Protocol for identification of beta in the mixed gamma beta fields was defined such that it resulted in nearly same correction factor for given beta source in both gamma beta mixed fields and pure beta fields. The beta dose evaluation algorithm has provided the beta dose estimation within the required accuracy for >90% cases obtained from national quality assurance test data from different laboratories. PMID- 27765889 TI - Epidemiological Features of Hand, Foot and Mouth Disease during the Period of 2008-14 in Wenzhou, China. AB - This study aimed to analyze the epidemiological characteristics of hand, foot and mouth disease (HFMD) during 2008-14 in Wenzhou, China. The epidemiological data of HFMD retrieved from the Wenzhou Center for Disease Control and Prevention were retrospectively analyzed. HFMD infections with enterovirus 71 (EV71), Cox A16 or other pathogens were further verified by polymerase chain reaction (PCR) and real time PCR. A total of 213 617 cases of HFMD were reported between 2008 and 2014 in Wenzhou. The average incidence was 384.31 of 100 000, and the fatality rate was 0.140/00. The incidence of HFMD peaked between April and July, and it occurred more frequently in males than in females. Approximately 92.68% of the HFMD patients were children aged <5 years. Nearly 80% of the cases were diagnosed within 2 days after onset. The major HFMD pathogen was EV71. This study suggested that appropriate comprehensive prevention and control measures should be taken to avoid the spread of HFMD. PMID- 27765891 TI - Evaluation of Reference Urinary Excretion Concentrations of Selected Radionuclides Corresponding to Clinical Decision Guides for Application in Radiological and in Nuclear Emergencies. AB - Radiological or nuclear emergency situations could lead to incorporation of radionuclides by the population. Intakes of radionuclides can be evaluated through measurements of radionuclides present in organs and tissues, or in urinary and/or fecal excretion. In an emergency situation involving a large number of people, the decision to provide medical treatment to an individual will likely be based on a single measurement. For that purpose, the National Council on Radiation Protection and Measurements (NCRP) has presented the Clinical Decision Guide (CDG) quantity, which corresponds to an intake amount of a radionuclide by an individual for which treatment is recommended. However, the NCRP recommends using one-fifth of the CDG for pregnant women and children which could result in an effective or equivalent dose in excess of the dose constraint. Tables of reference urinary excretion concentrations which are associated with an intake of one CDG for inhalation and ingestion intake scenarios of several forms of 60Co, 90Sr, 137Cs, 192Ir, 238Pu, 239Pu and 241Am have been calculated and are presented for the following categories of members of the public: 3 months old, 1 y, 5 y, 10 y, 15 y, adult and pregnant woman. PMID- 27765892 TI - ESTIMATION OF NEUTRON SCATTER CORRECTION FOR CALIBRATION OF PERSONNEL DOSIMETER AND DOSERATEMETER AGAINST 241Am-Be SOURCE-MONTE CARLO SIMULATION AND MEASUREMENTS. AB - Neutron scatter contributions as a function of distance along the transverse axis of 241Am-Be source were estimated by three different methods such as shadow cone, semi-empirical and Monte Carlo. The Monte Carlo-based FLUKA code was used to simulate the existing room used for the calibration of CR-39 detector as well as LB6411 doseratemeter for selected distances from 241Am-Be source. The modified 241Am-Be spectra at different irradiation geometries such as at different source detector distances, behind the shadow cone, at the surface of the water phantom were also evaluated using Monte Carlo calculations. Neutron scatter contributions, estimated using three different methods compare reasonably well. It is proposed to use the scattering correction factors estimated through Monte Carlo simulation and other methods for the calibration of CR-39 detector and doseratemeter at 0.75 and 1 m distance from the source. PMID- 27765893 TI - Effective Doses of Employees at the Former Uranium Processing Plant MAPE Mydlovary, Czechoslovakia. AB - Results are presented of a survey of almost 1000 dosimetric records of employees at the former uranium processing plant MAPE Mydlovary. Located ~20 km to the north-west of Ceske Budejovice in South Bohemia, it was the place where most of the uranium ore mined in Czechoslovakia in the years from 1962 to 1991 was processed. The records refer to incorporation of short-lived radon progeny and long-lived radionuclides as well as external gamma exposure. The average annual doses calculated from the recorded data were 2.7 +/- 1.4, 5.0 +/- 3.1 and 1.7 +/- 0.9 mSv from these three sources, respectively. Thus, the relative contributions of these components to the effective dose were 29 +/- 6, 53 +/- 14 and 18 +/- 13% , respectively. This is different from the findings in an earlier study for the exposure of uranium miners, where the overall doses were similar, but over 50% was contributed by short-lived radon progeny. No legal limits applicable at the time were exceeded, as the inclusion of long-lived radionuclides in the dose calculations was not yet obligatory. PMID- 27765895 TI - Transition of intestinal fatty acid-binding protein on hypothermic circulatory arrest with cardiopulmonary bypass. AB - INTRODUCTION: Intestinal fatty acid-binding protein (I-FABP) is increasingly employed as a highly specific marker of intestinal necrosis. However, the value of this marker associated with cardiovascular surgery with hypothermic circulatory arrest is unclear. The aim of this study was to measure serum I-FABP levels and provide the transition of I-FABP levels with hypothermic circulatory arrest to help in the management of intestinal perfusion. METHODS: From August 2011 to September 2013, 33 consecutive patients who had aortic arch surgery with hypothermic circulatory arrest or heart valve surgery performed were enrolled in the study. Twenty patients had aortic surgery with hypothermic (23-29 degrees C) circulatory arrest and 13 patients had heart valve surgery with cardiopulmonary bypass (33 degrees C). RESULTS: I-FABP levels increased, both in patients undergoing aortic surgery with hypothermic circulatory arrest and heart valve surgery with cardiopulmonary bypass, reaching peak levels shortly after the administration of protamine. I-FABP levels in patients with aortic surgery were significantly higher with circulatory arrest. They reached peak levels immediately after recirculation and there was a significant drop at the end of surgery (p<0.001). I-FABP levels in heart valve surgery were gradually increased, with the highest at the administration of protamine; they gradually decreased. Peak I-FABP levels were significantly higher in patients undergoing aortic surgery with hypothermic circulatory arrest than in patients with heart valve surgery. However, no postoperative reperfusion injury occurred in the intestinal tract due to the use of hypothermic organ protection. CONCLUSION: Plasma I-FABP monitoring could be a valuable method for finding an intestinal ischemia in patients with cardiovascular surgery. PMID- 27765896 TI - Assistive technologies at home for people with a memory disorder. AB - The aim of this study was to assess in practice whether assistive technologies support and facilitate the work of a family caregiver or care staff, and whether these technologies support the independence of a person with a memory disorder. A comprehensive set of supportive devices and alarm systems were experimentally tested in the care of five test subjects in an assisted living facility by eight nurses, and in the care of four test subjects in a home environment by three family caregivers and one care team. Questionnaires, diaries and logged data were used to evaluate the benefits of the devices. Simple aids and alarm systems that did not need much adjusting were considered most useful by caregivers and nurses, though multiple false alarms occurred during the test period. Technical connection problems, complex user interface, and inadequate sound quality were the primary factors reducing the utility of the tested devices. Further experimental research is needed to evaluate the utility of assistive technologies in different stages of a memory disorder. PMID- 27765894 TI - MicroRNA-30b regulates expression of the sodium channel Nav1.7 in nerve injury induced neuropathic pain in the rat. AB - Voltage-gated sodium channels, which are involved in pain pathways, have emerged as major targets for therapeutic intervention in pain disorders. Nav1.7, the tetrodotoxin-sensitive voltage-gated sodium channel isoform encoded by SCN9A and predominantly expressed in pain-sensing neurons in the dorsal root ganglion, plays a crucial role in nociception. MicroRNAs are highly conserved, small non coding RNAs. Through binding to the 3' untranslated region of their target mRNAs, microRNAs induce the cleavage and/or inhibition of protein translation. Based on bioinformatics analysis using TargetScan software, we determined that miR-30b directly targets SCN9A To investigate the roles of Nav1.7 and miR-30b in neuropathic pain, we examined changes in the expression of Nav1.7 in the dorsal root ganglion by miR-30b over-expression or knockdown in rats with spared nerve injury. Our results demonstrated that the expression of miR-30b and Nav1.7 was down-regulated and up-regulated, respectively, in the dorsal root ganglion of spared nerve injury rats. MiR-30b over-expression in spared nerve injury rats inhibited SCN9A transcription, resulting in pain relief. In addition, miR-30b knockdown significantly increased hypersensitivity to pain in naive rats. We also observed that miR-30b decreased Nav1.7 expression in PC12 cells. Taken together, our results suggest that miR-30b plays an important role in neuropathic pain by regulating Nav1.7 expression. Therefore, miR-30b may be a promising target for the treatment of chronic neuropathic pain. PMID- 27765897 TI - The Bifocal Lens Model and Equation: Examining the Linkage between Clinical Judgments and Decisions. AB - BACKGROUND: Brunswik's Lens Model and lens model equation (LME) have been applied extensively in medical decision making. Clinicians often face the dual challenge of formulating a judgment of patient risk for some adverse outcome and making a yes or no decision regarding a particular risk-reducing treatment option. OBJECTIVE: In this article, I examine the correlation between clinical risk judgments and treatment-related decisions, referring to this linkage as "cohesion". A novel form of the LME is developed to decompose cohesion. The approach is "bifocal" in that it focuses on 2 sets of linked responses from the same individual. METHODS: Data from 2 studies were analyzed to illustrate how individual differences in cohesion could be explained by differences in the parameters of the bifocal lens model equation (BiLME). RESULTS: Cohesion varied because of differences in cognitive control, similarities in the judgment and decision policies, and a possible reliance on a subjective threshold value applied to the judgments to make decisions. The parameters of the BiLME accounted for individual differences in cohesion; however, their relative influences differed between the two studies. CONCLUSION: The BiLME links the results from two regression models-one linear and one logistic-based on the same set of cases. In its current form, the equation holds promise for understanding cognitive individual differences that could underlie practice variation. With minor modifications, it becomes possible to apply the equation to traditional, dual system judgment analysis studies, where continuous judgments are compared with an ecology composed of dichotomous outcomes, or vice versa. In this regard, the BiLME is quite flexible and adds to the set of tools available to judgment analysts. PMID- 27765898 TI - Cerebral perfusion difference between hemispheres with symptomatic and asymptomatic intracranial arterial stenosis. PMID- 27765899 TI - Laparoscopy in Duodenal Switch: Safe and Halves Length of Stay in a Nationwide Cohort from the Scandinavian Obesity Registry. AB - BACKGROUND AND AIMS: Unsatisfactory weight loss after gastric bypass or sleeve gastrectomy in super-obese patients (body mass index > 50) is a growing concern. Biliopancreatic diversion with duodenal switch results in greater weight loss, but is technically challenging to perform, especially as a laparoscopic procedure (Lap-DS). The aim of this study was to compare perioperative outcomes of Lap-DS and the corresponding open procedure (O-DS) in Sweden. MATERIAL AND METHODS: The data source was a nationwide cohort from the Scandinavian Obesity Surgery Registry and 317 biliopancreatic diversion with duodenal switch patients (mean body mass index = 56.7 +/- 6.6 kg/m2, 38.4 +/- 10.2 years, and 57% females) were analyzed. Follow-up at 30 days was complete in 98% of patients. RESULTS: The 53 Lap-DS patients were younger than the 264 patients undergoing O-DS (35.0 vs 39.1 years, p = 0.01). Operative time was 163 +/- 38 min for lap-DS and 150 +/- 31 min for O-DS, p = 0.01, with less bleeding in Lap-DS (94 vs 216 mL, p < 0.001). There was one conversion to open surgery. Patients undergoing Lap-DS had a shorter length of stay than O-DS, 3.3 versus 6.6 days, p = 0.02. No significant differences in overall complications within 30 days were seen (12% and 17%, respectively). Interestingly, the two leaks in Lap-DS were located at the entero enteric anastomosis, while three out of four leaks in O-DS occurred at the top of the gastric tube. CONCLUSION: Lap-DS can be performed by dedicated bariatric surgeons as a single-stage procedure. The use of laparoscopic approach halved the length of stay, without increasing the risk for complications significantly. Any difference in long-term weight result is pending. PMID- 27765900 TI - An Embodied Account of Early Executive-Function Development. AB - The importance of executive functioning for later life outcomes, along with its potential to be positively affected by intervention programs, motivates the need to find early markers of executive functioning. In this study, 18-month-olds performed three executive-function tasks-involving simple inhibition, working memory, and more complex inhibition-and a motion-capture task assessing prospective motor control during reaching. We demonstrated that prospective motor control, as measured by the peak velocity of the first movement unit, is related to infants' performance on simple-inhibition and working memory tasks. The current study provides evidence that motor control and executive functioning are intertwined early in life, which suggests an embodied perspective on executive functioning development. We argue that executive functions and prospective motor control develop from a common source and a single motive: to control action. This is the first demonstration that low-level movement planning is related to higher order executive control early in life. PMID- 27765901 TI - A FASN-TGF-beta1-FASN regulatory loop contributes to high EMT/metastatic potential of cisplatin-resistant non-small cell lung cancer. AB - Cisplatin-resistant A549CisR and H157CisR cell lines were developed by treating parental A549 (A549P) and H157 (H157P) cells. These cisplatin-resistant cells showed slight growth retardation, but exhibited higher epithelial-mesenchymal transition (EMT) and increased metastatic potential compared to parental cells. We observed a highly up-regulated fatty acid synthase (FASN) level in A549CisR and H157CisR cells compared to parental cells and the up-regulation of FASN was also detected in A549P and H157P cells after short time treatment with cisplatin, suggesting that the high level of FASN in cisplatin-resistant cells may be from the accumulated cellular responses during cisplatin-resistance developmental process. We next investigated whether the inhibition of FASN by using a specific FASN inhibitor, cerulenin, can influence growth and EMT/metastatic potential of A549CisR and H157CisR cells. There was slight growth inhibition, but significantly reduced EMT/metastatic potential in cisplatin-resistant cells upon inhibitor treatment. The in vitro result was further investigated in orthotopic xenograft mouse models established with luciferase-tagged H157P and H157CisR cells. Mice were injected with cerulenin or vehicle after tumors were developed. No significant tumor regression was detected at the end of cerulenin treatment, but IHC staining showed higher expression of EMT/metastasis markers in H157CisR cell-derived tumors than H157P cell-derived tumors, and showed dramatic reduction of these markers in tumor tissues of cerulenin-treated mice, confirming the in vitro results. In mechanism dissection studies, we revealed the existence of the FASN-TGF-beta1-FASN positive loop in A549CisR and H157CisR cells, but not in parental cells, which is believed to augment the FASN function in cisplatin resistant cells. PMID- 27765902 TI - Delivery of a peptide-drug conjugate targeting the blood brain barrier improved the efficacy of paclitaxel against glioma. AB - The challenge of effectively delivering therapeutic agents to the brain has created an entire field of active research devoted to overcoming the blood brain barrier (BBB) and efficiently delivering drugs to the brain. Angiopep-2 can trigger transcytosis and traverse the BBB by recognizing low-density lipoprotein related protein-1 (LRP-1) expressed on the brain capillary endothelial cells. Here, we designed a novel strategy for the delivery of drugs to the brain. The novel drug delivery system was a combination of a receptor-targeting ligand, such as low-density lipoprotein related protein 1, and a cell-penetrating peptide (CPP). It was hypothesized that this conjugate will enhance the delivery of associated therapeutic cargo across the BBB and increase the permeability of a solid tumor. Our findings indicate that the combination of these two agents in a delivery vehicle significantly improved translocation of small molecules (paclitaxel) into the brain compared to the vehicle treatment, which contained only receptor-targeting ligand. The application of this strategy could potentially expand the horizons for the treatment of central nervous system disorders. PMID- 27765903 TI - Near-infrared photoimmunotherapy with galactosyl serum albumin in a model of diffuse peritoneal disseminated ovarian cancer. AB - Near-infrared photoimmunotherapy (NIR-PIT) is a highly cell-selective cancer therapy based on an armed antibody conjugated with a phthalocyanine-based photo absorber, IRDye700DX (IR700). NIR-PIT can quickly kill target cells that express specific proteins on the cellular membrane but only when the antibody-IR700 conjugate binds to the cell membrane and is then exposed to NIR light. NIR-PIT is highly selective based on the specificity of the antibody. Galactosyl serum albumin (GSA) is composed of albumin decorated with galactose molecules conjugated to the carboxyl groups of albumin. GSA binds to beta-D-galactose receptors, a surface lectin, which are overexpressed on the cell surface of many cancers, including ovarian cancers and is quickly internalized after binding. Here, we demonstrate the feasibility of NIR-PIT in a model of disseminated peritoneal ovarian cancer (SHIN3 cells) using GSA-IR700 that binds to beta-D galactose receptors. GSA-IR700 bound quickly to SHIN3 cells, then accumulated in the endo-lysosomes. Cell-specific killing was observed in vitro, yet a relatively large dose of NIR light exposure was required for cell killing compared to antibody-IR700 conjugates. To evaluate in vivo therapeutic effects of GSA-IR700 NIR-PIT, peritoneal disseminated SHIN3 tumor-bearing mice were separated into four groups: no treatment; NIR light only; GSA-IR700 only; and GSA-IR700 NIR-PIT. Repeated NIR-PIT showed significant suppression of tumor based on bioluminescence compared to the other groups (p < 0.05). Thus, repeated NIR-PIT using GSA-IR700 can achieve efficient antitumor effects, although GSA-IR700 NIR-PIT was less effective than antibody-IR700 NIR-PIT conjugates likely due to the rapid internalization of GSA-IR700. PMID- 27765904 TI - Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells. AB - Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a primary salinomycin resistance factor in OS cells. DNA-PKcs inhibitors (NU7026, NU7441 and LY294002) or DNA-PKcs shRNA knockdown dramatically potentiated salinomycin-induced death and apoptosis of OS cells (U2OS and MG-63 lines). Further, forced-expression of microRNA-101 ("miR-101") downregulated DNA-PKcs and augmented salinomycin's cytotoxicity against OS cells. Reversely, over-expression of DNA-PKcs in OS cells inhibited salinomycin's lethality. For the mechanism study, we show that DNA-PKcs is required for salinomycin-induced pro-survival autophagy activation. DNA-PKcs inhibition (by NU7441), shRNA knockdown or miR-101 expression inhibited salinomycin-induced Beclin-1 expression and autophagy induction. Meanwhile, knockdown of Beclin-1 by shRNA significantly sensitized salinomycin-induced OS cell lethality. In vivo, salinomycin administration suppressed U2OS xenograft tumor growth in severe combined immuno-deficient (SCID) mice, and its anti-tumor activity was dramatically potentiated with co administration of the DNA-PKcs inhibitor NU7026. Together, these results suggest that DNA-PKcs could be a primary resistance factor of salinomycin in OS cells. DNA-PKcs inhibition or silence may thus significantly increase salinomycin's sensitivity in OS cells. PMID- 27765905 TI - Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients. AB - Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts. Analysis of 5-hydroxymethylcytosine and ENCODE data indicate that at least five of these nine genes have an increase in 5 hydroxymethylcytosine and a more open chromatin structure in hypoxia versus normoxia and are putative targets of hypoxia inducible factor (HIF) as they contain HIF binding sites in their regulatory regions. Four of these genes are key components of the glycolytic pathway and another three are directly involved in cellular metabolism. We experimentally validated our computational findings demonstrating that seven of the nine genes are significantly up-regulated in response to hypoxia in the four neuroblastoma cell lines tested. This compact and robustly validated group of genes, is associated with the hypoxia response in aggressive neuroblastoma and may represent a novel target for biomarker and therapeutic development. PMID- 27765906 TI - Targeted NGS, array-CGH, and patient-derived tumor xenografts for precision medicine in advanced breast cancer: a single-center prospective study. AB - BACKGROUND: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient derived tumor xenografts (PDX) could be obtained in this population. RESULTS: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%). A targeted therapy could be proposed to 22 patients (64%), either through a clinical trial (n=15) and/or using already registered drugs (n=21). Ten patients (29%) eventually received targeted treatment, 2 of them deriving clinical benefit. Of 22 patients subjected to mouse implantation, 10 had successful xenografting (45%), mostly in triple-negative aBC. METHODS: aBC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Genomic profiling was established by whole-genome array comparative genomic hybridization (aCGH) and targeted next-generation sequencing (NGS) of 365 candidate cancer genes. For a subset of patients, a sample of fresh tumor was orthotopically implanted in humanized cleared fat pads of NSG mice for establishing PDX. CONCLUSIONS: Precision medicine can be implemented in a single center in the context of clinical practice and may allow genomic-driven treatment in approximately 30% of aBC patients. PDX may be obtained in a significant fraction of cases. PMID- 27765909 TI - In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC. AB - Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines.PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC 0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines.This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently. PMID- 27765907 TI - Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway. AB - OBJECTIVE: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. RESULTS: The expressions of ERS-related proteins (PEAK, eIF2alpha and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h. Compared with the blank group, the tunicamycin, BEZ235 and tunicamycin + BEZ235 groups exhibited decreased expressions of p-PI3K, p-AKT and p-mTOR, and increased expressions of autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis proteins (Bax and procaspase-3), and the most obvious changes were observed in the tunicamycin + BEZ235 group. MATERIALS AND METHODS: CCK-8 assay was applied to select the best cell line from five SCLC cell lines (NCI-H446, H69, H526, H146 and H209). Finally, NCI-H446 and H69 cells were selected for further experiments. NCI-H446/CDDP and H69/CDDP were selected and divided into the blank group, tunicamycin (an ESR inducer) group, BEZ235 (inhibitors of PI3K/AKT/mTOR pathway) group and tunicamycin + BEZ235 group. Cell apoptosis was detected by flow cytometry. Autophagy was observed by fluorescence microscopy and flow cytometry. Western blotting was used to detect the expressions of ERS-related proteins, autophagy-related proteins, apoptosis related proteins and PI3K/AKT/mTOR pathway-related proteins. CONCLUSIONS: Our findings provide evidence that the activation of ERS could promote autophagy and apoptosis and reverse chemoresistance of human SCLC cells by inhibiting the PI3K/AKT/mTOR pathway. PMID- 27765910 TI - Suppression of gain-of-function mutant p53 with metabolic inhibitors reduces tumor growth in vivo. AB - Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone proteins and ubiquitination all contributed to this process. Interestingly, phenformin and 2-deoxyglucose also reduced tumor growth in syngeneic mice harboring the p53 mutation. Thus, destabilizing mutant p53 protein in order to kill cells exhibiting "oncogene addiction" could be a promising strategy for combatting p53 mutant tumors. PMID- 27765912 TI - An assessment of the benefit-risk balance of FOLFIRINOX in metastatic pancreatic adenocarcinoma. AB - BACKGROUND: We sought to assess the benefit-risk balance of FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic adenocarcinoma. METHODS: We used generalized pairwise comparisons. This statistical method permits the simultaneous analysis of several prioritized outcome measures. The first priority outcome was survival time (OS). Differences in OS that exceeded two months were considered clinically relevant. The second priority outcome was toxicity. The overall treatment effect was quantified using the net chance of a better outcome, which can be interpreted as the net probability for a random patient treated in the FOLFIRINOX group to have a better overall outcome than a random patient in the gemcitabine group. RESULTS: In this trial 342 patients received either FOLFIRINOX or gemcitabine. The net chance of a better outcome favored strongly and significantly the FOLFIRINOX group (24.7; P<.001), suggesting a favorable benefit-risk balance of FOLFIRINOX versus gemcitabine. The positive benefit-risk balance of FOLFIRINOX was observed throughout all sensitivity analyses. CONCLUSIONS: Generalized pairwise comparisons are useful to perform a quantitative assessment of the benefit-risk balance of new treatments. It provides a clinically intuitive way of comparing patients with respect to all important efficacy and toxicity outcomes. Overall the benefit-risk balance of FOLFIRINOX was strongly positive. PMID- 27765911 TI - Integrin alpha2beta1 inhibits MST1 kinase phosphorylation and activates Yes associated protein oncogenic signaling in hepatocellular carcinoma. AB - The Hippo pathway regulates the down-stream target Yes-associated protein (YAP) to maintain organ homeostasis, which is commonly inactivated in many types of cancers. However, how cell adhesion dysregulates the Hippo pathway activating YAP oncogene in hepatocellular carcinoma (HCC) remains unclear. Our findings demonstrate that alpha2beta1 integrin (but not other beta1 integrins) expressed in HCC cells, after binding to collagen extracellular matrix, could inhibit MST1 kinase phosphorylation and activate YAP pro-oncogenic activities. Knockdown of integrin alpha2 gene (ITGA2) suppressed YAP targeted gene expression in vitro. alpha2beta1 and collagen binding resulted in suppressing Hippo signaling of mammalian sterile 20-like kinase 1 (MST1) and Large tumor suppressor homolog 1 (LATS1) with concomitant activation of YAP-mediated connective tissue growth factor (CTGF) gene expression. In vitro kinase assay showed that MST1 is an immediate downstream target of integrin alpha2 with S1180 residue as the critical phosphorylation site. Clinical correlational analysis using a gene expression dataset of 228 HCC tumors revealed that ITGA2 expression was significantly associated with tumor progression, and co-expression with YAP targeted genes (AXL receptor tyrosine kinase, CTGF, cyclin D1, glypican 3, insulin like growth factor 1 receptor, and SRY-box 4) correlated with survivals of HCC patients. In conclusion, alpha2beta1 integrin activation through cellular adhesion impacts the Hippo pathway in solid tumors and modulates MST1-YAP signaling cascade. Targeting integrin alpha2 holds promises for treating YAP-positive HCC. PMID- 27765913 TI - An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells. AB - One of the main limitations, when studying cancer-bone metastasis, is the complex nature of the native bone environment and the lack of reliable, simple, inexpensive models that closely mimic the biological processes occurring in patients and allowing the correct translation of results. To enhance the understanding of the mechanisms underlying human bone metastases and in order to find new therapies, we developed an in vitro three-dimensional (3D) cancer-bone metastasis model by culturing human breast or prostate cancer cells with human bone tissue isolated from female and male patients, respectively. Bone tissue discarded from total hip replacement surgery was cultured in a rolling apparatus system in a normoxic or hypoxic environment. Gene expression profile, protein levels, histological, immunohistochemical and four-dimensional (4D) micro-CT analyses showed a noticeable specificity of breast and prostate cancer cells for bone colonization and ingrowth, thus highlighting the species-specific and sex specific osteotropism and the need to widen the current knowledge on cancer-bone metastasis spread in human bone tissues. The results of this study support the application of this model in preclinical studies on bone metastases and also follow the 3R principles, the guiding principles, aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes. PMID- 27765914 TI - MiRNA-145 increases therapeutic sensibility to gemcitabine treatment of pancreatic adenocarcinoma cells. AB - Pancreatic adenocarcinoma is one of the most leading causes of cancer-related deaths worldwide. Although recent advances provide various treatment options, pancreatic adenocarcinoma has poor prognosis due to its late diagnosis and ineffective therapeutic multimodality. Gemcitabine is the effective first-line drug in pancreatic adenocarcinoma treatment. However, gemcitabine chemoresistance of pancreatic adenocarcinoma cells has been a major obstacle for limiting its treatment effect. Our study found that p70S6K1 plays an important role in gemcitabine chemoresistence. MiR-145 is a tumor suppressor which directly targets p70S6K1 for inhibiting its expression in pancreatic adenocarcinoma, providing new therapeutic scheme. Our findings revealed a new mechanism underlying gemcitabine chemoresistance in pancreatic adenocarcinoma cells. PMID- 27765915 TI - Variable but consistent pattern of Meningioma 1 gene (MN1) expression in different genetic subsets of acute myelogenous leukaemia and its potential use as a marker for minimal residual disease detection. AB - Meningioma 1 (MN1) gene overexpression has been reported in acute myeloid leukaemia (AML) patients and identified as a negative prognostic factor. In order to characterize patients presenting gene overexpression and to verify if MN1 transcript could be a useful marker for minimal residual disease detection, MN1 was quantified in 136 AML patients with different cytogenetic risk and in 50 normal controls. In 20 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment and in 8 patients with NPM1 mutation, we performed a simultaneous analysis of MN1 and the fusion-gene transcript or NPM1 mutation during follow-up. Sequential MN1 and WT1 analysis was also performed in 13 AML patients lacking other molecular markers. The data obtained show that normal cells consistently express low levels of MN1 transcript. In contrast, high levels of MN1 expression are present in 47% of patients with normal karyotype and in all cases with inv(16). MN1 levels during follow-up were found to follow the pattern of other molecular markers (fusion gene transcripts, NPM1 and WT1). Increased MN1 expression in the BM during follow up was always found to be predictive of an impending hematological relapse. PMID- 27765916 TI - Preoperative combined hemoglobin, albumin, lymphocyte and platelet levels predict survival in patients with locally advanced colorectal cancer. AB - More than 50% of patients with colorectal cancer (CRC) are initially diagnosed with locally advanced CRC (LACRC), and half of those patients develop recurrence or metastasis after resection. Here, we investigated whether the novel index HALP, which is a combination of preoperative hemoglobin, albumin, lymphocyte and platelet levels, correlates with survival in LACRC patients. A total of 820 patients with LACRC from two independent hospitals were included in our study. The correlations between HALP and overall and cancer-specific survival were calculated using training and validation sets. Lower HALP values correlated with an increased risk of death and cancer-related death in both sets. Moreover, the risk score based on HALP allowed stratification of patients into distinct prognostic groups with greater accuracy than previously proposed indexes. These results suggest that HALP may be useful as a clinical prognostic factor for patients with LACRC. PMID- 27765917 TI - Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers. AB - Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from its largely known female counterpart. We aimed at investigating whether MBC cases harbor somatic alterations of genes known as prognostic biomarkers and molecular therapeutic targets in female breast cancer.We examined 103 MBC cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, EGFR, ESR1 and CCND1 genes.Pathogenic mutations of PIK3CA were detected in 2% of MBCs. No pathogenic mutations were identified in ESR1 and EGFR. Gene copy number variations (CNVs) analysis showed amplification of PIK3CA in 8.1%, EGFR in 6.8% and CCND1 in 16% of MBCs, whereas deletion of ESR1 was detected in 15% of MBCs. Somatic mutations and gene amplification were found only in BRCA1/2 mutation negative MBCs.Significant associations emerged between EGFR amplification and large tumor size (T4), ER-negative and HER2-positive status, between CCND1 amplification and HER2-positive and MIB1-positive status, and between ESR1 deletion and ER-negative status.Our results show that amplification of targetable oncogenes is frequent in BRCA1/2 mutation negative MBCs and may identify MBC subsets characterized by aggressive phenotype that may benefit from potential targeted therapeutic approaches. PMID- 27765918 TI - beta-catenin interaction with NHERF1 and RASSF1A methylation in metastatic colorectal cancer patients. AB - There is an increasing need to identify new biomarkers in colorectal cancer (CRC) to further characterize this malignancy. beta-catenin plays a central role in the Wnt signaling pathway. It also binds Na+/H+ exchanger regulating factor 1 (NHERF1) and interacts with the RAS-association domain family 1, isoform A (RASSF1A), but the mechanisms of this possible crosstalk are still not fully understood. In this study, we analyzed for the first time the different subcellular expression of beta-catenin, NHERF1, and RASSF1A and their relationships with RASSF1A methylation in the progression of CRC. We assessed immunohistochemical expression and RASSF1A methylation in 51 patients with stage IV colorectal cancer. Biomarker expression analysis was carried out considering the tumor-adjacent normal tissue, the primary tumor, and the paired liver metastases. Regarding the tumor compartment, it was found that cytoplasmic beta catenin expression was positively correlated to membranous (r = 0.3002, p = 0.0323) and nuclear NHERF1 (r = 0.293, p = 0.0368). In the liver metastases, instead, we found a positive correlation of cytoplasmic and nuclear beta-catenin expression with RASSF1A methylation (r = 0.4019, p = 0.0068 and r = 0.3194, p = 0.0345, respectively).In conclusion, our results showed that beta-catenin was the crucial protagonist in metastatic CRC through different effector proteins involved in this developing process. In tumor tissues, beta-catenin was predominantly associated with NHERF1 in a dynamic context, while interestingly in liver metastases, we noted an increase of its oncogenic function through RASSF1A inactivation. PMID- 27765919 TI - Zoledronic acid is an effective radiosensitizer in the treatment of osteosarcoma. AB - To overcome radioresistance in the treatment of osteosarcoma, a primary malignant tumor of the bone, radiotherapy is generally combined with radiosensitizers. The purpose of this study was to investigate a third-generation bisphosphonate, zoledronic acid (ZOL), as a radiosensitizer for osteosarcoma. We found that exposure of KHOS/NP osteosarcoma cells to 20 MUM ZOL decreased the gamma radiation dose needed to kill 90% of cells. This radiosensitizing effect of ZOL was mediated through decreased mitochondrial membrane potential, increased levels of reactive oxygen species, increased DNA damage (as assessed by counting gamma H2AX foci), decreased abundance of proteins involved in DNA repair pathways (ATR, Rad52, and DNA-PKcs), and decreased phosphorylation of PI3K-Akt and MAPK pathway proteins (Raf1, MEK1/2, ERK1/2, and Akt), as compared to gamma-irradiation alone. Cells treated with ZOL plus gamma-irradiation showed impaired cell migration and invasion and reduced expression of epithelial-mesenchymal transition markers (vimentin, MMP9, and Slug). In Balb/c nude mice, the mean size of orthotopic osteosarcoma tumors 2 weeks post-inoculation was 195 mm3 following gamma irradiation (8 Gy), while it was 150 mm3 after gamma-irradiation plus ZOL treatment (0.1 mg/kg twice weekly for 2 weeks). These results provide a rationale for combining ZOL with radiotherapy to treat osteosarcoma. PMID- 27765920 TI - PAK4 suppresses PDZ-RhoGEF activity to drive invadopodia maturation in melanoma cells. AB - Cancer cells are thought to use actin rich invadopodia to facilitate matrix degradation. Formation and maturation of invadopodia requires the co-ordained activity of Rho-GTPases, however the molecular mechanisms that underlie the invadopodia lifecycle are not fully elucidated. Previous work has suggested a formation and disassembly role for Rho family effector p-21 activated kinase 1 (PAK1) however, related family member PAK4 has not been explored. Systematic analysis of isoform specific depletion using in vitro and in vivo invasion assays revealed there are differential invadopodia-associated functions. We consolidated a role for PAK1 in the invadopodia formation phase and identified PAK4 as a novel invadopodia protein that is required for successful maturation. Furthermore, we find that PAK4 (but not PAK1) mediates invadopodia maturation likely via inhibition of PDZ-RhoGEF. Our work points to an essential role for both PAKs during melanoma invasion but provides a significant advance in our understanding of differential PAK function. PMID- 27765921 TI - Triple-negative breast cancer: is there a treatment on the horizon? AB - Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3 hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC. PMID- 27765922 TI - G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion. AB - G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81 dependent activation of the PI3K/Akt signaling axis in tumor microenvironment. PMID- 27765923 TI - IL-1 drives breast cancer growth and bone metastasis in vivo. AB - BACKGROUND: We have recently identified interleukin 1B (IL-1B) as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In mouse models, IL-1B and its receptor (IL-1R1) are upregulated in breast cancer cells that metastasise to bone compared with cells that do not. We have now investigated the functional role of IL-1 by blocking IL-1R signalling with the clinically licensed antagonist, anakinra. METHODOLOGY: 6-week old female BALB/c mice received a subcutaneous or intra-venous injection of MDA-MB-231-IV or MCF7 cells. Anakinra (1mg/kg/day) or placebo was administered 3 days before (preventative) or 7 days later (treatment). Tumour volume, apoptosis (TUNEL, Caspase 3), proliferation (Ki67) and angiogenesis (CD34, VEGF and endothelin) were analysed. Effects on bone were measured by uCT, and TRAP, P1NP, IL-1B, TNF alpha and IL-6 ELISA. RESULTS: Anakinra significantly reduced growth of MDA-MB 231-IV tumours in bone from 6.50+/3.00mm2 (placebo) to 2.56+/-1.07mm2 (treatment) and 0.63+/-0.18mm2 (preventative). Anakinra also reduced the number of mice that developed bone metastasis from 90% (placebo) to 40% (treatment) and 10% (preventative). Anti-tumour effects were not confined to bone, subcutaneous tumour volumes reduced from 656.68mm3 (placebo) to 160.47mm3 (treatment) and 31.08mm3 (preventative). Anakinra did not increase tumour cell apoptosis but reduced proliferation and angiogenesis in addition to exerting significant effects on the tumour environment reducing bone turnover markers, IL-1B and TNF alpha. CONCLUSIONS: Our novel data demonstrate a functional role of IL-1 signalling in breast tumour progression and metastasis, supporting that anakinra could be repurposed for the treatment of breast cancer bone metastasis. PMID- 27765924 TI - Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma. AB - Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan-Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC. PMID- 27765925 TI - Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm. AB - Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy. PMID- 27765926 TI - NKp44 and NKp30 splice variant profiles in decidua and tumor tissues: a comparative viewpoint. AB - NKp44 and NKp30 splice variant profiles have been shown to promote diverse cellular functions. Moreover, microenvironment factors such as TGF-beta, IL-15 and IL-18 are able to influence both NKp44 and NKp30 splice variant profiles, leading to cytokine-associated profiles. Placenta and cancerous tissues have many similarities; both are immunologically privileged sites and both share immune tolerance mechanisms to support tissue development. Therefore, we studied the profiles of NKp44 and NKp30 splice variants in these states by comparing (i) decidua from pregnancy disorder and healthy gestation and (ii) matched normal and cancer tissue. Decidua samples had high incidence of both NKp44 and NKp30. In cancerous state it was different; while NKp30 expression was evident in most cancerous and matched normal tissues, NKp44 incidence was lower and was mostly associated with the cancerous tissues. A NKp44-1dominant inhibitory profile predominated in healthy pregnancy gestation. Interestingly, the NKp44-2/3 activation profile becomes the leading profile in spontaneous abortions, whereas balanced NKp44 profiles were observed in preeclampsia. In contrast, a clear preference for the NKp30a/b profile was evident in the 1st trimester decidua, yet no significant differences were observed for NKp30 profiles between healthy gestation and spontaneous abortions/preeclampsia. Both cancerous and matched normal tissues manifested balanced NKp30c inhibitory and NKp30a/b activation profiles with a NKp44-1dominant profile. However, a shift in NKp30 profiles between matched normal and cancer tissue was observed in half of the cases. To summarize, NKp44 and NKp30 splice variants profiles are tissue/condition specific and demonstrate similarity between placenta and cancerous tissues. PMID- 27765927 TI - Analysis of the association of single nucleotide polymorphisms of interleukin-23 receptor (IL-23R) and inflammatory bowel disease in a Chinese Han cohort. AB - Inflammatory bowel disease (IBD) is a chronic, complex genetic disease with rapidly increasing prevalence in China. The interactions of genetic, environmental, and microbial factors contribute to the development of IBD, however, the precise etiologies of IBD are not well understood yet. Interleukin 23 receptor (IL-23R) encodes a subunit of receptor for IL-23, which is an important proinflammatory cytokine. In this study, we investigated the relationship between the single nucleotide polymorphism (SNP) of IL-23R gene and IBD in Chinese Han population. We genotyped three nonsynonymous IL-23R SNPs with amino acid changes (rs11209026, p.Arg381Gln; rs41313262 p.Val362Ile and rs11465797 p.Thr175Asn) in 198 patients with IBD (124 UC and 74 CD) and 100 healthy controls. The prevalence of the A allele in IL-23R Arg381Gln of CD appeared less than controls, but it was not statistically significant (2.70% vs. 6.00%, p > 0.05). There was no statistical difference between UC and controls (5.65% vs. 6.00%, p = 0.91). The p.Val362Ile variant was present in 2.42% of UC patients, in 2.70% of CD patients, which was similar in the control (2.00%). There was no statistical difference among these three groups. We did not detect Thr175Asn (rs11465797 c.524 C>A) in all the three groups. In conclusion, our study demonstrated that the p.Val362Ile and Arg381Gln were not associated with susceptibility to IBD in Chinese Han population. PMID- 27765928 TI - RTEL1 polymorphisms are associated with lung cancer risk in the Chinese Han population. AB - RTEL1 (regulator of telomere elongation helicase 1; OMIM 608833) gene polymorphisms were linked to lung cancer (LC) susceptibility in a cancer genome wide association study (GWAS) Here, we assessed whether seven previously reported RTEL1 polymorphisms influenced LC risk in Han Chinese population. All study samples (554 LC cases and 696 cancer-free controls) were collected from the Affiliated Hospital of Xizang Minzu University in China. We assessed associations between SNPs and LC risk using various several genetic models (codominant, dominant, recessive, overdominant, and additive). Whereas rs2738780 showed a protective effect against LC (Odds ratio (OR) = 0.80 ;95% confidence interval (CI): 0.638 = 0.998; p = 0.048), rs7261546(OR = 4.16; 95% CI: 1.35-12.82; p = 0.007), rs6062299(OR=5.08; 95% CI: 1.43-18.10; p = 0.005) and rs3787098(OR = 5.10; 95% CI: 1.43-18.15; p = 0.004) were all associated with increased LC susceptibility (recessive model). Haplotype analysis suggested that ''CTC'' was associated with a 0.8-fold decrease in LC risk (OR = 0.80, 95% CI, 0.63-1.00; Pearson's p = 0.05). These findings suggest a potential association between RTEL1 polymorphisms and LC risk in a Chinese Han population. PMID- 27765929 TI - Association of the miR-17-5p variants with susceptibility to cervical cancer in a Chinese population. AB - MicroRNAs (miRNAs) are key regulators of gene expression; however, the extent to which single nucleotide polymorphisms (SNPs) interfere with miRNA gene regulation and affect cervical cancer (CC) susceptibility remains largely unknown. Here, we systematically analyzed miRNA-related SNPs and their association with CC risk, and performed a case-control study of miR-17-5p SNPs and CC risk in a Chinese population. Sixteen SNPs were genotyped in 247 CC cases and 285 controls. Three were associated with CC risk (p < 0.05): the minor allele (A) of rs217727 in H19 increased risk (OR = 1.53, p = 0.002), while the minor alleles (T) of rs9931702 and (T) of rs9302648 in AKTIP decreased CC risk (p = 0.018, p = 0.014). Analysis of the SNPs after stratification based on CC clinical stage and subtype revealed that rs1048512, rs6659346, rs217727, rs9931702, and rs9302648 were associated with CC risk in clinical stages I-II; rs2862833, rs2732044, rs1030389, and rs1045935 were associated with CC risk in clinical stages III-IV; and rs217727, rs9931702, and rs9302648 were associated with CC risk in squamous carcinomas. These data could serve as a useful resource for understanding the miR-17 function, identification of miRNAs associated with CC, and development of better CC screening strategies. PMID- 27765931 TI - The natural compound sulforaphene, as a novel anticancer reagent, targeting PI3K AKT signaling pathway in lung cancer. AB - Lung cancer is one of the leading causes of cancer death worldwide. Isothiocyanates from cruciferous vegetables been shown to possess anticarcinogenic activities in lung malignances. We previously found sulforaphene (4-methylsufinyl-3-butenyl isothiocyanate, SFE), one new kind of isothiocyanates, existing in a relative high abundance in radish seeds. An efficient methodology based on macroporous resin and preparative high-performance liquid chromatography was developed to isolate SFE in reasonably large quantities, high purity and low cost. However, it is still largely unclear whether SFE could function as an antineoplastic compound, especially in lung cancer. In this study, we systematically investigated the anti-cancer effects of SFE in vitro as well as its possible underling molecular mechanisms in lung cancer. The acute toxicity tests and pharmacokinetics tests for SFE were performed to evaluate its drugability in mice. Also, we evaluated the in vivo anti-cancer effects of SFE using nude Balb/C mice with lung cancer xenograft. SFE can induce apoptosis of multiple lung cancer celllines and, thus, inhibited cancer cell proliferation. Lung cancer cells treated with SFE exhibit significant inhibition of the PI3K-AKT signaling pathway, including depressed PTEN expression and inhibition of AKT phosphoralation. At well-tolerated doses, administration of SFE to mice bearing lung cancer xenografts leads to significant inhibitions of tumor growth. In summary, our work identifies SFE as a novel natural broad-spectrum small molecule inhibitor for lung cancer. PMID- 27765932 TI - Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1alpha, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation. AB - Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza deoxycytidine (Aza-dC) can induce ASS1 expression. Moreover, it was reported that cisplatin suppresses ASS1 expression through ASS1 promoter methylation, leading to synthetic lethality to ADI-PEG20 treatment. We report here that cisplatin supppresses ASS1 expression is due to upregulation of HIF-1alpha and downregulation of c-Myc, which function as negative and positive regulators of ASS1 expression, respectively, by reciprocal bindings to the ASS1 promoter. In contrast, we found that Aza-dC induces ASS1 expression by downregulation of HIF 1alpha but upregulation of c-Myc. We further demonstrated that the clock protein DEC1 is the master regulator of HIF-1alpha and c-Myc that regulate ASS1. cDDP upregulates DEC1, whereas Aza-dC suppresses its expression. Using two proteasomal inhibitors bortezomib and carfilzomib which induce HIF-1alpha accumulation, we further demonstrated that HIF-1alpha is involved in ASS1 silencing for the maintenance of Arg auxotrophy for targeted Arg-starvation therapy. PMID- 27765933 TI - IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. AB - M2 tumor-associated macrophage has been found to play a supportive role in the progression of glioma. The underlying mechanism, nevertheless, has been largely unknown. In our study, to investigate how M2 macrophage played role in glioma, firstly we've analyzed the clinicopathological significance of M2 macrophage existence on clinical tissues of glioma using detection of CD163 expression with immunohistochemistry. Then, we've artificially induced M2 macrophage from human monocyte cell line THP-1, followed by co-culture with glioma cell lines in vitro. It was found that M2 macrophage was shown to be markedly distributed in glioma relative to paired normal control; and high prevalence of M2 macrophage was significantly associated with poorer overall survival and tumor progression. Moreover, M2 macrophage was found to be able to promote the growth in vitro and tumorigenesis in vivo in xenografted mice model. Mechanistically, it is IL-10 from M2 macrophage that was shown to promote proliferation, dependent on activation of JAK2/STAT3 pathway. Further, IL-10 was found to be able to interact with JAK2 in glioma cells. Taking together, we for the first time found that IL 10 from M2 macrophage promoted proliferation of glioma through interaction with JAK2; thereby activating the JAK2/STAT3 pathway, indicative of IL-10 could be used as a therapeutic target in the curing of glioma. PMID- 27765934 TI - Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy. AB - Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models. A subcutaneous nude mouse model of HER-2 expressing cervical carcinoma was not sensitive to entinostat (a benzamide histone deactylase inhibitor), which also did not inhibit primary tumor growth in a PDOX model of the same tumor. However, in the PDOX model, entinostat alone significantly reduced the metastatic tumor burden, compared to the control. Thus, only the PDOX model could be used to discover the anti-metastatic activity of entinostat for this patient. The results of the present report indicate the importance of using mouse models that can recapitulate metastatic cancer for precisely individualizing cancer therapy. PMID- 27765935 TI - Gene polymorphisms are associated with clinical outcome in Chinese resected laryngeal carcinoma patients. AB - We examined the multigenetic index on the progression of laryngeal carcinoma in Chinese population. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) on survival of Laryngeal Carcinoma (LC) patients. Eighteen SNPs were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 170 resected Chinese LC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Overall, the median survival time (MST) was 38.00 months. The one, three and five year Kaplan Meier survival rate was 0.847 +/- 0.028, 0.572 +/- 0.038 and 0.471 +/- 0.041 respectively. The risks of death with the Hazard Ratio (HR) [95% confidence intervals] (CI) of 2.40 (1.15-4.50), 2.17 (1.45-3.25), 2.39 (1.58-3.62), 3.29 (2.10-5.18), respectively. There was significant associations between the SNPs and OS when the entire study population was examined. The rs1321311 TG genotype (vs.GG), rs2494938 AA genotype (vs. GG) and rs9363918 TG genotype (vs. GG) were associated with a worse prognosis for OS (adjusted HR = 1.64; 95%confidence interval = 1.07-2.51; P = 0.022, adjusted HR = 2.85; P =0.12; adjusted HR = 1.78; P = 0.009; respectively).The results suggest for the first time that these gene polymorphisms may serve as an independent prognostic marker for LC patients. PMID- 27765937 TI - Neither Isolated Hepatic Arterial Clamping nor Hepatic Arterial Ligation Induce Ischemic Type Biliary Lesions in Rats. AB - BACKGROUND Ischemic type biliary lesions (ITBL) is a troublesome complication after liver transplantation. Little is known about its pathogenesis and there is particularly little data about morphological alterations. Prolonged warm and cold ischemia time and reduced hepatic arterial perfusion are risk factors leading to ITBL. There are only a few animal models described in literature. Therefore, we examined the effects of 3 h of hepatic artery ischemia-reperfusion (3 h I/R) and hepatic arterial ligation (HAL), both combined with ligation of the peribiliary plexus (PBP). MATERIAL AND METHODS 3 h I/R was performed by clamping the hepatic artery with microvascular clamps for 3 h. HAL was performed by ligation of the hepatic artery. Both procedures were combined with stenting of the common bile duct with double ligation of the PBP. A sham group without clamping served as control. Serum activities of aspartate transaminase (AST) and alanine transaminase (ALT), direct and total bilirubin (DB/TB), and lactate dehydrogenase (LDH) were measured. Bile flow was analyzed and histological examinations of leukocyte infiltration (CAE), cell proliferation (PCNA), apoptotic cells (HE), and bile ducts morphology (CK7) were performed. Western blots of the vascular endothelial growth factor (VEGF) and caspase 3 were made to investigate vascular growth expression and apoptotic cell death. RESULTS 3 h I/R and HAL were associated with a significant hepatocellular injury and inflammation, shown through increased AST and ALT, leukocyte infiltration, and apoptotic cell death. An increase of bile ducts and a reduction of arteries/bile duct ratio after 30 days was observed in the 3 h I/R group and HAL, but no ITBL-typical bile duct necrosis, intrahepatic strictures, or dilatations of bile ducts occurred. CONCLUSIONS Morphological alterations in a rat animal model of 3 h I/R and HAL could be demonstrated. However, a model of intrahepatic biliary lesions could not be established through hepatic arterial ligation or through 3-h hepatic arterial ischemia and reperfusion. PMID- 27765936 TI - Myricetin, a potent natural agent for treatment of diabetic skin damage by modulating TIMP/MMPs balance and oxidative stress. AB - Foot ulceration is a major cause of morbidity in patients with diabetes, and abnormal peripheral neuropathy often results in hospitalization. Up-regulation of matrix metalloproteinases and down-regulation of tissue inhibitor of metalloproteinase 1 are noted to be distinctive biological functions of diabetic dermal fibroblasts. The aim of this study was to evaluate the biological effects of modified retinoids on diabetic fibroblasts. Myricetin, a natural compound, balances the TIMP1/MMP ratio and oxidative stress in diabetic fibroblasts. Our results indicate that myricetin significantly ameliorates the effects of diabetes on dermal fibroblasts. In addition, we found that the oxidative stress imbalance induced by a high glucose concentration plays an important role in the changes to dermal fibroblasts that occur in diabetes. Our findings support the hypothesis that myricetin has the potential to repair faulty skin function arising from diabetes. PMID- 27765938 TI - Long Non-Coding RNA (lncRNA) Urothelial Carcinoma-Associated 1 (UCA1) Enhances Tamoxifen Resistance in Breast Cancer Cells via Inhibiting mTOR Signaling Pathway. AB - BACKGROUND Long non-coding RNA (lncRNA) UCA1 is an oncogene in breast cancer. The purpose of this study was to investigate the role of UCA1 in tamoxifen resistance of estrogen receptor positive breast cancer cells. MATERIAL AND METHODS Tamoxifen sensitive MCF-7 cells were transfected for UCA1 overexpression, while tamoxifen resistant LCC2 and LCC9 cells were transfected with UCA siRNA for UCA1 knockdown. qRT-PCR was performed to analyze UCA1 expression. CCK-8 assay, immunofluorescence staining of cleaved caspase-9, and flow cytometric analysis of Annexin V/PI staining were used to assess tamoxifen sensitivity. Western blot analysis was performed to detect p-AKT and p-mTOR expression. RESULTS LncRNA UCA1 was significantly upregulated in tamoxifen resistant breast cancer cells compared to tamoxifen sensitive cells. LCC2 and LCC9 cells transfected with UCA1 siRNA had significantly higher ratio of apoptosis after tamoxifen treatment. UCA1 siRNA significantly decreased the protein levels of p-AKT and p-mTOR in LCC2 and LCC9 cells. Enforced UCA1 expression substantially reduced tamoxifen induced apoptosis in MCF-7 cells, while rapamycin treatment abrogated the protective effect of UCA1. CONCLUSIONS UCA1 upregulation was associated with tamoxifen resistance in breast cancer. Mechanistically, UCA1 confers tamoxifen resistance to breast cancer cells partly via activating the mTOR signaling pathway. PMID- 27765939 TI - Inadvertent Methylergonovine Administration to a Neonate. AB - BACKGROUND Methylergonovine is an ergot alkaloid used to treat post-partum hemorrhage secondary to uterine atony. Mistaking methylergonovine for vitamin K with accidental administration to the neonate is a rare iatrogenic illness occurring almost exclusively in the delivery room setting. Complications of ergot alkaloids in neonates include respiratory depression, seizures, and death. CASE REPORT A term infant was inadvertently given 0.1 mg of methylergonovine intramuscularly in the right thigh. The error was only noted when the vial of medication was scanned, after administration, identifying it as methylergonovine rather than vitamin K. The local poison center was notified, and the infant was transferred to the neonatal intensive care unit for observation. Two hours after transfer, the infant was noted to have oxygen desaturations and required oxygen via nasal cannula. Supplemental oxygen was continued for 4 hours until the neonate was able to maintain normal oxygen saturations in room air. Feeding was started by 10 hours of life, and the infant was discharged home in good condition after a 72-hour stay without further complications. CONCLUSIONS Because of the potential for serious adverse events, vigilance is required to prevent accidental administration of methylergonovine to the neonate as a result of possible confusion with vitamin K in the early post-partum period. PMID- 27765941 TI - Regulatory watch: Innovative drug availability in China. PMID- 27765942 TI - Integrating Candida albicans metabolism with biofilm heterogeneity by transcriptome mapping. AB - Candida albicans biofilm formation is an important virulence factor in the pathogenesis of disease, a characteristic which has been shown to be heterogeneous in clinical isolates. Using an unbiased computational approach we investigated the central metabolic pathways driving biofilm heterogeneity. Transcripts from high (HBF) and low (LBF) biofilm forming isolates were analysed by RNA sequencing, with 6312 genes identified to be expressed in these two phenotypes. With a dedicated computational approach we identified and validated a significantly differentially expressed subnetwork of genes associated with these biofilm phenotypes. Our analysis revealed amino acid metabolism, such as arginine, proline, aspartate and glutamate metabolism, were predominantly upregulated in the HBF phenotype. On the contrary, purine, starch and sucrose metabolism was generally upregulated in the LBF phenotype. The aspartate aminotransferase gene AAT1 was found to be a common member of these amino acid pathways and significantly upregulated in the HBF phenotype. Pharmacological inhibition of AAT1 enzyme activity significantly reduced biofilm formation in a dose-dependent manner. Collectively, these findings provide evidence that biofilm phenotype is associated with differential regulation of metabolic pathways. Understanding and targeting such pathways, such as amino acid metabolism, is potentially useful for developing diagnostics and new antifungals to treat biofilm-based infections. PMID- 27765940 TI - Epigenetic drug discovery: breaking through the immune barrier. AB - Immune-mediated diseases are clinically heterogeneous but they share genetic and pathogenic mechanisms. These diseases may develop from the interplay of genetic factors and environmental or lifestyle factors. Exposure to such factors, including infectious agents, is associated with coordinated changes in gene transcription owing to epigenetic alterations. A growing understanding of how epigenetic mechanisms control gene expression patterns and cell function has been aided by the development of small-molecule inhibitors that target these processes. These chemical tools have helped to reveal the importance of epigenetics in guiding cell fate decisions during immune responses and have also highlighted the potential for targeting epigenetic mechanisms for the treatment of inflammation and immune-mediated diseases. In this Review, we discuss the most advanced areas of epigenetic drug development for autoimmune and inflammatory diseases and summarize the promising preclinical data in this exciting and evolving field. These agents will inevitably begin to move into clinical trials for use in patients with immune-mediated diseases. PMID- 27765944 TI - Overexpression of ABCB1 as prediction marker for CML: How close we are to translation into clinics? PMID- 27765943 TI - Tissue, developmental, and caste-specific expression of odorant binding proteins in a eusocial insect, the red imported fire ant, Solenopsis invicta. AB - Insects interact with the surrounding environment via chemoreception, and in social insects such as ants, chemoreception functions to mediate diverse behaviors including food acquisition, self/non-self recognition, and intraspecific communication. The invasive red imported fire ant, Solenopsis invicta, has spread worldwide, displaying a remarkable environmental adaptability. Odorant binding proteins (OBPs) are chemical compound carriers, involved in diverse physiological processes including odor detection and chemical transport. S. invicta contains a highly divergent 17-member OBP gene family, that includes an ant-specific expansion and the social organization implicated Gp-9 (OBP3) gene. A systematic gene expression analysis of the SiOBP repertoire was performed across social caste (workers, male and female alates), tissues (antennae, head, thorax, and abdomen), and developmental stages (egg, larvae, and pupae), revealing that although SiOBPs were expressed in the antennae, the major regions of expression were in the head and thorax across all castes, and the abdomen in male and female alates. SiOBPs were very highly expressed in female alates and at somewhat lower levels in male alates and workers. SiOBPs were differentially expressed, with unique signatures in various castes and tissues, suggesting functionality of SiOBPs beyond olfaction Expression patterns of SiOBP subgroups also showed relationships with their evolutionary relatedness. PMID- 27765945 TI - Different populations of Wnt-containing vesicles are individually released from polarized epithelial cells. AB - Accumulating evidence suggests that exosomes are heterogeneous in molecular composition and physical properties. Here we examined whether epithelial cells secrete a heterogeneous population of exosomes, and if that is the case, whether epithelial cell polarity affects release of different populations of exosomes, especially that of those carrying Wnt. Sucrose-density ultracentrifugation and molecular marker analysis revealed that different populations of exosomes or exosome-like vesicles were released from MDCK cells depending on the cell polarity. Wnt3a associated with these vesicles were detectable in culture media collected from both apical and basolateral sides of the cells. Basolaterally secreted Wnt3a were co-fractionated with a typical exosomal protein TSG101 in fractions having typical exosome densities. In contrast, most of apically secreted Wnt3a, as well as Wnt11, were co-fractionated with CD63 and Hsp70, which are also common to the most exosomes, but recovered in higher density fractions. Wnt3a exhibiting similar floatation behavior to the apically secreted ones were also detectable in the culture media of Wnt3a-expressing L and HEK293 cells. The lipidation of Wnt3a was required for its basolateral secretion in exosomes but was dispensable for the apical one. Thus, epithelial cells release Wnt via distinct populations of vesicles differing in secretion polarity and lipidation dependency. PMID- 27765947 TI - Extraversion and neuroticism related to the resting-state effective connectivity of amygdala. AB - The amygdala plays a key role in emotion processing. Its functional connectivity with other brain regions has been extensively demonstrated to be associated with extraversion and neuroticism. However, how the amygdala affects other regions and is affected by others within these connectivity patterns associated with extraversion and neuroticism remains unclear. To address this issue, we investigated the effective connectivity of the amygdala using Granger causality analysis on the resting-state functional magnetic resonance imaging data of 70 participants. Results showed that extraversion was positively correlated with the influence from the right inferior occipital gyrus (IOG) to the left amygdala, and from the bilateral IOG to the right amygdala; such result may represent the neural correlates of social interactions in extraverts. Conversely, neuroticism was associated with an increased influence from right amygdala to right middle frontal gyrus and a decreased influence from right precuneus to right amygdala. This influence might affect the modulations of cognitive regulation function and self-referential processes in neurotic individuals. These findings highlight the importance of the causal influences of amygdala in explaining the individual differences in extraversion and neuroticism, and offer further insights into the specific neural networks underlying personality. PMID- 27765946 TI - Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex. AB - The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders. PMID- 27765948 TI - Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124. AB - Derepression of wild-type p53 by suppressing its negative inhibitor iASPP (Inhibitor of apoptosis-stimulating protein of p53) represents a potential therapeutic option for cervical cancer (CC). Here, we reported a novel functional significance of iASPP upregulation in cervical tumorigenesis: iASPP acts as a key promoter of CC cell proliferation, epithelial-mesenchymal transition, invasion and cancer stemness, by interacting with p53 to suppress p53-mediated transcription of target genes and reducing p53-responsive microRNA-34a levels. Moreover, we demonstrate that miR-124, directly targeting iASPP, reduces expression of iASPP and attenuates CC cell growth and invasiveness. Low miR-124 expression is inversely correlated with increased expression of iASPP mRNA in CC tissues. In a cohort of 40 patients with CC, the low miR-124 expression was correlated with poor 5-year overall survival (P = 0.0002) and shorter disease free survival 5-year (P = 0006). Treatment with the DNA methyltransferase inhibitor Zebularine increases miR-124 expression and retards CC cell growth and invasion with minimal toxicity to normal cells. Even at a non-toxic concentration, Zebularine was effective in suppressing CC cell invasion and migration. Altogether, the restoration of miR-124 reduces iASPP expression and leads to p53-dependent tumor suppression, suggesting a therapeutic strategy to treat iASPP-associated CC. PMID- 27765950 TI - Therapeutic effects of adipose-derived stem cells pretreated with pioglitazone in an emphysema mouse model. AB - There is no therapy currently available that influences the natural history of disease progression in patients with chronic obstructive pulmonary disease (COPD). Although stem cell therapy is considered a potential therapeutic option in COPD, there are no clinical trials proving definitive therapeutic effects in patients with COPD. Recently, it was reported that pioglitazone might potentiate the therapeutic effects of stem cells in patients with heart or liver disease. To test the capacity of pioglitazone pretreatment of stem cells for emphysema repair, we evaluated the therapeutic effects of pioglitazone-pretreated human adipose-derived mesenchymal stem cells (ASCs) on elastase-induced or cigarette smoke-induced emphysema in mice. We also investigated the mechanisms of action of pioglitazone-pretreated ASCs. Pioglitazone-pretreated ASCs had a more potent therapeutic effect than non-pretreated ASCs in the repair of both elastase induced and smoke-induced emphysema models (mean linear intercept, 78.1+/-2.5 MUm vs 83.2+/-2.6 MUm in elastase models and 75.6+/-1.4 MUm vs 80.5+/-3.2 MUm in smoke models, P<0.05). Furthermore, we showed that pioglitazone-pretreated ASCs increased vascular endothelial growth factor (VEGF) production both in vitro and in mouse lungs in the smoke-induced emphysema model. Pioglitazone-pretreated ASCs may have more potent therapeutic effects than non-pretreated ASCs in emphysema mouse models. PMID- 27765952 TI - Immunology: Metabolic changes modify Treg cell function. PMID- 27765951 TI - Hypoxia-inducible factor-2 alpha promotes the proliferation of human placenta derived mesenchymal stem cells through the MAPK/ERK signaling pathway. AB - Human placenta-derived mesenchymal stem cells (hPMSCs) reside in a physiologically low-oxygen microenvironment. Hypoxia influences a variety of stem cell cellular activities, frequently involving hypoxia-inducible factor-2 alpha (HIF-2alpha). This research showed that hPMSCs cultured in hypoxic conditions (5% O2) exhibited a more naive morphology and had a higher proliferative capability and higher HIF-2alpha expression than hPMSCs cultured in normoxic conditions (21% O2). Similar to the hypoxic cultures, hPMSCs over-expressing HIF-2alpha showed higher proliferative potential and higher expression of CCND1 (CyclinD1), MYC (c Myc), POU5F1 (Oct4) and the components of the MAPK/ERK pathway. In contrast, these genes were down-regulated in the HIF-2alpha-silenced hPMSCs. After adding the MAPK/ERK inhibitor PD0325901, cell growth and the expression of CCND1 and MYC were inhibited. Furthermore, the chromatin immunoprecipitation (ChIP) assay and electrophoretic mobility shift assay (EMSA) showed that HIF-2alpha bound to the MAPK3 (ERK1) promoter, indicative of its direct regulation of MAPK/ERK components at the transcriptional level during hPMSC expansion. Taken together, our results suggest that HIF-2alpha facilitated the preservation of hPMSC stemness and promoted their proliferation by regulating CCND1 and MYC through the MAPK/ERK signaling pathway. PMID- 27765953 TI - Rising soil temperature in China and its potential ecological impact. AB - Global warming influences a series of ecological processes and ecosystems' stability. Although comprehensive studies have been done to investigate responses of various ecosystem processes to rising air temperatures, less is known about changes in soil temperatures and their impact on below-ground processes, particularly in deep layers. Herein, we used 50 y of temperature data (1962-2011) from 360 sites in China to assess spatio-temporal changes in soil temperatures from the surface to a depth of 3.20 m. We determined, apparently for the first time, that soil surface temperature increased 31% more than air temperature, potentially leading to more carbon release to the atmosphere than predicted. Annual mean surface temperature increased by 2.07-4.04 and 0.66-2.21 degrees C in northern and southern China, respectively, with the greatest in winter. Warming occurred as deep as 3.20 m. The soil temperature rise was predicted to have increased soil respiration by up to 28%, reinforcing climate warming and extending the potential growing season by up to 20 d across China. However, use of only air temperature to estimate soil temperature changes would underestimate those impacts. In conclusion, these results highlighted the importance of soil warming and of using soil temperature to assess and predict soil processes. PMID- 27765954 TI - Both the anti- and pro-apoptotic functions of villin regulate cell turnover and intestinal homeostasis. AB - In the small intestine, epithelial cells are derived from stem cells in the crypts, migrate up the villus as they differentiate and are ultimately shed from the villus tips. This process of proliferation and shedding is tightly regulated to maintain the intestinal architecture and tissue homeostasis. Apoptosis regulates both the number of stem cells in the crypts as well as the sloughing of cells from the villus tips. Previously, we have shown that villin, an epithelial cell-specific actin-binding protein functions as an anti-apoptotic protein in the gastrointestinal epithelium. The expression of villin is highest in the apoptosis resistant villus cells and lowest in the apoptosis-sensitive crypts. In this study we report that villin is cleaved in the intestinal mucosa to generate a pro apoptotic fragment that is spatially restricted to the villus tips. This cleaved villin fragment severs actin in an unregulated fashion to initiate the extrusion and subsequent apoptosis of effete cells from the villus tips. Using villin knockout mice, we validate the physiological role of villin in apoptosis and cell extrusion from the gastrointestinal epithelium. Our study also highlights the potential role of villin's pro-apoptotic function in the pathogenesis of inflammatory bowel disease, ischemia-reperfusion injury, enteroinvasive bacterial and parasitic infections. PMID- 27765956 TI - Detecting Carbon in Carbon: Exploiting Differential Charging to Obtain Information on the Chemical Identity and Spatial Location of Carbon Nanotube Aggregates in Composites by Imaging X-ray Photoelectron Spectroscopy. AB - To better assess risks associated with nano-enabled products including multiwalled carbon nanotubes (MWCNT) within polymer matrices, it is important to understand how MWCNT are dispersed throughout the composite. The current study presents a method which employs imaging X-ray photoelectron spectroscopy (XPS) to chemically detect spatially segregated MWCNT rich regions at an epoxy composites surface by exploiting differential charging. MWCNT do not charge due to high conductivity and have previously been shown to energetically separate from their insulating surroundings when characterized by XPS. XPS in imaging mode revealed that these conductive regions were spatially separated due to micrometer-scale MWCNT aggregation and poor dispersion during the formation of the composite. Three MWCNT concentrations were studied; (1, 4 and 5) % by mass MWCNT within an epoxy matrix. Images acquired in periodic energy intervals were processed using custom algorithms designed to efficiently extract spectra from regions of interest. As a result, chemical and electrical information on aggregate and non aggregate portions of the composite was extracted. Raman imaging and scanning electron microscopy were employed as orthogonal techniques for validating this XPS-based methodology. Results demonstrate that XPS imaging of differentially charging MWCNT composite samples is an effective means for assessing dispersion quality. PMID- 27765955 TI - Fluorescence Visual Detection of Herbal Product Substitutions at Terminal Herbal Markets by CCP-based FRET technique. AB - Inaccurate labeling of materials used in herbal products may compromise the therapeutic efficacy and may pose a threat to medicinal safety. In this paper, a rapid (within 3 h), sensitive and visual colorimetric method for identifying substitutions in terminal market products was developed using cationic conjugated polymer-based fluorescence resonance energy transfer (CCP-based FRET). Chinese medicinal materials with similar morphology and chemical composition were clearly distinguished by the single-nucleotide polymorphism (SNP) genotyping method. Assays using CCP-based FRET technology showed a high frequency of adulterants in Lu-Rong (52.83%) and Chuan-Bei-Mu (67.8%) decoction pieces, and patented Chinese drugs (71.4%, 5/7) containing Chuan-Bei-Mu ingredients were detected in the terminal herbal market. In comparison with DNA sequencing, this protocol simplifies procedures by eliminating the cumbersome workups and sophisticated instruments, and only a trace amount of DNA is required. The CCP-based method is particularly attractive because it can detect adulterants in admixture samples with high sensitivity. Therefore, the CCP-based detection system shows great potential for routine terminal market checks and drug safety controls. PMID- 27765957 TI - Lithium batteries: Improving solid-electrolyte interphases via underpotential solvent electropolymerization. AB - Understanding the mechanism of formation of solid-electrolyte interphases (SEI) is key to the prospects of lithium metal batteries (LMB). Here, we investigate via cyclic voltammetry, impedance spectroscopy and chronoamperometry the role of kinetics in controlling the properties of the SEI generated from the reduction of propylene carbonate (PC, a typical solvent in LMB). Our observations are consistent with the operation of a radical chain PC electropolymerization into polymer units whose complexity increases at lower initiation rates. As proof-of concept, we show that slow initiation rates via one-electron PC reduction at underpotentials consistently yields compact, electronically insulating, Li+ conducting, PC-impermeable SEI films. PMID- 27765960 TI - Coleus aromaticus: a therapeutic herb with multiple potentials. AB - The herb Coleus aromaticus belonging to Lamiaceae family and Coleus genus is known by numerous names in different parts of the world and several language specific vernacular names. The herb has been extensively studied as well as reported in several fields of science. The multiple potential of the herb includes allelopathic potential, antibacterial property, antimicrobial activity, insecticidal property; free radical scavenging and radio-protective components from herb extracts and most recently the appetizing potential of the herb have been reported. The herb has carvacrol and thymol as the major components responsible for the flavour; while chlorogenic acid, rosmarinic acid etc. as the phenolic components. The herb has been used in therapeutic and medicinal applications as well as in culinary preparations. PMID- 27765958 TI - Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015. AB - Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynakologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft fur Gynakologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case. PMID- 27765961 TI - In-vitro antioxidant and functional properties of protein hydrolysates from golden grey mullet prepared by commercial, microbial and visceral proteases. AB - Bioactive Liza aurata protein hydrolysates (LAPHs) were prepared by treatment with Trypsine (PH-TR), Esperase (PH-ES), enzyme preparations from Pseudomonas aeruginosa A2 (PH-A2), Bacillus subtilis A26 (PH-A26) and Liza aurata (PH-LA). Their functional properties and antioxidant activities were evaluated. The hydrolysates had degree of hydrolysis (DH) values ranging from 8.15 % to 13.05 %. Reverse-phase HPLC analyses of the LAPHs showed considerable variation in peptide composition. All hydrolysates had high protein content (83.14 %-86.43 %). Glutamic acid, Glutamine (Glx) and Lysine (Lys) were the most abundant amino acids. All protein hydrolysates had a good solubility emulsifying and foam properties were found to be considerably improved by enzymatic hydrolysis. In addition, all hydrolysates showed varying degrees of antioxidant activities evaluated by various in vitro tests. Further, all LAPHs did not show hemolytic activity towards human erythrocytes. The results thus revealed that protein hydrolysates from golden grey mullet could be used as food additives possessing both antioxidant activity and functional properties. PMID- 27765959 TI - Machine Learning and Decision Support in Critical Care. AB - Clinical data management systems typically provide caregiver teams with useful information, derived from large, sometimes highly heterogeneous, data sources that are often changing dynamically. Over the last decade there has been a significant surge in interest in using these data sources, from simply re-using the standard clinical databases for event prediction or decision support, to including dynamic and patient-specific information into clinical monitoring and prediction problems. However, in most cases, commercial clinical databases have been designed to document clinical activity for reporting, liability and billing reasons, rather than for developing new algorithms. With increasing excitement surrounding "secondary use of medical records" and "Big Data" analytics, it is important to understand the limitations of current databases and what needs to change in order to enter an era of "precision medicine." This review article covers many of the issues involved in the collection and preprocessing of critical care data. The three challenges in critical care are considered: compartmentalization, corruption, and complexity. A range of applications addressing these issues are covered, including the modernization of static acuity scoring; on-line patient tracking; personalized prediction and risk assessment; artifact detection; state estimation; and incorporation of multimodal data sources such as genomic and free text data. PMID- 27765962 TI - Effect of seasonal variation on lipid and fatty acid profile in muscle tissue of male and female Silurus triostegus. AB - Fatty acid (FA) compositions of total lipid, phospholipid (PL) and triacylglycerol (TAG) fractions have been determined in muscle tissues of Silurus triostegus. The distributions of saturated fatty acid (SFA), monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) proportions were found to be different among total lipid, PL and TAG fractions from lipids in muscle tissues of the male and female S. triostegus in all seasons. Triacylglycerol contained a lower proportion of PUFA and a higher proportion of MUFA and SFA than PL while PL contained higher proportion of PUFA than proportion of MUFA and SFA compared to TAG. Triacylglycerol and PL fatty acid compositions in muscle tissues of the male and female fish species were found different. The most abundant fatty acids in the investigated seasons were palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1 n-9), palmitoleic acid (C16:1 n-7) and docosahexaenoic acid (C22:6 n-3). It was shown that the total lipid content and FA compositions in muscle tissues of the male and female S. triostegus were influenced by reproduction period and season. PMID- 27765963 TI - Comparison of the colloidal stability, bioaccessibility and antioxidant activity of corn protein hydrolysate and sodium caseinate stabilized curcumin nanoparticles. AB - The aims of this work were to construct corn protein hydrolysate (CPH)-based curcumin nanoparticles (Cur NPs) and to compare the colloidal stability, bioaccessibility and antioxidant activity of the Cur NPs stabilized CPH and sodium caseinate (NaCas) respectively. The results indicated that Cur solubility could be considerably improved after the Cur NPs fabrication. The spectroscopy results demonstrated that the solubilization of Cur should be attributed to its complexation with CPH or NaCas. The Cur NPs exhibited good colloidal stability after 1 week's storage but showed smaller (40 nm) size in CPH than in NaCas (100 nm). After lyophilization, the Cur NPs powders showed good rehydration properties and chemical stability, and compared with NaCas, the size of Cur NPs stabilized by CPH was still smaller. Additionally, the Cur NPs exhibited higher chemical stability against the temperature compared with free Cur, and the CPH could protect Cur from degradation more efficiently. Comparing with NaCas, the Cur NPs stabilized by CPH exhibited better bioaccessibility and antioxidant activity. This study demonstrated that CPH may be better than NaCas in Cur NPs fabrication and it opens up the possibility of using hydrophobic protein hydrolysate to construct the NPs delivery system. PMID- 27765964 TI - Properties and storage stability of whey protein edible film with spice powders. AB - The impact of spice powders on physical, mechanical, thermal and barrier properties, and on storage stability, of whey protein isolate (WPI)-based films was determined. Films with added spices were prepared from casting solution containing 10 % (w/w) heat-denatured WPI, glycerol (WPI:glycerol of 3:2 w/w), sodium chloride (0.4 g/100 g solution), garlic and pepper powders (<=3 g each/100 g solution). Water activity (aw) of all films was 0.53-0.57. Addition of spice powders increased thickness, darkness and yellowness of the WPI films. Films with added spices had lower tensile strength (TS), percent elongation (%E), and melting enthalpy of WPI matrices, but possessed higher water vapor permeability (WVP) than WPI film without sodium chloride and spices. The WPI film containing highest amount of garlic powder and lowest amount of pepper powder was selected for storage tests at 25-45 degrees C. Storage for up to 49 days resulted in reduced aw and %E, increased TS, and color changes at 35 and 45 degrees C, with few changes at 25 degrees C. However, film WVP and OP were not affected by storage conditions after 7 days storage. Active ingredients decreased over time with up to 81 % allicin and 37 % piperine retained in the film matrix after 47 days storage. PMID- 27765965 TI - Modified atmosphere packaging and post-packaging irradiation of Rumex induratus leaves: a comparative study of postharvest quality changes. AB - The effects of conventional and inert-gas enriched atmospheres, as well as those caused by different gamma-irradiation doses, on buckler sorrel (Rumex induratus) leaves quality were evaluated and compared after 12 days of storage at 4 degrees C. The green colour of the abaxial surface of the leaves was relatively stable, as well as the carbohydrates content and the calorific value. The storage time decreased the amounts of fructose, glucose, trehalose, alpha-tocopherol, and beta tocopherol and increased the levels of total organic acids and delta-tocopherol. The total tocopherols content was higher in air-packaged non-irradiated leaves, antioxidant compounds that may have contributed to the preservation of polyunsaturated fatty acids (PUFA). Some antioxidant properties were also favoured during storage. It was found that the overall postharvest quality of buckler sorrel leaves is better maintained with the argon-enriched atmospheres, while the 6 kGy dose was a suitable option to preserve PUF+A during cold storage. This study highlights the suitability of the applied postharvest treatments and the interest to include buckler sorrel leaves in contemporary diets. PMID- 27765967 TI - Potential of carboxymethyl cellulose coating and low dose gamma irradiation to maintain storage quality, inhibit fungal growth and extend shelf-life of cherry fruit. AB - Carboxymethyl cellulose (CMC) coatings alone and in combination with gamma irradiation was tested for maintaining the storage quality, inhibiting fungal incidence and extending shelf-life of cherry fruit. Two commercial cherry varieties viz. Misri and Double after harvest at commercial maturity were coated with CMC at levels 0.5-1.0 % w/v and gamma irradiated at 1.2 kGy. The treated fruit including control was stored under ambient (temperature 25 +/- 2 degrees C, RH 70 %) and refrigerated (temperature 3 +/- 1 degrees C, RH 80 %) conditions for evaluation of various physico-chemical parameters. Fruits were evaluated after every 3 and 7 days under ambient and refrigerated conditions. CMC coating alone at levels 0.5 and 0.75 % w/v was not found effective with respect to mold growth inhibition under either of the two conditions. Individual treatment of CMC coating at 1.0 % w/v and 1.2 kGy irradiation proved helpful in delaying the onset of mold growth up to 5 and 8 days of ambient storage. During post-refrigerated storage at 25 +/- 2 degrees C, RH 70 %, irradiation alone at 1.2 kGy gave further 4 days extension in shelf-life of cherry varieties following 28 days of refrigeration. All combinatory treatments of CMC coating and irradiation proved beneficial in maintaining the storage quality as well as delaying the decaying of cherry fruit during post-refrigerated storage at 25 +/- 2 degrees C, RH 70 % but, combination of CMC at 1.0 % w/v and 1.2 kGy irradiation was found significantly (p <= 0.05) superior to all other treatments in maintaining the storage quality and delaying the decaying of cherry fruit. The above combinatory treatment besides maintaining storage quality resulted in extension of 6 days in shelf life of cherry varieties during post-refrigerated storage at 25 +/- 2 degrees C, RH 80 % following 28 days of refrigeration. Above Combination treatment gave a maximum of 2.3 and 1.5 log reduction in yeast and mold count of cherry fruits after 9 and 28 days of ambient and refrigerated storage, thereby ensuring consumer safety. PMID- 27765966 TI - Maesa indica: a nutritional wild berry rich in polyphenols with special attention to radical scavenging and inhibition of key enzymes, alpha-amylase and alpha glucosidase. AB - The present study was aimed to evaluate the nutritional, antioxidant properties and inhibition of the key enzyme such as alpha-amylase and alpha-glucosidase from the fruits of Maesa indica. The results revealed that M. indica fruits possess an enormous amount of protein (45.68 mg/g), carbohydrates (25.12 mg/g) and mineral elements. The acetone extract were capable of hunting radicals by providing electrons and break chain reaction, especially in ABTS.+ (3719.23 umol TE/g extract), OH. (66.50 %) and NO. (81.50 %) radical scavenging assays. The methanol extract showed a strong inhibition towards alpha-amylase and alpha-glucosidase (IC50 of 37.80 and 23.74 ug/mL, respectively). HPLC analysis enumerate that both extracts illustrates the presence of polyphenolic compounds namely quercetin, caffeic acid, rutin and chlorogenic acid. PMID- 27765969 TI - Postharvest treatment of antioxidant reduces lenticel browning and improves cosmetic appeal of mango (Mangifera indica L.) fruits without impairing quality. AB - The present study reports the usefulness of ascorbic acid for reducing lenticels browning (LB) in mango, which impairs the cosmetic appeal and thereby the export. Postharvest dip treatment of ascorbic acid at different concentrations (100, 150 and 200 ppm) was given to four varieties of mango (Indian-'Dashehari', 'Langra'; Exotic-'Sensation', 'Eldon'). After treatment, fruits were stored at ambient conditions (35 +/- 4 degrees C and 65 +/- 5 % RH) for 10 days. At the end of storage period, observations were recorded on several parameters. Our results revealed that fruits of 'Langra' mango exhibited 100 % LB, followed by 'Dashehari' (52.8 %), 'Sensation' (42.9 %) and 'Eldon' (38.3 %). All concentrations of ascorbic acid reduced the LB to greater extent and improved the cosmetic appeal of fruits of all the varieties significantly over untreated fruits but the best results were obtained with 200 ppm concentration for LB (4.8, 1.6, 3.7, 3.2 %, respectively) and other attributes, non-significantly followed by 150 ppm concentration. All concentrations of ascorbic also reduced the activities of polyphenol oxidase, peroxidase and lipoxigenase enzymes, and also reduced respiration rate and ethylene evolution rate but without impairing eating quality attributes (soluble solids concentrates and total carotenoids). It can be concluded that postharvest dip application of ascorbic acid at 150 ppm reduced LB and improve face value without impairing fruit quality. PMID- 27765968 TI - Effect of popping and fermentation on proximate composition, minerals and absorption inhibitors, and mineral bioavailability of Amaranthus caudatus grain cultivated in Ethiopia. AB - This study evaluated the effect of popping and fermentation on the chemical composition of three types of Amaranthus caudatus grains cultivated in Ethiopia. Proximate composition, minerals and mineral absorption inhibitors were analyzed. Popping caused a decrease in protein content by 4 % and an increase in fat, ash, acid detergent fiber (ADF) and neutral detergent fiber (NDF) contents by 12, 10, 15 and 67 %, respectively. While fermentation increased protein, fat and ash content by 3, 22 and 14 %, respectively but did not significantly change ADF and NDF content. Fe, Ca and phytic acid (IP6) decreased during popping but Mg, Zn, galloyl and catechol did not change significantly. On the other hand, fermentation increased Fe and Mg content but decreased IP6, galloyl and catechol content. The decrease in mineral absorption inhibitors especially IP6 during popping and fermentation could contribute to enhance mineral bioavailability. However, due to the presence of high phytate content in raw amaranth, all IP6-to mineral molar ratios were above the recommended values. PMID- 27765970 TI - Immobilization of beta-glucosidase onto silicon oxide nanoparticles and augment of phenolics in sugarcane juice. AB - Purified beta-glucosidase was immobilized on SiO2 nanoparticles with 52 % efficiency and 14.1 % yield. It had a temperature optima at 60 degrees C and pH optima of 5.0. Immobilized enzyme was fairly stable at 60-70 degrees C. After immobilization, the Km value of beta-glucosidase for p-nitrophenyl-beta-d glucopyranoside (pNPG) increased from 0.9 to 1.074 mM and Vmax decreased from 3.5 to 1.513 U/mg. The immobilized enzyme showed improved storage stability at temperature 4 and 25 degrees C and was reusable for up to ten cycles with 70 % residual activity in pNPG and 60 % residual activity in sugarcane juice treatment. Sugarcane juice density, viscosity; surface tension etc. changed after treatment with immobilized beta-glucosidase. beta-Glucosidase treated sugarcane juice showed higher phenolics than untreated sugarcane juice. Caffeic acid which was absent in juice, was detected in beta-glucosidase treated juice at a concentration of about 1 mg/L. PMID- 27765971 TI - Reusable nanobiocatalysts for the efficient extraction of pigments from orange peel. AB - Nagpur mandarin orange (Citrus reticulata) peels were subjected to treatment with nanobiocatalysts in the form of cellulase and pectinase immobilized magnetic nanoparticles (MNPs). MNPs (Fe3O4) with average diameter in range of 40-90 nm were immobilized with cellulase and pectinase through APTES and glutaraldehyde. Treatment followed by extraction into organic solvents resulted in 8-9 fold increase in extraction of carotenoidic pigments compared to use of free enzymes. Optimum pH and temperature for the process were determined to be 5.0 and 50 degrees C, respectively. The nanobiocatalysts could be reused across three cycles with only 15 % drop in yield per cycle. Dinitrosalicylic acid assays showed that superior peel hydrolysis also led to greatest extent of pigment extraction. PMID- 27765972 TI - Microbicidal action of photoirradiated aqueous extracts from wine lees. AB - Wine lees, a major waste product of winemaking, is a rich source of polyphenolic compounds. LED-light irradiation at 400-nm elicited microbicidal activity of aqueous extract from wine lees (WLE) against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, in addition to reactive oxygen species (ROS) formation, including hydroxyl radical (.OH) and hydrogen peroxide (H2O2). Although treatment for 20 min of photoirradiation alone exerted bactericidal activity with a 2- to 3-log reduction, photoirradiated WLE for 20 min achieved a 5-log or greater reduction in viable S. aureus and P. aeruginosa cells. Regarding C. albicans, a 1-log reduction (90 % reduction) of viable cells was achieved by photoirradiated WLE for 40 min, whereas photoirradiation alone did not show any fungicidal effect. ROS analyses revealed that approximately 170 MUM .OH and 600 MUM H2O2 were generated in photoirradiated WLE for 20 min. Because the bactericidal activity of photoirradiated WLE was abolished by .OH scavengers, ROS, especially highly oxidative .OH, may be responsible for the microbicidal activity of photoirradiated WLE. In addition to its microbicidal activity, WLE may act as an antioxidant as it exerted radical scavenging activity against 2,2 diphenyl-1-picrylhydrazyl, a stable free radical. PMID- 27765973 TI - Enhancing antioxidant activity and antiproliferation of wheat bran through steam flash explosion. AB - The effect of steam flash explosion (SFE), a green processing technology, on the phenolic composition, antioxidant activity and antiproliferation to HepG2 of wheat bran was investigated. Moderate SFE treatment significantly enhanced the total soluble phenolic content of wheat bran. After SFE pretreatment, the free and conjugated ferulic acid content in the wheat bran were significantly increased. Antioxidant activities of SFE treated wheat bran were higher than those untreated wheat bran. The cellular antioxidant and antiproliferative activities of SFE treated wheat bran were also significantly ameliorated. It was suggested that SFE pretreatment could be applied to release the bound phenolic compounds and enhance the antioxidant activities and antiproliferative activities of wheat bran. PMID- 27765974 TI - The effect of ultraviolet treatment on enzymatic activity and total phenolic content of minimally processed potato slices. AB - In this work, potato slices were exposed to different doses of UV-C irradiation (i.e. 2.28, 6.84, 11.41, and 13.68 kJ m-2) with or without pretreatment [i.e. ascorbic acid and calcium chloride (AACCl) dip] and stored at 4 +/- 1 degrees C. Changes in enzymatic activities of polyphenol oxidase (PPO), peroxidase (POD) and phenylalanine ammonia lyase (PAL), as well as total phenolic content (TPC) were investigated after 0, 3, 7 and 10 days of storage. Results showed that untreated and UV-C treated potato slices at 13.68 kJ m-2 dosage level showed significantly higher PPO, POD and PAL activities. Conversely, untreated potato slices showed the lowest TPC during storage period. Potato slices subjected to AACCl dip plus UV-C at 6.84 kJ m-2 produced lower PPO, POD and PAL activities, as well as maintained a high TPC during storage. PMID- 27765975 TI - Characterization of vegetable fiber and its use in chicken burger formulation. AB - ABSTRACT: Vegetable fibers have been used lately as ingredients in popular meat products in order to increase its nutritional value. The objective of this study was the physical-chemical characterization of six vegetable fibers in order to apply them in chicken burger formulations as animal fat substitutes. The studied fibers showed moisture content below 14 %, low content of fat, protein and ash, and high levels of carbohydrates. The oat, wheat and bamboo fibers showed the highest content of total dietary fiber. All fibers presented good results of technological characterization, but bamboo, pea and wheat fibers showed the best hygroscopic property results, good emulsifying stability, and color compatible for application in meat products. The use of vegetable fibers in chicken burgers resulted in lower or equal hardness values when the experiments were compared to the control sample. Most samples showed elasticity, adhesiveness, cohesiveness and chewiness values significantly equal to the control sample. The sensory analysis results indicated that all samples had good acceptability. The use of vegetable fibers in chicken burgers proved to be a promising alternative for food manufacturers to combine products deemed unhealthy with functional ingredients that are more appealing for consumers. GRAPHICAL ABSTRACT: PMID- 27765976 TI - Effect of ultrafiltered milk permeate and non-dairy creamer powder concentration on low phenylalanine yoghurt's physicochemical properties during storage. AB - Phenylketonuria (PKU) is a genetic disorder that has no cure and all patients with this disorder must adhere to a special diet to prevent the onset of symptoms and mental retardation in children. In this study, analog yoghurt with good and acceptable nutrition benefit for PKU patients was produced. Accordingly, ultrafiltered milk permeate was added at two different concentrations of 4 and 5 w/w % and non-dairy creamer at two different concentrations of 1.5 and 2 w/w %. Subsequently, pH, acidity, protein, fat, dry matter, humidity, syneresis and Phe of the yogurts were determined. Protein content, dry matter, pH, acidity and Phe in the analog yogurt with 5 % permeate and 2 % non-dairy creamer were higher than other yoghurt samples, significantly (P < 0.05). During the storage, pH and syneresis of samples reduced, while acidity significantly increased. Phe content of analog yoghurt was low (274 mg/kg). PMID- 27765977 TI - Physicochemical characteristics of phytonutrient retained red palm olein and butter-fat blends and its utilization for formulating chocolate spread. AB - Phytonutrients retained palm olein (PRPOL) was prepared and blended into butterfat at different ratios. The physicochemical characteristics and the phytonutrient composition of blends, as well as its utilization in the preparation of functional chocolate spread were evaluated. The results showed that the redness, yellowness, slip melting point, free fatty acids, peroxide value, iodine value, unsaponifiable matter, diacylglycerol and monoacylglycerol increased while lightness, saponification value, and triacylglycerol significantly decreased upon incorporation of increased quantities of PRPOL into butterfat. The incorporation affected short chain, medium chain and long chain fatty acids content along with variation in the palmitic, stearic, oleic acids content of the blends as compared to butterfat alone. Improvement in carotenoids (6-27 fold), phytotosterols (3-15 fold), tocopherols and tocotrienols (4-17 fold), and squalene (1-6 fold) in blends was observed upon incorporation of PRPOL. Cholesterol level in the blends was reduced (10-50 %) as compared to the butterfat. The blends showed an intermediate solid fat content of PRPOL and butterfat. Moreover, radical scavenging activity of the blends increased with increase in PRPOL quantity. Prepared chocolate spreads showed similar fat, moisture, colour components (L*, a* and b*) and better emulsion stability. The hardness of the spreads was increased upon increasing quantity of PRPOL. The sensory evaluation showed that chocolate prepared by replacing butterfat with 20 % PRPOL had acceptable sensory attributes. PMID- 27765978 TI - Degradation kinetics of bioactive components, antioxidant activity, colour and textural properties of selected vegetables during blanching. AB - Bioactive components of fruit and vegetables play an important role in scavenging free radicals and protect the body from degenerative diseases. A kinetic study was conducted to quantify the losses occurring in bioactive components, antioxidant activity and changes in colour and firmness of four commonly used vegetables (beetroot, green pea, eggplant and green pepper) during heat treatment (70-90 degrees C). The study revealed that logistic model can predict the variation in bioactive components and antioxidant activity with higher R2 and lower root mean square error (RMSE) as compared to first order model due to logarithmic reduction in these properties in the beginning of the process itself. However zero and first order kinetic models were found suitable to predict the changes occurring in colour and firmness respectively during blanching. D, z value, activation energy (Ea), activation enthalpy and entropy were calculated for all measured parameters for selected vegetables in the temperature range of 70-90 degrees C. These finding would be useful in designing thermal processes and related calculations for these vegetables. PMID- 27765979 TI - The effects of production methods and storage on the chemical constituents of apple pekmez. AB - The purposes of this study were to investigate the effects of two different pekmez production methods namely open pan evaporation (OPE) and vacuum evaporation (VE) on the final products, and to observe the changes in constituents as well as aromatic components after 4 months of storage. The initial and poststorage (4 months) 5-hydroxymethyl furfural (HMF) content in OPE apple pekmez were respectively 5.48, and 7.04 mg/kg. No HMF was detected in VE apple pekmez. Both initial and poststorage content of phenolic compounds was higher in VE pekmez compared to OPE pekmez. The effects of production methods and storage time were statistically significant on phenolic compounds in apple pekmez. The content of all analyzed minerals except calcium has significantly decreased in pekmez compared to raw material on dry weight basis. OPE resulted in a 55.97 % loss in the amount of ascorbic acid, whereas the loss in VE has been 23.45 %. Poststorage loss in ascorbic acid has respectively been 69.54, and 89.28 %, for VE and OPE samples. None of the aromatic components of fresh apple was detected in pekmez. PMID- 27765980 TI - Assessment of total polyphenols, antioxidants and antimicrobial properties of aonla varieties. AB - Phenolic content, antioxidant activities and antimicrobial activities of methanolic, ethanolic and ethyl acetate extracts of five different varieties of aonla (Emblica officinalis) fruits as well their powders were evaluated. Total polyphenolic content in fresh aonla fruit extracts varied from 70.6 to 159.4 mg GAE/g and their EC 50 (effective concentration) values for antioxidant activity ranged from 46.72 to 359.7 ug/ml. Significant varietal difference were observed in antioxidant activity of the extracts of fresh aonla fruit and powder. Among the variety analyzed, Desi variety exhibited significantly higher TPC (total polyphenol content) and antioxidant activity in fresh as well as dried form in all the extracts. Methanolic extracts of various varieties had maximum TPC and antioxidant activity. Variety NA-7 showed high TPC and antioxidant activity. Almost, similar trend was observed among the extracts of aonla powders for TPC and AOA (antioxidant activity). A high positive correlation coefficient existed between TPC and AOA of different aonla extracts. All the extracts analyzed, exhibited a strong antimicrobial potential against E. coli, Salmonella typhi, Staphylococcus aureus and Candida albicans. This study suggests aonla as potential natural source of antioxidants and antimicrobial agents. PMID- 27765981 TI - Sea fennel (Crithmum maritimum L.): phytochemical profile, antioxidative, cholinesterase inhibitory and vasodilatory activity. AB - Sea fennel, a rediscovered star of the coastal cuisine, has been investigated for its phytochemical profile and biological potential. Sea fennel flowers, stems and leaves were analyzed for essential oils (EOs) isolated by hydrodistillation, as well as non-volatiles obtained by ethanolic extraction. Limonene were found to be a dominant compound in EOs and ethanolic extracts; ranging from 57.5-74.2 % and 0.7-8.1 mg/g dry plant material, respectively. In addition total phenolic content was determined for ethanolic extracts. All samples and their main phytochemicals were tested for various methods. EO and extract obtained from flowers were tested for vasodilatory activity on rat aortic rings. Antioxidant activity of EOs was extremely low in comparison to extracts, on the contrary to cholinesterase inhibition where EOs showed better activity than extracts. Flower extract and chlorogenic acid showed stronger vasodilators in comparison to EO and limonene. The obtained results point out the potential impact of the dominant compounds from EO and extract on the biological properties of the sea fennel. PMID- 27765982 TI - Application of response surface methodology for the optimization of supercritical fluid extraction of essential oil from pomegranate (Punica granatum L.) peel. AB - Essential oils and volatile components of pomegranate (Punica granatum L.) peel of the Malas variety from Meybod, Iran, were extracted using supercritical fluid extraction (SFE) and hydro-distillation methods. The experimental parameters of SFE that is pressure, temperature, extraction time, and modifier (methanol) volume were optimized using a central composite design after a (24-1) fractional factorial design. Detailed chemical composition of the essential oils and volatile components obtained by hydro-distillation and optimum condition of the supercritical CO2 extraction were analyzed by GC-MS, and seventy-three and forty six compounds were identified according to their retention indices and mass spectra, respectively. The optimum SFE conditions were 350 atm pressure, 55 degrees C temperature, 30 min extraction time, and 150 uL methanol. Results showed that oleic acid, palmitic acid and (-)-Borneol were major compounds in both extracts. The optimum extraction yield was 1.18 % (w/w) for SFE and 0.21 % (v/w) for hydro-distillation. PMID- 27765983 TI - Characterization of nutrients, amino acids, polyphenols and antioxidant activity of Ridge gourd (Luffa acutangula) peel. AB - Ridge gourd (Luffa acutangula) is consumed as a vegetable after peeling off the skin which is a domestic waste. Luffa acutangula peel (LAP) was observed to be a good source of fiber (20.6 %) and minerals (7.7 %). Amino acid analysis revealed presence of the highest content of Carnosine followed by aspartic acid and aminoadipic acid. Antioxidant activity of different extracts showed that ethyl acetate extract was more potent when compared to other solvent extractions. It exhibited a significant amount of phenolic acids like p-coumaric acid (68.64 mg/100 g of dry weight) followed by gallic acid (34.98 mg/100 g of dry weight), protocatechuic acid (30.52 mg/100 g of dry weight) in free form and ferulic acid (13.04 mg/100 g of dry weight) in bound form. PMID- 27765984 TI - Characterisation of seed oils from different grape cultivars grown in China. AB - To explore the potential of the large amount of grape pomace in wineries of China, oils of three Eurasian grape cultivars (Chardonnay, Merlot and Carbernet Sauvignon) and two Chinese traditional grape cultivars (Vitis amurensis and Vitis davidii), were characterised. The results showed seed oil properties differ for various grape varities. Grape seed oils were demonstrated to be good sources of polyunsaturated fatty acid (PUFA) (63.88-77.12 %), sterols (227.99-338.83 mg/100 g oil) and tocotrienols (320.08-679.24 mg/kg oil). Seed oil of V. amurensis exhibited the highest values of polyunsaturated fatty acid, total tocotrienols, total tocols and DPPH. scavenging capacity. Seed oil of Carbernet Sauvignon had the highest contents of squalene, total sterols, total tocopherols and total phenolics. Principal component analysis five grape cultivars differentiated on the basis of bioactive components content and antioxidant properties. PMID- 27765985 TI - First Report of Longidorus kuiperi and Rotylenchus eximius from Coastal Sand Dunes in Crete, Greece. AB - Plant-parasitic nematode species have been reported on several occasions from coastal sand dunes, including Longidorus and Rotylenchus species (Vovlas et al., 2008; De Luca et al., 2009; Mateille et al., 2014). In April 2016, 10 soil samples of 3 to 4 kg from the rhizosphere of Tamarix smyrnensis with different vegetation around (viz. Elymus farctus, Lycium schweinfurthii, Crithmum maritimum, and Arthrocnemum sp.) were collected for diagnosis of plant-parasitic nematodes. The area of sampling was a coastal sand dune near the archeological site of Komos, southwest of Crete, Greece. Low soil populations of a needle and a spiral nematode were detected (3 and 8 individuals/1,000 cm3 of soil, respectively), which prompted us to undertake a detailed morphological and molecular comparative study with previous reported data. Nematodes were extracted from soil with the wet sieving and decanting method (Cobb, 1918). Morphological and molecular analyses of females identified these species as Longidorus kuiperi Brinkman, Loof and Barbez, 1987, and Rotylenchus eximius Siddiqi, 1964. The morphology of L. kuiperi females (six specimens studied) was characterized by having a slender body; very broad lip region (27 +/- 1.5 [25 to 30] MUm in width); short, hemispherical tail; body length of (7.1 +/- 0.8 [6.5 to 8.5] mm); vulva position at 47% to 55% of body length; odontostyle length of (105 +/- 6.5 [90 to 115] MUm); males very common (but less frequent than females [45% vs 55%]); tail region with 15 to 20 supplements and bulged terminal cuticle. The morphology of R. eximius females (four specimens studied) was characterized by having a hemispherical lip region clearly set off; with four annuli; body without longitudinal striations; lateral fields areolated in the pharyngeal region only; stylet 36 to 38 MUm; and broadly rounded tail. The morphology of the isolated nematodes agreed with previous descriptions of L. kuiperi (Brinkman et al., 1987; De Luca et al., 2009), and R. eximius (Siddiqi, 1964; Castillo and Vovlas, 2005). A single individual was used for DNA extraction. Primers and polymerase chain reaction conditions used in this research were specified in Cantalapiedra et al. (2013) and Archidona-Yuste et al. (2016), and a single amplicon of 800 and 1,100 bp was obtained and sequenced, respectively. D2-D3 (KX398055-KX398056) and ITS sequence alignments (751 and 648 bp, respectively) from L. kuiperi (KX398057) showed 98% to 99% similarity, differing in 4, and from 6 to 12 nucleotides, respectively, to other sequences of L. kuiperi deposited in GenBank from Italy and Spain (AM911623, AM905267-AM905270, respectively), with a query coverage of 99%. Similarly, D2-D3 sequence alignment from R. eximius (KX398058) showed 100% to 99% to another sequence of R. eximius deposited in GenBank from Italy and Spain (EU280794, DQ328741), differing in zero to three nucleotides, respectively, and a query coverage of 81%. Phylogenetic analyses using Bayesian Inference placed L. kuiperi in a highly supported (100%) clade that included all L. kuiperi sequences deposited in GenBank (Archidona-Yuste et al., 2016), and R. eximius in a highly supported (100%) clade that included all R. eximius sequences deposited in GenBank (Cantalapiedra-Navarrete et al., 2013). All identification methods were consistent with L. kuiperi and R. eximius. To our knowledge, this is the first report of L. kuiperi and R. eximius in Greece. Consequently, all these data suggest that coastal sand dunes in Europe constitute environmental conditions optimal for colonization and development of L. kuiperi, as previously reported (De Luca et al., 2009). Similarly, R. eximius has been reported in several Mediterranean countries, including Italy, Morocco, Spain, and Tunisia (Castillo and Vovlas, 2005), and this report extend the geographical distribution of this species. PMID- 27765986 TI - First Report of the Spiral Nematode Rotylenchus incultus (Nematoda: Hoplolaimidae) from Cultivated Olive in Tunisia, with Additional Molecular Data on Rotylenchus eximius. AB - Spiral nematode species of the genus Rotylenchus have been reported on olive (Olea europaea L.) in several Mediterranean countries (Castillo et al., 2010; Ali et al., 2014). Nematological surveys for plant-parasitic nematodes on olive trees were carried out in Tunisia between 2013 and 2014, and two nematode species of Rotylenchus were collected from the rhizosphere of olive cv. Chemlali in several localities of Tunisia (Tables 1,2 [Table: see text] [Table: see text] ). Twenty two soil samples of 3 to 4 kg were collected with a shovel from the upper 50 cm of soil from arbitrarily chosen olive trees. Nematodes were extracted from 500 cm3 of soil by centrifugal flotation method (Coolen, 1979). Specimens were heat killed by adding hot 4% formaldehyde solution and processed to pure glycerin using the De Grisse's (1969) method. Measurements were done using a drawing tube attached to a Zeiss III compound microscope. Nematode DNA was extracted from single individuals and PCR assays were conducted as described by Castillo et al. (2003). Moderate-to-low soil populations of these spiral nematodes were detected (5.5-11.5, 1.5-5.0 individuals/500 cm3 of soil, respectively). This prompted us to undertake a detailed morphological and molecular comparative study with previous reported data. Morphological and molecular analyses of females identified these species as Rotylenchus eximius Siddiqi, 1964, and Rotylenchus incultus Sher, 1965. The morphology of R. eximius females (five specimens studied) was characterized by having a hemispherical lip region clearly off set, with four to five annuli, body without longitudinal striations, lateral fields areolated in the pharyngeal region only, stylet 32 to 36 MUm long, and broadly rounded tail. The morphology of R. incultus females (51 females and 16 males; Table 2) was characterized by a hemispherical lip region with the basal annulus subdivided by irregular longitudinal striations, with three, rarely four annuli; stylet 21.5 to 27.5 MUm long, female tail hemispherical with terminus regularly annulated; phasmids anterior to anus level (3-6 annuli above). The morphology of the isolated nematodes agreed with previous descriptions of R. eximius (Siddiqi, 1964; Castillo and Vovlas, 2005) and R. incultus (Sher, 1965; Castillo and Vovlas, 2005; Vovlas et al., 2008), respectively. A single individual was used for DNA extraction. Primers and PCR conditions used in this research were specified in Cantalapiedra-Navarrete et al. (2013), and a single amplicon of 800, 1,100, and 450 bp was obtained and sequenced for D2 to D3, ITS1, and cytochrome c oxidase subunit 1 (coxI), respectively. Sequence alignments for D2 to D3 (KX669231-KX669233), ITS1 (KX669238-KX669240), and coxI (KX669244-KX669245) from R. eximius, showed 99% to 97%, 98% to 94%, 93% similarity to other sequences of R. eximius deposited in GenBank (EU280794-DQ328741, EU373663-EU373664, JX015401 JX015402, respectively). Similarly, D2 to D3 (KX669234-KX669237), ITS1 (KX669241 KX669243), and coxI (KX669246-KX669249) sequence alignments from R. incultus, showed 99%, 99% to 95%, 99% to 90% similarity, respectively, to other sequences of R. incultus deposited in GenBank (EU280797, EU373672-EU373673, JX015403, respectively). The best fitted model of DNA evolution was obtained using jModelTest v. 2.1.7 (Darriba et al. 2012) with the Akaike information criterion. BI analyses were performed under the general time reversible (GTR) with invariable sites and a gamma-shaped distribution of substitution rates (GTR + I + G) model for ITS1 and coxI. Phylogenetic analyses of ITS1 and coxI using Bayesian inference (BI) placed R. eximius and R. incultus from Tunisia in subclades that included all R. eximius and R. incultus sequences deposited in GenBank (Fig. 1Fig. 1Phylogenetic relationships within Rotylenchus species found in Tunisia and other species from GenBank. Bayesian 50% majority rule consensus trees as inferred from ITS1 and coxI sequences alignments under the GTR + I + G model. Posterior probabilities more than 0.70 are given for appropriate clades. Newly obtained sequences in this study are in bold. Scale bar = expected changes per site.), which agrees with previous results (Cantalapiedra-Navarrete et al., 2013). Morphology, morphometry, and molecular and phylogenetic data obtained from these samples were consistent with R. eximius and R. incultus identification. To our knowledge, this is the first report of R. incultus in Tunisia. Consequently, all these data suggest that spiral nematode species of the genus Rotylenchus are predominant in olive as previously reported in other Mediterranean areas (Ali et al., 2014). PMID- 27765987 TI - First Report of Heterorhabditis amazonensis from Venezuela and Characterization of Three Populations. AB - During a survey in western Venezuela in 2011, three new populations of Heterorhabditis amazonensis (LPV081, LPV156, and LPV498) were isolated. Some differences were found in terms of morphometry compared with the original description; however, the distance from the anterior end to the excretory pore is the most variable character; significantly shorter in all infective juveniles and in other developmental stages depending on the population. According to a Principal Component Analysis, LPV498 possesses more differences in morphometric characteristics and can be separated from the other two. Those intraspecific differences could be attributed to the geographic origin of the nematode. Molecular studies of ITS regions demonstrated that the sequences of the Venezuelan strains were identical to those of the type species originally isolated in the Brazilian Amazonian forest. This is an interesting fact because in several studies on heterorhabditids, intraspecific variability has been recorded. Herein, we present the first report of H. amazonensis in Venezuela and the characterization of three populations of this species. PMID- 27765988 TI - Steinernema biddulphi n. sp., a New Entomopathogenic Nematode (Nematoda: Steinernematidae) from South Africa. AB - A new species of entomopathogenic nematode (EPN), Steinernema biddulphi n. sp., was isolated from a maize field in Senekal, Free State Province of South Africa. Morphological and molecular studies indicated the distinctness of S. biddulphi n. sp. from other Steinernema species. Steinernema biddulphi n. sp. is characterized IJs with average body length of 663 MUm (606-778 MUm), lateral fields with six ridges in mid-body region forming the formula 2,6,2. Excretory pore located anterior to mid-pharynx (D% = 46). Hyaline layer occupies approximately half of tail length. Male spicules slightly to moderately curved, with a sharp tip and golden brown in color. The first generation of males lacking a mucron on the tail tip while the second generation males with a short filamentous mucron. Genital papillae with 11 pairs and one unpaired preanal papilla. The new species is further characterized by sequences of the internal transcribed spacer (ITS) and partial 28S regions (D2-D3) of the ribosomal DNA (rDNA). Phylogenetic data show that S. biddulphi n. sp. belongs to the "bicornutum" clade within the Steinernematidae family. PMID- 27765989 TI - Coronostoma claireae n. sp. (Nematoda: Rhabditida: Oxyuridomorpha: Coronostomatidae) from the Indigenous Milliped Narceus gordanus (Chamberlain, 1943) (Diplopoda: Spirobolida) in Ocala National Forest, Florida. AB - Twenty-four individuals of Narceus gordanus (Diplopoda: Spirobolidae) were collected in Ocala National Forest, FL, between November 2013 and July 2014. Each specimen was dissected to extract the intestine, which was removed and examined for parasitic nematodes. Coronostoma claireae n. sp. was collected from the hindgut and midgut of 10 specimens, and its morphology was examined with brightfield, differential interference contrast, phase contrast, and scanning electron microscopy. This species is separated from other Coronostoma spp. by the following characteristics: body length less than 3 mm; head sense organs pit like; first annule long, extending past middle of corpus, width similar to that of second annule; basal bulb pyriform; eggs larger than 60 * 50 um. This species is the first North American record for the genus Coronostoma, which is removed from Thelastomatoidea: Thelastomatidae and reassigned to Coronostomatidae on the basis of presumed apomorphies. A key is provided for known Coronostoma spp. The superfamily Coronostomatoidea is re-established for Coronostomatidae and Traklosiidae. PMID- 27765990 TI - Curative Control of the Peachtree Borer Using Entomopathogenic Nematodes. AB - The peachtree borer, Synanthedon exitiosa (Say 1823), is a major pest of stone fruit trees in North America. Current management relies upon preventative control using broad-spectrum chemical insecticides, primarily chlorpyrifos, applied in the late summer or early fall. However, due to missed applications, poor application timing, or other factors, high levels of S. exitiosa infestation may still occur and persist through the following spring. Curative treatments applied in the spring to established infestations would limit damage to the tree and prevent the next generation of S. exitiosa from emerging within the orchard. However, such curative measures for control of S. exitiosa do not exist. Our objective was to measure the efficacy of the entomopathogenic nematode, Steinernema carpocapsae, as a curative control for existing infestations of S. exitiosa. In peach orchards, spring applications of S. carpocapsae (obtained from a commercial source) were made to infested trees and compared with chlorpyrifos and a water-only control in 2014 and 2015. Additionally, types of spray equipment were compared: nematodes were applied via boom sprayer, handgun, or trunk sprayer. To control for effects of application method or nematode source, in vivo laboratory-grown S. carpocapsae, applied using a watering can, was also included. Treatment effects were assessed 39 d (2014) or 19 d (2015) later by measuring percentage of trees still infested, and also number of surviving S. exitiosa larvae per tree. Results indicated that S. carpocapsae provided significant curative control (e.g., >80% corrected control for the handgun application). In contrast, chlorpyrifos failed to reduce S. exitiosa infestations or number of surviving larvae. In most comparisons, no effect of nematode application method was detected; in one assessment, only the handgun and watering can methods reduced infestation. In conclusion, our study indicates that S. carpocapsae may be used as an effective curative measure for S. exitiosa infestations. PMID- 27765991 TI - Effect of Application Timing of Oxamyl in Nonbearing Raspberry for Pratylenchus penetrans Management. AB - In 2012, the Washington raspberry (Rubus idaeus) industry received a special local needs (SLN) 24(c) label to apply Vydate L(r) (active ingredient oxamyl) to nonbearing raspberry for the management of Pratylenchus penetrans. This is a new use pattern of this nematicide for raspberry growers; therefore, research was conducted to identify the optimum spring application timing of oxamyl for the suppression of P. penetrans. Three on-farm trials in each of 2012 and 2013 were established in Washington in newly planted raspberry trials on a range of varieties. Oxamyl was applied twice in April (2013 only), May, and June, and these treatments were compared to each other as well as a nontreated control. Population densities of P. penetrans were determined in the fall and spring postoxamyl applications for at least 1.5 years. Plant vigor was also evaluated in the trials. Combined results from 2012 and 2013 trials indicated that application timing in the spring was not critical. Oxamyl application reduced root P. penetrans population densities in all six trials. Reductions in P. penetrans population densities in roots of oxamyl-treated plants, regardless of application timing, ranged from 62% to 99% of densities in nontreated controls. Phytotoxicity to newly planted raspberry was never observed in any of the trials. A nonbearing application of oxamyl is an important addition to current control methods used to manage P. penetrans in raspberry in Washington. PMID- 27765992 TI - Evaluation of Steam and Soil Solarization for Meloidogyne arenaria Control in Florida Floriculture Crops. AB - Steam and soil solarization were investigated for control of the root-knot nematode Meloidogyne arenaria in 2 yr of field trials on a commercial flower farm in Florida. The objective was to determine if preplant steam treatments in combination with solarization, or solarization alone effectively controlled nematodes compared to methyl bromide (MeBr). Trials were conducted in a field with naturally occurring populations of M. arenaria. Treatments were solarization alone, steam treatment after solarization using standard 7.6-cm-diameter perforated plastic drain tile (steam 1), steam treatment following solarization using custom-drilled plastic drain tile with 1.6-mm holes spaced every 3.8 cm (steam 2), and MeBr applied at 392 kg/ha 80:20 MeBr:chloropicrin. Drain tiles were buried approximately 35 cm deep with four tiles per 1.8 by 30 m plot. Steam application followed a 4-wk solarization period concluding in mid-October. All steam was generated using a Sioux propane boiler system. Plots were steamed for sufficient time to reach the target temperature of 70 degrees C for 20 min. Solarization plastic was retained on the plots during steaming and plots were covered with a single layer of carpet padding to provide additional insulation. The floriculture crops larkspur (Delphinium elatum and Delphinium * belladonna), snapdragon (Antirrhinum majus), and sunflower (Helianthus annuus) were produced according to standard commercial practices. One month after treatment in both years of the study, soil populations of M. arenaria were lower in both steam treatments and in MeBr compared to solarization alone. At the end of the season in both years, galling on larkspur, snapdragon, and sunflowers was lower in both steam treatments than in solarization. Both steam treatments also provided control of M. arenaria in soil at the end of the season comparable to, or exceeding that provided by MeBr. Both steam treatments also reduced M. arenaria in snapdragon roots comparable to, or exceeding control with MeBr. Meloidogyne arenaria in soil increased in solarization alone. Solarization alone also had higher gall ratings on larkspur, snapdragon, and sunflower than all other treatments. Steam provided excellent control of M. arenaria in this study. PMID- 27765993 TI - Mitochondrial Haplotype-based Identification of Root-knot Nematodes (Meloidogyne spp.) on Cut Foliage Crops in Florida. AB - Florida accounts for more than 75% of the national cut foliage production. Unfortunately, root-knot nematodes (RKN) (Meloidogyne spp.) are a serious problem on these crops, rendering many farms unproductive. Currently, information on the Meloidogyne spp. occurring on most commonly cultivated cut foliage crops in Florida, and tools for their rapid identification are lacking. The objectives of this study were to (i) identify specific RKN infecting common ornamental cut foliage crops in Florida and (ii) evaluate the feasibility of using the mtDNA haplotype as a molecular diagnostic tool for rapid identification of large samples of RKN. A total of 200 Meloidogyne females were collected from cut foliage plant roots. Meloidogyne spp. were identified by PCR and RFLP of mitochondrial DNA. PCR and RFLP of mitochondrial DNA were effective in discriminating the Meloidogyne spp. present. Meloidogyne incognita is the most dominant RKN on cut foliage crops in Florida and must be a high target for making management decisions. Other Meloidogyne spp. identified include M. javanica, M. hapla, Meloidogyne sp. 1, and Meloidogyne sp. 2. The results for this study demonstrate the usefulness of the mtDNA haplotype-based designation as a valuable molecular tool for identification of Meloidogyne spp. PMID- 27765994 TI - Morphological and Molecular Characterization of Gracilacus wuae n. sp. (Nematoda: Criconematoidea) Associated with Cow Parsnip (Heracleum maximum) in Ontario, Canada. AB - Gracilacus wuae n. sp. from soil associated with cow parsnip in Ontario, Canada is described and illustrated. Morphologically, females have a long stylet ranging from 80 to 93 um long, the lip region not offset from the body contour, without lateral lips but with large and flat submedian lobes, the mouth opening slit-like elongated laterally and surrounded by lateral flaps, the excretory pore is anterior to the knobs of the stylet; males without stylet and the pharynx degenerated. The fourth-stage juveniles lack a stylet, the pharynx degenerated, and can be differentiated into preadult females and males based on the position of the genital primordia. The third-stage juveniles are similar to females but smaller. Phylogenetic studies using the rDNA small subunit 18S, large subunit 28S D2/D3, and internal transcribed spacer (ITS) sequences collectively provide evidence of a grouping with other Gracilacus and some species of Paratylenchus with stylet length of females longer than 41 um deposited in GenBank. PMID- 27765995 TI - Discopersicus n. gen., a New Member of the Family Tylenchidae Orley, 1880 with Detailed SEM Study on Two Known Species of the Genus Discotylenchus Siddiqi, 1980 (Nematoda; Tylenchidae) from Iran. AB - Discopersicus iranicus n. gen., n. comb., previously described from Iran as a new species under the genus Discotylenchus, is illustrated using light microscope and scanning electron microscope (SEM) observations and further studied using molecular characters. SEM studies revealed the newly proposed genus has oblique amphidial apertures on the lateral sides of the lip region. SEM images are also provided for two species of Discotylenchus, namely D. discretus and D. brevicaudatus, as the first SEM study of the genus. These results confirmed longitudinal amphidial aperture type on lateral sides of the lip region in genus Discotylenchus, as noted by Siddiqi while erecting the genus with D. discretus as the type species. Molecular phylogenetic analyses using partial small subunit (SSU) and large subunit (LSU) rDNA sequences revealed the affinity of the genus Discopersicus n. gen. with members of the subfamily Boleodorinae, as supported by morphological characters (mainly, the oblique amphidial opening). PMID- 27765996 TI - Optimized first-order methods for smooth convex minimization. AB - We introduce new optimized first-order methods for smooth unconstrained convex minimization. Drori and Teboulle [5] recently described a numerical method for computing the N-iteration optimal step coefficients in a class of first-order algorithms that includes gradient methods, heavy-ball methods [15], and Nesterov's fast gradient methods [10,12]. However, the numerical method in [5] is computationally expensive for large N, and the corresponding numerically optimized first-order algorithm in [5] requires impractical memory and computation for large-scale optimization problems. In this paper, we propose optimized first-order algorithms that achieve a convergence bound that is two times smaller than for Nesterov's fast gradient methods; our bound is found analytically and refines the numerical bound in [5]. Furthermore, the proposed optimized first-order methods have efficient forms that are remarkably similar to Nesterov's fast gradient methods. PMID- 27765998 TI - A Longitudinal Investigation of Predictors of the Association Between Age 3 and Age 6 Behavioural Inhibition. AB - Children who exhibit elevated levels of the temperament trait behavioural inhibition (BI) across time may be at greatest risk for anxiety. However, little research has investigated the influence of other temperamental traits, particularly positive emotionality (PE), on the continuity of BI in childhood, nor whether parental overprotection influences associations between early and later child BI. To explore whether PE and overprotection shape associations between early and later BI, this longitudinal study of three-year-olds (N = 446) followed up at age 6 included tasks tapping child temperament, and parental overprotection was assessed via interview ratings and parent-report. Lower levels of child PE and higher levels of caregiver overprotection at baseline predicted stronger associations between laboratory-assessed BI at ages 3 and 6. Findings elucidate influences shaping the developmental continuity of BI. PMID- 27765997 TI - Metallacycle-Mediated Cross-Coupling in Natural Product Synthesis. PMID- 27765999 TI - Hydrophobic resorufamine derivatives: potent and selective red fluorescent probes of the endoplasmic reticulum of mammalian cells. AB - The endoplasmic reticulum (ER) of eukaryotic cells plays critical roles in the processing of secreted and transmembrane proteins. Defects in these functions are associated with a wide range of pathologies. To image this organelle, cells are often treated with fluorescent ER-Tracker dyes. Although these compounds are selective, existing red fluorescent probes of the ER are costly glibenclamide derivatives that inhibit ER-associated sulphonylurea receptors. To provide simpler and more cost-effective red fluorescent probes of the ER, we synthesized amino analogues of the fluorophore resorufin. By varying the polarity of linked substituents, we identified hexyl resorufamine (HRA) as a novel hydrophobic (cLogD (pH 7.4) = 3.8) red fluorescent (Ex. 565 nm; Em. 614 nm in ethanol) molecular probe. HRA is exceptionally bright in organic solvents (quantum yield = 0.70), it exclusively localizes to the ER of living HeLa cells as imaged by confocal microscopy, it is effective at concentrations as low as 100 nM, and it is non-toxic under these conditions. To examine its utility, we used HRA to facilitate visualization of small molecule-mediated release of a GFP-GPI fusion protein from the ER into the secretory pathway. HRA represents a potent, selective, and cost-effective probe for imaging and labeling the ER. PMID- 27766000 TI - Location, quality and choice of hospital: Evidence from England 2002-2013. AB - We investigate (a) how patient choice of hospital for elective hip replacement is influenced by distance, quality and waiting times, (b) differences in choices between patients in urban and rural locations, (c) the relationship between hospitals' elasticities of demand to quality and the number of local rivals, and how these changed after relaxation of constraints on hospital choice in England in 2006. Using a data set on over 500,000 elective hip replacement patients over the period 2002 to 2013 we find that patients became more likely to travel to a provider with higher quality or lower waiting times, the proportion of patients bypassing their nearest provider increased from 25% to almost 50%, and hospital elasticity of demand with respect to own quality increased. By 2013 average hospital demand elasticity with respect to readmission rates and waiting times were - 0.2 and - 0.04. Providers facing more rivals had demand that was more elastic with respect to quality and waiting times. Patients from rural areas have smaller disutility from distance. PMID- 27766002 TI - Conceptual energy and water recovery system for self-sustained nano membrane toilet. AB - With about 2.4 billion people worldwide without access to improved sanitation facilities, there is a strong incentive for development of novel sanitation systems to improve the quality of life and reduce mortality. The Nano Membrane Toilet is expected to provide a unique household-scale system that would produce electricity and recover water from human excrement and urine. This study was undertaken to evaluate the performance of the conceptual energy and water recovery system for the Nano Membrane Toilet designed for a household of ten people and to assess its self-sustainability. A process model of the entire system, including the thermochemical conversion island, a Stirling engine and a water recovery system was developed in Aspen Plus(r). The energy and water recovery system for the Nano Membrane Toilet was characterised with the specific net power output of 23.1 Wh/kgsettledsolids and water recovery rate of 13.4 dm3/day in the nominal operating mode. Additionally, if no supernatant was processed, the specific net power output was increased to 69.2 Wh/kgsettledsolids. Such household-scale system would deliver the net power output (1.9-5.8 W). This was found to be enough to charge mobile phones or power clock radios, or provide light for the household using low-voltage LED bulbs. PMID- 27766001 TI - Revising the Schizoparmaceae: Coniella and its synonyms Pilidiella and Schizoparme. AB - The asexual genera Coniella (1918) and Pilidiella (1927), including their sexual morphs in Schizoparme (1923), have a cosmopolitan distribution and are associated with foliar, fruit, leaf, stem and root diseases on a wide variety of hosts. Species of these genera sometimes occur as secondary invaders of plant tissues infected by other organisms or that are injured by other causes. Several studies published over the last few decades had conflicting ideas as to whether Coniella, Pilidiella and Schizoparme should be regarded as synonymous or as separate genera. The present study aims to resolve the generic classification of these genera through phylogenetic analyses of the concatenated alignment of partial LSU nrDNA, rpb2, ITS nrDNA and tef1 sequence data of 117 isolates, combined with their morphology. Results revealed that all strains cluster in a single well supported clade. Conidial colour, traditionally the distinguishing character between Coniella and Pilidiella, evolved multiple times throughout the clade, and is not a good character at generic level in Schizoparmaceae. The three genera should therefore be regarded as synonymous, with the older name Coniella having priority. Furthermore, this study delineated 13 new species, and new combinations were proposed for a further 15 species. PMID- 27766003 TI - Dynamics of SOX2 and CDX2 Expression in Barrett's Mucosa. AB - Barrett's esophagus (BE) is the replacement of the normal esophageal squamous epithelium by a columnar lining epithelium. It is a premalignant condition for the development of adenocarcinoma of the esophagus and esophagogastric junction. BE is associated with gastroesophageal reflux which might change the expression profile of key transcription factors involved in the establishment of tissue differentiation, namely, SOX2 (associated with esophageal and gastric differentiation) and CDX2 (associated with intestinal differentiation). Here, we sought to characterize the expression profile of SOX2 and CDX2 in the sequential alterations of the esophageal mucosa towards adenocarcinoma and compare it with the well-established gastric and intestinal mucin profiles (MUC5AC, MUC6, and MUC2). We observed that SOX2 and CDX2 expression correlates with gastric and intestinal differentiation in BE, defined by morphological parameters and mucin expression. We show the presence of a complete intestinal profile in BE, without gastric mucins and without SOX2, and we observed an evolutionary modulation of the metaplastic phenotype by SOX2 and CDX2. We observed that adenocarcinomas harbor more frequently a mixed gastric and intestinal phenotype. In conclusion, our study establishes a role for transcription factors SOX2 and CDX2 in the progression from gastric to gastrointestinal differentiation in Barrett's metaplasia. PMID- 27766005 TI - Portfolio choice in retirement: Health risk and the demand for annuities, housing, and risky assets. AB - In a life-cycle model, a retiree faces stochastic health depreciation and chooses consumption, health expenditure, and the allocation of wealth between bonds, stocks, and housing. The model explains key facts about asset allocation and health expenditure across health status and age. The portfolio share in stocks is low overall and is positively related to health, especially for younger retirees. The portfolio share in housing is negatively related to health for younger retirees and falls significantly in age. Finally, out-of-pocket health expenditure as a share of income is negatively related to health and rises in age. PMID- 27766004 TI - Quantitative and Qualitative Analysis of Circulating Cell-Free DNA Can Be Used as an Adjuvant Tool for Prostate Cancer Screening: A Meta-Analysis. AB - As part of "liquid biopsy," lots of literature indicated the potential diagnostic value of circulating cell-free DNA (cfDNA) in the management of prostate cancer (PCa). However, the literature on the accuracy of cfDNA detection in PCa has been inconsistent. Hence, we performed this meta-analysis to assess the diagnostic value of cfDNA in PCa. A total of 19 articles were included in this analysis according to the inclusion and exclusion criteria. We then investigated two main subgroups in this meta-analysis, including qualitative analysis of abnormal level of cfDNA and qualitative analysis of single-gene methylation alterations. Overall, the results of quantitative analysis showed sensitivity of 0.73 (95% CI, 0.62-0.82) and specificity of 0.80 (95% CI, 0.70-0.87), with an area under the curve (AUC) of 0.83 (95% CI, 0.80-0.86). For qualitative assessment, the values were 0.34 (95% CI, 0.22-0.48), 0.99 (95% CI, 0.97-1.00), and 0.91 (95% CI, 0.88 0.93), respectively. Our results suggest the pooled specificity of each subgroup is much higher than the specificity of prostate-specific antigen (PSA). However, they are not recommended for PCa screening alone, because their sensitivities are not higher than the conventional serum biomarkers PSA. We conclude that analysis of cfDNA can be used as an adjuvant tool for PCa screening. PMID- 27766007 TI - A Toast to Our History. PMID- 27766006 TI - Genome Editing in Large Animals. AB - Genome editing in large animals has tremendous practical applications, from more accurate models for medical research through improved animal welfare and production efficiency. Although genetic modification in large animals has a 30 year history, until recently technical issues limited its utility. The original methods - pronuclear injection and integrating viruses - were plagued with problems associated with low efficiency, silencing, poor regulation of gene expression, and variability associated with random integration. With the advent of site specific nucleases such as TALEN and CRISPR/Cas9, precision editing became possible. When used on their own, these can be used to truncate or knockout genes through non-homologous end joining (NHEJ) with relatively high efficiency. When used with a template containing desired gene edits, these can be used to allow insertion of any desired changes to the genome through homologous recombination (HR) with substantially lower efficiency. Consideration must be given to the issues of marker sets and off-target effects. Somatic cell nuclear transfer is most commonly used to create animals from gene edited cells, but direct zygote injection and use of spermatogonial stem cells are alternatives under development. In developing gene editing projects, priority must be given to understanding the potential for off-target or unexpected effects of planned edits, which have been common in the past. Because of the increasing technical sophistication with which it can be accomplished, genome editing is poised to revolutionize large animal genetics, but attention must be paid to the underlying biology in order to maximize benefit. PMID- 27766008 TI - More Than 7 Years of Hindsight: Revisiting the FDA's 2008 Guidance on Cardiovascular Outcomes Trials for Type 2 Diabetes Medications. AB - IN BRIEF Concerns raised about the cardiovascular safety of type 2 diabetes medications such as rosiglitazone prompted the U.S. Food and Drug Administration to issue draft guidance in 2008 that, in practice, has required large cardiovascular outcomes trials (CVOTs) for all new type 2 diabetes therapies. After more than 7 years and six completed and published trials to date, this is an opportune time to consider whether these studies, as currently designed and conducted, accurately assess the long-term benefit/risk profile of new therapies and whether they represent an optimal use of limited health care resources. This article presents and contextualizes opinions on CVOTs from 10 thought leaders in diabetes. It is intended to inform an exploration of the costs, medical ethics, and effectiveness of using large-scale CVOTs to assess the safety of new diabetes therapies. PMID- 27766009 TI - Cardiac Manifestations of Congenital Generalized Lipodystrophy. AB - IN BRIEF Congenital lipodystrophy is a rare genetic disorder characterized by a near-complete absence of fat cells, hypoleptinemia leading to a voracious appetite, and marked insulin resistance. This article focuses on the known cardiovascular manifestations of patients with congenital lipodystrophy, including cardiomyopathy, cardiac arrhythmias, and accelerated atherosclerosis arising from a markedly deranged metabolic milieu. Future research that targets leptin deficiency (metreleptin) and apoC3 mRNA (antisense oligonucleotide) could open a window for potential pharmacological treatment of this challenging disorder. PMID- 27766010 TI - Nurse Practitioner Perceptions of a Diabetes Risk Assessment Tool in the Retail Clinic Setting. AB - IN BRIEF This article describes a study to gain insight into the utility and perceived feasibility of the American Diabetes Association's Diabetes Risk Test (DRT) implemented by nurse practitioners (NPs) in the retail clinic setting. The DRT is intended for those without a known risk for diabetes. Researchers invited 1,097 NPs working in the retail clinics of a nationwide company to participate voluntarily in an online questionnaire. Of the 248 NPs who sent in complete responses, 114 (46%) indicated that they used the DRT in the clinic. Overall mean responses from these NPs indicated that they perceive the DRT as a feasible tool in the retail clinic setting. Use of the DRT or similar risk assessment tools in the retail clinic setting can aid in the identification of people at risk for type 2 diabetes. PMID- 27766011 TI - Hypoglycemia Prevention in Hospital Patients: A Quality Improvement Project to Prevent Severe and Recurrent Hypoglycemia. PMID- 27766012 TI - Regular Insulin Administered With the V-Go Disposable Insulin Delivery Device in a Clinical Diabetes Setting: A Retrospective Analysis of Efficacy and Cost. PMID- 27766013 TI - Clinical and Roentgenological Profiles of Five Patterns of Charcot Foot in Diabetes: A Case Series. PMID- 27766014 TI - Development of an Acceptance and Commitment Therapy Workshop for Diabetes. PMID- 27766015 TI - Sodium-Glucose Cotransporter 2 Inhibitors and Euglycemic Diabetic Ketoacidosis: Metabolic Acidosis With a Twist. PMID- 27766016 TI - Prevalence and risk factors of gastrointestinal parasitic infections in goats in low-input low-output farming systems in Zimbabwe. AB - A longitudinal study was conducted in low-input low-output farming systems to determine the prevalence of gastrointestinal parasitic infections in different age groups, sex and associated risk factors in goats. A total of 580 indigenous goats were randomly selected in areas representing the five agro-ecological regions of Zimbabwe in the dry and wet seasons. Blood and faecal samples were collected from each animal and egg/oocyst per gram of faeces (epg/opg), larval culture, and packed cell volumes (PCV) were determined. Factors affecting parasitic infections were evaluated. Highest prevalence was determined for Eimeria oocysts (43%), strongyles (31%) and lower levels in trematodes and cestodes. Parasites identified were Haemonchus, Strongyloides and Oesophagostomum. Area, season, sex and age significantly influenced patterns of gastrointestinal infections (P < 0.05). Cannonical correlations indicated that parasite species composition varied by area and impacts of risk factors also differed. Risk of infection was very high for goats sampled in Natural regions (NR) I, II, III (OR = 6.6-8.2; P < 0.05) as compared to those in NR IV and V. Highest helminths and Eimeria infections were observed in the wet vs. dry season (P < 0.05). Young animals were more susceptible to parasitic infections (P < 0.05). Prevalence was higher in males than females, with odds of infection for males being almost three times to that for females (P < 0.0001). Knowledge concerning gastrointestinal helminth biology and epidemiological infection patterns caused by these parasites is essential in the development of appropriate control strategies and this has a potential to reduce production losses. PMID- 27766017 TI - Benzylic Ammonium Ylide Mediated Epoxidations. AB - A high yielding synthesis of stilbene oxides using ammonium ylides has been developed. It turned out that the amine leaving group plays a crucial role as trimethylamine gives higher yields than DABCO or quinuclidine. The amine group also influences the diastereoselectivity, and detailed DFT calculations to understand the key parameters of these reactions have been carried out. PMID- 27766018 TI - From classroom environment to mathematics achievement: The mediating role of self perceived ability and subject interest. AB - Drawing on Bandura's triadic reciprocal causation model, perceived classroom environment and three intrapersonal factors (mathematics self-efficacy, maths interest and academic self-concept) were considered as predictors of test performance in two correlated mathematics assessments: a public examination (GCSE) and an on-line test, both taken by UK pupils at age 16 (n = 6689). Intrapersonal factors were significantly associated with both test scores, even when the alternative score was taken into account. Classroom environment did not correlate with mathematics achievement once intrapersonal factors and alternative test performance were included in the model, but was associated with subject interest and academic self-concept. Perceptions of classroom environment may exercise an indirect influence on achievement by boosting interest and self concept. In turn, these intrapersonal factors have direct relationships with achievement and were found to mediate the relationship between perceived classroom environment and maths performance. Findings and their implications for mathematics education are discussed. PMID- 27766019 TI - The larvae of Micropterna coiffaiti Decamps 1963, Micropterna taurica Martynov 1917, and Potamophylax goulandriorum (Trichoptera: Limnephilidae), including a key to the hitherto known Stenophylacini larvae of the Hellenic western Balkan region. AB - The paper gives a description of the hitherto unknown larvae of Micropterna coiffaiti, Micropterna taurica, and Potamophylax goulandriorum (Trichoptera: Limnephilidae). Information on the morphology of the larvae is given and the most important diagnostic features are illustrated. In the context of published keys, the larva of Micropterna coiffaiti keys together with Micropterna sequax, Stenophylax mitis, and Stenophylax permistus. Species can be easily diagnosed by presence/absence and the structure of posterior sclerites at the lateral protuberances, by the extent of head spinule fields, and by the number of posterolateral setae on abdominal dorsum IX. Micropterna taurica keys together with Micropterna nycterobia. This pair can be separated by the setae posterior of the dorsal protuberance which are lacking in M. nycterobia but present in M. taurica. Finally, Potamophylax goulandriorum keys together with P. cingulatus, P. latipennis, and P. luctuosus. Currently it is not possible to separate this species quartet morphologically. With respect to distribution, M. coiffaiti has been reported from the Eastern Aegean islands in Greece, the Levant, Turkey, and Cyprus, whereas M. taurica ranges from Bulgaria and Greece (Crete, Karpathos, mainland Greece) to Cyprus and Turkey. Potamophylax goulandriorum is known from mainland Greece and Macedonia only. In addition, ecological characteristics are briefly discussed, and a key to the hitherto known Stenophylacini larvae of European Ecoregion 6 (= Hellenic western Balkan region) is included. PMID- 27766020 TI - Determining the composition of gold nanoparticles: a compilation of shapes, sizes, and calculations using geometric considerations. AB - ABSTRACT: Size, shape, overall composition, and surface functionality largely determine the properties and applications of metal nanoparticles. Aside from well defined metal clusters, their composition is often estimated assuming a quasi spherical shape of the nanoparticle core. With decreasing diameter of the assumed circumscribed sphere, particularly in the range of only a few nanometers, the estimated nanoparticle composition increasingly deviates from the real composition, leading to significant discrepancies between anticipated and experimentally observed composition, properties, and characteristics. We here assembled a compendium of tables, models, and equations for thiol-protected gold nanoparticles that will allow experimental scientists to more accurately estimate the composition of their gold nanoparticles using TEM image analysis data. The estimates obtained from following the routines described here will then serve as a guide for further analytical characterization of as-synthesized gold nanoparticles by other bulk (thermal, structural, chemical, and compositional) and surface characterization techniques. While the tables, models, and equations are dedicated to gold nanoparticles, the composition of other metal nanoparticle cores with face-centered cubic lattices can easily be estimated simply by substituting the value for the radius of the metal atom of interest. GRAPHICAL ABSTRACT: PMID- 27766021 TI - Dehydroepiandrosterone Supplementation Combined with Whole-Body Vibration Training Affects Testosterone Level and Body Composition in Mice. AB - Dehydroepiandrosterone (DHEA), the most abundant sex steroid, is primarily secreted by the adrenal gland and a precursor hormone used by athletes for performance enhancement. Whole-body vibration (WBV) is a well-known light resistance exercise by automatic adaptations to rapid and repeated oscillations from a vibrating platform, which is also a simple and convenient exercise for older adults. However, the potential effects of DHEA supplementation combined with WBV training on to body composition, exercise performance, and hormone regulation are currently unclear. The objective of the study is to investigate the effects of DHEA supplementation combined with WBV training on body composition, exercise performance, and physical fatigue-related biochemical responses and testosterone content in young-adult C57BL/6 mice. In this study, male C57BL/6 mice were divided into four groups (n = 8 per group) for 6-weeks treatment: sedentary controls with vehicle (SC), DHEA supplementation (DHEA, 10.2 mg/kg), WBV training (WBV; 5.6 Hz, 2 mm, 0.13 g), and WBV training with DHEA supplementation (WBV+DHEA; WBV: 5.6 Hz, 2 mm, 0.13 g and DHEA: 10.2 mg/kg). Exercise performance was evaluated by forelimb grip strength and exhaustive swimming time, as well as changes in body composition and anti-fatigue levels of serum lactate, ammonia, glucose, creatine kinase (CK), and blood urea nitrogen (BUN) after a 15-min swimming exercise. In addition, the biochemical parameters and the testosterone content were measured at the end of the experiment. Six-week DHEA supplementation alone significantly increased mice body weight (BW), muscle weight, testosterone level, and glycogen contents (liver and muscle) when compared with SC group. DHEA supplementation alone had no negative impact on all tissue and biochemical profiles, but could not improve exercise performance. However, WBV+DHEA supplementation also significantly decreased BW, testosterone level and glycogen content of liver, as well as serum lactate and ammonia levels after the 15-min swimming exercise when compared with DHEA supplementation alone. Although DHEA supplementation alone had no beneficial effect in the exercise performance of mice, the BW, testosterone level and glycogen content significantly increased. On the other hand, WBV training combined with DHEA decreased the BW gain, testosterone level and glycogen content caused by DHEA supplementation. Therefore, WBV training could inhibit DHEA supplementation to synthesis the testosterone level or may decrease the DHEA supplement absorptive capacity in young-adult mice. PMID- 27766022 TI - Flooded Lung Generates a Suitable Acoustic Pathway for Transthoracic Application of High Intensity Focused Ultrasound in Liver. AB - Background: In recent years, high intensity focused ultrasound (HIFU) has gained increasing clinical interest as a non-invasive method for local therapy of liver malignancies. HIFU treatment of tumours and metastases in the liver dome is limited due to the adjacent ultrasound blocking lung. One-lung flooding (OLF) enables complete sonography of lung and adjoining organs including liver. HIFU liver ablation passing through the flooded lung could enable a direct intercostal beam path and thus improve dose deposition in liver. In this study, we evaluate the feasibility of an ultrasound guided transthoracic, transpulmonary HIFU ablation of liver using OLF. Methods: After right-side lung flooding, ultrasound guided HIFU was applied transthoracic- transpulmonary into liver to create thermal lesions in three pigs. The HIFU beam was targeted five times into liver, two times at the liver surface and three times deeper into the tissue. During autopsy examinations of lung, diaphragm and liver located in the HIFU path were performed. The focal liver lesions and lung tissue out of the beam path were examined histologically. Results: Fifteen thermal liver lesions were generated by transpulmonary HIFU sonication in all targeted regions. The lesions appeared well demarcated in grey color with a cigar-shaped configuration. The mean length and width of the superficial and deeper lesions were 15.8 mm (range: 13-18 mm) and 5.8 mm (range: 5-7 mm), and 10.9 mm (range: 9-13 mm) and 3.3 mm (range: 2-5 mm), respectively. Histopathological, all liver lesions revealed a homogeneous thermal necrosis lacking vitality. There were no signs of damage of the overlying diaphragm and lung tissue. Conclusions: Flooded lung is a suitable pathway for applying HIFU to the liver, thus enabling a transthoracic, transpulmonary approach. The enlarged acoustic window could enhance the ablation speed for targets in the hepatic dome. PMID- 27766023 TI - Lower Body Mass Index is a Risk Factor for In-Hospital Mortality of Elderly Japanese Patients Treated with Ampicillin/sulbactam. AB - Objectives: A retrospective examination was conducted to identify risk factors for in-hospital mortality of elderly patients (65 years or older) treated with the beta-lactam/beta-lactamase inhibitor combination antibiotic, ampicillin/sulbactam (ABPC/SBT). Methods: Clinical data from 96 patients who were hospitalized with infectious diseases and treated with ABPC/SBT (9 g/day or 12 g/day) were analyzed. Risk factors examined included demographic and clinical laboratory parameters. Parameter values prior to treatment and changes after treatment were compared between survivors and non-survivors. Results: The study patients had an average age of 81.9+/-8.4 years (+/-SD) and body mass index (BMI) of 19.9+/-4.2 kg/m2. They were characterized by anemia (low hemoglobin and hematocrit levels), inflammation (high leukocyte count, neutrophil count, C reactive protein level, and body temperature), and hepatic and renal dysfunction (high aspartate aminotransferase, alanine aminotransferase and blood urea nitrogen levels). The BMI of non-survivors, 16.2+/-2.9 kg/m2, was lower than that of survivors, 20.4+/-4.1 kg/m2. In addition, the hematological parameters deteriorated more remarkably, inflammation markers were not altered (or the decrease was marginal), and hepatic function was not improved, in non-survivors. Conclusions: A lower BMI value is a risk factor for in-hospital mortality of elderly patients treated with ABPC/SBT. PMID- 27766024 TI - Role of CAPE on cardiomyocyte protection via connexin 43 regulation under hypoxia. AB - Background: Cardiomyocyte under hypoxia cause cell death or damage is associated with heart failure. Gap junction, such as connexin 43 play a role in regulation of heart function under hypoxia. Caffeic acid phenethyl ester (CAPE) has been reported as an active component of propolis, has antioxidative, anti-inflammatory antiproliferative and antineoplastic biological properties. Aims: Connexin 43 appear to have a critical role in heart failure under hypoxia, there has been considerable interest in identifying the candidate component or compound to reduce cell death. Methods: In this study, we used human cardiomyocyte as a cell model to study the role of connexin 43 in hypoxia- incubated human cardiomyocyte in absence or presence of CAPE treatment. Results: Results showed that hypoxia induced connexin 43 expression, but not altered in connexin 40. Interestingly, CAPE attenuates hypoxia-caused connexin 43 down-regulation and cell death or cell growth inhibition. Conclusion: We suggested that reduction of cell death in cardiomyocytes by CAPE is associated with an increase in connexin 43 expression. PMID- 27766025 TI - Tissue factor: A potent stimulator of Von Willebrand factor synthesis by human umbilical vein endothelial cells. AB - Inflammation and dysfunction of endothelial cells are thought to be triggers for the secretion of Von Willebrand factor. The aim of this study was to examine the effects of the inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) and the coagulation factors, tissue factor and thrombin on the release and cleavage potential of ultra-large von Willebrand factor (ULVWF) and its cleavage protease by cultured human umbilical vein endothelial cells (HUVEC). HUVEC were treated with IL-6, IL-8, and TNF alpha, tissue factor (TF) and thrombin, and combinations thereof for 24 hours under static conditions. The cells were then exposed to shear stress after which the VWF-propeptide levels and the VWF cleavage protease, ADAMTS13 content were measured. All treatments and their combinations, excluding IL-6, significantly stimulated the secretion of VWF from HUVEC. The VWF secretion from the HUVEC was stimulated most by the combination of TF with TNF-alpha. Slightly lower levels of ADAMTS13 secretion were found with all treatments. This may explain the thrombogenicity of patients with inflammation where extremely high VWF levels and slightly lower ADAMTS13 levels are present. PMID- 27766026 TI - Immunohistochemical study of hair follicle stem cells in regenerated hair follicles induced by Wnt10b. AB - The regulation of the periodic regeneration of hair follicles is complicated. Although Wnt10b has been reported to induce hair follicle regeneration, the characteristics of induced hair follicles, especially the target cells of Wnt10b, have not yet been clearly elucidated. Thus, we systematically evaluated the expression and proliferation patterns of Wnt10b-induced hair follicles. We found that Wnt10b promoted the proliferation of hair follicle stem cells from 24 hours after AdWnt10b injection. Seventy-two hours after AdWnt10b injection, cells outside of bulge area began to proliferate. When the induced hair follicle entered full anagen, although the hair follicle stem cells were normal, canonical Wnt signaling was maintained in the hair precortex cells. Our results reveal that the target cells that overexpressed Wnt10b included hair follicle stem cells, hair precortex cells, and matrix cells. PMID- 27766028 TI - Targeting P38 Pathway Regulates Bony Formation via MSC Recruitment during Mandibular Distraction Osteogenesis in Rats. AB - Distraction osteogenesis (DO) is a widely used self-tissue engineering. However, complications and discomfort due to the long treatment period are still the bottleneck of DO. Novel strategies to accelerate bone formation in DO are still needed. P38 is capable of regulating the osteogenic differentiation of both mesenchymal stem cells (MSCs) and osteoblasts, which are crucial to bone regeneration. However, it is not clear whether targeting p38 could regulate bony formation in DO. The purpose of the current work was to investigate the effects of local application of either p38 agonist anisomycin or p38 inhibitor SB203580 in a rat model of DO. 30 adult rats were randomly divided into 3 groups: (A) rats injected with DMSO served as the control group; (B) rats injected with p38 agonist anisomycin; (C) rats injected with p38 inhibitor SB203580. All the rats were subjected to mandibular distraction and the injection was performed daily during this period. The distracted mandibles were harvested on days 15 and 30 after surgery and subjected to the following analysis. Micro-computed tomography and histological evaluation results showed that local application of p38 agonist anisomycin increased new bone formation in DO, whereas p38 inhibitor SB203580 decreased it. Immunohistochemical analysis suggested that anisomycin promoted MSC recruitment in the distraction gap. In conclusion, this study demonstrated that local application of p38 agonist anisomycin can increase new bone formation during DO. This study may lead to a novel cell-based strategy for the improvement of bone regeneration. PMID- 27766027 TI - Capping Agent-Dependent Toxicity and Antimicrobial Activity of Silver Nanoparticles: An In Vitro Study. Concerns about Potential Application in Dental Practice. AB - Objectives: In dentistry, silver nanoparticles (AgNPs) have drawn particular attention because of their wide antimicrobial activity spectrum. However, controversial information on AgNPs toxicity limited their use in oral infections. Therefore, the aim of the present study was to evaluate the antibacterial activities against a panel of oral pathogenic bacteria and bacterial biofilms together with potential cytotoxic effects on human gingival fibroblasts of 10 nm AgNPs: non-functionalized - uncapped (AgNPs-UC) as well as surface-functionalized with capping agent: lipoic acid (AgNPs-LA), polyethylene glycol (AgNPs-PEG) or tannic acid (AgNPs-TA) using silver nitrate (AgNO3) as control. Methods: The interaction of AgNPs with human gingival fibroblast cells (HGF-1) was evaluated using the mitochondrial metabolic potential assay (MTT). Antimicrobial activity of AgNPs was tested against anaerobic Gram-positive and Gram-negative bacteria isolated from patients with oral cavity and respiratory tract infections, and selected aerobic Staphylococci strains. Minimal inhibitory concentration (MIC) values were determined by the agar dilution method for anaerobic bacteria or broth microdilution method for reference Staphylococci strains and Streptococcus mutans. These strains were also used for antibiofilm activity of AgNPs. Results: The highest antimicrobial activities at nontoxic concentrations were observed for the uncapped AgNPs and the AgNPs capped with LA. It was found that AgNPs-LA and AgNPs-PEG demonstrated lower cytotoxicity as compared with the AgNPs-TA or AgNPs UC in the gingival fibroblast model. All of the tested nanoparticles proved less toxic and demonstrated wider spectrum of antimicrobial activities than AgNO3 solution. Additionally, AgNPs-LA eradicated Staphylococcus epidermidis and Streptococcus mutans 1-day biofilm at concentration nontoxic to oral cells. Conclusions: Our results proved that a capping agent had significant influence on the antibacterial, antibiofilm activity and cytotoxicity of AgNPs. Clinical significance: This study highlighted potential usefulness of AgNPs against oral anaerobic Gram-positive and Gram-negative bacterial infections and aerobic Staphylococci strains provided that pharmacological activity and risk assessment are carefully performed. PMID- 27766030 TI - Lacrimal Duct Occlusion Is Associated with Infectious Keratitis. AB - Background: To explore the prevalence of lacrimal duct obstruction in patients with infectious keratitis, and the necessity of lacrimal duct dredge in the treatment of human infectious keratitis. Methodology/Principle Findings: The design is prospective, non-control case series. Thirty-one eyes from twenty-eight continuous patients with infectious keratitis were included in this study. The presence/absence of lacrimal duct obstruction was determined by the lacrimal duct irrigation test. The diagnosis of infectious keratitis was made based on clinical manifestations, cornea scraping microscopic examination and bacterial/fungus culture. Diagnosis of viral keratitis was set up based on the recurrent history, deep neovascularization and typical outlook of the cornea scar. The treatment of keratitis included drugs, eye drops or surgery, while treatment of chronic dacryocystitis was lacrimal duct dredging with supporting tube implantation surgery. In the thirty-one eyes with infectious keratitis, fifteen suffered from fungal keratitis (48%), two bacterial keratitis (6%), and fourteen viral keratitis (45%). Eleven eyes (35%) from ten patients with infectious keratitis also suffered from lacrimal duct obstruction. In those cases, six eyes also suffered from lower canalicular obstruction, three nasolacrimal duct obstruction and chronic dacryocystitis, one a combination of upper and lower canalicular obstruction, one upper canalicular obstruction. After local and systemic applications of anti-bacterial, anti-viral, anti-fungal and anti-inflammatory drugs, twenty-eight eyes (90%) recovered within three weeks, while the ulceration of three patients required the lacrimal duct dredging and supporting tube implantation surgery for the healing. Conclusions: Herein, we first report that the prevalence of infectious keratitis is closely correlated to the occurrence of lacrimal duct obstruction. When both confirmed, simultaneous treatment of keratitis and lacrimal duct obstruction promptly is required. Further evaluation of mechanism, prevention and control of the diseases are warranted. PMID- 27766029 TI - Clinical importance of the middle meningeal artery: A review of the literature. AB - The middle meningeal artery (MMA) is a very important artery in neurosurgery. Many diseases, including dural arteriovenous fistula (DAVF), pseudoaneurysm, true aneurysm, traumatic arteriovenous fistula (AVF), moyamoya disease (MMD), recurrent chronic subdural hematoma (CSDH), migraine and meningioma, can involve the MMA. In these diseases, the lesions occur in either the MMA itself and treatment is necessary, or the MMA is used as the pathway to treat the lesions; therefore, the MMA is very important to the development and treatment of a variety of neurosurgical diseases. However, no systematic review describing the importance of MMA has been published. In this study, we used the PUBMED database to perform a review of the literature on the MMA to increase our understanding of its role in neurosurgery. After performing this review, we found that the MMA was commonly used to access DAVFs and meningiomas. Pseudoaneurysms and true aneurysms in the MMA can be effectively treated via endovascular or surgical removal. In MMD, the MMA plays a very important role in the development of collateral circulation and indirect revascularization. For recurrent CDSHs, after burr hole irrigation and drainage have failed, MMA embolization may be attempted. The MMA can also contribute to the occurrence and treatment of migraines. Because the ophthalmic artery can ectopically originate from the MMA, caution must be taken to avoid causing damage to the MMA during operations. PMID- 27766031 TI - Class A Scavenger Receptor Exacerbates Osteoclastogenesis by an Interleukin-6 Mediated Mechanism through ERK and JNK Signaling Pathways. AB - Osteoclasts originate from bone marrow monocyte/macrophage lineage cells, which are important for bone health. Class A scavenger receptor (SR-A) is a multifunctional molecule that functions during differentiation of monocyte into macrophages and osteoclasts. To further characterize the role of SR-A in osteoclasts, we used the murine tooth movement model (TM) and the murine anterior cruciate ligament transection model of osteoarthritis (ACLT OA). In these two models the bones involved are of different origin and have different properties. Bone resorption was decreased in SR-A-/- mice compared to SR-A+/+ mice. Further evaluation showed that the number of multinucleated osteoclasts in SR-A-/- mice, compared to SR-A+/+ mice, was significantly decreased both in vivo and in vitro. The levels of interleukin-6 (IL-6) produced by osteoclasts were reduced in SR-A-/ mice compared to SR-A+/+ mice. In the in vitro marrow-derived osteoclast formation assay and in both mouse models, osteoclastogenesis was restored to normal in SR-A-/- mice by administration of recombinant murine IL-6. Moreover, neutralization of IL-6 reduced the number of osteoclasts formed in SR-A+/+ mice of TM model. Both extracellular signal-regulated kinase (ERK) and c-Jun N terminal protein kinase (JNK), but not p38, signaling pathways were downregulated in receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated SR-A-/- osteoclasts. Importantly, when treated with either ERK or JNK inhibitor, the numbers of osteoclasts generated from RANKL-induced bone marrow derived macrophages of SR-A+/+ mice, and their IL-6 production, were significantly decreased. This suggests that SR-A activates the ERK and JNK signaling pathways, and promotes production of IL-6 by osteoclasts to further stimulate osteoclast formation. PMID- 27766032 TI - A Metabolomic Approach (1H HRMAS NMR Spectroscopy) Supported by Histology to Study Early Post-transplantation Responses in Islet-transplanted Livers. AB - Intrahepatic transplantation of islets requires a lot of islets because more than 50% of the graft is lost during the 24 hours following transplantation. We analyzed, in a rat model, early post-transplantation inflammation using systemic inflammatory markers, or directly in islet-transplanted livers by immunohistochemistry. 1H HRMAS NMR was employed to investigate metabolic responses associated with the transplantation. Inflammatory markers (Interleukin 6, alpha2-macroglobulin) are not suitable to follow islet reactions as they are not islet specific. To study islet specific inflammatory events, immunohistochemistry was performed on sections of islet transplanted livers for thrombin (indicator of the instant blood-mediated inflammatory reaction (IBMIR)) and granulocytes and macrophages. We observed a specific correlation between IBMIR and granulocyte and macrophage infiltration after 12 h. In parallel, we identified a metabolic response associated with transplantation: after 12 h, glucose, alanine, aspartate, glutamate and glutathione were significantly increased. An increase of glucose is a marker of tissue degradation, and could be explained by immune cell infiltration. Alanine, aspartate and glutamate are inter connected in a common metabolic pathway known to be activated during hypoxia. An increase of glutathione revealed the presence of antioxidant protection. In this study, IBMIR visualization combined with 1H HRMAS NMR facilitated the characterization of cellular and molecular pathways recruited following islet transplantation. PMID- 27766033 TI - Changes in the Expression of FUS/TLS in Spinal Cords of SOD1 G93A Transgenic Mice and Correlation with Motor-Neuron Degeneration. AB - In order to searching the possible pathogenesis of amyotrophic lateral sclerosis (ALS), we examined the expression and distribution of FUS/TLS protein in the different anatomic regions, segments and neural cells of adult spinal cord at the different stages of the SOD1 wild-type and G93A transgenic mice using the fluorescent immunohistochemistry. Result revealed that, in the SOD1 wild-type mice, the FUS/TLS expression almost wasn't detected. However, in the SOD1 G93A mice, the FUS/TLS expression in the white matter was significantly more than that in the gray matter. In the white matter, the FUS/TLS expression in the anterior funiculus was more than that in the lateral funiculus more than that in the posterior funiculus. In the gray matter, the FUS/TLS expression in the ventral horn was more than that surrounding the central canal more than that in the dorsal horn. The FUS/TLS expression in the thoracic segment was more than that in the cervical segment more than that in the lumbar segment. Almost all FUS/TLS expressed in the nuclear of the GFAP positive cell at the onset stage, but it expressed in both the nuclear and the cytoplasm of the GFAP positive cell at the progression stage, almost didn't detected FUS/TLS expression in the NeuN and Oligo positive cells. The FUS/TLS expression was positively correlated with the neuron death. Our data suggested that the expressive increase and mislocalization of FUS/TLS in the astrocyte cell might cause the motor neuron degenerative death in the SOD1 G93A transgenic mice. PMID- 27766035 TI - Dmp1 Null Mice Develop a Unique Osteoarthritis-like Phenotype. AB - Patients with hypophosphatemia rickets (including DMP1 mutations) develop severe osteoarthritis (OA), although the mechanism is largely unknown. In this study, we first identified the expression of DMP1 in hypertrophic chondrocytes using immunohistochemistry (IHC) and X-gal analysis of Dmp1-knockout-lacZ-knockin heterozygous mice. Next, we characterized the OA-like phenotype in Dmp1 null mice from 7-week-old to one-year-old using multiple techniques, including X-ray, micro CT, H&E staining, Goldner staining, scanning electronic microscopy, IHC assays, etc. We found a classical OA-like phenotype in Dmp1 null mice such as articular cartilage degradation, osteophyte formation, and subchondral osteosclerosis. These Dmp1 null mice also developed unique pathological changes, including a biphasic change in their articular cartilage from the initial expansion of hypertrophic chondrocytes at the age of 1-month to a quick diminished articular cartilage layer at the age of 3-months. Further, these null mice displayed severe enlarged knees and poorly formed bone with an expanded osteoid area. To address whether DMP1 plays a direct role in the articular cartilage, we deleted Dmp1 specifically in hypertrophic chondrocytes by crossing the Dmp1-loxP mice with Col X Cre mice. Interestingly, these conditional knockout mice didn't display notable defects in either the articular cartilage or the growth plate. Because of the hypophosphatemia remained in the entire life span of the Dmp1 null mice, we also investigated whether a high phosphate diet would improve the OA-like phenotype. A 8-week treatment of a high phosphate diet significantly rescued the OA-like defect in Dmp1 null mice, supporting the critical role of phosphate homeostasis in maintaining the healthy joint morphology and function. Taken together, this study demonstrates a unique OA-like phenotype in Dmp1 null mice, but a lack of the direct impact of DMP1 on chondrogenesis. Instead, the regulation of phosphate homeostasis by DMP1 via the axis of "FGF23-renal phosphorus reabsorption" is vital for maintaining a healthy joint. PMID- 27766034 TI - Expression of Iron Regulatory Protein 1 Is Regulated not only by HIF-1 but also pCREB under Hypoxia. AB - The inconsistent of responses of IRP1 and HIF-1 alpha to hypoxia and the similar tendencies in the changes of IRP1 and pCREB contents led us to hypothesize that pCREB might be involved in the regulation of IRP1 under hypoxia. Here, we investigated the role of pCREB in IRP1 expression in HepG2 cells under hypoxia using quantitative PCR, western blot, immunofluorescence, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). We demonstrated that 1) Hypoxia increased pCREB levels inside of the nucleus; 2) Putative CREs were found in the IRP1 gene; 3) Nuclear extracts of HepG2 cells treated with hypoxia could bind to CRE1 and CRE3, and 100-fold competitor of putative CREs could abolish the binding activity to varying degrees; 4) pCREB was found in the CRE1 and CRE3 DNA-protein complexes of EMSA; 5) CRE1 and CRE3 binding activity of IRP1 depended on CREB activation but not on HIF-1; 6) Increased IRP1 expression under hypoxia could be prevented by LY294002; 7) ChIP assays demonstrated that pCREB binds to IRP1 promoter; and 8) HIF-1 and/or HIF-2 siRNA had no effect on the expression of pCREB and IRP1 proteins in cells treated with hypoxia for 8 hours. Our findings evidenced for the involvement of pCREB in IRP1 expression and revealed a dominant role of PI3K/Akt pathway in CREB activation under hypoxia and also suggested that dual-regulation of IRP1 expression by HIF-1 and pCERB or other transcription factor(s) under hypoxia might be a common mechanism in most if not all of hypoxia-inducible genes. PMID- 27766036 TI - miR-628 Promotes Burn-Induced Skeletal Muscle Atrophy via Targeting IRS1. AB - Skeletal muscle atrophy is a common clinical feature among patients with severe burns. Previous studies have shown that miRNAs play critical roles in the regulation of stress-induced skeletal muscle atrophy. Our previous study showed that burn-induced skeletal muscle atrophy is mediated by miR-628. In this study, compared with sham rats, rats subjected to burn injury exhibited skeletal muscle atrophy, as well as significantly decreased insulin receptor substrate 1 (IRS1) protein expression and significantly increased skeletal muscle cell apoptosis. An miRNA array showed that the levels of miR-628, a potential regulator of IRS1 protein translation, were also clearly elevated. Second, L6 myocyte cell apoptosis increased after induction of miR-628 expression, and IRS1 and p-Akt protein expression decreased significantly. Expression of the cell apoptosis related proteins FoxO3a and cleaved caspase 3 also increased after induction of miR-628 expression. Finally, forced miR-628 expression in normal rats resulted in increased cell apoptosis and skeletal muscle atrophy, as well as changes in IRS1/Akt/FoxO3a signaling pathway activity consistent with the changes in protein expression described above. Inhibiting cell apoptosis with Z-VAD-FMK resulted in alleviation of burn-induced skeletal muscle atrophy. In general, our results indicate that miR-628 mediates burn-induced skeletal muscle atrophy by regulating the IRS1/Akt/FoxO3a signaling pathway. PMID- 27766037 TI - Deficiency of DJ-1 Ameliorates Liver Fibrosis through Inhibition of Hepatic ROS Production and Inflammation. AB - Liver fibrosis is a global health problem and previous studies have demonstrated that reactive oxygen species (ROS) play important roles in fibrogenesis. Parkinson disease (autosomal recessive, early onset) 7 (Park7) also called DJ-1 has an essential role in modulating cellular ROS levels. DJ-1 therefore may play functions in liver fibrogenesis and modulation of DJ-1 may be a promising therapeutic approach. Here, wild-type (WT) and DJ-1 knockout (DJ-1 KO) mice were administrated with carbon tetrachloride (CCl4) to induce liver fibrosis or acute liver injury. Results showed that DJ-1 depletion significantly blunted liver fibrosis, accompanied by marked reductions in liver injury and ROS production. In the acute CCl4 model, deficiency of DJ-1 showed hepatic protective functions as evidenced by decreased hepatic damage, reduced ROS levels, diminished hepatic inflammation and hepatocyte proliferation compared to WT mice. In vitro hepatic stellate cells (HSCs) activation assays indicated that DJ-1 has no direct effect on the activation of HSCs in the context of with or without TGFbeta treatment. Thus our present study demonstrates that in CCl4-induced liver fibrosis, DJ-1 deficiency attenuates mice fibrosis by inhibiting ROS production and liver injury, and further indirectly affecting the activation of HSCs. These results are in line with previous studies that ROS promote HSC activation and fibrosis development, and suggest the therapeutic value of DJ-1 in treatment of liver fibrosis. PMID- 27766038 TI - Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is a state of Klotho deficiency. The Klotho expression may be suppressed due to DNA hypermethylation in cancer cells so we have investigated the effects and possible mechanisms by which Klotho expression is regulated in human aortic smooth muscle cells (HASMCs). The vascular Klotho hypermethylation in radial arteries of patients with end-stage renal disease was described. Cultured HASMCs and 5/6-nephrectomized Sprague Dawley (SD) rats treated with indoxyl sulfate (IS) were used as in vitro and in vivo models, respectively. IS increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in HASMCs, and potentiated HASMCs calcification. The expression of DNA methyltransferase (DNMT) 1 and 3a in HASMCs treated with IS was significantly increased and specific inhibition of DNA methyltransferase 1 by 5 aza-2'-deoxycytidine(5Aza-2dc) caused demethylation of the Klotho gene and increased Klotho expression. In rats, injection of IS potentiated vascular calcification, increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in the aortic medial layer and all of these changes could be reverted by 5Aza-2dc treatment. Transcriptional suppression of vascular Klotho gene expression by IS and epigenetic modification of Klotho by IS may be an important pathological mechanism of vascular calcification in CKD. PMID- 27766042 TI - Retaining early career registered nurses: a case study. AB - BACKGROUND: A core objective of the Australian health system is to provide high quality, safe health care that meets the needs of all Australians. To achieve this, an adequate and effective workforce must support the delivery of care. With rapidly changing health care systems and consumer demographics, demand for care is increasing and retention of sufficient numbers of skilled staff is now a critical priority to meet current and future health care demands. Nurses are the largest cohort of professionals within the health workforce. Reducing the rates at which nurses leave the profession and supporting nurses to practice in their profession longer will have beneficial implications for the sustainability of a nursing workforce and, ultimately, to patient outcomes. The aim of the study was to describe and explain early career registered nurses' (ECRNs) experiences and support requirements during the first five years of practice for the purposes of identifying strategies that would support greater retention of ECRNs. METHODS: A single case study design focused on early career registered nurses (ECRNs) working in a hospital and health service in northern Australia. The research team adopted Djukic et al's definition of ECRNs as "RNs who have practiced for less than 5 years". Data was collected via three individual interviews and two focus groups. Thirty-five ECRNs participated in the study. RESULTS: Qualitative analysis of data generated during interviews and focus groups, identified the key themes of receiving career advice and choice or no choice. Analysis of study data in the context of the broader literature resulted in the researchers identifying six areas of focus for ECRN retention: 1) well-planned, supported and structured transition periods; 2) consideration of rotation through different areas with a six month minimum for skills development; 3) empowering decision making; 4) placement opportunities and choice in decisions of where to work; 5) career advice and support that considers ECRNs' personalities and skills; and 6) encouragement to reflect on career choices. CONCLUSIONS: Reducing turnover and improving retention relies on understanding the factors that influence nurses' decisions to leave or remain within an organisation and the profession. Ensuring nurses in the current workforce remain engaged and productive, rather than leave the profession, is reliant on addressing factors that cause attrition and implementing strategies that strengthen retention rates and workforce sustainability. PMID- 27766040 TI - Exosomes from Human Synovial-Derived Mesenchymal Stem Cells Prevent Glucocorticoid-Induced Osteonecrosis of the Femoral Head in the Rat. AB - Osteonecrosis of the femoral head (ONFH) represents a debilitating complication following glucocorticoid (GC)-based therapy. Synovial-derived mesenchymal stem cells (SMSCs) can exert protective effect in the animal model of GC-induced ONFH by inducing cell proliferation and preventing cell apoptosis. Recent studies indicate the transplanted cells exert therapeutic effects primarily via a paracrine mechanism and exosomes are an important paracrine factor that can be directly used as therapeutic agents for tissue engineering. Herein, we provided the first demonstration that the early treatment of exosomes secreted by human synovial-derived mesenchymal stem cells (SMSC-Exos) could prevent GC-induced ONFH in the rat model. Using a series of in vitro functional assays, we found that SMSC-Exos could be internalized into bone marrow derived stromal cells (BMSCs) and enhance their proliferation and have anti-apoptotic abilities. Finally, SMSC Exos may be promising for preventing GC-induced ONFH. PMID- 27766041 TI - An Efficient Light-Inducible P53 Expression System for Inhibiting Proliferation of Bladder Cancer Cell. AB - Optogenetic gene expression systems enable spatial-temporal modulation of gene transcription and cell behavior. Although applications in biomedicine are emerging, the utility of optogenetic gene switches remains elusive in cancer research due to the relative low gene activation efficiency. Here, we present an optimized CRISPR-Cas9-based light-inducible gene expression device that controls gene transcription in a dose-dependent manner. To prove the potential utility of this device, P53 was tested as a functional target in the bladder cancer cell models. It was illustrated that the light-induced P53 inhibited proliferation of 5637 and UMUC-3 cell effectively. The "light-on" gene expression system may demonstrate a novel therapeutic strategy for bladder cancer intervention. PMID- 27766043 TI - DOACs - advances and limitations in real world. AB - The group of new oral anticoagulants or NOACs, now termed direct oral anticoagulants or DOACs, with their favourable results from large scale phase III clinical trials, represent a major advancement and expanded armamentarium in antithrombotic therapy. Dabigatran, rivaroxaban, apixaban and edoxaban are now in clinical routine use for prevention and treatment of arterial and venous thrombotic diseases as addressed in their clinical trials. Usage of the DOACs is expected to increase as clinicians gain more experience and reassurance with data from the real world studies which are generally consistent with that from clinical trials. Development of specific antidotes in management of bleeding complications and development of coagulation assays for their plasma levels will further boost the confidence in the DOACs. Nonetheless, there are still limitations associated with the DOACs. Many patients in need of anticoagulant therapy for indications not studied in the clinical trials will not be eligible for treatment with a DOAC. Conditions where more data is required include DOACs use in the paediatric age group, patients with atrial fibrillation and valvular heart disease, thrombosis associated with the anti-phospholipid syndrome and cancer associated thrombosis. The affordability and access to these drugs may pose an issue for many patients under healthcare systems not providing for these medications. With four new anticoagulants coming onboard very quickly, the focus has shifted to the practical approach and management in real life as many clinicians are not yet familiar with the DOACs. Clinicians need to be educated on how to manage this new class for drugs, from choosing the appropriate drug to prevention and managing bleeding complications as a lack of knowledge and understanding in these drugs will lead to inappropriate use and compromise on patient safety. PMID- 27766044 TI - Anti-thrombotic agents derived from snake venom proteins. AB - Snake venoms affect blood coagulation and platelet function in a complex manner. However, two classes of venom proteins, snaclecs and disintegrins have been shown to specifically target receptors including GPIb, alpha2beta1, GPVI, CLEC-2 and integrins alphaIIbbeta3, alphavbeta3, alpha5beta1 expressed on platelets, endothelial cells, phagocytes, tumor cells, thus affecting cell-matrices and cell cell interactions. Here, we focus on disintegrins, a class of low molecular mass Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing, cysteine-rich polypeptide derived from various viper snake venoms. This review describes the potential applications of disintegrins in field of integrin-related diseases, especially arterial thrombosis, angiogenesis, tumor progression and septic inflammation. In addition, a novel RGD-containing disintegrin TMV-7 is being developed as a safer antithrombotic agent with minimal side effects, such as thrombocytopenia and bleeding. PMID- 27766045 TI - Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by defective complement regulation resulting in thrombotic microangiopathy (TMA). Patients can present as children or adults. The syndrome consists of hemolytic anemia with schistocytosis, thrombocytopenia, significant renal damage, and/or other organ system dysfunction(s). Patients with aHUS may succumb to the complications of the disease with the very first manifestation; surviving patients often suffer from progressive organ dysfunction with significant morbidity and mortality despite plasma infusion or plasma exchange. Eculizumab, a humanized monoclonal antibody to C5, was approved for treatment of aHUS in 2011. This is an expensive but highly effective therapy changing the lives and improving the outcome of patients with aHUS. Making timely and accurate diagnosis of aHUS can be life-saving if eculizumab treatment is begun promptly. Finding a genetic mutation in a complement regulatory protein is diagnostic with the appropriate clinical syndrome, but at least 30 % of patients do not have defined or reported mutations. Thus the diagnosis rests on the clinical acumen of the physician. However, the clinical manifestations of aHUS are shared by other etiologies of thrombotic microangiopathy. While laboratory finding of undetectable ADAMTS13 activity defines TTP, distinguishing aHUS from the other causes of TMA remains an art. In addition, aHUS can be unmasked by conditions with enhanced complement activation, such as systemic lupus erythematosus, pregnancy, malignant hypertension, and hematopoietic stem cell transplantation. Thus if TMA occurs in the setting of enhanced complement activation, one must consider aHUS as an underlying etiology, especially if treatment of the condition does not resolve the TMA. PMID- 27766039 TI - From Nutrient to MicroRNA: a Novel Insight into Cell Signaling Involved in Skeletal Muscle Development and Disease. AB - Skeletal muscle is a remarkably complicated organ comprising many different cell types, and it plays an important role in lifelong metabolic health. Nutrients, as an external regulator, potently regulate skeletal muscle development through various internal regulatory factors, such as mammalian target of rapamycin (mTOR) and microRNAs (miRNAs). As a nutrient sensor, mTOR, integrates nutrient availability to regulate myogenesis and directly or indirectly influences microRNA expression. MiRNAs, a class of small non-coding RNAs mediating gene silencing, are implicated in myogenesis and muscle-related diseases. Meanwhile, growing evidence has emerged supporting the notion that the expression of myogenic miRNAs could be regulated by nutrients in an epigenetic mechanism. Therefore, this review presents a novel insight into the cell signaling network underlying nutrient-mTOR-miRNA pathway regulation of skeletal myogenesis and summarizes the epigenetic modifications in myogenic differentiation, which will provide valuable information for potential therapeutic intervention. PMID- 27766047 TI - MicroRNA in atherothromobosis: is it useful as a disease marker? AB - Atherosclerosis is one of the major causes of death. Data from animal experiments suggest that atherosclerosis involves an inflammatory process of the vascular wall under hyperlipidemia. Atherothrombosis can become a serious complication of atherosclerosis leading to acute cardiovascular events such as myocardial infarction and stroke. Clinical applications to use this knowledge remain scarce. The plasma levels of vascular endothelium-enriched microRNA (miRNAs) in patients with atherosclerotic vascular disease could serve as a disease marker. In our laboratory vascular endothelium-enriched miRNA (miR-126) level was analyzed using quantitative RT polymerase chain reaction analysis (qRT-PCR) in plasma from patients with suspected coronary artery disease (CAD) according to the chest symptom or findings of electrocardiogram, or middle-aged male smokers. Endothelial function for peripheral small vessels was assessed using End-PAT 2000 and expressed as reactive hyperemia peripheral arterial tonometry (RH-PAT) index. In patients with suspected CAD miR-126 was not significantly changed in CAD patients. However, miR-126 was decreased in CAD patients who also have high levels of low-density lipoprotein (LDL) cholesterol. Interestingly, miR-126 was increased when LDL cholesterol was high in patients who did not have evident CAD on coronary angiography even though they have risk factors for CAD. In smokers serum cotinine levels were inversely correlated with endothelial function expressed as RH-PAT index and positively correlated with levels of metabolic parameters such as non-high-density lipoprotein (HDL) cholesterol and insulin resistance. More than half of the smokers could not completely attain smoking cessation and, thus, the RH-PAT index was not improved 8 weeks after the instruction of smoking cessation. However, changes in the RH-PAT index showed a significant correlation with those in systolic blood pressure. In smokers who completely attained smoking cessation, both RH-PAT index and plasma miR-126 values were increased. Thus, among patients with suspected CAD or subjects with coronary risk factors plasma levels of endothelium-enriched circulating miR-126 could be substantially altered. The results suggest a potential usefulness of miR 126 as a sensitive biomarker in assessing endothelial damage. Measurement of microRNA may serve as a useful tool for laboratory assays to determine high-risk patients for atherothromobotic vascular diseases. PMID- 27766046 TI - Posttranslational forms of beta 2-glycoprotein I in the pathogenesis of the antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is an autoimmune disease characterised by a procoagulant state that predisposes to recurrent thrombosis and miscarriages. Two major discoveries have advanced our understanding of the underlying complex pathogenesis of the APS. The first was the discovery that beta-2 glycoprotein-1 (beta2GPI) is the major auto antigen in APS. The second was the discovery in more recent years that beta2GPI contains allosteric disulphide bonds susceptible to posttranslational modification that may be involved in the development of autoantibodies in APS. The main allosteric disulphide bond in the fifth domain of beta2GPI can exist in two redox states: free thiol or oxidised. It is the conformational transformation of beta2GPI from its free thiol form to its more immunogenic oxidised form that exposes neo-epitopes on the first and fifth domains. The purpose of this review is to highlight the recent findings on the posttranslational forms of beta2GPI in the pathogenesis of APS. We suggest that novel assays quantitating the different redox forms of beta2GPI in plasma or serum may be used to supplement existing clinical and laboratory assays to more accurately stratify risk of thrombosis or miscarriage in APS patients. PMID- 27766048 TI - Current animal models of hemophilia: the state of the art. AB - Hemophilia is the most well-known hereditary bleeding disorder, with an incidence of one in every 5000 to 30,000 males worldwide. The disease is treated by infusion of protein products on demand and as prophylaxis. Although these therapies have been very successful, some challenging and unresolved tasks remain, such as reducing bleeding rates, presence of target joints and/or established joint damage, eliminating the development of inhibitors, and increasing the success rate of immune-tolerance induction (ITI). Many preclinical trials are carried out on animal models for hemophilia generated by the hemophilia research community, which in turn enable prospective clinical trials aiming to tackle these challenges. Suitable animal models are needed for greater advances in treating hemophilia, such as the development of better models for evaluation of the efficacy and safety of long-acting products, more powerful gene therapy vectors than are currently available, and successful ITI strategies. Mice, dogs, and pigs are the most commonly used animal models for hemophilia. With the advent of the nuclease method for genome editing, namely the CRISPR/Cas9 system, it is now possible to create animal models for hemophilia other than mice in a short period of time. This review presents currently available animal models for hemophilia, and discusses the importance of animal models for the development of better treatment options for hemophilia. PMID- 27766050 TI - Causes of venous thrombosis. AB - Venous thrombosis which mainly manifests as deep vein thrombosis of the leg or pulmonary embolism occurs in 1 per 1000 per year. It occurs due to interacting genetic, environmental and behavioral risk factors. The strongest risk factors are certain types of surgery and malignancies. Over the last decade many new risk factors for venous thrombosis have been identified. Venous thrombosis has a high recurrence rate, of around 5 % per year. Whereas clinically it would be most important to identify patients at risk of recurrence, only male sex and a previous unprovoked thrombosis are established determinants of recurrent thrombosis. PMID- 27766049 TI - Management of venous thromboembolism: an update. AB - Venous thromboembolism (VTE), which constitutes pulmonary embolism and deep vein thrombosis, is a common disorder associated with significant morbidity and mortality. Landmark trials have shown that direct oral anticoagulants (DOACs) are as effective as conventional anticoagulation with vitamin K antagonists (VKA) in prevention of VTE recurrence and associated with less bleeding. This has paved the way for the recently published guidelines to change their recommendations in favor of DOACs in acute and long-term treatment of VTE in patients without cancer. The recommended treatment of VTE in cancer patients remains low-molecular weight heparin. The initial management of pulmonary embolism (PE) should be directed based on established risk stratification scores. Thrombolysis is an available option for patients with hemodynamically significant PE. Recent data suggests that low-risk patients with acute PE can safely be treated as outpatients if home circumstances are adequate. There is lack of support for use of inferior vena cava filters in patients on anticoagulation. This review describes the acute, long-term, and extended treatment of VTE and recent evidence on the management of sub-segmental PE. PMID- 27766051 TI - Thrombophilia in East Asian countries: are there any genetic differences in these countries? AB - In recent years, genetic analyses of congenital deficiencies of three anticoagulant proteins, antithrombin, protein C (PC) and protein S (PS), in East Asian patients with venous thromboembolism (VTE) have greatly increased. The PS K196E mutation is often identified in the Japanese population with an allelic frequency of 0.86 %, and a total of approximately 10,000 Japanese are estimated to be homozygotes. The heterozygotes show PS anticoagulant activities ranging from 40 to 110 %, and 16 % lower mean anticoagulant activity than that in wild type individuals. Specific assay methods to identify carriers of this mutation have recently been developed. The mutation carriers are at risk of thrombosis during pregnancy but do not appear to be at risk for adverse pregnancy outcomes. To promote future research into this mutation and its relation to thrombosis, a thrombosis-prone mouse strain with the PS K196E mutation has been developed. We found the PS-K196E mutation and the heterozygous PS-deficiency in mice caused increased VTE, but did not cause aggravation of ischemic stroke, unlike factor V Leiden mutation. Importantly, the PS-K196E mutation is only identified in Japanese. This suggests that although East Asian populations including Japanese, Chinese, and Koreans are geographically and genetically close, the PS-K196E mutation seems to be Japanese-specific, suggesting that the mutation is a recent occurrence and fixed within the Japanese population. Some recurrent genetic mutations predisposing to VTE have been reported in Chinese and Korean populations. Although the genetic background for VTE is known to differ between populations with Caucasian descent and East Asian populations, some of the recurrent mutations differ even within the East Asian populations. PMID- 27766052 TI - Cancer-associated thrombosis in Asia. AB - Thrombosis is a common complication in cancer patients. Although the major inherited risk factors for thrombophilia are different between Asians and Caucasians, the main acquired risk factors that are associated with the development of venous thromboembolism (VTE) in Asians appear to be similar to those for Caucasians. Malignancy is the most important acquired risk factor for VTE in Asians. Recent studies have shown that the incidence of VTE is significant in Asian patients with cancer, particularly those in an advanced stage. Cancer associated VTE is more severe and associated with higher morbidity and mortality. Unprovoked VTE is associated with an increased risk of subsequent cancer diagnosis. A number of international and national guidelines are available to provide guidance to healthcare providers to treat and prevent this serious complication based on best-available evidence. Identifying cancer patients at risk for VTE and use of appropriate thromboprophylaxis in these patients can potentially improve morbidity and mortality. Although direct oral anticoagulants (DOACs) may become an attractive treatment for cancer-associated VTE, further clinical trials are needed to evaluate the safety and efficacy of DOACs directly against LMWH in cancer patients. PMID- 27766053 TI - New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2. AB - Platelets play a key role in the pathophysiological processes of hemostasis and thrombus formation. However, platelet functions beyond thrombosis and hemostasis have been increasingly identified in recent years. A large body of evidence now exists which suggests that platelets also play a key role in inflammation, immunity, malignancy, and furthermore in organ development and regeneration, such as the liver. We have recently identified CLEC-2 on the platelet membrane, which induces intracellular activation signals upon interaction of a snake venom, rhodocytin. Later we discovered that podoplanin, present in renal podocytes and lymphatic endothelial cells, both of which are not accessible to platelets in blood stream, is an endogenous ligand for CLEC-2. In accord with our expectation, platelet-specific CLEC-2 knockout mice have a phenotype of edema, lymphatic vessel dilatation, and the presence of blood cells in lymphatic vessels. It is suggested that lymphatic/blood vessel separation during the developmental stage is governed by cytokines released from platelets activated by the interaction between platelet CLEC-2 and podoplanin present on lymphatic endothelial cells. Recombinant CLEC-2 bound to early atherosclerotic lesions and normal arterial walls, co-localizing with vascular smooth muscle cells (VSMCs). Flow cytometry and immunocytochemistry showed that recombinant CLEC-2, but not an anti podoplanin antibody, bound to VSMCs, suggesting that CLEC-2 ligands other than podoplanin are present in VSMCs. Protein arrays and Biacore analysis were used to identify S100A13 as a CLEC-2 ligand in VSMCs. S100A13 was released upon oxidative stress, and expressed in the luminal area of atherosclerotic lesions. Megakaryopoiesis is promoted through the CLEC-2/podoplanin interaction in the vicinity of arterioles, not sinusoids or lymphatic vessels. There exist podoplanin-expressing bone-marrow (BM) arteriolar stromal cells, tentatively termed as BM fibroblastic reticular cell (FRC)-like cells, and megakaryocyte colonies were co-localized with periarteriolar BM FRC-like cells in the BM. CLEC 2/podoplanin interaction induces BM FRC-like cells to secrete CCL5 to facilitate proplatelet formation. These observations indicate that a reciprocal interaction with between CLEC-2 on megakaryocytes and podoplanin on BM FRC-like cells contributes to the periarteriolar megakaryopoietic microenvironment in mouse BM. PMID- 27766054 TI - The adaptor protein Disabled-2: new insights into platelet biology and integrin signaling. AB - Multiple functions of platelets in various physiological and pathological conditions have prompted considerable attention on understanding how platelets are generated and activated. Of the adaptor proteins that are expressed in megakaryocytes and platelets, Disabled-2 (Dab2) has been demonstrated in the past decades as a key regulator of platelet signaling. Dab2 has two alternative splicing isoforms p82 and p59. However, the mode of Dab2's action remains to be clearly defined. In this review, we highlight the current understanding of Dab2 expression and function in megakaryocytic differentiation, platelet activation and integrin signaling. Accordingly, Dab2 is upregulated when the human K562 cells, human CD34+ hematopoietic stem cells, and murine embryonic stem cells were undergone megakaryocytic differentiation. Appropriate level of Dab2 expression is essential for fate determination of mesodermal and megakaryocytic differentiation. Dab2 is also shown to regulate cell-cell and cell-fibrinogen adhesion, integrin alphaIIbbeta3 activation, fibrinogen uptake, and intracellular signaling of the megakaryocytic cells. In human platelets, p82 is the sole Dab2 isoform present in the cytoplasm and alpha-granules. Dab2 is released from the alpha-granules and forms two pools of Dab2 on the outer surface of the platelet plasma membrane, one at the sulfatide-bound and the other at integrin alphaIIbbeta3-bound forms. The balance between these two pools of Dab2 controls the extent of clotting reaction, platelet-fibrinogen interactions and outside-in signaling. In murine platelets, p59 is the only Dab2 isoform and is required for platelet aggregation, fibrinogen uptake, RhoA-ROCK activation, adenosine diphosphate release and integrin alphaIIbbeta3 activation stimulated by low concentration of thrombin. As a result, the bleeding time is prolonged and thrombus formation is impaired for the megakaryocyte lineage-restricted Dab2 deficient mouse. Although discrepancies of Dab2 function and isoform expression are noted between human and murine platelets, the studies up-to-date define Dab2 playing a pivotal role in integrin signaling and platelet activation. With the new tools such as CRISPR and TALEN in the generation of genetically modified animals, the progress in gaining new insights into the functions of Dab2 in megakaryocyte and platelet biology is expected to accelerate. PMID- 27766056 TI - Aspects of prophylactic treatment of hemophilia. AB - Retrospective and prospective studies unambiguously show that prophylactic treatment of severe hemophilia A or B should be started as primary prophylaxis at 1-2 years' of age and ideally before the first joint bleed. The dose and dose frequency should be individually tailored depending on the goal of treatment, venous access and the bleeding phenotype. The circumstances during the first exposures of factor VIII concentrates in hemophilia A may have an impact on the risk of developing inhibitors. Enhanced half-life products, in particular in hemophilia B, will facilitate treatment in patients with difficult venous access but also in achieving a higher trough level. Evidence accumulate that prophylactic treatment is beneficial also in adults and in patients with inhibitors. PMID- 27766057 TI - Different impact of factor VIII products on inhibitor development? AB - Inhibitors are the most serious side effect of haemophilia treatment; they occur in 25-30 % of all patients with severe haemophilia A. Over the last 2 decades, conflicting data on the impact of clotting products have been published. Due to small studies of selected cases, appreciation of the impact of any particular product has been difficult. Moreover, the emphasis on inhibitor testing has led to increased detection of low-titre inhibitors (to >10 %), while the percentage of high-titre inhibitors is still around 20 %. Other non-genetic risk factors, such as dosing and intensive treatment, are able to increase individual inhibitor risk. Early prophylaxis might reduce inhibitor risk. Well-defined large PUP studies including products should be considered. This can only be achieved in collaboration with all stakeholders. In conclusion, while the impact of FVIII products on inhibitor development is large, presently the actual impact of any specific product is unclear. PMID- 27766058 TI - Individualized prophylaxis for optimizing hemophilia care: can we apply this to both developed and developing nations? AB - Prophylaxis is considered optimal care for hemophilia patients to prevent bleeding and to preserve joint function thereby improving quality of life (QoL). The evidence for prophylaxis is irrefutable and is the standard of care in developed nations. Prophylaxis can be further individualized to improve outcomes and cost effectiveness. Individualization is best accomplished taking into account the bleeding phenotype, physical activity/lifestyle, joint status, and pharmacokinetic handling of specific clotting factor concentrates, all of which vary among individuals. Patient acceptance should also be considered. Assessment tools (e.g. joint status imaging and function studies/scores, QoL) for determining and monitoring risk factors and outcome, as well as population PK profiling have been developed to assist the individualization process. The determinants of optimal prophylaxis include (1) factor dose/dosing frequency, hence, cost/affordability (2) bleeding triggers (physical activity/lifestyle, chronic arthropathy and synovitis) and (3) bleeding rates. Altering one determinant results in adjustment of the other two. Thus, the trough level to protect from spontaneous bleeding can be increased in patients who have greater bleeding risks; and prophylaxis to achieve zero joint bleeds is achievable through optimal individualization. Prophylaxis in economically constrained nations is limited by the ill-affordability of clotting factor concentrates. However, at least 5 studies on children and adults from Thailand, China and India have shown superiority of low dose (~5-10 IU kg-1 2-3* per week) prophylaxis over episodic treatment in terms of bleed reduction, and quality of life, with improved physical activity, independent functioning, school attendance and community participation. In these nations, the prophylaxis goals should be for improved QoL rather than "zero bleeds" and perfect joints. Prophylaxis can still be individualized to affordability. Higher protective trough level can be achieved by using smaller doses given more frequently without an increase in consumption/cost. The bleeding trigger can also be down-regulated by avoiding unnecessary injury, and by engaging in judicious strengthening exercises appropriate to the joint status to improve balance and joint stabilization. Central to the success of prophylaxis are clinics with comprehensive care that provide the necessary professional expertise, support, and counseling, to educate patients, families, and other healthcare professionals, and to support research for improved hemophilia care. PMID- 27766055 TI - Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies. AB - Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e. adhesion and aggregation) constitutes the first wave of hemostasis. Blood coagulation, initiated by the coagulation cascades, is the second wave of thrombin generation and enhance phosphatidylserine exposure, can markedly potentiate cell-based thrombin generation and enhance blood coagulation. Recently, deposition of plasma fibronectin and other proteins onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that occurs prior to platelet accumulation (i.e. the classical first wave of hemostasis). These three waves of hemostasis, in the event of atherosclerotic plaque rupture, may turn pathogenic, and cause uncontrolled vessel occlusion and thrombotic disorders (e.g. heart attack and stroke). Current anti-platelet therapies have significantly reduced cardiovascular mortality, however, on-treatment thrombotic events, thrombocytopenia, and bleeding complications are still major concerns that continue to motivate innovation and drive therapeutic advances. Emerging evidence has brought platelet adhesion molecules back into the spotlight as targets for the development of novel anti-thrombotic agents. These potential antiplatelet targets mainly include the platelet receptors glycoprotein (GP) Ib-IX-V complex, beta3 integrins (alphaIIb subunit and PSI domain of beta3 subunit) and GPVI. Numerous efforts have been made aiming to balance the efficacy of inhibiting thrombosis without compromising hemostasis. This mini-review will update the mechanisms of thrombosis and the current state of antiplatelet therapies, and will focus on platelet adhesion molecules and the novel anti-thrombotic therapies that target them. PMID- 27766059 TI - Preimplantation genetic diagnosis of hemophilia A. AB - Preimplantation genetic diagnosis (PGD) is a powerful tool to tackle the transmission of monogenic inherited disorders in families carrying the diseases from generation to generation. It currently remains a challenging task, despite PGD having been developed over 25 years ago. The major difficulty is it does not have an easy and general formula for all mutations. Different gene locus needs individualized, customized design to make the diagnosis accurate enough to be applied on PGD, in which the quantity of DNA is scanty, whereas timely laboratory diagnosis is mandatory if fresh embryo transfer is desired occasionally. Indicators for outcome assessment of a successful PGD program include the successful diagnosis rate on blastomeres (Day 3 cleavage-stage embryo biopsy) or trophectoderm cells (Day 5/6 blastocyst biopsy), the implantation rate per embryo transferred, and the livebirth rate per oocyte retrieval cycle. Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by various types of pathological defects in the factor VIII gene (F8). The mutation spectrum of the F8 is complex, according to our previous report, including large segmental intra gene inversions, large segmental deletions spanning a few exons, point mutations, and total deletion caused by chromosomal structural rearrangements. In this review, the molecular methodologies used to tackle different mutants of the F8 in the PGD of HA are to be explained, and the experiences of successful use of amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) and linkage analysis for PGD of HA in our laboratory are also provided. PMID- 27766060 TI - Comorbidities of cardiovascular disease and cancer in hemophilia patients. AB - As life expectancy greatly increases in persons with hemophilia (PWH), more age related diseases such as cancer and cardiovascular disease (CVD) emerge among this patient group. The aim of this study was to review the available evidence on the epidemiology of CVD events, and incidence and survival of cancer in PWH. The prevalence of CVD events among PWH seems to be similar to that of the general population. Some known risk factors for the event, including aging, hypertension, and hyperlipidemia, are also associated with its occurrence in PWH. There is no evidence showing occurrence of the event directly to clotting factor concentrate administration. On the other hand, the incidence of non-virus related cancer seems to be higher in PWH than the general population. In addition, PWH with cancer were younger at the time of diagnosis. In regards to hemophilia effect on cancer prognosis, further basic and large-scale prospective studies are urgently needed. PMID- 27766061 TI - Extravascular FIX and coagulation. AB - This review summarizes the evidence that collagen IV binding is physiologically important, and that the extravascular compartment of FIX is composed of type IV collagen. As we have previously demonstrated, 7 days post-infusion, FIXWT (BeneFIX) is able to control bleeding as well as the same dosage of Alprolix in hemophilia B mice, tested using the saphenous vein bleeding model (Alprolix is a chimeric FIX molecule joined at its C terminus to a Fc domain). Furthermore, we have shown that in hemophilia B mice, doses of BeneFIX or Alprolix (up to a dose of 150 IU/kg) have increased bleeding-control effectiveness in proportion to the dose up to a certain limit: higher doses are no more effective than the 150 IU/kg dose. These studies suggest that in hemophilia B mice, tested using the saphenous vein bleeding model, three things are true: first, extravascular FIX is at least as important for coagulation as is circulating FIX; second, measuring circulating levels of FIX may not be the best criterion for designing new "longer lasting" FIX molecules; and third, trough levels are less diagnostic for FIX therapy than they are for FVIII therapy. PMID- 27766062 TI - De novo mutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD. AB - BACKGROUND: Von Willebrand disease (VWD) is not uncommon in Taiwan. In type 2 or type 3 VWD hemorrhagic symptoms are severer and laboratory data relatively more distinctive. De novo mutation and somatic mosaicism of type 2 VWD gene were rarely reported. Therefore clinical, laboratory and genetic studies of only type 2A, 2B and 2M VWD will be presented and issues of de novo mutation and somatic mosaicism will be explored. METHODS: Fifty-four patients belonging to 23 unrelated families from all around the country in whom type 2 VWD exclusive of type 2N has been diagnosed not only by clinical and routine laboratory studies but also by genetic confirmation during 1990-2015 were investigated. A novel technique named amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) was used to confirm the presence of somatic mosaicism. Informed consent was obtained for study. RESULTS: De novo mutation was identified in 4 families among 15 families (26.7 %) in whom family members including parents were available for examination. All their parents were free from bleeding symptoms and had no similar mutation as their respective affected daughter. An interesting example of somatic mosaicism of VWF gene mutation was found in a large family with type 2A VWD. The father carrying a mutated VWF gene, p.Arg1597Trp, transmitted this mutation to his 3 daughters, 1 son, 3 granddaughters and 2 grandsons. However, the father had normal laboratory findings and experienced no abnormal bleeding, while his offspring who inherited the mutation showed abnormal laboratory findings compatible with type 2A VWD and had history of abnormal bleedings. ARMS-qPCR revealed that the father had only 25.5 % mutant in his blood cells and 31.1 % mutant in his oral mucosal cells, while all his offspring had about 49 % mutant in their blood cells. CONCLUSION: De novo mutation of type 2 VWD gene was identified in 4 out of 15 families (26.7 %) examined. Since only one child was affected in each family, germline mosaicism was not likely. A somatic mosaicism of type 2A VWD gene was documented in a big family by a newly in-house developed technique ARMS-qPCR. PMID- 27766063 TI - Aspirin plus tirofiban inhibit the thrombosis induced by Russell's viper venom. AB - BACKGROUND: Thrombosis and coagulopathy are the commonest hematological manifestations of envenomation of Russell's viper venom (RVV). Factor X is activated by a factor X-activating enzyme from Russell's viper venom (RVV-X) to start the coagulation cascade. We established an animal model with local ischemic effects induced by RVV. We tried to treat RVV envenomation with antiplatelets and anticoagulants without recourse to antivenom. METHODS: RVV was injected into the foot pad of mice. We observed the effects at different intervals and compared local changes in ischemia with drug treatment after 30 min. RESULTS: A combination of aspirin plus tirofiban could prevent the ischemic change induced by RVV. The antithrombotic effects of single-use of aspirin or tirofiban were better than single-use of heparin or clopidogrel. CONCLUSION: The aspirin + tirofiban group had a better outcome with respect to prevention of tissue ischemia and gangrene. This indicates that the activation and aggregation of platelets is the major cause of thrombosis induced by RVV. PMID- 27766064 TI - Characteristics of Taiwanese patients of PNH in the international PNH registry. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and acquired hematopoietic stem cell disease, with florid clinical presentations. Although this disease has been characterized in the western countries, its clinical and laboratory features in Taiwan have not yet been reported. RESULTS: As a part of an international prospective, non-interventional, observational registration trial of PNH, we have analyzed 63 patients recruited between 2009 and 2015 in Taiwan, with comparison to the 3857 patients in the rest of the world (ROW). The median age of diagnosis of our patients is 46 (range 9-84), without sex preponderance. While most of the clinical and laboratory presentations of our patients are similar to the ROW, ours have higher lactate dehydrogenase levels, lower hemoglobin, and higher frequencies of symptoms including shortness of breath and erectile dysfunction at the time of diagnosis. The incidence of thromboembolism was not statistically different between ours and the ROW (6.7 % vs 13.5 %, P = 0.178). The patients in Taiwan were treated more frequently with corticosteroid (53.2 % vs 32 %, P < 0.001), but less frequently with cyclosporine/anti-thymocyte globulin and heparin/warfarin, both P < 0.001). CONCLUSIONS: This is the first systematic review on the Taiwanese PNH patients. Our analysis would provide key information about our PNH patients and would help understanding the basic characteristics of this rare disease in Taiwan. TRIAL REGISTRATION: This trial has been registered to ClinicalTrails.gov NCT01374360. PMID- 27766065 TI - Thrombopoietin and its receptor in normal and neoplastic hematopoiesis. AB - Thrombopoietin was posited to exist in 1958 and cloned in 1994, and in the ensuing two decades we have learned a great deal about the physiology and pathology of the primary regulator of thrombopoiesis. This paper will review the role of the hormone and its receptor, the product of the c-Mpl proto-oncogene, in health and disease, including many unexpected effects in both normal and neoplastic hematopoiesis. Amongst these unexpected properties are a non-redundant effect on hematopoietic stem cells, a critical role in all three of the acquired, chronic myeloproliferative neoplasms, as well as both gain-of-function and loss of-function mutations in congenital and acquired states of thrombocytopenia and thrombocythemia. PMID- 27766066 TI - Hemophilia A gene therapy via intraosseous delivery of factor VIII-lentiviral vectors. AB - Current treatment of hemophilia A (HemA) patients with repeated infusions of factor VIII (FVIII; abbreviated as F8 in constructs) is costly, inconvenient, and incompletely effective. In addition, approximately 25 % of treated patients develop anti-factor VIII immune responses. Gene therapy that can achieve long term phenotypic correction without the complication of anti-factor VIII antibody formation is highly desired. Lentiviral vector (LV)-mediated gene transfer into hematopoietic stem cells (HSCs) results in stable integration of FVIII gene into the host genome, leading to persistent therapeutic effect. However, ex vivo HSC gene therapy requires pre-conditioning which is highly undesirable for hemophilia patients. The recently developed novel methodology of direct intraosseous (IO) delivery of LVs can efficiently transduce bone marrow cells, generating high levels of transgene expression in HSCs. IO delivery of E-F8-LV utilizing a ubiquitous EF1alpha promoter generated initially therapeutic levels of FVIII, however, robust anti-FVIII antibody responses ensued neutralized functional FVIII activity in the circulation. In contrast, a single IO delivery of G-FVIII-LV utilizing a megakaryocytic-specific GP1balpha promoter achieved platelet-specific FVIII expression, leading to persistent, partial correction of HemA in treated animals. Most interestingly, comparable therapeutic benefit with G-F8-LV was obtained in HemA mice with pre-existing anti-FVIII inhibitors. Platelets is an ideal IO delivery vehicle since FVIII stored in alpha-granules of platelets is protected from high-titer anti-FVIII antibodies; and that even relatively small numbers of activated platelets that locally excrete FVIII may be sufficient to promote efficient clot formation during bleeding. Additionally, combination of pharmacological agents improved transduction of LVs and persistence of transduced cells and transgene expression. Overall, a single IO infusion of G-F8-LV can generate long-term stable expression of hFVIII in platelets and correct hemophilia phenotype for long term. This approach has high potential to permanently treat FVIII deficiency with and without pre-existing anti-FVIII antibodies. PMID- 27766067 TI - Barriers to Condom Use: Results for Men and Women Enrolled in HIV Risk Reduction Trials in Outpatient Drug Treatment. AB - HIV transmission often occurs through heterosexual high-risk sex. Even in the era of HIV combination prevention, promoting condom use, and understanding condom barriers, remain priorities, especially among substance-dependent individuals. Men and women (N=729) in outpatient drug treatment participated in a five-session gender-specific risk reduction group or one-session HIV Education group. Condom barriers (Motivation, Partner-related, Access/Availability, Sexual experience) were assessed at baseline and 6-month follow-up. Completing either intervention was associated with fewer motivation and partner-related barriers. Among women, reductions in motivation and sexual experience barriers were associated with less sexual risk with primary partners. Condom barriers are important to gender specific HIV prevention; given limited resources, brief interventions maximizing active components are needed. PMID- 27766070 TI - Impaired Levels of Gangliosides in the Corpus Callosum of Huntington Disease Animal Models. AB - Huntington Disease (HD) is a genetic neurodegenerative disorder characterized by broad types of cellular and molecular dysfunctions that may affect both neuronal and non-neuronal cell populations. Among all the molecular mechanisms underlying the complex pathogenesis of the disease, alteration of sphingolipids has been identified as one of the most important determinants in the last years. In the present study, besides the purpose of further confirming the evidence of perturbed metabolism of gangliosides GM1, GD1a, and GT1b the most abundant cerebral glycosphingolipids, in the striatal and cortical tissues of HD transgenic mice, we aimed to test the hypothesis that abnormal levels of these lipids may be found also in the corpus callosum white matter, a ganglioside enriched brain region described being dysfunctional early in the disease. Semi quantitative analysis of GM1, GD1a, and GT1b content indicated that ganglioside metabolism is a common feature in two different HD animal models (YAC128 and R6/2 mice) and importantly, demonstrated that levels of these gangliosides were significantly reduced in the corpus callosum white matter of both models starting from the early stages of the disease. Besides corroborating the evidence of aberrant ganglioside metabolism in HD, here, we found out for the first time, that ganglioside dysfunction is an early event in HD models and it may potentially represent a critical molecular change influencing the pathogenesis of the disease. PMID- 27766069 TI - An Increase in Alpha Band Frequency in Resting State EEG after Electrical Stimulation of the Ear in Tinnitus Patients-A Pilot Study. AB - In our clinic invasive transtympanal promontory positive DC stimulations were first used, with a success rate of 42%. However, non-invasive hydrotransmissive negative DC stimulations are now favored, with improvement being obtained in 37.8% directly after the treatment, and 51.3% in a follow up 1 month after treatment. The further improvement after 1 month may be due to neuroplastic changes at central level as a result of altered peripheral input. The aim of the study was to determine how/whether a single electrical stimulation of the ear influences cortical activity, and whether changes observed in tinnitus after electrical stimulation are associated with any changes in cortical activity recorded in EEG. The study included 12 tinnitus patients (F-6, M-6) divided into two groups. Group I comprised six patients with unilateral tinnitus - unilateral, ipsilateral ES was performed. Group II comprised six patients with bilateral tinnitus-bilateral ES was performed. ES was performed using a custom-made apparatus. The active, silver probe-was immersed inside the external ear canal filled with saline. The passive electrode was placed on the forehead. The stimulating frequency was 250 Hz, the intensity ranged from 0.14 to 1.08 mA. The voltage was kept constant at 3 V. The duration of stimulation was 4 min. The EEG recording (Deymed QEST 32) was performed before and after ES. The patients assessed the intensity of tinnitus on the VAS 1-10. Results: In both groups an improvement in VAS was observed-in group I-in five ears (83.3%), in group II-in seven ears (58.3%). In Group I, a significant increase in the upper and lower limit frequency of alpha band was observed in the central temporal and frontal regions following ES. These changes, however, were not correlated with improvement in tinnitus. No significant changes were observed in the beta and theta bands and in group II. Preliminary results of our research reveal a change in cortical activity after electrical stimulations of the ear. However, it remains unclear if it is primary or secondary to peripheral auditory excitation. No similar studies had been found in the literature. PMID- 27766068 TI - Mild Traumatic Brain Injury Produces Neuron Loss That Can Be Rescued by Modulating Microglial Activation Using a CB2 Receptor Inverse Agonist. AB - We have previously reported that mild TBI created by focal left-side cranial blast in mice produces widespread axonal injury, microglial activation, and a variety of functional deficits. We have also shown that these functional deficits are reduced by targeting microglia through their cannabinoid type-2 (CB2) receptors using 2-week daily administration of the CB2 inverse agonist SMM-189. CB2 inverse agonists stabilize the G-protein coupled CB2 receptor in an inactive conformation, leading to increased phosphorylation and nuclear translocation of the cAMP response element binding protein (CREB), and thus bias activated microglia from a pro-inflammatory M1 to a pro-healing M2 state. In the present study, we showed that SMM-189 boosts nuclear pCREB levels in microglia in several brain regions by 3 days after TBI, by using pCREB/CD68 double immunofluorescent labeling. Next, to better understand the basis of motor deficits and increased fearfulness after TBI, we used unbiased stereological methods to characterize neuronal loss in cortex, striatum, and basolateral amygdala (BLA) and assessed how neuronal loss was affected by SMM-189 treatment. Our stereological neuron counts revealed a 20% reduction in cortical and 30% reduction in striatal neurons bilaterally at 2-3 months post blast, with SMM-189 yielding about 50% rescue. Loss of BLA neurons was restricted to the blast side, with 33% of Thy1+ fear suppressing pyramidal neurons and 47% of fear-suppressing parvalbuminergic (PARV) interneurons lost, and Thy1-negative fear-promoting pyramidal neurons not significantly affected. SMM-189 yielded 50-60% rescue of Thy1+ and PARV neuron loss in BLA. Thus, fearfulness after mild TBI may result from the loss of fear suppressing neuron types in BLA, and SMM-189 may reduce fearfulness by their rescue. Overall, our findings indicate that SMM-189 rescues damaged neurons and thereby alleviates functional deficits resulting from TBI, apparently by selectively modulating microglia to the beneficial M2 state. CB2 inverse agonists thus represent a promising therapeutic approach for mitigating neuroinflammation and neurodegeneration. PMID- 27766071 TI - Editorial: CNS Recovery after Structural and / or Physiological / Psychological Damage. PMID- 27766072 TI - Long Non-coding RNA TUSC7, a Target of miR-23b, Plays Tumor-Suppressing Roles in Human Gliomas. AB - Tumour suppressor candidate 7 (TUSC7) is a novel tumor suppressor gene generating long non-coding RNA (lncRNAs) in several types of human cancers. The expression and function of TUSC7 in human brain glioma has yet to be elucidated. In this study, TUSC7 was poorly expressed in tissues and cell lines of glioma, and the lower expression was correlated with glioma of the worse histological grade. Moreover, TUSC7 is a prognostic biomarker of glioma patients. Up-regulation of TUSC7 suppressed cellular proliferation and invasion of glioma cells, and accelerated cellular apoptosis. Bioinformatics analysis showed that TUSC7 specifically binds to miR-23b. MiR-23b was up-regulated in glioma and negatively correlated with the expression of TUSC7. The miR-23b expression was inhibited remarkably by the upregulation of TUSC7 and the reciprocal inhibition was determined between TUSC7 and miR-23b.RNA pull-down and luciferase reporter assays were used to validate the sequence-specific correlation between miR-23b and TUSC7. TUSC7 inhibited the proliferation, migration and invasion of glioma cells and promoted cellular apoptosis largely bypassing miR-23b. We conclude that the lncRNA TUSC7 acted as a tumor suppressor gene negatively regulated by miR-23b, suggesting a novel therapeutic strategy against gliomas. PMID- 27766074 TI - Corrigendum: FIB/SEM technology and high-throughput 3D reconstruction of dendritic spines and synapses in GFP-labeled adult-generated neurons. AB - [This corrects the article on p. 60 in vol. 9, PMID: 26052271.]. PMID- 27766075 TI - Measures to Predict The Individual Variability of Corticospinal Responses Following Transcranial Direct Current Stimulation. AB - Individual responses to transcranial direct current stimulation (tDCS) are varied and therefore potentially limit its application. There is evidence that this variability is related to the contributions of Indirect waves (I-waves) recruited in the cortex. The latency of motor-evoked potentials (MEPs) can be measured through transcranial magnetic stimulation (TMS), allowing an individual's responsiveness to tDCS to be determined. However, this single-pulse method requires several different orientations of the TMS coil, potentially affecting its reliability. Instead, we propose a paired-pulse TMS paradigm targeting I waves as an alternative method. This method uses one orientation that reduces inter- and intra-trial variability. It was hypothesized that the paired-pulse method would correlate more highly to tDCS responses than the single-pulse method. In a randomized, double blinded, cross-over design, 30 healthy participants completed two sessions, receiving 20 min of either anodal (2 mA) or sham tDCS. TMS was used to quantify Short interval intracortical facilitation (SICF) at Inter stimulus intervals (ISIs) of 1.5, 3.5 and 4.5 ms. Latency was determined in the posterior-anterior (PA), anterior-posterior (AP) and latero medial (LM) coil orientations. The relationship between latency, SICF measures and the change in suprathreshold MEP amplitude size following tDCS were determined with Pearson's correlations. TMS measures, SICI and SICF were also used to determine responses to Anodal-tDCS (a-tDCS). Neither of the latency differences nor the SICF measures correlated to the change in MEP amplitude from pre-post tDCS (all P > 0.05). Overall, there was no significant response to tDCS in this cohort. This study highlights the need for testing the effects of various tDCS protocols on the different I-waves. Further research into SICF and whether it is a viable measure of I-wave facilitation is warranted. PMID- 27766073 TI - Differences in Motor Evoked Potentials Induced in Rats by Transcranial Magnetic Stimulation under Two Separate Anesthetics: Implications for Plasticity Studies. AB - Repetitive transcranial magnetic stimulation (rTMS) is primarily used in humans to change the state of corticospinal excitability. To assess the efficacy of different rTMS stimulation protocols, motor evoked potentials (MEPs) are used as a readout due to their non-invasive nature. Stimulation of the motor cortex produces a response in a targeted muscle, and the amplitude of this twitch provides an indirect measure of the current state of the cortex. When applied to the motor cortex, rTMS can alter MEP amplitude, however, results are variable between participants and across studies. In addition, the mechanisms underlying any change and its locus are poorly understood. In order to better understand these effects, MEPs have been investigated in vivo in animal models, primarily in rats. One major difference in protocols between rats and humans is the use of general anesthesia in animal experiments. Anesthetics are known to affect plasticity-like mechanisms and so may contaminate the effects of an rTMS protocol. In the present study, we explored the effect of anesthetic on MEP amplitude, recorded before and after intermittent theta burst stimulation (iTBS), a patterned rTMS protocol with reported facilitatory effects. MEPs were assessed in the brachioradialis muscle of the upper forelimb under two anesthetics: a xylazine/zoletil combination and urethane. We found MEPs could be induced under both anesthetics, with no differences in the resting motor threshold or the average baseline amplitudes. However, MEPs were highly variable between animals under both anesthetics, with the xylazine/zoletil combination showing higher variability and most prominently a rise in amplitude across the baseline recording period. Interestingly, application of iTBS did not facilitate MEP amplitude under either anesthetic condition. Although it is important to underpin human application of TMS with mechanistic examination of effects in animals, caution must be taken when selecting an anesthetic and in interpreting results during prolonged TMS recording. PMID- 27766077 TI - No Decrease in Muscle Strength after Botulinum Neurotoxin-A Injection in Children with Cerebral Palsy. AB - Spasticity and muscle weakness is common in children with cerebral palsy (CP). Spasticity can be treated with botulinum neurotoxin-A (BoNT-A), but this drug has also been reported to induce muscle weakness. Our purpose was to describe the effect on muscle strength in the lower extremities after BoNT-A injections in children with CP. A secondary aim was to relate the effect of BoNT-A to gait pattern and range of motion. Twenty children with spastic CP were included in the study, 8 girls and 12 boys (mean age 7.7 years). All were able to walk without support, but with increased muscle tone interfering with motor function and gait pattern. Sixteen children had unilateral spastic CP and four bilateral spastic CP. Twenty-four legs received injections with BoNT-A in the plantar flexor muscles. The children were tested before treatment, around 6 weeks after at the peak effect of BoNT-A, and at 6 months after treatment, with measurement of muscle strength, gait analysis, and range of motion. There were no differences in muscle strength in plantar flexors of treated legs at peak effect compared to baseline. Six months after treatment, there was still no change in untreated plantar flexor muscles, but an increasing trend in plantar flexor strength in legs treated with BoNT-A. Parents reported positive effects in all children, graded as: small in three children, moderate in eight, and large in nine children. The gait analysis showed a small improvement in knee extension at initial contact, and there was a small increase in passive range of motion for ankle dorsiflexion. Two children had a period with transient weakness and pain. We found that voluntary force production in plantar flexor muscles did not decrease after BoNT-A, instead there was a trend to increased muscle strength at follow-up. The increase may be explained as an effect of the blocking of involuntary nerve impulses, leading to an opportunity to using and training the muscles with voluntary control. Adequate muscle strength is important for maintaining the ability to walk and knowledge of how a treatment affects muscle strength is useful when selecting interventions. PMID- 27766076 TI - Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal. AB - The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; >=15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders; n = 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders; n = 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial prefrontal cortices (DMPFC) in responders, whereas non-responders showed increased connectivity between the ParsOp seed and LOC. Overall, our findings revealed distinct morphometric and functional brain changes in CM patients that reverted to EM following prophylactic treatment compared to CM patients that showed no change in disease status. Elucidating the CNS changes involved in disease reversal may be critical to discovering interventions that prevent or slow the progression of CM. Such changes may aid in the evaluation of treatments as well as provide markers for disease "de-chronification". PMID- 27766078 TI - Temporal Code-Driven Stimulation: Definition and Application to Electric Fish Signaling. AB - Closed-loop activity-dependent stimulation is a powerful methodology to assess information processing in biological systems. In this context, the development of novel protocols, their implementation in bioinformatics toolboxes and their application to different description levels open up a wide range of possibilities in the study of biological systems. We developed a methodology for studying biological signals representing them as temporal sequences of binary events. A specific sequence of these events (code) is chosen to deliver a predefined stimulation in a closed-loop manner. The response to this code-driven stimulation can be used to characterize the system. This methodology was implemented in a real time toolbox and tested in the context of electric fish signaling. We show that while there are codes that evoke a response that cannot be distinguished from a control recording without stimulation, other codes evoke a characteristic distinct response. We also compare the code-driven response to open-loop stimulation. The discussed experiments validate the proposed methodology and the software toolbox. PMID- 27766080 TI - Editorial: Mitochondria in Skeletal Muscle Health, Aging and Diseases. PMID- 27766081 TI - New Insights on the Use of Dietary Polyphenols or Probiotics for the Management of Arterial Hypertension. AB - Arterial hypertension (AH) is one of the most prevalent risk factors for cardiovascular diseases (CD) and is the main cause of deaths worldwide. Current research establish that dietary polyphenols may help to lower blood pressure (BP), thus contributing to the reduction of cardiovascular complications. In addition, the health benefits of probiotics on BP have also attracted increased attention, as probiotics administration modulates the microbiota, which, by interacting with ingested polyphenols, controls their bioavalability. The aim of the present mini-review is to summarize and clarify the effects of dietary polyphenols and probiotics administration on BP using combined evidence from clinical and experimental studies, as well as to discuss the current debate in the literature about the usefulness of this nutritional approach to manage BP. Clinical trials and experimental studies have demonstrated that consuming dietary polyphenols or probiotics in adequate amounts may improve BP, ranging from modest to greater effects. However, the mechanisms linking probiotic intake and reduced BP levels need to be further elucidated as a definitive consensus on the link between intake of polyphenols or probiotics and improvement of AH has not been reached yet. PMID- 27766079 TI - Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention. AB - The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNgamma) and TNFalpha can enhance MHC class I expression, PD L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer. PMID- 27766082 TI - Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given Ad libitum in Old ApoE-/- Mice. AB - Aim: Advanced atherosclerosis increases inflammation and stroke risk in the cerebral vasculature. Exercise is known to improve cardio-metabolic profiles when associated with a caloric restriction, but it remains debated whether it is still beneficial without the dietary control. The aim of this study was to determine both the peripheral and central effects of exercise training combined with a cholesterol-rich diet given ad libitum in old ApoE-/- mice. Methods: Forty-five weeks old obese ApoE-/- mice fed with a high cholesterol diet ad libitum were divided into Exercise-trained (EX; running wheel free access) and Sedentary (SED) groups. Insulin tolerance and brain imaging were performed before and after the twelve-weeks training. Tissue insulin resistance, oxidative stress, and inflammation markers in plasma, aorta, and brain were then assessed. Results: In EX ApoE-/- mice, no beneficial effect of exercise was observed on weight, abdominal fat, metabolic parameters, oxidative stress, or inflammation compared to SED. Despite the regular exercise training in ApoE-/- EX mice (mean of 12.5 km/week during 12 weeks), brain inflammation imaging score was significantly associated with increased blood brain barrier (BBB) leakage evaluated by imaging follow-up (r2 = 0.87; p = 0.049) with a faster evolution compared to SED ApoE-/ mice. Conclusion: We conclude that in a context of high cardio-metabolic risk, exercise does not provide any protective effect in old ApoE-/- animals under high cholesterol diet given ad libitum. Peripheral (insulin sensitivity and oxidative/inflammatory status) but also central features (BBB preservation and protection against inflammation) did not show any benefits of exercise. Indeed, there was a fast induction of irreversible brain damage that was more pronounced in exercise-trained ApoE-/- mice. PMID- 27766085 TI - Corrigendum: ADHD Rehabilitation through Video Gaming: A Systematic Review Using PRISMA Guidelines of the Current Findings and the Associated Risk of Bias. AB - [This corrects the article on p. 151 in vol. 6, PMID: 26557098.]. PMID- 27766084 TI - Vitamin D Deficiency in Adult Patients with Schizophreniform and Autism Spectrum Syndromes: A One-Year Cohort Study at a German Tertiary Care Hospital. AB - INTRODUCTION: Vitamin D has many immunomodulatory, anti-inflammatory, and neuroprotective functions, and previous studies have demonstrated an association between vitamin D deficiency and neuropsychiatric disease. The aim of our study was to analyze the prevalence of vitamin D deficiency in a 1-year cohort of adult inpatients with schizophreniform and autism spectrum syndromes in a naturalistic inpatient setting in Germany. PARTICIPANTS AND METHODS: Our study was comprised of 60 adult schizophreniform and 23 adult high-functioning autism spectrum patients who were hospitalized between January and December of 2015. We compared our findings with a historical German reference cohort of 3,917 adults using Pearson's two-sided chi-squared test. The laboratory measurements of 25 hydroxyvitamin D2/3 [25(OH)vitamin D] were obtained using a chemiluminescence immunoassay. RESULTS: In the schizophreniform group, we found decreased (<20 ng/ml) 25(OH)vitamin D levels in 48/60 (80.0%) of the patients. In the autism spectrum group, decreased levels were detected in 18/23 (78.3%) of the patients. 25(OH)vitamin D deficiencies were found in 57.3% of the historical control group. Particularly, severe deficiencies (<10 ng/ml) occurred much more frequently in the schizophreniform (38.3%) and autism spectrum groups (52.2%), when compared to the control group (16.3%). The recommended 25(OH)vitamin D values of >30 ng/ml were observed in only 5% of the schizophreniform patients, 8.7% of the autism spectrum patients, and 21.9% of the healthy controls. DISCUSSION: We found very high rates of 25(OH)vitamin D deficiencies in both patient groups and have discussed whether our findings might be related to alterations in the immunological mechanisms. Irrespective of the possible pathophysiological links between vitamin D deficiency and schizophrenia or autism spectrum disorders, a more frequent measurement of vitamin D levels seems to be justified in these patient groups. Further prospective, controlled, blinded, and randomized research should be conducted to analyze the effectiveness of vitamin D supplementation on the improvement of psychiatric symptoms. PMID- 27766083 TI - Behavioral Neuroadaptation to Alcohol: From Glucocorticoids to Histone Acetylation. AB - A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic-pituitary-adrenal axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents) from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit, including the prefrontal cortex (PFC), the hippocampus (HPC), and the amygdala (AMG). These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally AMG hyperactivity coupled with a hypofunction of the PFC and the HPC. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as [cAMP response element-binding protein (CREB)] and chromatin remodeling due to posttranslational modifications of histone proteins. We describe the role of prefrontal-HPC-AMG circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes how persistently increased glucocorticoid levels in PFC may be involved in mediating working memory impairments and neuroadaptive changes during withdrawal from chronic alcohol intake. It then highlights the role of cAMP-PKA CREB signaling cascade and histone acetylation within the PFC and limbic structures in alcohol-induced anxiety and behavioral impairments, and how an understanding of functional alterations of these pathways might lead to better treatments for neuropsychiatric disorders. PMID- 27766086 TI - Peripheral Visual Cues: Their Fate in Processing and Effects on Attention and Temporal-Order Perception. AB - Peripheral visual cues lead to large shifts in psychometric distributions of temporal-order judgments. In one view, such shifts are attributed to attention speeding up processing of the cued stimulus, so-called prior entry. However, sometimes these shifts are so large that it is unlikely that they are caused by attention alone. Here we tested the prevalent alternative explanation that the cue is sometimes confused with the target on a perceptual level, bolstering the shift of the psychometric function. We applied a novel model of cued temporal order judgments, derived from Bundesen's Theory of Visual Attention. We found that cue-target confusions indeed contribute to shifting psychometric functions. However, cue-induced changes in the processing rates of the target stimuli play an important role, too. At smaller cueing intervals, the cue increased the processing speed of the target. At larger intervals, inhibition of return was predominant. Earlier studies of cued TOJs were insensitive to these effects because in psychometric distributions they are concealed by the conjoint effects of cue-target confusions and processing rate changes. PMID- 27766088 TI - Effectiveness of Caregiver Training in Mindfulness-Based Positive Behavior Support (MBPBS) vs. Training-as-Usual (TAU): A Randomized Controlled Trial. AB - Caregivers of individuals with intellectual and developmental disabilities (IDD) often end up having their medical and psychological well-being compromised due to the stressful nature of caregiving, especially when those in their care engage in aggressive behavior. In this study, we provided caregivers with mindfulness-based training to enable them to better manage their psychological well-being and, through this, to also enhance specific indices of quality of life of the individuals in their care. Thus, the aim of the present study was to evaluate in a randomized controlled trial (RCT) the comparative effectiveness of Mindfulness Based Positive Behavior Support (MBPBS) and Training-as-Usual (TAU) for caregivers in a congregate care facility for individuals with severe and profound IDD. The comparative effects of the two training conditions were assessed in terms of caregiver variables care recipient variable (number of aggressive events), and agency variables Results showed that MBPBS was significantly more effective than TAU in enabling the caregivers to manage their perceived psychological stress, and to reduce the use of physical restraints and stat medications for aggressive behavior of the individuals in their care. In addition, there were significant reductions in aggressive events by the individuals in their care, 1:1 staffing of individuals with aggressive behavior, and staff turnover. Furthermore, the MBPBS training was significantly more cost effective than the TAU training. If replicated in future RCT studies, MBPBS may provide an effective means of enhancing socially acceptable bidirectional engagement of caregivers and care recipients within a person-centered context. PMID- 27766087 TI - Co-evolution of Friendships and Antipathies: A Longitudinal Study of Preschool Peer Groups. AB - We used stochastic actor-based models to test whether the developmental dynamics of friendships and antipathies in preschool peer groups (followed throughout three school years) were co-dependent. We combined choices from three sociometric tasks of 142 children to identify friendship and antipathy ties and used SIENA to model network dynamics. Our results show that different social processes drive the development of friendship and antipathy ties, and that they do not develop in association (i.e., friendship ties are not dependent on existing antipathies, and vice-versa). These results differ from those of older children (age range = 10 14) suggesting that the interplay of friendship and antipathy only plays a significant role in the peer group context in older children. We propose these differences to be likely related with preschool age children's inaccurate perceptions of their classmates' relationships, particularly of their antipathies, and/or with the absence of shared norms to deal with antipathetic relationships. PMID- 27766089 TI - Sleep Changes in Adolescents Following Procedural Task Training. AB - Recent research has suggested that some of the inter-individual variation in sleep spindle activity is due to innate learning ability. Sleep spindles have also been observed to vary following learning in both young and older adults. We examined the effect of procedural task acquisition on sleep stages and on sleep spindles in an adolescent sample. Participants were 32 adolescents (17 females) between the ages of 12 and 19 years. Spindle activity was examined in three different frequency ranges: 11.00-13.50 Hz (slow), 13.51-16.00 Hz (fast), and 16.01-18.50 Hz (superfast). No changes in spindle density were observed after successful learning of the pursuit rotor task. This result was in contrast to a number of studies reporting spindle density increases following successful learning. In the present study, participants who successfully learned the task showed no changes in their sleep stage proportions, but participants who were not successful showed a decrease in the proportion of stage 2 and increases in both SWS and REM sleep. We suggest that these changes in the sleep stages are consistent with the two stage model of sleep and memory proposed by Smith et al. (2004a). PMID- 27766090 TI - To Know or Not to Know? Theta and Delta Reflect Complementary Information about an Advanced Cue before Feedback in Decision-Making. AB - To investigate brain activity during the reinforcement learning process in social contexts is a topic of increasing research interest. Previous studies have mainly focused on using electroencephalograms (EEGs) for feedback evaluation in reinforcement learning tasks by measuring event-related potentials. Few studies have investigated the time-frequency (TF) profiles of a cue that manifested whether a following feedback is available or not after decision-making. Moreover, it remains unclear whether the TF profiles of the cue interact with different agents to whom the feedback related. In this study we used the TF approach to test EEG oscillations of the cue stimuli in three agents ('Self', 'Other', and 'Computer') conditions separately. The results showed that the increased central posterior delta power was elicited by the feedback unavailable cues more so than with the feedback available cue within 200-350 ms after the onset of the cue, but only in the self-condition. Moreover, a frontal-central theta oscillation had enhanced power when following the feedback unavailable cue as opposed to the feedback available cue across three agencies. These findings demonstrated that the cue for knowing an outcome produced reward prediction error-like signals, which were mirrored by the delta and theta oscillations during decision-making. More importantly, the present study demonstrated that the theta and delta oscillations reflected separable components of the advanced cue processing before the feedback in decision-making. PMID- 27766091 TI - Molecular Interaction and Cellular Location of RecA and CheW Proteins in Salmonella enterica during SOS Response and Their Implication in Swarming. AB - In addition to its role in DNA damage repair and recombination, the RecA protein, through its interaction with CheW, is involved in swarming motility, a form of flagella-dependent movement across surfaces. In order to better understand how SOS response modulates swarming, in this work the location of RecA and CheW proteins within the swarming cells has been studied by using super-resolution microscopy. Further, and after in silico docking studies, the specific RecA and CheW regions associated with the RecA-CheW interaction have also been confirmed by site-directed mutagenesis and immunoprecipitation techniques. Our results point out that the CheW distribution changes, from the cell poles to foci distributed in a helical pattern along the cell axis when SOS response is activated or RecA protein is overexpressed. In this situation, the CheW presents the same subcellular location as that of RecA, pointing out that the previously described RecA storage structures may be modulators of swarming motility. Data reported herein not only confirmed that the RecA-CheW pair is essential for swarming motility but it is directly involved in the CheW distribution change associated to SOS response activation. A model explaining not only the mechanism by which DNA damage modulates swarming but also how both the lack and the excess of RecA protein impair this motility is proposed. PMID- 27766092 TI - Identification of Differentially Expressed Genes during Bacillus subtilis Spore Outgrowth in High-Salinity Environments Using RNA Sequencing. AB - In its natural habitat, the soil bacterium Bacillus subtilis often has to cope with fluctuating osmolality and nutrient availability. Upon nutrient depletion it can form dormant spores, which can revive to form vegetative cells when nutrients become available again. While the effects of salt stress on spore germination have been analyzed previously, detailed knowledge on the salt stress response during the subsequent outgrowth phase is lacking. In this study, we investigated the changes in gene expression during B. subtilis outgrowth in the presence of 1.2 M NaCl using RNA sequencing. In total, 402 different genes were upregulated and 632 genes were downregulated during 90 min of outgrowth in the presence of salt. The salt stress response of outgrowing spores largely resembled the osmospecific response of vegetative cells exposed to sustained high salinity and included strong upregulation of genes involved in osmoprotectant uptake and compatible solute synthesis. The sigmaB-dependent general stress response typically triggered by salt shocks was not induced, whereas the sigmaW regulon appears to play an important role for osmoadaptation of outgrowing spores. Furthermore, high salinity induced many changes in the membrane protein and transporter transcriptome. Overall, salt stress seemed to slow down the complex molecular reorganization processes ("ripening") of outgrowing spores by exerting detrimental effects on vegetative functions such as amino acid metabolism. PMID- 27766093 TI - Isolation and Characterization of Gut Bacterial Proteases Involved in Inducing Pathogenicity of Bacillus thuringiensis Toxin in Cotton Bollworm, Helicoverpa armigera. AB - Bacillus thuringiensis toxin proteins are deployed in transgenic plants for pest management. The present studies were aimed at characterization of gut bacterial proteases involved in activation of inactive Cry1Ac protoxin (pro-Cry1Ac) to active toxin in Helicoverpa armigera. Bacterial strains were isolated from H. armigera midgut and screened for their proteolytic activation toward pro-Cry1Ac. Among 12 gut bacterial isolates seven isolates showed proteolytic activity, and proteases from three isolates (IVS1, IVS2, and IVS3) were found to be involved in the proteolytic conversion of pro-Cry1Ac into active toxin. The proteases from IVS1, IVS2, and IVS3 isolates were purified to 11.90-, 15.50-, and 17.20-fold, respectively. The optimum pH and temperature for gut bacterial protease activity was 8.0 and 40 degrees C. Maximum inhibition of total proteolytic activity was exerted by phenylmethane sulfonyl fluoride followed by EDTA. Fluorescence zymography revealed that proteases from IVS1, IVS2, and IVS3 were chymotrypsin like and showing protease band at ~15, 65, and 15 kDa, respectively. Active Cry1Ac formed from processing pro-Cry1Ac by gut bacterial proteases exhibited toxicity toward H. armigera. The gut bacterial isolates IVS1, IVS2, and IVS3 showed homology with B. thuringiensis (CP003763.1), Vibrio fischeri (CP000020.2), and Escherichia coli (CP011342.1), respectively. Proteases produced by midgut bacteria are involved in proteolytic processing of B. thuringiensis protoxin and play a major role in inducing pathogenicity of B. thuringiensis toxins in H. armigera. PMID- 27766094 TI - The First Report of a Fully Sequenced Resistance Plasmid from Shigella boydii. AB - The purpose of this study was to characterize mechanisms of plasmid-mediated antimicrobial resistance in Shigella boydii. S. boydii strain 2246 with resistance to ciprofloxacin, ceftriaxone and azithromycin was isolated from a human case of watery diarrhea in a Chinese public hospital. Resistance in strain 2246 to ceftriaxone and azithromycin was attributable to the presence of blaCTX-M 14, and erm(B) and mph(A), respectively, which were co-located on a multidrug resistant (MDR) plasmid p2246-CTXM. p2246-CTXM represented a novel IncFII-type MDR plasmid with a very complex chimera structure. Its master backbone was genetically closely related to the R100 plasmid, but p2246-CTXM had evolved to integrate additional R100-unrelated backbone regions as well as massive exogenous mobile elements that carried multiple resistance determinants. In p2246-CTXM, erm(B) together with its leading peptide gene erm(C), mph(A) together with its regulatory genes mrx and mphR(A), and blaCTX-M-14 were captured by three different mobile elements Tn6295, the IS26-mph(A)-mrx-mphR(A)-IS6100 unit, and a truncated ISEcp1-blaCTX-M-14-IS903D-iroN transposition unit, respectively, all of which were harbored in a large Tn3-family transposon Tn6285. p2246-CTXM still carried additional resistance determinants mer (mercury resistance), aacA4 (aminoglycoside resistance), cmlA1 (chloramphenicol resistance), and qacED1 (quaternary ammonium compound resistance). This is the first report of identifying a clinical S. boydii strain simultaneously resistant to ciprofloxacin, ceftriaxone, and azithromycin, and determining the complete sequence of a resistance plasmid from S. boydii. PMID- 27766095 TI - Co-diversification of Enterococcus faecium Core Genomes and PBP5: Evidences of pbp5 Horizontal Transfer. AB - Ampicillin resistance has greatly contributed to the recent dramatic increase of a cluster of human adapted Enterococcus faecium lineages (ST17, ST18, and ST78) in hospital-based infections. Changes in the chromosomal pbp5 gene have been associated with different levels of ampicillin susceptibility, leading to protein variants (designated as PBP5 C-types to keep the nomenclature used in previous works) with diverse degrees of reduction in penicillin affinity. Our goal was to use a comparative genomics approach to evaluate the relationship between the diversity of PBP5 among E. faecium isolates of different phylogenomic groups as well as to assess the pbp5 transferability among isolates of disparate clonal lineages. The analyses of 78 selected E. faecium strains as well as published E. faecium genomes, suggested that the diversity of pbp5 mirrors the phylogenomic diversification of E. faecium. The presence of identical PBP5 C-types as well as similar pbp5 genetic environments in different E. faecium lineages and clones from quite different geographical and environmental origin was also documented and would indicate their horizontal gene transfer among E. faecium populations. This was supported by experimental assays showing transfer of large (~180-280 kb) chromosomal genetic platforms containing pbp5 alleles, ponA (transglycosilase) and other metabolic and adaptive features, from E. faecium donor isolates to suitable E. faecium recipient strains. Mutation profile analysis of PBP5 from available genomes and strains from this study suggests that the spread of PBP5 C types might have occurred even in the absence of a significant ampicillin resistance phenotype. In summary, genetic platforms containing pbp5 sequences were stably maintained in particular E. faecium lineages, but were also able to be transferred among E. faecium clones of different origins, emphasizing the growing risk of further spread of ampicillin resistance in this nosocomial pathogen. PMID- 27766096 TI - Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins. AB - The monospecific and bivalent characteristics of naturally occurring immunoglobulin G (IgG) antibodies depend on homodimerization of the fragment crystallizable (Fc) regions of two identical heavy chains (HCs) and the subsequent assembly of two identical light chains (LCs) via disulfide linkages between each HC and LC. Immunoglobulin Fc heterodimers have been engineered through modifications to the CH3 domain interface, with different mutations on each domain such that the engineered Fc fragments, carrying the CH3 variant pair, preferentially form heterodimers rather than homodimers. Many research groups have adopted different strategies to generate Fc heterodimers, with the goal of high heterodimerization yield, while retaining biophysical and biological properties of the wild-type Fc. Based on their ability to enforce heterodimerization between the two different HCs, the established Fc heterodimers have been extensively exploited as a scaffold to generate bispecific antibodies (bsAbs) in full-length IgG and IgG-like formats. These have many of the favorable properties of natural IgG antibodies, such as high stability, long serum half life, low immunogenicity, and immune effector functions. As of July 2016, more than seven heterodimeric Fc-based IgG-format bsAbs are being evaluated in clinical trials. In addition to bsAbs, heterodimeric Fc technology is very promising for the generation of Fc-fused proteins and peptides, as well as cytokines (immunocytokines), which can present the fusion partners in the natural monomeric or heterodimeric form rather than the artificial homodimeric form with wild-type Fc. Here, we present relevant concepts and strategies for the generation of heterodimeric Fc proteins, and their application in the development of bsAbs in diverse formats for optimal biological activity. In addition, we describe wild-type Fc-fused monomeric and heterodimeric proteins, along with the difficulties associated with their preparations, and discuss the use of heterodimeric Fc as an alternative scaffold of wild-type Fc for naturally monomeric or heterodimeric proteins, to create Fc-fusion proteins with novel therapeutic modality. PMID- 27766098 TI - IL-9 Inhibits Viral Replication in Coxsackievirus B3-Induced Myocarditis. AB - Myocardial injuries in viral myocarditis (VMC) are caused by viral infection and related autoimmune disorders. Recent studies suggest that IL-9 mediated both antimicrobial immune and autoimmune responses in addition to allergic diseases. However, the role of IL-9 in viral infection and VMC remains controversial and uncertain. In this study, we infected Balb/c mice with Coxsackievirus B3 (CVB3), and found that IL-9 was enriched in the blood and hearts of VMC mice on days 5 and 7 after virus infection. Most of IL-9 was secreted by CD8+ T cells on day 5 and CD4+ T cells on day 7 in the myocardium. Further, IL-9 knockout exacerbated cardiac damage following CVB3 infection, along with a sharp increase in viral replication and IL-17a expression, as well as a decrease in TGF-beta. In contrast, the repletion of IL-9 in Balb/c mice with CVB infection induced the opposite effect. Studies in vitro further revealed that IL-9 directly inhibited viral replication in cardiomyocytes by reducing coxsackie and adenovirus receptor expression, which might be associated with upregulation of TGF-beta autocrine effect in these cells. However, IL-9 had no direct effect on apoptosis in cardiomyocytes. Our data indicated that IL-9 played a protective role in disease progression by inhibiting CVB3 replication in the early stages of VMC. PMID- 27766100 TI - Editorial: Mechanical Signaling in Plants: From Perception to Consequences for Growth and Morphogenesis (Thigmomorphogenesis) and Ecological Significance. PMID- 27766097 TI - Dysregulation of Chemokine/Chemokine Receptor Axes and NK Cell Tissue Localization during Diseases. AB - Chemokines are small chemotactic molecules that play key roles in physiological and pathological conditions. Upon signaling via their specific receptors, chemokines regulate tissue mobilization and trafficking of a wide array of immune cells, including natural killer (NK) cells. Current research is focused on analyzing changes in chemokine/chemokine receptor expression during various diseases to interfere with pathological trafficking of cells or to recruit selected cell types to specific tissues. NK cells are a heterogeneous lymphocyte population comprising several subsets endowed with distinct functional properties and mainly representing distinct stages of a linear development process. Because of their different functional potential, the type of subset that accumulates in a tissue drives the final outcome of NK cell-regulated immune response, leading to either protection or pathology. Correspondingly, chemokine receptors, including CXCR4, CXCR3, and CX3CR1, are differentially expressed by NK cell subsets, and their expression levels can be modulated during NK cell activation. At first, this review will summarize the current knowledge on the contribution of chemokines to the localization and generation of NK cell subsets in homeostasis. How an inappropriate chemotactic response can lead to pathology and how chemokine targeting can therapeutically affect tissue recruitment/localization of distinct NK cell subsets will also be discussed. PMID- 27766099 TI - NFAT2 Regulates Generation of Innate-Like CD8+ T Lymphocytes and CD8+ T Lymphocytes Responses. AB - Nuclear factor of activated T cells (NFAT) 2 null mutant mice die in utero of cardiac failure, precluding analysis of the role of NFAT2 in lymphocyte responses. Only the NFAT2-/-/Rag-1-/- chimeric mice model gave insight into the role of NFAT2 transcription factor in T lymphocyte development, activation, and differentiation. As reports are mainly focused on the role of NFAT2 in CD4+ T lymphocytes activation and differentiation, we decided to investigate NFAT2's impact on CD8+ T lymphocyte responses. We report that NFAT2 is phosphorylated and inactive in the cytoplasm of naive CD8+ T cells, and upon TCR stimulation, it is dephosphorylated and translocated into the nucleus. To study the role of NFAT2 in CD8+ T responses, we employed NFAT2fl/flCD4-Cre mice with NFAT2 deletion specifically in T cells. Interestingly, the absence of NFAT2 in T cells resulted in increased percentage of non-conventional innate-like CD8+ T cells. These cells were CD122+, rapid producer of interferon gamma (IFN-gamma) and had characteristics of conventional memory CD8+ T cells. We also observed an expansion of PLZF+ expressing CD3+ thymocyte population in the absence of NFAT2 and increased IL-4 production. Furthermore, we found that CD8+ T lymphocytes deficient in NFAT2 had reduced activation, proliferation, and IFN-gamma and IL-2 production at suboptimal TCR strength. NFAT2 absence did not significantly influence differentiation of CD8+ T cells into cytotoxic effector cells but reduced their IFN-gamma production. This work documents NFAT2 as a negative regulator of innate-like CD8+ T cells development. NFAT2 is required for complete CD8+ T cell responses at suboptimal TCR stimulation and regulates IFN-gamma production by cytotoxic CD8+ T cells in vitro. PMID- 27766101 TI - Altered Precipitation Impacts on Above- and Below-Ground Grassland Invertebrates: Summer Drought Leads to Outbreaks in Spring. AB - Climate change is predicted to result in altered precipitation patterns, which may reshape many grassland ecosystems. Rainfall is expected to change in a number of different ways, ranging from periods of prolonged drought to extreme precipitation events, yet there are few community wide studies to accurately simulate future changes. We aimed to test how above- and below-ground grassland invertebrate populations were affected by contrasting future rainfall scenarios. We subjected a grassland community to potential future rainfall scenarios including ambient, increased amount (+50% of ambient), reduced amount (-50% of ambient), reduced frequency (no water for 21 days, followed by the total ambient rainfall applied in a single application) and summer drought (no rainfall for 13 weeks during the growing season). During Austral spring (September 2015), we sampled aboveground invertebrates, belowground macro invertebrates and nematodes. Aboveground communities showed a significant response to altered rainfall regime with the greatest effects observed in summer drought plots. This was mostly due to a large increase in sucking herbivores (658% higher than ambient plots). Plots experiencing summer droughts also had higher populations of parasitoids, chewing herbivores and detritivores. These plots had 92% more plant biomass suggesting that primary productivity increased rapidly following the end of the summer drought 5 months earlier. We interpret these results as supporting the plant vigor hypothesis (i.e., that rapid plant growth is beneficial to aboveground invertebrates). While belowground invertebrates were less responsive to altered precipitation, we observed a number of correlations between the abundances of above- and below-ground invertebrate groups under ambient rainfall that dissipated under altered rainfall regimes. Mechanisms underpinning these associations, and reasons for them to become decoupled under altered precipitation regimes (we term this 'climatic decoupling'), remain speculative, but they provide the basis for formulating hypotheses and future work. In conclusion, we predict that shifts in rainfall patterns, especially summer drought, will likely have large, but probably short-term, impacts on grassland invertebrate communities. In particular, sucking herbivores show sensitivity to precipitation changes, which have the potential to cascade through the food chain and affect higher trophic levels. PMID- 27766102 TI - A Catalog of Regulatory Sequences for Trait Gene for the Genome Editing of Wheat. AB - Wheat has been cultivated for 10000 years and ever since the origin of hexaploid wheat it has been exempt from natural selection. Instead, it was under the constant selective pressure of human agriculture from harvest to sowing during every year, producing a vast array of varieties. Wheat has been adopted globally, accumulating variation for genes involved in yield traits, environmental adaptation and resistance. However, one small but important part of the wheat genome has hardly changed: the regulatory regions of both the x- and y-type high molecular weight glutenin subunit (HMW-GS) genes, which are alone responsible for approximately 12% of the grain protein content. The phylogeny of the HMW-GS regulatory regions of the Triticeae demonstrates that a genetic bottleneck may have led to its decreased diversity during domestication and the subsequent cultivation. It has also highlighted the fact that the wild relatives of wheat may offer an unexploited genetic resource for the regulatory region of these genes. Significant research efforts have been made in the public sector and by international agencies, using wild crosses to exploit the available genetic variation, and as a result synthetic hexaploids are now being utilized by a number of breeding companies. However, a newly emerging tool of genome editing provides significantly improved efficiency in exploiting the natural variation in HMW-GS genes and incorporating this into elite cultivars and breeding lines. Recent advancement in the understanding of the regulation of these genes underlines the needs for an overview of the regulatory elements for genome editing purposes. PMID- 27766103 TI - Development of Prediction Model and Experimental Validation in Predicting the Curcumin Content of Turmeric (Curcuma longa L.). AB - The drug yielding potential of turmeric (Curcuma longa L.) is largely due to the presence of phyto-constituent 'curcumin.' Curcumin has been found to possess a myriad of therapeutic activities ranging from anti-inflammatory to neuroprotective. Lack of requisite high curcumin containing genotypes and variation in the curcumin content of turmeric at different agro climatic regions are the major stumbling blocks in commercial production of turmeric. Curcumin content of turmeric is greatly influenced by environmental factors. Hence, a prediction model based on artificial neural network (ANN) was developed to map genome environment interaction basing on curcumin content, soli and climatic factors from different agroclimatic regions for prediction of maximum curcumin content at various sites to facilitate the selection of suitable region for commercial cultivation of turmeric. The ANN model was developed and tested using a data set of 119 generated by collecting samples from 8 different agroclimatic regions of Odisha. The curcumin content from these samples was measured that varied from 7.2% to 0.4%. The ANN model was trained with 11 parameters of soil and climatic factors as input and curcumin content as output. The results showed that feed-forward ANN model with 8 nodes (MLFN-8) was the most suitable one with R2 value of 0.91. Sensitivity analysis revealed that minimum relative humidity, altitude, soil nitrogen content and soil pH had greater effect on curcumin content. This ANN model has shown proven efficiency for predicting and optimizing the curcumin content at a specific site. PMID- 27766105 TI - Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial. AB - Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. PMID- 27766106 TI - The Effect of Different Cleaning Protocols on Post Space: A SEM Study. AB - Aim. Purpose of the present paper is to analyze the efficiency of different post space irrigation protocols. Methods. 28 single rooted teeth were endodontically treated. After post-space preparation every sample was assigned to one of three experimental groups and to one control group. In each group different irrigation protocols were performed as follows: EDTA (Group A), 37% orthophosphoric acid (Group B), and EDTA + 37% orthophosphoric acid with ultrasounds activation (Group C). In the control group (Group D) the irrigate association was not activated by ultrasounds. Three zones (coronal, middle, and apical) of each sample were analyzed by using Scan Electron Microscopy (SEM) without any metallization procedures. The presence of smear layer on the canal surface was qualitatively evaluated by applying Serafino's score with values included between 0 and 2. Results. The results of the research showed how Group C recorded the better results (0.81 +/- 0.72). Group A and Group B showed lower mean scores (1.06 +/- 0.69 and 1.08 +/- 0.77); Group D showed the lowest mean score of 1.30 +/- 0.69. The SEM observation analysis demonstrated how the smear layer presence decreased in the crown-apical direction. Conclusions. The different post-space treatments statistically determine significant differences on the dentinal surfaces cleansing. The absence of ultrasonic activation lowers the cleansing efficacy of endocanalar irrigants, showing sensible differences among each post-space zone. PMID- 27766107 TI - Case report: recurrent abdominal symptoms in a child with panhypopituitarism - there is always a differential. AB - BACKGROUND: We report the case of a 6 year old boy suffering from adenohypophysis aplasia as well as ectopic neurohypophysis and delayed diagnosis of familial Mediterranean fever (FMF). CASE PRESENTATION: The boy was diagnosed with panhypopituitarism during the neonatal period and suffered from recurrent episodes during the following years suggesting infections. He also showed signs of adrenal insufficiency. Finally, at the age of 6 years, an additional diagnosis of familial Mediterranean fever (FMF) was clinically suspected and later confirmed by molecular analysis. CONCLUSION: The clinical pictures of panhypopituitarism and FMF can be overlapping. It is imperative to take a detailed and accurate history in order to find the right diagnosis, particularly a precise family history. In conditions like FMF an early diagnosis is crucial, as initiation of treatment with colchicine is important to prevent long-term complications due to amyloid fibril deposition. PMID- 27766108 TI - Co-exposure to zymosan A and heat-inactivated Asian sand dust exacerbates ovalbumin-induced murine lung eosinophilia. AB - BACKGROUND: Epidemiological studies have implicated Asian sand dust (ASD) in the increased prevalence of respiratory disorders, including asthma. It has been observed that fungal elements such as beta-glucan can be adsorbed onto ASD. In the present study, the exacerbating effect of the combined exposure to zymosan A (ZymA) containing yeast beta-glucan and heat-inactivated ASD on ovalbumin (OVA) induced murine lung eosinophilia was investigated. METHODS: BALB/c mice were repeatedly instilled intratracheally with one of eight immunogenic formulations consisting of various combinations of (1) ZymA, (2) ASD that was briefly heated to remove organic substances (H-ASD), and (3) OVA in normal saline, or each of the above alone. Pathologic changes, cytological alterations in bronchoalveolar lavage fluid (BALF), changes in inflammatory cytokines and chemokines in BALF, and OVA-specific IgE and IgG1 antibodies in serum were investigated. RESULTS: Exposure to ZymA with or without OVA had no effect on most indicators of lung inflammation. Exposure to H-ASD with OVA increased the recruitment of inflammatory cells to the lungs and the serum levels of OVA-specific IgE and IgG1. The combination OVA + ZymA + H-ASD induced a marked recruitment of eosinophils and upregulation of T helper 2 (Th2) cytokines (interleukin [IL]-4 and IL-13), IL-6, eotaxin/CCL11, and monocyte chemotactic protein (MCP)-3/CCL7 in BALF and OVA-specific IgE in serum. This treatment also induced the most severe pathological changes in the lungs of mice. ZymA was found to boost the effects of H-ASD, thereby exacerbating the OVA-induced allergic inflammation, even though ZymA alone did not have such effect. CONCLUSIONS: The results suggest that fungal elements such as beta-1,3-glucan aggravate the allergic inflammation caused by ASD. Our findings may facilitate prophylaxis of some allergic diseases in Asia. PMID- 27766104 TI - Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications. AB - This review focuses on the contribution of white, brown, and perivascular adipose tissues to the pathophysiology of obesity and its associated metabolic and vascular complications. Weight gain in obesity generates excess of fat, usually visceral fat, and activates the inflammatory response in the adipocytes and then in other tissues such as liver. Therefore, low systemic inflammation responsible for insulin resistance contributes to atherosclerotic process. Furthermore, an inverse relationship between body mass index and brown adipose tissue activity has been described. For these reasons, in recent years, in order to combat obesity and its related complications, as a complement to conventional treatments, a new insight is focusing on the role of the thermogenic function of brown and perivascular adipose tissues as a promising therapy in humans. These lines of knowledge are focused on the design of new drugs, or other approaches, in order to increase the mass and/or activity of brown adipose tissue or the browning process of beige cells from white adipose tissue. These new treatments may contribute not only to reduce obesity but also to prevent highly prevalent complications such as type 2 diabetes and other vascular alterations, such as hypertension or atherosclerosis. PMID- 27766109 TI - Adrenal suppression in children treated with swallowed fluticasone and oral viscous budesonide for eosinophilic esophagitis. AB - BACKGROUND: Adrenal suppression (AS), a glucocorticoid (GC) side effect associated with significant morbidity, is well described related to inhaled corticosteroid therapy for asthma. Swallowed topical glucocorticoid therapy is the main pharmacotherapy treatment for eosinophilic esophagitis (EoE) and therefore children with EoE are potentially at increased risk of AS. METHODS: In this prospective cohort study, we included children and youth <18 years diagnosed with EoE and treated with swallowed fluticasone or oral viscous budesonide for more than 1 month. First morning cortisol and low dose adrenocorticotropic hormone stimulation test (LDST) were performed 2 weeks following GC discontinuation. AS was defined as an abnormal LDST result (cortisol peak <500 nmol/L). We determined the prevalence and duration of AS related to swallowed topical GC therapy in EoE by LDST, as well as the diagnostic accuracy of first morning cortisol compared to LDST. RESULTS: Of 29 participants enrolled, 26 (89.7 %) received oral viscous budesonide and 3 (10.3 %) received swallowed fluticasone. Nineteen (65.5 %) participants had AS. Median duration of AS was 43 weeks. Five (17.2 %) participants had persistent AS at 12 months. There were no identifiable risk factors for the development of AS. First morning cortisol was highly specific but had poor sensitivity for detection of AS. CONCLUSIONS: The majority of children with EoE had AS after discontinuation of swallowed topical GC therapy. Stress steroids should be considered in children treated with swallowed topical GC therapy for EoE, even after GC discontinuation, to prevent possible adrenal crisis. PMID- 27766111 TI - Plumage quality mediates a life-history trade-off in a migratory bird. AB - BACKGROUND: Moult is one of the most costly activities in the annual cycle of birds and most avian species separate moult from other energy-demanding activities, such as migration. To this end, young birds tend to undergo the first post-juvenile moult before the onset of migration, but in some species the time window for the pre-migratory feather replacement is too narrow. We hypothesized that in such species an increased investment in the structural quality of juvenile feathers may allow to retain juvenile plumage throughout the entire migratory period and delay moult until arriving at wintering grounds, thus avoiding a moult-migration overlap. METHODS: The effect of juvenile plumage quality on the occurrence of moult-migration overlap was studied in a migratory shorebird, the common snipe Gallinago gallinago. Ca. 400 of first-year common snipe were captured during their final stage of autumn migration through Central Europe. The quality of juvenile feathers was assessed as the mass-length residuals of retained juvenile rectrices. Condition of migrating birds was assessed with the mass of accumulated fat reserves and whole-blood hemoglobin concentration. Path analysis was used to disentangle complex interrelationships between plumage quality, moult and body condition. RESULTS: Snipe which grew higher-quality feathers in the pre-fledging period were less likely to initiate moult during migration. Individuals moulting during migration had lower fat loads and hemoglobin concentrations compared to non-moulting birds, suggesting a trade off in resource allocation, where energetic costs of moult reduced both energy reserves available for migration and resources available for maintenance of high oxygen capacity of blood. CONCLUSIONS: The results of this study indicate that a major life-history trade-off in a migratory bird may be mediated by the quality of juvenile plumage. This is consistent with a silver spoon effect, where early life investment in feather quality affects future performance of birds during migration period. Our results strongly suggest that the juvenile plumage, although retained for a relatively short period of time, may have profound consequences for individuals' fitness. PMID- 27766110 TI - Odonata (dragonflies and damselflies) as a bridge between ecology and evolutionary genomics. AB - Odonata (dragonflies and damselflies) present an unparalleled insect model to integrate evolutionary genomics with ecology for the study of insect evolution. Key features of Odonata include their ancient phylogenetic position, extensive phenotypic and ecological diversity, several unique evolutionary innovations, ease of study in the wild and usefulness as bioindicators for freshwater ecosystems worldwide. In this review, we synthesize studies on the evolution, ecology and physiology of odonates, highlighting those areas where the integration of ecology with genomics would yield significant insights into the evolutionary processes that would not be gained easily by working on other animal groups. We argue that the unique features of this group combined with their complex life cycle, flight behaviour, diversity in ecological niches and their sensitivity to anthropogenic change make odonates a promising and fruitful taxon for genomics focused research. Future areas of research that deserve increased attention are also briefly outlined. PMID- 27766112 TI - WSES classification and guidelines for liver trauma. AB - The severity of liver injuries has been universally classified according to the American Association for the Surgery of Trauma (AAST) grading scale. In determining the optimal treatment strategy, however, the haemodynamic status and associated injuries should be considered. Thus the management of liver trauma is ultimately based on the anatomy of the injury and the physiology of the patient. This paper presents the World Society of Emergency Surgery (WSES) classification of liver trauma and the management Guidelines. PMID- 27766113 TI - Triple diagnostics for early detection of ambivalent necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis is an uncommon, rapidly progressive and potential lethal condition. Over the last decade time to surgery decreased and outcome improved, most likely due to increased awareness and more timely referral. Early recognition is key to improve mortality and morbidity. However, early referral frequently makes it a challenge to recognize this heterogeneous disease in its initial stages. Signs and symptoms might be misleading or absent, while the most prominent skin marks might be in discrepancy with the position of the fascial necrosis. Gram staining and especially fresh frozen section histology might be a useful adjunct. METHODS: Retrospective analysis of 3 year period. Non transferred patients who presented with suspected necrotizing fasciitis are included. ASA classification was determined. Mortality was documented. RESULTS: In total, 21 patients are included. Most patients suffered from severe comorbidities. In 11 patients, diagnoses was confirmed based on intra-operative macroscopic findings. Histology and/or microbiotic findings resulted in 6/10 remaining patients in a change in treatment strategy. In total, 17 patients proved to suffer necrotizing fasciitis. In the cohort series 2 patients died due to necrotizing fasciitis. CONCLUSION: In the early phases of necrotizing fasciitis, clinical presentation can be ambivalent. In the present cohort, triple diagnostics consisting of an incisional biopsy with macroscopic, histologic and microbiotic findings was helpful in timely identification of necrotizing fasciitis. PMID- 27766114 TI - Poly-victimisation and health risk behaviours, symptoms of mental health problems and suicidal thoughts and plans among adolescents in Vietnam. AB - BACKGROUND: Limited evidence is available about poly-victimisation (exposure to multiple forms of victimisation) and mental health among adolescents in low and lower-middle-income countries. The aim of this study was to examine the associations between lifetime exposure to poly-victimisation, health risk behaviours, symptoms of common mental health problems and suicidal ideas in the previous year among high school students in Vietnam. METHODS: Participants were high school students in rural and urban districts of Hanoi, Vietnam. The data source was an anonymously-completed structured self-report survey. Lifetime exposure to poly-victimisation was assessed using the juvenile victimisation questionnaire revised 2 (JVQ R-2); mental health symptoms by the depression, anxiety and stress scale-21 (DASS-21); involvement in health risk behaviours and previous year suicidal thoughts and plans by questions adapted from the 2013 youth risk behaviour survey. Data were collected between October, 2013 and January, 2014 and were analysed using generalised structural equation modelling. RESULTS: In total 1616/1745 (92.6 %) eligible students provided complete data. Prior year suicidal thoughts were reported by 21.4 % (95 % CI 18.5-24.5 %) of the female respondents and 7.9 % (95 % CI 6.2-9.8 %) of the male respondents. Prior year suicidal plans were reported by 7.8 % (95 % CI 5.9-9.8 %) of the girls and 4.0 % (95 % CI 2.7-5.3 %) of the boys. Poly-victimisation was associated with increased likelihood of involvement in health risk behaviours and symptoms of common mental health problems among both sexes, which increased adolescents' risk of having suicidal ideas in the previous year. Compared to non-victims or victims of fewer forms, poly-victims were also more likely to report suicidal thoughts and plans among both girls and boys (p < 0.05). CONCLUSIONS: Overall, the results revealed that poly-victimisation was associated with increased involvement in health risk behaviours, poorer mental health and increased risks of suicidal ideas among Vietnamese adolescents. Suicidal ideas were prevalent among the students. Interventions to assist victims of violence and prevention of violence, especially poly-victimisation, among adolescents in Vietnam is therefore important. PMID- 27766115 TI - STRESS-testing clinical activity and outcomes for a combined prison in-reach and court liaison service: a 3-year observational study of 6177 consecutive male remands. AB - BACKGROUND: People with major mental illness are over-represented in prison populations however there are few longitudinal studies of prison in-reach services leading to appropriate healthcare over extended periods. AIMS: We aimed to examine measures of the clinical efficiency and effectiveness of a prison in reach, court diversion and liaison service over a 3 year period. Secondly, we aimed to compare rates of identification of psychosis and diversion with rates previously reported for the same setting in the 6 years previously. We adopted a stress testing model for service evaluation. METHOD: All new male remand committals to Ireland's main remand prison from 2012 to 2014 were screened in two stages. Demographic and clinical variables were recorded along with times to assessment and diversion. The DUNDRUM Toolkit was used to assess level of clinical urgency and level of security required. Binary logistic regression was used to assess factors relevant to diversion. RESULTS: All 6177 consecutive remands were screened of whom 1109 remand episodes (917 individuals) received a psychiatric assessment. 4.1 % (95 % CI 3.6-4.6) had active psychotic symptoms. Levels of self-harm were low. Median time to full assessment was 2 days and median time to admission was 15.0 days for local hospitals and 19.5 days for forensic admissions. Diversion to healthcare settings outside prison was achieved for 5.6 % (349/6177, 95 % CI 5.1-6.3) of all remand episodes and admissions for 2.3 % (95 % CI 1.9-2.7). Both were increased on the previous period reported. Mean DUNDRUM-1 and DUNDRUM-2 Triage Security Scores were appropriate to risk and need. CONCLUSIONS: We found that a two-stage screening and referral process followed by comprehensive assessment optimised identification of acute psychosis. The mapping approach described shows that it is possible for a relatively small team to sustainably achieve effective identification of major mental illness and diversion to healthcare in a risk-appropriate manner. The stress-testing structure adopted aids service evaluation and may help advise development of outcome standards for similar services. PMID- 27766117 TI - Assessing pretreatment reactor scaling through empirical analysis. AB - BACKGROUND: Pretreatment is a critical step in the biochemical conversion of lignocellulosic biomass to fuels and chemicals. Due to the complexity of the physicochemical transformations involved, predictively scaling up technology from bench- to pilot-scale is difficult. This study examines how pretreatment effectiveness under nominally similar reaction conditions is influenced by pretreatment reactor design and scale using four different pretreatment reaction systems ranging from a 3 g batch reactor to a 10 dry-ton/days continuous reactor. The reactor systems examined were an automated solvent extractor (ASE), steam explosion reactor (SER), ZipperClave(r)Reactor (ZCR), and large continuous horizontal screw reactor (LHR). To our knowledge, this is the first such study performed on pretreatment reactors across a range of reaction conditions and at different reactor scales. RESULTS: The comparative pretreatment performance results obtained for each reactor system were used to develop response surface models for total xylose yield after pretreatment and total sugar yield after pretreatment followed by enzymatic hydrolysis. Near- and very-near-optimal regions were defined as the set of conditions that the model identified as producing yields within one and two standard deviations of the optimum yield. Optimal conditions identified in the smallest scale system (the ASE) were within the near-optimal region of the largest scale reactor system evaluated. The maximum total sugar yields for the ASE and LHR were [Formula: see text], while [Formula: see text] was the optimum observed in the ZipperClave. CONCLUSIONS: The optimum condition identified using the automated and less costly to operate ASE system was within the very-near-optimal space for the total xylose yield of both the ZCR and the LHR, and was within the near-optimal space for total sugar yield for the LHR. This indicates that the ASE is a good tool for cost effectively finding near-optimal conditions for operating pilot-scale systems. Additionally, using a severity factor approach to optimization was found to be inadequate compared to a multivariate optimization method. Finally, the ASE and the LHR were able to enable significantly higher total sugar yields after enzymatic hydrolysis relative to the ZCR, despite having similar optimal conditions and total xylose yields. This underscores the importance of mechanical disruption during pretreatment to improvement of enzymatic digestibility. PMID- 27766116 TI - Examining Escherichia coli glycolytic pathways, catabolite repression, and metabolite channeling using Deltapfk mutants. AB - BACKGROUND: Glycolysis breakdowns glucose into essential building blocks and ATP/NAD(P)H for the cell, occupying a central role in its growth and bio production. Among glycolytic pathways, the Entner Doudoroff pathway (EDP) is a more thermodynamically favorable pathway with fewer enzymatic steps than either the Embden-Meyerhof-Parnas pathway (EMPP) or the oxidative pentose phosphate pathway (OPPP). However, Escherichia coli do not use their native EDP for glucose metabolism. RESULTS: Overexpression of edd and eda in E. coli to enhance EDP activity resulted in only a small shift in the flux directed through the EDP (~20 % of glycolysis flux). Disrupting the EMPP by phosphofructokinase I (pfkA) knockout increased flux through OPPP (~60 % of glycolysis flux) and the native EDP (~14 % of glycolysis flux), while overexpressing edd and eda in this DeltapfkA mutant directed ~70 % of glycolytic flux through the EDP. The downregulation of EMPP via the pfkA deletion significantly decreased the growth rate, while EDP overexpression in the DeltapfkA mutant failed to improve its growth rates due to metabolic burden. However, the reorganization of E. coli glycolytic strategies did reduce glucose catabolite repression. The DeltapfkA mutant in glucose medium was able to cometabolize acetate via the citric acid cycle and gluconeogenesis, while EDP overexpression in the DeltapfkA mutant repressed acetate flux toward gluconeogenesis. Moreover, 13C-pulse experiments in the DeltapfkA mutants showed unsequential labeling dynamics in glycolysis intermediates, possibly suggesting metabolite channeling (metabolites in glycolysis are pass from enzyme to enzyme without fully equilibrating within the cytosol medium). CONCLUSIONS: We engineered E. coli to redistribute its native glycolytic flux. The replacement of EMPP by EDP did not improve E. coli glucose utilization or biomass growth, but alleviated catabolite repression. More importantly, our results supported the hypothesis of channeling in the glycolytic pathways, a potentially overlooked mechanism for regulating glucose catabolism and coutilization of other substrates. The presence of channeling in native pathways, if proven true, would affect synthetic biology applications and metabolic modeling. PMID- 27766118 TI - Interstitial de novo 18q22.3q23 deletion: clinical, neuroradiological and molecular characterization of a new case and review of the literature. AB - BACKGROUND: Deletions of the long arm of chromosome 18 cause a common autosomal syndrome clinically characterized by a protean clinical phenotype. CASE PRESENTATION: We report on a 16-month-old male infant affected by fever attacks apparently unrelated with any infectious or inflammatory symptoms, growth retardation, bilateral vertical talus, congenital aural atresia, dysmorphisms, mild psychomotor delay, and peculiar neuroradiological features. Array-CGH analysis revealed one of the smallest 18q22.3q23 interstitial deletions involving five genes: TSHZ1, ZNF516, ZNF236, MBP, and GALR1. CONCLUSIONS: Herein we focus on previously unreported heralding symptoms and neuroradiological abnormalities which enlarge the spectrum of 18q deletion syndrome demonstrating that a small deletion can determine a complex phenotype. PMID- 27766119 TI - Study of Optimal Replacement of Thyroxine in the Elderly (SORTED) - results from the feasibility randomised controlled trial. AB - BACKGROUND: Hypothyroidism is a common condition, particularly in the older population. Thyroid hormone requirements change with age and serum TSH levels also alter, especially in older patients. However, in practice laboratory reference ranges for thyroid function are not age-specific and treatment in older patients aims to achieve a similar target thyroid function level as younger age groups. METHODS: A dual centre, single blind, randomised controlled trial was conducted to determine the feasibility of a future definitive RCT in hypothyroid individuals aged 80 years or older who were treated with levothyroxine. Potential participants were identified from 17 research-active GP practices (n = 377), by opportunistic invitations (n = 9) or in response to publicity (n = 4). Participants were randomly allocated to either usual (0.4-4.0 mU/L) or a higher (4.1-8.0 mU/L) target serum TSH range. Information on participants' willingness to enter the trial, acceptability of study design, length of time to complete recruitment and dose titration strategy was collected. RESULTS: Fifteen percent (57/390) of potentially eligible hypothyroid individuals consented to participate in this trial and 48 were randomised to trial medication for 24 weeks, giving a recruitment rate of 12 %. Recruitment averaged 5.5 participants per month over approximately 9 months. Eight participants withdrew (3/24 and 5/24 in the usual and higher TSH arms, respectively) with the commonest reason cited (5 patients) being tiredness. Interestingly, 3/5 participants withdrew from the site that required a visit to a Research Facility whereas only 5/43 participants withdrew from the site that offered home visits. In the higher TSH arm, of those participants who completed the study, approximately half of participants (10/19) reached target TSH. CONCLUSIONS: It is feasible to perform a randomised controlled trial of thyroid hormones in hypothyroid patients aged 80 or older. A definitive trial would require collaboration with a large number of General Practices and the provision of home visits to achieve recruitment to time and target. Power calculations should take into account that approximately 12 % of those approached will be randomised and 1 in 6 participants are likely to withdraw from the study. Finally, several dose adjustments may be required to achieve target serum TSH levels in this age group. TRIAL REGISTRATION: ISRCTN Number: 16043724 Registered 22 June 2012 Clinicaltrial.gov Number: NCT01647750 EudraCT Number: 2011-004425-27. PMID- 27766120 TI - New developments in the pathology of malignant lymphoma: a review of the literature published from June-August 2016. PMID- 27766121 TI - Transformation of CLL to ALCL: the role of clonality studies in diagnostic molecular haematopathology. AB - Clonality studies greatly assist in the diagnosis of challenging haematopathology cases. These robust and standardised tests aid the detection of clonal lymphoid populations and may assist in lymphocyte subtyping. In this case report, a gentleman presented with a high-grade transformation of a B cell neoplasm which histologically and immunophenotypically mimicked a T cell anaplastic large-cell lymphoma. With the aid of T cell and B cell receptor clonality studies, it was demonstrated that this tumour was in fact of B cell lineage. This report exemplifies the role of these increasingly used and relatively new molecular tests in unusual and difficult lymphoma presentations and highlights potential pitfalls in the interpretation of their results. PMID- 27766123 TI - Measuring Campaign Message Exposure and Public Communication Environment Exposure: Some Implications of the Distinction in the Context of Social Media. PMID- 27766122 TI - Preclinical Evaluation of Tolerability of a Selective, Bacteriostatic, Locally Active Vaginal Formulation. AB - BACKGROUND: Polybactum (Effik International, Brussels, Belgium) is a vaginal mucoadhesive product (medical device) designed to form a film that acts as a mechanical barrier with the aim of inhibiting colonization by specific pathogens. It contains polycarbophil, a bioadhesive agent, and lauryl glucoside (LG), a nonionic surfactant that reinforces the barrier effect through its tensioactive properties. OBJECTIVE: To assess the local safety profile, tolerability, and efficacy of Polybactum formulations. METHODS: The following studies were performed on 3 Polybactum formulations: 2 ovules (Type 1: LG 0.04% and Type 2: LG 0.1%) and 1 gel formulation. Bacteriologic tests assessing the effects on normal vaginal flora and pathogens; in vitro and in vivo tests designed to assess cytotoxicity, as well as irritant and sensitizing potentials; biocompatibility, barrier, residence time, and absorption tests using reconstituted human vaginal epithelium were performed. RESULTS: Polybactum is a selective bacteriostatic agent that is active against Streptococcus agalactiae and Gardnerella vaginalis while sparing normal vaginal flora; that is, Lactobacillus spp. It had no cytotoxic, irritant, and sensitizing effects nor did it impair barrier and fence functions of the vaginal epithelium. The Type 1 ovule showed film-forming properties in vitro. Finally, LG absorption through reconstituted human vaginal epithelium was negligible, ruling out the risk for possible systemic toxicity. CONCLUSIONS: This favorable preclinical profile is encouraging and supports clinical studies on Polybactum Type 1 ovules for the prevention and management of recurring bacterial vaginosis. PMID- 27766124 TI - A TWO-STATE MIXED HIDDEN MARKOV MODEL FOR RISKY TEENAGE DRIVING BEHAVIOR. AB - This paper proposes a joint model for longitudinal binary and count outcomes. We apply the model to a unique longitudinal study of teen driving where risky driving behavior and the occurrence of crashes or near crashes are measured prospectively over the first 18 months of licensure. Of scientific interest is relating the two processes and predicting crash and near crash outcomes. We propose a two-state mixed hidden Markov model whereby the hidden state characterizes the mean for the joint longitudinal crash/near crash outcomes and elevated g-force events which are a proxy for risky driving. Heterogeneity is introduced in both the conditional model for the count outcomes and the hidden process using a shared random effect. An estimation procedure is presented using the forward-backward algorithm along with adaptive Gaussian quadrature to perform numerical integration. The estimation procedure readily yields hidden state probabilities as well as providing for a broad class of predictors. PMID- 27766125 TI - Charge Carrier Dynamics and Mobility Determined by Time-Resolved Terahertz Spectroscopy on Films of Nano-to-Micrometer-Sized Colloidal Tin(II) Monosulfide. AB - Tin(II) monosulfide (SnS) is a semiconductor material with an intermediate band gap, high absorption coefficient in the visible range, and earth abundant, non toxic constituent elements. For these reasons, SnS has generated much interest for incorporation into optoelectronic devices, but little is known concerning the charge carrier dynamics, especially as measured by optical techniques. Here, as opposed to prior studies of vapor deposited films, phase-pure colloidal SnS was synthesized by solution chemistry in three size regimes, ranging from nanometer- to micron-scale (SnS small nanoparticles, SnS medium 2D nanosheets, and SnS large 2D MUm-sheets), and evaluated by time-resolved terahertz spectroscopy (TRTS); an optical, non-contact probe of the photoconductivity. Dropcast films of the SnS colloids were studied by TRTS and compared to both thermally annealed films and dispersed suspensions of the same colloids. TRTS results revealed that the micron scale SnS crystals and all of the annealed films undergo decay mechanisms during the first 200 ps following photoexcitation at 800 nm assigned to hot carrier cooling and carrier trapping. The charge carrier mobility of both the dropcast and annealed samples depends strongly on the size of the constituent colloids. The mobility of the SnS colloidal films, following the completion of the initial decays, ranged from 0.14 cm2/V.s for the smallest SnS crystals to 20.3 cm2/V.s for the largest. Annealing the colloidal films resulted in a ~ 20 % improvement in mobility for the large SnS 2D MUm-sheets and a ~ 5-fold increase for the small nanoparticles and medium nanosheets. PMID- 27766126 TI - Do Girls with Excess Adiposity Perform Poorer Motor Skills than Leaner Peers? AB - The main aim of this study was to analyze the joint association of body fat percentage and physical activity levels on motor coordination scores in girls with different adiposity status. Sixty-eight school-aged children between 12 and 14 years participated in the study. Skinfold thickness was measured and the Korperkoordinationstest fur Kinder test was administered. Participants completed a self-reporting questionnaire on physical activity. Children's adiposity status was attributed in according to age-specific cutoff points of a Brazilian database. Analysis of Variance was used to compare motor coordination scores among groups with different status of adiposity and physical activity. Girls with appropriate body fat percentage performed higher motor coordination scores than girls with excess adiposity, regardless of their physical activity levels (p < 0.05). Additionally, within groups with the same adiposity status, no differences were found in motor coordination scores (p > 0.05). Adiposity status was predominant over physical activity status when joint associations of body fat percentage and physical activity levels on motor coordination scores were analyzed in girls. In addition to metabolic and cardiovascular issues, the acquisition and/or maintenance of appropriate body fat levels in female students should be focused in physical education classes due to its association with motor skills performance. PMID- 27766128 TI - The Effect of Skinfold on the Assessment of the Mean Power Frequency at the Fatigue Threshold. AB - The purpose of this study was to determine if the amount of subcutaneous tissue over the quadriceps affects the assessment of mean power frequency at the fatigue threshold (MPFFT). It was hypothesized that greater skinfold values will result in lower power outputs associated to the MPFFT. Fourteen adults (Mean +/- SD age = 20.7 +/- 0.99; body weight = 72.8 +/- 12.6 kg) performed an incremental cycle ergometry test to exhaustion while surface electromyographic (EMG) signals were measured from the vastus lateralis. The skinfold thickness of each leg was taken prior to the test, and skinfold thicknesses were separated into a larger and a smaller groups. The independent t-test showed a significant difference (p = 0.01) between the power outputs associated to the MPFFT of groups with high (Mean +/- SD 130.4 +/- 34.5 W) versus low skinfold (212.5 +/- 61.2 W) values. The results suggested that higher subcutaneous fat may have affected the assessment of MPFFT during cycle ergometry. PMID- 27766127 TI - Effects of Static Stretching on Squat Performance in Division I Female Athletes. AB - Static stretching was once recognized as a method of preparation for physical activity that would inhibit performance and increase risk of injury. However, a growing body of research suggests that static stretching may not have an inhibitory effect. Regardless, the data have not examined gender differences or the fatigue index (FI) and flexibility effects of static stretching on the back squat over multiple sets. Therefore, the purpose of this study was to examine the relationship between a static-stretch condition (SC) and control condition (CC) on flexibility and the FI of Division I female athletes during 4 sets of the back squat. Eighteen subjects (mean +/- SD; age 20 +/- 1 yrs; height 164.5 +/- 14.6 cm; mass 74.1 +/- 26.8 kg; waist circumference 73.2 +/- 5.4 cm) participated in 3 testing days over the course of 3 weeks. Each subject's 1RM back squat was assessed during the first day of testing and verified during the second. On the third testing day, subjects assigned to the SC held 3 lower-body stretches twice for 30 second intervals and those assigned to the CC rested during the corresponding 7 minutes and 50 second time period. The subjects also performed a fatiguing squat protocol consisting of 4 sets of maximum repetitions on the third day of testing. A significant (p=0.04) interaction was noted for flexibility. No significant interaction (p=0.41) was observed between the FI of the CC (41.8 +/- 24.1%) or the SC (27.6 +/- 45.2%). These results indicate that static stretching does not have a significant effect on multiple sets of the back squat. Therefore, coaches may allow their athletes to engage in static stretching prior to resistance exercise ad libitum. PMID- 27766130 TI - Inter-Investigator Reliability of Anthropometric Prediction of 1RM Bench Press in College Football Players. AB - The purpose of this study was to determine the effect of inter-investigator differences in anthropometric assessments on the prediction of one-repetition maximum (1RM) bench press in college football players. Division-II players (n = 34, age = 20.4 +/- 1.2 y, 182.3 +/- 6.6 cm, 99.1 +/- 18.4 kg) were measured for selected anthropometric variables and 1RM bench press at the conclusion of a heavy resistance training program. Triceps, subscapular, and abdominal skinfolds were measured in triplicate by three investigators and used to estimate %fat. Arm circumference was measured around a flexed biceps muscle and was corrected for triceps skinfold to estimate muscle cross-sectional area (CSA). Chest circumference was measured at mid-expiration. Significant differences among the testers were evident in six of the nine anthropometric variables, with the least experienced tester being significantly different from the other testers on seven variables, although average differences among investigators ranged from 1-2% for circumferences to 4-9% for skinfolds. The two more experienced testers were significantly different on only one variable. Overall agreement among testers was high (ICC>0.895) for each variable, with low coefficients of variation (CV<10.7%). Predicted 1RMs for testers (126.9 +/- 20.6, 123.4 +/- 22.0, and 132.1 +/- 28.4 kg, respectively) were not significantly different from actual 1RM (129.2 +/- 20.6 kg). Individuals with varying levels of experience appear to have an acceptable level of ability to estimate 1RM bench press using a non performance anthropometric equation. Minimal experience in anthropometry may not impede strength and conditioning specialists from accurately estimating 1RM bench press. PMID- 27766129 TI - Adolescents' Perception of the Psychosocial Factors affecting Sustained Engagement in Sports and Physical Activity. AB - The purpose of this study was to explore adolescents' perceptions of psychosocial influences - personal characteristics, environmental factors and behavioural undertakings - influencing their prolonged involvement in sports and physical activity (PA). A qualitative approach was adopted wherein 16 adolescents (8 boys, 8 girls; mean age 15.9 years), who had been physically active for at least the last 8 years, and sixteen adults identified as their 'parents' or 'guardians' participated in semi-structured interviews. Interviews were transcribed verbatim and coded using the HyperRESEARCH software. Data were analysed using thematic analysis procedures. Four main themes pertaining to psychosocial influences were identified: 1) personal characteristics; 2) school and community resources; 3) parental support; and 4) social interaction. Except for social interaction, for which participants did not identify challenges, themes are discussed according to their motivational aspects and the challenges they represent for adolescents' PA involvement. The research has implications for health promotion endeavours directed toward parents of children and adolescents. Given the limitations of a qualitative study, readers are invited to apply the conclusions to their own context. PMID- 27766131 TI - Eight Weeks of Kettlebell Swing Training Does not Improve Sprint Performance in Recreationally Active Females. AB - The kettlebell swing (KBS), emphasizing cyclical, explosive hip extension in the horizontal plane, aligns with movement- and velocity-specificity of sprinting. The present study examined the effect of an eight-week KBS intervention on sprinting in recreationally-active females, in comparison to an eight-week intervention using the stiff-legged deadlift (SDL). Following a pre-testing session measuring 30 meter sprint and countermovement vertical jump performance, participants were divided evenly by sprint time into KBS (n=8) and SDL (n=10) cohorts. Following familiarization with the exercises, KBS met twice weekly to perform swings using the Tabata interval (20s work, 10s rest, 8 rounds), stressing a rapid, explosive tempo. In contrast, the SDL group performed their Tabata stiff-legged deadlifts at a conventional resistance training tempo (2 seconds concentric, 2 seconds eccentric). Following eight weeks and greater than 95% training adherence, the SDL group only had a slightly greater average training volume (~3%) than KBS. No significant differences in pre-test values, or changes were noted in sprint performance from pre- to post-intervention in either group. An improvement in vertical jump performance was noted across groups. Potential explanations for the lack of sprint improvement compared to previous studies include differences between recreationally-active and athletic females, and low exercise volume (~46% of a comparable study with improvements in vertical jump). Future studies should seek to determine the appropriate volume and intensity for KBS components of sprint programming. PMID- 27766132 TI - Physical Fitness and Self-Image: An Evaluation of the Exercise Self-Schema Questionnaire Using Direct Measures of Physical Fitness. AB - The purpose of this study was to perform a construct validity assessment of Kendzierski's exercise self-schema theory questionnaire using objective measures of health-related physical fitness. This study tested the hypothesis that individuals with an exercise self-schema would possess significantly greater physical fitness than those who did not across three domains of health-related physical fitness: Body composition, cardiovascular fitness, and upper-body muscular endurance. Undergraduate student participants from one private university on the west coast of the United States completed informed consent forms and the exercise self-schema questionnaire within a classroom setting or at an on-campus outside tabling session. Participants not meeting inclusion criteria for Kendzierski's three original schema groups were categorized as "unschematic," and were included within MANCOVA/ANCOVA analyses, where gender served as the covariate. Participants underwent lab-based fitness assessments administered in accordance with the 2013 American College of Sports Medicine Guidelines for Exercise Testing and Prescription. The hypothesis of this study was partially supported. Specifically, exerciser schematics were significantly leaner than aschematics (p = .002) and they had greater levels of upper-body muscular endurance compared to both aschematic and nonexerciser schematics (p = .002). However, no differences were observed for cardiovascular fitness (i.e., predicted V02Max p = .410). The findings of this study help to establish the construct validity of Kendizerski's self-report exercise self-schema categorization scheme. Visual inspection of the data, as well as computed effect size measures suggest exercise self-schema is associated with dimensions of one's physical fitness. PMID- 27766133 TI - The Effect of a Moderately Low and High Carbohydrate Intake on Crossfit Performance. AB - CrossFit is a metabolically demanding strength and conditioning method which performance may benefit from a carbohydrate (CHO)-rich diet. This study investigated the effect of three consecutive days of high CHO intake on CrossFit performance and corresponding metabolically -related variables in strength trained individuals. Eighteen subjects with a CHO intake of <6 g/kg/day were randomly assigned into a CHO (n = 9) or control (C) group (n =9) and underwent a 9-day training protocol. During days 1, 5, and 9, performance was measured as repetitions completed during a 12 minute CrossFit workout. Oxygen consumption (VO2), respiratory exchange ratio (RER), and blood lactate (BL) were also measured. Days 6-8, the CHO group increased CHO intake from <6 g/kg/day to 6-8 g/kg/day; the C group maintained their current intake of <6 g/kg/day. On days 6 and 7 both groups performed CrossFit workouts followed by a day of rest prior to day 9. There was a significant increase in repetitions completed in both groups in day 9 (vs. means score of day 1 + 5) (p = 0.002), but no differences between C and CHO groups (p = 0.111). However, the CHO group displayed a 15.2 repetition increase (+10.9%) in day 9, compared to 5.7 (+4.2%) by the C group. VO2, RER, and BL were not influenced by the experimental intervention. Our results suggest that the CrossFit-embraced practice of moderately-low CHO diets may be adequate in CHO during short periods of training, however, given the noted trend, extended training periods may be effected. PMID- 27766134 TI - Carotid Artery IMT, Blood Pressure, and Cardiovascular Risk Factors in Males and Females. AB - Previous studies have investigated carotid artery intima-media thickness (IMT) and blood pressure and found a direct correlation between the two. It is known that adult females have better cardiovascular health than males until a certain stage of life, yet limited research has examined gender differences in vascular function. Thus, the purpose of this study was to investigate vascular structure and function, blood pressure, and blood glucose/cholesterol levels in relation to gender differences in young healthy adults. On three separate days, 44 adults (26.30 +/- 11.9yrs; 24M, 20F) completed a carotid IMT ultrasound, a flow-mediated dilation (FMD), a fasted glucose and cholesterol test, a 24hr ambulatory blood pressure monitoring, a VO2max test, and a body composition measurement. Females had lower systolic blood pressure, lower diastolic blood pressure, lower LDL/HDL ratios, lower body mass index, a higher HDL count, and lower plasma glucose levels than males (p < 0.05 for all), all of which suggest better cardiovascular health. However, we found no gender differences in vascular health measures, IMT and FMD. Our results suggest that while young adult females have better cardiovascular health than males, endothelial function may not yet be affected in the young adult years. PMID- 27766135 TI - Sex Differences in Time Perception during Self-paced Running. AB - Time perception during exercise may be affected by chosen intensity, and may also affect enjoyment of exercise and subsequent long-term adherence. However, little is known about how individuals perceive the passage of time during exercise, or if factors such as sex are influential. The purpose of this study was to determine if there are sex related differences in perception of time during a bout of exercise in experienced runners. Twenty-two recreational runners (11 men, 11 women) participated in a bout of treadmill running where they were allowed to select their intensity. Sixty second prospective time estimations were taken before, during (at 33%, 66% and 90% of the completed distance), and after the run. Heart rate (HR) was also recorded throughout. The women (M = 91.9, SD = 3.3) ran at a significantly higher percentage of their maximum HR than the men (M = 86.5, SD = 6.4; p = 0.022), choosing to run at a higher relative intensity than the men when given the opportunity to self-pace. The women had relatively lower time estimations overall, showing that they perceived time to be passing by more slowly compared to the men. These results may help to explain sex related differences in exercise adherence. PMID- 27766136 TI - Effect of an Acute Bout of Kettlebell Exercise on Glucose Tolerance in Sedentary Men: A Preliminary Study. AB - Impaired glucose tolerance can have significant health consequences. The purposes of this preliminary study were to examine whether a single session of kettlebell exercise improves acute post-exercise glucose tolerance in sedentary individuals, and whether it was as effective as high-intensity interval running. Six sedentary male subjects underwent a two-hour oral glucose tolerance test following three different conditions: 1) control (no exercise); 2) kettlebell exercise (2 sets of 7 exercises, 15 repetitions per exercise with 30 seconds rest between each exercise); or 3) high-intensity interval running (10 one-minute intervals at a workload corresponding to 90% VO2max interspersed with one-minute active recovery periods). Blood glucose and insulin levels were measured before (0 minutes), and 60 and 120 minutes after glucose ingestion. Both kettlebell and high-intensity interval running exercise significantly lowered blood glucose 60 minutes after glucose ingestion compared with control. However, there was no significant difference in blood glucose between the two exercise conditions at any time point. In addition, there were no significant differences in insulin concentration between high intensity interval running, kettlebell, and control conditions at all time points. Results indicate that an acute bout of kettlebell exercise is as effective as high intensity interval running at improving glucose tolerance in sedentary young men. PMID- 27766137 TI - Epidemiology of colorectal cancer. AB - Colorectal cancer is currently the third deadliest cancer in the United States and will claim an estimated 49,190 U.S. lives in 2016. The purpose of this review is to summarize our current understanding of this disease, based on nationally published statistics and information presented in peer-reviewed journal articles. Specifically, this review will cover the following topics: descriptive epidemiology (including time and disease trends both in the United States and abroad), risk factors (environmental, genetic, and gene-environment interactions), screening, prevention and control, and treatment. Landmark discoveries in colorectal cancer risk factor research will also be presented. Based on the information reviewed for this report, we suggest that future U.S. public health efforts aim to increase colorectal cancer screening among African American communities, and that future worldwide colorectal cancer epidemiology studies should focus on researching nutrient-gene interactions towards the goal of improving personalized treatment and prevention strategies. PMID- 27766139 TI - Methodology for single nucleotide polymorphism selection in promoter regions for clinical use. An example of its applicability. AB - Genetic variability in humans can explain many differences in disease risk factors. Polymorphism-related studies focus mainly on the single nucleotide polymorphisms (SNPs) of coding regions of the genes. SNPs on DNA binding motifs of the promoter region have been less explored. On a recent study of SNPs in patients with non-Hodgkin lymphomas we faced the problem of SNP selection from promoter regions and developed a practical methodology for clinical studies. The process consists in identifying SNPs in the coding and promoter regions of the antigen-processing system using the 'dbSNP' database. With the 'HapMap' program, we select SNPs with frequencies >20% in Caucasian populations. For coding regions, we sought biologically and clinically relevant SNPs described in the literature. For the promoter regions, we determined their chromosomal location on 'QiagenSABioscience' site database. The nucleotide sequence of ancestral and variant alleles is available in the 'dbSNP'. These sequences were used in 'Promoter TESS' to determine binding differences of transcription factors. Each sequence may have affinity to different TFs. Thus, SNP selection on the promoter regions was based in the differences on TF binding pattern between the old and the new allele. The potential clinical relevance of the new TFs was also evaluated before the final selection. With this approach, we found that almost half of the relevant SNP fall within the promoter region. In conclusion, we were able to develop a methodology of oriented selection of promoter regions of human genes, comparing the TF with affinity to the ancestral allele with the TF to a variant allele. We selected those SNPs that change the TF's affinity to a pattern with functional significance. PMID- 27766138 TI - Association between vascular endothelial growth factor +936C/T polymorphism and breast cancer risk: a meta-analysis of 18 case-control studies. AB - Important in angiogenesis, vascular endothelial growth factor (VEGF) acts as a biomarker in the growth of and prognosis for breast cancer. Evidence suggests that single nucleotide polymorphisms of VEGF such as +936C/T (rs3025039) effects VEGF levels; however, current studies on the association between +936C/T and breast cancer risk are inconsistent. This meta-analysis was conducted to reach a more precise conclusion about this association. PubMed was searched for case control studies on the association between +936C/T levels and breast cancer risk. The quality of each study was scoring in term of some important criteria. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Subgroup analysis stratified by ethnicity and quality score was also conducted. Eighteen studies with 10,694 cases and 11,199 controls in accord with the selection criteria were included in our meta analysis. When all eligible studies were pooled, our meta-analysis showed that there was no significant association between +936C/T and breast cancer risk in the all ethnic group; however, in the subgroup analysis, we found that +936C/T was associated with reduced breast cancer risk in the Asian population. When stratified by the quality score, no significant association was found between +936C/T and breast cancer risk either in studies scored <8 or studies scored >7. Our findings suggested that +936C/T is not associated with breast cancer risk but may reduce the risk in the Asian population. PMID- 27766140 TI - A complex game of hide and seek: the search for new antifungals. AB - Fungal infections directly affect millions of people each year. In addition to the invasive fungal infections of humans, the plants and animals that comprise our primary food source are also susceptible to diseases caused by these eukaryotic microbes. The need for antifungals, not only for our medical needs, but also for use in agriculture and livestock causes a high demand for novel antimycotics. Herein, we provide an overview of the most commonly used antifungals in medicine and agriculture. We also present a summary of the recent progress (from 2010-2016) in the discovery/development of new agents against fungal strains of medical/agricultural relevance, as well as information related to their biological activity, their mode(s) of action, and their mechanism(s) of resistance. PMID- 27766142 TI - Hyperemesis Gravidarum is associated with substantial economic burden in addition to severe physical and psychological suffering. AB - Hyperemesis gravidarum (HG) affects 1 % of all pregnant women and in western societies it is the most common cause for hospital admission during first trimester. The economic burden of the disease has barely been studied. To estimate the Israeli national burden of HG, Konikoff and co-workers obtained data retrospectively on hospital costs as well as loss of workdays from 184 women hospitalized due to HG from December 2010 until December 2013. Their findings emphasise the need for better treatment to reduce the burden of this disease both for the individual as well as the society. PMID- 27766143 TI - What health care services does the public want and who should decide? Ask them! AB - Most of the parties involved in healthcare decisions - governments, politicians, healthcare professionals, pharmaceutical companies, special interest groups - actively work to make their desires known. In Israel the public is part of the decision committee; in Germany health care decision are made more or less without the public being involved. In a recently published IJHPR article, Giora Kaplan and Orna Baron-Epel raise the question of how well acquainted senior decision makers in the Israeli health system are with the public's priorities regarding the services being considered for inclusion in the public funding list. This commentary speculates about the reasons for the discrepancies found in that article between the decision makers' and the public's view. Furthermore, it reports on survey results from Germany about who should be part of the decision making committee and briefly touches upon the situation in other OECD countries. While public opinion may not be the determining factor, all authors advocate a strengthening of the public's contribution to the health care decision making process, including steps to make decision makers aware of public priorities on an ongoing basis. PMID- 27766141 TI - Multi-compartmental biomaterial scaffolds for patterning neural tissue organoids in models of neurodevelopment and tissue regeneration. AB - Biomaterials are becoming an essential tool in the study and application of stem cell research. Various types of biomaterials enable three-dimensional culture of stem cells, and, more recently, also enable high-resolution patterning and organization of multicellular architectures. Biomaterials also hold potential to provide many additional advantages over cell transplants alone in regenerative medicine. This article describes novel designs for functionalized biomaterial constructs that guide tissue development to targeted regional identities and structures. Such designs comprise compartmentalized regions in the biomaterial structure that are functionalized with molecular factors that form concentration gradients through the construct and guide stem cell development, axis patterning, and tissue architecture, including rostral/caudal, ventral/dorsal, or medial/lateral identities of the central nervous system. The ability to recapitulate innate developmental processes in a three-dimensional environment and under specific controlled conditions has vital application to advanced models of neurodevelopment and for repair of specific sites of damaged or diseased neural tissue. PMID- 27766144 TI - Household medical waste disposal policy in Israel. AB - BACKGROUND: Large amounts of expired and unused medications accumulate in households. This potentially exposes the public to hazards due to uncontrolled use of medications. Most of the expired or unused medications that accumulate in households (household medical waste) is thrown to the garbage or flushed down to the sewage, potentially contaminating waste-water, water resources and even drinking water. There is evidence that pharmaceutical active ingredients reach the environment, including food, however the risk to public health from low level exposure to pharmaceuticals in the environment is currently unknown. In Israel, there is no legislation regarding household medical waste collection and disposal. Furthermore, only less than 14 % of Israelis return unused medications to Health Maintenance Organization (HMO) pharmacies. METHODS: In this study, we investigated world-wide approaches and programs for household medical waste collection and disposal. RESULTS: In many countries around the world there are programs for household medical waste collection. In many countries there is legislation to address the issue of household medical waste, and this waste is collected in hospitals, clinics, law enforcement agencies and pharmacies. Furthermore, in many countries, medication producers and pharmacies pay for the collection and destruction of household medical waste, following the "polluter pays" principle. CONCLUSIONS: Several approaches and methods should be considered in Israel: (a) legislation and regulation to enable a variety of institutes to collect household medical waste (b) implementing the "polluter pays" principle and enforcing medical products manufactures to pay for the collection and destruction of household medical waste. (c) Raising awareness of patients, pharmacists, and other medical health providers regarding the health and environmental risks in accumulation of drugs and throwing them to the garbage, sink or toilet. (d) Adding specific instructions regarding disposal of the drug, in the medication label and leaflet. (e) Examining incentives for returning medications to pharmacies. (f) Examining drug collection from deceased in retirement homes and hospitals. PMID- 27766145 TI - Outcomes of a pilot study in chiropractic practices in Western Australia. AB - BACKGROUND: This paper reports the quantitative outcomes of a mixed-methods pilot study of the characteristics and demographics of chiropractic practices and patients in Western Australia. METHODS: This was a mixed-methods data transformation model (qualitative to quantitative) pilot study. A non-random sample of chiropractic practices across Western Australia was recruited and data collected anonymously from consecutive new patients using an online platform. Data covered practice and patient demographics and characteristics, alongside quality of life measures. A descriptive quantitative analysis characterised the sample, and the patient population was stratified by main reason for presentation to compare characteristics according to the presence of secondary complaints. Odds ratios were calculated to estimate the odds of a secondary complaint for various combinations of main complaints, from univariate logistic regression models. RESULTS: Of the 539 registered practitioners in WA in July 2014, 33 agreed to participate, from 20 different practices. Ten participating practices provided data on 325 adult new patients. The recruited practices (metropolitan n = 8, regional n = 2) had a positive response rate of 79.7 % (n = 301 metropolitan and n = 24 regional patients), mean age 36.3 years (range 18-74) (53.2 % female). Spinal problems were reported as the main reason for consultation by 67 % and as secondary reasons by 77.2 % of patients. People presented primarily for health maintenance or a general health check in 11.4 %, and as a secondary reason 14.8 %. There were 30 % of people below societal norms for the SF-12 Physical Component Score (mean 47.19, 95 % CI; 46.27-48.19) and 86 % for the Mental Component Score (mean 36.64, 95 % CI; 35.93-37.65), Pain Impact Questionnaire mean scores were 54.60 (95 % CI; 53.32-55.88). CONCLUSIONS: Patients presented to chiropractors in Western Australia with a fairly wide range of conditions, but primarily spinal and musculoskeletal-related problems. A significant proportion of patients had associated, or found to be at risk of, depression. Consequently, there are responsibilities and opportunities for chiropractors with respect to providing care services that include health promotion and well-being education related to musculoskeletal/spinal and mental health. This pilot study supports the feasibility of a future confirmatory study where the potential role of chiropractors in spinal/musculoskeletal health management may be explored. TRIAL REGISTRATION: ACTRN12616000434493: Australian New Zealand Clinical Trials Registry (ANZCTR), Registered 5 April 2016, First participant enrolled 01 July 2014 Retrospectively Registered. PMID- 27766146 TI - Review on colonization of residents and staff in Italian long-term care facilities by multidrug-resistant bacteria compared with other European countries. AB - BACKGROUND: Rates of colonization and infection with multidrug-resistant (MDR) bacteria are increasing worldwide, in both acute care hospitals and long-term care facilities (LTCFs). Italy has one of the highest prevalence of MDR bacteria in European countries, especially with regard to methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL) or carbapenemase producing Enterobacteriaceae (CPE). METHOD: Review of studies on colonization by MDR bacteria from Italian LTCFs, risk factors for colonization and molecular characteristics of surveillance and clinical isolates, compared with other European countries. RESULTS: High variability of MDR colonization has been reported within and especially between European countries. Only a few surveillance studies have been performed in Italian LTCFs; these show MRSA colonization prevalence of 7.8-38.7 % for residents and 5.2-7.0 % for staff members, ESBL prevalence of 49.0-64.0 % for residents and 5.2-14.5 % for staff and prevalence of CPE of 1.0-6.3 % for residents and 0.0-1.5 % for staff. In Italian LTCFs, as well as in other European countries, the most prevalent ESBLs from surveillance or clinical Escherichia coli isolates were found to be CTX-M type enzymes, particularly CTX-M-15, expressed by the pandemic ST131 clonal group; this lineage also expresses carbapenemase genes of the blaVIM and blaKPC types. Various risk factors for colonization of residents by MDR bacteria were identified. CONCLUSIONS: The limited data from Italian LTCFs confirms these settings as important reservoirs for MDR organisms, allowing important considerations regarding the infection risk by these organisms. Nevertheless, more extended and countrywide screening studies for MDR colonization in Italian LTCFs are required. To promote further studies of various microbiological aspects related to LTCFs, the Association of Italian Clinical Microbiologists (Associazione Microbiologi Clinici Italiani; AMCLI) in 2016 has set up a new Working Group for the Study of Infections in LTCFs (Gruppo di Lavoro per lo Studio delle Infezioni nelle Residenze Sanitarie Assistite e Strutture Territoriali assimilabili; GLISTer), consisting of Clinical Microbiologists represented by the authors of this review article. PMID- 27766147 TI - The effect of positive airway pressure therapy on neurocognitive functions, depression and anxiety in obesity hypoventilation syndrome. AB - BACKGROUND: The aim of this study is to evaluate the presence of neurocognitive dysfunctions, depression and anxiety and the effect of positive airway pressure (PAP) therapy on these alterations in Obesity Hypoventilation Syndrome (OHS) patients. METHODS: Ten healthy normal and obese controls, 10 OHS and 10 OSAS patients were included in the study. Short form-36, Beck Depression Scale and State-Trade Anxiety Inventory (STAI 1-2) were performed. Wisconsin Card Sorting Test (WCST), Montreal Cognitive Assessment Scale (MOCA), Enhanced Cued Recall (ECR) and Mini Mental Test (MMT) were used for neurocognitive evaluation. All tests were repeated after one night PAP therapy in OHS and OSAS groups. RESULTS: OHS patients had the lowest scores of physical (PF) and social functioning (SF) in SF-36. The total number of persistent errors and incorrect answers were the highest in OHS group in WCST. The scores of MOCA, ECR and MMT were lower; depression and anxiety scores were higher in OHS group than in controls (p = 0,00). There was a significant increase in the completed categories in OHS after PAP therapy (p = 0,03). There were also significant increases in MOCA, ECR and MMT scores and significant decreases in depression and anxiety scores with respect to PAP therapy. CONCLUSIONS: Cognitive dysfunction, depression and anxiety are important under-recognized comorbidities in OHS. It is suggested that short term PAP therapy had positive effects on neurocognitive functions, depression and anxiety but further multicentre, prospective studies with large number of cases are needed to evaluate the effect of long term PAP therapy on these parameters. PMID- 27766148 TI - Expression profile of novel cell surface molecules on different subsets of human peripheral blood antigen-presenting cells. AB - Although major steps have been recently made in understanding the role of the distinct subsets of dendritic cells (DC)/antigen-presenting cells (APC), further studies are required to unravel their precise role, including in-depth immunophenotypic characterisation of these cells. Here, we used eight-colour flow cytometry to investigate the reactivity of a panel of 72 monoclonal antibodies (including those clustered in seven new Cluster of Differentiation, CD) on different subsets of APC in peripheral blood (PB) samples from five healthy adults. These experiments were performed in the context of the Tenth International Workshop on Human Leukocyte Differentiation Antigens (HLDA10). Plasmacytoid DC was the only cell population that expressed CD85g and CD195, whereas they lacked all of the other molecules investigated. In contrast, myeloid DC mostly expressed inhibitory C-type lectin receptors (CLRs) and other inhibitory-associated molecules, whereas monocytes expressed both inhibitory and activating CLRs, together with other phagocytosis-associated receptors. Within monocytes, progressively lower levels of expression were generally observed from classical monocytes (cMo) to SLAN- and SLAN+ non-classical monocytes (ncMo) for most of the molecules expressed, except for the CD368 endocytic receptor. This molecule was found to be positive only in cMo, and the CD369 and CD371 modulating/signalling receptors. In addition, the CD101 inhibitory molecule was found to be expressed at higher levels in SLAN+ vs SLAN- ncMo. In summary, the pattern of expression of the different signalling molecules and receptors analysed in this work varies among the distinct subsets of PB APCs, with similar profiles for molecules within each functional group. These findings suggest unique pattern-recognition and signalling capabilities for distinct subpopulations of APCs, and therefore, diverse functional roles. PMID- 27766149 TI - Heavy with child? Pregnancy status and stable isotope ratios as determined from biopsies of humpback whales. AB - Understanding reproductive rates of wild animal populations is crucially important for management and conservation. Assessing pregnancy status of free ranging cetaceans has historically been difficult; however, recent advances in analytical techniques have allowed the diagnosis of pregnancy from small samples of blubber tissue. The primary objectives of this study were as follows: (i) to test the efficacy of blubber progesterone assays as a tool for diagnosing pregnancy in humpback whales (Megaptera novaeangliae); (ii) to estimate the pregnancy rate of humpback whales in Monterey Bay, California; and (iii) to investigate the relationship between stable isotopes and reproductive status of these whales. Progesterone concentrations of female whales fell into two distinct groups, allowing for diagnostic separation of pregnant and non-pregnant individuals. Pregnancy rate varied between years of the study (48.4%% in 2011 and 18.5% in 2012), but fell within the range of other estimates of reproductive success for this population. Stable carbon and nitrogen isotope ratios were examined to investigate the impacts of pregnancy on these values. Neither delta15N nor delta13C varied in a consistent way among animals of different sex or reproductive status. The relationship between delta15N and delta13C was strongly positive for male and non-pregnant female humpbacks; however, no relationship existed for pregnant whales. This difference may be indicative of the effects of pregnancy on delta15N, resulting from tissue synthesis and reduced excretion of nitrogenous waste, as well as on delta13C through increased mobilization of lipid stores to meet the energetic demands of pregnancy. Ultimately, our results support the use of blubber progesterone assays for diagnosing pregnancy in humpback whales and indicate that, when paired with other approaches (e.g. stable isotope analysis), pregnancy status can be an informative tool for addressing questions about animal physiology, ecology and population biology. This information will provide for more effective management and conservation efforts in a rapidly changing world. PMID- 27766150 TI - Maximal oxygen consumption increases with temperature in the European eel (Anguilla anguilla) through increased heart rate and arteriovenous extraction. AB - Global warming results in increasing water temperature, which may represent a threat to aquatic ectotherms. The rising temperature affects ecology through physiology, by exerting a direct limiting effect on the individual. The mechanism controlling individual thermal tolerance is still elusive, but some evidence shows that the heart plays a central role, and that insufficient transport of oxygen to the respiring tissues may determine the thermal tolerance of animals. In this study, the influence of the heart in thermal limitation was investigated by measurements of aerobic scope in the European eel (Anguilla anguilla) together with measurements of cardiac output during rest and activity. Aerobic capacity was not limited by an acutely increased temperature in the European eel. Oxygen demand was met by an increase in heart rate and arteriovenous extraction. These findings suggest that thermal tolerance during exposure to acute temperature changes is not defined by oxygen transport capacity in the eel, and other mechanisms may play a central role in limiting thermal tolerance in these fish. PMID- 27766151 TI - Coloured ornamental traits could be effective and non-invasive indicators of pollution exposure for wildlife. AB - Growth in human populations causes habitat degradation for other species, which is usually gauged by physical changes to landscapes. Corresponding habitat degradation to air and water is also common, but its effects on individuals can be difficult to detect until they result in the decline or disappearance of populations. More proactive measures of pollution usually combine abiotic samples of soil, water or air with invasive sampling of expendable species, but this approach sometimes creates ethical dilemmas and has limited application for threatened species. Here, we describe the potential to measure the effects of pollution on many species of birds and fish by using ornamental traits that are expressed as coloured skin, feathers and scales. As products of sexual selection, these traits are sensitive to environmental conditions, thereby providing honest information about the condition of their bearers as ready-made biomarkers. We review the documented effects of several classes of pollutants, including pharmaceuticals, pesticides, industry-related compounds and metals, on two classes of colour pigments, namely melanins and carotenoids. We find that several pollutants impede the expression of both carotenoids and brown melanin, while enhancing traits coloured by black melanin. We also review some of the current limitations of using ornamental colour as an indicator of pollution exposure, suggest avenues for future research and speculate about how advances in robotics and remote imagery will soon make it possible to measure these traits remotely and in a non-invasive manner. Wider awareness of this potential by conservation managers could foster the development of suitable model species and comparative metrics and lay a foundation for pollution monitoring that is more generalizable and biologically relevant than existing standards. PMID- 27766152 TI - Understanding invasion history and predicting invasive niches using genetic sequencing technology in Australia: case studies from Cucurbitaceae and Boraginaceae. AB - Part of the challenge in dealing with invasive plant species is that they seldom represent a uniform, static entity. Often, an accurate understanding of the history of plant introduction and knowledge of the real levels of genetic diversity present in species and populations of importance is lacking. Currently, the role of genetic diversity in promoting the successful establishment of invasive plants is not well defined. Genetic profiling of invasive plants should enhance our understanding of the dynamics of colonization in the invaded range. Recent advances in DNA sequencing technology have greatly facilitated the rapid and complete assessment of plant population genetics. Here, we apply our current understanding of the genetics and ecophysiology of plant invasions to recent work on Australian plant invaders from the Cucurbitaceae and Boraginaceae. The Cucurbitaceae study showed that both prickly paddy melon (Cucumis myriocarpus) and camel melon (Citrullus lanatus) were represented by only a single genotype in Australia, implying that each was probably introduced as a single introduction event. In contrast, a third invasive melon, Citrullus colocynthis, possessed a moderate level of genetic diversity in Australia and was potentially introduced to the continent at least twice. The Boraginaceae study demonstrated the value of comparing two similar congeneric species; one, Echium plantagineum, is highly invasive and genetically diverse, whereas the other, Echium vulgare, exhibits less genetic diversity and occupies a more limited ecological niche. Sequence analysis provided precise identification of invasive plant species, as well as information on genetic diversity and phylogeographic history. Improved sequencing technologies will continue to allow greater resolution of genetic relationships among invasive plant populations, thereby potentially improving our ability to predict the impact of these relationships upon future spread and better manage invaders possessing potentially diverse biotypes and exhibiting diverse breeding systems, life histories and invasion histories. PMID- 27766154 TI - Erratum: Condition-dependent migratory behaviour of endangered Atlantic salmon smolts moving through an inland sea. AB - [This corrects the article DOI: 10.1093/conphys/cow018.]. PMID- 27766153 TI - Physiological stress response, reflex impairment and delayed mortality of white sturgeon Acipenser transmontanus exposed to simulated fisheries stressors. AB - White sturgeon (Acipenser transmontanus) are the largest freshwater fish in North America and a species exposed to widespread fishing pressure. Despite the growing interest in recreational fishing for white sturgeon, little is known about the sublethal and lethal impacts of angling on released sturgeon. In summer (July 2014, mean water temperature 15.3 degrees C) and winter (February 2015, mean water temperature 6.6 degrees C), captive white sturgeon (n = 48) were exposed to a combination of exercise and air exposure as a method of simulating an angling event. After the stressor, sturgeon were assessed for a physiological stress response, and reflex impairments were quantified to determine overall fish vitality (i.e. capacity for survival). A physiological stress response occurred in all sturgeon exposed to a fishing-related stressor, with the magnitude of the response correlated with the duration of the stressor. Moreover, the stress from exercise was more pronounced in summer, leading to higher reflex impairment scores (mean +/- SEM, 0.44 +/- 0.07 and 0.25 +/- 0.05 in summer and winter, respectively). Reflex impairment was also correlated with lactate concentrations (e.g. physiological stress measures related to exhaustive exercise; r = 0.53) and recovery time (r = 0.76). Two mortalities occurred >24 h after the cessation of treatment in the summer. Given that natural habitats for white sturgeon can reach much higher temperatures than those presented in our study, we caution the use of this mortality estimate for a summer season, because latent mortality could be much higher when temperatures exceed 16 degrees C. This is the first experiment investigating the physiological disturbance and reflex impairment of capture and release at two temperatures on subadult/adult white sturgeon, and the results suggest that future research needs to examine the longer term and fitness consequences of extended play and air exposure times, because these are largely unknown for wild populations. PMID- 27766155 TI - Gill structural change in response to turbidity has no effect on the oxygen uptake of a juvenile sparid fish. AB - Turbidity as a result of increased suspended sediments in coastal waters is an environmental stress of worldwide concern. Recent research on fish suggests that detrimental changes to gill structure can occur in turbid waters, with speculation that these alterations diminish fitness variables, such as growth and development, by negatively impacting the O2 uptake capacity (respiration) of fish. Specifically to address this unknown, the impact of turbid water on the gill structure, somatic growth rate and O2 uptake rates of a juvenile sparid species (Pagrus auratus) was addressed following exposure to five different turbidity treatments (<10, 20, 40, 60 or 80 nephelometric turbidity units) for 30 days. Significant gill structural change was apparent with a progressive increase in turbidity and was quantified as a reduction in lamellar density, as well as an increase in basal hyperplasia, epithelial lifting and increased oxygen diffusion distance across the lamellae. The weight of control fish did not change throughout the experiment, but all fish exposed to turbid waters lost weight, and weight loss increased with nephelometric turbidity units, confirming that long term turbidity exposure is detrimental to growth productivity. The growth of fish could be impacted in a variety of ways, but the specific hypothesis that structural alteration of the gills impairs O2 uptake across the gills and limits growth fitness was not supported because there was no measurable difference in the standard metabolic rate, maximal metabolic rate, aerobic metabolic scope or critical oxygen saturation limit of fish measured in clear water after 30 days of exposure. Although impaired O2 uptake as a result of structurally adjusted gills is unlikely to be the cause of poor fish growth, the exact mechanism by which growth productivity is affected in turbid conditions remains unclear and warrants further investigation. PMID- 27766157 TI - The physiological, musculoskeletal and psychological effects of stand up paddle boarding. AB - BACKGROUND: Stand up paddle boarding (SUP) is a rapidly growing sport and recreational activity where anecdotal evidence exists for its proposed health, fitness and injury rehabilitation benefits. While limited scientific evidence exists to substantiate these claims, previous studies have shown that high levels of fitness, strength and balance exists amongst participants of this sport. The purpose of this study was to conduct a training intervention on a group of previously untrained individuals to ascertain the potential of SUP on various health parameters. METHODS: An intervention study was conducted where after being tested initially, subjects were left for 6 weeks to act as their own control before the SUP intervention began. A total of 13 SUP participants completed the training study (nine males, four females) which was comprised of three 1 h sessions per week for 6 weeks. RESULTS: No significant changes occurred during the initial control period. Significant (P < 0.05) improvements were made in aerobic (+23.57 %) and anaerobic fitness (+41.98 %), multidirectional core strength tests (prone +19.78 %, right side +26.19 %, left side +28.31 %, Biering Sorensen +21.33 %) and self-rated quality of life questionnaires in the physical (+19.99 %) and psychological (+17.49 %) domains. No significant changes were detected in static or dynamic balance over the duration of the training intervention. CONCLUSION: These results demonstrate the cardiovascular, musculoskeletal and psychological improvements achievable for the novice when utilizing SUP as a training tool. The result from this study provides some evidence to substantiate the claims of health and fitness benefits SUP. PMID- 27766158 TI - Corynebacterium phoceense sp. nov., strain MC1T a new bacterial species isolated from human urine. AB - Corynebacterium phoceense strain MC1 (= CSUR P1905 = DSM 100570) is a novel Corynebacterium species isolated from the urine of a kidney transplant recipient as a part of a culturomics study. Corynebacterium phoceense is a Gram-positive, sporogenous, strictly aerobic, and nonmotile coccobacillus. Here we describe strain MC1 and provide its complete annotated genome sequence according to the taxonogenomics concept. Its genome is 2 793 568 bp long and contains 2575 protein coding genes and 67 RNA genes, including eight rRNA genes. PMID- 27766159 TI - A new bioindicator, shell of Trachycardium lacunosum, and sediment samples to monitors metals (Al, Zn, Fe, Mn, Ni, V, Co, Cr and Cu) in marine environment: The Persian Gulf as a case. AB - BACKGROUND: The present work was designed to detect heavy metal contents of Al, Zn, Fe, Mn, Ni, V, Co, Cr and Cu in sediments and shells of the Trachycardium lacunosum collected in polluted and unpolluted areas along the Persian Gulf. METHODS: The samples were taken from surface sediments (0-10 cm) and shells of Trachycardium lacunosum in two separated areas (polluted and unpolluted) in northern part of the Persian Gulf, Asaluyeh Bay, during summer 2013. The prepared samples were analyzed by inductively coupled plasma-optical emission spectrometry (ICP-OES). RESULTS: Based on the results, all measured metals including Al, Zn, Fe, Mn, Ni, V, Co, Cr and Cu were meaningfully higher in the sediment samples of polluted area compared to unpolluted area and the order of metal concentrations in the sediment samples were Cr > Co > V > Ni > Zn > Cu > Fe > Al > Mn in polluted area. In the case of shell samples of Trachycardium lacunosum, polluted area contained significantly higher contents of Al, Zn, Fe, Mn, Ni, Co, Cr and Cu compared to unpolluted area and the order of metal concentrations in the shell samples were Fe > Zn > Al > Mn > Cu > Cr > Ni > Co in the polluted area. CONCLUSION: It was concluded that shells of the Trachycardium lacunosum can be used as a suitable bioindicator for heavy metals in the aquatic environment. Results confirmed that due to the possible contaminations by oil and gas activities near the polluted area perennial monitoring and mitigation measures is extremely necessary. PMID- 27766156 TI - Conservation physiology of marine fishes: state of the art and prospects for policy. AB - The state of the art of research on the environmental physiology of marine fishes is reviewed from the perspective of how it can contribute to conservation of biodiversity and fishery resources. A major constraint to application of physiological knowledge for conservation of marine fishes is the limited knowledge base; international collaboration is needed to study the environmental physiology of a wider range of species. Multifactorial field and laboratory studies on biomarkers hold promise to relate ecophysiology directly to habitat quality and population status. The 'Fry paradigm' could have broad applications for conservation physiology research if it provides a universal mechanism to link physiological function with ecological performance and population dynamics of fishes, through effects of abiotic conditions on aerobic metabolic scope. The available data indicate, however, that the paradigm is not universal, so further research is required on a wide diversity of species. Fish physiologists should interact closely with researchers developing ecological models, in order to investigate how integrating physiological information improves confidence in projecting effects of global change; for example, with mechanistic models that define habitat suitability based upon potential for aerobic scope or outputs of a dynamic energy budget. One major challenge to upscaling from physiology of individuals to the level of species and communities is incorporating intraspecific variation, which could be a crucial component of species' resilience to global change. Understanding what fishes do in the wild is also a challenge, but techniques of biotelemetry and biologging are providing novel information towards effective conservation. Overall, fish physiologists must strive to render research outputs more applicable to management and decision making. There are various potential avenues for information flow, in the shorter term directly through biomarker studies and in the longer term by collaborating with modellers and fishery biologists. PMID- 27766160 TI - Risk factors for lesions of the knee menisci among workers in South Korea's national parks. AB - BACKGROUND: This study was designed to investigate the prevalence of the menisci lesions in national park workers and work factors affecting this prevalence. METHODS: The study subjects were 698 workers who worked in 20 Korean national parks in 2014. An orthopedist visited each national park and performed physical examinations. Knee MRI was performed if the McMurray test or Apley test was positive and there was a complaint of pain in knee area. An orthopedist and a radiologist respectively read these images of the menisci using a grading system based on the MRI signals. To calculate the cumulative intensity of trekking of the workers, the mean trail distance, the difficulty of the trail, the tenure at each national parks, and the number of treks per month for each worker from the start of work until the present were investigated. Chi-square tests was performed to see if there were differences in the menisci lesions grade according to the variables. The variables used in the Chi-square test were evaluated using simple logistic regression analysis to get crude odds ratios, and adjusted odds ratios and 95 % confidence intervals were calculated using multivariate logistic regression analysis after establishing three different models according to the adjusted variables. RESULTS: According to the MRI signal grades of menisci, 29 % were grade 0, 11.3 % were grade 1, 46.0 % were grade 2, and 13.7 % were grade 3. The differences in the MRI signal grades of menisci according to age and the intensity of trekking as calculated by the three different methods were statistically significant. Multiple logistic regression analysis was performed for three models. In model 1, there was no statistically significant factor affecting the menisci lesions. In model 2, among the factors affecting the menisci lesions, the OR of a high cumulative intensity of trekking was 4.08 (95 % CI 1.00-16.61), and in model 3, the OR of a high cumulative intensity of trekking was 5.84 (95 % CI 1.09-31.26). CONCLUSION: The factor that most affected the menisci lesions among the workers in Korean national park was a high cumulative intensity of trekking. PMID- 27766161 TI - Spatial and compositional variation in the fungal communities of organic and conventionally grown apple fruit at the consumer point-of-purchase. AB - The fungal diversity in harvested apples from organic or conventional management practices was analyzed in different fruit locations (stem end, calyx end, peel, and wounded flesh) shortly after fruit purchase (T1) and after 2 weeks of storage (T5). A total of 5,760,162 high-quality fungal sequences were recovered and assigned to 8,504 Operational Taxonomic Units. Members of the phylum Ascomycota were dominant in all samples and accounted for 91.6% of the total number of detected sequences. This was followed by Basidiomycota (8%), Chytridiomycota (0.1%), and unidentified fungi (0.3%). Alpha and beta diversity analyses revealed the presence of significantly different fungal populations in the investigated fruit parts. Among detected fungi, the genus Penicillium prevailed in the peel and in the wounded flesh while Alternaria spp. prevailed in the calyx and stem end samples that included apple core tissues. Several taxonomic units that appear to be closely related to pathogenic fungi associated with secondary human infections were present in peel and wounds. Moreover, significantly different populations were revealed in organic and conventional apples and this result was consistent in all investigated fruit parts (calyx end, peel, stem end, and wounded flesh). Several unique taxa were exclusively detected in organic apples suggesting that management practices may have been a contributing factor in determining the taxa present. In contrast, little differences were revealed in the two assessment times (T1 and T5). Results of the present study represent an advancement of the current knowledge on the fungal microbiota in collected fruit tissues of apple. PMID- 27766162 TI - Maternal mosaicism for IDUA deletion clarifies recurrence risk in MPS I. AB - Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in IDUA, encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of IDUA exons 1 and 2, c.(?_ 88)_(299+1_300-1)del and a whole-gene deletion of IDUA (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder. PMID- 27766163 TI - KRIT1 mutations in three Japanese pedigrees with hereditary cavernous malformation. AB - Cerebral cavernous malformation is a neurovascular abnormality that can cause seizures, focal neurological deficits and intracerebral hemorrhage. Familial forms of this condition are characterized by de novo formation of multiple lesions and are autosomal-dominantly inherited via CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 mutations. We identified three truncating mutations in KRIT1 from three Japanese families with CCMs: a novel frameshift mutation, a known frameshift mutation and a known splice-site mutation that had not been previously analyzed for aberrant splicing. PMID- 27766165 TI - Association of Campylobacter Jejuni ssp. Jejuni Chemotaxis Receptor Genes with Multilocus Sequence Types and Source of Isolation. AB - Campylobacter jejuni's flagellar locomotion is controlled by eleven chemoreceptors. Assessment of the distribution of the relevant chemoreceptor genes in the C. jejuni genomes deposited in the National Center for Biotechnology Information (NCBI) database led to the identification of two previously unknown tlp genes and a tlp5 pseudogene. These two chemoreceptor genes share the same locus in the C. jejuni genome with tlp4 and tlp11, but the gene region encoding the periplasmic ligand binding domain differs significantly from other chemoreceptor genes. Hence, they were named tlp12 and tlp13. Consequently, it was of interest to study their distribution in C. jejuni subpopulations of different clonality, and their cooccurrence with the eleven previously reported chemoreceptor genes. Therefore, the presence of all tlp genes was detected by polymerase chain reaction (PCR) in 292 multilocus sequence typing (MLST)-typed C. jejuni isolates from different hosts. The findings show interesting trends: Tlp4, tlp11, tlp12, and tlp13 appeared to be mutually exclusive and cooccur in a minor subset of isolates. Tlp4 was found to be present in only 33.56% of all tested isolates and was significantly less often detected in turkey isolates. Tlp11 was tested positive in only 17.8% of the isolates, while tlp12 was detected in 29.5% of all isolates, and tlp13 was found to be present in 38.7%. PMID- 27766166 TI - Role of suPAR and Lactic Acid in Diagnosing Sepsis and Predicting Mortality in Elderly Patients. AB - This study investigated the diagnostic value of soluble urokinase plasminogen activator receptor (suPAR) and serum lactate in elderly patients with sepsis and evaluated their capacity to predict mortality and their correlation to Sequential Organ Failure Assessment (SOFA) score. The study included 80 participants, divided into two groups: 40 cases (mean age, 68.9 +/- 5.9) admitted to the intensive care unit and 40 healthy controls (mean age, 67.1 +/- 6.2). Elderly patients with sepsis had significantly higher levels of serum suPAR and lactic acid compared to healthy controls. Receiver operating characteristic (ROC) curve analysis showed that suPAR (cutoff value, >=4.37 ng/ml) has higher area under the curve (AUC) than lactic acid (cutoff value, >=1.95 mmol/l) for diagnosing sepsis. Serum lactate has superior prognostic value compared to suPAR with AUC of 0.82 (cutoff value, 2.2 mmol/l) and 0.72 (cutoff value, 6.3 ng/ml), respectively. The diagnostic power of combined usage of suPAR and lactate serum concentrations showed AUC of 0.988 (95% confidence interval 0.934 to 1.0). The combination of both biomarkers either together or with SOFA score may serve as a useful guide to patients who need more intensive resuscitation. PMID- 27766164 TI - Insights from 100 Years of Research with Probiotic E. Coli. AB - A century ago, Alfred Nissle discovered that intentional intake of particular strains of Escherichia coli could treat patients suffering from infectious diseases. Since then, one of these strains became the most frequently used probiotic E. coli in research and was applied to a variety of human conditions. Here, properties of that E. coli Nissle 1917 strain are compared with other commercially available E. coli probiotic strains, with emphasis on their human applications. A literature search formed the basis of a summary of research findings reported for the probiotics Mutaflor, Symbioflor 2, and Colinfant. The closest relatives of the strains in these products are presented, and their genetic content, including the presence of virulence, genes is discussed. A similarity to pathogenic strains causing urinary tract infections is noticeable. Historic trends in research of probiotics treatment for particular human conditions are identified. The future of probiotic E. coli may lay in what Alfred Nissle originally discovered: to treat gastrointestinal infections, which nowadays are often caused by antibiotic-resistant pathogens. PMID- 27766168 TI - Molecular Differentiation of Shigella Spp. from Enteroinvasive E. Coli. AB - A real-time polymerase chain reaction (PCR) assay, amplifying the genes encoding lactose permease (lacY) and invasion plasmid antigen H (ipaH), was run on 121 isolates phenotypically classified as Shigella spp., enteroinvasive Escherichia coli (EIEC), or EIEC O nontypable (ONT). The results were compared with data from a generic E. coli multiple-locus variable-number of tandem repeat analysis (MLVA) and a Shigella MLVA. The real-time PCR verified all Shigella spp. (n = 53) as Shigella (lacY negative) and all EIEC O121 (n = 15) and EIEC O124 (n = 2) as EIEC (lacY positive). However, the real-time PCR typed EIEC O164 as either EIEC (n = 2) or Shigella (n = 2) and, thus, was not suited for classifying this group of isolates. Interestingly, the majority (42/47, 89.4%) of the EIEC ONT were classified as Shigella (lacY negative) by the real-time PCR, and in nearly all cases, (92.9%, 39/42) data from both MLVA assays supported these findings. Overall, in 94.7% (114/121) of the isolates, the results from the real-time PCR were substantiated by the results from the MLVA assays. In conclusion, the real time PCR assay was fast and accurate in differentiating Shigella spp. from EIEC, with the exception of the EIEC O164 group. This molecular assay was particularly pragmatic for the challenging EIEC ONT group. PMID- 27766167 TI - A C-Terminal Coiled-Coil Region of CagL is Responsible for Helicobacter Pylori Induced Il-8 Expression. AB - Interleukin-8 (IL-8) is a potent neutrophil-activating chemokine which triggers the infiltration and migration of neutrophils into areas of bacterial infection. Helicobacter pylori-infected patient studies as well as animal models have revealed that H. pylori type I strains carrying an intact cytotoxin-associated gene pathogenicity island (cag-PAI) with a functional type IV secretion system (T4SS) induce IL-8 expression and secretion in gastric mucosa. This gastric mucosal IL-8 expression correlates with severe histological changes due to H. pylori infection. In the present study, we explored a new recognition pattern on the bacterial adhesion protein CagL inducing IL-8 expression in H. pylori infected host cells. To analyze the secreted IL-8 concentration, we performed IL 8 enzyme-linked immunosorbent assay (ELISA). To investigate the H. pylori-induced IL-8 expression on the transcriptional level, we transiently transfected gastric epithelial cells (AGS) with a human IL-8 luciferase reporter construct. The results of this study demonstrate that specifically the C-terminal coiled-coil region of the H. pylori CagL protein, a protein described to be located on the tip of the T4SS-pilus, is responsible for several in vitro observations: 1) H. pylori-induced IL-8 secretion via the transforming growth factor (TGF)-alpha activated epidermal growth factor-receptor (EGF-R) signaling pathway; 2) H. pylori-induced elongation of the cells, a typical CagA-induced phenotype; and 3) the bridging of the T4SS to its human target cells. This novel bacterial-host recognition sequence allows a new insight into how H. pylori induces the inflammatory response in gastric epithelial cells and facilitates the development of precancerous conditions. PMID- 27766170 TI - Laboratory Experience with the Liaison Analyzer in the Diagnosis of Clostridium Difficile-Associated Diarrhea. AB - BACKGROUND: Chemiluminescent or enzyme-linked fluorescent immunoassays are commonly used to diagnose Clostridium difficile-associated diarrhea. METHODS: The LIAISON analyzer (DiaSorin, Italy) was compared to miniVIDAS (bioMerieux, France) and, furthermore, to culture of toxigenic strains. In total, 249 native stool samples were analyzed. Sensitivities, specificities, and positive and negative predictive values were investigated. Furthermore, performance under routine conditions was assessed. RESULTS: The glutamate dehydrogenase chemiluminescent immunoassay (GDH-CLIA) assay revealed a high sensitivity and negative predictive value. The toxins A&B assays exhibited approximately the same low sensitivity and high specificity. Technical drawbacks experienced with the LIAISON analyzer in 48% of the analyses considerably delayed the time to the first diagnostic report and interfered with laboratory routine workflow. CONCLUSION: The analytical performance of the investigated platforms should be reflected in the context of implementation into the laboratory workflow. PMID- 27766169 TI - Microbial Etiology of Community-Acquired Pneumonia Among Infants and Children Admitted to the Pediatric Hospital, Ain Shams University. AB - BACKGROUND: While recognizing the etiology of community-acquired pneumonia is necessary for formulating local antimicrobial guidelines, limited data is published about this etiology in Egyptian pediatric patients. OBJECTIVES: To determine the frequency of bacterial and viral pathogens causing community acquired pneumonia (CAP) among immunocompetent Egyptian infants and preschool children. METHODS: Ninety infants and preschool-age children admitted to our hospital with CAP were prospectively included in the study. Etiological agents were identified using conventional bacteriological identification methods and IgM antibodies detection against common atypical respiratory bacteria and viruses. RESULTS: An etiology was identified in 59 patients (65.5%). Bacterial pathogens were detected in 43 (47.8%) of the cases while viral pathogens were detected in 23 (25.5%). Coinfection with more than one etiologic agent was evident in seven patients (7.8%). The most common typical bacterial cause of pneumonia was Staphylococcus aureus (n = 12, 13.3%), followed by Streptococcus pneumoniae and Klebsiella pneumoniae (n = 7, 7.8%, each). The commonest atypical bacterium was Mycoplasma pneumoniae (n = 10, 11.1%), whereas the commonest viral etiology was influenza viruses (n = 11, 12.2%). CONCLUSION: Although we could not determine the causative agent in some studied cases, this study provides preliminary data regarding the spectrum and frequency of microorganisms causing CAP in Egyptian infants and preschool children. PMID- 27766171 TI - Tissue-Specific Induction of CCR6 and Nrp1 During Early CD4+ T Cell Differentiation. AB - Upon differentiation, T cells acquire tissue-specific homing properties allowing efficient targeting of effector T cells into distinct inflamed organs. Priming of T cells within skin-draining, peripheral lymph nodes (pLNs) leads to the expression of E- and P-selectin ligands, which facilitate migration into inflamed skin, whereas activation within gut-draining, mesenteric LNs (mLNs) results in induction of chemokine receptor CCR9 and integrin alpha4beta7, both required for migration of effector T cells into mucosal tissues. In addition to the local tissue microenvironment, both organ-specific dendritic cells and LN-resident stromal cells are critical factors to shape T cell migration properties. Here, we identify two additional homing-related molecules, CCR6 and Neuropilin-1 (Nrp1), upregulated in T cells early during differentiation solely in pLNs, but not mLNs. Surprisingly, intestinal inflammation resulted in an ameliorated induction of CCR6 and Nrp1 in pLNs, suggesting that a local inflammation within the gut can systemically alter T cell differentiation. Finally, transplantation of mLNs to a skin-draining environment revealed that LN stromal cells also contribute to efficient CCR6 induction in pLNs. Collectively, these findings identify further aspects of early T cell differentiation within skin-draining pLNs, which could be utilized to further develop tailored and highly specialized vaccination strategies. PMID- 27766172 TI - Risk Reduction of Needle Stick Injuries Due to Continuous Shift from Unsafe to Safe Instruments at a German University Hospital. AB - This study assessed protective effects of a continuous introduction of safe instruments in terms of reduction of needle stick injuries. The retrospective study analyzed correlations between the increasing proportion of safe instruments and a reduction of the incidence of needle stick injuries linked to such instruments in a German university hospital over 5 years. Incidents declined about 17.6% from 80.3 incidents per 1000 employees to 66.2, associated with an increase in the proportions of injuries due to instruments without protective mechanisms such as scalpels or hypodermic needles by 12.2%. For injuries due to venipuncture cannulae in various surgical and internal medicine departments, there was a negative association between the proportion of safe instruments and the incidence of injuries. For injection needles, portacath needles, and lancets in selected internal medicine departments, the number of injuries also dropped during this study interval. However, there was no clear-cut association with the percentage of safe instruments. This observational study suggests a correlation between the implementation of use of safe instruments and the reduction of needle stick injuries in a case of a graduated implementation. However, the effects are much less pronounced than in previous interventional studies. PMID- 27766173 TI - Multidrug Resistance of Acinetobacter Baumannii in Ladoke Akintola University Teaching Hospital, Osogbo, Nigeria. AB - Acinetobacter baumannii is a ubiquitous pathogen that has emerged as a major cause of healthcare-associated infections at Ladoke Akintola University Teaching Hospital. Isolates were assayed according to standard protocol. The isolates were subjected to molecular techniques to detect blaOXA, blaTEM, blaCTX-M, and blaSHV genes in strains of the A. baumannii isolates. The prevalence of A. baumannii was 8.5% and was most prevalent among patients in the age group 51-60 (36%); the male patients (63.6%) were more infected than their female counterparts. Patients (72.7%) in the intensive care unit (ICU) were most infected with this organism. The isolates showed 100% resistance to both amikacin and ciprofloxacin and 90.9% to both ceftriaxone and ceftazidime, while resistance to the other antibiotics used in this study were: piperacillin (81.8%), imipenem (72.7%), gentamycin (72.2%), and meropenem (63.6%). None of the isolates was, however, resistant to colistin. PCR results showed that blaOXA, blaTEM, and blaCTX-M genes were positive in some isolates, while blaSHV was not detected in any of the isolates. This study has revealed that the strains of A. baumannii isolated are multiple drug resistant. Regular monitoring, judicious prescription, and early detection of resistance to these antibiotics are, therefore, necessary to check further dissemination of the organism. PMID- 27766174 TI - Comparison of Five Commercial Nucleic Acid Extraction Kits for the PCR-based Detection of Burkholderia Pseudomallei DNA in Formalin-Fixed, Paraffin-Embedded Tissues. AB - The extraction and further processing of nucleic acids (NA) from formalin-fixed paraffin-embedded (FFPE) tissues for microbiological diagnostic polymerase chain reaction (PCR) approaches is challenging. Here, we assessed the effects of five different commercially available nucleic acid extraction kits on the results of real-time PCR. FFPE samples from organs of Burkholderia pseudomallei-infected Swiss mice were subjected to processing with five different extraction kits from QIAGEN (FFPE DNA Tissue Kit, EZ1 DNA Tissue Kit, DNA Mini Kit, DNA Blood Mini Kit, and FlexiGene DNA Kit) in combination with three different real-time PCRs targeting B. pseudomallei-specific sequences of varying length after 16 years of storage. The EZ1 DNA Tissue Kit and the DNA Mini Kit scored best regarding the numbers of successful PCR reactions. In case of positive PCR, differences regarding the cycle-threshold (Ct) values were marginal. The impact of the applied extraction kits on the reliability of PCR from FFPE material seems to be low. Interfering factors like the quality of the dewaxing procedure or the sample age appear more important than the selection of specialized FFPE kits. PMID- 27766175 TI - Possible Relation between Lack of Posterior Vitreous Detachment and Severe Endogenous Endophthalmitis. AB - Purpose. Endogenous endophthalmitis (EE) is a rare ocular disease caused by bacterial or fungal infection of intraocular spaces by hematogenous spread of pathogens from distant infectious loci in the body. We investigated the clinical characteristics and management of eyes with EE in ten consecutive patients. Methods. Ten patients (10 eyes) with EE treated at Tokyo Medical University Hospital in 2014 were reviewed. We retrospectively studied the causative organisms, systemic complications, pre/postoperative mean best-corrected visual acuity (BCVA), and status of posterior vitreous detachment (PVD). Results. The 10 patients comprised 8 males and 2 females, with mean age of 71.2 years. The causative organisms were bacteria in 6 eyes and fungi in 4 eyes. Systemic complications included septicemia or disseminated intravascular coagulation in 5 patients and diabetes mellitus in 4 patients. Postoperative BCVA was improved by 0.2log?MAR or greater in 4 eyes and decreased in 4 eyes. Vitrectomy was performed in all eyes, and 4 required multiple surgeries. During vitrectomy, PVD was absent in 8 eyes, 4 of which showed retinal necrosis. The mean age of patients with no PVD was 71.2 years. Conclusion. Despite an advanced age, PVD was absent in the majority of patients with EE. PVD may be related to the pathogenesis and aggravation of EE. PMID- 27766176 TI - One-Step Posterior and Anterior Combined Approach for L5 Retroperitoneal Schwannoma Eroding a Lumbar Vertebra. AB - We report the case of a large lumbar schwannoma eroding the vertebra and originating from spinal canal with invasion of the retroperitoneal space. We also review all the cases in literature reporting lumbar schwannomas eroding the vertebral bodies and invading the retroperitoneal space focusing on the surgical strategies to manage them. Spinal CT-scan revealed a 44 mm * 55 mm inhomogeneous soft-tissue mass arising from the right L5-S1 neural foramen and its most anterior portion had a clear colliquative aspect. Magnetic resonance image showed a neoplastic lesion with homogeneous low signal in T1WI, heterogeneous signal in T2WI, and strong enhancement in postgadolinium examination. It developed as well in the retroperitoneal space, posteriorly to the iliac vein, up to the psoas muscle with wide erosion of the omolateral conjugate foramen. We performed a one step combined approach together with the vascular surgeon because the lesion was too huge to allow a complete resection via a posterior approach and furthermore its tight relationship with the psoas muscle and the iliac vessels in the retroperitoneal space should be more safely managed via a retroperitoneal approach. We strongly suggest a 1-step surgery first approaching the dumbbell and the intraspinal schwannomas posteriorly achieving the decompression of the spinal canal and the cleavage of the tumor cutting the root of origin and the vascular supply and valuating the stability of the spine for potential artrodesis procedure. The patient must be then operated on via a retroperitoneal approach achieving the complete en bloc resection of the tumor. PMID- 27766177 TI - Direct Analysis of Pharmaceutical Drugs Using Nano-DESI MS. AB - Counterfeit pharmaceutical drugs imply an increasing threat to the global public health. It is necessary to have systems to control the products that reach the market and to detect falsified medicines. In this work, molecules in several pharmaceutical tablets were directly analyzed using nanospray desorption electrospray ionization mass spectrometry (nano-DESI MS). Nano-DESI is an ambient surface sampling technique which enables sampling of molecules directly from the surface of the tablets without any sample pretreatment. Both the active pharmaceutical ingredients (APIs) and some excipients were detected in all analyzed tablets. Principal component analysis was used to analyze mass spectral features from different tablets showing strong clustering between tablets with different APIs. The obtained results suggest nano-DESI MS as future tool for forensic analysis to discern APIs present in unknown tablet samples. PMID- 27766178 TI - Total Arsenic, Cadmium, and Lead Determination in Brazilian Rice Samples Using ICP-MS. AB - This study is aimed at investigating a suitable method for rice sample preparation as well as validating and applying the method for monitoring the concentration of total arsenic, cadmium, and lead in rice by using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Various rice sample preparation procedures were evaluated. The analytical method was validated by measuring several parameters including limit of detection (LOD), limit of quantification (LOQ), linearity, relative bias, and repeatability. Regarding the sample preparation, recoveries of spiked samples were within the acceptable range from 89.3 to 98.2% for muffle furnace, 94.2 to 103.3% for heating block, 81.0 to 115.0% for hot plate, and 92.8 to 108.2% for microwave. Validation parameters showed that the method fits for its purpose, being the total arsenic, cadmium, and lead within the Brazilian Legislation limits. The method was applied for analyzing 37 rice samples (including polished, brown, and parboiled), consumed by the Brazilian population. The total arsenic, cadmium, and lead contents were lower than the established legislative values, except for total arsenic in one brown rice sample. This study indicated the need to establish monitoring programs for emphasizing the study on this type of cereal, aiming at promoting the Public Health. PMID- 27766179 TI - Construction of a Turn Off-On-Off Fluorescent System Based on Competitive Coordination of Cu2+ between 6,7-Dihydroxycoumarin and Pyrophosphate Ion for Sensitive Assay of Pyrophosphatase Activity. AB - The detection of pyrophosphatase (PPase) activity is of great significance in diagnosing diseases and understanding the function of PPase-related biological events. This study constructed a turn off-on-off fluorescent system for PPase activity assay based on PPase-regulated competitive coordination of Cu2+ between a water-soluble fluorescent probe 6,7-dihydroxycoumarin (DHC) and pyrophosphate (PPi). The probe DHC can coordinate with Cu2+ and consequently display on-off type fluorescence response. Furthermore, the in situ formed nonfluorescent Cu2+ DHC complex can act as an effective off-on type fluorescent probe for sensing PPi due to the higher coordination reactivity between Cu2+ and PPi than that between Cu2+ and DHC. The subsequent addition of PPase to the mixture containing Cu2+, DHC, and PPi leads to the fluorescence requenching of the system again (an off state) because PPase catalyzes the hydrolysis of PPi into orthophosphate in the reaction system. Under the optimum conditions, the decrease of the fluorescence intensity of DHC-Cu2+-PPi system was linear with the increase of the PPase activity in the range from 0.1 to 0.3 U. The detection limit was down to 0.028 U PPase (S/N = 3). Moreover, the as-established system was also applied to evaluate PPase inhibitor. This study offers a simple yet effective method for the detection of PPase activity. PMID- 27766180 TI - Investigation of a measles outbreak in Cordillera, Northern Philippines, 2013. AB - INTRODUCTION: Measles is a highly infectious viral illness that remains one of the leading causes of death among children worldwide. In the Philippines, decreasing routine vaccination coverage from 2007 to 2011 led to local measles outbreaks. A team investigated a measles outbreak reported in Cordillera of the Philippines in May 2013. METHODS: Measles case data with symptom onset from 2 February to 27 May 2013 were obtained from official sources and verified on site. Data included age, sex, residential address, signs and symptoms and vaccination status. Active case-findings were also conducted for contacts of these cases. The living environments of the cases were investigated. A survey was conducted with the cases and caregivers to understand their knowledge and attitudes about measles. RESULTS: There were 50 measles cases identified with an age range from six months to 32 years (median: 16 years). Thirty-two were male (64%). Twenty (40%) were hospitalized with one death. Thirty-two (64%) cases were laboratory confirmed, and 36 (72%) received a single dose of measles vaccine. Overcrowded living environments were observed among many cases. The majority of respondents (46/48, 96%) knew about measles, but there were misconceptions about the cause of measles and how it can be prevented and managed. CONCLUSION: This measles outbreak occurred in an area with low immunization coverage. Achieving 95% measles immunization coverage and strengthening routine immunization strategies to address high-risk populations are recommended. Also, we recommend health education campaigns to include components that address misconceptions about measles. PMID- 27766182 TI - Causal Clustering for 1-Factor Measurement Models. AB - Many scientific research programs aim to learn the causal structure of real world phenomena. This learning problem is made more difficult when the target of study cannot be directly observed. One strategy commonly used by social scientists is to create measurable "indicator" variables that covary with the latent variables of interest. Before leveraging the indicator variables to learn about the latent variables, however, one needs a measurement model of the causal relations between the indicators and their corresponding latents. These measurement models are a special class of Bayesian networks. This paper addresses the problem of reliably inferring measurement models from measured indicators, without prior knowledge of the causal relations or the number of latent variables. We present a provably correct novel algorithm, FindOneFactorClusters (FOFC), for solving this inference problem. Compared to other state of the art algorithms, FOFC is faster, scales to larger sets of indicators, and is more reliable at small sample sizes. We also present the first correctness proofs for this problem that do not assume linearity or acyclicity among the latent variables. PMID- 27766181 TI - Enhanced syndromic surveillance for mass gatherings in the Pacific: a case study of the 11th Festival of Pacific Arts in Solomon Islands, 2012. AB - Mass gatherings pose public health challenges to host countries, as they can cause or exacerbate disease outbreaks within the host location or elsewhere. In July 2012, the 11th Festival of Pacific Arts (FOPA), a mass gathering event involving 22 Pacific island states and territories, was hosted by Solomon Islands. An enhanced syndromic surveillance (ESS) system was implemented for the event. Throughout the capital city, Honiara, 15 sentinel sites were established and successfully took part in the ESS system, which commenced one week before the FOPA (25 June) and concluded eight days after the event (22 July). The ESS involved expanding on the existing syndromic surveillance parameters: from one to 15 sentinel sites, from four to eight syndromes, from aggregated to case-based reporting and from weekly to daily reporting. A web-based system was developed to enable data entry, data storage and data analysis. Towards the end of the ESS period, a focus group discussion and series of key informant interviews were conducted. The ESS was considered a success and played an important role in the early detection of possible outbreaks. For the period of the ESS, 1668 patients with syndrome presentations were received across the 15 sentinel sites. There were no major events of public health significance. Several lessons were learnt that are relevant to ESS in mass gathering scenarios, including the importance of having adequate lead in time for engagement and preparation to ensure appropriate policy and institutional frameworks are put in place. PMID- 27766184 TI - SUV measurement of normal vertebrae using SPECT/CT with Tc-99m methylene diphosphonate. AB - The purpose of this study is to perform quantitative measurement based on the standardized uptake value (SUV) of the uptake of Tc-99m methylene diphosphonate (MDP) in the normal vertebrae using a single photon emission tomography (SPECT)/computed tomography (CT) scanner. A retrospective study of patients with cancer or joint disorders was performed. We acquired data for a group of 29 patients (8 women and 21 men; mean age, 68.2 +/- 6.7 years; age range, 44-87 years) undergoing bone SPECT/CT scans with Tc-99m MDP between September and October 2015. Various SUVs were calculated based on body-weight, lean-body-weight (lbw), Japanese lean-body-weight (jlbw) and Japanese bone-mineral-content (jbmc). SUVs of normal vertebrae showed a wide range of values. Among these, the maximum body-weight based SUV showed the lowest coefficient of variation. The SUVs also showed relatively small intra-subject variability. In addition, all SUVs showed moderate and significant correlation with height. Moreover, lbw-, jlbw-, and jbmc based SUVs of men were significantly higher than those of women. In conclusions, SUVs of normal vertebrae showed a relatively large inter-individual variability and small intra-individual variability. As a quantitative imaging biomarker, SUVs might require standardization with adequate reference data for the same subject to minimize variability. PMID- 27766185 TI - Validation of true low-dose 18F-FDG PET of the brain. AB - The dosage of 18F-FDG must be sufficient to ensure adequate PET image quality. For younger patients and research controls, the lowest possible radiation dose should be used. The purpose of this study was to find a protocol for FDG-PET of the brain with reduced radiation dose and preserved quantitative characteristics. Eight patients with neurodegenerative disorders and nine controls (n=17) underwent FDG-PET/CT twice on separate occasions, first with normal-dose (3 MBq/kg), and second with low-dose (0.75 MBq/kg, 25% of the original). Five additional controls (total n=22) underwent FDG-PET twice, using normal-dose and ultra-low-dose (0.3 MBq/kg, 10% of original). All subjects underwent MRI. Ten minute summation images were spatially normalized and intensity normalized. Regional standard uptake value ratios (SUV-r) were calculated using an automated atlas. SUV-r values from the normal- and low-dose images were compared pairwise. No clinically significant bias was found in any of the three groups. The mean absolute difference in regional SUV-r values was 0.015 (1.32%) in controls and 0.019 (1.67%) in patients. The ultra-low-dose protocol produced a slightly higher mean difference of 0.023 (2.10%). The main conclusion is that 0.75 MBq/kg (56 MBq for a 75-kg subject) is a sufficient FDG dose for evaluating regional SUV-ratios in brain PET scans in adults with or without neurodegenerative disease, resulting in a reduction of total PET/CT effective dose from 4.54 to 1.15 mSv. The ultra low-dose (0.5 mSv) could be useful in research studies requiring serial PET in healthy controls or children. PMID- 27766186 TI - Prediction of positron emission tomography/computed tomography (PET/CT) positivity in patients with high-risk primary melanoma. AB - Positron emission tomography/computed tomography (PET/CT) is an important tool to identify occult melanoma metastasis. To date, it is controversial which patients with primary cutaneous melanoma should have staging PET/CT. In this retrospective analysis of more than 800 consecutive patients with cutaneous melanoma, we sought to identify factors predictive of PET/CT positivity in the setting of newly diagnosed high-risk primary melanoma to determine those patients most appropriate to undergo a PET/CT scan as part of their diagnostic work up. 167 patients with newly-diagnosed high-risk primary cutaneous melanoma underwent a PET/CT scan performed as part of their initial staging. Clinical and histologic factors were evaluated as possible predictors of melanoma metastasis identified on PET/CT scanning using both univariate and multivariate logistic regression. In all, 32 patients (19.2%) had a positive PET/CT finding of metastatic melanoma. In more than half of these patients (56.3%), PET/CT scanning identified disease that was not detectable on clinical examination. Mitotic rate, tumor thickness, lymphadenopathy, and bleeding were significantly predictive of PET/CT positivity. A combinatorial index constructed from these factors revealed a significant association between number of high-risk factors observed and prevalence of PET/CT positivity, which increased from 5.8% (with the presence of 0-2 factors) to 100.0%, when all four factors were present. These results indicate that combining clinical and histologic prognostic factors enables the identification of patients with a higher likelihood of a positive PET/CT scan. PMID- 27766187 TI - Summary of Human Ankle Mechanical Impedance During Walking. AB - The human ankle joint plays a critical role during walking and understanding the biomechanical factors that govern ankle behavior and provides fundamental insight into normal and pathologically altered gait. Previous researchers have comprehensively studied ankle joint kinetics and kinematics during many biomechanical tasks, including locomotion; however, only recently have researchers been able to quantify how the mechanical impedance of the ankle varies during walking. The mechanical impedance describes the dynamic relationship between the joint position and the joint torque during perturbation, and is often represented in terms of stiffness, damping, and inertia. The purpose of this short communication is to unify the results of the first two studies measuring ankle mechanical impedance in the sagittal plane during walking, where each study investigated differing regions of the gait cycle. Rouse et al. measured ankle impedance from late loading response to terminal stance, where Lee et al. quantified ankle impedance from pre-swing to early loading response. While stiffness component of impedance increases significantly as the stance phase of walking progressed, the change in damping during the gait cycle is much less than the changes observed in stiffness. In addition, both stiffness and damping remained low during the swing phase of walking. Future work will focus on quantifying impedance during the "push off" region of stance phase, as well as measurement of these properties in the coronal plane. PMID- 27766188 TI - Healthcare Commercialization Programs: Improving the Efficiency of Translating Healthcare Innovations From Academia Into Practice. AB - Academic investigators are generating a plethora of insights and technologies that have the potential to significantly improve patient care. However, to address the imperative to improve the quality, cost and access to care with ever more constrained funding, the efficiency and the consistency with which they are translated into cost effective products and/or services need to improve. Healthcare commercialization programs (HCPs) are described and proposed as an option that institutions can add to their portfolio to improve translational research. In helping teams translate specific healthcare innovations into practice, HCPs expand the skillset of investigators and enhance an institution's innovation capacity. Lessons learned are shared from configuring and delivering HCPs, which build on the fundamentals of the National Science Foundation's Innovation Corps program, to address the unique challenges in supporting healthcare innovations and innovators. PMID- 27766189 TI - Correction: Lumbosacral Osteomyelitis and Discitis with Phlegmon Following Laparoscopic Sacral Colpopexy. AB - [This corrects the article DOI: 10.7759/cureus.671.]. PMID- 27766183 TI - Genetic engineered molecular imaging probes for applications in cell therapy: emphasis on MRI approach. AB - Recent advances in stem cell-based regenerative medicine, cell replacement therapy, and genome editing technologies (i.e. CRISPR-Cas 9) have sparked great interest in in vivo cell monitoring. Molecular imaging promises a unique approach to noninvasively monitor cellular and molecular phenomena, including cell survival, migration, proliferation, and even differentiation at the whole organismal level. Several imaging modalities and strategies have been explored for monitoring cell grafts in vivo. We begin this review with an introduction describing the progress in stem cell technology, with a perspective toward cell replacement therapy. The importance of molecular imaging in reporting and assessing the status of cell grafts and their relation to the local microenvironment is highlighted since the current knowledge gap is one of the major obstacles in clinical translation of stem cell therapy. Based on currently available imaging techniques, we provide a brief discussion on the pros and cons of each imaging modality used for monitoring cell grafts with particular emphasis on magnetic resonance imaging (MRI) and the reporter gene approach. Finally, we conclude with a comprehensive discussion of future directions of applying molecular imaging in regenerative medicine to emphasize further the importance of correlating cell graft conditions and clinical outcomes to advance regenerative medicine. PMID- 27766190 TI - Somatization in Post-Concussion Syndrome: A Retrospective Study. AB - This is a retrospective study of concussion patient data conducted to analyze the prevalence of somatization in patients presenting with post-concussion symptoms. Patient records from June 2010 to December 2015 were examined for concussion history, psychosocial history, neuropsychological test results, validity scores, and a symptom severity scale. Records meeting inclusion criteria from 33 males and 27 females were located. The sample had an age range of 11-78 years with a mean age of 33.40 (SD +/- 7.5 years). A clinically significant number of patients (55%) were found to be somaticizing their symptoms and a significant majority (78%) of somaticizing patients reported no loss of consciousness, retrograde amnesia, or post-traumatic amnesia but their symptom validity scales were significantly exaggerated. Caution should be exercised by clinicians to ensure that the obtained results of neuropsychological testing are reliable and valid. It is very important for the clinician to take into account the entire patient history, including psychosocial factors (such as pre-existing psychological traits or conditions) and social influences (such as stressors in family dynamics or work/school activities that may be affecting the patient's complaints). PMID- 27766191 TI - Vertebral Column Resection for Kyphoscoliosis in a Patient with Ehlers-Danlos Syndrome: An Intraoperative Neurophysiological Monitoring Alert. AB - A 16-year-old male patient with Ehler-Danlos syndrome (EDS) and a back deformity since birth presented with severe kyphoscoliosis. The patient was neurologically intact but had respiratory and cardiac insufficiencies. A two-stage vertebral column resection (VCR) at T9-T10 with multiple level fusion with multimodality intraoperative neurophysiological monitoring (IONM) was planned. During the first stage, pedicle screws were placed at multiple spinal levels above and below the VCR level. Upper and lower somatosensory evoked potentials (SSEP), transcranial electrical motor evoked potentials (TCeMEP), and electromyography were monitored continuously and showed no significant changes. The second stage was performed one week later. Baseline SSEP and TCeMEP responses were present in all extremities. The surgeon was informed of a sudden 70% amplitude drop in TCeMEP in the lower limbs with stable SSEP after ligating one of the left nerves/vessels fully stretching the spinal cord. The surgeon removed the ligation, and an improvement in motor responses followed. Surgery proceeded with the highest levels of caution. Later, there was a sudden loss of TCeMEP and SSEP in the lower limbs bilaterally. The correction was released, mean arterial pressure was increased, and intravenous dexamethasone was administered. The surgical correction was aborted, and the decision was made to close the site. Lower SSEP and TCeMEP responses remained absent until closing, while upper SSEP and TCeMEP responses remained stable. A wake-up test was done after closing. The patient moved his upper limbs but was unable to move his lower limbs bilaterally. The patient was sent for a magnetic resonance imaging scan while intubated and then sent to the intensive care unit. At 24 hours and 36 hours post-operation, the patient had no sensory and motor function below the T8 level. Forty-eight hours post-operation, the patient started to feel sensory stimuli at the T10 level. At one week post-operation, the patient regained sphincter functions, and at four weeks postoperatively, the patient's hip flexors started to recover. VCR in patients with EDS has a very high risk of damaging the spinal cord due to the fragile vasculature of the spinal cord. Real-time IONM is useful in the early identification of spinal cord injury in cases of this nature. PMID- 27766193 TI - Kinematic analysis and fault-tolerant trajectory planning of space manipulator under a single joint failure. AB - A space manipulator plays an important role in spacecraft capturing, repairing, maintenance, and so on. However, the harsh space environment will cause its joints fail to work. For a non-redundant manipulator, single joint locked failure will cause it to lose one degree of freedom (DOF), hence reducing its movement ability. In this paper, the key problems related to the fault-tolerant including kinematics, workspace, and trajectory planning of a non-redundant space manipulator under single joint failure are handled. First, the analytical inverse kinematics equations are derived for the 5-DOF manipulator formed by locking the failure joint of the original 6-DOF manipulator. Then, the reachable end-effector pose (position and orientation) is determined. Further, we define the missions can be completed by the 5-DOF manipulator. According to the constraints of the on orbital mission, we determine the grasp envelope required for the end-effector. Combining the manipulability of the manipulator and the performance of its end effector, a fault tolerance parameter is defined and a planning method is proposed to generate the reasonable trajectory, based on which the 5-DOF manipulator can complete the desired tasks. Finally, typical cases are simulated and the simulation results verify the proposed method. PMID- 27766194 TI - Pediatric Kidney Stones - Avoidance and Treatment. AB - Pediatric stone disease is increasing in incidence and healthcare costs. With more years at-risk for stone recurrence during their lifetimes, children with nephrolithiasis constitute a high-risk patient population that requires focused intervention through both medical and surgical means. Through high-quality future studies to compare methods of stone prevention and treatment, the burden of stone disease on the youngest members of society may be ameliorated. PMID- 27766195 TI - Reversible cardiomyopathy secondary to Amphotericin-B. AB - We describe a 32-yr old woman with AIDS and cryptococcal meningitis that developed cardiomyopathy after 17 days of treatment with Deoxycholate Amphotericin-B (D-Amb) with reversal of the symptoms and transthoracic echocardiogram (TTE) findings after the drug had been stopped and switched to Fluconazole. PMID- 27766196 TI - A case of rhino-orbital mucormycosis in diabetes with haematogenous cerebral spread. AB - We document the first case of haematogenous cerebral spread in Rhizopus arrhizus rhino-orbital mucormycosis, and of posaconazole related adrenal insufficiency. A patient presenting with diabetic ketoacidosis and sinusitis was treated with right medial maxillectomy, ethmoidectomy and IV liposomal amphotericin. Orbital exenteration was performed after intraorbital spread of infection. IV caspofungin and posaconazole was added but complicated by adrenal insufficiency. MRI revealed a new left lentiform nucleus and thalamus rim-enhancing lesion indicating haematogenous cerebral spread. PMID- 27766192 TI - Aerobic Exercise in People with Schizophrenia: Neural and Neurocognitive Benefits. AB - Schizophrenia is characterized by extensive neurocognitive deficits, which are linked to greater disability, poorer functional outcome, and have been suggested to impact daily functioning more than clinical symptoms. Aerobic exercise (AE) has emerged as a potential intervention. This review examines the impact of AE on brain structure and function along with neurocognitive performance in individuals with schizophrenia. Preliminary evidence indicates that AE can increase hippocampal volume and cortical thickness, in addition to exerting a neuroprotective effect against hippocampal volume decrease and cortical thinning. There is also evidence that AE is able to significantly increase serum brain derived neurotrophic factor (BDNF) levels, which are implicated in neurogenesis, neuroplasticity, and cognitive improvement. Finally, evidence suggests that AE plays a significant role in improving overall cognition, including improvements in processing speed, working memory, and visual learning. The authors discuss the implications of the findings and provide recommendations for future research and areas of inquiry. PMID- 27766198 TI - IgG4 related lung disease extending to the thoracic vertebrae. AB - IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect practically every organ. Although it was first identified in pancreas and salivary glands, major organs like liver, biliary tree, kidney, thyroid glands and lungs are commonly involved, sometimes resulting in organ failure. We describe a case of an 41-year-old man presented with back pain after a rotator cuff injury. A Computed Tomography (CT) revealed incidentally a right lower lobe paravertebral lesion extending across the T5 and T6 vertebral levels and invading into the adjacent pleural surface. The laboratory findings and the CT guided biopsy were inconclusive. Morphological and immunohistochemical findings after a lung biopsy by video-assisted thoracic surgery (VATS) were suggestive to IgG4 related lung disease (IgG4-RLD), which was confirmed with high serum levels of IgG4. This represents the first case of a IgG4-RLD lesion located in the mediastinum and extending to the adjacent pleural surface and vertebrae and should be included in the differential diagnosis of posterior mediastinal masses. PMID- 27766197 TI - Uremic lung: The "calcified cauliflower" sign in the end stage renal disease. AB - Metastatic pulmonary calcification (MPC) is a rare pathological condition consisting of lung calcium salt deposits which commonly occurs in patients affected by chronic kidney disease probably for some abnormalities in calcium and phosphate metabolism. CT represents the technique of choice for detecting MPC findings including ground glass opacities and partially calcified nodules or consolidations. We present a case of MCP in a patient affected by hepato-renal autosomic-dominant polycystic disease; chest CT revealed extensive lobar segmental parenchymal calcification with a peculiar cauliflower shape which we called "calcified cauliflower" sign. The "calcified cauliflower" sign can be reported as a new CT pattern of uremic lung that needs to be identified for a correct diagnosis and patient management. PMID- 27766199 TI - A case of lipoid pneumonia caused by inhalation of vaporized paraffin from burning candles. AB - A 66-year-old woman was referred to our hospital for investigation of interstitial lung disease. She had spent most of her time in a shrine, and had always been exposed to vaporized paraffin from burning candles. Chest High resolution computed tomography (HRCT)showed ground-glass attenuation with thickening of septal lines, wh create the so-called "crazy-paving appearance". Although bronchoalveolar lavage(BAL) and transbronchial biopsy were performed to aid in diagnosis, the findings did not reveal any conclusive information. Improvements on chest radiographs and in the patient's symptoms were observed without any therapeutic intervention; however, one year later, her chest X-ray showed deteriorative changes. Surgical lung biopsy was performed, and the pathological findings were consistent with those of lipoid pneumonia. The patient showed spontaneous remission of the disease. The cause of exogenous lipoid pneumonia was attributed to inhalation of vaporized paraffin from burning candles in the shrine. This is the first case of lipoid pneumonia that was found to develop from exposure to vaporized paraffin. PMID- 27766200 TI - Glomus tumor in teen and repetition pneumonia: Case report. AB - Glomus tumors are uncommon tumors that are originated from smooth muscle cells of the neuromioarterials glomus bodies located in the arteriovenous anastomoses subcutaneous tissue or deep dermis of the extremities, mainly in the palms of the hands, wrists and subungual areas of the fingers. Carcinoid tumor, as the glomus tumor, can show an organoid pattern, increased vascularity, and uniform, round cells with eosinophilic cytoplasm, but usually are positive for cytokeratin and always stained with chromogranin and synaptophysin showing negative for smooth muscle markers which is presented in our case. Glomus tumors have a good prognosis and surgical resection is the treatment of choice. In our case, the patient underwent pulmonary bilobectomy because of the location of the tumor in the transition between the middle lobe and the basal bronchial trunk right lower lobe divisions. It is presented thus a glomus tumor with exceptional localization (pulmonary and bronchial) of benign histological features, according to most of the cases reported in the literature emphasizing their particular rare location, histological, and immunohistochemical profile, which helps the differential diagnosis with other most common tumors of bronchial location. PMID- 27766201 TI - Unusual complication of bronchoscopy. AB - In the last twenty years, the field of bronchoscopy has become increasingly more complex and invasive. It is now widely used in the management of pulmonary diseases and has the benefit of low mortality and complication rates. Overall incidence of complications and mortality reported ranges around 1% and 0.02% respectively. Common complications of bronchoscopy include pulmonary haemorrhage, desaturation, pneumothorax, and pulmonary oedema. However, facial and neck petechiae associated with subcutaneous hemorrhage post-bronchoscopy has not been reported before in the literature. We hereby report two novel cases of facial/neck petechiae post-bronchoscopy as a complication to be recognized by bronchoscopists. It is essential that bronchoscopists recognise such phenomenon as the clinical presentation is visually alarming to both the patient and clinician. It is usually self-resolving. However such presentation after bronchoscopy may trigger extensive and unnecessary investigations from the physician. PMID- 27766202 TI - Pharmaco fMRI: Determining the functional anatomy of the effects of medication. AB - Functional MRI studies have helped to elucidate underlying mechanisms in complex neurological and neuropsychiatric disorders. Disease processes often involve complex large-scale network interactions, extending beyond the presumed main disease focus. Given both the complexity of the clinical phenotype and the underlying dysfunctional brain circuits, so called pharmaco-fMRI (ph-MRI) studies probe pharmacological effects on functional neuro-anatomy, and can help to determine early treatment response, mechanisms of drug efficacy and side effects, and potentially advance CNS drug development. In this review, we discuss recent ph-MRI research in three major neuropsychiatric and neurological disorders and associated network alterations, namely selective serotonin and noradrenergic reuptake inhibitors in affective disorders and emotional processing circuits; antiepileptic drugs in epilepsy and cognitive networks; and stimulants in attention-deficit/hyperactivity disorder and networks of attention control. We conclude that ph-MRI studies show consistent and reproducible changes on disease relevant networks, and prove sensitive to early pharmacological effects on functional anatomy associated with disease. Further CNS drug research and development would benefit greatly from improved disease phenotyping, or biomarkers, using advanced imaging techniques. PMID- 27766206 TI - Transcript profiling in the liver of early-lactating dairy cows fed conjugated linoleic acid. AB - In the present study, transcript profiling was carried out in liver biopsies from high-yielding dairy cows at week 5 of lactation in order to identify genes and pathways regulated by feeding rumen-protected conjugated linoleic acid (CLA) during the transition period. Analysis of a bovine whole genome microarray revealed a total number of 130 annotated differentially expressed genes (DEGs) in the liver between cows of the CLA group and the control group (filter: P < 0.05 and fold change (FC) >= 1.3 or <=- 1.3). The number of DEGs in the liver being up regulated was markedly higher than that being down-regulated (86 vs. 44). Gene set enrichment analysis revealed that the most enriched biological processes and molecular functions assigned to the 86 up-regulated genes were S methyltransferase activity, ribonucleoprotein complex biogenesis, homocysteine S methyltransferase activity, methionine biosynthetic process and spliceosome assembly, while the most enriched biological processes and molecular functions assigned to the 44 down-regulated genes were exopeptidase activity, cytokinesis after mitosis, cytokinesis during cell cycle, protein serine/threonine kinase activity and cytokinesis. The microarray dataset from this study has been deposited in NCBI's Gene Expression Omnibus under the accession number GSE87391. PMID- 27766205 TI - High concordance between Illumina HiSeq2500 and NextSeq500 for reduced representation bisulfite sequencing (RRBS). AB - Reduced representation bisulfite sequencing (RRBS) provides an efficient method for measuring DNA methylation at single base resolution in regions of high CpG density. This technique has been extensively tested on the HiSeq2500, which uses a 4-colour detection method, however it is unclear if the method will also work on the NextSeq500 platform, which employs a 2-colour detection system. We created an RRBS library and sequenced it on both the HiSeq2500 and NextSeq500, and found no significant difference in the base composition of reads derived from either machine. Moreover, the methylation calls made from the data of each instrument were highly concordant, with methylation patterns across the genome appearing as expected. Therefore, RRBS can be sequenced on the Nextseq500 with comparable quality to that of the HiSeq2500. All sequencing data are deposited in the GEO database under accession number GSE87097. PMID- 27766204 TI - Draft genome sequence of Staphylococcus hominis strain Hudgins isolated from human skin implicates metabolic versatility and several virulence determinants. AB - Staphylococcus hominis is a predominant member of the human skin microbiome. We here report on the genomic analysis of Staphylococcus hominis strain Hudgins that was isolated from the wrist area of human skin. The partial genome assembly of S. hominis Hudgins consists of 2,211,863 bp of DNA with 2174 protein-coding genes and 90 RNA genes. Based on the genomic analysis of KEGG pathways, the organism is expected to be a versatile heterotroph potentially capable of hydrolyzing the sugars glucose, fructose, mannose, and the amino acids alanine, aspartate, glutamate, glycine, threonine, cysteine, methionine, valine, isoleucine, leucine, lysine, arginine, phenylalanine, tyrosine, and tryptophan for energy production through aerobic respiration, with occasional lactate and acetate fermentation. Evidence for poly-gamma glutamate capsule and type IV Com system pili were identified in the genome. Based on COG analysis, the genome of S. hominis Hudgins clusters away from the previously published S. hominis genome ZBW5. PMID- 27766207 TI - Leading edge analysis of transcriptomic changes during pseudorabies virus infection. AB - Eight RNA samples taken from the tracheobronchial lymph nodes (TBLN) of pigs that were either infected or non-infected with a feral isolate of porcine pseudorabies virus (PRV) were used to investigate changes in gene expression related to the pathogen. The RNA was processed into fastq files for each library prior to being analyzed using Illumina Digital Gene Expression Tag Profiling sequences (DGETP) which were used as the downstream measure of differential expression. Analyzed tags consisted of 21 base pair sequences taken from time points 1, 3, 6, and 14 days' post infection (dpi) that generated 1,927,547 unique tag sequences. Tag sequences were analyzed for differential transcript expression and gene set enrichment analysis (GSEA) to uncover transcriptomic changes related to PRV pathology progression. In conjunction with the DGETP and GSEA, the study also incorporated use of leading edge analysis to help link the TBLN transcriptome data to clinical progression of PRV at each of the sampled time points. The purpose of this manuscript is to provide useful background on applying the leading edge analysis to GSEA and expression data to help identify genes considered to be of high biological interest. The data in the form of fastq files has been uploaded to the NCBI Gene Expression Omnibus (GEO) (GSE74473) database. PMID- 27766203 TI - A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder. AB - Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI). Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc) to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes. PMID- 27766209 TI - High resolution imaging of impacted CFRP composites with a fiber-optic laser ultrasound scanner. AB - Damage induced in polymer composites by various impacts must be evaluated to predict a component's post-impact strength and residual lifetime, especially when impacts occur in structures related to human safety (in aircraft, for example). X ray tomography is the conventional standard to study an internal structure with high resolution. However, it is of little use when the impacted area cannot be extracted from a structure. In addition, X-ray tomography is expensive and time consuming. Recently, we have demonstrated that a kHz-rate laser-ultrasound (LU) scanner is very efficient both for locating large defects and evaluating the material structure. Here, we show that high-quality images of damage produced by the LU scanner in impacted carbon-fiber reinforced polymer (CFRP) composites are similar to those produced by X-ray tomograms; but they can be obtained with only single-sided access to the object under study. Potentially, the LU method can be applied to large components in-situ. PMID- 27766210 TI - In-vivo handheld optoacoustic tomography of the human thyroid. AB - We interrogated the application and imaging features obtained by non-invasive and handheld optoacoustic imaging of the thyroid in-vivo. Optoacoustics can offer complementary contrast to ultrasound, by resolving optical absorption-based and offering speckle-free imaging. In particular we inquired whether vascular structures could be better resolved using optoacoustics. For this reason we developed a compact handheld version of real-time multispectral optoacoustic tomography (MSOT) using a detector adapted to the dimensions and overall geometry of the human neck. For delivering high-fidelity performance, a curved ultrasound array was employed. The feasibility of handheld thyroid MSOT was assessed on healthy human volunteers at single wavelength. The results were contrasted to ultrasound and Doppler ultrasound images obtained from the same volunteers. Imaging findings demonstrate the overall MSOT utility to accurately retrieve optical features consistent with the thyroid anatomy and the morphology of surrounding structures. PMID- 27766208 TI - In vivo photoacoustic tomography of EGFR overexpressed in hepatocellular carcinoma mouse xenograft. AB - EGFR is a promising cell surface target for in vivo imaging that is highly overexpressed in hepatocellular carcinoma (HCC), a common cancer worldwide. Peptides penetrate easily into tumors for deep imaging, and clear rapidly from the circulation to minimize background. We aim to demonstrate use of an EGFR specific peptide to detect HCC xenograft tumors in mice with photoacoustic imaging. Nude mice implanted with human HCC cells that overexpress EGFR were injected intravenously with Cy5.5-labeled EGFR and scrambled control peptides respectively. Photoacoustic images collected from 0 to 24 h. Photoacoustic signal peaked in tumors at 3 h post-injection. Images from 0 to 1.8 cm beneath the skin revealed increased target-to-background (T/B) ratio from tumors. The T/B ratio was significantly greater for the EGFR versus control peptide. Clearance of signal was observed by ~24 h. EGFR overexpression was validated with immunofluorescence and immunohistochemistry. A peptide specific for EGFR delivered systemically can detect HCC xenograft tumors in vivo with photoacoustic imaging. PMID- 27766211 TI - Multiple irradiation sensing of the optical effective attenuation coefficient for spectral correction in handheld OA imaging. AB - Spectral optoacoustic (OA) imaging enables spatially-resolved measurement of blood oxygenation levels, based on the distinct optical absorption spectra of oxygenated and de-oxygenated blood. Wavelength-dependent optical attenuation in the bulk tissue, however, distorts the acquired OA spectrum and thus makes quantitative oxygenation measurements challenging. We demonstrate a correction for this spectral distortion without requiring a priori knowledge of the tissue optical properties, using the concept of multiple irradiation sensing: recording the OA signal amplitude of an absorbing structure (e.g. blood vessel), which serves as an intrinsic fluence detector, as function of irradiation position. This permits the reconstruction of the bulk effective optical attenuation coefficient MUeff,lambda . If performed at various irradiation wavelengths, a correction for the wavelength-dependent fluence attenuation is achieved, revealing accurate spectral information on the absorbing structures. Phantom studies were performed to show the potential of this technique for handheld clinical combined OA and ultrasound imaging. PMID- 27766212 TI - Vacuum system upgrade for extended Q-range small-angle neutron scattering diffractometer (EQ-SANS) at SNS. AB - The Extended Q-range Small-angle Neutron Scattering Diffractometer (EQ-SANS) instrument at the spallation neutron source (SNS), Oak Ridge, Tennessee, incorporates a 69 m3 detector vessel with a vacuum system which required an upgrade with respect to performance, ease of operation, and maintenance. The upgrade focused on improving pumping performance as well as optimizing system design to minimize opportunity for operational error. This upgrade provided the following practical contributions: *Reduced time required to evacuate from atmospheric pressure to 2 mTorr from 500 to 1000 min to 60-70 min*Provided turn key automated control with a multi-faceted interlock for personnel and machine safety. PMID- 27766214 TI - An Overview on Novel Microbial Determination Methods in Pharmaceutical and Food Quality Control. AB - Traditional microbiological methods tend to be labor-intensive and time consuming. Rapid and novel methods in microbiological tests provide more sensitive, precise and reproducible results compared with conventional methods. In microbiology, the most rapid testing methods belong to the field of biotechnology such as PCR, ELISA, ATP bioluminescence and etc. Nevertheless impedance microbiology, biosensors and analytical procedures to determine microbial constituents are of significance. The present review article was conducted using internet databases and related scientific literatures and articles that provide information on developments in the rapid methods in microbiology. The main focus is on the application of rapid methods in microbial quality control of pharmaceutical products. Reviewed literature showed that rapid methods and automation in microbiology is an advanced area for studying and applying of improved methods in the early detection, and characterization of microorganisms and their products in food, pharmaceutical and cosmetic industrials as well as environmental monitoring and clinical applications. It can be concluded that rapid methods and automation in microbiology should continue as potent and efficient technologies to develop the novel tests to be performed in the future because of the ever-increasing concerns about the safety of food and pharmaceutical products. However the main issues to be considered are the scale up of developed methods and the regulatory requirements. PMID- 27766215 TI - PEGylated Human Serum Albumin: Review of PEGylation, Purification and Characterization Methods. AB - Human serum albumin (HSA) is a non-glycosylated, negatively charged protein (Mw: about 65-kDa) that has one free cystein residue (Cys 34), and 17 disulfide bridges that these bridges have main role in its stability and longer biological life-time (15 to 19 days). As HSA is a multifunctional protein, it can also bind to other molecules and ions in addition to its role in maintaining colloidal osmotic pressure (COP) in various diseases. In critical illnesses changes in the level of albumin between the intravascular and extravascular compartments and the decrease in its serum concentration need to be compensated using exogenous albumin; but as the size of HSA is an important parameter in retention within the circulation, therefore increasing its molecular size and hydrodynamic radius of HSA by covalent attachment of poly ethylene glycol (PEG), that is known as PEGylation, provides HSA as a superior volume expander that not only can prevent the interstitial edema but also can reduce the infusion frequency. This review focuses on various PEGylation methods of HSA (solid phase and liquid phase), and compares various methods to purifiy and characterize the pegylated form. PMID- 27766213 TI - Mesenchymal Stem Cell-Derived Exosomes: New Opportunity in Cell-Free Therapy. AB - Mesenchymal stromal/stem cells (MSCs) are involved in tissue homeostasis through direct cell-to-cell interaction, as well as secretion of soluble factors. Exosomes are the sort of soluble biological mediators that obtained from MSCs cultured media in vitro. MSC-derived exosomes (MSC-DEs) which produced under physiological or pathological conditions are central mediators of intercellular communications by conveying proteins, lipids, mRNAs, siRNA, ribosomal RNAs and miRNAs to the neighbor or distant cells. MSC-DEs have been tested in various disease models, and the results have revealed that their functions are similar to those of MSCs. They have the supportive functions in organisms such as repairing tissue damages, suppressing inflammatory responses, and modulating the immune system. MSC-DEs are of great interest in the scope of regenerative medicine because of their unique capacity to the regeneration of the damaged tissues, and the present paper aims to introduce MSC-DEs as a novel hope in cell-free therapy. PMID- 27766217 TI - Evaluation of the Effect of Psyllium on the Viability of Lactobacillus Acidophilus in Alginate-Polyl Lysine Beads. AB - Purpose: Psylliumseeds are used in traditional herbal medicine to treat various disorders. Moreover, as a soluble fiber, psyllium has potential to stimulate bacterial growth in digestive system. We aimed to substitute alkali-extractable polysaccharides of psyllium for alginate in beads with second coat of poly-l lysine to coat Lactobacillus acidophilus. Methods: Beads were prepared using extrusion technique. Poly-l-lysine as second coat was incorporated on optimum alginate/psyllium beads using immersion technique. Beads were characterized in terms of size, encapsulation efficiency, integrity and bacterial survival in harsh conditions. Results: Beads with narrow size distribution ranging from 1.85 +/- 0.05 to 2.40 +/- 0.18 mm with encapsulation efficiency higher than 96% were achieved. Psyllium concentrations in beads did not produce constant trend in bead sizes. Surface topography by SEM showed that substitution of psyllium enhanced integrity of obtained beads. Psyllium successfully protected the bacteria against acidic condition and lyophilization equal to alginate in the beads. Better survivability with beads of alginate/psyllium-poly-l-lysine was achieved with around 2 log rise in bacterial count in acid condition compared to the corresponding single coat beads. Conclusion: Alginate/psyllium (1:2) beads with narrow size distribution and high encapsulation efficiency of the bacteria have been achieved. Presence of psyllium produced a much smoother and integrated surface texture for the beads with sufficient protection of the bacteria against acidic condition as much as alginate. Considering the health benefits of psyllium and its prebiotic activity, psyllium can be beneficially replaced in part for alginate in probiotic coating. PMID- 27766218 TI - Comparison of Different Nanosuspensions as Potential Ophthalmic Delivery Systems for Ketotifen Fumarate. AB - Purpose: The objective of this study was to develop, characterize, and comparatively investigate the ketotifen fumarate (KF) nanosuspensions (NSS) to enhance the permeability of KF. Methods: In the present work, the NSP and NSE were prepared by double-emulsion solvent evaporation/nanoprecipitation methods with poly (D,Llactide-co-glycolide) and Eudragit RL100 polymers, respectively. The loading efficiency, particle size, and polydispersity index of prepared different NSs were evaluated with scanning electron microscopy (SEM), X-ray diffraction, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro release and transcorneal permeation . NSs were also compared on the basis of particle size and polydispersity index. Results: Particle size, polydispersity index, and loading efficiency of NSP1 and NSE3 showed the best value (158 nm, 117 nm, 0.21, 0.43 and 43%, 95.23%, respectively). SEM showed spherical globules and DSC results showed the reduction in crystallinity. The NSE3 formulations demonstrated significantly (p<0.05) higher drug release rates than the NSP1 due to increases in the surface area. Comparative studies showed that NSE release and permeability are higher than NSP. Conclusion: It is concluded that both NSP and NSE provide a useful dosage form for the ocular drug delivery which can enhance the permeability of KF. PMID- 27766216 TI - Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective. AB - Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder. Method: We reviewed the PubMed databases and extracted several kinds of literature on neuro nanomedicines using keywords, CNS disorders, nanomedicine, and nanotechnology. The inclusion criteria included chemical and green synthesis methods for synthesis of nanoparticles encapsulated drugs and, their in-vivo and in-vitro studies. We excluded nanomedicine gene therapy and nanomaterial in brain imaging. Results: In this review, we tried to identify a highly efficient method for nanomedicine synthesis and their efficacy in neuronal disorders. SLN and PNP encapsulated drugs reported highly efficient by easily crossing BBB. Although, these neuro-nanomedicine play significant role in therapeutics but some metallic nanoparticles reported the adverse effect on developing the brain. Conclusion: Although impressive advancement has made via innovative potential drug development, but their efficacy is still moderate due to limited brain permeability. To overcome this constraint,powerful tool in CNS therapeutic intervention provided by nanotechnology-based drug delivery methods. Due to its small and biofunctionalization characteristics, nanomedicine can easily penetrate and facilitate the drug through the barrier. But still, understanding of their toxicity level, optimization and standardization are a long way to go. PMID- 27766220 TI - Enhanced in Vitro Anti-Tumor Activity of 5-Azacytidine by Entrapment into Solid Lipid Nanoparticles. AB - Purpose: In this study the effectiveness of encapsulating of 5-azacytidine into the lipid nanoparticles was investigated and in vitro effect of encapsulated 5 azacytidine studied on MCF-7 cell lines Methods: 5-azacytidine -loaded solid lipid nanoparticles were produced by double emulsification (w/o/w) method by using stearic acid as lipid matrix, soy lecithin and poloxamer 407 as surfactant and co-surfactant respectively. Particle size, zeta potential, surface morphology, entrapment efficiency and kinetic of drug release were studied. In vitro effect of 5-azacytidine on MCF-7 cell line studied by MTT assay, DAPI staining, Rhodamine B relative uptake, and also Real time RT-PCR was performed for studying difference effect of free and encapsulated drug on expression of RARbeta2 gene. Results: The formulation F5 with 55.84+/-0.46 % of entrapment efficiency shows zero order kinetic of drug release and selected for in vitro studies; the cytotoxicity of free drug and encapsulated drug in 48 h of incubation have significant difference. DAPI staining shows morphology of apoptotic nucleus in both free and encapsulated drug, Rhodamine B labeled SLNs show time dependency and accumulation of SLNs in cytoplasm. Real time qRT-PCR doesn't show any significant difference (p>0.05) in expression of RARbeta2 gene in both cells treated with free or encapsulated drug. Conclusion: The results of the present study indicated that the entrapment of 5-azacytidine into SLNs enhanced its cytotoxicity performance and may pave a way for the future design of a desired dosage form for 5-azacytidine. PMID- 27766219 TI - Osteogenic/Odontogenic Bioengineering with co-Administration of Simvastatin and Hydroxyapatite on Poly Caprolactone Based Nanofibrous Scaffold. AB - Purpose: Statin is an effective factor for promoting osteogenesis. The aim of the present study was to evaluate the effect of simvastatin (SIM) and/or HA addition on changes in osteogenesis levels by human DPSCs transferred onto three dimensional (3D) nanofibrous Poly (epsilon-caprolactone) (PCL)/Poly lactic acide (PLLA) polymeric scaffolds. Methods: For this purpose, a 3D nanofibrous composite scaffold of PCL/PLLA/HA was prepared by electrospinning method. SIM was added to scaffolds during DPSCs culturing step. Cell proliferation and osteogenic activity levels were assessed by using MTT assay and Alizarin Red assay methods. In addition, the expression of genes responsible for osteogenesis, including BMP2, Osteocalcin, DSPP and RUNX2, were determined before and 2 weeks after incorporation of SIM. Results: The MTT assay showed that PCL/PLLA/HA scaffolds seeded with DPSCs has significant (p<0.05) more proliferative effect than PCL/PLLA or DMEM cultured cells, additionally SIM administration improved this result over the PCL/PLLA/HA scaffolds without SIM treatment. SEM imaging revealed improved adhesion and probably osteogenic differentiation of DPSCs on PCL/PLLA/HA nanofibers treated with SIM, moreover the alizarin red assay ensured significant (p<0.05) higher mineralization of this group. Finally, real time PCR confirmed the positive regulation (P<0.05) of the expression of osteo/odontogenesis markers BMP2, Osteocalcin, DSPP and RUNX2 genes in PLLA-PCL-HA (0.1)-SIM group. Conclusion: As a result, addition of simvastatin with incorporation of hydroxyapatite in PCL-PLLA scaffolds might increase the expression of osteogenesis markers in the DPSCs, with a possible increase in cell differentiation and bone formation. PMID- 27766222 TI - Enhancement of Loperamide Dissolution Rate by Liquisolid Compact Technique. AB - Purpose: The aim of present study was to improve the dissolution rate of poorly soluble drug Loperamide (LPM) by liquisolid compact technique. Methods: Liquisolid compacts of LPM were prepared using Propylene glycol (PG) as a solvent, Avicel pH 102 as carrier, Aerosil as coating material and Sodium Starch Glycolate (SSG) as superdisintegrant. Interactions between the drug and excipients were examined by Fourier Transform Infrared (FTIR) spectroscopy. The dissolution studies for LPM liquisolid formulation, marketed product and pure drug were carried out in pH 1.2 HCl buffer as dissolution media. Results: Results confirmed the absence of chemical interactions between the drug and excipients. From the solubility studies, it was observed the LPM was highly soluble in PG thereby it was selected as a solvent. The dissolution efficiency of LPM at 15 min was increased from 9.99 % for pure drug and 54.57% for marketed product to 86.81% for the tablets prepared by liquisolid compact technique. Stability studies showed no significant change in percent cumulative drug release, hardness, disintegration time, friability and drug content for 3 months. Conclusion: Formulation F2 showed significant increase in dissolution rate compared to the marketed product at pH 1.2 where LPM is largely absorbed. Around 90% of the drug was released from F2 in 30 min compared to the marketed product and it might be due to the increased wetting and surface area of the particles. Hence, the liquisolid compact technique appears to be a promising approach for improving the dissolution rate of poorly soluble drug. PMID- 27766221 TI - Preliminary Safety Assessment of New Azinesulfonamide Analogs of Aripiprazole using Prokaryotic Models. AB - Purpose: Determination of the mutagenic potential of new biologically active compounds is of great concern for preliminary toxicity testing and drug development. Methods: The mutagenic and antimutagenic effects of some quinoline- and isoquinolinesulfonamide analogs of aripiprazole (1-8), which display potent antidepressant, anxiolytic, and antipsychotic properties, were evaluated using the Vibrio harveyi assay and OSIRIS Property Explorer software. Additionally, the Ames test was used as the reference. Results: In silico prediction showed that compounds 5 (N-(3-(4-(2,3- dichlorophenyl)piperazin-1-yl)propyl)quinoline-7 sulfonamide) and 6 (N-(4-(4-(2,3- Dichlorophenyl)piperazin-1-yl)butyl)quinoline-7 sulfonamide) trigger a mutagenic structural alert. However, this was not confirmed by in vitro assays, as none of the tested compounds displayed mutagenic activity against all tested strains of bacteria. Moreover, compounds 1-8 displayed a protective effect against the mutagenicity induced by a direct acting mutagen NQNO. The most beneficial antimutagenic properties showed compound 5 which exhibited strong antimutagenic properties in all tested V. harveyi strains. High antimutagenic potency of this compound was confirmed in the Ames TA100 assay system. Conclusion: Newly synthesized azinesulfonamide analogs of aripiprazole may be considered as genotoxically safe as they do not display mutagenic activity on the tester strains. Moreover, the tested compounds demonstrated significant antimutagenic properties that can be valuable for prevention of the NQNO genotoxicity. Additionally, it appears that the Vibrio harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of chemical substances, thus, representing a useful alternative tool for compounds safety evaluation. PMID- 27766223 TI - Design, Formulation and Evaluation of an Oral Gel from Punica Granatum Flower Extract for the Treatment of Recurrent Aphthous Stomatitis. AB - Purpose: Recurrent aphthous stomatitis is a disease with unknown etiology that's mostly treated symptomatically and has no definite cure. Pomegranate (Punica granatum) flowers have been used as medicinal herb that due to its antimicrobial, antioxidant, anti-inflammatory, analgesic and healing effects, has been useful in treatment of oral aphthous. Therefore, we decided to formulate a mucoadhesive gel with pomegranate flower extract to reduce the need for corticosteroid therapy in patients. Methods: Pomegranate flowers are extracted by percolation method. Several formulations with different amounts of carbomer 934, sodium carboxymethylcellulose (SCMC) and hydroxypropyl methylcellulose K4M were prepared and the condensed extract was dispersed in polyethyleneglycol (PEG) 400 and added to gel bases. Then the formulations underwent macroscopic and microscopic studies. The formulations that passed these tests successfully were studied through assay tests using spectrophotometry in 765 nm, drug release from mucoadhesive gel using cell diffusion method, viscosity test, mucoadhesion test and accelerated stability test. Results: The phenolic content of pomegranate flower dried extract was found to be 212.3+/-1.4 mg/g in dried extract. The F4-F6 formulations contains carbomer 934, SCMC, pomegranate flower extract, PEG 400, potassium sorbate and purified water passed all above tests. Conclusion: The F4 formulation had higher viscosity and mucoadhesion values due to its higher carbomer 934 and SCMC content. Since F4, F5 and F6 had no significant variation in drug release, the F4 formulation was chosen as the superior formulation because of proper appearance and uniformity, acceptable viscosity, mucoadhesion and stability in different temperatures. PMID- 27766224 TI - Improvement of Meloxicam Solubility Using a beta-Cyclodextrin Complex Prepared via the Kneading Method and Incorporated into an Orally Disintegrating Tablet. AB - Purpose: The aim of this research was to formulate and develop an orally disintegrating tablet (ODT) that incorporated a MEL/beta-CD complex, using a quality by design (QbD) approach to enhance solubility and drug release. Methods: Multiple regression linear analysis was conducted to develop the kneading process and ODT formulation. Mixing time and amount of solvent were used as independent variables in kneading process optimisation, while the superdisintegrants were used to obtain the desired formulation. Fourier transform infrared spectroscopy and differential scanning calorimetry were performed for complex characterization. Results: MEL/beta-CD complexation was successful in enhancing MEL solubility. The results suggest that increasing the amount of solvent and mixing time enhances drug loading and drug release. However, increased solvent amounts present the problem of removing the solvent. Primojel and Polyplasdone had a significant effect on the water wicking and tablet disintegration process (p<0.05), although Polyplasdone negatively affected tablet hardness. Both an optimized KN process and ODT formulation were obtained using a QbD approach. Conclusion: Incorporation of the MEL/beta-CD complex during ODT formulation using the QbD approach serves as a model for ODT product development, with optimal product performance based on the specification of quality target product profiles. To understand more specific phenomena, one point in the middle of the design for each factor should be added to more powerfully estimate this effect and avoid the lack of estimate due to an inadequate equation. PMID- 27766225 TI - Preparation and Bioavailability Analysis of Ferrous Bis Alanine Chelate as a New Micronutrient for Treatment of Iron Deficiency Anemia. AB - Purpose: One of the most nutritional disorders around the world is iron deficiency. A novel iron compound was synthesized by chelating ferrous ions with alanine for prevention and treatment of iron deficiency anemia. Methods: The newly synthesized compound was characterized both qualitatively and quantitatively by Fourier Transform Infrared (FT-IR) spectroscopy. The bioavailability of newly synthesized iron micronutrient was evaluated in four groups of Wistar rats. The group I was a negative control group and the other three groups received three different iron formulations. After 14 days, the blood samples were taken and analyzed accordingly. Results: Calculations showed that more than 91.8% of iron was incorporated in the chelate formulation. In vivo studies showed that serum iron, total iron binding capacity and hemoglobin concentrations were significantly increased in group IV, which received ferrous bis alanine chelate compared with the negative control group (p<0.05) and also group II, which received ferrous sulfate.7H2O (p<0.05). It indicates that the new formulation considerably improves the blood iron status compared with the conventional iron compounds. There were no significant differences (p<0.05) in the serum iron between group IV and group III, which received ferrous bis glycine. Conclusion: The results showed better bioavailability of ferrous bis alanine as a new micronutrient for treatment of iron deficiency anemia in comparison with ferrous sulfate. Ferrous bis alanine could be considered as a suitable supplement for prevention and treatment of iron deficiency anemia. PMID- 27766226 TI - NF-Kbeta Activation in U266 Cells on Mesenchymal Stem Cells. AB - Purpose: Mesenchymal Stem Cells (MSCs) are one of the essential members of Bone Marrow (BM) microenvironment and the cells affect normal and malignant cells in BM milieu. One of the most important hematological malignancies is Multiple Myeloma (MM). Numerous studies reported various effects of MSCs on myeloma cells. MSCs initiate various signaling pathways in myeloma cells, particularly NF-kbeta. NF-kbeta signaling pathway plays pivotal role in the survival, proliferation and resistance of myeloma cells to the anticancer drugs, therefore this pathway can be said to be a vital target for cancer therapy. This study examined the relationship between U266 cells and MSCs. Methods: U266 cells were cultured with Umbilical Cord Blood derived-MSCs (UCB-MSCs) and Conditioned Medium (C.M). Effect of UCB-MSCs and C.M on proliferation rate and CD54 expression of U266 cells were examined with MTT assay and Flowcytometry respectively. Furthermore, expression of CXCL1, PECAM-1, JUNB, CCL2, CD44, CCL4, IL-6, and IL-8 were analyzed by Real Time-PCR (RT-PCR). Moreover, status of p65 protein in NF-kbeta pathway assessed by western blotting. Results: Our findings confirm that UCB-MSCs support U266 cells proliferation and they increase CD54 expression. In addition, we demonstrate that UCB-MSCs alter the expression of CCL4, IL-6, IL-8, CXCL1 and the levels of phosphorylated p65 in U266 cells. Conclusion: Our study provides a novel sight to the role of MSCs in the activation of NF-kbeta signaling pathway. So, NF-kbeta signaling pathway will be targeted in future therapies against MM. PMID- 27766228 TI - Sodium Alginate with PEG/PEO Blends as a Floating Drug Delivery Carrier - In vitro Evaluation. AB - Purpose: Floating drug delivery system reduces the quantity of drug intake and the risk of overloading the organs with excess drug. Methods: In the present study, we prepared the blends of sodium alginate with polyethylene glycol (PEG) and polyethylene oxide (PEO) as a matrix, sodium hydrogen carbonate as a pore forming agent, methyl cellulose as a binder and barium chloride containing 10% acetic acid as a hardening agent. Different ratios of pore forming agent to the polymer blend was used to prepare the floating beads with different porosity and morphology. Ciprofloxacin hydrochloride was used as a model drug for the release kinetics studies. Results: The beads were characterized by optical and FESEM microscopy to study the morphology and pore dimensions. The results obtained shows decrease in beads size with increase in the concentration of the pore forming agent. The swelling properties of the beads were found to be in the range of 80% to 125%. The release kinetics of the ciprofloxacin from the beads was measured by UV-Visible spectroscopy at lambdamax of 278nm and the results shows for highly porous beads. Conclusion: By varying the amount of alginate and pore forming agent the release kinetics is found to get altered. As a result, ciprofloxacin hydrochloride release is found to be sustained from the blended beads. PMID- 27766227 TI - Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats. AB - Purpose: The aim of the present study was to determine the ability of grape seed extract (GSE) as a powerful antioxidant in preventing adverse effect of doxorubicin (DOX) on heart function. Methods: Male rats were divided into three groups: control, DOX (2 mg/kg/48h, for 12 days) and GSE (100 mg/kg/24h, for 16 days) plus DOX. Left ventricular (LV) function and hemodynamic parameters were assessed using echocardiography, electrocardiography and a Millar pressure catheter. Histopathological analysis and in vitro antitumor activity were also evaluated. Results: DOX induced heart damage in rats through decreasing the left ventricular systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening and contractility index as demonstrated by echocardiography, electrocardiography and hemodynamic parameters relative to control group. Our data demonstrated that GSE treatment markedly attenuated DOX-induced toxicity, structural changes in myocardium and improved ventricular function. Additionally, GSE did not intervene with the antitumor effect of DOX. Conclusion: Collectively, the results suggest that GSE is potentially protective against DOX-induced toxicity in rat heart and maybe increase therapeutic index of DOX in human cancer treatment. PMID- 27766229 TI - Evaluation of Betulin Mutagenicity by Salmonella/Microsome Test. AB - Purpose: Betulin is a pentacyclic triterpene found in the outer barks of innumerous plants. This secondary metabolite is easily isolated from plants with the major interest in converting it to betulinic acid, which pharmacological properties were much more exploited than betulin. But, investments in the own betulin have been grown since no chemical step is necessary. In this study we focused the precursor betulin in order to evaluate its mutagenicity by Salmonella/microsome assay (Ames test). Methods: The Ames test was carried out using a commercial betulin exposed to Salmonella typhimurium strains TA98, TA100, TA102, and TA97a, in experiments with (+S9) and without (-S9) metabolic activation. Results: Betulin was unable to increase the number of revertants (+S9 and -S9 metabolic activation) showing the absence of any mutagenic effect by Ames test. Conclusion: This study allowed attribute safety to betulin being important for exploiting its pharmacological uses. PMID- 27766230 TI - Investigating the Apoptosis Ability of Ethylenediamine 8-Hydroxyquinolinato Palladium (II) Complex. AB - Purpose: High solubility, low renal toxicity and apoptosis-inducing ability of palladium complexes are the reasons for their synthesis. Methods: In vitro cytotoxic study of previously synthesized [Pd(en)(8HQ)]NO3 , was carried out on breast cancer MCF-7 cell lines and prostate cancer DU145 cell lines. DNA fragmentation indicative of apoptotic was also evaluated by TUNEL assay on DU145 cell line. Results: FT-IR spectra of final complex confirmed the existence of chelating ligands. The DU145 cells unlike the MCF-7 cells, demonstrated the significant influence of the Pd (II) complex. The IC50 values of [Pd(en)(8HQ)]NO3 and cisplatin on DU145 cells were 27 and 8.3 MUM, respectively. Moreover, nearly 38% apoptosis was evident in DU145 cells after treatment with [Pd(en)(8HQ)]NO3. Conclusion: [Pd(en)(8HQ)]NO3 has great potential in DNA binding and induction of apoptosis; thus it can be used in the future against prostate cancer. PMID- 27766231 TI - Anti Pneumococcal Activity of Azithromycin-Eudragit RS100 Nano-Formulations. AB - Purpose: Bacterial pneumonia is a common lung infection caused by different types of bacteria. Azithromycin (AZI), an azalide antibiotic, is widely used to manage pneumococcal infections. Studies have shown that antibiotics in nanocarriers may lead to increased antibacterial activity and reduced toxicity. The aim of this work was to valuate in vitro antibacterial performance azithromycin-Eudragit RS100 nano-formulations against Streptococcus pneumoniae and Staphylococcus aureus. Methods: AZI-Eudragit RS100 nanoparticles were prepared via electrospinning technique and the in vitro antibacterial performance against S. pneumoniae and S. aureus were assessed using agar dilution method. Results: Nanofibers in the sizes about 100-300 nm in diameter and micro scale in length and nanobeads in the range of 100-500 nm were achieved. The Minimum Inhibitory Concentrations (MIC) showed an enhancement in the antimicrobial effect of AZI Eudragit RS100 nanofibers (40 ug/ml) compare to untreated AZI solution (>160 ug/ml) against S. pneumonia. The MIC value for AZI-Eudragit RS100 nanofibers against S. aureus was >128 ug/ml, same as that of the untreated AZI solution. Conclusion: The enhanced efficiency of AZI in nanofibers could be related to the more adsorption opportunity of nanofibers to S. pneumonia capsulated cell wall which provides an antibiotic depot on the bacterial surface compared to S. aureus. AZI-Eudragit RS100 nanofibers with enhanced antimicrobial effect against S. pneumonia can be considered as a candidate for in vivo evaluations in antibiotic therapy of Pneumococcal infections. PMID- 27766232 TI - Synergic Antibacterial Effect of Curcumin with Ampicillin; Free Drug Solutions in Comparison with SLN Dispersions. AB - Purpose: This study was designed to investigate benefit of using nanotechnology on increasing of synergic antibacterial effect of natural and chemical antibacterial agents. Methods: At first the MIC and MBC of Curcumin and Ampicillin as selected antibacterial agents was determined, after that Solid Lipid Nanoparticles (SLNs) of each active ingredients as well as Curcumin Ampicillin loaded SLNs were prepared using high pressure homogenization technique. Characterization of prepared SLNs was done, then MIC, MBC and contact killing time were investigated for Curcumin-Ampicillin loaded SLNs in comparison with free Curcumin and Ampicillin solutions as well as Ampicillin and Curcumin SLNs. Results: Based on results nanoparticles with the size of 150 nm show much more decreased MIC and MBC when Ampicillin and Curcumin were loaded together on SLNs than solutions in which free Ampicillin and Curcumin were mixed. Conclusion: It seems that using nanotechnology could cause decrease the dosage of antibiotics and risk of having antibiotic resistance bacteria strains. PMID- 27766233 TI - Implementation and analysis of initial trauma registry in Iquitos, Peru. AB - Background: In Peru, 11% of deaths are due to trauma. Iquitos is a large underserved Peruvian city isolated from central resources by its geography. Our objective was to implement a locally driven trauma registry to sustainably improve trauma healthcare in this region. Methods: All trauma patients presenting to the main regional referral hospital were included in the trauma registry. A pilot study retrospectively analyzed data from the first two months after implementation. Results: From March to April 2013, 572 trauma patients were entered into the database. Average age was 26.9 years. Ten percent of patients presented more than 24 hours after injury. Most common mechanisms of injury were falls (25.5%), motor vehicle collisions (23.3%), and blunt assault (10.5%). Interim analysis revealed that 99% of patients were entered into the database. However, documentation of vital signs was poor: 42% of patients had temperature, 26% had oxygen saturation documented. After reporting to registry staff, a significant increase in temperature (42 to 97%, P < 0.001) and oxygen saturation (26 to 92%, P < 0.001) documentation was observed. Conclusion: A trauma registry is possible to implement in a resource-poor setting. Future efforts will focus on analysis of data to enhance prevention and treatment of injuries in Iquitos. PMID- 27766234 TI - Executive function influences sedentary behavior: A longitudinal study. AB - Background: No study has evaluated the effects of executive function on follow-up sedentary behavior, which was this study's purpose. Methods: A longitudinal design was employed among 18 young adult college students (Mage = 23.7 years; 88.9% female). Accelerometer-determined sedentary behavior and physical activity, along with executive function, were assessed at baseline. Approximately 8 weeks later, re-assessment of accelerometer-determined sedentary behavior and physical activity occurred. Executive function was assessed using the Parametric Go/No-Go (PGNG) computer task. From this, 2 primary executive function outcome parameters were evaluated, including the Simple Rule and Repeating Rule. Results: After adjusting for baseline sedentary behavior, age, gender, body mass index and baseline moderate-to-vigorous physical activity (MVPA), for every 25% increase in the number of correctly identified targets for the Repeating rule at the baseline assessment, participants engaged in 91.8 fewer minutes of sedentary behavior at the follow-up assessment (beta = -91.8; 95% CI: -173.5, -10.0; P = 0.03). Results were unchanged when also adjusting for total baseline or follow-up physical activity. Conclusion: Greater executive function is associated with less follow up sedentary behavior. PMID- 27766235 TI - Sex differences in the physical inactivity and health-related quality of life relationship among rural adults. AB - Background: The purpose of this study was to investigate the relationship between physical inactivity (PIA) and health-related quality of life (HRQOL) in rural adults and examine the extent to which sex differences exist in this relationship. Methods: A total of 5617 adults 18 years of age and older who indicated residing in a rural county was included in this analysis. PIA status was assessed by questions regarding recreational physical activity during the previous month. Five HRQOL measures (physical health, mental health, inactivity health, general health, & unhealthy days) were used as primary outcome variables. PIA and HRQOL prevalence estimates were computed with 95% CIs. Multiple logistic regression was used to obtain odds ratios (ORs) and 95% CIs adjusted for age, ethnicity, and income. Results: Physically inactive rural adults were significantly more likely to report poor HRQOL in all overall crude models with ORs ranging from 1.59 to 2.16. Additionally, sex-by-PIA interactions were significant across all crude HRQOL models with ORs ranging from 2.27 to 3.08 and 1.56 to 2.42 for women and men, respectively. Sex differences were maintained in fully adjusted models, except for mental health and inactivity health with ORs ranging from 1.80 to 2.58 and 1.41 to 1.79 for women and men, respectively. Conclusion: Results from this study show that PIA is a strong predictor of poor HRQOL even after controlling for confounding variables. Furthermore, physically inactive rural women appear more likely to report poor levels of HRQOL than physically inactive rural men. PMID- 27766236 TI - Economic inequalities amongst women with osteoporosis-related fractures: an application of concentration index decomposition. AB - Background: Considering the renewed emphasis on women's health, attention to the new aspects of their health, such as equity, among different groups is warranted. The aim of this study was to investigate the economic inequalities among women with osteoporosis-related bone fractures (ORBFs) in Sanandaj, Iran. Methods: In this cross-sectional study, convenient sampling was employed to recruit 220 women with osteoporosis referring to the only rheumatology clinic in Sanandaj (the center of Kurdistan province in Iran) from January to April 2013. Main outcome was the history of fractures due to osteoporosis. Concentration index decomposition (CID) and logistic regression were used for data analysis. Results: In multivariate logistic analysis, the fourth and fifth quintiles of family economic status were found to be significantly associated with ORBFs. Risk difference and confidence interval (CI) for the relation between the history of bone fracture and family economic status was -0.115 (95% CI: -0.209, -0.021; P = 0.016), which reflected the higher prevalence of bone fractures among women with the lower economic levels. About 25% out of all ORBFs were happened among 20% of the women with low economic status. Conclusion: It was concluded that economic status plays an important role in happening ORBFs among underprivileged women. A reorientation on women's health care services in Iran with a focus on underprivileged postmenopausal women seems to be necessary. There is a need for inter-sectoral coalition between the policymakers of the health system and those of other organizations to reduce the economic inequalities among osteoporotic women. PMID- 27766237 TI - Sedentary behavior and residual-specific mortality. AB - Background: The purpose of this study was to examine the association of accelerometer-assessed sedentary behavior and residual-specific mortality. Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) were used (N = 5536), with follow-up through 2011. Sedentary behavior was objectively measured over 7 days via accelerometry. Results: When expressing sedentary behavior as a 60 min/day increase, the hazard ratio across the models ranged from 1.07-1.40 (P < 0.05). There was evidence of an interaction effect between sedentary behavior and total physical activity on residual-specific mortality (Hazard ratiointeraction [HR] = 0.9989; 95% CI: 0.9982-0.9997; P = 0.008). Conclusion: Sedentary behavior was independently associated with residual specific mortality. However, there was evidence to suggest that residual-specific mortality risk was a function of sedentary behavior and total physical activity. These findings highlight the need for future work to not only examine the association between sedentary behavior and health independent of total physical activity, but evaluate whether there is a joint effect of these two parameters on health. PMID- 27766238 TI - Performance of on-site Medical waste disinfection equipment in hospitals of Tabriz, Iran. AB - Background: The number of studies available on the performance of on-site medical waste treatment facilities is rare, to date. The aim of this study was to evaluate the performance of onsite medical waste treatment equipment in hospitals of Tabriz, Iran. Methods: A various range of the on-site medical waste disinfection equipment (autoclave, chemical disinfection, hydroclave, and dry thermal treatment) was considered to select 10 out of 22 hospitals in Tabriz to be included in the survey. The apparatus were monitored mechanically, chemically, and biologically for a six months period in all of the selected hospitals. Results: The results of the chemical monitoring (Bowie-Dick tests) indicated that 38.9% of the inspected autoclaves had operational problems in pre-vacuum, air leaks, inadequate steam penetration into the waste, and/or vacuum pump. The biological indicators revealed that about 55.55% of the samples were positive. The most of applied devices were not suitable for treating anatomical, pharmaceutical, cytotoxic, and chemical waste. Conclusion: Although on-site medical waste treating facilities have been installed in all the hospitals, the most of infectious-hazardous medical waste generated in the hospitals were deposited into a municipal solid waste landfill, without enough disinfection. The responsible authorities should stringently inspect and evaluate the operation of on-site medical waste treating equipment. An advanced off-site central facility with multi-treatment and disinfection equipment and enough capacity is recommended as an alternative. PMID- 27766239 TI - Healthy older adults balance pattern under dual task conditions: exploring the strategy and trend. AB - Background: In line with health promotion plans, early intervention and fall prevention in geriatric population, it is important to study healthy individuals balance mechanisms. The aim of this research was to investigate the effect of adding and removing visual input and dual task on elderly balance. Methods: Twenty healthy elderly recruited from four different senior citizen health club centers and from the University of Social Welfare and Rehabilitation Sciences (USWR) participated in this analytic cross-sectional study. At USWR's Motor Control Laboratory, the participants' postural sway were assessed using force plate in 4 distinct double leg standing conditions with and without presence of visual input and Stroop dual task. Postural and Stroop variables were compared. Results: Findings indicated that when the elderly encountered with either dual task or absence of visual input, they can still manage the situation in a way that changes in sway parameter would not become significant. But, when these two conditions occurred simultaneously, the participant's balance strategy fluctuated. Therefore, the mean velocity showed a significant difference between the "single quiet standing" condition and the condition of standing with eyes closed while the participants were answering Stroop dual task (Mean difference = 0.007, 95% CI = -0.012, -0.002). Conclusion: It appears that velocity parameter is sensitive to small changes, so it is recommended that researchers include this parameter in their future analyses. Balance in elderly can be manipulated by dual task and visual input deprivation. PMID- 27766240 TI - The most widely viewed YouTube videos with content related to multivitamins. AB - Background: Use of multivitamin/multimineral (MVM) and other dietary supplements is common among American adults. The purpose of this study was to describe the source and content of the most widely viewed YouTube videos associated with MVM supplements. Methods: Videos were filtered by number of views and the source of the video upload was recorded. A comparison of video characteristics and differences in video content was conducted. Results: Cumulatively, the videos in this sample were viewed 25 573 055 times. The majority of videos found in this sample were uploaded by a nutrition, wellness, or fitness channels. Most videos mentioned benefits (80.4%, 95% CI: 72.5%, 88.3%) and advocated for use of the supplement (72.2%, 95% CI: 63.3%, 81.1%). Over 84% (84.5%, 95% CI: 77.3, 91.7%) of the videos did not mention risks associated with taking a particular vitamin or supplement. Conclusion: The findings of this study indicate that MVMs are often promoted and encouraged, yet risks associated with MVMs were infrequently mentioned. Health professionals should be aware of the extent to which MVM related content appears on social media and, more importantly, be attuned to the content, which can be misleading, or missing information regarding risks and/or evidence of possible benefits. PMID- 27766241 TI - Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic agent for the treatment of type 2 diabetes mellitus. They increase endogenous levels of incretin hormones, which stimulate glucose-dependent insulin secretion, decrease glucagon secretion, and contribute to reducing postprandial hyperglycemia. Although DPP-4 inhibitors have similar benefits, they can be differentiated in terms of their chemical structure, pharmacology, efficacy and safety profiles, and clinical considerations. Gemigliptin (brand name: Zemiglo), developed by LG Life Sciences, is a potent, selective, competitive, and long acting DPP-4 inhibitor. Various studies have shown that gemigliptin is an optimized DPP-4 inhibitor in terms of efficacy, safety, and patient compliance for treatment of type 2 diabetes mellitus. In this review, we summarize the characteristics of gemigliptin and discuss its potential benefits in clinical practice. PMID- 27766243 TI - Blood Glucose Measurement: Is Serum Equal to Plasma? PMID- 27766242 TI - The Effect of Bariatric Surgery on Diabetic Retinopathy: Good, Bad, or Both? AB - Bariatric surgery, initially intended as a weight-loss procedure, is superior to standard lifestyle intervention and pharmacological therapy for type 2 diabetes in obese individuals. Intensive medical management of hyperglycemia is associated with improved microvascular outcomes. Whether or not the reduction in hyperglycemia observed after bariatric surgery translates to improved microvascular outcomes is yet to be determined. There is substantial heterogeneity in the data relating to the impact of bariatric surgery on diabetic retinopathy (DR), the most common microvascular complication of diabetes. This review aims to collate the recent data on retinal outcomes after bariatric surgery. This comprehensive evaluation revealed that the majority of DR cases remain stable after surgery. However, risk of progression of pre-existing DR and the development of new DR is not eliminated by surgery. Instances of regression of DR are also noted. Potential risk factors for deterioration include severity of DR at the time of surgery and the magnitude of glycated hemoglobin reduction. Concerns also exist over the detrimental effects of postprandial hypoglycemia after surgery. In vivo studies evaluating the chronology of DR development and the impact of bariatric surgery could provide clarity on the situation. For now, however, the effect of bariatric surgery on DR remains inconclusive. PMID- 27766246 TI - Effects of Body Weight Reduction on Serum Irisin and Metabolic Parameters in Obese Subjects. AB - BACKGROUND: Irisin is a myokine implicated in lipid and glucose metabolism. The objective of this study is to examine the effect of a body weight reduction on the serum irisin level and physical indicators in obese Japanese patients without diabetes. METHODS: The subjects were 22 patients (male/female, 5/17; age, 46.1+/ 16.0 years; body mass index [BMI], 36.9+/-5.0 kg/m2) who completed a 6-month body weight reduction program at our clinic. The program included diet, exercise therapy and cognitive behavioral therapy. Blood parameters, body composition, exercise tolerance, homeostasis model assessment of insulin resistance (HOMA-IR), and serum irisin were determined before and after intervention, and relationships among changes in these data were examined. RESULTS: There were significant decreases in body weight and BMI after the intervention. Irisin before the intervention was significantly positively correlated with HOMA-IR (r=0.434, P<0.05). The mean irisin level showed no significant change after the intervention in all participants. However, improvements in % body fat, subcutaneous fat area, triglycerides, and fasting glucose were significantly greater in patients with an increase in irisin compared to those with a decrease in irisin after the intervention. Patients with an increase in irisin also had significantly lower fasting insulin (9.7+/-4.8 vs. 16.4+/-8.2, P<0.05) and HOMA IR (2.2+/-1.1 vs. 3.7+/-1.6, P<0.05) after the intervention, compared to patients with a decrease in irisin. CONCLUSION: Body weight reduction did not alter irisin levels. However, irisin may play important roles in fat and glucose metabolism and insulin resistance, and the effects of body weight reduction on irisin kinetics may be a key for obesity treatment. PMID- 27766247 TI - Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor. AB - BACKGROUND: Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion. METHODS: PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions. RESULTS: Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl 2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells. CONCLUSION: Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis. PMID- 27766249 TI - A Potential Issue with Screening Prediabetes or Diabetes Using Serum Glucose: A Delay in Diagnosis. AB - The aim of this study was to compare the fasting serum glucose level with the fasting plasma glucose level for diagnosing hyperglycemic states in real-life clinical situations. Additionally, we investigated a usual delay in sample processing and how such delays can impact the diagnosis of hyperglycemic states. Among 1,254 participants who had normoglycemia or impaired fasting glucose (IFG) assessed by the fasting serum glucose level, 20.9% were newly diagnosed with diabetes based on the plasma fasting glucose level. Of the participants with normoglycemia, 62.1% and 14.2% were newly diagnosed with IFG and diabetes, respectively, according to the plasma fasting glucose level. In our clinical laboratory for performing health examinations, the time delay from blood sampling to glycemic testing averaged 78+/-52 minutes. These findings show that the ordinary time delay for sample processing of the serum glucose for screening hyperglycemic states may be an important reason for these diagnoses to be underestimated in Korea. PMID- 27766250 TI - Letter: Prevalence and Risk Factors of Gastroesophageal Reflux Disease in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2016;40:297-307). PMID- 27766251 TI - Response: Prevalence and Risk Factors of Gastroesophageal Reflux Disease in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2016;40:297-307). PMID- 27766252 TI - Type 2 Diabetes, Antidiabetic Medications, and Colorectal Cancer Risk: Two Case Control Studies from Italy and Spain. AB - BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of colorectal cancer, although the time-risk relationship is unclear, and there is limited information on the role of antidiabetic medications. AIM: We examined the association between type 2 diabetes, antidiabetic medications, and the risk of colorectal cancer, considering also duration of exposures. METHODS: We analyzed data derived from two companion case-control studies conducted in Italy and Spain between 2007 and 2013 on 1,147 histologically confirmed colorectal cancer cases and 1,594 corresponding controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional multiple logistic regression models, adjusted for socioeconomic factors and major potential confounding factors. RESULTS: Overall, 14% of cases and 12% of controls reported a diagnosis of diabetes, corresponding to an OR of colorectal cancer of 1.21 (95% CI 0.95-1.55). The OR was 1.49 (95% CI 0.97-2.29) for a duration of diabetes of at least 15 years. The OR was 1.53 (95% CI 1.06-2.19) for proximal colon cancer, 0.94 (95% CI 0.66-1.36) for distal colon cancer, and 1.32 (95% CI 0.94-1.87) for rectal cancer. In comparison with no use, metformin use was associated with a decreased colorectal cancer risk (OR 0.47, 95% CI 0.24-0.92), while insulin use was associated with an increased risk (OR 2.20, 95% CI 1.12-4.33); these associations were stronger for longer use (OR 0.36 and 8.18 for >=10 years of use of metformin and insulin, respectively). CONCLUSION: This study shows evidence of a positive association between diabetes and colorectal cancer, mainly proximal colon cancer. Moreover, it indicates a negative association between colorectal cancer and metformin use and a positive association for insulin use. PMID- 27766254 TI - Increased Cost of Motor Activity and Heat Transfer between Non-Shivering Thermogenesis, Motor Activity, and Thermic Effect of Feeding in Mice Housed at Room Temperature - Implications in Pre-Clinical Studies. AB - The components of energy expenditure, total metabolic rate (TMR), resting metabolic rate (RMR), thermogenic response to feeding (TEF), activity, and cost of activity were measured in fed and fasted mice housed at 22 and 30 degrees C. Mice housed at 22 degrees C had more than two times larger TMR and RMR. Mice at 22 degrees C were less active when fasted but more active when fed. Cost of activity was nearly doubled in the fasted and in the fed state. Analysis of the short-term relation between TMR, RMR, and bouts of activity showed that, at 22 degrees C, the bouts of activity induced a decrease in the intensity of RMR that reflected the reduced need for thermal regulation induced by the heat released from muscular contraction. This phenomenon induced a considerable underestimation of TEF and prevented its reliable measurement when mice were housed at 22 degrees C. Correlation between TMR and activity measured across time in individual mice was very strong at both 22 and 30 degrees C, but the correlation measured across mice was much weaker at 30 degrees C and no longer significant at 22 degrees C. We suspect that this phenomenon was due to the fact that RMR is a much more reliable predictor of TMR than activity. RMR is more variable at 22 degrees C than at 30 degrees C because of heat transfers between thermal regulation and heat released by other discontinuous processes, such as activity and TEF. Therefore, more noise is introduced into the correlations performed across multiple mice between TMR and activity at 22 degrees C. On the other hand, it should be kept in mind that the doubling of TMR and RMR at 22 degrees C is fueled by an increased non-shivering thermogenesis that can obviously modify how the mouse responds to pharmacological and nutritional challenges. Taken together, these results suggest that in pre-clinical studies, mice should be housed in conditions where thermal regulation is limited as is generally the case in humans. However, the increased sensitivity of mice to small changes in ambient temperature can also be used as a versatile tool to investigate the role of thermal regulation on the energy balance equation in humans. PMID- 27766253 TI - Unbalanced Immune System: Immunodeficiencies and Autoimmunity. AB - Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained. PMID- 27766255 TI - FapR: From Control of Membrane Lipid Homeostasis to a Biotechnological Tool. AB - Phospholipids and fatty acids are not only one of the major components of cell membranes but also important metabolic intermediates in bacteria. Since the fatty acid biosynthetic pathway is essential and energetically expensive, organisms have developed a diversity of homeostatic mechanisms to fine-tune the concentration of lipids at particular levels. FapR is the first global regulator of lipid synthesis discovered in bacteria and is largely conserved in Gram positive organisms including important human pathogens, such as Staphylococcus aureus, Bacillus anthracis, and Listeria monocytogenes. FapR is a transcription factor that negatively controls the expression of several genes of the fatty acid and phospholipid biosynthesis and was first identified in Bacillus subtilis. This review focuses on the genetic, biochemical and structural advances that led to a detailed understanding of lipid homeostasis control by FapR providing unique opportunities to learn how Gram-positive bacteria monitor the status of fatty acid biosynthesis and adjust the lipid synthesis accordingly. Furthermore, we also cover the potential of the FapR system as a target for new drugs against Gram-positive bacteria as well as its recent biotechnological applications in diverse organisms. PMID- 27766257 TI - Prevalence and Risk Factors of Colonization with Staphylococcus aureus in Healthy Pet Cats Kept in the City Households. AB - Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a significant pathogen in both human medicine and veterinary medicine. The importance of pets as reservoirs of human infections is still poorly understood. This article provides detailed information of a cross-sectional study of a S. aureus colonization in clinically healthy indoor cats. The study systematically assessed a number of different anatomical locations for the S. aureus colonization and the influence of a range of potential risk factors on the value of the final S. aureus colonization rate. The incidence rates observed for cats with at least one site positive for S. aureus or MRSA were 17.5% and 6.63%, respectively. The following risk factors were identified: one or more owners working in the healthcare industry (human or veterinary); dogs being kept with the cat under investigation; treatment of the cat under investigation with antibiotics or chemotherapeutics during the previous year. In conclusion, this study revealed a higher prevalence of MRSA than what has previously been reported in healthy pets. A combination of anatomical locations from which the samples were collected had a major influence on the final value of the S. aureus colonization rate. PMID- 27766256 TI - Histopathological Analysis of PEEK Wear Particle Effects on the Synovial Tissue of Patients. AB - Introduction. Increasing interest developed in the use of carbon-fiber-reinforced poly-ether-ether-ketones (CFR-PEEK) as an alternative bearing material in knee arthroplasty. The effects of CFR-PEEK wear in in vitro and animal studies are controversially discussed, as there are no data available concerning human tissue. The aim of this study was to analyze human tissue containing CFR-PEEK as well as UHMWPE wear debris. The authors hypothesized no difference between the used biomaterials. Methods and Materials. In 10 patients during knee revision surgery of a rotating-hinge-knee-implant-design, synovial tissue samples were achieved (tibial inserts: UHMWPE; bushings and flanges: CFR-PEEK). One additional patient received revision surgery without any PEEK components as a control. The tissue was paraffin-embedded, sliced into 2 MUm thick sections, and stained with hematoxylin and eosin in a standard process. A modified panoptical staining was also done. Results. A "wear-type" reaction was seen in the testing and the control group. In all samples, the UHMWPE particles were scattered in the tissue or incorporated in giant cells. CFR-PEEK particles were seen as conglomerates and only could be found next to vessels. CFR-PEEK particles showed no giant-cell reactions. In conclusion, the hypothesis has to be rejected. UHMWPE and PEEK showed a different scatter-behavior in human synovial tissue. PMID- 27766259 TI - High Efficient Expression, Purification, and Functional Characterization of Native Human Epidermal Growth Factor in Escherichia coli. AB - Human epidermal growth factor (hEGF) is a small, mitotic growth polypeptide that promotes the proliferation of various cells and is widely applied in clinical practices. However, high efficient expression of native hEGF in Escherichia coli has not been successful, since three disulfide bonds in monomer hEGF made it unable to fold into correct 3D structure using in vivo system. To tackle this problem, we fused Mxe GyrA intein (Mxe) at the C-terminal of hEGF followed by small ubiquitin-related modifier (SUMO) and 10x His-tag to construct a chimeric protein hEGF-Mxe-SUMO-H10. The fusion protein was highly expressed at the concentration of 281 mg/L and up to 59.5% of the total cellular soluble proteins. The fusion protein was purified by affinity chromatography and 29.4 mg/L of native hEGF can be released by thiol induced N-terminal cleavage without any proteases. The mitotic activity in Balb/c 3T3 cells is proliferated by commercial and recombinant hEGF measured with methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay which indicated that recombinant hEGF protein stimulates the cell proliferation similar to commercial protein. This study significantly improved the yield and reduced the cost of hEGF in the recombinant E. coli system and could be a better strategy to produce native hEGF for pharmaceutical development. PMID- 27766260 TI - The Prognosis of Cardiac Origin and Noncardiac Origin in-Hospital Cardiac Arrest Occurring during Night Shifts. AB - Background. The survival rates of in-hospital cardiac arrests (IHCAs) are reportedly low at night, but the difference between the survival rates of cardiac origin and noncardiac origin IHCAs occurring at night remains unclear. Methods. Outcomes of IHCAs during different shifts (night, day, and evening) were compared and stratified according to the etiology (cardiac and noncardiac origin). Result. The rate of return of spontaneous circulation (ROSC) was 24.7% lower for cardiac origin IHCA and 19.4% lower for noncardiac origin IHCA in the night shift than in the other shifts. The survival rate was 8.4% lower for cardiac origin IHCA occurring during the night shift, but there was no difference for noncardiac origin IHCA. After adjusting the potential confounders, chances of ROSC (aOR: 0.3, CI: 0.15-0.63) and survival to discharge (aOR: 0.1; CI: 0.01-0.90) related to cardiac origin IHCA were lower during night shifts. Regarding noncardiac origin IHCA, chances of ROSC (aOR: 0.5, CI: 0.30-0.78) were lower in the night shift, but chances of survival to discharge (aOR: 1.3, CI: 0.43-3.69) were similar in these two groups. Conclusion. IHCA occurring at night increases mortality, and this is more apparent for cardiac origin IHCAs than for noncardiac origin IHCA. PMID- 27766258 TI - A Review of Management of Inflammation in the HIV Population. AB - Advancements in antiretroviral therapy have drastically increased the life expectancy for those infected with HIV. Today, a new subgroup of older patients with long-term controlled HIV exists, and its populace is continuously mounting. Therefore, it is essential to understand the enduring effects of chronic suppressed HIV infection in order to further improve HIV management in these patients. This paper will examine the role of HIV in chronic inflammation and immune dysfunction, the dynamic interaction that exists between comorbidity and HIV, and the potential consequences of long-term antiretroviral therapy in an effort to provide the best management options for the virally suppressed HIV patient. PMID- 27766261 TI - Extrapedicular Infiltration Anesthesia as an Improved Method of Local Anesthesia for Unipedicular Percutaneous Vertebroplasty or Percutaneous Kyphoplasty. AB - Aim. This report introduces extrapedicular infiltration anesthesia as an improved method of local anesthesia for unipedicular percutaneous vertebroplasty or percutaneous kyphoplasty. Method. From March 2015 to March 2016, 44 patients (11 males and 33 females) with osteoporotic vertebral compression fractures with a mean age of 71.4 +/- 8.8 years (range: 60 to 89) received percutaneous vertebroplasty or percutaneous kyphoplasty. 24 patients were managed with conventional local infiltration anesthesia (CLIA) and 20 patients with both CLIA and extrapedicular infiltration anesthesia (EPIA). Patients evaluated intraoperative pain by means of the visual analogue score and were monitored during the procedure for additional sedative analgesia needs and for adverse nerve root effects. Results. VAS of CLIA + EPIA and CLIA group was 2.5 +/- 0.7 and 4.3 +/- 1.0, respectively, and there was significant difference (P = 0.001). In CLIA group, 1 patient required additional sedative analgesia, but in CLIA + EPIA group, no patients required that. In the two groups, no adverse nerve root effects were noted. Summary. Extrapedicular infiltration anesthesia provided good local anesthetic effects without significant complications. This method deserves further consideration for use in unipedicular percutaneous vertebroplasty and percutaneous kyphoplasty. PMID- 27766262 TI - Positive Impact on Physical Activity and Health Behaviour Changes of a 15-Week Family Focused Intervention Program: "Juniors for Seniors". AB - The promotion of physical activity (PA) in children and their parents requires effective planning and sometimes even interventions. This study shows the effect of PA during a 15-week intervention program "Junior for Seniors" by applying a socioecological model to the interpretation of the data. This comprehensive approach emphasizes the fact that health promotion should focus not only on intrapersonal factors but also on the multilevel factors that might be determinants and modulators of increased PA. In 2015, 24 children ("juniors," 14 girls and 10 boys, aged M = 7.96 +/- 0.69) and 22 parents ("seniors," 14 mothers aged M = 38.86 +/- 2.96 and 8 fathers aged M = 37.38 +/- 2.97) were voluntarily enrolled in a study spread across three primary schools in the city of Poznan, Poland. The effectiveness of the intervention was determined according to postintervention behavioural changes in PA in comparison to preintervention levels, as reported by the parents and children. Overall, the study found increases in PA levels and reductions in sedentary time. Although the changes are modest, there are some unrecognized benefits of the intervention which may have occurred, such as improved sport and motor skills, more frequent family social behaviours (walks, meals, and visiting relatives), or simply improved quality of "do-together" leisure time PA. PMID- 27766263 TI - Retrograde versus Antegrade Approach for the Management of Large Proximal Ureteral Stones. AB - Objective. To evaluate and compare the efficacy and safety of retrograde versus antegrade ureteroscopic lithotripsy for the treatment of large proximal ureteral stones. Patients and Methods. We retrospectively analyzed the medical records of patients with proximal ureteral stones >15 mm, treated in our institution from January 2011 to January 2016. Intraoperative parameters, postoperative outcomes, and complications were recorded and compared between the two techniques. Results. Our analysis included 57 patients. Thirty-four patients (59.6%) underwent retrograde and 23 patients (40.4%) underwent antegrade ureteroscopy. There was no significant difference in patients' demographics and stone characteristics between the groups. Stone-free rate was significantly higher (p = 0.033) in the antegrade group (100%) compared to retrograde one (82.4%). Fluoroscopy time, procedure duration, and length of hospitalization were significantly (p < 0.001) lower in retrograde approach. On the other hand, the need for postoperative stenting was significantly lower in the antegrade group (p < 0.001). No difference was found between the groups (p = 0.745) regarding postoperative complications. Conclusions. Antegrade ureteroscopy is an efficient and safe option for the management of large proximal ureteral stones. It may achieve high stone-free rates compared to retrograde ureteroscopy with the drawback of longer operative time, fluoroscopy time, and length of hospitalization. PMID- 27766264 TI - ABC Transporter Subfamily D: Distinct Differences in Behavior between ABCD1-3 and ABCD4 in Subcellular Localization, Function, and Human Disease. AB - ATP-binding cassette (ABC) transporters are one of the largest families of membrane-bound proteins and transport a wide variety of substrates across both extra- and intracellular membranes. They play a critical role in maintaining cellular homeostasis. To date, four ABC transporters belonging to subfamily D have been identified. ABCD1-3 and ABCD4 are localized to peroxisomes and lysosomes, respectively. ABCD1 and ABCD2 are involved in the transport of long and very long chain fatty acids (VLCFA) or their CoA-derivatives into peroxisomes with different substrate specificities, while ABCD3 is involved in the transport of branched chain acyl-CoA into peroxisomes. On the other hand, ABCD4 is deduced to take part in the transport of vitamin B12 from lysosomes into the cytosol. It is well known that the dysfunction of ABCD1 results in X-linked adrenoleukodystrophy, a severe neurodegenerative disease. Recently, it is reported that ABCD3 and ABCD4 are responsible for hepatosplenomegaly and vitamin B12 deficiency, respectively. In this review, the targeting mechanism and physiological functions of the ABCD transporters are summarized along with the related disease. PMID- 27766265 TI - SEM-EDS-Based Elemental Identification on the Enamel Surface after the Completion of Orthodontic Treatment: In Vitro Studies. AB - Braces as foreign bodies in the mouth carry a risk of side effects and toxicity to the human body. This article presents the results indicating the possible toxic effects of tools used for cleaning the enamel after the completion of orthodontic treatment. The studies were carried out in vitro. The procedure of enamel etching, bonding orthodontic metal brackets, and enamel cleaning after their removal was performed under laboratory conditions. The enamel microstructure and elements present on its surface were evaluated using the scanning electron microscope (SEM). Silicon and aluminium were found in addition to the tooth building elements. PMID- 27766266 TI - Developing and testing an online breastfeeding training among undergraduate nursing students. AB - The benefits of breastfeeding for mothers and babies have been well documented in the scientific literature, with new evidence about the benefits continuing to emerge. The Surgeon General's call to action to support breastfeeding recommends mandatory breastfeeding education and training for all healthcare providers that deliver care to mothers and babies. The purpose of this study is to analyze the development of an online computer based breastfeeding training (BT) and the preliminary outcomes of this training. The development of this training included consultation with content and technology experts. The collection of preliminary outcomes related to breastfeeding knowledge data and evaluation of the online BT was pre and posttest study. Eighty six undergraduate nursing students completed the online BT using Blackboard Learn. The online component of the BT consisted of five modules with a combined length of approximately 16 hours. After the completion of the modules, the students increased their levels of knowledge related to breastfeeding and the majority believed that they were fully able to perform skills to support breastfeeding. The results of this study indicate that a successful BT for nursing students can be effectively designed, which can in the future be disseminated to other healthcare providers and students. In addition, this online BT was cost-efficient and effective in improving students' knowledge and skills to support breastfeeding. PMID- 27766267 TI - Advanced Glycation End Products and its Soluble Receptors in the Pathogenesis of Thoracic Aortic Aneurysm. AB - BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL) Ibeta, IL-2, IL-6, and TNF-alpha)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs. METHODS: The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system. RESULTS: The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs. CONCLUSIONS: The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA. PMID- 27766268 TI - Type B Aortic Dissection Repair Using a Thoraflex Hybrid Prosthesis in a Complex Aortic Arch Anatomy. AB - Thoracic endovascular aortic repair (TEVAR) is recognized as an attractive option to treat complicated Type B aortic dissection. Nevertheless, TEVAR is not always technically possible. We report the case of a 53-year-old male with complicated Type B aortic dissection, in the setting of a complex anomalous aortic arch anatomy with an aneurysmal aberrant right subclavian artery. He was successfully treated by the frozen elephant trunk technique using the Thoraflex hybrid graft. PMID- 27766269 TI - Chronic Type A Aortic Dissection: Two Cases and a Review of Current Management Strategies. AB - Stanford Type A aortic dissection is a rapidly progressing disease process that is often fatal without emergent surgical repair. A small proportion of Type A dissections go undiagnosed in the acute phase and are found upon delayed presentation of symptoms or incidentally. These chronic lesions may have a distinct natural history that may have a better prognosis and could potentially be managed differently then those presenting acutely. The method of repair depends on location and extent of the false lumen, as well as involvement of critical structures and branch arteries. Surgical repair techniques similar to those employed for acute dissection management are currently first-line therapy for chronic cases that involve the aortic valve, sinuses of Valsalva, coronary arteries, and supra-aortic branch arteries. In patients with high-risk for surgery, endovascular repairs have been successful, and active development of delivery systems and grafts will continue to enhance outcomes. We present two cases of chronic Type A aortic dissection and review the current literature. PMID- 27766270 TI - Intimal Flap Vegetation Following Aortic Root Re-dissection. AB - A 75-year-old man who had undergone ascending aorta replacement for acute Type A aortic dissection presented with a recurring high fever. Transesophageal echocardiography revealed that a vegetation had formed on the re-dissected intimal flap of the noncoronary sinus of Valsalva. This didactic case suggests that antibiotic prophylactic measures be considered for aortic dissection flaps as for irregular valves susceptible to infective endocarditis. PMID- 27766271 TI - Complete Resolution of Wegener's Granulomatosis Lung Granuloma After Aortic Root Replacement. AB - Wegner's granulomatosis (WG) is an autoimmune systemic vasculitis that results in necrotizing granulomas. We report a WG patient with a lung granuloma and aortic root dilatation, who underwent aortic root replacement on cardiopulmonary bypass (CPB). Intraoperatively, the patient suffered an aortic dissection, which was repaired immediately under deep hypothermic circulatory arrest (DHCA). Follow-up imaging showed complete granuloma resolution, despite absence of immunosuppressive therapy. Immune stimulation following CPB is well described; here, the opposite was observed and DHCA effects are discussed. PMID- 27766272 TI - Single Stage Aortic Arch Replacement without Circulatory Arrest. AB - A 78-year-old man with a Kommerell diverticulum and aberrant right subclavian artery was admitted for thoracic pain and severe malnutrition due to esophageal compression. We performed an atypical surgical procedure including extra anatomical debranching and direct aortic repair, trying to avoid deep hypothermic circulatory arrest and shorten the cardiopulmonary bypass time. PMID- 27766273 TI - List of Upcoming Meetings. PMID- 27766275 TI - Quantifying Quadriceps Muscle Strength in Patients With ACL Injury, Focal Cartilage Lesions, and Degenerative Meniscus Tears: Differences and Clinical Implications. AB - BACKGROUND: Reduced quadriceps strength influences knee function and increases the risk of knee osteoarthritis. Thus, it is of significant clinical relevance to precisely quantify strength deficits in patients with knee injuries. PURPOSE: To evaluate isokinetic concentric quadriceps muscle strength torque values, assessed both from peak torque and at specific knee flexion joint angles, in patients with anterior cruciate ligament (ACL) injury, focal cartilage lesions, and degenerative meniscus tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were synthesized from patients included in 3 previously conducted research projects: 2 prospective cohort studies and 1 randomized controlled trial. At the time of inclusion, all patients were candidates for surgery. Isokinetic concentric quadriceps muscle strength measurements (60 deg/s) were performed at baseline (preoperative status) and after a period of progressive supervised exercise therapy (length of rehabilitation period: 5 weeks for ACL injury, 12 weeks for cartilage lesions and degenerative meniscus). Outcome measures were peak torque and torque at specific knee flexion joint angles from 20 degrees to 70 degrees . All patients had unilateral injuries, and side-to side deficits were calculated. For comparisons between and within groups, we utilized 1-way analysis of variance and paired t tests, respectively. RESULTS: In total, 250 patients were included. At baseline, cartilage patients had the most severe deficit (39.7% +/- 24.3%; P < .001). Corresponding numbers for ACL and degenerative meniscus subjects were 21.7% (+/-13.2%) and 20.7% (+/-16.3%), respectively. At retest, there was significant improvement in all groups (P < .001), with remaining deficits of 24.7% (+/-18.5%) for cartilage, 16.8% (+/ 13.9%) for ACL, and 3.3% (+/-17.8%) for degenerative meniscus. Peak torque was consistently measured at 60 degrees of knee flexion, whereas the largest mean deficits were measured at 30 degrees at baseline and 70 degrees at retest for the ACL group, at 70 degrees at baseline and retest for the degenerative meniscus group, and at 60 degrees at baseline and at 50 degrees at retest for the cartilage group. CONCLUSION: This study underlines the importance of including torque at specific knee flexion joint angles from isokinetic assessments to identify the most severe quadriceps muscle strength deficits. Furthermore, it confirms the importance of progressive exercise therapy interventions before potential surgery in patients with knee injuries. PMID- 27766274 TI - The Relationship Between Humeral Retrotorsion and Shoulder Range of Motion in Baseball Players With an Ulnar Collateral Ligament Tear. AB - BACKGROUND: Humeral retrotorsion has been investigated in relation to shoulder range of motion (ROM) in healthy baseball players. Currently, there is limited information on the osseous anatomy and development of ulnar collateral ligament (UCL) tears. PURPOSE: To determine the relationship between humeral retrotorsion and shoulder ROM in baseball players with a UCL tear. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: Fifty-four baseball players (mean age, 18.5 +/- 2.0 years) with a UCL tear volunteered for this study. Participants were measured bilaterally for shoulder internal (IR) and external rotation (ER) ROM and humeral retrotorsion. Differences between sides (involved to uninvolved) were used to calculate the glenohumeral internal rotation deficit (GIRD), external rotation ROM difference (ERDiff), total rotational motion difference (TRM), and humeral retrotorsion difference (HTDiff). A multivariate regression analysis was performed with GIRD, ERDiff, and TRM regressing on HTDiff. Univariate analysis was performed to further evaluate the effect of the predictors on each outcome separately. To control for the effect of age, weight, duration of symptoms, and years of experience, the variables were included as covariates. An a priori level was set at P < .05. RESULTS: There was a statistically significant relationship between the GIRD, ERDiff, and TRM results compared with HTDiff (P = .003). Independent analysis revealed a statistically significant relationship between GIRD and HTDiff (P = .004) and between ERDiff and HTDiff (P = .003) but no significant relationship between TRM and HTDiff (P = .999). After adjusting for age, weight, duration of symptoms, years of experience, dominant arm, and position, a significant relationship was found between GIRD and HTDiff (P = .05) and between ERDiff and HTDiff (P = .01). No significant relationship was found between TRM and HTDiff (P = .54). Adjusted univariate regression analysis determined that HTDiff explains approximately 16% of the variance in GIRD (r2 = 0.158) and approximately 24% of the variance in ERDiff (r2 = 0.237). CONCLUSION: In baseball players with a UCL tear, approximately 16% of the variance in GIRD and 24% of the variance in ERDiff can be attributed to differences found in humeral retrotorsion between sides. This indicates that humeral retroversion contributes significantly to GIRD and increased ER ROM in baseball players. Recognition of differences in humeral retrotorsion between the dominant and nondominant upper extremities may help explain some but not all of the changes in shoulder ROM commonly seen in baseball players. PMID- 27766276 TI - Complications of Distal Biceps Tendon Repair: A Meta-analysis of Single-Incision Versus Double-Incision Surgical Technique. AB - BACKGROUND: Anatomic reinsertion of the distal biceps is critical for restoring flexion and supination strength. Single- and double-incision surgical techniques have been reported, analyzing complications and outcomes measures. Which technique results in superior clinical outcomes and the lowest associated complications remains unclear. HYPOTHESIS: We hypothesized that rerupture rates would be similar between the 2 techniques, while nerve complications would be higher for the single-incision technique and heterotopic ossification would be more frequent with the double-incision technique. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: A systematic review was conducted using the PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), SPORTSDiscus, and the Cochrane Central Register of Controlled Trials databases to identify articles reporting distal biceps ruptures up to August 2013. We included English-language articles on adult patients with a minimum of 3 cases reporting single- and double-incision techniques. Frequencies of each complication as a percentage of total cases were calculated. Fisher exact tests were used to test the association between frequencies for each repair method, with P < .05 considered statistically significant. Odds ratios with 95% CIs were also computed. RESULTS: A total of 87 articles met the inclusion criteria. Lateral antebrachial cutaneous nerve neurapraxia was the most common complication in the single-incision group, occurring in 77 of 785 cases (9.8%). Heterotopic ossification was the most common complication in the double-incision group, occurring in 36 of 498 cases (7.2%). CONCLUSION: The overall frequency of reported complications is higher for single-incision distal biceps repair than for double-incision repair. The frequencies of rerupture and nerve complications are both higher for single-incision repairs while the frequency of heterotopic ossification is higher for double-incision repairs. These findings can help surgeons make better-informed decisions about surgical technique and provide their patients with detailed information about expected outcomes and possible complications. PMID- 27766278 TI - A metastatic castration resistant prostate cancer patient with multiple bone metastases has durable biochemical and radiological response to docetaxel chemotherapy. AB - Docetaxel chemotherapy for metastatic castration resistant prostate cancer patients has been thought palliative because the radiological response rate is low and durable response is rare. The patient was a 64-year-old man who was diagnosed with cT3aN0M0 prostate cancer and underwent external beam radiation therapy as the initial treatment. He underwent androgen deprivation therapy and 8 cycles of docetaxel chemotherapy. His PSA level decreased and became undetectable and the disease was confirmed to be stable by radiological examination. We report a rare case that a metastatic castration resistant prostate cancer patient with multiple bone metastases has durable radiological and biochemical response. PMID- 27766277 TI - Phase IIa, randomized placebo-controlled trial of single high dose cholecalciferol (vitamin D3) and daily Genistein (G-2535) versus double placebo in men with early stage prostate cancer undergoing prostatectomy. AB - INTRODUCTION AND OBJECTIVES: Prostate cancer (PCa) represents an important target for chemoprevention given its prolonged natural history and high prevalence. Epidemiologic and laboratory data suggest that vitamin D and genistein (soy isoflavone) may decrease PCa progression. The effect of vitamin D on prostate epithelial cell proliferation and differentiation is well documented and genistein may augment this affect through inhibition of the CYP24 enzyme, which is responsible for intracellular vitamin D metabolism. In addition, both genistein and vitamin D inhibit the intraprostatic synthesis of prostaglandin E2, an important mediator of inflammation. The objectives of this prospective multicenter trial were to compare prostate tissue calcitriol levels and down stream related biomarkers in men with localized prostate cancer randomized to receive cholecalciferol and genistein versus placebo cholecalciferol and placebo genistein during the pre-prostatectomy period. METHODS: Men undergoing radical prostatectomy were randomly assigned to one of two treatment groups: (1) cholecalciferol (vitamin D3) 200,000 IU as one dose at study entry plus genistein (G-2535), 600 mg daily or (2) placebo cholecalciferol day 1 and placebo genistein PO daily for 21-28 days prior to radical prostatectomy. Serum and tissue analyses were performed and side-effects recorded. RESULTS: A total of 15 patients were enrolled, 8 in the placebo arm and 7 in the vitamin D3 + genistein (VD + G) arm. All patients were compliant and completed the study. No significant differences in side effect profiles were noted. Utilization of the VD + G trended toward increased calcitriol serum concentrations when compared to placebo (0.104 +/- 0.2 vs. 0.0013 +/- 0.08; p=0.08); however, prostate tissue levels did not increase. Calcidiol levels did not change (p=0.5). Immunohistochemistry for marker analyses using VECTRA automated quantitation revealed a increase in AR expression (p=0.04) and a trend toward increased TUNEL staining (p=0.1) in prostate cancer tissues in men randomized to receive VD + G compared to placebo. CONCLUSIONS: In this first study testing the combination of a single, large dose of cholecalciferol and daily genistein, the agents were well tolerated. While an increase in AR expression suggesting differentiation was observed, it is difficult to draw firm conclusions regarding the bioactivity of the combination given the sample size. PMID- 27766279 TI - Intracellular Macrophage Infections with E. coli under Nitrosative Stress. AB - Escherichia coli (E. coli) produces disseminated infections of the urinary tract, blood, and central nervous system where it encounters professional phagocytes such as macrophages, which utilize reactive nitrogen intermediates (RNI) to arrest bacteria. In vitro, extraintestinal pathogenic E. coli (ExPEC) can survive within bone marrow-derived macrophages for greater than 24 h post-infection within a LAMP1+ vesicular compartment, and ExPEC strains, in particular, are better adapted to intracellular macrophage survival than commensal strains (Bokil et al., 2011). This protocol details an intracellular murine macrophage-like cell infection, including modulation of the host nitrosative stress response, to model this host-pathogen interaction in vitro. To accomplish this, RAW 264.7 murine macrophage-like cells are pre-incubated with either L-arginine, an NO precursor, or IFNgamma to yield a high nitric oxide (NO) physiological state, or L-NAME, an inducible NO synthase (iNOS)-specific inhibitor, to yield a low NO physiological state. This protocol has been successfully utilized to assess the contribution of a novel ExPEC regulator to intracellular survival and the nitrosative stress response during macrophage infections (Bateman and Seed, 2012), but can be adapted for use with a variety of E. coli strains or isogenic deletions. PMID- 27766280 TI - Genetic Transformation of Candida glabrata by Heat Shock. AB - Here, we report a method for the transformation of Candida glabrata using a heat shock method. The protocol can be used for transformations in single well or in 96-well scale. It has been employed as an alternative method to the electroporation protocol to construct a genome-scale gene deletion collection in the human fungal pathogen Candida glabrata ATCC2001 and related strains. Furthermore, the protocol can be used to generate gene deletions in clinical isolates of Candida glabrata (C. glabrata). PMID- 27766281 TI - Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. AB - OBJECTIVE: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow up after alemtuzumab treatment. METHODS: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined. RESULTS: In comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change. CONCLUSIONS: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS. PMID- 27766282 TI - Induction of gut regulatory CD39+ T cells by teriflunomide protects against EAE. AB - OBJECTIVE: To determine whether as an orally delivered treatment, teriflunomide, an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase approved to treat relapsing forms of multiple sclerosis, could affect gut-associated lymphoid tissue (GALT) immune responses functionally. METHODS: C57BL/6 mice were treated orally with teriflunomide and flow cytometric analysis of immune GALT cells performed ex vivo, and adoptive transfer experiments were used to test the protective effects of GALT regulatory T (Treg) cells. RESULTS: Teriflunomide reduced the percentages of antigen-presenting cells of Peyer patches when compared to controls. Conversely, a significant increase of the relative frequency of CD39+ Treg cells was observed. In vivo, the protective effect of GALT-derived teriflunomide-induced CD39+ Treg cells was established by adoptive transfer into recipient experimental autoimmune encephalomyelitis mice. CONCLUSIONS: Our results identify specific GALT-derived CD39+ Treg cells as a mechanism of action that may contribute to the efficacy of teriflunomide during CNS inflammatory demyelination and as an oral therapeutic in relapsing multiple sclerosis. PMID- 27766283 TI - Term Neonate With Liver Laceration, Obstructive Uropathy, and Ascites-Secondary to Extravasation of Total Parenteral Nutrition: A Complication of Malpositioned Umbilical Venous Catheter. AB - We report a rare, but serious, complication of a malpositioned umbilical venous catheter in a term male infant who developed laceration, hematoma, and necrosis of liver, ascites, and left-sided obstructive uropathy secondary to extravasation of total parenteral nutrition. Abdominal paracentesis confirmed the presence of parenteral nutrition in the peritoneal cavity. Although, the umbilical venous catheterization is a common intravenous access used in neonatal intensive care units, judicious continued monitoring of its use should be practiced to avoid serious complications. PMID- 27766285 TI - Acknowledging the Elephant in the Room: How Stressful Environmental Contexts Shape Relationship Dynamics. AB - Compared to affluent marriages, lower income marriages develop within a context filled with negative stressors that may prove quite toxic for marital stability. The current paper argues that stressful contexts may undermine marital well-being through two routes. First, external stressors create additional problems within the marriage by diverting time and attention away from activities that promote intimacy between partners. Second, external stress may render spouses ill equipped to cope with this increase in problems by draining spouses of the energy and resources necessary for responding to marital challenges in a constructive manner. In acknowledging the role of the marital context for relationship dynamics, this model suggests new directions for interventions designed to strengthen the marriages of lower income couples. PMID- 27766286 TI - Dataset of the molecular dynamics simulations of bilayers consisting of short amyloidogenic peptide VDSWNVLVAG from Bgl2p-glucantransferase of S. cerevisiae cell wall. AB - The amyloidogenic peptide VDSWNVLVAG from Bgl2p-glucantransferase of Saccharomyces cerevisiae cell wall and its modifying analog VESWNVLVAG were taken for the construction of four types of bilayers which differ by orientation of the peptides in the layers and of the layers relative to each other. These bilayers were used as starting models for the molecular dynamics (MD) at three charge states (neutral, pH3, and pH5). The changes of the fraction of secondary structure during 1 ns simulations were received for 96 MD trajectories. The data article contains the necessary information for the construction of models of beta strands organization in the oligomer structure. These results were used in the associated research article "Structural model of amyloid fibrils for amyloidogenic peptide from Bgl2p-glucantransferase of S. cerevisiae cell wall and its modifying analog. New morphology of amyloid fibrils" (Selivanova et al., 2016) [1]. PMID- 27766284 TI - Lessons to be learned: how a comprehensive neurobiological framework of atypical reading development can inform educational practice. AB - Dyslexia is a heritable reading disorder with an estimated prevalence of 5-17%. A multiple deficit model has been proposed that illustrates dyslexia as an outcome of multiple risks and protective factors interacting at the genetic, neural, cognitive, and environmental levels. Here we review the evidence on each of these levels and discuss possible underlying mechanisms and their reciprocal interactions along a developmental timeline. Current and potential implications of neuroscientific findings for contemporary challenges in the field of dyslexia, as well as for reading development and education in general, are then discussed. PMID- 27766287 TI - Genomics dataset on unclassified published organism (patent US 7547531). AB - Nucleotide (DNA) sequence analysis provides important clues regarding the characteristics and taxonomic position of an organism. With the intention that, DNA sequence analysis is very crucial to learn about hierarchical classification of that particular organism. This dataset (patent US 7547531) is chosen to simplify all the complex raw data buried in undisclosed DNA sequences which help to open doors for new collaborations. In this data, a total of 48 unidentified DNA sequences from patent US 7547531 were selected and their complete sequences were retrieved from NCBI BioSample database. Quick response (QR) code of those DNA sequences was constructed by DNA BarID tool. QR code is useful for the identification and comparison of isolates with other organisms. AT/GC content of the DNA sequences was determined using ENDMEMO GC Content Calculator, which indicates their stability at different temperature. The highest GC content was observed in GP445188 (62.5%) which was followed by GP445198 (61.8%) and GP445189 (59.44%), while lowest was in GP445178 (24.39%). In addition, New England BioLabs (NEB) database was used to identify cleavage code indicating the 5, 3 and blunt end and enzyme code indicating the methylation site of the DNA sequences was also shown. These data will be helpful for the construction of the organisms' hierarchical classification, determination of their phylogenetic and taxonomic position and revelation of their molecular characteristics. PMID- 27766288 TI - Data for the qualitative modeling of the osmotic stress response to NaCl in Escherichia coli. AB - Qualitative modeling approaches allow to provide a coarse-grained description of the functioning of cellular networks when experimental data are scarce and heterogeneous. We translate the primary literature data on the response of Escherichia coli to hyperosmotic stress caused by NaCl addition into a piecewise linear (PL) model. We provide a data file of the qualitative model, which can be used for simulation of changes of protein concentrations and of DNA coiling during the physiological response of the bacterium to the stress. The qualitative model predictions are directly comparable to the available experimental data. This data is related to the research article entitled "Piecewise linear approximations to model the dynamics of adaptation to osmotic stress by food borne pathogens" (Metris et al., 2016) [1]. PMID- 27766289 TI - Data on external walls from a multi-objective simulation for cold climates. AB - Data are related to the multi-objective optimization process applied to the building materials to obtain high energy-efficient precast walls for cold climate. The methodology has been explained on the paper entitled "High performance precast external walls for cold climate by a multi criteria methodology" (Baglivo and Congedo, 2016) [1]. The modeFRONTIER rel.4.3 optimization tool has been used to evaluate the dynamic behaviour of the building components in accordance with the UNI EN ISO 13786:2008 and to obtain a multitude of high efficiency configurations. The results are divided into three categories thick, thin and ultra-thin precast walls, in accordance with their thicknesses. The input data are the building materials with their thermal properties, sustainability characteristics and the supply and installation costs. The output values of the simulations are adapted to the cold climate and based on thermal properties, costs and sustainability score. Several combinations of external precast walls have been shown as optimal for cold climate. PMID- 27766290 TI - Contemporary data on low-density lipoprotein cholesterol target value attainment and distance to target in a cohort of 57,885 statin-treated patients by country and region across the world. AB - Data presented here refer to 57,885 patients on lipid-lowering statin therapy from the Dyslipidaemia International Study (DYSIS) registry. Subjects were divided into 3 discrete subsets: those at very high-risk, high-risk, and non-high risk for cardiovascular events, with assigned low density lipoprotein cholesterol (LDL-C) targets of 70 mg/dl, 100 mg/dl and 115 mg/dl, respectively. Overall, the highest proportion of patients meeting their LDL-C target was seen in the UAE and Kuwait (49.5%), while the lowest was seen in Germany (14.3%). The smallest median distance to target was documented in Canada (18.8 mg/dl), and the largest in the Baltics (42.1 mg/dl). Interpretation and discussion of this data can be found in the manuscript entitled "Low-density lipoprotein cholesterol in a global cohort of 57,885 statin-treated patients" (Gitt et al., 2016) [1]. PMID- 27766291 TI - Data from a fingerprint matching task with experts, trained students and untrained novices. AB - The data described here provide standard performance measures following administration of a fingerprint matching task to expert analysts, trained students and novice control participants. Measures include accuracy on 'same' and 'different' trials, and the associated measures of sensitivity of discrimination (d') and response bias (C). In addition, speed of correct response is provided. The provision of these data will enable the interested reader to conduct meta analyses relating to questions of fingerprint expertise and fingerprint training (see "Fact or friction: examination of the transparency, reliability and sufficiency of the ACE-V method of fingerprint analysis" (Stevenage and Pitfield, in press) [1]). PMID- 27766292 TI - Data on fluoride concentration level in villages of Asara (Alborz, Iran) and daily fluoride intake based on drinking water consumption. AB - In the present data article, fluoride concentration levels of drinking water (with spring or groundwater sources) in 10 villages of Asara area located in Alborz province were determined by the standard SPADNS method using a spectrophotometer (DR/2000 Spectrophotometer, USA). Daily fluoride intakes were also calculated based on daily drinking water consumption. The fluoride content were compared with EPA and WHO guidelines for drinking water. PMID- 27766293 TI - Data on proteins of lysenin family in coelomocytes of Eisenia andrei and E. fetida obtained by tandem mass spectrometry coupled with liquid chromatography. AB - The data described are related to the article "Lysenin family proteins in earthworm coelomocytes - comparative approach" (B. Swiderska, S. Kedracka-Krok, T. Panz, A.J. Morgan, A. Falniowski, P.Grzmil, B. Plytycz, 2016) [1]. Lysenin family proteins were identified based on unique peptides sequenced by tandem mass spectrometry coupled with liquid chromatography (LC-MS/MS) in lumbricid earthworms Eisenia andrei and E. fetida, the latter with or without the MUG-like fluorophore. Lysenin and lysenin-related protein 2 (LRP-2, fetidin) were identified in all 9 investigated specimens of Eisenia sp. LRP-1 was identified in 5 of 6 specimens of E. fetida, while LRP-3 was present in 2 of 3 investigated specimens of E. andrei. Here, the detailed characteristics of identified peptides unique to the particular members of lysenin family present in each particular earthworm specimen was provided. The information concerning mass to charge ratio, retention time, modifications and score of unique peptides was given. PMID- 27766294 TI - Data on regulation of the gene for the adipocyte-enriched micropeptide Adig/Smaf1 by qPCR analysis and luciferase reporter assay. AB - This article describes qPCR analysis for the Adig/Smaf1 gene in multiple in vitro adipocyte differentiation models including white and brown adipogenesis, cell lines and primary cultures. The article also contains qPCR data for transcript levels of Adig/Smaf1 in a wide panel of murine tissues. Expression of Adig/Smaf1 transcript in white and brown adipose tissue in fasted and refed mice is reported and also data for Adig/Smaf1 transcript expression in genetically obese ob/ob mice. Data on the effects of siRNA-mediated knockdown of Srebp1c on Adig/Smaf1 transcript levels in 3T3-L1 adipocytes are shown. Luciferase reporter assays provide data for regulation of an ~ 2 kb fragment of the 5' flanking region of Adig/Smaf1 gene by PPARgamma/RXRalpha. This data is related to a research article describing Adig/Smaf1 protein expression, "Expression, regulation and functional assessment of the 80 amino acid Small Adipocyte Factor 1 (Smaf1) protein in adipocytes" (G. Ren, P. Eskandari, S. Wang, C.M. Smas, 2016) [1]. PMID- 27766295 TI - Topology and parameter data of thirteen non-natural amino acids for molecular simulations with CHARMM22. AB - In this article we provide a data package containing the topology files and parameters compatible with the CHARMM22 force field for thirteen non-natural amino acids. The force field parameters were derived based on quantum mechanical (QM) calculations involving geometry optimization and potential energy surface scanning at the HF 6-31G(d) and HF 6-311G(d,p) levels of theory. The resulting energy data points were fitted to mathematical functions representing each component of the CHARMM22 force field. Further fine-tuning of the parameters utilized molecular mechanics energies, which were iteratively calculated and compared to the corresponding QM values until the latter were satisfactorily reproduced. The final force field data were validated with molecular dynamics simulations in explicit solvent conditions. PMID- 27766296 TI - Physico-mechanical analysis data in support of compatibility of chitosan/kappa carrageenan polyelectrolyte films achieved by ascorbic acid, and the thermal degradation theory of kappa-carrageenan influencing the properties of its blends. AB - This article presents the complementary data regarding compatibilization of chitosan/kappa-carrageenan polyelectrolyte complex for synthesizing of a soft film using ascorbic acid. It includes the thermal-theory for estimating the degradation of kappa-carrageenan, as reflected in alteration of the structural properties of the blend. The data has been provided to demonstrate that the blend solution based on chitosan, a polycation, and kappa-carrageenan, a polyanion polymer, produces an incompatible polyelectrolyte composite, susceptible to coaservative phase separation. We present further data on water resistance, water barrier property, mechanical parameters, scanning electron micrograph, as well as contact angle image dataset of the chitosan/kappa-carrageenan film. The physical data were collected by water solubility and water permeability assays, with a view to elucidate the role of ascorbic acid in the compatibility of polyelectrolyte blends. The mechanical data is obtained from a stress-strain curve for evaluation of tensile strength and elongation at break point of the chitosan/kappa-carrageenan film. The microstructure observations were performed using scanning electron micrograph. These dataset confirm fabrication of a soft film in the presence of ascorbic acid, with reduced heterogeneities in the polyelectrolyte film structure. The kappa-carrageenan was also treated by a thermal process, prior to inclusion into the chitosan solution, to investigate the impact of this on the mechanical and structural features of the resulting blend. We present the required data and the theoretical analysis supporting the thermal chain degradation of a polymer and its effects on behavior of the film. Additional information, characterizing the hydrophobicity of the surface of the blend layers is obtained by measuring water contact angles using a contact anglemeter. PMID- 27766297 TI - Data on Heavy metal in coastal sediments from South East Coast of Tamilnadu, India using Energy Dispersive X-ray Fluorescence (EDXRF) Technique. AB - This article contains the chemical and geographical data and figures for the chemical data in sediments of East Coast (Pattipulam to Dhevanampattinam) of Tamilnadu. The obtained data are related to the research article "Heavy Metal Assessment in Sediment Samples Collected From Pattipulam to Dhevanampattinam along the East Coast of Tamil Nadu Using EDXRF Technique" (Chandramohan et al., 2016) [1]. Chemical data are collected from Energy dispersive X-ray fluorescence spectrometer (EDXRF). Furthermore, the obtained chemical data describes it in more detail in the figures. PMID- 27766300 TI - An unusual presentation of Stewart-Treves syndrome on the lower extremity. PMID- 27766298 TI - Epithelial Regeneration After Gastric Ulceration Causes Prolonged Cell-Type Alterations. AB - BACKGROUND & AIMS: The peptic ulcer heals through a complex process, although the ulcer relapse often occurs several years later after healing. Our hypothesis is that even after visual evidence of healing of gastric ulceration, the regenerated epithelium is aberrant for an extended interval, increasing susceptibility of the regenerated epithelium to damage and further diseases. METHODS: Gastric ulcers were induced in mice by serosal topical application of acetic acid. RESULTS: Gastric ulcers induced by acetic acid visually healed within 30 days. However, regenerated epithelial architecture was poor. The gene profile of regenerated tissue was abnormal, indicating increased stem/progenitor cells, deficient differentiated gastric cell types, and deranged cell homeostasis. Despite up regulation of PDX1 in the regenerated epithelium, no mature antral cell type was observed. Four months after healing, the regenerated epithelium lacks parietal cells, trefoil factor 2 (TFF2) and (sex-determining region Y)-box 9 (SOX9) remain up-regulated deep in the gastric gland, and the Na/H exchanger 2 (a TFF2 effector in gastric healing) remains down-regulated. Gastric ulcer healing was strongly delayed in TFF2 knockout mice, and re-epithelialization was accompanied with mucous metaplasia. After Helicobacter pylori inoculum 30 days after ulceration, we observed that the gastric ulcer selectively relapses at the same site where it originally was induced. Follow-up evaluation at 8 months showed that the relapsed ulcer was not healed in H pylori-infected tissues. CONCLUSIONS: These findings show that this macroscopically regenerated epithelium has prolonged abnormal cell distribution and is differentially susceptible to subsequent damage by H pylori. PMID- 27766301 TI - White network in fibroepithelioma of Pinkus. PMID- 27766302 TI - Cryptococcal cellulitis in a heart transplant recipient. PMID- 27766303 TI - Cutaneous metastases from adenocarcinoma of the ovary. PMID- 27766304 TI - Remission of a long-lasting sarcoidosis after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. PMID- 27766306 TI - GLUT1-positive recurrent basal cell carcinoma of basosquamous subtype detected by positron emission tomography. PMID- 27766305 TI - Primary cutaneous apocrine carcinoma: 2 cases and review of the pertinent histologic findings. PMID- 27766299 TI - Role of Omega-3 Fatty Acids in the Etiology, Treatment, and Prevention of Depression: Current Status and Future Directions. AB - Over the past three decades a body of translational evidence has implicated dietary deficiency in long-chain omega-3 (LCn-3) fatty acids, including eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology and etiology of major depressive disorder (MDD). Cross-national and cross sectional data suggest that greater habitual intake of preformed EPA+DHA is associated with reduced risk for developing depressive symptoms and syndromal MDD. Erythrocyte EPA and DHA composition is highly correlated with habitual fish or fish oil intake, and case-control studies have consistently observed lower erythrocyte EPA and/or DHA levels in patients with MDD. Low erythrocyte EPA+DHA composition may also be associated with increased risk for suicide and cardiovascular disease, two primary causes of excess premature mortality in MDD. While controversial, dietary EPA+DHA supplementation may have antidepressant properties and may augment the therapeutic efficacy of antidepressant medications. Neuroimaging and rodent neurodevelopmental studies further suggest that low LCn-3 fatty acid intake or biostatus can recapitulate central pathophysiological features associated with MDD. Prospective findings suggest that low LCn-3 fatty acid biostatus increases risk for depressive symptoms in part by augmenting pro-inflammatory responsivity. When taken collectively, these translational findings provide a strong empirical foundation in support of dietary LCn-3 fatty acid deficiency as a modifiable risk factor for MDD. This review provides an overview of this translational evidence and then discusses future directions including strategies to translate this evidence into routine clinical screening and treatment algorithms. PMID- 27766307 TI - An Ecological Study of Social Fragmentation, Socioeconomic Deprivation, and Suicide in Rural China: 2008-2010. AB - China accounts for a large number of suicides worldwide, and most occur in rural areas. Suicide research in China has primarily focused on individual-level risk factors, few have studied the influence of neighborhood contexts. This ecological study examines the association of suicide rates with social fragmentation and socioeconomic deprivation in Chinese rural villages. Data from the community survey of the China Health and Retirement Longitudinal Study were analyzed using negative binomial regression. A total of 307 rural villages were included. The community survey collected data about the villages from local leaders. Suicide counts were measured by the leaders' report of the number of suicide deaths in the villages. Social fragmentation was indicated by out-migration, in-migration and ethnic diversity; socioeconomic deprivation was indicated by physical infrastructure, illiteracy rates and public transit accessibility. The results show that higher incidence rates of suicide occurred in villages with high proportions of out-migration (vs. low), inflow of migrants (vs. no migrants), mixes of Han and ethnic minority residents (vs. Han only), high degrees of infrastructure deficiency (vs. low) and poor access to public transportation (vs. excellent). Villages with higher percentages of older adults also had higher suicide rates. This is one of the first studies to examine the association between neighborhood contexts and suicide in China. The findings have implications for suicide prevention in rural China. PMID- 27766309 TI - Using Personification and Agency Reorientation to Reduce Mental-Health Clinicians' Stigmatizing Attitudes Toward Patients. AB - People with mental disorders are strongly stigmatized. Among mental-health professionals, stigmatizing attitudes often manifest as desire for social distance from people with mental disorders. Currently ascendant biomedical conceptualizations of psychopathology could exacerbate this problem by engendering dehumanization, which is linked to prejudice. Given the clinical implications of such an occurrence, the present research tested a possible mitigation strategy. In an online study of 216 U.S. mental-health clinicians, two strategies for mitigating dehumanization in healthcare were tested personification, highlighting personal traits of people with mental disorders rather than presenting them as malfunctioning brains, and agency reorientation, underscoring people's ability to make choices and decisions. This approach yielded significantly less desire for social distance, among clinicians, from a person with depression whose symptoms were explained biologically. These findings may suggest an avenue for decreasing stigma in clinical practice. PMID- 27766310 TI - Epidermolysis bullosa simplex with muscular dystrophy associated with PLEC deletion mutation. AB - Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM #226670) is an autosomal recessive disorder characterized by neonatal blistering and later onset muscle weakness. PMID- 27766311 TI - Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T). AB - OBJECTIVE: In this study, muscle involvement assessed by MRI and levels of GMPPB and glycosylation of alpha-dystroglycan expression in muscle were examined in patients with limb-girdle muscular dystrophy (LGMD) type 2T. METHODS: Six new patients with genetically verified mutations in GMPPB were studied. T1-weighted magnetic resonance images were obtained in 4 participants. Muscle strength and potential involvement of extramuscular organs were examined. Glycosylation of alpha-dystroglycan in muscle was studied, and GMPPB and alpha-dystroglycan expression was analyzed by Western blotting. Prevalence of LGMD2T was calculated from the total LGMD population in Denmark. GMPPB was sequenced in all unclassified cases. RESULTS: Two patients carried 3 new mutations in GMPPB. The other 4 patients carried previously described pathogenic mutations in GMPPB. MRI showed that the paraspinal muscles were the most affected, followed by involvement of hamstrings. Our results showed a loss of glycosylation of alpha dystroglycan as well as secondary loss of merosin expression on Western blotting. The prevalence of LGMD2T in the Danish cohort of patients with LGMD is 1.5%. CONCLUSIONS: The new findings of this study are (1) the consistent finding of a preferential affection of paraspinal and hamstring muscles in LGMD2T, (2) 3 new mutations in GMPPB, (3) variable loss of glycosylation tested with IIH6 and VIA4 antibodies, and (4) a prevalence of LGMD2T of 1.5% in a well-characterized Danish LGMD cohort. PMID- 27766308 TI - Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models. AB - The mouse is the second mammalian species, after the human, in which substantial amount of the genomic information has been analyzed. With advances in transgenic technology, mutagenesis is now much easier to carry out in mice. Consequently, an increasing number of transgenic mouse systems have been generated for the study of cardiac arrhythmias in ion channelopathies and cardiomyopathies. Mouse hearts are also amenable to physical manipulation such as coronary artery ligation and transverse aortic constriction to induce heart failure, radiofrequency ablation of the AV node to model complete AV block and even implantation of a miniature pacemaker to induce cardiac dyssynchrony. Last but not least, pharmacological models, despite being simplistic, have enabled us to understand the physiological mechanisms of arrhythmias and evaluate the anti-arrhythmic properties of experimental agents, such as gap junction modulators, that may be exert therapeutic effects in other cardiac diseases. In this article, we examine these in turn, demonstrating that primary inherited arrhythmic syndromes are now recognized to be more complex than abnormality in a particular ion channel, involving alterations in gene expression and structural remodelling. Conversely, in cardiomyopathies and heart failure, mutations in ion channels and proteins have been identified as underlying causes, and electrophysiological remodelling are recognized pathological features. Transgenic techniques causing mutagenesis in mice are extremely powerful in dissecting the relative contributions of different genes play in producing disease phenotypes. Mouse models can serve as useful systems in which to explore how protein defects contribute to arrhythmias and direct future therapy. PMID- 27766313 TI - Estimating the Impact of Randomised Control Trial Results on Clinical Practice: Results from a Survey and Modelling Study of Androgen Deprivation Therapy plus Radiotherapy for Locally Advanced Prostate Cancer. AB - BACKGROUND: Recent trials have shown that the addition of external beam radiotherapy (EBRT) to androgen deprivation therapy (ADT) improves survival among men with locally advanced prostate cancer. OBJECTIVE: To examine the potential impact of these trials on changes in clinical practice and life-years saved. DESIGN SETTING AND PARTICIPANTS: A model was developed to examine the impact of changes in clinical practice in the UK. A survey of clinicians who treat men with prostate cancer in the UK and Canada was performed. MEASUREMENTS: Outcomes of interest were the proportion of patients treated with different approaches and the predicted number of life-years saved due to changes in clinical practice. Survey data were cross-tabulated and Pearson's chi2 tests were applied. RESULTS AND LIMITATIONS: The survey was completed by 193 clinicians (105 from the UK, 80 from Canada), of whom 70% were clinical/radiation oncologists, 8% were medical oncologists, and 15% were urologists. UK respondents were more likely to report a change in practice in response to the results (44% UK vs 21% Canada). Canadians were more likely to have already been using ADT plus radiotherapy (77% Canada vs 56% UK). The increase in the proportion of patients in the UK treated with ADT + EBRT could result in around 3730-5177 extra life-years at 15 yr from a cohort of 7930 men diagnosed in a single calendar year, compared to if all had been treated with ADT alone. CONCLUSIONS: Trial findings have changed clinical practice, meaning that men with locally advanced prostate cancer are likely to survive longer. PATIENT SUMMARY: Doctors in the UK have changed practice in response to evidence on the superiority of hormone therapy plus radiotherapy to hormone therapy alone. These changes will improve the survival of men with locally advanced prostate cancer. Further reductions in the use of hormone therapy alone could further improve survival. PMID- 27766314 TI - Sensorimotor body-environment interaction serves to regulate emotional experience and exploratory behavior. AB - Almost all living species regularly explore environments that they experience as pleasant, aversive, arousing or frightening. We postulate that such exploratory behavior and emotional experience both are regulated based on the interdependent perception of one's body and stimuli that collectively define a spatial context such as a cliff. Here we examined this by testing if the interaction of the sensory input on one's gait and the sensory input on the spatial context is modulating both the emotional experience of the environment and its exploration through head motion. To this end, we asked healthy humans to explore a life-sized Virtual Reality simulation of a forest glade by physically walking around in this environment on two narrow rectangular platforms connected by a plank. The platforms and the plank were presented such that they were either placed on ground or on the top of two high bridge piers. Hence, the forest glade was presented either as a "ground" or as a "height" context. Within these two spatial contexts the virtual plank was projected either on the rigid physical floor or onto a bouncy physical plank. Accordingly, the gait of our participants while they crossed the virtual plank was either "smooth" or "bouncy." We found that in the height context bouncy gait compared to smooth gait increased the orientation of the head below the horizon and intensified the experience of the environment as negative. Whereas, within the ground context bouncy gait increased the orientation of the head towards and above the horizon and made that the environment was experienced as positive. Our findings suggest that the brain of healthy humans is using the interaction of the sensory input on their gait and the sensory input on the spatial context to regulate both the emotional experience of the environment and its exploration through head motion. PMID- 27766312 TI - Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations. AB - Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85alpha/p55alpha/p50alpha subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85alpha with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85alpha overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. PMID- 27766315 TI - Cross-Linking GPVI-Fc by Anti-Fc Antibodies Potentiates Its Inhibition of Atherosclerotic Plaque- and Collagen-Induced Platelet Activation. AB - To enhance the antithrombotic properties of recombinant glycoprotein VI fragment crystallizable (GPVI-Fc), the authors incubated GPVI-Fc with anti-human Fc antibodies to cross-link the Fc tails of GPVI-Fc. Cross-linking potentiated the inhibition of human plaque- and collagen-induced platelet aggregation by GPVI-Fc under static and flow conditions without increasing bleeding time in vitro. Cross linking with anti-human-Fc Fab2 was even superior to anti-human-Fc immunoglobulin G (IgG). Advanced optical imaging revealed a continuous sheath-like coverage of collagen fibers by cross-linked GPVI-Fc complexes. Cross-linking of GPVI into oligomeric complexes provides a new, highly effective, and probably safe antithrombotic treatment as it suppresses platelet GPVI-plaque interaction selectively at the site of acute atherothrombosis. PMID- 27766316 TI - Unilateral Carotid Body Resection in Resistant Hypertension: A Safety and Feasibility Trial. AB - Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension. PMID- 27766317 TI - Myocardial architecture and patient variability in clinical patterns of atrial fibrillation. AB - Atrial fibrillation (AF) increases the risk of stroke by a factor of 4-5 and is the most common abnormal heart rhythm. The progression of AF with age, from short self-terminating episodes to persistence, varies between individuals and is poorly understood. An inability to understand and predict variation in AF progression has resulted in less patient-specific therapy. Likewise, it has been a challenge to relate the microstructural features of heart muscle tissue (myocardial architecture) with the emergent temporal clinical patterns of AF. We use a simple model of activation wave-front propagation on an anisotropic structure, mimicking heart muscle tissue, to show how variation in AF behavior arises naturally from microstructural differences between individuals. We show that the stochastic nature of progressive transversal uncoupling of muscle strands (e.g., due to fibrosis or gap junctional remodeling), as occurs with age, results in variability in AF episode onset time, frequency, duration, burden, and progression between individuals. This is consistent with clinical observations. The uncoupling of muscle strands can cause critical architectural patterns in the myocardium. These critical patterns anchor microreentrant wave fronts and thereby trigger AF. It is the number of local critical patterns of uncoupling as opposed to global uncoupling that determines AF progression. This insight may eventually lead to patient-specific therapy when it becomes possible to observe the cellular structure of a patient's heart. PMID- 27766318 TI - Intra-Cluster Correlation Estimates for HIV-related Outcomes from Care and Treatment Clinics in Dar es Salaam, Tanzania. AB - INTRODUCTION: Researchers planning cluster-randomized controlled trials (cRCTs) require estimates of the intra-cluster correlation coefficient (ICC) from previous studies for sample size calculations. This paper fills a persistent gap in the literature by providing estimates of ICCs for many key HIV-related clinical outcomes. METHODS: Data from HIV-positive patients from 47 HIV care and treatment clinics in Dar es Salaam, Tanzania were used to calculate ICCs by site of enrollment or site of ART initiation for various clinical outcomes using cross sectional and longitudinal data. ICCs were estimated using linear mixed models where either clinic of enrollment or clinic of ART initiation served as the random effect. RESULTS: ICCs ranged from 0 to 0.0706 (95% CI: 0.0447, 0.1098). For most outcomes, the ICCs were large enough to meaningfully affect sample size calculations. For binary outcomes, the ICCs for event prevalence at baseline tended to be larger than the ICCs for later cumulative incidences. For continuous outcomes, the ICCs for baseline values tended to be larger than the ICCs for the change in values from baseline. CONCLUSION: The ICCs for HIV-related outcomes cannot be ignored when calculating sample sizes for future cluster-randomized trials. The differences between ICCs calculated from baseline data alone and ICCs calculated using longitudinal data demonstrate the importance of selecting an ICC that reflects a study's intended design and duration for sample size calculations. While not generalizable to all contexts, these estimates provide guidance for future researchers seeking to design adequately powered cRCTs in Sub Saharan African HIV treatment and care clinics. PMID- 27766319 TI - Integrated machine learning, molecular docking and 3D-QSAR based approach for identification of potential inhibitors of trypanosomal N-myristoyltransferase. AB - N-Myristoyltransferase (NMT) catalyzes the transfer of myristate to the amino terminal glycine of a subset of proteins, a co-translational modification involved in trafficking substrate proteins to membrane locations, stabilization and protein-protein interactions. It is a studied and validated pre-clinical drug target for fungal and parasitic infections. In the present study, a machine learning approach, docking studies and CoMFA analysis have been integrated with the objective of translation of knowledge into a pipelined workflow towards the identification of putative hits through the screening of large compound libraries. In the proposed pipeline, the reported parasitic NMT inhibitors have been used to develop predictive machine learning classification models. Simultaneously, a TbNMT complex model was generated to establish the relationship between the binding mode of the inhibitors for LmNMT and TbNMT through molecular dynamics simulation studies. A 3D-QSAR model was developed and used to predict the activity of the proposed hits in the subsequent step. The hits classified as active based on the machine learning model were assessed as the potential anti trypanosomal NMT inhibitors through molecular docking studies, predicted activity using a QSAR model and visual inspection. In the final step, the proposed pipeline was validated through in vitro experiments. A total of seven hits have been proposed and tested in vitro for evaluation of dual inhibitory activity against Leishmania donovani and Trypanosoma brucei. Out of these five compounds showed significant inhibition against both of the organisms. The common topmost active compound SEW04173 belongs to a pyrazole carboxylate scaffold and is anticipated to enrich the chemical space with enhanced potency through optimization. PMID- 27766321 TI - Highlights from Faraday Discussion on Nanoparticles with Morphological and Functional Anisotropy, Glasgow, UK, July 2015. PMID- 27766320 TI - Well-defined Ti4 pre-catalysts for the ring-opening polymerisation of lactide. AB - The synthesis and full characterisation of four discrete tetrametallic titanium complexes is reported. These well-defined compounds are isostructural in the solid state and share the same general formula: Ti4(MU-O)2L4 (L = 1, 2, 3 or 4). Using a combination of NMR techniques the complexes are found to be stable in solution, even at elevated temperatures. Further studies show that the carboxylate moieties of the supporting amine bis(phenolate) ligands can be displaced by a more strongly coordinating solvent. This reversible process causes the coordinatively saturated Ti4(MU-O)2L4 complexes to separate into two Ti2(MU O)L2 subunits which we envisaged would be catalytically active. Proof-of-concept experiments establish that all four of these complexes display catalytic activity in the ring-opening polymerisation of rac-lactide. These aggregates can therefore be viewed as air and moisture stable pre-catalysts for a range of reactions. PMID- 27766322 TI - Programmable assembly of heterogeneous microparts by an untethered mobile capillary microgripper. AB - At the sub-millimeter scale, capillary forces enable robust and reversible adhesion between biological organisms and varied substrates. Current human engineered mobile untethered micromanipulation systems rely on forces which scale poorly or utilize gripper-part designs that promote manipulation. Capillary forces, alternatively, are dependent upon the surface chemistry (which is scale independent) and contact perimeter, which conforms to the part surface. We report a mobile capillary microgripper that is able to pick and place parts of various materials and geometries, and is thus ideal for microassembly tasks that cannot be accomplished by large tethered manipulators. We achieve the programmable assembly of sub-millimeter parts in an enclosed three-dimensional aqueous environment by creating a capillary bridge between the targeted part and a synthetic, untethered, mobile body. The parts include both hydrophilic and hydrophobic components: hydrogel, kapton, human hair, and biological tissue. The 200 MUm untethered system can be controlled with five-degrees-of-freedom and advances progress towards autonomous desktop manufacturing for tissue engineering, complex micromachines, microfluidic devices, and meta-materials. PMID- 27766323 TI - Development of a functional point-of-need diagnostic for myeloperoxidase detection to identify neutrophilic bronchitis. AB - With over 4.8 million Canadians suffering from chronic airway diseases, respiratory exacerbations are currently the leading cause of hospitalization in Canada. In cases of bacterial infection, neutrophil cell density increases from ~10 million cells per gram to over 15 million cells per gram. As sputum is a direct discharge from the primarily affected areas of respiratory diseases, quantification of granulocytes (including neutrophils) can be used to effectively determine a course of patient treatment. Unfortunately this quantification is currently limited to labour-intensive and time-consuming cell counts. In the present study, we describe a simple one-step lateral flow test (LFT) that can semi-quantitatively determine myeloperoxidase (MPO), a biomarker found in neutrophils, in minimally-processed sputum samples. This point-of-need (PON) diagnostic device provides positive results observable to the naked eye after 15 minutes. 37 human sputum samples were quantified for MPO using the developed LFT and compared to neutrophil levels quantified through traditional cell counting. A trend between sputum MPO concentration and total neutrophils was observed, suggesting that the LFT has the potential to replace cell counting for neutrophil approximation to aid in directing therapies quickly at the point of need. PMID- 27766324 TI - Ionic liquid induced G-quadruplex formation and stabilization: spectroscopic and simulation studies. AB - Among different polymorphs of DNA, G-quadruplex (GQ) formation in guanine rich sequences has received special attention due to its direct relevance to cellular aging and abnormal cell growths. To date, smaller ions like Na+, K+, Li+, and NH4+ are the best possible selective GQ stabilizing materials. Herein, we report that an ionic liquid (IL), i.e. guanidinium tris(pentafluoroethyl)trifluorophosphate, can not only instigate the GQ formation in the absence of conventional GQ forming ions (like Na+, K+, NH4+, etc.), but also stabilizes the GQ structure. This conformational transition has been confirmed through different spectroscopic tools and molecular dynamics (MD) simulation studies. MD simulation shows that one of the guanidinium cations resides in the G-tetrad core, while bulky anions prefer to stay near the GQ surface resulting in GQ formation and stabilization. This study thus brings out a special type of ionic liquid that acts as a GQ stabilizer. The origin of GQ stabilization by IL presented here may also help in the future design of IL for GQ formation and stabilization. PMID- 27766325 TI - Density functional theory simulation of the adsorption of sulphur multilayers on Au(100). AB - The adsorption of sulphur multilayers on Au(100) has been studied using density functional theory (DFT) within the generalized gradient approximation (GGA). The first sulphur layer was adsorbed on the four-fold sites of the unreconstructed Au(100) surface forming a lattice. The experimental parameters of the lattice were reproduced taking into account the surface expansion of the topmost Au(100) layer. This expansion should occur when gold islands are formed after the lifting of hex-reconstruction, which allows the lateral movement of the gold atoms. The second sulphur layer, on top of the lattice, consisted of eight S atoms (octomer phase) in a quasi-rectangular arrangement. The structural optimization of the octomer phase was achieved in a specific spatial orientation with respect to the lattice. The analysis of Bader atomic charges and the projected density of states (PDOS) demonstrated that charge transfer from the Au(100) surface to the sulphur layers, sulphur chemisorption and sulphur-sulphur inter-layer mixing of electronic states control the formation of sulphur multilayers. PMID- 27766326 TI - Alkyl Grignard cross-coupling of aryl phosphates catalyzed by new, highly active ionic iron(ii) complexes containing a phosphine ligand and an imidazolium cation. AB - A novel family of ionic iron(ii) complexes of the general formula [HL][Fe(PR'3)X3] (HL = 1,3-bis(2,6-diisopropylphenyl)imidazolium cation, HIPr, R' = Ph, X = Cl, 2; HL = HIPr, R' = Cy, X = Cl, 3; HL = HIPr, R' = Ph, X = Br, 4; HL = HIPr, R' = Cy, X = Br, 5; HL = 1,3-bis(2,4,6-trimethylphenyl)imidazolium cation, HIMes, R' = Cy, X = Br, 6) was easily prepared via a stepwise approach in 88%-92% yields. In addition, an ionic iron(ii) complex, [HIPr][Fe(C4H8O)Cl3] (1), has been isolated from the reaction of FeCl2(THF)1.5 with one equiv. of [HIPr]Cl in 90% yield and it can further react with one equiv. of PPh3 or PCy3, affording the corresponding target iron(ii) complex 2 or 3, respectively. All these complexes were characterized by elemental analysis, electrospray ionization mass spectrometry (ESI-MS), 1H NMR spectroscopy and X-ray crystallography. These air insensitive complexes 2-6 showed high catalytic activities in the cross-coupling of aryl phosphates with primary and secondary alkyl Grignard reagents with a broad substrate scope, wherein [HIPr][Fe(PCy3)Br3] (5) was the most effective. Complex 5 also catalyzes the reductive cross-coupling of aryl phosphates with unactivated alkyl bromides in the presence of magnesium turnings and LiCl, as well as the corresponding one-pot acylation/cross-coupling sequence under mild conditions. PMID- 27766327 TI - Copper(i) 5-phenylpyrimidine-2-thiolate complexes showing unique optical properties and high visible light-directed catalytic performance. AB - Solvothermal reactions of 5-phenylpyrimidine-2-thiol (5-phpymtH) with equimolar CuBr afforded one hexanuclear cluster [Cu6(MU3-5-phpymt)6] (1) along with a tetranuclear by-product [{(Cu2Br)(MU-5-phpymtH)}(MU3-5-phpymt)]2 (2). A two dimensional (2D) polymer [Cu4(MU5-5-phpymt)2(MU-Br)2]n (3) was isolated from the reaction of 5-phpymtH with two equiv. of CuBr. Analogous reactions of 5-phpymtH with one or four equiv. of CuI produced one tetranuclear cluster [{Cu2(MU-5 phpymtH)(MU-5-phpymt)}(MU3-I)]2 (4) and one 2D polymer [Cu6I2(MU4-I)2(MU4-5 phpymt)2]n (5). Compound 1 possesses a water-wheel-shaped hexameric structure. Compound 2 has an H-shaped tetrameric structure. Compound 3 possesses a 2D network in which unique 1D [Cu8(MU-Br)2(MU5-5-phpymt)4]n chains are connected by MU-Br- ions. Compound 4 has another tetrameric structure in which two {Cu2(MU-5 phpymtH)2(MU-5-phpymt)} fragments are linked by a pair of MU3-I- ions. Compound 5 contains another 2D network in which hexanuclear {Cu6I2(MU4-I)2} units are linked by MU4-5-phpymt bridges. The 5-phpymt ligand shows four coordination modes: MU kappa1(S)-kappa1(N) (4), MU3-kappa2(S)-kappa1(N) (1 and 2), MU4-kappa1(N) kappa2(S)-kappa1(N') (5) and MU5-kappa1(N)-kappa3(S)-kappa1(N') (3). Complex 1 shows strong solvatochromic behaviour and displays reversible luminescence switching upon alternate addition of CF3COOH and Et3N into its CHCl3 solution. Complexes 1-5 exhibit a high photocatalytic activity towards the aerobic oxidative hydroxylation of arylboronic acids to phenols under visible light irradiation. Catalyst 5 can be reused in several cycles without any obvious decay of the catalytic efficiency. These results offer an interesting insight into how the CuX/5-phpymtH molar ratios and X- ions exert great impacts on the coordination modes of the 5-phpymt- ligand, the structures of the final complexes, and the luminescence and catalytic properties. PMID- 27766328 TI - A delicate case of unidirectional proton transfer from water to an aromatic heterocyclic anion. AB - We present the characteristic proton transfer process from water to the pyrazole anion, infrared signatures of hydroxyl groups and the free energy profile of the process in aqueous solution combining first principles simulations, wavelet analysis and metadynamics. Our results show that the presence of minimum three water molecules in the gas phase cluster with a particular arrangement is sufficient to facilitate the proton transfer process from water to the anion. The overall reaction is very rapid in aqueous solution, and the free energy barrier for this process is found to be 4.2 kcal mol-1. One of the earlier reported fundamental reasons for the transfer of proton from water to the anion is the change in the acidity of OH groups surrounding the anion. We have correlated the stretching frequencies of the surrounding OH groups with this acidity. We find that the development of less energetic vibrational states, and the OH mode having lowest average stretching frequency contains the most acidic proton. A large frequency shift of the OH mode belonging to one of the surrounding water molecules is observed during the transfer of proton from water to the anion; this shift is due to the change in acidity of the adjacent hydroxyl groups in the vicinity of the anion. PMID- 27766330 TI - Continuous high throughput nanofluidic separation through tangential-flow vertical nanoslit arrays. AB - Nanofluidic devices exhibit unique, tunable transport properties that may lead to breakthroughs in molecular separations and sensing. However, the throughput of these devices is orders of magnitude too small for the processing of macroscopic samples. Here we overcome this problem by combining two technological innovations. First, nanofluidic channels are made as vertical slits connecting the two sides of a silicon nitride membrane. Arbitrary arrays of such nanoslits down to 15 nm wide with <6 A uniformity were made by merging the idea of templating with chemical mechanical polishing to create a scalable, nanolithography-free wafer level process. Second, we provide for efficient solute transport to and from the openings of the nanoslits by incorporating the nanofluidic membrane into a microfluidic tangential-flow system, which is also fabricated at wafer level. As an exemplary application, we demonstrate charge based continuous flow separation of small molecules with a selectivity of 100 and constant flux over more than 100 hours of operation. This proves the exciting possibility of exploiting transport phenomena governed by precision-engineered nanofluidic devices at a macroscopic scale. PMID- 27766329 TI - Inertial focusing of ellipsoidal Euglena gracilis cells in a stepped microchannel. AB - Euglena gracilis (E. gracilis) has recently been attracting attention as a potential renewable source for the production of biofuels, livestock feed, cosmetics, and dietary supplements. Research has focused on strain isolation, productivity improvement, nutrient and resource allocation, and co-product production, key steps that ultimately determine the economic viability and compatibility of the biomass produced. To achieve these characteristics, approaches to select E. gracilis mutants with desirable properties, such as high wax ester content, high growth rate, and high environmental tolerance for biodiesel and biomass production, are needed. Flow-based analysis and sorting can be rapid and highly automated but calls for techniques that can precisely control the position of E. gracilis with varying sizes and shapes in a tightly focused stream in a high-throughput manner. In this work, we use a stepped microchannel consisting of a low-aspect-ratio straight channel and a series of expansion regions along the channel height. We study horizontal and vertical focusing, orientation, rotational, and translational behaviors of E. gracilis as a function of aspect ratio (AR) and channel Reynolds number (Re). By making use of inertial focusing and local secondary flows, E. gracilis with diverse shapes are directed to a single equilibrium position in a single focal stream. As an application of on-chip flow cytometry, we integrate a focusing microchip with a custom laser-two focus (L2F) optical system and demonstrate the detection of chlorophyll autofluorescence as well as the measurement of the velocity of E. gracilis cells flowing through the microchannel. PMID- 27766333 TI - Carbonyl-bridged energetic materials: biomimetic synthesis, organic catalytic synthesis, and energetic performances. AB - In order to obtain high-performance energetic materials, in this work, carbonyl groups (C[double bond, length as m-dash]O) have been newly introduced as sole bridging groups in the field of energetic materials. To this end, two tailored green methods for the synthesis of carbonyl-bridged energetic compounds have been developed for the first time. One is a biomimetic synthesis, in which the conversion route of heme to biliverdin has been used to obtain metal-containing energetic compounds. The other one is an organocatalysis, in which guanidinium serves as an energetic catalyst to afford other energetic compounds. Experimental studies and theoretical calculations have shown that carbonyl-bridged energetic compounds exhibit excellent energetic properties, which is promising for the carbonyl group as a new important and effective linker in energetic materials. PMID- 27766332 TI - The flux growth of single-crystalline CoTiO3 polyhedral particles and improved visible-light photocatalytic activity of heterostructured CoTiO3/g-C3N4 composites. AB - Highly crystalline and idiomorphic CoTiO3 single crystals with a well-defined polyhedral morphology were grown successfully for the first time by a facile flux method. Herein, the effects of the molten salt type and cobalt precursor on the phase composition, crystallization habit and morphology of the CoTiO3 products were also investigated. Importantly, using the flux-grown CoTiO3 crystal as the visible-light sensitizer due to its narrow band gap to couple with graphitic carbon nitride (g-C3N4) by a direct in situ thermal induced polycondensation route, novel CoTiO3/g-C3N4 composite photocatalysts were obtained. The as synthesized samples were systematically characterized by XRD, EDS, SEM, TEM, SAED, HRTEM, FT-IR, XPS, DRS and PL techniques. The results revealed that CoTiO3 polyhedral crystals were closely combined with g-C3N4 nanosheets leading to the formation of a heterojunction structure at the interface between CoTiO3 and g C3N4. Photocatalytic evaluation showed that the heterostructured CoTiO3/g-C3N4 composite exhibited much higher photocatalytic activity for the degradation of methyl orange under visible light irradiation than that of individual CoTiO3 and g-C3N4, which could be mainly ascribed to the synergistic effect between CoTiO3 and g-C3N4, including the enhanced visible-light harvesting ability and more efficient separation and longer lifetime of photogenerated charge carriers. Furthermore, the composite photocatalyst showed an excellent stability and reusability during four successive cycles. Finally, a possible mechanism responsible for the charge separation and improved photocatalytic activity was proposed. PMID- 27766331 TI - A centrifugal microfluidic device with integrated gold leaf electrodes for the electrophoretic separation of DNA. AB - Current conventional methods utilized for forensic DNA analysis are time consuming and labor-intensive requiring large and expensive equipment and instrumentation. While more portable Rapid DNA systems have been developed, introducing them to a working laboratory still necessitates a high cost of initiation followed by the recurrent cost of the devices. This has highlighted the need for an inexpensive, rapid and portable DNA analysis tool for human identification in a forensic setting. In order for an integrated DNA analysis system such as this to be realized, device operations must always be concluded by a rapid separation of short-tandem repeat (STR) DNA fragments. Contributing to this, we report the development of a unique, multi-level, centrifugal microdevice that can perform both reagent loading and DNA separation. The fabrication protocol was inspired by the print, cut and laminate (PCL) technique described previously by our group, and in accordance, offers a rapid and inexpensive option compared with existing approaches. The device comprises multiple polyester-toner fluidic layers, a cyclic olefin copolymer separation domain and integrated gold leaf electrodes. All materials are commercially-available and complement the PCL process in a way that permits fabrication of increasingly sought after single-use devices. All reagents, including a viscous sieving matrix, are loaded centrifugally, eliminating external pneumatic pumping, and the sample is separated in <5 minutes using an effective separation length of only 4 cm (reagent loading to completed separation, is <37 minutes). The protocol for gold leaf electrode manufacture yielded up to 30 electrodes for less than $3 (cost of a 79 mm * 79 mm gold leaf sheet) and when using a device combining these electrodes and centrifugal reagent/polymer loading, the electrophoretic separation of STR fragments with two base resolution was demonstrated. This exemplary performance makes the device an ideal candidate for further integration and development of an inexpensive, portable and rapid forensic human identification system. PMID- 27766334 TI - Divergent synthesis of indoles, oxindoles, isocoumarins and isoquinolinones by general Pd-catalyzed retro-aldol/alpha-arylation. AB - Divergent synthesis of indoles, oxindoles, isocoumarins and isoquinolinones is described in this report by using a general Pd-catalyzed tandem reaction of beta hydroxy carbonyl compounds with aryl halides bearing an ortho-nitro, -ester or cyano substituent. A key retro-aldol/alpha-arylation reaction is involved that merges classic Pd cross-coupling chemistry with novel Pd-promoted retro-aldol C-C activation to produce alpha-arylated ketones or esters. Subsequent intramolecular condensation of the carbonyl with the ortho-synthon gives target heterocycles. The use of common, commercially available and cheap substrates and catalyst system adds additional synthetic advantages to the conceptual significance. PMID- 27766335 TI - A femtosecond transient absorption study of charge photogeneration and recombination dynamics in photovoltaic polymers with different side-chain linkages. AB - A pair of 9-arylidene-9H-fluorene and benzothiadiazole based, low-bandgap copolymers differing merely in the para or meta substitution of alkoxy groups to the arylidene linkages, i.e. p-PAFDTBT and m-PAFDTBT respectively, were comparatively investigated by using morphological characterization, ultrafast spectroscopy and quantum chemical calculations. Despite the subtle difference in the alkoxy substitution patterns, p-PAFDTBT molecules in photoactive films were shown to have a higher degree of crystallinity owing to the relatively less rotational torsion of the arylidene linkages. As a result, in either neat or fullerene-blended films, p-PAFDTBT compared to m-PAFDTBT gave rise to a substantially higher charge yield and much slower charge recombination. This work demonstrates that the alkoxy substitution pattern and the arylidene linkage are highly influencing on the morphology of the photoactive layers and thereby on the photovoltaic performance of the semiconducting copolymers. PMID- 27766336 TI - Single electron transfer promoted photoaddition reactions of alpha-trimethylsilyl substituted secondary N-alkylamines with fullerene C60. AB - Single electron transfer (SET) promoted photoaddition reactions of secondary N alpha-trimethylsilyl-N-alkylamines to C60 were explored to gain a deeper understanding of the mechanistic pathways followed and to expand the library of novel types of organofullerenes that can be generated using this approach. The results show that photoreactions of 10% EtOH-toluene solutions containing C60 and N-alpha-trimethylsilyl-N-alkylamines produce either aminomethyl-1,2 dihydrofullerenes or symmetric fulleropyrrolidines as major products depending on the nature of alkyl substituents. In contrast, photoreactions of 10% EtOH-ODCB solutions of these amines with C60 mainly lead to the formation of symmetric fulleropyrrolidines. Based on the analysis of product distributions and the results of earlier studies, two feasible mechanistic pathways are proposed for these processes. One route is initiated by SET from the amine substrates to the triplet-excited state of C60 to form the corresponding aminium radicals and C60 anion radicals. EtOH-promoted desilylation of the aminium radicals then takes place to produce aminomethyl radicals which can either add to C60 or couple with the C60 radical anions to form respective radicals or anion precursors of aminomethyl-1,2-dihydrofullerene products. The competing pathway leading to the generation of symmetric fulleropyrrolidines also involves the formation of aminomethyl radicals by using the sequential SET-desilylation process. In this route, the aminomethyl radicals are oxidized by SET to C60 to form iminium ions, which are then transformed to azomethine ylides by a pathway involving a second molecule of the secondary amine. Dipolar cycloaddition of the azomethine ylides to C60 forms the symmetric fulleropyrrolidine cycloadducts. Importantly, the observation that symmetric fulleropyrrolidines are the sole products formed in photoreactions between N-alpha-trimethylsilyl-N-alkylamines and C60 in 10% EtOH ODCB has synthetic significance. PMID- 27766337 TI - Synthesis and sensing properties of D5h pentagonal silver star nanoparticles. AB - In this work, we use silver decahedral nanoparticle (AgDeNP) seeds to synthesize pentagonal silver stars (AgStDeNPs) and study the sensing properties of these nanoparticles. The regrowth process of AgStDeNPs is kinetically-controlled, so the purity of the seed NPs is critical to avoid secondary deposition in the highly non-equilibrium reduction. To control the regrowth process, surface blocking with sodium polyacrylate (PANa) was implemented. PANa moderates rough silver nanostructures typically obtained by reduction with ascorbic acid. To modulate polymer binding to the surface and thus to tune surface blocking, pH served as a key synthetic parameter. Under optimal regrowth conditions, new sliver was deposited on the highest energy sites of the decahedra - the vertices of the rims - to yield pentagonal stars. The universality of this regrowth process was established with several different seed particles. The sharpness and size of the stellated tips are tunable by the amount of added silver. Gold deposition onto AgStDeNPs enables the preparation of diverse structures with enhanced stability. Ease of transformation, e.g. rounding, of star branches opens a promising venue for enhanced SPR sensing. Also, AgStDeNPs enable femtomolar detection of 5,5-dithiobis(2-nitrobenzoic acid) in SERS. PMID- 27766338 TI - Polyacrylonitrile nanofiber membranes modified with ionically crosslinked polyelectrolyte multilayers for the separation of ionic impurities. AB - Nanofiltration membranes were prepared by forming multilayers of branched polyethylenimine (BPEI) and polyacrylic acid (PAA) on a polyacrylonitrile (PAN) nanofibrous mat by layer-by-layer (LbL) assembly. The degree of ionization (DI) of PAA, estimated using FTIR spectra both in the absence and presence of added salt, was shown to have a strong influence on the BPEI/PAA film growth. BPEI/PAA multilayers grew exponentially when the DI of PAA was less than 30%, or when the pH of PAA during LbL formation was less than 3.5. Subsequently, BPEI/PAA multilayers were formed on the PAN nanofiber mats by depositing the polyelectrolytes at the experimental conditions that favored maximum film growth. The separation layer formed with 15 bilayers of BPEI/PAA has a thickness of 1100 nm. PAA ionization was favored within the BPEI/PAA multilayers due to the presence of abundant amine groups in BPEI, and as a result, a strong negative charge was seen for PAN nanofibrous membranes for solution conditions above pH 4.5. Nanofiber membranes modified with 15 bilayers of BPEI/PAA multilayers at an applied pressure of 4 bar had a pure water flux of 19.7 Lm-2 h-1 and a MgSO4 rejection of 98.7%. This performance represents 1.6 times higher flux and 1.1 times higher salt rejection than the multilayers formed on a conventional asymmetric polymeric support. The higher separation and higher flux capabilities of BPEI/PAA multilayer modified PAN nanofiber membranes was due to the combined effect of high charge density and high porosity of the nanofiber membranes. PMID- 27766339 TI - Barluenga's reagent with HBF4 as an efficient catalyst for alkyne-carbonyl metathesis of unactivated alkynes. AB - Barluenga's reagent (IPy2BF4, Py = pyridine) treated with HBF4 efficiently catalyzes the inter- and intramolecular alkyne-carbonyl metathesis of unactivated alkynes with aldehydes or ketones, most of which proceed at room temperature. This work represents the first catalytic application of the Barluenga's reagent. PMID- 27766340 TI - Regioselective beta-silylation of porphyrins via iridium-catalyzed C-H bond activation. AB - An efficient approach to meso-unsubstituted beta-silylporphyrins was developed through highly regioselective Ir-catalyzed C-H activation, in the presence of HSiMe(OSiMe3)2 as the Si source, from meso-unsubstituted porphyrins. Further transformations of the silyl group, such as oxidation, halogenation, and cross coupling reactions, could be achieved under mild conditions, demonstrating the synthetic utility of beta-silylporphyrins as a multipurpose synthon for fabricating porphyrin derivatives. PMID- 27766341 TI - The compression of a heavy floating elastic film. AB - We study the effect of film density on the uniaxial compression of thin elastic films at a liquid-fluid interface. Using a combination of experiments and theory, we show that dense films first wrinkle and then fold as the compression is increased, similarly to what has been reported when the film density is neglected. However, we highlight the changes in the shape of the fold induced by the film's own weight and extend the model of Diamant and Witten [Phys. Rev. Lett., 2011, 107, 164302] to understand these changes. In particular, we suggest that it is the weight of the film that breaks the up-down symmetry apparent from previous models, but elusive experimentally. We then compress the film beyond the point of self-contact and observe a new behaviour dependent on the film density: the single fold that forms after wrinkling transitions into a closed loop after self-contact, encapsulating a cylindrical droplet of the upper fluid. The encapsulated drop either causes the loop to bend upward or to sink deeper as the compression is increased, depending on the relative buoyancy of the drop-film combination. We propose a model to qualitatively explain this behaviour. Finally, we discuss the relevance of the different buckling modes predicted in previous theoretical studies and highlight the important role of surface tension in the shape of the fold that is observed from the side-an aspect that is usually neglected in theoretical analyses. PMID- 27766342 TI - Fine tuning of optical signals in nanoporous anodic alumina photonic crystals by apodized sinusoidal pulse anodisation. AB - In this study, we present an advanced nanofabrication approach to produce gradient-index photonic crystal structures based on nanoporous anodic alumina. An apodization strategy is for the first time applied to a sinusoidal pulse anodisation process in order to engineer the photonic stop band of nanoporous anodic alumina (NAA) in depth. Four apodization functions are explored, including linear positive, linear negative, logarithmic positive and logarithmic negative, with the aim of finely tuning the characteristic photonic stop band of these photonic crystal structures. We systematically analyse the effect of the amplitude difference (from 0.105 to 0.840 mA cm-2), the pore widening time (from 0 to 6 min), the anodisation period (from 650 to 950 s) and the anodisation time (from 15 to 30 h) on the quality and the position of the characteristic photonic stop band and the interferometric colour of these photonic crystal structures using the aforementioned apodization functions. Our results reveal that a logarithmic negative apodisation function is the most optimal approach to obtain unprecedented well-resolved and narrow photonic stop bands across the UV-visible NIR spectrum of NAA-based gradient-index photonic crystals. Our study establishes a fully comprehensive rationale towards the development of unique NAA-based photonic crystal structures with finely engineered optical properties for advanced photonic devices such as ultra-sensitive optical sensors, selective optical filters and all-optical platforms for quantum computing. PMID- 27766343 TI - Syntheses via a direct arylation method of push-pull molecules based on triphenylamine and 3-cyano-4-hexyloxythiophene moieties. AB - Synthetic access to new push-pull molecules based on 3-cyano-4-hexyloxythiophene and triphenylamine moieties is presented herein using a clean methodology. The key step involves a direct heteroarylation coupling reaction in the presence of a homogeneous or heterogeneous [Pd] catalyst followed by Knoevenagel condensation performed in ethanol as a solvent. Structure-electronic property relationships of the new molecular materials are discussed and then their use as donors in bilayer planar heterojunction solar cells is investigated. PMID- 27766345 TI - The relationship between age and pelvic organ prolapse bother. AB - INTRODUCTION AND HYPOTHESIS: A variety of factors affect the amount of bother experienced by different women with equivalent pelvic organ prolapse (POP). The goal of this study was to describe the relationship between age and bother experienced from objectively equivalent stages of POP. METHODS: Records of all patients presenting to a pelvic floor subspecialty clinic between January 2014 and March 2015 were reviewed. Women with POP stage >= 2 were included. The level of bother experienced from prolapse symptoms was defined as the score on the validated Pelvic Organ Prolapse Distress Inventory (POPDI). Multiple linear regression was performed to examine the relationship between age and the POPDI score. A sample size of 150 patients was determined to have 80 % power to detect an effect of age equivalent to an increase in R2 of 0.05. RESULTS: A total of 229 charts were reviewed and 165 patients were included in the final analysis. The effect of age on prolapse bother in the entire population was quadratic (p = 0.0497). Women at both ends of the spectrum were less bothered by prolapse, whereas women in the 6th and 7th decades of life demonstrated the highest level of bother, irrespective of stage. This same quadratic relationship remained in women with stage 2 prolapse (p = 0.019). CONCLUSIONS: Women in the 6th and 7th decades of life experience higher levels of bother from POP than older or younger women with the same stage of prolapse. This suggests that women in these decades of life might be at a higher risk for impairment of quality of life from POP. PMID- 27766344 TI - Anterior laxity and patient-reported outcomes 7 years after ACL reconstruction with a fresh-frozen tibialis allograft. AB - PURPOSE: After reconstructing a torn ACL with a soft tissue allograft, the long term healing process of graft maturation following the short-term healing process of graft incorporation into the bone tunnels might lead to recurring instability and concomitant decreases in the activity level, function, and patient satisfaction. Relying on roentgen stereophotogrammetric analysis (RSA), the primary purpose was to determine whether anterior laxity increased and whether patient-reported outcomes declined between 1 and 7 years for a particular graft construct, surgical technique, and rehabilitation programme. METHODS: Eighteen of 19 patients, who participated in an earlier RSA study which extended to 1 year after the surgical procedure, were contacted 7 years after the surgical procedure. An examiner, different from the treating surgeon, measured anterior laxity under 150 N of anterior force using RSA in 16 patients and obtained outcome scores in 17 patients. One patient moved abroad and could not be contacted. One patient reinjured his reconstructed ACL and was excluded. RESULTS: The average increase in anterior laxity of 1.5 +/- 2.1 mm between 1 and 7 years after surgery was not significant (p = 0.08), and the average increase in anterior laxity of 2.7 +/- 2.3 mm between the day of surgery and 7 years was significant (p < 0.001). There were no significant declines in activity (median Tegner score, 6 at 1 year, 6 at 7 years), function (average Lysholm score, 94 at 1 year, 91 at 7 years), and subjective satisfaction (average International Knee Documentation Committee score, 90 at 1 year, 87 at 7 years) between 1 and 7 years after surgery. CONCLUSION: In demonstrating that the ACL graft construct remains functional in the long term, this study supports the use of a fresh-frozen tibialis allograft in patients with an average age of 37 years at the time of surgery when used in conjunction with a surgical technique which avoids roof and PCL impingement, uses slippage-resistant fixation devices, and allows brace-free, self-paced rehabilitation. LEVEL OF EVIDENCE: IV. PMID- 27766346 TI - Laparoscopic sacrocolpopexy: operative times and efficiency in a high-volume female pelvic medicine and laparoscopic surgery practice. AB - INTRODUCTION AND HYPOTHESIS: There has been a trend toward robotic sacrocolpopexy in the United States despite longer operating times and higher costs compared with traditional laparoscopy. The current study objective was to evaluate incision to closure times of laparoscopic sacrocolpopexy in a urogynecologic practice with extensive experience in the laparoscopic approach for pelvic reconstruction. METHODS: We conducted a single-center retrospective evaluation of consecutive patients undergoing laparoscopic sacrocolpopexy for vaginal vault prolapse using a permanent polypropylene Y-mesh over a 1-year period. Standard operative technique for sacrocolpopexy was used. Four to six sutures were placed on the anterior leaflet of the mesh, and six to eight sutures were placed posteriorly. Two sutures were placed in the presacral ligament. Mesh was retroperitonealized with a running 2-0 monocryl suture. Primary outcomes were total operating time and time to complete laparoscopic sacrocolpopexy. RESULTS: One hundred and twenty-seven consecutive patients with an average age of 60.04 +/ 10.14 years, body mass index (BMI) 25.79 +/- 4.52 kg/m2, underwent laparoscopic sacrocolpopexy for vaginal vault prolapse. Ninety-two patients had other procedures performed intraoperatively: laparoscopic-assisted vaginal hysterectomy, laparoscopic paravaginal repair, laparoscopic enterocele repair, and/or laparoscopic enterolysis. Mean total operative time for all laparoscopic procedures completed was 107.45 +/- 34.00 min. The average time to perform sacrocolpopexy, including incision and closure, was 52.78 +/- 13.09 min. CONCLUSION: This retrospective evaluation provides further evidence that traditional laparoscopic sacrocolpopexy should be considered a primary therapy for vaginal vault prolapse. PMID- 27766348 TI - Conservation/Mutation in the Splice Sites of Mitochondrial Solute Carrier Genes of Vertebrates. AB - The "canonical" introns begin by the dinucleotide GT and end by the dinucleotide AG. GT, together with a few downstream nucleotides, and AG, with a few of the immediately preceding nucleotides, are thought to be the strongest splicing signals (5'ss and 3'ss, respectively). We examined the composition of the intronic initial and terminal hexanucleotides of the mitochondrial solute carrier genes (SLC25A's) of zebrafish, chicken, mouse, and human. These genes are orthologous and we selected the transcripts in which the arrangement of exons and introns was superimposable in the species considered. Both 5'ss and 3'ss were highly polymorphic, with 104 and 126 different configurations, respectively, in our sample. In the line of evolution from zebrafish to chicken, as well as in that from zebrafish to mammals, the average nucleotide conservation in the four variable nucleotides was about 50 % at 5' and 40 % at 3'. In the divergent evolution of mouse and human, the conservation was about 80 % at 5' and 70 % at 3'. Despite these changes, the splicing signals remain strong enough to operate at the same site. At both 5' and 3', the frequency of a nucleotide at a given position in the zebrafish sequence is positively correlated with its conservation in chicken and mammals, suggesting that selection continued to operate in birds and mammals along similar lines. PMID- 27766350 TI - [The new medical treatment procedure of the German Statutory Accident Insurance: From the perspective of BG hospitals]. AB - The Hospital Group of the Statutory Accident Insurance (BG hospitals) was affected by the new requirements for severe injury procedures (SAV) in the same manner as all other maximum care hospitals. Simultaneously, the BG clinics were merged to form a centrally organized hospital group. A substantial need for adjustment existed for specialties, such as neurosurgery and visceral surgery at some sites. Needless to say, all trauma victims benefit from the high standards required by the Statutory Accident Insurance regardless of their insurance status. The provision of medical treatment with respect to its implementation into routine practice must be further optimized and additions, e.g. for the occurrence of complications are necessary. PMID- 27766347 TI - ACCORDION MIND: results of the observational extension of the ACCORD MIND randomised trial. AB - AIMS/HYPOTHESIS: The Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a double 2x2 factorial parallel group randomised clinical trial, tested whether intensive compared with standard management of hyperglycaemia, BP or lipid levels reduced cognitive decline and brain atrophy in 2977 people with type 2 diabetes. We describe the results of the observational extension study, ACCORDION MIND (ClinicalTrials.gov registration no. NCT00182910), which aimed to measure the long-term effects of the three ACCORD interventions on cognitive and brain structure outcomes approximately 4 years after the trial ended. METHODS: Participants (mean diabetes duration 10 years; mean age 62 years at baseline) received a fourth cognitive assessment and a third brain MRI, targeted at 80 months post-randomisation. Primary outcomes were performance on the Digit Symbol Substitution Test (DSST) and total brain volume (TBV). The contrast of primary interest compared glycaemic intervention groups at the ACCORDION visit; secondary contrasts were the BP and lipid interventions. RESULTS: Of the surviving ACCORD participants eligible for ACCORDION MIND, 1328 (68%) were re-examined at the ACCORDION follow-up visit, approximately 47 months after the intensive glycaemia intervention was stopped. The significant differences in therapeutic targets for each of the three interventions (glycaemic, BP and lipid) were not sustained. We found no significant difference in 80 month mean change from baseline in DSST scores or in TBV between the glycaemic intervention groups, or the BP and lipid interventions. Sensitivity analyses of the sites with >=70% participation at 80 months revealed consistent results. CONCLUSIONS/INTERPRETATION: The ACCORD interventions did not result in long-term beneficial or adverse effects on cognitive or brain MRI outcomes at approximately 80 months follow-up. Loss of separation in therapeutic targets between treatment arms and loss to follow-up may have contributed to the lack of detectable long-term effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00182910. PMID- 27766349 TI - Multi-parametric MR imaging of the anterior fibromuscular stroma and its differentiation from prostate cancer. AB - PURPOSE: To describe MP-MRI features of the normal anterior fibromuscular stroma (AFMS) and identify MR imaging findings that can differentiate it from anterior prostate cancer. METHODS: We reviewed MP-MR images and histopathology of patients who underwent pre-operative MRI and prostatectomy between October 2012 and August 2014. Thirty-seven patients with anterior prostate cancer larger than 5 mm and 40 patients with no anterior cancer were included in this study. After correlation with histology and MR images, the size, symmetry, T2, DWI characteristics, and enhancement pattern of normal AFMS and anterior prostate cancer were compared. RESULTS: Normal AFMS was hypointense and symmetric on T2-weighted images (37/40, 93%), whereas anterior prostate cancers, while also hypointense on T2-weighted images, were predominantly asymmetric (6/37, 16%) (P < 0.001). On high b-value DWI, AFMS was predominantly hypointense (36/40, 90%), whereas anterior prostate cancers were predominantly hyperintense (30/37, 81%) compared to the normal peripheral zone (P < 0.001). The mean ADC and tenth percentile ADC values of anterior prostate cancers were lower than normal AFMS (7.14 vs. 8.33 (10-4 mm2/s), P < 0.01) and (5.73 vs. 6.95 (10-4 mm2/s), P < 0.01), respectively. On DCE-MR images, AFMS demonstrated a type 1 enhancement curve (35/39, 90%), whereas anterior prostate cancers demonstrated only either a type 3 (23/37, 62%) or type 2 enhancement curve (14/37, 38%) (P < 0.001). CONCLUSIONS: Symmetric T2 appearance, hypointense high b-value DWI signal, relatively higher ADC values, and Type 1 enhancement pattern of the AFMS can be helpful in its differentiation from anterior prostate cancers. PMID- 27766351 TI - Cerebellar tDCS does not improve performance in probabilistic classification learning. AB - In this study, the role of the cerebellum in a cognitive learning task using transcranial direct current stimulation (tDCS) was investigated. Using a weather prediction task, subjects had to learn the probabilistic associations between a stimulus (a combination of cards) and an outcome (sun or rain). This task is a variant of a probabilistic classification learning task, for which it has been reported that prefrontal tDCS enhances performance. Using a between-subject design, all 30 subjects learned to improve their performance with increasing accuracies and shortened response times over a series of 500 trials. Subjects also became more confident in their prediction during the experiment. However, no differences in performance and learning were observed between subjects receiving sham stimulation (n = 10) or anodal stimulation (2 mA for 20 min) over either the right cerebellum (n = 10) or the left prefrontal cortex (n = 10). This suggests that stimulating the brain with cerebellar tDCS does not readily influence probabilistic classification performances, probably due to the rather complex nature of this cognitive task. PMID- 27766354 TI - Global transcriptomic analysis of the response of Corynebacterium glutamicum to ferulic acid. AB - Corynebacterium glutamicum can survive by using ferulic acid as the sole carbon source. In this study, we assessed the response of C. glutamicum to ferulic acid stress by means of a global transcriptional response analysis. The transcriptional data showed that several genes involved in degradation of ferulic acid were affected. Moreover, several genes related to the stress response; protein protection or degradation and DNA repair; replication, transcription and translation; and the cell envelope were differentially expressed. Deletion of the katA or sigE gene in C. glutamicum resulted in a decrease in cell viability under ferulic acid stress. These insights will facilitate further engineering of model industrial strains, with enhanced tolerance to ferulic acid to enable easy production of biofuels from lignocellulose. PMID- 27766352 TI - Dopamine D2-like receptors modulate freezing response, but not the activation of HPA axis, during the expression of conditioned fear. AB - Considering the complexity of aversive information processing and defensive response expression, a combined action of stress modulators may be required for an optimal performance during threatening situations. Dopamine is now recognized as one of the most active modulators underlying states of fear and anxiety. On the other hand, activation of hypothalamic-pituitary-adrenocortical (HPA) axis, which leads to the release of corticosterone in rodents, has been considered a key part of the stress response. The current study is an extension of prior work investigating modulatory effects of dopamine and corticosterone on conditioned fear expression. We have showed that corticosterone, acting through mineralocorticoid receptors in the ventral tegmental area (VTA), upregulates dopaminergic system in the basolateral amygdala (BLA), enabling the expression of conditioned freezing response. The novel question addressed here is whether VTA BLA dopaminergic signaling is necessary for increases in corticosterone during conditioned fear expression. Using site-specific treatment with D2-like agonist quinpirole (VTA) and D2-like antagonist sulpiride (BLA), we evaluated freezing and plasma corticosterone in rats exposed to a light used as aversive conditioned stimulus (CS). Intra-VTA quinpirole and intra-BLA sulpiride significantly decreased freezing expression in the conditioned fear test, but this anxiolytic like effect of the dopaminergic drugs was not associated with changes in plasma corticosterone concentrations. Altogether, data suggest that interferences with the ability of the CS to activate the dopaminergic VTA-BLA pathway reduce the expression of freezing, but activation of the HPA axis seems to occur upstream of the recruitment of dopaminergic mechanisms in conditioned fear states. PMID- 27766355 TI - Mariprofundus micogutta sp. nov., a novel iron-oxidizing zetaproteobacterium isolated from a deep-sea hydrothermal field at the Bayonnaise knoll of the Izu Ogasawara arc, and a description of Mariprofundales ord. nov. and Zetaproteobacteria classis nov. AB - A novel iron-oxidizing chemolithoautotrophic bacterium, strain ET2T, was isolated from a deep-sea sediment in a hydrothermal field of the Bayonnaise knoll of the Izu-Ogasawara arc. Cells were bean-shaped, curved short rods. Growth was observed at a temperature range of 15-30 degrees C (optimum 25 degrees C, doubling time 24 h) and a pH range of 5.8-7.0 (optimum pH 6.4) in the presence of NaCl at a range of 1.0-4.0 % (optimum 2.75 %). The isolate was a microaerophilic, strict chemolithoautotroph capable of growing using ferrous iron and molecular oxygen (O2) as the sole electron donor and acceptor, respectively; carbon dioxide as the sole carbon source; and either ammonium or nitrate as the sole nitrogen source. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the new isolate was related to the only previously isolated Mariprofundus species, M. ferrooxydans. Although relatively high 16S rRNA gene similarity (95 %) was found between the new isolate and M. ferrooxydans, the isolate was distinct in terms of cellular fatty acid composition, genomic DNA G+C content and cell morphology. Furthermore, genomic comparison between ET2T and M. ferrooxydans PV-1 indicated that the genomic dissimilarity of these strains met the standard for species level differentiation. On the basis of its physiological and molecular characteristics, strain ET2T (= KCTC 15556T = JCM 30585 T) represents a novel species of Mariprofundus, for which the name Mariprofundus micogutta is proposed. We also propose the subordinate taxa Mariprofundales ord. nov. and Zetaproteobacteria classis nov. in the phylum Proteobacteria. PMID- 27766356 TI - Development and evaluation of yeast-based GFP and luciferase reporter assays for chemical-induced genotoxicity and oxidative damage. AB - We aimed to develop the bioassays for genotixicity and/or oxidative damage using the recombinant yeast. A genotoxicity assay was developed using recombinant Saccharomyces cerevisiae strain BY4741 with a green fluorescent protein (GFP) reporter plasmid, driven by the DNA damage-responsive RNR3 promoter. Enhanced fluorescence induction was observed in DNA repair-deficient strains treated with methyl methanesulfonate, but not with hydrogen peroxide. A GFP reporter yeast strain driven by the oxidative stress-responsive TRX2 promoter was newly developed to assess oxidative damage, but fluorescence was poorly induced by oxidants. In place of GFP, yeast strains with luciferase gene reporter plasmids (luc2 and luc2CP, encoding stable and unstable luciferase, respectively) were prepared. Transient induction of luciferase activity was clearly detected only in a TRX2 promoter-driven luc2CP reporter strain within 90 min of oxidant exposure. However, luciferase was strongly induced by hydroxyurea in the RNR3 promoter driven luc2 and GFP reporter strains over 8 h after the exposure, suggesting that the RNR3 promoter is continuously upregulated by DNA damage, whereas the TRX2 promoter is transiently activated by oxidative agents. Luciferase activity levels were also increased in a TRX2-promoter-driven luc2CP reporter strain treated with tert-butyl hydroperoxide and menadione and weakly induced with diamide and diethyl maleate. Weakly enhanced luciferase activity induction was detected in the sod1Delta, sod2Delta, and rad27Delta strains treated with hydrogen peroxide compared with that in the wild-type strain. In conclusion, tests using GFP and stable luciferase reporters are useful for genotoxicity, and oxidative damage can be clearly detected by assay with an unstable luciferase reporter. PMID- 27766358 TI - GH115 alpha-glucuronidase and GH11 xylanase from Paenibacillus sp. JDR-2: potential roles in processing glucuronoxylans. AB - Paenibacillus sp. JDR-2 (Pjdr2) has been studied as a model for development of bacterial biocatalysts for efficient processing of xylans, methylglucuronoxylan, and methylglucuronoarabinoxylan, the predominant hemicellulosic polysaccharides found in dicots and monocots, respectively. Pjdr2 produces a cell-associated GH10 endoxylanase (Xyn10A1) that catalyzes depolymerization of xylans to xylobiose, xylotriose, and methylglucuronoxylotriose with methylglucuronate-linked alpha-1,2 to the nonreducing terminal xylose. A GH10/GH67 xylan utilization regulon includes genes encoding an extracellular cell-associated Xyn10A1 endoxylanase and an intracellular GH67 alpha-glucuronidase active on methylglucuronoxylotriose generated by Xyn10A1 but without activity on methylglucuronoxylotetraose generated by a GH11 endoxylanase. The sequenced genome of Pjdr2 contains three paralogous genes potentially encoding GH115 alpha-glucuronidases found in certain bacteria and fungi. One of these, Pjdr2_5977, shows enhanced expression during growth on xylans along with Pjdr2_4664 encoding a GH11 endoxylanase. Here, we show that Pjdr2_5977 encodes a GH115 alpha-glucuronidase, Agu115A, with maximal activity on the aldouronate methylglucuronoxylotetraose selectively generated by a GH11 endoxylanase Xyn11 encoded by Pjdr2_4664. Growth of Pjdr2 on this methylglucuronoxylotetraose supports a process for Xyn11-mediated extracellular depolymerization of methylglucuronoxylan and Agu115A-mediated intracellular deglycosylation as an alternative to the GH10/GH67 system previously defined in this bacterium. A recombinantly expressed enzyme encoded by the Pjdr2 agu115A gene catalyzes removal of 4-O-methylglucuronate residues alpha-1,2 linked to internal xylose residues in oligoxylosides generated by GH11 and GH30 xylanases and releases methylglucuronate from polymeric methylglucuronoxylan. The GH115 alpha-glucuronidase from Pjdr2 extends the discovery of this activity to members of the phylum Firmicutes and contributes to a novel system for bioprocessing hemicelluloses. PMID- 27766360 TI - A sensitive method for simultaneous quantitative determination of surfactin and iturin by LC-MS/MS. AB - Surfactin and iturin are antimicrobial lipopeptides produced from Bacillus spp. and have significant prospective applications in many fields. Therefore, accurate analysis of these lipopeptides in the fermented product of some Bacillus strains is important. A sensitive method for simultaneous quantitative determination of surfactin and iturin fermented by Bacillus natto NT-6 was developed and validated using liquid chromatography-tandem mass spectrometry. Crude extracts of antimicrobial lipopeptide samples were dissolved in a mixture of acetonitrile/water (7:3, v/v) in 0.1 % (v/v) formic acid and eluted with acetonitrile/water (7:3, v/v) containing 5 mmol L-1 ammonium acetate and 0.1 % (v/v) formic acid. The target compounds were detected by mass spectrometry (ESI+) using selective ion monitoring. A good linear regression in the range of 0.20 10.0 mg L-1 for both surfactin and iturin (R 2 >= 0.9995) was observed with spiked recoveries of 93.3-108.2 %, RSD values less than 15 %, precision 4.14 13.30 %, and a detection limit of 0.374 mg L-1. This method has a simple preprocessing operation, good repeatability, and provides an accurate quantitative analysis of surfactin and iturin. Graphical Abstract Surfactin and iturin from Bacillus natto NT-6 extraction and detection procedure. PMID- 27766357 TI - Klebsiella phages representing a novel clade of viruses with an unknown DNA modification and biotechnologically interesting enzymes. AB - Lytic bacteriophages and phage-encoded endolysins (peptidoglycan hydrolases) provide a source for the development of novel antimicrobial strategies. In the present study, we focus on the closely related (96 % DNA sequence identity) environmental myoviruses vB_KpnM_KP15 (KP15) and vB_KpnM_KP27 (KP27) infecting multidrug-resistant Klebsiella pneumoniae and Klebsiella oxytoca strains. Their genome organisation and evolutionary relationship are compared to Enterobacter phage phiEap-3 and Klebsiella phages Matisse and Miro. Due to the shared and distinct evolutionary history of these phages, we propose to create a new phage genus "Kp15virus" within the Tevenvirinae subfamily. In silico genome analysis reveals two unique putative homing endonucleases of KP27 phage, probably involved in unrevealed mechanism of DNA modification and resistance to restriction digestion, resulting in a broader host spectrum. Additionally, we identified in KP15 and KP27 a complete set of lysis genes, containing holin, antiholin, spanin and endolysin. By turbidimetric assays on permeabilized Gram-negative strains, we verified the ability of the KP27 endolysin to destroy the bacterial peptidoglycan. We confirmed high stability, absence of toxicity on a human epithelial cell line and the enzymatic specificity of endolysin, which was found to possess endopeptidase activity, cleaving the peptide stem between L-alanine and D-glutamic acid. PMID- 27766359 TI - Design and microfabrication of a miniature fiber optic probe with integrated lenses and mirrors for Raman and fluorescence measurements. AB - Fiber optics coupled to components such as lenses and mirrors have seen extensive use as probes for Raman and fluorescence measurements. Probes can be placed directly on or into a sample to allow for simplified and remote application of these optical techniques. The size and complexity of such probes however limits their application. We have used microfabrication in polydimethylsiloxane (PDMS) to create compact probes that are 0.5 mm thick by 1 mm wide. The miniature probes incorporate pre-aligned mirrors, lenses, and two fiber optic guides to allow separate input and output optical paths suitable for Raman and fluorescence spectroscopy measurements. The fabricated probe has 70 % unidirectional optical throughput and generates no spectral artifacts in the wavelength range of 200 to 800 nm. The probe is demonstrated for measurement of fluorescence within microfluidic devices and collection of Raman spectra from a pharmaceutical tablet. The fluorescence limit of detection was 6 nM when using the probe to measure resorufin inside a 150-MUm inner diameter glass capillary, 100 nM for resorufin in a 60-MUm-deep * 100-MUm-wide PDMS channel, and 11 nM for fluorescein in a 25-MUm-deep * 80-MUm-wide glass channel. It is demonstrated that the same probe can be used on different sample types, e.g., microfluidic chips and tablets. Compared to existing Raman and fluorescence probes, the microfabricated probes enable measurement in smaller spaces and have lower fabrication cost. Graphical abstract A microfabricated spectroscopic probe with integrated optics was developed for chemical detection in small spaces and in remote applications. PMID- 27766361 TI - Ethylene glycol improves electrospray ionization efficiency in bottom-up proteomics. AB - Liquid chromatography coupled online to nano-electrospray ionization (nESI) tandem mass spectrometry is the analytical workhorse in the field of proteome research. Dimethyl sulfoxide (DMSO) was recently shown to improve nESI efficiency by a factor of three to ten thus improving the sensitivity and coverage of proteomic experiments. However, relatively few investigations into which solvent additives promote nESI response have been performed at a proteomic scale. Here, we systematically evaluated the concept by screening about 30 compounds with various physico-chemical properties. Detailed further analysis showed that ethylene glycol performed similarly to DMSO and the results indicate that enhancing the nESI response of peptides by simple solvent additives is a valid and promising approach. Ethylene glycol may serve as a viable alternative to DMSO in applications where DMSO has disadvantages. In keeping with nESI theory, the key properties of an effective solvent additive for proteomic applications are a boiling point higher than water, low surface tension, and preferably high polarity for reversed phase LC-MS/MS applications. Graphical Abstract Ethylene glycol substantially improves peptide ionization. PMID- 27766362 TI - Ultrasensitive and rapid detection of beta-conglutin combining aptamers and isothermal recombinase polymerase amplification. AB - Lupin is increasingly being used in a variety of food products due to its nutritional, functional and nutraceutical properties. However, several examples of severe and even fatal food-associated anaphylaxis due to lupin inhalation or ingestion have been reported, resulting in the lupin subunit beta-conglutin, being defined as the Lup an 1 allergen by the International Union of Immunological Societies (IUIS) in 2008. Here, we report an innovative method termed aptamer-recombinase polymerase amplification (Apta-RPA) exploiting the affinity and specificity of a DNA aptamer selected against the anaphylactic beta conglutin allergen termed beta-conglutin binding aptamer II (beta-CBA II), facilitating ultrasensitive detection via isothermal amplification. Combining magnetic beads as the solid phase with Apta-RPA detection, the total assay time was reduced from 210 min to just 25 min, with a limit of detection of 3.5 * 10-11 M, demonstrating a rapid and ultrasensitive generic methodology that can be used with any aptamer. Future work will focus on further simplification of the assay to a lateral flow format. Graphical Abstract Schematic representation of the rapid and novel bead-based Apta-RPA assay. PMID- 27766363 TI - Using "spectral families" to assess the reproducibility of glycopeptide enrichment: human serum O-glycosylation revisited. AB - Growing evidence on the diverse biological roles of extracellular glycosylation as well as the need for quality control of protein pharmaceuticals make glycopeptide analysis both exciting and important again after a long hiatus. High throughput O-glycosylation studies have to tackle the complexity of glycosylation as well as technical difficulties and, up to now, have yielded only limited results mostly from single enrichment experiments. In this study, we address the technical reproducibility of the characterization of the most prevalent O glycosylation (mucin-type core 1 structures) in human serum, using a two-step lectin affinity-based workflow. Our results are based on automated glycopeptide identifications from higher-energy C-trap dissociation and electron transfer dissociation MS/MS data. Assignments meeting strict acceptance criteria served as the foundation for generating "spectral families" incorporating low-scoring MS/MS identifications, supported by accurate mass measurements and expected chromatographic retention times. We show that this approach helped to evaluate the reproducibility of the glycopeptide enrichment more reliably and also contributed to the expansion of the glycoform repertoire of already identified glycosylated sequences. The roadblocks hindering more in-depth investigations and quantitative analyses will also be discussed. PMID- 27766364 TI - Applicability of predictive toxicology methods for monoclonal antibody therapeutics: status Quo and scope. AB - Biopharmaceuticals, monoclonal antibody (mAb)-based therapeutics in particular, have positively impacted millions of lives. MAbs and related therapeutics are highly desirable from a biopharmaceutical perspective as they are highly target specific and well tolerated within the human system. Nevertheless, several mAbs have been discontinued or withdrawn based either on their inability to demonstrate efficacy and/or due to adverse effects. Approved monoclonal antibodies and derived therapeutics have been associated with adverse effects such as immunogenicity, cytokine release syndrome, progressive multifocal leukoencephalopathy, intravascular haemolysis, cardiac arrhythmias, abnormal liver function, gastrointestinal perforation, bronchospasm, intraocular inflammation, urticaria, nephritis, neuropathy, birth defects, fever and cough to name a few. The advances made in this field are also impeded by a lack of progress in bioprocess development strategies as well as increasing costs owing to attrition, wherein the lack of efficacy and safety accounts for nearly 60 % of all factors contributing to attrition. This reiterates the need for smarter preclinical development using quality by design-based approaches encompassing carefully designed predictive models during early stages of drug development. Different in vitro and in silico methods are extensively used for predicting biological activity as well as toxicity during small molecule drug development; however, their full potential has not been utilized for biological drug development. The scope of in vitro and in silico tools in early developmental stages of monoclonal antibody-based therapeutics production and how it contributes to lower attrition rates leading to faster development of potential drug candidates has been evaluated. The applicability of computational toxicology approaches in this context as well as the pitfalls and promises of extending such techniques to biopharmaceutical development has been highlighted. PMID- 27766365 TI - Current limitations and future opportunities for prediction of DILI from in vitro. AB - Drug-induced liver injury (DILI) is a major concern for drug developers, regulators and clinicians. It is triggered by drug and xenobiotic insults leading to liver impairment or damage, in the worst-case liver failure. In contrast to acute "intrinsic" hepatotoxicity, DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and inconsistent temporal patterns and is therefore termed an idiosyncratic event. Involved are multifactorial, compound-dependent mechanisms and host-specific factors, making the prediction in preclinical test systems very challenging. While preclinical safety studies in animals usually are able to capture direct, acute liver toxicities, they are less predictive for human DILI, where specific, human-derived in vitro models can potentially close the gap. On one hand, mechanistic approaches addressing key mechanisms involved in DILI in well characterized and standardized in vitro test systems have been developed. On the other hand, co-cultures of different cell types, including patient- and/or stem cell-derived cells, in a three-dimensional setup allow for prolonged incubations and multiplexed readouts. Such complex setups might better reflect multifactorial human DILI. One major challenge is that for many compounds with human DILI the underlying mechanisms are not yet fully understood, complicating establishment and validation of predictive cellular tools. A tiered approach including rapid mechanism-based in vitro screens followed by confirmatory tests in more physiologically relevant models might allow minimizing DILI risk early on in vitro. Such complex, integrated approaches will gain from larger collaborations in multidisciplinary groups bringing existing knowledge and state-of-the-art technology together. PMID- 27766366 TI - Erratum to: Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the osteoporotic fractures in men (MrOS) study. PMID- 27766367 TI - Increased levels of Dickkopf-1 are indicative of Wnt/beta-catenin downregulation and lower osteoblast signaling in children and adolescents with type 1 diabetes mellitus, contributing to lower bone mineral density. AB - : Higher levels of Dickkopf-1, which is an inhibitor of Wnt/beta-catenin bone metabolic pathway, could be indicative of downregulated Wnt system, with possible lower osteoblast activation and higher osteoclast signaling in type 1 diabetes mellitus children and adolescents. Dickkopf-1 could significantly contribute to diabetes osteopathy. INTRODUCTION: Increased fracture risk and elevated Dickkopf 1 levels, which is an inhibitor of Wnt/beta-catenin bone metabolic pathway, have been documented in adult patients with type 2 diabetes mellitus (T2D), while no relevant data exist on childhood type 1 diabetes (T1D). Our aim was to study plasma Dickkopf-1 distribution in children and adolescents with T1D and to correlate Dickkopf-1 with metabolic bone markers and bone mineral density (BMD). METHODS: We evaluated 40 children and adolescents with T1D (mean +/- SD age 13.04 +/- 3.53 years, T1D duration 5.15 +/- 3.33 years) and 40 healthy age-matched and gender-matched controls (age 12.99 +/- 3.3 years). Dickkopf-1 and bone metabolic markers were measured, while total body and lumbar spine BMD were evaluated with dual-energy X-ray absorptiometry (DXA). RESULTS: Dickkopf-1 demonstrated a Gaussian distribution, with higher levels in T1D patients (13.56 +/- 5.34 vs 11.35 +/- 3.76 pmol/L, p = 0.024). Higher values were found in boys and in prepubertal children. Dickkopf-1 correlated positively with osteoprotegerin and fasting glucose in patients, while positive correlation with sclerostin and total soluble receptor activator of nuclear factor-kappaB ligand (s-RANKL) was found in controls. Positive correlations with C-telopeptide cross-links (CTX), osteocalcin, alkaline phosphatase, phosphate, and insulin-like growth factor 1 (IGF1) were documented in both groups. Lumbar spine Z-score was positively associated with Dickkopf-1 in controls, while a negative trend was found in patients. CONCLUSIONS: Higher levels of Dickkopf-1 could indicate a downregulated Wnt/beta-catenin system with possible lower osteoblast activation and higher osteoclast signaling in T1D children and adolescents. Dickkopf-1 could possibly be a significant contributor of T1D osteopathy. Future therapies could focus on Wnt/beta-catenin metabolic pathway. PMID- 27766368 TI - Anti-osteoporotic treatments in France: initiation, persistence and switches over 6 years of follow-up. AB - : Limited information is available on anti-osteoporotic treatment initiation patterns in France. In 2006-2013, the most frequently prescribed first-line treatment class for osteoporosis was represented by bisphosphonates (alendronic acid and risedronic acid), followed by strontium ranelate. Persistence with anti osteoporotic treatment was low, with high proportions of treatment discontinuations and switches. INTRODUCTION: This epidemiological, longitudinal study described first-line treatment initiation, persistence, switches to second line treatment, and medical care consumption in osteoporotic patients in France during the 2007-2013 period. METHODS: Patients aged >=50 years, who were recorded in a French claims database and did not die during the observation period, were included if they met >=1 inclusion criteria for osteoporosis in 2007 (>=1 reimbursement for anti-osteoporotic treatment, hospitalisation for osteoporotic fracture (spine, hip, femur, forearm bones, humerus, wrist), or >=1 reimbursement for long-term osteoporosis-associated status). We collected data on consumption of anti-osteoporotic treatment (alendronic acid, ibandronic acid, risedronic acid, zoledronic acid, raloxifene, strontium ranelate, teriparatide) and of osteoporosis-related medical care after the date of first reimbursement for anti osteoporotic treatment. RESULTS: We obtained 2219 patients with a 6-year follow up and 1387 who initiated an anti-osteoporotic treatment in 2007 and who can be selected for the treatment regimen analysis. The most frequently used first-line treatments were alendronic acid (32.7 %), risedronic acid (22.4 %), strontium ranelate (19.3 %), ibandronic acid (13.1 %) and raloxifene (12.2 %). Among patients who received these treatments, the highest persistence after 6 years was observed for raloxifene (37.3 %), alendronic acid (35.1 %) and risedronic acid (32.3 %). Treatment discontinuations were reported for 35.5 % (raloxifene) to 53.4 % (strontium ranelate) and treatment switches for 27.4 % (alendronic acid) to 56.6 % (ibandronic acid) of these patients. CONCLUSIONS: This study showed that persistence with anti-osteoporotic treatment was relatively low in France, with high proportions of treatment discontinuations and switches, and that patients with osteoporosis were insufficiently monitored by bone specialists. PMID- 27766369 TI - Sensitivity and specificity of radiographic characteristics in atypical femoral fractures. AB - : Using the American Society for Bone and Mineral Research Task Force case definition for atypical femoral fractures, sensitivity and specificity of radiographic fracture characteristics were calculated. Fracture pattern was the most sensitive and specific characteristic. This suggests that some characteristics should be weighted more heavily when identifying these fractures. INTRODUCTION: To estimate the sensitivity and specificity of each radiographic criterion in the 2013 ASBMR atypical femoral fracture (AFF) case definition for distinguishing AFF from other subtrochanteric/diaphyseal fractures (non-AFF) among women enrolled in a large integrated health care organization. METHODS: Radiographs from 55 physician-confirmed AFFs and a sample of 39 non-AFFs were reviewed by four independent expert reviewers representing four medical specialties. One image per fracture was selected for review. Using a standardized data collection tool, based on the 2013 AFF case definition, reviewers indicated the presence or absence of the following characteristics viewable on radiograph: fracture pattern, comminution, periosteal and/or endosteal thickening, and cortical thickening. Sensitivity and specificity for each characteristic was calculated for each reviewer and summarized across reviewers with the mean and range. Agreement across reviewers was quantified using Fleiss's kappa (FK) statistic. RESULTS: The most sensitive factors distinguishing AFF from non-AFF were lateral cortex transverse fracture pattern (mean 93.6 %, range 85.5-98.2 %), medial cortex transverse or oblique fracture pattern (mean 84.1 %, range 72.7 98.2 %), and minimal/non-comminution (mean 93.2 %, range 89.1-98.2 %). Specificity was the greatest for lateral cortex transverse fracture pattern (mean 95.5 %, range 92.3-97.4 %). Agreement across reviewers was the highest for lateral cortex transverse fracture pattern (FK 0.83) and incomplete fracture through the lateral cortex only (FK 0.80). CONCLUSION: Lateral cortex transverse fracture pattern was the most sensitive and specific characteristic and the most highly agreed upon across reviewers. Other characteristics were less readily agreed upon across reviewers. Measurement of discrete combinations of individual characteristics may enhance sensitivity and/or specificity. PMID- 27766370 TI - Measurement of psychological state changes at low dopamine transporter occupancy following a clinical dose of mazindol. AB - RATIONALE: The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. OBJECTIVES: The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. METHODS: Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding. RESULTS: Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24-25 %, and the binding potential of [11C]raclopride was reduced by 2.8-4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum. CONCLUSIONS: A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. TRIAL REGISTRATION HTTPS://UPLOAD.UMIN.AC.JP/CGI-OPEN-BIN/CTR_E/CTR_VIEW.CGI?RECPTNO=R000009703 : UMIN000008232. PMID- 27766373 TI - [Waves of refugees represent challenge for European dermatologists]. AB - With the increasing number of asylum seekers in recent months, European dermatologists have been confronted with rising numbers of patients with formerly rare skin diseases and unusual infectious skin diseases that were previously scarcely observed at our latitude. Thorough examination of the patients medical history, including the routes of travel and the country of origin of the patients, detailed clinical and laboratory examinations, and - if necessary - referral to a special treatment center allow rapid and targeted treatment. PMID- 27766372 TI - Translational metagenomics and the human resistome: confronting the menace of the new millennium. AB - The increasing threat of antimicrobial resistance poses one of the greatest challenges to modern medicine. The collection of all antimicrobial resistance genes carried by various microorganisms in the human body is called the human resistome and represents the source of resistance in pathogens that can eventually cause life-threatening and untreatable infections. A deep understanding of the human resistome and its multilateral interaction with various environments is necessary for developing proper measures that can efficiently reduce the spread of resistance. However, the human resistome and its evolution still remain, for the most part, a mystery to researchers. Metagenomics, particularly in combination with next-generation-sequencing technology, provides a powerful methodological approach for studying the human microbiome as well as the pathogenome, the virolume and especially the resistome. We summarize below current knowledge on how the human resistome is shaped and discuss how metagenomics can be employed to improve our understanding of these complex processes, particularly as regards a rapid translation of new findings into clinical diagnostics, infection control and public health. PMID- 27766371 TI - Nicotine self-administration research: the legacy of Steven R. Goldberg and implications for regulation, health policy, and research. AB - BACKGROUND AND RATIONALE: Steven R. Goldberg was a pioneering behavioral pharmacologist whose intravenous drug self-administration studies advanced the understanding of conditioned stimuli and schedules of reinforcement as determinants of pattern and persistence of drug-seeking behavior, and in particular, the importance of nicotine in tobacco use. His passing in 2014 led to invitations to contribute articles to psychopharmacology dedicated to his work. OBJECTIVES: The objectives of this review are to summarize and put into historical perspective Goldberg's contributions to elucidate the reinforcing effects of nicotine and to summarize the implications of his research for medication development, tobacco regulation, and potential tobacco control policy options. This includes a review of intravenous nicotine self-administration research from the 1960s to 2016. RESULTS: Goldberg's application of behavioral pharmacology methods to investigate nicotine reinforcement and the influence of schedule of reinforcement and conditioned stimuli on nicotine administration contributed to the conclusions of the US National Institute on Drug Abuse, and the Surgeon General, that nicotine met the criteria as a dependence-producing drug and cigarette smoking as a prototypic drug dependency or "addiction." Equally important, this work has been systematically extended to other species and applied to address a range of factors relevant to tobacco use, medication development, regulation, and public health policy. CONCLUSIONS: Steven R. Goldberg was a pioneering scientist whose systematic application of the science of behavioral pharmacology advanced the understanding of tobacco and nicotine use and contributed to the scientific foundation for tobacco product regulation and potential public health tobacco control policy development. PMID- 27766375 TI - Interventions to prevent youth violence in Latin America: a systematic review. AB - OBJECTIVES: This review aims to summarise evidence on the effectiveness of interventions to prevent youth violence in Latin America. METHODS: A systematic search on 13 academic databases was conducted to locate studies evaluating a primary or secondary prevention intervention in Latin America. Studies could use any type of quantitative design to assess outcomes related to youth violence. A search of websites, references and citation searching was also carried out. The quality of each study was assessed. RESULTS: Nine studies were identified. Most documented positive effects of the interventions on the perception of youth violence present in the community/school. Evidence was found of a reduction in homicides and juvenile crimes in three studies, two of which evaluated a community-based intervention. There were mixed results for the self-report of participation on violent acts. The majority of the studies lacked of a rigorous design. CONCLUSIONS: Most of the interventions had some promising results, including the reduction of homicides within communities. Community-based programmes were the most consistent regarding an effectiveness to prevent violence. However, the evidence for Latin America is still scarce and relies on non-rigorously designed studies. PMID- 27766374 TI - Trends in external causes of child and adolescent mortality in Poland, 1999-2012. AB - OBJECTIVES: To examine the pattern and trend of deaths due to external causes among Polish children and adolescents in 1999-2012, and to compare trends in Poland's neighboring countries. METHODS: Death records were obtained from the Central Statistical Office of Poland. External causes mortality rates (MR) with 95 % confidence interval were calculated. The annual percentage change of MR was examined using linear regression. To compare MR with Belarus, Ukraine, Czech Republic and Germany, data from the European Mortality Database were used. RESULTS: MR were the highest in the age 15-19 years (33.7/100,000) and among boys (22.7/100,000). Unintentional injuries including transport accidents, drowning, and suicides (especially in children over 10 years old), were the main cause of death in the analyzed groups. Between 1999 and 2012 annual MR for unintentional injuries declined substantially. MR due to injuries and poisoning in Poland were higher compared with Czech Republic and Germany and lower in comparison with Belarus and Ukraine. CONCLUSIONS: Deaths due to unintentional injuries are still the leading cause of death among Polish children and adolescents. There are differences in death rates between Poland and neighboring countries. PMID- 27766376 TI - [Multidrug resistant bacteria in the intensive care unit : Reasonable measures for prevention]. AB - Multidrug resistant (MDR) bacteria present an increasing threat for intensive care patients. Whereas colonization of intensive care patients with methicillin resistant staphylococcus aureus (MRSA) in German ICUs has remained at a constant level in recent years and therapeutic options have improved, colonization and infections with MDR gram-negative bacteria and vancomycin-resistant enterococci are increasing year by year. Only a few or even no therapeutic options remain for the treatment of these bacteria. If recommendations and guidelines for the prevention of transmission of MDR bacteria do exist they often are of moderate evidence due to lack of randomized controlled trials. The single most important measure to avoid transmission and infection with sensible and MDR bacteria is still hand disinfection. Screening and barrier precautions must be adapted and implemented to pathogen and local conditions. In addition to those specific measures universal decolonization with antiseptics have been demonstrated to be effective at least in intensive care patients. PMID- 27766377 TI - [Diaphragm dysfunction : Facts for clinicians]. AB - Diaphragm function is crucial for patient outcome in the ICU setting and during the treatment period. The occurrence of an insufficiency of the respiratory pump, which is predominantly formed by the diaphragm, may result in intubation after failure of noninvasive ventilation. Especially patients suffering from chronic obstructive pulmonary disease are in danger of hypercapnic respiratory failure. Changes in biomechanical properties and fiber texture of the diaphragm are further cofactors directly leading to a need for intubation and mechanical ventilation. After intubation and the following inactivity the diaphragm is subject to profound pathophysiologic changes resulting in atrophy and dysfunction. Besides this inactivity-triggered mechanism (termed as ventilator induced diaphragmatic dysfunction) multiple factors, comorbidities, pharmaceutical agents and additional hits during the ICU treatment, especially the occurrence of sepsis, influence diaphragm homeostasis and can lead to weaning failure. During the weaning process monitoring of diaphragm function can be done with invasive methods - ultrasound is increasingly established to monitor diaphragm contraction, but further and better powered studies are in need to prove its value as a diagnostic tool. PMID- 27766378 TI - [Hypoxic respiratory failure in chronic lung disease]. PMID- 27766380 TI - Mathematical analysis of the homing flights of pigeons based on GPS tracks. AB - To analyse the effect of magnetic and olfactory deprivation on the homing flight of pigeons, we released birds from a familiar site with either their upper beak or their nostrils anaesthetized. The tracks were analysed by time lag embedding to calculate the short-term correlation dimension, a variable that reflects the degrees of freedom and thus the number of factors involved in a system. We found that higher natural fluctuations in the earth's magnetic field characterized by A P-indices of 8 and above caused a reduction of the correlation dimension of the control birds. We thus separated the data into two groups according to whether they were recorded on magnetically quiet days or on days with higher magnetic fluctuations. Anaesthetizing the upper beak had no significant effect. Making pigeons anosmic reduced the correlation dimension on magnetically quiet days, but did not cause any reduction on days with higher fluctuations. Altogether, our data suggest an involvement of magnetic cues and olfactory factors during the homing flight and point to a robust, multi-factorial map. PMID- 27766379 TI - Aryl-1,3,5-triazine ligands of histamine H4 receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide. AB - OBJECTIVE AND DESIGN: Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity. MATERIALS AND SUBJECTS: We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. TREATMENTS: In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 uM. METHODS: We examined anti-inflammatory and analgesic effects of the new H4R antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine H1 receptor in functional studies. RESULTS: Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenan-induced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as TNFalpha and IL-1beta. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H1 receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. CONCLUSIONS: Our results demonstrate the anti inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily H4R-dependent. PMID- 27766381 TI - Comparative and developmental patterns of amphibious auditory function in salamanders. AB - Early amphibious tetrapods may have detected aquatic sound pressure using sound induced lung vibrations, but their lack of tympanic middle ears would have restricted aerial sensitivity. Sharing these characteristics, salamanders could be models for the carryover of auditory function across an aquatic-terrestrial boundary without tympanic middle ears. We measured amphibious auditory evoked potential audiograms in five phylogenetically and ecologically distinct salamanders (Amphiuma means, Notophthalmus viridescens, Ambystoma talpoideum, Eurycea spp., and Plethodon glutinosus) and tested whether metamorphosis and terrestrial niche were linked to aerial sensitivity. Threshold differences between media varied between species. A. means' relative aerial sensitivity was greatest at 100 Hz and decreased with increasing frequency. In contrast, all other salamanders retained greater sensitivity up to 500 Hz, and in A. talpoideum and Eurycea, relative sensitivity at 500 Hz was higher than at 100 Hz. Aerial thresholds of terrestrial P. glutinosus above 200 Hz were similar to A. talpoideum and Eurycea, but lower than N. viridescens and A. means. Metamorphosis did not affect aerial sensitivity in N. viridescens or A. talpoideum. These results fail to support a hypothesis of terrestrial hearing specialization across ontogeny or phylogeny. We discuss methodological limitations to our amphibious comparisons and factors affecting variation in amphibious performance. PMID- 27766383 TI - ? PMID- 27766382 TI - [Cervical cancer : Update on morphology]. AB - The World Health Organization (WHO) classification from 2014 differentiates between different subtypes of mucinous adenocarcinoma of the uterine cervix. A gastric subtype was recently described that showed no association with high-risk human papillomavirus (HPV) infections, has a poor prognosis, is mainly diagnosed in women of Asian origin and can occur in patients with Peutz-Jeghers syndrome. Although no clear grading system has been recommended in the WHO classification, it is likely that grading of adenocarcinomas of the uterine cervix will partly be based on the different patterns of invasion. Deep stromal infiltration of macroinvasive carcinomas is defined as an infiltration of >66 % of the cervical stroma. In the near future a maximum tumor size of 2 cm could act as a discriminator for planning of less radical surgery. Parameters of the histopathological report that are relevant for the prognostic assessment as well as the choice of adjuvant treatment and function as quality indicators during certification are described. The histological type of an adenocarcinoma alone is of no predictive or prognostic relevance for patients undergoing primary surgical treatment, neoadjuvant chemotherapy, combined chemo-radiotherapy or treatment with angiogenesis inhibitors. Currently, molecular parameters and biomarkers are of no relevance. PMID- 27766384 TI - Reply to Letter to the Editor re: Should fat in the radiofrequency ablation zone of hepatocellular adenomas raise suspicion for residual tumour? PMID- 27766386 TI - [Botulinum toxin A induced protective ptosis for the treatment of recurrent epithelial defects in neurotrophic keratopathy]. AB - In this article, a case of recurrent epithelial defects in neurotrophic keratopathy is described. Multiple abrasions of the corneal epithelium with a therapeutic contact lens, corneal stitches, and amniotic membrane transplantation in combination with artificial tears brought only short-term success. However, a botulinum toxin A induced protective ptosis could finally achieve permanent epithelial closure. As this case shows, protective ptosis can be a promising approach in spite of multiple previous ineffective therapeutic efforts. PMID- 27766385 TI - Use of porous tantalum components in Paprosky two and three acetabular revision. A minimum five-year follow-up of fifty one hips. AB - INTRODUCTION: Recent studies have reported short-term favourable results of tantalum-made components in acetabular revisions with bone loss. However, there is a lack of information regarding the mid to long-term results of such components. OBJECTIVES: The objective of this study was to analyse the outcome and survivorship of acetabular revision hip arthroplasty using tantalum components for loosening associated with bone loss at a minimum of five-year follow-up. METHODS: We retrospectively reviewed 51 consecutive patients (51 hips) who had an acetabular revision using porous tantalum components at a minimum follow-up of five years. The mean age was 64 years (range, 31-87). There were 27 males and 24 females, 47 right hips and four left hips. Twenty-five (49 %) included a femoral revision. According to Paprosky's classification 18 hips were classified type 2A, 11 type 2B, ten type 2C, seven type 3A and five type 3B. No bone grafting was performed. Sixteen hips (31.3 %) required the use of additional tantalum-made augments stabilized by screws and cement at the cup-augment interface. RESULTS: At a mean followup of 6.8 years (range, 5.1-10 years), the Harris hip score improved from 44 pre- operatively (range, 23-72) to 84 post operatively (range, 33-98). The mean post-operative hip centre position in relation to the teardrop was 29 mm (range, 20-43 mm) horizontally and 21 mm (range, 8-36 mm) vertically. The mean acetabular inclination was 42 degrees (range, 17-60 degrees ). Six hips (11.7 %) required a re-operation without component revision (two for chronic instability, one ossification removal, one haematoma, one deep infection and one periprosthetic femoral fracture). One patient required a cup re-revision for septic loosening. No aseptic loosening occurred. At last followup the radiological analysis showed one evolutive osteolysis and one screw breakage. The global survivorship was 92.3 % at 64 months. If only aseptic loosening was defined as the end-point the survivorship was 100 % at 64 months. CONCLUSIONS: When facing an acetabular revision with severe bone loss, tantalum-made components can provide a stable fixation. This study at a minimum five-year follow-up compares favourably with other reconstruction techniques, but longer follow-up is still required. PMID- 27766387 TI - Learning curves and perioperative outcomes after endoscopic enucleation of the prostate: a comparison between GreenLight 532-nm and holmium lasers. AB - PURPOSE: To compare the learning curves, perioperative and early functional outcomes after HoLEP and GreenLEP. METHODS: Data from the first 100 consecutive cases treated by GreenLEP and HoLEP by two surgeons were prospectively collected from dedicated databases and analysed retrospectively. En-bloc GreenLEP and two lobar HoLEP enucleations were conducted using the GreenLight HPSTM 2090 laser and LumenisTM holmium laser. Patients' characteristics, perioperative outcomes and functional outcomes after 1, 3 and 6 months were compared between groups. RESULTS: Total energy delivered and operative times were significantly shorter for GreenLEP (58 vs. 110 kJ, p < 0.0001; 60 vs. 90 min, p < 0.0001). Operative time reached a plateau after 30 procedures in each group. Length of catheterization and hospital stay were significantly shorter in the HoLEP group (2 vs. 1 day, p < 0.0001; 2 vs. 1 day, p < 0.0001). Postoperative complications were comparable between GreenLEP and HoLEP (19 vs. 25 %; p = 0.13). There was a greater increase of Q max at 3 months and a greater IPSS decrease at 1 month for GreenLEP, whereas decreases in IPSS and IPSS-Q8 at 6 months were greater for HoLEP. Transient stress urinary incontinence was comparable between both groups (6 vs. 9 % at 3 months; p = 0.42). Pentafecta was achieved in four consecutive patients after the 18th and the 40th procedure in the GreenLEP and HoLEP group, respectively. Learning curves ranged from 14 to 30 cases for GreenLEP and 22 to 40 cases for HoLEP. CONCLUSION: Learning curves of GreenLEP and HoLEP provided roughly similar peri-operative and short-term functional outcomes. PMID- 27766388 TI - Turkish version of the Ureteral Stent Symptoms Questionnaire: linguistic and psychometric validation. AB - PURPOSE: Ureteric stents are frequently used in urology practice and can cause significant impairment in quality of life (QoL). The aim of this study was to validate the Ureteral Stent Symptoms Questionnaire (USSQ) to be used in the evaluation of stent-related symptoms and impairment in QoL in Turkish-speaking patients. METHODS: After linguistic validation of the original USSQ into Turkish language, the Turkish version of the USSQ (T-USSQ) was self-administered to all participants at week 1 and 4 after stent placement for test-retest reliability and internal consistency and at week 8 (4 weeks after stent removal) for sensitivity to change analysis. Control patients completed the form only once. Additionally male and female patients completed the validated Turkish versions of International Prostate Symptom Score (IPSS) and Marmara Overactive Bladder (mOAB) Symptom Scores, respectively. RESULTS: A total of 68 patients with ureteral stents and 37 controls were available for the final analysis. The Cronbach's alpha value was higher than 0.7 at week 1 for all sub-domains except additional problems domain. The test-retest reliability of the T-USSQ was high for all sub domains except the additional problems domain. Relatively high correlation coefficients were found for the visual analog scale for pain, IPSS (for males), mOAB score (for females) with the corresponding USSQ domains, suggesting good convergent validity. Also the T-USSQ could effectively differentiate between patients and controls. CONCLUSIONS: The T-USSQ is a reliable and robust instrument that can be self-administered to patients of Turkish population with ureteral stent in the clinical applications. PMID- 27766389 TI - Eriocitrin from lemon suppresses the proliferation of human hepatocellular carcinoma cells through inducing apoptosis and arresting cell cycle. AB - Hepatocellular carcinoma is a lethal cancer with high recurrence ratio and lacks effective therapeutics. In the past few years, it has been reported that increased intake of vegetables and fruits could reduce the cancer incidence, which suggests dietary agents might possess anticancer effects. Eriocitrin is a flavonoid isolated from lemon, which is known as a strong antioxidant agent. We here for the first time demonstrated that eriocitrin could inhibit the proliferation of hepatocellular carcinoma cell lines by arresting cell cycle in S phase through up-regulation of p53, cyclin A, cyclin D3 and CDK6. Furthermore, we found that eriocitrin could trigger apoptosis by activating mitochondria-involved intrinsic signaling pathway. Thus, eriocitrin might be regarded as a potential chemopreventive natural product to inhibit the early malignant transformation of hepatocellular carcinoma. PMID- 27766390 TI - JAK2V617F and calreticulin mutations in recurrent venous thromboembolism: results from the EDITH prospective cohort. AB - Cancer incidence in patients with recurrent unprovoked venous thromboembolism (VTE) is much higher than after a first event, but the incidence of myeloproliferative neoplasms (MPN) in this situation is still unknown. We tested for JAK2V617F and calreticulin mutants, 372 DNA samples of patients treated for (VTR). Among these patients, 10 (2.7%) were carrying JAK2V617F mutation and none of them any of the calreticulin (CALR) mutations. Among the 19 patients who had VTE recurrence under vitamin K antagonists, 4 patients (21.0%) were positive for JAK2V617F. Despite the identification of JAK2V617F mutation, only three patients were diagnosed for MPN despite a median follow-up of 4 years. We showed that the screening for JAK2V617F not CALR mutations should be helpful in this indication especially if recurrence happened under VKA therapy. PMID- 27766392 TI - HLA-haploidentical hematopoietic stem cell transplantation with low-dose thymoglobulin GVHD prophylaxis for an adult T cell leukemia/lymphoma patient treated with pretransplant mogamulizumab. PMID- 27766391 TI - The possible role of burden of therapy on the risk of myeloma extramedullary spread. AB - Extramedullary relapse (EMR) represents a poor prognostic marker in the course of multiple myeloma (MM). We reviewed data from 329 patients, diagnosed between 2000 and 2010, without extramedullary disease at onset to explore possible risk factors for EMR. The median overall survival of our study cohort was 6.4 years. The risk of EMR was 28 % with a median time from diagnosis to first EMR of 2.2 years (0.2-9.1 years). Patients with soft tissue masses located in extra-osseous organs (EMR-S) showed the worst outcome, compared to those with tumor masses arising from adjacent bone (EMR-B) (median OS 1.6 vs 2.4 years, p = 0.006). In addition, patients with EMR-S showed a significant trend for further development of extramedullary masses in a very short time (3.7 vs 5.7 months for EMR-B, p = 0.043). Multivariate analysis failed to identify any clinically presenting features predictive for EMR. The occurrence of EMR was higher in patients with more complex treatment history, defined on the basis of longer treatment duration (>=6 vs <6 months) and on elevated number of treatment lines administered (>2 vs <=2 lines) (HR = 4.5, p < 0.001 and HR = 9.0, p < 0.001, respectively, when one or both factors are present).In conclusion, increasing burden of treatment might be a possible risk factor for EMR. MM patients with multiple relapses should be comprehensively investigated including, when possible, a whole-body-targeted radiologic technique to accurately detect EMR. Treatment choice should take into account the very poor outcome for patients with soft tissue involvement. PMID- 27766393 TI - Mycophenolate mofetil is effective only for involved skin in the treatment for steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. PMID- 27766394 TI - Ultrasound-Guided Vascular Access Simulator for Medical Training: Proposal of a Simple, Economic and Effective Model. AB - OBJECTIVE: To present a simple and affordable model able to properly simulate an ultrasound-guided venous access. DESIGN: The simulation was made using a latex balloon tube filled with water and dye solution implanted in a thawed chicken breast with bones. RESULTS: The presented model allows the simulation of all implant stages of a central catheter. The obtained echogenicity is similar to that observed in human tissue, and the ultrasound identification of the tissues, balloon, needle, wire guide and catheter is feasible and reproducible. CONCLUSION: The proposed model is simple, economical, easy to manufacture and capable of realistically and effectively simulating an ultrasound-guided venous access. PMID- 27766395 TI - Evidence-Based Management of Pain After Excisional Haemorrhoidectomy Surgery: A PROSPECT Review Update. AB - BACKGROUND: The aim of this systematic review was to update previous PROSPECT ( http://www.postoppain.org ) review recommendations for the management of pain after excisional haemorrhoidectomy. METHODS: Randomized studies and reviews published in the English language from July 2006 (end date of last review) to March 2016, assessing analgesic, anaesthetic, and operative interventions pertaining to excisional haemorrhoidectomy in adults, and reporting pain scores, were retrieved from the EMBASE and MEDLINE databases. RESULTS: An additional 464 studies were identified of which 74 met the inclusion criteria. There were 48 randomized controlled trials and 26 reviews. Quantitative analyses were not performed, as there were limited numbers of trials with a sufficiently homogeneous design. CONCLUSION: Pudendal nerve block, with or without general anaesthesia, is recommended for all patients undergoing haemorrhoidal surgery. Either closed haemorrhoidectomy, or open haemorrhoidectomy with electrocoagulation of the pedicle is recommended as the primary procedure. Combinations of analgesics (paracetamol, non-steroidal anti-inflammatory drugs, and opioids), topical lignocaine and glyceryl trinitrate, laxatives, and oral metronidazole are recommended post-operatively. The recommendations are largely based on single intervention, not multimodal intervention, studies. PMID- 27766397 TI - Risk Factors for Cholangiocarcinoma After Initial Hepatectomy for Intrahepatic Stones. AB - BACKGROUND: Aggressive hepatectomy is effective in treating intrahepatic stones and may minimize the deleterious consequences of subsequent cholangiocarcinoma (S CCA). The risk factors of S-CCA after different methods of hepatectomy may vary with the resection scope of stone-affected segments. METHODS: We reviewed the records of 981 patients of primary intrahepatic stones with elective hepatectomy from January 2000 to December 2010. The clinical characteristics of patients in the S-CCA group (n = 55) and the control group (n = 926) were compared. The uniformity between extent of liver resection (ELR) with stone-affected segments (SAS) was segmented into 2 varieties: ELR = SAS with ELR < SAS according to the different hepatic resection scopes. Cox regression model with forward selection was used to identify the risk factors of S-CCA. RESULTS: In the univariate analysis, significant differences were observed between the S-CCA and control groups concerning stone location (unilateral 43.6 and 65.2 %, bilateral 56.4 and 34.8 %), residual stones (32.7 and 11.6 %), hepaticojejunostomy (43.6 and 30.9 %), and uniformity between ELR with SAS (ELR = SAS 20.0 and 42.6 %, ELR < SAS 80.0 and 57.4 %). Residual stones [hazard ratio (HR) 2.101, P = 0.016], hepaticojejunostomy (HR 1.837, P = 0.026) and uniformity between ELR and SAS (HR 2.442, P = 0.013) were independent prognostic factors for S-CCA by a Cox regression analysis with forward selection. In the subsection of ELR = SAS group, the 5- and 10-year postoperative tumor occurrence rates of unilateral and bilateral stones group were 0.9 versus 1.9 % and 3.0 versus 4.1 %, respectively (P = 0.663, log-rank). In the other subsection of ELR < SAS group, the 5- and 10 year postoperative tumor occurrence rates of unilateral and bilateral stones group were 3.4 versus 3.9 % and 6.8 versus 13.2 %, respectively (P = 0.047, log rank), and the 5- and 10-year postoperative tumor occurrence rates of residual stones and non-residual stones group were 5.8 versus 3.0 % and 16.0 versus 7.9 %, respectively (P = 0.015, log-rank). CONCLUSIONS: Patients who underwent aggressive hepatectomy and had ELR = SAS had better outcomes than those with ELR < SAS. In the patients with ELR = SAS, the S-CCA rates of unilateral and bilateral stones were low and comparable. However, patients with ELR < SAS and bilateral intrahepatic or residual stones should be monitored more carefully for high-risk factors of S-CCA. PMID- 27766398 TI - Enhanced Recovery Program in High-Risk Patients Undergoing Colorectal Surgery: Results from the PeriOperative Italian Society Registry. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) pathways represent the optimal approach for patients undergoing colorectal surgery. Elderly or low physical status patients have been often excluded from ERAS pathways because considered at high risk. The aim of this study is to assess the adherence to ERAS protocol and its impact on short-term postoperative outcome in patients with different surgical risk undergoing elective colorectal resection. METHODS: Prospectively collected data entered in an electronic Italian registry specifically designed for ERAS were reviewed. Patients were divided into four groups according to age (70-year-old cutoff) and preoperative physical status as measured by the ASA grade (I-II vs. III-IV). Adherence to 18 ERAS elements and postoperative outcomes were compared between groups. Regression analysis was used to identify independent factors associated with improved outcomes. RESULTS: Eleven Italian hospitals reported data on 706 patients undergoing elective colorectal surgery within an ERAS protocol. Patients with low physical status had reduced adherence to preoperative carbohydrate loading, epidural analgesia, PONV prophylaxis, and early urinary catheter removal. No difference was found between groups for adherence to other perioperative elements. Major complications occurred in 37 (5.2 %) patients without significant differences among groups (p = 0.384). Median (IQR) time to readiness for discharge (TRD) was 4 (3-6) days, length of hospital stay (LOS) was 6 (4-7) days, and both were significantly shorter by only 1 day in the groups of younger patients (p < 0.001). At multivariate analysis, laparoscopy increased adherence to ERAS items and reduced TRD, LOS, and morbidity. A high ASA grade was significantly associated with lower adherence, whereas older age significantly prolonged TRD and LOS. CONCLUSION: ERAS pathway can be safely applied in elderly and low physical status patients yielding slight differences in postoperative morbidity and time to recover. Laparoscopy was independently associated with increased adherence to ERAS protocol and improved short-term postoperative outcome. PMID- 27766399 TI - Patients Undergoing Breast-Conserving Surgery Can Benefit from the Opportunity to Participate in Choosing Their Surgical Technique. AB - BACKGROUND: Shared decision-making is increasingly advocated in many countries. The aims of this study were to investigate whether patients receiving breast conserving surgery at Skane University Hospital Malmo, Sweden, perceived an offered possibility to join in the decision-making process regarding the surgical method; to identify potential determinants for not having perceived such an offer; and to study how this perception of being offered an opportunity to take part in the decision-making process affected satisfaction with the aesthetic outcome. METHODS: Women offered breast-conserving surgery were consecutively recruited over a period of 4 years. In all, 324 women completed a study-specific questionnaire. RESULTS: A majority of the women (53 %) perceived that they had not, or had only partly, been offered a possibility to take part in the decision making process. Patients who reported that they had received enough preoperative information regarding the expected aesthetic result were more likely to have perceived such an offer (odds ratio (OR) 5.44; confidence interval (CI) 2.83 10.43). Women who had perceived an opportunity to be involved were more satisfied with the aesthetic result (OR 2.71; CI 1.18-6.25) and more likely to have had their expectations met regarding the aesthetic result (OR 5.91; CI 2.01-17.38). CONCLUSION: When deciding on a suitable surgical approach for women with early breast cancer, physicians could try to more clearly communicate to the women that they can choose whether or not to participate in the decision-making regarding surgical technique. This might improve satisfaction. An important part of patient involvement is sufficient preoperative information. PMID- 27766400 TI - The Correlation Between Poverty and Access to Essential Surgical Care in Ghana: A Geospatial Analysis. AB - BACKGROUND: Surgical disease burden falls disproportionately on individuals in low- and middle-income countries. These populations are also the least likely to have access to surgical care. Understanding the barriers to access in these populations is therefore necessary to meet the global surgical need. METHODS: Using geospatial methods, this study explores the district-level variation of two access barriers in Ghana: poverty and spatial access to care. National survey data were used to estimate the average total household expenditure (THE) in each district. Estimates of the spatial access to essential surgical care were generated from a cost-distance model based on a recent surgical capacity assessment. Correlations were analyzed using regression and displayed cartographically. RESULTS: Both THE and spatial access to surgical care were found to have statistically significant regional variation in Ghana (p < 0.001). An inverse relationship was identified between THE and spatial access to essential surgical care (beta -5.15 USD, p < 0.001). Poverty and poor spatial access to surgical care were found to co-localize in the northwest of the country. CONCLUSIONS: Multiple barriers to accessing surgical care can coexist within populations. A careful understanding of all access barriers is necessary to identify and target strategies to address unmet surgical need within a given population. PMID- 27766401 TI - Treatment-Based Three-Dimensional Classification and Management of Anorectal Infections. AB - This article provides a current overview on clinical anatomy, pathophysiology, workup and surgical management of anorectal abscesses. Based on the three dimensional nature of anorectal abscesses, a novel treatment-based classification is proposed. It examines the basis of a philosophic shift from simple drainage to concomitant definitive treatment of abscesses and their underlying primary fistulous trajectories. Complications are discussed specifically in this context. PMID- 27766402 TI - Management of Implant Exposure in One-Stage Breast Reconstruction Using Titanium Coated Polypropylene Mesh: Sub-Mammary Intercostal Perforator Flap. AB - INTRODUCTION: One-stage implant-based breast reconstruction using titanium-coated polypropylene mesh is a novel approach widely used in Europe. Complication rates in breast reconstruction with the use of titanium-coated meshes seem to be comparable to those in patients with implant-based breast reconstruction alone. However, the use of synthetic meshes in implant-based breast reconstructive surgery leads to new clinical scenarios with the need for the breast surgeon to face new complications. We present an innovative treatment of implant exposure in the absence of infection in patients who underwent nipple-sparing mastectomy and immediate breast reconstruction with silicone implants and titanium-coated polypropylene mesh by using a pedicled sub-mammary intercostal perforator flap. CASES PRESENTATION: Four patients who experienced implant exposure without infection have been treated with the use of a sub-mammary intercostal perforator flap. Whole coverage of the exposed implant/mesh with a sub-mammary intercostal perforator flap was obtained in all cases. No post-operative complications have been observed, whereas a pleasant aesthetic result has been achieved. Patients' post-operative quality of life and satisfaction levels were measured by the European Organisation for Research and Treatment of Cancer breast cancer-specific quality of life QLQ-BR23 questionnaire and showed an average good satisfaction with the post-operative outcomes (mean QLQ-BR23 score 1.9). DISCUSSION: For the first time, a sub-mammary intercostal perforator flap has been used with the aim of treating implant exposures without removing the prosthesis even in the presence of synthetic meshes, when wound infection was excluded. Although tested on a small series, the sub-mammary intercostal perforator flap might represent a simple, versatile and cost-effective procedure for the management of implant exposure following nipple-sparing mastectomy and immediate reconstruction with silicone implants and synthetic meshes. It should be considered to avoid implant removal followed by delayed free flap reconstruction as "salvage surgery." LEVEL OF EVIDENCE V: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27766403 TI - The Effect of Hyaluronic Acid Application on the Perisilicon Capsule Structure. AB - BACKGROUND: Silicon implants constitute a major part of plastic surgery practice. Although materials with high biocompatibility have been used around the implants, capsule formation still develops and progressive nature of this process results in capsule contraction. The aim of this study is to evaluate the effects of hyaluronic acid injected around the silicon block on the capsule structure. METHODS: Twenty Wistar albino rats were used in the study. Rats were divided into two main groups (group 1 and group 2) and two subgroups. Rats in group 1 were sacrificed in week 4 and rats in group 2 were sacrificed in week 8. A subcutaneous pouch was created in the dorsum of the rats and a silicon block was placed into the pouch in groups 1A and 2A. 0.2 ml of hyaluronic acid was injected around the silicon block in group 1B and group 2B. Rats were sacrificed and capsule structure and thickness were analyzed following macroscopic evaluation. Concentrations of transforming growth factor-beta1 (TGF-beta1) and heat shock protein-47 (HSP-47) were evaluated immunohistochemically, and statistical comparisons were made. RESULT: Capsule structure consisted of three layers in all the groups. A more intense collagen structure was observed in the middle layer. The capsule was thinnest in group 1A and thickest in group 2B; the difference between the groups was statistically significant. TGF-beta1 was most intense in group 2B and it was correlated with the amount of collagen. Involvement of HSP-47 was observed mainly in collagen and also in fibroblasts and vascular structures, and its concentration was found to be lower in groups 2A and 2B. CONCLUSION: Exogenously added cross-linked hyaluronic acid increased the capsular thickness and may increase the risk of developing capsular contracture around silicone implants. LEVEL OF EVIDENCE II: Evidence was obtained from the well-designed controlled trials without randomization. PMID- 27766404 TI - [Dipyrone (metamizole) : Considerations on monitoring for early detection of agranulocytosis]. AB - BACKGROUND: Dipyrone (metamizole) is a non-opioid analgesic commonly used in Germany, which can, in very rare cases, cause life-threatening agranulocytosis. The prescribing information calls for regular monitoring of the differential blood count in cases of long-term treatment. However, there is uncertainty about how this testing should be handled in practice. OBJECTIVES: Which recommendations can be derived from the published literature for evaluating blood cell counts during treatment with metamizole and which other options for monitoring exist? METHODS: Data from recent epidemiological studies, reviews, and spontaneously reported cases were evaluated. RESULTS: Agranulocytosis can emerge at highly variable intervals ranging from the first day of metamizole treatment to months after treatment has begun. As a result, there is no conclusive, evidence-based recommendation for the time intervals at which blood cell counts should be tested. Therefore, the onset of clinical symptoms should be used as trigger for monitoring blood cell counts to enable early diagnosis and avoid agranulocytosis related complications. In addition to general symptoms like fever, sore throat, fatigue, and muscle pain, mucosal ulcerations, severe angina, and systemic infections leading to sepsis are typical of agranulocytosis. CONCLUSIONS: Providing patients and medical staff with better information about early symptoms of agranulocytosis could be a sensible way to prevent complications. Any suspicion of agranulocytosis should immediately lead to a differential blood count and to the withdrawal of all drugs possibly associated with agranulocytosis. Patients should be monitored and treated according to the severity of their symptoms. PMID- 27766407 TI - The effects of gestational transient thyrotoxicosis on the perinatal outcomes: a case-control study. AB - PURPOSE: To study the effects of gestational transient thyrotoxicosis (GTT) on pregnancy outcomes. METHODS: This case-control study retrospectively analyzed 7976 women with singleton pregnancies whose thyroid function was measured before 16 weeks of gestation and who delivered at >=22 weeks of pregnancy. GTT was defined as hyperthyroidism (free thyroxine [FT4] level: >=95th percentile) in the early pregnancy, which normalized in mid-pregnancy without thyroid-stimulating hormone receptor antibodies. Using data extracted from electronic records, we examined the association between GTT and the pregnancy outcomes (preterm delivery, gestational age at delivery, pregnancy induced hypertension (PIH), preeclampsia, placental abruption, caesarian section, birth weight, low birth weight, Apgar score, cord pH, stillbirth at gestational week >=22, and neonatal death). We classified the cases into quartiles according to their FT4 values during the early pregnancy and investigated the association with the gestational age at delivery. RESULTS: Two hundred and eight cases of GTT and 6317 cases with normal thyroid assessments were reviewed. GTT was associated with hyperemesis gravidarum, but not with stillbirth, preterm delivery, PIH, preeclampsia, placental abruption, or low birth weight. The gestation period was shorter in patients with GTT than in those with a normal thyroid function (38.69 +/- 1.79 vs. 39.07 +/- 1.64 weeks, p < 0.01). Higher FT4 levels during the early pregnancy were associated with earlier delivery (p = 0.02). CONCLUSIONS: GTT was associated with a lower gestational age at delivery but not with adverse pregnancy outcomes. There was a negative correlation between the FT4 values in the early pregnancy and the gestational period. PMID- 27766408 TI - The effect of tourniquet and knee position during wound closure after total knee arthroplasty on early recovery of range of motion: a prospective, randomized study. AB - INTRODUCTION: There is no consensus on the position of the knee joint while performing wound closure after total knee arthroplasty (TKA). Further, there are no studies focusing on the association between early functional outcomes and different wound closure strategies. Therefore, we investigated the effects of tourniquet and knee position during wound closure on early recovery of range of motion (ROM) after primary TKA. To our knowledge, this is the first study to evaluate the influence of both tourniquet and knee position during wound closure in primary TKA. METHODS: One hundred-twenty eligible patients were consecutively enrolled in this study and randomly divided into four groups according to wound closure strategy. Wound closure was either performed with the knee in flexion at 90 degrees or in full extension, with the combination of an inflated or deflated tourniquet. Visual analogue score (VAS), knee ROM, ROM recovery, knee society score (KSS), and wound complications were evaluated in the early postoperative period. RESULTS: After the first postoperative week, ROM recovery in the group with knee in extension and inflated tourniquet was significantly lesser than the two groups with deflated tourniquets. Between the first and fourth postoperative weeks, ROM recovery in the group with knee inflection and deflated tourniquet was significantly higher than the two groups with knee in extension. After the first postoperative week, the visual analog score (VAS) for pain in the group with knee inflection and deflated tourniquet was significantly lesser than the two groups with inflated tourniquets. The differences in the outcomes between the four groups were not significant after the fourth postoperative week. The incidence of wound complications and KSS were not significantly different between the four groups. CONCLUSION: Following TKA, wound closure with the knee in flexion and after deflating the tourniquet significantly decreased postoperative pain and promoted the recovery of ROM in the early postoperative period. PMID- 27766406 TI - CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sezary syndrome: the Sezary signature genes, FCRL3, Tox, and miR-214. AB - Sezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sezary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sezary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sezary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker. PMID- 27766409 TI - Laser tracheobronchoplasty: a novel technique for the treatment of symptomatic tracheobronchomalacia. AB - The management of tracheobronchomalacia is a very challenging problem with few treatment options. This study aims to evaluate the outcomes of a novel surgical treatment for membranous tracheobronchomalacia. A consecutive series of patients with tracheobronchomalacia were treated with two to three holmium laser scarring surgeries of the hyperdynamic tracheal and bronchial walls for the purpose of stiffening them through fibrosis. Patients filled out a Dyspnea Index questionnaire before and after treatment. Ten patients were treated for their tracheobronchomalacia with a mean age of 54 years. Symptoms included severe dyspnea, dry cough, recurrent pulmonary infections, and respiratory failure. Fifty percent of patients presented with wheezing refractory to traditional treatment. Tracheobronchomalacia was associated with gastroesophageal reflux disease (n = 8), obstructive sleep apnea (n = 5), and tracheal stenosis (n = 3). Only 50 % of patients presented with morbid obesity. All cases showed significant improvement of their respiratory symptoms with a mean postoperative difference of 22.3 out of a maximum impairment score of 40 (P < 0.01) on the Dyspnea Index. The mean number of procedures was 2.3 per patient with the average laser energy delivered per procedure of 1600 J. Laser tracheobronchoplasty is a safe, easy to adopt, and effective technique for the treatment of membranous tracheobronchomalacia. It presents a simple alternative to the commonly used procedures like endoluminal stenting and open tracheobronchoplasty. PMID- 27766410 TI - The therapeutic effect of thymoquinone on acoustic trauma-induced hearing loss in rats. AB - Thymoquinone has antioxidant properties. We hypothesized that thymoquinone may prevent or alleviate hearing loss induced by acoustic trauma. We aimed to study thymoquinone's effect on hearing function with distortion-product otoacoustic emissions and auditory brainstem response. Thirty adult Spraque Dawley rats were randomized into four groups following exposure to acoustic trauma for 4 h. Control group (n = 7) did not receive further treatment. Thymoquinone-20 (n = 8) and Thymoquinone-40 (n = 8) received 20 and 40 mg/kg of intraperitoneal thymoquinone, respectively. Corn-oil group (n = 7) received 1 ml of corn oil intraperitoneally. Hearing function of both ears was tested with distortion product otoacoustic emission and auditory brainstem response before, and shortly after acoustic trauma, and 96 h following acoustic trauma. Post-trauma signal/noise ratios and wave V amplitude/latencies of all groups were significantly low compared with pre-trauma values, which indicate no preventive effect of thymoquinone. Rats in Thymoquinone-20 showed a significantly improved distortion-product otoacoustic emission and auditory brainstem response results at 4000 frequency and above in post-treatment tests (p < 0.05). Improvement in Thymoquinone-40 at the same frequencies was insignificantly inferior to Thymoquinone-20, yet superior to control and corn-oil groups (p < 0.05). We conclude that thymoquinone may not prevent acoustic trauma-induced hearing loss, however, at 20 mg/kg for 96 h, may repair the damage. PMID- 27766411 TI - Post-mortem CT: Hounsfield unit profiles obtained in the lungs with respect to the cause of death assessment. AB - Segmentation of the lungs using post-mortem computed tomography (PMCT) data was so far not feasible due to post-mortem changes such as internal livores. Recently, an Osirix plug-in has been developed allowing automatically segmenting lungs also in PMCT data. The aim of this study was to investigate if the Hounsfield unit (HU) profiles obtained in PMCT data of the segmented lung tissue present with specific behaviour in relation to the cause of death. In 105 PMCT data sets of forensic cases, the entire lung volumes were segmented using the Mia Lite plug-in on Osirix. HU profiles of the lungs were generated and correlated to cause of death groups as assessed after forensic autopsy (cardiac death, fatal haemorrhage, craniocerebral injury, intoxication, drowning, hypothermia, hanging and suffocation). Especially cardiac death cases, intoxication cases, fatal haemorrhage cases and hypothermia cases showed very specific HU profiles. In drowning, the profiles showed two different behaviours representing wet and dry drowning. HU profiles rather varied in craniocerebral injury cases, hanging cases as well as in suffocation cases. HU profiles of the lungs segmented from PMCT data may support the cause of death diagnosis as they represent specific morphological changes in the lungs such as oedema, congestion or blood loss. Especially in cardiac death, intoxication, fatal haemorrhage, hypothermia and drowning cases, HU profiles may be very supportive for the forensic pathologist. PMID- 27766412 TI - Reflectance-based determination of age and species of blowfly puparia. AB - Forensic entomology is primarily concerned with the estimation of time since death and involves determination of the age of immature insects colonising decomposing remains. Accurate age determination of puparia is usually accomplished by dissection, which means destructive sampling of evidence. As part of improving abilities to correctly identify species and developmental age, it is highly desirable to have available non-destructive methods. In this study, we acquired external hyperspectral imaging (HSI) data (77 spectral bands, 389-892 nm) from the dorsal and ventral sides of individual puparia of two species of blowfly (Diptera: Calliphoridae), Calliphora dubia Macquart 1855 and Chrysomya rufifacies Macquart 1842. Puparia were dissected to determine the presence/absence of eight internal morphological development characteristics (legs, wings, labella, abdominal segments, antennae, thoracic bristles, orbital/facial bristles and eye colour and arista). Based on linear discriminant analysis and independent validation of HSI data, reflectance features from puparia could be used to successfully (1) distinguish the two species (classification accuracy = 92.5 %), (2) differentiate dorsal and ventral sides of puparia (classification accuracy C. dubia = 81.5 %; Ch. rufifacies = 89.2 %) and (3) predict the presence of these morphological characteristics and therefore the developmental stage of puparia (average classification accuracy using dorsal imaging: C. dubia = 90.3 %; Ch. rufifacies = 94.0 %). The analytical approach presented here provides proof of concept for a direct puparial age relationship (i.e. days since the onset of pupation) between external puparial reflectance features and internal morphological development. Furthermore, this approach establishes the potential for further refinement by using a non-invasive technique to determine the age and developmental stage of blowflies of forensic importance. PMID- 27766416 TI - ? PMID- 27766415 TI - Membrane-tube-type glaucoma shunt device for refractory glaucoma surgery. AB - PURPOSE: To evaluate the safety and efficacy of a novel membrane-tube (MT)-type glaucoma shunt device for refractory glaucoma surgery. The device consists of an expanded polytetrafluoroethylene membranous reservoir, as well as a silicone tube (300-MUm external and 200-MUm internal diameter) with an intraluminal stent. We named the device "Finetube MT". METHODS: The Finetube MT was implanted into 44 glaucomatous eyes that had insufficient intraocular pressure (IOP) control despite medical treatment or previous trabeculectomy. The membranous reservoir was placed underneath the Tenon's capsule, with each end located below the recti muscles; the tube was placed in the anterior chamber through a partial-thickness scleral track. We investigated the baseline and post-operative IOP values, the number of IOP-lowering medications used, and complications. RESULTS: The mean age of the subjects was 51.6 +/- 17.2 years, and the mean follow-up duration was 22.5 +/- 12.0 months. One year after the surgery, the mean IOP had decreased from 32.8 +/- 12.2 mmHg to 16.9 +/- 6.4 mmHg (48.5 % reduction; p < 0.01), and the mean number of IOP-lowering medications used had decreased from 2.5 +/- 0.8 to 1.1 +/- 0.9 (p < 0.01). We considered the surgery as a success when the IOP was between 6 and 21 mmHg, and had been reduced by >= 20 % from baseline; by this standard, the success rate was 92.4 % after 1 year, and 85.0 % after 3 years. Neither postoperative ocular hypotony-related complications nor tube exposure occurred in any case. CONCLUSIONS: The Finetube MT showed promising surgical outcomes as a treatment for refractory glaucoma, with minimal risk of postoperative ocular hypotony or tube-related complications. PMID- 27766413 TI - Conversions in laparoscopic surgery for rectal cancer. AB - BACKGROUND: Laparoscopic surgery offers patients with rectal cancer short-term benefits and similar survival rates as open surgery. However, selecting patients who are suitable candidates for laparoscopic surgery is essential to prevent intra-operative conversion from laparoscopic to open surgery. Clinical and pathological variables were studied among patients who had converted laparoscopic surgeries within the COLOR II trial to improve patient selection for laparoscopic rectal cancer surgery. METHODS: Between January 20, 2004, and May 4, 2010, 1044 patients with rectal cancer enrolled in the COLOR II trial and were randomized to either laparoscopic or open surgery. Of 693 patients who had laparoscopic surgery, 114 (16 %) were converted to open surgery. Predictive factors were studied using multivariate analyses, and morbidity and mortality rates were determined. RESULTS: Factors correlating with conversion were as follows: age above 65 years (OR 1.9; 95 % CI 1.2-3.0: p = 0.003), BMI greater than 25 (OR 2.7; 95 % CI 1.7-4.3: p < 0.001), and tumor location more than 5 cm from the anal verge (OR 0.5; CI 0.3-0.9). Gender was not significantly related to conversion (p = 0.14). In the converted group, blood loss was greater (p < 0.001) and operating time was longer (p = 0.028) compared with the non-converted laparoscopies. Hospital stay did not differ (p = 0.06). Converted procedures were followed by more postoperative complications compared with laparoscopic or open surgery (p = 0.041 and p = 0.042, respectively). Mortality was similar in the laparoscopic and converted groups. CONCLUSIONS: Age above 65 years, BMI greater than 25, and tumor location between 5 and 15 cm from the anal verge were risk factors for conversion of laparoscopic to open surgery in patients with rectal cancer. PMID- 27766414 TI - Combining aneuploidy and dysplasia for colitis' cancer risk assessment outperforms current surveillance efficiency: a meta-analysis. AB - PURPOSE: Cancer risk assessment for ulcerative colitis patients by evaluating histological changes through colonoscopy surveillance is still challenging. Thus, additional parameters of high prognostic impact for the development of colitis associated carcinoma are necessary. This meta-analysis was conducted to clarify the value of aneuploidy as predictor for individual cancer risk compared with current surveillance parameters. METHODS: A systematic web-based search identified studies published in English that addressed the relevance of the ploidy status for individual cancer risk during surveillance in comparison to neoplastic mucosal changes. The resulting data were included into a meta analysis, and odds ratios (OR) were calculated for aneuploidy or dysplasia or aneuploidy plus dysplasia. RESULTS: Twelve studies addressing the relevance of aneuploidy compared to dyplasia were comprehensively evaluated and further used for meta-analysis. The meta-analysis revealed that aneuploidy (OR 5.31 [95 % CI 2.03, 13.93]) is an equally effective parameter for cancer risk assessment in ulcerative colitis patients as dysplasia (OR 4.93 [1.61, 15.11]). Strikingly, the combined assessment of dysplasia and aneuploidy is superior compared to applying each parameter alone (OR 8.99 [3.08, 26.26]). CONCLUSIONS: This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC. PMID- 27766417 TI - ? PMID- 27766418 TI - The effects of high serum growth hormone and IGF-1 levels on bone mineral density in acromegaly. AB - OBJECTIVE: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) play a major role in bone homeostasis. In this study, we aimed to assess bone mineral density (BMD) in active acromegaly. MATERIALS AND METHODS: A total of 29 patients with active acromegaly (age 46.10 +/- 13.27 years; body mass index [BMI]: 29.51 +/- 4.91 kg/m2) and 42 healthy individuals matched for age and BMI (age: 40.35 +/ 11.74 years; BMI: 28.18 +/- 7.35 kg/m2) were included in the study. BMD was measured by DXA. RESULTS: The mean levels of GH and IGF-1 were found to be 12.61 +/- 11.34 ng/ml and 676.47 +/- 316.19 ng/ml in acromegaly, respectively, while the mean levels of GH and IGF-1 were found to be 0.59 +/- 0.81 ng/ml (p = 0.0001) and 178.17 +/- 57.11 ng/ml (p = 0.0001) in the control group, respectively. Only total hip t-score was determined to be significantly lower in acromegaly compared to the control group (p = 0.037). No significant differences were found between the other parameters in DXA and only a positive correlation was found between IGF 1 levels and L1-L4 BMD (r = 0.259, p = 0.029). CONCLUSIONS: Although GH and IGF-1 levels were increased in acromegalic patients, no significant difference was found in terms of vertebral BMD. Only hip t-scores were found to be lower in acromegalic patients, but this low hip t-score did not reach the osteopenic level. The positive correlation between IGF-1 and lumbar vertebral BMD suggested a more prominent effect of IGF-1 on BMD compared to GH. PMID- 27766420 TI - Journal of Bone and Mineral Metabolism Best Paper Award 2016. PMID- 27766419 TI - Endoscopic mini/less open sublay technique (EMILOS)-a new technique for ventral hernia repair. AB - INTRODUCTION: The "MILOS concept" (mini/less open sublay repair) was developed to realize the benefits of minimally invasive surgery and avoid the disadvantages of traditional open techniques in repair of primary and secondary abdominal wall hernias. Utilizing the MILOS concept, the mesh can be placed in the retromuscular position without opening of the abdominal cavity or without the necessity to perform a large skin incision. The dissection of the retromuscular plane may be done by an open technique (MILOS) or endoscopically (EMILOS). PATIENTS AND METHODS: From June 2015 to July 2016, a total of 33 patients were operated using the MILOS concept, 8 patients underwent the original MILOS technique, and 25 patients had the EMILOS operation. The operative steps of this novel endoscopic variation, the EMILOS procedure (endoscopic mini/less open sublay), are described in detail. Operative indications were a midline umbilical, epigastric, or incisional hernia with a coexisting rectus diastasis. In all cases, a large mesh (20 * 30) was implanted in the retromuscular space without any fixation. RESULTS: The average skin incision was 5.2 cm; mean operative time was 157 min and 122 min in the last five cases. The average hospital stay was 3.2 days. The median pain score (VAS) under physical stress (e.g., climbing stairs) was 2.7. CONCLUSION: The EMILOS operation has the potential to become an important supplementary method in the spectrum of surgical techniques for repair of abdominal wall hernias. The technique is reliable, reproducible, and easy to standardize. PMID- 27766421 TI - Local delivery of recombinant human FGF7 enhances bone formation in rat mandible defects. AB - Fibroblast growth factor 7 (FGF7) plays an important role in regulating the proliferation, migration, and differentiation of cells. However, the role of FGF7 in bone formation is not yet fully understood. We examined the effect of FGF7 on bone formation using a rat model of mandible defects. Rats underwent mandible defect surgery and then either scaffold treatment alone (control group) or FGF7 impregnated scaffold treatment (FGF7 group). Micro-CT and histological analyses revealed that the FGF7 group exhibited greater bone formation than did the control group 10 weeks after surgery. With the exception of total porosity (%), all bone parameters had higher values in the FGF7 group than in the control group at each follow-up after surgery. The FGF7 group showed greater expression of osteogenic markers, such as runt-related transcription factor 2, osterix, osteocalcin, bone morphogenetic protein 2, osteopontin, and type I collagen in newly formed bone than did the control group. The delivery of FGF7 also increased the messenger RNA expression of stromal-cell-derived factor 1 (SDF-1) and CXCR4 in newly formed bone in the FGF7 group compared with the control group. Further, addition of exogenous FGF7 induced migration of rat bone marrow stromal cells and increased the expression of SDF-1 and CXCR4 in the cells. Furthermore, the addition of FGF7 augmented mineralization in the cells with increased expression of osteogenic markers, and this augmentation was significantly suppressed by an inhibitor specific for c-Jun N-terminal kinase (SP600125) or extracellular-signal regulated kinase (PD98059). Collectively, these results suggest that local delivery of FGF7 increases bone formation in a mandible defect with enhanced osteogenesis and chemoattraction. PMID- 27766422 TI - Characteristics associated with inter-individual differences in the trajectories of self-reported attentional function in oncology outpatients receiving chemotherapy. AB - PURPOSE: Between 14 and 85 % of patients report noticeable changes in cognitive function during chemotherapy (CTX). The purposes of this study were to determine which demographic, clinical, and symptom characteristics were associated with inter-individual variability in initial levels of attentional function as well as with changes in the trajectories of attentional function in a sample of oncology patients who received two cycles of CTX. METHODS: Oncology outpatients (n = 1329) were recruited from two comprehensive cancer centers, one veteran's affairs hospital, and four community-based oncology programs. The Attentional Function Index (AFI) was used to assess perceived effectiveness in completing daily tasks that required working memory and attention. Hierarchical linear modeling (HLM) was used to evaluate for inter-individual variability in initial levels and in the trajectories of attentional function. RESULTS: Demographic, clinical, and symptom characteristics associated with inter-individual differences of attentional function at enrollment (i.e., intercept) were as follows: employment status, functional status, trait anxiety, depressive symptoms, sleep disturbance, evening fatigue, and morning energy. Gender was the only characteristic associated with inter-individual differences in the trajectories of attentional function. Morning fatigue was the only characteristic associated with both initial levels and the trajectories of attentional function. CONCLUSIONS: Prior to their next dose of CTX, patients reported moderate levels of attentional function that persisted over two cycles of CTX. Many of the clinical and symptom characteristics associated with decrements in attentional function are amenable to interventions. Clinicians need to assess patients for changes in attentional function and associated characteristics and recommend evidence-based interventions. PMID- 27766423 TI - The assessment of ischaemic burden: validation of a functional jeopardy score against cardiovascular magnetic resonance perfusion imaging. AB - AIMS: This study assesses the relationship between classical anatomical jeopardy scores, functional jeopardy scores (combined anatomical and haemodynamic data), and the extent of ischaemia identified on cardiovascular magnetic resonance (CMR) perfusion imaging. METHODS AND RESULTS: In 42 patients with stable angina and suspected coronary artery disease (CAD), CMR perfusion imaging was performed. Fractional Flow Reserve (FFR) was measured in vessels with >=50 % stenosis. The APPROACH and BCIS jeopardy scores were calculated based on QCA results with both a 70 % (APP70 and BCIS70) and a 50 % stenosis (APP50, and BCIS50) used as the threshold for significance, as well as after integration of FFR and compared with the extent of ischaemia identified on CMR. The correlation between the extent of ischaemia measured by CMR and the anatomical jeopardy scores was moderate (APPROACH: r = 0.58; BCIS: r = 0.48, p = 0.001). Integrating physiological information improved this significantly to r = 0.82, p = 0.0001 for APPROACH and r = 0.82, p = 0.0001 for BCIS scores (z-statistic = -2.04, p = 0.04; z-statistic = -2.63, p = 0.009). In relation to CMR, the APPROACH and BCIS scores overestimated the volume of ischaemic myocardium by 29.2 and 25.2 %, respectively, which was reduced to 12.8 and 12 % after integrating functional data. CONCLUSIONS: Anatomical and functional jeopardy scores overestimate ischaemic burden when compared to CMR. Integrating physiological information from FFR to generate a functional score improves ischaemic burden estimation. PMID- 27766424 TI - Anti-MAG autoantibodies are increased in Parkinson's disease but not in atypical parkinsonism. AB - There is emerging evidence that glial cells are involved in the neuropathological process in Parkinson's disease (PD) in addition to degeneration of neuronal structures. Recently, we confirmed the presence of an adaptive immune response against different glial-derived antigens in PD, with a possible role of anti-MAG, anti-MBP and anti-PLP antibodies in the disease progression. The aim of the present study was to assess humoral response against myelin-associated glycoprotein (MAG) in patients with parkinsonism (both idiopathic and atypical) to check whether these antibodies could serve as biomarkers of PD, its severity and progression. Anti-MAG autoantibodies were measured by an ELISA system in 99 PD patients, 33 atypical parkinsonism patients, and 36 control subjects. In PD patients, anti-MAG IgM autoantibodies were significantly higher in comparison to healthy control subjects (p = 0.038). IgM anti-MAG autoantibodies titers were also significantly higher in the whole group of patients with parkinsonism (either idiopathic or atypical) in comparison to healthy control subjects (1.88 +/- 0.84 vs 1.70 +/- 1.19, p = 0.017). This difference was mainly driven by the PD group, as the atypical parkinsonism group did not differ significantly from the control group in anti-MAG antibody levels (p = 0.51). A negative correlation between anti-MAG levels and disease duration was found in PD patients. Our study provides evidence for an increased production of autoantibodies against a protein of glial origin in PD. The negative correlation between anti-MAG antibodies and disease duration may suggest possible involvement of the immune system in disease progression. Increasing evidence that glia are involved in the neurodegenerative process to a greater extent than previously thought may turn out be useful in the search for biomarkers of the neurodegenerative process in PD. PMID- 27766427 TI - Roles of bta-miR-29b promoter regions DNA methylation in regulating miR-29b expression and bovine viral diarrhea virus NADL replication in MDBK cells. AB - MicroRNAs (miRNAs) are an important class of small, non-coding RNAs that control target genes expression by degradation of target mRNAs or by inhibiting protein translation in many biological processes and cellular pathways. In a previous study, we found that miR-29b interfered with bovine viral diarrhea virus (BVDV) replication. However, the mechanisms of regulation of miR-29b expression are not well known. DNA methylation is an important epigenetic mechanism for silencing gene transcription, and plays an important role in promoter choice, protein expression, and regulation of miRNAs expression. In this study, we focused on the roles of DNA methylation of miR-29b promoter in regulating miR-29b expression and investigated the effects of DNA (cytosine-5) methyltransferase 1 (DNMT1) knockdown on miR-29b expression and BVDV (strain NADL) replication. Our results showed that methylation levels of miR-29b promoter were significantly decreased in BVDV NADL-infected MDBK cells. Furthermore, DNMT1 silencing significantly decreased the methylation levels of miR-29b promoter, up-regulated miR-29b expression and inhibited BVDV NADL replication, which supports the important roles of DNA methylation in regulating miRNA expression and further proves an evidence for our previous views. PMID- 27766426 TI - Identification of cleavage of NS5A of C-strain classical swine fever virus. AB - NS5A is a multifunctional non-structural protein of classical swine fever virus (CSFV) that plays an important role in viral replication, but how it exerts its functions is unknown. Here, we report the cleavage of NS5A of the vaccine C strain, resulting in two truncated forms (b and c). Further experiments using calpain- and caspase-family-specific inhibitors, followed by a caspase-6-specific shRNAs and inhibitor, showed that the cleavage of C-strain NS5A to produce truncated form c is mediated by caspase-6, mapping to 272DTTD275, while the cleavage producing truncated form b is probably mediated by another unknown protease. shRNA-mediated downregulation of caspase-6 and blocking of enzyme activity in ST cells significantly impaired genome replication and virus production, indicating that NS5A cleavage is required for CSFV replication. PMID- 27766425 TI - Reduced expression of SETD2 and SNX9 proteins in chemically induced mammary tumorigenesis in Wistar rats: a prognostic histological and proteomic study. AB - Breast cancer is a major global health concern, appealing for precise prognostic approaches. Thus, the need is to have studies focusing on the identification and recognition of preliminary events leading to the disease. The present study reports the tracing of precancerous progression and serum proteomic analysis in a breast cancer model developed as a result of 7,12-dimethylbenz[a]anthracene (DMBA) administration. Mammary gland histological changes of prime importance were examined by histopathology, and immunohistochemical analysis with Ki-67 was performed to monitor enhanced cell proliferation, right from the onset of hyperplasia till neoplasia. Serum proteomics (one-dimensional (1D) and two dimensional (2D) electrophoresis, followed by MALDI-TOF MS characterization) was performed to decipher the differentially expressed serum proteins in animals undergoing tumorigenesis vis-a-vis controls. The significance of our study lies in reporting the significantly reduced expression of two proteins: histone-lysine N-methyltransferase (SETD2) and sorting nexin-9 (SNX9) at very early stage (13 weeks) of tumorigenesis, while the full-fledged tumors developed after 6 months. The reduced expression of SETD2 and SNX9 was validated by western blotting and relative expression analysis using quantitative real-time PCR. These proteins may hence prove as potentially useful tools in search for prognostic markers for the early detection of mammary cancer. PMID- 27766428 TI - Multiple cerebral arterio-venous malformations: impact of multiplicity and hemodynamics on treatment strategies. AB - BACKGROUND: Multiple AVMs are exceptionally rare lesions and only a few larger series have been published, including other vascular pathologies, such as arterio venous fistulae (AVF) or patients with hereditary syndromes. Our study presents clinical, angiographic, and therapeutic characteristics of patients harboring sporadic multiple AVMs. METHODS: Basic demographic data, vascular architecture, clinical presentation, treatment strategies, and treatment outcome were analyzed retrospectively from patients with cerebral AVMs treated in our department between 1990 and 2015. RESULTS: Six out of 539 patients (1.1 %) harbored 15 multiple and distinct cerebral lesions. Nidus size was predominantly small, consequently determining a Spetzler-Martin grade degrees I- degrees II (three tier grading system). In three patients, AVMs shared a proximal feeding artery supply, whereas each AVM displayed its own venous drainage. Five of six patients (83 %) presented with hemorrhage. Four patients received therapy of the AVMs with complete elimination in 3/4 patients (75 %) and 8/9 treated AVMs (89 %). All patients with treatment of the AVM showed good-to-excellent recovery (n = 4, mRS <= 2). CONCLUSIONS: Multiple cerebral AVMs are complex vascular lesions. The multiplicity of hemodynamic and malformation-related variables influence treatment strategy and sequence. Thus, awareness of these parameters (of various malformations before and during treatment) is important. The high number of hemorrhagic events in the present series might justify a more aggressive treatment of multiple AVMs than previously thought. PMID- 27766429 TI - Answer to the Letter to the Editor of J. Li et al. concerning "Surgical treatment of sacral chordoma: survival and prognostic factors" by C. Ruosi et al. (Eur Spine J; 2015; 24(Suppl 7):S912-S917). PMID- 27766430 TI - Transcriptional profiling of arbuscular mycorrhizal roots exposed to high levels of phosphate reveals the repression of cell cycle-related genes and secreted protein genes in Rhizophagus irregularis. AB - The development of arbuscular mycorrhiza (AM) is strongly suppressed under high phosphate (Pi) conditions. To investigate AM fungal responses during the suppression of AM by high Pi, we performed an RNA-seq analysis of Rhizophagus irregularis colonizing Lotus japonicus roots at different levels of Pi (20, 100, 300, and 500 MUM). AM fungal colonization decreased markedly under high-Pi conditions. In total, 163 fungal genes were differentially expressed among the four Pi treatments. Among these genes, a cell cycle-regulatory gene, cyclin dependent kinase CDK1, and several DNA replication- and mitosis-related genes were repressed under high-Pi conditions. More than 20 genes encoding secreted proteins were also downregulated by high-Pi conditions, including the strigolactone-induced putative secreted protein 1 gene that enhances AM fungal colonization. In contrast, the expression of genes related to aerobic respiration and transport in R. irregularis were largely unaffected. Our data suggest that high Pi suppresses the expression of genes associated with fungal cell cycle progression or that encode secreted proteins that may be required for intercellular hyphal growth and arbuscule formation. However, high Pi has little effect on the transcriptional regulation of the primary metabolism or transport in preformed fungal structures. PMID- 27766431 TI - Ilizarov fixation for the treatment of scaphoid nonunion: a novel approach. AB - OBJECTIVES: To evaluate the safety and efficacy of the Ilizarov fine-wire compression/distraction technique in the treatment of scaphoid nonunion (SNU), without the use of bone graft. DESIGN: This is a prospective study of 20 consecutive patients in one center. PATIENTS AND METHODS: This study included 20 patients (19 males) with a mean SNU duration of 14.5 months. Four patients had proximal pole, 15 had waist, and 1 had a distal SNU. Patients with carpal instability, humpback deformities, carpal collapse, avascular necrosis, and marked degenerative change were excluded. Following frame application, the treatment comprises three stages: The frame is distracted by 1 mm per day until the radiographs show a 2-3 mm opening at the SNU site (mean 10 days); the SNU site is compressed for 5 days, at a rate of 1 mm per day, with the wrist in 15 degrees of flexion and 15 degrees of radial deviation; the wrist is then immobilized in the Ilizarov fixator for 8 weeks. RESULTS: Radiographic (radiography and CT scan) and clinical bony union was achieved in all 20 patients after a mean of 90.3 days (70-130 days). All patients returned to their pre injury occupations. Thirteen patients had excellent results, four good, and three fair, according to the Mayo wrist score. CONCLUSIONS: In these selected patients, this technique safely achieved bony union without the need to open the SNU site and without the requirement of bone graft. PMID- 27766396 TI - Safety of Nonsteroidal Anti-inflammatory Drugs in Major Gastrointestinal Surgery: A Prospective, Multicenter Cohort Study. AB - BACKGROUND: Significant safety concerns remain surrounding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) following gastrointestinal surgery, leading to wide variation in their use. This study aimed to determine the safety profile of NSAIDs after major gastrointestinal surgery. METHODS: Consecutive patients undergoing elective or emergency abdominal surgery with a minimum one night stay during a 3-month study period were eligible for inclusion. The administration of any NSAID within 3 days following surgery was the main independent variable. The primary outcome measure was the 30-day postoperative major complication rate, as defined by the Clavien-Dindo classification (Clavien Dindo III-V). Propensity matching with multivariable logistic regression was used to produce odds ratios (OR) and 95 % confidence intervals. RESULTS: From 9264 patients, 23.9 % (n = 2212) received postoperative NSAIDs. The overall major complication rate was 11.5 % (n = 1067). Following propensity matching and adjustment, use of NSAIDs were not significantly associated with any increase in major complications (OR 0.90, 0.60-1.34, p = 0.560). CONCLUSIONS: Early use of postoperative NSAIDs was not associated with an increase in major complications following gastrointestinal surgery. PMID- 27766435 TI - Role of local excision in the management of rectal cancer: what does the future hold? PMID- 27766432 TI - Multiple sclerosis: experimental models and reality. AB - One of the most frequent statements, provided in different variations in the introduction of experimental studies on multiple sclerosis (MS), is that "Multiple sclerosis is a demyelinating autoimmune disease and experimental autoimmune encephalomyelitis (EAE) is a suitable model to study its pathogenesis". However, so far, no single experimental model covers the entire spectrum of the clinical, pathological, or immunological features of the disease. Many different models are available, which proved to be highly useful for studying different aspects of inflammation, demyelination, remyelination, and neurodegeneration in the central nervous system. However, the relevance of results from such models for MS pathogenesis has to be critically validated. Current EAE models are mainly based on inflammation, induced by auto-reactive CD4+ T-cells, and these models reflect important aspects of MS. However, pathological data and results from clinical trials in MS indicate that CD8+ T cells and B-lymphocytes may play an important role in propagating inflammation and tissue damage in established MS. Viral models may reflect key features of MS like inflammatory demyelination, but are difficult to use due to their very complex pathogenesis, involving direct virus-induced and immune-mediated mechanisms. Furthermore, evidence for a role of viruses in MS pathogenesis is indirect and limited, and an MS-specific virus infection has not been identified so far. Toxic models are highly useful to unravel mechanisms of de- and remyelination, but do not reflect other important aspects of MS pathology and pathogenesis. For all these reasons, it is important to select the right experimental model to answer specific questions in MS research. PMID- 27766433 TI - Midbrain Synchrony to Envelope Structure Supports Behavioral Sensitivity to Single-Formant Vowel-Like Sounds in Noise. AB - Vowels make a strong contribution to speech perception under natural conditions. Vowels are encoded in the auditory nerve primarily through neural synchrony to temporal fine structure and to envelope fluctuations rather than through average discharge rate. Neural synchrony is thought to contribute less to vowel coding in central auditory nuclei, consistent with more limited synchronization to fine structure and the emergence of average-rate coding of envelope fluctuations. However, this hypothesis is largely unexplored, especially in background noise. The present study examined coding mechanisms at the level of the midbrain that support behavioral sensitivity to simple vowel-like sounds using neurophysiological recordings and matched behavioral experiments in the budgerigar. Stimuli were harmonic tone complexes with energy concentrated at one spectral peak, or formant frequency, presented in quiet and in noise. Behavioral thresholds for formant-frequency discrimination decreased with increasing amplitude of stimulus envelope fluctuations, increased in noise, and were similar between budgerigars and humans. Multiunit recordings in awake birds showed that the midbrain encodes vowel-like sounds both through response synchrony to envelope structure and through average rate. Whereas neural discrimination thresholds based on either coding scheme were sufficient to support behavioral thresholds in quiet, only synchrony-based neural thresholds could account for behavioral thresholds in background noise. These results reveal an incomplete transformation to average-rate coding of vowel-like sounds in the midbrain. Model simulations suggest that this transformation emerges due to modulation tuning, which is shared between birds and mammals. Furthermore, the results underscore the behavioral relevance of envelope synchrony in the midbrain for detection of small differences in vowel formant frequency under real-world listening conditions. PMID- 27766434 TI - MG132 plus apoptosis antigen-1 (APO-1) antibody cooperate to restore p53 activity inducing autophagy and p53-dependent apoptosis in HPV16 E6-expressing keratinocytes. AB - The E6 oncoprotein can interfere with the ability of infected cells to undergo programmed cell death through the proteolytic degradation of proapoptotic proteins such as p53, employing the proteasome pathway. Therefore, inactivation of the proteasome through MG132 should restore the activity of several proapoptotic proteins. We investigated whether in HPV16 E6-expressing keratinocytes (KE6 cells), the restoration of p53 levels mediated by MG132 and/or activation of the CD95 pathway through apoptosis antigen-1 (APO-1) antibody are responsible for the induction of apoptosis. We found that KE6 cells underwent apoptosis mainly after incubation for 24 h with MG132 alone or APO-1 plus MG132. Both treatments activated the extrinsic and intrinsic apoptosis pathways. Autophagy was also activated, principally by APO-1 plus MG132. Inhibition of E6 mediated p53 proteasomal degradation by MG132 resulted in the elevation of p53 protein levels and its phosphorylation in Ser46 and Ser20; the p53 protein was localized mainly at nucleus after treatment with MG132 or APO-1 plus MG132. In addition, induction of its transcriptional target genes such as p21, Bax and TP53INP was observed 3 and 6 h after treatment. Also, LC3 mRNA was induced after 3 and 6 h, which correlates with lipidation of LC3B protein and induction of autophagy. Finally, using pifithrin alpha we observed a decrease in apoptosis induced by MG132, and by APO-1 plus MG132, suggesting that restoration of APO-1 sensitivity occurs in part through an increase in both the levels and the activity of p53. The use of small molecules to inhibit the proteasome pathway might permit the activation of cell death, providing new opportunities for CC treatment. PMID- 27766436 TI - Kinetic and microbial community analysis of methyl ethyl ketone biodegradation in aquifer sediments. AB - Methyl ethyl ketone (MEK) is a common groundwater contaminant often present with more toxic compounds of primary interest. Because of this, few studies have been performed to determine the effect of microbial community structure on MEK biodegradation rates in aquifer sediments. Here, microcosms were prepared with aquifer sediments containing MEK following a massive spill event and compared to laboratory-spiked sediments, with MEK biodegradation rates quantified under mixed aerobic/anaerobic conditions. Biodegradation was achieved in MEK-contaminated site sediment microcosms at about half of the solubility (356 mg/L) with largely Firmicutes population under iron-reducing conditions. MEK was biodegraded at a higher rate [4.0 +/- 0.74 mg/(L days)] in previously exposed site samples compared to previously uncontaminated sediments [0.51 +/- 0.14 mg/(L days)]. Amplicon sequencing and denaturing gradient gel electrophoresis of 16S rRNA genes were combined to understand the relationship between contamination levels, biodegradation, and community structure across the plume. More heavily contaminated sediments collected from an MEK-contaminated field site had the most similar communities than less contaminated sediments from the same site despite differences in sediment texture. The more diverse microbial community observed in the laboratory-spiked sediments reduced MEK concentration 47 % over 92 days. Results of this study suggest lower rates of MEK biodegradation in iron-reducing aquifer sediments than previously reported for methanogenic conditions and biodegradation rates comparable to previously reported nitrate- and sulfate reducing conditions. PMID- 27766437 TI - Biological degradation of 4-chlorobenzoic acid by a PCB-metabolizing bacterium through a pathway not involving (chloro)catechol. AB - Cupriavidus sp. strain SK-3, previously isolated on polychlorinated biphenyl mixtures, was found to aerobically utilize a wide spectrum of substituted aromatic compounds including 4-fluoro-, 4-chloro- and 4-bromobenzoic acids as a sole carbon and energy source. Other chlorobenzoic acid (CBA) congeners such as 2 , 3-, 2,3-, 2,5-, 3,4- and 3,5-CBA were all rapidly transformed to respective chlorocatechols (CCs). Under aerobic conditions, strain SK-3 grew readily on 4 CBA to a maximum concentration of 5 mM above which growth became impaired and yielded no biomass. Growth lagged significantly at concentrations above 3 mM, however chloride elimination was stoichiometric and generally mirrored growth and substrate consumption in all incubations. Experiments with resting cells, cell free extracts and analysis of metabolite pools suggest that 4-CBA was metabolized in a reaction exclusively involving an initial hydrolytic dehalogenation yielding 4-hydroxybenzoic acid, which was then hydroxylated to protocatechuic acid (PCA) and subsequently metabolized via the beta-ketoadipate pathway. When strain SK-3 was grown on 4-CBA, there was gratuitous induction of the catechol-1,2 dioxygenase and gentisate-1,2-dioxygenase pathways, even if both were not involved in the metabolism of the acid. While activities of the modified ortho- and meta-cleavage pathways were not detectable in all extracts, activity of PCA 3,4-dioxygenase was over ten-times higher than those of catechol-1,2- and gentisate-1,2-dioxygenases. Therefore, the only reason other congeners were not utilized for growth was the accumulation of CCs, suggesting a narrow spectrum of the activity of enzymes downstream of benzoate-1,2-dioxygenase, which exhibited affinity for a number of substituted analogs, and that the metabolic bottlenecks are either CCs or catabolites of the modified ortho-cleavage metabolic route. PMID- 27766438 TI - Light effects on the multicellular magnetotactic prokaryote 'Candidatus Magnetoglobus multicellularis' are cancelled by radiofrequency fields: the involvement of radical pair mechanisms. AB - 'Candidatus Magnetoglobus multicellularis' is the most studied multicellular magnetotactic prokaryote. It presents a light-dependent photokinesis: green light decreases the translation velocity whereas red light increases it, in comparison to blue and white light. The present article shows that radio-frequency electromagnetic fields cancel the light effect on photokinesis. The frequency to cancel the light effect corresponds to the Zeeman resonance frequency (DC magnetic field of 4 Oe and radio-frequency of 11.5 MHz), indicating the involvement of a radical pair mechanism. An analysis of the orientation angle relative to the magnetic field direction shows that radio-frequency electromagnetic fields disturb the swimming orientation when the microorganisms are illuminated with red light. The analysis also shows that at low magnetic fields (1.6 Oe) the swimming orientation angles are well scattered around the magnetic field direction, showing that magnetotaxis is not efficiently in the swimming orientation to the geomagnetic field. The results do not support cryptochrome as being the responsible chromophore for the radical pair mechanism and perhaps two different chromophores are necessary to explain the radio frequency effects. PMID- 27766440 TI - The Effect of Pleistocene Climate Fluctuations on Distribution of European Abalone (Haliotis tuberculata), Revealed by Combined Mitochondrial and Nuclear Marker Analyses. AB - The genetic differentiation among the populations of the European abalone Haliotis tuberculata was investigated using different markers to better understand the evolutionary history and exchanges between populations. Three markers were used: mitochondrial cytochrome oxidase I (COI), the sperm lysin nuclear gene, and eight nuclear microsatellites. These markers present different characteristics concerning mutation rate and inheritance, which provided complementary information about abalone history and gene diversity. Genetic diversity and relationships among subspecies were calculated from a sample of approximately 500 individuals, collected from 17 different locations in the north eastern Atlantic Ocean, Macaronesia, and Mediterranean Sea. COI marker was used to explore the phylogeny of the species with a network analysis and two phylogenetic methods. The analysis revealed 18 major haplotypes grouped into two distinct clades with a pairwise sequence divergence up to 3.5 %. These clades do not correspond to subspecies but revealed many contacts along Atlantic coast during the Pleistocene interglaciations. The sperm lysin gene analysis separated two different subtaxa: one associated to Macaronesian islands, and the other to all other populations. Moreover, a small population of the northern subtaxon was isolated in the Adriatic Sea-probably before the separation of the two lineages and evolved independently. Microsatellites were analyzed by different genetics methods, including the Bayesian clustering method and migration patterns analysis. It revealed genetically distinct microsatellite patterns among populations from Mediterranean Sea, Brittany and Normandy, Morocco, and Canary and Balearic islands. Gene flow is asymmetric among the regions; the Azores and the Canary Islands are particularly isolated and have low effective population sizes. Our results support the hypothesis that climate changes since the Pleistocene glaciations have played a major role in the geographic distribution of the European abalone. Traces of these events related to maternal inheritance were shown on COI marker. PMID- 27766439 TI - delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS): discovery and perspectives. AB - The delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) tripeptide is the first dedicated intermediate in the biosynthetic pathway leading to the penicillin and cephalosporin classes of beta-lactam natural products in bacteria and fungi. It is synthesized nonribosomally by the ACV synthetase (ACVS) enzyme, which has been purified and partially characterized from many sources. Due to its large size and instability, many details regarding the reaction mechanism of ACVS are still not fully understood. In this review we discuss the chronology and associated methodology that led to the discovery of ACVS, some of the main findings regarding its activities, and some recent/current studies being conducted on the enzyme. In addition, we conclude with perspectives on what can be done to increase our understating of this very important protein in the future. PMID- 27766441 TI - Cryptosporidiosis Risk in New Zealand Children Under 5 Years Old is Greatest in Areas with High Dairy Cattle Densities. AB - The public health risks associated with dairy farming intensification are an emerging concern. We examine the association between dairy cattle density and cryptosporidiosis risk in children <5 years old in New Zealand from 1997 to 2008, a period of rapid intensification of the dairy industry. Multi-level Poisson regression was used to model reported cryptosporidiosis (N = 3869 cases) incidence in relation to dairy cattle densities across urban and rural areas separately, after controlling for microbiological quality of public drinking water supplies and neighbourhood socio-economic factors using the Census Area Unit of residence. Within urban areas, the risk of cryptosporidiosis in children less than 5 years old was significantly, positively associated with medium and high dairy cattle density IRR 1.3 (95% CI 1.2, 1.5) and 1.5 (95% CI 1.2, 1.9) respectively, when compared to areas with no dairy cattle. Within rural areas, the incidence risk of cryptosporidiosis in children less than 5 years old were significantly, positively associated with medium and high dairy cattle density: IRR 1.7 (95% CI 1.3, 2.3) and 2.0 (95% CI 1.5, 2.8) respectively, when compared to areas with no dairy cattle. These results have public health implications for children living on and in proximity to intensively stocked dairy cattle farms. PMID- 27766442 TI - Synergistic effect of high-intensity focused ultrasound and low-fluence Q switched Nd:YAG laser in the treatment of the aging neck and decolletage. AB - High-intensity focused ultrasound (HIFU) is regarded as an effective skin-lifting device; however, literature regarding treatment of the aging neck and decolletage with HIFU is scarce. Our study aimed to evaluate the efficacy of combination with HIFU and low-fluence Q-switched Nd:YAG (LQSNY) laser on the aging neck and decolletage. Nineteen women were assessed. HIFU at two visits and LQSNY laser at six visits were used to irradiate the neck and chest. At week 16, improvements were rated using the Dedo classification, Fabi/Bolton Chest Wrinkle Scale (FBCWS), and Global Aesthetic Improvement Scales (GAIS). Erythema and melanin indices (EMIs) and cervicomental angle were measured. Subject GAIS and satisfaction were evaluated at follow-up visits. At week 16, neck sagging and chest rhytides were improved on Dedo classification and FBCWS, respectively. Pigmentation and rhytides of the neck and chest were rated as improved in 30 % or more of the subjects by physician GAIS and in approximately 80 % of the subjects by subject GAIS. The above differences seemed to be attributable to the initial expectation level and mild severity pertaining to dress custom in Korea. Eighty four percent of subjects were satisfied with treatment outcomes. EMIs were decreased on the chest. The combination of HIFU and LQSNY is an effective treatment option to mitigate rhytides and pigmentation of the neck and decolletage. PMID- 27766443 TI - Improved Screening Mammogram Workflow by Maximizing PACS Streamlining Capabilities in an Academic Breast Center. AB - The aim of this study was to perform an operational improvement project targeted at the breast imaging reading workflow of mammography examinations at an academic medical center with its associated breast centers and satellite sites. Through careful analysis of the current workflow, two major issues were identified: stockpiling of paperwork and multiple worklists. Both issues were considered to cause significant delays to the start of interpreting screening mammograms. Four workflow changes were suggested (scanning of paperwork, worklist consolidation, use of chat functionality, and tracking of case distribution among trainees) and implemented in July 2015. Timestamp data was collected 2 months before (May-Jun) and after (Aug-Sep) the implemented changes. Generalized linear models were used to analyze the data. The results showed significant improvements for the interpretation of screening mammograms. The average time elapsed for time to open a case reduced from 70 to 28 min (60 % decrease, p < 0.001), report turn-around time with preliminary signature decreased from 151 to 107 min (29 % decrease, p < 0.001), and report turn-around time final signature from 153 to 139 min (9 % decrease, p = 0.002). These improvements were achieved while keeping the efficiency of the workflow for diagnostic mammograms at large unaltered even with increased volume of mammography examinations (31 % increase of 4344 examinations for May-Jun to 5678 examinations for Aug-Sep). In conclusion, targeted efforts to improve the breast imaging reading workflow for screening mammograms in a teaching environment provided significant performance improvements without affecting the workflow of diagnostic mammograms. PMID- 27766444 TI - Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease. AB - CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease, previously known as classic juvenile neuronal ceroid lipofuscinosis, NCL) is a pediatric-onset progressive neurodegenerative disease characterized by progressive vision loss, seizures, loss of cognitive and motor function, and early death. While no precise biochemical mechanism or therapies are known, the pathogenesis of CLN3 disease involves intracellular calcium accumulation that may trigger apoptosis. Our prior work in in vitro cell models of CLN3 deficiency suggested that FDA-approved calcium channel antagonists may have therapeutic value. To further evaluate the potential efficacy of this approach in an otherwise untreatable disorder, we sought to compare the therapeutic effects and underlying mechanisms in an animal model of CLN3 disease. Here, we used the well-characterized XT7 complete cln-3 knockout strain of C. elegans to evaluate the therapeutic efficacy of calcium channel antagonist therapy in a living animal model of Batten disease. Therapeutic effects of five calcium channel antagonists were evaluated on XT7 animal lifespan and in vivo mitochondrial physiology. Remarkably, maximal therapeutic efficacy in this model animal was observed with 1 MUM flunarizine, the identical concentration previously identified in cell-based neuronal models of CLN3 disease. Specifically, flunarizine rescued the short lifespan of XT7 worms and prevented their pathophysiologic mitochondrial accumulation. These results confirm the treatment efficacy and dosing of flunarizine in cln-3 disease in a translational model organism. Clinical treatment trials in CLN3 human patients are now needed to test the dosing regimen and efficacy of flunarizine in individuals suffering with this otherwise untreatable and ultimately lethal neurologic disease. PMID- 27766445 TI - Cystic parathyroid glands in MEN1: A rare entity? AB - Approximately 300 cases of sporadic parathyroid cyst (PCs) have been reported to date. Only two cases have been described in MEN1 so far. Detection by imaging could be challenging, especially in multiglandular primary hyperparathyroidism (HPT) and clinical outcome could be different. During the period 1990-2014, 71 MEN1 patients were operated for primary hyperparathyroidism in our centre. We report three cases of PCs in MEN1 patients affected by HPT, who underwent a total or subtotal parathyroidectomy with transcervical thymectomy. In our series, all three patients had an unsatisfactory postoperative course, at variance with the high percentage (over 90 %) of long-term success in MEN1 patients operated at our centre. One patient affected by cystic degeneration of all the four parathyroid glands reported persistent hypoparathyroidism, despite autografts of parathyroid tissue. For the other two cases, surgery failed to cure hyperparathyroidism, perhaps because of the presence of undetected ectopic parathyroid tissue. In the context of a multiglandular disease such as MEN1 syndrome, PCs seem rare but our experience shows about a 4 % incidence. Furthermore their presence, even in expert hands, could affect the preoperative identification of the parathyroid glands due to the difficult differential diagnosis between PC and other cystic lesions of the neck, and intraoperative detection of the glands as well as the postoperative outcome. PMID- 27766446 TI - Data analysis algorithm for DamID-seq profiling of chromatin proteins in Drosophila melanogaster. AB - Analysis of gene expression regulation typically requires identification of genomic sites bound by regulatory proteins. For this purpose, chromatin immunoprecipitation (ChIP) and Dam identification (DamID) methods can be applied to cell lines, whole organisms, or enriched cell populations. In this work, we present modifications to the experimental DamID protocol, as well as a custom data processing algorithm, that allow to confidently identify genomic sites enriched with the proteins of interest. This algorithm is implemented in Perl and is also available as executable files, thereby making DamID analysis relatively straightforward. Finally, we demonstrate how this pipeline performs when fed with real experimental data. PMID- 27766448 TI - Social Support in a Virtual Community: Analysis of a Clinic-Affiliated Online Support Group for Persons Living with HIV/AIDS. AB - Social support can improve outcomes for people living with HIV (PLWH) and could be provided through online support groups. The Positive Links smartphone app is a multicomponent intervention that allows users to interact in a clinic-affiliated anonymous online support group. We investigated how social support was exchanged in a group of 55 participants over 8 months, using an adaptation of the Social Support Behavior Code. Participant interviews assessed their experiences and perceptions of the app. Of 840 posts analyzed, 115 (14 %) were coded as eliciting social support and 433 (52 %) as providing social support. Messages providing support were predominantly emotional (41 %), followed by network (27 %), esteem (24 %), informational (18 %), and instrumental (2 %) support. Participants perceived connection and support as key benefits of the app. Technical issues and interpersonal barriers limited some participants in fully using the app. Mobile technology offers a useful tool to reach populations with barriers to in-person support and may improve care for PLWH. PMID- 27766450 TI - Erratum to: Association Between Celiac Disease and Asthma. PMID- 27766447 TI - Relationship Between beta-Amyloid and Mitochondrial Dynamics. AB - Mitochondria as dynamic organelles undergo morphological changes through the processes of fission and fusion which are major factors regulating their functions. A disruption in the balance of mitochondrial dynamics induces functional disorders in mitochondria such as failed energy production and the generation of reactive oxygen species, which are closely related to pathophysiological changes associated with Alzheimer's disease (AD). Recent studies have demonstrated a relationship between abnormalities in mitochondrial dynamics and impaired mitochondrial function, clarifying the effects of morphofunctional aberrations which promote neuronal cell death in AD. Several possible signaling pathways have been suggested for a better understanding of the mechanism behind the key molecules regulating mitochondrial morphologies. However, the exact machinery involved in mitochondrial dynamics still has yet to be elucidated. This paper reviews the current knowledge on signaling mechanisms involved in mitochondrial dynamics and the significance of mitochondrial dynamics in controlling associated functions in neurodegenerative diseases, particularly in AD. PMID- 27766449 TI - A Case of Thiopurine-Induced Acute Myocarditis in a Patient with Ulcerative Colitis. PMID- 27766452 TI - Erratum to: Patterns of multidisciplinary care in the management of non metastatic invasive breast cancer in the United States Medicare patient. PMID- 27766451 TI - High prevalence of subclinical atherosclerosis in Brazilian postmenopausal women with low and intermediate risk by Framingham score. AB - Cardiovascular diseases are the leading cause of mortality among women in several countries. Early detection of subclinical atherosclerosis (SA) could enable the adoption of preventive measures to avoid cardiovascular events. This study aimed to determine the prevalence of SA in Brazilian asymptomatic postmenopausal women in Framingham Risk Score (FRS) low and intermediate groups. Computed tomography (CT) and ultrasound (US) scans were performed in 138 asymptomatic postmenopausal women (56.1 +/- 4.9 years of age) to survey for coronary artery and aortic calcification (CT scan) and assess carotid intima-media thickness (CIMT) and identify carotid plaques (US). The mean FRS was 2.64 +/- 2.13 %. The prevalence of increased CIMT, carotid plaques, increased CIMT and/or plaques, coronary artery calcification (CAC) >0 and aortic calcification (AC) were, respectively, 45.7, 37.7, 62.3, 23.9 and 45.7 %. Normal imaging tests were found in 22.4 %. SA, defined as at least one abnormal imaging test, was associated with age, FRS, waist-to-rip ratio, systolic and diastolic blood pressure, HDL-c and ApoA1 levels, and ApoA1/ApoB ratio. In logistic regression, SA was associated with higher age (OR 1.108, 95 % CI 1.010-1.215, p = 0.029) and lower ApoA1 levels (OR 0.979, 95 % CI 0.960-0.998, p = 0.029). SA was prevalent in Brazilian postmenopausal women with low and intermediate risk groups (FRS) and was associated with higher age and lower levels of ApoA1. Carotid atherosclerosis was the most common presentation of SA in this group. PMID- 27766453 TI - Use of complementary and alternative medicine and breast cancer survival in the Health, Eating, Activity, and Lifestyle Study. AB - PURPOSE: Use of complementary and alternative medicine (CAM) is common among breast cancer patients, but less is known about whether CAM influences breast cancer survival. METHODS: Health Eating, Activity, and Lifestyle (HEAL) Study participants (n = 707) were diagnosed with stage I-IIIA breast cancer. Participants completed a 30-month post-diagnosis interview including questions on CAM use (natural products such as dietary and botanical supplements, alternative health practices, and alternative medical systems), weight, physical activity, and comorbidities. Outcomes were breast cancer-specific and total mortality, which were ascertained from the Surveillance Epidemiology and End Results registries in Western Washington, Los Angeles County, and New Mexico. Cox proportional hazards regression models were fit to data to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for mortality. Models were adjusted for potential confounding by sociodemographic, health, and cancer-related factors. RESULTS: Among 707 participants, 70 breast cancer-specific deaths and 149 total deaths were reported. 60.2 % of participants reported CAM use post-diagnosis. The most common CAM were natural products (51 %) including plant-based estrogenic supplements (42 %). Manipulative and body-based practices and alternative medical systems were used by 27 and 13 % of participants, respectively. No associations were observed between CAM use and breast cancer-specific (HR 1.04, 95 % CI 0.61 1.76) or total mortality (HR 0.91, 95 % CI 0.63-1.29). CONCLUSION: Complementary and alternative medicine use was not associated with breast cancer-specific mortality or total mortality. Randomized controlled trials may be needed to definitively test whether there is harm or benefit from the types of CAM assessed in HEAL in relation to mortality outcomes in breast cancer survivors. PMID- 27766454 TI - Delivering on the Promise of Pheromones - Part 2. PMID- 27766455 TI - Tardigrades in Space Research - Past and Future. AB - To survive exposure to space conditions, organisms should have certain characteristics including a high tolerance for freezing, radiation and desiccation. The organisms with the best chance for survival under such conditions are extremophiles, like some species of Bacteria and Archea, Rotifera, several species of Nematoda, some of the arthropods and Tardigrada (water bears). There is no denying that tardigrades are one of the toughest animals on our planet and are the most unique in the extremophiles group. Tardigrada are very small animals (50 to 2,100 MUm in length), and they inhabit great number of Earth environments. Ever since it was proven that tardigrades have high resistance to the different kinds of stress factors associated with cosmic journeys, combined with their relatively complex structure and their relative ease of observation, they have become a perfect model organism for space research. This taxon is now the focus of astrobiologists from around the world. Therefore, this paper presents a short review of the space research performed on tardigrades as well as some considerations for further studies. PMID- 27766456 TI - Erratum to: Atypical and malignant granular cell tumors in Japan: a Japanese Musculoskeletal Oncology Group (JMOG) study. PMID- 27766457 TI - Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations. AB - BACKGROUND: The oculocerebrorenal syndrome of Lowe gene (OCRL) is located on chromosome Xq25-26 and encodes an inositol polyphosphate-5-phosphatase (OCRL-1). Mutations in this gene cause Lowe syndrome (LS) or type 2 Dent disease, of which low-molecular-weight (LMW) proteinuria is a characteristic feature. Megalin is considered to play an important role in the development of renal tubular proteinuria. Two forms of megalin are excreted into the urine: full-length megalin (C-megalin) and megalin ectodomain (A-megalin). We have explored the role of megalin in the development of LMW proteinuria in patients with OCRL mutations by determining urinary megalin fractions. METHODS: We measured A- and C-megalin in spot urine samples from five male patients with OCRL mutations (median age 9 years), using sandwich enzyme-linked immunosorbent assays, and adjusted the obtained values for excreted creatinine. The results were compared with those of 50 control subjects and one patient with type 1 Dent disease (T1D). RESULTS: All patients demonstrated normal levels of urinary C-megalin. However, patients with OCRL mutations or T1D showed abnormally low levels of urinary A-megalin, with the exception of one 5-year-old boy with LS, who was the youngest patient enrolled in the study. CONCLUSIONS: Decreased excretion of urinary A-megalin in four out of five patients with OCRL mutations suggests that LMW proteinuria may be caused by impaired megalin recycling within the proximal tubular cells. Homologous enzymes, similar to inositol polyphosphate-5-phosphatase B in mice, may help to compensate for defective OCRL-1 function during early childhood. PMID- 27766459 TI - Absolute Power Spectral Density Changes in the Magnetoencephalographic Activity During the Transition from Childhood to Adulthood. AB - The aim of this study was to define the pattern of reduction in absolute power spectral density (PSD) of magnetoencephalography (MEG) signals throughout development. Specifically, we wanted to explore whether the human skull's high permeability for electromagnetic fields would allow us to question whether the pattern of absolute PSD reduction observed in the human electroencephalogram is due to an increase in the skull's resistive properties with age. Furthermore, the topography of the MEG signals during maturation was explored, providing additional insights about the areas and brain rhythms related to late maturation in the human brain. To attain these goals, spontaneous MEG activity was recorded from 148 sensors in a sample of 59 subjects divided into three age groups: children/adolescents (7-14 years), young adults (17-20 years) and adults (21-26 years). Statistical testing was carried out by means of an analysis of variance (ANOVA), with "age group" as between-subject factor and "sensor group" as within subject factor. Additionally, correlations of absolute PSD with age were computed to assess the influence of age on the spectral content of MEG signals. Results showed a broadband PSD decrease in frontal areas, which suggests the late maturation of this region, but also a mild increase in high frequency PSD with age in posterior areas. These findings suggest that the intensity of the neural sources during spontaneous brain activity decreases with age, which may be related to synaptic pruning. PMID- 27766458 TI - Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability. AB - BACKGROUND: More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS-the underlying genetic factors contributing to phenotypic variation. Part of the "missing heritability" for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless have a sufficient impact on protein function to cause disease. However, systematic evaluation in patients with NS for rare or low frequency risk alleles within single genes, or in combination across genes ("oligogenicity"), has not been reported. To determine whether, compared with a reference population, patients with NS have either a significantly increased burden of protein-altering variants ("risk-alleles"), or a unique combination of them ("oligogenicity"), in a set of 21 genes implicated in Mendelian forms of NS. METHODS: In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it with a variant call set of the same genes in a reference population composed of 2,535 individuals from phase 3 of the 1000 Genomes Project. We created both a "stringent" and a "relaxed" pathogenicity filtering pipeline, applied them to both cohorts, and computed the burden of variants in the entire gene set per cohort, the burden of variants in the entire gene set per individual, the burden of variants within a single gene per cohort, and unique combinations of variants across two or more genes per cohort. RESULTS: With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have a significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence for oligogenicity. This was true when using both the relaxed and the stringent variant pathogenicity filter. CONCLUSION: In our study, there were no significant differences in the burden or particular combinations of low-frequency or rare protein-altering variants in a previously implicated Mendelian NS genes cohort between North American patients with NS and a reference population. Studies in larger independent cohorts or meta analyses are needed to assess the generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases that was undetectable with this current sample size. It is still possible that rare protein-altering variants in these genes, insufficient to cause Mendelian disease, still contribute to NS as risk alleles and/or via oligogenicity. However, we suggest that more accurate bioinformatic analyses and the incorporation of functional assays would be necessary to identify bona fide instances of this form of genetic architecture as a contributor to the heritability of NS. PMID- 27766460 TI - Five novel transcription factors as potential regulators of OsNHX1 gene expression in a salt tolerant rice genotype. AB - KEY MESSAGE: This manuscript reports the identification and characterization of five transcription factors binding to the promoter of OsNHX1 in a salt stress tolerant rice genotype (Hasawi). Although NHX1 encoding genes are known to be highly regulated at the transcription level by different abiotic stresses, namely salt and drought stress, until now only one transcription factor (TF) binding to its promoter has been reported. In order to unveil the TFs regulating NHX1 gene expression, which is known to be highly induced under salt stress, we have used a Y1H system to screen a salt induced rice cDNA expression library from Hasawi. This approach allowed us to identify five TFs belonging to three distinct TF families: one TCP (OsPCF2), one CPP (OsCPP5) and three NIN-like (OsNIN-like2, OsNIN-like3 and OsNIN-like4) binding to the OsNHX1 gene promoter. We have also shown that these TFs act either as transcriptional activators (OsPCF2, OsNIN like4) or repressors (OsCPP5, OsNIN-like2) and their encoding genes are differentially regulated by salt and PEG-induced drought stress in two rice genotypes, Nipponbare (salt-sensitive) and Hasawi (salt-tolerant). The transactivation activity of OsNIN-like3 was not possible to determine. Increased soil salinity has a direct impact on the reduction of plant growth and crop yield and it is therefore fundamental to understand the molecular mechanisms underlying gene expression regulation under adverse environmental conditions. OsNHX1 is the most abundant K+-Na+/H+ antiporter localized in the tonoplast and its gene expression is induced by salt, drought and ABA. To investigate how OsNHX1 is transcriptionally regulated in response to salt stress in a salt-tolerant rice genotype (Hasawi), a salt-stress-induced cDNA expression library was constructed and subsequently screened using the yeast one-hybrid system and the OsNHX1 promoter as bait. Five transcription factors (TFs) belonging to three distinct TF families: one TCP (OsPCF2), one CPP (OsCPP5) and three NIN-like (OsNIN-like2, OsNIN-like3 and OsNIN-like4) were identified as binding to OsNHX1 promoter. Transactivation activity assays performed in Arabidopsis and rice protoplasts showed that OsPCF2 and OsNIN-like4 are activators of the OsNHX1 gene expression, while OsCPP5 and OsNIN-like2 act as repressors. The transactivation activity of OsNIN-like3 needs to be further investigated. Gene expression studies showed that OsNHX1 transcript level is highly induced by salt and PEG-induced drought stress in both shoots and roots in both Nipponbare and Hasawi rice genotypes. Nevertheless, OsNHX1 seems to play a particular role in shoots in response to drought. Most of the TFs binding to OsNHX1 promoter showed a modest transcriptional regulation under stress conditions, however, in response to most of the conditions studied, the OsPCF2 was induced earlier than OsNHX1, indicating that OsPCF2 may activate OsNHX1 gene expression. In addition, although the OsNHX1 response to salt and PEG-induced drought stress in either shoots or roots was quite similar in both rice genotypes, the expression of OsPCF2 in roots under salt stress and the OsNIN-like4 in roots subjected to PEG was mainly up-regulated in Hasawi, indicating that these TFs may be associated with the salt and drought stress tolerance observed for this genotype. PMID- 27766461 TI - Nuclear Lipids in the Nervous System: What they do in Health and Disease. AB - In the last 20 years it has been widely demonstrated that cell nucleus contains neutral and polar lipids localized in nuclear membranes, nucleoli, nuclear matrix and chromatin. Nuclear lipids may show specific organization forming nuclear lipid microdomains and have both structural and functional roles. Depending on their localization, nuclear lipids play different roles such as the regulation of nuclear membrane and nuclear matrix fluidity but they also can act as platforms for vitamin and hormone function, for active chromatin anchoring, and for the regulation of gene expression, DNA duplication and transcription. Crosstalk among different kinds of lipid signalling pathways influence the physiopathology of numerous cell types. In neural cells the nuclear lipids are involved in cell proliferation, differentiation, inflammation, migration and apoptosis. Abnormal metabolism of nuclear lipids might be closely associated with tumorigenesis and neurodegenerative diseases such as Alzheimer disease and Parkinson disease among others. PMID- 27766462 TI - Sugar-Modified Poly(propylene imine) Dendrimers Stimulate the NF-kappaB Pathway in a Myeloid Cell Line. AB - PURPOSE: Fourth-generation poly(propylene imine) dendrimers fully surface modified by maltose (dense shell, PPI-m DS) were shown to be biocompatible in cellular models, which is important for their application in drug delivery. We decided to verify also their inherent bioactivity, including immunomodulatory activity, for potential clinical applications. We tested their effects on the THP 1 monocytic cell line model of innate immunity effectors. METHODS: To estimate the cytotoxicity of dendrimers the reasazurin assay was performed. The expression level of NF-kappaB targets: IGFBP3, TNFAIP3 and TNF was determined by quantitative real-time RT-PCR. Measurement of NF-kappaB p65 translocation from cytoplasm to nucleus was conducted with a high-content screening platform and binding of NF-kappaB to a consensus DNA probe was determined by electrophoretic mobility shift assay. The cytokine assay was performed to measure protein concentration of TNFalpha and IL-4. RESULTS: We found that PPI-m DS did not impact THP-1 viability and growth even at high concentrations (up to 100 MUM). They also did not induce expression of genes for important signaling pathways: Jak/STAT, Keap1/Nrf2 and ER stress. However, high concentrations of 4th generation PPI-m DS (25-100 MUM), but not their 3rd generation counterparts, induced nuclear translocation of p65 NF-kappaB protein and its DNA-binding activity, leading to NF-kappaB-dependent increased expression of mRNA for NF kappaB targets: IGFBP3, TNFAIP3 and TNF. However, no increase in pro-inflammatory cytokine secretion was detected. CONCLUSION: We conclude that maltose-modified PPI dendrimers of specific size could exert a modest immunomodulatory effect, which may be advantageous in clinical applications (e.g. adjuvant effect in anti cancer vaccines). PMID- 27766464 TI - Calorie Intake and Gambling: Is Fat and Sugar Consumption 'Impulsive'? AB - Excessive calorie intake constitutes a global public health concern, due to its associated range of untoward outcomes. Gambling is commonplace and gambling disorder is now considered a behavioral addiction in DSM-5. The relationships between calorie intake, gambling, and other types of putatively addictive and impulsive behaviors have received virtually no research attention. Two-hundred twenty-five young adults who gamble were recruited from two Mid-Western university communities in the United States using media advertisements. Dietary intake over the preceding year was quantified using the Dietary Fat and Free Sugar Short questionnaire (DFS). Clinician rating scales, questionnaires, and cognitive tests germane to impulsivity were completed. Relationships between dietary fat/sugar intake and gambling behaviors, as well as other measures of psychopathology and cognition germane to addiction, were evaluated using correlational analyses controlling for multiple comparisons. Greater dietary fat and sugar intake were associated with lower educational levels and with male gender. Controlling for these variables, higher dietary fat and sugar intake were correlated significantly with worse gambling pathology and anxiety scores. Dietary sugar intake was also significantly associated with higher depressive scores, more alcohol intake, lower self-esteem, and with greater risk of having one or more mental disorders in general. Dietary intake did not correlate significantly with ADHD symptoms, presence of one or more impulse control disorders, Barratt impulsiveness, or cognitive functioning. These data suggest a particularly strong relationship between fat/sugar intake and symptoms of gambling pathology, but not most other forms of impulsivity and behavioral addiction (excepting alcohol intake). Providing education about healthy diet may be especially valuable in gamblers and in community settings where gambling advertisements feature prominently. Future work should explore the mediating mechanisms between calorie intake and gambling symptoms, such as whether this could be driven by environmental factors (e.g. advertising) or common dysfunction of brain reward pathways. PMID- 27766463 TI - Application of UV Imaging in Formulation Development. AB - Efficient drug delivery is dependent on the drug substance dissolving in the body fluids, being released from dosage forms and transported to the site of action. A fundamental understanding of the interplay between the physicochemical properties of the active compound and pharmaceutical excipients defining formulation behavior after exposure to the aqueous environments and pharmaceutical performance is critical in pharmaceutical development, manufacturing and quality control of drugs. UV imaging has been explored as a tool for qualitative and quantitative characterization of drug dissolution and release with the characteristic feature of providing real-time visualization of the solution phase drug transport in the vicinity of the formulation. Events occurring during drug dissolution and release, such as polymer swelling, drug precipitation/recrystallization, or solvent-mediated phase transitions related to the structural properties of the drug substance or formulation can be monitored. UV imaging is a non-intrusive and simple-to-operate analytical technique which holds potential for providing a mechanistic foundation for formulation development. This review aims to cover applications of UV imaging in the early and late phase pharmaceutical development with a special focus on the relation between structural properties and performance. Potential areas of future advancement and application are also discussed. PMID- 27766465 TI - Fun Seeking and Reward Responsiveness Moderate the Effect of the Behavioural Inhibition System on Coping-Motivated Problem Gambling. AB - Gray's Reinforcement Sensitivity Theory (RST) predicts that the Behavioral Inhibition System (BIS) may relate to coping-motivated problem gambling, given its central role in anxiety. Studies examining the BIS-problem gambling association, however, are mixed. The revised RST posits that the Behavioral Approach System (BAS) may moderate the effect of the BIS on coping-motivated problem gambling. A concurrently strong BAS may highlight the negatively reinforcing effects of gambling, which may strengthen coping motives and increase gambling-related harms. We examined these interactive effects to clarify the moderators and mediators of the negative reinforcement pathway to problem gambling. Data came from a larger investigation of problem gambling among individuals with mood disorders. All participants (N = 275) met criteria for a lifetime depressive or bipolar disorder. During a two-day assessment, participants completed a diagnostic assessment and self-reports. Mediated moderation path analysis showed positive indirect effects from the BIS to problem gambling via coping motives at high, but not at low, levels of BAS-Reward Responsiveness and BAS-Fun Seeking. Enhancement motives were also found to mediate the associations of BAS-Fun Seeking and BAS-Drive with problem gambling. Reward Responsiveness and Fun Seeking facets of the BAS may strengthen coping gambling motives within the mood disorders. PMID- 27766466 TI - Neurofibroma of the cervical spine in infants: a case-based update. PMID- 27766467 TI - Atypical imaging in a desmoplastic non-infantile astrocytoma. AB - INTRODUCTION: Desmoplastic infantile tumors, especially desmoplastic astrocytomas, are uncommon neoplasms that are generally seen within first 2 years of life. Their occurrence in slightly older children is very rare. The typical radiological appearance is a large cystic lesion with small enhancing solid part. CASE: In the present report, we describe a 10-year-old child with atypical appearance of desmoplastic non-infantile astrocytoma which was predominantly solid on imaging. CONCLUSION: Although rare, desmoplastic astrocytomas may present even in older children and should be considered in the differential diagnoses. These tumors may present as predominantly solid enhancing lesions and add to the radiological dilemma. PMID- 27766468 TI - Early diffusion restriction of white matter in infants with small subdural hematomas is associated with delayed atrophy. AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of infant morbidity and mortality. In these patients, magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) is the test of choice to describe the extent of microstructural injury. CASE PRESENTATION AND DISCUSSION: In this case series, we describe novel acute and chronic MRI findings in four infants (6-19 months) with small, unilateral subdural hematomas in whom the etiology of head injury was suspicious for non-accidental trauma (NAT). Acute (<1-week post-injury) DWI revealed extensive areas of restricted diffusion isolated to the cerebral white matter predominantly ipsilateral to the subdural hematoma. After prolonged pediatric intensive care treatment including subdural evacuation (n = 2) or decompressive craniectomy (n = 1), all patients survived albeit with significant motor and cognitive deficits. Delayed structural MRI (6-9-year post-injury) demonstrated cortical and subcortical atrophy well-correlated with areas of acute restricted diffusion. CONCLUSION: These four cases highlight that relatively small subdural hematomas can be associated with extensive white matter injury detectable only by early DWI-which have long-term structural and functional consequences. PMID- 27766469 TI - Long-term mortality rates in pediatric hydrocephalus-a retrospective single center study. AB - PURPOSE: Very long-term follow-up and outcome are rare for pediatric patients with hydrocephalus and shunt operations. The aim of this study was to determine the long-term mortality rates in these patients. METHODS: Pediatric patients with first shunt operation between 1982 and 1992 were included. For each patient, time and cause of death were determined. Further, patients with first operation from 1982 to 1987 were compared to those first operated from 1988 to 1992. RESULTS: One-hundred thirty-seven patients were included. Etiologies of hydrocephalus were intraventricular hemorrhage (31.4 %), meningomyelocele (25.5 %), postinfectious (11.7 %), congenital (10.2 %), posterior fossa cyst (8.8 %), aqueductal stenosis (8 %), and others (4.4 %). Overall, 53 patients (38.7 %) died. The percentage of patients surviving 1, 2, 10, and 20 years after first operation were 82.6, 73.6, 69.4, and 65.3 %, respectively. In 23 patients, the cause of death was related to shunt treatment: shunt infection was diagnosed in 18 and acute shunt dysfunction in 5 patients. Mortality was considerably higher for patients with their first operation in time period 1982-1987 compared to time period 1988-1992 (51 versus 25 %). The reduction of mortality was mainly due to an increased survival after shunt infection. Eighty-seven patients survived more than 20 years after initial shunt operation. Of those long-term survivors, three (3.4 %) patients died 22-24 years after first operation. CONCLUSION: Mortality in hydrocephalic pediatric patients is high especially in the first postoperative years but is even significant in adult patients with pediatric hydrocephalus. As deaths occur even after 20 years, routine follow-up of long-term survivors remains necessary. PMID- 27766470 TI - Familial paraganglioma syndrome: a rare cause of carotid artery occlusion. PMID- 27766471 TI - Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study. AB - The true extent of sequelae in encephalitis survivors relative to rates within the general population is not known. This study aimed to quantify increased risks of epilepsy, depressive disorders, anxiety disorders, psychotic disorders, bipolar disorder, cognitive problems, dementia, headache, and alcohol abuse among encephalitis cases. 2460 exposed individuals diagnosed with incident encephalitis in the Clinical Practice Research Datalink and 47,914 unexposed individuals without a history of encephalitis were included. Multivariable Poisson regression was used to estimate adjusted rate ratios in individuals with encephalitis compared to the general population and to estimate whether the effect of these outcomes varied over time. Individuals with encephalitis had an increased risk of all investigated outcomes. The highest RR was seen for epilepsy (adjusted RR 31.9; 95 % confidence interval 25.38-40.08), whereas the lowest was seen for anxiety disorders (1.46, 1.27-1.68). The second highest RRs were for particular psychiatric illnesses, including bipolar disorder (6.34, 3.34-12.04) and psychotic disorders (3.48, 2.18-5.57). The RR was highest in the first year of follow-up for all outcomes except headache; this was particularly true for epilepsy (adjusted RR in first year of follow-up 139.6, 90.62-215.03). This study shows that sequelae are common in survivors of encephalitis. We confirm the presence of outcomes more commonly linked to encephalitis and describe those less commonly identified as being associated with encephalitis. The results of this study have important implications for the management of encephalitis patients and for the design of tertiary prevention strategies, as many of these sequelae are treatable. PMID- 27766472 TI - Delayed vestibulopathy after heat exposure. AB - Even though dizziness is a common symptom of heat illness, comprehensive evaluation of the vestibular function has not been available in this potentially life-threatening disorder. Three patients developed vertigo about a week after heat exposure. Evaluation showed bilateral impairments of the vestibulo-ocular reflex during head impulses and the signs of vestibulocerebellar dysfunction that included spontaneous downbeat nystagmus, gaze-evoked nystagmus, and positional downbeat nystagmus. Exposure to excessive heat may give rise to delayed vestibulopathy by damaging the vestibulocerebellum. PMID- 27766473 TI - Endoscopic transnasal skull base surgery: pushing the boundaries. AB - The endoscopic endonasal approach (EEA) has significantly evolved since its initial uses in pituitary and sinonasal surgery. The literature is filled with reports and case series demonstrating efficacy and advantages for the entire ventral skull base. With competence in 'minimally invasive' parasellar approaches, larger and more complex approaches were developed to utilize the endonasal corridor to create maximally invasive endoscopic skull base procedures. The challenges of these more complex endoscopic procedures include a long learning curve and navigating in a narrow corridor; reconstruction of defects presented new challenges and early experience revealed a significantly higher risk of cerebrospinal fluid leak. Despite these challenges, there are many benefits to the EEA including avoidance of brain and neurovascular retraction, improved visualization, a direct corridor onto many tumors and the two-surgeon approach. Most importantly, the EEA provides a midline corridor to directly access tumors, which displace critical neurovascular structures laterally, giving it an inherent advantage of minimizing any manipulation of these structures and thus decreasing their potential injury. PMID- 27766475 TI - Universal Asymptotic Clone Size Distribution for General Population Growth. AB - Deterministically growing (wild-type) populations which seed stochastically developing mutant clones have found an expanding number of applications from microbial populations to cancer. The special case of exponential wild-type population growth, usually termed the Luria-Delbruck or Lea-Coulson model, is often assumed but seldom realistic. In this article, we generalise this model to different types of wild-type population growth, with mutants evolving as a birth death branching process. Our focus is on the size distribution of clones-that is the number of progeny of a founder mutant-which can be mapped to the total number of mutants. Exact expressions are derived for exponential, power-law and logistic population growth. Additionally, for a large class of population growth, we prove that the long-time limit of the clone size distribution has a general two parameter form, whose tail decays as a power-law. Considering metastases in cancer as the mutant clones, upon analysing a data-set of their size distribution, we indeed find that a power-law tail is more likely than an exponential one. PMID- 27766476 TI - Modelling Drug Abuse Epidemics in the Presence of Limited Rehabilitation Capacity. AB - The abuse of drugs is now an epidemic globally whose control has been mainly through rehabilitation. The demand for drug abuse rehabilitation has not been matched with the available capacity resulting in limited placement of addicts into rehabilitation. In this paper, we model limited rehabilitation through the Hill function incorporated into a system of nonlinear ordinary differential equations. Not every member of the community is equally likely to embark on drug use, risk structure is included to help differentiate those more likely (high risk) to abuse drugs and those less likely (low risk) to abuse drugs. It is shown that the model has multiple equilibria, and using the centre manifold theory, the model exhibits the phenomenon of backward bifurcation whose implications to rehabilitation are discussed. Sensitivity analysis and numerical simulations are performed. The results show that saturation in rehabilitation will in the long run lead to the escalation of drug abuse. This means that limited access to rehabilitation has negative implications in the fight against drug abuse where rehabilitation is the main form of control. This suggests that increased access to rehabilitation is likely to lower the drug abuse epidemic. PMID- 27766477 TI - Risk of Second Primary Malignancies in Lung Cancer Survivors - The Influence of Different Treatments. AB - BACKGROUND: Currently, no large study addressing the relationship between lung cancer patients with different therapies and second primary malignancies (SPMs) is available. METHODS: Using the Taiwan National Health Insurance Research Database, we conducted a population-based cohort study. Patients with newly diagnosed lung cancer between 1997 and 2005 were enrolled and followed up until Dec. 31, 2011. The endpoint of the study was SPM occurrence. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort to that of the general population. RESULTS: We identified 52,639 patients with lung cancer and excluded 34,267 patients who had expired within one year after diagnosis. The study included 18,372 subjects with a median follow-up period of 2.24 years. 590 patients developed an SPM. The overall cancer risk was significantly increased (SIR 1.33, 95% confidence interval [CI]: 1.22-1.44, p < 0.001), and there was a significant increase in the incidences of head and neck (SIR 1.60, 95% CI 1.21-2.07, p = 0.001), bone and soft tissue (SIR 2.65, 95% CI 1.27-4.87, p = 0.011), genitourinary (SIR 1.50, 95% CI 1.27-1.76, p < 0.001), and thyroid (SIR 3.85, 95% CI 2.28-6.08, p < 0.001) cancers. Importantly, after multivariate adjustment, the use of tyrosine kinase inhibitors (TKIs) statistically significantly reduced SPM incidence (HR, 0.41; 95% CI, 0.21-0.79; p = 0.008). CONCLUSIONS: Our study indicates that lung cancer may be a risk factor for SPM. TKI use was associated with a significantly lower risk of SPM development. However, because patients with epidermal growth factor receptor mutant lung adenocarcinoma (associated with non-smokers) tend to receive TKI treatment, they might have fewer smoking-related SPMs. PMID- 27766478 TI - Structural brain changes and all-cause mortality in the elderly population-the mediating role of inflammation. AB - While MRI brain changes have been related to mortality during ageing, the role of inflammation in this relationship remains poorly understood. Hence, this study aimed to investigate the impact of MRI changes on all-cause mortality and the mediating role of cytokines. All-cause mortality was evaluated in 268 community dwelling elderly (age 65-83 years) in the MEMO study (Memory and Morbidity in Augsburg elderly). MRI markers of brain atrophy and cerebral small vessel disease (SVD), C-reactive protein (CRP) and a panel of cytokines in serum were assessed. Cox proportional hazard models were used to estimate the association of MRI changes with survival over 9 years. Regression models were used to assess the hypothesis that inflammation is mediating the relationship between MRI-brain changes and mortality. In total, 77 (29 %) deaths occurred during a mean follow up of 9 years. After adjusting for confounders, the degree of global cortical atrophy and the level of the cytokines CRP, TNF-alpha and IL-8 were of higher significance in study participants who had died at follow-up in comparison to survivors. In Cox proportional hazard models, higher degrees of global cortical atrophy (HR 1.56, p = 0.003) and regional atrophy of the temporal lobe (HR 1.38, p = 0.011) were associated with a significantly increased risk of mortality. Mediation analyses revealed a partial mediation by IL-6 and IL-8 of the effects of global cortical atrophy on mortality. Global cortical brain atrophy is a significant indicator of survival in the elderly. Our study supports a possible role for inflammation in the atrophy pathogenesis. If replicated in other samples, IL-6 and IL-8 level assessment may improve risk prognosis for mortality. PMID- 27766479 TI - Subclassification of patients with intermediate-stage (Barcelona Clinic Liver Cancer stage-B) hepatocellular carcinoma using the up-to-seven criteria and serum tumor markers. AB - BACKGROUND: Intermediate-stage [Barcelona Clinic Liver Cancer stage-B (BCLC-B)] hepatocellular carcinoma (HCC) comprises of a heterogeneous population of patients with a wide range of tumor burdens. We therefore formulated a subclassification of BCLC-B HCC using the up-to-seven criteria and tumor markers according to the results of a retrospective analysis of these patients. METHODS: This study included 125 patients newly diagnosed with BCLC-B HCC who underwent transarterial chemoembolization. Among them, 39 and 86 were within or beyond the up-to-seven criteria, respectively. Multivariate Cox proportional hazards analysis was performed to investigate factors that contributed to better prognosis associated with the criteria. RESULTS: Cumulative overall survival (OS) and disease-free survival rates were significantly higher for patients within the up-to-seven criteria compared with those beyond (p = 0.034 and p = 0.001, respectively). Multivariate analysis revealed that low concentrations of des gamma-carboxy prothrombin (DCP) (<150 mAU/ml) and alpha-fetoprotein (AFP) (<100 ng/ml) were independent contributors to better OS of patients within or beyond the up-to-seven criteria, respectively. Accordingly, the patients were classified as follows: group A (patients within the up-to-seven criteria with DCP <150 mAU/ml), group C (patients beyond the up-to-seven criteria with AFP >=100 ng/ml), and group B (other patients). OS differed significantly among groups (p < 0.001), and the median survival times of group A, B, and C were 4.2, 2.7, and 1.5 years, respectively. CONCLUSION: The subclassification system incorporating the up-to seven criteria combined with DCP and AFP levels may serve as better predictors of prognosis that may guide efforts to improve treatment strategies. PMID- 27766481 TI - Examining acute bi-directional relationships between affect, physical feeling states, and physical activity in free-living situations using electronic ecological momentary assessment. AB - Current knowledge about the relationship of physical activity with acute affective and physical feeling states is informed largely by lab-based studies, which have limited generalizability to the natural ecology. This study used ecological momentary assessment to assess subjective affective and physical feeling states in free-living settings across 4 days from 110 non-physically active adults (Age M = 40.4, SD = 9.7). Light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) were measured objectively by an accelerometer. Multilevel modeling was used to test the bi-directional associations between affective and physical feeling states and LPA/MVPA minutes. Higher positive affect, lower negative affect and fatigue were associated with more MVPA over the subsequent 15 min, while higher negative affect and energy were associated with more LPA over the subsequent 15 and 30 min. Additionally, more LPA and MVPA were associated with feeling more energetic over the subsequent 15 and 30 min, and more LPA was additionally associated with feeling more negative and less tired over the subsequent 15 and 30 min. Positive and negative affective states might serve as antecedents to but not consequences of MVPA in adults' daily lives. Changes in LPA may be predicted and followed by negative affective states. Physical feeling states appear to lead up to and follow changes in both LPA and MVPA. PMID- 27766480 TI - Aged garlic extract suppresses platelet aggregation by changing the functional property of platelets. AB - Aged garlic extract (AGE), a garlic preparation rich in water-soluble cysteinyl moieties, has been reported to have multiple beneficial effects on cardiovascular disease including inhibition of platelet aggregation. However, the mode of AGE action on platelets has not been clear. In this study, we examined the effect of AGE on the functional property of platelet by administering AGE to rats and evaluating the platelet aggregation in response to collagen in vitro. We found that AGE treatment significantly reduced the ability of platelet to aggregate and this effect of AGE was manifested on the 14 day, but not 7 day of treatment. In addition, AGE treatment produced platelets that responded to collagen by significantly increasing the amount of both the extracellular ATP and the extra- and intracellular TXB2. AGE treatment also dose-dependently suppressed the phosphorylation of collagen-induced ERK, p38 and JNK. However, AGE administration did not affect the bleeding time. These findings suggest that AGE treatment results in suppression of platelet aggregation by changing the functional property of platelets to respond to collagen. PMID- 27766482 TI - Treatment adherence and illness self-management: introduction to the special issue. AB - The current issue is devoted broadly to research on treatment adherence and chronic illness self-management behavior. As the prevalence of chronic illness increases, the pervasive problem of treatment nonadherence is increasingly viewed as having a major impact on treatment outcomes, public health and healthcare costs, making this issue particularly timely. Sixteen articles spanning an array of topics are presented; articles include empirical studies, statistical simulations, systematic reviews, and theoretical commentaries. Studies conducted with diverse patient populations (e.g., chronic headache, diabetes, end-stage renal disease, HIV, hypertension, severe obesity), samples (e.g., adolescents, ethnic/racial minorities, low-income adults, parents, spousal dyads), and designs (e.g., cross-sectional, longitudinal assessment, randomized controlled trial), are represented. This issue highlights psychosocial factors associated with nonadherence, promising interventions to promote adherence, and state-of-the art methods for the study of illness self-management. We hope these articles engender even more high quality, methodologically rigorous research in this important subfield of behavioral medicine. PMID- 27766483 TI - Beyond borders: on the influence of the creationist movement on the educational landscape in the USA and Russia. AB - This paper provides a detailed look at how creationism originated in the United States and then explores how this evangelical trend was exported to Russia by American missionaries following the fall of the USSR. The comparison between these two countries is particularly interesting since the rivalry between the US and the USSR during the race to space caused both countries to revamp their science education. Yet, while political interests led both governments to focus on science education, creationist activities were simultaneously focused on diminishing the coverage of evolution in science classrooms. Now, decades following Sputnik's trip to space, the urgency to strengthen scientific learning has waned, while creationists are still equally focused on removing scientific naturalism in favor of supernatural explanations for the origin of species. This paper thus offers an in-depth look at which groups are currently responsible for promoting creationist activities in the US and in Russia and which groups are working hard to keep supernatural doctrines out of science curriculum. PMID- 27766474 TI - Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. AB - To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research. PMID- 27766485 TI - Removal of sulfur-containing organic molecules adsorbed on inorganic supports by Rhodococcus Rhodochrous spp. AB - OBJECTIVE: To remove dibenzothiophene (DBT) and 4,6-dimethyl-dibenzothiophene (4,6-DMDBT) adsorbed on alumina, silica and sepiolite through biodesulfurization (BDS) using Rhodococcus Rhodochrous spp., that selectively reduce sulfur molecules without generating of gaseous pollutants. RESULTS: The adsorption of DBT and 4,6-DMDBT was affected by the properties of the supports, including particle size and the presence of surface acidic groups. The highest adsorption of both sulfur-containing organic molecules used particle sizes of 0.43-0.063 mm. The highest percentage removal was with sepiolite (80 % for DBT and 56 % for 4,6 DMDBT) and silica (71 % for DBT and 37 % for 4,6-DMDBT). This is attributed to the close interaction between these supports and the bacteria. CONCLUSIONS: Biodesulfurization is effective for removing the sulfur-containing organic molecules adsorbed on inorganic materials and avoids the generation of gaseous pollutants. PMID- 27766484 TI - Bone Density and Dental External Apical Root Resorption. AB - When orthodontic patients desire shorter treatment times with aesthetic results and long-term stability, it is important for the orthodontist to understand the potential limitations and problems that may arise during standard and/or technology-assisted accelerated treatment. Bone density plays an important role in facilitating orthodontic tooth movement (OTM), such that reductions in bone density can significantly increase movement velocity. Lifestyle, genetic background, environmental factors, and disease status all can influence a patients' overall health and bone density. In some individuals, these factors may create specific conditions that influence systemic-wide bone metabolism. Both genetic variation and the onset of a bone-related disease can influence systemic bone density and local bone density, such as observed in the mandible and maxilla. These types of localized density changes can affect the rate of OTM and may also influence the risk of unwanted outcomes, i.e., the occurrence of dental external apical root resorption (EARR). PMID- 27766486 TI - Evaluation of posterior clinoid process pneumatization by multidetector computed tomography. AB - In the present study, we investigated the types and ratio of posterior clinoid process (PCP) pneumatization in paranasal sinus multidetector computed tomography (MDCT). Paranasal MDCT images of 541 subjects (227 males, 314 females), between 15 and 65 years old, were included into the study. Pneumatization of anterior clinoid process and pneumatization types (I, II, or III) were evaluated in the males and females. PCP pneumatization was detected in 20.7 % of the males and 11.5 % of the females. Right, left, and bilateral PCP pneumatizations were detected in 7.9, 5.7, and 7.0 % of the males and 2.9, 3.2, and 4.5 % of the females, respectively. PCP pneumatization of the males is significantly higher than the females. The most detected type of pneumatization was type I (61.2 %) for all groups. In right, left, and bilateral pneumatizations separately, type I pneumatization was the most detected pneumatization type with the ratio of the 70.4, 65.2, and 50.0 %, respectively. In males, type I (61.7 %), and similarly in females, type I (60.6 %) pneumatization were detected more. Type II and type III pneumatizations were detected in decreasing order in both groups. In younger subjects, pneumatization of posterior clinoid process was found as higher, and in older subjects, PCP pneumatization was found as lower. Sclerosis process related to the aging may be responsible for the lower pneumatization ratios in older subjects. Structure of the surrounding regions of PCP is important for surgical procedures related to cavernous sinus, basilar apex aneurysms, and mass lesions. Preoperative radiological examinations are useful for operative planning. Any anomalies to PCP can cause unnecessary injury to the neurovascular complex structure around the cavernous sinus or postclinoidectomy CSF fistulas. Posterior clinoidectomies should be avoided in patients with type III PCP pneumatization to prevent CSF fistulas. PMID- 27766487 TI - Dental anomalies in 14 patients with IP: clinical and radiological analysis and review. AB - OBJECTIVES: Current knowledge on dental anomalies in patients with incontinentia pigmenti (IP) has been obtained by examining case reports; however, an overall characterization of such alterations remains lacking. The objective of this study was to determine the frequency, type and location of dental alterations in IP using a case series. METHODS: Fourteen patients (9 children and 5 adults) with a clinical diagnosis of IP who presented dental anomalies were included in this study. All patients were administered a clinical questionnaire, dental examination and radiological investigation. RESULTS: In the present case series, agenesis of primary dentition was present in 60 % of patients and agenesis of permanent tooth was present in 92.8 % of patients. Most cases were missing at least 6 teeth. Second molar agenesis was present in 13 patients (92.8 %). Anomalies in dental crowns occurred in 71.4 % of cases, and the central incisor was most frequently affected. Two adult patients still had primary teeth. Malocclusion was found in 10 patients (71.4 %). High-arched palate was observed in 7 (50 %) patients. CONCLUSIONS: Patients with IP present alterations in both primary and permanent dentition. Because the agenesis of permanent teeth is more common, primary teeth are not always replaced. In addition, the durability of primary dentition appears to be greater in IP. CLINICAL SIGNIFICANCE: This study shows that patients with IP experience significant loss of teeth, especially in permanent dentition, and have an increased risk of high-arched palate compared to the general population. Prophylactic care of primary teeth in IP is relevant for improving functional and aesthetic outcomes until dental prostheses are implanted. PMID- 27766488 TI - Radio-opaque polyethylene for personalized craniomaxillofacial implants. AB - OBJECTIVE: This study aimed to present a new possibility to create radio-opaque implant material for craniomaxillofacial reconstruction. MATERIALS AND METHODS: The test disks made of the own compound of polyethylenes with addiction of 2, 4, and 6 % of weight TiO2 was investigated for cytotoxicity [each group 15 disks respectively]. Next, computed tomography of the disks was performed in environment of muscle and fat. Hardness, tensile modulus and strength, and compressive modulus and strength were tested too. RESULTS: Deterioration of mechanical properties of the composites containing titanium dioxide was observed [hardness, tensile modulus and strength, compressive modulus and strength, respectively: 56.7 +/- 1.6 shore D, 354 +/- 52, 22.5 +/- 1.3, 21.8 +/- 1.1, and 2995 +/- 327 MPa as addiction of 2 % TiO2; 52.0 +/- 0.9 shore D, 347 +/- 66, 18.0 +/- 0.7, 14.2 +/- 0.9, and 1396 +/- 477 MPa as 4 % TiO2; 51.3 +/- 1.3 shore D, 316 +/- 9, 17.4 +/- 0.2, 13.6 +/- 0.6, and 1100 +/- 144 MPa as 6 % TiO2 added]. The test disks revealed no cytotoxicity effect on human osteoblasts. The new material presents mild radio-opacity which was enough to observe the implant in relation to fat and muscle, but with no visible effect of beam hardening. CONCLUSION: In view of the performed tests, the polyethylene enriched by titanium dioxide seems to be a proper material to consider manufacturing of craniomaxillofacial implants. CLINICAL RELEVANCE: Maxilloafacial surgery is still looking for new implantologic materials. The proposed one is a new way to manufacture an implant visible in computed tomography which does not interfere with its shape in radiological examination and makes it possible to observe the surrounding soft tissues. PMID- 27766489 TI - No evidence for the growth-stimulating effect of monomers on cariogenic Streptococci. AB - BACKGROUND: In spite of contradicting results, the high susceptibility of composites for secondary caries is still often associated with the bacterial growth-stimulating effect of released methacrylate monomers. However, most studies that showed this effect were performed with techniques having inherent limitations (spectrophotometry). OBJECTIVES: Therefore, our objective was to determine the effect of four methacrylate monomers (2-Hydroxyethyl methacrylate (HEMA), triethylene glycol dimethacrylate (TEGDMA), ethylene glycol dimethacrylate (EGDMA), diethylene glycol dimethacrylate (DEGDMA)) on the growth of two caries-associated bacteria, Streptococcus mutans and sobrinus, and one non cariogenic species, Streptococcus sanguinis, using TaqMan quantitative polymerase chain reaction (qPCR) to quantify bacterial DNA. MATERIALS AND METHODS: Cultures were exposed to monomer solutions selected after spectrophotometric growth measurements. At baseline and predetermined time intervals, bacterial DNA was extracted and quantified with TaqMan qPCR. Biofilms grown in the presence of monomers were analyzed with scanning electron microscopy (SEM). RESULTS: Spectrophotometry indeed showed increased growth rates of all three strains with 5 mM TEGDMA, EGDMA, and DEGDMA and increased total biomass of S. sanguinis with 5 mM TEGDMA. However, qPCR failed to show any growth-stimulating effect of these monomers on S. mutans and S. sobrinus. In contrast, some monomers exhibited a growth-inhibiting effect on S. sanguinis. SEM revealed extracellular matter in S. sobrinus and S. sanguinis biofilms, which might be attributed to polymer formation. CONCLUSIONS: Techniques which quantify bacterial DNA are more appropriate to evaluate bacterial growth in the presence of monomers than spectrophotometry. CLINICAL RELEVANCE: Even though methacrylate monomers did not affect the growth of cariogenic species, growth inhibition of S. sanguinis, a non cariogenic antagonistic species, may lead to ecological shifts towards higher cariogenicity. PMID- 27766490 TI - Impact of smoking status and cumulative smoking exposure on tumor recurrence of non-muscle-invasive bladder cancer. AB - OBJECTIVE: To investigate the effect of smoking status, cumulative smoking exposure and smoking cessation on the outcomes of patient with non-muscle invasive bladder cancer (NMIBC). METHODS: We collected smoking data from 484 patients with NMIBC who were treated with transurethral resection (TUR); smoking status was categorized as (never smokers vs current smokers vs former smokers). Cumulative smoking exposure was categorized as high smoking exposure (cigarette index >=400) versus low smoking exposure (cigarette index <400). Association with outcomes was examined by multivariable analyses after adjusting for the effects of standard clinicopathologic factors, and the Kaplan-Meier method was used to estimate the effect of smoking status and cumulative smoking exposure on RFS. RESULTS: A total of 168 (34.7 %) patients were never smoker, 121 (25 %) patients were current smokers, and 195 (40.3 %) patients were former smokers. The median follow-up was 25 months. By multivariate analysis, pathological grade (p = 0.013), history of recurrence (p < 0.001), number of tumors (p < 0.001) and size of tumors (p = 0.013) were significantly associated with tumor recurrence; nevertheless, smoking status did not influence tumor recurrence (p = 0.063). Among current and former smokers, cumulative smoking exposure was significantly associated with tumor recurrence (p < 0.001), compared to current smokers, patients with smoking cessation >=10 years had a lower risk of tumor recurrence [hazard ratio (HR) 0.456, p = 0.007]. CONCLUSIONS: Smoking affects the prognosis of patient with NMIBC, which is still controversial; however, among ever smokers, a high cumulative exposure smoking can significantly increase the risk of tumor recurrence. Quitting smoking might be associated with a lower recurrence rate for patients with NMIBC. PMID- 27766491 TI - Does finger sense really have a delayed effect on children's addition performance? : [A comment of Newman, S.D. Does finger sense predict addition performance? Cognitive Processing, 17(2), 2016, pp. 139-146]. PMID- 27766493 TI - CCN2 reduction mediates protective effects of BMP7 treatment in obstructive nephropathy. AB - Treatment with rhBMP7 exerts profound protective effects in a wide variety of experimental models of renal disease. However, little is known about how these protective effects are mediated, and which cells in the kidney are targeted by exogenous rhBMP7 treatment. To determine if rhBMP7 increases glomerular and tubulointerstitial canonical BMP signaling, we performed Unilateral Ureteral Obstruction (UUO, a widely used obstructive nephropathy model) in mice reporting transcriptional activity downstream of canonical BMP signaling by the expression of GFP under the BMP Responsive Element of the Id1 promoter (BRE:gfp mice). We also analysed the impact of rhBMP7 treatment on severity of the UUO phenotype, on TGFbeta signaling, and on expression of CCN2 (CTGF). Despite profound protective effects with respect to morphological damage, macrophage infiltration, and fibrosis, no significant difference in GFP-expression was observed upon rhBMP7 administration. Also TGFbeta signalling was similar in rhBMP7 and vehicle treated mice, but CCN2 expression in obstructed kidneys was significantly reduced by rhBMP7 treatment. Of note, in heterozygous CCN2 mice (CCN2+/-) treatment with rhBMP7 did not (further) reduce the severity of kidney damage in the UUO-model. These data suggest that protection against obstructive nephropathy by exogenous rhBMP7 treatment relies primarily on non-canonical BMP signaling, and may be mediated in large part by downregulation of CCN2 expression. PMID- 27766494 TI - Perioperative nocturnal hypoxemia matters in surgical patients with obstructive sleep apnea. PMID- 27766492 TI - CO and NO bind to Fe(II) DiGeorge critical region 8 heme but do not restore primary microRNA processing activity. AB - The RNA-binding heme protein DiGeorge critical region 8 (DGCR8) and its ribonuclease partner Drosha cleave primary transcripts of microRNA (pri-miRNA) as part of the canonical microRNA (miRNA) processing pathway. Previous studies show that bis-cysteine thiolate-coordinated Fe(III) DGCR8 supports pri-miRNA processing activity, while Fe(II) DGCR8 does not. In this study, we further characterized Fe(II) DGCR8 and tested whether CO or NO might bind and restore pri miRNA processing activity to the reduced protein. Fe(II) DGCR8 RNA-binding heme domain (Rhed) undergoes a pH-dependent transition from 6-coordinate to 5 coordinate, due to protonation and loss of a lysine ligand; the ligand bound throughout the pH change is a histidine. Fe(II) Rhed binds CO and NO from 6- and 5-coordinate states, forming common CO and NO adducts at all pHs. Fe(II)-CO Rhed is 6-coordinate, low-spin, and pH insensitive with the histidine ligand retained, suggesting that the protonatable lysine ligand has been replaced by CO. Fe(II)-NO Rhed is 5-coordinate and pH insensitive. Fe(II)-NO also forms slowly upon reaction of Fe(III) Rhed with excess NO via a stepwise process. Heme reduction by NO is rate-limiting, and the rate would be negligible at physiological NO concentrations. Importantly, in vitro pri-miRNA processing assays show that both CO- and NO-bound DGCR8 species are inactive. Fe(II), Fe(II)-CO, and Fe(II)-NO Rhed do not bear either of the cysteine ligands found in the Fe(III) state. These data support a model in which the bis-cysteine thiolate ligand environment of Fe(III) DGCR8 is necessary for establishing proper pri-miRNA binding and enabling processing activity. PMID- 27766495 TI - In reply: Perioperative nocturnal hypoxemia matters in surgical patients with obstructive sleep apnea. PMID- 27766496 TI - Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan. AB - Among advanced gastric cancer cases, peritoneal dissemination is a life threatening mode of metastasis, and any strategy to control peritoneal metastasis will significantly improve treatment outcomes. Since intraperitoneal administration of anticancer drugs can induce an extremely high concentration of drugs in the peritoneal cavity, intraperitoneal chemotherapy would appear to be a reasonable and promising strategy to control the peritoneal dissemination. However, it has been reported in the past that intraperitoneal administration of mitomycin C or cisplatin resulted in no significant clinical effects against peritoneal metastasis of gastric cancer. In contrast, intraperitoneal paclitaxel is expected to remain inside the peritoneal cavity due to its large molecular weight and fat solubility, leading to a high concentration of the drug in the peritoneal cavity. In fact, promising results in several phase II clinical trials using intraperitoneal paclitaxel have been reported, including a median survival time of 16.2-24.6 months and a 1-year overall survival rate of 69-78 %. Thereafter, a phase III randomized control study (PHOENIX-GC trial) with intraperitoneal paclitaxel plus systemic S-1 and intravenous paclitaxel in comparison to systemic S-1 plus cisplatin was conducted in Japan. Moreover, a phase II clinical trial of combination chemotherapy of intraperitoneal paclitaxel with systemic capecitabine plus oxaliplatin is currently ongoing in Singapore. In this review, based on clinical experience from Singapore and Japan, the clinical significance of intraperitoneal chemotherapy for gastric cancer with peritoneal disease is discussed. PMID- 27766497 TI - Factors increasing mortality of the elderly following hip fracture surgery: role of body mass index, age, and smoking. AB - OBJECTIVES: Hip fracture is one of the most common public health problems with a significant financial burden on the patient and on the healthcare system. This study was conducted to assess the 3-month and 1-year mortality rates of patients with operated hip fractures and to determine the influence of predictors of mortality. METHODS: In this prospective cross-sectional study, all admitted patients aged more than 50 years with hip fracture at Chamran Hospital from January 2008 to August 2013 were enrolled. The characteristic data obtained included demographic information, body mass index (BMI), smoking, any previous history of osteoporotic fracture, and comorbidities. In addition, the mechanism of fracture, fracture type, and treatment method were recorded. A follow-up with the patients was conducted at 3 months and 1 year through a telephonic interview to ask about possible mortalities. Statistical analyses were performed using SPSS software version 17.0 for Windows. RESULTS: A total of 1015 patients aged 50 years and older with hip fracture underwent surgery. Only 724 patients (71.3 %) completed the survey and the 1-year follow-up interview. The mean age was 75.7 +/ 10.6 years. Overall, the 3-month and 1-year mortality rates were 14.5 and 22.4 %, respectively. Multivariate logistic regression analysis recognized age (OR 1.08; 95 % CI 1.05, 1.11, p < 0.001), BMI (OR 0.88; 95 % CI 0.82, 0.96, p = 0.003), and smoking (OR 1.76; 95 % CI 1.05, 2.96, p = 0.03) as major independent risk factors for mortality. CONCLUSION: It is clear that modifiable factors like quitting the habit of smoking and gaining more energy with better nutrition could reduce the mortality rate if hip fracture occurs in the elderly. PMID- 27766498 TI - Mood spectrum comorbidity in patients with anorexia and bulimia nervosa. AB - PURPOSE: To investigate the presence of mood spectrum signs and symptoms in patients with anorexia nervosa, restricting subtype (AN-R) or bulimia nervosa (BN). METHOD: 55 consecutive female patients meeting DSM-IV criteria for eating disorders (EDs) not satisfying DSM-IV criteria for Axis I mood disorders were evaluated with the Lifetime Mood Spectrum Self-Report (MOODS-SR) and the Mini International Neuropsychiatric Interview (MINI). The MOODS-SR explored the subthreshold comorbidity for mood spectrum symptoms in patients not reaching the threshold for a mood disorder Axis I diagnosis. MOODS-SR included 161 items. Separate factor analyses of MOODS-SR identified 6 'depressive factors' and 9 'manic-hypomanic factors'. RESULTS: The mean total score of MOODS-SR was significantly higher in BN than in AN-R patients (97.5 +/- 25.4 vs 61.1 +/- 38.5, respectively; p = 0.0001). 63.6 % of the sample (n = 35) endorsed the threshold of >=61 items, with a statistically significant difference between AN-R and BN (39.3 % vs 88.9 %; chi 2 = 14.6; df = 1; p = 0.0001). Patients with BN scored significantly higher than AN-R patients on several MOODS-SR factors: (a) MOODS-SR depressive component: 'depressive mood' (11.2 +/- 7.4 vs 16.0 +/- 5.8; p < 0.05), 'psychomotor retardation' (5.4 +/- 5.6 vs 8.9 +/- 3.8; p = 0.003), 'psychotic features' (2.0 +/- 1.8 vs 4.1 +/- 1.6; p = 0.001), 'neurovegetative symptoms' (5.0 +/- 2.6 vs 7.7 +/- 1.7; p = 0.001); (b) MOODS-SR manic/hypomanic component: 'psychomotor activation' (4.3 +/- 3.6 vs 7.4 +/- 3.1; p = 0.002), 'mixed instability' (1.0 +/- 1.5 vs 2.0 +/- 1.6; p < 0.05), 'mixed irritability' (2.5 +/ 1.8 vs 3.7 +/- 1.6; p < 0.05), 'inflated self-esteem' (1.1 +/- 1.4 vs 2.1 +/- 1.6; p < 0.05), and 'wastefulness/recklessness' (1.0 +/- 1.4 vs 2.0 +/- 1.2; p = 0.009). CONCLUSIONS: MOODS-SR identifies subthreshold mood signs/symptoms among patients with AN-R, and BN and with no Axis I comorbidity for mood disorders, and provides a better definition of clinical phenotypes. PMID- 27766499 TI - Arteries and Veins of the Cerebellum. AB - Surgery of the posterior fossa represents a technical challenge because of the proximity of the vessels of the cerebellum. If the arterial vascularization of the cerebellum is well known, the main arterial variations and the whole venous vascularization are probably under recognized. We describe the vascular organization and the main variations through photographs of colored latex perfused brains, obtained with a surgical microscope. The arterial vascularization of the cerebellum is based on three arteries which all originate from the vertebrobasilar system: the superior cerebellar artery (SCA), the anterior and inferior cerebellar artery (AICA), and the posterior and inferior cerebellar artery (PICA). The main arterial variations involve essentially the origin of these vessels. Concerning the SCA, its origin depends on the embryology. The AICA can arise from a common trunk AICA-PICA. It can be sometimes doubled and rarely absent. The PICA also can arise from a common trunk AICA-PICA and sometimes from the extradural segment of the vertebral artery. Concerning the venous organization, we distinguish the superficial and deep veins. The superficial veins drain the cerebellar cortex and transit on the surface of the cerebellum. The deep veins refer to the veins transiting in the fissures between the cerebellum and the brainstem. All these veins terminate as bridging veins that we can divide in three groups: a superior group emptying into the great vein, a posterior group emptying into the transtentorial sinus, and a lateral group ending into the superior petrosal sinus. The surgical implications are discussed. PMID- 27766500 TI - A quantitative comparison of ward-based clinical pharmacy activities in 7 acute UK hospitals. AB - Background Several clinical pharmacy activities are common to UK hospitals. It is not clear whether these are provided at similar levels, and whether they take similar amounts of time to carry out. Objective To quantify and compare clinical pharmacist ward activities between different UK hospitals. Setting Seven acute hospitals in the Greater London area (UK). Methods A list of common ward activities was developed. On five consecutive days, pharmacists visiting hospital wards documented total time spent and how many of each activity they undertook. Results were analysed by hospital. The range and number of activities per 100 occupied bed days, and per 24 beds were compared. Main outcome measure Time spent on wards and numbers of each activity undertaken. Results Pharmacists logged a total of 2291 h carrying out 40,000 activities. 4250 changes to prescriptions were made or recommended. 5901 individual medication orders were annotated for clarity or safety. For every 24 beds visited, mean time spent was 230 min-seeing 6.2 new patients, carrying out 3.9 calculations and 1.3 patient consultations, checking and authorising 1.8 discharge prescriptions, and providing staff with information twice. Other activities varied significantly, not all could be explained by differences in hospital specialties or Information Technology systems. Conclusion This is the first detailed comparison of clinical pharmacy ward activities between different hospitals. There are some typical levels of activities carried out. Wide variations in other activities could not always be explained. Despite a large number of contacts, pharmacists reported very few consultation sessions with patients. PMID- 27766501 TI - Pharmaceutical care as narrative practice? Rethinking patient-centered care through a pharmacist's perspective. AB - Illness is a disruptive experience that requires high-quality care. The best evidence-based medical treatment risks losing some of its efficacy, however, when patients feel misunderstood when faced with the complexity of their experiences. They might stop treatment, refuse to disclose relevant information or seek unsound alternatives. A narrative-based approach to health care understands the patient's case history as a narrative that can be read or analyzed like a story. In other words, this approach honors individual illness experiences through the stories that patients tell. While programs that train 'narrative competence' have been successfully implemented in medical education, an application to pharmaceutical training is missing so far. We argue for the necessity to complement evidence-based pharmaceutical practice with narrative-based approaches to ensure high-quality care. Using the perspective of a pharmacist in a case scenario, we exemplify the centrality of "narrative pharmacy" for improving the quality and safety of pharmaceutical health care. PMID- 27766502 TI - Dynamic domains of amyloid fibrils can be site-specifically assigned with proton detected 3D NMR spectroscopy. AB - Several amyloid fibrils have cores framed by highly dynamic, intrinsically disordered, domains that can play important roles for function and toxicity. To study these domains in detail using solid-state NMR spectroscopy, site-specific resonance assignments are required. Although the rapid dynamics of these domains lead to considerable averaging of orientation-dependent NMR interactions and thereby line-narrowing, the proton linewidths observed in these samples is far larger than what is regularly observed in solution. Here, we show that it is nevertheless possible to record 3D HNCO, HNCA, and HNcoCA spectra on these intrinsically disordered domains and to obtain site-specific assignments. PMID- 27766503 TI - Computational investigation of the properties of double furazan-based and furoxan based energetic materials. AB - As a kind of promising energetic materials, the double furazan-based and furoxan based compounds have raised concerns of many researchers in recent years. In this paper, the optimized structures, energetic properties, heat of formation (HOF), detonation properties, and bond dissociation energies of these compounds were calculated by density functional theory (DFT) method. The results show that the N O bond, which is close to the adjacent coordinated oxygen atom in furoxan ring, is more fragile than the other N-O bonds in the ring. The double furazan-based derivatives are more stable than the double furoxan-based derivatives. All the titled compounds are divided into five groups because of the different substitute groups on both ends. The HOFs of the substances offer the order of 4 group (the both ends are 1,2,3,4-tetrazine ) ~ 5 group (1,2,4,5-tetrazine) > 3 group (tetrazole) ~ 1 group (1,2,3-triazole) > 2 group (1,2,4-triazole). All the title compounds also can be divided into three types with the different linkages, -N=N , -N=N(O)-, and -NH-NH-. The results show that the HOFs of the compounds with different linkages obey the order -N=N- type > -N=N(O)- type> -NH-NH- type. For all titled compounds, bis(4-(1,2,4,5-tetrazin-3-yl)-1,2,5-oxadiazol-3-yl) diazene (E5) has the best gas-phase and solid-phase HOFs. The heat of detonation(Q) of bis(3-(1,2,3,4-tetrazin-5-yl)-1,2,5-oxidiazole-2 -oxide)diazene-1,2-diyl (B4) is the best of all titled compounds. The density of bis((3-2H-tetrazol-5-yl)-1,2,5 oxidiazole -2-oxide)oxidodiazene-1,2-diyl (A3) is the best and the second best is bis((4-2H-tetrazol-5-yl)-1,2,5-oxidiazol-3-yl) diazene (E3). The detonation velocities and detonation pressure of A3 and E3 are better than other titled compounds. 1,2-bis((4-2H-tetrazol-5-yl)-1,2,5 -oxidiazol-3-yl) diazene-1-oxide (D3) and 1,2-bis((4-2H-tetrazol-5-yl)-1,2,5-oxidiazol-3-yl) hydrazine (F3) have superior D and P with low sensitivity. The tetrazole ring plays a vital role in improving detonation velocities and pressure. The results can provide some foundational information for designing new high-density energetic materials. PMID- 27766504 TI - Curcumin inhibits paraquat induced lung inflammation and fibrosis by extracellular matrix modifications in mouse model. AB - OBJECTIVE: Paraquat (PQ), a potent herbicide can cause severe toxicity. We report here that fibroproliferation phase of acute lung injury (ALI) is initiated much earlier (within 48 h) after PQ intoxication than previously reported (after 2 weeks) and we aimed to study the protective effects of intranasal curcumin as new therapeutic strategy in mouse model. METHODS: Mice (Park's strain) were divided into five experimental groups (I) control, received only saline (0.9 % NaCl) (II) PQ, mice intoxicated with PQ (50 mg/kg, i.p., single dose); (III) curcumin, treated with curcumin (5 mg/kg, i.n) an hour before PQ administration; (IV)Veh, DMSO (equal volume to curcumin) given an hour before PQ exposure; (V) DEXA, mice treated with dexamethasone (1 mg/kg, i.p) before an hour of PQ intoxication. After 48 h of the PQ exposure, all mice were sacrificed and samples were analyzed. RESULTS: Pretreatment with intranasal curcumin (5 mg/kg) could modify the PQ-intoxication (50 mg/kg, i.p) induced structural remodeling of lung parenchyma at an early phase of acute lung injury. Significant increase in inflammatory cell count, reactive oxygen species and hydroxyproline levels were decreased after curcumin pretreatment (all p < 0.05). Histological examination and zymography results were also found consistent. CONCLUSION: Our results show that curcumin pretreatment decreased the expression of alpha smooth muscle actin (alpha-SMA), matrix metalloproteinases-9 (MMP-9) and changed the expression of tissue inhibitors of metalloproteinase (TIMP-1) after PQ intoxication. Single toxic dose of PQ has initiated fibroproliferation within 48 h and intranasal curcumin may prove as new therapeutic strategy for PQ induced ALI and fibroproliferation. PMID- 27766505 TI - Proper balance of omega-3 and omega-6 fatty acid supplements with topical cyclosporine attenuated contact lens-related dry eye syndrome. AB - Essential fatty acids had been applied in the treatment of dry eye syndrome (DES), but the effects of different combinations of fatty acids have not been investigated. 360 long-term contact lens wearers were included in this double blinded study. Omega-3 and omega-6 fatty acids were combined in different ratios and supplied to the participants that were randomly divided into six groups, and the effects of different essential fatty acids mixture on DES with or without topical cyclosporine were investigated. More than half of long-term contact lens wearers suffered from DES, which were found to be attenuated by oral supplement of properly balanced O3FA and O6FA fatty acid. The topical cyclosporine treatment considerably inhibited the production of cytokines compared to the cyclosporine negative groups, which further relieved DES. Proper balance of omega-3 and omega 6 fatty acid combination significantly alleviated contact lens-related DES. PMID- 27766506 TI - Correlates of Dominicans' Identification of Cancer as a Worrisome Health Problem. AB - There is a paucity of studies centering on the correlates of cancer worry among Hispanics from the Dominican Republic and the potential informatics strategies to address such worries. Data were analyzed using descriptive and correlational statistics, and logistic regression with the dependent variable of cancer worry. Independent variables for the regression were: age, gender, marital status, education, socioeconomic status, previous diagnosis of cancer, anxiety, depression, sleep disturbance, and chronic burden. Four variables significantly increased cancer worry: married marital status (OR = 1.19 [95% CI 1.01, 1.41]), younger age (OR = .992 [95% CI 0.987, 0.997]), less depression (OR = .96 [95% CI 0.94, 0.98]), and cancer diagnosis (OR = 2.12 [95% CI 1.24, 3.65]). New knowledge was generated on the contextual factors that influence these health concerns in a major Hispanic sub-group. Implications for practice, research and education are discussed. PMID- 27766507 TI - Systematic Review of the Effect of Lifestyle Interventions on the Components of the Metabolic Syndrome in South Asian Migrants. AB - A systematic review was undertaken to identify lifestyle intervention studies in South Asian migrant populations to determine the effect on the components of the metabolic syndrome. A total of seven studies were identified, of which six focused on educational advice and the seventh on intensive exercise intervention. Four studies were Randomised Controlled Trials of which two studies reported significant reductions in waist circumference. One of these studies focused on home based education with cooperation of the home cook (adjusted waist reduction of 1.9 cm, 95 % CI 0.52-3.3 cm; p = 0.007) and the other entailed an intensive physical activity program (adjusted waist reduction 3.4 cm, 95 % CI 2.0-4.7 cm). The evidence whether lifestyle intervention studies in South Asians can improve components of the metabolic system is not clear. Further lifestyle interventions for South Asians should be culturally adapted, involve friends and family, especially those with cooking responsibilities. PMID- 27766508 TI - Polyclonal Antibody Development Against Purified CC-NBS-LRR like Protein Fragment from Mature Lageneria siceraria Seeds and Immunolocalization. AB - CC-NBS-LRR (CNL) plant proteins are related with highly conserved family of disease resistance protein distinguished by a coiled-coil domain, which plays an important role in innate immunity. The present study reports the purification and identification of CNL like protein fragment (CNL-LPF) by two step chromatography and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF/MS), respectively. Furthermore, current study also illustrated the development of polyclonal antibody against purified CNL-LPF, which was used for immunolocalization of CNL-LPF in cytoplasm of cotyledon, using Fluorescence microscopy and Transmission electron microscopy. Lastly, present study also demonstrates in vitro oligomerization of purified CNL-LPF with multiple bands on 4-10 % gradient native-PAGE; each band representing a small fraction of each oligomer population as evident by immunoblots. In conclusion, the current study deals with the purification and polyclonal antibody development against CNL-LPF. PMID- 27766509 TI - Simulation-based approximate policy iteration for dynamic patient scheduling for radiation therapy. AB - We study radiation therapy scheduling problem where dynamically and stochastically arriving patients of different types are scheduled to future days. Unlike similar models in the literature, we consider cancellation of treatments. We formulate this dynamic multi-appointment patient scheduling problem as a Markov Decision Process (MDP). Since the MDP is intractable due to large state and action spaces, we employ a simulation-based approximate dynamic programming (ADP) approach to approximately solve our model. In particular, we develop Least square based approximate policy iteration for solving our model. The performance of the ADP approach is compared with that of a myopic heuristic decision rule. PMID- 27766511 TI - The Efficacy and Safety of Tolvaptan in Patients with Hyponatremia: A Meta Analysis of Randomized Controlled Trials. AB - BACKGROUND AND OBJECTIVES: Comprehensive evaluations regarding the benefits of tolvaptan in the treatment of hyponatremia are lacking. The objective of this meta-analysis was to assess the efficacy and safety of tolvaptan in patients with hyponatremia. METHODS: Pertinent studies were identified by searching PubMed, EMBASE, Web of Science, and the Cochrane Library for articles published between their respective inception dates and 31 April 2016. Summary relative risks (RRs) or weighted mean differences (WMDs) with their 95 % confidence intervals (CIs) were calculated using fixed-effects or randomized-effects models, depending on the degree of heterogeneity noted among the studies included in the analysis. RESULTS: Eleven articles comprising 5209 patients were ultimately included in the analysis. Our pooled results showed that tolvaptan was more effective than control with respect to increasing serum sodium concentrations (WMD = 3.99 mEq/L), 95 % CI 2.80-5.19, Z = 6.56, P < 0.001), improving serum sodium correction rates (RR = 3.35, 95 % CI 1.93-5.82, Z = 4.31, P < 0.001), improving 24-h urine output (WMD = 987.64 mL, 95 % CI 850.71-1124.57, Z = 14.14, P < 0.001), and improving net fluid balance (WMD = 795.97 mL, 95 % CI 418.56-1173.38, Z = 4.13, P < 0.001). Tolvaptan treatment also resulted in increased incidences of adverse events compared with control treatment (RR = 1.05, 95 % CI 1.02-1.07, Z = 3.83, P < 0.001). These events included dry mouth (RR = 2.38, 95 % CI 1.41 4.04, Z = 3.23, P = 0.001), thirst (RR = 3.85, 95 % CI 1.96-7.57, Z = 3.92, P < 0.001), pollakiuria (RR = 2.47, 95 % CI 1.41-4.33, Z = 3.16, P = 0.002), and overly rapid hyponatremia correction (RR = 8.43, 95 % CI 1.06-66.96, Z = 2.02, P = 0.04). No significant differences in all-cause mortality (RR = 0.99, 95 % CI 0.90-1.10, Z = 0.17, P = 0.86), serious adverse event rate (RR = 1.01, 95 % CI 0.80-1.29, Z = 0.11, P = 0.92), systolic blood pressure (WMD = 0.1 mmHg, 95 % CI 1.04 to 1.23, Z = 0.17, P = 0.87), or heart rate (WMD = -0.16 bpm, 95 % CI -1.14 to 0.82, Z = 0.31, P = 0.76) were noted between the two groups, based on the results of our meta-analysis. CONCLUSION: The results of this meta-analysis suggest that tolvaptan can increase serum sodium concentrations, serum sodium correction rates, 24-h urine output, net fluid balance, and total adverse event rates without significantly decreasing all-cause mortality rates or increasing serious adverse event rates in patients with hyponatremia. PMID- 27766512 TI - Extensive Diminution of Particle Size and Amorphization of a Crystalline Drug Attained by Eminent Technology of Solid Dispersion: A Comparative Study. AB - The present study emphasized on the use of solid dispersion technology to triumph over the drawbacks associated with the highly effective antihypertensive drug telmisartan using different polymers (poloxamer 188 and locust bean gum) and methods (modified solvent evaporation and lyophilization). It is based on the comparison between selected polymers and methods for enhancing solubility through particle size reduction. The results showed different profiles for particle size, solubility, and dissolution of formulated amorphous systems depicting the great influence of polymer/method used. The resulting amorphous solid dispersions were characterized using x-ray diffraction (XRD), differential scanning calorimetry, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and particle size analysis. The optimized solid dispersion (TEL 19) prepared with modified locust bean gum using lyophilization technique showed reduced particle size of 184.5 +/- 3.7 nm and utmost solubility of 702 +/- 5.47 MUg/mL in water, which is quite high as compared to the pure drug (<=1 MUg/mL). This study showed that the appropriate selection of carrier may lead to the development of solid dispersion formulation with desired solubility and dissolution profiles. The optimized dispersion was later formulated into fast-dissolving tablets, and further optimization was done to obtain the tablets with desired properties. PMID- 27766510 TI - Ivabradine in Patients with Stable Coronary Artery Disease: A Rationale for Use in Addition to and Beyond Percutaneous Coronary Intervention. AB - Heart rate is an established prognostic marker for longevity and is an important contributor in the pathophysiology of various cardiovascular diseases, including ischemic heart disease and heart failure. Most ischemic episodes are triggered by an increase in heart rate, which causes an imbalance between myocardial oxygen delivery and consumption. In addition, increased heart rate is a modifiable risk factor for chronic heart failure. Ivabradine, an inhibitor of If ion channels, is an approved second-line anti-ischemic drug for the treatment of angina. Ivabradine has been shown to decrease the risk of hospitalization in patients with chronic heart failure who were previously treated with beta-blockers, renin angiotensin system blockers or mineralocorticoid receptor antagonists. This review describes the rationale for the pathophysiological and clinical use of ivabradine as an anti-ischemic agent in patients with stable coronary disease and highlights its benefits and drawbacks compared with other first- and second-line anti-anginal drugs. The review also highlights the role of ivabradine as a treatment for patients with high-risk coronary artery disease in whom first-line anti-anginal drugs are insufficient or inadequate and percutaneous coronary intervention is contraindicated or revascularization is incomplete or unsuitable. PMID- 27766513 TI - Risk factors for postoperative delirium after spine surgery in middle- and old aged patients. AB - BACKGROUND: Postoperative delirium is a common complication following various operative procedures with an incidence rate of 10-77 %. AIM: To analyze various risk factors for postoperative delirium after spine surgery in the middle- and old-aged patients. METHODS: This study retrospectively reviewed 451 patients (226 males and 225 females, an average age of 65.1 +/- 18.3 years) who underwent spinal surgery in our hospital between January 2010 and August 2015. Patients who had features of acute onset and fluctuating course and any two of the other features were diagnosed with delirium. Cognitive tests consisting of Clinical Dementia Rating and Global Deterioration Scale were performed to evaluate delirium. T tests were used for statistical analysis of the difference between the two groups, and logistic regression analyses were used for determining the risk factors. RESULTS: A total of 42 (9.3 %) patients were diagnosed with delirium. Delirious and non-delirious patients had no difference in age, gender, BMI, education level, drug treatment, comorbid disease history, surgical history, preoperative blood pressure, intraoperative blood loss, blood transfusion, use of surgical implants, surgical site, use of fentanyl and propofol, and preoperative VAS score. Intraoperative hypotension and use of dezocine were related to postoperative delirium (P = 0.03 and P = 0.07). The multiple regression equation was Y = -0.11 + 0.52 * X 0 + 0.21 * X 1, where X 0 = amount of dezocine, X 1 = instances of intraoperative hypotension. CONCLUSION: Postoperative delirium commonly occurs after spine surgery. Intraoperative hypotension <80 mmHg and intraoperative use of dezocine represent valuable new predictors of the risk of delirium. PMID- 27766514 TI - The incremental benefit of non-pulmonary vein left atrial ablation in patients undergoing a repeat persistent atrial fibrillation ablation procedure. AB - PURPOSE: Atrial fibrillation (AF) recurrence after an initial persistent AF ablation procedure is high, frequently resulting in the need for a repeat AF ablation procedure. Guidance on the optimal strategy for repeat procedures is non existent. The objective of this study was to compare the freedom from recurrent atrial arrhythmia associated with two strategies for repeat persistent AF ablation procedure: (1) pulmonary vein re-isolation alone and (2) non-pulmonary vein LA ablation in addition to pulmonary vein re-isolation. METHODS: A retrospective multi-center case-controlled study was undertaken. Time-to recurrent AF with each strategy was assessed using Kaplan-Meier curves. A Cox proportional-hazards regression model was used to determine time-dependent predictors of recurrent AF after the repeat procedure in the entire cohort. RESULTS: Ninety-eight patients were included in the cohort-39 patients who did not undergo additional LA ablation and 59 patients who had did. AF after the repeat procedure occurred in 38 % of the cohort during a mean follow-up of 18 +/- 11 months. Additional LA ablation at the repeat procedure was not associated with a less arrhythmia recurrence (HR = 1.55, p = 0.28). The only variable associated with arrhythmia recurrence after the repeat procedure was additional LA ablation during the initial ablation procedure (HR = 4.13, p = 0.005). CONCLUSIONS: LA ablation in addition to pulmonary vein re-isolation during a repeat persistent AF ablation procedure was not associated with reduced arrhythmia recurrence after a repeat persistent AF ablation procedure. PMID- 27766516 TI - Proxy-reported quality of life in adolescents and adults with dyskinetic cerebral palsy is associated with executive functions and cortical thickness. AB - PURPOSE: Quality of life (QOL) is a key outcome for people with cerebral palsy (CP), and executive functioning is an important predictor of QOL in other health related conditions. Little is known about this association in CP or about its neural substrate. We aim to analyze the influence of executive functioning (including cognitive flexibility) as well as that of other psychological, motor, communication and socioeconomic variables on QOL and to identify neuroanatomical areas related to QOL in adolescents and adults with CP. METHODS: Fifty subjects diagnosed with dyskinetic CP (mean age 25.96 years) were recruited. Their caregivers completed the primary caregiver proxy report version of the CP QOL Teen questionnaire. Motor status, communication, IQ, four executive function domains, anxiety/depression and socioeconomic status were evaluated. Correlations and multiple linear regression models were used to relate CP QOL domains and total score to these variables. Thirty-six participants underwent an MRI assessment. Correlations were examined between cortical thickness and CP QOL total score and between cortical thickness and variables that might predict the CP QOL total score. RESULTS: Executive functions predict scores in four domains of CP QOL (General well-being and participation, Communication and physical health, Family health and Feelings about functioning) in the regression model. Among the cognitive domains that comprise executive function, only cognitive flexibility measured in terms of performance on the Wisconsin card sorting test (WCST) predicts the CP QOL total score. Monthly income, fine motor functioning and communication ability predict scores on the domains Access to services and Family Health, Feelings about functioning and School well-being, respectively. The clusters resulting from the correlation between cortical thickness and both CP QOL total score and WCST performance overlapped in the posterior cingulate and precuneus cortices. CONCLUSIONS: Cognitive flexibility predicts proxy report CP QOL-Teen total score in dyskinetic CP. This relationship has its anatomical correlate in the posterior cingulate and precuneus cortices. PMID- 27766515 TI - Patient-reported outcome measures in older people with hip fracture: a systematic review of quality and acceptability. AB - PURPOSE: Hip fracture is the most common serious injury of older people, often resulting in reduced mobility and loss of independence. However, guidance for the use of patient-reported outcome measures (PROMs) does not exist: we describe the first review to apply internationally endorsed criteria in support of PROM quality and acceptability in this group, and make recommendations for future applications. METHODS: Systematic literature searches of major databases (1980 2015) to identify published evidence of the application and quality of clearly defined measures. Evidence of measurement and practical properties, and the extent of active patient involvement, was sought. Study and PROM quality was assessed against recommended criteria. RESULTS: Seventy-one articles relating to 28 PROMs (Generic n = 12; Specific n = 16) were included. The SF-36 (v1) and EuroQoL EQ-5D 3L were the most widely evaluated measures with acceptable evidence of measurement properties, but limited evaluations of practical properties or relevance to this group. Evidence was mostly limited for the remaining measures. Hypothesized associations between variables were infrequently evaluated. Evidence of data quality, test-retest reliability, responsiveness, interpretation, acceptability and feasibility was also limited. Active patient involvement in PROM development or evaluation was not reported. There was limited evaluation of proxy completions. CONCLUSIONS: The paucity of robust evaluations is disappointing and prevents clear recommendations for PROM-based assessment. Further research must urgently seek to identify which outcomes really matter to this group. Future PROM selection must be underpinned by research which focuses on methodological quality, including issues of acceptability, relevance, feasibility of application, and proxy completion, whilst seeking to actively incorporate the perspective of patients and their advocates. PMID- 27766517 TI - Quality of life in people aged 65+ in Europe: associated factors and models of social welfare-analysis of data from the SHARE project (Wave 5). AB - PURPOSE: To analyse the clinical, sociodemographic and socioeconomic factors that influence perceived quality of life (QoL) in a community sample of 33,241 people aged 65+ and to examine the relationship with models of social welfare in Europe. METHODS: This was a cross-sectional study of data from Wave 5 (2013) of the Survey of Health, Ageing and Retirement in Europe (SHARE). The instruments used in the present study were as follows: sociodemographic data, CASP-12 (QoL), EURO D (depression), indicators of life expectancy and suicide (WHO), and economic indicators (World Bank). Statistical analysis included bivariate and multilevel analyses. RESULTS: In the multilevel analysis, greater satisfaction in life, less depression, sufficient income, better subjective health, physical activity, an absence of functional impairment, younger age and participation in activities were associated with better QoL in all countries. More education was only associated with higher QoL in Eastern European and Mediterranean countries, and only in the latter was caring for grandchildren also related to better QoL. Socioeconomic indicators were better and QoL scores higher (mean = 38.5 +/- 5.8) in countries that had a social democratic (Nordic cluster) or corporatist model (Continental cluster) of social welfare, as compared to Eastern European and Mediterranean countries, which were characterized by poorer socioeconomic conditions, more limited social welfare provision and lower QoL scores (mean = 33.5 +/- 6.4). CONCLUSIONS: Perceived quality-of-life scores are consistent with the sociodemographic and clinical characteristics of participants, as well as with the socioeconomic indicators and models of social welfare of the countries in which they live. PMID- 27766518 TI - Algorithm to improve accuracy of energy expended in a room calorimeter. AB - The whole-room indirect calorimeter is considered as important equipment for human energy expenditure measurement, but noise reduction in the system remains a challenge. A selective filtering method (SFM) was designed to improve the accuracy of the computation of O2 consumption rate ([Formula: see text]) and CO2 production rate ([Formula: see text]), based on two facts: (1) the rapid changes of [Formula: see text], [Formula: see text] and respiratory quotient (RQ) in human should be accompanied by physical activity; (2) the oxygen consumption and the carbon dioxide production should not be negative because living humans do not generate oxygen, nor consume carbon dioxide. The performance of SFM was compared with the moving average method, the central difference method and the wavelet de noising method. The range of [Formula: see text] and [Formula: see text] in the empty room (the background noise) is reduced from -130.00-146.00 ml/min to -26.00 24.00 ml/min, and from -20.50-12.50 ml/min to -3.99-4.19 ml/min, by SFM. The background noise was added to simulated rectangular and sinusoidal signals that were used to evaluate the four methods over different time periods (64, 32, 16 and 8 min). The highest signal-to-noise ratio and the lowest deviation were achieved by SFM. Abnormal metabolic rates and RQs were corrected and compensated with measurement accuracy of 98.51 +/- 0.3 % for 24-h alcohol burning tests. The results of the study showed that SFM can significantly improve [Formula: see text] and [Formula: see text] measurements. PMID- 27766519 TI - Sparse representation-based EMD and BLDA for automatic seizure detection. AB - Epilepsy is a serious chronic neurological disorder, which affects more than 50 million people worldwide, and automatic seizure detection on EEG recordings is extremely required in the diagnosis and monitoring of epilepsy. This paper presents a novel seizure detection method using sparse representation-based Earth Mover's Distance (SR-EMD). In the proposed algorithm, wavelet decomposition is executed on the original EEG recordings with five scales, and the scales 3, 4 and 5 are selected to structure the distributions of EEG signals. Then, the Gaussian mixture models (GMMs) of EEG signals are estimated and the distances between GMMs are computed using SR-EMD as EEG features. After that, EEG features are sent to Bayesian linear discriminant analysis classifier for classification. To improve the detection accuracy, the post-processing procedure is employed finally. The long-term intracranial EEG dataset with 21 patients is used to evaluate the performance of the method, and the satisfactory sensitivity of 93.54 %, specificity of 97.57 % and false detection rate of 0.223/h are achieved. The results indicate that SR-EMD is more effective and efficient than the conventional Earth Mover's Distance (EMD). Moreover, the good performance and fast speed of this algorithm make it suitable for the real-time seizure monitoring application. PMID- 27766520 TI - Application of artificial neural network model combined with four biomarkers in auxiliary diagnosis of lung cancer. AB - The purpose of the study was to explore the application of artificial neural network model in the auxiliary diagnosis of lung cancer and compare the effects of back-propagation (BP) neural network with Fisher discrimination model for lung cancer screening by the combined detections of four biomarkers of p16, RASSF1A and FHIT gene promoter methylation levels and the relative telomere length. Real time quantitative methylation-specific PCR was used to detect the levels of three gene promoter methylation, and real-time PCR method was applied to determine the relative telomere length. BP neural network and Fisher discrimination analysis were used to establish the discrimination diagnosis model. The levels of three gene promoter methylation in patients with lung cancer were significantly higher than those of the normal controls. The values of Z(P) in two groups were 2.641 (0.008), 2.075 (0.038) and 3.044 (0.002), respectively. The relative telomere lengths of patients with lung cancer (0.93 +/- 0.32) were significantly lower than those of the normal controls (1.16 +/- 0.57), t = 4.072, P < 0.001. The areas under the ROC curve (AUC) and 95 % CI of prediction set from Fisher discrimination analysis and BP neural network were 0.670 (0.569-0.761) and 0.760 (0.664-0.840). The AUC of BP neural network was higher than that of Fisher discrimination analysis, and Z(P) was 0.76. Four biomarkers are associated with lung cancer. BP neural network model for the prediction of lung cancer is better than Fisher discrimination analysis, and it can provide an excellent and intelligent diagnosis tool for lung cancer. PMID- 27766521 TI - A Bayesian approach of high impaired river reaches identification and total nitrogen load estimation in a sparsely monitored basin. AB - In this study, a modeling framework based on the theory of SPAtially Referenced Regression On Watershed attributes (SPARROW) model was developed to identify impaired river reaches with respect to total nitrogen (TN) and estimate the TN sources in the Xin'anjiang River basin, which had limited monitoring sites. A Bayesian approach was applied to estimate the mean values and uncertainties of parameters, including land use export coefficients and in-stream attention rates. Based on the parameters, the midranges (25-75 %) of annual TN concentrations were assessed by the model and 4.5 % of river reaches in the basin were found to be with higher impaired probabilities (namely [TN] > 1.5 mg/l) than other reaches. The amount and yields of TN discharged from diffuse sources were estimated for each county in the basin. The results suggested that Tunxi City had the highest TN yields from farm land and population, while the highest TN yields in Huangshan City were from tea plantations. The outcomes of this study will guide the implementation of practical management measures to reduce TN loads. PMID- 27766522 TI - Biofouling of leisure boats as a source of metal pollution. AB - The release of harmful metals from antifouling paints to water bodies is a well known problem. In this study, we measured both the amount of biofouling growth on leisure boats during one season as well as the concentration of metals accumulated by the biofouling matrix. Furthermore, the efficiency of antifouling paints and mechanical boat cleaning as well as the effect of hull colour on biofouling were evaluated. Unlike paint residues, biofouling waste has never been regarded as a source of metal contamination and has previously been neglected in the scientific literature. Our results revealed that the biofouling waste contained very high concentrations of metals, up to 28,000 mg copper/kg dw and 171,000 mg zinc/kg dw, which exceeds the guidance values for least sensitive land use in Sweden by factors of 140 and 340, respectively. This observation is important because the contaminated biofouling waste is commonly disposed of in boatyard soils at the end of each season, thus increasing the levels of metal pollution. Moreover, there was no significant difference in the amount of biofouling if the boats were coated with copper or zinc containing paints or no paint at all, indicating that biocide paints might not be necessary in low salinity areas such as the Stockholm archipelago. For boats that were not painted at all during the season, those washed on boat washers (mechanically) had on average half of the amount of biofouling compared to boats that were not cleaned mechanically. The results of the study indicate the importance of proper management of biofouling waste as well as the use of more environmentally friendly removal methods for biofouling such as boat washers. PMID- 27766524 TI - Effects of biochar and maize straw on the short-term carbon and nitrogen dynamics in a cultivated silty loam in China. AB - Application of maize straw and biochar can potentially improve soil fertility and sequester carbon (C) in the soil, but little information is available about the effects of maize straw and biochar on the mineralization of soil C and nitrogen (N). We conducted a laboratory incubation experiment with five treatments of a cultivated silty loam, biochar produced from maize straw and/or maize straw: soil only (control), soil + 1 % maize straw (S), soil + 4 % biochar (B1), soil + 4 % biochar + 1 % maize straw (B1S), and soil + 8 % biochar + 1 % maize straw (B2S). CO2 emissions, soil organic C, dissolved organic C, easily oxidized C, total N, mineral N, net N mineralization, and microbial biomass C and N of three replicates were measured periodically during the 60-day incubation using destructive sampling method. C mineralization was highest in treatment S, followed by B2S, B1S, the control, and B1. Total net CO2 emissions suggested that negative or positive priming effect may occur between the biochar and straw according to the biochar addition rate, and biochar mineralization was minimal. By day 35, maize straw, irrespective of the rate of biochar addition, significantly increased microbial biomass C and N but decreased dissolved organic N. Biochar alone, however, had no significant effect on either microbial biomass C or N but decreased dissolved organic N. Mixing the soil with biochar and/or straw significantly increased soil organic C, easily oxidized C and total N contents, and decreased dissolved organic N content. Dissolved organic C contents showed mixed results. Notably, N was immobilized in soil mixed with straw and/or biochar, but the effect was stronger for soil mixed with straw, which may cause N deficiency for plant growth. The application of biochar and maize straw can thus affect soil C and N cycles, and the appropriate proportion of biochar and maize straw need further studies to increase C sequestration. PMID- 27766523 TI - Chemical treatment of contaminated sediment for phosphorus control and subsequent effects on ammonia-oxidizing and ammonia-denitrifying microorganisms and on submerged macrophyte revegetation. AB - In this work, sediments were treated with calcium nitrate, aluminum sulfate, ferric sulfate, and Phoslock(r), respectively. The impact of treatments on internal phosphorus release, the abundance of nitrogen cycle-related functional genes, and the growth of submerged macrophytes were investigated. All treatments reduced total phosphorus (TP) and soluble reactive phosphorus (SRP) in interstitial water, and aluminum sulfate was most efficient. Aluminum sulfate also decreased TP and SRP in overlying water. Treatments significantly changed P speciations in the sediment. Phoslock(r) transformed other P species into calcium bound P. Calcium nitrate, ferric sulfate, and Phoslock(r) had negative influence on ammonia oxidizers, while four chemicals had positive influence on denitrifies, indicating that chemical treatment could inhibit nitrification but enhance denitrification. Aluminum sulfate had decreased chlorophyll content of the leaves of submerged macrophytes, while ferric sulfate and Phoslock(r) treatment would inhibit the growth of the root. Based on the results that we obtained, we emphasized that before application of chemical treatment, the effects on submerged macrophyte revegetation should be taken into consideration. PMID- 27766525 TI - Comparison of the qCON and qNOX indices for the assessment of unconsciousness level and noxious stimulation response during surgery. AB - The objective of this work is to compare the performances of two electroencephalogram based indices for detecting loss of consciousness and loss of response to nociceptive stimulation. Specifically, their behaviour after drug induction and during recovery of consciousness was pointed out. Data was recorded from 140 patients scheduled for general anaesthesia with a combination of propofol and remifentanil. The qCON 2000 monitor (Quantium Medical, Barcelona, Spain) was used to calculate the qCON and qNOX. Loss of response to verbal command and loss of eye-lash reflex were assessed during the transition from awake to anesthetized, defining the state of loss of consciousness. Movement as a response to laryngeal mask (LMA) insertion was interpreted as the response to the nociceptive stimuli. The patients were classified as movers or non-movers. The values of qCON and qNOX were statistically compared. Their fall times and rise times defined at the start and at the end of the surgery were calculated and compared. The results showed that the qCON was able to predict loss of consciousness such as loss of verbal command and eyelash reflex better than qNOX, while the qNOX has a better predictive value for response to noxious stimulation such as LMA insertion. From the analysis of the fall and rise times, it was found that the qNOX fall time (median: 217 s) was significantly longer (p value <0.05) than the qCON fall time (median: 150 s). At the end of the surgery, the qNOX started to increase in median at 45 s before the first annotation related to response to stimuli or recovery of consciousness, while the qCON at 88 s after the first annotation related to response to stimuli or recovery of consciousness (p value <0.05). The indices qCON and qNOX showed different performances in the detection of loss of consciousness and loss of response to stimuli during induction and recovery of consciousness. Furthermore, the qCON showed faster decrease during induction. This behaviour is associated with the hypothesis that the loss of response to stimuli (analgesic effect) might be reached after the loss of consciousness (hypnotic effect). On the contrary, the qNOX showed a faster increase at the end of the surgery, associated with the hypothesis that a higher probability of response to stimuli might be reached before the recovery of consciousness. PMID- 27766527 TI - High prevalence of congenital thrombophilia in patients with pregnancy-related or idiopathic venous thromboembolism/pulmonary embolism. AB - Congenital thrombophilia which is characterized by deficiencies in proteins such as antithrombin (AT), protein C (PC) and protein S (PS), is a major cause of venous thromboembolism (VTE). A total of 130 patients with VTE were evaluated for congenital thrombophilia based on the activity of AT, PC, or PS. Fifteen VTE patients with congenital AT deficiency (11.5 %), 16 with congenital PC deficiency (12.3 %) and eight with congenital PS deficiency (6.2 %) were diagnosed using DNA analysis. The frequency of congenital AT deficiency was significantly higher in subjects with pregnancy-related and idiopathic VTE than in those with VTE due to other causes, and congenital PC and PS deficiency were frequently associated with idiopathic VTE. Among the groups examined, the plasma levels of AT were the lowest in subjects with pregnancy-related VTE. Although our findings may have been influenced by some unintentional bias, congenital thrombophilia is nevertheless a major cause of VTE in pregnant patients as well as in young or middle-aged patients without any underlying diseases. PMID- 27766526 TI - Implementation of a novel postoperative monitoring system using automated Modified Early Warning Scores (MEWS) incorporating end-tidal capnography. AB - Modified Early Warning Scores (MEWS) provide real-time vital sign (VS) trending and reduce ICU admissions in post-operative patients. These early warning calculations classically incorporate oxygen saturation, heart rate, respiratory rate, systolic blood pressure, and temperature but have not previously included end-tidal CO2 (EtCO2), more recently identified as an independent predictor of critical illness. These systems may be subject to failure when physiologic data is incorrectly measured, leading to false alarms and increased workload. This study investigates whether the implementation of automated devices that utilize ongoing vital signs monitoring and MEWS calculations, inclusive of a score for end-tidal CO2 (EtCO2), can be feasibly implemented on the general care hospital floor and effectively identify derangements in a post-operative patient's condition while limiting the amount of false alarms that would serve to increase provider workload. From July to November 2014, post-operative patients meeting the inclusion criteria (BMI > 30 kg/m2, history of obstructive sleep apnea, or the use of patient-controlled analgesia (PCA) or epidural narcotics) were monitored using automated devices that record minute-by-minute VS included in classic MEWS calculations as well as EtCO2. Automated messages via pagers were sent to providers for instances when the device measured elevated MEWS, abnormal EtCO2, and oxygen desaturations below 85 %. Data, including alarm and message details from the first 133 patients, were recorded and analyzed. Overall, 3.3 alarms and pages sounded per hour of monitoring. Device-only alarms sounded 2.7 times per hour-21 % were technical alarms. The remaining device-only alarms for concerning VS sounded 2.0/h, 70 % for falsely recorded VS. Pages for abnormal EtCO2 sounded 0.4/h (82 % false recordings) while pages for low blood oxygen saturation sounded 0.1/h (55 % false alarms). 143 times (0.1 pages/h) the devices calculated a MEWS warranting a page (rise in MEWS by 2 or 5 or greater)-62 % were false scores inclusive of falsely recorded VS. An abnormal EtCO2 value resulted in or added to an elevated MEWS score in 29 % of notifications, but 50 % of these included a falsely abnormal EtCO2 value. To date, no adverse events have occurred. There were no statistically significant demographic, post-operative condition, or pre-existing comorbidity differences between patients who had a majority of true alarms from those who had mostly false-positive alarms. Although not statistically significant, the group of patients in whom automated MEWS suggested greater utility included those with a history of hypertension (p = 0.072) and renal disease (p = 0.084). EtCO2 monitoring was more likely to be useful in patients with a history of type 2 diabetes, coronary artery disease, and obstructive sleep apnea (p < 0.05). These patients were also more likely to have been on a PCA post-operatively (p < 0.05). Overall, non-invasive physiologic monitoring incorporating an automated MEWS system, modified to include end-tidal CO2 can be feasibly implemented in a hospital ward. Further study is needed to evaluate its clinical utility, including an end-tidal CO2 score, is feasibly implemented and can be useful in monitoring select post-operative patients for derangements in physiologic metrics. Like any other monitoring system, false alarms may occur at high rates. While further study is needed to determine the additive utility of EtCO2 in MEWS calculations, this study suggests utility of EtCO2 in select post-operative patients. PMID- 27766528 TI - Wnt signaling inhibitor FH535 selectively inhibits cell proliferation and potentiates imatinib-induced apoptosis in myeloid leukemia cell lines. AB - Wnt signaling pathway plays a major role in leukemogenesis of myeloid leukemia. Aberrancy in its regulation results in hyperactivity of the pathway contributing to leukemia propagation and maintenance. To investigate effects of Wnt pathway inhibition in leukemia, we used human leukemia cell lines (i.e., K562, HL60, THP1, and Jurkat) and several Wnt inhibitors, including XAV939, IWP2 and FH535. Our results showed that leukemia cell lines (>95 % cells) had increased endogenous levels of beta-catenin as compared to mononuclear cells from healthy donors (0 %). Among the tested inhibitors, FH535 demonstrated a markedly suppressive effect (IC50 = 358 nM) on mRNA levels of beta-catenin target genes (LEF1, CCND1, and cMYC). In addition, FH535 significantly potentiated imatinib induced apoptosis. Evaluation of erythrocyte and megakaryocyte lineage using flow cytometry demonstrated that the potentiation mechanism is independent of the developmental stage, and is more likely due to crosstalk between other pathways and beta-catenin. FH535 also displayed antiproliferative properties in other cell lines used in this study. In summary, FH535 showed significantly high antiproliferative effects at submicromolar dosages, and additionally enhanced imatinib-induced apoptosis in human leukemia cell lines. Our results highlight its potential antileukemic promise when used in conjunction with other conventional therapeutic regimens. PMID- 27766530 TI - EGFL7-overexpressing epidermal stem cells promotes fibroblast proliferation and migration via mediating cell adhesion and strengthening cytoskeleton. AB - Epidermal growth factor (EGF)-like family members mediate a wide range of biological activities including cell proliferation and migration. Increasing evidence indicated that EGF plays an important role in the process of wound healing by stimulating fibroblast motility. The aim of this study was to see whether EGF-like domain 7 (EGFL7)-overexpressing epidermal stem cells (EGFL7 ESCs) would promote fibroblast proliferation and migration. We found that mRNA and protein levels of EGFL7 expression were significantly increased in EGFL7 ESCs. The protein expression of EGFL7 was significantly elevated in conditioned media (CM) of EGFL7-ESCs compared to ESCs CM or vector-ESCs CM. The cell count and cell viability of EGFL7-ESCs CM-treated fibroblasts were also significantly increased compared to control. In addition, EGFL7-ESCs CM-treated fibroblasts showed elevated migration compared with control. Moreover, the expressions of beta1-integrin, beta-tubulin, beta-actin, and Vimentin were increased, while that of E-cadherin was decreased in EGFL7-ESCs CM-treated fibroblasts. These results indicate that EGFL7-ESCs contribute towards promoting fibroblast migration through enhancing cell adhesion, strengthening cytoskeleton, and reducing intercellular aggregation. These findings suggest that the stimulating effect of EGFL7-ESCs on fibroblast proliferation and migration may provide a useful strategy for wound healing. PMID- 27766531 TI - SP1 is a transcriptional regulator of URG-4/URGCP gene in hepatocytes. AB - URG-4/URGCP gene was implicated as an oncogene that contributes hepatocarcinogenesis regulated by Hepatitis-B-virus-encoded X antigen. However, the mechanism of transcriptional regulation of this gene remains largely unknown. For this reason, we focused on the functional analyses of URG4/URGCP promoter site. First, 545 bp of URG-4/URGCP, -482/+63, and three different 5'-truncated constructs, -109/+63, -261/+63, -344/+63 were cloned by PCR-based approach into pMetLuc luciferase reporter vector. Transient transfection assay showed that, 109/+63 construct has the highest activity. The promoter of URG-4/URGCP gene contained a CpG island region spanning 400 bp from translation start site. Many SP1/GC boxes, named GC-1 to GC-10 are present in 545 bp of URG-4/URGCP promoter. Because of presence of multiple SP1/GC boxes, promoter constructs were transiently co-transfected with SP1 expression vector to determine the effect of SP1 on URG-4/URGCP promoter activity. Co-transfection analyses induced the basal activity of -268/+63, -344/+63 and -482/+63 constructs. EMSA analysis of GC-4, GC 5, GC-6 and GC-7 binding sites located in -128/-148 bases, showed two DNA-protein binding complexes. Competition assay and super-shifted complexes indicated these complexes are resulted from SP1 binding. Also, site-directed mutagenesis of potential SP1 binding sites diminished both DNA-protein complexes and SP1 mediated upregulation of URG-4 promoter activity. These findings are valuable for understanding transcriptional regulation of URG4/URGCP that has a pivotal role in cancer progression. PMID- 27766529 TI - Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. AB - Heart disease causing cardiac cell death due to ischemia-reperfusion injury is a major cause of morbidity and mortality in the United States. Coronary heart disease and cardiomyopathies are the major cause for congestive heart failure, and thrombosis of the coronary arteries is the most common cause of myocardial infarction. Cardiac injury is followed by post-injury cardiac remodeling or fibrosis. Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and results in both systolic and diastolic dysfunctions. It has been suggested by both experimental and clinical evidence that fibrotic changes in the heart are reversible. Hence, it is vital to understand the mechanism involved in the initiation, progression, and resolution of cardiac fibrosis to design anti-fibrotic treatment modalities. Animal models are of great importance for cardiovascular research studies. With the developing research field, the choice of selecting an animal model for the proposed research study is crucial for its outcome and translational purpose. Compared to large animal models for cardiac research, the mouse model is preferred by many investigators because of genetic manipulations and easier handling. This critical review is focused to provide insight to young researchers about the various mouse models, advantages and disadvantages, and their use in research pertaining to cardiac fibrosis and hypertrophy. PMID- 27766532 TI - eHealth Intervention for Problematic Internet Use (PIU). AB - Excessive use of the Internet is considered a problematic behaviour by clinicians and researchers. Cognitive behaviour therapy (CBT) has been advocated for a long time as a treatment approach and has been extended to include family therapy in the recent years. As eTherapy (eHealth) has become an important component in the treatment of many mental health problems, it is prudent to explore the current status of the eHealth approach as an intervention option for this problem. This systematic review aims to examine the current development of online intervention programmes for this particular condition. The PRISMA guidelines for systematic reviews and meta-analysis were employed to conduct the search for literature following a systematic and structured approach. Of the 182 articles screened, three satisfied the selection criteria. Information was extracted and analysed systematically for each study and tabulated. All these studies were pilot studies with small sample sizes. Two of these articles aimed to explore the therapeutic efficacy of newly developed online intervention programmes for Internet addiction (IA) and online gaming addiction. The third article described the design and development of an App for smartphone addiction. The results obtained from this review have provided insight into the on-going development of eHealth interventions as well as the health informatics approaches in offering a possible and practical solution to tackle this growing problem. PMID- 27766533 TI - Integrated Behavioral Health in Pediatric Primary Care. AB - There are multiple barriers to accessing high quality, evidence-based behavioral health care for children and adolescents, including stigma, family beliefs, and the significant paucity of child and adolescent psychiatrists. Although equal access continues to be an unmet need in the USA, there is growing recognition that integrated behavioral health services in pediatric primary care have the potential to reduce health disparities and improve service utilization. In a joint position paper, the American Academy of Pediatrics (AAP) and the American Academy of Child and Adolescent Psychiatry (AACAP) highlighted the multiple benefits of children receiving initial behavioral health screening, assessment, and evidence-based behavioral health treatments in the medical home. The purpose of this paper is to review the current state of the literature related to integrated behavioral health services in pediatric primary care. Specifically, innovative models of integrated behavioral health care are discussed. PMID- 27766534 TI - The Good and the Bad of Glutamate Receptor RNA Editing. AB - Glutamate receptors play a key role in excitatory synaptic transmission and plasticity in the central nervous system (CNS). Their channel properties are largely dictated by the subunit composition of tetrameric receptors. Amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate channels are assembled from GluA1-4 AMPA or GluK1-5 kainate receptor subunits. However, their functional properties are highly modulated by a post-transcriptional mechanism called RNA editing. This process involves the enzymatic deamination of specific adenosines (A) into inosines (I) in pre-messenger RNA. This post-transcriptional modification leads to critical amino acid substitutions in the receptor subunits, which induce profound alterations of the channel properties. Three of the four AMPA and two of the five kainate receptor subunits are subjected to RNA editing. This study reviews the advances in understanding the importance of glutamate receptor RNA editing in finely tuning glutamatergic neurotransmission under physiological conditions and discusses the way in which the dis-regulation of RNA editing may be involved in neurological pathology. PMID- 27766536 TI - Genetic Variants and Multiple Sclerosis Risk Gene SLC9A9 Expression in Distinct Human Brain Regions. AB - A recent genome-wide association study reported a significant association between rs9828519 (G) and nonresponsiveness to interferon-beta (IFN-beta) treatment and dysregulation of SLC9A9 expression in multiple sclerosis (MS) cases. We hypothesize that disease-relevant tissues are necessary to detect the effects of rs9828519-tagged SNPs on SLC9A9 expression. Here, we investigated whether SLC9A9 expression is regulated by rs9828519-tagged SNPs in human brain tissue. We used HaploReg to identify the proxy SNPs of the rs9828519 variant based on linkage disequilibrium information from the 1000 Genomes Project. We evaluated the potential association between these SNPs and SLC9A9 expression using multiple expression quantitative trait loci datasets including 10 brain regions of 134 individuals from Braineac, 2 brain regions of 773 samples from brain expression GWAS datasets, and 12 brain regions from the GTEx. We discovered differential SLC9A9 expression in different brain regions and identified 15 rs9828519-tagged SNPs that significantly regulated SLC9A9 expression only in occipital cortex, intralobular white matter, and substantia nigra. Our results advance the understanding of the involvement of SLC9A9 and rs9828519 mechanisms in MS. PMID- 27766538 TI - Social media and your practice: navigating the surgeon-patient relationship. AB - Utilization of social media both in the private and professional arenas has grown rapidly in the last decade. The rise of social media use within health care can be viewed as the Internet-based corollary of the patient-centered care movement, in which patient perspectives and values are central to the delivery of quality care. For orthopedic surgeons and their practices, general-purpose online social networks, such as Facebook and Twitter, are convenient platforms for marketing, providing patient education and generating referrals. Virtual health communities are used less frequently by orthopedic surgeons but provide forums for patient engagement and active surgeon-to-patient communication via blogs and ask-the doctor platforms. This commentary reviews the current state of social media use in orthopedic practice, with particular emphasis on managing the extension of the surgeon-patient relationship online, including the unique practice risks social media poses, such as privacy concerns, potential liability, and time consumption. PMID- 27766535 TI - Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune Inflammatory and Oxidative and Nitrosative Pathways. AB - There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS. Findings show that activation of immune inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-alpha, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-beta, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness. PMID- 27766537 TI - A Novel Bioresorbable Device as a Controlled Release System for Protecting Cells from Oxidative Stress from Alzheimer's Disease. AB - Bioresorbable electrospun fibres have highly functional features that can preserve drug efficacy, avoiding premature degradation, and control drug release rates over long periods. In parallel, it is known that Alzheimer's disease (AD) has been linked to impaired insulin signalling in the brain. Glucagon-like peptide 1 (GLP-1) analogues have beneficial effects on insulin release and possess exceptional neuroprotective properties. Herein, we describe for the first time the incorporation of a GLP-1 analogue, liraglutide, into electrospun poly (lactic acid) (PLA) fibres with in situ gelatin capsules, in order to provide the controlled release of liraglutide, improving neuroprotective properties. In this study, PLA, a bioresorbable polymer in which degradation products have neurogenesis characteristics, was electrospun and loaded with liraglutide. Moreover, PLA/liraglutide fibres were encapsulated with gelatin and were shown to have better properties than the non-encapsulated fibres in terms of the controlled release of liraglutide, which was accomplished in the present study for up to 60 days. We observed that this biodevice was completely encapsulated with gelatin, which made the material more hydrophilic than PLA fibres alone and the biodevice was able to enhance fibroblast interaction and reduce mitochondrial stress in a neuroblastoma cell line. In this manner, this study introduces a new material which can improve neuroprotective properties from AD oxidative stress via the sustained long-lasting release of liraglutide. Graphical Abstract ?. PMID- 27766539 TI - Effect of Different Sugar Beet Pulp Pretreatments on Biogas Production Efficiency. AB - The objective of this study was to determine the effect of different sugar beet pulp (SBP) pretreatments on biogas yield from anaerobic digestion. SBP was subjected to grinding, thermal-pressure processing, enzymatic hydrolysis, or combination of these pretreatments. It was observed that grinding of SBP to 2.5 mm particles resulted in the cumulative biogas productivity of 617.2 mL/g volatile solids (VS), which was 20.2 % higher compared to the biogas yield from the not pretreated SBP, and comparable to that from not ground, enzymatically hydrolyzed SBP. The highest cumulative biogas productivity, 898.7 mL/g VS, was obtained from the ground, thermal-pressure pretreated and enzymatically hydrolyzed SBP. The latter pretreatment variant enabled to achieve the highest glucose concentration (24.765 mg/mL) in the enzymatic hydrolysates. The analysis of energy balance showed that the increase in the number of SBP pretreatment operations significantly reduced the gain of electric energy. PMID- 27766540 TI - Topical nonsteroidal anti-inflammatory drugs as adjuvant therapy in the prevention of macular edema after cataract surgery. AB - PURPOSE: The purpose of the study was to assess adjuvant treatment with topical nonsteroidal anti-inflammatory drugs (NSAIDs) (0.9 % bromfenac, 0.1 % nepafenac, 0.5 % indomethacin, or 0.1 % diclofenac) in addition to topical steroidal treatment with 0.1 % dexamethasone and 0.3 % netilmicin for prevention of cystoid macular edema (CME) after uneventful small incision cataract extraction with foldable intraocular lens (IOL) implantation. SETTING: Institute of Ophthalmology, Department of Scienze Mediche di Base, Neuroscienze ed Organi di Senso, Aldo Moro University, Policlinico Consorziale di Bari, Bari, Italy. DESIGN: A retrospective 6-month single center study. METHODS: Patients were divided into groups according to treatment with topical drugs for 2 weeks, after phacoemulsification with foldable IOL implantation. CME incidence was evaluated by assessing retinal foveal thickness changes using spectral domain optical coherence tomography. All patients were treated with a fixed combination of dexamethasone and netilmicin, and some patients were additionally treated with NSAIDs (bromfenac, nepafenac, indomethacin, or diclofenac). RESULTS: Fourteen patients were treated with bromfenac, 15 with nepafenac, 12 with indomethacin, and 14 with diclofenac; ten patients were treated with dexamethasone and netilmicin alone. At the end of the follow-up, macular thickness, evaluated at 1 week post-surgery, was reduced only in the group treated with nepafenac (-1.3 %, p = 0.048), was increased in the group treated with dexamethasone and netilmicin alone (+4.3 %, p = 0.04), and did not change in the groups treated with bromfenac (-1.1 %, p = 0.3), indomethacin (+0.1 %, p = 0.19), or diclofenac (+1.2 %, p = 0.74). There were no side effects in any group. CONCLUSIONS: Topical treatment with nepafenac, bromfenac, and indomethacin enhanced the efficacy of steroids to reduce postoperative macular edema. Diclofenac did not improve steroids efficacy. PMID- 27766541 TI - Early Identification of Lung Fungal Infections in Chronic Granulomatous Disease (CGD) Using Multidetector Computer Tomography. AB - PURPOSE: The purpose of this study is to evaluate the possibility of early detection of pulmonary fungal infections by lung CT scan in chronic granulomatous disease (CGD). METHODS: A retrospective study on 14 patients affected with CGD for a total of 18 infectious episodes was performed. Revision of clinical data and CT scan analysis before and after treatment was performed. RESULTS: The presence of lung nodules <30 mm was evaluated in 18 infectious episodes in 14 patients. A total of 125 nodules in 18 CT scans were identified. Identification of the infectious agent through biopsy and in vitro culture resulted positive only in 3/18 cases. The remaining cases received clinical/radiologic diagnosis of suspected pulmonary fungal infection. In all cases, the introduction of empirical antifungal treatment resulted in reduction in size or complete resolution of the pulmonary lung nodules in all patients affected with CGD. CONCLUSIONS: Lung CT scan allows for early detection of pulmonary fungal infection in CGD. Pulmonary nodules (<30 mm), single or multiple, uni- or bilateral, with or without a halo sign may represent the first radiologic sign of pulmonary fungal infection in CGD. PMID- 27766542 TI - The 2016 American College of Chest Physicians treatment guidelines for venous thromboembolism: a review and critical appraisal. AB - The American College of Chest Physicians recently updated their practice guidelines for the treatment of patients with venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism. The 2016 guidelines represent the tenth iteration of these guidelines, which are widely used, and are considered as the reference standard for practice guidelines related to venous thromboembolism. The objectives of this review are to highlight the key recommendations that are new in these guidelines, to address recommendations that may be considered controversial, and to touch on areas of ongoing research that may better inform some of these recommendations. PMID- 27766543 TI - Crohn's disease presenting as a ceco-urachal fistula. AB - We report the case of a patient with Crohn's disease who initially presented with a ceco-urachal fistula. The patient was a 31-year-old female who underwent an appendectomy 6 years before presenting to our institution. She had a one-year history of diarrhea, and had recently developed polyuria and a sensation of residual urine. She was admitted with fever and lower abdominal pain. Endoscopy and computed tomography revealed a ceco-urachal fistula, which was consistent with Crohn's disease. An urachal resection was performed, which included partial cystectomy and ileocecal resection. A ceco-urachal fistula is a rare initial symptom of Crohn's disease. During the surgical management of such cases, it is necessary to resect the urachus, the affected portion of the bladder, the fistula, and the affected part of the digestive tract in order to avoid recurrence. PMID- 27766545 TI - From 2000 to 2016: Which Second-Line Treatment in Advanced Non-Small Cell Lung Cancer? AB - OPINION STATEMENT: New treatments-as immunotherapies and new antiangiogenic agents-are now available in second-line setting for patients affected by EGFR wild-type and ALK-negative non-small-cell lung cancer (NSCLC). Nintedanib, ramucirumab, nivolumab and pembrolizumab have to be included in the therapeutic sequences for patients affected by NSCLC, but no clear selection criteria are to date offered, except for patients with PD-L1 expression >=50 %. Performance status, smoking habits and comorbidities should be considered as clinical criteria in order to select the appropriate treatment, but also tumour characteristics as histotype, platinum resistance and rapid progression after a first-line therapy should be taken into account. The aim of the present paper is to identify subgroups of patients eligible for different therapy sequences. PMID- 27766544 TI - Successful treatment of three patients with human immunodeficiency virus and hepatitis C virus genotype 1b co-infection by daclatasvir plus asunaprevir. AB - Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) often accelerates the course of HCV-associated liver disease. Daclatasvir (DCV) plus asunaprevir (ASV) have been shown to be highly effective for HCV-infected patients with genotype 1b. Three patients co-infected with HIV/HCV genotype 1b were enrolled in this study. Prior to initiation of HCV treatment, the variants associated with L31 and Y93 in the non-structural protein 5A (NS5A) region of the HCV genome were confirmed to be absent using a direct sequencing method. Taking into consideration the lower risk of drug-drug interaction and the need for immediate treatment, the patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. In one patient, the alanine aminotransferase level was elevated to 228 IU/L at 24 weeks after the start of treatment, but he completed the 24-week treatment course. All three patients achieved sustained viral response, without severe complications (including HIV virological rebound). Thus, in cases where NS5A variants are confirmed to be absent and patients are antiretroviral therapy-naive, with CD4+ over 500/MUL or HIV well controlled by RAL-based cART, DCV plus ASV may represent a good treatment option for HIV and HCV genotype 1b co-infected patients. PMID- 27766547 TI - Drug Combinations as the New Standard for Melanoma Treatment. AB - OPINION STATEMENT: Advanced melanoma is related to a very grim prognosis and fast progression. Until recently, there has been no indicated treatment that would affect the disease's outcome. However, the progress in immunotherapy and molecular therapy has significantly changed the unfavourable prognosis of melanoma progression and its short survival rate. Both approaches have improved patients' outcomes and provided renewed hope for successful treatment. Moreover, in order to further enhance patients' outcomes and to avoid mechanisms of tumour resistance, investigators attempted a combined approach. Targeted therapy combinations allowed a better response rate and progression-free survival than monotherapy with one of the agents. Another promising combination, but with limiting toxicities, is a concurrent immuno- and molecular-targeted therapy. It is suspected that complimentary usage of these drugs may lead to synergism, providing robust and quick tumour responses as well as long-lasting effects. Results of currently ongoing clinical trials that investigate combination strategies in melanoma are expected to provide more mature data about the effectiveness and the safety profile of those therapies. Until more robust results of these studies occur, the best management of advanced and metastatic melanoma is immunotherapy with anti-PD1 drugs or targeted therapy with concomitant BRAF and MEK inhibitor. However, which of these two options should be used first is still under discussion. PMID- 27766546 TI - Management of Skin Cancer in the High-Risk Patient. AB - OPINION STATEMENT: Skin cancer is the most common of human cancers and outnumbers all other types of cancer combined in the USA by over threefold. The majority of non-melanoma skin cancers are easily treated with surgery or locally destructive techniques performed under local anesthesia in the cost-effective outpatient setting. However, there is a subset of "high-risk" cases that prove challenging in terms of morbidity, mortality, adjuvant treatment required, as well as overall cost to the health care system. In our opinion, the term "high risk" when applied to skin cancer can mean one of three things: a high-risk tumor with aggressive histologic and/or clinical features with an elevated risk for local recurrence or regional/distant metastasis, a high-risk patient with the ongoing development of multiple skin cancers, and a high-risk patient based on immunosuppression. We have recently proposed classifying NMSC as a chronic disease in a certain subset of patients. Although no consensus definition exists for a chronic disease in medicine, there are three components that are present in most definitions: duration of at least 1 year, need for ongoing medical care, and functional impairment and/or alteration of activities of daily living (ADLs) and quality of life (QOL). Immunosuppression can refer to exogenous (organ or stem cell transplant patients,) or endogenous (HIV, leukemia, lymphoma, genodermatoses with DNA mismatch repair problems or other immunosuppression) causes. These patients are at risk for high-risk tumors and/or the development of multiple tumors. PMID- 27766548 TI - Ethical Hurdles in the Prioritization of Oncology Care. AB - With finite resources, healthcare payers must make difficult choices regarding spending and the ethical distribution of funds. Here, we describe some of the ethical issues surrounding inequity in healthcare in nine major European countries, using cancer care as an example. To identify relevant studies, we conducted a systematic literature search. The results of the literature review suggest that although prevention, access to early diagnosis, and radiotherapy are key factors associated with good outcomes in oncology, public and political attention often focusses on the availability of pharmacological treatments. In some countries this focus may divert funding towards cancer drugs, for example through specific cancer drugs funds, leading to reduced expenditure on other areas of cancer care, including prevention, and potentially on other diseases. In addition, as highly effective, expensive agents are developed, the use of value based approaches may lead to unacceptable impacts on health budgets, leading to a potential need to re-evaluate current cost-effectiveness thresholds. We anticipate that the question of how to fund new therapies equitably will become even more challenging in the future, with the advent of expensive, innovative, breakthrough treatments in other therapeutic areas. PMID- 27766549 TI - Daily life reflections of acromegaly guidelines. AB - PURPOSE: To determine the differences in acromegaly diagnosis, treatment, and follow-up among Turkish endocrinologists, and to investigate how the published guidelines are applied in clinical practice. METHODS: The questionnaire was formatted as an electronic survey, conducted between November and December 2015, and sent weekly for 6 weeks via e-mail to 528 endocrinologists in Turkey. RESULTS: The questionnaire was answered by 37.4 % of endocrinologists. Insulin like growth factor-1 and nadir growth hormone level after 75 g oral glucose tolerance test (nadir GH-OGTT) were the most commonly preferred methods for the initial diagnosis. A total of 49.5 % of the participants reported using preoperative medical therapy (MT) either routinely or on a case-to-case basis. Somatostatin analogs were the most commonly used drugs, both in pre- and postoperative MT. Disease activity following surgery was assessed in the 3rd postoperative month using IGF-1 levels. Similarly, IGF-1 monitoring was preferred in the follow-up period. Monitoring nadir GH-OGTT levels was the most commonly used method in the assessment of discordant test results. The dose titration was done at month 3 after the start of MT. Resistance to SRLs was considered after using the maximal dose for at least 6 months. Pegvisomant was generally used in second- and third-line therapy. Similarly, cabergoline was not preferred in monotherapy by the majority of participants. Radiotherapy was considered in patients with incomplete response to surgery and medical treatments. CONCLUSIONS: Although there were subtle differences, clinical practice guidelines were usually followed among Turkish endocrinologists. PMID- 27766550 TI - Predictors of electrocardiographic abnormalities in type 1 Diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. AB - PURPOSE: To determine the incidence and determinants of developing abnormalities on the 12-lead electrocardiogram (ECG) in persons with type 1 diabetes. METHODS: We evaluated the distribution of ECG abnormalities and risk factors for developing new abnormalities in 266 (mean age = 44 years +/- 9.0; 50 % female) people with type 1 diabetes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. This analysis included participants with complete ECG data from study visit 5 (2000-2001) and follow-up ECGs from study visit 7 (2012-2014). ECG abnormalities were classified as major and minor according to Minnesota Code Classification. RESULTS: At baseline, 94 (35 %) participants had at least one ECG abnormality, including 13 major ECG abnormalities. At follow-up, 117 (44 %) participants developed at least one new ECG abnormality, including 35 new major ECG abnormalities. In a multivariable logistic regression model, older age (per 5 year increase: OR = 1.31, 95 % CI = 1.08, 1.60) was associated with the development of at least one new ECG abnormality, while serum HDL cholesterol (per 10-unit increase: OR = 0.98, 95 % CI = 0.96, 1.00) was protective against developing new ECG abnormalities. CONCLUSIONS: The development of new ECG abnormalities is common in type 1 diabetes. Older age and HDL cholesterol are independent risk factors for developing new ECG abnormalities. Further research is needed to determine whether routine ECG screening is indicated in people with type 1 diabetes to identify those with underlying subclinical coronary heart disease. PMID- 27766551 TI - Validated cost comparison of open vs. robotic pyeloplasty in American children's hospitals. AB - The objective of this study is to determine the cost and charge differences between patients undergoing open vs. robotic pyeloplasty. This is a retrospective analysis of the Pediatric Health Information System (PHIS) database in patients undergoing pyeloplasty between 2004 and 2013 conducted in large pediatric children's hospitals in the United States which contribute to PHIS. The participants included all pediatric patients undergoing pyeloplasty at these institutions. We assessed RCC-based cost, charge details, length of stay, and the presence of complications, and compared them between open and robotic cases. When PHIS data were compared to matched local patients, all but five were perfectly matched by medical record number, demographics, and date of procedure. When we compared open vs. robotic cases in 18 institutions that commonly performed robotic cases, there was a similar age distribution, robotic cases had shorter length of stay (2.2 v, 1.6 days, p < 0.001), similar rates of surgical complications (open 4.5 %, robotic 3.6 %, p = 0.50), and robotic cases were more expensive by US $3991 (p < 0.001). OR charges and anesthesia charges accounted for the majority of the cost difference between open vs. robotic cases. There was no association between patient age or chronological year and the mean cost difference between open vs. robotic cases. Robotic pyeloplasty is more expensive, but has a lower (although non-significant) rate of complications and a significantly shorter length of stay. Charges for OR and anesthesia time dominate the cost difference; so efforts to reduce these specific costs should be the focus of future cost-containment efforts. PMID- 27766554 TI - Effective Research Mentorship for Residents: Meeting the Needs of Early Career Physicians. AB - OBJECTIVE: Challenges in pursuing research during residency may contribute to the shortage of clinician-scientists. Although the importance of mentorship in facilitating academic research careers has been described, little is understood about early career research mentorship for residents. The aim of this study was to better understand the mentorship process in the context of psychiatry residency. METHOD: Semi-structured interviews were conducted with experienced faculty mentors in a psychiatry department at a large academic medical center. Interviews were analyzed using inductive thematic analysis. Results from faculty interviews identified several key themes that were explored with an additional sample of resident mentees. RESULTS: Five themes emerged in our study: (1) being compatible: shared interests, methods, and working styles; (2) understanding level of development and research career goals in the context of residency training; (3) establishing a shared sense of expectations about time commitment, research skills, and autonomy; (4) residents' identity as a researcher; and (5) the diverse needs of a resident mentee. There was considerable congruence between mentor and mentee responses. CONCLUSIONS: There is an opportunity to improve research mentoring practice by providing guidance to both mentors and mentees that facilitates a more structured approach to the mentorship relationship. PMID- 27766552 TI - Synthesis, characterization, and in vitro evaluation of the selective P2Y2 receptor antagonist AR-C118925. AB - The Gq protein-coupled, ATP- and UTP-activated P2Y2 receptor is a potential drug target for a range of different disorders, including tumor metastasis, inflammation, atherosclerosis, kidney disorders, and osteoporosis, but pharmacological studies are impeded by the limited availability of suitable antagonists. One of the most potent and selective antagonists is the thiouracil derivative AR-C118925. However, this compound was until recently not commercially available and little is known about its properties. We therefore developed an improved procedure for the synthesis of AR-C118925 and two derivatives to allow up-scaling and assessed their potency in calcium mobilization assays on the human and rat P2Y2 receptors recombinantly expressed in 1321N1 astrocytoma cells. The compound was further evaluated for inhibition of P2Y2 receptor-induced beta arrestin translocation. AR-C118925 behaved as a competitive antagonist with pA 2 values of 37.2 nM (calcium assay) and 51.3 nM (beta-arrestin assay). Selectivity was assessed vs. related receptors including P2X, P2Y, and adenosine receptor subtypes, as well as ectonucleotidases. AR-C118925 showed at least 50-fold selectivity against the other investigated targets, except for the P2X1 and P2X3 receptors which were blocked by AR-C118925 at concentrations of about 1 MUM. AR C118925 is soluble in buffer at pH 7.4 (124 MUM) and was found to be metabolically highly stable in human and mouse liver microsomes. In Caco2 cell experiments, the compound displayed moderate permeability indicating that it may show limited peroral bioavailability. AR-C118925 appears to be a useful pharmacological tool for in vitro and in vivo studies. PMID- 27766555 TI - Safety and Efficacy of Terlipressin in Pediatric Distributive Shock: A Retrospective Analysis in 20 Children. AB - INTRODUCTION: Data are still lacking about the use of terlipressin or vasopressin in the treatment of pediatric patients who are in a state of therapy-refractory shock. OBJECTIVE: The aim of this study was to evaluate the effect of terlipressin on hemodynamics in children with distributive shock and to describe any severe side effects. METHODS: Consecutive patients (n = 20) with catecholamine-resistant distributive shock who were treated with terlipressin were retrospectively enrolled in this study. We analyzed response in terms of mean arterial blood pressure, heart rate, vasoactive inotropic score (VIS), urinary output, and serum lactate. RESULTS: The hemodynamics of 12 children significantly improved within 6 h of commencing terlipressin (mean blood pressure increase of >=20 % without VIS increase, or mean blood pressure increase of >=10 % with VIS decrease of >=10 %). The hemodynamics of eight patients did not improve, regardless of treatment dosage or duration. More children died in the responders group (n = 7 [58.3 %]) than in the non-responders group (n = 2 [25.0 %]), but this was not statistically significant. Two patients (one in each group) who received high dosages of terlipressin developed rhabdomyolysis. One case of Takotsubo cardiomyopathy was observed, which could be related to terlipressin. CONCLUSIONS: Although treatment with terlipressin resulted in rapid positive hemodynamic responses in some children, it did not seem to have a positive effect in other pediatric patients. Therefore, the possible benefits of terlipressin should be always weighed against potential severe adverse effects. PMID- 27766553 TI - Glucocorticoid-induced osteoporosis: pathophysiological role of GH/IGF-I and PTH/VITAMIN D axes, treatment options and guidelines. AB - Glucocorticoid-induced osteoporosis is the most frequent form of secondary osteoporosis caused by chronic exposure to glucocorticoid excess. Pathogenesis of glucocorticoid-induced osteoporosis is multifactorial including direct effects of glucocorticoids on bone cells and indirect effects of glucocorticoids on several neuroendocrine and metabolic pathways. Fragility fractures occur early in glucocorticoid-induced osteoporosis and anti-osteoporotic drugs along with calcium and vitamin D should be started soon after exposure to glucocorticoid excess. This paper summarizes some of the main topics discussed during the 9th Glucocorticoid-Induced Osteoporosis Meeting (Rome, April 2016) with a specific focus on the role of growth hormone/insulin-like growth factor-1 and parathyroid hormone/vitamin D axes in the pathogenesis of glucocorticoid-induced osteoporosis and the controversial aspects concerning therapeutic approach to skeletal fragility in this clinical setting. PMID- 27766556 TI - Women with Low-Risk DCIS Eligible for the LORIS Trial After Complete Surgical Excision: How Low Is Their Risk After Standard Therapy? AB - BACKGROUND: Identifying DCIS patients at low risk for disease progression could obviate need for standard therapy. The LORIS (surgery versus active monitoring for low-risk DCIS) trial is studying the safety of monitoring low-risk DCIS, although ipsilateral breast tumor recurrence (IBTR) rates in patients meeting enrollment criteria after complete surgical excision are unknown. METHODS: Women with pure DCIS treated with breast-conserving surgery (BCS) with/without radiation therapy (RT) from 1/1996-1/2011 were included from a prospectively maintained database. IBTR rates were compared between those who did and did not meet LORIS eligibility criteria (age >= 46 years, screen-detected calcifications, nipple discharge absence, minimal family history, non-high-grade DCIS) after complete surgical excision. RESULTS: A total of 2394 women were identified; 401 met LORIS criteria. Median follow-up was 5.9 years; 431 had >=10 years follow-up. LORIS cohort median age was 61 years (range 46-86 years); 207 (52 %) underwent RT, 79 (20 %) received endocrine therapy. Of 401 patients, 24 experienced an IBTR. Overall 10-year IBTR rates were 10.3 % (LORIS) versus 15.4 % (non-LORIS) (p = 0.08); without RT, 12.1 versus 21.4 %, respectively (p = 0.06). The 10-year invasive-IBTR rates for women meeting LORIS criteria were: 5.3 % BCS overall, 6.0 % without RT. CONCLUSIONS: Women meeting LORIS criteria (after complete surgical excision) are at somewhat lower risk for IBTR. Among such women undergoing excision without RT, the 10-year invasive-IBTR rate was 6 %. Given that approximately 20 % of women with core biopsy-proven non-high-grade DCIS have invasive cancer at excision, women managed without excision would be expected to incur higher invasive cancer rates. Additional criteria are needed to identify women not requiring intervention for DCIS. PMID- 27766557 TI - The Impact of Primary Care Providers on Patient Screening Mammography and Initial Presentation in an Underserved Clinical Setting. AB - INTRODUCTION: Cancer screening is a key component of primary care, and access to regular screening mammography (SMG) is highly dependent on recommendation and referral by a primary care provider (PCP). Women with no health insurance or who are underinsured often lack access to a regular PCP and thus access to routine screening. METHODS: We retrospectively reviewed the charts of 173 surgical patients diagnosed between January 2012 and December 2013. The main outcome variables were PCP status, method of cancer detection, and breast cancer stage at diagnosis. Additional variables included race, age at diagnosis, family history of breast and ovarian cancer, and medical comorbidities. RESULTS: Patients with a PCP received more mammograms (SMG) compared with patients without a PCP (61 vs. 37 %; p = 0.003). The majority (73 %) of patients without a PCP presented symptomatically with a palpable mass versus 42 % of patients with a PCP. A significant difference was noted with regard to final pathologic stage of breast cancer between the two groups (p = 0.019), and Caucasian and African American patients were more likely to have locally advanced breast cancer. CONCLUSIONS: Underserved patients with a PCP are more likely to present asymptomatically and at an earlier stage of breast cancer compared with patients without a PCP. Community engagement programs that build relationships with patients may help bring vulnerable patients into the healthcare system for routine screening. Moreover, PCP education regarding the subtleties of breast cancer screening guidelines and referral to a breast specialist is also critical in improving outcomes of underserved patients. PMID- 27766558 TI - Racial and Socioeconomic Treatment Disparities in Adolescents and Young Adults with Stage II-III Rectal Cancer. AB - INTRODUCTION: Stage II-III rectal cancer requires multidisciplinary cancer care, and adolescents and young adults (AYA, ages 15-39 years) often do not receive optimal cancer therapy. METHODS: Overall, 3295 AYAs with clinical stage II-III rectal cancer were identified in the National Cancer Database. Factors associated with the receipt of adjuvant and surgical therapies, as well as overall survival (OS), were examined. RESULTS: The majority of patients were non-Hispanic White (72.0 %), male (57.5 %), and without comorbidities (93.8 %). A greater proportion of Black and Hispanic patients did not receive radiation (24.5 and 27.1 %, respectively, vs. 16.5 % for non-Hispanic White patients), surgery (22.4 % and 21.6 vs. 12.3 %), or chemotherapy (21.5 % and 24.1 vs. 14.7 %) compared with non Hispanic White patients (all p < 0.05). After controlling for competing factors, Black (odds ratio [OR] 0.7, 95 % confidence interval [CI] 0.5-0.9) and Hispanic patients (OR 0.6, 95 % CI 0.4-0.9) were less likely to receive neoadjuvant chemoradiation compared with non-Hispanic White patients. Females, the uninsured, and those treated at a community cancer center were also less likely to receive neoadjuvant therapy. Having government insurance (OR 0.22, 95 % CI 010-0.49) was a predictor for not receiving surgery. Although 5-year OS was lower (p < 0.05) in Black (59.8 %) and Hispanic patients (65.9 %) compared with non-Hispanic White patients (74.9 %), on multivariate analysis race did not impact mortality. Not having surgery (hazard ratio [HR] 7.1, 95 % CI 2.8-18.2) had the greatest influence on mortality, followed by poorly differentiated histology (HR 3.0, 95 % CI 1.3-6.5), nodal positivity (HR 2.6, 95 % CI 1.9-3.6), no chemotherapy (HR 1.9, 95 % CI 1.03-3.6), no insurance (HR 1.7, 95 % CI 1.1-2.7), and male sex (HR 1.5, 95 % CI 1.1-2.0). CONCLUSION: There are racial and socioeconomic disparities in the treatment of stage II-III rectal cancer in AYAs, many of which impact OS. Interventions that can address and mitigate these differences may lead to improvements in OS for some patients. PMID- 27766559 TI - Survival Outcome and Risk of Metachronous Colorectal Cancer After Surgery in Lynch Syndrome. AB - BACKGROUND: The survival benefit of extensive colectomy is controversial in Lynch syndrome, and risk factors for metachronous colorectal cancer (CRC) after segmental colectomy are unclear. OBJECTIVE: The aim of this study was to investigate the survival outcome and risk of metachronous CRC after surgery in Lynch syndrome patients diagnosed with their first CRC. METHODS: Overall, 106 patients with Lynch syndrome who underwent surgery for CRC were included in the study. The demographics, genotype, clinicopathological characteristics of the index CRC, and follow-up data were reviewed from a single-institution Lynch syndrome database. RESULTS: Of 30 patients who underwent extensive surgery, no metachronous CRC was developed during a mean follow-up of 68.1 months. Of 76 patients who underwent segmental colectomy, 13 (17.1 %) developed metachronous CRC during a mean follow-up of 77.2 months. The cumulative risk of metachronous CRC was 8.4 % at 5 years and 20.4 % at 10 years after segmental colectomy. No difference in overall and CRC-specific survival was observed between segmental colectomy and extensive colectomy (p = 0.277 and p = 0.659, respectively). A 25 cm or longer resection of bowel decreased the risk of metachronous CRC after segmental colectomy compared with less extensive resection (hazard ratio 0.10, 95 % confidence interval 0.01-0.86). Annual surveillance colonoscopy did not decrease the risk of metachronous CRC compared with less frequent surveillance colonoscopy. Although not statistically significant, none of the MSH6 gene mutation carriers were diagnosed with metachronous CRC. CONCLUSIONS: Although no survival benefit was identified, surgeons and patients might consider extensive colectomy to prevent metachronous CRC in Lynch syndrome patients regardless of their clinicopathological characteristics. PMID- 27766560 TI - Dynamics of FLAIR Volume Changes in Glioblastoma and Prediction of Survival. AB - BACKGROUND: The extent of tumor resection (EOTR) calculated by enhanced T1 changes in glioblastomas has been previously reported to predict survival. However, fluid-attenuated inversion recovery (FLAIR) volume may better represent tumor burden. In this study, we report the first assessment of the dynamics of FLAIR volume changes over time as a predictive variable for post-resection overall survival (OS). METHODS: Contemporary data from 103 consecutive patients with complete imaging and clinical data who underwent resection of newly diagnosed glioblastoma followed by the Stupp protocol between 2010 and 2013 were analyzed. Clinical, radiographic, and outcome parameters were retrieved for each patient, including magnetic resonance imaging (MRI)-based volumetric tumor analysis before, immediately after, and 3 months post-surgery. RESULTS: OS rate was 17.6 months. A significant incremental OS advantage was noted, with as little as 85 % T1-weighted gadolinium-enhanced (T1Gd)-EOTR measured on contrast-enhanced MRI. Pre- and immediate postoperative FLAIR-based EOTR was not predictive of OS; however, abnormal FLAIR volume measured 3 months post-surgery correlated significantly with outcome when FLAIR residual tumor volume (RTV) was <19.3 cm3 and <46 % of baseline volume (p < 0.0001 for both). Age and isocitrate dehydrogenase (IDH)-1 mutation were predictive of OS (p < 0.0001, Cox proportional hazards). CONCLUSIONS: OS correlated with the immediate postoperative T1Gd-EOTR measured by enhanced T1 MRI, but not by FLAIR volume. Diminished abnormal FLAIR volume at 3 months post-surgery was associated with OS benefit when FLAIR-RTV was <19.3 cm3 or <46 % of baseline. These threshold values provide a new radiological variable that can be used for prediction of OS in patients with glioblastoma immediately after completion of standard chemoradiation. PMID- 27766561 TI - Deep Pelvic Surgical Site Infection After Radiotherapy and Surgery for Locally Advanced Rectal Cancer. AB - BACKGROUND: High morbidity, increased mortality, and impaired long-term oncologic outcome have been reported after deep surgical site infection (SSI) in rectal cancer surgery. The rate, risk factors and consequences of deep SSI after (chemo)radiotherapy [(C)RT], and surgery for locally advanced rectal cancer (LARC) in a tertiary university hospital single centre cohort of 540 patients are presented. METHODS: Patients with LARC, operated between January 1, 2007 and December 31, 2015, were identified in the institutional prospective database. All patients had tumours threatening the mesorectal fascia or invading adjacent organs, with a high rate of T4 tumours (60 %), and all received (C)RT. Risk factors for deep SSI were calculated by multivariable logistic regression analysis. Morbidity data were assessed. Overall survival (OS) and disease-free survival (DFS) between patients with or without deep SSI were estimated. RESULTS: Of 540 patients, 104 (19 %) experienced a deep SSI, with the highest rate in the abdominoperineal resection (APR) group with 25 %. APR, good response to (C)RT (low tumour regression grade), age, and operative blood loss were identified as significant (P < 0.05) risk factors for deep SSI in multivariable analysis. No difference was found in OS (P = 0.995) or DFS (P = 0.568). Hospital stay increased with 5 days (P < 0.001), and complete wound healing at the 3-month follow-up decreased from 86 to 45 % (P < 0.001) after deep SSI. CONCLUSIONS: Deep SSI is a frequent and major complication after rectal surgery for LARC, with high morbidity, increased hospital stay and protracted wound healing. Interestingly, deep SSI did not influence long-term oncologic outcome. PMID- 27766563 TI - Statistical learning and dyslexia: a systematic review. AB - The existing literature on developmental dyslexia (hereafter: dyslexia) often focuses on isolating cognitive skills which differ across dyslexic and control participants. Among potential correlates, previous research has studied group differences between dyslexic and control participants in performance on statistical learning tasks. A statistical learning deficit has been proposed to be a potential cause and/or a marker effect for early detection of dyslexia. It is therefore of practical importance to evaluate the evidence for a group difference. From a theoretical perspective, such a group difference would provide information about the causal chain from statistical learning to reading acquisition. We provide a systematic review of the literature on such a group difference. We conclude that there is insufficient high-quality data to draw conclusions about the presence or absence of an effect. PMID- 27766562 TI - A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways. AB - BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK). The model was developed in both non pregnant and pregnant women, and all physiological and enzymatic changes that could impact nevirapine PK were taken into account. Transplacental parameters estimated from ex vivo human placenta perfusion experiments were included in this PBPK model. To validate the model, observed maternal and cord blood concentrations were compared with predicted concentrations, and the impact of fetal clearance on fetal PK was investigated. RESULTS: By implementing physiological changes, including CYP3A4, 2D6 and 2B6 inductions, we predicted a clearance increase of 21 % in late pregnancy. The PBPK model successfully predicted the disposition for both non-pregnant and pregnant populations. Parameters obtained from the ex vivo experiments allowed the prediction of nevirapine concentrations that matched observed cord blood concentrations. The fetal-to-maternal area under the curve ratio (0-24 h interval) was 0.77, and fetal metabolism had no significant effect on fetal PK. CONCLUSIONS: The PBPK approach is a useful tool for quantifying a priori the drug exposure of metabolized drugs during pregnancy, and can be applied to evaluate alternative dosing regimens to optimize drug therapy. This approach, including ex vivo human placental perfusion parameters, is a promising approach for predicting human fetal exposure. PMID- 27766564 TI - Heavy metal distribution and water quality characterization of water bodies in Louisiana's Lake Pontchartrain Basin, USA. AB - The seasonal variation in physico-chemical properties, anions, and the heavy metal (Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) concentration was evaluated in water from nine different rivers in Lake Pontchartrain Basin, Louisiana, USA. The water quality parameters were compared with toxicity reference values (TRV), US Environmental Protection Agency (USEPA) drinking/aquatic life protection, and WHO standards. Among physico-chemical properties, pH, DO, and turbidity were high during spring, while, EC, temperature, and DOC were high during summer and vice versa. The anion study revealed that the concentrations of F-, Cl-, and NO3- were higher during summer and Br- and SO4- were higher during spring. Our research findings showed anion concentration decreased in the order of Cl- > SO4- > NO3- > Br- > F-, in accordance with the global mean anion concentration. The dissolved heavy metals (Cd, Co, Cr, Cu, Mn, Ni, Pb) except Zn were higher during spring than summer. None of the rivers showed any Cd pollution for both seasons. Co showed higher concentrations in Amite River, Mississippi River, Industrial Canal, and Lacombe Bayou during summer. The Cr concentration was higher than WHO drinking water standards, implicating water unsuitability for drinking purposes in all the rivers associated with the Lake Pontchartrain Basin. Cu showed no pollution risk for the study area. Mn and Co were similar to concentration in Lacombe Bayou, Liberty Bayou, Blind River, and Industrial Canal. Mn levels were greater than WHO standards for the Tickfaw River, Tangipahoa River, and Blind River in both seasons. Blind River, Tangipahoa River, Tickfaw River, and Amite River will require more monitoring for determining possible Mn pollution. Ni content in river water during both seasons showed low pollution risk. Liberty Bayou and Industrial Canal concentrations were closer to the WHO regulatory standards, indicating possible risk of Pb pollution in these water bodies. The Zn content was near the USEPA aquatic life standards in summer for all water bodies. None of the rivers showed any risk associated with Cd, Co, Cu, and Ni levels but medium to higher risk to aquatic life from Cr and Zn for both seasons for most of the rivers. Metal fractionation revealed the decreasing order of inert > labile > organic. The high inert fraction in the rivers under study reflects the major contribution of natural sources in Lake Pontchartrain Basin. The labile and organic forms of Cd, Cu, Ni, and Zn pose potential higher risk to the aquatic life in the Lake Pontchartrain Basin. PMID- 27766565 TI - Direct and Efficient Dehydrogenation of Tetrahydroquinolines and Primary Amines Using Corona Discharge Generated on Ambient Hydrophobic Paper Substrate. AB - The exposure of an aqueous-based liquid drop containing amines and graphite particles to plasma generated by a corona discharge results in heterogeneous aerobic dehydrogenation reactions. This green oxidation reaction occurring in ambient air afforded the corresponding quinolines and nitriles from tetrahydroquinolines and primary amines, respectively, at >96% yields in less than 2 min of reaction time. The accelerated dehydrogenation reactions occurred on the surface of a low energy hydrophobic paper, which served both as container for holding the reacting liquid drop and as a medium for achieving paper spray ionization of reaction products for subsequent characterization by ambient mass spectrometry. Control experiments indicate superoxide anions (O2*-) are the main reactive species; the presence of graphite particles introduced heterogeneous surface effects, and enabled the efficient sampling of the plasma into the grounded analyte droplet solution. Graphical Abstract ?. PMID- 27766566 TI - Isavuconazole: A Review in Invasive Aspergillosis and Mucormycosis. AB - Isavuconazole is a second-generation triazole with activity against a broad spectrum of clinically important fungi. Its water-soluble prodrug, isavuconazonium sulfate (Cresemba(r)), available in interchangeable intravenous and oral formulations, is approved in the USA and EU for the treatment of adults with invasive aspergillosis and mucormycosis. In international phase III clinical trials, isavuconazole was efficacious and generally well tolerated in the treatment of these life-threatening diseases. In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for the primary treatment of invasive mould disease (primarily aspergillosis) and was associated with fewer drug-related treatment-emergent adverse events (TEAEs) than voriconazole. In addition, the single-arm, phase III VITAL trial and a matched case-control analysis of isavuconazole- versus amphotericin B-treated patients provided evidence of the efficacy of isavuconazole in the treatment of mucormycosis. The most commonly reported TEAEs among isavuconazole recipients were gastrointestinal disorders such as nausea, vomiting and diarrhoea. Isavuconazole has several other attributes that make it a useful new treatment option for these invasive mould diseases, including predictable pharmacokinetics, excellent bioavailability, no food effect with the oral formulation, and its potential utility in renally impaired patients given the absence of cyclodextrin in the intravenous formulation. PMID- 27766567 TI - Ceftaroline Fosamil: A Review in Complicated Skin and Soft Tissue Infections and Community-Acquired Pneumonia. AB - Intravenous ceftaroline fosamil (ZinforoTM), a prodrug that is rapidly converted to its active metabolite ceftaroline, is approved for use in adults and children (from 2 months of age) with complicated skin and soft tissue infections (cSSTIs) or community-acquired pneumonia (CAP). In several multinational trials, ceftaroline fosamil was an effective and generally well tolerated treatment in adult and paediatric patients with cSSTIs or CAP. In the phase 3 CANVAS trials, ceftaroline fosamil treatment was noninferior to vancomycin plus aztreonam in adults with cSSTIs. Based on a meta-analysis of three similarly designed, phase 3 trials (FOCUS 1, FOCUS 2 and an Asian trial), ceftaroline fosamil treatment was superior to ceftriaxone in adults with CAP of Pneumonia Outcomes Research Teams (PORT) risk class III or IV. Ceftaroline fosamil was also associated with high clinical cure rates in hospitalized children (aged 2 months to 17 years) with cSSTIs or CAP. With its broad spectrum of in vitro activity against clinically relevant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA) and drug-resistant Streptococcus pneumoniae isolates] and Gram-negative pathogens implicated in cSSTIs and CAP, ceftaroline fosamil is an important treatment option for cSSTI and CAP in adults and children from the age of 2 months. PMID- 27766568 TI - ADPKD: clinical issues before and after renal transplantation. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the first genetic cause of end-stage renal disease (ESRD) and the number of these patients who are listed for or receive a kidney transplant (KTx) is continuously increasing over time. Hence, nephrologists are involved not only in the handling of ADPKD patients during the long course of the disease, but also in programming and performing a renal transplant. The handling of all these processes implies the complete awareness of a number of critical points related to the decisions to be taken both before and after the transplant intervention. In the present review, we will briefly deal with the main critical points related to the clinical handling of the patients both before and after KTx. PMID- 27766569 TI - Transposition mechanism, molecular characterization and evolution of IS6110, the specific evolutionary marker of Mycobacterium tuberculosis complex. AB - The mycobacterial insertion sequence IS6110 proved crucial in deciphering tuberculosis (TB) transmission dynamics. This sequence was also shown to play an important role in the pathogenicity (transmission ability and/or virulence) of Mycobacterium tuberculosis, the main causative agent of TB in humans. In this study, we explored the usefulness of IS6110 and its potential as a phylogenetic/typing marker. We also analyzed the genetic polymorphism and evolutionary trends (selective pressure) of its transposase-encoding open reading frames (ORFs), A and B, using the maximum likelihood method. Both ORFs evolved chronologically through random single nucleotide polymorphisms. They were subjected to strict purifying selection more tight on orfA, with no evidence of significant recombination events. OrfA proved to have a crucial role in regulating the transpositional process. Several analyses showed that IS6110 acquisition antedated the emergence of the Mycobacterium tuberculosis complex. This original copy of IS6110 element was functionally optimal. In conclusion, this study not only demonstrated the usefulness of IS6110 in terms of phylogenetic and typing purposes and its transpositional mechanism, but also informed the scientific community on its evolutionary history. PMID- 27766570 TI - Long noncoding RNA TCF7 promotes invasiveness and self-renewal of human non-small cell lung cancer cells. AB - Lung cancer is the most common solid tumor and the leading cause of cancer related death worldwide. Non-small cell lung cancer (NSCLC) represents the major histological subtype and accounts for about 80 % cases of lung cancer cases. Recently, lncRNA lncTCF7 was identified, which is highly expressed in hepatocellular carcinoma (HCC) tumors and liver cancer stem cells (CSCs). However, the role of lnTCF7 in NSCLC remains largely unknown. In this study, Gain and loss-of-function studies demonstrated the critical role of lncTCF7 in promoting invasion and self-renewal in NSCLC cells. We showed that lncTCF7 increased slug expression to promote the invasive capability of NSCLC cells and upregulated EpCAM expression to promote the self-renewal. Collectively, these findings provide new insights into the potential role of lncTCF7 upregulation in NSCLC metastasis and suggest a promising potential to suppress lncTCF7 for NSCLC patients. PMID- 27766571 TI - Strong Correlation between the Expression Levels of HDAC4 and SIRT6 in Hematological Malignancies of the Adults. AB - Histone deacetylase enzymes, confirmed to have important role in the pathogenesis of leukemia, are promising targets of epigenetic treatment. However, in acute myeloid leukemia, our knowledge on their expression levels is limited, and controversial data have been published about their potential oncogenic or tumorsuppressor properties in solid tumors. In our study, the expression levels of HDAC4 and SIRT6 were evaluated via Western blot analysis in 45 bone marrow samples (2 uninfiltrated and 43 concerned by different kinds of hematological malignancies), including 32 specimens obtained from patients with newly diagnosed AML. Significantly higher HDAC4 level was detected in case of FLT3-ITD mutation compared to the group of patients without carrying this mutation (p < 0.05). Compared to the non-infiltrated samples, the expression level of HDAC4 in AML M5 patients has been proved to be significantly higher (p < 0.05). Decreasing expression levels of both HDAC4 and SIRT6 were observed during the induction treatment of FAB M5 type AML. Strong correlation has been proved between the expression levels of HDAC4 and SIRT6 (r = 0.722 in full cohort and r = 0.794 in AML), that confirms the recently suggested cooperation between NAD+-independent and NAD+-dependent HDAC enzymes in leukemia. PMID- 27766574 TI - Academic promotion packages: crafting connotative frames. AB - Among the challenges of navigating the promotion and tenure (P&T) process is the need to describe one's career using the language of P&T expectations, while also framing that language to reflect the unique work involved in health professions education (HPE) scholarship. Drawing on the distinction between denotative and connotative meanings of words, we describe how the language of P&T standards can hold different meanings depending on how they are contextualized in the HPE field and the communities therein. To illustrate, we describe our experiences of adapting the language of 'teaching' to the expectations of the P&T committee while also reflecting the non-traditional 'teaching' we do in HPE. We also share three practical tips for navigating the P&T process: (1) find a local mentor, (2) craft the story of your expertise, and (3) seek feedback from your local stakeholders on the connotative story you have crafted. PMID- 27766572 TI - Mutation Profile of B-Raf Gene Analyzed by fully Automated System and Clinical Features in Japanese Melanoma Patients. AB - : BRAF gene mutations have been observed in 30-50 % of malignant melanoma patients. Recent development of therapeutic intervention using BRAF inhibitors requires an accurate and rapid detection system for BRAF mutations. In addition, the clinical characteristics of the melanoma associated with BRAF mutations in Japanese patients have not been investigated on a large scale evaluation. We recently established quenching probe system (QP) for detection of an activating BRAF mutation, V600E and evaluated 113 melanoma samples diagnosed in Saga University Hospital from 1982 to 2011. The QP system includes fully automated genotyping, based on analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe. BRAF mutations were detected in 54 of 115 (47 %) including 51 of V600E and 3 of V600 K in Japanese melanoma cases. Among clinical subtypes of melanoma, nodular melanoma showed high frequency (12 of 15; 80 %) of mutation followed by superficial spreading melanoma (13 of 26; 50 %). The QP system is a simple and sensitive method to determine BRAF V600E mutation, and will be useful tool for patient oriented therapy with BRAF inhibitors. INTRODUCTION: PMID- 27766573 TI - Diagnosis of myocardial ischemia combining multiphase postmortem CT-angiography, histology, and postmortem biochemistry. AB - PURPOSE: The aim of this study was to assess whether the identification of pathological myocardial enhancement at multiphase postmortem computed tomography angiography was correlated with increased levels of troponin T and I in postmortem serum from femoral blood as well as morphological findings of myocardial ischemia. We further aimed to investigate whether autopsy cases characterized by increased troponin T and I concentrations as well as morphological findings of myocardial ischemia were also characterized by pathological myocardial enhancement at multiphase postmortem computed tomography angiography. MATERIALS AND METHODS: Two different approaches were used. In one, 40 forensic autopsy cases that had pathological enhancement of the myocardium (mean Hounsfield units >=95) observed at postmortem angiography were retrospectively selected. In the second approach, 40 forensic autopsy cases that had a cause of death attributed to acute myocardial ischemia were retrospectively selected. RESULTS: The preliminary results seem to indicate that the identification of a pathological enhancement of the myocardium at postmortem angiography is associated with the presence of increased levels of cardiac troponins in postmortem serum and morphological findings of ischemia. Analogously, a pathological enhancement of the myocardium at postmortem angiography can be retrospectively found in the great majority of autopsy cases characterized by increased cardiac troponin levels in postmortem serum and morphological findings of myocardial ischemia. CONCLUSIONS: Multiphase postmortem computed tomography angiography is a useful tool in the postmortem setting for investigating ischemically damaged myocardium. PMID- 27766575 TI - Science: the slow march of accumulating evidence. AB - Recent crises over the credibility of research in psychology and the biomedical sciences have highlighted the need for researchers to view and treat replication research as essential to the accumulation of knowledge. In this article, the authors make the case for the utility of replication in medical education research. Specifically, the authors contend that because research in medical education often adopts theories from other disciplines, replication is necessary to gauge the applicability of those theories to the specific medical education context. This article introduces readers to the two major types of replication - direct and conceptual - and provides a primer on conceptual replication. In particular, the article presents key elements of conceptual replication and considers how it can be used to strengthen approaches to knowledge generation, theory testing, and theory development in medical education research. PMID- 27766576 TI - Navigating the unchartable: paths to promotion and tenure in health professions education. PMID- 27766577 TI - Education and the island of misfit toys. PMID- 27766578 TI - Inhibition of Respiratory Syncytial Virus Replication by Simultaneous Targeting of mRNA and Genomic RNA Using Dual-Targeting siRNAs. AB - We attempted to generate siRNAs with two active strands, which can simultaneously knock down the expression of mRNA and viral genomic RNA. In this study, short hairpin RNAs (shRNAs) against N and F genes were used. Expression of F and N mRNA transcripts as well as genomic RNA was determined with relative real-time RT-PCR. The RSV load in infected cell culture supernatant was determined by absolute quantitative real-time PCR. We found that (i) in the presence of shRNA-N, a greater reduction in viral genomic RNA was found; (ii) the level of expression at MOI 0.01 was reduced more than MOI 0.1; (iii) reduction in N transcript was greater than F; and (iv) finally, in combination pre-treatment with two shRNAs, the reduction was not significant as compared to single shRNA transfection. shRNAs also inhibited the production of RSV progeny as shown by viral load in infected HEp-2 cells. (i) Virus load reduction was greater at MOI 0.01 than 0.1 and (ii) significant load reduction was not seen with combination shRNA pre treatment. The antiviral potency was also confirmed by plaque assay and western blot analysis. Our results provided further evidence that RNAi could be a powerful treatment option against respiratory viruses. PMID- 27766580 TI - Urogenital Autonomic Dysfunction in Diabetes. AB - This review details the epidemiology, possible mechanisms, and risk factors associated with urogenital autonomic dysfunction in diabetes. Autonomic neuropathy in diabetes is associated with various urological complications including bladder and sexual dysfunction. Several studies have reported the high prevalence of bladder and sexual dysfunction in both men and women. The DCCT/EDIC UroEDIC study examined the association between cardiovascular autonomic neuropathy and bladder and sexual dysfunction in a large cohort of participants with type 1 diabetes and was the first to report significant associations. Future studies are needed to further evaluate the association of urogenital complications and autonomic dysfunction in diabetes. PMID- 27766579 TI - A Plethora of GLP-1 Agonists: Decisions About What to Use and When. AB - Incretin-based therapies are important addition to our armamentarium for the treatment of type 2 diabetes (T2DM). There are six Glucagon-like peptide-1 receptor agonists (GLP-1RAs) which have received regulatory approval for clinical use. The short-acting GLP-1RAs include exenatide twice daily, liraglutide once daily, and lixisenatide once daily. The approved long-acting GLP-1RAs are administered weekly and are exenatide, albiglutide, and dulaglutide. Although all of these therapies lower hemoglobin A1C (HbA1C), there also are unique features of GLP-1RAs that have been made manifest from clinical trial data with regard to weight-loss efficacy, fasting and post-prandial glucose control, cardiovascular safety and protection, and gastrointestinal and injection adverse effects. It is imperative to consider these features when tailoring the choice of a GLP-1RA to patient specific characteristics. PMID- 27766581 TI - Redesigning Diabetes Care: Defining the Role of Endocrinologists Among Alternative Providers. AB - The current diabetes epidemic threatens to overwhelm the healthcare system unless we redesign how diabetes care is delivered. The number of endocrinologists is grossly inadequate to provide care for all individuals with diabetes, but with the appropriate utilization of the primary care workforce and alternative healthcare providers working together in teams, effective diabetes care can be provided to all. We propose a patient-centered, goal-based approach with resources devoted to care coordination, measurement of outcomes, appropriate use of technology, and measurement of patient satisfaction. Financial incentives to healthcare systems and providers need to be based on defined outcome measures and reducing long-term total medical expenditures, rather than reimbursement based on number of visits and lengthy documentation. Endocrinologists have a responsibility in setting up effective diabetes care delivery systems within their organizations, in addition to delivering diabetes care and serving as a resource for the educational needs for other medical professionals in the community. There are major challenges to implementing such systems, both at the financial and organizational levels. We suggest a stepwise implementation of discrete components based on the local priorities and resources and provide some examples of steps we have taken at our institution. PMID- 27766582 TI - Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy. AB - The prevalence of diabetes is growing at epidemic rates in the USA. Diabetic retinopathy develops in a large proportion of patients and is a leading cause of blindness worldwide. Systemic management of diabetic retinopathy has included glycemic, hypertension, and lipid control. Local ophthalmic treatment in the form of focal/grid or panretinal laser photocoagulation has been shown to prevent vision loss in diabetic edema and proliferative diabetic retinopathy, respectively. The introduction of anti-vascular endothelial growth factor for diabetic macular edema and retinopathy has provided clinicians with improved clinical outcomes with potentially less damaging effects than laser. PMID- 27766583 TI - Optical Coherence Tomography Angiography in Diabetes. AB - Diabetic retinopathy is a progressive microvascular disease that leads to increased vessel permeability, retinal ischemia, and retinal neovascularization. Optical coherence tomography angiography (OCTA) is a novel angiography technique that has the capability to advance our understanding of diabetic eye disease by providing high-resolution images of retinal and choroidal microvasculature blood flow and structure. Using OCTA, the vascular changes of diabetic retinopathy including microaneurysms, retinal non-perfusion, intraretinal microvascular abnormalities, and neovascularization can be clearly visualized. OCTA offers several advantages over fluorescein angiography (FA) in that it is faster, safer, and non-invasive, allows better visualization of retinal vessels in both the superficial and deep capillary layers, and can provide quantitative measurements of areas of non-perfusion of the macula and nerve. OCTA capillary perfusion density maps and average perfusion density values provide an easy way to grade progressive vascular change. Despite these advantages, imaging with OCTA can only provide a limited view of the peripheral retina and is unable to demonstrate leakage, staining, or pooling. OCTA requires patients to maintain good fixation to obtain high-resolution images which can be a challenge for those with severe macular disease. In patients who cannot safely undergo FA, OCTA may serve as an alternative form of angiography that can be safely and more frequently performed for the management of diabetic retinopathy. PMID- 27766585 TI - Anatomical distribution of primary amine oxidase activity in four adipose depots and plasma of severely obese women with or without a dysmetabolic profile. AB - Semicarbazide-sensitive amine oxidase (SSAO), identical to primary amine oxidase or vascular adhesion protein-1, is a membrane enzyme that generates hydrogen peroxide. SSAO is highly expressed at the adipocyte surface, and its plasma levels increase with type 2 diabetes. Since visceral adipose tissue (AT) is more tightly associated with obesity complications than subcutaneous (SC) abdominal fat, we compared SSAO activity in plasma and 4 distinct AT locations in 48 severely obese women (body mass index (BMI), averaging 54 +/- 11 kg/m2), with or without a dysmetabolic profile. Higher glucose and triacylglycerol levels vs lower high-density lipoprotein (HDL)-cholesterol characterized dysmetabolic women (DYS; n = 25) from non-dysmetabolic (NDYS; n = 23), age- and weight-matched subjects. SC, mesenteric (ME), omental (OM), and round ligament (RL) fat locations were collected during bariatric surgery. SSAO capacity to oxidize up to 1 mM benzylamine was determined in AT and plasma with radiometric and fluorimetric methods. Plasma SSAO was higher in the DYS group. SSAO activity was higher in fat than in plasma, when expressed as radiolabeled benzaldehyde per milligram of protein. In ATs from DYS women, protein content was 10 % higher, and basal hydrogen peroxide release lower than in NDYS subjects, except for RL location. The SSAO affinity towards benzylamine did not exhibit regional variation and was not altered by a dysmetabolic profile (K m averaging 184 +/- 7 MUM; n = 183). Although radiometric and fluorimetric methods gave different estimates of oxidase activity, both indicated that AT SSAO activity did not vary according to anatomical location and/or metabolic status in severely obese women. PMID- 27766587 TI - Brain injury in women experiencing intimate partner-violence: neural mechanistic evidence of an "invisible" trauma. AB - Traumatic brain injury (TBI) in women experiencing intimate-partner violence (IPV) is common, and IPV afflicts 30 % of women worldwide. However, the neurobiology and related sequelae of these TBIs have never been systematically examined. Consequently, TBI treatments are typically absent and IPV interventions are inadequate. There has been a call for a comprehensive assessment of IPV related TBIs and their relationship to aspects of women's cognitive and neural functioning. In response, we examined brain-network organization associated with TBI and its cognitive effects using clinical interviews and neuropsychological measures as well as structural and functional Magnetic Resonance Imaging (fMRI) in women experiencing IPV-related TBI. We hypothesized that TBI severity would be related to poorer cognitive performance and be associated with structural and functional connectivity between cognitive networks previously implicated in other TBI populations. As predicted, severity of TBI was negatively associated with inter-network intrinsic functional connectivity indicative of TBI, between the right anterior insula and posterior cingulate cortex/precuneus (FLAME1 + 2; family-wise error-corrected Z > 2.3, cluster- based p < 0.05). This association remained significant when controlling for partner-abuse severity, age, head motion, childhood trauma and psychopathology. Additionally, intrinsic functional connectivity between the same regions correlated positively with cognitive performance on indices of memory and learning. These data provide the first mechanistic evidence of TBI and its association with cognitive functioning in women sustaining IPV-related TBI. These data underscore the need to address and consider the role TBI may be playing in the efficacy of IPV interventions ranging from emergency first responder interactions to specific treatment plans. PMID- 27766584 TI - Presence and Risk Factors for Glaucoma in Patients with Diabetes. AB - Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure-the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients. PMID- 27766586 TI - Brain structure and function in patients with ovarian cancer treated with first line chemotherapy: a pilot study. AB - Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy. PMID- 27766588 TI - Different spatial patterns of brain atrophy and global functional connectivity impairments in major depressive disorder. AB - Alterations in grey matter structure and functional connectivity (FC) are pathological features of major depressive disorder (MDD). However, the relationship between brain structural and functional impairments in MDD remains uncertain. Thus, the aim of this study was to investigate the relationship between alterations in grey matter volume (GMV) and resting-state global functional connectivity density (rs-gFCD) in MDD. Forty-five patients with MDD and 48 healthy controls underwent structural and resting-state functional magnetic resonance imaging (fMRI). GMV and rs-gFCD maps of each subject were created, and the intergroup differences in these neuroimaging metrics were evaluated. Compared to healthy controls, patients with MDD displayed reduced GMV in the left insula, putamen, amygdala and hippocampus (mainly in the limbic system). In contrast, decreased rs-gFCD was observed in the left postcentral and precentral gyri, right fusiform gyrus and lingual gyrus (mainly in the sensory system). Furthermore, we found no significant correlations between GMV and rs gFCD in these brain regions. Finally, overlap ratio analysis demonstrated that the spatial distribution patterns of intergroup differences on the GMV and rs gFCD maps were distinct. Our findings suggest that the presence of distinct spatial distribution patterns of brain atrophy and global FC impairments might be pathological features of MDD. PMID- 27766589 TI - Assessment of Distal Radius Bone Mineral Density in Osteoporosis Patients Receiving Denosumab, Including Those with Rheumatoid Arthritis and Those Receiving Oral Glucocorticoids. AB - BACKGROUND AND OBJECTIVES: Recently, the osteoporosis treatment has attracted attention, and several drugs have been developed. Among these, bisphosphonates (BPs), parathyroid hormone (PTH) and anti-receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal (MAb) denosumab (DMAb) are the major osteoporosis agents. Several studies demonstrated that the effect of osteoporosis agents is evaluated by lumar or hip dual energy X-ray absorptiometry (DXA). However, private clinic commonly use the radial DXA. On the other hand, rheumatoid arthritis (RA) is sometimes associated with osteoporosis but there is no established treatment approach. In addition, glucocorticoids (GCs) are often used in the treatment of RA and sometimes induce osteoporosis. The present study assessed the effect of DMAb on osteoporosis in patients divided into RA and RA + GC patients by radial DXA. PATIENTS: The therapeutic effect of denosumab was assessed in female osteoporosis patients using radial dual-energy X-ray absorptiometry (radial DXA) in three groups: those with postmenopausal osteoporosis (PO group), PO with rheumatoid arthritis (RA group), and PO with RA receiving glucocorticoids (RA + GC group). METHODS: In total, 427 PO patients 60 years of age or older with a young adult mean value of <70 %, as determined by radial DXA, were treated with denosumab. The denosumab treatment group comprised a PO group (n = 205), RA group (n = 156), and RA + GC group (n = 66). The control group comprised a PO group (n = 44) and RA group (n = 33) who received oral bisphosphonate. Bone mineral density (BMD) was determined by using radial DXA. The bone turnover marker type I collagen cross-linked N-telopeptide (NTx) was also measured. RESULTS AND CONCLUSIONS: Radial DXA revealed a significant increase in BMD in the denosumab treatment group but not in the bisphosphonate treatment group. The onset of an increase in BMD with denosumab was slower in the RA group than in those without RA. The effect of denosumab in preventing increased NTx levels was smaller in the RA and RA + GC groups than in the PO group. Adherence to denosumab treatment was statistically significantly greater than for bisphosphonate treatment. PMID- 27766592 TI - Measurement of cardiovascular function using a novel view-sharing PET reconstruction method and tracer kinetic analysis. AB - Recent advancements in PET instrumentation have made the non-invasive assessment of cardiovascular function in small animals a reality. The majority of small animal PET systems use stationary detector gantries, thus affording high temporal resolution imaging of cardiac function. Systems designed to maximize spatial resolution and detection sensitivity employing rotating gantry designs are suboptimal when high temporal resolution imaging is needed. To overcome this limitation, the current work developed a novel view-sharing data analysis scheme suitable for dynamic cardiac PET imaging using 18F-NaF as the tracer and tracer kinetic model analysis. This scheme was tested in a rat model of cardiovascular function where the relationship between direct transonic flow measures of cardiac output were highly correlated (f(x) = 1.0216x - 24.233, R = 0.9158, p < 0.001) with the new model. Similarly, derived measures of stroke volume were also highly correlated (f(x) = 0.9655x - 0.0428, R = 0.9453, p < 0.001) with the current approach. Administration of xylazine caused a statistically significant increase in stroke volume (0.32 +/- 0.07 ml, p = 0.003, n = 4) and a significant decrease in both heart rate (-155 +/- 7.1 beats/min, p < 0.001, n = 4) and cardiac output (-75.9 +/- 23.0 ml/kg min, p = 0.01, n = 4). These findings suggest that the new sinogram binning and kinetic modeling methods produce reliable cardiac function measures suitable for longitudinal monitoring of cardiovascular function. PMID- 27766593 TI - Pancreatic surgery. PMID- 27766591 TI - Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine. AB - PURPOSE: Glioblastoma (GBM) ranks among the deadliest solid cancers worldwide and its prognosis has remained dismal, despite the use of aggressive chemo irradiation treatment regimens. Limited drug delivery into the brain parenchyma and frequent resistance to currently available therapies are problems that call for a prompt development of novel therapeutic strategies. While only displaying modest efficacies as mono-therapy in pre-clinical settings, histone deacetylase inhibitors (HDACi) have shown promising sensitizing effects to a number of cytotoxic agents. Here, we sought to investigate the sensitizing effect of the HDACi trichostatin A (TSA) to the alkylating agent lomustine (CCNU), which is used in the clinic for the treatment of GBM. METHODS: Twelve primary GBM cell cultures grown as neurospheres were used in this study, as well as one established GBM-derived cell line (U87 MG). Histone deacetylase (HDAC) expression levels were determined using quantitative real-time PCR and Western blotting. The efficacy of either CCNU alone or its combination with TSA was assessed using various assays, i.e., cell viability assays (MTT), cell cycle assays (flow cytometry, FACS), double-strand DNA break (DSB) quantification assays (microscopy/immunofluorescence) and expression profiling assays of proteins involved in apoptosis and cell stress (Western blotting and protein array). RESULTS: We found that the HDAC1, 3 and 6 expression levels were significantly increased in GBM samples compared to non-neoplastic brain control samples. Additionally, we found that pre-treatment of GBM cells with TSA resulted in an enhancement of their sensitivity to CCNU, possibly via the accumulation of DSBs, decreased cell proliferation and viability rates, and an increased apoptotic rate. CONCLUSION: From our data we conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM. PMID- 27766590 TI - An Updated Overview on Therapeutic Drug Monitoring of Recent Antiepileptic Drugs. AB - Given the distinctive characteristics of both epilepsy and antiepileptic drugs (AEDs), therapeutic drug monitoring (TDM) can make a significant contribution to the field of epilepsy. The measurement and interpretation of serum drug concentrations can be of benefit in the treatment of uncontrollable seizures and in cases of clinical toxicity; it can aid in the individualization of therapy and in adjusting for variable or nonlinear pharmacokinetics; and can be useful in special populations such as pregnancy. This review examines the potential for TDM of newer AEDs such as eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, rufinamide, retigabine, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. We describe the relationships between serum drug concentration, clinical effect, and adverse drug reactions for each AED as well as the different analytical methods used for serum drug quantification. We discuss retrospective studies and prospective data on the serum drug concentration-efficacy of these drugs and present the pharmacokinetic parameters, oral bioavailability, reference concentration range, and active metabolites of newer AEDs. Limited data are available for recent AEDs, and we discuss the connection between drug concentrations in terms of clinical efficacy and nonresponse. Although we do not propose routine TDM, serum drug measurement can play a beneficial role in patient management and treatment individualization. Standardized studies designed to assess, in particular, concentration-efficacy toxicity relationships for recent AEDs are urgently required. PMID- 27766594 TI - Prospective survey to study factors which could influence same-day discharge after elective laparoscopic cholecystectomy in a tertiary care hospital of a developing country. AB - All laparoscopic cholecystectomy (LC) patients in our hospital setting are admitted overnight. This article assesses the contribution of factors like postoperative nausea and vomiting (PONV), postoperative pain and surgical complications to overnight stay after elective LC. This 1-year observational study included patients having normal liver functions undergoing elective LC before 1400 h. The collected data included patient demographics, co-morbidities, PONV, pain scores, complications, surgical time, anesthesia technique, use of prophylactic antiemetics, analgesics, patient satisfaction and desire to have this surgery as day case or in-patient procedure. From 930 LC done per annum, 45.2 % (430/950) patients were included in this study. Prophylactic antiemetic was given in 91.6 %, intraoperative narcotics in 94.2 % patients and multimodal analgesia in 85.3 %. The mean pain score in the recovery and ward was maintained to <4. In the ward, 99.1 % patients were able to start oral fluids after 6 h and were started on oral non-steroidal anti-inflammatory drugs and paracetamol, and none required parental opioid. The PONV score of more than 2 was observed in only 3.2 % of patients in the ward requiring parenteral antiemetic. Surgical complications in the form of bleeding, visceral injury and bile duct leak were observed in 2 % of patients, which was treated intra-operatively. Satisfaction was observed in 99.3 % and desire to stay overnight in 87.4 % of patients. Factors like postoperative pain, PONV and surgical complications were well managed and were not associated with significant morbidity to justify routine overnight admission. However, majority of the patients desired to stay overnight, which could be improved by counseling and education. PMID- 27766596 TI - Effects of acupuncture on quality of life and pain in patients with osteoporosis a pilot randomized controlled trial. AB - : In this sham-controlled study, 53 patients received 10 sessions of acupuncture treatment over 5 weeks to investigate the effects of acupuncture on the pain and quality of life of patients with osteoporosis. The results showed significant favorable effects of verum acupuncture on quality of life. Both interventions showed sustained and clinically relevant effects on pain. PURPOSE: Standard analgesic treatment is associated with adverse events in patients with osteoporosis, especially elderly and/or comorbid patients. As acupuncture has gained widespread acceptance as a complementary treatment modality with few side effects, the aim of this study was to evaluate the effects of acupuncture on the pain and quality of life of patients with osteoporosis. METHODS: In total, 53 patients with vertebral compression fractures, osteoporosis-associated spinal deformities, and resultant pain were randomly allocated to the verum acupuncture with deep needling of specific points following the principles of traditional Chinese medicine (n = 29) or control acupuncture group with superficial needling of non-acupuncture points (n = 24). All patients received 10 sessions of standardized verum or control acupuncture treatment over 5 weeks. Pain (VAS score 1-100) and quality of life (QUALEFFO-41) were measured at the start of treatment (T0), before each acupuncture session (T1), and at 1 (T2) and 3 months (T3) post treatment. RESULTS: Both acupuncture treatments significantly reduced activity related pain and pain at rest over time. The verum acupuncture group experienced a significantly greater reduction in mean pain intensity at rest than the control group. In the control group, quality of life improved only temporarily post treatment (T2) and slightly declined at the end of the follow-up period (T3). In contrast, patients in the verum acupuncture group experienced continuous and significant improvements in quality of life up to 3 months after treatment (T3). CONCLUSIONS: Both types of acupuncture were equally effective in producing sustained, clinically relevant pain relief in patients with osteoporosis. Verum acupuncture had stronger and longer-lasting effects on quality of life and pain at rest. The possible reasons for these findings include the specificity of acupuncture point selection and the performance of needle stimulation. PMID- 27766595 TI - A literature review of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): so far, so good. AB - Recently, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) emerged as a novel surgical strategy to induce a rapid and large hypertrophy of the future liver remnant (FLR). We conducted a computerized search using PubMed and Google Scholar for reports published between March 2012 and July 2016 using mesh headings and key words relating to the ALPPS surgical procedure. The promising results obtained up to date are difficult to interpret due to the heterogeneous group of patients with different underlying pathologies and different chemotherapy schemes. The ALPPS appears as a feasible strategy to be included in the multimodal treatment menu of selected oncological patients. The ALPPS approach can be implemented with acceptable postoperative morbidity and mortality in experienced centers and only in carefully selected patients. This strategy might substitute classic 2-stage hepatectomy in certain patients if future evidence shows superior or equal long-term outcomes. PMID- 27766597 TI - Ocular drug delivery-eye on innovation. PMID- 27766599 TI - Fatty acid microemulsion for the treatment of neonatal conjunctivitis: quantification, characterisation and evaluation of antimicrobial activity. AB - Fatty acids (FAs) are used by many organisms as defence mechanism against virulent bacteria. The high safety profile and broad spectrum of activity make them potential alternatives to currently used topical antibiotics for the treatment of eye infections in neonates. The current study utilised a Design of Experiment approach to optimise the quantification of five fatty acids namely; lauric acid, tridecanoic acid, myristoleic acid, palmitoleic acid and alpha linolenic acid. The significance of the influence of the experimental parameters such as volume of catalyst, volume of n-hexane, incubation temperature, incubation time and the number of extraction steps on derivatisation was established by statistical screening with a factorial approach. Derivatisation was confirmed using attenuated total reflectance infrared (ATR) and 1H NMR spectrum. A gas chromatographic method (GC-FID) was developed and validated according to ICH guidelines for the identification and quantification of fatty acids. The results were found to be linear over the concentration range studied with coefficient of variation greater than 0.99 and high recovery values and low intra-day and inter-day variation values for all FAs. Then, different alpha linolenic acid-based microemulsions (MEs) were prepared using Tween 80 as surfactant, polyethylene glycol 400 (PEG 400) as co surfactant and water as aqueous phase. The developed GC method was used to quantify the FA content in ME formulations. The results indicated that the developed GC method is very effective to quantify the FA content in the ME formulations. The antimicrobial efficacy of FA-based MEs were tested against Staphylococcus aureus. It was concluded that the FA-based MEs have strong antimicrobial effect against S. aureus. PMID- 27766600 TI - A feature study of innovative high-speed lancing device and safety lancet. AB - The study developed two models of an innovative high-speed lancing device and safety lancet, where the specially designed structure causes high-speed motion of the lancet, resulting in only one puncture of the skin. The two experimental models and other lancing devices sold on market were compared in order to: (1) measure the forces of lancets piercing animal skin by a load cell; (2) observe the wound areas caused by lancing devices under a microscope. The experimental results showed that, after using this innovative high-speed lancing device, the maximum force of a lancet piercing skin is only 1/3 of the force of conventional lancing devices, and the duration of the former under the skin is 1/6 of the latter. In addition, the wound area caused by the innovative lancing device is 20 % smaller than those of the conventional lancing devices. Usage of this innovative high-speed safety lancet shows that its maximum skin-piercing force is only 2/3 of conventional safety lancets, its duration under the skin is 1/4 of conventional safety lancets, and the wound area is 12 % smaller. In conclusion, both the innovative high-speed lancing device and safety lancet are proved effective in alleviating pain for diabetics and shortening the recovering time for wounds, thus, providing a more comfortable process for the self-monitoring of blood glucose. PMID- 27766601 TI - Genetic Diversity and Population Structure of Rice Varieties Cultivated in Temperate Regions. AB - BACKGROUND: After its domestication, rice cultivation expanded from tropical regions towards northern latitudes with temperate climate in a progressive process to overcome limiting photoperiod and temperature conditions. This process has originated a wide range of diversity that can be regarded as a valuable resource for crop improvement. In general, current rice breeding programs have to deal with a lack of both germplasm accessions specifically adapted to local agro environmental conditions and adapted donors carrying desired agronomical traits. Comprehensive maps of genome variability and population structure would facilitate genome-wide association studies of complex traits, functional gene investigations and the selection of appropriate donors for breeding purposes. RESULTS: A collection of 217 rice varieties mainly cultivated in temperate regions was generated. The collection encompasses modern elite and old cultivars, as well as traditional landraces covering a wide genetic diversity available for rice breeders. Whole Genome Sequencing was performed on 14 cultivars representative of the collection and the genomic profiles of all cultivars were constructed using a panel of 2697 SNPs with wide coverage throughout the rice genome, obtained from the sequencing data. The population structure and genetic relationship analyses showed a strong substructure in the temperate rice population, predominantly based on grain type and the origin of the cultivars. Dendrogram also agrees population structure results. CONCLUSIONS: Based on SNP markers, we have elucidated the genetic relationship and the degree of genetic diversity among a collection of 217 temperate rice varieties possessing an enormous variety of agromorphological and physiological characters. Taken together, the data indicated the occurrence of relatively high gene flow and elevated rates of admixture between cultivars grown in remote regions, probably favoured by local breeding activities. The results of this study significantly expand the current genetic resources available for temperate varieties of rice, providing a valuable tool for future association mapping studies. PMID- 27766598 TI - Pharmaceutical microscale and nanoscale approaches for efficient treatment of ocular diseases. AB - Efficient treatment of ocular diseases can be achieved thanks to the proper use of ophthalmic formulations based on emerging pharmaceutical approaches. Among them, microtechnology and nanotechnology strategies are of great interest in the development of novel drug delivery systems to be used for ocular therapy. The location of the target site in the eye as well as the ophthalmic disease will determine the route of administration (topical, intraocular, periocular, and suprachoroidal administration) and the most adequate device. In this review, we discuss the use of colloidal pharmaceutical systems (nanoparticles, liposomes, niosomes, dendrimers, and microemulsions), microparticles (microcapsules and microspheres), and hybrid systems (combination of different strategies) in the treatment of ophthalmic diseases. Emphasis has been placed in the therapeutic significance of each drug delivery system for clinical translation. PMID- 27766602 TI - Clinical study of Gene-Eden-VIR/Novirin in genital herpes: suppressive treatment safely decreases the duration of outbreaks in both severe and mild cases. AB - BACKGROUND: We conducted a clinical study that tested the effect of suppressive treatment with the botanical product Gene-Eden-VIR/Novirin on genital herpes. Our previous paper showed that the treatment decreased the number of genital herpes outbreaks without any side effects. It also showed that the clinical effects of Gene-Eden-VIR/Novirin are mostly better than those reported in the studies that tested acyclovir, valacyclovir, and famciclovir. The current paper reports the effect of suppressive treatment with Gene-Eden-VIR/Novirin on the duration of outbreaks, in severe and mild genital herpes cases. METHODS: The framework was a retrospective chart review. The population included 137 participants. The treatment was 1-4 capsules per day. The duration of treatment was 2-48 months. The study included three controls: baseline, no-treatment, and dose-response. RESULTS: The treatment decreased the duration of outbreaks in 87 % of participants and decreased the mean duration of outbreaks from 8.77 days and 6.7 days in the control groups to 2.87 days in the treatment group (P < 0.001, both groups). All participants reported no adverse experiences. CONCLUSIONS: This paper shows that suppressive treatment with Gene-Eden-VIR/Novirin decreased the duration of genital herpes outbreaks, in both severe and mild cases, without any side effects. Based on the results reported in this and our previous paper, we recommend suppressive treatment with Gene-Eden-VIR/Novirin as a natural alternative to both suppressive and episodic treatments with current drugs, in both severe and mild genital herpes cases. Trial registration ClinicalTrials.gov NCT02715752 Registered 17 March 2016 Retrospectively Registered. PMID- 27766603 TI - Role of physiotherapy in the mobilization of patients with spinal cord injury undergoing human embryonic stem cells transplantation. AB - BACKGROUND: The major complication faced by patients with chronic static spinal cord injury (SCI) is the loss of mobilization. With the aim to rehabilitate SCI patients, physiotherapy is performed worldwide. However, it only helps the patients to live with their disabilities. An interdisciplinary management involving human embryonic stem cell (hESC) therapy along with physiotherapy as a supportive therapy offers regenerative treatment of the patients with SCI. MAIN BODY: The present study focuses on the role of physiotherapy in the mobilization of patients with SCI (paraplegic 136; tetraplegics 90) undergoing hESC therapy. At admission, patients were assessed on the basis of clinical and American Spinal Injury Association Impairment Scale (AIS), where 153, 32, 36 and 5 patients were designated with AIS score A, B, C and D, respectively. After 8-12 weeks of hESC therapy and physiotherapy, the patients showed clinical and scoring improvement. The patients with AIS score A shifted to B (15.0 %) and C (37.3 %), whereas, patients with grade B moved to C (40.6 %) and D (3.1 %). Patients with AIS score C and D shifted to grade D (13.9 %) and E (60.0 %), respectively. Moreover, orthotic devices were reduced to simpler ones. CONCLUSION: The physiotherapy aided in training of cells and took care of atrophy of limbs, whereas hESC therapy resulted in an overall improvement of the patients with SCI. PMID- 27766604 TI - A braided cancer river connects tumor heterogeneity and precision medicine. AB - With the ever-increasing complexity of tumor heterogeneity (TH) discovered through cancer genome sequencing, it is apparent that TH has become the biggest hurdle for precision cancer therapeutics. Through studying the genomics of exceptional responders to targeted therapeutic agents in kidney cancer, we demonstrated parallel convergent gene/pathway/capability/function evolution of kidney cancer in the context of TH, which prompted us to propose a new cancer evolution model "the braided cancer river model". Based on this model, we might be able to outsmart a given cancer type within an individual patient through simultaneously inhibiting preferred parallel pathways or sequential nodes. Thus, the goals of this perspective are to define tumor heterogeneity, discuss tumor evolution, introduce braided cancer river model, and improve precision medicine. PMID- 27766605 TI - Evaluation of patients with multiple sclerosis using reverse nutech functional score and expanded disability status scale after human embryonic stem cell therapy. AB - BACKGROUND: The expanded disability status scale (EDSS) is a validated and reliable tool to assess the extent of disabilities in patients with multiple sclerosis (MS). However, the use of this tool has been found to be limited in assessing various symptoms of MS that are important. Our study aimed at evaluating the efficacy of a new scoring system, reverse nutech functional score (RNFS) as compared to EDSS in assessing patients with MS treated with human embryonic stem cell (hESC) therapy. METHODS: The MS patients were treated with hESC therapy for one treatment period. All the patients were evaluated with EDSS and RNFS at baseline and after the hESC therapy. RESULTS: The study included a total of 24 MS patients with mean age of 45 year. The patients showed an improvement in parameters (sleeping disorders, paralysis, paraesthesia, myalgia, muscle weakness, memory, language, irritability, eye pain, depression and coordination, communication, breathing pattern, attention and appetite) associated with MS when evaluated with RNFS. This improvement went unnoticed when the patients were assessed with EDSS. CONCLUSION: RNFS can efficiently assess the effectiveness of hESC therapy in treating patients with MS. It could be a suitable scoring system for patients with MS as it can assess the slightest improvements in the patients. Use in other settings would be helpful in assessing its utility. PMID- 27766606 TI - Structural and Magnetoresistive Properties of Nanometric Films Based on Iron and Chromium Oxides on the Si Substrate. AB - Ultraviolet photons of KrF laser (248 nm) was used for the synthesis of nanometric films based on iron and chromium oxides (Fe2O3 - X (0 <= x <= 1) and Cr3 - X O3 - Y (0 <= x <= 2; 0 <= y <= 2)) with variable thickness, stoichiometry, and electrical properties. Film deposition was carried out on the silicon substrate Si < 100 > at the substrate's temperature T S = 293 K. X-ray diffraction and X-ray reflectometry analysis were used for the obtained structure characterization. Such a combined investigation reveals the composition and texture for samples investigated and provides useful information about layer thickness and roughness. Fe2O3 - X (0 <= x <= 1) nanometric films demonstrate the negative magnetoresistance in magnetic fields up 7 kOe. At the same time, for hybrid systems of the alternate layers Fe2O3 - X (0 <= x <= 1)/Cr3 - X O3 - Y (0 <= x <= 2; 0 <= y <= 2), the positive magnetoresistance as well as the magnetic hysteresis and magnetoresistivity switching effect in the low magnetic fields were observed. PMID- 27766607 TI - Electrical Contacts on Silicon Nanowires Produced by Metal-Assisted Etching: a Comparative Approach. AB - Silicon nanowires fabricated by metal-assisted chemical etching can present low porosity and a rough surface depending on the doping level of the original silicon wafer. In this case, wiring of silicon nanowires may represent a challenging task. We investigated two different approaches to realize the electrical contacts in order to enable electrical measurement on a rough silicon nanowire device: we compared FIB-assisted platinum deposition for the fabrication of electrical contact with EBL technique. PMID- 27766608 TI - Ultrafine MnO2 Nanowire Arrays Grown on Carbon Fibers for High-Performance Supercapacitors. AB - Large-area ultrafine MnO2 nanowire arrays (NWA) directly grew on a carbon fiber (CF, used as a substrate) by a simple electrochemical method, forming three dimensional (3D) hierarchical heterostructures of a CF@MnO2 NWA composite. As an electrode for supercapacitors, the CF@MnO2 NWA composite exhibits excellent electrochemical performances including high specific capacitance (321.3 F g-1 at 1000 mA g-1) and good rate capability. Further, the overall capacitance retention is ~99.7 % capacitance after 3000 cycles. These outstanding electrochemical performances attribute to a large number of transport channels for the penetration of electrolyte and the transportation of ions and electrons of electrodes. The as-prepared CF@MnO2 NWA composite may be a promising electrode material for high-performance supercapacitors. PMID- 27766609 TI - Professor Aleksandra Krygier-Stojalowska (1923-2015). PMID- 27766610 TI - Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells. AB - INTRODUCTION: Sucla2, a beta subunit of succinyl coenzyme A synthase, is located in the mitochondrial matrix. Sucla2 catalyzes the reversible synthesis of succinate and adenosine triphosphate (ATP) in the tricarboxylic acid cycle. Sucla2 expression was found to be correlated with the capacitation of boar spermatozoa. We have previously reported that Sucla2 was decreased in the testes of rats with spermatogenesis failure after exposure to endocrine disruptor BDE47. Yet, the expression model of Sucla2 in spermatogenesis and the function of Sucla2 in spermatogenic cells are still unclear. Our objective was to explore the localization of Sucla2 during mouse spermatogenesis and its function in the mouse spermatocyte line (GC2). MATERIAL AND METHODS: The localization of Sucla2 in the mouse testis was explored through immunohistochemistry (IHC). Sucla2 was knocked down in GC2 cells and its expression was detected by Western blot (WB) to verify the efficiency of the siRNA transfection. Mitochondrial membrane potential (MMP), apoptosis and ROS of GC2 were detected by flow cytometry. ATP production was measured by the luminometric method and the presence of Bcl2 of GC2 was detected by WB. RESULTS: Sucla2 is highly expressed in all germ cells but not in interstitial cells. Coarse Sucla2 signals are found in spermatocytes in stages VII-XII of mouse spermatogenesis. In GC2 cells, knockdown of Sucla2 decreased cell viability and MMP, induced apoptosis of GC2 cells, decreased ATP production, and Bcl2 expression, and increased ROS levels. CONCLUSIONS: Sucla2 is related to the developmental stages of mouse spermatogenesis. Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis via decreased mitochondrial function of the cells PMID- 27766611 TI - JCV serology in time: 3 years of follow-up. AB - OBJECTIVES: Although many neurologists are reluctant to use natalizumab in MS (multiple sclerosis) given the increased risk for PML (progressive multifocal leukoencephalopathy), trust was regained with the introduction of JCV antibody titres as a potent disease-modifying therapy. Literature shows that in patients with a negative JCV serology, the risk of PML is virtually non-existent. Unfortunately, seroconversion causes concern amongst many neurologists. Furthermore, when patients seroconvert, it is still unclear what the risk is of passing the important threshold of 1.5. MATERIALS & METHODS: JCV serology data of 161 patients were analysed, upon treatment with natalizumab at the University Hospital in Lille, France, between May 2012 and November 2014. RESULTS: Of the 81 patients who tested negative for JCV antibody at baseline, 23 (28.3%) seroconverted but only seven (8.6%) passed the threshold of 1.5. Of the 80 patients testing positive for JCV antibody at baseline, eight had an initial JCV antibody titre of 0.9 or lower of which only one of eight (12.5%) patients passed the threshold of 1.5 in the following 3 years. Eight of 15 (53.3%) patients passed this threshold if the initial serology was higher than 0.9. CONCLUSIONS: JCV-negative patients and JCV-positive patients with antibody levels below or equal to 0.9 both have a low risk of surpassing the 1.5 threshold. PMID- 27766612 TI - Fear appeals, engagement, and examination performance: The role of challenge and threat appraisals. AB - BACKGROUND: Fear appeals are persuasive messages that draw attention to the negative consequences (e.g., academic failure) that follow a particular course of action (e.g., not engaging in lessons) and how negative consequences can be avoided with an alternate course of action. Previous studies have shown that when fear appeals are appraised as threatening, they are related to lower examination performance. AIM: In this study, we examined how challenge, as well as threat, appraisals are indirectly related to performance on a mathematics examination through behavioural engagement. SAMPLE: A total of 579 students from two secondary schools. METHOD: Data were collected over four waves at approximately 3 month intervals. Behavioural engagement data were collected at T1 and T3 , fear appeal frequency and appraisal at T3 , and examination performance at T2 and T4 . RESULTS: A challenge appraisal of fear appeals predicted better examination performance through higher behavioural engagement whereas a threat appraisal of fear appeals predicted worse examination performance through lower behavioural engagement. CONCLUSION: The relationship between fear appeals and examination performance depended on their appraisal. PMID- 27766613 TI - Carotid Doppler flowmetry correlates poorly with thermodilution cardiac output following cardiac surgery. AB - BACKGROUND: It remains unclear whether measuring carotid arterial flow by the time velocity integral using vascular Doppler ultrasound can be used to monitor cardiac output and volume responsiveness. METHODS: The carotid Doppler flow (time velocity integral and peak flow velocity variation) was assessed in triplicate by an intensivist with formal vascular ultrasound training. Thirty-three patients admitted following coronary by-pass surgery were studied before and after a passive leg-raising manoeuvre to investigate volume responsiveness (more than 10% increase in cardiac output) along with indices of arterial load measuring cardiac output by thermodilution. Pearson's correlation coefficient and area under the curve (AUC) by receiver operating characteristics were calculated. RESULTS: A significant correlation between carotid Doppler flow and cardiac output was demonstrated in post-operative cardiac surgery patients (r = 0.80 [95%CI 0.61 0.89]), including relative changes following passive leg raising (r = 0.79 [95%CI 0.60-0.89]) that showed a mean difference of 2% with wide limits of agreements ( 19% to 16%). Changes in carotid Doppler flow following passive leg raising correlated with the baseline arterial resistance but not with compliance or effective elastance. A peak flow variation > 10% before passive leg raising discriminated responders to the manoeuvre with an AUC of 0.81 [95% CI 0.55-0.95]. CONCLUSIONS: Weak correlations between common carotid Doppler flow and cardiac output mean that the methods cannot be used interchangeably in post-operative cardiac surgery patients. PMID- 27766614 TI - Comment on: Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia. PMID- 27766615 TI - Continuous improvement in national ART standards by the RTAC accreditation system in Australia and New Zealand. AB - BACKGROUND: Assisted reproductive technology (ART) clinics in Australia and New Zealand are accredited and licensed against a Code of Practice audited by certifying bodies accredited by the Joint Accreditation System for Australia and New Zealand (JAS-ANZ). The system is administered by the Reproductive Technology Accreditation Committee (RTAC) of the Fertility Society of Australia. AIMS: To review the incidence of variances and findings identified by certifying bodies in Australian and New Zealand ART clinics within the currency of a single version of the Code of Practice. METHODS: Retrospective analysis of certifying body findings against the RTAC Code of Practice incorporating 15 Critical Criteria audited annually and 16 Good Practice Criteria including a Quality Management System audited over a three year cycle. RESULTS: The incidence of clinics with variances against the Critical Criteria fell from 77 to 14% over two years, as did the mean number of variances per clinic which fell from 1.54 to 0.14. CONCLUSIONS: Implementation of the RTAC accreditation system in Australia and New Zealand has contributed to steady improvement in standards and a reduction in risk in ART treatments. PMID- 27766617 TI - Successful molecular targeted treatment of AML in pregnancy with Azacitidine and Sorafenib with no adverse fetal outcomes. PMID- 27766618 TI - Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease. AB - Human cystatin C (hCC) is a small protein belonging to the cystatin family of papain-like cysteine proteinase inhibitors. We review the recent literature concerning structural aspects of hCC related to disease. We focus on the mechanisms of hCC dimerization, oligomerization, and amyloid formation. Amyloid formation is associated with a number of neurodegenerative diseases that affect the independence and quality of life of aging populations. hCC is one of the second-wave proteins that have been found to undergo amyloidosis associated with disease. For hCC, this includes cerebral amyloid angiopathy, as well as a disorder resulting in reduced male fertility. PMID- 27766619 TI - Dynamic changes in CCL3 and CCL4 plasma concentrations in patients with chronic lymphocytic leukaemia managed with observation. PMID- 27766616 TI - Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia. AB - Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in paediatric and adult AML. PMID- 27766620 TI - Successful management of acute myeloid leukaemia in a twin pregnancy - a case report. PMID- 27766621 TI - Through the Looking Glass: Estimating Effects of Medical Homes for People with Severe Mental Illness. AB - OBJECTIVE: To examine whether medical homes have heterogeneous effects in different subpopulations, leveraging the interpretations from a variety of statistical techniques. DATA SOURCES/STUDY SETTING: Secondary claims data from the NC Medicaid program for 2004-2007. The sample included all adults with diagnoses of schizophrenia, bipolar disorder, or major depression who were not dually enrolled in Medicare or in a nursing facility. STUDY DESIGN: We modeled a number of monthly service use, adherence, and expenditure outcomes using fixed effects, generalized estimating equation with and without inverse probability of treatment weights, and instrumental variables analyses. DATA COLLECTION: Data were received from the Carolina Cost and Quality Initiative. PRINCIPAL FINDINGS: The four estimation techniques consistently revealed generally positive associations between medical homes and access to primary care, specialty mental health care, greater medication adherence, slightly lower emergency room use, and greater expenditures. These findings were consistent across all three major severe mental illness diagnostic groups. Some heterogeneity in effects were noted, especially in preventive screening. CONCLUSIONS: Expanding access to primary care-based medical homes for people with severe mental illness may not save money for insurance providers, due to greater access for important outpatient services with little cost offset. Health services research examining more of the treatment heterogeneity may contribute to more realistic projections about medical homes outcomes. PMID- 27766622 TI - Outcome of primary cutaneous anaplastic large cell lymphoma: a 20-year British Columbia Cancer Agency experience. AB - Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare CD30+ lymphoproliferative disorder with excellent outcomes reported despite frequent cutaneous relapses. Limited information exists on the development of systemic lymphoma. The British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify all adults diagnosed with PCALCL from 1993 to 2013. From 2005, the BCCA endorsed radiotherapy (RT) alone for limited stage with data failing to support chemotherapy. Forty-seven patients were identified with a male predominance (n = 31, 66%), median age of 64 years and predominantly limited stage (n = 40, 85%). Median follow-up was 8.4 years. The 5-year time to progression (TTP) was 58% (64% limited versus 29% advanced stage). The 5-year disease-specific survival (DSS) and overall survival was 86% and 75%, respectively. In an as-treated analysis, the 5-year DSS for limited stage patients was similar comparing RT to combined modality treatment or chemotherapy alone but the 5-year TTP favoured RT (82% vs. 33%, P = 0.004). The 5-year cumulative risk of developing systemic lymphoma was 14%. Our results confirm the favourable prognosis of PCALCL despite a high relapse rate. Limited stage patients treated with RT alone have excellent outcomes. There is a small risk of systemic lymphoma in PCALCL. PMID- 27766623 TI - Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and potential for therapy. AB - Central nervous system acute lymphoblastic leukaemia (CNS-ALL) is a major clinical problem. CNS-directed 'prophylactic' chemo- or radio - therapy is associated with significant early and long-term toxicity. Moreover, greater than a third of the relapses occur in the CNS. To design specific, more effective and less toxic therapy and for personalized precise adjustment of prophylactic therapy there is a need for better understanding of the biology of this disease. Specifically, the precise neurotropic mechanisms of ALL are currently unclear, as is the pathogenesis of CNS relapse. Here we review and contrast the recent findings with earlier studies of pathogenesis of CNS leukaemia. We also describe the challenges in research of this devastating complication of ALL. PMID- 27766624 TI - Enteropathy-associated T-cell lymphoma presenting as cutaneous deposits. PMID- 27766625 TI - Longitudinal Patterns of Emergency Department Visits: A Multistate Analysis of Medicaid Beneficiaries. AB - OBJECTIVE: The objective of this study was to examine the longitudinal patterns of emergency department (ED) visits among adult fee-for-service Medicaid. DATA SOURCES: Data were obtained from the Medicaid analytic eXtract files, Area Health Resource File, and County Health Rankings. STUDY DESIGN: A retrospective longitudinal study design, with four observations for each individual was used. The study population consisted of 33,393 Medicaid beneficiaries who met inclusion criteria. ED visits were time-lagged and time-varying patient-level factors were measured for each year. Time-invariant characteristics (gender and race/ethnicity) were measured in 2006. Multivariable hurdle models with logistic (ED use versus no ED use) and negative binomial regressions (ED visits among ED users) were used to analyze the ED visits over time. To account for correlation due to repeated observations, mixed effect models with robust standard errors were performed. PRINCIPAL FINDINGS: In both unadjusted and adjusted analysis, the likelihood of ED use did not change from year to year (AOR = 1.00, 95 percent CI: 0.99, 1.01). Among ED users, the estimated number of ED visits increased over time (IRR = 1.01, 95 percent CI: 1.01, 1.03). CONCLUSIONS: Primary care resources should be a major focus to reduce the increased burden on the EDs. PMID- 27766626 TI - Strategies for reducing the treatment-related physical burden of childhood acute myeloid leukaemia - a review. AB - Over the last four decades the survival of paediatric patients with acute myeloid leukaemia has gradually increased to 70% in high-income countries. The therapy is very intensive and associated with many acute and long-term side effects. The early death rate has been reduced to 1-4%. The acute toxicity is a limiting factor for improving survival in low-income countries. Transplant is associated with more endocrinological late effects while cardiotoxicity is more common after relapse. Reducing the physical costs of therapy without jeopardizing survival may be accomplished by optimal supportive care, less cardiotoxic anthracyclines, less consolidation courses and strict indications for stem cell transplantation. Analysing scenarios with different frequency of transplantation in first complete remission show similar overall survival rates, indicating that almost all patients can be spared the procedure in first remission. Reducing relapse risk is an effective way of reducing toxicity and more targeted therapy and improved risk group stratifications are needed. PMID- 27766627 TI - Whole body magnetic resonance imaging in newly diagnosed multiple myeloma: early changes in lesional signal fat fraction predict disease response. AB - Cross-sectional imaging techniques are being increasingly used for disease evaluation in patients with multiple myeloma. Whole body magnetic resonance imaging (WB-MRI) scanning is superior to plain radiography in baseline assessment of patients but changes following treatment have not been systematically explored. We carried out paired WB-MRI scans in 21 newly diagnosed patients prior to, and 8-weeks after, starting chemotherapy, and analysed stringently selected focal lesions (FLs) for parametric changes. A total of 323 FLs were evaluated, median 20 per patient. At 8 weeks, there was a reduction in estimated tumour volume (eTV), and an increase in signal fat fraction (sFF) and apparent diffusion coefficient (ADC) in the group as a whole (P < 0.001). Patients who achieved complete/very good partial response (CR/VGPR) to induction had a significantly greater increase in sFF compared to those achieving <= partial response (PR; P = 0.001). When analysed on a per-patient basis, all patients achieving CR/VGPR had a significant sFF increase in their FL's, in contrast to patients achieving <=PR. sFF changes in patients reaching maximal response within 100 days (fast responders) were greater compared to slow responders (P = 0.001). Receiver Operator Characteristic analysis indicated that sFF changes at 8 weeks were the best biomarker (area under the Curve 0.95) for an inferior response (<=PR). We conclude that early lesional sFF changes may provide important information on depth of response, and are worthy of further prospective study. PMID- 27766629 TI - A population-based study of the impact of dialysis on mortality in multiple myeloma. PMID- 27766628 TI - Physician EHR Adoption and Potentially Preventable Hospital Admissions among Medicare Beneficiaries: Panel Data Evidence, 2010-2013. AB - OBJECTIVE: To test for correlation between the growth in adoption of ambulatory electronic health records (EHRs) in the United States during 2010-2013 and hospital admissions and readmissions for elderly Medicare beneficiaries with at least one of four common ambulatory care-sensitive conditions (ACSCs). DATA SOURCES: SK&A Information Services Survey of Physicians, American Hospital Association General Survey and Information Technology Supplement; and the Centers for Medicare & Medicaid Services Chronic Conditions Data Warehouse Geographic Variation Database for 2010 through 2013. STUDY DESIGN: Fixed effects model estimated the relationship between hospital referral region (HRR) level measures of physician EHR adoption and ACSC admissions and readmissions. Analyzed rates of admissions and 30-day readmissions per beneficiary at the HRR level (restricting the denominator to beneficiaries in our sample), adjusted for differences across HRRs in Medicare beneficiary age, gender, and race. Calculated physician EHR adoption rates as the percentage of physicians in each HRR who report using EHR in ambulatory care settings. PRINCIPAL FINDINGS: Each percentage point increase in market-level EHR adoption by physicians is correlated with a statistically significant decline of 1.06 ACSC admissions per 10,000 beneficiaries over the study period, controlling for the overall time trend as well as market fixed effects and characteristics that changed over time. This finding implies 26,689 fewer ACSC admissions in our study population during 2010 to 2013 that were related to physician ambulatory EHR adoption. This represents 3.2 percent fewer ACSC admissions relative to the total number of such admissions in our study population in 2010. We found no evidence of a correlation between EHR use, by either physicians or hospitals, and hospital readmissions at either the market level or hospital level. CONCLUSIONS: This study extends knowledge about EHRs' relationship with quality of care and utilization. The results suggest a significant association between EHR use in ambulatory care settings and ACSC admissions that is consistent with policy goals to improve the quality of ambulatory care for patients with chronic conditions. The null findings for readmissions support the need for improved interoperability between ambulatory care EHRs and hospital EHRs to realize improvements in readmissions. PMID- 27766630 TI - Classical Hodgkin lymphoma producing macrophage colony-stimulating factor with resultant monocytosis. PMID- 27766631 TI - Pulmonary dysfunction in thalassaemia major: is there any relationship with body iron stores? AB - Although pulmonary function abnormalities in thalassaemia major (TM) were described in 1980, the pathogenetic mechanism is not clear and data are contradictory, probably because of study heterogeneity and the multifactorial nature of the pathogenesis. We retrospectively analysed 73 adult TM patients to evaluate the prevalence of pulmonary dysfunction in adult TM and investigate relationships with iron load. All patients underwent body plethysmography and carbon monoxide diffusion (DLCO) was assessed in 63, in addition to blood tests, echocardiogram and T2* myocardial and liver magnetic resonance imaging. Restrictive lung disease was present in 26 (35.6%) patients. Serum ferritin levels were higher in patients with restrictive pattern (1526 MUg/l vs. 975 MUg/l, P = 0.05). Restrictive lung disease did not correlate with cardiac or liver iron overload. However, considering only patients with serum ferritin >2500 MUg/l, those with restrictive pattern also had heart (T2* 14.28 +/- 9.99 ms vs. 31.59 +/- 7.43 ms) and liver iron overload (LIC 16.02 +/- 8.44 mg vs. 5.02 +/- 2.69 mg Fe/g dry weight) compared to those without restrictive pattern. Twenty five patients (39.7%) had decreased DLCO. No correlation was observed with iron parameters. In our data restrictive pattern was predominant; we observed a relationship with serum ferritin levels suggesting that iron, particularly its chronic effect, could play a role in the pathogenesis of pulmonary disease. PMID- 27766632 TI - Natural killer cell activity and dysfunction in Hermansky-Pudlak syndrome. AB - Hermansky-Pudlak syndrome (HPS) encompasses disorders with abnormal function of lysosomes and lysosome-related organelles, and some patients who develop immunodeficiency. The basic mechanisms contributing to immune dysfunction in HPS are ill-defined. We analysed natural killer (NK) cells from patients diagnosed with HPS-1, HPS-2, HPS-4, and an unreported HPS subtype. NK cells from an HPS-2 and an unreported HPS subtype share a similar cellular phenotype with defective granule release and cytotoxicity, but differ in cytokine exocytosis. Defining NK cell activity in several types of HPS provides insights into cellular defects of the disorder and understanding of mechanisms contributing to HPS pathogenesis. PMID- 27766633 TI - Inadvertent intrathecal injections and best practice management. AB - The intrathecal space has become an important anatomic site for medical intervention not only in anesthesia practice, but also in many other medical specialties. Undesired/inadvertent intrathecal injections (UII) are generally rare. There is tremendous variation in reported inadvertent administrations via an intrathecal route in the literature, mainly as individual cases and very small case-series reports. This review aims to identify potential sources of UII, its clinical presentations, and appropriate management. The inadvertent injectants are classified as anesthetic agents and pain medicines, chemotherapeutics, radiological contrast agents, antibiotics and corticosteroids, and miscellaneous chemical agents such as tranexamic acid. The clinical effects of UII are dependent upon inadvertent injectant(s) and dose being administered intrathecally, and can range from no adverse effect to profound neurological consequences and/or death. Prompt cerebrospinal fluid (CSF) lavage and cardiopulmonary support seem to be the mainstay of treatment. If serious consequences are anticipated, CSF lavage could be lifesaving. This review additionally provides some options for comprehensive management and preventing strategies. PMID- 27766634 TI - Reliability of 30-Day Readmission Measures Used in the Hospital Readmission Reduction Program. AB - OBJECTIVE: To assess the reliability of risk-standardized readmission rates (RSRRs) for medical conditions and surgical procedures used in the Hospital Readmission Reduction Program (HRRP). DATA SOURCES: State Inpatient Databases for six states from 2011 to 2013 were used to identify patient cohorts for the six conditions used in the HRRP, which was augmented with hospital characteristic and HRRP penalty data. STUDY DESIGN: Hierarchical logistic regression models estimated hospital-level RSRRs for each condition, the reliability of each RSRR, and the extent to which socioeconomic and hospital factors further explain RSRR variation. We used publicly available data to estimate payments for excess readmissions in hospitals with reliable and unreliable RSRRs. PRINCIPAL FINDINGS: Only RSRRs for surgical procedures exceeded the reliability benchmark for most hospitals, whereas RSRRs for medical conditions were typically below the benchmark. Additional adjustment for socioeconomic and hospital factors modestly explained variation in RSRRs. Approximately 25 percent of payments for excess readmissions were tied to unreliable RSRRs. CONCLUSIONS: Many of the RSRRs employed by the HRRP are unreliable, and one quarter of payments for excess readmissions are associated with unreliable RSRRs. Unreliable measures blur the connection between hospital performance and incentives, and threaten the success of the HRRP. PMID- 27766635 TI - Procoagulant profile in patients with immune thrombocytopenia. AB - Despite their low platelet count some immune thrombocytopenia (ITP) patients seldom bleed, indicating the presence of factors to compensate thrombocytopenia. Moreover, ITP patients may have an increased risk for thrombosis. These facts suggest the presence of procoagulant mechanisms that have not been clarified yet. The aim of this study was to identify these possible factors. Moreover, the utility of rotational thromboelastometry (ROTEM(r) ) to test haemostasis in these patients was also evaluated. Patients with ITP presented a procoagulant profile due to an increased amount of platelet- and red cell-microparticles, an increased resistance to protein C and the formation of a clot more resistant to fibrinolysis due to augmented levels of plasminogen activator inhibitor-1, which might reflect an endothelial damage/activation in ITP patients. Despite increased maximum clot firmness and reduced lysis, ROTEM(r) profiles showed a prolonged clotting time that might rely on the presence of anti-platelet antibodies as suggested by the increased lagtime in thrombin generation test caused by plasma from ITP patients on platelets from healthy controls. These results indicate the need to individualize therapeutic treatment for ITP patients, considering their procoagulant profile and the presence of concomitant risk factors. Moreover, ROTEM(r) appeared to be useful for evaluating haemostasis in ITP patients. PMID- 27766636 TI - Survival differences between patients with Hodgkin lymphoma treated inside and outside clinical trials. A study based on the EORTC-Netherlands Cancer Registry linked data with 20 years of follow-up. AB - The survival of patients diagnosed with Hodgkin lymphoma (HL) has improved from 70% to 90% in clinical trials. However, population-based data has shown lower survival. In this study, clinical trial data were linked with cancer registry to identify trial and non-trial participants and differences in overall survival and associated factors were assessed. In 1986-2004, 27% of HL patients aged 15-70 years participated in clinical trials. Compared to non-trial participants, trial participants were younger (median age, 31 vs. 34 years), had staging registered more accurately and had an 8% higher 20-year survival rate (73% vs. 65%). After adjusting for baseline differences, no differences in survival (hazard ratio = 0.96, 95% confidence interval 0.82-1.12), or in subgroup analysis according to stage, remained. Over time, increased administration of chemotherapy in combination with radiotherapy, together with the decreased use of radiotherapy alone was observed among the trial population. This trend was later followed in non-trial participants, coinciding with a similar 'take-up' in survival. The observed superior survival among patients with HL treated in clinical trials can be largely explained by the differences in baseline characteristics, particularly younger age. High trial participation rate and centralized expertise facilitates the implementation of trial findings to real-world practice. PMID- 27766638 TI - The Difficult Design of Epidemiologic Studies on Zika Virus and Pregnancy. PMID- 27766639 TI - Is a Skilled Nursing Facility's Rehospitalization Rate a Valid Quality Measure? AB - OBJECTIVE: To determine whether the observed differences in the risk-adjusted rehospitalization rates across skilled nursing facilities (SNFs) reflect true differences or merely differences in patient severity. SETTINGS: Elderly Medicare beneficiaries newly admitted to an SNF following hospitalization. STUDY DESIGN: We used 2009-2012 Medicare data to calculate SNFs' risk-adjusted rehospitalization rate. We then estimated the effect of these rehospitalization rates on the rehospitalization of incident patients in 2013, using an instrumental variable (IV) method and controlling for patient's demographic and clinical characteristics and residential zip code fixed effects. We used the number of empty beds in a patient's proximate SNFs during hospital discharge to create the IV. PRINCIPAL FINDINGS: The risk-adjusted rehospitalization rate varies widely; about one-quarter of the SNFs have a rehospitalization rate lower than 17 percent, and for one-quarter, it is higher than 23 percent. All the IV models result in a robust finding that an increase in a SNF's rehospitalization rate of 1 percentage point over the period 2009-2012 leads to an increase in a patient's likelihood of rehospitalization by 0.8 percentage points in 2013. CONCLUSIONS: Treatment in SNFs with historically low rehospitalization causally reduces a patient's likelihood of rehospitalization. Observed differences in rehospitalization rates reflect true differences and are not an artifact of selection. PMID- 27766640 TI - Tubulin transport in cilia: How many tubulin cargo-binding sites per IFT particle? (retrospective on DOI 10.1002/bies.201400007). PMID- 27766637 TI - Increased prevalence of potential right-to-left shunting in children with sickle cell anaemia and stroke. AB - 'Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12.7 +/- 4.8 years, 54.4% male) and a control group without SCA or stroke (n = 123; mean age 12.1 +/- 4.9 years, 53.3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45.6% vs. 23.6%, P < 0.001). The odds ratio for potential RLS in the SCA + stroke group was 2.7 (95% confidence interval: 1.6-4.6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23.8% vs. 5.7%, P < 0.001) but not intracardiac shunting (21.8% vs. 18.7%, P = 0.533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA. PMID- 27766641 TI - Physiological and neural correlates of worry and rumination: Support for the contrast avoidance model of worry. AB - The current experiments tested neural and physiological correlates of worry and rumination in comparison to thinking about neutral events. According to the avoidance model-stating that worry is a strategy to reduce intense emotions physiological and neurobiological activity during worried thinking should not differ from activation during neutral thinking. According to the contrast avoidance model-stating that worry is a strategy to reduce abrupt shifts of emotions-activity should be increased. To test these competing models, we induced worry and neutral thinking in healthy participants using personal topics. A rumination condition was added to investigate the specificity of changes induced by the mental process. Two experiments were conducted assessing the effects on different response levels: (1) neural activation using fMRI, and (2) physiological response mobilization using startle and autonomic measures. During worry, participants showed a potentiated startle response and BOLD activity indicative of emotional network activation. These data partly support the contrast avoidance model of worry. Both mental processes showed elevated activity in a common network referred to as default network indicating self-referential activity. PMID- 27766642 TI - New species of the miniature genus Gelanoglanis (Siluriformes: Auchenipteridae) from the Tocantins River basin (Brazil) and osteological description of G. nanonocticolus. AB - A new species of Gelanoglanis is described based on specimens collected in the Tocantins River, a tributary of the Amazon Basin. The new species is distinguished from congeners by unusual features to the genus such as the pelvic fin falling short of the urogenital opening by a distance larger than the anal fin length, the first unbranched dorsal and pectoral-fin rays not ossified as spines, the dorsal-fin spinelet absent and the adipose fin in adults preceded by a long fleshy ridge. The new species is further distinguished from congeners by its soft, sinuous snout tip and morphometric proportions of the body and head. The new species shares most putative synapomorphies of the genus, as well as the miniaturized condition evidenced by a diminutive body size and reduced ossifications and lateral sensory system. An elongate dorsal process of the cleithrum is posited as an additional synapomorphy for the genus. An osteological description of Gelanoglanis nanonocticolus based on high-resolution X-ray computed tomography is also provided. http://zoobank.org/urn:lsid:zoobank.org:pub:BA3FE72D-FEF84-7A7-B751-2A15EA52C203. PMID- 27766643 TI - Neural responses to affective pictures while anticipating and perceiving respiratory threat. AB - Emotional processes have an impact on the anticipation and perception of bodily threat sensations, such as breathlessness. However, little is known about the reverse influence of breathlessness on emotional processes, as well as its modulation by anxiety sensitivity (AS). Here, we investigated by means of visually evoked potentials how the perception versus anticipation of resistive load-induced breathlessness (RLIB) influences emotional processing. High (HA) and low anxious (LA) participants viewed pictures of positive, neutral, or negative content under conditions of perceived RLIB, anticipated RLIB, or an unloaded baseline. The P2 (230-290 ms) was significantly less positive under perceived RLIB. Furthermore, the early late positive potential (LPP; 300-500 ms) was significantly less positive during both RLIB conditions, as compared to baseline. Overall, the P1 was significantly more positive in HA as compared to LA individuals. Additionally, across conditions, the late LPP (600-1,000 ms) was enhanced for positive and negative pictures as opposed to neutral ones for the LA group. In contrast, for the HA group only, the positive pictures elicited the typical enhanced LPP. Notably, for the HA participants, negative pictures elicited significantly blunted late LPPs during perceived RLIB as compared to anticipated RLIB and baseline. A reversed effect (i.e., more positivity) was observed for LA participants, suggesting motivational priming. Taken together, these results highlight the impact of perceived and anticipated respiratory threat on the neural processing of emotional picture stimuli, as well as its modulation by anxiety sensitivity levels. PMID- 27766644 TI - A stand-alone compact EUV microscope based on gas-puff target source. AB - We report on a very compact desk-top transmission extreme ultraviolet (EUV) microscope based on a laser-plasma source with a double stream gas-puff target, capable of acquiring magnified images of objects with a spatial (half-pitch) resolution of sub-50 nm. A multilayer ellipsoidal condenser is used to focus and spectrally narrow the radiation from the plasma, producing a quasi-monochromatic EUV radiation (lambda = 13.8 nm) illuminating the object, whereas a Fresnel zone plate objective forms the image. Design details, development, characterization and optimization of the EUV source and the microscope are described and discussed. Test object and other samples were imaged to demonstrate superior resolution compared to visible light microscopy. PMID- 27766645 TI - Healthcare Professionals' Attitudes to Rehabilitation Programming for Male Cancer Survivors. AB - PURPOSE: The purpose of this study is to describe and interpret the attitudes and conduct of hospital healthcare professionals (HCPs) in association with male cancer survivors and their municipal rehabilitation participation. DESIGN: Ethnographic fieldwork was conducted, consisting of participant observation and nine semistructured focus group interviews with 58 hospital HCPs. METHODS: Using interpretive description methodology with symbolic interaction as a theoretical framework, data were collected through fieldwork in three oncology wards in Denmark. FINDINGS: Attitudes about both gender and rehabilitation were identified as overarching obstructions within hospital HCP conduct toward promoting men's participation in cancer rehabilitation. CONCLUSIONS: Gender and rehabilitation perceptions formed barriers in this context, suggesting that male cancer survivors' rehabilitation outcomes may be compromised by HCP attitudes and conduct. CLINICAL RELEVANCE: These findings provide insight into approaches to guide HCPs to take responsibility for rehabilitation and to take gender into account in their work. PMID- 27766646 TI - Establishing derived categorical responding in children with disabilities using the PEAK-E curriculum. AB - The purpose of the study was to evaluate a procedure to generate derived categorical responding by three children with disabilities and to promote the emergence of untrained intraverbal categorical responses. In the study, three 4 member equivalence classes including three stimuli (A, B, and C) and a category name (D) for each class were trained using a match-to-sample procedure. Test probes were conducted for categorical responding, including both a trained (D-A) and two derived (D-B, D-C) relational responses, as well as the emergence of untrained intraverbal categorical responding (D-A/B/C) throughout the study. Relational training was effective at promoting the emergence of categorical responding, and two of the three participants demonstrated the emergence of additional intraverbal responding without prior training. The results provide further evidence supporting the practical utility of stimulus equivalence as well as the PEAK-E curriculum. PMID- 27766647 TI - The effect of microenvironmental factors on the development of myeloma cells. AB - Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of monoclonal plasma cells (PCs) in the bone marrow and other tissues. Although there are several new therapies, MM remains fatal. The interaction between MM cells and the bone marrow microenvironment promotes drug resistance and cancer cells survival. In our present work, we compared the antigen expression pattern of normal and pathological PCs and investigated the possible connections between various surface receptors, adhesion molecules, and recurrent genetic aberrations. We showed that the expression of CD29, CD27, and CD81 is lower in MM cells than in normal PCs. We found correlation of chromosome 11 hyperdiploidity and the decrease of CD27 expression. We demonstrated that MM cells with CD20 positivity also have CD28 expression. Multiple myeloma patients with active CD29 showed better response to treatment. Our results suggest that these changes may result in an alteration of the interaction between stromal cell and MM cell facilitating cell survival and the development of a more aggressive and resistant phenotype. PMID- 27766648 TI - Tight control of nitrate acquisition in a plant species that evolved in an extremely phosphorus-impoverished environment. AB - Hakea prostrata (Proteaceae) has evolved in an extremely phosphorus (P)-limited environment. This species exhibits an exceptionally low ribosomal RNA (rRNA) and low protein and nitrogen (N) concentration in its leaves. Little is known about the N requirement of this species and its link to P metabolism, despite this being the key to understanding how it functions with a minimal P budget. H. prostrata plants were grown with various N supplies. Metabolite and elemental analyses were performed to determine its N requirement. H. prostrata maintained its organ N content and concentration at a set point, independent of a 25-fold difference nitrate supplies. This is in sharp contrast to plants that are typically studied, which take up and store excess nitrate. Plants grown without nitrate had lower leaf chlorophyll and carotenoid concentrations, indicating N deficiency. However, H. prostrata plants at low or high nitrate availability had the same photosynthetic pigment levels and hence were not physiologically compromised by the treatments. The tight control of nitrate acquisition in H. prostrata retains protein at a very low level, which results in a low demand for rRNA and P. We surmise that the constrained nitrate acquisition is an adaptation to severely P-impoverished soils. PMID- 27766649 TI - Functions of corazonin and histamine in light entrainment of the circadian pacemaker in the Madeira cockroach, Rhyparobia maderae. AB - The circadian pacemaker of the Madeira cockroach, Rhyparobia (Leucophaea) maderae, is located in the accessory medulla (AME). Ipsi- and contralateral histaminergic compound eyes are required for photic entrainment. Light pulses delay locomotor activity rhythm during the early night and advance it during the late night. Thus, different neuronal pathways might relay either light-dependent delays or advances to the clock. Injections of neuroactive substances combined with running-wheel assays suggested that GABA, pigment-dispersing factor, myoinhibitory peptides (MIPs), and orcokinins (ORCs) were part of both entrainment pathways, whereas allatotropin (AT) only delayed locomotor rhythms at the early night. To characterize photic entrainment further, histamine and corazonin were injected. Histamine injections resulted in light-like phase delays and advances, indicating that the neurotransmitter of the compound eyes participates in both entrainment pathways. Because injections of corazonin only advanced during the late subjective night, it was hypothesized that corazonin is only part of the advance pathway. Multiple-label immunocytochemistry in combination with neurobiotin backfills demonstrated that a single cell expressed corazonin in the optic lobes that belonged to the group of medial AME interneurons. It colocalized GABA and MIP but not AT or ORC immunoreactivity. Corazonin-immunoreactive (-ir) terminals overlapped with projections of putatively light-sensitive interneurons from the ipsi- and contralateral compound eye. Thus, we hypothesize that the corazonin-ir medial neuron integrates ipsi- and contralateral light information as part of the phase-advancing light entrainment pathway to the circadian clock. J. Comp. Neurol. 525:1250-1272, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27766650 TI - Neural correlates of proactive and reactive aggression in adolescent twins. AB - Verbal and physical aggression begin early in life and steadily decline thereafter in normal development. As a result, elevated aggressive behavior in adolescence may signal atypical development and greater vulnerability for negative mental and health outcomes. Converging evidence suggests that brain disturbances in regions involved in impulse control, emotional regulation, and sensation seeking may contribute to heightened aggression. However, little is known regarding the neural mechanisms underlying subtypes of aggression (i.e., proactive and reactive aggression) and whether they differ between males and females. Using a sample of 106 14-year-old adolescent twins, this study found that striatal enlargement was associated with both proactive and reactive aggression. We also found that volumetric alterations in several frontal regions including smaller middle frontal and larger orbitofrontal cortex were correlated with higher levels of aggression in adolescent twins. In addition, cortical thickness analysis showed that thickness alterations in many overlapping regions including middle frontal, superior frontal, and anterior cingulate cortex and temporal regions were associated with aggression in adolescent twins. Results support the involvement of fronto-limbic-striatal circuit in the etiology of aggression during adolescence. Aggr. Behav. 43:230-240, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27766651 TI - A standardized method for quantifying consistent individual differences in schooling behaviour. AB - A method for quantifying consistent individual differences in schooling behaviour is presented. This method, which utilizes a school of models, improves on previous methods by removing the unwanted variation that is introduced by live stimulus fish while still providing the physiological experience of schooling to the focal fish. Three-spined stickleback Gasterosteus aculeatus observed in the model school assay exhibited consistent individual differences in schooling behaviour. PMID- 27766652 TI - Characterization of autochthonous sweet cherry cultivars (Prunus avium L.) of southern Italy for fruit quality, bioactive compounds and antioxidant activity. AB - BACKGROUND: Characterizing germplasm collections of autochthonous cultivars for fruit quality traits could be a successful approach for selection, improvement of organoleptic quality and levels of antioxidants of crop produce, and development of new market opportunities and coherent strategies for conservation and valorization. The aim of the study was the evaluation of fruit physicochemical traits as well as the content of bioactive compounds and the antioxidant capacity in 25 sweet cherry autochthonous cultivars. RESULTS: Cultivars were a source of statistically significant variation for all evaluated traits. Notably, average fruit ascorbate levels ranged from 34.45 to 244.68 ug g-1 fresh weight (FW) , total flavonoids from 1396.40 to 4694.75 ug quercetin equiv. g-1 FW, monomeric anthocyanins from 4.80 to 360.90 ug g-1 FW, and total antioxidant capacity from 1.53 to 2.58 nmol Trolox equiv. mg-1 FW. Fruit profiling of eight cultivars by high-resolution mass spectrometry identified a total of eight different anthocyanins and twenty-five non-anthocyanin polyphenolic compounds - mostly coumaroylquinic acid and neochlorogenic acid. CONCLUSION: Among the better performing cultivars for fruit quality traits, Mulegnana Nera and Pagliarella shared high fruit levels of phenolics, flavonoids and antioxidant capacity. This is a forerunner work on the characterization of genetic resources, which is critical to researchers and breeders for exploitation of the genetic potential of cultivars and for their conservation. (c) 2016 Society of Chemical Industry. PMID- 27766654 TI - Using awareness training to decrease nervous habits during public speaking. AB - This study evaluated the effectiveness of awareness training for the reduction of three nervous habits that manifest during public speaking: filled pauses, tongue clicks, and inappropriate use of the word "like." Four university students delivered short speeches during baseline and assessment sessions. Awareness training resulted in meaningful reductions in target behaviors for all participants. Booster awareness training sessions were necessary for all participants to achieve further reductions in target behaviors. Generality probes conducted in front of a small audience indicated that treatment effects generally maintained. Social validity scores indicated that the treatment was acceptable, and participants indicated not only decreased use of verbal fillers, but also improved overall public speaking ability posttreatment. PMID- 27766653 TI - Changing Labor and Delivery Practice: Focus on Achieving Practice and Documentation Standardization with the Goal of Improving Neonatal Outcomes. AB - OBJECTIVE: To establish multifactorial shoulder dystocia response and management protocol to promote sustainable practice change. DATA SOURCES/STUDY SETTING: Primary data collection was conducted over 3 years. Implementation of the protocol spanned 13 months. Data collection occurred at five sites, which were chosen for their diversity in both patient mix and geographical location. STUDY DESIGN: Case study evaluation methodology was used to examine clinician engagement and protocol adoption. DATA COLLECTION METHODS: The training completion for all practice engagement team activities was collected by the site project manager and entered into a flat file. Data from the labor and delivery notes, medical records, and interviews with labor and delivery teams were gathered and analyzed by the senior investigator. PRINCIPAL FINDINGS: In the first year, there was a threefold increase in shoulder dystocia reporting, which continued in years 2 and 3. In the first year, 96 percent of clinicians completed all training elements and in subsequent years, 98 percent completed the follow-up training. Overall teams reached a 99 percent adoption rate of the shoulder dystocia protocol. CONCLUSIONS: System and site management teams implemented a standardized shoulder dystocia protocol that fostered effective teamwork and obstetric team readiness for managing shoulder dystocia emergencies. PMID- 27766655 TI - Further refinement of video-based brief multiple-stimulus without replacement preference assessments. AB - We compared the results of a brief video-based multiple-stimulus without replacement preference assessment with no access to chosen activities (MSWO-NO) to the results of the same assessment with access (MSWO-WA) with four children with autism. We also compared instructor rankings of activities to MSWO-WA results. Strong to moderate correlations between MSWO-NO and MSWO-WA assessment results were found across all participants. The correlation between MSWO-WA and instructor rankings ranged from strong to low across all participants. Implications and directions for future research are discussed. PMID- 27766656 TI - Comparison of arousal and preference assessment outcomes for sex offenders with intellectual disabilities. AB - We compared outcomes of arousal and preference assessments for five adult male alleged sexual offenders with intellectual disabilities. Arousal assessments involved the use of the penile plethysmograph to measure changes in penile circumference to both deviant (males and females under the age of 18) and nondeviant (males and females over the age of 18) video clips. Paired-stimulus preference assessments were arranged to present still images from the video clips used in the arousal assessments. Results showed correspondence between the assessments for four out of the five participants. Implications are discussed for the use of preference assessment methodology as a less intrusive assessment approach for sexual offender assessments. PMID- 27766657 TI - The histopathologic features of autoimmune progesterone dermatitis. AB - BACKGROUND: The histologic features of autoimmune progesterone dermatitis (APD) are generally non-specific and have been described only in brief case reports. We present a case of APD and review the literature with a focus on the histologic findings described. METHODS: A review of the English literature on APD was performed using PubMed and MEDLINE. RESULTS: A total of 39 patients, including our patient are included in this review. The most consistent histologic finding reported was a perivascular inflammatory infiltrate, being seen in 72% of cases. A non-specific or interstitial inflammatory infiltrate was described in 31% of the cases, with 41% having an eosinophilic component and 21% having a neutrophilic component mixed with the predominant lymphocytic infiltrate. Interface dermatitis was the second most common finding with 36% showing a mild to exaggerated interface dermatitis. CONCLUSION: Although histopathologic changes are non-specific, perivascular dermatitis with eosinophils and interface changes are common in APD. PMID- 27766658 TI - Do Bilinguals Automatically Activate Their Native Language When They Are Not Using It? AB - Most models of lexical access assume that bilingual speakers activate their two languages even when they are in a context in which only one language is used. A critical piece of evidence used to support this notion is the observation that a given word automatically activates its translation equivalent in the other language. Here, we argue that these findings are compatible with a different account, in which bilinguals "carry over" the structure of their native language to the non-native language during learning, and where there is no activation of translation equivalents. To demonstrate this, we describe a model in which language learning involves mapping native language phonological relationships to the non-native language, and we show how it can explain the results attributed to automatic activation of translation equivalents. PMID- 27766660 TI - A rare cutaneous manifestation of hemorrhagic bullae to low-molecular-weight heparin and fondaparinux: report of two cases. PMID- 27766661 TI - Fractions We Cannot Ignore: The Nonsymbolic Ratio Congruity Effect. AB - Although many researchers theorize that primitive numerosity processing abilities may lay the foundation for whole number concepts, other classes of numbers, like fractions, are sometimes assumed to be inaccessible to primitive architectures. This research presents evidence that the automatic processing of nonsymbolic magnitudes affects processing of symbolic fractions. Participants completed modified Stroop tasks in which they selected the larger of two symbolic fractions while the ratios of the fonts in which the fractions were printed and the overall sizes of the compared fractions were manipulated as irrelevant dimensions. Participants were slower and less accurate when nonsymbolic dimensions of printed fractions were incongruent with the symbolic comparison decision. Results indicated a robust basic sensitivity to nonsymbolic ratios that exceeds prior conceptions about the accessibility of fraction values. Results also indicated a congruity effect for overall fraction size, contrary to findings of prior research. These findings have implications for extending theory about the nature of human number sense and mathematical cognition more generally. PMID- 27766659 TI - Treatment of central venous catheter-associated deep venous thrombosis in cancer patients with rivaroxaban. PMID- 27766662 TI - A Prime Example of the Maluma/Takete Effect? Testing for Sound Symbolic Priming. AB - Certain nonwords, like maluma and takete, are associated with roundness and sharpness, respectively. However, this has typically been demonstrated using explicit tasks. We investigated whether this association would be detectable using a more implicit measure-a sequential priming task. We began with a replication of the standard Maluma/Takete effect (Experiments 1a and 1b) before examining whether round and sharp nonword primes facilitated the categorization of congruent shapes (Experiment 2). We found modest evidence of a priming effect in response accuracy. We next examined whether nonword primes affected categorization of ambiguous shapes, using visual (Experiment 3) and auditory primes (Experiment 4). We found that ambiguous shapes were categorized as round (sharp) more often following the presentation of a round (sharp) nonword. This suggests that phonemes may activate related shape information which then affects the processing of shapes, and that this association emerges even when participants are not explicitly searching for it. PMID- 27766664 TI - Neurofibroma with naevus of Ota. PMID- 27766663 TI - Effects of hydroxyurea on F-cells in sickle cell disease and potential impact of a second fetal globin inducer. PMID- 27766665 TI - Early lipofuscin accumulation in frontal lobe epilepsy. AB - OBJECTIVE: This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). METHODS: Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre-/postoperative clinical, imaging, and electrophysiological data. RESULTS: Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history. INTERPRETATION: We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882-895. PMID- 27766666 TI - Can Infinitival to Omissions and Provisions Be Primed? An Experimental Investigation Into the Role of Constructional Competition in Infinitival to Omission Errors. AB - An experimental study was conducted on children aged 2;6-3;0 and 3;6-4;0 investigating the priming effect of two WANT-constructions to establish whether constructional competition contributes to English-speaking children's infinitival to omission errors (e.g., *I want ___ jump now). In two between-participant groups, children either just heard or heard and repeated WANT-to, WANT-X, and control prime sentences after which to-infinitival constructions were elicited. We found that both age groups were primed, but in different ways. In the 2;6-3;0 year olds, WANT-to primes facilitated the provision of to in target utterances relative to the control contexts, but no significant effect was found for WANT-X primes. In the 3;6-4;0 year olds, both WANT-to and WANT-X primes showed a priming effect, namely WANT-to primes facilitated and WANT-X primes inhibited provision of to. We argue that these effects reflect developmental differences in the level of proficiency in and preference for the two constructions, and they are broadly consistent with "priming as implicit learning" accounts. The current study shows that (a) children as young as 2;6-3;0 years of age can be primed when they have only heard (not repeated) particular constructions, (b) children are acquiring at least two constructions for the matrix verb WANT, and (c) that these two WANT constructions compete for production. PMID- 27766667 TI - Captagon: use and trade in the Middle East. AB - BACKGROUND: Fenetheylline, a psychostimulant drug, often branded as Captagon, is a combination of amphetamine and theophylline. Since the cessation of its legal production in 1986, counterfeited products have been produced illicitly in south east Europe and far-east Asia. Its profitable trade has been linked to terrorist organizations, including Islamic State of Iraq and the Levant. This study aims to reach up-to-date data, concerning the Captagon e-commerce and use in the Middle East. METHODS: A multi-staged and multi-lingual literature search was carried out. A list of prespecified keywords was applied across medical and paramedical databases, web and Dark web, search engines, social communication media, electronic commerce websites, media networks, and the Global Public Health Intelligence Network database. RESULTS: The use of Captagon as a stimulant in terrorist settings has been marginally covered in the literature. Data can widely be retrieved from Google and AOL search engines, YouTube, and Amazon e-commerce websites, and to a lesser extent from Alibaba and eBay. On the contrary, Middle Eastern e-commerce websites yielded almost no results. Interestingly, the Dark web generated original data for Captagon e-commerce in the Middle East. CONCLUSION: Further investigations are needed on the role that psychoactive drugs play in terrorist attacks and civil war zones. Unless a comprehensive methodological strategy, inclusive of unconventional methods of research, is implemented, it will not be feasible to face such a threat to humanity. PMID- 27766669 TI - Familiarity, Priming, and Perception in Similarity Judgments. AB - We present a novel way of accounting for similarity judgments. Our approach posits that similarity stems from three main sources-familiarity, priming, and inherent perceptual likeness. Here, we explore each of these constructs and demonstrate their individual and combined effectiveness in explaining similarity judgments. Using these three measures, our account of similarity explains ratings of simple, color-based perceptual stimuli that display asymmetry effects, as well as more complicated perceptual stimuli with structural properties; more traditional approaches to similarity solve one or the other and have difficulty accounting for both. Overall, our work demonstrates the importance of each of these components of similarity in explaining similarity judgments, both individually and together, and suggests important implications for other similarity approaches. PMID- 27766668 TI - Two histopathological patterns of postinflammatory hyperpigmentation: epidermal and dermal. AB - BACKGROUND: Postinflammatory hyperpigmentation (PIH) commonly occurs, but the histopathological features are not well characterized. METHODS: A total of 21 PIH patients' medical charts were reviewed. Punch biopsies from lesional and perilesional normal skin were performed. Sections were stained with hematoxylin eosin, Fontana-Masson, NKI/beteb, microphthalmia-associated transcription factor (MITF), CD68, c-kit, factor XIIIa, MMP-2 and MMP-9. RESULTS: Fontana-Masson stained sections suggested two obvious PIH groups: epidermal (13 cases) and dermal (8 cases) pigmentation. The epidermal pigment group had increased epidermal basal pigmentation. The dermal pigment group had marked pigmentation within the upper dermis and decreased epidermal pigmentation. More intense perivascular lymphocytic infiltration was observed in the dermal pigment group. NKI/beteb levels were increased in lesional skin in both groups. The numbers of MITF+ melanocytes were not different between lesional and perilesional normal skin in either group. The expression of CD68 and c-kit was significantly higher in the dermis of lesional skin than in normal skin in the dermal pigment group. MMP-2 expression was upregulated in lesional skin in both groups. CONCLUSION: PIH patients can be classified into two histopathological groups: epidermal and dermal pigmentation. The dermal pigment group showed decreased levels of epidermal pigmentation. This study provides histopathological information that can improve the treatment of PIH. PMID- 27766670 TI - Spatial organization of the Schizosaccharomyces pombe genome within the nucleus. AB - The fission yeast Schizosaccharomyces pombe is a useful experimental system for studying the organization of chromosomes within the cell nucleus. S. pombe has a small genome that is organized into three chromosomes. The small size of the genome and the small number of chromosomes are advantageous for cytological and genome-wide studies of chromosomes; however, the small size of the nucleus impedes microscopic observations owing to limits in spatial resolution during imaging. Recent advances in microscopy, such as super-resolution microscopy, have greatly expanded the use of S. pombe as a model organism in a wide range of studies. In addition, biochemical studies, such as chromatin immunoprecipitation and chromosome conformation capture, have provided complementary approaches. Here, we review the spatial organization of the S. pombe genome as determined by a combination of cytological and biochemical studies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766671 TI - Solar urticaria induced by visible light: successful treatment with omalizumab. AB - We report the case of a 53-year-old man with solar urticaria (SU) not responding to histamine antagonist therapy. Using intradermal testing with the patient's irradiated serum, we demonstrated that his SU was elicited by visible light only. This type of SU is uncommon, and makes preventive measures such as sun block largely ineffective. However, the patient had an extraordinary response to the treatment with omalizumab. This case report highlights the diagnostic process and the success of omalizumab for the treatment of SU after 16 months of follow-up. PMID- 27766672 TI - Validating the 4A's test in screening for delirium in a culturally diverse geriatric inpatient population. AB - OBJECTIVE: To measure the diagnostic accuracy of the 4A's test in screening for delirium in geriatric inpatients from culturally diverse backgrounds. METHODS: A prospective study was conducted with patients admitted to the geriatric and orthogeriatric services of a tertiary teaching hospital. Consenting participants aged 65 years and over were screened for delirium with the 4AT by nursing staff within 72 h of admission. The diagnosis of delirium was made separately by expert assessors, responsible for the participant's clinical care, blinded to the 4AT score, within 30 min of the 4AT assessment using the DSM 5 criteria and the Confusion Assessment Method. Interpreters were used for non-English speaking patients. The Informant Questionnaire for Cognitive Decline in the Elderly was completed by a carer/relative to assess for probable dementia. RESULTS: A total of 257 participants (mean age 85) were recruited over five months. Delirium was diagnosed in 159 (62%) by the expert assessors and 158 (62%) by the 4AT assessment. A total of 205 participants (80% of total population) had probable dementia. The sensitivity and specificity of the 4AT were 87% and 80%, respectively, in detecting delirium overall, 86% and 71% in people with probable dementia and 91% and 71% for non-English speaking participants. The area under the receiver operating characteristic curve for delirium in the whole population was 0.92, 0.89 in the probable dementia subgroup and 0.90 in non-English speaking participants. CONCLUSIONS: The 4AT is a sensitive and specific screening tool for delirium in geriatric inpatients, including those with probable dementia or who are non-English speaking. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766673 TI - Plateaus, Dips, and Leaps: Where to Look for Inventions and Discoveries During Skilled Performance. AB - The framework of plateaus, dips, and leaps shines light on periods when individuals may be inventing new methods of skilled performance. We begin with a review of the role performance plateaus have played in (a) experimental psychology, (b) human-computer interaction, and (c) cognitive science. We then reanalyze two classic studies of individual performance to show plateaus and dips which resulted in performance leaps. For a third study, we show how the statistical methods of Changepoint Analysis plus a few simple heuristics may direct our focus to periods of performance change for individuals. For the researcher, dips become the marker of exploration where performance suffers as new methods are invented and tested. Leaps mark the implementation of a successful new method and an incremental jump above the path plotted by smooth and steady log-log performance increments. The methods developed during these dips and leaps are the key to surpassing one's teachers and acquiring extreme expertise. PMID- 27766674 TI - Cutaneous metastasis of inflammatory breast carcinoma mimicking an erythema annulare centrifugum: a sign of locally recurrent cancer. AB - Erythema annulare centrifugum (EAC) is a clinical reaction pattern that includes lupus erythematosus, spongiotic dermatitis (particularly pityriasis rosea), pseudolymphoma and cutaneous B-cell lymphoma. However, it can be the result of cutaneous metastasis by an internal carcinoma. We present the case of a 38-year old woman with bilateral inflammatory breast cancer following multimodal therapy. After chemotherapy, the patient developed EAC on her back, clinically suspect of subacute cutaneous lupus erythematosus. A skin biopsy of annular lesion revealed dermal lymphatic infiltration by inflammatory breast carcinoma. Immunohistochemically, HER2 overexpression and negativity for hormone receptor are the hallmarks of this disease. Cutaneous metastasis by inflammatory breast carcinoma mimicking EAC is rare, and it has not been described in extramammary locations. Its recognition by the dermatologist is important because it can be a clinical manifestation of locally recurrent cancer. PMID- 27766675 TI - Unilateral, erythematous, swollen, sclerosing patch with nodular progression on the right side of the face. PMID- 27766676 TI - Clinical pathways in chronic lymphocytic leukemia: Challenges and solutions. PMID- 27766677 TI - Surgical management of driveline infections in patients with left ventricular assist devices. AB - BACKGROUND AND AIM OF THE STUDY: Driveline infections in patients with implantable left ventricular assist devices (VAD) carry increasing risk for pump infection, thromboembolic events, decreased quality of life, and increased hospitalization. We report our experience with a surgical technique for refractory driveline infections without mediastinitis consisting of translocation and wrapping of the driveline with greater omentum tissue. METHODS: We retrospectively reviewed data of VAD patients who underwent surgical treatment by translocation and wrapping with omentum for severe chronic driveline infection. RESULTS: Thirteen patients were treated between January 2010 and October 2015; 12 (92%) were male, and the mean age was 56 +/- 14 years. Ten patients (77%) were managed with driveline sheathing with omentum and repositioning with a new exit site, and three (23%), suffering from driveline fistula, with driveline covering with omentum maintaining the previous exit site. Three episodes of postoperative bleeding (23%) required surgical revision. Twelve patients (92%) were discharged from the hospital and one (8%) died. Nine patients (69%) were free from infection at the time of discharge, and three (23%) had recurrence of infection within the first postoperative year. Only four patients (31%) required admission to the intensive care unit; overall median hospital stay was 23 days (range 7-205 days). CONCLUSIONS: Driveline relocation with use of omentum is a feasible and effective procedure in selected cases of chronic severe driveline infection. The risk for perioperative bleeding should be taken into consideration and carefully monitored. PMID- 27766678 TI - Improving participation outcomes and interventions in neurodisability: co designing future research. AB - There is an urgent, agreed need to improve participation outcomes and interventions for children and young people with neurodisability. We worked together with service users and providers to design research into participation outcomes and interventions in neurodisability. We built on existing evidence about participation outcomes and interventions and the WHO International Classification of Functioning, Disability and Health. We: (1) specified seven participation outcome categories for measurement; (2) prioritized these for improvement: self-care, friends and social, and physical activity ranked the highest; (3) identified 11 potential intervention categories for targeting the top priority, self-care, through eight hypothesized change mechanisms and agreed for the interventions to be delivered as a 'Menu of Interventions' for personalized self-care support; and (4) designed a before-and-after mixed methods feasibility study to evaluate the Menu with children and young people (0-12 years) and their parents and therapists. PMID- 27766679 TI - Hemodialysis Time and Kt/V: Less May Be Better. AB - Current guidelines focus on conventional dialysis defined as 3-5 hours, three times per week, and suggest that longer or more frequent dialysis be considered. This paper presents the case for considering that shorter or less frequent dialysis should also be considered. More frequent and/or longer dialysis facilitates control of fluid overload, blood pressure, and phosphate levels. These benefits will require time to translate into probable hard outcome improvement. Patients are unlikely to participate in productive or pleasurable activities while undergoing dialysis in center or traveling to treatment. So any increase in dialysis time or frequency, during awake hours, will result in an immediate and quantifiable reduction in quality of life. Conventional measures of dialysis adequacy consider only urea clearance. This poorly reflects middle molecule clearance, renal function, and management of fluid and phosphate overload, all of which have a greater impact on outcome than urea clearance. Fluid, phosphate, and uremic toxin overload may be better and less invasively controlled by continuous means such as dietary modification, binders, and preserving renal function. Bioimpedance, blood volume monitoring, and lung ultrasound provide means for improved control of fluid homeostasis. The probability of renal function recovery or preservation is increased by avoiding dehydration. An ideal strategy would be to preserve renal function and employ as little dialysis as possible (if it cannot be avoided altogether). Fluid overload, blood pressure, uremic toxin, and phosphate levels would be monitored and controlled using any means available, preferably by less invasive means than dialysis. Kt/V is useful in controlling the prescribed dose of dialysis, but the achievement of a universal target should not be an end in itself. PMID- 27766681 TI - A subtle streak. PMID- 27766680 TI - Molecular identification of unusual Mycetoma agents isolated from patients in Venezuela. AB - Mycetoma is a chronic granulomatous, subcutaneous disease endemic in tropical and subtropical countries. It is currently a health problem in rural areas of Africa, Asia and South America. Nine cases of mycetoma were analysed in a retrospective study. All isolates were identified by morphological features. The level of species identification was reached by molecular tools. Definitive identification of fungi was performed using sequence analysis of the ITS of the ribosomal DNA region and the ribosomal large-subunit D1/D2. Identification of actinomycetes was accomplished by the 16S rRNA gene sequence. Six unusual clinical isolates were identified: Aspergillus ustus, Cyphellophora oxyspora, Exophiala oligosperma, Madurella pseudomycetomatis, Nocardia farcinica and Nocardia wallacei. The prevalence of mycetoma in Venezuela remains unknown. This study represents the first report in the literature of mycetoma caused by unusual pathogens identified by molecular techniques. PMID- 27766682 TI - Controllable Reassembly of a Dynamic Metallocage: From Thermodynamic Control to Kinetic Control. AB - A temperature- and anion-induced coordination-driven self-assembly system based on a dynamic Ag6 L4 metallocage was developed. Induced by SbF6- anions, both kinetically controlled [Ag3 L2 (SbF6 )3 ]n and thermodynamically controlled [Ag2 L2 (SbF6 )2 ]n can be reassembled from discrete Ag6 L4 (SbF6 )6 metallocages at 30 degrees C, and increasing the temperature to 40 degrees C results in selective inhibition of the kinetic product. Under the influence of BF4- anions, dynamic Ag6 L4 (BF4 )6 metallocages self-assemble into the thermodynamically controlled polycage at 25 degrees C, and lowing the temperature to 0 degrees C leads to selective inhibition of the thermodynamic product. Thus, both kinetically and thermodynamically controlled assembly processes in a dynamic system can be selectively driven by suitable external stimuli. PMID- 27766683 TI - What are the Considerations in Balancing Benefits and Risks in Iron Treatment?: Balancing Benefits and Safety with Intravenous Iron Treatment. PMID- 27766684 TI - Multidrug-resistant Fusarium in keratitis: a clinico-mycological study of keratitis infections in Chennai, India. AB - In this study, we aimed to present the first molecular epidemiological data from Chennai, India, analyse keratitis cases that have been monitored in a university hospital during 2 years, identify the responsible Fusarium species and determine antifungal susceptibilities. A total of 10 cases of keratitis were included in the study. Fusarium isolates were identified using the second largest subunit of the RNA polymerase gene (RPB2) and the translation elongation factor 1 alpha (TEF1). Antifungal susceptibility was tested by the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) methodology. The aetiological agents belonged to Fusarium solani species complex (FSSC) (n = 9) and Fusarium sambucinum species complex (FSAMSC) (n = 1), and the identified species were Fusarium keratoplasticum (n = 7), Fusarium falciforme (n = 2) and Fusarium sporotrichioides (n = 1). All strains showed multidrug resistance to azoles and caspofungin but exhibited lower minimum inhibitory concentration (MIC) to natamycin and amphotericin B. Fusarium keratoplasticum and Fusarium falciforme belonging to the Fusarium solani species complex were the major aetiological agents of Fusarium keratitis in this study. Early presentation and 5% topical natamycin was associated with better patient outcome. Preventative measures and monitoring of local epidemiological data play an important role in clinical practice. PMID- 27766685 TI - Basicity of Very Weak Bases in 1,2-Dichloroethane. AB - The basicity scale of very weak bases has been set up in 1,2-dichloroethane to give, for the first time, reliable quantitative insights into the basic properties of weak bases in a low-polarity solvent. The scale contains 30 compounds, including anilines; phosphanes, and carbonyl bases, such as esters and amides, linked by 53 relative basicity measurements. The scale spans more than 12 pKip units, expanding to as low pKip values as possible with our current experimental methodology. PMID- 27766687 TI - Using Anilines as Masked Cross-Coupling Partners: Design of a Telescoped Three Step Flow Diazotization, Iododediazotization, Cross-Coupling Process. AB - The conversion of commercially available anilines into biaryl and biarylacetylene products was realized by using a telescoped, three-reactor flow diazotization/iododediazotization/cross-coupling process. The segmented flow stream created by off-gassing during the Sandmeyer sequence was restored to a continuous column of reaction solution by using a specially designed continuous flow unit controlled by custom software created in-house. The resultant aryl iodide was then combined with a stream of cross-coupling solution that fed into the final reactor. The system proved versatile as modifications to the diazotization/iododediazotization sequence could be made rapidly to account for any substrate specificity (e.g., solubility problems), leading to a wide substrate scope of Suzuki-Miyaura and Sonogashira cross-coupled products. PMID- 27766686 TI - Treatment-related neuroendocrine prostate cancer resulting in Cushing's syndrome. AB - Here we present, to the best of our knowledge, the first case of a paraneoplastic Cushing's syndrome (hypercortisolism) resulting from treatment-related neuroendocrine prostate cancer - a highly aggressive and difficult disease to treat. A 51-year-old man was started on androgen deprivation therapy after presenting with metastatic prostate cancer, characterized by diffuse osseous metastasis. Shortly thereafter, he developed progressive disease with biopsy proven neuroendocrine prostate cancer as well as symptoms of increased skin pigmentation, hypokalemia, hypertension, hyperglycemia and profound weakness, consistent with ectopic Cushing's syndrome. Molecular analysis of the patient's tumor through RNA sequencing showed high expression of several genes including CHGA, ASCL1, CALCA, HES6, PCSK1, CALCB and INSM1 confirming his neuroendocrine phenotype; elevated POMC expression was found, supporting the diagnosis of ectopic Cushing's syndrome. PMID- 27766688 TI - Effects of bisphosphonates on mandibular condyle of ovariectomized osteoporotic rats using micro-ct and histomorphometric analysis. AB - OBJECTIVE: To evaluate microarchitectural changes in condylar cartilage and associated subchondral bone after bisphosphonates treatment using an ovariectomized (OVX) osteoporosis rat model. METHODS: Thirty six-month-old female Sprague-Dawley rats were randomly divided into sham, OVX, and risedronate (RIS) treated groups. Both OVX and RIS groups received bilateral ovariectomy. OVX group was treated subcutaneously with saline, whereas RIS group received risedronate treatment (2.4 MUg/kg) subcutaneously for 3 months. At the end of 3 months, animals were sacrificed and the entire condyles were harvested for micro-CT and histological analyses. Immunohistochemistry (IHC) was performed to assess the expression of type I/II collagen protein by semiquantitative imaging analysis. RESULTS: Micro-CT analysis showed OVX group had significant condylar subchondral bone loss compared to sham as shown by significant decrease in bone volume fraction (P = 0.028), trabecular thickness (P = 0.041), and significant increase in trabecular spacing (P = 0.003). In RIS group, partial inhibition of OVX induced bone loss was detected. HE staining showed proliferative layer of condylar cartilage reduced, while hypertrophic chondrocyte layer increased significantly in RIS group compared to sham and OVX groups. IHC showed reduced expression of Col I in both the OVX and RIS groups, whereas expression of Col II was reduced in the OVX group but increased in the RIS group. CONCLUSION: Our findings suggest that systemic bisphosphonate treatment influences the structure and ossification of condylar cartilage and it has a dual action on condyle in a postmenopausal osteoporosis rat model which raises the concerns for the potential side effects of BPs on condyle to elder patients. PMID- 27766689 TI - A New Member of the Graphene Family: Graphene Acid. AB - A new member of the family of graphene derivatives, namely, graphene acid with a composition close to C1 (COOH)1 , was prepared by oxidation of graphene oxide. The synthetic procedure is based on repeated oxidation of graphite with potassium permanganate in an acidic environment. The oxidation process was studied in detail after each step. The multiple oxidations led to oxidative removal of other oxygen functional groups formed in the first oxidation step. Detailed chemical analysis showed only a minor amount of other oxygen-containing functional groups such as hydroxyl and the dominant presence of carboxyl groups in a concentration of about 30 wt %. Further oxidation led to complete decomposition of graphene acid. The obtained material exhibits unique sorption capacity towards metal ions and carbon dioxide. The highly hydrophilic nature of graphene acid allowed the assembly of ultrathin free-standing membranes with high transparency. PMID- 27766690 TI - Fluoride-Catalyzed Methylation of Amines by Reductive Functionalization of CO2 with Hydrosilanes. AB - An effective and inexpensive organocatalyst tetrabutylammonium fluoride (TBAF) was developed for the reductive functionalization of CO2 with amines to selectively afford formamides or methylamines by employing hydrosilanes. Hydrosilanes with different substituents show discriminatory reducing activity. Thus, the formation of formamides and further reduction products, that is, methylamines could be controlled by elegantly tuning hydrosilane types. Formamides were obtained exclusively under an atmospheric pressure of CO2 with triethoxysilane. Using phenylsilane as a reductant, methylamines were attained with up to 99 % yield at 50 degrees C coupled to a complete deoxygenation of CO2 . The crucial intermediate silyl formate in the formylation step was identified and thereby a tentative mechanism involving the fluoride-promoted hydride transfer from the hydrosilane to CO2 /formamide was proposed. Striking features of this metal-free protocol are formylation and methylation of amines by reductive functionalization of CO2 with hydrosilanes and mild reaction conditions. PMID- 27766691 TI - Chronic ascending aorta dissection. PMID- 27766692 TI - Differential expression of ISG 15 mRNA in peripheral blood mononuclear cells of nulliparous and multiparous pregnant versus non-pregnant Bos indicus cattle. AB - Embryonic mortality is found to be the main source of reproductive wastage in domestic ruminants. Many genes are involved in the growth and development of the embryo, and the interferon-stimulated gene 15 (ISG 15) is one of the major gene stimulated by interferon tau, the maternal recognition of pregnancy signal in ruminants. In this study, both genomic and cDNA sequences of ISG 15 from Bos indicus (Deoni breed) were amplified and characterized. The genomic sequence of Deoni ISG 15 exhibited 99% identity with Bos taurus and 97% identity with that of Bos mutus and Bubalus bubalis. Moreover qRT-PCR analysis revealed constitutive expression of the ISG 15 mRNA in peripheral blood mononuclear cells of Deoni heifers and multiparous cows during early pregnancy. Fourteen Deoni heifers and fifteen multiparous Deoni cows were synchronized for timed AI by CIDR-Ovsynch protocol, and six animals were kept as cyclic control in each group. Blood samples were collected on days 7, 14, 16, 18, 21, 30 and 45 from the day of AI. Pregnancy was confirmed by plasma progesterone level through ELISA. A significantly higher expression of ISG 15 mRNA was found on day 16 (p < .05) and day 18 (p < .05) of pregnancy in nulliparous heifers. Although in multiparous Deoni cows ISG 15 expression was greater in pregnant cows, difference was statistically non-significant. The result of this study indicates that ISG 15 gene expression is upregulated during 16-18 days of pregnancy and could be used as an early pregnancy marker in dairy cows especially in heifers. PMID- 27766693 TI - Implant survival following sinus membrane elevation without grafting and immediate implant installation with a one-stage technique: an up-to-40-month evaluation. AB - PURPOSE: Various augmentation procedures involving the maxillary sinus, using bone substitutes or bone, have been used to enhance bone support for dental implants. The aim of this study was to retrospectively evaluate the status of implants in patients who had undergone a maxillary sinus lift and immediate implant placement without the addition of graft material. MATERIALS AND METHODS: Nineteen patients who had required bone augmentation of their maxillary sinus floor were evaluated in this study. After a bone window in the lateral wall of the sinus has been prepared and the Schneiderian membrane had been carefully elevated, dental implants were inserted in the residual bone, creating a membrane elevation. Resorbable collagenous membrane was used to seal the lateral access window of the maxillary sinus after implant placement. Clinical and radiological follow-up was carried out up to 40 months after implant installation. RESULTS: A total of 28 implants in lengths of 10 and 12 mm were placed in a one-stage healing protocol, with an average residual bone height of 5.25 mm (SD = 1.48). All implants remained stable, with a survival rate of 100%. An increase in mean bone height of 4.75 mm (SD = 1.13) was gained. The marginal bone levels relative to the coronal aspect of the implant shoulder exhibited a mean change of 1.01 mm (SD = 0.49) from the baseline. Of the 19 patients, none showed a plaque index or gingival index greater than 2, and 14 patients showed no presence of plaque. CONCLUSION: The findings of the study regarding the immediate placement of implants without the use of bone grafts or other bone substitute materials demonstrate a successful approach for new bone formation around implants in the posterior part of the maxilla, when the preoperative height of the subantral bone is moderate and enough to achieve primary stability. PMID- 27766694 TI - Stable carbon isotope analyses of nanogram quantities of particulate organic carbon (pollen) with laser ablation nano combustion gas chromatography/isotope ratio mass spectrometry. AB - RATIONALE: Analyses of stable carbon isotope ratios (delta13 C values) of organic and inorganic matter remains have been instrumental for much of our understanding of present and past environmental and biological processes. Until recently, the analytical window of such analyses has been limited to samples containing at least several MUg of carbon. METHODS: Here we present a setup combining laser ablation, nano combustion gas chromatography and isotope ratio mass spectrometry (LA/nC/GC/IRMS). A deep UV (193 nm) laser is used for optimal fragmentation of organic matter with minimum fractionation effects and an exceptionally small ablation chamber and combustion oven are used to reduce the minimum sample mass requirement compared with previous studies. RESULTS: Analyses of the international IAEA CH-7 polyethylene standard show optimal accuracy, and precision better than 0.50/00, when measuring at least 42 ng C. Application to untreated modern Eucalyptus globulus (C3 plant) and Zea mays (C4 plant) pollen grains shows a ~ 160/00 offset between these species. Within each single Z. mays pollen grain, replicate analyses show almost identical delta13 C values. CONCLUSIONS: Isotopic offsets between individual pollen grains exceed analytical uncertainties, therefore probably reflecting interspecimen variability of ~0.5 0.90/00. These promising results set the stage for investigating both delta13 C values and natural carbon isotopic variability between single specimens of a single population of all kinds of organic particles yielding tens of nanograms of carbon. (c) 2016 The Authors. Rapid Communications in Mass Spectrometry Published by John Wiley & Sons Ltd. PMID- 27766695 TI - Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-alpha) inhibitors. AB - Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFalpha) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFalpha agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFalpha-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFalpha inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population. PMID- 27766696 TI - CLINICAL, ULTRASONOGRAPHIC, AND ARTHROSCOPIC CHARACTERISTICS OF HAIR SHAFTS WITHIN SYNOVIAL STRUCTURES OF SEVEN HORSES. AB - To the authors' knowledge, the ultrasonographic appearance of hair shafts within a synovial structure of the horse has not been described previously. The purpose of this descriptive study was to illustrate the clinical, ultrasonographic, and arthroscopic characteristics of confirmed hair shafts within synovial structures of seven horses. A review of medical records of the Farm and Equine Veterinary Medical Center at North Carolina State University College of Veterinary Medicine identified seven horses with clinical signs suspicious for inflammatory or septic synovitis/tenosynovitis that had hair shafts identified within those structures ultrasonographically. Imaging findings were confirmed by surgical arthroscopy, bursoscopy, tenoscopy, or necropsy. Unique ultrasound characteristics of intrasynovial hair included thin, linear, hyperechoic structures, which did not cast acoustic shadows. Findings supported the use of ultrasonography as a complementary diagnostic method for ruling out hair foreign material in horses with signs of inflammatory or septic synovitis/tenosynovitis. PMID- 27766697 TI - Development and feasibility of the computerized Turkish edition of the Composite International Diagnostic Interview [DIA-X/CIDI version 2.8(TR)]. AB - The Composite International Diagnostic Interview (CIDI), which has been widely applied in epidemiological research, is a standardized, clinically structured interview that enables the diagnosis of mental disorders based on DSM and ICD criteria. The computerized DIA-X CIDI Version 2.8 investigated in this study is an adaptation of the German DIA-X/Munich CIDI, which was translated in a multi step process into Turkish and used to survey the prevalence of mental disorders in individuals with Turkish migration backgrounds in Germany (N = 662). The bilingual lay interviewers were intensively trained and supervised during the data collection. The survey was accompanied by further quality measures, including editing and documenting. To investigate the instrument's feasibility, quality criteria were used based on the following data sources: (1) socio demographic sample characteristics; (2) interviewer assessments and (3) quantitative measures (interview duration, non-response items, error items). The results indicated that quality differences between the German and Turkish DIA X/CIDI are associated with age, educational level and socio-economic status and not with the CIDI version itself. In short, the Turkish DIA-X/CIDI Version 2.8 has comparatively good quality and feasibility relative to its German counterpart. PMID- 27766698 TI - Narrative Changes Predict a Decrease in Symptoms in CBT for Depression: An Exploratory Study. AB - OBJECTIVE: Innovative moments (IMs) are new and more adjusted ways of thinking, acting, feeling and relating that emerge during psychotherapy. Previous research on IMs has provided sustainable evidence that IMs differentiate recovered from unchanged psychotherapy cases. However, studies with cognitive behavioural therapy (CBT) are so far absent. The present study tests whether IMs can be reliably identified in CBT and examines if IMs and symptoms' improvement are associated. METHODS: The following variables were assessed in each session from a sample of six cases of CBT for depression (a total of 111 sessions): (a) symptomatology outcomes (Outcome Questionnaire-OQ-10) and (b) IMs. Two hierarchical linear models were used: one to test whether IMs predicted a symptom decrease in the next session and a second one to test whether symptoms in one session predicted the emergence of IMs in the next session. RESULTS: Innovative moments were better predictors of symptom decrease than the reverse. A higher proportion of a specific type of IMs-reflection 2-in one session predicted a decrease in symptoms in the next session. Thus, when clients further elaborated this type of IM (in which clients describe positive contrasts or elaborate on changes processes), a reduction in symptoms was observed in the next session. DISCUSSION: A higher expression and elaboration of reflection 2 IMs appear to have a facilitative function in the reduction of depressive symptoms in this sample of CBT. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Elaborating innovative moments (IMs) that are new ways of thinking, feeling, behaving and relating, in the therapeutic dialogue, may facilitate change. IMs that are more predictive of amelioration of symptoms in CBT are the ones focused on contrasts between former problematic patterns and new adjusted ones; and the ones in which the clients elaborate on processes of change. Therapists may integrate these kinds of questions (centred on contrasts and centred on what allowed change from the client's perspective), in the usual CBT techniques. When elaborating these IMs successfully, therapists may expect an improvement in symptoms in the next session of psychotherapy. PMID- 27766699 TI - Multishot cartesian turbo spin-echo diffusion imaging using iterative POCSMUSE Reconstruction. AB - PURPOSE: To report a diffusion imaging technique insensitive to off-resonance artifacts and motion-induced ghost artifacts using multishot Cartesian turbo spin echo (TSE) acquisition and iterative POCS-based reconstruction of multiplexed sensitivity encoded magnetic resonance imaging (MRI) (POCSMUSE) for phase correction. MATERIALS AND METHODS: Phase insensitive diffusion preparation was used to deal with the violation of the Carr-Purcell-Meiboom-Gill (CPMG) conditions of TSE diffusion-weighted imaging (DWI), followed by a multishot Cartesian TSE readout for data acquisition. An iterative diffusion phase correction method, iterative POCSMUSE, was developed and implemented to eliminate the ghost artifacts in multishot TSE DWI. The in vivo human brain diffusion images (from one healthy volunteer and 10 patients) using multishot Cartesian TSE were acquired at 3T and reconstructed using iterative POCSMUSE, and compared with single-shot and multishot echo-planar imaging (EPI) results. These images were evaluated by two radiologists using visual scores (considering both image quality and distortion levels) from 1 to 5. RESULTS: The proposed iterative POCSMUSE reconstruction was able to correct the ghost artifacts in multishot DWI. The ghost-to-signal ratio of TSE DWI using iterative POCSMUSE (0.0174 +/- 0.0024) was significantly (P < 0.0005) smaller than using POCSMUSE (0.0253 +/- 0.0040). The image scores of multishot TSE DWI were significantly higher than single-shot (P = 0.004 and 0.006 from two reviewers) and multishot (P = 0.008 and 0.004 from two reviewers) EPI-based methods. CONCLUSION: The proposed multishot Cartesian TSE DWI using iterative POCSMUSE reconstruction can provide high-quality diffusion images insensitive to motion-induced ghost artifacts and off-resonance related artifacts such as chemical shifts and susceptibility-induced image distortions. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:167-174. PMID- 27766700 TI - Use of statins offsets insulin-related cancer risk. AB - AIM: There is firm evidence of a relation between type 2 diabetes (T2DM) and increased risks of cancer at various sites, but it is still unclear how different antihyperglycaemic therapies modify site-specific cancer risks. The aim of this study was to provide a complete characterization of all possible associations between individual T2DM therapies, statin use and site-specific cancers in the Austrian population. METHODS: Medical claims data of 1 847 051 patients with hospital stays during 2006-2007 were used to estimate age- and sex-dependent co occurrences of site-specific cancer diagnoses and treatment with specific glucose lowering drugs and statins. RESULTS: Patients treated with insulin or insulin secretagogues showed up to ninefold increased risks for cancers of the colon [males only (m)], liver (m), pancreas, lung (m) and brain (m), as well as a strongly decreased risk for prostate cancer (m). In patients taking statins, the risks were generally decreased, with a greater risk reduction in patients not receiving antihyperglycaemic therapies. The strongest effects were observed for use of insulin and pancreatic cancer [m: OR 4.5, 95% CI: 3.1-6.6; females (f): OR 4.2, 95% CI: 2.5-7.1], sulfonylureas (m: OR 2.8, 95% CI: 1.7-4.6; f: OR 3.0, 95% CI: 2.1-4.2) or glitazones and skin cancer (f: OR 0.54, 95% CI: 0.36-0.80), as well as metformin and cancer of the prostate (m: OR 0.82, 95% CI: 0.75-0.91) and corpus uteri (f: OR 1.7, 95% CI: 1.4-2.0) and non-Hodgkin's lymphoma (f: OR 0.76, 95% CI: 0.64-0.91). CONCLUSIONS: The use of statins offsets insulin-related cancer risks in patients with diabetes independently of sex and age. Overall, our data support the hyperglycaemia-cancer hypothesis. A reduction in endogenous or exogenous hyperinsulinaemia may be beneficial for cancer prevention. Therefore, insulin-sparing and insulin-sensitizing drugs should be the preferred treatment choices. PMID- 27766702 TI - Membrane inlet laser spectroscopy to measure H and O stable isotope compositions of soil and sediment pore water with high sample throughput. AB - RATIONALE: The fast and accurate measurement of H and O stable isotope compositions (delta2 H and delta18 O values) of soil and sediment pore water remains an impediment to scaling-up the application of these isotopes in soil and vadose hydrology. Here we describe a method and its calibration to measuring soil and sediment pore water delta2 H and delta18 O values using a water vapor permeable probe coupled to an isotope ratio infrared spectroscopy analyzer. METHODS: We compare the water vapor probe method with a vapor direct equilibration method, and vacuum extraction with liquid water analysis. At a series of four study sites in a managed desert agroecosystem in the eastern Great Basin of North America, we use the water vapor probe to measure soil depth profiles of delta2 H and delta18 O values. RESULTS: We demonstrate the accuracy of the method to be equivalent to direct headspace equilibration and vacuum extraction techniques, with increased ease of use in its application, and with analysis throughput rates greater than 7 h-1 . The soil depth H and O stable isotope profiles show that soil properties such as contrasting soil texture and pedogenic soil horizons control the shape of the isotope profiles, which are reflective of local evaporation conditions within the soils. CONCLUSIONS: We conclude that this water vapor probe method has potential to yield large numbers of H and O stable isotope analyses of soil and sediment waters within shorter timeframes and with increased ease than with currently existing methods. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766703 TI - A simple and reliable anion-exchange resin method for sulfate extraction and purification suitable for multiple O- and S-isotope measurements. AB - RATIONALE: The O- and S-isotope compositions of sulfates can be used as key tracers of the fate and sink of sulfate in both terrestrial and extra-terrestrial environments. However, their application remains limited in those geological systems where sulfate occurs in low concentrations. Here we present a simple and reliable method to extract, purify and concentrate sulfate from natural samples. The method allows us to take into account the separation of nitrate, which is known to be an issue in O-isotope analysis. METHODS: The separation and concentration of sulfate from other anions in any aqueous solution are performed within a few hours via anion-exchange resin. The possible O- (delta18 O and Delta17 O) and S- (delta34 S, Delta33 S and Delta36 S) isotope exchanges, fractionations and/or contaminations are for the first time monitored during the whole procedure using initial O- and S-mass-dependent and mass-independent sulfate solutions. RESULTS: After elution in HCl, pure sulfate is fully retrieved and precipitated into BaSO4 , which is suitable for O- and S-isotopic measurements using established techniques. The analysis of retrieved barite presents no variation within 2sigma uncertainties: +/-0.50/00 and +/-0.10/00 in O (delta18 O, Delta17 O) and +/-0.20/00, +/-0.020/00 and +/-0.090/00 in S- (delta34 S, Delta33 S and Delta36 S) isotope ratios, respectively. CONCLUSIONS: This study shows that the resin method for sulfate extraction and purification, in addition to being cheap, simple and quick, is applicable for the measurements of all O- and S-isotopic ratios in sulfates (including the Delta17 O, Delta33 S and Delta36 S values). Therefore, this method can be easily used for a high range of natural samples in which sulfate occurs in low concentration including aerosols, ice cores, sediments, volcanic deposits, (paleo)soils and rainwater, and thus it can be a key to our understanding of the sulfur cycle on Earth. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766701 TI - Alpha-7 nicotinic acetylcholine receptor (nAChR) agonist inhibits the development of endometriosis by regulating inflammation. AB - OBJECTIVE: We investigated alpha-7 nAchR expression in human peritoneal macrophages and examined whether activation of nAchR might be a new therapy for endometriosis. MATERIALS AND METHODS: Human peritoneal fluid mononuclear cells (PFMC) were stimulated with lipopolysaccharide (LPS) in the presence of alpha-7 nAChR agonists. In a murine endometriosis model, alpha-7 nAChR modulators were administered. RESULTS: Human PFMC expressed alpha-7 nAChR at the mRNA and protein levels. Activation of alpha-7 nAChR with its agonists led to significant (P<.01) suppression of LPS-induced interleukin (IL) -1beta expression. In a murine endometriosis model, one week after inoculation of endometrium to the peritoneal cavity, alpha-7 nAChR agonist significantly suppressed the expression of IL-1beta mRNA (P<.01), which was negated when alpha-7 nAChR antagonist was administered simultaneously. alpha-7 nAChR agonist significantly suppressed the formation of endometriotic lesions, which was reversed with alpha-7 nAChR antagonist. CONCLUSION: Activation of nAChR might be a new candidate for treatment of endometriosis. PMID- 27766704 TI - Treatment of Recurrent Nonparoxysmal Atrial Fibrillation Using Focal Impulse and Rotor Mapping (FIRM)-Guided Rotor Ablation: Early Recurrence and Long-Term Outcomes. AB - INTRODUCTION: A patient-tailored ablation approach focused on the elimination of both pulmonary vein triggers as well as substrate drivers may result in favorable outcomes in recurrent persistent AF patients. OBJECTIVE: We evaluated the long term outcomes of rotor ablation combined with conventional pulmonary vein isolation (PVI) in patients with recurrent nonparoxysmal AF. METHODS: Fifty-eight consecutive patients underwent FIRM-guided rotor ablation followed by conventional PVI for the treatment of recurrent nonparoxysmal AF. A software algorithm was used to display rotational activity at rotor sites by creating propagation maps from unipolar electrograms recorded using a 64-electrode basket catheter. These rotor sites were targeted for ablation, followed by conventional PVI. RESULTS: All patients had nonparoxysmal AF (83% longstanding persistent) and a previously failed conventional ablation procedure. Stable rotors were identified in all patients (mean of 3.0 +/- 1.6 per patient), with 55.2% having right atrial rotors and 96.6% left atrial rotors, respectively. Complications occurred in 5.2% of patients, none related to the FIRM procedure. The median follow-up was 12 months. At 6 and 12 months of follow-up, 73.2% and 76.9% of patients remained free from AF/AT, respectively. Excluding 2 patients who underwent a successful redo ablation procedure/electrical cardioversion, at 12 months of follow-up, 69.2% were free from any AF/AT and 73.1% were free from AF after a single FIRM-guided ablation procedure. CONCLUSION: A high degree of success was observed in this cohort of primarily longstanding persistent AF patients treated for recurrent AF with FIRM-guided rotor ablation. Prospective randomized controlled trials are needed. PMID- 27766705 TI - Fatal acute poisonings in Australian children (2003-13). AB - BACKGROUND AND AIMS: Fatal poisonings in children comprise a small proportion of cases investigated by an Australian coroner; however, they present a major opportunity for death prevention. This study aimed to examine fatal child poisonings in Australia to (1) estimate the rate of acute poisoning deaths in children; (2) describe the key characteristics of the cohort; and (3) describe the outcomes of coronial recommendations made as a death prevention measure. DESIGN: Retrospective case series. SETTING: The National Coronial Information System (NCIS), a database of cases reported to an Australian coroner. PARTICIPANTS: Ninety poisoning deaths reported to an Australian coroner between January 2003 and December 2013 involving children (<= 16 years of age). MEASURES: Logistic regression, Pearson's correlation coefficient and descriptive statistics were used to examine the significance of associations. The primary outcome measures were poisoning type and cause of death. Covariates included age and mental illness. FINDINGS: There were marginally more males (52.2%) [confidence interval (CI) = 44.4-45.6] in the cohort and most occurred in the 13-16-year age group (58.9%) (CI = 7.5-12.5). Deaths were typically unintentional (61.1%) (CI = 17.9-27.1) and occurred in the home (68.9%) (CI = 6.8-15.7). The most common form of poisoning was due to opioids (24.4%), followed by carbon monoxide (20%) and volatile substances (18.9%) (CI = 18.5-19.6). Males had slightly higher odds of dying from prescription opioids compared with females [odds ratio (OR) = 1.9, CI = 0.7-5.1], but this was not statistically significant. A recommendation was made by a coroner in 12 cases, 10 of which related to poisons (including drugs). Of these, eight recommendations were implemented. CONCLUSIONS: In Australia between 2003 and 2013 there were on average eight acute poisoning deaths in children each year, most commonly involving prescription opioids and adolescents. There has been a downward trend in mortality since 2003. These cases generated more than twice as many recommendations for public safety compared with other Australian coroners' cases. PMID- 27766706 TI - Age-at-onset subsets of bipolar I disorders: A critical insight into admixture analyses. AB - Gaussian mixture analysis is frequently used to model the age-at-onset (AAO) in bipolar I disorder and identify homogeneous subsets of patients. This study aimed to examine whether, using admixture analysis of AAO, cross-sectional designs (which cause right truncation), unreliable diagnosis for individuals younger than 10 years old (which causes left truncation) and the selection criterion used for admixture analysis impact the number of identified subsets. A simulation study was performed. Different criteria - the likelihood ratio test (LRT), the Akaike information criterion (AIC), and the Bayesian information criterion (BIC) - were compared using no, left and/or right truncation simulated data. The error rate of each criterion (percentage of erroneous number of detected subsets) was estimated. An application to two real databases, including 2,876 and 1,393 patients, is provided. Without data truncation and regardless of the distribution of AAO, the LRT and the AIC had much higher error rates (12% and 33%, respectively) than the BIC (1%). For a homogeneous population, the error rate increased with the introduction of left truncation. This study shows that the number of subsets identified using admixture analysis may depend on the sample size, the selection criterion, and the study design. PMID- 27766707 TI - Quality of life and fear of cancer recurrence after endoscopic treatment for early Barrett's neoplasia: a prospective study. AB - Endoscopic therapy is the treatment of choice for high grade intraepithelial neoplasia (HGIN) or early cancer (<=T1sm1) in Barrett's esophagus (BE). We prospectively evaluated the effect of endoscopic treatment on quality of life (QOL) and fear of cancer (recurrence) and compared this with the effect of Barrett's surveillance or surgery. Patients treated endoscopically for early Barrett's neoplasia (n = 42, HGIN - T1sm1N0M0) were compared with three groups: patients with non-dysplastic BE undergoing surveillance (n = 44); patients treated surgically for early BE neoplasia (HGIN - T2N0M0, n = 21); patients treated surgically for advanced BE cancer (T1N1M0 - T3N1M0, n = 19). QOL (SF-36; EORTC-QLQ-C30; EORTC-QLQ-OES18) and fear of cancer recurrence (Worry of Cancer Scale [WOCS] and the Hospital Anxiety and Depression Scale [HADS]) were measured at baseline, 2 and 6 months after treatment. The endoscopic treatment group reported significantly better QOL in both physical and mental scales of SF-36 and EORTC-QLQ-C30 and less esophageal cancer related symptoms compared to both surgical groups. The endoscopic treatment group reported significant more worry for cancer recurrence (WOCS) compared to the early surgical group. Their scores on the WOCS were comparable with the scores of the advanced surgical group. Endoscopic treatment of early esophageal cancer has less negative impact on QOL and esophageal cancer symptoms than surgery. However, endoscopically treated patients worry as much about cancer recurrence as patients treated surgically for advanced cancer. PMID- 27766708 TI - Effect of neoadjuvant chemoradiotherapy on perioperative immune function of patients with locally advanced esophageal cancer. AB - This study aims to evaluate the effect of neoadjuvant chemoradiotherapy (NCRT) on perioperative immune function during surgery to treat resectable locally advanced esophageal cancer. Records were retrospectively analyzed for 220 patients with locally advanced esophageal cancer, of whom 112 received surgery alone and 98 received neoadjuvant NCRT plus surgery. The two groups were compared in terms of proportions of CD3+, CD4+, CD8+, and natural kill (NK) cells, as well as the ratio of CD4+ to CD8+ cells. These measurements were made using flow cytometry on preoperative day 1 and on postoperative days 1 and 7. Subgroup analysis were performed in terms of degrees of pathological response of NCRT. When the entire NCRT and no-NCRT (surgery alone) cohorts were compared, no significant differences in propocrtions of CD3+, CD4+, CD8+, or NK cells or in the CD4+/CD8+ ratio occurred at any of the three time points. Similar results were obtained using the subgroup of NCRT patients who were NCRT-sensitive, but the subgroup of NCRT-insensitive patients showed significantly lower CD4+ and NK proportions and lower CD4+/CD8+ ratio than the no-NCRT group. Our findings suggest that NCRT does not affect perioperative immune function in patients who are NCRT-sensitive, but it does significantly reduce such function in patients who are NCRT-insensitive. PMID- 27766711 TI - Exploration of conditioned pain modulation effect on long-term potentiation-like pain amplification in humans. AB - BACKGROUND: This study aimed to explore conditioned pain modulation (CPM) effect on long-term potentiation (LTP)-like pain amplification induced by cutaneous 10 Hz conditioning electrical stimulation (CES). METHODS: Conditioned pain modulation was induced by cold pressor conditioning stimulus (CPCS) (4 degrees C) which was applied immediately before CES in the active session. In the control session, water with a temperature of 32 degrees C was used. Twenty subjects participated in two sessions in a randomized crossover design with at least 1 week interval. Perceptual intensity ratings to single electrical stimulation (SES) at the conditioned skin site and to pinprick and light-stroking stimuli in the immediate vicinity of the CES electrodes were measured . Superficial blood flow (SBF), skin temperature (ST) and heat pain threshold (HPT) were measured covering both homotopic and heterotopic skin. The pain intensities during CES process were measured and short-form McGill Pain Questionnaire (SF-MPQ) was used for assessing CES pain experience. RESULTS: Cold pressor conditioning stimulus reduced pain perception increments to weak pinprick and light-stroking stimuli after 10-Hz CES compared with the control session. Moreover, CPCS resulted in lower pain intensity ratings during CES process but without affecting the SF-MPQ scores between two sessions. The SBF and ST increased after CES and then gradually declined but without differences between CPCS and control sessions. CPM did not affect HPT and pain intensity increments to SES. CONCLUSIONS: The CPCS inhibited heterotopic perception amplification to weak mechanical stimuli after CES. The results indicate that endogenous descending inhibitory systems might play a role against development of non-nociceptive perception amplificatory states (e.g. allodynia). SIGNIFICANCE: Conditioned pain modulation (CPM) may play a role in inhibiting the pain amplificatory process at the central nervous system and prompting central desensitization. CPM has a special inhibition effect for the development of perception amplification to non-painful mechanical stimuli. PMID- 27766709 TI - One-month apparent diffusion coefficient correlates with response to radiofrequency ablation of hepatocellular carcinoma. AB - PURPOSE: To assess whether apparent diffusion coefficient (ADC) values at 1 and 3 months after radiofrequency ablation (RFA) may be associated with a favorable response to therapy for hepatocellular carcinoma (HCC) and liver metastases. MATERIALS AND METHODS: Fifty-nine patients with HCC (n = 35) or liver metastases (n = 24) who underwent 1.5T diffusion-weighted magnetic resonance imaging (DWMRI) at 1 and 3 months post-RFA were included. ADC values of patients with local tumor recurrence were compared to those without local recurrence. A subgroup analysis was performed for HCC and metastases. RESULTS: Thirty-eight HCC and 27 metastases were evaluated. The ADC value of HCC at 1 month after RFA was lower in recurrent tumors (0.957 +/- 0.229 [SD] * 10-3 mm2 ) compared to tumors with complete response (1.414 +/- 0.322 [SD] * 10-3 mm2 /s, P = 0.006). At multivariate analysis, ADC at 1 month was the single independent variable associated with recurrence for HCC (area under the receiver operating characteristic curve = 0.860). No significant association was observed for liver metastases (P = 0.089). CONCLUSION: A low ADC value at 1 month after RFA is associated with an early local recurrence of HCC. This study does not confirm that such association exists for hepatic metastases. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;45:1648-1658. PMID- 27766712 TI - Effect of the addition of chlorhexidine and miswak extract on the clinical performance and antibacterial properties of conventional glass ionomer: an in vivo study. AB - BACKGROUND: Antibacterial restorations can increase the success rate of minimum invasive dentistry especially in young permanent molars with deep carious lesions as an attempt to preserve maximum dental structure and avoid pulp exposure. Further research is warranted to evaluate different antibacterial agents. OBJECTIVES: This study aimed to evaluate the efficacy of adding chlorhexidine gluconate (CHX) or aqueous miswak (Salvadora persica) extract on the clinical performance and in vivo antibacterial activity of conventional anhydrous glass ionomer cement (GIC). DESIGN: The study was a randomized clinical trial. Sixty young permanent molars, with deep carious lesions in 6- to 9-year-old children were included. After randomization, atraumatic restorative treatment (ART) or stepwise excavation was performed followed by bacterial sampling from the center of the remaining carious dentine in the floor of the pulp. GIC powder was mixed with 0.5% chlorhexidine gluconate liquid in group I; with 100% aqueous miswak in group II; and with deionized water in group III (control). Clinical performance for all groups was assessed at 3, 6, and 9 months. After 9 months, restorations were removed and a second bacterial sample was collected for Streptococcus mutans (S. mutans) quantification and analysis by real-time polymerase chain reaction (PCR) test. RESULTS: Results showed no statistically significant difference in the success rate of the three groups at the 3-month interval. At 6 and 9 months, however, restoration success was 75% then 60% in group I, 100% then 90% in group II, and 95% then 85% in control group. Group II and the control group showed statistically significant higher survival rates than group I. All groups showed reduction in S. mutans counts in underlying dentine, but the percent reduction was significantly higher in group I. (P < 0.001). CONCLUSIONS: The addition of CHX and miswak to GIC showed superior antibacterial properties than conventional GIC, without seriously affecting the clinical performance of the restoration until the 6-month follow-up, but failure significantly increased in terms of marginal defects at 9 months with CHX (group 1). PMID- 27766710 TI - Separation of benign and malignant breast lesions using dynamic contrast enhanced MRI in a biopsy cohort. AB - PURPOSE: To assess the diagnostic utility of contrast kinetic analysis for breast lesions and background parenchyma of women undergoing MRI-guided biopsies, for whom standard clinical analysis had failed to separate benign and malignant lesions. MATERIALS AND METHODS: This study included 115 women who had indeterminate lesions based on routine diagnostic breast MRI exams and underwent an MRI (3 Tesla) -guided biopsy of one or more lesions suspicious for breast cancer. Breast dynamic contrast-enhanced (DCE)-MRI was performed using a radial stack-of-stars three-dimensional spoiled gradient echo pulse sequence and modified k-space weighted image contrast image reconstruction. Contrast kinetic model analysis was conducted to characterize the contrast enhancement patterns measured in lesions and background parenchyma (BP). The transfer rate (Ktrans ), interstitial volume fraction (ve ), and vascular volume fraction (vp ) estimated from the lesion and BP were used to separate malignant from benign lesions. RESULTS: The patients with malignant lesions had significantly (P < 0.05) higher median lesion-Ktrans (0.081 min-1 ), higher median BP-Ktrans (0.032 min-1 ), and BP-vp (0.020) than those without malignant lesions (0.056 min-1 , 0.017 min-1 and 0.012, respectively). The area under the receiver operating characteristic curve (AUC) of the BP-Ktrans (0.687) was highest among the single parameters and higher than that of the lesion-Ktrans (0.664). The combined logistic regression model of lesion-Ktrans , lesion-ve , BP-Ktrans , BP-ve , and BP-vp had the highest AUC of 0.730. CONCLUSION: Our results suggest that the contrast kinetic analysis of DCE MRI data can be used to differentiate the malignant lesions from the benign and high-risk lesions among the indeterminate breast lesions recommended for MRI guided biopsy exams. LEVEL OF EVIDENCE: 3 J. MAGN. RESON. IMAGING 2017;45:1385 1393. PMID- 27766713 TI - Modified anastomotic technique for thoracolaparoscopic Ivor Lewis esophagectomy: early outcomes and technical details. AB - Thoracoscopic intrathoracic esophagogastrostomy is a technically demanding operation; these technical requirements restrict the extensive application of minimally invasive Ivor Lewis esophagectomy. In an attempt to reduce the difficulty of this surgical procedure, we developed a modified anastomotic technique for thoracolaparoscopic Ivor Lewis esophagectomy. During the entirety of this modified approach, neither technically challenging operations such as intrathoracic suturing, or knotting, nor special instruments such as an OrVil system or a reverse-puncture head are required. Between Octomber 2015 and January 2016, 15 consecutive patients with cancer in the distal third of the esophagus or the gastric cardia underwent this modified surgical procedure. The good short term outcomes that were achieved suggest that the modified anastomotic technique is safe and feasible for thoracolaparoscopic Ivor Lewis esophagectomy. PMID- 27766714 TI - Clinical significance of differentiating post-intubation and post-tracheostomy tracheal stenosis. AB - BACKGROUND AND OBJECTIVE: Post-intubation tracheal stenosis (PITS) and post tracheostomy tracheal stenosis (PTTS) are serious complications in mechanically ventilated patients. Although the aetiologies and mechanisms of PITS and PTTS are quite different, little is known about the clinical impact of differentiating one from the other. METHODS: We retrospectively conducted a chart review of 117 patients with PITS and 88 patients with PTTS who were treated with interventional bronchoscopy at Samsung Medical Center between January 2004 and December 2013. RESULTS: Compared to patients with PITS, patients with PTTS had a lower BMI, poorer performance status and more frequent neurological aetiologies, mid-to lower tracheal lesions, total obstruction and mixed stenosis types. Although there were no differences in the number of patients who received silicone stents between the two groups, Montgomery T-tubes were more frequently used in the PTTS group than in the PITS group. The final success rate without surgery, mortality or tracheostomy in situ was higher in the PITS group than in the PTTS group (76.9% vs 63.6%, P = 0.043). Additionally, airway prosthesis removal was achieved in 46.2% of patients in the PITS group and in 33.0% of the PTTS group (P = 0.063). CONCLUSION: There were significant differences between PITS and PTTS in terms of patient and stenosis characteristics, treatment modalities and clinical outcomes. Therefore, PITS and PTTS should be considered two different entities. PMID- 27766715 TI - The Tianjin Mental Health Survey (TJMHS): study rationale, design and methods. AB - Mental health in China is of growing concern to both policy-makers and researchers. The Tianjin Mental Health Survey (TJMHS) was conducted between July 2011 and March 2012 to assess the prevalence and risk factors of mental disorders in the context of recent economic growth and other socio-demographic changes in Tianjin, a municipality of 13 million on China's eastern seaboard. A multistage cluster random sample selected using probability proportionate to size methods participated in a two-phase screening procedure: 11,748 subjects 18 or older were screened for risk of psychopathology and then an enriched risk-proportional subsample of 4,438 subjects was interviewed by psychiatrists using an expanded Chinese version of the Structured Clinical Interview for Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) Axis I disorders (SCID). The study also collected information about the impairment associated with mental disorders, mental health literacy, the stigmatization of mental disorders, and help-seeking behavior for psychological problems. This paper provides a detailed overview of the study rationale, objectives, field procedures, and pattern of response. It highlights several of the methodological challenges of maintaining quality control of a complex epidemiological study in the Chinese setting, issues that are relevant to other community-based epidemiological studies in low- and middle income countries. PMID- 27766716 TI - D-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer. AB - BACKGROUND AND PURPOSE: The occurrence of stroke in cancer patients is caused by conventional vascular risk factors and cancer-specific mechanisms. However, cryptogenic stroke in patients with cancer was considered to be more related to cancer-specific hypercoagulability. In this study, we investigated the potential of the D-dimer level to serve as a predictor of early neurologic deterioration (END) in cryptogenic stroke patients with active cancer. METHODS: We recruited 109 cryptogenic stroke patients with active cancer within 72 h of symptom onset. We defined END as an increase of >=1 point in the motor National Institutes of Health Stroke Scale (NIHSS) score or >=2 points in the total NIHSS score within 72 h of admission. After adjusting for potential confounding factors in the multivariate analysis, we calculated the odds ratios (ORs) and confidence intervals (CIs) of D-dimer in the prediction of END. RESULTS: Among 109 patients, END events were identified in 34 (31%) patients within 72 h. END was significantly associated with systemic metastasis, multiple vascular territory lesions on the initial magnetic resonance imaging (MRI), initial NIHSS score and D-dimer levels. In the multivariate analysis, the D-dimer level (adjusted OR, 1.11; 95% CI, 1.04-1.17; P < 0.01) and initial NIHSS score (adjusted OR, 1.08; 95% CI, 1.01-1.15; P = 0.03) predicted END after adjusting for potential confounding factors. In the subgroup analysis of 72 follow-up MRIs, D-dimer level was also correlated with new territory lesions on the follow-up MRI in a dose dependent manner. CONCLUSION: Ischemic stroke patients with active cancer and elevated D-dimer levels appear to be at increased risk for END recurrent thromboembolic stroke. PMID- 27766718 TI - Transoral robotic surgery: implementation as a tool in head and neck surgery - a single-centre Australian experience. AB - BACKGROUND: Transoral robotic surgery (TORS) is now a well-validated technique for resection of head and neck cancers. Benefits include reduced patient morbidity, swallowing preservation and rationalization of adjuvant therapies. METHODS: This was a single-centre, retrospective review of 35 patients who underwent TORS of oro-, retro- and parapharyngeal tumours between March 2014 and August 2015. Outcome measures included resection margins, swallowing function and impact on post-operative radiotherapy. RESULTS: Median age was 63.7 years and the number of male patients was 22 (62.9%). Tongue base was the most common site (51.4%), followed by tonsil (25.7%). Nine patients (25.7%) had previous radiotherapy. A total of 24 patients had squamous cell carcinoma and the clear margin rate for primary TORS was 93.3%. Median hospital stay was 5.5 days, longer for previously irradiated patients (9 days). Median nasogastric tube dependence was 3.5 days. Four patients (11.4%) received a gastrostomy and two patients remained dependent on the tube at the time of last review. There were two major complications (5.7%): bleeding requiring return to theatre (1) and pulmonary embolism (1). Post-operative radiotherapy was either avoided or reduced in 22 patients (81.5%). CONCLUSION: TORS is a safe and effective tool, providing surgical access to oropharyngeal and other difficult to access areas. Patient selection and a multidisciplinary approach are essential to ensure adequate margins can be achieved and therefore to reduce adjuvant therapies. PMID- 27766719 TI - Collect and report accurate early gestational age birth data. PMID- 27766717 TI - Effect of Ventricular Arrhythmia Ablation in Patients With Heart Mate II Left Ventricular Assist Devices: An Evaluation of Ablation Therapy. AB - BACKGROUND: Patients with advanced heart failure (HF) are predisposed to ventricular arrhythmias (VAs), particularly following implantation of a left ventricular assist device (LVAD). There is minimal evidence for appropriate management strategies. OBJECTIVES: This study aimed to compare the burden of VA and response to ablation performed either before or following LVAD implantation. METHODS: We created a retrospective cohort of patients who underwent both VA ablation and Heart Mate II (Thoratec, Pleasanton, CA, USA) LVAD implantation at Mayo Clinic (Rochester, MN, USA). Patients were stratified based on whether they underwent VA ablation before (pre-LVAD) or after LVAD (post-LVAD) implantation. Descriptive analyses assessed 6-month arrhythmia burden in relation to LVAD implantation and VA ablation. RESULTS: A total of 9 patients underwent both LVAD implantation and VA ablation. There were 3 and 6 patients, respectively, in the pre-LVAD and post-LVAD cohorts. Among patients in the pre-LVAD cohort, the median number of VAs tended to increase after ablation (9 vs. 72) and decreased after LVAD implantation (72 vs. 63). Similarly among patients in the post-LVAD cohort, the median burden of VAs increased after LVAD implantation (1 vs. 22) and the median burden decreased after ablation (22 vs. 13). Two of 6 patients had substrate related to the LVAD inflow cannula site, while other substrate was not related directly to the cannula. CONCLUSIONS: In patients with progressive HF and LVAD implantation, ablation is associated with reduced VA rates. In LVAD patients, most VAs arise from substrate unrelated to the inflow cannula site. PMID- 27766720 TI - Rural pre-operative cataract assessment on the Lions Outback Vision Van. PMID- 27766721 TI - Community pharmacists require additional support to develop capacity in delivering alcohol-related health information to older adults. AB - OBJECTIVES: This qualitative study explored the barriers and enablers influencing Western Australian (WA) community pharmacists' knowledge, confidence, willingness and practice in engaging older clients (>60 years) in alcohol-related health discussions. METHODS: Two focus groups were conducted with a total of 14 community pharmacists who had previously completed a formative quantitative survey (n = 63), and indicated willingness to participate in a follow-up focus group. Focus group questions, informed by the survey results, explored participants' perceptions about barriers and enablers to delivering health information and advice about alcohol to older clients (60+ years). Shaw and colleagues' theoretical framework was used to understand barriers and enablers in relation to role legitimacy, role adequacy and role support. KEY FINDINGS: Participants acknowledged that providing health information about alcohol to older clients is a legitimate part of a community pharmacist's role, and most were confident performing this role in situations perceived as core to their professional practice, such as while dispensing medicines. However, many participants identified limited knowledge, skills and confidence in assisting older clients who may have alcohol issues, beyond advising them on medication and alcohol use. Structural barriers such as time and financial barriers were also identified. CONCLUSION: Routine professional practice including dispensing medicine and home medicine reviews may provide valuable opportunities to engage older clients in alcohol-related discussions. However, limited knowledge concerning appropriate strategies to assist older clients reduce their alcohol consumption, coupled with limited skills and confidence among community pharmacists in raising sensitive alcohol-related issues with clients, suggest the need for specific alcohol-related training and support. PMID- 27766722 TI - Mediating Order and Modulating Porosity by Controlled Hydrolysis in a Phosphonate Monoester Metal-Organic Framework. AB - A crystalline and permanently porous copper phosphonate monoester framework has been synthesized from a tetraaryl trigonal phosphonate monoester linker. This material has a surface area over 1000 m2 g-1 , as measured by N2 sorption, the highest reported for a phosphonate-based metal-organic framework (MOF). The monoesters result in hydrophobic pore surfaces that give a low heat of adsorption for CO2 and low calculated selectivity for CO2 over N2 and CH4 in binary mixtures. By careful manipulation of synthetic conditions, it is possible to selectively remove some of the monoesters lining the pore to form a hydrogen phosphonate while giving an isomorphous structure. This increases the affinity of the framework for CO2 giving higher ambient uptake, higher heat of adsorption, and much higher calculated selectivity for CO2 over both N2 and CH4 . Formation of the acid groups is noteworthy as complexation with the parent acid gives a different structure. PMID- 27766723 TI - Rumination syndrome: pathophysiology, diagnosis, and treatment. AB - BACKGROUND: Rumination syndrome is a functional gastrointestinal disorder characterized by effortless and repetitive regurgitation of recently ingested food from the stomach to the oral cavity followed by either re-swallowing or spitting. Rumination is thought to occur due to a reversal of the esophagogastric pressure gradient. This is achieved by a coordinated abdominothoracic maneuver consisting of a thoracic suction, crural diaphragm relaxation and an increase in intragastric pressure. Careful history is important in the diagnosis of rumination syndrome; patients often report "vomiting" or "reflux" and the diagnosis can therefore be missed. Objective testing is available with high resolution manometry or gastroduodenal manometry. Increase in intra-gastric pressure followed by regurgitation is the most important characteristic to distinguish rumination from other disorders such as gastroesophageal reflux. The mainstay of the treatment of rumination syndrome is behavioral therapy via diaphragmatic breathing in addition to patient education and reassurance. PURPOSE: The purpose of this review was to critically appraise recent key developments in the pathophysiology, diagnosis and therapy for rumination syndrome. A literature search using OVID (Wolters Kluwer Health, New York, NY, USA) to examine the MEDLINE database its inception until May 2016 was performed using the search terms "rumination syndrome," "biofeedback therapy," and "regurgitation." References lists and personal libraries of the authors were used to identify supplemental information. Articles published in English were reviewed in full text. English abstracts were reviewed for all other languages. Priority was given to evidence obtained from randomized controlled trials when possible. PMID- 27766724 TI - Effect of high-frequency subthalamic neurostimulation on gait and freezing of gait in Parkinson's disease: a systematic review and meta-analysis. AB - The aim of this meta-analysis was to summarize the short- and long-term effects of bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) on gait and freezing of gait (FOG) in Parkinson's disease and to detect predictors of post-stimulation outcome. A comprehensive review of the literature was conducted up to October 2015 using Medline Ovid databases for studies analyzing the effect of bilateral STN-DBS on FOG and/or gait. Sixteen studies with available data for the gait item (no. 29) of the Unified Parkinson's Disease Rating Scale (UPDRS) and six studies with the FOG item (no. 14) were included. Data were summarized for the following follow-up periods: 6-15, 24-48 and >48 months. For the medication (Med)-Off/stimulation(Stim)-On condition compared with baseline Med Off, STN-DBS significantly improved gait on average from 2.43 to 0.96, 2.53 to 1.31 and 2.56 to 1.40 points at 6-15, 24-48 and >48 months, respectively (P < 0.05). Pre-operative levodopa responsiveness of UPDRS-III and Med-Off severity of gait were the predictors of this beneficial effect. STN-DBS significantly improved FOG for the Med-Off/Stim-On condition compared with baseline on average from 2.26 to 0.82, 2.43 to 1.13 and 2.48 to 1.38 points at 6-15, 24-48 and >48 months, respectively (P < 0.05). There was no significant effect in the Med On/Stim-On condition. This meta-analysis showed a robust improvement of gait and FOG by STN-DBS for more than 4 years in the Med-Off/Stim-On condition. No beneficial effect was found for the On state of medication. Pre-operative levodopa responsiveness of global motor performance (UPDRS-III) is the strongest predictor of the effect of deep brain stimulation on gait. PMID- 27766726 TI - Hysteretic Four-Step Spin Crossover within a Three-Dimensional Porous Hofmann like Material. AB - Materials that display multiple stepped spin crossover (SCO) transitions with accompanying hysteresis present the opportunity for ternary, quaternary, and quinary electronic switching and data storage but are rare in existence. Herein, we present the first report of a four-step hysteretic SCO framework. Single crystal structure analysis of a porous 3D Hofmann-like material showed long-range ordering of spin states: HS, HS0.67 LS0.33 , HS0.5 LS0.5 , HS0.33 LS0.67 , and LS. These detailed structural studies provide insight into how multistep SCO materials can be rationally designed through control of host-host and host-guest interactions. PMID- 27766725 TI - Definitive chemoradiation for locoregional recurrences of esophageal cancer after primary curative treatment. AB - The aim of this study was to determine the outcome of salvage definitive chemoradiation (dCRT) for a locoregional recurrence after any prior curative treatment outside previously irradiated areas. Thirty-nine patients treated between January 2005 and December 2014 were reviewed for locoregional recurrent esophageal cancer outside previously irradiated areas. All patients received salvage treatment with external beam radiotherapy (50.4 Gy in 28 fractions) combined with weekly concurrent paclitaxel and carboplatin. The median follow-up period was 15 months (range 1.7-120). The median overall survival (OS) for all patients after salvage dCRT was 22 months (95% CI 6.2-37.6). The 1-, 3-, and 5 year OS was 72%, 31%, and 28%, respectively. Median survival after salvage dCRT for a regional lymph node recurrence was 33 months (95% CI 5.8-60.3) versus 14 months (95% CI 6.8-21.6) for a recurrence at the anastomosis (P = 0.022, logrank). Median OS was 35 months for the squamous cell carcinoma group and 19 months for the adenocarcinoma group (P = 0.67). Sixteen of 39 patients developed a locoregional recurrence after salvaged dCRT. The median locoregional recurrence free survival (LRFS) was 24 months. The 1-, 3-, and 5-year LRFS was 79%, 36%, and 36%, respectively. Median disease-free survival (DFS) was 15 months. The 1-, 3-, and 5-year DFS was 66%, 27%, and 27%, respectively. Of 16 patients, 8 (50%) with a primary failure at the site of the anastomosis developed a local recurrence after salvaged dCRT compared to 7 of 22 patients (32%) with a primary recurrence in a lymph node. Definitive chemoradiation is a feasible and effective treatment for locoregional recurrent esophageal cancer outside a previously irradiated area, and should be given with a curative intent. This holds true for recurrence of both squamous cell carcinoma and adenocarcinoma. Lymph node recurrences have a markedly better prognosis than recurrences at the site of the anastomosis. PMID- 27766727 TI - Robotic, laparoscopic, and open colectomy: a case-matched comparison from the ACS NSQIP. AB - BACKGROUND: This study aimed to compare perioperative outcomes of patients undergoing robotic, laparoscopic, and open colectomy using a procedure-targeted database. METHODS: Retrospective review of patients undergoing elective colectomy in 2013 was conducted using the procedure-targeted database of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Robotic, laparoscopic, and open groups were matched (1:1:1) based on age, gender, body mass index, surgical procedure, diagnosis and ASA classification. Demographics, comorbidities, and short-term (30 day) outcomes were compared. RESULTS: Out of 12 790 patients, 387 fulfilled criteria per group after matching. Univariate comparison showed operating time was longer (P < 0.001) and hospital stay was shorter (P < 0.001) in the robotic group. Morbidity (P < 0.001), superficial SSI (P < 0.001), bleeding requiring transfusion (P < 0.001), ventilator dependency (P = 0.003), and ileus (P < 0.001) rates were lower in the robotic group. After adjusting for confounders, outcomes were comparable between the groups except hospital stay which was shorter in the robotic group (P < 0.001). CONCLUSIONS: ACS-NSQIP data demonstrated several short-term advantages of robotic surgery compared with laparoscopic and open surgery. PMID- 27766728 TI - Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials. AB - Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin-to-creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean +/- standard deviation values: dulaglutide vs placebo: 87.8 +/- 17.7 vs 88.2 +/- 17.9 mL/min/1.73 m2 , P = .075; dulaglutide vs active comparators: 89.9 +/- 16.7 vs 88.8 +/- 16.3 mL/min/1.73 m2 , P = .223; and dulaglutide vs insulin glargine: 85.9 +/- 18.2 vs 83.9 +/- 18.6 mL/min/1.73 m2 , P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1-Q3] values were: dulaglutide vs placebo: 8.0 [4.4-20.4] vs 8.0 [4.4-23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4-21.2] vs 8.9 [4.4-27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4-29.2] vs 12.4 [5.3-50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient-years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria. PMID- 27766730 TI - Structure and Reaction Chemistry of Magnesium Organocuprates Derived from Magnesiacyclopentadienes and Copper(I) Salts. AB - The chemistry of magnesium organocuprates, including their synthesis, structures, and reactions, remains underexplored. In this work, by taking advantage of the high reactivity and ready availability of magnesiacyclopentadienes, a series of magnesiacyclopentadiene-based organocuprates were synthesized and structurally characterized. A variety of CuX salts (X=Cl, Br, I, or alkynyl) were successfully applied to react with magnesiacyclopentadienes. Besides CuX salts, AgX salts (X=Cl, alkynyl) also undergwent the above reaction to afford the corresponding magnesium organoargentates. Single-crystal X-ray structural analysis and DFT calculations of these butadienyl magnesium organocuprates revealed unique structural characteristics and bonding modes. These results are also very useful to understand the transmetalation process, since the product can be viewed as the resting-state intermediate of a transmetalation reaction between organomagnesium compounds and coinage-metal salts. Preliminary information on the reaction chemistry of these magnesium organocuprates is provided by their reactions with allyl bromide, benzoyl chloride, and CO2 . PMID- 27766729 TI - Testicular sperm extraction for patients with spinal cord injury-related anejaculation: A single-center experience. AB - OBJECTIVES: To present a single-center experience with testicular sperm extraction and intracytoplasmic sperm injection for fathering biological children in patients with ejaculatory dysfunction as a result of spinal cord injury. METHODS: Testicular sperm extraction was carried out in 52 male patients with ejaculatory dysfunction as a result of spinal cord injury. We investigated sperm retrieval rates and pregnancy rates from medical records. Data on age, testicular volume, hormonal status (luteinizing hormone, follicle stimulating hormone and testosterone), and time since spinal cord injury were obtained and analyzed to detect potential associations with the presence of spermatogenesis. RESULTS: Testicular sperm retrieval was achieved in 42 of 52 patients (80.7%). Intracytoplasmic sperm injection was carried out for 37 patients, and pregnancy was achieved in 32 (86.5%). The take-home baby rate was 70.2%. In the group with successful sperm extraction, testicular volume was significantly greater, time from spinal cord injury to extraction was significantly shorter, and serum luteinizing hormone and follicle-stimulating hormone levels were significantly lower. Serum follicle-stimulating hormone levels had the strongest association with feasibility of sperm retrieval by testicular sperm extraction. Furthermore, the sperm retrieval rates of patients injured within the preceding 12 years were significantly better than those injured longer before treatment (P = 0.045). CONCLUSIONS: Testicular sperm extraction and intracytoplasmic sperm injection seem to provide favorable results for patients with ejaculatory dysfunction as a result of spinal cord injury. However, early testicular sperm extraction is recommended, because sperm retrieval becomes more difficult with time from spinal cord injury. PMID- 27766731 TI - Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance. AB - We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels >=4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels. PMID- 27766732 TI - Kinematic and experimental investigation of manual resection tools for transurethral bladder tumor resection. AB - BACKGROUND: Transurethral Resection of Bladder Tumors (TURBT) is a challenging procedure partly due to resectoscope limitations. To date, manual resection performance has not been fully characterized. This work characterizes manual resection performance in the bladder while analyzing the effect of resection location on accuracy. METHODS: Kinematic simulations are used to assess kinematic measures of resection dexterity. An experimental protocol for manual resection accuracy assessment is developed. Cross correlations between the theoretical performance measures and the observed experimental accuracy are investigated. RESULTS: Tangential accuracy correlates relatively strongly with normal singular value and moderately with tangential kinematic conditioning index and tangential minimum singular value. Simulations also clarified difficulties in resecting close to the bladder neck. CONCLUSIONS: Measures to evaluate accuracy and dexterity of TURBT from a kinematic viewpoint are presented to provide a currently missing quantified dexterity baseline in manual TURBT. Limitations in various bladder regions are illustrated. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766734 TI - Program evaluation of neuroscience competency programs to implement evidence based practices. AB - RATIONALE: Program evaluation is essential to help determine the success of an evidence-based practice program and assist with translating these processes across settings. AIMS: The purpose of this study was to evaluate the usefulness of 2 competency programs that sought to improve neurocritical care nurses' knowledge of and adherence to evidence-based stroke and spinal cord injury guidelines. These programs consisted of 3 specific implementation strategies, including local opinion leaders, printed educational materials, and educational outreach. METHODS: A qualitative study using one-on-one interviews with 10 neurocritical care nurses was used. Semi-structured interview questions examined the nurses' perceptions of the competency programs and the implementation strategies used; themes were identified through first-level coding. The transcripts were deductively analyzed and categorized using a predetermined implementation outcomes framework, including the concepts of acceptability, appropriateness, adoption, and sustainability. RESULTS: Nurses reported that the 3 implementation strategies used for the competency programs were acceptable and appropriate. Further, the nurses perceived that the evidence-based practices reviewed during the programs were being adopted into practice and provided suggestions for sustaining improvements in nursing knowledge of and adherence to these evidence-based practices. CONCLUSIONS: Findings from this study support the success of the Stroke and Spinal Cord Injury Competency Programs, as well as the usefulness of the 3 implementation strategies used. This study provides insight for improvements for subsequent studies focused on implementing evidence-based practices. PMID- 27766733 TI - Variability of biomarkers in patients with chronic heart failure and healthy controls. AB - AIMS: Biomarkers can be used for diagnosis, risk stratification, or management of patients with heart failure (HF). Knowledge about the biological variation is needed for proper interpretation of serial measurements. Therefore, we aimed to determine and compare the biological variation of a large panel of biomarkers in healthy subjects and in patients with chronic HF. METHODS AND RESULTS: The biological variability of established biomarkers [NT-proBNP and high-sensitivity troponin T (hsTnT)], novel biomarkers [galectin-3, suppression of tumorigenicity 2 (ST2), and growth differentiation factor 15 (GDF-15)], and renal/neurohormonal biomarkers (aldosterone, phosphate, parathyroid hormone, plasma renin concentration, and creatinine) was determined in 28 healthy subjects and 83 HF patients, over a period of 4 months and 6 weeks, respectively. The analytical (CVa ), intraindividual (CVi ), and interindividual (CVg ) variations were calculated, as well as the reference change value (RCV), which reflects the percentage of change that may indicate a 'relevant' change. All crude biomarker levels were significantly increased or decreased in HF patients compared with controls (all P < 0.01). Variation indices were comparable in healthy individuals and HF patients. CVi was not influenced by the individual levels of the biomarker itself. NT-proBNP and GDF-15 had relatively high CVi (21.8% and 16.6%) and RCV (61.7% and 64.3%), whereas ST2 (CVi , 15.0; RCV, 42.9%), hsTnT (CVi , 11.1; RCV, 31.4%), and galectin-3 (CVi , 8.1; RCV, 25.0%) had lower indices of variation. CONCLUSION: Biological variation indices are comparable between healthy subjects and HF patients for a broad spectrum of biomarkers. NT-proBNP and GDF-15 have substantial variation, with lower variation for ST2, hsTnT, and galectin-3. These data are instrumental in proper interpretation of biomarker levels in HF patients. PMID- 27766735 TI - Perfusion of the gastric conduit during esophagectomy. AB - In esophageal cancer surgery, perfusion of the gastric conduit is a critical issue. Measurement of gastric intramucosal pH (pHi) is a method to identify anaerobic metabolism as a sign of impaired perfusion. In this study we aimed to monitor changes in the perfusion of the gastric conduit at key steps during and after esophagectomy. pHi was measured per- and postoperatively using intermittent gastric tonometry in 32 patients undergoing open, 65%, or video-assisted thoracoscopic esophagectomy for esophageal cancer. Measurements focused on the surgical steps when the vascular supply to the gastric conduit was altered. A tonometry catheter was successfully placed in all patients and a decrease in pHi (mean +/- SD) was observed from baseline to after the division of the short gastric vessels (7.33 +/- 0.07 to 7.29 +/- 0.07, P = 0.005). A further reduction after the ligation of the left gastric artery (7.26 +/- 0.08, P < 0.001) and after final linear stapling the gastric conduit (7.15 +/- 0.13, P < 0.001) was observed. Two hours after surgery, pHi increased (7.24 +/- 0.09, P = 0.002). In contrast to open surgery, a trend towards less reduction in pHi was seen in thoracoscopic surgery. Patients with anastomotic leaks had lower pHi on the first postoperative day (7.12 +/- 0.05 vs. 7.27 +/- 0.08, P = 0.040). It can be concluded that each surgical step altering the vascular supply to the gastric conduit resulted in detectable changes, however transient, in pHi. Patients with low pHi on the first postoperative day were more prone to have clinically relevant anastomotic leaks. PMID- 27766736 TI - Re-evaluation of re-hospitalization and rehabilitation in renal research. AB - INTRODUCTION: The use of administrative data to capture 30-day readmission rates in end-stage renal disease is challenging since Medicare combines claims from acute care, inpatient rehabilitation (IRF), and long-term care hospital stays into a single "Inpatient" file. For data prior to 2012, the United States Renal Data System does not contain the variables necessary to easily identify different facility types, making it likely that prior studies have inaccurately estimated 30-day readmission rates. METHODS: For this report, we developed two methods (a "simple method" and a "rehabilitation-adjusted method") to identify acute care, IRF, and long-term care hospital stays from United States Renal Data System claims data, and compared them to methods used in previously published reports. FINDINGS: We found that prior methods overestimated 30-day readmission rates by up to 12.3% and overestimated average 30-day readmission costs by up to 11%. In contrast, the simple and rehabilitation-adjusted methods overestimated 30-day readmission rates by 0.1% and average 30-day readmission costs by 1.8%. The rehabilitation-adjusted method also accurately identified 96.8% of IRF stays. DISCUSSION: Prior research has likely provided inaccurate estimates of 30-day readmissions in patients undergoing dialysis. In the absence of data on specific facility types particularly when using data prior to 2012, future researchers could employ our method to more accurately characterize 30-day readmission rates and associated outcomes in patients with end-stage renal disease. PMID- 27766737 TI - Micrometastasis in colorectal cancer: does it affect staging? AB - BACKGROUND: Micrometastasis (MM) in colorectal cancer (CRC) is not considered in tumour-node-metastasis (TNM) staging currently and also the prognostic significance of these occult tumoural cells is not proven yet. This study was designed to find whether MM to bone marrow (BM) and/or liver cause upstaging of the tumour according to conventional staging system and if it may alter the survival rate. METHODS: Thirty-eight CRC patients who were candidates of surgical procedure were enrolled in our cross-sectional study. Liver and BM biopsy were obtained during the surgery to be looked for tissue-specific marker of CRC, CK20. CK20 expression in BM and liver was assessed by the two methods of reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: Among the 38 submitted patients, a total number of 14 MM, including 10 BM (23%) and seven hepatic (18%) were detected. There was no significant difference in clinicopathological aspects including size, location, stage, grade, local invasion to vessels and neurons, TNM staging and relapse rate of tumour among patients with/without disseminated tumoural cells. The result did not demonstrate a survival difference between patients receiving neoadjuvant chemotherapy compared to other patients. CONCLUSION: Our study did not confirm that the presence of MM influences TNM staging and overall survival of the patients. Additional clinical investigations with longer follow-up period and larger number of cases are required to decide on administration of neoadjuvant therapy in CRC patients. PMID- 27766738 TI - Structural studies of G protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) comprise the largest membrane protein family. These receptors sense a variety of signaling molecules, activate multiple intracellular signal pathways, and act as the targets of over 40% of marketed drugs. Recent progress on GPCR structural studies provides invaluable insights into the structure-function relationship of the GPCR superfamily, deepening our understanding about the molecular mechanisms of GPCR signal transduction. Here, we review recent breakthroughs on GPCR structure determination and the structural features of GPCRs, and take the structures of chemokine receptor CCR5 and purinergic receptors P2Y1 R and P2Y12 R as examples to discuss the importance of GPCR structures on functional studies and drug discovery. In addition, we discuss the prospect of GPCR structure-based drug discovery. (c) 2016 IUBMB Life, 68(11):894-903, 2016. PMID- 27766739 TI - Thin-Film Transformation of NH4 PbI3 to CH3 NH3 PbI3 Perovskite: A Methylamine Induced Conversion-Healing Process. AB - Methylamine-induced thin-film transformation at room-temperature is discovered, where a porous, rough, polycrystalline NH4 PbI3 non-perovskite thin film converts stepwise into a dense, ultrasmooth, textured CH3 NH3 PbI3 perovskite thin film. Owing to the beneficial phase/structural development of the thin film, its photovoltaic properties undergo dramatic enhancement during this NH4 PbI3 -to-CH3 NH3 PbI3 transformation process. The chemical origins of this transformation are studied at various length scales. PMID- 27766742 TI - Intracranial translucency assessment at first trimester nuchal translucency ultrasound. AB - INTRODUCTION: The antenatal diagnosis of open spina bifida (OSB), a neural tube defect, is predominantly made at the second trimester morphology scan by ultrasound detection of structural abnormalities resulting from the associated Chiari II malformation. Evidence has emerged suggesting that these structural abnormalities can be detected earlier, by examination of the posterior fossa as part of the first trimester nuchal translucency scan. In particular, absence of the intra-cranial translucency (IT) of the fourth ventricle has shown promise as a diagnostic marker of OSB, although the sensitivity and specificity of this finding varies widely in the literature. The aim of this study is to assess the feasibility of obtaining the image of the IT at our institution as part of the routine first trimester scan. METHODS: This is a prospective study of 900 obstetric patients who presented to a tertiary women's imaging centre for routine first trimester nuchal translucency screening ultrasound for the year 2014. Their risk status was that of the general population (low risk) prior to presentation. A total of 158 patients were excluded, leaving a study group of 742. Sonographers obtained a mid-sagittal view of the fetal face with particular focus on optimum viewing of the IT. All images were examined by a Radiology Registrar for presence or absence of IT. Duration of each scan was documented. RESULTS: The IT image was successfully acquired in 94.9% of scans. Maternal pre-pregnancy BMI and fetal lie were shown to have a statistically significant effect on success of acquisition of the IT image. No cases of OSB were diagnosed during the study. Scan times were not lengthened by the addition of the image. CONCLUSION: We consider that acquisition of an image of the IT as part of the routine first trimester nuchal translucency scan is feasible, without lengthening appointment times. PMID- 27766740 TI - Comparison of ingestion and topical application of insecticides against the common bed bug, Cimex lectularius (Hemiptera: Cimicidae). AB - BACKGROUND: The global prevalence of Cimex lectularius infestations has challenged current intervention efforts, as pyrethroid resistance has become ubiquitous, availability of labeled insecticides for bed bugs is limited, and non chemical treatment options, such as heat, are often unaffordable. We evaluated representative insecticides toward the goal of developing a novel, ingestible liquid bait for hematophagous arthropods. RESULTS: LC50 values were estimated for adult males and first instar nymphs of an insecticide-susceptible strain for abamectin, clothianidin, fipronil and indoxacarb, after ingestion from an artificial feeder. LD50 values were calculated based on the ingested blood volume. Ingested abamectin, clothianidin and fipronil caused rapid mortality in both life stages. Fipronil was ~43-fold more effective by ingestion than by topical application. Indoxacarb and its bioactive metabolite decarbomethoxylated JW062 (DCJW) were ineffective at causing bed bug mortality even at concentrations as high as 1000 ng mL-1 blood. CONCLUSIONS: Fipronil, clothianidin and abamectin have potential for being incorporated into a liquid bait for bed bug control; indoxacarb and DCJW were not effective. Bed bugs are a good candidate for an ingestible liquid bait because systemic formulations generally require less active ingredient than residual sprays, they remain contained and more effectively target hematophagous arthropods. (c) 2016 Society of Chemical Industry. PMID- 27766741 TI - Development of lipopolysaccharide-mimicking peptides and their immunoprotectivity against Vibrio cholerae serogroup O1. AB - Vibrio cholerae serogroup O1 is the main causative agent of cholera diseases defined by life threatening rice watery diarrhea. Cholera routine vaccination has failed in controlling epidemics in developing countries because of their hard and expensive production. In this study, our aim was to investigate phage displayed mimotopes that could mimic V. cholerae lipopolysaccharide (LPS). Although LPS of Vibrio, as an endotoxin, can stimulate the immune system, thereby making it a suitable candidate for cholera vaccine, its toxicity remains as a main problem. Phage particles displaying 12 amino acid peptides were selected from phage library mimicking the antigenic epitopes of LPS from vibrio. The screening was carried out using single-domain antibody fragment VHH against LPS as target through three rounds of selection. Three clones with highest affinity to VHH were selected. To find out a new and efficient vaccine against cholera, these three phage particles containing high-affinity peptides were administered to mice to investigate the active and passive immunity. Out of 20 particles, three showed the highest affinity toward VHH. ELISA was carried out with immunized mice sera using LPS and three selected phages particles individually. ETEC, Shigella sonnei, and clinical isolates were used as bacterial targets. These three selected phages (individually or in combination) could stimulate mice immune system producing active and passive immunity. The mice immunized with phage particles could protect about 14 LD50 of V. cholerae. In conclusion, these peptides are mimicking LPS and can potentially act as vaccine candidates against V. cholerae. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27766743 TI - Proton Pump Inhibitors and the Risk of Osseointegrated Dental Implant Failure: A Cohort Study. AB - Proton pump inhibitors (PPIs) have a negative impact on bone accrual. Because osseointegration is influenced by bone metabolism, this study investigates the association between PPIs and the risk of osseointegrated implant failure. This retrospective cohort study included a total of 1,773 osseointegrated dental implants in 799 patients (133 implants in 58 PPIs users and 1,640 in 741 non users) who were treated at the East Coast Oral Surgery Clinic in Moncton, Canada, from January 2007 to September 2015. Kaplan-Meier estimator was used to describe the hazard function of dental implant failure by PPIs usage. Multilevel mixed effects parametric survival analyses were used to test the association between PPIs exposure and risk of implant failure adjusting for potential confounders. The failure rates were 6.8% for people using PPIs compared to 3.2% for non-users. Subjects using PPIs had a higher risk of dental implant failure (HR = 2.73; 95% CI = 1.10-6.78) compared to those who did not use the drugs. The findings suggest that treatment with PPIs may be associated with an increased risk of osseointegrated dental implant failure. PMID- 27766745 TI - China is catching up in life science research. PMID- 27766746 TI - Ecological factors associated with behavioral problems in vulnerable children. AB - AIM: Based on McLeroy's ecological perspective, this study aimed to identify the factors that are associated with behavioral problems among children who were enrolled in community child centers that provide public welfare services for vulnerable children. METHODS: A cross-sectional survey was conducted among 175 children aged 6-12 years and their parents who were recruited from 16 community child centers in a municipal county of Seoul, South Korea. The children's behavioral problems were reported by their parents and measured by the Child Behavior Checklist/6-18. As predictor variables, 14 potential factors were selected at multiple ecological levels; parents' health-related quality of life was measured by the World Health Organization Quality of Life-BREF. A multiple linear regression analysis was carried out. RESULTS: At the intrapersonal level, children's chronic illness was significantly associated with internalizing problems. At the interpersonal level, lower parental health-related quality of life was significantly associated with internalizing and externalizing problems. At the organizational level, more years since the community child centers were founded was significantly associated with social problems. At the community level, a lower population density in the district in which the community child center was located was significantly associated with internalizing problems. CONCLUSION: Among vulnerable children, behavioral problems were significantly associated with a comprehensive array of intrapersonal-, interpersonal-, organizational-, and community-level factors. These ecological factors that have been identified in the present study need to be considered when developing multilevel, community-based nursing strategies for preventing and managing vulnerable children's behavioral problems. PMID- 27766744 TI - PTTG1 Levels Are Predictive of Saracatinib Sensitivity in Ovarian Cancer Cell Lines. AB - Src kinase is recognized as a key target for molecular cancer therapy. However, methods to efficiently select patients responsive to Src inhibitors are lacking. We explored the sensitivity of ovarian cancer cell lines to the Src kinase inhibitor saracatinib to identify predictive markers of drug sensitivity using gene microarrays. Pituitary tumor transforming gene 1 (PTTG1) was selected as a potential biomarker as mRNA levels were correlated with saracatinib resistance, as well as higher PTTG1 protein expression. PTTG1 expression was correlated with proliferation, cell division, and mitosis in ovarian cancer tissues data sets. In sensitive cell lines, saracatinib treatment decreased PTTG1 and fibroblast growth factor 2 (FGF2) protein levels. Downregulating PTTG1 by siRNAs increased saracatinib sensitivity in two resistant cell lines. Our results indicate PTTG1 may be a valuable biomarker in ovarian cancer to predict sensitivity to saracatinib, and could form the basis of a targeted prospective saracatinib trial for ovarian cancer. PMID- 27766747 TI - Reduced absorption of glyphosate and decreased translocation of dicamba contribute to poor control of kochia (Kochia scoparia) at high temperature. AB - BACKGROUND: Plant growth temperature is one of the important factors that can influence postemergent herbicide efficacy and impact weed control. Control of kochia (Kochia scoparia), a major broadleaf weed throughout the North American Great Plains, often is unsatisfactory when either glyphosate or dicamba are applied on hot summer days. We tested effects of plant growth temperature on glyphosate and dicamba phytotoxicity on two Kansas kochia populations (P1 and P2) grown under the following three day/night (d/n) temperature regimes: T1, 17.5/7.5 degrees C; T2, 25/15 degrees C; and T3, 32.5/22.5 degrees C. RESULTS: Visual injury and above-ground dry biomass data from herbicide dose-response experiments indicated greater susceptibility to both glyphosate and dicamba when kochia was grown under the two cooler temperature regimes, i.e. T1 and T2. At T1, the ED50 of P1 and P2 kochia were 39 and 36 g ha-1 of glyphosate and 52 and 105 g ha-1 of dicamba, respectively. In comparison, at T3 the ED50 increased to 173 and 186 g ha-1 for glyphosate and 106 and 410 g ha-1 for dicamba, respectively, for P1 and P2. We also investigated the physiological basis of decreased glyphosate and dicamba efficacy under elevated temperatures. Kochia absorbed more glyphosate at T1 and T2 compared to T3. Conversely, there was more dicamba translocated towards meristems at T1 and T2, compared to T3. CONCLUSION: Reduced efficacy of dicamba or glyphosate to control kochia under elevated temperatures can be attributed to decreased absorption and translocation of glyphosate and dicamba, respectively. Therefore, it is recommended to apply glyphosate or dicamba when the temperature is low (e.g. d/n temperature at 25/15 degrees C) and seedlings are small (less than 12 cm) to maximize kochia control. (c) 2016 Society of Chemical Industry. PMID- 27766748 TI - Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. AB - Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter-regulatory hormones of the RAAS and SNS, and endothelin-1 become over-activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF. PMID- 27766750 TI - In vivo trapping of FtsH substrates by label-free quantitative proteomics. AB - FtsH is the only membrane-bound and essential protease in Escherichia coli. It is responsible for the degradation of regulatory proteins and enzymes such as the heat-shock sigma factor RpoH or LpxC, the key enzyme of lipopolysaccharide biosynthesis. To find new FtsH targets, we trapped substrates in E. coli cells from exponential and stationary growth phase by using a proteolytically inactive FtsH variant. Subsequent analysis of the isolated FtsH-substrate complexes by label-free nanoLC-MS/MS revealed more than 50 putative FtsH substrates, among them five already known substrates. Four out of thirty-seven tested candidates were found to be novel FtsH substrates as shown by in vivo degradation experiments. Six other candidates were degraded by one or more other protease(s). The FtsH substrates SecD and ExbD are involved in transport processes across the membrane, whereas the physiological roles of YlaC and YhbT are yet unknown. The presence of the previously identified YfgM degron in two of the novel substrates suggests general rules for substrate recognition of this unique protease. PMID- 27766751 TI - Commemorative Editorial: The Legacy of Franklin Stein, PhD, OTR/L, FAOTA. PMID- 27766749 TI - The sequence capture by hybridization: a new approach for revealing the potential of mono-aromatic hydrocarbons bioattenuation in a deep oligotrophic aquifer. AB - The formation water of a deep aquifer (853 m of depth) used for geological storage of natural gas was sampled to assess the mono-aromatic hydrocarbons attenuation potential of the indigenous microbiota. The study of bacterial diversity suggests that Firmicutes and, in particular, sulphate-reducing bacteria (Peptococcaceae) predominate in this microbial community. The capacity of the microbial community to biodegrade toluene and m- and p-xylenes was demonstrated using a culture-based approach after several hundred days of incubation. In order to reveal the potential for biodegradation of these compounds within a shorter time frame, an innovative approach named the solution hybrid selection method, which combines sequence capture by hybridization and next-generation sequencing, was applied to the same original water sample. The bssA and bssA-like genes were investigated as they are considered good biomarkers for the potential of toluene and xylene biodegradation. Unlike a PCR approach which failed to detect these genes directly from formation water, this innovative strategy demonstrated the presence of the bssA and bssA-like genes in this oligotrophic ecosystem, probably harboured by Peptococcaceae. The sequence capture by hybridization shows significant potential to reveal the presence of genes of functional interest which have low-level representation in the biosphere. PMID- 27766752 TI - Synthesis and biological activity of pyridazine amides, hydrazones and hydrazides. AB - BACKGROUND: Optimization studies on compounds initially designed to be herbicides led to the discovery of a series of [6-(3-pyridyl)pyridazin-3-yl]amides exhibiting aphicidal properties. Systematic modifications of the amide moiety as well as the pyridine and pyridazine rings were carried out to determine if these changes could improve insecticidal potency. RESULTS: Structure-activity relationship (SAR) studies showed that changes to the pyridine and pyridazine rings generally resulted in a significant loss of insecticidal potency against green peach aphids [Myzus persicae (Sulzer)] and cotton aphids [(Aphis gossypii (Glover)]. However, replacement of the amide moiety with hydrazines, hydrazones, or hydrazides appeared to be tolerated, with small aliphatic substituents being especially potent. CONCLUSIONS: A series of aphicidal [6-(3-pyridyl)pyridazin-3 yl]amides were discovered as a result of random screening of compounds that were intially investigated as herbicides. Follow-up studies of the structure-activity relationship of these [6-(3-pyridyl)pyridazin-3-yl]amides showed that biosteric replacement of the amide moiety was widely tolerated suggesting that further opportunities for exploitation may exist for this new area of insecticidal chemistry. Insecticidal efficacy from the original hit, compound 1, to the efficacy of compound 14 produced greater than 10-fold potency improvement against Aphis gossypii and greater than 14-fold potency improvement against Myzus persicae. (c) 2016 Society of Chemical Industry. PMID- 27766753 TI - Modified esophagogastrostomy in laparoscopy-assisted proximal gastrectomy: A reverse-Tornado anastomosis. AB - INTRODUCTION: The aim of this study was to introduce and examine a modified mechanical end-to-side esophagogastrostomy method ("reverse-Tornado" anastomosis) in laparoscopy-assisted proximal gastrectomy. METHODS: Five patients with gastric cancer who underwent laparoscopy-assisted proximal gastrectomy were analyzed retrospectively. Esophagogastrostomy in the anterior wall was performed in three patients, and esophagogastrostomy in the posterior wall was performed in two patients. Clinicopathological features, operative outcomes (operative time, operative blood loss), and postoperative outcomes (complications, postoperative hospital stay, reflux esophagitis) were evaluated. RESULTS: Operative time was normal (278 min). There was no marked operative blood loss, postoperative complications, prolonged hospital stay, or reflux esophagitis. CONCLUSION: Esophagogastrostomy was completed in a normal time with reverse-Tornado anastomosis. This method can be safe and can enable good postoperative quality of life. PMID- 27766754 TI - The emergence of intracellular metabolite signaling networks. AB - The signals of intracellular metabolites are integrated into cellular signaling networks by forming metabolite-derived posttranslational modifications or by non covalently binding to proteins. These signals serve to coordinate cell metabolism and to regulate various aspects of cell physiology. (c) 2016 IUBMB Life, 68(11):871-872, 2016. PMID- 27766755 TI - Explicit and Emergent Mechanisms of Information Status. AB - It is well established that language production and comprehension are influenced by information status, for example, whether information is given, new, topical, or predictable, and many scholars suggest that an important component of information status is keeping track of what information is in common ground (i.e., what is shared), and what is not. Information status affects both speakers' choices (e.g., word order, pronoun use, prosodic prominence) and how listeners interpret the speaker's meaning (e.g., Chafe, 1994; Prince, 1981). Although there is a wealth of scholarly work on information status (for a review, see Arnold, Kaiser, Kahn, & Kim, 2013), there is no consensus on the mechanisms by which it is used, and in fact relatively little discussion of the underlying representations and psycholinguistic mechanisms. Moreover, a major challenge to understanding information status is that its effects are notoriously variable. This study considers existing proposals about information status, focusing on two questions: (a) how is it represented; and (b) by what mechanisms is it used? I propose that it is important to consider whether representations and mechanisms can be classified as either explicit or emergent. Based on a review of existing evidence, I argue that information status representations are most likely emergent, but the mechanisms by which they are used are both explicit and emergent. This review provides one of the first considerations of information status processing across multiple domains. PMID- 27766757 TI - In vivo quantification of magnetically labelled cells by MRI relaxometry. AB - Cellular MRI, which visualizes magnetically labelled cells (cells*), is an active research field for in vivo cell therapy and tracking. The simultaneous relaxation rate measurements (R2 *, R2 , R1 ) are the basis of a quantitative cellular MRI method proposed here. U937 cells were labelled with Molday ION Rhodamine B, a bi functional superparamagnetic and fluorescent nanoparticle (U937*). U937* viability and proliferation were not affected in vitro. In vitro relaxometry was performed in a cell concentration range of [2.5 * 104 -108 ] cells/mL. These measurements show the existence of complementary cell concentration intervals where these rates vary linearly. The juxtaposition of these intervals delineates a wide cell concentration range over which one of the relaxation rates in a voxel of an in vivo image can be converted into an absolute cell concentration. The linear regime was found at high concentrations for R1 in the range of [106 - 2 * 108 ] cells/mL, at intermediate concentrations for R2 in [2.5 * 105 - 5 * 107 ] cells/mL and at low concentrations for R2 * in [8 * 104 - 5 * 106 ] cells/mL. In vivo relaxometry was performed in a longitudinal study, with labelled U937 cells injected into a U87 glioma mouse model. Using in vitro data, maps of in vivo U937* concentrations were obtained by converting one of the in vivo relaxation rates to cell concentration maps. MRI results were compared with the corresponding optical images of the same brains, showing the usefulness of our method to accurately follow therapeutic cell biodistribution in a longitudinal study. Results also demonstrate that the method quantifies a large range of magnetically labelled cells*. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766756 TI - Lactobacillus johnsonii glycolipids, their structure and immunoreactivity with sera from inflammatory bowel disease patients. AB - Structural studies of the major glycolipids produced by two Lactobacillus johnsonii (LJ) strains, LJ 151 isolated from intestinal tract of healthy mice and LJ 142 isolated from mice with experimentally induced inflammatory bowel disease (IBD), were performed. Two major glycolipids, GL1 and GL2, were present in lipid extracts from L. johnsonii 142 and 151 strains. Glycolipid GL1 has been identified as beta-D-Glcp-(1->6)-alpha-D-Galp-(1->2)-alpha-D-Glcp-diglyceride and GL2 as alpha-D-Galp-(1->2)-alpha-D-Glcp-diglyceride. The main fatty acid residues identified by gas-liquid chromatography-mass spectrometry were palmitic, stearic and lactobacillic acids. Besides structural elucidation of the major glycolipids, the aim of this study was to determine the immunochemical properties of these glycolipids and to compare their immunoreactivity to that of polysaccharides obtained from the same strains. Sera from rabbits immunized with bacterial cells possessed much higher serological reactivity with polysaccharides than with glycolipids. Inversely, reactivity of the glycolipids with human sera from patients with IBD was much higher than that determined for the polysaccharides, while reactivity of glycolipids with human sera from healthy individuals was much lower than one measured for the polysaccharides. Results indicate that glycoconjugates from Lactobacillus cell wall act as antigens and may represent new IBD diagnostic biomarkers. PMID- 27766758 TI - Training in hepato-pancreato-biliary surgery during residency: past, present and future perspectives. AB - The paradigm introduced by William Halsted for surgical residency training has been considered the most appropriate educational system to acquire the knowledge and surgical skills required to become a competent general surgeon. Hepato pancreato-biliary (HPB) surgery is considered an important part of general surgery training because of its high prevalence and complexity. Nowadays, we are faced with a worldwide shortage of general surgeons candidates, restrictive working hours and less surgical exposure, situations that can undermine the objectives of training in HPB surgery during residency. Moreover, new generations of resident graduates are concerned about their lack of preparedness for independence. We cannot escape from this reality and therefore it justifies a reflection in our HPB surgical world community. PMID- 27766760 TI - Korean infection control nurses' knowledge and awareness of infection control against Ebola virus disease. AB - AIM: To assess the level of knowledge and awareness of Ebola virus disease infection control among infection control nurses and to identify a correlation between these factors. METHODS: The data were collected from 125 infection control nurses by using a self-report questionnaire. The data were collected on sociodemographic and hospital characteristics, as well as the level of knowledge and awareness of Ebola virus disease infection control. RESULTS: The respondents' mean level of knowledge (correct-answer rate) was 87.7% and their mean level of awareness was 3.86 (1 = "not important at all" to 4 = "very important"). Knowledge of Ebola virus disease infection control was significantly higher among those nurses who had received some Ebola virus disease education. There was a significant positive correlation between the level of knowledge and the level of awareness. CONCLUSION: The development of effective education and training systems is necessary to improve infection control nurses' knowledge and awareness of Ebola virus disease infection control. Moreover, each hospital should build effective and systematic Ebola virus disease infection control strategies. PMID- 27766759 TI - Premenopausal abnormal uterine bleeding and risk of endometrial cancer. AB - BACKGROUND: Endometrial biopsies are undertaken in premenopausal women with abnormal uterine bleeding but the risk of endometrial cancer or atypical hyperplasia is unclear. OBJECTIVES: To conduct a systematic literature review to establish the risk of endometrial cancer and atypical hyperplasia in premenopausal women with abnormal uterine bleeding. SEARCH STRATEGY: Search of PubMed, Embase and the Cochrane Library from database inception to August 2015. SELECTION CRITERIA: Studies reporting rates of endometrial cancer and/or atypical hyperplasia in women with premenopausal abnormal uterine bleeding. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two reviewers and cross-checked. For each outcome, the risk and a 95% CI were estimated using logistic regression with robust standard errors to account for clustering by study. MAIN RESULTS: Sixty-five articles contributed to the analysis. Risk of endometrial cancer was 0.33% (95% CI 0.23-0.48%, n = 29 059; 97 cases) and risk of endometrial cancer or atypical hyperplasia was 1.31% (95% CI 0.96-1.80, n = 15 772; 207 cases). Risk of endometrial cancer was lower in women with heavy menstrual bleeding (HMB) (0.11%, 95% CI 0.04-0.32%, n = 8352; 9 cases) compared with inter-menstrual bleeding (IMB) (0.52%, 95% CI 0.23-1.16%, n = 3109; 14 cases). Of five studies reporting the rate of atypical hyperplasia in women with HMB, none identified any cases. CONCLUSIONS: The risk of endometrial cancer or atypical hyperplasia in premenopausal women with abnormal uterine bleeding is low. Premenopausal women with abnormal uterine bleeding should first undergo conventional medical management. Where this fails, the presence of IMB and older age may be indicators for further investigation. Further research into the risks associated with age and the cumulative risk of co-morbidities is needed. TWEETABLE ABSTRACT: Contrary to practice, premenopausal women with heavy periods or inter-menstrual bleeding rarely require biopsy. PMID- 27766761 TI - Outpatient psychodynamic group psychotherapy - outcomes related to personality disorder, severity, age and gender. AB - OBJECTIVES: Outpatient group psychotherapy is frequent within specialist services, recruits a mixed population, but effects are poorly documented. This study investigates long-term outcomes for patients with personality disorder (PD) treated in outpatient, psychodynamic groups within secondary mental health service. METHODS: A naturalistic study (N = 103) with repeated assessments of process and clinical outcomes. Longitudinal statistics are linear mixed models. RESULTS: The main PDs were avoidant, borderline and NOS PD, mean number of PDs 1.4(SD0.7), 60% females and mean initial age 38(SD10) years. Mean treatment duration was 1.5(SD 0.9) years. Therapist alliance and experienced group climate was satisfactory and stable. Improvements were significant (symptom distress, interpersonal problems, occupational functioning and additional mental health services), irrespective of general PD-severity, but not of PD-type, age or gender. The study demonstrates PD NOS benefits across all outcomes, occupational improvements for avoidant PD, despite prevailing symptoms, but generally poorer outcomes for males and age >38 years. For borderline PD, experienced conflict was stronger, treatment duration shorter and outcomes poor for early drop-outs (28%). CONCLUSION: Psychodynamic group psychotherapy is a recommendable treatment for moderate PDs, which may address avoidant strategies, but may not meet clinical challenges of borderline PD. The outcome differences related to gender and age are noteworthy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766762 TI - A Selective Near-Infrared Fluorescent Probe for In Vivo Imaging of Thiophenols from a Focused Library. AB - Thiophenols are highly toxic industrial materials that, once released, will accumulate in the environment, and ultimately in human bodies, thereby causing serious health problems. To achieve their selective and sensitive detection, a novel near-infrared (NIR) fluorescent probe (CCP-1) from a focused library was developed for thiophenol species. Our studies show that CCP-1 displays a thiophenol-triggered 28-fold fluorescence intensity enhancement at 706 nm, with a detection limit of 34 nm observed. It is also able to differentiate thiophenols from various other thiol-containing analytes including hydrogen sulfide, hydrogen persulfide, and aliphatic thiols. In total, the desirable properties (e.g., excitation/emission in the NIR region, good cell-membrane permeability, intracellular stability, and low cytotoxicity) make CCP-1 a potential candidate for thiophenol detection both in vitro and in vivo. In addition, CCP-1, for the first time, successfully visualized thiophenols in mice models of thiophenol inhalation. PMID- 27766763 TI - Nutrient Stress During Ontogeny Alters Patterns of Resource Allocation in two Species of Horned Beetles. AB - The elaboration of exaggerated, sexually selected weapons and ornaments often comes at a cost to other traits. For instance, by sustaining the growth of an exaggerated weapon during development, shared and limited resources such as morphogens, growth factors, and nutrients may become depleted and limit the size to which other structures can grow. Such interactions are characteristic of resource allocation trade-offs, which can constrain the production of phenotypic variation and bias evolutionary trajectories. Across many species of Onthophagus beetles, males produce extravagant horns that are used as weapons in male-male competition over mates. Previous studies have reported resource allocation trade offs between horns and both proximally and distally developing structures. However, more recent studies have largely failed to recover these patterns, leading to the hypothesis that trade-offs may manifest only in certain species, populations, or environmental conditions. Here, we investigate (i) patterns of resource allocation into horns, eyes, and genitalia in Onthophagus gazella and O. taurus, and assess (ii) how these patterns of resource allocation are influenced by nutrient stress during larval development. We find that nutrient stress alters patterns of resource allocation within and among traits, but recover a trade-off only in the species that invests most heavily into horn production (O. taurus), and in individuals of that species that invested a disproportionately large or small amount of resources into horn growth. These results suggest that resource allocation trade-offs may not be as prevalent as previously described, and that their presence and magnitude may instead be highly context dependent. PMID- 27766764 TI - ortho-C-H Arylation of Benzoic Acids with Aryl Bromides and Chlorides Catalyzed by Ruthenium. AB - A system consisting of catalytic amounts of [(p-cym)RuCl2 ]2 /PEt3 ?HBF4 , K2 CO3 as the base, and NMP as the solvent efficiently mediates the ortho-C-H arylation of benzoic acids with aryl bromides at 100 degrees C. Replacing the phosphine ligand with the amino acid dl-pipecolinic acid enables the analogous transformation with aryl chlorides. The key advantage of this broadly applicable transformation is the use of an inexpensive ruthenium catalyst in combination with simple carboxylates as directing groups, which can either be tracelessly removed or used as anchor points for decarboxylative ipso substitutions. PMID- 27766765 TI - Individual differences in positive and negative emotion regulation: Which strategies explain variability in loneliness? AB - Loneliness is the distressing feeling accompanying the perception that one's social needs are not being met by one's social relationships. Conceptual models point to a role for cognitive factors in this experience. Because research on determinants of loneliness is sparse, this study investigates associations between individual differences in emotion regulation (ER) and loneliness. Participants (N = 116) completed measures of loneliness, and a vignette-based measure of adaptive and maladaptive ER in response to positive and negative scenarios. Regression analyses indicated that the regulation of positive and negative emotions explained comparable variance in loneliness, and associations were only partially reduced by the inclusion of social support. The specific strategies positive reappraisal, being present and negative mental time travel explained the most variance in loneliness. The findings are consistent with both the cognitive and the social needs models of loneliness and suggest that variability in ER strategies should be considered relevant to loneliness. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766768 TI - Flavonoids and Their Glycosides as Anti-amyloidogenic Compounds: Abeta1-42 Interaction Studies to Gain New Insights into Their Potential for Alzheimer's Disease Prevention and Therapy. AB - Combining NMR spectroscopy, transmission electron microscopy, biochemical and in vitro toxicity assays, we characterized the effect of flavonoid glycosylation, a chemical modification found very frequently in nature, on their ability to recognize and bind Abeta1-42 oligomers, preventing their aggregation and their neurotoxicity. Our data allow the elucidation of their structure-activity relationships, showing that glycosylation has a modest impact on flavonoid affinity for Abeta oligomers but, at the same time, increases both solubility and chemical stability, thus promoting their beneficial properties against Alzheimer's disease (AD). As flavonoids and their glycosides are widely available in natural foods, our results provide important information for the evaluation of the role of a flavonoid-rich diet for the prevention of AD. In addition, the structural data collected can be exploited for the rational design of more potent Abeta oligomer inhibitors, useful for the development of new therapies against AD. PMID- 27766769 TI - Magnetic resonance imaging features of gemistocytic astrocytoma. AB - INTRODUCTION: Gemistocytic astrocytoma is the second most common subtype of World Health Organization grade 2 astrocytoma, but has a worse prognosis than other grade 2 lesions. We aim to describe the MR imaging features of histopathologically proven gemistocytic tumours. METHODS: Ethics approval was obtained from both institutions. Patient consent was not required for this retrospective study. We reviewed MR imaging findings of 16 consecutive cases of histopathologically proven gemistocytic astrocytoma and anaplastic astrocytoma with gemistocytic features. RESULTS: Average patient age was 48 years, with a 3:1 male to female ratio. Based on our series, the typical appearance of a gemistocytic astrocytoma is a large, heterogeneous mass most commonly supratentorial and lobar. Regions of cyst formation, partial signal suppression on FLAIR images and contrast enhancement are all common features. Additionally, contrary to previous literature that describes gemistocytic astrocytoma as a purely supratentorial lesion, we present two cases of gemistocytic astrocytoma involving the brainstem. CONCLUSIONS: The possibility of gemistocytic astrocytoma should be considered in patients presenting with large heterogeneous tumours that have regions of cyst formation, partial FLAIR suppression and contrast enhancement. This may be especially useful in reconciling a lesion with high grade MR imaging features with low-grade histopathology. An infratentorial location does not preclude the diagnosis of gemistocytic astrocytoma. PMID- 27766766 TI - Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents. AB - We previously reported that the kinase AKT is activated in the nucleus accumbens (NAc) of rodents in response to excessive consumption of alcohol. One of the important downstream targets of AKT is the mammalian Target Of Rapamycin in Complex 1 (mTORC1), which was also activated by alcohol intake. mTORC1 controls dendritic protein translation, and we showed that the mTORC1-dependent translational machinery is activated in the NAc in response to alcohol intake. Importantly, systemic or intra-NAc inhibition of the AKT/mTORC1 pathway attenuated alcohol-drinking behaviors. Here, we mapped the activation patterns of AKT and mTORC1 in corticostriatal regions of rodents consuming large amounts of alcohol. We found that the activation of AKT and mTORC1 in response to cycles of binge drinking of 20 percent alcohol was centered in the NAc shell. Both kinases were not activated in the dorsolateral striatum (DLS); however, AKT, but not mTORC1, was activated in the dorsomedial striatum (DMS) of mice but not rats. Interestingly, excessive intake of alcohol produced a selective activation of the AKT/mTORC1 pathway in the orbitofrontal cortex (OFC), which was not observed in medial prefrontal cortex (mPFC). Furthermore, this signaling pathway was not activated in the NAc shell or OFC of rats consuming moderate amounts of alcohol nor was it activated in rats consuming sucrose. Together, our results suggest that excessive alcohol intake produces a brain region selective activation of the AKT/mTORC1 pathway, which is likely to contribute to NAc shell and OFC-dependent mechanisms that underlie the development and maintenance of alcohol drinking behavior. PMID- 27766770 TI - Accounting for uncertainty in the historical response rate of the standard treatment in single-arm two-stage designs based on Bayesian power functions. AB - In phase II single-arm studies, the response rate of the experimental treatment is typically compared with a fixed target value that should ideally represent the true response rate for the standard of care therapy. Generally, this target value is estimated through previous data, but the inherent variability in the historical response rate is not taken into account. In this paper, we present a Bayesian procedure to construct single-arm two-stage designs that allows to incorporate uncertainty in the response rate of the standard treatment. In both stages, the sample size determination criterion is based on the concepts of conditional and predictive Bayesian power functions. Different kinds of prior distributions, which play different roles in the designs, are introduced, and some guidelines for their elicitation are described. Finally, some numerical results about the performance of the designs are provided and a real data example is illustrated. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27766771 TI - Continuous infusion of high-dose ulinastatin during surgery does not improve early postoperative clinical outcomes in patients undergoing radical lung cancer surgery: A pilot study. AB - BACKGROUND: Ulinastatin can prevent the perioperative increase in proinflammatory cytokines for lung resection surgery; however, its impact on early clinical outcomes remains unknown. METHODS: The study enrolled 108 non-small cell lung cancer (NSCLC) patients who were randomly allocated into two groups: ulinastatin (group U) and control (group C). Patients in group U ( n = 52) were continuously intravenously infused with ulinastatin at a rate of 20 000 U/kg/hour for the first hour after anesthesia induction, and then at a rate of 5000 U/kg/hour until the conclusion of surgery. Patients in group C ( n = 56) received an equivalent volume of normal saline. The primary outcome was to record the postoperative pulmonary complications that occurred during hospital stay. Other clinical courses, such as hospital mortality, blood loss, respiratory parameters, postoperative chest drainage, and duration of intensive care unit and postoperative hospital stay, were also observed and analyzed. RESULTS: There were no significant differences between the two groups in early postoperative pulmonary complications, hospital mortality, blood loss, or other perioperative laboratory values, except for the duration of postoperative chest drainage and serum creatinine level. The frequency of pulmonary complications was lower in patients treated with ulinastatin compared with the control (38.46% in group U vs. 48.21% in group C). CONCLUSION: Administration of high-dose ulinastatin during surgery did not reduce postoperative pulmonary complications, hospital mortality, or hospital stay for patients undergoing lung radical thoracotomy. However, a protective trend of ulinastatin was observed. PMID- 27766773 TI - ERRATUM. PMID- 27766772 TI - Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors combined with chemotherapy in first-line treatment in an advanced non-small cell lung cancer patient with EGFR sensitive mutation. AB - This article demonstrates a case of a lung adenocarcinoma patient in stage IV harboring an epidermal growth factor receptor (EGFR) 19 exon deletion mutation treated with 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin on day 1, sequenced with 250 mg gefitinib on prescription on days 4-28 for six cycles as first-line, then by gefitinib combined with pemetrexed as maintenance therapy. The patient achieved a partial response. Performance status increased from grade 2 to 1. The progression-free survival period was 17 months. Overall survival is now over three years. Side effects of grade two liver dysfunction and dermal toxicity were tolerable. Combined gefitinib with platinum-based chemotherapy as first-line treatment probably benefits non-small cell cancer patients in stage IV harboring sensitive EGFR gene mutations with a better local control rate, longer survival, and tolerable side effects. PMID- 27766774 TI - Incidence rate of female breast cancer in urban Shijiazhuang in 2012 and modifiable risk factors. AB - BACKGROUND: Breast cancer is diagnosed more frequently among urban than rural women in China; however, the incidence among women in Shijiazhuang is unknown. METHODS: As registered Chinese citizens are entitled to complete public medical insurance coverage, the incidence rate was estimated using reimbursement records of first hospitalization. RESULTS: Breast cancer is the most common cancer among women in Shijiazhuang. The crude rate and age-standardized incidence rates by China (ASRC) and world (ASRW) standards were 59.6, 48.5 and 45.5/100 000 in 2012. Mean age at diagnosis was 55.1 years. Incidence increased with age, peaking at 165.1 at 70-74. In comparison with urban women in other Chinese cities, incidence in Shijiazhuang was similar to Shanghai (ASRC 46.6) and Suzhou (ASRW 45). When compared with 31 other Chinese cities, Shijiazhuang ranked second highest behind Guangzhou (ASRW 46.6), and the ASRW correlated significantly with gross domestic product per capita among the 32 cities. The breast cancer ASRW in Shijiazhuang was 2.7 times the rate of 41 rural Chinese counties (17). When compared with GLOBOCAN 2012 data according to the Human Development Index, breast cancer incidence in Shijiazhuang matched countries with a high human development index (ASRW 45.2). CONCLUSION: Breast cancer incidence in Shijiazhuang in 2012 was the highest in China, matching the rate in countries with high social economic development. This rate may continue to rise, parallel with urbanization, and may be associated with changing reproductive patterns and Westernization. Prevention methods need to be incorporated. PMID- 27766775 TI - Claudin-1 correlates with poor prognosis in lung adenocarcinoma. AB - BACKGROUND: This study was conducted to investigate the clinical significance of claudin-1 (CLDN1) expression in patients with lung adenocarcinoma. METHODS: We examined CLDN1 protein expression by immunohistochemistry in a tissue microarray from 258 patients with lung adenocarcinoma. We investigated messenger ribonucleic acid (mRNA) expression in H358 (formerly bronchioloalveolar carcinoma) and lung adenocarcinoma cell lines (A549) by real-time reverse transcriptase-polymerase chain reaction. RESULTS: Multivariate analysis showed that prognostic factors for lung adenocarcinoma were histologic type, CLDN1, T stage and N stage. Patients with positive CLDN1 expression had a poorer prognosis than patients with negative CLDN1 expression. CLDN1 expression was correlated with Ras and epidermal growth factor receptor (EGFR) expression. Patients with positive expressions of both CLDN1 and Ras/EGFR had a poorer prognosis than patients with CLDN1 (+) Ras/EGFR( ) or CLDN1 (-) Ras/EGFR(+) and patients with negative expressions of both CLDN1 and Ras/EGFR. CLDN1 mRNA expression was lower in the H358 compared with the lung adenocarcinoma cell line (A549). CONCLUSION: The combination of CLDN1 and Ras/EGFR is a valuable independent prognostic predictor for lung adenocarcinoma. PMID- 27766776 TI - RUNX3 reverses cisplatin resistance in esophageal squamous cell carcinoma via suppression of the protein kinase B pathway. AB - BACKGROUND: Preoperative chemoradiation combined with surgery has been of focus recently in order to improve prognosis in esophageal squamous cell carcinoma (ESCC) patients. Finding biological markers that may assist in predicting the therapeutic effect of chemoradiation may benefit the treatment effect. In this study, the role of RUNX3 in the formation of cisplatin resistance in ESCC was examined. METHODS: The study enrolled 103 stage IIa-IIIb ESCC patients who had undergone esophagectomy. RUNX3 expression in ESCC tissue was detected. RESULTS: A higher expression of RUNX3 in ESCC patients correlated with a more sensitive response to cisplatin-based chemotherapy. A consistently lower expression of RUNX3 was found in the ESCC tissues of patients who agreed to perioperative chemotherapy compared with patients who had undergone no preoperative treatment. A lower RUNX3 expression in cisplatin-resistant ESCC cell lines, Eca109 and TE-1, was observed compared with parental cell lines. Heterologous RUNX3 expression significantly suppressed cisplatin resistance in Eca109 and TE-1, both in vitro and vivo. Meanwhile, heterologous RUNX3 expression could inhibit growth and induce apoptosis in cisplatin resistant Eca109 and TE-1 cell lines in vitro. Remarkable inhibition of the Akt pathway was observed in heterologous RUNX3 expression in Eca109 and TE-1. Silencing Akt1 could reverse cisplatin resistance in Eca109 and TE-1. CONCLUSION: Our results confirmed that a loss of RUNX3 in ESCC may contribute to cisplatin-resistance. RUNX3 could reverse cisplatin resistance via suppression of the Akt pathway in ESCC patients. PMID- 27766777 TI - Significance of different response evaluation criteria in predicting progression free survival of lung cancer with certain imaging characteristics. AB - BACKGROUND: Certain radiographic signs of a treatment response, such as cavitation, changes in density, or tumor change along a short axis, are not considered by Response Evaluation Criteria in Solid Tumors (RECIST). This study evaluates what additional prognostic information can be obtained by including these criteria in tumor assessment. METHODS: Data of 105 patients were included. Tumor cavitation was observed in 51 patients at baseline. An additional 23 patients developed tumor cavitation during treatment. A change in tumor density was the only radiographic treatment response observed in 22 patients. The only measureable treatment response in nine patients was a decrease along the short axis size of the tumor. Tumor response was assessed using various criteria. RESULTS: In patients with basic tumor cavitation, RECIST1.1 scores accurately predicted differences in progression-free survival (PFS; P = 0.076) while modified (m) RECIST did not (P = 0.550). mRECIST detected a significant difference between PFS in patients with post-therapeutic cavitation with different responses, but no significant difference using RECIST1.1 (P = 0.004 vs. P = 0.477). In patients with only tumor density changes, there was no significant difference in PFS when either RECIST1.1 or density criteria were used (P = 0.419). In patients with a change in size along the tumor's short axis, short axis criteria could predict significant difference in PFS (P = 0.004). CONCLUSIONS: RECIST1.1 provides the best assessment of tumor response and prediction of PFS in patients with basic tumor cavitation. mRECIST provides better PFS prognostic information in patients with post-therapeutic cavitation. Short axis criteria provides better PFS prognostic information in patients with changes in the short axis of tumor diameter. Changes in tumor density were not a useful prognostic sign. PMID- 27766778 TI - Autonomic nervous infiltration positively correlates with pathological risk grading and poor prognosis in patients with lung adenocarcinoma. AB - BACKGROUND: Perineural invasion has been found in several types of human tumors, and is associated with poor prognosis; however, few studies have examined perineural invasion in lung cancer. We evaluated the relationship between autonomic nervous densities, pathological risk grading, and prognosis in patients with lung adenocarcinoma (LADC). METHODS: Neural fiber expression was examined by immunofluorescence in resected lung specimens in control patients (n = 30), and low-risk (n = 22), and high-risk LADC patients (n = 43). The nerve densities of normal lung tissue and abnormal lung tissues in the tumor and surrounding tissues were evaluated by a semi-quantitative score method. RESULTS: Increased sympathetic fibers mainly infiltrated the paratumoral area, while increased parasympathetic fibers were largely restricted to the tumor (paratumor vs. tumor, P = 0.000 in high, P = 0.034 in low; each). In addition, high-risk patients presented the highest density of neural fibers, followed by low-risk and control patients ( P = 0.000; each). In Kaplan-Meier survival analysis, the densities of sympathetic fibers in paratumoral tissue and parasympathetic fibers in the tumor, respectively, correlated with poor recurrence-free survival in patients who were not treated with adjuvant therapy ( P < 0.001; each). Further multivariate analysis showed that these two factors were associated with poor prognosis in all LADC patients ( P = 0.024 sympathetic fibers; P = 0.037 parasympathetic fibers). CONCLUSION: These findings reveal a positive correlation between nervous infiltration and risk of poor prognosis in patients with LADC. PMID- 27766779 TI - Effect of percutaneous radiofrequency ablation after thoracoscopic pleurodesis for treating non-small cell lung cancer patients with malignant pleural effusion and/or pleural dissemination. AB - BACKGROUND: The purpose of this study was to retrospectively evaluate percutaneous radiofrequency ablation (RFA) combined with palliative thoracoscopic pleurodesis (TP) for malignant pleural effusion and/or pleural disseminated non small cell lung cancer (NSCLC), diagnosed by thoracoscopy. METHODS: The study was composed of 40 patients with primary NSCLC with malignant pleural effusion and/or pleural dissemination recognized for the first time during thoracoscopic exploration. Twenty patients received TPR (TP plus RFA group), while the remaining 20 patients who underwent TP (TP group) represented the control. We evaluated technical success, safety, initial response rate, progression-free survival (PFS), and overall survival (OS). RESULTS: No procedure-related deaths or major complications occurred in any of the 22 ablation procedures. Complete response was observed in 15% of patients, partial response in 50%, stable disease in 25%, and progressive disease in 15% of patients. The mean follow-up was 15.5 months. The PFS at years one, two, and three were 77.5%, 38.8%, and 25.8%, respectively. The OS at years one, two, and three were 77.5%, 41.4%, and 27.6%, respectively. The PFS and OS were longer in the TP-R group, indicating a better prognosis than that of the patients who underwent TP only (OS 24 vs. 18 months, P = 0.030; PFS 22 vs. 15 months, P = 0.036). CONCLUSIONS: Palliative TP combined with percutaneous RFA is a safe, feasible, and effective procedure in patients with malignant pleural effusion and/or pleural disseminated NSCLC. PMID- 27766780 TI - Lung adenocarcinoma with anomalous bronchi and pulmonary veins preoperatively identified by computed tomography. AB - A 69-year-old woman visited our hospital complaining of right chest pain. Chest computed tomography showed a 55 * 45 mm tumor in the right upper lobe. Bronchoscopy revealed displaced anomalous B 1 and B 2+3 arising from the right main bronchus, and the patient was diagnosed with lung adenocarcinoma by transbronchial lung biopsy from the displaced B 2+3 . Three-dimensional computed tomography with multiplanar reconstruction revealed a displaced anomalous B 1 and B 2+3 branching directly from the right main bronchus, respectively, and abnormal distribution of the aberrant pulmonary vein (V 2 ) descended dorsally to the right main bronchus and emptied into the left atrium. Video-assisted right upper lobectomy with nodal dissection was successfully performed. Attention should be paid to the anomalous bronchus and pulmonary vessels for safer lung cancer operations, especially for video-assisted thoracic surgery. PMID- 27766781 TI - Postoperative chemoradiotherapy improves survival in patients with stage II-III esophageal squamous cell carcinoma: An analysis of clinical outcomes. AB - BACKGROUND: We compared the efficacy of postoperative chemoradiation (POCRT) and surgery alone (SA) in patients with stage II-III esophageal squamous cell carcinoma (ESCC). METHODS: We analyzed the records of 265 patients with stage II III ESCC who had undergone transthoracic esophagectomy and lymphadenectomy; 105 patients received POCRT, while 160 had SA. RESULTS: The median disease-free survival (DFS) of the whole cohort was 22 months (95% confidence interval [CI], 19.2-24.8), while the median overall survival (OS) was 29 months (95% CI 25.5 32.5). The median DFS of the SA group was 21 months (95% CI 17.9-24.0), while that of the POCRT group was 29 months (95% CI 18.8-31.2; P = 0.048). Consistently, patients in the POCRT group had significantly longer median OS than patients in the SA group (34 vs. 26 months, respectively). Subgroup analysis showed that in patients with positive lymph nodes, pathological stage III, T3-4 stage, and poorly differentiated carcinoma, POCRT was apparently more effective than SA at improving OS and decreasing the rates of local recurrence and distant metastasis. Multivariate analysis demonstrated that lymph node involvement and treatment with POCRT were independent prognostic factors. CONCLUSION: Compared with SA, POCRT may be more effective in improving OS and decreasing the rates of local recurrence and distant metastasis, particularly in stage III or positive lymph node stage II-III ESCC patients. PMID- 27766782 TI - Comparison of three-dimensional and two-dimensional visualization in video assisted thoracoscopic lobectomy. AB - BACKGROUND: Video-assisted thoracoscopic surgery (VATS) lobectomy has emerged as a safe and effective technique for treating early-stage lung cancer. Novel three dimensional, high-definition (3D HD) imaging has removed this technical obstacle and is increasingly used in laparoscopic surgery. We compared our initial experience of 3D HD VATS with standard two-dimensional (2D) HD VATS to identify the advantages and disadvantages of 3D HD visualization in VATS. METHODS: The data of consecutive patients diagnosed with lung cancer who underwent 2D or 3D thoracoscopic lobectomy or bilobectomy at the Guangdong Lung Cancer Institute from July 2013 to October 2014 were retrospectively analyzed. Operation duration, estimated blood loss, length of postoperative stay, major complications, and mortality were recorded for each patient. RESULTS: In total, 359 patients were enrolled in the study. Lobectomy was performed in 339 patients and bilobectomy in 20; the 3D HD system was used for 178 of the 359 patients, and the 2D HD system for 181. Tumor size, distribution of the resected lobes, and the demographic characteristics of the patients were matched between the two groups. The mean operative time for 3D VATS was 163 minutes (range 60-330), whereas 2D VATS required 184 minutes (range 75-360; P < 0.001). The volume of blood loss was 109 and 144 mL in the 3D and 2D VATS groups, respectively (P = 0.064). CONCLUSIONS: The new-generation 3D HD imaging system is feasible and safe for thoracic lobectomy. The 3D system required a shorter operative duration. PMID- 27766783 TI - Long-lasting response to third-line crizotinib treatment in a patient with non small cell lung cancer with brain metastases and poor performance status. AB - Identification of the anaplastic lymphoma kinase (ALK) gene has refined the classification of non-small cell lung cancer (NSCLC) and promoted research on molecularly targeted drugs such as crizotinib, an ALK inhibitor with good efficacy, in ALK-rearranged NSCLC. At present, few studies have reported the efficacy of crizotinib in patients with ALK-rearranged NSCLC with brain metastases. In a patient with NSCLC harboring ALK-rearrangement who had brain metastases and poor performance status (PS), we obtained a durable response with crizotinib administered following multi-line chemotherapy regimens. PMID- 27766784 TI - Retrospective study of adjuvant icotinib in postoperative lung cancer patients harboring epidermal growth factor receptor mutations. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutations occur in about 50% of Asian patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC and EGFR mutations derive clinical benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of adjuvant icotinib without chemotherapy in EGFR-mutated NSCLC patients undergoing resection of stage IB-IIIA. METHODS: Our retrospective study enrolled 20 patients treated with icotinib as adjuvant therapy. Survival factors were evaluated by univariate and Cox regression analysis. RESULTS: The median follow-up time was 30 months (range 24-41). At the data cut-off, five patients (25%) had recurrence or metastasis and one patient had died of the disease. The two-year disease-free survival (DFS) rate was 85%. No recurrence occurred in the high-risk stage IB subgroup during the follow-up period. In univariate analysis, the micropapillary pattern had a statistically significant effect on DFS ( P = 0.040). Multivariate logistic regression analysis showed that there was no independent predictor. Drug related adverse events (AEs) occurred in nine patients (45.0%). The most common AEs were skin-related events and diarrhea, but were relatively mild. No grade 3 AEs or occurrences of intolerable toxicity were observed. CONCLUSIONS: Icotinib as adjuvant therapy is effective in patients harboring EGFR mutations after complete resection, with an acceptable AE profile. Further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients. PMID- 27766785 TI - Primary pulmonary angiosarcoma: Three case reports and literature review. AB - Primary pulmonary angiosarcoma is a rare type of malignant vascular tumor with a very aggressive clinical course and a grim prognosis. To date, only a handful of cases have been reported in English literature. Its rarity and consequent low index of suspicion makes clinical diagnosis difficult. In this report we present three cases of primary pulmonary angiosarcoma with cough, hemoptysis, and progressive dyspnea to contribute to the sparse literature on this disease. A review is made of previous reports of primary pulmonary angiosarcomas, and the clinical characteristics, diagnosed method, treatment options, and prognosis of pulmonary angiosarcoma are also discussed. PMID- 27766786 TI - Cytopathological findings of primary pulmonary Ewing family of tumors with EWSR1 translocation: A case report. AB - Primary pulmonary neoplasms of the Ewing family of tumors (EFT) are extremely rare and usually occur in adolescents or young adults. Only about 40 cases of pulmonary EFT have been reported in English literature, and no cytological studies have been documented. In this report, we describe the cytopathological findings of a primary pulmonary EFT in an elderly patient. A 70-year-old man sought care because of a progressing cough and dyspnea. Chest computed tomography revealed a circumscribed mass of 6 cm in the left upper lobe. Fine needle aspiration cytology and core needle biopsy revealed uniform round cell proliferation. The predominant population consisted of cells with thickened nuclear membranes, finely dispersed chromatin, single distinct nucleoli, and indistinct cytoplasm. The other population consisted of smaller cells with darker chromatin. The cytoplasm stained positive for periodic acid-Schiff stain and was digested by diastase. Immunohistochemistry showed positivity for MIC2 (CD99), and focal positivity for neuron specific enolase, synaptophysin, and chromogranin A. Fluorescence in situ hybridization (FISH) revealed EWSR1 translocation. Although rare, pulmonary EFT cannot be disregarded, regardless of age. When two populations of uniform, round cells are observed, immunohistochemistry with MIC2 (CD99) and cytogenetic analysis by reverse transcription polymerase chain reaction or FISH should be considered. Cytological diagnosis may play an important role in the early diagnosis and treatment of pulmonary EFT. PMID- 27766787 TI - Prognostic factors in patients after definitive chemoradiation using involved field radiotherapy for esophageal cancer in a phase II study. AB - BACKGROUND: A prospective study was performed on the use of chemoradiotherapy (CRT) for esophageal cancer (EC) with involved-field radiation therapy (IFRT), based on 18-fluorodeoxyglucose positron-emission tomography. Prognostic factors for overall survival (OS) were analyzed. METHODS: Eligible patients included 63 adults with newly diagnosed, untreated, inoperable stage I-IV EC with lymph node metastases. Patients received 80 mg/m2 nedaplatin per day on day 1, 800 mg/m2 5 fluorouracil on days 1-4 intravenously repeated every 28 days for two to four cycles, and combined IFRT. Irradiation was applied only to the primary tumor and positive lymph nodes. RESULTS: Three-year progression-free survival and OS rates were 44.9% and 47.5%, respectively. The median survival time was 31.5 months. In univariate analyses for OS, Karnofsy Performance Scale <90% (P = 0.027), initial stage (P = 0.0087), T stage (P = 0.066), N stage (P = 0.000086), M stage of M1 (P = 0.0042), dysphagia score (P = 0.00017), tumor marker squamous cell carcinoma antigen >1.5 ng/mL (P = 0.0054), gross tumor volume (GTV) > 60 cc (P = 0.00011), and relative dose intensity (RDI) of chemotherapy <=50% (P = 0.063) were found to be associated with significantly or marginally worse OS. In multivariate analyses for OS, GTV >= 60 cc (P = 0.00040), RDI < 50% (P = 0.00034), and cN2-3 (P = 0.0020) were associated with significantly worse OS. CONCLUSION: GTV, RDI and N grading, were associated with OS after definitive CRT using IFRT for EC. PMID- 27766789 TI - NANDA-I NIC and NOC, the EHR, and Meaningful Use. PMID- 27766788 TI - A mortality study of beryllium workers. AB - We aimed at investigating mortality among beryllium-exposed workers, according to solubility of beryllium and beryllium compounds. We conducted an historical cohort study of 16,115 workers employed during 1925-2008 in 15 facilities, including eight entailing exposure to insoluble beryllium and seven entailing exposure to soluble/mixed beryllium compounds, who were followed up for mortality until 2011. Data were analyzed using indirect standardization and Cox regression modeling. Lung cancer standardized mortality ratio (SMR, national reference rates) was 1.02 (95% confidence interval [CI]: 0.94-1.10) in the whole cohort, 0.88 (95% CI: 0.75-1.03) in the insoluble beryllium subcohort, and 1.09 (95% CI: 0.99-1.09) in the soluble/mixed beryllium subcohort. For lung cancer, there was an association with period of hire in soluble/mixed beryllium plants but not in insoluble plants, and, conversely, employment in soluble/mixed plants was associated with increased mortality only among workers hired before 1955. There was no trend with duration of employment. Mortality from chronic beryllium disease increased, in particular, among workers hired before 1955 in soluble/mixed beryllium facilities. There was no increase in lung cancer mortality in the entire cohort and lung cancer mortality was not increased among beryllium workers hired in 1955 or later in soluble/mixed beryllium facilities, or at any time among those employed in insoluble beryllium facilities. PMID- 27766790 TI - Risk Factors for the Development and Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Advanced Diabetic Retinopathy. AB - BACKGROUND: Some patients with type 2 diabetes mellitus (T2DM) do not develop diabetic kidney disease (DKD) despite the presence of advanced diabetic retinopathy (DR). We aimed to investigate the presence of DKD and its risk factors in patients with T2DM and advanced DR. METHODS: We conducted a cross sectional study in 317 patients with T2DM and advanced DR. The phenotypes of DKD were divided into three groups according to the urine albumin/creatinine ratio (uACR, mg/g) and estimated glomerular filtration rate (eGFR, mL/min/1.73 m2): no DKD (uACR <30 and eGFR >=60), non-severe DKD (uACR >=30 or eGFR <60), and severe DKD (uACR >=30 and eGFR <60). Mean systolic and diastolic blood pressure, mean glycosylated hemoglobin (HbA1c) level, and HbA1c variability (standard deviation [SD] of serial HbA1c values or HbA1c-SD) were calculated for the preceding 2 years. RESULTS: The prevalence of no DKD, non-severe DKD, and severe DKD was 37.2% (n=118), 37.0% (n=117), and 25.8% (n=82), respectively. HbA1c-SD and the triglyceride/high density lipoprotein cholesterol (TG/HDL-C) ratio correlated positively with uACR and negatively with eGFR. Multiple linear regression analyses showed that the HbA1c-SD and TG/HDL-C ratio were significantly related with eGFR. Multiple logistic regression analyses after adjusting for several risk factors showed that HbA1c-SD and the TG/HDL-C ratio were significant risk factors for severe DKD. CONCLUSION: The prevalence of DKD was about 60% in patients with T2DM and advanced DR. HbA1c variability and TG/HDL-C ratio may affect the development and progression of DKD in these patients. PMID- 27766791 TI - Factors Associated with Participation in Diabetes Education: The Korea National Health and Nutrition Examination Survey 2007 to 2009. AB - BACKGROUND: A recent study revealed that the participation rate in diabetes education among diabetic patients was only about 50% in Korea. We investigated the factors associated with participation in diabetes education. METHODS: The study included 1,255 patients (>=19 years old) diagnosed with diabetes drawn from the total Korea National Health and Nutrition Examination Survey 2007 to 2009 population comprising 30,705 individuals. We compared age, sex, and age- and sex adjusted clinical characteristics in patients who had received diabetes education versus those who had not. RESULTS: Of the 1,255 patients, 19.8% (n=248) had received diabetes education. Patients in the group who received diabetes education were younger, diagnosed at an earlier age, had a longer diabetes duration and were more likely to be using insulin therapy compared with the group who did not receive diabetes education (P<0.001). The group who received diabetes education included fewer manual workers (P<0.001) but more college graduates (P=0.004) compared with the group who did not receive diabetes education. Logistic regression analysis revealed that longer diabetes duration increased the likelihood of receiving diabetes education (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.06; P=0.004). Junior high school (OR, 0.47; 95% CI, 0.24 to 0.91; P=0.026) and elementary school education levels (OR, 0.34; 95% CI, 0.17 to 0.65; P=0.001) versus college graduation were inversely correlated with participation in diabetes self-management education. Non-insulin therapy reduced the likelihood of receiving diabetes education (OR, 0.37; 95% CI, 0.21 to 0.64; P<0.001). CONCLUSION: Longer diabetes duration, insulin therapy, and higher education level were positively associated with the completion of diabetes education. PMID- 27766792 TI - Baseline-Corrected QT (QTc) Interval Is Associated with Prolongation of QTc during Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: We investigated an association between baseline heart rate-corrected QT (QTc) interval before severe hypoglycemia (SH) and prolongation of QTc interval during SH in patients with type 2 diabetes mellitus (T2DM). METHODS: Between January 2004 and June 2014, 208 patients with T2DM, who visited the emergency department because of SH and underwent standard 12-lead electrocardiography within the 6-month period before SH were consecutively enrolled. The QTc interval was analyzed during the incidence of SH, and 6 months before and after SH. QTc intervals of 450 ms or longer in men and 460 ms or longer in women were considered abnormally prolonged. RESULTS: The mean age and diabetes duration were 68.1+/-12.1 and 14.1+/-10.1 years, respectively. The mean QTc intervals at baseline and SH episodes were 433+/-33 and 460+/-33 ms, respectively (P<0.001). One hundred and fourteen patients (54.8%) had a prolonged QTc interval during SH. There was a significant decrease in the prolonged QTc interval within 6 months after SH (QTc interval prolongation during SH vs. after recovery, 54.8% vs. 33.8%, P<0.001). The prolonged QTc interval was significantly associated with baseline QTc interval prolongation (odds ratio, 2.92; 95% confidence interval, 1.22 to 6.96; P=0.016) after adjusting for multiple confounders. CONCLUSION: A prolonged QTc interval at baseline was significantly associated with prolongation of the QTc interval during SH in patients with T2DM, suggesting the necessity of QTc interval monitoring and attention to those with a prolonged QTc interval to prevent SH. PMID- 27766793 TI - Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea. AB - BACKGROUND: We investigated clinical course and risk factors for diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 759 patients with T2DM without DR were included from January 2001 to December 2004. Retinopathy evaluation was performed at least annually by ophthalmologists. The severity of the DR was classified into five categories according to the International Clinical Diabetic Retinopathy Severity Scales. RESULTS: Of the 759 patients, 523 patients (68.9%) completed the follow-up evaluation. During the follow-up period, 235 patients (44.9%) developed DR, and 32 patients (13.6%) progressed to severe nonproliferative DR (NPDR) or proliferative DR (PDR). The mean duration of diabetes at the first diagnosis of mild NPDR, moderate NPDR, and severe NPDR or PDR were 14.8, 16.7, and 17.3 years, respectively. After adjusting multiple confounding factors, the significant risk factors for the incidence of DR risk in patients with T2DM were old age, longer duration of diabetes, higher mean glycosylated hemoglobin (HbA1c), and albuminuria. Even in the patients who had been diagnosed with diabetes for longer than 10 years at baseline, a decrease in HbA1c led to a significant reduction in the risk of developing DR (hazard ratio, 0.73 per 1% HbA1c decrement; 95% confidence interval, 0.58 to 0.91; P=0.005). CONCLUSION: This prospective cohort study demonstrates that glycemic control, diabetes duration, age, and albuminuria are important risk factors for the development of DR. More aggressive retinal screening for T2DM patients diagnosed with DR should be required in order to not miss rapid progression of DR. PMID- 27766796 TI - Cryptococcosis: The Ubiquitous Yeast. PMID- 27766797 TI - Clinical Diversity of CNS Cryptococcosis. AB - BACKGROUND: Though cryptococcal meningitis (CM) is recognized as a disease of the immunocompromised, studies have implicated that it also affect immunocompetent patients. METHODOLOGY: This was a cross sectional study conducted in the Department of Medicine of a tertiary teaching institution in North India. All the patients diagnosed with CM on the basis of detection of cryptococcal antigen or the presence of capsulated budding yeast cells on India ink preparation, from April 2009 to March2015 were included in the study. Demographical profile, clinical presentation, predisposing factors, CSFcharacteristics, imaging abnormalities and in patient outcome were noted and analyzed. RESULTS: Among the 40 patients diagnosed with CM, 62.5% of them were males. Patients who were immunocompetent constituted 20%, those with predisposing factors other than HIV were 25% and55% had HIV infection (initial presentation in 59%). Mean age of presentation was 44.75 +/- 15.58 years. Mean duration of symptoms in all three groups varied from few days to 4-5 weeks. Clinical presentations included fever (16), headache (14), altered sensorium (16), seizures (5), paraparesis (4), hemiparesis (2), lateral rectus palsy (3), VII nerve palsy (2), bilateral vision loss with ptosis (1) and ataxia (1). Neck stiffness was present in 50% patients of immunocompetent group, 45.45% of HIV patients and none in the 3rd group. Acellular CSF (37.5%) was not unusual. Mean CSF white cell count in HIV patients, in other immunocompromised patients and immunocompetent patients were 100+/- 158.53, 36.88 +/- 92.43 and 32.5 +/- 62.05 /mm3 respectively which was predominantly lymphocytic. Mean CSF protein were 136.73 +/- 139.82, 62.67 +/- 51.11 and 152.29 +/- 218.24 g/dl in these groups. Abnormalities detected on imaging included, meningeal enhancement, encephalomalacia, infarct, cerebellitis, hydrocephalus, cord hyper intensities and cervical spine intramedullary lesion. Mortality rate in CM patients was 20%. On mortality analysis, death was mostly attributed to the primary disease. CONCLUSIONS: Clinical presentation of CM in both immunocompetent and immunocompromised patients was similar. Though previous studies noted less inflammation in immunocompromised patients, in this series it was noted that both immunocompromised and immunocompetent patients mounted similar inflammatory response. Since the presentation of CM is variable, all cases of meningitis should be screened for the same. PMID- 27766795 TI - Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment. AB - BACKGROUND: There were a limited number of studies about beta-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of beta-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. METHODS: In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. RESULTS: Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. CONCLUSION: Long-acting basal insulin replacement could improve the glycemic status and restore beta-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain. PMID- 27766794 TI - Risk Factors and Adverse Outcomes of Severe Hypoglycemia in Type 2 Diabetes Mellitus. AB - Hypoglycemia has been considered as a major barrier to achieving the proper glycemic target in type 2 diabetes mellitus patients. In particular, severe hypoglycemia (SH), which is defined as a hypoglycemic episode requiring the assistance of another person to raise the patient's glucose level, is a serious complication of diabetes because of its possible fatal outcomes. Recently, the recommendations for diabetes care have emphasized a patient-centered approach, considering the individualized patient factors including hypoglycemia. Many studies have been performed which analyzed the risk factors and clinical outcomes for SH. From the studies, researchers recommend that targeting a less stringent glycosylated hemoglobin level and selecting a safer class of drugs for hypoglycemia are appropriate for patients with a high risk of SH. Also, careful clinical attention to prevent hypoglycemia, including intensive education, is necessary to minimize the risk of SH and SH-related fatal outcomes. PMID- 27766798 TI - To Study Efficacy of Medical Thoracoscopy in Undiagnosed Pleural Effusions. AB - BACKGROUND: Medical thoracoscopy has received interest in recent past for diagnostic as well as therapeutic uses. In this study we describe our experience with diagnostic medical thoracoscopy in pleural effusions of undiagnosed etiology. OBJECTIVE: 1.To detect diagnostic yield of medical thoracoscopy in pleural effusions of unknown etiology. 2.To find complication rate in these patients. METHODOLOGY: In a retrospective analysis of thoracoscopic procedures performed between March 2011 and December 2014, diagnostic yield and complications of thoracoscopic pleural biopsy for achieving a diagnosis in undiagnosed pleural effusions were evaluated. STATICAL ANALYSIS: Statistical analysis of all 60 patients underwent thoracoscopy was done and findings expressed in terms of percentages. RESULTS: A total of 60 patients (40 males and 20 females; mean age 45 years) underwent diagnostic pleuroscopy. Tuberculosis was diagnosed in 28 patients, Malignancy was found in 26 patients, three patients had pyogenic infections(empyema) and it was non diagnostic in three patients. There were no major complications, minor complications were observed in 10 patients(17%). INTERPRETATIONS: The diagnostic yield of medical thoracoscopy in our study was 95%. Minor complications were noted in ten patients (17%). CONCLUSIONS: Medical thoracoscopy is a valuable tool in the diagnosis of undiagnosed exudative pleural effusion. It is a simple and safe method with high diagnostic yield and with low complication rates. PMID- 27766800 TI - Cardiometabolic Risk Factors in Acute Coronary Syndrome with Special Reference to Non-HDL Cholesterol. AB - INTRODUCTION: Cardiovascular diseases are becoming the major cause of morbidity and mortality in most of the developing countries including India. Cardiometabolic risk factors play a vital role in causation of coronary artery disease. Present study was carried out to investigate the role of various risk factors in the occurrence of coronary artery disease (CAD) in population from Central India. SETTING AND DESIGN: This was a hospital-based age and sex matched case-control study, carried out at Lata Mangeshkar Hospital, Nagpur. MATERIAL AND METHODS: A total of 100 newly diagnosed cases of CAD and equal number of age and sex matched controls were studied. Patients and controls were screened for presence of traditional cardio metabolic risk factors. In addition, non-HDL-C was calculated in all the subjects. Significance of association between various risk factors and study groups was evaluated using Chi-square test. Odds ratios were obtained as a measure of risk associated with each factor. Unconditional multivariate logistic regression was used to obtain adjusted odds ratios. RESULTS: Males outnumber females with most of the cases belonged to age group of 51-60 years. Significant association was found between CAD and risk factors like hypertension, DM, dyslipidemia, smoking, tobacco consumption, WHR and BMI. With the increasing prevalence of CAD, it is pertinent to educate people, about the risk associated with key modifiable factors. An effective control on these factors may help in controlling occurrence of CAD to significant extent. PMID- 27766799 TI - Seroprevalence of Toxoplasma gondii Among Pregnant Women in Northeast India. AB - OBJECTIVE: Toxoplasma gondii infection is primarily asymptomatic and one third of world's population is estimated to be infected by this protozoan parasite. This study was carried out to determine the seroprevalence of T. gondii infection among pregnant women from north east India, where data on this important parasitic infection is scanty. METHODS: A total of 1141 serum archival samples collected from antenatal clinic attendees in 2007-09, were screened for T. gondii IgG by ELISA and analyzed with their socio demographic information. RESULTS: The median age of the subjects were 25 years with an overall IgG seroprevalence of 48% (95% CI=45% to 51%). Seroprevalence was significantly associated with geographical location (p=0.000), among Mongoloids compared to Caucasoid (p=0.005), regular employees (p=0.003) or unskilled labors (p=0.04) compared to housewives, high or middle income group (p=0.003) compared to low income group and with increasing gravida (p=0.04). However on logistic regression analysis, only significant association was with geographical location (p=0.000) and occupation (unskilled labor) (p=0.04). Highest prevalence of 66.7% was noted among subjects with history of blood transfusion and lowest among Rh negative blood group (14.3%). CONCLUSIONS: T. gondii infection prevalence is high among pregnant women living in hilly states of northeast India, which warrants a detail investigation on congenital toxoplasmosis as well as its economic impact. PMID- 27766801 TI - Dengue Outbreak 2012: Geo Mapping and Snapshot of Clinical Course from a Tertiary Referral Center in South India. AB - BACKGROUND: Using technology to track endemic areas of communicable diseases is possible nowadays. Effectual use of such facilities, especially in developing countries, will increase earlier detection of cases as well as aid in the formulation of effective prevention strategies. METHODS: A retrospective data analysis was carried out by collecting the details of patients presented with positive dengue serology, during the outbreak season in the second half of 2012, at Kovai Medical Center and Hospital, Coimbatore, India. Clinical variables were analysed statistically using SPSS 20 and geographical mapping of the cases was carried out using EPI INFO 7 software. RESULTS: 1004 dengue positive cases were identified during the study period. Geographical mapping of the case clusters showed specific areas in the city as well as neighbouring districts, which were an indirect evidence of the causative mosquito's endemic breeding places. Overall mortality noted in this group was 1.3% and mortality in cases with severe thrombocytopenia was 4 in 1000 cases. Severe thrombocytopenia (Plat<= 10,000) on admission increased odds ratio for mortality i.e. around 10 times higher than the rest of the cohorts. CONCLUSIONS: Identification of endemic mosquito breeding places and implementation of proper preventive measures is always a crucial step in the prevention of further outbreaks. Effective registry using softwares by tertiary care hospitals will be obligatory to track the location of the cases as these hospitals are the nodal point of care for most of the cases in developing countries. PMID- 27766802 TI - Infection Associated Secondary Hemophagocytic Lymphohistiocytosis in Sepsis Syndromes - A Tip of an Iceberg. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare, underdiagnosed, fatal and devastating hyperinflammatory syndrome that has gained increasing recognition over the past decade. Patients with HLH present with clinical and laboratory evidence of uncontrolled inflammation. Delay in diagnosis and management inevitably leads to a rapidly progressive and fatal course. In this case series, we present 7 cases of secondary HLH (sHLH) in adults with their presentation, course, and outcomes. MATERIAL AND METHODS: We retrospectively looked at the 7 cases of secondary HLH who were diagnosed and managed in our institute between January 2013 and august 2015. Medical records were retrieved from medical records department and data analyzed and tabulated. The median age at diagnosis was 35 years (age range 26-72 years). Diagnosis was based on HLH 2004 diagnostic criteria. RESULTS: We report profile of 7 adult patients with sHLH. All patients had a short history of illness (<2 weeks) and presented uniformly with prolonged fever, bi or trilineage cytopenia and multiorgan dysfunction syndrome (MODS) at admission or developed MODS during the course of their illness. None of them had prediagnosed HLH. All patients fulfilled 5 to 6 of 8 criteria as per HLH 2014 diagnostic criteria. The median length of hospital stay was 12 days (range 7-50 days) and the median time to diagnosis was 5 days (range 3 to 21 days). Mortality was 57%. CONCLUSIONS: HLH is a rare and under diagnosed clinical syndrome and is rapidly fatal if not diagnosed and managed timely. The cases reported in literature probably represent a tip of an iceberg of large number of undiagnosed cases mostly labeled as sepsis with MODS in critical care units. sHLH should be suspected in any patient who present with persistent and prolonged fever, transaminitis, cytopenia, and high serum Ferritin or dramatically rising serial serum Ferritin. Early diagnosis and prompt aggressive treatment are vital for patients' survival and favorable outcome. PMID- 27766803 TI - Detection, Management Approach of Depression and Antidepressant Utilization in Adult Patients: Results of a Cross-Sectional Survey. AB - AIM: The study was conducted to understand the demographics, prevalence of co morbid conditions and treatment modalities of depression. METHODS: A cross sectional, nationwide observational study was conducted to understand the management pattern of depression in India. Depression was majorly diagnosed with DSM-IV TR criteria. RESULTS: The data of 2276 Indian patients across 18 states were collected through 135 mental health professionals. The study population was predominantly from urban (81.2%) area. The prevalence of uneducated and employed patients in the study was 7.2% and 54.6% respectively. The main co-morbidities observed were diabetes, hypertension, anxiety and insomnia. Overall, escitalopram monotherapy was used in 67.2% patients. Escitalopram was found to be the preferred antidepressant in patients with co-morbid conditions including hypertension and diabetes. Counseling was the most common non-pharmacological therapy practiced. CONCLUSIONS: This large cross sectional study in real life settings demonstrates high prevalence of depression among employed and educated adult Indian patients. Hypertension and diabetes are the two most common co morbidites in patients with depression. Escitalopram is commonly used and preferred antidepressant in all studied age groups and even in co-morbid depression. PMID- 27766804 TI - Stroke Prevention in Atrial Fibrillation - Which is the BEST?: Balanced in Efficacy and Safety as a Thromboprophylactic. AB - Stroke prevention in atrial fibrillation (AF) has reached an exciting phase with a plethora of newer, potentially more efficacious and safer agents being introduced for physicians to select from. Dabigatran belongs to a class of anticoagulants called direct thrombin inhibitors, while rivaroxaban, apixaban, and edoxaban are direct Factor Xa inhibitors. Purely from a therapeutic endpoint perspective-based on the action of anticoagulants in reducing cardioembolic stroke-in clinical trials, one should look at whether a new anticoagulant in patients with AF prevents ischemic stroke. From a net clinical benefit perspective, one evaluates both efficacy and safety, which is when one includes association of stroke prevention with: hemorrhagic stroke; major, intracranial, life-threatening or total bleeding, etc. Interestingly, so far only dabigatran 150mg bid has been shown to be superior to well controlled warfarin in reducing the risk of ischemic stroke in patients with AF. Apixaban 5 mg bid, dabigatran 110 mg bid and both doses of edoxaban were superior to well controlled warfarin in being associated with a lower incidence of major bleeding. Apixaban 5 mg bid and edoxaban 30 mg od were superior to well controlled warfarin in reducing all cause mortality. Clinicians will need to judiciously prescribe the right drug for the right patient, keeping many factors in consideration, and individualize the therapy based on underlying comorbidities and response to therapy. PMID- 27766805 TI - Samples and their Size: The Bane of Researchers (Part II). PMID- 27766806 TI - Time to Revisit Recommendations on Doctor to Population Ratio in India. AB - A buzzword in Indian press and amongst the policy makers is that India is short of the WHO recommended doctor to population ratio of 1:1000. The recommendations were formulated to facilitate programs to achieve some of the health related UN Millennium Development Goals (MDGs). Infections and malnutrition, which can be comfortably handled by a basic MBBS doctor, were the dominant health issues at the time of the formulation of the MDGs. However, all countries worldwide are going through health epidemiological transition and health impact of the non communicable disorders (NCDs) can be no more ignored even by the low income nations. Very soon India will need large number of specialists and super specialists to meet the challenge posed by the avalanche of NCDs, as an ordinary MBBS is not trained to handle the NCDs. One of the major flaws in the recommendations is that for the purposes of computation of the ratio, doctors of all hue, basic doctors, specialists and super-specialists are lumped together. It is time to define the requirements discipline wise and tailor medical education to produce specialists and super-specialists on a fast track. Expansion of specialization in medicine should be associated with simultaneous strengthening of primary health care, a challenged faced even by the most developed nations. To provide health services for routine minor health problems a cadre of Nurse Practitioners (NPs), a concept developed 50 years ago in the USA and now endorsed by many nations, could be adopted. PMID- 27766807 TI - Kallmann Syndrome and Chronic Myeloid Leukemia: A Rare Occurrence. PMID- 27766808 TI - A Case of Lividoid Vasculopathy. PMID- 27766809 TI - Cavitating Lung Lesions with Encephalopathy in a Patient with Long Standing Sjogren's Syndrome: An Elusive Cause. AB - A known case of primary Sjogren's syndrome with chronic kidney disease presented with respiratory symptoms and subsequent altered sensorium. Chest imaging suggested cavitating lung lesions in both the lungs. Serum c-ANCA was positive without any upper respiratory tract involvement or active urinary sediments. Treatment with appropriate anti-microbials produced no improvement in the respiratory or neurological parameters. MRI brain revealed tell-tale signs of CNS vascultis. A diagnosis of GPA was made as per European Medical Agency algorithm and the patient was started on immune-suppressants to which there was dramatic response. Her respiratory and neurological parameters started recovering steadily. However her stay at hospital was complicated by severe hospital acquired pneumonia to which she succumbed. We review the intricacies of the case, discussing the diagnostic conundrum and treatment dilemma we faced, as well as the systematic approach employed to manage the patient. PMID- 27766810 TI - Pleural Lymphoma Presenting as Chylothorax. AB - Pleural disease in Non-Hodgkin's Lymphoma is well documented and commonly presents with pleural effusion in 20% of patients. However, solid pleural involvement is less common and is usually a secondary event. Primary pleural lymphomas are extremely rare. Hereby we report a rare case of primary pleural lymphoma presenting as chylothorax. PMID- 27766811 TI - Myopathy: Effect of Vitamin D Deficiency Beyond Bones. AB - Vitamin D functions as a vitamin as well as a hormone. Its major skeletal actions are complemented by varied extra-skeletal functions. During the past decade, association between Vitamin D and its role in various non-skeletal morbidities have been recognized. It plays a role in decreasing the risk of many chronic illnesses like allergies, asthma, autoimmune diseases, diabetes, cancers, infections and cardiovascular disease. We report the case of a middle aged female with chronic quadriparesis and new onset anemia associated with Vitamin D deficiency. Patient responded to vitamin D supplementation alone. PMID- 27766812 TI - Bottle Gourd (Lagenaria Siceraria) Juice Poisoning. AB - We present the case of a young woman who presented to us with multiple episodes of vomiting, followed by hematemesis and abdominal pain after consuming bottle gourd juice. The patient was resuscitated and stabilized with fluids, proton pump inhibitors and antiemetics and discharged in stable condition. As a member of the Cucurbitaceae family, bottle gourd contains toxic tetracyclic triterpenoid compounds called cucurbitacins which are responsible for the bitter taste and toxicity. There is no known antidote for this toxicity, and clinicians treat such patients symptomatically only. PMID- 27766813 TI - Familial Lecithin Cholesterol Acyl Transferase Deficiency with Chronic Kidney Disease. AB - Familial lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive (AR) disease caused by mutation in the LCAT gene. LCAT enzyme esterifies cholesterol molecules in high-density lipoprotein(HDL) and low density lipoprotein (LDL) particles. This enzyme deficiency is characterised by progressive corneal opacification, glomerulopathy, mild - moderate haemolytic anaemia and very low plasma levels of HDL. We here report a 34 year-old lady who presented with hypertension, nephrotic proteinuria, renal failure, corneal ring opacities, anemia and dyslipidemia. The diagnosis of familial LCAT deficiency was confirmed by clinical examination, characteristic dyslipidemia, undetectable LCAT levels in plasma and positive family history. PMID- 27766814 TI - Alstrom Syndrome with Portal Hypertension. AB - Alstrom syndrome is an autosomal recessive multisystem disorder caused by mutation in ALMS1 (2p13). Very few cases of same are reported so far of same. We report a case of Alstrom syndrome (AS) who presented with type II diabetes mellitus and portal hypertension. Unilateral anorchia with hypergonadotropic hypogonadism is another unique feature of our case. PMID- 27766815 TI - Rosai-Dorfman Disease. AB - A young male presented with recurrent neck swellings with initial leucocyte count of 16800/mm3, with non-caseating glands on ultrasonography neck. FNAC showed mixed cellularity with histiocytic and marked lymphophagocytosis as seen in Rosai Dorfman Disease. Immunohistochemistry demonstrated CD 25, Ki 67 and CD 68 in histiocytes. Her responded to supportive treatment alone. PMID- 27766816 TI - Synchronous Dual Primary Malignancies of Liver and Pancreas with Colonic Metastasis: An Unique Presentation. AB - Synchronous appearance of the primary gastrointestinal malignancies is rare. Coexistence of primary pancreatic and hepatocellular carcinoma as synchronous malignancy is even rarer. We report a case of such combination in a 50 year old female who presented with bleeding per rectum and while evaluating we found simultaneous appearance of primary malignancies of pancreas, liver and solitary colonic metastasis from the pancreas in the background of chronic calcific pancreatitis. To the best of our knowledge this combination of synchronous pancreatic and hepatocellular carcinoma and colonic metastasis from the pancreas is unique. PMID- 27766817 TI - Successful Management of Elizabethkingia meningoseptica Meningitis with Intraventricular Vancomycin. AB - Elizabethkingia meningoseptica, formerly Chryseobacterium meningosepticum usually causes neonatal meningitis and is a rare cause of nosocomial meningitis in adults. E. meningoseptica is resistant to most antibiotics, and the use of inactive drugs as empirical therapy may contribute to poor outcome in many patients. Vancomycin, alone or in combination with rifampicin, has been successful in the treatment of meningitis in infants1. We present a case of E. meningoseptica meningitis in an adult who was treated initially with intravenous vancomycin and oral rifampicin, but did not respond to the treatment. Thereafter, intraventricular vancomycin was added which resulted in good treatment response. PMID- 27766818 TI - Simultaneous Plaque Rupture in Two Coronary Arteries Presenting as Acute Coronary Syndrome. AB - A 45 yrs male presented with angina. ECG showed transient CHB, T wave inversion in V3 to V6 and inferior leads. It was difficult to predict the culprit vessel based on ECG. Coronary angiography showed thrombotic lesions in LAD, LCX and OM which can potentially impact identification of culprit vessel and hence affect the management with primary PCI. PMID- 27766819 TI - Rasmussen Aneurysm. AB - Angiographic findings in tuberculosis patients presenting with hemoptysis include hypervascularity, hypertrophy of systemic arteries, aneurysm, systemic to pulmonary anastomosis, and rarely, contrast extravasation. Bronchial arteries are the source of hemorrhage in majority of cases with non-bronchial systemic or pulmonary arteries being less common as the source. Rasmussen's Aneurysm is a very rare sequalae of Pulmonary Tuberculosis. We present one such case of Rasmussen's aneurysm and review of the relevant literature. PMID- 27766820 TI - Acute Scrotal Edema: An Atypical Manifestation of Dengue. AB - Acute scrotal edema associated with dengue fever is a rare and self limiting condition resolving in a few days without any complication or sequelae. We report two cases of dengue fever in father and son which presented simultaneously with acute scrotal edema. PMID- 27766821 TI - Gitelman Syndrome: Presenting During Pregnancy with Adverse Foetal Outcome. AB - Gitelman syndrome (GS) is a rare autosomal recessive salt-losing tubulopathy. The incidence of Gitelman syndrome is 25 cases in 1 million among western population. This patient presented with loose stool, vomiting and sudden onset quadriparesis. Investigations revealed hypokalaemia, metabolic acidosis, hypomagnesaemia, hypocalciuria, hypermagnesuria. Symptoms and hypokalemia improved after starting oral magnesium and potassium supplements. But the patient again presented with symptomatic hypokalemia and delivered a still born foetus with hydrocephalus. Patient was put on potassium sparing diuretics along with supplements and thereafter, has been asymptomatic. There have been very few case reports on Gitelman syndrome in pregnancy and most of them show favourable outcomes. This is a rare case report of a pregnant female with Gitelman syndrome with foetal loss. PMID- 27766822 TI - Kallman Syndrome. AB - Kallman syndrome (KS) is a rare genetic disorder characterized clinically by failure to attain puberty or failure to fully complete it along with an absent or impaired sense of smell with absence of bilateral olfactory bulbi and sulci alongwith absent olfactory tracts. Only very few cases of Kallman syndrome have been reported in females in Indian population. PMID- 27766823 TI - Indian Neurologists. PMID- 27766824 TI - Svante Arrhenius & Ionic Dissociation of Electrolytes. PMID- 27766825 TI - Dandy Walker Syndrome: A Rare Presentation in Adult. PMID- 27766826 TI - Sinus Node Dysfunction: A Rare Side Effect of Tigecyclin. PMID- 27766827 TI - Behcet's Disease Dilemma! PMID- 27766828 TI - Zoonotic influenza viruses: antigenic and genetic characteristics and development of candidatevaccine viruses for pandemic preparedness. PMID- 27766830 TI - Zero-Point Energy Leakage in Quantum Thermal Bath Molecular Dynamics Simulations. AB - The quantum thermal bath (QTB) has been presented as an alternative to path integral-based methods to introduce nuclear quantum effects in molecular dynamics simulations. The method has proved to be efficient, yielding accurate results for various systems. However, the QTB method is prone to zero-point energy leakage (ZPEL) in highly anharmonic systems. This is a well-known problem in methods based on classical trajectories where part of the energy of the high-frequency modes is transferred to the low-frequency modes leading to a wrong energy distribution. In some cases, the ZPEL can have dramatic consequences on the properties of the system. Thus, we investigate the ZPEL by testing the QTB method on selected systems with increasing complexity in order to study the conditions and the parameters that influence the leakage. We also analyze the consequences of the ZPEL on the structural and vibrational properties of the system. We find that the leakage is particularly dependent on the damping coefficient and that increasing its value can reduce and, in some cases, completely remove the ZPEL. When using sufficiently high values for the damping coefficient, the expected energy distribution among the vibrational modes is ensured. In this case, the QTB method gives very encouraging results. In particular, the structural properties are well-reproduced. The dynamical properties should be regarded with caution although valuable information can still be extracted from the vibrational spectrum, even for large values of the damping term. PMID- 27766831 TI - Interactions between Algal Extracellular Polymeric Substances and Commercial TiO2 Nanoparticles in Aqueous Media. AB - The implications of engineered nanomaterials (ENMs) in the environment are often investigated using pristine particles. However, there are several biogenic and geogenic materials in natural waters that interact with and modify the surface of ENMs, thereby influencing their fate and effects. Here we studied the influence of soluble extracellular polymeric substances (sEPS) produced by freshwater and marine algae on the surface properties and fate of three commercial TiO2 nanoparticles (nTiO2) with different coatings. Adsorption of sEPS by the various nTiO2 is dependent on particle surface area, intrinsic nTiO2 surface charge, and hydrophobicity. Interactions between sEPS and nTiO2 were driven by electrostatic interactions and chemical bonding (bridge-coordination) between the COO- group of sEPS and nTiO2. Charge reversal of positively charged nTiO2 was observed at pH 7 in the presence of 0.5 mg-C/L sEPS. In addition, the critical coagulation concentration (CCC) of nTiO2 increased in the presence of sEPS-from both freshwater and marine sources. CCC of all nTiO2 increased as sEPS concentrations increased. This study shows that naturally occurring sEPS can modify the surface properties and fate of nTiO2 in natural waters, and should be accounted for when predicting the fate and effects of engineered nanomaterials in the environment. PMID- 27766832 TI - Stabilized and Improved Photoelectrochemical Responses of Silicon Nanowires Modified with Ag@SiO2 Nanoparticles and Crystallized TiO2 Film. AB - Semiconductor nanostructure photoelectrochemical (PEC) cells for sunlight conversion have the potential to supply continuous, low-cost, high-efficiency and carbon-free energy; however, in order to provide economically competitive energy, long-time stability and high-efficiency are requisite. In this work, the saturation photocurrent density (Jsat) and stability of the silicon nanowires (SiNWs) in a PEC cell are significantly improved via surface modification with Ag@SiO2 nanoparticles and conformal TiO2 ultrathin film. Compared to the bare SiNWs, a 40% enhancement in Jsat, a cathodic shift of 0.8 V in the applied potential for Jsat, and over 10-h continuous operation with a high photocurrent density without decay are realized by using the properly modified SiNWs. Comparison of minority carrier lifetime indicates that the surface recombination of the modified SiNWs has been effectively suppressed. External quantum efficiency measurements reveal that the superstable and improved PEC responses of the modified SiNWs can be maintained for a broadband spectrum. This work provides an alternative route to the industrial applications for the semiconductor nanostructure PEC cells. PMID- 27766829 TI - Development of Rare Bacterial Monosaccharide Analogs for Metabolic Glycan Labeling in Pathogenic Bacteria. AB - Bacterial glycans contain rare, exclusively bacterial monosaccharides that are frequently linked to pathogenesis and essentially absent from human cells. Therefore, bacterial glycans are intriguing molecular targets. However, systematic discovery of bacterial glycoproteins is hampered by the presence of rare deoxy amino sugars, which are refractory to traditional glycan-binding reagents. Thus, the development of chemical tools that label bacterial glycans is a crucial step toward discovering and targeting these biomolecules. Here, we explore the extent to which metabolic glycan labeling facilitates the studying and targeting of glycoproteins in a range of pathogenic and symbiotic bacterial strains. We began with an azide-containing analog of the naturally abundant monosaccharide N-acetylglucosamine and discovered that it is not broadly incorporated into bacterial glycans, thus revealing a need for additional azidosugar substrates to broaden the utility of metabolic glycan labeling in bacteria. Therefore, we designed and synthesized analogs of the rare deoxy amino d-sugars N-acetylfucosamine, bacillosamine, and 2,4-diacetamido-2,4,6 trideoxygalactose and established that these analogs are differentially incorporated into glycan-containing structures in a range of pathogenic and symbiotic bacterial species. Further application of these analogs will refine our knowledge of the glycan repertoire in diverse bacteria and may find utility in treating a variety of infectious diseases with selectivity. PMID- 27766833 TI - Kinetic and Thermodynamic Analyses of Interaction between a High-Affinity RNA Aptamer and Its Target Protein. AB - AML1 (RUNX1) protein is an essential transcription factor involved in the development of hematopoietic cells. Several genetic aberrations that disrupt the function of AML1 have been frequently observed in human leukemia. AML1 contains a DNA-binding domain known as the Runt domain (RD), which recognizes the RD-binding double-stranded DNA element of target genes. In this study, we identified high affinity RNA aptamers that bind to RD by systematic evolution of ligands by exponential enrichment. The binding assay using surface plasmon resonance indicated that a shortened aptamer retained the ability to bind to RD when 1 M potassium acetate was used. A thermodynamic study using isothermal titration calorimetry (ITC) showed that the aptamer-RD interaction is driven by a large enthalpy change, and its unfavorable entropy change is compensated by a favorable enthalpy change. Furthermore, the binding heat capacity change was identified from the ITC data at various temperatures. The aptamer binding showed a large negative heat capacity change, which suggests that a large apolar surface is buried upon such binding. Thus, we proposed that the aptamer binds to RD with long-range electrostatic force in the early stage of the association and then changes its conformation and recognizes a large surface area of RD. These findings about the biophysics of aptamer binding should be useful for understanding the mechanism of RNA-protein interaction and optimizing and modifying RNA aptamers. PMID- 27766834 TI - From Bioprofiling and Characterization to Bioquantification of Natural Antibiotics by Direct Bioautography Linked to High-Resolution Mass Spectrometry: Exemplarily Shown for Salvia miltiorrhiza Root. AB - Phytochemicals are promising agents in the development of new antibiotics. A streamlined strategy for rapid screening and reliable characterization of antibiotics in botanicals was demonstrated in contrast to the commonly applied chromatographic column fractionation followed by microtiter plate assay. Modern direct bioautography hyphenated to structure elucidation techniques is a straightforward bioanalytical tool, especially if microbiological assays were taken into account. At one go, lipophilic antimicrobials in Salvia miltiorrhiza root samples were analyzed using high-performance thin-layer chromatography (HPTLC) in direct combination with Aliivibrio fischeri and Bacillus subtilis bioassays. The most intense antimicrobials were characterized via HPTLC-high resolution mass spectrometry. As proof of this streamlined strategy, dihydrotanshinone, cryptotanshinone, and tanshinone IIA were identified and also compared with a reference. Two further antimicrobial zones in the bioautograms were tentatively assigned to be methylenetanshinquinone and tetrahydrotanshinone I (or its structural isomer methylenedihydrotanshinquinone). In another run, a validation study was performed for the bioquantification of ciprofloxacin and marbofloxacin via HPTLC-Bacillus subtilis. This pointed out the improved quality of the performance that was reached. Cryptotanshinone was biologically quantified in two S. miltiorrhiza root samples. Antimicrobials without an available reference standard were calculated as cryptotanshinone-bioequivalents. The results were of relevance, as 1 ng of cryptotanshinone was calculated to be bioequivalent to 0.6 ng and 2 ng of the synthetic antibiotics, ciprofloxacin and marbofloxacin, respectively. For the first time, quantitative direct bioautography via HPTLC-B. subtilis was shown as a reliable tool for streamlined bioprofiling of complex samples. PMID- 27766835 TI - Base-Resolution Analysis of 5-Hydroxymethylcytosine by One-Pot Bisulfite-Free Chemical Conversion with Peroxotungstate. AB - 5-Hydroxymethylcytosine (hmC) is an essential intermediate in the active DNA demethylation pathway. Here we report a new base-resolution method for measuring hmC by combining peroxotungstate-mediated oxidation and sequencing analysis. We reveal that an oxidized product of hmC, trihydroxylated thymine (thT), tolerated the incorporation of dATP as a substrate in the process of DNA polymerase elongation. By comparing the results of Sanger sequencing before and after the oxidation, we observed that hmC sites on single-stranded DNAs could be discriminated from unmethylated cytosines. We found that a thermal cycle condition during peroxotungstate treatment enhanced the oxidation reaction of hmC in double-stranded DNA. Furthermore, Illumina sequencing analysis of hmC containing synthetic genome fragments enabled us to identify simultaneously the positions of hmC in base resolution. This bisulfite-free simple hmC detection technique could facilitate the acquisition of epigenomic information. PMID- 27766836 TI - C-H Activation on Co,O Sites: Isolated Surface Sites versus Molecular Analogs. AB - The activation and conversion of hydrocarbons is one of the most important challenges in chemistry. Transition-metal ions (V, Cr, Fe, Co, etc.) isolated on silica surfaces are known to catalyze such processes. The mechanisms of these processes are currently unknown but are thought to involve C-H activation as the rate-determining step. Here, we synthesize well-defined Co(II) ions on a silica surface using a metal siloxide precursor followed by thermal treatment under vacuum at 500 degrees C. We show that these isolated Co(II) sites are catalysts for a number of hydrocarbon conversion reactions, such as the dehydrogenation of propane, the hydrogenation of propene, and the trimerization of terminal alkynes. We then investigate the mechanisms of these processes using kinetics, kinetic isotope effects, isotopic labeling experiments, parahydrogen induced polarization (PHIP) NMR, and comparison with a molecular analog. The data are consistent with all of these reactions occurring by a common mechanism, involving heterolytic C-H or H-H activation via a 1,2 addition across a Co-O bond. PMID- 27766837 TI - Vinylene-Linked Oligothiophene-Difluorobenzothiadiazole Copolymer for Transistor Applications. AB - The synthesis of the novel donor-acceptor monomer 4,7-bis[(E)-2-(5-bromo-3 dodecylylthiophen-2-yl)ethenyl]-5,6-difluoro-2,1,3-benzothiadiazole (FBT-V2T2) is reported. Polymerization with 4,4'-ditetradecyl-5,5'-bistrimethylstannyl-2,2' bithiophene afforded a highly crystalline polymer that aggregated strongly in solution. Polymer films were well ordered resulting in high performance field effect transistors with low onset voltages, negligible hysteresis, high channel current on/off ratios, and peak hole mobilities of up to 0.5 cm2 V-1 s-1. Notably the transistors exhibited close to ideal behavior with extracted mobilities almost independent of gate of voltage. PMID- 27766838 TI - 3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study. AB - Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technology to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithography 3D bioprinter was employed to fabricate a series of bone matrices consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocrystalline hydroxyapatite (nHA). When BrCa cells were introduced into the stromal cell-laden bioprinted matrices, we found that the growth of BrCa cells was enhanced by the presence of osteoblasts or MSCs, whereas the proliferation of the osteoblasts or MSCs was inhibited by the BrCa cells. The BrCa cells co-cultured with MSCs or osteoblasts presented increased vascular endothelial growth factor (VEGF) secretion in comparison to that of monocultured BrCa cells. Additionally, the alkaline phosphatase activity of MSCs or osteoblasts was reduced after BrCa cell co-culture. These results demonstrate that the 3D bioprinted matrix, with BrCa cells and bone stromal cells, provides a suitable model with which to study the interactive effects of cells in the context of an artificial bone microenvironment and thus may serve as a valuable tool for the investigation of postmetastatic breast cancer progression in bone. PMID- 27766839 TI - Polytypism and Unique Site Preference in LiZnSb: A Superior Thermoelectric Reveals Its True Colors. AB - The first example of polytypism in the I-II-V semiconductors has been demonstrated with the synthesis of cubic LiZnSb by a low-temperature solution phase method. This phase exhibits a unique coloring pattern that is novel for this class of compounds. The choice of site configuration has a considerable impact on the band structure of these materials, which in turn affects the transport properties. While the hexagonal polytype has been suggested as a promising n-type and extremely poor p-type thermoelectric material, the cubic analogue is calculated to have high efficiencies for both the n- and p-type derivatives (1.64 and 1.43, respectively, at 600 K). Furthermore, the cubic phase is found to be the energetically favored polytype. This surprising result provides a rationale for the lack of success in synthesizing the hexagonal polytype in either stoichiometric or n-type compositions. PMID- 27766840 TI - Hyperpolarized Multi-Metal 13C-Sensors for Magnetic Resonance Imaging. AB - We introduce hyperpolarizable 13C-labeled probes that identify multiple biologically important divalent metals via metal-specific chemical shifts. These features enable NMR measurements of calcium concentrations in human serum in the presence of magnesium. In addition, signal enhancement through dynamic nuclear polarization (DNP) increases the sensitivity of metal detection to afford measuring micromolar concentrations of calcium as well as simultaneous multi metal detection by chemical shift imaging. The hyperpolarizable 13C-MRI sensors presented here enable sensitive NMR measurements and MR imaging of multiple divalent metals in opaque biological samples. PMID- 27766842 TI - Ion-Catalyzed Synthesis of Microporous Hard Carbon Embedded with Expanded Nanographite for Enhanced Lithium/Sodium Storage. AB - Hard carbons attract myriad interest as anode materials for high-energy rechargeable batteries due to their low costs and high theoretical capacities; practically, they deliver unsatisfactory performance due to their intrinsically disordered microarchitecture. Here we report a facile ion-catalyzed synthesis of a phenol-formaldehyde resin-based hard-carbon aerogel that takes advantage of the chelation effect of phenol and Fe3+, which consists of a three-dimensionally interconnected carbon network embedded with hydrogen-rich, ordered microstructures of expanded nanographites and carbon micropores. The chelation effect ensures the homodispersion of Fe in the polymer segments of the precursor, so that an effective catalytic conversion from sp3 to sp2 carbon occurs, enabling free rearrangement of graphene sheets into expanded nanographite and carbon micropores. The structural merits of the carbon offer chances to achieve lithium/sodium storage performance far beyond that possible with the conventional carbon anode materials, including graphite and mesocarbon microbeads, along with fast kinetics and long cycle life. In this way, our hard carbon proves its feasibility to serve as an advanced anode material for high-energy rechargeable Li/Na batteries. PMID- 27766843 TI - The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems. AB - Allostery plays a fundamental role in most biological processes. However, little theory is available to describe it outside of two-state models. Here we use a statistical mechanical approach to show that the allosteric coupling between two collective variables is not a single number, but instead a two-dimensional thermodynamic coupling function that is directly related to the mutual information from information theory and the copula density function from probability theory. On this basis, we demonstrate how to quantify the contribution of specific energy terms to this thermodynamic coupling function, enabling an approximate decomposition that reveals the mechanism of allostery. We illustrate the thermodynamic coupling function and its use by showing how allosteric coupling in the alanine dipeptide molecule contributes to the overall shape of the Phi/Psi free energy surface, and by identifying the interactions that are necessary for this coupling. PMID- 27766841 TI - Triple Isotope Effects Support Concerted Hydride and Proton Transfer and Promoting Vibrations in Human Heart Lactate Dehydrogenase. AB - Transition path sampling simulations have proposed that human heart lactate dehydrogenase (LDH) employs protein promoting vibrations (PPVs) on the femtosecond (fs) to picosecond (ps) time scale to promote crossing of the chemical barrier. This chemical barrier involves both hydride and proton transfers to pyruvate to form l-lactate, using reduced nicotinamide adenine dinucleotide (NADH) as the cofactor. Here we report experimental evidence from three types of isotope effect experiments that support coupling of the promoting vibrations to barrier crossing and the coincidence of hydride and proton transfer. We prepared the native (light) LDH and a heavy LDH labeled with 13C, 15N, and nonexchangeable 2H (D) to perturb the predicted PPVs. Heavy LDH has slowed chemistry in single turnover experiments, supporting a contribution of PPVs to transition state formation. Both the [4-2H]NADH (NADD) kinetic isotope effect and the D2O solvent isotope effect were increased in dual-label experiments combining both NADD and D2O, a pattern maintained with both light and heavy LDHs. These isotope effects support concerted hydride and proton transfer for both light and heavy LDHs. Although the transition state barrier-crossing probability is reduced in heavy LDH, the concerted mechanism of the hydride proton transfer reaction is not altered. This study takes advantage of triple isotope effects to resolve the chemical mechanism of LDH and establish the coupling of fs-ps protein dynamics to barrier crossing. PMID- 27766844 TI - One-Piece Triboelectric Nanosensor for Self-Triggered Alarm System and Latent Fingerprint Detection. AB - Tactile sensing is of great importance in developing human-machine interface, remote control, and security systems. Here, a self-triggered alarm system based on the one-piece triboelectric nanosensor (TENS) is reported. By using nitrocellulose (NC) membrane as the triboelectric material, the as-designed TENS can not only sensitively respond to physical contacts in a self-triggered mode but also securely detect the third-level details of latent fingerprint. The self triggered idea based on the triboelectric nanogenerator is compatible with intelligent interactive interface. Besides, this TENS can be conveniently fabricated and integrated into arrays at a large scale due to its freestanding, simple, and low-cost characteristics. This work presents alternative perspectives for the practical applications of the multifunctionalized TENS. PMID- 27766845 TI - Improved Performance and Stability of Inverted Planar Perovskite Solar Cells Using Fulleropyrrolidine Layers. AB - Inverted planar structure perovskite solar cells (PSCs), due to their low temperature precessing and lack of hysteretic problems, are attracting increased attention by researchers around the world. Fullerene derivatives are the most widely used electron transport materials (ETMs) in inverted planar perovskite solar cells, especially [6,6]-phenyl-C61-butyric acid methylester (PC61BM), which exhibits very good performance. However, to the best of our knowledge, the influence of adducts on fullerene-based PSCs performance has not been fully explored to date. In this work, two fullerene derivatives, 2,5-(dimethyl ester) C60 fulleropyrrolidine (DMEC60) and the analogous C70 derivative (DMEC70), were synthesized in high yield via a 1,3-dipolar cycloaddition reaction at room temperature and incorporated into CH3NH3PbI3 perovskite solar cells as electron transport materials. Possibly because the attached pyrrolidine ester groups are able to coordinate with the perovskite layer, the devices based on DMEC60 and DMEC70 achieved power conversion efficiencies (PCE) of 15.2% and 16.4%, respectively. Not only were both devices' efficiencies higher than those based on PC61BM and PC71BM, but their stabilities were also higher than those for PCBM based devices. The results suggest that DMEC60 and DMEC70 are better alternatives than PC61BM and PC71BM for the ETMs in PSCs. PMID- 27766847 TI - Electron-Triggered Metamorphism in Porphyrin-Based Self-Assembled Coordination Polymers. AB - Viologen-centered electron transfer is used to trigger a complete dissociation of a porphyrin-based supramolecular architecture. In the oxidized state, self assembly is induced by iterative association of individual porphyrin-based tectons. Dissociation of the self-assembled species is actuated upon changing the redox state of the bipyridium units involved in the tectons from their dicationic state to their radical cation state, the driving force of the disassembling process being the formation of an intramolecularly locked conformation partly stabilized by pi-dimerization of both viologen cation radicals. PMID- 27766848 TI - Debunking the Idea that Ligand Efficiency Indices Are Superior to pIC50 as QSAR Activities. AB - Several papers have appeared in which a ligand efficiency index instead of pIC50 is used as the activity in QSAR. The claim is that better fits and predictions are obtained with ligand efficiency. We show on both public-domain and in-house data sets that the apparent superiority is a statistical artifact that occurs when ligand efficiency indices are correlated with the physical property included in their definition (number of non-hydrogens, ALOGP, TPSA, etc.) and when the property is easier to predict than the original pIC50. PMID- 27766846 TI - Insights into the Structure of Sulfolobus Nucleoid Using Engineered Sac7d Dimers with a Defined Orientation. AB - The structure of Archaeal chromatin or nucleoid is believed to have characteristics similar to that found in both eukaryotes and bacteria. Recent comparative studies have suggested that DNA compaction in Archaea requires a bridging protein (e.g., Alba) along with either a wrapping protein (e.g., a histone) or a bending protein such as Sac7d. While X-ray crystal structures demonstrate that Sac7d binds as a monomer to create a significant kink in duplex DNA, the structure of a multiprotein-DNA complex has not been established. Using cross-linked dimers of Sac7d with a defined orientation, we present evidence that indicates that Sac7d is able to largely coat duplex DNA in vivo by binding in alternating head-to-head and tail-to-tail orientations. Although each Sac7d monomer promotes a significant kink of nearly 70 degrees , coated DNA is expected to be largely extended because of compensation of repetitive kinks with helical symmetry. PMID- 27766849 TI - Advances in Predictive Toxicology for Discovery Safety through High Content Screening. AB - High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile. In addition to customized mechanistic assays to evaluate target safety, routine screening assays can be applied to identify risk factors for frequently occurring organ toxicities. We discuss the current state of high content screening assays for hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, and genotoxicity, including recent developments and current advances. PMID- 27766850 TI - Improvement in Half-Life of Organic Solar Cells by Using a Blended Hole Extraction Layer Consisting of PEDOT:PSS and Conjugated Polymer Electrolyte. AB - In this study, we fabricated conventional structured organic solar cells (OSCs) by introducing a hole extraction layer (HEL) that consisted of poly(3,4 ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) and conjugated polymer electrolyte (CPE) poly[9,9-bis(4'-sulfonatobutyl)fluorene-alt-thiophene] (PFT-D). PFT-D has a -SO3- functional group that acts as a conjugate base against the SO3H of PSS. In addition, the molecular dipole of PFT-D can screen the Coulombic attraction between PEDOT chains and PSS chains. By blending PEDOT:PSS and PFT-D, the acidity of the HEL solution and changes to the surface morphology and potential of the HEL film as a function of exposure time in air were reduced. As a result, the half-life of the OSC fabricated with blended HEL was five times better at room temperature and 40% humidity without encapsulation as compared to the pristine PEDOT:PSS-based device. PMID- 27766852 TI - Study of the Interaction of Eu3+ with Microbiologically Induced Calcium Carbonate Precipitates using TRLFS. AB - The microbial induced biomineralization of calcium carbonate using the ureolytic bacterium Sporosarcina pasteurii in the presence of trivalent europium, a substitute for trivalent actinides, was investigated by time-resolved laser induced fluorescence spectroscopy (TRLFS) and a variety of physicochemical techniques. Results showed that the bacterial-driven hydrolysis of urea provides favorable conditions for CaCO3 precipitation and Eu3+ uptake due to subsequent increases in NH4+ and pH in the local environment. Precipitate morphologies were characteristic of biogenically formed CaCO3 and consistent with the respective mineral phase compositions. The formation of vaterite with some calcite was observed after 1 day, calcite with some vaterite after 1 week, and pure calcite after 2 weeks. The presence of organic material associated with the mineral was also identified and quantified. TRLFS was used to track the interaction and speciation of Eu3+ as a molecular probe with the mineral as a function of time. Initially, Eu3+ is incorporated into the vaterite phase, while during CaCO3 phase transformation Eu3+ speciation changes resulting in several species incorporated in the calcite phase either substituting at the Ca2+ site or in a previously unidentified, low-symmetry site. Comparison of the biogenic precipitates to an abiotic sample shows mineral origin can affect Eu3+ speciation within the mineral. PMID- 27766851 TI - Simultaneous Optimization of Biomolecular Energy Functions on Features from Small Molecules and Macromolecules. AB - Most biomolecular modeling energy functions for structure prediction, sequence design, and molecular docking have been parametrized using existing macromolecular structural data; this contrasts molecular mechanics force fields which are largely optimized using small-molecule data. In this study, we describe an integrated method that enables optimization of a biomolecular modeling energy function simultaneously against small-molecule thermodynamic data and high resolution macromolecular structural data. We use this approach to develop a next generation Rosetta energy function that utilizes a new anisotropic implicit solvation model, and an improved electrostatics and Lennard-Jones model, illustrating how energy functions can be considerably improved in their ability to describe large-scale energy landscapes by incorporating both small-molecule and macromolecule data. The energy function improves performance in a wide range of protein structure prediction challenges, including monomeric structure prediction, protein-protein and protein-ligand docking, protein sequence design, and prediction of the free energy changes by mutation, while reasonably recapitulating small-molecule thermodynamic properties. PMID- 27766853 TI - Electroless Nickel Deposition: An Alternative for Graphene Contacting. AB - We report the first investigation into the potential of electroless nickel deposition to form ohmic contacts on single layer graphene. To minimize the contact resistance on graphene, a statistical model was used to improve metal purity, surface roughness, and coverage of the deposited film by controlling the nickel bath parameters (pH and temperature). The metalized graphene layers were patterned using photolithography and contacts deposited at temperatures as low as 60 degrees C. The contact resistance was 215 +/- 23 Omega over a contact area of 200 MUm * 200 MUm, which improved upon rapid annealing to 107 +/- 9 Omega. This method shows promise toward low-cost and large-scale graphene integration into functional devices such as flexible sensors and printed electronics. PMID- 27766855 TI - Does Biotransformation of Aryl Phosphate Flame Retardants in Blood Cast a New Perspective on Their Debated Biomarkers? AB - Aryl phosphate flame retardants (aryl-PFRs), such as triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPHP), are emerging contaminants that can exhibit toxic properties, including severe aquatic toxicity and endocrine disruptive effects. Monitoring exposure to aryl-PFRs through specific biomarkers is necessary to assess the health risk associated with chronic exposure. Hydrolytic serum enzymes could play an important role in the formation of the hydrolysis product diphenyl phosphate (DPHP), the seemingly most abundant in vivo biomarker of TPHP in urine. Here, we assess whether serum enzymes have an impact on the toxicokinetics of TPHP and EHDPHP and on the contribution of both aryl PFRs to in vivo DPHP levels. TPHP and EHDPHP were incubated separately with pooled human serum to measure the formation of hydrolysis products DPHP and 2 ethylhexyl phenyl phosphate (EHPHP) by liquid chromatography-tandem mass spectrometry. Clearance of TPHP and EHDPHP was 70 and 8.6 mL/min/L serum (as measured by formation of DPHP and EHPHP, respectively). No discernible amount of DPHP was produced from EHDPHP by serum hydrolases. Our results suggest that serum hydrolases can significantly contribute to the in vivo levels of DPHP formed from TPHP and can play an important role in the toxicokinetics, toxicity, and selection of biomarkers for aryl-PFRs. PMID- 27766854 TI - Rheological Study and Molecular Dynamics Simulation of Biopolymer Blend Thermogels of Tunable Strength. AB - The temperature-induced gelation of chitosan/glycerophosphate (Chs/GP) systems through physical interactions has shown great potential for various biomedical applications. In the present work, hydroxyethyl cellulose (HEC) was added to the thermosensitive Chs/GP solution to improve the mechanical strength and gel properties of the incipient Chs/HEC/GP gel in comparison with the Chs/GP hydrogel at body temperature. The physical features of the macromolecular complexes formed by the synergistic interaction between chitosan and hydroxyethyl cellulose in the presence of beta-glycerophosphate disodium salt solution have been studied essentially from a rheological point of view. The temperature and time sweep rheological characterizations of the thermogelling systems revealed that the sol gel transition temperature of the Chs/HEC/GP blends is equal to 37 degrees C at neutral pH; with increasing HEC content in the solutions, more compact networks with considerably improved gel strength are formed without influencing the gelation time. The formed hydrogel matrix has enough mechanical integrity and adequate strength for using it as injectable in situ forming matrices for biomedical applications. The classical Winter-Chambon (W-C) and Fredrickson Larson (F-L) theories were applied to determine the gel point. In view of the obtained results, it is shown that the F-L theory can be employed as a robust and less tedious method than the W-C approach to precisely determine the gel point in these systems. At the end, molecular simulation studies were conducted by using ab initio quantum mechanics (QM) calculations carried out on Chs and HEC models, and molecular dynamics (MD) simulations of solvated Chs/HEC blend systems showed the binding behavior of Chs/HEC polymers. Analyses of interaction energy, radial distribution function, and hydrogen bonding from simulation studies strongly supported the experimental results; they all disclosed that hydrogen-bond formation between Chs moieties with regard to HEC chains plays an important role for the stabilization of the complexes. PMID- 27766856 TI - Measuring and Reporting Electrical Conductivity in Metal-Organic Frameworks: Cd2(TTFTB) as a Case Study. AB - Electrically conductive metal-organic frameworks (MOFs) are emerging as a subclass of porous materials that can have a transformative effect on electronic and renewable energy devices. Systematic advances in these materials depend critically on the accurate and reproducible characterization of their electrical properties. This is made difficult by the numerous techniques available for electrical measurements and the dependence of metrics on device architecture and numerous external variables. These challenges, common to all types of electronic materials and devices, are especially acute for porous materials, whose high surface area make them even more susceptible to interactions with contaminants in the environment. Here, we use the anisotropic semiconducting framework Cd2(TTFTB) (TTFTB4- = tetrathiafulvalene tetrabenzoate) to benchmark several common methods available for measuring electrical properties in MOFs. We show that factors such as temperature, chemical environment (atmosphere), and illumination conditions affect the quality of the data obtained from these techniques. Consistent results emerge only when these factors are strictly controlled and the morphology and anisotropy of the Cd2(TTFTB) single-crystal devices are taken into account. Most importantly, we show that depending on the technique, device construction, and/or the environment, a variance of 1 or even 2 orders of magnitude is not uncommon for even just one material if external factors are not controlled consistently. Differences in conductivity values of even 2 orders of magnitude should therefore be interpreted with caution, especially between different research groups comparing different compounds. These results allow us to propose a reliable protocol for collecting and reporting electrical properties of MOFs, which should help improve the consistency and comparability of reported electrical properties for this important new class of crystalline porous conductors. PMID- 27766857 TI - Zeolite Nanoparticles Inhibit Abeta-Fibrinogen Interaction and Formation of a Consequent Abnormal Structural Clot. AB - EMT-type zeolite nanoparticles (EMT NPs) with particle size of 10-20 nm and external surface area of 200 m2/g have shown high selective affinity toward plasma protein (fibrinogen). Besides, the EMT NPs have demonstrated no adverse effect on blood coagulation hemostasis. Therefore, it was envisioned that the EMT NPs could inhibit possible beta-amyloid (Abeta)-fibrinogen interactions that result in the formation of structurally abnormal clots, which are resistant to lysis, in cerebral vessels of patients with Alzheimer disease (AD). To evaluate this hypothesis, the clot formation and degradation of Abeta-fibrinogen in the presence and absence of the EMT zeolite NPs were assessed. The results clearly showed that the delay in clot dissolution was significantly reduced in the presence of zeolite NPs. By formation of protein corona, the EMT NPs showed a negligible reduction in their inhibitory strength. Docking of small molecules (Abeta-fibrinogen) introduced a novel potential inhibitory candidate. The zeolite NPs showed similar inhibitory effects on binding of fibrinogen to both Abeta(25 35) and/or Abeta(1-42). This indicates that the inhibitory strength of these NPs is independent of Abeta sequence, and it is suggested that the zeolite NPs adsorb fibrinogen and specifically obstruct their Abeta binding sites. Therefore, the zeolite NPs can be the safe and effective inhibitors in preventing Abeta fibrinogen interaction and consequent cognitive damage. PMID- 27766858 TI - Solid-State Nuclear Magnetic Resonance Investigation of the Structural Topology and Lipid Interactions of a Viral Fusion Protein Chimera Containing the Fusion Peptide and Transmembrane Domain. AB - The fusion peptide (FP) and transmembrane domain (TMD) of viral fusion proteins play important roles during virus-cell membrane fusion, by inducing membrane curvature and transient dehydration. The structure of the water-soluble ectodomain of viral fusion proteins has been extensively studied crystallographically, but the structures of the FP and TMD bound to phospholipid membranes are not well understood. We recently investigated the conformations and lipid interactions of the separate FP and TMD peptides of parainfluenza virus 5 (PIV5) fusion protein F using solid-state nuclear magnetic resonance. These studies provide structural information about the two domains when they are spatially well separated in the fusion process. To investigate how these two domains are structured relative to each other in the postfusion state, when the ectodomain forms a six-helix bundle that is thought to force the FP and TMD together in the membrane, we have now expressed and purified a chimera of the FP and TMD, connected by a Gly-Lys linker, and measured the chemical shifts and interdomain contacts of the protein in several lipid membranes. The FP-TMD chimera exhibits alpha-helical chemical shifts in all the membranes examined and does not cause strong curvature of lamellar membranes or membranes with negative spontaneous curvature. These properties differ qualitatively from those of the separate peptides, indicating that the FP and TMD interact with each other in the lipid membrane. However, no 13C-13C cross peaks are observed in two-dimensional correlation spectra, suggesting that the two helices are not tightly associated. These results suggest that the ectodomain six-helix bundle does not propagate into the membrane to the two hydrophobic termini. However, the loosely associated FP and TMD helices are found to generate significant negative Gaussian curvature to membranes that possess spontaneous positive curvature, consistent with the notion that the FP-TMD assembly may facilitate the transition of the membrane from hemifusion intermediates to the fusion pore. PMID- 27766859 TI - Differential Effects of High Atmospheric N and S Deposition on Bog Plant/Lichen Tissue and Porewater Chemistry across the Athabasca Oil Sands Region. AB - Oil extraction and development activities in the Athabasca Oil Sands Region of northern Alberta, Canada, release NOx, SOx, and NHy to the atmosphere, ultimately resulting in increasing N and S inputs to surrounding ecosystems through atmospheric deposition. Peatlands are a major feature of the northern Alberta landscape, with bogs covering 6-10% of the land area, and fens covering 21-53%. Bulk deposition of NH4+-N, NO3--N, dissolved inorganic N (DIN), and SO42--S, was quantified using ion-exchange resin collectors deployed at 23 locations, over 1-6 years. The results reveal maximum N and S deposition of 9.3 and 12.0 kg ha-1 yr 1, respectively, near the oil sands industrial center (the midpoint between the Syncrude and Suncor upgrader stacks), decreasing with distance to a background deposition of 0.9 and 1.1 kg ha-1 yr-1, respectively. To assess potential influences of high N and S deposition on bogs, we quantified N and S concentrations in tissues of two Sphagnum species, two lichen species, and four vascular plant species, as well as surface porewater concentrations of H+, NH4+ N, NO3--N, SO42--S and dissolved organic N in 19 ombrotrophic bogs, distributed across a 3255 km2 sampling area surrounding the oil sands industrial center. The two lichen species (Evernia mesomorpha and Cladonia mitis), two vascular plant species (Rhododendron groenlandicum and Picea mariana), and to a lesser extent one moss (Sphagnum fuscum), showed patterns of tissue N and S concentrations that were (1) highest near the oil sands industrial center and (2) positively correlated with bulk deposition of N or S. Concentrations of porewater H+ and SO42--S, but not of NH4+-N, NO3--N, DIN, or dissolved inorganic N, also were higher near the oil sands industrial center than at more distant locations. The oil sands region of northern Alberta is remote, with few roads, posing challenges to the monitoring of oil sands-related N and S deposition. Quantification of N and S concentrations in bog plant/lichen tissues and porewaters may serve as a monitoring tool to assess both the local intensity and the spatial extent of bulk N and S deposition, and as harbingers of potential shifts in ecosystem structure and function. PMID- 27766860 TI - Access to Indole-Fused Polyheterocycles via Pd-Catalyzed Base-Free Intramolecular Cross Dehydrogenative Coupling. AB - A base-free process to access indole-fused polyheterocycles via a highly efficient and atom-economic palladium-catalyzed intramolecular cross dehydrogenetive coupling (CDC) reaction of 4-aniline substituted coumarins, quinolinones, and pyrones has been developed. A wide range of indolo[3,2 c]coumarins, indolo[3,2-c]quinolinones, and indolo[3,2-c]pyrones can be facilely afforded in good to excellent yields (up to 99%). PMID- 27766862 TI - Viewpoints on the 2016 Theory and Applications of Computational Chemistry Conference. PMID- 27766861 TI - An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2 carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual Specificity Tyrosine Phosphorylation-Regulated Kinases. AB - Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a noncanonical binding mode of compounds 1 and 2 in DYRK2, explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinases. PMID- 27766863 TI - Expanding the Potential of Heteroaryl Vinyl Sulfones. AB - The easily available vinyl sulfone 3 showed great potential for new applications in several fields such as organic synthesis and bioconjugate formation. This was demonstrated by performing a systematic assessment of its reactivity in Michael, radical, and cycloaddition reactions. Heteroaryl vinyl sulfone 3 presented excellent output in terms of reactivity and selectivity, proving superior to phenyl vinyl sulfone 1 and with clear advantages over bis-sulfone 2. This behavior might be due to the conformational and orbital control exerted by the tetrazole unit according to DFT calculations. Moreover, some alternative transformations to the Julia-Kocienski olefination on the obtained products are also described. PMID- 27766864 TI - Synthesis of Ribonucleosidic Dimers with an Amide Linkage from d-Xylose. AB - An original and efficient stereocontrolled synthesis of ribonucleosidic homo- and heterodimers has been achieved from inexpensive d-xylose. This successful strategy involved the sequential introduction of nucleobases, using two stereocontrolled N-glycosidation reactions, from a common two-furanoside amide linked scaffold offering the possibility of obtaining any given base sequence. The pertinence of this approach is illustrated through the preparation of the homodimers UU-34 and TT-35 in 18 steps with an excellent overall yield of more than 10% from d-xylose, while the heterodimer route led to UT-39 in 19 steps with around 10% overall yield. PMID- 27766865 TI - The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain. AB - The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340. PMID- 27766866 TI - Electronic Circular Dichroism Spectroscopy of Jet-Cooled Phenylalanine and Its Hydrated Clusters. AB - We obtained resonant two-photon ionization circular dichroism (R2PICD) spectra of jet-cooled phenylalanine (Phe) and its hydrated clusters (Phe(H2O)n, n = 1-2) near the origin band of the S0-S1 transition. The R2PICD spectra of Phe exhibit well-resolved CD bands of six different conformers present in the jet, which vary in sign and magnitude depending on their conformations. We revised the previous structural assignments of the Phe conformers based on the comparison between the experimental and theoretical CD signs, infrared spectra, and rotational band contours. The R2PICD spectra of Phe(H2O)n reveal that hydration with one or two water molecule(s) does not affect the CD signs of Phe conformers but significantly increases their CD magnitudes. Furthermore, conformational selection by solvation alters relative populations of Phe conformers, leading to a sign inversion in the CD spectra of Phe(H2O)n compared with that of Phe monomer. PMID- 27766867 TI - Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors. AB - Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anticancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2) or via peroxisome proliferator-activated receptor alpha (PPAR-alpha) stimulation. FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolaminephospholipase D (NAPE PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase 2 (COX-2). Over the past decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their antinociceptive and anti-inflammatory effects, as well as to protect the nervous system. PMID- 27766869 TI - Valence and Rydberg Excitations of 2,4- and 2,6-Difluorotoluene as Studied by Vacuum Ultraviolet Synchrotron Radiation and ab Initio Calculations. AB - Here we report novel comprehensive investigations on the electronic state spectroscopies of isolated 2,4- and 2,6-difluorotoluene in the gas phase by high resolution vacuum ultraviolet (VUV) photoabsorption measurements in the 4.4-10.8 eV energy range, with absolute cross-section values derived. We also present the first set of ab initio calculations (vertical energies and oscillator strengths), which we have used in the assignment of valence transitions of the difluorotoluene molecules, together with calculated ionization energies to obtain the Rydberg transitions for both molecules. The measured absolute photoabsorption cross sections have been used to estimate the photolysis lifetimes of 2,4- and 2,6-difluorotoluene in the Earth's atmosphere. PMID- 27766868 TI - Photoadduct Formation from the FMN Singlet Excited State in the LOV2 Domain of Chlamydomonas reinhardtii Phototropin. AB - The two light, oxygen, and voltage domains of phototropin are blue-light photoreceptor domains that control various functions in plants and green algae. The key step of the light-driven reaction is the formation of a photoadduct between its FMN chromophore and a conserved cysteine, where the canonical reaction proceeds through the FMN triplet state. Here, complete photoreaction mapping of CrLOV2 from Chlamydomonas reinhardtii phototropin and AsLOV2 from Avena sativa phototropin-1 was realized by ultrafast broadband spectroscopy from femtoseconds to microseconds. We demonstrate that in CrLOV2, a direct photoadduct formation channel originates from the initially excited singlet state, in addition to the canonical reaction through the triplet state. This direct photoadduct reaction is coupled by a proton or hydrogen transfer process, as indicated by a significant kinetic isotope effect of 1.4 on the fluorescence lifetime. Kinetic model analyses showed that 38% of the photoadducts are generated from the singlet excited state. PMID- 27766871 TI - Condensation Oligomers with Sequence Control but without Coupling Reagents and Protecting Groups via Asymmetric Hydroformylation and Hydroacyloxylation. AB - A novel strategy, free of coupling reagents and protection/deprotection steps, for the synthesis of oligo(2-hydroxyacid)s containing up to four monomer units with atom economy, sequence specificity, and control of stereocenter configuration is described. The strategy comprises an iterative application of the sequence asymmetric hydroformylation/oxidation/alkyne hydroacyloxylation that features catalytic, atom-economical C-C and C-O bond forming reactions. Asymmetric hydroformylation with Rh-bisdiazaphospholane catalyst introduces each stereocenter with high enantio- (ca. 93% e.e.), diastereo- (up to 25:1 d.r.), and regioselectivity (>50:1) at low catalyst loadings and mild pressures. The side chain in each monomer is tailored by choosing from a variety of readily available alkynes. PMID- 27766870 TI - Reaction of C60 with Inactive Secondary Amines and Aldehydes and the Cu(OAc)2 Promoted Regioselective Intramolecular C-H Functionalization of the Generated Fulleropyrrolidines. AB - The thermal reaction of C60 with aromatic aldehydes and inactive secondary amines for the stereoselective synthesis of trans-1,2,5-trisubstituted fulleropyrrolidines has been developed. Moreover, when an o-hydroxyl group was located at the phenyl ring of the generated fulleropyrrolidines, the Cu(OAc)2 promoted regioselective intramolecular C-O coupling reaction occurred to generate unique tricycle-fused fullerene derivatives. PMID- 27766872 TI - Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5-Oxo-6,8,11,14-eicosatetraenoic Acid (5-Oxo ETE)-Induced Granulocyte Activation in Monkeys. AB - The potent eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5 oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential. We found that monkey leukocytes synthesize and respond to 5-oxo-ETE and that 230 is a potent antagonist of the OXE receptor in monkey eosinophils. Pharmacokinetic studies revealed that 230 appears rapidly in the blood following oral administration. Using chemically synthesized standards, we identified the major microsomal and plasma metabolites of 230 as products of omega2-hydroxylation of the alkyl side chain. These studies demonstrate that the monkey is a promising animal model to investigate the drug potential of OXE receptor antagonists. PMID- 27766873 TI - Ab Initio Molecular Dynamics Study of the Photoreaction of 1,1'-Dimethylstilbene upon S0 -> S1 Excitation. AB - Ab initio molecular dynamics (AIMD) simulations were carried out for pipi* excited 1,1'-dimethylstilbene (dmSB) at the spin-flip time-dependent density functional theory (SF-TDDFT) level with the TSF-index technique, to get insights into the substitution effects on the photoisomerization dynamics of stilbene (SB). It is found that the reaction path from the Franck-Condon structure of cis dmSB is oriented toward the 4,4-dihydrophenanthrene (DHP) side from the beginning, which is in contrast to the case of SB where the pathway is oriented toward the twist side in the initial stage. The optimized geometries of minima and the minimum-energy conical intersection (MECI) suggested that molecules in the DHP region could easily decay to the ground state. On the other hand, S1/S0 MECI and S1-minimum in the twist region have a relatively different geometry from each other, which is consistent with the experimental observation of the long lifetime of the perpendicular structure. AIMD simulations showed that more trajectories enter the well of the DHP side than the well of the twist side and that all of the trajectories going to the DHP side reached the S1/S0-CI region within ~0.2 ps on average, while very few trajectories reached S1/S0-CI even after 1 ps in the twist region. Decrease in the S1 population in the cis and twist regions qualitatively reproduced the temporal profiles of the transient absorption bands of dmSB observed in the visible and ultraviolet regions, respectively. PMID- 27766875 TI - Metal-Free Synthesis of meso-Aminoporphyrins through Reduction of meso Azidoporphyrins Generated in Situ by Nucleophilic Substitution Reactions of meso Bromoporphyrins. AB - A facile and metal-free method for the preparation of free base meso aminodiarylporphyrins from readily available meso-bromodiarylporphyrins is described. Simple treatment of meso-bromoporphyrins with sodium azide and sodium ascorbate in DMF affords the corresponding meso-aminoporphyrins in very good yields. This method involves the aromatic nucleophilic substitution (SNAr) of a bromo group with an azido group and the subsequent in situ reduction of the introduced azido group by sodium ascorbate. This amination reaction can be scaled up to gram scale without any decrease of the product yield. The amination reaction of free base meso-dibromoporphyrin affords a monoaminated product selectively, whereas that of the Ni(II) complex furnishes a diaminated product that is oxidized by air under ambient conditions but isolable as a trifluoroacetyl ester. Metal-insertion reactions of the obtained free base aminoporphyrins afford the corresponding metal complexes (Ni(II), Cu(II), Zn(II), and Pd(II)) all in good yields except the Pd(II) complex. Synthetic methods for the preparation of N-mono- or dialkylaminoporphyrins from the free base meso aminoporphyrins have been also established. PMID- 27766874 TI - Resolving the Origins of Crystalline Anharmonicity Using Terahertz Time-Domain Spectroscopy and ab Initio Simulations. AB - Anharmonicity has been shown to be an important piece of the fundamental framework that dictates numerous observable phenomena. In particular, anharmonicity is the driving force of vibrational relaxation processes, mechanisms that are integral to the proper function of numerous chemical processes. However, elucidating its origins has proven difficult due to experimental and theoretical challenges, specifically related to separating the anharmonic contributions from other unrelated effects. While no one technique is particularly suited for providing a complete picture of anharmonicity, by combining multiple complementary methods such a characterization can be made. In this study the role of individual atomic interactions on the anharmonic properties of crystalline purine, the building block of many DNA and RNA nucleobases, is studied by experimental terahertz time-domain spectroscopy and first-principles density functional theory (DFT) and ab initio molecular dynamics simulations (AIMD). In particular, the detailed vibrational information provided by the DFT calculations is used to interpret the atomic origins of anharmonic related effects as determined by the AIMD calculations, which are in good agreement with the experimental data. The results highlight that anharmonicity is especially pronounced in the intermolecular interactions, particularly along the amine hydrogen bond coordinate, and yields valuable insight into what is similarly observed complex biosystems and crystalline solids. PMID- 27766876 TI - Directly Modifying the Nonbonded Potential Based on the Standard Iterative Boltzmann Inversion Method for Coarse-Grained Force Fields. AB - Effective potentials are of great importance for coarse-grained (CG) simulations, which can be obtained by the structure-based iterative Boltzmann inversion (IBI) method. However, the standard IBI method is incapable of maintaining the mechanical and thermodynamic properties of the CG model in agreement with those of the all-atom model. Unlike the existing techniques, such as introducing friction force as the dissipative force to reduce the superatom motion while keeping the conservative force arising from the CG potential intact, we directly modified the standard IBI nonbonded potential by adding an empirical function. According to an analysis of the dissipative particle dynamics, the additional function did compensate for the friction reduction of the standard IBI CG model. In this work, the thermal fluctuation information from the nonbonded radial distribution function was incorporated into the additional empirical function. As an illustration of the new CG force fields, we presented simulations of the stress-strain relation and thermodynamic properties in terms of cis-polyisoprene and compared the statistical structure information of the superatoms with those of the IBI CG model and the all-atom model. It should be emphasized that the additional empirical function contributed to compensating for the friction reduction, irrespective of the functional form it took. In this sense, the proposed method was easily operable. PMID- 27766877 TI - Reactions of 2-Propanol Radical with Halogenated Organics in Aqueous Solution: Theoretical Evidence for Proton-Coupled Electron Transfer and Competing Mechanisms. AB - The reactions of alpha-hydroxyalkyl radicals in aqueous medium are of interest because they exhibit a rich variety of fundamentally important competing mechanisms, such as proton-coupled electron transfer (PCET), hydrogen atom transfer, free radical substitutions, abstractions and additions, etc. We present a theoretical study of the mechanism and kinetics of the aqueous reactions of alpha-hydroxyisopropyl (2-propanol) radical with four halogenated organic substrates: iodoacetate (IAc), iodoacetamide (IAm), 5-bromouracil (5-BrU), and carbon tetrachloride (CCl4). The reactions are studied using density functional theory (DFT) (M06-2X), and the solvent is modeled as a polarizable continuum, either without the explicit solvent molecules or with one added water molecule. For an additional refinement, the double hybrid DFT B2PLYP energies were calculated at the M06-2X stationary points. Within this framework, for each substrate, we determine the most favorable radical-induced decomposition pathway among the several found and compare the thermochemical predictions against the experimental kinetics. The following dominant decomposition mechanisms are inferred: PCET for IAc, PCET-H2O and the I-atom abstraction for IAm, the ortho addition to the double bond for 5-BrU, and the Cl-atom abstraction for CCl4. These pathways are invariably characterized by the negative apparent activation energies. Whereas for 5-BrU and CCl4 the transition state theory rate constants are in good agreement with the experiment, the rate constants for IAc and IAm-the two substrates reacting preferably via the PCET-are difficult to predict correctly. Consequently, the corresponding reaction barriers necessitate lowering by 1-3 kcal mol-1 to bring them in accord with experiment. The B2PLYP method provides a worthwhile improvement over the M06-2X energetics although the largest errors remain for the two PCET processes. PMID- 27766878 TI - alpha-Synuclein Oligomers Stabilize Pre-Existing Defects in Supported Bilayers and Propagate Membrane Damage in a Fractal-Like Pattern. AB - Phospholipid vesicles are commonly used to get insights into the mechanism by which oligomers of amyloidogenic proteins damage membranes. Oligomers of the protein alpha-synuclein (alphaS) are thought to create pores in phospholipid vesicles containing a high amount of anionic phospholipids but fail to damage vesicle membranes at low surface charge densities. The current understanding of how alphaS oligomers damage the membranes is thus incomplete. This incomplete understanding may, in part, result from the choice of model membrane systems. The use of free-standing membranes such as vesicles may interfere with the unraveling of some damage mechanisms because the line tension at the edge of a membrane defect or pore ensures defect closure. Here, we have used supported lipid bilayers (SLBs) of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2 oleoyl-sn-glycero-3-phospho-l-serine (POPC/POPS) to study the membrane damage caused by alphaS oligomers. Although alphaS oligomers were not able to initiate the disruption of POPC/POPS vesicles or intact SLBs, oligomers did stabilize and enlarge pre-existing SLB defects. The increased exposure of lipid acyl chains at the edges of defects very likely facilitates membrane-oligomer interactions, resulting in the growth of fractal domains devoid of lipids. Concomitant with the appearance of the fractal membrane damage patterns, lipids appear in solution, directly implicating alphaS oligomers in the observed lipid extraction. The growth of the membrane damage patterns is not limited by the binding of lipids to the oligomer. The analysis of the shape and growth of the lipid-free domains suggests the involvement of an oligomer-dependent diffusion-limited extraction mechanism. The observed alphaS oligomer-induced propagation of membrane defects offers new insights into the mechanisms by which alphaS oligomers can contribute to the loss in membrane integrity. PMID- 27766879 TI - Ensemble Linear Neighborhood Propagation for Predicting Subchloroplast Localization of Multi-Location Proteins. AB - In the postgenomic era, the number of unreviewed protein sequences is remarkably larger and grows tremendously faster than that of reviewed ones. However, existing methods for protein subchloroplast localization often ignore the information from these unlabeled proteins. This paper proposes a multi-label predictor based on ensemble linear neighborhood propagation (LNP), namely, LNP Chlo, which leverages hybrid sequence-based feature information from both labeled and unlabeled proteins for predicting localization of both single- and multi label chloroplast proteins. Experimental results on a stringent benchmark dataset and a novel independent dataset suggest that LNP-Chlo performs at least 6% (absolute) better than state-of-the-art predictors. This paper also demonstrates that ensemble LNP significantly outperforms LNP based on individual features. For readers' convenience, the online Web server LNP-Chlo is freely available at http://bioinfo.eie.polyu.edu.hk/LNPChloServer/ . PMID- 27766880 TI - Metal-Free and Versatile Synthetic Routes to Natural and Synthetic Prodiginines from Boron Dipyrrin. AB - Prodiginines, as a family of bacterial alkaloids, possess a number of interesting biological activities. New, concise synthetic routes for the facile preparation of both synthetic and natural prodiginines in good yields have been developed, which use BODIPY functionalization reactions, such as condensation, nucleophilic substitution, and BF2 deprotection. This new metal-free synthetic method opens the door toward a wide variety of C-ring functionalized prodiginines, including those that are not possible to obtain through current synthetic methods, for their advanced biological activities. PMID- 27766881 TI - Isomerism of Trimeric Aluminum Complexes in Aqueous Environments: Exploration via DFT-Based Metadynamics Simulation. AB - The chemistry of aluminum or oxo-aluminum in water is still relatively unknown, although it is the basis for many chemical and industrial processes, including flocculation in water treatment plants. Trimeric species have a predominant role in the formation of the Keggin cations, which are the basic building blocks of aluminum-based chemicals. Despite this, details of the structural evolution of these small solvated clusters and how this is related to the processes leading to the formation of larger aggregates are still an open issue. To address these questions, here, we have applied the metadynamics (MTD) simulation technique [ Barducci , A. ; Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2010 , 1 , 826 - 843 ] with density functional theory-based molecular dynamics to disclose the dynamics and structural conversions of trimeric aluminum complexes in an aqueous environment. The existence of a variety of competing metastable conformations, for example, book-like, cyclic boat, and linear shape conformations, is revealed in the MTD simulation. Furthermore, equilibrium simulations of the various intermediate states encountered along the MTD trajectory are used to assess their (meta)stability, determine the rearrangement of the OH ligands, and discuss the role of the solvating water. PMID- 27766882 TI - Salt Disproportionation in the Solid State: Role of Solubility and Counterion Volatility. AB - Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and cocrystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, "prototype" formulations of salts and cocrystal in tablet form were stored at 40 degrees C and several water vapor pressures. Disproportionation kinetics were studied in these prototype tablet formulations using two-dimensional X-ray diffractometry. Formulations containing the adipic acid cocrystal or heminapadisylate salt did not show disproportionation of API when stored at 40 degrees C/75% RH for 300 days. On the other hand, formulations containing HCl or HBr salt disproportionated. Though isostructural, the disproportionation propensity of HBr and HCl salts was quite different. The HCl salt highlighted the important role that volatility of the counterion plays in the physical stability of the formulations. Solution state stability (i.e., in dissolution medium) of salts and cocrystal was also assessed and compared with solid state stability, by determining their solubility at different pH's, and intrinsic dissolution rate. PMID- 27766884 TI - Strain-Induced Band Gap Engineering in Selectively Grown GaN-(Al,Ga)N Core-Shell Nanowire Heterostructures. AB - We demonstrate the selective area growth of GaN-(Al,Ga)N core-shell nanowire heterostructures directly on Si(111). Photoluminescence spectroscopy on as-grown nanowires reveals a strong blueshift of the GaN band gap from 3.40 to 3.64 eV at room temperature. Raman measurements relate this shift to compressive strain within the GaN core. On the nanoscale, cathodoluminescence spectroscopy and scanning transmission electron microscopy prove the homogeneity of strain-related luminescence along the nanowire axis and the absence of significant fluctuations within the shell, respectively. A comparison of the experimental findings with numerical simulations indicates the absence of a significant defect-related strain relaxation for all investigated structures, with a maximum compressive strain of -3.4% for a shell thickness of 50 nm. The accurate control of the nanowire dimensions, namely, core diameter, shell thickness, and nanowire period, via selective area growth allows a specific manipulation of the resulting strain within individual nanowires on the same sample. This, in turn, enables a spatially resolved adjustment of the GaN band gap with an energy range of 240 meV in a one-step growth process. PMID- 27766883 TI - High-Energy All-Solid-State Lithium Batteries with Ultralong Cycle Life. AB - High energy and power densities are the greatest challenge for all-solid-state lithium batteries due to the poor interfacial compatibility between electrodes and electrolytes as well as low lithium ion transfer kinetics in solid materials. Intimate contact at the cathode-solid electrolyte interface and high ionic conductivity of solid electrolyte are crucial to realizing high-performance all solid-state lithium batteries. Here, we report a general interfacial architecture, i.e., Li7P3S11 electrolyte particles anchored on cobalt sulfide nanosheets, by an in situ liquid-phase approach. The anchored Li7P3S11 electrolyte particle size is around 10 nm, which is the smallest sulfide electrolyte particles reported to date, leading to an increased contact area and intimate contact interface between electrolyte and active materials. The neat Li7P3S11 electrolyte synthesized by the same liquid-phase approach exhibits a very high ionic conductivity of 1.5 * 10-3 S cm-1 with a particle size of 0.4-1.0 MUm. All-solid-state lithium batteries employing cobalt sulfide-Li7P3S11 nanocomposites in combination with the neat Li7P3S11 electrolyte and Super P as the cathode and lithium metal as the anode exhibit excellent rate capability and cycling stability, showing reversible discharge capacity of 421 mAh g-1 at 1.27 mA cm-2 after 1000 cycles. Moreover, the obtained all-solid-state lithium batteries possesses very high energy and power densities, exhibiting 360 Wh kg-1 and 3823 W kg-1 at current densities of 0.13 and 12.73 mA cm-2, respectively. This contribution demonstrates a new interfacial design for all-solid-state battery with high performance. PMID- 27766885 TI - Nanofabricated Neural Probes for Dense 3-D Recordings of Brain Activity. AB - Computations in brain circuits involve the coordinated activation of large populations of neurons distributed across brain areas. However, monitoring neuronal activity in the brain of intact animals with high temporal and spatial resolution has remained a technological challenge. Here we address this challenge by developing dense, three-dimensional (3-D) electrode arrays for electrophysiology. The 3-D arrays constitute the front-end of a modular and configurable system architecture that enables monitoring neuronal activity with unprecedented scale and resolution. PMID- 27766886 TI - Reactions of HDDA-Derived Benzynes with Perylenes: Rapid Construction of Polycyclic Aromatic Compounds. AB - Benzynes produced by the thermal cycloisomerization of tetrayne substrates [i.e., by the hexadehydro-Diels-Alder (HDDA) reaction] react with perylenes to produce novel naphthoperylene derivatives. Cyclic voltammetry and absorption and emission properties of these compounds are described. DFT studies shed additional light on the dearomatization that accompanies the reaction as well as some of the spectroscopic behavior. PMID- 27766887 TI - Resonant Enhancement of Second-Harmonic Generation in the Mid-Infrared Using Localized Surface Phonon Polaritons in Subdiffractional Nanostructures. AB - We report on the strong enhancement of mid-infrared second-harmonic generation (SHG) from SiC nanopillars due to the resonant excitation of localized surface phonon polaritons within the Reststrahlen band. A strong dependence of the SHG enhancement upon the optical mode distribution was observed. One such mode, the monopole, exhibits an enhancement that is beyond what is anticipated from field localization and dispersion of the linear and nonlinear SiC optical properties. Comparing the results for the identical nanostructures made of 4H and 6H SiC polytypes, we demonstrate the interplay of localized surface phonon polaritons with zone-folded weak phonon modes of the anisotropic crystal. Tuning the monopole mode in and out of the region where the zone-folded phonon is excited in 6H-SiC, we observe a further prominent increase of the already enhanced SHG output when the two modes are coupled. Envisioning this interplay as one of the showcase features of mid-infrared nonlinear nanophononics, we discuss its prospects for the effective engineering of nonlinear-optical materials with desired properties in the infrared spectral range. PMID- 27766888 TI - Particle Zeta Potentials Remain Finite in Saturated Salt Solutions. AB - The zeta potential of a particle characterizes its motion in an electric field and is often thought to be negligible at high ionic strength (several moles per liter) due to thinning of the electrical double layer (EDL). Here, we describe zeta potential measurements on polystyrene latex (PSL) particles at monovalent salt concentrations up to saturation (~5 M NaCl) using electrophoresis in sinusoidal electric fields and high-speed video microscopy. Our measurements reveal that the zeta potential remains finite at even the highest concentrations. Moreover, we find that the zeta potentials of sulfated PSL particles continue to obey the classical Gouy-Chapman model up to saturation despite significant violations in the model's underlying assumptions. By contrast, amidine functionalized PSL particles exhibit qualitatively different behaviors such as zero zeta potentials at high concentrations of NaCl and KCl and even charge inversion in KBr solutions. The experimental results are reproduced and explained by Monte Carlo simulations of a simple lattice model of the EDL that accounts for effects due to ion size and ion-ion correlations. At high salt conditions, the model suggests that quantitative changes in the magnitude of surface charge can result in qualitative changes in the zeta potential-most notably, charge inversion of highly charged surfaces. These findings have important implications for electrokinetic phenomena such as diffusiophoresis within salty environments such as oceans, geological reservoirs, and living organisms. PMID- 27766890 TI - Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. AB - INTRODUCTION: Apigenin, a natural flavone, is widely distributed in plants such as celery, parsley and chamomile. It is present principally as glycosylated in nature. Higher intake of apigenin could reduce the risk of chronic diseases. It has gained particular interest in recent years as a beneficial, health-promoting agent with low intrinsic toxicity. Areas covered: This review summarizes and the absorption, distribution, metabolism and excretion (ADME) properties of apigenin, and drug-drug interaction of apigenin. Expert opinion: Since apigenin is a bioactive plant flavone and is widely distributed in common food, its consumption through the diet is recommended. Apigenin-enriched drugs are better for some chronic diseases, but may affect animal and human health if present in the daily diet. Dietary or therapeutic apigenin has value as a good cellular regulator in cancer, especially cancers of the gastrointestinal tract. Due to apigenin's limitations on absorption and bioavailability, novel carriers would need to be developed to enhance the oral bioavailability of apigenin. Further research about its ADME properties and drug-drug interactions are needed before apigenin can be brought to clinical trials. PMID- 27766889 TI - Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein-protein docking, peptide docking and molecular dynamics simulations. AB - The Klotho is known as lifespan enhancing protein involved in antagonizing the effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted exposure of Wnt proteins to the cell can cause stem and progenitor cell senescence, which may lead to aging. Keeping in mind the importance of Klotho in Wnt signaling, in silico approaches have been applied to study the important interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor virus (MMTV) integration site family members 3 and 3a). The main aim of the study is to identify important residues of the Klotho that help in designing peptides which can act as Wnt antagonists. For this aim, a protein engineering study is performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology models, unexpected role of number of disulfide bonds and secondary structure elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in silico experiments were carried out to observe the effect of correct number of disulfide bonds on 3D protein models. For this aim, total of 10 molecular dynamics (MD) simulations were carried out for each system. Based on the protein protein docking simulations of selected protein models of Klotho with Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3 and Wnt3a proteins have three important domains: Index finger, N-terminal domain and a patch of ~10 residues on the solvent exposed surface of palm domain. Protein peptide docking of designed peptides of Klotho against three important domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads better understanding of the Wnt protein inhibition by proposed Klotho peptides. Further in vitro studies can be carried out to verify effects of novel designed peptides as Wnt antagonists. PMID- 27766891 TI - Antimicrobial metal-based thiophene derived compounds. AB - A novel series of thiophene derived Schiff bases and their transition metal- [Co(II), Cu(II), Zn(II), Ni(II)] based compounds are reported. The Schiff bases act as tridentate ligands toward metal ions via azomethine-N, deprotonated-N of ammine substituents and S-atom of thienyl moiety. The synthesized ligands along with their metal complexes were screened for their in vitro antibacterial activity against six bacterial pathogens (Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi, Staphylococcus aureus and Bacillus subtilis) and for antifungal activity against six fungal pathogens (Trichophytonlongifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata). The results of antimicrobial studies revealed the free ligands to possess potential activity which significantly increased upon chelation. PMID- 27766893 TI - Optimal mechanical ventilation strategies to minimize ventilator-induced lung injury in non-injured and injured lungs. PMID- 27766892 TI - Isatin thiazoline hybrids as dual inhibitors of HIV-1 reverse transcriptase. AB - A series of 3-3-{2-[2-3-methyl-4-phenyl-2,3-dihydro-1,3-thiazol-2 ylidene]hydrazin-1-ylidene-2,3-dihydro-1H-indol-2-one derivatives has been designed and synthesized to study their activity on both HIV-1 (Human Immunodeficiency Virus type 1) RT (Reverse Transcriptase) associated functions. These derivatives are analogs of previously reported series whose biological activity and mode of action have been investigated. In this work we investigated the influence of the introduction of a methyl group in the position 3 of the dihydrothiazole ring and of a chlorine atom in the position 5 of the isatin nucleus. The new synthesized compounds are active towards both DNA polymerase and ribonuclease H in the uM range. The nature of the aromatic group in the position 4 of the thiazole was relevant in determining the biological activity. PMID- 27766894 TI - Nativity and language preference as drivers of health information seeking: examining differences and trends from a U.S. population-based survey. AB - OBJECTIVE: To examine differences in health information seeking between U.S.-born and foreign-born populations in the U.S. DESIGN: Data from 2008 to 2014 from the Health Information National Trends Survey were used in this study (n = 15,249). Bivariate analyses, logistic regression, and predicted probabilities were used to examine health information seeking and sources of health information. RESULTS: Findings demonstrate that 59.3% of the Hispanic foreign-born population reported looking for health information, fewer than other racial/ethnic groups in the sample. Compared with non-Hispanic White, non-Hispanic Black (OR = 0.62) and Hispanic foreign-born individuals (OR = 0.31) were the least likely to use the internet as a first source for health information. Adjustment for language preference explains much of the disparity in health information seeking between the Hispanic foreign-born population and Whites; controlling for nativity, respondents who prefer Spanish have 0.25 the odds of using the internet as a first source of health information compared to those who prefer English. CONCLUSION: Foreign-born nativity and language preference are significant determinants of health information seeking. Further research is needed to better understand how information seeking patterns can influence health care use, and ultimately health outcomes. To best serve diverse racial and ethnic minority populations, health care systems, health care providers, and public health professionals must provide culturally competent health information resources to strengthen access and use by vulnerable populations, and to ensure that all populations are able to benefit from evolving health information sources in the digital age. PMID- 27766895 TI - Insights into the role of reactive sulfhydryl groups of Carbonic Anhydrase III and VII during oxidative damage. AB - Carbonic anhydrases (CAs) III and VII are two cytosolic isoforms of the alpha-CA family which catalyze the physiological reaction of carbon dioxide hydration to bicarbonate and proton. Despite these two enzymes share a 49% sequence identity and present a very similar three-dimensional structure, they show profound differences when comparing the specific activity for CO2 hydration reaction, with CA VII being much more active than CA III. Recently, CA III and CA VII have been proposed to play a new role as scavenger enzymes in cells where oxidative damage occurs. Here, we will examine functional and structural features of these two isoforms giving insights into their newly proposed protective role against oxidative stress. PMID- 27766896 TI - Occurrence and genotypes of Campylobacter species in broilers during the rearing period. AB - Poultry are the main source of Campylobacter infection worldwide. To obtain information on Campylobacter-infected flocks and create a reference for preventing and controlling Campylobacter at farm level, Campylobacter isolates were recovered from broilers and the environments of nine chicken flocks in two farms during growth. The genetic relationship between the Campylobacter isolates was determined using multilocus sequence typing. Flocks were colonized as early as 3 weeks after introduction to the farm. The highest colonization rate was more than 90% and occurred 4-6 weeks after introduction to the farm. Quantitative data showed that the highest Campylobacter loads appeared at 1-2 weeks after initial colonization. Campylobacter loads in cloacal swabs in four flocks were significantly higher at 5 weeks than at 3 weeks (P < 0.05). Multilocus sequence typing of 171 selected isolates revealed 20 sequence types (STs), which consisted of 12 STs for Campylobacter jejuni and eight for Campylobacter coli isolates. The STs of the Campylobacter isolates recovered from farm 1 were more diversified than those from farm 2. The STs of environmental samples were highly consistent with those of the cloacal swab samples. The consistency between Campylobacter STs in the environmental and cloacal swab samples suggested that the environment might be one of the main sources of infection. Thus, our study highlights the prevalence and contamination load of Campylobacter in broilers during their rearing period and emphasizes the need for control and prevention measures for Campylobacter infection in broilers, which is also important for human health. PMID- 27766897 TI - Diethylalkylsulfonamido(4-methoxyphenyl)methyl)phosphonate/phosphonic acid derivatives act as acid phosphatase inhibitors: synthesis accompanied by experimental and molecular modeling assessments. AB - Purple acid phosphatases (PAPs) are binuclear metallo-hydrolases that have been isolated from various mammals, plants, fungi and bacteria. In mammals, PAP activity is associated with bone resorption and can lead to bone metabolic disorders such as osteoporosis; thus human PAP is an attractive target to develop anti-osteoporotic drugs. The aim of the present study was to investigate inhibitory effect of synthesized diethylalkylsulfonamido(4 methoxyphenyl)methyl)phosphonate/phosphonic acid derivatives as potential red kidney bean PAP (rkbPAP) inhibitors accompanied by experimental and molecular modeling assessments. Enzyme kinetic data showed that they are good rkbPAP inhibitors whose potencies improve with increasing alkyl chain length. Hexadecyl derivatives, as most potent compounds (Ki = 1.1 uM), inhibit rkbPAP in the mixed manner, while dodecyl derivatives act as efficient noncompetitive inhibitor. Also, analysis by molecular modeling of the structure of the rkbPAP-inhibitor complexes reveals factors, which may be important for the determination of inhibition specificity. PMID- 27766898 TI - Three new phenylpropanoids from Lavandula angustifolia and their bioactivities. AB - Three new phenylpropanoids, 3-(3,4-dimethoxy-5-methylphenyl)-3-oxopropyl acetate (1), 3-hydroxy-1-(3,4-dimethoxy-5-methylphenyl)propan-1-one (2), and 3-hydroxy-1 (4-methylbenzo[d][1,3]dioxol-6-yl) propan-1-one (3), together with three known phenylpropanoids (4-6) were isolated from the whole plant of Lavandula angustifolia. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-6 were tested for their anti tobacoo mosaic virus (TMV) activities and cytotoxicity activities. The results revealed that compounds 1-3 showed high anti-TMV activity with inhibition rate of 35.2, 38.4 and 33.9%. These rates are higher than that of positive control. The other compounds also showed potential anti-TMV activities with inhibition rates in the range of 26.8-28.9%, respectively. Compounds 1-6 also showed weak inhibitory activities against some tested human tumour cell lines with IC50 values in the range of 3.8-8.8 MUM. PMID- 27766899 TI - Impact of Shed/Soluble targets on the PK/PD of approved therapeutic monoclonal antibodies. AB - INTRODUCTION: Suboptimal treatment for monoclonal antibodies (mAbs) directed against endogenous circulating soluble targets and the shed extracellular domains (ECD) of the membrane-bound targets is an important clinical concern due to the potential impact of mAbs on the in vivo efficacy and safety. Consequently, there are considerable challenges in the determination of an optimal dose and/or dosing regimen. Areas covered: This review outlines the impact of shed antigen targets from membrane-bound proteins and soluble targets on the PK and/or PD of therapeutic mAbs that have been approved in the last decade. We discuss various bioanalytical techniques that have facilitated the interpretation of the PK/PD properties of therapeutic mAbs and also considered the factors that may impact such measurements. Quantitative approaches include target-mediated PK models and bi- or tri-molecular interaction PK/PD models that describe the relationships between the antibody PK and the ensuing effects on PD biomarkers, to facilitate the mAb PK/PD characterization. Expert commentary: The proper interpretation of PK/PD relationships through the integrated PK/PD modeling and bioanalytical strategy facilitates a mechanistic understanding of the disease processes and dosing regimen optimization, thereby offering insights into developing effective therapeutic regimens. This review provides an overview of the impact of soluble targets or shed ECD on mAb PK/PD properties. We provide examples of quantitative approaches that facilitate the characterization of mAb PK/PD characteristics and their corresponding bioanalytical strategies. PMID- 27766900 TI - Pathogenicity, tissue distribution, shedding and environmental detection of two strains of IBDV following infection of chickens at 0 and 14 days of age. AB - Infectious bursal disease virus (IBDV) is endemic to most poultry-producing countries worldwide. Immunosuppressive classical and variant IBDV strains endemic to Australia are genetically distinct from other international strains. We report the results of infection experiments with Australian classical strain 06/95 and variant strain 02/95 in SPF chickens. We tested the effects of strain and age of infection on bursal atrophy, viral RNA (vRNA) load in bursa of Fabricius (bursa), spleen, thymus, caecal tonsils, faeces, litter and exhaust dust as determined by real-time reverse transcriptase polymerase chain reaction. The two IBDV strains did not differ in the degree of bursal atrophy induced, lymphoid organ distribution and faecal shedding but variant strain 02/95 induced a greater antibody response to the infection than classical strain 06/95 which was associated with a more rapid decline in IBDV vRNA genome copy number (VCN) in lymphoid organs and faeces. Infection at 14 days of age induced greater bursal atrophy and higher vRNA copy number in lymphoid tissues than infection on the day of hatching, indicating true age susceptibility independent of maternal antibody (Mab) status. The direction of the association between rankings for IBDV vRNA load in bursa and relative bursal weight changed from positive at 3 and 6 days post-infection to negative at 28 days post-infection. Intra-tracheal administration of dust collected from chickens infected with IBDV resulted in successful transmission of IBDV. IBDV vRNA was detected successfully at high levels in the environmental litter and dust samples. PMID- 27766901 TI - The effects of nifedipine on respiratory mechanics investigated by theend inflation occlusion method in the rat. AB - CONTEXT: Calcium channel blockers may theoretically exhibit relaxing effects not only on vascular smooth muscle but also on airway smooth muscle. OBJECTIVE: To investigate possible effects of nifedipine on respiratory mechanics in the rat. METHODS: Respiratory system mechanical parameters were measured by the end inflation occlusion method in the rat in vivo before and after the intraperitoneal administration of nifedipine. RESULTS: We found that nifedipine affects respiratory mechanics, inducing a reduction of airway resistance and of respiratory system elastance, probably because of a relaxing action on airway and parenchimal smooth muscle cells. CONCLUSION: Should these results be further confirmed by human investigations, a possible role of nifedipine in pharmacological respiratory system's diseases treatment may be suggested. PMID- 27766902 TI - Separation of antioxidant and alpha-glucosidase inhibitory flavonoids from the aerial parts of Asterothamnus centrali-asiaticus. AB - A new flavonoid, along with 16 known ones, was separated from the aerial parts of Asterothamnus centrali-asiaticus. Their structures were elucidated by extensive spectroscopic methods, including 1D and 2D NMR techniques and HRESIMS. To confirm the structure of the new compound, computational prediction of its 13C chemical shifts was performed. All of the 17 flavonoids were reported from A. centrali asiaticus for the first time. In addition, all flavonoids were evaluated for their antioxidant and alpha-glucosidase inhibitory activities. The results showed that 10 of them exhibited antioxidant activity. Meanwhile, four flavonoids displayed alpha-glucosidase inhibitory effect with IC50 values ranging from 38.9 to 299.7 MUM. PMID- 27766903 TI - Synthesis of new Schiff bases bearing 1,2,4-triazole, thiazolidine and chloroazetidine moieties and their pharmacological evaluation. AB - New compounds based on oxindole moiety were synthesized via the reaction of 5 substitued isatins 1a-e with different nucleophiles such as benzidine, 3,3' dimethoxybenzidine 2a,b and 2,6-diaminopyridine 3 to afford three different classes of bis-Schiff bases 4a-e, 5a-e and 6a-e, respectively. The structures of the new compounds were elucidated on the basis of their FTIR, 1H NMR, 13C NMR, GC/MS spectral data and elemental analysis. The in vitro antimicrobial activity of the new compounds was evaluated using a broth dilution technique in terms of minimal inhibitory concentration (MIC) against four bacterial and two fungal pathogens and anticancer activities against HELA cervix. The revealed data showed that compound 9d has excellent activity against Gram + ve and Gram -ve bacteria, and compounds 11b presented promising anticancer activity against HELA cervix. [Formula: see text]. PMID- 27766904 TI - Intraspinal hypotension syndrome presents as transient quadriplegia. AB - Intracranial hypotension can be a complication of epidural anaesthesia. Pure clinical spinal hypotension manifesting as acute transient quadriplegia following epidural anaesthesia is a severe, life-threatening complication that have not been described before. This complication can be solved with an epidural blood patch; thus, it should be familiar to doctors across all specialities. PMID- 27766905 TI - Chronic breathlessness in patients with idiopathic pulmonary fibrosis: a major challenge for caregivers. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, with a median survival time of two to five years. Most patients with IPF experience chronic breathlessness, which is closely linked to poor perceived quality of life and significant restriction of daily activities; therefore, effective management of this distressing symptom is a major goal of patient care. Areas covered: This report summarizes the physiology of IPF during rest and exercise, outlines current concepts of the mechanisms of breathlessness, and provides a physiological rationale for optimal management of individual patients. It also examines the evidence for efficacy of a number of therapeutic interventions currently at our disposal for the management of breathlessness in IPF, which aim to reduce respiratory neural drive, reduce worsening of mechanical load, and alter central perception. Expert commentary: The current evidence supporting general measures in relieving chronic breathlessness is weak; hence, more carefully designed prospective studies are required. PMID- 27766906 TI - Unemployment as a chronic stressor: A systematic review of cortisol studies. AB - OBJECTIVE: Unemployment is a type of chronic stressor that impacts human health. The reasons for how the stress of unemployment affect health is still a matter of discussion. One of the pathways from chronic stress to ill health is mediated by cortisol, and so we set out to compile extant data on how its secretion is affected by unemployment. DESIGN: A systematic literature search was conducted to establish the cortisol dysregulatory effects of this stressor. MAIN OUTCOME MEASURES: Only studies that specifically examined the effects of unemployment on cortisol excretion, and were written in English were included. RESULTS: Ten reports were obtained and synthesised to determine the severity and complexity of the effect of unemployment on cortisol secretion. The resulting combined evidence is mixed in terms of degree or dynamic of relationship. CONCLUSIONS: The differences between the cumulate findings of the studies can be understood in the context of the lack of both standardised methodology and an absence of consensus on unemployment definition. We propose existing methodologies may be strengthened by acknowledging and accounting for the individual characteristics that may be relevant to the stress experience of unemployment. PMID- 27766908 TI - Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. AB - A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC50= 1.35 +/- 0.08 MUM), while compound 3 exhibited the highest inhibition against BuChE (IC50= 13.41 +/- 0.62 MUM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. PMID- 27766910 TI - Can gaming turn doctors into better tacticians? PMID- 27766909 TI - Patterns of marriage and reproductive practices: is there any relationship? AB - Today, a transition from traditional to modern marriages can be observed in many countries. This shift in patterns of marriage has evidently affected childbearing and reproductive practices. This study aimed to examine the relationship between patterns of marriage and reproductive practices in Iran. Hence, 880 married women, aged 15-49 years old, living in the North of Iran were selected using a multi-stage cluster sampling strategy and their patterns of marriage and reproductive practices were cross sectionally studied. The results revealed that there were no significant differences in the reproductive practices by three main patterns of marriage in Babol, Iran. The study also indicated that there were no significant differences in reproductive practices in three patterns of marriage after controlling for socio-economic variables. It seems that apart from the patterns of marriage, other influencing factors are the determinants of fertility in women, and the policy-makers of Iran need to pay attention to these determinants before making any decisions in this area. PMID- 27766911 TI - The minimally important difference for the Japanese version of the health assessment questionnaire in patients with rheumatoid arthritis in daily practice. AB - OBJECTIVE: To validate the minimally important difference (MID) of physical function using the Japanese version of the Health Assessment Questionnaire (J HAQ) in a cohort of rheumatoid arthritis (RA). METHODS: Patients who participated in a cohort study in both October 2008 and April 2009 were analyzed. Patients self-rated their change in overall status over 6 months using a 5-point Likert scale ("much better", "somewhat better", "same", "somewhat worse", or "much worse"). The MID for J-HAQ score was defined as the mean J-HAQ score change in patients who rated themselves "somewhat better". An effect size (ES) of 0.2-0.5 was considered to be suitable for MID. RESULTS: A total of 4560 patients were analyzed. The mean (standard deviation [SD]) MID for J-HAQ score was -0.06 (0.29), corresponding to an ES of 0.08. As exploratory analysis, 1999 patients with a J-HAQ score >=0.5 and 28-joint disease activity score (DAS28) >= 2.6 at baseline were assessed. The mean (SD) MID for J-HAQ score of these patients was 0.13 (0.01), corresponding to an ES of 0.21. CONCLUSIONS: The MID for J-HAQ score was 0.13 in patients with baseline J-HAQ score >=0.5 and DAS28 >= 2.6. The MID for J-HAQ score was influenced by disease status and functional disability. PMID- 27766912 TI - A dual perspective on peer teaching. PMID- 27766913 TI - Patient specific risk stratification for antimicrobial resistance and possible treatment strategies in gram-negative bacterial infections. AB - INTRODUCTION: The isolation of multi-drug-resistant gram-negative (MDRGN) pathogens has progressively increased worldwide and has been associated with important delays in the prescription of an adequate antibiotic treatment, resulting in increased mortality rates. Patient's stratification for MDRGN infections to optimize the prescription of an adequate empiric antimicrobial regimen is crucial. Areas covered: This article covers MDRGN epidemiology, with a specific focus on risk factors for harbouring infections sustained by extended spectrum-Beta-lactamase (ESBL), carbapenem resistant Enterobacteriacae (CRE), MDR Pseudomonas aeruginosa and MDR Acinetobacter baumanii. Moreover, we will propose an algorithm for the choice of empiric treatment when a MDRGN infection is suspected. Expert commentary: Although in clinical practice, a patient's stratification represents a challenge, whenever a MDRGN pathogen is suspected broad-spectrum, combination empiric treatment should be promptly started, looking for a balance between the prescription of an adequate empiric treatment and the risk of resistance selection. PMID- 27766914 TI - N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. AB - INTRODUCTION: N-acetylcysteine (NAC) is widely known for its role as a mucolytic and as an antidote to paracetamol overdose. There is increasing interest in the use of NAC in the treatment of several psychiatric disorders. The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and inflammatory pathways. Areas covered: This study reviews the available data regarding the use of NAC in different psychiatric disorders including substance use disorders, autism, obsessive-compulsive spectrum disorders, schizophrenia, depression, bipolar disorder. Promising results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin picking) disorder. Despite initial optimism, recent findings regarding NAC efficacy in autism have been disappointing. Expert opinion: These preliminary positive results require further confirmation in larger samples and with longer follow-ups. Given its high tolerability and wide availability, NAC represents an important target to investigate in the field of new adjunctive treatments for psychiatric conditions. PMID- 27766915 TI - Leaching of manganese from electrolytic manganese residue by electro-reduction. AB - In this study, an improved process for leaching manganese from electrolytic manganese residue (EMR) by electro-reduction was developed. The mechanisms of the electro-reduction leaching were investigated through X-ray diffraction, scanning electron microscopy, X-ray fluorescence, and Brunauer Emmett Teller. The results show that the electric field could change the surface charge distribution of EMR particles, and the high-valent manganese can be reduced by electric field. The leaching efficient of manganese reached 84.1% under the optimal leaching condition: 9.2 wt% H2SO4, current density of 25 mA/cm2, solid-to-liquid ratio of 1:5, and leaching time for 1 h. It is 37.9% higher than that attained without an electric field. Meanwhile, the manganese content in EMR decreased from 2.57% to 0.48%. PMID- 27766916 TI - A real-world risk analysis of biological treatment (adalimumab and etanercept) in a country with a high prevalence of tuberculosis and chronic liver disease: a nationwide population-based study. AB - OBJECTIVES: Few studies on tumour necrosis factor (TNF) inhibitor-associated tuberculosis (TB) and hepatic events have been performed in regions where these risks are elevated. This study aimed to provide a direct comparison between adalimumab and etanercept in a high-risk population and to address the implications for physicians working with patients in such an environment. METHOD: Data collected from the National Health Insurance Research Database (NHIRD) in Taiwan between 2007 and 2011 were analysed retrospectively for incidences of eight adverse events associated with TNF-alpha inhibitors. Hazard ratios (HRs) of adalimumab vs. etanercept were calculated using a Cox proportional hazards model. RESULTS: During this 5-year period, 86 events of TB were reported after 5317 person-years of exposure to adalimumab (1.62 events per 100 person-years), compared to 44 events after 7690 person-years of exposure to etanercept (0.57 events per 100 person-years). For serious hepatic events that led to hospitalization, 0.75 events were reported per 100 person-years of exposure to adalimumab compared to 0.39 events per 100 person-years of exposure to etanercept. Adjusted HRs for TB [aHR 3.06, 95% confidence interval (CI) 2.09 4.49, p < 0.0001], hospitalization due to a hepatic event (aHR 2.05, 95% CI 1.27 3.30, p = 0.0035), and serious infection (aHR 1.48, 95% CI 1.19-1.84, p = 0.0005) attained significance. CONCLUSIONS: TNF-alpha-targeting therapies with the monoclonal antibody adalimumab confers significant added risk of TB and serious hepatic events compared to therapies with the soluble fusion protein etanercept. Tailored strategies to attenuate these risks are warranted in high-risk regions such as Taiwan. PMID- 27766917 TI - Water treatment with exceptional virus inactivation using activated carbon modified with silver (Ag) and copper oxide (CuO) nanoparticles. AB - Continuous flow experiments (450 mL min-1) were performed in household filter in order to investigate the removal and/or inactivation of T4 bacteriophage, using granular activated carbon (GAC) modified with silver and/or copper oxide nanoparticles at different concentrations. GAC and modified GAC were characterized by X-ray diffractometry, specific surface area, pore size and volume, pore average diameter, scanning electron microscopy, transmission electron microscopy, zeta potential and atomic absorption spectroscopy. The antiviral activity of the produced porous media was evaluated by passing suspensions of T4 bacteriophage (~105 UFP/mL) through filters. The filtered water was analyzed for the presence of the bacteriophage and the release of silver and copper oxide. The porous media containing silver and copper oxide nanoparticles showed high inactivation capacity, even reaching reductions higher than 3 log. GAC6 (GAC/Ag0.5%Cu1.0%) was effective in the bacteriophage inactivation, reaching 5.53 log reduction. The levels of silver and copper released in filtered water were below the recommended limits (100 ppb for silver and 1000 ppb for copper) in drinking water. From this study, it is possible to conclude that activated carbon modified with silver and copper oxide nanoparticles can be used as a filter for virus removal in the treatment of drinking water. PMID- 27766918 TI - Endobronchial ultrasound-guided transbronchial needle aspiration rinse fluid polymerase chain reaction in the diagnosis of intrathoracic tuberculous lymphadenitis. AB - BACKGROUND: Intrathoracic tuberculous (TB) lymphadenitis is a diagnostic challenge to the clinician. Although endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) can obtain a sample from the affected lymph node, the diagnosis of TB lymphadenitis by cytopathology remains inaccurate. OBJECTIVE: To evaluate the efficacy of EBUS-TBNA rinse fluid TB polymerase chain reaction (PCR) assay for the diagnosis of intrathoracic TB lymphadenitis. METHODS: A retrospective study was conducted on 102 patients who underwent EBUS-TBNA for diagnostic evaluation of intrathoracic lymphadenopathy. EBUS-TBNA specimens were evaluated by cytopathological examination. Rinse fluid of the needle was routinely submitted for acid-fast bacillus (AFB) staining, mycobacterial culture, and TB-PCR using the AnyplexTM MTB/NTM real-time detection kit. RESULTS: Of 102 patients, 16 were diagnosed with intrathoracic TB lymphadenitis by either microbiology, cytopathology, or on clinical grounds. The sensitivity, specificity, positive predictive value, and negative predictive value of rinse fluid TB PCR assay were 56.2%, 100.0%, 100.0%, and 92.5%, respectively. Using the area under the ROC curve (AUC) as a measure of a diagnostic performance, TB-PCR had the highest AUC, compared with mycobacterial culture, AFB smear, and finding of necrotizing granulomatous inflammation (0.78, 0.75, 0.56, and 0.72, respectively). A combination of TB PCR, mycobacterial culture, and finding of necrotizing granulomatous inflammation provided the best diagnostic performance (sensitivity, specificity, positive predictive value, negative predictive value, and AUC of 75.0%, 100.0%, 100.0%, 95.6%, and 0.88, respectively). CONCLUSIONS: EBUS-TBNA rinse fluid TB-PCR is useful in the diagnosis of intrathoracic TB lymphadenitis. Combining TB-PCR with mycobacterial culture and cytopathological findings improved the diagnosis performance. PMID- 27766919 TI - Analysis of the costs for the laboratory of flow cytometry screening of urine samples before culture. AB - Urine culture samples comprise a large proportion of the workload in clinical microbiology laboratories, and most of the urine samples show no growth or insignificant growth. A flow cytometry-based analyzer (Sysmex Corporation, Japan) has been used to screen out negative urine samples prior to culture in the Paijat Hame district. We applied decision analytic modelling to analyze, from a laboratory perspective, the economic feasibility of the screening method as compared to culture only (conventional method) for diagnosis of urinary tract infection. Our model suggests that the least costly analytical strategy is the conventional method. The incremental cost of screening is ?0.29/sample. Although laboratory costs are higher, considerable savings on workload can be achieved. Furthermore, screening has numerous benefits on the treatment process of a patient that well warrant the use of the screening method. We conclude that the incremental cost of screening the samples is worth the expense. PMID- 27766920 TI - Assessment of liver slices for research on metabolic drug-drug interactions in cattle. AB - 1. Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse. 2. The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ). 3. Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system. 4. Tissue viability, assessed through both structural and functional markers, was preserved throughout 12 h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p < 0.001) in the rates of appearance of (+) ABZSO. Conversely, in presence of MTZ, the rates of appearance of (-) ABZSO increased under both systems (p < 0.05). 5. Both culture systems were suitable for assessing the interaction between ABZ and MTZ. 6. Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug-drug interactions in the bovine species. PMID- 27766921 TI - Clinical efficacy of laninamivir and peramivir in patients with seasonal influenza: a randomized clinical trial. PMID- 27766922 TI - Stabilization of carbon dioxide and chromium slag via carbonation. AB - As the main greenhouse gas, CO2 is considered as a threat in the context of global warming. Many available technologies to reduce CO2 emission was about CO2 separation from coal combustion and geological sequestration. However, how to deal with the cost-effective storage of CO2 has become a new challenge. Moreover, chromium pollution, the treatment of which requires huge energy consumption, has attracted people's widespread attention. This study is aimed to develop the sequestration of CO2 via chromium slag. A dynamic leaching experiment of chromium slag was designed to testify the ability of CO2 adsorption onto chromium slag and to release Cr(VI) for stabilization. The results showed that the accumulative amounts of Cr(VI) were ca. 2.6 mg/g released from the chromium slag after 24 h of leaching. In addition, ca. 89 mg/g CO2 was adsorbed by using pure CO2 in the experiment at 12 h. Calcite is the only carbonate species in the post-carbonated slag analyzed by powder X-ray diffraction and thermal analysis. The approach provides the feasibility of the utilization of chromium slag and sequestration of the carbon dioxide at the same time at ordinary temperatures and pressures. PMID- 27766923 TI - In vitro antiaggregation and deaggregation potential of Rhizophora mucronata and its bioactive compound (+)- catechin against Alzheimer's beta amyloid peptide (25 35). AB - OBJECTIVE: Amyloid hypothesis states that endogenous beta-amyloid peptides (Abeta), especially its aggregated oligomers and fibrils are the key pathogenic factors leading to Alzheimer's disease (AD). Therefore, inhibition of Abeta fibrillation rather than blocking its production is considered promising therapeutic intervention. Hence, the present study was carried out to assess the effect of methanolic leaf extract of R. mucronata (MERM) and its bioactive compound catechin on in vitro fibrillation of Abeta (25-35). METHODOLOGY: Antiaggregation and disaggregation effect by MERM and (+)- catechin against Abeta (25-35) were assessed in three different phases by thioflavin T (ThT) fluorescence assay and confocal microscopic analysis. The conformational changes in the aggregated Abeta fibrils in the presence and absence of MERM and catechin were analysed by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and CD spectroscopy. RESULTS: Results of ThT and confocal microscopic studies showed decrease in fluorescence intensity in MERM and catechin-treated groups illustrating that both MERM and catechin effectively inhibited fibril aggregation as well as destabilized preformed Abeta fibril. TEM revealed that MERM incubated samples were virtually devoid of structured fibrils but had an amorphous-like consistency, whereas the control contained structured fibrils of various width and length. FTIR analysis showed decrease in absorbance at 1630 cm-1 (amide I region) in MERM-treated groups substantiating the results of ThT assay. Circular dichroism data indicate that catechin prevents the formation of beta-structured aggregates of Abeta peptide. CONCLUSION: Results suggest that MERM and catechin might have direct interaction with Abeta peptide preventing its fibrillation. PMID- 27766924 TI - The birth beliefs scale - a new measure to assess basic beliefs about birth. AB - INTRODUCTION: Basic beliefs about birth as a natural and safe or a medical and risky process are central in the decisions on where and how to birth. Despite their importance, they have not been studied separately from other childbirth related constructs. Our aim was to develop a measure to assess these beliefs. METHOD: Pregnant Israeli women (N = 850, gestational week >=14) were recruited in women's health centers, in online natural birth forums, and through home midwives. Participants filled in questionnaires including sociodemographic and obstetric background, the Birth Beliefs Scale (BBS), dispositional desire for control (DC) and planned mode of delivery. RESULTS: Factor analyses revealed that the BBS is composed of two factors: beliefs about birth as a natural process and beliefs about birth as a medical process. Both subscales showed good internal and test-retest reliability. They had good construct validity, predicted birth choices, and were weakly correlated with DC. Women's medical obstetric history was associated with the BBS, further supporting the validity of the scale. DISCUSSION: Beliefs about birth may be the building blocks that make up perceptions of birth and drive women's preferences. The new scale provides an easy way to distinctly assess them so they can be used to further understand planned birth behaviors. Additional studies are needed to comprehend how these beliefs form in different cultural contexts and how they evolve over time. PMID- 27766925 TI - Is gentamicin necessary in the antimicrobial treatment for group B streptococcal infections in the elderly? An in vitro study with human blood products. AB - BACKGROUND: According to expert opinions, gentamicin should be administered as an adjunct to penicillin against severe group B streptococcal (GBS) infections. Whether the adjunct is important is of particular interest for elderly patients. Not only is the risk of aminoglycoside nephrotoxicity higher in elderly persons, but their immune defence to bacterial infections may also be impaired. METHOD: Time-kill assays with human blood products, such as serum, neutrophilic granulocytes (opsonophagocytic assays) and whole blood from healthy, elderly volunteers were performed to evaluate the effect of gentamicin in combination with penicillin. RESULTS: In time-kill assays with human serum and in opsonophagocytic assays, we saw a trend for faster killing with the penicillin gentamicin combination therapy. This effect was seen 4 and 6 h after antibiotic exposure but not at time points evaluated at >=8 h. In whole blood killing assays, no difference in killing rates was observed with adjunctive gentamicin therapy. CONCLUSION: The criteria for synergism were not fulfilled when the effect of penicillin-gentamicin combinations was compared with that of penicillin monotherapy. Rapid killing of GBS within the first few hours was observed in time kill assays with human blood products. Considering that elderly people are prone to gentamicin nephrotoxicity and that in severe GBS infection a high penicillin dose is administered every 4-6 h, the prolonged use of adjunctive aminoglycosides in these infections requires caution. PMID- 27766927 TI - Differences in holistic processing do not explain cultural differences in the recognition of facial expression. AB - The aim of this study was to investigate the causes of the own-race advantage in facial expression perception. In Experiment 1, we investigated Western Caucasian and Chinese participants' perception and categorization of facial expressions of six basic emotions that included two pairs of confusable expressions (fear and surprise; anger and disgust). People were slightly better at identifying facial expressions posed by own-race members (mainly in anger and disgust). In Experiment 2, we asked whether the own-race advantage was due to differences in the holistic processing of facial expressions. Participants viewed composite faces in which the upper part of one expression was combined with the lower part of a different expression. The upper and lower parts of the composite faces were either aligned or misaligned. Both Chinese and Caucasian participants were better at identifying the facial expressions from the misaligned images, showing interference on recognizing the parts of the expressions created by holistic perception of the aligned composite images. However, this interference from holistic processing was equivalent across expressions of own-race and other-race faces in both groups of participants. Whilst the own-race advantage in recognizing facial expressions does seem to reflect the confusability of certain emotions, it cannot be explained by differences in holistic processing. PMID- 27766926 TI - Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects. AB - A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies. PMID- 27766928 TI - Changes in vital signs as predictors of bacterial infection in home care: a multi center prospective cohort study. AB - OBJECTIVES: To explore whether the combination of changes in heart rate and body temperature can predict bacterial infection in home care patients. METHODS: This multicenter, prospective cohort study was conducted in Japan from March 2012 through December 2013 and involved three clinics. The study population comprised all patients who received regular home visit services for at least 3 months and met one of the following inclusion criteria: 1) fever over 37.5 degrees C at home visit, 2) physician's clinical suspicion of fever, or 3) physician's suspicion of bacterial infection. We collected temperature and heart rate data on the day of enrollment, and determined the probable causes of fever after treatment of febrile episodes. We defined the combination of changes in heart rate and body temperature as delta HR/BT. We calculated two types of delta HR/BT, averaged and assumed, using different baseline values for heart rate and body temperature. RESULTS: A total of 124 patients were enrolled and 194 episodes of fever were analyzed during the study period. The sensitivity, specificity, positive predictive value, and negative predictive value for the average delta HR/BT with a cut-off >= 20 were 20.4% (95% CI, 16.7-23.3), 84.2% (95% CI, 75.2-91.0), 75.7% (95% CI, 61.8-86.2), and 30.6% (95% CI, 27.3-33.0), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the assumed delta HR/BT with a cut-off >= 5 was 91.2% (95% CI, 89.2 94.0), 8.9% (95% CI, 4.1-15.7), 70.9% (95% CI, 69.3-73.0), and 29.4% (95% CI, 13.6-51.8), respectively. CONCLUSIONS: The combination of changes in heart rate and body temperature could help physicians determine whether home care patients have bacterial infections. PMID- 27766929 TI - Pulmonary sarcoidosis: an update. AB - Sarcoidosis is a multisystem disease characterized by the presence of noncaseating granulomas, the exact etiology of which is yet to be determined. Pulmonary involvement occurs in the majority of patients and its severity ranges from asymptomatic involvement of mediastinal lymph nodes to progressive pulmonary fibrosis and chronic respiratory failure that is insensitive to treatment. Diagnosis of pulmonary sarcoidosis requires a compatible clinical picture supported by radiologic and pathologic data. A recent development in establishing the diagnosis of pulmonary sarcoidosis is endobronchial ultrasound that increases the yield of transbronchial needle aspiration of hilar and/or mediastinal lymph nodes. Fluorodeoxyglucose positron emission tomography (FDG-PET) is highly sensitive in detecting occult sites of disease and is of value in guiding biopsies of these sites. A combined imaging modality using both FDG-PET and CT scan is more sensitive than PET alone and is now the standard of care in patients requiring biopsies of active lesions. Biologic agents like anti-tumor necrosis factor antibodies are being used as second line treatment in those patients dependent on steroids or in cases of refractory sarcoidosis. Lung transplantation is the final option in suitable patients with end-stage pulmonary sarcoidosis. PMID- 27766930 TI - Prevalence of climacteric symptoms comparing perimenopausal and postmenopausal Chinese women. AB - INTRODUCTION: The climacteric symptoms during peri- and postmenopause have not been extensively studied in China. To further understanding of the characteristics of Chinese women during their menopausal transition, the aim of the study was to compare the prevalence and severity of climacteric symptoms of peri- and postmenopausal Chinese women. METHODS: The retrospective descriptive study was carried out in perimenopausal and postmenopausal women from 20 provinces of China who visited Beijing Obstetrics & Gynecology hospital during 2008-2015. A total of 1225 women aged 34-76 years without hormone replacement therapy were analyzed. Menopausal status was defined by the "2011 Stages of Reproductive Aging Workshop criteria". The following climacteric symptoms were assessed: fatigue, insomnia, irritability, depression, palpitations, muscle and joint pain, dizziness, vaginal dryness, headache, urinary incontinence, hot flash, sweat, pain during intercourse, and formication. RESULTS: The most frequent five symptoms were fatigue (75.84%), insomnia (69.39%), irritability (67.02%), palpitations (62.78%), and depression (61.88%). The prevalence of 14 symptoms was significantly higher in the postmenopause compared with the perimenopause status group (all p < .05).The severity of fatigue, insomnia, irritability, palpitation, vaginal dryness, muscle, and joint pain and pain during intercourse was significantly different between the perimenopausal and postmenopausal groups. CONCLUSIONS: The most frequent five symptoms among the investigated 1225 Chinese women were fatigue, insomnia, irritability, palpitations, depression, nearly the same in perimenopausal and postmenopausal women. The prevalence and the severity of most of the symptoms were significantly different between the two groups. PMID- 27766932 TI - Going online - a tribute to John Simons. PMID- 27766933 TI - Proceedings of the 2016 MidSouth Computational Biology and Bioinformatics Society (MCBIOS) Conference. PMID- 27766931 TI - RENEB intercomparisons applying the conventional Dicentric Chromosome Assay (DCA). AB - PURPOSE: Two quality controlled inter-laboratory exercises were organized within the EU project 'Realizing the European Network of Biodosimetry (RENEB)' to further optimize the dicentric chromosome assay (DCA) and to identify needs for training and harmonization activities within the RENEB network. MATERIALS AND METHODS: The general study design included blood shipment, sample processing, analysis of chromosome aberrations and radiation dose assessment. After manual scoring of dicentric chromosomes in different cell numbers dose estimations and corresponding 95% confidence intervals were submitted by the participants. RESULTS: The shipment of blood samples to the partners in the European Community (EU) were performed successfully. Outside the EU unacceptable delays occurred. The results of the dose estimation demonstrate a very successful classification of the blood samples in medically relevant groups. In comparison to the 1st exercise the 2nd intercomparison showed an improvement in the accuracy of dose estimations especially for the high dose point. CONCLUSIONS: In case of a large scale radiological incident, the pooling of ressources by networks can enhance the rapid classification of individuals in medically relevant treatment groups based on the DCA. The performance of the RENEB network as a whole has clearly benefited from harmonization processes and specific training activities for the network partners. PMID- 27766934 TI - CC-PROMISE effectively integrates two forms of molecular data with multiple biologically related endpoints. AB - BACKGROUND: As new technologies allow investigators to collect multiple forms of molecular data (genomic, epigenomic, transcriptomic, etc) and multiple endpoints on a clinical trial cohort, it will become necessary to effectively integrate all these data in a way that reliably identifies biologically important genes. METHODS: We introduce CC-PROMISE as an integrated data analysis method that combines components of canonical correlation (CC) and projection onto the most interesting evidence (PROMISE). For each gene, CC-PROMISE first uses CC to compute scores that represent the association of two forms of molecular data with each other. Next, these scores are substituted into PROMISE to evaluate the statistical evidence that the molecular data show a biologically meaningful relationship with the endpoints. RESULTS: CC-PROMISE shows outstanding performance in simulation studies and an example application involving pediatric leukemia. In simulation studies, CC-PROMISE controls the type I error (misleading significance) rate very near the nominal level across 100 distinct null settings in which no molecular-endpoint association exists. Also, CC-PROMISE has better statistical power than three other methods that control type I error in 396 of 400 (99 %) alternative settings for which a molecular-endpoint association is present; the power advantage of CC-PROMISE exceeds 30 % in 127 of the 400 (32 %) alternative settings. These advantages of CC-PROMISE are also observed in an example application. CONCLUSION: CC-PROMISE very effectively identifies genes for which some form of molecular data shows a biologically meaningful association with multiple related endpoints. AVAILABILITY: The R package CCPROMISE is currently available from www.stjuderesearch.org/site/depts/biostats/software . PMID- 27766935 TI - Analysis of optimal alignments unfolds aligners' bias in existing variant profiles. AB - Efforts such as International HapMap Project and 1000 Genomes Project resulted in a catalog of millions of single nucleotides and insertion/deletion (INDEL) variants of the human population. Viewed as a reference of existing variants, this resource commonly serves as a gold standard for studying and developing methods to detect genetic variants. Our analysis revealed that this reference contained thousands of INDELs that were constructed in a biased manner. This bias occurred at the level of aligning short reads to reference genomes to detect variants. The bias is caused by the existence of many theoretically optimal alignments between the reference genome and reads containing alternative alleles at those INDEL locations. We examined several popular aligners and showed that these aligners could be divided into groups whose alignments yielded INDELs that agreed strongly or disagreed strongly with reported INDELs. This finding suggests that the agreement or disagreement between the aligners' called INDEL and the reported INDEL is merely a result of the arbitrary selection of one of the optimal alignments. The existence of bias in INDEL calling might have a serious influence in downstream analyses. As such, our finding suggests that this phenomenon should be further addressed. PMID- 27766936 TI - Dissecting the biological relationship between TCGA miRNA and mRNA sequencing data using MMiRNA-Viewer. AB - BACKGROUND: MicroRNAs (miRNA) are short nucleotides that interact with their target genes through 3' untranslated regions (UTRs). The Cancer Genome Atlas (TCGA) harbors an increasing amount of cancer genome data for both tumor and normal samples. However, there are few visualization tools focusing on concurrently displaying important relationships and attributes between miRNAs and mRNAs of both cancer tumor and normal samples. Moreover, a deep investigation of miRNA-mRNA target and biological relationships across multiple cancer types by integrating web-based analysis has not been thoroughly conducted. RESULTS: We developed an interactive visualization tool called MMiRNA-Viewer that can concurrently present the co-relationships of expression between miRNA-mRNA pairs of both tumor and normal samples into a single graph. The input file of MMiRNA Viewer contains the expression information including fold changes between normal and tumor samples for mRNAs and miRNAs, the correlation between mRNA and miRNA, and the predicted target relationship by a number of databases. Users can also load their own input data into MMiRNA-Viewer and visualize and compare detailed information about cancer-related gene expression changes, and also changes in the expression of transcription-regulating miRNAs. To validate the MMiRNA-Viewer, eight types of TCGA cancer datasets with both normal and control samples were selected in this study and three filter steps were applied subsequently. We performed Gene Ontology (GO) analysis for genes available in final selected 238 pairs and also for genes in the top 5 % (95 percentile) for each of eight cancer types to report a significant number of genes involved in various biological functions and pathways. We also calculated various centrality measurement matrices for the largest connected component(s) in each of eight cancers and reported top genes and miRNAs with high centrality measurements. CONCLUSIONS: With its user-friendly interface, dynamic visualization and advanced queries, we also believe MMiRNA-Viewer offers an intuitive approach for visualizing and elucidating co-relationships between miRNAs and mRNAs of both tumor and normal samples. We suggest that miRNA and mRNA pairs with opposite fold changes of their expression and with inverted correlation values between tumor and normal samples might be most relevant for explaining the decoupling of mRNAs and their targeting miRNAs in tumor samples for certain cancer types. PMID- 27766937 TI - Leveraging graph topology and semantic context for pharmacovigilance through twitter-streams. AB - BACKGROUND: Adverse drug events (ADEs) constitute one of the leading causes of post-therapeutic death and their identification constitutes an important challenge of modern precision medicine. Unfortunately, the onset and effects of ADEs are often underreported complicating timely intervention. At over 500 million posts per day, Twitter is a commonly used social media platform. The ubiquity of day-to-day personal information exchange on Twitter makes it a promising target for data mining for ADE identification and intervention. Three technical challenges are central to this problem: (1) identification of salient medical keywords in (noisy) tweets, (2) mapping drug-effect relationships, and (3) classification of such relationships as adverse or non-adverse. METHODS: We use a bipartite graph-theoretic representation called a drug-effect graph (DEG) for modeling drug and side effect relationships by representing the drugs and side effects as vertices. We construct individual DEGs on two data sources. The first DEG is constructed from the drug-effect relationships found in FDA package inserts as recorded in the SIDER database. The second DEG is constructed by mining the history of Twitter users. We use dictionary-based information extraction to identify medically-relevant concepts in tweets. Drugs, along with co-occurring symptoms are connected with edges weighted by temporal distance and frequency. Finally, information from the SIDER DEG is integrate with the Twitter DEG and edges are classified as either adverse or non-adverse using supervised machine learning. RESULTS: We examine both graph-theoretic and semantic features for the classification task. The proposed approach can identify adverse drug effects with high accuracy with precision exceeding 85 % and F1 exceeding 81 %. When compared with leading methods at the state-of-the-art, which employ un enriched graph-theoretic analysis alone, our method leads to improvements ranging between 5 and 8 % in terms of the aforementioned measures. Additionally, we employ our method to discover several ADEs which, though present in medical literature and Twitter-streams, are not represented in the SIDER databases. CONCLUSIONS: We present a DEG integration model as a powerful formalism for the analysis of drug-effect relationships that is general enough to accommodate diverse data sources, yet rigorous enough to provide a strong mechanism for ADE identification. PMID- 27766938 TI - Effective comparative analysis of protein-protein interaction networks by measuring the steady-state network flow using a Markov model. AB - BACKGROUND: Comparative analysis of protein-protein interaction (PPI) networks provides an effective means of detecting conserved functional network modules across different species. Such modules typically consist of orthologous proteins with conserved interactions, which can be exploited to computationally predict the modules through network comparison. RESULTS: In this work, we propose a novel probabilistic framework for comparing PPI networks and effectively predicting the correspondence between proteins, represented as network nodes, that belong to conserved functional modules across the given PPI networks. The basic idea is to estimate the steady-state network flow between nodes that belong to different PPI networks based on a Markov random walk model. The random walker is designed to make random moves to adjacent nodes within a PPI network as well as cross-network moves between potential orthologous nodes with high sequence similarity. Based on this Markov random walk model, we estimate the steady-state network flow - or the long-term relative frequency of the transitions that the random walker makes - between nodes in different PPI networks, which can be used as a probabilistic score measuring their potential correspondence. Subsequently, the estimated scores can be used for detecting orthologous proteins in conserved functional modules through network alignment. CONCLUSIONS: Through evaluations based on multiple real PPI networks, we demonstrate that the proposed scheme leads to improved alignment results that are biologically more meaningful at reduced computational cost, outperforming the current state-of-the-art algorithms. The source code and datasets can be downloaded from http://www.ece.tamu.edu/~bjyoon/CUFID . PMID- 27766939 TI - Phylogenetic tree construction using trinucleotide usage profile (TUP). AB - BACKGROUND: It has been a challenging task to build a genome-wide phylogenetic tree for a large group of species containing a large number of genes with long nucleotides sequences. The most popular method, called feature frequency profile (FFP-k), finds the frequency distribution for all words of certain length k over the whole genome sequence using (overlapping) windows of the same length. For a satisfactory result, the recommended word length (k) ranges from 6 to 15 and it may not be a multiple of 3 (codon length). The total number of possible words needed for FFP-k can range from 46=4096 to 415. RESULTS: We propose a simple improvement over the popular FFP method using only a typical word length of 3. A new method, called Trinucleotide Usage Profile (TUP), is proposed based only on the (relative) frequency distribution using non-overlapping windows of length 3. The total number of possible words needed for TUP is 43=64, which is much less than the total count for the recommended optimal "resolution" for FFP. To build a phylogenetic tree, we propose first representing each of the species by a TUP vector and then using an appropriate distance measure between pairs of the TUP vectors for the tree construction. In particular, we propose summarizing a DNA sequence by a matrix of three rows corresponding to three reading frames, recording the frequency distribution of the non-overlapping words of length 3 in each of the reading frame. We also provide a numerical measure for comparing trees constructed with various methods. CONCLUSIONS: Compared to the FFP method, our empirical study showed that the proposed TUP method is more capable of building phylogenetic trees with a stronger biological support. We further provide some justifications on this from the information theory viewpoint. Unlike the FFP method, the TUP method takes the advantage that the starting of the first reading frame is (usually) known. Without this information, the FFP method could only rely on the frequency distribution of overlapping words, which is the average (or mixture) of the frequency distributions of three possible reading frames. Consequently, we show (from the entropy viewpoint) that the FFP procedure could dilute important gene information and therefore provides less accurate classification. PMID- 27766940 TI - Prioritization, clustering and functional annotation of MicroRNAs using latent semantic indexing of MEDLINE abstracts. AB - BACKGROUND: The amount of scientific information about MicroRNAs (miRNAs) is growing exponentially, making it difficult for researchers to interpret experimental results. In this study, we present an automated text mining approach using Latent Semantic Indexing (LSI) for prioritization, clustering and functional annotation of miRNAs. RESULTS: For approximately 900 human miRNAs indexed in miRBase, text documents were created by concatenating titles and abstracts of MEDLINE citations which refer to the miRNAs. The documents were parsed and a weighted term-by-miRNA frequency matrix was created, which was subsequently factorized via singular value decomposition to extract pair-wise cosine values between the term (keyword) and miRNA vectors in reduced rank semantic space. LSI enables derivation of both explicit and implicit associations between entities based on word usage patterns. Using miR2Disease as a gold standard, we found that LSI identified keyword-to-miRNA relationships with high accuracy. In addition, we demonstrate that pair-wise associations between miRNAs can be used to group them into categories which are functionally aligned. Finally, term ranking by querying the LSI space with a group of miRNAs enabled annotation of the clusters with functionally related terms. CONCLUSIONS: LSI modeling of MEDLINE abstracts provides a robust and automated method for miRNA related knowledge discovery. The latest collection of miRNA abstracts and LSI model can be accessed through the web tool miRNA Literature Network (miRLiN) at http://bioinfo.memphis.edu/mirlin . PMID- 27766941 TI - Use of Robson classification to assess cesarean section rate in Brazil: the role of source of payment for childbirth. AB - BACKGROUND: Cesarean section (CS) rates are increasing worldwide but there is some concern with this trend because of potential maternal and perinatal risks. The Robson classification is the standard method to monitor and compare CS rates. Our objective was to analyze CS rates in Brazil according to source of payment for childbirth (public or private) using the Robson classification. METHODS: Data are from the 2011-2012 "Birth in Brazil" study, which used a national hospital based sample of 23,940 women. We categorized all women into Robson groups and reported the relative size of each Robson group, the CS rate in each group and the absolute and relative contributions made by each to the overall CS rate. Differences were analyzed through chi-square and Z-test with a significance level of < 0.05. RESULTS: The overall CS rate in Brazil was 51.9 % (42.9 % in the public and 87.9 % in the private health sector). The Robson groups with the highest impact on Brazil's CS rate in both public and private sectors were group 2 (nulliparous, term, cephalic with induced or cesarean delivery before labor), group 5 (multiparous, term, cephalic presentation and previous cesarean section) and group 10 (cephalic preterm pregnancies), which accounted for more than 70 % of CS carried out in the country. High-risk women had significantly greater CS rates compared with low-risk women in almost all Robson groups in the public sector only. CONCLUSIONS: Public policies should be directed at reducing CS in nulliparous women, particularly by reducing the number of elective CS in these women, and encouraging vaginal birth after cesarean to reduce repeat CS in multiparous women. PMID- 27766942 TI - Abrupt skin lesion border cutoff measurement for malignancy detection in dermoscopy images. AB - BACKGROUND: Automated skin lesion border examination and analysis techniques have become an important field of research for distinguishing malignant pigmented lesions from benign lesions. An abrupt pigment pattern cutoff at the periphery of a skin lesion is one of the most important dermoscopic features for detection of neoplastic behavior. In current clinical setting, the lesion is divided into a virtual pie with eight sections. Each section is examined by a dermatologist for abrupt cutoff and scored accordingly, which can be tedious and subjective. METHODS: This study introduces a novel approach to objectively quantify abruptness of pigment patterns along the lesion periphery. In the proposed approach, first, the skin lesion border is detected by the density based lesion border detection method. Second, the detected border is gradually scaled through vector operations. Then, along gradually scaled borders, pigment pattern homogeneities are calculated at different scales. Through this process, statistical texture features are extracted. Moreover, different color spaces are examined for the efficacy of texture analysis. RESULTS: The proposed method has been tested and validated on 100 (31 melanoma, 69 benign) dermoscopy images. Analyzed results indicate that proposed method is efficient on malignancy detection. More specifically, we obtained specificity of 0.96 and sensitivity of 0.86 for malignancy detection in a certain color space. The F-measure, harmonic mean of recall and precision, of the framework is reported as 0.87. CONCLUSIONS: The use of texture homogeneity along the periphery of the lesion border is an effective method to detect malignancy of the skin lesion in dermoscopy images. Among different color spaces tested, RGB color space's blue color channel is the most informative color channel to detect malignancy for skin lesions. That is followed by YCbCr color spaces Cr channel, and Cr is closely followed by the green color channel of RGB color space. PMID- 27766943 TI - Successful classification of cocaine dependence using brain imaging: a generalizable machine learning approach. AB - BACKGROUND: Neuroimaging studies have yielded significant advances in the understanding of neural processes relevant to the development and persistence of addiction. However, these advances have not explored extensively for diagnostic accuracy in human subjects. The aim of this study was to develop a statistical approach, using a machine learning framework, to correctly classify brain images of cocaine-dependent participants and healthy controls. In this study, a framework suitable for educing potential brain regions that differed between the two groups was developed and implemented. Single Photon Emission Computerized Tomography (SPECT) images obtained during rest or a saline infusion in three cohorts of 2-4 week abstinent cocaine-dependent participants (n = 93) and healthy controls (n = 69) were used to develop a classification model. An information theoretic-based feature selection algorithm was first conducted to reduce the number of voxels. A density-based clustering algorithm was then used to form spatially connected voxel clouds in three-dimensional space. A statistical classifier, Support Vectors Machine (SVM), was then used for participant classification. Statistically insignificant voxels of spatially connected brain regions were removed iteratively and classification accuracy was reported through the iterations. RESULTS: The voxel-based analysis identified 1,500 spatially connected voxels in 30 distinct clusters after a grid search in SVM parameters. Participants were successfully classified with 0.88 and 0.89 F-measure accuracies in 10-fold cross validation (10xCV) and leave-one-out (LOO) approaches, respectively. Sensitivity and specificity were 0.90 and 0.89 for LOO; 0.83 and 0.83 for 10xCV. Many of the 30 selected clusters are highly relevant to the addictive process, including regions relevant to cognitive control, default mode network related self-referential thought, behavioral inhibition, and contextual memories. Relative hyperactivity and hypoactivity of regional cerebral blood flow in brain regions in cocaine-dependent participants are presented with corresponding level of significance. CONCLUSIONS: The SVM-based approach successfully classified cocaine-dependent and healthy control participants using voxels selected with information theoretic-based and statistical methods from participants' SPECT data. The regions found in this study align with brain regions reported in the literature. These findings support the future use of brain imaging and SVM-based classifier in the diagnosis of substance use disorders and furthering an understanding of their underlying pathology. PMID- 27766944 TI - Incorporating topological information for predicting robust cancer subnetwork markers in human protein-protein interaction network. AB - BACKGROUND: Discovering robust markers for cancer prognosis based on gene expression data is an important yet challenging problem in translational bioinformatics. By integrating additional information in biological pathways or a protein-protein interaction (PPI) network, we can find better biomarkers that lead to more accurate and reproducible prognostic predictions. In fact, recent studies have shown that, "modular markers," that integrate multiple genes with potential interactions can improve disease classification and also provide better understanding of the disease mechanisms. RESULTS: In this work, we propose a novel algorithm for finding robust and effective subnetwork markers that can accurately predict cancer prognosis. To simultaneously discover multiple synergistic subnetwork markers in a human PPI network, we build on our previous work that uses affinity propagation, an efficient clustering algorithm based on a message-passing scheme. Using affinity propagation, we identify potential subnetwork markers that consist of discriminative genes that display coherent expression patterns and whose protein products are closely located on the PPI network. Furthermore, we incorporate the topological information from the PPI network to evaluate the potential of a given set of proteins to be involved in a functional module. Primarily, we adopt widely made assumptions that densely connected subnetworks may likely be potential functional modules and that proteins that are not directly connected but interact with similar sets of other proteins may share similar functionalities. CONCLUSIONS: Incorporating topological attributes based on these assumptions can enhance the prediction of potential subnetwork markers. We evaluate the performance of the proposed subnetwork marker identification method by performing classification experiments using multiple independent breast cancer gene expression datasets and PPI networks. We show that our method leads to the discovery of robust subnetwork markers that can improve cancer classification. PMID- 27766945 TI - Factors associated with unintended pregnancy in Brazil: cross-sectional results from the Birth in Brazil National Survey, 2011/2012. AB - BACKGROUND: Unintended pregnancy, a pregnancy that have been either unwanted or mistimed, is a serious public health issue in Brazil. It is reported for more than half of women who gave birth in the country, but the characteristics of women who conceive unintentionally are rarely documented. The aim of this study is to analyse the prevalence and the association between unintended pregnancy and a set of sociodemographic characteristics, individual-level variables and history of obstetric outcomes. METHODS: Birth in Brazil is a cross-sectional study with countrywide representation that interviewed 23,894 women after birth. The information about intendedness of pregnancy was obtained after birth at the hospital and classified into three categories: intended, mistimed or unwanted. Multinomial regression analysis was used to estimate the associations between intendedness of a pregnancy, and sociodemographic and obstetric variables, calculating odds ratios and 95 % confidence intervals. All significant variables in the bivariate analysis were included in the multinomial multivariate model and the final model retaining variables that remained significant at the 5 % level. RESULTS: Unintended pregnancy was reported by 55.4 % of postpartum women. The following variables maintained positive and significant statistical associations with mistimed pregnancy: maternal age < 20 years (OR = 1.89, 95 % CI: 1.68-2.14); brown (OR = 1.15, 95 % CI: 1.04-1.27) or yellow skin color (OR = 1.56, 95 % CI: 1.05-2.32); having no partner (OR = 2.32, 95 % CI: 1.99-2.71); having no paid job (OR = 1.15, 95 % CI: 1.04-1.27); alcohol abuse with risk of alcoholism (OR = 1.25, 95 % CI: 1.04-1.50) and having had three or more births (OR = 2.01, 95 % CI: 1.63-2.47). The same factors were associated with unwanted pregnancy, though the strength of the associations was generally stronger. Women with three or more births were 14 times more likely to have an unwanted pregnancy, and complication in the previous pregnancies and preterm birth were 40 % and 19 % higher, respectively. Previous neonatal death was a protective factor for both mistimed (OR = 0.61, 95 % CI: 0.44-0.85) and unwanted pregnancy (OR = 0.44, 95 % CI: 0.34 0.57). CONCLUSIONS: This study confirms findings from previous research about the influence of socioeconomic and individual risk factors on unintended pregnancy. It takes a new approach to the problem by showing the importance of previous neonatal death, preterm birth and complication during pregnancy as risk factors for unintended pregnancy. PMID- 27766947 TI - Vascular endothelial growth factor (VEGFA) gene variation in polycystic ovary syndrome in a Tunisian women population. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by the growth of a number of small cysts on the ovaries which leads to sex hormonal imbalance. Women who are affected by this syndrome suffer from irregular menstrual cycles, decline in their fertility, excessive hair growth, obesity, acne and most importantly cardiac function problems. The vascular endothelial growth factor (VEGF) plays a pivotal role in tissue vascularization in general and in the pathogenesis of many diseases. The PCOS was found to be associated with high expression levels of VEGF. In women who undergo assisted reproductive procedures (ART), VEGF was found to be a key mediator of other factors to control ovary angiogenesis. Here, we set out to examine the association of VEGFA gene polymorphism with PCOS and its components in a population of Tunisia women to enhance our understanding of the genetic background leading angiogenesis and vascularization abnormalities in PCOS. METHODS: The association of VEGFA gene with PCOS and its components was examined in a cohort of 268 women from Tunisia involving 118 PCOS patients and 150 controls. VEGFA gene variations were assessed through the analysis of the following SNPs rs699947 (A/C), rs833061 (C/T), rs1570360 (G/A), rs833068 (G/A), rs3025020 (C/T), and rs3025039 (C/T). The linkage disequilibrium between SNPs was assessed using HAPLOVIEW software while combination of SNPs into haplotypes in the population and the reconstruction of the cladogram were carried-out by PHASE and ARLEQUIN programs, respectively. Genetic association and genotype-phenotype correlations were calculated by logistic regression and non-parametric tests (Kruskall-Wallis and Mann-Whitney tests), respectively, using StatView program. RESULTS: We observed 10 haplotypes in our studied cohort whereH1 (ACGG), H2 (ACAG), H7 (CTGG) and H8 (CTGA) were the most frequent. We observed the association of the genotype CT of the SNP rs30225039 with PCOS phenotype (P = 0.03; OR 95 % CI = 2.05 [1.07-3.90]) and a trend for correlation of the pair of haplotypes H2/H2 with prolactin levels in plasma (P = 0.077; 193.5 +/- 94.3 vs 45.7 +/- 7.2). These data are consistent with literature and highlight one more time the role of vascularization in the pathogeny of PCOS. CONCLUSIONS: LD pattern in VEGF locus showed a similar LD pattern between the Tunisian population and the CEU. More haplotypes in the Tunisian population than in CEU was observed (22 haplotypes vs 16 haplotypes) suggesting higher recombination rate in Tunisians. The study showed that there was any advantage of using haplotypes compared with SNPs taken alone. PMID- 27766948 TI - Utilization of amplicon-based targeted sequencing panel for the massively parallel sequencing of sporadic hearing impairment patients from Saudi Arabia. AB - BACKGROUND: Hearing Impairment (HI) can have genetic or environmental causes and in some cases, an interplay of both. Genetic causes are difficult to determine as mutations in more than 90 genes have been shown recently to be responsible for HI. Providing a genetic diagnostic test for HI is therefore a challenge especially for ethnic groups where GJB2 mutations are shown to be rare. RESULTS: Here we show the design and implementation of an amplicon-based targeted sequencing panel that allows the simultaneous sequencing of 87 HI genes. Mutations identified included known pathogenic mutations and novel variants with unknown significance. The diagnostic rate of this panel is 28 % when only pathogenic variants were reported. However, an additional 28 % harbored recurrent combinations of novel or rare single nucleotide variants in the OTOF or PCDH15 genes. Such combinations were not identified in healthy individuals. CONCLUSIONS: Targeted sequencing approach is a very useful strategy for the identification of mutations affecting the HI genes because of its relatively fast turn-around time and cost effectiveness compared to whole-exome sequencing. Further novel or rare variants could be identified by implementing a large-scale screening of HI using our panel which will eventual lead to a higher diagnostic rate. PMID- 27766949 TI - Improving sensitivity of linear regression-based cell type-specific differential expression deconvolution with per-gene vs. global significance threshold. AB - BACKGROUND: The goal of many human disease-oriented studies is to detect molecular mechanisms different between healthy controls and patients. Yet, commonly used gene expression measurements from blood samples suffer from variability of cell composition. This variability hinders the detection of differentially expressed genes and is often ignored. Combined with cell counts, heterogeneous gene expression may provide deeper insights into the gene expression differences on the cell type-specific level. Published computational methods use linear regression to estimate cell type-specific differential expression, and a global cutoff to judge significance, such as False Discovery Rate (FDR). Yet, they do not consider many artifacts hidden in high-dimensional gene expression data that may negatively affect linear regression. In this paper we quantify the parameter space affecting the performance of linear regression (sensitivity of cell type-specific differential expression detection) on a per gene basis. RESULTS: We evaluated the effect of sample sizes, cell type-specific proportion variability, and mean squared error on sensitivity of cell type specific differential expression detection using linear regression. Each parameter affected variability of cell type-specific expression estimates and, subsequently, the sensitivity of differential expression detection. We provide the R package, LRCDE, which performs linear regression-based cell type-specific differential expression (deconvolution) detection on a gene-by-gene basis. Accounting for variability around cell type-specific gene expression estimates, it computes per-gene t-statistics of differential detection, p-values, t statistic-based sensitivity, group-specific mean squared error, and several gene specific diagnostic metrics. CONCLUSIONS: The sensitivity of linear regression based cell type-specific differential expression detection differed for each gene as a function of mean squared error, per group sample sizes, and variability of the proportions of target cell (cell type being analyzed). We demonstrate that LRCDE, which uses Welch's t-test to compare per-gene cell type-specific gene expression estimates, is more sensitive in detecting cell type-specific differential expression at alpha < 0.05 missed by the global false discovery rate threshold FDR < 0.3. PMID- 27766950 TI - Cyclin D1 as a therapeutic target of renal cell carcinoma- a combined transcriptomics, tissue microarray and molecular docking study from the Kingdom of Saudi Arabia. AB - BACKGROUND: Renal cell carcinoma (RCC) is a seventh ranked malignancy with poor prognosis. RCC is lethal at metastatic stage as it does not respond to conventional systemic treatments, and there is an urgent need to find out promising novel biomarkers for effective treatment. The goal of this study was to evaluate the biomarkers that can be potential therapeutic target and predict effective inhibitors to treat the metastatic stage of RCC. METHODS: We conducted transcriptomic profiling to identify differentially expressed genes associated with RCC. Molecular pathway analysis was done to identify the canonical pathways and their role in RCC. Tissue microarrays (TMA) based immunohistochemical stains were used to validate the protein expression of cyclinD1 (CCND1) and were scored semi-quantitatively from 0 to 3+ on the basis of absence or presence of staining intensity in the tumor cell. Statistical analysis determined the association of CCND1 expression with RCC. Molecular docking analyses were performed to check the potential of two natural inhibitors, rutin and curcumin to bind CCND1. RESULTS: We detected 1490 significantly expressed genes (1034, upregulated and 456, downregulated) in RCC using cutoff fold change 2 and p value < 0.05. Hes-related family bHLH transcription factor with YRPW motif 1 (HEY1), neuropilin 2 (NRP2), lymphoid enhancer-binding factor 1 (LEF1), and histone cluster 1 H3h (HIST1H3H) were most upregulated while aldolase B, fructose-bisphosphate (ALDOB), solute carrier family 12 (SLC12A1), calbindin 1 (CALB1) were the most down regulated genes in our dataset. Functional analysis revealed Wnt/beta-catenin signaling as the significantly activated canonical pathway (z score = 2.53) involving cyclin D1 (CCND1). CCND1 was overexpressed in transcriptomic studies (FC = 2.26, p value = 0.0047) and TMA results also showed the positive expression of CCND1 in 53 % (73/139) of RCC cases. The ligands - rutin and curcumin bounded with CCND1 with good affinity. CONCLUSION: CCND1 was one of the important upregulated gene identified in microarray and validated by TMA. Docking study showed that CCND1 may act as a potential therapeutic target and its inhibition could focus on the migratory, invasive, and metastatic potential of RCC. Further in vivo and in vitro molecular studies are needed to investigate the therapeutic target potential of CCND1 for RCC treatment. PMID- 27766951 TI - PGen: large-scale genomic variations analysis workflow and browser in SoyKB. AB - BACKGROUND: With the advances in next-generation sequencing (NGS) technology and significant reductions in sequencing costs, it is now possible to sequence large collections of germplasm in crops for detecting genome-scale genetic variations and to apply the knowledge towards improvements in traits. To efficiently facilitate large-scale NGS resequencing data analysis of genomic variations, we have developed "PGen", an integrated and optimized workflow using the Extreme Science and Engineering Discovery Environment (XSEDE) high-performance computing (HPC) virtual system, iPlant cloud data storage resources and Pegasus workflow management system (Pegasus-WMS). The workflow allows users to identify single nucleotide polymorphisms (SNPs) and insertion-deletions (indels), perform SNP annotations and conduct copy number variation analyses on multiple resequencing datasets in a user-friendly and seamless way. RESULTS: We have developed both a Linux version in GitHub ( https://github.com/pegasus-isi/PGen-GenomicVariations Workflow ) and a web-based implementation of the PGen workflow integrated within the Soybean Knowledge Base (SoyKB), ( http://soykb.org/Pegasus/index.php ). Using PGen, we identified 10,218,140 single-nucleotide polymorphisms (SNPs) and 1,398,982 indels from analysis of 106 soybean lines sequenced at 15X coverage. 297,245 non-synonymous SNPs and 3330 copy number variation (CNV) regions were identified from this analysis. SNPs identified using PGen from additional soybean resequencing projects adding to 500+ soybean germplasm lines in total have been integrated. These SNPs are being utilized for trait improvement using genotype to phenotype prediction approaches developed in-house. In order to browse and access NGS data easily, we have also developed an NGS resequencing data browser ( http://soykb.org/NGS_Resequence/NGS_index.php ) within SoyKB to provide easy access to SNP and downstream analysis results for soybean researchers. CONCLUSION: PGen workflow has been optimized for the most efficient analysis of soybean data using thorough testing and validation. This research serves as an example of best practices for development of genomics data analysis workflows by integrating remote HPC resources and efficient data management with ease of use for biological users. PGen workflow can also be easily customized for analysis of data in other species. PMID- 27766952 TI - The Third International Genomic Medicine Conference (3rd IGMC, 2015): overall activities and outcome highlights. AB - The Third International Genomic Medicine Conference (3rd IGMC) was organised by the Centre of Excellence in Genomic Medicine Research (CEGMR) at the King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia (KSA). This conference is a continuation of a series of meetings, which began with the first International Genomic Medicine Conference (1st IGMC, 2011) followed by the second International Genomic Medicine Conference (2nd IGMC, 2013). The 3rd IGMC meeting presented as a timely opportunity to bring scientists from across the world to gather, discuss, and exchange recent advances in the field of genomics and genetics in general as well as practical information on using these new technologies in different basic and clinical applications. The meeting undoubtedly inspired young male and female Saudi researchers, who attended the conference in large numbers, as evidenced by the oversubscribed oral and poster presentations. The conference also witnessed the launch of the first content for npj Genomic Medicine, a high quality new journal was established in partnership by CEGMR with Springer Nature and published as part of the Nature Partner Journal series. Here, we present a brief summary report of the 2-day meeting including highlights from the oral presentations, poster presentations, workshops, poster prize-winners and comments from the distinguished scientists. PMID- 27766946 TI - In vitro models of cancer stem cells and clinical applications. AB - Cancer cells, stem cells and cancer stem cells have for a long time played a significant role in the biomedical sciences. Though cancer therapy is more effective than it was a few years ago, the truth is that still none of the current non-surgical treatments can cure cancer effectively. The reason could be due to the subpopulation called "cancer stem cells" (CSCs), being defined as those cells within a tumour that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumours.The phenomenon of CSCs is based on their resistance to many of the current cancer therapies, which results in tumour relapse. Although further investigation regarding CSCs is still needed, there is already evidence that these cells may play an important role in the prognosis of cancer, progression and therapeutic strategy. Therefore, long-term patient survival may depend on the elimination of CSCs. Consequently, isolation of pure CSC populations or reprogramming of cancer cells into CSCs, from cancer cell lines or primary tumours, would be a useful tool to gain an in-depth knowledge about heterogeneity and plasticity of CSC phenotypes and therefore carcinogenesis. Herein, we will discuss current CSC models, methods used to characterize CSCs, candidate markers, characteristic signalling pathways and clinical applications of CSCs. Some examples of CSC-specific treatments that are currently in early clinical phases will also be presented in this review. PMID- 27766953 TI - Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency. AB - BACKGROUND: Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. METHODS: Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7). RESULTS: Depletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts. CONCLUSIONS: Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals. PMID- 27766954 TI - Identification of novel genetic variations affecting osteoarthritis patients. AB - BACKGROUND: Osteoarthritis (OA) is a progressive joint disease characterized by gradual degradation of extracellular matrix (ECM) components in the cartilage and bone. The ECM of cartilage is a highly specified structure that is mainly composed of type II collagen and provides tensile strength to the tissue via aggrecan and proteoglycans. However, changes in the ECM composition and structure can lead to loss of collagen type II and network integrity. Several risk factors have been correlated with OA including age, genetic predisposition, hereditary factors, obesity, mechanical injuries, and joint trauma. Certain genetic association studies have identified several genes associated with OA using genome wide association studies (GWASs). RESULTS: We identified several novel genetic variants affecting genes that function in several candidate causative pathways including immune responses, inflammatory and cartilage degradation such as SELP, SPN, and COL6A6. CONCLUSIONS: The approach of whole-exome sequencing can be a promising method to identify genetic mutations that can influence the OA disease. PMID- 27766955 TI - e-GRASP: an integrated evolutionary and GRASP resource for exploring disease associations. AB - BACKGROUND: Genome-wide association studies (GWAS) have become a mainstay of biological research concerned with discovering genetic variation linked to phenotypic traits and diseases. Both discrete and continuous traits can be analyzed in GWAS to discover associations between single nucleotide polymorphisms (SNPs) and traits of interest. Associations are typically determined by estimating the significance of the statistical relationship between genetic loci and the given trait. However, the prioritization of bona fide, reproducible genetic associations from GWAS results remains a central challenge in identifying genomic loci underlying common complex diseases. Evolutionary-aware meta-analysis of the growing GWAS literature is one way to address this challenge and to advance from association to causation in the discovery of genotype-phenotype relationships. DESCRIPTION: We have created an evolutionary GWAS resource to enable in-depth query and exploration of published GWAS results. This resource uses the publically available GWAS results annotated in the GRASP2 database. The GRASP2 database includes results from 2082 studies, 177 broad phenotype categories, and ~8.87 million SNP-phenotype associations. For each SNP in e GRASP, we present information from the GRASP2 database for convenience as well as evolutionary information (e.g., rate and timespan). Users can, therefore, identify not only SNPs with highly significant phenotype-association P-values, but also SNPs that are highly replicated and/or occur at evolutionarily conserved sites that are likely to be functionally important. Additionally, we provide an evolutionary-adjusted SNP association ranking (E-rank) that uses cross-species evolutionary conservation scores and population allele frequencies to transform P values in an effort to enhance the discovery of SNPs with a greater probability of biologically meaningful disease associations. CONCLUSION: By adding an evolutionary dimension to the GWAS results available in the GRASP2 database, our e-GRASP resource will enable a more effective exploration of SNPs not only by the statistical significance of trait associations, but also by the number of studies in which associations have been replicated, and the evolutionary context of the associated mutations. Therefore, e-GRASP will be a valuable resource for aiding researchers in the identification of bona fide, reproducible genetic associations from GWAS results. This resource is freely available at http://www.mypeg.info/egrasp . PMID- 27766956 TI - Application of dynamic topic models to toxicogenomics data. AB - BACKGROUND: All biological processes are inherently dynamic. Biological systems evolve transiently or sustainably according to sequential time points after perturbation by environment insults, drugs and chemicals. Investigating the temporal behavior of molecular events has been an important subject to understand the underlying mechanisms governing the biological system in response to, such as, drug treatment. The intrinsic complexity of time series data requires appropriate computational algorithms for data interpretation. In this study, we propose, for the first time, the application of dynamic topic models (DTM) for analyzing time-series gene expression data. RESULTS: A large time-series toxicogenomics dataset was studied. It contains over 3144 microarrays of gene expression data corresponding to rat livers treated with 131 compounds (most are drugs) at two doses (control and high dose) in a repeated schedule containing four separate time points (4-, 8-, 15- and 29-day). We analyzed, with DTM, the topics (consisting of a set of genes) and their biological interpretations over these four time points. We identified hidden patterns embedded in this time series gene expression profiles. From the topic distribution for compound-time condition, a number of drugs were successfully clustered by their shared mode-of action such as PPARalpha agonists and COX inhibitors. The biological meaning underlying each topic was interpreted using diverse sources of information such as functional analysis of the pathways and therapeutic uses of the drugs. Additionally, we found that sample clusters produced by DTM are much more coherent in terms of functional categories when compared to traditional clustering algorithms. CONCLUSIONS: We demonstrated that DTM, a text mining technique, can be a powerful computational approach for clustering time-series gene expression profiles with the probabilistic representation of their dynamic features along sequential time frames. The method offers an alternative way for uncovering hidden patterns embedded in time series gene expression profiles to gain enhanced understanding of dynamic behavior of gene regulation in the biological system. PMID- 27766957 TI - Copy number variations in Saudi family with intellectual disability and epilepsy. AB - BACKGROUND: Epilepsy is genetically complex but common brain disorder of the world affecting millions of people with almost of all age groups. Novel Copy number variations (CNVs) are considered as important reason for the numerous neurodevelopmental disorders along with intellectual disability and epilepsy. DNA array based studies contribute to explain a more severe clinical presentation of the disease but interoperation of many detected CNVs are still challenging. RESULTS: In order to study novel CNVs with epilepsy related genes in Saudi family with six affected and two normal individuals with several forms of epileptic seizures, intellectual disability (ID), and minor dysmorphism, we performed the high density whole genome Agilent sure print G3 Hmn CGH 2x 400 K array-CGH chips analysis. Our results showed de novo deletions, duplications and deletion plus duplication on differential chromosomal regions in the affected individuals that were not shown in the normal fathe and normal kids by using Agilent CytoGenomics 3.0.6.6 softwear. Copy number gain were observed in the chromosome 1, 16 and 22 with LCE3C, HPR, GSTT2, GSTTP2, DDT and DDTL genes respectively whereas the deletions observed in the chromosomal regions 8p23-p21 (4303127-4337759) and the potential gene in this region is CSMD1 (OMIM: 612279). Moreover, the array CGH results deletions and duplication were also validated by using primer design of deleted regions utilizing the flanked SNPs using simple PCR and also by using quantitative real time PCR. CONCLUSIONS: We found some of the de novo deletions and duplication in our study in Saudi family with intellectual disability and epilepsy. Our results suggest that array-CGH should be used as a first line of genetic test for epilepsy except there is a strong indication for a monogenic syndrome. The advanced high through put array-CGH technique used in this study aim to collect the data base and to identify new mechanisms describing epileptic disorder, may help to improve the clinical management of individual cases in decreasing the burden of epilepsy in Saudi Arabia. PMID- 27766958 TI - More comprehensive forensic genetic marker analyses for accurate human remains identification using massively parallel DNA sequencing. AB - BACKGROUND: Although the primary objective of forensic DNA analyses of unidentified human remains is positive identification, cases involving historical or archaeological skeletal remains often lack reference samples for comparison. Massively parallel sequencing (MPS) offers an opportunity to provide biometric data in such cases, and these cases provide valuable data on the feasibility of applying MPS for characterization of modern forensic casework samples. In this study, MPS was used to characterize 140-year-old human skeletal remains discovered at a historical site in Deadwood, South Dakota, United States. The remains were in an unmarked grave and there were no records or other metadata available regarding the identity of the individual. Due to the high throughput of MPS, a variety of biometric markers could be typed using a single sample. RESULTS: Using MPS and suitable forensic genetic markers, more relevant information could be obtained from a limited quantity and quality sample. Results were obtained for 25/26 Y-STRs, 34/34 Y SNPs, 166/166 ancestry-informative SNPs, 24/24 phenotype-informative SNPs, 102/102 human identity SNPs, 27/29 autosomal STRs (plus amelogenin), and 4/8 X-STRs (as well as ten regions of mtDNA). The Y chromosome (Y-STR, Y-SNP) and mtDNA profiles of the unidentified skeletal remains are consistent with the R1b and H1 haplogroups, respectively. Both of these haplogroups are the most common haplogroups in Western Europe. Ancestry informative SNP analysis also supported European ancestry. The genetic results are consistent with anthropological findings that the remains belong to a male of European ancestry (Caucasian). Phenotype-informative SNP data provided strong support that the individual had light red hair and brown eyes. CONCLUSIONS: This study is among the first to genetically characterize historical human remains with forensic genetic marker kits specifically designed for MPS. The outcome demonstrates that substantially more genetic information can be obtained from the same initial quantities of DNA as that of current CE-based analyses. PMID- 27766959 TI - Screening for clusters of charge in human virus proteomes. AB - BACKGROUND: The identification of charge clusters (runs of charged residues) in proteins and their mapping within the protein structure sequence is an important step toward a comprehensive analysis of how these particular motifs mediate, via electrostatic interactions, various molecular processes such as protein sorting, translocation, docking, orientation and binding to DNA and to other proteins. Few algorithms that specifically identify these charge clusters have been designed and described in the literature. In this study, 197 distinctive human viral proteomes were screened for the occurrence of charge clusters (CC) using a new computational approach. RESULTS: Three hundred and seventy three CC have been identified within the 2549 viral protein sequences screened. The number of protein sequences that are CC-free is 2176 (85.3 %) while 150 and 180 proteins contained positive charge (PCC) and negative charge clusters (NCC), respectively. The NCCs (211 detected) were more prevalent than PCC (162). PCC-containing proteins are significantly longer than those having NCCs (p = 2.10-16). The most prevalent virus families having PCC and NCC were Herpesviridae followed by Papillomaviridae. However, the single-strand RNA group has in average three times more NCC than PCC. According to the functional domain classification, a significant difference in distribution was observed between PCC and NCC (p = 2. 10-8) with the occurrence of NCCs being more frequent in C-terminal region while PCC more often fall within functional domains. Only 29 proteins sequences contained both NCC and PCC. Moreover, 101 NCC were conserved in 84 proteins while only 62 PCC were conserved in 60 protein sequences. To understand the mechanism by which the membrane translocation functionalities are embedded in viral proteins, we screened our PCC for sequences corresponding to cell-penetrating peptides (CPPs) using two online databases: CellPPd and CPPpred. We found that all our PCCs, having length varying from 7 to 30 amino-acids were predicted as CPPs. Experimental validation is required to improve our understanding of the role of these PCCs in viral infection process. CONCLUSIONS: Screening distinctive cluster charges in viral proteomes suggested a functional role of these protein regions and might provide potential clues to improve the current understanding of viral diseases in order to tailor better preventive and therapeutic approaches. PMID- 27766960 TI - Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update. AB - BACKGROUND: Preterm birth (PTB), birth at <37 weeks of gestation, is a significant global public health problem. World-wide, about 15 million babies are born preterm each year resulting in more than a million deaths of children. Preterm neonates are more prone to problems and need intensive care hospitalization. Health issues may persist through early adulthood and even be carried on to the next generation. Majority (70 %) of PTBs are spontaneous with about a half without any apparent cause and the other half associated with a number of risk factors. Genetic factors are one of the significant risks for PTB. The focus of this review is on single nucleotide gene polymorphisms (SNPs) that are reported to be associated with PTB. RESULTS: A comprehensive evaluation of studies on SNPs known to confer potential risk of PTB was done by performing a targeted PubMed search for the years 2007-2015 and systematically reviewing all relevant studies. Evaluation of 92 studies identified 119 candidate genes with SNPs that had potential association with PTB. The genes were associated with functions of a wide spectrum of tissue and cell types such as endocrine, tissue remodeling, vascular, metabolic, and immune and inflammatory systems. CONCLUSIONS: A number of potential functional candidate gene variants have been reported that predispose women for PTB. Understanding the complex genomic landscape of PTB needs high-throughput genome sequencing methods such as whole exome sequencing and whole-genome sequencing approaches that will significantly enhance the understanding of PTB. Identification of high risk women, avoidance of possible risk factors, and provision of personalized health care are important to manage PTB. PMID- 27766961 TI - VDJML: a file format with tools for capturing the results of inferring immune receptor rearrangements. AB - BACKGROUND: The genes that produce antibodies and the immune receptors expressed on lymphocytes are not germline encoded; rather, they are somatically generated in each developing lymphocyte by a process called V(D)J recombination, which assembles specific, independent gene segments into mature composite genes. The full set of composite genes in an individual at a single point in time is referred to as the immune repertoire. V(D)J recombination is the distinguishing feature of adaptive immunity and enables effective immune responses against an essentially infinite array of antigens. Characterization of immune repertoires is critical in both basic research and clinical contexts. Recent technological advances in repertoire profiling via high-throughput sequencing have resulted in an explosion of research activity in the field. This has been accompanied by a proliferation of software tools for analysis of repertoire sequencing data. Despite the widespread use of immune repertoire profiling and analysis software, there is currently no standardized format for output files from V(D)J analysis. Researchers utilize software such as IgBLAST and IMGT/High V-QUEST to perform V(D)J analysis and infer the structure of germline rearrangements. However, each of these software tools produces results in a different file format, and can annotate the same result using different labels. These differences make it challenging for users to perform additional downstream analyses. RESULTS: To help address this problem, we propose a standardized file format for representing V(D)J analysis results. The proposed format, VDJML, provides a common standardized format for different V(D)J analysis applications to facilitate downstream processing of the results in an application-agnostic manner. The VDJML file format specification is accompanied by a support library, written in C++ and Python, for reading and writing the VDJML file format. CONCLUSIONS: The VDJML suite will allow users to streamline their V(D)J analysis and facilitate the sharing of scientific knowledge within the community. The VDJML suite and documentation are available from https://vdjserver.org/vdjml/ . We welcome participation from the community in developing the file format standard, as well as code contributions. PMID- 27766962 TI - microRNA analysis of gastric cancer patients from Saudi Arabian population. AB - BACKGROUND: The role of small non-coding microRNAs (miRNAs) in several types of cancer has been evident. However, its expression studies have never been performed in gastric cancer (GC) patients from Saudi population. First time this study was conducted to identify miRNAs that are differentially expressed in GC patients compared with normal controls. METHODS: We investigated the role of miRNAs in GC patients using formalin-fixed paraffin-embedded (FFPE) tissues of 34 samples from GC patients (early stage = 7 and late-stage = 26) and 15 from normal control. We have used miRNA microarray analysis and validated the results by Real time quantitative PCR (RT-qPCR). RESULTS: We obtained data of 1082 expressed genes, from cancer tissues and noncancerous tissues (49 samples in total). Where 129 genes were up-regulated (P > 0.05) and 953 genes (P > 0.05) were down regulated in 49 FFPE tissue samples. Only 33 miRNAs had significant expression in early and late-stage cancer tissues. After candidate miRNAs were selected, RT qPCR further confirmed that four miRNAs (hsa-miR-200c-3p, hsa-miR-3613, hsa-miR 27b-3p, hsa-miR-4668-5p) were significantly aberrant in GC tissues compared to the normal gastric tissues. CONCLUSIONS: In this study we provide miRNAs profile of GC where many miRNAs showed aberrant expression from normal tissues, suggesting their involvement in the development and progression of gastric cancer. In early and late-stage miR-200c-3p showed significant down regulation as compare to control samples. Many of miRNAs reported in our study showing up regulation are new and not reported before may be due to population difference. In conclusion, our results suggest that miR-200c-3p had potential to use as diagnostic biomarker for distinguishing GC patients from normal individuals and can be used for diagnosis of cancer at early stage. PMID- 27766964 TI - Adequacy of public maternal care services in Brazil. AB - BACKGROUND: In Brazil, hospital childbirth care is available to all, but differences in access and quality of care result in inequalities of maternal health. The objective of this study is to assess the infrastructure and staffing of publicly financed labor and birth care in Brazil and its adequacy according to clinical and obstetric conditions potentially associated with obstetric emergencies. METHODS: Nationwide cross-sectional hospital-based study "Birth in Brazil: national survey into labor and birth" conducted in 2011-2012. Data from 209 hospitals classified as public (public funding and management) or mixed (public or private funding and private management) that generate estimates for 1148 Brazilian hospitals. Interview with hospital managers provided data for the structure adequacy assessment covering four domains: human resources, medications, equipment for women emergency care and support services. We conducted analysis of the structure adequacy rate according to type of hospital (public or mixed), availability of ICU and the woman obstetric risk using the X 2 test to detect differences in categorical variables with the level of statistical significance set at p <0.05. RESULTS: Global rate of adequacy of 34.8 %: 42.2 % in public hospitals and 29.0 % in mixed hospitals (p < 0.001). Public and mixed hospitals with ICU had higher scores of adequacy than hospitals without ICU (73.3 % * 24.4 % public hospitals; 40.3 % * 10.6 % mixed hospitals). At a national level, 32.8 % of women with obstetric risk were cared for in hospitals without ICU and 29.5 % of women without risk were cared for in hospitals with ICU. Inequalities were observed with the North, Northeast and non-capital regions having the lower rates of hospitals with ICU. CONCLUSIONS: The majority of maternity wards across the country have a low rate of adequacy that can affect the quality of labor and birth care. This holds true for women at high obstetric risk, who suffer the possibility of having their care compromised by failures of hospital infrastructure, and for women at low obstetric risk, who may not receive the appropriate care to support the natural evolution of their labor when in a technological hospital environment. PMID- 27766965 TI - Animal obesity: causes, consequences and comparative aspects. PMID- 27766963 TI - Associations of recurrent miscarriages with chromosomal abnormalities, thrombophilia allelic polymorphisms and/or consanguinity in Saudi Arabia. AB - BACKGROUND: Recurrent pregnancy loss (RPL) or recurrent spontaneous abortion is an obstetric complication that affects couples at reproductive age. Previous reports documented a clear relationship between parents with chromosomal abnormalities and both recurrent miscarriages and infertility. However, limited data is available from the Arabian Peninsula which is known by higher rates of consanguineous marriages. The main goal of this study was to determine the prevalence of chromosomal abnormalities and thrombophilic polymorphisms, and to correlate them with RPL and consanguinity in Saudi Arabia. METHODS: Cytogenetic analysis of 171 consent patients with RPL was performed by the standard method of 72-h lymphocyte culture and GTG banding. Allelic polymorphisms of three thrombophilic genes (Factor V Leiden, Prothrombin A20210G, MTHFR C677T) were performed using PCR-RFLP (restriction fragment length polymorphism) and gel electrophoresis. RESULTS: Data analysis revealed that 7.6 % of patients were carrier of numerical or structural chromosomal abnormalities. A high rate of translocations (46 %) was associated to increased incidence of RPL. A significant correlation between consanguineous RPL patients and chromosomal abnormalities (P < 0.05) was found. Both Factor V Leiden and Prothrombin A20210G allelic polymorphisms were significantly associated with a higher prevalence of RPL. CONCLUSIONS: This study demonstrated a strong association between RPL and the prevalence of chromosomal abnormalities and inherited thrombophilia. Given the high rate of consanguineous marriages in the Saudi population, these results underline the importance of systematic cytogenetic investigation and genetic counseling preferably at the premarital stage or at least during early pregnancy phase through preimplantation genetic diagnosis (PGD). PMID- 27766966 TI - Prevalence and risk factors for overweight horses at premises in Sweden assessed using official animal welfare control data. AB - BACKGROUND: There are Swedish animal welfare regulations concerning the body condition of horses and general advice on keeping horses including that horses should be fed so that they do not become over- or underweight relative to their use. Compliance is assessed by official animal welfare inspectors. The objective of this study was to determine whether the national animal welfare control database could be used to estimate the prevalence and risk factors for overweight horses in Sweden. The official animal welfare control checklist for horses contains 45 checkpoints (CP) of which CP-8 pertains to the acceptability of the horses' body condition including whether they were under- or overweight. Prevalence of non-compliance with CP-8, with 95 % confidence intervals (CI), were calculated for the years 2010-2013. Associations between risk factors and non compliance for overweight body condition were estimated using logistic regression and expressed as odds ratios (OR) with 95 % CIs. RESULTS: Of 7870 premises with registered horses that were inspected against CP-8, a total of 63 premises had non-compliant inspections due to overweight horses (0.80 %; CI 0.62, 1.02 %). In multivariable analyses, premises that were non-compliant with requirements for the care of sick or injured horses (OR 3.52; CI 1.51, 8.22) or with the requirements for feeding a balanced high-quality diet (OR 5.15; CI 2.49, 10.67) had greater odds of having overweight horses. Premises that also kept other species for meat production were more likely to have overweight horses (OR 2.12; CI 1.18, 3.81) whereas professional horse establishments were less likely (OR 0.09; 0.01, 0.64). Overweight horses were more likely in summer compared to winter (OR 2.18; CI 1.02, 4.70). Premises in regions of Sweden with more horses in relation to the human population were less likely to have overweight horses (OR 0.97; CI 0.95, 1.00). CONCLUSIONS: Official animal welfare control data may be used to monitor the premises prevalence of overweight horses in Sweden. Strategies to reduce the prevalence of overweight horses should focus on education about equine care and nutrition, especially summer grazing. PMID- 27766968 TI - Body condition score, morphometric measurements and estimation of body weight in mature Icelandic horses in Denmark. AB - BACKGROUND: Obesity is related to the development of several diseases like insulin resistance and laminitis in horses. The prevalence of obesity among mature Icelandic horses in Denmark has not been investigated previously. This study aimed to find the prevalence of obesity, to compare body condition score (BCS) based on owner perception with that of an experienced person and to correlate the BCS to body weight (BW) and morphometric measures in a group of mature Icelandic horses in Denmark. A total of 254 Icelandic horses (>=4 years; 140 geldings, 105 mares, 9 stallions) from 46 different farms were included. All horses were assigned a BCS on a scale from 1 to 9 (1 is poor, 5 is moderate and 9 is extremely fat) by their owner and by an experienced person. Two weight tapes were used to assess BW. Girth circumference (GC), neck circumference (NC) and height at withers (HW) were measured, and the GC:HW and NC:HW ratios were calculated. RESULTS: Categorising the horses into four groups, 5.9 % were underweight (BCS 3-4), 70.1 % were optimal (BCS 5-6), 13.8 % were overweight (BCS 7) and 10.2 % were obese (BCS 8-9). The GC:HW and NC:HW ratios increased with increasing BCS, as did the BW estimated with the weight tapes. A GC:HW ratio >1.21 might indicate overweight or obesity in Icelandic horses. Horse owners underestimated the BCS of their horses compared to an experienced person. CONCLUSIONS: The results from this study show that 24.0 % of mature Icelandic horses in Denmark are overweight or obese, and that owners tend to underestimate the BCS of their Icelandic horses. The GC:HW ratio might indicate overweight or obesity, however, the ratio for Icelandic horses is different than reported for horses and ponies of other breeds. PMID- 27766967 TI - An individual approach to feline diabetes care: a case report and literature review. AB - BACKGROUND: Achieving insulin independence is emerging as a realistic therapeutic goal in the management of feline diabetes mellitus. CASE PRESENTATION: The management of an 11-year-old spayed female Burmese cat presenting with diabetes mellitus after corticosteroid administration is described. Remission was achieved after the frequency of insulin administration was increased to four times a day, and supported by intensive home blood glucose monitoring and a high protein, low carbohydrate diet. CONCLUSION: Owners are important collaborators in feline diabetes care and, with intensive home monitoring, more frequent insulin treatment may lead to remission without hypoglycemia. More frequent insulin injections than recommended in the literature may be necessary to achieve glycemic control and used as an alternative to a longer-acting insulin. PMID- 27766969 TI - The baby-friendly hospital initiative and breastfeeding at birth in Brazil: a cross sectional study. AB - BACKGROUND: Breastfeeding in the first hour after birth is important for the success of breastfeeding and in reducing neonatal mortality. Government policies are being developed in this direction, highlighting the accreditation of hospitals in the Baby-Friendly Hospital (BFH) initiative. The aim of this study was to analyze the association between delivery in a BFH (main exposure), compared to non BFH, and timely initiation of breastfeeding (outcome). METHODS: Data came from the "Birth in Brazil" survey, a nationwide hospital-based study of postpartum women and their newborns, coordinated by the Oswaldo Cruz Foundation. A sample of 22,035 mothers/babies was analyzed through a hierarchical theoretical model on three levels, and all analyzes considered the complex sample design. Odds ratios were obtained by logistic regression, with a 99 % CI. RESULTS: Among all births, 40 % occurred in hospitals accredited or in accreditation process for the BFHI and 52 % of women underwent caesarean section. In the final model, at the distal level, mothers less than 35 years old, and those who lived in the North Region, had a higher chance of timely initiation of breastfeeding. At the intermediate level, prenatal care in the public sector and advice on breastfeeding during pregnancy were directly associated with the outcome. At the proximal level, being born in a Baby-Friendly Hospital and vaginal delivery increased the chance of timely initiation of breastfeeding, while prematurity and low birth weight reduced the chance of the outcome. CONCLUSIONS: The chance of being breastfed in the first hour after birth in Baby-Friendly hospitals was twice as high as at non-accredited hospitals, which shows the importance of this initiative for timely initiation of breastfeeding. PMID- 27766970 TI - Do cats with a cranial cruciate ligament injury and osteoarthritis demonstrate a different gait pattern and behaviour compared to sound cats? AB - BACKGROUND: Osteoarthritis (OA) is a common cause of chronic pain and dysfunction in older cats. The majority of cats with OA do not show signs of overt lameness, yet cats with orthopaedic disease are known to redistribute their body weight from the affected limb. OA can cause changes in the cat's behaviour, which is often misinterpreted as signs of aging. The aim of the present study was to investigate if cats with a previous cranial cruciate ligament (CCL) injury perform differently on the pressure mat and exhibit different behaviour compared to sound cats according to the owner's subjective assessment. Ten cats with a previous CCL injury were assessed with a pressure mat system and their owners were asked to complete an assessment questionnaire. The results were compared to those of 15 sound cats, matched to have the same weight and body condition score. RESULTS: The front/hind limb index for peak vertical force (PVF) was significantly higher for CCL cats, and there was a decreased PVF and vertical impulse (VI) on the affected hindlimb compared to the unaffected one. The results indicate that cats with a previous CCL injury put less weight, on the affected hindlimb but for a longer time. There was a significantly higher owner assessment questionnaire score for the group of cats with CCL injury compared to sound cats. CONCLUSIONS: Cats with a previous CCL injury have a different gait pattern compared to sound cats and a different behaviour according to owner subjective assessment. It is of great importance that further studies are performed to investigate the long term effects of CCL injury as a cause of pain and physical dysfunction, and its role in the development of OA in cats. Improved assessment tools for chronic pain caused by OA in cats are needed, both to facilitate diagnosis and to evaluate pain-relieving treatment. PMID- 27766972 TI - Insulin concentrations used in in vitro embryo production systems: a pilot study on insulin stability with an emphasis on concentrations measured in vivo. AB - BACKGROUND: Insulin has been used as a stimulatory factor for in vitro cell culture since many years. Even for routine in vitro embryo production (IVP), insulin is added to the media during different steps. There is a strong difference in concentrations used in vitro compared to what is measured in vivo in follicular fluid or serum. We performed a pilot study on insulin stability to explain possible reasons for that variation. RESULTS: We measured insulin concentrations before and after bovine oocyte maturation in an experiment by using a quantitative ELISA (Mercodia bovine insulin ELISA immunoassay) and found that concentrations were stable up to 22 h of incubation. We compared our results with eleven in vivo studies measuring insulin in either serum or follicular fluid and nine IVP-protocols using insulin. In all studies, in vitro concentrations were much higher compared with those found physiologically in vivo. Limited knowledge is available concerning the different activity and stability of insulin in vitro versus in vivo. CONCLUSIONS: The concentrations of insulin used in vitro are quite high in comparison to physiological concentrations found in serum or follicular fluid. One explanation may be a different stability or activity of insulin in vitro even if we could measure stable concentrations of insulin in our pilot study. More precise dose-effect studies have to be performed to draw clear conclusions about the consequences of the use of such high doses as they might have negative consequences for the developing embryo. Insulin has direct effects on the regulation of the metabolism and could even influence the epigenetic programming of the metabolism with unknown consequences for the offspring later in life. PMID- 27766971 TI - Labor and birth care by nurse with midwifery skills in Brazil. AB - BACKGROUND: The participation of nurses and midwives in vaginal birth care is limited in Brazil, and there are no national data regarding their involvement. The goal was to describe the participation of nurses and nurse-midwives in childbirth care in Brazil in the years 2011 and 2012, and to analyze the association between hospitals with nurses and nurse-midwives in labor and birth care and the use of good practices, and their influence in the reduction of unnecessary interventions, including cesarean sections. METHODS: Birth in Brazil is a national, population-based study consisting of 23,894 postpartum women, carried out in the period between February 2011 and October 2012, in 266 healthcare settings. The study included all vaginal births involving physicians or nurses/nurse-midwives. A logistic regression model was used to examine the association between the implementation of good practices and suitable interventions during labor and birth, and whether care was a physician or a nurse/nurse-midwife led care. We developed another model to assess the association between the use of obstetric interventions during labor and birth to the personnel responsible for the care of the patient, comparing hospitals with decisions revolving exclusively around a physician to those that also included nurses/nurse-midwives as responsible for vaginal births. RESULTS: 16.2 % of vaginal births were assisted by a nurse/nurse-midwife. Good practices were significantly more frequent in those births assisted by nurses/nurse-midwives (ad lib. diet, mobility during labor, non-pharmacological means of pain relief, and use of a partograph), while some interventions were less frequently used (anesthesia, lithotomy position, uterine fundal pressure and episiotomy). In maternity wards that included a nurse/nurse-midwife in labour and birth care, the incidence of cesarean section was lower. CONCLUSIONS: The results of this study illustrate the potential benefit of collaborative work between physicians and nurses/nurse-midwives in labor and birth care. The adoption of good practices in managing labor and birth could be the first step toward more effective obstetric and midwifery care in Brazil. It may be easier to introduce new approaches rather than to eliminate old ones, which may explain why the reduction of unnecessary interventions during labor and birth was less pronounced than the adoption of new practices. PMID- 27766973 TI - Factors associated with maternal near miss in childbirth and the postpartum period: findings from the birth in Brazil National Survey, 2011-2012. AB - BACKGROUND: Maternal near-miss (MNM) audits are considered a useful approach to improving maternal healthcare. The aim of this study was to evaluate the factors associated with maternal near-miss cases in childbirth and the postpartum period in Brazil. METHODS: The study is based on data from a nationwide hospital-based survey of 23,894 women conducted in 2011-2012. The data are from interviews with mothers during the postpartum period and from hospital medical files. Univariate and multivariable logistic regressions were performed to analyze factors associated with MNM, including estimation of crude and adjusted odds ratios and their respective 95 % confidence intervals (95 % CI). RESULTS: The estimated incidence of MNM was 10.2/1,000 live births (95 % CI: 7.5-13.7). In the adjusted analyses, MNM was associated with the absence of antenatal care (OR: 4.65; 95 % CI: 1.51-14.31), search for two or more services before admission to delivery care (OR: 4.49; 95 % CI: 2.12-9.52), obstetric complications (OR: 9.29; 95 % CI: 6.69-12.90), and type of birth: elective C-section (OR: 2.54; 95 % CI: 1.67-3.88) and forceps (OR: 9.37; 95 % CI: 4.01-21.91). Social and demographic maternal characteristics were not associated with MNM, although women who self-reported as white and women with higher schooling had better access to antenatal and maternity care services. CONCLUSION: The high proportion of elective C-sections performed among women in better social and economic situations in Brazil is likely attenuating the benefits that could be realized from improved prenatal care and greater access to maternity services. Strategies for reducing the rate of MNM in Brazil should focus on: 1) increasing access to prenatal care and delivery care, particularly among women who are at greater social and economic risk and 2) reducing the rate of elective cesarean section, particularly among women who receive services at private maternity facilities, where C-section rates reach 90 % of births. PMID- 27766974 TI - Weight management in obese pets: the tailoring concept and how it can improve results. AB - Obesity is now recognised as the most important medical disease in pets worldwide. All current strategies for weight management involve dietary energy restriction with a purpose-formulated diet. Whilst current weight management regimes can be successful, outcomes are often disappointing with the rate of weight loss progressively slowing down as time goes on. Success is most challenging for the most obese dogs and cats that are more likely to discontinue the programme before reaching target weight. To improve outcomes, clinicians must focus carefully on better tailoring programmes, paying particular to setting an appropriate target weight so as to maximise the benefits for the individual. In this opinionated review, the author will discuss findings from recent clinical research studies examining weight management in obese dogs and cats. A strategy for tailoring weight management targets will then be discussed, illustrated with case examples. PMID- 27766975 TI - In vivo assessment of subcutaneous fat in dogs by real-time ultrasonography and image analysis. AB - BACKGROUND: Systems for estimating body condition score (BCS) are currently used in canine practice to monitor fatness levels. These tools are cheap and easy to use but lack the necessary precision to monitor small changes in body fat, particularly during weight control treatments or in research. The present work aims to study the application of real-time ultrasonography (RTU) together with image analysis in the assessment of subcutaneous fat depots in dogs. Ultrasound images were collected from five anatomical locations (chest, flank, abdomen, thigh and lumbar) from 28 healthy dogs of different breeds and with a body weight (BW) ranging from 5.2 to 33.0 kg. BCS was collected by visual appraisal using a 5 point scale. Subcutaneous fat thickness (SFT) was estimated from RTU images, using the average of three measurements taken in fat deposits located above the muscles represented in each image. Correlations were established between SFT and BW or BCS as well as a classification of BCS-based fatness [overweight (BCS = 4), ideal (BCS = 3) and lean (BCS = 2)]. RESULTS: SFT was found to differ between the five regions considered (P < 0.001). Abdomen and thigh were the areas displaying the widest variation for the different dogs included in the study and also those correlating most with BW, in contrast to the chest, which showed the least variation. Overall, a strong correlation was found between BCS and SFT. The highest correlations were established for the flank, abdomen and lumbar areas. In every anatomical area, a decrease in SFT was observed across all three BCS classes, ranging from 48 to 65 % among overweight and ideal dogs, and from 46 to 83 % among ideal and lean dogs. CONCLUSIONS: Preliminary data showed that within this population there was a strong correlation between BCS and SFT estimated from RTU images. It was also observed that RTU measurements for fat thickness differed among the anatomical points surveyed suggesting differences in their sensitivity to a change in BCS. The images displaying the best prediction value for fatness variations were those collected at the lumbar and abdomen areas. PMID- 27766976 TI - Fetal life malnutrition was not reflected in the relative abundances of adiponectin and leptin mRNAs in adipose tissue in male mink kits at 9.5 weeks of age. AB - BACKGROUND: Malnutrition in fetal life and during suckling have in some animal studies resulted in adaptive changes related to the fat and glucose metabolism, which in the long term might predispose the offspring for metabolic disorders such as obesity later in life. The objective was to study the effect of fetal life malnutrition in male mink on the gene expression of leptin and adiponectin in different adipose tissue sites. RESULTS: Thirty-two male mink, strict carnivore species, exposed to low (FL) or adequate (FA) protein provision the last 16.3 +/- 1.8 days of fetal life and randomly assigned to a low (LP) or adequate (AP) protein diet from 7 to 9.5 weeks of age were used. Adipose tissues (subcutaneous, perirenal and mesenteric) were analyzed using qPCR. Fetal life or post-weaning protein provision did not affect the relative abundances of leptin and adiponectin mRNAs in adipose tissue at 9.5 weeks of age. Relative abundances of leptin and adiponectin mRNAs were different between adipose tissue sites and were significantly higher in subcutaneous than in perirenal and mesenteric tissues. CONCLUSION: Fetal life protein malnutrition in male mink, did not result in adaptive changes in the gene expression of leptin and adiponectin mRNAs in adipose tissue at 9.5 weeks of age as found in rodents. However, both leptin and adiponectin mRNAs were significantly differently expressed between tissue sites. PMID- 27766978 TI - Prevalence and risk factors related to preterm birth in Brazil. AB - BACKGROUND: The rate of preterm birth has been increasing worldwide, including in Brazil. This constitutes a significant public health challenge because of the higher levels of morbidity and mortality and long-term health effects associated with preterm birth. This study describes and quantifies factors affecting spontaneous and provider-initiated preterm birth in Brazil. METHODS: Data are from the 2011-2012 "Birth in Brazil" study, which used a national population based sample of 23,940 women. We analyzed the variables following a three-level hierarchical methodology. For each level, we performed non-conditional multiple logistic regression for both spontaneous and provider-initiated preterm birth. RESULTS: The rate of preterm birth was 11.5 % , (95 % confidence 10.3 % to 12.9 %) 60.7 % spontaneous - with spontaneous onset of labor or premature preterm rupture of membranes - and 39.3 % provider-initiated, with more than 90 % of the last group being pre-labor cesarean deliveries. Socio-demographic factors associated with spontaneous preterm birth were adolescent pregnancy, low total years of schooling, and inadequate prenatal care. Other risk factors were previous preterm birth (OR 3.74; 95 % CI 2.92-4.79), multiple pregnancy (OR 16.42; 95 % CI 10.56-25.53), abruptio placentae (OR 2.38; 95 % CI 1.27-4.47) and infections (OR 4.89; 95 % CI 1.72-13.88). In contrast, provider-initiated preterm birth was associated with private childbirth healthcare (OR 1.47; 95 % CI 1.09 1.97), advanced-age pregnancy (OR 1.27; 95 % CI 1.01-1.59), two or more prior cesarean deliveries (OR 1.64; 95 % CI 1.19-2.26), multiple pregnancy (OR 20.29; 95 % CI 12.58-32.72) and any maternal or fetal pathology (OR 6.84; 95 % CI 5.56 8.42). CONCLUSION: The high proportion of provider-initiated preterm birth and its association with prior cesarean deliveries and all of the studied maternal/fetal pathologies suggest that a reduction of this type of prematurity may be possible. The association of spontaneous preterm birth with socially disadvantaged groups reaffirms that the reduction of social and health inequalities should continue to be a national priority. PMID- 27766977 TI - Factors associated with the use of supplemental oxygen or positive pressure ventilation in the delivery room, in infants born with a gestational age >= 34 weeks. AB - BACKGROUND: Approximately 5-10 % of newborns require some form of resuscitationupon delivery; several factors, such as maternal abnormal conditions, gestational age and type of delivery could be responsible for this trend. This study aimed to describe the factors associated with the need for positive pressure ventilation (PPV) via a mask or endotracheal tube and the use of supplemental O2 in newborns with a gestational age greater than 34 weeks in Brazil. METHODS: We performed a cross-sectional study and obtained data from the Birth in Brazil Survey. The inclusion criterion was a gestational age >=34 weeks. Exclusion criteria were newborns with congenital malformations, and cases with undetermined gestational age or type of delivery (vaginal, pre labor cesarean section and cesarean section during labor). The primary outcomes were need of PPV via a mask or endotracheal tube and the use of supplemental oxygen without PPV. Confounding variables, including maternal age, source of birth payment, years of maternal schooling, previous birth, newborn presentation, multiple pregnancy, and maternal obstetric risk, were analyzed. RESULTS: We included 22,720 newborns. Of these, 2974 (13.1 %) required supplementary oxygen. PPV with a bag and mask was used for 727 (3.2 %) newborns and tracheal intubation for 192 (0.8 %) newborns. Chest compression was necessary for 136 (0.6 %) newborns and drugs administered in 114 (0.5 %). 51.3 % of newborns were delivered by cesarean section, with the majority of cesarean sections (88.7 %) being performed prior to labor. Gestational age (late preterm infants: (Relative Risk-(RR) 2.46; 95 % (Confidence interval-CI 1.79-3.39), maternal obstetric risk (RR 1.59; 95 % CI1.30-1.94), and maternal age of 12-19 years old (RR 1.36; 95 % CI1.06-1.74) contributed to rates of PPV in the logistic regression analysis. Newborns aged between 37-38 weeks of gestaional age weren't less likely to require PPV compared with those aged 39-41 weeks of gestational age. CONCLUSIONS: Late preterm infants, previous maternal obstetric risks and maternal age contributed to the higher needs of PPV and use of O2 in the delivery room. These variables need to be considered in planning care in the delivery room. PMID- 27766979 TI - Good practices according to WHO's recommendation for normal labor and birth and women's assessment of the care received: the "birth in Brazil" national research study, 2011/2012. AB - BACKGROUND: The World Health Organization recommends good practices for the conduct of uncomplicated labor and birth, with the aim of improving the quality of and assessment by women of childbirth care. The aim of this study was to evaluate the association between adoption of good practices according to WHO's recommendation for normal labor and birth and assessment by women of the care received. METHODS: Birth in Brazil is a national hospital-based study with countrywide representation consisting of 23,894 mothers and their newborns, conducted between February 2011 and October 2012. The present study analysed a subsample of this national survey. Postpartum women classified as low risk during pregnancy who had experienced either spontaneous or induced labor were included in this study, totalling 4102 mothers. To estimate the association between assessment by women of the childbirth care received (dependent variable) and good practices according to WHO's recommendation during normal labor and birth (independent variables), a multinomial logistic regression analysis was used and crude and adjusted odds ratios calculated with their 95 % confidence intervals. RESULTS: The good practices associated with positive assessment of the care received by women during labor and birth included the partner's presence, privacy in the birthing place, time available to ask questions, clarity of information received, and empathic support from caregivers during labor and birth. Freedom of movement, free nutrition offered, choice of companions, nonpharmacological analgesia, skin-to-skin contact and breastfeeding in the childbirth room were not associated with the assessment by women of the care received. CONCLUSIONS: Our findings reveal the importance to mothers of their relationship with the team of caregivers during labor and birth. Therefore, caregiver teams must be qualified within a more humanistic vision of childbirth health care. PMID- 27766980 TI - The impact of body condition after calving on metabolism and milk progesterone profiles in two breeds of dairy cows. AB - BACKGROUND: Optimal body condition in early lactation is generally accepted as a prerequisite for good reproductive performance. Examination of milk progesterone profiles offers an objective method for characterization of postpartum ovarian activity in dairy cows. The present study investigated the relationship between body condition after calving, some metabolic parameters in blood plasma, and fertility, as reflected by milk progesterone profiles in the two dairy breeds Swedish Red (SR) and Swedish Holstein (SH). RESULTS: Multiparous dairy cows (n = 73) of SR and SH breeds were selected and divided into three groups based on their body condition score (BCS) after parturition. Selected plasma metabolites were determined, milk progesterone profiles were identified and body condition was scored. Over-conditioned cows and atypical progesterone profiles were more common among SR cows. Insulin sensitivity was lower and IGF 1 higher among SR cows. Insulin was positively related to body condition, but not related to breed. CONCLUSIONS: Atypical progesterone profiles were more common and insulin sensitivity lower in SR than in SH cows, but the SR breed had a higher proportion of over-conditioned SR cows. It is reasonable to assume that breed differences in body condition contributed to these results. PMID- 27766981 TI - Glycaemic and insulinemic response to dietary carbohydrates in horses. AB - BACKGROUND: Dietary sugar and starch affect plasma glucose and insulin concentrations. Little information is available about the effect of dietary fibre on plasma glucose and insulin concentration. It is hypothesized that different dietary fibre compositions will alter post-prandial glycaemic- and insulinemic index of test meals. The objective was to measure postprandial glucose and insulin concentrations in horses fed meals of different fibre compositions. METHODS: Blood was drawn via jugular vein puncture and the glycaemic and insulinemic index were calculated. RESULTS: The meal effect on glycaemic and insulinemic response followed the expected pattern, where plasma concentrations increased after feeding and declined after peak concentration. Glycaemic index was 100 (H), 102 (OB), 102 (BB) and 106 (M) and did not differ significantly between meals. Insulinemic index was 100 (H), 140 (OB), 121 (BB) and 125 (M) and did not differ significantly between meals. CONCLUSIONS: In conclusion, meals containing different fibre compositions did not affect the glycaemic- and insulinemic index in horses. PMID- 27766983 TI - Factors associated with cesarean delivery during labor in primiparous women assisted in the Brazilian Public Health System: data from a National Survey. AB - BACKGROUND: The rate of cesarean delivery (CD) in Brazil has increased over the past 40 years. The CD rate in public services is three times above the World Health Organization recommended values. Among strategies to reduce CD, the most important is reduction of primary cesarean. This study aimed to describe factors associated with CD during labor in primiparous women with a single cephalic pregnancy assisted in the Brazilian Public Health System (SUS). METHODS: This study is part of the Birth in Brazil survey, a national hospital-based study of 23,894 postpartum women and their newborns. The rate of CD in primiparous women was estimated. Univariate and multivariable logistic regression was performed to analyze factors associated with CD during labor in primiparous women with a single cephalic pregnancy, including estimation of crude and adjusted odds ratios and their respective 95 % confidence intervals. RESULTS: The analyzed data are related to the 2814 eligible primiparous women who had vaginal birth or CD during labor in SUS hospitals. In adjusted analyses, residing in the Southeast region was associated with lower CD during labor. Occurrence of clinical and obstetric conditions potentially related to obstetric emergencies before delivery, early admission with < 4 cm of dilatation, a decision late in pregnancy for CD, and the use of analgesia were associated with a greater risk for CD. Favorable advice for vaginal birth during antenatal care, induction of labor, and the use of any good practices during labor were protective factors for CD. The type of professional who attended birth was not significant in the final analyses, but bivariate analysis showed a higher use of good practices and a smaller proportion of epidural analgesia in women cared for by at least one nurse midwife. CONCLUSIONS: The CD rate in primiparous women in SUS in Brazil is extremely high and can compromise the health of these women and their newborns. Information and support for vaginal birth during antenatal care, avoiding early admission, and promoting the use of good practices during labor assistance can reduce unnecessary CD. Considering the experience of other countries, incorporation of nurse midwives in childbirth care may increase the use of good practices during labor. PMID- 27766982 TI - A modified oral sugar test for evaluation of insulin and glucose dynamics in horses. AB - BACKGROUND: An oral sugar test (OST) using Karo(r) Light Corn Syrup has been developed in the USA as a field test for the assessment of insulin dysregulation in horses but the syrup is not available in Scandinavian grocery stores. The aim of the study was to compare the results of a modified OST between horses with equine metabolic syndrome (EMS) and healthy horses using a Scandinavian commercially available glucose syrup (Dansukker glykossirap). In addition, the effect of breed and the repeatability of the test were evaluated. In the present study, clinically healthy horses (7 Shetland ponies, 8 Icelandic horses, 8 Standardbred horses) and 20 horses of various breeds with EMS underwent the modified OST test. The Icelandic horses and Shetland ponies underwent the OST twice. Insulin and glucose data from the OST were used to calculate peak insulin concentration (PeakINS), time to peak insulin concentration (T-peakINS), area under the curve for insulin (AUCINS) and glucose (AUCGLU) as well as whole body insulin sensitivity index (ISICOMP). RESULTS: Compared to the healthy group, the EMS group had 6-7 times higher geometric mean for PeakINS and AUCINS and 8 times lower geometric mean for ISICOMP. The EMS group had a delayed T-peakINS compared to the healthy group. There was no effect of breed in the group of healthy horses on PeakINS, T-peakINS, AUCINS, AUCGLU and ISICOMP. Coefficient of variation for repeated tests was 19.8, 19.0 and 17.6 % for PeakINS, AUCINS and ISICOMP respectively. CONCLUSIONS: The results of the present study demonstrate that the modified OST appears to be a practical and useful diagnostic tool for assessment of insulin dysregulation in the horse. However, to make it possible to establish the most appropriate sampling interval and to evaluate the accuracy of the modified OST, further studies in horses with a variable degree of insulin resistance are needed, where results from the modified OST are compared with quantitative measurements for IS. PMID- 27766984 TI - Correlations between cresty neck scores and post-mortem nape fat measurements in horses, obtained after photographic image analysis. AB - BACKGROUND: Obesity and emaciation in horses have major detrimental effects on health and morbidity, reproductive failure, work performance or carcass quality. Scoring is a current management tool used to assess and monitor equine body condition due to its simplicity and low cost. However, accurate assessment of obesity remains a challenge, even though a number of approaches have been tested, particularly for research purposes on adiposity. Their merit is usually validated by comparison with standard scoring methods. The overall aim of this study was to establish the correlation between post-mortem nape fat measurements obtained after photographic image analysis and cresty neck score (CNS) in horses. Data were collected from seventeen horses with a hot carcass weight of 165 +/- 51 kg. Pre-slaughter CNS measurements were obtained using a six-point scale (from 0 to 5). Image capture was performed post-mortem, in the slaughter line; for each carcass, images of the dorsal and medial views were collected and afterwards transferred to a computer for analysis. After outlining the cresty neck fat, its area, major axis and thickness were determined. Correlation coefficients between nape fat measurements, CNS and carcass fatness were determined. RESULTS: The horses in the study show similar variation for CNS and hot carcass weight [Coefficient of variation (CV) = 32 and 31 %, respectively], but a high variation for carcass fattening (CV = 41 %). The nape fat area measurement was the parameter exhibiting the greatest variation (CV = 50 %). Correlations established between CNS and the variables tested revealed the existence of moderate to strong correlations among CNS, nape fat measurements, and carcass fatness. The highest correlation coefficients were found between CNS and nape fat thickness (r = 0.882; P < 0.01). The linear regression between CNS and nape fat thickness accounted for 77 % of the recorded variation for nape fat thickness. CONCLUSIONS: The present study showed that there is a strong correlation between horse CNS and post-mortem nape fat measurements or carcass fatness. PMID- 27766985 TI - Relationships between body condition score and ultrasound skin-associated subcutaneous fat depth in equids. AB - BACKGROUND: In equids, health and welfare depend on body composition. A growing number of equids are now used as leisure and companion animals, and often found overfeed. The need for a close monitoring of body fatness led to the search for tools allowing a rapid and non-invasive estimation of fatness. This study intends to assess real-time ultrasonography (RTU) usefulness in establishing a relationship between ultrasound measures of subcutaneous fat-plus-skin thickness (SF-Skin) and body condition score (BCS) in horses and donkeys. Forty-three healthy animals (16 donkeys and 27 horses) were used in this study to generate 95 records (RTU and BCS pairs), in multiple RTU sessions for 2 years. Using visual appraisal and palpation, BCS was graded in a 1-9 points scale. Real-time ultrasonography images were taken using a 7.5 MHz linear transducer, placed perpendicular to the backbone, over the 3rd lumbar vertebra. ImageJ was used to measure the SF-Skin on RTU images. The relation between BCS and SF-Skin measurements was tested by linear and polynomial regression analysis. RESULTS: The BCS values were similar in horses (5.50; from 3 to 8 points) and donkeys (5.14; from 3 to 7 points). The SF-Skin measures show a similar trend (a mean of 7.1 and 7.7 mm in horses and donkeys, respectively). A polynomial regression among BCS and SF-Skin explained 92 and 77 % of the variation in donkeys and horses respectively. The coefficient of determination was considerably higher for the regression developed for donkeys compared with that of horses (R2 = 0.92 vs. 0.77, respectively), which reduced the accuracy of the method in horses. Both the linear and polynomial models tested show a strong relationship among BCS and SF Skin for donkeys (R2 > 0.91; P < 0.01) and horses (R2 > 0.74; P < 0.01), despite that the extremes for BCS did not existed in our sample. CONCLUSIONS: Our results showed the potential RTU usefulness to monitor body fat in equids. Using a high frequency transducer and RTU together with image analysis allowed the identification of small SF-skin variations. This report will support further studies on the relationships between SF-Skin and BCS, particularly in extreme BCS scores. PMID- 27766986 TI - Blood pressure in Warmblood horses before and during a euglycemic hyperinsulinemic clamp. AB - BACKGROUND: Insulin resistance (IR) in humans is related to hypertension and impaired vasodilation. Insulin administration has been shown to lower blood pressure both in insulin resistant as well as in insulin sensitive individuals. The aim of the study was to investigate the association between insulin sensitivity and alterations in blood pressure in healthy horses before and after a euglycemic-hyperinsulinemic clamp (EHC). A 3-h EHC was performed in 13 healthy horses (11 mares, 2 geldings). Blood samples for measurement of plasma glucose and insulin were collected before the start of the EHC, every 10 min during the EHC and immediately after the EHC. Mean, systolic- and diastolic blood pressure was measured before and during the final 10 min of the EHC using an indirect high definition oscillometric monitor (HDO, horse model) applied to the middle of the coccygeal artery. Five consecutive measurements were made in each horse and on each occasion. Insulin and glucose data from the EHC were used to calculate the mean rate of glucose disposal per unit of insulin during steady state (M/I ratio). Insulin resistance was defined as a M/I ratio <5 mg/kg/min/mUL (Lindase et al. in Am J Vet Res 77:300-309, 2016). RESULTS: Insulin administration decreased systolic, diastolic and mean arterial pressure in all horses. The M/I ratio for all horses was negatively correlated with the decrease in systolic blood pressure (r2 = 0.55, P = 0.004) and mean arterial pressure (r2 = 0.31, P = 0.048) but not diastolic blood pressure (r2 = 0.12, P = 0.26). Eight horses were defined as insulin resistant (IR) and five horses had normal insulin sensitivity. The five horses with normal insulin sensitivity showed a greater decrease in systolic blood pressure (-17.0 +/- 7.4 vs. -3.4 +/- 4.6 mmHg, P = 0.001) and MAP (19.2 +/- 14.7 vs. 6.9 +/- 8.7 mmHg, P = 0.04) than IR horses. There was no difference in the decrease in diastolic blood pressure between groups (16 +/- 12.8 vs. 8.9 +/- 12.1 mmHg, P = 0.17). CONCLUSIONS: This study indicates that there is a relationship between insulin sensitivity and systolic and MAP in horses. However, studies on a larger number of horses are needed to confirm this association. PMID- 27766987 TI - Fear of Failure: Engaging Patients in Antimicrobial Stewardship after Fecal Transplantation for Recurrent Clostridium difficile Infection. PMID- 27766988 TI - Comparative genomic fingerprinting of Campylobacter: application in routine public health surveillance and epidemiological investigations. AB - A subtyping methodology for Campylobacter, Comparative Genomic Fingerprinting (CGF40), has been described recently. The objective of this study was to assess the utility of CGF40 as a tool to enhance routine public health surveillance of campylobacteriosis. Isolates of Campylobacter from across the province were requested and sent for CGF40 subtyping. Epidemiological data from cases reported to public health officials in Nova Scotia, Canada, from January 2012 to March 2015 were linked with blinded CGF40 subtyping results. CGF40 was epidemiologically valid; subtyping discerned known epidemiologically related isolates and augmented case-finding. Predominant sources and locations of subtype detection from the national reference database showed some study subtypes were rare and even novel to the database, while others were more commonly identified over multiple years and with exposures locally and internationally. A case-case study design was applied to examine risk factors for the most common CGF40 subtypes detected. Differences in the epidemiology of different CGF40 subtypes were observed. Statistically significant associations were noted for specific subtypes with rural residence, local exposure, contact with a pet dog or cat, contact with chickens, and drinking unpasteurized milk. With prospective use, CGF40 could potentially identify unrecognized outbreaks and contribute to epidemiological investigations of case clusters. PMID- 27766990 TI - Providing evidence to support the development of whole grain dietary recommendations in the United Kingdom. AB - Observational evidence suggests that increased whole grain (WG) intake reduces the risks of many non-communicable diseases, such as CVD, type 2 diabetes, obesity and certain cancers. More recently, studies have shown that WG intake lowers all-cause and cause-specific mortality. Much of the reported evidence on risk reduction is from US and Scandinavian populations, where there are tangible WG dietary recommendations. At present there is no quantity-specific WG dietary recommendation in the UK, instead we are advised to choose WG or higher fibre versions. Despite recognition of WG as an important component of a healthy diet, monitoring of WG intake in the UK has been poor, with the latest intake assessment from data collected in 2000-2001 for adults and in 1997 for children. To update this information we examined WG intake in the National Diet and Nutrition Survey rolling programme 2008-2011 after developing our database of WG food composition, a key resource in determining WG intake accurately. The results showed median WG intakes remain low in both adults and children and below that of countries with quantity-specific guidance. We also found a reduction in C reactive protein concentrations and leucocyte counts with increased WG intake, although no association with other markers of cardio-metabolic health. The recent recommendations by the UK Scientific Advisory Committee on Nutrition to increase dietary fibre intake will require a greater emphasis on consuming more WG. Specific recommendations on WG intake in the UK are warranted as is the development of public health policy to promote consumption of these important foods. PMID- 27766991 TI - Still not adult-like: lexical stress contrastivity in word productions of eight- to eleven-year-olds. AB - Lexical stress is the contrast between strong and weak syllables within words. Ballard et al. (2012) examined the amount of stress contrastivity across adjacent syllables in word productions of typically developing three- to seven-year-olds and adults. Here, eight- to eleven-year-olds are compared with the adults from Ballard et al. using acoustic measurements of relative contrast in duration, peak intensity, and peak fundamental frequency of the vowels within the initial two syllables of each word. While eight- to eleven-year-olds are closer to adult-like stress contrastivity than three- to seven-year-olds, they are not yet adult-like in terms of the intensity contrast for words beginning with a weak syllable. PMID- 27766989 TI - The influence of energy standardisation on the alternate Mediterranean diet score and its association with mortality in the Multiethnic Cohort. AB - The alternate Mediterranean diet (aMED) score is an adaptation of the original Mediterranean diet score. Raw (aMED) and energy-standardised (aMED-e) versions have been used. How the diet scores and their association with health outcomes differ between the two versions is unclear. We examined differences in participants' total and component scores and compared the association of aMED and aMED-e with all-cause, CVD and cancer mortality. As part of the Multiethnic Cohort, 193 527 men and women aged 45-75 years from Hawaii and Los Angeles completed a baseline FFQ and were followed up for 13-18 years. The association of aMED and aMED-e with mortality was examined using Cox's regression, with adjustment for total energy intake. The correlation between aMED and aMED-e total scores was lower among people with higher BMI. Participants who were older, leaner, more educated and consumed less energy scored higher on aMED-e components compared with aMED, except for the red and processed meat and alcohol components. Men reporting more physical activity scored lower on most aMED-e components compared with aMED, whereas the opposite was observed for the meat component. Higher scores of both aMED and aMED-e were associated with lower risk of all cause, CVD and cancer mortality. Although individuals may score differently with aMED and aMED-e, both scores show similar reductions in mortality risk for persons scoring high on the index scale. Either version can be used in studies of diet and mortality. Comparisons can be performed across studies using different versions of the score. PMID- 27766992 TI - NEOADJUVANT TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION FOR BILIARY TUMOR THROMBOSIS: A RETROSPECTIVE STUDY. AB - OBJECTIVES: Curative hepatectomy and tumor thrombectomy for hepatocellular carcinoma with complicating biliary tumor thrombosis (HCC/BTT) is associated with high surgical morbidity and mortality. This retrospective study evaluated the effectiveness and safety of neoadjuvant transcatheter arterial chemoembolization (TACE) in HCC/BTT patients scheduled for curative resection. METHODS: Thirty consecutive patients with diagnosed HCC/BTT were hospitalized for neoadjuvant TACE and elective curative liver resection (group A; n=20) or curative liver resection alone (group B; n=10). The primary outcome measure was median survival. RESULTS: Group A had a significantly shorter overall operative time (160+/-25 versus 190+/-35 min; p < .01) and duration of inflow control (14.3+/-3.6 versus 25.1+/-5.1 min; p < .01) and significantly less intraoperative blood loss (150+/ 35 versus 520+/-75 ml; p < .01) and transfusion (100+/-40 versus 375+/-55 ml; p < .01) as compared to group B. Among patients undergoing both thrombectomy and curative resection, the median survival of group A was significantly longer than that of group B (28.5 [9-54] versus 21.5 [6-39] months; p < .01); among those who received thrombectomy alone, the median survival of group A was also significantly longer than that of group B (12.8 [6-25] versus 4.5 [2-7] months; p < .01). CONCLUSIONS: Neoadjuvant TACE significantly reduced the surgical risk of curative liver resection and significantly prolonged median survival in HCC patients with complicating BTT. PMID- 27766993 TI - Female sexual function varies over time and is dependent on partner-specific factors: a population-based longitudinal analysis of six sexual function domains. AB - BACKGROUND: Most studies examining female sexual functions (FSFs) have used cross sectional designs, not allowing for studying temporal stability and possible relationships between different FSFs over time. Our aim was to study these relationships using a longitudinal approach. METHOD: The study sample consisted of 2173 Finnish women from two large-scale, population-based data collections 7 years apart. The Female Sexual Function Index was used. Analyses were further conducted separately for women in different relationship constellations. RESULTS: Standardized autoregressive paths ranged from 0.136 (sexual satisfaction) to 0.447 (orgasm function) in the full sample, suggesting that most of the variance in FSF was explained by something other than previous function. Orgasm, desire and satisfaction were the strongest predictors of other functions in the full sample and for women in the same relationship at both time points (higher orgasm function predicted higher function in other domains; greater sexual desire and satisfaction predicted lower function in other domains), however, with small effects sizes. For single women, orgasm function and sexual desire were the only significant autoregressive paths. Significant unidirectional cross-domain paths were found for women in the same relationship at both time points. One significant cross-domain path, not confirmed as unidirectional, was found for single women. CONCLUSIONS: FSFs varied considerably over 7 years and relationship status was of importance when assessing temporal stability and cross-domain effects. Our results advocate tailored psychobehavioural treatment interventions for female sexual dysfunctions that take partner-specific factors into account. PMID- 27766994 TI - Environmental influence of problematic social relationships on adolescents' daily cortisol secretion: a monozygotic twin-difference study. AB - BACKGROUND: This study investigated the potential environmental effects of peer victimization and the quality of relationships with parents and friends on diurnal cortisol secretion in mid-adolescence. METHOD: This study used the monozygotic (MZ) twin-difference design to control for genetic effects and thus estimate the unique environmental influences on diurnal cortisol. Participants were 136 MZ twin pairs (74 female pairs) for whom cortisol was assessed four times per day over four collection days grouped in a 2-week period in grade 8 (mean age = 14.07 years). Participants also provided self-reports of peer victimization from grade 4 to grade 8 and of the relationship quality with the mother, father and best friend in grade 8. RESULTS: The expected pattern of diurnal cortisol secretion was observed, with high levels at awakening followed by an increase 30 min later and a progressive decrease subsequently. Controlling for a host of confounders, only within-twin pair differences in peer victimization and a problematic relationship with the mother were significantly linked to twin differences in diurnal cortisol secretion. Specifically, whereas a more problematic mother-child relationship was associated with morning cortisol secretion, peer victimization was linked to cortisol secretion later in the day (diurnal slope). CONCLUSIONS: Controlling for genetic influences and other confounders, stressful relationships with peers and the mother exert unique and time-specific environmental influences on the pattern of diurnal cortisol secretion in mid-adolescence. PMID- 27766996 TI - Non-fluoroscopic cardiac ablation of neonates with CHD. AB - In current practice, children with anatomically normal hearts routinely undergo fluoroscopy-free ablations. Infants and children with congenital heart disease (CHD) represent the most difficult population to perform catheter ablation without fluoroscopy. We report two neonatal patients with CHD in whom cardiac ablations were performed without fluoroscopy. The first infant had pulmonary atresia with intact ventricular septum with refractory supraventricular tachycardia, and the second infant presented with Ebstein's anomaly of the tricuspid valve along with persistent supraventricular tachycardia. Both patients underwent uncomplicated, successful ablation without recurrence of arrhythmias. These cases suggest that current approaches to minimising fluoroscopy may be useful even in challenging patients such as neonates with CHD. PMID- 27766995 TI - The Outcome of Monochorionic Diamniotic Twins Discordant at 11 to 13+6 Weeks' Gestation. AB - BACKGROUND: Monochorionic diamniotic (MCDA) twin pregnancies are associated with adverse perinatal outcome. Intertwin discordances at the time of nuchal translucency (NT) screening may have a value in the prediction of fetal loss or twin-to-twin transfusion syndrome. We aimed to determine the ability of intertwin NT and crown rump length (CRL) discordances among MCDA twins to predict adverse outcomes. MATERIAL AND METHODS: All MCDA twins with a documented routine ultrasound at 11 to 13+6 weeks' gestation, and known pregnancy outcome between August 2003 and August 2012 were included. Receiver operating characteristic curves were used to determine the ideal NT and CRL discordances cut-off points that maximized the ability to predict adverse outcome, which was defined as any of: death of one or both twins, twin-to-twin transfusion syndrome, or estimated fetal weight or birth weight discordances >=25%. RESULTS: Of the 89 cases, 20 (22.5%) had at least one adverse outcome. NT discordance was more discriminatory of adverse outcome than was CRL discordance. The optimal values for predicting any adverse outcomes for NT were >23.7% and for CRL >3.5%. The positive predictive values for NT (52.4%) and CRL (29.8%) screening were relatively low; however, the lack of either NT or CRL discordances was more reassuring, with negative predictive values of 86.8% and 86.4%, respectively. CONCLUSIONS: NT discordance is more predictive for adverse fetal outcome in MCDA twins than CRL discordance. Neither NT nor CRL discordance are likely to modify the intensive monitoring required for these very high-risk pregnancies. PMID- 27766997 TI - Prevalence of anxiety disorders in community dwelling older adults in Hong Kong. AB - BACKGROUND: Anxiety disorders are prevalent yet under-recognized in late life. We examined the prevalence of anxiety disorders in a representative sample of community dwelling older adults in Hong Kong. METHOD: Data on 1,158 non-demented respondents aged 60-75 years were extracted from the Hong Kong Mental Morbidity survey (HKMMS). Anxiety was assessed with the revised Clinical Interview Schedule (CIS-R). RESULT: One hundred and thirty-seven respondents (11.9%, 95% CI = 10 13.7%) had common mental disorders with a CIS-R score of 12 or above. 8% (95% CI = 6.5-9.6%) had anxiety, 2.2% (95% CI = 1.3-3%) had an anxiety disorder comorbid with depressive disorder, and 1.7% (95% CI = 1-2.5%) had depression. Anxious individuals were more likely to be females (chi 2 = 25.3, p < 0.001), had higher chronic physical burden (t = -9.3, p < 0.001), lower SF-12 physical functioning score (t = 9.2, p < 0.001), and poorer delayed recall (t = 2.3, p = 0.022). The risk of anxiety was higher for females (OR 2.8, 95% C.I. 1.7-4.6, p < 0.001) and those with physical illnesses (OR 1.4, 95% C.I. 1.3-1.6, p < 0.001). The risk of anxiety disorders increased in those with disorders of cardiovascular (OR 1.9, 95% C.I. 1.2-2.9, p = 0.003), musculoskeletal (OR 2.0, 95% C.I. 1.5-2.7, p < 0.001), and genitourinary system (OR 2.0, 95% C.I. 1.3-3.2, p = 0.002). CONCLUSIONS: The prevalence of anxiety disorders in Hong Kong older population was 8%. Female gender and those with poor physical health were at a greater risk of developing anxiety disorders. Our findings also suggested potential risk for early sign of memory impairment in cognitively healthy individuals with anxiety disorders. PMID- 27766998 TI - CHANGING HEALTH TECHNOLOGY ASSESSMENT PARADIGMS? AB - OBJECTIVES: Health technology assessment (HTA) has to innovate to best support changing health system environments and to help provide access to valuable innovation under fiscal constraint. METHODS: Issues associated with changing HTA paradigms were identified through scoping and explored through deliberation at a meeting of industry and HTA leaders. RESULTS: Five broad areas of change (engagement, scientific dialogue, research prioritization, adaptive approaches, and real world data) were identified. The meeting focused on two themes derived from these: re-thinking scientific dialogue and multi-stakeholder engagement, and re-thinking value, affordability, and access. Earlier and ongoing engagement to steer the innovation process and help achieve appropriate use across the technology lifecycle was perceived as important but would be resource intensive and would require priority setting. Patients need to be involved throughout, and particularly at the early stages. Further discussion is needed on the type of body best suited to convening the dialogue required. There was agreement that HTA must continue to assess value, but views differed on the role that HTA should play in assessing affordability and on appropriate responses to challenges around affordability. Enhanced horizon scanning could play an important role in preparing for significant future investments. CONCLUSIONS: Early and ongoing multi-stakeholder engagement and revisiting approaches to valuing innovation are required. Questions remain as to the most appropriate role for HTA bodies. Changing HTA paradigms extend HTA's traditional remit of being responsive to decision-makers demands to being more proactive and considering whole system value. PMID- 27766999 TI - A systematic review of methods to assess intake of sugar-sweetened beverages among healthy European adults and children: a DEDIPAC (DEterminants of DIet and Physical Activity) study. AB - OBJECTIVE: Research indicates that intake of sugar-sweetened beverages (SSB) may be associated with negative health consequences. However, differences between assessment methods can affect the comparability of intake data across studies. The current review aimed to identify methods used to assess SSB intake among children and adults in pan-European studies and to inform the development of the DEDIPAC (DEterminants of DIet and Physical Activity) toolbox of methods suitable for use in future European studies. DESIGN: A literature search was conducted using three electronic databases and by hand-searching reference lists. English language studies of any design which assessed SSB consumption were included in the review. SETTING: Studies involving two or more European countries were included in the review. SUBJECTS: Healthy, free-living children and adults. RESULTS: The review identified twenty-three pan-European studies which assessed intake of SSB. The FFQ was the most commonly used (n 24), followed by the 24 h recall (n 6) and diet records (n 1). There were several differences between the identified FFQ, including the definition of SSB used. In total, seven instruments that were tested for validity were selected as potentially suitable to assess SSB intake among adults (n 1), adolescents (n 3) and children (n 3). CONCLUSIONS: The current review highlights the need for instruments to use an agreed definition of SSB. Methods that were tested for validity and used in pan-European populations encompassing a range of countries were identified. These methods should be considered for use by future studies focused on evaluating consumption of SSB. PMID- 27767000 TI - Comparative validity and repeatability of a single question, a twenty-eight-item FFQ and estimated food records to assess takeaway meal intake. AB - A single question (SQ) and a twenty-eight-item FFQ to measure takeaway meal intake were compared with two 7-d estimated food records (EFR; reference method). Test methods were completed after the reference period and repeated 6-8 d later for repeatability. The SQ asked about intake of high-SFA takeaway meals. FFQ items included low- and high-SFA meals. Test methods were compared with EFR for sensitivity, specificity, and positive and negative predictive values, using a goal of <=1 high-SFA weekly takeaway meals. Bland-Altman analyses were used to check agreement between measurement approaches, the kappa coefficient was used to summarise the observed level of agreement, and Spearman's correlation was used to assess the degree to which instruments ranked individuals. Young adults were recruited from two universities, and 109 participants (61 % female) completed the study. The mean age was 24.4 (sd 4.9) years, and the mean BMI was 23.5 (sd 3.7) kg/m2. The SQ and the FFQ had a sensitivity of 97 and 83 % and a specificity of 46 and 92 %, respectively. Both methods exhibited moderate correlation for measuring total and high-SFA takeaway meal intakes (r s ranging from 0.64 to 0.80). Neither instrument could measure precise, absolute intake at the group or individual level. Test methods ranged from fair (kappa w =0.24) to moderate agreement (kappa w =0.59). The repeatability for all was acceptable. The FFQ identified excessive high-SFA takeaway meal intake and measured individuals' category for total and high-SFA takeaway intakes. Both methods are suitable for ranking individuals for total or high-SFA takeaway meal intakes. PMID- 27767001 TI - Takayasu arteritis with coronary and pulmonary involvement in a young child presenting with acute coronary syndrome. PMID- 27767002 TI - Experience With Rapid Microarray-Based Diagnostic Technology and Antimicrobial Stewardship for Patients With Gram-Positive Bacteremia. AB - OBJECTIVE To describe the impact of rapid diagnostic microarray technology and antimicrobial stewardship for patients with Gram-positive blood cultures. DESIGN Retrospective pre-intervention/post-intervention study. SETTING A 1,200-bed academic medical center. PATIENTS Inpatients with blood cultures positive for Staphylococcus aureus, Enterococcus faecalis, E. faecium, Streptococcus pneumoniae, S. pyogenes, S. agalactiae, S. anginosus, Streptococcus spp., and Listeria monocytogenes during the 6 months before and after implementation of Verigene Gram-positive blood culture microarray (BC-GP) with an antimicrobial stewardship intervention. METHODS Before the intervention, no rapid diagnostic technology was used or antimicrobial stewardship intervention was undertaken, except for the use of peptide nucleic acid fluorescent in situ hybridization and MRSA agar to identify staphylococcal isolates. After the intervention, all Gram positive blood cultures underwent BC-GP microarray and the antimicrobial stewardship intervention consisting of real-time notification and pharmacist review. RESULTS In total, 513 patients with bacteremia were included in this study: 280 patients with S. aureus, 150 patients with enterococci, 82 patients with stretococci, and 1 patient with L. monocytogenes. The number of antimicrobial switches was similar in the pre-BC-GP (52%; 155 of 300) and post-BC GP (50%; 107 of 213) periods. The time to antimicrobial switch was significantly shorter in the post-BC-GP group than in the pre-BC-GP group: 48+/-41 hours versus 75+/-46 hours, respectively (P<.001). The most common antimicrobial switch was de escalation and time to de-escalation, was significantly shorter in the post-BC-GP group than in the pre-BC-GP group: 53+/-41 hours versus 82+/-48 hours, respectively (P<.001). There was no difference in mortality or hospital length of stay as a result of the intervention. CONCLUSIONS The combination of a rapid microarray diagnostic test with an antimicrobial stewardship intervention improved time to antimicrobial switch, especially time to de-escalation to optimal therapy, in patients with Gram-positive blood cultures. Infect Control Hosp Epidemiol 2016;1-6. PMID- 27767003 TI - Surgical Site Infections Following Birmingham Hip Resurfacing. AB - The Birmingham Hip Resurfacing procedure (BHR) is metal-on-metal resurfacing procedure for hip arthritis. BHR was associated with low risk of surgical site infection (SSI; 0.6%). In addition to antimicrobials, superficial SSIs were treated with incision and drainage, whereas deep incisional or organ-space SSIs required removal of prosthesis. Infect Control Hosp Epidemiol 2016;1-4. PMID- 27767004 TI - Household Transmission of Clostridium difficile to Family Members and Domestic Pets. AB - OBJECTIVE To determine the risk of Clostridium difficile transmission from index cases with C. difficile infection (CDI) to their household contacts and domestic pets. DESIGN A prospective study from April 2011 to June 2013. SETTING Patients with CDI from Canadian tertiary care centers. PARTICIPANTS Patients with CDI, their household human contacts, and pets. METHODS Epidemiologic information and stool or rectal swabs were collected from participants at enrollment and monthly for up to 4 months. Pulsed-field gel electrophoresis (PFGE) was performed on C. difficile isolates. Probable transmission was defined as the conversion of a C. difficile culture-negative contact to C. difficile culture-positive contact with a PFGE pattern indistinguishable or closely related to the index case. Possible transmission was defined as a contact with a positive C. difficile culture at baseline with a strain indistinguishable or closely related to the index case. RESULTS A total of 51 patients with CDI participated in this study; 67 human contacts and 15 pet contacts were included. Overall, 9 human contacts (13.4%) were C. difficile culture positive; 1 contact (1.5%) developed CDI; and 8 contacts were asymptomatic. Of 67 human contacts, probable transmission occurred in 1 human contact (1.5%) and possible transmission occurred in 5 human contacts (7.5%). Of 15 pet contacts, probable transmission occurred in 3 (20%) and possible transmission occurred in 1 (6.7%). CONCLUSIONS There was a high proportion of C. difficile culture positivity at 13.4% among human contacts and asymptomatic carriage of domestic pets reached 26.7%. These results suggest that household transmission of C. difficile may be a source of community-associated cases. Infect Control Hosp Epidemiol 2016;1-7. PMID- 27767005 TI - Research Methods in Healthcare Epidemiology and Antimicrobial Stewardship: Use of Administrative and Surveillance Databases - ERRATUM. PMID- 27767006 TI - Global Escherichia coli Sequence Type 131 Clade with blaCTX-M-27 Gene. AB - The Escherichia coli sequence type (ST) 131 C2/H30Rx clade with the blaCTX-M-15 gene had been most responsible for the global dissemination of extended-spectrum beta-lactamase (ESBL)-producing E. coli. ST131 C1/H30R with blaCTX-M-27 emerged among ESBL-producing E. coli in Japan during the late 2000s. To investigate the possible expansion of a single clade, we performed whole-genome sequencing for 43 Japan and 10 global ST131 isolates with blaCTX-M-27 (n = 16), blaCTX-M-14 (n = 16), blaCTX-M-15 (n = 13), and others (n = 8). We also included 8 ST131 genomes available in public databases. Core genome-based analysis of 61 isolates showed that ST131 with blaCTX-M-27 from 5 countries formed a distinct cluster within the C1/H30R clade, named C1-M27 clade. Accessory genome analysis identified a unique prophage-like region, supporting C1-M27 as a distinct clade. Our findings indicate that the increase of ESBL-producing E. coli in Japan is due mainly to emergence of the C1-M27 clade. PMID- 27767007 TI - Reassortant Eurasian Avian-Like Influenza A(H1N1) Virus from a Severely Ill Child, Hunan Province, China, 2015. AB - In 2015, a novel influenza A(H1N1) virus was isolated from a boy in China who had severe pneumonia. The virus was a genetic reassortant of Eurasian avian-like influenza A(H1N1) (EA-H1N1) virus. The hemagglutinin, neuraminidase, and matrix genes of the reassortant virus were highly similar to genes in EA-H1N1 swine influenza viruses, the polybasic 1 and 2, polymerase acidic, and nucleoprotein genes originated from influenza A(H1N1)pdm09 virus, and the nonstructural protein gene derived from classical swine influenza A(H1N1) (CS H1N1) virus. In a mouse model, the reassortant virus, termed influenza A/Hunan/42443/2015(H1N1) virus, showed higher infectivity and virulence than another human EA-H1N1 isolate, influenza A/Jiangsu/1/2011(H1N1) virus. In the respiratory tract of mice, virus replication by influenza A/Hunan/42443/2015(H1N1) virus was substantially higher than that by influenza A/Jiangsu/1/2011(H1N1) virus. Human-to-human transmission of influenza A/Hunan/42443/2015(H1N1) virus has not been detected; however, given the circulation of novel EA-H1N1 viruses in pigs, enhanced surveillance should be instituted among swine and humans. PMID- 27767008 TI - Immune Responses to Invasive Group B Streptococcal Disease in Adults. AB - Immunization of nonpregnant adults could help prevent invasive group B Streptococcus (GBS) infections, but adult immune responses have not been investigated. We defined capsular polysaccharide (CPS) and pilus island (PI) surface antigen distribution and expression and immune responses to GBS infection in nonpregnant adults. Prospective surveillance from 7 hospitals in Houston, Texas, USA, identified 102 adults with GBS bacteremia; 43% had skin/soft tissue infection, 16% bacteremia without focus, and 12% osteomyelitis. CPS-specific IgG was determined by ELISA and pilus-specific IgG by multiplex immunoassay. CPS types were Ia (24.5%), Ib (12.7%), II (9.8%), III (16.7%), IV (13.7%), and V (12.7%); 9.8% were nontypeable by serologic methods. Pili, expressed by 89%, were most often PI-2a. CPS and pilus-specific IgG increased during convalescence among patients with strains expressing CPS or PI. All GBS expressed CPS or PI; 79% expressed both. Increased antibodies to CPS and PI during recovery suggests that GBS bacteremia in adults is potentially vaccine preventable. PMID- 27767009 TI - Epidemiology of La Crosse Virus Emergence, Appalachia Region, United States. AB - La Crosse encephalitis is a viral disease that has emerged in new locations across the Appalachian region of the United States. Conventional wisdom suggests that ongoing emergence of La Crosse virus (LACV) could stem from the invasive Asian tiger (Aedes albopictus) mosquito. Efforts to prove this, however, are complicated by the numerous transmission routes and species interactions involved in LACV dynamics. To analyze LACV transmission by Asian tiger mosquitoes, we constructed epidemiologic models. These models accurately predict empirical infection rates. They do not, however, support the hypothesis that Asian tiger mosquitoes are responsible for the recent emergence of LACV at new foci. Consequently, we conclude that other factors, including different invasive mosquitoes, changes in climate variables, or changes in wildlife densities, should be considered as alternative explanations for recent increases in La Crosse encephalitis. PMID- 27767010 TI - Transmission of Babesia microti Parasites by Solid Organ Transplantation. AB - Babesia microti, an intraerythrocytic parasite, is tickborne in nature. In contrast to transmission by blood transfusion, which has been well documented, transmission associated with solid organ transplantation has not been reported. We describe parasitologically confirmed cases of babesiosis diagnosed ~8 weeks posttransplantation in 2 recipients of renal allografts from an organ donor who was multiply transfused on the day he died from traumatic injuries. The organ donor and recipients had no identified risk factors for tickborne infection. Antibodies against B. microti parasites were not detected by serologic testing of archived pretransplant specimens. However, 1 of the organ donor's blood donors was seropositive when tested postdonation and had risk factors for tick exposure. The organ donor probably served as a conduit of Babesia parasites from the seropositive blood donor to both kidney recipients. Babesiosis should be included in the differential diagnosis of unexplained fever and hemolytic anemia after blood transfusion or organ transplantation. PMID- 27767011 TI - Risk Factors for Middle East Respiratory Syndrome Coronavirus Infection among Healthcare Personnel. AB - Healthcare settings can amplify transmission of Middle East respiratory syndrome coronavirus (MERS-CoV), but knowledge gaps about the epidemiology of transmission remain. We conducted a retrospective cohort study among healthcare personnel in hospital units that treated MERS-CoV patients. Participants were interviewed about exposures to MERS-CoV patients, use of personal protective equipment, and signs and symptoms of illness after exposure. Infection status was determined by the presence of antibodies against MERS-CoV. To assess risk factors, we compared infected and uninfected participants. Healthcare personnel caring for MERS-CoV patients were at high risk for infection, but infection most often resulted in a relatively mild illness that might be unrecognized. In the healthcare personnel cohort reported here, infections occurred exclusively among those who had close contact with MERS-CoV patients. PMID- 27767013 TI - Models and applications for measuring the impact of health research: update of a systematic review for the Health Technology Assessment programme. AB - BACKGROUND: This report reviews approaches and tools for measuring the impact of research programmes, building on, and extending, a 2007 review. OBJECTIVES: (1) To identify the range of theoretical models and empirical approaches for measuring the impact of health research programmes; (2) to develop a taxonomy of models and approaches; (3) to summarise the evidence on the application and use of these models; and (4) to evaluate the different options for the Health Technology Assessment (HTA) programme. DATA SOURCES: We searched databases including Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature and The Cochrane Library from January 2005 to August 2014. REVIEW METHODS: This narrative systematic literature review comprised an update, extension and analysis/discussion. We systematically searched eight databases, supplemented by personal knowledge, in August 2014 through to March 2015. RESULTS: The literature on impact assessment has much expanded. The Payback Framework, with adaptations, remains the most widely used approach. It draws on different philosophical traditions, enhancing an underlying logic model with an interpretative case study element and attention to context. Besides the logic model, other ideal type approaches included constructionist, realist, critical and performative. Most models in practice drew pragmatically on elements of several ideal types. Monetisation of impact, an increasingly popular approach, shows a high return from research but relies heavily on assumptions about the extent to which health gains depend on research. Despite usually requiring systematic reviews before funding trials, the HTA programme does not routinely examine the impact of those trials on subsequent systematic reviews. The York/Patient-Centered Outcomes Research Institute and the Grading of Recommendations Assessment, Development and Evaluation toolkits provide ways of assessing such impact, but need to be evaluated. The literature, as reviewed here, provides very few instances of a randomised trial playing a major role in stopping the use of a new technology. The few trials funded by the HTA programme that may have played such a role were outliers. DISCUSSION: The findings of this review support the continued use of the Payback Framework by the HTA programme. Changes in the structure of the NHS, the development of NHS England and changes in the National Institute for Health and Care Excellence's remit pose new challenges for identifying and meeting current and future research needs. Future assessments of the impact of the HTA programme will have to take account of wider changes, especially as the Research Excellence Framework (REF), which assesses the quality of universities' research, seems likely to continue to rely on case studies to measure impact. The HTA programme should consider how the format and selection of case studies might be improved to aid more systematic assessment. The selection of case studies, such as in the REF, but also more generally, tends to be biased towards high-impact rather than low-impact stories. Experience for other industries indicate that much can be learnt from the latter. The adoption of researchfish(r) (researchfish Ltd, Cambridge, UK) by most major UK research funders has implications for future assessments of impact. Although the routine capture of indexed research publications has merit, the degree to which researchfish will succeed in collecting other, non-indexed outputs and activities remains to be established. LIMITATIONS: There were limitations in how far we could address challenges that faced us as we extended the focus beyond that of the 2007 review, and well beyond a narrow focus just on the HTA programme. CONCLUSIONS: Research funders can benefit from continuing to monitor and evaluate the impacts of the studies they fund. They should also review the contribution of case studies and expand work on linking trials to meta-analyses and to guidelines. FUNDING: The National Institute for Health Research HTA programme. PMID- 27767014 TI - Passive and active electroreception during agonistic encounters in the weakly electric fish Gymnotus omarorum. AB - Agonistic behaviour related to territorial defence is likely to be costly in terms of energy loss and risk of injury. Hence information about the fighting ability of a potential opponent could influence the outcome of the contest. We here study electric images of the territorial and aggressive weakly electric fish Gymnotus omarorum in the context of agonistic behaviour. We show that passive and active electric images may drive the approach towards an opponent. The likelihood of first attacks can be predicted in these fish based on electric image information, suggesting that aggressive interactions may in fact be triggered through the passive electrosensory information. PMID- 27767012 TI - Ambulatory Pediatric Surveillance of Hand, Foot and Mouth Disease as Signal of an Outbreak of Coxsackievirus A6 Infections, France, 2014-2015. AB - The clinical impact of enteroviruses associated with hand, foot and mouth disease (HFMD) is unknown outside Asia, and the prevalence of enterovirus A71 (EV-A71) in particular might be underestimated. To investigate the prevalence of enterovirus serotypes and the clinical presentations associated with HFMD in France, we conducted prospective ambulatory clinic-based surveillance of children during April 2014-March 2015. Throat or buccal swabs were collected from children with HFMD and tested for the enterovirus genome. Physical examinations were recorded on a standardized form. An enterovirus infection was detected in 523 (79.3%) of 659 children tested. Two epidemic waves occurred, dominated by coxsackievirus (CV) A6, which was detected in 53.9% of enterovirus-infected children. CV-A6 was more frequently related to atypical HFMD manifestations (eruptions extended to limbs and face). Early awareness and documentation of HFMD outbreaks can be achieved by syndromic surveillance of HFMD by ambulatory pediatricians and rapid enterovirus testing and genotyping. PMID- 27767015 TI - A water-walking robot mimicking the jumping abilities of water striders. AB - The highly efficient and agile water-surface locomotion of water striders has attracted substantial research attention. Compared with imitating the horizontal rowing motion, imitating the jumping capability of water striders is much more challenging because the strong interaction in the jumping process easily causes the robot to sink. This study focuses on designing a miniature robot capable of continuously jumping on the water surface. A spring-based actuating mechanism is proposed to produce a large jumping force. The center of gravity of the robot is carefully designed to allow the robot to jump on the surface continuously and smoothly. The influences of several critical factors, including the area of the supporting legs, the spring stiffness, the jumping angle, etc on jumping ability are analyzed by means of dynamic simulation and experiments. The jumping performance under different jumping angles is tested. The fabricated robot weighs approximately 10.2 g and can continuously jump on water with a maximum leap height and length of 120 and 410 mm, respectively. This study helps researchers understand the jumping mechanism of water striders and provides a reference for developing water-jumping robots that can perform various aquatic tasks in the future. PMID- 27767016 TI - Gate-dependent asymmetric transport characteristics in pentacene barristors with graphene electrodes. AB - We investigated the electrical characteristics and the charge transport mechanism of pentacene vertical hetero-structures with graphene electrodes. The devices are composed of vertical stacks of silicon, silicon dioxide, graphene, pentacene, and gold. These vertical heterojunctions exhibited distinct transport characteristics depending on the applied bias direction, which originates from different electrode contacts (graphene and gold contacts) to the pentacene layer. These asymmetric contacts cause a current rectification and current modulation induced by the gate field-dependent bias direction. We observed a change in the charge injection barrier during variable-temperature current-voltage characterization, and we also observed that two distinct charge transport channels (thermionic emission and Poole-Frenkel effect) worked in the junctions, which was dependent on the bias magnitude. PMID- 27767017 TI - Unique structure and surface-related elastic modulus of alumina nanobelts. AB - Single-crystalline alpha-Al2O3 nanobelts were synthesized by high-temperature chemical vapor deposition in a high-purity H2 atmosphere. The crystalline planes for the upper and side surfaces of the nanobelts were [Formula: see text] and [Formula: see text] and the orientations along height, length and width directions were [Formula: see text] [Formula: see text] and [Formula: see text] respectively. The formation of such a unique structure was dependent on the strong reducing atmosphere used in the growth process, and the deactivation of the [Formula: see text] plane by hydrogen could be the primary cause. The elastic modulus of the nanobelts was measured using a thermal resonance method. The moduli for the nanobelts were about 320 GPa for thicknesses above 40 nm, and slightly increased to 356 GPa as the thickness decreased to 31 nm. The slightly low modulus values compared to the theoretical value of 371 GPa is attributed to oxygen vacancies within the nanobelts, while the increase in modulus with decreased thickness comes from the stiffening effect caused by surface relaxation. PMID- 27767018 TI - Control over fuel cell performance through modulation of pore accessibility: investigation and modeling of carbon nanotubes effects on oxygen reduction at N graphene-based nanocomposite. AB - The lack of performance of graphene-based electrocatalysts for oxygen reduction (ORR) is a major concern for fuel cells which can be mastered using nanocomposites. This work is highlighted by the optimization of nitrogen(N)-doped graphene/carbon nanotubes (CNTs) nanocomposite's ORR performance examined by galvanostatic measurements in realistically approached glucose half-cells. Obtained results mark an essential step for the development of nanocarbon-based cathodes, as we specifically evaluate the electrode performance under real fuel cell conditions. The 2D simulations exclusively represent an important approach for understanding the catalytic efficiency of the nanocomposite with unique structure. The kinetics features extracted from simulations are consistent with the experimentally determined kinetics. The morphology analysis reveals a 3D porous structure. The results demonstrate that the incorporation of CNTs implements mesoscale channels for improved mass transport and leads to efficient 4-electron transfer and enhanced overall catalytic activity in pH-neutral media. The nanocomposite shows increased specific surface area of 142 m2 g-1, positively shifted ORR onset potential of 67 mV and higher open circuit potential of 268 mV versus Ag/AgCl compared to N-graphene (11 m2 g-1, -17, 220 mV). The findings are supported by 2D simulations giving qualitative evidence to the significant role of CNTs for achieving better accessibility of pores, i.e. enabling improved transfer of oxygen and OH-, and providing more reaction sites in the nanocomposite. The nanocomposite demonstrates better ORR performance than constituent components regarding potential application in miniaturized single compartment glucose-based fuel cells. PMID- 27767019 TI - Cobalt phosphide nanowall arrays supported on carbon cloth: an efficient monolithic non-noble-metal hydrogen evolution catalyst. AB - Hydrogen has been considered as an ideal energy carrier for replacing fossil fuels to mitigate global energy crises. Hydrolysis of sodium borohydride (NaBH4) is simple and effective for hydrogen production but needs active and durable catalysts to accelerate the kinetics. In this paper, we demonstrate that cobalt phosphide nanowall arrays supported on carbon cloth (CoP NAs/CC) efficiently catalyze the hydrolytic dehydrogenation of NaBH4 with an activation energy of 42.1 kJ mol-1 in alkaline media. These monolithic CoP NAs/CC show a maximum hydrogen generation rate of [Formula: see text] and are robust with superior durability and reusability. They are also excellent in activity and durability for electrochemical hydrogen evolution in 1.0 M KOH, with the need of an overpotential of only 80 mV to drive 10 mA cm-2. They offer us a promising low cost hydrogen-generating catalyst for applications. PMID- 27767020 TI - Nanocomposite scaffolds with tunable mechanical and degradation capabilities: co delivery of bioactive agents for bone tissue engineering. AB - Novel multifunctional nanocomposite scaffolds made of nanobioactive glass and alginate crosslinked with therapeutic ions such as calcium and copper were developed for delivering therapeutic agents, in a highly controlled and sustainable manner, for bone tissue engineering. Alendronate, a well-known antiresorptive agent, was formulated into microspheres under optimized conditions and effectively loaded within the novel multifunctional scaffolds with a high encapsulation percentage. The size of the cation used for the alginate crosslinking impacted directly on porosity and viscoelastic properties, and thus, on the degradation rate and the release profile of copper, calcium and alendronate. According to this, even though highly porous structures were created with suitable pore sizes for cell ingrowth and vascularization in both cases, copper-crosslinked scaffolds showed higher values of porosity, elastic modulus, degradation rate and the amount of copper and alendronate released, when compared with calcium-crosslinked scaffolds. In addition, in all cases, the scaffolds showed bioactivity and mechanical properties close to the endogenous trabecular bone tissue in terms of viscoelasticity. Furthermore, the scaffolds showed osteogenic and angiogenic properties on bone and endothelial cells, respectively, and the extracts of the biomaterials used promoted the formation of blood vessels in an ex vivo model. These new bioactive nanocomposite scaffolds represent an exciting new class of therapeutic cell delivery carrier with tunable mechanical and degradation properties; potentially useful in the controlled and sustainable delivery of therapeutic agents with active roles in bone formation and angiogenesis, as well as in the support of cell proliferation and osteogenesis for bone tissue engineering. PMID- 27767021 TI - Development and fabrication of a two-layer tissue engineered osteochondral composite using hybrid hydrogel-cancellous bone scaffolds in a spinner flask. AB - Biological treatment using engineered osteochondral composites has received growing attention for the repair of cartilage defects. Osteochondral composites combined with a dynamic culture provide great potential for improving the quality of constructs and cartilage regeneration as dynamic conditions mimic the in vivo condition where cells were constantly subjected to mechanical and chemical stimulation. In the present study, biophasic composites were produced in vitro consisting of cell-hydrogel (CH) and cell-cancellous bone (CB) constructs, followed by culturing in a dynamic system in a spinner flask. The aim of this study was to investigate cell behaviors (i.e. cell growth, differentiation, distribution and matrix deposition) cultured in different constructs under static and dynamic circumstances. As a result, we found that mechanical stimulation promoted osteogenic and chondrogenic differentiation of cells as indicated by the increased expression of ALP and glycosaminoglycan (GAG) in either bone or cartilage substitute materials. Dynamic culture yielded a preferable extracellular matrix production, particularly in hydrogel scaffolds. In addition, the enhanced mass transfer contributed to the interface formation, cells infiltration and distribution in the osteochondral composites. This study demonstrates that osteochondral composites incorporated with a dynamic culture improved the performance of the constructs, providing the basis for a promising tool and a better strategy for the rapid fabrication of osteochondral substitutes and regeneration of injured cartilage. PMID- 27767022 TI - Optimization of mechanical properties, biocorrosion properties and antibacterial properties of as-cast Ti-Cu alloys. AB - Ti-Cu sintered alloys have shown good antibacterial abilities. However, the sintered method (powder metallurgy) is not convenient to produce devices with a complex structure. In this paper, Ti-Cu alloys with 2.0, 3.0 and 4.0 wt.% Cu were prepared in an arc melting furnace and subjected to different heat treatments: solid solution and ageing, to explore the possibility of preparing an antibacterial Ti-Cu alloy by a casting method and to examine the effect of Cu content. Phase identification was conducted on an XRD diffraction meter, and the microstructure was observed by a metallographic microscope, a scanning electron microscope (SEM) with energy disperse spectroscopy (EDS) and transmission electron microscopy (TEM). Microhardness and the compressive property of Ti-Cu alloys were tested, and the corrosion resistance and antibacterial activity were assessed in order to investigate the effect of the Cu content. Results showed that the as-cast Ti-Cu alloys exhibited a very low antibacterial rate against Staphylococcus aureus (S. aureus). Heat treatment improved the antibacterial rate significantly, especially after a solid and ageing treatment (T6). Antibacterial rates as high as 90.33% and 92.57% were observed on Ti-3Cu alloy and Ti-4Cu alloy, respectively. The hardness, the compressive yield strength, the anticorrosion resistance and the antibacterial rate of Ti-Cu alloys increased with an increase of Cu content in all conditions. It was demonstrated that homogeneous distribution and a fine Ti2Cu phase played a very important role in the mechanical property, anticorrosion and antibacterial properties. Furthermore, it should be pointed out that the Cu content should be at least 3 wt.% to obtain good antibacterial properties (>90% antibacterial rate) as well as satisfactory mechanical properties. PMID- 27767025 TI - Erratum: A suppressor locus for MODY3-diabetes. PMID- 27767024 TI - Label-free in vivo analysis of intracellular lipid droplets in the oleaginous microalga Monoraphidium neglectum by coherent Raman scattering microscopy. AB - Oleaginous photosynthetic microalgae hold great promise as non-food feedstocks for the sustainable production of bio-commodities. The algal lipid quality can be analysed by Raman micro-spectroscopy, and the lipid content can be imaged in vivo in a label-free and non-destructive manner by coherent anti-Stokes Raman scattering (CARS) microscopy. In this study, both techniques were applied to the oleaginous microalga Monoraphidium neglectum, a biotechnologically promising microalga resistant to commonly applied lipid staining techniques. The lipid specific CARS signal was successfully separated from the interfering two-photon excited fluorescence of chlorophyll and for the first time, lipid droplet formation during nitrogen starvation could directly be analysed. We found that the neutral lipid content deduced from CARS image analysis strongly correlated with the neutral lipid content measured gravimetrically and furthermore, that the relative degree of unsaturation of fatty acids stored in lipid droplets remained similar. Interestingly, the lipid profile during cellular adaption to nitrogen starvation showed a two-phase characteristic with initially fatty acid recycling and subsequent de novo lipid synthesis. This works demonstrates the potential of quantitative CARS microscopy as a label-free lipid analysis technique for any microalgal species, which is highly relevant for future biotechnological applications and to elucidate the process of microalgal lipid accumulation. PMID- 27767023 TI - Radiographic Study of the Prevalence and Distribution of Hypodontia Associated with Unilateral and Bilateral Clef Lip and Palate in a Hungarian Population. AB - BACKGROUND Cleft defects are one of the most frequent birth-deformities of the orofacial region and they are commonly associated with anomalies of the tooth structure, size, shape, formation, eruption, and tooth number. The aim of our study was to evaluate the prevalence, distribution, and potential association of combined hypodontia in cleft-affected patients with regard to all types of teeth in both jaws in the permanent dentition. MATERIAL AND METHODS This retrospective radiographic analysis included patients with various types of clefts treated orthodontically in the Department of Orofacial Orthopedics and Orthodontics at Heim Pal Children's Hospital, Budapest. There were 150 patients (84 males, 66 females) with non-syndromic unilateral (UCLP; n=120 patients) or bilateral (BCLP; n=30 patients) cleft formation (lip, alveolus and palate) who met the inclusion criteria. Statistical analysis was performed using the chi-square test and Fisher's exact test (significance level p<0.05). RESULTS Hypodontia was significantly more frequent in patients with cleft-sided lateral incisor (104 patients, 69%), with a total of 235 missing teeth, followed by the second premolars of the upper and lower jaw. A significant correlation of congenital missing teeth was observed in left-sided clefts between the upper and lower second premolar in the cleft area CONCLUSIONS Hypodontia inside and outside the cleft area was frequently observed. This should affect the therapy plans, especially if the cleft-sided premolar is also absent. Further comprehensive research including numerous random samples is necessary for better estimating other possible associations. PMID- 27767026 TI - A biomimetic redox flow battery based on flavin mononucleotide. AB - The versatility in design of redox flow batteries makes them apt to efficiently store energy in large-scale applications at low cost. The discovery of inexpensive organic electroactive materials for use in aqueous flow battery electrolytes is highly attractive, but is thus far limited. Here we report on a flow battery using an aqueous electrolyte based on the sodium salt of flavin mononucleotide. Flavins are highly versatile electroactive molecules, which catalyse a multitude of redox reactions in biological systems. We use nicotinamide (vitamin B3) as a hydrotropic agent to enhance the water solubility of flavin mononucleotide. A redox flow battery using flavin mononucleotide negative and ferrocyanide positive electrolytes in strong base shows stable cycling performance, with over 99% capacity retention over the course of 100 cycles. We hypothesize that this is enabled due to the oxidized and reduced forms of FMN-Na being stabilized by resonance structures. PMID- 27767027 TI - Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies. AB - Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes. PMID- 27767029 TI - Re-entrant DNA gels. AB - DNA is acquiring a primary role in material development, self-assembling by design into complex supramolecular aggregates, the building block of a new materials world. Using DNA nanoconstructs to translate sophisticated theoretical intuitions into experimental realizations by closely matching idealized models of colloidal particles is a much less explored avenue. Here we experimentally show that an appropriate selection of competing interactions enciphered in multiple DNA sequences results into the successful design of a one-pot DNA hydrogel that melts both on heating and on cooling. The relaxation time, measured by light scattering, slows down dramatically in a limited window of temperatures. The phase diagram displays a peculiar re-entrant shape, the hallmark of the competition between different bonding patterns. Our study shows that it is possible to rationally design biocompatible bulk materials with unconventional phase diagrams and tuneable properties by encoding into DNA sequences both the particle shape and the physics of the collective response. PMID- 27767030 TI - Tuning thermal conductivity in molybdenum disulfide by electrochemical intercalation. AB - Thermal conductivity of two-dimensional (2D) materials is of interest for energy storage, nanoelectronics and optoelectronics. Here, we report that the thermal conductivity of molybdenum disulfide can be modified by electrochemical intercalation. We observe distinct behaviour for thin films with vertically aligned basal planes and natural bulk crystals with basal planes aligned parallel to the surface. The thermal conductivity is measured as a function of the degree of lithiation, using time-domain thermoreflectance. The change of thermal conductivity correlates with the lithiation-induced structural and compositional disorder. We further show that the ratio of the in-plane to through-plane thermal conductivity of bulk crystal is enhanced by the disorder. These results suggest that stacking disorder and mixture of phases is an effective mechanism to modify the anisotropic thermal conductivity of 2D materials. PMID- 27767028 TI - Genomic heterogeneity of multiple synchronous lung cancer. AB - Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events. PMID- 27767033 TI - Parkinson disease: LAG3 facilitates cell-to-cell spread of alpha-synuclein pathology. PMID- 27767031 TI - Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. AB - A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours. PMID- 27767034 TI - Neurodevelopmental disorders: Maternal antibodies induce autism-like phenotype in mice. PMID- 27767032 TI - Mixed functional microarchitectures for orientation selectivity in the mouse primary visual cortex. AB - A minicolumn is the smallest anatomical module in the cortical architecture, but it is still in debate whether it serves as functional units for cortical processing. In the rodent primary visual cortex (V1), neurons with different preferred orientations are mixed horizontally in a salt and pepper manner, but vertical functional organization was not examined. In this study, we found that neurons with similar orientation preference are weakly but significantly clustered vertically in a short length and horizontally in the scale of a minicolumn. Interestingly, the vertical clustering is found only in a part of minicolumns, and others are composed of neurons with a variety of orientation preferences. Thus, the mouse V1 is a mixture of vertical clusters of neurons with various degrees of orientation similarity, which may be the compromise between the brain size and keeping the vertical clusters of similarly tuned neurons at least in a subset of clusters. PMID- 27767035 TI - Therapy: Targeted delivery of thyroid hormone improves metabolic outcomes. PMID- 27767037 TI - Brain imaging: Cross-sex hormones alter grey matter structures. PMID- 27767038 TI - Isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from cats. AB - Carbapenem-resistant Enterobacteriaceae (CRE) are a pressing public health issue due to limited therapeutic options to treat such infections. CREs have been predominantly isolated from humans and environmental samples and they are rarely reported among companion animals. In this study we report on the isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from a companion animal. Carbapenemase-producing S. enterica Typhimurium carrying blaIMP-4 was identified from a systemically unwell (index) cat and three additional cats at an animal shelter. All isolates were identical and belonged to ST19. Genome sequencing revealed the acquisition of a multidrug resistant IncHI2 plasmid (pIMP4-SEM1) that encoded resistance to nine antimicrobial classes including carbapenems and carried the blaIMP-4-qacG-aacA4 catB3 cassette array. The plasmid also encoded resistance to arsenic (MIC-150 mM). Comparative analysis revealed that the plasmid pIMP4-SEM1 showed greatest similarity to two blaIMP-8 carrying IncHI2 plasmids from Enterobacter spp. isolated from humans in China. This is the first report of CRE carrying a blaIMP 4 gene causing a clinical infection in a companion animal, with presumed nosocomial spread. This study illustrates the broader community risk entailed in escalating CRE transmission within a zoonotic species such as Salmonella, and in a cycle that encompasses humans, animals and the environment. PMID- 27767036 TI - Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. AB - Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect. PMID- 27767039 TI - Tumor-targeted delivery of a C-terminally truncated FADD (N-FADD) significantly suppresses the B16F10 melanoma via enhancing apoptosis. AB - Fas-associated protein with death domain (FADD), a pivotal adaptor protein transmitting apoptotic signals, is indispensable for the induction of extrinsic apoptosis. However, overexpression of FADD can form large, filamentous aggregates, termed death effector filaments (DEFs) by self-association and initiate apoptosis independent of receptor cross-linking. A mutant of FADD, which is truncated of the C-terminal tail (m-FADD, 182-205 aa) named N-FADD (m-FADD, 1 181 aa), can dramatically up-regulate the strength of FADD self-association and increase apoptosis. In this study, it was found that over-expression of FADD or N FADD caused apoptosis of B16F10 cells in vitro, even more, N-FADD showed a more potent apoptotic effect than FADD. Meanwhile, Attenuated Salmonella Typhimurium strain VNP20009 was engineered to express FADD or N-FADD under the control of a hypoxia-induced NirB promoter and each named VNP-pN-FADD and VNP-pN-N-FADD. The results showed both VNP-pN-FADD and VNP-pN-N-FADD delayed tumor growth in B16F10 mice model, while VNP-pN-N-FADD suppressed melanoma growth more significantly than VNP-pN-FADD. Additionally, VNP-pN-FADD and VNP-pN-N-FADD induced apoptosis of tumor cells by activating caspase-dependent apoptotic pathway. Our results show that N-FADD is a more potent apoptotic inducer and VNP20009-mediated targeted expression of N-FADD provides a possible cancer gene therapeutic approach for the treatment of melanoma. PMID- 27767040 TI - Reproductive resource partitioning in two sympatric Goniothalamus species (Annonaceae) from Borneo: floral biology, pollinator trapping and plant breeding system. AB - The floral phenology, pollination ecology and breeding systems of two sympatric early-divergent angiosperms, Goniothalamus tapisoides and G. suaveolens (Annonaceae) are compared. The flowers are protogynous and morphologically similar, with anthesis over 23-25 h. Both species are predominantly xenogamous and pollinated by small beetles: G. tapisoides mainly by Curculionidae and G. suaveolens mainly by Nitidulidae. Coevolution and reproductive resource partitioning, reducing interspecific pollen transfer, is achieved by temporal isolation, due to contrasting floral phenologies; and ethological isolation, due to contrasting floral scents that contain attractants specific to the two beetle families. Analysis of floral scents revealed three volatiles (3-methylbutyl acetate, ethyl hexanoate and 2-phenylethanol) that are known to be nitidulid attractants in the floral scent of G. suaveolens, but absent from that of G. tapisoides. An effective pollinator trapping mechanism is demonstrated for both species, representing the first such report for the family. Trapping is achieved by the compression of the outer petals against the apertures between the inner petals. This trapping mechanism is likely to be a key evolutionary innovation for Goniothalamus, increasing pollination efficiency by increasing pollen loading on beetles during the staminate phase, promoting effective interfloral pollinator movements, and increasing seed-set by enabling rapid turn-over of flowers. PMID- 27767041 TI - Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse. AB - MicroRNA-143 (miR-143) plays a critical role in various cellular processes; however, the role of miR-143 in the maintenance of blood-brain barrier (BBB) integrity remains poorly defined. Silencing miR-143 in a genetic animal model or via an anti-miR-143 lentivirus prevented the BBB damage induced by methamphetamine. miR-143, which targets p53 unregulated modulator of apoptosis (PUMA), increased the permeability of human brain endothelial cells and concomitantly decreased the expression of tight junction proteins (TJPs). Silencing miR-143 increased the expression of TJPs and protected the BBB integrity against the effects of methamphetamine treatment. PUMA overexpression increased the TJP expression through a mechanism that involved the NF-kappaB and p53 transcription factor pathways. Mechanistically, methamphetamine mediated up regulation of miR-143 via sigma-1 receptor with sequential activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3' kinase (PI3K)/Akt and STAT3 pathways. These results indicated that silencing miR-143 could provide a novel therapeutic strategy for BBB damage-related vascular dysfunction. PMID- 27767043 TI - Miocene orographic uplift forces rapid hydrological change in the southern central Andes. AB - Rainfall in the central Andes associated with the South American Monsoon and the South American Low-Level Jet results from orographic effects on atmospheric circulation exerted by the Andean Plateau and the Eastern Cordillera. However, despite its importance for South American climate, no reliable records exist that allow decoding the evolution of thresholds and interactions between Andean topography and atmospheric circulation, especially regarding the onset of humid conditions in the inherently dry southern central Andes. Here, we employ multi proxy isotope data of lipid biomarkers, pedogenic carbonates and volcanic glass from the Eastern Cordillera of NW Argentina and present the first long-term evapotranspiration record. We find that regional eco-hydrology and vegetation changes are associated with initiation of moisture transport via the South American Low-Level Jet at 7.6 Ma, and subsequent lateral growth of the orogen at 6.5 Ma. Our results highlight that topographically induced changes in atmospheric circulation patterns, not global climate change, were responsible for late Miocene environmental change in this part of the southern hemisphere. This suggests that mountain building over time fundamentally controlled habitat evolution along the central Andes. PMID- 27767042 TI - Oxytocin modulates GABAAR subunits to confer neuroprotection in stroke in vitro. AB - Oxytocin protects against ischemia-induced inflammation and oxidative stress, and is associated with GABA (gamma-aminobutyric acid, an inhibitory neurotransmitter) signaling transduction in neurons. However, the molecular mechanism by which oxytocin affords neuroprotection, especially the interaction between oxytocin receptor and GABAA receptor (GABAAR), remains to be elucidated. Primary rat neural cells were exposed to oxytocin before induction of experimental acute stroke model via oxygen-glucose deprivation-reperfusion (OGD/R) injury. Pretreatment with oxytocin increased cell viability, decreased the cell damage against oxidative stress, and prevented the release of high mobility group box1 during OGD/R. However, introduction of oxytocin during OGD/R did not induce neuroprotection. Although oxytocin did not affect the glutathione-related cellular metabolism before OGD, oxytocin modulated the expression levels of GABAAR subunits, which function to remove excessive neuronal excitability via chloride ion influx. Oxytocin-pretreated cells significantly increased the chloride ion influx in response to GABA and THIP (delta-GABAAR specific agonist). This study provides evidence that oxytocin regulated GABAAR subunits in affording neuroprotection against OGD/R injury. PMID- 27767044 TI - Direct Analysis and Quantification of Metaldehyde in Water using Reactive Paper Spray Mass Spectrometry. AB - Metaldehyde is extensively used worldwide as a contact and systemic molluscicide for controlling slugs and snails in a wide range of agricultural and horticultural crops. Contamination of surface waters due to run-off, coupled with its moderate solubility in water, has led to increased concentration of the pesticide in the environment. In this study, for the first time, rapid analysis (<~1 minute) of metaldehyde residues in water is demonstrated using paper spray mass spectrometry (PS-MS). The observed precursor molecular ions of metaldehyde were confirmed from tandem mass spectrometry (MS/MS) experiments by studying the fragmentation patterns produced via collision-induced dissociation. The signal intensity ratios of the most abundant MS/MS transitions for metaldehyde (177 -> 149 for protonated ion) and atrazine (221 -> 179) were found to be linear in the range 0.01 to 5 ng/mL. Metaldehyde residues were detectable in environmental water samples at low concentration (LOD < 0.1 ng/mL using reactive PS-MS), with a relative standard deviation <10% and an R2 value >0.99, without any pre concentration/separation steps. This result is of particular importance for environmental monitoring and water quality analysis providing a potential means of rapid screening to ensure safe drinking water. PMID- 27767046 TI - Molecular dynamics simulation of nanoindentation on Cu/Ni nanotwinned multilayer films using a spherical indenter. AB - We performed molecular dynamics simulation of nanoindentation on Cu/Ni nanotwinned multilayer films using a spherical indenter, aimed to investigate the effects of hetero-twin interface and twin thickness on hardness. We found that both twinning partial slip (TPS) and partial slip parallel with twin boundary (PSPTB) can reduce hardness and therefore should not be ignored when evaluating mechanical properties at nanoscale. There is a critical range of twin thickness lambda (~25 A < lambda < ~31 A), in which hardness of the multilayer films is maximized. At a smaller lambda, TPSs appear due to the reaction between partial dislocations and twin boundary accounts for the softening-dominated mechanism. We also found that the combination of the lowered strengthening due to confined layer slips and the softening due to TPSs and PSPTBs results in lower hardness at a larger lambda. PMID- 27767045 TI - Association between allergic conditions and risk of prostate cancer: A Prisma Compliant Systematic Review and Meta-Analysis. AB - Association between allergic conditions and prostate cancer risk has been investigated for many years. However, the results from available evidence for the association are inconsistent. We conducted a meta-analysis to evaluate the relationship between allergic conditions (asthma, atopy, hay fever and "any allergy") and risk of prostate cancer. The PubMed and Embase databases were searched to screen observational studies meeting our meta-analysis criteria. Study selection and data extraction from included studies were independently performed by two authors. Twenty studies were considered eligible involving 5 case-control studies and 15 cohort studies. The summary relative risk (RR) for developing prostate cancer risk was 1.04 (95%CI: 0.92-1.17) for asthma, and 1.25 (95%CI: 0.74-2.10) for atopy, 1.04 (95%CI: 0.99-1.09) for hay fever, 0.96 (95%CI: 0.86-1.06) for any allergy. In the Subgroup and sensitivity analysis, similar results were produced. Little evidence of publication bias was observed. The present meta-analysis of observational studies indicates that no indication of an association between allergic conditions and risk of prostate cancer was found, and the meta-analysis does not support neither the original hypothesis of an overall cancer protective effect of allergic conditions, nor that of an opposite effect in the development of prostate cancer. PMID- 27767047 TI - Multi-Terminal Spin Valve on Channels with Spin-Momentum Locking. AB - It is experimentally established that charge current flowing in a channel with spin-momentum locking such as topological insulator surface states or Rashba interfaces induces a spin voltage, which can be electrically measured with a ferromagnetic contact along the current path. Using this fact in conjunction with Onsager reciprocity arguments, we make the surprising prediction that the anti parallel resistance of a spin valve can be either larger or smaller than the parallel resistance depending on the direction of spin flow relative to the direction of spin-momentum locking. However, we argue that this remarkable signature of spin-momentum locking can only be observed in multi-terminal measurements. Two-terminal measurements in the linear response regime, will show a single anti-parallel resistance larger than the parallel resistance as commonly observed in channels without spin-orbit coupling. We support this result with detailed numerical calculations based on a semiclassical model that provides insight into the underlying physics. PMID- 27767048 TI - The pressure sensitivity of wrinkled B-doped nanocrystalline diamond membranes. AB - Nanocrystalline diamond (NCD) membranes are promising candidates for use as sensitive pressure sensors. NCD membranes are able to withstand harsh conditions and are easily fabricated on glass. In this study the sensitivity of heavily boron doped NCD (B:NCD) pressure sensors is evaluated with respect to different types of supporting glass substrates, doping levels and membrane sizes. Higher pressure sensing sensitivities are obtained for membranes on Corning Eagle 2000 glass, which have a better match in thermal expansion coefficient with diamond compared to those on Schott AF45 glass. In addition, it is shown that larger and more heavily doped membranes are more sensitive. After fabrication of the membranes, the stress in the B:NCD films is released by the emergence of wrinkles. A better match between the thermal expansion coefficient of the NCD layer and the underlying substrate results in less stress and a smaller amount of wrinkles as confirmed by Raman spectroscopy and 3D surface imaging. PMID- 27767049 TI - Structures, Phase Transitions and Tricritical Behavior of the Hybrid Perovskite Methyl Ammonium Lead Iodide. AB - We have examined the crystal structures and structural phase transitions of the deuterated, partially deuterated and hydrogenous organic-inorganic hybrid perovskite methyl ammonium lead iodide (MAPbI3) using time-of-flight neutron and synchrotron X-ray powder diffraction. Near 330 K the high temperature cubic phases transformed to a body-centered tetragonal phase. The variation of the order parameter Q for this transition scaled with temperature T as Q ~ (Tc T)beta, where Tc is the critical temperature and the exponent beta was close to 1/4, as predicted for a tricritical phase transition. However, we also observed coexistence of the cubic and tetragonal phases over a range of temperature in all cases, demonstrating that the phase transition was in fact first-order, although still very close to tricritical. Upon cooling further, all the tetragonal phases transformed into a low temperature orthorhombic phase around 160 K, again via a first-order phase transition. Based upon these results, we discuss the impact of the structural phase transitions upon photovoltaic performance of MAPbI3 based solar cells. PMID- 27767050 TI - Nondestructive Detection and Quantification of Blueberry Bruising using Near infrared (NIR) Hyperspectral Reflectance Imaging. AB - Currently, blueberry bruising is evaluated by either human visual/tactile inspection or firmness measurement instruments. These methods are destructive, time-consuming, and subjective. The goal of this paper was to develop a non destructive approach for blueberry bruising detection and quantification. Experiments were conducted on 300 samples of southern highbush blueberry (Camellia, Rebel, and Star) and on 1500 samples of northern highbush blueberry (Bluecrop, Jersey, and Liberty) for hyperspectral imaging analysis, firmness measurement, and human evaluation. An algorithm was developed to automatically calculate a bruise ratio index (ratio of bruised to whole fruit area) for bruise quantification. The spectra of bruised and healthy tissues were statistically separated and the separation was independent of cultivars. Support vector machine (SVM) classification of the spectra from the regions of interest (ROIs) achieved over 94%, 92%, and 96% accuracy on the training set, independent testing set, and combined set, respectively. The statistical results showed that the bruise ratio index was equivalent to the measured firmness but better than the predicted firmness in regard to effectiveness of bruise quantification, and the bruise ratio index had a strong correlation with human assessment (R2 = 0.78 - 0.83). Therefore, the proposed approach and the bruise ratio index are effective to non destructively detect and quantify blueberry bruising. PMID- 27767051 TI - Isolation of a euryhaline microalgal strain, Tetraselmis sp. CTP4, as a robust feedstock for biodiesel production. AB - Bioprospecting for novel microalgal strains is key to improving the feasibility of microalgae-derived biodiesel production. Tetraselmis sp. CTP4 (Chlorophyta, Chlorodendrophyceae) was isolated using fluorescence activated cell sorting (FACS) in order to screen novel lipid-rich microalgae. CTP4 is a robust, euryhaline strain able to grow in seawater growth medium as well as in non sterile urban wastewater. Because of its large cell size (9-22 MUm), CTP4 settles down after a six-hour sedimentation step. This leads to a medium removal efficiency of 80%, allowing a significant decrease of biomass dewatering costs. Using a two-stage system, a 3-fold increase in lipid content (up to 33% of DW) and a 2-fold enhancement in lipid productivity (up to 52.1 mg L-1 d-1) were observed upon exposure to nutrient depletion for 7 days. The biodiesel synthesized from the lipids of CTP4 contained high levels of oleic acid (25.67% of total fatty acids content) and minor amounts of polyunsaturated fatty acids with >=4 double bonds (<1%). As a result, this biofuel complies with most of the European (EN14214) and American (ASTM D6751) specifications, which commonly used microalgal feedstocks are usually unable to meet. In conclusion, Tetraselmis sp. CTP4 displays promising features as feedstock with lower downstream processing costs for biomass dewatering and biodiesel refining. PMID- 27767054 TI - Real-space imaging of a topologically protected edge state with ultracold atoms in an amplitude-chirped optical lattice. AB - To describe a mobile defect in polyacetylene chains, Su, Schrieffer and Heeger formulated a model assuming two degenerate energy configurations that are characterized by two different topological phases. An immediate consequence was the emergence of a soliton-type edge state located at the boundary between two regions of different configurations. Besides giving first insights in the electrical properties of polyacetylene materials, interest in this effect also stems from its close connection to states with fractional charge from relativistic field theory. Here, using a one-dimensional optical lattice for cold rubidium atoms with a spatially chirped amplitude, we experimentally realize an interface between two spatial regions of different topological order in an atomic physics system. We directly observe atoms confined in the edge state at the intersection by optical real-space imaging and characterize the state as well as the size of the associated energy gap. Our findings hold prospects for the spectroscopy of surface states in topological matter and for the quantum simulation of interacting Dirac systems. PMID- 27767052 TI - Entanglement and manipulation of the magnetic and spin-orbit order in multiferroic Rashba semiconductors. AB - Entanglement of the spin-orbit and magnetic order in multiferroic materials bears a strong potential for engineering novel electronic and spintronic devices. Here, we explore the electron and spin structure of ferroelectric alpha-GeTe thin films doped with ferromagnetic Mn impurities to achieve its multiferroic functionality. We use bulk-sensitive soft-X-ray angle-resolved photoemission spectroscopy (SX ARPES) to follow hybridization of the GeTe valence band with the Mn dopants. We observe a gradual opening of the Zeeman gap in the bulk Rashba bands around the Dirac point with increase of the Mn concentration, indicative of the ferromagnetic order, at persistent Rashba splitting. Furthermore, subtle details regarding the spin-orbit and magnetic order entanglement are deduced from spin resolved ARPES measurements. We identify antiparallel orientation of the ferroelectric and ferromagnetic polarization, and altering of the Rashba-type spin helicity by magnetic switching. Our experimental results are supported by first-principles calculations of the electron and spin structure. PMID- 27767053 TI - Globoside accelerates the differentiation of dental epithelial cells into ameloblasts. AB - Tooth crown morphogenesis is tightly regulated by the proliferation and differentiation of dental epithelial cells. Globoside (Gb4), a globo-series glycosphingolipid, is highly expressed during embryogenesis as well as organogenesis, including tooth development. We previously reported that Gb4 is dominantly expressed in the neutral lipid fraction of dental epithelial cells. However, because its functional role in tooth development remains unknown, we investigated the involvement of Gb4 in dental epithelial cell differentiation. The expression of Gb4 was detected in ameloblasts of postnatal mouse molars and incisors. A cell culture analysis using HAT-7 cells, a rat-derived dental epithelial cell line, revealed that Gb4 did not promote dental epithelial cell proliferation. Interestingly, exogenous administration of Gb4 enhanced the gene expression of enamel extracellular matrix proteins such as ameloblastin, amelogenin, and enamelin in dental epithelial cells as well as in developing tooth germs. Gb4 also induced the expression of TrkB, one of the key receptors required for ameloblast induction in dental epithelial cells. In contrast, Gb4 downregulated the expression of p75, a receptor for neurotrophins (including neurotrophin-4) and a marker of undifferentiated dental epithelial cells. In addition, we found that exogenous administration of Gb4 to dental epithelial cells stimulated the extracellular signal-regulated kinase and p38 mitogen activated protein kinase signalling pathways. Furthermore, Gb4 induced the expression of epiprofin and Runx2, the positive regulators for ameloblastin gene transcription. Thus, our results suggest that Gb4 contributes to promoting the differentiation of dental epithelial cells into ameloblasts. PMID- 27767055 TI - Production and verification of a 2nd generation clonal group of Japanese flounder, Paralichthys olivaceus. AB - Clonal fishes are useful tools in biology and aquaculture studies due to their isogenicity. In Japanese flounder (Paralichthys olivaceus), a group of homozygous clones was created by inducing meiogynogenesis in eggs from a mitogynogenetic homozygous diploid. As the clones reached sexual maturity, meiogynogenesis was again induced in order to produce a 2nd generation clonal group of Japanese flounder. After 3 months, there were 611 healthy, surviving individuals. Twenty four microsatellite markers, that covered all the linkage groups of Japanese flounder, were used to identify the homozygosity of the 2nd generation clones; no heterozygous locus was detected. This indicates that the production of a 2nd generation clonal group of Japanese flounder was successful. Restriction-site DNA associated sequencing at the genomic level also confirmed the homozygosity and clonality of the 2nd generation clonal group. Furthermore, these 2nd generation clones had a small coefficient of variation for body shape indices at 210 days of age and showed a high degree of similarity in body characteristics among individuals. The successful production of 2nd generation clones has laid the foundation for the large-scale production of clonal Japanese flounder. PMID- 27767056 TI - Alteration of blood clot structures by interleukin-1 beta in association with bone defects healing. AB - The quality of hematomas are crucial for successful early bone defect healing, as the structure of fibrin clots can significantly influence the infiltration of cells, necessary for bone regeneration, from adjacent tissues into the fibrin network. This study investigated if there were structural differences between hematomas from normal and delayed healing bone defects and whether such differences were linked to changes in the expression of IL-1beta. Using a bone defect model in rats, we found that the hematomas in the delayed healing model had thinner fibers and denser clot structures. Moreover, IL-1beta protein levels were significantly higher in the delayed healing hematomas. The effects of IL 1beta on the structural properties of human whole blood clots were evaluated by thrombelastograph (TEG), scanning electronic microscopy (SEM), compressive study, and thrombolytic assays. S-nitrosoglutathione (GSNO) was applied to modulate de novo hematoma structure and the impact on bone healing was evaluated in the delayed healing model. We found that GSNO produced more porous hematomas with thicker fibers and resulted in significantly enhanced bone healing. This study demonstrated that IL-1beta and GSNO had opposing effects on clot architecture, the structure of which plays a pivotal role in early bone healing. PMID- 27767057 TI - A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis. AB - Gastrointestinal symptoms are common in children with autism spectrum disorder (ASD). A significant proportion of children with ASD and gastrointestinal symptoms have histologic evidence of ileocolitis (inflammation of the terminal ileum and/or colon). We previously reported the molecular characterization of gastrointestinal biopsy tissue from ASD children with ileocolitis (ASDIC+) compared to anatomically similar inflamed tissue from typically developing children with inflammatory bowel disease (IBD; i.e. Crohn's disease or ulcerative colitis) and typically developing children with gastrointestinal symptoms but no evidence of gastrointestinal mucosal inflammation (TDIC-). ASDIC+ children had a gene expression profile that, while primarily overlapping with known IBD, had distinctive differences. The present study confirms these findings and replicates this molecular characterization in a second cohort of cases (ASDIC+) and controls (TDIC-). In these two separate case/control mucosal-based cohorts, we have demonstrated overlap of 59 differentially expressed transcripts (DETs) unique to inflamed ileocolonic tissue from symptomatic ASDIC+ children. We now report that 9 of these 59 transcripts are also differentially expressed in the peripheral blood of the second cohort of ASDIC+ children. This set of transcripts represents a putative blood-based biomarker for ASD-associated ileocolonic inflammation. PMID- 27767059 TI - UPLC-PDA-QTOFMS-guided isolation of prenylated xanthones and benzoylphloroglucinols from the leaves of Garcinia oblongifolia and their migration-inhibitory activity. AB - A UPLC-PDA-QTOFMS-guided isolation strategy was employed to screen and track potentially new compounds from Garcinia oblongifolia. As a result, two new prenylated xanthones, oblongixanthones D and E (1-2), six new prenylated benzoylphloroglucinol derivatives, oblongifolins V-Z (3-7) and oblongifolin AA (8), as well as a known compound oblongifolin L (9), were isolated from the EtOAc soluble fraction of an acetone extract of the leaves of Garcinia oblongifolia guided by UPLC-PDA-QTOFMS analysis. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analysis and mass spectrometry. Experimental and calculated ECD spectra were used to determine the absolute configurations. The results of wound healing and transwell migration assay showed that oblongixanthones D (1), E (2), and oblongifolin L (9) have the ability to inhibit cancer cell migration in lower cytotoxic concentrations. Western blotting results showed that these compounds exhibited an anti-metastasis effect mainly through downregulating RAF protein levels. In addition, 2 and 9 could inhibit phospho-MEK and phospho-ERK at downstream. Moreover, 1, 2, and 9 could inhibit snail protein level, suggesting that they could regulate the EMT pathway. PMID- 27767058 TI - FAIM-L regulation of XIAP degradation modulates Synaptic Long-Term Depression and Axon Degeneration. AB - Caspases have recently emerged as key regulators of axonal pruning and degeneration and of long-term depression (LTD), a long-lasting form of synaptic plasticity. However, the mechanism underlying these functions remains unclear. In this context, XIAP has been shown to modulate these processes. The neuron specific form of FAIM protein (FAIM-L) is a death receptor antagonist that stabilizes XIAP protein levels, thus preventing death receptor-induced neuronal apoptosis. Here we show that FAIM-L modulates synaptic transmission, prevents chemical-LTD induction in hippocampal neurons, and thwarts axon degeneration after nerve growth factor (NGF) withdrawal. Additionally, we demonstrate that the participation of FAIM-L in these two processes is dependent on its capacity to stabilize XIAP protein levels. Our data reveal FAIM-L as a regulator of axonal degeneration and synaptic plasticity. PMID- 27767060 TI - Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model. AB - The effects of antithrombotic drugs on random and free flap survival have been investigated in the past, but the experimental and clinical results are not in agreement. A perforator-based critical ischaemia model was used to evaluate the effects of different perioperatively administered pharmaceutical agents on tissue ischaemia and to assess the potential additional haemorheological or vasodilative effects of antithrombotics on flap microcirculation. Combined laser Doppler flowmetry and remission spectroscopy revealed an increase in certain microcirculation parameters in most groups in comparison with saline controls, and these changes correlated with flap survival. Clopidogrel and hirudin significantly improved the amount of viable flap tissue in comparison with controls, while unfractioned heparin had a negative effect on flap survival. Low molecular weight heparin, aspirin, pentoxifylline, and hydroxyethyl starch had no impact on the amount of viable flap tissue. A higher complication rate was observed in all experimental groups, but only clopidogrel had a negative impact on the flap viability. Our results add to the body of evidence supporting the conclusion that perioperative antithrombotic treatment improves flap survival. Clopidogrel and hirudin are effective pharmacological agents that significantly increased the viability of perforator-based skin flaps in rats, but at a higher risk of postoperative bleeding. PMID- 27767062 TI - The first oviraptorosaur (Dinosauria: Theropoda) bonebed: evidence of gregarious behaviour in a maniraptoran theropod. AB - A monodominant bonebed of Avimimus from the Nemegt Formation of Mongolia is the first oviraptorosaur bonebed described and the only recorded maniraptoran bonebed from the Late Cretaceous. Cranial elements recovered from the bonebed provide insights on the anatomy of the facial region, which was formerly unknown in Avimimus. Both adult and subadult material was recovered from the bonebed, but small juveniles are underrepresented. The taphonomic and sedimentological evidence suggests that the Avimimus bonebed represents a perimortem gregarious assemblage. The near absence of juveniles in the bonebed may be evidence of a transient age-segregated herd or 'flock', but the behaviour responsible for this assemblage is unclear. Regardless, the Avimimus bonebed is the first evidence of gregarious behaviour in oviraptorosaurs, and highlights a potential trend of increasing gregariousness in dinosaurs towards the end of the Mesozoic. PMID- 27767061 TI - A dual-targeting approach to inhibit Brucella abortus replication in human cells. AB - Brucella abortus is an intracellular bacterial pathogen and an etiological agent of the zoonotic disease known as brucellosis. Brucellosis can be challenging to treat with conventional antibiotic therapies and, in some cases, may develop into a debilitating and life-threatening chronic illness. We used multiple independent assays of in vitro metabolism and intracellular replication to screen a library of 480 known bioactive compounds for novel B. abortus anti-infectives. Eighteen non-cytotoxic compounds specifically inhibited B. abortus replication in the intracellular niche, which suggests these molecules function by targeting host cell processes. Twenty-six compounds inhibited B. abortus metabolism in axenic culture, thirteen of which are non-cytotoxic to human host cells and attenuate B. abortus replication in the intracellular niche. The most potent non-cytotoxic inhibitors of intracellular replication reduce B. abortus metabolism in axenic culture and perturb features of mammalian cellular biology including mitochondrial function and receptor tyrosine kinase signaling. The efficacy of these molecules as inhibitors of B. abortus replication in the intracellular niche suggests "dual-target" compounds that coordinately perturb host and pathogen are promising candidates for development of improved therapeutics for intracellular infections. PMID- 27767063 TI - Continuous Force Decoding from Local Field Potentials of the Primary Motor Cortex in Freely Moving Rats. AB - Local field potential (LFP) signals recorded by intracortical microelectrodes implanted in primary motor cortex can be used as a high informative input for decoding of motor functions. Recent studies show that different kinematic parameters such as position and velocity can be inferred from multiple LFP signals as precisely as spiking activities, however, continuous decoding of the force magnitude from the LFP signals in freely moving animals has remained an open problem. Here, we trained three rats to press a force sensor for getting a drop of water as a reward. A 16-channel micro-wire array was implanted in the primary motor cortex of each trained rat, and obtained LFP signals were used for decoding of the continuous values recorded by the force sensor. Average coefficient of correlation and the coefficient of determination between decoded and actual force signals were r = 0.66 and R2 = 0.42, respectively. We found that LFP signal on gamma frequency bands (30-120 Hz) had the most contribution in the trained decoding model. This study suggests the feasibility of using low number of LFP channels for the continuous force decoding in freely moving animals resembling BMI systems in real life applications. PMID- 27767065 TI - Early warning signals for critical transitions in a thermoacoustic system. AB - Dynamical systems can undergo critical transitions where the system suddenly shifts from one stable state to another at a critical threshold called the tipping point. The decrease in recovery rate to equilibrium (critical slowing down) as the system approaches the tipping point can be used to identify the proximity to a critical transition. Several measures have been adopted to provide early indications of critical transitions that happen in a variety of complex systems. In this study, we use early warning indicators to predict subcritical Hopf bifurcation occurring in a thermoacoustic system by analyzing the observables from experiments and from a theoretical model. We find that the early warning measures perform as robust indicators in the presence and absence of external noise. Thus, we illustrate the applicability of these indicators in an engineering system depicting critical transitions. PMID- 27767064 TI - Angiopoietin-2 attenuates angiotensin II-induced aortic aneurysm and atherosclerosis in apolipoprotein E-deficient mice. AB - Angiogenesis and inflammation are implicated in aortic aneurysm and atherosclerosis and regulated by angiopoietin-2 (Angpt2). The effect of Angpt2 administration on experimental aortic aneurysm and atherosclerosis was examined. Six-month-old male apolipoprotein E deficient (ApoE-/-) mice were infused with angiotensin II (AngII) and administered subcutaneous human Fc-protein (control) or recombinant Angpt2 (rAngpt2) over 14 days. Administration of rAngpt2 significantly inhibited AngII-induced aortic dilatation and rupture of the suprarenal aorta (SRA), and development of atherosclerosis within the aortic arch. These effects were blood pressure and plasma lipoprotein independent and associated with Tie2 activation and down-regulation of monocyte chemotactic protein-1 (MCP-1) within the SRA. Plasma concentrations of MCP-1 and interleukin 6 were significantly lower in mice receiving rAngpt2. Immunostaining for the monocyte/macrophage marker MOMA-2 and the angiogenesis marker CD31 within the SRA were less in mice receiving rAngpt2 than controls. The percentage of inflammatory (Ly6Chi) monocytes within the bone marrow was increased while that in peripheral blood was decreased by rAngpt2 administration. In conclusion, administration of rAngpt2 attenuated angiotensin II-induced aortic aneurysm and atherosclerosis in ApoE-/- mice associated with reduced aortic inflammation and angiogenesis. Up regulation of Angpt2 may have potential therapeutic value in patients with aortic aneurysm and atherosclerosis. PMID- 27767066 TI - In-situ growth of superconducting SmO1-xFxFeAs thin films by pulsed laser deposition. AB - Oxypnictide thin film growth by pulsed laser deposition (PLD) is one of many insufficiently resolved issues in the research of iron-based superconductors. Here we report on the successful realization of superconducting SmO1-xFxFeAs oxypnictide thin film growth by in-situ PLD on CaF2 (fluorite) substrates. CaF2 acts as fluorine supplier by diffusion and thus enables superconducting oxypnictide thin film growth by PLD. Films are grown heteroepitaxially and characteristically have a broad resistive normal-to-superconducting transition. Best films have onset transition temperatures around 40 K. The proposed in-situ PLD film growth offers an alternative and cheap route for the fabrication of iron oxypnictides. PLD becomes now an additional option for iron oxypnictide synthesis. PMID- 27767068 TI - The significance of linoleic acid in food sources for detritivorous benthic invertebrates. AB - Chemical composition of organic matter (OM) is a key driver for detritus consumption by macroinvertebrates and polyunsaturated fatty acid (PUFA) content is considered a candidate indicator of food palatability. Since traditionally used complex natural OM covaries in many quality attributes, it remains uncertain whether benthic invertebrates developed an actual preference for PUFA-rich food. Therefore we aimed to test the influence of the PUFA linoleic acid on OM consumption by aquatic macroinvertebrates using standardized surrogate substrates (decomposition and consumption tablet, DECOTAB) with added linoleic acid (PUFA) in comparison to consumption of DECOTAB containing only cellulose (Standard) or ground macrophytes (Plant). In microcosms, we observed a higher consumption rate of PUFA DECOTAB in comparison to Standard DECOTAB in two functionally distinct invertebrate species (Lumbriculus variegatus and Asellus aquaticus). This effect appeared to be overruled in the field due to unknown sources of natural variation. Although we observed higher consumption rates in species-rich ditches compared to species-poor ditches, consumption rates were comparable for all three types of DECOTAB deployed. Upon reduced food quality and palatability, results presented here hint that PUFA like linoleic acid may be a key OM attribute driving the performance of benthic macroinvertebrates and inherent functioning of aquatic ecosystems. PMID- 27767069 TI - Ternary mixtures of ionic liquids for better salt solubility, conductivity and cation transference number improvement. AB - We hereby present the new class of ionic liquid systems in which lithium salt is introduced into the solution as a lithium cation-glyme solvate. This modification leads to the reorganisation of solution structure, which entails release of free mobile lithium cation solvate and hence leads to the significant enhancement of ionic conductivity and lithium cation transference numbers. This new approach in composing electrolytes also enables even three-fold increase of salt concentration in ionic liquids. PMID- 27767067 TI - The cytochrome bd-I respiratory oxidase augments survival of multidrug-resistant Escherichia coli during infection. AB - Nitric oxide (NO) is a toxic free radical produced by neutrophils and macrophages in response to infection. Uropathogenic Escherichia coli (UPEC) induces a variety of defence mechanisms in response to NO, including direct NO detoxification (Hmp, NorVW, NrfA), iron-sulphur cluster repair (YtfE), and the expression of the NO tolerant cytochrome bd-I respiratory oxidase (CydAB). The current study quantifies the relative contribution of these systems to UPEC growth and survival during infection. Loss of the flavohemoglobin Hmp and cytochrome bd-I elicit the greatest sensitivity to NO-mediated growth inhibition, whereas all but the periplasmic nitrite reductase NrfA provide protection against neutrophil killing and promote survival within activated macrophages. Intriguingly, the cytochrome bd-I respiratory oxidase was the only system that augmented UPEC survival in a mouse model after 2 days, suggesting that maintaining aerobic respiration under conditions of nitrosative stress is a key factor for host colonisation. These findings suggest that while UPEC have acquired a host of specialized mechanisms to evade nitrosative stresses, the cytochrome bd-I respiratory oxidase is the main contributor to NO tolerance and host colonisation under microaerobic conditions. This respiratory complex is therefore of major importance for the accumulation of high bacterial loads during infection of the urinary tract. PMID- 27767071 TI - Relaxation dynamics of glasses along a wide stability and temperature range. AB - While lots of measurements describe the relaxation dynamics of the liquid state, experimental data of the glass dynamics at high temperatures are much scarcer. We use ultrafast scanning calorimetry to expand the timescales of the glass to much shorter values than previously achieved. Our data show that the relaxation time of glasses follows a super-Arrhenius behaviour in the high-temperature regime above the conventional devitrification temperature heating at 10 K/min. The liquid and glass states can be described by a common VFT-like expression that solely depends on temperature and limiting fictive temperature. We apply this common description to nearly-isotropic glasses of indomethacin, toluene and to recent data on metallic glasses. We also show that the dynamics of indomethacin glasses obey density scaling laws originally derived for the liquid. This work provides a strong connection between the dynamics of the equilibrium supercooled liquid and non-equilibrium glassy states. PMID- 27767070 TI - Embryonic/fetal mortality and intrauterine growth restriction is not exclusive to the CBA/J sub-strain in the CBA * DBA model. AB - Inbred strains of mice are powerful models for understanding human pregnancy complications. For example, the exclusive mating of CBA/J females to DBA/2J males increases fetal resorption to 20-35% with an associated decline in placentation and maintenance of maternal Th1 immunity. More recently other complications of pregnancy, IUGR and preeclampsia, have been reported in this model. The aim of this study was to qualify whether the CBA/CaH substrain female can substitute for CBA/J to evoke a phenotype of embryonic/fetal mortality and IUGR. (CBA/CaH * DBA/2J) F1 had significantly higher embryonic/fetal mortality mortality (p = 0.0063), smaller fetuses (p < 0.0001), and greater prevalence of IUGR (<10th percentile; 47% vs 10%) than (CBA/CaH * Balb/c) F1. Placentae from IUGR fetuses from all mating groups were significantly smaller (p < 0.0001) with evidence of thrombosis and fibrosis when compared to normal-weight fetuses ( > 10th percentile). In addition, placentae of "normal-weight" (CBA/CaH * DBA/2J) F1 were significantly smaller (p < 0.0006) with a greater proportion of labyrinth (p = 0.0128) and an 11-fold increase in F4/80 + macrophage infiltration (p < 0.0001) when compared to placentae of (CBA/CaH * Balb/c) F1. In conclusion, the embryonic/fetal mortality and IUGR phenotype is not exclusive to CBA/J female mouse, and CBA/CaH females can be substituted to provide a model for the assessment of novel therapeutics. PMID- 27767072 TI - Evaluating the mobility potential of antibiotic resistance genes in environmental resistomes without metagenomics. AB - Antibiotic resistance genes are ubiquitous in the environment. However, only a fraction of them are mobile and able to spread to pathogenic bacteria. Until now, studying the mobility of antibiotic resistance genes in environmental resistomes has been challenging due to inadequate sensitivity and difficulties in contig assembly of metagenome based methods. We developed a new cost and labor efficient method based on Inverse PCR and long read sequencing for studying mobility potential of environmental resistance genes. We applied Inverse PCR on sediment samples and identified 79 different MGE clusters associated with the studied resistance genes, including novel mobile genetic elements, co-selected resistance genes and a new putative antibiotic resistance gene. The results show that the method can be used in antibiotic resistance early warning systems. In comparison to metagenomics, Inverse PCR was markedly more sensitive and provided more data on resistance gene mobility and co-selected resistances. PMID- 27767074 TI - Impact of migration on the multi-strategy selection in finite group-structured populations. AB - For large quantities of spatial models, the multi-strategy selection under weak selection is the sum of two competition terms: the pairwise competition and the competition of multiple strategies with equal frequency. Two parameters sigma1 and sigma2 quantify the dependence of the multi-strategy selection on these two terms, respectively. Unlike previous studies, we here do not require large populations for calculating sigma1 and sigma2, and perform the first quantitative analysis of the effect of migration on them in group-structured populations of any finite sizes. The Moran and the Wright-Fisher process have the following common findings. Compared with well-mixed populations, migration causes sigma1 to change with the mutation probability from a decreasing curve to an inverted U shaped curve and maintains the increase of sigma2. Migration (probability and range) leads to a significant change of sigma1 but a negligible one of sigma2. The way that migration changes sigma1 is qualitatively similar to its influence on the single parameter characterizing the two-strategy selection. The Moran process is more effective in increasing sigma1 for most migration probabilities and the Wright-Fisher process is always more effective in increasing sigma2. Finally, our findings are used to study the evolution of cooperation under direct reciprocity. PMID- 27767073 TI - The 2014 Ebola virus outbreak in West Africa highlights no evidence of rapid evolution or adaptation to humans. AB - Following its immergence in December 2013, the recent Zaire Ebola virus (EBOV) outbreak in West Africa has spread and persisted for more than two years, making it the largest EBOV epidemic in both scale and geographical region to date. In this study, a total of 726 glycoprotein (GP) gene sequences of the EBOV full length genome obtained from West Africa from the 2014 outbreak, combined with 30 from earlier outbreaks between 1976 and 2008 were used to investigate the genetic divergence, evolutionary history, population dynamics, and selection pressure of EBOV among distinct epidemic waves. Results from our dataset showed that no non synonymous substitutions occurred on the GP gene coding sequences of EBOV that were likely to have affected protein structure or function in any way. Furthermore, the significantly different dN/dS ratios observed between the 2014 West African outbreak and earlier outbreaks were more likely due to the confounding presence of segregating polymorphisms. Our results highlight no robust evidence that the 2014 EBOV outbreak is fast-evolving and adapting to humans. Therefore, the unprecedented nature of the 2014 EBOV outbreak might be more likely related to non-virological elements, such as environmental and sociological factors. PMID- 27767075 TI - Discrete bisoliton fiber laser. AB - Dissipative solitons, which result from the intricate balance between dispersion and nonlinearity as well as gain and loss, are of the fundamental scientific interest and numerous important applications. Here, we report a fiber laser that generates bisoliton - two consecutive dissipative solitons that preserve a fixed separation between them. Deviations from this separation result in its restoration. It is also found that these bisolitons have multiple discrete equilibrium distances with the quantized separations, as is confirmed by the theoretical analysis and the experimental observations. The main feature of our laser is the anomalous dispersion that is increased by an order of magnitude in comparison to previous studies. Then the spectral filtering effect plays a significant role in pulse-shaping. The proposed laser has the potential applications in optical communications and high-resolution optics for coding and transmission of information in higher-level modulation formats. PMID- 27767077 TI - Optical manipulation of the alpha subunits of heterotrimeric G proteins using photoswitchable dimerization systems. AB - Alpha subunits of heterotrimeric G proteins (Galpha) are involved in a variety of cellular functions. Here we report an optogenetic strategy to spatially and temporally manipulate Galpha in living cells. More specifically, we applied the blue light-induced dimerization system, known as the Magnet system, and an alternative red light-induced dimerization system consisting of Arabidopsis thaliana phytochrome B (PhyB) and phytochrome-interacting factor 6 (PIF6) to optically control the activation of two different classes of Galpha (Galphaq and Galphas). By utilizing this strategy, we demonstrate successful regulation of Ca2+ and cAMP using light in mammalian cells. The present strategy is generally applicable to different kinds of Galpha and could contribute to expanding possibilities of spatiotemporal regulation of Galpha in mammalian cells. PMID- 27767076 TI - Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics. AB - The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 A) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors. PMID- 27767078 TI - The temporal frequency tuning of continuous flash suppression reveals peak suppression at very low frequencies. AB - Continuous flash suppression (CFS) is a psychophysical technique where a rapidly changing Mondrian pattern viewed by one eye suppresses the target in the other eye for several seconds. Despite the widespread use of CFS to study unconscious visual processes, the temporal tuning of CFS suppression is currently unknown. In the present study we used spatiotemporally filtered dynamic noise as masking stimuli to probe the temporal characteristics of CFS. Surprisingly, we find that suppression in CFS peaks very prominently at approximately 1 Hz, well below the rates typically used in CFS studies (10 Hz or more). As well as a strong bias to low temporal frequencies, CFS suppression is greater for high spatial frequencies and increases with increasing masker contrast, indicating involvement of parvocellular/ventral mechanisms in the suppression process. These results are reminiscent of binocular rivalry, and unifies two phenomenon previously thought to require different explanations. PMID- 27767079 TI - SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy. AB - Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients. PMID- 27767080 TI - Structural Analysis of an Evolved Transketolase Reveals Divergent Binding Modes. AB - The S385Y/D469T/R520Q variant of E. coli transketolase was evolved previously with three successive smart libraries, each guided by different structural, bioinformatical or computational methods. Substrate-walking progressively shifted the target acceptor substrate from phosphorylated aldehydes, towards a non phosphorylated polar aldehyde, a non-polar aliphatic aldehyde, and finally a non polar aromatic aldehyde. Kinetic evaluations on three benzaldehyde derivatives, suggested that their active-site binding was differentially sensitive to the S385Y mutation. Docking into mutants generated in silico from the wild-type crystal structure was not wholly satisfactory, as errors accumulated with successive mutations, and hampered further smart-library designs. Here we report the crystal structure of the S385Y/D469T/R520Q variant, and molecular docking of three substrates. This now supports our original hypothesis that directed evolution had generated an evolutionary intermediate with divergent binding modes for the three aromatic aldehydes tested. The new active site contained two binding pockets supporting pi-pi stacking interactions, sterically separated by the D469T mutation. While 3-formylbenzoic acid (3-FBA) preferred one pocket, and 4-FBA the other, the less well-accepted substrate 3-hydroxybenzaldehyde (3-HBA) was caught in limbo with equal preference for the two pockets. This work highlights the value of obtaining crystal structures of evolved enzyme variants, for continued and reliable use of smart library strategies. PMID- 27767082 TI - Non-negligible Contributions to Thermal Conductivity From Localized Modes in Amorphous Silicon Dioxide. AB - Thermal conductivity is important for almost all applications involving heat transfer. The theory and modeling of crystalline materials is in some sense a solved problem, where one can now calculate their thermal conductivity from first principles using expressions based on the phonon gas model (PGM). However, modeling of amorphous materials still has many open questions, because the PGM itself becomes questionable when one cannot rigorously define the phonon velocities. In this report, we used our recently developed Green-Kubo modal analysis (GKMA) method to study amorphous silicon dioxide (a-SiO2). The predicted thermal conductivities exhibit excellent agreement with experiments and anharmonic effects are included in the thermal conductivity calculation for all the modes in a-SiO2 for the first time. Previously, localized modes (locons) have been thought to have a negligible contribution to thermal conductivity, due to their highly localized nature. However, in a-SiO2 our results indicate that locons contribute more than 10% to the total thermal conductivity from 400 K to 800 K and they are largely responsible for the increase in thermal conductivity of a-SiO2 above room temperature. This is an effect that cannot be explained by previous methods and therefore offers new insight into the nature of phonon transport in amorphous/glassy materials. PMID- 27767081 TI - Genome engineering in the yeast pathogen Candida glabrata using the CRISPR-Cas9 system. AB - Among Candida species, the opportunistic fungal pathogen Candida glabrata has become the second most common causative agent of candidiasis in the world and a major public health concern. Yet, few molecular tools and resources are available to explore the biology of C. glabrata and to better understand its virulence during infection. In this study, we describe a robust experimental strategy to generate loss-of-function mutants in C. glabrata. The procedure is based on the development of three main tools: (i) a recombinant strain of C. glabrata constitutively expressing the CRISPR-Cas9 system, (ii) an online program facilitating the selection of the most efficient guide RNAs for a given C. glabrata gene, and (iii) the identification of mutant strains by the Surveyor technique and sequencing. As a proof-of-concept, we have tested the virulence of some mutants in vivo in a Drosophila melanogaster infection model. Our results suggest that yps11 and a previously uncharacterized serine/threonine kinase are involved, directly or indirectly, in the ability of the pathogenic yeast to infect this model host organism. PMID- 27767084 TI - miR-181a is a negative regulator of GRIA2 in methamphetamine-use disorder. AB - A previous study reported that the miR-181a level in serum was significantly different between patients with methamphetamine-use disorder and healthy controls and that chronic methamphetamine use down-regulates the expression of miR-181a. Bioinformatic analysis predicted that miR-181a might bind the 3'-UTRs of the mRNA transcripts of the human glutamate receptor genes GRIA2 and GABRA1. In this study, we measured the expression of GRIA2 and GABRA1 in patients with methamphetamine-use disorder. In addition, we examined whether miR-181a down regulates GRIA2 and GABRA1 in a cell-based assay. We further examined the effects of chronic methamphetamine exposure on the expression of miR-181a, GRIA2 and GABRA1. The results demonstrated that serum GRIA2 is higher in patients with methamphetamine-use disorder than in healthy controls. Dual luciferase reporter assays and a cell-based model of methamphetamine exposure also showed that miR 181a directly regulates expression of GRIA2. This study supports the evidence that miR-181a and the glutamate AMPA receptor gene GRIA2 play a critical role in methamphetamine-use disorder. PMID- 27767083 TI - miR-200 family controls late steps of postnatal forebrain neurogenesis via Zeb2 inhibition. AB - During neurogenesis, generation, migration and integration of the correct numbers of each neuron sub-type depends on complex molecular interactions in space and time. MicroRNAs represent a key control level allowing the flexibility and stability needed for this process. Insight into the role of this regulatory pathway in the brain is still limited. We performed a sequential experimental approach using postnatal olfactory bulb neurogenesis in mice, starting from global expression analyses to the investigation of functional interactions between defined microRNAs and their targets. Deep sequencing of small RNAs extracted from defined compartments of the postnatal neurogenic system demonstrated that the miR-200 family is specifically induced during late neuronal differentiation stages. Using in vivo strategies we interfered with the entire miR-200 family in loss- and gain-of-function settings, showing a role of miR-200 in neuronal maturation. This function is mediated by targeting the transcription factor Zeb2. Interestingly, so far functional interaction between miR-200 and Zeb2 has been exclusively reported in cancer or cultured stem cells. Our data demonstrate that this regulatory interaction is also active during normal neurogenesis. PMID- 27767085 TI - Wireless inertial measurement of head kinematics in freely-moving rats. AB - While miniature inertial sensors offer a promising means for precisely detecting, quantifying and classifying animal behaviors, versatile inertial sensing devices adapted for small, freely-moving laboratory animals are still lacking. We developed a standalone and cost-effective platform for performing high-rate wireless inertial measurements of head movements in rats. Our system is designed to enable real-time bidirectional communication between the headborne inertial sensing device and third party systems, which can be used for precise data timestamping and low-latency motion-triggered applications. We illustrate the usefulness of our system in diverse experimental situations. We show that our system can be used for precisely quantifying motor responses evoked by external stimuli, for characterizing head kinematics during normal behavior and for monitoring head posture under normal and pathological conditions obtained using unilateral vestibular lesions. We also introduce and validate a novel method for automatically quantifying behavioral freezing during Pavlovian fear conditioning experiments, which offers superior performance in terms of precision, temporal resolution and efficiency. Thus, this system precisely acquires movement information in freely-moving animals, and can enable objective and quantitative behavioral scoring methods in a wide variety of experimental situations. PMID- 27767086 TI - Adenovirus vector carrying REIC/DKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy. AB - As the First-In-Human study of in situ gene therapy using an adenovirus vector carrying the human REIC (reduced expression in immortalized cell)/Dkk-3 gene (Ad REIC), we conducted neoadjuvant intraprostatic injections in patients with high risk localized prostate cancer undergoing radical prostatectomy (RP). Patients with recurrence probability of 35% or more within 5 years following RP, as calculated by Kattan's nomogram, were enrolled. Patients received two ultrasound guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. After confirming the safety of the therapeutic interventions with initially planned three escalating doses of 1.0 * 1010, 1.0 * 1011 and 1.0 * 1012 viral particles (vp) in 1.0-1.2 ml (n=3, 3 and 6), an additional higher dose of 3.0 * 1012 vp in 3.6 ml (n=6) was further studied. All four DLs including the additional dose level-4 (DL-4) were feasible with no adverse events, except for grade 1 or 2 transient fever. Laboratory toxicities were grade 1 or 2 elevated aspartate transaminase/alanine transaminase (n=4). Regarding antitumor activities, cytopathic effects (tumor degeneration with cytolysis and pyknosis) and remarkable tumor-infiltrating lymphocytes in the targeted tumor areas were detected in a clear dose-dependent manner. Consequently, biochemical recurrence-free survival in DL-4 was significantly more favorable than in patient groups DL-1+2+3. PMID- 27767087 TI - Adenovirus coxsackie adenovirus receptor-mediated binding to human erythrocytes does not preclude systemic transduction. AB - There is great skepticism in the capability of adenovirus vectors and oncolytic adenoviruses to reach specific organs or tumors upon systemic administration. Besides antibodies, the presence of CAR (coxsackie and adenovirus receptor) in human erythrocytes has been postulated to sequester CAR-binding adenoviruses, commonly used in gene therapy and oncolytic applications. The use of non-CAR binding fibers or serotypes has been postulated to solve this limitation. Given the lack of integrins in erythrocytes and therefore of internalization of the CAR bound virus, we hypothesized that the interaction of adenovirus type 5 (Ad5) with CAR in human erythrocytes could be reversible. In this work, we have studied the effects of Ad5 interaction with human erythrocytes via CAR. Although erythrocyte binding was observed, it did not reduce viral transduction of tumor cells in vitro after long-term incubations. Transplantation of human erythrocytes into nude mice did not reduce Ad5 extravasation and transduction of liver and human xenograft tumors after systemic administration. These findings indicate that despite human erythrocytes are able to bind to Ad5, this binding is reversible and does not prevent extravasation and organ transduction after systemic delivery. Thus, the poor bioavailability of systemically delivered CAR-binding adenoviruses in humans is likely due to other factors such as liver sequestration or neutralizing antibodies. PMID- 27767088 TI - S100A7 has an oncogenic role in oral squamous cell carcinoma by activating p38/MAPK and RAB2A signaling pathway. AB - Oral cancer consists of squamous cell carcinoma within the oral cavity or on the lip. The clinical prognosis of this cancer is mostly poor owing to delayed diagnosis and a lack of appropriate early detection biomarkers to identify the disease. In the current study, we investigated the role of the S100A7 calcium binding protein in oral squamous cell carcinoma as an activator of the p38/MAPK and RAB2A signaling pathway. The aim of the present study was to determine whether S100A7 and RAB2A have a role in tumor progression and to assess their potential as early detection biomarkers for oral cancer. This study elucidated the functional and molecular mechanisms of S100A7 and RAB2A activity in oral cancer, leading us to conclude that S100A7 is the major contributing factor in the occurrence of oral cancer and promotes local tumor progression by activating the MAPK signaling pathway via the RAB2A pathway. We hypothesize that S100A7 affects cell motility and invasion by regulating the RAB2A-associated MAPK signaling cascades. Also, the downregulation of S100A7 expression by RNA interference-mediated silencing inhibits oral cancer cell growth, migration and invasion. PMID- 27767089 TI - The effect of oxamflatin on the E-cadherin expression in gastric cancer cell line. AB - Gastric cancer is among the leading causes of cancer-related death, and the symptoms are commonly characterized in advanced stages. Histone acetylation is among the most important epigenetic alterations occurring during cancer development. In addition, reduced E-cadherin expression is a major contributor in the process of tumor cell invasion and metastasis. Oxamflatin is a histone deacetylase inhibitor that has been suggested as a promising anti-tumor agent; yet its effect on the viability and invasion of gastric tumor cells is unclear. We aimed to assess the impact of oxamflatin on the viability of gastric tumor cells and expression of E-cadherin as a marker of tumor invasion susceptibility. In this study, MKN-45 cells were treated with 1, 2.5 and 5 mM oxamflatin and followed by MTT assay after 24-48 h of incubation. To determine E-cadherin expression in treated cells, total RNA was extracted and reverse transcribed to complementary DNA, followed by quantitative real-time PCR. MTT results showed that the viability of MKN-45 cells declines with increasing concentrations of oxamflatin. The results of quantitative real-time PCR showed increased expression of E-cadherin following treatment with oxamflatin at the concentration of 2.5 mM compared with 1 mM. The present results showed that oxamflatin can induce E cadherin expression and also reduce cell viability in the MKN-45 cell line. On the basis of these findings, oxamflatin can be further considered for the prevention of tumor metastasis. PMID- 27767092 TI - Thermodynamic Calculation among Cerium, Oxygen, and Sulfur in Liquid Iron. AB - Thermodynamic calculation has been applied to predict the inclusion formation in molten SS400 steel. When the Cerium addition in liquid iron is 70 ppm and the initial Oxygen and Sulphur are both 110 ppm, the formation of oxides containing Cerium would experience the transformation from Ce2O3 to CeO2 and also the formation of sulfides containing Cerium would experience the transformation from CeS to Ce2S3 and then to Ce3S4. Below 2000 K the most thermodynamic stable matter is CeO2 and the less thermodynamic stable inclusion is CeS. Only when the amount of [O] is extremely low and the amount of [S] and [Ce] is relatively high, Ce2S3 has the possibility to form. PMID- 27767090 TI - Chimeric antigen receptors for treatment of glioblastoma: a practical review of challenges and ways to overcome them. AB - Glioblastoma (GBM) is by far the most common and the most aggressive of all the primary brain malignancies. No curative therapy exists, and median life expectancy hovers at around 1 year after diagnosis, with a minute fraction surviving beyond 5 years. The difficulty in treating GBM lies in the cancer's protected niche within the blood-brain barrier and the heterogeneity of the cancer cells, which possess varying degrees of susceptibility to various common modalities of treatment. Over time, it is the tumor heterogeneity of GBM and the ability of the cancer stem cells to evolve in response treatment that renders the cancer refractory to conventional treatment. Therefore, research has increasingly focused on treatment that incorporates knowledge of GBM molecular biology to therapeutic strategies. One type of therapy that shows great promise is the area of T-cell immunotherapy to target GBM-specific tumor antigens. One attractive strategy is to use T cells that have undergone genetic modification to express a chimeric antigen receptor capable of interacting with tumor antigens. In this article, we will review chimeric antigen receptor T-cell therapy, their advantages, drawbacks, challenges facing their use and how those challenges may be overcome. PMID- 27767094 TI - Warm feelings for TRPM2. AB - Two recent studies reveal a crucial role for the cation channel TRPM2 in sensing warm temperatures, both in the thermoregulatory center of the brain and in the somatosensory system. PMID- 27767091 TI - Extensive transcriptome analysis correlates the plasticity of Entamoeba histolytica pathogenesis to rapid phenotype changes depending on the environment. AB - Amoebiasis is a human infectious disease due to the amoeba parasite Entamoeba histolytica. The disease appears in only 20% of the infections. Diversity in phenotypes may occur within the same infectious strain in the gut; for instance, parasites can be commensal (in the intestinal lumen) or pathogenic (inside the tissue). The degree of pathogenesis of clinical isolates varies greatly. These findings raise the hypothesis that genetic derivation may account for amoebic diverse phenotypes. The main goal of this study was to analyse gene expression changes of a single virulent amoebic strain in different environmental contexts where it exhibit different degrees of virulence, namely isolated from humans and maintained through animal liver passages, in contact with the human colon and short or prolonged in vitro culture. The study reveals major transcriptome changes in virulent parasites upon contact with human colon explants, including genes related to sugar metabolism, cytoskeleton rearrangement, stress responses and DNA repair. Furthermore, in long-term cultured parasites, drastic changes in gene expression for proteins with functions for proteasome and tRNA activities were found. Globally we conclude that rapid changes in gene expression rather than genetic derivation can sustain the invasive phenotype of a single virulent isolate of E. histolytica. PMID- 27767093 TI - Turning rice meiosis into mitosis. AB - Introduction of clonal reproduction through seeds (apomixis) in crops has the potential to revolutionize agriculture by allowing self-propagation of any elite variety, in particular F1 hybrids. In the sexual model plant Arabidopsis thaliana synthetic clonal reproduction through seeds can be artificially implemented by (i) combining three mutations to turn meiosis into mitosis (MiMe) and (ii) crossing the obtained clonal gametes with a line expressing modified CENH3 and whose genome is eliminated in the zygote. Here we show that additional combinations of mutations can turn Arabidopsis meiosis into mitosis and that a combination of three mutations in rice (Oryza sativa) efficiently turns meiosis into mitosis, leading to the production of male and female clonal diploid gametes in this major crop. Successful implementation of the MiMe technology in the phylogenetically distant eudicot Arabidopsis and monocot rice opens doors for its application to any flowering plant and paves the way for introducing apomixis in crop species. PMID- 27767095 TI - Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan. AB - A unique feature of female germ cell development in mammals is their remarkably long arrest at the prophase of meiosis I, which lasts up to 50 years in humans. Both dormant and growing oocytes are arrested at prophase I and completely lack the ability to resume meiosis. Here, we show that the prolonged meiotic arrest of female germ cells is largely achieved via the inhibitory phosphorylation of Cdk1 (cyclin-dependent kinase 1). In two mouse models where we have introduced mutant Cdk1T14AY15F which cannot be inhibited by phosphorylation (Cdk1AF) in small meiotically incompetent oocytes, the prophase I arrest is interrupted, leading to a premature loss of female germ cells. We show that in growing oocytes, Cdk1AF leads to premature resumption of meiosis with condensed chromosomes and germinal vesicle breakdown followed by oocyte death, whereas in dormant oocytes, Cdk1AF leads to oocyte death directly, and both situations damage the ovarian reserve that maintains the female reproductive lifespan, which should be around 1 year in mice. Furthermore, interruption of the inhibitory phosphorylation of Cdk1 results in DNA damage, which is accompanied by induction of the Chk2 (checkpoint kinase 2)-p53/p63-dependent cell death pathway, which eventually causes global oocyte death. Together, our data demonstrate that the phosphorylation-mediated suppression of Cdk1 activity is one of the crucial factors that maintain the lengthy prophase arrest in mammalian female germ cells, which is essential for preserving the germ cell pool and reproductive lifespan in female mammals. PMID- 27767096 TI - Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. AB - Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPRmt) and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPRmt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPRmt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPRmt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system. PMID- 27767097 TI - Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice. AB - The roots of Scutellaria baicalensis has been used as a remedy for inflammatory and infective diseases for thousands of years. We evaluated the antiviral activity against respiratory syncytial virus (RSV) infection, the leading cause of childhood infection and hospitalization. By fractionation and chromatographic analysis, we determined that baicalin was responsible for the antiviral activity of S. baicalensis against RSV infection. The concentration for 50% inhibition (IC50) of RSV infection was determined at 19.9 +/- 1.8 MUM, while the 50% cytotoxic concentration (CC50) was measured at 370 +/- 10 MUM. We then used a mouse model of RSV infection to further demonstrate baicalin antiviral effect. RSV infection caused significant lung injury and proinflammatory response, including CD4 and CD8 T lymphocyte infiltration. Baicalin treatment resulted in reduction of T lymphocyte infiltration and gene expression of proinflammatory factors, while the treatment moderately reduced RSV titers recovered from the lung tissues. T lymphocyte infiltration and cytotoxic T lymphocyte modulated tissue damage has been identified critical factors of RSV disease. The study therefore demonstrates that baicalin subjugates RSV disease through antiviral and anti-inflammatory effect. PMID- 27767098 TI - A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin-fixed, paraffin-embedded specimens: analytical performance measuring HER2. AB - In clinical routine pathology today, detection of protein in intact formalin fixed, paraffin-embedded tissue is limited to immunohistochemistry, which is semi quantitative. This study presents a new and reliable quantitative immunohistochemistry method, qIHC, based on a novel amplification system that enables quantification of protein directly in formalin-fixed, paraffin-embedded tissue by counting of dots. The qIHC technology can be combined with standard immunohistochemistry, and assessed using standard bright-field microscopy or image analysis. The objective was to study analytical performance of the qIHC method. qIHC was tested under requirements for an analytical quantitative test, and compared with ELISA and flow cytometry for quantitative protein measurements. Human epidermal growth factor receptor 2 (HER2) protein expression was measured in five different cell lines with HER2 expression from undetectable with immunohistochemistry to strong positive staining (IHC 3+). Repeatability, reproducibility, robustness, linearity, dynamic range, sensitivity, and quantification limits were evaluated. Reproducibility and robustness were assessed in a setup to resemble daily work in a laboratory using a commercial immunohistochemistry platform. In addition, qIHC was correlated to standard HER2 immunohistochemistry in 44 breast cancer specimens. For all evaluated parameters, qIHC performance was either comparable or better than the reference methods. Furthermore, qIHC has a lower limit of detection than both immunohistochemistry and the ELISA reference method, and demonstrated ability to measure HER2 accurately and precise within a large dynamic range. In conclusion, the results show that qIHC provides a sensitive, quantitative, accurate, and robust assay for measurement of protein expression in formalin-fixed, paraffin-embedded cell lines, and tissue. PMID- 27767099 TI - Assessing HER2 testing quality in breast cancer: variables that influence HER2 positivity rate from a large, multicenter, observational study in Germany. AB - Despite >10 years of routine human epidermal growth factor receptor 2 (HER2) testing in breast cancer, testing quality is still an issue. Guidelines recommend assessing HER2 positivity rates as a quality indicator; however, the extent to which patient- or tumor-related factors influence HER2 positivity is still unknown. The present study analyzed these influences to identify pathology centers with HER2 positivity rates unexplained by patient- or tumor-related factors. This observational, prospective study monitored routine HER2 testing at 57 institutes of pathology in Germany (January 2013-August 2014). Data collected included HER2 test result, patient- and tumor-related factors, sample source, and method of sample retrieval. Factors influencing HER2 positivity rates were identified by multiple logistic regression. Individual center effects were assessed in an extended multiple logistic regression model by their statistical significance after adjusting for the combined effect of patient- or tumor-related covariates and multiple testing. Analyses included 15 332 invasive breast cancer samples. Histologic grade showed the strongest influence on HER2 positivity, followed by hormone receptor status, histologic subtype, age, and nodal status (all P<0.0001). The overall HER2 positivity rate across centers was 14.4% (range 7.1-27.3%). A statistically significant center effect on the HER2 positivity rate was identified for three centers (P<0.05), with a trend toward a center effect for a further three (P<0.2). This study, the first of its kind, highlights that assessing HER2 testing quality with HER2 positivity rates should include standardized assessment of patient- or tumor-related characteristics to identify centers with HER2 testing quality issues more effectively. As treatment options for HER2-positive breast cancer continue to evolve, identifying the right patients is key. PMID- 27767100 TI - CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. AB - Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms. PMID- 27767103 TI - Amorphous titanium-oxide supercapacitors. AB - The electric capacitance of an amorphous TiO2-x surface increases proportionally to the negative sixth power of the convex diameter d. This occurs because of the van der Waals attraction on the amorphous surface of up to 7 mF/cm2, accompanied by extreme enhanced electron trapping resulting from both the quantum-size effect and an offset effect from positive charges at oxygen-vacancy sites. Here we show that a supercapacitor, constructed with a distributed constant-equipment circuit of large resistance and small capacitance on the amorphous TiO2-x surface, illuminated a red LED for 37 ms after it was charged with 1 mA at 10 V. The fabricated device showed no dielectric breakdown up to 1,100 V. Based on this approach, further advances in the development of amorphous titanium-dioxide supercapacitors might be attained by integrating oxide ribbons with a micro electro mechanical system. PMID- 27767101 TI - Oxidative stress dependent microRNA-34a activation via PI3Kalpha reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells. AB - Sirtuin-1 (SIRT1) and SIRT6, NAD+-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kalpha activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases. PMID- 27767102 TI - A single nucleotide polymorphism in kidney anion exchanger 1 gene is associated with incomplete type 1 renal tubular acidosis. AB - Various conditions including distal renal tubular acidosis (dRTA) can induce stone formation in the kidney. dRTA is characterized by an impairment of urine acidification in the distal nephron. dRTA is caused by variations in genes functioning in intercalated cells including SLC4A1/AE1/Band3 transcribing two kinds of mRNAs encoding the Cl-/HCO3- exchanger in erythrocytes and that expressed in alpha-intercalated cells (kAE1). With the acid-loading test, 25% of urolithiasis patients were diagnosed with incomplete dRTA. In erythroid intron 3 containing the promoter region of kAE1, rs999716 SNP showed a significantly higher minor allele A frequency in incomplete dRTA compared with non-dRTA patients. The promoter regions of the kAE1 gene with the minor allele A at rs999716 downstream of the TATA box showed reduced promoter activities compared that with the major allele G. Patients with the A allele at rs999716 may express less kAE1 mRNA and protein in the intercalated cells, developing incomplete dRTA. PMID- 27767104 TI - Targeting erythrocyte carbonic anhydrase and 18O-isotope of breath CO2 for sorting out type 1 and type 2 diabetes. AB - The inability to envisage the acute onset and progression of type 1 diabetes (T1D) has been a major clinical stumbling block and an important area of biomedical research over the last few decades. Therefore there is a pressing need to develop a new and an effective strategy for early detection of T1D and to precisely distinguish T1D from type 2 diabetes (T2D). Here we describe the precise role of the enzymatic activity of carbonic anhydrase (CA) in erythrocytes in the pathogenesis of T1D and T2D. We show that CA activities are markedly altered during metabolism of T1D and T2D and this facilitates to the oxygen-18 (18O) isotopic fractionations of breath CO2. In our observations, T1D exhibited considerable depletions of 18O-isotopes of CO2, whereas T2D manifested isotopic enrichments of 18O in breath CO2, thus unveiling a missing link of breath18O isotopic fractionations in T1D and T2D. Our findings suggest that the alterations in erythrocytes CA activities may be the initial step of altered metabolism of T1D and T2D, and breath 18O-isotope regulated by the CA activity is a potential diagnostic biomarker that can selectively and precisely distinguish T1D from T2D and thus may open a potential unifying strategy for treating these diseases. PMID- 27767106 TI - Impact of smoking on tooth loss in adults. AB - DesignCohort studyCohort selectionParticipants were recruited between 1994 and 1998 from the general population with the preferred ages of 35 to 65 years in women and 40 to 65 years in men.Exposure measurementSmoking was assessed using a questionnaire from which pack years of smoking were calculated. Educational attainment, body mass index, hypertension, diabetes, alcohol consumption and vitamin or mineral supplements were assessed from measurements and questionnaires. Tooth loss was also assessed by questionnaire returned between 2004 and 2006. With the exception of the tooth loss data analysis was based on data collected at baseline.Data analysisThe 24,373 participants who returned the tooth loss questionnaire were analysed. Two hundred and eighty-six (1.2%) were excluded, as they did not respond to either of the tooth loss questions, and an additional 106 (0.4%) were excluded because they gave inconsistent responses to the questions on tooth loss. Four hundred and thirteen (1.7%) participants with missing data on cigarette smoking and 192 (0.8%) participants with missing data in any of the covariates were also excluded. The association between smoking and number of teeth at baseline was assessed using negative binomial regression models to obtain relative risks and 95% confidence intervals (CIs).ResultsThe sample of 23,376 included 9,032 men and 14,344 women of which 4,394 (19%) were current cigarette smokers, and 7,268 (31%) were cigarette smokers. 1,566 (6.7%) were edentulous at baseline. Compared with never smokers, current smokers were more likely to be male, less educated, more likely to be hypertensive, and less likely to take vitamins/mineral supplements, and they had higher alcohol consumption. Cigarette smoking was associated with higher prevalence of tooth loss at baseline as well as higher incidence of tooth loss during follow-up. The association between cigarette smoking and incident tooth loss during follow-up for the fully adjusted model (adjusted for age, sex, education, diabetes, body mass index, waist-to-hip ratio, hormone replacement therapy, contraception, intake of vitamin and mineral supplements, physical activity, alcohol intake, hypertension, and cardiovascular disease) is shown in the table.ConclusionsThere is a strong dose-dependent association between cigarette smoking and the risk of tooth loss. The risk declines after cessation of cigarette smoking; however, the risk may remain elevated for up to 20 years compared with never smokers. Efforts to improve the oral health of the population should include the prevention of smoking as well the promotion of smoking cessation. PMID- 27767105 TI - Monoacylglycerol Lipase: A Novel Potential Therapeutic Target and Prognostic Indicator for Hepatocellular Carcinoma. AB - Monoacylglycerol lipase (MAGL) is a key enzyme in lipid metabolism that is demonstrated to be involved in tumor progression through both energy supply of fatty acid (FA) oxidation and enhancing cancer cell malignance. The aim of this study was to investigate whether MAGL could be a potential therapeutic target and prognostic indicator for hepatocellular carcinoma (HCC). To evaluate the relationship between MAGL levels and clinical characteristics, a tissue microarray (TMA) of 353 human HCC samples was performed. MAGL levels in HCC samples were closely linked to the degree of malignancy and patient prognosis. RNA interference, specific pharmacological inhibitor JZL-184 and gene knock-in of MAGL were utilized to investigate the effects of MAGL on HCC cell proliferation, apoptosis, and invasion. MAGL played important roles in both proliferation and invasion of HCC cells through mechanisms that involved prostaglandin E2 (PGE2) and lysophosphatidic acid (LPA). JZL-184 administration significantly inhibited tumor growth in mice. Furthermore, we confirmed that promoter methylation of large tumor suppressor kinase 1 (LATS1) resulted in dysfunction of the Hippo signal pathway, which induced overexpression of MAGL in HCC. These results indicate that MAGL could be a potentially novel therapeutic target and prognostic indicator for HCC. PMID- 27767107 TI - Lack of association between overload and peri-implant tissue loss in healthy conditions. AB - Data sourcesPubMed, Ovid, EMBASE and LILACS were searched up to December 2011. In addition, the reference lists of the selected review papers were further hand searched. Language was limited to studies published only in English.Study selectionHuman and animal randomised clinical trials (RCT), systematic reviews of RCTs, non-randomised trials, case series that reported on the clinical, radiographic, and/or histological outcomes of dental/oral implants exposed to excessive load were considered eligible for inclusion.Data extraction and synthesisIdentified studies were evaluated by one non-blinded reviewer according to the selection criteria. When doubt arose co-authors assisted until consensus was reached. The data extracted from the clinical studies included study design, patients/implants/prostheses/loading time/follow-up time, type of intervention/methods, outcome, and, specific to animal studies, the animal model, intention to overload (ie yes or no), load mode, type of loading (ie dynamic or static), and microbial control if any. The heterogeneity among studies did not allow data to be combined.ResultsThe search strategy in addition to hand searching retrieved 726 potentially eligible studies after de-duplication. After screening the 41 full-text relevant studies and applying the selection criteria assessment, only three non-randomised split-mouth animal studies and one systematic review of animal experimental data were considered for inclusion. The non-randomised studies could not reveal any relationship between increased leverage on dental implants and marginal loss. The systematic review suggested that supra-occlusal contacts on uninflamed peri-implant bone tissue did not cause catabolism, whereas supra-occlusal contacts combined with inflammation significantly increased the plaque-induced catabolism.ConclusionsThe effect of implant overload on bone/implant loss in clinically well-integrated implants is poorly reported and provides little unbiased evidence to support a cause-and effect relationship. PMID- 27767108 TI - A systematic appraisal of the Evidence-Based Dentistry Journal. AB - BackgroundThis systematic appraisal was conducted to determine if the Evidence Based Dentistry Journal (EBDJ) acts as a reliable and contemporary source of knowledge for practitioners across all disciplines within dentistry.ObjectivesThe main objectives were to determine i) the year the articles were published and included in the EBDJ; ii) if the articles published covered all fields equally within dentistry; iii) the type of study design of the articles reported in the journal and; iv) the level of expertise of the writers of the commentaries.MethodsThis study used a systematic approach to assess the articles included in the journal. Data were extracted on the difference in the year the article was originally published and the year the article was included in the EBDJ, the number of articles in each dental discipline, the type of study designs included in the journal and the expertise of the commentators of each article. The information provided by the journal was validated by accessing the original articles through electronic databases.ResultsThe appraisal considered the 582 articles that met the inclusion criteria. Overall, 45.3% of the articles were included in the EBDJ in the same year and 44.8% of the articles were included a year after they were originally published. The number of articles varied across disciplines within dentistry: 23.7% from dental public health, 18.4% from periodontology and 11.8% from orthodontics, with only 4.6% from prosthodontics, 1% from oral pathology and 0.5% from dental materials. Most of the articles were systematic reviews and randomised controlled trials at 72% and 22.3% respectively. The writers of the commentaries were mostly academics and hospital consultants (71.2% and 13.6% commentators).ConclusionsOn the whole, it can be concluded that the journal acts as a reliable and contemporary source of knowledge/evidence for dentists, however, not all specialities within dentistry had equal coverage. PMID- 27767109 TI - Parasympathomimetic drugs for dry mouth due to radiotherapy. AB - Data sourcesCochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials, Medline, Embase and CINAHL databases. Reference lists of identified articles were checked and experts in the field and relevant pharmaceutical companies were contacted.Study selectionRandomised controlled trials, including parallel and crossover, carried out in any setting on any patient population with radiation-induced salivary dysfunction using parasympathomimetics drugs.Data extraction and synthesisThe two authors independently assessed for inclusion, established the risk of bias and abstracted data. The primary outcome was level of xerostomia. The authors intended to report risk ratio, odds ratio, risk difference and NNT for dichotomous data and mean difference and standard mean difference for continuous data.ResultsOf the three included studies, one (n=20) reported mean improvement on the VAS (22.5 mm on a 100 mm scale). The other two studies considered a change in 25 mm on the VAS a positive response. Of those one (n=207) reported positive response in 51% of subjects on 5mg of pilocapine TID and 47% for 10mg TID. The second (n= 162) reported a 42% positive response with a titrated dose regimen. The side effects rate was high,and the main reason for discontinuation.ConclusionsThere is limited evidence to support the use of pilocarpine hydrochloride in the treatment of radiation-induced xerostomia. Currently, there is little evidence to support the use of other parasympathomimetic drugs in the treatment of radiation-induced xerostomia. Available studies suggest that approximately half of patients will respond, but side effects can be problematic. The conclusions of the update are the same as the conclusions of the original review, since no new relevant studies have been published in the interim. PMID- 27767110 TI - Oral cryotherapy reduced oral mucositis in patients having cancer treatments. AB - Data sourcesCochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CANCERLIT, CINAHL, the US National Institutes of Health Trials Registry and the WHO Clinical Trials Registry Platform.Study selectionRandomised controlled trials (RCTs) assessing the effects of oral cryotherapy in patients with cancer receiving treatment compared to usual care, no treatment or other interventions to prevent mucositis. The primary outcome was incidence of mucositis and its severity.Data extraction and synthesisTwo reviewers carried out study assessment and data extraction independently. Treatment effect for continuous data was calculated using mean values and standard deviations and expressed as mean difference (MD) and 95% confidence interval. Risk ratio (RR) was calculated for dichotomous data. Meta analysis was performed.ResultsFourteen studies with 1280 participants were included. Subgroup analysis was undertaken according to the main cancer treatment type. Cryotherapy reduced the risk of developing mucositis by 39% (RR = 0.61; 95%CI, 0.52 to 0.72) on patients treated with fluorouracil (5FU). For melphalan based treatment the risk of developing mucositis was reduced by 41% (RR =0.59; 95%CI, 0.35 to 1.01). Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, numbness/taste disturbance and tooth pain. This appears to contribute to the high rates of compliance seen in the included studies.ConclusionsThere is confidence that oral cryotherapy leads to a large reduction in oral mucositis in adults treated with 5FU. Although there is less certainty on the size of the reduction on patients treated with melphalan, it is certain there is reduction of severe mucositis. PMID- 27767111 TI - Psychosocial determinants of oral health behaviour in adolescents. AB - Data sourcesPubMed, Embase, Ebsco/PsycInfo, Ebsco/CINAHL and ISI/Web of Science databases.Study selectionStudies that evaluated the association between the psychosocial correlates and oral hygiene behaviour varying from self-reports to clinical measurements, including plaque and bleeding scores were considered.Data extraction and synthesisTwo reviewers independently selected studies, abstracted data and assessed study quality using a modified version of the Newcastle-Ottawa Scale.ResultsTwenty-four studies were included providing 31 datasets. Three studies were prospective, the remainder being cross-sectional. 39% of the studies based their research on a behavioural theory, 61% of the studies did not refer to a specific theoretical framework. The theory of planned behaviour was the most commonly used. Meta-analysis of 27 data sets; for both tooth brushing and oral hygiene behaviour, random effect models revealed significant weighted average correlation (r+) for the psychosocial factors: 'intention', 'self-efficacy', 'attitude' (not significant for tooth brushing), 'social influence', 'coping planning' and 'action planning' (r+ ranging from 0.18 to 0.57). Little or no associations were found for 'locus of control', 'self-esteem' and 'sense of coherence' (r+ ranges from 0.01 to 0.08).ConclusionsThe data at present indicate that 'self-efficacy', 'intention', 'social influences', 'coping planning' and 'action planning' are potential psychosocial determinants of oral health behaviour. Future studies should consider a range of psychological factors that have not been studied, but have shown to be important psychosocial determinants of health behaviours, such as 'self-determination', 'anticipated regret', 'action control' and 'self-identity'. Effectiveness of addressing these potential determinants to induce behaviour change should be further examined by intervention trials. PMID- 27767113 TI - Commentary on two reviews of anterior composite restorations. PMID- 27767114 TI - Review suggests direct pulp capping with MTA more effective than calcium hydroxide. AB - Data sourcesPubMed, the Cochrane Library, Embase, and the Web of Knowledge.Study selectionRandomised controlled trials (RCTs) or retrospective non-randomised trials (RNTs) of direct pulp capping in patients comparing mineral trioxide aggregate (MTA) with calcium hydroxide (CH) were considered.Data extraction and synthesisTwo reviewers independently abstracted data. Risk of bias for the RCTs was assessed using the Cochrane risk of bias tool and RNTs were assessed according to the methodological index for non-randomised studies. Different study designs were analysed separately.ResultsThirteen studies were included, ten of which were RCTs. Meta-analysis demonstrated a significantly higher success rate for MTA compared with the CH-capped groups. For RCT studies (2 studies, 405 teeth): OR = 2.26; (95% CI, 1.33-3.85; P = .003) and for RNTs (3 studies - 526 teeth): OR = 2.88; (95% CI, 1.86-4.44; P < .00001). Nine studies (325 teeth) compared the inflammatory response with MTA showing significantly less inflammation compared with CH samples (OR = 4.56; 95% CI, 2.65 7.83; P < .00001). Nine studies (325 teeth) compared dentine bridge formation with a higher percentage of calcified dentin bridge formation in the MTA than CH-capped groups (OR = 3.56; 95% CI, 1.89 6.70; P < .0001).ConclusionsMTA has a higher success rate and results in less pulpal inflammatory response and more predictable hard dentin bridge formation than CH. MTA appears to be a suitable replacement of CH used for direct pulp capping. PMID- 27767115 TI - Enamel bevelling and retention of composite restorations in non-carious cervical lesions. AB - Data sourcesMedline, Web of Science, Latin American and Caribbean Health Sciences Literature database (LILACS), Brazilian Library in Dentistry (BBO), the Cochrane Library, abstracts of the annual conference of the International Association for Dental Research (IADR), System for Information on Grey literature in Europe (SIGLE), ProQuest Dissertations and Theses Fulltext database as well as the Periodicos Capes Theses, Current Controlled Trials, International Clinical trials registry platform, the ClinicalTrials.gov, Rebec and the EU Clinical Trials Register.Study selectionRandomised clinical trials (RCTs) that compared the retention rates of restorations in NCCLs placed with or without bevel with at least one year follow-up were considered.Data extraction and synthesisData were abstracted using standardised forms and study quality was assessed using the Cochrane risk of bias tool. Marginal discolouration scores were dichotomised into yes and no, and risk differences for retention rate and marginal discolouration were calculated for each study for analysis.ResultsFour studies were included. Two studies were considered to be at high risk of bias and not included in the meta-analysis. The overall risk difference was 0.0 (95%CI; 0.04 to 0.04) for the retention rate and 0.05 ((95%CI; 0.02 to 0.13) for the marginal discolouration, suggesting that enamel beveling does not influence retention rate or marginal discolouration.ConclusionsOne may conclude that there is no difference between bevelled and non-bevelled technique over the short-term follow-up of 12-18 months of clinical service, although this conclusion was based on only two low risk of bias RCTs. Additionally, there is not enough evidence to support this conclusion over longer-term follow-ups. There is a need for better standardisation and the reporting of RCTs investigating this technique variation after longer-term follow up periods. PMID- 27767116 TI - Fissure seal or fluoride varnish? AB - Data sourcesCochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the US National Institutes of Health Trials Register and the World Health Organization (WHO) Clinical Trials Registry PlatformStudy selectionRandomised controlled trials (RCTs) with at least 12 months follow-up, in which fissure sealants, or fissure sealants together with fluoride varnishes, were compared with fluoride varnishes alone for preventing caries in occlusal surfaces of permanent teeth of children and adolescents.Data extraction and synthesisTwo reviewers independently screened search results, extracted data and assessed risk of bias of included studies. Studies were grouped and analysed on the basis of sealant material type (resin based sealant and glass ionomer-based sealant, glass ionomer and resin-modified glass ionomer) and different follow-up periods. Odds ratio were calculated for caries or no caries on occlusal surfaces of permanent molar teeth. Mean differences were calculated for continuous outcomes and data. Evidence quality was assessed using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods.ResultsEight RCTs involving a total of 1747 children aged five to ten years of age were included. Three trials compared resin-based fissure sealant versus fluoride varnish. Results from two studies (358 children) after two years were combined. Sealants prevented more caries, pooled odds ratio (OR) = 0.69 (95%CI; 0.50 to 0.94). One trial with follow-up at four and nine years found that the caries-preventive benefit for sealants was maintained, with 26% of sealed teeth and 55.8% of varnished teeth having developed caries at nine years. Evidence for glass-ionomer sealants was of low quality. One split-mouth trial analysing 92 children at two-year follow-up found a significant difference in favour of resin-based fissure sealant together with fluoride varnish compared with fluoride varnish only (OR 0.30, 95% CI 0.17 to 0.55). The evidence was assessed as low quality. Three studies assessed but did not report any adverse effects.ConclusionsCurrently, scarce and clinically diverse data are available on the comparison of sealants and fluoride varnish applications; therefore it is not possible to draw clear conclusions about possible differences in effectiveness for preventing or controlling dental caries on occlusal surfaces of permanent molars. The conclusions of this updated review remain the same as those of the last update (in 2010). We found some low quality evidence suggesting the superiority of resin-based fissure sealants over fluoride varnish applications for preventing occlusal caries in permanent molars, and other low-quality evidence for benefits of resin-based sealant and fluoride varnish over fluoride varnish alone. Regarding glass ionomer sealant versus fluoride varnish comparisons, we assessed the quality of the evidence as very low and could draw no conclusions. PMID- 27767117 TI - Single dose oral analgesics for postoperative pain have few adverse events. AB - Data sourcesThe Cochrane Database of Systematic Reviews on the Cochrane Library.Study selectionAll Cochrane reviews of RCTs between 1999 to 2015, conducted in adults examining the adverse events associated with single dose oral analgesics used for acute post-operative pain were considered.Data extraction and synthesisStudies were searched, reviewed and assessed independently by two reviewers and standard data items extracted. Methodological quality was assessed using criteria adapted from AMSTAR (Assessing the Methodological Quality of Systematic Reviews).ResultsData from 39 Cochrane reviews of 41 different analgesics or analgesic combinations involving a total of 350 studies involving 35,000 adults were included. Most analgesics were tested in a narrow dose range. For most NSAIDs, paracetamol (acetaminophen), and combinations not containing opioids, the rates of adverse events were similar to that of placebos (NSAID 3% - 44% vs 4 - 46%; paracetamol 7-18% vs 6-16%; combination 11-30% vs 6-48%). However, for higher dosages, like 1000 mg aspirin, 1000 mg diflunisal, and opioids or drug combinations containing opioids, there was a statistically significant difference in the incidence of adverse events reported (NNH 7.7(95%CI; 4.8 - 20) for 1000 mg aspirin; 7.5(95%CI; 4.8-17) for 1000 mg diflunisal; 3.5-8.6 for opioids and combinations). Serious adverse events were rare, occurring at about 1 in 3,200.ConclusionsDespite ongoing problems with the measurement, recording and reporting of adverse events in clinical trials and in systematic reviews, the large amount of information available for single oral doses of analgesics provides evidence that adverse events rates are generally similar with active drug and placebo in these circumstances, except at higher doses of some drugs, and in combinations including opioids. PMID- 27767118 TI - Precision of multi-frequency electronic apex locators. AB - Data sourcesCochrane Central Register of Controlled Trials, Medline, Embase and Scopus databases.Study selectionStudies that reported the precision of electronic apex locators (EALs) in locating the apical constriction (AC) in primary root canal treatment of human teeth compared with a histologic evaluation of the AC were considered.Data extraction and synthesisData were extracted and quality assessed independently by two reviewers.ResultsTen studies were included, reporting on 1105 EAL measurements. Seven studies were considered to be at high risk of bias and three at low risk. Four different EALs were evaluated; Root ZX (J Morita, Tokyo, Japan), Justy II (Hager & Werken GmbH & Co, Duisburg, Germany), Endy 5000 (Loser Co, Leverkusen, Germany) and Endox (Lysis Co, Milan, Italy). Three EALs, Root ZX, Justy II and Endy 5000 were more accurate than the Endox in determining the distance between the file tip and the apical constriction. Pulp status was only available for 194 (17.55%) of the measurements. The status of the pulp (vital or necrotic) had no significant effect on precision.ConclusionsThe precision of electronic working length measurement depends on the device used and the type of irrigation and is not influenced by the status of the pulp tissue. PMID- 27767119 TI - Antibiotics are not useful to reduce pain associated with irreversible pulpitis. AB - Data sourcesCochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Clinical Trials.gov and the WHO International Clinical Trials Registry Platform. There were no language restrictions.Study selectionRandomised controlled trials which compared the relief of pain with systemic antibiotics and analgesics against placebo and analgesics in the preoperative phase of irreversible pulpitis. The primary interest was pain control with an antibiotic or without one in the presence of analgesics. The secondary outcomes were type, dose and frequency of medication for pain relief and any adverse effects related to hypersensitivity or other reactions to either the antibiotic or analgesics.Data extraction and synthesisTwo authors independently assessed the results of the searches. Data extraction and risk bias assessment were also carried out independently. A third reviewer settled any disagreement on inclusion. Since only one study was included a meta analysis could not be performed.ResultsOnly one double blind randomised clinical trial involving 40 participants with a diagnosis of irreversible pulpitis in one of their teeth was included in this review. This was a low risk, well-constructed double blind study. Half of the participants were treated with penicillin 500 mg, the other with a placebo every six hours over a seven- day period. In addition, all the participants were instructed to initially take one tablet of ibuprofen every 4-6 hours as needed and to take acetaminophen with codeine (two tablets every 4-6 hours) only if the ibuprofen did not relieve the pain.There was no significant difference in the mean total number of ibuprofen tablets over the study period; 9.2(standard deviation (SD) 6.02) in the penicillin group versus, 9.6 (SD 6.34) in the placebo group; mean difference -0.40 (95% CI -4.23 to 3.43); P value = 0.84.The mean total number of Tylenol tablets, 6.9 (SD 6.87), used in the penicillin group versus 4.45 (SD4.42) in the placebo group; mean difference 2.45 (95%CI -1.23 to 6.13; P value = 0.19). The study did not address adverse events.ConclusionsThere is insufficient evidence to accept or refute the benefit of using penicillin to control pain intensity associated with irreversible pulpitis. This study primarily found that antibiotics given preoperatively (before definitive root canal therapy) do not appear to significantly reduce toothache caused by irreversible pulpitis. Between the two groups, those taking the antibiotics and those taking the placebo, there was no statistical difference in the amount of oral analgesics taken to relieve the pain. PMID- 27767120 TI - Psychology of behaviour change is key to effective oral health promotion. AB - Data sourcesAMED, CINAHL, Cochrane Library, Embase, Medline, PsycINFO, PsycARTICLES, ScienceDirect, SocINDEX, ASSIA, Social Policy and Practice, HMIC (Health Management Information Consortium), The Knowledge Network, Intute, MedNar, Copac, EPPI-Centre, EThOS, OpenGrey and TRIP databases. Searches were limited to publications in the English language published after 1994.Study selectionStudies set in general practice that investigated promoting good oral health in adult or child patients were considered. Study quality was assessed using NICE public health guidance checklists.Data extraction and synthesisStudies were grouped according to the evidence they offered in relation to the research questions and key findings and themes identified. No meta-analysis was conducted. Qualitative studies underwent thematic analysis. The evidence was synthesised after considering the studies' homogeneity, quality and applicability and studying the evidence tables.ResultsForty-four studies reported in 52 papers were considered. Fifteen studies were randomised controlled trials (RCTs), two cluster RCTs and one controlled trial. Five quasi-experimental studies, two before and after studies without controls, three surveys, 11 qualitative studies, three mixed methods studies, one audit and one pilot study were included.The studies were very heterogeneous; the quality of reporting highly variable with many using patient reported behaviours rather than objective measures. Follow-up periods were also short. Narrative summaries of psychological and behavioural models, verbal advice, written advice, other methods of conveying advice, message content, sender characteristics, receiver factors, 'framing' of advice, barriers and facilitators and patient satisfaction were provided.ConclusionsThe results of this review suggest that the psychology of behaviour change is the key to oral health promotion, and greater emphasis on teaching oral health professionals about health psychology would make oral health promotion in the dental surgery more effective. PMID- 27767121 TI - Breastfeeding up to 12 months of age not associated with increased risk of caries. AB - Data sourcesPubMed Central, CINAHL, Embase and reference lists of identified articles.Study selectionObservational and experimental studies published in English where breastfeeding was the exposure and development of caries was the outcome of interest were considered. Two reviewers independently selected studies for inclusionData extraction and synthesisStudy quality was assessed independently by two researchers using the Newcastle Ottawa Scale (NOS). Key data items, exposure and outcome definitions and effect estimates (odds ratios (OR), relative risks, prevalence ratios) with 95% Confidence Interval (95%CI) were abstracted where available for inclusion in a meta-analysis. The aim was to assess breastfeeding in two specific time windows; up to 12 months of age and beyond 12 months of age.ResultsSixty-three papers were included. These consisted of 14 cohort studies of which six were nested within RCTs of breastfeeding promotion interventions, three case-control studies and 46 cross-sectional studies. The studies were predominantly conducted in high and middle income countries with only eight studies from low income countries. Forty-six studies were not included in the meta-analysis because of methodological differences in the measures of exposure and outcomes, or reporting of correlational analyses only.Meta-analysis of one prospective cohort and four cross-sectional studies reported odds ratios for the association between children who were exposed to more versus less breastfeeding up to 12 months OR= 0.50; (95%CI; 0.25-0.99, I2 86.8%).In the two studies which compared ever breastfeeding in the first 12 months with never breastfeeding, both showed a marked protective effect of breastfeeding on dental caries compared with other feeding. Whereas the three studies which compared a longer duration of breastfeeding in the first 12 months to a comparison group which included children who had had some exposure to breastfeeding did not (34,52,59). A meta-analysis of this three study subgroup found OR= 0.92; (95%CI; 0.69-1.23, I2 0%)Meta-analysis of two cohort studies, one case-control study and four cross-sectional studies reported odds ratios for the association between more or less breastfeeding after the age of 12 months and dental caries.Comparison groups for these studies included both those who had never been breastfed and those who had been breastfed for shorter durations. The pooled estimate was OR= 1.99; (95% CI: 1.35-2.95, I2 69.3%).Meta-analysis of one cohort, one case-control and three cross-sectional studies reported odds ratios for the association between more versus less nocturnal breastfeeding and the risk of dental caries amongst the subgroup of children breastfed longer than 12 months. OR= 7.14; (95%CI; 3.14-16.23, I2 77.1%).ConclusionsBreastfeeding up to 12 months of age is not associated with an increased risk of dental caries and in fact may offer some protection compared with formula. However, children breastfed beyond 12 months, a time during which all deciduous teeth erupt, had an increased risk of dental caries. This may be due to other factors which are linked with prolonged breastfeeding including nocturnal feeding during sleep, cariogenic foods/drinks in the diet or inadequate oral hygiene practices. Further research with careful control of pertinent confounding factors is needed to elucidate this issue and better inform infant feeding guidelines. PMID- 27767122 TI - No evidence that magnification devices improve the success of endodontic therapy. AB - Data sourcesCochrane Oral Health group Trials Register, the Cochrane Central Register of Controlled Trials, Medline, US National Institutes of Health Trials Register, WHO-Clinical Trials Registry Platform for ongoing trials.Study selectionOnly randomised and quasi-randomised studies were pursued. No restrictions were placed on language or date of publication. The primary outcome sought was treatment success (complete healing or incomplete healing), uncertain healing and failure after one year of treatment, between one and four years and more than four years after treatment. Secondary outcomes considered for the inclusion criteria included outcomes related to the advantage of using a given magnification device in the clinical procedure such as; greater accuracy, the ease of removing broken instruments from the canal, quality of visualisation, quality of root end filling for the retrograde treatment, quality of perforation repair and the total time required for completing the clinical procedure.Data extraction and synthesisData would have been extracted by two review authors independently using a standardised data extraction form, and any disagreement would have been resolved by discussion and a third reviewer would have been consulted. Two review authors would have independently undertaken an assessment of the risk of bias.ResultsThe searches retrieved 1,234 studies. None of these satisfied the selection criteria, therefore no analysis was completed.ConclusionsNo article was identified in the current literature for the review that satisfied the inclusion criteria. It is unknown if and how the type of magnification device affects the treatment outcome considering the high number of factors that may have a significant impact on the success of endodontic therapy. PMID- 27767124 TI - Correlations in quantum thermodynamics: Heat, work, and entropy production. AB - We provide a characterization of energy in the form of exchanged heat and work between two interacting constituents of a closed, bipartite, correlated quantum system. By defining a binding energy we derive a consistent quantum formulation of the first law of thermodynamics, in which the role of correlations becomes evident, and this formulation reduces to the standard classical picture in relevant systems. We next discuss the emergence of the second law of thermodynamics under certain-but fairly general-conditions such as the Markovian assumption. We illustrate the role of correlations and interactions in thermodynamics through two examples. PMID- 27767123 TI - Differentially expressed circulating LncRNAs and mRNA identified by microarray analysis in obese patients. AB - Circulating long non-coding RNAs (lncRNAs) serve as valuable biomarkers in a number of human diseases. However, lncRNA biomarkers have yet to be identified in obesity. We aim to characterize circulating lncRNA expression in obese and non obese human subjects. First, we assessed the genome-wide circulating lncRNA expression profiles in blood from 3 obese and 3 non-obese human subjects. We found a significant decrease in circulating levels of three lncRNAs (lncRNA p5549, lncRNA-p21015 and lncRNA-p19461) in obese human subjects only. Next, using RT-PCR we measured the expression levels of these three lncRNAs in 33 obese and 33 non-obese human subjects and found similar differences. Moreover, we found a negative correlation between circulating levels of these three lncRNAs and body mass index (BMI), waist circumference, waist to hip ratio and fasting insulin. There was also a significant negative correlation between expression of lncRNA p19461 and homeostasis model assessment-estimated insulin resistance. Finally, we tested the circulating levels of these three lncRNAs in 8 obese human subjects after a 12-week diet-induced weight loss program. We found that only lncRNA p19461 expression level significantly increased. In summary, circulating lncRNAs are deregulated in obesity. Weight loss-induced changes in this profile support this observation and suggest a potential mechanistic relevance. PMID- 27767125 TI - Marginal evidence for cosmic acceleration from Type Ia supernovae. AB - The 'standard' model of cosmology is founded on the basis that the expansion rate of the universe is accelerating at present - as was inferred originally from the Hubble diagram of Type Ia supernovae. There exists now a much bigger database of supernovae so we can perform rigorous statistical tests to check whether these 'standardisable candles' indeed indicate cosmic acceleration. Taking account of the empirical procedure by which corrections are made to their absolute magnitudes to allow for the varying shape of the light curve and extinction by dust, we find, rather surprisingly, that the data are still quite consistent with a constant rate of expansion. PMID- 27767127 TI - The complexity of patient safety reporting systems in UK dentistry. AB - Since the 'Francis Report', UK regulation focusing on patient safety has significantly changed. Healthcare workers are increasingly involved in NHS England patient safety initiatives aimed at improving reporting and learning from patient safety incidents (PSIs). Unfortunately, dentistry remains 'isolated' from these main events and continues to have a poor record for reporting and learning from PSIs and other events, thus limiting improvement of patient safety in dentistry. The reasons for this situation are complex.This paper provides a review of the complexities of the existing systems and procedures in relation to patient safety in dentistry. It highlights the conflicting advice which is available and which further complicates an overly burdensome process. Recommendations are made to address these problems with systems and procedures supporting patient safety development in dentistry. PMID- 27767128 TI - Dental research: Trigeminal neuralgia. PMID- 27767131 TI - The healthcare system and the provision of oral healthcare in European Union Member States. Part 6: Poland. AB - Poland is one of the largest European countries in terms of area and population. The country's economic situation does not allow for the allocation of sufficient public funds for healthcare in general and oral healthcare in particular. The health policy of the state focuses primarily on prophylaxis and treatment of diseases, directly threatening the health and lives of the inhabitants. Currently, expenditure on oral health accounts for only 2.7% of the public funds allocated to healthcare. In this context, providing oral care financed from public funds at an appropriate level constitutes a challenge for state institutions, centres providing medical and dental services and private practices. Despite difficult financial conditions in Poland, therapeutic and prophylactic programmes are implemented, aimed at improving the oral health of the society, especially children and adolescents, pregnant women and patients with disabilities or developmental disorders such as cleft palate. In Poland, apart from the oral care system financed by the state, there is also an extremely well developed system of private practices and clinics providing clinical services on a commercial basis. In 2014, oral services, financed by the state, were utilised by about 30% of the population of children and youths aged 0-18 years (2,212,792 patients) and about 15% of the adult population (5,026,383 patients). Training of Polish dentists is conducted in ten state-owned universities, from which 700 graduate each year. Dentists work mainly in private practices or medical centres, some of which provide services guaranteed by the public insurer - the National Health Fund. The other dentists find employment in state clinics, hospitals, and universities and their associated clinics. In Poland dentistry is a predominantly female profession and 75% of the just over 40,000 Polish dentists are female. Accession of Poland to the European Union meant that some Polish dentists have taken up employment abroad. It is estimated that the most common destination is the United Kingdom (UK), where 803 Polish dentists were registered, according to the General Dental Council in 2015. PMID- 27767133 TI - Diagnosing and treatment planning inadequate tooth display. AB - Some of the most challenging patients to produce a pleasing smile for are those who present with inadequate tooth display (either due to tooth position, the patient has normal size teeth, but they aren't exposed adequately to fill out the smile) or due to tooth size (the teeth are small, often due to tooth wear). The key to understanding how to manage these patients is to learn to understand the possible aetiologies that could produce the condition, and learn how to diagnose which aetiologies exist for your patient. Potential aetiologies for inadequate tooth display in patients with normal length unworn anterior teeth: excessive lip length; inadequate lip mobility; inadequate vertical eruption of the anterior teeth; inadequate facial prominence of the maxillary anterior teeth; vertical maxillary deficiency; and anterior maxillary deficiency.This article, the first in a British Dental Journal series on the topic of aesthetic dentistry, reviews the clinical findings consistent with diagnosing each of the above etiologies, and then reviews the treatment options available for correcting the inadequate tooth display. PMID- 27767136 TI - 'Magical' developments in paediatric dentistry explored. PMID- 27767138 TI - Paul Castle. PMID- 27767140 TI - Oral surgery: Too much information. PMID- 27767141 TI - BoTN-A: The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: a systematic review with meta-analyses. AB - There is moderate evidence as to the efficacy of the use of botulinum toxin to treat trigeminal neuralgia and postherpetic neuralgia. PMID- 27767142 TI - David Robert Stirrups. PMID- 27767143 TI - Tooth wear: Plaque and caries. PMID- 27767145 TI - Dental education: Screening or discrimination? PMID- 27767147 TI - Self-regulation in dentistry and the social contract. AB - This article looks at the General Dental Council (GDC) and dental regulation from the perspective of social contract theory. Self-regulation is a requirement for the dental profession to exist within such a contract with society and this article seeks to examine the effects of the GDC upon the social contract. The GDC maintains that it is independent of the dental profession and while this may be true when discussing impartiality, the existence and purpose of the GDC is intrinsically intertwined with the dental profession. This article will show that the GDC has acted in a manner that has a negative impact upon the social contract between the dental profession and society and that for the dental profession to maintain its status and ability to place patients first, the GDC needs to re evaluate its role and attitudes. PMID- 27767148 TI - Oral trauma: Camel bite. PMID- 27767149 TI - New patient guide to cosmetic surgery launched. PMID- 27767155 TI - Access to orthodontists to be increased. PMID- 27767153 TI - Patterns of care and service use amongst children in England, Wales and Northern Ireland 2013. AB - Background The 2013 Children's Dental Health survey is the fifth in a series of national surveys.Aims This paper describes children's reported use of dental services, their experience of receiving dental treatment and parental satisfaction with services.Methodology A representative sample of children (aged 5, 8, 12 and 15 years) in England, Wales and Northern Ireland were invited to participate in dental examinations. Older children and all parents were invited to complete a questionnaire about oral health behaviours and attitudes.Results Over 80% of 12- and 15-year-olds reported attending for a check-up. According to parents, 9 in 10 children of all ages had visited a dentist in the last year and 9 in 10 parents reported they were satisfied with the last dental practice their child had visited. There was some variation by country with respect to children's experiences of fillings and extractions.Conclusions There has been little change in the reported attendance patterns of children since the 2003 survey. Family deprivation (measured by children's eligibility for free school meals) negatively influenced dental attendance for regular check-ups, attendance within the last 12 months and the likelihood of having experienced difficulties accessing NHS dental services for children. PMID- 27767152 TI - A survey of undergraduate orthodontic teaching and factors affecting pursuit of postgraduate training. AB - Background Undergraduate orthodontic teaching has been focused on developing an understanding of occlusal development in an effort to equip practitioners to make appropriate referrals for specialist-delivered care. However, there is a growing interest among general dentists in delivering more specialised treatments, including short-term orthodontic alignment. This study aimed to assess the levels of knowledge of occlusal problems among final year undergraduate dental students, as well as their interest in various orthodontics techniques and training.Methods A 36-item electronic questionnaire was sent to all final year undergraduate students in four dental institutes in the UK (Barts and the London, Kings College London, Cardiff and Dundee). The questionnaire explored satisfaction with undergraduate orthodontic teaching; students' perception of knowledge, based on General Dental Council learning outcomes; perceptions of the need for specialist involvement in the management of dental problems; interest in further training in orthodontics; and potential barriers to undertaking specialist training.Results The overall response rate was 66% (239/362). The majority of students (84.1%) were aware of GDC guidance in terms of undergraduate teaching. Students reported a preference for case-based and practical teaching sessions in orthodontics, with less interest in lectures or problem-based learning approaches. A high percentage were interested in further teaching in interceptive orthodontics (60.3%) and fixed appliance therapy (55.7%). Further training including specialist orthodontic training (36.4%), Invisalign (59%) and Six Month Smiles (41%) courses appealed to undergraduates. Levels of student debt, course fees and geographical issues were seen as potential barriers to formal, specialist training pathways.Conclusions Satisfaction with undergraduate orthodontic teaching is high and interest in further training, including specialist training pathways, continues to be high. While short-term orthodontics is not taught at undergraduate level, there appears to be an appetite to undertake alternatives to conventional orthodontics among dental students. PMID- 27767157 TI - Dragons' Den for dentists? PMID- 27767158 TI - 'State of the art' in aesthetic dentistry. PMID- 27767161 TI - Teeth Team is a real success in the North East. PMID- 27767160 TI - Defining patient-centred care in dentistry? A systematic review of the dental literature. AB - Objective This paper presents the results of a systematic review, designed to explore how patient-centred care (PCC) is defined in the dental literature.Method An electronic search of MEDLINE (1946-2012), Embase (1980-2012) PsycINFO (1806 2012), the Cochrane Library and non-peer reviewed literature was conducted using a standardised search protocol. Definitions of patient centred care were identified and scored on two criteria to evaluate quality of definition and quality/type of evidence.Results Of the 28 papers included in the review the majority provided definitions of PCC synonymous with good quality general care (holistic, humanitarian). Only three mentioned the provision of information and the tools to facilitate informed choice. Less than a third of the papers included in this review were based on empirical evidence, and of those that were, only one was an RCT study.Conclusion The evidence suggests that the concept of PCC is neither clearly understood nor empirically and systematically assessed in dental settings. Whilst most authors seem to suggest that PCC is about delivering care that is humane, involving good communication and shared decision-making, there is no work assessing these concepts empirically or relating them to practical outcomes. PMID- 27767162 TI - Antibiotic prophylaxis: Questions about NICE. PMID- 27767165 TI - Smile aesthetics: The impact of occlusal plane cant along with gingival display on smile attractiveness. AB - Inverse relationship between occlusal cant and gingival display. PMID- 27767163 TI - Guidelines for the selection, use, and maintenance of LED light-curing units - Part 1. AB - Light curing is a critical step in the restorative process when using light activated resin-based composites, but it is frequently not given the attention it deserves. The selection of a reliable light curing unit (LCU) that meets the practitioner's needs is an important equipment purchase. Using an inappropriate LCU may seriously compromise the quality of care without the practitioner realising their mistake until years later. The importance of the subject is reflected by the rapidly increasing use of light-cured composites and the decline in the use of amalgam. Many changes have occurred in the equipment and materials available for making light-cured restorations in the last twenty years. This article is part of a two-part series that will describe those changes and recommend guidelines for the selection, use, and maintenance of light emitting diode light-curing units (LED LCUs). This paper (Part 1) discusses terminology, clinical studies, the development of LCUs in dentistry, the aims of light-curing, and the need to deliver an adequate amount of energy. The interaction between light source and material is briefly described to demonstrate the complex nature of the resin photopolymerisation process. PMID- 27767166 TI - Reflection on fitness to practise. AB - Aim The focus of this review was to identify the role of reflection in continuing dental education. By understanding the expectations that our statutory regulative authority has of their registrants there is an opportunity to help to shape the continued professional development activities undertaken by current registrants in the future.Objective Conduct a review of General Dental Council (GDC) Fitness to Practise cases which were given conditions (restrictions) between February 2012 and November 2015, identifying relevant emergent outcomes in relation the Fitness to Practise (FTP) process.Design A Framework Approach (FA) was used to interrogate the qualitative data generated from GDC cases, the data were reviewed by a secondary person to ensure inter-rater reliability. Ethical approval was not sought for this research project as the GDC cases are published and available for open access via the internet. However, this does not negate the need for consideration of those GDC registrants who have been reviewed by the FTP process, indeed information regarding their identities was removed during data collection, as individual identification as part of this research project may have impacted on these individuals (bearing in mind the principle of non-maleficence; do no harm) and disclosure of personal information would not have contributed to the findings of this review. Although FTP cases are in the public domain, the information is still sensitive to those registrants, therefore it was not possible to review those cases which were not available for public view. To ensure that individual identification of registrants did not occur for the available to view cases (n = 56), each case file was individually downloaded from the GDC website and immediately given an individual numerical identifier before the frame work analysis. For the purpose of this research only the data from the FTP cases which resulted in 'conditions' were subject to review, as these were cases where it was felt that the registrants were able to remedy their personal professional practices. PMID- 27767168 TI - Post Gillick: Adolescent autonomy revisited: clinicians need clearer guidance. AB - In addition to the court, those with parental responsibility have the authority 'to override the refusal of a Gillick-competent child, if it was in his or her best interests to do so'. PMID- 27767169 TI - Dental sedation: Regional demographics. PMID- 27767170 TI - Paediatric dentistry: No added sugar. PMID- 27767172 TI - Dual PI3K/ERK inhibition induces necroptotic cell death of Hodgkin Lymphoma cells through IER3 downregulation. AB - PI3K/AKT and RAF/MEK/ERK pathways are constitutively activated in Hodgkin lymphoma (HL) patients, thus representing attractive therapeutic targets. Here we report that the PI3K/ERK dual inhibitor AEZS-136 induced significant cell proliferation inhibition in L-540, SUP-HD1, KM-H2 and L-428 HL cell lines, but a significant increase in necroptotic cell death was observed only in two out of four cell lines (L-540 and SUP-HD1). In these cells, AEZS-136-induced necroptosis was associated with mitochondrial dysfunction and reactive oxygen species (ROS) production. JNK was activated by AEZS-136, and AEZS-136-induced necroptosis was blocked by the necroptosis inhibitor necrostatin-1 or the JNK inhibitor SP600125, suggesting that JNK activation is required to trigger necroptosis following dual PI3K/ERK inhibition. Gene expression analysis indicated that the effects of AEZS 136 were associated with the modulation of cell cycle and cell death pathways. In the cell death-resistant cell lines, AEZS-136 induced the expression of immediate early response 3 (IER3) both in vitro and in vivo. Silencing of IER3 restored sensitivity to AEZS-136-induced necroptosis. Furthermore, xenograft studies demonstrated a 70% inhibition of tumor growth and a 10-fold increase in tumor necrosis in AEZS-136-treated animals. Together, these data suggest that dual PI3K/ERK inhibition might be an effective approach for improving therapeutic outcomes in HL. PMID- 27767173 TI - Euchromatin histone methyltransferase 1 regulates cortical neuronal network development. AB - Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome. PMID- 27767174 TI - Bactrocera dorsalis male sterilization by targeted RNA interference of spermatogenesis: empowering sterile insect technique programs. AB - RNA interference (RNAi) is a genetic technique which has novel application for sustainable pest control. The Sterile Insect Technique (SIT) uses releases of mass-produced, sterile male insects to out-compete wild males for mates to reduce pest populations. RNAi sterilization of SIT males would have several advantages over radiation sterilization, but to achieve this appropriate target genes must first be identified and then targeted with interference technology. With this goal, eight spermatogenesis related candidate genes were cloned and tested for potential activity in Bactrocera dorsalis. The knockdown of candidate genes by oral delivery of dsRNAs did not influence the mating of male flies, but significantly affected the daily average number of eggs laid by females, and reduced egg hatching rate by 16-60%. RNAi negatively affected spermatozoa quantitatively and qualitatively. Following the mating of lola-/topi-/rac-/rho /upd-/magu-silenced males, we recorded a significant decrease in number and length of spermatozoa in female spermatheca compared to gfp-silenced control group. In a greenhouse trial, the number of damaged oranges and B. dorsalis larvae were significantly reduced in a dsrho-treated group compared with the dsgfp group. This study provides strong evidence for the use RNAi in pest management, especially for the improvement of SIT against B. dorsalis and other species. PMID- 27767177 TI - Optimal bioenergy power generation for climate change mitigation with or without carbon sequestration. AB - Restricting global warming below 2 degrees C to avoid catastrophic climate change will require atmospheric carbon dioxide removal (CDR). Current integrated assessment models (IAMs) and Intergovernmental Panel on Climate Change scenarios assume that CDR within the energy sector would be delivered using bioenergy with carbon capture and storage (BECCS). Although bioenergy-biochar systems (BEBCS) can also deliver CDR, they are not included in any IPCC scenario. Here we show that despite BECCS offering twice the carbon sequestration and bioenergy per unit biomass, BEBCS may allow earlier deployment of CDR at lower carbon prices when long-term improvements in soil fertility offset biochar production costs. At carbon prices above $1,000 Mg-1 C, BECCS is most frequently (P>0.45, calculated as the fraction of Monte Carlo simulations in which BECCS is the most cost effective) the most economic biomass technology for climate-change mitigation. At carbon prices below $1,000 Mg-1 C, BEBCS is the most cost-effective technology only where biochar significantly improves agricultural yields, with pure bioenergy systems being otherwise preferred. PMID- 27767175 TI - Genetic polymorphisms in glycolytic pathway are associated with the prognosis of patients with early stage non-small cell lung cancer. AB - This study was conducted to investigate whether polymorphisms of genes involved in glycolysis are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Forty-four single nucleotide polymorphisms (SNPs) of 17 genes in glycolytic pathway were investigated in a total of 782 patients with NSCLC who underwent curative surgical resection. The association of the SNPs with overall survival (OS) and disease free survival (DFS) were analyzed. Among the 44 SNPs investigated, four SNPs (ENO1 rs2274971A > G, PFKM rs11168417C > T, PFKP rs1132173C > T, PDK2 rs3785921G > A) were significantly associated with survival outcomes in multivariate analyses. When stratified by tumor histology, three SNPs (ENO1 rs2274971A > G, PFKM rs11168417C > T, and PDK2 rs3785921G > A) were significantly associated with OS and/or DFS only in squamous cell carcinoma, whereas PFKP rs1132173C > T exhibited a significant association with survival outcomes only in adenocarcinoma. When the four SNPs were combined, OS and DFS decreased as the number of bad genotypes increased (Ptrend = 8 * 10-4 and 3 * 10-5, respectively). Promoter assays showed that ENO1 rs2274971G allele had significantly higher promoter activity compared to the rs2274971A allele. The four SNPs, especially ENO1 rs2274971A > G, may be useful for the prediction of prognosis in patients with surgically resected NSCLC. PMID- 27767178 TI - Platinum recycling going green via induced surface potential alteration enabling fast and efficient dissolution. AB - The recycling of precious metals, for example, platinum, is an essential aspect of sustainability for the modern industry and energy sectors. However, due to its resistance to corrosion, platinum-leaching techniques rely on high reagent consumption and hazardous processes, for example, boiling aqua regia; a mixture of concentrated nitric and hydrochloric acid. Here we demonstrate that complete dissolution of metallic platinum can be achieved by induced surface potential alteration, an 'electrode-less' process utilizing alternatively oxidative and reductive gases. This concept for platinum recycling exploits the so-called transient dissolution mechanism, triggered by a repetitive change in platinum surface oxidation state, without using any external electric current or electrodes. The effective performance in non-toxic low-concentrated acid and at room temperature is a strong benefit of this approach, potentially rendering recycling of industrial catalysts, including but not limited to platinum-based systems, more sustainable. PMID- 27767176 TI - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy. AB - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~107 primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (DeltaGG). Surprisingly, DeltaGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway. PMID- 27767179 TI - The serologically defined colon cancer antigen-3 (SDCCAG3) is involved in the regulation of ciliogenesis. AB - A primary cilium is present on most eukaryotic cells and represents a specialized organelle dedicated to signal transduction and mechanosensing. Defects in cilia function are the cause for several human diseases called ciliopathies. The serologically defined colon cancer antigen-3 (SDCCAG3) is a recently described novel endosomal protein mainly localized at early and recycling endosomes and interacting with several components of membrane trafficking pathways. Here we describe localization of SDCCAG3 to the basal body of primary cilia. Furthermore, we demonstrate that decreased expression levels of SDCCAG3 correlate with decreased ciliary length and a reduced percentage of ciliated cells. We show that SDCCAG3 interacts with the intraflagellar transport protein 88 (IFT88), a crucial component of ciliogenesis and intraciliary transport. Mapping experiments revealed that the N-terminus of SDCCAG3 mediates this interaction by binding to a region within IFT88 comprising several tetratricopeptide (TRP) repeats. Finally, we demonstrate that SDCCAG3 is important for ciliary localization of the membrane protein Polycystin-2, a protein playing an important role in the formation of polycystic kidney disease, but not for Rab8 another ciliary protein. Together these data suggest a novel role for SDCCAG3 in ciliogenesis and in localization of cargo to primary cilia. PMID- 27767180 TI - 3D texture analysis for classification of second harmonic generation images of human ovarian cancer. AB - Remodeling of the collagen architecture in the extracellular matrix (ECM) has been implicated in ovarian cancer. To quantify these alterations we implemented a form of 3D texture analysis to delineate the fibrillar morphology observed in 3D Second Harmonic Generation (SHG) microscopy image data of normal (1) and high risk (2) ovarian stroma, benign ovarian tumors (3), low grade (4) and high grade (5) serous tumors, and endometrioid tumors (6). We developed a tailored set of 3D filters which extract textural features in the 3D image sets to build (or learn) statistical models of each tissue class. By applying k-nearest neighbor classification using these learned models, we achieved 83-91% accuracies for the six classes. The 3D method outperformed the analogous 2D classification on the same tissues, where we suggest this is due the increased information content. This classification based on ECM structural changes will complement conventional classification based on genetic profiles and can serve as an additional biomarker. Moreover, the texture analysis algorithm is quite general, as it does not rely on single morphological metrics such as fiber alignment, length, and width but their combined convolution with a customizable basis set. PMID- 27767181 TI - Efficient recellularisation of decellularised whole-liver grafts using biliary tree and foetal hepatocytes. AB - A whole-organ regeneration approach, using a decellularised xenogeneic liver as a scaffold for the construction of a transplantable liver was recently reported. Deriving suitable scaffolds was the first step towards clinical application; however, effective recellularisation remains to be achieved. This report presents a strategy for the improvement of the recellularisation process, using novel cell seeding technique and cell source. We evaluated recellularised liver grafts repopulated through the portal vein or the biliary duct with mice adult hepatocytes or E14.5 foetal hepatocytes. More than 80% of the cells seeded through the biliary tree entered the parenchyma beyond the ductule-lining matrix barrier and distributed throughout the liver lobule. In contrast, about 20% of the cells seeded through the portal tree entered the parenchyma. The gene expression levels of foetal hepatocyte albumin, glucose 6-phosphatase, transferrin, cytokeratin 19, and gamma-glutamyl transpeptidase were increased in three-dimensional cultures in the native liver-derived scaffolds, and the activation of liver detoxification enzymes and formation of biliary duct-like structures were supported. The metabolic functions of liver grafts recellularised with different cell types were similar. These results suggest that biliary tree cell-seeding approach is promising, and that liver progenitor cells represent a good cell source candidate. PMID- 27767182 TI - Biofluid metabotyping of occupationally exposed subjects to air pollution demonstrates high oxidative stress and deregulated amino acid metabolism. AB - Occupational exposure to air pollution induces oxidative stress and prolonged exposure increases susceptibility to cardiovascular and respiratory diseases in several working groups. Biofluid of these subjects may reflect perturbed metabolic phenotypes. In this study we carried out a comparative molecular profiling study using parallel biofluids collected from subjects (n = 85) belonging to auto rickshaw drivers (ARD), traffic cops (TC) and office workers (OW). Higher levels of oxidative stress and inflammation markers in serum of ARD subjects were observed as compared to OW and TC. Uni and multivariate analyses of metabolites identified in urine by 1H NMR revealed 11 deregulated molecules in ARD subjects and involved in phenylalanine, histidine, arginine and proline metabolism. Despite contribution of confounding factors like exposure period, dietary factors including smoking and alcohol status, our results demonstrate existence of exposure specific metabotypes in biofluids of ARD, OW and TC groups. Monitoring serum oxidative stress and inflammation markers and urine metabolites by NMR may be useful to characterize perturbed metabolic phenotypes in populations exposed to urban traffic air pollution. PMID- 27767184 TI - Process and Microstructure to Achieve Ultra-high Dielectric Constant in Ceramic Polymer Composites. AB - Influences of process conditions on microstructure and dielectric properties of ceramic-polymer composites are systematically studied using CaCu3Ti4O12 (CCTO) as filler and P(VDF-TrFE) 55/45 mol.% copolymer as the matrix by combining solution cast and hot-pressing processes. It is found that the dielectric constant of the composites can be significantly enhanced-up to about 10 times - by using proper processing conditions. The dielectric constant of the composites can reach more than 1,000 over a wide temperature range with a low loss (tan delta ~ 10-1). It is concluded that besides the dense structure of composites, the uniform distribution of the CCTO particles in the matrix plays a key role on the dielectric enhancement. Due to the influence of the CCTO on the microstructure of the polymer matrix, the composites exhibit a weaker temperature dependence of the dielectric constant than the polymer matrix. Based on the results, it is also found that the loss of the composites at low temperatures, including room temperature, is determined by the real dielectric relaxation processes including the relaxation process induced by the mixing. PMID- 27767183 TI - Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala. AB - Molecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or 'Fear-Off' neurons during behaviour. We use cell-type-specific optogenetics and chemogenetics (DREADDs) to modulate activity in this population during behaviour to block or enhance fear extinction. Dissociated Thy1-eYFP neurons are isolated using FACS. RNA sequencing identifies genes strongly upregulated in RNA of this population, including Ntsr2, Dkk3, Rspo2 and Wnt7a. Pharmacological manipulation of neurotensin receptor 2 confirms behavioural effects observed in optogenetic and chemogenetic experiments. These experiments identify and validate Ntsr2-expressing neurons within the BLA, as a putative 'Fear-Off' population. PMID- 27767185 TI - A multimodality imaging model to track viable breast cancer cells from single arrest to metastasis in the mouse brain. AB - Cellular MRI involves sensitive visualization of iron-labeled cells in vivo but cannot differentiate between dead and viable cells. Bioluminescence imaging (BLI) measures cellular viability, and thus we explored combining these tools to provide a more holistic view of metastatic cancer cell fate in mice. Human breast carcinoma cells stably expressing Firefly luciferase were loaded with iron particles, injected into the left ventricle, and BLI and MRI were performed on days 0, 8, 21 and 28. The number of brain MR signal voids (i.e., iron-loaded cells) on day 0 significantly correlated with BLI signal. Both BLI and MRI signals decreased from day 0 to day 8, indicating a loss of viable cells rather than a loss of iron label. Total brain MR tumour volume on day 28 also correlated with BLI signal. Overall, BLI complemented our sensitive cellular MRI technologies well, allowing us for the first time to screen animals for successful injections, and, in addition to MR measures of cell arrest and tumor burden, provided longitudinal measures of cancer cell viability in individual animals. We predict this novel multimodality molecular imaging framework will be useful for evaluating the efficacy of emerging anti-cancer drugs at different stages of the metastatic cascade. PMID- 27767186 TI - Recombinant Reg3beta protein protects against streptozotocin-induced beta-cell damage and diabetes. AB - Regenerating genes (Reg) have been found during the search for factors involved in pancreatic islet regeneration. Our recent study discovered that pancreatic beta-cell-specific overexpression of Reg3beta protects against streptozotocin (Stz) -induced diabetes in mice. To investigate its potential roles in the treatment of diabetes, we produced a recombinant Reg3beta protein and provided evidence that it is active in promoting islet beta-cell survival against Stz- triggered cell death. Though ineffective in alleviating preexisting diabetes, pretreatment of recombinant Reg3beta was capable of minimizing the Stz-induced hyperglycemia and weight loss, by preserving serum and pancreatic insulin levels, and islet beta-cell mass. No obvious changes were observed in the rate of cell proliferation and hypertrophy in alpha- or acinar-cells after treatment with recombinant Reg3beta. The underlying mechanism of Reg3beta-mediated protection seems to involve Akt activation which upregulates Bcl-2 and Bcl-xL levels and consequently promotes cell survival. PMID- 27767187 TI - Management of fluoroscopy-induced radiation ulcer: One-stage radical excision and immediate reconstruction. AB - With increasing use of cardiac fluoroscopic intervention, the incidence of fluoroscopy-induced radiation ulcer is increasing. Radiation ulcer is difficult to manage and currently there are no treatment guidelines. To identify the optimal treatment approaches for managing cardiac fluoroscopy-induced radiation ulcers, we retrospectively reviewed medical records of 13 patients with fluoroscopy-induced radiation ulcers receiving surgical interventions and following up in our hospital from 2012 to 2015. Conventional wound care and hyperbaric oxygen therapy were of little therapeutic benefit. Twelve patients received reconstruction with advancement flap or split thick skin graft. One stage radical excision of radiation damaged area in eight cases with immediate reconstruction led to better outcomes than conservative excisions in four cases. Radical surgical excision to remove all the radiation damaged tissues in combination with immediate reconstruction appears to offer the optimal treatment results for cardiac fluoroscopy-induced radiation ulcers. Adequate excision of the damaged areas in both vertical (to the muscular fascia) and horizontal (beyond the sclerotic areas) dimension is pivotal to achieve good treatment outcomes. PMID- 27767188 TI - Detection of Gravitational Wave Emission by Supermassive Black Hole Binaries Through Tidal Disruption Flares. AB - Galaxy mergers produce supermassive black hole binaries, which emit gravitational waves prior to their coalescence. We perform three-dimensional hydrodynamic simulations to study the tidal disruption of stars by such a binary in the final centuries of its life. We find that the gas stream of the stellar debris moves chaotically in the binary potential and forms accretion disks around both black holes. The accretion light curve is modulated over the binary orbital period owing to relativistic beaming. This periodic signal allows to detect the decay of the binary orbit due to gravitational wave emission by observing two tidal disruption events that are separated by more than a decade. PMID- 27767189 TI - An analog of photon-assisted tunneling in a periodically modulated waveguide array. AB - We theoretically report an analog of photon-assisted tunneling (PAT) originated from dark Floquet state in a periodically driven lattice array without a static biased potential by studying a three-channel waveguide system in a non-high frequency regime. This analog of PAT can be achieved by only periodically modulating the top waveguide and adjusting the distance between the bottom and its adjacent waveguide. It is numerically shown that the PAT resonances also exist in the five-channel waveguide system and probably exist in the waveguide arrays with other odd numbers of waveguides, but they will become weak as the number of waveguides increases. With origin different from traditional PAT, this type of PAT found in our work is closely linked to the existence of the zero energy (dark) Floquet states. It is readily observable under currently accessible experimental conditions and may be useful for controlling light propagation in waveguide arrays. PMID- 27767190 TI - d-PET-controlled "off-on" Polarity-sensitive Probes for Reporting Local Hydrophilicity within Lysosomes. AB - Polarity-sensitive fluorescent probes are powerful chemical tools for studying biomolecular structures and activities both in vitro and in vivo. However, the lack of "off-on" polarity-sensing probes has limited the accurate monitoring of biological processes that involve an increase in local hydrophilicity. Here, we design and synthesize a series of "off-on" polarity-sensitive fluorescent probes BP series consisting of the difluoroboron dippyomethene (BODIPY) fluorophore connected to a quaternary ammonium moiety via different carbon linkers. All these probes showed low fluorescence quantum yields in nonpolar solution but became highly fluorescent in polar media. BP-2, which contains a two-carbon linker and a trimethyl quaternary ammonium, displayed a fluorescence intensity and quantum yield that were both linearly correlated with solvent polarity. In addition, BP-2 exhibited high sensitivity and selectivity for polarity over other environmental factors and a variety of biologically relevant species. BP-2 can be synthesized readily via an unusual Mannich reaction followed by methylation. Using electrochemistry combined with theoretical calculations, we demonstrated that the "off-on" sensing behavior of BP-2 is primarily due to the polarity-dependent donor-excited photoinduced electron transfer (d-PET) effect. Live-cell imaging established that BP-2 enables the detection of local hydrophilicity within lysosomes under conditions of lysosomal dysfunction. PMID- 27767191 TI - The first complete mitochondrial genome for the subfamily Limacodidae and implications for the higher phylogeny of Lepidoptera. AB - The mitochondrial genome (mitogenome) provides important information for understanding molecular evolution and phylogeny. To determine the systematic status of the family Limacodidae within Lepidoptera, we infer a phylogenetic hypothesis based on the complete mitogenome of Monema flavescens (Lepidoptera: Limacodidae). The mitogenome of M. flavescens is 15,396 base pairs (bp), and includes 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a control region (CR). The AT skew of this mitogenome is slightly negative and the nucleotide composition is also biased towards A + T nucleotides (80.5%). All PCGs are initiated by ATN codons, except for the cytochrome c oxidase subunit 1 (cox1) gene, which is initiated by CGA. All tRNAs display the typical clover-leaf structure characteristic of mitochondrial tRNAs, with the exception of trnS1 (AGN). The mitogenome CR is 401 bp and consists of several features common to Lepidoptera. Phylogenetic analysis using Bayesian Inference (BI) and Maximum Likelihood (ML) based on nucleotide and amino acid sequences of 13 mitochondrial PCGs indicates that M. flavescens belongs to Zygaenoidea. We obtain a well-supported phylogenetic tree consisting of Yponomeutoidea + (Tortricoidea + Zygaenoidea + (Papilionoidea + (Pyraloidea + (Noctuoidea + (Geometroidea + Bombycoidea))))). PMID- 27767192 TI - Novel Natural Product-like Caged Xanthones Bearing a Carbamate Moiety Exhibit Antitumor Potency and Anti-Angiogenesis Activity In vivo. AB - DDO-6101, a simplified structure obtained from the Garcinia natural product (NP) gambogic acid (GA), has been previously shown to possess high cytotoxicity to a variety of human tumour cell lines. To improve its physicochemical properties and in vivo cytotoxic potency, a series of novel carbamate-bearing derivatives based on DDO-6101 was synthesized and characterized. The structural modifications revealed that the presence of a carbamate moiety was useful for obtaining comparable cytotoxicity and improved aqueous solubility and permeability. 8n, which contains a bipiperidine carbamate moiety, displayed better drug properties and potential in in vivo antitumor activity. In addition, an antitumor mechanistic study suggested that 8n (DDO-6337) inhibited the ATPase activity of Hsp90 (Heat shock protein 90), leading to the inhibition of HIF-1a and ultimately contributing to its anti-angiogenesis and antitumor properties. PMID- 27767193 TI - Magnetomitotransfer: An efficient way for direct mitochondria transfer into cultured human cells. AB - In the course of mitochondrial diseases standard care mostly focuses on treatment of symptoms, while therapeutic approaches aimed at restoring mitochondrial function are currently still in development. The transfer of healthy or modified mitochondria into host cells would open up the possibilities of new cell therapies. Therefore, in this study, a novel method of mitochondrial transfer is proposed by anti-TOM22 magnetic bead-labeled mitochondria with the assistance of a magnetic plate. In comparison to the passive transfer method, the magnetomitotransfer method was more efficient at transferring mitochondria into cells (78-92% vs 0-17% over 3 days). This transfer was also more rapid, with a high ratio of magnetomitotransferred cells and high density of transferred mitochondria within the first day of culture. Importantly, transferred mitochondria appeared to be functional as they strongly enhanced respiration in magnetomitotransferred cells. The novel method of magnetomitotransfer may offer potential for therapeutic approaches for treatment of a variety of mitochondria associated pathologies, e.g. various neurodegenerative diseases. PMID- 27767194 TI - Kinesin-5 Contributes to Spindle-length Scaling in the Evolution of Cancer toward Metastasis. AB - During natural evolution, the spindles often scale with cell sizes to orchestrate accurate chromosome segregation. Whether in cancer evolution, when the constraints on genome integrity are relaxed, cancer cells may evolve the spindle to confer other advantages has not been investigated. Using invasion as a selective pressure in vitro, we found that a highly metastatic cancer clone displays a lengthened metaphase spindle, with faster spindle elongation that correlates with transiently elevated speed of cell migration. We found that kinesin-5 is upregulated in this malignant clone, and weak inhibition of kinesin 5 activity could revert the spindle to a smaller aspect ratio, decrease the speed of spindle pole separation, and suppress post-mitotic cell migration. A correlation was found between high aspect ratio and strong metastatic potential in cancers that evolved and were selected in vivo, implicating that the spindle aspect ratio could serve as a promising cellular biomarker for metastatic cancer clones. PMID- 27767195 TI - Replication of a pathogenic non-coding RNA increases DNA methylation in plants associated with a bromodomain-containing viroid-binding protein. AB - Viroids are plant-pathogenic molecules made up of single-stranded circular non coding RNAs. How replicating viroids interfere with host silencing remains largely unknown. In this study, we investigated the effects of a nuclear replicating Potato spindle tuber viroid (PSTVd) on interference with plant RNA silencing. Using transient induction of silencing in GFP transgenic Nicotiana benthamiana plants (line 16c), we found that PSTVd replication accelerated GFP silencing and increased Virp1 mRNA, which encodes bromodomain-containing viroid binding protein 1 and is required for PSTVd replication. DNA methylation was increased in the GFP transgene promoter of PSTVd-replicating plants, indicating involvement of transcriptional gene silencing. Consistently, accelerated GFP silencing and increased DNA methylation in the of GFP transgene promoter were detected in plants transiently expressing Virp1. Virp1 mRNA was also increased upon PSTVd infection in natural host potato plants. Reduced transcript levels of certain endogenous genes were also consistent with increases in DNA methylation in related gene promoters in PSTVd-infected potato plants. Together, our data demonstrate that PSTVd replication interferes with the nuclear silencing pathway in that host plant, and this is at least partially attributable to Virp1. This study provides new insights into the plant-viroid interaction on viroid pathogenicity by subverting the plant cell silencing machinery. PMID- 27767196 TI - Multilayer Dye Aggregation at Dye/TiO2 Interface via pi...pi Stacking and Hydrogen Bond and Its Impact on Solar Cell Performance: A DFT Analysis. AB - Multilayer dye aggregation at the dye/TiO2 interface of dye-sensitized solar cells is probed via first principles calculations, using p-methyl red azo dye as an example. Our calculations suggest that the multilayer dye aggregates at the TiO2 surface can be stabilized by pi...pi stacking and hydrogen bond interactions. Compared with previous two-dimensional monolayer dye/TiO2 model, the multilayer dye aggregation model proposed in this study constructs a three dimensional multilayer dye/TiO2 interfacial structure, and provides a better agreement between experimental and computational results in dye coverage and dye adsorption energy. In particular, a dimer forms by pi...pi stacking interactions between two neighboring azo molecules, while one of them chemisorbs on the TiO2 surface; a trimer may form by introducing one additional azo molecule on the dimer through a hydrogen bond between two carboxylic acid groups. Different forms of multilayer dye aggregates, either stabilized by pi...pi stacking or hydrogen bond, exhibit varied optical absorption spectra and electronic properties. Such variations could have a critical impact on the performance of dye sensitized solar cells. PMID- 27767198 TI - Hydrothermal preparation of perovskite structures DyCrO3 and HoCrO3. AB - Perovskite structured rare-earth chromites are one of the most promising families of functional materials in solid oxide fuel cells, multiferroic materials, and sensors. Here, we report a mild hydrothermal method to synthesize DyCrO3 and HoCrO3 monodispersed single crystals. The synthesis conditions, crystal structure, Raman spectra and temperature- and field-dependent magnetic properties were studied. The two samples are indexed to the Pbnm space group. The shapes of the crystals are plates with a narrow particle size distribution in the range of 4-5 MUm. Raman spectra of the samples show typical vibration modes of CrO6 clusters and stretching modes of RE3+. Temperature dependent magnetization shows a weak antiferromagnetism to paramagnetism transition at ca. 100 K for the two samples. PMID- 27767199 TI - Lectin-based lateral flow assay: proof-of-concept. AB - Lateral flow assays (LFAs) enable the simple and rapid detection and quantification of analytes and is popular for point-of-care (PoC), point-of-use and outdoor testing applications. LFAs typically depend on antibody or nucleic acid based recognition. We present the innovative concept of a LFA using lectins in the role of the biorecognition element. Lectins are a special kind of glycan binding protein and the lectin-based LFA herein described was developed for the determination of the glycosylation of free prostate specific antigen (PSA). PSA is routinely used as a biomarker of prostate cancer (PCa) and the glycosylation status of PSA is a more specific marker of disease progress than only the PSA level. Using the lectin-based LFA we were able to detect alpha-2,6 sialic acid present in fPSA using Sambucus nigra (SNA) lectin. As a negative control, we employed Maackia amurensis lectin II (MAA II) which specifically binds alpha-2,3 sialic acid. The novel approach presented here can be applied to a wide range of biomarkers that have a significant impact on clinical diagnosis and prognosis, providing an alternative to standard lectin-based assays. The assay uses commercial components and is easily performed by applying a sample to the sampling pad on the lectin-based LFA strip, with results obtained within 10 minutes. PMID- 27767200 TI - Structural snapshots in the copper(ii) induced azide-nitrile cycloaddition: effects of peripheral ligand substituents on the formation of unsupported MU1,1 azido vs.MU1,4-tetrazolato bridged complexes. AB - The azido ligand is widely used in coordination chemistry both as a ligand and as a metal-bound reactant. Its role as a bridge for magnetic exchange coupling has attracted a lot of attention in polynuclear metal complexes. However, only a very limited number of complexes are known in which a single azide anion, particularly in the MU1,1-mode, is the only unsupported connection between two metal centers. We present here a series of copper(ii)-azido complexes with amine anchored, triazole-based tripodal ligands containing varying substituents. In the mononuclear copper-azido complexes there is only a negligible effect of these substituents on the structure of the metal complexes. However, the substituents seem to play a decisive role in the type and formation of the dinuclear complexes. Using the tripodal ligand TBTA with flexible benzyl substituents resulted in a rare example of an unsupported and solely MU1,1-azido-bridged dinuclear complex. The use of the TDTA ligand with 2,6-diisopropylphenyl moieties as rigid and sterically demanding substituents resulted in the formation of a scarce example of a solely MU1,4-tetrazolato-bridged dinuclear complex by in situ cycloaddition between the azide and solvent nitrile. This observation of a reaction of unactivated aliphatic nitrile with the azide anion at room temperature is very unusual. The isolation and characterization (by means of X ray diffraction) of intermediates allows for mechanistic insights into the cycloaddition reaction. The isolated bridges in both dinuclear complexes render them ideal model compounds for the investigation of the magnetic exchange mediated by these ligands usually employed in polynuclear complexes and frameworks together with additional bridging ligands. Magnetic measurements and broken-symmetry DFT calculations were used to shed light on the magnetic exchange revealing weak and moderate antiferromagnetic exchange for the azide and tetrazolate, respectively. PMID- 27767197 TI - Multilocus sequence analysis reveals high genetic diversity in clinical isolates of Burkholderia cepacia complex from India. AB - Burkholderia cepacia complex (Bcc) is a complex group of bacteria causing opportunistic infections in immunocompromised and cystic fibrosis (CF) patients. Herein, we report multilocus sequence typing and analysis of the 57 clinical isolates of Bcc collected over the period of seven years (2005-2012) from several hospitals across India. A total of 21 sequence types (ST) including two STs from cystic fibrosis patient's isolates and twelve novel STs were identified in the population reflecting the extent of genetic diversity. Multilocus sequence analysis revealed two lineages in population, a major lineage belonging to B. cenocepacia and a minor lineage belonging to B. cepacia. Split-decomposition analysis suggests absence of interspecies recombination and intraspecies recombination contributed in generating genotypic diversity amongst isolates. Further linkage disequilibrium analysis indicates that recombination takes place at a low frequency, which is not sufficient to break down the clonal relationship. This knowledge of the genetic structure of Bcc population from a rapidly developing country will be invaluable in the epidemiology, surveillance and understanding global diversity of this group of a pathogen. PMID- 27767201 TI - Polymer versus phosphine stabilized Rh nanoparticles as components of supported catalysts: implication in the hydrogenation of cyclohexene model molecule. AB - The solution synthesis of rhodium nanoparticles (Rh NPs) was achieved from the organometallic complex [Rh(eta3-C3H5)3] under mild reaction conditions in the presence of a polymer (PVP), a monophosphine (PPh3) and a diphosphine (dppb) as a stabilizer, leading to very small Rh NPs of 2.2, 1.3 and 1.7 nm mean size, with PVP, PPh3 and dppb, respectively. The surface properties of these nanoparticles were compared using a model catalysis reaction namely, hydrogenation of cyclohexene, first under colloidal conditions and then under supported conditions after their immobilization onto an amino functionalized silica-coated magnetite support. PVP-stabilized Rh NPs were the most active catalyst whatever the catalytic conditions as a result of a strong coordination of the phosphine ligands at the metal surface that blocks some surface atoms even after several recycles of the supported nanocatalysts and limit the reactivity of the metallic surface. PMID- 27767202 TI - Quality of life after paediatric ischaemic stroke. AB - AIM: Paediatric arterial ischaemic stroke can lead to reduced quality of life (QoL). It is important to identify predictors of QoL to support recovery. We examined long-term QoL after arterial ischaemic stroke concerning different variables. METHOD: Children registered in the Swiss Neuropediatric Stroke Registry and suffering from arterial ischaemic stroke between 2000 and 2008 were included. Two years post-stroke, assessments included intelligence quotient tests for cognitive impairment and modified Rankin Scale (mRS) for neurological impairment; 5 years post-stroke, the Kidscreen-27 was used for QoL, DSM-IV criteria screening was used for attention deficits, and the ABILHAND-Kids was used for manual motor skills. Age at stroke, sex, socioeconomic status, lesion characteristics, neuropsychological and motor outcome, and mRS were correlated with QoL measures. RESULTS: Seventy children were examined (49 males, 21 females; mean age 7y 2wks). Age at stroke, sex, socioeconomic status, and lesion characteristics did not influence QoL; IQ below average and attention deficits partially influenced QoL. The highest predictive value for QoL was found for manual motor impairment (p=0.002) and mRS scores (p=0.013). Combined motor, cognitive, and attention impairment negatively affected QoL (p=0.001). INTERPRETATION: Neurological and cognitive impairments after paediatric arterial ischaemic stroke negatively influence QoL. Children with motor and neurological problems, as well as those with combined motor, cognitive, and attention problems, are at higher risk for low QoL. PMID- 27767203 TI - Access to Care for Medicare-Medicaid Dually Eligible Beneficiaries: The Role of State Medicaid Payment Policies. AB - STUDY OBJECTIVES: Medicaid programs are not required to pay the full Medicare coinsurance and deductibles for Medicare-Medicaid dually eligible beneficiaries. We examined the association between the percentage of Medicare cost sharing paid by Medicaid and the likelihood that a dually eligible beneficiary used evaluation and management (E&M) services and safety net provider services. DATA SOURCES: Medicare and Medicaid Analytic eXtract enrollment and claims data for 2009. STUDY DESIGN: Multivariate analyses used fee-for-service dually eligible and Medicare only beneficiaries in 20 states. A comparison group of Medicare-only beneficiaries controlled for state factors that might influence utilization. PRINCIPAL FINDINGS: Paying 100 percent of the Medicare cost sharing compared to 20 percent increased the likelihood (relative to Medicare-only) that a dually eligible beneficiary had any E&M visit by 6.4 percent. This difference in the percentage of cost sharing paid decreased the likelihood of using safety net providers, by 37.7 percent for federally qualified health centers and rural health centers, and by 19.8 percent for hospital outpatient departments. CONCLUSIONS: Reimbursing the full Medicare cost-sharing amount would improve access for dually eligible beneficiaries, although the magnitude of the effect will vary by state and type of service. PMID- 27767205 TI - Disparities in Diabetes Care Quality by English Language Preference in Community Health Centers. AB - OBJECTIVE: To conduct a parallel analysis of disparities in diabetes care quality among Latino and Asian community health center (CHC) patients by English language preference. STUDY SETTING/DATA COLLECTION: Clinical outcomes (2011) and patient survey data (2012) for Type 2 diabetes adults from 14 CHCs (n = 1,053). STUDY DESIGN: We estimated separate regression models for Latino and Asian patients by English language preference for Clinician & Group-Consumer Assessment of Healthcare Providers and System, Patient Assessment of Chronic Illness Care, hemoglobin A1c, and self-reported hypoglycemic events. We used the Blinder-Oaxaca decomposition method to parse out observed and unobserved differences in outcomes between English versus non-English language groups. PRINCIPAL FINDINGS: After adjusting for socioeconomic and health characteristics, disparities in patient experiences by English language preference were found only among Asian patients. Unobserved factors largely accounted for linguistic disparities for most patient experience measures. There were no significant differences in glycemic control by language for either Latino or Asian patients. CONCLUSIONS: Given the importance of patient retention in CHCs, our findings indicate opportunities to improve CHC patients' experiences of care and to reduce disparities in patient experience by English preference for Asian diabetes patients. PMID- 27767207 TI - Risk of osteoporosis in elderly individuals attending a dental clinic. AB - OBJECTIVE: Osteoporosis has become a critical public health problem with the rapidly aging population in Japan. It is necessary for dentists to know their patients' status because it influences dental treatment. The purpose of this study was to predict the risk of osteoporosis in elderly patients visiting a dental clinic by assessing mandibular cortical morphology on panoramic radiographs. METHOD: Three-hundred and thirty patients were divided into three classes based on the morphology of their mandibular cortex on panoramic radiographs. Mandibular cortical bone width at the mental foramen was also measured. Bone mineral density (BMD) was determined at the calcaneus using a quantitative ultrasound device. RESULTS: The mandibular cortical width decreased significantly from Class 1 (normal cortex), to Class 2 (moderately eroded cortex) and to Class 3 (severely eroded cortex). BMD was negatively correlated with age in both female and male patients. Most (108/186) female patients had a class 3 cortex with a low BMD. Among women, mandibular cortical width was significantly correlated with BMD. Thirty-three percent of the female had received a previous diagnosis of osteoporosis. In contrast, only 13.9% (20/144) of the male had a Class 3 cortex. In men, mandibular cortical width did not significantly correlate with BMD. Only a few of the men had received a previous diagnosis of osteoporosis. The number of remaining teeth did not correlate with low BMD in either sex. CONCLUSION: Our findings reveal that most elderly female patients visiting the dental clinic had a high risk of osteoporosis and a low BMD. PMID- 27767206 TI - Reliability and discriminant validity of ataxia rating scales in early onset ataxia. AB - AIM: To determine whether ataxia rating scales are reliable disease biomarkers for early onset ataxia (EOA). METHOD: In 40 patients clinically identified with EOA (28 males, 12 females; mean age 15y 3mo [range 5-34y]), we determined interobserver and intraobserver agreement (interclass correlation coefficient [ICC]) and discriminant validity of ataxia rating scales (International Cooperative Ataxia Rating Scale [ICARS], Scale for Assessment and Rating of Ataxia [SARA], and Brief Ataxia Rating Scale [BARS]). Three paediatric neurologists independently scored ICARS, SARA and BARS performances recorded on video, and also phenotyped the primary and secondary movement disorder features. When ataxia was the primary movement disorder feature, we assigned patients to the subgroup 'EOA with core ataxia' (n=26). When ataxia concurred with other prevailing movement disorders (such as dystonia, myoclonus, and chorea), we assigned patients to the subgroup 'EOA with comorbid ataxia' (n=12). RESULTS: ICC values were similar in both EOA subgroups of 'core' and 'comorbid' ataxia (0.92 0.99; ICARS, SARA, and BARS). Independent of the phenotype, the severity of the prevailing movement disorder predicted the ataxia rating scale scores (beta=0.83 0.88; p<0.05). INTERPRETATION: In patients with EOA, the reliability of ataxia rating scales is high. However, the discriminative validity for 'ataxia' is low. For adequate interpretation of ataxia rating scale scores, application in uniform movement disorder phenotypes is essential. PMID- 27767204 TI - Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful? AB - LINKED ARTICLES: This article is commented on in the editorial by Holford NHG and Anderson BJ. Why standards are useful for predicting doses. Br J Clin Pharmacol 2017; 83: 685-7. doi: 10.1111/bcp.13230 AIM: When different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model-based meta-analyses. This study aimed to compare published models with the proposed standard model (allometric weight0.75 and sigmoidal maturation function). METHODS: A systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison, we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike information criteria (AIC) and visual predictive checks were used for evaluation. RESULTS: No model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters), -4.1 (5), -9.2 (4), -10.8 (5) and -10.1 (5), respectively. The 95% confidence interval of estimated CL for all top performing models overlapped. CONCLUSION: No evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended. PMID- 27767208 TI - Is the switch to an ectomycorrhizal state an evolutionary key innovation in mushroom-forming fungi? A case study in the Tricholomatineae (Agaricales). AB - Although fungi are one of the most diverse groups of organisms, little is known about the processes that shape their high taxonomic diversity. This study focuses on evolution of ectomycorrhizal (ECM) mushroom-forming fungi, symbiotic associates of many trees and shrubs, in the suborder Tricholomatineae of the Agaricales. We used the BiSSE model and BAMM to test the hypothesis that the ECM habit represents an evolutionary key innovation that allowed the colonization of new niches followed by an increase in diversification rate. Ancestral state reconstruction (ASR) supports the ancestor of the Tricholomatineae as non-ECM. We detected two diversification rate increases in the genus Tricholoma and the Rhodopolioid clade of the genus Entoloma. However, no increases in diversification were detected in the four other ECM clades of Tricholomatineae. We suggest that diversification of Tricholoma was not only due to the evolution of the ECM lifestyle, but also to the expansion and dominance of its main hosts and ability to associate with a variety of hosts. Diversification in the Rhodopolioid clade could be due to the unique combination of spore morphology and ECM habit. The spore morphology may represent an exaptation that aided spore dispersal and colonization. This is the first study to investigate rate shifts across a phylogeny that contains both non-ECM and ECM lineages. PMID- 27767210 TI - Morphology and phylogeny of a new wall-less freshwater volvocalean flagellate, Hapalochloris nozakii gen. et sp. nov. (Volvocales, Chlorophyceae). AB - New strains of a wall-less unicellular volvocalean flagellate were isolated from a freshwater environment in Japan. Observations of the alga, described here as Hapalochloris nozakii Nakada, gen. et sp. nov., were made using light, fluorescence, and electron microscopy. Each vegetative cell had two flagella, four contractile vacuoles, and a spirally furrowed cup-shaped chloroplast with an axial pyrenoid, and mitochondria located in the furrows. Based on the morphology, H. nozakii was distinguished from other known wall-less volvocalean flagellates. Under electron microscopy, fibrous material, instead of a cell wall and dense cortical microtubules, was observed outside and inside the cell membrane, respectively. Based on the phylogenetic analyses of 18S rRNA gene sequences, H. nozakii was found to be closely related to Asterococcus, Oogamochlamys, Rhysamphichloris, and "Dunaliella" lateralis and was separated from other known wall-less flagellate volvocaleans, indicating independent secondary loss of the cell wall in H. nozakii. In the combined 18S rRNA and chloroplast gene tree, H. nozakii was sister to Lobochlamys. PMID- 27767209 TI - Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials. AB - KEY POINTS: We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive. Neurones in the principal olivary nucleus receive monosynaptic extra-somatic glutamatergic input from the neocortex. Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component. Small conductance calcium-activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals <= 20 ms. Active integration of synaptic input within the inferior olive may play a central role in control of olivo-cerebellar climbing fibre signals. ABSTRACT: The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long-range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium-activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium-activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals <= 20 ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours. PMID- 27767212 TI - In reference to Asbestos exposure and laryngeal cancer mortality. PMID- 27767211 TI - FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension. AB - KEY POINTS: Muscle atrophy is a debilitating condition that affects a high percentage of the population with a negative impact on quality of life. Dissecting the molecular level of the atrophy process, and the similarities/dissimilarities among different catabolic conditions, is a necessary step for designing specific countermeasures to attenuate/prevent muscle loss. The FoxO family transcription factors represent one of the most important regulators of atrophy programme stimulating the expression of many atrophy-related genes. The findings of the present study clearly indicate that the signalling network controlling the atrophy programme is specific for each catabolic condition. ABSTRACT: Muscle atrophy is a complex process that is in common with many different catabolic diseases including disuse/inactivity and ageing. The signalling pathways that control the atrophy programme in the different disuse/inactivity conditions have not yet been completely dissected. The inhibition of FoxO is considered to only partially spare muscle mass after denervation. The present study aimed: (i) to determine the involvement of FoxOs in hindlimb suspension disuse model; (ii) to define whether the molecular events of protein breakdown are shared among different unloaded muscles; and finally (iii) to compare the data obtained in this model with another model of inactivity such as denervation. Both wild-type and muscle-specific FoxO1,3,4 knockout (FoxO1,3,4-/- ) mice were unloaded for 3 and 14 days and muscles were characterized by functional, morphological, biochemical and molecular assays. The data obtained show that FoxOs are required for muscle loss and force drop during unloading. Moreover, we found that FoxO-dependent atrogenes vary in different unloaded muscles and that they diverge from denervation. The findings of the present study clearly indicate that the signalling network that controls the atrophy programme is specific for each catabolic condition. PMID- 27767213 TI - The copper microRNAs. AB - 1030 I. 1030 II. 1030 III. 1031 IV. 1031 V. 1032 VI. 1033 VII. 1034 VIII. 1034 1034 References 1034 SUMMARY: Copper (Cu) microRNAs are upregulated by Cu deficiency and mediate the post-transcriptional downregulation of transcripts that encode Cu proteins, suggesting a role directly related to Cu. However, expression and phenotypic analyses of copper microRNA mutants and over-expressors have suggested roles mainly in tolerance to abiotic stresses. To reconcile available data, a model is proposed which emphasizes the mobile nature of copper microRNA molecules in the regulation of Cu homeostasis. It is proposed that the Cu-microRNA regulatory circuits are further co-opted by plants to regulate both beneficial and pathogenic interactions with microbes. Further exploration of Cu microRNA functions that account for the cell-to-cell mobility should give novel insight into plant microbe interactions and the integration of micronutrition and development. PMID- 27767216 TI - Systematic review for surgical treatment of adult and adolescent laryngotracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: To determine if open surgical treatment options for adult and adolescent laryngotracheal stenosis are more successful than endoscopic procedures. STUDY DESIGN: Systematic review. METHODS: Embase and MEDLINE were searched for publications on adult and adolescent patients (>13 years old) with laryngotracheal stenosis. Cause of stenosis (intubation, idiopathic, or trauma) and treatments (open laryngotracheal resection with anastomosis, open laryngotracheal reconstruction with expansion grafting, or endoscopic procedures) were included. Primary outcomes are decreased additional surgery performed and success of decannulation, if previously tracheostomy. RESULTS: There were 297 abstracts reviewed, 104 articles selected for full-text review, and 39 articles, with 834 pooled patients, included in the analysis. Patients who had an open procedure (resection with anastomosis or reconstruction with expansion grafting) had significantly different outcomes rates; 32% versus 38% (P <.001) received additional surgery and 89%and 83% (P <.001) were decannulated, respectively. For patients who had endoscopic repair, 44% received additional surgery, and 63% were decannulated. Patients with idiopathic stenosis were more likely to receive additional surgery than those with traumatic (54% vs. 25%) and intubation/tracheostomy etiologies (54% vs. 35%). Etiology of stenosis did affect decannulation rates, patients with intubation/tracheostomy etiology had decannulation rates of 88%, compared to traumatic etiologies (78%, P <.001) and idiopathic stenosis (63%, P <.001). Risk of bias did not impact study results and was assessed using a validated instrument, Methodological Index for Non randomized Studies criteria. CONCLUSIONS: Patients with adult laryngotracheal stenosis who undergo laryngotracheal resection with anastomosis receive less surgery compared to those who undergo endoscopic treatment or laryngotracheal reconstruction with augmentation/grafting. Patients with idiopathic stenosis are less likely to receive further surgery compared to those from trauma or intubation/tracheostomy, but have the lowest rate of decannulation. LEVEL OF EVIDENCE: NA Laryngoscope, 127:191-198, 2017. PMID- 27767215 TI - Patch testing with hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) - a multicentre study of the Swedish Contact Dermatitis Research Group. AB - BACKGROUND: In 2014, the fragrance hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) was excluded from the Swedish baseline series. OBJECTIVES: To study (i) whether fragrance mix (FM) II with 5% HICC detects more positive reactions than usual FM II with 2.5% HICC, and (ii) the reproducibility of patch testing with HICC. METHODS: Two thousand one hundred and eighteen dermatitis patients at five Swedish dermatology departments were consecutively tested with FM II 14% pet., FM II 16.5% pet., and duplicate preparations of HICC 5% pet. RESULTS: Of the patients, 3.2% reacted to FM II 14%, and 1.5% reacted to HICC. Separate testing with HICC detected 0.3% reactions without concomitant reactivity to FM II. FM II with 5% HICC did not give rise to more irritant reactions or signs of active sensitization than FM II with 2.5% HICC. Patch testing with duplicate applications of HICC increased the overall prevalence of HICC contact allergy to 1.9%. CONCLUSION: FM II with 5% HICC does not detect more positive reactions than FM II with 2.5% HICC. Separate testing with HICC does not detect a sufficient proportion of patients who react only to HICC, without concomitant reactions to FM II, to warrant its inclusion in a baseline series. PMID- 27767218 TI - Bioethics, General Ethics and CAM. PMID- 27767219 TI - Assisted Suicide in Switzerland: Clarifying Liberties and Claims. AB - Assisting suicide is legal in Switzerland if it is offered without selfish motive to a person with decision-making capacity. Although the 'Swiss model' for suicide assistance has been extensively described in the literature, the formally and informally protected liberties and claims of assistors and recipients of suicide assistance in Switzerland are incompletely captured in the literature. In this article, we describe the package of rights involved in the 'Swiss model' using the framework of Hohfeldian rights as modified by Wenar. After outlining this framework, we dissect the rights involved in suicide assistance in Switzerland, and compare it with the situation in England and Germany. Based on this approach, we conclude that in Switzerland, claim rights exist for those requesting suicide assistance, and for those who are considering providing such assistance, even though no entitlements exist toward suicide assistance. We then describe the implementation of the 'Swiss model' and difficulties arising within it. Clarifying these issues is important to understand the Swiss situation, to evaluate what features of it may or may not be worth correcting or emulating, and to understand how it can impact requests for suicide assistance in other countries due to 'suicide tourism'. It is also important to understand exactly what sets Switzerland apart from other countries with different legislations regarding suicide assistance. PMID- 27767217 TI - Applicant characteristics associated with successful matching into otolaryngology. AB - OBJECTIVE: To identify resident applicant characteristics that increase the odds of matching to otolaryngology residency. STUDY DESIGN: Cross-sectional analysis. METHODS: Residency applications to our institution from 2009 through 2013 were reviewed. The available data represented 81.1% of applicants to otolaryngology programs nationwide. Online public records were searched to determine whether an applicant matched to an otolaryngology residency position. Factors that were significantly associated with the odds of matching were determined using logistic regression. RESULTS: A total of 1,479 unique applications were analyzed. On univariate analysis, 27 demographic, academic, personal, medical school, prior training, and application-specific factors were associated with the odds of matching into otolaryngology. On multivariate analysis, indicators of academic achievement, such as Alpha Omega Alpha Honor Medical Society (AOA) status, whether applicant received awards, and publications, were significantly associated with the odds of matching (odds ratio [OR] 2.03, 1.39, 1.66, respectively). The odds of matching increased with increasing step 1 scores (P < 0.001). Attending a medical school ranked by the U.S. News & World Report and being a U.S. citizen born in the United States significantly increased the odds of matching (OR 1.55 and 2.04, respectively), whereas being a non-U.S. senior medical student significantly decreased the odds of matching (OR 0.33). CONCLUSION: Multiple factors are associated with successfully matching into an otolaryngology residency. Although this information allows medical students to determine the strength of their application, these criteria have not been correlated with resident success. We urge selection committees to begin identifying applicant selection methods that reflect the values we want to cultivate in our future colleagues. LEVEL OF EVIDENCE: N/A. Laryngoscope, 127:1052-1057, 2017. PMID- 27767214 TI - Cajal body function in genome organization and transcriptome diversity. AB - Nuclear bodies contribute to non-random organization of the human genome and nuclear function. Using a major prototypical nuclear body, the Cajal body, as an example, we suggest that these structures assemble at specific gene loci located across the genome as a result of high transcriptional activity. Subsequently, target genes are physically clustered in close proximity in Cajal body-containing cells. However, Cajal bodies are observed in only a limited number of human cell types, including neuronal and cancer cells. Ultimately, Cajal body depletion perturbs splicing kinetics by reducing target small nuclear RNA (snRNA) transcription and limiting the levels of spliceosomal snRNPs, including their modification and turnover following each round of RNA splicing. As such, Cajal bodies are capable of shaping the chromatin interaction landscape and the transcriptome by influencing spliceosome kinetics. Future studies should concentrate on characterizing the direct influence of Cajal bodies upon snRNA gene transcriptional dynamics. Also see the video abstract here. PMID- 27767220 TI - Misplaced Paternalism and other Mistakes in the Debate over Kidney Sales. AB - Erik Malmqvist defends the prohibition on kidney sales as a justifiable measure to protect individuals from harms they have not autonomously chosen. This appeal to 'group soft paternalism' requires that three conditions be met. It must be shown that some vendors will be harmed, that some will be subject to undue pressure to vend, and that we cannot feasibly distinguish between the autonomous and the non-autonomous. I argue that Malmqvist fails to demonstrate that any of these conditions are likely to obtain. His argument involves two common errors. First, he, like many, proceeds on a mistaken understanding of how to assess harm. What matters is not the balance of costs and benefits of vending, but a comparison of potential vendors' welfare across two possible courses of action. Second, Malmqvist's concerns about third-party pressure are predicated on an empirically unrealistic understanding of the operation of a regulated market. A widely underappreciated fact is that kidney sales will be relatively rare, and most who try to vend will be unable to. Because pressure on another to vend will not result in the desired outcome, few will exert it. PMID- 27767221 TI - From Gutenberg to Open Science: An Unfulfilled Odyssey. AB - Preclinical Research With the almost global availability of the Internet comes the expectation of universal accessibility to knowledge, including scientific knowledge-particularly that generated by public funding. Currently this is not the case. In this Commentary we discuss access to this knowledge, the politics that govern peer review and publication, and the role of this knowledge as a public good in medicine. Gutenberg's invention of the printing press in 1440 opened an avenue for the distribution of scholarly information to the entire world. The scientific literature first appeared in 1665 with Le Journal des Scavans followed in the same year by Philosophical Transactions. Today there are more than 5000 scientific publishing companies, 25,000 journals and 1.5 million articles published/year generating revenue of $25 billion USD. The European Union and the Organization for Economic Cooperation and Development have argued for open access (OA) to scientific data for all publicly funded research by 2020 with a similar initiative in the USA via the Fair Access to Science and Technology Research Act (FASTR). However, OA to published science is but one step in this odyssey. If the products of science are not openly available then it can be argued that the norms of science as defined by Merton including "universalism" and "communalism" have yet to be accomplished. Nowhere is this more apparent than in the delivery of medicines to the poor and for rare diseases, the attempts to privatize human genetic information and, not least, dealing with the challenges of antibiotic resistance and new disease pandemics exacerbated by climate change. Drug Dev Res 78 : 3-23, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27767223 TI - Host innate immunity: More a need to feed the world (comment on DOI: 10.1002/bies.201600101). PMID- 27767222 TI - Long-term clinical response to treatment and maintenance of localized aggressive periodontitis: a cohort study. AB - AIM: To evaluate long-term clinical response to periodontal therapy and maintenance in localized aggressive periodontitis (LAP). MATERIALS AND METHODS: One hundred forty-one African Americans diagnosed with LAP, aged 5-25 years, were enrolled. Patients underwent periodontal mechanical debridement plus 1 week of amoxicillin/metronidazole. Mechanical therapy was repeated as needed and clinical parameters were recorded at baseline, 3, 6, 12, 18 and 24 months, and two additional annual follow-up visits after treatment. Radiographs from primary dentition of patients with LAP in permanent dentition, and additional healthy siblings (HS) were analysed retrospectively. RESULTS: Periodontal therapy significantly improved probing depth and clinical attachment level up to 4 years (mean reductions: 2.18 +/- 1.03 and 2.80 +/- 1.43 mm, respectively). Percentage of affected sites was reduced at all time points and maintained up to 4 years. Non-compliance with antibiotics/appointments negatively affected the treatment response. Ninety per cent of LAP patients in permanent dentition and 32% of HS presented radiographic bone loss in primary dentition. CONCLUSIONS: Mechanical debridement with 1 week of systemic antibiotics along with proper periodontal maintenance was effective in the treatment and successful maintenance of LAP for up to 4 years. LAP in permanent dentition may be preceded in the primary dentition. Clinicaltrials.gov #NCT01330719. PMID- 27767224 TI - Ethical, Legal, and Social Implications of Personalized Genomic Medicine Research: Current Literature and Suggestions for the Future. AB - PURPOSE: This review identifies the prominent topics in the literature pertaining to the ethical, legal, and social issues (ELSI) raised by research investigating personalized genomic medicine (PGM). METHODS: The abstracts of 953 articles extracted from scholarly databases and published during a 5-year period (2008 2012) were reviewed. A total of 299 articles met our research criteria and were organized thematically to assess the representation of ELSI issues for stakeholders, health specialties, journals, and empirical studies. RESULTS: ELSI analyses were published in both scientific and ethics journals. Investigational research comprised 45% of the literature reviewed (135 articles) and the remaining 55% (164 articles) comprised normative analyses. Traditional ELSI concerns dominated the discourse including discussions about disclosure of research results. In fact, there was a dramatic increase in the number of articles focused on the disclosure of research results and incidental findings to research participants. Few papers focused on particular disorders, the use of racial categories in research, international communities, or special populations (e.g., adolescents, elderly patients, or ethnic groups). CONCLUSION: Considering that strategies in personalized medicine increasingly target individuals' unique health conditions, environments, and ancestries, further analysis is needed on how ELSI scholarship can better serve the increasingly global, interdisciplinary, and diverse PGM research community. PMID- 27767226 TI - Time to Take Another Serious Look at Conscientious Objection. PMID- 27767228 TI - Predictors of left ventricular systolic function recovery in the setting of sinus tachycardia in patients with cancer. AB - OBJECTIVES: To identify unique echocardiographic features that could be used to reliably predict LVEF recovery upon resolution of sinus tachycardia in patients with cancer. BACKGROUND: Sinus tachycardia may be a manifestation of underlying cardiomyopathy or can lead to a reversible form of dilated cardiomyopathy known as tachycardia-mediated cardiomyopathy. While distinguishing the two can be challenging, predicting recovery regardless of cause can be of significant clinical importance in the cancer population. METHODS: Results of echocardiograms performed were collected. Patients with a repeat echocardiogram within 6 months of the initial echocardiogram were included. Patients with structural heart disease, acute coronary syndrome, sepsis, and pericardial disease were excluded. A comparison between baseline echocardiogram and subsequent echocardiogram was made to determine whether specific echocardiographic parameters predicted LVEF recovery. Two groups of patients were defined at the outset of the study. The recovered group was comprised of patients with reduced LVEF in the setting of sinus tachycardia and normal LVEF with resolution of tachycardia to normal sinus rhythm (NSR). The unrecovered group was comprised of subjects with low LVEF in the setting of both sinus tachycardia and NSR. RESULTS: A total of 40 patients were included in the study. LVEF in the recovered group (n=18) was 42.8% with sinus tachycardia and increased to 58.3% with NSR. Average LVEF in the unrecovered group (n=22) was 35.1% with tachycardia and improved to 38.5% with NSR. Medial TDI (E') was significantly greater in the recovered group with both tachycardia (7.95 cm/s versus 4.56 cm/s, P<.001) and NSR (8.11 cm/s versus 5.13 cm/s, P<.001). Similarly, lateral TDI (E') was significantly greater in the recovered group than in the unrecovered group during tachycardia (8.97 cm/s versus 5.13 cm/s, P<.001) and NSR (9.05 cm/s versus 5.13 cm/s, P<.001). Multivariable logistic regression analysis showed that medial TDI >6.5 cm/s (OR=30.9, P=.001) and lateral TDI >7.8 cm/s (OR=52.5, P=.002) are positively associated with the probability of LVEF recovery. CONCLUSIONS: In conclusion, TDI (medial E'>6.5 cm/s; lateral E'>7.8 cm/s) appears to predict LVEF recovery in patients with sinus tachycardia upon resolution of the tachycardia in patients with cancer. PMID- 27767229 TI - Anionic Oligothiophenes Compete for Binding of X-34 but not PIB to Recombinant Abeta Amyloid Fibrils and Alzheimer's Disease Brain-Derived Abeta. AB - Deposits comprised of amyloid-beta (Abeta) are one of the pathological hallmarks of Alzheimer's disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X-34, a Congo Red analogue, but not Pittsburgh compound B (PIB) from recombinant Abeta amyloid fibrils and Alzheimer's disease brain-derived Abeta. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high-affinity ligands for Abeta pathology only found in human AD brain, targeting a different site than PIB. PMID- 27767230 TI - A school-based programme for tobacco and alcohol prevention in special education: effectiveness of the modified 'healthy school and drugs' intervention and moderation by school subtype. AB - AIMS: To test the effectiveness of the Healthy School and Drugs (HSD) programme on tobacco and alcohol use in Dutch secondary special education (SE) schools, and whether this depends upon subtypes of SE schools and the level of implementation. DESIGN: In a quasi-experimental design with baseline and post-treatment follow up, 363 students were allocated arbitrarily or depending on teacher motivation to either intervention condition (n = 205) or usual curriculum (n = 158). SETTING: Thirteen secondary SE schools spread throughout the Netherlands. PARTICIPANTS: Participants were recruited during the autumn of 2013 from three school subtypes: SE for adolescents with intellectual/physical disabilities (SEI; n = 13), behavioural/emotional difficulties (SEB; n = 136) and learning disabilities/developmental disorders (SEL; n = 214). MEASUREMENTS: Self-reported life-time smoking prevalence and life-time drinking frequency as outcomes, and school subtype (SEL/SEB) and implementation fidelity (high/low) as moderators. FINDINGS: No significant differences were found at follow-up in life-time smoking [odds ratio (OR) = 1.52; 95% confidence interval (CI) = 0.74-3.12] and drinking frequency (d = 0.01; 95% CI = -0.16 to 0.18). Interaction analyses revealed adverse effects in SEB students for alcohol use (d = 0.43; 95% CI = 0.16-0.69). Effect on tobacco refusal self-efficacy was moderated positively by implementation fidelity (d = 0.35; 95% CI = 0.07-0.63). CONCLUSION: The Healthy School and Drugs programme adapted for secondary special education in the Netherlands lacked clear evidence for effects on all outcomes. This pilot study suggests further that, within special education, substance use interventions may need to be targeted at school subtypes, as these may have harmful effects among students with behavioural difficulties. Finally, limited evidence was found that programme effectiveness may depend upon implementation fidelity. PMID- 27767232 TI - Comparative electrophysiology of retinal Muller glial cells-A survey on vertebrate species. AB - Muller cells are the dominant macroglial cells in the retina of all vertebrates. They fulfill a variety of functions important for retinal physiology, among them spatial buffering of K+ ions and uptake of glutamate and other neurotransmitters. To this end, Muller cells express inwardly rectifying K+ channels and electrogenic glutamate transporters. Moreover, a lot of voltage- and ligand-gated ion channels, aquaporin water channels, and electrogenic transporters are expressed in Muller cells, some of them in a species-specific manner. For example, voltage-dependent Na+ channels are found exclusively in some but not all mammalian species. Whereas a lot of data exist from amphibians and mammals, the results from other vertebrates are sparse. It is the aim of this review to present a survey on Muller cell electrophysiology covering all classes of vertebrates. The focus is on functional studies, mainly performed using the whole cell patch-clamp technique. However, data about the expression of membrane channels and transporters from immunohistochemistry are also included. Possible functional roles of membrane channels and transporters are discussed. Obviously, electrophysiological properties involved in the main functions of Muller cells developed early in vertebrate evolution. GLIA 2017;65:533-568. PMID- 27767233 TI - Forest management scenarios in a changing climate: trade-offs between carbon, timber, and old forest. AB - Balancing economic, ecological, and social values has long been a challenge in the forests of the Pacific Northwest, where conflict over timber harvest and old growth habitat on public lands has been contentious for the past several decades. The Northwest Forest Plan, adopted two decades ago to guide management on federal lands, is currently being revised as the region searches for a balance between sustainable timber yields and habitat for sensitive species. In addition, climate change imposes a high degree of uncertainty on future forest productivity, sustainability of timber harvest, wildfire risk, and species habitat. We evaluated the long-term, landscape-scale trade-offs among carbon (C) storage, timber yield, and old forest habitat given projected climate change and shifts in forest management policy across 2.1 million hectares of forests in the Oregon Coast Range. Projections highlight the divergence between private and public lands under business-as-usual forest management, where private industrial forests are heavily harvested and many public (especially federal) lands increase C and old forest over time but provide little timber. Three alternative management scenarios altering the amount and type of timber harvest show widely varying levels of ecosystem C and old-forest habitat. On federal lands, ecological forestry practices also allowed a simultaneous increase in old forest and natural early-seral habitat. The ecosystem C implications of shifts away from current practices were large, with current practices retaining up to 105 Tg more C than the alternative scenarios by the end of the century. Our results suggest climate change is likely to increase forest productivity by 30-41% and total ecosystem C storage by 11-15% over the next century as warmer winter temperatures allow greater forest productivity in cooler months. These gains in C storage are unlikely to be offset by wildfire under climate change, due to the legacy of management and effective fire suppression. Our scenarios of future conditions can inform policy makers, land managers, and the public about the potential effects of land management alternatives, climate change, and the trade-offs that are inherent to management and policy in the region. PMID- 27767231 TI - Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. AB - With the recent introduction of Poly(ADP-ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue, we have developed a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach. Our smMIP-based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin-induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation-negative results. Multiplex ligation-dependent probe amplification (MLPA) and Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients. PMID- 27767234 TI - Functions of Nonsuicidal Self-Injury Are Differentially Associated with Suicide Ideation and Past Attempts among Childhood Trauma Survivors. AB - Research into factors for suicide has revealed relations between trauma exposure and suicidality (e.g., Bridge, Goldstein, & Brent, ; Joiner, Sachs-Ericson, Wingate, Brown, Anestis, & Selby, ) wherein painful and provocative experiences (e.g., nonsuicidal self-injury [NSSI]) are an important link (e.g., Van Orden, Witte, Cukrowicz, Braithwaite, Selby, & Joiner, ; Smith, ). No prior research has assessed the relationship between functions of NSSI and suicidality among childhood trauma survivors. Participants who endorsed childhood trauma exposure (N = 121; Mage = 18.69, range 18-22) completed measures of posttraumatic stress disorder (PTSD) symptoms, NSSI, and suicidality. Multiple regressions assessing whether the four functions of NSSI predicted suicide ideation and past attempts after controlling for PTSD symptom severity found that only social negative reinforcement was associated with SI (beta = .304, SE = .243, t = 2.23, p = .028), while only automatic negative reinforcement was associated with past attempts (beta = .470, SE = .066, t = 2.25, p = .028). Findings highlight the importance of assessing NSSI functions when assessing suicidality among trauma survivors. PMID- 27767236 TI - Morphological Simulation of Different Incisal Embrasures: Perception of Laypersons, Orthodontic Patients, General Dentists and Orthodontists. AB - OBJECTIVE: This study aimed to evaluate how different forms of incisal embrasures influence the esthetic perception of the smile, the preferences of each group of evaluators, and the influence of gingival display. MATERIAL AND METHODS: Two photographs of a broad male and female smiles were digitally manipulated to remove imperfections and asymmetries. A second manipulation was performed on the four maxillary incisors, creating 3 different forms of incisal embrasures: rounded, semi-rounded and squared. The lower region of the upper lip was shifted down to simulate a smile with and without gingival display, resulting in a total of 12 photos. A presentation in digital media was structured with instructions and the photos to be studied by 240 evaluators, who were divided into four groups: laypersons, patients undergoing orthodontic treatment, general dentists and orthodontists. The statistical analysis comprised the Multiple Factor ANOVA (SPANOVA), and the Tukey's post-test was applied at a 5% significance level. RESULTS: The semi-rounded form was generally preferred, with a score of 70.83 for the male smile, and 77.26 for the female smile. Gingival display generated a statistically significant influence on how the embrasures were perceived, with the semi-rounded being preferred when associated with gingival display. Orthodontists were the most stringent in their evaluations. Patients and laypersons exhibited different patterns of esthetic perception. CONCLUSIONS: The form of the incisal embrasures associated with gingival display influenced the evaluators' esthetic perception. There was a statistically significant difference between the groups of patients and orthodontists. CLINICAL SIGNIFICANCE: Incisal embrasures play an important role in smile esthetics and influence the attractiveness perception. In general, the semi-rounded embrasure form is the most preferred. Different groups' perceptions on tooth morphology reinforce the importance of patient participation in treatment planning. (J Esthet Restor Dent 29:68-78, 2017). PMID- 27767235 TI - Demographic trends among older cannabis users in the United States, 2006-13. AB - BACKGROUND AND AIMS: The ageing US population is providing an unprecedented population of older adults who use recreational drugs. We aimed to estimate the trends in the prevalence of past-year use of cannabis, describe the patterns and attitudes and determine correlates of cannabis use by adults age 50 years and older. DESIGN: Secondary analysis of the National Survey on Drug Use and Health survey from 2006 to 2013, a cross-sectional survey given to a nationally representative probability sample of populations living in US households. SETTING: USA. PARTICIPANTS: A total of 47 140 survey respondents aged >= 50 years. MEASURES: Estimates and trends of past-year use of cannabis. FINDINGS: The prevalence of past-year cannabis use among adults aged >= 50 increased significantly from 2006/07 to 2012/13, with a 57.8% relative increase for adults aged 50-64 (linear trend P < 0.001) and a 250% relative increase for those aged >= 65 (linear trend P = 0.002). When combining data from 2006 to 2013, 6.9% of older cannabis users met criteria for cannabis abuse or dependence, and the majority of the sample reported perceiving no risk or slight risk associated with monthly cannabis use (85.3%) or weekly use (79%). Past-year users were more likely to be younger, male, non-Hispanic, not have multiple chronic conditions and use tobacco, alcohol or other drugs compared with non-past-year cannabis users. CONCLUSIONS: The prevalence of cannabis use has increased significantly in recent years among US adults aged >= 50 years. PMID- 27767238 TI - Squamous cell carcinoma of the penis successfully treated with imiquimod 5% cream in a porphyria cutanea tarda patient. PMID- 27767237 TI - IL-7/IL-7R signaling pathway might play a role in recurrent pregnancy losses by increasing inflammatory Th17 cells and decreasing Treg cells. AB - PROBLEM: We aim to investigate a possible role of IL-7/IL-7R signaling pathway in recurrent pregnancy losses (RPL). MATERIAL AND METHODS: Using the abortion-prone (AP) and non-abortion-prone (NP) mice model, fetal resorption rates (FRR), Th17 and Treg cells-related factors, and the effect of IL-7 and IL-7R antagonist were investigated by flow cytometry, quantitative real-time PCR, and immunohistochemistry. IL-7 and IL-7R expressions in human decidua were investigated by immunohistochemistry. RESULTS: In the AP mice, IL-7R antagonist treatment significantly decreased FRR by downregulating Th17 and upregulating Treg-related factors. When the NP mice were treated with IL-7, FRR was significantly increased by upregulating Th17 and downregulating Treg-related factors. In decidual stromal cells of women with RPL, increased IL-7 and decreased IL-7R expressions were present when compared to normal controls. CONCLUSION: IL-7/IL-7R signaling pathway plays a possible role in RPL by upregulating Th17 immunity, meanwhile downregulating Treg immunity. Regulation of IL-7/IL-7R may be a new therapeutic strategy for RPL. PMID- 27767240 TI - A somatosensory-to-motor cascade of cortical areas engaged in perceptual decision making during tactile pattern discrimination. AB - The processes underlying perceptual decision making are diverse and typically engage a distributed network of brain areas. It is a particular challenge to establish a sensory-to-motor functional hierarchy in such networks. This is because single-cell recordings mainly study the nodes of decision networks in isolation but seldom simultaneously. Moreover, imaging methods, which allow simultaneously accessing information from overall networks, typically suffer from either the temporal or the spatial resolution necessary to establish a detailed functional hierarchy in terms of a sequential recruitment of areas during a decision process. Here we report a novel analytical approach to work around these latter limitations: using temporal differences in human fMRI activation profiles during a tactile discrimination task with immediate versus experimentally delayed behavioral responses, we could derive a linear functional gradient across task related brain areas in terms of their relative dependence on sensory input versus motor output. The gradient was established by comparing peak latencies of activation between the two response conditions. The resulting time differences described a continuum that ranged from zero time difference, indicative for areas that process information related to the sensory input and, thus, are invariant to the response delay instruction, to time differences corresponding to the delayed response onset, thus indicating motor-related processing. Taken together with our previous findings (Li Hegner et al. []: Hum Brain Mapp 36:3339-3350), our results suggest that the anterior insula reflects the ultimate perceptual stage within the uncovered sensory-to-motor gradient, likely translating sensory information into a categorical abstract (non-motor) decision. Hum Brain Mapp 38:1172-1181, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27767239 TI - Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis. AB - AIMS: Gastric pyloric gland adenomas (PGAs) are rare epithelial polyps that are found more commonly in autoimmune atrophic gastritis and familial adenomatous polyposis (FAP). Little is known about the morphology and genetics of PGAs in FAP. PGAs in FAP are studied morphologically and genetically. Findings in FAP associated PGAs are compared to sporadic PGAs and related lesions such as oxyntic gland adenoma (OGA) to increase our understanding of these rare polyps. METHODS AND RESULTS: Seven PGAs and 18 fundic gland polyps (FGPs) from FAP patients were collected. KRAS and GNAS mutations were determined in six PGAs and 18 FGPs. Immunohistochemistry was applied on five PGAs to provide further confirmation of the histological subtypes and genetic alterations. Morphology of all PGAs was studied and compared to literature on sporadic PGAs and related lesions. All successfully sequenced PGAs (six of six) carried GNAS mutations and half of the successfully sequenced PGAs carried a KRAS mutation (three of six). Nuclear beta catenin was seen only in one PGA with focal high-grade dysplasia. Morphologically, PGAs in FAP showed overlapping features with OGA. CONCLUSION: Familial adenomatous polyposis-associated PGAs have a similar genetic background as sporadic PGAs, i.e. KRAS and GNAS mutation. Based on morphological findings in FAP associated PGAs, it is hypothesized that PGAs and OGAs are closely related lesions. PMID- 27767241 TI - A roadmap for knowledge exchange and mobilization research in conservation and natural resource management. AB - Scholars across all disciplines have long been interested in how knowledge moves within and beyond their community of peers. Rapid environmental changes and calls for sustainable management practices mean the best knowledge possible is needed to inform decisions, policies, and practices to protect biodiversity and sustainably manage vulnerable natural resources. Although the conservation literature on knowledge exchange (KE) and knowledge mobilization (KM) has grown in recent years, much of it is based on context-specific case studies. This presents a challenge for learning cumulative lessons from KE and KM research and thus effectively using knowledge in conservation and natural resources management. Although continued research on the gap between knowledge and action is valuable, overarching conceptual frameworks are now needed to enable summaries and comparisons across diverse KE-KM research. We propose a knowledge-action framework that provides a conceptual roadmap for future research and practice in KE/KM with the aim of synthesizing lessons learned from contextual case studies and guiding the development and testing of hypotheses in this domain. Our knowledge-action framework has 3 elements that occur at multiple levels and scales: knowledge production (e.g., academia and government), knowledge mediation (e.g., knowledge networks, actors, relational dimension, and contextual dimension), and knowledge-based action (e.g., instrumental, symbolic, and conceptual). The framework integrates concepts from the sociology of science in particular, and serves as a guide to further comprehensive understanding of knowledge exchange and mobilization in conservation and sustainable natural resource management. PMID- 27767242 TI - Solubility and Stability of Baclofen 3 mg/mL Intrathecal Formulation and Its Compatibility With Implantable Programmable Intrathecal Infusion Systems. AB - BACKGROUND: Commercial baclofen formulations used with infusion pumps are available at therapeutic concentrations of 0.5-2.0 mg/mL. However, patients who receive higher daily doses of baclofen may benefit from products with greater baclofen concentrations since their refill frequency would be reduced (up to a maximum of 180 days). We evaluated baclofen solubility, baclofen 3 mg/mL intrathecal (IT) formulation stability, and chemical and physical compatibility with Medtronic SynchroMed(r) II and Codman Medstream(r) programmable IT infusion pumps. METHODS: For solubility evaluations, baclofen powder was dissolved into isotonic saline and tested at 5 degrees C, 25 degrees C, and 40 degrees C. To demonstrate drug product stability, both physical and chemical stability attributes of baclofen 3 mg/mL in prefilled syringes were evaluated over 36 months with storage at 25 degrees C. For a simulated in-use stability (compatibility) study, a 3 mg/mL baclofen IT formulation was placed in SynchroMed II and Codman Medstream pumps at 37oC for study durations, and evaluated at different flow rates. Pump effluent was collected at various times and analyzed by high-performance liquid chromatography for baclofen content. On completion of the in-use stability study, pumps exposed to baclofen 3 mg/mL were dissected and visually evaluated for signs of deterioration. RESULTS: Baclofen solubility was found to be 3.2 mg/mL at 5 degrees C, 3.6 mg/mL at 25 degrees C, and 3.9 mg/mL at 40 degrees C. During the 36-month stability study of prefilled syringes stored at 25 degrees C, baclofen content remained unchanged and no precipitation was observed. The simulated in-use pump study performed at 37oC showed that a baclofen 3 mg/mL IT formulation was stable at different flow rates and throughout different expected residence times for both pump models. Components from both pumps exhibited no noticeable deterioration after exposure to the 3 mg/mL formulation. CONCLUSION: Baclofen 3 mg/mL IT formulation was stable during long term storage at 25 degrees C and remained stable under conditions matching those encountered in clinical practice (37 degrees C). PMID- 27767243 TI - Semantic fluency in aphasia: clustering and switching in the course of 1 minute. AB - BACKGROUND: Verbal fluency tasks are included in a broad range of aphasia assessments. It is well documented that people with aphasia (PWA) produce fewer items in these tasks. Successful performance on verbal fluency relies on the integrity of both linguistic and executive control abilities. It remains unclear if limited output in aphasia is solely due to their lexical retrieval difficulties or has a basis in their executive control abilities. Analysis techniques, such as temporal characteristics of word retrieved, clustering and switching, are better positioned to inform the debate surrounding the lexical and/or executive control contribution for success in verbal fluency. AIMS: To investigate the differences in quantitative (i.e., number of correct words) and qualitative (i.e., switching, clustering and word-retrieval times) performances on animal fluency task as a function of time between PWA and healthy control speakers (CS). METHODS & PROCEDURES: Animal fluency data for 60 s were collected from 34 PWA and 34 CS, and responses were time stamped. The 60-s period was divided into four equal intervals of 15 s each (i.e., 15, 30, 45 and 60 s). The number of correct words, cluster size, number of switches, within-cluster pause and between-cluster pause were evaluated as a function of four 15-s time intervals between PWA and CS. OUTCOMES & RESULTS: Compared with CS, PWA produced fewer words, had smaller cluster sizes and switched a fewer number of times. A decrease in the number of switches correlated with an increase in between-cluster pause durations. PWA showed longer within- and between-cluster pauses than CS. The two groups showed specific differences in the temporal pattern of the responses: as time evolved both PWA and CS showed decreased productivity for the number of correct words, but PWA reached the asymptote earlier in the time course than CS, neither group showed a change in cluster size, and the number of switches decreased as a function of time only for CS. CONCLUSIONS & IMPLICATIONS: The findings suggest that for PWA the search and retrieval process is less productive and more effortful. This is indicated by smaller cluster size, fewer switches associated with increased between-cluster pause durations, as well as overall slowed retrieval times for the words. This shows that the difficulties with verbal fluency performance in aphasia have a strong basis in their lexical retrieval processes, as well as some difficulties in the executive component of the task. PMID- 27767244 TI - Evidence for superior neurobiological and behavioral inhibitory control abilities in non-offending as compared to offending pedophiles. AB - Neurobehavioral models of pedophilia and child sexual offending suggest a pattern of temporal and in particular prefrontal disturbances leading to inappropriate behavioral control and subsequently an increased propensity to sexually offend against children. However, clear empirical evidence for such mechanisms is still missing. Using a go/nogo paradigm in combination with functional magnetic resonance imaging (fMRI) we compared behavioral performance and neural response patterns among three groups of men matched for age and IQ: pedophiles with (N = 40) and without (N = 37) a history of hands-on sexual offences against children as well as healthy non-offending controls (N = 40). As compared to offending pedophiles, non-offending pedophiles exhibited superior inhibitory control as reflected by significantly lower rate of commission errors. Group-by-condition interaction analysis also revealed inhibition-related activation in the left posterior cingulate and the left superior frontal cortex that distinguished between offending and non-offending pedophiles, while no significant differences were found between pedophiles and healthy controls. Both areas showing distinct activation pattern among pedophiles play a critical role in linking neural networks that relate to effective cognitive functioning. Data therefore suggest that heightened inhibition-related recruitment of these areas as well as decreased amount of commission errors is related to better inhibitory control in pedophiles who successfully avoid committing hands-on sexual offences against children. Hum Brain Mapp 38:1092-1104, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27767246 TI - Adaptive contextualization: A new role for the default mode network in affective learning. AB - Safety learning describes the ability to learn that certain cues predict the absence of a dangerous or threatening event. Although incidental observations of activity within the default mode network (DMN) during the processing of safety cues have been reported previously, there is as yet no evidence demonstrating that the DMN plays a functional rather than a corollary role in safety learning. Using functional magnetic resonance imaging and a Pavlovian fear conditioning and extinction paradigm, we investigated the neural correlates of danger and safety learning. Our results provide evidence for a functional role of the DMN by showing that (i) the DMN is activated by safety but not danger cues, (ii) the DMN is anti-correlated with a fear-processing network, and (iii) DMN activation increases with safety learning. Based on our results, we formulate a novel proposal, arguing that activity within the DMN supports the contextualization of safety memories, constrains the generalization of fear, and supports adaptive fear learning. Our findings have important implications for our understanding of affective and stress disorders, which are characterized by aberrant DMN activity, as they suggest that therapies targeting the DMN through mindfulness practice or brain stimulation might help prevent pathological over-generalization of fear associations. Hum Brain Mapp 38:1082-1091, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27767247 TI - Quantum Computation using Arrays of N Polar Molecules in Pendular States. AB - We investigate several aspects of realizing quantum computation using entangled polar molecules in pendular states. Quantum algorithms typically start from a product state |00?0? and we show that up to a negligible error, the ground states of polar molecule arrays can be considered as the unentangled qubit basis state |00?0? . This state can be prepared by simply allowing the system to reach thermal equilibrium at low temperature (<1 mK). We also evaluate entanglement, characterized by concurrence of pendular state qubits in dipole arrays as governed by the external electric field, dipole-dipole coupling and number N of molecules in the array. In the parameter regime that we consider for quantum computing, we find that qubit entanglement is modest, typically no greater than 10-4 , confirming the negligible entanglement in the ground state. We discuss methods for realizing quantum computation in the gate model, measurement-based model, instantaneous quantum polynomial time circuits and the adiabatic model using polar molecules in pendular states. PMID- 27767248 TI - Visible Light-Induced Living Radical Polymerization of Butyl Acrylate: Photocatalyst-Free, Ultrafast, and Oxygen Tolerance. AB - Butyl acrylate is polymerized in the living way under the irradiation of purple light-emitting diode (LED) or sunlight without photocatalyst at ambient temperature. 2-((Phenoxycarbonothioyl)thio) ethyl propanoate) is exclusively added and acted as an initiator and a chain transfer agent simultaneously in the current system. Poly(butyl acrylate) with well-regulated molecular weight and relatively narrow molecular weight distribution (D < 1.30) is synthesized. High conversion (>95%) can be achieved within several minutes. Polymerization shows oxygen tolerance. Near quantitative end-group fidelity of polymer is demonstrated by 1 H NMR and matrix-assisted laser desorption/ionization time-of-flight mass spectra. PMID- 27767245 TI - Post-translational control of ABA signalling: the roles of protein phosphorylation and ubiquitination. AB - The plant phytohormone abscisic acid (ABA) plays significant roles in integrating environmental signals with embryogenesis, germination, seedling establishment, the floral transition and the adaptation of plants to stressful environments by modulating stomatal movement and stress-responsive gene expression. ABA signalling consists of ABA perception, signal transduction and ABA-induced responses. ABA receptors such as members of the PYR/PYL family, group A type 2C protein phosphatases (as negative regulators), SnRK2 protein kinases (as positive regulators), bZIP transcription factors and ion channels are key components of ABA signalling. Post-translational modifications, including dephosphorylation, phosphorylation and ubiquitination, play important roles in regulating ABA signalling. In this review, we focus on the roles of post-translational modifications in ABA signalling. The studies presented provide a detailed picture of the ABA signalling network. PMID- 27767249 TI - Predictors of outcomes in patients with type 2 diabetes in the lixisenatide GetGoal clinical trials. AB - AIMS: To explore the treatment outcomes in adult patients with type 2 diabetes (T2D) enrolled in the GetGoal trials of lixisenatide (LIXI), and the predictive effects of baseline characteristics on outcomes. METHODS: This study was a pooled analysis of patient-level data from the LIXI GetGoal studies comparing LIXI and placebo. Patients were divided into baseline therapy groups: those receiving oral antidiabetes drugs (OADs) at baseline (n = 2760) or those receiving basal insulin at baseline (n = 1198). RESULTS: Compared with placebo, LIXI treatment led to significantly greater reductions in glycated haemoglobin (HbA1c), and greater achievement of the composite endpoint of HbA1c <7.0% (53 mmol/mol) with no symptomatic hypoglycaemia and no weight gain in either the OAD (34% vs 18%; P < .0001) or the basal insulin groups (19% vs 10%; P < .0001). Treatment with LIXI was associated with a greater percentage of patients experiencing a symptomatic hypoglycaemic event compared with placebo in both the OAD (5% vs 3%; P = .0098) and basal insulin groups (27% vs 17%; P < .0001). In assessing baseline factors that were predictors of treatment outcomes, only baseline HbA1c and LIXI treatment were strong predictors of outcomes in both the OAD and basal insulin groups. No other baseline characteristic had such a large or consistent clinically relevant predictive effect across treatment outcomes. CONCLUSIONS: The results from this study show that irrespective of baseline characteristics, LIXI treatment, as an add-on to OAD or basal insulin therapy, is effective in reducing HbA1c and achieving composite endpoints. PMID- 27767250 TI - Carboxylated Photoswitchable Diarylethenes for Biolabeling and Super-Resolution RESOLFT Microscopy. AB - Reversibly photoswitchable 1,2-bis(2-ethyl-6-phenyl-1-benzothiophene-1,1-dioxide 3-yl)perfluorocyclopentenes (EBT) having fluorescent "closed" forms were decorated with four or eight carboxylic groups and attached to antibodies. Low aggregation, efficient photoswitching in aqueous buffers, specific staining of cellular structures, and good photophysical properties were demonstrated. Alternating light pulses of UV and blue light induce numerous reversible photochemical transformations between two stables states with distinct structures. Using relatively low light intensities, EBTs were applied in biology related super-resolution microscopy based on the reversible saturable (switchable) optical linear fluorescence transitions (RESOLFT) and demonstrated optical resolution of 75 nm. PMID- 27767251 TI - Integrin Targeting and Toxicological Assessment of Peptide-Conjugated Liposome Delivery Systems to Activated Endothelial Cells. AB - Utilization of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines after exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin alpha5beta1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells. PMID- 27767252 TI - Enhancement of cell internalization and photostability of red and green emitter quantum dots upon entrapment in novel cationic nanoliposomes. AB - Two quantum dots (QDs), a green emitter, CdSe and a red emitter, CdSe with ZnS shell are encapsulated into novel liposomes in two different formulations including cationic liposomes. Quantum dots have proven themselves as powerful inorganic fluorescent probes, especially for long-term, multiplexed imaging and detection. Upon delivery into a cell, in endocytic vesicles such as endosomes, their fluorescence is quenched. We have investigated the potential toxic effects, photophysical properties and cell internalization of QDs in new formulation of liposomes as an in vitro vesicle model. Entrapment of QDs into liposomes is brought about with a decrease in their intrinsic fluorescence and toxicities and an increase in their photostability and lifetime. The biomimetic lipid bilayer of liposomes provides high biocompatibility, thereby enhancing the effectiveness of fluorescent nanoparticles for biological recognition in vitro and in vivo. The prepared lipodots could effectively prevent QDs from photo-oxidation during storage and when exposed to ultraviolet (UV) light. Moreover, the flow cytometry of HEK 293 T cells showed that the cell internalization of encapsulated QDs in (DSPC/CHO/DOPE/DOAB) liposome is enhanced 10 times compared with non-encapsulated QD (bare QDs). PMID- 27767253 TI - Blood pressure in patients with atrial fibrillation: part 2-treatment. PMID- 27767255 TI - Effective Release of Lignin Fragments from Lignocellulose by Lewis Acid Metal Triflates in the Lignin-First Approach. AB - Adding value to lignin, the most complex and recalcitrant fraction in lignocellulosic biomass, is highly relevant to costefficient operation of biorefineries. We report the use of homogeneous metal triflates to rapidly release lignin from biomass. Combined with metal-catalyzed hydrogenolysis, the process separates woody biomass into few lignin-derived alkylmethoxyphenols and cellulose under mild conditions. Model compound studies show the unique catalytic properties of metal triflates in cleaving lignin-carbohydrate interlinkages. The lignin fragments can then be disassembled by hydrogenolysis. The tandem process is flexible and allows obtaining good aromatic monomer yields from different woods (36-48 wt %, lignin base). The cellulose-rich residue is an ideal feedstock for established biorefining processes. The highly productive strategy is characterized by short reaction times, low metal triflate catalyst requirement, and leaving cellulose largely untouched. PMID- 27767254 TI - The chemiluminescence immunoassay for aflatoxin B1 based on functionalized magnetic nanoparticles with two strategies of antigen probe immobilization. AB - A rapid and sensitive chemiluminescence immunoassay (CLIA) based on magnetic nanoparticles (MNPs) was developed to detect aflatoxin B1 (AFB1), which is a potent carcinogen in nature. We prepared monodisperse MNPs (300 nm in diameter) according to the solvothermal synthesis reaction and the MNPs were coated with silica by the Stober method. Triethox was used as a one-step carboxylation reagent, and 3-aminopropyltriethoxysilane (APTES) an amination reagent, to modify the MNPs. We prepared two types of solid phase antigens using the above synthesized functionalized MNPs coupled with the later prepared AFB1-oxime active ester and the purchased BSA-AFB1 respectively. 2',6'-dimethylcarbonylphenyl-10 sulfopropylacridinium-9-carboxylate 4'-N-hydroxysuccinimide (4'-NHS) ester (NSP DMAE-NHS), as a novel luminescent reagent, was used to label anti-AFB1 antibodies. The two CLIA calibration curves based on the two types of solid phase antigens were obtained and compared. The acquired limit of detection (LOD) was about 0.001 ng/mL for the two functionalized MNPs-based immunoassays, and the half maximal inhibitory concentration (IC50 ) was 0.51 ng/mL for the MNPs-AFB1 based method and 0.72 ng/mL for the MNPs-BSA-AFB1-based method. PMID- 27767256 TI - Digital Evaluation of Three Splinting Materials Used to Fabricate Verification Jigs for Full-Arch Implant Prostheses: A Comparative Study. AB - PURPOSE: The primary aim of this study was to assess the accuracy of different splinting materials to make implant cast verification jigs. The secondary aim was to assess the effect of 20 degrees implant angulation on the accuracy of casts. MATERIALS AND METHODS: An edentulous mandibular arch with five internal connection tissue level implants served as control. The three implants in the anterior region were parallel to each other and the two implants in the posterior region were distally tilted 20 degrees bilaterally. Verification jigs were fabricated with three different materials by splinting prefabricated bars to temporary abutments, resulting in three different groups (n = 15 specimens). Test casts were fabricated with low expansion type IV stone, and subsequently digitized with reference scanner. The STL files from the test casts and the control were superimposed, in order to determine the three-dimensional (3D) deviations. RESULTS: Group 1 (GC Pattern Resin) had a mean (SD) value of 36.59 (12.47) MUm; Group 2 (Fixpeed Resin) had a mean (SD) value of 35.9 (10.13) MUm; and Group 3 (Triad Gel) had a mean (SD) of 34.12 (7.10) MUm. One-way ANOVA showed no statistically significant difference between groups (p = 0.790). For the comparative analysis of the effect of implant angulation, data were normally distributed for Groups 1 and 3 (GC Resin and Triad Gel), but not for group 2 (Fixpeed Resin). The difference between parallel and tilted implants was significant for all three groups: GC Resin (p = 0.024; paired t-test), Fixpeed Resin (p = 0.002; Wilcoxon signed-rank test), and Triad Gel (p = 0.002; paired t test). CONCLUSIONS: There were no statistically significant differences between the 3D deviations of the test casts fabricated from verification jigs made by three materials (GC Pattern Resin, Fixpeed Resin, and Triad Gel). Parallel implants had nominally significantly less 3D deviations compared with 20 degrees distally tilted implants, but not clinically significant. CLINICAL SIGNIFICANCE: The results of the present study indicate that more than 20 degrees of angulation, has an effect on the 3D accuracy. However, even though the tilted implants had nominally significantly more 3D deviation, it was not clinically significant. The clinical implications of this in vitro study are relevant to the popular full-arch implant rehabilitation concept of tilted and axial implants such as the All-on-four concept. Tilting the posterior implants to increase the antero-posterior spread increases the implant angulation which is then corrected with 30 degrees angulated abutments. This in vitro study shows that even after correction with angulated abutments if the remaining angulation is up to 20 degrees , framework fit may still be achieved. Verification jig is essential tool to achieve the framework fit. (J Esthet Restor Dent 29:102-109, 2017). PMID- 27767257 TI - Capacity Decay Mitigation by Asymmetric Positive/Negative Electrolyte Volumes in Vanadium Redox Flow Batteries. AB - Capacity decay in vanadium redox flow batteries during charge-discharge cycling has become an important issue because it lowers the practical energy density of the battery. The battery capacity tends to drop rapidly within the first tens of cycles and then drops more gradually over subsequent cycles during long-term operation. This paper analyzes and discusses the reasons for this early capacity decay. The imbalanced crossover rate of vanadium species was found to remain high until the total difference in vanadium concentration between the positive and negative electrolytes reached almost 1 mol dm-3 . To minimize the initial crossover imbalance, we introduced an asymmetric volume ratio between the positive and negative electrolytes during cell operation. Changing this ratio significantly reduced the capacity fading rate of the battery during the early cycles and improved its capacity retention at steady state. As an example, the practical energy density of the battery increased from 15.5 to 25.2 Wh L-1 simply after reduction of the positive volume by 25 %. PMID- 27767258 TI - Design and Printing Strategies in 3D Bioprinting of Cell-Hydrogels: A Review. AB - Bioprinting is an emerging technology that allows the assembling of both living and non-living biological materials into an ideal complex layout for further tissue maturation. Bioprinting aims to produce engineered tissue or organ in a mechanized, organized, and optimized manner. Various biomaterials and techniques have been utilized to bioprint biological constructs in different shapes, sizes and resolutions. There is a need to systematically discuss and analyze the reported strategies employed to fabricate these constructs. We identified and discussed important design factors in bioprinting, namely shape and resolution, material heterogeneity, and cellular-material remodeling dynamism. Each design factors are represented by the corresponding process capabilities and printing parameters. The process-design map will inspire future biomaterials research in these aspects. Design considerations such as data processing, bio-ink formulation and process selection are discussed. Various printing and crosslinking strategies, with relevant applications, are also systematically reviewed. We categorized them into 5 general bioprinting strategies, including direct bioprinting, in-process crosslinking, post-process crosslinking, indirect bioprinting and hybrid bioprinting. The opportunities and outlook in 3D bioprinting are highlighted. This review article will serve as a framework to advance computer-aided design in bioprinting technologies. PMID- 27767260 TI - Spotlights on our sister journals: Chem. Eur. J. 45/2016. PMID- 27767259 TI - Catalytic Upstream Biorefining through Hydrogen Transfer Reactions: Understanding the Process from the Pulp Perspective. AB - Catalytic upstream biorefining (CUB) encompasses processes for plant biomass deconstruction through the early-stage conversion of lignin by the action of a hydrogenation catalyst. CUB processes produce lignin as an extensively depolymerised product (i.e., a viscous lignin oil) and render highly delignified pulps. In this report, we examine CUB from the pulp perspective. Notably, Raney Ni plays an indirect role in the processes that occur within the lignocellulose matrix. As there are negligible points of contact between the poplar wood chips and Raney Ni, the catalyst action is limited to the species leached from the matrix into the liquor. Nevertheless, the substantial changes in the liquor composition (through the decomposition of carboxylic acids and H-transfer reductive processes on the lignin fragments) have significant implications for the pulp composition, degree of polymerisation and morphology. Compared with organosolv pulps, CUB pulps show higher xylan retention, higher delignification, and higher polymerisation degree. Moreover, the correlation between these properties and the performance of the enzymatic hydrolyses of CUB and organosolv pulps reveals that the high susceptibility of CUB pulps is mostly caused by their lower residual lignin contents. PMID- 27767261 TI - Myokardszintigraphie - eine Methode zur Erfassung der kardialen Komorbiditat bei Psoriasis-Patienten? AB - HINTERGRUND: Kardiale Komorbiditaten bei Patienten mit Psoriasis stehen seit Jahren im Fokus. Ziel dieser Arbeit war es, im Rahmen einer Pilotstudie die Myokardszintigraphie als mogliche Fruherkennungsmethode zu evaluieren. PATIENTEN UND METHODIK: Es wurden bei insgesamt 50 kardial asymptomatischen Patienten mit einer Psoriasis der Haut verschiedene Begleiterkrankungen erfasst. Dabei kam zur Erkennung von kardialem Risiko/ belastungsinduzierter Ischamie die Myokardszintigraphie zum Einsatz. ERGEBNISSE: Bei 28 Patienten (56 %) fanden sich pathologische Befunde in der Myokardszintigraphie. Davon zeigten 14 Patienten Zeichen einer sogenannten Small Vessel Disease (Kardiales Syndrom X). Daruber hinaus fanden sich weitere Begleiterkrankungen wie Adipositas, arterielle Hypertonie, Nikotinkonsum, Alkoholkonsum und erhohte CRP-Werte. Die Haufigkeiten entsprachen im Wesentlichen den aktuellen Daten aus der Literatur. Wir konnten keinen signifikanten Zusammenhang von Schwere der Psoriasis oder der angegebenen Komorbiditaten mit einem pathologischen Befund in der Myokardszintigraphie feststellen. SCHLUSSFOLGERUNGEN: Mit der Myokardszintigraphie scheint ein sehr empfindliches, nicht invasives Fruherkennungsverfahren zur Detektion kardialer Komorbiditat bei Psoriasis-Patienten zur Verfugung zu stehen. Weitere grobetaere Arbeiten mit Kontrollkollektiven und Kotrollmethoden, wie beispielsweise der Koronarangiographie, sind zur Uberprufung der Wertigkeit notig. PMID- 27767262 TI - Trizentrische Analyse von Kofaktoren und Komorbiditat des Pyoderma gangraenosum. AB - EINLEITUNG: Das Pyoderma gangraenosum (PG) ist eine seltene, inflammatorische destruktiv-ulzerierende neutrophile Erkrankung mit weitgehend unklarer Pathophysiologie. MATERIAL UND METHODIK: In dieser Studie wurden die potenziell relevanten Kofaktoren und Begleiterkrankungen von Patienten mit PG aus drei dermatologischen Wundzentren in Deutschland differenziert ausgewertet. ERGEBNISSE: Von den insgesamt 121 analysierten Patienten waren Frauen (66,9 %) haufiger betroffen als Manner. Das Alter der Patienten war 18-96 Jahre (Mittelwert [MW]: 59,8); die Wunden hatten eine Grobetae von 1-600 cm2 (MW: 65,6 cm2) und waren uberwiegend sehr schmerzhaft (VAS 1-10, MW: 7). Die Unterschenkel waren am haufigsten (71,9 %) betroffen. Bei 12 (9,9 %) Patienten bestanden chronisch entzundliche Darmerkrankungen (5,8 % Colitis ulcerosa; 4,1 % Morbus Crohn), bei 14,1 % der Patienten wurde eine Begleiterkrankung aus dem rheumatischen Formenkreis beschrieben. Neoplasien bestanden bei 20,6 % der Patienten, von denen 6,6 % als hamatologische und 14,1 % als solide Neoplasien klassifiziert wurden. Aus dem Kreis des metabolischen Syndroms wurde bei 69,4 % Patienten eine Adipositas, bei 57,9 % eine arterielle Hypertonie und bei 33,9 % ein Diabetes mellitus diagnostiziert. SCHLUSSFOLGERUNGEN: Diese Datenanalyse bestatigt Assoziationen des PG mit dem metabolischen Syndrom und mit Neoplasien, die zukunftig fruhzeitig bei einer zielgerichteten Diagnostik der Patienten beachtet und behandelt werden sollten. PMID- 27767263 TI - Die Kombination von Etanercept und Ciclosporin bei einem 6-jahrigen Kind mit schwerer Psoriasis vulgaris. PMID- 27767265 TI - Anaphylactic reaction to para-phenylenediamine. PMID- 27767266 TI - Chronisches Ulkus der Haut nach Defibrillation. PMID- 27767267 TI - Zweites Netzwerktreffen der zertifizierten Hauttumorzentren. PMID- 27767268 TI - Temporal course of avascular femoral head necrosis in patients with pemphigus vulgaris. AB - BACKGROUND AND OBJECTIVES: Pemphigus vulgaris (PV) is typically treated with systemic corticosteroids and immunosuppressive agents. Avascular necrosis (AVN) of the femoral head is a well-recognized major complication of corticosteroid therapy. The characteristics of this serious complication in PV remain unknown. PATIENTS AND METHODS: Uncontrolled, retrospective study of all PV-related AVN cases diagnosed at an Iranian autoimmune bullous disease clinic between 1985 and 2013. RESULTS: Of the 2,321 medical records of PV patients reviewed, 45 (1.93 %) cases showed femoral AVN, with 30 (66.7 %) individuals being male. The mean age at diagnosis of AVN was 47.4 +/- 14.2 years. The mean interval between the diagnosis of PV and the onset of AVN was 25.3 +/- 18.3 months. With the exception of eight cases (17.8 %), the majority of patients developed AVN within three years after the diagnosis of PV. The mean cumulative dose of prednisolone in patients with AVN was 13,115.8 +/- 7041.1 mg. There was a strong correlation between the total prednisolone dose and the time of onset of AVN (p = 0.001). In patients with a history of alendronate intake, that interval was significantly shorter (p = 0.01). CONCLUSIONS: Occurring in about 2 % of patients, AVN is a serious complication of corticosteroid treatment in patients with PV, predominantly in the first three years of treatment. In individuals receiving higher doses of prednisolone, AVN tends to occur earlier. PMID- 27767269 TI - Inzidenz von bullosen Autoimmunerkrankungen in Serbien: eine retrospektive Studie uber 20 Jahre. AB - HINTERGRUND UND ZIELE: Die meisten fruheren Arbeiten zu den klinisch epidemiologischen Merkmalen von bullosen Autoimmunerkrankungen (AIBD) konzentrierten sich vor allem auf eine einzige Krankheitsentitat oder nur eine Krankheitsgruppe; nur in wenigen Studien wurde die Inzidenz verschiedener AIBD untersucht. Bei der vorliegenden Studie war es unser Ziel, das gesamte Spektrum der AIBD zu betrachten, die Inzidenz der haufigsten AIBD zu ermitteln und die zeitlichen Trends ihres Auftretens in Zentralserbien uber einen Zeitraum von 20 Jahren zu untersuchen. METHODEN: Wir rekrutierten retrospektiv 1161 AIBD-Falle, die in Zentralserbien von Januar 1991 bis Dezember 2010 neu diagnostiziert wurden. Die Diagnose stutzte sich auf eine strikte klinische, histologische und immunhistologische Beurteilung. ERGEBNISSE: Folgende Inzidenzraten wurden fur die einzelnen Erkrankungen ermittelt: 4,35 pro eine Million Einwohner/Jahr (pME/Jahr) fur Pemphigus, 4,47 pME/Jahr fur Pemphigoid, 1,42 pME/Jahr fur Dermatitis herpetiformis (DH), 0,25 pME/Jahr IgA-Dermatose und 0,08 pME/Jahr fur Epidermolysis bullosa acquisita. Im betrachteten Zeitraum stieg die altersbereinigte Inzidenzrate fur Pemphigus und insbesondere fur Pemphigoid signifikant an, wahrend sie fur DH, allerdings nicht signifikant, abnahm. SCHLUSSFOLGERUNGEN: Unsere Studie befasst sich zum ersten Mal mit den Inzidenzraten des gesamten Spektrums der AIBD in Serbien und untersucht die zeitlichen Trends ihres Auftretens uber einen Zeitraum von 20 Jahren. Nach unserem besten Wissen wurde ein ahnlicher Befund wie der unsere, dass namlich die Inzidenzraten von Pemphigus und Pemphigoid vergleichbar sind, bisher noch nicht publiziert. PMID- 27767271 TI - Dermatologische Lehre und Nationale Kompetenzbasierte Lernzielkataloge. PMID- 27767270 TI - A multistep approach to the diagnosis of rare genodermatoses. AB - Recent advances in genetic technology have found their way into clinical dermatology. Approximately one third of all hereditary disorders show characteristic cutaneous findings. Moreover, human skin easily provides samples for studying the mechanisms of genetic mosaicism, as well as the underlying functional defects due to mutated proteins. Diagnosing hereditary skin disorders remains, however, a challenging task due to the rarity of genodermatoses and their diversity, overlapping or heterogeneous phenotypes, huge amount of new information, and complicated nomenclature and classifications. In order to support the clinicians' interest for this complex and rapidly developing field of dermatology, we are going to present a multistep approach with some useful clues for the evaluation of patients suspected of having a genodermatosis. PMID- 27767272 TI - Myocardial scintigraphy - a method for detecting cardiac comorbidity in psoriasis patients? AB - BACKGROUND: In recent years, cardiac comorbidities in psoriasis patients have increasingly moved into the focus of clinical research. The objective of the present study was to evaluate myocardial scintigraphy as a screening method in patients with psoriasis. PATIENTS AND METHODS: Assessment of various comorbidities in 50 psoriasis patients without clinical symptoms of cardiac disease. Myocardial scintigraphy was employed to detect cardiac risk/exercise induced ischemia. RESULTS: Twenty-eight patients (56 %) had pathological findings on myocardial scintigraphy. Fourteen individuals showed evidence of small-vessel disease (cardiac syndrome X). Other comorbidities included obesity, arterial hypertension, nicotine and alcohol abuse, as well as elevated CRP levels. Frequencies largely corresponded to those reported in the recent literature. There was no significant correlation between the severity of psoriasis or any comorbidities and pathological findings on myocardial scintigraphy. CONCLUSIONS: Myocardial scintigraphy seems to be a very sensitive, noninvasive method for the early detection of cardiac comorbidities in psoriasis patients. However, determining its true diagnostic value will require larger studies with control subjects and control methods such as coronary angiography. PMID- 27767275 TI - Kongresskalender 2016. PMID- 27767273 TI - Incidence of autoimmune bullous diseases in Serbia: a 20-year retrospective study. AB - BACKGROUND AND OBJECTIVES: While most previous surveys on the clinico epidemiological features of autoimmune bullous diseases (AIBDs) have predominantly focused on a single disease entity or just one disease group, there have been only few studies examining the incidence of various AIBDs. In the present study, we set out to determine the spectrum of AIBDs, to estimate the incidence of the most common AIBDs, and to examine their temporal trends in Central Serbia over a period of 20 years. METHODS: We retrospectively recruited 1,161 new AIBD cases diagnosed in Central Serbia during the period from January 1991 to December 2010. The diagnosis was based on strict clinical, histological, and immunohistological evaluation. RESULTS: The incidence rates were: 4.35 per million population/year (pmp/year) for pemphigus, 4.47 pmp/year for pemphigoid, 1.42 pmp/year for dermatitis herpetiformis (DH), 0.25 pmp/year for linear IgA disease, and 0.08 pmp/year for epidermolysis bullosa acquisita. In the period observed, age-adjusted incidence rates significantly increased for pemphigus and particularly for pemphigoid, whereas they decreased, albeit not significantly, for DH. CONCLUSIONS: For the first time, our study evaluates the incidence rates of the entire spectrum of AIBDs in Serbia, and examines their temporal trends over a 20-year period. To the best of our knowledge, our finding of similar incidence rates for pemphigus and pemphigoid has previously not been reported. PMID- 27767274 TI - A case of Hailey-Hailey herpeticum. PMID- 27767276 TI - Necrobiosis lipoidica der Peniseichel: ein Fallbericht mit Literaturuberblick. PMID- 27767277 TI - Zeitlicher Verlauf der avaskularen Nekrose des Huftkopfes bei Patienten mit Pemphigus vulgaris. AB - HINTERGRUND UND ZIELE: Pemphigus vulgaris (PV) wird in der Regel mit systemischen Corticosteroiden und Immunsuppressiva behandelt. Avaskulare Nekrose (AVN) des Huftkopfes ist eine gut bekannte schwerere Komplikation einer Corticosteroid Therapie. Die Charakteristika dieser schweren Komplikation bei PV sind nach wie vor unbekannt. PATIENTEN UND METHODEN: Nicht kontrollierte, retrospektive Untersuchung aller PV-bedingten AVN-Falle, die in einer iranischen Klinik fur bullose Autoimmunerkrankungen zwischen 1985 und 2013 diagnostiziert wurden. ERGEBNISSE: Anhand der Krankenakten von 2321 untersuchten PV-Patienten wurden 45 Falle (1,93 %) von femoraler AVN identifiziert. Dreibetaig davon waren Manner. Das mittlere Alter bei der Diagnose der AVN betrug 47,4 +/- 14,2 Jahre. Der mittlere Zeitraum zwischen der Diagnose des PV und dem Einsetzen der AVN lag bei 25,3 +/- 18,3 Monaten. Mit Ausnahme von acht Fallen (17,8 %) setzte die AVN bei der Mehrheit der Patienten innerhalb von drei Jahren nach Diagnose des PV ein. Die mittlere kumulative Dosis von Prednisolon bei Patienten mit AVN betrug 13.115,8 +/- 7041,1 mg. Zwischen der Prednisolon-Gesamtdosis und dem Zeitraum bis zum Einsetzen der AVN bestand eine starke Korrelation (p = 0,001). Bei Patienten mit Alendronateinnahme in der Vorgeschichte war dieser Zeitraum signifikant kurzer (p = 0,01). SCHLUSSFOLGERUNGEN: Die AVN ist eine schwere Komplikation einer Corticosteroid-Behandlung bei Patienten mit PV. Sie wird bei 2 % der Patienten beobachtet und tritt vor allem in den ersten drei Behandlungsjahren auf. Bei Patienten, die hohere Dosen von Prednisolon erhalten, setzt die AVN tendenziell fruher ein. PMID- 27767279 TI - Etanercept combined with cyclosporine in a 6-year-old child with severe plaque psoriasis. PMID- 27767278 TI - Wells syndrome. AB - A rare eosinophilic dermatosis, Wells syndrome, also referred to as eosinophilic cellulitis, is characterized by great clinical variability. Typical findings include infiltrated erythematous plaques arising on the extremities. Lesions initially resemble erysipelas/cellulitis, however, they do not improve with antibiotic treatment. Eosinophilic cellulitis is a diagnosis of exclusion that may only be made over the course of the disease, taking into account clinical and characteristic histological findings (flame figures). Although multiple potential triggers have been proposed, the exact etiology remains unresolved. Involvement of abnormal Th2 cells, IL-5, and activated eosinophilic granulocytes suggest a nonspecific hypersensitivity response to exogenous or endogenous stimuli. Corticosteroids may have a beneficial effect on the chronic, recurrent course frequently observed. The disease is often self-limiting, healing without sequelae. Given that transitions to hematological and oncological disorders have been observed, patients should be closely followed up. PMID- 27767280 TI - Refractory edema and erythema of the abdominal wall. PMID- 27767281 TI - Ein mehrstufiger Algorithmus zur Diagnose seltener Genodermatosen. AB - Jungste Fortschritte der Genforschung haben ihren Weg in die klinische Dermatologie gefunden. Nahezu ein Drittel aller Erbkrankheiten zeigt charakteristische Hautveranderungen. Zudem konnen Proben menschlicher Haut als Untersuchungsmaterial zur Detektion genetischer Mosaike und der zu Grunde liegenden Defekte eingesetzt werden. Die Diagnose von Genodermatosen bleibt jedoch aufgrund ihrer unterschiedlich ausgepragten und uberlappenden Phanotypen sowie ihrer Seltenheit und Vielzahl neuer Informationen wegen eine Herausforderung fur die Kliniker. Um das Interesse fur dieses, sich schnell entwickelnde Feld der Dermatologie zu wecken und den Blick fur einige seltene Erbkrankheiten zu scharfen, stellen wir in der hiesigen Ubersicht einen Algorithmus fur die Diagnostik und Evaluierung von Patienten mit fraglichen Genodermatosen vor. PMID- 27767282 TI - Wells-Syndrom. AB - Das Wells-Syndrom, auch als eosinophile Zellulitis bezeichnet, ist eine seltene, sporadisch auftretende eosinophile Dermatose mit polymorphem klinischem Bild. Als typisch gelten entzundliche Erytheme oder Plaques an den Extremitaten, die initial als Erysipel imponieren konnen, unter antimikrobieller Behandlung aber persistieren. Die eosinophile Zellulitis ist eine Ausschlussdiagnose, die in Zusammenschau von klinischem Befund und charakteristischem histologischem Bild (Flammenfiguren) nur im Verlauf gestellt werden kann. Mit einer Vielzahl moglicher Triggerfaktoren ist die Atiologie nicht geklart. Die Beteiligung abnormer Th2-Zellen, des Zytokins IL-5 und aktivierter eosinophiler Granulozyten lasst eine unspezifische Hypersensitivitatsreaktion auf exo- und endogene Stimuli vermuten. Die haufiger vorkommenden chronisch- rezidivierenden Formen lassen sich durch Glukokortikoide gunstig beeinflussen. Der Verlauf ist meist selbstlimitierend, ohne Residuen. Aufgrund von Ubergangen in hamatoonkologische Erkrankungen sind Verlaufskontrollen angezeigt. PMID- 27767283 TI - Anaphylaxie auf Paraphenylendiamin. PMID- 27767284 TI - Ein Fall von Morbus Hailey-Hailey in Verbindung mit einem Eczema Herpeticatum. PMID- 27767285 TI - Therapierefraktare Schwellung und Rotung der Bauchdecke. PMID- 27767286 TI - Rote Beulen am Rucken eines Neugeborenen. PMID- 27767287 TI - Necrobiosis lipoidica of the glans penis: a case report and literature review. PMID- 27767289 TI - A red, bumpy back in a neonate. PMID- 27767290 TI - Nachbericht uber den Kurs "Pathology of Melanocytic Tumors" in New York vom 09. 10. Mai 2016. PMID- 27767288 TI - Tricenter analysis of cofactors and comorbidity in patients with pyoderma gangrenosum. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a rare neutrophilic, ulcerative skin disease of largely unknown pathophysiology. MATERIAL AND METHODS: In this study, potentially relevant cofactors and comorbidities in patients with PG from three dermatological wound care centers in Germany were evaluated. RESULTS: Of the 121 patients assessed, women (66.9 %) were more frequently affected than men. Patient age ranged from 18 to 96 years (mean 59.8). Wound size varied from 1-600 cm2 (mean 65.6 cm2), and the pain intensity was predominantly very high (VAS 1-10, mean 7). The lower legs were most commonly (71.9 %) affected. Overall, 12 (9.9 %) patients had inflammatory bowel disease (ulcerative colitis, 5.8 %; Crohn's disease, 4.1 %), 14.1 % exhibited rheumatic comorbidities. Neoplasms were found in 20.6 % of patients, with 6.6 % classified as hematological and 14.0 % as solid neoplasms. With respect to criteria for the metabolic syndrome, obesity was found in 69.4 %, arterial hypertension in 57.9 %, and diabetes mellitus in 33.9 % of patients. CONCLUSIONS: The present data analysis confirms the association of PG with metabolic syndrome and neoplasms. In the future, these aspects should be included in the targeted diagnostic workup of patients with PG and subsequently treated in a timely fashion. PMID- 27767291 TI - A Modified Polysaccharide-Based Hydrogel for Enhanced Osteogenic Maturation and Mineralization Independent of Differentiation Factors. AB - Bone related problems are increasing as a consequence of increased life expectancy, disorders in life style, and other medical conditions enforcing the need for functional bones prepared in vitro at affordable cost. Lack of suitable surface which promotes growth of both osteogenic and nonosteogenic cells is a major limitation. Here a novel biomaterial is reported that is synthesized from natural polysaccharide, namely, tamarind kernel polysaccharide (TKP), which is grafted with hydrophilic acrylic acid (AA) by radical polymerization. Modification in surface functionality removes unwanted proteins and alters hydrophilic/hydrophobic balance. TKP-AA is suitable for the growth of different nonosteogenic and osteogenic cells. This material is suitable for osteoblasts and promotes in vitro mineralization and differentiation without the addition of exogenous growth factors. TKP-AA can be used for the growth of mesenchymal stem cell-derived osteoblasts. It is suggested that TKP-AA can potentially be used as a scaffold for diverse cell types and particularly for bone tissue engineering at low cost. PMID- 27767293 TI - X-ray Analyses of Lead Adsorption on the (001), (110), and (012) Hematite Surfaces. AB - Predicting the environmental fate of lead relies on a detailed understanding of its coordination to mineral surfaces, which in turn reflects the innate reactivity of the mineral surface. In this research, we investigated fundamental dependencies in lead adsorption to hematite by coupling extended X-ray absorption fine structure (EXAFS) spectroscopy on hematite particles (10 and 50 nm) with resonant anomalous X-ray reflectivity (RAXR) to single crystals expressing the (001), (012), or (110) crystallographic face. The EXAFS showed that lead adsorbed in a bidentate inner-sphere manner in both edge and corner sharing arrangements on the FeO6 octahedra for both particle sizes. The RAXR measurements confirmed these inner-sphere adsorption modes for all three hematite surfaces and additionally revealed outer-sphere adsorption modes not seen in the EXAFS. Lead uptake was larger and pH dependence was greater for the (012) and (110) surfaces, than the (001) surface, due to their expressing singly- and triply coordinated oxygen atoms the (001) surface lacks. In coupling these two techniques we provide a more detailed and nuanced picture of the coordination of lead to hematite while also providing fundamental insight into the reactivity of hematite. PMID- 27767292 TI - Low Blood Pressure Is Associated With Greater Risk for Cardiovascular Events in Treated Adults With and Without Apparent Treatment-Resistant Hypertension. AB - Apparent treatment-resistant hypertension (aTRH) may confound the reported relationship between low blood pressure (BP) and increased cardiovascular disease (CVD) in treated hypertensive patients. Incident CVD was assessed in treated hypertensive patients with and without aTRH (BP >=140 and/or >=90 mm Hg on >=3 medications or <140/<90 mm Hg on >=4 BP medications) at three BP levels: 1: <120 and/or <70 mm Hg and <140/<90 mm Hg; 2: 120-139/70-89 mm Hg; and 3: >=140 and/or >=90 mm Hg. Electronic health data were matched to emergency and hospital claims for incident CVD in 118 356 treated hypertensive patients. In adults with and without aTRH, respectively, CVD was greater in level 1 versus level 2 (multivariable hazard ratio, 1.88 [95% confidence interval [CI], 1.70-2.07]; 1.71 [95% CI, 1.59-1.84]), intermediate in level 1 versus level 3 (hazard ratio, 1.32 [95% CI, 1.21-1.44]; 0.99, [95% CI, 0.92-1.07]), and lowest in level 2 versus level 3 (hazard ratio, 0.70 [95% CI, 0.65-0.76]; 0.58, [95% CI, 0.54-0.62]). Low treated BP was associated with more CVD than less stringent BP control irrespective of aTRH. PMID- 27767294 TI - Manipulating and Visualizing Molecular Interactions in Customized Nanoscale Spaces. AB - We present a dynamically adjustable nanofluidic platform for formatting the conformations of and visualizing the interaction kinetics between biomolecules in solution, offering new time resolution and control of the reaction processes. This platform extends convex lens-induced confinement (CLiC), a technique for imaging molecules under confinement, by introducing a system for in situ modification of the chemical environment; this system uses a deep microchannel to diffusively exchange reagents within the nanoscale imaging region, whose height is fixed by a nanopost array. To illustrate, we visualize and manipulate salt induced, surfactant-induced, and enzyme-induced reactions between small-molecule reagents and DNA molecules, where the conformations of the DNA molecules are formatted by the imposed nanoscale confinement. In response to dynamically modifying the local salt concentration, we report two salt-induced transitions in DNA molecules which occur on separate time scales: a rapid change in polymer extension due to modified local ionic screening and a gradual change in polymer brightness, reflecting release of intercalated YOYO-1 dye. Our time-resolved measurements provide new insights into the influence of YOYO-1 dye on polymer stiffness. In response to introducing cationic surfactants in solution, we temporally resolve single-molecule compaction trajectories of DNA polymers, guided by the confining nanogroove environment; this is in contrast to the uncontrolled collapse which would occur in free solution under similar conditions. In the presence of restriction enzymes, we directly visualize the cleavage of multiple DNA sites under adjustable nanoscale confinement. By using nanofabricated, nonabsorbing, low-background glass walls to confine biomolecules, our nanofluidic platform facilitates quantitative exploration of physiologically and biotechnologically relevant processes at the nanoscale. This device provides new kinetic information about dynamic chemical processes at the single-molecule level, using advancements in the CLiC design including a microchannel-based diffuser and postarray-based dialysis slit. PMID- 27767296 TI - Size-Dependent Filling Behavior of UV-Curable Di(meth)acrylate Resins into Carbon Coated Anodic Aluminum Oxide Pores of around 20 nm. AB - Ultraviolet (UV) nanoimprint lithography is a promising nanofabrication technology with cost efficiency and high throughput for sub-20 nm size semiconductor, data storage, and optical devices. To test formability of organic resist mask patterns, we investigated whether the type of polymerizable di(meth)acrylate monomer affected the fabrication of cured resin nanopillars by UV nanoimprinting using molds with pores of around 20 nm. We used carbon-coated, porous, anodic aluminum oxide (AAO) films prepared by electrochemical oxidation and thermal chemical vapor deposition as molds, because the pore diameter distribution in the range of 10-40 nm was suitable for combinatorial testing to investigate whether UV-curable resins comprising each monomer were filled into the mold recesses in UV nanoimprinting. Although the UV-curable resins, except for a bisphenol A-based one, detached from the molds without pull-out defects after radical photopolymerization under UV light, the number of cured resin nanopillars was independent of the viscosity of the monomer(s) in each resin. The number of resin nanopillars increased and their diameter decreased as the number of hydroxy groups in the aliphatic diacrylate monomers increased. It was concluded that the filling of the carbon-coated pores having diameters of around 20 nm with UV-curable resins was promoted by the presence of hydroxy groups in the aliphatic di(meth)acrylate monomers. PMID- 27767295 TI - Carbon Coated SnS/SnO2 Heterostructures Wrapping on CNFs as an Improved Performance Anode for Li-Ion Batteries: Lithiation-Induced Structural Optimization upon Cycling. AB - Carbon coated SnS/SnO2 heterostructures wrapping on carbon nanofibers (C@SnS/SnO2@CNFs) was demonstrated to have excellent performance as an anode material for Li-ion batteries. C@SnS/SnO2@CNFs electrode delivers high reversible capacity of 826.8 mA h g-1 (500th cycle) at the current density of 1.0 A g-1. However, an interesting phenomenon of increasing capacity on cycling can be observed. According to the analysis of the evolution of structure and electrochemical property, C@SnS/SnO2@CNFs is demonstrated to experience the progress of conversion from nanowalls containing polycrystals into amorphous nanosheets with high porosity and larger surface upon cycling. The above lithiation-induced structural optimization provides larger effective surface areas and encourages the conversion reactions, which can promote charge transfer and also enhance the reversibility of the conversion reactions of SnS and SnO2 inducing the increasing reversible capacity. The study explains the progress of increasing capacity of C@SnS/SnO2@CNFs and likewise provides a perspective on optimization of the electrochemical performance of electrodes. PMID- 27767297 TI - Improving the Working Efficiency of a Triboelectric Nanogenerator by the Semimetallic PEDOT:PSS Hole Transport Layer and Its Application in Self-Powered Active Acetylene Gas Sensing. AB - Herein we report an enhanced triboelectric nanogenerator (TENG) based on the contact-separation mode between a patterned film of polydimethylsiloxane (PDMS) with a semimetallic elastomer of poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and a nylon fiber film. The addition of ethylene glycol to the PEDOT:PSS film improves the functionality of the TENG significantly, yielding promising applicability in both indoor and outdoor (i.e., under sunlight) environments, with the maximum instantaneous power of 0.09 mW (indoors) and 0.2 mW (outdoors) for the load resistance of 3.8 MOmega. The device can also generate 11.2 V and 0.08 MUA cm-2 in response to the forearm movement of a human. Additionally, by replacing the bare nylon fiber in the TENG design with a Ag@ZnO/nylon fiber film, a self powered active sensor (triboelectric nanogenerator-based sensor; TENS) has been realized to detect acetylene (C2H2) gas. The TENS exhibits excellent sensitivity of 70.9% (indoors) and 89% (outdoors) to C2H2 gas of 1000 ppm concentration. The proposed approach for harvesting energy and sensing can be advantageous in practical applications and may stimulate new research that will enhance nanogenerators as well as wearable, self-powered active sensors. PMID- 27767298 TI - Advances in Quantum Mechanochemistry: Electronic Structure Methods and Force Analysis. AB - In quantum mechanochemistry, quantum chemical methods are used to describe molecules under the influence of an external force. The calculation of geometries, energies, transition states, reaction rates, and spectroscopic properties of molecules on the force-modified potential energy surfaces is the key to gain an in-depth understanding of mechanochemical processes at the molecular level. In this review, we present recent advances in the field of quantum mechanochemistry and introduce the quantum chemical methods used to calculate the properties of molecules under an external force. We place special emphasis on quantum chemical force analysis tools, which can be used to identify the mechanochemically relevant degrees of freedom in a deformed molecule, and spotlight selected applications of quantum mechanochemical methods to point out their synergistic relationship with experiments. PMID- 27767299 TI - Replacement of Calcite (CaCO3) by Cerussite (PbCO3). AB - The mobility of toxic elements, such as lead (Pb) can be attenuated by adsorption, incorporation, and precipitation on carbonate minerals in subsurface environments. Here, we report a study of the bulk transformation of single crystal calcite (CaCO3) into polycrystalline cerussite (PbCO3) through reaction with acidic Pb-bearing solutions. This reaction began with the growth of a cerussite shell on top of calcite surfaces followed by the replacement of the remaining calcite core. The external shape of the original calcite was preserved by a balance between calcite dissolution and cerussite growth controlled by adjusting the Pb2+ concentration and pH. The relation between the rounded calcite core and the surrounding lath-shaped cerussite aggregates was imaged by transmission X-ray microscopy, which revealed preferentially elongated cerussite crystals parallel to the surface and edge directions of calcite. The replacement reaction involved concurrent development of ~100 nm wide pores parallel to calcite c-glide or (120) planes, which may have provided permeability for chemical exchange during the reaction. X-ray reflectivity measurements showed no clear epitaxial relation of cerussite to the calcite (104) surface. These results demonstrate Pb sequestration through mineral replacement reactions and the critical role of nanoporosity (3% by volume) on the solid phase transformation through a dissolution-recrystallization mechanism. PMID- 27767300 TI - Configuration Interaction Study on the AlBr Molecule Including Spin-Orbit Coupling. AB - High-level ab initio calculations on the ground and the excited states of aluminum monobromide (AlBr) have been carried out by utilizing the internally contracted multireference configuration interaction method plus Davidson correction (icMRCI+Q) method. The core-valence correlation (CV) correction and spin-orbit coupling (SOC) effect have been investigated in the calculations. The potential energy curves (PECs) of the 13 Lambda-S states, as well as those of the 24 Omega states generated from the Lambda-S states under the SOC effect, have been obtained. The spectroscopic constants of the bound states have been determined, which are in accordance with the available experiment results. The SOC induced predissociation mechanisms of the a3Pi and A1Pi states have been analyzed with the aid of the spin-orbit matrix element. The transition properties of 0+(2)-X0+, 1(1)-X0+ and 1(2)-X0+ transitions are predicted, including the transition dipole moments (TDMs), Franck-Condon factors (FCFs), and the radiative lifetimes. Finally, the possibility of AlBr to be used for molecular laser cooling has been discussed based on our calculations. PMID- 27767301 TI - Simulating Protein Fold Switching by Replica Exchange with Tunneling. AB - Recent experiments suggest that an amino acid sequence encodes not only the native fold of a protein but also other forms that are essential for its function or are important during folding or association. These various forms populate a multifunnel folding and association landscape where mutations, changes in environment, or interaction with other molecules switch between the encoded folds. We introduce replica exchange with tunneling as a way to efficiently simulate switching between distinct folds of proteins and protein aggregates. The correctness and efficiency of our approach are demonstrated in a series of simulations covering a wide range of proteins, from a small 11-residue large designed peptide to two 56-residue large mutants of the A and B domains of protein G. PMID- 27767302 TI - Condensation of Carboxylic Acids with Non-Nucleophilic N-Heterocycles and Anilides Using Boc2O. AB - A novel condensation reaction of carboxylic acids with various non-nucleophilic N heterocycles and anilides was developed. The reaction proceeds in the presence of di-tert-butyl dicarbonate (Boc2O), catalytic 4-(dimethylamino)pyridine (DMAP), and 2,6-lutidine and is applicable to the acylation of a wide range of non nucleophilic nitrogen compounds, including indoles, pyrroles, pyrazole, carbazole, lactams, oxazolidinones, and anilides with high functional group compatibility. The scope of indoles, carboxylic acids, and anilides was also studied. PMID- 27767303 TI - Coarse-Grained Simulations Complemented by Atomistic Molecular Dynamics Provide New Insights into Folding and Unfolding of Human Telomeric G-Quadruplexes. AB - G-quadruplexes are the most important noncanonical DNA architectures. Many quadruplex-forming sequences, including the human telomeric sequence d(GGGTTA)n, have been investigated due to their implications in cancer and other diseases, and because of their potential in DNA-based nanotechnology. Despite the availability of atomistic structural studies of folded G-quadruplexes, their folding pathways remain mysterious, and mutually contradictory models of folding coexist in the literature. Recent experiments convincingly demonstrated that G quadruplex folding often takes days to reach thermodynamic equilibrium. Based on atomistic simulations of diverse classes of intermediates in G-quadruplex folding, we have suggested that the folding is an extremely multipathway process combining a kinetic partitioning mechanism with conformational diffusion. However, complete G-quadruplex folding is far beyond the time scale of atomistic simulations. Here we use high-resolution coarse-grained simulations to investigate potential unfolding intermediates, whose structural dynamics are then further explored with all-atom simulations. This multiscale approach indicates how various pathways are interconnected in a complex network. Spontaneous conversions between different folds are observed. We demonstrate the inability of simple order parameters, such as radius of gyration or the number of native H bonds, to describe the folding landscape of the G-quadruplexes. Our study also provides information relevant to further development of the coarse-grained force field. PMID- 27767304 TI - TiO2 Nanotubes Arrays Loaded with Ligand-Free Au Nanoparticles: Enhancement in Photocatalytic Activity. AB - A new protocol to synthesize size-controlled Au nanoparticles (NPs) loaded onto vertically aligned anatase TiO2 nanotubes arrays (TNTAs) prepared by electrochemical anodization is reported. Ligand-free Au NPs (<10 nm) were deposited onto anatase TNTAs supports, finely tuning the Au loading by controlling the immersion time of the support into metal vapor synthesis (MVS) derived Au-acetone solutions. The Au/TNTAs composites were characterized by electron microscopies (SEM, (S)TEM), X-ray diffraction, X-ray photoelectron spectroscopy, and UV-vis spectroscopy. Their photocatalytic efficiency was evaluated in toluene degradation in air under ambient conditions without thermal or chemical postsynthetic treatments. The role of Au loadings was pointed out, obtaining a three times enhancement of the pristine anatase TNTAs activity with the best sample containing 3.3 MUg Au cm-2. PMID- 27767305 TI - BSA Protein-Mediated Synthesis of Hollow Mesoporous Silica Nanotubes, and Their Carbohydrate Conjugates for Targeting Cancer Cells and Detecting Mycobacteria. AB - A straightforward method was developed to synthesize hollow mesoporous silica nanotubes (HMSNTs) using bovine serum protein (BSA) as the protective coating and phosphate buffered saline (PBS) as the etching agent at room temperature. Galactose-grafted HMSNTs significantly reduced phagocytosis by macrophages, and enhanced cellular uptake by A549 cells via caveolae-mediated uptake pathway. Trehalose-conjugated HMSNTs interacted strongly with mycobacteria, showing the linear detection range from 1 * 104 to 1 * 108 bacteria/mL and the detection limit of 1 * 103 bacteria/mL. In all cases, the hollow nanotube structure showed higher cellular uptake, bacterial binding, and detection efficiency than their spherical counterpart. PMID- 27767306 TI - Surface Modification of C3N4 through Oxygen-Plasma Treatment: A Simple Way toward Excellent Hydrophilicity. AB - We developed a universal method to prepare hydrophilic carbon nitrogen (C3N4) nanosheets. By treating C3N4 nanosheets with oxygen plasma, hydroxylamine groups (N-OH) with intense protonation could be introduced on the surface; moreover, the content of N-OH groups increased linearly with the oxygen-plasma treatment time. Thanks to the excellent hydrophilicity, uniformly dispersed C3N4 solution were prepared, which was further translated into C3N4 paper by simple vacuum filtration. Pure C3N4 paper with good stability, excellent hydrophilicity, and biocompatibility were proved to have excellent performance in tissue repair. Further research demonstrated that the oxygen-plasma treatment method can also introduce N-OH groups into other nitrogen-containing carbon materials (NCMs) such as N-doped graphene, N-doped carbon nanotube, and C2N, which offers a new perspective on the surface modification and functionalization of these carbon nanomaterials. PMID- 27767307 TI - H-Bonding Interactions Induced Two Isostructural Cd(II) Metal-Organic Frameworks Showing Different Selective Detection of Nitroaromatic Explosives. AB - Two luminescent Cd(II) metal-organic frameworks (MOFs) were prepared from electron-rich pi-conjugated fluorescent ligands. They are isostructural with sql nets. Their strong luminescences can be quenched by a series of nitroaromatic explosives. Notably, MOF 1 shows highly selective and sensitive detection of 4 nitrophenol (4-NP), while MOF 2 exhibits good responses toward picric acid (PA) compared with other nitroaromatic explosives. This different order of quenching efficiency is because there are H-bonding interactions between MOF 1 and 4-NP, while MOF 2 lacks these H-bonding interactions. MOF 1 displays highly selective and sensitive detection of 4-NP with the high quenching constant (6.74* 104 M-1) and low detection limit (34.48 ppb), which is better than those of known MOFs. MOF 1 and MOF 2 have highly sensitive and selective detection of 4-NP and PA in the practical application, respectively. PMID- 27767308 TI - Gadolinium (Gd) Oxide, Carbide, and Carbonyl Cation Bond Energies and Evaluation of the Gd + O -> GdO+ + e- Chemi-Ionization Reaction Enthalpy. AB - Guided ion beam mass spectrometry (GIBMS) is used to measure the kinetic energy dependent product ion cross sections for reactions of the lanthanide metal gadolinium cation (Gd+) with O2, CO2, and CO and for reactions of GdO+ with CO, O2, and Xe. GdO+ is formed through barrierless and exothermic processes in the reactions of Gd+ with O2 and CO2. All other reactions observed are endothermic, and analyses of their kinetic energy dependent cross sections yield 0 K bond dissociation energies (BDEs) for GdO+, GdC+, and GdCO+. The 0 K BDE for GdO+ is determined from five different reactions to be 7.69 +/- 0.10 eV, and this value is combined with literature data to derive the ionization energy (IE) of GdO as 5.82 +/- 0.16 eV. Additionally, GdC+ and GdCO+ BDEs of 3.18 +/- 0.18 eV and 0.65 +/- 0.06 eV are obtained from analysis of the Gd+ reactions with CO and CO2, respectively. Theoretical GdO+, GdC+, and GdCO+ BDEs are calculated for comparison with experiment using various Gd basis sets with an effective core potential and several levels of theory. For calculations that correctly predict a 10D ground state for Gd+, good agreement between theoretical and measured GdC+ and GdCO+ BDEs is obtained, whereas the GdO+ BDE is underestimated in these calculations by about 0.8 eV. Additional BDEs for GdO+ and GdC+ are calculated using triple- and quadruple-zeta correlation consistent all-electron basis sets for Gd. Calculations with these basis sets provide better agreement with experiment for GdO+ but not for GdC+. The measured Gd+ oxide, carbide, and carbonyl BDEs are similar to those for the group 3 metal ions, Sc+ and Y+. This is attributed to similarities in the ground state electronic configurations of these metal ions leading to similar interaction strengths. The experimental GdO+ BDE measured here combined with the known IE of Gd is used to determine an exothermicity of 1.54 +/- 0.10 eV for the Gd chemi-ionization reaction with atomic oxygen. This value is consistent with but more precise than previous literature values. PMID- 27767309 TI - Scaling Atomic Partial Charges of Carbonate Solvents for Lithium Ion Solvation and Diffusion. AB - Lithium-ion solvation and diffusion properties in ethylene carbonate (EC) and propylene carbonate (PC) were studied by molecular simulation, experiments, and electronic structure calculations. Studies carried out in water provide a reference for interpretation. Classical molecular dynamics simulation results are compared to ab initio molecular dynamics to assess nonpolarizable force field parameters for solvation structure of the carbonate solvents. Quasi-chemical theory (QCT) was adapted to take advantage of fourfold occupancy of the near neighbor solvation structure observed in simulations and used to calculate solvation free energies. The computed free energy for transfer of Li+ to PC from water, based on electronic structure calculations with cluster-QCT, agrees with the experimental value. The simulation-based direct-QCT results with scaled partial charges agree with the electronic structure-based QCT values. The computed Li+/PF6- transference numbers of 0.35/0.65 (EC) and 0.31/0.69 (PC) agree well with NMR experimental values of 0.31/0.69 (EC) and 0.34/0.66 (PC) and similar values obtained here with impedance spectroscopy. These combined results demonstrate that solvent partial charges can be scaled in systems dominated by strong electrostatic interactions to achieve trends in ion solvation and transport properties that are comparable to ab initio and experimental results. Thus, the results support the use of scaled partial charges in simple, nonpolarizable force fields in future studies of these electrolyte solutions. PMID- 27767310 TI - Influence of Soil Factors on the Stereoselective Fate of a Novel Chiral Insecticide, Paichongding, in Flooded Paddy Soils. AB - In this study, the fate of paichongding was investigated in three soils with contrasting soil properties. In general, low soil pH has the potential to retard the mineralization and promote the dissipation of paichongding and the formation of its primary transformation product and to accelerate the formation of bound residue. The dissipation of paichongding stereoisomers was very fast and diastereoselective. This selectivity was found only between diastereomers and not between enantiomers and was observed to be soil dependent. In the acidic soil, the enantiomers (5R,7R)- and (5S,7S)-paichongding were degraded more quickly than (5R,7S)- and (5S,7R)-paichongding, whereas a contrary trend was observed in the neutral soil, and such selectivity did not occur in the alkaline soil. The OM and clay contents also played important roles in the fate of paichongding. This effect of soil properties should be considered in risk assessment of chiral pesticides and their application in the field. PMID- 27767312 TI - Tuning the Luminescent Properties of a Ag/Au Tetranuclear Complex Featuring Metallophilic Interactions via Solvent-Dependent Structural Isomerization. AB - In this paper the reaction products of the basic gold(I) species [Au(C6Cl5)2]- against the acid salt Ag(OClO3) in the presence of the S-donor macrocyclic ligand 1,4,7-trithiacyclononane ([9]aneS3) are studied in different solvents. Two different isomers of stoichiometry [{Au(C6Cl5)2}Ag([9]aneS3)]2 were isolated depending on the solvent used, dichloromethane or tetrahydrofuran, which show different luminescence in the solid state. X-ray diffraction studies of these compounds reveals that both show the same heteropolynuclear Ag...Au...Au...Ag system but with different Au...Au interaction distances and different relative positions of the cationic fragment [Ag([9]aneS3)]+ in the structure with respect the bimetallic Au...Au core. This work includes a study of the optical properties of both isomers, as well as time-dependent density functional theory calculations that were performed to determine the origin of their different luminescence. PMID- 27767311 TI - Bioinspired Multifunctional Membrane for Aquatic Micropollutants Removal. AB - Micropollutants present in water have many detrimental effects on the ecosystem. Membrane technology plays an important role in the removal of micropollutants, but there remain significant challenges such as concentration polarization, membrane fouling, and variable permeate quality. The work reported here uses a multifunctional membrane with rejection, adsorption, and catalysis functions to solve these problems. On the basis of mussel-inspired chemistry and biological membrane properties, a multifunctional membrane was prepared by applying "reverse filtration" of a laccase solution and subsequent "dopamine coating" on a nanofiltration (NF) membrane support, which was tested on bisphenol A (BPA) removal. Three NF membranes were chosen for the preparation of the multifunctional membranes on the basis of the membrane properties and enzyme immobilization efficiency. Compared with the pristine membrane, the multifunctional membrane exhibited significant improvement of BPA removal (78.21 +/- 1.95%, 84.27 +/- 7.30%, and 97.04 +/- 0.33% for NT103, NF270, and NF90, respectively), all of which are clearly superior to the conventional Fenton treatment (55.0%) under similar conditions and comparable to soluble laccase coupled with NF270 membrane filtration (89.0%). The improvement would appear to be due to a combination of separation (reducing the enzymatic burden), adsorption (enriching the substrate concentration as well as prolonging the residence time), and lastly, catalysis (oxidizing the pollutants and breaking the "adsorption saturation limits"). Furthermore, the synergistic effect of the polydopamine (PDA) layer on the enzymatic oxidation of BPA was confirmed, which was due to its enhanced adsorption and electron transfer performance. The multifunctional membrane could be reused for at least seven cycles with an acceptable activity loss, demonstrating good potential for removal of micropollutants. PMID- 27767313 TI - Plastic Crystals with Polar Halochromate Anion: Thermosensitive Dielectrics Based upon Plastic Transition and Dipole Rotation. AB - Plastic crystals functioning with rotatable components offer new opportunities in areas such as modern optoelectronic materials. Here, by taking advantage of controllable rotation of the polar component within the ion-pair plastic-crystal system, we present two such crystals, namely, (Et4N)(CrO3X) (X = Cl or Br), which are unusual examples exhibiting two-staged thermosensitive dielectric responses above room temperature. The frequency-dependent response in the first stage is due to the structural phase transitions, whereas that in the second stage is induced by dynamic rotation of the polar halochromate anions in their NaCl-type plastic-crystal phases. The intrinsic mechanisms were also explicated by molecular dynamics simulations, providing a direct insight into the dynamic characteristics of these two compounds. These studies show that ionic plastic crystals functioning with polar groups are an attractive candidate as sensitive thermoresponsive dielectric materials. PMID- 27767314 TI - Correction to "Improved False Discovery Rate Estimation Procedure for Shotgun Proteomics". PMID- 27767315 TI - Inconsistencies in the Electronic Properties of Phosphorene Nanotubes: New Insights from Large-Scale DFT Calculations. AB - Contrary to recent reports, we show that the electronic properties of phosphorene nanotubes are surprisingly rich and much more complex than previously assumed. We find that all phosphorene nanotubes exhibit an intricate direct-to-indirect band gap transition as the nanotube diameter decreases, a unique property not identified in any prior studies (which claimed either direct or indirect band gaps only) that we uncover with large-scale DFT calculations. We address these previous inconsistencies by detailed analyses of orbital interactions, which reveal that the strain associated with decreasing the nanotube diameter causes a transition from a direct to an indirect band gap for all of the phosphorene nanotubes. We show that our findings are completely general, and extensive calculations across several exchange-correlation functionals verify our conclusions. Most importantly, our results and analyses resolve a long-standing question on the electronic properties of phosphorus nanotubes and bring closure to previously conflicting findings in these unique nanostructures. PMID- 27767317 TI - Asymmetric Induction in Hydroacylation by Cooperative Iminium Ion-Transition Metal Catalysis. AB - A new strategy for the rhodium-catalyzed enantioselective hydroacylation is described. This has been achieved through the merger of iminium ion catalysis and transition-metal catalysis such that asymmetric induction derives from a readily accessible, inexpensive chiral nonracemic secondary amine catalyst rather than a chiral nonracemic phosphine as is typical of conventional asymmetric hydroacylation methods. PMID- 27767316 TI - The Phenol-Ene Reaction: Biaryl Synthesis via Trapping Reactions between HDDA Generated Benzynes and Phenolics. AB - Benzynes produced thermally by the cycloisomerization of triyne-containing precursors [i.e., by the hexadehydro-Diels-Alder (HDDA) reaction] react with phenols at the carbon ortho to the hydroxyl in an enelike fashion. Following tautomerization of the intermediate cyclohexadienones, this produces biaryl derivatives. DFT calculations of model reactions support this mechanistic interpretation. Substituted, unsymmetrical phenols and bis-phenols react in a fashion that can be explained by engagement of the most readily available (non hydrogen-bonded) hydroxyl in the phenol-ene process. PMID- 27767319 TI - One-Pot Synthesis of Decahydropyrene via Tandem C-H Activation/Intramolecular Diels-Alder/1,3-Dipolar Cycloaddition. AB - A novel decahydropyrene synthesis has been successfully developed involving a tandem rhodium-catalyzed C-H activation/intramolecular Diels-Alder reaction/1,3 dipolar cycloaddition cascade process by using diazole as a traceless directing group. The advantage of this one-pot strategy is a quite simple, efficient, highly stereoselective, and unique product structure. PMID- 27767318 TI - Diacyl Disulfide: A Reagent for Chemoselective Acylation of Phenols Enabled by 4 (N,N-Dimethylamino)pyridine Catalysis. AB - A general and excellent acylation reagent, diacyl disulfide, was uncovered for efficient ester formation enabled by DMAP (4-(N,N-dimethylamino)pyridine) catalysis. This protocol offered a promising synthetic platform on site-selective acylation of phenolic and primary aliphatic hydroxyl groups, which greatly expanded the realm of protecting group chemistry. The importance of the reagent was also reflected by its excellent moisture tolerance, high efficiency, and potential in synthetic chemistry and biologically meaningful natural product modification. PMID- 27767320 TI - Sterically Hindered Chiral Ferrocenyl P,N,N-Ligands for Highly Diastereo /Enantioselective Ir-Catalyzed Hydrogenation of alpha-Alkyl-beta-ketoesters via Dynamic Kinetic Resolution. AB - A new class of sterically hindered chiral ferrocenyl P,N,N-ligands have been prepared through a two-step transformation from (Sc,Rp)-PPFNH2, in which a new (R)-stereogenic center at the pyridinylmethyl position was generated in high diastereoselectivity. With these newly developed P,N,N-ligands, Ir-catalyzed asymmetric hydrogenation of various alpha-alkyl-substituted beta-aryl-beta ketoesters via dynamic kinetic resolution has been realized in high diastereo- and enantioselectivities for the first time, which led to a variety of optically active anti-beta-hydroxyesters in up to 99% ee. The study indicated that the additional stereocenter at the pyridinylmethyl position of these ligands is crucial to realize this hydrogenation. PMID- 27767321 TI - Phosphine-Catalyzed Enantioselective [4 + 3] Annulation of Allenoates with C,N Cyclic Azomethine Imines: Synthesis of Quinazoline-Based Tricyclic Heterocycles. AB - With the use of a commercially available chiral phosphine as the catalyst, the first catalytic enantioselective [4 + 3] annulation of allenoates with C,N-cyclic azomethine imines is developed. The reaction works efficiently under mild reaction conditions to afford seven-membered ring-fused quinazoline-based tricyclic heterocycles in high yields with good to excellent diastereo- and enantioselectivities. PMID- 27767322 TI - Correction to "On the Importance of Well-Calibrated Scores for Identifying Shotgun Proteomics Spectra". PMID- 27767323 TI - Site-Selective Plasmonic Etching of Silver Nanocubes. AB - Plasmon-induced charge separation (PICS) at the interface between a plasmonic nanoparticle and semiconductor is now widely used for photovoltaics and photocatalysis. Here we take advantage of PICS for site-selective nanoetching of silver nanocubes on TiO2 beyond the diffraction limit. A silver nanocube exhibits two resonance modes localized at the top and bottom of the nanocube (distal and proximal modes, respectively) when it is placed on TiO2. We achieved selective etching at the top and the bottom of the nanocubes by PICS based on the distal and proximal modes, respectively. The site-selective nanophotonic etching reveals that the anodic reaction involved in PICS is induced by the plasmonic near field, which causes an external photoelectric effect. In particular, the distal mode etching at the top edges is explained in terms of ejection of energetic electrons (or hot electrons) from the distal site to TiO2 across the nanocube. PMID- 27767325 TI - Fulfilled preferences, perceived control, life satisfaction, and loneliness in elderly long-term care residents. AB - OBJECTIVES: Person-centered care constructs such as fulfilled preferences, sense of control, and life satisfaction might contribute to loneliness among nursing home residents, but these relationships have not been thoroughly explored. The aim of this study was to examine the relationship between fulfilled preferences and loneliness in nursing home residents with perceived control and life satisfaction as potential mediators. METHODS: The study utilized a cross sectional design, examining the targeted variables with a questionnaire administered by trained research staff. A convenience sample of 65 residents (median age = 71) of eight nursing homes were interviewed. Linear regression analysis was utilized to examine the mediation hypotheses. RESULTS: The relationships between fulfilled preferences and loneliness (beta = -.377, p = .002), fulfilled preferences and perceived control (beta = -.577, p < .001), and perceived control and loneliness (beta = .606, p < .001) were significant, and the relationship between fulfilled preferences and loneliness (beta = -.040, p = .744) became non-significant when perceived control was included in the model. The relationships between fulfilled preferences and life satisfaction (beta = .420, p < .001) and life satisfaction and loneliness (beta = -.598, p < .001) were significant, and the relationship between fulfilled preferences and loneliness (beta = -.152, p = .174) became non-significant when life satisfaction was included in the model. CONCLUSION: The findings suggest an important association between person-centered care, particularly fulfilling personal care and recreation preferences, and social-affective needs of long-term care residents. Fulfilling preferences may be an appropriate intervention target for loneliness. PMID- 27767324 TI - Brain diffusion changes in Eisenmenger syndrome. AB - OBJECTIVE: This preliminary study aimed to evaluate whether there are changes in the apparent diffusion coefficient (ADC) values of the brain in patients presenting with Eisenmenger syndrome (ES). METHODS: This cross-sectional study included 10 consecutively recruited patients with ES and 10 healthy control subjects. In the patients and controls, eight distinct neuroanatomical locations were selected for analysis. Quantitative measurements of ADC values of the frontal white matter (FWM), occipital white matter, lentiform nucleus (LN), thalamus, frontal cortex, anterior and posterior limbs of the internal capsule and caudate nucleus were measured. Statistical analysis was performed using SPSS(r) (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) for Windows v. 20. Data were presented as mean +/- standard deviation values. The Kruskal-Wallis test was used to assess differences in the ADC values of each brain location between the ES group and the control group. Statistical significance was accepted at the level of p < 0.05. RESULTS: The ADC values of the FWM and LN were significantly higher in the ES group than that in the control group. The mean ADC levels of other brain regions were not significantly different between the groups. CONCLUSION: Chronic hypoxia in patients with ES may lead to diffusion changes in the brain tissue. There is a need for further studies to assess the clinical significance of cerebral ADC values in patients with ES. Advances in knowledge: The ratio of extracellular volume to intracellular volume in the FWM and LN can be considered to be increased in patients with ES. PMID- 27767326 TI - Delirium in people living with dementia: a call for global solutions. PMID- 27767327 TI - Lung Dendritic Cells: Shaping Immune Responses throughout Chronic Obstructive Pulmonary Disease Progression. AB - Hallmarks of chronic obstructive pulmonary disease (COPD) include innate inflammation and remodeling of small airways, which begin in early disease, and the development of lung lymphoid follicles (LLF), indicative of adaptive immunity, in more spirometrically severe stages. Common to these processes in all stages is orchestration by dendritic cells (DCs). Recently improved understanding of the analogous lung DC subsets in humans and mice has allowed for better integration and interpretation of the experimental and clinical pathological literature. In this review, we summarize the evidence from human and animal studies to place lung DCs into the context of COPD pathogenesis. We highlight recent studies that demonstrate a potential role for DCs in airway remodeling and that call into question the long-standing belief that intraepithelial DCs actively sample airway lumens. We discuss how DCs drive LLF formation directly and indirectly and also examine the ability of DCs within LLF to instruct downstream effector functions of natural killer cells, CD4+ T cells, and regulatory T cells. Greater awareness of the multifaceted functions of DCs will be essential in the quest to identify new therapeutic modalities to treat COPD. PMID- 27767328 TI - Effect of Fluticasone Furoate and Vilanterol on Exacerbations of Chronic Obstructive Pulmonary Disease in Patients with Moderate Airflow Obstruction. AB - RATIONALE: Inhaled corticosteroids have been shown to decrease exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Their effects in patients with milder airflow obstruction remain unclear. OBJECTIVES: This was an analysis of exacerbations in the SUMMIT (Study to Understand Mortality and Morbidity) study. METHODS: In a double-blind, randomized controlled trial, once-daily inhaled placebo, fluticasone furoate (FF; 100 MUg), vilanterol (VI; 25 MUg), or the combination of FF/VI was administered. The primary outcome was all-cause mortality. Exacerbations of COPD were an additional predefined endpoint. A total of 1,368 centers in 43 countries and 16,485 patients with moderate COPD and heightened cardiovascular risk were included in the study. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, FF/VI reduced the rate of moderate and/or severe exacerbations by 29% (95% confidence interval [CI], 22-35; P < 0.001) and the rate of hospitalized exacerbations by 27% (95% CI, 13-39; P < 0.001). These relative effects were similar regardless of whether subjects had a history of exacerbation in the year before the study or an FEV1 <60% or >=60% of predicted. The number needed to treat was not influenced by baseline FEV1 but was influenced by the history of exacerbations. FF/VI also reduced the rate of exacerbations treated with corticosteroids alone or with corticosteroids and antibiotics but not the rates of those treated with antibiotics alone. CONCLUSIONS: Patients with moderate chronic airflow obstruction experienced a reduction in exacerbations with FF/VI compared with placebo, irrespective of a history of exacerbations or baseline FEV1. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676; GSK Study number 113782). PMID- 27767329 TI - The human microbiome and metabolomics: Current concepts and applications. AB - The mammalian gastrointestinal tract has co-developed with a large number of microbes in a symbiotic relationship over millions of years. Recent studies indicate that indigenous bacteria are intimate with the intestine and play essential roles in health and disease. In the quest to maintain a stable niche, these prokaryotes influence multiple host metabolic pathways, resulting from an interactive host-microbiota metabolic signaling and impacting strongly on the metabolic phenotypes of the host. Since dysbiosis of the gut bacteria result in alteration in the levels of certain microbial and host co-metabolites, identifying these markers could enhance early detection of diseases. Also, identification of these metabolic fingerprints could give us clues as to how to manipulate the microbiome to promote health or treat diseases. This review provides an overview of our current knowledge of the microbiome and metablomics, applications and the future perspectives. PMID- 27767330 TI - Prospective comparison of MR with diffusion-weighted imaging, endoscopic ultrasound, MDCT and positron emission tomography-CT in the pre-operative staging of oesophageal cancer: results from a pilot study. AB - OBJECTIVE: To compare the diagnostic performance of MR and diffusion-weighted imaging (DWI), multidetector CT, endoscopic ultrasonography (EUS) and 18F-FDG (fluorine-18 fludeoxyglucose) positron emission tomography CT (PET-CT) in the pre operative locoregional staging of oesophageal cancer. METHODS: 18 patients with oesophageal or Siewert I tumour (9 directly treated with surgery and 9 addressed to chemo-/radiotherapy before) underwent 1.5-T MR and DWI, 64-channel multidetector CT, EUS and PET-CT before (n = 18) and also after neoadjuvant treatment (n = 9). All images were analysed and staged blindly by dedicated operators (seventh TNM edition). Two radiologists calculated independently the apparent diffusion coefficient from the first scan. Results were compared with histopathological findings. After the population had been divided according to local invasion (T1-T2 vs T3-T4) and nodal involvement (N0 vs N+), sensitivity, specificity, accuracy, positive- and negative-predictive values were calculated and compared. Quantitative measurements from DWI and PET-CT were also analysed. RESULTS: For T staging, EUS showed the best sensitivity (100%), whereas MR showed the highest specificity (92%) and accuracy (83%). For N staging, MR and EUS showed the highest sensitivity (100%), but none of the techniques showed adequate results for specificity. Overall, MR showed the highest accuracy (66%) for N stage, although this was not significantly different to the other modalities. The apparent diffusion coefficient was different between surgery-only and chemo /radiotherapy groups (1.90 vs 1.30 * 10-3 mm2 s-1, respectively; p = 0.005) optimal cut off for local invasion: 1.33 * 10-3 mm2 s-1 (p = 0.05). Difference in standardized uptake value was also very close to conventional levels of statistical significance (8.81 vs 13.97 g cm-3, respectively; p = 0.05)-optimal cut off: 7.97 g cm-3 (p = 0.44). CONCLUSION: In this pilot study, we have shown that MR with DWI could enrich the current pre-operative work-up for oesophageal cancer and could be used for T and N staging. However, larger studies will need to be carried out before introducing this technique in the standard diagnostic pathway, in order to understand if MR with DWI could change its management and replace more costly or invasive tests such as PET-CT or EUS. Advances in knowledge: This pilot study represents the first effort where the four techniques have been prospectively compared together for oesophageal cancer staging. The combination of MR and DWI could provide important, additional information for staging and initial treatment decision-making. PMID- 27767331 TI - Medical conditions associated with the use of CT in children and young adults, Great Britain, 1995-2008. AB - OBJECTIVE: To describe the medical conditions associated with the use of CT in children or young adults with no previous cancer diagnosis. METHODS: Radiologist reports for scans performed in 1995-2008 in non-cancer patients less than 22 years of age were collected from the radiology information system in 44 hospitals of Great Britain. By semantic search, an automated procedure identified 185 medical conditions within the radiologist reports. Manual validation of a subsample by a paediatric radiologist showed a satisfactory performance of the automatic coding procedure. RESULTS: Medical information was extracted for 37,807 scans; 19.5% scans were performed in children less than 5 years old; 52.0% scans were performed in 2000 or after. Trauma, diseases of the nervous (mainly hydrocephalus) or the circulatory system were each mentioned in 25-30% of scans. Hydrocephalus was mentioned in 19% of all scans, 59% of scans repeated >=5 times in a year, and was the most frequent condition in children less than 5 years of age. Congenital diseases/malformations, disorders of the musculoskeletal system/connective tissues and infectious or respiratory diseases were each mentioned in 5-10% of scans. Suspicionor diagnosis of benign or malignant tumour was identified in 5% of scans. CONCLUSION: This study describes the medical conditions that likely underlie the use of CT in children in Great Britain. It shows that patients with hydrocephalus may receive high cumulative radiation exposures from CT in early life, i.e. at ages when they are most sensitive to radiation. Advances in knowledge: The majority of scans were unrelated to cancer suspicion. Repeated scans over time were mainly associated with the management of hydrocephalus. PMID- 27767333 TI - Face Threats and Additional Reasons for Perceiving Support as Unwanted: A Study of Recently Diagnosed Cancer Patients. AB - This study investigated instances of support that were deemed unwanted by a recipient in the wake of a cancer diagnosis. The investigation was framed by politeness theory and considered the face threats evident in cancer patients' descriptions of unwanted support. Additional reasons for viewing support as unwanted, as well as the outcomes of receiving unwanted support, were also explored. Interviews (N = 15) were conducted with cancer patients who had been initially diagnosed within the previous 12 months. Analyses demonstrated that face threats are among the reasons for viewing some support as problematic; however, additional reasons beyond face threats also occurred. The most frequently occurring reasons for regarding support as unwanted were threats to the receiver's negative face and messages failing to convey empathy. Finally, the influence of receiving unwanted support on cancer patients is discussed in terms of recipients' ability to manage emotions, respond to the support, potentially view the support provider negatively, and assert greater control over future supportive interactions. PMID- 27767332 TI - Immune Regulation of Toll-Like Receptor 2 Engagement on CD4+ T Cells in Murine Models of Malignant Pleural Effusion. AB - Toll-like receptor (TLR) 2 has a well-known role in sensing multiple ligands that include microbial products, endotoxin, and some extracellular matrix molecules; however, its role in the development of malignant pleural effusion (MPE) remains unknown. We performed the present study to explore the impact of TLR2 signaling on the development of MPE and to define the underlying mechanisms by which TLR2 works. Development of MPE was compared between TLR2-/- and wild-type (WT) mice. The effect of TLR2 on differentiation of T helper type 17 (Th17), Th9, and Th2 cells in MPE was explored. The mechanisms of TLR2 on survival of mice bearing MPE were also investigated. MPE volume in TLR2-/- mice was lower than that in WT mice, and the survival of TLR2-/- mice bearing MPE was longer than that of WT mice. TLR2 deficiency increased, and TLR2 activation decreased, Th17 cells in MPE, whereas TLR2 signaling showed the contrary effects on Th2 cells. Th9 cells were increased in MPE of TLR2-/- mice but were not influenced by TLR2 signaling. Intraperitoneal injection of anti-IL-17 monoclonal antibody (mAb), anti-IL-9 mAb, or recombinant mouse IL-4 accelerated the death of TLR2-/- mice bearing MPE, and intraperitoneal injection anti-IL-17 mAb in TLR2-/- mice was associated with a significantly shorter survival time than in WT mice. We have demonstrated, for the first time, that TLR2 signaling promotes the development of MPE and accelerates the death of mice bearing MPE by directly suppressing Th17 cell differentiation and directly promoting Th2 cell differentiation, and also by indirectly suppressing Th9 cell differentiation via an IL-17-dependent mechanism. PMID- 27767334 TI - DNA-based identification of invasive alien species in relation to Canadian federal policy and law, and the basis of rapid-response management. AB - Managing invasive alien species in Canada requires reliable taxonomic identification as the basis of rapid-response management. This can be challenging, especially when organisms are small and lack morphological diagnostic features. DNA-based techniques, such as DNA barcoding, offer a reliable, rapid, and inexpensive toolkit for taxonomic identification of individual or bulk samples, forensic remains, and even environmental DNA. Well suited for this requirement, they could be more broadly deployed and incorporated into the operating policy and practices of Canadian federal departments and should be authorized under these agencies' articles of law. These include Fisheries and Oceans Canada, Canadian Food Inspection Agency, Transport Canada, Environment Canada, Parks Canada, and Health Canada. These efforts should be harmonized with the appropriate provisions of provincial jurisdictions, for example, the Ontario Invasive Species Act. This approach necessitates that a network of accredited, certified laboratories exists, and that updated DNA reference libraries are readily accessible. Harmonizing this approach is vital among Canadian federal agencies, and between the federal and provincial levels of government. Canadian policy and law must also be harmonized with that of the USA when detecting, and responding to, invasive species in contiguous lands and waters. Creating capacity in legislation for use of DNA-based identifications brings the authority to fund, train, deploy, and certify staff, and to refine further developments in this molecular technology. PMID- 27767336 TI - The Power of Visualizing Fear. AB - Throughout the Fear Project, the author visualizes other people's fears, many of which revolve around health-related issues. Through her illustrations, which accompany the words of her subjects, fears become a tangible representation of what people are most afraid of. The collaboration between the illustrator and the subjects shapes a health narrative that allows the subjects themselves to become more involved in their journey of self-discovery, by telling their own stories in ways that are outside the strict conventions of academia. PMID- 27767335 TI - Rates and patterns of molecular evolution in freshwater versus terrestrial insects. AB - Insect lineages have crossed between terrestrial and aquatic habitats many times, for both immature and adult life stages. We explore patterns in molecular evolutionary rates between 42 sister pairs of related terrestrial and freshwater insect clades using publicly available protein-coding DNA sequence data from the orders Coleoptera, Diptera, Lepidoptera, Hemiptera, Mecoptera, Trichoptera, and Neuroptera. We furthermore test for habitat-associated convergent molecular evolution in the cytochrome c oxidase subunit I (COI) gene in general and at a particular amino acid site previously reported to exhibit habitat-linked convergence within an aquatic beetle group. While ratios of nonsynonymous-to synonymous substitutions across available loci were higher in terrestrial than freshwater-associated taxa in 26 of 42 lineage pairs, a stronger trend was observed (20 of 31, pbinomial = 0.15, pWilcoxon = 0.017) when examining only terrestrial-aquatic pairs including fully aquatic taxa. We did not observe any widespread changes at particular amino acid sites in COI associated with habitat shifts, although there may be general differences in selection regime linked to habitat. PMID- 27767337 TI - Barcoding the food chain: from Sanger to high-throughput sequencing. AB - Society faces the complex challenge of supporting biodiversity and ecosystem functioning, while ensuring food security by providing safe traceable food through an ever-more-complex global food chain. The increase in human mobility brings the added threat of pests, parasites, and invaders that further complicate our agro-industrial efforts. DNA barcoding technologies allow researchers to identify both individual species, and, when combined with universal primers and high-throughput sequencing techniques, the diversity within mixed samples (metabarcoding). These tools are already being employed to detect market substitutions, trace pests through the forensic evaluation of trace "environmental DNA", and to track parasitic infections in livestock. The potential of DNA barcoding to contribute to increased security of the food chain is clear, but challenges remain in regulation and the need for validation of experimental analysis. Here, we present an overview of the current uses and challenges of applied DNA barcoding in agriculture, from agro-ecosystems within farmland to the kitchen table. PMID- 27767338 TI - "If You Rely on the River, You Can Probably Die by the River": Stories Told about Access, Quality, and Living With Water. PMID- 27767340 TI - New lignan glycosides from Justicia procumbens. AB - Four new lignan glycosides (1-4), named procumbenosides I, K, L, and M, together with cleistanthin B (5) reported for the first time in the genus Justicia, and 5 other known arylnaphthalene lignan glycosides (6-10) were isolated from the whole plant of Justicia procumbens. The structures of the new compounds were elucidated by extensive one-dimensional (1D) and two-dimensional (2D) NMR experiments and mass spectrometry. Procumbenoside M (4) was a rare sesquilignan glycoside never previously reported in the species of Justicia. The paper also provided insight into the conformational equilibria existing in the lignan glycosides of the plant. PMID- 27767339 TI - Method/Group Factors: Inconsequential but Meaningful-A Comment on Donnellan, Ackerman, and Brecheen (2016). PMID- 27767341 TI - A Survey of Challenges Experienced by New Learners Coding the Rorschach. AB - Learning to code the imagery, communication, and behavior associated with Rorschach responding is challenging. Although there is some survey research on graduate students' impressions of their Rorschach training, research has not identified which coding decisions students find to be the most problematic and time-consuming. We surveyed students to identify what they struggled with most when learning coding and to quantify how difficult it is to learn how to code. Participants (n = 191) from the United States, Brazil, Denmark, Israel, and Italy rated 57 aspects of coding using a 4-point scale that encompassed both the time required to code and the subjective difficulty of doing so. Mean ratings for coding in general indicated that students considered the overall task challenging. Ratings also revealed that students struggled most with Cognitive Special Scores, Determinants, and extrapolating from the tables to code Form Quality for objects that were not specifically listed. The findings offer suggestions about how to improve the guidelines for some of the more difficult variables and where it is most necessary to focus teaching time. Taking these steps might help new students in learning the Rorschach. PMID- 27767342 TI - The Development and Validation of Brief and Ultrabrief Measures of Values. AB - Values are a central personality construct and the importance of studying them has been well established. To encourage researchers to integrate measures of values into their studies, brief and ultrabrief instruments were developed to recapture the 10 values measured by the 40-item Portrait Values Questionnaire (PVQ; Schwartz, 2003 ). Rigorous psychometric procedures based on separate derivation (N = 38,049) and evaluation (N = 29,143) samples yielded 10- and 20 item measures of values, which proved to be successful at capturing the patterns and magnitude of correlations associated with the original PVQ. These instruments should be useful to researchers who would like to incorporate a values scale into their study but do not have the space to administer a longer measure. PMID- 27767343 TI - Acute to chronic estimation of Daphnia magna toxicity within the QSAAR framework. AB - We constructed models for acute to chronic estimation of the Daphnia magna reproductive toxicities of chemical substances from their Daphnia magna acute immobilization toxicities. The models combined the acute toxicities with structural and physicochemical descriptors. We used multiregression analysis and selected the descriptors for the models by means of a genetic algorithm. Of the best 100 models (as indicated by the lack of fit score), 90% included the following descriptors: acute toxicity (i.e. an activity parameter), distribution coefficient (log D) and structural indicator variables that indicate the presence of -NH2 attached to aromatic carbon and the presence of a chlorine atom. We compared the predictive abilities of five of these quantitative structure activity-activity relationship (QSAAR) acute to chronic estimation models with the predictive ability of a simple linear regression model. The comparison revealed that inclusion of structural and physicochemical descriptors such as those in QSAAR models can improve models for extrapolation from acute to chronic toxicity. Our results also provide a QSAAR framework that is expected to be useful for the further development of chronic toxicity estimation models. PMID- 27767344 TI - The Development of the Inventory of Problems-29: A Brief Self-Administered Measure for Discriminating Bona Fide From Feigned Psychiatric and Cognitive Complaints. AB - This article describes the development of the Inventory of Problems-29 (IOP-29), a new, short, paper-and-pencil, self-administered measure of feigned mental and cognitive disorders. Four clinical comparison simulation studies were conducted. Study 1 (n = 451) selected the items and produced an index of potential feigning. Study 2 (n = 331) scaled this index to produce a probability score, and examined its psychometric properties. Study 3 tested the generalizability of Study 2's findings with 2 additional samples (ns = 128 and 90). Results supported the utility of the IOP-29 for discriminating bona fide from feigned psychiatric and cognitive complaints. Validity was demonstrated in feigning mild traumatic brain injury, psychosis, posttraumatic stress disorder, and depression. Within the independent samples of Studies 2 and 3, the brief IOP-29 performed similarly to the MMPI-2 and Personality Assessment Inventory, and perhaps better than the Test of Memory Malingering. Classifications within these samples with base rates of .5 produced sensitivity, specificity, positive predictive power, and negative predictive power statistics of about .80. Further research is needed testing the IOP-29 in ecologically valid field studies. PMID- 27767346 TI - The Doctor Versus the Internet: Effects of Low-, Medium-, and High-Quality Websites on Intentions to Follow the Doctor's Advice. AB - How do patients respond when advice on health websites differs from advice given by a doctor? To test effects of advice concordance, 418 participants 25-80 years old were randomly assigned to read real websites that varied in quality of information about diabetes: high (medically accurate and complete), medium (accurate but incomplete), and low (inaccurate). The control group read travel sites. Participants then watched a video of a physician making treatment recommendations for a diabetic patient, and indicated how they would respond if they were the patient. There was no direct effect of condition on ratings of doctor credibility or intentions to adhere to the treatment plan, but there was an indirect effect: Those who read high-quality websites gave higher ratings of doctor-website concordance, which predicted greater confidence in the doctor's recommendations, which in turn predicted greater intention to comply. PMID- 27767345 TI - Bayer Filter Snapshot Hyperspectral Fundus Camera for Human Retinal Imaging. AB - PURPOSE: To demonstrate the versatility and performance of a compact Bayer filter snapshot hyperspectral fundus camera for in-vivo clinical applications including retinal oximetry and macular pigment optical density measurements. METHODS: 12 healthy volunteers were recruited under an Institutional Review Board (IRB) approved protocol. Fundus images were taken with a custom hyperspectral camera with a spectral range of 460-630 nm. We determined retinal vascular oxygen saturation (sO2) for the healthy population using the captured spectra by least squares curve fitting. Additionally, macular pigment optical density was localized and visualized using multispectral reflectometry from selected wavelengths. RESULTS: We successfully determined the mean sO2 of arteries and veins of each subject (ages 21-80) with excellent intrasubject repeatability (1.4% standard deviation). The mean arterial sO2 for all subjects was 90.9% +/- 2.5%, whereas the mean venous sO2 for all subjects was 64.5% +/- 3.5%. The mean artery-vein (A-V) difference in sO2 varied between 20.5% and 31.9%. In addition, we were able to reveal and quantify macular pigment optical density. CONCLUSIONS: We demonstrated a single imaging tool capable of oxygen saturation and macular pigment density measurements in vivo. The unique combination of broad spectral range, high spectral-spatial resolution, rapid and robust imaging capability, and compact design make this system a valuable tool for multifunction spectral imaging that can be easily performed in a clinic setting. PMID- 27767348 TI - Rapid 3D mandibular superimposition for growing patients. AB - OBJECTIVE: To evaluate the precision and reproducibility of a protocol to perform rapid voxel-based superimposition of the mandible in growing patients using CBCT. MATERIALS AND METHODS: The sample comprised two cone-beam computed tomography scans taken at least 1 year apart from each of 24 growing patients. Voxel-based superimposition was performed by two examiners independently. The internal part of the symphysis extending to the first molar was used as the reference. The superimposition process took approximately 5 minutes. Once the mandibles were superimposed, surface models were created and root mean square (RMS) changes were obtained by means of iterative closest point. To evaluate precision, differences in three areas were measured between time point 1 (T1) and time point 2 (T2) superimposed. To evaluate reproducibility between different examiners, the distances between T2 superimposed by each operator were measured in five different areas. Descriptive statistics were used to evaluate the precision of the superimposition and the interexaminer reproducibility measurements for each case were reported individually. RESULTS: The superimposition mean error between T1 and T2 for the right and left sides of the mandible and chin were 0.23 mm, 0.25 mm, and 0.33 mm, respectively. Interexaminer reproducibility error was <=0.3 mm in 20 of 24 cases for measurements near the registration area. In the ramus area, two cases had errors >1 mm (1 mm-1.3 mm). CONCLUSION: The rapid superimposition was precise for assessing dentoalveolar changes and structures close to the registration area. However, evaluation of the condyles and ramus area had limitations and needs improvement. PMID- 27767349 TI - A Patient-Centered Radiology Quality Process Map: Opportunities and Solutions. AB - OBJECTIVE: The purpose of this article is to review the tools and opportunities available for patient-centered care in radiology and to create a quality patient centered care process map to organize them for radiology practices. CONCLUSION: This article provides a review of the many opportunities to increase and improve patient-centered care in radiology. A process map that organizes and highlights key elements of patient-centered care throughout the radiology care process is provided that can be implemented to enhance the patient experience of our services and improve the quality of care provided. PMID- 27767347 TI - Idiopathic Pulmonary Fibrosis: The Association between the Adaptive Multiple Features Method and Fibrosis Outcomes. AB - RATIONALE: Adaptive multiple features method (AMFM) lung texture analysis software recognizes high-resolution computed tomography (HRCT) patterns. OBJECTIVES: To evaluate AMFM and visual quantification of HRCT patterns and their relationship with disease progression in idiopathic pulmonary fibrosis. METHODS: Patients with idiopathic pulmonary fibrosis in a clinical trial of prednisone, azathioprine, and N-acetylcysteine underwent HRCT at study start and finish. Proportion of lung occupied by ground glass, ground glass-reticular (GGR), honeycombing, emphysema, and normal lung densities were measured by AMFM and three radiologists, documenting baseline disease extent and postbaseline change. Disease progression includes composite mortality, hospitalization, and 10% FVC decline. MEASUREMENTS AND MAIN RESULTS: Agreement between visual and AMFM measurements was moderate for GGR (Pearson's correlation r = 0.60, P < 0.0001; mean difference = -0.03 with 95% limits of agreement of -0.19 to 0.14). Baseline extent of GGR was independently associated with disease progression when adjusting for baseline Gender-Age-Physiology stage and smoking status (hazard ratio per 10% visual GGR increase = 1.98, 95% confidence interval [CI] = 1.20 3.28, P = 0.008; and hazard ratio per 10% AMFM GGR increase = 1.36, 95% CI = 1.01 1.84, P = 0.04). Postbaseline visual and AMFM GGR trajectories were correlated with postbaseline FVC trajectory (r = -0.30, 95% CI = -0.46 to -0.11, P = 0.002; and r = -0.25, 95% CI = -0.42 to -0.06, P = 0.01, respectively). CONCLUSIONS: More extensive baseline visual and AMFM fibrosis (as measured by GGR densities) is independently associated with elevated hazard for disease progression. Postbaseline change in AMFM-measured and visually measured GGR densities are modestly correlated with change in FVC. AMFM-measured fibrosis is an automated adjunct to existing prognostic markers and may allow for study enrichment with subjects at increased disease progression risk. PMID- 27767351 TI - Sometimes It Is Better to Be Vaguely Right Than Precisely Wrong. PMID- 27767350 TI - Transradial Approach for Hepatic Radioembolization: Initial Results and Technique. AB - OBJECTIVE: The transradial approach (TRA) has been shown to reduce the morbidity and mortality associated with arterial coronary interventions. Selective internal radiation therapy (SIRT) performed via the TRA can enhance patient comfort, compared with the traditional transfemoral approach (TFA), by allowing immediate ambulation and precluding potential complications associated with the TFA, such as closure device injury or retroperitoneal hematoma. We report our initial experience with and technique for using the TRA for SIRT. MATERIALS AND METHODS: Between May 1, 2012, and April 30, 2015, a total of 574 procedures, including planning angiograms (n = 329) and infusions of 90Y (n = 245), were performed for 318 patients (mean age, 64.5 years). Of the 245 patients who received 90Y infusions, 52 had SIRT performed with the use of a permanent single-use implant of 90Y resin microspheres and 193 had SIRT performed with the use of millions of small glass microspheres containing radioactive 90Y. Procedural details, technical success, the radial artery (RA) occlusion rate noted at 30 days (as assessed via pulse examination), and the major and minor adverse events noted at 30 days were evaluated. RESULTS: Technical success was achieved in 561 of 574 cases (97.7%). The reasons for crossover to use of the TFA included an RA loop (n = 2), RA occlusion (n = 9), and type D response as determined by use of a Barbeau test (n = 2). Patients had undergone between zero and six previous TRA procedures. The mortality rate at 30 days was 0%. Superficial bruising occurred in 13 of 574 cases (2.3%). A grade 2 hematoma that required a second nonocclusive hemostasis cuff occurred in one case. Transient forearm numbness or pain occurred in two of 574 cases. One patient had a transient convulsive event occur after receiving intraarterial infusion of verapamil. RA occlusion occurred in nine of 574 cases (1.6%). CONCLUSION: Use of the TRA for SIRT is safe, feasible, and well tolerated and is associated with high rates of technical success and rare complications. PMID- 27767352 TI - Section Editor's Notebook. Patient Centeredness in Radiology: What's Next? PMID- 27767353 TI - A Tale of Two Stories: An Exploration of Identification, Message Recall, and Narrative Preferences Among Low-Income, Mexican American Women. AB - Additional research is needed to guide the design of narratives for use in practice-oriented, naturalistic settings to maximize health behavior change, particularly among populations affected by health disparities. This mixed-methods study explored the influence of cultural tailoring and emotional arousal on identification and message recall in narratives promoting childhood obesity prevention among 40 Mexican American mothers. Participants were also asked about narrative exposure, narrative preferences, and beliefs about the purpose of a story. Participants were randomly assigned to listen to two stories: (a) a story tailored on noncultural or cultural variables, and (b) a story designed to enhance or minimize emotional arousal. Participants reported high engagement and identification with all stories. Participants generally envisioned protagonists as Latina, despite limited cues, and identified with protagonists in four ways: sharing personal characteristics; having similar thoughts and feelings; engaging in similar actions; and experiencing similar situations. Mothers were most interested in narratives that helped them to improve their lives. Findings from this study yield several hypotheses for consideration in future study, including ways in which story setting and message enactment may moderate message recall. PMID- 27767355 TI - Persian version of the Moorong Self-Efficacy Scale: psychometric study among subjects with physical disability. AB - PURPOSE: Self-efficacy plays a key role in varying areas of human conditions which can be measured by different scales. The present study was aimed to evaluate the psychometric properties of Moorong Self-Efficacy Scale (MSES) in Iranian Subjects with Physical Disability (SWPD). METHOD: Data were collected by face-to-face interviews and self-report surveys from 214 subjects. The face and content validity, and reliability were evaluated. Discriminates were evaluated between the sub-groups of disability levels, physical activity, and health condition levels. The concurrent, convergent, divergent, and construct validity were assessed by short form health survey scale (SF-36), general self-efficacy scale (GSES), hospital anxiety and depression scale (HADS), respectively. Replaceable exploratory factor analysis was evaluated. SPSS software was used for statistical analysis. RESULTS: There were acceptable face and content validity, and reliability. Furthermore, significant correlation was found between PSES and SF-36 (p < 0.001). Self-efficacy was statistically different among the disability levels (p = 0.02), physical activity levels (p < 0.001), and health status (p = 0.001). The correlation of Persian Self-Efficacy Scale (PSES) scores with GSES (r = 0.61, p < 0.001), and HADS (R = -0.53, p < 0.001) was significant. This scale yielded a two-dimensional structure, with a good internal replicability. The external replicability was satisfactory when we compared factor loadings with the original study. CONCLUSIONS: The PSES is a valid, reliable and sensitive tool to measure the self-efficacy among SWPD for planning and managing of disability problems. Implications for rehabilitation Psychometric properties of the Persian version of self-Efficacy scale (PSES) appear to be similar to original, English version. The PSES has been shown to have validity and reliability in Persian physical disables and can be used for patients with more different types of physical disability than individuals suffering from only Spinal Cord Injury (SCI). The PSES can be used in clinical practice and research work to evaluate the patients' confidence in performing daily activities. PMID- 27767354 TI - Long-term Efficacy of Orthokeratology Contact Lens Wear in Controlling the Progression of Childhood Myopia. AB - PURPOSE: The primary outcome of this study is to compare the axial length growth of white European myopic children wearing orthokeratology contact lenses (OK) to a control group (CT) over a 7-year period. METHODS: Subjects 6-12 years of age with myopia -0.75 to -4.00DS and astigmatism <=1.00DC were prospectively allocated OK or distance single-vision spectacles (SV) correction. Measurements of axial length (Zeiss IOLMaster), corneal topography, and cycloplegic refraction were taken at 6-month intervals over a 2-year period. Subjects were invited to return to the clinic approximately 5 years later (i.e., 7 years after the beginning of the study) for assessment of their ocular refractive and biometric components. The CT consisted of 4 SV and 12 subjects who switched from SV to soft contact lens wear after the initial 2 years of SV lens wear. Changes in axial length relative to baseline over a 7-year period were compared between groups. RESULTS: Fourteen and 16 subjects from the OK and CT groups, respectively, were examined 6.7 +/- 0.5 years after the beginning of the study. Statistically significant changes in the axial length were found over time and between groups (both p < 0.001), but not for the time*group interaction (p = 0.125). The change in the axial length for the OK group was 22% (p = 0.328), 42% (p = 0.007), 40% (p = 0.020), 41% (p = 0.013), and 33% (p = 0.062) lower than the CT group following 6, 12, 18, 24, and 84 months of lens wear, respectively. CONCLUSION: A trend toward a reduction in the rate of axial elongation of the order of 33% was found in the OK group in comparison to the CT group following 7 years of lens wear. PMID- 27767356 TI - Etiology, clinical profile and short-term outcome of acute kidney injury in children at a tertiary care pediatric nephrology center in Pakistan. AB - BACKGROUND: The reported prevalence rates and etiologies of acute kidney injury (AKI) are quite variable in different regions of the world. The current study was planned to determine the etiology, clinical profile, and short-term outcome of pediatric AKI at our hospital. METHODS: A prospective, observational study was carried out from April 2014 to March 2015. All pediatric patients (1 month to <=15 years) diagnosed as AKI using modified pRIFLE criteria were studied and followed for 3 months to document short-term outcome. RESULTS: AKI was diagnosed in 116 children. The mean age was 7.5 +/- 4.4 years and males were predominant (60.3%). At presentation, 83.6% had oliguria/anuria, 37.1% hypertension and 17.2% severe anemia. Etiology included primary renal (74/116; 63.8%), postrenal (28/116; 24.1%) and prerenal (11/116; 9.5%) causes. Postinfectious glomerulonephritis (PIGN) and crescentic glomerulonephritis in primary renal, obstructive urolithiasis in postrenal and sepsis in prerenal, were the most common etiologies. At presentation, 89/116 (76.7%) patients were in pRIFLE Failure category. Regarding outcome, 68 (58.6%) patients recovered, six (5.2%) died, 18 (15.5%) developed chronic kidney disease (CKD) and 22 (19%) end-stage renal disease (ESRD). Comparison of recovered and unrecovered AKI showed that characteristics such as hypertension, severe anemia, edema, volume overload, requirement of mechanical ventilation, initiation of dialysis and need of >5 sessions of dialysis had statistically significant (p <0.05) association with nonrecovery. CONCLUSION: Glomerulonephritides (PIGN and crescentic) and obstructive urolithiasis are major causes of pediatric AKI at our center. A fairly high percentage of cases recovered and these mainly comprised of PIGN and obstructive urolithiasis. PMID- 27767357 TI - Laser Vision Correction with Q Factor Modification for Keratoconus Management. AB - PURPOSE: To evaluate the outcomes of corneal laser ablation with Q factor modification for vision correction in patients with progressive keratoconus. METHODS: In this prospective study, 50 eyes of 50 patients were divided into two groups based on Q factor (>-1 in Group I and <=-1 in Group II). All patients underwent a detailed ophthalmic examination including uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), subjective acceptance and corneal topography using the Pentacam. The topolyzer was used to measure the corneal asphericity (Q). Ablation was performed based on the preoperative Q values and thinnest pachymetry to obtain a target of near normal Q. This was followed by corneal collagen crosslinking to stabilize the progression. RESULTS: Statistically significant improvement (p <= 0.05) was noticed in refractive, topographic, and Q values posttreatment in both groups. The improvement in higher order aberrations and total aberrations were statistically significant in both groups; however, the spherical aberration showed statistically significant improvement only in Group II. CONCLUSION: Ablation based on the preoperative Q and pachymetry for a near normal postoperative Q value appears to be an effective method to improve the visual acuity and quality in patients with keratoconus. PMID- 27767359 TI - Efficacy of Infliximab for Early Remission Induction in Refractory Uveoretinitis Associated with Behcet Disease: A 2-year Follow-up Study. AB - PURPOSE: To compare the efficacy of infliximab (IFX) on refractory uveoretinitis between Behcet disease (BD) patients with short duration (<=18 months, n = 6) versus long duration (>18 months, n = 7) of their ocular disease. METHODS: Records of 13 BD patients treated with IFX for 24 months were retrospectively reviewed. RESULTS: Frequency of ocular attacks decreased with IFX treatment in both groups, with no significant difference. Retinal and disc vascular leakage scores also decreased in both groups, however was significantly lower in the short-duration group. Percentage of eyes with a best-corrected visual acuity (BCVA) of 1.0 or better at year 2 was 100% in the short-duration and 21% in the long-duration group. CONCLUSIONS: Induction of early remission using IFX appeared to be more effective in reducing background vascular leakage and in maintaining good visual acuity in BD patients. PMID- 27767358 TI - Urinary l-type fatty acid-binding protein is a predictor of early renal function after partial nephrectomy. AB - PURPOSE: Urinary biomarkers of renal injury urinary may identify loss of renal function following nephron-sparing surgery (NSS). This study was designed to evaluate whether urinary l-type fatty acid-binding protein (l-FABP) is an early biomarker of loss of renal function after NSS. Specifically, the kinetics of urinary l-FABP level after NSS and its correlation with factors related to ischemic renal injury were analyzed. METHODS: This study prospectively evaluated 18 patients who underwent NSS between July and December 2014, including 12 who underwent laparoscopic and six who underwent robot-assisted partial nephrectomy. Urinary l-FABP concentrations were measured preoperatively and 1, 2, 3, 6, 12, 24, 48, and 72 h after renal artery declamping. Loss of renal function loss was calculated by comparing the effective renal plasma flow, as determined by 99mTc mercaptoacetyltriglycine (MAG3) clearance, on the operated and normal sides. The decrease in estimated glomerular filtration rate from before surgery to six months after surgery was also measured. RESULTS: Urinary l-FABP concentration peaked within 2 h of declamping, which may quantify nephron damage caused by ischemia. The decrease in MAG3 reduction ratio correlated with both the ischemia time and peak urinary l-FABP concentration. Peak urinary l-FABP concentration showed a significant correlation with MAG3 reduction ratio. CONCLUSIONS: l-FABP is a suitable urinary biomarker for predicting the extent of ischemic renal injury. PMID- 27767360 TI - A Novel Approach to Analyze the Progression of Measured Corneal Sub-Basal Nerve Fiber Length in Continuously Expanding Mosaic Images. AB - : Purpose/Aim of the study: A recently proposed technique enables the generation of continuously increasing mosaic images of the corneal sub-basal nerve plexus (SNP) using in vivo corneal confocal microscopy (CCM). The aim of the present study was to investigate the progression of the corneal nerve fiber length (CNFL) measured in the growing mosaic images with regard to their increasing area. MATERIALS AND METHODS: Five large datasets from three healthy volunteers were examined using the proposed CCM technique. Intermediate mosaic images were created and assessed for CNFL. RESULTS: The measured CNFL progression shows both over- and underestimation of the CNFL for small observed areas. Increasing the mosaic image area stabilizes the CNFL values and reduces the moving variance in all five datasets. The relative deviation of means from values of first and second examination of two of the subjects shows high differences for an observed area of <1.5 mm2. CONCLUSIONS: The present examination provides two measures to quantify different area-dependent aspects of the CNFL measured in an expanding mosaic image. The moving variance measures how stable the CNFL can be considered at a certain mosaic size. The relative deviation of means from two repeated CCM examinations on the other hand gives some indication on the level of reliability that can be expected from the measured CNFL. The progression of CNFL in the examined datasets manifests a potentially very high variability for mosaic sizes of less than about 1.5 mm2. Above that size, CNFL progression and the intra patient relative deviations both stabilize significantly in all five datasets. The results of the present examination suggest a recommendation for a minimum sampled area of the central SNP of 1.5 mm2 for reliable and meaningful measurement of CNFL. PMID- 27767361 TI - Translation and psychometric properties of the German version of the University of the West of England Interprofessional Questionnaire (UWE-IP). AB - The implementation of a bachelor degree in Interprofessional Health Care at the University of Heidelberg, Germany, has fostered the need to evaluate the impact of this innovative programme. The University of the West of England Interprofessional Questionnaire (UWE-IP) was developed for longitudinal evaluation of an interprofessional curriculum. The UWE-IP consists of 35 items in four scales: "Communication and Teamwork Scale," "Interprofessional Learning Scale," "Interprofessional Interaction Scale," and "Interprofessional Relationships Scale." The UWE-IP was translated to German according to international guidelines. Psychometrics were assessed: reliability of the four scales was tested with Cronbach's alpha and confirmatory factor analysis was performed to examine the underlying factor structure. The sample consisted of 326 datasets. Reliability for the scales was between 0.75 and 0.90. The underlying factor structure showed a good fit. We conclude that the German UWE-IP shows good psychometrics and recommend its use for evaluation of interprofessional learning activities. These results add to the body of knowledge on evaluation instruments in interprofessional education. PMID- 27767362 TI - Elvitegravir for the treatment of HIV. AB - INTRODUCTION: Current antiretrovirals (ARVs) have demonstrated the ability to prolong the life of an HIV infected individual via suppression of the virus and subsequent restoration of immune function. Despite significant advancement, there remains an opportunity for improvement. One ARV that attempts to fill global HIV therapeutic needs by balancing convenience, safety, and efficacy is elvitegravir (EVG). Areas covered: Using MEDLINE/PubMed, a literature search was conducted for published articles on the safety and efficacy of EVG in the treatment of HIV infection. Expert opinion: EVG offers clinicians a convenient choice for HIV positive patients that is safe and effective for both treatment-naive and experienced patients, as well as an option for regimen simplification in virologically suppressed patients. EVG is conveniently co-formulated in fixed dose combination tablets to be taken once daily with food. EVG does not require dose adjustment for patients with severe renal impairment or mild to moderate liver disease. Importantly, EVG requires co-administration with a pharmacokinetic enhancer (i.e., ritonavir or cobicistat) in order to achieve therapeutic levels and facilitate once daily dosing. As a consequence, clinicians must carefully review concomitant medications and navigate potential drug-drug interactions mediated through potent inhibition of cytochrome P450 3A enzymes by ritonavir and cobicistat. PMID- 27767364 TI - Pattern of Pediatric Uveitis at a Tertiary Referral Institute in North India. AB - PURPOSE: To report the pattern of pediatric uveitis in a tertiary care referral center in North India. METHODS: In a retrospective study, records of pediatric uveitis cases presenting at our center between 1996 and 2015 were reviewed for demographic data, anatomic distribution, and diagnosis. RESULTS: Out of 9600 patients with uveitis, 369 children (3.84%; age <=16 years; males: 54.20%) were included in the study. Anterior uveitis was the commonest presentation (n = 158; 42.81%), followed by posterior uveitis (n = 102; 27.64%). Uveitis was bilateral in 57.18% (n = 211). Infective etiology was seen in 99 children, of which tuberculosis was the commonest cause (n = 55; 14.91%). Among non-infectious etiologies, juvenile idiopathic arthritis (JIA) was the commonest cause (n = 59; 15.99%). CONCLUSIONS: While anterior uveitis is the commonest uveitis in children, our cohort reported a high number of posterior uveitis cases compared to previous studies. Tuberculosis and JIA were the commonest causes of pediatric uveitis. PMID- 27767363 TI - The Role of Advanced Practice Registered Nurses in the Completion of Physician Orders for Life-Sustaining Treatment. AB - BACKGROUND: The Physician Orders for Life-Sustaining Treatment (POLST) Paradigm records advance care planning for patients with advanced illness or frailty as actionable medical records. The National POLST Paradigm Task Force recommends that physicians, advanced practice registered nurses (APRNs), and physician assistants (PAs) be permitted to execute POLST forms. OBJECTIVE: To investigate the percentage of Oregon POLST forms signed by APRNs, and examine the obstacles faced by states attempting to allow APRNs to sign POLST forms. DESIGN: Cross sectional. SETTING/SUBJECTS: 226,101 Oregon POLST Registry forms from 2010 to 2015. MEASUREMENTS: POLST forms in the Oregon Registry were matched with signer type (MD, DO, APRN, PA). RESULTS: 226,101 POLST forms have been added to the Oregon POLST Registry from 2010 to 2015: 85.3% of forms were signed by a physician, 10.9% of forms were signed by an APRN, and 3.8% of forms were signed by a PA. From 2010 to 2015, the overall percentage of POLST forms signed by an APRN has increased from 9.0% in 2010 to 11.9% in 2015. Physicians are authorized signers in all 19 states with endorsed POLST Paradigm programs; 16 of these states also authorize APRN signature, and 3 states (LA, NY, and GA) allow only physicians to sign. CONCLUSIONS: More than 10% of Oregon POLST forms are signed by APRNs. Given the need for timely POLST form completion, ideally by a member of the interdisciplinary team who knows the patient's preferences best, these data support authorizing APRNs to complete POLST forms. PMID- 27767366 TI - The Influence of Engagement and Satisfaction on Smoking Cessation Interventions: A Qualitative Study. AB - BACKGROUND: Tobacco use remains the leading cause of preventable disease and death. Most smokers are not motivated to quit; however, most smoking cessation interventions are designed for smokers who are ready to take action. OBJECTIVES: The aim of the present study was to describe participant engagement and satisfaction with telephonic smoking cessation coaching with a population of smokers at different stages of readiness to quit. METHODS: Qualitative description was used to capture the experiences of 62 individuals who participated in telephonic smoking cessation coaching using semistructured interviews. RESULTS: Results indicate that person-centered communication facilitated engagement and was valued equally or more than perceived coach smoking cessation knowledge. Engagement with the intervention was associated with increased satisfaction, smoking cessation/reduction and perceived convenience of intervention. Conclusions/Importance: Findings indicate that unmotivated smokers can be proactively recruited and engaged in telephonic smoking cessation treatment and that person-centered communication and convenience are important variables that should be considered when implementing health interventions. Telephonic coaching has the potential to reach a large segment of the population with access barriers and could lead to important health behavior change. Intensive provider training that includes person-centered communication strategies is strongly recommended. Specific suggestions for successful implementation and dissemination are provided. PMID- 27767365 TI - Early septic insult in neonatal pigs increases serum and urinary soluble Fas ligand and decreases kidney function without inducing significant renal apoptosis. AB - Apoptosis of renal tubular and glomerular cells during kidney disease involves activation of Fas ligand (FasL)-dependent death pathway. The significance of FasL in neonates with septic acute kidney injury (AKI) is unresolved, but an increase in renal FasL production, and/or infiltration of circulating FasL into the kidneys may occur following initial septic insult. Here, we examined whether soluble Fas ligand (sFasL) levels are altered during early phase of septic AKI in neonates. Six hours of polymicrobial sepsis elicited by cecal ligation and puncture (CLP) elevated serum C-reactive protein (CRP) (a bacteremia and sepsis marker) concentration in anesthetized and mechanically ventilated neonatal pigs. Serum creatinine and urea nitrogen concentrations were increased by ~39% and 46%, respectively, following 6 h of CLP in the pigs. The urinary level of NGAL, an early marker of AKI was also elevated by ~71% in the septic pigs. The basal concentration of sFasL in the serum and urine of neonatal pigs was similar. Six hours of CLP significantly increased serum and urine sFasL levels in the pigs by ~24% and 68%, respectively. However, there was no evidence of caspase activation to suggest an induction of cellular apoptotic process in the kidneys of the septic pigs. These findings suggest that an increase in circulating and urinary sFasL during early septic AKI in neonatal pigs is not associated with renal apoptosis. PMID- 27767367 TI - The Spatial-Temporal Pattern of Policing Following a Drug Policy Reform: Triangulating Self-Reported Arrests With Official Crime Statistics. AB - BACKGROUND: In 2009, Mexico enacted a drug policy reform (Narcomenudeo) designed to divert persons possessing small amounts of illicit drugs to treatment rather than incarceration. To assess reform impact, this study examines the spatial temporal trends of drug-related policing in Tijuana, Mexico post-enactment. METHOD: Location of self-reported arrests (N = 1,160) among a prospective, community-recruited cohort of people who inject drugs (PWID) in Tijuana (N = 552) was mapped across city neighborhoods. Official police reports detailing drug related arrests was triangulated with PWID self-reported arrests. Exploratory spatial data analysis examined the distribution of arrests and spatial association between both datasets across three successive years, 2011-2013. RESULTS: In 2011, over half of PWID reported being detained but not officially charged with a criminal offense; in 2013, 90% of arrests led to criminal charges. Official drug-related arrests increased by 67.8% (p <.01) from 2011 to 2013 despite overall arrest rates remaining stable throughout Tijuana. For each successive year, we identified a high degree of spatial association between the location of self-reported and official arrests (p <.05). CONCLUSION: Two independent data sources suggest that intensity of drug law enforcement had risen in Tijuana despite the promulgation of a public health-oriented drug policy reform. The highest concentrations of arrests were in areas traditionally characterized by higher rates of drug crime. High correlation between self reported and official arrest data underscores opportunities for future research on the role of policing as a structural determinant of public health. PMID- 27767368 TI - Cigarette Smoking Status Among Latino/Hispanic Middle and High School Students in the United States. AB - Although Latino/Hispanic adolescent substance use is a growing research area in the United States, there is little research examining the prevalence and factors associated with adolescent cigarette smoking status in this population. A nationally representative sample of 5,929 middle and high Latino/Hispanic students in the 2009 US National Youth Tobacco Survey was selected to assess the prevalence and various risk and protective factors associated with cigarette smoking status. Results revealed one in five (20%) were experimental smokers, nearly one in eleven (8.5%) were occasional smokers, and 4% were regular smokers. Multinomial logistic regression analyses showed that, controlling for demographics, family members' smoking, refusal to smoke, school absence, and exposure to tobacco marketing were associated with experimental smoking; awareness of harmful effects of secondhand smoking, refusal to smoke, exposure to tobacco advertising, and receptivity to tobacco marketing were associated with occasional smoking; and refusal to smoke, school absence, and receptivity to tobacco marketing were associated with regular smoking. This study highlights the need to integrate various risk and proactive factors associated with different smoking status into practices and policies for Latino/Hispanic adolescent smokers. PMID- 27767369 TI - Drinking Goals and Their Association With Treatment Retention and Treatment Outcomes Among Clients in Outpatient Alcohol Treatment. AB - BACKGROUND: Few studies have compared characteristics of clients entering alcohol treatment who differ in their drinking goal preferences or have investigated the relevance of drinking goals as a predictor of treatment outcomes. OBJECTIVES: To investigate associations between baseline drinking goal preferences and client characteristics as well as treatment retention and outcomes among clients in outpatient alcohol treatment. METHODS: Secondary data analyses on a longitudinal multicenter study investigating the effectiveness of outpatient alcohol treatment in Switzerland among 805 clients. Assessments were conducted at treatment admission, discharge, and at 6- and 12-month follow ups. At-risk drinking was assessed through the alcohol use disorders identification test. Treatment retention was defined as regular discharge with or without transition into another institution. RESULTS: Clients aiming to abstain from drinking were more likely to be in retreatment, to be assigned to treatment by a health institution, to have no at-risk alcohol use, and to be already alcohol abstinent at the time of admission relative to clients who aimed to control their drinking. Clients without at-risk alcohol use at admission showed higher treatment retention when aiming for controlled drinking than for abstinence, while there was no difference in treatment retention among clients with at-risk use. Clients with at-risk use at admission were more likely to reach not-at-risk alcohol use status when aiming for alcohol abstinence than for controlled drinking. CONCLUSIONS: Drinking goals are associated with variables of alcohol use and treatment assignment. They have different effects on treatment retention and treatment outcomes according to alcohol use at the time of admission. PMID- 27767370 TI - Electronic Cigarette Use Among Adolescents in the Russian Federation. AB - BACKGROUND: Information on e-cigarettes among youth in the Russian Federation is lacking. OBJECTIVE: We examined prevalence of and factors associated with youth e cigarette use in the Russian Federation. METHODS: A cross-sectional, anonymous survey, conducted among 716 (females 51.5%) high school students in three cities (i.e., Ufa, Sterlitamak, Karagaevo) within the Republic of Bashkortostan, Russian Federation in 2015, assessed e-cigarette use and its correlates (i.e., sex, age, ethnicity, family structure, parents' highest degrees, antisocial behaviors, stress coping strategies, lifetime cigarette, hookah, alcohol, and marijuana use). RESULTS: Lifetime use of e-cigarettes was 28.6% and past-30-day use was 2.2%. Multilevel modeling showed that belonging to Tatar/Bashkir ethnicity relative to Russian ethnicity (OR = 1.60) and lifetime use of cigarettes (OR = 21.64), hookah (OR = 4.21), and alcohol (OR = 1.90) was associated with greater odds of lifetime use of e-cigarettes. Furthermore, use of social support coping strategies (i.e., utilizing parents for support) were associated with lower odds of lifetime use of e-cigarettes (OR = 0.94). CONCLUSIONS: Despite high lifetime e cigarette use, past-30-day use was low. Greater knowledge of the reasons for e cigarette discontinuation through continued surveillance is needed in the Russian Federation. Social coping strategies involving parents may inform e-cigarette use prevention. PMID- 27767371 TI - Transapical versus transfemoral approach and risk of acute kidney injury following transcatheter aortic valve replacement: a propensity-adjusted analysis. AB - BACKGROUND: The aim of this study was to compare the incidence of post-procedural acute kidney injury (AKI) and other renal outcomes in patients undergoing transapical (TA) and transfemoral (TF) approaches for transcatheter aortic valve replacement (TAVR). METHODS: All consecutive adult patients undergoing TAVR for aortic stenosis from 1 January 2008 to 30 June 2014 at a tertiary referral hospital were included. AKI was defined based on Kidney Disease Improving Global Outcomes (KDIGO) criteria. Logistic regression adjustment, propensity score stratification, and propensity matching were performed to assess the independent association between procedural approach and AKI. RESULTS: Of 366 included patients, 171 (47%) underwent TAVR via a TA approach. AKI occurrence in this group was significantly higher compared to the TF group (38% vs. 18%, p < .01). The TA approach remained significantly associated with increased risk of AKI after logistic regression (OR 3.20; CI 1.68-4.36) and propensity score adjustment: OR 2.83 (CI 1.66-4.80) for stratification and 3.82 (CI 2.04-7.44) for matching. Nonetheless, there was no statistically significant difference among the TA and TF groups with respect to major adverse kidney events (MAKE) or estimated glomerular filtration rate (eGFR) at six months post-procedure. CONCLUSION: In a cohort of patients undergoing TAVR for aortic stenosis, a TA approach significantly increases the AKI risk compared with a TF approach. However, the TAVR approach did not affect severe renal outcomes or long-term renal function. PMID- 27767372 TI - The prognostic value of oxidative stress and inflammation in Chinese hemodialysis patients. AB - BACKGROUND: There is limited information about oxidative stress and inflammation on the mortality of Chinese hemodialysis (HD) patients. SUBJECTS AND METHODS: A total of 177 HD patients and 35 healthy controls were enrolled. Their demographic information, clinical characteristics, oxidant and inflammation markers were compared. Multivariate Cox regression analysis was used to assess the risk factors for mortality. RESULTS: Twenty-seven (15.3%) HD patients died during the one-year follow-up. The mean age, age >=70 years, serum level of cardiac troponin T (cTnT), malondialdehyde (MDA) > 5 nmol/L, as well as CRP >10 mg/L and the level of interleukin (IL)-6 were significantly different between the nonsurvival and survival HD patients. Multivariate Cox's regression analysis identified age, age >=70 years, cTnT, and IL-6 were independent predictors of mortality in HD patients. CONCLUSIONS: Age, age >=70 years, cTnT, and IL-6 were independent predictors of mortality in Chinese HD patients. Elevated IL-6 level, instead of MDA, was predictive of poor outcome in Chinese hemodialysis patients. PMID- 27767373 TI - Autoregulation of Optic Nerve Head Blood Flow Induced by Elevated Intraocular Pressure during Vitreous Surgery. AB - PURPOSE: To investigate optic nerve head (ONH) blood flow changes resulting from intraocular pressure (IOP) elevation in subjects without systemic disorders. MATERIALS AND METHODS: Eighteen eyes of 18 patients who underwent vitrectomy to treat an epiretinal membrane or macular hole at Toho University Sakura Medical Center were included. Following standard 25-gauge microincision vitreous surgery, mean blur rate (MBR) in tissue (MT), an index of ONH blood flow, was measured using laser speckle flowgraphy. Measurements were taken before and 5 and 10 minutes after a 15 mmHg IOP elevation. RESULTS: The ONH blood flow was initially lower than baseline (P = 0.001) after elevating IOP from 14.8 +/- 2.8 mmHg to approximately 30 mmHg. Between 5 and 10 minutes after elevating IOP, ONH blood flow partially recovered (P = 0.004), even though ocular perfusion pressure was 20.2% lower than at baseline. CONCLUSIONS: The ONH blood flow in subjects without systemic disorders was initially lower, but began to recover 5-10 minutes after a 15 mmHg elevation in IOP. These results indicate that autoregulatory mechanisms of ONH blood flow may help to minimize the effects of IOP elevations and fluctuations during vitreous surgery. PMID- 27767374 TI - Validity, reliability and ease of use of the disabilities of arm, shoulder and hand questionnaire in adults following stroke. AB - PURPOSE: The Disabilities of Arm, Shoulder and Hand (DASH) questionnaire is a patient reported outcome measure for evaluating upper limb function in people with musculoskeletal conditions. While the DASH has good psychometric properties when used with people with musculoskeletal conditions, it has not been tested with adults after stroke. METHODS: Data for n = 61 adults following stroke (aged 32-93 years, 44% male) were analyzed to test validity and reliability of the DASH for use with a stroke population. Data included demographic and clinical attributes, DASH scores (baseline and four weeks later) and Patient Rated Wrist Evaluation (PRWE) measures. RESULTS: Internal consistency was good (Cronbach alpha 0.92, SEM 6.65). Factor analysis and Rasch modeling suggested that the questionnaire comprised three subscales: pain, impact and function. Concurrent validity between the DASH and PRWE (Spearman's Rho rs = 0.41) was moderate. The scale was perceived by clinicians to be useful, quick and simple to administer. The DASH had low four-week test-retest reliability (ICC 0.56 [95% Cl 0.05-0.79]). CONCLUSIONS: The DASH is considered to have acceptable validity when used with adults following stroke. Test-retest reliability was low but further research is needed to establish whether this is a result of condition-related change or the stability of the measure. Implications for Rehabilitation The DASH questionnaire examines upper limb function in task performance and appears to be a useful tool, which is simple to administer in the clinical setting with adults following stroke. Upper limb function post stroke can be meaningfully assessed using the DASH as it has good internal consistency and moderate concurrent validity. Rasch analysis and factor analysis suggests that the tool appears to consist of three subscales: pain, impact and function. The total score of the DASH may be less meaningful than the totals of these subscales. The test-retest reliability of the DASH requires further research; over a four-week period DASH stability was poor in a group of people with moderate to severe upper limb impairment. PMID- 27767375 TI - Adapted Tango improves aspects of participation in older adults versus individuals with Parkinson's disease. AB - PURPOSE: Our aims were to determine (1) the impact of aging versus combined aging and disease on participation and (2) participation before and after a 12-week, Adapted Tango dance intervention (AT) in older adults with and without Parkinson's disease (PD). METHODS: Participant responses to open and closed-ended questions on the Impact on Participation and Autonomy questionnaire (IPA) were recorded before, one-week-after, and three-months after 20 lessons of AT. Twenty five older individuals with PD and 63 older adults without PD were initially enrolled and assessed, and 44 older adults and 22 individuals with PD finished the program with post-testing. RESULTS: Thematic analysis revealed major themes of difficulty with mobility, transportation and financial management, feelings of being forced to limit activities, and interest in work or volunteering for both groups at baseline and post-test. At post-test, additional emphasis on resilience in the face of challenges was noted. No differences were noted between groups on the IPA subscales at baseline. Quantitative analysis with a 2 (group) * 3 (time) MANOVA revealed a main effect of time (p < 0.001), with improved Social Life (p < 0.001), marginally improved Autonomy Indoors (p = 0.073), and Family Role (p = 0.057). CONCLUSIONS: Adapted Tango improved aspects of participation for these cohorts of older adults with and without PD. Implications for Rehabilitation Both Parkinson's disease and neurotypical aging can negatively impact participation in life's activities in older adults. Adapted Tango is an alternative therapy that has improved quality of life and mobility in people with PD and older adults. Quantitative data show that Adapted Tango may improve some aspects of participation for older adults with and without PD. Open-ended responses reveal aging and combined aging and disease-related issues have a lasting impact upon participation. PMID- 27767377 TI - The split between Gall and Spurzheim (1813-1818). AB - An acerbic footnote in Volume 3 (1818) of the five-volume great work of Franz Joseph Gall and Johann Gaspar Spurzheim, Anatomy and Physiology of the Nervous System in General and of the Brain in Particular with Observations on the Possibility of Understanding the Many Moral and Intellectual Dispositions of Man and Animals by the Configuration of Their Heads, marked the end of the collaboration between Gall, the founder of organologie, and Spurzheim, promoter of phrenology. We discuss the background of this note and the nature of the rift that marked the end of Gall and Spurzheim's collaboration. PMID- 27767376 TI - Pharmacogenomics and histone deacetylase inhibitors. AB - The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping. PMID- 27767380 TI - Landscape of warfarin and clopidogrel pharmacogenetic variants in Qatari population from whole exome datasets. AB - AIM: Pharmacogenetic landscapes of commonly used antiplatelet drugs, warfarin and clopidogrel have been studied in-depth in many countries. However, there is a paucity of data to understand their patterns in the Arab populations. MATERIALS & METHODS: We analyzed the whole exome sequencing datasets of 100 Qatar individuals available in public domain with this perspective. RESULTS: We characterized the allelic distribution of variants routinely tested for warfarin and clopidogrel. We additionally evaluated the population stratification and its effect on allele frequency distribution. Our analysis points to ethnic differences in the frequency distribution even for the small population studied. CONCLUSION: This is one of the first and most comprehensive pharmacogenetic maps of variants associated with warfarin and clopidogrel for an Arab population, which can help tailor the drug dosage to the population. PMID- 27767378 TI - RNA-binding protein QKI-5 inhibits the proliferation of clear cell renal cell carcinoma via post-transcriptional stabilization of RASA1 mRNA. AB - Clear cell renal cell carcinoma (ccRCC) is a common pathological subtype of renal cancer. Although the recent application of molecular-targeted agents has modestly improved the prognosis of ccRCC patients, their outcome is still poor. It is therefore important to characterize the molecular and biological mechanisms responsible for the development of ccRCC. Approximately 25% ccRCC patients involves the loss of RNA-binding protein QKI at 6q26, but the role of QKI in ccRCC is unknown. Here, we found that QKI-5 was frequently downregulated in ccRCC patients and its down-regulation was significantly associated with clinical features including T status, M status, and differentiation grade, and poorer patient prognosis. Moreover, QKI-5 inhibited the proliferation of kidney cancer cells both in vitro and in vivo. The subsequent functional studies showed that QKI-5 stabilized RASA1 mRNA via directly binding to the QKI response element region of RASA1, which in turn prevented the activation of the Ras-MAPK signaling pathway, suppressed cellular proliferation and induced cell cycle arrest. Overall, our data demonstrate a suppressive role of QKI in ccRCC tumourigenesis that involves the QKI-mediated post-transcriptional regulation of the Ras-MAPK signaling pathway. PMID- 27767379 TI - Identification and characterization of PKF118-310 as a KDM4A inhibitor. AB - Epigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete. We describe the in silico, in vitro, and cell-based characterization of the compound PKF118-310, an antagonist of transcription factor 4 (TCF4)/beta catenin signaling, as inhibitor of KDM4A. PKF118-310 potential inhibitor activity was discovered via virtual screening on the crystal structure of KDM4A. A peptide based histone trimethylation assay developed in-house confirmed its potent KDM4A inhibitor activity. Its protein target was identified by cellular thermal shift assay experiments. PKF118-310 anticancer activity was observed in both liquid and solid tumor cells, and shown to have a dose- and time-dependent effect. We demonstrate the previously unreported inhibitory action of PKF118-310 on KDM4A. Our findings open up the possibility of developing the first KDM4A-specific inhibitors and derivatives. PMID- 27767381 TI - The effect of SNPs in CYP450 in chloroquine/primaquine Plasmodium vivax malaria treatment. AB - BACKGROUND: Chloroquine/primaquine is the current therapy to eliminate Plasmodium vivax infection in the Amazon region. AIMS: This study investigates CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 genetic polymorphisms influence on cloroquine/primaquine treatment. PATIENTS & METHODS: Generalized estimating equations analyses were performed to determine the genetic influence in parasitemia and/or gametocytemia clearance over treatment time in 164 patients. RESULTS: An effect of CYP2C8 low-activity alleles on treatment was observed (p = 0.01). From baseline to first day of treatment, wild-type individuals achieved greater reduction of gametocytes than low-activity allele carriers. CYP2C9 and CYP3A5 genes showed a trend for gametocytemia and parasitemia clearance rates. CONCLUSION: Future studies should be performed to access the extent of CYP2C8, CYP2C9 and CYP3A5 gene polymorphisms influence on cloroquine/primaquine treatment. PMID- 27767382 TI - Metacognition and cognitive control: behavioural adaptation requires conflict experience. AB - Cognitive control allows adapting our behaviour to improve performance. A behavioural signature of cognitive control is the Gratton effect. This effect is observed in conflict tasks and indicates smaller congruency effects after incongruent trials than after congruent trials. Metacognitive experience may play a role in this effect: When participants introspect on their conflict experience, the Gratton effect follows the conflict introspection instead of the stimulus congruency. However this Gratton effect could also be triggered by the labelling that the introspective method implies and/or by a misperception of the stimulus conflict. The current study investigated whether the experiential component of the introspection is necessary to trigger cognitive control or whether labelling a trial as conflicting or not can be sufficient. In a priming task, Gratton effects following metacognitive conflict experience and conflict label were contrasted. Replicating earlier reports, results showed that the metacognitive experience of conflict can trigger a Gratton effect. However a conflict label, either generated by the participants themselves or presented to the participants via feedback was not able to induce cognitive control. Results are discussed in light of current theories of cognitive control. PMID- 27767383 TI - Pyridine nucleotides induce changes in cytosolic pools of calcium in Arabidopsis. AB - NAD is a pyridine nucleotide that is involved in cell metabolism and signaling of plant growth and stress. Recently, we reported on the multifaceted nature of NAD inducible immunity in Arabidopsis. We identified NAD as an integral regulator of multiple defense layers such as production of ROS, deposition of callose, stimulation of cell death and modulation of defense metabolism including the defense hormones SA, JA and ABA, and other defense-associated metabolites. Altogether, NAD-induced immune effects confer resistance to diverse pathogenic microbes. Our addendum to this work further demonstrates an impact of NAD on the cytosolic calcium pool, a well-known component of early plant defense response. PMID- 27767384 TI - Baseball fans don't like lumpy batters: Influence of domain knowledge on the access of subordinate meanings. AB - Two experiments investigated the effects of domain knowledge on the resolution of ambiguous words with dominant meanings related to baseball. When placed in a sentence context that strongly biased toward the non-baseball meaning (positive evidence), or excluded the baseball meaning (negative evidence), baseball experts had more difficulty than non-experts resolving the ambiguity. Sentence contexts containing positive evidence supported earlier resolution than did the negative evidence condition for both experts and non-experts. These experiments extend prior findings, and can be seen as support for the reordered access model of lexical access, where both prior knowledge and discourse context influence the availability of word meanings. PMID- 27767385 TI - Distinction between fear and surprise: an interpretation-independent test of the perceptual-attentional limitation hypothesis. AB - The perceptual-attentional limitation hypothesis posits that the confusion between emotional facial expressions of fear and surprise may be due to their visual similarity, with shared muscle movements. In Experiment 1 full face images of fear and surprise varying as a function of distinctiveness (mouth index, brow index, or both indices) were displayed in a gender oddball task. Experiment 2, in a similar task, directed attention toward the eye or mouth region with a blurring technique. The current two studies used response time and event-related potentials (ERP) to test the perceptual-attentional limitation hypothesis. While ERP results for Experiment 1 suggested that individuals may not have perceived a difference between the emotional expressions in any of the conditions, response time results suggested that individuals processed a difference between fear and surprise when a distinctive cue was in the mouth. With directed attention in Experiment 2, ERP results indicated that individuals were capable of detecting a difference in all the conditions. In effect, the current two experiments suggest that participants display difficulty in distinguishing the prototypes of fear and surprise with the eye region, which may be due to a lack of attention to that region, providing support for the attentional limitation hypothesis. PMID- 27767386 TI - Relationship Between Implant Stability Measurements Obtained by Two Different Devices: A Systematic Review. AB - BACKGROUND: The aim of this systematic review is to evaluate the relationship between two methods used to assess implant stability, investigating whether both provide similar implant stability assessments for the same clinical case. METHODS: A literature search was conducted on MEDLINE-PubMed and Scopus databases, without limitation of the publication period, up to November 2015. The following key words were used, with associations among them: "dental implant," "dental implants," "Osstell," "resonance frequency analysis," "implant stability quotient," "ISQ," "Periotest," "Periotest value," and "PTV." Inclusion criteria were English language, prospective, retrospective, and randomized controlled clinical trials that evaluated implant stability through use of resonance frequency analysis (RFA) and damping capacity analysis (DCA). The study should assess implant stability of only a specific region for all patients or discriminate results evaluated for each region if the analysis had been made in various regions; RFA and DCA should have been applied in the same implants and periods. Studies have been carefully selected, and data of interest were tabulated. RESULTS: Six studies met the inclusion criteria. Although there was significant numerical correlation between values obtained by both methods, data showed that less than half (46%) of cases coincided in relation to implant stability classification. CONCLUSIONS: It can be considered that there is not always a consensus and standardization in the classification of implant stability related to the values obtained by RFA and DCA devices, which could create disagreements and miscommunication among dentistry professionals. PMID- 27767388 TI - The Effect of Locally Delivered Statins on Treating Periodontal Intrabony Defects: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Use of statins on adult patients with chronic periodontitis shows a positive effect on their periodontal status. However, effect of locally delivered statins on periodontal treatment has not yet been systematically analyzed. Hence, the present systematic review and meta-analysis aims to evaluate efficacy of statins on treating localized periodontal intrabony defects (IBDs). METHODS: An electronic search of three databases (PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature) between January 1, 1965 and March 1, 2016, and a hand search of peer-reviewed journals for relevant articles were performed. Controlled randomized clinical trials (RCTs) and prospective studies with data on comparison between adjunctive locally delivered statin use to mechanical scaling and root planing (SRP) and placebo in each group, with minimum 10 participants and follow-up period of at least 6 months, were included. RESULTS: Ten studies, eight RCTs and two prospective studies, were included. Each study included 15 to 105 patients between 25 and 55 years of age. Statistical results were recorded; weighted mean difference (WMD) and confidence interval (CI) were calculated; and meta-analyses were performed for defect fill, probing depth (PD) reduction, and clinical attachment level (CAL) gain in both statin and placebo/no treatment groups. Overall analysis of defect fill presented WMD of 1.37 mm (95% CI = 0.96 to 1.77; P <0.0001), PD reduction presented WMD of 1.76 mm (95% CI = 1.04 to 2.47; P <0.0001), and CAL gain presented WMD of 1.58 mm (95% CI = 0.89 to 2.28; P <0.0001). However, comparison presented considerable heterogeneity among studies. CONCLUSIONS: This systematic review and meta-analysis find that adjunctive use of locally delivered statins to mechanical SRP is beneficial to increasing bone fill percentage. Improved inflammatory and bleeding control as well as PD reduction and CAL gain are possible advantages to using these drugs in treating patients with periodontal IBDs. PMID- 27767387 TI - A Randomized Double-Masked Clinical Trial Comparing Four Periodontitis Treatment Strategies: 5-Year Tooth Loss Results. AB - BACKGROUND: Tooth loss is the ultimate negative consequence of periodontitis, and reports of the extent to which different treatment strategies may influence long term tooth loss are hard to find. This study aims to test the hypothesis that there is no difference in 5-year clinical outcome of therapy in terms of tooth mortality between groups of patients treated with conventional scaling and root planing (SRP) over weeks or same-day full-mouth disinfection (FDIS), with or without adjunctive metronidazole (MET). METHODS: One hundred eighty-four patients with moderate-to-severe periodontitis were randomly allocated to one of four treatment groups: 1) FDIS+MET; 2) FDIS+placebo; 3) SRP+MET; and 4) SRP+placebo. Total 161 patients (88%) completed the 5-year follow-up examination, and data on number and timing of tooth extractions as well as pre-extraction diagnoses and reasons for extractions were analyzed. RESULTS: No differences were observed between groups with regard to number of, reasons for, or time of extractions in the four groups at baseline and 1, 3, and 5 years after treatment. CONCLUSION: If extraction or retention of teeth is regarded as a measure of failure or success 5 years after completion of periodontal therapy, none of the four strategies produced an end result better than the other. PMID- 27767389 TI - Correlation of SIN3A genomic variants with beta-hemoglobinopathies disease severity and hydroxyurea treatment efficacy. AB - AIMS: Hemoglobinopathies, particularly beta-thalassemia and sickle cell disease, are characterized by great phenotypic variability in terms of disease severity, while notable differences have been observed in hydroxyurea treatment efficacy. In both cases, the observed phenotypic diversity is mostly dependent on the elevated fetal hemoglobin levels, resulting from the persistent fetal globin gene expression in the adult erythroid stage orchestrated by intricate mechanisms that still remain only partly understood. We have previously shown that several protein factors act as modifiers of fetal hemoglobin production, exerting their effect via different pathways. MATERIALS & METHODS: Here, we explored whether SIN3A could act as a modifier of fetal globin gene expression, as it interacts with KLF10, a known modifier of fetal hemoglobin production. RESULTS: We show that SIN3A genomic variants are associated both with beta-thalassemia disease severity (rs11072544) as well as hydroxyurea treatment response (rs7166737) in beta-hemoglobinopathies patients. CONCLUSION: Our findings further underline that fetal hemoglobin production is the result of a complex interplay in which several human globin gene cluster variants interact with protein factors encoded by modifier genes to produce the observed clinical outcome. PMID- 27767390 TI - Exceptionalist naturalism: Human agency and the causal order. AB - This paper addresses a fundamental question in folk metaphysics: How do we ordinarily view human agency? According to the transcendence account, we view human agency as standing outside of the causal order and imbued with exceptional powers. According to a naturalistic account, we view human agency as subject to the same physical laws as other objects and completely open to scientific investigation. According to exceptionalist naturalism, the truth lies somewhere in between: We view human agency as fitting broadly within the causal order while still being exceptional in important respects. In this paper, I report seven experiments designed to decide between these three competing theories. Across a variety of contexts and types of action, participants agreed that human agents can resist outcomes described as inevitable, guaranteed, and causally determined. Participants viewed non-human animal agents similarly, whereas they viewed computers, robots, and simple inanimate objects differently. At the same time, participants judged that human actions are caused by many things, including psychological, neurological, and social events. Overall, in folk metaphysics, human and non-human animals are viewed as exceptional parts of the natural world. PMID- 27767391 TI - Assessment of genotoxic, mutagenic, and recombinogenic potential of water resources in the Paranaiba River basin of Brazil: A case study. AB - Exposure to certain pollutants induces a series of alterations in deoxyribonucleic acid (DNA) that may result in genotoxic/mutagenic effects in exposed individuals. The present study aimed to monitor genotoxic, mutagenic, and recombinogenic potential and consequently water quality in two streams in the Paranaiba River basin in the state of Minas Gerais, Brazil, using two bioindicator fish (Rhamdia quelen and Geophagus brasiliensis). The micronucleus (MN) test and somatic recombination and mutation test (SMART) were employed to assess DNA damage. The water quality index (WQI) at the reference site control (S1) due to its proximity to the river source was compared to Corrego do Oleo (S2) with respect to chemical parameter levels of biochemical oxygen demand (BOD), dissolved-oxygen rates (DO), and total solid and fecal coliform counts. These chemical parameters were above the permitted limits at Corrego do Oleo (S2). At a third site, Corrego Liso (S3), a poor WQI was detected, attributed to the influence of domestic and industrial activities where BOD, DO, total solid, fecal coliform, total phosphorus, and turbidity rates exceeded premissible limits. The MN frequencies and the numbers of MN per cell (CMN) at sites S2 and S3 were significantly higher than those at S1 in both species. It is of interest that the increased frequency of MN was similar to the positive control cyclophosphamide only at S3, suggesting that the effects of water contaminants were most severe at this site. At sites assessed (S2 and S3), there was a significant rise in somatic mutation and recombination in the wings of Drosophila melanogaster, indicating the presence of trace elements, mainly lead (Pb) and cadmium (Cd), in the effluents in the Paranaiba River basin sites. PMID- 27767392 TI - Testing of Schefflera vinosa extract in mammalian cells in vitro and in vivo for potential toxicity, genetic damage, and role of oxidation. AB - The aim of this study was to examine the cytotoxic and genotoxic potential of a hydroethanolic extract of Schefflera vinosa (SV), a plant with schistosomicidal activity, as well as its influence on DNA damage induced by different mutagens, methyl methane sulfonate (MMS) and hydrogen peroxide (H2O2), in V79 cells and Swiss mice. Schefflera vinosa extract produced cytotoxicity at concentrations of 312.5 ug/ml or higher using the XTT cell proliferation assay kit. Treatment of V79 cell cultures with the highest SV concentration tested (150 ug/ml) significantly increased the frequency of micronuclei (MN) compared to controls. All SV concentrations significantly reduced the frequency of MN induced by hydrogen peroxide in V79 cell cultures. Further, SV was able to scavenge free radicals in the DPPH assay. In the in vivo test system, treatment with the highest dose tested (1,000 mg/kg body weight) induced a significant rise in frequency of DNA damage using the comet assay. However, animals treated with different doses of SV demonstrated absence of genotoxicity in the bone marrow MN test. For assessment of modulatory effects, the lower concentration of SV (250 mg/kg body weight) administered to MMS-treated mice significantly reduced frequency of DNA damage compared to the positive control (MMS alone). In contrast, the highest concentration tested (1,000 mg/kg body weight) significantly increased the rate of MN induced by MMS. The lack of genotoxic damage at biologically relevant SV concentrations, as well as the SV-mediated antigenotoxic and antioxidant activities, indicate the potential therapeutic usefulness of this plant extract. These activities may be attributed, at least in part, to the flavonoid quercitrin, its major component. PMID- 27767393 TI - Quenching of fluorescence by meclizine, a probe study for structural and conformational changes in human serum albumin. AB - The goal of this study was to investigate the interactions between meclizine (MEC) and human serum albumin (HSA) under physiological conditions by different spectroscopies and molecular modeling technique. The drug, MEC quenched the intrinsic fluorescence of HSA and the analysis of the results revealed that static quenching mechanism. The binding of MEC quenches the HSA fluorescence; stoichiometry was 1:1 interaction. Thermodynamic quantities were calculated at different temperatures suggested that hydrophobic and van der Waals interaction with HSA-MEC. The molecular distance, r, between donor and acceptor was estimated according to Forster's theory of non-radiation energy transfer. CD and FT-IR studies confirm changes of secondary structure of HSA. Molecular docking studies validate MEC molecule interact to HSA in sub domain IIA. PMID- 27767394 TI - Resolution of intractable retching following mobilization of a dolichoectatic vertebral artery: case report of a unique brainstem-cranial nerve compression syndrome. AB - The authors present the case of a 53-year-old man who was referred with disabling retching provoked by left arm abduction. At the time of his initial evaluation, a cervical MRI study was available for review and revealed an anatomical variation of the ipsilateral juxtamedullary vertebrobasilar junction. After brain imaging revealed contact of the medulla by a dolichoectatic vertebral artery at the dorsal root entry zone of the glossopharyngeal and vagus nerves, the patient was successfully treated by microvascular decompression of the brainstem and cranial nerves. This case demonstrates how a dolichoectatic vertebral artery-a common anatomical variation that typically has no clinical consequence-should be considered in cases of cranial nerve dysfunction. PMID- 27767395 TI - Endoscopic endonasal transclival resection of a ventral pontine cavernous malformation: technical case report. AB - Brainstem cavernous malformations are challenging due to the critical anatomy and potential surgical risks. Anterolateral, lateral, and dorsal surgical approaches provide limited ventral exposure of the brainstem. The authors present a case of a midline ventral pontine cavernous malformation resected through an endoscopic endonasal transclival approach based on minimal brainstem transection, negligible cranial nerve manipulation, and a straightforward trajectory. Technical and reconstruction technique advances in endoscopic endonasal skull base surgery provide a direct, safe, and effective corridor to the brainstem. PMID- 27767396 TI - A systematic review of 30-day readmission after cranial neurosurgery. AB - OBJECTIVE The 30-day readmission rate has emerged as an important marker of the quality of in-hospital care in several fields of medicine. This review aims to summarize available research reporting readmission rates after cranial procedures and to establish an association with demographic, clinical, and system-related factors and clinical outcomes. METHODS The authors conducted a systematic review of several databases; a manual search of the Journal of Neurosurgery, Neurosurgery, Acta Neurochirurgica, Canadian Journal of Neurological Sciences; and the cited references of the selected articles. Quality review was performed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) criteria. Findings are reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS A total of 1344 articles published between 1947 and 2015 were identified; 25 were considered potentially eligible, of which 12 met inclusion criteria. The 30-day readmission rates varied from 6.9% to 23.89%. Complications arising during or after neurosurgical procedures were a prime reason for readmission. Race, comorbidities, and longer hospital stay put patients at risk for readmission. CONCLUSIONS Although readmission may be an important indicator for good care for the subset of acutely declining patients, neurosurgery should aim to reduce 30 day readmission rates with improved quality of care through systemic changes in the care of neurosurgical patients that promote preventive measures. PMID- 27767397 TI - FLAIR signal increase of the fluid within the resection cavity after glioma surgery: generally valid as early recurrence marker? AB - OBJECTIVE Recent studies have indicated that a signal intensity increase of the fluid within the resection cavity on FLAIR images may predict tumor recurrence after glioma surgery. The aim of this study was to assess the increase in FLAIR signal intensity in a large patient cohort and in subgroups to assess its prognostic value for early tumor recurrence in glioma patients. METHODS A total of 212 patients (213 cases) who had undergone surgery for an intracranial glioma (WHO Grade IV [n = 103], WHO Grade III [n = 57], and WHO Grade II [n = 53]) were included in this retrospective study. FLAIR signal within the resection cavity at the time of tumor recurrence/last contact and on the previous MRI study was assessed qualitatively and quantitatively. Appearance of FLAIR signal increase was studied over time using Kaplan-Meier estimates in subgroups. RESULTS Patients with WHO Grade II glioma and connection of the resection cavity to CSF who did not undergo radiotherapy did not regularly develop this sign and were excluded from further analysis. For the remaining 87 cases, FLAIR signal intensity increase was observed in 27 cases. Recurrent disease was found in 26 of these 27 cases, resulting in a specificity of 80.0%, a sensitivity of 31.7%, and positive and negative predictive values of 96.3% and 6.7%, respectively. In 4 cases this sign had been observed prior (range 2.8-8.5 months) to tumor recurrence defined by standard criteria. Quantitative analysis underlined the results of qualitative analysis, but it did not add a diagnostic value. CONCLUSIONS Signal intensity increase of the fluid within the resection cavity on FLAIR images is a rare but highly specific and early sign for tumor recurrence/tumor progression in completely and incompletely resected high-grade glioma without connection of the resection cavity to CSF and with radiotherapy. PMID- 27767398 TI - Decompressive craniectomy in hemorrhagic cerebral venous thrombosis: clinicoradiological features and risk factors. AB - OBJECTIVE Decompressive craniectomy (DC) is a life-saving treatment for severe hemorrhagic cerebral venous thrombosis (CVT). However, the correlations between the clinicoradiological features and surgical outcomes of this disease are not well established. Therefore, the authors endeavored to analyze the potential risk factors for this more severe subtype of CVT and to provide more evidence regarding the benefits of DC in patients with hemorrhagic CVT. METHODS The clinical features, radiological findings, and surgical outcomes of patients with severe hemorrhagic CVT who had undergone DC treatment in the period from January 2005 to March 2015 were retrospectively analyzed, and the risk factors for this disease were evaluated. RESULTS Fifty-eight patients, 39 females (67.2%) and 19 males (32.8%), with a mean age of 39.7 +/- 12.5 years, were included in this study. The mean duration from symptom onset to surgery was 3.3 +/- 1.9 days, and 21 patients experienced acute courses. On neuroimaging, the mean mass lesion volume was 114.7 +/- 17.7 ml. Nine patients had bilateral lesions, and 7 patients had deep CVT. According to their hemorrhagic proportion, cases were divided into hemorrhage-dominated (27 [46.6%]) and edema-dominated (31 [53.4%]) groups. After 6 months of follow-up, 56.9% of patients had achieved a favorable outcome, and 8 patients had died. The hemorrhage-dominated lesions (p = 0.026) and deep cerebral venous involvement (p = 0.026) were significantly associated with a poor outcome. CONCLUSIONS In patients suffering from severe hemorrhagic CVT, DC is an effective life-saving treatment that is associated with favorable outcomes. Hemorrhage dominated lesions and deep cerebral venous involvement have a significant impact on the outcome of this disease. PMID- 27767399 TI - Pineal cysts and other pineal region malignancies: determining factors predictive of hydrocephalus and malignancy. AB - OBJECTIVE Cystic lesions of the pineal gland are most often uncomplicated benign lesions with typical MRI characteristics. The authors aimed to study pineal lesion characteristics on MRI to better distinguish benign pineal cysts from other pineal region malignancies as well as to determine which characteristics were predictive of the latter malignancies. They also aimed to study risk factors predictive of hydrocephalus or malignancy in patients harboring these lesions. METHODS The authors performed a retrospective review of a prospectively compiled database documenting the outcomes of patients with suspected pineal cysts on MRI who had presented in the period from 1998 to 2004. Inherent patient and lesion characteristics were assessed in a univariate logistic regression analysis to predict the following dependent variables: development of hydrocephalus, biopsy confirmed malignancy, and intervention. Possible inherent patient and lesion characteristics included age, sex, T1 and T2 MRI signal pattern, contrast enhancement pattern, presence of cyst, presence of blood, complexity of lesion, presence of calcification, and duration of follow-up. Inherent patient and lesion characteristics that were predictive in the univariate analysis (p < 0.15) were included in the multivariable logistic regression analysis. RESULTS Of the 79 patients with benign-appearing pineal cysts, 26 (33%) were male and 53 (67%) were female, with a median age of 38 years (range 9-86 years). The median cyst radius was 5 mm (range 1-20 mm). Two patients (2.5%) had evidence of calcifications, 7 (9%) had multicystic lesions, and 25 (32%) had some evidence of contrast enhancement. The median follow-up interval was 3 years (range 0.5-13 years). Seven patients (9%) had an increase in the size of their lesion over time. Eight patients (10%) had a hemorrhage, and 11 patients (14%) developed hydrocephalus. Nine (11%) received ventriculoperitoneal shunts for the development of hydrocephalus, and 12 patients (16%) were found to have malignancies following biopsy or resection. In the multivariate analysis, contrast enhancement on MRI (OR 1.6, 95% CI 2.86-74.74, p = 0.013) and hemorrhage (OR 26.9, 95% CI 3.4-212.7, p = 0.022) were predictive of hydrocephalus. Increasing lesion size and hydrocephalus were near perfect predictors of malignancy and thus were removed from multivariate analysis. In addition, contrast enhancement on MRI (OR 8.8, 95% CI 2.0-38.6, p = 0.004) and hemorrhage (OR 6.8, 95% CI 1.1-40.5, p = 0.036) were predictive of malignancy. CONCLUSIONS Although cystic abnormalities of the pineal gland are often benign lesions, they are frequently monitored over time, as other pineal region pathologies may appear similarly on MRI. Patients with growing lesions, contrast enhancement, and hemorrhage on MRI are more likely to develop hydrocephalus and have malignant pathology on histological examination and should therefore be followed up with serial MRI with a lower threshold for neurosurgical intervention. PMID- 27767402 TI - Letter to the Editor: Lateral sinus thrombosis: antithrombotic therapy and the issue of management of cerebellar swelling. PMID- 27767401 TI - "Awake" clipping of cerebral aneurysms: report of initial series. AB - OBJECTIVE Risk of ischemia during aneurysm surgery is significantly related to temporary clipping time and final clipping that might incorporate a perforator. In this study, the authors attempted to assess the potential added benefit to patient outcomes of "awake" neurological testing when compared with standard neurophysiological testing performed under general anesthesia. The procedure is performed after the induction of conscious sedation, and for the neurological testing, the patient is fully awake. METHODS The authors conducted an institutional review board-approved prospective study of clipping unruptured intracranial aneurysms (UIAs) in 30 consecutive adult patients who underwent awake clipping. The end points were the incidence of stroke/cerebrovascular accident (CVA), death, discharge to a long-term facility, length of stay, and 30 day modified Rankin Scale score. All clinical and neurophysiological intraoperative monitoring data were recorded. RESULTS The median patient age was 52 years (range 27-63 years); 19 (63%) female and 11 (37%) male patients were included. Twenty-seven (90%) aneurysms were anterior, and 3 (10%) were posterior circulation aneurysms. Five (17%) had been coiled previously, 3 (10%) had been clipped previously, 2 (7%) were partially calcified, and 2 (7%) were fusiform aneurysms. Three patients developed synchronous clinical neurological and neurophysiological changes during temporary clipping with consequent removal of the temporary clip and reversal of those clinical and neurophysiological changes. Three patients developed asynchronous clinical neurological and neurophysiological changes. These 3 patients developed hemiparesis without changes in neurophysiological monitoring results. One patient developed linked clinical neurological and neurophysiological changes during final clipping that were not reversed by reapplication of the clip, and the patient had a CVA. Four patients with internal carotid artery ophthalmic segment aneurysms underwent visual testing with final clipping, and 1 of these patients required repositioning of the clip. Three patients who required permanent occlusion of a vessel as part of their aneurysm treatment underwent a 10-minute intraoperative clinical respective-vessel test occlusion. The median length of stay was 3 days (range 1-5 days). The median modified Rankin Scale score was 1 (range 0-3). All of the patients were discharged to home from the hospital except for 1 who developed a CVA and was discharged to a rehabilitation facility. There were no deaths in this series. CONCLUSIONS The 3 patients who developed neurological deterioration without a concomitant neurophysiological finding during temporary clipping revealed a potential advantage of awake aneurysm surgery (i.e., in decreasing the risk of ischemic injury). PMID- 27767400 TI - Reliability assessment of the Biffl Scale for blunt traumatic cerebrovascular injury as detected on computer tomography angiography. AB - OBJECTIVE Blunt traumatic cerebrovascular injury (TCVI) represents structural injury to a vessel due to high-energy trauma. The Biffl Scale is a widely accepted grading scheme for these injuries that was developed using digital subtraction angiography. In recent years, screening CT angiography (CTA) has been used to identify patients with TCVI. The reliability of this scale, with injuries assessed using CTA, has not yet been determined. METHODS Seven independent raters, including 2 neurosurgeons, 2 neuroradiologists, 2 neurosurgical residents, and 1 neurosurgical vascular fellow, independently reviewed each presenting CTA of the neck performed in 40 patients with confirmed TCVI and assigned a Biffl grade. Ten images were repeated to assess intrarater reliability, for a total of 50 CTAs. Fleiss' multirater kappa (kappa) and interclass correlation were calculated as a measure of interrater reliability. Weighted Cohen's kappa was used to assess intrarater reliability. RESULTS Fleiss' multirater kappa was 0.65 (95% CI 0.61-0.69), indicating substantial agreement as to the Biffl grade assignment among the 7 raters. Interclass correlation was 0.82, demonstrating excellent agreement among the raters. Intrarater reliability was perfect (weighted Cohen's kappa = 1) in 2 raters, and near perfect (weighted Cohen's kappa > 0.8) in the remaining 5 raters. CONCLUSIONS Grading of TCVI with CTA using the Biffl Scale is reliable. PMID- 27767403 TI - Erratum: Foramen magnum meningiomas: surgical results and risks predicting poor outcomes based on a modified classification. PMID- 27767404 TI - Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. AB - OBJECTIVE Patients with hereditary hemorrhagic telangiectasia (HHT) are known to suffer from high rates of cerebral arteriovenous malformations (AVMs). The authors performed a systematic review and meta-analysis of the literature examining prevalence rates, characteristics, and clinical presentation of cerebral AVMs in the HHT population. METHODS To identify studies on AVM prevalence and characteristics in the HHT population, 4 databases (MEDLINE, EMBASE, Scopus and Web of Science) were searched by a reference librarian with over 30 years experience in systematic reviews and meta-analysis. The search period was January 1, 1990-March 2016. The following search terms were used: hereditary hemorrhagic telangiectasia, Osler-Weber-Rendu syndrome, AVM, brain AVM, arteriovenous malformation, arteriovenous fistula, prevalence, and epidemiology. The authors identified studies that examined the prevalence rates, characteristics, and clinical presentation of cerebral AVMs in patients with HHT. They assessed overall AVM prevalence rates as well as prevalence rates by age, sex, HHT type, and country/region. They also systematically reviewed the characteristics of AVMs, including rupture status, location, clinical presentation, angioarchitecture, and Spetzler-Martin grade. Data were analyzed using a random-effects meta-analysis model. RESULTS Thirty-nine studies were included in this meta-analysis. Thirty studies examined brain AVM prevalence rates in various HHT patient populations, and 18 studies examined AVM clinical and angiographic characteristics (9 studies examined both prevalence rates and AVM characteristics). The prevalence of brain AVMs in HHT patients was 10.4% (95% CI 7.9%-13.0%) with no significant difference between males (8.5%, 95% CI 4.9% 12.0%) and females (11.0%, 95% CI 5.9%-16.1%). Patients with HHT Type 1 (HHT1) had a significantly higher brain AVM prevalence (13.4%, 95% CI 9.5%-17.4%) compared with those with HHT Type 2 (HHT2) (2.4%, 95% CI 1.0%-3.8%) (p < 0.0001). In 55.2% (95% CI 38.3%-72.1%) of cases, the AVMs were symptomatic. Spetzler Martin grade was 2 or less in 86.9% (95% CI 67.5%-95.2%) of patients. CONCLUSIONS The prevalence of brain AVMs in the HHT population is about 10%. HHT1 patients are significantly more likely to have brain AVMs than HHT2 patients. Most AVMs in the HHT population are symptomatic. The Spetzler-Martin grade for these lesions is 2 or less in nearly 90% of patients. PMID- 27767405 TI - Estimating relative bioavailability of soil lead in the mouse. AB - Lead (Pb) in soil is an important exposure source for children. Thus, determining bioavailability of Pb in soil is critical in evaluating risk and selecting appropriate strategies to minimize exposure. A mouse model was developed to estimate relative bioavailability of Pb in NIST SRM 2710a (Montana 1 Soil). Based on Pb levels in tissues, the mean relative bioavailability of this metal in this soil was 0.5. Estimates of relative bioavailabilities derived from mouse compared favorably with those obtained in juvenile swine. The mouse model is thus an efficient and inexpensive method to obtain estimates of relative bioavailability of soil Pb. PMID- 27767407 TI - Addressing ethical challenges at the intersection of pharmacogenomics and primary care using deliberative consultations. AB - AIM: Primary care physicians will play a central role in the successful implementation of pharmacogenomics (PGx); however, important challenges remain. We explored the perspectives of stakeholders on key challenges of the PGx translation process in primary care using deliberative consultations. METHODS: Primary care physicians, patients and policy-makers attended deliberations, where they discussed four ethical questions raised by PGx research and implementation in the primary care context. RESULTS: Stakeholders voiced skepticism regarding PGx funding, commercialization, regulation, maintenance of an equal access healthcare system and restructuring of health research incentives and priorities in the public sector. CONCLUSION: Deliberants developed governing principles for a PGx-specific charter of ethics, aiming to protect the interests of patients, and outlined recommendations for the future of PGx in primary care. PMID- 27767406 TI - Racial and Ethnic Differences in Substance Use Diagnoses, Comorbid Psychiatric Disorders, and Treatment Initiation among HIV-Positive and HIV-Negative Women in an Integrated Health Plan. AB - Access to substance use disorder (SUD) treatment is a critical issue for women with HIV. This study examined differences in SUD diagnoses, comorbid psychiatric diagnoses, and predictors of SUD treatment initiation among a diverse sample of HIV-positive women (n = 228) and a demographically similar cohort of HIV-negative women (n = 693). Diagnoses and service utilization data were obtained from electronic health records of members of a large integrated healthcare system in Northern California. HIV-positive women were less likely to initiate SUD treatment. Significant racial/ethnic differences were found among both HIV positive and HIV-negative women with respect to SUD diagnosis type and diagnosis of comorbid psychiatric disorders. Among the HIV-negative women, rates of SUD treatment initiation were lower for black women than for white or Latina women. Multivariable logistic regression models showed that alcohol, cannabis, and opiate diagnoses were predictive of SUD treatment initiation for both cohorts, while amphetamine diagnoses, comorbid depressive disorder, and being white or Latina were predictive of SUD treatment initiation for HIV-negative, but not HIV positive, women. Findings suggest that clinicians need to be aware of differences in substances of abuse, comorbid psychiatric disorders, and to consider the demographic and social factors that may contribute to differences in SUD treatment initiation among HIV-positive and HIV-negative women. PMID- 27767408 TI - A Case of Acute Pericarditis Following Intravenous Injection of Crushed Morphine Tablets. AB - A 37-year-old male presented with sharp, severe chest pain following seven days of intravenous injection of crushed morphine tablets. The chest pain was positional and pleuritic in nature and resolved with leaning forward. Work-up was notable for an ECG with inferior and anterolateral PR depressions as well as a CT chest with diffuse centrilobular nodules. Per radiology, the CT findings along with the patient's history were concerning for pulmonary granulomatosis from deposition of talc or some other foreign body. Cardiology was consulted and diagnosed the patient with acute pericarditis, given his typical symptoms and ECG changes. On review of the literature, pulmonary granulomatosis following intravenous injection of foreign bodies is well documented. There are numerous studies documenting foreign body deposition and granulomatosis in organs other than the lungs on post-mortem analyses of individuals with a history of IV injection of crushed tablets. We are suggesting that intravenous injection of crushed morphine tablets can cause pericardial irritation and a syndrome of acuter pericarditis. To our knowledge, there has not been a previous report of acute pericarditis secondary to intravenous injection of crushed tablets. PMID- 27767422 TI - ECG of the Month. PMID- 27767423 TI - What Is Your Neurologic Diagnosis? PMID- 27767424 TI - Providing specialized care to our animal patients. PMID- 27767425 TI - In This Issue * November 1, 2016. PMID- 27767426 TI - Proximal duodenoileal anastomosis for treatment of small intestinal obstruction and volvulus in a green iguana (Iguana iguana). AB - CASE DESCRIPTION A 13-year-old female green iguana (Iguana iguana) was examined because of a 6-day history of vomiting, anorexia, and lethargy and a 4-day history of decreased fecal and urate output. CLINICAL FINDINGS Physical examination revealed a distended abdomen, signs of depression, pallor, tachycardia, harsh lung sounds, and vomiting. Abdominal radiographs revealed gas distention of the stomach and small intestine with fluid lines evident on the lateral view. Plasma biochemical analysis indicated hypochloremic metabolic alkalosis, hyperglycemia, and hyperuricemia. TREATMENT AND OUTCOME Exploratory laparotomy confirmed a diagnosis of small intestinal entrapment and 170 degrees volvulus involving approximately 80% (20 to 30 cm) of the small intestine. The portion of the small intestine extending from the middle portion of the duodenum to the caudal extent of the ileum was resected, and end-to-end anastomosis of the remaining small intestine was performed. The iguana recovered without apparent complications and was reportedly doing well 1 year after surgery. CLINICAL RELEVANCE Findings suggested that iguanas, as hindgut fermenters, may tolerate > 70% resection of the small intestine with a good outcome and no clinical evidence of residual gastrointestinal dysfunction. PMID- 27767427 TI - Effects of perioperative topical dorzolamide hydrochloride-timolol maleate administration on incidence and severity of postoperative ocular hypertension in dogs undergoing cataract extraction by phacoemulsification. AB - OBJECTIVE To assess the effects of topically applied 2% dorzolamide hydrochloride 0.5% timolol maleate ophthalmic solution (DHTM) on incidence and severity of postoperative ocular hypertension (POH; ie, intraocular pressure [IOP] > 25 mm Hg) in dogs undergoing cataract extraction by phacoemulsification. DESIGN Randomized, masked, controlled study. ANIMALS 103 dogs (180 eyes). PROCEDURES Pertinent history, signalment, and ophthalmic examination findings were recorded. Dogs received 1 drop of DHTM or sham treatment solution (sterile, buffered, isotonic eye drops) in both eyes 14 hours and 2 hours before anesthetic induction and at the time of corneal incision closure (ie, end of surgery); IOPs were assessed by rebound tonometry 2, 4, 6, and 8 hours after surgery and between 7:30 and 8:00 am on the following day. Dogs with IOPs of 26 to 45 mm Hg received 1 drop of 0.005% latanoprost solution topically; the surgeon's treatment of choice was used for dogs with IOPs > 45 mm Hg. Incidence of POH and postoperative IOPs were compared between treatment groups. RESULTS DHTM treatment resulted in significantly lower incidence of POH than did sham treatment at the level of the dog (18/53 [34%] vs 31/50 [62%]) and the eye (24/94 [26%] vs 42/86 [48%]). Mean IOP did not differ between groups at the time of POH detection. The DHTM-treated eyes that developed POH were significantly more likely to have a 1-hour follow-up IOP < 25 mm Hg after latanoprost administration than were sham-treated eyes (19/25 [76%] vs 18/35 [51%]; OR, 3.87). CONCLUSIONS AND CLINICAL RELEVANCE Multidose perioperative administration of DHTM in dogs undergoing phacoemulsification reduced the incidence of POH and improved responsiveness of POH to latanoprost treatment. PMID- 27767429 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 27767431 TI - What Is Your Diagnosis? PMID- 27767430 TI - A systematic review of adverse event reporting in companion animal clinical trials evaluating cancer treatment. AB - OBJECTIVE To evaluate methods used to ascertain, define, and report adverse events (AEs) in companion animal clinical trials involving cancer treatment. DESIGN Systematic review. SAMPLE English-language articles describing prospective clinical trials involving dogs and cats with naturally occurring cancer published in peer-reviewed journals between 2008 and 2014. PROCEDURES Reports were identified via MEDLINE and CAB database searches combined with a hand-searching strategy. General article characteristics were abstracted and summarized. Data for AE reporting were collected with a 14-item checklist adapted from the 2004 CONSORT extension for reporting harms. Study characteristics associated with the AE reporting checklist score were identified by means of linear regression analysis. RESULTS 168 articles with data for 6,132 animals were included. Standardized terminology was significantly more likely to be used to describe AEs for trials that included chemotherapy (92/115 [80.0%]) than for trials that did not (16/53 [30.2%]). Median AE reporting checklist score was 5 out of 14 (range, 0 to 12). Poorly reported items included methods and time frame of AE ascertainment, AE data analysis, and reasons for treatment discontinuation and death. Trials with industry funding, a single-arm design, and treatment with chemotherapy were associated with a significantly higher quality of AE reporting. CONCLUSIONS AND CLINICAL RELEVANCE Reporting of adverse events in veterinary clinical trials evaluating cancer treatment was selective and heterogeneous. Harms associated with cancer treatments could be underestimated because of suboptimal collection and reporting of AE data. Findings supported the adoption of a higher standard for AE surveillance and reporting in veterinary patients. PMID- 27767432 TI - Pathology in Practice. PMID- 27767433 TI - Owner assessment of chronic pain intensity and results of gait analysis of dogs with hip dysplasia treated with acupuncture. AB - OBJECTIVE To evaluate pain intensity and kinetic variables in dogs with hip dysplasia (HD) treated with acupuncture, carprofen, or a placebo. DESIGN Randomized, controlled clinical study. ANIMALS 54 HD-affected dogs and 16 healthy dogs. PROCEDURES Seven HD-affected dogs were removed from the study. Dogs with HD were treated in a blinded manner for 30 days with acupuncture (once weekly for 5 sessions; n = 15), carprofen (4.4 mg/kg [2.0 mg/lb], PO, q 24 h; n = 16), or placebo capsules containing lactose (1 mg/kg [0.45 mg/lb], PO, q 24 h; n = 16). Dogs were evaluated 2 weeks and immediately before (baseline) and 2, 4, and 6 weeks after the onset of treatment. Owners evaluated the dogs' pain intensity with 2 validated questionnaires and a visual analogue scale (VAS) for pain and evaluated degree of lameness with a VAS for locomotion. Kinetics of the hind limbs were also evaluated. Sixteen HD-free dogs were used to assess the evaluation protocol. RESULTS Owners' assessments revealed that outcomes of the 3 treatments did not differ significantly. The Canine Brief Pain Inventory and VAS pain intensity assessments were decreased from baseline at weeks 4 and 6, respectively, but only in acupuncture-treated dogs. The locomotion VAS values were decreased at week 4 in acupuncture-treated and carprofen-treated dogs. Kinetic evaluation findings did not differ among the groups or over time. CONCLUSIONS AND CLINICAL RELEVANCE Neither acupuncture nor carprofen was significantly different from placebo. Acupuncture and carprofen reduced the degree of subjectively evaluated lameness, and acupuncture was associated with a decrease in validated chronic pain scores. PMID- 27767434 TI - Primary nodal hemangiosarcoma in four dogs. AB - CASE DESCRIPTION 4 dogs with a slow-growing mass in the cervical region were evaluated. CLINICAL FINDINGS All dogs had no clinical signs at the time of the evaluation. There was no apparent evidence of visceral metastases or other primary tumor based on available CT or MRI data for any dog. TREATMENT AND OUTCOME For each dog, surgery to remove the mass was performed. Histologic examination of the excised tissue revealed a completely excised grade 1 or 2 lymph node hemangiosarcoma. All dogs received adjuvant chemotherapy; 2 dogs underwent curative intent chemotherapy, 1 dog underwent metronomic treatment with cyclophosphamide, and 1 dog underwent metronomic treatment with chlorambucil. The survival time was 259 days in 1 dog; 3 dogs were still alive 615, 399, and 365 days after surgery. CLINICAL RELEVANCE Primary nodal hemangiosarcoma in dogs is a rare and, to the authors' knowledge, previously undescribed disease that appears to develop in the cervical lymph nodes as a slow-growing mass or masses. Surgical excision and adjunct treatment resulted in long survival times for 3 of the 4 dogs of the present report. Given the aggressive biologic behavior of hemangiosarcomas in other body locations, adjunct chemotherapy should be considered for affected dogs, although its role in the cases described in this report was unclear. Additional clinical information is required to further characterize the biologic behavior of this tumor type and determine the expected survival times and associated risk factors in dogs. PMID- 27767435 TI - Diagnosis and treatment of dental disease in guinea pigs. PMID- 27767436 TI - Pathology in Practice. PMID- 27767437 TI - A randomized controlled trial of the effect of prednisone omission from a multidrug chemotherapy protocol on treatment outcome in dogs with peripheral nodal lymphomas. AB - OBJECTIVE To determine the effect of prednisone omission from a multidrug chemotherapy protocol on outcome in dogs with peripheral nodal lymphomas. DESIGN Single-center, nonblinded, parallel-group, randomized, controlled trial. ANIMALS 40 client-owned dogs with a histopathologically confirmed diagnosis of peripheral nodal lymphoma and an expected survival time of > 4 weeks with treatment. PROCEDURES Treatment consisted of a combination of L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone (L-CHOP) or an identical protocol except for the omission of prednisone (L-CHO). The primary outcome of interest was progression-free survival time. Veterinary caregivers and assessors of outcome were not blinded to treatment assignment. Treatment assignment was concealed from the owners of study dogs prior to enrollment, but was revealed after written informed consent was provided. RESULTS The trial was terminated early because of slow enrollment. The 40 dogs successfully enrolled in the study were randomly assigned to the L-CHOP (n = 18) or L-CHO (22) group; results for all 40 dogs were analyzed with respect to the primary outcome. Median progression-free survival time was 142.5 days for dogs receiving L-CHO and 292 days for dogs receiving L-CHOP (hazard ratio, 1.79; 95% confidence interval, 0.85 to 3.75). Serious adverse events were more common among dogs receiving L-CHO. However, this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE The exclusion of prednisone from the L-CHOP protocol did not appear to result in improved progression-free survival time for dogs with peripheral nodal lymphomas. However, the present trial was likely underpowered to detect a clinically meaningful difference in progression-free survival time between groups. PMID- 27767438 TI - Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention. AB - INTRODUCTION: Clopidogrel, which is activated by the CYP2C19 enzyme, is among the drugs for which all major regulatory agencies recommend genetic testing to be performed to identify a patient's CYP2C19 genotype in order to determine the optimal antiplatelet therapeutic scheme. The CYP2C19*2 and CYP2C19*3 variants are loss-of-function alleles, leading to abolished CYP2C19 function and thus have the risk of thrombotic events for carriers of these alleles on standard dosages, while the CYP2C19*17 allele results in CYP2C19 hyperactivity. AIMS: Here, we report our findings from a retrospective study to assess whether genotyping for the CYP2C19*2 allele was cost effective for myocardial infarction patients receiving clopidogrel treatment in the Serbian population compared with the nongenotype-guided treatment. RESULTS: We found that 59.3% of the CYP2C19*1/*1 patients had a minor or major bleeding event versus 42.85% of the CYP2C19*1/*2 and *2/*2, while a reinfarction event occurred only in 2.3% of the CYP21C9*1/*1 patients, compared with 11.2% of the CYP2C19*1/*2 and CYP2C19*2/*2 patients. There were subtle differences between the two patient groups, as far as the duration of hospitalization and rehabilitation is concerned, in favor of the CYP2C19*1/*1 group. The mean cost for the CYP2C19*1/*1 patients was estimated at ?2547 versus ?2799 in the CYP2C19*1/*2 and CYP2C19*2/*2 patients. Furthermore, based on the overall CYP2C19*1/*2 genotype frequencies in the Serbian population, a break-even point analysis indicated that performing the genetic test prior to drug prescription represents a cost-saving option, saving ?13 per person on average. CONCLUSION: Overall, our data demonstrate that pharmacogenomics-guided clopidogrel treatment may represent a cost-saving approach for the management of myocardial infarction patients undergoing primary percutaneous coronary intervention in Serbia. PMID- 27767581 TI - The case for workforce development in social marketing. AB - The Centers for Disease Control and Prevention, Association of Schools and Programs of Public Health, and the Council on Linkages Between Academia and Public Health Practice have emphasized the increasing need to train the public health workforce in social marketing. With only 21 U.S. academic institutions offering course work in social marketing and only four institutions offering degrees in social marketing there is a gap between what academic institutions are offering and these recommendations (Kelly, 2013 ). The successful application of social marketing in public health practice relies on academic institutions creating and promoting social marketing-related programs. PMID- 27767680 TI - Postoperative urinary retention in patients undergoing elective spinal surgery. AB - OBJECTIVE Postoperative urinary retention (POUR) is a common problem leading to morbidity and an increased hospital stay. There are limited data regarding its baseline incidence in patients undergoing spinal surgery and the risk factors with which it may be associated. The purpose of this study was to evaluate the incidence of POUR in elective spine surgery patients and determine the factors associated with its occurrence. METHODS The authors retrospectively reviewed the records of patients who had undergone elective spine surgery and had been prospectively monitored for POUR during an 18-month period. Collected data included operative positioning, surgery duration, volume of intraoperative fluid, length of hospital stay, and patient characteristics such as age, sex, and medical comorbidities. Dialysis patients or those with complete urinary retention preoperatively were excluded from analysis. RESULTS Of the 397 patients meeting the study inclusion criteria, 35 (8.8%) developed POUR. An increased incidence of POUR was noted in those who underwent posterior lumbar surgery, those with benign prostatic hypertrophy (BPH), those with chronic constipation or prior urinary retention, and those using a patient-controlled analgesia pump postoperatively. An increased incidence of POUR was seen with a longer operative time but not with intraoperative intravenous fluid administration. A significant relationship between the female sex and POUR was noted after controlling for BPH, yet there was no association between POUR and diabetes or intraoperative instrumentation. Postoperative retention significantly prolonged the hospital stay. Three patients developed epidural hematomas necessitating operative reexploration, and while they experienced POUR, they also developed the full constellation of cauda equina syndrome. CONCLUSIONS Awareness of the risk factors for POUR may be useful in perioperative Foley catheter management and in identifying patients who need particular vigilance when they are due to void postprocedure. A greater understanding of POUR may also prevent longer hospital stays in select at-risk patients. Postoperative retention is rarely caused by a postoperative cauda equina syndrome due to epidural hematoma, which is also associated with saddle anesthesia, leg pain, and weakness, yet the delineation of isolated POUR from this urgent complication is necessary for optimal patient care. PMID- 27767681 TI - Percutaneous transoral clivoplasty and upper cervical vertebroplasties for multifocal skeletal lymphangiomatosis resulting in complete resolution of pain: case report. AB - Lymphangiomatosis is a rare congenital disorder that results in multiorgan system lymphatic invasion. Symptoms due to axial skeletal involvement can range from chronic bone pain to severe deformity resulting in radiculopathy, myelopathy, and even paralysis. The authors present a case of lymphangiomatosis of the clivus, C 1, and C-2, resulting in chronic pain. The patient was successfully treated with percutaneous transoral clivoplasty and vertebroplasty, without disease progression or return of symptoms at 2 years. PMID- 27767835 TI - The Intersection of Anthropology and Agricultural Health. PMID- 27767682 TI - Utility of multilevel lateral interbody fusion of the thoracolumbar coronal curve apex in adult deformity surgery in combination with open posterior instrumentation and L5-S1 interbody fusion: a case-matched evaluation of 32 patients. AB - OBJECTIVE The aim of this study was to evaluate the utility of supplementing long thoracolumbar posterior instrumented fusion (posterior spinal fusion, PSF) with lateral interbody fusion (LIF) of the lumbar/thoracolumbar coronal curve apex in adult spinal deformity (ASD). METHODS Two multicenter databases were evaluated. Adults who had undergone multilevel LIF of the coronal curve apex in addition to PSF with L5-S1 interbody fusion (LS+Apex group) were matched by number of posterior levels fused with patients who had undergone PSF with L5-S1 interbody fusion without LIF (LS-Only group). All patients had at least 2 years of follow up. Percutaneous PSF and 3-column osteotomy (3CO) were excluded. Demographics, perioperative details, radiographic spinal deformity measurements, and HRQoL data were analyzed. RESULTS Thirty-two patients were matched (LS+Apex: 16; LS: 16) (6 men, 26 women; mean age 63 +/- 10 years). Overall, the average values for measures of deformity were as follows: Cobb angle > 40 degrees , sagittal vertical axis (SVA) > 6 cm, pelvic tilt (PT) > 25 degrees , and mismatch between pelvic incidence (PI) and lumbar lordosis (LL) > 15 degrees . There were no significant intergroup differences in preoperative radiographic parameters, although patients in the LS+Apex group had greater Cobb angles and less LL. Patients in the LS+Apex group had significantly more anterior levels fused (4.6 vs 1), longer operative times (859 vs 379 minutes), and longer length of stay (12 vs 7.5 days) (all p < 0.01). For patients in the LS+Apex group, Cobb angle, pelvic tilt (PT), lumbar lordosis (LL), PI-LL (lumbopelvic mismatch), Oswestry Disability Index (ODI) scores, and visual analog scale (VAS) scores for back and leg pain improved significantly (p < 0.05). For patients in the LS-Only group, there were significant improvements in Cobb angle, ODI score, and VAS scores for back and leg pain. The LS+Apex group had better correction of Cobb angles (56% vs 33%, p = 0.02), SVA (43% vs 5%, p = 0.46), LL (62% vs 13%, p = 0.35), and PI-LL (68% vs 33%, p = 0.32). Despite more LS+Apex patients having major complications (56% vs 13%; p = 0.02) and postoperative leg weakness (31% vs 6%, p = 0.07), there were no intergroup differences in 2-year outcomes. CONCLUSIONS Long open posterior instrumented fusion with or without multilevel LIF is used to treat a variety of coronal and sagittal adult thoracolumbar deformities. The addition of multilevel LIF to open PSF with L5-S1 interbody support in this small cohort was often used in more severe coronal and/or lumbopelvic sagittal deformities and offered better correction of major Cobb angles, lumbopelvic parameters, and SVA than posterior-only operations. As these advantages came at the expense of more major complications, more leg weakness, greater blood loss, and longer operative times and hospital stays without an improvement in 2-year outcomes, future investigations should aim to more clearly define deformities that warrant the addition of multilevel LIF to open PSF and L5-S1 interbody fusion. PMID- 27767899 TI - Prologue to special issue of 'International Perspectives on Education, Training and Practice in Clinical Neuropsychology'. PMID- 27767896 TI - International perspectives on education, training, and practice in clinical neuropsychology: comparison across 14 countries around the world. AB - OBJECTIVE: To review and summarize data provided by special issue authors regarding the education, training, and practice of neuropsychologists from 14 surveyed countries. METHOD: A table was constructed to present an overview of variables of interest. RESULTS: There is considerable diversity among surveyed countries regarding the education and training required to enter practice as a clinical neuropsychologist. Clinical neuropsychologists are typically well compensated, at least in comparison to what constitutes an average salary in each country. CONCLUSIONS: Despite substantial variations in education and training pathways, and availability of neuropsychologists from country to country, two common areas for future development are suggested. First, identification, development, and measurement of core competencies for neuropsychological education and practice are needed that can serve as a unifying element for the world's clinical neuropsychologists. Second, greater emphasis on recognizing and addressing the need for assessment and treatment of diverse populations is needed if the world's citizens can hope to benefit from the expertise of practitioners in our field. PMID- 27767901 TI - Ten-year survival of Ugandan infants after myelomeningocele closure. AB - OBJECTIVE Myelomeningocele (MM) is a neural tube defect complicated by neurological deficits below the level of the spinal lesion and, in many cases, hydrocephalus. Long-term survival of infants treated for MM in a low- and middle income country has never been reported. This retrospective cohort study reports 10-year outcomes and factors affecting survival for infants undergoing MM repair at CURE Children's Hospital of Uganda. METHODS Patients were traced by telephone or home visit. Survival was estimated using the Kaplan-Meier method. Multivariate survival was analyzed using the Cox proportional hazards model, investigating the following variables: sex, age at surgery, weight-for-age at surgery, motor level, and presence and management of hydrocephalus. RESULTS A total of 145 children underwent MM repair between 2000 and 2004; complete data were available for 133 patients. The probability of 10-year survival was 55%, with 78% of deaths occurring in the first 5 years. Most of the deaths were not directly related to MM; infection and neglect were most commonly described. Lesions at motor level L 2 or above were associated with increased mortality (HR 3.176, 95% CI 1.557 6.476). Compared with repair within 48 hours of birth, surgery at 15-29 days was associated with increased mortality (HR 9.091, 95% CI 1.169-70.698). CONCLUSIONS Infants in low- and middle-income countries with MM can have long-term survival with basic surgical intervention. Motor level and age at surgery were significant factors influencing outcome. Education of local health care workers and families to ensure both urgent referral for initial treatment and subsequent access to basic medical care are essential to survival. PMID- 27767902 TI - Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia. AB - OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3ach mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 +/- 1.393 in untreated Fgfr3ach mice and 6.125 +/- 2.029 in meclozine-treated Fgfr3ach mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 +/- 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 +/- 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3ach mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH. PMID- 27767903 TI - Neurosurgical sequelae of domestic dog attacks in children. AB - OBJECTIVE The authors' goals in this study were to describe a series of dog attacks on children that required neurosurgical consultation and to better understand the pattern of injuries inflicted, the circumstances that place children at risk for attack, and the dog breeds involved. In addition, the authors review the surgical and medical management of these patients. METHODS The authors performed a retrospective review of all children requiring neurosurgical consultation for dog bite at a regional Level 1 pediatric trauma center over a 15 year period. RESULTS A total of 124 children with dog bites to the head, face, and neck were evaluated in the emergency department. Of these, 17 children (13.7%) incurred injuries requiring neurosurgical consultation. Fifty-three percent of victims were female. The mean age at the time of attack was 30 months. Twelve (71%) of the attacks were perpetrated by the family pet, and 13 (76%) occurred at the patient's home. Breeds involved in the attacks included German Shepherd, Pit Bull, American Bulldog, large mixed breed, Labrador Retriever, and Akita, with German Shepherds and Akitas being the most frequently involved. Neurosurgical injuries included nondepressed skull fracture in 5, depressed skull fracture in 10, intracranial hemorrhage in 5, cerebral contusions in 4, dural laceration in 4, pneumocephalus in 5, clinically evident CSF leak in 3, spinal fracture with complete spinal cord injury in 1, stroke in 2, vascular injury in 2, and cranial nerve injury (hypoglossal and facial nerve) in 1. Prophylactic antibiotics were administered in 16 patients (94%). Only 1 patient had a confirmed infection involving the site of injury. Neurosurgical intervention was required in 10 patients (59%) and ranged in severity from debridement and closure of a complex scalp wound to decompressive craniectomy. Neurological deficits, all of which were considered catastrophic, developed in 3 patients (18%). CONCLUSIONS Dog attacks on children requiring neurosurgical consultation commonly involve the family pet, which is usually a large-breed dog with no history of prior aggression. Neurosurgical injuries often involve the cranial vault, with depressed skull fractures being the most common injury pattern. Most patients do not suffer a neurological deficit, although catastrophic neurological injury may occur. Prophylactic antibiotics are commonly used and surgical intervention is required in the majority of cases. PMID- 27767906 TI - Novel Levofloxacin-Resistant Multidrug-Resistant Streptococcus pneumoniae Serotype 11A Isolates, South Korea. AB - Of 608 Streptococcus pneumoniae clinical strains isolated at a hospital in South Korea during 2009-2014, sixteen (2.6%) were identified as levofloxacin resistant. The predominant serotype was 11A (9 isolates). Two novel sequence types of multidrug-resistant S. pneumoniae with serotype 11A were identified, indicating continuous diversification of resistant strains. PMID- 27767905 TI - Group B Streptococcus Sequence Type 283 Disease Linked to Consumption of Raw Fish, Singapore. AB - An outbreak of invasive group B Streptococcus (GBS) disease occurred in Singapore in mid-2015. We conducted a case-control study of 22 adults with invasive GBS infections during June 21-November 21, 2015. Consumption of raw fish was strongly associated with invasive sequence type 283 infections, but not with non-sequence type 283 infections. PMID- 27767904 TI - Group B Streptococcus Serotype III Sequence Type 283 Bacteremia Associated with Consumption of Raw Fish, Singapore. AB - We conducted a retrospective study of 40 case-patients and 58 controls as part of a nationwide investigation of a group B Streptococcus outbreak in Singapore in 2015. Eating a Chinese-style raw fish dish (yusheng) was a major risk factor for bacteremia, particularly caused by serotype III sequence type 283. PMID- 27767907 TI - Neutralizing Antibodies to Severe Fever with Thrombocytopenia Syndrome Virus 4 Years after Hospitalization, China. AB - Severe fever with thrombocytopenia syndrome is an emerging hemorrhagic fever disease in eastern Asia, caused by a tickborne bunyavirus. Of 25 patients hospitalized with this disease in China, 100% produced and maintained neutralizing antibodies to severe fever with thrombocytopenia syndrome virus for the study period of 4 years. PMID- 27767908 TI - Imported Chikungunya Virus Strains, Taiwan, 2006-2014. AB - We identified 78 imported chikungunya cases in Taiwan during 2006-2014. Sixty-six (84.6%) cases were initially suspected to be dengue, which indicates the necessity for laboratory diagnostics in differentiation between dengue and chikungunya. Results also emphasize the need for active surveillance of febrile illness at points of entry. PMID- 27767909 TI - Severe Fever with Thrombocytopenia Syndrome in Patients Suspected of Having Scrub Typhus. AB - To determine prevalence of severe fever with thrombocytopenia syndrome in South Korea, we examined serum samples from patients with fever and insect bite history in scrub typhus-endemic areas. During the 2013 scrub typhus season, prevalence of this syndrome among patients suspected of having scrub typhus was high (23.0%), suggesting possible co-infection. PMID- 27767910 TI - Travel-Associated Vibrio cholerae O1 El Tor, Russia. PMID- 27767911 TI - Dog-Mediated Human Rabies Death, Haiti, 2016. AB - Haiti has experienced numerous barriers to rabies control over the past decades and is one of the remaining Western Hemisphere countries to report dog-mediated human rabies deaths. We describe the circumstances surrounding a reported human rabies death in 2016 as well as barriers to treatment and surveillance reporting. PMID- 27767912 TI - Increased Community-Associated Infections Caused by Panton-Valentine Leukocidin Negative MRSA, Shanghai, 2005-2014. AB - During 2005-2014, community-associated methicillin-resistant Staphylococcus aureus infections increased in Shanghai, China. Most infections were caused by sequence type 59 S. aureus that lacked Panton-Valentine leukocidin. This finding challenges the notion that Panton-Valentine leukocidin is necessary for epidemiologic success of community-associated methicillin-resistant S. aureus. PMID- 27767913 TI - Spotted Fever Group Rickettsia in the Pampa Biome, Brazil, 2015-2016. PMID- 27767915 TI - Shigella flexneri with Ciprofloxacin Resistance and Reduced Azithromycin Susceptibility, Canada, 2015. PMID- 27767914 TI - Co-infections with Chikungunya and Dengue Viruses, Guatemala, 2015. AB - We screened serum samples referred to the national reference laboratory in Guatemala that were positive for chikungunya or dengue viruses in June 2015. Co infection with both viruses was detected by reverse transcription PCR in 46 (32%) of 144 samples. Specimens should be tested for both arboviruses to detect co infections. PMID- 27767916 TI - Severe Pneumonia Associated with Adenovirus Type 55 Infection, France, 2014. PMID- 27767917 TI - HIV/Hepatitis C Virus Co-infection among Adults Beginning Antiretroviral Therapy, Malawi. PMID- 27767918 TI - Marseillevirus in the Pharynx of a Patient with Neurologic Disorders. PMID- 27767919 TI - Nasopharyngeal Pneumococcal Density and Evolution of Acute Respiratory Illnesses in Young Children, Peru, 2009-2011. AB - We examined nasopharyngeal pneumococcal colonization density patterns surrounding acute respiratory illnesses (ARI) in young children in Peru. Pneumococcal densities were dynamic, gradually increasing leading up to an ARI, peaking during the ARI, and decreasing after the ARI. Rhinovirus co-infection was associated with higher pneumococcal densities. PMID- 27767920 TI - Staphylococcus aureus Colonization and Long-Term Risk for Death, United States. AB - To examine the association of colonization by Staphylococcus aureus and general population mortality, we followed 10,598 adults for 8.5 years on average. Methicillin-susceptible S. aureus colonization was not associated with death. Methicillin-resistant S. aureus carriage predicted death in a crude analysis but not after adjustment for socioeconomic status and co-morbidities. PMID- 27767921 TI - Severe Fever with Thrombocytopenia Syndrome Complicated by Co-infection with Spotted Fever Group Rickettsiae, China. AB - During 2013-2015 in central China, co-infection with spotted fever group rickettsiae was identified in 77 of 823 patients infected with severe fever with thrombocytopenia syndrome virus. Co-infection resulted in delayed recovery and increased risk for death, prompting clinical practices in the region to consider co-infection in patients with severe fever with thrombocytopenia syndrome. PMID- 27767922 TI - Serotype IV Sequence Type 468 Group B Streptococcus Neonatal Invasive Disease, Minnesota, USA. AB - To further understand the emergence of serotype IV group B Streptococcus (GBS) invasive disease, we used whole-genome sequencing to characterize 3 sequence type 468 strains isolated from neonates in Minnesota, USA. We found that strains of tetracycline-resistant sequence type 468 GBS have acquired virulence genes from a putative clonal complex 17 GBS donor by recombination. PMID- 27767923 TI - Meningococcal Disease in US Military Personnel before and after Adoption of Conjugate Vaccine. PMID- 27767924 TI - Mayaro Virus in Child with Acute Febrile Illness, Haiti, 2015. AB - Mayaro virus has been associated with small outbreaks in northern South America. We isolated this virus from a child with acute febrile illness in rural Haiti, confirming its role as a cause of mosquitoborne illness in the Caribbean region. The clinical presentation can mimic that of chikungunya, dengue, and Zika virus infections. PMID- 27767925 TI - Capsular Switching and Other Large-Scale Recombination Events in Invasive Sequence Type 1 Group B Streptococcus. AB - We report several cases of recombination events leading to capsular switching among sequence type (ST) 1 group B Streptococcus strains. These strains otherwise shared a common genome backbone with serotype V ST1 strains. However, the genomes of ST1 serotype V strains and those of serotypes VI, VII, and VIII strains differed substantially. PMID- 27767926 TI - Multidrug-Resistant Corynebacterium striatum Associated with Increased Use of Parenteral Antimicrobial Drugs. PMID- 27767927 TI - Changing Pattern of Chlamydia trachomatis Strains in Lymphogranuloma Venereum Outbreak, France, 2010-2015. AB - We describe a change in the molecular epidemiology of Chlamydia trachomatis strains involved in an outbreak of rectal lymphogranuloma venereum in France during January 2010-April 2015. Until 2012, the C. trachomatis L2b strain predominated; however, starting in 2013, most cases involved the L2 strain. We also identified 4 genetic L2b ompA variants. PMID- 27767928 TI - Molecular Evidence of Oysters as Vehicle of Norovirus GII.P17-GII.17. PMID- 27767929 TI - ESBL-Producing and Macrolide-Resistant Shigella sonnei Infections among Men Who Have Sex with Men, England, 2015. AB - In England in 2015, Shigella sonnei isolates from men who have sex with men produced extended-spectrum beta-lactamases and exhibited macrolide resistance. Whole-genome sequencing showed a close relationship among the isolates, which harbored a plasmid that was previously identified in a shigellosis outbreak among this population but has acquired a mobile element. PMID- 27767930 TI - Leishmania major Cutaneous Leishmaniasis in 3 Travelers Returning from Israel to the Netherlands. PMID- 27767931 TI - Early Growth and Neurologic Outcomes of Infants with Probable Congenital Zika Virus Syndrome. AB - We report the early growth and neurologic findings of 48 infants in Brazil diagnosed with probable congenital Zika virus syndrome and followed to age 1-8 months. Most of these infants had microcephaly (86.7%) and craniofacial disproportion (95.8%). The clinical pattern included poor head growth with increasingly negative z-scores, pyramidal/extrapyramidal symptoms, and epilepsy. PMID- 27767932 TI - Automated tests for diagnosing and monitoring cognitive impairment: a diagnostic accuracy review. AB - BACKGROUND: Cognitive impairment is a growing public health concern, and is one of the most distinctive characteristics of all dementias. The timely recognition of dementia syndromes can be beneficial, as some causes of dementia are treatable and are fully or partially reversible. Several automated cognitive assessment tools for assessing mild cognitive impairment (MCI) and early dementia are now available. Proponents of these tests cite as benefits the tests' repeatability and robustness and the saving of clinicians' time. However, the use of these tools to diagnose and/or monitor progressive cognitive impairment or response to treatment has not yet been evaluated. OBJECTIVES: The aim of this review was to determine whether or not automated computerised tests could accurately identify patients with progressive cognitive impairment in MCI and dementia and, if so, to investigate their role in monitoring disease progression and/or response to treatment. DATA SOURCES: Five electronic databases (MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science and PsycINFO), plus ProQuest, were searched from 2005 to August 2015. The bibliographies of retrieved citations were also examined. Trial and research registers were searched for ongoing studies and reviews. A second search was run to identify individual test costs and acquisition costs for the various tools identified in the review. REVIEW METHODS: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. The results of the data extraction and quality assessment for each study are presented in structured tables and as a narrative summary. RESULTS: The electronic searching of databases, including ProQuest, resulted in 13,542 unique citations. The titles and abstracts of these were screened and 399 articles were shortlisted for full text assessment. Sixteen studies were included in the diagnostic accuracy review. No studies were eligible for inclusion in the review of tools for monitoring progressive disease. Eleven automated computerised tests were assessed in the 16 included studies. The overall quality of the studies was good; however, the wide range of tests assessed and the non-standardised reporting of diagnostic accuracy outcomes meant that meaningful synthesis or statistical analysis was not possible. LIMITATIONS: The main limitation of this review is the substantial heterogeneity of the tests assessed in the included studies. As a result, no meta analyses could be undertaken. CONCLUSION: The quantity of information available is insufficient to be able to make recommendations on the clinical use of the computerised tests for diagnosing and monitoring MCI and early dementia progression. The value of these tests also depends on the costs of acquisition, training, administration and scoring. FUTURE WORK: Research is required to establish stable cut-off points for automated computerised tests that are used to diagnose patients with MCI or early dementia. Additionally, the costs associated with acquiring and using these tests in clinical practice should be estimated. STUDY REGISTRATION: The study is registered as PROSPERO CRD42015025410. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27767934 TI - Erratum. AB - [This corrects the article DOI: 10.5014/ajot.2016.021949.]. PMID- 27767933 TI - A Changing Publishing Landscape. PMID- 27767936 TI - Coming Home to Family: Now Is the Time! AB - Family is a metaphor for the connectedness that occupational therapy practitioners and students feel for one another, for the American Occupational Therapy Association (AOTA), and toward those served. Exploring values and cultural practices that emanate from family experiences affects how we practice occupational therapy and engage with families; how we serve and lead; and how, as the profession approaches its 100th anniversary in the United States, we strengthen AOTA by welcoming all 213,000 practitioners and students who could become active, engaged members. The heartfelt connections experienced across our worldwide occupational therapy communities, giving support and nurturance to those who show promise, breaking down barriers and creating community as extended family, creating a sense of home and belonging, encouraging participation, and building excellence, strengthen the AOTA family. AOTA Vision 2025 serves as a means to facilitate the profession's future, where health, well-being, and quality of life are the outcomes of effective occupational therapy. PMID- 27767935 TI - State of the Journal, 2016. AB - The American Journal of Occupational Therapy (AJOT) had a successful 2016. From September 2015 to September 2016, the number of manuscripts submitted remained steady at 255. Manuscripts were received from 30 non-U.S. countries, compared with 23 countries in 2015. AJOT continues to have the highest impact factor and to be the highest ranked of the occupational therapy journals listed in Journal Citation Reports. AJOT continues to focus on publishing research articles on aspects of occupational therapy among varied populations with diverse acute and chronic conditions. Changes in 2016 include requiring authors to register clinical trials at public trial registration sites and welcoming new associate editors and reviewers to the AJOT family. PMID- 27767937 TI - The Power of Authenticity. AB - Occupational therapy practitioners can embrace the distinct value of occupational therapy by harnessing the power of authenticity in our daily practice. Practitioners, educators, students, and researchers being true to our core values, as well as the historical roots of the profession, will demonstrate how occupational therapy enhances clients' quality of life and positively affects their everyday lives. By harnessing the power of authenticity, we can drive the profession of occupational therapy into the future as practitioners with influence to meet the dynamic needs of health care and education systems. PMID- 27767939 TI - AOTA Official Documents in the AJOT Online Supplement. PMID- 27767938 TI - The Prepared Mind. AB - Every day, in clinics and hospitals around the world, occupational therapists care for patients with serious problems requiring viable solutions. Each patient is unique, and his or her problem does not necessarily correspond to existing practice models. Practitioners must adapt standard approaches to provide effective outcomes, yet problems exist for which few or no beneficial approaches have been identified. Such clinical issues require solutions to be generated de novo from the practitioner's body of knowledge and past experience. Yet, no single new intervention can be used without prior validation of its efficacy. Only a therapist with a prepared mind can accept such challenges, recognize what is known and not yet known, design studies to acquire that needed knowledge, and translate it into successful clinical treatment strategies. The occupational therapist with a prepared mind is one willing to seize unexpected opportunities and construct new paradigms of practice. Innovation through scientific inquiry requires a prepared mind. PMID- 27767940 TI - Children With Celiac Disease: Health-Related Quality of Life and Leisure Participation. AB - OBJECTIVE: We compared health-related quality-of-life (HRQOL) perceptions of children with celiac disease (CD) with those of their parents to determine whether their leisure participation differs from that of children without CD and whether relationships exist between leisure participation and HRQOL. METHOD: Children with CD and their parents completed a disease-specific HRQOL self-report questionnaire, the Celiac Disease DUX. These children and matched controls without CD completed the Children's Leisure Assessment Scale (CLASS). RESULTS: Parents perceived HRQOL significantly more negatively than did children. No significant group differences were found in leisure participation. However, specific CLASS food-related activities and HRQOL significantly correlated. CONCLUSION: Hearing the child's voice in addition to the parents' is important in determining the HRQOL of children with a chronic condition. Findings contribute to understanding of CD in the context of participation and well-being and can lead to development of occupational performance-based assessments and interventions for children with CD. PMID- 27767941 TI - Predicting Handwriting Legibility in Taiwanese Elementary School Children. AB - This study investigates handwriting characteristics and potential predictors of handwriting legibility among typically developing elementary school children in Taiwan. Predictors of handwriting legibility included visual-motor integration (VMI), visual perception (VP), eye-hand coordination (EHC), and biomechanical characteristics of handwriting. A total of 118 children were recruited from an elementary school in Taipei, Taiwan. A computerized program then assessed their handwriting legibility. The biomechanics of handwriting were assessed using a digitizing writing tablet. The children's VMI, VP, and EHC were assessed using the Beery-Buktenica Developmental Test of Visual-Motor Integration. Results indicated that predictive factors of handwriting legibility varied in different age groups. VMI predicted handwriting legibility for first-grade students, and EHC and stroke force predicted handwriting legibility for second-grade students. Kinematic factors such as stroke velocity were the only predictor for children in fifth and sixth grades. PMID- 27767942 TI - Reliability of Electrodermal Activity: Quantifying Sensory Processing in Children With Autism. AB - OBJECTIVE: We established test-retest reliability of electrodermal markers used to quantify physiological response to sensation using the Sensory Challenge Protocol in children with and without autism spectrum disorder (ASD). METHOD: Electrodermal activity (EDA) was measured during rest and in response to sensory inputs. Fourteen children with ASD and 18 typically developing children were tested and retested after 2-6 wk on skin conductance response, skin conductance level, nonspecific skin conductance response, and habituation. RESULTS: Test retest reliability was evaluated with intraclass correlation coefficients (ICCs). Rest-phase coefficients for both groups were moderate (.65-.73). ICCs during response to sensation ranged from moderate to good for amplitude (.60-.81) and magnitude (.50-.75). In addition, moderate to excellent reliability (.51-.93) was observed for nonspecific response measures. CONCLUSION: EDA measures are reliable physiological markers that can quantify response to sensation in children with and without ASD. PMID- 27767944 TI - Feasibility of Using an Arm Weight-Supported Training System to Improve Hand Function Skills in Children With Hemiplegia. AB - OBJECTIVE: This investigation was a pilot feasibility trial evaluating the use of an arm-weight-supported training device to improve upper-extremity function in children with hemiplegia. METHOD: A single-group within-subject design was used. Participants were 6 children ages 7-17 yr with upper-extremity weakness secondary to hemiplegia. The intervention consisted of 15-18 treatment sessions using an arm-weight-supported training device with the affected upper extremity. Fine motor function was assessed using the Jebsen-Taylor Hand Function Test, the Box and Block Test, and the Assisting Hand Assessment. We examined participants' interactions with the device and assessment scores pre- and postintervention. RESULTS: Five of the 6 children exhibited some changes after the therapy. The system required significant modifications to ensure appropriate positioning. CONCLUSION: The arm-weight-supported system may be viable for therapeutic use. Future studies should use randomized controlled designs and compare effectiveness of weight-supported training with that of other rehabilitation strategies. PMID- 27767943 TI - Equine-Assisted Occupational Therapy: Increasing Engagement for Children With Autism Spectrum Disorder. AB - Engagement in meaningful activities is essential to development and is often reduced in children with autism spectrum disorder (ASD) who have limited engagement in activities or relationships. A multiple-baseline design was used with 7 children with ASD ages 4-8 yr to assess the effect of including a horse in occupational therapy intervention on task engagement. The children showed improvements in engagement. Including horses in occupational therapy sessions may be a valuable addition to conventional treatments to increase task engagement of children with ASD. Factors related to the environment, therapeutic strategies, and individual participation need to be considered in understanding why this intervention may be effective and developing a theoretical basis for implementation. PMID- 27767945 TI - Mothers With Physical Disability: Child Care Adaptations at Home. AB - OBJECTIVE: This study describes how women with physical disability experience caregiving for a new infant and how they adapt their home environment and care tasks. METHOD: In 2013, we conducted 2-hr telephone interviews with 22 women with significant physical disability who had delivered babies within the previous 10 yr. The semistructured, open-ended interview protocol addressed wide-ranging pregnancy-related topics. NVivo was used to sort the texts for content analysis. RESULTS: Night care, bathing, and carrying the baby were identified as the biggest challenges. Typical adaptations (with and without occupational therapy consultation) included use of a wrap for carrying the infant, furniture adaptations for mothers using wheelchairs, and assistance from caregivers. CONCLUSION: Women with physical disability can be fully capable of caring for an infant and can find ways to adapt their environment. Further research may determine the role of occupation therapy. PMID- 27767946 TI - Improving Academic Performance and Working Memory in Health Science Graduate Students Using Progressive Muscle Relaxation Training. AB - Research involving working memory has indicated that stress and anxiety compete for attentional resources when a person engages in attention-dependent cognitive processing. The purpose of this study was to investigate the impact of perceived stress and state anxiety on working memory and academic performance among health science students and to explore whether the reduction of stress and anxiety was achieved through progressive muscle relaxation (PMR) training. A convenience sample of 128 graduate students participated in this study. Using an experimental pretest-posttest design, we randomly assigned participants to a PMR group or a control group. Results indicated that PMR reduced state anxiety, F(1, 126) = 15.58, p < .001, thereby freeing up working memory and leading to improved academic performance in the treatment group. The results of this study contribute to the literature on Attentional Control Theory by clarifying the process through which working memory and anxiety affect cognitive performance. PMID- 27767947 TI - Intervention Promoting Medication Adherence: A Randomized, Phase I, Small-N Study. AB - OBJECTIVE: Many people with chronic health conditions fail to take their medications as prescribed, resulting in declines in health and function. The purpose of this study was to perform a Phase I feasibility study to understand whether an integrated occupational therapy intervention could help people with chronic health conditions improve their adherence to medications. METHOD: Using a small-N design, we report single-subject analyses of the medication adherence of 11 participants before and after either an occupational therapy intervention or a standard care intervention. We used a multiple baseline approach with intersubject replication and blinding. RESULTS: The occupational therapy intervention was found to decrease performance variability and to increase medication adherence rates in some people with chronic conditions. CONCLUSION: These findings suggest that an occupational therapy intervention can improve medication adherence in people with chronic health conditions. The intervention tested in this study is feasible and would benefit from further research. PMID- 27767948 TI - Experiences of Veterans Transitioning to Postsecondary Education. AB - An increasing number of U.S. military veterans are entering postsecondary education with problems attributed to deployed military service. The primary objective of this research was to describe the lived experiences of student veterans transitioning from active military service to postsecondary education. Phenomenological interviews were performed with 13 student veterans who had transitioned from military deployment to postsecondary education. An overall essential meaning of "emerging in college culture" was manifested from three themes, supported by rich textural and structural descriptions of student veterans' experiences: (1) repurposing military experiences for life as a student veteran, (2) reconstructing civilian identity, and (3) navigating postsecondary context and interactions. These findings highlight implications that may facilitate occupational therapists' efforts in supporting the needs of student veterans. PMID- 27767949 TI - Scoping Review of Self-Regulation: What Are Occupational Therapists Talking About? AB - Although the term self-regulation is appearing more frequently in the occupational therapy literature, the extent to which it is consistently conceptualized is not clear. The aim of this scoping review was to examine how the term self-regulation is used by occupational therapists in research and practice literature. A total of 58 publications that included occupational therapy and self-regulation in the title, key words, or abstract were identified. Self-regulation was not explicitly defined by more than half of the authors. Four theoretical orientations seem to guide conceptualization: synactive development, sensory integration, cognitive-behavioral theory, and self-regulation theory. Conceptualization differed according to the population, levels of strategy use, source of strategy implementation, and desired outcomes. A lack of definitional clarity and conceptual consistency of the term self-regulation was noted. Use of an explicit definition in relation to an identified theoretical framework is recommended to promote intra- and interprofessional communication, education, and research. PMID- 27767950 TI - Systematic Review of Educational Interventions for Rheumatoid Arthritis. AB - OBJECTIVE: In this study, we systematically reviewed the effectiveness of educational interventions falling within the scope of occupational therapy practice for people with rheumatoid arthritis (RA). These interventions included disease education, joint protection and energy conservation, psychosocial techniques, pain management, and a combination category. METHOD: Two databases, MEDLINE and CINAHL, and select journals were searched for randomized controlled trials published between January 2002 and June 2015. Qualitative synthesis was used for between-study comparisons. RESULTS: Twenty-two studies, with approximately 2,600 participants, were included. The interventions were found to have strong evidence for constructs that dealt with increasing coping with pain and fatigue as well as maintaining positive affect. There was limited or no evidence supporting the effectiveness of these interventions on most other measured constructs. CONCLUSION: Interventions in which a combination of educational techniques is used may complement pharmacological therapies in the care of people with RA. Future research is needed to identify specific mechanisms of change. PMID- 27767951 TI - Description of and Preliminary Findings for Occupational Connections, an Intervention for Inpatient Psychiatry Settings. AB - People with mental health conditions (MHCs) frequently experience participation and functional restrictions. Today, hospitals still serve a significant number of people with MHCs. However, there is little evidence for occupation-oriented interventions to support participation, health, and well-being in these hospital settings. This article describes a newly developed, short-term, structured intervention for the inpatient setting, Occupational Connections (OC), that focuses on promoting everyday functions and participation in daily life and presents preliminary findings for its effectiveness. Ten people with schizophrenia participated in the program during their stay in acute open inpatient units and completed evaluations both pre- and postintervention. Statistics for a small-sample study design were applied to investigate OC's impact. The results showed OC's contribution to participation dimensions, functional capacity, cognitive functioning, and reduction in schizophrenia symptoms. On the basis of this pilot study's results, extended research is now being conducted to strengthen the evidence for OC's effectiveness. PMID- 27767952 TI - Comparison of Spinal Angles in a Typing Task on a Laptop and a Desktop Computer: A Preliminary Study. AB - OBJECTIVE: This study's objective was to discover whether a difference exists in four postural angles while performing a typing task on a laptop and a desktop computer. METHOD: Twenty healthy participants performed a 5-min typing task on each computer. RESULTS: Statistically significant differences for all angles were found when comparing sitting at the desktop computer with sitting at the laptop. Neck angle (p < .0005), head tilt (p < .0005), and lumbar lordosis (p = .018) were significantly higher when using the laptop. The greatest posterior pelvic tilt was associated with the desktop (p = .018). CONCLUSION: A desktop appears to be more appropriate for the cervical and lumbar regions; however, using a laptop may be more suitable for pelvic tilt. PMID- 27767953 TI - Role of Occupational Therapy in Combating Human Trafficking. AB - Human trafficking is a modern-day form of slavery that includes sex trafficking, labor trafficking, and trafficking of children. It is estimated that 35.8 million people are enslaved around the world. Because of the traumatic experiences that victims of human trafficking encounter, the needs of victims are extensive and require the services of several providers, including health care providers, for victims to transform into survivors and thrivers. Currently, the role of occupational therapy is minimal and unexplored. The profession of occupational therapy has the capacity of having a profound role in both providing client centered care services to victims and survivors of human trafficking and partaking in preventive advocacy efforts to combat human trafficking. Further advocacy efforts are required to promote the profession of occupational therapy in combating human trafficking. PMID- 27767954 TI - Research Opportunities in the Area of Adults With Traumatic Brain Injury. AB - The American Occupational Therapy Association (AOTA) Evidence-Based Practice Project has developed a table summarizing the research opportunities in the area of adults with traumatic brain injury. The table provides an overview of the state of current available evidence on interventions within the scope of occupational therapy practice and is based on the systematic reviews from the AOTA Practice Guidelines Series. Researchers, students, and clinicians can use this information in developing innovative research to answer important questions within the occupational therapy field. PMID- 27767958 TI - Noncavernous arteriovenous shunts mimicking carotid cavernous fistulae. AB - PURPOSE: The classic symptoms and signs of carotid cavernous sinus fistula or cavernous sinus dural arteriovenous fistula (AVF) consist of eye redness, exophthalmos, and gaze abnormality. The angiography findings typically consist of arteriovenous shunt at cavernous sinus with ophthalmic venous drainage with or without cortical venous reflux. In rare circumstances, the shunts are localized outside the cavernous sinus, but mimic symptoms and radiography of the cavernous shunt. We would like to present the other locations of the arteriovenous shunt, which mimic the clinical presentation of carotid cavernous fistulae, and analyze venous drainages. METHODS: We retrospectively examined the records of 350 patients who were given provisional diagnoses of carotid cavernous sinus fistulae or cavernous sinus dural AVF in the division of Interventional Neuroradiology, Ramathibodi Hospital, Bangkok between 2008 and 2014. Any patient with cavernous arteriovenous shunt was excluded. RESULTS: Of those 350 patients, 10 patients (2.85%) were identified as having noncavernous sinus AVF. The angiographic diagnoses consisted of three anterior condylar (hypoglossal) dural AVF, two traumatic middle meningeal AVF, one lesser sphenoid wing dural AVF, one vertebro vertebral fistula (VVF), one intraorbital AVF, one direct dural artery to cortical vein dural AVF, and one transverse-sigmoid dural AVF. Six cases (60%) were found to have venous efferent obstruction. CONCLUSION: Arteriovenous shunts mimicking the cavernous AVF are rare, with a prevalence of only 2.85% in this series. The clinical presentation mainly depends on venous outflow. The venous outlet of the arteriovenous shunts is influenced by venous afferent-efferent patterns according to the venous anatomy of the central nervous system and the skull base, as well as by architectural disturbance, specifically, obstruction of the venous outflow. PMID- 27767957 TI - Factors essential for L,D-transpeptidase-mediated peptidoglycan cross-linking and beta-lactam resistance in Escherichia coli. AB - The target of beta-lactam antibiotics is the D,D-transpeptidase activity of penicillin-binding proteins (PBPs) for synthesis of 4->3 cross-links in the peptidoglycan of bacterial cell walls. Unusual 3->3 cross-links formed by L,D transpeptidases were first detected in Escherichia coli more than four decades ago, however no phenotype has previously been associated with their synthesis. Here we show that production of the L,D-transpeptidase YcbB in combination with elevated synthesis of the (p)ppGpp alarmone by RelA lead to full bypass of the D,D-transpeptidase activity of PBPs and to broad-spectrum beta-lactam resistance. Production of YcbB was therefore sufficient to switch the role of (p)ppGpp from antibiotic tolerance to high-level beta-lactam resistance. This observation identifies a new mode of peptidoglycan polymerization in E. coli that relies on an unexpectedly small number of enzyme activities comprising the glycosyltransferase activity of class A PBP1b and the D,D-carboxypeptidase activity of DacA in addition to the L,D-transpeptidase activity of YcbB. PMID- 27767959 TI - Evaluation of efficacy of thermographic breast imaging in breast cancer: A pilot study. AB - BACKGROUND: Thermographic imaging is a non-invasive and radiation free imaging modality that measures the infrared radiation released by the body. Recently, there is a renewed interest regarding the scope of thermal imaging for breast cancer. OBJECTIVE: To evaluate the efficacy of thermographic breast imaging in detecting breast cancer. METHODS: A Prospective observational study was carried out from January 2014 to December 2014 at Kasturba Hospital, Manipal, India. Patients in whom breast cancer was confirmed on FNAC or biopsy, were included in the study and further evaluated with thermographic imaging of the breast. RESULTS: 65 patients with FNAC or biopsy proven breast carcinoma were included in the study. Using thermographic imaging, malignancy was accurately detected in 60 patients (92.31%). Mammography was able to detect malignancy in 62 out of the 65 patients (95.38%). Thermography was able to detect malignancy in all 3 cases in which conventional mammography missed it. CONCLUSION: Thermography may have a role in detection of breast cancer. However, it is too early to recommend thermographic imaging as a standard imaging modality for breast cancer. Larger studies are required to evaluate the usefulness of thermography in diagnosis and/or screening of breast cancer. PMID- 27767956 TI - Regulation of neuronal axon specification by glia-neuron gap junctions in C. elegans. AB - Axon specification is a critical step in neuronal development, and the function of glial cells in this process is not fully understood. Here, we show that C. elegans GLR glial cells regulate axon specification of their nearby GABAergic RME neurons through GLR-RME gap junctions. Disruption of GLR-RME gap junctions causes misaccumulation of axonal markers in non-axonal neurites of RME neurons and converts microtubules in those neurites to form an axon-like assembly. We further uncover that GLR-RME gap junctions regulate RME axon specification through activation of the CDK-5 pathway in a calcium-dependent manner, involving a calpain clp-4. Therefore, our study reveals the function of glia-neuron gap junctions in neuronal axon specification and shows that calcium originated from glial cells can regulate neuronal intracellular pathways through gap junctions. PMID- 27767960 TI - Osteoarthritic synovial fluid rheology and correlations with protein concentration. AB - BACKGROUND: Osteoarthritis is a common, localized joint disease that causes pain, stiffness and reduced mobility. Osteoarthritis is particularly common in the knees. The effects of osteoarthritis on the rheology of synovial fluid in the knees are not fully understood and consequently require further study. OBJECTIVE: The purpose of this study is to investigate the effects of protein content on synovial fluid shear rheology. A secondary study outcome will include study of the temperature dependence of synovial fluid behaviour. METHODS: 38 osteoarthritic synovial fluid samples were studied under shear flow. Shear properties were correlated with protein concentration. Viscosupplement was used as a comparison and to verify measurement reliability. The effects of temperature were investigated at 20, 29 and 37 degrees C. RESULTS: Shear rheological properties were found to vary widely between samples, however all samples demonstrated clear non-Newtonian shear thinning behaviour. In general viscoelastic properties were lower in osteoarthritic samples than previously studied healthy synovial fluid. A moderate correlation was observed between synovial fluid dynamic moduli at a frequency of 2.5 Hz and protein concentration. Temperature was found to affect the rheology of osteoarthritic synovial fluid and was fitted with the Arrhenius model. CONCLUSIONS: Increased protein concentration has been correlated with decreased shear rheological parameters. Temperature dependence of synovial fluid was also demonstrated and modelled for use in Part 2 of this article. PMID- 27767961 TI - Osteoarthritic synovial fluid and correlations with protein concentration. AB - BACKGROUND: Osteoarthritis is a common, localized joint disease that causes pain, stiffness and reduced mobility. The effects of osteoarthritis on the extensional rheology of synovial fluid in the knees are not fully understood and consequently require further study. OBJECTIVE: The purpose of this work is to study the extensional rheology of osteoarthritic synovial fluid and to investigate a possible correlation between synovial fluid protein concentration and extensional rheology. The study will also investigate possible correlations with the shear rheology. METHODS: 21 osteoarthritic synovial fluid samples were studied under extensional flow with a capillary breakup extensional rheometer. Extensional rheological properties were correlated with protein concentration and with shear rheological properties measured in a prior study. Viscosupplement was also studied under extensional flow for comparison. RESULTS: Extensional rheological properties were found to vary widely between samples, but in general were found to agree with previous studies. No statistically significant correlation was identified between extensional rheological properties and protein concentration. Positive correlations were identified between zero shear viscosity and terminal extensional viscosity (R-squared = 0.73), zero shear viscosity and extensional relaxation time (R-squared = 0.84), and shear relaxation time and extensional relaxation time (R-squared = 0.75). CONCLUSIONS: Appropriate CaBER operating parameters for study of osteoarthritic synovial fluid were identified. No statistically significant correlation was found to exist between protein concentration and extensional rheological parameters. Positive correlations were identified between several shear and extensional rheological parameters. The reported values for extensional viscosity and relaxation times for synovial fluid were found to be within one order of magnitude with a recent study of post mortem synovial fluid. PMID- 27767962 TI - Changes in whole blood viscosity during hemodialysis and mortality in patients with end-stage renal disease. AB - Whole blood viscosity (WBV) plays a role in hemorheology and is determined by many factors such as red blood cell factors, plasma protein and blood volume. As WBV changes during hemodialysis, mortality may be due to changes in WBV in patients on hemodialysis. However, there are few prospective data on the relationship between changes in WBV and overall mortality in dialysis patients. We tried to investigate the correlations between values of WBV at variable shear rates before and after hemodialysis and overall or atherosclerosis-related mortality in patients with end-stage kidney disease.Forty-three patients receiving hemodialysis were enrolled in this study. In this 5.8-year prospective observational study, analyses of the effects of WBV at shear rates of 300 s-1 (systolic WBV; SBV), 5 s-1 (diastolic WBV5; DBV5), and 1 s-1 (diastolic WBV1; DBV1) during dialysis on all-cause and atherosclerotic mortality was performed.Among a total of 43 patients, 27 (62.7%) died over the course of the study. Thirteen deaths were caused by atherosclerotic events. A high degree of change in WBV at shear rates of 300 s-1 and 5 s-1 during hemodialysis (DeltaSBV, DeltaDBV5) was positively correlated with overall mortality (HR = 4.688, 95% confidence interval [CI], 1.269-17.319, p = 0.020; HR = 3.941, 95% CI, 1.057 14.701, p = 0.041, respectively). A high degree of change in diastolic blood pressure (DeltaDBP) during hemodialysis was also positively correlated with overall mortality (HR = 3.035, 95% CI, 1.039-8.867, p = 0.042). However, comparative analysis between WBV at shear rates of 300 s-1, 5 s-1, and 1 s-1 and overall mortality did not reveal any significant relationships. Kaplan-Meier analysis revealed that the all-cause mortality was significantly higher in patients from a high degree of change of WBV at shear rates of 300 s-1, compared to those from the moderate or low degree of changes of WBV at shear rates of 300 s-1 (p = 0.020, log-rank test). Survival rate in high DeltaDBP was lower than that of moderate or low DeltaDBP group in Kaplan-Meier survival analysis (p = 0.004, log-rank test).Our data showed that a high degree of change in WBV at variable shear rates during hemodialysis might impact overall survival in patients with end-stage kidney disease. However, large-scale studies to evaluate the relationship of WBV with overall mortality and atherosclerotic mortality will be needed. PMID- 27767963 TI - Rheopheresis in vascular diseases. AB - Rheopheresis is an extracorporal selective double-filtration procedure. In the first part of the treatment the blood is passes through the plasma filter, which separates blood cells from the plasma. Then the plasma flow to a second filter called MONET (Membranefiltration Optimised Novel Extracorporal Treatment). The MONET filter retains high molecular weight proteins such LDL, Lp(a), fibrinogen, alpha2 macroglobulin, vWF and IgM. Hereby the whole blood and plasma viscosity decrease, improves microcirculation, and has a positive effect on lipid profile as well.Accorging to ASFA recommendation rheopheresis is a first line treatment in age-related dry macular degeneration and in sudden sensorineural hearing loss. There are other clinical situations in which rheopheresis has been used effectivly. But only few data are available and large clinical trials have not been done in these diseases. In this paper we describe a case history and laboratory findings of a patient who suffers from age related dry macular degeneration and was successfully treated by rheopheresis. PMID- 27767964 TI - Monolayer formation and shear- resistance of human vein endothelial cells on gelatin-based hydrogels with tailorable elasticity and degradability. AB - The formation of a functionally-confluent and shear-resistant endothelial cell (EC) monolayer on cardiovascular implants is a promising strategy to prevent thrombogenic processes after implantation. On the basis of existing studies with arterial endothelial cells adhering after two hours on gelatin-based hydrogels in marked higher numbers compared to tissue culture plates, we hypothesized that also venous endothelial cells (HUVEC) should be able to adhere and form an endothelial monolayer on these hydrogels after days. Furthermore, variation of the hydrogel composition, which slightly influences the materials elasticity and even more the degradation behaviour, should have no considerable effect on HUVEC. Therefore, the monolayer formation and shear resistance of HUVEC were explored on two gelatin-based hydrogels differing in their elasticity (Young's moduli between 35 and 55 kPa) in comparison to a positive control (HUVEC on glass cover slips) and a negative control (HUVEC on glass cover slips activated with interleukin 1beta) after 9 days of culturing. HUVEC density after 9 days of culturing under static conditions was lower on the hydrogels compared to both controls (p < 0.05 each). On G10_LNCO8 slightly more EC adhered than on G10_LNCO5. Staining of the actin cytoskeleton and VE-cadherin revealed a pronounced cell-substrate interaction while the cell-cell interaction was comparable to the controls (HUVEC on glass). The secretion of vasoactive and inflammatory mediators did not differ between the hydrogels and the controls. Adherent HUVEC seeded on the hydrogels were able to resist physiological shear forces and the release of cyto- and chemokines in response to the shear forces did not differ from controls (HUVEC on glass). Therefore, both gelatin-based hydrogels are a suitable substrate for EC and a promising candidate for cardiovascular applications. PMID- 27767965 TI - Hematocrit and hematocrit viscosity ratio during exercise in athletes: Even closer to predicted optimal values? AB - The hemorheological theory of optimal hematocrit suggests that the best value of hematocrit (hct) should be that which results in the highest value of the hematocrit/viscosity (h/eta) ratio. Trained athletes compared to sedentary subjects have a lower hct, but a higher h/eta, and endurance training reduces the discrepancy between the actual hct and the ?ideal? hct that can be predicted with a theoretical curve of h/eta vs hct constructed with Quemada's model. In this study we investigated what becomes this homeostasis of h/eta and hct during acute exercise in 19 athletes performing a 25 min exercise test. VO2max is negatively correlated to resting hct and positively correlated to discrepancy between actual and ideal resting hct which is correlated to the maximal rise in hct during exercise. Predicted and actual values of the h/eta were fairly correlated (r = 0.970 p < 0.001) but the actual value was lower at rest and this discrepancy vanished at 25 min exercise. Exercise-induced decrease in discrepancy between actual and theoretical h/eta was negatively correlated with the score of overtraining. All these findings suggest that h/eta is a regulated parameter and that its model-predicted ?optimal? values yield a ?theoretical optimal? hct which is close to the actual value and even closer when athletes are well trained. In addition, acute exercise sets h/eta closer from its predicted ideal value and this adaptation is impaired when athletes quote elevated scores on the overtraining questionnaire. PMID- 27767966 TI - " Optimal " vs actual hematocrit in obesity and overweight. AB - Equations of blood viscosity provide a prediction of the 'optimal' hematocrit' (hct) as the hct resulting in the highest value of the bell-shaped curve of hematocrit/viscosity ratio h/eta. We investigated if overweight and obesity have an influence on these parameters. We compared 32 normal weight subjects, 40 overweight (BMI 25-30) and 38 obese subjects. There was no difference in the theoretical curve of h/eta. The actual h/eta is the same in the 3 groups but is always higher than the theoretical h/eta in all groups. The actual h/eta is lower in overweight than controls (p = 0.011). Modeling yields the same value of theoretical optimal hct across BMI classes. The 3 groups have the same values of actual hct, but actual is significantly lower than optimal in all cases (p < 0.001). Hematocrit is lower than predicted due to a discrepancy between predicted and actual h/eta which is due to the inter-subject variability of RBC rigidity ... The discrepancy between optimal and actual h/eta is negatively correlated to RBC rigidity indexes even if the model uses a fixed value of these indexes. Thus keeping in mind that the optimal hct should not be the same in the various parts of the vascular bed, its theoretical prediction with Quemada's equation appears to predict a value higher than actual hematocrit but well correlated to it, and the agreement between optimal and actual hct is dependent on RBC flexibility. This leads to think that the body sets hematocrit below its ideal value in sedentary subjects in order to cope with the need of increasing blood viscosity factors in case of exercise without impairing O2 supply to tissues. PMID- 27767967 TI - One-year follow-up of blood viscosity factors and hematocrit/viscosity ratio in elite soccer players. AB - We investigated to what extent a prediction of the 'ideal' hematocrit based on individual hemorheological profile with an equation of viscosity is relevant in trained athletes, and how the agreement between theoretical and actual values is modified by changes in training volume and performance. Elite soccer players (national level: 18-32 yr, weight 61-83 kg, body mass index 20.9-25.8 kg/m2) were seen twice at one year interval. Hemorheologic parameters were measured with the MT90 viscometer and the Myrenne aggregometer the theoretical bell-shaped curve of hematocrit/viscosity ratio as a function of hematocrit was reconstructed with Quemada's equation using actual plasma viscosity and red cell rigidity to predict hematocrit/viscosity at various hematocrit levels. RBC aggregation is correlated at baseline with fat mass (M1 = 0.552 p < 0.02) and changes in aggregation are related to changes in fat mass (M = 0.652, p < 0.05; M1 = 0.647, p < 0.05). Predicted and actual hematocrit are correlated (r = 0.644, p < 0.05) but exhibit discrepancies (mean difference -1% range [3.24 to 1.24]) and those discrepancies are inversely correlated to the level of predicted hematocrit (r = -0.912, p < 0.01), to systolic blood pressure (r = -0.626, p < 0.05), and to the overtraining score (r = -0.693, p < 0.05). After one year changes in hematocrit are a close reflect of the change in training volume (r = -0.877, p < 0.01) but are not correlated to fitness changes. Therefore in these athletes i) systemic hematocrit is close to its predicted 'ideal value", suggesting the accuracy of the prediction; ii) red cell aggregation is correlated to fat mass even in nonobese subjects; iii) hematocrit is lower than predicted by the model when markers of sympathetic tone (systolic blood pressure, overtraining score) are increased; iv) weekly training volume appears the main determinant of the reduction of hematocrit. PMID- 27767968 TI - Rise in RBC aggregability and concomitant decrease in blood pressure 10 days after injection of the long acting erythropoietin analogue methoxy polyethylene glycol-epoetin-beta (MIRCERA(r)). AB - Erythropoietin (EPO) is a major regulator of blood viscosity. Its long lasting action analogue methoxy polyethylene glycol-epoetin-beta (MIRCERA(r)) seems to be also employed in modern doping. We took the opportunity of a study aiming at developing a detection of recent MIRCERATM injection in the context of doping detection to assess the effects of this EPO analogue on red blood cells (RBC) aggregation. A single dose 200 MUg of MIRCERA(r) was injected to 10 male volunteers and blood samplings were drawn over 24 days. After injection a decrease in mean corpuscular volume at day 2 (p < 0.01) and day 10 (p < 0.02), a rise in reticulocyte count (p < 0.001) between day 4 and day 17 and a decrease in ferritin a day 5 (p < 0.05) was observed. Hemoglobin decreased at day 4 (p < 0.005). Hematocrit was unchanged. There was a dramatic (+67%) increase in RBC aggregation index "M" (from 9.49+/-1.01 to 17.66+/-1.8, p < 0.01). A decrease in systolic blood pressure was observed during the period from day 4 to day 17 (at day 10: -11.90+/-2.28 mmHg, p < 0.001; at day 17: -15.80+/-2.83, p < 0.001). There was also a decrease in diastolic blood pressure, mean and pulse pressure. Correlations between this decrease in blood pressure and "M" did not reach significance but pulse pressure was positively correlated to "M" (r = 0.743, p < 0.05).These data show that the long acting erythropoietin analogue MIRCERA(r) strongly increases RBC aggregation parallel to a decrease in blood pressure, but a possible causative link between the two events is not clearly evidenced. PMID- 27767970 TI - Endothelial function, fluid dynamics, hemorheology implications for clinical and preclinical vascular disease and implications for the ESCHM. AB - Vascular homeostasis involves endothelial function, smooth muscle function, central hemodynamics, and their interactions with blood. In this complex balance, the role of hemorheological parameters still needs to be defined, particularly with regards to its clinical implications. While the importance of microcirculation is being increasingly appreciated, the mechanisms of hemorheology and their implications are still not. This will be the challenge of our Society for the next years. PMID- 27767969 TI - Actual vs optimal fetal hematocrit measured with punctures of cord blood in utero: Relationship with umbilical artery resistance. AB - Physiological studies on fetal blood in narrow glass tubes have suggested that fetal optimal hematocrit (hct) might be as high as 60%. A theoretical 'ideal' hct can also be predicted with a theoretical curve of hematocrit/viscosity (h/eta) ratio vs hct constructed with Quemada's model. We used the database of one of our previous papers on fetal hemorheology to reinterpret its results with this concept. A series of 28 intrauterine cord punctures (between 19 and 33 weeks gestation) with doppler measurements of resistance in umbilical arteries was studied. The theoretical 'optimal hematocrit' was well correlated to actual (r = 0.857, p < 0.01) but systematically lower (Bland-Altman plot +12.1[8.52-15.7]) than the actual one. Umbilical artery resistance index is correlated with actual hematocrit (r = 0.407, p < 0.05), the discrepancy between ideal and actual (r = - 0.542, p < 0.05) but not predicted ideal hematocrit, suggesting that the discrepancy between ideal and actual may reflect an adaptative decrease aiming at reducing vascular resistance. These findings indicate that prediction of ideal hematocrit with Quemada's equation makes sense in fetal blood, and suggest that a 'viscoregulatory mechanism' maintains hematocrit below this theoretical value in order to avoid excess vascular resistance. PMID- 27767971 TI - Inflammation-induced microvascular dysfunction in obesity - A translational approach. AB - Obesity is a crescent epidemic in the world, affecting more than half a billion of adults worldwide. Obesity is associated to main cardiovascular risk factors, such as insulin resistance, type 2 diabetes mellitus, high blood pressure and dyslipidemia. The excessive adiposity causes a dysregulation of adipokines secretion by adipose tissue, upregulating the expression of pro-inflammatory adipokines and downregulating the anti-inflammatory ones. This scenario contributes for the appearance of atherosclerosis. Since endothelium dysfunction is considered the earliest known marker of the atherosclerotic process, several methods to assess precociously the manifestations of endothelial dysfunction in microvessels, such as venous occlusion plethysmography, laser Doppler flowmetry and nailfold videocapillaroscopy, have been developed. Clinical and experimental studies have shown an impairment of microvascular function, capillary rarefaction and increase in inflammatory status in obesity and the introduction of lifestyle modifications, mainly physical activity and diet, constitute effective interventions to restore microvascular function in obesity. PMID- 27767972 TI - Erythrocyte interactions - Comparison of the aggregation power of polymer molecules used in medicine - Not only size does matter. AB - BACKGROUND: Different colloids are used as a part of solutions for fluid resuscitation and organ preservation: hydroxyethyl starches (HES), dextran (Dx), polyethylene glycols (PEG), polyvinyl pyrrolidone (PVP). Some of the problems associated with their application are addressed to alteration in erythrocyte (ERY) rheology. OBJECTIVE: We intended to estimate in vitro and compare the aggregation power (AP) of these molecules related to ERY interactions. METHODS: Washed human ERY are used during the study. The zeta sedimentation technique is used to quantify the cell aggregation. Zeta sedimentation ratio (ZSR) based indices (AI) are calculated. The hydrodynamic radius (Rh) of the polymer molecules is determined using viscometry. RESULTS: For all polymers tested a linear range in the relationship AI - concentration was found. The slope of the calculated line was interpreted as measure of the molecule's AP. The following ranking was obtained: PEG >PVP >DX >HES. Within the same chemical type of polymer, increasing Rh of the molecules leads to elevated AI. Comparison of the AP of molecules with similar Rh reveals a significant dependence on their chemical nature. CONCLUSIONS: Our results show that molecule's AP is significantly dependent on their chemical nature - i.e. not only molecular size does matter. PMID- 27767973 TI - Characterization of shear stress preventing red blood cells aggregation at the individual cell level: The temperature dependence. AB - BACKGROUND: The novel measure of the red blood cells (RBC) aggregation (RBC-A) - the critical (minimum) shear stress (CSS) to prevent the cells from aggregation was found to be a promising clinically significant parameter. However, the absolute values of this parameter were found to change significantly depending on the shearing geometry (cup-and-bob, cone-plate or microchannel-flow) and have different temperature dependences along with it. The direct confirmation of these dependences aimed to find out the correct values is still pending. OBJECTIVE: In this work, we aim to assess the absolute values of CSS at different temperatures. METHODS: The single cell level measurements of CSS were performed using optical tweezers. The measurements were carried out in heavily diluted suspensions of RBCs in plasma. RESULTS: The temperature dependent changes in CSS were measured at the points (22 and 38 degrees C), in which the cup-and-bob and cone-plate systems yielded about 1.5-fold different values, while the microchannel-flow system yielded a constant value. The single cell CSS were found to be 362+/-157 mPa (22 degrees C) and 312+/-57 mPa (38 degrees C). CONCLUSIONS: Our results prove that the microfluidic-flow approach is reflecting the RBC-A correctly. While the CSS values measured with other systems show the temperature dependent effect of the shearing geometry. PMID- 27767974 TI - Experimental cannabidiol treatment reduces early pancreatic inflammation in type 1 diabetes. AB - BACKGROUND: Destruction of the insulin-producing beta cells in type 1 diabetes (T1D) is induced by invasion of immune cells causing pancreatic inflammation. Cannabidiol (CBD), a phytocannabinoid, derived from the plant, Cannabis sativa, was shown to lower the incidence of diabetes in non-obese diabetic (NOD) mice, an animal model of spontaneous T1D development. OBJECTIVE: The goal of this study was to investigate the impact of experimental CBD treatment on early pancreatic inflammation in T1D by intravital microscopy (IVM) in NOD mice. METHODS: Seven week-old female NOD mice were prophylactically administered daily 5 mg/kg CBD or control vehicle i.p. five times weekly for ten weeks. Animals underwent IVM following confirmation of T1D diagnosis by blood glucose testing. Leukocyte activation and functional capillary density (FCD) were quantified via IVM. RESULTS: CBD-treated NOD mice developed T1D later and showed significantly reduced leukocyte activation and increased FCD in the pancreatic microcirculation. CONCLUSIONS: Experimental CBD treatment reduced markers of inflammation in the microcirculation of the pancreas studied by intravital microscopy. PMID- 27767975 TI - Assessing the evidence: Exploring the effects of exercise on diabetic microcirculation. AB - Diabetes mellitus (DM) is associated with cardiovascular complications. Impairment of glycemic control induces noxious glycations, an increase in oxydative stress and dearangement of various metabolic pathways. DM leads to dysfunction of micro- and macrovessels, connected to metabolic, endothelial and autonomic nervous system. Thus, assessing vascular reactivity might be one of the clinical tools to evaluate the impact of harmful effects of DM and potential benefit of treatment; skin and skeletal muscle microcirculation have usually been tested. Physical exercise improves vascular dysfunction through various mechanisms, and is regarded as an additional effective treatment strategy of DM as it positively impacts glycemic control, improves insulin sensitivity and glucose uptake in the target tissues, thus affecting glucose and lipid metabolism, and increases the endothelium dependent vasodilation. Yet, not all patients respond in the same way so titrating the exercise type individualy would be desirable. Resistance training has, apart from aerobic one, been shown to positively correlate to glycemic control, and improve vascular reactivity. It has been prescribed in various forms or in combination with aerobic training. This review would assess the impact of different modes of exercise, the mechanisms involved, and its potential positive and negative effects on treating patients with Type I and Type II DM, focusing on the recent literature. PMID- 27767976 TI - An ex vivo study of nitric oxide efflux from human erythrocytes in both genders. AB - INTRODUCTION: Acetylcholinesterase (AChE) is located on outer surface of erythrocyte membrane. Gender-related differences in erythrocyte AChE enzyme activity had been verified in young adults. It is also known that binding of acetylcholine (ACh) with AChE on erythrocyte membrane initiates a signal transduction mechanism that stimulates nitric oxide (NO) efflux. AIMS: This ex vivo study was done to compare the amount of NO efflux obtained from erythrocytes of healthy donors in males and females. METHODS: We included 66 gender age matched healthy donors (40-60 years old). We performed quantification of erythrocyte NO efflux from erythrocytes and of the membrane AChE enzyme activity. RESULTS: There are no significant differences in NO efflux from erythrocytes between men and women. Regarding AChE enzyme activity values, in this range of age, no differences between genders were obtained. However, the values of AChE enzyme activity in the third quartile of NO efflux values were significantly higher (p < 0.05) in women than in men. CONCLUSIONS: The efflux of NO from erythrocyte of healthy humans did not change with gender. For the same range of values of NO efflux from erythrocytes, in both gender, it was verified higher values of AChE enzyme activity in women. PMID- 27767977 TI - Can leukocyte antisedimentation rate (LAR) predict septic complications and critical care survival early in polytrauma and burn victims? AB - BACKGROUND: In polytrauma and burn injury Systemic Inflammatory Response Syndrome (SIRS) develops. SIRS is presented in many hospitalized patients, including those who never develop infection or sepsis. Both in SIRS and sepsis the leukocyte activation occurs. In acute phase reaction leukocytes' upward flotation i.e. leukocyte antisedimentation rate (LAR) can indicate infectious origin. OBJECTIVE: To evaluate the predictive power of LAR, serum C-reactive protein (CRP) and procalcitonin (PCT) levels regarding mortality risk and development of septic complications. METHODS: In a prospective, observational study, 36 patients were followed for 5 days (T1-T5) after admission to a critical care unit immediately with severe polytrauma or burn injury. Eleven patients developed septic complications, their LAR, CRP and PCT levels were analyzed before and after 3 days of sepsis was declared. RESULTS: Ten patients died due to septic complications. In survivors LAR at T1 (p < 0.001) and T2 (p < 0.001) as well as CRP at T1 (p < 0.05) were significantly higher compared to controls and non survivors. In septic patients LAR (p < 0.05) and CRP (p < 0.05) showed a significant drop one day before sepsis was declared. PCT levels failed to predict this. CONCLUSIONS: Drop in LAR and CRP levels may be warning signs regarding the onset of septic complications after severe polytrauma and burn injury. PMID- 27767978 TI - Effect of oxidized LDL on erythrocyte nitric oxide metabolism. AB - AIMS: Oxidized low density lipoprotein (ox-LDL) has been reported as an inhibitor of nitric oxide (NO)-mediated dilatation in microcirculation. Oxidized LDL effect on NO metabolism of erythrocytes is not known. Therefore, this study aims to evaluate the effect of ox-LDL on erythrocytes NO metabolism. METHODS: The effect of different concentrations of human purified ox-LDL (25, 50 and 100 MUg/mL) on NO metabolism was evaluated on blood of healthy subjects. RESULTS: An inhibitory effect of higher concentrations of ox-LDL on erythrocyte NO efflux levels was verified. Concentrations of NO efflux from erythrocytes were lower as consequence of treatments with 50 MUg/mL ox-LDL treatment (1.6+/-0.27 nM) and 100 MUg/mL ox LDL treatment (1.3+/-0.22 nM) than control (1.9+/-0.28 nM). Opposite, ox-LDL incubation has a positive effect on GSNO content of erythrocytes. That effect is proportional to concentrations of ox-LDL treatments (10.8+/-1.4 nM for 25 MUg/mL, 12.9+/-1.5 nM for 50 MUg/mL and 12.1+/-1.9 nM for 100 MUg/mL) and is significant relative to control (8.56+/-0.76 MUM) and ACh (8.9+/-0.52 MUM) aliquots. CONCLUSIONS: Presence of oxidized LDL in erythrocyte NO metabolism induces a decrease of NO efflux amount and an increase on intra-erythrocyte GSNO concentrations. These results suggest a role of ox-LDL in mobilization of NO between NO derivatives molecules in dependence of oxidized LDL concentration. An anti - reactive nitrogene role can be attributed to ox-LDL for its contribution in the erythrocyte scavenged ability for nitric oxide. PMID- 27767980 TI - Hemorheological factors can be informative in comparing treatment possibilities of abdominal compartment syndrome. AB - BACKGROUND: Abdominal compartment syndrome (ACS) is a life-threatening condition, of which pathomechanism hasn't been completely clarified, yet. Furthermore, surgical therapy still needs optimization. OBJECTIVE: We aimed to investigate microcirculatory and micro-rheological alterations in ACS, using various temporary abdominal closure methods, including three settings of vacuum-assisted closure technique (negative pressure wound therapy, NPWT). METHODS: On anesthetized pigs, by intraabdominally placed and filled-up silicone bags, intraabdominal pressure at 30 mmHg was maintained for 3 hours, and afterwards, decompressive laparotomy happened. In different experimental groups Bogota-bag or Vivano abdominal sets were applied (-50, -100, -150 mmHg) for 2 hours. Pressure monitoring was done by implanted sensors, hemorheological parameters were determined, and laser Doppler flowmetry tests were performed on the surface of intraabdominal organs. RESULTS: Treatment with Bogota-bag and -150 mmHg vacuum increased erythrocyte aggregation, while deformability declined. Blood viscosity increased after treatment with -150 mmHg vacuum. The microcirculatory parameters of the NPWT groups were better in small intestine. CONCLUSIONS: ACS resulted in impairment of macro- and micro-rheological parameters and abdominal organs' microcirculation. All of the used techniques improved the results, however, applying Bogota-bag or -150 mmHg vacuum set showed worse microcirculatory and micro-rheological data than the settings at -100 or -50 mmHg. PMID- 27767979 TI - Soluble CD40 ligand profiles in patients with septic shock. AB - AIM: Soluble CD40 ligand (sCD40L) has been considered as a marker of thrombosis and inflammation in several diseases, including sepsis. Recent studies challenge this view and point to a role of sCD40L in vascular and endothelial function. An indication of that association in sepsis has not been obtained so far. Therefore, herein we evaluated association between sCD40L and markers of hemorheology and inflammation on context of septic shock. METHODS: Time-changes of sCD40L levels over 72 hours of Intensive Care Unit (ICU) internment were assessed in 22 patients with septic shock and compared with 36 healthy volunteers. Association of sCD40L levels with erythrocyte deformability and aggregation (as markers of hemorheology), plasma concentrations of haemoglobin (Hb, as markers of endothelial function) and white blood cells (WBC) count (as marker of low-grade inflammation) were assessed in patients with septic shock. RESULTS: At ICU admission, sCD40L concentrations in patients with septic shock were lower (p = 0.024) than levels of healthy volunteers. However, sCD40L did not change over 72 hours of internment (F = 2.1, p = 0.137). Soluble CD40L levels in patients with septic shock at ICU admission correlate with concentrations of Hb (r = 0.61, p = 0.00) and WBC count (r = 0.63, p = 0.00), but not to erythrocyte deformability (r>=0.157, p<=0.235) and aggregation (r>=-0.109, p<=0.192). CONCLUSIONS: These results seem to highlight a possible association of sCD40L to endothelial function and inflammation in septic shock context. PMID- 27767981 TI - Physiological role of erythrocyte nitric oxide. AB - Nitric oxide (NO) produced by endothelial cells interacts with erythrocyte through band 3 protein, being scavenged by haemoglobin. A signal transduction mechanism involving protein Gi and protein band 3 stimulates erythrocyte NO efflux when acetylcholine (ACh) binds to erythrocyte membrane acetylcholinesterase. Binding of normal plasma fibrinogen (Fib) levels, to erythrocyte membrane CD47 decreases the NO efflux. When high Fib concentration and ACh were present the efflux of NO from erythrocytes was normalized. The increased NO efflux from erythrocytes in presence of high Fib concentration and band 3 phosphorylation is reinforced in the presence of 4N1K an agonist peptide of CD47. When both Fib and 4N1K are present the NO efflux from erythrocytes is higher or not affected according lower or high levels of cAMP. Erythrocyte NO efflux in patients with systemic lupus erythematous and rheumatoid attrite was significantly negative associated with carotid intima-media thickness. In patients with amyotrophic lateral sclerosis erythrocyte NO content is preserved and an inverse association between respiratory function and NO efflux from the erythrocyte was verified. Sepsis patients before dead at 24 h showed higher efflux of NO from erythrocytes that worsening the blood sub lingual microcirculation observed by high unequal blood flow and high microvascular flow index. The in vivo animal models either of inflammation or of hypertension evidenced that the NO efflux from erythrocyte decrease as a compensatory mechanism. All studies conducted since 2000 where we demonstrated the existence NO inside the erythrocyte by fluorescence microscopy, and after their signaling pathway needs more development translational research for news therapeutics and further application in not invasive therapy to vascular inflammatory diseases. PMID- 27767982 TI - Intrasurgical dignity assessment of hepatic tumors using semi-quantitative strain elastography and contrast-enhanced ultrasound for optimisation of liver tumor surgery. AB - OBJECTIVE: To evaluate the efficacy of strain elastography (SE) using semi quantitative measurement methods compared to constrast enhanced ultrasound during liver tumor surgery (Io-CEUS) for dignity assessment of focal liver lesions(FLL). MATERIAL AND METHODS: Prospective data acquisition and retrospective analysis of US data of 100 patients (116 lesions) who underwent liver tumor surgery between 10/2010 and 03/2016. Retrospective reading of SE color patterns was performed establishing groups depending on dominant color (>50% blue = stiff, inhomogenous, >50% yellow/red/green = soft tissue). Semi-quantitative analysis was performed by Q-analysis based on a scale from 0 (soft) to 6 (stiff). 2 ROIs were placed centrally, 5 ROIs in the lesion's surrounding tissue. Io-CEUS was performed by bolus injection of 5-10 ml sulphurhexaflourid microbubbles evaluating wash-in- and -out- kinetics in arterial, portal venous and late phase. Histopathology after surgical resection served as goldstandard. RESULTS: 100 patients (m: 65, f: 35, mean age 60.5 years) with 116 liver lesions were included. Lesion's size ranged from 0.5 to 8.4 cm (mean 2.42 cm SD+/-1.44 cm). Postoperative histology showed 105 malignant and 11 benign lesions. Semi-quantitative analysis showed central indurations of >2.5 in 76/105 cases suggesting malignancy. 7 benign lesions displayed no central indurations correctly characterized benign by SE. ROC-analysis and Youden index showed a sensitivity of 72.4% and specificity of 63.6% assuming a cut-off of 2.5. Io-CEUS correctly characterized 103/105 as malignant. Sensitivity was 98%, specificity 72.7%. CONCLUSION: Strain elastography is a valuable tool for non-invasive characterization of FLLs. Semi quantitative intratumoral stiffness values of >2.5 suggested malignancy. However, sensitivity of Io-CEUS in detecting malignant lesions was higher compared to SE. In conclusion SE should be considered for routine use during intraoperative US in addition to Io-CEUS for optimization of curative liver surgery. PMID- 27767983 TI - Potentialities of laser trapping and manipulation of blood cells in hemorheologic research. AB - Laser trapping and manipulation of blood cells without mechanical contact have become feasible with implication of laser tweezers. They open up new horizons for the hemorheologic researches, offer new possibilities for studying live cells interactions on individual cell level under the influence of different endogenous and exogenous factors. The operation principle of laser tweezers is based on the property of strongly focused laser beam to act on a dielectric microparticle located in the vicinity of the beam waist with a force that drives the particle to the equilibrium location and holds it there. If the beam waist position is manipulated, so is the position of the particle. The displacement of the particle from the equilibrium position by external forces can be calibrated so that these forces can be precisely measured in the range ca. 0.1-100 pN. This is the range of forces of elastic deformation of blood cells and of their interaction with each other and with vessel walls. Being able to measure these forces without mechanical contact allows for studying on single cell level the mechanisms of interactions that was impossible earlier. Here we discuss the basic features of these techniques and give some examples of challenging hemorheologic studies. PMID- 27767984 TI - The optimum hematocrit. AB - The hematocrit (Hct) determines the oxygen carrying capacity of blood, but also increases blood viscosity and thus flow resistance. From this dual role the concept of an optimum Hct for tissue oxygenation has been derived. Viscometric studies using the ratio Hct/blood viscosity at high shear rate showed an optimum Hct of 50-60% for red blood cell (RBC) suspensions in plasma. For the perfusion of an artificial microvascular network with 5-70MUm channels the optimum Hct was 60-70% for high driving pressures. With lower shear rates or driving pressures the optimum Hct shifted towards lower values. In healthy, well trained athletes an increase of the Hct to supra-normal levels can increase exercise performance. These data with healthy individuals suggest that the optimum Hct for oxygen transport may be higher than the physiological range (35-40% in women, 39-50% in men). This is in contrast to clinical observations. Large clinical studies have repeatedly shown that a correction of anemia in a variety of disorders such as chronic kidney disease, heart failure, coronary syndrome, oncology, acute gastrointestinal bleeding, critical care, or surgery have better clinical outcomes when restrictive transfusion strategies are applied. Actual guidelines, therefore, recommend a transfusion threshold of 7-8 g/dL hemoglobin (Hct 20-24%) in stable, hospitalized patients. The discrepancy between the optimum Hct in health and disease may be due to factors such as decreased perfusion pressures (low cardiac output, vascular stenoses, change in vascular tone), endothelial cell dysfunction, leukocyte adhesion and others. PMID- 27767985 TI - Comparison of magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in the evaluation of unclear solid renal lesions. AB - PURPOSE: To compare the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI) in the evaluation of unclear renal lesions to the histopathological outcome. MATERIALS AND METHODS: A total of 36 patients with a single unclear solid renal lesion with initial imaging studies between 2005 and 2015 were included. CEUS and MRI were used for determining malignancy or benignancy and initial findings were correlated with the histopathological outcome. Out of the 36 renal masses a total of 28 lesions were malignant (77.8%) and 8 were found to be benign (22.2%). Diagnostic accuracy was testes by using the histopathological diagnosis as the gold standard. RESULTS: CEUS showed a sensitivity of 96.4%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 88,9%. MRI showed a sensitivity of 96.4%, a specificity of 75.0%, a PPV of 93.1% and a NPV of 85.7%. Out of the 28 malignant lesions a total of 18 clear cell renal carcinomas, 6 papillary renal cell carcinomas and 4 other malignant lesions, e.g. metastases, were diagnosed. Out of the 8 benign lesions a total 3 angiomyolipomas, 2 oncocytomas, 1 benign renal cyst and 2 other benign lesions, e.g. renal adenomas were diagnosed. Using CEUS, 1 lesion was falsely identified as benign. Using MRI, 2 lesions were falsely identified as benign and 1 lesion was falsely identified as malignant. CONCLUSION: CEUS is an useful method which can be additionally used to clinically differentiate between malignant and benign renal lesions. CEUS shows a comparable sensitivity, specificity, PPV and NPV to MRI. In daily clinical routine, patients with contraindications for other imaging modalities can particularly benefit using this method. PMID- 27767986 TI - Serum SHBG Levels are not Associated with Longitudinal Cognitive Decline in Mild Cognitive Impairment. AB - BACKGROUND: Prior studies have noted gender differences in cognition, imaging, and pathological markers in mild cognitive impairment (MCI) subjects. Sex hormone binding globulin (SHBG), a major controlling factor in the proportion of bioavailable versus bound testosterone and estrogen, has been proposed to contribute to links between hormones and dementia, but has not yet been investigated fully in a prospective biomarker trial. OBJECTIVE: This study examined whether, among subjects with MCI, SHBG levels predict future rate of cognitive decline. METHODS: We examine the effect of gender on cognitive decline and factors modulating potential gender differences in 378 MCI subjects (134 females, 244 males) in the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI 1), followed for up to 8 years (mean +/- SE, 4.0 +/- 0.1 years). Cognition was assessed using the ADAS-cog-11. Multivariate models examined the effect of gender covarying for age, ApoE4, baseline cognition, years of education, and SHBG levels. RESULTS: MCI women declined significantly faster than men in cognition over the follow up period. Baseline SHBG levels differed significantly between men and women (p < 0.0001), and by age in men, but not by ApoE4 status. In the multivariate models, SHBG levels were not a significant predictor of cognitive decline in men or women but ApoE4 status, baseline cognition, years of education, and female gender were. CONCLUSION: SHBG levels did not influence the rate of cognitive decline in MCI. Further studies to confirm these findings and uncover other potential mechanisms of gender differences in the risk for AD may be warranted. PMID- 27767987 TI - Impaired Center-Surround Suppression in Patients with Alzheimer's Disease. AB - Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression- a hallmark property in the visual system- are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway. PMID- 27767988 TI - A Novel Loss-of-Function GRN Mutation p.(Tyr229*): Clinical and Neuropathological Features. AB - Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype. PMID- 27767989 TI - Intensive 'Brain Training' Intervention Fails to Reduce Amyloid Pathologies or Cognitive Deficits in Transgenic Mouse Models of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-beta protein (Abeta) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Abeta deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health. PMID- 27767990 TI - The Proactive Self in Space: How Egocentric and Allocentric Spatial Impairments Contribute to Anosognosia in Alzheimer's Disease. AB - In addition to impairments in episodic and spatial memory, anosognosia (i.e., loss of awareness of the deficient aspect of own cognitive functioning) may be considered an important cognitive marker of Alzheimer's disease (AD). However, although a growing body of interesting models have been proposed to explain this early symptom, what is still missing is a unifying framework of all the characteristic signs occurring in patients with AD that may guide the search for its causal neuropathological process and, ultimately, the etiological process. This contribution will first show how anosognosia may be related to the above mentioned episodic and spatial memory impairment through a unifying framework of all these characteristic signs, i.e., the continuous interaction between different spatial representations. Second, we hypothesize that a break in the interaction between different spatial representations, as we suggest occurs in AD, may contribute significantly both to the early impairments in spatial and episodic memory, and to a deficient self-awareness since it may interfere with the capacity of the brain to detect predictive errors. PMID- 27767991 TI - AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. AB - AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (beta secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of >=5 mg, a >=70% reduction was observed in mean plasma Abeta40 and Abeta42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (>=64% at 15 mg and >=78% at >=50 mg) and cerebrospinal fluid (>=51% at 15 mg and >=76% at >=50 mg) Abeta peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Abeta with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing. PMID- 27767993 TI - Effect Size Analyses of Souvenaid in Patients with Alzheimer's Disease. AB - BACKGROUND: Souvenaid(r) (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramer's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. RESULTS: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD. CONCLUSIONS: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD. PMID- 27767992 TI - Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by brain deposition of amyloid plaques and tau neurofibrillary tangles along with steady cognitive decline. Synaptic damage, an early pathological event, correlates strongly with cognitive deficits and memory loss. Mitochondria are essential organelles for synaptic function. Neurons utilize specialized mechanisms to drive mitochondrial trafficking to synapses in which mitochondria buffer Ca2+ and serve as local energy sources by supplying ATP to sustain neurotransmitter release. Mitochondrial abnormalities are one of the earliest and prominent features in AD patient brains. Amyloid-beta (Abeta) and tau both trigger mitochondrial alterations. Accumulating evidence suggests that mitochondrial perturbation acts as a key factor that is involved in synaptic failure and degeneration in AD. The importance of mitochondria in supporting synaptic function has made them a promising target of new therapeutic strategies for AD. Here, we review the molecular mechanisms regulating mitochondrial function at synapses, highlight recent findings on the disturbance of mitochondrial dynamics and transport in AD, and discuss how these alterations impact synaptic vesicle release and thus contribute to synaptic pathology associated with AD. PMID- 27767994 TI - Cholinergic Basal Forebrain Lesion Decreases Neurotrophin Signaling without Affecting Tau Hyperphosphorylation in Genetically Susceptible Mice. AB - Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and are a major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in sporadic AD are unknown. Here we investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or a resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Our results reveal that the loss of BFCNs in pre-symptomatic pR5 (P301L) tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals' performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology. PMID- 27767996 TI - Aortic Valve Calcification and the Risk of dementia: A Population-Based Study. AB - The association of aortic valve calcification (AVC) with dementia remains unknown. In 2,428 non-demented participants from the population-based Rotterdam Study, we investigated the association of CT-assessed AVC with risk of dementia and cognitive decline. AVC was present in 33.1% of the population. During a median follow-up of 9.3 years, 160 participants developed dementia. We found no association between presence of AVC and risk of all-cause dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI):0.63;1.26)]. Presence of AVC was not associated with cognitive decline on any of the cognitive tests, nor with a measure of global cognition. PMID- 27767995 TI - Association of Kidney Function Biomarkers with Brain MRI Findings: The BRINK Study. AB - BACKGROUND: Chronic kidney disease (CKD) studies have reported variable prevalence of brain pathologies, in part due to low inclusion of participants with moderate to severe CKD. OBJECTIVE: To measure the association between kidney function biomarkers and brain MRI findings in CKD. METHODS: In the BRINK (BRain IN Kidney Disease) study, MRI was used to measure gray matter volumes, cerebrovascular pathologies (white matter hyperintensity (WMH), infarctions, microhemorrhages), and microstructural changes using diffusion tensor imaging (DTI). We performed regression analyses with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) as primary predictors, and joint models that included both predictors, adjusted for vascular risk factors. RESULTS: We obtained 240 baseline MRI scans (150 CKD with eGFR <45 in ml/min/1.73 m2; 16 mild CKD: eGFR 45-59; 74 controls: eGFR>=60). Lower eGFR was associated with greater WMH burden, increased odds of cortical infarctions, and worsening diffusion changes throughout the brain. In eGFR models adjusted for UACR, only cortical infarction associations persisted. However, after adjusting for eGFR, higher UACR provided additional information related to temporal lobe atrophy, increased WMH, and whole brain microstructural changes as measured by increased DTI mean diffusivity. CONCLUSIONS: Biomarkers of kidney disease (eGFR and UACR) were associated with MRI brain changes, even after accounting for vascular risk factors. UACR adds unique additional information to eGFR regarding brain structural and diffusion biomarkers. There was a greater impact of kidney function biomarkers on cerebrovascular pathologies and microstructural brain changes, suggesting that cerebrovascular etiology may be the primary driver of cognitive impairment in CKD. PMID- 27767997 TI - Impact of the Relationship of Stress and the Immune System in the Appearance of Alzheimer's Disease. AB - The understanding of how the immune system works, as well as its relationship with the stress level, seems to be important at the start of the Alzheimer's disease (AD). To analyze this, immunoglobulin A (IgA) and cortisol in saliva were measured using ELISA in patients with mild AD and healthy volunteers, and the production of both biomarkers was compared and correlated. In participants without AD, IgA was higher when cortisol was lower, and the opposite happened in participants with AD, with the quantification in saliva being a suitable method to determine it. PMID- 27768001 TI - Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts. AB - BACKGROUND: Injury to the white matter may lead to impaired neuronal signaling and is commonly observed following traumatic brain injury (TBI). Although endogenous repair of TBI-induced white matter pathology is limited, oligodendrocyte progenitor cells (OPCs) may be stimulated to proliferate and regenerate functionally myelinating oligodendrocytes. Even though OPCs are present throughout the adult brain, little is known about their proliferative activity following axonal injury caused by TBI. OBJECTIVE: We hypothesized that central fluid percussion injury (cFPI) in mice, a TBI model causing wide-spread axonal injury, results in OPC proliferation. METHODS: Proliferation of OPCs was evaluated in 27 cFPI mice using 5-ethynyl-2'-deoxyuridine (EdU) labeling and a cell proliferation assay at 2 (n = 9), 7 (n = 8) and 21 (n = 10) days post injury (dpi). Sham-injured mice (n = 14) were used as controls. OPC proliferation was quantified by immunohistochemistry using the OPC markers NG2 and Olig2 in several white matter loci including the corpus callosum, external capsule, fimbriae, the internal capsule and cerebral peduncle. RESULTS: The number of EdU/DAPI/Olig2 positive cells were increased in the cFPI group compared to sham-injured animals at 7 days post-injury (dpi; p<=0.05) in the majority of white matter regions. The OPC proliferation had subsided by 21 dpi. The number of EdU/DAPI/NG2 cells was also increase at 7 dpi in the external capsule and fimbriae. CONCLUSION: These results suggest that traumatic axonal injury in the mouse induces a transient proliferative response of residing OPCs. These proliferating OPCs may replace dead oligodendrocytes and contribute to remyelination, which needs evaluation in future studies. PMID- 27768002 TI - Differential patterns of laptop use and associated musculoskeletal discomfort in male and female college students. AB - BACKGROUND: Laptop computers have surpassed desktop computers in popularity, especially among college student users. The portability of these devices raises concerns regarding healthy usage patterns in different settings and there is a need to investigate the postures with which these devices are being used and associated reports of musculoskeletal discomfort. OBJECTIVE: This study investigated the configurations in which laptops are used and the prevalence of musculoskeletal discomfort associated with laptop use in a survey of college students. The purpose of this was to identify differences in discomfort and/or postural choice between males and females. METHODS: A sample of 90 male and 96 female college students completed an online questionnaire consisting of demographic questions, musculoskeletal discomfort indicators and questions regarding configurations of laptop use. RESULTS: Over 53% of participants reported experiencing musculoskeletal discomfort while using a laptop computer, with females reporting a higher prevalence of neck discomfort (p = 0.05) and shoulder discomfort (p = 0.006) than males. Participants reported using a laptop most commonly in positions at a desk and on a bed. Females were more likely than males to use a laptop on a bed with the computer positioned on their lap or with their legs crossed (p < 0.05). Males were more likely than females to work in positions necessitating a large trunk deviation to operate the laptop (p < 0.05), such as "sitting on a sofa with your feet on the floor (knees at 90 degrees ), bending over to use laptop that is resting on a coffee table or ottoman in front of you". CONCLUSIONS: A significant proportion of college students report experiencing musculoskeletal discomfort associated with laptop computer use. Sex differences exist in both choice of configurations and musculoskeletal discomfort associated with laptop use. Due to the portability of laptop computers, they are used in a variety of configurations and environments. This study identifies a number of different ways that laptop computers are used that have not been considered in previous research. These patterns of laptop use can be used to inform future work on the impact of technology use on discomfort. PMID- 27768004 TI - Office noise: Can headphones and masking sound attenuate distraction by background speech? AB - BACKGROUND: Background speech is one of the most disturbing noise sources at shared workplaces in terms of both annoyance and performance-related disruption. Therefore, it is important to identify techniques that can efficiently protect performance against distraction. It is also important that the techniques are perceived as satisfactory and are subjectively evaluated as effective in their capacity to reduce distraction. OBJECTIVE: The aim of the current study was to compare three methods of attenuating distraction from background speech: masking a background voice with nature sound through headphones, masking a background voice with other voices through headphones and merely wearing headphones (without masking) as a way to attenuate the background sound. Quiet was deployed as a baseline condition. METHODS: Thirty students participated in an experiment employing a repeated measures design. RESULTS: Performance (serial short-term memory) was impaired by background speech (1 voice), but this impairment was attenuated when the speech was masked - and in particular when it was masked by nature sound. Furthermore, perceived workload was lowest in the quiet condition and significantly higher in all other sound conditions. Notably, the headphones tested as a sound-attenuating device (i.e. without masking) did not protect against the effects of background speech on performance and subjective work load. CONCLUSIONS: Nature sound was the only masking condition that worked as a protector of performance, at least in the context of the serial recall task. However, despite the attenuation of distraction by nature sound, perceived workload was still high - suggesting that it is difficult to find a masker that is both effective and perceived as satisfactory. PMID- 27768003 TI - The cost and distribution of firefighter injuries in a large Canadian Fire Department. AB - BACKGROUND: There is limited data available regarding the cost of firefighter injuries. This information is necessary to develop targeted injury prevention strategies. OBJECTIVE: To categorize the cost of injuries filed in 2012 by firefighters from a from a large department by job duty, injury type, body part affected, and the general motion pattern employed at the time of injury. METHODS: Data were taken from reports filed by CFD personnel and claims filed with the Workers' Compensation Board (WCB) of Alberta between January 1, 2012 and December 31, 2012. RESULTS: Of the 244 injuries reported, 65% were categorized as sprains and strains, the most frequent of which affected the back (32%). The total cost of all claims was $555,955; 77% were sprain/strain-related. Knee and back injuries were most costly ($157,383 and $100,459). Categorized by job duty, most sprains/strains (31%) were sustained while attending to fire station responsibilities, although physical training was associated with the highest costs (34%). Fireground operations were attributed to 18% of sprains/strains and 16% of costs. Lifting injuries were more frequent (23%) and costly (20%) than all injuries. CONCLUSIONS: The most common and costly injuries occurred while attending to fire station-related responsibilities and during physical training. PMID- 27768005 TI - The effects of Labisia pumila extracts on bone microarchitecture of ovariectomized-induced osteoporosis rats: A micro-CT analysis. AB - BACKGOUND: Labisia pumila (LP) is a popular herb used by women over the past few decades. This herb has shown potentials as an alternative agent for treatment and prevention of postmenopausal osteoporosis. It was observed in previous studies that supplementation to ovariectomized rats were associated with increased bone antioxidative enzymes and reduced lipid peroxidation activity. It had also improved bone formation markers in ovariectomized rats. This study aimed to evaluate the effects of giving different forms of LP extracts on the trabecular bone microarchitecture of ovariectomised rats. METHODS: Forty-eight female Sprague-Dawley rats were randomly divided into sham-operated (Sham), ovariectomized control (OVX), ovariectomized and given estrogen at 64.5 MUg/kg (ERT), ovariectomized and given LP aqueous extract (LPaq), LP methanol extract (LPmet) and LP ethanol extract (LPet) at 100 mg/kg, respectively. Treatments were given daily via oral gavages for nine weeks. Following sacrifice, femora were dissected out for bone microarchitectural analysis using an in vitro micro-CT, which provided three dimensional informations on bone microarchitecture. RESULTS: LPaq was the most effective extract found to improve the bone microarchitectural paramaters which comprised ofBone volume fraction (BV/TV), Trabecular separation (Tb.Sp), Trabecular number (Tb.N), Connective density (Conn.dens), Structure model index (SMI) and Degree of anisotropy (DA). CONCLUSION: LPaq was effective in protecting the bone of postmenopausal osteoporosis rat model against microarchitectural deterioration. PMID- 27768006 TI - Application of low concentration contrast medium in spectral CT imaging for CT portal venography. AB - OBJECTIVE: To investigate the effect of low-concentration contrast medium on spectral computed tomography (CT) image quality for portal venography CT. METHODS: 150 patients with suspected portal diseases were divided into three groups and had spectral CT examination using a GE Discovery CT 750 HD scanner. The patients in three groups were injected with different concentrations of iodine (350 mgI/mL, 315 mgI/mL and 280 mgI/mL) at an injection rate of 4.0-5.0 mL/s with 1.2 mL/kg (body weight) of contrast medium, respectively. During the portal vein imaging phase, 0.625 mm-slice-thickness monochromatic images and optimal monochromatic images were obtained. Optimal keV mono-energy was achieved using the optimal contrast-to-noise ratio (CNR) in the portal vein relative to the erector spinae muscle. Volume rendering and maximum intensity projection methods were applied to generate portal venography. The CT values and standard deviations were measured at the portal vein, the erector spinae muscle, and the abdomen fat, respectively. These values were used to calculate the signal-to noise ratio (SNR); while CNR was calculated using CT values of the portal vein and erector spinae muscle. The overall imaging quality was evaluated on a five point scale by two radiologists with at least five years' experience. Comparisons among the three groups were performed using One-Way ANOVA test. RESULTS: Monochromatic images at 50-53 keV demonstrated the best CNR for both the portal vein and erector spinae muscle. SNR and CNR of images with different contrast medium concentrations were similar (P > 0.05). The five-point scores were also similar (P > 0.05) for the three groups. The total iodine intake at 280 mgI/mL was 25.4% lower than that at 350 mgI/mL. CONCLUSIONS: Spectral CT with monochromatic images at 50-53 keV allows significant reduction in iodine load while improving portal vein signal intensity and maintaining image quality. PMID- 27768008 TI - Corrigendum to "Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats" by Hai-Tao Shan et al. AB - [This corrects the article DOI: 10.4103/1008-682X.184271.]. PMID- 27768009 TI - LigasureTM hemorrhoidectomy: how we do. AB - BACKGROUND: Hemorrhoidectomy is considered the gold standard and the most effective and definitive treatment for grades 3 or 4 hemorrhoids, and Milligan Morgan's and Ferguson's procedures are the most widely used techniques throughout the world. The aim of the study was to present our surgical technique using LigasureTM vessel sealing, focus on technical aspects and surgical tricks showing our results with a huge number of patients and a long-term follow-up. METHODS: Between June 2001 and June 2014 at the University Hospital of Tor Vergata, Rome, Italy, 1000 patients were selected to underwent LigasureTM hemorrhoidectomy for III and IV degree hemorrhoids. Age range 19-80 years, ASA I-II-III. Operating time, postoperative pain score, hospital stay, early and late postoperative complications, wound healing time and time to return to normal activities were assessed. Patients were followed-up at one week, one month, six, and twelve months after the operation and after 60 months they responded to the follow-up telephone interview and replied to the questionnaire. RESULTS: One-thousand patients were undergone LigasureTM hemorrhoidectomy. The mean follow-up was 7 years and 110 (11%) patients was lost from the follow-up after the first postoperative month. Among early postoperative complications, 21 patients (2.1%) has urinary retention treated with a urinary catheter and removed before the discharge. 3 (0.3%) patients had a minor bleeding that required a package of hemostatic absorbable sponge, as late complications, in 35 patients (4%) anal fissure due to hard stool, an incomplete healing was observed in 11 patients (1.1%) after the first month. Three transphincteric anal fistulas (0.3%) were collected and four perianal abscess (0.4%) were observed during the first month of the follow-up and they required a delayed surgical treatment. At the end of the seven years of follow-up 70 recurrences (7.8%) and 35 anal stenosis (4%) were detected. CONCLUSIONS: If technical guidelines are respected rigorously and the device is applied correctly, feared late complications, such as impaired fecal continence, anal stricture and postoperative pain can be minimized. PMID- 27768007 TI - The effectiveness of zinc supplementation in men with isolated hypogonadotropic hypogonadism. AB - A multicenter, open-label, randomized, controlled superiority trial with 18 months of follow-up was conducted to investigate whether oral zinc supplementation could further promote spermatogenesis in males with isolated hypogonadotropic hypogonadism (IHH) receiving sequential purified urinary follicular-stimulating hormone/human chorionic gonadotropin (uFSH/hCG) replacement. Sixty-seven Chinese male IHH patients were recruited from the Departments of Endocrinology in eight tertiary hospitals and randomly allocated into the sequential uFSH/hCG group (Group A, n = 34) or the sequential uFSH plus zinc supplementation group (Group B, n = 33). In Group A, patients received sequential uFSH (75 U, three times a week every other 3 months) and hCG (2000 U, twice a week) treatments. In Group B, patients received oral zinc supplementation (40 mg day-1 ) in addition to the sequential uFSH/hCG treatment given to patients in Group A. The primary outcome was the proportion of patients with a sperm concentration >=1.0 * 106 ml-1 during the 18 months. The comparison of efficacy between Groups A and B was analyzed. Nineteen of 34 (55.9%) patients receiving sequential uFSH/hCG and 20 of 33 (60.6%) patients receiving sequential uFSH/hCG plus zinc supplementation achieved sperm concentrations >=1.0 * 106 ml-1 by intention to treat analyses. No differences between Group A and Group B were observed as far as the efficacy of inducing spermatogenesis (P = 0.69). We concluded that the sequential uFSH/hCG plus zinc supplementation regimen had a similar efficacy to the sequential uFSH/hCG treatment alone. The additional improvement of 40 mg day-1 oral zinc supplementation on spermatogenesis and masculinization in male IHH patients is very subtle. PMID- 27768010 TI - Update on hepatitis C treatment: systematic review of clinical trials. AB - Chronic hepatitis C is a major public health problem. The chronicity of the hepatitis C can lead to advanced liver disease, cirrhosis and even hepatocellular carcinoma. Chronic hepatitis C is the leading indication of for liver transplantation in the United States. Since the introduction of directly acting antiviral agents (DAAs), there have been there have been dramatic advances in treatment of hepatitis C in terms of tolerability, duration of therapy with significant increases in the rates of sustained virologic response (SVR). This review summarizes the findings of recently published clinical trials of DAAs in the treatment of hepatitis C by genotype and in patients co-infected with HCV/HIV. PMID- 27768011 TI - Previous lower limb dominance does not affect measures of impairment and activity after stroke. AB - BACKGROUND: Similar to the findings with the upper limbs, previous dominance of the lower limbs could also interfere with measures of impairment and activity of individuals with stroke. If this occurs, rehabilitation interventions should be planned, considering previous lower limb dominance. AIM: To investigate the impact of having the dominant versus the non-dominant lower limb affected by the stroke on measures of impairment and activity. DESIGN: Cross-sectional study. SETTING: University laboratory. POPULATION: Ninety subjects with chronic stroke, divided into dominant (n=44) and non-dominant (N.=46) groups. METHODS: The sub groups were classified according to the severity of motor impairments into mild and severe. Impairment measures included sensation, tonus, isometric strength and motor coordination, whereas activity measures included walking speed, and stair ascent/descent cadences. RESULTS: The MANOVAs did not reveal any significant interactions between dominance and severity of motor impairments for both the impairment and activity models. Significant main effects of severity of motor impairments were found for both the impairment and activity models, but not for dominance. All dependent variables were significantly affected by the severity of motor impairments, but not by dominance. CONCLUSIONS: The findings suggested that individuals, who had their dominant lower limb affected by the stroke, demonstrated similar impairments, than those who had the non-dominant lower limb affected. Furthermore, significant effects of severity of motor impairments, but not of dominance, were found on all measures of impairment and activity. CLINICAL REHABILITATION IMPACT: The findings emphasize the importance of not training the lower limbs based upon previous dominance, but giving priority to bilateral training. When both limbs are simultaneously used in tasks, the movement of the non-dominant limb improves the quality of the movement, accuracy, and speed, because bilateral training helps the unaffected side to train the affected side. PMID- 27768013 TI - Prospective multicenter survey on the clinical management of pediatric contact dermatitis. AB - BACKGROUND: Contact dermatitis can be defined as an inflammatory process affecting the skin surface and induced by contact with chemical, physical and/or biotic agents in the environment. It causes lesions to skin, mucosae and semi mucosae by means of allergic and irritant pathogenic mechanisms. Among the main triggers of contact dermatitis in the pediatric age are chemical or physical agents, which cause irritant contact dermatitis (ICD), and sensitizers, which cause a tissue damage through an allergic mechanism (allergic contact dermatitis [ACD]). METHODS: A prospective, multicenter, observational study was carried out in 204 children affected by contact dermatitis, aged up to 14 years, and enrolled by pediatricians from 7 different Italian provinces. The diagnosis of contact dermatitis was based on the pediatrician's clinical evaluation. The data were collected through a series of simple and multiple choice questions, anonymously filled out by pediatricians. RESULTS: In 90% of cases (184 of 204 patients), there was complete remission of contact dermatitis, with no cases of worsening. No adverse events were observed, either. The effectiveness of the therapy was rated as "very effective" by 84.4% of the parents and 86.8% of the pediatricians. In only 10 patients a new therapy had to be prescribed. CONCLUSIONS: Contact dermatitis is a heterogeneous inflammatory skin disease induced by contact with different kinds of environmental agents. Cutaneous manifestations are highly variable and depend on the modality of contact, on the causative agent and on the pathogenesis. This Italian experience of a clinical approach to contact dermatitis stresses the need of daily skin care through different therapeutic strategies, based on the diagnosis, the clinical severity and the parents and children compliance. The first therapeutic measure to be implemented is prevention, through the removal of the causative agent and the use of protective devices. Indeed, preserving the skin's barrier function is an important goal and a priority of treatment algorithms. PMID- 27768012 TI - Test-retest reliability, internal consistency and concurrent validity of Fatigue Severity Scale in measuring post-stroke fatigue. AB - BACKGROUND: Post-stroke fatigue (PSF) is a common complaint among stroke survivors and has significant impacts on recovery and quality of life. Limited tools that measure fatigue have been validated in stroke. AIM: The purpose of this study was to determine the psychometric properties of Fatigue Severity Scale (FSS) in patients with stroke. DESIGN: Cross-sectional study. SETTING: Teaching hospital outpatient setting. POPULATION: Fifty healthy controls (mean age 61.1+/ 7.4 years; 22 males) and 50 patients with stroke (mean age 63.6+/-10.3 years; 34 males). METHODS: FSS was administered twice approximately a week apart through face-to-face interview. In addition, we measured fatigue with Visual Analogue Scale - Fatigue (VAS-F) and Short-Form Health Survey 36 version 2 vitality scale. We used Cronbach alpha to determine internal consistency of FSS. Reliability and validity of FSS were determined by intraclass correlation coefficient (ICC) and Spearman correlation coefficient (r). RESULTS: FSS showed excellent internal consistency for both stroke and healthy groups (Cronbach's alpha >0.90). FSS had excellent test-retest reliability for stroke patients and healthy controls (ICC=0.93 and ICC=0.90, respectively). The scale demonstrated good concurrent validity with VAS-Fatigue (all r>.60) and a moderate validity with the SF36 vitality scale. Furthermore, FSS was sensitive to distinguish fatigue in stroke from the healthy controls (P<0.01). CONCLUSIONS: FSS has excellent internal consistency, test-retest reliability and good concurrent validity with VAS-F for both groups. CLINICAL REHABILITATION IMPACT: This study provides evidence that FSS is a reliable and valid tool to measure post-stroke fatigue and is readily to be used in clinical settings. PMID- 27768014 TI - Time spent in sedentary activities in a pediatric population in Pretoria Central, South Africa. AB - BACKGROUND: Scant information exist on screen time behavior of South Africa children and whether they do not meet the recommendation of American Association of Pediatrics (AAP) concerning screen time activity for children is only speculative. Therefore, the purpose of this study was to examine the time spent in sedentary activities, especially screen time of South African children with regard to gender. METHODS: This cross-sectional study involved a random sample of 1136 school children (548 boys; 588 girls) aged 9-13 years attending public schools in Central Pretoria, South Africa. Questionnaire was used to collect data on the participants' sedentary behaviors. The prevalence estimates for sedentary time activity was based on the guidelines (i.e., <2 or >=2 hours per day) of AAP. RESULTS: The mean age of the children was 11.1+/-1.4 years. Sedentary activity data were collected from 548 boys (48.2%) and 588 (51.8%) girls. The majority of children spent more than two hours per day (exceeding the AAP recommendation for sedentary activity) watching TV (3.0%), worked or played on the computer (25.4%), read (1.0%), played music (27.9%), played board games (14.7%), washing clothes (8.0%), floor sweeping (10.5%), art work (18.2%), and spent time on other unspecified activities (28.6%). Boys spent more time (2 hours, 3-4 hours) watching TV (38.3%; P=0.001), playing computer (31.8 %; P=0.024) and board games (17.4%; P=0.012) than girls. The corresponding figures for girls were 35.7%, 19.2% and 12.5% for TV, computer and board games, respectively. However, the proportion of those who spent more time playing music was higher among girls (32.7%) than boys (22.4%) (P=0.002). Overall, the time spent exceeding AAP recommendation (>= 2 hours) was not statistically (P=0.427) different between boys and girls. CONCLUSIONS: The time spent in sedentary activities, particularly in screen time activity among urban primary school children in Pretoria Central is excessively higher than the recommendation (i.e., >=2 hours per day) set for children. Also, gender differences exist in the sedentary activities of the children, with boys having higher screen time and other sedentary activities than girls. Children's screen time activity needs to be monitored to reduce the time children spend in front of the TV, computer gaming, video watching and other sedentary activities. PMID- 27768015 TI - Hemolytic uremic syndrome in children. AB - Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, non-immune microangiopathic hemolytic anemia and acute renal failure. HUS is typically classified into two primary types: 1) HUS due to infections, often associated with diarrhea (D+HUS, Shiga toxin-producing Escherichia Coli-HUS), with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus; 2) HUS related to complement, such HUS is also known as "atypical HUS" and is not diarrhea associated (D-HUS, aHUS); but recent studies have shown other forms of HUS, that can occur in the course of systemic diseases or physiopathological conditions such as pregnancy, after transplantation or after drug assumption. Moreover, new studies have shown that the complement system is an important factor also in the typical HUS, in which the infection could highlight an underlying dysregulation of complement factors. Clinical signs and symptoms may overlap among the different forms of HUS. Shiga toxin-producing Escherichia Coli (STEC) infection cause a spectrum of clinical sings ranging from asymptomatic carriage to non-bloody diarrhea, hemorrhagic colitis, HUS and death. The average interval between ingestion of STEC and illness manifestation is approximately 3 days, although this can vary between 2 and 12 days. Patients with pneumococcal HUS usually have a severe clinical picture with microangiopathic hemolytic anemia, respiratory distress, neurological involvement. The atypical HUS, in contrast to STEC-HUS which tends to occur as a single event, is a chronic condition and involves a poorer prognosis. Early diagnosis and identification of underlying pathogenic mechanism allow instating specific support measures and therapies. Typical management of STEC-HUS patients relies on supportive care of electrolyte and water imbalance, anemia, hypertension and renal failure. For the aHUS the initial management is supportive and similar to the approach for STEC-HUS; currently we have moved from the historic plasma therapy to new therapeutic approaches, first of all eculizumab, a monoclonal antibody that blocks the C5 cascade. This drug has shown an improvement in platelet count, cessation of hemolysis, improvement of renal function within a few days after the treatment. In patients with end-stage renal disease (ESRD) renal transplantation from a non-related donor and prophylactic administration of eculizumab to prevent recurrent disease in the allograft could be considered. PMID- 27768016 TI - Distal intestinal obstruction syndrome: a rare complication of cystic fibrosis in infants. PMID- 27768017 TI - Green teeth caused by neonatal hyperbilirubinemia. PMID- 27768018 TI - Autoimmune hepatitis: clinical findings in six pediatric patients. PMID- 27768019 TI - Incidence of galactose metabolic disorders in Greece. PMID- 27768020 TI - Clinical efficacy of a solution composed by sodium bicarbonate and alginate, aloe vera, propoli, chamomile, calendula and honey, in the treatment of minor recurrent aphthous stomatitis in children. PMID- 27768021 TI - Current position of diagnostics and surgical treatment for upper tract urothelial carcinoma. AB - BACKGROUND: The applicability of urinary biomarkers and optical diagnostics in upper urinary tract carcinoma (UUT-UC) are increasingly debated. To receive insight in the opinion of the urological community involved in this field, a survey was sent out to identify the most promising techniques and understand the need for new diagnostics. Primary objective of this study was to provide an overview of current diagnostics in upper urinary tract urothelial carcinoma. Secondary objectives of this study was to assess the need for additional diagnostic techniques in the current diagnostic work-up for UUT-UC and to assess knowledge of novel techniques. METHODS: An electronic survey was distributed to all participants of the upper urinary tract tumor registration study by the Clinical Research Office of the Endourological Society. Additionally, based on publications, experts in the field were contacted. Analysis was performed on the results overviewed by the survey monkey website. RESULTS: In total 81 of the 112 invited individuals responded resulting in a response rate of 72.3%. Most urologists involved in the treatment of upper urinary tract tumors follow the guidelines in their diagnostic work-up of patients suspected for UUT-UC. 61.4% of all responders consider current available diagnostic methods insufficient to select patient candidates for conservative renal sparing surgery. According to the responders, digital endoscopes for retrograde intrarenal surgery (RIRS) including narrow-band imaging (NBI) are best known and most likely to be beneficial compared to all evaluated diagnostic tools currently available. CONCLUSIONS: Urologists consider current diagnostic techniques for upper urinary tract tumors insufficient for optimal patient selection for conservative renal sparing surgery. Among the new techniques, NBI and digital RIRS are best known and considered to be beneficial in the diagnostic work-up. PMID- 27768022 TI - Advantages of the supine transgluteal approach for distal ureteral stone extracorporeal shock wave lithotripsy: outcomes based on CT characteristics. AB - BACKGROUND: Extracorporeal shock wave lithotripsy (ESWL) for distal ureteral stones can be performed in prone or supine position. The aim of this study was to investigate the advantages brought by the supine transgluteal ESWL approach for distal ureteral stones treatment using real-time ultrasound (US), and to show how computerized tomography (CT) scan parameters may be related to the outcomes. METHODS: Seventy consecutive supine transgluteal ESWL of distal ureteral stones were performed. All patients had a pre-treatment CT scan. The following parameter were evaluated: stone size, Hounsfield Units, skin-to-stone distance, sciaticum majus foramen width, stone to ureteral ostium distance, fragmentation and expulsion perception during the treatment, and the stone-free status. Stone focusing was obtained US, which allows a real-time visualization of stone location and fragmentation. Follow-up included a kidney ureter bladder (KUB) film and US examination at 2-3 weeks after treatment (median time: 18 days). Stone free condition was defined as the complete absence of stone fragments. A linear regression analysis was used to assess the possible variables mostly related to stone-free status. P<0.05 was considered as significant. RESULTS: Median number of SWL sessions for patient was 1 (IQR: 1-1), mean 1.2+/-0.5. The re-treatment rate for stone-free patients was 18.3%. Stone-free rate was 85.7%. A clear and real time US stone fragmentation was perceived by the surgeon during the treatment in 42/70 (60%) of patients and correlated to the definitive stone-free status (P=0.04). Stone to ureteral ostium distance was the only variable affecting the stone-free condition (P=0.01). CONCLUSIONS: Supine transgluteal SWL of distal ureteral stones provide satisfactory outcomes in terms of stone-free rate. The distance of the stone to the ureteral ostium, measured by CT, appeared to be the only significant variable connected to SWL success. PMID- 27768023 TI - Prognostic significance of NGAL in early stage chronic kidney disease. AB - BACKGROUND: Neutrophilgelatinase-associated lipocalin (NGAL) has been proven to be a useful biomarker for early detection of acute kidney injury, but it is not known whether adding NGAL measurements to conventional risk factors will improve the risk assessment in the setting of chronic kidney disease (CKD). The aim of the present study was to examine the correlation of NGAL with early stage renal impairment in CKD and to evaluate its prognostic value in these subjects. METHODS: This is a prospective observational cohort study of 54 patients with early stage (stage 1-2) CKD. Patients aged between 18 and 65 years with stable disease were enrolled in this study. Patients with a history of primary glomerulonephritis, diabetes mellitus, acute kidney injury, systemic diseases and stage 3-4-5 CKD were excluded from the study group. Estimated glomerular filtration (eGFR) rate was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The patients were followed for two years to determine the ability of baseline NGAL for prediction of renal outcome. In our study disease progression was defined as changes in eGFR (DeltaeGFR) and proteinuria (Deltaproteinuria). Patients divided into two groups according to NGAL cut-off value as group 1 (N.=23, NGAL <=98.71 ng/mL) and group 2 (N.=31, NGAL >98.71 ng/mL). RESULTS: Out of 54 patients (mean age: 45.6+/-7.6 years, 64.8% female, baseline eGFR: 84.6+/-16.8 mL/min/1.73 m2, baseline NGAL level: 157.47+/-121.52 ng/mL); 18 patients were stage 1 and 36 patients were stage 2 CKD. In the ROC analysis, we found that the optimal cut-off value of NGAL for predicting stage 2 CKD was 98.71ng/mL (P=0.005) with the 72.2% sensitivity and 72.2% specificity. In correlation analysis, we evaluated significantly positive correlations between NGAL and CKD stage (r=0.389, P=0.004), baseline/last serum creatinine level (r=0.530, P<0.001 and r=0.439, P=0.003; respectively), last proteinuria level (r=0.359, P=0.043). There were significantly negative correlation between NGAL and baseline/last eGFR (r=-0.498, P<0.001 and r=-0.462, P=0.002; respectively). Compared to the group 1, we determined that group 2 patients had further deterioration in renal functions regarding DeltaeGFR ( 1.12+/-12.6 mL/min vs. -1.46+/-12.4 mL/min: respectively, P=0.930) and Deltaproteinuria (98.1+/-569.3 mg/day vs. 339+/-701.6 mg/day; respectively, P=0.305); however these differences were not statistically significant at the end of the two years follow-up period. CONCLUSIONS: Altough NGAL has a positive correlation with disease severity, it does not seem to be a marker of disease progression in patients with early stage CKD. But further studies stated in different patient groups may also explain the usability of NGAL in clinical practice. PMID- 27768024 TI - The treatment of vertebral metastases from renal cell carcinoma: a retrospective study. AB - BACKGROUND: Renal cell carcinoma (RCC) is among the ten most common cancers in both men and women. It comprises 2-3% of all malignancies. The most common site for metastasis from RCC is the lung (50% of patients), followed by the skeleton (20% to 50% of patients). METHODS: We retrospectively reviewed our consecutive series of 63 patients surgically treated for spinal metastases from RCC. The surgical treatment for spinal metastases varied in each patient. Factors influencing the choice of surgery included age, disease status, symptoms, morbidity of the patient, the location, the number of repetitive lesions and the existence of extra-osseous metastases. For 42 patients (66.66%) the treatment included radiation two weeks after the surgical procedure. RESULTS: A total of 68 surgical procedures were performed in 63 patients. For all patients we collected data about type of RCC, locations of metastasis, type of spine metastasis, type of surgery and complications. In this way we had an exahustive vision of the natural history of this kind of patients. CONCLUSIONS: Spine metastatic RCC has a poor prognosis. The favorable prognostic factor is solitary spinal metastasis without involvement of visceral organs where the gold standard treatment is corpectomy en bloc. The negative prognostic factors are the presence of one or more pathological fractures and neurological deficits. Bisphosphonate as zoledronic acid reduce significantly skeletal morbidity and significantly prolong time to bone lesion progression in patients with spine metastases from renal cell carcinoma. PMID- 27768025 TI - Rapid Scan Electron Paramagnetic Resonance Opens New Avenues for Imaging Physiologically Important Parameters In Vivo. AB - We demonstrate a superior method of 2D spectral-spatial imaging of stable radical reporter molecules at 250 MHz using rapid-scan electron-paramagnetic-resonance (RS-EPR), which can provide quantitative information under in vivo conditions on oxygen concentration, pH, redox status and concentration of signaling molecules (i.e., OH*, NO*). The RS-EPR technique has a higher sensitivity, improved spatial resolution (1 mm), and shorter acquisition time in comparison to the standard continuous wave (CW) technique. A variety of phantom configurations have been tested, with spatial resolution varying from 1 to 6 mm, and spectral width of the reporter molecules ranging from 16 uT (160 mG) to 5 mT (50 G). A cross-loop bimodal resonator decouples excitation and detection, reducing the noise, while the rapid scan effect allows more power to be input to the spin system before saturation, increasing the EPR signal. This leads to a substantially higher signal-to-noise ratio than in conventional CW EPR experiments. PMID- 27768026 TI - Combined Near-infrared Fluorescent Imaging and Micro-computed Tomography for Directly Visualizing Cerebral Thromboemboli. AB - Direct thrombus imaging visualizes the root cause of thromboembolic infarction. Being able to image thrombus directly allows far better investigation of stroke than relying on indirect measurements, and will be a potent and robust vascular research tool. We use an optical imaging approach that labels thrombi with a molecular imaging thrombus marker - a Cy5.5 near-infrared fluorescent (NIRF) probe that is covalently linked to the fibrin strands of the thrombus by the fibrin-crosslinking enzymatic action of activated coagulation factor XIIIa during the process of clot maturation. A micro-computed tomography (microCT)-based approach uses thrombus-seeking gold nanoparticles (AuNPs) functionalized to target the major component of the clot: fibrin. This paper describes a detailed protocol for the combined in vivo microCT and ex vivo NIRF imaging of thromboemboli in a mouse model of embolic stroke. We show that in vivo microCT and fibrin-targeted glycol-chitosan AuNPs (fib-GC-AuNPs) can be used for visualizing both in situ thrombi and cerebral embolic thrombi. We also describe the use of in vivo microCT-based direct thrombus imaging to serially monitor the therapeutic effects of tissue plasminogen activator-mediated thrombolysis. After the last imaging session, we demonstrate by ex vivo NIRF imaging the extent and the distribution of residual thromboemboli in the brain. Finally, we describe quantitative image analyses of microCT and NIRF imaging data. The combined technique of direct thrombus imaging allows two independent methods of thrombus visualization to be compared: the area of thrombus-related fluorescent signal on ex vivo NIRF imaging vs. the volume of hyperdense microCT thrombi in vivo. PMID- 27768027 TI - Nutrient Regulation by Continuous Feeding for Large-scale Expansion of Mammalian Cells in Spheroids. AB - In this demonstration, spheroids formed from the beta-TC6 insulinoma cell line were cultured as a model of manufacturing a mammalian islet cell product to demonstrate how regulating nutrient levels can improve cell yields. In previous studies, bioreactors facilitated increased culture volumes over static cultures, but no increase in cell yields were observed. Limitations in key nutrients such as glucose, which were consumed between batch feedings, can lead to limitations in cell expansion. Large fluctuations in glucose levels were observed, despite the increase in glucose concentrations in the media. The use of continuous feeding systems eliminated fluctuations in glucose levels, and improved cell growth rates when compared with batch fed static and SSB culture methods. Additional increases in growth rates were observed by adjusting the feed rate based on calculated nutrient consumption, which allowed the maintenance of physiological glucose over three weeks in culture. This method can also be adapted for other cell types. PMID- 27768028 TI - Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies. AB - Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor pieces are injected subcutaneously into athymic nude mice (immunocompromised, T cell deficient) to create a bank of tumors and subsequently are passaged into different generations of mice in order to maintain these tumors from patients. Importantly, cellular heterogeneity of the original tumor is closely emulated in this model, which provides a more clinically relevant model for evaluation of drug efficacy studies (single agent and combination), biomarker analysis, resistant pathways and cancer stem cell biology. Some limitations of the PDTX model include the replacement of the human stroma with mouse stroma after the first generation in mice, inability to investigate treatment effects on metastasis due to the subcutaneous injections of the tumors, and the lack of evaluation of immunotherapies due to the use of immunocompromised mice. However, even with these limitations, the PDTX model provides a powerful preclinical platform in the drug discovery process. PMID- 27768029 TI - Intra-iliac Artery Injection for Efficient and Selective Modeling of Microscopic Bone Metastasis. AB - Intra-iliac artery (IIA) injection is an efficient approach to introduce metastatic lesions of various cancer cells in animals. Compared to the widely used intra-cardiac and intra-tibial injections, IIA injection brings several advantages. First, it can deliver a large quantity of cancer cells specifically to hind limb bones, thereby providing spatiotemporally synchronized early-stage colonization events and allowing robust quantification and swift detection of disseminated tumor cells. Second, it injects cancer cells into the circulation without damaging the local tissues, thereby avoiding inflammatory and wound healing processes that confound the bone colonization process. Third, IIA injection causes very little metastatic growth in non-bone organs, thereby preventing animals from succumbing to other vital metastases, and allowing continuous monitoring of indolent bone lesions. These advantages are especially useful for the inspection of progression from single cancer cells to multi-cell micrometastases, which has largely been elusive in the past. When combined with cutting-edge approaches of biological imaging and bone histology, IIA injection can be applied to various research purposes related to bone metastases. PMID- 27768030 TI - Mimicking the Function of Signaling Proteins: Toward Artificial Signal Transduction Therapy. AB - Signal transduction pathways, which control the response of cells to various environmental signals, are mediated by the function of signaling proteins that interact with each other and activate one other with high specificity. Synthetic agents that mimic the function of these proteins might therefore be used to generate unnatural signal transduction steps and consequently, alter the cell's function. We present guidelines for designing 'chemical transducers' that can induce artificial communication between native proteins. In addition, we present detailed protocols for synthesizing and testing a specific 'transducer', which can induce communication between two unrelated proteins: platelet-derived growth factor (PDGF) and glutathione-S-transferase (GST). The way by which this unnatural PDGF-GST communication could be used to control the cleavage of an anticancer prodrug is also presented, indicating the potential for using such systems in 'artificial signal transduction therapy'. This work is intended to facilitate developing additional 'transducers' of this class, which may be used to mediate intracellular protein-protein communication and consequently, to induce artificial cell signaling pathways. PMID- 27768031 TI - Patch Clamp Recordings on Intact Dorsal Root Ganglia from Adult Rats. AB - Patch clamp studies from dorsal root ganglia (DRGs) neurons have increased our understanding of the peripheral nervous system. Currently, the majority of recordings are conducted on dissociated DRG neurons, which is a standard preparation for most laboratories. Neuronal properties, however, can be altered by axonal injury resulting from enzyme digestion used in acquiring dissociated neurons. Further, dissociated neuron preparations cannot fully represent the microenvironment of the DRG since loss of contact with satellite glial cells that surround the primary sensory neurons is an unavoidable consequence of this method. To overcome the limitations in using conventional dissociated DRG neurons for patch clamp recordings, in this report we describe a method to prepare intact DRGs and conduct patch clamp recordings on individual primary sensory neurons ex vivo. This approach permits the fast and straightforward preparation of intact DRGs, mimicking in vivo conditions by keeping DRG neurons associated with their surrounding satellite glial cells and basement membrane. Furthermore, the method avoids axonal injury from manipulation and enzyme digestion such as when dissociating DRGs. This ex vivo preparation can additionally be used to study the interaction between primary sensory neurons and satellite glial cells. PMID- 27768032 TI - Aggregate Size Optimization in Microwells for Suspension-based Cardiac Differentiation of Human Pluripotent Stem Cells. AB - Cardiac differentiation of human pluripotent stems cells (hPSCs) is typically carried out in suspension cell aggregates. Conventional aggregate formation of hPSCs involves dissociating cell colonies into smaller clumps, with size control of the clumps crudely controlled by pipetting the cell suspension until the desired clump size is achieved. One of the main challenges of conventional aggregate-based cardiac differentiation of hPSCs is that culture heterogeneity and spatial disorganization lead to variable and inefficient cardiomyocyte yield. We and others have previously reported that human embryonic stem cell (hESC) aggregate size can be modulated to optimize cardiac induction efficiency. We have addressed this challenge by employing a scalable, microwell-based approach to control physical parameters of aggregate formation, specifically aggregate size and shape. The method we describe here consists of forced aggregation of defined hPSC numbers in microwells, and the subsequent culture of these aggregates in conditions that direct cardiac induction. This protocol can be readily scaled depending on the size and number of wells used. Using this method, we can consistently achieve culture outputs with cardiomyocyte frequencies greater than 70%. PMID- 27768033 TI - The Visual Colorimetric Detection of Multi-nucleotide Polymorphisms on a Pneumatic Droplet Manipulation Platform. AB - A simple and visual method to detect multi-nucleotide polymorphism (MNP) was performed on a pneumatic droplet manipulation platform on an open surface. This approach to colorimetric DNA detection was based on the hybridization-mediated growth of gold nanoparticle probes (AuNP probes). The growth size and configuration of the AuNP are dominated by the number of DNA samples hybridized with the probes. Based on the specific size- and shape-dependent optical properties of the nanoparticles, the number of mismatches in a sample DNA fragment to the probes is able to be discriminated. The tests were conducted via droplets containing reagents and DNA samples respectively, and were transported and mixed on the pneumatic platform with the controlled pneumatic suction of the flexible PDMS-based superhydrophobic membrane. Droplets can be delivered simultaneously and precisely on an open-surface on the proposed pneumatic platform that is highly biocompatible with no side effect of DNA samples inside the droplets. Combining the two proposed methods, the multi-nucleotide polymorphism can be detected at sight on the pneumatic droplet manipulation platform; no additional instrument is required. The procedure from installing the droplets on the platform to the final result takes less than 5 min, much less than with existing methods. Moreover, this combined MNP detection approach requires a sample volume of only 10 ul in each operation, which is remarkably less than that of a macro system. PMID- 27768034 TI - Primary Outcome Assessment in a Pig Model of Acute Myocardial Infarction. AB - Mortality after acute myocardial infarction remains substantial and is associated with significant morbidity, like heart failure. Novel therapeutics are therefore required to confine cardiac damage, promote survival and reduce the disease burden of heart failure. Large animal experiments are an essential part in the translational process from experimental to clinical therapies. To optimize clinical translation, robust and representative outcome measures are mandatory. The present manuscript aims to address this need by describing the assessment of three clinically relevant outcome modalities in a pig acute myocardial infarction (AMI) model: infarct size in relation to area at risk (IS/AAR) staining, 3 dimensional transesophageal echocardiography (TEE) and admittance-based pressure volume (PV) loops. Infarct size is the main determinant driving the transition from AMI to heart failure and can be quantified by IS/AAR staining. Echocardiography is a reliable and robust tool in the assessment of global and regional cardiac function in clinical cardiology. Here, a method for three dimensional transesophageal echocardiography (3D-TEE) in pigs is provided. Extensive insight into cardiac performance can be obtained by admittance-based pressure-volume (PV) loops, including intrinsic parameters of myocardial function that are pre- and afterload independent. Combined with a clinically feasible experimental study protocol, these outcome measures provide researchers with essential information to determine whether novel therapeutic strategies could yield promising targets for future testing in clinical studies. PMID- 27768035 TI - A Robotic Platform for High-throughput Protoplast Isolation and Transformation. AB - Over the last decade there has been a resurgence in the use of plant protoplasts that range from model species to crop species, for analysis of signal transduction pathways, transcriptional regulatory networks, gene expression, genome-editing, and gene-silencing. Furthermore, significant progress has been made in the regeneration of plants from protoplasts, which has generated even more interest in the use of these systems for plant genomics. In this work, a protocol has been developed for automation of protoplast isolation and transformation from a 'Bright Yellow' 2 (BY-2) tobacco suspension culture using a robotic platform. The transformation procedures were validated using an orange fluorescent protein (OFP) reporter gene (pporRFP) under the control of the Cauliflower mosaic virus 35S promoter (35S). OFP expression in protoplasts was confirmed by epifluorescence microscopy. Analyses also included protoplast production efficiency methods using propidium iodide. Finally, low-cost food grade enzymes were used for the protoplast isolation procedure, circumventing the need for lab-grade enzymes that are cost-prohibitive in high-throughput automated protoplast isolation and analysis. Based on the protocol developed in this work, the complete procedure from protoplast isolation to transformation can be conducted in under 4 hr, without any input from the operator. While the protocol developed in this work was validated with the BY-2 cell culture, the procedures and methods should be translatable to any plant suspension culture/protoplast system, which should enable acceleration of crop genomics research. PMID- 27768036 TI - Safety Precautions and Operating Procedures in an (A)BSL-4 Laboratory: 3. Aerobiology. AB - Aerosol or inhalational studies of high-consequence pathogens have recently been increasing in number due to the perceived threat of intentional aerosol releases or unexpected natural aerosol transmission. Specific laboratories designed to perform these experiments require tremendous engineering controls to provide a safe and secure working environment and constant systems maintenance to sustain functionality. Class III biosafety cabinets, also referred to as gloveboxes, are gas-tight enclosures with non-opening windows. These cabinets are maintained under negative pressure by double high-efficiency-particulate-air (HEPA)-filtered exhaust systems and are the ideal primary containment for housing aerosolization equipment. A well planned workflow between staff members within high containment from, for instance, an animal biosafety level-4 (ABSL-4) suit laboratory to the ABSL-4 cabinet laboratory is a crucial component for successful experimentation. For smooth study execution, establishing a communication network, moving equipment and subjects, and setting up and placing equipment, requires staff members to meticulously plan procedures prior to study initiation. Here, we provide an overview and a visual representation of how aerobiology research is conducted at the National Institutes of Health, National Institute of Allergy and Infectious Diseases Integrated Research Facility at Fort Detrick, Maryland, USA, within an ABSL-4 environment. PMID- 27768037 TI - Probing C84-embedded Si Substrate Using Scanning Probe Microscopy and Molecular Dynamics. AB - This paper reports an array-designed C84-embedded Si substrate fabricated using a controlled self-assembly method in an ultra-high vacuum chamber. The characteristics of the C84-embedded Si surface, such as atomic resolution topography, local electronic density of states, band gap energy, field emission properties, nanomechanical stiffness, and surface magnetism, were examined using a variety of surface analysis techniques under ultra, high vacuum (UHV) conditions as well as in an atmospheric system. Experimental results demonstrate the high uniformity of the C84-embedded Si surface fabricated using a controlled self-assembly nanotechnology mechanism, represents an important development in the application of field emission display (FED), optoelectronic device fabrication, MEMS cutting tools, and in efforts to find a suitable replacement for carbide semiconductors. Molecular dynamics (MD) method with semi-empirical potential can be used to study the nanoindentation of C84-embedded Si substrate. A detailed description for performing MD simulation is presented here. Details for a comprehensive study on mechanical analysis of MD simulation such as indentation force, Young's modulus, surface stiffness, atomic stress, and atomic strain are included. The atomic stress and von-Mises strain distributions of the indentation model can be calculated to monitor deformation mechanism with time evaluation in atomistic level. PMID- 27768038 TI - The Synthesis of RGD-functionalized Hydrogels as a Tool for Therapeutic Applications. AB - The use of polymers as biomaterials has provided significant advantages in therapeutic applications. In particular, the possibility to modify and functionalize polymer chains with compounds that are able to improve biocompatibility, mechanical properties, or cell viability allows the design of novel materials to meet new challenges in the biomedical field. With the polymer functionalization strategies, click chemistry is a powerful tool to improve cell compatibility and drug delivery properties of polymeric devices. Similarly, the fundamental need of biomedicine to use sterile tools to avoid potential adverse side effects, such as toxicity or contamination of the biological environment, gives rise to increasing interest in the microwave-assisted strategy. The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible. PMID- 27768039 TI - Isolation of Perivascular Multipotent Precursor Cell Populations from Human Cardiac Tissue. AB - Multipotent mesenchymal stem/stromal cells (MSC) were conventionally isolated, through their plastic adherence, from primary tissue digests whilst their anatomical tissue location remained unclear. The recent discovery of defined perivascular and MSC cell marker expression by perivascular cells in multiple tissues by our group and other researchers has provided an opportunity to prospectively isolate and purify specific homogenous subpopulations of multipotent perivascular precursor cells. We have previously demonstrated the use of fluorescent activated cell sorting (FACS) to purify microvascular CD146+CD34- pericytes and vascular CD34+CD146- adventitial cells from human skeletal muscle. Herein we describe a method to simultaneously isolate these two perivascular cell subsets from human myocardium by FACS, based on the expression of a defined set of cell surface markers for positive and negative selections. This method thus makes available two specific subpopulations of multipotent cardiac MSC-like precursor cells for use in basic research and/or therapeutic investigations. PMID- 27768040 TI - A Detailed Protocol for Characterizing the Murine C1498 Cell Line and its Associated Leukemia Mouse Model. AB - The intravenous injection of C1498 cells into syngeneic or congenic mice has been performed since 1941. These injections result in the development of acute leukemia. However, the nature of this disease has not been well documented in the literature. Here, we provide a technical protocol for characterizing C1498 cells in vitro and for determining the nature of the induced leukemia in vivo. The first part of this procedure is focused on determining the hematopoietic lineage and the stage of differentiation of cultured C1498 cells. To achieve this, multi parametric flow cytometric staining is used to detect hematopoietic cell markers. Immunofluorescence microscopy, cytochemistry and a May-Grunwald Giemsa staining are then performed to assess the expression of myeloperoxidase, the activity of esterases and cellular morphology, respectively. The second part of this protocol is dedicated to describing the leukemia disease that is induced in vivo. The latter can be achieved by determining the frequencies of leukemic and inherent cells in the blood, hematopoietic organs (e.g., bone marrow and spleen) and non lymphoid tissues (e.g., the liver and lungs) using specific staining and flow cytometry analyses. The nature of the leukemia is then confirmed using May Grunwald Giemsa staining and staining for specific esterases in the bone marrow. Here, we present the results that were obtained using this protocol in age matched C1498- and PBS-injected mice. PMID- 27768041 TI - The Evolution of Silica Nanoparticle-polyester Coatings on Surfaces Exposed to Sunlight. AB - Corrosion of metallic surfaces is prevalent in the environment and is of great concern in many areas, including the military, transport, aviation, building and food industries, amongst others. Polyester and coatings containing both polyester and silica nanoparticles (SiO2NPs) have been widely used to protect steel substrata from corrosion. In this study, we utilized X-ray photoelectron spectroscopy, attenuated total reflection infrared micro-spectroscopy, water contact angle measurements, optical profiling and atomic force microscopy to provide an insight into how exposure to sunlight can cause changes in the micro- and nanoscale integrity of the coatings. No significant change in surface micro topography was detected using optical profilometry, however, statistically significant nanoscale changes to the surface were detected using atomic force microscopy. Analysis of the X-ray photoelectron spectroscopy and attenuated total reflection infrared micro-spectroscopy data revealed that degradation of the ester groups had occurred through exposure to ultraviolet light to form COO., H2C., -O., -CO. radicals. During the degradation process, CO and CO2 were also produced. PMID- 27768043 TI - Investigating the 'Uncatchable Smile' in Leonardo da Vinci's La Bella Principessa: A Comparison with the Mona Lisa and Pollaiuolo's Portrait of a Girl. AB - This paper discusses how the 'Uncatchable Smile' illusion in Leonardo da Vinci's La Bella Principessa portrait was discovered. Kemp and Cotte1 described the expression of the Princess as ambiguous and "subtle to an inexpressible degree". A combination of three methods was used (inter-observation, structured interviews, and psychophysical experiments) to identify what may underlie this 'ambiguity'. The inter-observation and the structured interview methods were firstly applied to generate experimental hypotheses that were successively tested by a series of psychophysical experiments. The combination of these research methods minimizes the impact of the researcher's beliefs and biases in the development of the research design. It emerged that the ambiguity in La Bella Principessa is triggered by a change in the perceived level of contentment in her facial expression and that this perceptual change is attributable to a visual illusion relating to her mouth. Moreover, it was found that a similar effect can be observed in the Mona Lisa. As the smile in La Bella Principessa disappears as soon as the viewer tries to 'catch it', we named this visual illusion the 'Uncatchable Smile'. The elusive quality of the Mona Lisa's smile2 is probably why the portrait is so famous, and so the existence of a similar ambiguity in a portrait painted by Leonardo prior to the Mona Lisa is even more interesting. PMID- 27768042 TI - The Terroir Concept Interpreted through Grape Berry Metabolomics and Transcriptomics. AB - Terroir refers to the combination of environmental factors that affect the characteristics of crops such as grapevine (Vitis vinifera) according to particular habitats and management practices. This article shows how certain terroir signatures can be detected in the berry metabolome and transcriptome of the grapevine cultivar Corvina using multivariate statistical analysis. The method first requires an appropriate sampling plan. In this case study, a specific clone of the Corvina cultivar was selected to minimize genetic differences, and samples were collected from seven vineyards representing three different macro-zones during three different growing seasons. An untargeted LC-MS metabolomics approach is recommended due to its high sensitivity, accompanied by efficient data processing using MZmine software and a metabolite identification strategy based on fragmentation tree analysis. Comprehensive transcriptome analysis can be achieved using microarrays containing probes covering ~99% of all predicted grapevine genes, allowing the simultaneous analysis of all differentially expressed genes in the context of different terroirs. Finally, multivariate data analysis based on projection methods can be used to overcome the strong vintage-specific effect, allowing the metabolomics and transcriptomics data to be integrated and analyzed in detail to identify informative correlations. PMID- 27768044 TI - Anionic Polymerization of an Amphiphilic Copolymer for Preparation of Block Copolymer Micelles Stabilized by pi-pi Stacking Interactions. AB - In this study, an amphiphilic copolymer that includes a core-forming block with phenyl groups was synthesized by living anionic polymerization of phenyl glycidyl ether (PheGE) on methoxy-polyethylene glycol (mPEG-b-PPheGE). Characterization of the copolymer revealed a narrow molecular distribution (PDI < 1.03) and confirmed the degree of polymerization of mPEG122-b-(PheGE)15. The critical micelle concentration of the copolymer was evaluated using an established fluorescence method with the aggregation behavior evaluated by dynamic light scattering and transmission electronic microscopy. The potential of the copolymer for use in drug delivery applications was evaluated in a preliminary manner including in vitro biocompatibility, loading and release of the hydrophobic anti-cancer drug doxorubicin (DOX). A stable micelle formulation of DOX was prepared with drug loading levels up to 14% (wt%), drug loading efficiencies > 60% (w/w) and sustained release of drug over 4 days under physiologically relevant conditions (acidic and neutral pH, presence of albumin). The high drug loading level and sustained release is attributed to stabilizing pi-pi interactions between DOX and the core-forming block of the micelles. PMID- 27768045 TI - 1,3,5-Triphenylbenzene and Corannulene as Electron Receptors for Lithium Solvated Electron Solutions. AB - The authors report on conductivity studies carried out on lithium solvated electron solutions (LiSES) prepared using two types of polyaromatic hydrocarbons (PAH), namely 1,3,5-triphenylbenzene and corannulene, as electron receptors. The solid PAHs were first dissolved in tetrahydrofuran (THF) to form a solution. Metallic lithium was then dissolved into these PAH/THF solutions to yield either blue or greenish blue solutions, colors which are indicative of the presence of solvated electrons. Conductivity measurements at ambient temperature carried out on 1,3,5-triphenylbenzene-based LiSES, denoted by LixTPB(THF)24.7 (x = 1, 2, 3, 4), showed an increase of conductivity with increase of Li:PAH ratio from x = 1 to 2. However, the conductivity gradually decreased upon further increasing the ratio. Indeed the conductivity of LixTPB(THF)24.7 for x = 4 is even lower than for x = 1. Such behavior is similar to that of the previously reported LiSES prepared from biphenyl and naphthalene. Conductivity versus temperature measurements on corannulene-based LiSES, denoted by LixCor(THF)247 (x = 1, 2, 3, 4, 5), showed linear relationships with negative slopes, indicating a metallic behavior similar to biphenyl and naphthalene-based LiSES. PMID- 27768046 TI - The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease. AB - This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of four mountains within a computer-generated landscape is tested using a delayed match to-sample paradigm. Allocentric spatial memory is assessed by altering the viewpoint, colors and textures between the initially presented and target images. Allocentric spatial memory is a key function of the hippocampus, one of the earliest brain regions to be affected in Alzheimer's disease (AD) and impairment of hippocampal function predates the onset of dementia. It was hypothesized that performance on the 4MT would aid the diagnosis of predementia AD, which manifests clinically as Mild Cognitive Impairment (MCI). The 4MT was applied to patients with MCI, stratified further based on cerebrospinal fluid (CSF) AD biomarker status (10 MCI biomarker positive, 9 MCI biomarker negative), and with mild AD dementia, as well as healthy controls. Comparator tests included tests of episodic memory and attention widely accepted as sensitive measures of early AD. Behavioral data were correlated with quantitative MRI measures of the hippocampus, precuneus and posterior cingulate gyrus. 4MT scores were significantly different between the two MCI groups (p = 0.001), with a test score of <=8/15 associated with 100% sensitivity and 78% specificity for the classification of MCI with positive AD biomarkers, i.e., predementia AD. 4MT test scores correlated with hippocampal volume (r = 0.42) and cortical thickness of the precuneus (r = 0.55). In conclusion, the 4MT is effective in identifying the early stages of AD. The short duration, easy application and scoring, and favorable psychometric properties of the 4MT fulfil the need for a simple but accurate diagnostic test for predementia AD. PMID- 27768048 TI - Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications. AB - Many attempts have been made to manufacture multi-contact nerve cuff electrodes that are safe, robust and reliable for long term neuroprosthetic applications. This protocol describes a fabrication technique of a modified cylindrical nerve cuff electrode to meet these criteria. Minimum computer-aided design and manufacturing (CAD and CAM) skills are necessary to consistently produce cuffs with high precision (contact placement 0.51 +/- 0.04 mm) and various cuff sizes. The precision in spatially distributing the contacts and the ability to retain a predefined geometry accomplished with this design are two criteria essential to optimize the cuff's interface for selective recording and stimulation. The presented design also maximizes the flexibility in the longitudinal direction while maintaining sufficient rigidity in the transverse direction to reshape the nerve by using materials with different elasticities. The expansion of the cuff's cross sectional area as a result of increasing the pressure inside the cuff was observed to be 25% at 67 mm Hg. This test demonstrates the flexibility of the cuff and its response to nerve swelling post-implant. The stability of the contacts' interface and recording quality were also examined with contacts' impedance and signal-to-noise ratio metrics from a chronically implanted cuff (7.5 months), and observed to be 2.55 +/- 0.25 kOmega and 5.10 +/- 0.81 dB respectively. PMID- 27768047 TI - Eye-Tracking Control to Assess Cognitive Functions in Patients with Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with pathological involvement of upper and lower motoneurons, subsequently leading to progressive loss of motor and speech abilities. In addition, cognitive functions are impaired in a subset of patients. To evaluate these potential deficits in severely physically impaired ALS patients, eye-tracking is a promising means to conduct cognitive tests. The present article focuses on how eye movements, an indirect means of communication for physically disabled patients, can be utilized to allow for detailed neuropsychological assessment. The requirements, in terms of oculomotor parameters that have to be met for sufficient eye-tracking in ALS patients are presented. The properties of stimuli, including type of neuropsychological tests and style of presentation, best suited to successfully assess cognitive functioning, are also described. Furthermore, recommendations regarding procedural requirements are provided. Overall, this methodology provides a reliable, easy to administer and fast approach for assessing cognitive deficits in patients who are unable to speak or write such as patients with severe ALS. The only confounding factor might be deficits in voluntary eye movement control in a subset of ALS patients. PMID- 27768049 TI - Treating Clinical Depression with Repetitive Deep Transcranial Magnetic Stimulation Using the Brainsway H1-coil. AB - Repetitive transcranial magnetic stimulation (rTMS) is an emerging non pharmacological approach to treating many brain-based disorders. rTMS uses electromagnetic coils to stimulate areas of the brain non-invasively. Deep transcranial magnetic stimulation (dTMS) with the Brainsway H1-coil system specifically is a type of rTMS indicated for treating patients with major depressive disorder (MDD) who are resistant to medication. The unique H1-coil design of this device is able to stimulate neuronal pathways that lie deeper in the targeted brain areas than those reached by conventional rTMS coils. dTMS is considered to be low-risk and well tolerated, making it a viable treatment option for people who have not responded to medication or psychotherapy trials for their depression. Randomized, sham-control studies have demonstrated that dTMS produces significantly greater improvement in depressive symptoms than sham dTMS treatment in patients with major depression that has not responded to antidepressant medication. In this paper, we will review the methodology for treating major depression with dTMS using an H1-coil. PMID- 27768050 TI - Patch Clamp Recording of Starburst Amacrine Cells in a Flat-mount Preparation of Deafferentated Mouse Retina. AB - The mammalian retina is a layered tissue composed of multiple neuronal types. To understand how visual signals are processed within its intricate synaptic network, electrophysiological recordings are frequently used to study connections among individual neurons. We have optimized a flat-mount preparation for patch clamp recording of genetically marked neurons in both GCL (ganglion cell layer) and INL (inner nuclear layer) of mouse retinas. Recording INL neurons in flat mounts is favored over slices because both vertical and lateral connections are preserved in the former configuration, allowing retinal circuits with large lateral components to be studied. We have used this procedure to compare responses of mirror-partnered neurons in retinas such as the cholinergic starburst amacrine cells (SACs). PMID- 27768052 TI - RNA Interference-based Investigation of the Function of Heat Shock Protein 27 during Corneal Epithelial Wound Healing. AB - Small interfering RNA (siRNA) is among the most widely used RNA interference methods for the short-term silencing of protein-coding genes. siRNA is a synthetic RNA duplex created to specifically target a mRNA transcript to induce its degradation and it has been used to identify novel pathways in various cellular processes. Few reports exist regarding the role of phosphorylated heat shock protein 27 (HSP27) in corneal epithelial wound healing. Herein, cultured human corneal epithelial cells were divided into a scrambled control-siRNA transfected group and a HSP27-specific siRNA-transfected group. Scratch-induced directional wounding assays, and western blotting, and flow cytometry were then performed. We conclude that HSP27 has roles in corneal epithelial wound healing that may involve epithelial cell apoptosis and migration. Here, step-by-step descriptions of sample preparation and the study protocol are provided. PMID- 27768051 TI - An Optimized Protocol for the Efficient Radiolabeling of Gold Nanoparticles by Using a 125I-labeled Azide Prosthetic Group. AB - Here, we demonstrate a detailed protocol for the radiosynthesis of a 125I-labeled azide prosthetic group and its application to the efficient radiolabeling of DBCO group-functionalized gold nanoparticles using a copper-free click reaction. Radioiodination of the stannylated precursor (2) was carried out by using [125I]NaI and chloramine T as an oxidant at room temperature for 15 min. After HPLC purification of the crude product, the purified 125I-labeled azide (1) was obtained with high radiochemical yield (75 +/- 10%, n = 8) and excellent radiochemical purity (>99%). For the synthesis of radiolabeled 13-nm-sized gold nanoparticles, the DBCO-functionalized gold nanoparticles (3) were prepared by using a thiolated polyethylene glycol polymer. A copper-free click reaction between 1 and 3 gave the 125I-labeled gold nanoparticles (4) with more than 95% of radiochemical yield as determined by radio-thin-layer chromatography (radio TLC). These results clearly indicate that the present radiolabeling method using a strain-promoted copper-free click reaction will be useful for the efficient and convenient radiolabeling of DBCO-group-containing nanomaterials. PMID- 27768053 TI - An Alternative Approach for Sample Preparation with Low Cell Number for TEM Analysis. AB - Transmission electron microscopy (TEM) provides details of the cellular organization and ultrastructure. However, TEM analysis of rare cell populations, especially cells in suspension such as hematopoietic stem cells (HSCs), remains limited due to the requirement of a high cell number during sample preparation. There are a few cytospin or monolayer approaches for TEM analysis from scarce samples, but these approaches fail to get significant quantitative data from the limited number of cells. Here, an alternative and novel approach for sample preparation in TEM studies is described for rare cell populations that enables quantitative analysis. A relatively low cell number, i.e., 10,000 HSCs, was successfully used for TEM analysis compared to the millions of cells typically used for TEM studies. In particular, Evans blue staining was performed after paraformaldehyde-glutaraldehyde (PFA-GA) fixation to visualize the tiny cell pellet, which facilitated embedding in agarose. Clusters of numerous cells were observed in ultra-thin sections. The cells had a well preserved morphology, and the ultra-structural details of the Golgi complex and several mitochondria were visible. This efficient, easy and reproducible protocol allows sample preparation from a low cell number and can be used for qualitative and quantitative TEM analysis on rare cell populations from limited biological samples. PMID- 27768054 TI - Novel RNA-Binding Proteins Isolation by the RaPID Methodology. AB - RNA-binding proteins (RBPs) play important roles in every aspect of RNA metabolism and regulation. Their identification is a major challenge in modern biology. Only a few in vitro and in vivo methods enable the identification of RBPs associated with a particular target mRNA. However, their main limitations are the identification of RBPs in a non-cellular environment (in vitro) or the low efficiency isolation of RNA of interest (in vivo). An RNA-binding protein purification and identification (RaPID) methodology was designed to overcome these limitations in yeast and enable efficient isolation of proteins that are associated in vivo. To achieve this, the RNA of interest is tagged with MS2 loops, and co-expressed with a fusion protein of an MS2-binding protein and a streptavidin-binding protein (SBP). Cells are then subjected to crosslinking and lysed, and complexes are isolated through streptavidin beads. The proteins that co-purify with the tagged RNA can then be determined by mass spectrometry. We recently used this protocol to identify novel proteins associated with the ER associated PMP1 mRNA. Here, we provide a detailed protocol of RaPID, and discuss some of its limitations and advantages. PMID- 27768056 TI - Safety Precautions and Operating Procedures in an (A)BSL-4 Laboratory: 4. Medical Imaging Procedures. AB - Medical imaging using animal models for human diseases has been utilized for decades; however, until recently, medical imaging of diseases induced by high consequence pathogens has not been possible. In 2014, the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Integrated Research Facility at Fort Detrick opened an Animal Biosafety Level 4 (ABSL-4) facility to assess the clinical course and pathology of infectious diseases in experimentally infected animals. Multiple imaging modalities including computed tomography (CT), magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography are available to researchers for these evaluations. The focus of this article is to describe the workflow for safely obtaining a CT image of a live guinea pig in an ABSL-4 facility. These procedures include animal handling, anesthesia, and preparing and monitoring the animal until recovery from sedation. We will also discuss preparing the imaging equipment, performing quality checks, communication methods from "hot side" (containing pathogens) to "cold side," and moving the animal from the holding room to the imaging suite. PMID- 27768055 TI - Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart. AB - The mammalian heart is a major consumer of ATP and requires a constant supply of energy substrates for contraction. Not surprisingly, alterations of myocardial metabolism have been linked to the development of contractile dysfunction and heart failure. Therefore, unraveling the link between metabolism and contraction should shed light on some of the mechanisms governing cardiac adaptation or maladaptation in disease states. The isolated working rat heart preparation can be used to follow, simultaneously and in real time, cardiac contractile function and flux of energy providing substrates into oxidative metabolic pathways. The present protocol aims to provide a detailed description of the methods used in the preparation and utilization of buffers for the quantitative measurement of the rates of oxidation for glucose and fatty acids, the main energy providing substrates of the heart. The methods used for sample analysis and data interpretation are also discussed. In brief, the technique is based on the supply of 14C- radiolabeled glucose and a 3H- radiolabeled long-chain fatty acid to an ex vivo beating heart via normothermic crystalloid perfusion. 14CO2 and 3H2O, end byproducts of the enzymatic reactions involved in the utilization of these energy providing substrates, are then quantitatively recovered from the coronary effluent. With knowledge of the specific activity of the radiolabeled substrates used, it is then possible to individually quantitate the flux of glucose and fatty acid in the oxidation pathways. Contractile function of the isolated heart can be determined in parallel with the appropriate recording equipment and directly correlated to metabolic flux values. The technique is extremely useful to study the metabolism/contraction relationship in response to various stress conditions such as alterations in pre and after load and ischemia, a drug or a circulating factor, or following the alteration in the expression of a gene product. PMID- 27768058 TI - Methodologies for Studying B. subtilis Biofilms as a Model for Characterizing Small Molecule Biofilm Inhibitors. AB - This work assesses different methodologies to study the impact of small molecule biofilm inhibitors, such as D-amino acids, on the development and resilience of Bacillus subtilis biofilms. First, methods are presented that select for small molecule inhibitors with biofilm-specific targets in order to separate the effect of the small molecule inhibitors on planktonic growth from their effect on biofilm formation. Next, we focus on how inoculation conditions affect the sensitivity of multicellular, floating B. subtilis cultures to small molecule inhibitors. The results suggest that discrepancies in the reported effects of such inhibitors such as D-amino acids are due to inconsistent pre-culture conditions. Furthermore, a recently developed protocol is described for evaluating the contribution of small molecule treatments towards biofilm resistance to antibacterial substances. Lastly, scanning electron microscopy (SEM) techniques are presented to analyze the three-dimensional spatial arrangement of cells and their surrounding extracellular matrix in a B. subtilis biofilm. SEM facilitates insight into the three-dimensional biofilm architecture and the matrix texture. A combination of the methods described here can greatly assist the study of biofilm development in the presence and absence of biofilm inhibitors, and shed light on the mechanism of action of these inhibitors. PMID- 27768057 TI - Light-mediated Formation and Patterning of Hydrogels for Cell Culture Applications. AB - Click chemistries have been investigated for use in numerous biomaterials applications, including drug delivery, tissue engineering, and cell culture. In particular, light-mediated click reactions, such as photoinitiated thiol-ene and thiol-yne reactions, afford spatiotemporal control over material properties and allow the design of systems with a high degree of user-directed property control. Fabrication and modification of hydrogel-based biomaterials using the precision afforded by light and the versatility offered by these thiol-X photoclick chemistries are of growing interest, particularly for the culture of cells within well-defined, biomimetic microenvironments. Here, we describe methods for the photoencapsulation of cells and subsequent photopatterning of biochemical cues within hydrogel matrices using versatile and modular building blocks polymerized by a thiol-ene photoclick reaction. Specifically, an approach is presented for constructing hydrogels from allyloxycarbonyl (Alloc)-functionalized peptide crosslinks and pendant peptide moieties and thiol-functionalized poly(ethylene glycol) (PEG) that rapidly polymerize in the presence of lithium acylphosphinate photoinitiator and cytocompatible doses of long wavelength ultraviolet (UV) light. Facile techniques to visualize photopatterning and quantify the concentration of peptides added are described. Additionally, methods are established for encapsulating cells, specifically human mesenchymal stem cells, and determining their viability and activity. While the formation and initial patterning of thiol-alloc hydrogels are shown here, these techniques broadly may be applied to a number of other light and radical-initiated material systems (e.g., thiol-norbornene, thiol-acrylate) to generate patterned substrates. PMID- 27768059 TI - Determination of the Relative Cell Surface and Total Expression of Recombinant Ion Channels Using Flow Cytometry. AB - Inherited or de novo mutations in cation-selective channels may lead to sudden cardiac death. Alteration in the plasma membrane trafficking of these multi spanning transmembrane proteins, with or without change in channel gating, is often postulated to contribute significantly in this process. It has thus become critical to develop a method to quantify the change of the relative cell surface expression of cardiac ion channels on a large scale. Herein, a detailed protocol is provided to determine the relative total and cell surface expression of cardiac L-type calcium channels CaV1.2 and membrane-associated subunits in tsA 201 cells using two-color fluorescent cytometry assays. Compared with other microscopy-based or immunoblotting-based qualitative methods, flow cytometry experiments are fast, reproducible, and large-volume assays that deliver quantifiable end-points on large samples of live cells (ranging from 104 to 106 cells) with similar cellular characteristics in a single flow. Constructs were designed to constitutively express mCherry at the intracellular C-terminus (thus allowing a rapid assessment of the total protein expression) and express an extracellular-facing hemagglutinin (HA) epitope to estimate the cell surface expression of membrane proteins using an anti-HA fluorescence conjugated antibody. To avoid false negative, experiments were also conducted in permeabilized cells to confirm the accessibility and proper expression of the HA epitope. The detailed procedure provides: (1) design of tagged DNA (deoxyribonucleic acid) constructs, (2) lipid-mediated transfection of constructs in tsA-201 cells, (3) culture, harvest, and staining of non-permeabilized and permeabilized cells, and (4) acquisition and analysis of fluorescent signals. Additionally, the basic principles of flow cytometry are explained and the experimental design, including the choice of fluorophores, titration of the HA antibody and control experiments, is thoroughly discussed. This specific approach offers objective relative quantification of the total and cell surface expression of ion channels that can be extended to study ion pumps and plasma membrane transporters. PMID- 27768060 TI - Imaging Cleared Embryonic and Postnatal Hearts at Single-cell Resolution. AB - Single clonal tracing and analysis at the whole-heart level can determine cardiac progenitor cell behavior and differentiation during cardiac development, and allow for the study of the cellular and molecular basis of normal and abnormal cardiac morphogenesis. Recent emerging technologies of retrospective single clonal analyses make the study of cardiac morphogenesis at single cell resolution feasible. However, tissue opacity and light scattering of the heart as imaging depth is increased hinder whole-heart imaging at single cell resolution. To overcome these obstacles, a whole-embryo clearing system that can render the heart highly transparent for both illumination and detection must be developed. Fortunately, in the last several years, many methodologies for whole-organism clearing systems such as CLARITY, Scale, SeeDB, ClearT, 3DISCO, CUBIC, DBE, BABB and PACT have been reported. This lab is interested in the cellular and molecular mechanisms of cardiac morphogenesis. Recently, we established single cell lineage tracing via the ROSA26-CreERT2; ROSA26-Confetti system to sparsely label cells during cardiac development. We adapted several whole embryo-clearing methodologies including Scale and CUBIC (clear, unobstructed brain imaging cocktails and computational analysis) to clear the embryo in combination with whole mount staining to image single clones inside the heart. The heart was successfully imaged at single cell resolution. We found that Scale can clear the embryonic heart, but cannot effectively clear the postnatal heart, while CUBIC can clear the postnatal heart, but damages the embryonic heart by dissolving the tissue. The methods described here will permit the study of gene function at a single clone resolution during cardiac morphogenesis, which, in turn, can reveal the cellular and molecular basis of congenital heart defects. PMID- 27768061 TI - Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts. AB - Human signal transducer and activator of transcription 3 (STAT3) is one of many genes containing a tandem splicing site. Alternative donor splice sites 3 nucleotides apart result in either the inclusion (S) or exclusion (DeltaS) of a single residue, Serine-701. Further downstream, splicing at a pair of alternative acceptor splice sites result in transcripts encoding either the 55 terminal residues of the transactivation domain (alpha) or a truncated transactivation domain with 7 unique residues (beta). As outlined in this manuscript, measuring the proportions of STAT3's four spliced transcripts (Salpha, Sbeta, DeltaSalpha and DeltaSbeta) was possible using absolute qPCR (quantitative polymerase chain reaction). The protocol therefore distinguishes and measures highly similar splice variants. Absolute qPCR makes use of calibrator plasmids and thus specificity of detection is not compromised for the sake of efficiency. The protocol necessitates primer validation and optimization of cycling parameters. A combination of absolute qPCR and efficiency-dependent relative qPCR of total STAT3 transcripts allowed a description of the fluctuations of STAT3 splice variants' levels in eosinophils treated with cytokines. The protocol also provided evidence of a co-splicing interdependence between the two STAT3 splicing events. The strategy based on a combination of the two qPCR techniques should be readily adaptable to investigation of co-splicing at other tandem splicing sites. PMID- 27768063 TI - Safety Precautions and Operating Procedures in an (A)BSL-4 Laboratory: 1. Biosafety Level 4 Suit Laboratory Suite Entry and Exit Procedures. AB - Biosafety level 4 (BSL-4) suit laboratories are specifically designed to study high-consequence pathogens for which neither infection prophylaxes nor treatment options exist. The hallmarks of these laboratories are: custom-designed airtight doors, dedicated supply and exhaust airflow systems, a negative-pressure environment, and mandatory use of positive-pressure ("space") suits. The risk for laboratory specialists working with highly pathogenic agents is minimized through rigorous training and adherence to stringent safety protocols and standard operating procedures. Researchers perform the majority of their work in BSL-2 laboratories and switch to BSL-4 suit laboratories when work with a high consequence pathogen is required. Collaborators and scientists considering BSL-4 projects should be aware of the challenges associated with BSL-4 research both in terms of experimental technical limitations in BSL-4 laboratory space and the increased duration of such experiments. Tasks such as entering and exiting the BSL-4 suit laboratories are considerably more complex and time-consuming compared to BSL-2 and BSL-3 laboratories. The focus of this particular article is to address basic biosafety concerns and describe the entrance and exit procedures for the BSL-4 laboratory at the NIH/NIAID Integrated Research Facility at Fort Detrick. Such procedures include checking external systems that support the BSL-4 laboratory, and inspecting and donning positive-pressure suits, entering the laboratory, moving through air pressure-resistant doors, and connecting to air supply hoses. We will also discuss moving within and exiting the BSL-4 suit laboratories, including using the chemical shower and removing and storing positive-pressure suits. PMID- 27768062 TI - Establishment of Cancer Stem Cell Cultures from Human Conventional Osteosarcoma. AB - The current improvements in therapy against osteosarcoma (OS) have prolonged the lives of cancer patients, but the survival rate of five years remains poor when metastasis has occurred. The Cancer Stem Cell (CSC) theory holds that there is a subset of tumor cells within the tumor that have stem-like characteristics, including the capacity to maintain the tumor and to resist multidrug chemotherapy. Therefore, a better understanding of OS biology and pathogenesis is needed in order to advance the development of targeted therapies to eradicate this particular subset and to reduce morbidity and mortality among patients. Isolating CSCs, establishing cell cultures of CSCs, and studying their biology are important steps to improving our understanding of OS biology and pathogenesis. The establishment of human-derived OS-CSCs from biopsies of OS has been made possible using several methods, including the capacity to create 3 dimensional stem cell cultures under nonadherent conditions. Under these conditions, CSCs are able to create spherical floating colonies formed by daughter stem cells; these colonies are termed "cellular spheres". Here, we describe a method to establish CSC cultures from primary cell cultures of conventional OS obtained from OS biopsies. We clearly describe the several passages required to isolate and characterize CSCs. PMID- 27768065 TI - Design and Use of a Low Cost, Automated Morbidostat for Adaptive Evolution of Bacteria Under Antibiotic Drug Selection. AB - We describe a low cost, configurable morbidostat for characterizing the evolutionary pathway of antibiotic resistance. The morbidostat is a bacterial culture device that continuously monitors bacterial growth and dynamically adjusts the drug concentration to constantly challenge the bacteria as they evolve to acquire drug resistance. The device features a working volume of ~10 ml and is fully automated and equipped with optical density measurement and micro pumps for medium and drug delivery. To validate the platform, we measured the stepwise acquisition of trimethoprim resistance in Escherichia coli MG 1655, and integrated the device with a multiplexed microfluidic platform to investigate cell morphology and antibiotic susceptibility. The approach can be up-scaled to laboratory studies of antibiotic drug resistance, and is extendible to adaptive evolution for strain improvements in metabolic engineering and other bacterial culture experiments. PMID- 27768064 TI - Applications of In Vivo Functional Testing of the Rat Tibialis Anterior for Evaluating Tissue Engineered Skeletal Muscle Repair. AB - Despite the regenerative capacity of skeletal muscle, permanent functional and/or cosmetic deficits (e.g., volumetric muscle loss (VML) resulting from traumatic injury, disease and various congenital, genetic and acquired conditions are quite common. Tissue engineering and regenerative medicine technologies have enormous potential to provide a therapeutic solution. However, utilization of biologically relevant animal models in combination with longitudinal assessments of pertinent functional measures are critical to the development of improved regenerative therapeutics for treatment of VML-like injuries. In that regard, a commercial muscle lever system can be used to measure length, tension, force and velocity parameters in skeletal muscle. We used this system, in conjunction with a high power, bi-phase stimulator, to measure in vivo force production in response to activation of the anterior crural compartment of the rat hindlimb. We have previously used this equipment to assess the functional impact of VML injury on the tibialis anterior (TA) muscle, as well as the extent of functional recovery following treatment of the injured TA muscle with our tissue engineered muscle repair (TEMR) technology. For such studies, the left foot of an anaesthetized rat is securely anchored to a footplate linked to a servomotor, and the common peroneal nerve is stimulated by two percutaneous needle electrodes to elicit muscle contraction and dorsiflexion of the foot. The peroneal nerve stimulation induced muscle contraction is measured over a range of stimulation frequencies (1 200 Hz), to ensure an eventual plateau in force production that allows for an accurate determination of peak tetanic force. In addition to evaluation of the extent of VML injury as well as the degree of functional recovery following treatment, this methodology can be easily applied to study diverse aspects of muscle physiology and pathophysiology. Such an approach should assist with the more rational development of improved therapeutics for muscle repair and regeneration. PMID- 27768066 TI - Long-term High-Resolution Intravital Microscopy in the Lung with a Vacuum Stabilized Imaging Window. AB - Metastasis to secondary sites such as the lung, liver and bone is a traumatic event with a mortality rate of approximately 90% 1. Of these sites, the lung is the most difficult to assess using intravital optical imaging due to its enclosed position within the body, delicate nature and vital role in sustaining proper physiology. While clinical modalities (positron emission tomography (PET), magnetic resonance imaging (MRI) and computed tomography (CT)) are capable of providing noninvasive images of this tissue, they lack the resolution necessary to visualize the earliest seeding events, with a single pixel consisting of nearly a thousand cells. Current models of metastatic lung seeding postulate that events just after a tumor cell's arrival are deterministic for survival and subsequent growth. This means that real-time intravital imaging tools with single cell resolution 2 are required in order to define the phenotypes of the seeding cells and test these models. While high resolution optical imaging of the lung has been performed using various ex vivo preparations, these experiments are typically single time-point assays and are susceptible to artifacts and possible erroneous conclusions due to the dramatically altered environment (temperature, profusion, cytokines, etc.) resulting from removal from the chest cavity and circulatory system 3. Recent work has shown that time-lapse intravital optical imaging of the intact lung is possible using a vacuum stabilized imaging window 2,4,5 however, typical imaging times have been limited to approximately 6 hr. Here we describe a protocol for performing long-term intravital time-lapse imaging of the lung utilizing such a window over a period of 12 hr. The time lapse image sequences obtained using this method enable visualization and quantitation of cell-cell interactions, membrane dynamics and vascular perfusion in the lung. We further describe an image processing technique that gives an unprecedentedly clear view of the lung microvasculature. PMID- 27768067 TI - Highly Sensitive and Rapid Fluorescence Detection with a Portable FRET Analyzer. AB - Recent improvements in Forster resonance energy transfer (FRET) sensors have enabled their use to detect various small molecules including ions and amino acids. However, the innate weak signal intensity of FRET sensors is a major challenge that prevents their application in various fields and makes the use of expensive, high-end fluorometers necessary. Previously, we built a cost effective, high-performance FRET analyzer that can specifically measure the ratio of two emission wavelength bands (530 and 480 nm) to achieve high detection sensitivity. More recently, it was discovered that FRET sensors with bacterial periplasmic binding proteins detect ligands with maximum sensitivity in the critical temperature range of 50 - 55 degrees C. This report describes a protocol for assessing sugar content in commercially-available beverage samples using our portable FRET analyzer with a temperature-specific FRET sensor. Our results showed that the additional preheating process of the FRET sensor significantly increases the FRET ratio signal, to enable more accurate measurement of sugar content. The custom-made FRET analyzer and sensor were successfully applied to quantify the sugar content in three types of commercial beverages. We anticipate that further size reduction and performance enhancement of the equipment will facilitate the use of hand-held analyzers in environments where high-end equipment is not available. PMID- 27768068 TI - Laser-assisted Cytoplasmic Microinjection in Livestock Zygotes. AB - Cytoplasmic microinjection into one-cell embryos is a very powerful technique. As an example, it enables the delivery of genome editing tools that can create genetic modifications that will be present in every cell of an adult organism. It can also be used to deliver siRNA, mRNAs or blocking antibodies to study gene function in preimplantation embryos. The conventional technique for microinjecting embryos used in rodents consists of a very thin micropipette that directly penetrates the plasma membrane when advanced into the embryo. When this technique is applied to livestock animals it usually results in low efficiency. This is mainly because in contrast to mice and rats, bovine, ovine, and porcine zygotes have a very dark cytoplasm and a highly elastic plasma membrane that makes visualization during injection and penetration of the plasma membrane hard to achieve. In this protocol, we describe a suitable microinjection method for the delivery of solutions into the cytoplasm of cattle zygotes that has proved to be successful for sheep and pig embryos as well. First, a laser is used to create a hole in the zona pellucida. Then a blunt-end glass micropipette is introduced through the hole and advanced until the tip of the needle reaches about 3/4 into the embryo. Then, the plasma membrane is broken by aspiration of cytoplasmic content inside the needle. Finally, the aspirated cytoplasmic content followed by the solution of interest is injected back into the embryonic cytoplasm. This protocol has been successfully used for the delivery of different solutions into bovine and ovine zygotes with 100% efficiency, minimal lysis, and normal blastocysts development rates. PMID- 27768069 TI - A Repetitive Concussive Head Injury Model in Mice. AB - Despite the concussion/ mild traumatic brain injury (mTBI) being the most frequent occurrence of traumatic brain injury, there is still a lack of knowledge on the injury and its effects. To develop a better understanding of concussions, animals are often used because they provide a controlled, rigorous, and efficient model. Studies have adapted traditional animal models to perform mTBI to stimulate mild injury severity by changing the injury parameters. These models have been used because they can produce morphologically similar brain injuries to the clinical condition and provide a spectrum of injury severities. However, they are limited in their ability to present the identical features of injuries in patients. Using a traditional impact system, a repetitive concussive injury (rCHI) model can induce mild to moderate human-like concussion. The injury degree can be determined by measuring the period of loss of consciousness (LOC) with a sign of a transient termination of breathing. The rCHI model is beneficial to use for its accuracy and simplicity in determining mTBI effects and potential treatments. PMID- 27768070 TI - Establishment of a Segmental Femoral Critical-size Defect Model in Mice Stabilized by Plate Osteosynthesis. AB - The use of tissue-engineered bone constructs is an appealing strategy to overcome drawbacks of autografts for the treatment of massive bone defects. As a model organism, the mouse has already been widely used in bone-related research. Large diaphyseal bone defect models in mice, however, are sparse and often use bone fixation which fills the bone marrow cavity and does not provide optimal mechanical stability. The objectives of the current study were to develop a critical-size, segmental, femoral defect in nude mice. A 3.5-mm mid-diaphyseal femoral ostectomy (approximately 25% of the femur length) was performed using a dedicated jig, and was stabilized with an anterior located locking plate and 4 locking screws. The bone defect was subsequently either left empty or filled with a bone substitute (syngenic bone graft or coralline scaffold). Bone healing was monitored noninvasively using radiography and in vivo micro-computed-tomography and was subsequently assessed by ex vivo micro-computed-tomography and undecalcified histology after animal sacrifice, 10 weeks postoperatively. The recovery of all mice was excellent, a full-weight-bearing was observed within one day following the surgical procedure. Furthermore, stable bone fixation and consistent fixation of the implanted materials were achieved in all animals tested throughout the study. When the bone defects were left empty, non-union was consistently obtained. In contrast, when the bone defects were filled with syngenic bone grafts, bone union was always observed. When the bone defects were filled with coralline scaffolds, newly-formed bone was observed in the interface between bone resection edges and the scaffold, as well as within a short distance within the scaffold. The present model describes a reproducible critical-size femoral defect stabilized by plate osteosynthesis with low morbidity in mice. The new load-bearing segmental bone defect model could be useful for studying the underlying mechanisms in bone regeneration pertinent to orthopaedic applications. PMID- 27768071 TI - A CFSE-based Assay to Study the Migration of Murine Skin Dendritic Cells into Draining Lymph Nodes During Infection with Mycobacterium bovis Bacille Calmette Guerin. AB - Dendritic cells (DCs) are important for initiating immune responses, in part through their ability to acquire and shuttle antigen to the draining lymph node (DLN). The mobilization of DCs to the DLN is complex and remains to be fully elucidated during infection. Herein described is the use of an innovative, simple assay that relies on the fluorochrome 5- and 6-carboxyfluorescein diacetate succinimidyl ester (CFSE) to track the migration of DCs during footpad infection with Mycobacterium bovis Bacille Calmette-Guerin (BCG) in C57BL/6 mice. This assay enables the characterization of skin DC sub-populations that actively relocate to the draining, popliteal LN in response to BCG. This protocol originates from a BCG model where migratory skin DCs were identified by flow cytometry. The assay is amiable to the study and identification of DCs or other cells that home to the popliteal LN after inoculation of microbes, their metabolites or other inflammatory stimuli in the footpad, and consequently to study factors that regulate the migration of these cells. PMID- 27768072 TI - Rapid High-throughput Species Identification of Botanical Material Using Direct Analysis in Real Time High Resolution Mass Spectrometry. AB - We demonstrate that direct analysis in real time-high resolution mass spectrometry can be used to produce mass spectral profiles of botanical material, and that these chemical fingerprints can be used for plant species identification. The mass spectral data can be acquired rapidly and in a high throughput manner without the need for sample extraction, derivatization or pH adjustment steps. The use of this technique bypasses challenges presented by more conventional techniques including lengthy chromatography analysis times and resource intensive methods. The high throughput capabilities of the direct analysis in real time-high resolution mass spectrometry protocol, coupled with multivariate statistical analysis processing of the data, provide not only class characterization of plants, but also yield species and varietal information. Here, the technique is demonstrated with two psychoactive plant products, Mitragyna speciosa (Kratom) and Datura (Jimsonweed), which were subjected to direct analysis in real time-high resolution mass spectrometry followed by statistical analysis processing of the mass spectral data. The application of these tools in tandem enabled the plant materials to be rapidly identified at the level of variety and species. PMID- 27768073 TI - Sheathless Capillary Electrophoresis-Mass Spectrometry for Metabolic Profiling of Biological Samples. AB - In metabolomics, a wide range of analytical techniques is used for the global profiling of (endogenous) metabolites in complex samples. In this paper, a protocol is presented for the analysis of anionic and cationic metabolites in biological samples by capillary electrophoresis-mass spectrometry (CE-MS). CE is well-suited for the analysis of highly polar and charged metabolites as compounds are separated on the basis of their charge-to-size ratio. A recently developed sheathless interfacing design, i.e., a porous tip interface, is used for coupling CE to electrospray ionization (ESI) MS. This interfacing approach allows the effective use of the intrinsically low-flow property of CE in combination with MS, resulting in nanomolar detection limits for a broad range of polar metabolite classes. The protocol presented here is based on employing a bare fused-silica capillary with a porous tip emitter at low-pH separation conditions for the analysis of a broad array of metabolite classes in biological samples. It is demonstrated that the same sheathless CE-MS method can be used for the profiling of cationic metabolites, including amino acids, nucleosides and small peptides, or anionic metabolites, including sugar phosphates, nucleotides and organic acids, by only switching the MS detection and separation voltage polarity. Highly information-rich metabolic profiles in various biological samples, such as urine, cerebrospinal fluid and extracts of the glioblastoma cell line, can be obtained by this protocol in less than 1 hr of CE-MS analysis. PMID- 27768074 TI - Enumeration of Neural Stem Cells Using Clonal Assays. AB - Neural stem cells (NSCs) have the ability to self-renew and generate the three major neural lineages - astrocytes, neurons and oligodendrocytes. NSCs and neural progenitors (NPs) are commonly cultured in vitro as neurospheres. This protocol describes in detail how to determine the NSC frequency in a given cell population under clonal conditions. The protocol begins with the seeding of the cells at a density that allows for the generation of clonal neurospheres. The neurospheres are then transferred to chambered coverslips and differentiated under clonal conditions in conditioned medium, which maximizes the differentiation potential of the neurospheres. Finally, the NSC frequency is calculated based on neurosphere formation and multipotency capabilities. Utilities of this protocol include the evaluation of candidate NSC markers, purification of NSCs, and the ability to distinguish NSCs from NPs. This method takes 13 days to perform, which is much shorter than current methods to enumerate NSC frequency. PMID- 27768075 TI - Combustion Characterization and Model Fuel Development for Micro-tubular Flame assisted Fuel Cells. AB - Combustion based power generation has been accomplished for many years through a number of heat engine systems. Recently, a move towards small scale power generation and micro combustion as well as development in fuel cell research has created new means of power generation that combine solid oxide fuel cells with open flames and combustion exhaust. Instead of relying upon the heat of combustion, these solid oxide fuel cell systems rely on reforming of the fuel via combustion to generate syngas for electrochemical power generation. Procedures were developed to assess the combustion by-products under a wide range of conditions. While theoretical and computational procedures have been developed for assessing fuel-rich combustion exhaust in these applications, experimental techniques have also emerged. The experimental procedures often rely upon a gas chromatograph or mass spectrometer analysis of the flame and exhaust to assess the combustion process as a fuel reformer and means of heat generation. The experimental techniques developed in these areas have been applied anew for the development of the micro-tubular flame-assisted fuel cell. The protocol discussed in this work builds on past techniques to specify a procedure for characterizing fuel-rich combustion exhaust and developing a model fuel-rich combustion exhaust for use in flame-assisted fuel cell testing. The development of the procedure and its applications and limitations are discussed. PMID- 27768076 TI - Measurement of X-ray Beam Coherence along Multiple Directions Using 2-D Checkerboard Phase Grating. AB - A procedure for a technique to measure the transverse coherence of synchrotron radiation X-ray sources using a single phase grating interferometer is reported. The measurements were demonstrated at the 1-BM bending magnet beamline of the Advanced Photon Source (APS) at Argonne National Laboratory (ANL). By using a 2-D checkerboard pi/2 phase-shift grating, transverse coherence lengths were obtained along the vertical and horizontal directions as well as along the 45 degrees and 135 degrees directions to the horizontal direction. Following the technical details specified in this paper, interferograms were measured at different positions downstream of the phase grating along the beam propagation direction. Visibility values of each interferogram were extracted from analyzing harmonic peaks in its Fourier Transformed image. Consequently, the coherence length along each direction can be extracted from the evolution of visibility as a function of the grating-to-detector distance. The simultaneous measurement of coherence lengths in four directions helped identify the elliptical shape of the coherence area of the Gaussian-shaped X-ray source. The reported technique for multiple direction coherence characterization is important for selecting the appropriate sample size and orientation as well as for correcting the partial coherence effects in coherence scattering experiments. This technique can also be applied for assessing coherence preserving capabilities of X-ray optics. PMID- 27768077 TI - The Use of Induced Somatic Sector Analysis (ISSA) for Studying Genes and Promoters Involved in Wood Formation and Secondary Stem Development. AB - Secondary stem growth in trees and associated wood formation are significant both from biological and commercial perspectives. However, relatively little is known about the molecular control that governs their development. This is in part due to physical, resource and time limitations often associated with the study of secondary growth processes. A number of in vitro techniques have been used involving either plant part or whole plant system in both woody and non-woody plant species. However, questions about their applicability for the study of secondary stem growth processes, the recalcitrance of certain species and labor intensity are often prohibitive for medium to high throughput applications. Also, when looking at secondary stem development and wood formation the specific traits under investigation might only become measurable late in a tree's lifecycle after several years of growth. In addressing these challenges alternative in vivo protocols have been developed, named Induced Somatic Sector Analysis, which involve the creation of transgenic somatic tissue sectors directly in the plant's secondary stem. The aim of this protocol is to provide an efficient, easy and relatively fast means to create transgenic secondary plant tissue for gene and promoter functional characterization that can be utilized in a range of tree species. Results presented here show that transgenic secondary stem sectors can be created in all live tissues and cell types in secondary stems of a variety of tree species and that wood morphological traits as well as promoter expression patterns in secondary stems can be readily assessed facilitating medium to high throughput functional characterization. PMID- 27768078 TI - Manufacture and Drug Delivery Applications of Silk Nanoparticles. AB - Silk is a promising biopolymer for biomedical and pharmaceutical applications due to its outstanding mechanical properties, biocompatibility and biodegradability, as well its ability to protect and subsequently release its payload in response to a trigger. While silk can be formulated into various material formats, silk nanoparticles are emerging as promising drug delivery systems. Therefore, this article covers the procedures for reverse engineering silk cocoons to yield a regenerated silk solution that can be used to generate stable silk nanoparticles. These nanoparticles are subsequently characterized, drug loaded and explored as a potential anticancer drug delivery system. Briefly, silk cocoons are reverse engineered first by degumming the cocoons, followed by silk dissolution and clean up, to yield an aqueous silk solution. Next, the regenerated silk solution is subjected to nanoprecipitation to yield silk nanoparticles - a simple but powerful method that generates uniform nanoparticles. The silk nanoparticles are characterized according to their size, zeta potential, morphology and stability in aqueous media, as well as their ability to entrap a chemotherapeutic payload and kill human breast cancer cells. Overall, the described methodology yields uniform silk nanoparticles that can be readily explored for a myriad of applications, including their use as a potential nanomedicine. PMID- 27768079 TI - Exergaming in Older People Living with HIV Improves Balance, Mobility and Ameliorates Some Aspects of Frailty. AB - Approximately 1.2 million people in the United States live with HIV infection. Medical advancements have increased the life expectancy and this cohort is aging. HIV-positive individuals have a high incidence of frailty (~20%) characterized by depression and sedentary behavior. Exercise would be healthy, but due to the frail status of many HIV-positive individuals, conventional exercise is too taxing. The aim of this study was to evaluate the effectiveness and acceptability of a novel game-based training program (exergame) in ameliorating some aspects of frailty in HIV-infected individuals. Ten older people living with HIV were enrolled in an exergame intervention. Patients performed balance exercises such as weight shifting, ankle reaching, and obstacle crossing. Real-time visual/audio lower-extremity joint motion feedback was provided using wearable sensors to assist feedback and encourage subjects to accurately execute each exercise task. Patients trained twice a week for 45 min for 6 weeks. Changes in balance, gait, psychosocial parameters and quality of life parameters were assessed at the beginning, midterm and at conclusion of the training program. Ten patients completed the study and their results analyzed. The mean age was 57.2 +/- 9.2 years. The participants showed a significant reduction in center of mass sway (78.2%, p = .045) during the semi-tandem balance stance with eyes closed and showed a significant increase in gait speed during a dual task motor-cognitive assessment (9.3%, p = .048) with an increase in stride velocity of over 0.1 m/sec. A significant reduction in reported pain occurred (43.5%, p = .041). Preliminary results of this exergame intervention show promise in improving balance and mobility while requiring older people living with HIV to be more active. The exergame can be continued at home and may have long term as well as short-term benefits for ameliorating frailty associated with HIV infection. PMID- 27768080 TI - Integrating Remote Sensing with Species Distribution Models; Mapping Tamarisk Invasions Using the Software for Assisted Habitat Modeling (SAHM). AB - Early detection of invasive plant species is vital for the management of natural resources and protection of ecosystem processes. The use of satellite remote sensing for mapping the distribution of invasive plants is becoming more common, however conventional imaging software and classification methods have been shown to be unreliable. In this study, we test and evaluate the use of five species distribution model techniques fit with satellite remote sensing data to map invasive tamarisk (Tamarix spp.) along the Arkansas River in Southeastern Colorado. The models tested included boosted regression trees (BRT), Random Forest (RF), multivariate adaptive regression splines (MARS), generalized linear model (GLM), and Maxent. These analyses were conducted using a newly developed software package called the Software for Assisted Habitat Modeling (SAHM). All models were trained with 499 presence points, 10,000 pseudo-absence points, and predictor variables acquired from the Landsat 5 Thematic Mapper (TM) sensor over an eight-month period to distinguish tamarisk from native riparian vegetation using detection of phenological differences. From the Landsat scenes, we used individual bands and calculated Normalized Difference Vegetation Index (NDVI), Soil-Adjusted Vegetation Index (SAVI), and tasseled capped transformations. All five models identified current tamarisk distribution on the landscape successfully based on threshold independent and threshold dependent evaluation metrics with independent location data. To account for model specific differences, we produced an ensemble of all five models with map output highlighting areas of agreement and areas of uncertainty. Our results demonstrate the usefulness of species distribution models in analyzing remotely sensed data and the utility of ensemble mapping, and showcase the capability of SAHM in pre processing and executing multiple complex models. PMID- 27768081 TI - Safety Precautions and Operating Procedures in an (A)BSL-4 Laboratory: 2. General Practices. AB - Work in a biosafety level 4 (BSL-4) containment laboratory requires time and great attention to detail. The same work that is done in a BSL-2 laboratory with non-high-consequence pathogens will take significantly longer in a BSL-4 setting. This increased time requirement is due to a multitude of factors that are aimed at protecting the researcher from laboratory-acquired infections, the work environment from potential contamination and the local community from possible release of high-consequence pathogens. Inside the laboratory, movement is restricted due to air hoses attached to the mandatory full-body safety suits. In addition, disinfection of every item that is removed from Class II biosafety cabinets (BSCs) is required. Laboratory specialists must be trained in the practices of the BSL-4 laboratory and must show high proficiency in the skills they are performing. The focus of this article is to outline proper procedures and techniques to ensure laboratory biosafety and experimental accuracy using a standard viral plaque assay as an example procedure. In particular, proper techniques to work safely in a BSL-4 environment when performing an experiment will be visually emphasized. These techniques include: setting up a Class II BSC for experiments, proper cleaning of the Class II BSC when finished working, waste management and safe disposal of waste generated inside a BSL-4 laboratory, and the removal of inactivated samples from inside a BSL-4 laboratory to the BSL-2 laboratory. PMID- 27768082 TI - The Drosophila Imaginal Disc Tumor Model: Visualization and Quantification of Gene Expression and Tumor Invasiveness Using Genetic Mosaics. AB - Drosophila melanogaster has emerged as a powerful experimental system for functional and mechanistic studies of tumor development and progression in the context of a whole organism. Sophisticated techniques to generate genetic mosaics facilitate induction of visually marked, genetically defined clones surrounded by normal tissue. The clones can be analyzed through diverse molecular, cellular and omics approaches. This study describes how to generate fluorescently labeled clonal tumors of varying malignancy in the eye/antennal imaginal discs (EAD) of Drosophila larvae using the Mosaic Analysis with a Repressible Cell Marker (MARCM) technique. It describes procedures how to recover the mosaic EAD and brain from the larvae and how to process them for simultaneous imaging of fluorescent transgenic reporters and antibody staining. To facilitate molecular characterization of the mosaic tissue, we describe a protocol for isolation of total RNA from the EAD. The dissection procedure is suitable to recover EAD and brains from any larval stage. The fixation and staining protocol for imaginal discs works with a number of transgenic reporters and antibodies that recognize Drosophila proteins. The protocol for RNA isolation can be applied to various larval organs, whole larvae, and adult flies. Total RNA can be used for profiling of gene expression changes using candidate or genome-wide approaches. Finally, we detail a method for quantifying invasiveness of the clonal tumors. Although this method has limited use, its underlying concept is broadly applicable to other quantitative studies where cognitive bias must be avoided. PMID- 27768083 TI - Synthesis of Cyclic Polymers and Characterization of Their Diffusive Motion in the Melt State at the Single Molecule Level. AB - We demonstrate a method for the synthesis of cyclic polymers and a protocol for characterizing their diffusive motion in a melt state at the single molecule level. An electrostatic self-assembly and covalent fixation (ESA-CF) process is used for the synthesis of the cyclic poly(tetrahydrofuran) (poly(THF)). The diffusive motion of individual cyclic polymer chains in a melt state is visualized using single molecule fluorescence imaging by incorporating a fluorophore unit in the cyclic chains. The diffusive motion of the chains is quantitatively characterized by means of a combination of mean-squared displacement (MSD) analysis and a cumulative distribution function (CDF) analysis. The cyclic polymer exhibits multiple-mode diffusion which is distinct from its linear counterpart. The results demonstrate that the diffusional heterogeneity of polymers that is often hidden behind ensemble averaging can be revealed by the efficient synthesis of the cyclic polymers using the ESA-CF process and the quantitative analysis of the diffusive motion at the single molecule level using the MSD and CDF analyses. PMID- 27768084 TI - Hand Controlled Manipulation of Single Molecules via a Scanning Probe Microscope with a 3D Virtual Reality Interface. AB - Considering organic molecules as the functional building blocks of future nanoscale technology, the question of how to arrange and assemble such building blocks in a bottom-up approach is still open. The scanning probe microscope (SPM) could be a tool of choice; however, SPM-based manipulation was until recently limited to two dimensions (2D). Binding the SPM tip to a molecule at a well defined position opens an opportunity of controlled manipulation in 3D space. Unfortunately, 3D manipulation is largely incompatible with the typical 2D paradigm of viewing and generating SPM data on a computer. For intuitive and efficient manipulation we therefore couple a low-temperature non-contact atomic force/scanning tunneling microscope (LT NC-AFM/STM) to a motion capture system and fully immersive virtual reality goggles. This setup permits "hand controlled manipulation" (HCM), in which the SPM tip is moved according to the motion of the experimenter's hand, while the tip trajectories as well as the response of the SPM junction are visualized in 3D. HCM paves the way to the development of complex manipulation protocols, potentially leading to a better fundamental understanding of nanoscale interactions acting between molecules on surfaces. Here we describe the setup and the steps needed to achieve successful hand controlled molecular manipulation within the virtual reality environment. PMID- 27768085 TI - Extraction of Structural Extracellular Polymeric Substances from Aerobic Granular Sludge. AB - To evaluate and develop methodologies for the extraction of gel-forming extracellular polymeric substances (EPS), EPS from aerobic granular sludge (AGS) was extracted using six different methods (centrifugation, sonication, ethylenediaminetetraacetic acid (EDTA), formamide with sodium hydroxide (NaOH), formaldehyde with NaOH and sodium carbonate (Na2CO3) with heat and constant mixing). AGS was collected from a pilot wastewater treatment reactor. The ionic gel-forming property of the extracted EPS of the six different extraction methods was tested with calcium ions (Ca2+). From the six extraction methods used, only the Na2CO3 extraction could solubilize the hydrogel matrix of AGS. The alginate like extracellular polymers (ALE) recovered with this method formed ionic gel beads with Ca2+. The Ca2+-ALE beads were stable in EDTA, formamide with NaOH and formaldehyde with NaOH, indicating that ALE are one part of the structural polymers in EPS. It is recommended to use an extraction method that combines physical and chemical treatment to solubilize AGS and extract structural EPS. PMID- 27768086 TI - A Non-invasive and Technically Non-intensive Method for Induction and Phenotyping of Experimental Bacterial Pneumonia in Mice. AB - Although community-acquired pneumonia remains a major public health problem, murine models of bacterial pneumonia have recently facilitated significant preclinical advances in our understanding of the underlying cellular and molecular pathogenesis. In vivo mouse models capture the integrated physiology and resilience of the host defense response in a manner not revealed by alternative, simplified ex vivo approaches. Several methods have been described in the literature for intrapulmonary inoculation of bacteria in mice, including aerosolization, intranasal delivery, peroral endotracheal cannulation under 'blind' and visualized conditions, and transcutaneous endotracheal cannulation. All methods have relative merits and limitations. Herein, we describe in detail a non-invasive, technically non-intensive, inexpensive, and rapid method for intratracheal delivery of bacteria that involves aspiration (i.e., inhalation) by the mouse of an infectious inoculum pipetted into the oropharynx while under general anesthesia. This method can be used for pulmonary delivery of a wide variety of non-caustic biological and chemical agents, and is relatively easy to learn, even for laboratories with minimal prior experience with pulmonary procedures. In addition to describing the aspiration pneumonia method, we also provide step-by-step procedures for assaying the subsequent in vivo pulmonary innate immune response of the mouse, in particular, methods for quantifying bacterial clearance and the cellular immune response of the infected airway. This integrated and simple approach to pneumonia assessment allows for rapid and robust evaluation of the effect of genetic and environmental manipulations upon pulmonary innate immunity. PMID- 27768087 TI - Delivery of Nucleic Acids through Embryo Microinjection in the Worldwide Agricultural Pest Insect, Ceratitis capitata. AB - The Mediterranean fruit fly (medfly) Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) is a pest species with extremely high agricultural relevance. This is due to its reproductive behavior: females damage the external surface of fruits and vegetables when they lay eggs and the hatched larvae feed on their pulp. Wild C. capitata populations are traditionally controlled through insecticide spraying and/or eco-friendly approaches, the most successful being the Sterile Insect Technique (SIT). The SIT relies on mass-rearing, radiation based sterilization and field release of males that retain their capacity to mate but are not able to generate fertile progeny. The advent and the subsequent rapid development of biotechnological tools, together with the availability of the medfly genome sequence, has greatly boosted our understanding of the biology of this species. This favored the proliferation of new strategies for genome manipulation, which can be applied to population control. In this context, embryo microinjection plays a dual role in expanding the toolbox for medfly control. The ability to interfere with the function of genes that regulate key biological processes, indeed, expands our understanding of the molecular machinery underlying medfly invasiveness. Furthermore, the ability to achieve germ-line transformation facilitates the production of multiple transgenic strains that can be tested for future field applications in novel SIT settings. Indeed, genetic manipulation can be used to confer desirable traits that can, for example, be used to monitor sterile male performance in the field, or that can result in early life-stage lethality. Here we describe a method to microinject nucleic acids into medfly embryos to achieve these two main goals. PMID- 27768088 TI - Genetic Manipulation of the Plant Pathogen Ustilago maydis to Study Fungal Biology and Plant Microbe Interactions. AB - Gene deletion plays an important role in the analysis of gene function. One of the most efficient methods to disrupt genes in a targeted manner is the replacement of the entire gene with a selectable marker via homologous recombination. During homologous recombination, exchange of DNA takes place between sequences with high similarity. Therefore, linear genomic sequences flanking a target gene can be used to specifically direct a selectable marker to the desired integration site. Blunt ends of the deletion construct activate the cell's DNA repair systems and thereby promote integration of the construct either via homologous recombination or by non-homologous-end-joining. In organisms with efficient homologous recombination, the rate of successful gene deletion can reach more than 50% making this strategy a valuable gene disruption system. The smut fungus Ustilago maydis is a eukaryotic model microorganism showing such efficient homologous recombination. Out of its about 6,900 genes, many have been functionally characterized with the help of deletion mutants, and repeated failure of gene replacement attempts points at essential function of the gene. Subsequent characterization of the gene function by tagging with fluorescent markers or mutations of predicted domains also relies on DNA exchange via homologous recombination. Here, we present the U. maydis strain generation strategy in detail using the simplest example, the gene deletion. PMID- 27768089 TI - Synthesis of a Water-soluble Metal-Organic Complex Array. AB - We demonstrate a method for the synthesis of a water-soluble multimetallic peptidic array containing a predetermined sequence of metal centers such as Ru(II), Pt(II), and Rh(III). The compound, named as a water-soluble metal-organic complex array (WSMOCA), is obtained through 1) the conventional solution chemistry-based preparation of the corresponding metal complex monomers having a 9-fluorenylmethyloxycarbonyl (Fmoc)-protected amino acid moiety and 2) their sequential coupling together with other water-soluble organic building units on the surface-functionalized polymeric resin by following the procedures originally developed for the solid-phase synthesis of polypeptides, with proper modifications. Traces of reactions determined by mass spectrometric analysis at the representative coupling steps in stage 2 confirm the selective construction of a predetermined sequence of metal centers along with the peptide backbone. The WSMOCA cleaved from the resin at the end of stage 2 has a certain level of solubility in aqueous media dependent on the pH value and/or salt content, which is useful for the purification of the compound. PMID- 27768090 TI - The Preparation of Oblique Spinal Cord Slices for Ventral Root Stimulation. AB - Electrophysiological recordings from spinal cord slices have proven to be a valuable technique to investigate a wide range of questions, from cellular to network properties. We show how to prepare viable oblique slices of the spinal cord of young mice (P2 - P11). In this preparation, the motoneurons retain their axons coming out from the ventral roots of the spinal cord. Stimulation of these axons elicits back-propagating action potentials invading the motoneuron somas and exciting the motoneuron collaterals within the spinal cord. Recording of antidromic action potentials is an immediate, definitive and elegant way to characterize motoneuron identity, which surpasses other identification methods. Furthermore, stimulating the motoneuron collaterals is a simple and reliable way to excite the collateral targets of the motoneurons within the spinal cord, such as other motoneurons or Renshaw cells. In this protocol, we present antidromic recordings from the motoneuron somas as well as Renshaw cell excitation, resulting from ventral root stimulation. PMID- 27768091 TI - MPL mutations and palpable splenomegaly are independent risk factors for fibrotic progression in essential thrombocythemia. PMID- 27768092 TI - Prevalence, incidence and survival of smoldering multiple myeloma in the United States. PMID- 27768094 TI - Translational, rotational and vibrational relaxation dynamics of a solute molecule in a non-interacting solvent. AB - Spectroscopically observing the translational and rotational motion of solute molecules in liquid solutions is typically impeded by their interactions with the solvent, which conceal spectral detail through linewidth broadening. Here we show that unique insights into solute dynamics can be made with perfluorinated solvents, which interact weakly with solutes and provide a simplified liquid environment that helps to bridge the gap in our understanding of gas- and liquid phase dynamics. Specifically, we show that in such solvents, the translational and rotational cooling of an energetic CN radical can be observed directly using ultrafast transient absorption spectroscopy. We observe that translational-energy dissipation within these liquids can be modelled through a series of classic collisions, whereas classically simulated rotational-energy dissipation is shown to be distinctly faster than experimentally measured. We also observe the onset of rotational hindering from nearby solvent molecules, which arises as the average rotational energy of the solute falls below the effective barrier to rotation induced by the solvent. PMID- 27768093 TI - The role of maintenance therapy in multiple myeloma. AB - Multiple myeloma is the second most common type of blood cancer and remains incurable despite advances in therapy. Current therapy for multiple myeloma includes a phased-approach, often consisting of initial induction therapy, consolidation and maintenance therapy. With an ever-growing landscape of treatment options, the approach to optimal therapy has become increasingly complex. Specifically, controversy surrounds the optimal use and duration of maintenance therapy. We conducted a comprehensive literature search to analyze the most current literature and to provide recommendations for maintenance therapy in multiple myeloma. PMID- 27768096 TI - MOFs move to market. PMID- 27768095 TI - Small-molecule control of protein function through Staudinger reduction. AB - Using small molecules to control the function of proteins in live cells with complete specificity is highly desirable, but challenging. Here we report a small molecule switch that can be used to control protein activity. The approach uses a phosphine-mediated Staudinger reduction to activate protein function. Genetic encoding of an ortho-azidobenzyloxycarbonyl amino acid using a pyrrolysyl transfer RNA synthetase/tRNACUA pair in mammalian cells enables the site-specific introduction of a small-molecule-removable protecting group into the protein of interest. Strategic placement of this group renders the protein inactive until deprotection through a bioorthogonal Staudinger reduction delivers the active wild-type protein. This developed methodology was applied to the conditional control of several cellular processes, including bioluminescence (luciferase), fluorescence (enhanced green fluorescent protein), protein translocation (nuclear localization sequence), DNA recombination (Cre) and gene editing (Cas9). PMID- 27768099 TI - Actinide chemistry: New compounds on the Bk menu. PMID- 27768098 TI - Nickel-centred proton reduction catalysis in a model of [NiFe] hydrogenase. AB - Hydrogen production through water splitting is one of the most promising solutions for the storage of renewable energy. [NiFe] hydrogenases are organometallic enzymes containing nickel and iron centres that catalyse hydrogen evolution with performances that rival those of platinum. These enzymes provide inspiration for the design of new molecular catalysts that do not require precious metals. However, all heterodinuclear NiFe models reported so far do not reproduce the Ni-centred reactivity found at the active site of [NiFe] hydrogenases. Here, we report a structural and functional NiFe mimic that displays reactivity at the Ni site. This is shown by the detection of two catalytic intermediates that reproduce structural and electronic features of the Ni-L and Ni-R states of the enzyme during catalytic turnover. Under electrocatalytic conditions, this mimic displays high rates for H2 evolution (second-order rate constant of 2.5 * 104 M-1 s-1; turnover frequency of 250 s-1 at 10 mM H+ concentration) from mildly acidic solutions. PMID- 27768097 TI - Materials and methods for delivery of biological drugs. AB - Biological drugs generated via recombinant techniques are uniquely positioned due to their high potency and high selectivity of action. The major drawback of this class of therapeutics, however, is their poor stability upon oral administration and during subsequent circulation. As a result, biological drugs have very low bioavailability and short therapeutic half-lives. Fortunately, tools of chemistry and biotechnology have been developed into an elaborate arsenal, which can be applied to improve the pharmacokinetics of biological drugs. Depot-type release systems are available to achieve sustained release of drugs over time. Conjugation to synthetic or biological polymers affords long circulating formulations. Administration of biological drugs through non-parenteral routes shows excellent performance and the first products have reached the market. This Review presents the main accomplishments in this field and illustrates the materials and methods behind existing and upcoming successful formulations and delivery strategies for biological drugs. PMID- 27768100 TI - MIDA boronates are hydrolysed fast and slow by two different mechanisms. AB - MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for small-molecule construction based on building blocks, largely because of the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, which has hindered efforts to address the current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base mediated and the other neutral. The former can proceed more than three orders of magnitude faster than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative 'neutral' hydrolysis does not require an exogenous acid or base and involves rate-limiting B-N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by 18O incorporation. Whether hydrolysis is 'fast' or 'slow' is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis. PMID- 27768101 TI - Organometallic chemistry: Heavyweight isomer brings stability. PMID- 27768104 TI - Corrigendum: Dearomative dihydroxylation with arenophiles. PMID- 27768102 TI - Fast and selective ring-opening polymerizations by alkoxides and thioureas. AB - Ring-opening polymerization of lactones is a versatile approach to generate well defined functional polyesters. Typical ring-opening catalysts are subject to a trade-off between rate and selectivity. Here we describe an effective catalytic system combining alkoxides with thioureas that catalyses rapid and selective ring opening polymerizations. Deprotonation of thioureas by sodium, potassium or imidazolium alkoxides generates a hydrogen-bonded alcohol adduct of the thiourea anion (thioimidate). The ring-opening polymerization of L-lactide mediated by these alcohol-bonded thioimidates yields highly isotactic polylactide with fast kinetics and living polymerization behaviour, as evidenced by narrow molecular weight distributions (Mw/Mn < 1.1), chain extension experiments and minimal transesterifications. Computational studies indicate a bifunctional catalytic mechanism whereby the thioimidate activates the carbonyl of the monomer and the alcohol initiator/chain end to effect the selective ring-opening of lactones and carbonates. The high selectivity of the catalyst towards monomer propagation over transesterification is attributed to a selective activation of monomer over polymer chains. PMID- 27768106 TI - Correction. PMID- 27768105 TI - DNA charge transfer: Hot holes break the speed limit. PMID- 27768103 TI - Peptide tessellation yields micrometre-scale collagen triple helices. AB - Sticky-ended DNA duplexes can associate spontaneously into long double helices; however, such self-assembly is much less developed with proteins. Collagen is the most prevalent component of the extracellular matrix and a common clinical biomaterial. As for natural DNA, the ~103-residue triple helices (~300 nm) of natural collagen are recalcitrant to chemical synthesis. Here we show how the self-assembly of short collagen-mimetic peptides (CMPs) can enable the fabrication of synthetic collagen triple helices that are nearly a micrometre in length. Inspired by the mathematics of tessellations, we derive rules for the design of single CMPs that self-assemble into long triple helices with perfect symmetry. Sticky ends thus created are uniform across the assembly and drive its growth. Enacting this design yields individual triple helices that, in length, match or exceed those in natural collagen and are remarkably thermostable, despite the absence of higher-order association. The symmetric assembly of CMPs provides an enabling platform for the development of advanced materials for medicine and nanotechnology. PMID- 27768107 TI - Deep-hole transfer leads to ultrafast charge migration in DNA hairpins. AB - Charge transport through the DNA double helix is of fundamental interest in chemistry and biochemistry, but also has potential technological applications such as for DNA-based nanoelectronics. For the latter, it is of considerable interest to explore ways to influence or enhance charge transfer. In this Article we demonstrate a new mechanism for DNA charge transport, namely 'deep-hole transfer', which involves long-range migration of a hole through low-lying electronic states of the nucleobases. Here, we demonstrate, in a combined experimental and theoretical study, that it is possible to achieve such transfer behaviour by changing the energetics of charge injection. This mechanism leads to an enhancement in transfer rates by up to two orders of magnitude and much weaker distance dependence. This transfer is faster than relaxation to the lowest-energy state, setting this mechanism apart from those previously described. This opens up a new direction to optimize charge transfer in DNA with unprecedented charge transfer rates. PMID- 27768109 TI - Active actinium. PMID- 27768108 TI - Identification of (S)-selective transaminases for the asymmetric synthesis of bulky chiral amines. AB - The use of transaminases to access pharmaceutically relevant chiral amines is an attractive alternative to transition-metal-catalysed asymmetric chemical synthesis. However, one major challenge is their limited substrate scope. Here we report the creation of highly active and stereoselective transaminases starting from fold class I. The transaminases were developed by extensive protein engineering followed by optimization of the identified motif. The resulting enzymes exhibited up to 8,900-fold higher activity than the starting scaffold and are highly stereoselective (up to >99.9% enantiomeric excess) in the asymmetric synthesis of a set of chiral amines bearing bulky substituents. These enzymes should therefore be suitable for use in the synthesis of a wide array of potential intermediates for pharmaceuticals. We also show that the motif can be engineered into other protein scaffolds with sequence identities as low as 70%, and as such should have a broad impact in the field of biocatalytic synthesis and enzyme engineering. PMID- 27768110 TI - A stable heavier group 14 analogue of vinylidene. AB - Vinylidene (H2C=C) is a member of the family of compounds of composition CH (and isomeric with ethyne, HC=CH), but it has been observed only transiently-with a lifetime in the region of 0.1 ns. Indeed, no simple (non-base-stabilized) compounds of the type R2E=E have been characterized structurally for any of the group 14 elements. Here we show that by employing the bulky and strongly electron donating boryl ligand (HCDippN)2B (Dipp, 2,6-iPr2C6H3), a simple monomeric digermavinylidene compound, (boryl)2GeGe, can be synthesized and is stable at room temperature. Both its formation via the two-electron chemical oxidation of the symmetrical Ge0 compound K2[(boryl)GeGe(boryl)] and its subsequent reaction chemistry (for example, with H2), are consistent with a high substituent lability and the accessibility of both 1,1- and 1,2-substitution patterns. Structural and computational studies of [(HCDippN)2B]2GeGe reveal a weak Ge-Ge double bond-the pi component of which contributes to the highest occupied molecular orbital (HOMO)-with a Ge-centred lone pair as the HOMO-1. PMID- 27768113 TI - Slow chemistry. PMID- 27768114 TI - Nanomaterials: Two sides to every particle. PMID- 27768112 TI - Observation of trapped-hole diffusion on the surfaces of CdS nanorods. AB - In CdS nanocrystals, photoexcited holes rapidly become trapped at the particle surface. The dynamics of these trapped holes have profound consequences for the photophysics and photochemistry of these materials. Using a combination of transient absorption spectroscopy and theoretical modelling, we demonstrate that trapped holes in CdS nanorods are mobile and execute a random walk at room temperature. In CdS nanorods of non-uniform width, we observe the recombination of spatially separated electrons and trapped holes, which exhibits a t-1/2 power law decay at long times. A one-dimensional diffusion-annihilation model describes the time-dependence of the recombination over four orders of magnitude in time, from one nanosecond to ten microseconds, with a single adjustable parameter. We propose that diffusive trapped-hole motion is a general phenomenon in CdS nanocrystals, but one that is normally obscured in structures in which the wavefunctions of the electron and trapped hole spatially overlap. This phenomenon has important implications for the oxidation photochemistry of CdS nanocrystals. PMID- 27768111 TI - Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors. AB - G proteins are key mediators of G protein-coupled receptor signalling, which facilitates a plethora of important physiological processes. The cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq subfamily of G proteins; however, no synthetic route has been reported previously for these complex natural products and they are not easily isolated from natural sources. Here we report the first total synthesis of YM-254890 and FR900359, as well as of two known analogues, YM-385780 and YM-385781. The versatility of the synthetic approach also enabled the design and synthesis of ten analogues, which provided the first structure-activity relationship study for this class of compounds. Pharmacological characterization of all the compounds at Gq-, Gi- and Gs-mediated signalling provided succinct information on the structural requirements for inhibition, and demonstrated that both YM-254890 and FR900359 are highly potent inhibitors of Gq signalling, with FR900359 being the most potent. These natural products and their analogues represent unique tools for explorative studies of G protein inhibition. PMID- 27768115 TI - Frameworks for commercial success. PMID- 27768116 TI - Correction. PMID- 27768117 TI - Long-term results of allogenic penetrating limbo-keratoplasty: 20 years of experience. AB - AimThe objective of the study was to evaluate the long-term results of allogenic penetrating limbo-keratoplasy. This method allows simultaneous transplantation of a corneal graft and limbal stem cells of the donor by means of eccentric trephination of the donor button.MethodThe data of 192 consecutive cases of allogenic penetrating limbo-keratoplasty from 1995 to 2015 were reviewed. These had been performed exclusively in eyes with complete failure of the limbal stem cells, in combination with deep corneal scarring. Indications were predominantly eye burns, inflammatory conditions, and congenital aniridia. Graft survival and rejection rates were assessed using Kaplan-Meier analysis.ResultsFollow-up averaged 2.1+/-2.2 years. Median graft survival was 3.4 years in eye burns, 3.9 years in inflammatory disease, and 3.2 years in congenital aniridia. Median survival was 3.9 years in the heterogenous group of other indications.ConclusionAllogenic limbo-keratoplasty is a suitable option used to treat patients with bilateral complete failure of the limbal stem cells and deep opacification of the central cornea. The main reasons for graft failure are the loss of graft-limbal stem cell functioning and endothelial graft rejection. PMID- 27768118 TI - Clinical features and long-term progression of reticular pseudodrusen in age related macular degeneration: findings from a multicenter cohort. AB - PurposeTo determine whether reticular pseudodrusen (RPD) confer a long-term increased risk of progression to late age-related macular degeneration (AMD) in the fellow eye of patients with unilateral wet-AMD.Patients and methodsThis was a multicenter, combined prospective and retrospective, longitudinal, observational, study. Patients with wet-AMD in one eye were recruited from two centers and evaluated on the risk of progression to late-AMD in the second eye (study eye). A minimum follow-up of 5 years was required, unless progression occurred first. Baseline retinal profile of patients was evaluated using multimodal imaging. Baseline images were graded by two separate centers.ResultsWe recruited 88 patients (48 female) with a mean age of 75.6+/-7.1 years and mean follow-up of 65.7+/-20.9 months. Baseline prevalence of RPD was 58% (n=51). There was no statistically significant association of RPD with increased age (P=0.29) or sex distribution (P=0.39). The most sensitive image modality for RPD was IR (93%), followed by FAF (92%), OCT (74%, RF (33%) and CFP (29%). After 5 years, 54.50% (n=48) of the study eyes progressed to late-AMD. Of those, 81.25% (n=39) developed CNV and 18.75% (n=9) geographic atrophy. After correcting for age and sex, the presence of RPD was significantly associated with development of late stage AMD (OR=2.55, P=0.03).ConclusionA multimodal approach is mandatory for RPD detection. RPD are highly prevalent in the fellow eyes of patients with unilateral neovascular AMD. Presence of RPD is associated with increased long term risk of progression, highlighting the importance of comprehensive multimodal retinal imaging and careful monitoring of at-risk patients. PMID- 27768119 TI - Effect of glucosamine on intraocular pressure: a randomized clinical trial. AB - PurposeThe purpose of the study was to investigate ocular hypertensive effect of exogenous glucosamine in comparison with placebo in patients with osteoarthritis.Patients and methodsIn this double-masked randomized clinical trial, 88 patients with osteoarthritis were included. Forty-four patients were randomized into either glucosamine sulfate or the placebo group.Comprehensive ophthalmologic exam including intraocular pressure (IOP) at baseline, month 1, and 3 was performed. Ocular response analyzer parameters were also checked at baseline and month 3.ResultsThe mean IOP at the time of presentation was 12.4+/ 2.7 mm Hg in glucosamine and 13+/-2.8 mm Hg in the placebo group (P=0.329). At month 1 the corresponding values were 12.6+/-2.4 and 12.9+/-2.4 mm Hg (P=0.868), and at 3 months follow-up were 13.5+/-2.3 and 13+/-2.7 mm Hg (P=0.002), respectively. About 34.1% in treatment and 12.5% in the placebo group had clinically significant (defined as >= 2 mm Hg) rise in IOP at final follow-up (P=0.023). Mean age in those with significant rise in IOP was 66 vs 57.7 years in patients with <2 mm Hg (P=0.034). The ORA parameters remained unchanged in both the groups during the course of study.ConclusionGlucosamine supplement therapy causes statistically significant rise of IOP, which is more pronounced in elderly patients. Clinical implication of this finding needs further evaluation. PMID- 27768120 TI - Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survival. AB - PurposeTo describe prognostic factors and survival outcomes in patients who underwent orbital exenteration for periocular non-melanoma cutaneous malignancies.MethodsThe authors performed an institutional review board-approved retrospective review of all patients who underwent orbital exenteration for non melanoma periocular cutaneous malignancies at a tertiary care hospital system over a 10-year period. Patient demographics, tumor, and treatment data were recorded. Survival outcomes included disease-free survival (DFS) and overall survival (OS). Log-rank tests were used to test for difference in survival curves among various potential prognostic indicators, and multivariate analysis was performed using Cox's proportional hazards model.ResultsForty-nine patients with an average age of 70.3 years were followed with a median follow-up of 17.5 months. At 2 years the OS was 78% while the DFS was 61%. The mean DFS for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC) were 52.6, 39.2 and 28.1 months, respectively. Multivariate analysis demonstrated that only positive final surgical margin was predictive of worse outcome (P=0.002). Recurrences were most frequent in the first 2 years.ConclusionsDespite the relatively more aggressive nature of periocular malignancies that have invaded the orbit, orbital exenteration offers an overall 2-year DFS of ~60%. BCC had the greatest mean survival time, however this was not statistically significant. We found worse prognosis with positive final surgical margins and recommend a multidisciplinary surgical approach to achieve complete resection when indicated. PMID- 27768121 TI - p53 on the crossroad between regeneration and cancer. AB - Regeneration and tumorigenesis share common molecular pathways, nevertheless the outcome of regeneration is life, whereas tumorigenesis leads to death. Although the process of regeneration is strictly controlled, malignant transformation is unrestrained. In this review, we discuss the involvement of TP53, the major tumor suppressor gene, in the regeneration process. We point to the role of p53 as coordinator assuring that regeneration will not shift to carcinogenesis. The fluctuation in p53 activity during the regeneration process permits a tight control. On one hand, its inhibition at the initial stages allows massive proliferation, on the other its induction at advanced steps of regeneration is essential for preservation of robustness and fidelity of the regeneration process. A better understanding of the role of p53 in regulation of regeneration may open new opportunities for implementation of TP53-based therapies, currently available for cancer patients, in regenerative medicine. PMID- 27768123 TI - Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage. AB - Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage. PMID- 27768122 TI - Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets. AB - Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhos-DLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. PMID- 27768125 TI - Distress and Coping Self-Efficacy in Inpatient Oncology Nurses. AB - PURPOSE/OBJECTIVES: To examine distress and coping self-efficacy in inpatient oncology nurses. ?. DESIGN: Cross-sectional survey design.?. SETTING: Oncology Nursing Society (ONS) chapter meetings and Hunter-Bellevue School of Nursing, both in New York, New York, as well as social media.?. SAMPLE: 163 oncology nurses who work with an inpatient adult population.?. METHODS: Participants were recruited through the ONS New York, New York, area chapter meetings, Hunter College, and ONS Facebook pages. An adapted Nurse Distress Thermometer (NDT) measured distress levels. The Occupational Coping Self-Efficacy Questionnaire for Nurses (OCSE-N) used a Likert-type scale to measure coping self-efficacy. Open ended questions elicited additional perceptions of nurse respondents. ?. MAIN RESEARCH VARIABLES: Descriptive statistics summarized sample demographics. A Pearson correlation between distress levels and coping self-efficacy scores was calculated. Low, normal, and high coping scores were compared to mean distress levels. ?. FINDINGS: Survey participants showed high levels of distress, with a mean NDT score of 8.06. Those with higher coping self-efficacy scores reported less distress. A moderate, negative correlation was shown, with a statistically significant Pearson coefficient of -0.371. Responses to the open-ended questions revealed common stressors and pointed to solutions that institutions might implement to support nurses.?. CONCLUSIONS: Because coping self-efficacy related to lower distress levels in inpatient oncology nurses, institutional-level support for oncology nurses should be provided. ?. IMPLICATIONS FOR NURSING: Interventions aimed at coping self-efficacy may prepare oncology nurses to cope better with their professional demands. Future research should explore how nurse distress affects patients. PMID- 27768124 TI - Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism. AB - Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC containing CD34+ cells, EPC-mobilizing cytokines - vascular endothelial growth factor and stromal cell-derived factor-1alpha - and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines neovascularization, brain repair and neurological recovery after ICH. This study is the first in which the Pro allele of Tp53 is linked to vascular repair and ability to functionally recover from stroke. PMID- 27768126 TI - Navigating the Transition From Cancer Care to Primary Care: Assistance of a Survivorship Care Plan. AB - PURPOSE/OBJECTIVES: To examine symptom and quality-of-life (QOL) trajectories in breast cancer and lymphoma survivors enrolled in a survivorship navigation intervention and to explore patient, caregiver, and primary care provider (PCP) satisfaction with receipt of a survivorship care plan (SCP). ?. DESIGN: Prospective, cohort, longitudinal.?. SETTING: The Billings Clinic, an integrated cancer center in Montana. ?. SAMPLE: 67 patients with breast cancer or lymphoma who recently completed cancer treatment, along with 39 of their caregivers and 23 PCPs. ?. METHODS: Data collection at one, three, and six months by the Functional Assessment of Cancer Therapy-General and satisfaction surveys.?. MAIN RESEARCH VARIABLES: Symptoms, QOL, and satisfaction with the survivorship navigator and the SCP.?. FINDINGS: Symptoms persisted six months following treatment. Symptoms and QOL indicators with worst intensity were energy, sleep, coping, and satisfaction with sex life. Patients with more comorbidities reported worse QOL, telephoned the survivorship navigator more often, and were more satisfied with the SCP. Patients with lymphoma reported higher QOL, but it was not significantly different from patients with breast cancer. Patients were significantly more satisfied than caregivers with the SCP at time 1. PCPs were highly satisfied with the SCP.?. CONCLUSIONS: Some symptoms persist, even when cancer treatment has ended. Patients with comorbidities are at higher risk for more severe symptoms and worse QOL and may benefit from ongoing support. SCPs can facilitate patients' transition to primary care following cancer treatment. ?. IMPLICATIONS FOR NURSING: Healthcare professionals who care for breast cancer survivors need to routinely assess them for the presence of comorbid conditions. Obese breast cancer survivors may benefit from weight reduction interventions to possibly decrease their risk of developing lymphedema and improve their overall health status. PMID- 27768127 TI - Fatigue Self-Management Behaviors in Patients With Advanced Cancer: A Prospective Longitudinal Survey. AB - PURPOSE/OBJECTIVES: To explore the fatigue self-management behaviors and factors associated with effectiveness of these behaviors in patients with advanced cancer.?. DESIGN: Prospective longitudinal interviewer-administered survey.?. SETTING: Royal Brisbane and Women's Hospital in Queensland, Australia.?. SAMPLE: 152 outpatients with metastatic breast, lung, colorectal, and prostate cancer experiencing fatigue were recruited.?. METHODS: Patients were surveyed on three occasions. MAIN RESEARCH VARIABLES: Fatigue self-management behavior (perceived effectiveness, self-efficacy, and frequency), medical and demographic characteristics (sites of primary cancer and metastasis, comorbidity, performance status), social support, depression, anxiety, and other symptoms were assessed.?. FINDINGS: The participants reported moderate levels of fatigue at baseline and maintained moderate levels at four and eight weeks. On average, participants consistently used about nine behaviors at each time point. Factors significantly associated with higher levels of perceived effectiveness of fatigue self management behaviors were higher self-efficacy, higher education level, and lower levels of depressive symptoms. ?. CONCLUSIONS: The findings of this study demonstrate that patients with cancer, even those with advanced disease, still want and are able to use a number of behaviors to control their fatigue. Self management interventions that aim to enhance self-efficacy and address any concurrent depressive symptoms have the potential to reduce fatigue severity.?. IMPLICATIONS FOR NURSING: Nurses are well positioned to play a key role in supporting patients in their fatigue self-management. PMID- 27768128 TI - Developing a Hypnotic Relaxation Intervention to Improve Body Image: A Feasibility Study. AB - PURPOSE/OBJECTIVES: To determine the content, feasibility, and best outcome of a mind-body intervention involving self-directed hypnotic relaxation to target body image.?. DESIGN: A five-week, uncontrolled, unblinded feasibility intervention study.?. SETTING: Behavioral therapy offices in Ann Arbor, Michigan, and Waco, Texas.?. SAMPLE: 10 female breast cancer survivors and 1 breast and gynecologic cancer survivor. ?. METHODS: Adult women with a history of breast and gynecologic cancer and no major psychiatric history were eligible. The intervention included four face-to-face sessions with a research therapist lasting 40-60 minutes, logged home practice, one telephone check-in call at week 5, and one intervention feedback telephone call to complete the study. Descriptive statistics and paired t-tests were used to test feasibility and content validity.?. MAIN RESEARCH VARIABLES: Stress from body changes as measured by the Impact of Treatment Scale, sexual function as measured by the Female Sexual Function Index, and sexual self image as measured by the Sexual Self-Schema Scale for women were the variables of interest.?. FINDINGS: The intervention content was confirmed. Changes in scores from the baseline to week 5 suggested that stress from body changes decreased and sexual self-schema and function improved during the intervention. Nine of the 11 women were satisfied with the intervention, and all 11 indicated that their body image improved. ?. CONCLUSIONS: Hypnotic relaxation therapy shows promise for improving body image and, in doing so, improving sexual health in this population. Additional testing of this intervention is warranted.?. IMPLICATIONS FOR NURSING: Hypnotic relaxation therapy is feasible to improve body image and sexual health in women diagnosed with cancer and may be an important intervention that could be offered by nurses and other behavioral therapists. PMID- 27768129 TI - Nursing Management of Advanced Merkel Cell Carcinoma. AB - Merkel cell carcinoma (MCC) is a rare and lethal skin cancer with few known treatment options. Management of this disease is challenging, and oncology nurses must understand the medical, physical, and psychosocial burden that MCC places on the patient and family caregivers. Patients must navigate a complex medical and insurance network that often fails to support patients with rare cancers. Nurses must advocate for these patients to ensure quality comprehensive cancer care. PMID- 27768130 TI - Representational Approach: A Conceptual Framework to Guide Patient Education Research and Practice. AB - Illness representations are cognitive structures that individuals rely on to understand and explain their illnesses and associated symptoms. The Representational Approach (RA) to patient education offers a theoretically based, clinically useful model that can support oncology nurses to develop a shared understanding of patients' illness representations to collaboratively develop highly personalized plans for symptom management and other important self management behaviors. This article discusses theoretical underpinnings, practical applications, challenges, and future directions for incorporating illness representations and the RA in clinical and research endeavors. PMID- 27768132 TI - Grief and Gracefulness Regarding Cancer Experiences Among Young Women. AB - PURPOSE/OBJECTIVES: To gain a unique perspective of young women with cancer aged 20-39 years who are experiencing challenges with fertility and parenting through analysis of cancer blogs.?. RESEARCH APPROACH: A secondary analysis of online narratives using a focused thematic analysis approach, comparing women who were mothers prior to diagnosis with women who are exploring the possibility of motherhood after diagnosis.?. SETTING: Blogs found through websites and social media venues for young adults with cancer.?. PARTICIPANTS: 10 women aged 20-39 who maintained blogs about their cancer experiences.?. METHODOLOGIC APPROACH: Thematic analysis using line-by-line coding. Construction of comparative themes and meanings were guided by the analytic framework of the stages of grief.?. FINDINGS: Themes emerged along the grieving trajectory of denial (maintaining routines and discussing "eggs"), depression (losing motherhood and anticipatory grief), and acceptance (finding joy moment to moment and hope for pregnancy).?. CONCLUSIONS: Motherhood and infertility are unique experiences for young women with cancer but are expressed similarly through the stages of grief. INTERPRETATION: Understanding the grief trajectories of young women with cancer will help nurses to develop screening tools and supportive interventions. PMID- 27768133 TI - Upon Further Review: Peer Process Vital to Publishing. AB - Peer review is one of the hallmarks of professional publishing and one that I appreciate every day in my work as editor of this journal. I simply could not do this work without reviewers, and all of my editor colleagues across the globe would agree. I have been a reviewer for various journals for many years, and now, as editor of the Oncology Nursing Forum, I am even more aware of how important my reviews are for others. Just this morning, I reviewed a manuscript-for a noncompeting journal, of course-and as I entered my comments, I thought about what I, as editor, would find useful.?. PMID- 27768131 TI - Increasing Cardiomyopathy Screening in Childhood Cancer Survivors: A Cost Analysis of Advanced Practice Nurse Phone Counseling. AB - PURPOSE/OBJECTIVES: To document the per survivor and per additional survivor screening costs of a mailed survivorship care plan (SCP) with advanced practice nurse (APN) telephone counseling (SCP+C) or without APN telephone counseling (SCP).?. DESIGN: Randomized, longitudinal clinical trial.?. SETTING: St. Jude Children's Research Hospital in Memphis, Tennessee.?. SAMPLE: 411 at-risk pediatric cancer survivors (aged 26-59 years), stratified by age (younger than 30 years versus 30 years or older), recommended screening frequency (every one, two, or five years), gender, and cancer diagnosis (hematologic versus solid tumor).?. METHODS: Clinical and resource data costs were derived from trial data and external estimates.?. MAIN RESEARCH VARIABLES: The cost-effectiveness of left ventricular systolic function screening per survivor and per each additional survivor screened.?. FINDINGS: The per-survivor costs of SCP (n = 206) and SCP+C (n = 205) were $74.91 and $224.69, respectively. The estimated costs of SCP and SCP+C per additional survivor screened for two years disseminated in a medium sized clinic (n = 101 survivors annually) were $345.41 and $293.85, respectively.?. CONCLUSIONS: Adding APN counseling to a printed SCP may help preserve cardiac health at little or no cost per additional survivor screened.?. IMPLICATIONS FOR NURSING: APN counseling is cost-effective and superior to the standard of care in supporting at-risk survivors' cardiac screening participation. PMID- 27768134 TI - Emerging Role of Nutri-Epigenetics in Inflammation and Cancer. AB - Nutrition is a factor involved in inflammation and a modulator of risk toward some cancers, and the complexity of linkages between dietary components and epigenetics mechanisms (e.g., DNA methylation, histone modification, chromatin remodeling) may affect the inflammation phenotype and the development of cancer. An increasing number of studies support the role of diet in cancer development, prevention, and treatment. Although current knowledge regarding nutri-epigenetics is expanding, more work is needed, and nurse scientists have the potential to significantly contribute to the expansion of this knowledge. PMID- 27768136 TI - Empowering Oncology Nurses to Lead Change Through a Shared Governance Project. AB - Nurses at the bed- or chairside are knowledgeable about clinical and operational concerns that need improvement and, consequently, are in the best position to generate and evaluate practical options and potential solutions to improve efficacy and care processes. Implementation of a shared governance model is effective in engaging staff nurses to make meaningful and sustainable change in patient care processes. PMID- 27768135 TI - Message Framing and Physical Activity Promotion in Colorectal Cancer Survivors. AB - PURPOSE/OBJECTIVES: To test effects of gain-framed versus loss-framed mailed brochures on increasing physical activity (PA) among colorectal cancer (CRC) survivors.?. DESIGN: Randomized trial with repeated measures at baseline, 1 month, and 12 months postintervention.?. SETTING: Mail recruitment from tumor registries.?. SAMPLE: 148 inactive CRC survivors who had completed primary therapy. ?. METHODS: PA and constructs from the Theory of Planned Behavior (TPB) were assessed at baseline, 1 month, and 12 months. Participants were randomized to receive pamphlets describing PA benefits (gain framed) or disadvantages of not being physically active (loss framed). Baseline characteristics were compared using descriptive statistics. Repeated measures linear models were used to test PA changes.?. MAIN RESEARCH VARIABLES: Minutes of PA and TPB constructs.?. FINDINGS: Significant PA increases were observed in both study arms. Results did not differ by message frame. At one month, about 25% of previously inactive participants increased activity to national recommendations. Those who increased PA compared to those who did not had higher baseline scores on subjective norms, perceived behavioral control, and PA intentions. ?. CONCLUSIONS: Independent of message framing, mailed brochures are highly effective in producing within subject short- and long-term increases in PA.?. IMPLICATIONS FOR NURSING: CRC survivors may increase short- and long-term levels of PA by receiving inexpensive print brochures. PMID- 27768137 TI - Response to "The Value of Mentoring in Nursing: An Honor and a Gift". AB - I would like to thank Marcia Gruber-Page, MSN, MS, RN, for highlighting the value of mentorships for the profession of nursing (Gruber-Page, 2016). As she emphasized, mentorships in the workplace contribute to the professional success of the mentor and mentee. Another population that is in need of sound guidance during a critical stage of professional development is undergraduate student nurses. ?. PMID- 27768138 TI - Optimizing the Benefits of Self-Monitoring Among Patients With Cancer. AB - PURPOSE/OBJECTIVES: To investigate oncology professionals' perspectives about, experience with, and envisioned feasibility of incorporating patient self monitoring as a patient-centered practice. ?. RESEARCH APPROACH: An interpretive, descriptive study.?. SETTING: Four health systems and five cancer centers in three states. ?. PARTICIPANTS: 38 nurses, nurse practitioners, oncologists, physician assistants, and radiation therapists.?. METHODOLOGIC APPROACH: Individual and focus group interviews.?. FINDINGS: Three themes were revealed. CONCLUSIONS: This study uncovers the potential contribution of patient self monitoring as a means of providing patient-generated data that informs clinical decision making, going beyond self-monitoring for self-management only. Because the term self-monitoring is not used by clinicians, adoption of an agreed-upon term is recommended as the first step toward developing and implementing a self monitoring strategy. Findings support the need to reenvision patient education to ensure self-monitoring is clinically useful while preventing an excessive focus on the negative, which may contribute to patient anxiety.?. INTERPRETATION: The full potential for self-monitoring by patients is not entirely reached. Because nurses are charged with providing patient education, they are strategically positioned to adopt the term self-monitoring and integrate a self-monitoring strategy into patient-centered practice. PMID- 27768139 TI - Assessing the Impact of Acupuncture on Pain, Nausea, Anxiety, and Coping in Women Undergoing a Mastectomy. AB - PURPOSE/OBJECTIVES: To compare the effect of acupuncture to a standard-of-care (control) group on pain, nausea, anxiety, and ability to cope. ?. DESIGN: Pilot randomized, controlled trial. ?. SETTING: Abbott Northwestern Hospital, a large, urban, tertiary care hospital in Minneapolis, Minnesota.?. SAMPLE: 30 adult women undergoing surgery for breast cancer.?. METHODS: Women were randomly assigned to two hospital-based acupuncture treatments versus usual care after breast cancer surgery. Pain, nausea, anxiety, and the patient's ability to cope pre- and post treatment were compared within and between groups at two different time points postoperatively. ?. MAIN RESEARCH VARIABLES: Mean change in pain, nausea, anxiety, and ability to cope by treatment group.?. FINDINGS: Compared to women assigned to the control group, women who received acupuncture reported a statistically significant greater reduction in pain, nausea, anxiety, and increase in ability to cope on the first postoperative day and in pain on the second postoperative day following mastectomy surgery.?. CONCLUSIONS: Acupuncture delivered postoperatively in the hospital after mastectomy can reduce the severity of symptoms experienced, as well as increase the patient's ability to cope with her symptoms. However, before implementation as a standard of care, further research needs to be conducted.?. IMPLICATIONS FOR NURSING: Acupuncture adds a nonpharmacologic intervention for symptom management in women undergoing mastectomies for breast cancer. PMID- 27768140 TI - Informed Consent: A Clinical Trials Perspective. AB - The primary goal of the thousands of registered trials in cancer research is to extend survival. With evaluation of efficacy, safety, and tolerability, healthcare providers must ensure that the principles described in the Belmont Report are upheld and that patients are truly informed when signing a consent form. In this article, two cases are highlighted, and reasons for participating in clinical trials are discussed. Challenges, such as healthcare literacy, patients' dedication to their healthcare providers, and choosing between multiple trials, are also explored. PMID- 27768141 TI - Factors Associated With Post-Traumatic Growth, Quality of Life, and Spiritual Well-Being in Outpatients Undergoing Bone Marrow Transplantation: A Pilot Study. AB - PURPOSE/OBJECTIVES: To examine the relationships between spiritual, religious, and sociodemographic factors and post-traumatic growth, quality of life, and spiritual well-being in outpatients undergoing bone marrow and/or stem cell transplantation (BMSCT).?. DESIGN: Cross-sectional, descriptive, exploratory.?. SETTING: Outpatient bone marrow transplantation clinic at the Tom Baker Cancer Centre in Calgary, Alberta, Canada.?. SAMPLE: 100 patients (21 pre-BMSCT and 79 post-BMSCT) accrued consecutively via non-probability sampling.?. METHODS: Study participants completed the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT), the Post-Traumatic Growth Inventory (PTGI), the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp), and a demographic questionnaire. Data analysis included descriptive statistics, t tests, and correlational analyses.?. MAIN RESEARCH VARIABLES: Demographic variables, FACT-BMT scores, PTGI scores, FACIT-Sp scores. ?. FINDINGS: The majority of participants identified themselves as being at least somewhat spiritual. Significant differences were noted between those who identified as being not religious at all versus having at least some religiosity in several subscales of the PTGI, as well as on the FACIT-Sp. Similarly, significant differences were observed between participants who identified as being not spiritual at all versus having at least some spirituality for several subscales on the PTGI. Most participants indicated they would be at least somewhat likely to recommend spiritual care to a new patient. ?. CONCLUSIONS: Most patients in this study within a publicly funded healthcare system self-identified with spirituality, used spiritual resources, and would recommend that other patients undergoing BMSCT seek the support of a spiritual care professional or chaplain. Spirituality, along with practical and relational factors, had a positive impact on certain aspects of post-traumatic growth, quality of life, and spiritual and physical well-being.?. IMPLICATIONS FOR NURSING: Oncology nurses are encouraged to routinely address spiritual issues. Findings from this study suggest that spirituality is not only important to patients undergoing BMSCT, but also may be an integral component of patients' post-traumatic growth, quality of life, and spiritual well-being. PMID- 27768143 TI - Copper-catalyzed cascade cyclization of 1,5-enynes via consecutive trifluoromethylazidation/diazidation and click reaction: self-assembly of triazole fused isoindolines. AB - Copper-catalyzed cascade cyclization of 1,5-enynes with two types of hypervalent reagents was developed via consecutive trifluoromethylazidation/diazidation and intramolecular click reaction (CUAAC), providing one-pot self-assembly of triazole fused isoindolines bearing a trifluoromethyl or an azide moiety. Moreover, the construction of a trifluoromethylcyclopropyl unit, which has been considered as a metabolically stable replacement for a tert-butyl moiety and was difficult to access, was also achieved under trifluoromethylazidation conditions. All these reactions exhibited excellent chemoselectivity, good to excellent yields and broad functional group tolerance. PMID- 27768142 TI - Experiences of Family Members of Dying Patients Receiving Palliative Sedation. AB - PURPOSE/OBJECTIVES: To describe the experience of family members of patients receiving palliative sedation at the initiation of treatment and after the patient has died and to compare these experiences over time.?. DESIGN: Descriptive comparative study.?. SETTING: Oncology ward at Shaare Zedek Medical Center in Jerusalem, Israel.?. SAMPLE: A convenience sample of 34 family members of dying patients receiving palliative sedation. ?. METHODS: A modified version of a questionnaire describing experiences of family members with palliative sedation was administered during palliative sedation and one to four months after the patient died. Descriptive statistics were used to describe the results of the questionnaire, and appropriate statistical analyses were conducted for comparisons over time.?. MAIN RESEARCH VARIABLES: Experiences of family members and time.?. FINDINGS: Most relatives were satisfied with the sedation and staff support. Palliative sedation was experienced as an ethical way to relieve suffering. However, one-third felt that it shortened the patient's life. An explanation of the treatment was given less than half of the time and was usually given on the same day treatment was started. This explanation was given by physicians and nurses. Many felt that they were not ready for changes in the patient's condition and wanted increased opportunities to discuss the treatment with oncology care providers. No statistically significant differences in experiences were found over time. ?. CONCLUSIONS: Relatives' experiences of palliative sedation were generally positive and stable over time. Important experiences included timing of the initiation of sedation, timing and quality of explanations, and communication.?. IMPLICATIONS FOR NURSING: Nurses should attempt to initiate discussions of the possible role of sedation in the event of refractory symptoms and follow through with continued discussions. The management of refractory symptoms at the end of life, the role of sedation, and communication skills associated with decision making related to palliative sedation should be a part of the core nursing curriculum. Nursing administrators in areas that use palliative sedation should enforce good nursing clinical practice as recommended by international practice guidelines, such as those of the European Association for Palliative Care. PMID- 27768144 TI - Regio- and stereo-selective intermolecular [2+2] cycloaddition of allenol esters with C60 leading to alkylidenecyclobutane-annulated fullerenes. AB - The intermolecular [2+2] cycloaddition of allenol esters, which were in situ generated by Pt-catalyzed 1,3-acyloxy migration of propargylic esters, with C60 proceeded regio- and stereo-selectively to give a novel class of alkylidenecyclobutane-annulated fullerenes. The cyclobutane-annulated fullerene derivatives have high-lying LUMO levels, which gave a high open-circuit voltage in organic solar cell applications. The observed high electron mobility provided a good fill factor compared with the PCBM-based devices. PMID- 27768145 TI - A Cr(salen)-based metal-organic framework as a versatile catalyst for efficient asymmetric transformations. AB - A porous Cr(salen)-MOF can serve as an efficient and effective heterogeneous catalyst for a series of important asymmetric transformations including the Nazarov cyclization, aminolysis reaction, and Diels-Alder and hetero Diels-Alder reactions, resulting in comparable or superior diastereo- or enantioselectivity with respect to the corresponding homogeneous systems. PMID- 27768146 TI - Synthesis of the fluorohydridoborate anions [BHF3]- and [1-HF2B-9,12-X2-closo-1,2 C2B10H9]- (X = H, I): deboronation of 1,2- and 1,7-dicarba-closo-dodecaboranes with anhydrous [Me4N]F. AB - Deboronation of closo-1,7-C2B10H12 and 1-R1-closo-1,2-C2B10H12 (R1 = Me, Ph) with anhydrous [Me4N]F yields [Me4N][BHF3] that is the first structurally characterized anion of the series [BHxF4-x]- (x = 1-3). Deboronation of 9,12-R22 closo-1,7-C2B10H12 (R2 = H, I) gives a mixture of [Me4N][BHF3] and [Me4N][1-HF2B 9,12-R22-closo-1,2-C2B10H9]. PMID- 27768148 TI - Optical vs. chemical driving for molecular machines. AB - Molecular machines use external energy to drive transport, to do mechanical, osmotic, or electrical work on the environment, and to form structure. In this paper the fundamental difference between the design principles necessary for a molecular machine to use light or external modulation of thermodynamic parameters as an energy source vs. the design principle for using an exergonic chemical reaction as a fuel will be explored. The key difference is that for catalytically driven motors microscopic reversibility must hold arbitrarily far from equilibrium. Applying the constraints of microscopic reversibility assures that a coarse grained model is consistent with an underlying model for motion on a single time-independent potential energy surface. In contrast, light-driven processes, and processes driven by external modulation of the thermodynamic parameters of a system cannot in general be described in terms of motion on a single time-independent potential energy surface, and the rate constants are not constrained by microscopic reversibility. The results presented here call into question the value of the so-called power stroke model as an explanation of the function of autonomous chemically-driven molecular machines such as are commonly found in biology. PMID- 27768147 TI - Near-infrared photothermal therapy of Prussian-blue-functionalized lanthanide-ion doped inorganic/plasmonic multifunctional nanostructures for the selective targeting of HER2-expressing breast cancer cells. AB - We report the synthesis, characterization, and application of Prussian blue (PB) functionalized CaMoO4:Eu@SiO2@Au nanorod hybrid nanoparticles (HNPs), with multimodal capabilities such as fluorescence imaging, surface-enhanced Raman spectroscopy (SERS) detection and photothermal therapy (PTT). The average size of CaMoO4:Eu@SiO2 NPs was 206 nm. The HNPs are highly dispersible in water for several weeks without settling and show a strong absorption in the near-infrared region, overlapping with the PB absorption between 600 nm and 1000 nm and the surface plasmon resonance of Au nanorods around 800 nm. Upon 808 nm laser excitation, HNPs show hyperthermia temperature (~43 degrees C). Moreover, PB functionalized NPs can be used in clinical trials for the treatment of radioactive exposure, and PB acts as a Raman reporter molecule (2152 cm-1 characteristic peak) with good biosafety and stability in the human body. In addition, coating the surface of CaMoO4:Eu NPs with both SiO2 and Au nanorods increases the biocompatibility of the HNPs. Furthermore, the PTT efficiency of human epidermal growth factor receptor 2 (HER2) antibody-conjugated HNPs on MDA MB-435 cancerous cells was significantly higher than that of hepatocyte cells (noncancerous). This is due to the greater uptake of HNPs on cancerous cells than on noncancerous cells. Together, this study shows the potential applications of these HNPs in fluorescence imaging, SERS detection, and PTT functionalities with good photostability and biocompatibility. PMID- 27768149 TI - Synthesis of 2,3-disubstituted indenones by cobalt-catalyzed [3+2] annulation of o-methoxycarbonylphenylboronic acid with alkynes. AB - Treatment of alkynes with o-methoxycarbonylphenylboronic acid in the presence of a cobalt catalyst resulted in the corresponding 2,3-disubstituted indenones in good yields. Excellent regioselectivities were observed, when silyl aryl alkynes were used. The intermediate 3-silyl-2-aryl-substituted indenones were converted to 2,3-diaryl indenones by a three-step protocol involving C-Si bromination and Suzuki-Miyaura coupling reaction. PMID- 27768150 TI - Ruthenium(ii)-catalyzed C-H functionalizations on benzoic acids with aryl, alkenyl and alkynyl halides by weak-O-coordination. AB - C-H arylations of weakly coordinating benzoic acids were achieved by versatile ruthenium(ii) catalysis with ample substrate scope. Thus, user-friendly ruthenium(ii) biscarboxylate complexes modified with tricyclohexylphosphine enabled C-H functionalizations with aryl electrophiles. The unique versatility of the ruthenium(ii) catalysis manifold was reflected by facilitating effective C-H activations with aryl, alkenyl and alkynyl halides. PMID- 27768151 TI - Convective mass transport dominates surfactant adsorption in a microfluidic Y junction. AB - Surfactant adsorption during emulsification can be quantified by measuring the acting interfacial tension using a Y-junction microfluidic device. To obtain insight into the surfactant transport mechanism to the interface, the effect of shear force on the acting interfacial tension was assessed by systematically varying the continuous phase viscosity and velocity. Varying the continuous phase viscosity did not affect the acting interfacial tension, indicating that surfactant adsorption during Y-junction emulsification is not diffusion-limited. The acting interfacial tension was inversely dependent on the continuous phase velocity, which indicates that surfactant adsorption is governed by convective mass transfer resulting from the continuous phase velocity. The acting interfacial tension can be measured in the sub-millisecond time scale and under convective transport conditions using the Y-junction. These conditions are relevant to industrial emulsification and cannot be assessed by conventional tensiometry techniques (e.g., drop tensiometers) where surfactant adsorption is mostly driven by diffusion. We believe, therefore, that this method can be used to understand emulsifier adsorption during industrial emulsification, which can, in turn, be used to rationally design emulsion formulations and processes. PMID- 27768152 TI - Topological defects in cholesteric liquid crystal shells. AB - We investigate experimentally and numerically the defect configurations emerging when a cholesteric liquid crystal is confined to a spherical shell. We uncover a rich scenario of defect configurations, some of them non-existent in nematic shells, where new types of defects are stabilized by the helical ordering of the liquid crystal. In contrast to nematic shells, here defects are not simple singular points or lines, but have a large structured core. Specifically, we observe five different types of cholesteric shells. We study the statistical distribution of the different types of shells as a function of the two relevant geometrical dimensionless parameters of the system. By playing with these parameters, we are able to induce transitions between different types of shells. These transitions involve interesting topological transformations in which the defects recombine to form new structures. Surprisingly, the defects do not approach each other by taking the shorter distance route (geodesic), but by following intricate paths. PMID- 27768153 TI - Sequencing and de novo assembly of the Asian gypsy moth transcriptome using the Illumina platform. AB - The Asian gypsy moth (Lymantria dispar) is a serious pest of forest and shade trees in many Asian and some European countries. However, there have been few studies of L. dispar genetic information and comprehensive genetic analyses of this species are needed in order to understand its genetic and metabolic sensitivities, such as the molting mechanism during larval development. In this study, high-throughput sequencing technology was used to sequence the transcriptome of the Asian subspecies of the gyspy moth, after which a comprehensive analysis of chitin metabolism was undertaken. We generated 37,750,380 high-quality reads and assembled them into contigs. A total of 37,098 unigenes were identified, of which 15,901 were annotated in the NCBI non redundant protein database and 9,613 were annotated in the Swiss-Prot database. We mapped 4,329 unigenes onto 317 pathways using the Kyoto Encyclopedia of Genes and Genomes Pathway database. Chitin metabolism unigenes were found in the transcriptome and the data indicated that a variety of enzymes was involved in chitin catabolic and biosynthetic pathways. PMID- 27768154 TI - Investigator Argus X-12 study on the population of northern Croatia. AB - X chromosome STR typing has emerged recently as a powerful tool, complementary to autosomal STR typing, in solving complex forensic and missing person cases. Investigator(r) Argus X-12 is a commercial product that allows co-amplification of 12 X chromosomal markers belonging to four linkage groups (LGs). In this study, we analyzed by capillary electrophoresis blood samples from 100 females and 102 males from a population of northern Croatia. Statistical analysis included calculation of allele and haplotype frequencies, as well as forensic parameters. The most informative marker for the northern Croatia population was DXS10135 with PIC=0.9211 and a total of 27 alleles. The least polymorphic marker was DXS8378 with 6 alleles. The proportion of observed haplotypes from the number of possible haplotypes varied from 2.74-8.57% across all LGs, with LG1 being the most informative. Of the 11 tested world populations compared to the population of northern Croatia, significant differences in genetic distance (FST) were found for Greenlandic and all non-European populations. We found that all tested markers are in HWE and can thus be used for match probability calculation. Because of high combined power of discrimination in both men and women, Investigator(r) Argus X-12 is applicable for the northern Croatia population in routine forensic casework. PMID- 27768156 TI - Contribution of WUSCHEL-related homeobox (WOX) genes to identify the phylogenetic relationships among Petunia species. AB - Developmental genes are believed to contribute to major changes during plant evolution, from infrageneric to higher levels. Due to their putative high sequence conservation, developmental genes are rarely used as molecular markers, and few studies including these sequences at low taxonomic levels exist. WUSCHEL related homeobox genes (WOX) are transcription factors exclusively present in plants and are involved in developmental processes. In this study, we characterized the infrageneric genetic variation of Petunia WOX genes. We obtained phylogenetic relationships consistent with other phylogenies based on nuclear markers, but with higher statistical support, resolution in terminals, and compatibility with flower morphological changes. PMID- 27768155 TI - Gene expression analysis reveals important pathways for drought response in leaves and roots of a wheat cultivar adapted to rainfed cropping in the Cerrado biome. AB - Drought limits wheat production in the Brazilian Cerrado biome. In order to search for candidate genes associated to the response to water deficit, we analyzed the gene expression profiles, under severe drought stress, in roots and leaves of the cultivar MGS1 Alianca, a well-adapted cultivar to the Cerrado. A set of 4,422 candidate genes was found in roots and leaves. The number of down regulated transcripts in roots was higher than the up-regulated transcripts, while the opposite occurred in leaves. The number of common transcripts between the two tissues was 1,249, while 2,124 were specific to roots and 1,049 specific to leaves. Quantitative RT-PCR analysis revealed a 0.78 correlation with the expression data. The candidate genes were distributed across all chromosomes and component genomes, but a greater number was mapped on the B genome, particularly on chromosomes 3B, 5B and 2B. When considering both tissues, 116 different pathways were induced. One common pathway, among the top three activated pathways in both tissues, was starch and sucrose metabolism. These results pave the way for future marker development and selection of important genes and are useful for understanding the metabolic pathways involved in wheat drought response. PMID- 27768157 TI - Initial Experience With Low-Dose Methotrexate as an Adjuvant Treatment for Rapidly Recurrent Nonvasculitic Laryngotracheal Stenosis. AB - Importance: Adult laryngotracheal stenosis (LTS) is typically managed surgically, but some patients fail treatment because of rapid restenosis or granulation tissue formation. The need for frequent surgery or tracheostomy reduces the quality of life in these patients and poses a significant challenge for the treating physician. New adjuvant treatments are required to reduce the surgical burden of this condition. Objective: To examine whether patients with rapidly recurrent nonvasculitic LTS who fail surgical management of their stenosis (ie, requiring dilation more frequently than every 6 months) experience longer intervals between surgical procedures when receiving adjuvant treatment with low dose methotrexate. Design, Setting, and Participants: This study was a retrospective case series study of patients treated with methotrexate from January 2014 to January 2016 at a tertiary academic medical center. Participants were 10 patients with LTS without any diagnosis of vasculitis or granulomatous disease who underwent low-dose methotrexate therapy. Interventions: Once-weekly treatment with oral methotrexate, 15 or 20 mg. Main Outcomes and Measures: The mean number of days between operations before and after starting methotrexate therapy was compared. Clinical courses and adverse effects of each patient were also reviewed. Results: Among 10 patients, the mean (SD) age at the outset of study inclusion was 52 (19) years; 8 were female and 2 were male. All 10 patients experienced some clinical improvement. Three patients who were previously tracheostomy dependent were able to be decannulated. Two other patients who were tracheostomy dependent and had failed endoscopic management of their granulation tissue had complete resolution. In 6 patients who underwent at least 1 surgical procedure before and after the initiation of methotrexate treatment, the mean (SD) interval between operations increased from 61 (35) days (95% CI, 26-96 days) before starting methotrexate therapy to 312 (137) days (95% CI, 175-449 days) after starting methotrexate therapy, for an absolute difference of 251 (58) days (95% CI, 193-309 days). The median number of days between surgical procedures was 44 days before starting methotrexate therapy and 289 days after starting methotrexate therapy. Adverse effects observed included mild hair thinning and onychomycosis in 2 patients and herpes zoster infection in 1 patient. Conclusions and Relevance: Low-dose methotrexate appears to be an effective adjunct to surgery in select patients with LTS that is resistant to surgical management and leads to a substantial increase in the number of days between surgical procedures. The patient and clinician must be aware of the adverse effects of methotrexate therapy and balance these factors against the risk of poorly controlled airway stenosis. Randomized, placebo-controlled, double-blind trials are needed to examine whether the clinical efficacy in this series of patients translates to a larger population. PMID- 27768158 TI - Unanswered Questions Concerning Locoregional Irradiation in Breast Cancer. PMID- 27768159 TI - Long-term Survival After Chemoradiotherapy Without Surgery for Rectal Adenocarcinoma: A Word of Caution. PMID- 27768160 TI - Integrating Morbidity and Mortality Core Competencies and Quality Improvement in Otolaryngology. AB - Importance: To date, an otolaryngology-specific morbidity and mortality (M&M) conference has never been reported or evaluated. Objective: To propose a novel otolaryngology-specific M&M format and to assess its success using a validated assessment tool. Design, Setting, and Participants: Preintervention and postintervention cohort study spanning 14 months (September 2014 to November 2015), with 32 faculty, residents, and medical students attending the department of otolaryngology M&M conference, conducted at the the San Antonio Uniformed Services Health Education Consortium. Interventions: A novel quality assurance conference was implemented in the department of otolaryngology at the San Antonio Uniformed Services Health Education Consortium. This conference incorporates patient safety reports, otolaryngology-specific quality metrics, and individual case presentations. The revised format integrates the Accreditation Council for Graduate Medical Education (ACGME) core competencies and Quality Improvement and Patient Safety (QI/PS) system. This format was evaluated by faculty, residents, and medical students every other month for 14 months to assess changes in attitudes regarding the M&M conference as well as changes in presentation quality. Results: Overall, 13 faculty, 12 residents, and 7 medical students completed 232 evaluations. Summary statistics of both resident and faculty attitudes about the success of the M&M format seem to improve over the 14 months between the prequestionnaires and postquestionnaires. General attitudes for both residents and faculty significantly improved from the pretest to posttest (odds ratio, 0.32 per month; 95% CI, 0.29-0.35). In the pretest period, "established presentation format" was considered the most necessary improvement, whereas in the posttest period this changed to "incorporate more QI." For resident presentations evaluated using the situation, background, assessment, and review/recommendations (SBAR) tool, all evaluations, from all participants, improved over time. Conclusions and Relevance: The M&M conference is an essential component of all otolaryngology residency programs and provides a unique opportunity to successfully incorporate the ACGME core competencies and regularly implement QI/PS. PMID- 27768161 TI - Integrating Quality Improvement Into the Otolaryngology Morbidity and Mortality Conference. PMID- 27768162 TI - Headaches and Foggy Vision in a 21-Year-Old Woman. PMID- 27768163 TI - Choice of Analgesics After Adenotonsillectomy: Are We Between a Rock and a Hard Place? PMID- 27768164 TI - Myopia-The Silent Epidemic That Should Not Be Ignored. PMID- 27768165 TI - Better Outcomes for Lower Costs in Breast Cancer Care: Finding a Way. PMID- 27768166 TI - Oral Fluoroquinolone Use and Retinal Detachment. PMID- 27768167 TI - Active Surveillance for Low-Risk Prostate Cancer-An Evolving International Standard of Care. PMID- 27768168 TI - Uptake of Active Surveillance for Very-Low-Risk Prostate Cancer in Sweden. AB - Importance: Active surveillance is an important option to reduce prostate cancer overtreatment, but it remains underutilized in many countries. Models from the United States show that greater use of active surveillance is important for prostate cancer screening to be cost-effective. Objectives: To perform an up-to date, nationwide, population-based study on use of active surveillance for localized prostate cancer in Sweden. Design, Setting, and Participants: Cross sectional study in the National Prostate Cancer Register (NPCR) of Sweden from 2009 through 2014. The NPCR has data on 98% of prostate cancers diagnosed in Sweden and has comprehensive linkages to other nationwide databases. Overall, 32 518 men with a median age of 67 years were diagnosed with favorable-risk prostate cancer, including 4693, 15 403, and 17 115 men with very-low-risk (subset of the low-risk group) (clinical stage, T1c; Gleason score, <=6; prostate-specific antigen [PSA], <10 ng/mL; PSA density <0.15 ng/mL/cm3; and <8-mm total cancer length in <=4 positive biopsy cores), low-risk (including all men in the very-low risk group) (T1-T2; Gleason score, <=6; and PSA, <10 ng/mL), and intermediate risk disease (T1-T2 with Gleason score, 7 and/or PSA, 10-20 ng/mL). Exposures: Diagnosis with favorable-risk prostate cancer. Main Outcomes and Measures: Utilization of active surveillance. Results: The use of active surveillance increased in men of all ages from 57% (380 of 665) to 91% (939 of 1027) for very low-risk prostate cancer and from 40% (1159 of 2895) to 74% (1951 of 2644) for low-risk prostate cancer, with the strongest increase occurring from 2011 onward. Among men aged 50 to 59 years, 88% (211 of 240) with very-low-risk and 68% (351 of 518) with low-risk disease chose active surveillance in 2014. Use of active surveillance for intermediate-risk disease remained lower, 19% (561 of 3030) in 2014. Conclusions and Relevance: Active surveillance has become the dominant management for low-risk prostate cancer among men in Sweden, with the highest rates yet reported and almost complete uptake for very-low-risk cancer. These data should serve as a benchmark to compare the use of active surveillance for favorable-risk disease around the world. PMID- 27768169 TI - Oral Fluoroquinolone Use and Retinal Detachment-Reply. PMID- 27768170 TI - Noncolorectal Gastrointestinal Cancers-What Did We Learn in 2016? PMID- 27768172 TI - Pharmaceuticals and Public Health. PMID- 27768171 TI - Association of Axial Length With Risk of Uncorrectable Visual Impairment for Europeans With Myopia. AB - Importance: Myopia (ie, nearsightedness) is becoming the most common eye disorder to cause blindness in younger persons in many parts of the world. Visual impairment due to myopia is associated with structural changes of the retina and the globe because of elongation of the eye axis. How axial length-a sum of the anterior chamber depth, lens thickness, and vitreous chamber depth-and myopia relate to the development of visual impairment over time is unknown. Objectives: To evaluate the association between axial length, spherical equivalent, and the risk of visual impairment and to make projections of visual impairment for regions with high prevalence rates. Design, Setting, and Participants: This cross sectional study uses population-based data from the Rotterdam Study I (1990 to 1993), II (2000 to 2002), and III (2006 to 2008) and the Erasmus Rucphen Family Study (2002 to 2005) as well as case-control data from the Myopia Study (2010 to 2012) from the Netherlands. In total, 15 404 individuals with data on spherical equivalent and 9074 individuals with data on axial length were included in the study; right eyes were used for analyses. Data were analyzed from September 2014 to May 2016. Main Outcomes and Measures: Visual impairment and blindness (defined according to the World Health Organization criteria as a visual acuity less than 0.3) and predicted rates of visual impairment specifically for persons with myopia. Results: Of the 15 693 individuals included in this study, the mean (SD) age was 61.3 (11.4) years, and 8961 (57.1%) were female. Axial length ranged from 15.3 to 37.8 mm; 819 individuals had an axial length of 26 mm or greater. Spherical equivalent ranged from -25 to +14 diopters; 796 persons had high myopia (ie, a spherical equivalent of -6 diopters or less). The prevalence of visual impairment varied from 1.0% to 4.1% in the population-based studies, was 5.4% in the Myopia Study, and was 0.3% in controls. The prevalence of visual impairment rose with increasing axial length and spherical equivalent, with a cumulative incidence (SE) of visual impairment of 3.8% (1.3) for participants aged 75 years with an axial length of 24 to less than 26 mm and greater than 90% (8.1) with an axial length of 30 mm or greater. The cumulative risk (SE) of visual impairment was 5.7% (1.3) for participants aged 60 years and 39% (4.9) for those aged 75 years with a spherical equivalent of -6 diopters or less. Projections of these data suggest that visual impairment will increase 7- to 13-fold by 2055 in high risk areas. Conclusions and Relevance: This study demonstrated that visual impairment is associated with axial length and spherical equivalent and may be unavoidable at the most extreme values in this population. Developing strategies to prevent the development of myopia and its complications could help to avoid an increase of visual impairment in the working-age population. PMID- 27768173 TI - Translating Pivotal Trial Findings to Clinical Practice. PMID- 27768174 TI - A Modeling Study of the Effects of Vocal Tract Movement Duration and Magnitude on the F2 Trajectory in CV Words. AB - Purpose: This study used a computational vocal tract model to investigate the relationship of diphthong duration and vocal tract movement magnitude to measures of the F2 trajectory in CV words. Method: Three words (bough, boy, and buy) were simulated on the basis of an adult female vocal tract model, in which the model parameters were estimated from audio recordings of a female talker. Model parameters were then modified to generate 35 simulations of each word corresponding to 7 different durations and 5 movement magnitude settings. In addition, these simulations were repeated with vocal tract lengths representative of an adult male and an approximately 6-year-old child. Results: On the basis of univariate analysis, measures of frequency predicted changes in magnitude, and temporal measures predicted changes in speaking rate consistent with the hypothesis. The combined effects of duration and magnitude showed that F2 was more sensitive to changes in magnitude at shorter word durations compared with longer word durations. This finding held across words and vocal tract length. Conclusions: Results suggest that there is an interaction between duration and magnitude that affects the slope of the F2 trajectory. The next step is to relate kinematics to F2 trajectory output using real speakers. PMID- 27768176 TI - An Item Analysis of the French Version of the Test for Reception of Grammar Among Children and Adolescents With Down Syndrome or Intellectual Disability of Undifferentiated Etiology. AB - Purpose: An item analysis of Bishop's (1983) Test for Reception of Grammar (TROG) in its French version (F-TROG; Lecocq, 1996) was conducted to determine whether the difficulty of items is similar for participants with or without intellectual disability (ID). Method: In Study 1, responses to the 92 F-TROG items by 55 participants with Down syndrome (DS), 55 with ID of undifferentiated etiology (UND), and 55 typical children (TYP) matched on their F-TROG total score were compared using the transformed item difficulties method, a statistical approach designed to detect differential item functioning (DIF) between groups. In Study 2, an additional comparison involving 526 TYP participants and 526 participants with UND was conducted to increase the statistical power of the analysis. Results: The difficulty of items was highly similar whatever the sample size or clinical status of participants. Fewer than 3.5% of the items were flagged as showing DIF. Conclusions: Tests such as the TROG can be used with confidence in clinical practice as well as in research studies comparing participants with or without ID. Methods designed for investigating potential internal test bias-such as done here-should be more regularly employed in the developmental disability field to affirm the absence of DIF. PMID- 27768175 TI - Exploring the Clinical Utility of Relative Fundamental Frequency as an Objective Measure of Vocal Hyperfunction. AB - Purpose: Vocal hyperfunction, related to abnormal laryngeal muscle activity, is considered the proximal cause of primary muscle tension dysphonia (pMTD). Relative fundamental frequency (RFF) has been proposed as an objective acoustic marker of vocal hyperfunction. This study examined (a) the ability of RFF to track changes in vocal hyperfunction after treatment for pMTD and (b) the influence of dysphonia severity, among other factors, on the feasibility of RFF computation. Method: RFF calculations and dysphonia severity ratings were derived from pre- and posttreatment recordings from 111 women with pMTD and 20 healthy controls. Three vowel-voiceless consonant-vowel stimuli were analyzed. Results: RFF onset slope consistently varied as a function of group (pMTD vs. controls) and time (pretherapy vs. posttherapy). Significant correlations between RFF onset cycle 1 and dysphonia severity were observed. However, in many samples, RFF could not be computed, and adjusted odds ratios revealed that these unanalyzable data were linked to dysphonia severity, phonetic (vowel-voiceless consonant-vowel) context, and group (pMTD vs. control). Conclusions: RFF onset appears to be sensitive to the presence and degree of suspected vocal hyperfunction before and after therapy. The large number of unanalyzable samples (related especially to dysphonia severity in the pMTD group) represents an important limitation. PMID- 27768177 TI - Addressing Practice Gaps in Cutaneous Surgery: Advances in Diagnosis and Treatment. AB - Importance: Cutaneous surgery is performed by otolaryngologists, plastic surgeons, oculoplastic surgeons, dermatologic surgeons, and some primary care physicians. Practice gaps exist among cutaneous surgeons, as do differences in how different physicians approach preoperative, intraoperative, and postoperative decision-making. Objective: To present the newest and best evidence to close common practice gaps in cutaneous surgery. Evidence Review: We performed a detailed search of peer-reviewed publications that were identified through a search of PubMed/MEDLINE (January 1, 2000, through June 30, 2016) using the literature search terms "cutaneous surgery," "Mohs micrographic surgery," "plastic surgery," in combination with "safety," "cost," "anesthesia," "anti coagulation," "bleeding," "pain," "analgesia," "anxiety," or "infection," among others. Bibliographies from these references, as well as meta-analyses, were also reviewed. Findings: A total of 73 peer-reviewed studies, including randomized clinical trials, were selected to support the conclusions of the article. Levels of evidence were analyzed for selected studies using recommendations from the American Association of Plastic Surgeons based on guidelines from the Oxford Centre for Evidence-Based Medicine. Large cutaneous surgical resections can be done effectively and safely, taking steps to assure patient comfort under local anesthesia. Medically necessary anticoagulant and antiplatelet medication should be continued during cutaneous surgery. In preparation for surgery, patient anxiety and pain must be addressed. Music and anxiolytics limit anxiety, prevent cardiovascular compromise, and improve patient satisfaction. Cutaneous surgeons and support staff should carefully consider the dose and injection angle of local anesthetic. Postoperative opioids and topical antibiotics might cause harm to patients and should be avoided. Acetaminophen and ibuprofen provide adequate pain control with fewer adverse effects than opioid medications. Conclusions and Relevance: Clinicians performing cutaneous surgery should understand the importance of patient safety and comfort, as guided by recent evidence. PMID- 27768178 TI - How Hearing Loss and Age Affect Emotional Responses to Nonspeech Sounds. AB - Purpose: The purpose of this study was to evaluate the effects of hearing loss and age on subjective ratings of emotional valence and arousal in response to nonspeech sounds. Method: Three groups of adults participated: 20 younger listeners with normal hearing (M = 24.8 years), 20 older listeners with normal hearing (M = 55.8 years), and 20 older listeners with mild-to-severe acquired hearing loss (M = 65.6 years). Stimuli were presented via headphones at either 35 and 65 dB SPL or 50 and 80 dB SPL on the basis of random assignment within each group. Participants rated the emotional valence and arousal for previously normed nonspeech auditory stimuli. Results: Linear mixed model analyses were conducted separately for ratings of valence and arousal. Results revealed that listeners with hearing loss exhibited a reduced range of emotional ratings. Furthermore, for stimuli presented at 80 dB SPL, valence ratings from listeners with hearing loss were significantly lower than ratings from listeners with normal hearing. Conclusions: Acquired hearing loss, not increased age, affected emotional responses by reducing the range of subjective ratings and by reducing the reported valence of the highest intensity stimuli. These results have potentially important clinical implications for aural rehabilitation. PMID- 27768179 TI - Unanswered Questions Concerning Locoregional Irradiation in Breast Cancer-Reply. PMID- 27768180 TI - Association of a Bundled-Payment Program With Cost and Outcomes in Full-Cycle Breast Cancer Care. AB - Importance: Value-driven payment system reform is a potential tool for aligning economic incentives with the improvement of quality and efficiency of health care and containment of cost. Such a payment system has not been researched satisfactorily in full-cycle cancer care. Objective: To examine the association of outcomes and medical expenditures with a bundled-payment pay-for-performance program for breast cancer in Taiwan compared with a fee-for-service (FFS) program. Design, Setting, and Participants: Data were obtained from the Taiwan Cancer Database, National Health Insurance Claims Data, the National Death Registry, and the bundled-payment enrollment file. Women with newly diagnosed breast cancer and a documented first cancer treatment from January 1, 2004, to December 31, 2008, were selected from the Taiwan Cancer Database and followed up for 5 years, with the last follow-up data available on December 31, 2013. Patients in the bundled-payment program were matched at a ratio of 1:3 with control individuals in an FFS program using a propensity score method. The final sample of 17 940 patients included 4485 (25%) in the bundled-payment group and 13 455 (75%) in the FFS group. Main Outcomes and Measures: Rates of adherence to quality indicators, survival rates, and medical payments (excluding bonuses paid in the bundled-payment group). The Kaplan-Meier method was used to calculate 5 year overall and event-free survival rates by cancer stage, and the Cox proportional hazards regression model was used to examine the effect of the bundled-payment program on overall and event-free survival. Sensitivity analysis for bonus payments in the bundled-payment group was also performed. Results: The study population included 17 940 women (mean [SD] age, 52.2 [10.3] years). In the bundled-payment group, 1473 of 4215 patients (34.9%) with applicable quality indicators had full (100%) adherence to quality indicators compared with 3438 of 12 506 patients (27.5%) with applicable quality indicators in the FFS group (P < .001). The 5-year event-free survival rates for patients with stages 0 to III breast cancer were 84.48% for the bundled-payment group and 80.88% for the FFS group (P < .01). Although the 5-year medical payments of the bundled-payment group remained stable, the cumulative medical payments for the FFS group steadily increased from $16 000 to $19 230 and exceeded pay-for-performance bundled payments starting in 2008. Conclusions and Relevance: In Taiwan, compared with the regular FFS program, bundled payment may lead to better adherence to quality indicators, better outcomes, and more effective cost-control over time. PMID- 27768181 TI - Unanswered Questions Concerning Locoregional Irradiation in Breast Cancer-Reply. PMID- 27768183 TI - Internet and Audiology: A Review of the Second International Meeting. AB - Purpose: This article describes the Second International Meeting on Internet and Audiology, which took place at the Eriksholm Research Centre, Oticon A/S, Denmark September 24 to 25, 2015, and introduces the research forum arising from the meeting. Method: The potential gains of the Internet within audiology are framed within the central role of quality connections among people, ideas, and objects. First, the meeting is summarized. Second, the 11 articles arising from the meeting and collected in this research forum are grouped into 2 themes: design and evaluation. Last, the benefits of interoperability and standardization are discussed. Conclusion: We look forward to the day when the Internet is an integral part of audiology, and we invite readers to attend future editions of the International Meeting on Internet and Audiology. PMID- 27768184 TI - Hearing Device Manufacturers Call for Interoperability and Standardization of Internet and Audiology. AB - Purpose: This article describes the perspectives of hearing device manufacturers regarding the exciting developments that the Internet makes possible. Specifically, it proposes to join forces toward interoperability and standardization of Internet and audiology. Method: A summary of why such a collaborative effort is required is provided from historical and scientific perspectives. A roadmap toward interoperability and standardization is proposed. Results: Information and communication technologies improve the flow of health care data and pave the way to better health care. However, hearing-related products, features, and services are notoriously heterogeneous and incompatible with other health care systems (no interoperability). Standardization is the process of developing and implementing technical standards (e.g., Noah hearing database). All parties involved in interoperability and standardization realize mutual gains by making mutually consistent decisions. De jure (officially endorsed) standards can be developed in collaboration with large national health care systems as well as spokespeople for hearing care professionals and hearing device users. The roadmap covers mutual collaboration; data privacy, security, and ownership; compliance with current regulations; scalability and modularity; and the scope of interoperability and standards. Conclusions: We propose to join forces to pave the way to the interoperable Internet and audiology products, features, and services that the world needs. PMID- 27768185 TI - Community-Based Intervention Determines Tele-Audiology Site Candidacy. AB - Purpose: Sections of the community face barriers to accessing audiology services. The aim of this study was to assess the barriers faced by people in typically underserved community settings and to provide audiology services in their natural environment. Information gathered by questionnaire was used to determine each site's candidacy as a potential tele-audiology site. Method: Sixty-three participants were recruited across 3 community sites that were identified as gathering places for individuals who experience barriers to accessing traditional clinical audiology services. Information about demographics and participant experience with barriers to access was gathered by a locally generated, self administered questionnaire. Pure-tone air-conduction audiometric exams were performed on participants with an automated portable diagnostic audiometer. Afterward, the investigator provided counseling regarding hearing loss rehabilitation or hearing protection. Referrals were made when appropriate. Results: Pure-tone averages were similar within sites but varied across sites. At least 30% of individuals at each site reported they wanted to visit the audiologist more often. Each site reported different principal barriers to access, among them transportation, motivation, and money. Eleven individuals were referred to the next level of care. Questionnaire results revealed special accommodations should be considered at each potential tele-audiology site. Conclusion: The present study provided audiology services to individuals in their natural environment, identified many of the obstacles preventing individuals from pursuing traditional audiology services and provided information for the foundation of a tele-audiology practice. PMID- 27768186 TI - A Participatory Design Approach to Develop an Interactive Sound Environment Simulator. AB - Purpose: Our purpose is to provide insight into the added value of applying a participatory design approach in the design of an interactive sound environment simulator to facilitate communication and understanding between patients and audiologists in consultation situations. Method: We have applied a qualitative approach, presenting results and discussion in the form of a story, following 3 consecutive steps: problem investigation, design, and evaluation. Results: We provide an overview of lessons learned, emphasizing how patients and audiologists took roles and responsibilities in the design process and the effects of this involvement. Conclusion: Our results suggest that participatory design is a viable and practical approach to address multifaceted problems directly affecting patients and practitioners. PMID- 27768182 TI - Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. AB - Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials. PMID- 27768187 TI - Design Considerations for Internet-Delivered Self-Management Programs for Adults With Hearing Impairment. AB - Purpose: Hearing impairment (HI) is a chronic condition; thus, even with treatment, residual participation restrictions and activity limitations typically remain. Individuals must learn to self-manage their HI. The purpose of this research note is to review components of successful Internet-based self management programs and to evaluate group auditory rehabilitation (AR) programs with varying content, in order to make recommendations for the design of future Internet-based self-management programs. Method: Effect sizes for changes in HI specific quality of life following group AR activities from 4 published studies were calculated to determine if effect size varied systematically as a function of group activities. These findings are described using a self-management framework. Results: Successful group AR activities include (a) psychosocial activities to promote role management, emotional management, and social support; (b) informational lectures and group discussion to promote education; (c) communication strategy exercises to promote self-efficacy and self-management skills; and (d) the inclusion of a frequent communication partner to promote social support and self-tailoring. Conclusions: It is recommended that future Internet-based self-management programs focus on the mechanisms of social support and education to promote learning and self-management skills. Future research will determine if these AR activities may be implemented effectively via the Internet. PMID- 27768188 TI - Use and Mediating Effect of Interactive Design Features in Audiology Rehabilitation and Self-Management Internet-Based Interventions. AB - Purpose: The purpose of this study is to explore the presence of key interactive design features across Internet-based audiology rehabilitation and self management interventions, and whether there is evidence of them mediating effects of the intervention. Method: Adult audiology interventions relevant to this review were identified through a literature search in Google Scholar and a hand search of key journals. Four key interactive design features that have been proposed to mediate the effects of Internet-based health interventions were reported for each intervention: social context and support, contacts with the intervention, tailoring, and self-management. Results: Five interventions were identified as representative examples of work in the field. Social context and support and contacts with the intervention were provided in most interventions, mainly through clinician guidance. Only 1 intervention utilized tailoring to personalize intervention content to individual users, but use was minimal. Self management features were also used in all interventions but the precise nature of these features was poorly reported. Conclusion: Future studies should assess the optimal dose and combinations of intervention features for maximizing efficacy in audiology intervention. To be specific, the role of tailoring should be explored, which has been identified as a potential mediator of intervention outcome in the wider e-health literature. PMID- 27768189 TI - Usability and Online Audiological Rehabilitation. AB - Purpose: This paper describes the results from the iterative development and usability testing of an online audiological rehabilitation (OAR) program. The OAR was based on previous experience with Internet interventions and OAR. Method: The described OAR consisted of weekly learning modules, each of which had a specific topic and contained information and learning activities. A virtual coach, a trained audiologist, led the participants through the modules. The participants' feedback was collected using the "think-aloud" method in which the participants gave their feedback in a structured manner. Results: The early findings from the first version of the OAR showed that participants had difficulty navigating the system. As a result of the usability testing, a second major edition of the OAR program was developed, and the participants found it easier to manage and that it enhanced the learning experience. The participants appreciated the testimonial videos as well as the option to study more in-depth material for a given subject. Conclusions: The early findings from the usability test of the program provided useful information as to how content can be developed and delivered for optimal user accessibility within the scope of OAR. PMID- 27768190 TI - Development and Technical Validation of the Mobile Based Assistive Listening System: A Smartphone-Based Remote Microphone. AB - Purpose: The purpose of this research note is to describe the development and technical validation of the Mobile Based Assistive Listening System (MoBALS), a free-of-charge smartphone-based remote microphone application. Method: MoBALS Version 1.0 was developed for Android (Version 2.1 or higher) and was coded with Java using Eclipse Indigo with the Android Software Development Kit. A Wi-Fi router with background traffic and 2 affordable smartphones were used for debugging and technical validation comprising, among other things, multicasting capability, data packet loss, and battery consumption. Results: MoBALS requires at least 2 smartphones connected to the same Wi-Fi router for signal transmission and reception. Subscriber identity module cards or Internet connections are not needed. MoBALS can be used alone or connected to a hearing aid or cochlear implant via direct audio input. Maximum data packet loss was 99.28%, and minimum battery life was 5 hr. Other relevant design specifications and their implementation are described. Conclusions: MoBALS performed as a remote microphone with enhanced accessibility features and avoids overhead expenses by using already-available and affordable technology. The further development and technical revalidation of MoBALS will be followed by clinical evaluation with persons with hearing impairment. PMID- 27768191 TI - International Survey of Audiologists' Attitudes Toward Telehealth. AB - Purpose: A better understanding of the attitudes of audiologists toward teleaudiology and their willingness to use teleaudiology is required to progress the application of teleaudiology technologies and services into clinical practice. Audiologists around the world were surveyed on their attitudes toward teleaudiology and their willingness to use it. Method: An online survey was sent to audiologists through professional associations' mailing lists. The survey included questions on the use of computer and video-conferencing technologies, awareness and previous use of teleaudiology, and willingness to use teleaudiology. Results: Responses were provided by 269 people from 28 different countries, representing a wide cross-section of experience, qualification, and work settings; 77.8% of respondents were women. Almost all respondents had used PC-based video-conferencing; most had used related technologies and reported positive attitudes toward using these. However, less than 25% had used teleaudiology. Conclusions: Despite positive attitudes toward telehealth and associated technology, the low number of audiologists who have used teleaudiology for services indicates limited clinical adoption. PMID- 27768192 TI - Have Cochlear Implant, Won't Have to Travel: Introducing Telemedicine to People Using Cochlear Implants. AB - Purpose: This research note describes a planned project to design, implement, and evaluate remote care for adults using cochlear implants and compare their outcomes with those of individuals following the standard care pathway. Method: Sixty people with cochlear implants will be recruited and randomized to either the remote care group or a control group. The remote care group will use new tools for 6 months: remote and self-monitoring, self-adjustment of device, and a personalized online support tool. The main outcome measure is patient empowerment, with secondary outcomes of stability in hearing and quality of life, patient and clinician preference, and use of clinic resources. Conclusion: The clinical trial ends in summer 2016. Remote care may offer a viable method of follow-up for some adults with cochlear implants. PMID- 27768193 TI - Internet Competency Predicts Practical Hearing Aid Knowledge and Skills in First Time Hearing Aid Users. AB - Purpose: The purpose of the study was to assess whether Internet competency predicted practical hearing aid knowledge and handling skills in first-time hearing aid users. Method: The design was a prospective, randomized controlled trial of a multimedia educational intervention consisting of interactive video tutorials (or reusable learning objects [RLOs]). RLOs were delivered through DVD for TV or PC, and online. Internet competency was measured at the hearing aid fitting appointment, whereas hearing aid knowledge and practical handling skills were assessed 6 weeks postfitting. Results: Internet competency predicted practical hearing aid knowledge and handling skills, controlling for age, hearing sensitivity, educational status, and gender for the group that received the RLOs. Internet competency was inversely related to the number of times the RLOs were watched. Conclusion: Associations between Internet competency and practical hearing aid knowledge, handling skills, and watching the RLOs fewer times may have arisen because of improved self-efficacy. Therefore, first-time hearing aid users who are more competent Internet users may be better equipped to apply newly learned information to effectively manage their hearing loss. PMID- 27768194 TI - Can a Commercially Available Auditory Training Program Improve Audiovisual Speech Performance? AB - Purpose: The goal of this study was to determine whether hearing aids in combination with computer-based auditory training improve audiovisual (AV) performance compared with the use of hearing aids alone. Method: Twenty-four participants were randomized into an experimental group (hearing aids plus ReadMyQuips [RMQ] training) and a control group (hearing aids only). The Multimodal Lexical Sentence Test for Adults (Kirk et al., 2012) was used to measure auditory-only (AO) and AV speech perception performance at three signal to-noise ratios (SNRs). Participants were tested at the time of hearing aid fitting (pretest), after 4 weeks of hearing aid use (posttest I), and again after 4 weeks of RMQ training (posttest II). Results: Results did not reveal an effect of training. As expected, interactions were found between (a) modality (AO vs. AV) and SNR and (b) test (pretest vs. posttests) and SNR. Conclusion: Data do not show a significant effect of RMQ training on AO or AV performance as measured using the Multimodal Lexical Sentence Test for Adults. PMID- 27768195 TI - Online Data Collection to Evaluate a Theoretical Cognitive Model of Tinnitus. AB - Purpose: The purpose of this article is to describe data collection considerations, methods, and response rates for a survey available both online and on paper. Methodological issues in the design of online data collection, and advantages and disadvantages of different data collection methods are discussed. Method: A survey was compiled that included 9 full or partial clinical questionnaires designed to measure different components relevant to tinnitus distress. It was completed once by 342 members of the public with tinnitus. Respondents could choose whether to complete the survey online or on paper. Results: Ninety-five percent of participants chose to complete the survey online. The advantages of an online self-administered questionnaire include low numbers of unanswered questions, convenience (particularly in a longer survey such as this), a fast return rate, and reduced expense. Age emerged as an important variable, with those opting to complete the paper-based version of the survey being older. Conclusions: Online data collection has several advantages to both participants and researchers. However, cross-sectional studies such as that presented here should also offer paper questionnaires to avoid excluding certain subgroups of the population. Ethics and reporting guidelines for Internet delivered questionnaire studies are available. These can usefully inform study design and guide high-quality reporting. PMID- 27768196 TI - Correction of Age-Related Midface Volume Loss With Low-Volume Hyaluronic Acid Filler. AB - Importance: The pivotal approval trial for a smooth, highly cohesive, viscous, 20 mg/mL hyaluronic acid filler demonstrated sustained aesthetic improvement, with a mean injection volume of 6.65 mL. In daily practice, however, it is not often practical or necessary to use large injection volumes to achieve the desired cosmetic outcome. Objective: To assess the efficacy, longevity, and patient satisfaction associated with correction of age-related midface volume loss using the low volumes of hyaluronic acid filler more commonly used in day-to-day practice. Design, Setting, and Participants: A 2-center, retrospective cohort study examined medical records of 61 healthy patients who underwent treatment for facial volume loss with hyaluronic acid filler from November 1, 2013, through April 31, 2014. Follow-up visits were conducted at 1, 3, 6, and 12 months after the procedure. Data were pooled from a private facial plastic surgery practice in Weston, Florida, and a private cosmetic dermatology practice in San Diego, California. Interventions: Patients were treated with hyaluronic acid filler according to the investigator's usual practices. Main Outcomes and Measures: The main outcome measure was patient-graded Global Aesthetic Improvement Scale scores at 1, 3, 6, and 12 months after treatment. Scores range from 1 to 5; 1 indicates very much improved and 5, worse. Results: A total of 61 consecutive, healthy adult patients (mean [SD] age, 57.4 [12.8] years) with mild to severe facial volume loss were enrolled in the study. A total of 46 patients (75%) were white, 3 (5%) were black/African American, 9 (15%) were Hispanic/Latino, 1 (2%) was Asian/Pacific Islander, and 2 (3%) were other. Three patients (5%) were male, and 58 (95%) were female. Mean initial treatment volume was 1.6 mL. At follow-up, 29 patients (48%) elected to have a touch-up treatment; mean total touch-up volume was 1.4 mL. The patient-graded Global Aesthetic Improvement Scale scores at 1, 3, 6, and 12 months after treatment demonstrated that 73% (41 of 56) to 89% (24 of 27) of the study patients reported being very much or moderately improved. Most patients were rated by investigators on the Global Aesthetic Improvement Scale as very much or moderately improved at the 12-month follow-up. At 12 months after the procedure, 43 of 51 patients (84%) reported satisfaction with their outcome. At all time points, most patients would elect to undergo the procedure again (range, 17 [68%] to 61 [100%]). Adverse events were mild, and all resolved spontaneously within 14 days. At the 2-year follow-up, there were no reports of delayed adverse events. Conclusions and Relevance: Midface volumization using the low volumes of hyaluronic acid filler more commonly used in daily clinical practice is effective and well tolerated. Level of Evidence: 3. PMID- 27768197 TI - Updated Affiliation and Contact Information. PMID- 27768200 TI - Study of the inhibition effect of thiazone on muscle optical clearing. AB - We investigated the effect of thiazone, a widely used penetration enhancer, on in vitro porcine skin and muscle tissue by single-integrating sphere technique during optical clearing (OC) treatment. The results showed that thiazone induced an increase on the total transmittance of skin which led to a reduction in that of muscle in the spectral range from 400 to 800 nm. Small particles crystalized out from the thiazone-treated muscle were observed by microscopy imaging. With the help of x-ray diffraction measurement, we ascertained that the crystal was a single-crystal of thiazone, which mainly induced an increase of the scattering. Contrast transmittance measurements carried on the mixture of water, thizaone propylene glycol solution showed that the free water in muscle could be the main reason for the thiazone crystallization. Therefore, during OC treatment of thiazone, the remarkable effect on skin and the noticeable inhibition effect on subcutaneous muscle tissue after penetrating into the skin should be considered. The experimental results provide such a reference for the choice of penetration enhancer. PMID- 27768201 TI - Correction. PMID- 27768202 TI - Genomic Disruption of VEGF-A Expression in Human Retinal Pigment Epithelial Cells Using CRISPR-Cas9 Endonuclease. AB - Purpose: To employ type II clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonuclease to suppress ocular angiogenesis by genomic disruption of VEGF-A in human RPE cells. Methods: CRISPR sequences targeting exon 1 of human VEGF-A were computationally identified based on predicted Cas9 on- and off-target probabilities. Single guide RNA (gRNA) cassettes with these target sequences were cloned into lentiviral vectors encoding the Streptococcuspyogenes Cas9 endonuclease (SpCas9) gene. The lentiviral vectors were used to infect ARPE 19 cells, a human RPE cell line. Frequency of insertion or deletion (indel) mutations was assessed by T7 endonuclease 1 mismatch detection assay; mRNA levels were assessed with quantitative real-time PCR; and VEGF-A protein levels were determined by ELISA. In vitro angiogenesis was measured using an endothelial cell tube formation assay. Results: Five gRNAs targeting VEGF-A were selected based on the highest predicted on-target probabilities, lowest off-target probabilities, or combined average of both scores. Lentiviral delivery of the top-scoring gRNAs with SpCas9 resulted in indel formation in the VEGF-A gene at frequencies up to 37.0% +/- 4.0% with corresponding decreases in secreted VEGF-A protein up to 41.2% +/- 7.4% (P < 0.001), and reduction of endothelial tube formation up to 39.4% +/- 9.8% (P = 0.02). No significant indel formation in the top three putative off-target sites tested was detected. Conclusions: The CRISPR-Cas9 endonuclease system may reduce VEGF-A secretion from human RPE cells and suppress angiogenesis, supporting the possibility of employing gene editing for antiangiogenesis therapy in ocular diseases. PMID- 27768203 TI - Comprehensive Three-Dimensional Analysis of the Neuroretinal Rim in Glaucoma Using High-Density Spectral-Domain Optical Coherence Tomography Volume Scans. AB - Purpose: To describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter. Methods: Neuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-MUm reference surface-based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves. Results: The MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-MUm reference surface had diagnostic capabilities similar to RNFL thickness. Conclusions: The 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors. PMID- 27768205 TI - Fibonacci-compliant finger design. AB - PURPOSE: This work presents the mechanical design of 4 configurations of compliant fingers in order to address the need for commercially feasible prosthetic and robotic hands. METHODS: The fingers consist of a single part and utilize a compliant mechanism to reduce the cost and control complexity. The geometric parameters of the compliant finger designs follow the Fibonacci series. The first and second compliant fingers have 2 joints and 2 degrees of freedom. The others have 3 joints and 3 degrees of freedom. The type of flexure hinges of the compliant finger are single and multiple nonsymmetrical circular hinges. RESULTS: The finite element method (FEM) was used to verify the range of motion of the joints in the compliant finger. In addition, the study defines the finger tip trajectory of these configurations. The multiple flexure hinges have minimum stress. CONCLUSIONS: This study presents affordable, single-element, compliant finger designs and their presumable hypothetical design variables are defined by the Fibonacci series. This method is faster and simpler than optimization. The study identifies the application of each finger design for either prosthetic or robotic purposes. PMID- 27768204 TI - In vitro performance investigation of SynCardiaTM Freedom(r) driver via patient simulator mock loop. AB - PURPOSE: The gold standard therapy for patients with advanced heart failure is heart transplant. The gap between donors and patients in waiting lists promoted the development of circulatory support devices, such as the total artificial heart (TAH). Focusing on in vitro tests performed with CardioWestTM TAH (CW) driven by the SynCardia Freedom(r) portable driver (FD) the present study goals are: i) prove the reliability of a hydraulic circuit used as patient simulator to replicate a quasi-physiological scenario for various hydrodynamic conditions, ii) investigate the hydrodynamic performance of the CW FD, iii) help clinicians in possible interpretation of clinical cases outcomes. METHODS: In vitro tests were performed using a mechanic-hydraulic patient simulator. Cardiac output (CO), CW ventricles filling, atrial, ventricles, aortic and pulmonary artery pressures were measured for different values of vascular resistance in both systemic (SVR) and pulmonary (PVR) physiological range. RESULTS: After increasing the PVR, the left atrial pressure decreased according to the expected physiological trend, while aortic pressure remained almost stable, proving the ability of the simulator to mimic a physiological scenario. Unexpectedly, the mean pulmonary artery pressure (PPA) was found to increase above 30 mmHg in the range of physiological PVR (2.6 WU) and for constant CO. CONCLUSIONS: The increase in PPA is probably associated with the pre-set driving setup of the FD. The finding suggests a possible explanation of the clinical course of a patient who experienced complications soon after being supported by the FD, with the occurrence of dyspnea and pulmonary edema despite a high cardiac index. PMID- 27768206 TI - Straight configuration saphenous vein transposition to popliteal artery for vascular access. AB - INTRODUCTION: The saphenous vein is commonly used as a vascular graft in peripheral artery surgery but rarely used for vascular access. The literature on straight configuration saphenous vein transposition to the popliteal artery is scarce. Here we present two cases of straight configuration saphenous vein transposition to the popliteal artery for vascular access, the surgical technique and respective follow-up. CASE REPORT: Two young men, aged 29 and 36 years, were chosen for lower-limb vascular access for hemodialysis. The first patient was paraplegic since birth. He used his arms to move so upper extremity vascular access was avoided. The second patient presented with an infected upper extremity arteriovenous graft (AVG) and after multiple closed AVFs he had no more available arm veins. Both patients received autologous lower extremity straight configuration saphenous vein transpositions to the popliteal artery under spinal anesthesia in May and October 2012, respectively. Cannulation of the fistula was allowed after one month. There were no early complications. Slight swelling on the leg appeared in one of the patients. Both fistulas were still functional after 36 and 32 months, respectively. CONCLUSIONS: The straight configuration saphenous vein transposition to popliteal artery is simple to perform, offers a long and straight segment for cannulation and may be a suitable autologous vascular access in selected patients. PMID- 27768207 TI - Repeated mappings of arm veins by physical examination: role of nephrologists in the selection of suitable veins for AV fistula surgery. AB - Multidisciplinary team work is important for a successful hemodialysis vascular access program. The authors present a clinical case to illustrate the potential dynamic factors that can affect vein sizes, independent from the operators' skills and experiences. Therefore, if the first examination fails to detect suitable veins, repeated examinations of arm veins by nephrologists during routine office visits may greatly assist the surgeons in the selection of suitable arm veins for arteriovenous fistula surgery. PMID- 27768208 TI - Subscapular abscess associated with buttonhole cannulation technique of arteriovenous fistula for hemodialysis access. PMID- 27768209 TI - Distinct impact of three different statins on arteriovenous fistula outcomes: a retrospective analysis. AB - PURPOSE: Whether statins improve arteriovenous fistula (AVF) outcomes is still a matter of debate. Taking into consideration the existing physicochemical differences between individual drugs, this study evaluates the impact of three different statins (atorvastatin, rosuvastatin and simvastatin) on one-stage and two-stage AVF outcomes. METHODS: Using a retrospective cohort of 535 patients, we analyzed the effects of each statin on primary failure and primary patency using multivariate logistic regressions and Cox proportional hazard models. RESULTS: Out of the three statins analyzed, only atorvastatin improved the overall primary failure of AVF (odds ratio [OR] = 0.18, p = 0.005). Comparisons between the two AVF types demonstrated that this effect was due to a prominent reduction in primary failure of one-stage (OR = 0.03; p = 0.005), but not two-stage fistulas (OR = 0.43; p = 0.25). In contrast, primary patency of two-stage (hazards ratio [HR] = 0.51; p = 0.024), but not one-stage fistulas (HR = 0.98; p = 0.95), was improved by all statins as a group, but not by individual drugs. CONCLUSIONS: Our results suggest that the potential benefit of statins on AVF outcomes is a drug specific and not a class effect, and that such effect is also influenced by the type of fistula. PMID- 27768210 TI - Fracture of totally implanted central venous access devices: a propensity-score matched comparison of risks for Groshong silicone versus polyurethane catheters. AB - PURPOSE: To evaluate retrospectively the fracture risk of totally implanted venous access devices connected to Groshong silicone (SC) versus polyurethane (PU) catheters, inserted via the internal jugular vein. MATERIALS AND METHODS: The study population comprised 384 SC and 221 PU central venous catheters implanted via the internal jugular vein. The presence of catheter fracture was evaluated. Variables possibly related to catheter fracture were evaluated. First, in order to determine the factors associated with fracture, fracture rates were compared with the log-rank test between the two groups divided by each of the variables. Then, in order to adjust for potential confounders, propensity-score matching of the variables was employed in the two catheter groups. Finally, the rates of fracture were compared between the two propensity-score-matched catheter groups. RESULTS: There were 16 cases of catheter fracture, for an overall fracture percentage of 2.6% (16/605). All 16 cases of fracture occurred in the SC catheter group. Smaller patient body mass index (p = 0.039), deeper catheter tip position (p = 0.022), and SC catheters (p = 0.019) were significantly associated with fracture. With the propensity-score-matching method, 180 cases were selected in each catheter group. Comparison of the two propensity-score-matched groups showed that fracture rates for SC catheters remained significantly (p = 0.018) higher than those for PU catheters. CONCLUSIONS: Ports connected to Groshong SC catheters - when implanted via the internal jugular vein - posed a higher risk of fracture than did ports connected to PU catheters. PMID- 27768211 TI - Quality-of-life assessment: arm TIVAD versus chest TIVAD. AB - INTRODUCTION: Venous access devices are essential for the provision of care for patients requiring chemotherapy. Totally implanted venous access devices (TIVADs), also known as ports, are an option for infusion care. Medical devices have an impact upon patient quality of life. We assessed the impact on quality of life and satisfaction with their venous device, for patients with a chest TIVAD versus an upper arm TIVAD. MATERIALS AND METHODS: Sequential subjects were administered a questionnaire, "Quality of Life Assessment, Venous Device - Port (QLAVD-P)" at the time of their TIVAD removal. All subjects consented to complete the questionnaire and volunteered for this assessment. The TIVADs were all implanted and removed in the medical imaging department. RESULTS: Between March 1, 2014 and August 30, 2015, 127 subjects completed the QLAVD-P. At the time of their port removal, 51 had chest ports while 76 had arm ports. There were some negative features of the chest ports that were statistically significant in comparison to the arm ports. Most of the subjects felt that their port had a positive impact upon their treatment and they would have another port inserted if required for future treatment. DISCUSSION: Quality of life for those requiring intravenous chemotherapy is very important. This should be considered when selecting an infusion device. Venous ports were positively received by the subjects in our study and there were fewer negative impacts upon subject satisfaction and quality of life for those with upper-arm devices. PMID- 27768212 TI - Foreword. AB - If we think about the launch date of Mitomycin C, we could think that this supplement is very much focused on history of Medicine, and, yes, Mitomycin certainly has been a main contributor to the history of Urology. However, it is even more striking to think that even after fifty years of its use by Urologists worlwide, Mitomycin C remains an absolute "Must". The simplicity of use, the efficacy and the tolerability of Mitomycin explain its established role. In fact, "long standing" does not mean "old". The new technologies, introduced progressively in the last decades, have fully confirmed the present and future role of this drug, that is well illustrated in the articles contained in this supplement. I hope you will enjoy reading it and (re)discovering Mitomycin C. PMID- 27768213 TI - Radiofrequency-induced thermo-chemotherapy effect (RITE) for non muscle invasive bladder cancer treatment: current role and perspectives. AB - OBJECTIVE: An updated review of intravesical radiofrequency (RF)-induced thermo chemotherapy effect (RITE) for NMIBC with regard to efficacy, adverse events (AEs) and perspectives. EVIDENCE ACQUISITION: An extensive and sensitive search for RF-induced chemo-hyperthermia in Medline, Embase, Cochrane and ClinicalTrials.gov databases was performed. A table of published clinical trials up to 2016 was constructed. No meta-analysis could be performed on the basis of new papers. EVIDENCE SYNTHESIS: Recurrence was seen 59% less after RITE than after mitomycin C (MMC) alone in adjuvant clinical setting with an overall bladder preservation rate after RITE of 85%. The efficacy was proved to be comparable to that of Bacillus Calmette-Guerin (BCG), based on a single comparative multicentric study. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The AE rate in RITE was higher, although not statistically significant, than MMC alone and similar to that of BCG, albeit different in the type of AE. In almost all studies, no severe AEs are reported. CONCLUSIONS: RITE appears as a promising treatment option for NMIBC, particularly for high-risk patients with recurrent tumors, for those unsuitable for radical cystectomy and when Bacillus Calmette-Guerin treatment is contraindicated. Further high-level evidence is needed for both reliable and reproducible data on efficacy and adverse events. PMID- 27768214 TI - Metal-on-polyethylene is not an option after the fracture of a ceramic component of a total hip arthroplasty. PMID- 27768215 TI - Refixation, allograft and adjuvant cell therapy to treat nonunion of the femoral neck in a child. AB - INTRODUCTION: Idiopathic posttraumatic nonunion is a rare condition in children; the treatment of this complication is still controversial in this peculiar population. CASE REPORT: We report a case of a subcapital type II femoral neck fracture, in a 12-year-old boy, which was initially treated by internal fixation and subsequently went on to a nonunion at the femoral neck, in absence of infection or other disease.1 year after index surgery we performed surgical debridement and refixation with plate and bone allograft, added with autologous bone marrow aspiration concentrate (BMAC) and platelet-rich fibrin (PRF).After 3 months the nonunion healed and the boy was allowed full weight-bearing. CONCLUSIONS: Combined surgery and adjuvant cell therapy can be considered an option of treatment in nonunion of the femoral neck in the paediatric population. PMID- 27768216 TI - Effects of various anchoring components and loading conditions on primary stability of acetabular revision implant. AB - PURPOSE: In revision total hip arthroplasty, until today, orthopaedic surgeons are missing evidence-based guidelines on cementless acetabular cup fixation. METHODS: 5 finite element models were generated featuring the following anchorage strategies: 1 short peg, 1 long peg, 2 long screws, 3 short screws and zero anchoring components for reference. The micromotions at the implant-bone interface were analyzed for 3 different loadcases, "Seated leg-crossing" (joint force 940 N, impingement force 750 N), "Normal gait" (joint force 1820 N), and "Stumbling" (joint force 4520 N). RESULTS: Within the same loadcase, percentages of interface area below 28 um are nearly identical in all anchorage strategies. The average percentage of interface area below 28 um is 31% for "Seated leg crossing", 17% for "Normal gait", and 11% for "Stumbling". Maximal von Mises stresses in "Normal gait", for example, reach 12 MPa in the short peg, 48 MPa in the long peg, 15 MPa in 1 of the 2 long screws, and 85 MPa in 1 of the 3 short screws. CONCLUSIONS: Common orthopaedic practice, to use peg or screw fixation alternatively according to bone availability or other clinical aspects, can be confirmed. The short peg may be a good alternative to the long peg with regard to the preservation of bone stock. However, the current study implies that the extent of potential osseointegration depends less on the chosen anchorage strategy but strongly on postoperative loading conditions. Total hip patients should be instructed on adequate postoperative activities. PMID- 27768217 TI - Normal values and variation of radiographic and CT infant lateral iliac wall angles in normal and dysplastic hips. AB - PURPOSE: Indices from 3-D ultrasound may have a role in developmental dysplasia of the hip (DDH) assessment, but require a way to determine spatial orientation relative to body axes. The lateral iliac wall angle is a potentially suitable reference axis in 3-D ultrasound. We sought to quantify normal values and variations of the infant iliac wall angle on radiography, and compare with computed tomography (CT). METHODS: Acetabular and lateral iliac angles were measured on frontal pelvic radiographs of 200 patients (400 hips, 183 with DDH) and coronal CT of 20 patients (40 hips) aged 0-12 months. Relationships among morphologic indices and demographics were assessed using linear regression, Welch's t-test, Pearson's correlation coefficient (r) and coefficients of variance (CoV). Reliability was assessed using intra-class correlation coefficients (ICC). RESULTS: The radiographic iliac angle averaged 53.0 degrees +/- 7.7 degrees (mean +/- standard deviation; 95% CI, 38 degrees -68 degrees ) in DDH vs. 56.2 degrees +/- 6.7 degrees (95% CI, 43 degrees -69 degrees ) in normal hips (p<0.001), correlated weakly with age (r = 0.25), and showed no inter sex differences (p = 0.79). Inter-reader and intra-reader reliability were ICC = 0.946 and 0.965. CT iliac angle had mean difference 5.8 degrees +/- 6.2 degrees (p<0.01), CoV = 10% and r = 0.68 vs. corresponding radiographs. CONCLUSIONS: The radiographic infant lateral iliac wall angle has mean value 53-56 degrees in dysplastic and normal hips with consistent range of variation approximately +/-15 degrees , was measured with high reliability, does not differ by sex, and is only slightly lower in the youngest infants. The iliac wall angle is an unbiased reference axis that may be suitable to establish general spatial orientation of 3 D hip ultrasound images. PMID- 27768218 TI - Varus will have varus; a radiological study to assess and predict varus stem placement in uncemented femoral stems. AB - BACKGROUND: Varus inclination of the uncemented stem is not necessarily a technical error. The proximal femoral anatomy of hips with a coxa vara deformity frequently predisposes varus inclination. METHODS: We reviewed a series of 200 patients undergoing primary uncemented THA with the Corail(r) hip system. Preoperative data were based on patient demographics, diagnosis, and radiographic information (preoperative templating-CT measurements), and compared postoperative alignment for each stem and type of stem used. Proximal femoral traits which can alert surgeons, when templating preoperatively, to potential varus alignment were noted. RESULTS: All stems were inserted either in neutral or varus alignments. Low neck shaft angle is strongly predictive of increased varus stem alignment (p<0.001). Stems inserted with higher varus alignment were associated with the preoperative morphological traits associated with coxa vara hip deformities - increased femoral offset (p<0.001), greater trochanteric overhang (p<0.001), greater trochanteric height (p<0.046), and a lower canal flare index (p<0.046). CONCLUSIONS: Varus stem alignment is neither unexpected nor necessarily a technical failure when using this particular uncemented stem system. Coxa vara deformities, due to a combination of morphological traits, are more likely to be inserted with higher varus alignment than hips with normal or higher neck shaft angles. Surgeons need to be aware of this when carrying out preoperative templating and intraoperative assessment, in order to prevent over-compensation for offset, length or stability. PMID- 27768219 TI - Head-neck taper corrosion following total hip arthroplasty with Stryker Meridian stem. AB - BACKGROUND: Taper corrosion at the modular junctions of total hip arthroplasty (THA) femoral stems are known to cause locally destructive adverse local tissue reaction (ALTR). However, the implants at risk remain to be fully elucidated. CASE REVIEW: We report the case of a 76-year-old woman with hip pain, abductor weakness, and sciatic nerve symptoms 2 years following metal-on-polyethylene THA. Serum cobalt levels were elevated, while chromium levels were normal. Magnetic resonance imaging demonstrated ALTR. The patient's symptoms resolved following head and liner exchange with ceramic head and titanium sleeve. LITERATURE REVIEW: Previous studies have reported ALTR secondary to head-neck taper corrosion in cobalt chrome alloy and titanium alloy stems used in metal-on-polyethylene (MoP) THA. The stems described above span 4 manufacturers with varying taper geometries. To our knowledge, this is the first report of ALTR due to head-neck taper corrosion in a Stryker Meridian titanium-molybdenum-zirconium-iron (TMZF) alloy stem. CLINICAL RELEVANCE: Close surveillance for ALTR may be considered in patients with this prosthesis. Further investigation of the TMZF alloy and V40 taper geometry of this stem may guide future implant design. PMID- 27768220 TI - GNRH-agonist or antagonist in the treatment of prostate cancer: a comparision based on oncological results. AB - On the basis of the trials available, are we ready to consider GnRH antagonists better than agonists? Is there a population of patients who may benefit from antagonists more than agonists?We specifically focused our analysis on the significance of oncological results obtained in phase III trials directly comparing Degarelix with GnRH agonists. Oncological results were evaluated only in 1 trial (CS21) with some subanalysis and they were not the primary endpoints of the study. The follow-up duration was 364 days, and therefore, the number of events (all causes deaths and prostate cancer (PC), Prostate Specific Antigen (PSA), Hazard ratio (HR)-related deaths) was very low in both groups and this aspect strongly reduces the significance of overall survival evaluation. In our opinion, the CS21A open-label extension does not consent to obtain useful clinical data and the design of the study loses the possibility to have a longer randomized comparison between degarelix and agonist. Moreover, the fact that the crossover from leuprolide to degarelix was pre-defined at 12 months and not at agonist failure does not allow to gather data also on the effect of sequential treatment.The answer to the question whether we are ready to consider antagonists better than agonists, based on oncological results, is probably no. We have data in terms of testosterone suppression and PSA control rather than overall survival or clinical progression free survival. A PSA progression-free survival is a secondary endpoint that in our opinion is not sufficient. Large prospective comparative trials with long-term follow-up are needed to clarify this critical clinical question. PMID- 27768221 TI - Renal fungus ball: a challenging clinical problem. AB - INTRODUCTION: We describe a case of renal pelvi-ureteric fungus ball managed with placement of two nephrostomy tubes and amphotericin B irrigation through a nephrostomy tube with the other to free drain. CASE REPORT: A 46-year-old man with uncontrolled Type 2 diabetes mellitus was referred to the urology clinic for workup of recurrent urinary tract infection. Urine culture grew Candida albicans. The patient was started on oral fluconazole therapy. Cystoscopy and cystogram revealed a grade 3 left vesicoureteral reflux and right retrograde pyelogram revealed a filling defect in the right renal pelvis extending into the proximal ureter with severe hydroureteronephrosis. Two nephrostomy tubes were placed (mid pole and lower pole) to ensure that the system was not obstructed. Amphotericin B (50 mg/1000 ml normal saline) irrigation was then instilled through the mid-pole nephrostomy tube at a rate of 30 ml/h with the lower pole nephrostomy tube to free drain. An antegrade nephrostogram was performed after 5 days of amphotericin B instillation, showing complete resolution of the fungus ball. The patient is awaiting definitive minimally invasive management of the distal ureteral narrowing. COMMENTS: Renal and pelvi-ureteric fungus ball is a challenging clinical entity. It must be addressed promptly and efficiently to be successful. We describe a minimally invasive approach that was tolerated well and resulted in complete clearance of the fungus ball in a relatively short time frame. PMID- 27768222 TI - Histologic subtypes of ovarian carcinoma: selected diagnostic and classification problems in Bulgaria: is low hospital volume an issue? AB - PURPOSE: To provide an overview of the morphologic subtypes of ovarian carcinomas in Bulgaria in relation to current healthcare organization using Bulgarian National Cancer Registry data. Further, we investigated hospital volume as a factor influencing the quality of care for patients with ovarian cancer. METHODS: Bulgarian National Cancer Registry ovarian carcinoma data were retrieved (2009 2011) and distribution of histologic types was analyzed. Cases were divided and compared with respect to main treatment: no surgery, surgery at hospitals dealing with >=30 ovarian cancer patients/year (high volume), and surgery at hospitals dealing with <30 ovarian cancer patients/year (low volume). We then estimated the odds of being diagnosed with adenocarcinoma and carcinoma not otherwise specified (NOS) vs specified morphologies (serous, endometrioid, clear cell, and mucinous), including age, grade, stage, and hospital volume, in a logistic regression model. RESULTS: A total of 2,041 ovarian carcinomas were distributed as follows: serous 47.7%, mucinous 11.9%, endometrioid 5.8%, clear cell 1.8%, and adenocarcinoma and carcinoma NOS 32.5%. More than half of cancer patients (n = 1,100, 53.9%) were surgically treated in low-volume hospitals and they had a larger proportion of cases with adenocarcinoma and carcinoma NOS: 33.3%, in comparison with 24.0% in high-volume hospitals (p<0.0001). The odds of being diagnosed with unspecified morphology, assumed as a proxy of suboptimal quality of care, are higher for patients surgically treated in low-volume hospitals (odds ratio 1.50 [95% confidence interval 1.21-1.87]) compared with high-volume hospitals after adjustment for age, stage, and grade. CONCLUSIONS: The results of our study may serve policymakers and healthcare professionals when optimizing diagnosis and treatment of ovarian cancer in Bulgaria. PMID- 27768223 TI - Study on the significance of Cofilin 1 overexpression in human bladder cancer. AB - PURPOSE: Cofilin 1 is a type of cytoskeletal protein. The overexpression of this gene has been regarded to hold a special relationship with the development and progress of some cancers. However, the detailed position of Cofilin 1 in human bladder cancer has not been investigated intensively. METHODS: In this study, we mainly explored the relationship between human bladder cancer and the expression of Cofilin 1. The expression of Cofilin 1 in bladder cancer tissues and paracancerous tissues of patients was evaluated with quantitative polymerase chain reaction, Western blot, and immunohistochemical staining. Downregulation of Cofilin 1 expression model was established with siRNA in human RT4 bladder cancer cell line, and the changing cell viability was analyzed to determine the role of Cofilin 1 in human bladder cancer. RESULTS: Our results showed that the expression of Cofilin 1 was much higher in both RNA level and protein level in human bladder cancer tissues than paracancerous tissues for 3 patients. Downregulation of Cofilin 1 expression could inhibit cell proliferation, cell migration, cell adhesion, and colony formation ability, and increase the percentage of cell apoptosis in RT4 cells. CONCLUSIONS: Our study indicates that Cofilin 1 holds an important position in the development and progression of human bladder cancer, and this gene might become a novel target in the diagnosis and treatment of human bladder cancer. PMID- 27768225 TI - Comments to: Ranibizumab for persistent diabetic macular edema after bevacizumab treatment. PMID- 27768224 TI - Acquired ectropion uveae and secondary glaucoma due to trauma: report of 3 cases. AB - PURPOSE: To investigate the possible association between acquired ectropion uveae and blunt trauma to the eye. We present 3 cases of acquired ectropion uveae that occurred after blunt trauma to the eye. There are no previously published data on possible association of these conditions. METHODS:: A retrospective review was conducted of patients with ectropion uveae and eye injury at University Eye Hospital over a 10-year period (2006-2016). We analyzed medical records and clinical findings. RESULTS:: Three eyes of 3 male patients with ocular trauma and ectropion uveae, ages 71, 68, and 5 years, were reviewed. The period between the eye injury and the diagnosis of ectropion uveae ranged from 10 to 36 months. All 3 eyes developed clinical evidence of secondary glaucoma with moderately to severely elevated intraocular pressure (IOP) (ranging from 29 to 48 mm Hg). Surgical treatment (trabeculectomy) was needed in 2 cases in order to control secondary glaucoma and conservative treatment was sufficient in 1 case. Mean patient follow-up was 19.3 +/- 4.6 months. CONCLUSIONS:: Trauma can be considered as a cause of acquired ectropion uveae. Acquired ectropion uveae following eye trauma may be associated with significant increase in IOP. All patients in our series had secondary glaucoma and 2 of 3 required surgical treatment for IOP control. PMID- 27768226 TI - Novel variants of RPGR in X-linked retinitis pigmentosa families and genotype phenotype correlation. AB - PURPOSE: To identify novel mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene and retinitis pigmentosa 2 (RP2) gene underlying X-linked retinitis pigmentosa (XLRP) and assess genotype-phenotype correlations. METHODS: The patient cohort, consisting of 13 individuals from 3 unrelated XLRP families, underwent comprehensive ophthalmologic examination. The open reading frames of RPGR and RP2 were analyzed with Sanger sequencing in each patient. The identified genetic variants were defined as mutations or polymorphisms on the basis of their pathological effect. RESULTS: We found 3 genetic variants: a novel mutation c.1591G>T in exon 14 and a novel polymorphism c.1105C>T in exon 10, resulting in p.Glu531* and p.Arg369Cys of RPGR gene, respectively, and one already known mutation c.413A>G in exon 2, resulting in a p.Glu138Gly of RP2 gene. Considering our XLRP probands, RPGR-related phenotypic damages were similar and less severe than those of the patient with the RP2 mutation. On the other hand, the female carriers of XLRP variants showed different RPGR-related consequences, ranging from rods hypofunctionality in c.1591G>T nonsense heterozygosity to no retinal changes in c.1105C>T polymorphic heterozygosity. CONCLUSIONS: These findings broaden the spectrum of RPGR mutations and phenotypic variability of the disease, which will be useful for genetic consultation and diagnosis in the future. PMID- 27768227 TI - A novel fecal stable isotope approach to determine the timing of age-related feeding transitions in wild infant chimpanzees. AB - OBJECTIVES: Determining nutritional development in wild primates is difficult through observations because confirming dietary intake is challenging. Physiological measures are needed to determine the relative contributions of maternal milk and other foods at different ages, and time of weaning. We used fecal stable carbon and nitrogen isotopes (delta13 C, delta15 N) and fecal nitrogen concentrations (%N) from wild chimpanzees at Ngogo, Uganda, to derive physiological dietary indicators during the transition from total reliance on maternal milk to adult foods after weaning. MATERIALS AND METHODS: We analyzed 560 fecal samples collected non-invasively from 48 infants, their mothers, and 6 juvenile siblings. Most infant and juvenile samples (90%) were matched to samples collected from mothers on the same day. Isotopic assessments were compared with observations of nursing and feeding. RESULTS: Infants <=1 year old showed average delta15 N, delta13 C and %N ratios that were 2.00/00, 0.80/00 and 1.3% greater than their mothers, respectively, interpreted as trophic level effects. Although data collected on newborns were few, results suggest that solid foods were consumed within 2-5 months after birth. Trophic level differences decreased steadily after 1 year, which indicates a decreasing relative contribution of milk to the diet. Isotopic results indicated infants were weaned by 4.5 years old-more than a year earlier than observations of nipple contacts ceased, which revealed the occurrence of "comfort nursing." Juvenile isotopic signatures indicate no nursing overlap between siblings. DISCUSSION: Our results resemble the stable isotope differences of human babies. This study contributes to a model of chimpanzee nutritional development required to understand early life history patterns in hominins. PMID- 27768228 TI - Quantification of 3D curvature in the iliac crest: Ontogeny and implications for sex determination in juveniles. AB - OBJECTIVES: Sex-specific differences in the shape of the iliac crest have been reported based on quantification of simplified curvature using two-dimensional variables or qualitative identification of faint/marked S-shaped curvature. An objective and quantitative approach for the evaluation of iliac crest curvature in juveniles was developed. Using three-dimensional data, ontogenetic variation in iliac curvature was investigated in relation to size and chronological age and its accuracy for sex estimation among juveniles was evaluated. MATERIALS AND METHODS: Three-dimensional geometric morphometric landmarks were collected from virtual models of 53 surface-scanned ilia and used to: (1) quantify differences between male and female shape, and (2) to calculate a measure of sinuosity by extracting linear measurements relative to a plane constructed in virtual space. RESULTS: Males were found to exhibit on average more pronounced curvature of the iliac crest than females in equivalent age groups, and the difference between sexes was more marked on the posterior section of the bone than on the anterior section. Classification accuracy was higher for measurements of sinuosity relative to a three-dimensional plane (62-87%) than for landmarks describing crest shape (64-74%). CONCLUSIONS: An increased likelihood of correct male identification (reduced rate of false positive identification) was observed in older children (>5 years). This reflects divergence of male and female iliac crest shape with size (or age), and the development of a unique, more curved iliac crest shape in males. The results suggest more conspicuous male trait expression than female trait expression. PMID- 27768229 TI - Higher copeptin levels are associated with worse outcome in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Correlation of increased copeptin levels with various cardiovascular diseases has been described. The clinical use of copeptin levels in patients with hypertrophic cardiomyopathy (HCM) has not been investigated before. HYPOTHESIS: In this study, we aimed to investigate the prognostic value of copeptin levels in patients with hypertrophic cardiomyopathy (HCM). METHODS: HCM was defined as presence of left ventricular wall thickness >=15 mm in a subject without any concomitant disease that may cause left ventricular hypertrophy. Levels of copeptin and plasma N-terminal probrain natriuretic peptide (NT-proBNP) were evaluated prospectively in 24 obstructive HCM patients, 36 nonobstructive HCM patients, and 36 age- and sex-matched control subjects. Blood samples were collected in the morning between 7 and 9 am after overnight fasting. Patients were followed for 24 months. Hospitalization with diagnosis of heart failure/arrhythmia, implantable cardioverter-defibrillator implantation, and cardiac mortality were accepted as adverse cardiac events. RESULTS: Copeptin and NT-proBNP levels were higher in the HCM group compared with controls (14.1 vs 8.4 pmol/L, P < 0.01; and 383 vs 44 pg/mL, P < 0.01, respectively). Copeptin and NT proBNP levels were higher in the obstructive HCM subgroup compared with the nonobstructive HCM subgroup (18.3 vs 13.1 pmol/L, P < 0.01; and 717 vs 223 pg/mL, P < 0.01, respectively). In multivariable logistic regression analysis, copeptin and NT-proBNP levels remained as independent predictors of heart failure (P < 0.01 for both) and adverse cardiac events (P < 0.01 for both). CONCLUSIONS: Copeptin and NT-proBNP levels were significantly higher in patients with obstructive HCM, and higher levels were associated with worse outcome. PMID- 27768230 TI - An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. AB - BACKGROUND: Recently, a 23-gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. METHODS: A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. RESULTS: The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. CONCLUSIONS: These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617-628. (c) 2016 American Cancer Society. PMID- 27768231 TI - Combined Post- and Precapillary Pulmonary Hypertension in Patients With Heart Failure. AB - BACKGROUND: Pulmonary hypertension (PH) is a well-recognized complication of left ventricular heart failure (HF). HYPOTHESIS: Differences exist in demographic, clinical, hemodynamic, and survival characteristics of patients with left ventricular HF who have combined postcapillary and precapillary PH (CpcPH), isolated postcapillary PH, or no PH. METHODS: A secondary data analysis was conducted using a large prospective database of patients undergoing right heart catheterization from 1994 to 2012. One-year mortality postcatheterization was assessed between PH groups using Kaplan-Meier and log-rank techniques, as well as a multivariate Cox proportional hazards model adjusted for age, sex, diabetes, chronic kidney disease, atrial fibrillation, and chronic obstructive pulmonary disease. Mortality rates were calculated for each group as deaths per 100 person years. RESULTS: Of the 724 patients identified, 29.4% (n = 213) had no evidence of PH, 63.1% (n = 457) had isolated postcapillary PH, and 7.5% (n = 54) had CpcPH. Compared with no PH, there was an increased mortality rate within 1 year for CpcPH patients (crude hazard ratio: 5.22, 95% confidence interval: 2.06 13.22), but not for isolated postcapillary PH patients (crude hazard ratio: 2.12, 95% confidence interval: 0.99-4.57). Adjusted analyses revealed similar results. Mortality rates per 100 person-years were 3.9, 8.4, and 21.0 for no PH, isolated postcapillary PH, and CpcPH patients, respectively. CONCLUSIONS: Heart failure patients with CpcPH are associated with increased death rate 1 year post-cardiac catheterization, compared with patients without PH. They are a high-risk PH group and should be evaluated and diagnosed earlier in the disease state. PMID- 27768233 TI - Quantifying the Tunable Conjugated Area of Graphene Oxide by Using Pyrene as a Fluorescent Probe. AB - The determination of oxygenous groups, conjugated area ratio, and reduction efficiency of graphene oxide (GO) is a difficult task because of its heterogeneous structure. Herein, a novel approach is described for a detailed understanding of the surface chemistry of GO by using pyrene as a fluorescent probe through pi-pi stacking interactions. PMID- 27768232 TI - X-linked inhibitor of apoptosis-associated factor 1 regulates TNF receptor 1 complex stability. AB - X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a cytokine regulated, tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain containing protein that has a poorly defined cellular function. Here, we show that ectopically expressed XAF1 inhibits TNF-alpha-induced NF-kappaB activation, whereas shRNA silencing of endogenous XAF1 augments it. Our data suggest that XAF1 may inhibit TNF-alpha-induced NF-kappaB activation by disrupting the assembly of the TRADD/TRAF2/RIP1 complex (complex I) downstream of TNF receptor activation. XAF1 interacts with TRAF2 and inhibits TRAF2-dependent NF-kappaB activation, in part, by blocking TRAF2 polyubiquitination. Our findings also indicate that although XAF1 does not directly inhibit RIP1-dependent NF-kappaB activation, it binds RIP1 and disrupts RIP1/TRADD association. Our data suggest that XAF1 acts as a feedback regulator of the TNF receptor signaling pathway to suppress NF-kappaB activation. PMID- 27768234 TI - Infant bald patch: ultrasonographic diagnosis of aplasia cutis congenita. PMID- 27768235 TI - Genetic backgrounds and modifier genes of NTD mouse models: An opportunity for greater understanding of the multifactorial etiology of neural tube defects. AB - Neurulation, the early embryonic process of forming the presumptive brain and spinal cord, is highly complex and involves hundreds of genes in multiple genetic pathways. Mice have long served as a genetic model for studying human neurulation, and the resulting neural tube defects (NTDs) that arise when neurulation is disrupted. Because mice appear to show mostly single gene inheritance for NTDs and humans show multifactorial inheritance, mice sometimes have been characterized as a simpler model for the identification and study of NTD genes. But are they a simple model? When viewed on different genetic backgrounds, many genes show significant variation in the penetrance and expressivity of NTD phenotypes, suggesting the presence of modifier loci that interact with the target gene to affect the phenotypic expression. Looking at mutations on different genetic backgrounds provides us with an opportunity to explore these complex genetic interactions, which are likely to better emulate similar processes in human neurulation. Here, we review NTD genes known to show strain-specific phenotypic variation. We focus particularly on the gene Cecr2, which is studied using both a hypomorphic and a presumptive null mutation on two different backgrounds: one susceptible (BALB/c) and one resistant (FVB/N) to NTDs. This strain difference has led to a search for genetic modifiers within a region on murine chromosome 19. Understanding how genetic variants alter the phenotypic outcome in NTD mouse models will help to direct future studies in humans, particularly now that more genome wide sequencing approaches are being used. Birth Defects Research 109:140-152, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27768236 TI - Characterization of a Rare Nonpathogenic Methylenetetrahydrofolatereductase (MTHFR) Gene Mutation p.Lys215del in a Southern Italian family. PMID- 27768237 TI - A Cascade "Prins-Pinacol-Type Rearrangement and C4-OBn Participation" on Carbohydrate Substrates: Synthesis of Bridged Tricyclic Ketals, Annulated Sugars and C2-Branched Heptoses. AB - A "Prins pinacol type rearrangement followed by C4-OBn participation" in a cascade manner has been observed while probing the fate of carbocation in some carbohydrate derived homoallylic alcohols in the Prins reaction. This has led to an easy access to tetrahydrofuran-fused bridged bicyclic ketals (or tetrahydrofuran-fused 1,6-anhydro-heptopyranose frameworks) which are further converted into some annulated sugars and C2-branched heptoses. PMID- 27768240 TI - Beryllium-Based Anion Sponges: Close Relatives of Proton Sponges. AB - Through the use of high-level ab initio and density functional calculations it is shown that 1,8-diBeX-naphthalene (X=H, F, Cl, CN, CF3 , C(CF3 )3 ) derivatives behave as anion sponges, very much as 1,8-bis(dimethylamino)naphthalene derivatives behave as proton sponges. The electron-deficient nature of the BeX substituents, which favors strong charge transfer from the anion towards the former, results in anion affinities that are among the largest ones reported for single neutral molecules. PMID- 27768239 TI - Experience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients: A case series from Spain. AB - The incidence of visceral leishmaniasis (VL) after solid organ transplantation (SOT) is increasing. The optimal therapy for post-transplant VL remains unclear, as relapses after liposomal amphotericin B (L-AmB) are common. Miltefosine has been shown to be effective for treating VL in immunocompetent patients, although data in the specific population of SOT recipients are lacking. In the setting of an outbreak of leishmaniasis occurring in Southwest Madrid, we reviewed our experience in 6 SOT recipients with persistent or relapsing VL who received a 28 day course of miltefosine (2.5 mg/kg/day) as salvage therapy. All patients had been treated previously with L-AmB as first-line therapy. The incident episode of VL occurred at a median of 14 months after transplantation. Two patients experienced persistent infection and the remaining 4 had a relapse after a median interval of 168 days since the completion of the course of L-AmB. All the patients had an apparent initial clinical improvement with miltefosine. However, VL relapsed in 3 of them (after a median interval of 46 days), which required retreatment with L-AmB-based regimens. Miltefosine therapy was followed by a prolonged secondary prophylaxis with L-AmB in the only 2 cases with sustained clinical response and ongoing immunosuppression. No adverse effects associated with miltefosine were observed. Albeit limited, our experience suggests that miltefosine monotherapy likely has a limited utility to obtain a long-lasting clinical response in complicated (persistent or relapsing) forms of post transplant VL, although its role in association with L-AmB-based secondary prophylaxis may merit further investigation. PMID- 27768241 TI - Factors associated with combined hand and foot eczema. AB - BACKGROUND: As for hand eczema, the aetiology of foot eczema is multifactorial and not very well understood. The aim of the present study was to identify factors associated with foot eczema in a cohort of hand eczema patients being classified into different subgroups. METHODS: Associations between foot and hand eczema were studied in a cross-sectional design in a cohort of hand eczema patients. Consecutive patients were recruited from nine different European Centres during the period October 2011-September 2012. Data on demographic factors, presence of foot eczema, hand eczema duration and severity, and whether the hand eczema was work-related or not were available, as well as patch-test results. RESULTS: Of a total of 427 hand eczema patients identified, information on foot eczema was available in 419 patients who were included in the present study. A total of 125 patients (29.8%) had concomitant foot and hand eczema. It was found more often in association with hyperkeratotic hand eczema (P = 0.007) and was less often associated with irritant hand eczema (P < 0.001). However, foot eczema was nevertheless found in 18% of patient with irritant hand eczema and in 25% of patients with occupational hand eczema. Combined foot and hand eczema was associated with more severe and long-standing hand eczema (P < 0.001 and P = 0.004, respectively). Contact allergy was found in 51.8% with no difference between patients with combined foot and hand eczema and patients with hand eczema only. CONCLUSION: Occurrence of combined foot and hand eczema is a common finding and not restricted to endogenous hand eczema. PMID- 27768243 TI - Prenatal exposure to environmental factors and congenital limb defects. AB - Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27768242 TI - The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). AB - BACKGROUND: Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: Evaluate efficacy and safety of apremilast vs. placebo in biologic naive patients with moderate-to-severe plaque psoriasis and safety of switching from etanercept to apremilast in a phase IIIb, randomized, double-blind, placebo controlled study (NCT01690299). METHODS: Two hundred and fifty patients were randomized to placebo (n = 84), apremilast 30 mg BID (n = 83) or etanercept 50 mg QW (n = 83) through Week 16; thereafter, all patients continued or switched to apremilast through Week 104. The primary efficacy endpoint was achievement of PASI-75 at Week 16 with apremilast vs. placebo. Secondary endpoints included achievement of PASI-75 at Week 16 with etanercept vs. placebo and improvements in other clinical endpoints vs. placebo at Week 16. Outcomes were assessed through Week 52. This study was not designed for apremilast vs. etanercept comparisons. RESULTS: At Week 16, PASI-75 achievement was greater with apremilast (39.8%) vs. placebo (11.9%; P < 0.0001); 48.2% of patients achieved PASI-75 with etanercept (P < 0.0001 vs. placebo). PASI-75 response was maintained in 47.3% (apremilast/apremilast), 49.4% (etanercept/apremilast) and 47.9% (placebo/apremilast) of patients at Week 52. Most common adverse events (>=5%) with apremilast, including nausea, diarrhoea, upper respiratory tract infection, nasopharyngitis, tension headache and headache, were mild or moderate in severity; diarrhoea and nausea generally resolved in the first month. No new safety or tolerability issues were observed through Week 52 with apremilast. CONCLUSION: Apremilast demonstrated significant efficacy vs. placebo at Week 16 in biologic-naive patients with psoriasis, which was sustained over 52 weeks, and demonstrated safety consistent with the known safety profile of apremilast. Switching from etanercept to apremilast did not result in any new or clinically significant safety findings, and efficacy was maintained with apremilast through Week 52. PMID- 27768244 TI - Detection limits of quantitative and digital PCR assays and their influence in presence-absence surveys of environmental DNA. AB - A set of universal guidelines is needed to determine the limit of detection (LOD) in PCR-based analyses of low-concentration DNA. In particular, environmental DNA (eDNA) studies require sensitive and reliable methods to detect rare and cryptic species through shed genetic material in environmental samples. Current strategies for assessing detection limits of eDNA are either too stringent or subjective, possibly resulting in biased estimates of species' presence. Here, a conservative LOD analysis grounded in analytical chemistry is proposed to correct for overestimated DNA concentrations predominantly caused by the concentration plateau, a nonlinear relationship between expected and measured DNA concentrations. We have used statistical criteria to establish formal mathematical models for both quantitative and droplet digital PCR. To assess the method, a new Grass Carp (Ctenopharyngodon idella) TaqMan assay was developed and tested on both PCR platforms using eDNA in water samples. The LOD adjustment reduced Grass Carp occupancy and detection estimates while increasing uncertainty indicating that caution needs to be applied to eDNA data without LOD correction. Compared to quantitative PCR, digital PCR had higher occurrence estimates due to increased sensitivity and dilution of inhibitors at low concentrations. Without accurate LOD correction, species occurrence and detection probabilities based on eDNA estimates are prone to a source of bias that cannot be reduced by an increase in sample size or PCR replicates. Other applications also could benefit from a standardized LOD such as GMO food analysis and forensic and clinical diagnostics. PMID- 27768245 TI - A comparison of DNA extraction methods for high-throughput DNA analyses. AB - The inclusion of next-generation sequencing technologies in population genetic and phylogenetic studies has elevated the need to balance time and cost of DNA extraction without compromising DNA quality. We tested eight extraction methods - ranging from low- to high-throughput techniques - and eight phyla: Annelida, Arthropoda, Cnidaria, Chordata, Echinodermata, Mollusca, Ochrophyta and Porifera. We assessed DNA yield, purity, efficacy and cost of each method. Extraction efficacy was quantified using the proportion of successful polymerase chain reaction (PCR) amplification of two molecular markers for metazoans (mitochondrial COI and nuclear histone 3) and one for Ochrophyta (mitochondrial nad6) at four time points - 0.5, 1, 2 and 3 years following extraction. DNA yield and purity were quantified using NanoDrop absorbance ratios. Cost was estimated in terms of time and material expense. Results show differences in DNA yield, purity and PCR success between extraction methods and that performance also varied by taxon. The traditional time-intensive, low-throughput CTAB phenol chloroform extraction performed well across taxa, but other methods also performed well and provide the opportunity to reduce time spent at the bench and increase throughput. PMID- 27768246 TI - A framework for developing and validating taxon-specific primers for specimen identification from environmental DNA. AB - Taxon-specific DNA tests are applied to many ecological and management questions, increasingly using environmental DNA (eDNA). eDNA facilitates noninvasive ecological studies but introduces additional risks of bias and error. For effective application, PCR primers must be developed for each taxon and validated in each system. We outline a nine step framework for the development and validation of taxon-specific primers for eDNA analysis in ecological studies, involving reference database construction, phylogenetic evaluation of the target gene, primer design, primer evaluation in silico, and laboratory evaluation of primer specificity, sensitivity and utility. Our framework makes possible a rigorous evaluation of likely sources of error. The first five steps can be conducted relatively rapidly and (where reference DNA sequences are available) require minimal laboratory resources, enabling assessment of primer suitability before investing in further work. Steps six to eight require more costly laboratory analyses but are essential to evaluate risks of false-positive and false-negative results, while step 9 relates to field implementation. As an example, we have developed and evaluated primers to specifically amplify part of the mitochondrial ND2 gene from Australian bandicoots. If adopted during the early stages of primer development, our framework will facilitate large-scale implementation of well-designed DNA tests to detect specific wildlife from eDNA samples. This will provide researchers and managers with an understanding of the strengths and limitations of their data and the conclusions that can be drawn from them. PMID- 27768248 TI - A combined field survey and molecular identification protocol for comparing forest arthropod biodiversity across spatial scales. AB - Obtaining fundamental biodiversity metrics such as alpha, beta and gamma diversity for arthropods is often complicated by a lack of prior taxonomic information and/or taxonomic expertise, which can result in unreliable morphologically based estimates. We provide a set of standardized ecological and molecular sampling protocols that can be employed by researchers whose taxonomic skills may be limited, and where there may be a lack of robust a priori information regarding the regional pool of species. These protocols combine mass sampling of arthropods, classification of samples into parataxonomic units (PUs) and selective sampling of individuals for mtDNA sequencing to infer biological species. We sampled ten lowland rainforest plots located on the volcanic oceanic island of Reunion (Mascarene archipelago) for spiders, a group with limited taxonomic and distributional data for this region. We classified adults and juveniles into PUs and then demonstrated the reconciliation of these units with presumed biological species using mtDNA sequence data, ecological data and distributional data. Because our species assignment protocol is not reliant upon prior taxonomic information, or taxonomic expertise, it minimizes the problem of the Linnean shortfall to yield diversity estimates that can be directly compared across independent studies. Field sampling can be extended to other arthropod groups and habitats by adapting our field sampling protocol accordingly. PMID- 27768247 TI - Associations between Maternal Water Consumption and Birth Defects in the National Birth Defects Prevention Study (2000-2005). AB - BACKGROUND: Water and water-based beverages constitute a major part of daily fluid intake for pregnant women, yet few epidemiologic studies have investigated the role of water consumption on birth outcomes. METHODS: We used data from the National Birth Defects Prevention Study to conduct a case-control study investigating associations between maternal water consumption during pregnancy and birth defects (BD). We used interview data on water consumption during the first trimester of pregnancy in 14,454 cases (major BDs n >= 50) and 5,063 controls. Total water consumption was analyzed as a continuous variable and in quartiles. We evaluated the role of dietary quality and sugar sweetened beverage consumption. Logistic regression models were used to assess effects of water consumption on risk of BDs with adjustment for relevant covariates. RESULTS: Mean daily maternal water consumption among controls was 4.4 eight-ounce glasses. We observed decreases in estimated risk associated with increases in water consumption for several BDs, including neural tube defects (spina bifida), oral clefts (cleft lip), musculoskeletal defects (gastroschisis, limb deficiencies), and congenital heart defects (hypoplastic left heart syndrome, right-sided obstructions, pulmonary valve stenosis). Our results were generally unchanged when an indicator for overall dietary quality was included; however, there was evidence of effect measure modification by heavy consumption of sugar-sweetened beverages for some defects, but not all. CONCLUSION: These analyses suggest the importance of sufficient water consumption during early pregnancy, above and beyond it being a marker of higher diet quality. Additional analyses are warranted to understand the biological mechanism for this association. Birth Defects Research 109:193-202, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27768249 TI - Modified low-salt CTAB extraction of high-quality DNA from contaminant-rich tissues. AB - The increasing use of high-throughput sequencing platforms has made the isolation of pure, high molecular weight DNA a primary concern for studies of a diverse range of organisms. Purification of DNA remains a significant challenge in many tissue and sample types due to various organic and inorganic molecules that coprecipitate with nucleic acids. Molluscs, for example, contain high concentrations of polysaccharides which often coprecipitate with DNA and can inhibit downstream enzymatic reactions. We modified a low-salt CTAB (MoLSC) extraction protocol to accommodate contaminant-rich animal tissues and compared this method to a standard CTAB extraction protocol and two commercially available animal tissue DNA extraction kits using oyster adductor muscle. Comparisons of purity and molecular integrity showed that our in-house protocol yielded genomic DNA generally free of contaminants and shearing, whereas the traditional CTAB method and some of the commercial kits yielded DNA unsuitable for some applications of massively parallel sequencing. Our open-source MoLSC protocol provides a cost-effective, scalable, alternative DNA extraction method that can be easily optimized and adapted for sequencing applications in other contaminant rich samples. PMID- 27768250 TI - Identification of sawflies and horntails (Hymenoptera, 'Symphyta') through DNA barcodes: successes and caveats. AB - The 'Symphyta' is a paraphyletic assemblage at the base of the order Hymenoptera, comprising 14 families and about 8750 species. All have phytophagous larvae, except for the Orussidae, which are parasitoids. This study presents and evaluates the results of DNA barcoding of approximately 5360 specimens of 'Symphyta', mainly adults, and 4362 sequences covering 1037 species were deemed of suitable quality for inclusion in the analysis. All extant families are represented, except for the Anaxyelidae. The majority of species and specimens are from Europe, but approximately 38% of the species and 13% of the specimens are of non-European origin. The utility of barcoding for species identification and taxonomy of 'Symphyta' is discussed on the basis of examples from each of the included families. A significant level of cryptic species diversity was apparent in many groups. Other attractive applications include the identification of immature stages without the need to rear them, community analyses based on metabarcoding of bulk samples and association of the sexes of adults. PMID- 27768251 TI - Fine-needle aspiration versus core needle biopsy: Reconsidering the evidence of superiority. PMID- 27768252 TI - DNA barcoding of tuberous Orchidoideae: a resource for identification of orchids used in Salep. AB - Tubers of terrestrial orchids are harvested and traded from the eastern Mediterranean to the Caspian Sea for the traditional product Salep. Overexploitation of wild populations and increased middle-class prosperity have escalated prices for Salep, causing overharvesting, depletion of native populations and providing an incentive to expand harvesting to untapped areas in Iran. Limited morphological distinctiveness among traded Salep tubers renders species identification impossible, making it difficult to establish which species are targeted and affected the most. In this study, a reference database of 490 nrITS, trnL-F spacer and matK sequences of 133 taxa was used to identify 150 individual tubers from 31 batches purchased in 12 cities in Iran to assess species diversity in commerce. The sequence reference database consisted of 211 nrITS, 158 trnL-F and 121 matK sequences, including 238 new sequences from collections made for this study. The markers enabled unambiguous species identification with tree-based methods for nrITS in 67% of the tested tubers, 58% for trnL-F and 59% for matK. Species in the genera Orchis (34%), Anacamptis (27%) and Dactylorhiza (19%) were the most common in Salep. Our study shows that all tuberous orchid species in this area are threatened by this trade, and further stresses the urgency of controlling illegal harvesting and cross-border trade of Salep tubers. PMID- 27768253 TI - Changes in body mass index and waist circumference and concurrent mortality among Swedish women. AB - OBJECTIVE: Most studies on obesity and mortality use a single anthropometric measure. Less is known about the effects of weight change on mortality. This study examined changes in body mass index (DeltaBMI) and waist circumference (DeltaWC) and subsequent all-cause and cause-specific mortality. METHODS: The study was conducted in the Women's Lifestyle and Health cohort, using self reported anthropometric measures from 1991 to 1992 and 2003. Hazard ratios of mortality and 95% confidence intervals were calculated using Cox proportional hazards models. DeltaBMI and DeltaWC were examined in quartiles of absolute and relative change, with the second quartile (moderate gain) as the reference. RESULTS: There was a higher risk of death in the first quartile of relative DeltaBMI: HR 1.28 (1.04-1.56). Absolute DeltaBMI suggested the same pattern, but the result was nonsignificant. DeltaWC was not associated with mortality. In cause-specific analyses, the association remained significant for cancer mortality only. In sensitivity analyses excluding the first 5 years of follow-up, the association was, however, attenuated. CONCLUSIONS: This study found a higher risk of death among women in the first quartile of relative DeltaBMI compared with the second. It was driven by cancer mortality but may be ascribed to reverse causality. DeltaWC was not associated with mortality. PMID- 27768254 TI - Reduced expression of chemerin in visceral adipose tissue associates with hepatic steatosis in patients with obesity. AB - OBJECTIVE: This study aimed to evaluate whether circulating levels and/or visceral adipose tissue (VAT) expression of recently described adipokines associate with histopathological severity of nonalcoholic fatty liver disease (NAFLD), independent of obesity and insulin resistance. METHODS: Serum levels of adiponectin, omentin, chemerin, monocyte chemoattractant protein-1, and secreted frizzled-related protein 4 were measured using enzyme-linked immunosorbent assay in 81 patients with obesity and NAFLD and 18 lean control subjects. Expression in VAT was measured using real-time PCR and histopathological grading was scored using the NAFLD activity score (NAS). RESULTS: When NAFLD patients were subdivided into groups with simple steatosis, borderline nonalcoholic steatohepatitis (NASH), and NASH, adiponectin serum levels and omentin expression were lower in NASH versus simple steatosis patients. Serum adiponectin was generally lower with higher histopathological grading. Chemerin VAT expression was negatively associated with NAS (r = -0.331, P = 0.022) and steatosis score (r = -0.335, P = 0.020), independent of age, BMI, and HOMA-IR. In addition, adjusting for chemerin VAT expression in a multivariate model explained part of the association between NAS and HOMA-IR. CONCLUSIONS: These findings suggest that lower VAT expression of chemerin in patients with obesity may be involved in the pathophysiology of hepatic steatosis, potentially by modulating the link between insulin resistance and NAFLD. PMID- 27768257 TI - Findings of Scientific Misconduct. PMID- 27768255 TI - The obesity associated FTO gene variant and the risk of adverse pregnancy outcomes: Evidence from the SCOPE study. AB - OBJECTIVE: To investigate whether the FTO rs9939609 single nucleotide polymorphism (SNP), which is a risk factor for obesity and vascular diseases, is also associated with pregnancy complications including pre-eclampsia, gestational hypertension, small for gestational age pregnancy (SGA), and spontaneous preterm birth (sPTB). METHODS: A case-control study of 1,741 nulliparous Caucasian women, their partners, and infants was conducted. DNA was extracted from peripheral blood or saliva from parents and cord blood from infants and genotyped using the Sequenom MassARRAY system. RESULTS: The prevalence of maternal and infant AA genotype of FTO rs9939609 was increased in the SGA group compared with the uncomplicated pregnancy group (19.2% vs. 13.4%, OR = 1.7, 95% CI = 1.1-2.6, P = 0.02 and 24.6% vs. 12.5%, OR = 2.7, 95% CI = 1.6-4.6, P = 0.0002). The prevalence of maternal and infant AA genotype of FTO rs9939609 was also increased in the sPTB group compared with the uncomplicated pregnancy group (20.8% vs. 13.4%, OR = 2.1, 95% CI = 1.2-3.8, P = 0.009 and 20.0% vs. 12.5%, OR = 2.4, 95% CI = 1.0-5.3, P = 0.03). CONCLUSIONS: The maternal and infant AA genotype of the obesity associated FTO rs9939609 SNP associates with increased risk for SGA and sPTB. This SNP may be important in predicting the risk of these pregnancy complications and subsequent vascular diseases. PMID- 27768256 TI - High phylogenetic utility of an ultraconserved element probe set designed for Arachnida. AB - Arachnida is an ancient, diverse and ecologically important animal group that contains a number of species of interest for medical, agricultural and engineering applications. Despite their importance, many aspects of the arachnid tree of life remain unresolved, hindering comparative approaches to arachnid biology. Biologists have made considerable efforts to resolve the arachnid phylogeny; yet, limited and challenging morphological characters, as well as a dearth of genetic resources, have hindered progress. Here, we present a genomic toolkit for arachnids featuring hundreds of conserved DNA regions (ultraconserved elements or UCEs) that allow targeted sequencing of any species in the arachnid tree of life. We used recently developed capture probes designed from conserved regions of available arachnid genomes to enrich a sample of loci from 32 diverse arachnids. Sequence capture returned an average of 487 UCE loci for all species, with a range from 170 to 722. Phylogenetic analysis of these UCEs produced a highly resolved arachnid tree with relationships largely consistent with recent transcriptome-based phylogenies. We also tested the phylogenetic informativeness of UCE probes within the spider, scorpion and harvestman orders, demonstrating the utility of these markers at shallower taxonomic scales and suggesting that these loci will be useful for species-level differences. This probe set will open the door to phylogenomic and population genomic studies across the arachnid tree of life, enabling systematics, species delimitation, species discovery and conservation of these diverse arthropods. PMID- 27768258 TI - Findings of Scientific Misconduct. PMID- 27768259 TI - Findings of Scientific Misconduct. PMID- 27768261 TI - Findings of Scientific Misconduct. PMID- 27768260 TI - Findings of Scientific Misconduct. PMID- 27768263 TI - Findings of Scientific Misconduct. PMID- 27768262 TI - Findings of Scientific Misconduct. PMID- 27768265 TI - Findings of Research Misconduct. PMID- 27768264 TI - Findings of Research Misconduct. PMID- 27768266 TI - Procedures for the Handling of Retaliation Complaints Under Section 1558 of the Affordable Care Act. Final rule. AB - This document provides the final text of regulations governing employee protection (retaliation or whistleblower) claims under section 1558 of the Affordable Care Act, which added section 18C to the Fair Labor Standards Act to provide protections to employees who may have been subject to retaliation for seeking assistance under certain affordability assistance provisions (for example, health insurance premium tax credits) or for reporting potential violations of the Affordable Care Act's consumer protections (for example, the prohibition on rescissions). An interim final rule (IFR) governing these provisions and request for comments was published in the Federal Register on February 27, 2013. Thirteen comments were received; eleven were responsive to the IFR. This rule responds to those comments and establishes the final procedures and time frames for the handling of retaliation complaints under section 18C, including procedures and time frames for employee complaints to the Occupational Safety and Health Administration (OSHA), investigations by OSHA, appeals of OSHA determinations to an administrative law judge (ALJ) for a hearing de novo, hearings by ALJs, review of ALJ decisions by the Administrative Review Board (ARB) (acting on behalf of the Secretary of Labor), and judicial review of the Secretary of Labor's (Secretary's) final decision. It also sets forth the Secretary's interpretations of the Affordable Care Act whistleblower provision on certain matters. PMID- 27768267 TI - Hydrothermal Synthesis and Magnetic Characterization of the Quaternary Oxide CoMo2Sb2O10. AB - The new quaternary layered oxide CoMo2Sb2O10 was synthesized by hydrothermal synthesis techniques, and its structure was determined from single-crystal X-ray diffraction data. CoMo2Sb2O10 crystallizes in the monoclinic space group C2/c with one Sb3+, Mo6+, and Co2+ atom site per unit cell, respectively. The crystal structure contains building units consisting of [Co2O8]n, [Mo2O8]n, and [SbO2]n chains. These are connected through corner sharing to form charge-neutral [CoMo2Sb2O10]n layers. Thermal decomposition of CoMo2Sb2O10 starts at 550 degrees C. The magnetic susceptibility follows a Curie-Weiss law above 50 K with a Curie constant of C = 3.46 emu.K.mol-1 corresponding to an effective moment of MUeff = 5.26 MUB per cobalt atom and a Curie-Weiss temperature theta = -13.2 K. Short-range anti-ferromagnetic ordering dominates below 5 K. Magnetic susceptibility and heat capacity data can be successfully modeled by the predictions from an Ising linear chain with an intrachain spin exchange of ca. 7.8 K. PMID- 27768268 TI - Fabrication of a Nanogold-Dot Array for Rapid and Sensitive Detection of Vascular Endothelial Growth Factor in Human Serum. AB - A simple and accurate device for early detection of malignancies is paramount for prompt treatment and prevention of metastases. In this study, we describe a novel fabrication method for producing an ordered nanogold-dot array with strong localized surface plasmon resonance (LSPR) and narrow bandwidth. The array was used as an optical biosensing chip for the detection of vascular endothelial growth factor 165 (VEGF165) in human serum. The biochip was constructed by conjugating an anti-VEGF antibody, a specific biorecognition element for VEGF165, onto the array via the fragment crystallizable (Fc) region of the antibody, ultimately increasing the efficiency of VEGF165 detection. The resulting biochip was sensitive, had a wide linear detection range (0.01-100 ng/mL), was specific for VEGF165 (showing no interference when challenged with glucose and ascorbic acid), and characterized by an excellent stability (allowing storage and transportation at room temperature). Owing to the good correlations of VEGF165 measurements obtained with ELISA, we believe that our chip holds promise as a tool for early diagnosis of cancer. PMID- 27768269 TI - Aziridine-Functionalized Multiwalled Carbon Nanotubes: Robust and Versatile Catalysts for the Oxygen Reduction Reaction and Knoevenagel Condensation. AB - This paper describes the exohedral N-decoration of multiwalled carbon nanotubes (MWCNTs) with NH-aziridine groups via [2 + 1] cycloaddition of a tert-butyl oxycarbonyl nitrene followed by controlled thermal decomposition of the cyclization product. The chemical grafting with N-containing groups deeply modifies the properties of the starting MWCNTs, generating new surface microenvironments with specific base (Bronsted) and electronic properties. Both of these features translate into a highly versatile single-phase heterogeneous catalyst (MW@NAz) with remarkable chemical and electrochemical performance. Its surface base character promotes the Knoevenagel condensation with activity superior to that of related state of the art N-doped and N-decorated carbon nanomaterials; the N-induced electronic surface redistribution drives the generation of high-energy surface "C" sites suitable for O2 activation and its subsequent electrochemical reduction (ORR). PMID- 27768270 TI - Versatile Antireflection Coating for Plastics: Partial Embedding of Mesoporous Silica Nanoparticles onto Substrate Surface. AB - Antireflection (AR) coating for transparent plastic substrates is constructed by partially embedding mesoporous silica nanoparticles (MSNs) onto the surface of the substrates. Simulation of optical properties of polymer substrates coated with a single-particle MSN layer indicates that the surface has a low and graded refractive index in the direction of the thickness and effectively decreases the reflectance of visible light. The MSN-coated surfaces can be prepared by exposure of the MSN-painted substrates to a solvent vapor, irrespective of the shape of the polymer substrates. The plastic substrates with a single-particle layer of MSNs with diameters of 145-165 nm exhibit high transparency and good AR behavior as simulated. The mesoporous structures of MSNs play important roles not only in decreasing the refractive index but also in strengthening the adhesion between MSNs and substrate surfaces. Moreover, fixation of MSNs onto a thermosetting epoxy resin is successfully achieved by transfer of a single layer of MSNs from flexible films for which MSNs are weakly bonded. The present simple AR coating is applicable to a wide range of substrates with various materials and shapes, and useful for various applications such as optical devices, displays, and solar cells. PMID- 27768271 TI - Cross-Linking and Bundling of Self-Assembled Protein-Based Polymer Fibrils via Heterodimeric Coiled Coils. AB - Previously, we developed triblock protein polymers that form fibrillar hydrogels at low protein polymer concentrations (denoted C2-SH48-C2). We here demonstrate that the structure of these hydrogels can be tuned via heterodimeric coiled coils that cross-link and bundle the self-assembled protein polymer fibrils. We fused well-characterized, 47 amino acids-long heterodimeric coiled coil "linkers" (DA or DB) to the C-terminus of the triblock polymer. The resulting C2-SH48-C2-DA and C2-SH48-C2-DB polymers, were successfully produced as secreted proteins in Pichia pastoris, with titers of purified protein in the order of g L-1 of clarified broth. Atomic force microscopy showed that fibrils formed by either C2-SH48-C2-DA or C2-SH48-C2-DB alone already displayed extensive bundling, apparently as a result of homotypic (DA/DA and DB/DB) interactions. For fibrils prepared from protein polymers having no linkers, plus a small fraction of polymers containing either DA or DB linkers, no cross-linking and bundling was observed. At these same low concentrations of linkers, fibrils containing both the DA and the DB linkers did show cross-linking and bundling as a consequence of heterodimer formation. This work shows that we can control the extent of bundling and cross linking of supramolecular fibrils by varying the density of heterodimerizing coiled coils in the fibrils, which is promising for the further development of materials that mimic the extracellular matrix. PMID- 27768272 TI - Platinum-Catalyzed C-H Functionalization. AB - Recent developments in C-H bond activation and functionalization by Pt complexes are surveyed. Topics include the following: fundamental mechanistic investigations of C-H activation; stoichiometric intra- and intermolecular C-H activation; reactions of dioxygen with Pt(II) complexes that may be relevant to substrate oxygenation; and both stoichiometric and catalytic formation of C-O, C C, and C-B bonds via C-H activation. Current interests and trends are discussed, both in the context of historical work and to forecast future directions and opportunities for the field. PMID- 27768273 TI - Sweet Polymers: Poly(2-ethyl-2-oxazoline) Glycopolymers by Reductive Amination. AB - Carbohydrates are important in signaling, energy storage, and metabolism. Depending on their function, carbohydrates can be part of larger structures, such as glycoproteins, glycolipids, or other functionalities (glycoside). To this end, polymers can act as carriers of carbohydrates in so-called glycopolymers, which mimic the multivalent carbohydrate functionalities. We chose a biocompatible poly(2-ethyl-2-oxazoline) (PEtOx) as the basis for making glycopolymers. Via the partial hydrolysis of PEtOx, a copolymer of PEtOx and polyethylenimine (PEI) was obtained; the subsequent reductive amination with the linear forms of glucose and maltose yielded the glycopolymers. The ratios of PEtOx and carbohydrates were varied systematically, and the solution behaviors of the resulting glycoconjugates are discussed. Dynamic light scattering (DLS) revealed that, depending on the carbohydrate ratio, the glycopolymers were either fully water soluble or formed agglomerates in a temperature-dependent manner. Finally, these polymers were tested for their biological availability by studying their lectin binding ability with Concanavalin A. PMID- 27768275 TI - Integrating Weak Anion Exchange and Ultraviolet Photodissociation Mass Spectrometry with Strategic Modulation of Peptide Basicity for the Enrichment of Sulfopeptides. AB - Tyrosine sulfation is an important post-translational modification but remains difficult to detect in biological samples owing to its low stoichiometric abundance and the lack of effective enrichment methods. In the present study, weak anion exchange (WAX) is evaluated for the enrichment of sulfopeptides that have been modified via carbamylation to convert all primary amines to less basic carbamates. The decrease in basicity enhanced the binding of carbamylated sulfopeptides to WAX resin relative to nonsulfated peptides. Upon elution and electrospray ionization in the negative mode, ultraviolet photodissociation (UVPD) was applied for peptide sequencing. Application of the method to a tryptic digest of bovine coagulation factor V resulted in identification of sulfation on tyrosine 1513. PMID- 27768274 TI - Products of in Situ Corrosion of Depleted Uranium Ammunition in Bosnia and Herzegovina Soils. AB - Hundreds of tons of depleted uranium (DU) ammunition were used in previous armed conflicts in Iraq, Bosnia and Herzegovina, and Serbia/Kosovo. The majority (>90%) of DU penetrators miss their target and, if left in the environment, corrode in these postconflict zones. Thus, the best way to understand the fate of bulk DU material in the environment is to characterize the corrosion products of intact DU penetrators under field conditions for extended periods of time. However, such studies are scarce. To fill this knowledge gap, we characterized corrosion products formed from two intact DU penetrators that remained in soils in Bosnia and Herzegovina for over seven years. We used a combination of X-ray powder diffraction, electron microscopy, and X-ray absorption spectroscopy. The results show that metaschoepite (UO3(H2O)2) was a main component of the two DU corrosion products. Moreover, studtite ((UO2)O2(H2O)2.2(H2O)) and becquerelite (Ca(UO2)6O4(OH)6.8(H2O)) were also identified in the corrosion products. Their formation through transformation of metaschoepite was a result of the geochemical conditions under which the penetrators corroded. Moreover, we propose that the transformation of metaschoepite to becquerelite or studtite in the DU corrosion products would decrease the potential for mobilization of U from corroded DU penetrators exposed to similar environments in postconflict areas. PMID- 27768276 TI - Dnmt3b Methylates DNA by a Noncooperative Mechanism, and Its Activity Is Unaffected by Manipulations at the Predicted Dimer Interface. AB - The catalytic domains of the de novo DNA methyltransferases Dnmt3a-C and Dnmt3b-C are highly homologous. However, their unique biochemical properties could potentially contribute to differences in the substrate preferences or biological functions of these enzymes. Dnmt3a-C forms tetramers through interactions at the dimer interface, which also promote multimerization on DNA and cooperativity. Similar to the case for processive enzymes, cooperativity allows Dnmt3a-C to methylate multiple sites on the same DNA molecule; however, it is unclear whether Dnmt3b-C methylates DNA by a cooperative or processive mechanism. The importance of the tetramer structure and cooperative mechanism is emphasized by the observation that the R882H mutation in the dimer interface of DNMT3A is highly prevalent in acute myeloid leukemia and leads to a substantial loss of its activity. Under conditions that distinguish between cooperativity and processivity, we show that in contrast to that of Dnmt3a-C, the activity of Dnmt3b-C is not cooperative and confirm the processivity of Dnmt3b-C and the full length Dnmt3b enzyme. Whereas the R878H mutation (mouse homologue of R882H) led to the loss of cooperativity of Dnmt3a-C, the activity and processivity of the analogous Dnmt3b-C R829H variant were comparable to those of the wild-type enzyme. Additionally, buffer acidification that attenuates the dimer interface interactions of Dnmt3a-C had no effect on Dnmt3b-C activity. Taken together, these results demonstrate an important mechanistic difference between Dnmt3b and Dnmt3a and suggest that interactions at the dimer interface may play a limited role in regulating Dnmt3b-C activity. These new insights have potential implications for the distinct biological roles of Dnmt3a and Dnmt3b. PMID- 27768277 TI - Well-Controlled Dielectric Nanomeshes by Colloidal Nanosphere Lithography for Optoelectronic Enhancement of Ultrathin Cu(In,Ga)Se2 Solar Cells. AB - Ultrathin Cu(In,Ga)Se2 (CIGSe) solar cells pose challenges of incomplete absorption and back contact recombination. In this work, we applied the simple collodial nanosphere lithography and fabricated 2D SiO2 nanomeshes (NMs), which simultaneously benefit ultrathin CIGSe solar cells electrically and optically. Electrically, the NMs are capable of passivating the back contact recombination and increasing the minimum bandgap of absorbers. Optically, the parasitic absorption in Mo as a main optical loss is reduced. Consequently, the SiO2 NMs give rise to an increase of 3.5 mA/cm2 in short circuit current density (Jsc) and of 57 mV in open circuit voltage increase (Voc), leading to an absolute efficiency enhancement as high as 2.6% (relatively 30%) for CIGSe solar cells with an absorber thickness of only 370 nm and a steep back Ga/[Ga + In] grading. PMID- 27768278 TI - Electrospun Photochromic Hybrid Membranes for Flexible Rewritable Media. AB - Ink-free rewritable media has attracted great attention as a potential alternative to current paper prints, owing to its benefits to reducing paper production and consumption for environmental protection. It is desirable to develop rewritable media based on cheap, robust, and fast-response photochromic systems. Herein, we report the design and fabrication of flexible and photorewritable PVP/a-WO3 hybrid membranes through electrospinning, on which images with high resolution can be photoprinted and heat-erased for over 40 cycles. The well conjugated organic-inorganic hybrid structure endows a fast "electron-proton double injection" from PVP to a-WO3 in the coloration process and greatly improves the photochromic responses. The coloration times can be as short as tens of seconds and the erasure times can be as long as 10 days in ambient conditions. As-formed photochromic membranes are low-cost, environmental benign and easy for large-scale production, indicate their great potential as flexible rewritable media for practical usage. PMID- 27768279 TI - Efficient Photoelectrochemical Hydrogen Evolution on Silicon Photocathodes Interfaced with Nanostructured NiP2 Cocatalyst Films. AB - Increasing attention has now been focused on the photoelectrochemical (PEC) hydrogen evolution as a promising route to transforming solar energy into chemical fuels. Silicon is one of the most studied PEC electrode materials, but its performance is still limited by its inherent PEC instability and electrochemical inertness toward water splitting. To achieve significant PEC activities, silicon-based photoelectrodes usually have to be coupled with proper cocatalysts, and thus, the formed semiconductor-cocatalyst interface presents a critical structural parameter in the rational design of efficient PEC devices. In this study, we directly grow nanostructured pyrite-phase nickel phosphide (NiP2) cocatalyst films on textured pn+-Si photocathodes via on-surface reaction at high temperatures. The areal loading of the cocatalyst film can be tailored to achieve an optimal balance between its optical transparency and electrocatalytic activity. As a result, our pn+-Si/Ti/NiP2 photocathodes demonstrate a great PEC onset potential of 0.41 V versus reversible hydrogen electrode (RHE), a decent photocurrent density of ~12 mA/cm2 at the thermodynamic potential of hydrogen evolution, and an impressive operation durability for at least 6 h in 0.5 M H2SO4. Comparable PEC performance is also observed in 1 M potassium borate buffer (pH = 9.5) using this device. PMID- 27768280 TI - Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drugs. AB - The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis, and treatment resistance, yet therapeutic targeting, drug discovery, or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with submicromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new cocrystal structures delineated drug-EPHA2 interactions in full detail. The combination of selectivity profiling, structure determination, and kinome wide sequence alignment allowed the development of a classification system in which amino acids in the drug binding site of EPHA2 are categorized into key, scaffold, potency, and selectivity residues. This scheme should be generally applicable in kinase drug discovery, and we anticipate that the provided information will greatly facilitate the development of selective EPHA2 inhibitors in particular and the repurposing of clinical kinase inhibitors in general. PMID- 27768281 TI - Constraints on Arctic Atmospheric Chlorine Production through Measurements and Simulations of Cl2 and ClO. AB - During springtime, unique halogen chemistry involving chlorine and bromine atoms controls the prevalence of volatile organic compounds, ozone, and mercury in the Arctic lower troposphere. In situ measurements of the chlorine monoxide radical, ClO, and its precursor, Cl2, along with BrO and Br2, were conducted using chemical ionization mass spectrometry (CIMS) during the Bromine, Ozone, and Mercury Experiment (BROMEX) near Barrow, Alaska, in March 2012. To our knowledge, these data represent the first ClO measurements made using CIMS. A maximum daytime ClO concentration of 28 ppt was observed following an early morning peak of 75 ppt of Cl2. A zero-dimensional photochemistry model was constrained to Cl2 observations and used to simulate ClO during a 7-day period of the field campaign. The model simulates ClO within the measurement uncertainty, and the model results highlight the importance of chlorine chemistry participation in bromine radical cycling, as well as the dependence of halogen chemistry on NOx levels. The ClO measurements and simulations are consistent with Cl2 being the dominant Cl atom source in the Arctic boundary layer. Simulated Cl atom concentrations, up to ~1 * 106 molecules cm-3, highlight the importance of chlorine chemistry in the degradation of volatile organic compounds, including the greenhouse gas methane. PMID- 27768282 TI - In Situ Ion-Transmission Mass Spectrometry for Paper-Based Analytical Devices. AB - Current detection methods for paper-based analytical devices (PADs) rely on spectroscopic and electrochemical properties, which place special requirements on the analyte or need analyte labeling. Here, ion-transmission mass spectrometry (MS) was proposed for coupling with PADs to enable rapid in situ MS analysis of the sample on paper. The sample was analyzed directly on paper via analyte ionization by ions transmitted through the paper, generated by a low-temperature plasma probe. Prior to MS analysis, the sample can be separated by paper electrophoresis or by paper chromatography, among a variety of other features offered by PADs. The versatility of this technique was demonstrated by MS analysis of a paper microarray, a mixture of amino acids, and whole blood doped with drugs on PADs. PMID- 27768283 TI - Independent Validation of National Satellite-Based Land-Use Regression Models for Nitrogen Dioxide Using Passive Samplers. AB - Including satellite observations of nitrogen dioxide (NO2) in land-use regression (LUR) models can improve their predictive ability, but requires rigorous evaluation. We used 123 passive NO2 samplers sited to capture within-city and near-road variability in two Australian cities (Sydney and Perth) to assess the validity of annual mean NO2 estimates from existing national satellite-based LUR models (developed with 68 regulatory monitors). The samplers spanned roadside, urban near traffic (<=100 m to a major road), and urban background (>100 m to a major road) locations. We evaluated model performance using R2 (predicted NO2 regressed on independent measurements of NO2), mean-square-error R2 (MSE-R2), RMSE, and bias. Our models captured up to 69% of spatial variability in NO2 at urban near-traffic and urban background locations, and up to 58% of variability at all validation sites, including roadside locations. The absolute agreement of measurements and predictions (measured by MSE-R2) was similar to their correlation (measured by R2). Few previous studies have performed independent evaluations of national satellite-based LUR models, and there is little information on the performance of models developed with a small number of NO2 monitors. We have demonstrated that such models are a valid approach for estimating NO2 exposures in Australian cities. PMID- 27768284 TI - Pseudocapacitive Na-Ion Storage Boosts High Rate and Areal Capacity of Self Branched 2D Layered Metal Chalcogenide Nanoarrays. AB - The abundant reserve and low cost of sodium have provoked tremendous evolution of Na-ion batteries (SIBs) in the past few years, but their performances are still limited by either the specific capacity or rate capability. Attempts to pursue high rate ability with maintained high capacity in a single electrode remains even more challenging. Here, an elaborate self-branched 2D SnS2 (B-SnS2) nanoarray electrode is designed by a facile hot bath method for Na storage. This interesting electrode exhibits areal reversible capacity of ca. 3.7 mAh cm-2 (900 mAh g-1) and rate capability of 1.6 mAh cm-2 (400 mAh g-1) at 40 mA cm-2 (10 A g 1). Improved extrinsic pseudocapacitive contribution is demonstrated as the origin of fast kinetics of an alloying-based SnS2 electrode. Sodiation dynamics analysis based on first-principles calculations, ex-situ HRTEM, in situ impedance, and in situ Raman technologies verify the S-edge effect on the fast Na+ migration and reversible and sensitive structure evolution during high-rate charge/discharge. The excellent alloying-based pseudocapacitance and unsaturated edge effect enabled by self-branched surface nanoengineering could be a promising strategy for promoting development of SIBs with both high capacity and high rate response. PMID- 27768286 TI - Bipyridyltriazolium Chlorobismuthate with Thermo-/Photochromic and Photoluminescent Switching Behaviors Based on ET and CT?. AB - Matched with 3,5-bis(pyridine-2-yl)-1,2,4-triazole (2-bpt), a new electron donor acceptor-based chlorobismuthate(III) hybrid, [2-bpt]2[Bi2Cl10(H2O)].5H2O was prepared solvothermally and characterized. The title compound (hydrated form) and its dehydrated form exhibit photo- and thermo-induced intermolecular electron transfer (ET), which correspond to dual ET photo/thermochromism for hydrated form, charge transfer thermochromism during dehydration, and simultaneously photoluminescent responses, respectively. PMID- 27768288 TI - Toward Metal-Organic Framework-Based Solar Cells: Enhancing Directional Exciton Transport by Collapsing Three-Dimensional Film Structures. AB - Owing to their ability to act as light-harvesting scaffolds, porphyrin-containing metal-organic frameworks (MOFs) are in the forefront of research on the application of highly ordered molecular materials to problems in solar-energy conversion. In this work, solvent-assisted linker exchange (SALE) is performed on a pillared paddlewheel porphyrin containing MOF thin film to collapse a 3D framework to a 2D framework. The change in dimensionality of the framework is confirmed by a decrease in the film thickness, the magnitude of which is in agreement with crystallographic parameters for related bulk materials. Furthermore, NMR spectroscopy performed on the digested sample suggests a similar change in geometry is achieved in bulk MOF samples. The decreased distance between the porphyrin chromophores in the 2D MOF film compared to the 3D film results in enhanced energy transfer through the film. The extent of energy transport was probed by assembling MOF thin film where the outermost layers are palladium porphyrin (P2) units, which act as energy traps and fluorescence quenchers. Steady-state emission spectroscopy together with time-resolved emission spectroscopy indicates that excitons can travel through about 9-11 layers (porphyrin layers) in 2D films, whereas in 3D films energy transfer occurs through no more than about 6-8 layers. The results are difficult to understand if only changes in MOF interlayer spacing are considered but become much more understandable if dipole-dipole coupling distances are considered. PMID- 27768285 TI - Aspects of Weak Interactions between Folate and Glycine Betaine. AB - Folate, or vitamin B9, is an important compound in one-carbon metabolism. Previous studies have found weaker binding of dihydrofolate to dihydrofolate reductase in the presence of osmolytes. In other words, osmolytes are more difficult to remove from the dihydrofolate solvation shell than water; this shifts the equilibrium toward the free ligand and protein species. This study uses vapor-pressure osmometry to explore the interaction of folate with the model osmolyte, glycine betaine. This method yields a preferential interaction potential (MU23/RT value). This value is concentration-dependent as folate dimerizes. The MU23/RT value also tracks the deprotonation of folate's N3-O4 keto enol group, yielding a pKa of 8.1. To determine which folate atoms interact most strongly with betaine, the interaction of heterocyclic aromatic compounds (as well as other small molecules) with betaine was monitored. Using an accessible surface area approach coupled with osmometry measurements, deconvolution of the MU23/RT values into alpha values for atom types was achieved. This allows prediction of MU23/RT values for larger molecules such as folate. Molecular dynamics simulations of folate show a variety of structures from extended to L shaped. These conformers possess MU23/RT values from -0.18 to 0.09 m-1, where a negative value indicates a preference for solvation by betaine and a positive value indicates a preference for water. This range of values is consistent with values observed in osmometry and solubility experiments. As the average predicted folate MU23/RT value is near zero, this indicates folate interacts almost equally well with betaine and water. Specifically, the glutamate tail prefers to interact with water, while the aromatic rings prefer betaine. In general, the more protonated species in our small molecule survey interact better with betaine as they provide a source of hydrogens (betaine is not a hydrogen bond donor). Upon deprotonation of the small molecule, the preference swings toward water interaction because of its hydrogen bond donating capacities. PMID- 27768287 TI - CrIII-Substituted Heteropoly-16-Tungstates [CrIII2(B-beta-XIVW8O31)2]14- (X = Si, Ge): Magnetic, Biological, and Electrochemical Studies. AB - The dichromium(III)-containing heteropoly-16-tungstates [CrIII2(B-beta SiIVW8O31)2]14- (1) and [CrIII2(B-beta-GeIVW8O31)2]14- (2) were prepared via a one-pot reaction of the composing elements in aqueous, basic medium. Polyanions 1 and 2 represent the first examples of CrIII-containing heteropolytungstates comprising the octatungstate unit {XW8O31} (X = Si, Ge). Magnetic studies demonstrated that, in the solid state, the two polyanions exhibit a weak antiferromagnetic interaction between the two CrIII centers with J = -3.5 +/- 0.5 cm-1, with no long-range ordering down to 1.8 K. The ground-state spin of polyanions 1 and 2 was thus deduced to be 0, but the detection of a complex set of EPR signals implies that there are thermally accessible excited states containing unpaired spins resulting from the two S = 3/2 CrIII ions. A comprehensive electrochemistry study on 1 and 2 in solution was performed, and biological tests showed that both polyanions display significant antidiabetic and anticancer activities. PMID- 27768289 TI - Large-Scale Prediction of Collision Cross-Section Values for Metabolites in Ion Mobility-Mass Spectrometry. AB - The rapid development of metabolomics has significantly advanced health and disease related research. However, metabolite identification remains a major analytical challenge for untargeted metabolomics. While the use of collision cross-section (CCS) values obtained in ion mobility-mass spectrometry (IM-MS) effectively increases identification confidence of metabolites, it is restricted by the limited number of available CCS values for metabolites. Here, we demonstrated the use of a machine-learning algorithm called support vector regression (SVR) to develop a prediction method that utilized 14 common molecular descriptors to predict CCS values for metabolites. In this work, we first experimentally measured CCS values (OmegaN2) of ~400 metabolites in nitrogen buffer gas and used these values as training data to optimize the prediction method. The high prediction precision of this method was externally validated using an independent set of metabolites with a median relative error (MRE) of ~3%, better than conventional theoretical calculation. Using the SVR based prediction method, a large-scale predicted CCS database was generated for 35 203 metabolites in the Human Metabolome Database (HMDB). For each metabolite, five different ion adducts in positive and negative modes were predicted, accounting for 176 015 CCS values in total. Finally, improved metabolite identification accuracy was demonstrated using real biological samples. Conclusively, our results proved that the SVR based prediction method can accurately predict nitrogen CCS values (OmegaN2) of metabolites from molecular descriptors and effectively improve identification accuracy and efficiency in untargeted metabolomics. The predicted CCS database, namely, MetCCS, is freely available on the Internet. PMID- 27768290 TI - Redesigning Multilayer Ceramic Capacitors by Preservation of Electrode Conductivity and Localized Doping. AB - Both Li2CO3-coated nickel particles and fast firing technique were utilized in the manufacturing of MLCCs. They preserved the conductivity of Ni electrodes and provided the possibility of sintering the devices in oxidizing atmospheres. By using our method, the partial pressure of oxygen increased from 10-10 atm in conventional methods to 10-4 atm. The oxidizing atmosphere reduced the oxygen vacancy concentration as illustrated by the color change of the samples, and the results of EELS (electron energy loss spectroscopy). A systematic test with variable parameters, Li2CO3 coating, the sintering schedule, and the oxygen flow during sintering were executed, and the dissipation factor and the capacitance of the MLCCs were documented. Three type of MLCCs were studied: Conventional (fired with the conventional technique), Uncoated (fast fired with uncoated Ni particles), and Coated (fast fired with the coated Ni particles). The maximum oxygen activity during sintering (i.e., pO2 = 1.2 * 10-4 atm) was obtained for coated samples, and due to the minimum VO** concentration, their dissipation factor decreased up to 60% relative to the Conventional ones. In addition, the impedance spectroscopy, together with the map of Li ion distribution, suggested that Li ions accumulated around the electrode-dielectric interface and amplified the activation energy at these interfaces. This eventually caused the coated MLCCs to show higher capacitance than their uncoated counterparts. As a conclusion, it is shown that the manufacturing process described in this paper can provide a better MLCC with higher capacitance, and lower dissipation factor and leakage current. PMID- 27768291 TI - Active Site Desolvation and Thermostability Trade-Offs in the Evolution of Catalytically Diverse Triazine Hydrolases. AB - The desolvation of ionizable residues in the active sites of enzymes and the subsequent effects on catalysis and thermostability have been studied in model systems, yet little about how enzymes can naturally evolve to include active sites with highly reactive and desolvated charges is known. Variants of triazine hydrolase (TrzN) with significant differences in their active sites have been isolated from different bacterial strains: TrzN from Nocardioides sp. strain MTD22 contains a catalytic glutamate residue (Glu241) that is surrounded by hydrophobic and aromatic second-shell residues (Pro214 and Tyr215), whereas TrzN from Nocardioides sp. strain AN3 has a noncatalytic glutamine residue (Gln241) at an equivalent position, surrounded by hydrophilic residues (Thr214 and His215). To understand how and why these variants have evolved, a series of TrzN mutants were generated and characterized. These results show that desolvation by second shell residues increases the pKa of Glu241, allowing it to act as a general acid at neutral pH. However, significant thermostability trade-offs are required to incorporate the ionizable Glu241 in the active site and to then enclose it in a hydrophobic microenvironment. Analysis of high-resolution crystal structures shows that there are almost no structural changes to the overall configuration of the active site due to these mutations, suggesting that the changes in activity and thermostability are purely based on the altered electrostatics. The natural evolution of these enzyme isoforms provides a unique system in which to study the fundamental process of charged residue desolvation in enzyme catalysis and its relative contribution to the creation and evolution of an enzyme active site. PMID- 27768292 TI - Tuning the Band Bending and Controlling the Surface Reactivity at Polar and Nonpolar Surfaces of ZnO through Phosphonic Acid Binding. AB - ZnO is a prime candidate for future use in transparent electronics; however, development of practical materials requires attention to factors including control of its unusual surface band bending and surface reactivity. In this work, we have modified the O-polar (0001), Zn-polar (0001), and m-plane (1010) surfaces of ZnO with phosphonic acid (PA) derivatives and measured the effect on the surface band bending and surface sensitivity to atmospheric oxygen. Core level and valence band synchrotron X-ray photoemission spectroscopy was used to measure the surface band bending introduced by PA modifiers with substituents of opposite polarity dipole moment: octadecylphosphonic acid (ODPA) and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctylphosphonic acid (F13OPA). Both PAs act as surface electron donors, increasing the downward band bending and the strength of the two-dimensional surface electron accumulation layer on all of the ZnO surfaces investigated. On the O-polar (0001) and m-plane (1010) surfaces, the ODPA modifier produced the largest increase in downward band bending relative to the hydroxyl-terminated unmodified surface of 0.55 and 0.35 eV, respectively. On the Zn-polar (0001) face, the F13OPA modifier gave the largest increase (by 0.50 eV) producing a total downward band bending of 1.00 eV, representing ~30% of the ZnO band gap. Ultraviolet (UV) photoinduced surface wettability and photoconductivity measurements demonstrated that the PA modifiers are effective at decreasing the sensitivity of the surface toward atmospheric oxygen. Modification with PA derivatives produced a large increase in the persistence of UV-induced photoconductivity and a large reduction in UV-induced changes in surface wettability. PMID- 27768294 TI - Understanding the Magnetic Anisotropy toward Single-Ion Magnets. AB - Single-molecule magnets (SMMs) can retain their magnetization status preferentially after removal of the magnetic field below a certain temperature. The unique property, magnetic bistable status, enables the molecule-scale SMM to become the next-generation high-density information storage medium. SMMs' new applications are also involved in high-speed quantum computation and molecular spintronics. The development of coordination chemistry, especially in transition metal (3d) and lanthanide (4f) complexes, diversifies SMMs by introducing new ones. In both 3d and 4f SMMs, the ligands play a fundamental role in determining the SMMs' magnetic properties. The strategies for rationally designing and synthesizing high-performance SMMs require a comprehensive understanding of the effects of a crystal field. In this Account, we focus mainly on the magneto structural correlations of 4f or 3d single-ion magnets (SIMs), within which there is only one spin carrier. These one-spin carrier complexes benefit from getting rid of exchange interactions and relatively large distances of magnetic centers in the lattice, providing the ease to construct high-performance SIMs from the crystal field perspective. We will briefly introduce the crystal field approach for 4f or 3d complexes and then the magnetic anisotropy analysis via the displaced-charge electrostatic model. This idea has been proposed for years, and the related work is also highlighted. The angular-resolved magnetometry method, predominating in determining the magnetic anisotropic axes direction, is discussed. We also give a brief introduction of the quantum chemistry ab initio method, which has shown to be powerful in understanding the magnetic anisotropy and low-lying states. In the constructing and characterizing part, we give an overview of the SIMs based on lanthanide and transition ions, reported by our group in the past 5 years. In the 4f-SIMs survey, we discuss how beta-diketonates and cyclomultienes, and their combination, as ligands to influence magnetic anisotropy and provide some suggestion on designing SIMs based on different lanthanide ions. In the 3d-SIMs survey, we fully discuss the correlation between zero-field-splitting parameter D and molecular geometrical angle parameters. Finally, we lay out the challenges and further development of SIMs. We hope the understanding we provide about single-ion magnetic properties will be helpful to design high-performance SMMs. PMID- 27768293 TI - Advanced Photoemission Spectroscopy Investigations Correlated with DFT Calculations on the Self-Assembly of 2D Metal Organic Frameworks Nano Thin Films. AB - Metal-organic frameworks (MOFs) deposited from solution have the potential to form 2-dimensional supramolecular thin films suitable for molecular electronic applications. However, the main challenges lie in achieving selective attachment to the substrate surface, and the integration of organic conductive ligands into the MOF structure to achieve conductivity. The presented results demonstrate that photoemission spectroscopy combined with preparation in a system-attached glovebox can be used to characterize the electronic structure of such systems. The presented results demonstrate that porphyrin-based 2D MOF structures can be produced and that they exhibit similar electronic structure to that of corresponding conventional porphyrin thin films. Porphyrin MOF multilayer thin films were grown on Au substrates prefunctionalized with 4-mercaptopyridine (MP) via incubation in a glovebox, which was connected to an ultrahigh vacuum system outfitted with photoelectron spectroscopy. The thin film growth process was carried out in several sequential steps. In between individual steps the surface was characterized by photoemission spectroscopy to determine the valence bands and evaluate the growth mode of the film. A comprehensive evaluation of X-ray photoemission spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), and inverse photoemission spectroscopy (IPES) data was performed and correlated with density functional theory (DFT) calculations of the density of states (DOS) of the films involved to yield the molecular-level insights into the growth and the electronic properties of MOF-based 2D thin films. PMID- 27768295 TI - [CH3NH3]2Ag4SnIV2SnIIS8: An Open-Framework Mixed-Valent Chalcogenidostannate. AB - An open-framework chalcogenidostannate, namely, [CH3NH3]2Ag4SnIV2SnIIS8 (1), has been solvothermally synthesized and structurally characterized, which represents the first organically templated three-dimensional (3D) Ag-Sn-S compound containing the mixed valence of Sn(IV)/Sn(II) and displays visible-light-driven photocatalytic activity for degradation of crystal violet (CV). PMID- 27768296 TI - Access to Thiazole via Copper-Catalyzed [3+1+1]-Type Condensation Reaction under Redox-Neutral Conditions. AB - A new strategy for thiazoles via copper-catalyzed [3+1+1]-type condensation reaction from oximes, anhydrides and potassiumthiocyanate (KSCN) is developed herein. The transformation has good functional group tolerance and various thiazoles were formed smoothly in good to excellent yields under mild reaction conditions. This process involves copper-catalyzed N-O/C-S bond cleavages, activation of vinyl sp2 C-H bond, and C-S/C-N bond formations which are under redox-neutral conditions as well as operational simplicity. PMID- 27768297 TI - Framework-Topology-Dependent Catalytic Activity of Zirconium-Based (Porphinato)zinc(II) MOFs. AB - Catalytic activity for acyl transfer from N-acetylimidazole (NAI) to different pyridylcarbinol (PC) regioisomers (2-PC, 3-PC, and 4-PC) is demonstrated for a set of topologically diverse, zirconium-based (porphinato)zinc metal-organic frameworks (MOFs). The MOFs studied are PCN-222, MOF-525, and NU-902, which are based on the csq, ftw, and scu topologies, respectively. The experimentally obtained reaction kinetics are discussed in light of molecular modeling results. The catalytic activity is shown to vary across the series of MOFs due to the different extent to which each topology facilitates reactant preconcentration and alignment of PC and NAI via coordination to framework porphyrin sites (orientation effects). Trends of experimental initial reaction rates with MOF topology and PC regioisomer are consistent with preconcentration effects, which depend on the number of porphyrin sites per volume of MOF, as well as with orientation effects, which depend on the number of porphyrin pairs per volume of MOF that bind PC and NAI in such a way that they are primed to form the required transition state. The present work shows how the proper alignment of catalytic linkers can enhance reaction rates in MOFs. PMID- 27768299 TI - A Bifunctional Monomer for On-Resin Synthesis of Polyfunctional PNAs and Tailored Induced-Fit Switching Probes. AB - A synthetic strategy for the production of polyfunctional PNAs bearing substituent groups both on the nucleobase and on the backbone C5 carbon of the same monomer is described; this is based on the use of a tris-orthogonally protected monomer and subsequent solid-phase selective functionalization. This strategy can be used for synthesizing PNAs that are not readily accessible by use of preformed modified monomers. As an example, a PNA-based probe that undergoes a switch in its fluorescence emission upon hybridization with a target oligonucleotide, induced by tailor-made movement of two pyrene substituent groups, was synthesized. PMID- 27768300 TI - Quantum Mechanics/Molecular Mechanics Free Energy Maps and Nonadiabatic Simulations for a Photochemical Reaction in DNA: Cyclobutane Thymine Dimer. AB - The absorption of ultraviolet radiation by DNA may result in harmful genetic lesions that affect DNA replication and transcription, ultimately causing mutations, cancer, and/or cell death. We analyze the most abundant photochemical reaction in DNA, the cyclobutane thymine dimer, using hybrid quantum mechanics/molecular mechanics (QM/MM) techniques and QM/MM nonadiabatic molecular dynamics. We find that, due to its double helix structure, DNA presents a free energy barrier between nonreactive and reactive conformations leading to the photolesion. Moreover, our nonadiabatic simulations show that most of the photoexcited reactive conformations return to standard B-DNA conformations after an ultrafast nonradiative decay to the ground state. This work highlights the importance of dynamical effects (free energy, excited-state dynamics) for the study of photochemical reactions in biological systems. PMID- 27768298 TI - Site-Specific Bioorthogonal Labeling for Fluorescence Imaging of Intracellular Proteins in Living Cells. AB - Over the past years, fluorescent proteins (e.g., green fluorescent proteins) have been widely utilized to visualize recombinant protein expression and localization in live cells. Although powerful, fluorescent protein tags are limited by their relatively large sizes and potential perturbation to protein function. Alternatively, site-specific labeling of proteins with small-molecule organic fluorophores using bioorthogonal chemistry may provide a more precise and less perturbing method. This approach involves site-specific incorporation of unnatural amino acids (UAAs) into proteins via genetic code expansion, followed by bioorthogonal chemical labeling with small organic fluorophores in living cells. While this approach has been used to label extracellular proteins for live cell imaging studies, site-specific bioorthogonal labeling and fluorescence imaging of intracellular proteins in live cells is still challenging. Herein, we systematically evaluate site-specific incorporation of diastereomerically pure bioorthogonal UAAs bearing stained alkynes or alkenes into intracellular proteins for inverse-electron-demand Diels-Alder cycloaddition reactions with tetrazine functionalized fluorophores for live cell labeling and imaging in mammalian cells. Our studies show that site-specific incorporation of axial diastereomer of trans-cyclooct-2-ene-lysine robustly affords highly efficient and specific bioorthogonal labeling with monosubstituted tetrazine fluorophores in live mammalian cells, which enabled us to image the intracellular localization and real-time dynamic trafficking of IFITM3, a small membrane-associated protein with only 137 amino acids, for the first time. Our optimized UAA incorporation and bioorthogonal labeling conditions also enabled efficient site-specific fluorescence labeling of other intracellular proteins for live cell imaging studies in mammalian cells. PMID- 27768301 TI - Synthesis of C-4 Substituted Amido Nicotine Derivatives via Copper(I)- and (II) Catalyzed Cross-Coupling Reactions. AB - The syntheses of seven novel amido nicotine derivatives 12-18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross coupled with the corresponding amides 6-10 at the C-4 position of the pyridine ring via copper(I)-mediated reactions. Derivatives 16-18 were also obtained via copper(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs. PMID- 27768302 TI - Application of Ru(II)-Catalyzed Enyne Cyclization in the Synthesis of Brefeldin A. AB - The approach to brefeldin A described herein hinges on Ru(II)-catalyzed cycloisomerization of an enyne obtained by the reaction of an alkynylzinc reagent with an alpha-chloro sulfide. Other key steps include Mislow-Evans rearrangement, cross-metathesis, and macrocyclization using a Roush-Masamune protocol. PMID- 27768303 TI - Design, Synthesis, and Structural Characterization of a Bisantimony(III) Compound for Anion Binding and the Density Functional Theory Evaluation of Halide Binding through Antimony Secondary Bonding Interactions. AB - Density functional theory calculations were used to design an anion receptor that utilizes antimony(III) secondary bonding interactions. Calculations were performed on promising motifs found in the chemical literature where two antimony sites were found in close proximity to a halide anion. The study was extended to a structurally related class of 1,3,2-benzodioxastibole derivatives to elucidate their potential for binding halide ions. Multiple geometric conformations were evaluated and various ratios of halide anions were considered. According to the computation results, this class of anion receptors shows strong affinities toward charge-dense halides. These 1,3,2-benzodioxastibole derivatives were prepared to evaluate their synthetic accessibility. Structural characterization of one species revealed the ability to bind up to three electron donors through secondary bonding interactions. This gates the future experimental study of these antimony systems for anion binding and recognition. PMID- 27768304 TI - Iron-Catalyzed Cyclization of Nitrones with Geminal-Substituted Vinyl Acetates: A Direct [4 + 2] Assembly Strategy Leading to 2,4-Disubstituted Quinolines. AB - An iron-catalyzed intermolecular [4 + 2] cyclization of arylnitrones with geminal substituted vinyl acetates was developed for the synthesis of 2,4-disubstituted quinolines in moderate to good yields with good functional group compatibilities. Preliminary mechanistic studies suggest a plausible iron-catalyzed C-H activation process under external-oxidant-free conditions. PMID- 27768306 TI - Effects of Hydration on the Zwitterion Trialanine Conformation by Electronic Structure Theory. AB - Exploration of interfacial hydration networks of zwitterion and nonionized trialanine has been performed using DFT-M062X quantum chemical computations explicitly considering up to 41 water molecules. The step-by-step water molecules peptide surrounding, carried out for unfolded extended (beta), polyproline II (PPII) conformations reveals the crucial importance of explicit solvent effects in stabilizing the zwitterion form and the left-handed PPII-helix ubiquitously found at room temperature for short polyalanines. Hydration effects are much greater for the ionized form of the peptide; thus, the zwitterion is about 10 kcal mol-1 more stable than the nonionized form. For the beta -> PPII transformation, the two components of free Gibbs energy act in the opposite direction; thus, it is favored by enthalpy but not by entropy. These findings agree with experimental data that report an equilibrium between these conformers modulated by temperature. Thermodynamic functions of the four conformers (beta beta, beta-PPII, PPII-beta, and PPII-PPII) for zwitterion trialanine are similar to those derived for the protonated one (Ala3H+); therefore, the peptidic conformation is independent of the pH of the solution. Rather, it reflects the high propensity of alanine toward PPII helix. The enthalpic preference of the PPII has electrostatic origin and it is owing to a more favorable interaction of dipole of each peptidic residue with water dipole of H-bonded molecules. PMID- 27768307 TI - Cyanomethylation and Cyclization of Aryl Alkynoates with Acetonitrile under Transition-Metal-Free Conditions: Synthesis of 3-Cyanomethylated Coumarins. AB - Cyanomethylated coumarins were synthesized via cyanomethylation and cyclization of aryl alkynoates using cheap and available reagent acetonitrile as the cyanomethyl source in the presence of TBPB (tert-butyl peroxybenzoate) under transition-metal-free conditions. For the substrates with various substituents on benzene ring, the reaction proceeded smoothly to give the corresponding products in moderate to good yields. The resulting products could be simply converted into some other related coumarin derivatives. PMID- 27768308 TI - Synthesis of (-)-Chamobtusin A from (+)-Dehydroabietylamine. AB - Chamobtusin A, a unique diterpene alkaloid isolated from Chamaecyparis obtusa cv. tetragon, is considered to be biosynthesized from an abietane diterpenoid. On the basis of this biosynthetic hypothesis, ferruginol (15) was synthesized from (+) dehydroabietylamine and then biomimetically transformed into (-)-chamobtusin A in 6 steps (12 steps from (+)-dehydroabietylamine). PMID- 27768305 TI - Self-Assembly of Catenanes from Lasso Peptides. AB - Lasso peptides exist naturally in a threaded state as [1]rotaxanes, and we reasoned that lasso peptides cleaved in their loop region could serve as building blocks for catenanes. Mutagenesis of the lasso peptide microcin J25 (MccJ25) with two cysteine residues followed by cleavage of the peptide with trypsin led to a [2]rotaxane structure that self-assembled into a [3]catenane and [4]catenanes at room temperature in aqueous solution. The [3]catenane represents the smallest ring size of a catenane composed solely of polypeptide segments. The NMR structure of the [3]catenane was determined, suggesting that burial of hydrophobic residues may be a driving force for assembly of the catenane structure. PMID- 27768309 TI - Phosphenium Versus Pro-Phosphide Character of P-tert-butyl dicyclopropeniophosphine: Zwitterionic Palladate Complexes of a Dicationic Phosphido Ligand. AB - With the view to enhancing the unique coordinating ability of the known phenyl tetrakis(diisopropylamino)dicyclopropeniophosphine (Ph-DCP), replacement of the phenyl substituent by a tert-butyl substituent was envisaged. Both alpha dicationic R-DCP phosphines, with R = Ph and tBu, were prepared in 54%-55% yield by substitution of RPCl2 with two equivalents of bis(diisopropylamino) dicyclopropenylidene (BAC) and metathesis with NaBF4. This method is implicitly consistent with the representation of R-DCPs as BAC-phosphenium adducts. The R DCP salts were found to coordinate hard and soft Lewis acids such as a promoted oxygen atom (in the singlet spin state) in the corresponding R-DCP oxides, and electron-rich transition-metal centers in eta1-R-DCP complexes with AuCl, PtCl3-, or PdCl3-, respectively. Coordination of Ph-DCP with PdCl2, which is a more electron-deficient Pd(II) center, leads to pentachlorinated dinuclear complexes [(Ph-DCP)PdCl2]2Cl-, where the dicoordinate Cl- bridge screens the repelling pairs of positive charges from each other. The same behavior is inferred for the tBu-DCP ligand, from which addition of an excess of (MeCN)2PdCl2 was found to trigger a heterolytic cleavage of the DCP-tBu bond, releasing tBu+ and a dicationic phosphide, DCP-: the latter is evidenced as a ligand in a tetranuclear complex ion [(MU2-DCP-)Pd2Cl4]2, which, upon HCl treatment, dissociates to a doubly zwitterionic dipalladate complex. All the complexes were isolated in 82% 97% yield, and five of them were characterized by X-ray crystallography. PMID- 27768310 TI - Sodium Diisopropylamide in N,N-Dimethylethylamine: Reactivity, Selectivity, and Synthetic Utility. AB - The reactivities and chemoselectivities of sodium diisopropylamide (NaDA) in N,N dimethylethylamine (DMEA) are compared with those of lithium diisopropylamide (LDA) in tetrahydrofuran (THF). Metalations of arenes, epoxides, ketones, hydrazones, dienes, and alkyl and vinyl halides are represented. The positive attributes of NaDA-DMEA include high solubility, stability, resistance to solvent decomposition, and ease of preparation. The high reactivities and chemoselectivities often complement those of LDA-THF. PMID- 27768311 TI - IP3 Mediates Nitric Oxide-Guanosine 3',5'-Cyclic Monophosphate (NO-cGMP)-Induced Isoflavone Accumulation in Soybean Sprouts under UV-B Radiation. AB - In this study, to investigate the role of inositol 1,4,5-trisphosphate (IP3) in nitric oxide-guanosine 3',5'-cyclic monophosphate (NO-cGMP)-induced isoflavone accumulation in soybean sprouts under UV-B radiation, the sprouts were treated with donors and inhibitors of NO and cGMP as well as IP3 inhibitor. Results showed that NO, with cGMP as a second messenger, stimulates IP3 accumulation under UV-B radiation. Consistent with the increase in IP3 content, the up regulation of gene and protein expression of phosphoinositide-specific phospholipase C (PI-PLC) in response to sodium nitroprusside (SNP) (exogenous NO donor) and 8-Br-cGMP (cGMP analogue) was also observed. In addition, protein kinase G (PKG) participated in NO-cGMP-induced IP3 production. IP3 induced by the NO-cGMP pathway was involved in isoflavone synthesis by elevating the activity and gene and protein expressions of chalcone synthase (CHS) and isoflavone synthase (IFS). Overall, IP3 mediates NO-cGMP-induced isoflavone accumulation in soybean sprouts under UV-B stress. PMID- 27768312 TI - A Multiscale Study on the Penetration Enhancement Mechanism of Menthol to Osthole. AB - Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. However, details of the penetration enhancement mechanism of menthol on the molecular level is rarely involved in the discussion. In this work, the penetration enhancement (PE) mechanism of menthol is explored by a multiscale method containing molecular dynamics simulations, in vitro penetration experiments, and transmission electron microscopy. Osthole is chosen to be the tested drug due to its common use in external preparations and because it often accompanies menthol as a PE in the preparations. The results show that menthol in each testing concentration can impair the lipid packing of stratum corneum (SC) and promote osthole permeating into SC, and the penetration promoting effect has an optimal concentration. At a low concentration, menthol causes the bilayer to relax with a reduction in thickness and increment in the lipid headgroup area. At a high concentration, menthol destroys the bilayer structure of SC and causes lipids to form a reversed micelle structure. The penetration enhancement mechanism of menthol is characterized mainly by the disruption of the highly ordered SC lipid in low concentrations and an improvement in the partitioning of drugs into the SC in high concentrations. The results can provide some assistance for additional studies and applications of menthol as a penetration enhancer. PMID- 27768313 TI - Sesterterpenoids Isolated from the Sponge Phorbas sp. Activate Latent HIV-1 Provirus Expression. AB - Eight new sesterterpenoids, alotaketals D (8) and E (9), ansellones D (10), E (11), F (12), and G (13), and anvilones A (14) and B (15), have been isolated from extracts of the marine sponge Phorbas sp. collected in Howe Sound British Columbia, and their structures have been elucidated by analysis of NMR and MS data. Ansellone F (12) contains a rare 1,2-3,4-bis-epoxydecalin substructure. Anvilones A (14) and B (15) have an unprecedented tetracylic anvilane terpenoid carbon skeleton. Using a cell culture model of latent HIV-1 infection, ansellone A (3), alotaketal D (8), and anvilone A (14) were found to induce HIV proviral gene expression similar to the control compound prostratin (1), while the known sesterterpenoid alotaketal C (2), isolated from the same extract, was more potent and gave a stronger response than prostratin (1). Like prostratin (1), all of the Phorbas sesterterpenoids with latency reversal agent properties appear to activate protein kinase C signaling. PMID- 27768315 TI - Access toward Fluorenone Derivatives through Solvent-Free Ruthenium Trichloride Mediated [2 + 2 + 2] Cycloadditions. AB - An efficient and practical route for the preparation of highly substituted fluorenones and analogues via solvent-free ruthenium trichloride mediated [2 + 2 + 2] cycloaddition of alpha,omega-diynes and alkynes has been developed. This green chemistry approach involves a solventless and atom-economical catalytic process to generate densely functionalized fluorenones and related derivatives of high synthetic utility. PMID- 27768314 TI - Monomer/Oligomer Quasi-Racemic Protein Crystallography. AB - Racemic or quasi-racemic crystallography recently emerges as a useful technology for solution of the crystal structures of biomacromolecules. It remains unclear to what extent the biomacromolecules of opposite handedness can differ from each other in racemic or quasi-racemic crystallography. Here we report a finding that monomeric d-ubiquitin (Ub) has propensity to cocrystallize with different dimers, trimers, and even a tetramer of l-Ub. In these cocrystals the unconnected monomeric d-Ubs can self-assemble to form pseudomirror images of different oligomers of l-Ub. This monomer/oligomer cocrystallization phenomenon expands the concept of racemic crystallography. Using the monomer/oligomer cocrystallization technology we obtained, for the first time the X-ray structures of linear M1 linked tri- and tetra-Ubs and a K11/K63-branched tri-Ub. PMID- 27768316 TI - The Two Alternative Rate-Determining Steps in Benzylic Lithiation Reactions of Esters and Carbamates. AB - Lithiation reactions of tertiary benzylic esters and carbamates have been studied. Kinetic methodology revealed that a two-step reaction pathway should be considered for these reactions, where either the lithium precomplexation and/or the proton transfer steps can be rate determining. Kinetic isotopic effects were evaluated by comparison of the lithiations of the corresponding protio/deutero substrates, and the results obtained support the notion that lithium precomplexation is taking place on the reaction pathway and that it is the rate determining step in this transformation. PMID- 27768317 TI - Synthesis of Enantiomerically Pure Ring-Substituted l-Pyridylalanines by Biocatalytic Hydroamination. AB - Current routes to nitrogen-containing heteroarylalanines involve complex multistep synthesis and are often reliant on protection/deprotection steps and wasteful chromatographic purifications. In order to complement existing methodologies, a convenient telescopic strategy was developed for the synthesis of l-pyridylalanine analogues (12 examples) and other l-heteroarylalanines (5 examples) starting from the corresponding aldehydes. A phenylalanine ammonia lyase (PAL) from Anabaena variabilis was used as the biocatalyst to give conversions ranging between 88 and 95%, isolated yields of 32-60%, and perfect enantiopurity (>99% ee) by employing an additional deracemization cascade where necessary. PMID- 27768318 TI - Chiral Aryliodine-Mediated Enantioselective Organocatalytic Spirocyclization: Synthesis of Spirofurooxindoles via Cascade Oxidative C-O and C-C Bond Formation. AB - An enantioselective organocatalytic oxidative spirocyclization of alkyl 3 oxopentanedioate monoamide derivatives leading to the formation of diverse spirofurooxindoles with high enantioselectivity has been realized via chiral aryliodine-mediated cascade C-O and C-C bond formations. The reaction is postulated to proceed via oxidative C-O bond formation followed by oxidative C-C bond formation, with the latter being the enantioselectivity-determining step. PMID- 27768319 TI - Single-Flask Multicomponent Synthesis of Highly Substituted alpha-Pyrones via a Sequential Enolate Arylation and Alkenylation Strategy. AB - Trisubstituted alpha-pyrones are obtained by a Pd-catalyzed three-component, single-flask operation via an alpha-arylation, subsequent alpha-alkenylation, alkene isomerization, and dienolate lactonization. A variety of coupling components under mild conditions afforded isolated yields of up to 93% of the pyrones with complete control of regioselectivity. Metal dependence was noted for three of the steps of the pathway. Utility of the pyrone products was demonstrated by further transformations providing convenient access to polyaromatic compounds, exhibiting broad molecular diversity. PMID- 27768320 TI - Mono- and Dihydroxylated Symmetrical Octamethylcucurbiturils and Allylated Derivatives. AB - Mono- and dihydroxylated symmetrical octamethylcucurbit[6]urils {(OH)OMeQ[6] and (OH)2OMeQ[6]} were prepared using a photochemical method to introduce limited alcohol group(s) directly to the parent symmetrical octamethylcucurbit[6]uril (OMeQ[6]), and the resulting compounds were verified by 1H NMR, Xevo Q-TOF MS, and X-ray crystallography. Further chemical modification of mono- and dihydroxylated OMeQ[6] was also performed. PMID- 27768321 TI - An Endoperoxide Reactivity-Based FRET Probe for Ratiometric Fluorescence Imaging of Labile Iron Pools in Living Cells. AB - Iron is essential for sustaining life, as its ability to cycle between multiple oxidation states is critical for catalyzing chemical transformations in biological systems. However, without proper regulation, this same redox capacity can trigger oxidative stress events that contribute to aging along with diseases ranging from cancer to cardiovascular and neurodegenerative disorders. Despite its importance, methods for monitoring biological iron bound weakly to cellular ligands-the labile iron pool-to generate a response that preserves spatial and temporal information remain limited, owing to the potent fluorescence quenching ability of iron. We report the design, synthesis, and biological evaluation of FRET Iron Probe 1 (FIP-1), a reactivity-based probe that enables ratiometric fluorescence imaging of labile iron pools in living systems. Inspired by antimalarial natural products and related therapeutics, FIP-1 links two fluorophores (fluorescein and Cy3) through an Fe(II)-cleavable endoperoxide bridge, where Fe(II)-triggered peroxide cleavage leads to a decrease in fluorescence resonance energy transfer (FRET) from the fluorescein donor to Cy3 acceptor by splitting these two dyes into separate fragments. FIP-1 responds to Fe(II) in aqueous buffer with selectivity over competing metal ions and is capable of detecting changes in labile iron pools within living cells with iron supplementation and/or depletion. Moreover, application of FIP-1 to a model of ferroptosis reveals a change in labile iron pools during this form of cell death, providing a starting point to study iron signaling in living systems. PMID- 27768322 TI - A Redox-Sensitive and RAGE-Targeting Nanocarrier for Hepatocellular Carcinoma Therapy. AB - Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer death worldwide. Most current therapeutic agents lack the tumor targeting efficiency and result in a nonselective biodistribution in the body. In our previous study, we identified a peptide Ala-Pro-Asp-Thr-Lys-Thr-Gln (APDTKTQ) that can selectively bind to the receptor of advanced glycation end-products (RAGE), an immunoglobulin superfamily cell surface molecule overexpressed during HCC malignant progression. Here, we report the design of a mixed micelles system modified with this peptide to target HCC cells. Specifically, we modified Pluronic F68 (F68) with APDTKTQ (F68-APDTKTQ), and we conjugated d-alpha tocopheryl polyethylene glycol succinate (TPGS) with poly(lactic-co-glycolic acid) (PLGA) by a disulfide linker (TPGS-S-S-PLGA). We mixed TPGS-S-S-PLGA and F68-APDTKTQ (TSP/FP) to form a micelle, followed by the loading of oridonin (ORI). The prepared micelles showed a homogeneously spherical shape without aggregation, triggered an increased cellular uptake, and induced apoptosis in more cells than did the free ORI. Taken together, these results demonstrate the potential of this APDTKTQ-modified ORI-loaded TSP/FP mixed micelle system as a promising strategy for HCC-targeting therapy. PMID- 27768324 TI - Thermodynamic Measurement of Angular Anisotropy at the Hidden Order Transition of URu_{2}Si_{2}. AB - The heavy fermion compound URu_{2}Si_{2} continues to attract great interest due to the unidentified hidden order it develops below 17.5 K. The unique Ising character of the spin fluctuations and low-temperature quasiparticles is well established. We present detailed measurements of the angular anisotropy of the nonlinear magnetization that reveal a cos^{4}theta Ising anisotropy both at and above the ordering transition. With Landau theory, we show this implies a strongly Ising character of the itinerant hidden order parameter. PMID- 27768325 TI - Anisotropic Polar Magneto-Optic Kerr Effect of Ultrathin Fe/GaAs(001) Layers due to Interfacial Spin-Orbit Interaction. AB - We report the observation of the anisotropic polar magneto-optical Kerr effect in thin layers of epitaxial Fe/GaAs(001) at room temperature. A clear twofold symmetry of the Kerr rotation angle depending on the orientation of the linear polarization of the probing laser beam with respect to the crystallographic directions of the sample is detected for ultrathin magnetic films saturated out of the film plane. The amplitude of the anisotropy decreases with increasing Fe film thickness, suggesting that the interfacial region is the origin of the anisotropy. The twofold symmetry is fully reproduced by model calculations based on an interference of interfacial Bychkov-Rashba and Dresselhaus spin-orbit coupling. PMID- 27768327 TI - Fractional Spin Fluctuations as a Precursor of Quantum Spin Liquids: Majorana Dynamical Mean-Field Study for the Kitaev Model. AB - Experimental identification of quantum spin liquids remains a challenge, as the pristine nature is to be seen in asymptotically low temperatures. We here theoretically show that the precursor of quantum spin liquids appears in the spin dynamics in the paramagnetic state over a wide temperature range. Using the cluster dynamical mean-field theory and the continuous-time quantum Monte Carlo method, which are newly developed in the Majorana fermion representation, we calculate the dynamical spin structure factor, relaxation rate in nuclear magnetic resonance, and magnetic susceptibility for the honeycomb Kitaev model whose ground state is a canonical example of the quantum spin liquid. We find that dynamical spin correlations show peculiar temperature and frequency dependence even below the temperature where static correlations saturate. The results provide the experimentally accessible symptoms of the fluctuating fractionalized spins evincing the quantum spin liquids. PMID- 27768326 TI - Manipulating Smith-Purcell Emission with Babinet Metasurfaces. AB - Swift electrons moving closely parallel to a periodic grating produce far-field radiation of light, which is known as the Smith-Purcell effect. In this letter, we demonstrate that designer Babinet metasurfaces composed of C-aperture resonators offer a powerful control over the polarization state of the Smith Purcell emission, which can hardly be achieved via traditional gratings. By coupling the intrinsically nonradiative energy bound at the source current sheet to the out-of-plane electric dipole and in-plane magnetic dipole of the C aperture resonator, we are able to excite cross-polarized light thanks to the bianisotropic nature of the metasurface. The polarization direction of the emitted light is aligned with the orientation of the C-aperture resonator. Furthermore, the efficiency of the Smith-Purcell emission from Babinet metasurfaces is significantly increased by 84%, in comparison with the case of conventional gratings. These findings not only open up a new way to manipulate the electron-beam-induced emission in the near-field region but also promise compact, tunable, and efficient light sources and particle detectors. PMID- 27768328 TI - Deciphering the Dipole Anisotropy of Galactic Cosmic Rays. AB - Recent measurements of the dipole anisotropy in the arrival directions of Galactic cosmic rays (CRs) indicate a strong energy dependence of the dipole amplitude and phase in the TeV-PeV range. We argue here that these observations can be well understood within standard diffusion theory as a combined effect of (i) one or more local sources at Galactic longitude 120 degrees ?l?300 degrees dominating the CR gradient below 0.1-0.3 PeV, (ii) the presence of a strong ordered magnetic field in our local environment, (iii) the relative motion of the solar system, and (iv) the limited reconstruction capabilities of ground-based observatories. We show that an excellent candidate of the local CR source responsible for the dipole anisotropy at 1-100 TeV is the Vela supernova remnant. PMID- 27768323 TI - Search for Sterile Neutrinos Mixing with Muon Neutrinos in MINOS. AB - We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a nu_{MU}-dominated beam with a peak energy of 3 GeV. The data, from an exposure of 10.56*10^{20} protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters theta_{24} and Deltam_{41}^{2} and set limits on parameters of the four-dimensional Pontecorvo-Maki-Nakagawa-Sakata matrix, |U_{MU4}|^{2} and |U_{tau4}|^{2}, under the assumption that mixing between nu_{e} and nu_{s} is negligible (|U_{e4}|^{2}=0). No evidence for nu_{MU}->nu_{s} transitions is found and we set a world-leading limit on theta_{24} for values of Deltam_{41}^{2}?1 eV^{2}. PMID- 27768329 TI - Comment on "Estimating Excitonic Effects in the Absorption Spectra of Solids: Problems and Insight from a Guided Iteration Scheme". PMID- 27768330 TI - Erratum: Axion Dark Matter Coupling to Resonant Photons via Magnetic Field [Phys. Rev. Lett. 116, 161804 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.116.161804. PMID- 27768331 TI - First Test of Long-Range Collisional Drag via Plasma Wave Damping. AB - This paper presents the first experimental confirmation of a new theory predicting enhanced drag due to long-range collisions in a magnetized plasma. The experiments measure damping of Langmuir waves in a multispecies pure ion plasma, which is dominated by interspecies collisional drag in certain regimes. The measured damping rates in these regimes exceed classical predictions of collisional drag damping by as much as an order of magnitude, but agree with the new theory. PMID- 27768332 TI - Nonergodic Phases in Strongly Disordered Random Regular Graphs. AB - We combine numerical diagonalization with semianalytical calculations to prove the existence of the intermediate nonergodic but delocalized phase in the Anderson model on disordered hierarchical lattices. We suggest a new generalized population dynamics that is able to detect the violation of ergodicity of the delocalized states within the Abou-Chakra, Anderson, and Thouless recursive scheme. This result is supplemented by statistics of random wave functions extracted from exact diagonalization of the Anderson model on ensemble of disordered random regular graphs (RRG) of N sites with the connectivity K=2. By extrapolation of the results of both approaches to N->infinity we obtain the fractal dimensions D_{1}(W) and D_{2}(W) as well as the population dynamics exponent D(W) with the accuracy sufficient to claim that they are nontrivial in the broad interval of disorder strength W_{E}10^{5} reveals a singularity in D_{1,2}(W) dependencies which provides clear evidence for the first order transition between the two delocalized phases on RRG at W_{E}~10.0. We discuss the implications of these results for quantum and classical nonintegrable and many-body systems. PMID- 27768333 TI - Comment on "What Determines the Static Force Chains in Stressed Granular Media?" PMID- 27768334 TI - Atomic Resolution Imaging at an Ultralow Accelerating Voltage by a Monochromatic Transmission Electron Microscope. AB - Transmission electron microscopy using low-energy electrons would be very useful for atomic resolution imaging of specimens that would be damaged at higher energies. However, the resolution at low voltages is degraded because of geometrical and chromatic aberrations. In the present study, we diminish the effect of these aberrations by using a delta-type corrector and a monochromator. The dominant residual aberration in a delta-type corrector, which is the sixth order three-lobe aberration, is counterbalanced by other threefold aberrations. Defocus spread caused by chromatic aberration is reduced by using a monochromated beam with an energy spread of 0.05 eV. We obtain images of graphene and demonstrate atomic resolution at an ultralow accelerating voltage of 15 kV. PMID- 27768335 TI - Suppression of Noise-Induced Modulations in Multidelay Systems. AB - Many physical systems involve time-delayed feedback or coupling. In such delay systems, noise can give rise to undesirable oscillations at frequencies resonant to the delay times. We investigate how an additional feedback term can suppress noise-induced modulations in delay systems with self-feedback that exhibit deterministic oscillatory dynamics. A simple characteristic equation is derived to predict optimal delay times for the prototypical example of a Stuart-Landau oscillator subject to two feedback terms. We then show that a characteristic equation of the same form accurately describes the dominant Floquet modes of more complex oscillatory systems and hence can be used to optimize the suppression of noise-induced modulations. This is shown for mode-locked lasers and FitzHugh Nagumo oscillators subject to self-feedback. PMID- 27768336 TI - Controlling Strain Bursts and Avalanches at the Nano- to Micrometer Scale. AB - We demonstrate, through three-dimensional discrete dislocation dynamics simulations, that the complex dynamical response of nano- and microcrystals to external constraints can be tuned. Under load rate control, strain bursts are shown to exhibit scale-free avalanche statistics, similar to critical phenomena in many physical systems. For the other extreme of displacement rate control, strain burst response transitions to quasiperiodic oscillations, similar to stick slip earthquakes. External load mode control is shown to enable a qualitative transition in the complex collective dynamics of dislocations from self-organized criticality to quasiperiodic oscillations. PMID- 27768337 TI - Nondestructive Measurement of Orbital Angular Momentum for an Electron Beam. AB - Free electrons with a helical phase front, referred to as "twisted" electrons, possess an orbital angular momentum (OAM) and, hence, a quantized magnetic dipole moment along their propagation direction. This intrinsic magnetic moment can be used to probe material properties. Twisted electrons thus have numerous potential applications in materials science. Measuring this quantity often relies on a series of projective measurements that subsequently change the OAM carried by the electrons. In this Letter, we propose a nondestructive way of measuring an electron beam's OAM through the interaction of this associated magnetic dipole with a conductive loop. Such an interaction results in the generation of induced currents within the loop, which are found to be directly proportional to the electron's OAM value. Moreover, the electron experiences no OAM variations and only minimal energy losses upon the measurement, and, hence, the nondestructive nature of the proposed technique. PMID- 27768339 TI - Skyrmions with Attractive Interactions in an Ultrathin Magnetic Film. AB - We determined the parameters of a classical spin Hamiltonian describing an Fe monolayer on Pd(111) surface with a Pt_{1-x}Ir_{x} alloy overlayer from ab initio calculations. While the ground state of the system is ferromagnetic for x=0.00, it becomes a spin spiral state as Ir is intermixed into the overlayer. Although the Dzyaloshinsky-Moriya interaction is present in the system, we will demonstrate that the frustrated isotropic exchange interactions play a prominent role in creating the spin spiral state, and these frustrated couplings lead to an attractive interaction between Skyrmions at short distances. Using spin dynamics simulations, we show that under these conditions the individual Skyrmions form clusters, and that these clusters remain stable at finite temperature. PMID- 27768340 TI - Ligament Mediated Fragmentation of Viscoelastic Liquids. AB - The breakup and atomization of complex fluids can be markedly different than the analogous processes in a simple Newtonian fluid. Atomization of paint, combustion of fuels containing antimisting agents, as well as physiological processes such as sneezing are common examples in which the atomized liquid contains synthetic or biological macromolecules that result in viscoelastic fluid characteristics. Here, we investigate the ligament-mediated fragmentation dynamics of viscoelastic fluids in three different canonical flows. The size distributions measured in each viscoelastic fragmentation process show a systematic broadening from the Newtonian solvent. In each case, the droplet sizes are well described by Gamma distributions which correspond to a fragmentation-coalescence scenario. We use a prototypical axial step strain experiment together with high-speed video imaging to show that this broadening results from the pronounced change in the corrugated shape of viscoelastic ligaments as they separate from the liquid core. These corrugations saturate in amplitude and the measured distributions for viscoelastic liquids in each process are given by a universal probability density function, corresponding to a Gamma distribution with n_{min}=4. The breadth of this size distribution for viscoelastic filaments is shown to be constrained by a geometrical limit which can not be exceeded in ligament-mediated fragmentation phenomena. PMID- 27768342 TI - Anisotropic Expansion of a Thermal Dipolar Bose Gas. AB - We report on the anisotropic expansion of ultracold bosonic dysprosium gases at temperatures above quantum degeneracy and develop a quantitative theory to describe this behavior. The theory expresses the postexpansion aspect ratio in terms of temperature and microscopic collisional properties by incorporating Hartree-Fock mean-field interactions, hydrodynamic effects, and Bose-enhancement factors. Our results extend the utility of expansion imaging by providing accurate thermometry for dipolar thermal Bose gases. Furthermore, we present a simple method to determine scattering lengths in dipolar gases, including near a Feshbach resonance, through observation of thermal gas expansion. PMID- 27768343 TI - Enhanced Constraints for Accurate Lower Bounds on Many-Electron Quantum Energies from Variational Two-Electron Reduced Density Matrix Theory. AB - A central challenge of physics is the computation of strongly correlated quantum systems. The past ten years have witnessed the development and application of the variational calculation of the two-electron reduced density matrix (2-RDM) without the wave function. In this Letter we present an orders-of-magnitude improvement in the accuracy of 2-RDM calculations without an increase in their computational cost. The advance is based on a low-rank, dual formulation of an important constraint on the 2-RDM, the T2 condition. Calculations are presented for metallic chains and a cadmium-selenide dimer. The low-scaling T2 condition will have significant applications in atomic and molecular, condensed-matter, and nuclear physics. PMID- 27768344 TI - Charge Redistribution from Anomalous Magnetovorticity Coupling. AB - We investigate novel transport phenomena in a chiral fluid originated from an interplay between a vorticity and strong magnetic field, which induces a redistribution of vector charges in the system and an axial current along the magnetic field. The corresponding transport coefficients are obtained from an energy-shift argument for the chiral fermions in the lowest Landau level due to a spin-vorticity coupling and also from diagrammatic computations on the basis of the linear response theory. Based on consistent results from both methods, we observe that the transport coefficients are proportional to the anomaly coefficient and are independent of temperature and chemical potential. We therefore speculate that these transport phenomena are connected to quantum anomaly. PMID- 27768345 TI - Localized AdS_{5}*S^{5} Black Holes. AB - According to heuristic arguments, global AdS_{5}*S^{5} black holes are expected to undergo a phase transition in the microcanonical ensemble. At high energies, one expects black holes that respect the symmetries of the S^{5}; at low energies, one expects "localized" black holes that appear pointlike on the S^{5}. According to anti-de Sitter/conformal field theory correspondence, N=4 supersymmetric Yang-Mills (SYM) theory on a 3-sphere should therefore exhibit spontaneous R-symmetry breaking at strong coupling. In this Letter, we numerically construct these localized black holes. We extrapolate the location of this phase transition, and compute the expectation value of the broken scalar operator with lowest conformal dimension. Via the correspondence, these results offer quantitative predictions for N=4 SYM theory. PMID- 27768346 TI - Superconductivity near a Quantum-Critical Point: The Special Role of the First Matsubara Frequency. AB - Near a quantum-critical point in a metal strong fermion-fermion interaction mediated by a soft collective boson gives rise to incoherent, non-Fermi liquid behavior. It also often gives rise to superconductivity which masks the non-Fermi liquid behavior. We analyze the interplay between the tendency to pairing and fermionic incoherence for a set of quantum-critical models with effective dynamical interaction between low-energy fermions. We argue that superconducting T_{c} is nonzero even for strong incoherence and/or weak interaction due to the fact that the self-energy from dynamic critical fluctuations vanishes for the two lowest fermionic Matsubara frequencies omega_{m}=+/-piT. We obtain the analytic formula for T_{c}, which reproduces well earlier numerical results for the electron-phonon model at vanishing Debye frequency. PMID- 27768347 TI - Defect Interactions in Anisotropic Two-Dimensional Fluids. AB - Disclinations in liquid crystals bear striking analogies to defect structures in a wide variety of physical systems, and their straightforward optical observability makes them excellent models to study fundamental properties of defect interactions. We employ freely suspended smectic-C films, which behave as quasi-two-dimensional polar nematics. A procedure to capture high-strength disclinations in localized spots is introduced. These disclinations are released in a controlled way, and the motion of the mutually repelling topological charges with strength +1 is studied quantitatively. We demonstrate that the classical models, which employ elastic one-constant approximation, fail to describe their dynamics correctly. In realistic liquid crystals, even small differences between splay and bend constants lead to the selection of pure splay or pure bend +1 defects. For those, the models work only in very special configurations. In general, additional director walls are involved which reinforce the repulsive interactions substantially. PMID- 27768348 TI - Nematic Quantum Critical Fluctuations in BaFe_{2-x}Ni_{x}As_{2}. AB - We have systematically studied the nematic fluctuations in the electron-doped iron-based superconductor BaFe_{2-x}Ni_{x}As_{2} by measuring the in-plane resistance change under uniaxial pressure. While the nematic quantum critical point can be identified through the measurements along the (110) direction, as studied previously, quantum and thermal critical fluctuations cannot be distinguished due to similar Curie-Weiss-like behaviors. Here we find that a sizable pressure-dependent resistivity along the (100) direction is present in all doping levels, which is against the simple picture of an Ising-type nematic model. The signal along the (100) direction becomes maximum at optimal doping, suggesting that it is associated with nematic quantum critical fluctuations. Our results indicate that thermal fluctuations from striped antiferromagnetic order dominate the underdoped regime along the (110) direction. We argue that either there is a strong coupling between the quantum critical fluctuations and the fermions, or more exotically, a higher symmetry may be present around optimal doping. PMID- 27768349 TI - Gendelman et al. Reply. PMID- 27768350 TI - Multiple Rabi Splittings under Ultrastrong Vibrational Coupling. AB - From the high vibrational dipolar strength offered by molecular liquids, we demonstrate that a molecular vibration can be ultrastrongly coupled to multiple IR cavity modes, with Rabi splittings reaching 24% of the vibration frequencies. As a proof of the ultrastrong coupling regime, our experimental data unambiguously reveal the contributions to the polaritonic dynamics coming from the antiresonant terms in the interaction energy and from the dipolar self-energy of the molecular vibrations themselves. In particular, we measure the opening of a genuine vibrational polaritonic band gap of ca. 60 meV. We also demonstrate that the multimode splitting effect defines a whole vibrational ladder of heavy polaritonic states perfectly resolved. These findings reveal the broad possibilities in the vibrational ultrastrong coupling regime which impact both the optical and the molecular properties of such coupled systems, in particular, in the context of mode-selective chemistry. PMID- 27768338 TI - H.E.S.S. Limits on Linelike Dark Matter Signatures in the 100 GeV to 2 TeV Energy Range Close to the Galactic Center. AB - : A search for dark matter linelike signals iss performed in the vicinity of the Galactic Center by the H.E.S.S. experiment on observational data taken in 2014. An unbinned likelihood analysis iss developed to improve the sensitivity to linelike signals. The upgraded analysis along with newer data extend the energy coverage of the previous measurement down to 100 GeV. The 18 h of data collected with the H.E.S.S. array allow one to rule out at 95% C.L. the presence of a 130 GeV line (at l=-1.5 degrees , b=0 degrees and for a dark matter profile centered at this location) previously reported in Fermi-LAT data. This new analysis overlaps significantly in energy with previous Fermi-LAT and H.E.S.S. RESULTS: No significant excess associated with dark matter annihilations was found in the energy range of 100 GeV to 2 TeV and upper limits on the gamma-ray flux and the velocity weighted annihilation cross section are derived adopting an Einasto dark matter halo profile. Expected limits for present and future large statistics H.E.S.S. observations are also given. PMID- 27768351 TI - Self-Referenced Coherent Diffraction X-Ray Movie of Angstrom- and Femtosecond Scale Atomic Motion. AB - Time-resolved femtosecond x-ray diffraction patterns from laser-excited molecular iodine are used to create a movie of intramolecular motion with a temporal and spatial resolution of 30 fs and 0.3 A. This high fidelity is due to interference between the nonstationary excitation and the stationary initial charge distribution. The initial state is used as the local oscillator for heterodyne amplification of the excited charge distribution to retrieve real-space movies of atomic motion on angstrom and femtosecond scales. This x-ray interference has not been employed to image internal motion in molecules before. Coherent vibrational motion and dispersion, dissociation, and rotational dephasing are all clearly visible in the data, thereby demonstrating the stunning sensitivity of heterodyne methods. PMID- 27768352 TI - Doubly Magic Optical Trapping for Cs Atom Hyperfine Clock Transitions. AB - We analyze doubly magic trapping of Cs hyperfine transitions including previously neglected contributions from the ground state hyperpolarizability and the interaction of the laser light and a static magnetic field. Extensive numerical searches do not reveal any doubly magic trapping conditions for any pair of hyperfine states. However, including the hyperpolarizability reveals light intensity insensitive traps for a wide range of wavelengths at specific intensities. We then investigate the use of bichromatic trapping light fields. Deploying a bichromatic scheme, we demonstrate doubly magic red and blue detuned traps for pairs of states separated by one or two single photon transitions. PMID- 27768341 TI - Improved Search for a Light Sterile Neutrino with the Full Configuration of the Daya Bay Experiment. AB - This Letter reports an improved search for light sterile neutrino mixing in the electron antineutrino disappearance channel with the full configuration of the Daya Bay Reactor Neutrino Experiment. With an additional 404 days of data collected in eight antineutrino detectors, this search benefits from 3.6 times the statistics available to the previous publication, as well as from improvements in energy calibration and background reduction. A relative comparison of the rate and energy spectrum of reactor antineutrinos in the three experimental halls yields no evidence of sterile neutrino mixing in the 2*10^{ 4}?|Deltam_{41}^{2}|?0.3 eV^{2} mass range. The resulting limits on sin^{2}2theta_{14} are improved by approx imately a factor of 2 over previous results and constitute the most stringent constraints to date in the |Deltam_{41}^{2}|?0.2 eV^{2} region. PMID- 27768353 TI - Uncoupled Dark States Can Inherit Polaritonic Properties. AB - When a collection of quantum emitters interacts with an electromagnetic field, the whole system can enter into the collective strong coupling regime in which hybrid light-matter states, i.e., polaritons can be created. Only a small portion of excitations in the emitters are coupled to the light field, and there are many dark states that, in principle, retain their pure excitonic nature. Here we theoretically demonstrate that these dark states can have a delocalized character, which is inherent to polaritons, despite the fact that they do not have a photonic component. This unexpected behavior only appears when the electromagnetic field displays a discrete spectrum. In this case, when the main loss mechanism in the hybrid system stems from the radiative losses of the light field, dark states are even more efficient than polaritons in transferring excitations across the structure. PMID- 27768354 TI - Proton Conductivity in Phosphoric Acid: The Role of Quantum Effects. AB - Phosphoric acid has one of the highest intrinsic proton conductivities of any known liquids, and the mechanism of this exceptional conductivity remains a puzzle. Our detailed experimental studies discovered a strong isotope effect in the conductivity of phosphoric acids caused by (i) a strong isotope shift of the glass transition temperature and (ii) a significant reduction of the energy barrier by zero-point quantum fluctuations. These results suggest that the high conductivity in phosphoric acids is caused by a very efficient proton transfer mechanism, which is strongly assisted by quantum effects. PMID- 27768355 TI - Erratum: First Measurements of Fuel-Ablator Interface Instability Growth in Inertial Confinement Fusion Implosions on the National Ignition Facility [Phys. Rev. Lett. 117, 075002 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.117.075002. PMID- 27768357 TI - Warm Little Inflaton. AB - We show that inflation can naturally occur at a finite temperature T>H that is sustained by dissipative effects, when the inflaton field corresponds to a pseudo Nambu-Goldstone boson of a broken gauge symmetry. Similar to the Little Higgs scenarios for electroweak symmetry breaking, the flatness of the inflaton potential is protected against both quadratic divergences and the leading thermal corrections. We show that, nevertheless, nonlocal dissipative effects are naturally present and are able to sustain a nearly thermal bath of light particles despite the accelerated expansion of the Universe. As an example, we discuss the dynamics of chaotic warm inflation with a quartic potential and show that the associated observational predictions are in very good agreement with the latest Planck results. This model constitutes the first realization of warm inflation requiring only a small number of fields; in particular, the inflaton is directly coupled to just two light fields. PMID- 27768358 TI - Three-Jet Production in Electron-Positron Collisions at Next-to-Next-to-Leading Order Accuracy. AB - We introduce a completely local subtraction method for fully differential predictions at next-to-next-to-leading order (NNLO) accuracy for jet cross sections and use it to compute event shapes in three-jet production in electron positron collisions. We validate our method on two event shapes, thrust and C parameter, which are already known in the literature at NNLO accuracy and compute for the first time oblateness and the energy-energy correlation at the same accuracy. PMID- 27768359 TI - Laser-Induced Charge-Density-Wave Transient Depinning in Chromium. AB - We report on time-resolved x-ray diffraction measurements following femtosecond laser excitation in pure bulk chromium. Comparing the evolution of incommensurate charge-density-wave (CDW) and atomic lattice reflections, we show that, a few nanoseconds after laser excitation, the CDW undergoes different structural changes than the atomic lattice. We give evidence for a transient CDW shear strain that breaks the lattice point symmetry. This strain is characteristic of sliding CDWs, as observed in other incommensurate CDW systems, suggesting the laser-induced CDW sliding capability in 3D systems. This first evidence opens perspectives for unconventional laser-assisted transport of correlated charges. PMID- 27768361 TI - Rigamonti et al. Reply. PMID- 27768362 TI - Diffractive Imaging of Coherent Nuclear Motion in Isolated Molecules. AB - Observing the motion of the nuclear wave packets during a molecular reaction, in both space and time, is crucial for understanding and controlling the outcome of photoinduced chemical reactions. We have imaged the motion of a vibrational wave packet in isolated iodine molecules using ultrafast electron diffraction with relativistic electrons. The time-varying interatomic distance was measured with a precision 0.07 A and temporal resolution of 230 fs full width at half maximum. The method is not only sensitive to the position but also the shape of the nuclear wave packet. PMID- 27768363 TI - Heteronuclear Efimov Scenario with Positive Intraspecies Scattering Length. AB - We investigate theoretically and experimentally the heteronuclear Efimov scenario for a three-body system that consists of two bosons and one distinguishable particle with positive intraspecies scattering lengths. The three-body parameter at the three-body scattering threshold and the scaling factor between consecutive Efimov resonances are found to be controlled by the scattering length between the two bosons, approximately independent of short-range physics. We observe two excited-state Efimov resonances in the three-body recombination spectra of an ultracold mixture of fermionic ^{6}Li and bosonic ^{133}Cs atoms close to a Li-Cs Feshbach resonance, where the Cs-Cs interaction is positive. Deviation of the obtained scaling factor of 4.0(3) from the universal prediction of 4.9 and the absence of the ground state Efimov resonance shed new light on the interpretation of the universality and the discrete scaling behavior of heteronuclear Efimov physics. PMID- 27768365 TI - Scheme Variations of the QCD Coupling and Hadronic tau Decays. AB - The quantum chromodynamics (QCD) coupling alpha_{s} is not a physical observable of the theory, since it depends on conventions related to the renormalization procedure. We introduce a definition of the QCD coupling, denoted by alpha[over ^]_{s}, whose running is explicitly renormalization scheme invariant. The scheme dependence of the new coupling alpha[over ^]_{s} is parametrized by a single parameter C, related to transformations of the QCD scale Lambda. It is demonstrated that appropriate choices of C can lead to substantial improvements in the perturbative prediction of physical observables. As phenomenological applications, we study e^{+}e^{-} scattering and decays of the tau lepton into hadrons, both being governed by the QCD Adler function. PMID- 27768366 TI - Anisotropic X-Ray Dark-Field Tomography: A Continuous Model and its Discretization. AB - The x-ray dark-field signal measured in grating interferometers is anisotropic, depending on both the beam direction and the grating orientation with respect to the sample. We present a novel general closed-form, continuous forward model of the anisotropic dark-field signal. Furthermore, we derive a discretization using spherical harmonics, leading to a large-scale linear inverse problem. We present first experimental results of a wooden sample, demonstrating marked advantages over previous results, in particular, the resolution of multiple scattering directions in one volume element. PMID- 27768367 TI - Preferential Rotation of Chiral Dipoles in Isotropic Turbulence. AB - We introduce a new particle shape which shows preferential rotation in three dimensional homogeneous isotropic turbulence. We call these particles chiral dipoles because they consist of a rod with two helices of opposite handedness, one at each end. 3D printing is used to fabricate these particles with a length in the inertial range and their rotations are tracked in a turbulent flow between oscillating grids. High aspect ratio chiral dipoles preferentially align with their long axis along the extensional eigenvectors of the strain rate tensor, and the helical ends respond to the extensional strain rate with a mean spinning rate that is nonzero. We use Stokesian dynamics simulations of chiral dipoles in pure strain flow to quantify the dependence of spinning on particle shape. Based on the known response to pure strain, we build a model that gives the spinning rate of small chiral dipoles using velocity gradients along Lagrangian trajectories from high resolution direct numerical simulations. The statistics of chiral dipole spinning determined with this model show surprisingly good agreement with the measured spinning of much larger chiral dipoles in the experiments. PMID- 27768368 TI - Tunable Magnon Weyl Points in Ferromagnetic Pyrochlores. AB - The dispersion relations of magnons in ferromagnetic pyrochlores with Dzyaloshinskii-Moriya interaction are shown to possess Weyl points, i. e., pairs of topologically nontrivial crossings of two magnon branches with opposite topological charge. As a consequence of their topological nature, their projections onto a surface are connected by magnon arcs, thereby resembling closely Fermi arcs of electronic Weyl semimetals. On top of this, the positions of the Weyl points in reciprocal space can be tuned widely by an external magnetic field: rotated within the surface plane, the Weyl points and magnon arcs are rotated as well; tilting the magnetic field out of plane shifts the Weyl points toward the center Gamma[over -] of the surface Brillouin zone. The theory is valid for the class of ferromagnetic pyrochlores, i. e., three-dimensional extensions of topological magnon insulators on kagome lattices. In this Letter, we focus on the (111) surface, identify candidates of established ferromagnetic pyrochlores which apply to the considered spin model, and suggest experiments for the detection of the topological features. PMID- 27768369 TI - Coherence Constraints and the Last Hidden Optical Coherence. AB - We have discovered a new domain of optical coherence, and show that it is the third and last member of a previously unreported fundamental triad of coherences. These are unified by our derivation of a parallel triad of coherence constraints that take the form of complementarity relations. We have been able to enter this new coherence domain experimentally and we describe the novel tomographic approach devised for that purpose. PMID- 27768364 TI - ^{7}Be(n,alpha)^{4}He Reaction and the Cosmological Lithium Problem: Measurement of the Cross Section in a Wide Energy Range at n_TOF at CERN. AB - The energy-dependent cross section of the ^{7}Be(n,alpha)^{4}He reaction, of interest for the so-called cosmological lithium problem in big bang nucleosynthesis, has been measured for the first time from 10 meV to 10 keV neutron energy. The challenges posed by the short half-life of ^{7}Be and by the low reaction cross section have been overcome at n_TOF thanks to an unprecedented combination of the extremely high luminosity and good resolution of the neutron beam in the new experimental area (EAR2) of the n_TOF facility at CERN, the availability of a sufficient amount of chemically pure ^{7}Be, and a specifically designed experimental setup. Coincidences between the two alpha particles have been recorded in two Si-^{7}Be-Si arrays placed directly in the neutron beam. The present results are consistent, at thermal neutron energy, with the only previous measurement performed in the 1960s at a nuclear reactor. The energy dependence reported here clearly indicates the inadequacy of the cross section estimates currently used in BBN calculations. Although new measurements at higher neutron energy may still be needed, the n_TOF results hint at a minor role of this reaction in BBN, leaving the long-standing cosmological lithium problem unsolved. PMID- 27768356 TI - Limits on Active to Sterile Neutrino Oscillations from Disappearance Searches in the MINOS, Daya Bay, and Bugey-3 Experiments. AB - Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the Liquid Scintillator Neutrino Detector (LSND) and MiniBooNE experiments in a minimally extended four neutrino flavor framework. Stringent limits on sin^{2}2theta_{MUe} are set over 6 orders of magnitude in the sterile mass-squared splitting Deltam_{41}^{2}. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for Deltam_{41}^{2}<0.8 eV^{2} at 95% CL_{s}. PMID- 27768370 TI - Highly Anisotropic and Twofold Symmetric Superconducting Gap in Nematically Ordered FeSe_{0.93}S_{0.07}. AB - FeSe exhibits a novel ground state in which superconductivity coexists with a nematic order in the absence of any long-range magnetic order. Here, we report on an angle-resolved photoemission study on the superconducting gap structure in the nematic state of FeSe_{0.93}S_{0.07}, without the complications caused by Fermi surface reconstruction induced by magnetic order. We find that the superconducting gap shows a pronounced twofold anisotropy around the elliptical hole pocket near Z (0, 0, pi), with gap minima at the end points of its major axis, while no detectable gap is observed around Gamma (0, 0, 0) and the zone corner (pi, pi, k_{z}). The large anisotropy and nodal gap distribution demonstrate the substantial effects of the nematicity on the superconductivity and thus put strong constraints on current theories. PMID- 27768371 TI - Ab Initio Quantum Monte Carlo Simulation of the Warm Dense Electron Gas in the Thermodynamic Limit. AB - We perform ab initio quantum Monte Carlo (QMC) simulations of the warm dense uniform electron gas in the thermodynamic limit. By combining QMC data with the linear response theory, we are able to remove finite-size errors from the potential energy over the substantial parts of the warm dense regime, overcoming the deficiencies of the existing finite-size corrections by Brown et al. [Phys. Rev. Lett. 110, 146405 (2013)]. Extensive new QMC results for up to N=1000 electrons enable us to compute the potential energy V and the exchange correlation free energy F_{xc} of the macroscopic electron gas with an unprecedented accuracy of |DeltaV|/|V|,|DeltaF_{xc}|/|F|_{xc}~10^{-3}. A comparison of our new data to the recent parametrization of F_{xc} by Karasiev et al. [Phys. Rev. Lett. 112, 076403 (2014)] reveals significant deviations to the latter. PMID- 27768372 TI - Phase-Field-Crystal Model for Electromigration in Metal Interconnects. AB - We propose an atomistic model of electromigration (EM) in metals based on a recently developed phase-field-crystal (PFC) technique. By coupling the PFC model's atomic density field with an applied electric field through the EM effective charge parameter, EM is successfully captured on diffusive time scales. Our framework reproduces the well-established EM phenomena known as Black's equation and the Blech effect, and also naturally captures commonly observed phenomena such as void nucleation and migration in bulk crystals. A resistivity dipole field arising from electron scattering on void surfaces is shown to contribute significantly to void migration velocity. With an intrinsic time scale set by atomic diffusion rather than atomic oscillations or hopping events, as in conventional atomistic methods, our theoretical approach makes it possible to investigate EM-induced circuit failure at atomic spatial resolution and experimentally relevant time scales. PMID- 27768373 TI - Demonstration of Cosmic Microwave Background Delensing Using the Cosmic Infrared Background. AB - Delensing is an increasingly important technique to reverse the gravitational lensing of the cosmic microwave background (CMB) and thus reveal primordial signals the lensing may obscure. We present a first demonstration of delensing on Planck temperature maps using the cosmic infrared background (CIB). Reversing the lensing deflections in Planck CMB temperature maps using a linear combination of the 545 and 857 GHz maps as a lensing tracer, we find that the lensing effects in the temperature power spectrum are reduced in a manner consistent with theoretical expectations. In particular, the characteristic sharpening of the acoustic peaks of the temperature power spectrum resulting from successful delensing is detected at a significance of 16sigma, with an amplitude of A_{delens}=1.12+/-0.07 relative to the expected value of unity. This first demonstration on data of CIB delensing, and of delensing techniques in general, is significant because lensing removal will soon be essential for achieving high precision constraints on inflationary B-mode polarization. PMID- 27768374 TI - Coherent Control of the Exciton-Biexciton System in an InAs Self-Assembled Quantum Dot Ensemble. AB - Coherent control of a strongly inhomogeneously broadened system, namely, InAs self-assembled quantum dots, is demonstrated. To circumvent the deleterious effects of the inhomogeneous broadening, which usually masks the results of coherent manipulation, we use prepulse two-dimensional coherent spectroscopy to provide a size-selective readout of the ground, exciton, and biexciton states. The dependence on the timing of the prepulse is due to the dynamics of the coherently generated populations. To further validate the results, we performed prepulse polarization dependent measurements and confirmed the behavior expected from selection rules. All measured spectra can be excellently reproduced by solving the optical Bloch equations for a 4-level system. PMID- 27768375 TI - Quantum Change Point. AB - Sudden changes are ubiquitous in nature. Identifying them is crucial for a number of applications in biology, medicine, and social sciences. Here we take the problem of detecting sudden changes to the quantum domain. We consider a source that emits quantum particles in a default state, until a point where a mutation occurs that causes the source to switch to another state. The problem is then to find out where the change occurred. We determine the maximum probability of correctly identifying the change point, allowing for collective measurements on the whole sequence of particles emitted by the source. Then, we devise online strategies where the particles are measured individually and an answer is provided as soon as a new particle is received. We show that these online strategies substantially underperform the optimal quantum measurement, indicating that quantum sudden changes, although happening locally, are better detected globally. PMID- 27768376 TI - Relaxor Ferroelectrics: Back to the Single-Soft-Mode Picture. AB - The fluctuations of electric polarization in a disordered ferroelectric substance, relaxor crystal PbMg_{1/3}Nb_{2/3}O_{3} (PMN), were studied using a nonlinear inelastic light-scattering technique, hyper-Raman scattering, within a 5-100 cm^{-1} spectral interval and in a broad temperature range from 20 to 900 K. The split ferroelectric mode reveals a local anisotropy of up to about 400 K. Spectral anomalies observed at higher temperatures are explained as due to avoided crossing of the single primary polar soft mode with a temperature independent, nonpolar spectral feature near 45 cm^{-1}, known from Raman scattering. The temperature changes of the vibrational modes involved in the measured fluctuation spectra of PMN were captured in a simple model that accounts for the temperature dependence of the dielectric permittivity as well. The observed slowing down of the relaxational dynamics directly correlates with the huge increase of the dielectric permittivity. PMID- 27768377 TI - Quantum Correlations Are Stronger Than All Nonsignaling Correlations Produced by n-Outcome Measurements. AB - We show that, for any n, there are m-outcome quantum correlations, with m>n, which are stronger than any nonsignaling correlation produced from selecting among n-outcome measurements. As a consequence, for any n, there are m-outcome quantum measurements that cannot be constructed by selecting locally from the set of n-outcome measurements. This is a property of the set of measurements in quantum theory that is not mandatory for general probabilistic theories. We also show that this prediction can be tested through high-precision Bell-type experiments and identify past experiments providing evidence that some of these strong correlations exist in nature. Finally, we provide a modified version of quantum theory restricted to having at most n-outcome quantum measurements. PMID- 27768378 TI - Recombination-Enhanced Surface Expansion of Clusters in Intense Soft X-Ray Laser Pulses. AB - We studied the nanoplasma formation and explosion dynamics of single large xenon clusters in ultrashort, intense x-ray free-electron laser pulses via ion spectroscopy. The simultaneous measurement of single-shot diffraction images enabled a single-cluster analysis that is free from any averaging over the cluster size and laser intensity distributions. The measured charge state resolved ion energy spectra show narrow distributions with peak positions that scale linearly with final ion charge state. These two distinct signatures are attributed to highly efficient recombination that eventually leads to the dominant formation of neutral atoms in the cluster. The measured mean ion energies exceed the value expected without recombination by more than an order of magnitude, indicating that the energy release resulting from electron-ion recombination constitutes a previously unnoticed nanoplasma heating process. This conclusion is supported by results from semiclassical molecular dynamics simulations. PMID- 27768379 TI - Adiabatic Quantum Search in Open Systems. AB - Adiabatic quantum algorithms represent a promising approach to universal quantum computation. In isolated systems, a key limitation to such algorithms is the presence of avoided level crossings, where gaps become extremely small. In open quantum systems, the fundamental robustness of adiabatic algorithms remains unresolved. Here, we study the dynamics near an avoided level crossing associated with the adiabatic quantum search algorithm, when the system is coupled to a generic environment. At zero temperature, we find that the algorithm remains scalable provided the noise spectral density of the environment decays sufficiently fast at low frequencies. By contrast, higher order scattering processes render the algorithm inefficient at any finite temperature regardless of the spectral density, implying that no quantum speedup can be achieved. Extensions and implications for other adiabatic quantum algorithms will be discussed. PMID- 27768380 TI - Inhibited Temperament and Hippocampal Volume in Offspring of Parents with Bipolar Disorder. AB - BACKGROUND: Prior studies have suggested that inhibited temperament may be associated with an increased risk for developing anxiety or mood disorder, including bipolar disorder. However, the neurobiological basis for this increased risk is unknown. The aim of this study was to examine temperament in symptomatic and asymptomatic child offspring of parents with bipolar disorder (OBD) and to investigate whether inhibited temperament is associated with aberrant hippocampal volumes compared with healthy control (HC) youth. METHODS: The OBD group consisted of 45 youth, 24 of whom had current psychiatric symptoms (OBD+s) and 21 without any psychiatric symptoms (OBD-s), and were compared with 24 HC youth. Temperament characteristics were measured by using the Revised Dimensions of Temperament Survey. Magnetic resonance imaging was used to measure hippocampal volumes. The association between temperament and hippocampal volumes was tested by using multiple regression analysis. RESULTS: Compared with the OBD-s group, the OBD+s group had significantly more inhibited temperament traits, less flexibility, more negative mood, and less regular rhythm in their daily routines. In contrast, the OBD-s group was more likely to approach novel situations compared with OBD+s or HC groups. Within the OBD+s group, a more inhibited temperament was associated with smaller right hippocampal volumes. CONCLUSIONS: In this study, symptomatic OBD were characterized by an inhibited temperament that was inversely correlated with hippocampal volume. Additional longitudinal studies are needed to determine whether inverse correlations between hippocampal volume and inhibited temperament represent early markers of risk for later developing bipolar disorder. PMID- 27768381 TI - 4-Chlorbenzoyl Berbamine, a Novel Derivative of the Natural Product Berbamine, Potently Inhibits the Growth of Human Myeloma Cells by Modulating the NF-kappaB and JNK Signalling Pathways. AB - Multiple myeloma (MM) remains incurable despite the development and the use of new agents. In our studies, we found that 4-chlorbenzoyl berbamine (BBMD9), a novel synthetic derivative of berbamine, inhibited the proliferation of MM cells in dose- and time-dependent manners. Flow cytometric (FCM) analysis revealed that MM cells were arrested in the G1 phase and that apoptotic cells increased in a time-dependent manner. Moreover, the BBMD9 treatment downregulated IKKalpha and IKKbeta, inhibited p-IkappaBalpha, and blocked p65 nuclear localization. Consistently, NF-kappaB downstream targets, such as cyclinD1 and survivin, were also reduced. In addition, BBMD9 phosphorylated the activity of JNK and c-Jun. PMID- 27768382 TI - Phenotypic and Molecular Characterization of Salmonella 1,4,[5],12:i:- R-Type ASSuT Isolates from Humans, Animals, and Environment in Portugal, 2006-2011. AB - The increase in prevalence of Salmonella 1,4,[5],12:i:- related infections over the last few years has been considered a public health issue in many European countries, especially as this serovar may be associated with tetraresistance to ampicillin, streptomycin, sulfonamides, and tetracyclines (R-type ASSuT). Salmonella 1,4,[5],12:i:- isolates (n = 187) obtained by the Portuguese National Laboratory from different sources, including human clinical cases (n = 170), veterinary (n = 10), environmental (n = 6), and food samples (n = 1), were collected from 15 districts between 2006 and 2011. All isolates were serotyped using the slide agglutination method and results were confirmed by multiplex PCR for the monophasic variant. From the confirmed Salmonella 1,4,[5],12:i:-, R-type ASSuT isolates were selected by disc diffusion and minimal inhibitory concentration (MIC) determination for further characterization by pulsed-field gel electrophoresis restriction with XbaI, virulence genes determination by PCR, additional antimicrobial resistance profiling by disc diffusion, and epidemiological distribution evaluation. Out of the 187 serotyped isolates, 133 were confirmed as Salmonella 1,4,[5],12:i:- with a R-type ASSuT occurrence of 61.7%. Distribution among Portuguese districts showed a higher percentage of reported cases in coastal areas, in particular, in Porto (24.8%), Setubal (13.5%), and Aveiro (12.8%), probably due to the higher population density. Clonality analysis revealed a high diversity of pulsotypes with the majority of human salmonellosis cases being attributed to sporadic events. All isolates harbored 14 out of the 18 virulence genes evaluated and 87.8% of the isolates showed all the resistance genes frequently associated with the European clone, blaTEM+sul2+straA-straB+tetB+. This study shows that Salmonella 1,4,[5],12:i:- resistant isolates are widely distributed in Portugal. This may be related to a selective advantage offered by R-type ASSuT profile, the presence of multiple virulent features, including the ability to form biofilms, which along with a high diversity of pulsotypes may be responsible for the dissemination through the country. PMID- 27768383 TI - Treatment of Salmonella-Contaminated Eggs and Pork with a Broad-Spectrum, Single Bacteriophage: Assessment of Efficacy and Resistance Development. AB - Numerous studies have assessed the efficacy of phage-based methods to inhibit Salmonella contamination in food products. As with most antibacterials, bacteria can develop resistance to phage in vitro. Here, we applied a single broad spectrum Salmonella phage, vB_SalS_SJ_2 (SJ2; 108 PFU; MOI = 10), to Salmonella contaminated meat and eggs to quantify the development of resistance in actual food matrices. Treatment with a single phage significantly reduced Salmonella Typhimurium contamination in both ground pork and liquid egg at various time points. Similarly, the same phage significantly reduced Salmonella Enteritidis in both food matrices. Efficacy was temperature dependent as larger reductions were seen at higher temperatures (21 degrees C) versus lower temperatures (4 degrees C) at 24 h. Following phage treatment, over 10,000 Salmonella isolates were examined for resistance to the treatment phage. The percentages of phage resistant Salmonella (either serovar) recovered from phage-treated versus untreated pork did not differ. Conversely, significantly (p < 0.05) higher percentages of phage-resistant Salmonella Typhimurium (92.50% vs. 0.56% of control) and Salmonella Enteritidis (50.83% vs. 0.56% of control) isolates were observed in phage-treated versus untreated egg samples after incubation at room temperature for 48 h. Taken together, these data indicate that the food matrix may influence the emergence of phage resistance with resistance developing more rapidly in foods with less complex microbial communities. Future studies will focus on the impact the development of resistance in production and processing settings may have on the efficacy of phage treatments for longer term biocontrol of pathogens. PMID- 27768385 TI - Influence of Naltrexone/Bupropion Combination Treatment on Body Mass Index in Prader-Willi Syndrome Re: "Prader-Willi Syndrome, Management of Impulsivity, and Hyperphagia in an Adolescent" by Puri et al. PMID- 27768386 TI - Sleep and Developmental Psychopathology: Introduction to the Special Issue. AB - Research in the field of pediatric sleep has grown significantly in the past 25 years. However, because much remains to be learned about the complex and dynamic relationship between sleep and developmental psychopathology, this special issue of the Journal of Clinical Child and Adolescent Psychology was created to provide an influx of cutting-edge research on this important topic. This introduction provides an overview of the special issue, with articles focusing on what different measurement approaches tells us about the intersection of sleep and developmental psychopathology; the overlap between interventions for sleep and anxiety; sleep as a potential mechanism for the development of social, emotional, and behavioral problems; and how population-based studies can be used to consider the interaction between sleep, well-being, and symptoms of psychopathology. PMID- 27768384 TI - Anxiety and Depression in Children of Depressed Parents: Dynamics of Change in a Preventive Intervention. AB - The current study examined effects of a preventive intervention on patterns of change in symptoms of anxiety and depression in a sample of children of depressed parents. Parents with a history of depression (N = 180) and their children (N = 242; 50% female; Mage = 11.38; 74% Euro-American) enrolled in an intervention to prevent psychopathology in youth. Families were randomized to a family group cognitive behavioral intervention (FGCB) or a written information (WI) control condition. Parents and youth completed the Child Behavior Checklist and Youth Self Report at baseline, 6-, 12-, 18-, and 24-month follow up. Youth in the FGCB intervention reported significantly greater declines in symptoms of both anxiety and depression at 6, 12, and 18 months compared to youth in the WI condition. Youth with higher baseline levels of each symptom (e.g., anxiety) reported greater declines in the other symptom (e.g., depression) from 0 to 6 months in the FGCB intervention only. Changes in anxiety symptoms from 0 to 6 months predicted different patterns of subsequent changes in depressive symptoms from 6 to 12 months for the two conditions, such that declines in anxiety preceded and predicted greater declines in depression for FGCB youth but lesser increases in depression for WI youth. Findings inform transdiagnostic approaches to preventive interventions for at-risk youth, suggesting that both initial symptom levels and initial magnitude of change in symptoms are important to understand subsequent patterns of change in response to intervention. PMID- 27768387 TI - Antimicrobial-Resistant Campylobacter in Organically and Conventionally Raised Layer Chickens. AB - Poultry is a major source of Campylobacter, which can cause foodborne bacterial gastroenteritis in humans. Additionally, poultry-associated Campylobacter can develop resistance to important antimicrobials, which increases the risk to public health. While broiler chickens have been the focus of many studies, the emergence of antimicrobial-resistant Campylobacter on layer farms has not received equal attention. However, the growing popularity of cage-free and organic layer farming necessitates a closer assessment of (1) the impact of these farming practices on the emergence of antimicrobial-resistant Campylobacter and (2) layers as a potential source for the transmission of these pathogens. Here, we showed that the prevalence of Campylobacter on organic and conventional layer farms was statistically similar (p > 0.05). However, the average number of Campylobacter jejuni-positive organically grown hens was lower (p < 0.05) in comparison to conventionally grown hens. Campylobacter isolated from both production systems carried antimicrobial resistance genes. The tet(O) and cmeB were the most frequently detected genes, while the occurrence of aph-3-1 and blaOXA-61 was significantly lower (p < 0.05). Farming practices appeared to have an effect on the antimicrobial resistance phenotype, because the isolates from organically grown hens on two farms (OF-2 and OF-3) exhibited significantly lower resistance (p < 0.05) to ciprofloxacin, erythromycin, and tylosin. However, on one of the sampled organic farms (OF-1), a relatively high number of antimicrobial-resistant Campylobacter were isolated. We conclude that organic farming can potentially impact the emergence of antimicrobial-resistant Campylobacter. Nevertheless, this impact should be regularly monitored to avoid potential relapses. PMID- 27768388 TI - Preschool Oppositional Defiant Disorder: A Disorder of Negative Affect, Surgency, and Disagreeableness. AB - Oppositional defiant disorder (ODD) is conceptualized as a disorder of negative affect and low effortful control. Yet empirical tests of trait associations with ODD remain limited. The current study examined the relationship between temperament and personality traits and Diagnostic and Statistical Manual of Mental Disorders (5th ed.) ODD symptom domains and related impairment in a preschool-age sample. Participants were 109 children ages 3-6 (59% male), overrecruited for ODD from the community, and their primary caregivers (87% mothers). ODD symptoms and impairment were measured using the Kiddie-Disruptive Behavior Disorder Schedule, temperament traits were measured using parent report on the Child Behavior Questionnaire and the Laboratory Temperament Assessment Battery, and personality traits were measured using examiner report on the California Child Q-Sort. Results suggest that high negative affect was associated with all three ODD symptom domains, whereas low agreeableness was specifically associated with the angry/irritable ODD symptom domain, and high surgency was associated with the argumentative/defiant and vindictive ODD symptom domains. Negative affect and surgency interacted with agreeableness to predict impairment, but not symptoms: Low agreeableness was associated with high impairment, regardless of other trait levels, whereas high negative affect and high surgency predicted high impairment in the presence of high agreeableness. Overall, results suggest ODD is a disorder of high negative affect. Furthermore, low agreeableness is differentially associated with affective ODD symptoms, and high surgency is associated with behavioral ODD symptoms. These traits interact in complex ways to predict impairment. Therefore, negative affect, agreeableness, and surgency may be useful early markers of ODD symptoms and impairment. PMID- 27768390 TI - Unpredictability of soft tissue changes after camouflage treatment of Class II division 1 malocclusion with maximum anterior retraction using miniscrews. AB - OBJECTIVE: To compare soft and hard tissue responses based on the degree of maxillary incisor retraction using maximum anchorage in patients with Class II division 1 malocclusion. MATERIALS AND METHODS: This retrospective study sample was divided into moderate retraction (<8.0 mm; n = 28) and maximum retraction (>=8.0 mm; n = 29) groups based on the amount of maxillary incisor retraction after extraction of the maxillary and mandibular first premolars for camouflage treatment. Pre- and posttreatment lateral cephalograms were analyzed. RESULTS: There were 2.3 mm and 3.0 mm of upper and lower lip retraction, respectively, in the moderate group; and 4.0 mm and 5.3 mm, respectively, in the maximum group. In the moderate group, the upper lip was most influenced by posterior movement of the cervical point of the maxillary incisor (beta = 0.94). The lower lip was most influenced by posterior movement of B-point (beta = 0.84) and the cervical point of the mandibular incisor (beta = 0.83). Prediction was difficult in the maximum group; no variable showed a significant influence on upper lip changes. The lower lip was highly influenced by posterior movement of the cervical point of the maxillary incisor (beta = 0.50), but this correlation was weak in the maximum group. CONCLUSIONS: Posterior movement of the cervical point of the anterior teeth is necessary for increased lip retraction. However, periodic evaluation of the lip profile is needed during maximum retraction of the anterior teeth because of limitations in predicting soft tissue responses. PMID- 27768389 TI - A Missense Genetic Variant in LRRC16A/CARMIL1 Improves Acute Respiratory Distress Syndrome Survival by Attenuating Platelet Count Decline. AB - RATIONALE: Platelets are believed to contribute to acute respiratory distress syndrome (ARDS) pathogenesis through inflammatory coagulation pathways. We recently reported that leucine-rich repeat-containing 16A (LRRC16A) modulates baseline platelet counts to mediate ARDS risk. OBJECTIVES: To examine the role of LRRC16A in ARDS survival and its mediating effect through platelets. METHODS: A total of 414 cases with ARDS from intensive care units (ICUs) were recruited who had exome-wide genotyping data, detailed platelet counts, and follow-up data during ICU hospitalization. Association of LRRC16A single-nucleotide polymorphisms (SNPs) and ARDS prognosis, and the mediating effect of SNPs through platelet counts were analyzed. LRRC16A mRNA expression levels for 39 cases with ARDS were also evaluated. MEASUREMENTS AND MAIN RESULTS: Missense SNP rs9358856G>A within LRRC16A was associated with favorable survival within 28 days (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.38-0.87; P = 0.0084) and 60 days (P = 0.0021) after ICU admission. Patients with ARDS who carried the variant genotype versus the wild-type genotype showed an attenuated platelet count decline (?PLT) within 28 days (difference of ?PLT, -27.8; P = 0.025) after ICU admission. Patients with ?PLT were associated with favorable ARDS outcomes. Mediation analysis indicated that the SNP prognostic effect was mediated through ?PLT within 28 days (28-day survival: HRIndirect, 0.937; 95% CI, 0.918-0.957; P = 0.0009, 11.53% effects mediated; 60-day survival: HRIndirect, 0.919; 95% CI, 0.901-0.936; P = 0.0001, 14.35% effects mediated). Functional exploration suggested that this SNP reduced LRRC16A expression at ICU admission, which was associated with a lesser ?PLT during ICU hospitalization. CONCLUSIONS: LRRC16A appears to mediate ?PLT after ICU admission to affect the prognosis in patients with ARDS. PMID- 27768391 TI - Single-Nucleotide Polymorphism rs17611 of Complement Component 5 Shows Association with Ischemic Stroke in Northeast Chinese Population. AB - BACKGROUND: Complement component 5 (C5) has been described to play an important role in the development and progression of atherosclerosis and cardiovascular disease. Our aim was to determine whether genetic variation of C5 was associated with ischemic stroke (IS) in northeast Chinese population. METHODS: We used a case-control study involving 386 IS patients and 386 non-IS controls from a rural population and determined the genotypes of five polymorphisms (rs12237774, rs17611, rs4837805, rs7026551, and rs1017119) of C5 gene by Snapshot single nucleotide polymorphism genotyping assays to assess any links with IS. RESULTS: In univariate analysis, rs17611 was significantly associated with IS in the additive model, the dominant model, and recessive model (additive p 0.031, dominant p 0.034, and recessive p 0.027). After adjustment for Binary Logistic Regression, rs17611 polymorphism was still significant in three models (adjusted odds ratio (OR) = 1.306, 95% confidence interval (CI) = 1.069-1.595, p-value = 0.009 in an additive model; OR = 1.378, 95% CI = 1.024-1.856, p-value = 0.035 in a dominant model; and OR = 1.511, 95% CI = 1.048-2.18, p-value = 0.027 in a recessive model). CONCLUSION: In this sample of patients, genetic variation of rs17611 in C5 is associated with higher prevalence of IS. PMID- 27768392 TI - Pulmonary Embolism Masquerading as High Altitude Pulmonary Edema at High Altitude. AB - Pandey, Prativa, Benu Lohani, and Holly Murphy. Pulmonary embolism masquerading as high altitude pulmonary edema at high altitude. High Alt Med Biol. 17:353-358, 2016.-Pulmonary embolism (PE) at high altitude is a rare entity that can masquerade as or occur in conjunction with high altitude pulmonary edema (HAPE) and can complicate the diagnosis and management. When HAPE cases do not improve rapidly with descent, other diagnoses, including PE, ought to be considered. From 2013 to 2015, we identified eight cases of PE among 303 patients with initial diagnosis of HAPE. Upon further evaluation, five had deep vein thrombosis (DVT). One woman had a contraceptive ring and seven patients had no known thrombotic risks. PE can coexist with or mimic HAPE and should be considered in patients presenting with shortness of breath from high altitude regardless of thrombotic risk. PMID- 27768393 TI - Care home manager attitudes to balancing risk and autonomy for residents with dementia. AB - OBJECTIVE: To determine how care home managers negotiate the conflict between maintaining a safe environment while enabling the autonomy of residents with dementia. This is important because there is limited research with care home managers; yet, they are key agents in the implementation of national policies. METHOD: Semi-structured interviews were conducted with 18 managers from care homes offering dementia care in the Northwest of England. Data were analysed using a thematic analysis approach. RESULTS: There were three areas in which care home staff reported balancing safety and risk against the individual needs of residents. First, the physical environment created a tension between safety and accessibility to the outside world, which meant that care homes provided highly structured or limited access to outdoor space. Second, care home managers reflected a balancing act between an individual's autonomy and the need to protect their residents' dignity. Finally, care home managers highlighted the ways in which an individual's needs were framed by the needs of other residents to the extent that on some occasions an individual's needs were subjugated to the needs of the general population of a home. CONCLUSION: There was a strong, even dominant, ethos of risk management and keeping people safe. Managing individual needs while maintaining a safe care home environment clearly is a constant dynamic interpersonal process of negotiating and balancing competing interests for care home managers. PMID- 27768360 TI - Search for Structure in the B_{s}^{0}pi^{+/-} Invariant Mass Spectrum. AB - The B_{s}^{0}pi^{+/-} invariant mass distribution is investigated in order to search for possible exotic meson states. The analysis is based on a data sample recorded with the LHCb detector corresponding to 3 fb^{-1} of pp collision data at sqrt[s]=7 and 8 TeV. No significant excess is found, and upper limits are set on the production rate of the claimed X(5568) state within the LHCb acceptance. Upper limits are also set as a function of the mass and width of a possible exotic meson decaying to the B_{s}^{0}pi^{+/-} final state. The same limits also apply to a possible exotic meson decaying through the chain B_{s}^{*0}pi^{+/-}, B_{s}^{*0}->B_{s}^{0}gamma where the photon is excluded from the reconstructed decays. PMID- 27768394 TI - Fetal MRI at 3T-ready for routine use? AB - Fetal MR now plays an important role in the clinical work-up of pregnant females. It is performed mainly at 1.5 T. However, the desire to obtain a more precise fetal depiction or the fact that some institutions have access only to a 3.0 T scanner has resulted in a growing interest in performing fetal MR at 3.0 T. The aim of this article was to provide a reference for the use of 3.0 T MRI as a prenatal diagnostic method. PMID- 27768395 TI - Feasibility of a Friendship Network-Based Pediatric Obesity Intervention. AB - BACKGROUND: There is growing evidence supporting social network-based interventions for adolescents with obesity. This study's aim was to determine the feasibility of a social network-based intervention by assessing adolescents' friendship networks, willingness to involve friends in treatment, and how these factors influence enjoyment. METHODS: Adolescents (N = 42) were recruited from a tertiary care obesity clinic. Participants gave a list of closest friends, friendship characteristics, and which of their friends they would involve in treatment. A subset (N = 14) participated in group treatment, were encouraged to bring friends, and invited to a second interview. RESULTS: Participants nominated a mean of 4.0 (standard deviation [SD] = 1.6) friends and were more likely to nominate closer friends (p = 0.003). Friends who attended group sessions were more likely to have multiple friendships in common with the participant's own network (p = 0.04). CONCLUSIONS: Involving friends in treatment is feasible and desired by adolescents and may be a novel approach for augmenting obesity treatment outcomes. PMID- 27768396 TI - Effort to Breathe with Various Spontaneous Breathing Trial Techniques. A Physiologic Meta-analysis. AB - RATIONALE: Spontaneous breathing trials (SBTs) are designed to simulate conditions after extubation, and it is essential to understand the physiologic impact of different methods. OBJECTIVES: We conducted a systematic review and pooled measures reflecting patient respiratory effort among studies comparing SBT methods in a meta-analysis. METHODS: We searched Medline, Excerpta Medica Database, and Web of Science from inception to January 2016 to identify randomized and nonrandomized clinical trials reporting physiologic measurements of respiratory effort (pressure-time product) or work of breathing during at least two SBT techniques. Secondary outcomes included the rapid shallow breathing index (RSBI), and effort measured before and after extubation. The quality of physiologic measurement and research design was appraised for each study. Outcomes were analyzed using ratio of means. MEASUREMENTS AND MAIN RESULTS: Among 4,138 citations, 16 studies (n = 239) were included. Compared with T-piece, pressure support ventilation significantly reduced work by 30% (ratio of means [RoM], 0.70; 95% confidence interval [CI], 0.57-0.86), effort by 30% (RoM, 0.70; 95% CI, 0.60-0.82), and RSBI by 20% (RoM, 0.80; 95% CI, 0.75-0.86). Continuous positive airway pressure had significantly lower pressure-time product by 18% (RoM, 0.82; 95% CI, 0.68-0.999) compared with T-piece, and reduced RSBI by 16% (RoM, 0.84; 95% CI, 0.74-0.95). Studies comparing SBTs with the postextubation period demonstrated that pressure support induced significantly lower effort and RSBI; T-piece reduced effort, but not the work, compared with postextubation. Work, effort, and RSBI measured while intubated on the ventilator with continuous positive airway pressure of 0 cm H2O were no different than extubation. CONCLUSIONS: Pressure support reduces respiratory effort compared with T-piece. Continuous positive airway pressure of 0 cm H2O and T-piece more accurately reflect the physiologic conditions after extubation. PMID- 27768400 TI - Single Anastomosis Sleeve Ileal Bypass: New Step in the Evolution of Bariatric Surgeries. AB - PURPOSE: Single anastomosis sleeve ileal bypass (SASI) procedure appears as a new metabolic and bariatric surgery based on Santoro's operation, in which a sleeve gastrectomy is followed by a side-to-side gastroileal anastomosis. The study is aimed to evaluate the short-term outcomes of laparoscopic single anastomosis sleeve ileal bypass with respect to postoperative weight loss and metabolic and nutritional effects on patients. METHODS: Forty-five morbidly obese patients with a mean age of 31.2 years and a mean body mass index (BMI) of 43.2 kg/m2 underwent SASI bypass. Postoperatively, all patients were followed up at 1, 3, 6, and 12 months, and during each visit data about their BMI, obesity-related comorbidities, and nutritional status were collected. RESULTS: One year after the surgery, mean BMI decreased to 29.1 kg/m2 and there was significant decrease in plasma level of fasting blood glucose, insulin, and low-density lipoprotein. On the other hand, there was significant increase in high-density lipoprotein plasma level, whereas hemoglobin and albumin plasma level remained normal. Six months after the surgery, calcium plasma level showed mild decrease in two cases, which was improved with multivitamin tablets. In 93% of our patients, multivitamin supplements were stopped after six months of surgery. CONCLUSIONS: Laparoscopic SASI bypass has been shown to be an effective, safe, and simple procedure for the treatment of morbid obesity and its associated metabolic consequences. Moreover, it results in minimal postoperative nutritional complications in comparison to other bariatric procedures. PMID- 27768399 TI - Coconut Water Does Not Improve Markers of Hydration During Sub-maximal Exercise and Performance in a Subsequent Time Trial Compared with Water Alone. AB - The purpose of this study was to compare markers of hydration during submaximal exercise and subsequent time trial performance when consuming water (PW) or coconut water (CW). There was also a secondary aim to assess the palatability of CW during exercise and voluntary intake during intense exercise. 10 males (age 27.9 +/- 4.9 years, body mass 78.1 +/- 10.1kg, average max minute power 300.2 +/- 28.2W) completed 60-min of submaximal cycling followed by a 10-km time trial on two occasions. During these trials participants consumed either PW or CW in a randomized manner, drinking a 250 ml of the assigned drink between 10-15 min, 25 30 min and 40-45 min, and then drinking ad libitum from 55-min until the end of the time trial. Body mass and urine osmolality were recorded preexercise and then after 30-min, 60-min, and post time trial. Blood glucose, lactate, heart rate, rate of perceived exertion (RPE; 6-20) and ratings of thirst, sweetness, nausea, fullness and stomach upset (1 =very low/none, 5= very high) were recorded during each drink period. CW did not significantly improve time trial performance compared with PW (971.4 +/- 50.5 and 966.6 +/- 44.8 s respectively; p = .698) and there was also no significant differences between trials for any of the physiological variables measured. However there were subjective differences between the beverages for taste, resulting in a significantly reduced volume of voluntary intake in the CW trial (115 +/- 95.41 ml and 208.7 +/- 86.22 ml; p < .001). PMID- 27768398 TI - Presentation and Management of Pseudoaneurysmogastric Fistula: A Life Threatening Emergency. AB - Pseudoaneurysmogastric fistula is a rare consequence of pseudoaneurysms occurring in the vicinity of stomach. They are the result of pseudoaneurysms eroding into the stomach, and represent a life threatening emergency. Urgent surgical intervention is often necessary to salvage the patient. Data regarding the presentation and management of this condition is sparse. Herein, we present our experience with four cases of pseudoaneurysmogastric fistula, their clinical context, presentation, management and outcomes. We attempt to outline an algorithm for the diagnosis and management of this unusual complication. PMID- 27768401 TI - Biosynthetic Nanostructured Cellulose Patch for Chest Wall Reconstruction: Five Month Follow-up in a Porcine Model. AB - PURPOSE: Ideal approaches and materials for reconstruction of large chest wall defects remain a topic of debate. We sought to explore the suitability of a reinforced nanostructured cellulose (NC) patch for chest wall reconstruction in an animal model. MATERIALS AND METHODS: In four domestic pigs, a standardized 10 * 10 cm chest wall defect was created by resecting three rib segments. Subsequently the defect was reconstructed via a biosynthetic NC patch (16 * 12 cm) reinforced by polytetrafluoroethylene mesh. After 1, 2, 4, and 5 months respectively, gross examination of NC patches was performed following sacrifice of the animals. Specimens of NC patches and surrounding connective tissue underwent histological examinations after staining with Hematoxylin-eosin and Elastica van Gieson. RESULTS: All animals survived their observation period without encountering major adverse events. On gross examination all NC patches were intact and well integrated into the surrounding tissue. Histological examination showed clearly demarked zones of foreign body reaction at the patch/host-tissue interface. After 5 months a slight increase in foreign body reaction, fibrous capsule formation and cellular infiltration were observed. No signs of fibroblast proliferation or neovascularization were seen within NC patches at any point. CONCLUSIONS: Our findings suggest a quick healing process and good overall biocompatibility following NC patch implantation.NC might prove an efficient and suitable biomaterial for complex chest wall reconstruction. PMID- 27768397 TI - Creatine Monohydrate Supplementation Does Not Augment Fitness, Performance, or Body Composition Adaptations in Response to Four Weeks of High-Intensity Interval Training in Young Females. AB - High-intensity interval training (HIIT) has been shown to improve cardiorespiratory fitness, performance, body composition, and insulin sensitivity. Creatine (Cr) supplementation may augment responses to HIIT, leading to even greater physiological adaptations. The purpose of this study was to determine the effects of 4 weeks of HIIT (three sessions/week) combined with Cr supplementation in recreationally active females. Seventeen females (age = 23 +/- 4 yrs; BMI = 23.4 +/- 2.4) were randomly assigned to either Cr (Cr; 0.3 g?kg-1?d 1 for 5 d followed by 0.1 g?kg-1?d-1 for 23 days; n = 9) or placebo (PLA; n = 8). Before and after the intervention, VO2peak, ventilatory threshold (VT), time trial performance, lean body mass and fat mass, and insulin sensitivity were assessed. HIIT improved VO2peak (Cr = +10.2%; PLA = +8.8%), VT (Cr = +12.7%; PLA = +9.9%), and time-trial performance (Cr = -11.5%; PLA = -11.6%) with no differences between groups (time main effects, all p < .001). There were no changes over time for fat mass (Cr = -0.3%; PLA = +4.3%), whole-body lean mass (Cr = +0.5%; PLA = -0.9%), or insulin resistance (Cr = +3.9%; PLA = +18.7%). In conclusion, HIIT is an effective way to improve cardiorespiratory fitness, VT, and time-trial performance. The addition of Cr to HIIT did not augment improvements in cardiorespiratory fitness, performance or body composition in recreationally active females. PMID- 27768402 TI - Deferiprone Enhances Temozolomide Cytotoxicity in Glioma Cells. AB - Glioblastoma is the most malignant primary brain tumor with a median survival of 15 months. Temozolomide (TMZ) is the standard of care for these patients. Iron chelators have been shown to have anti-tumor activity; however, deferiprone (DFP), an orally administered iron chelator, has not been previously evaluated in gliomas. In the present study, we found that combination treatment in glioma cells with TMZ and DFP significantly reduced cell viability, produced cell cycle arrest at G2/M phase, and enhanced apoptosis. TMZ and DFP might be a potent new combination treatment for glioblastoma. PMID- 27768405 TI - Role of Proprioceptive Input During Abdominal Bending-Reflex Motor Activity in the Tobacco Hawkmoth Manduca sexta. PMID- 27768404 TI - Evidence for the Use of Urine Signals in Agonistic Interactions of the American Lobster. PMID- 27768403 TI - A Comparison of the Tuning Properties of Chemoreceptor Cells in the First and Fourth Walking Legs of Female American Lobsters. PMID- 27768406 TI - Effects of Macroalgae, Night and Day, on Ammonium Profiles in Waquoit Bay. PMID- 27768407 TI - Modeling the Apparent Diffusion Constant of Calcium Ions Emanating From a Channel: Implications for Calcium Wave Propagation. PMID- 27768408 TI - Electrical Properties of Electroreceptor Cells Isolated from Skate Ampulla of Lorenzini. PMID- 27768410 TI - Steady-State Calcium Efflux from Aplysia Neurons: Perturbation by H202 and Protection by Stress Protein, HSP70. PMID- 27768409 TI - Activity-Dependent Inhibition of Neurotransmitter Release by Brefeldin A. PMID- 27768411 TI - Ca2+-Induced Axosome Formation in Internally Dialyzed Giant Axons of Loligo pealei. PMID- 27768412 TI - Fluorescence Imaging of NMDA Receptor-Activated Calcium Influx in Granule Cells in Thin Cerebellar Slices. PMID- 27768413 TI - Ultrastructural Histochemistry of Marthasterias glacialis (Echinodermata, Asteroidea) Gametes Before and After Fertilization. AB - The gametes of the starfish Marthasterias glacialis were studied, both before and after fertilization, using several histochemical methods at the ultrastructural level. Results showed that the oocyte jelly coat (JC) could be morphologically differentiated into a fibrillar network of acidic polysaccharides, probably containing glycosaminoglycans (GAGs), and a loose component made of neutral polysaccharides that occupies the interstices of the former. Results also suggested that it is the fibrillar component of the JC to which the spermatozoon attaches and reacts. Staining of the acrosomal vesicle contents confirmed that the peripheral dense component attaches the spermatozoon to the JC, whereas the central and apical electron-lucent component coats the acrosomal process as it extends through the oocyte investments. The acrosomal process membrane was also shown to be negatively charged. Staining of cortical vesicles confirmed their tripartite compartmentalization: the spiral lamellae fused with the fertilization envelope (FE), transferring its staining to the inner layer of the FE, whereas the matrix could be subdivided into two components--a fibrillar mesh of acidic polysaccharides that fused with the FE and some amorphous aggregates that seem to become dispersed in the perivitelline space. PMID- 27768415 TI - Co-Activation of Antagonistic Motoneurons as a Mechanism of High-Speed Hydraulic Inflation of Prey Capture Appendages in the Pteropod Mollusk Clione limacina. AB - The predatory pteropod mollusk Clione limacina catches its prey by using specialized oral appendages called buccal cones. Eversion and elongation of buccal cones is a hydraulic phenomenon. In the cerebral ganglia, two groups of motoneurons have been identified that underlie functionally opposite movements of buccal cones: extrusion and retraction. We suggest that the remarkably rapid inflation of buccal cones (50 ms) is achieved through initial co-activation of antagonistic neurons, which presumably produces high pressure in the head hemocoel prior to buccal cone extrusion. The subsequent sudden inhibition of retractor motoneuron activity results in a very rapid and powerful inflation of the buccal cones. Cerebral interneurons that evoke co-activation are described. PMID- 27768414 TI - Abundance of Food Affects Relative Size of Larval and Postlarval Structures of a Molluscan Veliger. AB - Veliger larvae of mollusks were predicted to develop a larger velum relative to the larval shell when reared with scarce food. The functional consequences of such developmental plasticity would be (1) greater maximum capacity for capturing particles when food is scarce and (2) greater growth of structures retained in the postlarva when food is abundant. The hypothesis was tested by rearing veligers of the oyster Crassostrea gigas at high (near satiating) and low (growth limiting) concentrations of food. Veligers at the measured shell lengths (>200 {mu}m) had significantly larger velar lobes and longer prototrochal cilia than veligers reared in low concentrations of food. An analogous response to food levels (relatively longer ciliated band when food is scarce) has now been found for larvae as disparate as oyster veligers and sea urchin plutei. These observations suggest that functionally similar examples of developmental plasticity in the growth of larval parts have evolved more than once and may be widespread. An alternative interpretation is that differential mortality or growth in a genetically heterogeneous batch of oyster larvae results in advanced veligers of different forms at different concentrations of food. Both interpretations suggest an adaptive advantage to growing a larger apparatus for clearing particles from suspension when food is scarce and shifting materials to growth of postlarval structures (shell and associated structures) when food is abundant. PMID- 27768417 TI - GABA Responses on Retinal Bipolar Cells. PMID- 27768416 TI - FMRFamide and GABA Produce Functionally Opposite Effects on Prey-Capture Reactions in the Pteropod Mollusk Clione limacina. AB - The effects of FMRFamide and gamma-aminobutyric acid (GABA) on prey-capture reactions in Clione and on cerebral A and B neurons, which control opposite movements of prey capture appendages, have been studied. FMRFamide hyperpolarized A neurons and depolarized and increased spike activity in B neurons. FMRFamide thus had a reciprocal effect on A and B neurons, triggering buccal cone withdrawal. In addition, FMRFamide inhibited swimming, acceleration of which is a component of feeding arousal. Many neurons throughout the central nervous system showed FMRFamide immunoreactivity. Dense networks of immunoreactive fibers were localized in the head wall, buccal mass and in buccal cones, adjacent to striated longitudinal muscle cells. In wings, immunoreactive processes were found mainly in association with smooth retractor muscles. GABA depolarized and activated A neurons but hyperpolarized and inhibited B neurons. The overall effect of GABA thus resulted in extrusion of buccal cones. Both direct GABA responses and inhibitory postsynaptic potentials (IPSPs) induced in B neurons by A neuron activity were chloride-mediated. However, picrotoxin and bicuculline did not block IPSPs or direct GABA responses in B cells. PMID- 27768418 TI - Glycosaminoglycans in Anodonta californiensis, a Freshwater Mussel. AB - The synthesis of glycosaminoglycans (GAG) in a freshwater mussel was studied in organ culture using labeled precursors. The major GAGs synthesized were determined and characterized by chemical and enzymatic methods. They were shown to be heparin and an unusual type of heparan sulfate. Gills produced about 50% of each polymer; mantles synthesized little heparin and mostly the heparan-sulfate like compound, which is similar to a GAG isolated previously from lobsters. No significant amounts of chondroitin sulfates were present. Histological data showed that the sulfate-labeled GAGs were present mainly in exterior pericellular and basement membrane locations of gills and mantle. That is, they would be in contact with the external aqueous environment, suggesting a potential role in calcium transport and storage. PMID- 27768419 TI - The Specificity of an Adaptive Filter That Suppresses Unwanted Reafference in Electrosensory Neurons of the Skate Medulla. PMID- 27768420 TI - Metabolic Rates in Early Life History Stages of Elopomorph Fishes. AB - The respiratory electron transport system (ETS) assay was used to estimate metabolic rates in four species of eel (Anguilliformes: Ophichthidae and Congridae) leptocephali (Myrophis punctatus, Ophichthus sp., Hildebrandia flava, and one unidentified congrid) and the bonefish (Albuliformes: Albulidae: Albula sp.). Wet-weight-specific ETS values in whole-body homogenates, assayed at physiological temperatures, ranged from 4-20 {mu}-at O h-1 (g wet wt)-1. Arrhenius activation energies (Ea) ranged from 11.0-15.7 kcal mole-1. Both wet weight-specific ETS activity and oxygen consumption rate increased approximately fivefold during metamorphosis of leptocephali of Albula sp. Wet-weight-specific ETS activity showed little change as leptocephali of M. punctatus transformed into glass eels, but increased about fivefold as glass eels metamorphosed into elvers. No significant difference was found in ETS activity measured in fresh early metamorphic leptocephali of Albula sp. and leptocephali that had been stored frozen at -70{deg}C for up to 15 months. The data suggest that metabolic rates are low in leptocephali, which implies that the demand for nutrients is also relatively low. We argue that the apparent diet of these larvae seems capable of providing a sufficient supply of nutrients under these conditions. PMID- 27768421 TI - A Comparative Study of Reproduction and Development in the Polychaete Family Terebellidae. AB - The reproduction and development of four species of terebellid polychaetes from the west coast of North America were studied and compared with several other terebellid species to reveal the covariation of life history traits in the group, and assess any limitations on terebellid life history evolution that may be imposed by ancestry or body design. The four species in the present study span the range of reproductive and developmental modes known for the family Terebellidae. Eupolymnia crescentis and Neoamphitrite robusta are both free spawners that reproduce during discrete 3-month breeding periods. In E. crescentis, oogenesis takes from 5 to 8 months and spawning occurs from July to September, maximum oocyte diameter is 210 {mu}m, and fecundity reaches {approx}128,500 during a single breeding period. The E. crescentis larva develops near the bottom for about 7 days before settling as a five-setiger juvenile. Neoamphitrite robusta reproduces from April to July after a 12-month oogenic cycle; oocytes in this species measure up to 180 {mu}m, and fecundity reaches ~830,000. The two brooders in the study, Ramex californiensis and Thelepus crispus, brood their larvae in the maternal tube. T. crispus reproduces continuously for at least 6 months, and has up to 51,500 larvae in a single brood. The oocytes in this species (400 {mu}m) give rise to larvae that are brooded to the one-setiger stage and then emerge to undergo a one-day planktonic period before the larvae settle and become juveniles at eight setigers. Ramex californiensis reproduces continuously year round; larvae are brooded in cocoons that are laid sequentially in the tube, with up to 44 larvae in a single cocoon. Development from the 410 {mu}m oocytes is direct, and juveniles have 11 setigers. Unlike E. crescentis and N. robusta, in which oogenesis is synchronized within individuals to produce a peak of large oocytes during the discrete spawning period, R. californiensis and T. crispus females have a wide range of oocyte sizes throughout the year. Correlation analysis and analysis of variance of reproductive and developmental traits of these and several other terebellid species revealed some expected trends. For example, egg size varies according to the mode of reproduction (free spawning, extratubular brooding, or intratubular brooding), and is also correlated with juvenile size. However, egg size does not predict fecundity in terebellids when body size is held constant, and brooding is not restricted to small-bodied species. Indeed, the largest and smallest species in the study brood their larvae intratubularly, suggesting that allometric constraints may not be important in determining mode of reproduction in these polychaetes. The Terebellidae is a diverse family found in all marine habitats, yet all known terebellid larvae are non-feeding; this contrasts with the occurrence of both planktotrophy and lecithotrophy in other polychaete families, and leads to the proposal that larval development in terebellids has been constrained during the evolution of the lineage. The results of this study demonstrate that generalizations regarding complex relationships among life history traits are often inappropriate. The need for more comparative studies of marine invertebrate reproduction and development, and the integration of phylogenetic analyses into the study of life history evolution in marine invertebrates is highlighted. PMID- 27768422 TI - Distinct Reproductive Types of Male Spider Crabs Libinia emarginata Differ in Circulating and Synthesizing Methyl Farnesoate. AB - Levels of methyl farnesoate in the blood and in vitro rates of methyl farnesoate synthesis by the mandibular organ were investigated to determine whether this compound is related to the differences in morphology and reproductive states of distinct types of male spider crabs described by Homola et al. (1992) in winter populations. Three male types, selected from a summer population, were investigated in detail: (1) males with relatively large propoduses (claws) and worn exoskeletons (abraded), (2) males with relatively large propoduses and exoskeletons covered with epicuticle (unabraded), and (3) males with small propoduses and unabraded exoskeletons (small). All males examined had sperm, but abraded males, identical in propodus and body size to unabraded males, had a reproductive system that weighed twice as much. Large-clawed unabraded males had relatively small reproductive systems. Small-clawed males possessed a small reproductive system. Abraded males possessed larger mandibular organs, containing almost twice the total protein, and their mandibular organs synthesized significantly more methyl farnesoate in vitro than did the other types of males. Circulating levels of methyl farnesoate, in the hemolymph of the abraded males, were more then twice as high as the levels detected in any other type of male. The strong relationship between methyl farnesoate levels, male morphology, and reproductive system development calls for further studies on the role of methyl farnesoate in the regulation of reproduction and morphogenesis in male crustaceans. PMID- 27768423 TI - Spermatophores and Plug Substance of the Marine Shrimp Trachypenaeus similis (Crustacea: Decapoda: Penaeidae): Formation in the Male Reproductive Tract and Disposition in the Inseminated Female. AB - Sperm are packaged into many small spermatophores of variable size in the median vas deferens (MVD) of the male. A substance is intermixed with sperm in the proximal coils of the MVD, separating groups of sperm that will be ejaculated as spermatophores. Most of the ejaculatory duct is occupied by a chamber filled with a transparent, viscous fluid termed the "plug substance." When males are artificially ejaculated, spermatophores are emitted, followed by plug substance that quickly solidifies. This latter material fills and stoppers a space on the female, the median pocket, which serves as an antechamber to the apertures of the internalized seminal receptacles, where sperm from ruptured spermatophores are stored. The slit-like openings to the receptacles are functionally divided into a posterior aperture, stoppered by plug substance after insemination, a closed mid section, and an anterior exit for sperm release during spawning. Direct insemination by an everted male gonopore is considered more likely than transmission of spermatophores and plug substance via the male gonopod (petasma). In addition to its hypothesized roles during insemination and sperm release, the mass of plug substance (mating plug) may act as a paternity assurance device that prevents subsequent inseminations by other males. PMID- 27768424 TI - A Novel Tegumental Gland in the Nephropore of the Lobster, Homarus americanus: A Site for the Production of Chemical Signals? PMID- 27768425 TI - Morphogenesis of Maternal and Paternal Genomes in Fertilized Oyster Eggs (Crassostrea gigas): Effects of Cytochalasin B at Different Periods During Meiotic Maturation. AB - Fertilized oyster (Crassostrea gigas) eggs, treated with and without cytochalasin B (CB) at varying periods during meiotic maturation, were examined following 7 aminoactinomycin D (7-AAD) and anti-{beta} tubulin staining for DNA and microtubular patterns, respectively. Electron microscopic observations of untreated fertilized eggs revealed the development of an extensive network of endoplasmic reticulum during germinal vesicle breakdown. Germinal vesicle breakdown was not accompanied by the disappearance of the nucleolus; the latter persisted morphologically unchanged throughout fertilization. The first meiotic spindle [12.4 +/- 1.0 {mu}m (1) x 5.4 +/- 0.55 {mu}m (diameter (d); metaphase plate)] was oriented with its long axis perpendicular to the egg's surface. In contrast, the second meiotic spindle was approximately one half the size of the first [7.4 +/- 0.65 {mu}m (1) x 2.91 +/- 0.29 {mu}m (d)] and initially oriented with its long axis parallel to the egg's surface. Just prior to anaphase II, the spindle rotated so that its long axis became perpendicular to the egg's surface. Following its incorporation into the egg cytoplasm, the sperm nucleus dispersed but did not form a nuclear envelope until the completion of polar body formation. Just prior to pronuclear migration, an array of microtubules assembled around the female pronucleus, and then regressed; concomitantly, a sperm aster formed in conjunction with the centrosome associated with the developing male pronucleus. Following their migration and apposition with one another, both pronuclei underwent prophase as independent structures. Chromosomes from the male and female pronuclei became organized on a mitotic spindle in preparation for first cleavage. In zygotes treated with CB continuously or for just meiosis I, anaphase I occurred; however, a polar body failed to form. Consequently, all the diads were retained within the zygote and became situated on a tripolar spindle. In such cases, anaphase II resulted in the production of a variable number of chromosomal aggregations that developed into pronuclei (3 to 6). In contrast, zygotes treated with CB during meiosis II developed spindles characteristic of untreated specimens; however, polar body formation was blocked, resulting in the development of usually two maternal pronuclei. Morphogenesis of C. gigas fertilized eggs is discussed in reference to similar processes in other species and with respect to strategies of triploid embryo production using CB. PMID- 27768426 TI - Histochemical Studies of Jelly Coat of Marthasterias glacialis (Echinodermata, Asteroidea) Oocytes. AB - Histochemical studies revealed the presence of two major polysaccharides in the oocyte jelly coat (JC) of Marthasterias glacialis: a fibrillar component that contains carboxylic and sulfated groups and a loose component composed of neutral or weakly acidic polysaccharides. When isolated JC was submitted to cellulose acetate electrophoresis (CAE) and then stained with alcian blue, three bands appeared, of which one remained at the origin and two migrated toward the anode. Glycosaminoglycan-like molecules isolated from JC were separated by CAE into three main moving bands, two that present an Rf similar to that of the intermediary moving band of total JC and one that has an Rf similar to that of the faster moving band of total JC. These bands also have critical electrolyte points similar to those of total JC. Chondroitinase ABC mainly attacked the faster moving band, whereas protease and hyaluronidase seemed to digest all bands. These results and the Rfs of isolated and standard glycosaminoglycans after mono- and bidimensional CAE suggest that the glycosaminoglycan-like molecules bear some resemblance to chondroitan sulfate, heparan sulfate, and hyaluronic acid. PMID- 27768427 TI - Heme Biosynthesis in Fish and Land Vertebrates: Enzyme and cDNA Comparisons. PMID- 27768428 TI - Identification and Partial Characterization of an Extracorporeal Protease Activity Secreted by the Triclad Turbellarid Worm, Bdelloura candida. PMID- 27768429 TI - Limulus Vision in the Ocean: Comparing Neural and Behavioral Thresholds. PMID- 27768431 TI - Near-UV Radiation Effects on Dogfish (Mustelus canis) Lens Catalase and Antioxidant Protection. PMID- 27768430 TI - RFLP Analysis of a Fragment of the Large-Subunit Ribosomal RNA Gene of Globally Distributed Populations of the Toxic Dinoflagellate Alexandrium. PMID- 27768432 TI - Cerebral Blood Flow and Ventral Aortic Blood Pressure Response During Elevation of Intracranial Pressure in Bluefish (Pomatomus saltatrix). PMID- 27768433 TI - Noise Modulated Persistence of the Metastable State in a Simulated Neural Network. PMID- 27768434 TI - Calcium Pulses During the Activation of a Protostome Egg. PMID- 27768435 TI - Magnetic Localization of the Origins of Self-sustained Oscillation in Squid Giant Axons. PMID- 27768437 TI - Limulin and C-reactive Protein From the Plasma of Limulus polyphemus Are Different Proteins. PMID- 27768436 TI - The Impact of Feeding by Mussels and Scallops on Production of Dimethylsulfide From Marine Phytoplankton. PMID- 27768438 TI - Endogenous Currents During Wound Healing and Regeneration in Sabellid Fanworms. PMID- 27768439 TI - Ca2+ Fluxes Around Pollen Grains and Pollen Tubes of Lily; Normal Development and Effects of Thermal Shock, BAPTA-Type Buffer Microinjection and Depletion of Boric Acid From the Medium. PMID- 27768440 TI - Sperm-Specific Basic Proteins in the Holocephalan Fish Hydrolagus colliei (Chondrichthyes, Chimaeriformes) and Comparison with Protamines from an Elasmobranch. AB - Seven basic proteins can be isolated from sperm nuclei of the holocephalan ratfish Hydrolagus colliei. Two of these proteins (R3 and m0) are devoid of cysteine, whereas five of them (R1, R2, m1, m2, and m3) contain low levels of this amino acid residue. The proteins R1, R2, and R3 are major ones in the sperm nuclei of H. colliei, and they are analogous to basic proteins Z1, Z2, and Z3 (scylliorhinines) from the sperm of the elasmobranch Scyliorhinus canicula. However, taking into account the partial sequence of R3 protein and the number of cysteines in R1 and R2, these proteins do not seem to be homologous to the scylliorhinines. A comparison of sperm basic proteins between H. colliei (a holocephalan) and S. canicula (an elasmobranch) suggests a remarkable divergence of these proteins from a common ancestral pattern during the evolution of Chondrichthyes. PMID- 27768441 TI - Asters in Lysates of Spisula Oocytes Observed with a New Type of Polarized Light Microscope. PMID- 27768442 TI - Agonistic Encounters in the American Lobster, Homarus americanus: Do They Remember Their Opponents? PMID- 27768444 TI - Mechanically Induced Calcium Release From Xenopus Cell Cycle Extracts. PMID- 27768443 TI - The Role of Chemical and Visual Cues in Agonistic Interactions of the American Lobster. PMID- 27768445 TI - The Presence of the GABA-synthesizing Enzyme, Glutamate Decarboxylase, in Spisula Sperm. PMID- 27768446 TI - Cytoplasmic Microtubule Arrays in Oryzias latipes (Medaka) Eggs During Ooplasmic Segregation. PMID- 27768447 TI - Equivalent Sine Wave Frequency for Interpretation of Responses to Frequency-Swept Sinusoids Defined: an Algorithm From Studies in Skate Ganglion Cells. PMID- 27768448 TI - A Settlement Bioassay Assessing the Response of Soft Shell Clam Larvae to Sediments from Various Sites in Massachusetts Bay. PMID- 27768449 TI - Inhibitors of Protein Phosphatases (Okadaic Acid and Tautomycin) Block Sea Urchin Development. PMID- 27768452 TI - Leukotriene B4 Induces Release of Calcium From Endomembrane Stores In Vivo in Eggs and Second Cell Cycle Blastomeres of the Sand Dollar Echinaracnius parma. PMID- 27768451 TI - The Effect of Residential and Forested Watershed Land Cover on Nutrient Loading to Hamblin and Jehu Ponds, Waquoit Bay, Massachusetts. PMID- 27768453 TI - Anaphase Spindle Dynamics Under D20-enhanced Microtubule Polymerization. PMID- 27768454 TI - Land Cover Effects on Inorganic Nutrients in Groundwater and the Role of Salt Marshes in Interception of Land-Derived Nutrients Entering Estuaries of Waquoit Bay, Massachusetts. PMID- 27768455 TI - Differences in Benthic Invertebrate Assemblages in Two Estuaries of Waquoit Bay Receiving Disparate Nutrient Loads. PMID- 27768456 TI - Impact on Marine Species of New England Recreational Fishing Policies. PMID- 27768457 TI - Effect of Algal Cover on Size-Selective Predation of Gammarus mucronatus by the Striped Killifish, Fundulus majalis. PMID- 27768458 TI - Effect of Macroalgal Species and Nitrogen-Loading Rates on Colonization of Macroalgae by Herbivorous Amphipods. PMID- 27768459 TI - Invertebrate Response to Nutrient-Induced Changes in Macrophyte Assemblages in Waquoit Bay. PMID- 27768460 TI - Effect of Changing Plant Morphology on Invertebrate Susceptibility to Predation in Eelgrass Beds. PMID- 27768463 TI - Pelagic Metabolism in the Parker River/Plum Island Sound Estuarine System. PMID- 27768465 TI - Nutrient Limitation of Phytoplankton Growth in Waquoit Bay, Massachusetts. PMID- 27768464 TI - Effect of Nutrient Enrichment on Phytoplankton Growth in Waquoit Bay, Massachusetts. PMID- 27768466 TI - Effects of Nitrogen Loading and Salt Marsh Habitat on Gross Primary Production and Chlorophyll a in Estuaries of Waquoit Bay. PMID- 27768467 TI - Macrophyte Abundances in Waquoit Bay Estuaries Subject to Different Nutrient Loads and the Potential Role of Fringing Salt Marsh in Groundwater Nitrogen Interception. PMID- 27768470 TI - Growth of Epiphytes on Zostera marina in Estuaries Subject to Different Nutrient Loading. PMID- 27768468 TI - Total System Metabolism of the Plum Island Sound Estuarine System. PMID- 27768471 TI - Foliar Release of Ammonium and Dissolved Organic Nitrogen by Spartina alterniflora. PMID- 27768472 TI - Effect of Epiphyte Biomass on Growth Rate of Zosteru marina in Estuaries Subject to Different Nutrient Loading. PMID- 27768473 TI - Preliminary Investigations on the Scavenger Receptors of the Amebocyte of the American Horseshoe Crab, Limulus polyphemus. PMID- 27768474 TI - Regulation of the Plasma Cytolytic Pathway of Limulus polyphemus by {alpha}2 Macroglobulin. PMID- 27768476 TI - Dogfish (Mustelus canis) Lens Catalase Reduces H202-Induced Opacification. PMID- 27768475 TI - Sulfotransferase Activities in the Marine Sponge Microciona prolifera: Correlation with Sulfated Glycan Adhesive Structures. PMID- 27768478 TI - Form and Motion of Donax variabilis in Flow. AB - The coquina clam, Donax variabilis, rides flow from waves, migrating shoreward during rising tides and seaward during falling tides. This method of locomotion, swash-riding, is controlled not only behaviorally but also morphologically. The shape of this clam causes it to orient passively; a clam rotates in flow, usually in backwash, until its anterior end is upstream. Rotation is about a vertical axis through a pivotal point where the shell touches the sand. The density, weight distribution, and wedge-like shape are all important in effecting orientation. Such orientation is significant because it contributes to stability of motion. On an unoriented clam, upward lift can be higher than its underwater weight--a circumstance that results in uncontrollable tumbling. In contrast, once oriented with its anterior end upstream, a clam experiences downward lift that contributes to its stability while sliding in backwash. Furthermore, when the anterior end is upstream, drag is reduced relative to when the ventral, dorsal, or posterior ends are upstream. Since orientation occurs only above a minimum velocity, it has the effect of slowing a clam's motion over the substratum in rapid flows. Stability, drag, and speed reduction enhance a clam's ability to gain a foothold and dig in after a swashride, before wave flows can wash it off the beach and out to sea. PMID- 27768479 TI - Morphology and Physiology of the Thoracic and Abdominal Stretch Receptors of the Isopod Crustacean Ligia exotica. AB - In the terrestrial isopod Ligia exotica, paired stretch receptors, each comprising a separate rapidly and slowly adapting receptor cell, were found in the third to eighth thoracic segments and first five abdominal segments. The dendritic endings of the two sensory cells in each receptor terminate on a common receptor muscle; the cross-striation of this fiber is homogeneous throughout the segments. But the dendritic endings of the receptor cells differ: the rapidly adapting cell has a club-shaped ending restricted to the middle of the receptor muscle, whereas the slowly adapting receptor cell has a bifurcating ending that extends along the entire length of the muscle. Stretch applied to the receptor muscle evokes characteristically different responses in the two sensory cells. The slowly adapting receptor cell has a lower firing threshold and fires continuously for the duration of the stretch, while the rapidly adapting receptor cell has a higher threshold and fires a brief burst at the beginning of the stimulus. However, application of an intense stimulus will evoke continuous firing of the rapidly adapting receptor, which then changes to intermittent bursts. The adaptive significance of such a response is not known, nor is it likely to occur in nature. However, this unusual response is intrinsic to the rapidly adapting cell, as it can be evoked by current injection. In the second thoracic segment, instead of rapidly and slowly adapting cells, we found a single slowly adapting cell with a long robust dendrite attached to the extensor muscle. PMID- 27768480 TI - Transport and Metabolism of Alanine and Palmitic Acid by Field-Collected Larvae of Tedania ignis (Porifera, Demospongiae): Estimated Consequences of Limited Label Translocation. AB - The epidermis of larvae of Tedania ignis (Porifera, Demospongiae) is uniformly ciliated except for the posterior pole. The epidermal cells are long, columnar, and monociliate; each cilium arises from an epidermal crypt; symbiotic bacteria were not observed in larval cells. These lecithotrophic ("nonfeeding") larvae can feed by assimilating dissolved organic materials (DOM) from seawater. Larvae transported both the amino acid alanine (mean = 2.73 pmol larva-1 h-1; [S] = 1 {mu}M) and the fatty acid palmitic acid (mean = 16.27 pmol larva-1 h-1; [S] = 1 {mu}M) from seawater. Following assimilation, the label from alanine was recovered primarily in small molecular weight compounds; the label from palmitic acid was localized chiefly in the lipid fraction. Estimates of the contribution of transport to metabolism (mean respiration rate = 940.7 pmol O2 larva-1 h-1) reveal that alanine transport is energetically insignificant. Palmitic acid transport, in contrast, could account for 21%-55% of larval metabolism. Autoradiographic analysis of the distribution of the label in larvae suggests that epidermal cells are the chief recipients of the assimilated materials. Thus, the contribution of transport to whole-larva metabolism may underestimate the tissue-specific value. At palmitic acid concentrations of 1 and 0.25 {mu}M, the contribution of transport to the estimated metabolism of the epidermis would be 131% and 33% of energy requirements. Thus, the potential benefits of DOM to larvae are dependent not only on the nature of the epidermal transporters and the solute concentration, but also the degree to which materials are distributed among tissues. PMID- 27768481 TI - Role of Digestive Gland in the Energetic Metabolism of Penaeus setiferus. AB - We determined the role of the digestive gland in the respiratory metabolism of Penaeus setiferus adult males as a step toward proposing a feeding schedule based on the cycle of activity in the digestive gland. We measured pre- and postprandial values for oxygen consumption rate and hemolymph glucose concentrations in live animals, and oxygen consumption rate and glycogen concentration in excised digestive gland. After the animals were fed, which enhanced general metabolic activity, these indices changed. There was a high correlation between the oxygen consumption rate of the animal and the glucose concentration in the hemolymph, and between the oxygen consumption rate by the digestive gland and the glycogen concentration in the digestive gland, all in relation to time after feeding. Correlations support the hypothesis that the energy demand depends upon the metabolic substrate concentration. In this theory, glucose sustains muscle activity (during ingestion of food) and glycogen is the product of the digestive gland during food assimilation. Our observations of metabolic dynamics during the feeding period allowed us to examine the feeding process. The metabolic activity of the digestive gland was highest 6 h after feeding. This could mean that assimilation, having started 2 h after food intake, peaked 6 h after feeding. Eight hours after feeding, the oxygen consumption rate of the digestive gland decreased and fell to values similar to those recorded for animals subjected to 72 h of fasting. PMID- 27768482 TI - Bioassay and Preliminary Characterization of Ovigerous-Hair Stripping Substance (OHSS) in Hatch Water of Crab Larvae. AB - Hatch water (the filtrated medium into which zoea larvae have been released) of the estuarine terrestrial crab Sesarma haematocheir (akate-gani) contains a substance that causes premature detachment of embryos from ovigerous females. Detachment occurs when the ovigerous hairs along the female's ovigerous setae slip out of the investment coat that binds them to the embryos through stalks, or funiculi. The active factor, which I call ovigeroushair stripping substance (OHSS), is released outside of the egg capsule at the time of hatching, and is not secreted by the female. This study describes the results of a quantitative assay for measuring the activity of OHSS. Activity is measured as the percentage of hairs on a seta that can be induced to slip out of the coat without damage. Experiments with an extract of crushed embryos indicated that OHSS is present up to 2 days before hatching. Its activity was destroyed by heat and trypsin, suggesting that it is a protein. Its molecular size was estimated by gel filtration to be 15-20 kDa in S. haematocheir and 30 kDa in S. pictum. Reciprocal tests among different species indicated that OHSS occurs widely in intertidal and estuarine crabs. PMID- 27768483 TI - Characterization and Use of Isolated Toadfish Hepatocytes for Studies of Heme Synthesis and Utilization. PMID- 27768485 TI - Coexistence and Possible Parasitism of Somatic and Germ Cell Lines in Chimeras of the Colonial Urochordate Botryllus schlosseri. AB - Fusion between conspecifics (chimerism) is a well-documented phenomenon in a variety of taxa. Chimerism and the subsequent mixing of genetically different stem cell lines may lead to competition between cell lineages for positions in the germ line and to somatic and germ cell parasitism. It is suggested that somatic compatibility systems evolved to alleviate the costs and the threat of such cell lineage competition. Allogeneic colonies of the ascidian Botryllus schlosseri form vascular chimeras based on matching in one or both alleles on one highly polymorphic fusibility haplotype. Thereafter, one of the partners is completely or partially resorbed. Here we used a polymorphic molecular marker (PCR typing at a microsatellite locus) to follow somatic and gametic consequences of chimera formation. Twenty-two chimeras and subclone samples were established from 12 different genotype combinations, in which blood cells, zooids, and gonads were typed 45-130 days thereafter. Somatic coexistence of both partners was recorded in 73% of the subcloned chimeras (83% of chimeric entities) up to 100 days after disconnection between genotypes and in all chimeras where colony resorption was completed. Both genotypes were present in 23% of the sampled gonads (in 33% of the chimeras), and in 22% of the cases, germ cells of the second partner only were detected. Injection of allogeneic but compatible blood cells into three recipient colonies revealed proliferation of the donor cells in one case, 100 days after injection. To further evaluate somatic and germ cell parasitism in chimeric organisms, we propose four key features that characterize cell lineage competition processes. These include the somatic embryogenesis mode of development, the capability for independent existence of stem cells, the disproportionate share of gametic output within chimeras, and the existence of hierarchial responses. PMID- 27768487 TI - Behavioral Control of Swash-Riding in the Clam Donax variabilis. AB - Clams of the species Donax variabilis migrate shoreward during rising tides and seaward during falling tides. These clams spend most of the time in the sand, emerging several times per tidal cycle to ride waves. Migration is not merely a passive result of waves eroding clams out of the sand; rather clams actively jump out of the sand and ride specific waves. Such active migration is experimentally demonstrated during a falling tide by comparing the motion of dead and live clams; live clams emerge from the sand and move seaward even when dead ones do not. As low tide approaches, live clams become progressively less active. They cease migrating for 2 hours around low tide and resume jumping to migrate shoreward after the tide has turned. During the rising tide, far from being passive, the clams jump out to ride only the largest 20% of waves. Specifically, they choose swash that have the largest excursion, i.e., those swash that move furthest on the beach. PMID- 27768486 TI - Sexual Dimorphism and Niche Divergence in a Mid-Water Octopod (Cephalopoda: Bolitaenidae). AB - In the translucent mid-water octopod Eledonella pygmaea, the posterior salivary glands that release proteolytic enzymes into the esophageal crop grow five times faster in males than in females. I suggest that the sexes vertically partition the water column and that large glands have evolved in males as a result of their deepwater habitat. Members of the species undergo ontogenetic vertical descent and are suggested to mate at the lower end of the adult depth range where receptive females signal males with light organs. Selection for increased fitness is inferred to result in females increasing their fecundity by feeding at the upper limit of the adult range and in mature males increasing their encounters with mates by living at depths where mating occurs. To further increase their fitness, mature males--despite occurring in a prey-limited habitat--must expend energy to visually detect potential mates, to travel over wide areas, and to attempt to copulate. To increase the energy available to them, males at depth may exploit bioluminescent prey. The large glands protect the translucent males from increased predation by physically blocking light emitted by bioluminescent prey in their crops, and by speeding digestion. PMID- 27768488 TI - Discrimination Among Wave-Generated Sounds by a Swash-Riding Clam. AB - Clams, Donax variabilis, responded to sound stimuli presented to them in a laboratory aquarium by jumping out of the sand, lying on the sand for several seconds, and digging in again. On a beach, clams jump out of the sand and ride waves, migrating shoreward with the rising tide and seaward with the falling tide. Parallels between clam behavior on a beach and that elicited in the laboratory suggest that clams cue on wave sounds to jump out of the sand. Three aspects of the response to sound were parallel. (i) Clams were most responsive to low-frequency sounds similar to those produced on a beach by waves rolling onto shore. (ii) Clams were also more responsive to louder sounds; on a beach, clams jump preferentially for the largest (loudest) 20% of waves, (iii) Responsiveness in the laboratory had an endogenous tidal rhythm, with highest activity occurring at high tide and no activity occurring at low tide; this rhythm corresponds to the activity of clams on the beach from which they were collected. By using sounds to identify large waves, clams can ride selected waves and continuously maintain position at the sea's edge as the tide floods and ebbs. PMID- 27768490 TI - Axial Specification in a Basal Member of the Spiralian Glade: Lineage Relationships of the First Four Cells to the Larval Body Plan in the Polyclad Turbellarian Hoploplana inquilina. PMID- 27768489 TI - Sex on the Brain but the Heart Is Not Really In It: Developmental Heart Defects Associated with Aquatic Pollution and Microinjection of Hexachlorobenzene into the Japanese Medaka Embryo. PMID- 27768491 TI - The Experimental Alteration of Cell Lineages in the Nemertean Cerebratulus lacteus: Implications for the Precocious Establishment of Embryonic Axial Properties. PMID- 27768492 TI - Diagonal Development: Establishment of the Anal Axis in the Ctenophore Mnemiopsis leidyi. PMID- 27768493 TI - Localization of Digestion Activities in the Sea Anemone Haliplanella luciae. PMID- 27768494 TI - Accumulation of Dimethylsulfoniopropionate in Geukensia demissa Depends on Trophic Interactions. PMID- 27768495 TI - Effects of Varying Plume Turbulence on Temporal Concentration Signals Available to Orienting Lobsters. PMID- 27768496 TI - Accumulation and Retention of Dimethylsulfoniopropionate by Bivalve Molluscs: High and Nonnormal Variation. PMID- 27768498 TI - Explorations of Turbulent Odor Plumes with an Autonomous Underwater Robot. PMID- 27768499 TI - Sulfide as a Chemical Stimulus for Deep-Sea Hydrothermal Vent Shrimp. AB - Organisms dependent on deep-sea hydrothermal vents for their existence face extinction when their vents expire, unless they can establish populations on neighboring vents or on new vent sites. Propagules, including larvae and motile adults, are readily dispersed broadly by seafloor currents, but how they recognize active hydrothermal sites is problematical. Compelling evidence that vent organisms can find and colonize hydrothermal sites has been provided by a series of observations on the East Pacific Rise (1). New hydrothermal vents created there following a volcanic eruption on the seafloor in March 1991 were colonized by sessile invertebrates in less than one year. On the Mid-Atlantic Ridge, shrimp that normally cluster on sulfide surfaces have been observed to swim directly back to the surfaces when displaced from them. How do vent animals locate new or existing vents? Passive transport by currents (2) or active swimming without guidance by some physical cue is not likely to result in success (3). Chemicals present in hydrothermal fluids have been proposed as attractants. We provide the first evidence of a chemosensory response in a vent invertebrate to sulfides, which are prevalent in vent fluids and provide the energy,for chemosynthetic primary production at vents. PMID- 27768500 TI - Cephalopods Occupy the Ecological Niche of Epipelagic Fish in the Antarctic Polar Frontal Zone. AB - Recent data from research cruises and explorator fishing in the Antarctic Polar Frontal Zone (APFZ) of the Scotia Sea, together with data from dietary studies of Antarctic vertebrate predators, have revealed a large, previously overlooked trophic system in the Southern Ocean (Fig. 1). The upper trophic levels of this open-ocean epipelagic community are exceptional in that they contain no fish species. Fishes are replaced by cephalopods, including the ommastrephid squid, Martialia hyadesi. This squid preys on mesopelagic m.yctophids (lanternfish), which feed largely on copepods. We identify here a geographically distinct, Antarctic, open-ocean food chain which is of importance to air breathing predator species but where Antarctic krill, Euphausia superba, is absent. This system is probably prevalent in areas of higher primary productivity, especially the Scotia Sea and near the peri-Antarctic islands. Squid stocks in the APFZ may have potential for commercial exploitation, but they, and the predators they support, are likely to be sensitive to overfishing. Squid have a short, semelparous lifecycle, so overfishing in a single year can cause a stock to collapse. PMID- 27768501 TI - The Incidence and Morphology of Subcuticular Bacteria in the Echinoderm Fauna of New Zealand. AB - New Zealand echinoderms (33 species drawn from all five extant classes) were examined for the presence of symbiotic bacteria by fluorescence and electron microscopy. Gram-negative, subcuticular bacteria (SCB) were found in 17 species from four classes. The SCB could be classified into two major morphological types. Some species had both types of SCB. The distribution of SCB was not obviously linked to host ecology but did appear to be related to host phylogeny. Related species usually all have SCB or all lack them. The number of SCB in five species was estimated to be between 8.41 x 108 and 4.96 x 109 g-1 ash-free dry weight of host tissue. Significant differences in bacterial load and relative proportions of the different types of bacteria were found among three congeneric echinoids (Pseudechinus huttoni, P. albocinctus and P. novaezealandia). Ophiocoma bollonsi was peculiar in having groups of bacteria enclosed in host cells (bacteriocytes) within the connective tissue of the tube feet. PMID- 27768502 TI - The Effect of Temperature on the Relationship Between a Ciliated Protozoan, Trichodina cottidarum, and the Longhorn Sculpin, Myoxocephalus octodecemspinosus. PMID- 27768503 TI - Effect of Alcohol Consumption on Recovery From Eccentric Exercise Induced Muscle Damage in Females. AB - This study was designed to investigate the effects of alcohol consumption on recovery of muscle force when consumed immediately postexercise in young females. Eight young women completed 300 maximal eccentric actions of the quadriceps femoris muscle on an isokinetic dynamometer on two occasions in a randomized, cross-over design after which an alcoholic beverage (0.88g ethanol/kg body weight) or an iso-caloric placebo was consumed. Maximal isokinetic (concentric and eccentric) torque and isometric tension produced across the knee were measured in both the exercised and control leg predamage, 36 hr post, and 60 hr post damage. Venous blood creatine kinase (CK) activity and muscle soreness ratings were taken before damage and once per day to 60 hr post damage. Significant differences were observed between the exercised and control leg for maximal concentric, and eccentric torque and isometric tension (p < .05). A near significant Treatment * Time interaction was observed for isometric tension (p = .077), but not for concentric or eccentric torque. No main effects of treatment (alcohol) or interactions with Time * Leg or Leg * Treatment were observed. Perceived muscle soreness during box stepping and squatting showed significant time effects (p < .05), and CK activity did not significantly change. Our results indicate that the consumption of 0.88g ethanol/kg body weight following eccentric exercise-induced muscle damage does not affect recovery in the days following damage in females. PMID- 27768504 TI - An Evaluation of Functional Sit-to-Stand Power in Cohorts of Healthy Adults Aged 18-97 Years. AB - This investigation examined differences in functional sit-to-stand power/velocity between cohorts of adults aged 18-97 years. This study included 264 healthy adults classified into four cohorts (18-40, C1; 60-69, C2; 70-79, C2; >= 80, C4). Participants completed the sit-to-stand task five times. Power and velocity were measured via the TENDO power analyzer. Absolute average power was maintained from C1-C3, but decreased (p < .01) in C4. Absolute peak power decreased between C1-C2 (p < .01), was similar between C2-C3, and decreased in C4 (p < .01). Relative (to body weight) average and peak power decreased between C1-C2 (p < .01), was similar between C2-C3, and decreased in C4 (p < .01). Average velocity was similar between C1 and C2, but decreased in C3 (p < .01) and C4 (p < .01), respectively. Peak velocity was significantly different between all cohorts (p < .01). Declines in functional power may plateau during the seventh and eighth decades, accelerating after 80 years. PMID- 27768506 TI - Changes in Running Mechanics During a 6-Hour Running Race. AB - PURPOSE: To investigate changes in running mechanics during a 6-h running race. METHODS: Twelve ultraendurance runners (age 41.9 +/- 5.8 y, body mass 68.3 +/- 12.6 kg, height 1.72 +/- 0.09 m) were asked to run as many 874-m flat loops as possible in 6 h. Running speed, contact time (tc), and aerial time (ta) were measured in the first lap and every 30 +/- 2 min during the race. Peak vertical ground-reaction force (Fmax), stride length (SL), vertical downward displacement of the center of mass (Deltaz), leg-length change (DeltaL), vertical stiffness (kvert), and leg stiffness (kleg) were then estimated. RESULTS: Mean distance covered by the athletes during the race was 62.9 +/- 7.9 km. Compared with the 1st lap, running speed decreased significantly from 4 h 30 min onward (mean -5.6% +/- 0.3%, P < .05), while tc increased after 4 h 30 min of running, reaching the maximum difference after 5 h 30 min (+6.1%, P = .015). Conversely, kvert decreased after 4 h, reaching the lowest value after 5 h 30 min (-6.5%, P = .008); ta and Fmax decreased after 4 h 30 min through to the end of the race (mean -29.2% and -5.1%, respectively, P < .05). Finally, SL decreased significantly (-5.1%, P = .010) during the last hour of the race. CONCLUSIONS: Most changes occurred after 4 h continuous self-paced running, suggesting a possible time threshold that could affect performance regardless of absolute running speed. PMID- 27768505 TI - The cost-effectiveness of palivizumab in infants with cystic fibrosis in the Canadian setting: A decision analysis model. AB - BACKGROUND: Children with cystic fibrosis (CF) are at higher risk of severe respiratory syncytial virus (RSV) infection, which can lead to a decline in lung function. A monoclonal antibody, palivizumab (PMB), effectively prevents RSV hospitalizations; however, the high cost of PMB, approximately C$10,000 per patient per RSV season, limits its widespread use. We assess the cost effectiveness of PMB prophylaxis in CF children less than 2 y of age from the Canadian healthcare payer's perspective. METHODS: In 2014, a Markov cohort model of CF disease and infant RSV infections in the Canadian setting was developed based on literature data. Infants were treated with monthly PMB injections over the 5-month RSV season. Lifetime health outcomes, quality-adjusted life years (QALYs) and 2013 $CAD costs, discounted at 5%, were estimated. Findings are summarized as incremental cost-effectiveness ratios (ICERs) and budget impact. Deterministic sensitivity analysis was conducted to assess parameter uncertainty. RESULTS: Implementation of a hypothetical Canadian RSV prophylaxis program resulted in ICERs of C$652,560 (all CF infants) and C$157,332 (high-risk CF infants) per QALY gained and an annual budget impact of C$1,400,000 (all CF infants) and C$285,000 (high-risk CF infants). The analysis was highly sensitive to the probability of severe RSV, the degree of lung deterioration following infection, and the cost of PMB. CONCLUSIONS: Our results suggest PMB is not cost effective in Canada by commonly used thresholds. However, given the rarity of CF and relatively small budget impact, consideration may be given for the selective use of PMB for immunoprophylaxis of RSV in high-risk CF infants on a case-by-case scenario basis. PMID- 27768507 TI - Postural Stability During Standing Balance and Sit-to-Stand in Master Athlete Runners Compared With Nonathletic Old and Young Adults. AB - The aim of this study was to compare postural sway during a series of static balancing tasks and during five chair rises between healthy young (mean [SEM], age 26 [1] years), healthy old (age 67 [1] years) and master athlete runners (age 67 [1] years; competing and training for the previous 51 [5] years) using the Microsoft Kinect One. The healthy old had more sway than the healthy young in all balance tasks. The master athletes had similar sway to young athletes during two leg balancing and one-leg standing with eyes open. When balancing on one leg with eyes closed, both the healthy old and the master athletes had around 17-fold more sway than the young athletes. The healthy old and master athletes also had less anterio-posterior movement during chair rising compared with young athletes. These results suggest that masters runners are not spared from the age-associated decline in postural stability and may benefit from specific balance training. PMID- 27768509 TI - Adolescent and Young Adult Cancer Survivors' Valuation of Post-Treatment Recommended Care. AB - PURPOSE: Examine whether survivors of adolescent and young adult (AYA) cancer value recommended post-treatment care using focus groups and a willingness to pay (WTP) survey. WTP, a measure of value, indicates the dollar amount individuals are willing to pay to use a service. METHODS: Participants were recruited through the Utah Cancer Registry. N = 28 survivors diagnosed with cancer at ages 15-39 and currently aged >=18 participated in focus groups, and N = 4 in phone interviews (participation rate = 50%). All participants responded to a demographic survey and WTP questions based on one-time and monthly payments for annual visits. Focus group participants responded to an open-ended question on the value of follow-up care. Interval regressions identified factors associated with WTP. Qualitative analysis summarized themes for the open-ended question. RESULTS: Focus group participants reported valuing follow-up care as it brings peace of mind and helps them manage their health. Yet, 38% reported not having a cancer-related visit in the previous year. Only 27% and 43% of survivors agreed to pay any one-time and monthly payments, respectively. The monthly payment mean WTP was $41 (95% confidence interval [CI]: 31-84), equating to $494 annually, which is greater than the mean WTP for one-time payment ($362, 95% CI: 293-432, p < 0.001), suggesting that survivors may prefer monthly payments. Several factors, including being female and in better health, predicted higher WTP. CONCLUSION: Many AYA cancer survivors report not visiting their doctors annually for post treatment care despite verbally valuing care. Models that demonstrate high quality and distribute costs over time should be evaluated to encourage survivors to receive recommended care. PMID- 27768508 TI - Asynchronous Alterations of Muscle Force and Tendon Stiffness Following 8 Weeks of Resistance Exercise with Whole-Body Vibration in Older Women. AB - This study aimed to examine whether muscle force and tendon stiffness in a muscle tendon complex alter synchronously following 8-week whole-body vibration (WBV) training in older people. Forty older women aged 65 years and older were randomly assigned into control (CON, n = 15) and whole-body vibration (WBV) training groups (exposure time, n = 13; vibration intensity, n = 12). For the training groups, a 4-week detraining period was completed following the training period. Throughout the training/detraining period, force of the medial gastrocnemius (MG) muscle and stiffness of the Achilles tendon were assessed four times (0, 4, 8, and 12 weeks) using a combined system of dynamometer and ultrasonography. While muscle force gradually increased throughout the training period (p < .05), a significant increase in tendon stiffness was observed after 8 weeks (p < .05). These findings indicated that, during the early phase of WBV training, muscle force and tendon stiffness changed asynchronously, which might be a factor in possible musculotendinous injuries. PMID- 27768510 TI - Habitual Dietary Nitrate Intake in Highly Trained Athletes. AB - Although beetroot juice, as a nitrate carrier, is a popular ergogenic supplement among athletes, nitrate is consumed through the regular diet as well. We aimed to assess the habitual dietary nitrate intake and identify the main contributing food sources in a large group of highly trained athletes. Dutch highly trained athletes (226 women and 327 men) completed 2-4 web-based 24-hr dietary recalls and questionnaires within a 2- to 4-week period. The nitrate content of food products and food groups was determined systematically based on values found in regulatory reports and scientific literature. These were then used to calculate each athlete's dietary nitrate intake from the web-based recalls. The median[IQR] habitual nitrate intake was 106[75-170] mg/d (range 19-525 mg/d). Nitrate intake correlated with energy intake (rho = 0.28, p < .001), and strongly correlated with vegetable intake (rho = 0.78, p < .001). In accordance, most of the dietary nitrate was consumed through vegetables, potatoes and fruit, accounting for 74% of total nitrate intake, with lettuce and spinach contributing most. When corrected for energy intake, nitrate intake was substantially higher in female vs male athletes (12.8[9.2-20.0] vs 9.4[6.2-13.8] mg/MJ; p < .001). This difference was attributed to the higher vegetable intake in female vs male athletes (150[88 236] vs 114[61-183] g/d; p < .001). In conclusion, median daily intake of dietary nitrate in highly trained athletes was 106 mg, with large interindividual variation. Dietary nitrate intake was strongly associated with the intake of vegetables. Increasing the intake of nitrate-rich vegetables in the diet might serve as an alternative strategy for nitrate supplementation. PMID- 27768512 TI - Heart-Rate Variability During Deep Sleep in World-Class Alpine Skiers: A Time Efficient Alternative to Morning Supine Measurements. AB - BACKGROUND: It is increasingly popular to use heart-rate variability (HRV) to tailor training for athletes. A time-efficient method is HRV assessment during deep sleep. AIM: To validate the selection of deep-sleep segments identified by RR intervals with simultaneous electroencephalography (EEG) recordings and to compare HRV parameters of these segments with those of standard morning supine measurements. METHODS: In 11 world-class alpine skiers, RR intervals were monitored during 10 nights, and simultaneous EEGs were recorded during 2-4 nights. Deep sleep was determined from the HRV signal and verified by delta power from the EEG recordings. Four further segments were chosen for HRV determination, namely, a 4-h segment from midnight to 4 AM and three 5-min segments: 1 just before awakening, 1 after waking in supine position, and 1 in standing after orthostatic challenge. Training load was recorded every day. RESULTS: A total of 80 night and 68 morning measurements of 9 athletes were analyzed. Good correspondence between the phases selected by RR intervals vs those selected by EEG was found. Concerning root-mean-squared difference of successive RR intervals (RMSSD), a marker for parasympathetic activity, the best relationship with the morning supine measurement was found in deep sleep. CONCLUSION: HRV is a simple tool for approximating deep-sleep phases, and HRV measurement during deep sleep could provide a time-efficient alternative to HRV in supine position. PMID- 27768511 TI - Low hemagglutinin antigen dose influenza vaccines adjuvanted with AS03 alter the long-term immune responses in BALB/c mice. AB - We investigated the long-term immune profiles of dose-sparing, AS03-adjuvanted vaccines compared to a traditional high-dose, unadjuvated influenza vaccine formulation. BALB/c mice received 2 IM injections of influenza A/Uruguay/716/2007 (H3N2) split vaccine antigen: high-dose (HD) (3 ug hemagglutinin (HA)/dose) or low-dose (LD) formulations (0.03 ug or 0.003 ug HA) with AS03 and were followed to 34 weeks post-boost (pb). We examined serologic responses, spleen and bone marrow (BM) HA-specific antibody-secreting cells (ASCs) by ELISpot, influenza specific cytokine/chemokine production in re-stimulated splenocytes by multiplex ELISA, and antigen-specific CD4+ T cells that express cytokines (IL-2, IFNgamma, TNFalpha and IL-5) by flow cytometry. All formulations elicited robust serum antibody titers that persisted for at least 34 weeks. The number of antigen specific ASCs in the spleen and BM were higher in the 2 LD +AS03 groups, but despite having fewer ASCs, the average spot size in the HD-unadjuvanted group was larger at later time-points, suggesting greater antibody production per cell. Striking differences in the long-term profiles induced by the different vaccine formulations may contribute to these different ASC profiles. The HD-unadjuvanted vaccine elicited strong Th2 cytokines during the first 6 weeks pb but LD+AS03 groups generated broader, more durable responses at later timepoints. Finally, the 0.03 ug HA+AS03 group generated the greatest number of antigen-specific CD4+ T cells and the highest percentage of poly-functional cells that expressed 2 or more cytokines. Although all of the tested vaccines induced durable antibody responses, we show that different vaccine formulations (dose-sparing, adjuvant) generate distinct long-term immune profiles. Furthermore, our data suggest that the different profiles may be generated through unique mechanisms. PMID- 27768514 TI - Complexity of Exercise Behavior Among Older African American Women. AB - Despite the exercise benefits, disparities among diverse older adults continue to exist, where African American women have the lowest percentage of any population group in meeting national recommended activity guidelines. Drawing on the philosophical tradition of phronesis (practical reasoning) introduced by Aristotle, we studied perceptions of the exercise value among 14 older African American women. Three themes included: (1) exercise goals (e.g., effort exerted), (2) exercise reasons (e.g., health benefits, enjoyment and convenience, and activity recommendation), and (3) inactivity reasons (e.g., health issues, lack of motivation, and family responsibilities/priorities). Although most women reported being active, only three participants met the Healthy People 2020 guidelines for aerobic and muscle-strengthening activities, while two individuals were inactive. Exercise promoters should consider the values that motivate older African American women to exercise, such as the provision of accessible, nondiscriminatory exercise facilities, and not to exercise, such as concerns about neighborhood safety, in designing programs. PMID- 27768513 TI - Memories of Parent Behaviors and Adult Attachment in Childhood Cancer Survivors. AB - PURPOSE: Childhood cancer is stressful for the entire family. Preoccupation and anxiety surrounding the child's illness may result in parents of children with cancer being overprotective or less emotionally responsive toward their children. Such parenting in response to a negative life event like childhood cancer may cause survivors to be more insecurely attached than healthy peers, which could have downstream effects on survivors' romantic relationships later in life. Therefore, we examined survivors' perspectives on parent behaviors, adult attachment, and marital status among adult survivors of childhood cancer relative to controls. METHODS: One hundred forty-nine young adult survivors and 149 matched controls (Mage = 28, range 20-40) indicated their relationship status (single vs. partnered) and completed standardized questionnaires assessing memories of upbringing (warmth, overprotection, rejection) and adult attachment (avoidance, anxiety). RESULTS: Adult survivors of childhood cancer remembered mothers and fathers as emotionally warmer (d = 0.53/0.30), and mothers as less rejecting than controls (d = 0.30). Adult attachment was overall similar between survivors and controls, but partnered survivors reported particularly low attachment-related anxiety. Childhood cancer was related to higher mother and father warmth, which were associated with lower attachment-related avoidance and in turn with a greater likelihood of being in a relationship. CONCLUSION: Adult childhood cancer survivors did not remember their parents as overprotective, but reported more positive parenting relative to controls; and similar adult attachment and relationship status. The results were unexpected, but offer novel insights for future prospective studies, which are necessary to better understand psychosocial late effects of childhood cancer. PMID- 27768515 TI - Safety, immunogenicity and persistence of immune response to the combined diphtheria, tetanus, acellular pertussis, poliovirus and Haemophilus influenzae type b conjugate vaccine (DTPa-IPV/Hib) administered in Chinese infants. AB - We conducted 3 phase III, randomized, open-label, clinical trials assessing the safety, reactogenicity (all studies), immunogenicity (Primary vaccination study) and persistence of immune responses (Booster study) to the combined diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Chinese infants and toddlers. In the Pilot study (NCT00964028), 50 infants (randomized 1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 months of age (Group B). In the Primary study (NCT01086423), 984 healthy infants (randomized 1:1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 (Group B) months of age, or concomitant DTPa/Hib and poliomyelitis (IPV) vaccination at 2-3-4 months of age (Control group); 825 infants received a booster dose of DTPa/Hib and IPV at 18-24 months of age (Booster study; NCT01449812). In the Pilot study, unsolicited symptoms were more frequent in Group A (16 versus 1 infant; mostly upper respiratory tract infection and pyrexia); this observation was attributed to an epidemic outbreak of viral infections. Non-inferiority of 3-dose primary vaccination with DTPa-IPV/Hib over separately administered DTPa/Hib and IPV was demonstrated for Group A (primary objective). Similar antibody concentrations were observed in all groups, except for anti-polyribosyl-ribitol phosphate and anti-poliovirus types 1-3 which were higher in DTPa-IPV/Hib recipients. Protective antibody levels against all vaccine antigens remained high until booster vaccination. Three-dose vaccination with DTPa-IPV/Hib had a clinically acceptable safety profile. PMID- 27768517 TI - Mild Dehydration Does Not Influence Performance Or Skeletal Muscle Metabolism During Simulated Ice Hockey Exercise In Men. AB - This study determined whether mild dehydration influenced skeletal muscle glycogen use, core temperature or performance during high-intensity, intermittent cycle-based exercise in ice hockey players vs. staying hydrated with water. Eight males (21.6 +/- 0.4 yr, 183.5 +/- 1.6 cm, 83.9 +/- 3.7 kg, 50.2 +/- 1.9 ml.kg 1.min-1) performed two trials separated by 7 days. The protocol consisted of 3 periods (P) containing 10 * 45-s cycling bouts at ~133% VO2max, followed by 135 s of passive rest. Subjects drank no fluid and dehydrated during the protocol (NF), or maintained body mass by drinking WATER. Muscle biopsies were taken at rest, immediately before and after P3. Subjects were mildly dehydrated (-1.8% BM) at the end of P3 in the NF trial. There were no differences between the NF and WATER trials for glycogen use (P1+P2; 350.1 +/- 31.9 vs. 413.2 +/- 33.2, P3; 103.5 +/- 16.2 vs. 131.5 +/- 18.9 mmol.kg dm-1), core temperature (P1; 37.8 +/- 0.1 vs. 37.7 +/- 0.1, P2; 38.2 +/- 0.1 vs. 38.1 +/- 0.1, P3; 38.3 +/- 0.1 vs. 38.2 +/- 0.1 degrees C) or performance (P1; 156.3 +/- 7.8 vs. 154.4 +/- 8.2, P2; 150.5 +/ 7.8 vs. 152.4 +/- 8.3, P3; 144.1 +/- 8.7 vs. 148.4 +/- 8.7 kJ). This study demonstrated that typical dehydration experienced by ice hockey players (~1.8% BM loss), did not affect glycogen use, core temperature, or voluntary performance vs. staying hydrated by ingesting water during a cycle-based simulation of ice hockey exercise in a laboratory environment. PMID- 27768516 TI - Rho GTPases in mammalian spinal neural tube closure. AB - Neural tube closure is an important morphogenetic event that involves dramatic reshaping of both neural and non-neural tissues. Rho GTPases are key cytoskeletal regulators involved in cell motility and in several developmental processes, and are thus expected to play pivotal roles in neurulation. Here, we discuss 2 recent studies that shed light on the roles of distinct Rho GTPases in different tissues during neurulation. RhoA plays an essential role in regulating actomyosin dynamics in the neural epithelium of the elevating neural folds, while Rac1 is required for the formation of cell protrusions in the non-neural surface ectoderm during neural fold fusion. PMID- 27768519 TI - Five-Year Single Center Experience for Retroperitoneoscopic Ureterolithotomy. AB - INTRODUCTION: Narrow working space is a major problem to overcome during retroperitoneoscopic ureterolithotomy. We evaluated initial 5 years experience of retroperitoneoscopic ureterolithotomy for large impacted upper ureteral calculi. PATIENTS AND METHODS: Between January 2011 and December 2015, a total of 37 consecutive patients were evaluated. A 12-mm camera port at middle of midaxillary line and two 5-mm working ports in posterior axillary line were created. The stone was extracted through the site of camera trocar. A Double-J catheter (DJC) was placed antegradely by four steps (elevating of the proximal shaft, introducing the end of curl, advancing, and twisting) during retroperitoneoscopic ureterolithotomy. A knotless unidirectional barbed suture was applied to the incision site of the ureter in all cases. All patients were followed up at 2 weeks after discharge to remove a DJC and at 6 weeks after discharge to evaluate urinary drainage with intravenous urography. RESULTS: The mean +/- standard deviation for age (years), body mass index (kg/m2), stone size (mm), and postoperative hospital days were 57.9 +/- 13.3, 24.6 +/- 4.5, 15.5 +/- 4.0, and 3.2 +/- 1.2, respectively. Stones were successively removed without critical complications such as ureteral stricture in all cases. Total operation time, the time for placing a DJC, and ureteral suturing time at initial three trials were more than 150 minutes, more than 30 minutes, and about 15 minutes, respectively; however, they were about 60 minutes, less than 10 minutes, and about 5 minutes, respectively, in 25 case experiences. CONCLUSIONS: Retroperitoneoscopic ureterolithotomy is a safe and excellent alternative for large impacted upper ureter stone. When performing retroperitoneoscopic ureterolithotomy in the narrow space, our step by step methods, including working port creation, DJC placement, and suturing, will be helpful for surgeons to learn the procedure easily. PMID- 27768518 TI - Preclinical evaluation of a chemically detoxified pneumolysin as pneumococcal vaccine antigen. AB - The use of protein antigens able to protect against the majority of Streptococcus pneumoniae serotypes is envisaged as stand-alone and/or complement to the current capsular polysaccharide-based pneumococcal vaccines. Pneumolysin (Ply) is a key virulence factor that is highly conserved in amino acid sequence across pneumococcal serotypes, and therefore may be considered as a vaccine target. However, native Ply cannot be used in vaccines due to its intrinsic cytolytic activity. In the present work a completely, irreversibly detoxified pneumolysin (dPly) has been generated using an optimized formaldehyde treatment. Detoxi fication was confirmed by dPly challenge in mice and histological analysis of the injection site in rats. Immunization with dPly elicited Ply-specific functional antibodies that were able to inhibit Ply activity in a hemolysis assay. In addition, immunization with dPly protected mice against lethal intranasal challenge with Ply, and intranasal immunization inhibited nasopharyngeal colonization after intranasal challenge with homologous or heterologous pneumococcal strain. Our findings supported dPly as a valid candidate antigen for further pneumococcal vaccine development. PMID- 27768521 TI - Parameters of the 3-Minute All-Out Test: Overestimation of Competitive-Cyclist Time-Trial Performance in the Severe-Intensity Domain. AB - PURPOSE: To verify the accuracy of predicting performance in the severe-intensity domain by means of end-test power output (EP) and the work performed above EP (WEP) obtained from a 3-min all-out test in competitive cyclists. METHODS: Ten welltrained cyclists performed a ramp incremental test and a 3-min all-out familiarization test. Subsequently, they performed a 3-min all-out experimental test to obtain EP and WEP and a 10-min time trial (TT). The actual 10-min-TT mean power output was then compared with the power output predicted as P = WEP/Tlim + EP, where Tlim corresponds to 600 s. The ramp-test peak power output (PPO) was compared with PPO predicted as [Formula: see text], where S represents the ramp slope (0.5 W/s). RESULTS: The actual (347 +/- 30 W) and predicted (376 +/- 48 W) 10-min TT mean power output were correlated (r = .87, P = .001) but significantly different (P < .01). The coefficient of variation (CV) between the predicted and actual performance was 5.6% +/- 4.4%. The error of prediction was positively correlated to EP (r = .80, P = .005) and negatively correlated to WEP (r = -.71, P = .021). No significant difference was found between the 10-min-TT mean power output and EP (351 +/- 53 W). The actual (438 +/- 30 W) and predicted (472 +/- 41 W) ramp PPO were correlated (r = .88, P < .001) but significantly different (P < .001). The CV between the predicted and actual PPO was 5.2% +/- 3%. The error of prediction was positively correlated to EP (r = .63, P = .051). CONCLUSIONS: EP and WEP obtained from a 3-min all-out test overestimate severe-intensity performance in competitive cyclists. PMID- 27768520 TI - Synthesis of magnetic epichlorohydrin cross-linked carboxymethyl cellulose microspheres and their adsorption behavior for methylene blue. AB - Epichlorohydrin cross-linked carboxymethyl cellulose microspheres (ECH/CMC) obtained by inverse suspension method and magnetic Fe3O4 nanoparticles encasing the ECH/CMC microspheres (M-ECH/CMC) obtained by two different methods were successfully prepared and compared. Their structures and morphologies were analyzed using polarizing microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. The adsorption behaviors of M1-ECH/CMC for methylene blue (MB) in the single cationic dye wastewater, the cationic/anionic dye mixture in the absence or presence of co-existed additives (salt and surfactant) wastewater, were also investigated with UV-vis spectrometer. The results showed that the magnetic Fe3O4 nanoparticles were loaded readily in situ into ECH/CMC by specific, chemical interactions between COO- groups of ECH/CMC and magnetic responsive Fe3O4. The Langmuir isotherm and pseudo-second-order kinetic model provide best correlation with the experimental data for the adsorption of MB onto ECH/CMC and M1-ECH/CMC microspheres, while the Langmuir isotherm and pseudo-first-order kinetic model for M2-ECH/CMC. These microspheres are easily recyclable and exhibit high desorption and adsorption, which suggests that they can be applied as potential environmental adsorbents. PMID- 27768522 TI - Masters Athletes: Exemplars of Successful Aging? AB - Global population aging has raised academic interest in successful aging to a public policy priority. Currently there is no consensus regarding the definition of successful aging. However, a synthesis of research shows successful aging can be defined as a late-life process of change characterized by high physical, psychological, cognitive, and social functioning. Masters athletes systematically train for, and compete in, organized forms of team and individual sport specifically designed for older adults. Masters athletes are often proposed as exemplars of successful aging. However, their aging status has never been examined using a comprehensive multidimensional successful aging definition. Here, we examine the successful aging literature, propose a successful aging definition based on this literature, present evidence which suggests masters athletes could be considered exemplars of successful aging according to the proposed definition, and list future experimental research directions. PMID- 27768523 TI - The Impact of Central and Peripheral Cyclooxygenase Enzyme Inhibition on Exercise Induced Elevations in Core Body Temperature. AB - PURPOSE: Exercise increases core body temperature (TC) due to metabolic heat production. However, the exercise-induced release of inflammatory cytokines including interleukin-6 (IL-6) may also contribute to the rise in TC by increasing the hypothalamic temperature set point. This study investigated whether the exercise-induced increase in TC is partly caused by an altered hypothalamic temperature set point. METHODS: Fifteen healthy, active men age 36 +/- 14 y were recruited. Subjects performed submaximal treadmill exercise in 3 randomized test conditions: (1) 400 mg ibuprofen and 1000 mg acetaminophen (IBU/APAP), (2) 1000 mg acetaminophen (APAP), and (3) a control condition (CTRL). Acetaminophen and ibuprofen were used to block the effect of IL-6 at a central and peripheral level, respectively. TC, skin temperature, and heart rate were measured continuously during the submaximal exercise tests. RESULTS: Baseline values of TC, skin temperature, and heart rate did not differ across conditions. Serum IL-6 concentrations increased in all 3 conditions. A significantly lower peak TC was observed in IBU/APAP (38.8 degrees C +/- 0.4 degrees C) vs CTRL (39.2 degrees C +/- 0.5 degrees C, P = .02) but not in APAP (38.9 degrees C +/- 0.4 degrees C) vs CTRL. Similarly, a lower DeltaTC was observed in IBU/APAP (1.7 degrees C +/- 0.3 degrees C) vs CTRL (2.0 degrees C +/- 0.5 degrees C, P < .02) but not in APAP (1.7 degrees C +/- 0.5 degrees C) vs CTRL. No differences were observed in skin temperature and heart-rate responses across conditions. CONCLUSIONS: The combined administration of acetaminophen and ibuprofen resulted in an attenuated increase in TC during exercise compared with a CTRL. This observation suggests that a prostaglandin-E2-induced elevated hypothalamic temperature set point may contribute to the exercise-induced rise in TC. PMID- 27768525 TI - Typical airborne quinones modulate oxidative stress and cytokine expression in lung epithelial A549 cells. AB - Quinones that exist in ambient particulate matter (PM) are hypothesized to be associated with adverse health effects through the generation of reactive oxygen species (ROS). However, the impacts of the quinones on the inflammatory processes have yet to be clearly understood. In this study, we examined the oxidative potentials and biological effects of typical airborne quinones in the human lung epithelial A549 cells. Significant change of redox status, loss of mitochondrial membrane potentials (?Psi) and increase of superoxide dismutase (SOD) activity were induced by exposure to quinones. Some pro-inflammatory genes including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1); two aromatic hydrocarbon receptor regulated genes, cytochromes P450 1A1 (Cyp1a1) and cytochromes P450 1B1 (Cyp1b1); and oxidative stress-related gene heme oxygenase-1 (HO-1) were up-regulated after quinones treatment. Among these quinones, 1,2-naphthoquinone (1,2-NQ) up regulated expressions of IL-6, IL-8, TNF-alpha, Cyp1a1, and HO-1; 2-methoxy-1,4 naphthoquinone (MNQ) up-regulated MCP-1, Cyp1b1, Cyp1a1, and HO-1; 2 methylanthraquinone (MAQ) up-regulated IL-6, IL-8, TNF-alpha, MCP-1, Cyp1b1, and Cyp1a1; acenaphthenequinone (ACQ) up-regulated IL-8, TNF-alpha, MCP-1, Cyp1b1, and Cyp1a1. These results suggested that all these five quinones had a considerable pro-inflammatory potential by inducing oxidative stress and releasing different types of cytokines/chemokines. PMID- 27768524 TI - C9orf72 plays a central role in Rab GTPase-dependent regulation of autophagy. AB - A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients. In a recent study, we investigated this possibility by reducing expression of C9orf72 in cell lines and primary neurons and found that C9orf72 regulates the initiation of autophagy. C9orf72 interacts with Rab1a, preferentially in its GTP-bound state, as well as the ULK1 autophagy initiation complex. As an effector of Rab1a, C9orf72 controls the Rab1a-dependent trafficking of the ULK1 initiation complex prior to autophagosome formation. In line with this function, C9orf72 depletion in cell lines and primary neurons caused the accumulation of p62/sequestosome-1 positive inclusions. In support of a role in disease pathogenesis, C9ALS/FTD patient-derived iNeurons showed markedly reduced levels of autophagy. In this Commentary we summarise recent findings supporting the key role of C9orf72 in Rab GTPase-dependent regulation of autophagy and discuss autophagy dysregulation as a pathogenic mechanism in ALS/FTD. PMID- 27768526 TI - Reaction of antibiotic sulfadiazine with manganese dioxide in aqueous phase: Kinetics, pathways and toxicity assessment. AB - Sulfonamide antibiotics are often detected in terrestrial and aquatic environment, but little is known about abiotic degradation of these antibiotics. In the present study, the degradation of the sulfonamide antibiotic sulfadiazine by a synthesized delta-MnO2 was investigated. The initial reaction rate of sulfadiazine oxidized by manganese dioxide increased as the solution pH decreased by weakening electrostatic attraction between sulfadiazine and MnO2 and enhancing the reduction potential of MnO2. The presence of metal ions (Mn2+, Na+ and Ca2+), especially Mn2+, decreased the initial reaction rate by competitively adsorbing and reacting with MnO2. Two different products were identified during the reaction of sulfadiazine with MnO2 and the transformation of parent compound started with the formation of sulfadiazine radicals. Furthermore, toxicity assay results showed that the toxicity of products produced by bacteria decreased with elapse of reaction time. Results from the present study indicate that manganese dioxides in environmental matrix could be helpful in dissipation of sulfadiazine released into the environment. PMID- 27768527 TI - Epidemiological and etiological characteristics of herpangina and hand foot mouth diseases in Jiangsu, China, 2013-2014. AB - Herpangina (HA) and hand, foot, and mouth disease (HFMD) are common infectious diseases caused by human enteroviruses and frequently occurr in young children. Previous published studies have mainly focused on HFMD, while the HA epidemiological and etiological characteristics in mainland China have not been described. From June, 2013 to March, 2014, HA and HFMD patients were monitored in participants from clinical trial of EV-A71 vaccine conducted during 2012-2013. A total of 95 HA patients and 161 HFMD patients were defined. Enteroviruses of HA samples were differentiated into 17 serotypes (EV-A71, CV-A16, CV-A24, E6, CV-B5, CV-A22, CV-A6, CV-A10, CV-B3, E9, CV-A9, CV-B4, CV-B2, E1, E7, E21 and CV-A20), the most common serotypes were EV-A71(10/95,10.5%), CV-A16(4/95,4.2%) and CV A24(4/95,4.2%); while enteroviruses detected from HFMD samples were classfied into 21 serotypes ( EV-A71, CV-A16, CV-A10, CV-A6, E6, CV-B3, CV-B5, CV-A9, E9, CV-B2, CV-B4, E3, E11, E15, E16, CV-A1, EV-A69, E5, CA22, CA24 and EV99), the most common serotypes were EV-A71(28/161,17.4%), CV-A16(7/161,4.4%) and CV A10(5/161,3.1%). The first HA epidemic peak occurred in summer and a second smaller peak occurred in January. In HA patients, the body temperature (P < 0.0001) and the incidence of fever (P < 0.05) were significant higher than those in HFMD patients. Between HA and HFMD patients infected with EV-A71, no significant differences were found in age, sex, circulating season, and the viral genome diversity. In summary, we firstly reported the epidemiological and etiological characteristics of HA in mainland China. Developing a multivalent vaccine will be helpful for the control of the HA/HFMD epidemic. PMID- 27768528 TI - Focus Groups of Parents and Teens Help Develop Messages to Prevent Early Marijuana Use in the Context of Legal Retail Sales. AB - OBJECTIVES: The changes in Washington State and Colorado marijuana laws call for the development of new brief family-focused adolescent marijuana use preventive interventions that are relevant for and tailored to the context of legalization for retail sale. To that end, focus groups with parents and teens were conducted to find out about their concerns and needs in the context of legalization. METHODS: Six semi-structured focus groups (3 with parents, 3 with teens) were conducted in Washington State in 2013 related to consequences of teen marijuana use and messages that would be effective in helping to prevent teens from using marijuana in the context of legal adult use. A total of 33 teens and 35 parents participated. RESULTS: Three primary themes were common to these parents and teens: the negative consequences of marijuana use during adolescence on mental, physical, and social health; the need for more or better information; and the need for information/messages to come from trusted sources. The themes related to potential prevention messages include the use of fear; stories about real people; focusing on short-term consequences; and teens needing alternative activities (something better to do). CONCLUSIONS: The results suggest that parents and teens need information about the new retail marijuana legalization law. Teens are open to both information and guidance from parents as long as it is calm and respectful. Firsthand accounts of consequences of marijuana use from peers and adults, rather than threats from authority figures, could hold some promise for persuading teens to avoid marijuana use. PMID- 27768529 TI - Effects of nozzle types and 2,4-D formulations on spray deposition. AB - The objective of this study was to evaluate the effects of nozzle types and 2,4-D formulations on spray deposition on different targets. Two field experiments were carried out in a completely randomized design, and treatments were arranged in a factorial scheme. Species in experiment 1 were Sumatran fleabane (Conyza sumatrensis) and Brazil pusley (Richardia brasiliensis) and in experiment 2 were soybeans (Glycine max) and Benghal dayflower (Commelina benghalensis). For both experiments, the first factor corresponded to spray nozzles with different settings (AD 110.015 - 61 and 105 L ha-1; AD 015-D - 75 and 146 L ha-1; XR 110.0202 - 200 L ha-1; and ADIA-D 110.02 - 208 L ha-1) and the second factor consisted of two formulations of 2,4-D (amine and choline). The formulation of 2,4-D choline has contained Colex-DTM Technology. Similar or higher spray deposition was observed on the leaves and artificial targets when using 2,4-D choline as compared to the 2,4-D amine formulation, and these differences in deposition were more evident for nozzles applying lower spray volumes. Deposition was more affected by nozzle type when amine formulation was used, compared to choline formulation. PMID- 27768531 TI - Factors associated with relationship dissolution and post-dissolution adjustment among lesbian adoptive couples. AB - Same-sex adoptive couples are increasingly visible, yet few studies have addressed relationship stability and dissolution among these couples. In this study, using a theoretical framework based on Investment Models and Vulnerability Stress-Adaptation Theory, factors associated with dissolution and post dissolution adjustment among 27 lesbian adoptive couples were examined across two points. At Wave 1, all 27 couples were together; children were on average 3 years old. Results revealed that nearly one third broke up over 5 years (between Waves 1 and 2). Factors related to shorter relationship length and undermining coparenting at Wave 1 distinguished women who later broke up versus stayed together. Worse mental health at Wave 2 characterized women in dissolved rather than sustained relationships, even with comparable individual adjustment at Wave 1. Weaker parenting alliance and greater dissatisfaction with childcare divisions were reported by women no longer with their partners at Wave 2 as compared with those in enduring partnerships. This research has implications for understanding lesbian relationship dynamics and associations with individual adjustment. PMID- 27768533 TI - COD and nitrogen removal and microbial communities in a novel waterfall biofilm reactor operated at different COD/TN ratios. AB - The aim of this study was to characterize the pollutant removal efficiency and the microbial communities that arose in a newly designed waterfall biofilm reactor (WFBR) at different chemical oxygen demand/total nitrogen (COD/TN) ratios. The reactor was operated continuously for 28 days at different COD/TN ratios, and its efficiency was evaluated. Results showed that as the thickness of the biofilm increased, the structure of the biofilm encouraged anaerobic-aerobic, anoxic-anaerobic, and fully anaerobic conditions in one reactor. The COD/TN ratios used had a significant effect on the removal of COD and nitrogen components. At a COD/TN ratio of 14, the ammonium nitrogen removal efficiency reached its highest value (99%), but the COD removal efficiency remained at approximately 90%. High-throughput sequencing revealed that the highest community diversity and richness were seen at a COD/TN ratio of 18, and the major phyla were Proteobacteria (average abundance of 47%), Actinobacteria (24%), and Bacteroidetes (13%). As the COD/TN ratios increased from 7 to 18, the abundance of Proteobacteria gradually increased from 25% to 68%. These results could provide important guidance for the design of new wastewater treatment systems and also enrich our theoretical understanding of microbial ecology. PMID- 27768534 TI - Perforation of the Interior Vena Cava with Aortic and Vertebral Penetration by a Suprarenal Greenfield Filter. PMID- 27768535 TI - Visual Search Strategy During Regatta Starts in a Sailing Simulation. AB - In a sport conditioned by natural elements such as sailing, visual perception is a key factor for the performance. Research has shown that the visual behavior of athletes at different skill levels varies, which may cause differences in the performance achieved. The aim of this research was to examine the visual behavior of sailors from different ranking positions at the start of a race in a simulated situation. Twenty junior sailors (N = 10 top and N = 10 bottom ranking) participated in this study. The visual behavior was recorded at the start of a sailing simulation. The top-ranking sailors performed more visual fixations on the locations that have more highly relevant information, such as "telltales" and "rivals," than do bottom-ranking sailors (p < .005). The top-ranking sailors are closer to the start line at the time of the start signal. The analysis of the visual search strategy shows that top-ranking sailors employed a more active visual search strategy. More experienced athletes can make better use of the information obtained from the important locations. PMID- 27768537 TI - Three critical questions for future research on lesbian relationships. AB - In this article I discuss three questions that should be priorities for future research on lesbian love and relationships. The first question concerns the very definition of "lesbian relationship," given how many women may be engaged in same sex relationships without identifying as lesbian. The second question concerns the potential influence of childhood neglect and abuse on adult women's same-sex relationships, a topic that has important implications for both psychological well-being and relationship functioning. The third question concerns the potential downsides of legal marriage for women's same-sex relationships, a topic that is particularly important in light of the newfound legal recognition of same sex marriage in all 50 states. Although there are many understudied questions in the domain of women's same-sex relationships, research on these three questions has particularly strong potential to advance our understanding of lesbian love and relationships in important ways. PMID- 27768538 TI - Delayed Compensatory Postural Adjustments After Lateral Perturbations Contribute to the Reduced Ability of Older Adults to Control Body Balance. AB - The goal of this study was to investigate the timing of compensatory postural adjustments in older adults during body perturbations in the mediolateral direction, circumstances that increase their risk of falls. The latencies of leg and trunk muscle activation to body perturbations at the shoulder level and variables of center of pressure excursion, which characterize postural stability, were analyzed in 40 older adults (nonfallers and fallers evenly split) and in 20 young participants. The older adults exhibited longer latencies of muscular activation in eight out of 15 postural muscles as compared with young participants; for three muscles, the latencies were longer for the older fallers than nonfallers. Simultaneously, the time for the center of pressure displacement reached its peak after the perturbation was significant longer in both groups of older adults. The observed delays in compensatory postural adjustments may affect the older adults' ability to prompt control body balance after postural disturbances and predispose them to falls. PMID- 27768539 TI - Therapeutic Effects of CT-guided Radiofrequency Ablation with Concurrent Platinum Doublet Chemotherapy in a Rabbit VX2 Lung Tumor Model. AB - Purpose To evaluate survival time with concurrent, combined use of radiofrequency ablation (RFA) and one of the commonly used platinum-doublet chemotherapies (cisplatin [CDDP]/paclitaxel [PTX], CDDP/vinorelbine [VNR], CDDP/adriamycin [ADR], or CDDP/pemetrexed [MTA] combinations) by using a rabbit VX2 lung tumor model. Materials and Methods The experiment was approved by the institutional animal care committee. VX2 cells were implanted into the lungs of 60 rabbits randomized into groups treated with supportive care (control group), RFA alone, chemotherapy alone (CDDP/PTX, CDDP/VNR, CDDP/ADR, or CDDP/MTA), or a combination of RFA and chemotherapy (RFA/CDDP/PTX, RFA/CDDP/VNR, RFA/CDDP/ADR, or RFA/CDDP/MTA). RFA was performed and followed by intravenous chemotherapy. Survival time was evaluated by using the Kaplan-Meier method. Results The median survival time of the control, RFA-alone, CDDP/PTX, CDDP/VNR, CDDP/ADR, CDDP/MTA, RFA/CDDP/PTX, RFA/CDDP/VNR, RFA/CDDP/ADR, and RFA/CDDP/MTA groups was 26.5, 40, 39, 26.5, 28, 26, 120, 16.5, 42, and 26.5 days, respectively. Survival of the RFA/CDDP/PTX group was significantly longer than that of the control (P = .0006), CDDP/PTX (P = .0117), and RFA-alone (P = .0495) groups. Survival was also significantly prolonged with combined RFA/CDDP/ADR treatment versus supportive care (P = .026), but not with RFA alone (P = .765) or CDDP/ADR (P = .167). Survival times in the RFA/CDDP/VNR and RFA/CDDP/MTA groups were significantly shorter than that in the RFA-alone group (P = .0282 and P = .0197, respectively). Conclusion The combination of RFA and systemic chemotherapy with CDDP/PTX may benefit survival. However, RFA with systemic CDDP may have a survival disadvantage when combined with VNR or MTA. (c) RSNA, 2016. PMID- 27768540 TI - Gender Differences in Academic Rank of Radiologists in U.S. Medical Schools. AB - Purpose To determine whether there were gender differences in full professorship after accounting for factors known to influence academic advancement. Materials and Methods Institutional review board approval was obtained for this HIPAA compliant study, with waiver of informed consent. In this cross-sectional study, the authors used a comprehensive 2014 physician database (5089 academic radiologists, inclusive of all U.S. academic radiologists in 2014; 11.3% of all U.S. radiologists) containing information on physician age, years since residency, National Institutes of Health funding, scientific publications (first or last author and total), clinical trial investigation, and clinical volume measured according to 2013 Medicare reimbursement. Primary outcome of gender differences in full professorship was estimated by using a multilevel logistic regression model adjusting for these factors. Results Among 5089 academic radiologists, 3638 (71.5%) were men. The average age for male and female radiologists was 52 and 49 years, respectively. Overall, 239 women (16.5%) and 948 (26.1%) men were full professors (P < .001). Women had fewer total and first or last author publications than men (total, 12.2 vs 17.6; first or last, 6.8 vs 10.7; P < .001 for both comparisons). Women were less likely than men to have National Institutes of Health funding (2.0% vs 3.6%; P = .004) and generated less annual Medicare revenue ($63 346 vs $75 854; P = .001). After multivariate adjustment, rates of full professorship among female and male radiologists were not significantly different (absolute adjusted difference for female vs male radiologists, -1.5%; 95% confidence interval: -3.8%, 0.9%). Conclusion Among radiologists with U.S. medical school faculty appointments in 2014, men and women were similarly likely to be full professor after several factors known to influence promotion were taken into account. However, unadjusted differences in promotion and research productivity were present, which suggests that female radiologists may lack equal research opportunities. (c) RSNA, 2016. PMID- 27768541 TI - "Lesbian"/female same-sex sexualities in Africa. AB - Understandings of African lesbian sexualities have been affected by silence, repression, and uncertainty. The subject of lesbian experiences and sexualities in Africa constitutes an opportunity for feminist scholars to address the transnational politics of knowledge production about African lesbians' lives and the contours of lesbian art, activism, and relationships in African nations. This article contextualizes the state of research on African lesbian sexualities and introduces the special issue. PMID- 27768542 TI - Why Thyroid Surgeons Are Frustrated with Radiologists: Lessons Learned from Pre- and Postoperative US. AB - Optimal treatment of thyroid cancer is highly dependent on accurate staging of the extent of disease at presentation. Preoperative ultrasonography (US) is the most sensitive method for detecting metastatic lymph nodes and is recommended as part of the standard preoperative workup. Missed findings on preoperative scans may lead to understaging and inadequate surgical management, which subsequently predispose these patients to residual disease postoperatively and a higher risk for recurrence, possibly requiring repeat surgery. Traditionally, thyroid US for pre- and postoperative staging has been performed by radiologists. However, there is a growing trend away from radiologist-performed US in favor of surgeon performed US. Recent surgical and endocrinology literature has shown that, when compared with surgeon-performed US, radiologist-performed preoperative staging US is less accurate and is inadequate for presurgical planning, with higher local recurrence rates. This review highlights the importance of accurate preoperative US for patients with differentiated thyroid cancer, with specific attention to deficiencies that exist in general radiology department thyroid US reports. We present a standardized approach to neck US reporting that incorporates the newly updated 2015 recommendations from the American Thyroid Association and also addresses the pertinent questions for thyroid surgeons. By ensuring comprehensive preoperative assessment and improving thyroid US reporting, we seek to improve patient access to optimized care. (c)RSNA, 2016. PMID- 27768543 TI - Artifacts at Cardiac CT: Physics and Solutions. AB - Computed tomography is vulnerable to a wide variety of artifacts, including patient- and technique-specific artifacts, some of which are unique to imaging of the heart. Motion is the most common source of artifacts and can be caused by patient, cardiac, or respiratory motion. Cardiac motion artifacts can be reduced by decreasing the heart rate and variability and the duration of data acquisition; adjusting the placement of the data window within a cardiac cycle; performing single-heartbeat scanning; and using multisegment reconstruction, motion-correction algorithms, and electrocardiographic editing. Respiratory motion artifacts can be minimized with proper breath holding and shortened scan duration. Partial volume averaging is caused by the averaging of attenuation values from all tissue contained within a voxel and can be reduced by improving the spatial resolution, using a higher x-ray energy, or displaying images with a wider window width. Beam-hardening artifacts are caused by the polyenergetic nature of the x-ray beam and can be reduced by using x-ray filtration, applying higher-energy x-rays, altering patient position, modifying contrast material protocols, and applying certain reconstruction algorithms. Metal artifacts are complex and have multiple causes, including x-ray scatter, underpenetration, motion, and attenuation values that exceed the typical dynamic range of Hounsfield units. Quantum mottle or noise is caused by insufficient penetration of tissue and can be improved by increasing the tube current or peak tube potential, reconstructing thicker sections, increasing the rotation time, using appropriate patient positioning, and applying iterative reconstruction algorithms. (c)RSNA, 2016. PMID- 27768545 TI - Comparative reduction of Giardia cysts, F+ coliphages, sulphite reducing clostridia and fecal coliforms by wastewater treatment processes. AB - Advanced wastewater treatment processes are applied to prevent the environmental dissemination of pathogenic microorganisms. Giardia lamblia causes a severe disease called giardiasis, and is highly prevalent in untreated wastewater worldwide. Monitoring the microbial quality of wastewater effluents is usually based on testing for the levels of indicator microorganisms in the effluents. This study was conducted to compare the suitability of fecal coliforms, F+ coliphages and sulfide reducing clostridia (SRC) as indicators for the reduction of Giardia cysts in two full-scale wastewater treatment plants. The treatment process consists of activated sludge, coagulation, high rate filtration and either chlorine or UV disinfection. The results of the study demonstrated that Giardia cysts are highly prevalent in raw wastewater at an average concentration of 3600 cysts/L. Fecal coliforms, F+ coliphages and SRC were also detected at high concentrations in raw wastewater. Giardia cysts were efficiently removed (3.6 log10) by the treatment train. The greatest reduction was observed for fecal coliforms (9.6 log10) whereas the least reduction was observed for F+ coliphages (2.1 log10) following chlorine disinfection. Similar reduction was observed for SRC by filtration and disinfection by either UV (3.6 log10) or chlorine (3.3 log10). Since F+ coliphage and SRC were found to be more resistant than fecal coliforms for the tertiary treatment processes, they may prove to be more suitable as indicators for Giardia. The results of this study demonstrated that advanced wastewater treatment may prove efficient for the removal of Giardia cysts and may prevent its transmission when treated effluents are applied for crop irrigation or streams restoration. PMID- 27768544 TI - Removal of Ni and Zn in contaminated neutral drainage by raw and modified wood ash. AB - In the present study, wood ash was modified by alkaline fusion, prior to hydrothermal synthesis, for potential application in the treatment of mine drainage impacted water. With this objective, two types of wood ash (both raw and modified) were evaluated for the treatment of Ni and Zn in contaminated neutral drainage (CND). Batch adsorption experiments were initially conducted on synthetic CND, and then on two real CND, sampled on two active mine sites, contaminated by either Ni (3.7 mg/L) or Zn (9.1 mg/L). Leaching of Zn was observed during the kinetic tests for the raw wood ash, whereas its modification suppressed the leaching. The cation exchange capacity acquired by modification of the two samples of wood ash exceeded 300 meq/100 g (which is two to fourfold higher than those of the raw ash), while sorption capacity for Ni and Zn tripled relative to the raw material. The Langmuir model best described the sorption process for all materials, while potential mechanisms of metal removal include adsorption, precipitation and ion exchange, following pseudo second-order kinetics. Results also showed that within 2 h of contact of mine effluents with one modified wood ash, Ni and Zn concentrations decreased below the maximum authorized monthly mean concentration allowed by the Canadian law (0.5 mg/L), whereas the other modified wood ash allowed reaching the regulatory conformity after 2 h for Ni but 7 days for Zn (although 93% removed after 2 h). Nonetheless, the pH was raised (10.9-11.8) above the legally allowed limits (6-9.5). Based on these findings, modified wood ash could be considered as a promising option for the treatment of Ni and Zn in CND, but the pH correction of final effluent might be necessary. PMID- 27768546 TI - Exercise Training Improved Body Composition,Cardiovascular Function, and Physical Fitness of 5-Year-Old Children With Obesity or Normal Body Mass. AB - OBJECTIVES: To explore the effects of exercise training on body composition, cardiovascular function, and physical fitness in 5-year-old obese and lean children. METHODS: 42 obese and 62 lean children were randomly allocated into exercise and control groups separately. Body composition, cardiovascular function, and physical fitness were measured at baseline and the end of the intervention. The exercise groups participated in 10 weeks of supervised moderate intensity exercise training (at 50% of heart rate reserve), 50 training sessions in total. RESULTS: The physical activity program was successfully completed and no sport injury occurred. Exercise training decreased BMI, waist circumference, body fat%, and fat mass; and slowed down the growth speed of body mass of both trained obese and lean children. Exercise training significantly decreased systolic blood pressure of obese children and decreased their heart rate responses during exercise. Trained obese children improved the performances of long jump, 10-m * 4 shuttle run, and 3-m balance beam walk; while trained lean children improved more items of physical fitness. CONCLUSIONS: 10 weeks of moderate intensity exercise training is an effective and safe treatment for children aged 5 years, either obese or with normal body mass. PMID- 27768547 TI - Perspectives on contemporary lesbian relationships. AB - This article introduces the special issue on contemporary lesbian relationships. The beginning notes some of the prominent changes that have occurred in the past 15 years in the visibility and positive representation of lesbian couples in our popular U.S. culture. The remainder focuses on identifying and summarizing the primary themes of the special issue, including the implications of changes in marriage rights, the acknowledgment and exploration of the effects of sexual minority stress, and a shift in the framing of research to better reflect the diversity of lesbian relationship experiences. PMID- 27768550 TI - Websites Related to Volume 30, Issue 4. PMID- 27768548 TI - The Shift in Emphasis From Risk-Based to Age-Based Hepatitis C Virus (HCV) Testing in the US Tends to Remove Injection Drug Use From Discourse on HCV. AB - BACKGROUND: Hepatitis C virus (HCV) infection is hyperendemic among people who inject drugs; nonsterile drug injection is the principle risk for HCV acquisition. Due to gaps in the HCV care continuum, there have been recommendations in the United States emphasizing age-rather than risk-based testing strategies. The central research focus of this project is to explore the meanings and implications of the shift in emphasis from risk-based to age-based HCV testing with regard to people who use drugs. METHODS: Content analysis and critical discourse analysis, informed by eco-social theory, were used to examine relevant documents. RESULTS: Fifteen documents were assessed for eligibility; 6 documents comprised the final set reviewed. In content analysis, age-based testing was both mentioned more frequently and was supported more strongly than risk-based testing. Risk-based testing was frequently mentioned in terms minimizing its use and drug use was often mentioned only euphemistically. The reframed emphasis largely removed discussion of injection drug use from discussion of HCV risks. CONCLUSION: Shifting the emphasis of HCV testing from testing based on specific routes of transmission and risk to testing based on age removes injection drug use from HCV discourse. This has the potential to either facilitate HCV care for drug users or to further stigmatize and marginalize drug use and people who use drugs. The potential implications of this shift in testing emphasis for public health merit further investigation. PMID- 27768552 TI - Intracorporeal Versus Extracorporeal Anastomosis in Laparoscopic Right Colectomy: A Systematic Review and Meta-Analysis. AB - AIM: To compare intracorporeal anastomosis (IA) and extracorporeal anastomosis (EA) in laparoscopic right colectomy (LRC) in terms of intraoperative and postoperative outcomes. METHODS: A systematic literature search with no limits was performed in PubMed and Embase. The last search was performed on April 9, 2016. The outcomes of interests included intraoperative outcomes (operative time, blood loss, length of incision, conversion, lymph nodes harvested, and intraoperative complications) and postoperative outcomes (time to first flatus, time to first defecation, time to liquid diet, length of hospital stay, postoperative complications, mortality, ileus, anastomotic leakage, anastomotic bleeding, wound infection, hernia, and intra-abdominal abscess). RESULTS: Fifteen articles and four conference abstracts published between 2004 and 2016 with a total of 1957 patients were enrolled in this meta-analysis. IA was associated with significant less blood loss, smaller length of incision, shorter time to first defecation, shorter time to liquid diet, and shorter length of hospital stay. No differences were found for operative time, conversion, lymph nodes harvested, intraoperative complications, time to first flatus, postoperative complications, mortality, anastomotic leakage, anastomotic bleeding, ileus, wound infection, intra-abdominal abscess, or hernia between IA and EA. CONCLUSION: Our meta-analysis suggests that the IA for LRC improves cosmesis and results in better postoperative recovery outcomes without increasing intraoperative and postoperative complications. Furthermore, a large randomized control study is warranted to compare the short-term and long-term outcomes of those two anastomosis techniques. PMID- 27768553 TI - Development of an Electronic Version of The Children's Self-Perceptions of Adequacy in and Predilection for Physical Activity (CSAPPA) Scale. AB - PURPOSE: To develop an electronic version of the Children's Self-Perceptions of Adequacy in and Predilection for Physical Activity (eCSAPPA), which would allow individual administration to children younger than nine years of age. METHODS: Fifty-four, four-nine-year-old children completed the eCSAPPA and the Test of Gross Motor Development-2 (TGMD-2). Parental measures of physical activity, and body mass index were obtained. Twenty-one participants additionally completed the paper version of the CSAPPA. RESULTS: All children successfully completed the eCSAPPA with interclass correlation coefficients of .76 for Adequacy and .86 for Total Score. Correlations and linear predictive equations for eCSAPPA revealed the TGMD-2's Locomotor subtest, age, and parent's activity rating explained 28 30% of the variability in Total and Adequacy eCSAPPA scores. Predilection and Enjoyment of Physical Education (PE) scores were less stable, with the TGMD-2's Locomotor subtest and age predicting 17% of the Predilection score and the TGMD 2's Object Control subtest demonstrating 17% of Enjoyment of PE. CONCLUSION: Children ages four-nine years can feasibly complete the electronic version of the CSAPPA and results hint that self-efficacy may be more plastic in younger children. The eCSAPPA is a promising instrument allowing the exploration of young children's development of adequacy and predilection toward physical activity as well as enjoyment of PE. PMID- 27768554 TI - The Influence of Familiarization on Physical Fitness Test Results in Primary School-Aged Children. AB - PURPOSE: The number of familiarization sessions in fitness assessments seems to be critical and inconsistent. Therefore, the primary aim of this research was to determine the number of familiarization attempts that stabilize the results in particular physical fitness tests. The secondary aim was to establish the test reliability through familiarization sessions. METHODS: Thirty-nine primary school children participated in this research (age: 10.8 years, body mass: 40.6 +/- 8.9 kg, and body height: 145.3 +/- 7.2 cm). During six sessions, with one session every third day, participants performed the following tests to assess explosive strength (vertical jump and standing long jump), coordination (polygon backward and polygon with turn) and flexibility (toe touch). RESULTS: The results of repeated analysis of variance (ANOVA) showed that there were significant increases (p < .05) in the polygon backward and polygon with turn performances from the first to third familiarization session. The standard error of measurement decreased as sessions progressed, indicating little within subject variation between the coordination test results following a familiarization period. Statistically significant differences were identified in the vertical jump test from the fourth test session compared with the first session. On the other hand, statistically significant differences for the standing long jump test were only found in the final session compared with the initial session. In the toe touch test, there were no significant increases from the first to the final familiarization session. All tests showed high a reliability coefficients, ranging from 0.979 to 0.991. CONCLUSION: Polygon backward and polygon with turn performance may be a practical, reliable method to assess coordination in primary school-aged children. However, completion of at least 3 practice sessions is suggested for participants to obtain a stable score. In addition, both jump tests are feasible for assessing skill-related fitness in young children, although the scientific reliability of the two tests should be questioned and the tests should be tailored to fit the age group of the children. PMID- 27768556 TI - Early Mention of the Term Epidemiology. PMID- 27768557 TI - Describing the population health burden of depression: health-adjusted life expectancy by depression status in Canada. AB - INTRODUCTION: Few studies have evaluated the impact of depression in terms of losses to both premature mortality and health-related quality of life (HRQOL) on the overall population. Health-adjusted life expectancy (HALE) is a summary measure of population health that combines both morbidity and mortality into a single summary statistic that describes the current health status of a population. METHODS: We estimated HALE for the Canadian adult population according to depression status. National Population Health Survey (NPHS) participants 20 years and older (n = 12 373) were followed for mortality outcomes from 1994 to 2009, based on depression status. Depression was defined as having likely experienced a major depressive episode in the previous year as measured by the Composite International Diagnostic Interview Short Form. Life expectancy was estimated by building period abridged life tables by sex and depression status using the relative risks of mortality from the NPHS and mortality data from the Canadian Chronic Disease Surveillance System (2007-2009). The Canadian Community Health Survey (2009/10) provided estimates of depression prevalence and Health Utilities Index as a measure of HRQOL. Using the combined mortality, depression prevalence and HRQOL estimates, HALE was estimated for the adult population according to depression status and by sex. RESULTS: For the population of women with a recent major depressive episode, HALE at 20 years of age was 42.0 years (95% CI: 40.2-43.8) compared to 57.0 years (95% CI: 56.8-57.2) for women without a recent major depressive episode. For the population of Canadian men, HALE at 20 was 39.0 years (95% CI: 36.5-41.5) for those with a recent major depressive episode compared to 53.8 years (95% CI: 53.6-54.0) for those without. For the 15.0-year difference in HALE between women with and without depression, 12.3 years can be attributed to the HRQOL gap and the remaining 2.7 years to the mortality gap. The 14.8 fewer years of HALE observed for men with depression equated to a 13.0-year HRQOL gap and a 1.8-year mortality gap. CONCLUSION: The population of adult men and women with depression in Canada had substantially lower healthy life expectancy than those without depression. Much of this gap is explained by lower levels of HRQOL, but premature mortality also plays a role. PMID- 27768558 TI - Developing indicators for evaluation of age-friendly communities in Canada: process and results. AB - INTRODUCTION: In 2006, the World Health Organization launched the Global Age Friendly Cities Project to support active aging. Canada has a large number of age friendly initiatives; however, little is known about the effectiveness and outcomes of age-friendly community (AFC) initiatives. In addition, stakeholders report that they lack the capacity and tools to develop and conduct evaluations of their AFC initiatives. In order to address these gaps, the Public Health Agency of Canada developed indicators to support the evaluation of AFC initiatives relevant to a wide range of Canadian communities. These indicators meet the varied needs of communities, but are not designed to evaluate collective impact or enable crosscommunity comparisons. METHODS: An evidence-based, iterative consultation approach was used to develop indicators for AFCs. This involved a literature review and an environmental scan. Two rounds of key expert and stakeholder consultations were conducted to rate potential indicators according to their importance, actionability and feasibility. A final list of indicators and potential measures were developed based on results from these consultations, as well as key policy considerations. RESULTS: Thirty-nine indicators emerged across eight AFC domains plus four indicators related to long term health and social outcomes. All meet the intended purpose of evaluating AFC initiatives at the community level. A user-friendly guide is available to support and share this work. CONCLUSION: The AFC indicators can help communities evaluate age-friendly initiatives, which is the final step in completing a cycle of the Pan-Canadian AFC milestones. Communities are encouraged to use the evaluation results to improve their AFC initiatives, thereby benefiting a broad range of Canadians. PMID- 27768559 TI - Estimating chronic disease rates in Canada: which population-wide denominator to use? AB - INTRODUCTION: Chronic disease rates are produced from the Public Health Agency of Canada's Canadian Chronic Disease Surveillance System (CCDSS) using administrative health data from provincial/territorial health ministries. Denominators for these rates are based on estimates of populations derived from health insurance files. However, these data may not be accessible to all researchers. Another source for population size estimates is the Statistics Canada census. The purpose of our study was to calculate the major differences between the CCDSS and Statistics Canada's population denominators and to identify the sources or reasons for the potential differences between these data sources. METHODS: We compared the 2009 denominators from the CCDSS and Statistics Canada. The CCDSS denominator was adjusted for the growth components (births, deaths, emigration and immigration) from Statistics Canada's census data. RESULTS: The unadjusted CCDSS denominator was 34 429 804, 3.2% higher than Statistics Canada's estimate of population in 2009. After the CCDSS denominator was adjusted for the growth components, the difference between the two estimates was reduced to 431 323 people, a difference of 1.3%. The CCDSS overestimates the population relative to Statistics Canada overall. The largest difference between the two estimates was from the migrant growth component, while the smallest was from the emigrant component. CONCLUSION: By using data descriptions by data source, researchers can make decisions about which population to use in their calculations of disease frequency. PMID- 27768560 TI - Report summary Prevalence and monetary costs of dementia in Canada (2016): a report by the Alzheimer Society of Canada. AB - Dementia prevalence estimates vary among population-based studies, depending on the definitions of dementia, methodologies and data sources and types of costs they use. A common approach is needed to avoid confusion and increase public and stakeholder confidence in the estimates. Since 1994, five major studies have yielded widely differing estimates of dementia prevalence and monetary costs of dementia in Canada. These studies variously estimated the prevalence of dementia for the year 2011 as low as 340 170 and as high as 747 000. The main reason for this difference was that mild cognitive impairment (MCI) was not consistently included in the projections. The estimated monetary costs of dementia for the same year also varied, from $910 million to $33 billion. This discrepancy is largely due to three factors: (1) the lack of agreed-upon methods for estimating financial costs; (2) the unavailability of prevalence estimates for the various stages of dementia (mild, moderate and severe), which directly affect the amount of money spent; and (3) the absence of tools to measure direct, indirect and intangible costs more accurately. Given the increasing challenges of dementia in Canada and around the globe, reconciling these differences is critical for developing standards to generate reliable information for public consumption and to shape public policy and service development. PMID- 27768561 TI - Legal responses to neuroscience. PMID- 27768562 TI - Clozapine for the management of persistent catatonia. PMID- 27768563 TI - Concepts and misconceptions regarding clinical staging models. PMID- 27768564 TI - Concepts and misconceptions regarding clinical staging models : Author response. PMID- 27768565 TI - Accreditation Council for Graduate Medical Education Core Competencies at a Community Teaching Hospital: Is There a Gap in Awareness? AB - CONTEXT: Reports evaluating faculty knowledge of the Accreditation Council for Graduate Medical Education (ACGME) core competencies in community hospitals without a dedicated residency program are uncommon. OBJECTIVE: Faculty evaluation regarding knowledge of ACGME core competencies before a residency program is started. DESIGN: Physicians at the Kaiser Permanente Fontana Medical Center (N = 480) were surveyed for their knowledge of ACGME core competencies before starting new residency programs. MAIN OUTCOME MEASURES: Knowledge of ACGME core competencies. RESULTS: Fifty percent of physicians responded to the survey, and 172 (71%) of respondents were involved in teaching residents. Of physicians who taught residents and had complete responses (N = 164), 65 (39.7%) were unsure of their knowledge of the core competencies. However, most stated that they provided direct teaching to residents related to the knowledge, skills, and attitudes stated in each of the 6 competencies as follows: medical knowledge (96.3%), patient care (95.7%), professionalism (90.7%), interpersonal and communication skills (86.3%), practice-based learning (85.9%), and system-based practice (79.6%). Physician specialty, years in practice (1-10 vs > 10), and number of rotations taught per year (1-6 vs 7-12) were not associated with knowledge of the competencies (p > 0.05); however, full-time faculty (teaching 10-12 rotations per year) were more likely to provide competency-based teaching. CONCLUSION: Objective assessment of faculty awareness of ACGME core competencies is essential when starting a residency program. Discrepancy between knowledge of the competencies and acclaimed provision of competency-based teaching emphasizes the need for standardized teaching methods that incorporate the values of these competencies. PMID- 27768567 TI - Form Follows Function: A Functional Medicine Overview. PMID- 27768566 TI - Development and Application of a Plant-Based Diet Scoring System for Japanese Patients with Inflammatory Bowel Disease. AB - CONTEXT: Plant-based diets (PBDs) are a healthy alternative to westernized diets. A semivegetarian diet, a PBD, has been shown to prevent a relapse in Crohn disease. However, there is no way to measure adherence to PBDs. OBJECTIVE: To develop a simple way of evaluating adherence to a PBD for Japanese patients with inflammatory bowel disease (IBD). DESIGN: PBD scores were assigned according to the frequency of consumption provided on a food-frequency questionnaire, obtained on hospitalization for 159 patients with ulcerative colitis and 70 patients with Crohn disease. Eight items considered to be preventive factors for IBD were scored positively, and 8 items considered to be IBD risk factors were scored negatively. The PBD score was calculated from the sum of plus and minus scores. Higher PBD scores indicated greater adherence to a PBD. The PBD scores were evaluated on hospitalization and 2 years after discharge for 22 patients with Crohn disease whose dietary pattern and prognosis were established. MAIN OUTCOME MEASURE: Plant-Based Diet score. RESULTS: The PBD scores differed significantly, in descending order, by dietary type: pro-Japanese diet, mixed type, and pro westernized diet (Wilcoxon/Kruskal-Wallis test). The PBD scores in the ulcerative colitis and Crohn disease groups were 10.9 +/- 9.5 and 8.2 +/- 8.2, respectively. For patients with Crohn disease, those with long-term remission and normal C reactive protein concentration were significantly more likely to have PBD scores of 25 or greater than below 25 (chi2). CONCLUSION: The PBD score is a valid assessment of PBD dietary adherence. PMID- 27768569 TI - Refractory Depression, Fatigue, Irritable Bowel Syndrome, and Chronic Pain: A Functional Medicine Case Report. AB - INTRODUCTION: Single-disorder or single-organ-system clinical practice guidelines are often of limited usefulness in guiding effective management of patients with chronic multidimensional signs and symptoms. The presence of multiple long standing medical problems in a given patient despite intensive medical effort suggests that addressing systemic core imbalances could complement more narrowly focused approaches. CASE PRESENTATION: A 72-year-old man experiencing longstanding depression, fatigue, irritable bowel syndrome, and chronic pain in the context of additional refractory illnesses was assessed and treated, guided by a system-oriented approach to underlying core imbalances termed functional medicine. This patient was referred from a team of clinicians representing primary care, cardiology, gastroenterology, hematology, and psychology. Prior treatment had been unsuccessful in managing multiple chronic comorbidities. Diagnostic assessment included comprehensive stool and nutritional/metabolic laboratory testing. RESULTS: The blood-, urine-, or stool-based measurements of relevant markers for multiple systemic issues, including digestion/absorption, inflammation, oxidative stress, and methylation, identified previously unrecognized root causes of his constellation of symptoms. These functional measurements guided rational recommendations for dietary choices and supplementation. The patient experienced steady and significant improvement in his mental health, fatigue, chronic pain, and irritable bowel syndrome-as well as the unexpected resolution of his chronic idiopathic pancytopenia. CONCLUSION: The success in this case suggests that other patients with chronic, complex, and treatment-refractory illness may benefit from a system-oriented assessment of core imbalances guided by specialized nutritional/metabolic and digestive laboratory testing. PMID- 27768568 TI - Association of Unplanned Reintubation with Higher Mortality in Old, Frail Patients: A National Surgical Quality-Improvement Program Analysis. AB - BACKGROUND: Unplanned postoperative reintubation increases the risk of mortality, but associated factors are unclear. OBJECTIVE: To elucidate factors associated with increased mortality risk in patients with unplanned postoperative reintubation. DESIGN: Retrospective study. Patients older than 40 years who underwent unplanned reintubation from 2005 to 2010 were identified using the American College of Surgeons National Surgical Quality Improvement Program database. Multiple regression models were used to examine the impact on mortality of factors that included the modified frailty index (mFI) we developed, American Society of Anesthesiologists (ASA) score, age decile, and days to reintubation. MAIN OUTCOME MEASURE: Mortality. RESULTS: A total of 17,051 postoperative reintubations in adults were analyzed. Overall mortality was 29.4% (n = 5009). On postoperative day 1, 4434 patients were reintubated and 878 (19.8%) died. On postoperative day 7 and beyond, 6329 patients were reintubated and 2215 (35.0%) died. Increasing mFI resulted in increasing incidence of mortality (mFl of 0 = 20.5% mortality vs mFl of 0.37-0.45 = 41.7% mortality). As ASA score increased from 1 to 5, reintubation was associated with a mortality of 12.1% to 41.6%, respectively. Similarly, increasing age decile was associated with increasing incidence of mortality (40-49 years, 17.9% vs 80-89 years, 42.1%). After adjustment for confounding factors, mFI, ASA score, age decile, and increasing number of days to reintubation were independently and significantly associated with increased mortality in the study population. CONCLUSION: Among patients who underwent unplanned reintubation, older and more frail patients had an increased risk of mortality. PMID- 27768570 TI - Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. AB - INTRODUCTION: Anxiety and sleep disorders are often the result of posttraumatic stress disorder and can contribute to an impaired ability to focus and to demonstration of oppositional behaviors. CASE PRESENTATION: These symptoms were present in our patient, a ten-year-old girl who was sexually abused and had minimal parental supervision as a young child under the age of five. Pharmaceutical medications provided partial relief, but results were not long lasting, and there were major side effects. A trial of cannabidiol oil resulted in a maintained decrease in anxiety and a steady improvement in the quality and quantity of the patient's sleep. DISCUSSION: Cannabidiol oil, an increasingly popular treatment of anxiety and sleep issues, has been documented as being an effective alternative to pharmaceutical medications. This case study provides clinical data that support the use of cannabidiol oil as a safe treatment for reducing anxiety and improving sleep in a young girl with posttraumatic stress disorder. PMID- 27768571 TI - The Effect of Polyhexanide, Octenidine Dihydrochloride, and Tea Tree Oil as Topical Antiseptic Agents on In Vivo Microcirculation of the Human Skin: A Noninvasive Quantitative Analysis. AB - BACKGROUND: Antiseptics are indispensable for wound management and should focus not only on the efficacy in reducing the bacterial burden but also on how much they interfere in wound healing. In this study, the authors analyzed the direct effect of topical antiseptic agents on the microcirculation of intact human skin. METHODS: The perfusion dynamics were assessed before, and 10 minutes after, the volunteers' fingers of the right hand (n = 20) were immersed in the following solutions - octenidine dihydrochloride, polyhexanide, tea tree oil, and saline solution. The authors used the Oxygen to See (LEA Medizintechnik GmbH, Giessen, Germany) diagnostic device for noninvasive determination of oxygen supply in microcirculation of blood perfused tissues, which combines a laser light to determine blood flow, as well as white light to determine hemoglobin oxygenation and the relative amount of hemoglobin. RESULTS: Tea tree oil (÷19.0%) (B. Braun Melsungen AG, Melsungen, Germany) and polyhexanide (÷12.4%) (Lavanid, Serag Wiessner GmbH, Naila, Germany) caused a significant increase in blood flow compared to the negative control (-25.6%). Octenidine (Octenisept, Schulke & Mayr GmbH, Norderstedt, Germany) showed a nonsignificant trend towards an increase in blood flow (÷7.2%). There were alterations in the values of hemoglobin oxygenation and the relative amount of hemoglobin, but these were not significant. CONCLUSION: Perfusion is an important factor for wound healing. Therefore, it might be advantageous if antiseptic agents would increase blood flow. Tea tree oil and polyhexanide have a positive effect on skin blood flow and can therefore be used especially in critically perfused wounds, provided the adverse reactions and the antimicrobial efficacy are comparable. PMID- 27768572 TI - Evaluation of Epidermal Skin Grafts for the Treatment of Complex Wounds in a Wound Care Center: A 94-Patient Case Series. AB - BACKGROUND: In recent years, a new technology for autologous epidermal harvesting has been developed to produce epidermal skin grafts (ESGs) for use over wounds. This technology employs negative pressure and heat to raise the epidermal skin layer, allowing for consistent and reproducible epidermal harvesting. The aim of this case series is to present the authors' experience using an automated, epidermal harvesting system to produce ESGs to treat wounds of patients with multiple comorbidities. MATERIALS AND METHODS: This case series was conducted between January 1, 2013 and December 31, 2014. Patients with wounds (<= 25 cm2) that failed to heal were treated with ESGs by a group of 3 wound care physicians in 2 outpatient wound care centers in a community health center setting. RESULTS: A total of 94 patients with 102 wounds were identified. Of the 94 patients, 3 were noncompliant and 9 were lost to follow-up. Therefore, 82 patients with 90 wounds were included in the analysis. The majority of wounds demonstrated epithelialization (83/90, 92.2%). Of the 90 wounds, 75 (83.3%) healed following epidermal grafting, 4 (4.4%) wounds displayed improvement, and 11 (12.2%) did not heal. Minimal or no pain at the donor site was reported by the patients, and all donor sites healed without complications. CONCLUSION: This case series provides additional evidence for the use of ESGs for the treatment of wounds that fail to heal. PMID- 27768573 TI - The Effect of Peritoneal Prednisolone Lavage in Bacterial Peritonitis: An Experimental Study. AB - OBJECTIVE: This study investigated and compared the effects of antibiotic and steroid lavage on survival and cytokine levels in an experimental abdominal sepsis model. BACKGROUND: In abdominal sepsis, abdominal lavage with saline or antibiotic solutions is a well-documented intervention known to have positive impact on survival; however, the effects of steroid lavage in abdominal sepsis have not yet been investigated. MATERIALS AND METHODS: Ninety-six Wistar rats were divided into 4 groups (n = 24). Abdominal sepsis was induced by cecal ligation and puncture. Six hours after laparotomy, the authors performed a relaparatomy followed by cecal resection and an abdominal lavage. Abdominal lavage was performed using saline in group 1, equal volumes of cefazolin sodium in group 2, low-dose methylprednisolone (1 mg/kg) in group 3, and high-dose methylprednisolone (2 mg/kg) in group 4. After division of 2 subgroups from each of the 4 groups, the first of the rats (n = 12) were euthanized 6 hours later for evaluation of cytokines (ie, interleukin [IL] 1beta, 2, 4, 10, and tumor necrosis factor alpha [TNF-alpha]), and the others were followed for 30 days for analysis of mortality rates. RESULTS: The mortality rate of the rats in group 2 was significantly higher than group 4, which had no mortality (P = 0.032). Although insignificant, the lowest mean value of IL-1beta, IL-2, and TNF-alpha were in group 1, and the highest was in group 2. The lowest IL-4 level was in group 3, and the highest level was in group 2 (P = 0.41). Interleukin-10 levels were significantly lower in group 4 and higher in group 2 (P = 0.014). CONCLUSION: The authors state that peritoneal lavage with prednisolone improved survival rates with increasing doses in abdominal sepsis. PMID- 27768574 TI - The Hanikoda Method: 3-layered Negative Pressure Wound Therapy in Wound Bed Preparation. AB - INTRODUCTION: Negative pressure wound therapy is a widely used method of wound dressing with various commercially available brands. The authors created the Hanikoda Method (HM) for effective wound bed preparation or definite wound closure. METHODS: In this case series, the authors discuss 8 different wound cases that presented to their Plastics Unit from January 2014 to June 2015. Patients with traumatic or infected wounds were selected for treatment with the HM. Selected patients underwent multiple cycles of this method until their wounds were ready for definite wound closure or the wounds had closed by secondary closure. DISCUSSION: The purpose of any wound dressing is to encourage epithelization while ensuring no factors impede wound healing. An additional benefit is to reduce wound bed size so that it may close by secondary intention or require less skin graft coverage. Each layer of the dressing is described, along with its function in wound bed preparation or in closure. CONCLUSION: The HM facilitates reduction of wound size, wound bed preparation, and overall management. PMID- 27768575 TI - Wound Healing Effects of Quercus Brantii and Pelargonium Graveolens Extracts in Male Wistar Rats. PMID- 27768576 TI - Evidence Corner: Dressings Can Prevent Pressure Injury. PMID- 27768577 TI - Fournier's Gangrene and Negative Pressure Wound Therapy: A Case Report. AB - INTRODUCTION: Fournier's gangrene is a rare disease that affects the genital, abdominal, and perineal regions and leads to death if not treated promptly. CASE REPORT: A 42-year-old, obese woman presented to the authors' department affected by Fournier's gangrene. In order to treat her abdominal and genital regions, the authors performed a surgical debridement followed by combined therapy with antibiotics and topical negative pressure wound therapy (NPWT) with instillation plus saline solution. RESULTS: The combined therapy, but most of all the application of the NPWT, cleaned and decontaminated the wounds. As a direct result of this decontamination, after 20 days, the patient was able to undergo surgery; after 40 days of follow-up, there was no sign of recurrence. CONCLUSION: Negative pressure wound therapy can be a good and useful treatment in the therapy of serious diseases and for the wound bed preparation in advance of surgery. PMID- 27768579 TI - The Prevalence of Ostomy-related Complications 1 Year After Ostomy Surgery: A Prospective, Descriptive, Clinical Study. AB - Despite advancements in the creation and care of stomas, ostomy and peristomal skin complications are common immediately following surgery as well as in the months and years thereafter. A prospective study to determine the prevalence of ostomy and peristomal skin complications and the influence of ostomy configuration on such complications was conducted 1 year after ostomy surgery among all patients at a university hospital in Sweden. All participants received regular (10 to 14 days post discharge, 6 weeks, 3 months, 6 months, and 1 year post surgery) ostomy follow-up care by a wound ostomy continence (WOC) nurse. All consecutive elective and emergency patients who had undergone surgery to create a colostomy (end colostomy), end ileostomy, or loop ileostomy were eligible to participate. Patients who were reoperated during their first year post-surgery, patients with a urostomy, and patients with double ostomies were excluded from the study. Patient data collected included age, gender, diagnosis, elective or emergency surgery, open or laparoscopic surgical procedure, presence of a colorectal surgeon specialist at surgery, type of ostomy (colostomy, end ileostomy, loop ileostomy), preoperative ostomy siting, counseling, body mass index, American Society of Anesthesiologists classification, and radiation and/or chemotherapy status. Ostomies were evaluated by 4 WOC nurses as to stoma configuration, convexity use, patient self-sufficiency in stoma care, and complications. All 207 patients (53% women) who were eligible agreed to participate in the study. Patient median age was 70 years (range 19-94); 74% underwent elective surgery. Main diagnoses were colorectal cancer (62%) and inflammatory bowel disease (19%). Ostomy types were: colostomy (71%), end ileostomy (26%), and loop ileostomy (3%). One or more complications occurred in 35% of the patients (27% ostomy complications, 11% peristomal skin complications). A colostomy hernia was the most common surgical complication (20%), and significantly more women (69%) and emergency surgeries were noted among patients with a colostomy and an ostomy height of <=5 mm. The use of convexity was significantly more common among patients with a stoma height of <=5 mm than patients with stomas >5 mm (P = 0.016) and among patients having emergency operations than among patients having elective surgery (P = 0.045). Of the emergency surgeries, 37% had not been ostomy-sited (P <0.0001). With regular WOC nurse follow-up, the prevalence of peristomal skin complications in this population was low, and adequate ostomy height might have prevented the frequent use of convexity. Explorative studies are needed that consider differences in body configuration when determining optimal stoma height, especially for patients who require emergency surgery. PMID- 27768578 TI - A Prospective, Observational Study to Assess the Use of Thermography to Predict Progression of Discolored Intact Skin to Necrosis Among Patients in Skilled Nursing Facilities. AB - Skin temperature may help prospectively determine whether an area of skin discoloration will evolve into necrosis. A prospective, observational study was conducted in 7 skilled nursing facilities to determine if skin temperature measured using infrared thermography could predict the progression of discolored intact skin (blanchable erythema, Stage 1 pressure ulcer, or sus- pected deep tissue injury [sDTI]) to necrosis and to evaluate if nurses could effectively integrate thermography into the clinical setting. Patients residing in or presenting to the facility between October 2014 and August 2015 with a pressure related area of discolored skin determined to be blanchable erythema, a Stage 1 pressure ulcer, or sDTI and anticipated length of stay >6 days were assessed at initial presentation of the discolored area and after 7 and 14 days by facility nurses trained on camera operation and study protocol. Variables included patient demographic and clinical data, data related to the discolored area (eg, size, date of initial discovery), and temperature and appearance differences between discolored and adjacent intact skin. Skin temperatures at the discolored and adjacent areas were measured during the initial assessment. All facility pressure ulcer prevention and treatment protocols derived from evidence-based clinical practice guidelines remained in use during the study time period. Participating nurses completed a 2-part, pencil/paper survey to examine the feasibility of incorporating thermography for skin assessment into practice. Data analyses were performed using descriptive statistics (frequency analyses) and bivariate analysis (t-tests and chi-squared tests); logistic regression was used to assess associations among patient and pressure ulcer variables. Of the 67 patients studied, the overall mean age was 85 years (SD 10); 52 were women; 63 were Caucasian; and the top 3 diagnoses, accounting for 60% of the study sample, included neurologic (ie, cardiovascular acci- dent/dementia [14, 21%]), cardiac related (14, 21%), and orthopedic (13, 19%) conditions. Twenty-eight (28) participants were long-term care patients, and 39 were admitted as short-stay patients. The most frequently reported location of discolored intact skin on presentation was the heel (27, 40%). The mean temperature at the site of the discolored skin was 33.6 C (SD 3) and at the adjacent skin was 33.5 C (SD 2.5). The mean size of the areas of discoloration was 11 cm2 (SD 21). Capillary refill of the discolored area was absent on initial presentation in 49 patients (72%), and demarcation of the discolored borders was evident for 45 (66%). Of the 67 patients, 30 (45%) experienced complete resolution of the discolored area. At day 7, 8 (16%) of the remaining 50 patients in the sample exhibited skin necrosis and at day 14, a total of 12 patients of the remaining 37 (32%) exhibited skin necrosis. At day 7, skin necrosis was significantly associated with admission to a subacute unit (P = 0.01) and at day 14 to negative capillary refill at initial presentation (P = 0.02). Regardless of skin temperature, negative capillary refill at presentation was significantly associated with skin necrosis at day 7 (P = 0.04). A dichotomous variable was constructed to examine patients with cooler temperatures at the site as compared to their adjacent skin and persons with warmer skin temperatures at the center of the discolored skin for the presence of skin necrosis at both day 7 and day 14. In multivariate analysis, patients with cooler rather than warmer skin temperatures at the center of the discolored area as compared to the adjacent skin were more likely to develop necrosis by day 7 (OR 18.8; P = 0.05; CI: 104-342.44). Participating nurses were uncertain about the feasibility of integrating thermography into practice. Larger prospective studies with more heterogeneous samples are needed to determine the validity of skin temperature measurement as a predictor of skin necrosis and the utility of implementing thermography into clinical practice. PMID- 27768580 TI - A Cross-sectional Study to Determine Whether Adjustment to an Ostomy Can Predict Health-related and/or Overall Quality of Life. AB - Ostomy-specific adjustment may or may not predict health-related quality of life (HRQoL) and/or overall quality of life (QoL). A cross-sectional study was conducted among patients recruited from the customer registers of 8 surgical suppliers and pharmacies across Norway between November 2010 and March 2011 to determine which of the 34 items of the Ostomy Adjustment Scale (OAS) are the strongest predictors for HRQoL and overall QoL and to determine the HRQoL and overall QoL of individuals with an ostomy compared to a control group representing the general population. Persons who were >18 years old; had a permanent colostomy, ileostomy, or urostomy for >3 months; and could read and write Norwegian were invited to participate. The participants received information about the study in a letter from the researcher and returned their demographic information (addressing gender, age, marital status, education, diagnosis, time since surgery, and ostomy type) and study questionnaires using prepaid envelopes. The 158 participants (mean age 64 years [range 29-91], 89 [56%] men and 69 [44%] women) completed and returned by mail a sociodemographic questionnaire, the 34-item OAS (questions scored on a scale of 1 to 6, totally disagree to totally agree, score range 34 to 204), the Short Form-36 (SF-36, including 2 main components [physical and mental issues] divided into 8 subscales, scored from 0 to 100), and the 16-item Quality of Life Scale (QOLS) instrument (each response scored 1 to 7, from very dissatisfied to very satisfied; total score ranging from 16 to 112). Statistical analysis, including ordinary least square regression analyses, assessed whether the OAS independently predicted the sum scores of the SF-36 (physical component summary [PCS] and mental component summary [MCS]) and the QOLS score after adjusting for age, gender, marital status, education, diagnosis, time since surgery, and ostomy type. The OAS significantly predicted the SF-36 (PCS and MCS) and QOLS scores (P <0.001). Five (5) OAS items ("living a fulfilling life," "being free to travel where I want despite my ostomy," "realizing that this ostomy will be there forever," "worries about being left alone," and "embarrassing accidents in sexual activities") strongly predicted the composite score of the SF-36 (PCS and MCS) and QOLS measurements. The SF-36 scores in physical role functioning, general health, vitality, and MCS were lower in ostomy patients than controls (P < 0.05), whereas no difference was found for QOLS. Overall, ostomy-specific adjustment may be an important predictor of HRQoL and overall QoL, with the OAS factors described above having greater influence. More research such as prospective cohort studies are needed regarding patient adjustment to an ostomy. PMID- 27768581 TI - The structural and functional changes of blood cells and molecular components in diabetes mellitus. AB - It is known fact that diabetes mellitus (DM) affects blood cells. Changes in the erythrocyte membrane, disorder in hemoglobin oxygen-binding and modification in mechanical characteristics, are effects of hyperglycemia on red blood cells. Altered susceptibility infection of patients with diabetes has been ascribed to a depression in the function of polymorphonuclear leukocytes. Neutrophil function in patients with diabetes with good glucose control is slightly different than in healthy ones. DM causes significant changes in lymphocytes metabolism and their functions. Patients with diabetes, presenting with acute coronary syndrome, are at higher risk of cardiovascular complications and recurrent ischemic events in comparison to non-diabetic counterparts. Various mechanisms, including endothelial dysfunction, platelet hyperactivity, and abnormalities in coagulation and fibrynolysis have been implicated for this increased atherothrombotic risk. There are many other alterations of blood cells due to DM. In the present review we focused on modifications of blood cells due to DM. Then, as a second point, we explored how the changes affect functions of red blood cells, white blood cells and platelets. PMID- 27768582 TI - Pitfalls of analysis of circulating miRNA: role of hematocrit. PMID- 27768583 TI - Factors that promote and impede other-sex friendships: a qualitative study of Iranian adolescent girls. AB - AIM: The aim of this study was to identify factors that promote and impede other sex (OS) friendships in adolescent girls. METHODS: A qualitative study conducted with 20 adolescent girls recruited in public places in Tehran, Iran. Information was collected through semi-structured interviews and coded via the conventional qualitative content analysis approach. RESULTS: Four factors were identified that appeared to promote entry into OS friendships. These factors include (a) a poor understanding of perceived risks, (b) weak religious beliefs, (c) processes of identity formation, and (d) low self-esteem. In addition, six factors appeared to impede entry into these friendships: (a) self-confidence, (b) prioritizing education, (c) maintaining particular entertainment preferences, (d) awareness of prior unpleasant experiences with boys, (e) having strong religious convictions, and (f) shaming from significant others. CONCLUSION: These findings provide unique insights into the factors that stem from different levels of social complexity, which affect participation in a fundamental form of human experience. PMID- 27768584 TI - Maternal complications in settings where two-thirds of extremely preterm births are delivered by cesarean section. AB - OBJECTIVE: To investigate the maternal complications associated with cesarean section (CS) in the extremely preterm period according to the gestational week (GW) and to indication of delivery. STUDY DESIGN: This is a retrospective case referent study with a review of medical records of women who delivered at 22-27 weeks of gestation (n=647) at two level III units in Sweden. For abdominal delivery, gestational length was stratified into 22-24 (n=105) and 25-27 (n=301) weeks. For comparison, data on women who underwent a CS at term were identified in a register-based database. RESULTS: The rate of CS in extremely preterm births was 62.8%. There was no difference in the complication rates, but types of incisions other than the low transverse incision were required more often at 22 24 (18.1%) weeks than at 25-27 GWs (9.6%) (P=0.02). Major maternal complications occurred in 6.6% compared with 2.1% in the extremely preterm and term CS, respectively (P<0.01). A maternal indication of extremely preterm CS increased the risk of complications. CONCLUSIONS: Almost two-thirds of the births at 22-27 GWs had an abdominal delivery. No increase in short-term morbidity was observed at 22-24 weeks compared to 25-27 weeks. CS performed extremely preterm had more major complications recorded than cesarean at term. The complications are driven by the underlying maternal condition. PMID- 27768586 TI - The chemical composition, antimicrobial, and antioxidant activities of Pycnocycla spinosa and Pycnocyla flabellifolia essential oils. AB - The purpose of our study was to compare the chemical compositions and antimicrobial and antioxidant activities of Pycnocycla spinosa and Pycnocycla flabellifolia essential oils. cis-Asarone (62.5%) and widdra-2,4(14)-diene (9%) were the main components of P. spinosa aerial part essential oil, while elemicin (60.1%) and caryophyllene oxide (9.8%) were the main components of P. spinosa seed essential oil. alpha-Phellandrene (25.5%), p-cymene (15.3%), and limonene (13.3%) were found in P. flabellifolia essential oil. The inhibition zone diameters for P. flabellifolia essential oil were significantly higher than for the two other essential oils from P. spinosa (p<0.05). In broth dilution assay (uL/mL), the sensitive microorganism to Pycnocycla sp. (P. spinosa, P. flabellifolia) was Aspergillus niger, followed by Candida albicans. In 2,2 diphenyl-1-picrylhydrazyl (DPPH) system, P. spinosa aerial parts essential oil (IC50=548 ug/mL) had higher antioxidant activity than that of two other essential oils. PMID- 27768587 TI - Antiproliferative effect of synthetic cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against human cancer cell lines. AB - This work describes the antiproliferative potential of 14 cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against several human cancer cell lines. The antiproliferative effect was evaluated using the sulforhodamine B assay. Although some compounds from methylphtalimide and carboxylic acid phtalimide classes exhibited a selective antiproliferative activity, the itaconimides (11-14) exhibited the best results, especially compound 14, which presented a TGI (concentration that produces total growth inhibition) value of 0.0043 MUM against glioma (U251), being inactive against the non-tumor cell line (HaCat). Absorption, distribution, metabolism and excretion in silico evaluations suggest that these compounds are promising candidates. PMID- 27768585 TI - Future of environmental research in the age of epigenomics and exposomics. AB - Environmental research and public health in the 21st century face serious challenges such as increased air pollution and global warming, widespread use of potentially harmful chemicals including pesticides, plasticizers, and other endocrine disruptors, and radical changes in nutrition and lifestyle typical of modern societies. In particular, exposure to environmental and occupational toxicants may contribute to the occurrence of adverse birth outcomes, neurodevelopmental deficits, and increased risk of cancer and other multifactorial diseases such as diabetes and asthma. Rapidly evolving methodologies of exposure assessment and the conceptual framework of the Exposome, first introduced in 2005, are new frontiers of environmental research. Metabolomics and adductomics provide remarkable opportunities for a better understanding of exposure and prediction of potential adverse health outcomes. Metabolomics, the study of metabolism at whole-body level, involves assessment of the total repertoire of small molecules present in a biological sample, shedding light on interactions between gene expression, protein expression, and the environment. Advances in genomics, transcriptomics, and epigenomics are generating multidimensional structures of biomarkers of effect and susceptibility, increasingly important for the understanding of molecular mechanisms and the emergence of personalized medicine. Epigenetic mechanisms, particularly DNA methylation and miRNA expression, attract increasing attention as potential links between the genetic and environmental determinants of health and disease. Unlike genetics, epigenetic mechanisms could be reversible and an understanding of their role may lead to better protection of susceptible populations and improved public health. PMID- 27768588 TI - Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T DM1. AB - BACKGROUND: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. RESULTS: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. MATERIALS AND METHODS: SK-BR-3, NCI-N87, BT-474, MDA MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. CONCLUSIONS: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo. PMID- 27768590 TI - Prognostic role of extracellular matrix metalloproteinase inducer/CD147 in gastrointestinal cancer: a meta-analysis of related studies. AB - The prognostic role of Extracellular matrix metalloproteinase inducer (EMMPRIN/ CD147) in gastrointestinal cancer remains controversial. We systematically reviewed the evidence of assessment of CD147 expression in gastrointestinal cancer to help clarify this issue. Pubmed, Embase, Cochrane Library and Web of Science databases were searched to identify eligible studies to evaluate the association of CD147 expression and disease-free and overall survival of gastrointestinal cancer. Hazard ratios (HRs) were pooled to estimate the effect. CD147 overexpression was significantly correlated with poor disease-free survival (HR 2.38, 95% CI 1.43-3.97) and overall survival (HR 1.64, 95% CI 1.25-2.14) of cancer patients. Furthermore, CD147 overexpression was significantly association with TNM stage (TIII/TIV vs TI/TII: OR 3.60, 95% CI 1.85-7.01), the depth of invasion (T3/T4 vs T1/T2: OR 2.04, 95% CI 1.25-3.33), lymph node metastasis (positive vs negative: 2.35, 95% CI 1.14-4.86), distant metastasis (positive vs negative: OR 4.78, 95% CI 1.43-16.00). Our analyses demonstrate that CD147 was effectively predictive of worse prognosis in gastrointestinal cancer. Moreover, Identifying CD147 may help identify new drug targets for cancer therapy. PMID- 27768589 TI - Nucleotide excision repair pathway gene polymorphisms are linked to breast cancer risk in a Chinese population. AB - Polymorphisms in nucleotide excision repair (NER) pathway genes are associated with the risk of breast cancer, but the relevance of these associations appeared to vary according to the ethnicity of the subjects. To systemically evaluate the potential associations between NER polymorphisms and breast cancer risk in a Chinese population, we carried out a case-control study on 450 breast cancer patients and 430 healthy controls. Sequenom MassARRAY was used for genotyping, and immunohistochemistry was performed to detect estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression in tumor tissue. Our results showed that ERCC1 rs11615 (additive model: ORadjusted: 1.36, 95% CI: 1.08-1.71, p = 0.009), XPC rs2228000 (additive model: ORadjusted: 1.39, 95% CI: 1.13-1.72, p = 0.002) and ERCC2/XPD rs50872 (additive model: ORadjusted: 1.32, 95% CI: 1.04-1.67, p = 0.021) were associated with an increased risk of breast cancer. Stratified analysis revealed three polymorphisms (rs11615, rs1800975, and rs50872) to be associated with breast cancer in menopausal females. Three polymorphisms were associated with specific breast cancer grades (rs11615 with grade 3, rs2228000 and rs50872 with grade 1 2). Two polymorphisms (rs2228001 and rs50872) were associated with the risk of breast cancer with negative lymph node involvement. rs1800975 and rs50872 were associated with the risk of ER- and PR- breast cancer, whereas rs11615 was associated with the risk of ER+ and PR+ breast cancer. We found that carriers of the T allele of ERCC1 rs11615, XPC rs2228000 and rs50872, particularly in postmenopausal females, have an increased risk of breast cancer. PMID- 27768591 TI - Preclinical evaluation of the safety and pathogenicity of a live attenuated recombinant influenza A/H7N9 seed strain and corresponding MF59-adjuvanted split vaccine. AB - Developing a safe and effective H7N9 influenza vaccine was initiated in early spring 2013, following human infections with a novel avian influenza A (H7N9) virus. In this study, a candidate H7N9 vaccine seed strain is produced using reverse genetics, with HA and NA derived from a human H7N9 virus and the remaining genes from the PR8 backbone virus which grows well in eggs. We verified that the virulence and transmissibility of the recombinant H7N9 vaccine seed strain were decreased as compared to wild-type H7N9 virus, to levels comparable with PR8. Using the seed virus, we produced a monovalent split influenza A (H7N9) MF59-adjuvanted vaccine that was immunogenic in mice. Our H7N9 vaccine is selected for clinical investigation and potential human use. To assess the safety of our H7N9 vaccine, we performed acute toxicity, repeated dose toxicity and active systemic anaphylaxis tests. Our results showed that, under the conditions used in this study, the NOEAL (no obvious adverse effect level) was 30 MUg/0.5 mL. PMID- 27768592 TI - Genetic polymorphisms in leptin, adiponectin and their receptors affect risk and aggressiveness of prostate cancer: evidence from a meta-analysis and pooled review. AB - Leptin and adiponectin signaling was associated with development and progression of various cancers. The present study aimed to clarify the role of genetic variants in leptin, adiponectin and their receptors in prostate cancer. After comprehensive search and manuscript scanning, a total of 49 genetic variants were enrolled and examined for their relations to cancer risk and aggressiveness. In the meta-analysis, LEP rs7799039 (allele contrast: OR 1.133, 95%CI 1.024-1.254), ADIPOQ rs2241766 (allele contrast: OR 1.201, 95%CI 1.015-1.422) and ADIPOR1 rs10920531 (allele contrast: OR 1.184, 95%CI 1.075-1.305) variants were identified to be correlated with increased risk of prostate cancer. On the contrary, LEPR rs1137101 (allele contrast: OR 0.843, 95%CI 0.730-0.973) and ADIPOR1 rs2232853 (allele contrast: OR 0.638, 95%CI 0.535-0.760) variants were associated with decreased risk of prostate cancer. From the pooled-review, we additionally recognized eight variants associated with cancer risk and another eight variants associated with cancer aggressiveness, respectively. These observations indicated important roles of leptin, adiponectin and their receptors in the development and progression of prostate cancer. The identified polymorphisms might assist in developing better risk-assessment tools, as well as generating novel targeted therapies, especially for obese cancer patients with impaired leptin and adiponectin signaling. PMID- 27768593 TI - Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma. AB - The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS 4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin alphavbeta3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the alphavbeta3 overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of gammaH2A.X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the alphavbeta3 integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma. PMID- 27768594 TI - Hepatitis B virus X protein influences enrichment profiles of H3K9me3 on promoter regions in human hepatoma cell lines. AB - We previously showed that hepatitis B virus (HBV) X protein (HBx) could promote the trimethylation of histone H3 lysine 9 (H3K9me3) to repress tumor suppressor genes in hepatocellular carcinoma (HCC). In this work, we analyze 23,148 human promoters using ChIP-chip to determine the effects of HBx on H3K9me3 enrichments in hepatoma cells with transfection of HBx-expressing plasmid. Immunohistochemistry for HBx and H3K9me3 was performed in 21 cases of HBV associated HCC tissues. We identified that H3K9me3 immunoreactivity was significantly correlated with HBx staining in HCC tissues. ChIP-chip data indicated that HBx remarkably altered promoter enrichments of H3K9me3 in hepatoma cells. We identified 25 gene promoters, whose H3K9me3 enrichments are significantly altered in hepatoma cells transfected HBx-expressing plasmid, including 19 gaining H3K9m3, and six losing this mark. Most of these genes have not been previously reported in HCC, and BTBD17, MIR6089, ZNF205-AS1 and ZP1 have not previously been linked to cancer; only two genes (DAB2IP and ZNF185) have been reported in HCC. Genomic analyses suggested that genes with the differential H3K9me3 enrichments function in diverse cellular pathways and many are involved in cancer development and progression. PMID- 27768595 TI - Is senescence-associated beta-galactosidase a marker of neuronal senescence? AB - One of the features of cellular senescence is the activity of senescence associated- beta-galactosidase (SA-beta-gal). The main purpose of this study was to evaluate this marker of senescence in aging neurons. We found that cortical neurons exhibited noticeable SA-beta-gal activity quite early in culture. Many SA beta-gal-positive neurons were negative for another canonical marker of senescence, namely, double-strand DNA breaks (DSBs). Moreover, DDR signalling triggered by low doses of doxorubicin did not accelerate the appearance of neuronal SA-beta-gal. In vivo, we observed pronounced induction of SA-beta-gal activity in the hippocampus of 24-month-old mice, which is consistent with previous findings and supports the view that at this advanced age neurons developed a senescence-like phenotype. Surprisingly however, relatively high SA beta-gal activity, probably unrelated to the senescence process, was also observed in much younger, 3-month-old mice. In conclusion, we propose that SA beta-gal activity in neurons cannot be attributed uniquely to cell senescence either in vitro or in vivo. Additionally, we showed induction of REST protein in aging neurons in long-term culture and we propose that REST could be a marker of neuronal senescence in vitro. PMID- 27768597 TI - Celastrol increases osteosarcoma cell lysis by gammadelta T cells through up regulation of death receptors. AB - gammadelta T cells has been shown to exhibit profound antitumor effects in a broad range of tumor entities, including OS. However, resistance to gammadelta T cells is a serious problem in the management of OS. This study investigates the impact of celastrol on the expression of death receptors 4/5 (DR4/5) on OS cell lines (HOS, U2OS) and cancer cell lysis by gammadelta T cells. The results showed that celastrol increased transcription of DR4/5 in HOS and U2OS, leading to increased cell surface, and total DR4/5 protein expression. Celastrol sensitizes OS cell lines or autologous OS cells to healthy donors-derived or OS patient derived gammadelta T cell cytotoxicity in vitro. The induction of DR4/5 molecules increased lysis of HOS and U2OS by gammadelta T cells which was abolished by addition of a blocking TRAIL antibody. Importantly, the cytotoxic activity of gammadelta T cells was unaltered by small-dose celastrol. Taken together, our data show that celastrol up-regulated DR4/5 on OS cells to be responsible for intercellular TRAIL/APO-2L crosslink that confers increased cancer cell lysis by gammadelta T cells. These results suggest the clinical evaluation of celastrol in OS, especially in combination with immunotherapy approaches employing adoptive gammadelta T cell transfer. PMID- 27768596 TI - Elevated expression of ZNF217 promotes prostate cancer growth by restraining ferroportin-conducted iron egress. AB - Although we and other studies indicated ZNF217 expression was increased in prostate cancer (PCa), the factors mediating its misregulated expression and their oncogenic activity remain largely unexplored. Recent evidence demonstrated that ferroportin (FPN) reduction lead to decreased iron export and increased intercellular iron that consequently aggravates the oncogenic effects of iron. In the present study, ZNF217 was identified as a transcriptional repressor that inhibits FPN expression. Increased of ZNF217 expression led to decreased FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth. In contrast, decreased of ZNF217 expression restrained tumor cell growth by promoting FPN driven iron egress. Mechanistic investigation manifested that ZNF217 facilitated the H3K27me3 levels of FPN promoter by interacting with EZH2. Besides, we also found that MAZ increased the transcription level of ZNF217, and subsequently inhibited the FPN expression and their iron-related activities. Strikingly, the expression of MAZ, EZH2 and ZNF217 were concurrently upregulated in PCa, leading to decreased expression of FPN, which induce disordered iron metabolism. Collectively, this study underscored that elevated expression of ZNF217 promotes prostate cancer growth by restraining FPN-conducted iron egress. PMID- 27768600 TI - Transport properties of a quantum dot-mediated fractional Josephson junction. AB - We consider a model of a Josephson junction mediated by a quantum dot. An additional normal electrode coupled to the dot allows its density of states to be probed. The junction is made out of two topological superconducting wires with Majorana end states. The two of them, on each side and in the proximity of the junction, convert into a Dirac fermion inside the dot. It is shown that both the density of states of the dot and the phase-biased current through the junction can exhibit [Formula: see text] periodicity in the superconducting phase difference, when the particle-hole symmetry of the junction is broken. It is realized by detuning of the dot level from the Fermi level by the gate voltage. The width of zero-bias peak in differential conductance, produced by an unpaired Majorana state, also possesses [Formula: see text] periodicity under this condition. PMID- 27768598 TI - Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface. AB - BACKGROUND: Although most triple-negative breast cancer (TNBC) patients initially respond to chemotherapy, residual tumor cells frequently persist and drive recurrent tumor growth. Previous studies from our laboratory and others' indicate that TNBC is heterogeneous, being composed of chemo-sensitive and chemo-resistant tumor cell subpopulations. In the current work, we studied the invasive behaviors of chemo-resistant TNBC, and sought to identify markers of invasion in chemo residual TNBC. METHODS: The invasive behavior of TNBC tumor cells surviving short term chemotherapy treatment in vitro was studied using transwell invasion assays and an experimental metastasis model. mRNA expression levels of neural cadherin (N-cadherin), an adhesion molecule that promotes invasion, was assessed by PCR. Expression of N-cadherin and its precursor form (pro-N-cadherin) was assessed by immunoblotting and flow cytometry. Pro-N-cadherin immunohistochemistry was performed on tumors obtained from patients pre- and post- neoadjuvant chemotherapy treatment. RESULTS: TNBC cells surviving short-term chemotherapy treatment exhibited increased invasive behavior and capacity to colonize metastatic sites compared to untreated tumor cells. The invasive behavior of chemo-resistant cells was associated with their increased cell surface expression of precursor N-cadherin (pro-N-cadherin). An antibody specific for the precursor domain of N-cadherin inhibited invasion of chemo-resistant TNBC cells. To begin to validate our findings in humans, we showed that the percent cell surface pro-N cadherin (+) tumor cells increased in patients post- chemotherapy treatment. CONCLUSIONS: TNBC cells surviving short-term chemotherapy treatment are more invasive than bulk tumor cells. Cell surface pro-N-cadherin expression is associated with the invasive and chemo-resistant behaviors of this tumor cell subset. Our findings indicate the importance of future studies determining the value of cell surface pro-N-cadherin as: 1) a biomarker for TNBC recurrence and 2) a therapeutic target for eliminating chemo-residual disease. PMID- 27768601 TI - Magnetic control of dipolaritons in quantum dots. AB - Dipolaritons are quasiparticles that arise in coupled quantum wells embedded in a microcavity, they are a superposition of a photon, a direct exciton and an indirect exciton. We propose the existence of dipolaritons in a system of two coupled quantum dots inside a microcavity in direct analogy with the quantum well case and find that, despite some similarities, dipolaritons in quantum dots have different properties and can lead to true dark polariton states. We use a finite system theory to study the effects of the magnetic field on the system, including the emission, and find that it can be used as a control parameter of the properties of excitons and dipolaritons, and the overall magnetic behaviour of the structure. PMID- 27768599 TI - A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis. AB - Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/beta-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter beta catenin nuclear localization and directly suppress beta-catenin/TCF mediated transcriptional activity. We treated VDR null mice with the carcinogen azoxymethane (AOM) and generated mice bearing a mutated APC (hypomorph) on a VDR null background (Apc1638N/+Vdr-/-). VDR null mice do not develop GI or extra colonic tumors but loss of VDR decreased intestinal tumor latency and increased progression to adenocarcinoma in both models. AOM treatment of VDR null mice also caused squamous cell carcinoma of the anus. Although levels and distribution of total or activated beta-catenin in the epithelial component of tumors were unaffected by loss of VDR, beta-catenin dependent cyclin D1 expression was affected suggesting a direct VDR effect on beta-catenin co-activator activity. Extra-colonic mucosa manifestations in Apc1638N/+Vdr-/- animals included increased nuclear beta-catenin in submucosal stromal cells, spleno- and cardiomegaly and large epidermoid cysts characteristic of the FAP variant, Gardner's syndrome. Consistent with this, SNPs in the VDR, vitamin D binding protein and CYP24 as well as mutations in APC distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner's syndrome, as well as in the etiology of anal cancer. PMID- 27768602 TI - Crossover from magnetostatic to exchange coupling in La0.67Ca0.33MnO3/YBa2Cu3O7/La0.67Ca0.33MnO3 heterostructures. AB - The influence of YBa2Cu3O7 (YBCO) superconductor layer (S-layer) with a varying thickness d YBCO = 20-50 nm on the magnetic coupling between two La0.67Ca0.33MnO3 (LCMO) ferromagnet layers (F-layer, thickness d LCMO = 50 nm) in F/S/F heterostructures (HSs) was investigated by measuring global magnetization (M) in a temperature (T) range = 2-300 K and a magnetic field (H) range = 0-10 kOe. All the HSs were superconducting with the critical temperature (T C) decreasing from = 78 to 36 K with decrease in d YBCO, whereas the ferromagnetic ordering temperature T M = 250 K did not change much. Systematically measured M-H loops of all HSs at both T > T C and T < T C show three main results (a) the two step magnetic reversal above T C converts into a four step reversal below T C in HSs with d YBCO ? 30 nm, (b) the magnitude and magnetic field corresponding to the additional two switching steps show characteristic evolution with T and d YBCO; and (c) the HS with d YBCO = 20 nm shows radically different behaviour, where the two step magnetic reversal above T C continues to persist below T C and converts into a single step reversal at T [Formula: see text] T C. The first two results indicate magnetostatic coupling between the magnetic domains and the vortices across the two F/S interfaces resulting in reversal dynamics different from that deep within the LCMO layers. Whereas, the result 'c' reveals indirect exchange coupling between LCMO layers through the superconducting YBCO layer, which is a clear experimental evidence of coexistence of ferromagnetism and superconductivity in nm scale F/S/F HSs expected theoretically by Sa de Melo (2003 Physica C 387 17-25). PMID- 27768603 TI - Hofstadter butterfly in the Falicov-Kimball model on some finite 2D lattices. AB - Spinless, interacting electrons on a finite size triangular lattice moving in an extremely strong perpendicular magnetic field are studied in comparison to a square lattice. Using a Falicov-Kimball model, the effects of Coulomb correlation, magnetic field and finite system size on their energy spectrum are observed. Exact diagonalization and Monte Carlo simulation methods (based on a modified Metropolis algorithm) have been employed to examine the recursive structure of the Hofstadter spectrum in the presence of several electronic correlation strengths for different system sizes. It is possible to introduce a gap in the density of states even in the absence of electron correlation, which is anticipated as a metal to insulator transition driven by an orbital magnetic field. With further inclusion of the interaction, the gap in the spectrum is modified and in some cases the correlation is found to suppress extra states manifested by the finite size effects. At a certain flux, the opened gap due to magnetic field is reduced by the Coulomb interaction. An orbital current is calculated for both the square and the triangular lattice with and without electron correlation. In the non-interacting limit, the bulk current shows several patterns, while the edge current shows oscillations with magnetic flux. The oscillations persist in the interacting limit for the square lattice, but not for the triangular lattice. PMID- 27768604 TI - Ferrimagnetism in delta chain with anisotropic ferromagnetic and antiferromagnetic interactions. AB - We consider analytically and numerically an anisotropic spin-[Formula: see text] delta-chain (sawtooth chain) in which exchange interactions between apical and basal spins are ferromagnetic and those between basal spins are antiferromagnetic. In the limit of strong anisotropy of exchange interactions this model can be considered as the Ising delta chain with macroscopic degenerate ground state perturbed by transverse quantum fluctuations. These perturbations lift the ground state degeneracy and the model reduces to the basal XXZ spin chain in the magnetic field induced by static apical spins. We show that the ground state of such a model is ferrimagnetic. The excitations of the model are formed by ferrimagnetic domains separated by domain walls with a finite energy. At low temperatures the system is effectively divided into two independent subsystems, the apical subsystem described by the Ising spin-[Formula: see text] chain and the basal subsystem described by the XXZ chain with infinite zz interactions. PMID- 27768605 TI - A 50/50 electronic beam splitter in graphene nanoribbons as a building block for electron optics. AB - Based on the investigation of the multi-terminal conductance of a system composed of two graphene nanoribbons, in which one is on top of the other and rotated by [Formula: see text], we propose a setup for a 50/50 electronic beam splitter that neither requires large magnetic fields nor ultra low temperatures. Our findings are based on an atomistic tight-binding description of the system and on the Green function method to compute the Landauer conductance. We demonstrate that this system acts as a perfect 50/50 electronic beam splitter, in which its operation can be switched on and off by varying the doping (Fermi energy). We show that this device is robust against thermal fluctuations and long range disorder, as zigzag valley chiral states of the nanoribbons are protected against backscattering. We suggest that the proposed device can be applied as the fundamental element of the Hong-Ou-Mandel interferometer, as well as a building block of many devices in electron optics. PMID- 27768607 TI - Procedural Pain in Palliative Care: Is It Breakthrough Pain? A Multicenter National Prospective Study to Assess Prevalence, Intensity, and Treatment of Procedure-related Pain in Patients With Advanced Disease. AB - OBJECTIVE: To assess the prevalence of breakthrough pain (BTP) provoked by 6 common procedures in patients with advanced disease. METHODS: A prospective, cross-sectional, multicenter, national study was performed in 23 palliative care units in Italy. Patients were recruited if they were undergoing one of the following procedures as part of normal care: turning, personal hygiene care, transfer from bed to chair, bladder catheterization, pressure ulcer care, and subcutaneous drug administration. The Numerical Rating Scale was used to measure pain intensity before, during, and after the procedure. RESULTS: One thousand seventy-nine eligible patients were enrolled: 49.7% were male and their mean age was 78.0+/-11.2 years. Of all patients, 20.9% had experienced a BTP episode within the 24 hours before recruitment. The overall prevalence of procedure induced BTP was 11.8%, and the mean intensity score (Numeric Rating Scale) was 4.72+/-1.81. Notably, patients experienced a significant increase in pain intensity during all procedures (P<0.0001). A small proportion of patients (12.7%) received analgesics before undergoing any of the procedures, and almost none (1.7%) received analgesics during the procedures to alleviate acute pain. DISCUSSION: Our findings highlight that simple daily care procedures can lead to BTP among patients with advanced disease. Because such procedures are performed very often during palliative care, more individualized attention to procedural pain control is necessary. Additional research on procedural pain in patients with advanced disease should be encouraged to provide further evidence-based guidance on the use of the available medication for predictable pain flares. PMID- 27768606 TI - Comparison of survival with somatostatin analog and chemotherapy and prognostic factors for treatment in 165 advanced neuroendocrine tumor patients with Ki-67 20% or less. AB - The objectives of this study were to compare progression-free survival (PFS) with somatostatin analog (SSA) versus chemotherapy (CTx) in first-line therapy and to determine the patient group in which these treatments were more effective in neuroendocrine tumors (NETs) with a Ki-67 index of 20% or less. Patients who received SSA or CTx and had unresectable locally advanced and metastatic NETs with a Ki-67 index of 20% or less were retrospectively selected from 13 centers in the Turkish database between 2000 and 2015. One hundred and sixty-five patients were enrolled. The median age was 56 years and the male-to-female ratio was 1.09. Seventy-four (45%) patients were of grade 1 NET and 91 (55%) were of grade 2. SSA was given to 104 patients, whereas 61 were treated with CTx. The objective response rate after SSA was 15.4%; another 73.1% had stable disease. The objective response rate after CTx was 36.1%, and 40.9% had stable disease (P=0.008). The median PFS in SSA patients was 21 months (95% confidence interval: 12.4-29.6), and 8 months for CTx (95% confidence interval: 5.5-10.6) (P<0.001). There was no significant difference between PFS of receiving SSA and CTx in pancreatic neuroendocrine tumor (PNET) patients; however, the PFS of receiving SSA was longer in non-PNET patients (P<0.001). SSA was better treatment in advanced NET patients with a Ki-67 index of less than 5%, having a primary resected and a performance status of 0 (P<0.05). SSA may be preferred over CTx in advanced NET patients with low-to-intermediate grade. PMID- 27768608 TI - Testing the Interpersonal Theory of Suicide in Chronic Pain. AB - OBJECTIVE: The interpersonal theory of suicide offers a conceptual framework for understanding suicidal ideation (SI) that may be applicable to individuals with chronic pain. The theory emphasizes the importance of 2 interpersonal constructs as precursors to SI: perceived burdensomeness (the belief that one has become a burden to others) and thwarted belongingness (a lack of social integration or connection). Our objective was to test the interpersonal theory of suicide in people with chronic pain. METHODS: Hierarchical regression analysis was used in a cross-sectional study of 282 patients of an interdisciplinary pain clinic. The Beck Scale for Suicide Ideation was the criterion measure of SI, and independent variables included both general and pain-specific predictors. RESULTS: After adjusting for other known or putative risk factors related to pain and mental health, perceived burdensomeness significantly predicted SI, whereas thwarted belongingness did not. As expected according to theory, the interaction between perceived burdensomeness and thwarted belongingness was also significant; perceived burdensomeness was a strong predictor of SI at high levels of thwarted belongingness, but only marginally at low levels. Other independent predictors were male sex, number of prior suicide attempts, and hopelessness. DISCUSSION: These findings are in line with some, but not all, of the major predictions of the interpersonal theory of suicide. In general, however, they support the relevance of the theory for individuals with chronic pain. PMID- 27768609 TI - Long-chain omega-6 plasma phospholipid polyunsaturated fatty acids and association with colon adenomas in adult men: a cross-sectional study. AB - Dietary lipid intake can be associated with an increased risk for colorectal cancer depending on its composition. Carcinogenesis alters lipid metabolism to facilitate cell growth and survival. For instance, metabolites of polyunsaturated fatty acids (PUFAs) are associated with increasing colon cell proliferation. Moreover, precancerous colon lesions (i.e. adenomas) increase the risk for colorectal cancer. In this study, we investigated associations between plasma PUFAs and the number of colon polyps and polyp type (i.e. hyperplastic and adenoma). Healthy male participants (n=126) of 48-65 years of age were recruited before a routine colonoscopy screening. Plasma phospholipid (PPL) PUFAs were isolated by means of solid phase extraction and methylated. Fatty acid methyl esters were analyzed using gas chromatography. Factor analysis was used to cluster PUFAs into groups, and then generated factors and individual PUFAs were analyzed using polytomous logistic regression. In our age-adjusted and smoking adjusted polytomous logistic regression, for each unit increase in PPL docosatetraenoic acid (DTA), individuals were 1.43 (1.00-2.06) and 1.33 (0.99 1.80) times more likely to have hyperplastic polyps and adenomas rather than no polyps, respectively. In our factor analysis, high PPL omega-6 PUFA and trans fatty acid loading scores were associated with increased odds of adenoma presence rather than no polyps. Increases in long-chain PPL omega-6 PUFAs are associated with an increased risk for adenomas. As relative levels of DTA increase in PPLs, individuals had increased odds of having hyperplastic polyps and adenomas. Elevated conversion of omega-6 PUFAs to longer-chain omega-6s such as DTA may indicate altered PUFA metabolism at the tissue level. PMID- 27768610 TI - Biologic and Synthetic Grafts in the Reconstruction of Large to Massive Rotator Cuff Tears. AB - Rotator cuff injuries are common in both young and elderly patients. Despite improvements in instrumentation and surgical techniques, the failure rates following tendon reconstruction remain unacceptably high. To improve outcomes, graft patches have been developed to provide mechanical strength and to furnish a scaffold for biologic growth across the delicate tendon-bone junction. Although no patch effectively re-creates the structured, highly organized system of prenatal tendon development, augmenting rotator cuff repair may help restore native tendon-to-bone attachment while reproducing the mechanical and biologic properties of native tendon. An understanding of biologically and synthetically derived grafts, along with knowledge of the preliminary data available regarding their combined use with growth factors and stem cells, is needed to improve management and treatment outcomes. The current literature has not been consistent in showing patch augmentation to be beneficial over traditional repair, but novel scaffolding materials may help facilitate rotator cuff tendon repair that is histologically and biomechanically comparable to native tendon. PMID- 27768611 TI - Spectral Ripple Discrimination in Normal-Hearing Infants. AB - OBJECTIVES: Spectral resolution is a correlate of open-set speech understanding in postlingually deaf adults and prelingually deaf children who use cochlear implants (CIs). To apply measures of spectral resolution to assess device efficacy in younger CI users, it is necessary to understand how spectral resolution develops in normal-hearing children. In this study, spectral ripple discrimination (SRD) was used to measure listeners' sensitivity to a shift in phase of the spectral envelope of a broadband noise. Both resolution of peak to peak location (frequency resolution) and peak to trough intensity (across-channel intensity resolution) are required for SRD. DESIGN: SRD was measured as the highest ripple density (in ripples per octave) for which a listener could discriminate a 90 degrees shift in phase of the sinusoidally-modulated amplitude spectrum. A 2 * 3 between-subjects design was used to assess the effects of age (7-month-old infants versus adults) and ripple peak/trough "depth" (10, 13, and 20 dB) on SRD in normal-hearing listeners (experiment 1). In experiment 2, SRD thresholds in the same age groups were compared using a task in which ripple starting phases were randomized across trials to obscure within-channel intensity cues. In experiment 3, the randomized starting phase method was used to measure SRD as a function of age (3-month-old infants, 7-month-old infants, and young adults) and ripple depth (10 and 20 dB in repeated measures design). RESULTS: In experiment 1, there was a significant interaction between age and ripple depth. The infant SRDs were significantly poorer than the adult SRDs at 10 and 13 dB ripple depths but adult-like at 20 dB depth. This result is consistent with immature across-channel intensity resolution. In contrast, the trajectory of SRD as a function of depth was steeper for infants than adults suggesting that frequency resolution was better in infants than adults. However, in experiment 2 infant performance was significantly poorer than adults at 20 dB depth suggesting that variability of infants' use of within-channel intensity cues, rather than better frequency resolution, explained the results of experiment 1. In experiment 3, age effects were seen with both groups of infants showing poorer SRD than adults but, unlike experiment 1, no significant interaction between age and depth was seen. CONCLUSIONS: Measurement of SRD thresholds in individual 3 to 7-month old infants is feasible. Performance of normal-hearing infants on SRD may be limited by across-channel intensity resolution despite mature frequency resolution. These findings have significant implications for design and stimulus choice for applying SRD for testing infants with CIs. The high degree of variability in infant SRD can be somewhat reduced by obscuring within-channel cues. PMID- 27768612 TI - Which Models Can I Use to Predict Adult ICU Length of Stay? A Systematic Review. AB - OBJECTIVE: We systematically reviewed models to predict adult ICU length of stay. DATA SOURCES: We searched the Ovid EMBASE and MEDLINE databases for studies on the development or validation of ICU length of stay prediction models. STUDY SELECTION: We identified 11 studies describing the development of 31 prediction models and three describing external validation of one of these models. DATA EXTRACTION: Clinicians use ICU length of stay predictions for planning ICU capacity, identifying unexpectedly long ICU length of stay, and benchmarking ICUs. We required the model variables to have been published and for the models to be free of organizational characteristics and to produce accurate predictions, as assessed by R across patients for planning and identifying unexpectedly long ICU length of stay and across ICUs for benchmarking, with low calibration bias. We assessed the reporting quality using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies. DATA SYNTHESIS: The number of admissions ranged from 253 to 178,503. Median ICU length of stay was between 2 and 6.9 days. Two studies had not published model variables and three included organizational characteristics. None of the models produced predictions with low bias. The R was 0.05-0.28 across patients and 0.01-0.64 across ICUs. The reporting scores ranged from 49 of 78 to 60 of 78 and the methodologic scores from 12 of 22 to 16 of 22. CONCLUSION: No models completely satisfy our requirements for planning, identifying unexpectedly long ICU length of stay, or for benchmarking purposes. Physicians using these models to predict ICU length of stay should interpret them with reservation. PMID- 27768613 TI - A Randomized Trial of Palliative Care Discussions Linked to an Automated Early Warning System Alert. AB - OBJECTIVE: To determine whether an Early Warning System could identify patients wishing to focus on palliative care measures. DESIGN: Prospective, randomized, pilot study. SETTING: Barnes-Jewish Hospital, Saint Louis, MO (January 15, 2015, to December 12, 2015). PATIENTS: A total of 206 patients; 89 intervention (43.2%) and 117 controls (56.8%). INTERVENTIONS: Palliative care in high-risk patients targeted by an Early Warning System. MEASUREMENTS AND MAIN RESULTS: Advanced directive documentation was significantly greater prior to discharge in the intervention group (37.1% vs 15.4%; p < 0.001) as were first-time requests for advanced directive documentation (14.6% vs 0.0%; p < 0.001). Documentation of resuscitation status was also greater prior to discharge in the intervention group (36.0% vs 23.1%; p = 0.043). There was no difference in the number of patients requesting a change in resuscitation status between groups (11.2% vs 9.4%; p = 0.666). However, changes in resuscitation status occurred earlier and on the general medicine units for the intervention group compared to the control group. The number of patients transferred to an ICU was significantly lower for intervention patients (12.4% vs 27.4%; p = 0.009). The median (interquartile range) ICU length of stay was significantly less for the intervention group (0 [0 0] vs 0 [0-1] d; p = 0.014). Hospital mortality was similar (12.4% vs 10.3%; p = 0.635). CONCLUSIONS: This study suggests that automated Early Warning System alerts can identify patients potentially benefitting from directed palliative care discussions and reduce the number of ICU transfers. PMID- 27768614 TI - Irregular Corneas: Improve Visual Function With Scleral Contact Lenses. AB - OBJECTIVES: To assess visual function in patients with irregular cornea who do not tolerate gas permeable (GP) corneal contact lenses and are fitted with GP scleral contact lenses (Rose K2 XL). METHODS: In this prospective study, we analyzed 15 eyes of 15 patients who did not tolerate GP corneal contact lenses and were fitted with scleral contact lenses (Rose K2 XL). We assessed visual function using visual acuity and the visual function index (VF-14); we used the VF-14 as an indicator of patient satisfaction. The measurements were taken with the optical correction used before and 1 month after the fitting of the Rose K2 XL contact lenses. We also recorded the number of hours lenses had been worn over the first month. RESULTS: Using Rose K2 XL contact lenses, visual acuity was 0.06+/-0.07 logMAR. In all cases, visual acuity had improved compared with the measurement before fitting the lenses (0.31+/-0.18 logMAR; P=0.001). VF-14 scores were 72.74+/-12.38 before fitting of the scleral lenses, and 89.31+/-10.87 after 1 month of lens use (P=0.003). Patients used these scleral lenses for 9.33+/-2.99 comfortable hours of wear. CONCLUSIONS: Both visual acuity and VF-14 may improve after fitting Rose K2 XL contact lenses in patients with irregular corneas. In addition, in our patients, these lenses can be worn for a longer period than GP corneal contact lenses. PMID- 27768615 TI - Daily Wear Contact Lenses Manufactured in Etafilcon A Are Noninferior to Two Silicone Hydrogel Lens Types With Respect to Hypoxic Stress. AB - PURPOSE: This study hypothesized that a traditional high-water contact lens of moderate oxygen transmissibility (Dk/t) is noninferior to common silicone hydrogel (SH) lenses worn for daily wear with respect to measures of hypoxic stress. METHODS: Thirty-six habitual contact lens wearers completed wear of three lens types worn in a randomized order: etafilcon A (ACUVUE 2, control), lotrafilcon B (Air Optix Aqua), and comfilcon A (Biofinity). Central corneal thickness (CT) and limbal hyperemia were measured >2 hr after waking and after 6 to 8 hr of wear on days 1 and 7. Endothelial bleb formation was measured on day 1 of each lens type. Noninferiority of etafilcon A, with respect to the other two lens types, was assumed if the following difference margins of equivalence were met: <1.5% for corneal swelling, <0.5 grade for limbal hyperemia, and <1% area of endothelial blebs. Outcomes were modeled using generalized linear mixed modeling techniques. RESULTS: All lenses showed reductions in least-square mean estimates of CT on both days: etafilcon A -0.26% at day 1 and -0.31% at day 7; lotrafilcon B -1.11% at day 1 and -1.06% at day 7; comfilcon A -0.63% at day 1 and -0.84% at day 7. The difference in mean swelling between etafilcon A and lotrafilcon B was 0.85% at day 1 (95% confidence interval [0.4%-1.3%]) and 0.75% at day 7 (0.3% 1.2%). The difference in mean swelling between etafilcon A and comfilcon A was 0.37% at day 1 (-0.1% to 0.8%) and 0.53% at day 7 (0.1%-1.0%). For limbal redness, etafilcon A fell within 0.1 grade of lotrafilcon B and 0.18 grade of comfilcon A. For endothelial bleb formation, etafilcon A fell within 0.45% of lotrafilcon B and 0.23% of comfilcon A. CONCLUSION: The etafilcon A control lens resulted in corneal deswelling throughout the day as did the SH lens types. Limbal hyperemia and endothelial bleb formation with all lenses were negligible, and noninferiority assumptions were met between the lens types for all outcomes. Equivalence of etafilcon A with respect to the two SH lenses for three measures of hypoxic stress was demonstrated. PMID- 27768616 TI - In Reply to "Texting Rhythm With Temporal Predominance". PMID- 27768617 TI - Performance of Gadoxetic Acid-Enhanced Liver Magnetic Resonance Imaging for Predicting Patient Eligibility for Liver Transplantation Based on the Milan Criteria. AB - PURPOSE: This study aimed to evaluate the accuracy of gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) in predicting eligibility for liver transplantation in patients with hepatocellular carcinoma (HCC) based on Milan criteria (MC). MATERIALS AND METHODS: We reviewed Gd-EOB-MRI of 44 patients who underwent liver transplantation for HCC with cirrhosis for the presence/size of HCCs, vascular invasion, and transplant eligibility based on MC. Hepatocellular carcinoma was diagnosed based on conventional radiological hallmarks (arterial enhancement and washout) or the modified criteria. RESULTS: Among 44 patients, 16 was beyond MC. Sensitivity, specificity, and accuracy of conventional radiological hallmark and the modified criteria for predicting eligibility by MC were 31.3%, 96.3%, and 72.7%, and 68.8%, 96.3%, and 86.4%, respectively. CONCLUSIONS: Gd-EOB-MRI showed high specificity but poor sensitivity for assessing transplant eligibility based on MC when adopting the conventional radiological hallmarks of HCC. Our modified criteria showed significantly better sensitivity and accuracy than the conventional radiological hallmarks. PMID- 27768618 TI - Absent Vascular Signal on Time-of-Flight Magnetic Resonance Angiography Due to Recent Ferumoxytol Infusion. AB - Time-of-flight magnetic resonance angiography is used for craniocervical arterial evaluation. Absent flow-related signal may be the result of slow flow, complex flow, or focal susceptibility effects. We report a case with complete absence of flow-related signal in the intracranial and cervical vessels due to ferumoxytol infusion given 5 days before magnetic resonance angiography. Ferumoxytol is a newly approved parenteral therapy for iron-deficiency anemia in patients with renal failure and awareness of this drug-magnetic resonance imaging interaction is needed. PMID- 27768619 TI - White Paper of the Society of Computed Body Tomography and Magnetic Resonance on Dual-Energy CT, Part 2: Radiation Dose and Iodine Sensitivity. AB - This is the second of a series of 4 white papers that represent Expert Consensus Documents developed by the Society of Computed Body Tomography and Magnetic Resonance through its task force on dual-energy computed tomography. This paper, part 2, addresses radiation dose and iodine sensitivity in dual-energy computed tomography. PMID- 27768620 TI - Computed Tomographic Appearance of Organizing Pneumonia in an Oncologic Patient Population. AB - OBJECTIVE: The aims of this study were to describe the computed tomographic features of organizing pneumonia (OP) in an oncologic patient population and to also identify features associated with lung cancer and patients undergoing hematopoietic stem cell transplant (HSCT). METHODS: In retrospective computed tomographies from 151 patients with pathologically confirmed OP between January 2009 and September 2014, number of lesions, location, size, margin type, and consistency, as well as volume of lymphadenopathy and the presence and size of pleural effusions, were recorded. Associated malignancy was noted. RESULTS: Organizing pneumonia most commonly presented as a diffuse process (n = 62, 41%), frequently occupied both a central and peripheral location (n = 79, 53%), and commonly presented with a solid appearance (n = 67, 44%) or with ground glass opacity (n = 80, 53%). Pleural effusions were seen in 68 patients (45%). Organizing pneumonia less frequently contained air bronchograms, cavitation, necrosis, surrounding ground glass opacity, or adjacent bronchiectasis. In patients with lung cancer (n = 25, 17%), OP more likely presented as discrete lesions and occupied a peripheral location as compared with patients with other malignancies (Ps = 0.025 and 0.002). In HSCT patients (n = 29, 19%), a diffuse process was more commonly seen than in non-HSCT patients (P = 0.038). CONCLUSIONS: Organizing pneumonia more commonly presents as discrete lesions with a peripheral location in patients with lung cancer and as a diffuse process in patients who had undergone HSCT. PMID- 27768621 TI - Biological Mesh Closure of the Pelvic Floor After Extralevator Abdominoperineal Resection for Rectal Cancer: A Multicenter Randomized Controlled Trial (the BIOPEX-study). AB - OBJECTIVE: To determine the effect of biological mesh closure on perineal wound healing after extralevator abdominoperineal resection (eAPR). BACKGROUND: Perineal wound complications frequently occur after eAPR with preoperative radiotherapy for rectal cancer. Cohort studies have suggested that biological mesh closure of the pelvic floor improves perineal wound healing. METHODS: Patients were randomly assigned to primary closure (standard arm) or biological mesh closure (intervention arm). A non-cross-linked porcine acellular dermal mesh was sutured to the pelvic floor remnants in the intervention arm, followed by a layered closure of the ischioanal and subcutaneous fat and skin similar to the control intervention. The outcome of the randomization was concealed from the patient and perineal wound assessor. The primary endpoint was the rate of uncomplicated perineal wound healing defined as a Southampton wound score of less than 2 at 30 days postoperatively. Patients were followed for 1 year. RESULTS: In total, 104 patients were randomly assigned to primary closure (n = 54; 1 dropouts) and biological mesh closure (n = 50; 2 dropouts). Uncomplicated perineal wound healing rate at 30 days was 66% (33/50; 3 not evaluable) after primary closure, which did not significantly differ from 63% (30/48) after biological mesh closure [relative risk 1.056; 95% confidence interval (CI) 0.7854 1.4197; P = 0.7177). Freedom from perineal hernia at 1 year was 73% (95% CI 60.93 85.07) versus 87% (95% CI 77.49-96.51), respectively (P = 0.0316). CONCLUSIONS: Perineal wound healing after eAPR with preoperative radiotherapy for rectal cancer was not improved when using a biological mesh. A significantly lower 1 year perineal hernia rate after biological mesh closure is a promising secondary finding that needs longer follow-up to determine its clinical relevance. PMID- 27768622 TI - Survival Benefit of Kidney Transplantation in HIV-infected Patients. AB - OBJECTIVE: To determine the survival benefit of kidney transplantation in human immunodeficiency virus (HIV)-infected patients with end-stage renal disease (ESRD). SUMMARY BACKGROUND DATA: Although kidney transplantation (KT) has emerged as a viable option for select HIV-infected patients, concerns have been raised that risks of KT in HIV-infected patients are higher than those in their HIV negative counterparts. Despite these increased risks, KT may provide survival benefit for the HIV-infected patient with ESRD, yet this important clinical question remains unanswered. METHODS: Data from the Scientific Registry of Transplant Recipients were linked to IMS pharmacy fills (January 1, 2001 to October 1, 2012) to identify and study 1431 HIV-infected KT candidates from the first point of active status on the waiting list. Time-dependent Cox regression was used to establish a counterfactual framework for estimating survival benefit of KT. RESULTS: Adjusted relative risk (aRR) of mortality at 5 years was 79% lower after KT compared with dialysis (aRR 0.21; 95% CI 0.10-0.42; P <0.001), and statistically significant survival benefit was achieved by 194 days of KT. Among patients coinfected with hepatitis C, aRR of mortality at 5 years was 91% lower after KT compared with dialysis (aRR 0.09; 95% CI 0.02-0.46; P < 0.004); however, statistically significant survival benefit was not achieved until 392 days after KT. CONCLUSIONS: Evidence suggests that for HIV-infected ESRD patients, KT is associated with a significant survival benefit compared with remaining on dialysis. PMID- 27768624 TI - Introduction. PMID- 27768623 TI - Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model. AB - We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels. PMID- 27768625 TI - Current Evidence: Plate Versus Intramedullary Nail for Fixation of Distal Tibia Fractures in 2016. AB - Displaced distal tibia shaft fractures are effectively treated with standard plates and intramedullary nails. Plate fixation performed with meticulous soft tissue handling results in minimal risks of infection and poor wound healing. Standard plates have high rates of primary union, whereas locking plates may delay union because of increased stiffness. Tibial healing may also be delayed after plating of the fibula, although fibula reduction and fixation may aid accuracy of reduction of the tibia. Malalignment occurs more often with infrapatellar intramedullary nailing versus plates, and early results of suprapatellar nailing appear promising in minimizing intraoperative malalignment. Long-term function after fixation of the distal tibia is good for most, with poor outcomes often associated with baseline social and mental health issues. PMID- 27768626 TI - Intramedullary Nail Fixation of Distal Tibia Fractures: Tips and Tricks. AB - The objective of this article is to highlight the salient points of preoperative planning, intraoperative considerations for fracture reduction methods, and implant fixation when treating distal diaphyseal or diametaphyseal tibia fractures with an intramedullary nail. Through review of the necessary preoperative considerations, techniques available to hold and maintain a reduction, and lastly how to maximize the selected implant of intramedullary nail, we hope to assist the treating surgeon in simplifying these sometimes complex fractures into manageable injuries that can be treated successfully with an intramedullary implant. PMID- 27768627 TI - Intramedullary Tibial Nail Fixation of Simple Intraarticular Distal Tibia Fractures. AB - The optimal treatment strategy for distal tibia fractures, especially those with intraarticular extension, remains controversial. Although open reduction and internal fixation with a plate and screw device is commonly performed for these injuries, the risk of soft tissue complications using this approach is significant. Staged treatment protocols and alternative means of fixation have been proposed to address these undesired events. Although potentially more technically demanding than fixation of diaphyseal or extraarticular tibial fractures, intramedullary nail (IMN) fixation of simple intraarticular distal tibia fractures is a viable treatment alternative with unique advantages. This article presents a review of the literature and rationale for intramedullary tibial nail fixation of simple intraarticular distal tibia fractures and a surgical approach commonly utilized for successful implementation. PMID- 27768628 TI - Intramedullary Nail and Plate Combination Fixation for Complex Distal Tibia Fractures: When and How? AB - Intramedullary nail and plate combination techniques have been described mostly for use in the proximal tibia. However, the nail and plate combination technique can also be used in the distal tibia, to counteract the deforming forces that cause construct failure and nonunion. In this article, we review pertinent anatomy and biomechanics and offer case examples that highlight the indications and applications of the nail and plate combination technique for distal tibia fractures. PMID- 27768629 TI - Fibular Fixation in Distal Tibia Fractures: Reduction Aid or Nonunion Generator? AB - The role of fibular fixation in patients with distal tibia fractures is controversial. Although the stability of the fibula is critical in patients with syndesmotic instability or highly comminuted pilon fractures, fibular fixation in extraarticular distal tibia fractures or elementary intraarticular distal tibia fractures is more controversial. Biomechanical studies, as performed in sawbones or cadaveric models, denote advantages to fibular fixation with respect to specific uniplanar motion. However, the increased stability is susceptible to the fracture pattern of the tibia, fixation strategy for the tibia, fixation strategy for the fibula, and loading pattern of the entire construct. Clinical studies examining fibular fixation in patients with concomitant distal third tibia fractures have also not been definitive in their conclusions. Fibular fixation may improve the ability to obtain and maintain reduction in complex fractures of the distal tibia, but as a result of the increased stability of the construct, may also increase rates of nonunion in this challenging patient population. PMID- 27768630 TI - Definitive Management of Distal Tibia and Simple Plafond Fractures With Circular External Fixation. AB - Obtaining optimal results in the treatment of extraarticular distal tibia fractures can be challenging. Plate and screw and intramedullary fixation have proven to be effective treatments, but are associated with significant complication rates when used for open fractures and patient with severe medical comorbidities. External fixation is a third alternative that is less often employed, but provides a very effective means of treatment. Circular external fixation offers great flexibility in obtaining anatomic alignment and stable fixation for even the most challenging distal tibia fractures. In addition, it provides advantages in limiting the risk of deep infection, dealing with bone loss, and obtaining soft tissue coverage. The greater ease of treatment and potential economic advantage in patient cohorts with low complication rates, such as closed fractures, supports the preferential use of internal fixation. However, circular external fixation may be the preferred treatment for patients with higher-grade open fractures, a poor soft tissue envelope with limited fixation options distally, and major comorbidities (diabetes, immune deficiency) with an associated high risk of complications. PMID- 27768631 TI - Coronary-Pulmonary Artery Fistulas: A Systematic Review. AB - PURPOSE: Coronary-pulmonary arterial fistulas (CPAFs) are rare coronary artery anomalies that have been described only in limited case reports. This study aims to evaluate the clinical presentation and imaging findings of CPAFs collected from 6 participating medical centers along with CPAFs reported in the literature, to discern any general trends present in CPAFs. MATERIALS AND METHODS: A total of 25 cases of CPAF diagnosed by coronary computed tomography angiography were collected across 6 participating institutions. In addition, utilizing a PubMed literature search, 78 additional CPAF cases were obtained. The imaging findings and relevant clinical history were reviewed. RESULTS: Of the 103 CPAF patients, 60 (63% of patients with sex known) were male, with ages ranging from newborn to 88 years (mean=46.1 y). The most common symptoms reported were chest pain (n=40, 39%) and dyspnea (n=26, 25%), with a murmur as the most common physical examination finding (n=38, 37%). The most common coronary artery of origin for a CPAF was the left main/left anterior descending (n=87, 84%), followed by the right coronary artery (n=39, 38%). The fistula most commonly terminated in the main pulmonary artery (n=92, 89%). Multiple CPAFs were present in 46 cases (45%). Coronary artery aneurysms were identified in 20 cases (19%). Pediatric CPAF cases were usually associated with pulmonary atresia with ventricular septal defect. CONCLUSIONS: CPAFs are seen in a variety of clinical settings, from infants with advanced congenital heart disease to elderly patients who have undergone revascularization surgery. Although coronary artery fistulas have previously been described as rarely involving multiple coronary arteries, with the right coronary artery being most often involved, our series demonstrates that multiple fistulas are commonly present, with the most common pattern being between the left main/left anterior descending and the main pulmonary trunk. PMID- 27768632 TI - Long-term Imaging of the Lungs After Sealant Bronchoscopic Lung Volume Reduction. AB - PURPOSE: The aim of the study was to assess the pulmonary temporal changes after bronchoscopic lung volume reduction (BLVR) using sealants for treatment of emphysema. MATERIALS AND METHODS: We retrospectively assessed all chest computerized tomography (CT) and F-18 fluorodeoxyglucose (FDG) positron emission tomography CT scans of patients treated at our institution with BLVR. RESULTS: Eleven patients were treated with sealants: 4 with biological sealants and 7 with synthetic sealants. The first CT scan after biological sealant treatment showed no abnormalities in 8 lobes and 5 nodules, and 3 consolidations in 7 lobes. All findings resolved within 3 months, except for a nodule that decreased after 2 months and remained stable for 9 years. The first CT scan after utilizing the synthetic sealant showed abnormalities in each treated lobe: 19 nodules/masses (16 cavitary, 3 solid) and 3 consolidations. Follow-up CT scans were available for 16 nodules/masses: 1 resolved, 12 slowly decreased in size, 1 remained unchanged, and 2 grew. Of 3 consolidations 1 resolved and 2 decreased in size. FDG positron emission tomography CT scans performed in 2 patients showed FDG uptake higher than mediastinal background activity in 2 nodules in the same patient. CONCLUSIONS: Pulmonary changes after BLVR are variable. After treatment with biological sealants, most findings resolve within 3 months. In contrast, after synthetic sealants, although the majority regress over time, some show waxing and waning in growth that can mimic malignancy. FDG uptake in some of these lesions is suggestive of chronic inflammation. Radiologists should be aware of the spectrum of these pulmonary changes to avoid misdiagnosis of lung cancer. PMID- 27768633 TI - A Case of Disseminated Mycobacterium avium Complex Infection Mimicking Systemic Metastases From Lung Cancer. PMID- 27768634 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: A Case With Long term Follow-up. PMID- 27768635 TI - Lymphomatoid Granulomatosis: Two Different Phenotypes of Computed Tomography Findings. PMID- 27768636 TI - USE OF FIBEROPTIC-GUIDED CO2 LASER IN THE TREATMENT OF UVEAL EFFUSION. AB - BACKGROUND/PURPOSE: To report a new technique for treating patients with uveal effusion syndrome by the fiberoptic-guided CO2 laser. METHODS: Interventional case report. A 74-year-old man presented with exudative detachment of the choroid secondary to uveal effusion syndrome. Partial-thickness sclerotomy and full thickness sclerotomy were performed to treat the disease using a fiberoptic guided CO2 laser. RESULTS: After the surgery, the patient's visual acuity improved and choroidal folds disappeared. CONCLUSION: This technique allows concomitant coagulation and cutting, thereby reducing the risk of bleeding and providing better depth control. PMID- 27768638 TI - BILATERAL CHOROIDAL NEOVASCULARIZATION IN A PATIENT WITH BETA-THALASSEMIA MAJOR AND ITS MANAGEMENT. AB - PURPOSE: To describe a case of bilateral choroidal neovascularization in a patient with beta-thalassemia major and an interventional therapeutic attempt. METHOD: Retrospective case report. RESULT: A known case of beta-thalassemia major presented with gradual vision loss. Fundoscopy revealed bilateral macular edema accompanied by intraretinal hemorrhages. Optical coherence tomography and fluorescein angiography were compatible with the diagnosis of choroidal neovascularization. No signs of angioid streaks or other related abnormalities were noticed in examination and imaging. The patient was treated with intravitreal bevacizumab, and visual acuity improved within 6 months of follow up. CONCLUSION: Bilateral choroidal neovascularization can be a presenting pathology in patients with beta-thalassemia major. Anti-vascular endothelial growth factor is a promising treatment option. PMID- 27768637 TI - FUNDUS AUTOFLUORESCENCE FINDINGS IN EARLY CHLOROQUINE MACULOPATHY. AB - BACKGROUND/PURPOSE: Toxic maculopathy is a rare but severe complication of chloroquine intake. Although the phenotype of established maculopathy was analyzed in detail, few data exist on the ophthalmologic findings in the early stage. METHODS: The authors present 4 female patients with unequivocal signs of chloroquine maculopathy (bilateral [peri-]central scotoma in the visual fields, structural alterations of the macula in the optical coherence tomography) but normal or atypical findings as to fundus autofluorescence imaging. RESULTS: In all patients, optical coherence tomography showed perifoveal thinning and subtle alterations of the outer retinal layers. In one patient, the latter was limited to the pericentral region, whereas it showed a more diffuse distribution in two other patients. One patient showed a combination of pericentral and diffuse damage. Multifocal electroretinography was recorded in three patients and revealed the typical (peri-)central amplitude reductions. CONCLUSION: A normal fundus autofluorescence does not rule out toxic maculopathy. Optical coherence tomography and multifocal electroretinography seem to be more sensitive in the early stage of the disease. In case of typical complaints and visual fields, the optical coherence tomography has to be evaluated for subtle alterations of the outer retina. Their presence justifies the cessation of the drug. Multifocal electroretinography may be of special value in these problematic cases. PMID- 27768640 TI - INTRAVITREAL DEXAMETHASONE IMPLANT AS ADJUVANT TREATMENT FOR BEVACIZUMAB- AND RANIBIZUMAB-RESISTANT NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Prospective Pilot Study. AB - PURPOSE: To study the benefit of intravitreal dexamethasone implant in the management of neovascular age-related macular degeneration resistant to bevacizumab and ranibizumab. METHODS: Patients with persistent macular fluid on optical coherence tomography despite monthly treatment with at least three consecutive bevacizumab injections followed by at least three ranibizumab injections were prospectively enrolled. A single dexamethasone implant was administered followed by intravitreal ranibizumab 1 week later. Ranibizumab was continued afterward on an as-needed basis. Main outcomes were improvement in central retinal thickness and best-corrected visual acuity. RESULTS: Nineteen patients (19 eyes) were enrolled. There was no significant change in best corrected visual acuity over 6 months. Greatest reduction in mean central retinal thickness, from 295.2 MUm to 236.2 MUm, occurred 1 month after dexamethasone implant (P < 0.0001). By Month 6, mean central retinal thickness was 287.3 MUm (P = 0.16). Eyes with only intraretinal fluid (13 eyes) achieved a fluid-free macula. Eyes with predominantly subretinal fluid (6 eyes) did not improve central retinal thickness and continued monthly ranibizumab. Mean baseline intraocular pressure was 13.2 mmHg, which peaked at 15.6 mmHg by Month 2 (P = 0.004). CONCLUSION: Intravitreal dexamethasone implant improved only macular intraretinal fluid in eyes with neovascular age-related macular degeneration resistant to bevacizumab and ranibizumab. However, this treatment had a limited duration. PMID- 27768639 TI - High cytotoxic T-lymphocyte-associated antigen 4 and phospho-Akt expression in tumor samples predicts poor clinical outcomes in ipilimumab-treated melanoma patients. AB - Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival (OS) benefit. However, ipilimumab is associated with significant immune-related adverse events. We hypothesized that biomarker exploration of pretreatment tumor samples and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy. At the University of Texas MD Anderson Cancer Center, a total of 81 advanced melanoma patients were treated on the Ipilimumab Expanded Access Program from 2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune checkpoint (CTLA-4, PD 1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor tissue. Associations between these biomarkers and progression-free survival (PFS) and OS were analyzed with univariate and multivariate Cox proportional-hazards models. There was a significant correlation between high CTLA-4 protein expression levels in tumor cells and risk of death (P=0.02) and decreased PFS (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes correlated with poor OS (P=0.023). In multivariate analysis, patients with high CTLA-4 and phospho-Akt (p Akt) expression correlated with poor OS (log-rank test, P=0.039) and PFS (log rank test, P=0.014). High levels of CTLA-4 and p-Akt expression in pretreatment tumor cells in melanoma patients were associated with poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in pretreatment tumor samples provides useful biomarkers that may enable improved patient selection for ipilimumab therapy. Prospective clinical studies are warranted to investigate the predictive value of these biomarkers. PMID- 27768641 TI - SAFETY OF INTRAVITREAL DEXAMETHASONE IMPLANT (OZURDEX): The SAFODEX study. Incidence and Risk Factors of Ocular Hypertension. AB - PURPOSE: To analyze the incidence, risk factors, and time course of intraocular pressure elevation after intravitreal dexamethasone implant (Ozurdex). METHODS: The medical charts of 421 consecutive eyes (361 patients) receiving one or more Ozurdex implant between October 2010 and February 2015 were reviewed retrospectively. Ocular hypertension was defined as intraocular pressure of at least 25 mmHg or an increase of at least 10 mmHg from baseline. The main indications for treatment were retinal vein occlusion (34%), diabetic macular edema (30%), postsurgical macular edema (17%), uveitis (14%), and other etiologies (5%). RESULTS: Among 1,000 intravitreal injections, ocular hypertension was recorded for 28.5% of injected eyes over a mean follow-up period of 16.8 months (3-55). Intraocular pressure-lowering medication was required for 31% of eyes. Only three eyes with preexisting glaucoma required filtering surgery to manage postinjection intraocular pressure elevation. Early retreatment between the third and fourth month does not increase the risk of intraocular pressure elevation. Younger age, male sex, Type 1 diabetes, preexisting glaucoma treated with dual or triple therapy, and a history of retinal vein occlusion or uveitis were significant risk factors for ocular hypertension after dexamethasone implant injection (P < 0.05 for all the above). CONCLUSION: Episodes of ocular hypertension after Ozurdex implant were generally transient and successfully managed with topical treatment. An analysis of the risk factors may help to determine the risk-benefit ratio for individual patients treated with dexamethasone implants. PMID- 27768642 TI - Retrobulbar Injection of Amphotericin B for Orbital Mucormycosis. AB - A 68-year-old immunocompromised man with rhino-orbital-cerebral mucormycosis was treated with retrobulbar injections of amphotericin B deoxycholate in conjunction with intravenous antifungals and endoscopic sinus debridement. Transient episodes of orbital inflammation were noted after retrobulbar injections, but progression of orbital infection was halted and visual acuity restored with eventual hospital discharge. To the authors' knowledge, clearance of orbital mucormycosis with retrobulbar amphotericin B injections has not been previously reported. This intervention may be a viable therapeutic option in cases of orbital mucormycosis where aggressive orbital debridement is not favored and/or the burden of orbital disease is not substantial. However, physicians should be aware of the risk of transient orbital inflammation secondary to retrobulbar amphotericin B deoxycholate. PMID- 27768644 TI - A Case of Idiopathic Bilateral Hemolacria in an 11-Year-Old Girl. AB - An 11-year-old healthy girl was noted to have intermittent, spontaneous, and bilateral hemolacria of 14 months' duration. Examination and workup failed to identify an organic or psychogenic cause. The patient was expectantly managed with eventual spontaneous resolution. This report draws attention to this unusual and often concerning clinical entity. The case report is in compliance with the Health Insurance Portability and Accountability Act. PMID- 27768643 TI - Transcanalicular Laser-Assisted Dacryocystorhinostomy With Endonasal Augmentation in Primary Nasolacrimal Duct Obstruction: Our Experience. AB - PURPOSE: To evaluate and compare the success rate of transcanalicular laser assisted dacryocystorhinostomy with endonasal augmentation, with and without intubation, in patients suffering from primary acquired nasolacrimal duct obstruction, at 1 year of follow up. METHODS: A prospective, randomized interventional pilot study was conducted at a tertiary care center, in accordance with the guidelines of Declaration of Helsinki. Sixty eyes of 60 adult patients with primary acquired nasolacrimal duct obstruction were included. The participants were divided randomly into 2 equal groups (A and B-without and with bicanalicular intubation, respectively). An osteotomy was first created using 980 nm diode laser (set at 8W continuous mode) transcanalicularly and then enlarged intranasally using Blakesley's nasal forceps, followed by bicanalicular silicon intubation in group B patients. The tubes were removed at the end of 8 weeks. The ostium size was assessed endoscopically at 8 weeks and again at the end of follow up, at 1 year. A successful outcome was defined in terms of ostium patency at the end of 1 year. The results were analyzed at the end of a follow up of 1 year, using various statistical tests (p < 0.05). RESULTS: The mean age of the patients was 35.3 +/- 15.89 years, with 23 male and 37 female patients, the 2 groups having a similar male:female ratio. An overall success rate of 90% was achieved at the end of 1 year with no statistically significant difference between the groups. Postoperative complications like tube displacement and punctal, canalicular injury were more in the intubated group. The average osteotomy size was 8.06 +/- 5.4 mm at the end of 1 year. CONCLUSIONS: Transcanalicular laser assisted dacryocysto rhinostomy, with endonasal augmentation, is a scarless, effective, daycare procedure, for treatment of primary acquired nasolacrimal duct obstruction with no additional advantage offered by silicone intubation. PMID- 27768645 TI - Non-Exenteration Management of Sino-Orbital Fungal Disease. AB - PURPOSE: To describe the non-exenteration management of sino-orbital fungal infection, a life-threatening condition for which orbital exenteration is generally considered a first-line treatment. METHODS: A retrospective case series is presented of 7 orbits in 6 consecutive patients admitted and treated at 2 major metropolitan tertiary teaching hospitals in Sydney, New South Wales, Australia. RESULTS: Seven orbits in 6 consecutive patients with sino-orbital fungal infection were treated conservatively with surgical debridement and intravenous antifungal agents. Four patients were immunosuppressed and the other 2 patients were otherwise healthy. All presented with pain, proptosis, or loss of vision. Causative organisms found were Mucormycoses, Aspergillus, and Scedosporium prolificans. Exenteration was avoided in all patients as part of their planned management and 5 patients, including 1 with bilateral disease, survived their disease without exenteration. Medical treatment included intravenous liposomal amphotericin B or voriconazole. A single immunosuppressed patient deteriorated and as a last resort, exenteration was performed, but this made no difference to his clinical course and in retrospect could have been avoided as he died of multiple cerebral metastases diagnosed shortly after his deterioration. CONCLUSION: The authors recommend that patients with sino-orbital fungal disease preferably be treated conservatively, without orbital exenteration. PMID- 27768646 TI - A Case of a Spontaneous Self-resolving Retrobulbar Hemorrhage Following 3,4 Methylenedioxy-methamphetamine Use. AB - This case report discusses the case of a 23-year-old male patient who experienced retrobulbar pain, diplopia, proptosis, and mild lower eyelid bruising after consuming 3,4-methylenedioxy-methamphetamine. The symptoms settled over 10 days and vision returned to normal without intervention. The authors discuss the differential diagnosis relevant to the presenting complaints and propose several mechanisms linking 3,4-methylenedioxy-methamphetamine use to spontaneous nontraumatic intraorbital hematoma. PMID- 27768647 TI - Relationship of Psychosocial Resources With Allostatic Load: A Systematic Review. AB - OBJECTIVE: Allostatic load (AL) represents cumulative wear-and-tear on the body and is operationalized as a multisystem index of biomarkers. Allostatic load is associated with morbidities and mortality, leading to a growing body of literature that uses AL as an outcome in its own right. Psychosocial resources (PSRs), such as mastery and social support, may influence health outcomes in part via AL, and the current review seeks to characterize the relations between PSRs and AL. METHODS: A systematic review was conducted by searching PubMed, CINAHL Plus, PsycINFO, Scopus, and Embase for studies examining the relation between PSR(s) and AL in humans. From 1,417 abstracts screened, 60 full-text articles were reviewed, and 24 studies met inclusion criteria. RESULTS: Mixed evidence exists for a relationship between PSRs and AL. Most (14/24) studies used a cross sectional design, and only one study investigated whether a PSR predicted change in AL. Compared to cross-sectional studies, longitudinal studies were more likely to report a significant relationship (8/14 versus 8/10, respectively). Studies with statistically significant main or moderated effects had larger sample sizes than those reporting null effects. Whether a study reported a significant main or moderated relationship did not differ by whether psychological (8/11) or social (10/16) resources were assessed. CONCLUSIONS: Evidence for a relationship between PSRs and AL is equivocal, and obtained significant relationships are generally small in magnitude. Gaps in the current literature and directions for future research are discussed. Longitudinal studies are needed that repeatedly assess PSRs and AL. PMID- 27768648 TI - Epigenetic Mediators Between Childhood Socioeconomic Disadvantage and Mid-Life Body Mass Index: The New England Family Study. AB - OBJECTIVE: Childhood socioeconomic disadvantage is associated with adulthood obesity risk; however, epigenetic mechanisms are poorly understood. This work's objective was to evaluate whether associations of childhood socioeconomic disadvantage with adulthood body mass index (BMI) are mediated by DNA methylation. METHODS: Participants were 141 men and women from the New England Family Study, prospectively followed prenatally through a mean age of 47 years. Epigenomewide DNA methylation was evaluated in peripheral blood and adipose tissue obtained at adulthood, using the Infinium HumanMethylation450K BeadChip. Childhood socioeconomic status (SES) at age 7 years was assessed directly from parents' reports. Offspring adiposity was directly assessed using BMI at a mean age of 47 years. Associations of SES, DNA methylation, and BMI were estimated using least square estimators. Statistical mediation analyses were performed using joint significance test and bootstrapping. RESULTS: Of CpG sites significant at the 25% false discovery rate level in epigenomewide methylation BMI analyses, 91 sites in men and 71 sites in women were additionally significant for SES-methylation associations (p < .001) in adipose tissue. Many involved genes biologically relevant for development of obesity, including fatty acid synthase, transmembrane protein 88, signal transducer and activator of transcription 3, and neuritin 1. There was no evidence of epigenetic mediation in peripheral blood leukocytes. CONCLUSIONS: DNA methylation at specific genes may be mediators of associations between childhood socioeconomic disadvantage and mid life BMI in adipose tissue. Findings motivate continued efforts to study if and how childhood socioeconomic disadvantage is biologically embedded at the level of the epigenome in regions etiologically relevant for adiposity. PMID- 27768650 TI - Transition of Care for Adolescents and Young Adults With Inflammatory Bowel Disease: The More We Learn, The Less We Know. PMID- 27768649 TI - Long-Term Outcome of Bodily Distress Syndrome in Primary Care: A Follow-Up Study on Health Care Costs, Work Disability, and Self-Rated Health. AB - OBJECTIVE: The upcoming International Classification of Diseases, 11th Revision for primary care use suggests inclusion of a new diagnostic construct, bodily (di)stress syndrome (BDS), for individuals with medically unexplained symptoms. We aimed to explore the long-term outcome of BDS in health care costs, work disability, and self-rated health. METHODS: Consecutive patients consulting their family physician for a new health problem were screened for physical and mental symptoms by questionnaires (n = 1785). A stratified subsample was examined with a standardized diagnostic interview (n = 701). Patients with single-organ BDS (n = 124) and multiorgan BDS (n = 35), and a reference group with a family physician verified medical condition (n = 880) were included. All included patients completed a questionnaire at 3, 12, and 24 months of follow-up. Register data on health care costs and work disability were obtained after 2 and 10 years of follow-up, respectively. RESULTS: Patients with BDS displayed poorer self-rated health and higher illness worry at index consultation and throughout follow-up than the reference group (p <= .001). The annual health care costs were higher in the BDS groups (2270 USD and 4066 USD) than in the reference group (1392 USD) (achieved significance level (ASL) <= 0.001). Both BDS groups had higher risk of sick leave during the first 2 years of follow-up (RRsingle-organ BDS = 3.0; 95% confidence interval [CI] = 1.8-5.0; RRmultiorgan BDS = 3.4; 95% CI = 1.5-7.5) and substantially higher risk of newly awarded disability pension than the reference group (HRsingle-organ BDS = 4.9; 95% CI = 2.8-8.4; HRmultiorgan BDS = 8.7; 95% CI = 3.7-20.7). CONCLUSIONS: Patients with BDS have poor long-term outcome of health care costs, work disability, and subjective suffering. These findings stress the need for adequate recognition and management of BDS. PMID- 27768651 TI - Proposal for An Algorithm for Screening for Undernutrition in Hospitalized Children. AB - The prevalence of disease-related undernutrition in hospitalized children has not decreased significantly in the last decades in Europe. A recent large multicentric European study reported a percentage of underweight children ranging across countries from 4.0% to 9.3%. Nutritional screening has been put forward as a strategy to detect and prevent undernutrition in hospitalized children. It allows timely implementation of adequate nutritional support and prevents further nutritional deterioration of hospitalized children. In this article, a hands-on practical guideline for the implementation of a nutritional care program in hospitalized children is provided. The difference between nutritional status (anthropometry with or without additional technical investigations) at admission and nutritional risk (the risk of the need for a nutritional intervention or the risk for nutritional deterioration during hospital stay) is the focus of this article. Based on the quality control circle principle of Deming, a nutritional care algorithm, with detailed instructions specific for the pediatric population was developed and implementation in daily practice is proposed. Further research is required to prove the applicability and the merit of this algorithm. It can, however, serve as a basis to provide European or even wider guidelines. PMID- 27768652 TI - Physicians and Students Take to the Streets to Ask: What Do People Want From Their Health Care? AB - With the aim of better understanding what the public (as opposed to "patients") wants from health care, this study asked people on the street, "What does the right health care mean to you?" Responses ranged from "Caring about me more than just in the appointment" to "That everyone should see exactly what medical treatment costs." A qualitative analysis revealed that all responses fell into 2 overarching categories: health care at the interpersonal level and health care at the system level. Approximately 66.7% of responses included system-level factors, whereas 59% of responses included interpersonal-level factors. We conclude that the public is cognizant of and concerned about issues that also concern patients and others working to improve health care and, thus, should be engaged in the process to design care in a way that meets their needs and preferences before they become ill or interact with the delivery system. PMID- 27768653 TI - Clinical Risk Factors for Orthostatic Hypotension: Results Among Elderly Fallers in Long-Term Care. AB - BACKGROUND: Patients at greatest risk for fall-related injuries are older adults with orthostatic hypotension (OH), a condition which drops blood pressure. This study sought to determine salient demographic and patient-level factors increasing risk for OH among a sample of elderly fallers. METHODS: Data analysis for this retrospective study sought to assess the relationship between various demographic and clinical risk factors and the likelihood of OH. Because fallers could experience multiple falls, generalized estimating equations were used to account for patient-level correlations. RESULTS: One hundred seventeen falls occurred in 47 patients, who were primarily female with a mean age of 90.7 years. Falls resulted in 18 cases of OH. Orthostatic hypotension cases were less likely to have a gait in a steady line (5.6% vs 55.6%, P = 0.001). Patients with decreased muscular coordination were almost 5 times more likely to experience OH than those with no coordination problems (odds ratio = 4.86, P = 0.02). Patients with gait in a steady line were less likely to experience OH after a fall (OR = 0.06, P = 0.006). CONCLUSIONS: Orthostatic hypotension is potentially modifiable once detected. Evidenced-based protocol for assessment and management of OH among patients with gait and balance impairment is presented. PMID- 27768654 TI - Measuring Patient Safety: The Medicare Patient Safety Monitoring System (Past, Present, and Future). AB - The explicit declaration in the landmark 1999 Institute of Medicine report "To Err Is Human" that, in the United States, 44,000 to 98,000 patients die each year as a consequence of "medical errors" gave widespread validation to the magnitude of the patient safety problem and catalyzed a number of U.S. federal government programs to measure and improve the safety of the national healthcare system. After more than 10 years, one of those federal programs, the Medicare Patient Safety Monitoring System (MPSMS), has reached a level of maturity and stability that has made it useful for the consistent measurement of the safety of inpatient care. The MPSMS is a chart review-based national patient safety surveillance system that provides rates of 21 specific hospital inpatient adverse event measures, which have been divided into 4 clinical domains (general, hospital acquired infections, postprocedure adverse events, and adverse drug events) for analysis. The 2014 MPSMS national sample was drawn from 1109 hospitals and includes approximately 20,000 medical records of patients admitted to the hospital (all payors) for at least 1 of the 4 conditions of congestive heart failure, acute myocardial infarction, pneumonia, and major surgical procedures as defined by the Centers for Medicare and Medicaid Services Surgical Care Improvement Project. The MPSMS is now going through a major transformation to capture additional types of adverse events and is being redeveloped as the Quality and Safety Review System (QSRS). As an example of this transformation, QSRS will electronically import electronic data, which are standardized according to the Centers for Medicare and Medicaid Services billing definitions and will be updated and evolve over time to incorporate expanded standardized data available from electronic health records. This article reviews the development of MPSMS, the strengths and limitations of MPSMS, and expected future directions in patient safety measurement, focusing on those issues that are informing the development and implementation of QSRS. PMID- 27768655 TI - Measures to Improve Diagnostic Safety in Clinical Practice. AB - Timely and accurate diagnosis is foundational to good clinical practice and an essential first step to achieving optimal patient outcomes. However, a recent Institute of Medicine report concluded that most of us will experience at least one diagnostic error in our lifetime. The report argues for efforts to improve the reliability of the diagnostic process through better measurement of diagnostic performance. The diagnostic process is a dynamic team-based activity that involves uncertainty, plays out over time, and requires effective communication and collaboration among multiple clinicians, diagnostic services, and the patient. Thus, it poses special challenges for measurement. In this paper, we discuss how the need to develop measures to improve diagnostic performance could move forward at a time when the scientific foundation needed to inform measurement is still evolving. We highlight challenges and opportunities for developing potential measures of "diagnostic safety" related to clinical diagnostic errors and associated preventable diagnostic harm. In doing so, we propose a starter set of measurement concepts for initial consideration that seem reasonably related to diagnostic safety and call for these to be studied and further refined. This would enable safe diagnosis to become an organizational priority and facilitate quality improvement. Health-care systems should consider measurement and evaluation of diagnostic performance as essential to timely and accurate diagnosis and to the reduction of preventable diagnostic harm.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 27768656 TI - Origins and importance of the joint trauma system. PMID- 27768657 TI - Genitourinary injuries and extremity amputation in Operations Enduring Freedom and Iraqi Freedom: Early findings from the Trauma Outcomes and Urogenital Health (TOUGH) project. AB - BACKGROUND: In Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF), genitourinary (GU) wounds have occurred in unprecedented numbers. Severe concomitant injuries, including extremity amputations, are common. The epidemiology of GU injury and extremity amputation in OEF/OIF has not been described. MATERIALS AND METHODS: The Department of Defense Trauma Registry was queried from October 2001 through August 2013 to identify all surviving US male service members with GU injuries sustained in OEF/OIF. Genitourinary injury was defined as sustaining one or more injuries to any organ or structure within the genitourinary and/or reproductive system(s) based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Injury severity was quantified based on Abbreviated Injury Scale scores and overall Injury Severity Scores. The incidence, nature, and severity of GU injuries and extremity amputations are described. RESULTS: Of the 1,367 service members with GU injury included in this analysis, 433 (31.7%) had one or more extremity amputations. Most GU injuries were to the external genitalia [scrotum (55.6%), testes (33.0%), penis (31.0%), and urethra (9.1%)] vs. the kidneys (21.1%). Those with amputation(s) had greater GU injury severity (Abbreviated Injury Scale score >= 3) than those without amputations (50.1% vs. 30.5%, respectively; p < 0.0001). Approximately 3.4% of male service members with GU injury had an upper extremity amputation only, 8.9% had both lower and upper extremity amputation(s), and 19.4% had lower extremity amputation(s) only. Of the 387 patients with GU injury and lower extremity amputations, 87 (22.5%) had amputations below the knee and 300 (77.5%) had amputation(s) at/above the knee. CONCLUSION: In OEF/OIF, concomitant GU injury and extremity amputation are common and have serious implications for health and quality of life. This wounding pattern presents new challenges to the military medical and research and development communities to prevent, mitigate, and treat these battlefield injuries. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. PMID- 27768658 TI - The Military Orthopedic Trauma Registry: The potential of a specialty specific process improvement tool. AB - BACKGROUND: The Military Orthopaedic Trauma Registry (MOTR) was designed to replicate the Department of Defense Trauma Registry's (DoDTR's) role as pillar for data-driven management of extremity war wounds. The MOTR continuously undergoes quality assurance checks to optimize the registry data for future quality improvement efforts. We conducted a quality assurance survey of MOTR entrants to determine if a simple MOTR data pull could provide robust orthopedic specific information toward the question of causes for late amputation. METHODS: Forty-five entrants into the DoDTR with late transtibial amputation were sequentially abstracted into MOTR by MOTR data abstractors. The MOTR record was then examined by an independent reviewer for three data fields pertaining to the events leading up to the late amputation: injury before limb amputation, complications before and after amputation, and complication or other factor directly contributing to the decision for amputation. RESULTS: Thirty-nine subjects had at least one fracture of the tibial diaphysis, tibial pilon, calcaneus, or multiple foot fractures. Twenty-nine fractures were described as open injuries for which 27 included a Gustilo and Anderson classification in the available data fields. Complications could be identified along the treatment course for 43 of the 45 entrants specific to the amputated limb. A directly contributing factor to late amputation was identified in 36 (80%) of the subjects. Infection, either alone or associated with fracture nonunion, was a contributing factor in 46% of late amputations. Wound infection was the most common complication both before and after the amputation. CONCLUSION: The MOTR, using a simple data extraction from a few registry fields, can provide a robust amount of information that can direct process and care improvement for severely injured limbs by providing the level of detail pertinent to an orthopedic surgeon. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level IV. PMID- 27768659 TI - Combat MEDEVAC: A comparison of care by provider type for en route trauma care in theater and 30-day patient outcomes. AB - BACKGROUND: Medical evacuation (MEDEVAC) is the movement and en route care of injured and medically compromised patients by medical care providers via helicopter. Military MEDEVAC platforms provide lifesaving interventions that improve survival in combat. There is limited evidence to support decision making related to en route care and allocation of resources. The association between provider type and en route care is not well understood. Our objective was to describe MEDEVAC providers and identify associations between provider type, procedures performed, and outcomes. METHODS: We conducted an institutional review board-approved, retrospective record review of patients traumatically injured in combat, evacuated by MEDEVAC from the point of injury, between 2011 and 2014. Data abstracted included injury description, provider type, procedures performed, medications administered, survival, and 30-day outcomes. Subjects were grouped according to provider type: medics, paramedics, and ADVs (advanced-level providers to include nurses, physician assistants, and physicians). Groups were compared. Analyses were performed using chi tests for categorical variables and analysis of variance tests (Kruskal-Wallis tests) for continuous variables; p < 0.05 was considered significant. RESULTS: The MEDEVAC records were reviewed, and data were abstracted from 1,237 subjects. The providers were composed of medics, 76%; paramedics, 21%; and ADVs, 4%. Patient and injury demographics were similar among groups. The ADVs were most likely to perform intubation, chest needle decompressions (p < 0.0001), and hypothermia prevention (p = 0.01). Paramedics were most likely to administer blood en route (p < 0.0001). All other procedures were similar between groups. Paramedics were most likely to administer ketamine (p < 0.0001), any analgesic (p < 0.0001), or any medication en route (p < 0.0001). Incidence rates of en route events (pain, hypoxia, abnormal hemodynamics, vital signs) were similar between provider types. In-theater and 30 day survival rates were similar between provider types. CONCLUSION: Providers with higher-level training were more likely to perform more advanced procedures during en route care. Our study found no significant association between provider type and in-theater or 30-day mortality rates. Upon subgroup analysis, no difference was found in patients with an injury severity score greater than 16. More evidence is needed to determine the appropriate level of MEDEVAC personnel training and skill maintenance necessary to minimize combat mortality. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 27768660 TI - Identifying potential utility of resuscitative endovascular balloon occlusion of the aorta: An autopsy study. AB - BACKGROUND: Resuscitative thoracotomy (RT) has been the standard therapy in patients with acute arrest due to hemorrhagic shock. However, with the development of resuscitative endovascular balloon occlusion of the aorta (REBOA), its role as a potential adjunct to a highly morbid intervention such as RT is being discussed. The aim of this study was to identify patients who most likely would have potentially benefited from REBOA use based on autopsy findings. METHODS: We performed a 4-year retrospective review of all RTs performed at our Level I trauma center. Patients with in-hospital mortality and who underwent subsequent autopsies were included. Patients were divided into blunt and penetrating trauma with and without thoracic injuries. Autopsy reports were reviewed to identify vascular and solid organ injuries. Outcome measure was potential benefit with REBOA. Potential benefit with REBOA was defined based on the ability to safely deploy REBOA. In patients without cardiac, aortic, and major pulmonary vasculature injuries, REBOA was considered potentially beneficial. In all other patients, it was considered as nonbeneficial. RESULTS: A total of 98 patients underwent an RT, of whom 87 had subsequent autopsies and were reviewed. The mean age was 35.25 (SD, 17.85) years, mean admission systolic blood pressure was 51.38 (SD, 70.11) mm Hg, median Injury Severity Score was 29 (interquartile range [IQR], 25-42), and 44 had penetrating injury. Resuscitative endovascular balloon occlusion of the aorta would have been potentially beneficial in 51.2% of patients (22 of 43 patients) with blunt mechanism of trauma, whereas REBOA would have been potentially beneficial in 38.6% of patients (17 of 44 patients) with penetrating mechanism of trauma. A subgroup analysis showed that REBOA use would have been potentially beneficial in 50.0% of blunt thoracic and 33.3% of penetrating thoracic trauma patients. CONCLUSIONS: There are a great enthusiasm and premature efforts to introduce REBOA as an alternative to RT. While there exists a great potential for benefit with REBOA use in the management of noncompressible torso hemorrhage, the current indications for REBOA need to be defined better. Patients with penetrating chest trauma in extremis should be considered an absolute contraindication for REBOA use. The majority of patients with blunt trauma in extremis may potentially benefit from REBOA. However, better criteria will help increase these patients who may potentially benefit from REBOA placement. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 27768661 TI - Direct-site endovascular repair (DSER): A novel approach to vascular trauma. AB - Peripheral vascular injuries carry significant risk for permanent functional impairment, limb loss, and death. Definitive correction of these injuries requires significant operative time and has traditionally been resource and skill set intensive. In the initial surgical treatment of the physiologically depleted trauma patient, faster techniques may prove more appropriate. Damage control techniques, including vascular shunting, rapidly restore distal flow but require additional vascular intervention and risk shunt thrombosis with prolonged use. To address these challenges, we present a technique, using an off-the-shelf endovascular device, for treatment of peripheral arterial injuries. Direct-site endovascular repair (DSER) is an open vascular surgical reconstruction technique using conventional endovascular stent grafts to create a "sutureless" anastomosis. We believe this technique to be a valuable adjunct to current repair options.The values of this technique are that it is (1) rapid, (2) of low technical complexity, (3) requires very little equipment, and (4) may offer extended durability in damage control scenarios.We describe three patients where this technique was used. In the first case, the technique was used to provide a temporary arterial shunt in a patient with a local infection and arterial disruption. In the second case, DSER was used for definitive repair of an injured artery after penetrating trauma. The third case involves DSER for definitive of both an artery and vein after penetrating trauma. PMID- 27768662 TI - Predicting the proportion of full-thickness involvement for any given burn size based on burn resuscitation volumes. AB - INTRODUCTION: The depth of burn has been an important factor often overlooked when estimating the total resuscitation fluid needed for early burn care. The goal of this study was to determine the degree to which full-thickness (FT) involvement affected overall 24-hour burn resuscitation volumes. METHODS: We performed a retrospective review of patients admitted to our burn intensive care unit from December 2007 to April 2013, with significant burns that required resuscitation using our computerized decision support system for burn fluid resuscitation. We defined the degree of FT involvement as FT Index (FTI; percentage of FT injury/percentage of total body surface area (TBSA) burned [%FT / %TBSA]) and compared variables on actual 24-hour fluid resuscitation volumes overall as well as for any given burn size. RESULTS: A total of 203 patients admitted to our burn center during the study period were included in the analysis. Mean age and weight were 47 +/- 19 years and 87 +/- 18 kg, respectively. Mean %TBSA was 41 +/- 20 with a mean %FT of 18 +/- 24. As %TBSA, %FT, and FTI increased, so did actual 24-hour fluid resuscitation volumes (mL/kg). However, increase in FTI did not result in increased volume indexed to burn size (mL/kg per %TBSA). This was true even when patients with inhalation injury were excluded. Further investigation revealed that as %TBSA increased, %FT increased nonlinearly (quadratic polynomial) (R = 0.994). CONCLUSION: Total burn size and FT burn size were both highly correlated with increased 24-hour fluid resuscitation volumes. However, FTI did not correlate with a corresponding increase in resuscitation volumes for any given burn size, even when patients with inhalation injury were excluded. Thus, there are insufficient data to presume that those who receive more volume at any given burn size are likely to be mostly full thickness or vice versa. This was influenced by a relatively low sample size at each 10%TBSA increment and larger burn sizes disproportionately having more FT burns. A more robust sample size may elucidate this relationship better. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 27768663 TI - Incidence, risk factors, and mortality associated with acute respiratory distress syndrome in combat casualty care. AB - BACKGROUND: The overall incidence and mortality of acute respiratory distress syndrome (ARDS) in civilian trauma settings have decreased over the past four decades; however, the epidemiology and impact of ARDS on modern combat casualty care are unknown. We sought to determine the incidence, risk factors, resource utilization, and mortality associated with ARDS in current combat casualty care. METHODS: This was a retrospective review of mechanically ventilated US combat casualties within the Department of Defense Trauma Registry (formerly the Joint Theater Trauma Registry) during Operation Iraqi Freedom/Enduring Freedom (October 2001 to August 2008) for ARDS development, resource utilization, and mortality. RESULTS: Of 18,329 US Department of Defense Trauma Registry encounters, 4,679 (25.5%) required mechanical ventilation; ARDS was identified in 156 encounters (3.3%). On multivariate logistic regression, ARDS was independently associated with female sex (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.21-5.71; p = 0.02), higher military-specific Injury Severity Score (Mil ISS) (OR, 4.18; 95% CI, 2.61-6.71; p < 0.001 for Mil ISS >=25 vs. <15), hypotension (admission systolic blood pressure <90 vs. >=90 mm Hg; OR, 1.76; 95% CI, 1.07-2.88; p = 0.03), and tachycardia (admission heart rate >=90 vs. <90 beats per minute; OR, 1.53; 95% CI, 1.06-2.22; p = 0.02). Explosion injury was not associated with increased risk of ARDS. Critical care resource utilization was significantly higher in ARDS patients as was all-cause hospital mortality (ARDS vs. no ARDS, 12.8% vs. 5.9%; p = 0.002). After adjustment for age, sex, injury severity, injury mechanism, Mil ISS, hypotension, tachycardia, and admission Glasgow Coma Scale score, ARDS remained an independent risk factor for death (OR, 1.99; 95% CI, 1.12-3.52; p = 0.02). CONCLUSIONS: In this large cohort of modern combat casualties, ARDS risk factors included female sex, higher injury severity, hypotension, and tachycardia, but not explosion injury. Patients with ARDS also required more medical resources and were at greater risk of death compared with patients without ARDS. Thus, ARDS remains a significant complication in current combat casualty care. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 27768664 TI - Bridging the gap: Hybrid cardiac echo in the critically ill. AB - BACKGROUND: Point-of-care ultrasound often includes cardiac ultrasound. It is commonly used to evaluate cardiac function in critically ill patients but lacks the specific quantitative anatomic assessment afforded by standard transthoracic echocardiography (TTE). We developed the Focused Rapid Echocardiographic Examination (FREE), a hybrid between a cardiac ultrasound and TTE that places an emphasis on cardiac function rather than anatomy. We hypothesized that data obtained from FREE correlate well with TTE while providing actionable information for clinical decision making. METHODS: FREE examinations evaluating cardiac function (left ventricular ejection fraction), diastolic dysfunction (including early mitral Doppler flow [E] and early mitral tissue Doppler [E']), right ventricular function, cardiac output, preload (left ventricular internal dimension end diastole), stroke volume, stroke volume variation, inferior vena cava diameter, and inferior vena cava collapse were performed. Patients who underwent both a TTE and FREE on the same day were identified as the cohort, and quantitative measurements were compared. Correlation analyses were performed to assess levels of agreement. RESULTS: A total of 462 FREE examinations were performed, in which 69 patients had both a FREE and TTE. FREE ejection fraction was strongly correlated with TTE (r = 0.89, 95% confidence interval). Left ventricular outflow tract, left ventricular internal dimension end diastole, E, and lateral E' derived from FREE were also strongly correlated with TTE measurements (r = 0.83, r = 0.94, r = 0.77, and r = 0.88, respectively). In 82% of the patients, right ventricular function for FREE was the same as that reported for TTE; pericardial effusion was detected on both examinations in 94% of the cases. No significant valvular anatomy was missed with the FREE examination. CONCLUSION: Functionally rather than anatomically based hybrid ultrasound examinations, like the FREE, facilitate decision making for critically ill patients. The FREE's functional assessment correlates well with TTE measurements and may be of significant clinical value in critically ill patients, especially when used in remote operating environments where resources are limited. LEVEL OF EVIDENCE: Diagnostic test, level III. PMID- 27768665 TI - Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock. AB - BACKGROUND: Clinical studies have demonstrated that the early and empiric use of plasma improves survival after hemorrhagic shock. We have demonstrated in rodent models of hemorrhagic shock that resuscitation with plasma is protective to the lungs compared with lactated Ringer's solution. As our long-term objective is to determine the molecular mechanisms that modulate plasma's protective effects in injured bleeding patients, we have used human plasma in a mouse model of hemorrhagic shock. The goal of the current experiments is to determine if there are significant adverse effects on lung injury when using human versus mouse plasma in an established murine model of hemorrhagic shock and laparotomy. METHODS: Mice underwent laparotomy and 90 minutes of hemorrhagic shock to a mean arterial pressure (MAP) of 35 +/- 5 mm Hg followed by resuscitation at 1* shed blood using either mouse fresh frozen plasma (FFP), human FFP, or human lyophilized plasma. Mean arterial pressure was recorded during shock and for the first 30 minutes of resuscitation. After 3 hours, animals were killed, and lungs collected for analysis. RESULTS: There was a significant increase in early MAP when mouse FFP was used to resuscitate animals compared with human FFP or human lyophilized plasma. However, despite these differences, analysis of the mouse lungs revealed no significant differences in pulmonary histopathology, lung permeability, or lung edema between all three plasma groups. Analysis of neutrophil infiltration in the lungs revealed that mouse FFP decreased neutrophil influx as measured by neutrophil staining; however, myeloperoxidase immunostaining revealed no significant differences in between groups. CONCLUSION: The study of human plasma in a mouse model of hemorrhagic shock is feasible but does reveal some differences compared with mouse plasma-based resuscitation in physiologic measures such as MAP postresuscitation. Measures of end organ function such as lung injury appear to be comparable in this acute model of hemorrhagic shock and resuscitation. PMID- 27768666 TI - A novel therapy to promote axonal fusion in human digital nerves. AB - BACKGROUND: Peripheral nerve injury can have a devastating impact on our military and veteran population. Current strategies for peripheral nerve repair include techniques such as nerve tubes, nerve grafts, tissue matrices, and nerve growth guides to enhance the number of regenerating axons. Even with such advanced techniques, it takes months to regain function. In animal models, polyethylene glycol (PEG) therapy has shown to improve both physiologic and behavioral outcomes after nerve transection by fusion of a portion of the proximal axons to the distal axon stumps. The objective of this study was to show the efficacy of PEG fusion in humans and to retrospectively compare PEG fusion to standard nerve repair. METHODS: Patients with traumatic lacerations involving digital nerves were treated with PEG after standard microsurgical neurorrhaphy. Sensory assessment after injury was performed at 1 week, 2 weeks, 1 month, and 2 months using static two-point discrimination and Semmes-Weinstein monofilament testing. The Medical Research Council Classification (MRCC) for Sensory Recovery Scale was used to evaluate the level of injury. The PEG fusion group was compared to patient-matched controls whose data were retrospectively collected. RESULTS: Four PEG fusions were performed on four nerve transections in two patients. Polyethylene glycol therapy improves functional outcomes and speed of nerve recovery in clinical setting assessed by average MRCC score in week 1 (2.8 vs 1.0, p = 0.03). At 4 weeks, MRCC remained superior in the PEG fusion group (3.8 vs 1.3, p = 0.01). At 8 weeks, there was improvement in both groups with the PEG fusion cohort remaining statistically better (4.0 vs 1.7, p = 0.01). CONCLUSION: Polyethylene glycol fusion is a novel therapy for peripheral nerve repair with proven effectiveness in animal models. Clinical studies are still in early stages but have had encouraging results. Polyethylene glycol fusion is a potential revolutionary therapy in peripheral nerve repair but needs further investigation. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27768667 TI - Aortocaval fistula and celiac artery transection after gunshot wound. PMID- 27768671 TI - Introduction to the Proceedings of the Fifth PANDA Symposium on "Anesthesia and Neurodevelopment in Children". PMID- 27768670 TI - Quetiapine Extended Release Open-Label Treatment Associated Changes in Amygdala Activation and Connectivity in Anxious Depression: An fMRI Study. AB - BACKGROUND: This study investigated extended release quetiapine (quetiapine XR) associated changes in functional MRI (fMRI) measures of task-induced amygdalar activation and resting state connectivity in anxious unipolar major depressive disorder (AMDD). METHODS: Anxious unipolar major depressive disorder patients (n = 15) (17-item Hamilton Depression Rating Scale (HAM-D) >18 and Hamilton Anxiety Scale (HAM-A) >18) and closely matched healthy control (HC) subjects were compared at baseline for task induced amygdala activation and resting state connectivity on fMRI. Subsequently, AMDD patients were treated for 8 weeks with open-label quetiapine XR. Weekly HAM-D and HAM-A ratings were obtained, and the fMRI scan was repeated at weeks 2 and 8. Changes in fMRI measures were calculated using repeated-measures analysis of variance and correlation with decrease in HAM D and HAM-A scores was examined. RESULTS: At baseline, AMDD compared with HC exhibited increased task-induced left amygdalar activation (P = 0.05 clusterwise corrected) and decreased resting state amygdala-cortical and amygdala-pons connectivity (P < 0.05 clusterwise corrected). Quetiapine XR treatment was associated with significant decrease in HAM-D (df = 1,28; female [F] = 39; P = 0.001) and HAM-A scores (df = 1,28; F = 55; P = 0.001). The AMDD group showed increased amygdala-cortical connectivity (P < 0.05 [clusterwise corrected]) at week 2, which was maintained at week 8. At week 8, additional areas showed increased connectivity including insula and putamen. At 8 weeks, decrease in HAM D scores correlated with increase in amygdala-mid cingulate and amygdala-cuneus connectivity (P = 0.05 [clusterwise corrected]). Decrease in HAM-A scores correlated with increase in amygdala-cuneus and parietal cortex connectivity (P = 0.05 [clusterwise corrected]). LIMITATIONS: Small sample-size, open-label single arm design, HC only tested at baseline, focused only on amygdala. CONCLUSIONS: Quetiapine XR effects in the treatment of AMDD are associated with modulation of amygdala connectivity. PMID- 27768672 TI - Report on the Fifth PANDA Symposium on "Anesthesia and Neurodevelopment in Children". AB - On April 16 and 17, 2016, the Pediatric Anesthesia and Neurodevelopment Assessment (PANDA) study held its fifth biennial symposium at the Morgan Stanley Children's Hospital of New York. The PANDA symposium has served as a key forum for clinicians, researchers, and other major stakeholders to gather and review the current state of preclinical and clinical research related to anesthetic neurotoxicity in children. Goals of the meeting included assessing how current knowledge has translated and impacted clinical care of patients who may be at risk, and future directions for research and policy. The program participants represented a diverse group with a shared concern of potential anesthetic neurotoxicity in children. It included clinicians, preclinical and clinical researchers as well as representatives from government organizations (FDA [Food and Drug Administration] and National Institutes of Health). A total of 135 attended the symposium. PMID- 27768673 TI - Summary of the Update Session on Clinical Neurotoxicity Studies. AB - During the Fifth Pediatric Anesthesia Neurodevelopmental Assessment Symposium, experts and stakeholders met to present and discuss recent advances made in the study of neurodevelopmental outcomes after exposure to anesthetic drugs in infants and children. This article summarizes the update of 5 ongoing clinical studies: General Anesthesia compared to Spinal Anesthesia, Toxicity of Remifentanil and Dexmedetomidine, Mayo Anesthesia Safety in Kids, the University of California San Francisco human cohort study, and Columbia University Medical Center Neonatal Magnetic Resonance Imaging study. The purpose of this summary is to discuss the contributions and limitations of these studies, how they fit into the published literature, and what questions remain to be answered. PMID- 27768674 TI - Physical Activity and Cognitive Development: A Meta-Analysis. AB - RESEARCH QUESTION: Is there an association between regular exercise, defined as a structured program of increased physical activity at least 1 month in duration, and improvements in measures of executive functions compared with children who engage in their normal daily activities? CONTEXT: The association between increased physical activity and changes in performance on tasks of executive functions have not been well elucidated in children. Executive functioning is important to intellectual development and academic success in children, and inexpensive, nonpharmacological methods for the treatment of executive dysfunction represent an attractive interventional target. OBJECTIVE: To estimate the effect of a structured regular exercise program on neuropsychological domains of executive function in children ages 7 to 12. DATA SOURCES: We performed a systematic review of English and non-English articles using Cochrane Library, EBSCO CINAHL, Ovid MEDLINE, PSYCInfo, Pubmed, and Web of Science, including all years allowed by each individual search engine. The search string used was "(exercise OR phys*) AND (cognit* OR executive) AND (child* OR preadolesc*)." The authors of the studies selected for review were contacted for any unpublished data. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, which enrolled children between the ages of 7 and 12, with randomization to either normal activity or a structured physical activity intervention consisting of scheduled aerobic exercise, at least once per week, for a period of at least 1 month. Eligible studies must have included a neuropsychological battery of tests that measured at least 1 executive function both before and after the intervention was completed. STUDY APPRAISAL: Two independent reviewers examined the screened studies in detail for potential inclusion. The results of the individual examinations were compared; if any discrepancies were present, a third party analyzed the study to determine if it should be included in the meta-analysis. RESULTS: A total of 18 studies were identified by abstract as candidates for inclusion. From these 18 studies, 8 were independently selected by 2 authors for inclusion in the final analysis; there were no selection discrepancies between authors with regard to the studies to be included. In all, 770 subjects were included, 339 in the control group and 431 in the intervention group. All 8 studies contained a measure of inhibitory control; no other domain of executive function was measured frequently enough to perform meta-analysis, so only measures of inhibitory control were pooled and analyzed. A Cohen d effect size was calculated for each measure using the method of Morris for controlled pre post control measurement studies. The studies were then combined in a random effects model using Comprehensive Meta Analysis software (Biostat, Englewood, NJ) for Windows (Microsoft, Redmond, WA). All studies showed a positive effect of regular exercise with improvements in measures of inhibitory control, but none were statistically significant for this measure. When pooled, the model revealed a combined Cohen d effect size of 0.2 (95% confidence interval, 0.03-0.37; P=0.021), indicating a small improvement of inhibitory control with long-term physical activity. Heterogeneity was very low (I=0). LIMITATIONS: Many studies used different neuropsychological tests to assess inhibitory control, which may have introduced unforeseen confounders. Other domains of executive functions were not measured frequently enough to perform meta-analysis. Despite attempts to gather unpublished data, positive results were observed in all of the included studies, raising the possibility of publication bias. CONCLUSIONS AND IMPLICATIONS: Increased regular physical activity is associated with a small and measurable, improvement in neuropsychological tests of executive functions, specifically inhibitory control. Executive functions play an important role in complex behavior, and may contribute to academic and career achievement as well as success in social interaction. This finding provides support for the important interaction between exercise and cognitive functioning. PMID- 27768675 TI - Optimal Timing of Surgical Procedures in Pediatric Patients. AB - The Pediatric Anesthesia Neuro Development Assessment (PANDA) team at the Anesthesiology Department at Columbia University Medical Center held its fifth biennial symposium to discuss issues regarding potential neurotoxicity of anesthetic agents in pediatric patients. Overall optimal surgical timing as well as a "critical window" for surgery on a specialty specific basis are areas of focus for the American Academy of Pediatrics Surgical Advisory Panel. An ad hoc panel of pediatric surgical experts representing general surgery, urology, neurosurgery, and ophthalmology was assembled for this meeting and provided a dialogue focused on the benefits of early intervention versus potential anesthetic risk, addressing parental concerns, and the need for continued interdisciplinary collaboration in this area. PMID- 27768677 TI - Invited Commentary Related to: "An Evaluation of the OTA-OFC System in Clinical Practice: A Multicenter Study With 90-Day Outcomes". PMID- 27768676 TI - Sevoflurane Impairs Growth Cone Motility in Dissociated Murine Neurons. AB - BACKGROUND: Early postnatal exposure to general anesthetic agents causes a lasting impairment in learning and memory in animal models. One hypothesis to explain this finding is that exposure to anesthetic agents during critical points in neural development disrupts the formation of brain circuitry. Here, we explore the effects of sevoflurane on the neuronal growth cone, a specialization at the growing end of axons and dendrites that is responsible for the targeted growth that underlies connectivity between neurons. METHODS: Dissociated neuronal cultures were prepared from embryonic mouse neocortex. Time-lapse images of live growth cones exposed to anesthetics were taken using differential interference contrast microscopy, and the rate of change of the area of the lamellipodia and the speed of the filopodial tip were quantified as measures of motility. The involvement of the p75 neurotropin receptor (p75NTR) was tested using inhibitors applied to the media and by a coimmunoprecipitation assay. RESULTS: The rate of lamellipodial area change and filopodial tip velocity in both axonal and dendritic growth cones was significantly reduced with sevoflurane exposure between 2% and 6%. Motility could be substantially restored by treatment with Y27632 and TAT-peptide 5, which are inhibitors of Rho Kinase and p75NTR, respectively. Sevoflurane results in reduced coimmunoprecipitation of Rho Guanosine-5'-diphosphate dissociation inhibitor after pulldown with p75NTR. CONCLUSIONS: Sevoflurane interferes with growth cone motility, which is a critical process in brain circuitry formation. Our data suggest that this may occur through an action on the p75NTR, which promotes growth inhibitory signaling by the Rho pathway. PMID- 27768679 TI - Medial Knee Approach: An Anatomical Study of Minimally Invasive Plate Osteosynthesis in Medial Femoral Condylar Fracture. AB - OBJECTIVES: To determine the location of distal medial neurovascular structures, identifying a medial "safe zone" for minimally invasive plate osteosynthesis to treat displaced femoral condylar fractures. METHODS: Eleven uninjured lower-half torsos were dissected on the bilateral medial lower thigh. A longitudinal incision was made at the midsagittal plane of the medial thigh starting 1 cm proximal to the knee joint and extending to the proximal one-third of the femur. Superficial and deep neurovascular structures were dissected. Distances to the medial vastus and adductor compartment were measured. RESULTS: Mean distances were 160 +/- 31.4 mm from the adductor tubercle to Hunter canal; 94 +/- 18.3 mm from adductor tubercle to adductor hiatus; 31.8 +/- 9.21 mm from Hunter canal to the femoral shaft; and 31.7 +/- 7.78 mm from adductor hiatus to femoral shaft. All specimens had a descending genicular artery (DGA) with a mean distance to the adductor tubercle of 98.4 +/- 16.0 mm. The muscular branch of the DGA crossed the femoral shaft at approximately 50 mm from the adductor tubercle; the osteoarticular branch ran along the adductor magnus tendon. The nerve to the vastus medialis was at the posterior border of the vastus medialis, entering at a mean 143 +/- 63.0 mm from the adductor tubercle. CONCLUSIONS: Minor neurovascular branches of the DGA may be vulnerable during medial femoral condyle plating. Careful blunt dissection, proper instrumentation, and plate length within 160 mm allow distal medial femur fixation without additional proximal dissection. PMID- 27768678 TI - Case-Match Controlled Comparison of Minimally Invasive Plate Osteosynthesis and Intramedullary Nailing for the Stabilization of Humeral Shaft Fractures. AB - OBJECTIVES: To compare the risk of major complications after either minimally invasive plate osteosynthesis (MIPO) or intramedullary nailing (IMN) of humeral shaft fractures. DESIGN: Retrospective, case-match controlled study. SETTING: A major metropolitan tertiary referral trauma center in Australia. PATIENTS: Thirty patients with fractures of the humeral shaft. INTERVENTION: Either MIPO or IMN were performed on 15 patients each with traumatic humeral shaft fractures. PRIMARY OUTCOME MEASURE: The cumulative risk of 3 major complications associated with these procedures: nonunion, infection, and iatrogenic radial nerve injury. RESULTS: An overall major complication rate of 53% was observed in the patients treated with IMN; one complication (7%) was identified in those managed with humeral MIPO, a nonunion. Complications after IMN included 4 patients (27%) with nonunion, 3 patients (20%) with iatrogenic radial nerve injuries, and 1 patient (7%) with a wound infection. Statistical analysis revealed a significant between group difference (P = 0.01) in the cumulative rate of major complications. When each of these complications was considered independently, no statistically significant difference was demonstrated. CONCLUSIONS: This study suggests that humeral MIPO results in a significantly lower pooled major complication rate than that of IMN, and it should therefore be considered an attractive alternative to IMN in those patients requiring surgical stabilization of a traumatic humeral shaft fracture. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27768680 TI - Treatment of Periprosthetic Humerus Fractures With Open Reduction and Internal Fixation. AB - Periprosthetic humerus fractures are relatively uncommon occurrence that can be difficult to manage nonoperatively. Locking plate technology has enhanced the surgical management of these fractures. However, adequate fixation around the stem remains of some concern. We describe an osteosynthesis technique using a locking plate utilizing eccentrically placed screw holes to place "skive screws" in the proximal end of the plate to achieve fixation around the stem of the implant. A clinical series of 5 consecutive patients treated with this technique is presented with an average follow-up of 29 months (range, 12-48). Two additional patients had less than 1-year follow-up. All patients demonstrated fracture healing. Functional outcomes were limited with only 1 patient achieving forward elevation above 90 degree, and the average American Shoulder and Elbow Surgeons Function score was 28. Pain relief was nearly uniform with an average visual analog scale pain score of 0.5. PMID- 27768681 TI - Degree of Enhancement on Contrast Enhanced Spectral Mammography (CESM) and Lesion Type on Mammography (MG): Comparison Based on Histological Results. AB - BACKGROUND Contrast enhanced spectral mammography (CESM) is a new method of breast cancer diagnosis in which an iodinated contrast agent is injected and dual energy mammography is obtained in multiple views of the breasts. The aim of this study was to compare the degree of enhancement on CESM with lesion characteristics on mammography (MG) and lesion histology in women with suspicious breast lesions. MATERIAL AND METHODS The degree of enhancement on CESM (absent, weak, medium, or strong) was compared to lesion characteristics on MG (mass, mass with microcalcifications, or microcalcifications alone) and histology (infiltrating carcinoma, intraductal carcinoma, or benign) to compare sensitivity of the two modalities and to establish correlations that might improve diagnostic accuracy. RESULTS Among 225 lesions identified with CESM and MG, histological evaluation revealed 143 carcinomas (127 infiltrating, 16 intraductal) and 82 benign lesions. This is the largest cohort investigated with CESM to date. The sensitivity of CESM was higher than that of MG (100% and 90%, respectively, p=0.010). Medium or strong enhancement on CESM and the presence of a mass on MG was the most likely indictor of malignancy (55.1% p=0.002). Among benign lesions, 60% presented as enhancement on CESM (were false-positive), and most frequently as medium or weak enhancement, together with a mass on MG (53%, p=0.047). Unfortunately, the study did not find combinations of MG findings and CESM enhancement patterns that would be helpful in defining false-positive lesions. We observed systematic overestimation of maximum lesion diameter on CESM compared to histology (mean difference: 2.29 mm). CONCLUSIONS Strong or medium enhancement on CESM and mass or mass with microcalcifications on MG were strong indicators of malignant transformation. However, we found no combination of MG and CESM characteristics helpful in defining false-positive lesions. PMID- 27768682 TI - Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90. AB - The protein-folding chaperone Hsp90 has been proposed to buffer the phenotypic effects of mutations. The potential for Hsp90 and other putative buffers to increase robustness to mutation has had major impact on disease models, quantitative genetics, and evolutionary theory. But Hsp90 sometimes contradicts expectations for a buffer by potentiating rapid phenotypic changes that would otherwise not occur. Here, we quantify Hsp90's ability to buffer or potentiate (i.e., diminish or enhance) the effects of genetic variation on single-cell morphological features in budding yeast. We corroborate reports that Hsp90 tends to buffer the effects of standing genetic variation in natural populations. However, we demonstrate that Hsp90 tends to have the opposite effect on genetic variation that has experienced reduced selection pressure. Specifically, Hsp90 tends to enhance, rather than diminish, the effects of spontaneous mutations and recombinations. This result implies that Hsp90 does not make phenotypes more robust to the effects of genetic perturbation. Instead, natural selection preferentially allows buffered alleles to persist and thereby creates the false impression that Hsp90 confers greater robustness. PMID- 27768683 TI - Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen Controlled Bistable Genetic Switches. AB - During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules-morphogens-guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the corresponding Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, the dramatic increase in patterning time close to the boundary predicted from the deterministic case is substantially reduced. The resulting stochastic switching introduces differences in patterning time along the morphogen gradient that result in a patterning wave propagating away from the morphogen source with a velocity determined by the intrinsic noise. The wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively alter developmental patterning. PMID- 27768684 TI - Long-Range Signaling in MutS and MSH Homologs via Switching of Dynamic Communication Pathways. AB - Allostery is conformation regulation by propagating a signal from one site to another distal site. This study focuses on the long-range communication in DNA mismatch repair proteins MutS and its homologs where intramolecular signaling has to travel over 70 A to couple lesion detection to ATPase activity and eventual downstream repair. Using dynamic network analysis based on extensive molecular dynamics simulations, multiple preserved communication pathways were identified that would allow such long-range signaling. The pathways appear to depend on the nucleotides bound to the ATPase domain as well as the type of DNA substrate consistent with previously proposed functional cycles of mismatch recognition and repair initiation by MutS and homologs. A mechanism is proposed where pathways are switched without major conformational rearrangements allowing for efficient long-range signaling and allostery. PMID- 27768685 TI - Profitability and Market Value of Orphan Drug Companies: A Retrospective, Propensity-Matched Case-Control Study. AB - BACKGROUND: Concerns about the high cost of orphan drugs has led to questions being asked about the generosity of the incentives for development, and associated company profits. METHODS: We conducted a retrospective, propensity score matched study of publicly-listed orphan companies. Cases were defined as holders of orphan drug market authorisation in Europe or the USA between 2000-12. Control companies were selected based on their propensity for being orphan drug market authorisation holders. We applied system General Method of Moments to test whether companies with orphan drug market authorization are valued higher, as measured by the Tobin's Q and market to book value ratios, and are more profitable based on return on assets, than non-orphan drug companies. RESULTS: 86 companies with orphan drug approvals in European (4), USA (61) or both (21) markets were matched with 258 controls. Following adjustment, orphan drug market authorization holders have a 9.6% (95% confidence interval, 0.6% to 18.7%) higher return on assets than non-orphan drug companies; Tobin's Q was higher by 9.9% (1.0% to 19.7%); market to book value by 15.7% (3.1% to 30.0%) and operating profit by 516% (CI 19.8% to 1011%). For each additional orphan drug sold, return on assets increased by 11.1% (0.6% to 21.3%), Tobin's Q by 2.7% (0.2% to 5.2%), and market to book value ratio by 5.8% (0.7% to 10.9%). CONCLUSIONS: Publicly listed pharmaceutical companies that are orphan drug market authorization holders are associated with higher market value and greater profits than companies not producing treatments for rare diseases. PMID- 27768687 TI - PreTIS: A Tool to Predict Non-canonical 5' UTR Translational Initiation Sites in Human and Mouse. AB - Translation of mRNA sequences into proteins typically starts at an AUG triplet. In rare cases, translation may also start at alternative non-AUG codons located in the annotated 5' UTR which leads to an increased regulatory complexity. Since ribosome profiling detects translational start sites at the nucleotide level, the properties of these start sites can then be used for the statistical evaluation of functional open reading frames. We developed a linear regression approach to predict in-frame and out-of-frame translational start sites within the 5' UTR from mRNA sequence information together with their translation initiation confidence. Predicted start codons comprise AUG as well as near-cognate codons. The underlying datasets are based on published translational start sites for human HEK293 and mouse embryonic stem cells that were derived by the original authors from ribosome profiling data. The average prediction accuracy of true vs. false start sites for HEK293 cells was 80%. When applied to mouse mRNA sequences, the same model predicted translation initiation sites observed in mouse ES cells with an accuracy of 76%. Moreover, we illustrate the effect of in silico mutations in the flanking sequence context of a start site on the predicted initiation confidence. Our new webservice PreTIS visualizes alternative start sites and their respective ORFs and predicts their ability to initiate translation. Solely, the mRNA sequence is required as input. PreTIS is accessible at http://service.bioinformatik.uni-saarland.de/pretis. PMID- 27768686 TI - Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study. AB - Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development. PMID- 27768688 TI - Prolonged Intermittent Trunk Flexion Increases Trunk Muscles Reflex Gains and Trunk Stiffness. AB - The goal of the present study was to determine the effects of prolonged, intermittent flexion on trunk neuromuscular control. Furthermore, the potential beneficial effects of passive upper body support during flexion were investigated. Twenty one healthy young volunteers participated during two separate visits in which they performed 1 hour of intermittent 60 seconds flexion and 30 seconds rest cycles. Flexion was set at 80% lumbar flexion and was performed with or without upper body support. Before and after intermittent flexion exposure, lumbar range of motion was measured using inertial measurement units and trunk stability was assessed during perturbations applied in the forward direction with a force controlled actuator. Closed-loop system identification was used to determine the trunk translational admittance and reflexes as frequency response functions. The admittance describes the actuator displacement as a function of contact force and to assess reflexes muscle activation was related to actuator displacement. Trunk admittance gain decreased after unsupported flexion, while reflex gain and lumbar range of motion increased after both conditions. Significant interaction effects confirmed a larger increase in lumbar range of motion and reflex gains at most frequencies analysed following unsupported flexion in comparison to supported flexion, probably compensating for decreased passive tissue stiffness. In contrast with some previous studies we found that prolonged intermittent flexion decreased trunk admittance, which implies an increase of the lumped intrinsic and reflexive stiffness. This would compensate for decreased stiffness at the cost of an increase in cumulative low back load. Taking into account the differences between conditions it would be preferable to offer upper body support during activities that require prolonged trunk flexion. PMID- 27768689 TI - Near-Infrared Spectroscopy, a Rapid Method for Predicting the Age of Male and Female Wild-Type and Wolbachia Infected Aedes aegypti. AB - Estimating the age distribution of mosquito populations is crucial for assessing their capacity to transmit disease and for evaluating the efficacy of available vector control programs. This study reports on the capacity of the near-infrared spectroscopy (NIRS) technique to rapidly predict the ages of the principal dengue and Zika vector, Aedes aegypti. The age of wild-type males and females, and males and females infected with wMel and wMelPop strains of Wolbachia pipientis were characterized using this method. Calibrations were developed using spectra collected from their heads and thoraces using partial least squares (PLS) regression. A highly significant correlation was found between the true and predicted ages of mosquitoes. The coefficients of determination for wild-type females and males across all age groups were R2 = 0.84 and 0.78, respectively. The coefficients of determination for the age of wMel and wMelPop infected females were 0.71 and 0.80, respectively (P< 0.001 in both instances). The age of wild-type female Ae. aegypti could be identified as < or >= 8 days old with an accuracy of 91% (N = 501), whereas female Ae. aegypti infected with wMel and wMelPop were differentiated into the two age groups with an accuracy of 83% (N = 284) and 78% (N = 229), respectively. Our results also indicate NIRS can distinguish between young and old male wild-type, wMel and wMelPop infected Ae. aegypti with accuracies of 87% (N = 253), 83% (N = 277) and 78% (N = 234), respectively. We have demonstrated the potential of NIRS as a predictor of the age of female and male wild-type and Wolbachia infected Ae. aegypti mosquitoes under laboratory conditions. After field validation, the tool has the potential to offer a cheap and rapid alternative for surveillance of dengue and Zika vector control programs. PMID- 27768691 TI - Modeling and Simulation of the Economics of Mining in the Bitcoin Market. AB - In January 3, 2009, Satoshi Nakamoto gave rise to the "Bitcoin Blockchain", creating the first block of the chain hashing on his computer's central processing unit (CPU). Since then, the hash calculations to mine Bitcoin have been getting more and more complex, and consequently the mining hardware evolved to adapt to this increasing difficulty. Three generations of mining hardware have followed the CPU's generation. They are GPU's, FPGA's and ASIC's generations. This work presents an agent-based artificial market model of the Bitcoin mining process and of the Bitcoin transactions. The goal of this work is to model the economy of the mining process, starting from GPU's generation, the first with economic significance. The model reproduces some "stylized facts" found in real time price series and some core aspects of the mining business. In particular, the computational experiments performed can reproduce the unit root property, the fat tail phenomenon and the volatility clustering of Bitcoin price series. In addition, under proper assumptions, they can reproduce the generation of Bitcoins, the hashing capability, the power consumption, and the mining hardware and electrical energy expenditures of the Bitcoin network. PMID- 27768690 TI - Resolution of Pulsatile Tinnitus after Venous Sinus Stenting in Patients with Idiopathic Intracranial Hypertension. AB - OBJECTIVE: Evaluate the role of venous sinus stenting in the treatment of pulsatile tinnitus among patients with Idiopathic Intracranial Hypertension (IIH) and significant venous sinus stenosis. SUBJECTS AND METHODS: A written informed consent approved by the Weill Cornell institutional review board was signed and obtained from the study participants. Thirty-seven consecutive patients with IIH and venous sinus stenosis who were treated with venous sinus stenting between Jan.2012-Jan.2016 were prospectively evaluated. Patients without pulsatile tinnitus were excluded. Tinnitus severity was categorized based on "Tinnitus Handicap Inventory" (THI) at pre-stent, day-0, 1-month, 3-month, 6-month, 12 month, 18-month and 2-year follow-up. Demographics, body-mass index (BMI), pre and post VSS trans-stenotic pressure gradient were documented. Statistical analysis performed using Pearson's correlation, Chi-square analysis and Fischer's exact test. RESULTS: 29 patients with a mean age of 29.5+/-8.5 years M:F = 1:28. Median (mean) THI pre and post stenting were: 4 (3.7) and 1 (1) respectively. Median time of tinnitus resolution post VSS was 0-days. There was significant improvement of THI (Delta Mean: 2.7 THI [95% CI: 2.3-3.1 THI], p<0.001) and transverse-distal sigmoid sinus gradient (Delta Mean: -15.3 mm Hg [95% CI: 12.7 18 mm Hg], p<0.001) post-stenting. Mean follow-up duration of 26.4+/-9.8 months (3-44 months). VSS was feasible in 100% patients with no procedural complications. Three-patients (10%) had recurrent sinus stenosis and tinnitus at mean follow-up of 12 months (6-30 months). CONCLUSION: Venous sinus stenting is an effective treatment for pulsatile tinnitus in patients with IIH and venous sinus stenosis. PMID- 27768693 TI - A Comparison of Different Algorithms for the Assessment of Cardiovascular Risk in Patients at Waiting List for Kidney Transplantation. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death after renal transplantation with a high prevalence in dialysis patients. It is still a matter of debate how to assess the cardiovascular risk in kidney transplant candidates. Several approaches and scores exist and found their way into the guidelines. METHODS AND RESULTS: We herein assessed PROCAM, Framingham, ESC-SCORE and our own dedicated algorithm in patients applying for renal transplantation at our transplantation center between July 2006 and August 2009. Data of 347 consecutive patients were recorded at baseline and during a follow-up of 4.1 years regarding cardiovascular (CV) events and event-free and overall survival. During follow-up 31 (8.9%) patients died, 24 (6.9%) myocardial infarctions occurred and 19 (5.5%) patients received a new diagnosis of cerebrovascular disease. Predictors for event-free survival identified by univariable Cox regression analysis were age at start of dialysis, ESC-SCORE as well as our own score. Final multivariable model with a stepwise model building procedure revealed age at start of dialysis and smoking to be prognostic for event-free (hazard ratio 1.07/year and 2.15) and overall survival (1.10/year and 3.72). CONCLUSION: Comparison of CV risk assessment scores showed that ESC-SCORE most robustly predicted event-free and overall survival in our cohort. We conclude that CV risk assessment by ESC-SCORE can be reasonably performed in kidney transplant candidates. PMID- 27768692 TI - Genetic Dissection of Aversive Associative Olfactory Learning and Memory in Drosophila Larvae. AB - Memory formation is a highly complex and dynamic process. It consists of different phases, which depend on various neuronal and molecular mechanisms. In adult Drosophila it was shown that memory formation after aversive Pavlovian conditioning includes-besides other forms-a labile short-term component that consolidates within hours to a longer-lasting memory. Accordingly, memory formation requires the timely controlled action of different neuronal circuits, neurotransmitters, neuromodulators and molecules that were initially identified by classical forward genetic approaches. Compared to adult Drosophila, memory formation was only sporadically analyzed at its larval stage. Here we deconstruct the larval mnemonic organization after aversive olfactory conditioning. We show that after odor-high salt conditioning larvae form two parallel memory phases; a short lasting component that depends on cyclic adenosine 3'5'-monophosphate (cAMP) signaling and synapsin gene function. In addition, we show for the first time for Drosophila larvae an anesthesia resistant component, which relies on radish and bruchpilot gene function, protein kinase C activity, requires presynaptic output of mushroom body Kenyon cells and dopamine function. Given the numerical simplicity of the larval nervous system this work offers a unique prospect for studying memory formation of defined specifications, at full-brain scope with single-cell, and single-synapse resolution. PMID- 27768694 TI - Biological Activity of Coumarin Derivatives as Anti-Leishmanial Agents. AB - Cutaneous leishmaniasis affects nearly 0.7 to 1.3 million people annually. Treatment of this disease is difficult due to lack of appropriate medication and the growing problem of drug resistance. Natural compounds such as coumarins serve as complementary therapeutic agents in addition to the current treatment modalities. In this study, we have performed an in-silico screening of the coumarin derivatives and their anti-leishmanial properties has been explored both in-vitro and in-vivo. One of the compounds (compound 2) exhibited leishmanicidal activity and to further study its properties, nanoliposomal formulation of the compound was developed. Treatment of cutaneous lesions in BALB/c mice with compound 2 showed significantly reduced lesion size as compared to the untreated mice (p<0.05) suggesting that compound 2 may possess anti-leishmanial properties. PMID- 27768695 TI - Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. AB - The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773. PMID- 27768696 TI - Fine Mapping of a Dravet Syndrome Modifier Locus on Mouse Chromosome 5 and Candidate Gene Analysis by RNA-Seq. AB - A substantial number of mutations have been identified in voltage-gated sodium channel genes that result in various forms of human epilepsy. SCN1A mutations result in a spectrum of severity ranging from mild febrile seizures to Dravet syndrome, an infant-onset epileptic encephalopathy. Dravet syndrome patients experience multiple seizures types that are often refractory to treatment, developmental delays, and elevated risk for SUDEP. The same sodium channel mutation can produce epilepsy phenotypes of varying clinical severity. This suggests that other factors, including genetic, modify the primary mutation and change disease severity. Mouse models provide a useful tool in studying the genetic basis of epilepsy. The mouse strain background can alter phenotype severity, supporting a contribution of genetic modifiers in epilepsy. The Scn1a+/ mouse model has a strain-dependent epilepsy phenotype. Scn1a+/- mice on the 129S6/SvEvTac (129) strain have a normal phenotype and lifespan, while [129xC57BL/6J]F1-Scn1a+/- mice experience spontaneous seizures, hyperthermia induced seizures and high rates of premature death. We hypothesize the phenotypic differences are due to strain-specific genetic modifiers that influence expressivity of the Scn1a+/- phenotype. Low resolution mapping of Scn1a+/- identified several Dravet syndrome modifier (Dsm) loci responsible for the strain dependent difference in survival. One locus of interest, Dsm1 located on chromosome 5, was fine mapped to a 9 Mb region using interval specific congenics. RNA-Seq was then utilized to identify candidate modifier genes within this narrowed region. Three genes with significant total gene expression differences between 129S6/SvEvTac and [129xC57BL/6J]F1 were identified, including the GABAA receptor subunit, Gabra2. Further analysis of Gabra2 demonstrated allele-specific expression. Pharmological manipulation by clobazam, a common anticonvulsant with preferential affinity for the GABRA2 receptor, revealed dose-dependent protection against hyperthermia-induced seizures in Scn1a+/- mice. These findings support Gabra2 as a genetic modifier of the Scn1a+/- mouse model of Dravet syndrome. PMID- 27768697 TI - Cooperative Stimulation of Megakaryocytic Differentiation by Gfi1b Gene Targets Kindlin3 and Talin1. AB - Understanding the production and differentiation of megakaryocytes from progenitors is crucial for realizing the biology and functions of these vital cells. Previous gene ablation studies demonstrated the essential role of the transcriptional repressor Gfi1b (growth factor independence 1b) in the generation of both erythroid and megakaryocytic cells. However, our recent work has demonstrated the down-regulation of this factor during megakaryocytic differentiation. In this study we identify two new gene targets of Gfi1b, the cytoskeletal proteins Kindlin3 and Talin1, and demonstrate the inverse expression and functions of these cytoskeletal targets relative to Gfi1b, during megakaryocytic differentiation. Both kindlin3 and talin1 promoters exhibit dose dependent Gfi1b and LSD1 (lysine specific demethylase 1; a Gfi1b cofactor) enrichment in megakaryocytes and repression in non-hematopoietic cells. Accordingly the expression of these genes is elevated in gfi1b mutant and LSD1 inhibited hematopoietic cells, while during megakaryocytic differentiation, declining Gfi1b levels fostered the reciprocal upregulation of these cytoskeletal factors. Concordantly, manipulation of Kindlin3 and Talin1 expression demonstrated positive correlation with megakaryocytic differentiation with over expression stimulating, and inhibition diminishing, this process. Co-operativity between these factors and integrins in promoting differentiation was further underscored by physical interactions between them and integrinbeta3/CD61 and by stimulation of differentiation by the Talin1 head domain, which is necessary and sufficient for integrin activation. Therefore this study demonstrates the significance of Gfi1b regulated Kindlin3-Talin1 expression in driving megakaryocytic differentiation and highlights the contribution of cytoskeletal agents in the developmental progression of these platelet progenitors. PMID- 27768698 TI - Combining Attractants and Larvicides in Biodegradable Matrices for Sustainable Mosquito Vector Control. AB - BACKGROUND: There is a global need for cost-effective and environmentally friendly tools for control of mosquitoes and mosquito-borne diseases. One potential way to achieve this is to combine already available tools to gain synergistic effects to reduce vector mosquito populations. Another possible way to improve mosquito control is to extend the active period of a given control agent, enabling less frequent applications and consequently, more efficient and longer lasting vector population suppression. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the potential of biodegradable wax emulsions to improve the performance of semiochemical attractants for gravid female culicine vectors of disease, as well as to achieve more effective control of their aquatic larval offspring. As an attractant for gravid females, we selected acetoxy hexadecanolide (AHD), the Culex oviposition pheromone. As toxicant for mosquito larvae, we chose the biological larvicides Bacillus thuringiensis israelensis (Bti) and Bacillus sphaericus (Bs). These attractant and larvicidal agents were incorporated, separately and in combination, into a biodegradable wax emulsion, a commercially available product called SPLAT (Specialized Pheromone & Lure Application Technology) and SPLATbac, which contains 8.33% Bti and 8.33% Bs. Wax emulsions were applied to water surfaces as buoyant pellets of 20 mg each. Dose mortality analyses of Culex quinquefasciatus Say larvae demonstrated that a single 20 mg pellet of a 10-1 dilution of SPLATbac in a larval tray containing 1 L of water caused 100% mortality of neonate (1st instar) larvae for at least five weeks after application. Mortality of 3rd instar larvae remained equally high with SPLATbac dilutions down to 10-2 for over two weeks post application. Subsequently, AHD was added to SPLAT (emulsion only, without Bs or Bti) to attract gravid females (SPLATahd), or together with biological larvicides to attract ovipositing females and kill emerging larvae (SPLATbacAHD, 10-1 dilution) in both laboratory and semi-field settings. The formulations containing AHD, irrespective of presence of larvicides, were strongly preferred as an oviposition substrate by gravid female mosquitoes over controls for more than two weeks post application. Experiments conducted under semi-field settings (large screened greenhouse, emulating field conditions) confirmed the results obtained in the laboratory. The combination of attractant and larvicidal agents in a single formulation resulted in a substantial increase in larval mosquito mortality when compared to formulations containing the larvicide agents alone. CONCLUSIONS/SIGNIFICANCE: Collectively, our data demonstrate the potential for the effective use of wax emulsions as slow release matrices for mosquito attractants and control agents. The results indicate that the combination of an oviposition attractant with larvicides could synergize the control of mosquito disease vectors, specifically Cx. quinquefasciatus, a nuisance pest and circumtropical vector of lymphatic filariasis and encephalitis. PMID- 27768700 TI - Physicians' Trust in the FDA's Use of Product-Specific Pathways for Generic Drug Approval. AB - BACKGROUND: Generic drugs are cost-effective versions of brand-name drugs approved by the Food and Drug Administration (FDA) following proof of pharmaceutical equivalence and bioequivalence. Generic drugs are widely prescribed by physicians, although there is disagreement over the clinical comparability of generic drugs to brand-name drugs within the physician community. The objective of this survey was to assess physicians' perceptions of generic drugs and the generic drug approval process. METHODS AND FINDINGS: A survey was administered to a national sample of primary care internists and specialists between August 2014 and January 2015. In total, 1,152 physicians comprising of internists with no reported specialty certification and those with specialty certification in hematology, infectious diseases, and endocrinology were surveyed. The survey assessed physicians' perceptions of the FDA's generic drug approval process, as well as their experiences prescribing six generic drugs approved between 2008 and 2012 using product-specific approval pathways and selected comparator drugs. Among 718 respondents (62% response rate), a majority were comfortable with the FDA's process in ensuring the safety and effectiveness of generic drugs overall (91%) and with letting the FDA determine which tests were necessary to determine bioequivalence in a particular drug (92%). A minority (13-26%) still reported being uncomfortable prescribing generic drugs approved using product-specific pathways. Overall, few physicians heard reports of concerns about generic versions of the study drugs or their comparators, with no differences between the two groups. Physicians tended to hear about concerns about the safety or effectiveness of generic drugs from patients, pharmacists, and physician colleagues. CONCLUSIONS: Physicians hold largely positive views of the FDA's generic drug approval process even when some questioned the performance of certain generic drugs in comparison to brand-name drugs. Better education about the generic drug approval process and standards may alleviate concerns among the physician community and support the delivery of cost-effective health care. PMID- 27768699 TI - Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern. AB - During meiosis, chromosomes undergo a homology search in order to locate their homolog to form stable pairs and exchange genetic material. Early in prophase, chromosomes associate in mostly non-homologous pairs, tethered only at their centromeres. This phenomenon, conserved through higher eukaryotes, is termed centromere coupling in budding yeast. Both initiation of recombination and the presence of homologs are dispensable for centromere coupling (occurring in spo11 mutants and haploids induced to undergo meiosis) but the presence of the synaptonemal complex (SC) protein Zip1 is required. The nature and mechanism of coupling have yet to be elucidated. Here we present the first pairwise analysis of centromere coupling in an effort to uncover underlying rules that may exist within these non-homologous interactions. We designed a novel chromosome conformation capture (3C)-based assay to detect all possible interactions between non-homologous yeast centromeres during early meiosis. Using this variant of 3C qPCR, we found a size-dependent interaction pattern, in which chromosomes assort preferentially with chromosomes of similar sizes, in haploid and diploid spo11 cells, but not in a coupling-defective mutant (spo11 zip1 haploid and diploid yeast). This pattern is also observed in wild-type diploids early in meiosis but disappears as meiosis progresses and homologous chromosomes pair. We found no evidence to support the notion that ancestral centromere homology plays a role in pattern establishment in S. cerevisiae post-genome duplication. Moreover, we found a role for the meiotic bouquet in establishing the size dependence of centromere coupling, as abolishing bouquet (using the bouquet-defective spo11 ndj1 mutant) reduces it. Coupling in spo11 ndj1 rather follows telomere clustering preferences. We propose that a chromosome size preference for centromere coupling helps establish efficient homolog recognition. PMID- 27768701 TI - The Economic Burden of Road Traffic Injuries on Households in South Asia. AB - Globally, road traffic injuries accounted for about 1.36 million deaths in 2015 and are projected to become the fourth leading cause of disability-adjusted life years (DALYs) lost by 2030. One-fifth of these deaths occurred in South Asia where road traffic injuries are projected to increase by 144% by 2020. Despite this rapidly increasing disease burden there is limited evidence on the economic burden of road traffic injuries on households in South Asia. We applied a novel coarsened exact matching method to assess the household economic burden of road traffic injuries using nationally representative World Health Survey data from five South Asian countries- Bangladesh, India, Nepal, Pakistan and Sri Lanka collected during 2002-2003. We examined the impact of road traffic injuries on household out-of-pocket (OOP) health spending, household non-medical consumption expenditure and the employment status of the traffic injury-affected respondent. We exactly matched a household (after 'coarsening') where a respondent reported being involved in a road traffic injury to households where the respondent did not report a road traffic injury on each of multiple observed household characteristics. Our analysis found that road traffic injury-affected households had significantly higher levels of OOP health spending per member (I$0.75, p<0.01), higher OOP spending on drugs per member (I$0.30, p = 0.03), and higher OOP hospital spending per member (I$0.29, p<0.01) in the four weeks preceding the survey. Indicators of "catastrophic spending" were also significantly higher in road traffic injury-affected households: 6.45% (p<0.01) for a threshold of OOP health spending to total household spending ratio of 20%, and 7.40% (p<0.01) for a threshold of OOP health spending to household 'capacity to pay' ratio of 40%. However, no statistically significant effects were observed for household non medical consumption expenditure, and employment status of the road traffic injury affected individual. Our analysis points to the need for financial risk protection against the road traffic injury-related OOP health expenditure and a focus on prevention. PMID- 27768702 TI - Genomic Regions Associated with Root Traits under Drought Stress in Tropical Maize (Zea mays L.). AB - An association mapping panel, named as CIMMYT Asia association mapping (CAAM) panel, involving 396 diverse tropical maize lines were phenotyped for various structural and functional traits of roots under drought and well-watered conditions. The experiment was conducted during Kharif (summer-rainy) season of 2012 and 2013 in root phenotyping facility at CIMMYT-Hyderabad, India. The CAAM panel was genotyped to generate 955, 690 SNPs through GBS v2.7 using Illumina Hi seq 2000/2500 at Institute for Genomic Diversity, Cornell University, Ithaca, NY, USA. GWAS analysis was carried out using 331,390 SNPs filtered from the entire set of SNPs revealed a total of 50 and 67 SNPs significantly associated for root functional (transpiration efficiency, flowering period water use) and structural traits (rooting depth, root dry weight, root length, root volume, root surface area and root length density), respectively. In addition to this, 37 SNPs were identified for grain yield and shoot biomass under well-watered and drought stress. Though many SNPs were found to have significant association with the traits under study, SNPs that were common for more than one trait were discussed in detail. A total 18 SNPs were found to have common association with more than one trait, out of which 12 SNPs were found within or near the various gene functional regions. In this study we attempted to identify the trait specific maize lines based on the presence of favorable alleles for the SNPs associated with multiple traits. Two SNPs S3_128533512 and S7_151238865 were associated with transpiration efficiency, shoot biomass and grain yield under well-watered condition. Based on favorable allele for these SNPs seven inbred lines were identified. Similarly, four lines were identified for transpiration efficiency and shoot biomass under drought stress based on the presence of favorable allele for the common SNPs S1_211520521, S2_20017716, S3_57210184 and S7_130878458 and three lines were identified for flowering period water-use, transpiration efficiency, root dry weight and root volume based on the presence of favorable allele for the common SNPs S3_162065732 and S3_225760139. PMID- 27768703 TI - Contrasting Influences of Geographic Range and Distribution of Populations on Patterns of Genetic Diversity in Two Sympatric Pilbara Acacias. AB - The influence of geographic range on species persistence has long been of interest and there is a need for a better understanding of the genetic consequences for species with restricted distributions, particularly with the increasing rate of global species extinctions. However, the genetic effects of restricted range are often confounded by the impacts of population distribution. We compared chloroplast and nuclear genetic diversity and differentiation in two acacias, the restricted, patchily distributed Acacia atkinsiana and the widespread, semi-continuously distributed A. ancistrocarpa. Lower intra population diversity and higher differentiation between populations were seen in A. atkinsiana compared to its widespread congener, A. ancistrocarpa. There was little evidence of geographical influences on population genetic structure in A. ancistrocarpa whereas A. atkinsiana exhibited nuclear genetic structure with isolation by distance, differentiation of near-coastal populations from those in the ranges, and differentiation of peripheral populations from those in the centre of the distribution. These results are consistent with expectations of the effect of geographic range and population distribution on genetic diversity, but indicate that distribution of populations rather than geographic range has influenced the observed genetic structure. The contrasting patterns observed here demonstrate that conservation approaches for species management and ecological restoration need to consider the distribution of populations in geographically restricted species. PMID- 27768705 TI - Urbanized White Ibises (Eudocimus albus) as Carriers of Salmonella enterica of Significance to Public Health and Wildlife. AB - Worldwide, Salmonella spp. is a significant cause of disease for both humans and wildlife, with wild birds adapted to urban environments having different opportunities for pathogen exposure, infection, and transmission compared to their natural conspecifics. Food provisioning by people may influence these factors, especially when high-density mixed species flocks aggregate. White Ibises (Eudocimus albus), an iconic Everglades species in decline in Florida, are becoming increasingly common in urbanized areas of south Florida where most are hand-fed. We examined the prevalence of Salmonella shedding by ibises to determine the role of landscape characteristics where ibis forage and their behavior, on shedding rates. We also compared Salmonella isolated from ibises to human isolates to better understand non-foodborne human salmonellosis. From 2010 2013, 13% (n = 261) adult/subadult ibises and 35% (n = 72) nestlings sampled were shedding Salmonella. The prevalence of Salmonella shedding by ibises significantly decreased as the percent of Palustrine emergent wetlands and herbaceous grasslands increased, and increased as the proportion of open developed land types (e.g. parks, lawns, golf courses) increased, suggesting that natural ecosystem land cover types supported birds with a lower prevalence of infection. A high diversity of Salmonella serotypes (n = 24) and strain types (43 PFGE types) were shed by ibises, of which 33% of the serotypes ranked in the top 20 of high significance for people in the years of the study. Importantly, 44% of the Salmonella Pulsed-Field Gel Electrophoresis patterns for ibis isolates (n = 43) matched profiles in the CDC PulseNet USA database. Of these, 20% came from Florida in the same three years we sampled ibis. Importantly, there was a negative relationship between the amount of Palustrine emergent wetland and the number of Salmonella isolates from ibises that matched human cases in the PulseNet database (p = 0.056). Together, our results indicate that ibises are good indicators of salmonellae strains circulating in their environment and they have both the potential and opportunity to transmit salmonellae to people. Finally, they may act as salmonellae carriers to natural environments where other more highly-susceptible groups (nestlings) may be detrimentally affected. PMID- 27768704 TI - A Meta-Analysis of the Association between Gender and Protective Behaviors in Response to Respiratory Epidemics and Pandemics. AB - Respiratory infectious disease epidemics and pandemics are recurring events that levy a high cost on individuals and society. The health-protective behavioral response of the public plays an important role in limiting respiratory infectious disease spread. Health-protective behaviors take several forms. Behaviors can be categorized as pharmaceutical (e.g., vaccination uptake, antiviral use) or non pharmaceutical (e.g., hand washing, face mask use, avoidance of public transport). Due to the limitations of pharmaceutical interventions during respiratory epidemics and pandemics, public health campaigns aimed at limiting disease spread often emphasize both non-pharmaceutical and pharmaceutical behavioral interventions. Understanding the determinants of the public's behavioral response is crucial for devising public health campaigns, providing information to parametrize mathematical models, and ultimately limiting disease spread. While other reviews have qualitatively analyzed the body of work on demographic determinants of health-protective behavior, this meta-analysis quantitatively combines the results from 85 publications to determine the global relationship between gender and health-protective behavioral response. The results show that women in the general population are about 50% more likely than men to adopt/practice non-pharmaceutical behaviors. Conversely, men in the general population are marginally (about 12%) more likely than women to adopt/practice pharmaceutical behaviors. It is possible that factors other than pharmaceutical/non-pharmaceutical status not included in this analysis act as moderators of this relationship. These results suggest an inherent difference in how men and women respond to epidemic and pandemic respiratory infectious diseases. This information can be used to target specific groups when developing non-pharmaceutical public health campaigns and to parameterize epidemic models incorporating demographic information. PMID- 27768706 TI - TCS1, a Microtubule-Binding Protein, Interacts with KCBP/ZWICHEL to Regulate Trichome Cell Shape in Arabidopsis thaliana. AB - How cell shape is controlled is a fundamental question in developmental biology, but the genetic and molecular mechanisms that determine cell shape are largely unknown. Arabidopsis trichomes have been used as a good model system to investigate cell shape at the single-cell level. Here we describe the trichome cell shape 1 (tcs1) mutants with the reduced trichome branch number in Arabidopsis. TCS1 encodes a coiled-coil domain-containing protein. Pharmacological analyses and observations of microtubule dynamics show that TCS1 influences the stability of microtubules. Biochemical analyses and live-cell imaging indicate that TCS1 binds to microtubules and promotes the assembly of microtubules. Further results reveal that TCS1 physically associates with KCBP/ZWICHEL, a microtubule motor involved in the regulation of trichome branch number. Genetic analyses indicate that kcbp/zwi is epistatic to tcs1 with respect to trichome branch number. Thus, our findings define a novel genetic and molecular mechanism by which TCS1 interacts with KCBP to regulate trichome cell shape by influencing the stability of microtubules. PMID- 27768707 TI - Dom34 Links Translation to Protein O-mannosylation. AB - In eukaryotes, Dom34 upregulates translation by securing levels of activatable ribosomal subunits. We found that in the yeast Saccharomyces cerevisiae and the human fungal pathogen Candida albicans, Dom34 interacts genetically with Pmt1, a major isoform of protein O-mannosyltransferase. In C. albicans, lack of Dom34 exacerbated defective phenotypes of pmt1 mutants, while they were ameliorated by Dom34 overproduction that enhanced Pmt1 protein but not PMT1 transcript levels. Translational effects of Dom34 required the 5'-UTR of the PMT1 transcript, which bound recombinant Dom34 directly at a CA/AC-rich sequence and regulated in vitro translation. Polysomal profiling revealed that Dom34 stimulates general translation moderately, but that it is especially required for translation of transcripts encoding Pmt isoforms 1, 4 and 6. Because defective protein N- or O glycosylation upregulates transcription of PMT genes, it appears that Dom34 mediated specific translational upregulation of the PMT transcripts optimizes cellular responses to glycostress. Its translational function as an RNA binding protein acting at the 5'-UTR of specific transcripts adds another facet to the known ribosome-releasing functions of Dom34 at the 3'-UTR of transcripts. PMID- 27768708 TI - Diversity in Secondary Metabolites Including Mycotoxins from Strains of Aspergillus Section Nigri Isolated from Raw Cashew Nuts from Benin, West Africa. AB - In a previous study, raw cashew kernels were assayed for the fungal contamination focusing on strains belonging to the genus Aspergillus and on aflatoxins producers. These samples showed high contamination with Aspergillus section Nigri species and absence of aflatoxins. To investigate the diversity of secondary metabolites, including mycotoxins, the species of A. section Nigri may produce and thus threaten to contaminate the raw cashew kernels, 150 strains were isolated from cashew samples and assayed for their production of secondary metabolites using liquid chromatography high resolution mass spectrometry (LC HRMS). Seven species of black Aspergilli were isolated based on morphological and chemical identification: A. tubingensis (44%), A. niger (32%), A. brasiliensis (10%), A. carbonarius (8.7%), A. luchuensis (2.7%), A. aculeatus (2%) and A. aculeatinus (0.7%). From these, 45 metabolites and their isomers were identified. Aurasperone and pyranonigrin A, produced by all species excluding A. aculeatus and A. aculeatinus, were most prevalent and were encountered in 146 (97.3%) and 145 (95.7%) isolates, respectively. Three mycotoxins groups were detected: fumonisins (B2 and B4) (2.7%) ochratoxin A (13.3%), and secalonic acids (2%), indicating that these mycotoxins could occur in raw cashew nuts. Thirty strains of black Aspergilli were randomly sampled for verification of species identity based on sequences of beta-tubulin and calmodulin genes. Among them, 27 isolates were positive to the primers used and 11 were identified as A. niger, 7 as A. tubingensis, 6 as A. carbonarius, 2 as A. luchuensis and 1 as A. welwitschiae confirming the species names as based on morphology and chemical features. These strains clustered in 5 clades in A. section Nigri. Chemical profile clustering also showed also 5 groups confirming the species specific metabolites production. PMID- 27768709 TI - Maternal and Birth Characteristics and Childhood Embryonal Solid Tumors: A Population-Based Report from Brazil. AB - BACKGROUND: Several maternal and birth characteristics have been reported to be associated with an increased risk of many childhood cancers. Our goal was to evaluate the risk of childhood embryonal solid tumors in relation to pre- and perinatal characteristics. METHODS: A case-cohort study was performed using two population-based datasets, which were linked through R software. Tumors were classified as central nervous system (CNS) or non-CNS-embryonal (retinoblastoma, neuroblastoma, renal tumors, germ cell tumors, hepatoblastoma and soft tissue sarcoma). Children aged <6 years were selected. Adjustments were made for potential confounders. Odds ratios (OR) with 95% confidence intervals (CI) were computed by unconditional logistic regression analysis using SPSS. RESULTS: Males, high maternal education level, and birth anomalies were independent risk factors. Among children diagnosed older than 24 months of age, cesarean section (CS) was a significant risk factor. Five-minute Apgar <=8 was an independent risk factor for renal tumors. A decreasing risk with increasing birth order was observed for all tumor types except for retinoblastoma. Among children with neuroblastoma, the risk decreased with increasing birth order (OR = 0.82 (95% CI 0.67-1.01)). Children delivered by CS had a marginally significantly increased OR for all tumors except retinoblastoma. High maternal education level showed a significant increase in the odds for all tumors together, CNS tumors, and neuroblastoma. CONCLUSION: This evidence suggests that male gender, high maternal education level, and birth anomalies are risk factors for childhood tumors irrespective of the age at diagnosis. Cesarean section, birth order, and 5-minute Apgar score were risk factors for some tumor subtypes. PMID- 27768710 TI - Loss to Follow-Up from HIV Screening to ART Initiation in Rural China. AB - BACKGROUND: Patients who are newly screened HIV positive by EIA are lost to follow-up due to complicated HIV testing procedures. Because this is the first step in care, it affects the entire continuum of care. This is a particular concern in rural China. OBJECTIVE(S): To assess the routine HIV testing completeness and treatment initiation rates at 18 county-level general hospitals in rural Guangxi. METHODS: We reviewed original hospital HIV screening records. Investigators also engaged with hospital leaders and key personnel involved in HIV prevention activities to characterize in detail the routine care practices in place at each county. RESULTS: 699 newly screened HIV-positive patients between January 1 and June 30, 2013 across the 18 hospitals were included in the study. The proportion of confirmatory testing across the 18 hospitals ranged from 14% to 87% (mean of 43%), and the proportion of newly diagnosed individuals successfully initiated antiretroviral treatment across the hospitals ranged from 3% to 67% (mean of 23%). The average interval within hospitals for individuals to receive the Western Blot (WB) and CD4 test results from HIV positive screening (i.e. achieving testing completion) ranged from 14-116 days (mean of 41.7 days) across the hospitals. The shortest interval from receiving a positive EIA screening test result to receiving WB and CD4 testing and counseling was 0 day and the longest was 260 days. CONCLUSION: The proportion of patients newly screened HIV positive that completed the necessary testing procedures for HIV confirmation and received ART was very low. Interventions are urgently needed to remove barriers so that HIV patients can have timely access to HIV/AIDS treatment and care in rural China. PMID- 27768711 TI - Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis. AB - A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin. Further discovery efforts will require separating reported mammalian cell activity from both antibacterial activity and inhibition of Mtb FtsZ. Modeling studies suggest that these analogs bind in a specific region of the Mtb FtsZ polymer that differs from human tubulin and, in combination with a pharmacophore model presented herein, future hybrid analogs of the reported active molecules that more efficiently bind in this pocket may improve antibacterial activity while improving other drug characteristics. PMID- 27768713 TI - Religious Fragmentation, Social Identity and Conflict: Evidence from an Artefactual Field Experiment in India. AB - We examine the impact of religious identity and village-level religious fragmentation on behavior in Tullock contests. We report on a series of two player Tullock contest experiments conducted on a sample of 516 Hindu and Muslim participants in rural West Bengal, India. Our treatments are the identity of the two players and the degree of religious fragmentation in the village where subjects reside. Our main finding is that the effect of social identity is small and inconsistent across the two religious groups in our study. While we find small but statistically significant results in line with our hypotheses in the Hindu sample, we find no statistically significant effects in the Muslim sample. This is in contrast to evidence from Chakravarty et al. (2016), who report significant differences in cooperation levels in prisoners' dilemma and stag hunt games, both in terms of village composition and identity. We attribute this to the fact that social identity may have a more powerful effect on cooperation than on conflict. PMID- 27768714 TI - Computational Analysis of Distance Operators for the Iterative Closest Point Algorithm. AB - The Iterative Closest Point (ICP) algorithm is currently one of the most popular methods for rigid registration so that it has become the standard in the Robotics and Computer Vision communities. Many applications take advantage of it to align 2D/3D surfaces due to its popularity and simplicity. Nevertheless, some of its phases present a high computational cost thus rendering impossible some of its applications. In this work, it is proposed an efficient approach for the matching phase of the Iterative Closest Point algorithm. This stage is the main bottleneck of that method so that any efficiency improvement has a great positive impact on the performance of the algorithm. The proposal consists in using low computational cost point-to-point distance metrics instead of classic Euclidean one. The candidates analysed are the Chebyshev and Manhattan distance metrics due to their simpler formulation. The experiments carried out have validated the performance, robustness and quality of the proposal. Different experimental cases and configurations have been set up including a heterogeneous set of 3D figures, several scenarios with partial data and random noise. The results prove that an average speed up of 14% can be obtained while preserving the convergence properties of the algorithm and the quality of the final results. PMID- 27768712 TI - c.*84G>A Mutation in CETP Is Associated with Coronary Artery Disease in South Indians. AB - BACKGROUND: Coronary artery disease (CAD) is one of the leading causes of mortality worldwide. It is a multi-factorial disease and several studies have demonstrated that the genetic factors play a major role in CAD. Although variations in cholesteryl ester transfer protein (CETP) gene are reported to be associated with CAD, this gene has not been studied in South Indian populations. Hence we evaluated the CETP gene variations in CAD patients of South Indian origin. METHODS: We sequenced all the exons, exon-intron boundaries and UTRs of CETP in 323 CAD patients along with 300 ethnically and age matched controls. Variations observed in CETP were subjected to various statistical analyses. RESULTS AND DISCUSSION: Our analysis revealed a total of 13 variations. Of these, one3'UTRvariant rs1801706 (c.*84G>A) was significantly associated with CAD (genotype association test: OR = 2.16, 95% CI: 1.50-3.10, p = 1.88x10-5 and allelic association test: OR = 1.92, 95% CI: 1.40-2.63, p = 2.57x10-5). Mutant allele "A" was observed to influence the higher concentration of mRNA (p = 7.09*10-3, R2 = 0.029 and beta = 0.2163). Since expression of CETP has been shown to be positively correlated with the risk of CAD, higher frequency of "A" allele (patients: 22.69% vs.controls: 13%) reveals that c.*84G>A is a risk factor for CAD in South Indians. CONCLUSIONS: This is the first report of the CETP gene among South Indians CAD patients. Our results suggest that rs1801706 (c.*84G>A) is a risk factor for CAD in South Indian population. PMID- 27768715 TI - Functional and Structural Characterization of Purine Nucleoside Phosphorylase from Kluyveromyces lactis and Its Potential Applications in Reducing Purine Content in Food. AB - Consumption of foods and beverages with high purine content increases the risk of hyperuricemia, which causes gout and can lead to cardiovascular, renal, and other metabolic disorders. As patients often find dietary restrictions challenging, enzymatically lowering purine content in popular foods and beverages offers a safe and attractive strategy to control hyperuricemia. Here, we report structurally and functionally characterized purine nucleoside phosphorylase (PNP) from Kluyveromyces lactis (KlacPNP), a key enzyme involved in the purine degradation pathway. We report a 1.97 A resolution crystal structure of homotrimeric KlacPNP with an intrinsically bound hypoxanthine in the active site. KlacPNP belongs to the nucleoside phosphorylase-I (NP-I) family, and it specifically utilizes 6-oxopurine substrates in the following order: inosine > guanosine > xanthosine, but is inactive towards adenosine. To engineer enzymes with broad substrate specificity, we created two point variants, KlacPNPN256D and KlacPNPN256E, by replacing the catalytically active Asn256 with Asp and Glu, respectively, based on structural and comparative sequence analysis. KlacPNPN256D not only displayed broad substrate specificity by utilizing both 6-oxopurines and 6-aminopurines in the order adenosine > inosine > xanthosine > guanosine, but also displayed reversal of substrate specificity. In contrast, KlacPNPN256E was highly specific to inosine and could not utilize other tested substrates. Beer consumption is associated with increased risk of developing gout, owing to its high purine content. Here, we demonstrate that KlacPNP and KlacPNPN256D could be used to catalyze a key reaction involved in lowering beer purine content. Biochemical properties of these enzymes such as activity across a wide pH range, optimum activity at about 25 degrees C, and stability for months at about 8 degrees C, make them suitable candidates for food and beverage industries. Since KlacPNPN256D has broad substrate specificity, a combination of engineered KlacPNP and other enzymes involved in purine degradation could effectively lower the purine content in foods and beverages. PMID- 27768716 TI - Do Children Copy an Expert or a Majority? Examining Selective Learning in Instrumental and Normative Contexts. AB - This study examined whether instrumental and normative learning contexts differentially influence 4- to 7-year-old children's social learning strategies; specifically, their dispositions to copy an expert versus a majority consensus. Experiment 1 (N = 44) established that children copied a relatively competent "expert" individual over an incompetent individual in both kinds of learning context. In experiment 2 (N = 80) we then tested whether children would copy a competent individual versus a majority, in each of the two different learning contexts. Results showed that individual children differed in strategy, preferring with significant consistency across two different test trials to copy either the competent individual or the majority. This study is the first to show that children prefer to copy more competent individuals when shown competing methods of achieving an instrumental goal (Experiment 1) and provides new evidence that children, at least in our "individualist" culture, may consistently express either a competency or majority bias in learning both instrumental and normative information (Experiment 2). This effect was similar in the instrumental and normative learning contexts we applied. PMID- 27768717 TI - Statistical Evidence Suggests that Inattention Drives Hyperactivity/Impulsivity in Attention Deficit-Hyperactivity Disorder. AB - BACKGROUND: Numerous factor analytic studies consistently support a distinction between two symptom domains of attention-deficit/hyperactivity disorder (ADHD), inattention and hyperactivity/impulsivity. Both dimensions show high internal consistency and moderate to strong correlations with each other. However, it is not clear what drives this strong correlation. The aim of this paper is to address this issue. METHOD: We applied a sophisticated approach for causal discovery on three independent data sets of scores of the two ADHD dimensions in NeuroIMAGE (total N = 675), ADHD-200 (N = 245), and IMpACT (N = 164), assessed by different raters and instruments, and further used information on gender or a genetic risk haplotype. RESULTS: In all data sets we found strong statistical evidence for the same pattern: the clear dependence between hyperactivity/impulsivity symptom level and an established genetic factor (either gender or risk haplotype) vanishes when one conditions upon inattention symptom level. Under reasonable assumptions, e.g., that phenotypes do not cause genotypes, a causal model that is consistent with this pattern contains a causal path from inattention to hyperactivity/impulsivity. CONCLUSIONS: The robust dependency cancellation observed in three different data sets suggests that inattention is a driving factor for hyperactivity/impulsivity. This causal hypothesis can be further validated in intervention studies. Our model suggests that interventions that affect inattention will also have an effect on the level of hyperactivity/impulsivity. On the other hand, interventions that affect hyperactivity/impulsivity would not change the level of inattention. This causal model may explain earlier findings on heritable factors causing ADHD reported in the study of twins with learning difficulties. PMID- 27768718 TI - A Composite Network Approach for Assessing Multi-Species Connectivity: An Application to Road Defragmentation Prioritisation. AB - One of the biggest challenges in large-scale conservation is quantifying connectivity at broad geographic scales and for a large set of species. Because connectivity analyses can be computationally intensive, and the planning process quite complex when multiple taxa are involved, assessing connectivity at large spatial extents for many species turns to be often intractable. Such limitation results in that conducted assessments are often partial by focusing on a few key species only, or are generic by considering a range of dispersal distances and a fixed set of areas to connect that are not directly linked to the actual spatial distribution or mobility of particular species. By using a graph theory framework, here we propose an approach to reduce computational effort and effectively consider large assemblages of species in obtaining multi-species connectivity priorities. We demonstrate the potential of the approach by identifying defragmentation priorities in the Italian road network focusing on medium and large terrestrial mammals. We show that by combining probabilistic species graphs prior to conducting the network analysis (i) it is possible to analyse connectivity once for all species simultaneously, obtaining conservation or restoration priorities that apply for the entire species assemblage; and that (ii) those priorities are well aligned with the ones that would be obtained by aggregating the results of separate connectivity analysis for each of the individual species. This approach offers great opportunities to extend connectivity assessments to large assemblages of species and broad geographic scales. PMID- 27768719 TI - rLj-RGD3, a Novel Recombinant Toxin Protein from Lampetra japonica, Protects against Cerebral Reperfusion Injury Following Middle Cerebral Artery Occlusion Involving the Integrin-PI3K/Akt Pathway in Rats. AB - BACKGROUND: The RGD-toxin protein Lj-RGD3 is a naturally occurring 118 amino acid peptide that can be obtained from the salivary gland of the Lampetra japonica fish. This unique peptide contains 3 RGD (Arg-Gly-Asp) motifs in its primary structure. Lj-RGD3 is available in recombinant form (rLj-RGD3) and can be produced in large quantities using DNA recombination techniques. The pharmacology of the three RGD motif-containing peptides has not been studied. This study investigated the protective effects of rLj-RGD3, a novel polypeptide, against ischemia/reperfusion-induced damage to the brain caused by middle cerebral artery occlusion (MCAO) in a rat stroke model. We also explored the mechanism by which rLj-RGD3 acts by measuring protein and mRNA expression levels, with an emphasis on the FAK and integrin-PI3K/Akt anti-apoptosis pathways. METHODS: rLj-RGD3 was obtained from the buccal secretions of Lampetra japonica using gene recombination technology. Sprague Dawley (SD) rats were randomly divided into the following seven groups: a sham group; a vehicle-treated (VT) group; 100.0 MUg.kg-1, 50.0 MUg.kg-1 and 25.0 MUg.kg-1 dose rLj-RGD3 groups; and two positive controls, including 1.5 mg.kg-1 Edaravone (ED) and 100.0 MUg.kg-1 Eptifibatide (EP). MCAO was induced using a model consisting of 2 h of ischemia and 24 h of reperfusion. Behavioral changes were observed in the normal and operation groups after focal cerebral ischemia/reperfusion was applied. In addition, behavioral scores were evaluated at 4 and 24 h after reperfusion. Brain infarct volumes were determined based on 2,3,5-triphenyltetrazolium chloride (TTC) staining. Pathological changes in brain tissues were observed using hematoxylin and eosin (H&E) staining. Moreover, neuronal apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assays. We determined the expression levels of focal adhesion kinase (FAK), phosphatidyl inositol 3 kinase (PI3K), protein kinase B (Akt, PKB), caspase-3 and Bcl-2 in the brain using western blot analysis and RT-PCR assays. The research protocol was approved by the Institutional Ethics Committee of Dalian Medical University. RESULTS: The behavioral scores and cerebral infarct volumes of the rLj-RGD3 groups were markedly lower at 4 and 24 h/RF. The rLj-RGD3 protein significantly ameliorated pathological changes in the brain and reduced the number of apoptotic neurons. Furthermore, the FAK and PI3K/Akt pathways were activated. rLj-RGD3 significantly increased the expression of FAK, p-FAK and Bcl-2 proteins. In contrast, caspase-3 expression was inhibited. CONCLUSION/SIGNIFICANCE: We conclude that recombinant Lampetra japonica RGD-peptide (rLj-RGD3) exerts a protective effect against cerebral ischemia/reperfusion injury in the brain. In addition, the mechanism of this protection is associated with the activation of the integrin-PI3K/Akt pathway. These results provide a theoretical foundation and an experimental basis for using RGD peptides as novel drugs for treating ischemic cerebral vascular diseases in addition to promoting the research and development of marine biotechnology drugs. PMID- 27768721 TI - Regulation of Srpr Expression by miR-330-5p Controls Proliferation of Mouse Epidermal Keratinocyte. AB - Srpr is a gene encoding alpha subunit of the signal recognition particle receptor which is involved in the targeting and translocation of nascent secretory and membrane proteins to the endoplasmic reticulum. Previous studies showed aberrant expression of Srpr in several cell types with abnormal growth rate. Although Srpr is expressed in various tissues including skin, the role of Srpr in keratinocytes and regulation of its expression by miRNAs have not been studied. In this study, we investigated the role of SRPR and regulation of its expression by miRNA in skin keratinocytes. We found that SRPR was highly expressed in epidermal keratinocytes and regulated keratinocyte proliferation by affecting cell cycle progression. We also demonstrated that miR-330-5p directly inhibits Srpr expression. These data suggest that miR-330-5p-mediated regulation of the SRPR level is needed for the regulation of proliferation of epidermal keratinocytes. PMID- 27768720 TI - Risk Factors for Fatal Hyperglycaemia Confirmed by Forensic Postmortem Examination - A Nationwide Cohort in Sweden. AB - AIMS/HYPOTHESIS: The aim of this study was to identify risk factors associated with confirmed fatal hyperglycaemia, which could predispose potentially preventable deaths in individuals on glucose lowering drugs. METHODS: A retrospective register-based case-control study conducted on a nationwide cohort with individuals who died due to hyperglycaemia as determined by forensic postmortem examination, in Sweden August 2006 to December 2012. Vitreous glucose was used to diagnose hyperglycaemia postmortem. The forensic findings stored in the National Forensic Medicine Database were linked to nationwide registers. Cases that died due to confirmed hyperglycemia with dispensed glucose lowering drugs were identified and living controls with dispensed glucose lowering drugs were randomly selected in the Swedish prescribed drug register and matched on age and sex. Information on comorbidities, dispensed pharmaceuticals, clinical data and socioeconomic factors were obtained for cases and controls. Adjusted multiple logistic regression models were used to identify risk factors associated with fatal hyperglycaemia. RESULTS: During the study period 322 individuals, mostly males (79%) with the mean age of 53.9 years (SD.+/- 14) died due to confirmed hyperglycaemia. Risk factors for fatal hyperglycaemia included; insulin treatment (OR = 4.40; 95%CI,1.96, 9.85), poor glycaemic control (OR = 2.00 95%CI,1.23, 3.27), inadequate refill-adherence before death (OR = 3.87; 95%CI,1.99, 7.53), microvascular disease (OR = 3.26; 95% CI, 1.84, 5.79), psychiatric illness (OR = 2.30; 95% CI,1.32, 4.01), substance abuse (OR = 8.85; 95%CI,2.34, 35.0) and/or living alone (OR = 2.25; 95%CI,1.21, 4.18). CONCLUSIONS/INTERPRETATION: Our results demonstrate the importance of clinical attention to poor glycaemic control in subjects with psychosocial problems since it may indicate serious non adherence, which consequently could lead to fatal hyperglycaemia. PMID- 27768722 TI - The Heparan Sulfate Proteoglycan Glypican-6 Is Upregulated in the Failing Heart, and Regulates Cardiomyocyte Growth through ERK1/2 Signaling. AB - Pressure overload is a frequent cause of heart failure. Heart failure affects millions of patients worldwide and is a major cause of morbidity and mortality. Cell surface proteoglycans are emerging as molecular players in cardiac remodeling, and increased knowledge about their regulation and function is needed for improved understanding of cardiac pathogenesis. Here we investigated glypicans (GPC1-6), a family of evolutionary conserved heparan sulfate proteoglycans anchored to the extracellular leaflet of the cell membrane, in experimental and clinical heart failure, and explored the function of glypican-6 in cardiac cells in vitro. In mice subjected to pressure overload by aortic banding (AB), we observed elevated glypican-6 levels during hypertrophic remodeling and dilated, end-stage heart failure. Consistently, glypican-6 mRNA was elevated in left ventricular myocardium from explanted hearts of patients with end-stage, dilated heart failure with reduced ejection fraction. Glypican-6 levels correlated negatively with left ventricular ejection fraction in patients, and positively with lung weight after AB in mice. Glypican-6 mRNA was expressed in both cardiac fibroblasts and cardiomyocytes, and the corresponding protein displayed different sizes in the two cell types due to tissue-specific glycanation. Importantly, adenoviral overexpression of glypican-6 in cultured cardiomyocytes increased protein synthesis and induced mRNA levels of the pro hypertrophic signature gene ACTA1 and the hypertrophy and heart failure signature genes encoding natriuretic peptides, NPPA and NPPB. Overexpression of GPC6 induced ERK1/2 phosphorylation, and co-treatment with the ERK inhibitor U0126 attenuated the GPC6-induced increase in NPPA, NPPB and protein synthesis. In conclusion, our data suggests that glypican-6 plays a role in clinical and experimental heart failure progression by regulating cardiomyocyte growth through ERK signaling. PMID- 27768725 TI - Failure to Genotype: A Cautionary Note on an Elusive loxP Sequence. AB - Here we report on a technical difficulty we encountered while optimizing genotyping strategies to identify mice derived from Exoc3l2tm1a(KOMP)Wtsi embryonic stem cells obtained from the Knockout Mouse Project Repository. The Exoc3l2tm1a(KOMP)Wtsi construct encodes a "knockout-first" design with loxP sites that confer conditional potential (KO1st). We designed primers that targeted wild type sequences flanking the most downstream element of the construct, an 80 base pair synthetic loxP region, which BLAST alignment analysis reveals is an element common to over 10,000 conditional gene-targeting mouse models. As PCR products amplified from KO1st and wild-type templates would have different lengths (and different mobility in an agarose gel) this strategy was designed to determine the zygosity of individual mice from a single PCR. In parallel we performed PCR with a primer specifically targeting the synthetic loxP sequence. Unexpectedly, while the latter strategy detected the synthetic loxP region and correctly genotyped KO1st chimeric mice, the same individuals were genotyped as wild-type when using the primers that flanked the synthetic loxP region. We discuss the possibility that secondary DNA structures, formed due to the palindromic nature of the synthetic loxP region, may have caused the KO1st template to elude the PCR when using primers that flanked this region. This brief report aims to raise awareness regarding this potential source of false-negative genotype results, particularly for those who are devising genotyping strategies for similarly engineered animal models. PMID- 27768723 TI - Dissecting the Origin of Breast Cancer Subtype Stem Cell and the Potential Mechanism of Malignant Transformation. AB - BACKGROUND: Breast cancer is the most common incident form of cancer in women including different subtypes. Cancer stem cells (CSCs) have been confirmed to exist in breast cancer. But the research on the origin of breast cancer subtype stem cells (BCSSCs) is still inadequate. METHODS: We identified the putative origin cells of BCSSCs through comparing gene signatures between BCSSCs and normal mammary cells from multiple perspectives: common signature, expression consistency, functional similarity and shortest path length. First, the potential origin cells were ranked according to these measures separately. Then Q statistic was employed to combine all rank lists into a unique list for each subtype, to prioritize the origin cells for each BCSSC. Next, we identified origin-related gene modules through integrating functional interaction network with differentially expressed genes. Finally, transcription factors of significant gene modules were predicted by MatchTM. RESULTS: The results showed that Luminal A CSC was most relevant to luminal progenitor cell or mature luminal cell; luminal B and HER2 CSC were most relevant to bipotent-enriched progenitor cell; basal-like CSC was most relevant to bipotent-enriched progenitor cell or mature luminal cell. Network modules analysis revealed genes related to mitochondrial respiratory chain (MRC) were significantly dysregulated during the origin of luminal B CSC. In addition, SOX10 emerged as a key regulator of MRC. CONCLUSIONS: Our study supports substantive evidence for the possible origin of four kinds of BCSSCs. Dysfunction of MRC may contribute to the origin of luminal B CSC. These findings may have important implications to treat and prevent breast cancer. PMID- 27768724 TI - Three Toxic Heavy Metals in Open-Angle Glaucoma with Low-Teen and High-Teen Intraocular Pressure: A Cross-Sectional Study from South Korea. AB - BACKGROUND: To investigate the association between heavy metal levels and open angle glaucoma (OAG) with low- and high-teen baseline intraocular pressure (IOP) using a population-based study design. METHODS: This cross-sectional study included 5,198 participants older than 19 years of age who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) from 2008 to 2012 and had blood heavy metal levels available. The OAG with normal baseline IOP (IOP <= 21 mmHg) subjects were stratified into low-teen OAG (baseline IOP <= 15 mmHg) and high-teen OAG (15 mmHg < baseline IOP <= 21 mmHg), and the association between blood lead, mercury, and cadmium levels and glaucoma prevalence was assessed for low- and high-teen OAG. RESULTS: The adjusted geometric mean of blood cadmium levels was significantly higher in subjects with low-teen OAG than that of the non-glaucomatous group (P = 0.028), whereas there were no significant differences in blood lead and mercury levels. After adjusting for potential confounders, the low-teen OAG was positively associated with log-transformed blood cadmium levels (OR, 1.41; 95% confidence interval (CI), 1.03-1.93; P = 0.026). For high-teen OAG, log-transformed blood levels of the three heavy metals were not associated with disease prevalence. The association between log transformed blood cadmium levels and low-teen OAG was significant only in men (OR, 1.65; 95% CI, 1.10-2.48; P = 0.016), and not in women (OR, 1.10; 95% CI, 0.66-1.85; P = 0.709). CONCLUSIONS: The results of this study suggest that cadmium toxicity could play a role in glaucoma pathogenesis, particularly in men and in OAG with low-teen baseline IOP. PMID- 27768726 TI - IBMPFD Disease-Causing Mutant VCP/p97 Proteins Are Targets of Autophagic Lysosomal Degradation. AB - The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone. We showed that, unlike commonly studied R155C or R191Q mutants, the P137L mutant protein stimulated both autophagosome and autolysosome formation. Moreover, P137L mutant protein itself was a substrate of autophagy. Starvation- and mTOR inhibition-induced autophagy led to the degradation of the P137L mutant protein, while preserving the wild type and functional VCP/p97. Strikingly, similar to the P137L mutant, other IBMPFD-related VCP/p97 mutants, namely R93C and G157R mutants induced autophagosome and autolysosome formation; and G157R mutant formed aggregates that could be cleared by autophagy. Therefore, cellular phenotypes caused by P137L mutant expression were not isolated observations, and some other IBMPFD disease related VCP/p97 mutations could lead to similar outcomes. Our results indicate that cellular mechanisms leading to IBMPFD disease may be various, and underline the importance of studying different disease-associated mutations in order to better understand human pathologies and tailor mutation-specific treatment strategies. PMID- 27768728 TI - Severity of Carpal Tunnel Syndrome and Diagnostic Accuracy of Hand and Body Anthropometric Measures. AB - OBJECTIVE: To study the diagnostic properties of hand/wrist and body measures according to validated clinical and electrophysiological carpal tunnel syndrome (CTS) severity scales. METHODS: We performed a prospective case-control study. For each case, two controls were enrolled. Two five-stage clinical and electrophysiological scales were used to evaluate CTS severity. Anthropometric measurements were collected and obesity indicators and hand/wrist ratios were calculated. Area under the receiver operating characteristic curves (AUC), sensitivity, specificity, and likelihood ratios were calculated separately by gender. RESULTS: We consecutively enrolled 370 cases and 747 controls. The wrist palm ratio, waist-hip-height ratio and waist-stature ratio showed the highest proportion of cases with abnormal values in the severe stages of CTS for clinical and electrophysiological severity scales in both genders. Accuracy tended to increase with CTS severity for females and males. In severe stage, most of the indexes presented moderate accuracy in both genders. Among subjects with severe CTS, the wrist-palm ratio presented the highest AUC for hand measures in the clinical and electrophysiological severity scales both in females (AUC 0.83 and 0.76, respectively) and males (AUC 0.91 and 0.82, respectively). Among subjects with severe CTS, the waist-stature ratio showed the highest AUC for body measures in the clinical and electrophysiological severity scales both in females (AUC 0.78 and 0.77, respectively) and males (AUC 0.84 and 0.76, respectively). The results of waist-hip-height ratio AUC were similar. CONCLUSIONS: Wrist-palm ratio, waist-hip-height ratio and waist-stature ratio could contribute to support the diagnostic hypothesis of severe CTS that however has to be confirmed by nerve conduction study. PMID- 27768729 TI - Segregation Analysis Suggests That a Genetic Reason May Contribute to "the Dress" Colour Perception. AB - In early 2015, the debate of blue-black and white-gold color perception from "the dress" became an overnight internet phenomenon. According to the vote from the online social network Twitter, more people observed white-gold colors than those who observed blue-black colors. Biological explanations have been proposed by neurologist and other scientists, most of which mainly focus on the bias of color perception from visual cortex assuming different illuminants as backgrounds. The goal of this study was to investigate the genetic reason that might be underlying this phenomenon. We carried out a preliminary survey study using four complex pedigrees and examined the inheritance mode influencing the ability to perceive the real colors, blue-black, from the photograph. We evaluated the likelihood of sporadic, major gene in Mendelian mode, major gene in non-Mendelian mode and environmental models. Complex segregation analyses indicated that the inheritance was probably due to a non-Mendelian major gene effect. Our study also indicated the importance of environmental or epigenetic factors in this color perception trait. PMID- 27768727 TI - Addition of Alanyl-Glutamine to Dialysis Fluid Restores Peritoneal Cellular Stress Responses - A First-In-Man Trial. AB - BACKGROUND: Peritonitis and ultrafiltration failure remain serious complications of chronic peritoneal dialysis (PD). Dysfunctional cellular stress responses aggravate peritoneal injury associated with PD fluid exposure, potentially due to peritoneal glutamine depletion. In this randomized cross-over phase I/II trial we investigated cytoprotective effects of alanyl-glutamine (AlaGln) addition to glucose-based PDF. METHODS: In a prospective randomized cross-over design, 20 stable PD outpatients underwent paired peritoneal equilibration tests 4 weeks apart, using conventional acidic, single chamber 3.86% glucose PD fluid, with and without 8 mM supplemental AlaGln. Heat-shock protein 72 expression was assessed in peritoneal effluent cells as surrogate parameter of cellular stress responses, complemented by metabolomics and functional immunocompetence assays. RESULTS: AlaGln restored peritoneal glutamine levels and increased the primary outcome heat-shock protein expression (effect 1.51-fold, CI 1.07-2.14; p = 0.022), without changes in peritoneal ultrafiltration, small solute transport, or biomarkers reflecting cell mass and inflammation. Further effects were glutamine like metabolomic changes and increased ex-vivo LPS-stimulated cytokine release from healthy donor peripheral blood monocytes. In patients with a history of peritonitis (5 of 20), AlaGln supplementation decreased dialysate interleukin-8 levels. Supplemented PD fluid also attenuated inflammation and enhanced stimulated cytokine release in a mouse model of PD-associated peritonitis. CONCLUSION: We conclude that AlaGln-supplemented, glucose-based PD fluid can restore peritoneal cellular stress responses with attenuation of sterile inflammation, and may improve peritoneal host-defense in the setting of PD. PMID- 27768730 TI - A Novel Method for Verifying War Mortality while Estimating Iraqi Deaths for the Iran-Iraq War through Operation Desert Storm (1980-1993). AB - OBJECTIVES: We estimated war-related Iraqi mortality for the period 1980 through 1993. METHOD: To test our hypothesis that deaths reported by siblings (even dating back several decades) would correspond with war events, we compared sibling mortality reports with the frequency of independent news reports about violent historic events. We used data from a survey of 4,287 adults in 2000 Iraqi households conducted in 2011. Interviewees reported on the status of their 24,759 siblings. Death rates were applied to population estimates, 1980 to 1993. News report data came from the ProQuest New York Times database. RESULTS: About half of sibling-reported deaths across the study period were attributed to direct war related injuries. The Iran-Iraq war led to nearly 200,000 adult deaths, and the 1990-1991 First Gulf War generated another approximately 40,000 deaths. Deaths during peace intervals before and after each war were significantly lower. We found a relationship between total sibling-reported deaths and the tally of war events across the period, p = 0.02. CONCLUSIONS: We report a novel method to verify the reliability of epidemiological (household survey) estimates of direct war-related injury mortality dating back several decades. PMID- 27768732 TI - An Optimal Schedule for Urban Road Network Repair Based on the Greedy Algorithm. AB - The schedule of urban road network recovery caused by rainstorms, snow, and other bad weather conditions, traffic incidents, and other daily events is essential. However, limited studies have been conducted to investigate this problem. We fill this research gap by proposing an optimal schedule for urban road network repair with limited repair resources based on the greedy algorithm. Critical links will be given priority in repair according to the basic concept of the greedy algorithm. In this study, the link whose restoration produces the ratio of the system-wide travel time of the current network to the worst network is the minimum. We define such a link as the critical link for the current network. We will re-evaluate the importance of damaged links after each repair process is completed. That is, the critical link ranking will be changed along with the repair process because of the interaction among links. We repair the most critical link for the specific network state based on the greedy algorithm to obtain the optimal schedule. The algorithm can still quickly obtain an optimal schedule even if the scale of the road network is large because the greedy algorithm can reduce computational complexity. We prove that the problem can obtain the optimal solution using the greedy algorithm in theory. The algorithm is also demonstrated in the Sioux Falls network. The problem discussed in this paper is highly significant in dealing with urban road network restoration. PMID- 27768731 TI - Predictors of Patient Dissatisfaction with Services for Prevention of Mother-To Child Transmission of HIV in Dar es Salaam, Tanzania. AB - BACKGROUND: Mother-to-child transmission (MTCT) of HIV remains a major source of new HIV infections in children. Prevention of mother-to-child transmission of HIV (PMTCT) using lifelong antiretroviral treatment (ART) for all pregnant and breastfeeding women living with HIV (Option B+) is the major strategy for eliminating paediatric HIV. Ensuring that patients are satisfied with PMTCT services is important for optimizing uptake, adherence and retention in treatment. METHODS: We conducted a facility based quantitative cross-sectional survey in Dar-es-Salaam, Tanzania, between March and April 2014, when the country was transitioning to the implementation of PMTCT Option B+. We interviewed 595 pregnant and breastfeeding women living with HIV, who received PMTCT care in 36 public health facilities. Predictors of overall dissatisfaction with PMTCT services were identified using a multiple logistic regression. RESULTS: Overall 8% of the patients expressed dissatisfaction with PMTCT services. Patients who perceived health care workers (HCW) communication skills as poor, had a 5-fold (OR 4.9, 95% CI 1.8-13.4) increased risk of dissatisfaction and those who perceived HCW capacity to understand client concerns as poor, had a 6-fold (OR 5.7, 95% CI 2.3-14.0) increased risk. Having a total visit time longer than two hours was associated with a 2-fold increased risk of being dissatisfied (OR 2.3, 95% CI 1.1-4.7). Every 30-minute increment in total visit time was associated with a 10% higher (OR 1.1, 95% CI 1.0-1.2) risk of being dissatisfied. The probability of being dissatisfied ranged from 4% (95% CI 2% - 6%) in the presence of patient-perceived good communication, good understanding of patient concerns, and a total visit time below two hours, to 70% (95% CI 47% - 86%) if HCW failed in all of these aspects. CONCLUSION: Patient dissatisfaction with PMTCT services was generally low; reflecting that quality of care was maintained during Tanzania's transition to Option B+ strategy aiming to increase the number of women initiating life-long ART in PMTCT clinics. Improved HCW communication with clients, their understanding of patient concerns and a reduction of the total visit time would further optimize women's overall satisfaction with PMTCT services in Tanzania. PMID- 27768733 TI - Quinoline Alkaloids Isolated from Choisya Aztec-Pearl and Their Contribution to the Overall Antinociceptive Activity of This Plant. AB - Choisya 'Aztec-Pearl', a hybrid of Choisya ternata and Choisya dumosa var. arizonica, had the antinociceptive activity in the ethanol extract (EECA) of its leaves evaluated. Two quinoline alkaloids, anhydroevoxine (A) and choisyine (C), isolated from these leaves were also tested. The results obtained pointed out to a very high antinociceptive activity measured by the hot plate model for EECA (at doses of 10, 30 and 100 mg/kg) as well as for A and C (at doses of 1, 3 and 10 mg/kg). The magnitude of the activity was two-fold higher than the one observed for the morphine treated animals for the higher doses of extracts/compounds (30, 100 mg/kg and 3, 10 mg/kg respectively). The mechanism of action for this activity was also investigated and it seems that for EECA as well as A and C, the opiate system plays an important role. Results have also shown that the nitric oxide (NO) system also play a pivotal role in the case of EECA and A while for C it seems that the cholinergic system have some involvement. The acute toxicity was evaluated for EECA with results showing no important toxic effect. PMID- 27768734 TI - Inhibition of an Erythrocyte Tyrosine Kinase with Imatinib Prevents Plasmodium falciparum Egress and Terminates Parasitemia. AB - With half of the world's population at risk for malaria infection and with drug resistance on the rise, the search for mutation-resistant therapies has intensified. We report here a therapy for Plasmodium falciparum malaria that acts by inhibiting the phosphorylation of erythrocyte membrane band 3 by an erythrocyte tyrosine kinase. Because tyrosine phosphorylation of band 3 causes a destabilization of the erythrocyte membrane required for parasite egress, inhibition of the erythrocyte tyrosine kinase leads to parasite entrapment and termination of the infection. Moreover, because one of the kinase inhibitors to demonstrate antimalarial activity is imatinib, i.e. an FDA-approved drug authorized for use in children, translation of the therapy into the clinic will be facilitated. At a time when drug resistant strains of P. falciparum are emerging, a strategy that targets a host enzyme that cannot be mutated by the parasite should constitute a therapeutic mechanism that will retard evolution of resistance. PMID- 27768735 TI - Wild Carrot Differentiation in Europe and Selection at DcAOX1 Gene? AB - By definition, the domestication process leads to an overall reduction of crop genetic diversity. This lead to the current search of genomic regions in wild crop relatives (CWR), an important task for modern carrot breeding. Nowadays massive sequencing possibilities can allow for discovery of novel genetic resources in wild populations, but this quest could be aided by the use of a surrogate gene (to first identify and prioritize novel wild populations for increased sequencing effort). Alternative oxidase (AOX) gene family seems to be linked to all kinds of abiotic and biotic stress reactions in various organisms and thus have the potential to be used in the identification of CWR hotspots of environment-adapted diversity. High variability of DcAOX1 was found in populations of wild carrot sampled across a West-European environmental gradient. Even though no direct relation was found with the analyzed climatic conditions or with physical distance, population differentiation exists and results mainly from the polymorphisms associated with DcAOX1 exon 1 and intron 1. The relatively high number of amino acid changes and the identification of several unusually variable positions (through a likelihood ratio test), suggests that DcAOX1 gene might be under positive selection. However, if positive selection is considered, it only acts on some specific populations (i.e. is in the form of adaptive differences in different population locations) given the observed high genetic diversity. We were able to identify two populations with higher levels of differentiation which are promising as hot spots of specific functional diversity. PMID- 27768736 TI - The Effect of a Unilateral Orchiectomy before Gonadotoxic Treatment on the Contralateral Testis in Adult and Prepubertal Rats. AB - PURPOSE: Previous studies have shown that the removal of one testis leads to a compensatory mechanism in the contralateral one, but this was species and age dependent. The aim of this study was to check whether this compensation would still occur after the combination of a unilateral orchiectomy and gonadotoxic treatment, since this resembles the clinical situation of patients who have to undergo highly toxic cancer treatment and therefore choose to cryopreserve a testicular biopsy for fertility restoration purposes. MATERIALS & METHODS: Sprague Dawley rats underwent either unilateral orchiectomy, gonadotoxic busulfan treatment, the combination of both or served as fertile control. A comparison of the compensatory effects was made between adult and prepubertal treated rats. Mating experiments were performed, testosterone levels were followed-up, testicular weight was recorded and histology was analysed. RESULTS: Adult treated rats were able to restore fertility spontaneously in all treatment groups. On the other hand, 30% of the rats that underwent a unilateral orchiectomy and gonadotoxic treatment at prepubertal age showed hampered spermatogenesis, low testosterone levels, decreased testicular weights and were not able to reproduce. CONCLUSION: This study emphasizes the need of fertility preservation strategies in prepubertal patients before gonadotoxic interventions. PMID- 27768737 TI - Does the Decline in Caries Prevalence of Latin American and Caribbean Children Continue in the New Century? Evidence from Systematic Review with Meta-Analysis. AB - OBJECTIVE: To carry out a systematic review with meta-analysis of prevalence of caries in Latin America and Caribbean children considering studies performed in this new century. METHODS: Two reviewers searched PubMed, Embase, LILACS and governmental databases through May 2016 to identify papers published in English, Portuguese or Spanish. Studies in those countries performed with 5-6 or 11-13 year-old children and that presented separate prevalence figures from primary and permanent teeth were selected. We performed a descriptive analysis of studies and meta-analysis to calculate the overall prevalence and 95% confidence intervals (95% CI) in both primary and permanent teeth. We also analyzed the trends of prevalence of caries through the years and influence of other variables on caries prevalence using multilevel analysis. RESULTS: Seventy-five studies were included from the 1,306 articles initially retrieved. The meta-analysis of caries prevalence grouped for Latin American and the Caribbean countries were highly different from Brazil and other investigated countries for primary teeth (5-6 years-old-Brazil: 0.52, other countries:0.70) and permanent teeth (11-12 years old-Brazil: 0.56, other countries: 0.63). For studies conducted only in Brazil the prevalence was significant lower for primary but not for permanent teeth. In Brazil, a downward trend of caries prevalence was observed in 11-13-year-old children. CONCLUSION: Despite the decline of caries prevalence in permanent teeth, mainly in Brazil, the disease still affects more than half of the children population in Latin American and Caribbean countries in the 21st Century. PMID- 27768738 TI - MUC1-ARF-A Novel MUC1 Protein That Resides in the Nucleus and Is Expressed by Alternate Reading Frame Translation of MUC1 mRNA. AB - Translation of mRNA in alternate reading frames (ARF) is a naturally occurring process heretofore underappreciated as a generator of protein diversity. The MUC1 gene encodes MUC1-TM, a signal-transducing trans-membrane protein highly expressed in human malignancies. Here we show that an AUG codon downstream to the MUC1-TM initiation codon initiates an alternate reading frame thereby generating a novel protein, MUC1-ARF. MUC1-ARF, like its MUC1-TM 'parent' protein, contains a tandem repeat (VNTR) domain. However, the amino acid sequence of the MUC1-ARF tandem repeat as well as N- and C- sequences flanking it differ entirely from those of MUC1-TM. In vitro protein synthesis assays and extensive immunohistochemical as well as western blot analyses with MUC1-ARF specific monoclonal antibodies confirmed MUC1-ARF expression. Rather than being expressed at the cell membrane like MUC1-TM, immunostaining showed that MUC1-ARF protein localizes mainly in the nucleus: Immunohistochemical analyses of MUC1-expressing tissues demonstrated MUC1-ARF expression in the nuclei of secretory luminal epithelial cells. MUC1-ARF expression varies in different malignancies. While the malignant epithelial cells of pancreatic cancer show limited expression, in breast cancer tissue MUC1-ARF demonstrates strong nuclear expression. Proinflammatory cytokines upregulate expression of MUC1-ARF protein and co immunoprecipitation analyses demonstrate association of MUC1-ARF with SH3 domain containing proteins. Mass spectrometry performed on proteins coprecipitating with MUC1-ARF demonstrated Glucose-6-phosphate 1-dehydrogenase (G6PD) and Dynamin 2 (DNM2). These studies not only reveal that the MUC1 gene generates a previously unidentified MUC1-ARF protein, they also show that just like its 'parent' MUC1-TM protein, MUC1-ARF is apparently linked to signaling and malignancy, yet a definitive link to these processes and the roles it plays awaits a precise identification of its molecular functions. Comprising at least 524 amino acids, MUC1-ARF is, furthermore, the longest ARF protein heretofore described. PMID- 27768740 TI - The Characteristics of TB Epidemic and TB/HIV Co-Infection Epidemic: A 2007-2013 Retrospective Study in Urumqi, Xinjiang Province, China. AB - OBJECTIVE: This study was aimed to find out epidemiologic characteristic of tuberculosis (TB) cases, and Human Immunodeficiency Virus (HIV) positive cases among TB patients (TB/HIV co-infection) through demographic, temporal, and spatial study in Urumqi. METHODS: Descriptive statistics and multivariate logistic regression were applied to identify the epidemiologic characteristics and risk factors of TB epidemic and TB/HIV co-infection epidemic. All addresses of each TB case, TB/HIV co-infection case, and administrative street were transformed into geographical coordinate. Subsequently, the geocoded address for 82 streets was transformed into a dot map used as the basis of spatial datasets. In addition, the paper also used quantile map and the spatial scan statistic in order to identify the spatial distribution and spatial clusters of TB epidemic and TB/HIV co-infection epidemic. RESULT: There was a declining trend of the notification rates of TB epidemic from 2007 to 2009, as well as a rising trend from 2010 to 2013. However, the notification rates of TB/HIV co-infection epidemic showed a rising trend from 2007 to 2010, and a declining trend from 2011 to 2013. Moreover, a significant share of TB epidemic and TB/HIV co-infection epidemic happened between the age of 15 to 45 years old, indicating an increase in risk of TB and TB/HIV infection. It is worth noting that the risk of HIV infection for male TB patients was 2.947 times (95% CI [2.178, 3.988]) than that of female patients. Han ethnicity and Uygur ethnicity in urban region accounted for a large proportion of total TB and TB/HIV co-infection cases. Most of the TB cases of minorities in Urumqi showed a statistically significant increase in risk of HIV infection than Han ethnicity in Urumqi. In addition, the spatial distribution of TB epidemic and TB/HIV co-infection epidemic was highly skewed. Most of the local clusters were located in urban area and rural-urban continuum where showed an increase in risk of TB and TB/HIV infection. CONCLUSION: The epidemiologic and spatial-temporal analysis of TB epidemic and TB/HIV co infection epidemic demonstrates a potential connection between TB and HIV in Urumqi. Demographic, temporal, geographic factors are the reasons of causing TB and TB/HIV co-infection epidemic. PMID- 27768739 TI - Remote Liver Ischemic Preconditioning Protects against Sudden Cardiac Death via an ERK/GSK-3beta-Dependent Mechanism. AB - BACKGROUND: Preconditioning stimuli conducted in remote organs can protect the heart against subsequent ischemic injury, but effects on arrhythmogenesis and sudden cardiac death (SCD) are unclear. Here, we investigated the effect of remote liver ischemia preconditioning (RLIPC) on ischemia/reperfusion (I/R) induced cardiac arrhythmia and sudden cardiac death (SCD) in vivo, and determined the potential role of ERK/GSK-3betasignaling. METHODS/RESULTS: Male Sprague Dawley rats were randomized to sham-operated, control, or RLIPC groups. RLIPC was induced by alternating four 5-minute cycles of liver ischemia with 5-minute intermittent reperfusions. To investigate I/R-induced arrhythmogenesis, hearts in each group were subsequently subjected to 5-minute left main coronary artery ligation followed by 20-minute reperfusion. RLIPC reduced post-I/R ventricular arrhythmias, and decreased the incidence of SCD >threefold. RLIPC increased phosphorylation of cardiac ERK1/2, and GSK-3beta Ser9 but not Tyr216 post-I/R injury. Inhibition of either GSK-3beta (with SB216763) or ERK1/2 (with U0126) abolished RLIPC-induced antiarrhythmic activity and GSK-3beta Ser9 and ERK1/2 phosphorylation, leaving GSK-3beta Tyr216 phosphorylation unchanged. CONCLUSIONS: RLIPC exerts a powerful antiarrhythmic effect and reduces predisposition to post IR SCD. The underlying mechanism of RLIPC cardioprotection against I/R-induced early arrhythmogenesis may involve ERK1/2/GSK-3beta Ser9-dependent pathways. PMID- 27768741 TI - A Simple and Rapid Method for Preparing a Cell-Free Bacterial Lysate for Protein Synthesis. AB - Cell-free protein synthesis (CFPS) systems are important laboratory tools that are used for various synthetic biology applications. Here, we present a simple and inexpensive laboratory-scale method for preparing a CFPS system from E. coli. The procedure uses basic lab equipment, a minimal set of reagents, and requires less than one hour to process the bacterial cell mass into a functional S30-T7 extract. BL21(DE3) and MRE600 E. coli strains were used to prepare the S30-T7 extract. The CFPS system was used to produce a set of fluorescent and therapeutic proteins of different molecular weights (up to 66 kDa). This system was able to produce 40-150 MUg-protein/ml, with variations depending on the plasmid type, expressed protein and E. coli strain. Interestingly, the BL21-based CFPS exhibited stability and increased activity at 40 and 45 degrees C. To the best of our knowledge, this is the most rapid and affordable lab-scale protocol for preparing a cell-free protein synthesis system, with high thermal stability and efficacy in producing therapeutic proteins. PMID- 27768742 TI - Antibody Binding Studies Reveal Conformational Flexibility of the Bacillus cereus Non-Hemolytic Enterotoxin (Nhe) A-Component. AB - The non-hemolytic enterotoxin complex (Nhe) is supposed to be the main virulence factor of B. cereus causing a diarrheal outcome of food poisoning. This tripartite toxin consists of the single components NheA, -B and -C all of them being necessary for maximum toxicity. In the past, research activities aiming to elucidate the mode-of-action of Nhe were mostly focused on the B- and C component. In this study the generation of novel monoclonal antibodies (mAb) and their thorough characterization enabled the determination of key features for NheA. By the means of immunoaffinity chromatography it could be shown that NheA does not interact with -B and -C in solution. Additionally, the establishment of a highly sensitive sandwich-EIA now enables the detection of NheA in B. cereus supernatants down to 20 pg ml-1.Peptide-based epitope mapping in combination with partially deleted recombinant NheA fragments allowed the allocation of the binding regions for the three mAbs under study. Furthermore, by different EIA set ups the conformational flexibility of NheA could be shown. For two of the antibodies under study different mechanisms of NheA neutralization were proven. Due to prevention of complete pore formation by one of the antibodies, NheA could be detected in an intermediate stage of the tripartite complex on the cell surface. Taken together, the results obtained in the present study allow a refinement of the mode-of-action for the Nhe toxin-complex. PMID- 27768743 TI - Evaporimeter and Bubble-Imaging Measures of Sweat Gland Secretion Rates. AB - Beta-adrenergically-stimulated sweat rates determined by evaporimetry or by sweat bubble imaging are useful for measuring CFTR function because they provide a near linear readout across almost the full range of CFTR function. They differentiate cystic fibrosis (CF) subjects from CF carriers and carriers from controls. However, evaporimetry, unlike bubble imaging, appears to be unable to detect improved levels of CFTR function in G551D subjects taking the CFTR modulator ivacaftor. Here, we quantify the sensitivity of evaporimetry and bubble imaging methods for assessing low levels of CFTR-dependent sweat rates. To establish sensitivity, we did dose-ranging studies using intradermally injected [cAMP]i elevating cocktails. We reduced isoproterenol/aminophylline levels while maintaining a high level of atropine to block muscarinic elevation of [Ca2+]i. We stimulated the same sets of glands for both assays and recorded responses for 20 min. In response to a 3-log dilution of the stimulating cocktail (0.1%), bubble responses were detected in 12/12 tests (100%), with 49% +/- 3% of glands secreting to produce an aggregate volume of 598 nl across the 12, 20-min tests. This was ~5% of the response to full cocktail. Evaporimetry detected responses in 3/12 (25%) tests with an aggregate secretion volume of 175 nl. After stimulation with a still more dilute cocktail (0.03%), bubble imaging detected 15 +/- 13% of glands secreting at a rate ~0.9% of the response to full cocktail, while zero responding was seen with evaporimetry. The bubble imaging method detected secretion down to aggregate rates of <0.2 nl/(cm2.min), or ~1/30th of the average basal transepithelial water loss (TEWL) in the test subject of 4 g/m2.hr or 6.7 nl/(cm2.min). The increased sensitivity of bubble imaging may be required to detect small but physiologically important increases in secretion rates produced by CFTR modulators. PMID- 27768744 TI - Molecular Insight into Human Lysozyme and Its Ability to Form Amyloid Fibrils in High Concentrations of Sodium Dodecyl Sulfate: A View from Molecular Dynamics Simulations. AB - Changes in the tertiary structure of proteins and the resultant fibrillary aggregation could result in fatal heredity diseases, such as lysozyme systemic amyloidosis. Human lysozyme is a globular protein with antimicrobial properties with tendencies to fibrillate and hence is known as a fibril-forming protein. Therefore, its behavior under different ambient conditions is of great importance. In this study, we conducted two 500000 ps molecular dynamics (MD) simulations of human lysozyme in sodium dodecyl sulfate (SDS) at two ambient temperatures. To achieve comparative results, we also performed two 500000 ps human lysozyme MD simulations in pure water as controls. The aim of this study was to provide further molecular insight into all interactions in the lysozyme SDS complexes and to provide a perspective on the ability of human lysozyme to form amyloid fibrils in the presence of SDS surfactant molecules. SDS, which is an anionic detergent, contains a hydrophobic tail with 12 carbon atoms and a negatively charged head group. The SDS surfactant is known to be a stabilizer for helical structures above the critical micelle concentration (CMC) [1]. During the 500000 ps MD simulations, the helical structures were maintained by the SDS surfactant above its CMC at 300 K, while at 370 K, human lysozyme lost most of its helices and gained beta-sheets. Therefore, we suggest that future studies investigate the beta-amyloid formation of human lysozyme at SDS concentrations above the CMC and at high temperatures. PMID- 27768745 TI - Anterograde Amnesia during Electroconvulsive Therapy: A Prospective Pilot-Study in Patients with Major Depressive Disorder. AB - Electroconvulsive therapy (ECT) is considered an effective treatment for major depression with melancholic features. However, neurocognitive side-effects such as anterograde amnesia still regularly occur. The present study aims to evaluate the severity and course of anterograde amnesia in severely depressed patients undergoing ECT. In a prospective naturalistic study, anterograde memory function was assessed among inpatients who underwent ECT (n = 11). Subjects met DSM-IV criteria for major depressive disorder. Recruitment took place between March 2010 March 2011 and March 2012-March 2013. Controls treated with antidepressants (n = 9) were matched for age, gender and depression severity. Primary outcome measure was immediate recall; secondary outcome measures were delayed recall, recognition, and visual association. Differences were tested using repeated measures ANOVA and paired t-tests. Correlations with hypothesized covariates were calculated. In patients with major depressive disorder, ECT had a significant effect on delayed memory function (p<0.01 with large effect sizes). Findings on immediate recall were less consistent. Four weeks after treatment discontinuation, these memory functions had recovered. Age was identified as a very important covariate. The main limitations of our study are its naturalistic design, possibly compromising internal validity, and its small sample size. However, if these findings can be reproduced in a more comprehensive study group, then the possible induction of anterograde amnesia is not a justifiable reason for clinicians to disregard ECT as a treatment option. PMID- 27768746 TI - Ratio of C-Reactive Protein to Albumin Predicts Muscle Mass in Adult Patients Undergoing Hemodialysis. AB - Recent studies have indicated that the ratio of C-reactive protein to albumin (CRP-Alb ratio) is associated with clinical outcomes in patients with disease. We examined the predictive value of this ratio in patients undergoing hemodialysis (HD). In this cross-sectional study, 91 eligible adult HD patients were analyzed, and the correlation between the CRP-Alb ratio and skeletal muscle mass normalized for body weight (SMM/wt; estimated using a bioelectrical impedance analyzer) was investigated. The mean age of the study participants was 54.9 +/- 6.6 years (ranging from 27 to 64 years); 43 (47.2%) were men. The mean values for the SMM/wt were 39.1% +/- 5.4%. The CRP-Alb ratio was found to be negatively correlated with SMM/wt (r = -0.33, P = 0.002) and creatinine (r = -0.20, P = 0.056). All the univariate significant and nonsignificant relevant covariates were selected for multivariable stepwise regression analysis. We determined that the homeostasis model assessment-estimated insulin resistance and CRP-Alb ratio were independent risk determinants for SMM/wt (betaHOMA-IR = -0.18 and betaCRP Alb ratio = -3.84, adjusted R2 = 0.32). This study indicated that the CRP-Alb ratio may help clinicians in predicting muscle mass in adult patients undergoing HD. PMID- 27768747 TI - Exercise-Induced Fatigue and Caffeine Supplementation Affect Psychomotor Performance but Not Covert Visuo-Spatial Attention. AB - Fatigue resulting from strenuous exercise can impair cognition and oculomotor control. These impairments can be prevented by administering psychostimulants such as caffeine. This study used two experiments to explore the influence of caffeine administered at rest and during fatiguing physical exercise on spatial attention-a cognitive function that is crucial for task-based visually guided behavior. In independent placebo-controlled studies, cohorts of 12 healthy participants consumed caffeine and rested or completed 180 min of stationary cycling. Covert attentional orienting was measured in both experiments using a spatial cueing paradigm. We observed no alterations in attentional facilitation toward spatial cues suggesting that covert attentional orienting is not influenced by exercise fatigue or caffeine supplementation. Response times were increased (impaired) after exercise and this deterioration was prevented by caffeine supplementation. In the resting experiment, response times across all conditions and cues were decreased (improved) with caffeine. Covert spatial attention was not influenced by caffeine. Together, the results of these experiments suggest that covert attentional orienting is robust to the effects of fatiguing exercise and not influenced by caffeine. However, exercise fatigue impairs response times, which can be prevented by caffeine, suggesting that pre motor planning and execution of the motor responses required for performance of the cueing task are sensitive to central nervous system fatigue. Caffeine improves response time in both fatigued and fresh conditions, most likely through action on networks controlling motor function. PMID- 27768749 TI - Discovering Numerical Differences between Animal and Plant microRNAs. AB - Previous studies have confirmed that there are many differences between animal and plant microRNAs (miRNAs), and that numerical features based on sequence and structure can be used to predict the function of individual miRNAs. However, there is little research regarding numerical differences between animal and plant miRNAs, and whether a single numerical feature or combination of features could be used to distinguish animal and plant miRNAs or not. Therefore, in current study we aimed to discover numerical features that could be used to accomplish this. We performed a large-scale analysis of 132 miRNA numerical features, and identified 17 highly significant distinguishing features. However, none of the features independently could clearly differentiate animal and plant miRNAs. By further analysis, we found a four-feature subset that included helix number, stack number, length of pre-miRNA, and minimum free energy, and developed a logistic classifier that could distinguish animal and plant miRNAs effectively. The precision of the classifier was greater than 80%. Using this tool, we confirmed that there were universal differences between animal and plant miRNAs, and that a single feature was unable to adequately distinguish the difference. This feature set and classifier represent a valuable tool for identifying differences between animal and plant miRNAs at a molecular level. PMID- 27768748 TI - Plasma miR-19b and miR-183 as Potential Biomarkers of Lung Cancer. AB - Lung cancer is a complex disease that often manifests at the point when treatment is not effective. Introduction of blood-based complementary diagnostics using molecular markers may enhance early detection of this disease and help reduce the burden of lung cancer. Here we evaluated the diagnostic potential of seven plasma miRNA biomarkers (miR-21, -19b, -126, -25, -205, -183, -125b) by quantitative reverse transcription PCR. Influence clinical and demographical characteristics, including age, tumor stage and cancer subtype on miRNA levels was investigated. Four miRNAs were significantly dysregulated (miR-19b, -21, -25, -183) in lung cancer patients. Combination of miR-19b and miR-183 provided detection of lung cancer with 94.7% sensitivity and 95.2% specificity (AUC = 0.990). Thus, miRNAs have shown the potential to discriminate histological subtypes of lung cancer and reliably distinguish lung cancer patients from healthy individuals. PMID- 27768750 TI - Key Microbiota Identification Using Functional Gene Analysis during Pepper (Piper nigrum L.) Peeling. AB - Pepper pericarp microbiota plays an important role in the pepper peeling process for the production of white pepper. We collected pepper samples at different peeling time points from Hainan Province, China, and used a metagenomic approach to identify changes in the pericarp microbiota based on functional gene analysis. UniFrac distance-based principal coordinates analysis revealed significant changes in the pericarp microbiota structure during peeling, which were attributed to increases in bacteria from the genera Selenomonas and Prevotella. We identified 28 core operational taxonomic units at each time point, mainly belonging to Selenomonas, Prevotella, Megasphaera, Anaerovibrio, and Clostridium genera. The results were confirmed by quantitative polymerase chain reaction. At the functional level, we observed significant increases in microbial features related to acetyl xylan esterase and pectinesterase for pericarp degradation during peeling. These findings offer a new insight into biodegradation for pepper peeling and will promote the development of the white pepper industry. PMID- 27768752 TI - Use of a Diagnostic Score to Prioritize Computed Tomographic (CT) Imaging for Patients Suspected of Ischemic Stroke Who May Benefit from Thrombolytic Therapy. AB - BACKGROUND: A shortage of computed tomographic (CT) machines in low and middle income countries often results in delayed CT imaging for patients suspected of a stroke. Yet, time constraint is one of the most important aspects for patients with an ischemic stroke to benefit from thrombolytic therapy. We set out to assess whether application of the Siriraj Stroke Score is able to assist physicians in prioritizing patients with a high probability of having an ischemic stroke for urgent CT imaging. METHODS: From the Malaysian National Neurology Registry, we selected patients aged 18 years and over with clinical features suggesting of a stroke, who arrived in the hospital 4.5 hours or less from ictus. The prioritization of receiving CT imaging was left to the discretion of the treating physician. We applied the Siriraj Stroke Score to all patients, refitted the score and defined a cut-off value to best distinguish an ischemic stroke from a hemorrhagic stroke. RESULTS: Of the 2176 patients included, 73% had an ischemic stroke. Only 33% of the ischemic stroke patients had CT imaging within 4.5 hours. The median door-to-scan time for these patients was 4 hours (IQR: 1;16). With the recalibrated score, it would have been possible to prioritize 95% (95% CI: 94% 96%) of patients with an ischemic stroke for urgent CT imaging. CONCLUSIONS: In settings where CT imaging capacity is limited, we propose the use of the Siriraj Stroke Score to prioritize patients with a probable ischemic stroke for urgent CT imaging. PMID- 27768753 TI - Origin of Infrared Light Modulation in Reflectance-Mode Photoplethysmography. AB - We recently pointed out the important role of dermis deformation by pulsating arterial pressure in the formation of a photoplethysmographic signal at green light. The aim of this study was to explore the role of this novel finding in near-infrared (NIR) light. A light-emitting diode (LED)-based imaging photoplethysmography (IPPG) system was used to detect spatial distribution of blood pulsations under frame-to-frame switching green and NIR illumination in the palms of 34 healthy individuals. We observed a significant increase of light intensity modulation at the heartbeat frequency for both illuminating wavelengths after a palm was contacted with a glass plate. Strong positive correlation between data measured at green and NIR light was found, suggesting that the same signal was read independently from the depth of penetration. Analysis of the data shows that an essential part of remitted NIR light is modulated in time as a result of elastic deformations of dermis caused by variable blood pressure in the arteries. Our observations suggest that in contrast with the classical model, photoplethysmographic waveform originates from the modulation of the density of capillaries caused by the variable pressure applied to the skin from large blood vessels. Particularly, beat-to-beat transmural pressure in arteries compresses/decompresses the dermis and deforms its connective-tissue components, thus affecting the distance between the capillaries, which results in the modulation of absorption and scattering coefficients of both green and NIR light. These findings are important for the correct interpretation of this widely used medical technique, which may have novel applications in diagnosis and treatment monitoring of aging and skin diseases. PMID- 27768751 TI - Chronology of Onset of Mental Disorders and Physical Diseases in Mental-Physical Comorbidity - A National Representative Survey of Adolescents. AB - BACKGROUND: The objective was to estimate temporal associations between mental disorders and physical diseases in adolescents with mental-physical comorbidities. METHODS: This article bases upon weighted data (N = 6483) from the National Comorbidity Survey Adolescent Supplement (participant age: 13-18 years), a nationally representative United States cohort. Onset of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition lifetime mental disorders was assessed with the fully structured World Health Organization Composite International Diagnostic Interview, complemented by parent report. Onset of lifetime medical conditions and doctor-diagnosed diseases was assessed by self report. RESULTS: The most substantial temporal associations with onset of mental disorders preceding onset of physical diseases included those between affective disorders and arthritis (hazard ratio (HR) = 3.36, 95%-confidence interval (CI) = 1.95 to 5.77) and diseases of the digestive system (HR = 3.39, CI = 2.30 to 5.00), between anxiety disorders and skin diseases (HR = 1.53, CI = 1.21 to 1.94), and between substance use disorders and seasonal allergies (HR = 0.33, CI = 0.17 to 0.63). The most substantial temporal associations with physical diseases preceding mental disorders included those between heart diseases and anxiety disorders (HR = 1.89, CI = 1.41 to 2.52), epilepsy and eating disorders (HR = 6.27, CI = 1.58 to 24.96), and heart diseases and any mental disorder (HR = 1.39, CI = 1.11 to 1.74). CONCLUSIONS: Findings suggest that mental disorders are antecedent risk factors of certain physical diseases in early life, but also vice versa. Our results expand the relevance of mental disorders beyond mental to physical health care, and vice versa, supporting the concept of a more integrated mental-physical health care approach, and open new starting points for early disease prevention and better treatments, with relevance for various medical disciplines. PMID- 27768754 TI - Duloxetine Inhibits Microglial P2X4 Receptor Function and Alleviates Neuropathic Pain after Peripheral Nerve Injury. AB - P2X4 receptors (P2X4R) are a family of ATP-gated non-selective cation channels. We previously demonstrated that activation of P2X4R in spinal microglia is crucial for neuropathic pain, a highly debilitating chronic pain condition, suggesting that P2X4R is a potential therapeutic target for treating neuropathic pain. Thus, the identification of a compound that has a potent inhibitory effect on P2X4R is an important clinical challenge. In the present study, we screened a chemical library of clinically approved drugs and show for the first time that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rodent and human P2X4R. In primary cultured microglial cells, duloxetine also inhibited P2X4R-, but not P2X7R-, mediated responses. Moreover, intrathecal administration of duloxetine in a model of neuropathic pain produced a reversal of nerve injury-induced mechanical allodynia, a cardinal symptom of neuropathic pain. In rats that were pretreated with a serotonin-depleting agent and a noradrenaline neurotoxin, the antiallodynic effect of duloxetine was reduced, but still remained. Based on these results, we suggest that, in addition to duloxetine's primary inhibitory action on serotonin and noradrenaline transporters, an inhibitory effect on P2X4R may be involved at least in part in an antiallodynic effect of intrathecal duloxetine in a model of neuropathic pain. PMID- 27768756 TI - Improving Children's Knowledge of Fraction Magnitudes. AB - We examined whether playing a computerized fraction game, based on the integrated theory of numerical development and on the Common Core State Standards' suggestions for teaching fractions, would improve children's fraction magnitude understanding. Fourth and fifth-graders were given brief instruction about unit fractions and played Catch the Monster with Fractions, a game in which they estimated fraction locations on a number line and received feedback on the accuracy of their estimates. The intervention lasted less than 15 minutes. In our initial study, children showed large gains from pretest to posttest in their fraction number line estimates, magnitude comparisons, and recall accuracy. In a more rigorous second study, the experimental group showed similarly large improvements, whereas a control group showed no improvement from practicing fraction number line estimates without feedback. The results provide evidence for the effectiveness of interventions emphasizing fraction magnitudes and indicate how psychological theories and research can be used to evaluate specific recommendations of the Common Core State Standards. PMID- 27768755 TI - In Vivo Evaluation of the Visual Pathway in Streptozotocin-Induced Diabetes by Diffusion Tensor MRI and Contrast Enhanced MRI. AB - Visual function has been shown to deteriorate prior to the onset of retinopathy in some diabetic patients and experimental animal models. This suggests the involvement of the brain's visual system in the early stages of diabetes. In this study, we tested this hypothesis by examining the integrity of the visual pathway in a diabetic rat model using in vivo multi-modal magnetic resonance imaging (MRI). Ten-week-old Sprague-Dawley rats were divided into an experimental diabetic group by intraperitoneal injection of 65 mg/kg streptozotocin in 0.01 M citric acid, and a sham control group by intraperitoneal injection of citric acid only. One month later, diffusion tensor MRI (DTI) was performed to examine the white matter integrity in the brain, followed by chromium-enhanced MRI of retinal integrity and manganese-enhanced MRI of anterograde manganese transport along the visual pathway. Prior to MRI experiments, the streptozotocin-induced diabetic rats showed significantly smaller weight gain and higher blood glucose level than the control rats. DTI revealed significantly lower fractional anisotropy and higher radial diffusivity in the prechiasmatic optic nerve of the diabetic rats compared to the control rats. No apparent difference was observed in the axial diffusivity of the optic nerve, the chromium enhancement in the retina, or the manganese enhancement in the lateral geniculate nucleus and superior colliculus between groups. Our results suggest that streptozotocin-induced diabetes leads to early injury in the optic nerve when no substantial change in retinal integrity or anterograde transport along the visual pathways was observed in MRI using contrast agent enhancement. DTI may be a useful tool for detecting and monitoring early pathophysiological changes in the visual system of experimental diabetes non-invasively. PMID- 27768757 TI - Human Adipose Tissue Derived Extracellular Matrix and Methylcellulose Hydrogels Augments and Regenerates the Paralyzed Vocal Fold. AB - Vocal fold paralysis results from various etiologies and can induce voice changes, swallowing complications, and issues with aspiration. Vocal fold paralysis is typically managed using injection laryngoplasty with fat or synthetic polymers. Injection with autologous fat has shown excellent biocompatibility. However, it has several disadvantages such as unpredictable resorption rate, morbidities associated with liposuction procedure which has to be done in operating room under general anesthesia. Human adipose-derived extracellular matrix (ECM) grafts have been reported to form new adipose tissue and have greater biostability than autologous fat graft. Here, we present an injectable hydrogel that is constructed from adipose tissue derived soluble extracellular matrix (sECM) and methylcellulose (MC) for use in vocal fold augmentation. Human sECM derived from adipose tissue was extracted using two major steps-ECM was isolated from human adipose tissue and was subsequently solubilized. Injectable sECM/MC hydrogels were prepared by blending of sECM and MC. Sustained vocal fold augmentation and symmetric vocal fold vibration were accomplished by the sECM/MC hydrogel in paralyzed vocal fold which were confirmed by laryngoscope, histology and a high-speed imaging system. There were increased number of collagen fibers and fatty granules at the injection site without significant inflammation or fibrosis. Overall, these results indicate that the sECM/MC hydrogel can enhance vocal function in paralyzed vocal folds without early resorption and has potential as a promising material for injection laryngoplasty for stable vocal fold augmentation which can overcome the shortcomings of autologous fat such as unpredictable duration and morbidity associated with the fat harvest. PMID- 27768758 TI - Using Risk Assessment and Habitat Suitability Models to Prioritise Invasive Species for Management in a Changing Climate. AB - Accounting for climate change in invasive species risk assessments improves our understanding of potential future impacts and enhances our preparedness for the arrival of new non-native species. We combined traditional risk assessment for invasive species with habitat suitability modeling to assess risk to biodiversity based on climate change. We demonstrate our method by assessing the risk for 15 potentially new invasive plant species to Alberta, Canada, an area where climate change is expected to facilitate the poleward expansion of invasive species ranges. Of the 15 species assessed, the three terrestrial invasive plant species that could pose the greatest threat to Alberta's biodiversity are giant knotweed (Fallopia sachalinensis), tamarisk (Tamarix chinensis), and alkali swainsonpea (Sphaerophysa salsula). We characterise giant knotweed as 'extremely invasive', with 21 times the suitable habitat between baseline and future projected climate. Tamarisk is 'extremely invasive' with a 64% increase in suitable habitat, and alkali swainsonpea is 'highly invasive' with a 21% increase in suitable habitat. Our methodology can be used to predict and prioritise potentially new invasive species for their impact on biodiversity in the context of climate change. PMID- 27768759 TI - Side Effects in Time Discounting Procedures: Fixed Alternatives Become the Reference Point. AB - Typical research on intertemporal choice utilizes a two-alternative forced choice (2AFC) paradigm requiring participants to choose between a smaller sooner and larger later payoff. In the adjusting-amount procedure (AAP) one of the alternatives is fixed and the other is adjusted according to particular choices made by the participant. Such a method makes the alternatives unequal in status and is speculated to make the fixed alternative a reference point for choices, thereby affecting the decision made. The current study shows that fixing different alternatives in the AAP influences discount rates in intertemporal choices. Specifically, individuals' (N = 283) choices were affected to just the same extent by merely fixing an alternative as when choices were preceded by scenarios explicitly imposing reference points. PMID- 27768760 TI - The Influence of Peer Reviewer Expertise on the Evaluation of Research Funding Applications. AB - Although the scientific peer review process is crucial to distributing research investments, little has been reported about the decision-making processes used by reviewers. One key attribute likely to be important for decision-making is reviewer expertise. Recent data from an experimental blinded review utilizing a direct measure of expertise has found that closer intellectual distances between applicant and reviewer lead to harsher evaluations, possibly suggesting that information is differentially sampled across subject-matter expertise levels and across information type (e.g. strengths or weaknesses). However, social and professional networks have been suggested to play a role in reviewer scoring. In an effort to test whether this result can be replicated in a real-world unblinded study utilizing self-assessed reviewer expertise, we conducted a retrospective multi-level regression analysis of 1,450 individual unblinded evaluations of 725 biomedical research funding applications by 1,044 reviewers. Despite the large variability in the scoring data, the results are largely confirmatory of work from blinded reviews, by which a linear relationship between reviewer expertise and their evaluations was observed-reviewers with higher levels of self-assessed expertise tended to be harsher in their evaluations. However, we also found that reviewer and applicant seniority could influence this relationship, suggesting social networks could have subtle influences on reviewer scoring. Overall, these results highlight the need to explore how reviewers utilize their expertise to gather and weight information from the application in making their evaluations. PMID- 27768762 TI - The Short- and Long-Term Risk of Stroke after Herpes Zoster: A Meta-Analysis. AB - BACKGROUND: Accumulating evidence indicates that stroke risk may be increased following herpes zoster. The aim of this study is to perform a meta-analysis of current literature to systematically analyze and quantitatively estimate the short and long-term effects of herpes zoster on the risk of stroke. METHODS: Embase, PubMed and Cochrane library databases were searched for relevant studies up to March 2016. Studies were selected for analysis based on certain inclusion and exclusion criteria. Relative risks with 95% confidence interval (CI) were extracted to assess the association between herpes zoster and stroke. RESULTS: A total of 8 articles were included in our analysis. The present meta-analysis showed that the risks of stroke after herpes zoster were 2.36 (95% CI: 2.17-2.56) for first 2 weeks, 1.56 (95% CI: 1.46-1.66) for first month, 1.17 (95% CI: 1.13 1.22) for first year, and 1.09 (95% CI: 1.02-1.16) for more than 1 year, respectively. CONCLUSION: The results of our study demonstrated that herpes zoster was associated with a higher risk of stroke, but the risks decreased along with the time after herpes zoster. PMID- 27768761 TI - Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease. AB - Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer's disease (AD)-like pathology, specifically Abeta-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Abeta pathology with scyllo-inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of scyllo-inositol treatment. The prolonged exposure to Abeta pathology leads to deficits in the neurogenic niche, thus targeting Abeta alone is insufficient to rescue neurogenesis. To support the neurogenic niche, we combined scyllo-inositol treatment with leteprinim potassium (neotrofin), the latter of which stimulates neurotrophin expression. We show that the combination treatment of scyllo-inositol and neotrofin enhances neuronal survival and differentiation. We propose this proof of concept combination therapy of targeting Abeta-pathology and neurotrophin deficits as a potential treatment for AD. PMID- 27768763 TI - Reactivation of FMR1 by CRISPR/Cas9-Mediated Deletion of the Expanded CGG-Repeat of the Fragile X Chromosome. AB - Fragile X syndrome (FXS) is a common cause of intellectual disability that is most often due to a CGG-repeat expansion mutation in the FMR1 gene that triggers epigenetic gene silencing. Epigenetic modifying drugs can only transiently and modestly induce FMR1 reactivation in the presence of the elongated CGG repeat. As a proof-of-principle, we excised the expanded CGG-repeat in both somatic cell hybrids containing the human fragile X chromosome and human FXS iPS cells using the CRISPR/Cas9 genome editing. We observed transcriptional reactivation in approximately 67% of the CRISPR cut hybrid colonies and in 20% of isolated human FXS iPSC colonies. The reactivated cells produced FMRP and exhibited a decline in DNA methylation at the FMR1 locus. These data demonstrate the excision of the expanded CGG-repeat from the fragile X chromosome can result in FMR1 reactivation. PMID- 27768765 TI - Correction: Effects of Porphyromonas gingivalis LipopolysaccharideTolerized Monocytes on Inflammatory Responses in Neutrophils. AB - [This corrects the article DOI: 10.1371/journal.pone.0161482.]. PMID- 27768764 TI - Combination of Cancer Stem Cell Markers CD44 and CD24 Is Superior to ALDH1 as a Prognostic Indicator in Breast Cancer Patients with Distant Metastases. AB - The combination of CD44 and CD24, or aldehyde dehydrogenase 1 (ALDH1) alone, is a widely used cancer stem cell marker in breast cancer. However, no conclusion has yet been reached as to which marker is the best for characterizing cancer stemness. Immunohistochemical evaluation using cancer stem cell markers is clearly less common clinically than in basic experiments and how the expressions of these markers relate to patient outcomes remains controversial. To investigate whether combining these markers might improve the prediction of patient outcomes, we immunohistochemically examined clinical samples. Primary invasive breast cancer samples from 61 patients who eventually developed distant metastases after curative surgery were immunohistochemically examined. All patients were free of metastatic disease at the time of surgery and received standard adjuvant systemic treatments. CD44+/24- and ALDH1-positive rates in primary tumors differed according to intrinsic subtype. ER-positive patients with CD44+/24- tumors had significantly longer disease-free-survival than all other ER-positive patients (p = 0.0047). On the other hand, CD44+/24- tumors were associated with poor outcomes of ER-negative patients (p = 0.038). Finally, expression patterns of CD44 and ALDH1 in single tumors were strikingly different and there were virtually no individual double-stained cells. Thus, this combination does not allow evaluation of relationships with patient outcomes. Our results raise the possibility of CD44+/24- being a good prognostic marker, one which would allow treatment effects and outcomes to be predicted in patients with recurrent breast cancer. PMID- 27768766 TI - Correction: Environmental DNA Marker Development with Sparse Biological Information: A Case Study on Opossum Shrimp (Mysis diluviana). AB - [This corrects the article DOI: 10.1371/journal.pone.0161664.]. PMID- 27768767 TI - Correction: Importance of Glutamate Dehydrogenase (GDH) in Clostridium difficile Colonization In Vivo. AB - [This corrects the article DOI: 10.1371/journal.pone.0160107.]. PMID- 27768768 TI - Correction: Do Laboratory Mouse Females that Lose Their Litters Behave Differently around Parturition? AB - [This corrects the article DOI: 10.1371/journal.pone.0161238.]. PMID- 27768769 TI - Depletion of Tip60 from In Vivo Cardiomyocytes Increases Myocyte Density, Followed by Cardiac Dysfunction, Myocyte Fallout and Lethality. AB - Tat-interactive protein 60 (Tip60), encoded by the Kat5 gene, is a member of the MYST family of acetyltransferases. Cancer biology studies have shown that Tip60 induces the DNA damage response, apoptosis, and cell-cycle inhibition. Although Tip60 is expressed in the myocardium, its role in cardiomyocytes (CMs) is unclear. Earlier studies here showed that application of cardiac stress to globally targeted Kat5+/-haploinsufficient mice resulted in inhibition of apoptosis and activation of the CM cell-cycle, despite only modest reduction of Tip60 protein levels. It was therefore of interest to ascertain the effects of specifically and substantially depleting Tip60 from CMs using Kat5LoxP/-;Myh6-Cre mice in the absence of stress. We report initial findings using this model, in which the effects of specifically depleting Tip60 protein from ventricular CMs, beginning at early neonatal stages, were assessed in 2-12 week-old mice. Although 5'-bromodeoxyuridine immunostaining indicated that CM proliferation was not altered at any of these stages, CM density was increased in 2 week-old ventricles, which persisted in 4 week-old hearts when TUNEL staining revealed inhibition of apoptosis. By week 4, levels of connexin-43 were depleted, and its patterning was dysmorphic, concomitant with an increase in cardiac hypertrophy marker expression and interstitial fibrosis. This was followed by systolic dysfunction at 8 weeks, after which extensive apoptosis and CM fallout occurred, followed by lethality as mice approached 12 weeks of age. In summary, chronic depletion of Tip60 from the ventricular myocardium beginning at early stages of neonatal heart development causes CM death after 8 weeks; hence, Tip60 protein has a crucial function in the heart. PMID- 27768770 TI - Development of an Immunoperoxidase Monolayer Assay for the Detection of Antibodies against Peste des Petits Ruminants Virus Based on BHK-21 Cell Line Stably Expressing the Goat Signaling Lymphocyte Activation Molecule. AB - From 2013 to 2015, peste des petits ruminants (PPR) broke out in more than half of the provinces of China; thus, the application and development of diagnostic methods are very important for the control of PPR. Here, an immunoperoxidase monolayer assay (IPMA) was developed to detect antibodies against PPR. However, during IPMA development, we found that Vero cells were not the appropriate choice because staining results were not easily observed. Therefore, we first established a baby hamster kidney-goat signaling lymphocyte activation molecule (BHK-SLAM) cell line that could stably express goat SLAM for at least 20 generations. Compared with Vero cells, the PPR-mediated cytopathic effect occurred earlier in BHK-SLAM cells, and large syncytia appeared after virus infection. Based on this cell line and recombinant PPR virus expressing the green fluorescent protein (GFP) (rPPRV-GFP), an IPMA for PPR diagnosis was developed. One hundred and ninety-eight PPR serum samples from goats or sheep were tested by the IPMA and virus neutralization test (VNT). Compared with the VNT, the sensitivity and specificity of the IPMA were 91% and 100%, respectively, and the coincidence rate of the two methods was 95.5%. The IPMA assay could be completed in 4 h, compared with more than 6 d for the VNT using rPPRV-GFP, and it is easily performed, as the staining results can be observed under a microscope. Additionally, unlike the VNT, the IPMA does not require antigen purification, which will reduce its cost. In conclusion, the established IPMA will be an alternative method that replaces the VNT for detecting antibodies against PPRV in the field. PMID- 27768771 TI - Silencing of ASC in Cutaneous Squamous Cell Carcinoma. AB - Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis in tumor cells, acting as a tumor-suppressor gene, which is lost in several human cancers. The aim of this study was to evaluate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC). Initially, ASC expression was immunohistochemically evaluated in non-metastic and metastatic SCC. While ASC expression does not correlate with metastatic potential, it correlates with the degree of dedifferentiation. Using methylation specific PCR we were able to demonstrate ASC silencing by promotor specific methylation and impaired inflammasome function in methylated cell lines, linking epigenetic modifications to innate immune activation in keratinocytes. Interestingly, upon ASC restoration by treatment with demethylating agents, we were able to restore AIM2 and NLRP3 activation. In summary, loss of ASC driven tumor development is counterbalanced in the identical cell by the inhibition of pro-tumorigenic inflammation in the tumor cell itself. PMID- 27768772 TI - De Novo Transcriptomes of Forsythia koreana Using a Novel Assembly Method: Insight into Tissue- and Species-Specific Expression of Lignan Biosynthesis Related Gene. AB - Forsythia spp. are perennial woody plants which are one of the most extensively used medicinal sources of Chinese medicines and functional diets owing to their lignan contents. Lignans have received widespread attention as leading compounds in the development of antitumor drugs and healthy diets for reducing the risks of lifestyle-related diseases. However, the molecular basis of Forsythia has yet to be established. In this study, we have verified de novo deep transcriptome of Forsythia koreana leaf and callus using the Illumina HiSeq 1500 platform. A total of 89 million reads were assembled into 116,824 contigs using Trinity, and 1,576 of the contigs displayed the sequence similarity to the enzymes responsible for plant specialized metabolism including lignan biosynthesis. Notably, gene ontology (GO) analysis indicated the remarkable enrichment of lignan-biosynthetic enzyme genes in the callus transcriptome. Nevertheless, precise annotation and molecular phylogenetic analyses were hindered by partial sequences of open reading frames (ORFs) of the Trinity-based contigs. To obtain more numerous contigs harboring a full-length ORF, we developed a novel overlapping layout consensus-based procedure, virtual primer-based sequence reassembly (VP-seq). VP seq elucidated 709 full-length ORFs, whereas only 146 full-length ORFs were assembled by Trinity. The comparison of expression profiles of leaf and callus using VP-seq-based full-length ORFs revealed 50-fold upregulation of secoisolariciresinol dehydrogenase (SIRD) in callus. Expression and phylogenetic cluster analyses predicted candidates for matairesinol-glucosylating enzymes. We also performed VP-seq analysis of lignan-biosynthetic enzyme genes in the transcriptome data of other lignan-rich plants, Linum flavum, Linum usitatissimum and Podophyllum hexandrum. The comparative analysis indicated both common gene clusters involved in biosynthesis upstream of matairesinol such as SIRD and plant lineage-specific gene clusters, in particular, genes responsible for biosynthetic pathways for production of podophyllotoxin; CYP71BE54, a key enzyme gene for podophyllotoxin biosynthesis in P. hexandrum, was not found in L. flavum, although both P. hexandrum. and L. flavum yield podophyllotoxin. Altogether, these data have established the fruitful molecular basis of Forsythia and provided insight into the molecular evolution and diversity of lignan biosynthetic pathways. PMID- 27768773 TI - Optochemokine Tandem for Light-Control of Intracellular Ca2. AB - An optochemokine tandem was developed to control the release of calcium from endosomes into the cytosol by light and to analyze the internalization kinetics of G-protein coupled receptors (GPCRs) by electrophysiology. A previously constructed rhodopsin tandem was re-engineered to combine the light-gated Ca2+ permeable cation channel Channelrhodopsin-2(L132C), CatCh, with the chemokine receptor CXCR4 in a functional tandem protein tCXCR4/CatCh. The GPCR was used as a shuttle protein to displace CatCh from the plasma membrane into intracellular areas. As shown by patch-clamp measurements and confocal laser scanning microscopy, heterologously expressed tCXCR4/CatCh was internalized via the endocytic SDF1/CXCR4 signaling pathway. The kinetics of internalization could be followed electrophysiologically via the amplitude of the CatCh signal. The light induced release of Ca2+ by tandem endosomes into the cytosol via CatCh was visualized using the Ca2+-sensitive dyes rhod2 and rhod2-AM showing an increase of intracellular Ca2+ in response to light. PMID- 27768774 TI - Super-Resolution Real Imaging in Microsphere-Assisted Microscopy. AB - Microsphere-assisted microscopy has received a lot of attention recently due to its simplicity and its capability to surpass the diffraction limit. However, to date, sub-diffraction-limit features have only been observed in virtual images formed through the microspheres. We show that it is possible to form real, super resolution images using high-refractive index microspheres. Also, we report on how changes to a microsphere's refractive index and size affect image formation and planes. The relationship between the focus position and the additional magnification factor is also investigated using experimental and theoretical methods. We demonstrate that such a real imaging mode, combined with the use of larger microspheres, can enlarge sub-diffraction-limit features up to 10 times that of wide-field microscopy's magnification with a field-of-view diameter of up to 9 MUm. PMID- 27768775 TI - Dexmedetomidine Acts via the JAK2/STAT3 Pathway to Attenuate Isoflurane-Induced Neurocognitive Deficits in Senile Mice. AB - BACKGROUND: Previous studies showed that isoflurane-induced cognitive deficits could be alleviated by dexmedetomidine in young animal subjects. In the current study, we examine whether dexmedetomidine could also alleviate isoflurane-induced cognitive deficits in senile animals. METHODS: Senile male C57BL/6 mice (20 months) received dexmedetomidine (50 MUg/kg, i.p.) or vehicle 30 minutes prior to isoflurane exposure (1.3% for 4 h). Cognitive function was assessed 19 days later using a 5-day testing regimen with Morris water maze. Some subjects also received pretreatment with alpha2 adrenoreceptor antagonist atipamezole (250 MUg/kg, i.p.), JAK2 inhibitor AG490 (15 mg/kg i.p.) or STAT3 inhibitor WP1066 (40 mg/kg i.p.) 30 minutes prior to dexmedetomidine. RESULTS: Isoflurane exposure increased and reduced the time spent in the quadrant containing the target platform in training sessions. The number of crossings over the original target quadrant was also decreased. Dexmedotomidine attenuated such effects. Effects of dexmedotomidine were reduced by pretreatment with atipamezole, AG490 and WP1066. Increased phosphorylation of JAK2 and STAT3 in the hippocampus induced by isoflurane was augmented by dexmedetomidine. Effects of dexmedetomidine on JAK2/STAT3 phosphorylation were attenuated by atipamezole, AG490 and WP1066. Isoflurane promoted neuronal apoptosis and increased the expression of cleaved caspase-3 and BAD, and reduced Bcl-2 expression. Attenuation of such effects by dexmedotomidine was partially blocked by atipamezole, AG490 and WP1066. CONCLUSION: Dexmedetomidine could protect against isoflurane-induced spatial learning and memory impairment in senile mice by stimulating the JAK2/STAT3 signaling pathway. Such findings encourage the use of dexmedetomidine in geriatric patients receiving isoflurane anesthesia. PMID- 27768776 TI - In Vivo Effects of Pichia Pastoris-Expressed Antimicrobial Peptide Hepcidin on the Community Composition and Metabolism Gut Microbiota of Rats. AB - Hepcidin, one kind of antimicrobial peptides, is one of the promising alternatives to antibiotics with broad spectrum of antimicrobial activity. Hepcidins cloned from different kinds of fishes have been produced using exogenous expression systems, and their in vitro antimicrobial effects have been verified. However their in vivo effects on gut microbiota and gut health of hosts remain unclear. Here we performed a safety study of hepcidin so that it can be used to reduce microbial contaminations in the food and feed. In this study, Pichia pastoris-expressed Pseudosciaena crocea hepcidin (PC-hepc) was first assessed by simulated digestion tests and then administered to male and female Sprague-Dawley (SD) rats in different concentrations. Subchronic toxicity testing, high throughput 16S rRNA sequencing of gut microbiota, and examinations on gut metabolism and permeability were conducted. The results showed PC-hepc could be digested in simulated intestinal fluid but not in simulated gastric fluid. PC-hepc had no adverse effects on general health, except causing increase of blood glucose (still in the normal value range of this index) in all trial groups of female rats and intestinal inflammation in HD group of female rats. Community composition of gut microbiota of female MD and HD groups shifted compared with control group, of which the decrease of genus Akkermansia might be related to the increase of blood glucose and intestinal inflammation. Significant increase of fecal nitroreductase activity was also observed in female MD and HD groups. Our results suggest the uses of exogenous PC-hepc in normal dosage are safe, however excess dosage of it may cause intestinal disorder of animals. PMID- 27768777 TI - The Associations of Serum Lipids with Vitamin D Status. AB - AIMS: Vitamin D deficiency has been associated with some disorders including cardiovascular diseases. Dyslipidemia is a major risk factor for cardiovascular diseases. However, data about the relationships between vitamin D and lipids are inconsistent. The relationship of vitamin D and Atherogenic Index of Plasma (AIP), as an excellent predictor of level of small and dense LDL, has not been reported. The objective of this study was to investigate the effects of vitamin D status on serum lipids in Chinese adults. METHODS: The study was carried out using 1475 participants from the Center for Physical Examination, 306 Hospital of PLA in Beijing, China. Fasting blood samples were collected and serum concentrations of 25(OH)D, total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were measured. AIP was calculated based on the formula: log [TG/HDL-C]. Multiple linear regression analysis was used to estimate the associations between serum 25(OH)D and lipids. The association between the occurrences of dyslipidemias and vitamin D levels was assessed by multiple logistic regression analysis. Confounding factors, age and BMI, were used for the adjustment. RESULTS: The median of serum 25(OH)D concentration was 47 (27-92.25) nmol/L in all subjects. The overall percentage of 25(OH)D ? 50 nmol/L was 58.5% (males 54.4%, females 63.7%). The serum 25(OH)D levels were inversely associated with TG (beta coefficient = -0.24, p < 0.001) and LDL-C (beta coefficient = -0.34, p < 0.001) and positively associated with TC (beta coefficient = 0.35, p < 0.002) in men. The associations between serum 25(OH)D and LDL-C (beta coefficient = -0.25, p = 0.01) and TC (beta coefficient = 0.39, p = 0.001) also existed in women. The serum 25(OH)D concentrations were negatively associated with AIP in men (r = 0.111, p < 0.01) but not in women. In addition, vitamin D deficient men had higher AIP values than vitamin D sufficient men. Furthermore, the occurrences of dyslipidemias (reduced HDL-C, elevated TG and elevated AIP) correlated with lower 25(OH)D levels in men, whereas the higher TC and LDL-C associated with higher 25(OH)D levels in women. CONCLUSION: It seems that the serum 25(OH)D levels are closely associated with the serum lipids and AIP. Vitamin D deficiency may be associated with the increased risk of dyslipidemias, especially in men. The association between vitamin D status and serum lipids may differ by genders. PMID- 27768778 TI - Pupil Diameter Tracks Lapses of Attention. AB - Our ability to sustain attention for prolonged periods of time is limited. Studies on the relationship between lapses of attention and psychophysiological markers of attentional state, such as pupil diameter, have yielded contradicting results. Here, we investigated the relationship between tonic fluctuations in pupil diameter and performance on a demanding sustained attention task. We found robust linear relationships between baseline pupil diameter and several measures of task performance, suggesting that attentional lapses tended to occur when pupil diameter was small. However, these observations were primarily driven by the joint effects of time-on-task on baseline pupil diameter and task performance. The linear relationships disappeared when we statistically controlled for time-on-task effects and were replaced by consistent inverted U shaped relationships between baseline pupil diameter and each of the task performance measures, such that most false alarms and the longest and most variable response times occurred when pupil diameter was both relatively small and large. Finally, we observed strong linear relationships between the temporal derivative of pupil diameter and task performance measures, which were largely independent of time-on-task. Our results help to reconcile contradicting findings in the literature on pupil-linked changes in attentional state, and are consistent with the adaptive gain theory of locus coeruleus-norepinephrine function. Moreover, they suggest that the derivative of baseline pupil diameter is a potentially useful psychophysiological marker that could be used in the on line prediction and prevention of attentional lapses. PMID- 27768779 TI - A Microplate-Based Nonradioactive Protein Synthesis Assay: Application to TRAIL Sensitization by Protein Synthesis Inhibitors. AB - Non-radioactive assays based on incorporation of puromycin into newly synthesized proteins and subsequent detection using anti-puromycin antibodies have been previously reported and well-validated. To develop a moderate- to high-throughput assay, an adaptation is here described wherein cells are puromycin-labeled followed by simultaneously probing puromycin-labeled proteins and a reference protein in situ. Detection using a pair of near IR-labeled secondary antibodies (InCell western, ICW format) allows quantitative analysis of protein synthesis in 384-well plates. After optimization, ICW results were compared to western blot analysis using cycloheximide as a model protein synthesis inhibitor and showed comparable results. The method was then applied to several protein synthesis inhibitors and revealed good correlation between potency as protein synthesis inhibitors to their ability to sensitize TRAIL-resistant renal carcinoma cells to TRAIL-induced apoptosis. PMID- 27768781 TI - Correction: The Post-Embargo Open Access Citation Advantage: It Exists (Probably), It's Modest (Usually), and the Rich Get Richer (of Course). AB - [This corrects the article DOI: 10.1371/journal.pone.0159614.]. PMID- 27768780 TI - Over Expression of NANOS3 and DAZL in Human Embryonic Stem Cells. AB - The mechanisms underlying human germ cell development are largely unknown, partly due to the scarcity of primordial germ cells and the inaccessibility of the human germline to genetic analysis. Human embryonic stem cells can differentiate to germ cells in vitro and can be genetically modified to study the genetic requirements for germ cell development. Here, we studied NANOS3 and DAZL, which have critical roles in germ cell development in several species, via their over expression in human embryonic stem cells using global transcriptional analysis, in vitro germ cell differentiation, and in vivo germ cell formation assay by xenotransplantation. We found that NANOS3 over expression prolonged pluripotency and delayed differentiation. In addition, we observed a possible connection of NANOS3 with inhibition of apoptosis. For DAZL, our results suggest a post transcriptional regulation mechanism in hES cells. In addition, we found that DAZL suppressed the translation of OCT4, and affected the transcription of several genes associated with germ cells, cell cycle arrest, and cell migration. Furthermore, DAZL over expressed cells formed spermatogonia-like colonies in a rare instance upon xenotransplantation. These data can be used to further elucidate the role of NANOS3 and DAZL in germ cell development both in vitro and in vivo. PMID- 27768783 TI - Real-time three-dimensional digital image correlation for biomedical applications. AB - Digital image correlation (DIC) has been successfully applied for evaluating the mechanical behavior of biological tissues. A three-dimensional (3-D) DIC system has been developed and applied to examining the motion of bones in the human foot. To achieve accurate, real-time displacement measurements, an algorithm including matching between sequential images and image pairs has been developed. The system was used to monitor the movement of markers which were attached to a precisely motorized stage. The accuracy of the proposed technique for in-plane and out-of-plane measurements was found to be ?0.25% and 1.17%, respectively. Two biomedical applications were presented. In the experiment involving the foot arch, a human cadaver lower leg and foot specimen were subjected to vertical compressive loads up to 700 N at a rate of 10??N/s and the 3-D motions of bones in the foot were monitored in real time. In the experiment involving distal tibio fibular syndesmosis, a human cadaver lower leg and foot specimen were subjected to a monotonic rotational torque up to 5 Nm at a speed of 5 deg per min and the relative displacements of the tibia and fibula were monitored in real time. Results showed that the system could reach a frequency of up to 16 Hz with 6 points measured simultaneously. This technique sheds new lights on measuring 3-D motion of bones in biomechanical studies. PMID- 27768782 TI - Quantitative T1, T2, and T2* Mapping and Semi-Quantitative Neuromelanin-Sensitive Magnetic Resonance Imaging of the Human Midbrain. AB - PURPOSE: Neuromelanin is a dark pigment granule present within certain catecholamine neurons of the human brain. Here, we aimed to clarify the relationship between contrast of neuromelanin-sensitive magnetic resonance imaging (MRI) and MR relaxation times using T1, T2, and T2* mapping of the lower midbrain. METHODS: The subjects were 14 healthy volunteers (11 men and 3 women, mean age 29.9 +/- 6.9 years). Neuromelanin-sensitive MRI was acquired using an optimized T1-weighted two-dimensional (2D)-turbo spin-echo sequence. To quantitatively evaluate the relaxation time, 2D-image data for the T1, T2, and T2* maps were also acquired. The regions of interest (substantia nigra pars compacta [SNc], superior cerebellar peduncles [SCP], cerebral peduncles [CP], and midbrain tegmentum [MT]) were manually drawn on neuromelanin-sensitive MRI to measure the contrast ratio (CR) and on relaxation maps to measure the relaxation times. RESULTS: The CR in the SNc was significantly higher than the CRs in the SCP and CP. Compared to the SCP and CP, the SNc had significantly higher T1 relaxation times. Moreover, the SNc had significantly lower T2 and T2* relaxation times than the other three regions (SCP, CP, and MT). Correlation analyses showed no significant correlations between the CRs in the SNc, SCP, and CP and each relaxation time. CONCLUSIONS: We demonstrated the relationship between the CR of neuromelanin-sensitive MRI and the relaxation times of quantitative maps of the human midbrain. PMID- 27768784 TI - Quantitative phase imaging of live cells with near on-axis digital holographic microscopy using constrained optimization approach. AB - We demonstrate a single-shot near on-axis digital holographic microscope that uses a constrained optimization approach for retrieval of the complex object function in the hologram plane. The recovered complex object is back-propagated from the hologram plane to image plane using the Fresnel back-propagation algorithm. A numerical aberration compensation algorithm is employed for correcting the aberrations in the object beam. The reference beam angle is calculated automatically using the modulation property of Fourier transform without any additional recording. We demonstrate this approach using a United States Air Force (USAF) resolution target as an object on our digital holographic microscope. We also demonstrate this approach by recovering the quantitative phase images of live yeast cells, red blood cells and dynamics of live dividing yeast cells. PMID- 27768785 TI - The Effects of Diabetic Retinopathy Stage and Light Flicker on Inner Retinal Oxygen Extraction Fraction. AB - Purpose: We determined the effects of light flicker and diabetic retinopathy (DR) stage on retinal vascular diameter (D), oxygen saturation (SO2), and inner retinal oxygen extraction fraction (OEF). Methods: Subjects were categorized as nondiabetic control (NC, n = 42), diabetic with no clinical DR (NDR; n = 32), nonproliferative DR (NPDR; n = 42), or proliferative DR (PDR; n = 14). Our customized optical imaging system simultaneously measured arterial and venous D (DA, DV) and SO2 (SO2A, SO2V) before and during light flicker. Inner retinal OEF was derived from SO2 values. Light flicker-induced ratios of metrics (DAR, DVR, SO2AR, SO2VR, OEFR) were calculated. Results: Arterial D was larger in NPDR compared to NC (P = 0.01) and PDR (P = 0.002), whereas DV was similar among groups (P >= 0.16). Light flicker increased DA and DV (P <= 0.004), but DAR and DVR were similar among groups (P >= 0.09). Arterial SO2 was higher in all groups compared to NC (P <= 0.02) and higher in PDR compared to NDR and NPDR (P<0.001). Arterial SO2 did not change with light flicker (P >= 0.1). Venous SO2 was higher in NPDR and PDR compared to NC and NDR (P <= 0.02). Light flicker increased SO2V in NC, NDR, and PDR (P <= 0.003), and SO2VR was lower in NPDR compared to NC and NDR (P <= 0.05). Inner retinal OEF was lower in NPDR compared to NDR and PDR (P <= 0.02). Light flicker decreased OEF (P <= 0.03), but OEFR was greater in NPDR compared to NC and NDR (P <= 0.03). Conclusions: The findings of alterations in retinal D, SO2, OEF, and their light flicker-induced responses at stages of DR may be useful to elucidate the pathophysiology of DR. PMID- 27768786 TI - The Glymphatic System: A New Player in Ocular Diseases? PMID- 27768787 TI - "Black Holes" and the Ocular Glymphatic System: Author Response to "The Glymphatic System: A New Player in Ocular Diseases?" PMID- 27768788 TI - MicroRNA Profiles Qualify Phenotypic Features of Cultured Human Corneal Endothelial Cells. AB - Purpose: To elucidate a noninvasive method to qualify and identify cultured human corneal endothelial cells (cHCECs) devoid of cell-state transition and adaptable for cell-based therapy. Methods: The variations of cHCECs in their composition of heterogeneous subpopulations (SPs) were verified in relation to their surface cluster-of-differentiation (CD) markers and their morphology. The profiles of microRNA (miRNA) in cultured cells or supernatants were detected by 3D-Gene Human microRNA Chips (Toray Industries, Inc.). The profiles were also analyzed for fresh corneal tissues with distinct endothelial cell densities (ECD) with or without gutatta. To validate the 3D-Gene results, quantitative real-time polymerase chain reaction (PCR) was performed. RNAs were extracted from cHCECs transfected with selected miRNA, and target genes were presumed by PCR array (Qiagen). Results: Among a variety of morphologically different cHCECs, miRNA expression profiles were distinctively revealed. The one miRNA capable of discriminating CD44- SP from SPs with CD44++~CD44+++ phenotypes was identified as miR34a. The downregulation of miRNAs in the 378 family paralleled the upregulation of surface CD44 on cHCECs. Interestingly, upregulated miRNAs in the 378 family in corneal endothelium dramatically decreased in the tissues with lower ECD with advanced gutatta, providing new insight on the pathogenesis of Fuchs' endothelial corneal dystrophy. Conclusions: The specified cultured SPs sharing the CD44- surface phenotypes with matured HCECs showed the highest expression of miR-378. Conversely, SPs with upregulated CD44+++ showed a reduction of miR-378. Thus, miRNA in cultured cells may serve as an alternative method to qualify cHCECs. PMID- 27768789 TI - Impact of Genetic Loci Identified in Genome-Wide Association Studies on Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes. AB - Purpose: Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DR susceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort. Methods: Cross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed. Results: The strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 * 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted= 1.12 * 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models. Conclusions: We demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR. PMID- 27768791 TI - Extraocular Muscle Compartments in Superior Oblique Palsy. AB - Purpose: To investigate changes in volumes of extraocular muscle (EOM) compartments in unilateral superior oblique (SO) palsy using magnetic resonance imaging (MRI). Methods: High-resolution, surface-coil MRI was obtained in 19 patients with unilateral SO palsy and 19 age-matched orthotropic control subjects. Rectus EOMs and the SO were divided into two anatomic compartments for volume analysis in patients with unilateral SO palsy, allowing comparison of total compartmental volumes versus controls. Medial and lateral compartmental volumes of the SO muscle were compared in patients with isotropic (round shape) versus anisotropic (elongated shape) SO atrophy. Results: The medial and lateral compartments of the ipsilesional SO muscles were equally atrophic in isotropic SO palsy, whereas the lateral compartment was significantly smaller than the medial in anisotropic SO palsy (P = 0.01). In contrast to the SO, there were no differential compartmental volume changes in rectus EOMs; however, there was significant total muscle hypertrophy in the ipsilesional inferior rectus (IR) and lateral rectus (LR) muscles and contralesional superior rectus (SR) muscles. Medial rectus (MR) volume was normal both ipsi- and contralesionally. Conclusions: A subset of patients with SO palsy exhibit selective atrophy of the lateral, predominantly vertically acting SO compartment. Superior oblique atrophy is associated with whole-muscle volume changes in the ipsilesional IR, ipsilesional LR, and contralesional SR; however, SO muscle atrophy is not associated with compartmentally selective volume changes in the rectus EOMs. Selective compartmental SO pathology may provide an anatomic mechanism that explains some of the variability in clinical presentations of SO palsy. PMID- 27768790 TI - Thy-1 Regulates VEGF-Mediated Choroidal Endothelial Cell Activation and Migration: Implications in Neovascular Age-Related Macular Degeneration. AB - Purpose: This study addresses the hypothesis that age-related stresses upregulate Thy-1 in choroidal endothelial cells (CECs) and contribute to CEC activation and migration, processes important in choroidal neovascularization (CNV). Methods: Measurements were made of Thy-1 protein (Western blot) in CECs and Thy-1 mRNA (real time quantitative PCR) in CECs treated with VEGF, CCL11, or PBS or in RPE/choroids from young or old donors or lasered or nonlasered mice. Immunolabeled Thy-1 in ocular sections was compared from young versus old human donor eyes or those with or without neovascular AMD or from lasered versus nonlasered mice. Choroidal endothelial cells transfected with Thy-1 or control siRNA or pretreated with Thy-1 blocking peptide or control were stimulated with VEGF or 7-ketocholesterol (7-KC). Choroidal endothelial cell migration, proliferation, cytoskeletal stress fibers, Rac1 activation, and phosphorylated VEGF receptor 2 (VEGFR2), integrin beta3, and Src were measured. Statistics were performed using ANOVA. Results: Thy-1 was expressed in retinal ganglion cells and in vascular endothelial-cadherin-labeled choroid and localized to human or mouse laser-induced CNV lesions. Thy-1 protein and mRNA were significantly increased in CECs treated with VEGF or CCL11 and in RPE/choroids from aged versus young donor eyes or from lasered mice versus nonlasered controls. Knockdown or inhibition of Thy-1 in CECs significantly reduced VEGF-induced CEC migration and proliferation, stress fiber formation and VEGFR2, Src, integrin beta3 and Rac1 activation, and 7 KC-induced Rac1 and Src activation. Conclusions: Thy-1 in CECs regulates VEGF induced CEC activation and migration and links extracellular 7-KC to intracellular signaling. Future studies elucidating Thy-1 mechanisms in neovascular AMD are warranted. PMID- 27768792 TI - Vision-Related Quality of Life Outcomes in the BEVORDEX Study: A Clinical Trial Comparing Ozurdex Sustained Release Dexamethasone Intravitreal Implant and Bevacizumab Treatment for Diabetic Macular Edema. AB - Purpose: To determine the patient-centered effectiveness of treatment with the slow-release dexamethasone intravitreal implant (DEX implant) and intravitreal bevacizumab using the Impact of Vision Impairment Questionnaire (IVI), a vision related quality of life (VRQoL) measure, in patients with visual impairment secondary to center-involving diabetic macular edema (DME). Methods: Patients with DME were enrolled in a phase 2, prospective, multicenter, randomized, single masked clinical trial and received either DEX implant 4 monthly or bevacizumab monthly, both pro re nata. Vision-related quality of life was measured at baseline and 24 months, using the IVI's three component scales, namely reading, mobility, and emotional well-being. Rasch analysis was used to generate interval level estimates of VRQoL, which were then analyzed using t-tests to assess changes over time. Results: Forty-eight patients completed the main study; 43 (90%) answered the IVI at the baseline and 24-month (final efficacy) visits. Vision-related quality of life improved significantly, with average increases of 1.44, 0.99, and 1.49 logits, for the reading, mobility, and emotional well-being scales respectively, from baseline to 24 months, (P < 0.001). There was no significant between-group difference in improvement in VRQoL in the DEX implant only compared with the bevacizumab-only group, in any of the three scales listed above (with 1.41, 1.08, and 2.11 logits improvement, in reading, mobility, and emotional well-being, respectively, for DEX implant group, compared with 1.48, 1.06, and 2.11 for bevacizumab; P values > 0.1.). Conclusions: We found that both DEX implant and bevacizumab treatment result in significant and similar improvements in VRQoL in patients with DME over a 24-month period. (Clinicaltrials.gov identifier NCT01298076). PMID- 27768793 TI - Telomere Length Measurement in Different Ocular Structures: A Potential Implication in Corneal Endothelium Pathogenesis. AB - Purpose: Human chromosomes are protected at their end by a long portion of hexameric tandem repeats, the telomere. In somatic cells, telomere attrition caused by endogenous and exogenous oxidative stress as well as DNA replication can threaten genomic integrity and lead to the deterioration of tissue functions and an age-related physiological decline. The human eye is a complex organ in which cells of different ocular tissues are exposed to photo-oxidation, high mitochondrial metabolic activity, and/or replicative pressure. Methods: We employed a highly sensitive quantitative PCR technique to determine relative telomere length in different human ocular structures. Results: The longest telomeres in all ocular structures analyzed are found in neural retina, and the shortest are in the cornea. Within the retina, retinal pigment epithelium has four times shorter telomeres when compared to neural retina. However, no age dependent telomere attrition in the retina and no difference between telomere lengths in the macular region and the rest of the retina have been found. In the cornea, stroma has the longer telomeres. In the corneal endothelium, we found a clear age-dependent telomere shortening. Since the endothelium is one of the most metabolically active ocular structure, this result suggests that endogenous oxidative stress from high mitochondrial activity is a major determinant of telomere loss in this structure. Conclusions: Taken together, our results imply that the aging process and telomere attrition in the different ocular structures are the result of multiple factors and could not be attributed to solely exogenous or endogenous oxidation or DNA replication. PMID- 27768795 TI - Longitudinal Changes in Optic Nerve Head Blood Flow in Normal Rats Evaluated by Laser Speckle Flowgraphy. AB - Purpose: To investigate longitudinal changes in mean blur rate (MBR) measured by laser speckle flowgraphy (LSFG) in the rat optic nerve head (ONH), and the reproducibility of MBR. Methods: Rats were dilated under general anesthesia. Intraocular pressure (IOP), blood pressure, ocular perfusion pressure (OPP), heart rate, and LSFG were measured 30 minutes later. Mean blur rate in the ONH was determined using LSFG-Micro and was subdivided into MBR of the total area (MA), vessel region (MV), and tissue region (MT). Mean blur rate measurements were repeated at 10, 11, 13, 19, and 20 weeks, then every 5 weeks until 60 weeks of age. Intrasession repeatability, intrasession reproducibility, and intersession reproducibility were evaluated. Results: Coefficient of variation of MBR was 0.3 to 6.2%, 1.3 to 5.2%, and 5.8 to 30.4% for intrasession repeatability, intrasession reproducibility, and intersession reproducibility, respectively. Mean blur rate of the total area, MV, and MT increased similarly until 19 weeks of age, but stabilized thereafter until 60 weeks. Mean blur rate of the total area in the inferior quadrant was significantly higher than in the temporal quadrant from 19 to 55 weeks. These changes exceeded a range of corresponding coefficient of reproducibility. There were no significant changes in IOP, blood pressure, or OPP during the experimental period. Conclusions: Mean blur rate in the rat ONH changed over time, increased from 10 to 19 weeks of age, then stabilized until 60 weeks. Mean blur rate of the total area exhibited regional differences: higher in the inferior quadrant than in the temporal quadrant. Laser speckle flowgraphy-Micro may provide reliable information for evaluating longitudinal changes of rat ONH blood flow. PMID- 27768794 TI - Fundus Camera-Delivered Light-Induced Retinal Degeneration in Mice With the RPE65 Leu450Met Variant is Associated With Oxidative Stress and Apoptosis. AB - Purpose: Oxidative stress, partly due to light, has an important role in many retinal diseases, including macular degeneration and retinal dystrophies. The Leu450Met variant of RPE65 is expressed in C57BL/6 and in many genetically modified mice. It confers significant resistance to light induced retinal degeneration (LIRD). Our goal was to develop an effective and efficient method to induce LIRD in resistant mice that would recapitulate mechanisms seen in known models of LIRD. Methods: The retinas of C57BL/6J mice were exposed to light using a murine fundus camera. Two protocols (with and without intraperitoneal fluorescein) were used. Optical coherence tomography (OCT) helped determine the location and extent of retinal damage. Histology, TUNEL assay, quantitative (q) PCR, and immunohistochemistry were performed. Results: Both protocols consistently generated LIRD in C57BL/6J mice. Optical coherence tomography and histology demonstrated that retinal damage starts at the level of the photoreceptor/outer retina and is more prominent in the superior retina. Fundus camera-delivered light-induced retinal degeneration (FCD-LIRD) is associated with apoptosis, subretinal microglia/macrophages, increased expression of oxidative stress response genes, and C3d deposition. Conclusions: We characterize two new models of light-induced retinal degeneration that are effective in C57BL/6J mice, and can be modulated in terms of severity. We expect FCD-LIRD to be useful in exploring mechanisms of LIRD in resistant mice, which will be important in increasing our understanding of the retinal response to light damage and oxidative stress. PMID- 27768796 TI - Epidemiology of Reticular Pseudodrusen in Age-Related Macular Degeneration: The Rotterdam Study. AB - Purpose: Reticular pseudodrusen (RPD) are considered to be a distinct feature in AMD. Population studies have studied the epidemiology of RPD using standard color fundus photographs (CFP). However, recent studies have shown that RPD are better imaged using near-infrared (NIR) imaging. We studied the epidemiology of RPD in a large population-based study using NIR and CFP. Methods: Participants aged 65+ years from the Rotterdam Study underwent ophthalmologic examination including NIR and CFP. Both images were graded for the presence of RPD and soft indistinct drusen (SID). Associations with demographic and environmental factors, 26 genetic variants, and total genetic risk score were analyzed using logistic regression analysis. Results: Reticular pseudodrusen were detected in 137 (4.9%) of 2774 study participants; of these, 92.7% were detected with NIR imaging and 38% on CFP. Most eyes with RPD showed presence of SID, whereas other drusen types coincided less frequently. Reticular pseudodrusen were significantly associated with age (odds ratio [OR] 1.21, 95% Confidence Interval [CI] 1.17-1.24) and female sex (OR 2.10, 95% CI 1.41-3.13). Environmental factors did not show a significant association with RPD. Major AMD risk variants were significantly associated with RPD and SID; however, ARMS2, C3, and VEGFA were more associated with RPD (RPD vs. SID P < 0.05). Total genetic risk score did not differ significantly (P = 0.88). Conclusion: Detection of RPD was better with NIR imaging than on CFP in a population-based setting. Presence of RPD often coincided with presence of SID; however, they showed quantitative differences in genetic risk profile. PMID- 27768797 TI - Lack of Visual Field Improvement After Initiation of Intraocular Pressure Reducing Treatment in the Early Manifest Glaucoma Trial. AB - Purpose: We evaluate how visual fields are affected by the initiation of IOP reducing therapy in previously untreated glaucoma individuals. Methods: Qualifying individuals with newly diagnosed glaucoma having normal to moderately elevated IOP were prospectively randomized either to IOP-reducing therapy or to no treatment. Before randomization, individuals underwent repeatedly Standard Automated Perimetry (SAP) testing and Goldmann tonometry. Three months after randomization, patients again underwent SAP and tonometry. Changes between baseline and the 3-month follow-up visit in the perimetric summary index, mean deviation (MD), and total deviation values at significantly depressed test points were compared between the treated and untreated groups. Results: Of 255 individuals studied, 129 were randomized to treatment and 126 to no treatment. Intraocular pressure decreased by an average of 24% among treated and by 0.6% in the untreated patients. Mean deviation deteriorated slightly in both groups; mean change was -0.15 and -0.44 dB in the treated and untreated groups, respectively; the difference was not statistically significant, (P = 0.16). No association was seen between IOP reduction and change in MD. Sensitivities decreased slightly in significantly depressed test points, mean change was -0.45 dB in the untreated and -0.38 dB in the treated groups (P = 0.88). Conclusions: Observed visual field changes among glaucoma patients receiving initial IOP-reducing therapy were not significantly different to changes seen in patients who received no treatment. Thus, our results did not support the idea that visual field status improves after initiation of IOP- reducing therapy in glaucoma individuals, at least not in individuals with initially normal to moderately elevated IOPs. PMID- 27768798 TI - Melimine-Coated Antimicrobial Contact Lenses Reduce Microbial Keratitis in an Animal Model. AB - Purpose: To determine the ability of antimicrobial peptide melimine-coated contact lenses to reduce the incidence of microbial keratitis (MK) in a rabbit model of contact lens wear. Methods: In vitro antimicrobial activity of melimine coated contact lenses was determined against Pseudomonas aeruginosa by viable count and a radiolabeled assay. The amount of lipopolysaccharide (LPS) associated with bacteria bound to melimine-coated and control lenses was determined. Ocular swabs from rabbit eyes were collected for assessment of ocular microflora. A rabbit model for MK was developed that used overnight wear of contact lenses colonized by P. aeruginosa in the absence of a corneal scratch. During lens wear, detailed ocular examinations were performed, and the incidence of MK was investigated. Bacteria associated with worn lenses and infected corneas were determined by viable plate count. Results: Inhibition in viable and total P. aeruginosa adhesion by melimine-coated contact lenses was 3.1 log10 and 0.4 log10, respectively. After colonization, the amount of LPS on lenses was approximately the same with or without melimine. Gram-positive bacteria were found in all the ocular swabs followed by fungus (42%). Melimine-coated lens wear was protective and significantly (odds ratio 10.12; P = 0.012) reduced the incidence of P. aeruginosa-driven MK in the rabbit model. The antimicrobial lenses were associated with significantly (P < 0.001) lower ocular scores, indicating improved ocular signs compared with controls. Conclusions: This study showed that contaminated contact lenses can produce MK without corneal epithelial defect in an animal model. Melimine-coated contact lenses reduced the incidence of MK associated with P. aeruginosa in vivo. Development of MK requires viable bacteria adherent to contact lenses, and bacterial debris adherent at the lens surface did not cause keratitis. PMID- 27768800 TI - Erratum. PMID- 27768801 TI - Erratum. PMID- 27768802 TI - Subjective Reports of Trouble Tolerating Sound in Daily Life versus Loudness Discomfort Levels. AB - Purpose: A retrospective analysis of tonal and speech loudness discomfort levels (LDLs) relative to a subjective report of sound tolerance (SRST) was performed to explore the relation between the 2 commonly used clinical measures. Method: Tonal LDLs and SRST were measured for 139 U.S. military veterans who were recruited into a study providing intervention for tinnitus. Spearman's rank correlation coefficients were computed to assess the relation between the tonal and speech LDLs and the SRST. Results: Only weak correlations were found between tonal LDLs and SRST and between speech LDLs and SRST. Conclusion: If LDLs ratings of SRST measured the same phenomenon, the measures would be strongly negatively correlated. The weak correlations found between the measures suggest that LDLs do not accurately represent a patient's ability to tolerate sound in daily life. PMID- 27768799 TI - Altered Protein Composition and Gene Expression in Strabismic Human Extraocular Muscles and Tendons. AB - Purpose: To determine whether structural protein composition and expression of key regulatory genes are altered in strabismic human extraocular muscles. Methods: Samples from strabismic horizontal extraocular muscles were obtained during strabismus surgery and compared with normal muscles from organ donors. We used proteomics, standard and customized PCR arrays, and microarrays to identify changes in major structural proteins and changes in gene expression. We focused on muscle and connective tissue and its control by enzymes, growth factors, and cytokines. Results: Strabismic muscles showed downregulation of myosins, tropomyosins, troponins, and titin. Expression of collagens and regulators of collagen synthesis and degradation, the collagenase matrix metalloproteinase (MMP)2 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2, was upregulated, along with tumor necrosis factor (TNF), TNF receptors, and connective tissue growth factor (CTGF), as well as proteoglycans. Growth factors controlling extracellular matrix (ECM) were also upregulated. Among 410 signaling genes examined by PCR arrays, molecules with downregulation in the strabismic phenotype included GDNF, NRG1, and PAX7; CTGF, CXCR4, NPY1R, TNF, NTRK1, and NTRK2 were upregulated. Signaling molecules known to control extraocular muscle plasticity were predominantly expressed in the tendon rather than the muscle component. The two horizontal muscles, medial and lateral rectus, displayed similar changes in protein and gene expression, and no obvious effect of age. Conclusions: Quantification of proteins and gene expression showed significant differences in the composition of extraocular muscles of strabismic patients with respect to important motor proteins, elements of the ECM, and connective tissue. Therefore, our study supports the emerging view that the molecular composition of strabismic muscles is substantially altered. PMID- 27768803 TI - Human Environmental Disease Network: A computational model to assess toxicology of contaminants. AB - During the past decades, many epidemiological, toxicological and biological studies have been performed to assess the role of environmental chemicals as potential toxicants associated with diverse human disorders. However, the relationships between diseases based on chemical exposure rarely have been studied by computational biology. We developed a human environmental disease network (EDN) to explore and suggest novel disease-disease and chemical-disease relationships. The presented scored EDN model is built upon the integration of systems biology and chemical toxicology using information on chemical contaminants and their disease relationships reported in the TDDB database. The resulting human EDN takes into consideration the level of evidence of the toxicant-disease relationships, allowing inclusion of some degrees of significance in the disease-disease associations. Such a network can be used to identify uncharacterized connections between diseases. Examples are discussed for type 2 diabetes (T2D). Additionally, this computational model allows confirmation of already known links between chemicals and diseases (e.g., between bisphenol A and behavioral disorders) and also reveals unexpected associations between chemicals and diseases (e.g., between chlordane and olfactory alteration), thus predicting which chemicals may be risk factors to human health. The proposed human EDN model allows exploration of common biological mechanisms of diseases associated with chemical exposure, helping us to gain insight into disease etiology and comorbidity. This computational approach is an alternative to animal testing supporting the 3R concept. PMID- 27768804 TI - Keratinocytes improve prediction of sensitization potential and potency of chemicals with THP-1 cells. AB - In vitro approaches to address key steps of chemical-induced skin sensitization have been developed, but there is uncertainty how keratinocytes, which play a crucial role not only regarding xenobiotic metabolism but also skin inflammation, impact on a chemical's potential and potency to activate dendritic cells. We investigated these aspects by coculturing THP-1 cells, as surrogate dendritic cells, with HaCaT keratinocytes. We tested our HaCaT/THP-1 model with a set of 14 sensitizers, containing 7 prohaptens, and 10 non-sensitizers. Compared to exposing THP-1 alone, coculturing resulted in up to 3.1-fold enhanced maximal CD86 and/or CD54 upregulation on THP-1, and improved concentration-dependency. All 14 sensitizers were found positive for CD86 and/or CD54 upregulation based on ? mean fluorescence intensity (MFI) >= 10 for CD86 and ?MFI >= 50 for CD54. Only 1 of 10 non-sensitizers was false-positive. Remarkably, coculture with HaCaT keratinocytes improved the rank correlation of the estimated minimum chemical concentrations inducing a positive response in vitro with in vivo data on sensitization potency, especially for CD54 (Spearman: r = 0.739, p = 0.006; CD86: r = 0.571, p = 0.041). These promising data suggest that the coculture model has the potential to support the prediction of sensitization potency based on in vitro data. PMID- 27768805 TI - Ex vivo culture platform for assessment of cartilage repair treatment strategies. AB - There is a great need for valuable ex vivo models that allow for assessment of cartilage repair strategies to reduce the high number of animal experiments. In this paper we present three studies with our novel ex vivo osteochondral culture platform. It consists of two separated media compartments for cartilage and bone, which better represents the in vivo situation and enables supply of factors specific to the different needs of bone and cartilage. We investigated whether separation of the cartilage and bone compartments and/or culture media results in the maintenance of viability, structural and functional properties of cartilage tissue. Next, we evaluated for how long we can preserve cartilage matrix stability of osteochondral explants during long-term culture over 84 days. Finally, we determined the optimal defect size that does not show spontaneous self-healing in this culture system. It was demonstrated that separated compartments for cartilage and bone in combination with tissue-specific medium allow for long-term culture of osteochondral explants while maintaining cartilage viability, matrix tissue content, structure and mechanical properties for at least 56 days. Furthermore, we could create critical size cartilage defects of different sizes in the model. The osteochondral model represents a valuable preclinical ex vivo tool for studying clinically relevant cartilage therapies, such as cartilage biomaterials, for their regenerative potential, for evaluation of drug and cell therapies, or to study mechanisms of cartilage regeneration. It will undoubtedly reduce the number of animals needed for in vivo testing. PMID- 27768807 TI - A new method to estimate photosynthetic parameters through net assimilation rate intercellular space CO2 concentration (A-Ci ) curve and chlorophyll fluorescence measurements. AB - Gas exchange (GE) and chlorophyll fluorescence (CF) measurements are widely used to noninvasively study photosynthetic parameters, for example the rates of maximum Rubisco carboxylation (Vcmax ), electron transport rate (J), daytime respiration (Rd ) and mesophyll conductance (gm ). Existing methods for fitting GE data (net assimilation rate-intercellular space CO2 concentration (A-Ci ) curve) are based on two assumptions: gm is unvaried with CO2 concentration in the intercellular space (Ci ); and light absorption (alpha) and the proportion of quanta absorbed by photosystem II (beta) are constant in the data set. These may result in significant bias in estimating photosynthetic parameters. To avoid the above-mentioned hypotheses, we present a new method for fitting A-Ci curves and CF data simultaneously. This method was applied to a data set obtained from cucumber (Cucumis sativus) leaves of various leaf ages and grown under eight different light conditions. The new method had significantly lower root mean square error and a lower rate of failures compared with previously published methods (6.72% versus 24.1%, respectively) and the effect of light conditions on Vcmax and J was better observed. Furthermore, the new method allows the estimation of a new parameter, the fraction of incoming irradiance harvested by photosystem II, and the dependence of gm on Ci . PMID- 27768806 TI - Outcomes of three universal eating disorder risk reduction programs by participants with higher and lower baseline shape and weight concern. AB - OBJECTIVE: To investigate if baseline shape and weight concern (SWC) moderated outcomes in Prevention Across the Spectrum, a randomized-controlled trial (RCT) of 3 school-based programs aimed at reducing eating disorder and obesity risk factors. METHOD: N = 1,316 Grade 7 and 8 girls and boys (M age = 13.21 years) across three Australian states were randomly allocated to: Media Smart; Life Smart; Helping, Encouraging, Listening and Protecting Peers Initiative (HELPP) or control (usual school class). Moderation was explored by testing interaction effects for group (Media Smart; Life Smart; HELPP; Control) * moderator (SWC: higher-SWC; lower-SWC) * time (post-program; 6-month follow-up; 12-month follow up), with baseline risk factor scores entered as covariates. RESULTS: Moderation effects were found for shape concern, weight concern, eating concern, regular eating (i.e., meal skipping), physical activity, body dissatisfaction, dieting, and perfectionism. Post-hoc testing found eating concern at post-program was the only variable where higher-SWC Media Smart participants experienced a reduction in risk relative to controls. Both higher-SWC Life Smart and HELPP participants reported an increase in eating concern relative to controls and both groups were skipping more meals than controls at 12-month follow-up. Amongst lower-SWC participants, Media Smart was the only group to experience a benefit relative to controls (physical activity). CONCLUSIONS: This study highlights the need for moderator analyses to become more routinely conducted in universal trials, to ensure that participants across baseline risk levels are benefiting and not harmed from program participation. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2017; 50:66-75). PMID- 27768808 TI - Fine endophytes (Glomus tenue) are related to Mucoromycotina, not Glomeromycota. PMID- 27768809 TI - Heteroleptic Copper Photosensitizers: Why an Extended pi-System Does Not Automatically Lead to Enhanced Hydrogen Production. AB - A series of heteroleptic copper(I) photosensitizers of the type [(P^P)Cu(N^N)]+ with an extended pi-system in the backbone of the diimine ligand has been prepared. The structures of all complexes are completely characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. These novel photosensitizers were assessed with respect to the photocatalytic reduction of protons in the presence of triethylamine and [Fe3 (CO)12 ]. Although the solid state structures and computational results show no significant impact of the pi extension on the structural properties, decreased activities were observed. To explain this drop, a combination of electrochemical and photophysical measurements including time-resolved emission as well as transient absorption spectroscopy in the femto- to nanosecond time regime was used. Consequently, shortened excited state lifetimes caused by the rapid depopulation of the excited states located at the diimine ligand are identified as a major reason for the low photocatalytic performance. PMID- 27768810 TI - Patterns of milk macronutrients and bioactive molecules across lactation in a western lowland gorilla (Gorilla gorilla) and a Sumatran orangutan (Pongo abelii). AB - In addition to nutrients, milk contains signaling molecules that influence offspring development. Human milk is similar in nutrient composition to that of apes, but appears to differ in other aspects such as immune function. We examine the longitudinal patterns across lactation of macronutrients, the metabolic hormone adiponectin, the growth factors epidermal growth factor (EGF) and transforming growth factor beta2 (TGF-beta2), and two receptors for these growth factors (EGF-R and TGF-beta2-RIII) in milk samples collected between days 175 and 313 postpartum from a Sumatran orangutan (Pongo abelii) and between days 3 and 1,276 from a western lowland gorilla (Gorilla gorilla), and compare the results with human data from the literature. Milk macronutrients and hormones were measured using standard nutritional assays and commercially available enzyme immunoassay kits. Ape milk fat content was lower than human milk values, but protein and sugar were similar. Concentrations of all bioactive molecules were consistently detectable except for TGF-beta2 in orangutan milk. Concentrations of adiponectin, EGF, and TGF-beta2 in both ape milks were lower than found in human breast milk. Concentrations declined with infant age in orangutan milk; in gorilla milk concentrations were high in the first months, and then declined to stable levels until 2-3 years after birth when they increased. However, when expressed on a per energy basis milk constituent values did not differ with age for orangutan and the variation was reduced at all ages in gorilla. In orangutan milk, the ratio of EGF-R to EGF was constant, with EGF-R at 7.7% of EGF; in gorilla milk the EGF-R concentration was 4.4 +/- 0.2% of the EGF concentration through 3 years and then increased. These data indicate that potent signaling molecules such as EGF and adiponectin are present in ape milk at physiological concentrations. However, human breast milk on average contains higher concentrations. PMID- 27768811 TI - The variation of productivity and its allocation along a tropical elevation gradient: a whole carbon budget perspective. AB - Why do forest productivity and biomass decline with elevation? To address this question, research to date generally has focused on correlative approaches describing changes in woody growth and biomass with elevation. We present a novel, mechanistic approach to this question by quantifying the autotrophic carbon budget in 16 forest plots along a 3300 m elevation transect in Peru. Low growth rates at high elevations appear primarily driven by low gross primary productivity (GPP), with little shift in either carbon use efficiency (CUE) or allocation of net primary productivity (NPP) between wood, fine roots and canopy. The lack of trend in CUE implies that the proportion of photosynthate allocated to autotrophic respiration is not sensitive to temperature. Rather than a gradual linear decline in productivity, there is some limited but nonconclusive evidence of a sharp transition in NPP between submontane and montane forests, which may be caused by cloud immersion effects within the cloud forest zone. Leaf-level photosynthetic parameters do not decline with elevation, implying that nutrient limitation does not restrict photosynthesis at high elevations. Our data demonstrate the potential of whole carbon budget perspectives to provide a deeper understanding of controls on ecosystem functioning and carbon cycling. PMID- 27768812 TI - Preparation of an 18 F-Labeled Hydrocyanine Dye as a Multimodal Probe for Reactive Oxygen Species. AB - Hydrocyanine dyes are sensitive "turn-on" type optical probes that can detect reactive oxygen species (ROS). We have developed a method to prepare an 18 F labeled hydrocyanine dye as a multi-modal PET and optical "turn-on" probe. A commercially available near infrared (NIR) dye was modified with a fluorinated prosthetic group that did not alter its ROS sensing properties in the presence of superoxide and hydroxyl radicals. The 18 F-labeled analogue was produced using a single-step terminal fluorination procedure. Positron emission tomography (PET) imaging and quantitative in vivo biodistribution studies indicated this novel probe had remarkably different pharmacokinetics compared to the oxidized cyanine analogue. The chemistry reported enables the use of quantitative and dynamic PET imaging for the in vivo study of hydrocyanine dyes as ROS probes. PMID- 27768814 TI - Non-specific transient mutualism between the plant parasitic nematode, Bursaphelenchus xylophilus, and the opportunistic bacterium Serratia quinivorans BXF1, a plant-growth promoting pine endophyte with antagonistic effects. AB - The aim of this study is to understand the biological role of Serratia quinivorans BXF1, a bacterium commonly found associated with Bursaphelenchus xylophilus, the plant parasitic nematode responsible for pine wilt disease. Therefore, we studied strain BXF1 effect in pine wilt disease. We found that strain BXF1 promoted in vitro nematode reproduction. Moreover, the presence of bacteria led to the absence of nematode chitinase gene (Bxcht-1) expression, suggesting an effect for bacterial chitinase in nematode reproduction. Nevertheless, strain BXF1 was unable to colonize the nematode interior, bind to its cuticle with high affinity or protect the nematode from xenobiotic stress. Interestingly, strain BXF1 was able to promote tomato and pine plant-growth, as well as to colonize its interior, thus, acting like a plant-growth promoting endophyte. Consequently, strain BXF1 failed to induce wilting symptoms when inoculated in pine shoot artificial incisions. This bacterium also presented strong antagonistic activities against fungi and bacteria isolated from Pinus pinaster. Our results suggest that B. xylophilus does not possess a strict symbiotic community capable of inducing pine wilt disease symptoms as previously hypothesized. We show that bacteria like BXF1, which possess plant-growth promoting and antagonistic effects, may be opportunistically associated with B. xylophilus, possibly acquired from the bacterial endophytic community of the host pine. PMID- 27768813 TI - Therapeutics for tendon regeneration: a multidisciplinary review of tendon research for improved healing. AB - Tendon injuries, known as tendinopathies, are common musculoskeletal injuries that affect a wide range of the population. Canonical tendon healing is characterized by fibrosis, scar formation, and the loss of tissue mechanical and structural properties. Understanding the regenerative tendon environment is an area of increasing interest in the field of musculoskeletal research. Previous studies have focused on utilizing individual elements from the fields of biomechanics, developmental biology, cell and growth factor therapy, and tissue engineering in an attempt to develop regenerative tendon therapeutics. Still, the specific mechanism for regenerative healing remains unknown. In this review, we highlight some of the current approaches of tendon therapeutics and elucidate the differences along the tendon midsubstance and enthesis, exhibiting the necessity of location-specific tendon therapeutics. Furthermore, we emphasize the necessity of further interdisciplinary research in order to reach the desired goal of fully understanding the mechanisms underlying regenerative healing. PMID- 27768816 TI - Growth phase-dependent control of R27 conjugation is mediated by the interplay between the plasmid-encoded regulatory circuit TrhR/TrhY-HtdA and the cAMP regulon. AB - Plasmids of the incompatibility group HI1 (IncHI1) have been isolated from several Gram-negative pathogens and are associated with the spread of multidrug resistance. Their conjugation is tightly regulated and it is inhibited at temperatures higher than 30 degrees C, indicating that conjugation occurs outside warm-blooded hosts. Using R27, the prototype of IncHI1 plasmids, we report that plasmid transfer efficiency in E. coli strongly depends on the physiological state of the donor cells. Conjugation frequency is high when cells are actively growing, dropping sharply when cells enter the stationary phase of growth. Accordingly, our transcriptomic assays show significant downregulation of numerous R27 genes during the stationary phase, including several tra (transfer) genes. Growth phase-dependent regulation of tra genes transcription is independent of H-NS, a silencer of horizontal gene transfer, and ppGpp and RpoS, regulators of the stationary phase, but highly dependent on the plasmid-encoded regulatory circuit TrhR/TrhY-HtdA. The metabolic sensor cAMP, whose synthesis is chromosomally encoded, is also involved in the growth phase regulation of R27 conjugation by modulating htdA expression. Our data suggest that the involvement of regulators encoded by both chromosome and plasmid are required for efficient physiological control of IncHI1 plasmid conjugation. PMID- 27768815 TI - Root avoidance of toxic metals requires the GeBP-LIKE 4 transcription factor in Arabidopsis thaliana. AB - Plants reorganize their root architecture to avoid growth into unfavorable regions of the rhizosphere. In a screen based on chimeric repressor gene silencing technology, we identified the Arabidopsis thaliana GeBP-LIKE 4 (GPL4) transcription factor as an inhibitor of root growth that is induced rapidly in root tips in response to cadmium (Cd). We tested the hypothesis that GPL4 functions in the root avoidance of Cd by analyzing root proliferation in split medium, in which only half of the medium contained toxic concentrations of Cd. The wild-type (WT) plants exhibited root avoidance by inhibiting root growth in the Cd side but increasing root biomass in the control side. By contrast, GPL4 suppression lines exhibited nearly comparable root growth in the Cd and control sides and accumulated more Cd in the shoots than did the WT. GPL4 suppression also altered the root avoidance of toxic concentrations of other essential metals, modulated the expression of many genes related to oxidative stress, and consistently decreased reactive oxygen species concentrations. We suggest that GPL4 inhibits the growth of roots exposed to toxic metals by modulating reactive oxygen species concentrations, thereby allowing roots to colonize noncontaminated regions of the rhizosphere. PMID- 27768817 TI - Glycerol metabolism of haloarchaea. AB - Haloarchaea are heterotrophic members of the Archaea that thrive in hypersaline environments, often feeding off the glycerol that is produced as an osmolyte by eucaryotic Dunaliella during primary production. In this study we analyzed glycerol metabolism genes in closed genomes of haloarchaea and examined published data describing the growth properties of haloarchaea and experimental data for the enzymes involved. By integrating the genomic data with knowledge from the literature, we derived an understanding of the ecophysiology and evolutionary properties of glycerol catabolic pathways in haloarchaea. PMID- 27768818 TI - Global transcriptional response of solvent-sensitive and solvent-tolerant Pseudomonas putida strains exposed to toluene. AB - Pseudomonas putida strains are generally recognized as solvent tolerant, exhibiting varied sensitivity to organic solvents. Pan-genome analysis has revealed that 30% of genes belong to the core-genome of Pseudomonas. Accessory and unique genes confer high degree of adaptability and capabilities for the degradation and synthesis of a wide range of chemicals. For the use of these microbes in bioremediation and biocatalysis, it is critical to understand the mechanisms underlying these phenotypic differences. In this study, RNA-seq analysis compared the short- and long-term responses of the toluene-sensitive KT2440 strain and the highly tolerant DOT-T1E strain. The sensitive strain activates a larger number of genes in a higher magnitude than DOT-T1E. This is expected because KT2440 bears one toluene tolerant pump, while DOT-T1E encodes three of these pumps. Both strains activate membrane modifications to reduce toluene membrane permeability. The KT2440 strain activates the TCA cycle to generate energy, while avoiding energy-intensive processes such as flagellar biosynthesis. This suggests that KT2440 responds to toluene by focusing on survival mechanisms. The DOT-T1E strain activates toluene degradation pathways, using toluene as source of energy. Among the unique genes encoded by DOT-T1E is a 70 kb island composed of genes of unknown function induced in response to toluene. PMID- 27768820 TI - Could the resource depletion model of self-control help the field to better understand momentary processes that lead to binge eating? PMID- 27768819 TI - Habitat and taxon as driving forces of carbohydrate catabolism in marine heterotrophic bacteria: example of the model algae-associated bacterium Zobellia galactanivorans DsijT. AB - The marine flavobacterium Zobellia galactanivorans DsijT was isolated from a red alga and by now constitutes a model for studying algal polysaccharide bioconversions. We present an in-depth analysis of its complete genome and link it to physiological traits. Z. galactanivorans exhibited the highest gene numbers for glycoside hydrolases, polysaccharide lyases and carbohydrate esterases and the second highest sulfatase gene number in a comparison to 125 other marine heterotrophic bacteria (MHB) genomes. Its genome contains 50 polysaccharide utilization loci, 22 of which contain sulfatase genes. Catabolic profiling confirmed a pronounced capacity for using algal polysaccharides and degradation of most polysaccharides could be linked to dedicated genes. Physiological and biochemical tests revealed that Z. galactanivorans stores and recycles glycogen, despite loss of several classic glycogen-related genes. Similar gene losses were observed in most Flavobacteriia, suggesting presence of an atypical glycogen metabolism in this class. Z. galactanivorans features numerous adaptive traits for algae-associated life, such as consumption of seaweed exudates, iodine metabolism and methylotrophy, indicating that this bacterium is well equipped to form profitable, stable interactions with macroalgae. Finally, using statistical and clustering analyses of the MHB genomes we show that their carbohydrate catabolism correlates with both taxonomy and habitat. PMID- 27768821 TI - Neuronal systems and circuits involved in the control of food intake and adaptive thermogenesis. AB - With the still-growing prevalence of obesity worldwide, major efforts are made to understand the various behavioral, environmental, and genetic factors that promote excess fat gain. Obesity results from an imbalance between energy intake and energy expenditure, which emphasizes the importance of deciphering the mechanisms behind energy balance regulation to understand its physiopathology. The control of energy balance is assured by brain systems/circuits capable of generating adequate ingestive and thermogenic responses to maintain the stability of energy reserves, which implies a proper integration of the homeostatic signals that inform about the status of the energy stores. In this article, we overview the organization and functionality of key neuronal circuits or pathways involved in the control of food intake and energy expenditure. We review the role of the corticolimbic (executive and reward) and autonomic systems that integrate their activities to regulate energy balance. We also describe the mechanisms and pathways whereby homeostatic sensing is achieved in response to variations of homeostatic hormones, such as leptin, insulin, and ghrelin, while putting some emphasis on the prominent importance of the mechanistic target of the rapamycin signaling pathway in coordinating the homeostatic sensing process. PMID- 27768822 TI - Genomics and the evolution of antibiotic resistance. AB - Antibiotic resistance arises as a consequence of complex interactions among genes, mobile elements, and their bacterial hosts, coupled with the intense selection pressures imposed by humans in an attempt to control bacterial growth. Understanding the evolution of resistance requires an understanding of interacting cellular and genetic components. Here, we review how DNA analysis has helped reconstruct the origins of the mosaic, multiresistant mobile elements that have spread through pathogens in the last 60 years. This history helps inform the future, such that resistance might be better managed. Whole-genome sequencing has great potential for epidemiological tracking and for understanding the development of resistance via experimental evolution. DNA analysis also offers the opportunity for constructing databases that record genes of interest, the mobile elements that move these genes, and the cells or species that acquire such genes. Linking these DNA elements to their human and animal hosts and to the environments where they occur should help us establish a more robust ecological and evolutionary framework for controlling and managing resistance. Such efforts need to be well coordinated because, like many other issues that face humanity, antibiotic resistance is a global problem that requires global solutions. PMID- 27768823 TI - The sensitivity of photosynthesis to O2 and CO2 concentration identifies strong Rubisco control above the thermal optimum. AB - The biochemical model of C3 photosynthesis by Farquhar, von Caemmerer and Berry (FvCB) assumes that photosynthetic CO2 assimilation is limited by one of three biochemical processes that are not always easily discerned. This leads to improper assessments of biochemical limitations that limit the accuracy of the model predictions. We use the sensitivity of rates of CO2 assimilation and photosynthetic electron transport to changes in O2 and CO2 concentration in the chloroplast to evaluate photosynthetic limitations. Assessing the sensitivities to O2 and CO2 concentrations reduces the impact of uncertainties in the fixed parameters to a minimum and simultaneously entirely eliminates the need to determine the variable parameters of the model, such as Vcmax , J, or TP . Our analyses demonstrate that Rubisco limits carbon assimilation at high temperatures, while it is limited by triose phosphate utilization at lower temperatures and at higher CO2 concentrations. Measurements can be assigned a priori to one of the three functions of the FvCB model, allowing testing for the suitability of the selected fixed parameters of the model. This approach can improve the reliability of photosynthesis models on scales from the leaf level to estimating the global carbon budget. PMID- 27768824 TI - Fluorescence-free flow cytometry for measurement of shape index distribution of resting, partially activated, and fully activated platelets. AB - Whereas commercially available hematological analyzers measure volume of individual platelets, angle-resolved light-scattering provides unique ability to additionally measure their shape index. We utilized the scanning flow cytometer to measure light-scattering profiles (LSPs) of individual platelets taken from 16 healthy donors and the solution of the inverse light-scattering problem to retrieve the volume and shape index of each platelet. In normal conditions, the platelet shape index distribution (PSID) demonstrates three peaks, which relate to resting, partially activated, and fully activated platelets. We developed an algorithm, based on fitting PSID by a sum of three peak functions, to determine the percentage, mean platelet shape index, and distribution width of each platelet fraction. In total, this method gives eight additional parameters of platelet morphology and function to be used in clinical hematological analysis. We also stimulated the platelets with adenosine diphosphate (ADP) and measured the dependence of equilibrium PSID, including the total percentage of activated platelets, on ADP concentration. (c) 2016 International Society for Advancement of Cytometry. PMID- 27768826 TI - Intensive cryptic microbial iron cycling in the low iron water column of the meromictic Lake Cadagno. AB - Iron redox reactions play an important role in carbon remineralization, supporting large microbial communities in iron-rich terrestrial and aquatic sediments. Stratified water columns with comparably low iron concentrations are globally widespread, but microbial iron cycling in these systems has largely been ignored. We found evidence for unexpectedly high iron turnover rates in the low (1-2 umol.l-1 ) iron waters of Lake Cadagno. Light-dependent, biological iron oxidation rates (1.4-13.8 umol.l-1 .d-1 ) were even higher than in ferruginous lakes with well-studied microbial iron cycles. This photoferrotrophic iron oxidation may account for up to 10% of total primary production in the chemocline. Iron oxides could not be detected and were presumably reduced immediately by iron-reducing microorganisms. Sequences of putative iron oxidizers and reducers were retrieved from in situ 16S rRNA gene amplicon libraries and some of these bacteria were identified in our enrichment cultures supplemented with Fe(II) and FeS. Based on our results, we propose a model in which iron is oxidized by photoferrotrophs and microaerophiles, and iron oxides are immediately reduced by heterotrophic iron reducers, resulting in a cryptic iron cycle. We hypothesize that microbial iron cycling may be more prevalent in water column redoxclines, especially those within the photic zone, than previously believed. PMID- 27768828 TI - Mode of resistance to viral lysis affects host growth across multiple environments in the marine picoeukaryote Ostreococcus tauri. AB - Viruses play important roles in population dynamics and as drivers of evolution in single-celled marine phytoplankton. Viral infection of Ostreococcus tauri often causes cell lysis, but two spontaneously arising resistance mechanisms occur: resistant cells that cannot become infected and resistant producer cells that are infected but not lysed, and which may slowly release viruses. As of yet, little is known about how consistent the effects of viruses on their hosts are across different environments. To measure the effect of host resistance on host growth, and to determine whether this effect is environmentally dependent, we compared the growth and survival of susceptible, resistant and resistant producer O. tauri cells under five environmental conditions with and without exposure to O. tauri virus. While the effects of exposure to virus on growth rates did not show a consistent pattern in populations of resistant cells, there were several cases where exposure to virus affected growth in resistant hosts, sometimes positively. In the absence of virus, there was no detectable cost of resistance in any environment, as measured by growth rate. In fact, the opposite was the case, with populations of resistant producer cells having the highest growth rates across four of the five environments. PMID- 27768827 TI - Cell size assays for mass cytometry. AB - Mass cytometry offers the advantage of allowing the simultaneous measurement of a greater number parameters than conventional flow cytometry. However, to date, mass cytometry has lacked a reliable alternative to the light scatter properties that are commonly used as a cell size metric in flow cytometry (forward scatter intensity-FSC). Here, we report the development of two plasma membrane staining assays to evaluate mammalian cell size in mass cytometry experiments. One is based on wheat germ agglutinin (WGA) staining and the other on Osmium tetroxide (OsO4 ) staining, both of which have preferential affinity for cell membranes. We first perform imaging and flow cytometry experiments to establish a relationship between WGA staining intensity and traditional measures of cell size. We then incorporate WGA staining in mass cytometry analysis of human whole blood and show that WGA staining intensity has reproducible patterns within and across immune cell subsets that have distinct cell sizes. Lastly, we stain PBMCs or dissociated lung tissue with both WGA and OsO4 ; mass cytometry analysis demonstrates that the two staining intensities correlate well with one another. We conclude that both WGA and OsO4 may be used to acquire cell size-related parameters in mass cytometry experiments, and expect these stains to be broadly useful in expanding the range of parameters that can be measured in mass cytometry experiments. (c) 2016 International Society for Advancement of Cytometry. PMID- 27768830 TI - Class struggle under the microscope. PMID- 27768829 TI - The Ralstonia solanacearum type III effector RipAY targets plant redox regulators to suppress immune responses. AB - The subversion of plant cellular functions is essential for bacterial pathogens to proliferate in host plants and cause disease. Most bacterial plant pathogens employ a type III secretion system to inject type III effector (T3E) proteins inside plant cells, where they contribute to the pathogen-induced alteration of plant physiology. In this work, we found that the Ralstonia solanacearum T3E RipAY suppresses plant immune responses triggered by bacterial elicitors and by the phytohormone salicylic acid. Further biochemical analysis indicated that RipAY associates in planta with thioredoxins from Nicotiana benthamiana and Arabidopsis. Interestingly, RipAY displays gamma-glutamyl cyclotransferase (GGCT) activity to degrade glutathione in plant cells, which is required for the reported suppression of immune responses. Given the importance of thioredoxins and glutathione as major redox regulators in eukaryotic cells, RipAY activity may constitute a novel and powerful virulence strategy employed by R. solanacearum to suppress immune responses and potentially alter general redox signalling in host cells. PMID- 27768825 TI - Genomic and functional techniques to mine the microbiome for novel antimicrobials and antimicrobial resistance genes. AB - Microbial communities contain diverse bacteria that play important roles in every environment. Advances in sequencing and computational methodologies over the past decades have illuminated the phylogenetic and functional diversity of microbial communities from diverse habitats. Among the activities encoded in microbiomes are the abilities to synthesize and resist small molecules, yielding antimicrobial activity. These functions are of particular interest when viewed in light of the public health emergency posed by the increase in clinical antimicrobial resistance and the dwindling antimicrobial discovery and approval pipeline, and given the intimate ecological and evolutionary relationship between antimicrobial biosynthesis and resistance. Here, we review genomic and functional methods that have been developed for accessing the antimicrobial biosynthesis and resistance capacity of microbiomes and highlight outstanding examples of their applications. PMID- 27768833 TI - A Tale of Two Thumbs, a Dog, and a Wooden Table. PMID- 27768831 TI - Repair of Bone Erosion in Rheumatoid Arthritis by Denosumab: A High-Resolution Peripheral Quantitative Computed Tomography Study. AB - OBJECTIVE: To compare the bone healing effects of denosumab and alendronate in female rheumatoid arthritis (RA) patients by high-resolution peripheral quantitative computed tomography. METHODS: This is a post hoc analysis of a randomized controlled trial. Forty patients were randomized in a 1:1 ratio to receive either subcutaneous denosumab (60 mg) once or oral alendronate (70 mg) weekly for 6 months. The size of individual bone erosions and the presence and extent of erosion-associated sclerosis (marginal osteosclerosis) were measured in the second metacarpal head of the nondominant hand at baseline, 3 months, and 6 months. RESULTS: Forty-two erosions were identified at baseline. After 6 months, the width, depth, and volume of erosion significantly decreased in the denosumab group (-0.23 mm, -0.16 mm, -0.91 mm3 , respectively; all P < 0.01), whereas these parameters significantly increased in the alendronate group (0.19 mm, 0.32 mm, and 1.38 mm3 , respectively; all P < 0.01; between-group differences, P < 0.01 for all). Quantitative analysis showed that the bone mineral density of the erosion margin significantly increased only after treatment by denosumab (19.75 mg/cm3 ; P < 0.05 for denosumab, and -5.44 mg/cm3 ; P = 0.51 for alendronate; P < 0.05 for between-group differences). CONCLUSION: Inhibition of receptor activator of NF-kappaB ligand by denosumab can induce partial repair of erosions in patients with RA, while erosions continued to progress in patients treated with alendronate. Combining denosumab with disease-modifying antirheumatic drugs may be considered for RA patients with progressive bone erosions. PMID- 27768832 TI - Rapid Activation of Transforming Growth Factor beta-Activated Kinase 1 in Chondrocytes by Phosphorylation and K63 -Linked Polyubiquitination Upon Injury to Animal Articular Cartilage. AB - OBJECTIVE: Mechanical injury to cartilage predisposes to osteoarthritis (OA). Wounding of the articular cartilage surface causes rapid activation of MAP kinases and NF-kappaB, mimicking the response to inflammatory cytokines. This study was undertaken to identify the upstream signaling mechanisms involved. METHODS: Cartilage was injured by dissecting it from the articular surface of porcine metacarpophalangeal (MCP) joints or by avulsing murine proximal femoral epiphyses. Protein phosphorylation was assayed by Western blotting of cartilage lysates. Immunolocalization of phosphorylated activating transcription factor 2 (ATF-2) and NF-kappaB/p65 was detected by confocal microscopy. Messenger RNA (mRNA) was measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Receptor associated protein 80 (RAP-80) ubiquitin interacting motif agarose was used in a pull-down assay to obtain K63 -polyubiquitinated proteins. Ubiquitin linkages on immunoprecipitated transforming growth factor beta-activated kinase 1 (TAK-1) were analyzed with deubiquitinases. RESULTS: Sharp injury to porcine cartilage caused rapid activation of JNK and NF-kappaB pathways and the upstream kinases MKK-4, IKK, and TAK-1. Pharmacologic inhibition of TAK-1 in porcine cartilage abolished JNK and NF-kappaB activation and reduced the injury-dependent inflammatory gene response. High molecular weight species of phosphorylated TAK-1 were induced by injury, indicating its ubiquitination. An overall increase in K63 -linked polyubiquitination was detected upon injury, and TAK-1 was specifically linked to K63 - but not K48 -polyubiquitin chains. In mice, avulsion of wild-type femoral epiphyses caused similar intracellular signaling that was reduced in cartilage-specific TAK-1-null mice. Epiphyseal cartilage of MyD88-null and TRAF-6-null mice responded to injury, suggesting the involvement of a ubiquitin E3 ligase other than TRAF-6. CONCLUSION: Activation of TAK-1 by phosphorylation and K63 -linked polyubiquitination by injury indicates its role in driving cell activation. Further studies are needed to identify the upstream ubiquitination mechanisms, including the E3 ligase involved. PMID- 27768834 TI - Relation between neutrophil/lymphocyte ratio and primary tumor metabolic activity in patients with malign pleural mesothelioma. AB - The aim of this study was to evaluate the relationship of the pre-treatment blood neutrophil/lymphocyte count ratio (NLR) with the maximum standard uptake value (SUVmax) of primary masses on positron emission tomography/computed tomography (PET/CT) taken before treatment in patients diagnosed with malignant pleural mesothelioma (MPM) and to evaluate the contribution to prognosis. A retrospective evaluation was made of 73 patients diagnosed with MPM in our hospital between January 2006 and January 2014. The SUVmax value of the primary mass on pre treatment PET/CT, the haemogram parameters (Hb, Hct, NLR, MPV, PLT) at the time of diagnosis, the progression history, the date of the final visit, and the date of death of exitus patients was recorded from patient files PET/CT. The study group comprised 37 males (50.7%) with a mean age of 56.1 +/- 11.4 years. The median survival time of these patients was 13 months. The survival time of the patient group aged <55 years was significantly longer (P = .006). Although the survival time of patients with NLR < 3 and SUVmax < 5 was longer, the difference was not statistically significant (P = .63, P = 0.08). A statistically significant difference was determined between the mean (or median) SUVmax values of the patient groups with NLR < 3 and NLR >=3 (P = .019) with the SUVmax value of the NLR < 3 group found to be low. In conclusion, in patients with MPM, NLR >=3 and high SUVmax values at the time of diagnosis can be considered an indicator of poor prognosis but are not a guide in the prediction of progression. PMID- 27768837 TI - Functional Significance of Interleukin-9 and Its Receptor System in the Pathogenesis of Psoriatic Arthritis: Comment on the Article by Ciccia et al. PMID- 27768835 TI - Endoscopic radiofrequency ablation may be preferable in the management of malignant biliary obstruction: A systematic review and meta-analysis. AB - OBJECTIVE: Endoscopic biliary radiofrequency ablation (RFA) has been increasingly used to treat unresectable malignant biliary obstruction (MBO). We aimed to perform this systematic review and meta-analysis to evaluate the efficacy and safety for the treatment of malignant biliary obstruction (MBO) and its impact on patient's survival. METHODS: A comprehensive search of the Cochrane Library, PubMed and EMBASE databases was conducted. A meta-analysis was performed by extracting the data from the included studies with regard to technical effectiveness, overall survival, adverse events and mortality of endoscopic RFA. RESULTS: A total of nine studies comprising 263 patients with MBO were included in the analysis. There was a significant increase in the diameter of stricture (3.446 mm, 95% confidence interval [CI] 3.356-3.536 mm) after the endoscopic biliary RFA. The overall survival time was 9.62 months, with pooled 30-day, 90 day and 2-year mortality rates of 2% (95% CI 0.5-5.9%), 21% (95% CI 5-37%), and 48% (95% CI 37-59%), respectively. The pooled rate of adverse events was 17% (95% CI 10-25%), and most complications were mild and managed conservatively. Severe adverse events occurred in three patients (two deaths due to hemobilia and one with partial liver infarction). CONCLUSIONS: Endoscopic biliary RFA is effective and generally safe in the management of unresectable biliary malignancies, and may improve patients' overall survival. Prospective, randomized controlled studies are required to further support the results. PMID- 27768836 TI - Lung cancer in patients with combined pulmonary fibrosis and emphysema revisited with the 2015 World Health Organization classification of lung tumors. AB - OBJECTIVE: Combined pulmonary fibrosis and emphysema (CPFE) is a newly defined entity that comprises upper lobe emphysema and lower lobe fibrosis. Patients with CPFE are at high risk for lung cancer and have poor prognoses. To investigate the clinical and pathological characteristics of lung cancer with CPFE, lung cancers with CPFE and non-CPFE interstitial lung disease (ILD) were reevaluated by 2015 WHO classification and compared. METHODS: A total of 60 patients with histologically proven lung cancer were selected from the database of two institutional medical centers. The subjects included 35 patients with combined lung cancer and CPFE, and 25 patients with lung cancer and non-CPFE ILD. The clinical and pathological characteristics were evaluated and compared between the two groups. RESULTS: CPFE group had more current smokers but relatively normal pulmonary function compared with non-CPFE group. The majority of the cancers in CPFE were located in the lower lobes (24 of 35 cases), where the pulmonary fibrosis visualized as reticular opacities was predominant. Keranitizing subtype of squamous cell carcinoma was prevalent in lung cancers with CPFE. Poor prognoses were found both for CPFE and non-CPFE group because of advanced stage. CONCLUSIONS: Lung cancers with CPFE show some unique clinical characteristics, and the distinct histological subtype may have therapeutic implication. PMID- 27768838 TI - Are Foot and Ankle Characteristics Associated With Falls in People With Rheumatoid Arthritis? A Prospective Study. AB - OBJECTIVE: To determine whether foot and ankle characteristics are associated with falls in people with rheumatoid arthritis (RA). METHODS: A total of 201 adults with RA were recruited from rheumatology outpatient clinics in Auckland, New Zealand. Clinical characteristics, common fall risk factors, and foot and ankle variables were measured. Participants were prospectively studied for 12 months to record the occurrence of falls using falls diaries. Logistic regression analysis identified baseline variables that were independent predictors of falls over the 12 months. RESULTS: Eighty-four participants (42%) fell at least once and 39 (19%) experienced multiple (>1) falls over the 12-month followup period. In logistic regression analysis, including age and significant baseline variables in bivariate analysis but not baseline fall history, presence of foot or ankle tender joints (odds ratio [OR] 1.95, P = 0.034) and psychotropic medication (OR 2.35, P = 0.025) were independent predictors of prospective falls. However, when baseline fall history was included in the analysis, psychotropic medication (OR 2.34, P = 0.025) and baseline fall history (over the preceding 12 months) (OR 2.27, P = 0.008) were independent predictors of prospective falls. CONCLUSION: Foot and ankle characteristics are not associated with falls in people with RA, independent of prior falls. Inquiry about prior falls and psychotropic medications may assist in identifying patients with RA who are at high risk of future falls. PMID- 27768839 TI - Diagnostic investigation of BIRC6 and SIRT1 protein expression level as potential prognostic biomarkers in patients with non-small cell lung cancer. AB - BACKGROUND/AIM: Lung cancer is the major contributor to overall cancer-related mortality. Biomarkers are important in early detection and prognosis, in addition to developing treatment regimes, which may improve the patient survival rates. Therefore, the present study was designed to evaluate the prognostic and diagnostic value of SIRT1/BIRC6 expression in non-small cell lung cancer (NSCLC). METHODS: The data on the prognostic impact of SIRT1/BIRC6 in NSCLC were collected from September 11, 2006 to July 10, 2014. Immunoexpressions and real-time quantitative reverse transcription-PCR of SIRT1/BIRC6 were analyzed and the outcomes were correlated with clinicopathological features and patient survivals. RESULTS: MRNA level of SIRT1 was upregulated in NSCLC tissues as compared to normal tissues (3.18 +/- 0.77 vs. 1.27 +/- 0.62; P = .001). BIRC6 mRNA was upregulated in cancer tissues when compared with normal tissues (4.13 +/- 0.91 vs. 1.51 +/- 0.72; P = .001). SIRT1 protein was overexpressed in 27 patients (67.5%), while normal tissues showed weak or negative staining to SIRT1 (P = .002). Furthermore, these findings suggested that advanced pathological T stage, and poor differentiation were significantly associated with expression of SIRT1 (P < .05). Increased expression of BIRC6 was detected in 75% of patients, while weak or negative expression were detected in normal tissues (P = .001). Furthermore, increased expression of BIRC6 was linked to advanced pathological T stage, poor differentiation, and lymph node metastasis (P < .05). CONCLUSIONS: SIRT1 and BIRC6 may be linked to tumor progression and could be useful for the treatment of NSCLC. PMID- 27768840 TI - Epidemiology of Polymyalgia Rheumatica 2000-2014 and Examination of Incidence and Survival Trends Over 45 Years: A Population-Based Study. AB - OBJECTIVE: To determine time trends in the incidence and survival of polymyalgia rheumatica (PMR) over a 15-year period in Olmsted County, Minnesota, and to examine trends in incidence of PMR in the population by comparing this time period to a previous incidence cohort from the same population base. METHODS: All cases of incident PMR among Olmsted County, Minnesota residents in 2000-2014 were identified to extend the previous 1970-1999 cohort. Detailed review of all individual medical records was performed. Incidence rates were age- and sex adjusted to the US white 2010 population. Survival rates were compared with the expected rates in the population of Minnesota. RESULTS: There were 377 incident cases of PMR during the 15-year study period. Of these, 64% were female and the mean age at incidence was 74.1 years. The overall age- and sex-adjusted annual incidence of PMR was 63.9 (95% confidence interval [95% CI] 57.4-70.4) per 100,000 population ages >=50 years. Incidence rates increased with age in both sexes, but incidence fell after age 80 years. There was a slight increase in incidence of PMR in the recent time period compared to 1970-1999 (P = 0.063). Mortality among individuals with PMR was not significantly worse than that expected in the general population (standardized mortality ratio 0.70 [95% CI 0.57-0.85]). CONCLUSION: The incidence of PMR has increased slightly in the past 15 years compared to previous decades. Survivorship in patients with PMR is not worse than in the general population. PMID- 27768841 TI - O6-2'-Deoxyguanosine-butylene-O6-2'-deoxyguanosine DNA Interstrand Cross-Links Are Replication-Blocking and Mutagenic DNA Lesions. AB - DNA interstrand cross-links (ICLs) are cytotoxic DNA lesions derived from reactions of DNA with a number of anti-cancer reagents as well as endogenous bifunctional electrophiles. Deciphering the DNA repair mechanisms of ICLs is important for understanding the toxicity of DNA cross-linking agents and for developing effective chemotherapies. Previous research has focused on ICLs cross linked with the N7 and N2 atoms of guanine as well as those formed at the N6 atom of adenine; however, little is known about the mutagenicity of O6-dG-derived ICLs. Although less abundant, O6-alkylated guanine DNA lesions are chemically stable and highly mutagenic. Here, O6-2'-deoxyguanosine-butylene-O6-2' deoxyguanosine (O6-dG-C4-O6-dG) is designed as a chemically stable ICL, which can be induced by the action of bifunctional alkylating agents. We investigate the DNA replication-blocking and mutagenic properties of O6-dG-C4-O6-dG ICLs during an important step in ICL repair, translesion DNA synthesis (TLS). The model replicative DNA polymerase (pol) Sulfolobus solfataricus P2 DNA polymerase B1 (Dpo1) is able to incorporate a correct nucleotide opposite the cross-linked template guanine of ICLs with low efficiency and fidelity but cannot extend beyond the ICLs. Translesion synthesis by human pol kappa is completely inhibited by O6-dG-C4-O6-dG ICLs. Moderate bypass activities are observed for human pol eta and S. solfataricus P2 DNA polymerase IV (Dpo4). Among the pols tested, pol eta exhibits the highest bypass activity; however, 70% of the bypass products are mutagenic containing substitutions or deletions. The increase in the size of unhooked repair intermediates elevates the frequency of deletion mutation. Lastly, the importance of pol eta in O6-dG-derived ICL bypass is demonstrated using whole cell extracts of Xeroderma pigmentosum variant patient cells and those complemented with pol eta. Together, this study provides the first set of biochemical evidence for the mutagenicity of O6-dG-derived ICLs. PMID- 27768843 TI - Consumptive Water Use from Electricity Generation in the Southwest under Alternative Climate, Technology, and Policy Futures. AB - This research assesses climate, technological, and policy impacts on consumptive water use from electricity generation in the Southwest over a planning horizon of nearly a century. We employed an integrated modeling framework taking into account feedbacks between climate change, air temperature and humidity, and consequent power plant water requirements. These direct impacts of climate change on water consumption by 2095 differ with technology improvements, cooling systems, and policy constraints, ranging from a 3-7% increase over scenarios that do not incorporate ambient air impacts. Upon additional factors being changed that alter electricity generation, water consumption increases by up to 8% over the reference scenario by 2095. With high penetration of wet recirculating cooling, consumptive water required for low-carbon electricity generation via fossil fuels will likely exacerbate regional water pressure as droughts become more common and population increases. Adaptation strategies to lower water use include the use of advanced cooling technologies and greater dependence on solar and wind. Water consumption may be reduced by 50% in 2095 from the reference, requiring an increase in dry cooling shares to 35-40%. Alternatively, the same reduction could be achieved through photovoltaic and wind power generation constituting 60% of the grid, consistent with an increase of over 250% in technology learning rates. PMID- 27768842 TI - Enantioselective Palladium-Catalyzed Alkenylation of Trisubstituted Alkenols To Form Allylic Quaternary Centers. AB - In this report, we describe the generation of remote allylic quaternary stereocenters beta, gamma, and delta relative to a carbonyl in high enantioselectivity. We utilize a redox-relay Heck reaction between alkenyl triflates and acyclic trisubstituted alkenols of varying chain-lengths. A wide array of terminal (E)-alkenyl triflates are suitable for this process. The utility of this functionalization is validated further by conversion of the products, via simple organic processes to access remotely functionalized chiral tertiary acid, amine, and alcohol products. PMID- 27768844 TI - Adsorption Behavior of I3- and I- Ions at a Nanoporous NiO/Acetonitrile Interface Studied by X-ray Photoelectron Spectroscopy. AB - The adsorption of I- and I3- anions, i.e., the two species constituting the most common redox couple of dye-sensitized solar cells (DSCs), onto the surface of screen-printed nanoporous NiO was studied by means of X-ray photoelectron spectroscopy (XPS). Nanoporous NiO films were deposited on transparent metallic fluorine-doped tin oxide (FTO) and polarized as working electrodes in a three electrode cell with differently concentrated I-/I3- electrolytes to simulate the different conditions experienced by the NiO cathodes during the lifecycle of a p type DSC (p-DSC) at those atomic sites not passivated by the dye. Bare NiO films were tested also as photocathodes of nonsensitized p-DSCs. The ex situ XPS analysis of I 4d ionization region of both reference and electrochemically treated NiO films showed that the presence of native and electrochemically generated Ni3+ and Ni4+ centers induces fast adsorption/desorption of I- ions and catalyzes their oxidation to I3- ions. The adsorption phenomena generated by I- and I3- species on nanoporous NiO electrodes can also induce an effect of electrochemical passivation toward a fraction of charged Ni sites. Such an effect would render these sites inactive for the further realization of those photoelectrochemical processes at the basis of the operation of a p-DSC. PMID- 27768845 TI - Understanding the Mutagenicity of O-Linked and C-Linked Guanine DNA Adducts: A Combined Experimental and Computational Approach. AB - The formation of DNA adducts by the attack of intermediates derived from toxic substances at C8 of 2'-deoxyguanosine (dG) is a common damaging event. Although the majority of studies on C8-dG adducts have focused on lesions containing a C8 N-C tether between the bulky moiety and the nucleobase, the formation of O-linked lesions with a similar tether topology and C-linked adducts involving direct C8-C connectivity have also been uncovered. Several studies have been done to try to better understand the structural impact and mutagenicity of O-linked and C-linked aryl C8-dG adducts, including lesions arising from unsubstituted and chloro substituted phenols and the food mutagen ochratoxin A (OTA). Information about the structural preferences of the adducts in duplexes containing the NarI sequence has been gained from optical spectroscopy (UV-vis, CD, and fluorescence), 19F NMR spectroscopy, and computational chemistry (density functional theory calculations at the nucleobase, nucleoside, and nucleotide levels and molecular dynamics simulations of adducted duplexes). The replication of select adducts has also been investigated using primer-elongation assays, and model high-fidelity and Y-family polymerases. Although the (unsubstituted) O linked phenoxy-dG adduct preferentially induces a single duplex conformation and is replicated as per natural dG, chloro substitution blocks DNA replication. In contrast, the unsubstituted C-linked phenyl-dG adduct induces mismatches, while the C-linked ortho- and para-phenoxy-dG lesions lead to conformational heterogeneity of adducted DNA indicative of strong mutagenic potential. Finally, the C-linked OTA-derived lesion exhibits the greatest conformational flexibility in duplexes, which provides structural explanations for observed outcomes in OTA exposed cells. Overall, the variation in the conformational preferences of DNA containing O-linked and C-linked aryl-dG adducts highlights the fact that the type of C8 linkage, the presence and location of functional groups in the bulky moiety, the adduct ionization state, and the sequence context can have profound effects on the conformational outcomes of adducted DNA, which directly dictate the activity of the original toxin. PMID- 27768846 TI - Using Chemical-Induced Gene Expression in Cultured Human Cells to Predict Chemical Toxicity. AB - Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by animal testing may not correlate with human responses. To develop an alternative method for assessing chemical toxicity, we investigated the feasibility of using chemical-induced genome-wide expression changes in cultured human cells to predict the potential of a chemical to cause specific organ injuries in humans. We first created signatures of chemical-induced gene expression in a vertebral-cancer of the prostate cell line for ~15,000 chemicals tested in the US National Institutes of Health Library of Integrated Network-Based Cellular Signatures program. We then used the signatures to create naive Bayesian prediction models for chemical-induced human liver cholestasis, interstitial nephritis, and long QT syndrome. Detailed cross validation analyses indicated that the models were robust with respect to false positives and false negatives in the samples we used to train the models and could predict the likelihood that chemicals would cause specific organ injuries. In addition, we performed a literature search for drugs and dietary supplements, not formally categorized as causing organ injuries in humans but predicted by our models to be most likely to do so. We found a high percentage of these compounds associated with case reports of relevant organ injuries, lending support to the idea that in vitro cell-based experiments can be used to predict the toxic potential of chemicals. We believe that this approach, combined with a robust technique to model human exposure to chemicals, may serve as a promising alternative to animal-based chemical toxicity assessment. PMID- 27768848 TI - Spatially Resolved Electronic Properties of Single-Layer WS2 on Transition Metal Oxides. AB - There is a substantial interest in the heterostructures of semiconducting transition metal dichalcogenides (TMDCs) among each other or with arbitrary materials, through which the control of the chemical, structural, electronic, spintronic, and optical properties can lead to a change in device paradigms. A critical need is to understand the interface between TMDCs and insulating substrates, for example, high-kappa dielectrics, which can strongly impact the electronic properties such as the optical gap. Here, we show that the chemical and electronic properties of the single-layer (SL) TMDC, WS2, can be transferred onto high-kappa transition metal oxide substrates TiO2 and SrTiO3. The resulting samples are much more suitable for measuring their electronic and chemical structures with angle-resolved photoemission than their native-grown SiO2 substrates. We probe the WS2 on the micron scale across 100 MUm flakes and find that the occupied electronic structure is exactly as predicted for free-standing SL WS2 with a strong spin-orbit splitting of 420 meV and a direct band gap at the valence band maximum. Our results suggest that TMDCs can be combined with arbitrary multifunctional oxides, which may introduce alternative means of controlling the optoelectronic properties of such materials. PMID- 27768849 TI - Use of Physiologically Based Kinetic Modeling-Based Reverse Dosimetry to Predict in Vivo Toxicity from in Vitro Data. AB - The development of reliable nonanimal based testing strategies, such as in vitro bioassays, is the holy grail in current human safety testing of chemicals. However, the use of in vitro toxicity data in risk assessment is not straightforward. One of the main issues is that concentration-response curves from in vitro models need to be converted to in vivo dose-response curves. These dose-response curves are needed in toxicological risk assessment to obtain a point of departure to determine safe exposure levels for humans. Recent scientific developments enable this translation of in vitro concentration response curves to in vivo dose-response curves using physiologically based kinetic (PBK) modeling-based reverse dosimetry. The present review provides an overview of the examples available in the literature on the prediction of in vivo toxicity using PBK modeling-based reverse dosimetry of in vitro toxicity data, showing that proofs-of-principle are available for toxicity end points ranging from developmental toxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity to DNA adduct formation. This review also discusses the promises and pitfalls, and the future perspectives of the approach. Since proofs-of-principle available so far have been provided for the prediction of toxicity in experimental animals, future research should focus on the use of in vitro toxicity data obtained in human models to predict the human situation using human PBK models. This would facilitate human- instead of experimental animal-based approaches in risk assessment. PMID- 27768847 TI - Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump. AB - Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for the development of effective EPIs, especially in light of constantly emerging resistance. Here, we describe EPIs that interact with periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes, and potentiate the activities of antibiotics in Escherichia coli and other Gram-negative bacteria. Our findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria. PMID- 27768851 TI - Analysis of HbA1c on an automated multicapillary zone electrophoresis system. AB - Hemoglobin A1c (HbA1c) is a frequently requested laboratory test and there is thus a need for high throughput instruments for this assay. We evaluated a new automated multicapillary zone electrophoresis instrument (Capillarys 3 Tera, Sebia, Lisses, France) for analysis of HbA1c in venous samples. Routine requested HbA1c samples were analyzed immunologically on a Roche c6000 instrument (n = 142) and then with the Capillarys 3 Tera instrument. The Capillarys 3 Tera instrument performed approximately 70 HbA1c tests/hour. There was a strong linear correlation between Capillarys 3 Tera and Roche Tina-Quant HbA1c Gen 3 assay (y = 1.003x - 0.3246 R2 = .996). The total CV for the 12 capillaries varied between 0.8 and 2.2% and there was a good agreement between duplicate samples (R2 = .997). In conclusion, the Capillarys 3 Tera instrument has a high assay capacity for HbA1c. It has a good precision and agreement with the Roche Tina-Quant HbA1c method and is well suited for high volume testing of HbA1c. PMID- 27768850 TI - Probing the Heterogeneity of Protein Kinase Activation in Cells by Super resolution Microscopy. AB - Heterogeneity of mitogen-activated protein kinase (MAPK) activation in genetically identical cells, which occurs in response to epidermal growth factor receptor (EGFR) signaling, remains poorly understood. MAPK cascades integrate signals emanating from different EGFR spatial locations, including the plasma membrane and endocytic compartment. We previously hypothesized that in EGF stimulated cells the MAPK phosphorylation (pMAPK) level and activity are largely determined by the spatial organization of the EGFR clusters within the cell. For experimental testing of this hypothesis, we used super-resolution microscopy to define EGFR clusters by receptor numbers (N) and average intracluster distances (d). From these data, we predicted the extent of pMAPK with 85% accuracy on a cell-to-cell basis with control data returning 54% accuracy (P < 0.001). For comparison, the prediction accuracy was only 61% (P = 0.382) when the diffraction limited averaged fluorescence intensity/cluster was used. Large clusters (N >= 3) with d > 50 nm were most predictive for pMAPK level in cells. Electron microscopy revealed that these large clusters were primarily localized to the limiting membrane of multivesicular bodies (MVB). Many tighter packed dimers/multimers (d < 50 nm) were found on intraluminal vesicles within MVBs, where they were unlikely to activate MAPK because of the physical separation. Our results suggest that cell-to-cell differences in N and d contain crucial information to predict EGFR-activated cellular pMAPK levels and explain pMAPK heterogeneity in isogenic cells. PMID- 27768852 TI - Associations among Neighborhood, Race, and Sleep Apnea Severity in Children. A Six-City Analysis. AB - RATIONALE: Prior researchers found that individual-level environmental and social indicators did not explain the racial disparity in obstructive sleep apnea syndrome. Neighborhood socioeconomic variables, as well as risk factors for a range of adverse behavioral and health outcomes, may better explain this racial disparity and help identify modifiable intervention targets. OBJECTIVES: To evaluate the associations of neighborhood socioeconomic variables with obstructive sleep apnea severity and to assess whether the neighborhood variables explain the association between race and obstructive sleep apnea severity. METHODS: We performed a cross-sectional analysis of data of 774 children in six cities who participated in the Childhood Adenotonsillectomy Trial. The outcome variable was the apnea-hypopnea index (AHI). Neighborhood socioeconomic variables were obtained on the basis of the children's residential addresses and information in the American Community Survey. Regression models were used to assess the associations among neighborhood conditions, race, and AHI. MEASUREMENTS AND MAIN RESULTS: Higher poverty rate and percentage of single female-headed households were associated with higher AHI (P = 0.008 and 0.002, respectively). African American race was associated with a 1.33 (1.08-1.64 95% confidence interval)-fold increase in AHI, adjusting for age and sex. After controlling for poverty rate or percentage of single-female-headed households with children, the association between race and AHI levels was no longer significant (P = 0.15 and 0.26, respectively), and the magnitude of race association decreased 34 or 55%, suggesting that the association between race and AHI levels was largely explained by poverty rate or percentage of single-female headed households with children. CONCLUSIONS: Neighborhood socioeconomic variables in comparison with individual-level socioeconomic indicators provides better explanations for the racial disparity in pediatric obstructive sleep apnea syndrome. Further research aimed at identifying factors that aggregate in disadvantaged neighborhoods and increase sleep apnea risk may suggest modifiable intervention targets. Clinical trial registered with clinicaltrials.gov (NCT00560859). PMID- 27768854 TI - Gastric-type H+,K+-ATPase in mouse vestibular end organs. AB - CONCLUSION: Gastric type H+,K+-ATPase in the vestibular end organs may be of importance for K+ circulation and may also be related to pH regulation in vestibular end organs and endolymphatic sac. OBJECTIVE: To analyze the expression of gastric-type H+,K+-ATPase in normal mouse vestibular end organs. METHODS: 8 weeks old CBA/J mice were used in this study. The presence of gastric-type H+,K+ ATPase alpha and beta in the vestibular end organs, viz. utricle, saccule, ampulla, vestibular ganglion, and endolymphatic sac, was investigated using immunohistochemistry. RESULTS: In the vestibular end organs, H+,K+-ATPase alpha and beta were almost identical. H+,K+-ATPase was expressed in sensory cells, the basolateral surface of dark cells, fibrocytes, in vestibular ganglion cells, and in the upper region of the endolymphatic sac epithelial cells. PMID- 27768853 TI - Retrospective Analysis of Factors Leading to Pediatric Tracheostomy Decannulation Failure. A Single-Institution Experience. AB - RATIONALE: There is a lack of evidence regarding factors associated with failure of tracheostomy decannulation. OBJECTIVES: We aimed to identify characteristics of pediatric patients who fail a tracheostomy decannulation challenge Methods: A retrospective review was performed on all patients who had a decannulation challenge at a tertiary care center from June 2006 to October 2013. Tracheostomy decannulation failure was defined as reinsertion of the tracheostomy tube within 6 months of the challenge. Data on demographics, indications for tracheostomy, home mechanical ventilation, and comorbidities were collected. Data were also collected on specific airway endoscopic findings during the predecannulation bronchoscopy and airway surgical procedures before decannulation. We attempted to predict the decannulation outcome by analyzing associations. MEASUREMENTS AND MAIN RESULTS: 147 of 189 (77.8%) patients were successfully decannulated on the first attempt. Tracheostomy performed due to chronic respiratory failure decreased odds for decannulation failure (odds ratio = 0.34, 95% confidence interval = 0.15-0.77). Genetic abnormalities (45%) and feeding dysfunction (93%) were increased in the population of patients failing their first attempt. The presence of one comorbidity increased the odds of failure by 68% (odds ratio = 1.68, 95% confidence interval = 1.23-2.29). Decannulation pursuit based on parental expectation of success, rather than medically determined readiness, was associated with a higher chance of failure (P = 0.01). CONCLUSIONS: Our study highlights the role of genetic abnormalities, feeding dysfunction, and multiple comorbidities in patients who fail decannulation. Our findings also demonstrate that the outcome of decannulation may be predicted by the indication for tracheostomy. Patients who had tracheostomy placed for chronic respiratory support had a higher likelihood of success. Absence of a surgically treatable airway obstruction abnormality on the predecannulation bronchoscopy increased the chances of success. PMID- 27768855 TI - Population Survey of Iodine Deficiency and Environmental Disruptors of Thyroid Function in Young Children in Haiti. AB - Context: Iodine deficiency is the leading cause of preventable neurodevelopmental delay in children worldwide and a possible public health concern in Haiti. Objective: To determine the prevalence of iodine deficiency in Haitian young children and its influence by environmental factors. Design: Cross-sectional study, March through June 2015. Setting: Community churches in 3 geographical regions in Haiti. Participants: 299 healthy Haitian children aged 9 months to 6 years; one-third each enrolled in a coastal, mountainous, and urban region. Main Outcome Measures: Urinary iodide, serum thyrotropin (TSH), goiter assessment, and urinary perchlorate and thiocyanate. Results: Mean age was 3.3+/-1.6 years, with 51% female, median family income USD 30/week, and 16% malnutrition. Median urinary iodide levels were normal in coastal (145 MUg/L, interquartile range [IQR] 97 to 241) and urban regions (187 MUg/L, IQR 92 to 316), but revealed mild iodine deficiency in a mountainous region (89 MUg/L, IQR 56 to 129), P < 0.0001. Grade 1 goiters were palpated in 2 children, but TSH values were normal. Urinary thiocyanate and perchlorate concentrations were not elevated. Predictors of higher urinary iodide included higher urinary thiocyanate and perchlorate, breastfeeding, and not living in a mountainous region. Conclusions: Areas of mild iodine deficiency persist in Haiti's mountainous regions. Exposure to two well understood environmental thyroid function disruptors is limited. PMID- 27768858 TI - March 2016 (vol. 214, no. 3, page 340). PMID- 27768856 TI - Elevated Serum Tetrac in Graves Disease: Potential Pathogenic Role in Thyroid Associated Ophthalmopathy. AB - Context: The sources and biological impact of 3,3',5,5' tetraiodothyroacetic acid (TA4) are uncertain. CD34+ fibrocytes express several proteins involved in the production of thyroid hormones. They infiltrate the orbit in Graves disease (GD), an autoimmune process known as thyroid-associated ophthalmopathy. It appears that the thyrotropin receptor plays an important role in the pathogenesis of thyroid associated ophthalmopathy. Objective: To quantify levels of TA4 in healthy participants and those with GD, determine whether fibrocytes generate this thyroid hormone analogue, and determine whether TA4 influences the actions of thyroid-stimulating hormone and thyroid-stimulating immunoglobulins in orbital fibroblasts. Design/Setting/Participants: Patients with GD and healthy donors in an academic medical center clinical practice were recruited. Main Outcome Measures: Liquid chromatography-tandem mass spectrometry, autoradiography, real time polymerase chain reaction, hyaluronan immunoassay. Results: Serum levels of TA4 are elevated in GD. TA4 levels are positively correlated with those of thyroxine and negatively correlated with serum levels of triiodothyronine. Several cell types in culture generate TA4 from ambient thyroxine, including fibrocytes, HELA cells, human Muller stem cells, and retinal pigmented epithelial cells. Propylthiouracil inhibits TA4 generation. TA4 enhances the induction by thyrotropin and thyroid-stimulating immunoglobulins of several participants in the pathogenesis of thyroid-associated ophthalmopathy, including interleukin 6, hyaluronan synthase 1, prostaglandin endoperoxide H synthase 2, and haluronan production. Conclusion: TA4 may be ubiquitously generated in many tissues and enhances the biological impact of thyrotropin and thyroid-stimulating immunoglobulins in orbital connective tissue. These findings may identify a physiologically important determinant of extrathyroidal thyroid-stimulating hormone action. PMID- 27768857 TI - Effects of Genetic and Nongenetic Factors on Total and Bioavailable 25(OH)D Responses to Vitamin D Supplementation. AB - Context: Little is known about how genetic and nongenetic factors modify responses of vitamin D supplementation in nonwhite populations. Objective: To investigate factors modifying 25-hydroxyvitamin D [25(OH)D] and bioavailable 25(OH)D [25(OH)DBio] responses after vitamin D3 supplementation. Design, Setting, Participants, and Intervention: In this 20-week, randomized, double-blinded, placebo-controlled trial, 448 Chinese with vitamin D deficiency received 2000 IU/d vitamin D3 or placebo. Main Outcome Measures: Serum 25(OH)D, vitamin D binding protein (VDBP), parathyroid hormone (PTH) and calcium were measured, and 25(OH)DBio was calculated based on VDBP levels. Six common polymorphisms in vitamin D metabolism genes were genotyped. Results: Between-arm net changes were +30.6 +/- 1.7 nmol/L for 25(OH)D, +2.7 +/- 0.2 nmol/L for 25(OH)DBio, and -5.2 +/ 1.2 pg/mL for PTH, corresponding to 70% [95% confidence interval (CI), 62.8% to 77.2%] net reversion rate for vitamin D deficiency at week 20 (P < 0.001). Only 25(OH)DBio change was positively associated with calcium change (P < 0.001). Genetic factors (GC-rs4588/GC-rs7041, VDR-rs2228570, and CYP2R1-rs10741657; P <= 0.04) showed stronger influences on 25(OH)D or 25(OH)DBio responses than nongenetic factors, including baseline value, body mass index, and sex. An inverse association of PTH-25(OH)D was demonstrated only at 25(OH)D of <50.8 (95% CI, 43.6 to 59.0) nmol/L. Conclusions: Supplemented 2000 IU/d vitamin D3 raised 25(OH)D and 25(OH)DBio but was unable to correct deficiency in 25% of Chinese participants, which might be partially attributed to the effect of genetic modification. More studies are needed to elucidate appropriate vitamin D recommendations for Asians and the potential clinical implications of 25(OH)DBio. PMID- 27768859 TI - 4-Hydroxyalkenal-activated PPARdelta mediates hormetic interactions in diabetes. AB - Activated peroxisome proliferator-activated receptor-delta (PPARdelta) induces the expression of genes encoding enzymes that metabolize fatty acids and carbohydrate. Attempts to identify cellular activators of PPARdelta produced large lists of various fatty acids and their metabolic derivatives; however, there is no consensus on specific and selective binding interactions of natural ligands with PPARdelta. Most models on binding interactions within the ligand binding domain (LBD) of PPARdelta have been derived from analyses of PPARdelta LBD crystals formed with synthetic low molecular weight ligands. Nonetheless, crystals of the whole receptor with natural ligands or of its heterodimer with its cognate retinoid X receptor (RXR) are not yet available for analysis. We have found that 4-hydroxyalkenals, non-enzymatic peroxidation products of polyunsaturated fatty acids (PUFA), namely, 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) and 4-hydroxy-2E-nonenal (4-HNE), activate PPARdelta in vascular endothelial cells and insulin-secreting beta cells, respectively. In both cases activated PPARdelta induced adaptive responses that allowed the cells to adjust to ambient stressful metabolic conditions. This review article addresses the interactions of 4-hydroxyalkenals with PPARdelta and the resulting hormetic interactions in cells exposed to nutrient overload conditions. PMID- 27768861 TI - Factors impacting upon timely and adequate allocation of prehospital medical assistance and resources to cardiac arrest patients. AB - AIM: Explore, understand and address issues that impact upon timely and adequate allocation of prehospital medical assistance and resources to out-of-hospital cardiac arrest (OHCA) patients. METHODS: Mixed-methods design obtaining data for one year in three emergency medical communication centres (EMCC); Oslo-Akershus (OA), Vestfold-Telemark (VT) and Ostfold (O). Data collection included quantitative data from analysis of dispatch logs, ambulance records and audio files. Qualitative data were collected through in-depth interviews and non participant observations. RESULTS: OA-, VT- and O-EMCC responded to 1095 OHCAs and 579 of these calls were included for further analysis (333, 143 and 103, respectively). There were significant site differences in their recognition of OHCA (89, 94 and 78%, respectively, p<0.001), provision of CPR instructions (83, 83 and 61%, respectively, p<0.001), time from call answered to initial CPR instructions (1.4min (1.2, 1.6), 1.1min (0,9, 1.2) and 1.3 (1.2, 1.7) respectively, p=0.002). The most frequent reason for delayed or failed recognition of OHCA was misinterpretation of agonal breathing. Interviews and observations revealed individual differences in protocol use, interrogation strategy and assessment of breathing. Use of protocol was only part of decision making, dispatchers trusted their own clinical experience and intuition, and used assumptions about the patient and the situation as part of decision making. CONCLUSION: Agonal breathing continues to be the main barrier to recognition of cardiac arrest. Individual differences among dispatchers' strategies can directly impact on performance, mainly due to the wide definition of cardiac arrest and lack of uniform tools for assessment of breathing. PMID- 27768863 TI - Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity: Early Role for IL 1beta. AB - Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. In vitro and ex vivo assays were applied to evaluate cytotoxic effects of IL-1beta on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1beta was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1beta was found to be cytotoxic to choroid in vitro, ex vivo, and in vivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1beta receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist treated OIR animals. Together, these findings suggest a critical role for IL 1beta-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1beta as a potential therapeutic target in ROP. PMID- 27768860 TI - Means to the ends: The role of telomeres and telomere processing machinery in metastasis. AB - Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions. Although telomere shortening occurs in nearly all somatic cells, telomeres may be elongated via two seemingly disjoint pathways: (i) telomerase-mediated extension, and (ii) homologous recombination-based alternative lengthening of telomeres (ALT). Both telomerase and ALT are activated in various human cancers, with more recent evidence implicating both pathways as potential mediators of metastasis. Here we review the known roles of telomere homeostasis in metastasis and posit a mechanism whereby metastatic activity is determined by a dynamic fluctuation between ALT and telomerase, as opposed to the mere activation of a generic telomere elongation program. Additionally, the pleiotropic nature of the telomere processing machinery makes it an attractive therapeutic target for metastasis, and as such, we also explore the therapeutic implications of our proposed mechanism. PMID- 27768864 TI - RAF Inhibitors, Fishing Bacterial Transporters Out of Metagenomes, and Yeast Based, Industrial Scale Production of Isoprenoids. AB - Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our October 2016 selection includes systematic structural, biochemical, and cellular characterization of B-RAF inhibitors; connecting bacterial transporters with their physiologically relevant ligands; and rewiring yeast metabolism for industrial scale production of isoprenoids. PMID- 27768862 TI - Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization. AB - The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mammalian/mechanistic target of rapamycin complex 1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver. The Dermo1-Cre-driven Tsc2 conditional knockout mice had body growth retardation and died approximately 3 weeks after birth. Significant phenotypes were observed in the postnatal kidney and lung. Inactivation of Tsc2 in kidney mesenchyme caused polycystic lesions starting from the second week of age, with increased cell proliferation, tubular epithelial hyperplasia, and epithelial-mesenchymal transition. In contrast, Tsc2 deletion in lung mesenchyme led to decreased cell proliferation, reduced postnatal alveolarization, and decreased differentiation with reduced numbers of alveolar myofibroblast and type II alveolar epithelial cells. Two major findings thus result from this model: inactivation of Tsc2 in mesoderm-derived cells causes increased cell proliferation in the kidneys but reduced proliferation in the lungs, and inactivation of Tsc2 in mesoderm-derived cells causes epithelial lined renal cysts. Therefore, Tsc2-mTOR signaling in mesenchyme is essential for the maintenance of renal structure and for lung alveolarization. PMID- 27768865 TI - Cutting Choline with Radical Scissors. AB - The human gut microbiome is the source of not only microbial diversity, but also of interesting chemical reactions and enzymology. An excellent example of this is CutC, an enzyme that makes trimethylamine (TMA). In this issue of Cell Chemical Biology, Bodea et al. (2016) show how CutC uses a glycyl radical to perform C-N bond cleavage needed for TMA production. PMID- 27768866 TI - Adding Lyso-Lipids to Arachidonate Metabolism Sets the Stage for New Biology. AB - Prostaglandins have been characterized as the metabolic products of arachidonic acid released from glycerophospholipids following hydrolysis by phospholipase A2s and enzymatic oxidation by the COX1 and COX2. In this issue of Cell Chemical Biology, Liu et al. (2016) examine the metabolism of 2-arachidonoyl-lyso phosphatidylcholine and 2-arachidonoyl-lyso-phosphatidylethanolamine by COX2 and conversion to glycerolipid linked prostanoids, raising a series of interesting and important questions. PMID- 27768867 TI - RNA Binding: Getting Specific about Specificity. AB - Sequence-specific nucleic acid binding proteins do not recognize one sequence out of all possibilities; rather, they bind to many sequences with a range of affinities. In this issue of Cell Chemical Biology, Lin et al. (2016), describe the entire landscape of affinities between different RNA molecules and an RNA binding protein, thus providing a comprehensive description of the factors affecting specificity. PMID- 27768868 TI - Triggering Selective Autophagy at the Right Place and the Right Time. AB - In this issue of Molecular Cell, Torggler et al. (2016) leverage innovative synthetic biology approaches to dissect the spatiotemporal activation of Atg1 kinase during selective autophagy, revealing two distinct pathways that coordinately initiate autophagosome formation at the yeast vacuole. PMID- 27768869 TI - In the Middle of a Chain Interaction. AB - In this issue of Molecular Cell, Fu et al. (2016) present a detailed structural analysis of death-inducing signaling complex (DISC) assembly and regulation through flexible caspase-8 interactions with cFLIPL, cFLIPS, and the viral inhibitor MC159, thereby identifying novel apoptosis control mechanisms. PMID- 27768870 TI - RNA Structure Switches RBP Binding. AB - RNA sequence motifs are not sufficient for association with RBPs. In this issue of Molecular Cell, Taliaferro et al. (2016) demonstrate that, other than sequence motif, RNA secondary structure plays a repressive role on RBP binding, both in vitro and in vivo. PMID- 27768871 TI - Two Independent Pathways within Selective Autophagy Converge to Activate Atg1 Kinase at the Vacuole. AB - Autophagy is a potent cellular degradation pathway, and its activation needs to be tightly controlled. Cargo receptors mediate selectivity during autophagy by bringing cargo to the scaffold protein Atg11 and, in turn, to the autophagic machinery, including the central autophagy kinase Atg1. Here we show how selective autophagy is tightly regulated in space and time to prevent aberrant Atg1 kinase activation and autophagy induction. We established an induced bypass approach (iPass) that combines genetic deletion with chemically induced dimerization to evaluate the roles of Atg13 and cargo receptors in Atg1 kinase activation and selective autophagy progression. We show that Atg1 activation does not require cargo receptors, cargo-bound Atg11, or Atg13 per se. Rather, these proteins function in two independent pathways that converge to activate Atg1 at the vacuole. This pathway architecture underlies the spatiotemporal control of Atg1 kinase activity, thereby preventing inappropriate autophagosome formation. PMID- 27768872 TI - Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription. AB - The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide. Using pharmacological and genetic approaches, we identified mitogen- and stress activated protein kinases (MSKs) as primary mediators of H3S28ph in macrophages. Cell-free transcription assays demonstrated that H3S28ph directly promotes p300/CBP-dependent transcription. Further, MSKs can activate both signal responsive transcription factors and the chromatin template with additive effects on transcription. Specific inhibition of MSKs in macrophages selectively reduced transcription of stimulation-induced genes. Our results suggest that MSKs incorporate upstream signaling inputs and control multiple downstream regulators of inducible transcription. PMID- 27768873 TI - Positive Feedback Keeps Duration of Mitosis Temporally Insulated from Upstream Cell-Cycle Events. AB - Cell division is characterized by a sequence of events by which a cell gives rise to two daughter cells. Quantitative measurements of cell-cycle dynamics in single cells showed that despite variability in G1-, S-, and G2 phases, duration of mitosis is short and remarkably constant. Surprisingly, there is no correlation between cell-cycle length and mitotic duration, suggesting that mitosis is temporally insulated from variability in earlier cell-cycle phases. By combining live cell imaging and computational modeling, we showed that positive feedback is the molecular mechanism underlying the temporal insulation of mitosis. Perturbing positive feedback gave rise to a sluggish, variable entry and progression through mitosis and uncoupled duration of mitosis from variability in cell cycle length. We show that positive feedback is important to keep mitosis short, constant, and temporally insulated and anticipate it might be a commonly used regulatory strategy to create modularity in other biological systems. PMID- 27768876 TI - An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. PMID- 27768874 TI - FANCD2 Facilitates Replication through Common Fragile Sites. AB - Common fragile sites (CFSs) are genomic regions that are unstable under conditions of replicative stress. Although the characteristics of CFSs that render them vulnerable to stress are associated mainly with replication, the cellular pathways that protect CFSs during replication remain unclear. Here, we identify and describe a role for FANCD2 as a trans-acting facilitator of CFS replication, in the absence of exogenous replicative stress. In the absence of FANCD2, replication forks stall within the AT-rich fragility core of CFS, leading to dormant origin activation. Furthermore, FANCD2 deficiency is associated with DNA:RNA hybrid formation at CFS-FRA16D, and inhibition of DNA:RNA hybrid formation suppresses replication perturbation. In addition, we also found that FANCD2 reduces the number of potential sites of replication initiation. Our data demonstrate that FANCD2 protein is required to ensure efficient CFS replication and provide mechanistic insight into how FANCD2 regulates CFS stability. PMID- 27768877 TI - Fighting Infection in a Globalized World. PMID- 27768878 TI - A New SV2A Ligand for Epilepsy. AB - Since the 1970s, racetams have been in use as cognitive enhancers. Levetiracetam was discovered to have antiseizure activity in animal models and was then found to bind to SV2A in synaptic and endocrine vesicles. Brivaracetam, an analog of levetiracetam, was identified in a medicinal chemistry campaign with the objective of discovering analogs with higher affinity at racetam-binding sites and greater antiseizure potency. PMID- 27768879 TI - A Microbial Anthropologist in the Jungle. PMID- 27768875 TI - High-Resolution Mapping of RNA-Binding Regions in the Nuclear Proteome of Embryonic Stem Cells. AB - Interactions between noncoding RNAs and chromatin proteins play important roles in gene regulation, but the molecular details of most of these interactions are unknown. Using protein-RNA photocrosslinking and mass spectrometry on embryonic stem cell nuclei, we identified and mapped, at peptide resolution, the RNA binding regions in ~800 known and previously unknown RNA-binding proteins, many of which are transcriptional regulators and chromatin modifiers. In addition to known RNA-binding motifs, we detected several protein domains previously unknown to function in RNA recognition, as well as non-annotated and/or disordered regions, suggesting that many functional protein-RNA contacts remain unexplored. We identified RNA-binding regions in several chromatin regulators, including TET2, and validated their ability to bind RNA. Thus, proteomic identification of RNA-binding regions (RBR-ID) is a powerful tool to map protein-RNA interactions and will allow rational design of mutants to dissect their function at a mechanistic level. PMID- 27768880 TI - Eradicating Malaria: Discoveries, Challenges, and Questions. PMID- 27768881 TI - Unwinding Limb Development. AB - The molecular mechanisms underpinning vertebrate body plan evolution are beginning to be unravelled. In this issue of Cell, Kvon et al. spectacularly demonstrate how transplanting snake-specific genetic changes found uniquely in serpent enhancers leads to limb loss in mice. PMID- 27768882 TI - Stringing Nucleosome Necklaces in the Yeast Genome. AB - Using a reconstituted system containing genomic DNA and purified proteins from yeast, Krietenstein et al. uncover the direct contributions of key factors in nucleosome positioning and conceptualize the process into four distinct stages. PMID- 27768883 TI - GPCR Signaling Rides a Wave of Conformational Changes. AB - The ability of structurally distinct ligands to "bias" G protein-coupled receptor signaling affords the opportunity to tailor efficacy to suit specific therapeutic needs. Furness et al. demonstrate that ligand structure controls not only which effectors are activated, but also the way they are activated and the kinetics of downstream signaling. PMID- 27768884 TI - Glucagon and Thyroid Hormone: A Championship Team. AB - A bioactive peptide that combines glucagon with the thyroid hormone T3 lowers lipid levels, improves glucose tolerance, and promotes energy expenditure to treat symptoms and underlying causes of metabolic disease. The two active components both maximize their combined benefits and mitigate the negative consequences of treatment with each alone. PMID- 27768885 TI - p62 in Cancer: Signaling Adaptor Beyond Autophagy. AB - Adaptor proteins participate in selective autophagy, which is critical for cellular detoxification and stress relief. However, new evidence supports an autophagy-independent key role of the adaptor p62 (encoded by the gene Sqstm1) in signaling functions central to tumor initiation in the epithelium and suppression of tumor progression in the stroma. PMID- 27768886 TI - Malaria: Biology and Disease. AB - Malaria has been a major global health problem of humans through history and is a leading cause of death and disease across many tropical and subtropical countries. Over the last fifteen years renewed efforts at control have reduced the prevalence of malaria by over half, raising the prospect that elimination and perhaps eradication may be a long-term possibility. Achievement of this goal requires the development of new tools including novel antimalarial drugs and more efficacious vaccines as well as an increased understanding of the disease and biology of the parasite. This has catalyzed a major effort resulting in development and regulatory approval of the first vaccine against malaria (RTS,S/AS01) as well as identification of novel drug targets and antimalarial compounds, some of which are in human clinical trials. PMID- 27768889 TI - Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens. AB - Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. A total of 9.3% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are key to controlling infection. PMID- 27768887 TI - Progressive Loss of Function in a Limb Enhancer during Snake Evolution. AB - The evolution of body shape is thought to be tightly coupled to changes in regulatory sequences, but specific molecular events associated with major morphological transitions in vertebrates have remained elusive. We identified snake-specific sequence changes within an otherwise highly conserved long-range limb enhancer of Sonic hedgehog (Shh). Transgenic mouse reporter assays revealed that the in vivo activity pattern of the enhancer is conserved across a wide range of vertebrates, including fish, but not in snakes. Genomic substitution of the mouse enhancer with its human or fish ortholog results in normal limb development. In contrast, replacement with snake orthologs caused severe limb reduction. Synthetic restoration of a single transcription factor binding site lost in the snake lineage reinstated full in vivo function to the snake enhancer. Our results demonstrate changes in a regulatory sequence associated with a major body plan transition and highlight the role of enhancers in morphological evolution. PAPERCLIP. PMID- 27768888 TI - Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations. AB - Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations. PMID- 27768890 TI - Rickettsia Sca4 Reduces Vinculin-Mediated Intercellular Tension to Promote Spread. AB - Spotted fever group (SFG) rickettsiae are human pathogens that infect cells in the vasculature. They disseminate through host tissues by a process of cell-to cell spread that involves protrusion formation, engulfment, and vacuolar escape. Other bacterial pathogens rely on actin-based motility to provide a physical force for spread. Here, we show that SFG species Rickettsia parkeri typically lack actin tails during spread and instead manipulate host intercellular tension and mechanotransduction to promote spread. Using transposon mutagenesis, we identified surface cell antigen 4 (Sca4) as a secreted effector of spread that specifically promotes protrusion engulfment. Sca4 interacts with the cell adhesion protein vinculin and blocks association with vinculin's binding partner, alpha-catenin. Using traction and monolayer stress microscopy, we show that Sca4 reduces vinculin-dependent mechanotransduction at cell-cell junctions. Our results suggest that Sca4 relieves intercellular tension to promote protrusion engulfment, which represents a distinctive strategy for manipulating cytoskeletal force generation to enable spread. PMID- 27768891 TI - Cross-Neutralizing and Protective Human Antibody Specificities to Poxvirus Infections. AB - Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. We generated a large panel of orthopoxvirus-specific human monoclonal antibodies (Abs) from immune subjects to investigate the molecular basis of broadly neutralizing antibody responses for diverse orthopoxviruses. Detailed analysis revealed the principal neutralizing antibody specificities that are cross reactive for VACV, CPXV, MPXV, and VARV and that are determinants of protection in murine challenge models. Optimal protection following respiratory or systemic infection required a mixture of Abs that targeted several membrane proteins, including proteins on enveloped and mature virion forms of virus. This work reveals orthopoxvirus targets for human Abs that mediate cross-protective immunity and identifies new candidate Ab therapeutic mixtures to replace VIG. PMID- 27768892 TI - Genomic Nucleosome Organization Reconstituted with Pure Proteins. AB - Chromatin remodelers regulate genes by organizing nucleosomes around promoters, but their individual contributions are obfuscated by the complex in vivo milieu of factor redundancy and indirect effects. Genome-wide reconstitution of promoter nucleosome organization with purified proteins resolves this problem and is therefore a critical goal. Here, we reconstitute four stages of nucleosome architecture using purified components: yeast genomic DNA, histones, sequence specific Abf1/Reb1, and remodelers RSC, ISW2, INO80, and ISW1a. We identify direct, specific, and sufficient contributions that in vivo observations validate. First, RSC clears promoters by translating poly(dA:dT) into directional nucleosome removal. Second, partial redundancy is recapitulated where INO80 alone, or ISW2 at Abf1/Reb1sites, positions +1 nucleosomes. Third, INO80 and ISW2 each align downstream nucleosomal arrays. Fourth, ISW1a tightens the spacing to canonical repeat lengths. Such a minimal set of rules and proteins establishes core mechanisms by which promoter chromatin architecture arises through a blend of redundancy and specialization. PMID- 27768893 TI - MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria. AB - A functional crosstalk between epigenetic regulators and metabolic control could provide a mechanism to adapt cellular responses to environmental cues. We report that the well-known nuclear MYST family acetyl transferase MOF and a subset of its non-specific lethal complex partners reside in mitochondria. MOF regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA in aerobically respiring cells. MOF binds mtDNA, and this binding is dependent on KANSL3. The mitochondrial pool of MOF, but not a catalytically deficient mutant, rescues respiratory and mtDNA transcriptional defects triggered by the absence of MOF. Mof conditional knockout has catastrophic consequences for tissues with high-energy consumption, triggering hypertrophic cardiomyopathy and cardiac failure in murine hearts; cardiomyocytes show severe mitochondrial degeneration and deregulation of mitochondrial nutrient metabolism and oxidative phosphorylation pathways. Thus, MOF is a dual transcriptional regulator of nuclear and mitochondrial genomes connecting epigenetics and metabolism. PMID- 27768894 TI - Crystal Structure of the Human Cannabinoid Receptor CB1. AB - Cannabinoid receptor 1 (CB1) is the principal target of Delta9 tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 A crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals. PMID- 27768895 TI - The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs. AB - The Polycystic Kidney Disease 2 (Pkd2) gene is mutated in autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic disorders. Here, we present the cryo-EM structure of PKD2 in lipid bilayers at 3.0 A resolution, which establishes PKD2 as a homotetrameric ion channel and provides insight into potential mechanisms for its activation. The PKD2 voltage sensor domain retains two of four gating charges commonly found in those of voltage-gated ion channels. The PKD2 ion permeation pathway is constricted at the selectivity filter and near the cytoplasmic end of S6, suggesting that two gates regulate ion conduction. The extracellular domain of PKD2, a hotspot for ADPKD pathogenic mutations, contributes to channel assembly and strategically interacts with the transmembrane core, likely serving as a physical substrate for extracellular stimuli to allosterically gate the channel. Finally, our structure establishes the molecular basis for the majority of pathogenic mutations in Pkd2 related ADPKD. PMID- 27768898 TI - Pancreaticogastrostomy has advantages over pancreaticojejunostomy on pancreatic fistula after pancreaticoduodenectomy. A meta-analysis of randomized controlled trials. AB - OBJECTIVE: To examine whether pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ) is the better reconstructive method to reduce postoperative complications, especially pancreatic fistula (PF), after pancreaticoduodenectomy (PD). BACKGROUND: PF is a severe complication after PD. The best reconstructive method to reduce occurrence of PF is controversial. We carried out this meta-analysis to compare PG with PJ. METHODS: A systematic review was conducted on PubMed, EMBASE, and Cochrane Library published up to October 2015 to identify studies comparing PG with PJ. Postoperative complications and mortality were evaluated. A meta-analysis was carried out by Review Manager 5.0. RESULTS: 10 RCTs representing 1629 patients (826 PG, 803 PJ) were included. There was a significant difference in favor of PG over PJ (OR 0.72, 95% CI 0.56-0.92, P = 0.009, I2 = 10%). No significant differences were found in biliary fistula (OR 0.58, 95% CI 0.31-1.06, P = 0.08, I2 = 38%), DGE (OR 1.08, 95% CI 0.68-1.70, P = 0.75, I2 = 53%), overall morbidity (OR 0.97, 95% CI 0.77-1.23, P = 0.82, I2 = 28%), and mortality (OR 0.98, 95% CI 0.60-1.61, P = 0.94, I2 = 0%). CONCLUSIONS: The meta-analysis showed a significant difference between PG and PJ on PF: PG was associated with significantly less PF when compared to PJ, indicating that PG is superior to PJ for reconstruction after PD. PMID- 27768897 TI - Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers. AB - Two complementary approaches were used in search of the intracellular targets of the toxic PR poly-dipeptide encoded by the repeat sequences expanded in the C9orf72 form of amyotrophic lateral sclerosis. The top categories of PRn-bound proteins include constituents of non-membrane invested cellular organelles and intermediate filaments. PRn targets are enriched for the inclusion of low complexity (LC) sequences. Evidence is presented indicating that LC sequences represent the direct target of PRn binding and that interaction between the PRn poly-dipeptide and LC domains is polymer-dependent. These studies indicate that PRn-mediated toxicity may result from broad impediments to the dynamics of cell structure and information flow from gene to message to protein. PMID- 27768896 TI - C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane Less Organelles. AB - Expansion of a hexanucleotide repeat GGGGCC (G4C2) in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Transcripts carrying (G4C2) expansions undergo unconventional, non-ATG-dependent translation, generating toxic dipeptide repeat (DPR) proteins thought to contribute to disease. Here, we identify the interactome of all DPRs and find that arginine-containing DPRs, polyGly-Arg (GR) and polyPro-Arg (PR), interact with RNA-binding proteins and proteins with low complexity sequence domains (LCDs) that often mediate the assembly of membrane-less organelles. Indeed, most GR/PR interactors are components of membrane-less organelles such as nucleoli, the nuclear pore complex and stress granules. Genetic analysis in Drosophila demonstrated the functional relevance of these interactions to DPR toxicity. Furthermore, we show that GR and PR altered phase separation of LCD-containing proteins, insinuating into their liquid assemblies and changing their material properties, resulting in perturbed dynamics and/or functions of multiple membrane less organelles. PMID- 27768899 TI - Pain prevalence, characteristics and associated factors in human T-cell lymphotropic virus type 1 infected patients: a systematic review of the literature. AB - OBJECTIVE: To describe the pain in patients infected with human T-cell lymphotropic virus type 1, clinically and epidemiologically. METHODS: This systematic review was based on The PRISMA Statement. Four reviewers searched PUBMED, SciELO, LILACS and BIREME for data from observational studies and clinical trials (n>=30) regarding pain prevalence, characteristics, and associated factors in patients with human T-cell lymphotropic virus type 1. No limits on publication date or language were established. Studies that did not have pain as an outcome measure or not involving human T-cell lymphotropic virus type 1 infected patients were excluded. RESULTS: A total of 3013 articles (including duplicates) were found of which seven met the predetermined criteria. The most common pain region was the lower back (53.0%). Non-neuropathic type (ranging from 52.6% to 86.8%) was more frequent in human T-cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis participants, and neuropathic pain was more common in human T-cell lymphotropic virus type 1 carriers (53.1%). The pain was mostly reported as moderate or severe. One study showed that chronic pain was negatively associated with quality of life. DISCUSSION: Pain is a common complaint in human T-cell lymphotropic virus type 1 infected patients, with lower back pain as the most frequent site. Pain can either be nociceptive, neuropathic, or both, is frequently severe, and negatively affects quality of life. Only studies of two countries were included in this review, limiting the external validity of the conclusions. The heterogeneity of variables prevented us from implementing a meta-analysis. Further research should better characterize the pain and explore its impact on quality of life, especially using longitudinal study design. PMID- 27768900 TI - Is chronic toxoplasmosis a risk factor for diabetes mellitus? A systematic review and meta-analysis of case-control studies. AB - INTRODUCTION: The global protozoan parasite, Toxoplasma gondii, infects many warm blooded animals and humans by employing different transmission routes. There have been some recent studies on the probable relevance of infectious agents and diabetes. Therefore, we conducted a systematic review and meta-analysis to identify the possible association between chronic toxoplasmosis and diabetes mellitus. METHODS: This study was conducted following the general methodology recommended for systematic reviews and meta-analysis. Nine English literature databases (Google scholar, PubMed, Scopus, Web of science, Science Direct, Ovid, ProQuest, IngentaConnect, and Wiley Online Library) were searched, up to January 2016. Random effects model was used to determine odds ratios and their 95% confidence intervals. RESULTS: Our review resulted in a total of seven publications meeting the inclusion criteria. Because of significant heterogeneity, we estimated a common OR by a random effects model at 1.10 (95% CI=0.13-9.57) with p=0.929 and 2.39 (95% CI=1.20-4.75) with p=0.013 for type 1 and type 2 diabetes mellitus, respectively. CONCLUSION: Despite the limitations such as low number of studies, this meta-analysis suggests chronic toxoplasmosis as a possible risk factor for type 2 DM. However, based on random effects model no statistically significant association was observed between T. gondii and type 1 DM. It is highly recommended for researchers to carry out more accurate studies aiming to better understand this association. PMID- 27768901 TI - Hearing testing in the U.S. Department of Defense: Potential impact on Veterans Affairs hearing loss disability awards. AB - Hearing loss is the second most common disability awarded by the U.S. Department of Veterans Affairs (VA) to former members of the U.S. uniformed services. Hearing readiness and conservation practices differ among the four largest uniformed military services (Air Force, Army, Marine Corps, and Navy). Utilizing a data set consisting of all hearing loss claims submitted to the VA from fiscal years 2003-2013, we examined characteristics of veterans submitting claims within one year of separation from military service. Our results indicate that having a hearing loss disability claim granted was significantly more likely for men, individuals over the age of 26 years at the time of the claim, individuals most recently serving in the U.S. Army, and those with at least one hearing loss diagnosis. Importantly, individuals with at least one test record in the Defense Occupational and Environmental Health Readiness System-Hearing Conservation (DOEHRS-HC) system were significantly less likely to have a hearing loss disability claim granted by the VA. Within the DOEHRS-HC cohort, those with at least one threshold shift or clinical hearing loss diagnosis while on active duty were more than two and three times more likely to have a hearing loss disability claim granted, respectively. These findings indicate that an established history of reduced hearing ability while on active duty was associated with a significantly increased likelihood of an approved hearing loss disability claim relative to VA claims without such a history. Further, our results show a persistent decreased rate of hearing loss disability awards overall. These findings support increased inclusion of personnel in DoD hearing readiness and conservation programs to reduce VA hearing loss disability awards. PMID- 27768902 TI - Regulation of proteasome activity by P2Y2 receptor underlies the neuroprotective effects of extracellular nucleotides. AB - The Ubiquitin-Proteasome System (UPS) is essential for the regulation of the cellular proteostasis. Indeed, it has been postulated that an UPS dysregulation is the common mechanism that underlies several neurological disorders. Considering that extracellular nucleotides, through their selective P2Y2 receptor (P2Y2R), play a neuroprotective role in various neurological disorders that course with an UPS impairment, we wonder if this neuroprotective capacity resulted from their ability to modulate the UPS. Using a cellular model expressing two different UPS reporters, we found that the stimulation of P2Y2R by its selective agonist Up4U induced a significant reduction of UPS reporter levels. This reduction was due to an increase in two of the three peptidase proteasome activities, chymotrypsin and postglutamyl, caused by an increased expression of proteasome constitutive catalytic subunits beta1 and beta5. The intracellular signaling pathway involved required the activation of IP3/MEK1/2/ERK but was independent of PKC or PKA. Interestingly, the P2Y2R activation was able to revert both UPS-reporter accumulation and the cell death induced by a prolonged inhibition of UPS. Finally, we also observed that intracerebroventricular administration of Up4U induced a significant increase both of chymotrypsin and postglutamyl activities as well as an increased expression of proteasome subunits beta1 and beta5 in the hippocampus of wild-type mice, but not in P2Y2R KO mice. All these results strongly suggest that the capacity to modulate the UPS activity via P2Y2R is the molecular mechanism which is how the nucleotides play a neuroprotective role in neurological disorders. PMID- 27768904 TI - Gill remodelling and growth rate of striped catfish Pangasianodon hypophthalmus under impacts of hypoxia and temperature. AB - Gill morphometric and gill plasticity of the air-breathing striped catfish (Pangasianodon hypophthalmus) exposed to different temperatures (present day 27 degrees C and future 33 degrees C) and different air saturation levels (92% and 35%) during 6weeks were investigated using vertical sections to estimate the respiratory lamellae surface areas, harmonic mean barrier thicknesses, and gill component volumes. Gill respiratory surface area (SA) and harmonic mean water - blood barrier thicknesses (HM) of the fish were strongly affected by both environmental temperature and oxygen level. Thus initial values for 27 degrees C normoxic fish (12.4+/-0.8g) were 211.8+/-21.6mm2g-1 and 1.67+/-0.12MUm for SA and HM respectively. After 5weeks in same conditions or in the combinations of 33 degrees C and/or PO2 of 55mmHg, this initial surface area scaled allometrically with size for the 33 degrees C hypoxic group, whereas branchial SA was almost eliminated in the 27 degrees C normoxic group, with other groups intermediate. In addition, elevated temperature had an astounding effect on growth with the 33 degrees C group growing nearly 8-fold faster than the 27 degrees C fish. PMID- 27768903 TI - Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases. AB - Lipids in the body are transported via lipoproteins that are nanoparticles comprised of lipids and amphipathic proteins termed apolipoproteins. This family of lipid surface-binding proteins is over-represented in human amyloid diseases. In particular, all major proteins of high-density lipoproteins (HDL), including apoA-I, apoA-II and serum amyloid A, can cause systemic amyloidoses in humans upon protein mutations, post-translational modifications or overproduction. Here, we begin to explore how the HDL lipid composition influences amyloid deposition by apoA-I and related proteins. First, we summarize the evidence that, in contrast to lipoproteins that are stabilized by kinetic barriers, free apolipoproteins are labile to misfolding and proteolysis. Next, we report original biochemical and biophysical studies showing that increase in triglyceride content in the core of plasma or reconstituted HDL destabilizes the lipoprotein assembly, making it more labile to various perturbations (oxidation, thermal and chemical denaturation and enzymatic hydrolysis), and promotes apoA-I release in a lipid-poor/free aggregation-prone form. Together, the results suggest that decreasing plasma levels of triglycerides will shift the dynamic equilibrium from the lipid-poor/free (labile) to the HDL-bound (protected) apolipoprotein state, thereby decreasing the generation of the protein precursor of amyloid. This prompts us to propose that triglyceride-lowering therapies may provide a promising strategy to alleviate amyloid diseases caused by the deposition of HDL proteins. PMID- 27768905 TI - Influence of feature set reduction on breast cancer malignancy classification of fine needle aspiration biopsies. AB - Grading of breast cancer malignancy is a key step in its diagnosis, which in turn helps to determine its prognosis and a course of treatment. In this paper, we consider the application of pattern recognition and image processing techniques to perform computer-assisted automatic breast cancer malignancy grading from cytological slides of fine needle aspiration biopsies. To determine a classification of the malignancy of the slide, a feature set is first determined from imagery of the slides. In this paper we investigated the nature of a wide set of features extracted from biopsy images to determine their discriminatory power and cross-correlation. Feature vector reduction is studied using a correlation map of the features, determining discriminatory power using the Kolmogorov-Smirnov test, significant feature selection, and stepwise feature selection. The reduction of the feature vector simplifies the complexity of classification scheme and does not impair the classification accuracy. In some cases a decrease of the error rate is noted. Based on this analysis, we present an improved classification system for cancer malignancy grading. PMID- 27768906 TI - Ultrasound fusion image error correction using subject-specific liver motion model and automatic image registration. AB - PURPOSE: Ultrasound fusion imaging is an emerging tool and benefits a variety of clinical applications, such as image-guided diagnosis and treatment of hepatocellular carcinoma and unresectable liver metastases. However, respiratory liver motion-induced misalignment of multimodal images (i.e., fusion error) compromises the effectiveness and practicability of this method. The purpose of this paper is to develop a subject-specific liver motion model and automatic registration-based method to correct the fusion error. METHODS: An online-built subject-specific motion model and automatic image registration method for 2D ultrasound-3D magnetic resonance (MR) images were combined to compensate for the respiratory liver motion. The key steps included: 1) Build a subject-specific liver motion model for current subject online and perform the initial registration of pre-acquired 3D MR and intra-operative ultrasound images; 2) During fusion imaging, compensate for liver motion first using the motion model, and then using an automatic registration method to further correct the respiratory fusion error. Evaluation experiments were conducted on liver phantom and five subjects. RESULTS: In the phantom study, the fusion error (superior inferior axis) was reduced from 13.90+/-2.38mm to 4.26+/-0.78mm by using the motion model only. The fusion error further decreased to 0.63+/-0.53mm by using the registration method. The registration method also decreased the rotation error from 7.06+/-0.21 degrees to 1.18+/-0.66 degrees . In the clinical study, the fusion error was reduced from 12.90+/-9.58mm to 6.12+/-2.90mm by using the motion model alone. Moreover, the fusion error decreased to 1.96+/-0.33mm by using the registration method. CONCLUSIONS: The proposed method can effectively correct the respiration-induced fusion error to improve the fusion image quality. This method can also reduce the error correction dependency on the initial registration of ultrasound and MR images. Overall, the proposed method can improve the clinical practicability of ultrasound fusion imaging. PMID- 27768907 TI - Chemical characteristics of PM1/PM2.5 and influence on visual range at the summit of Mount Tai, North China. AB - Daytime and night-time PM1 and PM2.5 samples were simultaneously collected at the summit of Mount Tai during summer and autumn 2014. The mass concentrations and chemical compositions were analysed to determine the temporal variations of PM1 and PM2.5 and their contributions to visibility impairment. In summer, the average mass concentrations of PM1 and PM2.5 were 38.16MUg/m3 and 53.33MUg/m3, respectively. In autumn, the values were 42.75MUg/m3 and 59.16MUg/m3. Water soluble inorganic ions were the most abundant species in both PM1 and PM2.5, followed by organic mass (OM). Among the major water-soluble ions, SO42- and NH4+ had higher concentrations in summer than in autumn, whereas the concentration of NO3- showed the opposite seasonal trend. Lower concentrations of organic carbon (OC), elemental carbon (EC) and water-soluble organic carbon (WSOC) were obtained in summer than in autumn. The water-soluble components (SO42-, NO3-, NH4+ and WSOC) showed a clear diurnal variation due to the specific meteorological conditions of Mount Tai. The water content in PM1 and PM2.5 was enhanced by the water-soluble components, especially NH4NO3. The decreased visibility resulted from the combined influence of particulate matter and relative humidity (RH). The threshold PM2.5 concentration corresponding to a visibility of <10km was 56.60MUg/m3, which decreased with an increase in RH. A revised IMPROVE equation was applied to estimate the light-extinction coefficient bext, which was found to be lower for these chemicals in autumn (364Mm-1) than in summer (482Mm-1). (NH4)2SO4 made the largest contribution to bext in both summer and autumn, with an average rate of 56.97%. OM (17.32%) and NH4NO3 (15.13%) were also important contributors, with similar contribution rates. The contribution of NH4NO3 to bext was higher during summer, and OM contributions were higher during autumn. PMID- 27768908 TI - Regulation of voltage gated calcium channels by GPCRs and post-translational modification. AB - Calcium entry via voltage gated calcium channels mediates a wide range of physiological functions, whereas calcium channel dysregulation has been associated with numerous pathophysiological conditions. There are myriad cell signaling pathways that act on voltage gated calcium channels to fine tune their activities and to regulate their cell surface expression. These regulatory mechanisms include the activation of G protein-coupled receptors and downstream phosphorylation events, and their control over calcium channel trafficking through direct physical interactions. Calcium channels also undergo post translational modifications that alter both function and density of the channels in the plasma membrane. Here we focus on select aspects of these regulatory mechanisms and highlight recent developments. PMID- 27768909 TI - High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation. AB - High-fructose corn syrup-55 (HFCS-55) has been suggested to be more lipogenic than sucrose, which increases the risk for nonalcoholic fatty liver disease (NAFLD) and dyslipidemia. The study objectives were to determine the effects of drinking different sugar-sweetened solutions on hepatic gene expression in relation to liver fatty acid composition and risk of NAFLD. Female rats were randomly assigned (n=7 rats/group) to drink water or water sweetened with 13% (w/v) HFCS-55, sucrose or fructose for 8 weeks. Rats drinking HFCS-55 solution had the highest (P=.03) hepatic total lipid and triglyceride content and histological evidence of fat infiltration. Rats drinking HFCS-55 solution had the highest hepatic de novo lipogenesis indicated by the up-regulation of stearoyl CoA desaturase-1 and the highest (P<.001) oleic acid (18:1n-9) content. This was accompanied by reduced beta-oxidation indicated by down-regulation of hepatic peroxisome proliferator-activated receptor alpha. Disposal of excess lipids by export of triglyceride-rich lipoprotein from the liver was increased as shown by up-regulation of gene expression of microsomal triglyceride transfer protein in rats drinking sucrose, but not HFCS-55 solution. The observed lipogenic effects were attributed to the slightly higher fructose content of HFCS-55 solution in the absence of differences in macronutrient and total caloric intake between rats drinking HFCS-55 and sucrose solution. Results from gene expression and fatty acid composition analysis showed that, in a hypercaloric state, some types of sugars are more detrimental to the liver. Based on these preclinical study results, excess consumption of caloric sweetened beverage, particularly HFCS sweetened beverages, should be limited. PMID- 27768910 TI - Self dispersing mixed micelles forming systems for enhanced dissolution and intestinal permeability of hydrochlorothiazide. AB - Mixed micelles provide promising strategy for enhancing dissolution and permeability of drugs. However, their fluid nature limited the stability of the loaded drug and hindered the development of stable oral dosage form. Accordingly, the objective was to develop solid self dispersing mixed micelle forming systems (MMFS) for enhanced dissolution and intestinal permeability of hydrochlorothiazide. Pseudoternary phase diagrams were constructed using sodium cholate, lecithin with either poloxamer 407 or PEG 4000 to determine the composition of MMFS. Both polymer free and poloxamer or PEG containing MMFS were prepared as homogenous matrices or as solid self dispersing powder. The later was developed by adsorption of MMFS on avicel-aerosil mixture. Differential scanning calorimetry provided an evidence for existence of hydrochlorothiazide as molecular dispersion in the MMFS. Dispersing polymer free, PEG 4000 or poloxamer based MMFS in aqueous medium produced micelles having size values of 119, 52.6 and 28nm, respectively. The zeta potential values were -61.8, -59.5 and -19.5mV for the same systems, respectively. Preparation of solid self dispersing MMFS enhanced the dissolution rate of hydrochlorothiazide. The intestinal absorption of hydrochlorothiazide from its aqueous solution and polymer incorporating mixed micellar systems was monitored using in situ rabbit intestinal perfusion technique. The permeability results showed a clear trend for enhanced membrane transport of the drug after being incorporated into poloxamer containing mixed micellar system. The study thus introduced a versatile easily formulated solid self dispersing system with high potential for solving the dissolution and permeability problems of class IV drugs. PMID- 27768911 TI - Enhancement of neurite adhesion, alignment and elongation on conductive polypyrrole-poly(lactide acid) fibers with cell-derived extracellular matrix. AB - Extracellular matrix (ECM) can promote peripheral nerve repair. In this study, a conductive fiber-film (CFF) with core-sheath structure and conductivity of ~10Scm 1 was prepared by electrospinning of aligned poly(l-lactide acid) (PLLA) fibers and electrochemical deposition of polypyrole (PPy) nanoparticles. Then the multiple components of ECM, including laminin, fibronectin and collagen, were coated on the surface of CFF by culturing and lysing L929 cells to fabricate the bioactive scaffold of ECM-linked CFF (ECM-CFF). The electrical stimulation (ES) of 100mV/cm for 14days and 2h per day did not significantly decrease the conductivity of ECM-CFF. The results of PC12 cells test indicated that, cells adhesion rate, neurite-bearing cell rate and neurite alignment rate on ECM-CFF were ~95%, ~77%, ~70%, respectively, significantly larger than the corresponding values on bare CFF (17%, 29% and 14%, respectively). The neurites length on ECM CFF (~79mm) was also larger than that on bare CFF (~25mm). ES of 100mV/cm onto PC12 cells through ECM-CFF could significantly promote neurite extension in first 3days of the neurite growth. These results indicated that, the combination of ECM CFF with ES could improve the nerve regeneration by encouraging neural-cell adhesion, neurite growth and extension. PMID- 27768912 TI - Effects of Ca2+ ions on bestrophin-1 surface films. AB - Human bestrophin-1 (hBest1) is a transmembrane calcium-activated chloride channel protein - member of the bestrophin family of anion channels, predominantly expressed in the membrane of retinal pigment epithelium (RPE) cells. Mutations in the protein cause ocular diseases, named Bestrophinopathies. Here, we present the first Fourier transform infrared (FTIR) study of the secondary structure elements of hBest1, pi/A isotherms and hysteresis, Brewster angle microscopy (BAM) and atomic force microscopy (AFM) visualization of the aggregation state of protein molecules dispersed as Langmuir and Langmuir-Blodgett films. The secondary structure of hBest1 consists predominantly of 310-helices (27.2%), alpha-helixes (16.3%), beta-turns and loops (32.2%). AFM images of hBest1 suggest approximate lateral dimensions of 100*160A and 75A height. Binding of calcium ions (Ca2+) induces conformational changes in the protein secondary structure leading to assembly of protein molecules and changes in molecular and macro-organization of hBest1 in monolayers. These data provide basic information needed in pursuit of molecular mechanisms underlying retinal and other pathologies linked to this protein. PMID- 27768913 TI - Recombinant human bone morphogenetic protein 2 (rhBMP-2) immobilized on laser fabricated 3D scaffolds enhance osteogenesis. AB - The regeneration of bone via a tissue engineering approach involves components from the macroscopic to the nanoscopic level, including appropriate 3D scaffolds, cells and growth factors. In this study, hexagonal scaffolds of different diagonals were fabricated by Direct Laser Writing using a photopolymerizable hybrid material. The proliferation of bone marrow (BM) mesenchymal stem cells (MSCs) cultured on structures with various diagonals, 50, 100, 150 and 200MUm increased significantly after 10days in culture, however without significant differences among them. Next, recombinant human bone morphogenetic protein 2 (rhBMP-2) was immobilized onto the hybrid material both via covalent binding and physical adsorption. Both immobilization types exhibited similar high releaseate bioactivity profiles and a sustained delivery of rhBMP-2. The collagen and calcium levels produced in the extracellular matrix (ECM) were significantly elevated for the samples functionalized with BMP-2 compared to those in the osteogenic medium. Furthermore, significant upregulation of gene expression in both types of BMP-2 immobilized scaffolds was observed for alkaline phosphatase (ALPL) and osteocalcin (BGLAP) at days 7, 14, and 21, for RUNX2 at day 21, and for osteonectin (SPARC) at days 7 and 14. The results suggest that the release of bioactive rhBMP-2 from the hybrid scaffolds enhance the control over the osteogenic differentiation during cell culture. PMID- 27768914 TI - Tuning the non-covalent confinement of Gd(III) complexes in silica nanoparticles for high T1-weighted MR imaging capability. AB - The present work introduces deliberate synthesis of Gd(III)-doped silica nanoparticles with high relaxivity at magnetic field strengths below 1.5T. Modified microemulsion water-in-oil procedure was used in order to achieve superficial localization of Gd(III) complexes within 40-55nm sized silica spheres. The relaxivities of the prepared nanoparticles were measured at 0.47, 1.41 and 1.5T with the use of both NMR analyzer and whole body NMR scanner. Longitudinal relaxivities of the obtained silica nanoparticles reveal significant dependence on the confinement mode, changing from 4.1 to 49.6mM-1s-1 at 0.47T when the localization of Gd(III) complexes changes from core to superficial zones of the silica spheres. The results highlight predominant contribution of the complexes located close to silica/water interface to the relaxivity of the nanoparticles. Low effect of blood proteins on the relaxivity in the aqueous colloids of the nanoparticles was exemplified by serum bovine albumin. T1- weighted MRI data indicate that the nanoparticles provide strong positive contrast at 1.5T, which along with low cytotoxicity effect make a good basis for their application as contrast agents. PMID- 27768915 TI - Co-delivery of multiple drug resistance inhibitors by polymer/inorganic hybrid nanoparticles to effectively reverse cancer drug resistance. AB - To effectively reverse multiple drug resistance (MDR) in tumor treatments, a functional nano-sized drug delivery system with active targeting function and pH sensitivity was prepared for the co-delivery of multiple drug resistance inhibitors. Buthionine sulfoximine (BSO) to inhibit GSH synthesis and celecoxib (CXB) to down-regulate P-gp expression were co-loaded in polymer/inorganic hybrid nanoparticles to form buthionine sulfoximine/celecoxib@biotin heparin/heparin/calcium carbonate/calcium phosphate nanoparticles (BSO/CXB@BNP). To investigate the reversal of MDR, the drug resistant cells (MCF-7/ADR) were pretreated by the dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) followed by the treatment of doxorubicin (DOX) loaded nanoparticles (DOX@BNP). The dual inhibitor loaded nanoparticles (BSO/CXB@BNP) exhibited greatly enhanced efficiency in down-regulation of GSH and P-gp since BSO and CXB had combined effects on the reduction of GSH and P-gp in drug resistant tumor cells. As a result, BSO/CXB@BNP exhibited a significantly improved capability in reversal of MDR compared with mono-inhibitor loaded nanoparticles (CXB@BNP and BSO@BNP). As compared with free drug resistance inhibitors, delivery of drug resistance inhibitors by functional nanocarriers could obviously improve the therapeutic efficiency due to enhanced cellular uptake and increased intracellular drug accumulation. The study on immunostimulatory effects of different treatments showed that BSO/CXB@BNP treatment resulted in the lowest concentration of interleukin 10, a cytokine related to tumor development. These results suggest the nanoparticulate drug delivery platform developed in this study has promising applications in multiple drug delivery to overcome drug resistance in tumor treatments. PMID- 27768916 TI - Evidence for cell-free nucleic acids as continuously arising endogenous DNA mutagens. AB - There is extensive literature to show that nucleic acids can be taken up by cells under experimental conditions and that foetal DNA can be detected in maternal tissues. The uptaken DNA can integrate into host cell genomes and can be transcribed and translated into proteins. They can also cause chromosomal damage and karyotype alterations. Cell-free nucleic acids (cfNAs)-based non-invasive DNA diagnostic techniques are being extensively researched in the field of cancer with the potential to advance new prognostic parameters and direct treatment decisions. However, whether extracellular cfNAs that are released into circulation from dying cells as a consequence of normal physiology have any functional significance has not been explored. A recent study has demonstrated that circulating cfNAs have the ability to cause DNA damage and mutagenesis by illegitimately integrating into healthy cells of the body, thereby acting as mobile genetic elements. Fluorescently-labeled cfNAs isolated from sera of cancer patients and healthy volunteers were shown to be readily taken up by host cells followed by activation of a DNA-damage-repair-response which led their large scale integration into the host cell genomes. The latter caused dsDNA breaks and apoptosis in cells in vitro and in those of vital organs when injected intravenously into mice. Cell-free chromatin was consistently more active than cell-free DNA, while cfNAs derived from cancer patients were significantly more active than those from healthy volunteers. This study suggests that circulating extracellular cfNAs act as physiological continuously arising DNA mutagens with implications for ageing, cancer and a host of other degenerative human pathologies. PMID- 27768917 TI - Early predictors of maturing out of marijuana use among young men. AB - OBJECTIVE: Although several studies have delineated risk factors for adolescent regular marijuana use, few studies have identified those factors that differentiate who will and will not eventually stop using marijuana during young adulthood. This study examined the extent to which adolescent risk factors, including individual attitudes, temperament, and behaviors and peer, family, and neighborhood factors, could prospectively identify which adolescence-onset monthly marijuana users (AMMU) would stop using marijuana in young adulthood and whether race moderated these associations. METHOD: Data came from 503 young men who were followed annually from the first grade through mean age 20 and then re interviewed at mean ages 26 and 29. Young men who used marijuana at least monthly at least one year between ages 14 and 17 (N=140) were compared to their peers who had not tried marijuana by age 17 (N=244). The former group was divided into those who used at least weekly in adulthood (N=54) and those who did not use at all in adulthood (N=66) and these groups were compared to each other. RESULTS: Logistic regression analyses indicated that all except one of the adolescent risk factors significantly differentiated AMMU from nonusers. None of the predictors differentiated those who matured out from those who used weekly in young adulthood. CONCLUSIONS: Future research on marijuana cessation should incorporate subjective life experiences, such as reasons for using and negative consequences from use, to help identify adolescents who are at risk for problematic use in adulthood. PMID- 27768918 TI - Current perspectives of sentinel lymph node dissection at the time of radical surgery for prostate cancer. AB - The sentinel lymph node dissection (SLND) concept relies on the accurate detection of primary nodal landing sites and could represent a major advancement towards accurate, non-invasive pelvic staging in prostate cancer (PCa). Different iterations of the technique have now been validated and reproduced mostly in large-volume centres. The existing evidence denotes the feasibility and sensitivity of SLND, with encouraging pre- and intraoperative detection rates of 98% and 96%. Yet, current surgical practice mandates a backup template dissection due to a false negative rate, up to 7.1%, of tracer-guided surgery. In practice, SLND failed to achieve nodal detection in up to 20% of pelvic sidewalls. Despite scarce validated evidence, current consensus mainly attributes these false negative cases to altered prostatic drainage secondary to malignant obliteration of lymphovascular structures. In parallel, multiple SLND studies have highlighted the complex and variable drainage pathways from the prostate, furthering the established anatomical atlases. The most promising approach may therefore rely in magnetic nanoparticles and PCa-targeting ligands. However, in the absence of a clear sentinel node or region for the prostate, formal SLND is difficult to integrate in routine surgical practice for now. As such, tracer-guided dissection is only used as a complementary intervention to highlight first- echelon nodes and aberrant lymphatic pathways found beyond the commonly adopted pelvic lymphadenectomy templates. PMID- 27768919 TI - Stereotactic ablative radiotherapy for early stage non-small cell lung cancer: A critical literature review of predictive factors of relapse. AB - Stereotactic ablative radiation therapy (SABR) has become the standard treatment for peripheral medically non-operable patients with early stage non-small cell lung cancer (NSCLC). Previous attempts of trials to compare SABR and surgery have failed and new randomized studies (SABRtooth, STABLEMATES, and VALOR) are ongoing. While predictive factors of relapse have been extensively studied in patients receiving surgery, there is scarce data on such putative factors in SABR patients. The purpose of this review is to analyze such predictive factors through a critical review of the literature. PMID- 27768920 TI - Nano-LC-MS/MS for the identification of proteins trapped in sorbent cartridges used for coupled plasma filtration-adsorption treatments of healthy pigs. AB - A dedicated proteomic approach based on nano-Liquid Chromatography coupled with tandem mass spectrometry in ion trap is proposed for the analysis of proteins trapped in sorbent resin cartridges used to remove inflammatory mediators from blood by coupled plasma filtration adsorption (CPFA). The final purpose of the proposed proteomic approach was to obtain a reference map of plasma proteins trapped in CPFA sorbents used for the extracorporeal blood purification of healthy pigs, with the potential impact to design new bio-filters able to control the inflammatory imbalance under pathological conditions, such as severe sepsis. The five main steps of the proteomics analysis, (i) protein extraction from resin cartridges, (ii) two-dimensional gel electrophoresis (2D-PAGE) for protein separation and profiling, (iii) in-gel proteolytic digestion, (iv) tandem mass analysis of peptides resulting from enzymatic cleavage and (v) bioinformatics, for protein identification and post-processing validation of MS/MS data sets, have been carefully evaluated. Prior to electrophoresis, the efficiency of different extraction solutions and procedures to recovery plasma proteins trapped into the sorbents were tested. Then, a rapid one-step procedure for protein extraction was optimized. Protein bands corresponding to the main plasma proteins, namely porcine serum albumin, serotransferrin and immunoglobulins, were identified. In addition, the presence of haptoglobin, hemopexin, alpha-1 acid glycoprotein and fetuin-A, that are known as acute-phase reaction proteins, was observed, suggesting that CPFA resins led to a non-specifically protein depletion from plasma, rather than targeting specific molecules. PMID- 27768921 TI - A simple and rapid UHPLC-MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma. AB - The Aurora kinase family facilitates cell division through various processes and is overexpressed in a wide variety of human cancers, leading to aneuploidy. For that reason, these enzymes are currently targets of a rising class of anticancer drugs, with some molecules already in therapeutic use. In this study, a new UHPLC MS/MS method was developed and validated to quantitate a new pan Aurora kinase inhibitor still in preclinical development, SCH-1473759. This bioanalytical method employed a liquid-liquid extraction from plasma using ethyl acetate before evaporation. Calibration range encompassed 0.5-2500ng/mL. The inter- and intra day accuracy and precision were assessed over five quality control levels; all within limits required by the FDA guidelines. Assay applicability was demonstrated in a first-in-animals study with oral administration, where the maximum plasma concentration (34ng/mL) occurred at 1h, the half-life (1h) was consistent with a previous IV study, and oral bioavailability was poor (F=0.002). PMID- 27768922 TI - An UPLC-MS/MS method for the quantitation of alectinib in rat plasma. AB - Currently, crizotinib is the first generation drug, which has been used in the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). However, more and more patients are found in crizotinib-resistance. In the last year, alectinib has been approved for treatment of patients with crizotinib-resistance. In this study, we aim to develop and validate a simple, rapid and sensitive tandem mass spectrometry (UHPLC-MS/MS) method for determination of alectinib in rat plasma. Diazepam was chosen as an internal standard (IS). Protein precipitation by acetonitrile was utilized to prepare plasma samples. Chromatographic separation was achieved on a RRHD Eclipse Plus C18 (2.1*50mm, 1.8MU) column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The analytes were detected by an electrospray ionization (ESI) source in positive mode. A dynamic multiple reaction monitoring (MRM) method was developed to detect specific precursor and product ions. The target fragment ions were m/z 483.2 >396.1 for alectinib and m/z 285.0->192.9 for diazepam (IS). Linear calibration plots were achieved in the range of 1-500ng/ml for alectinib (R2=0.997) in rat plasma. Mean recoveries of alectinib in rat plasma ranged from 84.2% to 92.2%. The intra- and inter-day precision was below 9.3% and accuracy was from -1.4% to 12.1%. No obvious matrix effect was found. This method shows a good performance: accuracy, precision and stability. It has been fully validated and successfully applied to pharmacokinetic study of alectinib. PMID- 27768924 TI - The 21-gene recurrence score assay in node-negative early breast cancer: Prognostic, predictive or presumptuous? PMID- 27768923 TI - Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer. AB - BACKGROUND: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. METHODS: Irinotecan (180 mg/m2), 5 fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. RESULTS: Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter <=57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4 100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses. CONCLUSIONS: Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228. PMID- 27768925 TI - Emodin alleviates jejunum injury in rats with sepsis by inhibiting inflammation response. AB - Emodin is an anthraquinone derived from Chinese herb that exerts anti inflammation effects. This study aimed to investigate whether emodin provides the protection for jejunum injury by inhibiting inflammation. We established a model of sepsis caused by cecal ligation and puncture. Forty-eight male Wistar rats were divided into four groups (n=12). Jejunum injury was assessed by pathological examination. The activity of pJAK1/pSTAT3 and protein levels of Bcl-2 and Bax were detected by Western blot analysis. Inflammatory factors IL-6, TNF-alpha and procalcitonin were detected by ELISA. Apoptosis was detected by TUNEL. We found that emodin alleviated jejunum damage and apoptosis induced by sepsis and decreased the levels of IL-6, TNF-alpha and procalcitonin in septic rats. Furthermore, we observed that emodin increased the levels of pJAK1 and of pSTAT3, which were decreased in rats with sepsis. In addition, emodin enhanced the expression of Bcl-2 which was downregulated by sepsis and decreased the expression of Bax which was upregulated by sepsis. In conclusion, these results indicate that emodin suppresses inflammatory response induced by sepsis. Emodin activates JAK1/STAT3 signaling pathway and regulates Bcl-2 and Bax expression to protect the jejunum in rats with sepsis. PMID- 27768926 TI - Prunella vulgaris L. active components and their hypoglycemic and antinociceptive effects in alloxan-induced diabetic mice. AB - Prunella vulgaris L. (Lamiaceae) (PV) is a herbaceous plant traditionally utilized in management of diabetes and it has immunomodulatory activity. In this study, acute and subchronic antidiabetic, in-vivo antioxidant and antinociceptive effects of PV were evaluated in alloxan-induced type 1 diabetes (T1D) in a mouse model. Bio-guided fractionation, isolation, RP-HPLC, and 1H and 13C NMR identification of the active components responsible for PV effects were determined. RP-HPLC analysis showed that PV contained rosmarinic acid (RA) 4.5%, caffeic acid (CA) 9.8% and p-coumaric acid (pCA) 11.6%. Bio-guided fractionation showed that PV most active fraction was rich in caffeic acid, hence named, caffeic acid-rich fraction (CARF). RP-HPLC, and 1H and 13C NMR experiments showed that CARF contained CA (93.4%) and RA (6.6%). CARF reduced blood glucose levels and improved in-vivo oxidative-stress. It also inhibited the carbohydrate hydrolyzing enzymes (alpha-amylase and alpha-glucosidase) and reduced HbA1c levels more significantly (p<=0.05) than that of PV and equivalent amounts of CA or RA. For longer times, CARF had significantly (p<=0.05) increased serum insulin, ameliorated thermal hyperalgesia and tactile allodynia more significantly (p<=0.05) than the effects of PV and equivalent amounts of CA or RA. Moreover, the tested compounds showed potential restoration of the lipid peroxide levels. Consequently, CARF and PV observed increase in serum-insulin, attenuation of alpha-amylase and alpha-glucosidase, and their antioxidant potentials might be responsible for their antidiabetogenic and antinociceptive properties. In conclusion, CARF isolated from PV could be a potential therapeutic agent to ameliorate T1D and related complications. PMID- 27768927 TI - Evaluation of cytotoxic effect of the combination of a pyridinyl carboxamide derivative and oxaliplatin on NCI-H1299 human non-small cell lung carcinoma cells. AB - Even with all improvements in both diagnostic and therapeutic techniques, lung cancer remains as the most lethal and prevalent cancer in the world. Therefore, new therapeutic drugs and new strategies of drug combination are necessary to provide treatments that are more efficient. Currently, standard therapy regimen for lung cancer includes platinum drugs, such as cisplatin, oxaliplatin, and carboplatin. Besides of the better toxicity profile of oxaliplatin when compared with cisplatin, peripheral neuropathy remains as a limitation of oxaliplatin dose. This study presents LabMol-12, a new pyridinyl carboxamide derivative with antileishmanial and antichagasic activity, as a new hit for lung cancer treatment, which induces apoptosis dependent of caspases in NCI-H1299 lung cancer cells both in monolayer and 3D culture. Moreover, LabMol-12 allows a reduction of oxaliplatin dose when they are combined, thereby, it is a relevant strategy for reducing the side effects of oxaliplatin with the same response. Molecular modeling studies corroborated the biological findings and suggested that the combined therapy can provide a better therapeutically profile effects against NSCLC. All these findings support the fact that the combination of oxaliplatin and LabMol-12 is a promising drug combination for lung cancer. PMID- 27768929 TI - Metabolite variations between acute-on-chronic liver failure and chronic liver failure caused by hepatitis B virus based on ultra-performance liquid chromatography mass spectrometry. AB - OBJECTIVE: The present study aims to compare serum metabolite alterations between acute-on-chronic liver failure (ACLF) and chronic liver failure (CLF), and find the specific biomarkers associated with the diseases. METHODS: Serum samples were collected from patients with ACLF (n=76) and CLF (n=56) as well as healthy individuals (n=20) and assayed by ultra-performance liquid chromatography mass spectrometry (UPLC-MS). The acquired data was analyzed using principal components analysis (PCA) and partial least squares discriminate analysis (PLS-DA). RESULTS: The PLS-DA model with satisfactory explanatory and predictive ability (R2=0.979, Q2=0.918) is capable of discriminate ACLF patients from CLF patients. Significant difference in the metabolomics among the three groups was observed, metabolites that decreased significantly in the serum of ACLF and CLF included phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs), whereas conjugated bile acids (GCDCA, GUDCA) increased significantly, these metabolites considered as common biomarkers of liver failure. Linoleyl carnitine showed significant increase in CLF compared with controls while no significant change was observed in ACLF, it could be special biomarkers of ACLF and CLF. CONCLUSION: Metabolomics based on ultra-performance liquid chromatography mass spectrometry provide a new way to diagnose and reveal the pathogenesis of ACLF and CLF. PMID- 27768928 TI - Valproic acid (VPA) promotes the epithelial mesenchymal transition of hepatocarcinoma cells via transcriptional and post-transcriptional up regulation of Snail. AB - Due to the low cost and favorable safety profile, valproic acid (VPA) has been considered as a potential candidate drug for therapy of various cancers. Our present study revealed that VPA, at the concentration (1mM) which has no effect on cell proliferation, can significantly increase the in vitro migration and invasion of hepatocarcinoma (HCC) HepG2 and Huh7 cells via induction of epithelial mesenchymal transition (EMT). VPA treatment can significantly increase the mRNA and protein expression of Snail, the key transcription factor of EMT. While knockdown of Snail can abolish VPA induced EMT of HCC cells. It suggested that Snail is essential for VPA induced EMT of HCC cells. VPA treatment also increased the phosphorylation of NF-kappaB p65. BAY 11-7082, the inhibitor of NF kappaB, can significantly abolish VPA induced up regulation of Snail mRNA. Furthermore, VPA can increase the protein expression of Snail since 1h treatment via up regulation of half-lives of Snail protein. The increased protein stabilization of Snail can be attributed to VPA induced phosphorylation of Akt and GSK-3beta. Collectively, our present study revealed that VPA can promote the EMT of HCC cells via up regulation of Snail through activation of NF-kappaB and Akt/GSK-3beta signals. PMID- 27768931 TI - Fruit maturity and post-harvest environmental conditions influence the pre penetration stages of Monilinia infections in peaches. AB - Brown rot caused by the fungi Monilinia laxa (Aderhold and Ruhland) Honey, M. fructicola (Winter) Honey, or M. fructigena (Aderhold and Ruhland) is a serious fungal disease of peaches. The fungal infection process begins when fungal conidia germinate on the fruit surface to produce germ tubes and/or appressoria, and the incidence of brown rot increases as fruit approaches maturity. The interaction between the fungal infection process, peach maturity, and the environmental conditions is not well understood. Accordingly, the objectives of this investigation were to investigate germ tube and appressorial formation by M. laxa and M. fructicola when they were exposed to peach skin from mature and immature fruit at various temperatures and relative humidities (RHs). The greatest number of germ tubes was found when M. laxa or M. fructicola was incubated in culture medium which contained a skin extract of mature peaches. In contrast, the greatest number of appressoria was found when M. laxa or M. fructicola was incubated in culture medium which contained a skin extract of immature peaches. Although M. fructicola produced the same number of germ tubes and appressoria at 4 degrees C, M. fructicola produced more germ tubes than appressoria at temperatures higher than 10 degrees C. M. laxa produced more germ tubes than appressoria at any temperature, except when it was incubated for 48h on culture medium which contained a skin extract of immature peaches at 10 degrees C at 80% or 100% RH, or at 25 degrees C at 60% RH. M. laxa conidia germinated better than M. fructicola conidia at low temperatures. Germ tube and appressorial formation by Monilinia spp. were influenced by fruit postharvest handling. The number of germ tubes that were formed by M. laxa conidia was significantly greater than that for M. fructicola when the conidia were incubated at 100% RH, and this number increased after 3days of refrigeration. The number of appressoria that were formed by both Monilinia spp. also increased after 3 consecutive days of refrigeration. Negligible or no germination of M. fructicola and M. laxa conidia occurred when the RH was 60%. We concluded that the dissimilar abilities of M. laxa and M. fructicola to germinate and form appressoria at low temperatures conferred a competitive advantage to M. laxa to survive during fruit postharvest refrigeration and cold storage at 4 degrees C. PMID- 27768930 TI - Survey for the presence of ascaridoid larvae in the cinnamon flounder Pseudorhombus cinnamoneus (Temminck & Schlegel) (Pleuronectiformes: Paralichthyidae). AB - The cinnamon flounder Pseudorhombus cinnamoneus is a frequently consumed marine fish in China. However, the occurrence of ascaridoid larvae in P. cinnamoneus remains unclear. In the present study, a total of 85 P. cinnamoneus caught from the Yellow Sea (off Shidao, 36 degrees 52'57"N, 122 degrees 26'42"E) in 2011, which is located between mainland China and the Korean Peninsula, was investigated for ascaridoid larval infection. Four ascaridoid larval types, including Anisakis type I of Berland (1961), Hysterothylacium type of Smith (1983), Hysterothylacium type HL of Guo et al. (2014) and Raphidascaris type of Zhao et al. (2016), were detected in this important food fish. These larval types were identified as Anisakis pegreffii, Hysterothylacium aduncum, H. sinense and Raphidascaris lophii, respectively, using PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis and sequencing of the ITS region of nuclear ribosomal DNA (rDNA). The third-stage larvae of H. sinense are reported from Chinese waters for the first time. The prevalence of H. sinense was 100% and represents the predominant species of the ascaridoid larvae found in P. cinnamoneus. The prevalences of A. pegreffii and H. aduncum were 44.7% and 81.2%, respectively. Phylogenetic analyses based on ITS sequences were performed to elucidate the genetic relationships of these ascaridoid nematodes. The present study increases the knowledge and distribution of ascaridoid larvae in this area of Yellow Sea. The high prevalence of ascaridoid larvae in P. cinnamoneus shows that an assessment needs to be undertaken to assess the risk these parasites may pose to public health. PMID- 27768932 TI - Phenotyping and genetic characterization of Salmonella enterica isolates from Turkey revealing arise of different features specific to geography. AB - 192 Food samples (commonly consumed 8 food types), 355 animal samples (animal feces of bovine, ovine, goat and chicken) and 50 samples from clinical human cases in Sanliurfa city, Turkey in a year were collected to determine the Salmonella enterica subsp. enterica mosaic in Turkey. 161 Salmonella isolates represented 17 serotypes, 20 sequence types (STs) and 44 PFGE patterns (PTs). 3 serotypes, S. Enteritidis, S. Typhimurium and S. Kentucky, were recovered from three different hosts. The highest discriminatory power was obtained by PFGE (SID=0.945), followed by MLST (SID=0.902) and serotyping (SID=0.885) for all isolates. The prevalence of antimicrobial resistance genes (aadA1, aadA2, strA, strB, aphA1-Iab, blaTEM-1, blaPSE-1, tetA) was highly correlated with phenotypic profiles of aminoglycoside, beta-lactam and tetracycline groups (kappa >0.85). From our knowledge, this is the first study reporting spatial and temporal distribution of Salmonella species through phenotypic and genetic approaches over farm to fork chain in Turkey. Thus, our data provided further information for evolution, ecology and transmission of Salmonella in Turkey. PMID- 27768933 TI - A novel p38 MAPK indentified from Crassostrea hongkongensis and its involvement in host response to immune challenges. AB - p38 mitogen-activated protein kinases (MAPKs) are conserved serine/threonine specific kinases that are activated by various extracellular stimuli and play crucial regulatory roles in immunity, development and homeostasis. However, the function of p38s in mollusks, the second most diverse group of animals, is still poorly understood. In this study, a novel molluscan p38 (designated Chp38) was cloned and characterized from the Hong Kong oyster Crassostrea hongkongensis. Its full-length cDNA encoded a putative protein of 353 amino acids with a calculated molecular weight of approximately 40.3kDa. Similar to other reported p38 family proteins, the deduced Chp38 sequence contained a conserved dual phosphorylation TGY motif and a substrate binding site of ATRW. Phylogenetic analysis revealed that Chp38 was closest to its homolog from the Pacific oyster and belonged to the mollusk cluster. Quantitative real-time PCR analysis showed that Chp38 was constitutively expressed in all examined oyster tissues and developmental stages and that its expression in hemocytes was significantly up-regulated after pathogen (Vibrio alginolyticus and Staphylococcus haemolyticus) and PAMP (lipopolysaccharide and peptidoglycan) infections. Moreover, overexpression analysis revealed that Chp38 was localized in both the cytoplasm and nucleus of HEK293T cells and that it could significantly enhance AP-1 reporter gene activation in a dose-dependent manner. Altogether, these results provide the first experimental evidence of a functional p38 in oysters and suggest its involvement in the innate immunity of C. hongkongensis. PMID- 27768934 TI - The proteasome regulates collagen-induced platelet aggregation via nuclear-factor kappa-B (NFKB) activation. AB - INTRODUCTION: Platelets possess critical hemostatic functions in the system of thrombosis and hemostasis, which can be affected by a multitude of external factors. Previous research has shown that platelets have the capacity to synthesize proteins de novo and more recently a multicatalytic protein complex, the proteasome, has been discovered in platelets. Due to its vital function for cellular integrity, the proteasome has become a therapeutic target for anti proliferative drug therapies in cancer. Clinically thrombocytopenia is a frequent side-effect, but the aggregatory function of platelets also appears to be affected. Little is known however about underlying regulatory mechanisms and functional aspects of proteasome inhibition on platelets. Our study aims to investigate the role of the proteasome in regulating collagen-induced platelet aggregation and its interaction with NFkB in this context. MATERIAL AND METHODS: Using fluorescence activity assays, platelet aggregometry and immunoblotting, we investigate regulatory interactions of the proteasome and Nuclear-factor-kappa-B (NFkB) in collagen-induced platelet aggregation. RESULTS: We show that collagen induces proteasome activation in platelets and collagen-induced platelet aggregation can be reduced with proteasome inhibition by the specific inhibitor epoxomicin. This effect does not depend on Rho-kinase/ROCK activation or thromboxane release, but rather depends on NFkB activation. Inhibition of the proteasome prevented cleavage of NFkappaB-inhibitor protein IkappaBalpha and decreased NFkappaB activity after collagen stimulation. Inhibition of the NFkappaB-pathway in return reduced collagen-induced platelet proteasome activity and cleavage of proteasome substrates. CONCLUSIONS: This work offers novel explanations how the proteasome influences collagen-dependent platelet aggregation by involving non-genomic functions of NFkB. PMID- 27768935 TI - Recurrent pulmonary embolism during dabigatran treatment in a patient with immune thrombocytopenic purpura. PMID- 27768936 TI - Calcium-induced calmodulin conformational change. Electrochemical evaluation. AB - Calmodulin (CaM) is an essential protein present in all eukaryote cells, ranging from vertebrates to unicellular organisms. CaM is the most important Ca2+ signalling protein, composed of two domains, N- and C-terminal domains, linked by a flexible central alpha-helix, and is responsible for the regulation of numerous calcium-mediated signalling pathways. Four calcium ions bind to CaM, changing its conformation and determining how it recognizes and regulates its cellular targets. The oxidation mechanism of native and denatured CaM, at a glassy carbon electrode, was investigated using differential pulse voltammetry and electrochemical impedance spectroscopy. Native and denatured CaM presented only one oxidation peak, related to the tyrosine amino acid residue oxidation. Calcium induced calmodulin conformational change and the influence of Ca2+ concentration on the electrochemical behaviour of CaM were evaluated, and significant differences, in the tyrosine amino acid residue peak potential and current, in the absence and in the presence of calcium ions, were observed. Gravimetric measurements were performed with a graphite coated piezoelectric quartz crystal with adsorbed CaM, and calcium aggregation by CaM was demonstrated. PMID- 27768937 TI - Homeodomain proteins in action: similar DNA binding preferences, highly variable connectivity. AB - Homeodomain proteins are evolutionary conserved proteins present in the entire eukaryote kingdom. They execute functions that are essential for life, both in developing and adult organisms. Most homeodomain proteins act as transcription factors and bind DNA to control the activity of other genes. In contrast to their similar DNA binding specificity, homeodomain proteins execute highly diverse and context-dependent functions. Several factors, including genome accessibility, DNA shape, combinatorial binding and the ability to interact with many transcriptional partners, diversify the activity of homeodomain proteins and culminate in the activation of highly dynamic, context-specific transcriptional programs. Clarifying how homeodomain transcription factors work is central to our understanding of development, disease and evolution. PMID- 27768938 TI - Hyperammonaemia and associated factors in unprovoked convulsive seizures: A cross sectional study. AB - PURPOSE: Hyperammonaemia is frequently observed in patients who have experienced convulsive seizures. Although excessive muscle contraction is presumed to be responsible for the elevated levels of ammonia, the underlying mechanism is poorly understood. The present study aimed to identify the independent factors associated with ammonia elevation using large-scale multivariate analysis. METHODS: We conducted a cross-sectional study involving 379 adult patients who had been transported to our emergency department and treated for unprovoked convulsive seizures between August 2010 and September 2015. Elevation of venous plasma ammonia levels was set as the primary endpoint, and patients' clinical and laboratory data were obtained. Those with severe liver dysfunction, known hepatic encephalopathy, or convulsions due to cardiovascular or psychogenic causes, and those taking valproate were excluded. RESULTS: Using a cut-off value of 50MUg/dL, 183 patients (48.3%) were found to have elevated levels of plasma ammonia. Four factors were identified as independent variables associated with hyperammonaemia following seizures: elevated venous lactate, lowered venous pH, sex (male), and longer duration of convulsion. CONCLUSIONS: The results of the present study revealed independent factors associated with hyperammonaemia following unprovoked convulsive seizures in a larger scale and with more plausible statistical analysis. The authors further suggest that the excessive skeletal muscle contraction and/or respiratory failure during/after convulsive seizure may be the primary mechanism of hyperammonaemia. PMID- 27768939 TI - Encoding of low-quality DNA profiles as genotype probability matrices for improved profile comparisons, relatedness evaluation and database searches. AB - Many DNA profiles recovered from crime scene samples are of a quality that does not allow them to be searched against, nor entered into, databases. We propose a method for the comparison of profiles arising from two DNA samples, one or both of which can have multiple donors and be affected by low DNA template or degraded DNA. We compute likelihood ratios to evaluate the hypothesis that the two samples have a common DNA donor, and hypotheses specifying the relatedness of two donors. Our method uses a probability distribution for the genotype of the donor of interest in each sample. This distribution can be obtained from a statistical model, or we can exploit the ability of trained human experts to assess genotype probabilities, thus extracting much information that would be discarded by standard interpretation rules. Our method is compatible with established methods in simple settings, but is more widely applicable and can make better use of information than many current methods for the analysis of mixed-source, low template DNA profiles. It can accommodate uncertainty arising from relatedness instead of or in addition to uncertainty arising from noisy genotyping. We describe a computer program GPMDNA, available under an open source licence, to calculate LRs using the method presented in this paper. PMID- 27768940 TI - Solute lean Ti-Nb-Fe alloys: An exploratory study. AB - In this study, we explored the Ti-Nb-Fe system to find an optimal cost-effective composition with the lowest elastic modulus and the lowest added Nb content. Six Ti-(31-4x)Nb-(1+0.5x)Fe ingots were prepared and Nb was substituted with Fe, starting at Ti-31Nb-1.0Fe and going up to Ti-11Nb-3.5Fe (wt%). The ingots were subjected to cold rolling, recrystallization and solution treatment, followed by water-quenching (WQ), furnace cooling (FC) or step-quenching to 350 degrees C, which caused massive formation of isothermal omega phase. All the water-quenched alloys displayed athermal omega phase, which is apparently the result of fully collapsed beta phase. The Fe content improved the compressive strength of the alloys. In the FC alloys, substitution with Fe favored the formation of alpha phase instead of omega phase, giving rise to a solute-rich beta phase with a lattice parameter of 0.3249nm. Among the FC alloys, the lowest modulus of 83+/ 4GPa was obtained in the Ti-19Nb-2.5Fe alloy, which exhibited fine and well dispersed alpha precipitation and absence of omega phase. DSC experiments indicated that the experimental alloys showed varying phase stability during heating. PMID- 27768941 TI - Experimental evidence of large complete bandgaps in zig-zag lattice structures. AB - In this paper, experimental evidence of large complete bandgaps in a kind of light-weighted zig-zag lattice structure (ZLS) is presented. Ultrasonic experiments are conducted on the stainless steel slab designed with ZLS to detect the complete bandgaps. Also, the numerical simulations of the experiments by the finite element method are carried out. For comparison, we conduct the same experiments and numerical simulations on the stainless steel slab with straight lattice structure (SLS). Good agreement is obtained between the experimental and numerical results. The complete bandgaps of ZLS are successfully tested and no complete bandgap is found in SLS. The band structures and vibration modes of both ZLS and SLS are calculated via the finite element method to understand the experimental data. The effects of the geometry parameters of ZLS on the complete bandgaps are discussed in detail. PMID- 27768942 TI - Decolonization and life expectancy in the Caribbean. AB - Decolonization has brought political independence to half the Caribbean states in the last half of the 20th century, while the other states remain affiliated. Previous studies suggested a beneficial impact of affiliated status on population health, which may be mediated by more favorable economic development. We assessed how disparities in life expectancy between currently sovereign and affiliated states developed over time, whether decolonization coincided with changes in life expectancy, and whether decolonization coincided with similar changes in GDP per capita. Time-series data on life expectancy and related variables, GDP per capita and political status were collected from harmonized databases. We quantified variations in life expectancy by current political status during the 1950-2010 period. We assessed whether decolonization coincided with life expectancy trend changes by: 1. calculating the annual changes before and after independence, and 2. evaluating trend breaks in a predefined period during decolonization using joinpoint analyses. Similar analyses were undertaken for GDP per capita. Life expectancy in currently sovereign Caribbean states was already lower than in affiliated states before political independence. Overall, decolonization coincided with reductions in life expectancy growth, but not with reductions in economic growth, and changes in life expectancy growth in the decade after independence did not correspond with changes in economic performance. The widening of the life expectancy gap between currently sovereign and affiliated states accelerated in the 1990's and continues to increase. Despite considerable life expectancy gains in all Caribbean states, life expectancy in currently sovereign states increasingly lags behind that of states which remained affiliated. Our results indicate that changing economic conditions were not the main determinant of the unfavorable trends in life expectancy during and after decolonization. Circumstantial evidence points to the weakening of bureaucracies during decolonization underlying the uneven life expectancy developments of currently affiliated and sovereign states. PMID- 27768943 TI - State risk discourse and the regulatory preservation of traditional medicine knowledge: The case of acupuncture in Ontario, Canada. AB - Several United Nations bodies have advised countries to actively preserve Traditional Medicine (TM) knowledge and prevent its misappropriation in regulatory structures. To help advance decision-making around this complex regulatory issue, we examine the relationship between risk discourse, epistemology and policy. This study presents a critical, postcolonial analysis of divergent risk discourses elaborated in two contrasting Ontario (Canada) government reports preceding that jurisdiction's regulation of acupuncture, the world's most widely practised TM therapy. The earlier (1996) report, produced when Ontario's regulatory lobby was largely comprised of Chinese medicine practitioners, presents a risk discourse inclusive of biomedical and TM knowledge claims, emphasizing the principle of regulatory 'equity' as well as historical and sociocultural considerations. Reflecting the interests of an increasingly biomedical practitioner lobby, the later (2001) report uses implicit discursive means to exclusively privilege Western scientific perspectives on risk. This report's policy recommendations, we argue, suggest misappropriation of TM knowledge. We advise regulators to consider equitable adaptations to existing policy structures, and to explicitly include TM evidentiary perspectives in their pre-regulatory assessments. PMID- 27768944 TI - Attentional and motor impulsivity interactively predict 'food addiction' in obese individuals. AB - BACKGROUND: Impulsivity is a multifaceted construct and constitutes a common risk factor for a range of behaviors associated with poor self-control (e.g., substance use or binge eating). The short form of the Barratt Impulsiveness Scale (BIS-15) measures impulsive behaviors related to attentional (inability to focus attention or concentrate), motor (acting without thinking), and non-planning (lack of future orientation or forethought) impulsivity. Eating-related measures appear to be particularly related to attentional and motor impulsivity and recent findings suggest that interactive effects between these two facets may play a role in eating- and weight-regulation. METHODS: One-hundred thirty-three obese individuals presenting for bariatric surgery (77.4% female) completed the BIS-15 and the Yale Food Addiction Scale (YFAS) 2.0, which measures addiction-like eating based on the eleven symptoms of substance use disorder outlined in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders. RESULTS: Sixty-three participants (47.4%) were classified as being 'food addicted'. Scores on attentional and motor impulsivity interactively predicted 'food addiction' status: higher attentional impulsivity was associated with a higher likelihood of receiving a YFAS 2.0 diagnosis only at high (+1 SD), but not at low (-1 SD) levels of motor impulsivity. CONCLUSIONS: Results support previous findings showing that non-planning impulsivity does not appear to play a role in eating-related self-regulation. Furthermore, this is the first study that shows interactive effects between different impulsivity facets when predicting 'food addiction' in obese individuals. Self-regulatory failure in eating-regulation (e.g., addiction-like overeating) may particularly emerge when both attentional and motor impulsivity levels are elevated. PMID- 27768945 TI - Right atrial ball thrombus after an intraatrial repair in a 3-year-old girl. AB - We describe the case of a 3-year-old girl who presented with a large, mobile, ball mass in the right atrium on routine transthoracic echocardiography at one year after an intraatrial repair. Considering the risk of pulmonary embolization, emergent surgery was successfully performed to remove the mass, and histopathological examination revealed that it was a ball thrombus with a fibrin clot. PMID- 27768946 TI - Hypoxia alters testicular functions of marine medaka through microRNAs regulation. AB - Hypoxia is a global environmental concern and poses a significant threat to aquatic ecosystems, including the sustainability of natural fish populations. The deleterious effects of hypoxia on fish reproductive fitness, as mediated by disruption of sex hormones and gene expression along the Brain-Pituitary-Gonad axis, have been well documented. Recently, we further demonstrated that the observed disruption of steroidogenesis in the ovary of marine medaka Oryzias melastigma is mediated through microRNAs (miRNAs). More importantly, we reported the transgenerational epigenetic effect of hypoxia on the male reproductive impairment of marine medaka. This study attempts to elucidate the function of miRNAs and its potential role in the transgenerational effect of hypoxia in the male medaka testis, using small RNA sequencing. A total of 558 miRNAs were found in the testis, of which 9 were significant upregulated and 5 were downregulated by hypoxia. Bioinformatics analysis further revealed that among the 2885 genes targeted by the hypoxia-responsive miRNAs, many are closely related to stress response, cell cycle, epigenetic modification, sugar metabolism and cell motion. Furthermore, the integrated analysis of transcriptome data and the result of target gene prediction demonstrated 108 genes and 65 genes were concordantly upregulated and downregulated, respectively. In which, euchromatic histone-lysine N-methyltransferase 2, the epigenetic regulator of transgenerational reproductive impairment caused by hypoxia, is found to be targeted by miR-125-5p. The present findings not only reveal that miRNAs are crucial downstream mediators of hypoxic stress in fish male gonad, but also shed light on the underlying epigenetic mechanism for the reproductive impairments of hypoxia on male fish, including the observed transgenerational effects. PMID- 27768947 TI - Effects of crude oil on in situ cardiac function in young adult mahi-mahi (Coryphaena hippurus). AB - Exposure to polycyclic aromatic hydrocarbons (PAH) negatively impacts exercise performance in fish species but the physiological modifications that result in this phenotype are poorly understood. Prior studies have shown that embryonic and juvenile mahi-mahi (Coryphaeus hippurus) exposed to PAH exhibit morphological abnormalities, altered cardiac development and reduced swimming performance. It has been suggested that cardiovascular function inhibited by PAH exposure accounts for the compromised exercise performance in fish species. In this study we used in-situ techniques to measure hemodynamic responses of young adult mahi mahi exposed to PAH for 24h. The data indicate that stroke volume was reduced 44% in mahi-mahi exposed to 9.6+/-2.7MUgl-1 geometric mean PAH (?PAH) and resulted in a 39% reduction in cardiac output and a 52% reduction in stroke work. Maximal change in pressure over change in time was 28% lower in mahi-mahi exposed to this level of ?PAH. Mean intraventricular pressures and heart rate were not significantly changed. This study suggests exposure to environmentally relevant PAH concentrations impairs aspects of cardiovascular function in mahi-mahi. PMID- 27768948 TI - Biocatalysts for methane conversion: big progress on breaking a small substrate. AB - Nature utilizes two groups of enzymes to catalyze methane conversions, methyl coenzyme M reductases (MCRs) and methane monooxygenases (MMOs). These enzymes have been difficult to incorporate into industrial processes due to their complexity, poor stability, and lack of recombinant tractability. Despite these issues, new ways of preparing and stabilizing these enzymes have recently been discovered, and new mechanistic insight into how MCRs and MMOs break the C-H bond in nature's most inert hydrocarbon have been obtained. This review focuses on recent findings in the methane biocatalysis field, and discusses the impact of these finding on designing MMO and MCR-based biotechnologies. PMID- 27768950 TI - Molecular mechanism of the binding of 3,4,5-tri-O-caffeoylquinic acid to human serum albumin: Saturation transfer difference NMR, multi-spectroscopy, and docking studies. AB - As a natural dietary polyphenol, 3,4,5-tri-O-caffeoylquinic acid (3,4,5-triCQA) exhibits numerous stronger pharmacological activities than that of its analogues. Studies on interaction between 3,4,5-triCQA and protein are very helpful for understanding the mechanism of these enhanced biological functions. In this study, 1H saturation transfer difference NMR (1H STD-NMR) combined with multi spectroscopy were used to probe the interaction of 3,4,5-triCQA with human serum albumin (HSA). Both qualitative and quantitative 1H STD-NMR indicated that 3,4,5 triCQA can specifically bind to HSA at the favored Sudlow's site II with caffeoyl groups as the main recognizable moiety. Fluorescence emission spectra showed that Stern-Volmer quenching constant (KSV) decreases from 10.132*104M-1 to 9.711*104M 1 with temperature raise, indicating that 3,4,5-triCQA quenches HSA fluorescence through a static mechanism. Binding constant (Kb=5.557*105M-1) and the number of binding sites (n~1) at 298K suggested that 3,4,5-triCQA only occupies one site in HSA with high affinity. Enthalpy (DeltaH=-28.802kJ/mol) and entropy (DeltaS=12.429J/mol/K) change proved the dominant role of electrostatic interaction in binding process. Multi-spectroscopic analysis also confirmed that the protein secondary structure and hydrophobicity were significantly affected. Molecular docking further verified the NMR and spectroscopic results. Overall, 3,4,5-triCQA exhibited a strong albumin affinity owing to the plural caffeoyl groups, which lead to the enhanced pharmacological activities. This study clarified the molecular mechanism of 3,4,5-triCQA in binding to HSA, and the findings are beneficial for the research on polyphenol-like drugs and antioxidants in foods or cosmetics. PMID- 27768949 TI - Biofuel metabolic engineering with biosensors. AB - Metabolic engineering offers the potential to renewably produce important classes of chemicals, particularly biofuels, at an industrial scale. DNA synthesis and editing techniques can generate large pathway libraries, yet identifying the best variants is slow and cumbersome. Traditionally, analytical methods like chromatography and mass spectrometry have been used to evaluate pathway variants, but such techniques cannot be performed with high throughput. Biosensors - genetically encoded components that actuate a cellular output in response to a change in metabolite concentration - are therefore a promising tool for rapid and high-throughput evaluation of candidate pathway variants. Applying biosensors can also dynamically tune pathways in response to metabolic changes, improving balance and productivity. Here, we describe the major classes of biosensors and briefly highlight recent progress in applying them to biofuel-related metabolic pathway engineering. PMID- 27768951 TI - Protective effect of gelatin peptides from pacific cod skin against photoaging by inhibiting the expression of MMPs via MAPK signaling pathway. AB - Chronic exposure to ultraviolet (UV) irradiation causes skin photoaging. This study was undertaken to identify the anti-photoaging mechanisms of gelatin hydrolysate (CH) derived from pacific cod skin. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA assays were used to investigate the effects of CH on matrix metalloproteinases (MMPs) and the signaling pathways after UV irradiation by using a mice skin photoaging model. The average molecular weight of CH was 1200Da, and 273/1000 residues were hydrophobic, Gly-Pro and Gly-Leu sequences and Arg at C-terminus appeared frequently in CH. CH improved pathological changes of collagen fibers and significantly inhibited collagen content reduction in photoaging skin. Moreover, CH blocked the up-regulated expression of interstitial collagenase (MMP-1), stromelysin 1 (MMP-3), and gelatinase (MMP-9) in photoaging skin. Besides, CH suppressed the activities of MMPs by increasing the contents of tissue inhibitors of matrix metalloproteinases (TIMPs). CH significantly reduced the UV irradiation dependent up-regulated phosphorylation of ERK and p38 in the mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, it inhibited the activation of activator protein 1 (AP-1) by down-regulating the mRNA level of c-Jun and c Fos, which are the two transcription factors responsible for the regulation of MMPs expression. CH can effectively protect against UV irradiation-induced skin photoaging by inhibiting the expression and the activity of MMPs. PMID- 27768952 TI - A biophysical investigation on the binding of proflavine with human hemoglobin: Insights from spectroscopy, thermodynamics and AFM studies. AB - Interaction of proflavine with hemoglobin (Hgb) was studied employing spectroscopy, calorimetry, and atomic force microscopy. The equilibrium constant was found to be of the order 104M-1. The quenching of Hgb fluorescence by proflavine was due to the complex formation. Calculation of the molecular distance (r) between the donor (beta-Trp37 of Hgb) and acceptor (proflavine) suggested that energy can be efficiently transferred from the beta-Trp37 residue at the alpha1beta2 interface of the protein to the dye. Proflavine induced significant secondary structural changes in Hgb. Synchronous fluorescence studies showed that proflavine altered the microenvironment around the tryptophan residues to a greater extent than the tyrosine residues. Circular dichroism spectral studies showed that proflavine caused significant reduction in the alpha helical content of Hgb. The esterase activity assay further complemented the circular dichroism data. The Soret band intensity of Hgb decreased upon complexation. Differential scanning calorimetry and circular dichroism melting results revealed that proflavine induced destabilization of Hgb. The binding was driven by both positive entropy and negative enthalpy. Atomic force microscopy studies revealed that the essential morphological features of hemoglobin were retained in the presence of proflavine. Overall, insights on the photophysical aspects and energetics of the binding of proflavine with Hgb are presented. PMID- 27768953 TI - Photodynamic inactivation of methicillin-resistant Staphylococcus aureus and Escherichia coli: A metalloporphyrin comparison. AB - Increasing rates of antibiotic resistance coupled with the lack of novel antibiotics threatens proper clinical treatment and jeopardizes their use in prevention. A photodynamic approach appears to be an innovative treatment option, even for multi-drug resistant strains of bacteria. Three components are utilized in photodynamic inactivation: a photosensitizer, light source, and oxygen. Variations in photosensitizers strongly influence microbial binding and bactericidal activity. In this study, four different cationic metalloporphyrins (Cu2+, Fe2+, Pd2+, Zn2+) were compared to the free-base ligand 5,10,15,20 tetrakis(N-methylpyridinium-4-yl)porphyrin regarding their electronic properties and generation of reactive oxygen species upon subsequent 405nm violet-blue irradiation. Staphylococcus aureus and Escherichia coli were used as representatives of Gram-positive and -negative, respectively, to assess bactericidal effects by the photodynamic process. Bacterial cultures were pre incubated with porphyrins and exposed to varying doses of 405nm irradiation (0 30J/cm2). Metalloporphyrins containing Cu2+ and Fe2+ demonstrated minimal effects on viability. Pronounced bactericidal activity was evident with free-base ligand, Zn2+, and Pd2+; though significantly stronger effects were apparent with Pd2+. Photodynamic killing was directly proportional to reactive oxygen species production post-illumination. These data provide new insight into the influence of metal chelation on photosensitizer activity on bactericidal singlet oxygen production. The strong anti-microbial photodynamic action through the use of a portable light-emitting diode over short time intervals (seconds) provides support for its potential use in self-treatment. PMID- 27768954 TI - Oxygen toxicity and antioxidative responses in arsenic stressed Helianthus annuus L. seedlings against UV-B. AB - In order to know the impact of elevated level of UV-B on arsenic stressed Helianthus annuus L. var. DRSF-113 plants, certain physiological (growth - root and shoot lengths, their fresh masses and leaf area; photosynthetic competence and respiration) and biochemical parameters (pigments - Chl a and b, Car, anthocyanin and flavonoids; reactive oxygen species - superoxide radicals, H2O2; reactive carbonyl group, electrolyte leakage; antioxidants - superoxide dismutase, peroxidise, catalase, glutathione-S-transferase, proline) of their seedlings were analysed under the simultaneous exposures of two arsenic doses (6mgkg-1 soil, As1; and 12mgkg-1 soil, As2) and two UV-B doses (1.2kJm-2d-1, UV B1; and 3.6kJm-2d-1, UV-B2). As1 and As2 alone declined all the studied growth parameters - along with photosynthetic pigments which were further aggravated after the simultaneous exposures of predefined levels of UV-B. Each As exposure was accompanied by significant accumulation of As in root, shoot and leaves and was substantiated by simultaneous exposures of UV-B doses which manifested into suppressed growth, decreased chlorophyll contents and photosynthesis. In similar conditions, other photo-shielding pigments, viz. carotenoids, anthocyanin and flavonoids along with respiration and oxidative stress markers such as O2*-, H2O2; and indicators of cell membrane damage like MDA (malondialdehyde), RCG (reactive carbonyl group), electrolyte leakage were enhanced by As, and became more pronounced after the simultaneous exposures of UV-B doses. As doses stimulated the activities of SOD, POD, CAT, GST and Pro which got further accelerated after the simultaneous exposures of UV-B doses. PMID- 27768955 TI - Seasonal variations in photosystem I compared with photosystem II of three alpine evergreen broad-leaf tree species. AB - Low temperature associated with high light can induce photoinhibition of photosystem I (PSI) and photosystem II (PSII). However, the photosynthetic electron flow and specific photoprotective responses in alpine evergreen broad leaf plants in winter is unclear. We analyzed seasonal changes in PSI and PSII activities, and energy quenching in PSI and PSII in three alpine broad-leaf tree species, Quercus guyavifolia (Fagaceae), Rhododendron decorum (Ericaceae), Euonymus tingens (Celastraceae). In winter, PSII activity remained stable in Q. guyavifolia but decreased significantly in R. decorum and E. tingens. Q. guyavifolia showed much higher capacities of cyclic electron flow (CEF), water water cycle (WWC), non-photochemical quenching (NPQ) than R. decorum and E. tingens in winter. These results indicated that in alpine evergreen broad-leaf tree species the PSII activity in winter was closely related to these photoprotective mechanisms. Interestingly, unlike PSII, PSI activity was maintained stable in winter in the three species. Meanwhile, photosynthetic electron flow from PSII to PSI (ETRII) was much higher in Q. guyavifolia, suggesting that the mechanisms protecting PSI activity against photoinhibition in winter differed among the three species. A high level of CEF contributed the stability of PSI activity in Q. guyavifolia. By comparison, R. decorum and E. tingens prevented PSI photoinhibition through depression of electron transport to PSI. Taking together, CEF, WWC and NPQ played important roles in coping with excess light energy in winter for alpine evergreen broad-leaf tree species. PMID- 27768956 TI - Umbilical cord blood PBDEs concentrations are associated with placental DNA methylation. AB - BACKGROUND: In utero polybrominated diphenyl ethers (PBDEs) exposure has been associated with adverse fetal growth. Alterations in placental DNA methylation might mediate those adverse effects. OBJECTIVES: To examine the associations between in utero PBDEs exposure and DNA methylation in human placenta. METHODS: Eighty apparently healthy mother-newborn pairs delivering at the Second Affiliated Hospital of Wenzhou Medical College were enrolled in this study. Placental DNA methylation of LINE1, NR3C1 and IGF2 was measured by quantitative polymerase chain reaction-pyrosequencing. In utero PBDEs exposure was assessed by measuring umbilical cord blood PBDEs concentrations. RESULTS: For LINE-1, higher levels of BDE-66 exposure were associated with decreased DNA methylation (beta= 0.9, 95% CI, -1.8 to -0.1); For NR3C1, BDE-153 concentrations was significantly inversely associated with DNA methylation (beta=-2.0, 95% CI, -3.7 to -0.2); For IGF2, elevated concentrations of both BDE-153 (beta=-1.7; 95% CI, -3.0 to -0.4) and BDE-209 (beta=-1.0; 95% CI, -1. 9 to -0.1) were significantly associated with decreased DNA methylation. CONCLUSIONS: We found that placental DNA methylation is associated with in utero PBDEs exposure. Changes in placental DNA methylation might be part of the underlying biological pathway between in utero PBDEs exposure and adverse fetal growth. PMID- 27768957 TI - CNS disease models with human pluripotent stem cells in the CRISPR age. AB - In vitro differentiation of human pluripotent stem cells provides a systematic platform to investigate the physiological development and function of the human nervous system, as well as the etiology and consequence when these processes go awry. Recent development in three-dimensional (3D) organotypic culture systems allows modeling of the complex structure formation of the human CNS, and the intricate interactions between various resident neuronal and glial cell types. Combined with an ever-expanding genome editing and regulation toolkit such as CRISPR/Cas9, it is now a possibility to study human neurological disease in the relevant molecular, cellular and anatomical context. In this article, we review recent progress in 3D neural culture and the implications for disease modeling. PMID- 27768958 TI - Impaired toll like receptor 9 response in pulmonary tuberculosis. AB - BACKGROUND & AIM: Innate immune responses are important in susceptibility to pulmonary tuberculosis (TB). In order to test the hypothesis that Toll-like receptor (TLR) 2 function would be abnormal in patients with active pulmonary TB we compared the cytokine responses of peripheral blood mononuclear cells (PBMC) to innate immune ligands in a case-control study. METHODS: PBMC from 19 untreated pulmonary TB patients, 17 healthy controls, and 11 treated pulmonary TB patients, were cultured for 24h with TLR 2 ligand (PAM-CSK) and other TLR ligands (muramyl dipeptide, flagellin, lipopolysaccharide (LPS), CpG oligodeoxynucleotide (CpG ODN)). Interleukin-8 (IL-8) was estimated in the supernatant by ELISA. Messenger RNA expression for inflammatory cytokines was quantitated using real time PCR. RESULTS: The important findings were (1) reduced PBMC secretion of IL-8 in response to all ligands in active TB; (2) normal to increased PBMC secretion of IL-8 in response to all ligands except CpG ODN (TLR 9 ligand) in TB patients who had recovered; (3) absence of difference in mRNA expression for a consortium of inflammatory pathway genes between healthy controls, active pulmonary tuberculosis and treated pulmonary tuberculosis patients. CONCLUSION: There was a generalized post-translational suppression of the IL-8 response to innate immune ligands in active TB. There appears to be a defect of TLR 9 signaling in patients with tuberculosis, the nature of which needs to be further explored. PMID- 27768959 TI - Silencing IGF-II impairs C-myc and N-ras expressions of SMMC-7721 cells via suppressing FAK/PI3K/Akt signaling pathway. AB - Emerging evidence confirms that insulin-like growth factor -II (IGF-II), oncogenes C-myc and N-ras are an essential regulator for development and growth in hepatocellular carcinoma (HCC). Although our previous study also indicated that IGF-II might upregulate levels of oncogenes C-myc and N-ras in hepatoma carcinoma cells, the molecular mechanism had not been fully elucidated. Herein, we successfully silenced IGF-II expression in SMCC-7721 cells by small RNA interference. Functional analysis showed that knockdown of IGF-II significantly suppressed growth and proliferation of SMMC-7721 cells and decreased C-myc and N ras mRNA and protein levels. And this function was mediated by the FAK/PI3K/Akt signaling pathway. Taken together, IGF-II siRNA inactivates the FAK/PI3K/Akt signaling pathway, and further reduces cell proliferation, N-ras and C-myc levels in SMMC-7721 cells. Especially, understanding the relationship between IGF-II and oncogenes N-ras and C-myc in cancer cells will provide novel clues for clinic HCC treatment in the future. PMID- 27768960 TI - Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases. AB - Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occur in other types of dementia such dementia with Lewy bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n-3 long-chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the beta-amyloidogenic pathway, including beta-amyloid precursor protein, presenilin 1, beta-secretase, and PrP, are redistributed between lipid rafts and nonraft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy body diseases. In addition, redistribution of proteins linked to the beta amyloidogenic pathway in DLB can facilitate generation of beta-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly beta-amyloid deposition, in DLB. PMID- 27768961 TI - Physcion 8-O-beta-glucopyranoside suppresses the metastasis of breast cancer in vitro and in vivo by modulating DNMT1. AB - BACKGROUND: The present study is designed to explore the metastasis-inhibitory effect of physcion 8-O-beta-glucopyranoside (PG) in human breast cancer, and the mechanisms underlying its role in tumor metastasis. METHODS: Both in vitro and in vivo studies were conducted. Cell migration and invasion were analyzed by transwell assay. The translocation of beta-catenin from the nucleus to cytoplasm membrane was demonstrated by immunofluorescent staining. The expression of signaling molecules was determined by Western blot or qRT-PCR. RESULTS: The present study showed that PG suppressed the migration, invasion, and EMT of breast cancer cells MDA-MB-231 in a dose-dependent manner. The results also revealed that impairment of the metastatic potential caused by PG was associated with the activation of AMPK and downregulation of both DNMT1 and Sp1. Moreover, the data from the in vivo model also supported the in vitro findings, which showed that inhibition of metastasis by PG was associated with the downregulation of DNMT1 and Sp1 as well as increased level of phosphorylated AMPK. CONCLUSION: The present study showed that PG could suppress the metastasis of breast cancer, which highlighted a novel pharmacological application of this compound. Given the aggressive properties of breast cancer, the current study suggests that PG can serve as a safe therapeutic agent for suppressing breast cancer metastasis, although additional data is necessitated. PMID- 27768962 TI - Multiconfigurational and DFT analyses of the electromeric formulation and UV-vis absorption spectra of the superoxide adduct of ferrous superoxide reductase. AB - The putative initial adduct of ferrous superoxide reductase (SOR) with superoxide has been alternatively formulated as ferric-peroxo or ferrous-superoxo. The ~600 nm UV-vis absorption band proposed to be assigned to this adduct (either as sole intermediate in the SOR catalytic cycle, or as one of the two intermediates) has recently been interpreted as due to a ligand-to-metal charge transfer, involving thiolate and superoxide in a ferrous complex, contrary to an alternative assignment as a predominantly cysteine thiolate-to-ferric charge transfer in a ferric-peroxo electromer. In an attempt to clarify the electromeric formulation of this adduct, we report a computational study using a multiconfigurational complete active space self-consistent field (MC-CASSCF) wave function approach as well as modelling the UV-vis absorption spectra with time-dependent density functional theory (TD-DFT). The MC-CASSCF calculations disclose a weak interaction between iron and the dioxygenic ligand and a dominant configuration with an essentially ferrous-superoxo character. The computed UV-vis absorption spectra reveal a marked dependence on the choice of density functional - both in terms of location of bands and in terms of orbital contributors. For the main band in the visible region, besides the recently reported thiolate-to-superoxide charge transfer, a more salient, and less functional-dependent, feature is a thiolate-to-ferric iron charge transfer, consistent with a ferric-peroxo electromer. By contrast, the computed UV-vis spectra of a ferric-hydroperoxo SOR model match distinctly better (and with no qualitative dependence on the DFT methodology) the 600-nm band as due to a mainly thiolate-to-ferric character - supporting the assignment of the SOR "600-nm intermediate" as a S=5/2 ferric hydroperoxo species. PMID- 27768963 TI - The influence of knee alignment on lower extremity kinetics during squats. AB - The squat is an assessment of lower extremity alignment during movement, however there is little information regarding altered joint kinetics during poorly performed squats. The purpose of this study was to examine changes in joint kinetics and power from altered knee alignment during a squat. Thirty participants completed squats while displacing the knee medially, anteriorly, and with neutral alignment (control). Sagittal and frontal plane torques at the ankle, knee, and hip were altered in the descending and ascending phase of the squat in both the medial and anterior malaligned squat compared to the control squat. Ankle and trunk power increased and hip power decreased in the medial malaligned squat compared to the control squat. Ankle, knee, and trunk power increased and hip power decreased in the anterior malaligned squat compared to the control squat. Changes in joint torques and power during malaligned squats suggest that altered knee alignment increases ankle and trunk involvement to execute the movement. Increased anterior knee excursion during squatting may also lead to persistent altered loading of the ankle and knee. Sports medicine professionals using the squat for quadriceps strengthening must consider knee alignment to reduce ankle and trunk involvement during the movement. PMID- 27768964 TI - Spontaneous coronary dissection misdiagnosed as Takotsubo's Cardiomyopathy. PMID- 27768965 TI - Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular disease in adult patients with type 1 diabetes. AB - BACKGROUND: Recent studies suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased prevalence of cardiovascular disease (CVD) in type 1 diabetes. We assessed whether NAFLD also predicts the risk of incident CVD events in type 1 diabetic adults. METHODS: We studied a retrospective cohort of 286 type 1 diabetic outpatients (mean age 43+/-14years; median duration of diabetes 17 [10-30] years) without secondary causes of chronic liver diseases, who were followed for a mean period of 5.3years for the occurrence of incident CVD events (a combined endpoint inclusive of nonfatal ischemic heart disease, nonfatal ischemic stroke or coronary/peripheral artery revascularizations). NAFLD was diagnosed by ultrasonography. RESULTS: Overall, 150 patients (52.4%) had NAFLD at baseline. During a mean follow-up of 5.3+/ 2.1years, 28 patients developed incident CVD events. Patients with NAFLD had a higher incidence of CVD events than those without NAFLD (17.3% vs. 1.5%, p<0.001). NAFLD was associated with an increased risk of CVD events (hazard ratio [HR] 8.16, 95% confidence interval [CI] 1.9-35.1, p<0.005). Adjustments for age, sex, body mass index, smoking, diabetes duration, hemoglobin A1c, dyslipidemia, hypertension, chronic kidney disease, prior ischemic heart disease and serum gamma-glutamyltransferase levels did not appreciably attenuate the association between NAFLD and incident CVD (adjusted-HR 6.73, 95% CI 1.2-38.1, p=0.031). CONCLUSIONS: This is the first observational study to demonstrate that NAFLD is associated with an increased risk of incident CVD events in type 1 diabetic adults, independently of established CVD risk factors and diabetes-related variables. PMID- 27768966 TI - A multicenter study assessing uterine cavity width in over 400 nulliparous women seeking IUD insertion using 2D and 3D sonography. AB - BACKGROUND: In the selection of an appropriate IUD little consideration is placed on device size or adequacy of fit. Properly fitting IUDs will likely lead to less adverse effects or patient discomfort resulting in enhanced continuation of use. METHODS: A multicenter study conducted at 7 centers in 410 nulliparous women, to measure the width of the uterine cavity using 2D and 3D ultrasound. RESULTS: Measurements of maximal fundal cavity width was performed by either 2D or 3D ultrasound by experienced sonographists. The mean width of the uterine cavity in the fundus was 22.2mm (range 6.0-41.1mm). There was no statistical difference in the values whether determined by 2D (n=258) or 3D (n=152) measurements having a median value of 22.5mm and 21.6mm, respectively, 79% of women had a uterine cavity width between 15mm and 28mm, 32%<20mm and 6.8%<15mm, respectively. DISCUSSION: Uterine cavities in nulliparous women are narrow and rarely wide enough to fit conventional IUDs. Gross discrepancy between the IUD and the uterine cavity leads to side effect (e.g., expulsion, embedment, bleeding, pain) and early discontinuation. Historically, devices too large for the uterine cavity have been routinely inserted which may account for their 5-year continuation rates being only 40 to 50%. Our study suggests that preprocedural 2D or 3D sonography to measure the width of the uterine cavity may result in the selection of a suitable IUD to maximize continuation of use. Measurement of the cavity width is not necessary with a frameless IUD. PMID- 27768967 TI - The impact of maternal adiposity specialization on infant birthweight: upper versus lower body fat. AB - BACKGROUND: The specialization of human fat deposits is an inquiry of special importance in the study of fetal growth. It has been theorized that maternal lower-body fat is designated specifically for lactation and not for the growth of the fetus. OBJECTIVE: Our goal was to compare the contributions of maternal upper body versus lower-body adiposity to infant birth weight. We hypothesized that upper-body adiposity would be strongly associated with infant birth weight and that lower-body adiposity would be weakly or negligibly associated with infant birth weight-after adjusting for known determinants. STUDY DESIGN: In this prospective cohort study, 355 women initiated medical pre-natal care during the first trimester of pregnancy at The University of Oklahoma Health Sciences Center during 1990-1993. Maternal anthropometric measurements were assessed at the first clinic visit: (a) height; (b) weight; (c) circumferences of the upper arm, forearm, and thigh; and, (d) skin-fold measurements of the bicep, subscapular region, and thigh. RESULTS: Infant birth weight was regressed on known major determinants to create the foundational model. Maternal anthropometric variables subsequently were added one at a time into this multiple regression model. The highest contribution by a single anthropometric variable to infant birthweight was, in order: subscapular skin-fold, forearm circumference, and thigh circumference. With one upper-body (subscapular skin-fold) and one lower-body (circumference of the thigh) adiposity measure in the model, the z-score regression coefficient (s.e.) was 85.7g (30.8) [p=0.0057] for maternal subscapular skin-fold and 19.0g (31.6) [p=0.5477] for circumference of the thigh. When the second-best upper-body contributor to infant birthweight (circumference of the forearm) was entered with one lower-body measure into the model, the z score regression coefficient (s.e.) was 77.5g (38.5) [p=0.0451] for maternal forearm circumference and 14.1g (38.5) [p=0.7146] for circumference of the thigh. When both subscapular skinfold and forearm circumference were added to the model in place of BMI, the explained variance (r2=0.5478) was similar to the model using BMI (r2=0.5487). CONCLUSION: Upper-body adiposity - whether operationalized by subscapular skin-fold or circumference of the forearm - was a markedly larger determinant of infant birth weight than lower-body adiposity. PMID- 27768968 TI - Expanding clinical laboratory tobacco product evaluation methods to loose-leaf tobacco vaporizers. AB - BACKGROUND: Novel tobacco products entering the US market include electronic cigarettes (ECIGs) and products advertised to "heat, not burn" tobacco. There is a growing literature regarding the acute effects of ECIGs. Less is known about "heat, not burn" products. This study's purpose was to expand existing clinical laboratory methods to examine, in cigarette smokers, the acute effects of a "heat, not burn" "loose-leaf tobacco vaporizer" (LLTV). METHODS: Plasma nicotine and breath carbon monoxide (CO) concentration and tobacco abstinence symptom severity were measured before and after two 10-puff (30-s interpuff interval) product use bouts separated by 60min. LLTV effects were compared to participants' own brand (OB) cigarettes and an ECIG (3.3V; 1.5ohm; 18mg/ml nicotine). RESULTS: Relative to OB, LLTV increased plasma nicotine concentration to a lesser degree, did not increase CO, and did not appear to reduce abstinence symptoms as effectively. Relative to ECIG, LLTV nicotine and CO delivery and abstinence symptom suppression did not differ. Participants reported that both the LLTV and ECIG were significantly less satisfying than OB. CONCLUSIONS: Results demonstrate that LLTVs are capable of delivering nicotine and suppressing tobacco abstinence symptoms partially; acute effects of these products can be evaluated using existing clinical laboratory methods. Results can inform tobacco product regulation and may be predictive of the extent that these products have the potential to benefit or harm overall public health. PMID- 27768969 TI - Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1alpha pathway. AB - Substantial evidence has shown that the oxidative damage to hippocampal neurons is associated with the cognitive impairment induced by adverse stimuli during gestation named prenatal stress (PS). Taurine, a conditionally essential amino acid, possesses multiple roles in the brain as a neuromodulator or antioxidant. In this study, to explore the roles of taurine in PS-induced learning and memory impairment, prenatal restraint stress was set up and Morris water maze (MWM) was employed for testing the cognitive function in the one-month-old rat offspring. The mitochondrial reactive oxygen species (ROS) level,mitochondrial membrane potential (MMP), ATP and cytochrome c oxidase (CcO) activity and apoptosis related proteins in the hippocampus were detected. The activity of the Akt-cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha) pathway in the hippocampus was measured. The results showed that high dosage of taurine administration in the early postnatal period attenuated impairment of spatial learning and memory induced by PS. Meanwhile, taurine administration diminished the increase in mitochondrial ROS, and recovered the reduction of MMP, ATP level and the activities of CcO, superoxide dismutase 2 (SOD2) and catalase induced by PS in the hippocampus. In addition, taurine administration recovered PS-suppressed SOD2 expression level. Taurine administration blocked PS-induced decrease in the ratio of Bcl-2/Bax and increase in the ratio of cleaved caspase-3/full-length caspase 3. Notably, taurine inhibited PS-decreased phosphorylation of Akt (pAkt) and phosphorylation of CREB (pCREB), which consequently enhanced the mRNA and protein levels of PGC1alpha. Taken together, these results suggest that high dosage of taurine administration during the early postnatal period can significantly improve the cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1alpha pathway. Therefore, taurine has therapeutic potential for prenatal stressed offspring rats in future. PMID- 27768970 TI - Polymeric nanoparticles promote macrophage reversal from M2 to M1 phenotypes in the tumor microenvironment. AB - Immunotherapy has shown promising treatment effects for a variety of cancers. However, the immune treatment efficiency for solid tumors is limited owing to insufficient infiltration of immune cells into solid tumors. The conversion of tumor-supportive macrophages to tumor-suppressive macrophages, inducing the functional reversal of macrophages, is an effective method and contributes to a subsequent antitumor response. The current challenge in the field is the poor distribution and systemic side effects associated with the use of cytokines. As a solution to this issue, we designed and synthesized microenvironment-responsive nanoparticles (P) with IL-12 payload (IL-12?P1). These nanoparticles could promote the systemic administration and release of IL-12 in the tumor microenvironment, and the locally responsive property of IL-12?P1 could subsequently re-educate tumor-associated macrophages (TAMs). In particular, our results illustrated the great therapeutic effects derived from the functional conversion of macrophages. Our strategy was to design a microenvironment responsive material for local macrophage modification to overcome the physiological barrier of solid tumors. The shifting of macrophage phenotypes via IL-12?P1 achieved immunomodulation in the microenvironment for cancer therapy, with negligible cytotoxicity. We expect that the functional regulation of TAMs by pH-responsive nanomaterials is a promising therapeutic approach for cancer immunotherapy. PMID- 27768971 TI - Synergistic thermoradiotherapy based on PEGylated Cu3BiS3 ternary semiconductor nanorods with strong absorption in the second near-infrared window. AB - In this work, we report a successful synthesis of copper bismuth sulfide nanorods (NRs) with broad and strong photoabsorption ranging from ultraviolet (UV) to near infrared (NIR) wavelengths, which can be used as a 1064 nm-laser-driven photothermal agent with the photothermal conversion efficiency of 40.7%, noticeably higher than most of the reported PTT agents working in NIR-II window. The as-prepared PEGylated Cu3BiS3 NRs were used as photoacoustic imaging (PAI) and CT imaging agents due to their strong NIR absorption and large X-ray attenuation coefficient of bismuth. We are the first to demonstrate that a small quantity of PEGylated Cu3BiS3 NRs in tumors can concentrate radiation energy and trigger mild PTT under NIR-II irradiation and thus, these particles could be used as a novel, synergistic thermoradiotheraputic agent that enhances the efficacy of radiotherapy. PMID- 27768973 TI - Non-invasive visualization of mast cell recruitment and its effects in lung cancer by optical reporter gene imaging and glucose metabolism monitoring. AB - The inability to monitor the in vivo dynamics of mast cells (MCs) limits the better understanding of its role in cancer progression. Here, we report on noninvasive imaging of MC migration to tumor lesions in mice and evaluation of the effects of migrated MCs on tumor progression through reporter gene-based in vivo optical imaging and glucose metabolism monitoring in cancer with 18F fluorodeoxyglucose (18F-FDG) in vitro and in vivo. Murine MCs (MC-9) and Lewis lung cancer cells (LLC) expressing an enhanced firefly luciferase (effluc) gene were established, termed MC-9/effluc and LLC/effluc, respectively. MC-9/effluc cell migration to LLC tumor lesions was initially detected within 1 h post transfer and distinct bioluminescence imaging signals emitted from MC-9/effluc cells were observed at tumor sites until 96 h. In vivo optical imaging as well as a biodistribution study with 18F-FDG demonstrated more rapid tumor growth and upregulated glucose uptake potentially associated with MC migration to tumor lesions. These results suggest that the combination of a reporter gene-based optical imaging approach and glucose metabolism status monitoring with 18F-FDG represents a promising tool to better understand the biological role of MCs in tumor microenvironments and to develop new therapeutic drugs to regulate their involvement in enhanced tumor growth. PMID- 27768972 TI - Micellar nanocomplexes for biomagnetic delivery of intracellular proteins to dictate axon formation during neuronal development. AB - During mammalian embryonic development, neurons polarize to create distinct cellular compartments of axon and dendrite that inherently differ in form and function, providing the foundation for directional signaling in the nervous system. Polarization results from spatio-temporal segregation of specific proteins' activities to discrete regions of the neuron to dictate axonal vs. dendritic fate. We aim to manipulate axon formation by directed subcellular localization of crucial intracellular protein function. Here we report critical steps toward the development of a nanotechnology for localized subcellular introduction and retention of an intracellular kinase, LKB1, crucial regulator of axon formation. This nanotechnology will spatially manipulate LKB1-linked biomagnetic nanocomplexes (LKB1-NCs) in developing rodent neurons in culture and in vivo. We created a supramolecular assembly for LKB1 rapid neuronal uptake and prolonged cytoplasmic stability. LKB1-NCs retained kinase activity and phosphorylated downstream targets. NCs were successfully delivered to cultured embryonic hippocampal neurons, and were stable in the cytoplasm for 2 days, sufficient time for axon formation. Importantly, LKB1-NCs promoted axon formation in these neurons, representing unique proof of concept for the sufficiency of intracellular protein function in dictating a central developmental event. Lastly, we established NC delivery into cortical progenitors in live rat embryonic brain in utero. Our nanotechnology provides a viable platform for spatial manipulation of intracellular protein-activity, to dictate central events during neuronal development. PMID- 27768974 TI - Artificially controlled degradable inorganic nanomaterial for cancer theranostics. AB - Multifunctional nanomaterials for cancer diagnosis and therapy have recently prompted widespread concern. To avoid nanotoxicity, the development of novel degradable functional materials must be our main focus. In this study, we firstly developed ethylenediaminetetraacetic acid calcium disodium salt (EDTA)- and bovine serum albumin (BSA)-capped Mn3O4 nanoparticles (MONPs-BSA-EDTA) as a novel inorganic nanomaterials for multifunctional imaging-guided photothermal therapy, which can be degraded in a progress-controlled way by artificially introduced ascorbic acid. The degradation products can also be captured and their excretion accelerated. Careful studies suggested that the toxicity of the MONPs-BSA-EDTA and its degradation products is low. The degradation mechanism also suggests a new method of controlled drug release. The development of artificially controlled degradable inorganic nanomaterials also provides a new way to degrade nanomaterials and minimize ion release, which may have potential applications in cancer theranostics without nanotoxicity. PMID- 27768975 TI - Anti-angiogenesis through noninvasive to minimally invasive intraocular delivery of the peptide CC12 identified by in vivo-directed evolution. AB - Anti-vascular endothelial growth factor (VEGF) therapies are widely used for the treatment of neovascular fundus diseases such as diabetic retinopathy. However, these agents need to be injected intravitreally, because their strong hydrophilicity and high molecular weight prevent them from penetrating cell membranes and complex tissue barriers. Moreover, the repeated injections that are required can cause infection and tissue injury. In this study, we used in vivo directed evolution phage display technology to identify a novel dodecapeptide, named CC12, with the ability to penetrate the ocular barrier in a noninvasive (via conjunctival sac instillation) or minimally invasive (via retrobulbar injection) manner. KV11, an antiangiogenesis peptide previously demonstrated to inhibit pathological neovascularization in the retina, was then used as a model antiangiogenesis cargo for CC12. We found that conjugation of KV11 peptide with CC12 peptide facilitated the delivery of KV11 to the retina, resulting in significant inhibition of retinal neovascularization development via topical application without tissue toxicity. Collectively, our data of multilevel evaluations demonstrate that CC12 may enable the noninvasive to minimally invasive intraocular delivery of antiangiogenic therapeutics. PMID- 27768976 TI - Drug self-delivery systems for cancer therapy. AB - Carrier-assistant drug delivery systems (DDSs) have been rapidly established for cancer therapy and great strides have been made in recent years. However, further development of DDSs is retarded by the aspects such as the low drug carrying capacity, carrier-induced toxicity and immunogenicity, complex synthesis manipulation. Drug self-delivery systems (DSDSs), in which active drugs exhibit nanoscale characteristic to realize intracellular delivery by themselves without the help of nanocarriers, have been rapidly developed to address these issues. In this review, we present a comprehensive summary of the recent advances in DSDSs for cancer therapy. After a brief introduction to the major types of DSDSs and their fabrication strategies, we emphatically discuss some representative achievements of these DSDSs for passive or/and positive targeting therapy, combinational therapy as well as theranostics. The design principle is explained and justified, which can cast a new light on developing drug delivery systems for cancer treatments. PMID- 27768977 TI - Temperature responsive chemical crosslinkable UV pretreated hydrogel for application to injectable tissue regeneration system via differentiations of encapsulated hMSCs. AB - An injectable hydrogel showing temperature-dependent chemical crosslinking was developed to combine injectabilities of physical hydrogels with dense structures of chemical hydrogels for applications in stem cell delivery-mediated tissue regeneration systems showing easy administration and maintenance of well dispersed cells within the hydrogel. Hydrophobic methacryl groups were applied to thermosensitive poly(organophosphazenes) to induce temperature mediated hydrophobic interaction and chemical crosslinking. UV pretreated polymer solution showed chemical crosslinking not before injection only after injection into the body even it was already exposed to UV. As this injectable hydrogel showed small pore-sizes, it was guessed cell holding without any adhesive moieties were available and showed the potentials for a cell scaffold. In this study, temperature dependent chemical crosslinking and proliferation and differentiation of the encapsulated hMSCs into various tissues were observed in the hydrogels after injection. PMID- 27768978 TI - TaOx decorated perfluorocarbon nanodroplets as oxygen reservoirs to overcome tumor hypoxia and enhance cancer radiotherapy. AB - Cancer radiotherapy (RT) is a clinically used tumor treatment strategy applicable for a wide range of solid tumors. However, during RT treatment of tumors, only a small portion of applied ionizing irradiation energy is absorbed by the tumor, in which the largely hypoxic microenvironment also limits the anti-tumor efficacy of RT. In this work, we rationally fabricate polyethylene glycol (PEG) stabilized perfluorocarbon (PFC) nano-droplets decorated with TaOx nanoparticles (TaOx@PFC PEG) as a multifunctional RT sensitizer. The obtained TaOx@PFC-PEG nanoparticles on one hand can absorb X-ray by TaOx to concentrate radiation energy within tumor cells, on the other hand after saturating PFC with oxygen will act as an oxygen reservoir to gradually release oxygen and improve tumor oxygenation. As the result, remarkably enhanced in vivo RT treatment is achieved with TaOx@PFC-PEG nanoparticles in our mouse tumor model experiments. Our work thus presents a new nanotechnology strategy to enhance RT-induced tumor treatment by simultaneously concentrating radiation energy within tumors and improving tumor oxygenation, using one multifunctional agent. PMID- 27768979 TI - Cortisol profiles differ by race/ethnicity among young sexual minority men. AB - Much of the extant scientific research examining hypothalamic-pituitary-adrenal (HPA)-axis functioning is conducted among White heterosexuals. Very little research examines HPA-axis functioning between different minority groups. Individuals who identify as both sexual and racial minorities may experience increased stigma and discrimination that can affect HPA-axis functioning. In the current study, we examined diurnal cortisol rhythm in young White gay men (WGM) compared to young Black gay men (BGM). The sample consisted of 70 healthy gay men (mean [SD] age=22.9 [3.2]: 68% White and 38% Black) who collected four saliva samples daily for five days. Repeated measures analysis of covariance and post hoc tests revealed that BGM had higher cortisol levels than WGM in the evening. Secondary analyses revealed no significant group differences for the cortisol awakening response or systemic output throughout the day. However, BGM compared to WGM had a lower drop from peak (morning) to lowest (evening) cortisol concentrations. Taken together, these findings reveal a flatter diurnal cortisol rhythm among BGM compared to WGB. The functional significance of these preliminary findings must be explored further with assessment of psychosocial factors among sexual minorities at the intersection of multiple identities. In summary, we expand health disparities research aimed at delineating sexual minority and race/ethnic variation in stress physiology. PMID- 27768980 TI - A human chemosignal modulates frontolimbic activity and connectivity in response to emotional stimuli. AB - Evidence suggests the putative human pheromone Delta4,16-androstadien-3-one (androstadienone), a natural component of human sweat, increases attention to emotional information when passively inhaled, even in minute amounts. However, the neural mechanisms underlying androstadienone's impact on the perception of emotional stimuli have not been clarified. To characterize how the compound modifies neural circuitry while attending to emotional information, 22 subjects (11 women) underwent two fMRI scanning sessions, one with an androstadienone solution and one with a carrier control solution alone on their upper lip. During each session, participants viewed blocks of emotionally positive, negative, or neutral images. The BOLD response to emotional images (relative to neutral images) was greater during exposure to androstadienone in right orbitofrontal and lateral prefrontal cortex, particularly during positive image blocks. Androstadienone did not impact the response to social images, compared to nonsocial images, and results were not related to participant sex or olfactory sensitivity. To examine how androstadienone influences effective connectivity of this network, a dynamic causal model was employed with primary visual cortex (V1), amygdala, prefrontal cortex, and orbitofrontal cortex on each side. These models indicated that emotional images increased the drive from V1 to the amygdala during the control session. With androstadienone present, this drive to amygdala was decreased specifically for positive images, which drove downstream increases in orbitofrontal and prefrontal activity. This evidence suggests that androstadienone may act as a chemical signal to increase attention to positively valenced information via modifications to amygdala connectivity. PMID- 27768982 TI - Socioeconomic status, perceived control, diurnal cortisol, and physical symptoms: A moderated mediation model. AB - Social class is a robust predictor of health, with risk for disease and mortality increasing towards the lower end of the socioeconomic (SES) spectrum. While certain psychological characteristics, such as high sense of control, can protect low-SES individuals from adverse health outcomes, very few studies have investigated the biological mechanisms underlying these relationships. In this study, we tested whether sense of control mitigated the associations between SES and cortisol activity, and SES and physical health in daily life (i.e., number and severity of physical symptoms). Next, we tested whether individual differences in cortisol secretion would act as a mechanism by which SES and perceived control influenced physical health. In a large national sample from the Midlife in the United States (MIDUS) survey, we found that SES interacted with perceived control in predicting morning cortisol levels, cortisol slopes, number of physical symptoms, and severity of physical symptoms. Specifically, SES disparities in these health outcomes were more pronounced among individuals reporting low levels of perceived control than among individuals endorsing high levels of perceived control. Further, we found that a flatter cortisol slope mediated the link between lower SES and greater number and severity of physical symptoms for those individuals who reported lower levels of perceived control, but not for individuals reporting higher levels of perceived control. These findings suggest that perception of greater control may act as a buffer against the effect of low SES on health-related physiological processes. PMID- 27768981 TI - Do sex hormones or hormone therapy modify the relation of n-3 fatty acids with incident depressive symptoms in postmenopausal women? The MESA Study. AB - INTRODUCTION: Considering that estradiol (E2) and n-3 polyunsaturated fatty acids (PUFAs) have roles in neurogenesis and in neurotransmission, we examined whether the association of PUFAs with incident depressive symptoms in postmenopausal women is modified by hormone therapy (HT) use or estrogen status. METHODS: Women (N=1616) free of depressive symptoms at baseline (2000-2002) in the Multi-Ethnic Study of Atherosclerosis were classified by HT usage and quartiles of dietary eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and the sum EPA+DHA. Women with serum E2 <=0.073 nmol/L (sample median), were classified low on E2. Poisson regression was used to model incident depressive symptoms at examination 3 (2004-05), defined by the Center for Epidemiological Studies Depression Scale >=16 or taking an antidepressant, first as a function of HT use and n-3 PUFA quartiles, and second, as a function of low E2 status and n-3 PUFA quartiles. RESULTS: Among HT non- users, positive, graded relationships (p-trends<=0.003) were found between PUFAs and incident depressive symptoms. Compared to the lowest quartile, the adjusted risk ratios (RRs) for the highest were 2.10, 2.39, and 2.04 for EPA, DHA, and EPA+DHA, respectively. For HT users, no associations were seen. When analyses were run for E2 status, the RRs over quartiles of the PUFAs were positive and graded for low E2 women, but were null for High E2 women. CONCLUSIONS: Higher intakes of DHA and EPA were associated with higher risk of depressive symptoms in nonusers of HT, contrary to hypothesis. PMID- 27768983 TI - Optimizing laboratory animal stress paradigms: The H-H* experimental design. AB - Major advances in behavioral neuroscience have been facilitated by the development of consistent and highly reproducible experimental paradigms that have been widely adopted. In contrast, many different experimental approaches have been employed to expose laboratory mice and rats to acute versus chronic intermittent stress. An argument is advanced in this review that more consistent approaches to the design of chronic intermittent stress experiments would provide greater reproducibility of results across laboratories and greater reliability relating to various neural, endocrine, immune, genetic, and behavioral adaptations. As an example, the H-H* experimental design incorporates control, homotypic (H), and heterotypic (H*) groups and allows for comparisons across groups, where each animal is exposed to the same stressor, but that stressor has vastly different biological and behavioral effects depending upon each animal's prior stress history. Implementation of the H-H* experimental paradigm makes possible a delineation of transcriptional changes and neural, endocrine, and immune pathways that are activated in precisely defined stressor contexts. PMID- 27768984 TI - A randomized-controlled trial of heart rate variability biofeedback for psychotic symptoms. AB - Arousal and the way it is coped with are relevant to the emergence of psychotic symptoms. Heart rate variability (HRV) stems from autonomic responses to environmental demands such as stress and is an index of physiological arousal, adaptability, and homeostatic reflexes forming autonomic balance. A randomized controlled between-subjects trial that compared HRV-biofeedback (BF) to an active relaxation and to a waiting control condition was conducted in a sample with attenuated subclinical psychotic symptoms (N = 84). A 20-min intervention was preceded and followed by repeated assessments of stress responses. Change scores of the post-stress periods were analyzed using ANOVAs for HRV, subjective stress, perceived control, and state paranoia. As expected, BF participants showed greater improvements in perceived control than waiting controls (p = 0.006). However, no group differences occurred in HRV, paranoid symptoms or subjective stress. In exploratory analyses in a subset of participants who were breathing per protocol, the expected effects were found for total HRV and state paranoia. Thus, this trial of HRV-BF for people with attenuated psychotic symptoms indicates that the intervention may hold potential if conducted per protocol. To reach this, longer training might be inevitable. Future studies are needed to further elucidate efficacy and applicability of HRV-BF in clinical samples. PMID- 27768985 TI - The impact of general practice nursing care on patient satisfaction and enablement in Australia: A mixed methods study. AB - BACKGROUND: The numbers of nurses in general practice in Australia tripled between 2004 and 2012. However, evidence on whether nursing care in general practice improves patient outcomes is scarce. Although patient satisfaction and enablement have been examined extensively as outcomes of general practitioner care, there is little research into these outcomes from nursing care in general practice. The aim of this study was to examine the relationships between specific general practice characteristics and nurse consultation characteristics, and patient satisfaction and enablement METHODS: A mixed methods study examined a cross-section of patients from 21 general practices in the Australian Capital Territory. The Patient Enablement and Satisfaction Survey was distributed to 1665 patients who received nursing care between September 2013 and March 2014. Grounded theory methods were used to analyse interviews with staff and patients from these same practices. An integrated analysis of data from both components was conducted using multilevel mixed effect models. RESULTS: Data from 678 completed patient surveys (response rate=42%) and 48 interviews with 16 nurses, 23 patients and 9 practice managers were analysed. Patients who had longer nurse consultations were more satisfied (OR=2.50, 95% CI: 1.43-4.35) and more enabled (OR=2.55, 95% CI: 1.45-4.50) than those who had shorter consultations. Patients who had continuity of care with the same general practice nurse were more satisfied (OR=2.31, 95% CI: 1.33-4.00) than those who consulted with a nurse they had never met before. Patients who attended practices where nurses worked with broad scopes of practice and high levels of autonomy were more satisfied (OR=1.76, 95% CI: 1.09-2.82) and more enabled (OR=2.56, 95% CI: 1.40-4.68) than patients who attended practices where nurses worked with narrow scopes of practice and low levels of autonomy. Patients who received nursing care for the management of chronic conditions (OR=2.64, 95% CI: 1.32-5.30) were more enabled than those receiving preventive health care. CONCLUSIONS: This study provides the first evidence of the importance of continuity of general practice nurse care, adequate time in general practice nurse consultations, and broad scopes of nursing practice and autonomy for patient satisfaction and enablement. The findings of this study provide evidence of the true value of enhanced nursing roles in general practice. They demonstrate that when the vision for improved coordination and multidisciplinary primary health care, including expanded roles of nurses, is implemented, high quality patient outcomes can be achieved. PMID- 27768986 TI - Nurses' perceptions of feedback to nursing teams on quality measurements: An embedded case study design. AB - BACKGROUND: Providing nursing teams with feedback on quality measurements is used as a quality improvement instrument in healthcare organizations worldwide. Previous research indicated contradictory results regarding the effect of such feedback on both nurses' well-being and performance. OBJECTIVES: Building on the Job Demands-Resources model this study explores: (1) whether and how nurses' perceptions of feedback on quality measurements (as a burdening job demand or rather as an intrinsically or extrinsically motivating job resource) are respectively related to nurses' well-being and performance; and (2) whether and how team reflection influences nurses' perceptions. DESIGN: An embedded case study. SETTINGS: Four surgical wards within three different acute teaching hospital settings in the Netherlands. METHODS: During a period of four months, the nurses on each ward were provided with similar feedback on quality measurements. After this period, interviews with eight nurses and the ward manager for each ward were conducted. Additionally, observational data were collected from three oral feedback moments on each of the participating wards. RESULTS: The data revealed that individual nurses perceive the same feedback on quality measurements differently, leading to different effects on nurses' well being and performance: 1) feedback can be perceived as a job demand that pressures nurses to improve the results on the quality measurements; 2) feedback can be perceived as an extrinsically motivating job resource, that is instrumental to improve the results on quality measurements; 3) feedback can be perceived as an intrinsically motivating job resource that stimulates nurses to improve the results on the quality measurements; and 4) feedback can be perceived neither as a job demand, nor as a job resource, and has no effect on nurses' well being and performance. Additionally, this study indicates that team reflection after feedback seems to be very low in practice, while our data also provides evidence that nursing teams using the feedback to jointly reflect and analyse their performance and strategies will be able to better translate information about quality measurements into corrective behaviours, which may result in more positive perceptions of feedback on quality measurements among individual nurses. CONCLUSIONS: To better understand the impact of feedback to nursing teams on quality measurements, we should take nurses' individual perceptions of this feedback into account. Supporting nursing teams in team reflection after them having received feedback on quality measurements may help in eliciting positive perceptions among nurses, and therewith create positive effects of feedback on both their well-being and performance. PMID- 27768987 TI - Parental, child, and adolescent experience of chronic skin conditions: A meta ethnography and review of the qualitative literature. AB - Childhood skin conditions can affect the quality of life of children, adolescents, and families. As such, paediatric dermatological conditions have been the focus of a number of qualitative studies and there is now a need to integrate the findings. A meta-ethnography was carried out with the existing 12 studies, which included nine studies examining parental experiences and three studies of child experiences. Meta-ethnographic analysis of the studies identified themes focused on the child's sense of stigmatisation and the challenges for families that arose from this. Common experiences across studies were feelings of difference relating to the appearance of the skin. The results highlight that children and adolescents can experience negative social reactions and that parents may struggle with some aspects of the physical management of the condition. The studies indicate the need to examine in more detail the psychosocial aspects of childhood skin conditions and the role played by stigmatisation. PMID- 27768988 TI - Pyrogallol abates VSMC migration via modulation of Caveolin-1, matrix metalloproteinase and intima hyperplasia in carotid ligation mouse. AB - Migration of vascular smooth muscle cells (VSMCs) contributes to intimal hyperplasia and other vascular diseases. Caveolin-1 (Cav-1) has been recognized as a proliferative inhibitor of VSMCs and is likely to be an important regulator of VSMC migration. The underlying mechanism of pyrogallol on the VSMC migration is not fully understood. This study attempted to dissect the role of Cav-1 and matrix metalloproteinase (MMP) in VSMC migration and to investigate the effect of pyrogallol on VSMC mobility during carotid artery ligation mice. The mRNA expression of MMP-3 and MMP-13 was down-regulated in cultured VSMC prepared from Cav-1-deficient (Cav-1 KO) mice whereas MMP-14 expression was up-regulated. Pyrogallol effectively inhibited the migration of Cav-1 KO VSMC by promoting the expression of tissue inhibitors of metalloproteinase (TIMP)-2. Pyrogallol also inhibited the migration of Cav-1 wild type (WT) VSMC, however, by increasing TIMP 1 expression and repressing MMP-2 activity. In a parallel in vivo study, intra peritoneal (ip) of pyrogallol to carotid artery ligated mice significantly suppressed intima formation in mice carotid artery. Furthermore, the proMMP-9 activity in pyrogallol-treated mice serum significantly increased from Day 0 to Day 2 and decreased from Day 2 to Day 7 in a time-dependent manner. In addition, WT mice treated with pyrogallol had significantly reduced neointima formation, whereas no differences were observed in Cav-1 knock out (KO) mice. These results suggest that pyrogallol not only inhibited VSMC migration but also effectively diminishes the severity of neointima hyperplasia, implying that pyrogallol possesses potential anti-atherogenic effects for the treatment of vascular diseases. PMID- 27768989 TI - Effects of Astragalus and Codonopsis pilosula polysaccharides on alveolar macrophage phagocytosis and inflammation in chronic obstructive pulmonary disease mice exposed to PM2.5. AB - Astragalus and Codonopsis pilosula are used for their immunomodulatory and anti inflammatory effects. Here, we investigated the effects of Astragalus polysaccharides (APS) and Codonopsis pilosula polysaccharides (CPP) on alveolar macrophage (AM) phagocytosis and inflammation in chronic obstructive pulmonary disease (COPD) associated with exposure to particulate matter with a mean aerodynamic diameter <=2.5MUm (PM2.5). A mouse model of COPD was established by cigarette smoke exposure. PM2.5 exposure was performed by inhalation of a PM2.5 solution aerosol. APS and CPP were administered intragastrically. COPD showed defective AM phagocytosis and increased levels of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid and serum. PM2.5 exposure aggravated the damage, and this effect was reversed by APS and CPP gavage. The results indicate that APS and CPP may promote defective AM phagocytosis and ameliorate the inflammatory response in COPD with or without PM2.5 exposure. PMID- 27768990 TI - Injection-site vein loss and soft tissue abscesses associated with black tar heroin injection: A cross-sectional study of two distinct populations in USA. AB - BACKGROUND: Injection-site vein loss and skin abscesses impose significant morbidity on people who inject drugs (PWID). The two common forms of street heroin available in the USA include black tar and powder heroin. Little research has investigated these different forms of heroin and their potential implications for health outcomes. METHODS: A multiple-choice survey was administered to a sample of 145 participants seeking services at reduction facilities in both Sacramento, CA and greater Boston, MA, USA. Multivariate regression models for reporting one or more abscesses in one year, injection-site veins lost in six months, and soft tissue injection. RESULTS: Participants in Sacramento exclusively used black tar (99%), while those in Boston used powder heroin (96%). Those who used black tar heroin lost more injection-site veins (beta=2.34, 95% CI: 0.66-4.03) and were more likely to report abscesses (AOR=7.68, 95% CI: 3.01 19.60). Soft tissue injection was also associated with abscesses (AOR=4.68, 95% CI: 1.84-11.93). Consistent venous access (AOR: 0.088, 95% CI: 0.011-0.74) and losing more injection sites (AOR: 1.22, 95% CI: 1.03-1.45) were associated with soft tissue injection. CONCLUSION: Use of black tar heroin is associated with more frequent abscesses and more extensive vein loss. Poor venous access predisposes people who inject drugs to soft tissue injection, which may constitute a causal pathway between black tar heroin injection and abscess formation. The mechanisms by which black tar heroin contributes to vein loss and abscess formation must be further elucidated in order to develop actionable interventions for maintaining vein health and decreasing the abscess burden. Potential interventions include increased access to clean injection equipment and education, supervised injection facilities, opioid substitution therapy, and supply chain interventions targeting cutting agents. PMID- 27768991 TI - Medicine, religion and ayahuasca in Catalonia. Considering ayahuasca networks from a medical anthropology perspective. AB - Ayahuasca is a psychoactive beverage from the Amazon, traditionally used by indigenous and mestizo populations in the region. Widespread international use of the beverage began in the 1990s in both secular contexts and religious/spiritual networks. This article offers an analysis of these networks as health care systems in general and for the case of Spain and specifically Catalonia, describing the emergence and characteristics of their groups, and the therapeutic itineraries of some participants. The medical anthropology perspective we take enables us to reflect on the relationship between medicine and religion, and problematize the tensions between medicalization and medical pluralism. Closely linked to the process of medicalization, we also analyze prohibitionist drug policies and their tensions and conflicts with the use of ayahuasca in ritual and 'health care' contexts. The paper ends with a reflection on the problem of ayahuasca as 'medicine', since the connection between religion and medicine is a very difficult one to separate. PMID- 27768992 TI - Factors associated with syphilis seroreactivity among polydrug users in Northeast Brazil: A cross-sectional study using Respondent Driven Sampling. AB - BACKGROUND: The burden of sexually transmitted infections (STIs), such as syphilis, is higher in low-income countries, with serious consequences and profound impact on sexual and reproductive health and human immunodeficiency virus (HIV) spread. Syphilis prevalence tend to be higher among people who misuse drugs than in the general population. OBJECTIVE: To assess syphilis and associated factors among polydrug users (PDU) in the city of Salvador, Northeast Brazil. METHODS: A cross-sectional study was conducted in 10 Brazilian cities between September and November 2009 using Respondent Driven Sampling (RDS). Participants answered an Audio Computer-Assisted Self Interview (ACASI) and were rapid tested for HIV and syphilis. We performed multivariable regression models for correlates of syphilis on Stata 10.0. Estimates were weighted by the inverse size of the individual social network size and homophily. RESULTS: Mean age was 29.3 years (range: 18-62), 74.0% were males, and 89.8% were non-white. Syphilis prevalence was 16.6%. Females (adjwOR:2.14; 95%CI:1.09-4.20), individuals over 29 years old (adjwOR:4.44; 95%CI:2.41-8.19), those who exchanged sex for money or drugs (adjwOR:3.51; 95%CI:1.84-6.71), "No/low" self-perceived risk of HIV infection (adjwOR:5.13; 95%CI:1.36-19.37), and having nine or less years of education (adjwOR:2.92; 95%CI:1.08-7.88) were associated with syphilis. CONCLUSION: One of the most pressing needs for syphilis prevention/control is the availability of rapid point-of-care diagnostic tests and treatment. Interventions should be tailored to PDU needs and their multiple burdens as shown in the present study, that may contribute to future studies aiming to better understand the relationships between drug use and syphilis. PMID- 27768993 TI - Maritime transportation of illegal drugs from South America. AB - BACKGROUND: The US invests considerable effort in searching and interdicting drug trafficking vessels in the Caribbean and Eastern Pacific regions. While some vessels are indeed interdicted, resulting in confiscation of substantial quantities of drugs, many such vessels manage to avoid detection and arrive safely at their destinations in Central America and Mexico with their drug load intact. The agency in charge of interdicting this traffic, Joint Interagency Task Force South-JIATF-S, sends out both aerial and surface assets for search and interdiction missions. METHODS: An important parameter for planning search and interdiction missions is an estimate of the expected steady-state number of the various types of drug trafficking vessels present in the search regions at any given time. In this paper we use various publicly available sources to estimate these numbers. RESULTS: We estimate that the number of drug shipments initiated per month ranges between four and six dozen, and at any given time there are between two and four vessels, of all types, on the high seas. These estimates remain quite robust over a relatively large range of assumptions and estimates regarding the size and distribution of the drug flow, mix of vessel types, and physical characteristics of those vessels. CONCLUSION: Our analysis provides insight for how to allocate assets to search, detect, and interdict drug trafficking vessels. The results can also be useful to vet informants to check if their information is consistent with our flow estimates. To the best of our knowledge this is the first time such flow estimates appear in the open literature. PMID- 27768994 TI - Creating visual differences: Methamphetamine users perceptions of anti-meth campaigns. AB - BACKGROUND: Because of increased law enforcement and subsequent media attention, methamphetamine users appear in the public's imagination as diseased, zombie-like White trash. We explore methamphetamine users' perceptions about whether the images, people, and situations in anti-methamphetamine campaigns reflect their own lives and experiences using meth. METHODS: To explore these perceptions, we used photo-elicitation interviews with 47 people who used methamphetamine (30 former and 17 active). Specifically, we presented participants with images from the Faces of Meth and the Montana Meth Project campaigns to stimulate discussion. RESULTS: We found that participants believed these ads did not reflect their personal experiences and consequently were ineffective at curtailing their own methamphetamine use. They believed that the ads represented a certain type of methamphetamine user, particularly those they defined as dysfunctional users. They created symbolic boundaries between themselves and those portrayed in the ads to show how they differed, which allowed them to believe that the ads were not relevant to their experiences. CONCLUSIONS: Findings suggest that there are unintended consequences to inauthentic/dramatic imagery. Participants did not believe they were like those in the ads-thus saw no reason to quit or seek help. Consequently, overly stigmatizing portraits of users may act as barriers to desistence. The findings have implications for designing anti-methamphetamine campaigns. PMID- 27768995 TI - Non-medical use of prescription drugs among illicit drug users: A case study on an online drug forum. AB - BACKGROUND: The non-medical use of prescription drugs is a growing phenomenon associated with increasing health-related harms. However, little is known about the drivers of this process among illicit drug users. Our aim is to show how the qualities of pharmaceutical drugs, pharmaceutical related knowledge, online communities sharing this knowledge and medical professionals mediate and transform the consumption behaviour related to pharmaceutical drugs. METHODS: The data consist of discussion threads from an online drug use forum. Using actor network theory (ANT), we analysed translations that mediate the online user community's relationship with pharmaceutical drugs. RESULTS: Differences in experienced drug effects are explained both as a process of 'learning' and as differences in brain chemistry at the receptor level. Both science- and experience-based information are shared on best practices to optimise use, avoid adverse health effects and maximise the experience of intoxication. The expanded context of doctors' practices places stress on the medical framework for drug use. Our analysis shows how the non-medical use of psychoactive pharmaceuticals relates to joint, medicalised ideas of bodies as sites of medical experimentation, as well as to the collective process of constructing 'pharmaceutical competences' in user networks. Understandings of intoxication have increasingly been permeated with the pharmacological and scientific logic of knowledge. CONCLUSION: The forum works as a platform for harm reduction inspired exchange of knowledge. However, the user community's knowledge sharing practices can generate a shared perception of a sufficient or even superior drug use experience and knowledge. This may lead to overdoses and other risky behaviour, and thereby contribute to increased harms related to non-medical use of prescription drugs. PMID- 27768997 TI - Exploring the social lives of image and performance enhancing drugs: An online ethnography of the Zyzz fandom of recreational bodybuilders. AB - BACKGROUND: As a result of the mainstreaming of bodybuilding, the majority of image and performance enhancing drug (IPED) users are now not athletes or competitive bodybuilders, but recreational bodybuilders. Previous approaches provide little insight into how the shift from competitive to recreational contexts impacts the use of IPEDs. METHODS: In this study an online ethnographic approach is used to explore the social lives of IPEDs in a recreational context. The study focusses on the Zyzz fandom, an international online community of thousands of recreational bodybuilders who idolise the alleged IPED user Zyzz. RESULTS: Zyzz fans see IPED prohibition as failing, as causing harm to users, and as sexist. Their IPED use is informed by not only instrumental benefits, but social benefits such as altering gendered power relations. IPEDs have been normalised in this community, and new patterns of use are emerging. CONCLUSION: IPEDS have moved through different hands, contexts and uses, and in so doing the values, norms and meanings attached to IPEDs have changed. The results suggest that intervention efforts may be best directed towards harm minimisation, and in particular towards bridging the divides between the medical and bodybuilding communities. PMID- 27768996 TI - Drug use in business bathrooms: An exploratory study of manager encounters in New York City. AB - BACKGROUND: Though public bathroom drug injection has been documented from the perspective of people who inject drugs, no research has explored the experiences of the business managers who oversee their business bathrooms and respond to drug use. These managers, by default, are first-responders in the event of a drug overdose and thus of intrinsic interest during the current epidemic of opioid related overdoses in the United States. This exploratory study assists in elucidating the experiences that New York City business managers have with people who inject drugs, their paraphernalia, and their overdoses. METHODS: A survey instrument was designed to collect data on manager encounters with drug use occurring in their business bathrooms. Recruitment was guided by convenience and purposive approaches. RESULTS: More than half of managers interviewed (58%, n=50/86) encountered drug use in their business bathrooms, more than a third (34%) of these managers also found syringes, and the vast majority (90%) of managers had received no overdose recognition or naloxone training. Seven managers encountered unresponsive individuals who required emergency assistance. CONCLUSION: The results from this study underscore the need for additional research on the experiences that community stakeholders have with public injection as well as educational outreach efforts among business managers. This research also suggests that there is need for a national dialogue about potential interventions, including expanded overdose recognition and naloxone training and supervised injection facilities (SIF)/drug consumption rooms (DCR), that could reduce public injection and its associated health risks. PMID- 27768998 TI - A simple preparation of graphite/gelatin composite for electrochemical detection of dopamine. AB - In this study, we demonstrate a simple preparation of graphite (GR) sheets assisted with gelatin (GLN) polypeptide composite was developed for sensitive detection of dopamine (DA) sensor. The GR/GLN composite was prepared by GR powder in GLN solution (5mg/mL) via sonication process. The prepared GR/GLN composite displays well dispersion ability in biopolymer matrix and characterized via scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectroscopy and electrochemical impedance spectroscopy (EIS) studies. The GR/GLN modified electrode showed an excellent electrocatalytic activity toward the oxidation of DA, suggesting that the successful formation of GR sheets crosslinked with the functional groups of GLN polypeptide. In addition, the GR/GLN modified electrode achieved a wide linear response ranging from 0.05 to 79.5MUM with a detection limit of 0.0045MUM. The calculated analytical sensitivity of the sensor was 1.36+/-0.02MUAMUM-1cm-2. Conversely, the modified electrode demonstrates a good storage stability, reproducibility and repeatability. In addition, the sensor manifests the determination of DA in human serum and urine samples for practical applications. PMID- 27768999 TI - Nanoclay assisted electrochemical exfoliation of pencil core to high conductive graphene thin-film electrode. AB - Nanoclay assisted electrochemical exfoliation was developed to in-situ form functionalized graphene electrode materials from pencil core with different ratios of graphite and clay. This method made a positive transformation from solid graphite to graphene colloidal solution, which can be used to construct binder- and additive-free thin-film electrodes. Exfoliated graphene can be served as both conductive current collector (film resistance of 33Omega/square) and electrode materials. Graphene thin-film electrodes from pencil cores displayed higher capacity of 224 than 80mAh/g of that from pure graphite. The electrochemical performance can be controlled by the ratio of graphite and clay and the oxidation reaction of surface oxygen functional groups. The described nanoclay-assisted electrochemical oxidation route shows great potential for the synthesis of functionalized graphene electrode materials for high-conductive thin film lithium ion batteries and supercapacitors. PMID- 27769000 TI - Tailoring porosity in carbon spheres for fast carbon dioxide adsorption. AB - Highly-porous carbon spheres were prepared by modified Stober method combined with silica templating and CO2 activation. Silica was delivered in the form of either colloids or tetraethyl orthosilicate and used to create porosity. Subsequently, CO2 activation was used to develop microporosity. CO2 activation was done either: (1) on carbon spheres, following silica etching or (2) on silica carbon composites, before silica removal. Both methods delivered carbon materials with well-developed structures and, importantly, preserved spherical morphology. Still, activation of the silica-carbon composites with subsequent silica etching afforded carbons with better structural properties and CO2 adsorption. Between materials prepared with silica colloids and TEOS-generated silica, the former showed more developed structures. The best material had specific surface area reaching 1500 m2 g-1 and total pore volume exceeding 1.2 cm3 g-1 and showed CO2 uptakes as high as 7.8 mmol g-1 (0 degrees C, 1 bar) and 4.0 mmol g-1 (23 degrees C, 1 bar). Mesoporosity improved mass transfer, which directly translated to faster CO2 equilibration (30-40% on average). The proposed synthesis afforded carbons with high and fast CO2 adsorption, which makes them good candidates for CO2 sorption applications. Moreover, it was shown that both, microporosity and mesoporosity, are important in development of prospective CO2 sorbents. PMID- 27769001 TI - Adsorption removal of tannic acid from aqueous solution by polyaniline: Analysis of operating parameters and mechanism. AB - Polyaniline (PANI) prepared by chemical oxidation was studied for adsorption removal of tannic acid (TA) from aqueous solution. Batch adsorption studies were carried out under different adsorbent dosages, pH, ionic strength, initial TA concentration and coexisting anions. Solution pH had an important impact on TA adsorption onto PANI with optimal removal in the pH range of 8-11. TA adsorption on PANI at three ionic strength levels (0.02, 0.2 and 2molL-1 NaCl) could be well described by Langmuir model (monolayer adsorption process) and the maximum adsorption capacity was 230, 223 and 1023mgg-1, respectively. Kinetic data showed that TA adsorption on PANI fitted well with pseudo-second-order model (controlled by chemical process). Among the coexisting anions tested, PO43- significantly inhibited TA adsorption due to the enhancement of repulsive interaction. Continuous flow adsorption studies indicated good flexibility and adaptability of the PANI adsorbent under different flow rates and influent TA concentrations. The mechanism controlling TA adsorption onto PANI under different operating conditions was analyzed with the combination of electrostatic interactions, hydrogen bonding, pi-pi interactions and Van der Waals interactions. PMID- 27769002 TI - Nonviral gene-delivery by highly fluorinated gemini bispyridinium surfactant based DNA nanoparticles. AB - Biological and thermodynamic properties of a new homologous series of highly fluorinated bispyridinium cationic gemini surfactants, differing in the length of the spacer bridging the pyridinium polar heads in 1,1' position, are reported for the first time. Interestingly, gene delivery ability is closely associated with the spacer length due to a structural change of the molecule in solution. This conformation change is allowed when the spacer reaches the right length, and it is suggested by the trends of the apparent and partial molar enthalpies vs molality. To assess the compounds' biological activity, they were tested with an agarose gel electrophoresis mobility shift assay (EMSA), MTT proliferation assay and Transient Transfection assays on a human rhabdomyosarcoma cell line. Data from atomic force microscopy (AFM) allow for morphological characterization of DNA nanoparticles. Dilution enthalpies, measured at 298K, enabled the determination of apparent and partial molar enthalpies vs molality. All tested compounds (except that with the longest spacer), at different levels, can deliver the plasmid when co-formulated with 1,2-dioleyl-sn-glycero-3-phosphoethanolamine (DOPE). The compound with a spacer formed by eight carbon atoms gives rise to a gene delivery ability that is comparable to that of the commercial reagent. The compound with the longest spacer compacts DNA in loosely condensed structures by forming bows, which are not suitable for transfection. Regarding the compounds' hydrogenated counterparts, the tight relationship between the solution thermodynamics data and their biological performance is amazing, making "old" methods the foundation to deeply understanding "new" applications. PMID- 27769003 TI - In silico identification of outer membrane protein (Omp) and subunit vaccine design against pathogenic Vibrio cholerae. AB - Virulence-related outer membrane proteins (Omps) are expressed in bacteria (Gram negative) such as V. cholerae and are vital to bacterial invasion in to eukaryotic cell and survival within macrophages that could be best candidate for development of vaccine against V. cholerae. Applying in silico approaches, the 3 D model of the Omp was developed using Swiss model server and validated byProSA and Procheck web server. The continuous stretch of amino acid sequences 26mer: RTRSNSGLLTWGDKQTITLEYGDPAL and 31mer: FFAGGDNNLRGYGYKSISPQDASGALTGAKY having B cell binding sites were selected from sequence alignment after B cell epitopes prediction by BCPred and AAP prediction modules of BCPreds. Further, the selected antigenic sequences (having B-cell epitopes) were analyzed for T-cell epitopes (MHC I and MHC II alleles binding sequence) by using ProPred 1 and ProPred respectively. The epitope (9mer: YKSISPQDA) that binds to both the MHC classes (MHC I and MHC II) and covers maximum MHC alleles were identified. The identified epitopes can be useful in designing comprehensive peptide vaccine development against V. cholerae by inducing optimal immune response. PMID- 27769004 TI - Letter to the editor of the Journal of Affective Disorders: Supporting the guideline's quest for real direct costs of depression care. PMID- 27769005 TI - A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model. AB - BACKGROUND: Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity. METHODS: We conducted a GWAS of early-onset BD (onset of mania/hypomania <=19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls. RESULTS: No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression. LIMITATIONS: The sample sizes of the early-onset BD subgroups were relatively small. CONCLUSIONS: Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model. PMID- 27769006 TI - Younger or older parental age and risk of suicidality, premature death, psychiatric illness, and criminality in offspring. AB - BACKGROUND: Younger or older parental age has been linked with a range of adverse offspring endpoints. We investigated associations between parental age and nine adverse offspring outcomes in three correlated domains: (i) Premature death: suicide, unnatural death, natural death; (ii) Psychiatric morbidity: any mental illness, suicide attempt, substance misuse; (iii) Criminality: violent offending, imprisonment, driving whilst intoxicated. METHODS: Persons born in Denmark 1966 1996 were followed from their 15th until 40th birthday or December 2011 (N=1,793,681). Incidence rate ratios were estimated. RESULTS: Offspring of teenage mothers had the greatest risks for all nine adverse outcomes, especially for imprisonment, violent offending, substance misuse, and attempted suicide. Teenage fatherhood was also associated with elevated risks for offspring adverse psychiatric and criminality outcomes, but not premature mortality (at ages 15-39 years). For the psychiatric and criminality outcomes there was a U-shape trend linked with paternal age, but risks for premature mortality tended to increase with rising paternal age. On the contrary, maternal age 30 years and over was not linked with raised risks for any of the outcomes examined. LIMITATIONS: Parental links are based on legal and not biological relationships. CONCLUSIONS: The substantially elevated risks linked with teenage motherhood for a variety of poor offspring outcomes is a concern for clinicians and policymakers. The associations observed across such a wide array of adverse outcomes also suggest that multiple causal mechanisms may be implicated. PMID- 27769008 TI - Myelodysplastic syndromes: Aiming at deciphering their secrets. PMID- 27769007 TI - Health risk assessment of exposures to a high molecular weight plasticizer present in automobile interiors. AB - This study provides an exposure and risk assessment of diundecyl phthalate (DUP), a high molecular weight phthalate plasticizer present in automobile interiors. Total daily intake of DUP was calculated from DUP measured in wipe samples from vehicle seats from six automobiles. Four of the vehicles exhibited atypical visible surface residue on the seats. Two vehicles with no visible surface residue were sampled as a comparison. DUP was the predominant organic compound identified in each of the wipes from all seats. A risk assessment of DUP via oral, dermal, and inhalation routes resulting from contact with automobile seats was conducted. The mean, standard deviation, and maximum DUP concentrations on the seats with visible surface residue were 6983 +/- 7823 MUg/100 cm2 and 38300 MUg/100 cm2, respectively. The mean and 95th percentile of the mean for daily cumulative dose of DUP for all exposure routes for the seats with no visible surface residue ranged from 7 * 10-4 to 4 * 10-3 mg/kg-day and from 8 * 10-4 to 5 * 10-3 mg/kg-day, respectively. For seats with visible surface residue, cumulative doses ranged from 2 * 10-3 to 2 * 10-2 mg/kg-day and from 4 * 10-3 to 2 * 10-2 mg/kg-day, respectively. The estimated daily intake (contact or absorbed dose) of DUP from automobile seats were far lower than the NOAELs reported in and derived from animal studies, and are well below the reported Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Derived No Effect Levels (DNELs) for the general population. Based on this analysis, using virtually any benchmark for evaluating safety, exposure to DUP via automobile seat covers did not pose a measureable increased health-risk in any population under any reasonably plausible exposure scenario. PMID- 27769009 TI - Role of G protein-coupled estrogen receptor-1 in estradiol 17beta-induced alterations in protein synthesis and protein degradation rates in fused bovine satellite cell cultures. AB - In feedlot steers, estradiol-17beta (E2) and combined E2 and trenbolone acetate (a testosterone analog) implants enhance rate and efficiency of muscle growth; and, consequently, these compounds are widely used as growth promoters in several countries. Treatment with E2 stimulates protein synthesis rate and suppresses protein degradation rate in fused bovine satellite cell (BSC) cultures; however, the mechanisms involved in these effects are not known with certainty. Although the genomic effects of E2 mediated through the classical estrogen receptors have been characterized, recent studies indicate that binding of E2 to the G protein coupled estrogen receptor (GPER)-1 mediates nongenomic effects of E2 on cellular function. Our current data show that inhibition of GPER-1, matrix metalloproteinases 2 and 9 (MMP2/9), or heparin binding epidermal growth factor like growth factor (hbEGF) suppresses E2 stimulate protein synthesis rate in cultured BSCs (P < 0.001) suggesting that all of these are required in order for E2 to stimulate protein synthesis in these cultures. In contrast, inhibition of GPER-1, MMP2/9, or hbEGF has no effect on the ability of E2 to suppress protein degradation rates in fused BSC cultures indicating that these factors are not required in order for E2 to suppress protein degradation rate in these cells. Furthermore, treatment of fused BSC cultures with E2 increased (P < 0.05) pAKT levels indicating that the pAKT pathway may play a role in E2-stimulated effects on cultured BSC. In summary, our current data show that active GPER-1, MMP2/9, and hbEGF are necessary for E2-stimulated protein synthesis but not for E2 simulated suppression of protein degradation in cultured BSC. In addition, E2 treatment increases pAKT levels in cultured BSC. PMID- 27769010 TI - Secrecy inhibits support: A grounded theory of community perspectives of women suffering from obstetric fistula, in Kenya. AB - AIM: this study aimed to gain understanding of the views of community members in relation to obstetric fistula. DESIGN AND METHOD: a qualitative, grounded theory approach was adopted. Data were collected using in-depth interviews with 45 community members. The constant comparison method enabled generation of codes and subsequent conceptualisations, from the data. SETTING: participants were from communities served by two hospitals in Kenya; Kisii and Kenyatta. Interviews took place either in the home, place of work, or hospital. FINDINGS: the core category (central concept) is 'secrecy hinders support'. This was supported by three themes: 'keeping fistula hidden', 'treatment being a lottery' and 'multiple barriers to support.' These themes represent the complexities around exposure of individual fistula sufferers and the impact that lack of information and women's status can have on treatment. Keeping fistula secret reinforces uncertainties around fistula, which in itself fuels myths and ignorance regarding causes and treatments. Lack of openness, at an individual level, prevents support being sought or offered. CONCLUSIONS: A multi-layered strategy is required to support women with fistula. At a societal level, the status of women in LMIC countries needs elevation to a level that provides equity in health services. At a national level, laws need to protect vulnerable women from mistreatment as a direct result of fistula. Furthermore, resources should be available to ensure provision of timely management, as part of routine services. At community level, awareness and education is required to actively engage members to support women locally. Peer support before and after fistula repair may be beneficial, but requires further research. PMID- 27769011 TI - Exploring Dutch midwives' attitudes to promoting physiological childbirth: A qualitative study. AB - OBJECTIVE: to describe Dutch midwives' attitudes toward, and motivations for, the promotion of physiological childbirth and to identify factors associated with those attitudes and motivations. DESIGN: exploratory, qualitative design using focus groups. SETTING: The Netherlands. PARTICIPANTS: hospital- and community based midwives. FINDINGS: four themes emerged: physiological birth as a continuum, navigating the settings, woman-centeredness and competence and confidence. Midwives view the safeguarding and promotion of physiological childbirth as central to their role. They define physiological childbirth along a continuum that is related to the context of their practice. Hospital culture is seen as an inhibitor of practices that promote physiological birth. Midwives believe that woman-centred ways of working and challenging practices that are not evidence-based will promote physiological childbirth. KEY CONCLUSIONS: in order to become competent and confident practitioners of physiological childbirth midwives need to be aware of the factors that inhibit and encourage practices that support this way of giving birth. IMPLICATIONS FOR PRACTICE: midwives should consciously employ strategies that promote physiological birth in both home and hospital settings. Midwifery education and midwifery science research should focus on developing strategies that support midwives in this endeavor. PMID- 27769012 TI - A scoping review of how new midwifery practitioners transition to practice in Australia, New Zealand, Canada, United Kingdom and The Netherlands. AB - BACKGROUND: contemporary knowledge related to the experiences of new midwifery practitioners is limited to countries that run hospital-based transition to practice programmes within an employment contract arrangement, such as the United Kingdom, and Australia. Less is known of the experiences of New Midwifery Practitioners (NMPs) who transition into autonomous private practice in New Zealand, Canada and the Netherlands. PURPOSE: the purpose of this paper is to report on a scoping review of the way NMPs are transitioned to practice in the first year of registered practice across the selected countries. METHODS: this review accessed literature and government and professional sites to make comparisons between the transition to practice processes within five countries, and discusses the benefits and issues, associated with public hospital employment programs versus community based government funded midwifery group practices. FINDINGS: comparison of the way in which NMPs are transitioned to practice in the first year of registered practice between the selected countries shows important differences based on occupational organisation. Funding of maternity services influences how NMPs in each country are orientated and supported in their transition to registered practice. Direct comparisons between countries were difficult. More research is recommended to investigate NMPs' experiences of transition to practice in private practice. PMID- 27769013 TI - Reaction kinetics of the jasmonate-isoleucine complex formation during wound induced plant defense responses: A model-based re-analysis of published data. AB - Three studies were considered in which jasmonate-isoleucine levels were observed for several hours after plant wounding. The data from these studies were fitted to a first order kinetical model describing jasmonate-isoleucine complex formation and dissociation. It was found that the model could explain up to 97 percent of the variations in the data sets. In general, the data re-analysis confirmed that the protein-protein interactions involved in the biosynthesis and dissociation of the jasmonate-isoleucine complex are fast relative to the dynamics of the jasmonate levels themselves. Moreover, the data re-analysis supported the notion that transgenic plant manipulations affecting the defense responses in plants not only affect the jasmonate-isoleucine levels indirectly by affecting jasmonate levels during plant responses. Rather, it seems that transgenic plant manipulations affect kinetic rate parameters of the jasmonate isoleucine complex formation and dissociation reactions. In addition to these general findings, several specific conclusions for the three experimental studies were obtained. PMID- 27769014 TI - The interaction of adenovirus E1A with the mammalian protein Ku70/XRCC6. AB - Human adenovirus infects terminally differentiated cells and to replicate it must induce S-phase. The chief architects that drive adenovirus-infected cells into S phase are the E1A proteins, with 5 different isoforms expressed during infection. E1A remodels the infected cell by associating with cellular factors and modulating their activity. The C-terminus of E1A is known to bind to only a handful of proteins. We have identified a novel E1A C-terminus binding protein, Ku70 (XRCC6), which was found to bind directly within the CR4 of E1A from human adenovirus type 5. Depletion of Ku70 reduced virus growth, possibly by activating the DNA damage response pathway. Ku70 was found to localize to viral replication centers and associate with the viral genome. Ku70 was also recruited to cellular cell cycle regulated promoters following viral infection. Our study has identified, for the first time, Ku70 as a novel E1A-binding protein which affects virus life cycle. PMID- 27769015 TI - Breast density (BD) assessment with digital breast tomosynthesis (DBT): Agreement between QuantraTM and 5th edition BI-RADS(r). AB - PURPOSE: To assess the agreement between digital breast tomosynthesis (DBT) breast density (BD) assessment made using QuantraTM and fifth edition BI-RADS(r). MATERIALS AND METHODS: This board approved study involved BD assessment of 234 women undergoing DBT investigation. BD estimation was performed from the raw DBT images using QuantraTM 3 (v.2.1.1, Hologic, Bedford MA). BI-RADS(r) assessment was performed using prior digital mammograms displayed simultaneously with 2D images synthesized from DBT by three radiologists using the fifth edition BI RADS(r) (A, B, C, D). Kappa (k) was used to assess inter-reader agreement, agreement between QuantraTM and each reader, as well as the majority report of all readers. Receiver Operating Characteristic (ROC) analysis was used to assess the performance of QuantraTM in reproducing the majority BI-RADS(r) assessment. Data was then grouped into a two-category scale [almost entirely fatty and scattered fibroglandular tissue (A-B) versus heterogeneously dense and extremely dense (C-D)], and a further analysis performed. RESULTS: Inter-reader agreement varied from fair [0.38 (95%CI: 0.30-0.46)] to substantial [0.68 (95%CI: 0.61 0.75)] on a four-category scale and substantial [0.70 (95%CI: 0.61-0.78)] to almost perfect [0.85 (95%CI: 0.78-0.92)] on a two-category scale. Using the majority report, the agreement between BI-RADS(r) and QuantraTM was 0.68 (95%CI: 0.59-0.75) on a four-category scale and 0.86 (95%CI: 0.79-0.93) on a two-category scale. QuantraTM distinguished BI-RADS(r) A-B from C-D with 97.1% sensitivity and 83.1% specificity. CONCLUSION: Data demonstrate moderate to substantial agreement in BD assessment between fifth edition BI-RADS(r) and QuantraTM. PMID- 27769016 TI - The efficient physiological strategy of a tomato landrace in response to short term salinity stress. AB - Landraces represent an important part of the biodiversity well-adapted under limiting environmental conditions. We investigated the response of two Southern Italy tomato landraces, the well-known San Marzano (our commercial standard) and a local accession called "Ciettaicale", to different levels of sodium chloride in water irrigation (from 0 up to 600 mM) for a short-time exposure (one week). The combination of the chlorophyll a fluorescence and gas exchange analyses suggested that Ciettaicale maintained a higher efficiency of photosystem II (PSII) photochemistry and CO2 utilization at high salinity concentrations than San Marzano. Stomatal and non-stomatal limitations occurred in San Marzano according to the reduction of maximum efficiency of PSII photochemistry and the increase of intercellular CO2 concentration. Higher Na+/K+ ratio and higher concentration of total soluble sugars contributed to non-stomatal limitations in San Marzano leaves. These effects were significantly less evident in Ciettaicale. We also observed changes in total antioxidant capacity and leaf pigment content that emphasized the occurrence of modifications in the photosynthetic apparatus according to salt gradient. The more efficient assimilates supply and an integrated root protection system provided by sugars and antioxidants can explain the significantly higher root/shoot ratio in Ciettaicale. Overall, our results suggest that a comprehensive assessment of salinity tolerance in a genotypes comparison could be also obtained evaluating plant response to high salinity levels at early vegetative stage. In addition, further studies will be carried out in order to evaluate the possibility of using Ciettaicale in tomato improvement programs. PMID- 27769017 TI - Infant mortality in coroner/medical examiner investigations. AB - Infant mortality rate is generally regarded as a fundamental indicator of population health and is often used to validate public health interventions. Hamilton County, Ohio, has one of the highest rates in the nation. Most deaths that do not occur in the hospital fall under the jurisdiction of a coroner/medical examiner. We reviewed all infant deaths evaluated by the Hamilton County Coroner from 2006 to 2013 in order to identify opportunities for public health interventions. We predicted that the majority of these infant deaths were unintentional, but preventable. The eligible population included live born infants, who died less than one year of age. There were 217 cases of infant deaths during this time frame and 14 primary causes of death identified in this cohort. Sleep related deaths made up the majority of deaths (n = 141, 65%), a mean of 17.6 per year. This analysis identifies unsafe sleep patterns, particularly co-bedding and inappropriate sleep surface, as the most frequent contributing factors. Therefore, the coroner/medical examiner, working with public health and healthcare providers can generate information to drive targeted improvements in the outcome for infants. PMID- 27769018 TI - Simulated settings; powerful arenas for learning patient safety practices and facilitating transference to clinical practice. A mixed method study. AB - Poor teamwork is an important factor in the occurrence of critical incidents because of a lack of non-technical skills. Team training can be a key to prevent these incidents. The purpose of this study was to explore the experience of nursing and medical students after a simulation-based interprofessional team training (SBITT) course and its impact on professional and patient safety practices, using a concurrent mixed-method design. The participants (n = 262) were organized into 44 interprofessional teams. The results showed that two training sequences the same day improved overall team performance. Making mistakes during SBITT appeared to improve the quality of patient care once the students returned to clinical practice as it made the students more vigilant. Furthermore, the video-assisted oral debriefing provided an opportunity to strengthen interprofessional teamwork and share situational awareness. SBITT gave the students an opportunity to practice clinical reasoning skills and to share professional knowledge. The students conveyed the importance of learning to speak up to ensure safe patient practices. Simulated settings seem to be powerful arenas for learning patient safety practices and facilitating transference of this awareness to clinical practice. PMID- 27769019 TI - In pursuit of an optimal model of undergraduate nurse clinical education: An integrative review. AB - Clinical learning experiences are an essential part of nurse education programs. Numerous approaches to clinical education and student supervision exist. The aim of this integrative review was to explore how studies have compared or contrasted different models of undergraduate nurse clinical education. A search of eight databases was undertaken to identify peer-reviewed literature published between 2006 and 2015. Eighteen studies met the inclusion criteria. A diverse range of methodologies and data collection methods were represented, which primarily explored student experiences or perceptions. The main models of undergraduate nurse clinical education identified were: traditional or clinical facilitator model; the preceptorship or mentoring model; and the collaborative education unit model in addition to several novel alternatives. Various limitations and strengths were identified for each model with no single optimal model evident. Thematic synthesis identified four common elements across the models: the centrality of relationships; the need for consistency and continuity; the potential for variety of models; and the viability/sustainability of the model. The results indicate that effective implementation and key elements within a model may be more important than the overarching concept of any given model. Further research is warranted to achieve an agreed taxonomy and relate model elements to professional competence. PMID- 27769020 TI - Between two roles - Experiences of newly trained nurse practitioners in surgical care in Sweden: A qualitative study using repeated interviews. AB - The position of Nurse Practitioner is a new role in Nordic countries. The transition from a registered nurse to the Nurse Practitioner role has been reported to be a personal challenge. This study, guided by the Nordic theoretical model for use in the education of advanced practice nurses, represents a unique opportunity to describe this transition for newly graduated Nurse Practitioners in an interprofessional surgical care team in Sweden. The aim was to explore how the first Nurse Practitioners in surgical care experienced the transition into a new role and what competences they used in the team. Eight new Nurse Practitioners with parallel work in clinical practice were interviewed twice around the time of their graduation. The qualitative analyses show that the participants integrated several central competences, but the focus in this early stage in their new role was on direct clinical praxis, consultation, cooperation, case management, and coaching. Transition from the role of clinical nurse specialist to nurse practitioner was a challenging process in which the positive response from patients was a driving force for the new Nurse Practitioners. The participants felt prepared for and determined to solve the challenging situations they approached working in the interprofessional team. PMID- 27769021 TI - The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling. AB - Neuroinflammation remains the primary cause of morbidity and mortality in stroke induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro. SINO administration intraperitoneally alleviated the cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency after MCAO induction. SINO also attenuated astrocytic and microglial activation in the ischemic hemisphere. NLRP3 inflammasome activation after MCAO and OGD induction, with the up-regulation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and pro-inflammatory cytokines, was significantly inhibited by SINO treatment both in vivo and in vitro. In addition, SINO reversed the OGD-induced inhibition of AMPK phosphorylation in vitro. Further, the suppressive effect of SINO on NLRP3 inflammasomes was blocked by an AMPK inhibitor, Compound C. Our findings demonstrate that SINO exerts a neuroprotective effect in ischemic stroke by inhibiting NLRP3 inflammasomes via the AMPK pathway, which also provides evidence of a novel treatment for clinical stroke therapy. PMID- 27769022 TI - Tadalafil reduces airway hyperactivity and protects against lung and respiratory airways dysfunction in a rat model of silicosis. AB - Silicosis is a crippling respiratory disorder characterized by massive lung inflammation and fibrosis. The current study provides evidence on the protective potential of tadalafil; a specific phosphodiesterase-5 (PDE-5) inhibitor against experimentally-induced pulmonary silicosis in rats. Silicosis was induced by intranasal instillation of crystalline silica (50mg/rat). Halofuginone hydrobromide; a standard collagen-1 synthesis inhibitor was selected as a reference anti-fibrotic. Daily oral administration of tadalafil (1mg/kg) for 8weeks significantly ameliorated silica-induced pulmonary damage. BALF content of inflammatory cells, lung total protein, MDA, nitrite/nitrate, tumor necrosis factor alpha (TNFalpha), transforming growth factor beta1 (TGFbeta1) and collagen contents significantly declined with concomitant reduction in serum LDH activity; confirming reduction of silica-induced oxidative stress and inflammation. Meanwhile, lung SOD activity and GSH content significantly increased; confirming restoration of anti-oxidant defenses. Immunohistochemical analysis of lung TGFbeta1 expression was correlated with observed biochemical improvements. There was a significant decline in thickness of the walls of the blood vessels and in macrophages and alveolar septal expression of TGFbeta1 paralleled with reduction in collagen and extracellular matrix (ECM) components deposition. Ultimately, biochemical and histopathological improvements were accompanied by restoration of normal respiratory functions and reduction in airway hyperactivity and responses to both of carbachol and 5-HT. In conclusion; down-regulation of inflammatory and fibrogenic cytokines expression, restoration of oxidants/antioxidant hemostasis, antioxidant boost and promotion of angiogenesis are implicated in the observed protective effect of tadalafil. PMID- 27769023 TI - The important roles of type I interferon and interferon-inducible genes in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a severe autoimmune disease that causes multiple-organ dysfunction mainly affecting women in their childbearing years. Type I IFN synthesis is usually triggered by viruses, and its production is tightly regulated and limited in time in health individuals. However, many patients with systemic autoimmune diseases including SLE have signs of aberrant production of type I interferon (IFN) and display an increased expression of IFN inducible genes. Continuous type I IFNs derived from activated plasmacytoid dendritic cells (pDCs) by interferogenic immune complexes (ICs) and migration of these cells to tissues both break immune tolerance and promote an on-going autoimmune reaction in human body. By the means of detecting type I IFNs and IFN inducible genes, it can help with diagnosis and evaluation of SLE in early stage and more efficiently. Anti-IFN-alpha monoclonal antibodies in SLE patients were recently reported and is now being investigated in phase II clinical trails. In this review, we focus on recent research progress in type I IFN and IFN-inducible genes. Possible mechanisms behind the dysregulated type I IFN system in SLE and how they contribute to the development of an autoimmune process, and act as a biomarker and therapeutic target will be reviewed. PMID- 27769024 TI - Complex hepatic injury involving a liver transplant recipient: A case report and review of literature. PMID- 27769025 TI - Primary retroperitoneal mature cystic teratoma in an adult: A case report. AB - BACKGROUND: Mature cystic teratoma is one of the most common tumors of the ovaries; however, primary retroperitoneal lesions are rare entities in adults. CASE SUMMARY: We report a case of a 33 year-old woman noticing a mass in her epigastric and left upper abdominal region without any specific signs and symptoms. Radiological evaluation revealed a retroperitoneal mass with extension from the posterior aspect of the pancreas to the pelvic cavity, composed of calcifications and cystic elements. CONCLUSION: The tumor was resected through a midline laparotomy and the pathology report confirmed the diagnosis of a mature cystic teratoma with no evidence of malignancy or immature components. PMID- 27769026 TI - Aneurysmal degeneration of vein conduit used for vascular reconstruction-Case report and literature review. AB - INTRODUCTION: Popliteal artery aneurysms (PAA) are the most prevalent form of peripheral arterial aneurysms. Greater saphenous vein grafts and endoaneurysmorrhaphy remains the mainstay therapy for open repair of PAA. True aneurysmal degeneration of lower extremity infrainguinal autologous vein grafts are relatively rare and its etiology is not completely understood. CASE PRESENTATION: We present a case of a 57-year-old man with recurrent autologous venous graft aneurysmal dilatations following a surgical popliteal artery aneurysm repair. DISCUSSION: The pathogenesis of true aneurysmal graft dilatation remains speculative with possible pathogenesis including progression of underlying atherosclerosis, systemic dilating diathesis, autologous venous graft varicosities, low-grade infections and post-stenotic dilatations. Management of venous graft aneurysms should be subjected to the same criteria as other aneurysms. Diagnosis requires a high index of suspicion. The initial study of choice is duplex ultrasonography as it can diagnose the aneurysm and distinguish it from other popliteal masses, provide accurately measurements and identify thrombus within the aneurysm. Once diagnosed, surgical repair should be performed as soon as possible as graft dilatation tends to occur overtime and is typically followed by a rapid increase in size over a short period of time. CONCLUSION: Aneurysmal degeneration of autologous saphenous venous graft following PAA repairs occur infrequently. Its etiology remains largely speculative. Accurate diagnosis and early surgical intervention can prevent progression of aneurysmal dilatation and minimize the potential of complications. PMID- 27769027 TI - Choledochal cyst Todani IA case report. AB - BACKGROUND: Choledochal cyst is a congenital dilatation of the biliary tree. It may affect only the extrahepatic bile duct (type I, II and III), intrahepatic (type V) or both (type IVa). Vater first described choledochal cyst in 1723. Open excision was the standard procedure made a great impact in the treatment but since 1995 Farello et al. first reported laparoscopic choledochal cyst excision and this has been used worldwide. CASE REPORT: Female, 17 years old, past medical history two years ago a laparoscopic cholecystectomy for gallbladders. Chief complain epigastric pain one that begins one week ago intensity 10/10, accompanying nausea and jaundiced skin. An ERCP is performed and shows choledochal cyst and a dilator is placed with improved jaundiced tint, cholangiopancretography requested, which reports that the cyst does not invade continuous areas. Then it was performed resection of the cyst by laparoscopy. DISCUSSION: Choledochal cyst is a well described albeit rare clinical entity. Diagnosis and management are important because patients may develop cholangiocarcinoma. The elective treatment for type IA choledochal cyst is resection of the cyst with Roux-en-Y hepaticojejunostomy or hepaticoduodenostomy. CONCLUSION: Laparoscopic surgery is a safe way with a shorter length of stay, less postoperative morbidity and a lower blood loss when compared with open approach. This technique is also favorable from a cosmetic viewpoint. With the improvement of laparoscopic techniques and deftness of surgeons practice, laparoscopic surgery may become the first choice procedure for choledochal cyst. PMID- 27769028 TI - Insulin-like growth factor 1 (IGF1) affects proliferation and differentiation and wound healing processes in an inflammatory environment with p38 controlling early osteoblast differentiation in periodontal ligament cells. AB - OBJECTIVE: The objective of this study was to investigate effects of insulin-like growth factor 1 (IGF1) on proliferation, wound healing and differentiation processes of human periodontal ligament (PDL) cells under inflammatory conditions and whether the protective, anabolic effects of IGF1 can attenuate unfavorable effects of interleukin-1beta (IL-1beta). DESIGN: Inflammation was mimicked through cell stimulation with IL-1beta. PDL cells were characterized in respect to the presence of components of the IGF system and the responsive potential on IL-1beta incubation. Gene expression levels were analyzed by quantitative real time PCR. Cellular localization of target proteins was visualized using fluorescent-based immunohistochemistry. Effects on cell division were investigated by proliferation assays. Wound healing was analyzed using light microscopic techniques. Differentiation was quantified by measuring biomineralization and osteoblast-specific alkaline phosphatase enzyme activity. RESULTS: PDL cell proliferation and wound healing were positively affected by IGF1 and the combination of IGF1 with IL-1beta, while only IL-1beta showed negative effects. Biomineralization was enhanced by IGF1, IL-1beta, and the combination of both stimulants. Osteoblast differentiation was increased by IL 1beta and the combination of IL-1beta with IGF1, whereas only IGF1 negatively affected ALP activity. Phosphorylation of p38 was regulated by IL-1beta and IGF1. CONCLUSIONS: The data presented in this work showed a potential of IGF1 to improve wound healing and proliferation processes and to sustain cell differentiation under inflammatory stimuli in PDL cells. PMID- 27769029 TI - Synthesis, nematocidal activity and SAR study of novel difluoromethylpyrazole carboxamide derivatives containing flexible alkyl chain moieties. AB - A series of novel difluoromethylpyrazole carboxamides derivatives were synthesized by introduction of flexible alkyl chain. Nematicidal bioassay results showed that some of them exhibited good control efficacy against M. incognita, which indicated that these difluoromethylpyrazole carboxamides derivatives might be potential novel lead compounds for discovery new nematicides. The nematicidal activity was affected by the substituted position in the molecule, especially the substitution group on the alkyl chain. It was found that the compound 6-9 and 6 23 possess about 50% inhibition effect against M. incognita even at 5.0 and 1.0 mg L-1. Meanwhile, greenhouse field trial showed the nematicidal activity of compound 6-9 is a litter weaker than that of Abamectin. The mammalian toxicology results indicated that compound 6-9 was a low-toxicity and low-sensitive compound. In conclusion compound 6-9 is a potential candidate for further development. In addition, the molecular docking simulations revealed that compounds 6 with a flexible NHCOO show its binding affinities for the acetylcholine receptor (AChR), which may provide useful information for further design novel nematicides. PMID- 27769030 TI - Differential characterization using readily accessible NMR experiments of novel N and O-alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives with antimycobacterial activity. AB - During the construction of bioactive molecules, regioselective alkylation of heterocyclic, N/O ambident nucleophiles is a frequently encountered synthetic transformation. In this framework, specific attention is required to unambiguously determine the structures of obtained reaction products. As part of our project on quinoloxyacetamide based antimycobacterial agents, a series of N- or O- alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives were prepared during the course of which we observed unexpected selectivity issues. After finding that no consistent procedure existed in the literature for assigning regioisomers of this type, we applied three readily accessible NMR experiment types (13C NMR, HSQC/HMBC and NOE) to resolve any uncertainties regarding the obtained regioisomeric structures. Furthermore, the antimycobacterial activity of all final compounds was evaluated with the best compound 23 showing potent antitubercular activity (MIC = 1.25 MUM) without cytotoxic effects. PMID- 27769031 TI - Synthesis, SAR and pharmacological characterization of novel anthraquinone cation compounds as potential anticancer agents. AB - Emodin, a natural anthraquinone derivative isolated from Rheum palmatum L., has been demonstrated to exhibit good anti-cancer effect. In this study, a series of novel quaternary ammonium salts of emodin, anthraquinone and anthrone were synthesized and their anticancer activities were tested in vitro. The effects of emodin quaternary ammonium salts on cell viability, apoptosis, intracellular ROS, and mitochondrial membrane potential were investigated in A375, BGC-823, HepG2 and HELF cells. The results demonstrated that compound 4a induced morphological changes and decreased cell viability. Apoptosis triggered by compound 4a was visualized using DAPI staining and Annexin V-FITC/PI staining. Compound 4a induced apoptosis of A375 cells were showed to be associated with the dissipation of mitochondrial membrane potential (DeltaPsim) as a result of the up-regulation of P53 and Caspase-3. When cancer cells were treated with emodin derivative, their ability to generate reactive oxygen species (ROS) rose significantly and the mitochondrial membrane potential decreased. Additionally, confocal microscopy assay confirmed that compound 4a was primarily located in the mitochondria of A375 cells. These results suggested that compound 4a has the potential for use in cancer therapy. PMID- 27769032 TI - Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells. AB - Doxorubicin (DOX) belongs to the anthracycline class of drugs that are used in the treatment of various cancers. It has limited cystostatic effects in therapeutic doses, but higher doses can cause cardiotoxicity. In the current approach, we conjugated a peptidomimetic (Arg-aminonaphthylpropionic acid-Phe, compound 5) known to bind to HER2 protein to DOX via a glutaric anhydride linker. Antiproliferative assays suggest that the DOX-peptidomimetic conjugate has activity in the lower micromolar range. The conjugate exhibited higher toxicity in HER2-overexpressed cells than in MCF-7 and MCF-10A cells that do not overexpress HER2 protein. Cellular uptake studies using confocal microscope experiments showed that the conjugate binds to HER2-overexpressed cells and DOX is taken up into the cells in 4 h compared to conjugate in MCF-7 cells. Binding studies using surface plasmon resonance indicated that the conjugate binds to the HER2 extracellular domain with high affinity compared to compound 5 or DOX alone. The conjugate was stable in the presence of cells with a half-life of nearly 4 h and 1 h in human serum. DOX is released from the conjugate and internalized into the cells in 4 h, causing cellular toxicity. These results suggest that this conjugate can be used to target DOX to HER2-overexpressing cells and can improve the therapeutic index of DOX for HER2-positive cancer. PMID- 27769033 TI - Urea-containing peptide boronic acids as potent proteasome inhibitors. AB - A novel class of urea-containing peptide boronic acids as proteasome inhibitors was designed by introducing a urea scaffold to replace an amido bond. Compounds were synthesized and their antitumor activities were evaluated. After two rounds of optimizations, the compound I-14 was found to be a potent proteasome inhibitor. Compared with Bortezomib, I-14 showed higher potency against the chymotrypsin-like activity of human 20S proteasome (IC50 < 1 pM), similar potency against four different cancer cell lines (IC50 < 10 nM), and better pharmacokinetic profile. Furthermore, I-14 significantly inhibited tumor growth in Bel7404 mouse xenograft model. The excellent proteasome inhibition by I-14 was rationalized through docking and molecular dynamics studies. PMID- 27769034 TI - Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors. AB - A new series of [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 inhibitors were designed, synthesized, and further evaluated for their cytotoxicity against MGC 803, EC109, A549 and PC-9 cells as well as the ability of inhibiting LSD1. Some of these compounds showed potent inhibition toward LSD1 and selectively inhibited growth of A549 and PC-9 cells. Compound 6l potently inhibited growth of PC-9 cells (IC50 = 0.59 MUM), about 4-fold more potent than 5-FU. Further SARs studies led to the identification of compounds 6l-m, which had good growth inhibition against all the tested cancer cell lines and were much more potent than 5-FU and GSK2879552. Besides, compounds 5p, 5q and 6i inhibited LSD1 potently (IC50 = 0.154, 1.19 and 0.557 MUM, respectively). Docking studies revealed that compound 5p formed arene-H interactions with Val333 and hydrogen bonds with surrounding Ala331, Met332, and Ala539 residues. Compound 5p significantly inhibited migration of A549 and PC-9 cells in a concentration-dependent manner, but had different effect on the expression of E-cadherin and N-cadherin. The [1,2,4]triazolo[1,5-a]pyrimidine scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy. PMID- 27769035 TI - Synthesis and biological evaluation of chemical tools for the study of Dolichol Linked Oligosaccharide Diphosphatase (DLODP). AB - Citronellyl- and solanesyl-based dolichol linked oligosaccharide (DLO) analogs were synthesized and tested along with undecaprenyl compounds for their ability to inhibit the release of [3H]OSP from [3H]DLO by mammalian liver DLO diphosphatase activity. Solanesyl (C45) and undecaprenyl (C55) compounds were 50 500 fold more potent than their citronellyl (C10)-based counterparts, indicating that the alkyl chain length is important for activity. The relative potency of the compounds within the citronellyl series was different to that of the solanesyl series with citronellyl diphosphate being 2 and 3 fold more potent than citronellyl-PP-GlcNAc2 and citronellyl-PP-GlcNAc, respectively; whereas solanesyl PP-GlcNAc and solanesyl-PP-GlcNAc2 were 4 and 8 fold more potent, respectively, than solanesyl diphosphate. Undecaprenyl-PP-GlcNAc and bacterial Lipid II were 8 fold more potent than undecaprenyl diphosphate at inhibiting the DLODP assay. Therefore, at least for the more hydrophobic compounds, diphosphodiesters are more potent inhibitors of the DLODP assay than diphosphomonoesters. These results suggest that DLO rather than dolichyl diphosphate might be a preferred substrate for the DLODP activity. PMID- 27769036 TI - Green fluorescent protein chromophore derivatives as a new class of aldose reductase inhibitors. AB - A number of (Z)-4-arylmethylene-1H-imidazol-5(4H)-ones, which are related to the fluorescent chromophore of the Aequorea green fluorescent protein (GFP), have been synthesized and evaluated their in vitro inhibitory activity against recombinant human aldose reductase for the first time. The GFP chromophore model 1a, with a p-hydroxy group on the 4-benzylidene and a carboxymethyl group on the N1 position, exhibited strong bioactivity with an IC50 value of 0.36 MUM. This efficacy is higher than that of sorbinil, a known highly potent aldose reductase inhibitor. Compound 1h, the 2-naphtylmethylidene analogue of 1a, exhibited the best inhibitory effect among the tested copounds with an IC50 value of 0.10 MUM. Structure-activity relationship studies combined with docking simulations revealed the interaction mode of the newly synthesized inhibitors toward the target protein as well as the structural features required to gain a high inhibitory activity. In conclusion, the GFP chromophore model compounds synthesized in this study have proved to be potential drugs for diabetic complications. PMID- 27769037 TI - Multi-targeting exploration of new 2-aminothiazolyl quinolones: Synthesis, antimicrobial evaluation, interaction with DNA, combination with topoisomerase IV and penetrability into cells. AB - A series of new potentially multi-targeting antimicrobial 2-aminothiazolyl quinolones were designed, synthesized and characterized by 1H NMR, 13C NMR, IR, MS and HRMS spectra. Bioactive assay manifested that some of the prepared compounds showed moderate to good antibacterial and antifungal activities. Noticeably, compound 10f could effectively inhibit the growth of B. typhi and MRSA with MIC values of 1 and 8 MUg/mL, respectively. Experimental results revealed that compound 10f was membrane-active and had the ability to rapidly kill the tested strains and effectively prevent the development of bacterial resistance. Moreover, this compound also exhibited low toxicity against L929 cells. Molecular docking indicated that compound 10f could bind with topoisomerase IV-DNA complexes through hydrogen bonds and hydrophobic interactions. Quantum chemical studies were also performed on 10f to understand the structural features essential for activity. The preliminary mechanism research suggested that compound 10f could intercalate into calf thymus DNA to form a steady supramolecular complex which might block DNA replication to exert the powerful bioactivities. PMID- 27769038 TI - Epstein-Barr virus associated with a lymphoma-mimicking lesion of the uterine cervix. PMID- 27769039 TI - Unusual infant eosinophilia: myeloid neoplasm with FGFR1 abnormality. PMID- 27769040 TI - MicroRNA-like viral small RNA from porcine reproductive and respiratory syndrome virus negatively regulates viral replication by targeting the viral nonstructural protein 2. AB - Many viruses encode microRNAs (miRNAs) that are small non-coding single-stranded RNAs which play critical roles in virus-host interactions. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically impactful viruses in the swine industry. The present study sought to determine whether PRRSV encodes miRNAs that could regulate PRRSV replication. Four viral small RNAs (vsRNAs) were mapped to the stem-loop structures in the ORF1a, ORF1b and GP2a regions of the PRRSV genome by bioinformatics prediction and experimental verification. Of these, the structures with the lowest minimum free energy (MFE) values predicted for PRRSV-vsRNA1 corresponded to typical stem-loop, hairpin structures. Inhibition of PRRSV-vsRNA1 function led to significant increases in viral replication. Transfection with PRRSV-vsRNA1 mimics significantly inhibited PRRSV replication in primary porcine alveolar macrophages (PAMs). The time dependent increase in the abundance of PRRSV-vsRNA1 mirrored the gradual upregulation of PRRSV RNA expression. Knockdown of proteins associated with cellular miRNA biogenesis demonstrated that Drosha and Argonaute (Ago2) are involved in PRRSV-vsRNA1 biogenesis. Moreover, PRRSV-vsRNA1 bound specifically to the nonstructural protein 2 (NSP2)-coding sequence of PRRSV genome RNA. Collectively, the results reveal that PRRSV encodes a functional PRRSV-vsRNA1 which auto-regulates PRRSV replication by directly targeting and suppressing viral NSP2 gene expression. These findings not only provide new insights into the mechanism of the pathogenesis of PRRSV, but also explore a potential avenue for controlling PRRSV infection using viral small RNAs. PMID- 27769041 TI - MiR-384 inhibits human colorectal cancer metastasis by targeting KRAS and CDC42. AB - Colorectal cancer (CRC) is the third most common cancer worldwide. Metastatic progression is a primary factor contributing to lethality of CRC patients. However, the molecular mechanisms forming early local invasion and distant metastatic colonies are still unclear and the present therapeutic approaches for CRC are unsatisfactory. Therefore, novel therapies targeting metastatic invasion that could prevent tumor spreading and recurrence are urgently needed. Our study showed that the decrease of miR-384 was found in 83.0% (83/100) CRC patients. And low-leveled expression of miR-384 was closely correlated with the invasive depth, lymph node and distant metastasis of CRC. Overexpression of miR-384 could inhibit the invasive and migrating abilities of CRC cells in vitro and the metastatic potential in vivo. Luciferase assays showed that miR-384 repressed the expression of Kirsten Ras (KRAS) and Cell division cycle 42 (CDC42) by directly targeting their 3'-untranslated regions. There is functional and mechanistic relationship between miRNA-384 and KRAS, CDC42 in the invasion and metastasis of CRC. And our findings suggest that miR-384could be a potent therapeutic target for CRC. Restoration of miR-384 expression might provide novel therapeutic approach to the reduction of CRC metastasis. PMID- 27769042 TI - ALK FISH patterns and the detection of ALK fusions by next generation sequencing in lung adenocarcinoma. AB - Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK -FISH patterns to next -generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib. 72 (4%) of 2116 lung adenocarcinoma were positive by ALK- FISH. Of 28 ALK-FISH positive cases selected for the study, FISH patterns included 15 (54%) cases with split signal, 10 (36%) with single orange signal and 3 (10%) with "mixed pattern". 12 (80%) cases with split signal and 4 (40%) cases with single orange signal were positive by NGS and IHC, while mixed cases were all negative. Mutation analysis of discordant cases revealed multiple mutations including oncogenic mutations in EGFR, KRAS, BRAF and ATM genes. All discordant cases in groups with split and mixed signal showed a lower number of cells with rearrangement (mean 28.5%; range 20.5-36.9%). No statistically significant association between response to crizotinib and FISH patterns was observed (p=0.73). In contrast, NGS fusion positive cases were associated with more responses to crizotinib than NGS negative cases (p= 0.016). Our study suggests that ALK FISH alone may not be the most reliable assay for detection of ALK gene rearrangements, and probably should be used in parallel with ALK IHC and NGS for detection of gene fusions and mutations. PMID- 27769044 TI - Diagnostic value of fibulin-3 for malignant pleural mesothelioma: A systematic review and meta-analysis. AB - BACKGROUND: Several studies have investigated the diagnostic value of fibulin-3 for malignant pleural mesothelioma (MPM), but the results were various. Therefore, we performed a systematic review and meta-analysis to evaluate the diagnostic value of fibulin-3 for MPM. RESULTS: Eight studies were included in this work. The overall sensitivity of blood fibulin-3 were 0.87 (95% CI, 0.58 - 0.97) and 0.89 (95% CI, 0.77 - 0.95), respectively. The overall sensitivity and specificity of PF fibulin-3 for MPM were 0.73 (95% CI, 0.54 - 0.86) and 0.80 (95% CI, 0.60 - 0.91), respectively. The area under curve of blood and pleural effusion (PF) Fibulin-3 were 0.94 (95% CI, 0.91 - 0.96) 0.83 (95% CI, 0.79 - 0.86), respectively. METHODS: PubMed and EMBASE databases were searched up to July 29, 2016 to verify studies investigating the diagnostic value of fibulin-3 for MPM. The quality of eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy tool (QUADAS-2). The overall sensitivity and specificity were pooled using a bivariate model. CONCLUSION: Fibuoin-3 is a useful diagnostic marker for MPM. PMID- 27769046 TI - Association of FCGR2A/FCGR3A variant rs2099684 with Takayasu arteritis in the Han Chinese population. AB - Takayasu arteritis (TA) is a chronic large-vessel vasculitis of unclear pathogenesis. A recent genome-wide association study (GWAS) has revealed that the FCGR2A/FCGR3A, EEFSEC, RPS9/LILRB3, RIPPLY2 and MLX genes confer susceptibility to TA. We investigated the linkage between presumptive TA-related genes (FCGR2A/FCGR3A, EEFSEC, RPS9/LILRB3, RIPPLY2 and MLX) and TA in the Han Chinese population.We performed a large case-control multi-center study of 412 Han Chinese TA patients and 597 ethnically matched healthy controls. Five single nucleotide polymorphisms (SNPs) were assessed and genotyped using Sequenom MassArray system (iPLEX assay, Sequenom, San Diego, CA, USA).The frequency of the rs2099684 variant G allele in the FCGR2A/FCGR3A gene was significantly higher in the TA patients than in the controls (37.5% compared with 25.4%, OR =1.77, 95% CI: 1.46-2.14, Pc =1.5*10-8). Similar results were observed in genotype distribution analysis and logistic regression analyses conducted using three genetic models. The allele and genotype distributions for the other polymorphisms were not significantly associated with TA among the Han Chinese patients.The SNP rs2099684 in FCGR2A/FCGR3A can be considered a genetic risk factor for TA in the Chinese Han population. These findings provide further insights into the etiopathogenesis of TA. PMID- 27769045 TI - Inducible expression of cancer-testis antigens in human prostate cancer. AB - Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors. PMID- 27769047 TI - The microRNA miR-33a suppresses IL-6-induced tumor progression by binding Twist in gallbladder cancer. AB - Cytokine is a key molecular link between chronic inflammation and gallbladder cancer (GBC) progression. The potential mechanism of cytokine-associated modulation of microRNAs (miRNAs) expression in GBC progression is not fully understood. In this study, we investigated the biological effects and prognostic significance of interleukin-6 (IL-6) -induced miRNAs in the development of GBC. We identify that inflammatory cytokine, IL-6 promotes proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GBC both in vitro and in vivo. Among all the changed miRNAs in miRNA profiling, miR-33a expression was significantly decreased in IL-6 treated GBC cell lines, as well as in GBC tissues compared with case-matched normal tissues and cholecystitis tissues. In turn, miR 33a suppresses IL-6-induced tumor metastasis by directly binding Twist which was identified as an EMT marker. High expression of miR-33a suppressed xenograft tumor growth and dissemination in nude mice. The downregulation of miR-33a was closely associated with advanced clinical stage, lymph node metastasis, and poor clinical outcomes in patients with GBC. miR-33a acts as a tumor suppressor miRNA in GBC progression and may be considered for the development of potential therapeutics against GBC. PMID- 27769048 TI - FAM83D associates with high tumor recurrence after liver transplantation involving expansion of CD44+ carcinoma stem cells. AB - To investigate the potential oncogene promoting recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT), throughput RNA sequencing was performed in a subgroup of HCC patients. The up-regulated FAM83D in HCC tissues was found and further verified in 150 patients by real-time PCR and immunohistochemistry. FAM83D overexpression significantly correlated with high HCC recurrence rate following LT and poor HCC characteristics such as high AFP, poor differentiation. Of cancer stem cells (CSCs) markers, CD44 expression was effectively suppressed when FAM83D was knocked down by siRNA. Meanwhile, the siRNA transfected cells suppressed formation of sphere and ability of self-renew. In a xenograft tumorigenesis model, FAM83D knockdown apparently inhibited tumor growth and metastasis. Microarray assays revealed that FAM83D promotes CD44 expression via activating the MAPK, TGF-beta and Hippo signaling pathways. Furthermore, CD44 knockdown presented reverse effect on above signaling pathways, which suggested that FAM83D was a key activator of loop between CD44 and above signaling pathways. In conclusion, FAM83D promotes HCC recurrence by promoting CD44 expression and CD44+ CSCs malignancy. FAM83D provides a novel therapeutic approach against HCC recurrence after LT. PMID- 27769049 TI - miR-424 acts as a tumor radiosensitizer by targeting aprataxin in cervical cancer. AB - Previous studies have shown that some dysregulated miRNAs are involved in radioresistance of tumor cells. Here, we identified significantly decreased miR 424 expression in radioresistant cervical cancer cells and specimens from cervical cancer patients with radioresistance compared to their radiosensitive parental cells and specimens from radiosensitive patients, respectively. Ectopic expression of miR-424 significantly increased radiation-induced DNA damage, cell apoptosis and G2/M cell cycle arrest in radioresistant cervical cancer cells. Notably, miR-424 agomiR treatment can sensitize radioresistant cervical cancer cells to radiation in a xenograft model. Furthermore, we demonstrated that miR 424 regulated radiosensitivity by directly targeting aprataxin. Taken together, these findings suggest that miR-424 acts as a radiosensitizing miRNA and reveal a new therapeutic strategy for radioresistant cervical cancers. PMID- 27769050 TI - Protein phosphatase Mg2+/Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated-p53-induced signals. AB - We previously demonstrated that the activation of alpha9-nicotinic acetylcholine receptor (alpha9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in alpha9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F-knockdown and -overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro, nicotine induced PPM1F expression, whereas alpha9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of alpha9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy. PMID- 27769051 TI - Melatonin promotes goat spermatogonia stem cells (SSCs) proliferation by stimulating glial cell line-derived neurotrophic factor (GDNF) production in Sertoli cells. AB - Melatonin has been reported to be an important endogenous hormone for regulating neurogenesis, immunityand the biological clock. Recently, the effects of melatonin on neural stem cells (NSCs), mesenchymal stem cells(MSCs), and induced pluripotent stem cells(iPSCs) have been reported; however, the effects of melatonin on spermatogonia stem cells (SSCs) are not clear. Here, 1MUM and 1nM melatonin was added to medium when goat SSCs were cultured in vitro, the results showed that melatonin could increase the formation and size of SSC colonies. Real time quantitative PCR (QRT-PCR) and western blot analysis showed that the expression levels of SSC proliferation and self-renewal markers were up regulated. Meanwhile, QRT-PCR results showed that melatonin inhibit the mRNA expression level of SSC differentiation markers. ELISA analysis showed an obvious increase in the concentration of GDNF (a niche factor secreted by Sertoli cells) in the medium when treated with melatonin. Meanwhile, the phosphorylation level of AKT, a downstream of GDNF-GFRa1-RET pathway was activated. In conclusion, melatonin promotes goat SSC proliferation by stimulating GDNF production in Sertoli cells. PMID- 27769053 TI - Effect of marital status on the survival of patients with hepatocellular carcinoma treated with surgical resection: an analysis of 13,408 patients in the surveillance, epidemiology, and end results (SEER) database. AB - Marital status has been reported as an independent prognostic factor for survival in various cancers, but it has been rarely studied in hepatocellular carcinoma (HCC) treated by surgical resection. We retrospectively investigated Surveillance, Epidemiology, and End Results (SEER) population-based data and identified 13,408 cases of HCC with surgical treatment between 1998 and 2013. The patients were categorized according to marital status, as "married," "never married," "widowed," or "divorced/separated." The 5-year HCC cause-specific survival (HCSS) data were obtained, and Kaplan-Meier methods and multivariate Cox regression models were used to ascertain whether marital status is also an independent prognostic factor for survival in HCC. Patients in the widowed group had the higher proportion of women, a greater proportion of older (>60 years) patients, more frequency in latest year of diagnosis (2008-2013), a greater number of tumors at TNM stage I/II, and more prevalence at localized SEER Stage, all of which were statistically significant within-group comparisons (P < 0.001). Marital status was demonstrated to be an independent prognostic factor by multivariate survival analysis (P < 0.001). Married patients had better 5-year HCSS than did unmarried patients (46.7% vs 37.8%) (P < 0.001); conversely, widowed patients had lowest HCSS compared with all other patients, overall, at each SEER stage, and for different tumor sizes. Marital status is an important prognostic factor for survival in patients with HCC treated with surgical resection. Widowed patients have the highest risk of death compared with other groups. PMID- 27769052 TI - Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration. AB - Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with Delta9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggesting their use in combination therapy. In the current study, we evaluated the effects of THC alone and in combination with CBD in MM cell lines. We found that CBD and THC, mainly in combination, were able to reduce cell viability by inducing autophagic-dependent necrosis. Moreover, we showed that the CBD-THC combination was able to reduce MM cells migration by down regulating expression of the chemokine receptor CXCR4 and of the CD147 plasma membrane glycoprotein. Furthermore, since the immuno-proteasome is considered a new target in MM and also since carfilzomib (CFZ) is a new promising immuno proteasome inhibitor that creates irreversible adducts with the beta5i subunit of immuno-proteasome, we evaluated the effect of CBD and THC in regulating the expression of the beta5i subunit and their effect in combination with CFZ. Herein, we also found that the CBD and THC combination is able to reduce expression of the beta5i subunit as well as to act in synergy with CFZ to increase MM cell death and inhibits cell migration. In summary, these results proved that this combination exerts strong anti-myeloma activities. PMID- 27769054 TI - Biopsy proportion of tumour predicts pathological tumour response and benefit from chemotherapy in resectable oesophageal carcinoma: results from the UK MRC OE02 trial. AB - BACKGROUND: Neoadjuvant chemotherapy followed by surgery is the standard of care for UK patients with locally advanced resectable oesophageal carcinoma (OeC). However, not all patients benefit from multimodal treatment and there is a clinical need for biomarkers which can identify chemotherapy responders. This study investigated whether the proportion of tumour cells per tumour area (PoT) measured in the pre-treatment biopsy predicts chemotherapy benefit for OeC patients. PATIENTS AND METHODS: PoT was quantified using digitized haematoxylin/eosin stained pre-treatment biopsy slides from 281 OeC patients from the UK MRC OE02 trial (141 treated by surgery alone (S); 140 treated by 5 fluorouracil/cisplatin followed by surgery (CS)). The relationship between PoT and clinicopathological data including tumour regression grade (TRG), overall survival and treatment interaction was investigated. RESULTS: PoT was associated with chemotherapy benefit in a non-linear fashion (test for interaction, P=0.006). Only patients with a biopsy PoT between 40% and 70% received a significant survival benefit from neoadjuvant chemotherapy (N=129; HR (95%CI):1.94 (1.39-2.71), unlike those with lower or higher PoT (PoT<40%, N=39, HR:1.25 (0.66-2.35); PoT>70% (N=28, HR:0.65 (0.36-1.18)). High pre-treatment PoT was related to lack of primary tumour regression (TRG 4 or 5), P=0.0402. CONCLUSIONS: This is the first study to identify in a representative subgroup of OeC patients from a large randomized phase III trial that the proportion of tumour in the pre-chemotherapy biopsy predicts benefit from chemotherapy and may be a clinically useful biomarker for patient treatment stratification.Proportion of tumour is a novel biomarker which can be measured in the pre-treatment diagnostic biopsy and which may enable the identification of chemotherapy responders and non-responders among patients with oesophageal carcinoma. Proportion of tumour could easily become part of the routine reporting of oesophageal cancer biopsies and may aid in managing patients with borderline resectable cancer. PMID- 27769055 TI - Progesterone potentiates the growth inhibitory effects of calcitriol in endometrial cancer via suppression of CYP24A1. AB - Here, we evaluated the expression of CYP24A1, a protein that inactivates vitamin D in tissues. CYP24A1 expression was increased in advanced-stage endometrial tumors compared to normal tissues. Similarly, endometrial cancer cells expressed higher levels of CYP24A1 than immortalized endometrial epithelial cells. RT-PCR and Western blotting were used to examine CYP24A1 mRNA and protein levels in endometrial cancer cells after 8, 24, 72, and 120 h of exposure to progesterone, progestin derivatives and calcitriol, either alone or in combination. Progestins inhibited calcitriol-induced expression of CYP24A1 and splice variant CYP24SV mRNA and protein in cancer cells. Furthermore, actinomycin D, but not cycloheximide, blocked calcitriol-induced CYP24A1 splicing. siRNA-induced knockdown of CYP24A1 expression sensitized endometrial cancer cells to calcitriol induced growth inhibition. These data suggest that CYP24A1 overexpression reduces the antitumor effects of calcitriol in cancer cells and that progestins may be beneficial for maintaining calcitriol's anti-endometrial cancer activity. PMID- 27769056 TI - Nuclear FOXO3 predicts adverse clinical outcome and promotes tumor angiogenesis in neuroblastoma. AB - Neuroblastoma is the most frequent, extracranial solid tumor in children with still poor prognosis in stage IV disease. In this study, we analyzed FOXO3 phosphorylation and cellular localization in tumor biopsies and determined the function of this homeostasis regulator in vitro and in vivo. FOXO3 phosphorylation at threonine-32 (T32) and nuclear localization in biopsies significantly correlated with stage IV disease. DNA-damaging drugs induced nuclear accumulation of FOXO3, which was associated with elevated T32 phosphorylation in stage IV-derived neuroblastoma cells, thereby reflecting the in situ results. In contrast, hypoxic conditions repressed PKB-activity and caused dephosphorylation of FOXO3 in both, stroma-like SH-EP and high-stage derived STA-NB15 cells. The activation of an ectopically-expressed FOXO3 in these cells reduced viability at normoxia, but promoted growth at hypoxic conditions and elevated VEGF-C-expression. In chorioallantoic membrane (CAM) assays STA-NB15 tumors with ectopic FOXO3 showed increased micro-vessel formation and, when xenografted into nude mice, a gene-dosage-dependent effect of FOXO3 in high-stage STA-NB15 cells became evident: low-level activation increased tumor vascularization, whereas hyper-activation repressed tumor growth.The combined data suggest that, depending on the mode and intensity of activation, cellular FOXO3 acts as a homeostasis regulator promoting tumor growth at hypoxic conditions and tumor angiogenesis in high-stage neuroblastoma. PMID- 27769058 TI - Bortezomib-resistance is associated with increased levels of proteasome subunits and apoptosis-avoidance. AB - Bortezomib (BTZ), a proteasome inhibitor, is the first proteasome inhibitor to be used in clinical practice. Here we investigated the mechanisms underlying acquired bortezomib resistance in hepatocellular carcinoma (HCC) cells. Using stepwise selection, we established two acquired bortezomib-resistant HCC cell lines, a bortezomib-resistant HepG2 cell line (HepG2/BTZ) and bortezomib resistant HuH7 cell line (HuH7/BTZ). The 50% inhibitory concentration values of HepG2/BTZ and HuH7/BTZ were respectively 15- and 39-fold higher than those of parental cell lines. Sequence analysis of the bortezomib-binding pocket in the beta5-subunit showed no mutation. However, bortezomib-resistant HCC cells had increased expression of beta1 and beta5 proteasome subunits. These alterations of proteasome expression were accompanied by a weak degree of proteasome inhibition in bortezomib-resistant cells than that in wild-type cells after bortezomib exposure. Furthermore, bortezomib-resistant HCC cells acquired resistance to apoptosis. Bortezomib up-regulated pro-apoptotic proteins of the Bcl-2 protein family, Bax and Noxa in wild-type HCC cells. However, in bortezomib-resistant HCC cells, resistance to apoptosis was accompanied by loss of the ability to stabilize and accumulate these proteins. Thus, increased expression and increased activity of proteasomes constitute an adaptive and auto regulatory feedback mechanism to allow cells to survive exposure bortezomib. PMID- 27769057 TI - The relationship between total and phosphorylated STAT1 and STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer. AB - The aim of the present study was to examine the relationship between tumour cell expression of total and phosphorylated STAT1 (ph-STAT1) and STAT3 (ph-STAT-3), components of tumour microenvironment and survival in patients with invasive ductal breast cancer.Immunohistochemical analysis of total and ph-STAT1, and STAT3 were performed on tissue microarray of 384 breast cancer specimens. Tumour cell expression of STAT1 and STAT3 at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were related to cancer specific survival (CSS) and phenotypic features of the tumour and the host.High ph-STAT1 and ph-STAT3 tumour cell expression were associated with increased ER (both P<=0.001) and PR (both P <0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (both P=0.001). Ph-STAT1 was associated with increased general inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ infiltration (P=0.024). In multivariate survival analysis, only high ph-STAT3 tumour cell expression was a predictor of improved CSS (P=0.010) independent of other tumour and host-based factors.STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STAT1 and STAT3 may affect disease outcome through direct impact on tumour cells, counteracting aggressive tumour features, as well as interaction with the surrounding microenvironment. PMID- 27769059 TI - Microarray analysis on the lncRNA expression profile in male hepatocelluar carcinoma patients with chronic hepatitis B virus infection. AB - Long non-coding RNAs are involved with development and progression of cancer, and the advance of microarray technology allows the researchers to investigate the complete expression profile of lncRNA in various kinds of sample. We enrolled 5 male primary HCC cases with chronic HBV infection and the HCC and normal tissues have been obtained during the resection surgery. After total RNA extraction, the lncRNA microarray analysis was conducted to determine the lncRNA and mRNA expression signals. 612 lncRNAs and 1,064 mRNAs were significantly up-regulated in HCC tissue while 656 lncRNAs and 1,532 mRNAs were down-regulated in HCC tissues. Compared with normal tissues, XLOC_007433 (fold change: 12.80) and AC144449.1 (fold change: 27.20) were the most over- and under-expressed lncRNAs in HCC tissues. As for the mRNA, THBS4 (fold change:41.13) and CXCL14 (fold change: 58.03) were the most over- and under-expressed mRNAs in HCC tissues when comparing with their normal counterparts. In total, 4,552 pairs of lncRNA-mRNA were identified and the co-expression network was constructed. Moreover, the gene ontology enrichment analysis showed that the significantly different transcript between HCC and normal tissues were mainly associated with response to wounding, inflammatory response, protein hetrodimerization activity, response to stress which involved with biological process and molecular function. The pathway analysis suggested that the most significant pathways consisted of alcoholism, regulatory RNA pathways and RNA polymerase transcription. Several novel differentially expressed lncRNAs and mRNAs were identified in the present study. PMID- 27769060 TI - MiR-185/AKT and miR-29a/collagen 1a pathways are activated in IPF BAL cells. AB - MicroRNA signatures of BAL cells and alveolar macrophages are currently lacking in IPF. Here we sought to investigate the expression of fibrosis-related microRNAs in the cellular component of the BAL in IPF. We thus focused on microRNAs previously associated with fibrosis (miR-29a, miR-29b, miR-29c, let-7d, and miR-21) and rapid IPF progression (miR-185, miR-210, miR-302c-3p miR-376c and miR-423-5p). Among the tested microRNAs miR-29a and miR-185 were found significantly downregulated in IPF while miR-302c-3p and miR-376c were not expressed by BAL cells. Importantly, the downregulation of miR-29a inversely correlated with the significantly increased levels of COL1A1 mRNA in IPF BAL cells. Collagen 1 a was found mainly overexpressed in alveolar macrophages and not other cell types of the BAL by immunofluorescence. In view of the downregulation of miR-185, we tested the response of THP-1 macrophages to profibrotic cytokine TGFb and observed the downregulation of miR-185. Conversely, proinflammatory stimulation lead to miR-185 upregulation. Upon examination of the mRNA levels of known miR-185 targets AKT1, DNMT1 and HMGA2, no significant correlations were observed in the BAL cells. However, increased levels of total AKT and AKTser473 phosphorylation were observed in the IPF BAL cells. Furthermore, miR-185 inhibition in THP-1 macrophages resulted in significant increase of AKTser473 phosphorylation. Our study highlights the importance of BAL microRNA signatures in IPF and identifies significant differences in miR-185/AKT and miR-29a/collagen axes in the BAL cells of IPF patients. PMID- 27769062 TI - Bcr-abl regulates Stat5 through Shp2, the interferon consensus sequence binding protein (Icsbp/Irf8), growth arrest specific 2 (Gas2) and calpain. AB - Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2 expression in Bcr-abl+ cells stabilized betacatenin; a Calpain substrate. This was of interest, because betacatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5. In the current study, we hypothesized that Stat5 activity in CML is regulated by Gas2/Calpain. We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor. The consequent decrease in Calpain activity stabilized Stat5 protein; increasing the absolute abundance of both phospho and total Stat5. This enhanced repression of the IRF8 promoter by Stat5 in a manner dependent on Icsbp, Gas2 and Calpain, but not Stat5 tyrosine phosphorylation. During normal myelopoiesis, increased expression and phosphorylation of Icsbp inhibits Calpain. In contrast, constitutive activation of Shp2 in Bcr-abl+ cells impairs regulation of Gas2/Calpain by Icsbp, aberrantly stabilizing Stat5 and enhancing IRF8 repression. This novel feedback mechanism enhances leukemogenesis by increasing Stat5 and decreasing Icsbp. Bcr-abl targeted tyrosine kinase inhibitors (TKIs) provide long term disease control, but CML is not cured by these agents. Our studies suggest targeting Calpain might be a rational therapeutic approach to decrease persistent leukemia stem cells (LSCs) during TKI-treatment. PMID- 27769061 TI - Recent development of ATP-competitive small molecule phosphatidylinostitol-3 kinase inhibitors as anticancer agents. AB - Phosphatidylinostitol-3-kinase (PI3K) is the potential anticancer target in the PI3K/Akt/ mTOR pathway. Here we reviewed the ATP-competitive small molecule PI3K inhibitors in the past few years, including the pan Class I PI3K inhibitors, the isoform-specific PI3K inhibitors and/or the PI3K/mTOR dual inhibitors. PMID- 27769063 TI - Risk of eighteen genome-wide association study-identified genetic variants for colorectal cancer and colorectal adenoma in Han Chinese. AB - BACKGROUND: Recent genome-wide association studies (GWAS) identified eighteen single-nucleotide polymorphisms (SNPs) to be significantly associated with the risk of colorectal cancer (CRC). However, overall results of the following replications are inconsistent and little is known about whether these associations also exit in colorectal adenomas (CRA). METHODS: The SNP genotyping was performed using a Sequenom MassARRAY to investigate the association of these eighteen SNPs with colorectal neoplasm in a case-control study consisted of 1049 colorectal cancers, 283 adenomas, and 1030 controls. RESULTS: Two of these SNPs, rs10505477 and rs719725, showed evidence of an association in both CRC and CRA in our study population. Besides, seven SNPs (rs10808555, rs7014346, rs7837328, rs704017, rs11196172, rs4779584, and rs7229639) were significantly associated with CRC, and another one SNP rs11903757 was over-represented in CRA compared with controls. The strongest association was provided by rs11196172 (OR = 2.02, 95% CI = 1.66 - 2.46, P < 0.0001) and rs11903757 (OR = 1.96, 95% CI = 1.28 - 3.00, P = 0.0026). CONCLUSION: These results suggest that some previously reported SNP associations also have impact on CRC and CRA predispositions in the Han Chinese population. A part of genetic risk to CRC is possibly mediated by susceptibility to adenomas. PMID- 27769065 TI - The serum protein profile of early parity which induces protection against breast cancer. AB - Early parity reduces the risk of breast cancer in women while nulliparity and late parity increase the risk of breast cancer. In order to translate this protection to women where early pregnancy is not feasible, much work has focused on understanding how parity confers protection against breast cancer, the molecular mechanisms by which this occurs is still not well understood. Healthy parous and nulliparous women were recruited for this study. We assessed serum protein profiles of early parous, late parous, and nulliparous women using the Phospho Explorer antibody array. Significantly altered proteins identified were validated by Western blot analysis. In silico analysis was performed with the data obtained. Our findings indicate increased phosphorylation levels of CDK1, AKT1 and Epo-R increased cell cycle and cell proliferation in late/nulliparous women. Increased levels of LIMK1, paxillin, caveolin-1, and tyrosine hydroxylase in late/nulliparous women demonstrate enhanced cell stress while decreased activity of p-p53 and pRAD51 in late/nulliparous women indicates decreased apoptosis and increased genomic instability. Further, increased levels of pFAK, pCD3zeta, pSTAT5B, MAP3K8 in early parous women favor enhanced innate/adaptive immunity. Overall, we have identified a unique protein signature that is responsible for the decreased risk of breast cancer and these proteins can also serve as biomarkers to predict the risk of breast cancer. PMID- 27769064 TI - Genetic polymorphisms of Wnt/beta-catenin pathway genes are associated with the efficacy and toxicities of radiotherapy in patients with nasopharyngeal carcinoma. AB - Radiotherapy (RT) is the normative therapeutic treatment for primary nasopharyngeal carcinoma (NPC). Single nucleotide polymorphisms (SNPs) of genes in Wnt/beta-catenin pathway are correlated to the development, prognosis, and treatment benefit of various cancers. However, it has not been established whether SNPs of Wnt/beta-catenin pathway are associated with nasopharyngeal tumorigenesis and the efficacy of RT in NPC patients. Therefore, in this study, we aimed to investigate the nine potentially functional SNPs of four genes in the Wnt/beta-catenin pathway and genotyped these in 188 NPC patients treated with RT. To achieve this goal, associations between these SNPs and the RT's curative efficacy, as well as acute radiation-induced toxic reaction were determined by multifactorial logistic regression. We observed that catenin beta 1 gene (CTNNB1) rs1880481 and rs3864004, and glycogen synthase kinase 3 beta gene (GSK3beta) rs3755557 polymorphisms were significantly associated with poorer efficacy of RT in NPC patients. Moreover, GSK3beta rs375557 and adenomatous polyposis coli gene (APC) rs454886 polymorphisms were correlated with acute grade 3-4 radiation induced dermatitis and oral mucositis, respectively. In conclusion, this study suggests that gene polymorphisms of Wnt/beta-catenin may be novel prognostic factors for NPC patients treated with RT. PMID- 27769066 TI - Elevation of n-3/n-6 PUFAs ratio suppresses mTORC1 and prevents colorectal carcinogenesis associated with APC mutation. AB - Although epidemiological and preclinical studies have shown the preventative effect of n-3 polyunsaturated fatty acids (PUFAs) on colorectal cancer (CRC), the underlying molecular mechanisms are not clear. In this study, we revealed that elevation of n-3/n-6 PUFAs ratio suppress the mechanistic target of rapamycin complex 1 (mTORC1) and prevent colorectal tumorigenesis. The transgenic expression of fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously, repressed colorectal tumor cell growth and remarkably reduced tumor burden, and alleviated anemia as well as hyperlipidemia in APCMin/+ (adenomatous polyposis coli) mice, a classic CRC model that best simulates most clinical cases. In contrast to arachidonic acid (AA, C20:4 n-6), either Docosahexaenoic acid (DHA, C22:6 n-3), eicosapentaenoic acid (EPA, C20:5 n-3), or a combination of DHA and AA, efficiently inhibited the proliferation of CRC cell lines and promoted apoptosis in these cells. The ectopic expression of fat-1 had similar effects in colon epithelial cells with APC depletion. Mechanistically, elevation of n-3/n-6 ratio suppressed mTORC1 activity in tumors of APCMin/+ mice, CRC cell lines with APC mutation, and in normal colon epithelial cells with APC depletion. In addition, elevation of n-3/n 6 ratio repressed mTORC1 activity and inhibited adipogenic differentiation in preadipocytes with APC knockdown, as well as alleviated hyperlipidemia in APCMin/+ mice. Taken together, our findings have provided novel insights into the potential mechanism by which increase in n-3/n-6 PUFAs ratio represses CRC development, and also a new rationale for utilizing n-3 PUFAs in CRC prevention and treatment. PMID- 27769067 TI - CFTR is a potential marker for nasopharyngeal carcinoma prognosis and metastasis. AB - While there is an increasing interest in the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) and cancer incidence, the role of CFTR in nasopharyngeal carcinoma (NPC) development remains unknown. In this study, we aimed to explore the prognostic value of CFTR in NPC patients. The expression of CFTR was determined in NPC cell lines and tissues. Statistical analysis was utilized to evaluate the correlation between CFTR expression levels and clinicopathological characteristics and prognosis in 225 cases of NPC patients. The results showed that CFTR was down-regulated in NPC tissues and cell lines. Low expression of CFTR was correlated with advanced stage (p = 0.026), distant metastasis (p < 0.001) and poor prognosis (p < 0.01). Multivariate analysis identified CFTR as an independent prognostic factor (p = 0.003). Additionally, wound healing and transwell assays revealed that overexpression of CFTR inhibited NPC cell migration and invasion, whereas knockdown of CFTR promoted cell migration and invasion. Thus, the current study indicates that CFTR, as demonstrated to play an important role in tumor migration and invasion, may be used as a potential prognostic indicator in NPC. PMID- 27769068 TI - Phosphorylation of PPARgamma at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4. AB - Peroxisome proliferator-activating receptor gamma (PPARgamma), a transcription factor, is involved in many important biological processes, including cell terminal differentiation, survival and apoptosis. However, the role of PPARgamma, which regulates tumour promoter and oncogene expression, is not well understood in hepatocellular carcinoma (HCC). In the present study, based on evidence from clinical samples that phosphorylation of PPARgamma at Ser84 is up-regulated in human liver tumours, we confirmed that phosphorylation of PPARgamma was also significantly increased in an HCC mouse model and was increased by Mitogen activated protein kinase (MEK)/ Extracellular-signal-regulated kinases (ERK) kinase. Next, we performed an RNA microarray analysis, and our data indicated that dephosphorylation of PPARgamma at Ser84 affects the expression of glycolysis related genes and pro-proliferation genes, which supposedly promote proliferation of HCC cells. Using a chromatin immunoprecipitation (ChIP) assay, we demonstrated that the observed PPARgamma-mediated induction of 6-phosphofructo-2 kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression was directly modulated by the transcriptional activity of its promoter. Furthermore, using knockdown of PFKFB4, we elucidated that the stimulation of PPARgamma phosphorylation on glycolysis and proliferation in HCC is dependent on PFKFB4. Together, these findings extend our understanding of how liver tumour cells reprogram their glycolytic pathways by post-translational modification of specific transcription factors and lay a foundation for the screening of new targets for the treatment of HCC. PMID- 27769069 TI - Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: the role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways. AB - A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer. PMID- 27769070 TI - Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells. AB - Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4 inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies. PMID- 27769071 TI - The deubiquitinase USP54 is overexpressed in colorectal cancer stem cells and promotes intestinal tumorigenesis. AB - Ubiquitin-Specific Proteases (USPs) are deubiquitinating enzymes frequently deregulated in human malignancies. Here, we show that USP54 is overexpressed in intestinal stem cells and demonstrate that its downregulation in colorectal carcinoma cells impedes tumorigenesis. We have generated mutant mice deficient for this deubiquitinase, which are viable and fertile, and protected against chemically-induced colorectal carcinoma. Furthermore, we show that USP54 is upregulated in human colon cancer and associates with poor prognosis. In agreement with these results, Usp54 downregulation in mouse melanoma cells inhibits lung metastasis formation. Collectively, this work has uncovered the pro tumorigenic properties of USP54, highlighting the importance of deubiquitinating enzymes as promising targets for the development of specific anti-cancer therapies. PMID- 27769072 TI - Crossing the perspectives of patients, families, and physicians on cancer treatment: A qualitative study. AB - PURPOSE: Patients, family members, and physicians participate in cancer care, but their perspectives about what is helpful during cancer treatment have rarely been compared. The aim of this study was to compare these three perspectives. METHODS: Multicenter qualitative study (with previously published protocol) based on 90 semi-structured interviews. Participants (purposively selected until data saturation) came from three different subsamples: (i) patients with cancer (n=30), (ii) their relatives (n=30), and (iii) their referring physicians (n=10, interviewed more than once). RESULTS: Our analysis found 3 main axes (perceived positive effects of cancer treatment, perceived negative effects of cancer treatment, doctor-physician relationship), each composed of 2 main themes. The findings showed that patients, families, and physicians shared the long-term objective of increasing survival (while reducing side effects). However, patients and relatives also pointed out the importance of living with cancer each day and thus of factors helping them to live as well as possible in daily life. The physicians' difficulty in coping with patients' suffering may limit their access to elements that can improve patients' capacity to live as well as possible. CONCLUSIONS: During cancer treatment (and not only at the end of life), attention should be given to enhancing the capacity of patients to live as well as possible (not only as long as possible) to meet the goals of patient-centered care and satisfy this important need of patients and families. PMID- 27769073 TI - Total Hip Arthroplasty for Femoral Neck Fractures: Improved Outcomes With Higher Hospital Volumes. AB - OBJECTIVES: To determine if hospital arthroplasty volume affects patient outcomes after undergoing total hip arthroplasty (THA) for displaced femoral neck fractures. METHODS: The Statewide Planning and Research Cooperative System database from the New York State Department of Health was used to group hospitals into quartiles based on overall THA volume from 2000 to 2010. The database was then queried to identify all patients undergoing THA specifically for femoral neck fracture during this time period. The data were analyzed to investigate outcomes between the 4 volume quartiles in 30-day and 1-year mortality, 1-year revision rate, and 90-day complication rate (readmission for dislocation, deep vein thrombosis, pulmonary embolism, prosthetic joint infection, or other complications related to arthroplasty in the treatment of femoral neck fractures with THA). RESULTS: Patients undergoing THA for femoral neck fracture at hospitals in the top volume quartile had significantly lower 30-day (0.9%) and 1 year (7.51%) mortality than all other volume quartiles. There were no significant differences on pairwise comparisons between the second, third, and fourth quartiles with regard to postoperative mortality. There was no significant difference in revision arthroplasty at 1 year between any of the volume quartiles. On Cox regression analysis, THA for fracture at the lowest volume (fourth) quartile [hazard ratio (HR), 1.91; P = 0.016, 95% confidence interval (CI), (1.13-3.25)], second lowest volume (third) quartile (HR, 2.01; P = 0.013, 95% CI, 1.16-3.5) and third lowest volume (second) quartile (HR, 2.13; P = 0.005, 95% CI, 1.26-3.62) were associated with increased risk for a 1-year postoperative mortality event. Hospital volume quartile was also a significant risk factor for increased 90-day complication (pulmonary embolism/deep vein thrombosis, acute dislocation, prosthetic joint infection) following THA for femoral neck fracture. Having surgery in the fourth quartile (HR, 2.71; P < 0.001, 95% CI, 1.7-4.31), third quartile (HR, 2.61; P < 0.001, 95% CI, 1.61-4.23), and second quartile (HR, 2.41; P < 0.001, 95% CI, 1.51-3.84), all were significant risk factors for increased 90-day complication risk. CONCLUSIONS: The results of this population based study indicate that THA for femoral neck fractures at high-volume arthroplasty centers is associated with lower mortality and 90-day complication rates but does not influence 1-year revision rate. THA for femoral neck fractures at top arthroplasty volume quartile hospitals are performed on healthier patients more quickly. Patient health is a critical factor that influences mortality outcomes following THA for femoral neck fractures. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 27769074 TI - The Detection of Prominent Hardware in Volar Locked Plating of Distal Radius Fractures: Intraoperative Fluoroscopy Versus Computed Tomography. AB - OBJECTIVES: To assess the utility of the dorsal tangential view (DTV) in detecting intraoperative dorsal screw penetration in distal radius fractures treated with volar locked plating. DESIGN: Retrospective cohort study. SETTING: Academic level 1 trauma center. PATIENTS/PARTICIPANTS: Skeletally mature patients where open reduction internal fixation with volar locked plating was the definitive treatment. A total of twenty-six patients were evaluated. INTERVENTION: Intraoperative anteroposterior, lateral, 20 degree tilted lateral, and DTVs were obtained through fluoroscopy in all wrists. Screw exchange and position by fluoroscopic view was recorded. A computed tomography (CT) was taken postoperatively to identify residual prominent screws. MAIN OUTCOME MEASURES: Data points included frequency of screw exchange by standard fluoroscopic views, the DTV, and residual prominent screws detected by CT. RESULTS: Eight constructs of thirty (27%) had prominent screws evident on the DTV but not seen on standard fluoroscopic analysis. CT identified 5 additional screws with >=1 mm dorsal penetration not identified by the DTV. All except 1 screw was in the second dorsal wrist compartment. The DTV was 67% sensitive with a negative predictive value of 97%. CONCLUSION: It is risky and unnecessary to place bicortical screws in the distal part of a volar plate. Given that the DTV view was not sufficient to avoid dorsal screw prominence, distal screws should be intentionally 2-4 mm shorter than measured. Recent studies propose bicortical distal locking screws are not needed for sufficient construct stiffness in volar locked plating. We suggest caution when using this view to verify acceptable placement of screws in proximity to the second dorsal compartment. LEVEL OF EVIDENCE: Diagnostic level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27769075 TI - Tibial Plateau Fracture Characteristics: Reliability and Diagnostic Accuracy: Erratum. PMID- 27769076 TI - The role of dietary supplements in inflammatory bowel disease: a systematic review. AB - Inflammatory bowel diseases (IBD) are chronic immune disorders of unclear aetiology. Dietary deficiencies may be a potential pathogenic factor in their development. Patients often take food supplements without knowledge of any evidence base. We have therefore assessed the evidence for food supplementation in the management of IBD. A PubMed search was performed for the terms Inflammatory bowel disease; nutritional deficiencies; dietary supplements; curcumin; green tea; vitamin D/other vitamins; folic acid; iron; zinc; probiotics; andrographis paniculata; and boswellia serrate. PubMed was used to search for all relevant articles published between January 1975 and September 2015. Curcumin supplementation has been reported to be effective in reducing the symptoms and the inflammatory indices in IBD patients. Similar results have been observed for green tea; however, pertinent studies are limited. Vitamin D supplementation may help to increase bone mineral density in IBD patients and to reduce disease activity. IBD patients with ileal resections higher than 20 cm may develop vitamin B12 deficiency that requires parenteral supplementation. There is no current evidence to support fat-soluble vitamin supplementation in IBD patients. Zinc and iron should be supplemented in selected cases. Probiotics (VSL#3) may reduce disease activity in IBD patients with pouchitis. Complementary and alternative medicines are used by IBD patients and some studies have shown promising results. In summary, attention to dietary factors such as curcumin, green tea and vitamins, including vitamins D and B12, appears to be beneficial and, if necessary, supplementation may be appropriate. PMID- 27769077 TI - Early detection of pancreatic cancer: impact of high-resolution imaging methods and biomarkers. AB - High-resolution imaging methods (HRIMs) and biomarkers present the second step of pancreatic cancer (PC) diagnostics in at-risk individuals. These include patients with positive risk factors, early symptoms, nonresponders to the initial antidiabetic therapy, patients older than 50 years of age with new-onset unstable diabetes requiring insulin as well as patients with long-term insulin-non dependent diabetes and recent (up to 6 months) failure of antidiabetic therapy. The procedures should be started without delay and the co-operation between the primary and tertiary medical centers is highly desirable. An early indication of HRIMs and biomarkers is a prerequisite for the diagnosis of a resectable PC. This publication reviews the recent contribution of HRIMs and biomarkers toward an early diagnosis of PC. PMID- 27769079 TI - Massive Reflux and Aspiration After Radiographically Inserted Gastrostomy Tube Placement: Erratum. PMID- 27769078 TI - Measuring gaze patterns during colonoscopy: a useful tool to evaluate colon inspection? AB - BACKGROUND AND OBJECTIVE: Considerable variation in adenoma detection has been shown between endoscopists, which may be explained by differences in colon inspection. Eye-tracking technology is an objective tool that detects differences in viewing patterns. We investigated the feasibility of eye-tracking technology during real-time, self-performed colonoscopies. METHODS: In this pilot study, 10 endoscopists performed two colonoscopies each. A mobile eye-tracking system to register the right eye position was used to determine the gaze across four areas of interest of the endoscopy monitor (upper, lower, left, and right quadrant). The measured gaze across the endoscopy monitor was correlated with the gaze across the endoscopically visualized colonic surface. RESULTS: Gaze patterns were measured successfully in 18 of 20 procedures. Significant differences in the time spent per area of interest were observed between endoscopists. The measured total gaze time per area of interest correlated strongly with the time spent on the corresponding area of the colonic surface (Pearson correlation coefficients ranging between 0.91 and 0.97). Endoscopists with more years of colonoscopy experience showed significantly higher percentages of overlap between the measured gaze position in the different areas of interest and the actual inspected area of the colonic surface (r=0.65, P=0.02). More experienced endoscopists had nonsignificantly longer mean gaze times per area of interest (r=0.52, P=0.06). CONCLUSION: Eye-tracking technology to measure gaze patterns of endoscopists during real-time, self-performed colonoscopies is feasible and may be used to evaluate and compare viewing behavior across the colonic surface of experienced endoscopists. PMID- 27769080 TI - First Counseling Revealing the Diagnosis of Childhood Cancer: Parent Preferences From an Indian Perspective. AB - BACKGROUND: The first counseling or the exchange between the physician and the parent(s) of children with cancer is of vital importance as it sets the tone for the rest of the treatment. The goal of our study was to find out the preferences among parents of Indian children with cancer regarding communication and breaking of bad news when fully informed about the diagnosis. MATERIALS AND METHODS: A sample of 60 parents who had been counseled within 3 months from diagnosis were interviewed with a prepared questionnaire directed at eliciting their experiences with the physicians who broke the bad news to them and also suggestions to improve the exchange. RESULTS: Sixty parents of children diagnosed with cancer participated in the study. All parents agreed on the importance of first counseling and asked for a second round of counseling to reinforce concepts learned during the first counseling. An overall 83% of parents wanted a comparison with another child having the same diagnosis, 57% wanted immediate or extended family to be present, and 92% did not want support staff to be present during counseling. In all, 68% of parents did not want to reveal the diagnosis to the child, 77% wanted as much information about the disease as possible, including estimated cost of treatment, and 90% wanted access to other information services and information about other centers where treatment was available. CONCLUSIONS: Parents have preferences about the ways in which information is presented to them during the first counseling. Knowing these preferences will help physicians to better their ability to interact with parents in the future during first counseling and help them decide a culturally appropriate course of action. PMID- 27769081 TI - An Unusual Case of LCHAD Deficiency Presenting With a Clinical Picture of Hemophagocytic Lymphohistiocytosis: Secondary HLH or Coincidence? AB - There are published reports stating that some of the congenital metabolic diseases, such as lysinuric protein intolerance, multiple sulphatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, might lead to secondary hemophagocytic lymphohistiocytosis (HLH). However, to date, to our knowledge, the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has never been investigated among patients with HLH. Here, we report on a patient who was referred to our institution for a differential diagnosis of pancytopenia, liver failure, and rhabdomyolysis. The patient was diagnosed with HLH. Further investigation revealed an underlying diagnosis of the LCHAD deficiency. Our case was reported to contribute to the literature, as well as the HLH clinic, emphasizing the consideration of LCHAD deficiency, especially in 1 to 6 months' old infants with laboratory findings of hypoglycemia, metabolic acidosis, and elevated creatine kinase. PMID- 27769082 TI - Nursing Student Self-efficacy in Psychomotor Skills: Findings From a Validation, Longitudinal, and Correlational Study. AB - Student perceptions of self-efficacy (SE) prevent stress and burnout and improve engagement in nursing education, thus increasing learning outcomes. The study aims were to (1) validate a scale measuring nursing SE in psychomotor skills (NSE PS), (2) describe changes in NSE-PS over time, and (3) explore NSE-PS correlations with burnout and engagement. A total of 1117 nursing students participated. A significant increase in the NSE-PS scores over the years has emerged; in addition, all NSE-PS dimensions were correlated negatively with burnout and positively with engagement. PMID- 27769083 TI - Neurochemical changes following combined hypoxemia and hemorrhagic shock in a rat model of penetrating ballistic-like brain injury: A microdialysis study. AB - BACKGROUND: Energy metabolic dysfunction is a key determinant of cellular damage following traumatic brain injury and may be worsened by additional insults. This study evaluated the acute/subacute effects of combined hypoxemia (HX) and hemorrhagic shock (HS) on cerebral interstitial levels of glucose, lactate, and pyruvate in a rat model of penetrating ballistic-like brain injury (PBBI). METHODS: Rats were randomly assigned into the sham control, PBBI, and combined injury (P + HH) groups. The P + HH group received PBBI followed by 30-minute HX and 30 minute HS. Samples were collected from striatum (perilesional region) using intracerebral microdialysis at 1 to 3 hours after injury and then at 1 to 3, 7, and 14 days after injury. Glucose, lactate, and pyruvate were measured in the dialysate samples. RESULTS: Glucose levels dropped significantly up to 24 hours following injury in both PBBI and P + HH groups (p < 0.05). A reduction in pyruvate was observed in the PBBI group from 24 to 72 hours after injury (vs. sham). In the P + HH group, the pyruvate was significantly reduced from 2 to 24 hours after injury (p < 0.05 vs. PBBI). This prominent reduction persisted for 14 days after injury. In contrast, lactate levels were significantly increased in the PBBI group during the first 24 hours after injury and remained elevated out to 7 days. The P + HH group exhibited a similar trend of lactate increase as did the PBBI group. Critically, P + HH further increased the lactate-to-pyruvate ratio by more than twofold (vs. PBBI) during the first 24 hours. The ratio reached a peak at 2 hours and then gradually decreased, but the level remained significantly higher than that in the sham control from 2 to 14 days after injury (p < 0.05). CONCLUSION: This study identified the temporal profile of energy related neurochemical dysregulation induced by PBBI and combined injury in the perilesional region. Furthermore, combined HX and HS further reduced the pyruvate level and increased the lactate-to-pyruvate ratio following PBBI, indicating the exacerbation of posttraumatic metabolic perturbation. PMID- 27769084 TI - Pulmonary Embolism Response Teams. AB - Pulmonary embolism is a common and often life-threatening event. Treatment options include anticoagulation alone, catheter-directed therapies, and surgical thromboembolectomy. While guidelines exist, there is often controversy over which treatment is most appropriate, particularly for intermediate-risk patients. The traditional care model, in which the primary team is responsible for consulting the appropriate specialists, may be inadequate and inefficient for emergent situations, as ensuring coordination and communication between various consulting services can be a time consuming and confusing process. The Pulmonary Embolism Response Team (PERT) model was developed to improve the quality and efficiency of care for patient with intermediate- and high-risk pulmonary embolism. Activation of the PERT allows for rapid, multidisciplinary discussion among dedicated specialists, which typically includes members of the cardiology, emergency medicine, hematology, pulmonary/critical care, and surgical services. While the majority of patients are still treated with anticoagulation alone, in the event that a more invasive approach is deemed necessary, the team expedites this process. Over the last several years, the PERT model has been adopted at more than 75 health care institutions and may represent a new standard of care. PMID- 27769085 TI - Role of Intraluminal Esophageal Impedance Baseline in the Diagnosis of Esophagitis in Children. AB - Introduction Low values of esophageal impedance baseline (EIB) have been related to esophagitis. The aim of this study was to evaluate the diagnostic performance of EIB for erosive esophagitis (ErE) and histological esophagitis (HiE) in children studied for gastroesophageal reflux. Material and Methods Children who underwent esophageal multichannel intraluminal impedance-pH monitoring (MII-pH) and upper-endoscopy with esophageal biopsies were studied retrospectively. EIB values were obtained by MII-pH. ErE was assessed by endoscopy following the Hetzel-Dent classification; HiE was defined by basal zone hyperplasia, papillary lengthening, or inflammatory infiltration. EIB was compared between groups. Receiver operating characteristic (ROC) curves were obtained to calculate the global diagnostic performance of EIB and to find cut-off values for sensitivity and specificity. Logistic regression was used for age adjustment. Results Fifty one patients were studied: 11 had ErE and 23 had HiE. EIB median values were 1,159 in ErE versus 2,583 in non-ErE (U = 80, p < 0.01). The adjusted ROC curve analysis for ErE was 0.85 (95% CI = 0.74-0.96); the EIB cut-off value = 2,379 determined sensitivity = 100% and specificity = 52.6% in children < 4 years old. and sensitivity = 100% and specificity = 63.2% in children > 4 years old. EIB median values were 1,666 in HiE versus 2,669 in non-HiE (U = 80, p < 0.01). The adjusted ROC curve analysis for HiE was 0.75 (95% CI = 0.59-0.90); the EIB cut off value = 2,296 determined sensitivity = 71.2% and specificity = 83.1% in children < 4 years old, and sensitivity = 75.1% and specificity = 80.1% in children > 4 years old. Conclusion EIB provides statistically significant diagnostic performances for ErE and HiE. It could become a useful tool, especially to discriminate between ErE and non-ErE, avoiding other invasive tests. PMID- 27769086 TI - Risk Factors for Anastomotic Strictures after Esophageal Atresia Repair: Prophylactic Proton Pump Inhibitors Do Not Reduce the Incidence of Strictures. AB - Background Since 2005, infants with esophageal atresia (EA) in our unit are given prophylactic proton pump inhibitors (PPI) after repair until 1 year of age. The aims of this study were to identify risk factors for anastomotic strictures (AS) and to assess the efficacy of postoperative PPI prophylaxis in reducing the incidence of AS compared with symptomatic PPI. Methods Patients who underwent EA repair from 1994 to 2013 in our unit were included in this retrospective observational study approved by the local ethics review board. They were divided into two subgroups; symptomatic PPI-group with EA repair from 1994 to 2004 and prophylactic PPI-group with EA repair from 2005 to 2013. Data were collected from the patient records. Potential risk factors for AS analyzed were gender, long gap EA, birth weight, premature birth (<37 gestational weeks), anastomotic tension, and anastomotic leakage. Number of dilatations until the age of 1 and 5 years were recorded. To evaluate risk factors for AS and the effect of prophylactic PPI Logistic, Cox and Poisson regression models were used. For descriptive statistics Fisher exact test and Wilcoxon rank sum test were used. Results A total of 128 patients were included. Patient characteristics, surgical method, grading of anastomotic tension, complications, and survival rates did not differ significantly between the symptomatic PPI-group (n = 71) and the prophylactic PPI group (n = 57). Comparing the symptomatic and prophylactic PPI-group, there was no significant difference in the median age at the first AS (9.3 vs 6 mo), the number of dilatations until 1 year (2 vs 2) and 5 years (5 vs 4), or the incidence of anastomotic stricture (56.5% vs 50.9%). Long gap EA, high birth weight, and anastomotic tension were found to be independent risk factors. Conclusion Surgeons should aim to perform anastomosis under less tension at EA repair. Prophylactic PPI-treatment does not appear to reduce the rate of AS. Randomized controlled trials with larger study populations are needed to further evaluate the efficacy of prophylactic PPI. PMID- 27769087 TI - The Involvement of Speed-of-Processing in Story Listening in Preschool Children: A Functional and Structural Connectivity Study. AB - Story listening in children relies on brain regions supporting speech perception, auditory word recognition, syntax, semantics, and discourse abilities, along with the ability to attend and process information (part of executive functions). Speed-of-processing is an early-developed executive function. We used functional and structural magnetic resonance imaging (MRI) to demonstrate the relationship between story listening and speed-of-processing in preschool-age children. Eighteen participants performed story-listening tasks during MRI scans. Functional and structural connectivity analysis was performed using the speed-of processing scores as regressors. Activation in the superior frontal gyrus during story listening positively correlated with speed-of-processing scores. This region was functionally connected with the superior temporal gyrus, insula, and hippocampus. Fractional anisotropy in the inferior frontooccipital fasciculus, which connects the superior frontal and temporal gyri, was positively correlated with speed-of-processing scores. Our results suggest that speed-of-processing skills in preschool-age children are reflected in functional activation and connectivity during story listening and may act as a biomarker for future academic abilities. PMID- 27769088 TI - Accuracy of Transvaginal Ultrasonography, Hysteroscopy and Uterine Curettage in Evaluating Endometrial Pathologies. AB - Objective To evaluate the accuracy of transvaginal ultrasonography, hysteroscopy and uterine curettage in the diagnosis of endometrial polyp, submucous myoma and endometrial hyperplasia, using as gold standard the histopathological analysis of biopsy samples obtained during hysteroscopy or uterine curettage. Methods Cross sectional study performed at the Hospital Universitario de Brasilia (HUB). Data were obtained from the charts of patients submitted to hysteroscopy or uterine curettage in the period from July 2007 to July 2012. Results One-hundred and ninety-one patients were evaluated, 134 of whom underwent hysteroscopy, and 57, uterine curettage. Hysteroscopy revealed a diagnostic accuracy higher than 90% for all the diseases evaluated, while transvaginal ultrasonography showed an accuracy of 65.9% for polyps, 78.1% for myoma and 63.2% for endometrial hyperplasia. Within the 57 patients submitted to uterine curettage, there was an accuracy of 56% for polyps and 54.6% for endometrial hyperplasia. Conclusion Ideally, after initial investigation with transvaginal ultrasonography, guided biopsy of the lesion should be performed by hysteroscopy, whenever necessary, in order to improve the diagnostic accuracy and subsequent clinical management. PMID- 27769089 TI - [Retrospective Analysis of Diabetics with Regard to Treatment Duration and Costs]. AB - Background: The increasing incidence of diabetes mellitus is also reflected in the patient population of a trauma and orthopaedic centre. Diabetics also exhibit more comorbidities than non-diabetics. In addition to surgical problems in these patients, hospitalisation is often accompanied by complications, which can prolong treatment and increase costs. The aim of this retrospective study is to analyse hospitalisation of diabetics compared to non-diabetics, as well as differences in treatment costs, depending on associated age and comorbidities. Patients/Material and Methods: 17,185 patients were treated at a transregional trauma and orthopaedic centre and were included in this retrospective analysis between 2012 and 2015. Comorbidities and hospitalisation of diabetics and non diabetics were recorded. All costs charged by DRG were evaluated to calculate the cost per day and per patient, on the basis of the specific case rate. In this calculation, patient-related case rates were divided by the average residence time and the means of the calculated daily rates were calculated. Inclusion criteria were treatment within the various departments and a minimum hospitalisation of one day. Statistical analysis was performed with the SPSS program (version 22.0, SPSS Inc., Chicago, USA). Results: In comparison to non diabetics (ND), diabetics (D) exhibited significantly more comorbidities, including: obesity, arterial hypertension, coronary heart disease, myocardial infarction (in the history), peripheral arterial disease, chronic kidney disease and hyperlipidaemia. Pneumonia in hospital was considerably commoner in diabetics (2.45 % [D] vs. 1.02 % [ND], p < 0.001). Time in hospital was significantly longer in diabetics (endoprosthetics 13.52 days [D] vs. 12.54 days [ND], p < 0.001; septic surgery 18.62 days [D] vs. 16.31 days [ND], p = 0.007; traumatology 9.82 days [D] vs. 7.07 days [ND], p < 0.001). For patients aged under 60 years, time in hospital was significantly longer for diabetics than for non-diabetics (9.98 days [D] vs. 6.43 days [ND] p < 0.001). Because of the longer time in hospital, treatment costs were higher by ? 1,932,929.42 during the investigated time period. Conclusion: Because of their comorbidities, diabetics need to be categorised at an early stage as high-risk patients in traumatological and orthopaedic departments. Hospitalisation and the associated increased treatment costs, as well as postoperative complications, could be minimised in patients with diabetes by implementing an interdisciplinary treatment concept. PMID- 27769091 TI - ? PMID- 27769090 TI - [Treatment of Osteochondral Lesions in the Ankle: A Guideline from the Group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology (DGOU)]. AB - Background: Osteochondral lesions (OCL) of the ankle are a common cause of ankle pain. Although the precise pathophysiology has not been fully elucidated, it can be assumed that a variety of factors are responsible, mainly including traumatic events such as ankle sprains. Advances in arthroscopy and imaging techniques, in particular magnetic resonance imaging (MRI), have improved the possibilities for the diagnosis of OCLs of the ankle. Moreover, these technologies aim at developing new classification systems and modern treatment strategies. Material and Methods: This article is a review of the literature. Recommendations of the group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Traumatology (DGOU) for the treatment of OCLs of the ankle are presented. The review gives a concise overview on the results of clinical studies and discusses advantages and disadvantages of different treatment strategies. Results: Non operative treatment shows good results for selected indications in children and adolescents, especially in early stages of osteochondritis dissecans (OCD). However, surgical treatment is usually indicated in OCLs in adolescents and adults, depending on the size and location of the lesion. Various arthroscopic and open procedures are frequently employed, including reattachment of the fragment, local debridement of the lesion with fragment removal and curettage of the lesion, bone marrow-stimulation by microfracture or microdrilling (antegrade or retrograde), and autologous matrix-induced chondrogenesis (AMIC(r)) - with or without reconstruction of a subchondral bone defect or cyst by autologous cancellous bone grafting. Isolated subchondral cysts with an intact cartilage surface can be treated by retrograde drilling and possibly additional retrograde bone grafting. For larger defects or as salvage procedure, osteochondral cylinder transplantation (OATS(r) or Mosaicplasty(r)) or matrix-induced autologous chondrocyte transplantation (MACT) are recommended. Transplantation of so-called (osteochondral) mega grafts, such as autologous bone grafts or allografts, are used for very large osteochondral defects that cannot be reconstructed otherwise. Implantation of the so-called "small metal implants" - such as HemiCAP Talus(r) - is reserved for selected cases after failed primary reconstruction. Corrective osteotomies are indicated in accompanying axial malalignments. Conclusions: There are several different treatment strategies for OCLs, but clinical studies are rare and evidence is limited. Therefore, interventional studies, e.g. randomised controlled trials (RCTs), but also observational studies, e.g. based on data of the Cartilage Registry of the German Society of Orthopaedics and Traumatology (www.knorpelregister-dgou.de), are needed and are recommended by the authors. PMID- 27769093 TI - ? PMID- 27769092 TI - ? PMID- 27769094 TI - A Comparison of the Minimal-Touch Technique and the Eversion Technique for Microvascular Anastomosis in a Rat Model. AB - Background During microvascular anastomosis, needle placement is facilitated by inserting the tips of the forceps into the lumen of the vessel, rather than grasping and everting the luminal wall, to minimize trauma to the vessel. This study examines whether the vessel wall can be grasped and everted during microvascular anastomosis without compromising surgical outcomes. Methods A total of 20 Sprague-Dawley rats weighing between 252 and 483 g were used. Bilateral anastomoses of the animals' femoral arteries (mean size: 0.90 mm) were performed using two different techniques: the classic minimal-touch approach and the eversion technique. The first 10 animals were survived for 48 hours and the second 10 animals were survived for 2 weeks. Patency was assessed immediately after surgery and just before sacrifice. Hematoxylin and eosin stains were performed and each anastomosis scored according to a grading rubric assessing endothelial cell loss, neointimal proliferation, medial necrosis, adventitial inflammation, and inflammation thickness. Results The patency rates of both techniques were identical (100%). There was no difference in the patency rates of anastomoses evaluated 48 hours after surgery (100%) and 2 weeks after surgery (100%). Histological outcomes between the minimal-touch technique and the eversion method were similar. The thickness of adventitial inflammation at 2 weeks was the only outcome found to be statistically different (p = 0.046) between the two treatments and this difference favored the eversion technique (i.e., less inflammation thickness). Conclusion The eversion method of performing microvascular anastomosis provides comparable results to the classic minimal touch approach in rat femoral artery anastomoses. PMID- 27769095 TI - Morphological Study of the Proximal Fibular Articular Surface Using Computed Tomography: Which Side Is Preferred for Proximal Fibular Flap in Wrist Arthroplasty? AB - Background Although proximal fibular flaps have been widely applied in wrist arthroplasty, controversy remains regarding which side of the proximal fibula is better for reconstruction of the distal radius. If the articular surface of the proximal fibula shows dorsal tilting, the ipsilateral (right) proximal fibula should be harvested in right wrist arthroplasty because the articular surface of the distal radius normally has volar tilt. This study investigated anatomical similarities between the proximal fibular articular surface and the distal radius articular surface based on morphologic analysis of the proximal fibula using computed tomography (CT). Methods A total of 18 proximal fibulae from 18 adult volunteers were analyzed using CT. Tilt and length of the proximal fibular articular surface were measured in the section plane parallel to the proximal tibiofibular articular surface (simulated sagittal plane). The inclination angle of the articular surface was measured in the section plane perpendicular to the proximal tibiofibular articular surface (simulated coronal plane). Results In the simulated sagittal plane, the articular surface of the proximal fibula showed a mean dorsal tilt of 4.1 degrees; the articular surface for each scan was 17.1 mm. In the simulated coronal plane, two articular surfaces were studied. The inclination angle of these surfaces was measured as 32.2 and 54.4 degrees, respectively. Conclusion CT analysis of the proximal fibular articular surfaces suggested that ipsilateral proximal fibular transfer can result in improved anatomic restoration of normal volar tilt of the distal radius due to dorsal tilt of the proximal fibular articular surface. PMID- 27769096 TI - Mechanistic modeling of pesticide exposure: The missing keystone of honey bee toxicology. AB - The role of pesticides in recent honey bee losses is controversial, partly because field studies often fail to detect effects predicted by laboratory studies. This dissonance highlights a critical gap in the field of honey bee toxicology: there exists little mechanistic understanding of the patterns and processes of exposure that link honey bees to pesticides in their environment. The authors submit that 2 key processes underlie honey bee pesticide exposure: 1) the acquisition of pesticide by foraging bees, and 2) the in-hive distribution of pesticide returned by foragers. The acquisition of pesticide by foraging bees must be understood as the spatiotemporal intersection between environmental contamination and honey bee foraging activity. This implies that exposure is distributional, not discrete, and that a subset of foragers may acquire harmful doses of pesticide while the mean colony exposure would appear safe. The in-hive distribution of pesticide is a complex process driven principally by food transfer interactions between colony members, and this process differs importantly between pollen and nectar. High priority should be placed on applying the extensive literature on honey bee biology to the development of more rigorously mechanistic models of honey bee pesticide exposure. In combination with mechanistic effects modeling, mechanistic exposure modeling has the potential to integrate the field of honey bee toxicology, advancing both risk assessment and basic research. Environ Toxicol Chem 2017;36:871-881. (c) 2016 SETAC. PMID- 27769097 TI - Cancer-associated fibroblasts mediated chemoresistance by a FOXO1/TGFbeta1 signaling loop in esophageal squamous cell carcinoma. AB - Previous studies on the mechanisms underlying ESCC (esophageal squamous cell carcinoma) chemoresistance only focused on tumor cells while tumor microenvironment has been completely ignored. Our study aimed to clarify the effect of CAFs (cancer-associated fibroblasts), one major component of tumor microenvironment, on the chemoresistance of ESCC. By primary culture, two pairs of CAFs and matched NFs (normal fibroblasts) were isolated from tumor tissues of ESCC patients and matched normal esophageal epithelial tissues, respectively. The association of CAFs and chemoresistance was assessed in esophageal carcinoma cells, in xenograft tumor models and in clinical specimens of ESCC patients. We found CAFs conferred ESCC cells significant resistance to several common chemotherapeutic drugs including cisplatin, taxol, irinotecan (CPT-11), 5 fluorouracil (5-Fu), carboplatin, docetaxel, pharmorubicin, and vincristine. Mechanism studies revealed that blockage of CAFs-secreted TGFbeta1 signaling by its receptor TGFbetaR1 inhibitor LY2157299 significantly reversed the chemoresistance in vitro and in vivo. Furthermore, the crosstalk of CAFs and ESCC cells enhanced the expression and activation of FOXO1, a member of the forkhead transcription factors in the O-box sub-family, inducing TGFbeta1 expression in an autocrine/paracrine signaling loop. In 130 ESCC patients, the expression of TGFbeta1 in CAFs was significantly associated with overall survival of patients treated with chemoradiotherapy. Together, our study highlighted TGFbeta1 expressed in CAFs as an attractive target to reverse tumor chemoresistance, and can be used as an independent prognostic factor of ESCC patients treated with chemoradiotherapy. (c) 2016 Wiley Periodicals, Inc. PMID- 27769099 TI - Dose-dependent antiviral activity of released-active form of antibodies to interferon-gamma against influenza A/California/07/09(H1N1) in murine model. AB - The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile, and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose dependent manner (at doses of 0.13, 0.2, 0.4, 0.8 ml/mouse/day) in a murine model of acute pneumonia induced by influenza virus pandemic strain A/California/07/09 (H1N1). Administration of the drug at the two highest doses led to: a reduction in the virus infectious titer in lung tissue up to 4.2 lgEID50/20 mg of tissue; infected animals' life prolongation up to 6.7 days; an increase in the survival rate of up to 40% and a decrease in morphological signs of inflammation when compared to the control animals. In this study, the dose-response effect of Anaferon for Children was demonstrated on mice for the first time. This finding is especially important for drugs with a principally novel mechanism of action like drugs based on released-active forms of antibodies. J. Med. Virol. 89:759 766, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27769100 TI - Detection of viruses in weekly stool specimens collected during the first 2 years of life: A pilot study of five healthy Australian infants in the rotavirus vaccine era. AB - Several viruses are associated with gastroenteritis in infants. This pilot study, nested within a larger community-based project of early childhood infections, collected daily symptom data and 511 weekly stool samples from five healthy, fully vaccinated, term infants from birth until their second birthday. Real-time PCR assays were used to detect six enteric viruses. Frequent, silent shedding of one or more of the six viruses was observed, particularly involving adenovirus where shedding could be for up to 3 months without gastrointestinal symptoms. These pilot data demonstrate that a positive PCR result for enteric viruses may not always indicate the cause of childhood gastroenteritis. J. Med. Virol. 89:917 921, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27769098 TI - Expression of Noggin and Gremlin1 and its implications in fine-tuning BMP activities in mouse cartilage tissues. AB - Increasing evidence supports the idea that bone morphogenetic proteins (BMPs) regulate cartilage maintenance in the adult skeleton. The aim of this study is to obtain insight into the regulation of BMP activities in the adult skeletal system. We analyzed expression of Noggin and Gremlin1, BMP antagonists that are known to regulate embryonic skeletal development, in the adult skeletal system by Noggin-LacZ and Gremlin1-LacZ knockin reporter mouse lines. Both reporters are expressed in the adult skeleton in a largely overlapping manner with some distinct patterns. Both are detected in the articular cartilage, pubic symphysis, facet joint in the vertebrae, and intervertebral disk, suggesting that they regulate BMP activities in these tissues. In a surgically induced knee osteoarthritis model in mice, expression of Noggin mRNA was lost from the articular cartilage, which correlated with loss of BMP2/4 and pSMAD1/5/8, an indicator of active BMP signaling. Both reporters are also expressed in the sterna and rib cartilage, suggesting an extensive role of BMP antagonism in adult cartilage tissue. Moreover, Noggin-LacZ was detected in sutures in the skull and broadly in the nasal cartilage, while Gremlin1-LacZ exhibits a weaker and more restricted expression domain in the nasal cartilage. These results suggest broad regulation of BMP activities by Noggin and Gremlin1 in cartilage tissues in the adult skeleton, and that BMP signaling and its antagonism by NOGGIN play a role in osteoarthritis development. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1671-1682, 2017. PMID- 27769101 TI - Antiviral response is not sustained after cessation of lamivudine treatment in chronic hepatitis B patients: A 10-year follow-up study. AB - Although the ideal end point for antiviral treatment in patients with chronic hepatitis B (CHB) is loss of HBsAg, the typical clinical end points are HBeAg seroconversion in HBeAg-positive patients and long-term DNA suppression in HBeAg negative patients. We evaluated the long-term antiviral response after cessation of lamivudine treatment in CHB patients. A total of 157 patients who had discontinued lamivudine between 1997 and 2014 were enrolled (97 HBeAg-positive and 60 HBeAg-negative CHB patients). The long-term durability of the antiviral response (viralogical relapse; HBV DNA >=104 copies/ml) and the clinical course of these patients were analyzed retrospectively. In HBeAg-positive patients, the mean follow-up period after discontinuation was 72.3 months. The cumulative probabilities of virological relapse at 1, 12, 24, 48, 60, 96, and 120 months were 10.3%, 40.2%, 55.6%, 62.8%, 65.9%, 67.0%, and 67.0%, respectively. In HBeAg negative patients, the cumulative probabilities of a virological relapse at 1, 12, 24, 48, 60, 96, and 120 months were 25.0%, 35.0%, 41.7%, 43.3%, 43.3%, 46.7%, and 48.3%, respectively. Younger age (HR 1.732, 95%CI: 1.058-2.835, P = 0.02) was predictive of non-virological relapse in HBeAg-positive patients. And achievement of undetectable HBV DNA level within 3 months of treatment discontinuation was associated with decreased rate of virological relapse (HR 0.159, 95%CI: 0.069 0.367 P < 0.01) in HBeAg-negative patients. Despite meeting the requirements for treatment discontinuation, approximately half of the CHB patients treated with lamivudine relapsed. Thus, the antiviral response is not reliably sustained after lamivudine treatment cessation. J. Med. Virol. 89:849-856, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27769102 TI - How Strong is the "Fake ID Effect?" An Examination Using Propensity Score Matching in Two Samples. AB - BACKGROUND: Underage college students who obtain and use false identification (fake ID) are at risk for negative outcomes. However, it is currently unclear how uniquely the fake ID itself serves as a vehicle to subsequent harm (i.e., the "fake ID effect") over and above general and trait-related risk factors (e.g., deviant peers, low self-control). METHODS: To investigate whether the "fake ID effect" would hold after accounting for phenotypic risk, we utilized propensity score matching (PSM) in a cross-sectional sample of 1,454 students, and a longitudinal replication sample of 3,720 undergraduates. Individuals with a fake ID were matched with individuals without a fake ID, in terms of a number of trait based and social risk factors. These matched groups were then compared on 5 problematic outcomes (i.e., frequent binge drinking, alcohol-related problems, arrests, marijuana use, and hard drug use). RESULTS: Findings showed that "fake ID effects" were substantially-although not fully-diminished following PSM. The "fake ID effect" remained strongest for alcohol-related arrests. This may relate to issues of enforcement and students' willingness to engage in deviant behavior with a fake ID, or it may be a function of combined processes. CONCLUSIONS: Overall, the findings suggest that interventions should not only be aimed at reducing the fake ID-related alcohol access specifically, but should also be aimed more generally toward at-risk youths' access to alcohol. Future research might examine whether fake IDs have their strongest potency as moderators of the effects of risky traits-such as impulsiveness-on drinking outcomes. PMID- 27769106 TI - Erratum. PMID- 27769103 TI - Kinetic activity, membrane mitochondrial potential, lipid peroxidation, intracellular pH and calcium of frozen/thawed bovine spermatozoa treated with metabolic enhancers. AB - Owing to the progressive decline of sperm motility during storage there is a need to find substances capable of enhancing sperm energy metabolism and motility and/or preserving it from oxidative damage. The aim of this study was to evaluate in frozen/thawed bovine spermatozoa the effect of several compounds, such as myo inositol, pentoxifylline, penicillamine + hypotaurine + epinephrine mixture (PHE), caffeine and coenzyme Q10+ zinc + d-aspartate mixture (CZA), on either kinetic or metabolic parameters. Sperm kinetics was evaluated by Sperm Class Analyser whereas specific fluorochromes were used to evaluated mitochondrial membrane potential (MMP), intracellular pH, intracellular calcium concentration and lipid peroxidation. Lipid peroxidation was also evaluated by TBARS analysis. Treatments significantly affected total and progressive motility with different dynamics in relation to the incubation time. After the first hour of incubation, CZA treatment produced the best performance in total and progressive sperm motility as well as in curvilinear velocity, average path velocity and amplitude of head displacement, whereas pentoxifylline stimulated the highest straight-line velocity. MMP showed higher values (p < 0.01) after treatment with pentoxifylline and PHE. Intracytoplasmic calcium concentration and lipid peroxidation were significantly (p < 0.05) affected by the incubation time rather than the treatments. Intracellular pH varied significantly (p < 0.01) in relation to either the incubation time or treatments. In particular, it showed a progressive increase throughout incubation with values in control group significantly higher than in myo-inositol, PHE, caffeine, pentoxifylline and CZA groups (7.37 +/- 0.03 vs. 7.29 +/- 0.03, 7.28 +/- 0.03, 7.26 +/- 0.03, 7.22 +/- 0.03 and 7.00 +/- 0.03, respectively; p < 0.01).; however, among treatments, CZA displayed the lowest values. Significant correlations were found between sperm kinetic and metabolic parameters. These findings provide new comparative information on the effects of putative metabolic enhancers on kinetics and metabolic activities of bovine spermatozoa. In this study, a rapid methodological approach for evaluating sperm quality is proposed. PMID- 27769104 TI - Overexpression of CYP19A1 aromatase in Leydig cells is associated with steroidogenic dysfunction in subjects with Sertoli cell-only syndrome. AB - Several observational studies have showed a combination of lower testosterone (T) to LH ratio and higher estradiol (E2 ) to T ratio in secretory infertile men compared to men with normal spermatogenesis, suggesting a steroidogenic dysfunction of Leydig cells (Lc) that may involve increased aromatase activity. Low T/LH ratio is associated with Lc hyperplasia, which together with LH hyperstimulation may represent compensation for impaired T production. Aromatase expression and oestrogen production are mainly detected in Lc of the testis, although Sertoli and germ cells also contribute to testicular aromatase activity. The aim of this study was to assess the transcriptional expression of CYP19A1 (aromatase) in isolated Lc of subjects with Sertoli cell-only syndrome (SCOS) and signs of Lc impairment. Nineteen patients with SCOS and 10 controls with normal spermatogenesis who had medical indication of testicular biopsy for sperm retrieval were studied. Leydig cells were isolated by Laser Capture Microdissection (LCM) and CYP19A1 mRNA expression was quantified by SYBR(r) Green based qPCR. In addition, testicular T and E2 and serum hormonal levels were measured. Relative to control group, CYP19A1 was overexpressed more than twofold in 10/19 cases (2.3-12.2-fold increase), showing a significant increment in cases with low T/LH ratio (T/LH < 2) compared to cases with T/LH >= 2 (p = 0.038, REST(r) ). Moreover, Rq data for CYP19A1 had a direct correlation with testicular levels of E2 and the E2 /T ratio (r = 0.869; p < 0.001 and r = 0.633; p = 0.005). In summary, Lc from infertile patients with signs of Lc dysfunction overexpressed aromatase and showed an increment of testicular E2 . Our results suggest that increased expression of aromatase in Lc leads to higher E2 production and may account for the functional impairment of the Lc in patients with SCOS. PMID- 27769108 TI - Fibro markers for prediction of hepatocellular carcinoma in Egyptian patients with chronic liver disease. AB - It is well known that hepatocellular carcinoma (HCC) develops as a consequence of hepatic fibrosis progression. In this study, we aimed to evaluate the inflammatory and fibrosis markers as predictors for HCC development among patients with hepatitis C virus (HCV) related chronic liver disease to help in early diagnosis and management of HCC. A total of 280 patients with chronic liver disease were included in this retrospective study, out of them 140 had liver cirrhosis with HCC and 140 had cirrhosis without HCC. Eight readily available blood indices King score, Fibro Q, AST-ALT ratio (AAR), APRI, LOK index, Goteborg University Cirrhosis Index (GUCI), fibro alpha, and Biotechnology Research Center (BRC) were constructed to compare the accuracies of these non invasive scores in predicting HCC development. All fibrosis scores except APRI were significantly higher in HCC. We found that Fibro alpha and BRC had superior diagnostic performance in prediction of HCC based on area under curve of 0.91 and 0.93, respectively compared to other scores with area under curve ranged from poor to failure (0.59-0.66). Almost all cirrhotic cases were secondary to HCV (93.6%), while HBV was detected in 2.1% of cases only. Anti-HCV positive was reported in 100% of HCC cases (P = 0.002). Fibro alpha and BRC scores can be used for prediction of HCC. J. Med. Virol. 89:1062-1068, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27769107 TI - Assessment of magnetic field interactions and radiofrequency-radiation-induced heating of metallic spinal implants in 7 T field. AB - The safety of metallic spinal implants in magnetic resonance imaging (MRI) performed using ultrahigh fields has not been established. Hence, we examined whether the displacement forces caused by a static magnetic field and the heating induced by radiofrequency radiation are substantial for spinal implants in a 7 T field. We investigated spinal rods of various lengths and materials, a screw, and a cross-linking bridge in accordance with the American Society for Testing and Materials guidelines. The displacement forces of the metallic implants in static 7 T and 3 T static magnetic fields were measured and compared. The temperature changes of the implants during 15-min-long fast spin-echo and balanced gradient echo image acquisition sequences were measured in the 7 T field. The deflection angles of the metallic spinal materials in the 7 T field were 5.0-21.0 degrees [median: 6.7 degrees ], significantly larger than those in the 3 T field (1.0-6.3 degrees [2.2 degrees ]). Among the metallic rods, the cobalt-chrome rods had significantly larger deflection angles (17.8-21.0 degrees [19.8 degrees ]) than the pure titanium and titanium alloy rods (5.0-7.7 degrees [6.2 degrees ]). The temperature changes of the implants, including the cross-linked rods, were 0.7 1.0 degrees C [0.8 degrees C] and 0.6-1.0 degrees C [0.7 degrees C] during the fast spin-echo and balanced gradient-echo sequences, respectively; these changes were slightly larger than those of the controls (0.4-1.1 degrees C [0.5 degrees C] and 0.3-0.9 degrees C [0.6 degrees C], respectively). All of the metallic spinal implants exhibited small displacement forces and minimal heating, indicating that MRI examinations using 7 T fields may be performed safely on patients with these implants. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1831-1837, 2017. PMID- 27769109 TI - Association of mRNA expression of toll-like receptor 2 and 3 with hepatitis B viral load in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. AB - During Hepatitis B virus infection, the pathogen sensors Toll-like receptors (TLRs) play a role in innate immunity system. The study aimed to investigate mRNA expression levels of TLR2 and TLR3 in Hepatitis B virus (HBV) mediated chronic hepatitis B (CHB), cirrhosis (CIRR), and hepatocellular carcinoma (HCC), and to correlate viral load with severity of these diseases and expression of TLRs. A total of 180 HBV DNA positive samples were selected for the study. HVB-DNA was detected by multiplex PCR. Viral load estimation was done by using the Ampisure HBV Quantitative kit as per manufacture instructions. Expression levels of TLR2 and TLR3 were determined by real time PCR. The viral load was estimated to be 6.64log10 IU/ml in CHB, 4.88log10 IU/ml in CIRR, and 4.86log10 IU/ml in HCC. No significant association of viral load was found with increasing age. Upregulation of TLR2 expression in CHB when individually compared with CIRR and HCC was found to be statistically significant. Downregulation of TLR3 expressions in CIRR when compared to both CHB and HCC individually were found to be statistically significant. No significant effect of viral load on the expression of TLR2 and 3 were found. With severity of the disease from CHB to HCC, the HBV load decreases. The study suggests the possibility of HBV interacting with signalling of both analysed TLR receptors which partially explains the induction of immune tolerance pathways by Hepatitis B virus. J. Med. Virol. 89:1008-1014, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27769110 TI - High seroprevalence of human herpesvirus 8 and herpes simplex virus 2 infections in men who have sex with men in Shanghai, China. AB - Men who have sex with men (MSM) are an important risk group for human immunodeficiency virus (HIV) and at high-risk of herpesvirus infection. However, limited information on epidemiologic patterns of HHV8 and HSV2 among MSM is available in mainland China. A cross-sectional study of 486 participants was performed in Shanghai, China from January 2013 to December 2014 to explore epidemiologic features of HHV8 and HSV2 among MSM. Serum samples were collected and tested for HHV8 by immunofluoresence assay and HSV2 antibodies by ELISA. Logistic regression analysis was conducted to determine the risk factors of HHV8 and HSV2 infections, respectively. The overall seroprevalence was 23.0% for HHV8 infection and 22.4% for HSV2 infection. HHV8 seropositivity was significantly associated with being a money boy (odds ratio (OR) = 1.64; 95%CI: 1.04-2.58), having a steady sex partner (OR = 0.52; 95%CI: 0.31-0.87), having ever had anal sex with men (OR = 2.05; 95%CI: 1.09-3.86), and being HSV2 positive (OR = 2.14; 95%CI: 1.22-3.76). HSV2 seropositivity was significantly associate with being positive for HIV (OR = 2.12; 95%CI: 1.01-4.42), syphilis (OR = 1.98; 95%CI: 1.12 3.52), HHV8 (OR = 2.17; 95%CI: 1.24-3.83), and was marginally associated with being a money boy (OR = 1. 61; 95%CI: 0.97-2.86), and having ever had unprotected casual sex (OR = 1. 72; 95%CI: 0.99-2.99). HHV8 and HSV2 infections are common in Chinese MSM. It is important to implement programs for preventing herpes virus infection among MSM, particularly high-risk groups such as money buys. And protected sexual intercourse should be propagated. J. Med. Virol. 89:887-894, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27769111 TI - Cytochrome P450 Mediated Bioactivation of Saracatinib. AB - Saracatinib is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anticancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib. An ortho-quinone derived reactive metabolite existing as a GSH conjugate (M5) was found in microsomes fortified with GSH as a trapping agent. The formation of the metabolites detected was NADPH dependent. Metabolites M2-M4 were also observed in bile and urine of rats given saracatinib, and M5 was only detected in bile. Inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the primary enzyme responsible for the metabolic activation of saracatinib. The metabolism study facilitates the understanding of correlation between saracatinib-induced hepatotoxicity and bioactivation. PMID- 27769112 TI - Quantitative Proteomics Illuminates a Functional Interaction between mDia2 and the Proteasome. AB - Formin mDia2 is a cytoskeleton-regulatory protein that switches reversibly between a closed, autoinhibited and an open, active conformation. Although the open conformation of mDia2 induces actin assembly thereby controlling many cellular processes, mDia2 possesses also actin-independent and conformation insensitive scaffolding roles related to microtubules and p53, respectively. Thus, we hypothesize that mDia2 may have other unappreciated functions and regulatory modes. Here we identify and validate proteasome and Ubiquitin as mDia2 interacting partners using stable isotope labeling with amino acids in cell culture-based quantitative proteomics and biochemistry, respectively. Although mDia2 is ubiquitinated, binds ubiquitinated proteins and free Ubiquitin, it is not a proteasome substrate. Surprisingly, knockdown of mDia2 increases the activity of the proteasome in vitro, whereas mDia2 overexpression has opposite effects only when it adopts the open conformation and cannot induce actin assembly. Consistently, a combination of candidate and unbiased proteome-wide analyses indicates that mDia2 regulates the cellular levels of proteasome substrate beta-catenin and a number of ubiquitinated actin-regulatory proteins. Hence, these findings add more complexity to the mDia2 activity cycle by showing that the open conformation may control actin dynamics also through actin independent regulation of the proteasome. PMID- 27769114 TI - Serum Protein Markers for the Early Detection of Lung Cancer: A Focus on Autoantibodies. AB - Lung cancer has the highest mortality rate among cancer patients in the world, in particular because most patients are only diagnosed at an advanced and noncurable stage. Computed tomography (CT) screening on high-risk individuals has shown that early detection could reduce the mortality rate. However, the still high false positive rate of CT screening may harm healthy individuals because of unnecessary follow-up scans and invasive follow-up procedures. Alternatively, false-negative and indeterminate results may harm patients due to the delayed diagnosis and treatment of lung cancer. Noninvasive biomarkers, complementary to CT screening, could lower the false-positive and false-negative rate of CT screening at baseline and thereby reduce the number of patients that need follow-up and diagnose patients at an earlier stage of lung cancer. Lung cancer tissue generates lung cancer-associated proteins to which the immune system might produce high-affinity autoantibodies. This autoantibody response to tumor associated antigens starts during early stage lung cancer and may endure over years. Identification of tumor-associated antigens or the corresponding autoantibodies in body fluids as potential noninvasive biomarkers could thus be an effective approach for early detection and monitoring of lung cancer. We provide an overview of differentially expressed protein, antigen, and autoantibody biomarkers that combined with CT imaging might be of clinical use for early detection of lung cancer. PMID- 27769115 TI - Molecular Mechanism Behind the Fast Folding/Unfolding Transitions of Villin Headpiece Subdomain: Hierarchy and Heterogeneity. AB - Proteins involve motions over a wide range of spatial and temporal scales. While the large conformational changes, such as folding and functioning, are slow and appear to occur in a highly cooperative manner, how the hierarchical dynamics over different time scales play a role during these slow transitions has been of great interest over the decades. Here we study the folding mechanism of the villin headpiece subdomain (HP35) to understand the molecular mechanism behind this prototypical fast-folding protein. The ~400 MUs molecular dynamics (MD) trajectories obtained by Piana et al. [ Piana , S. ; Lindorff-Larsen , K. ; Shaw , D. E. Proc. Natl. Acad. Sci. U.S.A. 2012 , 109 , 17845 ] are analyzed in detail. By extracting the slowest mode from the trajectories, which is responsible for the folding/unfolding transitions, and by analyzing the transition events along this mode, we find that the transitions occur in a heterogeneous manner. Detailed analysis of the individual transition events shows that the folding/unfolding transitions occur via two qualitatively different pathways, i.e., the unfolding triggered from the C-terminal (alpha3 helix) and from the N-terminal (alpha1-alpha2 loop). Non-native contacts are also found to contribute in slowing down the transitions. The folding of HP35 thus proceeds in a segmental manner rather than cooperatively at the submicrosecond time scale. The Lys->Nle mutation is found to speed up the transitions by rigidifying the alpha3 helix, i.e., suppressing one transition pathway. The analysis of the microsecond dynamics in the single-molecule Forster resonance energy transfer efficiency trajectories, which are calculated from the MD data, reveals that the folding/unfolding transitions in the NleNle mutant can be fitted with a two-state model, whereas those in WT appear to be more complex and involves multiple time scales. This is due to the coupling between the folding/unfolding transitions and conformational transitions within the unfolded and intermediate states. The present study demonstrates that a protein as small as HP35 already involves heterogeneous characters during folding/unfolding transitions when the hierarchical dynamics at the molecular level is considered, thus heterogeneity can be a general characteristic in protein folding. PMID- 27769113 TI - Proteomic Analysis, Immune Dysregulation, and Pathway Interconnections with Obesity. AB - Proteomic studies can offer information on hundreds to thousands of proteins and potentially provide researchers with a comprehensive understanding of signaling response during stress and disease. Large data sets, such as those obtained in high-dimensional proteomic studies, can be leveraged for pathway analysis to discover or describe the biological implications of clinical disease states. Obesity is a worldwide epidemic that is considered a risk factor for numerous other diseases. We performed analysis on plasma proteomic data from 3 separate sample sets of postmenopausal women to identify the pathways that are altered in subjects with a high body mass index (BMI) compared to normal BMI. We found many pathways consistently and significantly associated with inflammation dysregulated in plasma from obese/overweight subjects compared to plasma from normal BMI subjects. These pathways indicate alterations of soluble inflammatory regulators, cellular stress, and metabolic dysregulation. Our results highlight the importance of high-dimensional pathway analysis in complex diseases as well as provide information on the interconnections between pathways that are dysregulated with obesity. Specifically, overlap of obesity related pathways with those activated during cancer and infection could help describe why obesity is a risk factor for disease and help devise treatment options that mitigate its effect. PMID- 27769117 TI - Web-based remote psychological intervention improves cancer treatment. AB - Web-based-remote (WBR) intervention is a new approach that incorporates smart control technology and modern medicine to monitor patient compliance. It is based on computer control and communication technology. This study is to explore the benefits of WBR psychological intervention for cancer treatment. 128 patients diagnosed with cancer by Pathology Department of our hospital between 1 February 2013 and 1 August 2013 were included. Patients were randomly assigned to intervention and control group (n = 64). The Questionnaire-Core 30 (QLQ-C30) was used for the survey. Intervention group received WBR psychological intervention in addition to regular clinical follow-up care. Control group only received regular clinical follow-up care. The QLQ-C30 score was significantly better in the intervention group than the control group when the intervention and control groups were followed for three months. In conclusion, WBR psychological intervention substantially improves the quality of life in patients during cancer treatment. PMID- 27769116 TI - Structure-Reactivity Effects on Intrinsic Primary Kinetic Isotope Effects for Hydride Transfer Catalyzed by Glycerol-3-phosphate Dehydrogenase. AB - Primary deuterium kinetic isotope effects (1 degrees DKIE) on (kcat/KGA, M-1 s-1) for dianion (X2-) activated hydride transfer from NADL to glycolaldehyde (GA) catalyzed by glycerol-3-phosphate dehydrogenase were determined over a 2100-fold range of enzyme reactivity: (X2-, 1 degrees DKIE); FPO32-, 2.8 +/- 0.1; HPO32-, 2.5 +/- 0.1; SO42-, 2.8 +/- 0.2; HOPO32-, 2.5 +/- 0.1; S2O32-, 2.9 +/- 0.1; unactivated; 2.4 +/- 0.2. Similar 1 degrees DKIEs were determined for kcat. The observed 1 degrees DKIEs are essentially independent of changes in enzyme reactivity with changing dianion activator. The results are consistent with (i) fast and reversible ligand binding; (ii) the conclusion that the observed 1 degrees DKIEs are equal to the intrinsic 1 degrees DKIE on hydride transfer from NADL to GA; (iii) similar intrinsic 1 degrees DKIEs on GPDH-catalyzed reduction of the substrate pieces and the whole physiological substrate dihydroxyacetone phosphate. The ground-state binding interactions for different X2- are similar, but there are large differences in the transition state interactions for different X2-. The changes in transition state binding interactions are expressed as changes in kcat and are proposed to represent changes in stabilization of the active closed form of GPDH. The 1 degrees DKIEs are much smaller than observed for enzyme-catalyzed hydrogen transfer that occurs mainly by quantum-mechanical tunneling. PMID- 27769120 TI - Some Thoughts on Empathy. PMID- 27769119 TI - Behavioral Treatment of Hysterical Neurosis: Symptom Substitution and Symptom Return Reconsidered. PMID- 27769121 TI - A Rear Unit for the Treatment of Combat Reactions in the Wake of the Yom Kippur War. PMID- 27769123 TI - What are the short-term and long-term effects of occupation-focused and occupation-based occupational therapy in the home on older adults' occupational performance? A systematic review. AB - BACKGROUND: There is a lack of evidence-based knowledge about the effectiveness of home-based OT for older adults aimed at improving occupational performance by practicing activities and tasks. AIM: This review synthesizes and discusses evidence for the effectiveness of occupation-focused and occupation-based OT for older adults at home. MATERIAL AND METHODS: Peer-reviewed quantitative papers were included. PARTICIPANTS: >= 60-year-old adults with functional limitations. INTERVENTION: OT aiming at improving occupational performance, primarily through the practice of activities and tasks. OUTCOME: Occupational performance. CONTEXT: Home. Three reviewers critically appraised 13 of 995 detected papers. Extracted data were presented and summarized descriptively. RESULTS: Eight high-quality papers showed that occupation-focused and occupation-based OT using cognitive, behavioral and environmental strategies may significantly improve occupational performance in older, home-dwelling adults with physical health problems. Maintaining achieved improvements was a consistent challenge. CONCLUSIONS AND SIGNIFICANCE: Evidence suggests that older adults' occupational performance can be significantly improved through low-intensity occupation-focused and occupation based intervention. It is recommended to develop and test high-intensity OT programs and maintenance programs. PMID- 27769132 TI - Anthropophohia and Japanese Performance. PMID- 27769131 TI - Approaching a Comparative Typology of Assaultive Female Offenders. PMID- 27769133 TI - Mommy and the Midnight Visitor: A Study of Occasional Co-Sleeping. PMID- 27769136 TI - Peripartum management of bipolar disorder: what do the latest guidelines recommend? AB - INTRODUCTION: Many women with bipolar disorder experience significant morbidity during pregnancy and the postpartum period. The use of evidence-based and up-to date guidelines has the potential to improve maternal and neonatal care. We review the latest clinical practice guidelines to gather recommendations for the peripartum management of bipolar disorder. Areas covered: Three electronic databases, MEDLINE/PubMed, the Cochrane Library, and the National Guidelines Clearinghouse were searched using various combinations of the following terms: bipolar disorder, pregnancy, postpartum, peripartum, puerperal, antenatal, postnatal, and guidelines. All guidelines retrieved were published, revised, or reaffirmed during the period from November 2010-June 2016. Expert commentary: To date there are no exclusive guidelines for the peripartum management of bipolar disorder. Currently available guidelines do not provide sufficient guidance for clinicians to deliver optimal care to women before, during, and after pregnancy. The guidelines reflect the paucity of available literature on the peripartum management of bipolar disorder. Further research is urgently needed to strengthen the evidence supporting the guidelines recommendations. PMID- 27769147 TI - Effects of a 12-week aerobic exercise intervention on eating behaviour, food cravings, and 7-day energy intake and energy expenditure in inactive men. AB - This study examined effects of 12 weeks of moderate-intensity aerobic exercise on eating behaviour, food cravings, and weekly energy intake and expenditure in inactive men. Eleven healthy men (mean +/- SD: age, 26 +/- 5 years; body mass index, 24.6 +/- 3.8 kg.m-2; maximum oxygen uptake, 43.1 +/- 7.4 mL.kg-1.min-1) completed the 12-week supervised exercise programme. Body composition, health markers (e.g., blood pressure), eating behaviour, food cravings, and weekly energy intake and expenditure were assessed before and after the exercise intervention. There were no intervention effects on weekly free-living energy intake (p = 0.326, d = -0.12) and expenditure (p = 0.799, d = 0.04) or uncontrolled eating and emotional eating scores (p > 0.05). However, there was a trend with a medium effect size (p = 0.058, d = 0.68) for cognitive restraint to be greater after the exercise intervention. Total food cravings (p = 0.009, d = 1.19) and specific cravings of high-fat foods (p = 0.023, d = -0.90), fast-food fats (p = 0.009, d = -0.71), and carbohydrates/starches (p = 0.009, d = -0.56) decreased from baseline to 12 weeks. Moreover, there was a trend with a large effect size for cravings of sweets (p = 0.052, d = -0.86) to be lower after the exercise intervention. In summary, 12 weeks of moderate-intensity aerobic exercise reduced food cravings and increased cognitive restraint, but these changes were not accompanied by changes in other eating behaviours or weekly energy intake and expenditure. The results indicate the importance of exercising for health improvements even when reductions in body mass are modest. PMID- 27769148 TI - Similar substrate oxidation rates in concentric and eccentric cycling matched for aerobic power output. AB - This study investigated substrate oxidation in concentric and eccentric cycling matched for aerobic power output in the postprandial state. Energy expenditure, respiratory exchange ratio, and fat and carbohydrate oxidation rates were measured at rest and after 15, 30, and 45 min of eccentric and concentric cycling in 12 men. Absolute and relative aerobic power output and energy expenditure were similar during concentric and eccentric exercise. No effect of exercise modality was observed for substrate metabolism. PMID- 27769162 TI - A comparative study of ChIP-seq sequencing library preparation methods. AB - BACKGROUND: ChIP-seq is the primary technique used to investigate genome-wide protein-DNA interactions. As part of this procedure, immunoprecipitated DNA must undergo "library preparation" to enable subsequent high-throughput sequencing. To facilitate the analysis of biopsy samples and rare cell populations, there has been a recent proliferation of methods allowing sequencing library preparation from low-input DNA amounts. However, little information exists on the relative merits, performance, comparability and biases inherent to these procedures. Notably, recently developed single-cell ChIP procedures employing microfluidics must also employ library preparation reagents to allow downstream sequencing. RESULTS: In this study, seven methods designed for low-input DNA/ChIP-seq sample preparation (Accel-NGS(r) 2S, Bowman-method, HTML-PCR, SeqPlexTM, DNA SMARTTM, TELP and ThruPLEX(r)) were performed on five replicates of 1 ng and 0.1 ng input H3K4me3 ChIP material, and compared to a "gold standard" reference PCR-free dataset. The performance of each method was examined for the prevalence of unmappable reads, amplification-derived duplicate reads, reproducibility, and for the sensitivity and specificity of peak calling. CONCLUSIONS: We identified consistent high performance in a subset of the tested reagents, which should aid researchers in choosing the most appropriate reagents for their studies. Furthermore, we expect this work to drive future advances by identifying and encouraging use of the most promising methods and reagents. The results may also aid judgements on how comparable are existing datasets that have been prepared with different sample library preparation reagents. PMID- 27769161 TI - Growth conditions that increase or decrease lifespan in Saccharomyces cerevisiae lead to corresponding decreases or increases in rates of interstitial deletions and non-reciprocal translocations. AB - BACKGROUND: Accumulation of DNA damage, mutations, and chromosomal abnormalities is associated with aging in many organisms. How directly various forms of genomic instability contribute to lifespan in different aging contexts is still under active investigation. Testing whether treatments that alter lifespan change mutation rates early during lifespan could provide support for genomic instability being at least partly responsible for changes in the rates of aging. RESULTS: Rates of mutations, direct repeat recombination, or retrotransposition were measured in young cell populations from two strain backgrounds of Saccharomyces cerevisiae exposed to several growth conditions that shortened or extended yeast chronological lifespan. In most cases, rates of genomic instability did not consistently increase in young cells exposed to lifespan shortening conditions or decrease in young cells exposed to lifespan-extending conditions. The mutation rate for a copy of the CAN1 gene integrated onto the right arm of chromosome VIII did show expected increases or decreases in young cells in the lifespan-altering growth conditions. These mutations were determined to frequently result from non-allelic recombination events, including non reciprocal translocations, and were more strongly stimulated by using hydroxyurea to induce DNA replication stress than by the general DNA-damaging agent methyl methanesulfonate. CONCLUSIONS: The results are not consistent with changes in mutation rates in general mediating the influence of alternative growth conditions on yeast lifespan. The strong correlation between non-allelic recombination events and the effects of the alternative growth conditions on lifespan indicates that genomic instability due to changes in recombination rates may directly contribute to the rate of aging or that lifespan-altering treatments may consistently increase or decrease DNA replication stress. These results further support the connection between DNA replication stress and aging observed in multiple organisms. Chromosomal abnormalities that likely arise from recombination events are more prevalent in multiple human tissues with increasing age, and further work in yeast could help to define mechanisms responsible for this observation and the impact of chromosomal abnormalities on aging. PMID- 27769163 TI - Unraveling the early molecular and physiological mechanisms involved in response to phenanthrene exposure. AB - BACKGROUND: Higher plants have to cope with increasing concentrations of pollutants of both natural and anthropogenic origin. Given their capacity to concentrate and metabolize various compounds including pollutants, plants can be used to treat environmental problems - a process called phytoremediation. However, the molecular mechanisms underlying the stabilization, the extraction, the accumulation and partial or complete degradation of pollutants by plants remain poorly understood. RESULTS: Here, we determined the molecular events involved in the early plant response to phenanthrene, used as a model of polycyclic aromatic hydrocarbons. A transcriptomic and a metabolic analysis strongly suggest that energy availability is the crucial limiting factor leading to high and rapid transcriptional reprogramming that can ultimately lead to death. We show that the accumulation of phenanthrene in leaves inhibits electron transfer and photosynthesis within a few minutes, probably disrupting energy transformation. CONCLUSION: This kinetic analysis improved the resolution of the transcriptome in the initial plant response to phenanthrene, identifying genes that are involved in primary processes set up to sense and detoxify this pollutant but also in molecular mechanisms used by the plant to cope with such harmful stress. The identification of first events involved in plant response to phenanthrene is a key step in the selection of candidates for further functional characterization, with the prospect of engineering efficient ecological detoxification systems for polycyclic aromatic hydrocarbons. PMID- 27769164 TI - Phylogenomic analysis of carangimorph fishes reveals flatfish asymmetry arose in a blink of the evolutionary eye. AB - BACKGROUND: Flatfish cranial asymmetry represents one of the most remarkable morphological innovations among vertebrates, and has fueled vigorous debate on the manner and rate at which strikingly divergent phenotypes evolve. A surprising result of many recent molecular phylogenetic studies is the lack of support for flatfish monophyly, where increasingly larger DNA datasets of up to 23 loci have either yielded a weakly supported flatfish clade or indicated the group is polyphyletic. Lack of resolution for flatfish relationships has been attributed to analytical limitations for dealing with processes such as nucleotide non stationarity and incomplete lineage sorting (ILS). We tackle this phylogenetic problem using a sequence dataset comprising more than 1,000 ultraconserved DNA element (UCE) loci covering 45 carangimorphs, the broader clade containing flatfishes and several other specialized lineages such as remoras, billfishes, and archerfishes. RESULTS: We present a phylogeny based on UCE loci that unequivocally supports flatfish monophyly and a single origin of asymmetry. We document similar levels of discordance among UCE loci as in previous, smaller molecular datasets. However, relationships among flatfishes and carangimorphs recovered from multilocus concatenated and species tree analyses of our data are robust to the analytical framework applied and size of data matrix used. By integrating the UCE data with a rich fossil record, we find that the most distinctive carangimorph bodyplans arose rapidly during the Paleogene (66.0-23.03 Ma). Flatfish asymmetry, for example, likely evolved over an interval of no more than 2.97 million years. CONCLUSIONS: The longstanding uncertainty in phylogenetic hypotheses for flatfishes and their carangimorph relatives highlights the limitations of smaller molecular datasets when applied to successive, rapid divergences. Here, we recovered significant support for flatfish monophyly and relationships among carangimorphs through analysis of over 1,000 UCE loci. The resulting time-calibrated phylogeny points to phenotypic divergence early within carangimorph history that broadly matches with the predictions of adaptive models of lineage diversification. PMID- 27769167 TI - Erratum to: An integrative genomics approach for identifying novel functional consequences of PBRM1 truncated mutations in clear cell renal cell carcinoma (ccRCC). PMID- 27769165 TI - Distinct gene expression program dynamics during erythropoiesis from human induced pluripotent stem cells compared with adult and cord blood progenitors. AB - BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) are a potentially invaluable resource for regenerative medicine, including the in vitro manufacture of blood products. HiPSC-derived red blood cells are an attractive therapeutic option in hematology, yet exhibit unexplained proliferation and enucleation defects that presently preclude such applications. We hypothesised that substantial differential regulation of gene expression during erythroid development accounts for these important differences between hiPSC-derived cells and those from adult or cord-blood progenitors. We thus cultured erythroblasts from each source for transcriptomic analysis to investigate differential gene expression underlying these functional defects. RESULTS: Our high resolution transcriptional view of definitive erythropoiesis captures the regulation of genes relevant to cell-cycle control and confers statistical power to deploy novel bioinformatics methods. Whilst the dynamics of erythroid program elaboration from adult and cord blood progenitors were very similar, the emerging erythroid transcriptome in hiPSCs revealed radically different program elaboration compared to adult and cord blood cells. We explored the function of differentially expressed genes in hiPSC-specific clusters defined by our novel tunable clustering algorithms (SMART and Bi-CoPaM). HiPSCs show reduced expression of c-KIT and key erythroid transcription factors SOX6, MYB and BCL11A, strong HBZ-induction, and aberrant expression of genes involved in protein degradation, lysosomal clearance and cell-cycle regulation. CONCLUSIONS: Together, these data suggest that hiPSC-derived cells may be specified to a primitive erythroid fate, and implies that definitive specification may more accurately reflect adult development. We have therefore identified, for the first time, distinct gene expression dynamics during erythroblast differentiation from hiPSCs which may cause reduced proliferation and enucleation of hiPSC-derived erythroid cells. The data suggest several mechanistic defects which may partially explain the observed aberrant erythroid differentiation from hiPSCs. PMID- 27769166 TI - Expansion of the phosphatidylethanolamine binding protein family in legumes: a case study of Lupinus angustifolius L. FLOWERING LOCUS T homologs, LanFTc1 and LanFTc2. AB - BACKGROUND: The Arabidopsis FLOWERING LOCUS T (FT) gene, a member of the phosphatidylethanolamine binding protein (PEBP) family, is a major controller of flowering in response to photoperiod, vernalization and light quality. In legumes, FT evolved into three, functionally diversified clades, FTa, FTb and FTc. A milestone achievement in narrow-leafed lupin (Lupinus angustifolius L.) domestication was the loss of vernalization responsiveness at the Ku locus. Recently, one of two existing L. angustifolius homologs of FTc, LanFTc1, was revealed to be the gene underlying Ku. It is the first recorded involvement of an FTc homologue in vernalization. The evolutionary basis of this phenomenon in lupin has not yet been deciphered. RESULTS: Bacterial artificial chromosome (BAC) clones carrying LanFTc1 and LanFTc2 genes were localized in different mitotic chromosomes and constituted sequence-specific landmarks for linkage groups NLL-10 and NLL-17. BAC-derived superscaffolds containing LanFTc genes revealed clear microsyntenic patterns to genome sequences of nine legume species. Superscaffold 1 carrying LanFTc1 aligned to regions encoding one or more FT-like genes whereas superscaffold-2 mapped to a region lacking such a homolog. Comparative mapping of the L. angustifolius genome assembly anchored to linkage map localized superscaffold-1 in the middle of a 15 cM conserved, collinear region. In contrast, superscaffold-2 was found at the edge of a 20 cM syntenic block containing highly disrupted collinearity at the LanFTc2 locus. 118 PEBP-family full-length homologs were identified in 10 legume genomes. Bayesian phylogenetic inference provided novel evidence supporting the hypothesis that whole-genome and tandem duplications contributed to expansion of PEBP-family genes in legumes. Duplicated genes were subjected to strong purifying selection. Promoter analysis of FT genes revealed no statistically significant sequence similarity between duplicated copies; only RE-alpha and CCAAT-box motifs were found at conserved positions and orientations. CONCLUSIONS: Numerous lineage-specific duplications occurred during the evolution of legume PEBP-family genes. Whole-genome duplications resulted in the origin of subclades FTa, FTb and FTc and in the multiplication of FTa and FTb copy number. LanFTc1 is located in the region conserved among all main lineages of Papilionoideae. LanFTc1 is a direct descendant of ancestral FTc, whereas LanFTc2 appeared by subsequent duplication. PMID- 27769168 TI - Comparative genomics of Clostridium bolteae and Clostridium clostridioforme reveals species-specific genomic properties and numerous putative antibiotic resistance determinants. AB - BACKGROUND: Clostridium bolteae and Clostridium clostridioforme, previously included in the complex C. clostridioforme in the group Clostridium XIVa, remain difficult to distinguish by phenotypic methods. These bacteria, prevailing in the human intestinal microbiota, are opportunistic pathogens with various drug susceptibility patterns. In order to better characterize the two species and to obtain information on their antibiotic resistance genes, we analyzed the genomes of six strains of C. bolteae and six strains of C. clostridioforme, isolated from human infection. RESULTS: The genome length of C. bolteae varied from 6159 to 6398 kb, and 5719 to 6059 CDSs were detected. The genomes of C. clostridioforme were smaller, between 5467 and 5927 kb, and contained 5231 to 5916 CDSs. The two species display different metabolic pathways. The genomes of C. bolteae contained lactose operons involving PTS system and complex regulation, which contribute to phenotypic differentiation from C. clostridioforme. The Acetyl-CoA pathway, similar to that of Faecalibacterium prausnitzii, a major butyrate producer in the human gut, was only found in C. clostridioforme. The two species have also developed diverse flagella mobility systems contributing to gut colonization. Their genomes harboured many CDSs involved in resistance to beta-lactams, glycopeptides, macrolides, chloramphenicol, lincosamides, rifampin, linezolid, bacitracin, aminoglycosides and tetracyclines. Overall antimicrobial resistance genes were similar within a species, but strain-specific resistance genes were found. We discovered a new group of genes coding for rifampin resistance in C. bolteae. C. bolteae 90B3 was resistant to phenicols and linezolide in producing a 23S rRNA methyltransferase. C. clostridioforme 90A8 contained the VanB-type Tn1549 operon conferring vancomycin resistance. We also detected numerous genes encoding proteins related to efflux pump systems. CONCLUSION: Genomic comparison of C. bolteae and C. clostridiofrome revealed functional differences in butyrate pathways and in flagellar systems, which play a critical role within human microbiota. Most of the resistance genes detected in both species were previously characterized in other bacterial species. A few of them were related to antibiotics inactive against Clostridium spp. Some were part of mobile genetic elements suggesting that these commensals of the human microbiota act as reservoir of antimicrobial resistances. PMID- 27769170 TI - dupRadar: a Bioconductor package for the assessment of PCR artifacts in RNA-Seq data. AB - BACKGROUND: PCR clonal artefacts originating from NGS library preparation can affect both genomic as well as RNA-Seq applications when protocols are pushed to their limits. In RNA-Seq however the artifactual reads are not easy to tell apart from normal read duplication due to natural over-sequencing of highly expressed genes. Especially when working with little input material or single cells assessing the fraction of duplicate reads is an important quality control step for NGS data sets. Up to now there are only tools to calculate the global duplication rates that do not take into account the effect of gene expression levels which leaves them of limited use for RNA-Seq data. RESULTS: Here we present the tool dupRadar, which provides an easy means to distinguish the fraction of reads originating in natural duplication due to high expression from the fraction induced by artefacts. dupRadar assesses the fraction of duplicate reads per gene dependent on the expression level. Apart from the Bioconductor package dupRadar we provide shell scripts for easy integration into processing pipelines. CONCLUSIONS: The Bioconductor package dupRadar offers straight-forward methods to assess RNA-Seq datasets for quality issues with PCR duplicates. It is aimed towards simple integration into standard analysis pipelines as a default QC metric that is especially useful for low-input and single cell RNA-Seq data sets. PMID- 27769169 TI - Unexpected effects of different genetic backgrounds on identification of genomic rearrangements via whole-genome next generation sequencing. AB - BACKGROUND: Whole genome next generation sequencing (NGS) is increasingly employed to detect genomic rearrangements in cancer genomes, especially in lymphoid malignancies. We recently established a unique mouse model by specifically deleting a key non-homologous end-joining DNA repair gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in germinal center B cells. This mouse model spontaneously develops mature B cell lymphomas (termed G1XP lymphomas). RESULTS: Here, we attempt to employ whole genome NGS to identify novel structural rearrangements, in particular inter-chromosomal translocations (CTXs), in these G1XP lymphomas. We sequenced six lymphoma samples, aligned our NGS data with mouse reference genome (in C57BL/6J (B6) background) and identified CTXs using CREST algorithm. Surprisingly, we detected widespread CTXs in both lymphomas and wildtype control samples, majority of which were false positive and attributable to different genetic backgrounds. In addition, we validated our NGS pipeline by sequencing multiple control samples from distinct tissues of different genetic backgrounds of mouse (B6 vs non-B6). Lastly, our studies showed that widespread false positive CTXs can be generated by simply aligning sequences from different genetic backgrounds of mouse. CONCLUSIONS: We conclude that mapping and alignment with reference genome might not be a preferred method for analyzing whole-genome NGS data obtained from a genetic background different from reference genome. Given the complex genetic background of different mouse strains or the heterogeneity of cancer genomes in human patients, in order to minimize such systematic artifacts and uncover novel CTXs, a preferred method might be de novo assembly of personalized normal control genome and cancer cell genome, instead of mapping and aligning NGS data to mouse or human reference genome. Thus, our studies have critical impact on the manner of data analysis for cancer genomics. PMID- 27769172 TI - Randomized controlled trials vs. observational studies: why not just live together? AB - Randomized controlled trials (RCTs) are considered the gold standard for clinical research, thus having a high impact on clinical guidelines and our daily patients' care. However, various treatment strategies which we consider "evidence based" have never been subject to a prospective RCT, as we would rate it unethical to withheld an established treatment to individuals in an placebo controlled trial.In a recent BMC Anesthesiology publication, Trentino et al. analyzed the usefulness of observational studies in assessing benefit and risk of different transfusion strategies. The authors nicely reviewed and summarized similarities and differences, advantages and limitations, between different study types frequently used in transfusion medicine. In this interesting article, the authors conclude, that 'when comparing the results of observational studies with RCTs assessing transfusion outcomes, it is important that one consider not only the study method, but also the key elements of the study design'. Thus, in this commentary we now discuss the pro's and con's of different study types, even irrespective of transfusion medicine. PMID- 27769171 TI - De novo transcriptome sequencing of black pepper (Piper nigrum L.) and an analysis of genes involved in phenylpropanoid metabolism in response to Phytophthora capsici. AB - BACKGROUND: Piper nigrum L., or "black pepper", is an economically important spice crop in tropical regions. Black pepper production is markedly affected by foot rot disease caused by Phytophthora capsici, and genetic improvement of black pepper is essential for combating foot rot diseases. However, little is known about the mechanism of anti- P. capsici in black pepper. The molecular mechanisms underlying foot rot susceptibility were studied by comparing transcriptome analysis between resistant (Piper flaviflorum) and susceptible (Piper nigrum cv. Reyin-1) black pepper species. RESULTS: 116,432 unigenes were acquired from six libraries (three replicates of resistant and susceptible black pepper samples), which were integrated by applying BLAST similarity searches and noted by adopting Kyoto Encyclopaedia of Genes and Gene Ontology (GO) genome orthology identifiers. The reference transcriptome was mapped using two sets of digital gene expression data. Using GO enrichment analysis for the differentially expressed genes, the majority of the genes associated with the phenylpropanoid biosynthesis pathway were identified in P. flaviflorum. In addition, the expression of genes revealed that after susceptible and resistant species were inoculated with P. capsici, the majority of genes incorporated in the phenylpropanoid metabolism pathway were up regulated in both species. Among various treatments and organs, all the genes were up-regulated to a relatively high degree in resistant species. Phenylalanine ammonia lyase and peroxidase enzyme activity increased in susceptible and resistant species after inoculation with P. capsici, and the resistant species increased faster. The resistant plants retain their vascular structure in lignin revealed by histochemical analysis. CONCLUSIONS: Our data provide critical information regarding target genes and a technological basis for future studies of black pepper genetic improvements, including transgenic breeding. PMID- 27769173 TI - Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction. AB - BACKGROUND: Insulin-like growth factor binding protein-7 (IGFBP-7) modulates the biological activities of insulin-like growth factor-1 (IGF-1). Previous studies demonstrated the prognostic value of IGFBP-7 and IGF-1 among patients with systolic heart failure (HF). This study aimed to evaluate the IGF1/IGFBP-7 axis in HF patients with preserved ejection fraction (HFpEF). METHODS: Serum IGF-1 and IGFBP-7 levels were measured in 300 eligible consecutive patients who underwent comprehensive cardiac assessment. Patients were categorized into 3 groups including controls with normal diastolic function (n = 55), asymptomatic left ventricular diastolic dysfunction (LVDD, n = 168) and HFpEF (n = 77). RESULTS: IGFBP-7 serum levels showed a significant graded increase from controls to LVDD to HFpEF (median 50.30 [43.1-55.3] vs. 54.40 [48.15-63.40] vs. 61.9 [51.6-69.7], respectively, P < 0.001), whereas IGF-1 levels showed a graded decline from controls to LVDD to HFpEF (120.0 [100.8-144.0] vs. 112.3 [88.8-137.1] vs. 99.5 [72.2-124.4], p < 0.001). The IGFBP-7/IGF-1 ratio increased from controls to LVDD to HFpEF (0.43 [0.33-0.56] vs. 0.48 [0.38-0.66] vs. 0.68 [0.55-0.88], p < 0.001). Patents with IGFB-7/IGF1 ratios above the median demonstrated significantly higher left atrial volume index, E/E' ratio, and NT-proBNP levels (all P <= 0.02). CONCLUSION: In conclusion, this hypothesis-generating pilot study suggests the IGFBP-7/IGF-1 axis correlates with diastolic function and may serve as a novel biomarker in patients with HFpEF. A rise in IGFBP-7 or the IGFBP-7/IGF-1 ratio may reflect worsening diastolic function, adverse cardiac remodeling, and metabolic derangement. PMID- 27769174 TI - Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study. AB - BACKGROUND: According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa. METHODS: We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment. RESULTS: Across the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (<=50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43.8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45 246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts <=100 cells/mm3 and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95 % CI: 1.30-5.84 and sHR: 3.07, 95 % CI: 1.46-6.46, respectively). CONCLUSION: Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment. PMID- 27769175 TI - Warfarin use and stroke, bleeding and mortality risk in patients with end stage renal disease and atrial fibrillation: a systematic review and meta-analysis. AB - BACKGROUND: Patients with end stage renal disease (ESRD), including stage 5 chronic kidney disease (CKD), hemodialysis (HD) and peritoneal dialysis (PD), are at high risk for stroke-related morbidity, mortality and bleeding. The overall risk/benefit balance of warfarin treatment among patients with ESRD and AF remains unclear. METHODS: We systematically reviewed the associations of warfarin use and stroke outcome, bleeding outcome or mortality in patients with ESRD and AF. We conducted a comprehensive literature search in Feb 2016 using key words related to ESRD, AF and warfarin in PubMed, Embase and Cochrane Library without language restriction. We searched for randomized trials and observational studies that compared the use of warfarin with no treatment, aspirin or direct oral anticoagulants (DOACs), and reported quantitative risk estimates on these outcomes. Paired reviewers screened articles, collected data and performed qualitative assessment using the Cochrane Risk of Bias Assessment Tool for Non randomized Studies of Interventions. We conducted meta-analyses using the random effects model with the DerSimonian - Laird estimator and the Knapp-Hartung methods as appropriate. RESULTS: We identified 2709 references and included 20 observational cohort studies that examined stroke outcome, bleeding outcome and mortality associated with warfarin use in 56,146 patients with ESRD and AF. The pooled estimates from meta-analysis for the stroke outcome suggested that warfarin use was not associated with all-cause stroke (HR = 0.92, 95 % CI 0.74 1.16) or any stroke (HR = 1.01, 95 % CI 0.81-1.26), or ischemic stroke (HR = 0.80, 95 % CI 0.58-1.11) among patients with ESRD and AF. In contrast, warfarin use was associated with significantly increased risk of all-cause bleeding (HR = 1.21, 95 % CI 1.01-1.44), but not associated with major bleeding (HR = 1.18, 95 % CI 0.82-1.69) or gastrointestinal bleeding (HR = 1.19, 95 % CI 0.81-1.76) or any bleeding (HR = 1.21, 95 % CI 0.99-1.48). There was insufficient evidence to evaluate the association between warfarin use and mortality in this population (pooled risk estimate not calculated due to high heterogeneity). Results on DOACs were inconclusive due to limited relevant studies. CONCLUSIONS: Given the absence of efficacy and an increased bleeding risk, these findings call into question the use of warfarin for AF treatment among patients with ESRD. PMID- 27769176 TI - Genome-wide association analysis of forage quality in maize mature stalk. AB - BACKGROUND: Plant digestibility of silage maize (Zea mays L.) has a large influence on nutrition intake for animal feeding. Improving forage quality will enhance the utilization efficiency and feeding value of forage maize. Dissecting the genetic basis of forage quality will improve our understanding of the complex nature of cell wall biosynthesis and degradation, which is also helpful for breeding good quality silage maize. RESULTS: Acid detergent fiber (ADF), neutral detergent fiber (NDF) and in vitro dry matter digestibility (IVDMD) of stalk were evaluated in a diverse maize population, which is comprised of 368 inbred lines and planted across seven environments. Using a mixed model accounting for population structure and polygenic background effects, a genome-wide association study was conducted to identify single nucleotide polymorphisms (SNPs) significantly associated with forage quality. Scanning 559,285 SNPs across the whole genome, 73, 41 and 82 SNPs were found to be associated with ADF, NDF, and IVDMD, respectively. Each significant SNP explained 4.2 %-6.2 % of the phenotypic variation. Underlying these associated loci, 56 genes were proposed as candidate genes for forage quality. CONCLUSIONS: Of all the candidate genes proposed by GWAS, we only found a C3H gene (ZmC3H2) that is directly involved in cell wall component biosynthesis. The candidate genes found in this study are mainly involved in signal transduction, stress resistance, and transcriptional regulation of cell wall biosynthetic gene expression. Adding high digestibility maize into the association panel would be helpful for increasing genetic variability and identifying more genes associated with forage quality traits. Cloning and functional validation of these genes would be helpful for understanding the molecular mechanism of the fiber content and digestibility. These findings provide us new insights into cell wall formation and deposition. PMID- 27769177 TI - Application of a nonrandomized stepped wedge design to evaluate an evidence-based quality improvement intervention: a proof of concept using simulated data on patient-centered medical homes. AB - BACKGROUND: Stepped wedge designs have gained recognition as a method for rigorously assessing implementation of evidence-based quality improvement interventions (QIIs) across multiple healthcare sites. In theory, this design uses random assignment of sites to successive QII implementation start dates based on a timeline determined by evaluators. However, in practice, QII timing is often controlled more by site readiness. We propose an alternate version of the stepped wedge design that does not assume the randomized timing of implementation while retaining the method's analytic advantages and applying to a broader set of evaluations. To test the feasibility of a nonrandomized stepped wedge design, we developed simulated data on patient care experiences and on QII implementation that had the structures and features of the expected data from a planned QII. We then applied the design in anticipation of performing an actual QII evaluation. METHODS: We used simulated data on 108,000 patients to model nonrandomized stepped wedge results from QII implementation across nine primary care sites over 12 quarters. The outcome we simulated was change in a single self-administered question on access to care used by Veterans Health Administration (VA), based in the United States, as part of its quarterly patient ratings of quality of care. Our main predictors were QII exposure and time. Based on study hypotheses, we assigned values of 4 to 11 % for improvement in access when sites were first exposed to implementation and 1 to 3 % improvement in each ensuing time period thereafter when sites continued with implementation. We included site-level (practice size) and respondent-level (gender, race/ethnicity) characteristics that might account for nonrandomized timing in site implementation of the QII. We analyzed the resulting data as a repeated cross-sectional model using HLM 7 with a three-level hierarchical data structure and an ordinal outcome. Levels in the data structure included patient ratings, timing of adoption of the QII, and primary care site. RESULTS: We were able to demonstrate a statistically significant improvement in adoption of the QII, as postulated in our simulation. The linear time trend while sites were in the control state was not significant, also as expected in the real life scenario of the example QII. CONCLUSIONS: We concluded that the nonrandomized stepped wedge design was feasible within the parameters of our planned QII with its data structure and content. Our statistical approach may be applicable to similar evaluations. PMID- 27769178 TI - Autonomic remodeling may be responsible for decreased incidence of aortic dissection in STZ-induced diabetic rats via down-regulation of matrix metalloprotease 2. AB - BACKGROUND: Epidemiological studies reported that diabetic patients had a lower incidence of aortic dissection (AD), but the definite mechanism is unknown. We aim to investigate the possible protective effect of diabetes mellitus (DM) on AD formation with an emphasis on autonomic remodeling. METHODS: Streptozotocin (STZ) intraperitoneal injection was applied to induce diabetes, unilateral renal artery stenosis (URAS) together with beta-amino propionitrile (BAPN) oral treatment was used to induce AD. Sixty SD rats were equally and randomly divided into four groups (normal group, DM group, URAS + BAPN oral treatment group, DM + URAS + BAPN oral treatment group). Rats were fed for 6 weeks, the number of AD was recorded and remained rats were sacrificed. Thoracic aorta were harvested, morphological changes were assessed. Expression of tyrosine hydroxylase (TH), choline acetylase (ChAT), matrix metalloprotease 2 (MMP2) and matrix metalloprotease 9 (MMP9) were evaluated. RESULTS: A total of 7 AD was noted in S + B group, DM rats did not develop AD. Diabetic rats had a lower incidence of AD (P < 0.01). In dissected aorta, collagen deposition increased while elastic fiber became fragmented. These pathological changes diminished in diabetic rats. Diabetic rats had a lower expression of ChAT (P < 0.01). URAS + BAPN treatment elevated expression of TH in normal rat and ChAT in diabetic rats (P < 0.001). Expression of MMP2 and MMP9 elevated in all the rats after URAS + BAPN, but the elevation range of MMP2 in diabetic rats was smaller (P < 0.001). CONCLUSIONS: STZ-induced diabetic rats have a lower incidence of AD after URAS and BAPN treatment, this protective effect could be possibly attributed to autonomic innervation modification and possible related down-regulation of MMP2. PMID- 27769179 TI - Immune recovery in acute and chronic HIV infection and the impact of thymic stromal lymphopoietin. AB - BACKGROUND: Symptomatic primary HIV infection is associated with an adverse prognosis, and immediate initiation of combination antiretroviral therapy (cART) is recommended. However, little is known about immunological predictors of immune recovery. Thymic Stromal Lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cells homeostatic polyclonal proliferation and regulates Th17/regulatory T-cell balance, immunological functions known to be affected during primary HIV infection. The aim of this study was to describe immune recovery in primary and chronic HIV infection and possible impact of TSLP. METHODS: Prospective study including 100 HIV-infected individuals (primary HIV infection (N = 14), early presenters (>350 CD4+ T cells/MUL, N = 42), late presenters without advanced disease (200-350 CD4+ T cells/MUL, N = 24) and with advanced disease (<200 CD4+ T cells/MUL, N = 20) and). Immune recovery was defined as increase in CD4+ T cells count from baseline to a given time of follow-up. Plasma TSLP was determined using ELISA and CD4+ T cell subpopulations (recent thymic emigrants, naive and memory cells) were measured using flow cytometry at baseline and after 6, 12 and 24 months of cART. RESULTS: Immune recovery was comparable in all groups, and no differences in immune homeostasis were found between primary HIV infection and early presenters, whereas differences in absolute counts and proportions of CD4+ T cell subpopulations were found between primary HIV infection and late presenters. TSLP was elevated in primary HIV infection at baseline and after 24 months of cART. Interestingly, TSLP was negatively associated with proportion of recent thymic emigrants (correlation coefficient -0.60, p = 0.030). TSLP was not associated with immune recovery in primary HIV infection. CONCLUSIONS: Immune recovery was comparable in primary and chronic HIV infection whereas differences in absolute counts and proportions of CD4+ T cell subpopulations were found between primary HIV infection and late presenters supporting early initiation of cART. Higher plasma TSLP was found in primary HIV infection, and TSLP was associated with lower thymic output, but not with immune recovery. These findings indicate a possible role of TSLP in immune homeostasis in HIV infection but do not support TSLP to affect immune recovery in primary HIV infection. PMID- 27769180 TI - Comparison of antimicrobial resistance patterns of ESBL and non ESBL bacterial isolates among patients with secondary peritonitis at Bugando Medical Centre, Mwanza - Tanzania. AB - BACKGROUND: Secondary peritonitis is a common surgical emergence with deadly outcomes when not timely and promptly intervened. The emergence of Extended spectrum beta lactamase producing bacteria (ESBL) poses treatment challenge at Bugando Medical Centre (BMC); hence a need to evaluate the magnitude of ESBL so as to guide specific therapy. METHODS: This was a cross sectional study conducted at BMC from May 2014 to April 2015 involving patients with secondary peritonitis. A questionnaire was used to collect patients' information. Peritoneal aspirate sample was collected intra-operatively and processed using standard operating procedures to identify bacteria species and their susceptibility profiles. RESULTS: The study involved 97 patients with the median age (IQR) of 32 (21-47) years, males were 62 (63.9 %) and about 27 (27.8 %) patients had co-morbid illnesses. The prevalence of ESBL among patients with secondary peritonitis was 23.7 % (23/97). Of 53 gram negative Enterobacteriaceae isolated, 47.2 % (25/53) were ESBL producers, with predominance of Escherichia coli 7 (28.0 %) and Klebsiella spp 5 (20.0 %). The ESBL isolates exhibited more resistance rates to trimethoprim sulfamethoxazole and ciprofloxacin compared to non ESBL isolates 96.0 % versus 60.7 %, p value = 0.003 and 16.0 % versus 0.0 %, p value = 0.043 respectively). All isolates were sensitive to meropenem. CONCLUSIONS: The prevalence of ESBL among patients with secondary peritonitis at BMC is high; with more resistance rates among ESBL compared to non ESBL isolates. There is a need for strengthen ESBL surveillance in this setting so as to guide specific therapy. PMID- 27769181 TI - Performance of point-of-care CD4 testing technologies in resource-constrained settings: a systematic review and meta-analysis. AB - BACKGROUND: Point-of-care (POC) CD4 testing increases patient accessibility to assessment of antiretroviral therapy eligibility. This review evaluates field performance in low and middle-income countries (LMICs) of currently available POC CD4 technologies. METHODS: Eight electronic databases were searched for field studies published between January 2005 and January 2015 of six POC CD4 platforms: PointCare NOWTM, Alere PimaTM CD4, DaktariTM CD4 Counter, CyFlow(r) CD4 miniPOC, BD FACSPrestoTM, and MyT4TM CD4. Due to limited data availability, meta-analysis was conducted only for diagnostic performance of Pima at a threshold of 350 cells/MUl, applying a bivariate multi-level random-effects modelling approach. A covariate extended model was also explored to test for difference in diagnostic performance between capillary and venous blood. RESULTS: Twenty seven studies were included. Published field study results were found for three of the six POC CD4 tests, 24 of which used Pima. For Pima, test failure rates varied from 2 to 23 % across study settings. Pooled sensitivity and specificity were 0.92 (95 % CI = 0.88-0.95) and 0.87 (95 % CI = 0.85-0.88) respectively. Diagnostic performance by blood sample type (venous vs. capillary) revealed non-significant differences in sensitivity (0.94 vs 0.89) and specificity (0.86 vs 0.87), respectively in the extended model (Wald chi2(2) = 4.77, p = 0.09). CONCLUSIONS: POC CD4 testing can provides reliable results for making treatment decision under field conditions in low-resource settings. The Pima test shows a good diagnostic performance at CD4 cut-off of 350 cells/MUl. More data are required to evaluate performance of POC CD4 testing using venous versus capillary blood in LMICs which might otherwise influence clinical practice. PMID- 27769182 TI - Validation of genotype cluster investigations for Mycobacterium tuberculosis: application results for 44 clusters from four heterogeneous United States jurisdictions. AB - BACKGROUND: Tracking the dissemination of specific Mycobacterium tuberculosis (Mtb) strains using genotyped Mtb isolates from tuberculosis patients is a routine public health practice in the United States. The present study proposes a standardized cluster investigation method to identify epidemiologic-linked patients in Mtb genotype clusters. The study also attempts to determine the proportion of epidemiologic-linked patients the proposed method would identify beyond the outcome of the conventional contact investigation. METHODS: The study population included Mtb culture positive patients from Georgia, Maryland, Massachusetts and Houston, Texas. Mtb isolates were genotyped by CDC's National TB Genotyping Service (NTGS) from January 2006 to October 2010. Mtb cluster investigations (CLIs) were conducted for patients whose isolates matched exactly by spoligotyping and 12-locus MIRU-VNTR. CLIs were carried out in four sequential steps: (1) Public Health Worker (PHW) Interview, (2) Contact Investigation (CI) Evaluation, (3) Public Health Records Review, and (4) CLI TB Patient Interviews. Comparison between patients whose links were identified through the study's CLI interviews (Step 4) and patients whose links were identified earlier in CLI (Steps 1-3) was conducted using logistic regression. RESULTS: Forty-four clusters were randomly selected from the four study sites (401 patients in total). Epidemiologic links were identified for 189/401 (47 %) study patients in a total of 201 linked patient-pairs. The numbers of linked patients identified in each CLI steps were: Step 1 - 105/401 (26.2 %), Step 2 - 15/388 (3.9 %), Step 3 - 41/281 (14.6 %), and Step 4 - 28/119 (30 %). Among the 189 linked patients, 28 (14.8 %) were not identified in previous CI. No epidemiologic links were identified in 13/44 (30 %) clusters. CONCLUSIONS: We validated a standardized and practical method to systematically identify epidemiologic links among patients in Mtb genotype clusters, which can be integrated into the TB control and prevention programs in public health settings. The CLI interview identified additional epidemiologic links that were not identified in previous CI. One-third of the clusters showed no epidemiologic links despite being extensively investigated, suggesting that some improvement in the interviewing methods is still needed. PMID- 27769183 TI - Role of low protein diet in management of different stages of chronic kidney disease - practical aspects. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem and more so in India. With limited availability and high cost of therapy, barely 10 % of patients with incident end stage renal disease (ESRD) cases get treatment in India. Therefore, all possible efforts should be made to retard progression of CKD. This article reviews the role of low protein diet (LPD) in management of CKD subjects and suggests how to apply it in clinical practice. DISCUSSION: The role of LPD in retarding progression of CKD is well established in animal experimental studies. However, its role in human subjects with CKD is perceived to be controversial based on the modification of diet in renal disease (MDRD) study. We believe that beneficial effect of LPD could not be appreciated due to shorter duration of follow-up in the MDRD study. Had the study been continued longer, it may have been possible to appreciate beneficial effect of LPD. It is our contention that in all cases of CKD that are slowly progressive, LPD can significantly retard progression of CKD and delay the need for renal replacement therapy (RRT). To be able to apply LPD for a long period, it is important to prescribe LPD at earlier stages (1,2,3) of CKD and not at late stage as recommended by KDIGO guidelines. Many clinicians are concerned about worsening nutritional status and hence reluctant to prescribe LPD. This actually is true for patients with advanced CKD in whom there is spontaneous decrease in calorie and protein intake. In our experience, nutritional status of patients in early stages (1,2,3) of CKD is as good as that of healthy subjects. Prescribing LPD at an early stage is unlikely to worsen status. The role of LPD in retarding progression of CKD is well established in animal experimental studies. Even in human subjects, there is enough evidence to suggest that LPD retards progression of CKD in carefully selected subjects. It should be prescribed to those with good appetite, good nutritional status and a slowly progressive CKD at an early stage (stage 1,2,3). It may also be prescribed at stage 4 & 5 of CKD if the appetite and nutritional status are good. PMID- 27769184 TI - Distinct phenotypic subpopulations of circulating CD4+CXCR5+ follicular helper T cells in children with active IgA vasculitis. AB - BACKGROUND: Circulating follicular helper T (Tfh) cells are a heterogeneous population of CD4+ helper T cells that promotes pathogenic immune responses in autoimmune diseases. In this study, we examined the status of different subpopulations of Tfh cells in peripheral circulation and their associations with various clinical characteristics of IgA vasculitis (IgAV). METHODS: According to the phenotypic expressions of different molecules, focus was given on six subpopulations of Tfh cells: CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high, CD4+CXCR5+ICOS-PD-1+, and CXCR5+CD45RA-IL-21+. The frequencies of these six subpopulations and the circulating level of Tfh-related cytokine interleukin 21 (IL-21) were measured from 27 patients with IgAV and 15 healthy controls (HC) by flow cytometry and flow cytometric bead array, respectively. RESULTS: Significantly higher frequencies of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high and CXCR5+CD45RA-IL-21+ Tfh cells, as well as higher levels of plasma IL-21, were detected in IgAV patients compared to HC. The level of each Tfh subpopulation varied by the presenting symptoms of IgAV, but did not differ between patients treated or not treated with glucocorticoids. When the disease entered the remission stage following treatment, circulating levels of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high and CXCR5+CD45RA-IL-21+ Tfh cells, as well as plasma IL-21 levels were reduced. Among the six subpopulations of Tfh cells, both CD4+CXCR5+ICOS+ and CXCR5+CD45RA-IL-21+ significantly and positively correlated with serum IgA and plasma IL-21 levels, but only CXCR5+CD45RA-IL-21+ significantly and negatively correlated with the serum C4 level. CONCLUSIONS: Tfh cells may differentially contribute to the development of IgAV or predict disease progression. These findings provide novel insights in the pathogenesis of IgAV and may benefit treatment development targeting organ-specific presenting symptoms of IgAV. PMID- 27769185 TI - Genetic analysis of phytoene synthase 1 (Psy1) gene function and regulation in common wheat. AB - BACKGROUND: Phytoene synthase 1 (PSY1) is the most important regulatory enzyme in carotenoid biosynthesis, whereas its function is hardly known in common wheat. The aims of the present study were to investigate Psy1 function and genetic regulation using reverse genetics approaches. RESULTS: Transcript levels of Psy1 in RNAi transgenic lines were decreased by 54-76 % and yellow pigment content (YPC) was reduced by 26-35 % compared with controls, confirming the impact of Psy1 on carotenoid accumulation. A series of candidate genes involved in secondary metabolic pathways and core metabolic processes responded to Psy1 down regulation. The aspartate rich domain (DXXXD) was important for PSY1 function, and conserved nucleotides adjacent to the domain influenced YPC by regulating gene expression, enzyme activity or alternative splicing. Compensatory responses analysis indicated that three Psy1 homoeologs may be coordinately regulated under normal conditions, but separately regulated under stress. The period 14 days post anthesis (DPA) was found to be a key regulation node during grain development. CONCLUSION: The findings define key aspects of flour color regulation in wheat and facilitate the genetic improvement of wheat quality targeting color/nutritional specifications required for specific end products. PMID- 27769186 TI - Biosensor-based spatial and developmental mapping of maize leaf glutamine at vein level resolution in response to different nitrogen rates and uptake/assimilation durations. AB - BACKGROUND: The amino acid glutamine (Gln) is a primary transport form of nitrogen in vasculature following root uptake, critical for the location/timing of growth in maize and other cereals. Analytical chemistry methods do not permit in situ analysis of Gln, including visualization within the vascular network. Their cost and tissue requirement are barriers to exploring the complexity of Gln dynamics. We previously reported a biosensor, GlnLux, which can measure relative Gln levels inexpensively with tiny amounts of tissue. RESULTS: Here, maize seedlings were given different N rates for multiple uptake/assimilation durations, after which > 1500 leaf disk extracts were analyzed. A second technique permitted in situ imaging of Gln for all leaves sampled simultaneously. We demonstrate that multifactorial interactions govern Gln accumulation involving position within each leaf (mediolateral/proximodistal), location of leaves along the shoot axis, N rate, and uptake duration. In situ imaging localized Gln in leaf veins for the first time. A novel hypothesis is that leaf Gln may flow along preferential vascular routes, for example in response to mechanical damage or metabolic needs. CONCLUSIONS: The GlnLux technology enabled the most detailed map of relative Gln accumulation in any plant, and the first report of in situ Gln at vein-level resolution. The technology might be used with any plant species in a similar manner. PMID- 27769187 TI - Microbiota of wild-caught Red Snapper Lutjanus campechanus. AB - BACKGROUND: The microbiota plays an essential role in host health, particularly through competition with opportunistic pathogens. Changes in total bacterial load and microbiota structure can indicate early stages of disease, and information on the composition of bacterial communities is essential to understanding fish health. Although Red Snapper (Lutjanus campechanus) is an economically important species in recreational fisheries and a primary aquaculture candidate, no information is available on the microbial communities of this species. The aim of this study was to survey the microbiota of apparently healthy, wild-caught Red Snapper from the Gulf of Mexico. Sampled Red Snapper showed no physical signs of disease. Tissues that are either primary entry routes for pathogens (feces, gill) or essential to disease diagnosis (blood) were sampled. Bacteria were enumerated using culture-based techniques and characterized by pyrosequencing. RESULTS: Aerobic counts of feces and gill samples were 107 and 104 CFU g-1, respectively. All individuals had positive blood cultures with counts up to 23 CFU g-1. Gammaproteobacteria dominated the microbiota of all sample types, including the genera Pseudoalteromonas and Photobacterium in feces and Pseudomonas in blood and gill. Gill samples were also dominated by Vibrio while blood samples had high abundances of Nevskia. High variability in microbiota composition was observed between individuals, with percent differences in community composition ranging from 6 to 76 % in feces, 10 to 58 % in gill, and 52 to 64 % in blood. CONCLUSIONS: This study provides the first characterization of the microbiota of the economically significant Red Snapper via pyrosequencing. Its role in fish health highlights the importance of understanding microbiota composition for future work on disease prevention using microbial manipulation. PMID- 27769188 TI - Characteristic of Enterococcus faecium clinical isolates with quinupristin/dalfopristin resistance in China. AB - BACKGROUND: Quinupristin/dalfopristin (Q/D) is a valuable alternative antibiotic to vancomycin for the treatment of multi-drug resistant Enterococcus faecium infections. However, resistance to Q/D in E. faecium clinical isolates and nosocomial dissemination of Q/D-resistant E. faecium have been reported in several countries and should be of concern. RESULTS: From January 2012 to December 2015, 911 E. faecium clinical isolates were isolated from various specimens of inpatients at the first Affiliated Hospital of Wenzhou Medical University located in Wenzhou, east China. Of 911 E. faecium clinical isolates, 9 (1.0 %, 9/911) were resistant to Q/D, with the Q/D MIC values of 64 mg/L(1), 32 mg/L(1), 16 mg/L(3), 8 mg/L(1) and 4 mg/L(3) determined by broth microdilution. All Q/D-resistant isolates were susceptible to vancomycin, tigecycline and teicoplanin but resistant to penicillin, ampicillin and erythromycin. vatE was only found in one Q/D-resistant E. faecium isolate while vatD was not detected in any of the isolates tested. 8 of 9 Q/D-resistant E. faecium isolates were found be positive for both ermB and msrC. The combinations of Q/D resistance determinants were ermB-msrC (7 isolates) and ermB-msrC-vatE (one isolate). ST78, ST761, ST94, ST21 and ST323 accounted for 4, 2, 1, 1 and 1 isolate, respectively, among which ST78 was the prevalent ST. CONCLUSION: Q/D-resistant E. faecium clinical isolates were first described in China. Carriage of vatE, ermB and msrC was responsible for Q/D resistance. PMID- 27769189 TI - The collateral circulation determines cortical infarct volume in anterior circulation ischemic stroke. AB - BACKGROUND: Acute ischemic stroke (AIS) is a common neurological event that causes varying degrees of disability. AIS outcome varies considerably, from complete recovery to complete loss of tissue and function. This diversity is partly explained by the compensatory ability of the collateral circulation and the ensuing cerebral flow grade. The collateral flow to the anterior circulation largely supplies the cortical areas. The deep brain tissue is supplied by penetrating arteries and has little or no collateral supply. Although these brain compartments differ substantially in their collateral supply, there are no published data on the different effects the collateral circulation has on them. In addition, the influence of baseline collateral flow on the final infarct size following endovascular or reperfusion therapies remains unknown. This study was designed to determine the effect of the collateral circulation on cortical infarct volume and deep infarct volume, and to investigate the relation between the collateral grade, response to reperfusion therapy and clinical outcome. METHODS: We studied consecutive patients presenting to our medical center between April 2008 and April 2012 with AIS and anterior proximal artery occlusion. To be included patients had to undergo a computerized tomographic angiographic study within 12 h of symptom onset demonstrating the occlusion. Imaging data and clinical and laboratory values were extracted retrospectively from the original scans and medical records. Cortical infarct volume (CIV) and deep infarct volume (DIV) were calculated as well as collateral grade. Clinical outcome was assessed at discharge using the modified Rankin Scale (mRS). RESULTS: Of the 51 study patients, 13 were treated conservatively, 22 received intravenous recombinant tissue plasminogen activator, and 16 received intra-arterial thrombolysis. The collateral grading was similar for all three treatment groups. While there was a moderate inverse correlation between the collateral grade and CIV (Spearman's rho = -0.49, P < 0.001), no comparable correlation was observed between the collateral grade and DIV (Spearman's rho =0.03, P = 0.85). Clinical outcome was significantly related to CIV but not to DIV (Spearman's rho =0.6 P < 0.001 versus Spearman's rho =0.09 P = 0.54, respectively). The correlation between the collateral grade and CIV was greatly diminished and lost its statistical significance in patients with successful recanalization (Spearman's rho = 0.2, p = 0.3). CONCLUSIONS: Our data shows that the collateral circulation is an important determinant of cortical infarct volume and, in turn, of clinical outcome in the setting of anterior circulation major artery occlusion. Our findings further demonstrate the benefit of recanalization in sparing cortical tissue from injury. Additional studies are needed to determine the impact of stroke therapy on the final infarct volume in relation to the collateral grade. PMID- 27769190 TI - DECIDE: a cluster randomized controlled trial to reduce non-medically indicated caesareans in Burkina Faso. AB - BACKGROUND: Since 2006, Burkina Faso has subsidized the cost of caesarean sections to increase their accessibility. Caesareans are performed by obstetricians, general practitioners, and nurses trained in emergency surgery. While the national caesarean rate is still too low (only 2 % in 2010), 12 to 24 % of caesareans performed in hospital are, in fact, not medically indicated. The objective of this study is to evaluate the effectiveness and analyze the implementation of a multi-faceted intervention to lower the rate of non-medically indicated caesareans in Burkina Faso. METHODS: This study combines a multicentre cluster randomized controlled trial with an implementation analysis in a mixed methods approach. The evidence-based intervention will consist of three strategies to improve the competencies of maternity teams: 1) clinical audits based on objective criteria; 2) training of personnel; and 3) decision-support reminders of indications for caesareans via text messages. The unit of randomization and of intervention is the public hospital equipped with a functional operating room. Using stratified randomization on hospital type and staff qualifications, 11 hospitals have been assigned to the intervention group and 11 to the control group. The intervention will cover 1 year. Every patient who delivered by caesarean during a 6-month period in the year preceding the intervention and the 6 months following its end will be included in the trial. The change in the rate of non-medically indicated caesareans is the main criterion by which the intervention's impact will be assessed. To analyze the intervention process, a longitudinal qualitative study consisting of deliberative workshops and individual in-depth interviews will be conducted. The target outcome is a 50 % reduction in the rate of non-medically indicated caesareans. DISCUSSION: This study will provide evidence regarding the effectiveness of a multi-faceted intervention for reducing non-medically indicated caesareans in a low-income country. By combining qualitative and quantitative methods, the study's findings will allow understanding the factors that could influence the intervention process and ultimately the intended outcomes. TRIAL REGISTRATION: The DECIDE trial is registered on the Current Controlled Trials website under the number ISRCTN48510263 on January 28, 2014. PMID- 27769191 TI - Protocol of the Low Birth Weight South Asia Trial (LBWSAT), a cluster-randomised controlled trial testing impact on birth weight and infant nutrition of Participatory Learning and Action through women's groups, with and without unconditional transfers of fortified food or cash during pregnancy in Nepal. AB - BACKGROUND: Low birth weight (LBW, < 2500 g) affects one third of newborn infants in rural south Asia and compromises child survival, infant growth, educational performance and economic prospects. We aimed to assess the impact on birth weight and weight-for-age Z-score in children aged 0-16 months of a nutrition Participatory Learning and Action behaviour change strategy (PLA) for pregnant women through women's groups, with or without unconditional transfers of food or cash to pregnant women in two districts of southern Nepal. METHODS: The study is a cluster randomised controlled trial (non-blinded). PLA comprises women's groups that discuss, and form strategies about, nutrition in pregnancy, low birth weight and hygiene. Women receive up to 7 monthly transfers per pregnancy: cash is NPR 750 (~US$7) and food is 10 kg of fortified sweetened wheat-soya Super Cereal per month. The unit of randomisation is a rural village development committee (VDC) cluster (population 4000-9200, mean 6150) in southern Dhanusha or Mahottari districts. 80 VDCs are randomised to four arms using a participatory 'tombola' method. Twenty clusters each receive: PLA; PLA plus food; PLA plus cash; and standard care (control). Participants are (mostly Maithili-speaking) pregnant women identified from 8 weeks' gestation onwards, and their infants (target sample size 8880 birth weights). After pregnancy verification, mothers may be followed up in early and late pregnancy, within 72 h, after 42 days and within 22 months of birth. Outcomes pertain to the individual level. Primary outcomes include birth weight within 72 h of birth and infant weight-for-age Z-score measured cross-sectionally on children born of the study. Secondary outcomes include prevalence of LBW, eating behaviour and weight during pregnancy, maternal and newborn illness, preterm delivery, miscarriage, stillbirth or neonatal mortality, infant Z-scores for length-for-age and weight-for-length, head circumference, and postnatal maternal BMI and mid-upper arm circumference. Exposure to women's groups, food or cash transfers, home visits, and group interventions are measured. DISCUSSION: Determining the relative importance to birth weight and early childhood nutrition of adding food or cash transfers to PLA women's groups will inform design of nutrition interventions in pregnancy. TRIAL REGISTRATION: ISRCTN75964374 , 12 Jul 2013. PMID- 27769193 TI - Maternal Near Miss and quality of care in a rural Rwandan hospital. AB - BACKGROUND: The WHO Maternal Near Miss (MNM) approach was developed to evaluate and improve quality of obstetric care worldwide. This study aimed to study the incidence of MNM and quality of care at a district hospital in rural Rwanda by applying this approach. METHODS: A facility based, prospective cohort study conducted at a district hospital in rural Rwanda between June 2013 and December 2014. Subjects were followed from time of admission to discharge or death. RESULTS: In 3979 deliveries, 3827 singletons and 152 twins pairs were born. Among the 4131 neonates, there were 3994 live births and 137 stillbirths. Ninety-nine women suffered severe maternal outcome (SMO): 86 maternal near misses and 13 deaths. This adds up to a maternal near miss ratio of 21.5 per 1000 live births (95 % CI 17.3-26.5), a maternal mortality ratio of 325 per 100 000 live births (95 % CI 181-543) and a mortality index of 13.1 % (95 % CI 7.3-21.9). Hemorrhage (n = 49, 57 %) and hypertensive disorders (n = 27, 31.4 %) were the commonest MNM conditions. Eclampsia (n = 4/13; 30.7 %) was the leading cause of maternal mortality, while sepsis/peritonitis following cesarean section (n = 2/6; 33.3 %) had the highest mortality index. Seventy-seven out of 99 SMO cases (77.9 %) were referred from other facilities with critical conditions and 28 out of 99 SMO cases (28.3 %) were admitted into the Intensive Care Unit. Several indicators such as administration of oxytocin, magnesium sulfate and antibiotics were found to be suboptimal. CONCLUSIONS: MNM is common at district level in Rwanda. The MNM approach enabled us to identify shortfalls in clinical practice and the referral system. PMID- 27769192 TI - Bioinformatic Identification and Analysis of Hydroxyproline-Rich Glycoproteins in Populus trichocarpa. AB - BACKGROUND: Hydroxyproline-rich glycoproteins (HRGPs) constitute a plant cell wall protein superfamily that functions in diverse aspects of growth and development. This superfamily contains three members: the highly glycosylated arabinogalactan-proteins (AGPs), the moderately glycosylated extensins (EXTs), and the lightly glycosylated proline-rich proteins (PRPs). Chimeric and hybrid HRGPs, however, also exist. A bioinformatics approach is employed here to identify and classify AGPs, EXTs, PRPs, chimeric HRGPs, and hybrid HRGPs from the proteins predicted by the completed genome sequence of poplar (Populus trichocarpa). This bioinformatics approach is based on searching for biased amino acid compositions and for particular protein motifs associated with known HRGPs with a newly revised and improved BIO OHIO 2.0 program. Proteins detected by the program are subsequently analyzed to identify the following: 1) repeating amino acid sequences, 2) signal peptide sequences, 3) glycosylphosphatidylinositol lipid anchor addition sequences, and 4) similar HRGPs using the Basic Local Alignment Search Tool (BLAST). RESULTS: The program was used to identify and classify 271 HRGPs from poplar including 162 AGPs, 60 EXTs, and 49 PRPs, which are each divided into various classes. This is in contrast to a previous analysis of the Arabidopsis proteome which identified 162 HRGPs consisting of 85 AGPs, 59 EXTs, and 18 PRPs. Poplar was observed to have fewer classical EXTs, to have more fasciclin-like AGPs, plastocyanin AGPs and AG peptides, and to contain a novel class of PRPs referred to as the proline-rich peptides. CONCLUSIONS: The newly revised and improved BIO OHIO 2.0 bioinformatics program was used to identify and classify the inventory of HRGPs in poplar in order to facilitate and guide basic and applied research on plant cell walls. The newly identified poplar HRGPs can now be examined to determine their respective structural and functional roles, including their possible applications in the areas plant biofuel and natural products for medicinal or industrial uses. Additionally, other plants whose genomes are sequenced can now be examined in a similar way using this bioinformatics program which will provide insight to the evolution of the HRGP family in the plant kingdom. PMID- 27769194 TI - Comparisons between mild and severe cases of hand, foot and mouth disease in temporal trends: a comparative time series study from mainland China. AB - BACKGROUND: Over recent decades, hand, foot and mouth disease (HFMD) has emerged as a serious public health threat in the Asia-Pacific region because of its high rates of severe complications. Understanding the differences and similarities between mild and severe cases can be helpful in the control of HFMD. In this study, we compared the two types of HFMD cases in their temporal trends. METHODS: We retrieved the daily series of disease counts of mild and severe HFMD cases reported in mainland China in the period of 2009-2014. We applied a quasi-Poisson regression model to decompose each series into the long-term linear trend, periodic variations, and short-term fluctuations, and then we compared each component between two series separately. RESULTS: A total of 11,101,860 clinical HFMD cases together with 115,596 severe cases were included into this analysis. We found a biennial increase of 24.46 % (95 % CI: 22.80-26.14 %) for the baseline of disease incidence of mild cases, whereas a biennial decrease of 8.80 % (95 % CI: 7.26-10.31 %) was seen for that of severe cases. The periodic variations of both two series could be characterized by a mixture of biennial, annual, semi annual and eight-monthly cycles. However, compared to the mild cases, we found the severe cases vary more widely for the biennial and annual cycle, and started its annual epidemic earlier. We also found the short-term fluctuations between two series were still significantly correlated at the current day with a correlation coefficient of 0.46 (95 % CI: 0.43-0.49). CONCLUSIONS: We found some noticeable differences and also similarities between the daily series of mild and severe HFMD cases at different time scales. Our findings can help us to deepen the understanding of the transmission of different types of HFMD cases, and also provide evidences for the planning of the associated disease control strategies. PMID- 27769195 TI - Banning traditional birth attendants from conducting deliveries: experiences and effects of the ban in a rural district of Kazungula in Zambia. AB - BACKGROUND: In 2010 the government of the republic of Zambia stopped training traditional birth attendants and forbade them from conducting home deliveries as they were viewed as contributing to maternal mortality. This study explored positive and negative maternal health related experiences and effects of the ban in a rural district of Kazungula. METHODS: This was a phenomenological study and data were collected through focus group discussions as well as in-depth interviews with trained traditional birth attendants (tTBAs) and key informant interviews with six female traditional leaders that were selected one from each of the six zones. All 22 trained tTBAs from three clinic catchment areas were included in the study. Content analysis was used to analyse the data after coding it using NVIVO 8 software. RESULTS: Home deliveries have continued despite the community and tTBAs being aware of the ban. The ban has had both negative and positive effects on the community. Positive effects include early detection and management of pregnancy complications, enhanced HIV/AIDS prevention and better management of post-natal conditions, reduced criticisms of tTBAs from the community in case of birth complications, and quick response at health facilities in case of an emergency. Negatives effects of the ban include increased work load on the part of health workers, high cost for lodging at health facilities and traveling to health facilities, as well as tTBAs feeling neglected, loss of respect and recognition by the community. CONCLUSION: Countries should design their approach to banning tTBAs differently depending on contextual factors. Further, it is important to consider adopting a step wise approach when implementing the ban as the process of banning tTBAs may trigger several negative effects. PMID- 27769196 TI - Cardiotocography in breech versus vertex delivery: an examiner-blinded, cross sectional nested case-control study. AB - BACKGROUND: The safety of vaginal breech delivery has been debated for decades. Although it has been shown to predispose infants to immediate depression, several observational studies have also shown that attempting vaginal breech delivery does not increase perinatal morbidity or low Apgar score at the age of five minutes. Cardiotocography monitoring is recommended during vaginal breech delivery, but comparative data describing differences between cardiotocography tracings in breech and vertex deliveries is scarce. This study aims to evaluate differences in intrapartum cardiotocography tracings between breech and vertex deliveries in the final 60 min of delivery. A secondary goal is to identify risk factors for suboptimal neonatal outcome in the study population. METHODS: One hundred eight breech and 108 vertex singleton, intended vaginal deliveries at term from a tertiary hospital with 5000 annual deliveries were included. Two experienced obstetricians, blinded to fetal presentation, neonatal outcome and actual mode of delivery, evaluated traces recorded 60 min before delivery. They provided a three-tier classification and evaluated different trace features according to FIGO (1987) guidelines. Factors associated with acidemia and low Apgar scores were identified by univariate and multivariable analyses performed with binary logistic regression. Student's T-test and chi-square test were used, as appropriate. RESULTS: Late decelerations were seen in 13.9 % of breech and 2.8 % of vertex deliveries (p = 0.003) and decreased variability in 26.9 % of breech and 8.3 % of vertex deliveries (p < 0.001). In multivariable analysis complicated variable decelerations and breech presentation were identified as risk factors for neonatal acidemia and low Apgar score at the age of five minutes. Pathological trace and breech presentation were independent risk factors for low Apgar score at the age of one minute. CONCLUSIONS: Decreased variability and late decelerations were more prevalent in breech compared to vertex deliveries. Pathological trace predicts immediate neonatal depression and especially complicated variable decelerations may signal more severe distress. Further research is needed to create guidelines for safe management of vaginal breech delivery. PMID- 27769197 TI - Transport of pregnant women and obstetric emergencies in India: an analysis of the '108' ambulance service system data. AB - BACKGROUND: The transport of pregnant women to an appropriate health facility plays a pivotal role in preventing maternal deaths. In India, state-run call centre based ambulance systems ('108' and '102'), along with district-level Janani Express and local community-based innovations, provide transport services for pregnant women. We studied the role of '108' ambulance services in transporting pregnant women routinely and obstetric emergencies in India. METHODS: This study was an analysis of '108' ambulance call-centre data from six states for the year 2013-14. We estimated the number of expected pregnancies and obstetric complications for each state and calculated the proportions of these transported using '108'. The characteristics of the pregnant women transported, their obstetric complications, and the distance and travel-time for journeys made, are described for each state. RESULTS: The estimated proportion of pregnant women transported by '108' ambulance services ranged from 9.0 % in Chhattisgarh to 20.5 % in Himachal Pradesh. The '108' service transported an estimated 12.7 % of obstetric emergencies in Himachal Pradesh, 7.2 % in Gujarat and less than 3.5 % in other states. Women who used the service were more likely to be from rural backgrounds and from lower socio-economic strata of the population. Across states, the ambulance journeys traversed less than 10-11 km to reach 50 % of obstetric emergencies and less than 10-21 km to reach hospitals from the pick-up site. The overall time from the call to reaching the hospital was less than 2 h for 89 % to 98 % of obstetric emergencies in 5 states, although this percentage was 61 % in Himachal Pradesh. Inter-facility transfers ranged between 2.4 % -11.3 % of all '108' transports. CONCLUSION: A small proportion of pregnant women and obstetric emergencies made use of '108' services. Community-based studies are required to study knowledge and preferences, and to assess the potential for increasing or rationalising the use of '108' services. PMID- 27769198 TI - Knowledge, attitude, practice and associated factors towards spectacles use among adults in Gondar town, northwest Ethiopia. AB - BACKGROUND: Refractive error is the main cause of visual impairment in the world. Spectacles are the most frequently used options for correcting refractive errors. In addition, they can be used for protection and fashion. It is the simplest, cheapest and only method used in developing countries like Ethiopia. This study aims to explore the knowledge, attitude, practice and associated factors towards spectacles use among adult population of Gondar town, northwest Ethiopia. METHODS: Community based cross sectional study was conducted on 780 participants using a pre-tested structured questionnaire in Gondar. Data were analyzed using Statistical Package for Social Sciences (SPSS) 20 version computer software. Association and strength between variables was determined using odds ratio with 95 % confidence interval. RESULT: A total of 780 study subjects participated in this study. The male to female ratio was 1:2.4. The median age of the participants was 29 (+/-22 IQR) with a range of 18-86 years. About fifty percent of participants were married and 284 (36.4 %) were educated up to secondary school. Seven hundred and three (90.6 %) participants had adequate knowledge about spectacles and 90.4 % had favorable attitude towards spectacle use. About 25 % of the participants have been using spectacles during the study. Participants with primary school education (AOR: 2.79, 95 % CI 1.20-6.50) had good knowledge about spectacles. Housewives (AOR = 3.40, 95 % CI; 1.35-8.54) and participants who unable to read and write (AOR: 3.51, 95 % CI 14-10.72) had favorable attitude towards spectacles use. CONCLUSION: Gondar town adult population has adequate knowledge and favorable attitude towards spectacles. However, practice of spectacles use is poor. Eye health education related to spectacles utilization need to be given due emphasis by eye care professionals in collaboration with University of Gondar and Gondar town administration. PMID- 27769199 TI - The relevance of cortical lesions in patients with multiple sclerosis. AB - BACKGROUND: Recent studies suggest that cortical lesions in multiple sclerosis (MS) substantially contribute to clinical disease severity. The present study aimed at investigating clinical, neuroanatomical, and cognitive correlates of these cortical lesions with a novel approach, i.e. by comparing two samples of relapsing-remitting multiple sclerosis (RRMS) patients, one group with and the other without cortical lesions. METHODS: High-resolution structural MRI was acquired from 42 RRMS patients and 43 controls (HC). The patient group was dichotomized based on the presence versus absence of DIR-hyperintense cortex involving lesions, resulting in a cortical lesion group (CL, n = 32) and a non cortical lesion group (nCL, n =10). Cognitive functioning was assessed in all participants with a comprehensive neuropsychological battery, covering mnestic, executive, and attentional functions. RESULTS: Highest densities of cortical lesions in the CL group were observed in the bilateral parahippocampal gyrus. Relative to HC, patients with cortical lesions - but not those without - showed significant global cortical thinning and mnestic deficits. The two patient groups did not differ from each other regarding demographic and basic disease characteristics such as EDSS scores. CONCLUSION: The appearance of cortical lesions in MS patients is associated with cortical thinning as well as mnestic deficits, which might be key characteristics of a 'cortically dominant' MS subtype. PMID- 27769200 TI - Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells. AB - BACKGROUND: Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism. METHODS: After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB 231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again. RESULTS: Selumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR 302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed. CONCLUSIONS: MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer. PMID- 27769201 TI - Reactivity to smartphone-based ecological momentary assessment of depressive symptoms (MoodMonitor): protocol of a randomised controlled trial. AB - BACKGROUND: Ecological momentary assessment (EMA) of mental health symptoms may influence the symptoms that it measures, i.e. assessment reactivity. In the field of depression, EMA reactivity has received little attention. We aim to investigate whether EMA of depressive symptoms induces assessment reactivity. Reactivity will be operationalised as an effect of EMA on depressive symptoms measured by a retrospective questionnaire, and, secondly, as a change in response rate and variance of the EMA ratings. METHODS: This study is a 12-week randomised controlled trial comprising three groups: group 1 carries out EMA of mood and completes a retrospective questionnaire, group 2 carries out EMA of how energetic they feel and completes a retrospective questionnaire, group 3 is the control group, which completes only the retrospective questionnaire. The retrospective questionnaire (Centre for Epidemiologic Studies Depression scale; CES-D) assesses depressive symptoms and is administered at baseline, 6 weeks after baseline and 12 weeks after baseline. We aim to recruit 160 participants who experience mild to moderate depressive symptoms, defined as a Patient Health Questionnaire (PHQ 9) score of 5 to 15. This study is powered to detect a small between-groups effect, where no clinically relevant effect is defined as the effect size margin 0.25< d <0.25. DISCUSSION: To our knowledge, this is the first study to investigate whether self-rated EMA of depressive symptoms could induce assessment reactivity among mildly depressed individuals. TRIAL REGISTRATION: Netherlands Trial Register NTR5803. Registered 12 April 2016. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5803 . PMID- 27769203 TI - The effects of living environment on disaster workers: a one-year longitudinal study. AB - BACKGROUND: Defense Force workers engaged in disaster relief activities might suffer from strong psychological stress due to the tasks that they had been involved. We evaluated how living environments, work environments, and individual factors psychologically affect those who engaged in disaster relief activities. METHOD: Data generated with 1506 personnel engaged in the Great East Japan Earthquake relief activity were analyzed. Those who scored >=25 points on the Impact of Events Scale-Revised and the Kessler Psychological Distress Scale (K10) were allocated into the high post-traumatic stress response (high-PTSR) group, and the high general psychological distress (high-GPD) group, respectively. RESULTS: The multiple logistic regression analysis extracted living environment (camping within the shelter sites) as the significant risk factor for both high PTSR (OR = 3.39, 95 % CI 2.04-5.64, p < 0.001) and high-GPD (OR = 3.35, 95 % CI 1.77-6.34, p < 0.001) groups. CONCLUSION: It is desirable for disaster workers to have a living environment in which they can keep an appropriate distance from the victims. PMID- 27769202 TI - A double-blind randomized controlled trial to assess the effect of bright light therapy on depression in patients with Parkinson's disease. AB - BACKGROUND: A disturbed circadian rhythm seems to be a causal factor in the occurrence of depressive disorders in patients with Parkinson's disease (PD). The circadian rhythm can be restored with light. Therefore, Bright Light Therapy (BLT) might be a new treatment option for depression in PD patients. METHODS/DESIGN: In this double-blind controlled trial, 84 subjects with idiopathic PD are randomized to either BLT or a control light condition. The BLT condition emits white light with an intensity of 10,000 Lux, while the control device emits dim white light of 200 Lux, which is presumed to be too low to influence the circadian rhythm. Subjects receive 30 min of home treatment twice daily for three months. Timing of treatment is based on the individual chronotype. After finishing treatment, subjects enter a follow-up period of six months. The primary outcome of the study is the severity of depressive symptoms, as measured with the Hamilton Depression Rating Scale. Secondary outcomes are alternative depression measures, objective and subjective sleep measures, and salivary melatonin and cortisol concentrations. For exploratory purposes, we also assess the effects on motor symptoms, global cognitive function, comorbid psychiatric disorders, quality of life and caregiver burden. Data will be analyzed using a linear mixed models analysis. DISCUSSION: Performing a placebo controlled trial on the effects of BLT in PD patients is challenging, as the appearance of the light may provide clues on the treatment condition. Moreover, fixed treatment times lead to an improved sleep-wake rhythm, which also influences the circadian system. With our study design, we do not compare BLT to placebo treatment, i.e. an ineffective control treatment. Rather, we compare structuring of the sleep-wake cycle in both conditions with additional BLT in the experimental condition, and additional dim light in the control condition. Participants are not informed about the exact details of the two light devices and the expected therapeutic effect, and expectancies are rated prior to the start of treatment. Ideally, the design of a future study on BLT should include two extra treatment arms where BLT and control light are administered at random times. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on May 17th 2012 (ClinicalTrials.gov Identifier: NCT01604876 ). PMID- 27769205 TI - Addressing medical absenteeism in pre-vocational secondary students: effectiveness of a public health intervention, using a quasi-experimental design. AB - BACKGROUND: Students' health and school absenteeism affect educational level, with adverse effects on their future health. This interdependence is reflected in medical absenteeism. In the Netherlands, a public health intervention has been developed to address medical absenteeism in pre-vocational secondary education. This study aims to investigate the effectiveness of this intervention on students' medical absenteeism, compared to "medical absenteeism policy as usual". METHODS: A quasi-experimental design with an intervention group (493 students) and a control group (445 students) was applied. Multilevel analysis was used to study differences in the development of the level of a student's medical absence over time (after 3 and 12 months). RESULTS: In the intervention group, the level of absenteeism decreased from 8.5 days reported sick in 12 school weeks to 5.7 days after 3 months, and to 4.9 days after 12 months. The number of absence periods fell from 3.9 in 12 school weeks to 2.5 after 3 months, and to 2.2 after 12 months. In the control group, the absence days initially decreased from 9.9 days reported sick in 12 school weeks to 8.4 days after 3 months, after which an increase to 8.9 days was measured. The number of absence periods initially decreased from 4.5 in 12 school weeks to 3.5, after which an increase to 3.7 was measured. The number of absence days per period remained about the same in both groups. CONCLUSIONS: The study provides first indications for the intervention to be effective for Dutch pre-vocational secondary students with increased medical absence rates. The intervention, which consists of personalised management of medical absenteeism by systematic identification of students with extensive medical absenteeism and consistent referral to youth health care physicians, appears to reduce the absence rates more effectively than "medical absenteeism policy as usual". The effectiveness of the intervention is shown primarily by a decrease in the number of periods reported sick. PMID- 27769204 TI - The need for a culturally-tailored gatekeeper training intervention program in preventing suicide among Indigenous peoples: a systematic review. AB - BACKGROUND: Suicide is a leading cause of death among Indigenous youth worldwide. The aim of this literature review was to determine the cultural appropriateness and identify evidence for the effectiveness of current gatekeeper suicide prevention training programs within the international Indigenous community. METHOD: Using a systematic strategy, relevant databases and targeted resources were searched using the following terms: 'suicide', 'gatekeeper', 'training', 'suicide prevention training', 'suicide intervention training' and 'Indigenous'. Other internationally relevant descriptors for the keyword "Indigenous" (e.g. "Maori", "First Nations", "Native American", "Inuit", "Metis" and "Aboriginal") were also used. RESULTS: Six articles, comprising five studies, met criteria for inclusion; two Australian, two from USA and one Canadian. While pre and post follow up studies reported positive outcomes, this was not confirmed in the single randomised controlled trial identified. However, the randomised controlled trial may have been underpowered and contained participants who were at higher risk of suicide pre-training. CONCLUSION: Uncontrolled evidence suggests that gatekeeper training may be a promising suicide intervention in Indigenous communities but needs to be culturally tailored to the target population. Further RCT evidence is required. PMID- 27769207 TI - Neonatal outcomes in pregnancies resulting from oocyte donation: a cohort study in Sweden. AB - BACKGROUND: Pregnancies resulting through oocyte donation have been associated with increased risk for adverse outcomes for the mother, such as gestational hypertensive disorders. However, little is known about possible neonatal complications of such pregnancies. The purpose of this study was to evaluate the neonatal health outcomes among singleton pregnancies in a population of relatively young and healthy oocyte recipients in Sweden, taking into account the medical indication leading to treatment. METHODS: This cohort study involved 76 women conceiving with donated oocytes, 149 age-matched nulliparous women conceiving spontaneously and 63 women conceiving after non-donor IVF. Participants were recruited during 2005-2008 and followed up until delivery. Data on neonatal outcomes were retrieved from the National Birth Medical Register and the medical records of oocyte recipients from seven Swedish University Hospitals with IVF clinics. Logistic regression analyses were performed to examine the association of mode of conception and neonatal outcomes, adjusted for maternal age and BMI, gestational age and delivery by cesarean section. RESULTS: Infants conceived through oocyte donation had higher odds for premature delivery [OR 2.36, 95 % CI (1.02-5.45)], for being small for gestational age [OR 4.23, 95 % CI (1.03-17.42)] and having Apgar score below 7 at 5 min [OR 10.57, 95 % CI (1.21 92.20)] compared to spontaneously conceived infants. Similar trends were observed when comparing infants conceived through oocyte donation to those conceived by traditional IVF. Furthermore, donor oocyte infants had a lower mean birthweight and length compared to autologous oocyte neonates (p = 0.013); however no differences were noted among infants born at term. Neonatal outcomes were more favorable among women with diminished ovarian reserve compared to those with other indications for oocyte donation. CONCLUSIONS: Infants conceived after oocyte donation in Sweden have higher odds of being born prematurely and having lower mean birthweight in comparison to non-donor infants. It seems that these unfavorable neonatal outcomes are present despite the age, weight and health restrictions applied to recipients before oocyte donation treatment in Sweden. PMID- 27769206 TI - Coverage, efficacy or dosing interval: which factor predominantly influences the impact of routine childhood vaccination for the prevention of varicella? A model based study for Italy. AB - BACKGROUND: Varicella is a highly infectious disease with a significant public health and economic burden, which can be prevented with childhood routine varicella vaccination. Vaccination strategies differ by country. Some factors are known to play an important role (number of doses, coverage, dosing interval, efficacy and catch-up programmes), however, their relative impact on the reduction of varicella in the population remains unclear. This paper aims to help policy makers prioritise the critical factors to achieve the most successful vaccination programme with the available budget. METHODS: Scenarios assessed the impact of different vaccination strategies on reduction of varicella disease in the population. A dynamic transmission model was used and adapted to fit Italian demographics and population mixing patterns. Inputs included coverage, number of doses, dosing intervals, first-dose efficacy and availability of catch-up programmes, based on strategies currently used or likely to be used in different countries. The time horizon was 30 years. RESULTS: Both one- and two-dose routine varicella vaccination strategies prevented a comparable number of varicella cases with complications, but two-doses provided broader protection due to prevention of a higher number of milder varicella cases. A catch-up programme in susceptible adolescents aged 10-14 years old reduced varicella cases by 27-43 % in older children, which are often more severe than in younger children. Coverage, for all strategies, sustained at high levels achieved the largest reduction in varicella. In general, a 20 % increase in coverage resulted in a further 27-31 % reduction in varicella cases. When high coverage is reached, the impact of dosing interval and first-dose vaccine efficacy had a relatively lower impact on disease prevention in the population. Compared to the long (11 years) dosing interval, the short (5 months) and medium (5 years) interval schedules reduced varicella cases by a further 5-13 % and 2-5 %, respectively. Similarly, a 10 % increase in first-dose efficacy (from 65 to 75 % efficacy) prevented 2-5 % more varicella cases, suggesting it is the least influential factor when considering routine varicella vaccination. CONCLUSIONS: Vaccination strategies can be implemented differently in each country depending on their needs, infrastructure and healthcare budget. However, ensuring high coverage remains the critical success factor for significant prevention of varicella when introducing varicella vaccination in the national immunisation programme. PMID- 27769208 TI - Inequalities in pediatric avoidable hospitalizations between Aboriginal and non Aboriginal children in Australia: a population data linkage study. AB - BACKGROUND: Australian Aboriginal children experience a disproportionate burden of social and health disadvantage. Avoidable hospitalizations present a potentially modifiable health gap that can be targeted and monitored using population data. This study quantifies inequalities in pediatric avoidable hospitalizations between Australian Aboriginal and non-Aboriginal children. METHODS: This statewide population-based cohort study included 1 121 440 children born in New South Wales, Australia, between 1 July 2000 and 31 December 2012, including 35 609 Aboriginal children. Using linked hospital data from 1 July 2000 to 31 December 2013, we identified pediatric avoidable, ambulatory care sensitive and non-avoidable hospitalization rates for Aboriginal and non-Aboriginal children. Absolute and relative inequalities between Aboriginal and non Aboriginal children were measured as rate differences and rate ratios, respectively. Individual-level covariates included age, sex, low birth weight and/or prematurity, and private health insurance/patient status. Area-level covariates included remoteness of residence and area socioeconomic disadvantage. RESULTS: There were 365 386 potentially avoidable hospitalizations observed over the study period, most commonly for respiratory and infectious conditions; Aboriginal children were admitted more frequently for all conditions. Avoidable hospitalization rates were 90.1/1000 person-years (95 % CI, 88.9-91.4) in Aboriginal children and 44.9/1000 person-years (44.8-45.1) in non-Aboriginal children (age and sex adjusted rate ratio = 1.7 (1.7-1.7)). Rate differences and rate ratios declined with age from 94/1000 person-years and 1.9, respectively, for children aged <2 years to 5/1000 person-years and 1.8, respectively, for ages 12- < 14 years. Findings were similar for the subset of ambulatory care sensitive hospitalizations, but in contrast, non-avoidable hospitalization rates were almost identical in Aboriginal (10.1/1000 person-years, (9.6-10.5)) and non Aboriginal children (9.6/1000 person-years (9.6-9.7)). CONCLUSIONS: We observed substantial inequalities in avoidable hospitalizations between Aboriginal and non Aboriginal children regardless of where they lived, particularly among young children. Policy measures that reduce inequities in the circumstances in which children grow and develop, and improved access to early intervention in primary care, have potential to narrow this gap. PMID- 27769209 TI - Study Protocol: A randomized controlled trial evaluating the effect of family based behavioral treatment of childhood and adolescent obesity-The FABO-study. AB - BACKGROUND: The purpose of the FABO-study is to evaluate the effect of family based behavioral social facilitation treatment (FBSFT), designed to target children's family and social support networks to enhance weight loss outcomes, compared to the standard treatment (treatment as usual, TAU) given to children and adolescents with obesity in a routine clinical practice. METHODS: Randomized controlled trial (RCT), in which families (n = 120) are recruited from the children and adolescents (ages 6-18 years) referred to the Obesity Outpatient Clinic (OOC), Haukeland University Hospital, Norway. Criteria for admission to the OOC are BMI above the International Obesity Task Force (IOTF) cut-off >= 35, or IOTF >= 30 with obesity related co-morbidity. Families are randomized to receive FBSFT immediately or following one year of TAU. All participants receive a multidisciplinary assessment. For TAU this assessment results in a plan and a contract for chancing specific lifestyle behaviors. Thereafter each family participates in monthly counselling sessions with their primary health care nurse to work on implementing these goals, including measuring their weight change, and also meet every third month for sessions at the OOC. In FBSFT, following assessment, families participate in 17 weekly sessions at the OOC, in which each family works on changing lifestyle behaviors using a structured cognitive behavioral, socio-ecological approach targeting both parents and children with strategies for behavioral maintenance and sustainable weight change. Outcome variables include body mass index (BMI; kg/m2), BMI standard deviation score (SDS) and percentage above the IOTF definition of overweight, waist circumference, body composition (bioelectric impedance (BIA) and dual-X-ray absorptiometry (DXA)), blood tests, blood pressure, activity/inactivity and sleep pattern (measured by accelerometer), as well as questionnaires measuring depression, general psychological symptomatology, self-esteem, disturbed eating and eating disorder symptoms. Finally, barriers to treatment and parenting styles are measured via questionnaires. DISCUSSION: This is the first systematic application of FBSFT in the treatment of obesity among youth in Norway. The study gives an opportunity to evaluate the effect of FBSFT implemented in routine clinical practice across a range of youth with severe obesity. TRIAL REGISTRATION: ClinicalTrails.gov NCT02687516 . Registered 16th of February, 2016. PMID- 27769210 TI - Efficacy and safety profile of nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer treated to disease progression: a subanalysis from a phase 3 trial (MPACT). AB - BACKGROUND: The phase 3 MPACT trial in patients with metastatic pancreatic cancer demonstrated superior efficacy of nab-paclitaxel (nab-P) + gemcitabine (Gem) vs Gem monotherapy for all endpoints examined including overall survival, the primary endpoint. In the MPACT trial, patients were treated until progressive disease (PD) or unacceptable toxicity. The current exploratory analysis investigated outcomes of patients from the MPACT trial who were treated until PD, in order to understand how to maximize treatment benefit from nab-P + Gem. METHODS: The trial design has been described in detail previously. Progressive disease was determined by the investigator on the basis of radiological imaging. RESULTS: Among patients who were treated until PD, overall survival was significantly longer for those who received nab-P + Gem vs Gem (median, 9.8 vs 7.5 months; P < 0.001). Independently assessed progression-free survival and overall response rate were significantly greater among patients in the treatment to-PD cohort who received nab-P + Gem compared with Gem (P < 0.001 for each). Although not compared statistically, patients who were treated until PD received greater treatment exposure and experienced more favourable efficacy than the intent-to-treat population of the MPACT trial. Among patients who were treated with nab-P + Gem until PD, > 50 % went on to receive a subsequent therapy. The safety profile for patients treated until PD was similar to what was reported in the overall MPACT trial. CONCLUSION: The nab-P + Gem regimen is an active first line treatment option; most patients were treated until PD, and this exposure was associated with improved efficacy outcomes. Prolonged first-line treatment exposure and ability to receive subsequent therapies likely contributed to the improved survival among these patients. Our data highlight the importance of managing adverse events and indicate that patients should be treated until PD when possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT00844649 (MPACT trial); Registration date of this prospective phase III trial: February 13, 2009; current exploratory subanalysis was conducted retrospectively. PMID- 27769211 TI - The forgotten guidelines: cross-sectional analysis of participation in muscle strengthening and balance & co-ordination activities by adults and older adults in Scotland. AB - BACKGROUND: In 2011, the UK physical activity guidelines were updated to include recommendations for muscle strengthening and balance & coordination (at least two sessions of relevant activities per week). However, monitoring and policy efforts remain focussed on aerobic activity. This study aimed to assess differences by gender and age in the a) prevalence of muscle strengthening and balance & co ordination guidelines, and b) participation in guideline-specific activities. METHODS: The sample for the muscle strengthening analyses was 10,488 adult (16-64 years) and 3857 older adult (>=65 years) 2012-2014 Scottish Health Survey respondents. The balance & co-ordination analyses used only the older adult responses. Differences by gender and (where possible) age in guideline prevalence and activity participation were assessed using logistic regression and t-tests. RESULTS: Thirty-one percent of men and 24 % of women met the muscle strengthening guideline, approximately half that of published figures for aerobic physical activity. Nineteen percent of older men and 12 % of older women met the balance & co-ordination guidelines. The oldest age groups were less likely to meet both guidelines compared to the youngest age groups. Differences by gender were only evident for muscle strengthening: more men met the guidelines than women in all age groups, with the largest difference amongst 16-24 year olds (55 % men compared with 40 % women). Participation in relevant activities differed by gender for both guidelines. 'Workout at gym' was the most popular activity to improve muscle strength for men (18 % participated), while swimming was for women (15 % participated). Golf was the most popular activity to improve balance & co ordination for older men (11 % participated) and aerobics was for older women (6 % participated). Participation decreased in most muscle strengthening activities for both men and women. One exception was golf, where participation levels were as high amongst older men as in younger age groups, although overall levels were low (3 % of all men). CONCLUSIONS: Physical activity policy should aim to increase prevalence of these 'forgotten' guidelines, particularly amongst young women (for muscle strengthening) and older age groups (both guidelines). Gender and age participation differences should be considered when designing population level interventions. PMID- 27769212 TI - Validation of the CancerMath prognostic tool for breast cancer in Southeast Asia. AB - BACKGROUND: CancerMath is a set of web-based prognostic tools which predict nodal status and survival up to 15 years after diagnosis of breast cancer. This study validated its performance in a Southeast Asian setting. METHODS: Using Singapore Malaysia Hospital-Based Breast Cancer Registry, clinical information was retrieved from 7064 stage I to III breast cancer patients who were diagnosed between 1990 and 2011 and underwent surgery. Predicted and observed probabilities of positive nodes and survival were compared for each subgroup. Calibration was assessed by plotting observed value against predicted value for each decile of the predicted value. Discrimination was evaluated by area under a receiver operating characteristic curve (AUC) with 95 % confidence interval (CI). RESULTS: The median predicted probability of positive lymph nodes is 40.6 % which was lower than the observed 43.6 % (95 % CI, 42.5 %-44.8 %). The calibration plot showed underestimation for most of the groups. The AUC was 0.71 (95 % CI, 0.70 0.72). Cancermath predicted and observed overall survival probabilities were 87.3 % vs 83.4 % at 5 years after diagnosis and 75.3 % vs 70.4 % at 10 years after diagnosis. The difference was smaller for patients from Singapore, patients diagnosed more recently and patients with favorable tumor characteristics. Calibration plot also illustrated overprediction of survival for patients with poor prognosis. The AUC for 5-year and 10-year overall survival was 0.77 (95 % CI: 0.75-0.79) and 0.74 (95 % CI: 0.71-0.76). CONCLUSIONS: The discrimination and calibration of CancerMath were modest. The results suggest that clinical application of CancerMath should be limited to patients with better prognostic profile. PMID- 27769213 TI - Cervical and breast cancer screening uptake among women with serious mental illness: a data linkage study. AB - BACKGROUND: Breast and cancer screening uptake has been found to be lower among women with serious mental illness (SMI). This study aims to corroborate these findings in the UK and to identify variation in screening uptake by illness/treatment factors, and primary care consultation frequency. METHODS: Linked population-based primary and secondary care data from the London borough of Lambeth (UK) were used to compare breast and cervical screening receipt among linked eligible SMI patients (n = 625 and n = 1393), to those without SMI known only to primary care (n = 106,554 and n = 25,385) using logistic regression models adjusted first for socio-demographic factors and second, additionally for primary care consultation frequency. RESULTS: Eligible SMI patients were less likely to have received breast (adjusted odds ratio (OR) 0.69, 95 % confidence interval (CI), 0.57 - 0.84, p < 0.001) or cervical screening (adjusted OR 0.72, CI: 0.60 - 0.85, p < 0.001). Schizophrenia diagnosis, depot injectable antipsychotic prescription, and illness severity and risk were associated with the lowest odds of uptake of breast (adjusted ORs 0.46 to 0.59, all p < 0.001) and cervical screening (adjusted ORs 0.48 - 0.65, all p < 0.001). Adjustments for consultation frequency further reduced effect sizes for all subgroups of SMI patient, in particular for cervical screening. CONCLUSIONS: Women with SMI are less likely to receive breast and cervical cancer screening than comparable women without SMI. Higher primary care consultation rates among SMI patients is likely a mediating factor between SMI status and uptake, particularly for cervical screening - a service organised in primary care. To tackle health disparities linked to SMI, efforts at increasing screening uptake are key and should be targeted at women with other markers of illness severity or risk, beyond SMI status alone. PMID- 27769214 TI - INNOVATE: A prospective cohort study combining serum and urinary biomarkers with novel diffusion-weighted magnetic resonance imaging for the prediction and characterization of prostate cancer. AB - BACKGROUND: Whilst multi-parametric magnetic resonance imaging (mp-MRI) has been a significant advance in the diagnosis of prostate cancer, scanning all patients with elevated prostate specific antigen (PSA) levels is considered too costly for widespread National Health Service (NHS) use, as the predictive value of PSA levels for significant disease is poor. Despite the fact that novel blood and urine tests are available which may predict aggressive disease better than PSA, they are not routinely employed due to a lack of clinical validity studies. Furthermore approximately 40 % of mp-MRI studies are reported as indeterminate, which can lead to repeat examinations or unnecessary biopsy with associated patient anxiety, discomfort, risk and additional costs. METHODS/DESIGN: We aim to clinically validate a panel of minimally invasive promising blood and urine biomarkers, to better select patients that will benefit from a multiparametric prostate MRI. We will then test whether the performance of the mp-MRI can be improved by the addition of an advanced diffusion-weighted MRI technique, which uses a biophysical model to characterise tissue microstructure called VERDICT; Vascular and Extracellular Restricted Diffusion for Cytometry in Tumours. INNOVATE is a prospective single centre cohort study in 365 patients. mp-MRI will act as the reference standard for the biomarker panel. A clinical outcome based reference standard based on biopsy, mp-MRI and follow-up will be used for VERDICT MRI. DISCUSSION: We expect the combined effect of biomarkers and VERDICT MRI will improve care by better detecting aggressive prostate cancer early and make mp-MRI before biopsy economically viable for universal NHS adoption. TRIAL REGISTRATION: INNOVATE is registered on ClinicalTrials.gov, with reference NCT02689271 . PMID- 27769216 TI - Kirner's deformity of the fifth finger: a case report. AB - BACKGROUND: Kirner's deformity is a rare bony deformity that is characterized by radial and volar curvature of the distal phalanx of the fifth finger. Affected patients usually present after the age of 5 years, with girls more affected than boys and bilateral involvement more common than unilateral. CASE PRESENTATION: We report a case of an eight-year-old girl who presented with progressive deformity of the right little finger. Radiographic evaluation revealed volar and radial curvature of the distal phalanx of the right fifth digit. Magnetic resonance imaging (MRI) further revealed the deformity along with widening of the physeal plate, lack of soft tissue enhancement and normal insertion of the flexor digitorum profundus tendon. The patient was followed conservatively for two years and is now being considered for corrective osteotomy. CONCLUSION: Kirner's deformity is a rare abnormality of unknown etiology. Diagnosis is made with clinical examination and imaging evaluation. Clinicians should be aware of this uncommon deformity and differentiate it from other mimickers such as infection, physeal fracture, camptodactyly, and clinodactyly. PMID- 27769215 TI - Eye movements in patients with Whiplash Associated Disorders: a systematic review. AB - BACKGROUND: Many people with Whiplash Associated Disorders (WAD) report problems with vision, some of which may be due to impaired eye movements. Better understanding of such impaired eye movements could improve diagnostics and treatment strategies. This systematic review surveys the current evidence on changes in eye movements of patients with WAD and explains how the oculomotor system is tested. METHODS: Nine electronic data bases were searched for relevant articles from inception until September 2015. All studies which investigated eye movements in patients with WAD and included a healthy control group were screened for inclusion. Qualifying studies were retrieved and independently assessed for methodological quality using the Methodology Checklists provided by the Scottish Intercollegiate Guidelines Network. RESULTS: Fourteen studies out of 833 unique hits were included. Ten studies reported impaired eye movements in patients with WAD and in four studies no differences compared to healthy controls were found. Different methods of eye movement examination were used in the ten studies: in five studies, the smooth pursuit neck torsion test was positive, in two more the velocity and stability of head movements during eye-coordination tasks were decreased, and in another three studies the cervico-ocular reflex was elevated. CONCLUSIONS: Overall the reviewed studies show deficits in eye movement in patients with WAD, but studies and results are varied. When comparing the results of the 14 relevant publications, one should realise that there are significant differences in test set-up and patient population. In the majority of studies patients show altered compensatory eye movements and smooth pursuit movements which may impair the coordination of head and eyes. PMID- 27769217 TI - Disseminated carcinomatosis of the bone marrow from pancreatic cancer: a case report. AB - BACKGROUND: Most cases of disseminated carcinomatosis of the bone marrow (DCBM) arise from gastric cancer. DCBM from pancreatic cancer is very rare. We herein present a case of DCBM from pancreatic cancer. CASE PRESENTATION: A 57-year-old man was referred to our hospital for severe lumbago. Laboratory data indicated that he suffered from disseminated intravascular coagulation (DIC). Non-contrast abdominal computed tomography (CT) revealed multiple bone masses but no other abnormal findings. Left iliac bone marrow biopsy revealed poorly differentiated adenocarcinoma cells. Positron emission tomography (PET)-CT showed diffuse abnormal uptake in the bones and tail of the pancreas. Contrast whole-body CT showed a tumor measuring approximately 28 mm in diameter with poor enhancement in the tail of the pancreas. The patient's final diagnosis was pancreatic cancer located in the tail of the pancreas with diffuse bone metastases and DIC. His DCBM was thus believed to originate from the pancreatic cancer. He succumbed to the disease approximately 2 months after admission to our hospital. CONCLUSION: We herein describe a case of pancreatic cancer located in the tail of the pancreas with diffuse bone metastases and DIC, which, in our case, was DCBM. Therefore, in cases of DCBM with an unknown primary tumor, pancreatic cancer should be considered during differential diagnosis. PMID- 27769218 TI - In vivo sedative activity of methanolic extract of Stericulia villosa Roxb. leaves. AB - BACKGROUND: This plant is very popular ingredient of local made drinks during hot summer. After drinking this drink people feels fresh, relaxed and can enjoy sound sleep. Present study was aimed to assess the sedative properties of a plant Sterculia villosa leaves. Therefore, we tried to find out the methanolic extract from the leaves of Sterculia villosa leaves having any sedative activity or not. METHODS: The extract were subjected to various in vivo methods like hole cross test, open field test, elevated plus-maze (EPM) test, thiopental sodium induced sleeping time test. Diazepam was used as the standard drug. RESULTS: From the study, it is clear that the extract has excellent CNS depressant activity by reducing locomotors activity of mice in every cases of hole cross test, open field test, elevated plus-maze (EPM) test compared to the standard diazepam. In addition, the extract prolong the sleeping time (230 min) with quick onset of action (9 min) in contrast to the standard and control group. CONCLUSIONS: From the present study it can be conclude that the extract posses significant a sedative property that may lead to new drug development and further investigation is necessary to understand the underlying mechanisms and to isolate the active principles. PMID- 27769219 TI - Advanced Practice Pharmacists: a retrospective evaluation of the efficacy and cost of ClinicaL Pharmacist PractitionErs managing ambulatory Medicare patients in North Carolina (APPLE-NC). AB - BACKGROUND: Clinical Pharmacist Practitioners are advanced practicing pharmacists in North Carolina that provide disease-specific management. The purpose of this retrospective cohort study was to compare the efficacy and charges from referrals to a Clinical Pharmacist Practitioner by the primary care provider, to those managed by a primary care provider alone. METHODS: Patients were separated into cohorts depending if they had at least two appointments with a Clinical Pharmacist Practitioner from November 2008 to November 2011. A primary care provider saw all patients at least twice during the study period. Cohorts were then matched by age, gender, and disease states. Medicare billed data was evaluated from outpatient visits related to hypertension, diabetes mellitus, and peripheral neuropathy, as well as emergency department visits and inpatient admissions. Cost of medications was estimated using 2009 AWP data corresponding to medication histories within the electronic medical record. Efficacy was defined as ability to reach disease state goal determined using national guidelines and reduction in pain score. Efficacy was analyzed by difference-in differences test and all other numerical data tested by paired t-tests. RESULTS: The Clinical Pharmacist Practitioners cohort experienced more outpatient visits (1338 vs. 858, p < 0.001), fewer emergency department visits (115 vs. 190, p < 0.05), and similar inpatient admissions (88 vs. 117, p > 0.05) than the primary care providers cohort, respectively. The Clinical Pharmacist Practitioners cohort showed changes in charges of +22.6 % for outpatient visits, -45.5 % emergency department visits, and -13.2 % inpatient admissions relative to the primary care provider cohort. There was no difference in average daily medication cost (Clinical Pharmacist Practitioners $38.52 vs. primary care providers $38.23, p = 0.97) or achievement of disease state goals. CONCLUSION: APPLE-NC demonstrated that through referrals, Clinical Pharmacist Practitioners provide services comparable in charges and efficacy to primary care providers. Consequently, the current increased need for primary care practitioners can be met in part by increasing the utilization of advanced practice pharmacists for chronic disease management. TRIAL REGISTRATION: This does not apply for this retrospective cohort study. PMID- 27769220 TI - Utilization of contraception among sexually active HIV positive women attending art clinic in University of Gondar Hospital: a hospital based cross-sectional study. AB - BACKGROUND: Contraception helps to prevent unplanned pregnancies among human immune virus positive women. The contraceptive utilization status and associated factors were not well addressed in the study area. Therefore, this study aimed to assess utilization of contraceptives and associated factors among human immune virus positive reproductive age group women appearing at anti-retroviral therapy clinic at the University of Gondar Hospital, North West Ethiopia. METHOD: An institution based cross-sectional study was conducted among 397 systematically selected HIV positive reproductive age women who visited ART unit of the University of Gondar teaching referral hospital from January 8-20, 2014. The data were collected using pre tested and structured questionnaires through face-to face interviews. The data were entered into Epi-Info version 3.5, and cleaned and analyzed using SPSS version 20. Descriptive summary of the data and logistic regression were used to identify possible predictors using odds ratio with 95 % confidence interval and P-value of 0.05. RESULTS: The study revealed that the overall utilization of any type of contraception was 50 %. Of them, 4.1 % got contraception from anti-retroviral therapy unit. Fear of side effects was the most common (42 %) reason for not using contraception. Women who attended secondary education, married and who had 4-6 children were more likely to use contraception than their counterparts were; (AOR: 5.63; 95 % CI: 1.74-18.21), (AOR: 8.07; 95 % CI: 3.10-20.99) and (AOR: 3.61; 95 % CI: 1.16-11.26) respectively. However, Women between 35-49 years, had no intention to have another child and discordant couples were 83 %, 76 % and 65 % less likely to use contraception respectively than their counterparts. CONCLUSIONS: The results of this study revealed that the utilization of contraception was low. Women between 35-49 years, those who had no intention to have another child and whose partner was HIV sero-negative and fear of side effect of the contraception played an important role for not using contraception. Therefore, there is a need to give attention about integration of family planning service with HIV care and support service. PMID- 27769221 TI - Estimating healthcare mobility in the Veterans Affairs Healthcare System. AB - BACKGROUND: Healthcare mobility, defined as healthcare utilization in more than one distinct healthcare system, may have detrimental effects on outcomes of care. We characterized healthcare mobility and associated characteristics among a national sample of Veterans. METHODS: Using the Veterans Health Administration Electronic Health Record, we conducted a retrospective cohort study to quantify healthcare mobility within a four year period. We examined the association between sociodemographic and clinical characteristics and healthcare mobility, and characterized possible temporal and geographic patterns of healthcare mobility. RESULTS: Approximately nine percent of the sample were healthcare mobile. Younger Veterans, divorced or separated Veterans, and those with hepatitis C virus and psychiatric disorders were more likely to be healthcare mobile. We demonstrated two possible patterns of healthcare mobility, related to specialty care and lifestyle, in which Veterans repeatedly utilized two different healthcare systems. CONCLUSIONS: Healthcare mobility is associated with young age, marital status changes, and also diseases requiring intensive management. This type of mobility may affect disease prevention and management and has implications for healthcare systems that seek to improve population health. PMID- 27769223 TI - The activities of a dietitian-led gastroenterology clinic using extended scope of practice. AB - BACKGROUND: Extending the scope of practice of allied health professionals has been a strategy adopted in the United Kingdom to address issues within the health system. Australia's health system is currently undermined by similar issues, heightening government interest in adopting the extended scope health care model. The aim of the current study was to describe the activities and outcomes of a dietitian-led gastroenterology clinic which operated under an extended scope of practice model in an outpatient gastroenterology department at a tertiary hospital in regional Queensland, Australia, and to assess patient satisfaction with the initiative. METHODS: A descriptive, cross-sectional case series undertaken over 50 clinics involving 82 category 2 and 3 patients with suspected/confirmed coeliac disease or inflammatory bowel disease; low haemoglobin; gastroesophageal reflux disease, or; malnutrition. Data was analysed using Microsoft Excel 2010, and presented as descriptive statistics. RESULTS: Sixty out of 82 selected patients (median age 51 years) attended an initial appointment with the dietitian. Twenty-four review appointments were attended. Average waiting period for an initial appointment was 148 days (range 31-308 days). A total of 149 management strategies were provided, and 94 (63 %) of these involved the dietitian utilising extended scope of practice. The dietitian managed 47 (78 %) patients without need for gastroenterologist referral, and 25 (42 %) were discharged after dietetic management. Patients reported high levels of satisfaction with the clinic. CONCLUSIONS: Seventy-eight percent of category 2 and 3 patients referred to the gastroenterologist could be managed exclusively in the dietitian-led clinic. This extended scope model of care could potentially benefit the efficiency and acceptability of Australia's public health system. PMID- 27769222 TI - Utilization and prescription patterns of traditional Chinese medicine for patients with hepatitis C in Taiwan: a population-based study. AB - BACKGROUND: To characterize the utilization of Traditional Chinese Medicine (TCM) among patients with hepatitis C (HC). METHODS: This study examined datasets from the National Health Insurance Research Database in Taiwan. One cohort, including one million patients randomly sampled from the beneficiaries of the National Health Insurance Programme from January 1 to December 31 in 2010, was chosen for this analysis. People who had at least three outpatient or inpatient records and had been diagnosed with hepatitis C virus infection from 2000 to 2010 were defined as patients with HC. Patients with HC who had at least one TCM outpatient clinical record from 2000 to 2010 were defined as TCM users (N = 5,691), whereas patients with no TCM outpatient records were defined as non-TCM users (N = 2,876). The demographic data, treatment modalities and disease distributions of TCM users were analysed. RESULTS: Overall, 66.4 % of the patients with HC had used TCM from 2000 to 2010. Of the TCM users, 54.1 % were female. The utilization rate of TCM increased with age and peaked in the age group of those 40 - 64 years old. Herbal remedies (52.4 %) were the most commonly used agents, followed by combination therapy (46.4 %) and acupuncture alone (1.2 %). Patients who had more extrahepatic diseases and were taking more antiviral agents tended to visit TCM clinics. Jia-Wei-Xiao-Yao-San and Dan-Shen (Salvia miltiorrhiza) were the most commonly used formula and single herb, with 88,124 person-days and 59,252 person days, respectively. CONCLUSIONS: Our nationwide population-based study revealed a high prevalence and specific usage patterns of TCM in patients with HC in Taiwan. PMID- 27769224 TI - Barriers and facilitators to disease-modifying antirheumatic drug use in patients with inflammatory rheumatic diseases: a qualitative theory-based study. AB - BACKGROUND: Although disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of treatment for inflammatory rheumatic diseases, medication adherence to DMARDs is often suboptimal. Effective interventions to improve adherence to DMARDs are lacking, and new targets are needed to improve adherence. The aim of the present study was to explore patients' barriers and facilitators of optimal DMARD use. These factors might be used as targets for adherence interventions. METHODS: In a mixed method study design, patients (n = 120) with inflammatory arthritis (IA) completed a questionnaire based on an existing adapted Theoretical Domains Framework (TDF) to identify facilitators and barriers of DMARD use. A subgroup of these patients (n = 21) participated in focus groups to provide insights into their facilitators and barriers. The answers to the questionnaires and responses of the focus groups were thematically coded by three researchers independently and subsequently categorized. RESULTS: The barriers and facilitators that were reported by IA patients presented large inter-individual variations. The identified barriers and facilitators could be captured in the following domains based on an adapted TDF: (i) knowledge, (ii) emotions, (iii) attention, memory, and decision processes, (iv) social influences, (v) beliefs about capability, (vi) beliefs about consequences, (vii) motivation and goals, (viii) goal conflict, (ix) environmental context and resources, and (x) skills. CONCLUSIONS: Patients with IA have a variety of barriers and facilitators with regard to their DMARD use. All of these barriers and facilitators could be categorized into adapted domains of the TDF. Interventions that address individual facilitators and barriers, based on capability, opportunity, and motivation, are needed to develop strategies for medication adherence that are tailored to individual patient needs. PMID- 27769225 TI - Implementing a video-based intervention to empower staff members in an autism care organization: a qualitative study. AB - BACKGROUND: Implementing good-quality health and social care requires empowerment of staff members within organizations delivering care. Video Interaction Guidance (VIG) is an intervention using positive video feedback to empower staff through reflection on practice. This qualitative study explored the implementation of VIG within an autism care organization in England, from the perspective of staff members undergoing training to deliver VIG. METHODS: Semi-structured interviews were conducted with a purposive sample of 7 participants working within the organization (5 staff undergoing training to deliver VIG; 2 senior managers influencing co-ordination of training). Participants were asked about their views of VIG and its implementation. The topic guide was informed by Normalization Process Theory (NPT). Data were analysed inductively and emerging issues were related to NPT. RESULTS: Five broad themes were identified: (1) participants reported that they and other staff did not understand VIG until they became involved, initially believing it would highlight negative rather than positive practice; (2) enthusiastic feedback from staff who had been involved seemed to encourage other staff to become involved; (3) key implementation challenges included demands of daily work and securing managers' support; (4) ideas for future practice arising from empowerment through VIG seemed difficult to realise within an organizational culture reportedly unreceptive to creative ideas from staff; (5) individuals' emotional responses to implementation seemed beyond the reach of NPT, which focused more upon collective processes. CONCLUSIONS: Implementation of VIG may require recognition that it is not a 'quick fix'. Peer advocacy may be a fruitful implementation strategy. Senior managers may need to experience VIG to develop their understanding so that they can provide appropriate implementation support. NPT may lack specificity to explain how individual agency weaves with collective processes and social systems to embed innovation in routine practice. This exploratory study has provided broad insights into facilitators and barriers to the implementation of an intervention to empower staff within an autism care organization. Further research is needed into similar interventions, including a focus upon staff members' emotional responses and resources, and how such interventions may relate to the culture of the organization in which implementation occurs. PMID- 27769227 TI - Describing the linkages of the immigration, refugees and citizenship Canada permanent resident data and vital statistics death registry to Ontario's administrative health database. AB - BACKGROUND: Ontario, the most populous province in Canada, has a universal healthcare system that routinely collects health administrative data on its 13 million legal residents that is used for health research. Record linkage has become a vital tool for this research by enriching this data with the Immigration, Refugees and Citizenship Canada Permanent Resident (IRCC-PR) database and the Office of the Registrar General's Vital Statistics-Death (ORG VSD) registry. Our objectives were to estimate linkage rates and compare characteristics of individuals in the linked versus unlinked files. METHODS: We used both deterministic and probabilistic linkage methods to link the IRCC-PR database (1985-2012) and ORG-VSD registry (1990-2012) to the Ontario's Registered Persons Database. Linkage rates were estimated and standardized differences were used to assess differences in socio-demographic and other characteristics between the linked and unlinked records. RESULTS: The overall linkage rates for the IRCC PR database and ORG-VSD registry were 86.4 and 96.2 %, respectively. The majority (68.2 %) of the record linkages in IRCC-PR were achieved after three deterministic passes, 18.2 % were linked probabilistically, and 13.6 % were unlinked. Similarly the majority (79.8 %) of the record linkages in the ORG-VSD were linked using deterministic record linkage, 16.3 % were linked after probabilistic and manual review, and 3.9 % were unlinked. Unlinked and linked files were similar for most characteristics, such as age and marital status for IRCC-PR and sex and most causes of death for ORG-VSD. However, lower linkage rates were observed among people born in East Asia (78 %) in the IRCC-PR database and certain causes of death in the ORG-VSD registry, namely perinatal conditions (61.3 %) and congenital anomalies (81.3 %). CONCLUSIONS: The linkages of immigration and vital statistics data to existing population-based healthcare data in Ontario, Canada will enable many novel cross-sectional and longitudinal studies to be conducted. Analytic techniques to account for sub-optimal linkage rates may be required in studies of certain ethnic groups or certain causes of death among children and infants. PMID- 27769226 TI - The effectiveness of a Housing First adaptation for ethnic minority groups: findings of a pragmatic randomized controlled trial. AB - BACKGROUND: Little is known about the effectiveness of Housing First (HF) among ethnic minority groups, despite its growing popularity for homeless adults experiencing mental illness. This randomized controlled trial tests the effectiveness of a HF program using rent supplements and intensive case management, enhanced by anti-racism and anti-oppression practices for homeless adults with mental illness from diverse ethnic minority backgrounds. METHODS: This unblinded pragmatic field trial was carried out in community settings in Toronto, Canada. Participants were 237 adults from ethnic minority groups experiencing mental illness and homelessness, who met study criteria for moderate needs for mental health services. Participants were randomized to either adapted HF (n = 135) or usual care (n = 102) and followed every 3 months for 24 months. The primary study outcome was housing stability; secondary outcomes included physical and mental health, social functioning, quality of life, arrests and health service use. Intention to treat statistical analyses examined the effectiveness of the intervention compared to usual care. RESULTS: During the 24 month study period, HF participants were stably housed a significantly greater proportion of time compared to usual care participants, 75 % (95 % CI 70 to 81) vs. 41 % (95 % CI 35 to 48), respectively, for a difference of 34 %, 95 % CI 25 to 43. HF also led to improvements in community integration over the course of the study: the change in the mean difference between treatment groups from baseline to 24-months was significantly greater among HF participants compared to those in usual care (change in mean difference = 2.2, 95 % CI 0.06 to 4.3). Baseline diagnosis of psychosis was associated with reduced likelihood of being housed >= 50 % of the study period (OR = 0.37, 95 % CI 0.18 to 0.72). CONCLUSION: Housing First enhanced with anti-racism and anti-oppression practices can improve housing stability and community functioning among ethnically diverse homeless adults with mental illness. TRIAL REGISTRATION: International Standard Randomized Control Trial Number Register Identifier: ISRCTN42520374 , assigned August 18, 2009. PMID- 27769228 TI - Quantifying the effect of complications on patient flow, costs and surgical throughputs. AB - BACKGROUND: Postoperative adverse events are known to increase length of stay and cost. However, research on how adverse events affect patient flow and operational performance has been relatively limited to date. Moreover, there is paucity of studies on the use of simulation in understanding the effect of complications on care processes and resources. In hospitals with scarcity of resources, postoperative complications can exert a substantial influence on hospital throughputs. METHODS: This paper describes an evaluation method for assessing the effect of complications on patient flow within a cardiac surgical department. The method is illustrated by a case study where actual patient-level data are incorporated into a discrete event simulation (DES) model. The DES model uses patient data obtained from a large hospital in Oman to quantify the effect of complications on patient flow, costs and surgical throughputs. We evaluated the incremental increase in resources due to treatment of complications using Poisson regression. Several types of complications were examined such as cardiac complications, pulmonary complications, infection complications and neurological complications. RESULTS: 48 % of the patients in our dataset experienced one or more complications. The most common types of complications were ventricular arrhythmia (16 %) followed by new atrial arrhythmia (15.5 %) and prolonged ventilation longer than 24 h (12.5 %). The total number of additional days associated with infections was the highest, while cardiac complications have resulted in the lowest number of incremental days of hospital stay. Complications had a significant effect on perioperative operational performance such as surgery cancellations and waiting time. The effect was profound when complications occurred in the Cardiac Intensive Care (CICU) where a limited capacity was observed. CONCLUSIONS: The study provides evidence supporting the need to incorporate adverse events data in resource planning to improve hospital performance. PMID- 27769229 TI - Herbal remedies and functional foods used by cancer patients attending specialty oncology clinics in Trinidad. AB - BACKGROUND: Cancer is a major disease worldwide, and many patients use complementary and alternative treatments. The purpose of this study was to identify the herbal remedies and functional foods used as complementary medicine by prostate, breast and colorectal cancer patients at speciality care facilities in Trinidad. We also sought to determine how patients rated the efficacy of these modalities compared with conventional treatment. METHODS: A descriptive, cross sectional survey was conducted using an interviewer-administered pilot-tested de novo questionnaire during the period June to August 2012 at two speciality treatment centres on the island. Data was analysed using chi2 analyses. RESULTS: Among the 150 patients who reported use of herbal remedies/functional foods, soursop (Annona muricata L.) was the most popular; with 80.7 % using the leaves, bark, fruit and seeds on a regular basis. Other common herbal remedies/functional foods included wheatgrass (Triticum aestivum L.), saffron (Crocus sativus L.) and Aloe vera (L.) Burm. f. The most commonly used functional foods were beetroot (Beta vulgaris L.), carrots (Daucus carata L.) and papaya (Carica papaya L.) used by 43.3 % of patients; and these were mostly blended as a mixture. Herbal remedies and functional foods were used on a daily basis and patients believed that this modality was equally (32.0 %) or more efficacious (14.7 %) than conventional treatment. CONCLUSIONS: This survey identified the most common herbal remedies and functional foods used among prostate, breast and colorectal cancer patients in Trinidad. Although functional foods rarely pose a problem, herbs may interact with conventional chemotherapy and physicians need to inform patients regarding probable herb-drug interactions. PMID- 27769230 TI - Bypassing birthing centres for child birth: a community-based study in rural Chitwan Nepal. AB - BACKGROUND: Child delivery in a health facility is important to reduce maternal mortality. Bypassing nearby birthing facility to deliver at a hospital is common in developing countries including Nepal. Very little is known about the extent and determinants of bypassing the birthing centres in Nepal. This study measures the status of bypassing, characteristics of bypassers and their reasons for bypassing. METHODS: A community-based cross-sectional study was carried out in six rural village development committees of Chitwan district of Nepal. Structured interviews were conducted with 263 mothers who had given birth at a health facility and whose nearest facility was a birthing centre. Descriptive statistics, univariate and multivariable logistic regression analysis were performed. RESULTS: More than half of the mothers had bypassed the nearer birthing centres to deliver at hospital. Living in plain area [aOR: 2.467; 95 % CI: 1.005-6.058], higher wealth index [aOR: 4.981; 95 % CI: 2.482-9.999], advantaged caste/ethnicity [aOR: 2.172; 95 % CI: 1.153-4.089], older age [aOR: 2.222; 95 % CI: 1.050-4.703] and first birth [aOR: 2.032; 95 % CI: 1.060-3.894] were associated with higher likelihood of bypassing. Among the reasons of bypassing as reported by the bypassers, lack of operation, video x-ray, and blood test facilities were the most common ones, followed by the lack of medicines/drugs and equipment, lack of skilled service provider, and inadequate physical facilities, among others. CONCLUSIONS: Quality of service at the birthing centres needs to be given a high consideration to increase their use as well as to ensure an equitable access to the quality care by all. PMID- 27769231 TI - A dynamic approach to communication in health literacy education. AB - BACKGROUND: Research within the framework of Self-Determination Theory (SDT) indicates that patients' autonomy is to be considered a critical health care outcome in its own right since it promotes improved mental and physical health. This paper presents an analysis of studies addressing communication and interaction interventions in health literacy curricula for medical and health care practitioners, focusing on patient-oriented skills in "making sense" and "to adapt and self-manage". For evaluating interventions, underlying communication models were traced. The criteria for good practice are "making sense" and "supporting autonomy in making choices". For the search of interventions, keywords from both the framework of the EU-project, Intervention Research on Health Literacy among Ageing population (IROHLA (The IROHLA project received financial support from the European Union through FP7 Grant 305831)), as well as the SDT (Self Determination Theory) were applied. The research question of this paper is to what degree is autonomy supporting communication skills part of the curricula of health literacy (HL) for medical and health care practitioners and providers? A Pubmed search revealed: a) that "making sense" is clearly represented in HL interventions in curricula; however, b) very few interventions teach medical and health care practitioners how to give autonomy support in the interaction with their (future) patients. Four promising, beneficial practices were identified. Several recommendations were presented encouraging curriculum developers to adapt skills of supporting autonomy into their programs. METHODS: A qualitative content analysis of interventions in the curricula of communication and interaction skills for medical students and practitioners. RESULTS: A review of literature indicates: a) most interventions in curricula for medical students and practitioners are focusing on skills in adequately providing information to patients by using an underlying (advanced) Sender-Message-Receiver Model; and b) only a few interventions in curricula are available for providing the acquisition of interaction skills in supporting autonomy. CONCLUSIONS: The proposal of Huber and others to change the emphasis in the definition of the WHO definition on health towards "to adapt and self manage" has impact on the training of medical students and practioners in dealing with patients with low levels of health literacy. From the present study it can be concluded that a dynamic approach to communication can be linked to theoretical constructs on self-management. In such an approach interaction techniques like scaffolding can increase the level of HL of the patient. PMID- 27769232 TI - Research in disaster settings: a systematic qualitative review of ethical guidelines. AB - BACKGROUND: Conducting research during or in the aftermath of disasters poses many specific practical and ethical challenges. This is particularly the case with research involving human subjects. The extraordinary circumstances of research conducted in disaster settings require appropriate regulations to ensure the protection of human participants. The goal of this study is to systematically and qualitatively review the existing ethical guidelines for disaster research by using the constant comparative method (CCM). METHODS: We performed a systematic qualitative review of disaster research ethics guidelines to collect and compare existing regulations. Guidelines were identified by a three-tiered search strategy: 1) searching databases (PubMed and Google Scholar), 2) an Internet search (Google), and 3) a search of the references in the included documents from the first two searches. We used the constant comparative method (CCM) for analysis of included guidelines. RESULTS: Fourteen full text guidelines were included for analysis. The included guidelines covered the period 2000-2014. Qualitative analysis of the included guidelines revealed two core themes: vulnerability and research ethics committee review. Within each of the two core themes, various categories and subcategories were identified. CONCLUSIONS: Some concepts and terms identified in analyzed guidelines are used in an inconsistent manner and applied in different contexts. Conceptual clarity is needed in this area as well as empirical evidence to support the statements and requirements included in analyzed guidelines. PMID- 27769233 TI - Informal care and gifts to and from older people in Europe: The interlinks between giving and receiving. AB - BACKGROUND: Transfers of money and help with daily activities by family and friends are important sources of support for older people and contribute to their well being. On the other hand, older adults are not only recipients of support but also important providers of support and financial transfers as giving and receiving are often reciprocal. For this, it is important to understand the determinants of receiving and giving money and help as well as the relationship between these two. METHODS: The aim of this paper is to explore the relationship between giving and receiving of the same or of different types of transfers as well as to get more insights in the motivation behind giving and receiving of money gifts or informal care. We use data from the Survey of Health Aging and Retirement in Europe and employ a multinomial logit model to analyse 16 different categories resulting from combining information on the incidence of giving and receiving of both informal care and financial gifts. RESULTS: We show that despite the differences that exist in the incidence of giving and receiving of both informal care and financial gifts there are clearly a few patterns that are consistent between the European countries in our analysis. Both 'altruistic-like' and 'exchange-like' motives are more likely to increase by age, gender and physical proximity of network members, while 'reciprocal-like' giving and receiving is more likely among females and those with a network at close distance. CONCLUSIONS: Our results show that the incidence of informal care and gifts to and from older people is related to particular characteristics and transfers patterns. Further research should be dedicated to exploring the situations leading to the 'altruistic-like' and 'exchange-like' combinations of transfers. PMID- 27769234 TI - Health system's barriers hindering implementation of public-private partnership at the district level: a case study of partnership for improved reproductive and child health services provision in Tanzania. AB - BACKGROUND: Public-private partnership (PPP) has been suggested as a tool to assist governments in lower to middle income countries fulfil their responsibilities in the efficient delivery of health services. In Tanzania, although the idea of PPP has existed for many years in the health sector, there has been limited coordination, especially at a district level - which has contributed to limited health gains or systems strengthening obviously seen as a result of PPP. METHODS: This case study was conducted in the Bagamoyo district of Tanzania, and employed in-depth interviews, document reviews, and observations methods. A stakeholder analysis was conducted to understand power distribution and the interests of local actors to engage non-state actors. In total 30 in depth interviews were conducted with key informants that were identified from a stakeholder mapping activity. The initial data analysis guided further data collection in an iterative process. The provision of Reproductive and Child Health Services was used as a context. This study draws on the decision-space framework. RESULTS: Study findings reveal several forms of informal partnerships, and the untapped potential of non-state actors. Lack of formal contractual agreements with private providers including facilities that receive subsidies from the government is argued to contribute to inappropriate distribution of risk and reward leading to moral hazards. Furthermore, findings highlight weak capacity of governing bodies to exercise oversight and sanctions, which is acerbated by weak accountability linkages and power differences. Disempowered Council Health Services Board, in relation to engaging non-state actors, is shown to impede PPP initiatives. CONCLUSION: Effective PPP policy implementation at a local level depends on the capacity of local government officials to make choices that would embrace relational elements dynamics in strategic plans. Orientation towards collaborative efforts that create value and enable its distribution is argued to facilitate healthy partnership, and in return, strengthen a district health system. This study highlights a need for new social contracts that will support integrative collaboration at the local level and bring all non-state actors to the centre of the district health system. PMID- 27769235 TI - Health professions' students have an alarming prevalence of depressive symptoms: exploration of the associated factors. AB - BACKGROUND: There is a need to better understand the depression phenomenon and to clarify why some students become depressed and others don't. The purpose of this study was to compare the prevalence of depressive symptoms among health professions' (HP) students, and to explore the association between socio demographic factors (e.g. year of study, discipline, gender) and depressive symptoms. METHODS: In this descriptive-analytic, cross-sectional study, stratified proportionate sampling strategy was used to select the study sample during the academic year 2012-2013. The students from four health professions' schools situated within a large, public university located in Riyadh, Saudi Arabia were screened for depressive symptoms using the 21-item Beck Depression Inventory (BDI II). Chi-square test, student t-test and ANOVA were used to compare different categorical variables. RESULTS: The overall response rate was 79.0 %, the highest among dental students 86.1 %, and lowest among nursing (49.7 %). The overall prevalence rate of depressive symptoms was 47.0 %; it was highest among dentistry students (51.6 %), followed by medicine (46.2 %), applied medical sciences (AMS) (45.7 %) and lowest among nursing students (44.2 %). A statistically significant association was found between the presence and severity of depressive symptoms on one hand and the female gender (p = 0.000) and year of study on the other hand. CONCLUSION: This study seems to indicate an alarming rate of depressive symptoms. Female gender, dentistry, the third year for all schools and fifth year for medicine and dentistry have the highest association with depressive symptoms. Future studies may be needed to explore further the reasons and explanations for the variation in the prevalence of depressive symptoms among these groups. The factors that deserve exploration include curricular variables and personal factors such as the students' study skills. PMID- 27769237 TI - Improving prevention and care for HIV and sexually transmitted infections among men who have sex with men in Cambodia: the sustainable action against HIV and AIDS in communities (SAHACOM). AB - BACKGROUND: The prevalence of HIV and sexually transmitted infections (STIs) among key populations in Cambodia continues to rise. To address this issue, KHANA, the largest national HIV organization in the country developed and implemented the Sustainable Action against HIV and AIDS in Communities (SAHACOM) project. This study aims to determine the impacts of the SAHACOM on sexual behaviors and the uptake of HIV/STI services among men who have sex with men (MSM) in Cambodia. METHODS: We compared outcome indicators at midterm (n = 352) and endline (n = 394). Surveys were conducted in 2012 and 2014 in Battambang and Siem Reap provinces. A two-stage cluster sampling method was employed to select the study sample for structured interviews. RESULTS: The midterm and endline samples were similar. The average number of sexual partners in the past three months decreased significantly from 6.2 to 4.0 (p = 0.03). The proportion of MSM who reported paying for sex with men in the past three months also decreased significantly from 19.0 % to 9.7 % (OR = 2.0, 95 % CI = 1.3-3.0). No significant change was found in condom and lubricant use in all types of relationships. Regarding STIs, 28.1 % of MSM at midterm reported having at least one STI symptom in the past three months compared to 6.1 % at endline (OR = 4.6, 95 % CI = 2.9 7.4); out of them, 14.1 % of MSM at midterm sought treatment compared to 20.7 % at endline (OR = 2.6, 95 % CI = 1.1-6.9). The proportion of MSM who reported using illicit drugs in the past three months also decreased significantly from 12.2 % to 5.1 % (OR = 2.4, 95 % CI = 1.4-4.2). However, the proportion of MSM who reported having been tested for HIV in the past six months decreased significantly from 94.1 % to 77.1 % (OR = 2.9, 95 % CI = 1.8-3.6). CONCLUSIONS: Findings from this study indicate that the SAHACOM was effective in improving sexual behaviors and related health outcomes among MSM under the project. However, it could not increase condom use and HIV testing rates among this key population. Tailored intervention programs are needed to improve condom use and HIV testing among MSM in Cambodia. PMID- 27769236 TI - Adding non-randomised studies to a Cochrane review brings complementary information for healthcare stakeholders: an augmented systematic review and meta analysis. AB - BACKGROUND: To reduce the burden of asthma, chronic disease management (CDM) programmes have been widely implemented and evaluated. Reviews including randomised controlled trials (RCTs) suggest that CDM programmes for asthma are effective. Other study designs are however often used for pragmatic reasons, but excluded from these reviews because of their design. We aimed to examine what complementary information could be retrieved from the addition of non-randomised studies to the studies included in a published Cochrane review on asthma CDM programmes, for healthcare stakeholders involved in the development, implementation, conduct or long-term sustainability of such programmes. METHODS: Extending a previously published Cochrane review, we performed a systematic review (augmented review) including any type of study designs instead of only those initially accepted by Cochrane and the Effective Practice and Organization of Care Review group. After double data selection and extraction, we compared study and intervention characteristics, assessed methodological quality and ran meta-analyses, by study design. RESULTS: We added 37 studies to the 20 studies included in the Cochrane review. The applicability of results was increased because of the larger variety of settings and asthma population considered. Also, adding non-randomised studies provided new evidence of improvements associated with CDM intervention (i.e. healthcare utilisation, days off work, use of action plan). Finally, evidence of CDM effectiveness in the added studies was consistent with the Cochrane review in terms of direction of effects. CONCLUSIONS: The evidence of this augmented review is applicable to a broader set of patients and settings than those in the original Cochrane review. It also strengthens the message that CDM programmes have a beneficial effect on quality of life and disease severity, meaningful outcomes for the everyday life of patients with asthma. Despite the moderate to low methodological quality of all studies included, calling for caution in results interpretation and improvements in CDM evaluation methods and reporting, the inclusion of a broader set of study designs in systematic reviews of complex interventions, such as chronic disease management, is likely to be of high value and interest to patients, policymakers and other healthcare stakeholders. PMID- 27769238 TI - BCM: toolkit for Bayesian analysis of Computational Models using samplers. AB - BACKGROUND: Computational models in biology are characterized by a large degree of uncertainty. This uncertainty can be analyzed with Bayesian statistics, however, the sampling algorithms that are frequently used for calculating Bayesian statistical estimates are computationally demanding, and each algorithm has unique advantages and disadvantages. It is typically unclear, before starting an analysis, which algorithm will perform well on a given computational model. RESULTS: We present BCM, a toolkit for the Bayesian analysis of Computational Models using samplers. It provides efficient, multithreaded implementations of eleven algorithms for sampling from posterior probability distributions and for calculating marginal likelihoods. BCM includes tools to simplify the process of model specification and scripts for visualizing the results. The flexible architecture allows it to be used on diverse types of biological computational models. In an example inference task using a model of the cell cycle based on ordinary differential equations, BCM is significantly more efficient than existing software packages, allowing more challenging inference problems to be solved. CONCLUSIONS: BCM represents an efficient one-stop-shop for computational modelers wishing to use sampler-based Bayesian statistics. PMID- 27769240 TI - Feedback using an ePortfolio for medicine long cases: quality not quantity. AB - BACKGROUND: The evidence for the positive impact of an electronic Portfolio (ePortfolio) on feedback in medicine is mixed. An ePortfolio for medical long cases in a Graduate Medical Program was developed. The purpose of this study was to explore the perceptions of medical students and faculty of the impact of the ePortfolio on the feedback process. METHODS: In total, 130 Year 3 medical students, and six faculty participated in the study. This is a mixed methods study, using a combination of both quantitative and qualitative approaches. Quantitative methods were used to quantify the number of long cases performed. Qualitative methods were used to explore the relationship between quantity and quality of feedback, and provide a rich understanding of both students' and faculty's experience and perceptions of the ePortfolio. RESULTS: Students received a variable quantity of feedback at each of the three studied clinical schools, with an average of between 4 - 5.4 feedback episodes per student. Feedback that was constructive, specific and timely and delivered by a senior academic was important. Quantity was not an essential factor, with two episodes of detailed feedback reported to be adequate. The barriers to the use of the ePortfolio were technical aspects of the platform that interfered with student engagement. CONCLUSIONS: Feedback using the ePortfolio for medical long cases is a valuable tool providing a senior clinician delivers detailed, constructive and personalized feedback in a timely fashion. The ePortfolio system needs to be user friendly to engage students. PMID- 27769239 TI - Obesity and type 2 diabetes in sub-Saharan Africans - Is the burden in today's Africa similar to African migrants in Europe? The RODAM study. AB - BACKGROUND: Rising rates of obesity and type 2 diabetes (T2D) are impending major threats to the health of African populations, but the extent to which they differ between rural and urban settings in Africa and upon migration to Europe is unknown. We assessed the burden of obesity and T2D among Ghanaians living in rural and urban Ghana and Ghanaian migrants living in different European countries. METHODS: A multi-centre cross-sectional study was conducted among Ghanaian adults (n = 5659) aged 25-70 years residing in rural and urban Ghana and three European cities (Amsterdam, London and Berlin). Comparisons between groups were made using prevalence ratios (PRs) with adjustments for age and education. RESULTS: In rural Ghana, the prevalence of obesity was 1.3 % in men and 8.3 % in women. The prevalence was considerably higher in urban Ghana (men, 6.9 %; PR: 5.26, 95 % CI, 2.04-13.57; women, 33.9 %; PR: 4.11, 3.13-5.40) and even more so in Europe, especially in London (men, 21.4 %; PR: 15.04, 5.98-37.84; women, 54.2 %; PR: 6.63, 5.04-8.72). The prevalence of T2D was low at 3.6 % and 5.5 % in rural Ghanaian men and women, and increased in urban Ghanaians (men, 10.3 %; PR: 3.06; 1.73-5.40; women, 9.2 %; PR: 1.81, 1.25-2.64) and highest in Berlin (men, 15.3 %; PR: 4.47; 2.50-7.98; women, 10.2 %; PR: 2.21, 1.30-3.75). Impaired fasting glycaemia prevalence was comparatively higher only in Amsterdam, and in London, men compared with rural Ghana. CONCLUSION: Our study shows high risks of obesity and T2D among sub-Saharan African populations living in Europe. In Ghana, similarly high prevalence rates were seen in an urban environment, whereas in rural areas, the prevalence of obesity among women is already remarkable. Similar processes underlying the high burden of obesity and T2D following migration may also be at play in sub-Saharan Africa as a consequence of urbanisation. PMID- 27769242 TI - Maternal and child health voucher scheme in Myanmar: a review of early stage implementation. AB - BACKGROUND: The Maternal and Child Health Voucher Scheme (MCHVS) was introduced in Myanmar to address the high rate of maternal and infant mortalities. It aimed to increase access to maternal and child health (MCH) services by skilled birth attendants (SBAs) and improve the health of pregnant women and their babies. A study to pilot a voucher scheme was implemented in May 2013 in Yedarshey Township. This paper provides a report on a mid-term review of the programme after 7 months of implementation to determine the outcomes of the programme and its impediments. METHODS: Quantitative and qualitative approaches were used. Secondary quantitative data were analysed in order to measure the coverage and utilisation of the programme. Semi-structured interviews were conducted in groups and individually with 79 key informants to explore qualitative information on voucher communication, beneficiary's identification, voucher distribution, and challenges for beneficiaries and providers under the MCHVS. RESULTS: The results showed that 63 % of eligible pregnant women who registered to the programme received voucher booklets, while the utilisation of most of the MCH services increased over time; in particular, delivery by SBAs increased significantly (P < 0.01) after implementing MCHVS. Overall, the programme was implemented well in terms of promoting and communicating the programme to people in Yedarshey Township. Although a number of targeted poor pregnant women were included in the programme, some beneficiaries were overlooked for a variety of reasons. Nevertheless, both providers and beneficiaries who experienced the MCHVS service utilisation were satisfied with the programme. The evaluation indicated several programme challenges, i.e. external and internal programme communication, voluntary voucher distributor recruitment, incentive and support for voucher distributors, beneficiary screening criteria, and approaches to increase access of services for pregnant women living in remote areas. CONCLUSIONS: Generally, the MCHVS pilot programme is a promising initiative to increase access to and utilisation of the MCH services for pregnant women and their babies in Myanmar. However, increasing coverage of the programme and overcoming the barriers should be considered as high-priority issues that need to be addressed. PMID- 27769241 TI - Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS. AB - BACKGROUND: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS. Berberine, a traditional herbal medicine, is an inhibitor of mTOR signal and an activator for autophagy. Berberine has been implicated in several kinds of diseases, including the neuronal-related pathogenesis, such as Parkinson's, Huntington's and Alzheimer's diseases. However, the therapeutic effect of berberine on FTLD or ALS pathology has never been investigated. RESULTS: Here we studied the molecular mechanism of berberine in cell culture model with TDP-43 proteinopathies, and found that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. And inhibition of autophagy by specific autophagosome inhibitor, 3-MA, reverses the effect of berberine on reducing the accumulation of insoluble TDP-43 and aggregates formation. These results gave us the notion that inhibition of autophagy by 3-MA reverses the effect of berberine on TDP-43 pathogenesis, and activation of mTOR-regulated autophagy plays an important role in berberine-mediated therapeutic effect on TDP-43 proteinopathies. CONCLUSION: We supported an important notion that the traditional herb berberine is a potential alternative therapy for TDP-43-related neuropathology. Here we demonstrated that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. mTOR autophagy signals plays an important role in berberine-mediated autophagic clearance of TDP-43 aggregates. Exploring the detailed mechanism of berberine on TDP-43 proteinopathy provides a better understanding for the therapeutic development in FTLD and ALS. PMID- 27769243 TI - The potential for non-adaptive origins of evolutionary innovations in central carbon metabolism. AB - BACKGROUND: Biological systems are rife with examples of pre-adaptations or exaptations. They range from the molecular scale - lens crystallins, which originated from metabolic enzymes - to the macroscopic scale, such as feathers used in flying, which originally served thermal insulation or waterproofing. An important class of exaptations are novel and useful traits with non-adaptive origins. Whether such origins could be frequent cannot be answered with individual examples, because it is a question about a biological system's potential for exaptation. We here take a step towards answering this question by analyzing central carbon metabolism, and novel traits that allow an organism to survive on novel sources of carbon and energy. We have previously applied flux balance analysis to this system and predicted the viability of 1015 metabolic genotypes on each of ten different carbon sources. RESULTS: We here use this exhaustive genotype-phenotype map to ask whether a central carbon metabolism that is viable on a given, focal carbon source C - the equivalent of an adaptation in our framework - is usually or rarely viable on one or more other carbon sources C new - a potential exaptation. We show that most metabolic genotypes harbor potential exaptations, that is, they are viable on one or more carbon sources C new . The nature and number of these carbon sources depends on the focal carbon source C itself, and on the biochemical similarity between C and C new . Moreover, metabolisms that show a higher biomass yield on C, and that are more complex, i.e., they harbor more metabolic reactions, are viable on a greater number of carbon sources C new . CONCLUSIONS: A high potential for exaptation results from correlations between the phenotypes of different genotypes, and such correlations are frequent in central carbon metabolism. If they are similarly abundant in other metabolic or biological systems, innovations may frequently have non-adaptive ("exaptive") origins. PMID- 27769244 TI - Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells. AB - BACKGROUND: High-grade non-muscle invasive bladder cancer (NMIBC) has a high risk of recurrence and progression to muscle-invasive forms, which seems to be largely related to the presence of tumorigenic stem-like cell populations that are refractory to conventional therapies. Here, we evaluated the therapeutic potential of Natural Killer (NK) cell-based adoptive immunotherapy against chemoresistant bladder cancer stem-like cells (CSCs) in a pre-clinical relevant model, using NK cells from healthy donors and NMIBC patients. METHODS: Cytokine activated NK cells from healthy donors and from high-grade NMIBC patients were phenotypically characterized and assayed in vitro against stem-like and bulk differentiated bladder cancer cells. Stem-like cells were isolated from two bladder cancer cell lines using the sphere-forming assay. The in vivo therapeutic efficacy was evaluated in mice bearing a CSC-induced orthotopic bladder cancer. Animals were treated by intravesical instillation of interleukin-activated NK cells. Tumor response was evaluated longitudinally by non-invasive bioluminescence imaging. RESULTS: NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition. In addition to cell killing, NK cells shifted CSCs towards a more differentiated phenotype, rendering them more susceptible to cisplatin, highlighting the benefits of a possible combined therapy. On the contrary, NK cells from NMIBC patients displayed a low density on NK cytotoxicity receptors, adhesion molecules and a more immature phenotype, losing their ability to kill and drive differentiation of CSCs. The local administration, via the transurethral route, of activated NK cells from healthy donors provides an efficient tumor infiltration and a subsequent robust tumoricidal activity against bladder cancer with high selective cytolytic activity against CSCs, leading to a dramatic reduction in tumor burden from 80 % to complete remission. CONCLUSION: Although pre-clinical, our results strongly suggest that an immunotherapeutic strategy using allogeneic activated NK cells from healthy donors is effective and should be exploited as a complementary therapeutic strategy in high-risk NMIBC patients to prevent tumor recurrence and progression. PMID- 27769245 TI - N-methyl-D-aspartate receptor activation mediates lung fibroblast proliferation and differentiation in hyperoxia-induced chronic lung disease in newborn rats. AB - BACKGROUND: Previous studies have suggested that endogenous glutamate and its N methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions. METHODS: In order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4 days after cessation of hyperoxia exposure (on postnatal day 8). The role of NMDAR activation in hyperoxia-induced lung fibroblast proliferation and differentiation was examined in vitro using primary cells derived from the lungs of 8-day-old Sprague-Dawley rats exposed to hyperoxic conditions. RESULTS: Hyperoxia for 3 days induced acute lung injury in newborn rats. The acute injury almost completely disappeared 4 days after cessation of hyperoxia exposure. However, pulmonary fibrosis, impaired alveolarization, and decreased pulmonary compliance were observed on postnatal days 15 and 22. MK-801 treatment during the recovery period was found to alleviate the chronic damage induced by hyperoxia. Four NMDAR 2 s were found to be upregulated in the lung fibroblasts of newborn rats exposed to hyperoxia. In addition, the proliferation and upregulation of alpha-smooth muscle actin and (pro) collagen I in lung fibroblasts were detected in hyperoxia-exposed rats. MK 801 inhibited these changes. CONCLUSIONS: NMDAR activation mediated lung fibroblast proliferation and differentiation and played a role in the development of hyperoxia-induced chronic lung damage in newborn rats. PMID- 27769247 TI - Coping with worry while waiting for diagnostic results: a qualitative study of the experiences of pregnant couples following a high-risk prenatal screening result. AB - BACKGROUND: It is well documented that pregnant women experience increased worry and uncertainty following a high-risk prenatal screening result. While waiting for diagnostic results this worry continues to linger. It has been suggested that high-risk women put the pregnancy mentally 'on hold' during this period, however, not enough is known about how high-risk women and their partners cope while waiting for diagnostic results. The aim of this study was to identify the strategies employed to cope with worry and uncertainty. METHODS: Qualitative, semi-structured interviews with 16 high-risk couples who underwent diagnostic testing. The couples were recruited at a university hospital fetal medicine unit in Denmark. Data were analysed using thematic analysis. RESULTS: All couples reported feeling worried and sad upon receiving a high-risk screening result. While waiting for diagnostic results, the couples focused on coming to their own understanding of the situation and employed both social withdrawal and social engagement as strategies to prevent worry from escalating. Additionally, couples used gratitude, reassuring reasoning and selective memory as means to maintain hopes for a good outcome. Discussions about what to do in case of an abnormal test result were notably absent in the accounts of waiting. This bracketing of the potential abnormal result allowed the couples to hold on to a 'normal' pregnancy and to employ an 'innocent-till-proven-guilty' approach to their worries about the fetus's health. None of the interviewed couples regretted having prenatal screening and all of them expected to have prenatal screening in a future pregnancy. CONCLUSIONS: The couples in this study did not put the pregnancy mentally 'on hold'. Worry and uncertainty must be understood as managed through a diverse range of practical and emotional strategies that change and overlap in the process of waiting. Clinicians may support appropriate ways of coping with worry and waiting through empathetic and empowering clinical communication. In addition to providing adequate information and presenting options available, clinicians may support high-risk women/couples by encouraging them to seek their own personal understandings and management strategies as a way to gain some control in an uncertain situation. PMID- 27769248 TI - Erratum to: Maternal allergic disease history affects childhood allergy development through impairment of neonatal regulatory T-cells. PMID- 27769246 TI - Predictors of viral suppression and rebound among HIV-positive men who have sex with men in a large multi-site Canadian cohort. AB - BACKGROUND: Gay, bisexual and other men who have sex with men (MSM) are disproportionately affected by HIV in Canada. Combination antiretroviral therapy has been shown to dramatically decrease progression to AIDS, premature death and HIV transmission. However, there are no comprehensive data regarding combination antiretroviral therapy outcomes among this population. We sought to identify socio-demographic and clinical correlates of viral suppression and rebound. METHODS: Our analysis included MSM participants in the Canadian Observational Cohort, a multi-site cohort of HIV-positive adults from Canada's three most populous provinces, aged >=18 years who first initiated combination antiretroviral therapy between 2000 and 2011. We used accelerated failure time models to identify factors predicting time to suppression (2 measures <50 copies/mL >=30 days apart) and subsequent rebound (2 measures >200 copies/mL >=30 days apart). RESULTS: Of 2,858 participants, 2,448 (86 %) achieved viral suppression in a median time of 5 months (Q1-Q3: 3-7 months). Viral suppression was significantly associated with later calendar year of antiretroviral therapy initiation, no history of injection drug use, lower baseline viral load, being on an initial regimen consisting of non-nucleoside reverse-transcriptase inhibitors, and older age. Among those who suppressed, 295 (12 %) experienced viral rebound. This was associated with earlier calendar year of antiretroviral therapy initiation, injection drug use history, younger age, higher baseline CD4 cell count, and living in British Columbia. CONCLUSIONS: Further strategies are required to optimize combination antiretroviral therapy outcomes in men who have sex with men in Canada, specifically targeting younger MSM and those with a history of injection drug use. PMID- 27769249 TI - Multi-dimensional knowledge of malaria among Nigerian caregivers: implications for insecticide-treated net use by children. AB - BACKGROUND: Poor malaria knowledge can negatively impact malaria control programmes. This study evaluates knowledge distribution in the domains of causation, transmission, vulnerability, symptoms, and treatment of malaria. It assesses the association between a caregiver's knowledge about malaria and ownership and use of insecticide-treated nets (ITNs) by children. METHODS: Some 1939 caregivers of young children were recruited through a school-based survey in two Nigerian states. A 20-item, multi-dimensional survey instrument was developed and used to rank each caregiver's knowledge in five dimensions (cause, transmission, vulnerability, symptoms, treatment of malaria). Scores for each domain were used to create an aggregate knowledge score for each caregiver. The outcome measures were ITN ownership, and ITN use the night and week before the study. Regression models were used to evaluate the relationship between caregiver's knowledge (individual domains and aggregate score) and ownership and use of ITN after controlling for likely confounders. RESULTS: The main predictor of ITN use was ITN ownership (r = 0.653; p < 0.001); however, ownership only explains 43 % of variance in net use. Total knowledge index for the study population was significantly associated with both ITN ownership (r = 0.122; p = 0.001) and use (r = 0.095; p = 0.014). The spectrum of caregiver's knowledge of malaria and its causes captured in the various domains was, however, found to be poor. Fifty percent of the respondents knew that malaria is transmitted by female mosquitoes and 65 % still believe that too much exposure to the sun is a risk factor for malaria. Knowledge of populations most vulnerable to malaria (83 %) and knowledge of malaria transmission (32 %) were the domains with the highest and lowest average correct answers. CONCLUSIONS: There is a need to improve ITN coverage in Nigeria as ITN ownership was associated with ITN use. Additionally, treating knowledge as a multi-dimensional phenomenon revealed that a lot of misperceptions about malaria still exist. Distribution of ITNs through the public/private sector may need to be augmented with tailored behavioural change communication to dispel myths and improve the multi-dimensional knowledge of malaria in the local population. PMID- 27769250 TI - Assessment of primary rehabilitation needs in neurological rehabilitation: translation, adaptation and face validity of the Danish version of Rehabilitation Complexity Scale-Extended. AB - BACKGROUND: Assessing primary rehabilitation needs in patients with acquired brain injury is a challenge due to case complexity and the heterogeneity of symptoms after brain injury. The Rehabilitation Complexity Scale-Extended (RCS-E) is an instrument used in assessment of rehabilitation complexity in patients with severe brain injury. The aim of the present study was to translate and test the face validity of the RCS-E as a referral tool for primary rehabilitation. Face validity was tested in a sample of patients with acquired brain injury. METHODS: Ten clinicians and records from 299 patients with acquired brain injury were used in the translation, cross-cultural adaptation and face validation study of the RCS-E. RCS-E was translated into Danish by a standardized forward-backward translation by experts in the field. Face validity was assessed by a multi professional team assessing 299 patients. The team was asked their opinion on whether the RCS-E presents a sufficient description of the patients. RESULTS: The RCS-E was translated according to international guidelines and tested by health professionals; some adaptations were required due to linguistic problems and differences in the national health system structures. The patients in the study had a mean age of 63.9 years (SD 14.7); 61 % were male. We found an excellent face validity with a mean score of 8.2 (SD 0.34) assessed on a 0-10 scale. CONCLUSIONS: The RCS-E demonstrated to be a valid assessment of primary rehabilitation needs in patients with acquired brain injury. Excellent face validity indicates that the RCS-E is feasible for assessing primary rehabilitation needs and the present study suggests its applicability to the Danish health care system. PMID- 27769251 TI - KLHL21, a novel gene that contributes to the progression of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) has very high prevalence and associated-mortality. However, targeted therapies that are currently used in clinical practice for HCC have certain limitations, in part because of the lack of reliable and clinically applicable biomarkers that can be used for diagnosis and prognosis assessments and for the surveillance of treatment effectiveness. METHODS: Meta-analysis was used to analyze the integrated microarray data for global identification of a set of robust biomarkers for HCC. Quantitative RT-PCR (qRT-PCR) was performed to validate the expression levels of selected genes. Gene expression was inhibited by siRNA. CellTiter 96(r) AQueous One Solution Cell Proliferation assays were used to determine cell proliferation, and Transwell assays were used to determine cell migration and invasion potential. RESULTS: Meta-analysis of the expression data provided a gene expression signature from a total of 1525 patients with HCC, showing 1529 up-regulated genes and 478 down regulated genes in cancer samples. The expression levels of genes having strong clinical significance were validated by qRT-PCR using primary HCC tissues and the paired adjacent noncancerous liver tissues. Up-regulation of VPS45, WIPI1, TTC1, IGBP1 and KLHL21 genes and down-regulation of FCGRT gene were confirmed in clinical HCC samples. KLHL21 was the most promising gene for potential use as a bioclinical marker in this analysis. Abrogating expression of it significantly inhibited cell proliferation, migration and invasion. CONCLUSIONS: Our study suggests that KLHL21 is a potential target for therapeutic intervention. Our findings also provide novel candidate genes on a genome-wide scale, which may have significant impact on the design and execution of effective therapy of HCC patients. PMID- 27769252 TI - Genomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism. AB - BACKGROUND: Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. METHODS: Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio(r) 3D Digital PCR System. RESULTS: The meta-analysis identified 373 genome wide significant (p < 5X10-4) genes/loci including 49 genes/loci with deletions and 324 with duplications. Among them, 17 genes with deletion and 1 gene with duplication were identified in CNV-based association results in both Group 1 and Group 2. Only 2 genes (NUCB2 and UPF2) containing deletions passed CNV quality control in both groups and signal intensity visualization examination, but laboratory validation failed to verify these deletions. CONCLUSIONS: Our data do not support that structural variation is a major cause of nonsyndromic cryptorchidism. PMID- 27769253 TI - The role of anti-aquaporin 4 antibody in the conversion of acute brainstem syndrome to neuromyelitis optica. AB - BACKGROUND: Acute brainstem syndrome (ABS) may herald multiple sclerosis (MS), neuromyelitis optica (NMO), or occur as an isolated syndrome. The aquaporin 4 (AQP4)-specific serum autoantibody, NMO-IgG, is a biomarker for NMO. However, the role of anti-AQP4 antibody in the conversion of ABS to NMO is unclear. METHODS: Thirty-one patients with first-event ABS were divided into two groups according to the presence of anti-AQP4 antibodies, their clinical features and outcomes were retrospectively analyzed. RESULTS: Fourteen of 31 patients (45.16 %) were seropositive for NMO-IgG. The 71.43 % of anti-AQP4 (+) ABS patients converted to NMO, while only 11.76 % of anti-AQP4 (-) ABS patients progressed to NMO. Anti AQP4 (+) ABS patients demonstrated a higher IgG index (0.68 +/- 0.43 vs 0.42 +/- 0.13, p < 0.01) and Kurtzke Expanded Disability Status Scale (4.64 +/- 0.93 vs 2.56 +/- 0.81, p < 0.01) than anti-AQP4 (-) ABS patients. Area postrema clinical brainstem symptoms occurred more frequently in anti-AQP4 (+) ABS patients than those in anti-AQP4 (-) ABS patients (71.43 % vs 17.65 %, p = 0.004). In examination of magnetic resonance imaging (MRI), the 78.57 % of anti-AQP4 (+) ABS patients had medulla-predominant involvements in the sagittal view and dorsal predominant involvements in the axial view. CONCLUSIONS: ABS represents an inaugural or limited form of NMO in a high proportion of anti-AQP4 (+) patients. PMID- 27769254 TI - Effects of clobazam for treatment of refractory status epilepticus. AB - BACKGROUND: Clobazam (CLB) is a well characterized antiepileptic drug (AED) that differs from other benzodiazepines by its basic chemical structure and pharmacodynamic properties. Only one previous study examined the efficacy of CLB as add-on therapy in refractory status epilepticus (RSE). METHODS: We analyzed RSE episodes treated in our institution between 2001 and 2012. Successful treatment with CLB was scored if CLB was the last AED added to therapy before RSE termination. We assessed the differences between patients with and without CLB and correlated CLB with outcome. Among patients treated with CLB, we studied responders and non-responders and compared our CLB cohort with recently published data. RESULTS: CLB was part of the AED regimen in 24/70 (34.3 %) RSE episodes. In six of these (25.0 %) RSE resolution was attributed to CLB. Baseline characteristics of episodes with and without CLB treatment showed no significant differences and RSE termination rates were very similar (83.3 % vs. 80.4 %). CLB was administered in clinically more complex RSE with longer RSE duration and worse outcome, but CLB was not related independently to outcome. Comparison of our results with previously published data revealed that baseline characteristics as well as CLB maintenance doses and time of treatment initiation were similar in both cohorts. CLB was less frequently the last AED added to RSE therapy in our patients indicating a lower treatment success rate than previously reported. CONCLUSIONS: CLB represents a reasonable AED and promising add-on agent for treatment of RSE. However, rates of successful CLB response were substantially lower than in a recently published study. Differing RSE characteristics and treatment strategies may account for the discrepancy between study results, as RSE etiologies and seizures types associated with unfavorable prognosis were more common in our cohort, while anesthetics tended to be less frequently applied to achieve seizure control. PMID- 27769256 TI - Copayment and recommended strategies to mitigate its impacts on access to emergency medical services under universal health coverage: a case study from Thailand. AB - BACKGROUND: Although bodies of evidence on copayment effects on access to care and quality of care in general have not been conclusive, allowing copayment in the case of emergency medical conditions might pose a high risk of delayed treatment leading to avoidable disability or death. METHODS: Using mixed-methods approach to draw evidence from multiple sources (over 40,000 records of administrative dataset of Thai emergency medical services, in-depth interviews, telephone survey of users and documentary review), we are were able to shed light on the existence of copayment and its related factors in the Thai healthcare system despite the presence of universal health coverage since 2001. RESULTS: The copayment poses a barrier of access to emergency care delivered by private hospitals despite the policy proclaiming free access and payment. The copayment differentially affects beneficiaries of the major 3 public-health insurance schemes hence inducing inequity of access. CONCLUSIONS: We have identified 6 drivers of the copayment i.e., 1) perceived under payment, 2) unclear operational definitions of emergency conditions or 3) lack of criteria to justify inter hospital transfer after the first 72 h of admission, 4) limited understanding by the service users of the policy-directed benefits, 5) weak regulatory mechanism as indicated by lack of information systems to trace private provider's practices, and 6) ineffective arrangements for inter-hospital transfer. With demand-side perspectives, we addressed the reasons for bypassing gatekeepers or assigned local hospitals. These are the perception of inferior quality of care and age-related tendency to use emergency department, which indicate a deficit in the current healthcare systems under universal health coverage. Finally, we have discussed strategies to address these potential drivers of copayment and needs for further studies. PMID- 27769255 TI - Complement component 3 (C3) expression in the hippocampus after excitotoxic injury: role of C/EBPbeta. AB - BACKGROUND: The CCAAT/enhancer-binding protein beta (C/EBPbeta) is a transcription factor implicated in the control of proliferation, differentiation, and inflammatory processes mainly in adipose tissue and liver; although more recent results have revealed an important role for this transcription factor in the brain. Previous studies from our laboratory indicated that CCAAT/enhancer binding protein beta is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. More recently, we have shown that the complement component 3 gene (C3) is a downstream target of CCAAT/enhancer-binding protein beta and it could be a mediator of the proinflammatory effects of this transcription factor in neural cells. METHODS: Adult male Wistar rats (8-12 weeks old) were used throughout the study. C/EBPbeta+/+ and C/EBPbeta-/- mice were generated from heterozygous breeding pairs. Animals were injected or not with kainic acid, brains removed, and brain slices containing the hippocampus analyzed for the expression of both CCAAT/enhancer-binding protein beta and C3. RESULTS: In the present work, we have further extended these studies and show that CCAAT/enhancer-binding protein beta and C3 co-express in the CA1 and CA3 regions of the hippocampus after an excitotoxic injury. Studies using CCAAT/enhancer-binding protein beta knockout mice demonstrate a marked reduction in C3 expression after kainic acid injection in these animals, suggesting that indeed this protein is regulated by C/EBPbeta in the hippocampus in vivo. CONCLUSIONS: Altogether these results suggest that CCAAT/enhancer-binding protein beta could regulate brain disorders, in which excitotoxic and inflammatory processes are involved, at least in part through the direct regulation of C3. PMID- 27769257 TI - Genetic diversity of the merozoite surface protein-3 gene in Plasmodium falciparum populations in Thailand. AB - BACKGROUND: An effective malaria vaccine is an urgently needed tool to fight against human malaria, the most deadly parasitic disease of humans. One promising candidate is the merozoite surface protein-3 (MSP-3) of Plasmodium falciparum. This antigenic protein, encoded by the merozoite surface protein (msp-3) gene, is polymorphic and classified according to size into the two allelic types of K1 and 3D7. A recent study revealed that both the K1 and 3D7 alleles co-circulated within P. falciparum populations in Thailand, but the extent of the sequence diversity and variation within each allelic type remains largely unknown. METHODS: The msp-3 gene was sequenced from 59 P. falciparum samples collected from five endemic areas (Mae Hong Son, Kanchanaburi, Ranong, Trat and Ubon Ratchathani) in Thailand and analysed for nucleotide sequence diversity, haplotype diversity and deduced amino acid sequence diversity. The gene was also subject to population genetic analysis (F st ) and neutrality tests (Tajima's D, Fu and Li D* and Fu and Li' F* tests) to determine any signature of selection. RESULTS: The sequence analyses revealed eight unique DNA haplotypes and seven amino acid sequence variants, with a haplotype and nucleotide diversity of 0.828 and 0.049, respectively. Neutrality tests indicated that the polymorphism detected in the alanine heptad repeat region of MSP-3 was maintained by positive diversifying selection, suggesting its role as a potential target of protective immune responses and supporting its role as a vaccine candidate. Comparison of MSP-3 variants among parasite populations in Thailand, India and Nigeria also inferred a close genetic relationship between P. falciparum populations in Asia. CONCLUSION: This study revealed the extent of the msp-3 gene diversity in P. falciparum in Thailand, providing the fundamental basis for the better design of future blood stage malaria vaccines against P. falciparum. PMID- 27769258 TI - Reasons for transferral to emergency departments of terminally ill patients - a French descriptive and retrospective study. AB - BACKGROUND: Patients under palliative care and in hospital-at-home services are frequently transferred to emergency departments. We set out to identify the reasons for these presentations to determine the proportion that might be avoidable. METHODS: We conducted a retrospective study by assessment of patient files. We studied admissions to four emergency departments in an area of France (Puy-de-Dome) between September 2011 and August 2013. Reasons for transfer and diagnostic conclusion by emergency doctors were noted. We collected date of admission, time spent, investigations and treatments performed and patients' outcomes after the medical conclusions. We also determined whether patients called the hospital-at-home service before going to the emergency department. From these data we discerned potentially avoidable and unavoidable consultations. RESULTS: We identified 52 transfers of patients from home to emergency departments. The most frequent reasons were: generalized weakness (11 cases), social isolation (8 cases) and end of life (7 cases). For 58 % of presentations, the investigations and treatments performed did not require presentation to an emergency department; 34 % of patients returned home after the visit, 41 % remained for simple observation and 20 % remained to receive special care. Two patients died in the emergency department. In 86 % of cases, presentations occurred when primary care was less readily available, and patients called home care services in only 42 % of cases before going to emergency departments. CONCLUSIONS: Half of the transfers to emergency departments were potentially avoidable for terminally ill patients in home care. To reduce this proportion we need to promote access to primary care, educate patients in hospital-at-home service and train care-givers and doctors in palliative medicine. PMID- 27769260 TI - Submucous uterine adenosarcoma-minimally invasive treatment. AB - BACKGROUND: Uterine adenosarcomas are rare malignant gynaecological tumours. Due to its submucous localization, they can be easily confound with benign tumours like endometrial polyps or submucous myomas. However, the treatment of uterine adenosarcomas requires an oncologic surgical approach. CASE PRESENTATION: In the following case report, we present the minimally invasive treatment of a uterine adenosarcoma by hysteroscopy and laparoscopy in a 37-year-old patient and discuss the special role of hysteroscopy in such cases. CONCLUSIONS: In case of unknown or suspect intrauterine tumours, a diagnostic and operative hysteroscopy with biopsy could be realized prior to laparoscopic hysterectomy especially when the use of a laparoscopic electric morcellation is planned. Thus, a correct oncologic approach can be guaranteed if an adenosarcoma is diagnosed. TRIAL REGISTRATION: ISRCTN. PMID- 27769261 TI - Steroid resistance in COPD is associated with impaired molecular chaperone Hsp90 expression by pro-inflammatory lymphocytes. AB - BACKGROUND: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD. METHODS: Blood was collected from COPD (n = 10) and aged-matched controls (n = 10). To assess response to steroids, cytotoxic mediators, intracellular pro-inflammatory cytokines, CD28, GCR, Hsp70 and Hsp90 were determined in T and NKT-like cells in the presence of +/- 10 MUM prednisolone and 2.5 ng/mL cyclosporine A (binds to GCR-Hsp70/90 complex) using flow cytometry, western blot and fluorescence microscopy. RESULTS: A loss of expression of Hsp90 and GCR from CD28null CD8+ T and NKT-like cells in COPD was noted (Hsp70 unchanged). Loss of Hsp90 expression correlated with the percentage of CD28null CD8+ T and NKT-like cells producing IFNgamma or TNFalpha in all subjects (eg, COPD: R = -0.763, p = 0.007 for T-cell IFNgamma). Up-regulation of Hsp90 and associated decrease in pro-inflammatory cytokine production was found in CD28nullCD8+ T and NKT-like cells in the presence of 10 MUM prednisolone and 2.5 ng/mL cyclosporine A. CONCLUSIONS: Loss of Hsp90 from cytotoxic/pro inflammatory CD28nullCD8+ T and NKT-like cells could contribute to steroid resistance in COPD. Combination prednisolone and low-dose cyclosporine A therapy inhibits these pro-inflammatory cells and may reduce systemic inflammation in COPD. PMID- 27769259 TI - Rapid enzyme regeneration results in the striking catalytic longevity of an engineered, single species, biocatalytic biofilm. AB - BACKGROUND: Engineering of single-species biofilms for enzymatic generation of fine chemicals is attractive. We have recently demonstrated the utility of an engineered Escherichia coli biofilm as a platform for synthesis of 5 halotryptophan. E. coli PHL644, expressing a recombinant tryptophan synthase, was employed to generate a biofilm. Its rapid deposition, and instigation of biofilm formation, was enforced by employing a spin-down method. The biofilm presents a large three-dimensional surface area, excellent for biocatalysis. The catalytic longevity of the engineered biofilm is striking, and we had postulated that this was likely to largely result from protection conferred to recombinant enzymes by biofilm's extracellular matrix. SILAC (stable isotopic labelled amino acids in cell cultures), and in particular dynamic SILAC, in which pulses of different isotopically labelled amino acids are administered to cells over a time course, has been used to follow the fate of proteins. To explore within our spin coated biofilm, whether the recombinant enzyme's longevity might be in part due to its regeneration, we introduced pulses of isotopically labelled lysine and phenylalanine into medium overlaying the biofilm and followed their incorporation over the course of biofilm development. RESULTS: Through SILAC analysis, we reveal that constant and complete regeneration of recombinant enzymes occurs within spin coated biofilms. The striking catalytic longevity within the biofilm results from more than just simple protection of active enzyme by the biofilm and its associated extracellular matrix. The replenishment of recombinant enzyme is likely to contribute significantly to the catalytic longevity observed for the engineered biofilm system. CONCLUSIONS: Here we provide the first evidence of a recombinant enzyme's regeneration in an engineered biofilm. The recombinant enzyme was constantly replenished over time as evidenced by dynamic SILAC, which suggests that the engineered E. coli biofilms are highly metabolically active, having a not inconsiderable energetic demand. The constant renewal of recombinant enzyme highlights the attractive possibility of utilising this biofilm system as a dynamic platform into which enzymes of interest can be introduced in a "plug and-play" fashion and potentially be controlled through promoter switching for production of a series of desired fine chemicals. PMID- 27769262 TI - A treatment planning study of proton arc therapy for para-aortic lymph node tumors: dosimetric evaluation of conventional proton therapy, proton arc therapy, and intensity modulated radiotherapy. AB - BACKGROUND: The purpose of this study is to evaluate the dosimetric benefits of a proton arc technique for treating tumors of the para-aortic lymph nodes (PALN). METHOD: In nine patients, a proton arc therapy (PAT) technique was compared with intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) techniques with respect to the planning target volume (PTV) and organs at risk (OAR). PTV coverage, conformity index (CI), homogeneity index (HI) and OAR doses were compared. Organ-specific radiation induced cancer risks were estimated by applying organ equivalent dose (OED) and normal tissue complication probability (NTCP). RESULTS: The PAT techniques showed better PTV coverage than IMRT and PBT plans. The CI obtained with PAT was 1.19 +/- 0.02, which was significantly better than that for the IMRT techniques. The HI was lowest for the PAT plan and highest for IMRT. The dose to the OARs was always below the acceptable limits and comparable for all three techniques. OED results calculated based on a plateau dose-response model showed that the risk of secondary cancers in organs was much higher when IMRT or PBT were employed than when PAT was used. NTCPs of PAT to the stomach (0.29 %), small bowel (0.69 %) and liver (0.38 %) were substantially lower than those of IMRT and PBT. CONCLUSION: This study demonstrates that there is a potential role for PAT as a commercialized instrument in the future to proton therapy. PMID- 27769263 TI - A multifaceted implementation strategy versus passive implementation of low back pain guidelines in general practice: a cluster randomised controlled trial. AB - BACKGROUND: Guidelines are often slowly adapted into clinical practice. However, actively supporting healthcare professionals in evidence-based treatment may speed up guideline implementation. Danish low back pain (LBP) guidelines focus on primary care treatment of LBP, to reduce referrals from primary care to secondary care. The primary aim of this project was to reduce secondary care referral within 12 weeks by a multifaceted implementation strategy (MuIS). METHODS: In a cluster randomised design, 189 general practices from the North Denmark Region were invited to participate. Practices were randomised (1:1) and stratified by practice size to MuIS (28 practices) or a passive implementation strategy (PaIS; 32 practices). Included were patients with LBP aged 18 to 65 years who were able to complete questionnaires, had no serious underlying pathology, and were not pregnant. We developed a MuIS including outreach visits, quality reports, and the STarT Back Tool for subgrouping patients with LBP. Both groups were offered the usual dissemination of guidelines, guideline-concordant structuring of the medical record, and a new referral opportunity for patients with psycho-social problems. In an intention-to-treat analysis, the primary and secondary outcomes pertained to the patient, and a cost-effectiveness analysis was performed from a healthcare sector perspective. Patients and the assessment of outcomes were blinded. Practices and caregivers delivering the interventions were not blinded. RESULTS: Between January 2013 and July 2014, 60 practices were included, of which 54 practices (28 MuIS, 26 PaIS) included 1101 patients (539 MuIS, 562 PaIS). Follow-up data for the primary outcome were available on 100 % of these patients. Twenty-seven patients (5.0 %) in the MuIS group were referred to secondary care vs. 59 patients (10.5 %) in the PaIS group. The adjusted odds ratio (AOR) was 0.52 [95 % CI 0.30 to 0.90; p = 0.020]. The MuIS was cost-saving L-93.20 (L406.51 vs. L499.71 per patient) after 12 weeks. Conversely, the MuIS resulted in less satisfied patients after 52 weeks (AOR 0.50 [95 % CI 0.31 to 0.81; p = 0.004]). CONCLUSIONS: Using a MuIS changed general practice referral behaviour and was cost effective, but patients in the MuIS group were less satisfied. This study supports the application of a MuIS when implementing guidelines. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01699256. PMID- 27769264 TI - Occupation, industry, and the risk of prostate cancer: a case-control study in Montreal, Canada. AB - BACKGROUND: Age, family history and ancestry are the only recognized risk factors for prostate cancer (PCa) but a role for environmental factors is suspected. Due to the lack of knowledge on the etiological factors for PCa, studies that are both hypothesis-generating and confirmatory are still needed. This study explores relationships between employment, by occupation and industry, and PCa risk. METHODS: Cases were 1937 men aged <=75 years with incident PCa diagnosed across Montreal French hospitals in 2005-2009. Controls were 1994 men recruited concurrently from electoral lists of French-speaking Montreal residents, frequency-matched to cases by age. In-person interviews elicited occupational histories. Unconditional logistic regression estimated odds ratios (OR) and 95 % confidence intervals (CI) for the association between employment across 696 occupations and 613 industries and PCa risk, adjusting for potential confounders. Multinomial logistic models assessed risks by PCa grade. Semi-Bayes (SB) adjustment accounted for the large number of associations evaluated. RESULTS: Consistently positive associations-and generally robust to SB adjustment-were found for occupations in forestry and logging (OR 1.9, 95 % CI: 1.2-3.0), social sciences (OR 1.6, 95 % CI: 1.1-2.2) and for police officers and detectives (OR: 1.8, 95 % CI 1.1-2.9). Occupations where elevated risk of high grade PCa was found included gasoline station attendants (OR 4.3, 95 % CI 1.8-10.4) and textile processing occupations (OR 1.8, 95 % CI 1.1-3.2). Aside from logging, industries with elevated PCa risk included provincial government and financial institutions. Occupations with reduced risk included farmers (OR 0.6, 95 % CI 0.4-1.0) and aircraft maintenance workers (OR 0.1, 95 % CI 0.0-0.7). CONCLUSIONS: Excess PCa risks were observed across several occupations, including predominantly white collar workers. Further analyses will focus on specific occupational exposures. PMID- 27769265 TI - Clinical trials registries are underused in the pregnancy and childbirth literature: a systematic review of the top 20 journals. AB - BACKGROUND: Systematic reviews and meta-analyses that do not include unpublished data in their analyses may be prone to publication bias, which in some cases has been shown to have deleterious consequences on determining the efficacy of interventions. METHODS: We retrieved systematic reviews and meta-analyses published in the past 8 years (January 1, 2007-December 31, 2015) from the top 20 journals in the Pregnancy and Childbirth literature, as rated by Google Scholar's h5-index. A meta-epidemiologic analysis was performed to determine the frequency with which authors searched clinical trials registries for unpublished data. RESULTS: A PubMed search retrieved 372 citations, 297 of which were deemed to be either a systematic review or a meta-analysis and were included for analysis. Twelve (4 %) of these searched at least one WHO-approved clinical trials registry or clinicaltrials.gov. CONCLUSION: Systematic reviews and meta-analyses published in pregnancy and childbirth journals do not routinely report searches of clinical trials registries. Including these registries in systematic reviews may be a promising avenue to limit publication bias if registry searches locate unpublished trial data that could be used in the systematic review. PMID- 27769266 TI - Internet-based cognitive behavioural therapy for subthreshold depression: a systematic review and meta-analysis. AB - BACKGROUND: Subthreshold depression has a considerable impact on individuals' subjective well-being and psychosocial functioning and is a predictor of major depressive disorder. Internet-based cognitive behavioural treatments (iCBTs) have been used to reduce the symptoms of subthreshold depression. This meta-analysis aims to systematically review evidence indicating the efficacy of iCBT programs on the improvement of depressive symptoms in this population. METHODS: Articles published from January 2005 to July 2016 were searched in the following databases: Medline, PubMed, Web of Science, ScienceDirect, PsycArticles and the Cochrane Central Register of Controlled Trials. Only randomized controlled trials comparing the efficacy of iCBT programs with control groups for participants with subthreshold depression were selected. Both quantitative and qualitative analyses were conducted to examine the efficacy of iCBT interventions. RESULTS: Tenarticles from 8 randomized controlled trials were identified in this systematic review. The results suggested that iCBT programs had a superior efficacy compared to results from a non-active control group at the post intervention stage (SMD = - 0.28, CI [- 0.42, - 0.14]; I2 = 49 %). However, evidence on the long-term efficacy of iCBT programs is still insufficient and needs further exploration. CONCLUSION: There has been substantial evidence that iCBT intervention has a superior short-term efficacy compared to the results of control groups, while its long-term efficacy of iCBT for subthreshold depressive symptoms is inconclusive and must be examined in further research. TRIAL REGISTRATION: The protocol of this review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO), Protocol No. CRD42015023390 . PMID- 27769267 TI - Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412. AB - BACKGROUND: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis. RESULTS: We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells. PKC412 reactivated HIV-1 expression in ACH2 cells in a dose- and time-dependent manner. Our results also suggest that the nuclear factor kappaB (NF-kappaB) signaling could be one of cellular pathways activated during PKC412-mediated activation of latent HIV-1 expression. Additionally, combining PKC412 with the HDAC inhibitor vorinostat (VOR) had an additive effect on HIV-1 reactivation in both ACH2 cells and infected resting CD4+ T cells. CONCLUSIONS: These studies provide evidence that PKC412 is a new compound with the potential for optimization as a latency-reactivator to eradicate HIV-1 infection. PMID- 27769268 TI - Second Harmonic Generation microscopy reveals collagen fibres are more organised in the cervix of postmenopausal women. AB - BACKGROUND: During labour, the cervix undergoes a series of changes to allow the passage of the fetoplacental unit. While this visible transformation is well described, the underlying and causative microscopic changes, in which collagen plays a major role, are poorly understood and difficult to visualise. Recent studies in mice and humans have shown that Second Harmonic Generation (SHG) microscopy, a non-destructive imaging technique, can detect changes in the cervical collagen. However, the question of whether SHG can identify changes in the arrangement of cervical collagen at different physiological stages still needs addressing. Therefore, this study aimed to compare the cervical collagen alignment between pre- and postmenopausal women using SHG and to generate proof of-concept data prior to assessing this technique in pregnancy. METHODS: Cervical biopsies from premenopausal (n = 4) and postmenopausal (n = 4) multiparous women undergoing hysterectomy for benign conditions were cross-sectionally scanned using an upright confocal microscope. SHG images were collected in Z-stacks and qualitatively evaluated using semi-quantitative scoring (0-3 in ascending degree of alignment) by assessors who were unaware of the classification of the SHG images, and quantitatively, using 2D Fourier transformation analysis. The dominant orientation and difference in dispersion of collagen fibres in each z stack (X +/- SD) was calculated and compared between groups. RESULTS: Qualitatively, collagen fibres appeared more organised in postmenopausal women, [premenopausal: median 0, range (0-1), postmenopausal: median 1.25, range (1-3); X 2 (df = 5) = 19.35, p = 0.002]. Quantitatively, there was a statistically significant difference in collagen fibre dispersion between premenopausal (5.39 degrees +/- 12.68 degrees ) and postmenopausal women (-1.58 degrees +/- 8.24 degrees ), [Welch's t-test (245.54) = 5.54, p < 0.01], with no significant differences in dispersion within each group [premenopausal, Welch's F (7, 57.23) = 1.84, p = 0.098; postmenopausal, Welch's F (7, 57.28) = 1.39, p = 0.23]. CONCLUSION: These results suggest an increased alignment of cervical collagen in postmenopausal women which may result in increased stiffness and reduced compliance, confirm that SHG microscopy can provide qualitative and quantitative information about cervical collagen orientation without sample preparation, and support further research to explore SHG as a means of assessing cervical remodelling to predict the timing of term and preterm labour. PMID- 27769269 TI - Explaining parent-child (dis)agreement in generic and short stature-specific health-related quality of life reports: do family and social relationships matter? AB - BACKGROUND: In the context of health-related quality of life (HrQoL) assessment in pediatric short stature, the present study aimed to examine the levels of agreement/disagreement between parents' and children's reports of generic and condition-specific HrQoL, and to identify socio-demographic, clinical and psychosocial variables associated with the extent and direction of parent-child discrepancies. METHODS: This study was part of the retest phase of the QoLISSY project, which was a multicenter study conducted simultaneously in France, Germany, Spain, Sweden and UK. The sample comprised 137 dyads of children/adolescents between 8 and 18 years of age, diagnosed with growth hormone deficiency (GHD) or idiopathic short stature (ISS), and one of their parents. The participants completed child- and parent-reported questionnaires on generic (KIDSCREEN-10 Index) and condition-specific HrQoL (QoLISSY Core Module). Children/adolescents also reported on social support (Oslo 3-items Social Support Scale) and parents assessed the parent-child relationships (Parental Role subscale of the Social Adjustment Scale) and burden of short stature on parents (QoLISSY- additional module). RESULTS: The parent-child agreement on reported HrQoL was strong (intraclass correlation coefficients between .59 and .80). The rates of parent-child discrepancies were 61.5 % for generic and 35.2 % for condition-specific HrQoL, with the parents being more prone to report lower generic (42.3 %) and condition-specific HrQoL (23.7 %) than their children. The extent of discrepancies was better explained by family and social relationships than by clinical and socio-demographic variables: poorer parent-child relationships and better children's social support were associated with larger discrepancies in generic HrQoL, while more parental burden was associated with larger discrepancies in condition-specific HrQoL reports. Regarding the direction of discrepancies, higher parental burden was significantly associated with parents' underrating, and better children's social support was significantly associated with parents' overrating of condition-specific HrQoL. CONCLUSIONS: Routine assessment of pediatric HrQoL in healthcare and research contexts should include child- and parent-reported data as complementary sources of information, and also consider the family and social context. PMID- 27769270 TI - Building the capacity of policy-makers and planners to strengthen mental health systems in low- and middle-income countries: a systematic review. AB - BACKGROUND: Little is known about the interventions required to build the capacity of mental health policy-makers and planners in low- and middle-income countries (LMICs). We conducted a systematic review with the primary aim of identifying and synthesizing the evidence base for building the capacity of policy-makers and planners to strengthen mental health systems in LMICs. METHODS: We searched MEDLINE, Embase, PsycINFO, Web of Knowledge, Web of Science, Scopus, CINAHL, LILACS, ScieELO, Google Scholar and Cochrane databases for studies reporting evidence, experience or evaluation of capacity-building of policy makers, service planners or managers in mental health system strengthening in LMICs. Reports in English, Spanish, Portuguese, French or German were included. Additional papers were identified by hand-searching references and contacting experts and key informants. Database searches yielded 2922 abstracts and 28 additional papers were identified. Following screening, 409 full papers were reviewed, of which 14 fulfilled inclusion criteria for the review. Data were extracted from all included papers and synthesized into a narrative review. RESULTS: Only a small number of mental health system-related capacity-building interventions for policy-makers and planners in LMICs were described. Most models of capacity-building combined brief training with longer term mentorship, dialogue and/or the establishment of networks of support. However, rigorous research and evaluation methods were largely absent, with studies being of low quality, limiting the potential to separate mental health system strengthening outcomes from the effects of associated contextual factors. CONCLUSIONS: This review demonstrates the need for partnership approaches to building the capacity of mental health policy-makers and planners in LMICs, assessed rigorously against pre-specified conceptual frameworks and hypotheses, utilising longitudinal evaluation and mixed quantitative and qualitative approaches. PMID- 27769272 TI - Erratum to: A novel mathematical model of ATM/p53/NF-kappaB pathways points to the importance of the DDR switch-off mechanisms. PMID- 27769271 TI - Serologic and genotypic characterization of hepatitis B virus in HIV-1 infected patients from South West and Littoral Regions of Cameroon. AB - BACKGROUND: HBV and HIV share similar transmission routes. Concurrent infection with the two viruses usually results in more severe and progressive liver disease, and a higher incidence of cirrhosis, liver cancer and mortality. Further, this co-infection may lead to cross-resistance between HIV and HBV drugs and increased liver injury, either due to direct hepatotoxicity or drug-related immune-reconstitution hepatitis. These challenges necessitate continuous surveillance for HBV among HIV infected individuals to guide patient management. We conducted this study to understand the serologic and genotypic characteristics of HBV among HIV/HBV infected patients in South West and Littoral Regions of Cameroon. METHODS: Plasma samples were screened for HBsAg, HBeAg, Anti-HBs and anti-HBc using ELISA followed by DNA extraction from all HBsAg positive samples. A 366 bp region covering the overlapping surface/polymerase gene was amplified by a nested PCR and the product sequenced using Big Dye sequencing chemistry. The resulting sequences were then analyzed for genotypes and both escape and drug resistance mutations. RESULTS: Of the 455 samples in this study, 25.5 % (n = 116) were HBsAg positive and 46 of these had their DNA successfully amplified. Genotype E was found in 32 samples (69.6 %) and genotype A in the rest of the samples. Escape mutations associated with failure of diagnosis (Y100C, R122K and Q129H) and with vaccine escape (Q129R and T131N) were detected in varying frequencies in the population. Polymerase mutations implicated in resistance to lamivudine and other L-nucleoside analogues were detected in seven patients (15.2 %), while all the samples lacked mutations associated with resistance to adefovir and tenofovir. CONCLUSIONS: These findings suggest the endemicity of HBV and the predominance of genotypes A and E in the study population. Also, drug resistance findings support the use of tenofovir based ART regimens among HIV/HBV co infected persons. There is need for continuous HBV screening and monitoring in HIV infected individuals in these regions. PMID- 27769273 TI - Communicating BRCA research results to patients enrolled in international clinical trials: lessons learnt from the AGO-OVAR 16 study. AB - BACKGROUND: The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. METHODS: An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may be beneficial to patients and their families. RESULTS: Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. CONCLUSION: This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. TRIAL REGISTRATION: This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees (Additional file 1). PMID- 27769275 TI - Calcium-silicate mesoporous nanoparticles loaded with chlorhexidine for both anti Enterococcus faecalis and mineralization properties. AB - BACKGROUND: In infected periapical tissues, Enterococcus faecalis is one of the most common dominant bacteria. Chlorhexidine has been proved to show strong antibacterial ability against E. faecalis but is ineffective in promoting mineralization for tissues around root apex. Mesoporous calcium-silicate nanoparticles are newly synthesized biomaterials with excellent ability to promote mineralization and carry-release bioactive molecules in a controlled manner. In this study, mesoporous calcium-silicate nanoparticles were functionalized with chlorhexidine and their releasing profile, antibacterial ability, effect on cell proliferation and in vitro mineralization property were evaluated. RESULTS: The chlorhexidine was successfully incorporated into mesoporous calcium-silicate nanoparticles by a mixing-coupling method. The new material could release chlorhexidine as well as Ca2+ and SiO32- in a sustained manner with an alkaline pH value under different conditions. The antimicrobial ability against planktonic E. faecalis was dramatically improved after chlorhexidine incorporation. The nanoparticles with chlorhexidine showed no negative effect on cell proliferation with low concentrations. On dentin slices, the new synthesized material demonstrated a similar inhibitory effect on E. faecalis as the chlorhexidine. After being immersed in SBF for 9 days, numerous apatite crystals could be observed on surfaces of the material tablets. CONCLUSIONS: Mesoporous calcium-silicate nanoparticles loaded with chlorhexidine exhibited release of ions and chlorhexidine, low cytotoxicity, excellent antibacterial ability and in vitro mineralization. This material could be developed into a new effective intra-canal medication in dentistry or a new bone defect filling material for infected bone defects. PMID- 27769274 TI - Impact of imposed exercise on energy intake in children at risk for overweight. AB - BACKGROUND: Exercise not only has a direct effect on energy balance through energy expenditure (EE), but also has an indirect effect through its impact on energy intake (EI). This study examined the effects of acute exercise on daily ad libitum EI in children at risk for becoming overweight due to family history. METHODS: Twenty healthy-weight children (ages 9-12 years, 12 male/8 female) with at least one overweight biological parent (body mass index >= 25 kg/m2) participated. Children reported to the laboratory for one baseline and two experimental visits (EX = exercise, SED = sedentary) each separated by 1 week in a randomized crossover design. Two hours into the EX day session, children exercised at 70 % estimated VO2max for 30 min on a cycle ergometer. Objective EI (kcal) was measured at a standard breakfast (~285 kcal) and ad libitum lunch, snack and dinner. Meals were identical on the EX and SED days. Activity-related EE (kcal) was estimated with accelerometers worn on the non-dominant wrist and ankle. Relative EI (kcal) was computed as the difference between Total EI and Activity-related EE for each testing day. Paired t-tests were performed to test differences in Total EI, Activity-related EE and Relative EI between the EX and SED days. RESULTS: Across all meals, Total EI was not statistically different between the EX and SED days (t = 1.8, p = 0.09). Activity-related EE was greater on the EX day compared to the SED day (t = 10.1, p < 0.001). By design, this difference was predominantly driven by activity during the morning (t = 20.4, p < 0.001). Because children consumed a similar number of kcal on each day, but had greater Activity-related EE on the EX day, Relative EI was lower (t = -5.15, p < 0.001) for the EX day (1636 +/- 456 kcal) relative to the SED day (1862 +/- 426 kcal). CONCLUSIONS: Imposed exercise was effective in reducing Relative EI compared to being sedentary. Morning exercise may help children at risk for becoming overweight to better regulate their energy balance within the course of a day. PMID- 27769276 TI - Quality of life of residents living in a city hosting mega-sport events: a longitudinal study. AB - BACKGROUND: It remains unknown whether and when the hosting of mega-sport events increases quality of life of host city residents. The aim of this study is to assess the changes in quality of life of host city residents over the course of hosting a mega-sport event until three months after the event, depending on residents' perception of the atmosphere during the event. METHODS: The study was conducted in Rio de Janeiro, one of the host cities of the 2014 FIFA World Cup in soccer. Participants were recruited from a Brazilian market research agency's panel and surveyed online. The WHOQOL-BREF was used to measure quality of life of residents of Rio de Janeiro (n = 281) in three waves in the context of the 2014 FIFA World Cup. Perceived atmosphere at the event was measured via an established scale. Piecewise latent growth models were used to analyze individual changes in the four domains of quality of life per se and depending on perceived atmosphere. RESULTS: There was no change in quality of life with respect to physical, social, psychological, and environmental health for all participants during the course of the event. However, residents who perceived a positive atmosphere rated the social and environmental domains of quality of life more positively right after the end (vs. at the beginning) of the World Cup. This increase sustained until three months after the event. Physical health (particularly at high levels of perceived atmosphere) and psychological health decreased from right after the event until three months after. CONCLUSIONS: There was no positive effect of the hosting of the mega-sport event on the four quality of life domains of the panel members (who were residents of a city hosting a mega-sport event) per se. The individual changes in quality of life vary by perception of atmosphere and by domain of quality of life. PMID- 27769277 TI - Pedometer-determined physical activity among youth in the Tokyo Metropolitan area: a cross-sectional study. AB - BACKGROUND: Providing large-scale descriptive data of objectively measured physical activity in youth is informative for practitioners, epidemiologists, and researchers. The purpose of this study was to present the pedometer-determined physical activity among Japanese youth using the Tokyo Metropolitan Survey of Physical Fitness, Physical Activity and Lifestyle 2011. METHODS: This study used a school-based survey. The Tokyo Metropolitan Board of Education originally collected pedometer-determined steps per day in the fall of 2011. Data were collected from 15,471 youth aged 6 to 18 years living in Tokyo. Participants were asked to wear pedometers for 14 consecutive days, and daily steps logged in the final 7 days were selected for this analysis. RESULTS: At the primary and junior high school levels, boys (12,483 and 9476, respectively) had a significantly higher mean number of steps per day than did girls (10,053 and 8408, respectively). There was no significant difference in the mean number of steps per day between the sexes at the high school level. Mean steps per day decreased consistently with age and grade level; the lowest overall steps per day was observed in the last year of junior high school, although there was a slight increase in the subsequent year, the first year of high school. CONCLUSIONS: This study demonstrates a trend toward reduced physical activity with age in Japanese youth and a substantial difference in the number of steps per day between boys and girls in Tokyo. The age-related reduction in steps per day was greater in boys because they attained a higher peak value prior to this reduction, and sex related differences in the step count disappeared in high school students. PMID- 27769279 TI - Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties? AB - BACKGROUND: After focused high dose radiotherapy of brain metastases, differentiation between tumor recurrence and radiation-induced lesions by conventional MRI is challenging. This study investigates the usefulness of dynamic O-(2-18F-Fluoroethyl)-L-Tyrosine positron emission tomography (18F-FET PET) in patients with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy of brain metastases. METHODS: Twenty-two patients with 34 brain metastases (median age 61.9 years) were included. Due to follow-up scan evaluations after repeated treatment in a subset of patients, a total of 50 lesions with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy could be evaluated. 18F-FET PET analysis included the assessment of maximum and mean tumor-to-background ratio (TBRmax and TBRmean) and analysis of time-activity-curves (TAC; increasing vs. decreasing) including minimal time-to peak (TTPmin). PET parameters were correlated with histological findings and radiological-clinical follow-up evaluation. RESULTS: Tumor recurrence was found in 21/50 cases (15/21 verified by histology, 6/21 by radiological-clinical follow up) and radiation-induced changes in 29/50 cases (5/29 verified by histology, 24/29 by radiological-clinical follow-up). Median clinical-radiological follow-up was 28.3 months (range 4.2-99.1 months). 18F-FET uptake was higher in tumor recurrence compared to radiation-induced changes (TBRmax 2.9 vs. 2.0, p < 0.001; TBRmean 2.2 vs. 1.7, p < 0.001). Receiver-operating-characteristic (ROC) curve analysis revealed optimal cut-off values of 2.15 for TBRmax and 1.95 for TBRmean (sensitivity 86 %, specificity 79 %). Increasing TACs and long TTPmin were associated with radiation-induced changes, decreasing TACs with tumor recurrence (p = 0.01). By combination of TBR and TACs, sensitivity and specificity could be increased to 93 and 84 %. CONCLUSIONS: In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions. PMID- 27769278 TI - Evaluation of three enzyme-linked immunosorbent assays for sarcoptic mange diagnosis and assessment in the Iberian ibex, Capra pyrenaica. AB - BACKGROUND: Sarcoptic mange is a contagious skin disease caused by the mite Sarcoptes scabiei, affecting different mammalian species worldwide including the Iberian ibex (Capra pyrenaica), in which mortalities over 90 % of the population have been reported. No efficient diagnostic methods are available for this disease, particularly when there are low mite numbers and mild or no clinical signs. In this study, three enzyme-linked immunosorbent assays (ELISA) developed for dog (ELISA A), Cantabrian chamois (Rupicapra pyrenaica parva) (ELISA B) and Alpine chamois (Rupicapra rupicapra) (ELISA C), were evaluated to detect specific antibodies (IgG) to sarcoptic mange in Iberian ibex sera. METHODS: Serum samples from 131 Iberian ibexes (86 healthy and 45 scabietic) were collected from 2005 to 2012 in the Sierra Nevada Natural and National Parks (southern Spain). Based on visual inspection, ibexes were classified into one of three categories, namely healthy (without scabietic compatible lesions), mildly affected (skin lesions over less than 50 % of the body surface) and severely affected (skin lesions over more than 50 % of the body surface). The optimal cut-off point, specificity, sensitivity and the area under the curve (AUC) were calculated, and the agreement between tests was determined. Moreover, differences in the optical density (OD) related to scabies severity have been evaluated for the best test. RESULTS: ELISA C showed better performance than the two other tests, reaching higher values of sensitivity (93.0 %) and specificity (93.5 %) against the visual estimation of the percentage of affected skin, chosen as the gold standard. Significantly higher concentrations of specific antibodies were observed with this test in the mildly and severely infested ibexes than in healthy ones. CONCLUSIONS: Our results revealed that ELISA C was an optimal test to diagnose sarcoptic mange in the Iberian ibex. Further studies characterizing immune response during the course of the disease, including spontaneous or drug induced recovery, should follow in order to better understand sarcoptic mange in Iberian ibex populations. PMID- 27769280 TI - Generalized method of moments for estimating parameters of stochastic reaction networks. AB - BACKGROUND: Discrete-state stochastic models have become a well-established approach to describe biochemical reaction networks that are influenced by the inherent randomness of cellular events. In the last years several methods for accurately approximating the statistical moments of such models have become very popular since they allow an efficient analysis of complex networks. RESULTS: We propose a generalized method of moments approach for inferring the parameters of reaction networks based on a sophisticated matching of the statistical moments of the corresponding stochastic model and the sample moments of population snapshot data. The proposed parameter estimation method exploits recently developed moment based approximations and provides estimators with desirable statistical properties when a large number of samples is available. We demonstrate the usefulness and efficiency of the inference method on two case studies. CONCLUSIONS: The generalized method of moments provides accurate and fast estimations of unknown parameters of reaction networks. The accuracy increases when also moments of order higher than two are considered. In addition, the variance of the estimator decreases, when more samples are given or when higher order moments are included. PMID- 27769281 TI - Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum. AB - BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. METHODS: We describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months. RESULTS: MRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased. CONCLUSIONS: Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms. PMID- 27769282 TI - Comparing the effectiveness of the BPMAP (Blood Pressure Management Application) and usual care in self-management of primary hypertension and adherence to treatment in patients aged 30-60 years: study protocol for a randomized controlled trial. AB - BACKGROUND: Hypertension is one of the most important and well-known risk factors for cardiovascular diseases. Unfortunately, in spite of effective treatments, adherence to the regular use of drugs and other nondrug treatments, such as lifestyle improvement, is often poor. This study evaluates the effectiveness of an educational, supportive intervention - in the form of a Blood Pressure Management Application (BPMAP) - on self-management in patients with primary hypertension on controlling the determinant factors of hypertension, and on adherence to treatment. METHODS/DESIGN: A two-arm, parallel-design randomized controlled clinical trial will be conducted on 30 to 60 year-old patients with primary hypertension who are attending the Tehran Heart Center. One hundred and thirty-two (132) patients will be randomly assigned to the intervention and control (usual method) groups. The most important inclusion criteria are, having primary hypertension and being pharmacologically treated for it, and not having developed the complications of hypertension, such as myocardial infarction, cerebral stroke and cardiac insufficiency. The participants should be able to read Persian and be able to use the application. The most important outcomes of the study include adherence to treatment, weight control, and regular monitoring of blood pressure which are assessed in the primary assessment (baseline data questionnaire) and again at the 8th and 24th weeks. The intervention is a mobile application that has capabilities such as reminders and scientific and supportive information. DISCUSSION: This application has been programmed to reduce many of the nonadherence factors of hypertension treatment. Therefore, the findings may contribute to a rise in adherence to treatment. If proven to have an appropriate impact, it may be extended for use in the national hypertension control plan. TRIAL REGISTRATION: This study was registered in the Iran Randomized Clinical Trial Center under the number IRCT2015111712211N2 on 1 January 2016. PMID- 27769283 TI - Behavioral and molecular studies of quantitative differences in hygienic behavior in honeybees. AB - BACKGROUND: Hygienic behavior (HB) enables honeybees to tolerate parasites, including infection with the parasitic mite Varroa destructor, and it is a well known example of a quantitative genetic trait. The understanding of the molecular processes underpinning the quantitative differences in this behavior remains limited. RESULTS: We performed gene expression studies in worker bees that displayed quantitative genetic differences in HB. We established a high and low genetic source of HB performance and studied the engagements into HB of single worker bees under the same environmental conditions. We found that the percentage of worker bees that engaged in a hygienic behavioral task tripled in the high versus low HB sources, thus suggesting that genetic differences may mediate differences in stimulated states to perform HB. We found 501 differently expressed genes (DEGs) in the brains of hygienic and non-hygienic performing workers in the high HB source bees, and 342 DEGs in the brains of hygienic performing worker bees, relative to the gene expression in non-hygienic worker bees from the low HB source group. "Cell surface receptor ligand signal transduction" in the high and "negative regulation of cell communication" in the low HB source were overrepresented molecular processes, suggesting that these molecular processes in the brain may play a role in the regulation of quantitative differences in HB. Moreover, only 21 HB-associated DEGs were common between the high and low HB sources. CONCLUSIONS: The better HB colony performance is primarily achieved by a high number of bees engaging in the hygienic tasks that associate with distinct molecular processes in the brain. We propose that different gene products and pathways may mediate the quantitative genetic differences of HB. PMID- 27769284 TI - The effect of berberine on insulin resistance in women with polycystic ovary syndrome: detailed statistical analysis plan (SAP) for a multicenter randomized controlled trial. AB - BACKGROUND: Although Traditional Chinese Medicine (TCM) has been widely used in clinical settings, a major challenge that remains in TCM is to evaluate its efficacy scientifically. This randomized controlled trial aims to evaluate the efficacy and safety of berberine in the treatment of patients with polycystic ovary syndrome. In order to improve the transparency and research quality of this clinical trial, we prepared this statistical analysis plan (SAP). METHODS: The trial design, primary and secondary outcomes, and safety outcomes were declared to reduce selection biases in data analysis and result reporting. We specified detailed methods for data management and statistical analyses. Statistics in corresponding tables, listings, and graphs were outlined. DISCUSSION: The SAP provided more detailed information than trial protocol on data management and statistical analysis methods. Any post hoc analyses could be identified via referring to this SAP, and the possible selection bias and performance bias will be reduced in the trial. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, NCT01138930 , registered on 7 June 2010. PMID- 27769285 TI - Eliminate now: seven critical actions required to accelerate elimination of Plasmodium falciparum malaria in the Greater Mekong Subregion. AB - The emergence in 2009 of Plasmodium falciparum parasites resistant to the primary therapies currently in use (artemisinin-based combination therapy, ACT) in Southeast Asia threatens to set back decades of global progress in malaria control and elimination. Progress to date through multiple sets of initiatives and partners to contain or eliminate these parasites has been hampered due to a wide range of organizational, financial, and health systems-level challenges. In this commentary, a set of seven specific and concrete actions are proposed to directly address these issues and to accelerate P. falciparum elimination within the Greater Mekong Subregion to avert a wider public health crisis. These actions are specifically needed to elevate the situation and response mechanisms to those of a true emergency; to address systems-level challenges with personnel limitations and stock-outs of key commodities; and to restructure the response mechanisms to be well-aligned with the required outcomes. Consideration of these issues is especially pressing with planning meetings for renewal of the Regional Artemisinin-resistance Initiative (RAI) framework slated for late 2016 and into 2017, but these suggestions are also relevant for malaria programmes globally. PMID- 27769287 TI - Effects of Rho1, a small GTPase on the production of recombinant glycoproteins in Saccharomyces cerevisiae. AB - BACKGROUND: To humanize yeast N-glycosylation pathways, genes involved in yeast specific hyper-mannosylation must be disrupted followed by the introduction of genes catalyzing the synthesis, transport, and addition of human sugars. However, deletion of these genes, for instance, OCH1, which initiates hyper-mannosylation, could cause severe defects in cell growth, morphogenesis and response to environmental challenges. RESULTS: In this study, overexpression of RHO1, which encodes the Rho1p small GTPase, is confirmed to partially recover the growth defect of Saccharomyces cerevisiae Deltaalg3Deltaoch1 double mutant strain. In addition, transmission electron micrographs indicated that the cell wall structure of RHO1-expressed cells have an enhanced glucan layer and also a recovered mannoprotein layer, revealing the effect of Rho1p GTPase on cell wall biosynthesis. Similar complementation phenotypes have been confirmed by overexpression of the gene that encodes Fks2 protein, a catalytic subunit of a 1,3-beta-glucan synthase. Besides the recovery of cell wall structure, the RHO1 overexpressed Deltaalg3Deltaoch1 strain also showed improved abilities in temperature tolerance, osmotic potential and drug sensitivity, which were not observed in the Deltaalg3Deltaoch1-FKS2 cells. Moreover, RHO1 overexpression could also increase N-glycan site occupancy and the amount of secreted glycoproteins. CONCLUSIONS: Overexpression of RHO1 in 'humanized' glycoprotein producing yeasts could significantly facilitate its future industrial applications for the production of therapeutic glycoproteins. PMID- 27769286 TI - Relationship between Advanced Glycation End Products and Steroidogenesis in PCOS. AB - BACKGROUND: Women with PCOS have elevated levels of the harmful Advanced Glycation End Products (AGEs), which are highly reactive molecules formed after glycation of lipids and proteins. Additionally, AGEs accumulate in the ovaries of women with PCOS potentially contributing to the well-documented abnormal steroidogenesis and folliculogenesis. MAIN BODY: A systematic review of articles and abstracts available in PubMed was conducted and presented in a systemic manner. This article reports changes in steroidogenic enzyme activity in granulosa and theca cells in PCOS and PCOS-models. It also described the changes in AGEs and their receptors in the ovaries of women with PCOS and presents the underlying mechanism(s) whereby AGEs could be responsible for the PCOS-related changes in granulosa and theca cell function thus adversely impacting steroidogenesis and follicular development. AGEs are associated with hyperandrogenism in PCOS possibly by altering the activity of various enzymes such as cholesterol side-chain cleavage enzyme cytochrome P450, steroidogenic acute regulatory protein, 17alpha-hydroxylase, and 3beta-hydroxysteroid dehydrogenase. AGEs also affect luteinizing hormone receptor and anti-Mullerian hormone receptor expression as well as their signaling pathways in granulosa cells. CONCLUSIONS: A better understanding of how AGEs alter granulosa and theca cell function is likely to contribute meaningfully to a conceptual framework whereby new interventions to prevent and/or treat ovarian dysfunction in PCOS can ultimately be developed. PMID- 27769288 TI - Comparing routine administrative data with registry data for assessing quality of hospital care in patients with myocardial infarction using deterministic record linkage. AB - BACKGROUND: Assessment of quality of care in patients with myocardial infarction (MI) should be based on data that effectively enable determination of quality. With the need to simplify measurement techniques, the question arises whether routine data can be used for this purpose. We therefore compared data from a German sickness fund (AOK) with data from the Berlin Myocardial Infarction Registry (BMIR). METHODS: We included patients hospitalised for treatment of MI in Berlin from 2009-2011. We matched 2305 patients from AOK and BMIR by using deterministic record linkage with indirect identifiers. For matched patients we compared the frequency in documentation between AOK and BMIR for quality assurance variables and calculated the kappa coefficient (KC) as a measure of agreement. RESULTS: There was almost perfect agreement in documentation between AOK and BMIR data for matched patients for: catheter laboratory (KC: 0.874), ST elevation MI (KC: 0.826), diabetes (KC: 0.818), percutaneous coronary intervention (KC: 0.860) and hospital mortality (KC: 0.952). The remaining variables compared showed moderate or less than moderate agreement (KC < 0.6), and were grouped in Category II with less frequent documentation in AOK for risk factors and aspects of patients' history; in Category III with more frequent documentation in AOK for comorbidities; and in Category IV for medication at and after hospital discharge. CONCLUSIONS: Routine data are primarily collected and defined for reimbursement purposes. Quality assurance represents merely a secondary use. This explains why only a limited number of variables showed almost perfect agreement in documentation between AOK and BMIR. If routine data are to be used for quality assessment, they must be constantly monitored and further developed for this new application. Furthermore, routine data should be complemented with registry data by well-established methods of record linkage to realistically reflect the situation - also for those quality-associated variables not collected in routine data. PMID- 27769289 TI - Effects of oily fish intake on cardiovascular risk markers, cognitive function, and behavior in school-aged children: study protocol for a randomized controlled trial. AB - BACKGROUND: Most children in Western populations do not meet recommendations for fish consumption. Oily fish is an important source of n-3 long-chain polyunsaturated fatty acids (LCPUFA), which reduce blood pressure and plasma triacylglycerol in adults and may affect cognitive development and behavior. However, to our knowledge, the potential effects of oily fish on cardiometabolic health, cognitive function, and behavior in children have not been investigated. The aim of the FiSK Junior study is to investigate the effects of oily fish consumption on cardiovascular risk markers, cognitive function, and behavior in healthy children. METHODS/DESIGN: We are conducting a randomized controlled trial with 8- to 9-year-old Danish children, comparing the effect of consuming 300 g/week of oily fish with poultry (control) for 12 weeks between August 2016 and June 2017. The primary outcomes are blood pressure and fasting plasma triacylglycerol, which will be measured at baseline and endpoint. In addition, we will assess erythrocyte fatty acid composition (compliance), heart rate, plasma cholesterol, markers of glucose homeostasis, growth and body composition, dietary intake, and physical activity and sleep. We will also examine effects on cognitive function (attention, memory, and executive functions) by using standardized tests, behavior and emotions by administering parent-rated questionnaires and child interviews, and we will measure physiological stress response and cortisol levels. We need 150 children to complete the trial to detect a between-groups difference of 2.7 mmHg in diastolic blood pressure and 0.13 mmol/L in plasma triacylglycerol; thus, we aim to recruit 200 children. All outcomes will be analyzed in completer analysis supplemented with sensitivity analyses for the primary outcomes, and attention will be given to potential sex and genotype specificity. DISCUSSION: The results of the FiSK Junior study are expected to fill important gaps in the current knowledge about the importance of dietary fish and n-3 LCPUFA for children's health and development, and may be used when setting dietary recommendations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02809508 . Registered on 22 June 2016. PMID- 27769290 TI - IPC - Isoelectric Point Calculator. AB - BACKGROUND: Accurate estimation of the isoelectric point (pI) based on the amino acid sequence is useful for many analytical biochemistry and proteomics techniques such as 2-D polyacrylamide gel electrophoresis, or capillary isoelectric focusing used in combination with high-throughput mass spectrometry. Additionally, pI estimation can be helpful during protein crystallization trials. RESULTS: Here, I present the Isoelectric Point Calculator (IPC), a web service and a standalone program for the accurate estimation of protein and peptide pI using different sets of dissociation constant (pKa) values, including two new computationally optimized pKa sets. According to the presented benchmarks, the newly developed IPC pKa sets outperform previous algorithms by at least 14.9 % for proteins and 0.9 % for peptides (on average, 22.1 % and 59.6 %, respectively), which corresponds to an average error of the pI estimation equal to 0.87 and 0.25 pH units for proteins and peptides, respectively. Moreover, the prediction of pI using the IPC pKa's leads to fewer outliers, i.e., predictions affected by errors greater than a given threshold. CONCLUSIONS: The IPC service is freely available at http://isoelectric.ovh.org Peptide and protein datasets used in the study and the precalculated pI for the PDB and some of the most frequently used proteomes are available for large-scale analysis and future development. REVIEWERS: This article was reviewed by Frank Eisenhaber and Zoltan Gaspari. PMID- 27769291 TI - Unusual sub-genus associations of faecal Prevotella and Bacteroides with specific dietary patterns. AB - BACKGROUND: Diet has a recognized effect in shaping gut microbiota. Many studies link an increase in Prevotella to high-fibre diet, while Bacteroides abundance is usually associated with the consumption of animal fat and protein-rich diets. Nevertheless, closely related species and strains may harbour different genetic pools; therefore, further studies should aim to understand whether species of the same genus are consistently linked to dietary patterns or equally responsive to diet variations. Here, we used oligotyping of 16S rRNA gene sequencing data to exploit the diversity within Prevotella and Bacteroides genera in faecal samples of omnivore and non-omnivore subjects from a previously studied cohort. RESULTS: A great heterogeneity was found in oligotype composition. Nevertheless, different oligotypes within the same genus showed distinctive correlation patterns with dietary components and metabolome. We found that some Prevotella oligotypes are significantly associated with the plant-based diet but some are associated with animal-based nutrients, and the same applies to Bacteroides. Therefore, an indiscriminate association of Bacteroidetes genera with specific dietary patterns may lead to an oversimplified vision that does not take into account sub-genus diversity and the different possible responses to dietary components. CONCLUSIONS: We demonstrated that Prevotella and Bacteroides oligotypes show distinctive correlation patterns with dietary components and metabolome. These results substantiate a current oversimplification of diet-dependent microbe-host associations and highlighted that sub-genus differences must be taken into account when planning gut microbiota modulation for health benefits. PMID- 27769292 TI - Exceptionally long-range haplotypes in Plasmodium falciparum chromosome 6 maintained in an endemic African population. AB - BACKGROUND: Previous genome-wide analyses of single nucleotide variation in Plasmodium falciparum identified evidence of an extended haplotype region on chromosome 6 in West Africa, suggesting recent positive selection. Such a pattern is not seen in samples from East Africa or South East Asia, so it could be marking a selective process specific to West Africa. Analyses of the haplotype structure in samples taken at different times could give clues to possible causes of selection. METHODS: This study investigates chromosome 6 extended haplotypes in The Gambia by analysing alleles at multiple microsatellite loci using genome sequence data previously obtained from clinical isolates collected in 2008, followed by genotyping of 13 loci in 439 isolates from 1984, 1991, 2008 and 2014. Temporal changes in haplotype structure and frequencies were determined. RESULTS: A region of high linkage disequilibrium spanning over 170 kilobases (kb) was identified with both NGS and laboratory determined microsatellite alleles. Multiple long haplotypes were found in all temporal populations from The Gambia. Two of the haplotypes were detected in samples from 1984 and 1991. The frequency of long-range haplotypes increased in 2008 and 2014 populations. There was higher Fst between older and more recent populations at loci in proximity to genes involved in drug metabolism pathways. CONCLUSIONS: The occurrence of several long haplotypes at intermediate frequencies suggests an unusual mode of selection in chromosome 6, possibly combined with recombination suppression on specific haplotypes. Such selection apparently occurred before the emergence of known anti malarial drug resistance alleles, and could be due to effects of other drugs or unknown processes that have long been operating in this endemic region. PMID- 27769293 TI - BRACAVENIR - impact of a psychoeducational intervention on expectations and coping in young women (aged 18-30 years) exposed to a high familial breast/ovarian cancer risk: study protocol for a randomized controlled trial. AB - BACKGROUND: Young women exposed to a high hereditary breast and ovarian cancer (HBOC) risk are particularly vulnerable. They are ignored by health prevention measures but exposed to a stream of contradictory information (medicine, media, Internet). They may feel concerned about surgical prevention issues at a key moment of their identity construction (self, relationship, sexuality). We designed a special psychoeducational intervention to help these women cope better with these difficulties. METHODS/DESIGN: The BRACAVENIR study consists of a prospective, randomized superiority phase II trial with a wait list control group. Participants are childless young female counselees (aged 18-30 years) seen at the oncogenetics department of the Centre Jean Perrin and belonging to HBOC families either with or without BRCA mutations. They will be invited to attend a weekend group session at a spa resort and to participate in short expert conferences and focus group activities (group sharing, Moreno role game) supervised by a psychotherapist. Two sessions separated by a 6-month delay (wait list) will enable us to evaluate the intervention's effect by comparing questionnaire scores between the 6-month time points. The main endpoint is an increase of the Herth Hope Index by at least 1 SD. Secondary endpoints are self esteem, anxiety trait, anxiety state, coping, and quality of life. With a one sided alpha = 0.05 and beta = 0.20, 12 participants will be needed by group, plus an additional 2 in anticipation of dropouts. Participants will be randomized 1:1 to the first or the second session so that the groups will be comparable. DISCUSSION: The intent of this trial is to bridge the gap on a psychosocial level in these young women with HBOC. A particularity of the design is the use of a waiting list, which should allow for avoiding major bias. The intervention consists of a short session that could be proposed to other young counselees if successful. The results may bring complementary information to facilitate the intervention and also influence the contents of the oncogenetic consultation. TRIAL REGISTRATION: Ethics committee CPP SUD-EST-6: IRB00008526. Registered on 18 March 2016. ClinicalTrials.gov identifier: NCT02705924 . Registered on 2 March 2016. PMID- 27769294 TI - Incidence of left atrial abnormalities under treatment with dabigatran, rivaroxaban, and vitamin K antagonists. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran or rivaroxaban are alternatives to vitamin K antagonists (VKAs) for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) and atrial flutter (AFL). Incidences of risk factors for left atrium (LA) and left atrial appendage (LAA) thrombus formation, such as dense spontaneous echo contrast (SEC), low LAA velocity (LAAV) <20 cm/s under treatment with dabigatran and rivaroxaban in comparison with VKAs are unknown. METHODS: We studied 306 patients with AF (94 %) and AFL (6 %) undergoing transesophageal echocardiography. Patients received VKAs (n = 138), dabigatran (n = 68), or rivaroxaban (n = 100) for at least 3 weeks prior to investigation. Time in therapeutic range was 67 % for VKA. Mean CHADS2 score and CHA2DS2-VASc score were 1.3 and 2.5, respectively. Left atrial abnormality was defined as either dense SEC, low LAAV <20 cm/s, or thrombus. RESULTS: Any LA abnormality occurred in 9, 3, and 5 % of patients receiving VKA, dabigatran, and rivaroxaban, respectively. The most frequent abnormality was LAA thrombus (VKA: 4 %, dabigatran: 0 %, rivaroxaban: 2 %) and low LAAV of less than 20 cm/s (VKA: 4 %, dabigatran: 1 %, rivaroxaban: 1 %), followed by dense SEC (VKA: 2 %, dabigatran: 1 %, rivaroxaban: 2 %). Results of uni- and multivariate analyses revealed a numerically lower but not significantly different frequency of any LA abnormality under dabigatran (OR 0.4, 95 % Cl 0.08 - 1.88, p = 0.25) and rivaroxaban (OR 0.65, 95 % Cl 0.22 - 1.98, p = 0.45) compared to VKA. CONCLUSION: With respect to the incidence of LA abnormalities, dabigatran and rivaroxaban are not inferior to VKA. PMID- 27769295 TI - A home calendar and recall method of last menstrual period for estimating gestational age in rural Bangladesh: a validation study. AB - BACKGROUND: The best method of gestational age assessment is by ultrasound in the first trimester; however, this method is impractical in large field trials in rural areas. Our objective was to assess the validity of gestational age estimated from prospectively collected date of last menstrual period (LMP) using crown-rump length (CRL) measured in early pregnancy by ultrasound. METHODS: As part of a large, cluster-randomized, controlled trial in rural Bangladesh, we collected dates of LMP by recall and as marked on a calendar every 5 weeks in women likely to become pregnant. Among those with a urine-test confirmed pregnancy, a subset with gestational age of <15 weeks (n = 353) were enrolled for ultrasound follow-up to measure CRL. We compared interview-assessed LMP with CRL gestational age estimates and classification of preterm, term, and post-term births. RESULTS: LMP-based gestational age was higher than CRL by a mean (SD) of 2.8 (10.7) days; differences varied by maternal education and preterm birth (P < 0.05). Lin's concordance correlation coefficient was good at ultrasound [0.63 (95 % CI 0.56, 0.69)] and at birth [0.77 (95 % CI 0.73, 0.81)]. Validity of classifying preterm birth was high but post-term was lower, with specificity of 96 and 89 % and sensitivity of 86 and 67 %, respectively. Results were similar by parity. CONCLUSIONS: Prospectively collected LMP provided a valid estimate of gestational age and preterm birth in a rural, low-income setting and may be a suitable alternative to ultrasound in programmatic settings and large field trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00860470. PMID- 27769296 TI - Assessing the burden of medical impoverishment by cause: a systematic breakdown by disease in Ethiopia. AB - BACKGROUND: Out-of-pocket (OOP) medical expenses often lead to catastrophic expenditure and impoverishment in low- and middle-income countries. Yet, there has been no systematic examination of which specific diseases and conditions (e.g., tuberculosis, cardiovascular disease) drive medical impoverishment, defined as OOP direct medical costs pushing households into poverty. METHODS: We used a cost and epidemiological model to propose an assessment of the burden of medical impoverishment in Ethiopia, i.e., the number of households crossing a poverty line due to excessive OOP direct medical expenses. We utilized disease specific mortality estimates from the Global Burden of Disease study, epidemiological and cost inputs from surveys, and secondary data from the literature to produce a count of poverty cases due to OOP direct medical costs per specific condition. RESULTS: In Ethiopia, in 2013, and among 20 leading causes of mortality, we estimated the burden of impoverishment due to OOP direct medical costs to be of about 350,000 poverty cases. The top three causes of medical impoverishment were diarrhea, lower respiratory infections, and road injury, accounting for 75 % of all poverty cases. CONCLUSIONS: We present a preliminary attempt for the estimation of the burden of medical impoverishment by cause for high mortality conditions. In Ethiopia, medical impoverishment was notably associated with illness occurrence and health services utilization. Although currently used estimates are sensitive to health services utilization, a systematic breakdown of impoverishment due to OOP direct medical costs by cause can provide important information for the promotion of financial risk protection and equity, and subsequent design of health policies toward universal health coverage, reduction of direct OOP payments, and poverty alleviation. PMID- 27769297 TI - A novel methanol-free Pichia pastoris system for recombinant protein expression. AB - BACKGROUND: As one of the most popular expression systems, recombinant protein expression in Pichia pastoris relies on the AOX1 promoter (P AOX1 ) which is strongly induced by methanol. However, the toxic and inflammatory nature of methanol restricts its application, especially in edible and medical products. Therefore, constructing a novel methanol-free system becomes necessary. The kinases involved in P AOX1 activation or repression by different carbon sources may be promising targets. RESULTS: We identified two kinase mutants: Deltagut1 and Deltadak, both of which showed strong alcohol oxidase activity under non methanol carbon sources. Based on these two kinases, we constructed two methanol free expression systems: Deltagut1-HpGCY1-glycerol (P AOX1 induced by glycerol) and Deltadak-DHA (P AOX1 induced by DHA). By comparing their GFP expression efficiencies, the latter one showed better potential. To further test the Deltadak-DHA system, three more recombinant proteins were expressed as examples. We found that the expression ability of our novel methanol-free Deltadak-DHA system was generally better than the constitutive GAP promoter, and reached 50-60 % of the traditional methanol induced system. CONCLUSIONS: We successfully constructed a novel methanol-free expression system Deltadak-DHA. This modified expression platform preserved the favorable regulatable nature of P AOX1 , providing a potential alternative to the traditional system. PMID- 27769298 TI - Past climate changes, population dynamics and the origin of Bison in Europe. AB - BACKGROUND: Climatic and environmental fluctuations as well as anthropogenic pressure have led to the extinction of much of Europe's megafauna. The European bison or wisent (Bison bonasus), one of the last wild European large mammals, narrowly escaped extinction at the onset of the 20th century owing to hunting and habitat fragmentation. Little is known, however, about its origin, evolutionary history and population dynamics during the Pleistocene. RESULTS: Through ancient DNA analysis we show that the emblematic European bison has experienced several waves of population expansion, contraction, and extinction during the last 50,000 years in Europe, culminating in a major reduction of genetic diversity during the Holocene. Fifty-seven complete and partial ancient mitogenomes from throughout Europe, the Caucasus, and Siberia reveal that three populations of wisent (Bison bonasus) and steppe bison (B. priscus) alternately occupied Western Europe, correlating with climate-induced environmental changes. The Late Pleistocene European steppe bison originated from northern Eurasia, whereas the modern wisent population emerged from a refuge in the southern Caucasus after the last glacial maximum. A population overlap during a transition period is reflected in ca. 36,000-year-old paintings in the French Chauvet cave. Bayesian analyses of these complete ancient mitogenomes yielded new dates of the various branching events during the evolution of Bison and its radiation with Bos, which lead us to propose that the genetic affiliation between the wisent and cattle mitogenomes result from incomplete lineage sorting rather than post-speciation gene flow. CONCLUSION: The paleogenetic analysis of bison remains from the last 50,000 years reveals the influence of climate changes on the dynamics of the various bison populations in Europe, only one of which survived into the Holocene, where it experienced severe reductions in its genetic diversity. The time depth and geographical scope of this study enables us to propose temperate Western Europe as a suitable biotope for the wisent compatible with its reintroduction. PMID- 27769299 TI - Ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia compared to Thailand. AB - BACKGROUND: The recent dramatic decline in dihydroartemisinin-piperaquine (DHA PPQ) efficacy in northwestern Cambodia has raised concerns about the rapid spread of piperaquine resistance just as DHA-PPQ is being introduced as first-line therapy in neighbouring countries. METHODS: Ex vivo parasite susceptibilities were tracked to determine the rate of progression of DHA, PPQ and mefloquine (MQ) resistance from sentinel sites on the Thai-Cambodian and Thai-Myanmar borders from 2010 to 2015. Immediate ex vivo (IEV) histidine-rich protein 2 (HRP-2) assays were used on fresh patient Plasmodium falciparum isolates to determine drug susceptibility profiles. RESULTS: IEV HRP-2 assays detected the precipitous emergence of PPQ resistance in Cambodia beginning in 2013 when 40 % of isolates had an IC90 greater than the upper limit of prior years, and this rate doubled to 80 % by 2015. In contrast, Thai-Myanmar isolates from 2013 to 14 remained PPQ sensitive, while northeastern Thai isolates appeared to have an intermediate resistance profile. The opposite trend was observed for MQ where Cambodian isolates appeared to have a modest increase in overall sensitivity during the same period, with IC50 declining to median levels comparable to those found in Thailand. A significant association between increased PPQ IC50 and IC90 among Cambodian isolates with DHA-PPQ treatment failure was observed. Nearly all Cambodian and Thai isolates were deemed artemisinin resistant with a >1 % survival rate for DHA in the ring-stage assay (RSA), though there was no correlation among isolates to indicate cross-resistance between PPQ and artemisinins. CONCLUSIONS: Clinical DHA-PPQ failures appear to be associated with declines in the long-acting partner drug PPQ, though sensitivity appears to remain largely intact for now in western Thailand. Rapid progression of PPQ resistance associated with DHA-PPQ treatment failures in northern Cambodia limits drugs of choice in this region, and urgently requires alternative therapy. The temporary re-introduction of artesunate AS-MQ is the current response to PPQ resistance in this area, due to inverse MQ and PPQ resistance patterns. This will require careful monitoring for re-emergence of MQ resistance, and possible simultaneous resistance to all three drugs (AS, MQ and PPQ). PMID- 27769300 TI - A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement. AB - BACKGROUND: The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. RESULTS: We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c.1423 + 2 T > A) in ELAC2 gene that disrupted the canonical donor splice site of intron 15 of all known isoforms. A noticeable reduction in ELAC2 expression was observed in patients compared to controls. In addition, patients exhibited significantly increased levels of 5' end unprocessed mt-RNAs compared to the control fibroblast cells. CONCLUSIONS: The only three previously reported families with defects in ELAC2 gene exhibited infantile hypertrophic cardiomyopathy and complex I deficiency. In contrast, our patients exhibited intellectual disability as the main feature with minimal cardiac involvement. Therefore our findings expand the phenotypic spectrum of ELAC2- associated disorders illustrating clinical heterogeneity of mutations in this gene. In addition, ELAC2 mutations should be considered when evaluating patient with mainly intellectual disability phenotypes. PMID- 27769301 TI - Quantifying selective elbow movements during an exergame in children with neurological disorders: a pilot study. AB - BACKGROUND: It is difficult to distinguish between restorative and compensatory mechanisms underlying (pediatric) neurorehabilitation, as objective measures assessing selective voluntary motor control (SVMC) are scarce. METHODS: We aimed to quantify SVMC of elbow movements in children with brain lesions. Children played an airplane game with the glove-based YouGrabber system. Participants were instructed to steer an airplane on a screen through a cloud-free path by correctly applying bilateral elbow flexion and extension movements. Game performance measures were (i) % time on the correct path and (ii) similarity between the ideal flight path and the actually flown path. SVMC was quantified by calculating a correlation coefficient between the derivative of the ideal path and elbow movements. A therapist scored whether the child had used compensatory movements. RESULTS: Thirty-three children with brain lesions (11 girls; 12.6 +/- 3.6 years) participated. Clinical motor and cognitive scores correlated moderately with SVMC (0.50-0.74). Receiver Operating Characteristics analyses showed that SVMC could differentiate well and better than clinical and game performance measures between compensatory and physiological movements. CONCLUSIONS: We conclude that a simple measure assessed while playing a game appears promising in quantifying SVMC. We propose how to improve the methodology, and how this approach can be easily extended to other joints. PMID- 27769302 TI - E-cigarette use and smoking reduction or cessation in the 2010/2011 TUS-CPS longitudinal cohort. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are heavily marketed and widely perceived as helpful for quitting or reducing smoking intensity. We test whether ever-use of e-cigarettes among early adopters was associated with: 1) increased cigarette smoking cessation; and 2) reduced cigarette consumption. METHODS: A representative cohort of U.S. smokers (N = 2454) from the 2010 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) was re-interviewed 1 year later. Outcomes were smoking cessation for 30+ days and change in cigarette consumption at follow-up. E-cigarettes use was categorized as for cessation purposes or for another reason. Multivariate regression was used to adjust for demographics and baseline cigarette dependence level. RESULTS: In 2011, an estimated 12 % of adult U.S. smokers had ever used e-cigarettes, and 41 % of these reported use to help quit smoking. Smokers who had used e-cigarettes for cessation were less likely to be quit for 30+ days at follow-up, compared to never-users who tried to quit (11.1 % vs 21.6 %; ORadj = 0.44, 95 % CI = 0.2 0.8). Among heavier smokers at baseline (15+ cigarettes per day (CPD)), ever-use of e-cigarettes was not associated with change in smoking consumption. Lighter smokers (<15 CPD) who had ever used e-cigarettes for quitting had stable consumption, while increased consumption was observed among all other lighter smokers, although this difference was not statistically significant. CONCLUSIONS: Among early adopters, ever-use of first generation e-cigarettes to aid quitting cigarette smoking was not associated with improved cessation or with reduced consumption, even among heavier smokers. PMID- 27769303 TI - Short-term and long-term outcomes of intrathoracic vacuum therapy of empyema in debilitated patients. AB - BACKGROUND: This retrospective study analyzed the effectiveness of intrathoracic negative pressure therapy for debilitated patients with empyema and compared the short-term and long-term outcomes of three different intrapleural vacuum-assisted closure (VAC) techniques. METHODS: We investigated 43 consecutive (pre)septic patients with poor general condition (Karnofsky index <= 50 %) and multimorbidity (>= 3 organ diseases) or immunosuppression, who had been treated for primary, postoperative, or recurrent pleural empyema with VAC in combination with open window thoracostomy (OWT-VAC) with minimally invasive technique (Mini-VAC), and instillation (Mini-VAC-Instill). RESULTS: The overall duration of intrathoracic vacuum therapy was 14 days (5-48 days). Vacuum duration in the Mini-VAC and Mini VAC-Instill groups (12.4 +/- 5.7 and 10.4 +/- 5.4 days) was significantly shorter (p = 0.001) than in the group treated with open window thoracostomy (OWT)-VAC (20.3 +/- 9.4 days). No major complication was related to intrathoracic VAC therapy. Chest wall closure rates were significantly higher in the Mini-VAC and Mini-VAC-Instill groups than in the OWT-VAC group (p = 0.034 and p = 0.026). Overall, the mean postoperative length of stay in hospital (LOS) was 21 days (median 18, 6-51 days). LOS was significantly shorter (p = 0.027) in the Mini-VAC Instill group (15.1 +/- 4.8) than in the other two groups (23.8 +/- 12.3 and 22.7 +/- 1.5). Overall, the 30-day and 60-day mortality rates were 4.7 % (2/43) and 9.3 % (4/43), and none of the deaths was related to infection. CONCLUSIONS: For debilitated patients, immediate minimally invasive intrathoracic vacuum therapy is a safe and viable alternative to OWT. Mini-VAC-Instill may have the fastest clearance and healing rates of empyema. PMID- 27769305 TI - Genetic diversity of the Tibetan antelope (Pantholops hodgsonii) population of Ladakh, India, its relationship with other populations and conservation implications. AB - BACKGROUND: The Tibetan antelope (Pantholops hodgsonii), or chiru, is an endangered antelope, distributed in China [Xinjiang, Xizang, Qinghai, Zhuolaihu Lake (Breeding habitat)], and India (Aksai Chin and Ladakh). There is a global demand for the species prized wool, which is used in weaving shahtoosh shawls. Over the years, the population of the Tibetan antelope has drastically declined from more than a million to a few thousand individuals, mainly due to poaching. Field studies undertaken in Ladakh, India also indicated winter migration of the population to Tibet. Migration between winter and calving habitats is well established to be female-biased across the Qinghai Tibetan Plateau (QTP). For effective conservation planning, genetic characterization is considered the best way to understand the likely impact of threats for ensuring the long-term viability of the population. In this regard, genetic characteristics of all Chinese populations are well-studied using mitochondrial and microsatellite markers, but information is lacking for the Indian population. Therefore, using the control region marker, we document for the first time the genetic variation of the Indian population of the Tibetan antelope, the extent of migration and its relationships with other populations of China. RESULTS: The partial fragment of control region (259 bp) marker was successfully amplified in 30 Tibetan antelope samples that were collected from the Chang Chenmo Valley in eastern Ladakh, India. We also retrieved control region sequences (n = 88) available in the public domain from GenBank of different Chinese populations. Low levels of nucleotide (pi; 0.004) and haplotype (hd; 0.543) diversity were observed in the Indian population when compared to Chinese populations (pi = 0.01357-0.02048 and hd = 0.889-0.986). Commonly used indices (Tajima's D and Fu's Fs) were analyzed for inferring the demographic history of the Indian populations, and all values were negative indicating population expansion or demographic equilibrium, though nonsignificant. We observed five haplotypes in the Indian population, and these were not reported in previously studied populations of QTP. Bayesian-based phylogenetic analysis indicates the presence of four clades, however, the posterior probability support for three of these clades is weak (<0.5). Of these, the Indian population formed a distinct clade, whereas the Chinese populations exhibited shared haplotypes, and no geographic structure was observed. Median joining network analysis was conducted for 46 haplotypes in the overall population, except the samples from India which showed a star-like topology. The Indian population is separated by one median vector from the Chinese population. CONCLUSIONS: The present study revealed the presence of different sub-clades in the Bayesian phylogenetic tree and five new haplotypes only in the Indian population or sampling location. Furthermore, in the phylogenetic tree, Indian haplotypes of Tibetan antelopes were clustered with the haplotype reported in the Chinese population of the Xinjiang region. Median-joining network analysis showed shared haplotypes pattern in all populations of QTP except the samples from India which showed new haplotypes. Given the presence of low nucleotide and haplotype diversity in eastern Ladakh populations and limited information available for populations of the western side in its range, we suggest to include genetic studies of Tibetan antelope populations around Aksai Chin (Fig. 1) under the proposed transboundary agenda between India and China and assess relationships with other populations. Such understanding would enable the planning of conservation strategies for ensuring long-term survival of westernmost populations in its range, and if required, it would establish connectivity with the other populations. PMID- 27769306 TI - Improved application technique of albumin-glutaraldehyde glue for repair of superficial lung defects. AB - BACKGROUND: Albumin-glutaraldehyde glue has gained widespread acceptance for treatment of alveolar air leaks (AAL) in thoracic surgery. As liquid run-off during application is detrimental to its sealing efficacy, we developed a modified technique and assessed it in vitro. METHODS: Caudal lobes of freshly excised swine lungs (n = 20) were intubated and ventilated. A standardized focal superficial parenchymal defect (40 * 25 mm) was created on the inflated lung. AAL was assessed under exposure to increasing inspired tidal volume (TVi). Lung lobes were randomly selected and subjected to either a standard sealing suggested by the manufacturer (control group) or a modified technique relying on placement of a square silicone frame around the lesion site (study group). AAL was subsequently assessed until burst failure occurred and the occuring lesions length was recorded on the inflated lung to evaluate elasticity of underlying tissue. RESULTS: Superficial parenchymal defects resulted in AAL increasing with ascending TVi. AAL prior to sealant application was comparable in both groups. An application error occurred once in our control group. At TVi = 400, 500, 600 and 700 ml, the albumin-glutaraldehyde glue achieved complete sealing in 10, 10, 9 and 8 lungs respectively in our study group, as opposed to 9, 7, 6 and 4 lobes in the control group. The required mean burst pressure was significantly higher in our study group (41.0 +/- 1.0 vs. 37.5 +/- 4.2 cmH2O, p = 0.0195), but there was no difference in expansion of covered defect between both groups (1.0 +/- 0.4 vs. 1.5 +/- 1.7 mm, p = 0.3772). CONCLUSIONS: Our tests suggest that frame-assisted sealant application might prevent glue run-off and thus improves its sealing efficacy. We encourage further investigation of this technique in well-designed, controlled clinical trials. PMID- 27769304 TI - 3D-printing techniques in a medical setting: a systematic literature review. AB - BACKGROUND: Three-dimensional (3D) printing has numerous applications and has gained much interest in the medical world. The constantly improving quality of 3D printing applications has contributed to their increased use on patients. This paper summarizes the literature on surgical 3D-printing applications used on patients, with a focus on reported clinical and economic outcomes. METHODS: Three major literature databases were screened for case series (more than three cases described in the same study) and trials of surgical applications of 3D printing in humans. RESULTS: 227 surgical papers were analyzed and summarized using an evidence table. The papers described the use of 3D printing for surgical guides, anatomical models, and custom implants. 3D printing is used in multiple surgical domains, such as orthopedics, maxillofacial surgery, cranial surgery, and spinal surgery. In general, the advantages of 3D-printed parts are said to include reduced surgical time, improved medical outcome, and decreased radiation exposure. The costs of printing and additional scans generally increase the overall cost of the procedure. CONCLUSION: 3D printing is well integrated in surgical practice and research. Applications vary from anatomical models mainly intended for surgical planning to surgical guides and implants. Our research suggests that there are several advantages to 3D-printed applications, but that further research is needed to determine whether the increased intervention costs can be balanced with the observable advantages of this new technology. There is a need for a formal cost-effectiveness analysis. PMID- 27769307 TI - Effects of financial support on treatment of adolescents with growth hormone deficiency: a retrospective study in Japan. AB - BACKGROUND: Treatment costs for children with growth hormone (GH) deficiency are subsidized by the government in Japan if the children meet clinical criteria, including height limits (boys: 156.4 cm; girls: 145.4 cm). However, several funding programs, such as a subsidy provided by local governments, can be used by those who exceed the height limits. In this study, we explored the impacts of financial support on GH treatment using this natural allocation. METHODS: A retrospective analysis of 696 adolescent patients (451 boys and 245 girls) who reached the height limits was conducted. Associations between financial support and continuing treatment were assessed using multiple logistic regression analyses adjusting for age, sex, height, growth velocity, bone age, and adverse effects. RESULTS: Of the 696 children in the analysis, 108 (15.5 %) were still eligible for financial support. The proportion of children who continued GH treatment was higher among those who were eligible for support than among those who were not (75.9 % vs. 52.0 %, P < 0.001). The odds ratios of financial support to continuing treatment were 4.04 (95 % confidence interval [CI]: 1.86-8.78) in boys and 1.72 (95 % CI: 0.80-3.70) in girls, after adjusting for demographic characteristics and clinical factors. CONCLUSIONS: Financial support affected decisions on treatment continuation for children with GH deficiency. Geographic variations in eligibility for financial support pose an ethical problem that needs policy attention. An appropriate balance between public spending on continuation of therapy and improved quality of life derived from it should be explored. PMID- 27769309 TI - Analytical characteristics and comparative evaluation of Aptima HIV-1 Quant Dx assay with Ampliprep/COBAS TaqMan HIV-1 test v2.0. AB - BACKGROUND: Quantitation of HIV-RNA is critically important for diagnosis, prognosis, treatment, monitoring and assessment of infectivity in HIV-1 infection. The objective of this study was to assess performance characteristics of the Aptima HIV-1 Quant Dx assay (Aptima), a new transcription mediated amplification (TMA), fully integrated and automated assay from Hologic Inc., San Diego, CA, USA. The analytical sensitivity, analytical specificity, precision and detection of HIV-1 subtypes were tested based on commercially available international standards or panels. A selected group of 244 anti-HIV-1 (+) plasma samples was used for comparison with Roche COBAS Ampliprep/COBAS TaqMan HIV- 1 test v2.0 (Roche CAP/CTM), (Roche Molecular Systems, Pleasanton, CA). RESULTS: The 50 and 95 % limit of detection were estimated at 4.9 (95 % CI 3.9-5.7) and 17.6 (15.2-21.2) IU/mL respectively. The specificity was found 99.83 (99.06 99.97) %. The standard deviations and coefficient of variations for panels with 50 and 100 copies/mL (1.7 and 2 log copies/mL) were 0.14 log copies/mL (8.67 %CV) and 0.18 log copies/mL (9.91 %CV) respectively. The detection rate for Aptima and Roche assays was 220/244 (90.2 %) and 217/244 (88.9 %) respectively. CONCLUSION: The Aptima assay is a sensitive, specific, precise and accurate test for measuring HIV-1 viral loads and for the detection of HIV-1 infections. PMID- 27769308 TI - The modified SAVE score: predicting survival using urgent veno-arterial extracorporeal membrane oxygenation within 24 hours of arrival at the emergency department. AB - BACKGROUND: Although many risk models have been tested in patients who undergo extracorporeal membrane oxygenation, few have been assessed for patients who received veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support in the emergency department (ED). This study aimed to successfully predict outcomes of patients with cardiac or noncardiac failure who received VA-ECMO in the ED within 24 hours of arrival at the ED. METHOD: This retrospective, observational cohort study included 154 patients, who were classified as cardiac (n = 127) and noncardiac (n = 27) patients and received VA-ECMO within 24 hours after arrival at the China Medical University Hospital ED in Taiwan between January 2009 and September 2014. We recorded mechanical ventilation settings, arterial blood gases, laboratory parameters including plasma lactate level, requirement of catecholamines, and risk scores at time of ECMO initiation. ECMO and mechanical ventilation support duration, length of stay in the hospital, and 90-day mortality data were also examined. RESULTS: The overall mortality rate was 64.9 %. We used "survival after veno-arterial ECMO (SAVE)" scores to assess survival prediction in survival and nonsurvival groups, which was statistically different (-3.2 vs. -8.3, p <0.001). According to multivariate Cox proportional regression of survival, lactate (hazard ratio [HR] = 1.01, 95 % confidence interval [CI], 1.01-1.01, p <0.001) and SAVE score (HR = 0.92, [95 % CI, 0.88-0.96], p = 0.001) were independent predictors of outcome. Excellent discrimination (area under curve (AUC) = 0.843) was observed when lactate and SAVE score were combined, which we referred to as "the modified SAVE score." CONCLUSIONS: Modified SAVE scores improved outcome prediction for patients who underwent urgent VA-ECMO in the ED. PMID- 27769310 TI - Wristband Accelerometers to motiVate arm Exercise after Stroke (WAVES): study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Loss of upper limb function affects up to 85 % of acute stroke patients. Recovery of upper limb function requires regular intensive practise of specific upper limb tasks. To enhance intensity of practice interventions are being developed to encourage patients to undertake self-directed exercise practice. Most interventions do not translate well into everyday activities and stroke patients continue to find it difficult remembering integration of upper limb movements into daily activities. A wrist-worn device has been developed that monitors and provides 'live' upper limb activity feedback to remind patients to use their stroke arm in daily activities (The CueS wristband). The aim of this trial is to assess the feasibility of a multi-centre, observer blind, pilot randomised controlled trial of the CueS wristband in clinical stroke services. METHODS/DESIGN: This pilot randomised controlled feasibility trial aims to recruit 60 participants over 15 months from North East England. Participants will be within 3 months of stroke which has caused new reduced upper limb function and will still be receiving therapy. Each participant will be randomised to an intervention or control group. Intervention participants will wear a CueS wristband (between 8 am and 8 pm) providing "live" feedback towards pre-set movement goals through a simple visual display and vibration prompts whilst undertaking a 4-week upper limb therapy programme (reviewed twice weekly by an occupational/physiotherapist). Control participants will also complete the 4-week upper limb therapy programme but will wear a 'sham' CueS wristband that monitors upper limb activity but provides no feedback. Outcomes will determine study feasibility in terms of recruitment, retention, adverse events, adherence and collection of descriptive clinical and accelerometer motor performance data at baseline, 4 weeks and 8 weeks. DISCUSSION: The WAVES study will address an important gap in the evidence base by reporting the feasibility of undertaking an evaluation of emerging and affordable technology to encourage impaired upper limb activity after stroke. The study will establish whether the study protocol can be supported by clinical stroke services, thereby informing the design of a future multi-centre randomised controlled trial of clinical and cost-effectiveness. TRIAL REGISTRATION: ISRCTN:82306027 . Registered 12 July 2016. PMID- 27769311 TI - Failed surrogate conceptions: social and ethical aspects of preconception disruptions during commercial surrogacy in India. AB - BACKGROUND: During a commercial surrogacy arrangement, the event of embryo transfer can be seen as the formal starting point of the arrangement. However, it is common for surrogates to undergo a failed attempt at pregnancy conception or missed conception after an embryo transfer. This paper attempts to argue that such failed attempts can be understood as a loss. It aims to reconstruct the experiences of loss and grief of the surrogates and the intended parents as a consequence of their collective failure to conceive a surrogate pregnancy. METHODS: Drawing on a qualitative study conducted over a period of eight months between 2014 and 2015 at two fertility clinics in Delhi and two in Kolkata, India, this paper examines the experiences of the surrogates and the intended parents when faced with missed conceptions or failed conceptions during a surrogacy arrangement. RESULTS: We argue that while the surrogate grieves the non arrival of a 'good news' as an uncertain loss, the intended parents experience yet another, failure in addition to the losses they might have incurred during their previous fertility treatments. The body of the surrogate becomes a site of 'a lost opportunity'. The surrogate embodies a loss in her quest to achieve social mobility and the intended parents experience a disembodied pregnancy loss. This very emotional experience stands in stark contrast to the conceptualisation of such failed attempts as non-events within the discourse of the surrogacy industry. The experience of loss of the intended parents is recognised but their grief is given no space. We argue that such ambiguity around the nature of losses resulting out of a missed or failed conception during surrogacy is an outcome of lack of interpersonal relationship between the surrogate and the intended parents. CONCLUSIONS: Since commercial surrogacy is a relational process, the only way in which the experiences of losses and failures of the actors at the preconception stage can be better addressed is through developing close sharing and understanding between each other through an ethics of care. Therefore, to nurture caring relationships, surrogacy needs to be understood as a moral commitment by -the surrogates and intended parents. To enable such a commitment, there is a need to reconsider the pre-defined and legally regulated professional duty of the doctors, agents and agencies. It cannot be a one-sided commitment, but has to have elements of mutuality. PMID- 27769312 TI - Community health worker in hard-to-reach rural areas of Myanmar: filling primary health care service gaps. AB - BACKGROUND: Myanmar is classified as critical shortage of health workforce. In responses to limited number of trained health workforce in the hard-to-reach and remote areas, the MOH trained the Community Health Worker (CHW) as health volunteers serving these communities on a pro bono basis. This study aimed to assess the socio-economic profiles, contributions of CHW to primary health care services and their needs for supports to maintain their quality contributions in rural hard to reach areas in Myanmar. METHODS: In 2013, cross-sectional census survey was conducted on all three groups of CHW classified by their training dates: (1) prior to 2000, (2) between 2000 and 2011, and (3) more recently trained in 2012, who are still working in 21 townships of 17 states and regions in Myanmar, using a self-administered questionnaire survey in the Burmese language. FINDINGS: The total 715 CHWs from 21 townships had completely responded to the questionnaire. CHWs were trained to support the work of midwives in the sub-centres and health assistant and midwives in rural health centres (RHCs) such as community mobilization for immunization, advocates of safe water and sanitation, and general health education and health awareness for the citizens. CHWs were able to provide some of the services by themselves, such as treatment of simple illnesses, and they provided services to 62 patients in the last 6 months. Their contributions to primary health care services were well accepted by the communities as they are geographically and culturally accessible. However, supports from the RHC were inadequate in particular technical supervision, as well as replenishment of CHW kits and financial support for their work and transportation. In practice, 6 % of service provided by CHWs was funded by the community and 22 % by the patients. The CHW's confidence in providing health services was positively associated with their age, education, and more recent training. A majority of them intended to serve as a CHW for more than the next 5 years which was determined by their ages, confidence, and training batch. CONCLUSIONS: CHWs are the health volunteers in the community supporting the midwives in hard-to-reach areas; given their contributions and easy access, policies to strengthen support to sustain their contributions and ensure the quality of services are recommended. PMID- 27769313 TI - Experimental Piscine orthoreovirus infection mediates protection against pancreas disease in Atlantic salmon (Salmo salar). AB - Viral diseases are among the main challenges in farming of Atlantic salmon (Salmo salar). The most prevalent viral diseases in Norwegian salmon aquaculture are heart and skeletal muscle inflammation (HSMI) caused by Piscine orthoreovirus (PRV), and pancreas disease (PD) caused by Salmonid alphavirus (SAV). Both PRV and SAV target heart and skeletal muscles, but SAV additionally targets exocrine pancreas. PRV and SAV are often present in the same locations and co-infections occur, but the effect of this crosstalk on disease development has not been investigated. In the present experiment, the effect of a primary PRV infection on subsequent SAV infection was studied. Atlantic salmon were infected with PRV by cohabitation, followed by addition of SAV shedder fish 4 or 10 weeks after the initial PRV infection. Histopathological evaluation, monitoring of viral RNA levels and host gene expression analysis were used to assess disease development. Significant reduction of SAV RNA levels and of PD specific histopathological changes were observed in the co-infected groups compared to fish infected by SAV only. A strong correlation was found between histopathological development and expression of disease related genes in heart. In conclusion, experimentally PRV infected salmon are less susceptible to secondary SAV infection and development of PD. PMID- 27769314 TI - Maternal and Congenital cytomegalovirus infection and zero rubella IgM prevalence in newborns in St.Paul's Hospital Millennium Medical College. AB - BACKGROUND: Maternal cytomegalovirus (CMV) and Rubella infections result in adverse neonatal outcomes. Both CMV and Rubella are more widespread in developing countries and in communities with lower socioeconomic status. Thus, the aim of this study was to determine IgM specific to CMV and Rubella among newborns and Maternal CMV-seroprevalence and to identify risk factors. METHOD AND FINDING: Using cross sectional study design a total of 312 (156 newborns and 156 mothers) study participants were recruited by simple random sampling technique from gynecology outpatient department (OPD) and ward, starting from April 1, 2015 to June 30, 2015. Cord and venous blood samples were collected from all participants and structured questionnaire was introduced to gather risk factor related data. ELISA was used to detect CMV and Rubella-IgM. SPSS version 20 was used to analyze the data, and regression analysis was also performed. Out of 156 newborns, 2 [1.3 %; 95 % CI: 0.0-3.8] were positive for CMV-IgM and no single rubella was detected. Association was not computed between risk related variables and cytomegalovirus infected newborns due to the low positivity rate. Multiple independent predictors were found between maternal CMV-IgM and Obstetrical characteristics. Cytomegalovirus-IgM was significantly isolated from mothers with history of transfusion (25.0 %, OR 0.09, 95 % CI 0.0-0.3, P = 0.006), history of abortion (OR 0.02, 95 % CI 0.0-0.6, P = 0.023), HIV sero-status (OR 5.0, 95 % CI 1.5-15.8, P = 0.034), and multi parity (OR 0.08, 95 % CI 0.01-0.7, P = 0.022). CONCLUSION: Although low congenital CMV and no Rubella are reported among newborns, more effort is needed to screen for congenital infectious viral disease as well as usage of advanced techniques should be taken into consideration. PMID- 27769315 TI - Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2. AB - BACKGROUND: Accumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis. Leptin, a key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is also involved in EMT. However, the potential mechanism remains unknown. This study aims to explore the effect of leptin on EMT in breast cancer cells and the underlying mechanism. METHODS: With the assessment of EMT-associated marker expression in MCF-7, SK-BR 3, and MDA-MB-468 cells, the effect of leptin on breast cancer cells was analyzed. Besides, an array of pathway inhibitors as well as RNA interference targeting pyruvate kinase M2 (PKM2) were used to clarify the underlying mechanism of leptin-mediated EMT in vitro and in vivo. RESULTS: The results demonstrated that leptin promoted breast cancer cells EMT, visibly activated the PI3K/AKT signaling pathway, and upregulated PKM2 expression. An antibody against the leptin receptor (anti-ObR) and the PI3K/AKT signaling pathway inhibitor LY294002 significantly abolished leptin-induced PKM2 expression and EMT-associated marker expression. SiRNA targeting PKM2 partially abolished leptin-induced migration, invasion, and EMT-associated marker expression. In vivo xenograft experiments indicated that RNA interference against PKM2 suppressed breast cancer growth and metastasis. CONCLUSIONS: Our data suggest that leptin promotes EMT in breast cancer cells via the upregulation of PKM2 expression as well as activation of PI3K/AKT signaling pathway, and PKM2 might be one of the key points and potential targets for breast cancer therapy. PMID- 27769316 TI - Neurodevelopmental profile in Angelman syndrome: more than low intelligence quotient. AB - BACKGROUND: Angelman Syndrome (AS) is a rare neurodevelopment disorder resulting from deficient expression or function of the maternally inherited allele of UBE3A gene. The aim of the study is to attempt at providing a detailed definition of neurodevelopmental profile in AS, with particular regard to motor, cognitive, communicative, behavioural and neurovisual, features by using standardized instruments. METHOD: A total of ten subjects aged from 5 to 11 years (4 males and 6 females) with molecular confirmed diagnosis of AS (7 15q11.2-q13 deletion and 3 UBE3A mutation) were enrolled in our study. All of them underwent an assessment protocol including neurological and neurovisual examination and the evaluation of motor (Gross Motor Function Measure Scale), cognitive (Griffiths Mental Development Scale and Uzgiris-Hunt Scale); adaptive (Vineland Adaptive Behavioural Scale); communication (MacArthur-Bates Communicative Development Inventory and video-recordings children's verbal expression), behavioural aspects (IPDDAG Scale) and neurovisual aspects. RESULTS: All children presented motor function involvement. A severe cognitive impairment was detected with different profiles according to the test applied. In all cases, communicative disability (phonemic inventory, word/gesture comprehension and production) and symptoms of inattention disorder were revealed. Neurovisual impairment was characterized by refractive errors, fundus oculi anomalies, strabismus and/or oculomotor dysfunction. CONCLUSION: AS presents a complex neurodevelopmental profile in which several aspects play a negative role in global development leading to a severe functional impairment. Intellectual disability is not the only component because neurovisual functions and behavioural disorders may worsen the global function and are needed of specific rehabilitation programs. PMID- 27769317 TI - Protocol for a thematic synthesis to identify key themes and messages from a palliative care research network. AB - BACKGROUND: Research networks that facilitate collaborative research are increasing both regionally and globally and such collaborations contribute greatly to knowledge transfer particularly in health research. The Palliative Care Research Network is an Irish-based network that seeks to create opportunities and engender a collaborative environment to encourage innovative research that is relevant for policy and practice. The current review outlines a methodology to identify cross-cutting messages to identify how dissemination outputs can be optimized to ensure that key messages from this research reaches all knowledge users. METHODS/DESIGN: Preferred reporting items for systematic review and meta-analysis protocol guidelines will inform the search and analysis plan to ensure that the synthesis of the data is as rigorous as possible. An approach based on critical interpretative synthesis will be adapted to include a thematic synthesis for the identification of higher-order themes and messages from a body of dissemination products generated by the Palliative Care Research Network. DISCUSSION: The thematic synthesis outlined in the present protocol offers a novel method of synthesising data from a focused research network that employs a variety of dissemination materials as a means of identifying key themes and messages from a specific body of research. The high-level themes and messages will be identified from the thematic synthesis, widely disseminated and targeted towards a range of stakeholders and knowledge users such as carers, health and social care professionals, policy makers and researchers. PMID- 27769318 TI - Perspectives on Canadian Postgraduate Education in Ophthalmology. PMID- 27769319 TI - Canadian ophthalmic microsurgery course: an innovative spin on wet lab-based surgical education. AB - Wet lab and surgical simulation can reduce the learning curve of difficult surgical techniques, accelerate the rate for trainees to achieve surgical competency, and improve patient safety. To provide the most up-to-date information and hands-on experiences with novel ophthalmic surgical techniques and instruments, the Department of Ophthalmology at Western University has created a wet lab-based, multilevel microsurgery skills transfer course through collaboration with various industry partners. Several elements in the course goal and design differentiate this type of surgical course from typical wet labs: the format is multileveled surgical training, with a beginner level targeting undergraduate medical students, an intermediate level for ophthalmology residents, and an advanced level for trained ophthalmologist. In addition, the level of industry participation allows the development of true partnership and offers a method to introduce awareness and innovation in a cost-effective manner. This article presents the organization, course setup, and feedback from the pilot course. PMID- 27769320 TI - Intravenous fluorescein angiography-associated adverse reactions. AB - OBJECTIVES: To assess (i) the adverse reactions (ARs) associated with intravenous fluorescein angiography (IVFA); (ii) the relationship between a known history of IVFA-associated AR and ARs on the subsequent IVFA test; and (iii) the dose response relationship between intravenous sodium fluorescein (NaFl) injection and ARs associated with IVFA. DESIGN: Retrospective chart review. PARTICIPANTS: A total of 2247 patients with 3381 consecutive IVFAs between May 2013 and April 2014. METHODS: Fisher's exact tests or chi2 tests were used to compare the percentage difference of IVFA-associated ARs for different categorical variables. Logistic regressions were used to assess the relationship between a known history of IVFA-associated AR and any AR(s) on a subsequent IVFA test. RESULTS: The overall percentage for IVFA-associated ARs was 3.3%. Adjusted for age and sex, patients who had a previous IVFA-associated AR(s) were 6.2 times more likely (adjusted odds ratio 95% CI 3.4-11.2, p < 0.0001) to have an AR compared to those who did not. Among 17 patients who had 2 repeated IVFA tests and an AR on the first IVFA test, the rate of AR on the second test was lower in patients who received a reduced dosage of NaFl (n = 14) compared to those with the standard dosage (n = 3) (35.7% vs 66.7%); however, this finding was not statistically significant (p = 0.5368). CONCLUSIONS: The rate of IVFA-associated ARs in this study was low. Patients who had a known IVFA-associated AR were more likely to re experience an AR on a subsequent test compared to those who did not. In addition, a reduced NaFl dose did not significantly reduce the chance of experiencing an AR on a subsequent test, which is likely because of the insufficient power of this comparison. PMID- 27769321 TI - Single-Exome sequencing identified a novel RP2 mutation in a child with X-linked retinitis pigmentosa. AB - OBJECTIVE: To present an efficient and successful application of a single-exome sequencing study in a family clinically diagnosed with X-linked retinitis pigmentosa. DESIGN: Exome sequencing study based on clinical examination data. PARTICIPANTS: An 8-year-old proband and his family. METHODS: The proband and his family members underwent comprehensive ophthalmologic examinations. Exome sequencing was undertaken in the proband using Agilent SureSelect Human All Exon Kit and Illumina HiSeq 2000 platform. Bioinformatic analysis used Illumina pipeline with Burrows-Wheeler Aligner-Genome Analysis Toolkit (BWA-GATK), followed by ANNOVAR to perform variant functional annotation. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation. RESULTS: Analysis of exome sequence data identified a novel frameshift mutation in RP2 gene resulting in a premature stop codon (c.665delC, p.Pro222fsTer237). Sanger sequencing revealed this mutation co-segregated with the disease phenotype in the child's family. CONCLUSIONS: We identified a novel causative mutation in RP2 from a single proband's exome sequence data analysis. This study highlights the effectiveness of the whole-exome sequencing in the genetic diagnosis of X-linked retinitis pigmentosa, over the conventional sequencing methods. Even using a single exome, exome sequencing technology would be able to pinpoint pathogenic variant(s) for X-linked retinitis pigmentosa, when properly applied with aid of adequate variant filtering strategy. PMID- 27769322 TI - Pars plana vitrectomy with silicone oil tamponade in failed scleral buckle surgery. AB - OBJECTIVE: This study aimed to evaluate the anatomical and functional outcomes of secondary pars plana vitrectomy (PPV) after failed scleral buckling (SB) surgery and to compare it with primary PPV for rhegmatogenous retinal detachment (RRD), including complicated proliferative vitreoretinopathy cases. DESIGN: Retrospective series in a tertiary care centre. PARTICIPANTS: One hundred and twenty consecutive patients. METHODS: The medical records of patients who underwent PPV with silicone oil tamponade for RRD were reviewed. Forty-four eyes were operated on for primary RRD (primary PPV group), and 76 eyes were operated on for failed SB surgery (secondary PPV group). The single-operation anatomical success rate, final anatomical success rate, and best-corrected visual acuity preoperatively, at 6 months, at 1 year, and at final follow-up were analyzed. RESULTS: The single-operation anatomical success rate was 74.2% in the primary PPV group and 77% in the secondary PPV group (p = 0.48). The final anatomical success rate was 90.3% in the primary PPV group and 91.8% in the secondary PPV group (p = 0.55). The number of cases with visual acuities of 3 visual categories (20/50 or better, 20/200 to 20/50, less than 20/200) was not statistically different at each time point. CONCLUSIONS: Consequent PPV with silicone oil tamponade for failed SB surgery seems not to have inferior anatomical and functional outcomes when compared with primary PPV for RRD. PMID- 27769323 TI - Test characteristics of point-of-care ultrasonography for the diagnosis of acute posterior ocular pathology. AB - OBJECTIVES: The objective of this study was to determine the test characteristics of point-of-care ultrasonography (POCUS) for the diagnosis of retinal tear (RT), retinal detachment (RD), posterior vitreous detachment (PVD), and vitreous hemorrhage (VH). DESIGN: A prospective observation study on a convenience sample of patients presenting to a tertiary care emergency general ophthalmology clinic was performed. PARTICIPANTS: Adult patients with acute flashes/floaters or new visual field defects were included (n = 62). METHODS: POCUS was performed by a study sonographer and compared with a retina specialist examination without sonography imaging. Sonographers were masked to clinical information. Follow-up was performed by a 6-week health records review. The primary outcome was the diagnosis of RD/RT, PVD, and VH. Analyses included descriptive statistics and test characteristics. RESULTS: A total of 62 patients with a mean age of 60.8 years were enrolled; 62.9% were female. The mean time to scan required was 7.4 minutes. There was no change in diagnosis at 6 weeks. The sensitivities and specificities, respectively, are as follows: any pathology (n = 60) 88.3% (95% CI 86.8%-89.9%) and 50% (95% CI 2.7%-97.3%); RD (n = 6) 100% (95% CI 53.9%-100%) and 67.9% (95% CI 62.9%-67.9%); RD/RT (n = 23) 47.8% (95% CI 30.8%-62.2%) and 82.1% (95% CI 72.0%-90.6%); PVD (n = 47) 80.9% (95% CI 74.7%-88.0%) and 33.3% (95% CI 14.0%-55.7%); and VH (n = 14) 43.0% (95% CI 21.4%-58.0%) and 93.8% (95% CI 87.5% 98.2%). CONCLUSIONS: Ocular POCUS detected all RDs but has limited use for the diagnosis of RTs. Patients with suspected acute ocular posterior pathology should be referred to ophthalmology independent of ocular POCUS. PMID- 27769324 TI - Effect of aflibercept on refractory macular edema associated with central retinal vein occlusion. AB - OBJECTIVE: To report short-term visual and anatomic outcomes of patients who were switched to aflibercept for persistent macular edema associated with central retinal vein occlusion (CRVO). METHODS: Retrospective, consecutive, interventional case series of 17 patients with persistent macular edema secondary to CRVO (defined as intraretinal edema and either <50 um reduction in central foveal thickness [CFT] or worsening or no improvement in visual acuity [VA] compared to baseline) despite anti-VEGF treatment who were switched to aflibercept treatment. Main outcome measures included VA, anti-VEGF treatment history, and spectral-domain optical coherence tomography evaluation of macular edema and CFT. RESULTS: The mean age was 77 years, and the mean VA at CRVO diagnosis was 20/135 with a CFT of 523.4 um. Mean number of injections before switching to aflibercept was 12.9 (range: 3-40) and mean number of months of anti VEGF treatment before switching to aflibercept was 18.7. Mean VA at switch to aflibercept was 20/182 (p = 0.50) with mean CFT of 547.9 um (p = 0.66). Mean aflibercept injections were 4.0, and mean follow-up from switch to last follow-up was 5.2 months. Final mean VA was 20/115 (p = 0.017), with a CFT of 315.2 um (p = 0.0012). Of the patients, 35.2% gained >=3 lines. 29% of patients had complete resolution of macular edema, and the mean change in CFT was -233 um. CONCLUSIONS: Aflibercept appears to have a beneficial effect on anatomic and VA outcomes in a subset of patients with macular edema secondary to CRVO that is refractory to treatment with bevacizumab and/or ranibizumab. PMID- 27769325 TI - Hypertension as a risk factor for recurrent subretinal hemorrhage in polypoidal choroidal vasculopathy. AB - OBJECTIVE: To investigate the relationship between hypertension and recurrent subretinal hemorrhage (SRH) in eyes with polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective, comparative case series. PARTICIPANTS: Thirty-eight eyes of 38 patients with PCV. METHODS: Ocular findings and clinical features were analyzed retrospectively in patients with PCV enrolled from January 2011 to December 2013. The patients were divided into 2 groups according to the presence of recurrent SRH after successful initial treatment (rebleeding vs nonrebleeding) and were subdivided into those with and without hypertension, based on history of hypertension, systolic blood pressure (SBP) >150 mm Hg. The relationship between hypertension and recurrent SRH was analyzed. RESULTS: Thirty-eight patients (38 eyes) were included in this analysis. High SBP or history of hypertension was significantly more frequent in the rebleeding group than in the nonrebleeding group (p = 0.014). Subgroup analysis showed that mean time until recurrent SRH was significantly shorter in the hypertensive group than in the nonhypertensive group (p = 0.025). The cumulative incidence of recurrent SRH at 2 years was 43% in the hypertensive group and 20% in the nonhypertensive group. Cox regression after adjustment for age showed that hypertension was associated with a 3.9-fold greater risk of recurrent SRH (p = 0.039). CONCLUSIONS: Recurrent SRH in patients with PCV was more common in hypertensive subjects. Undiagnosed hypertension should be considered when assessing the prognosis of patients with PCV. PMID- 27769327 TI - Characteristics of the preferred retinal loci of better and worse seeing eyes of patients with a central scotoma. AB - OBJECTIVE: Patients with central vision loss develop preferred retinal loci (PRLs) in the eccentric retina. The characteristics of the PRLs for the better eye (BE) are well studied, but not those of the worse eye (WE). We examined the distribution of monocular PRLs in the visual field (VF), as well as visual acuity, fixation stability, and PRL eccentricity for the BE and WE of patients with central vision loss. DESIGN: Retrospective consecutive case series. PARTICIPANTS: A total of 87 BE and 50 WE of patients with central vision loss. METHODS: Visual acuity, fixation stability, PRL location, and PRL eccentricity measures were retrieved from our database. PRL location was categorized into 5 VF segments: central, superior, inferior, left, and right. RESULTS: For BE, PRL frequency distribution was significantly different for the 5 VF segments, chi2(4) = 19.9, p = 0.001. Most PRLs occurred in inferior (31%) and left (31%) VF segments. Visual acuity, fixation stability, and PRL eccentricity depended on the VF segment. Visual acuity correlated with fixation stability and PRL eccentricity. For WE, PRL frequency distribution was not different for the 5 VF segments and visual acuity was not dependent on the VF segment. No relationships between visual acuity and PRL eccentricity or fixation stability were found. CONCLUSIONS: Different patterns of PRL characteristics were found for BEs and for WEs. These findings are important to consider when factors such as PRL eccentricity, visual acuity, fixation stability, and PRL location are used as outcome measures after treatment or rehabilitation and when monitoring disease progression. PMID- 27769326 TI - Topographic profile of choroid in eyes after acute primary angle-closure. AB - OBJECTIVE: To characterize and compare the topographic profile of choroid in eyes after acute primary angle-closure (APAC) and in normal controls. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was conducted. Forty-four consecutive patients who had experienced unilateral APAC that was resolved by treatment were recruited. Seventy age- and sex-matched normal individuals were recruited as controls. METHODS: Enhanced depth imaging-optical coherence tomography was used to measure choroidal thickness (CT) in 9 diffuse locations of macular region. The average CT was compared among each location in the APAC and control groups and between the same locations in the 2 groups. RESULTS: Variants of CT at different macular locations were found in both groups; it was greatest at subfoveal locations and spread thinner around them, to reach a significant decrease (all p <= 0.05) 3 mm away in all directions from the fovea except for the superior direction in normal controls (p = 0.472). Among the 4 directions, the superior had the thickest CT in both groups, followed by the temporal, inferior, and nasal directions in both groups, whereas the APAC had a thicker choroid profile at each location (all p < 0.05). Univariate analysis showed that age, sex, anterior chamber depth, axial length, and spherical equivalent were all associated with the subfoveal choroidal thickness (SFCT) (all p < 0.1). Multivariable linear regression analysis showed that the SFCT was significantly thicker in association with an APAC diagnosis, shorter axial length, greater spherical equivalent refractive error, and younger female subjects (all p <= 0.05). CONCLUSIONS: APAC eyes have a thicker choroid than normal eyes in the macular region, and the increase in CT in APAC eyes follows topographic distribution as in normal control eyes. PMID- 27769328 TI - Low power and type II errors in recent ophthalmology research. AB - OBJECTIVE: To investigate the power of unpaired t tests in prospective, randomized controlled trials when these tests failed to detect a statistically significant difference and to determine the frequency of type II errors. DESIGN: Systematic review and meta-analysis. METHODS: We examined all prospective, randomized controlled trials published between 2010 and 2012 in 4 major ophthalmology journals (Archives of Ophthalmology, British Journal of Ophthalmology, Ophthalmology, and American Journal of Ophthalmology). Studies that used unpaired t tests were included. Power was calculated using the number of subjects in each group, standard deviations, and alpha = 0.05. The difference between control and experimental means was set to be (1) 20% and (2) 50% of the absolute value of the control's initial conditions. Power and Precision version 4.0 software was used to carry out calculations. Finally, the proportion of articles with type II errors was calculated. beta = 0.3 was set as the largest acceptable value for the probability of type II errors. RESULTS: In total, 280 articles were screened. Final analysis included 50 prospective, randomized controlled trials using unpaired t tests. The median power of tests to detect a 50% difference between means was 0.9 and was the same for all 4 journals regardless of the statistical significance of the test. The median power of tests to detect a 20% difference between means ranged from 0.26 to 0.9 for the 4 journals. The median power of these tests to detect a 50% and 20% difference between means was 0.9 and 0.5 for tests that did not achieve statistical significance. A total of 14% and 57% of articles with negative unpaired t tests contained results with beta > 0.3 when power was calculated for differences between means of 50% and 20%, respectively. CONCLUSIONS: A large portion of studies demonstrate high probabilities of type II errors when detecting small differences between means. The power to detect small difference between means varies across journals. It is, therefore, worthwhile for authors to mention the minimum clinically important difference for individual studies. Journals can consider publishing statistical guidelines for authors to use. Day-to-day clinical decisions rely heavily on the evidence base formed by the plethora of studies available to clinicians. Prospective, randomized controlled clinical trials are highly regarded as a robust study and are used to make important clinical decisions that directly affect patient care. The quality of study designs and statistical methods in major clinical journals is improving overtime,1 and researchers and journals are being more attentive to statistical methodologies incorporated by studies. The results of well-designed ophthalmic studies with robust methodologies, therefore, have the ability to modify the ways in which diseases are managed. PMID- 27769329 TI - Evaluation of Canadian undergraduate ophthalmology medical education at Western University. AB - To assess and evaluate the current level of ophthalmology knowledge and teaching curriculum in undergraduate year 3 (MS-3) at Western University. The Undergraduate Medical Education Curriculum at Western University has instituted additional ophthalmology lecture series to all MS-3 students. A test on basic ophthalmic knowledge was administered to MS-3 students immediately before and after lecture series to evaluate the level of knowledge at baseline and after ophthalmology didactic teaching. An evaluation survey was also given to MS-3 students to assess students' self-perceived level of competency, exposure, and interests in ophthalmology. A total of 134 students attended the ophthalmology lecture series in the study, and 88.1% of students completed the pretest, post test, and Ophthalmology Education Survey. The average pretest and post-test scores were 40.7% and 75.6% (p < 0.01), respectively. The average rating from MS 3 students for ophthalmology exposure during medical school education was 2.11 (1 = "very minimal" and 5 = "more than adequate"). The average rating for desire for additional didactic ophthalmology lectures was 4.02 (1 = "strongly disagree" and 5 = "strongly agree"). The average rating for interest in ophthalmology was 2.74 (1 = "very little interest" and 5 = "very strong interest"). The additional ophthalmology lecture series had a positive impact on the level of ophthalmic knowledge among MS-3 students, and a strong desire for more ophthalmology teaching during medical school education was identified, as evidenced by the survey undertaken by students after the lectures. PMID- 27769330 TI - Discrepancies in physician-patient agreement in reporting ocular history. AB - OBJECTIVE: The purpose of this study was to investigate the extent of agreement between physicians and patients in reporting ocular history and to determine whether there are any predictive factors for physician-patient consensus. DESIGN: Retrospective chart review. PARTICIPANTS: Between June and September 2014, adult patients undergoing cataract surgery were recruited for the study. METHODS: Before surgery, patient demographics and self-reported ocular history were extracted from a prospectively collected database. Medical charts were retrospectively examined to retrieve physician-reported ocular history. RESULTS: One hundred and thirty-eight patients participated. Mean cohort logMAR visual acuity was 0.46 +/- 0.34 (Snellen equivalent of approximately 20/60) and mean age was 74.1 +/- 8.3 years. For glaucoma, Cohen's kappa revealed a moderate-to-good concordance between physicians and patients (kappa = 0.604), whereas a poor-to fair level of agreement existed in reporting maculopathy, such as age-related macular degeneration and macular holes (kappa = 0.254). The logistic regression model revealed that preoperative visual acuity (p = 0.223), sex (p = 0.736), age (p = 0.910), and education (p = 0.738) were not significant predictors of physician-patient agreement. CONCLUSIONS: The accuracy of patient-reported ocular history varies by pathology. Self-reported glaucoma history is consistent between patients and physicians; however, patients under-report the diagnosis of maculopathy. Age, sex, and level of education do not appear to influence patient reported accuracy of ocular comorbidities. PMID- 27769331 TI - Purpureocillium lilacinum keratitis: a case series and review of the literature. AB - OBJECTIVE: To describe the clinical features and risk factors of and optimal antifungal therapy for Purpureocillium lilacinum keratitis. DESIGN: Retrospective case series in a quaternary referral hospital setting. METHODS: Comprehensive chart review of patients diagnosed with P. lilacinum keratitis in the past 10 years. PARTICIPANTS: Four patients were identified. All were aged 60 years or greater, with none having prior ocular trauma. Two had significant potential environmental exposure risks, and 3 were using systemic immunosuppressants for scleritis. RESULTS: All cases received empirical treatment that included topical corticosteroids. Three were treated with combined oral, topical, and intracameral voriconazole, but developed endophthalmitis necessitating surgery with poor outcomes, including enucleation in 2. One case received combined oral and topical voriconazole with terbinafine, and maintained visual acuity without the need for surgery. All P. lilacinum isolates were susceptible to voriconazole. CONCLUSIONS: P. lilacinum keratitis is rare, with the major risk factor being immunosuppression. There may be no history of ocular trauma. Microbiological diagnosis and antifungal susceptibility testing is essential. Combination synergistic antifungal therapy with topical voriconazole and oral terbinafine, with addition of systemic voriconazole if needed, results in the best outcome. PMID- 27769332 TI - "Low-tech" simulation of corneal foreign body removal. PMID- 27769333 TI - Truth-telling and deception in the management of nonorganic vision loss. PMID- 27769334 TI - Generic glaucoma drop bottle cap colours. PMID- 27769335 TI - Dissociated optic nerve fibre layer after Nd:YAG laser membranotomy for premacular hemorrhage. PMID- 27769336 TI - Transient macular edema after standard dose of intracameral cefuroxime injection during phacoemulsification. PMID- 27769337 TI - Aids to statistics literacy for ophthalmologists. PMID- 27769338 TI - Orbital dermoid masquerading as allergic lid swelling. PMID- 27769340 TI - TegadermTMdressing and Lacri-lube ointment moisture chamber to manage exposure keratopathy. PMID- 27769339 TI - Case of Actinomyces lacrimal sac abscess mimicking malignancy. PMID- 27769341 TI - Sebaceous adenomas in the absence of Muir-Torre syndrome. PMID- 27769342 TI - Quizzical optical coherence tomography. PMID- 27769343 TI - Acute myelogenous leukemia presenting with uveitis, optic disc edema, and granuloma annulare: Case report. PMID- 27769344 TI - Epibulbar schwannoma: a case report and review of the literature. PMID- 27769345 TI - Abducens neuromyotonia: a delayed neuro-ophthalmic complication of cranial radiation. PMID- 27769346 TI - [Questioning about "young schizophrenics"]. PMID- 27769347 TI - [A model of care for first-episode psychosis: the RAISE-ETP project]. PMID- 27769348 TI - [Schizophrenia and addictions: dangerous links]. PMID- 27769349 TI - [Attenuated psychosis syndrome in DSM-5]. PMID- 27769350 TI - [Trauma and post-traumatic stress disorder in schizophrenia]. PMID- 27769351 TI - Bromodomains as targets for therapeutic intervention. PMID- 27769352 TI - Phospho-BRD4: transcription plasticity and drug targeting. AB - BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment necessitates a better understanding of alternative pathways underlying not only the resistance but also persistent BET protein dependence for identifying new targets and effective combination therapy strategies. PMID- 27769354 TI - Role of BET proteins in castration-resistant prostate cancer. AB - Castration resistant prostate cancer (CRPC) is a deadly disease with few therapeutic options once patients become resistant to second generation drugs targeting the AR-transcriptional program. The BET-BRD readers of chromatin are key regulators of AR-, ERG-, and c-Myc-mediated transcription in CRPC. BET-BRD inhibitors have demonstrated pre-clinical efficacy in models of CRPC and are currently being evaluated in several clinical trials. These novel drugs have the potential to transform the way we treat CRPC in the near future. PMID- 27769353 TI - Erythropoiesis provides a BRD's eye view of BET protein function. AB - Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping functions of BET protein family members BRD2, BRD3, and BRD4. These studies have important ramifications for our understanding of the molecular and physiologic roles of BET proteins, and provide a framework for elucidating some of the beneficial and adverse effects of pharmacologic inhibitors. PMID- 27769356 TI - Suppression of TH17-mediated pathology through BET bromodomain inhibition. AB - Epigenetic control of gene expression is enforced in part through histone modifications. Bromodomain and extra terminal domain (BET) proteins function as crucial chromatin readers, responsible for interpretation of the chromatin code in diverse cellular contexts, ultimately impacting gene transcription. BET proteins can play a major role in inflammation by profoundly affecting the biology of the Thelper 17 (TH17) lineage. We summarize recent studies focusing on BET inhibition as a viable therapeutic alternative for the control of autoimmune diseases driven by aberrant activation of TH17 cells. PMID- 27769355 TI - Structural features and inhibitors of bromodomains. AB - Bromodomains are conserved structural modules responsible for recognizing acetylated-lysine residues on histone tails and other transcription-associated proteins, such as transcription factors and co-factors. Owing to their important functions in the regulation of ordered gene transcription in chromatin, bromodomains of the BET family proteins have recently been shown as druggable targets for a wide array of human diseases, including cancer and inflammation. Here we review the structural and functional features of the bromodomains and their small-molecule inhibitors. Additional new insights provided herein highlight the landscape of the ligand binding sites in the bromodomains that will hopefully facilitate further development of new inhibitors with optimal affinity and selectivity. PMID- 27769358 TI - The exploitation of FRET probes to track bromodomain/histone interactions in cells for bromodomain inhibitors. AB - Bromodomain-containing proteins are epigenetic readers of histone codes, which recognize acetylated histones and are involved in transcription, nucleosome remodeling and DNA repair. Chromosomal translocations of bromodomain-containing proteins have been implicated in many diseases. In this regard, small molecules that inhibit bromodomains are promising as therapeutic agents. A fluorescence microscopy-based approach provides information on bromodomain inhibitors that abrogate the interaction between acetylated histones and bromodomains in living cells. We have developed genetically encoded fluorescent probes for histone acetylation called Histacs. We review how these recently developed probes can serve as useful tools to evaluate the intracellular activity of bromodomain inhibitors. PMID- 27769357 TI - Clinical trials for BET inhibitors run ahead of the science. AB - Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles. PMID- 27769359 TI - Regulation of gene expression in human cancers by TRIM24. AB - Tripartite Motif-containing protein 24 (TRIM24) functions as an E3 ligase targeting p53 for ubiquitination, a histone 'reader' that interacts with a specific signature of histone post-translational modifications and a co-regulator of nuclear receptor-regulated transcription. Although mouse models of Trim24 depletion suggest that TRIM24 may be a liver-specific tumor suppressor, several studies show that human TRIM24 is an oncogene when aberrantly over expressed. This review focuses on the mechanisms of TRIM24 functions in oncogenesis and metabolic reprogramming, which underlie recent interest in therapeutic targeting of aberrant TRIM24 in human cancers. PMID- 27769360 TI - Development of small molecule inhibitors of BRPF1 and TRIM24 bromodomains. AB - The entry of small molecule inhibitors of the bromodomain and extra C-terminal domain (BET) family of bromodomains into the clinic has demonstrated the therapeutic potential for this class of epigenetic acetyl-lysine reader proteins. Within the past two years, the development of potent inhibitors for the bromodomain and PHD finger containing protein (BRPF) family and the tripartite motif containing protein 24 (TRIM24) have been reported and are the subject of this review. Both proteins contain other domains with diverse functions and can also be part of a complex of proteins which have implications in epigenetic signaling and disease. These new small molecule tools will be useful for unraveling the biological contribution of the bromodomain and enable pharmacological validation of these proteins. PMID- 27769361 TI - Development of chemical probes for the bromodomains of BRD7 and BRD9. AB - The bromodomain family of proteins are 'readers' of acetylated lysines of histones, a key mark in the epigenetic code of gene regulation. Without high quality chemical probes with which to study these proteins, their biological function, and potential use in therapeutics, remains unknown. Recently, a number of chemical ligands were reported for the previously unprobed bromodomain proteins BRD7 and BRD9. Herein the development and characterisation of probes against these proteins is detailed, including the preliminary biological activity of BRD7 and BRD9 assessed using these probes. Future studies utilising these chemically-diverse compounds in parallel will allow for a confident assessment of the role of BRD7/9, and give multiple entry points into any subsequent pharmaceutical programs. PMID- 27769362 TI - Fragment-based in silico screening of bromodomain ligands. AB - We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low micromolar affinity and favorable ligand efficiency. Importantly, the binding modes predicted by docking have been validated by X-ray crystallography. One of the hits for the CREBBP bromodomain has been optimized by medicinal chemistry into a series of potent and selective ligands. PMID- 27769363 TI - Should Ultrasound Be Used Routinely to Guide Botulinum Toxin Injections for Spasticity? PMID- 27769364 TI - Re: Electrosonodiagnosis in Carpal Tunnel Syndrome: A Proposed Diagnostic Algorithm Based on an Analytic Literature Review. PMID- 27769365 TI - Reply. PMID- 27769366 TI - Disability Stigma in Rehabilitation. PMID- 27769367 TI - What can synthetic biology offer to artificial intelligence (and vice versa)? PMID- 27769368 TI - Mercury(II) selective sensors based on AlGaN/GaN transistors. AB - This work presents the first polymer approach to detect metal ions using AlGaN/GaN transistor-based sensor. The sensor utilised an AlGaN/GaN high electron mobility transistor-type structure by functionalising the gate area with a polyvinyl chloride (PVC) based ion selective membrane. Sensors based on this technology are portable, robust and typically highly sensitive to the target analyte; in this case Hg2+. This sensor showed a rapid and stable response when it was introduced to solutions of varying Hg2+ concentrations. At pH 2.8 in a 10 2 M KNO3 ion buffer, a detection limit below 10-8 M and a linear response range between 10-8 M-10-4 M were achieved. This detection limit is an order of magnitude lower than the reported detection limit of 10-7 M for thioglycolic acid monolayer functionalised AlGaN/GaN HEMT devices. Detection limits of approximately 10-7 M and 10-6 M in 10-2 M Cd(NO3)2 and 10-2 M Pb(NO3)2 ion buffers were also achieved, respectively. Furthermore, we show that the apparent gate response was near-Nernstian under various conditions. X-ray photoelectron spectroscopy (XPS) experiments confirmed that the sensing membrane is reversible after being exposed to Hg2+ solution and rinsed with deionised water. The success of this study precedes the development of this technology in selectively sensing multiple ions in water with use of the appropriate polymer based membranes on arrays of devices. PMID- 27769369 TI - Resonance energy transfer between ZnCdHgSe quantum dots and gold nanorods enhancing photoelectrochemical immunosensing of prostate specific antigen. AB - Gold nanorods (AuNRs) integrated with ZnCdHgSe near-infrared quantum dots (AuNRs ZnCdHgSe QDs) were successfully synthesized and characterized by transmission electron microscope, X-ray photoelectron spectroscopy, and X-ray diffraction. A glassy carbon electrode was decorated with the aforementioned AuNRs-ZnCdHgSe QDs nanocomposite, which provides a biocompatible interface for the subsequent immobilization of prostate specific antibody (anti-PSA). After being successively treated with glutaraldehyde vapor and bovine serum albumin solution, a photoelectrochemical immunosensing platform based on anti-PSA/AuNRs-ZnCdHgSe QDs/GCE was established. The photocurrent response of ZnCdHgSe QDs was tremendously improved by AuNRs due to the effect of resonance energy transfer which can be deduced from the dependence of the enhanced efficiency on the AuNRs with different length-to-diameter ratios and spectral absorption characteristics. A maximum photocurrent was obtained when the absorption spectrum of AuNRs matched well with the emission spectrum of ZnCdHgSe QDs. A photoelectrochemical immunosensor for prostate specific antigen (PSA) was achieved by monitoring the photocurrent variation. The photocurrent variation before and after being interacted with PSA solution exhibits a good linear relationship with the logarithm of its concentration (logcPSA) in the range from 1.0 pg mL-1 to 50.0 ng mL-1. The detection limit of this photoelectrochemical immunosensor is able to reach 0.1 pg mL-1 (S/N = 3). Determining PSA in clinical human serum was also demonstrated by using the developed anti-PSA(BSA)/AuNRs-ZnCdHgSe QDs/GCE electrode. The results were comparable with those obtained from an enzyme-linked immunosorbent assay method. PMID- 27769370 TI - G-quadruplex fluorescent probe-mediated real-time rolling circle amplification strategy for highly sensitive microRNA detection. AB - Real-time PCR has revolutionized PCR from qualitative to quantitative. As an isothermal DNA amplification technique, rolling circular amplification (RCA) has been demonstrated to be a versatile tool in many fields. Development of a simple, highly sensitive, and specific strategy for real-time monitoring of RCA will increase its usefulness in many fields. The strategy reported here utilized the specific fluorescence response of thioflavin T (ThT) to G-quadruplexes formed by RCA products. Such a real-time monitoring strategy works well in both traditional RCA with linear amplification efficiency and modified RCA proceeded in an exponential manner, and can be readily performed in commercially available real time PCR instruments, thereby achieving high-throughput detection and making the proposed technique more suitable for biosensing applications. As examples, real time RCA-based sensing platforms were designed and successfully used for quantitation of microRNA over broad linear ranges (8 orders of magnitude) with a detection limit of 4 aM (or 0.12 zmol). The feasibility of microRNA analysis in human lung cancer cells was also demonstrated. This work provides a new method for real-time monitoring of RCA by using unique nucleic acid secondary structures and their specific fluorescent probes. It has the potential to be extended to other isothermal single-stranded DNA amplification techniques. PMID- 27769371 TI - A solid colorimetric sensor for the analysis of amphetamine-like street samples. AB - A solid sensor obtained by embedding 1,2-naphthoquinone-4-sulfonate (NQS) into polydimethylsiloxane/tetraethylortosilicate/silicon dioxide nanoparticles composite has been developed to identify and determine amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxymetamphetamine (MDMA) and 3,4 methylenedioxyamphetamine (MDA). The analytes are derivatized inside the composite for 10 min to create a colored product which can be then quantified by measuring the diffuse reflectance or the color intensity after processing the digitalized image. Satisfactory limits of detection (0.002-0.005 g mL-1) and relative standard deviations (<10%) have been achieved. The proposed kit has been successfully validated and applied to the analysis of amphetamine-like drugs street samples. The kit allows the in-situ screening of the mentioned illicit drugs owing to its simplicity, rapidity and portability, with excellent sensor stability and at a very low-cost. PMID- 27769372 TI - An integrated device of electrodialytic membrane suppressor and charge detector for ion chromatography. AB - An integrated device of electrodialytic membrane suppressor and charge detector (CHD) for ion chromatography (IC) is described, aiming to simplify system complexity and reduce possible extra-column dispersion as well. The device is a flow-through design consisting of five chambers isolated by ion exchange membranes and ionic screens. Two independent electric sources are used to respectively supply CHD and suppressor sections of the device, and a common electrode serves both the cathode of CHD and the anode of suppressor simultaneously. The integrated device has similar performance as a separate suppressor or a CHD while its dead volume and dispersion are reduced ~18% and ~37% compared with the combination of a CHD and a suppressor. To our knowledge, this is the first description of such an integrated device with dual functionalities of suppression and CHD. PMID- 27769374 TI - Fluorescence based fiber optic and planar waveguide biosensors. A review. AB - The application of optical biosensors, specifically those that use optical fibers and planar waveguides, has escalated throughout the years in many fields, including environmental analysis, food safety and clinical diagnosis. Fluorescence is, without doubt, the most popular transducer signal used in these devices because of its higher selectivity and sensitivity, but most of all due to its wide versatility. This paper focuses on the working principles and configurations of fluorescence-based fiber optic and planar waveguide biosensors and will review biological recognition elements, sensing schemes, as well as some major and recent applications, published in the last ten years. The main goal is to provide the reader a general overview of a field that requires the joint collaboration of researchers of many different areas, including chemistry, physics, biology, engineering, and material science. PMID- 27769373 TI - Hydrophilic molecularly imprinted melamine-urea-formaldehyde monolithic resin prepared in water for selective recognition of plant growth regulators. AB - New hydrophilic molecularly imprinted melamine-urea-formaldehyde monolithic resin (MIMR) is synthesized using dopamine hydrochloride as a dummy template via in situ polymerization directly within pipette tips and it presents special molecular recognition to plant growth regulators in aqueous matrices. Hydrophilic groups (such as hydroxyl groups, imino groups, and amino groups) can be introduced into MIMR by melamine- urea-formaldehyde resin, which make MIMR materials compatible with aqueous media and show their specific molecular recognition in aqueous sample solutions. Meanwhile, monolithic structures avoid the influence of uneven filling on the extraction efficiency. Various parameters affecting the selective recognition of MIMR have been optimized, such as molar ratio of melamine to urea, molar ratio of melamine and urea to formaldehyde, the amount of template and porogen. The prepared MIMR is applied as the sorbents of solid phase extraction (SPE) for sensitive and selective recognition of three plant growth regulators (p-chlorophenoxyacetic acid, 1-naphthaleneacetic acid and 2.4-dichlorophenoxyacetic acid) in bean sprouts. Considering its excellent hydrophilicity and specificity, MIMR-SPE is promising to be a potential pretreatment strategy in biological, environmental, and clinical fields. PMID- 27769375 TI - Species specific isotope dilution for the accurate and SI traceable determination of arsenobetaine and methylmercury in cuttlefish and prawn. AB - Methods based on species specific isotope dilution were developed for the accurate and SI traceable determination of arsenobetaine (AsBet) and methylmercury (MeHg) in prawn and cuttlefish tissues by LC-MS/MS and SPME GC ICPMS. Quantitation of AsBet and MeHg were achieved by using a 13C-enriched AsBet spike (NRC CRM CBET-1) and an enriched spike of Me198Hg (NRC CRM EMMS-1), respectively, wherein analyte mass fractions in enriched spikes were determined by reverse isotope dilution using natural abundance AsBet and MeHg primary standards. Purity of these primary standards were characterized by quantitative 1H-NMR with the use of NIST SRM 350b benzoic acid as a primary calibrator, ensuring the final measurement results traceable to SI. Validation of employed methods of ID LC-MS/MS and ID SPME GC-ICPMS was demonstrated by analysis of several biological CRMs (DORM-4, TORT-3, DOLT-5, BCR-627 and BCR-463) with satisfying results. The developed methods were applied for the determination of AsBet and MeHg in two new certified reference materials (CRMs) prawn (PRON-1) and cuttlefish (SQID-1) produced jointly by Thailand Institute of Scientific and Technological Research (TISTR) and National Research Council Canada (NRC). With additional measurements of AsBet using LC-ICPMS with standard additions calibration and external calibration at NRC and TISTR, respectively, certified values of 1.206 +/- 0.058 and 13.96 +/- 0.54 mg kg-1 for AsBet as As (expanded uncertainty, k = 2) were obtained for the new CRMs PRON-1 and SQID-1, respectively. The reference value of 0.324 +/- 0.028 mg kg-1 as Hg (expanded uncertainty, k = 2) for MeHg was obtained for the SQID-1 based on the results obtained by ID SPME GC-ICPMS method only, whereas MeHg in PRON-1 was found to be < 0.015 mg kg-1. It was found that AsBet comprised 69.7% and 99.0% of total As in the prawn and cuttlefish, respectively, whereas MeHg comprised 94.5% of total Hg in cuttlefish. PMID- 27769376 TI - Solid contact ion sensor with conducting polymer layer copolymerized with the ion selective membrane for determination of calcium in blood serum. AB - A new solid contact ion selective electrode with intermediate conducting polymer (CP) layer formed by electropolymerization on a gold electrode of a bifunctional monomer, n-phenyl-ethylenediamine-methacrylamide (NPEDMA), which contains a methacrylamide group attached to aniline, is presented. The conducting polymer was studied by means of optical spectroscopy, cyclic voltammetry and potentiometric measurements. Ca2+-ion-selective membrane based on acrylated urethane polymer was shown to co-polymerize with the CP forming highly adhesive boundary that prevents formation of water layers between the CP and membrane, thus enhancing the stability and life-time of the sensor. The designed ion selective electrode was successfully used for determination of total calcium ion concentration in blood serum samples. PMID- 27769377 TI - Identification of glutathione by voltammetric analysis with rolling circle amplification. AB - Glutathione (GSH), a common tripeptide, plays an essential role in a variety of cellular functions. GSH level is reported to be closely related to human health. In this study, we fabricate an ultrasensitive electrochemical biosensor for GSH quantification. DNA probes are firstly modified on the electrode surface and thymine-Hg2+-thymine is formed. Since GSH is able to chelate Hg2+ from the DNA mismatched sites effectively, which leads to DNA structural switching from hairpin to linear strand, rolling circle amplification (RCA) could be initiated with the released linear primer probe. The RCA product with multiple repeating sequences further captures numerous DNA modified silver nanoparticles (AgNPs) by the hybridization of complementary sequences. Stripping voltammetric responses of AgNPs are then detected to reveal GSH concentration. The linear detection range is from 0.1 pM to 10 nM and the limit of detection is 0.1 pM, which is lower than most current analytical methods. This method is also highly selective and functions well against a series of interferents. Additionally, the proposed method has been successfully utilized in human serum samples, which shows fairly good potential in clinical applications. PMID- 27769378 TI - Micro-electromembrane extraction using multiple free liquid membranes and acceptor solutions - Towards selective extractions of analytes based on their acid-base strength. AB - This work investigated selective micro-electromembrane extractions (MU-EMEs) of the colored indicators metanil yellow and congo red (visual proof-of-principle) and the small drug substances nortriptyline, papaverine, mianserin, and citalopram (model analytes) based on their acid-base strength. With two free liquid membranes (FLMs), the target analytes were extracted from aqueous donor solution, across FLM 1 (1-pentanol, 1-ethyl-2-nitrobenzene (ENB) or 4-nitrocumene (4-NC)), into aqueous acceptor solution 1, further across FLM 2 (1-pentanol, ENB or 4-NC), and finally into aqueous acceptor solution 2. All phases had volumes between 1.0 and 1.5 MUL and extractions were promoted by 200-300 V d.c. applied across the five-phase MU-EME system formed in a perfluoroalkoxy capillary tubing. The anode was located in acceptor solution 2 and the cathode was located in donor solution for MU-EMEs of acidic analytes, and locations of the electrodes were vice versa for MU-EMEs of basic analytes. After MU-EME, donor solution and acceptor solution 1 and 2 were analyzed by capillary electrophoresis or liquid chromatography-mass spectrometry. The model analytes migrated efficiently in the proposed MU-EME system, their migration behavior was controlled by pH in aqueous solutions and their selective fractionation into acceptor solution 1 and 2 was demonstrated based on their acid-base strength. Under optimal conditions, acceptor solution 2 contained 60% nortriptyline (pKa = 10.5) and less than 1% papaverine (pKa = 6.0) and acceptor solution 1 contained 17% nortriptyline and 27% papaverine after 15 min of MU-EME. The five-phase MU-EME system was also compatible with human plasma samples. Work is in progress to further increase the fractionation capability, and to implement the concept into microfluidic platforms. PMID- 27769379 TI - Polydopamine-sheathed electrospun nanofiber as adsorbent for determination of aldehydes metabolites in human urine. AB - In this paper, a novel polydopamine modified polystyrene/graphene electrospun nanofiber membrane (PS/G@PDA) was fabricated on the surface of filter paper and used for thin film microextraction (TFME) for the first time. Benefiting from the hydrophilic polydopamine (PDA) coating and the porous fibrous structure, the PS/G@PDA membrane exhibited large surface area, high extraction efficiency, rapid extraction equilibrium, special selectivity and excellent biocompatibility. A thin film microextraction-high performance liquid chromatography method was developed and applied for the analysis of six aldehyde metabolites in human urine samples. Under the optimal conditions, the recoveries of the aldehyde compounds varied in the range of 83%-115%, with the relative standard deviation values lower than 14.5% (n = 5). Moreover, satisfactory sensitivities with the limits of detection in the range of 2.3-6.5 nmol L-1 and good linearity with excellent correlation coefficients (R2) being larger than 0.9936 had also been achieved. In general, a fast, convenient, sensitive, high-efficient and matrix-free method was successfully proposed and expected becoming a promising approach for the determination of trace aldehyde metabolites in complex biological samples. PMID- 27769380 TI - Liquid phase separation methods for N-glycosylation analysis of glycoproteins of biomedical and biopharmaceutical interest. A critical review. AB - Comprehensive carbohydrate analysis of glycoproteins from human biological samples and biotherapeutics are important from diagnostic and therapeutic points of view. This review summarizes the current state-of-the-art liquid phase separation techniques used in N-glycosylation analysis. The different liquid chromatographic techniques and capillary electrophoresis methods are critically discussed in detail. Miniaturization of these methods is also important to increase throughput and decrease analysis time. The sample preparation and labeling methods for asparagine linked oligosaccharides are also addressed. PMID- 27769381 TI - Confirmatory and quantitative analysis of fatty acid esters of hydroxy fatty acids in serum by solid phase extraction coupled to liquid chromatography tandem mass spectrometry. AB - A novel class of endogenous mammalian lipids endowed with antidiabetic and anti inflammatory properties has been recently discovered. These are fatty acid esters of hydroxy fatty acids (FAHFAs) formed by condensation between a hydroxy fatty acid and a fatty acid. FAHFAs are present in human serum and tissues at low nanomolar concentrations. Therefore, high sensitivity and selectivity profiling analysis of these compounds in clinical samples is demanded. An automated qualitative and quantitative method based on on-line coupling between solid phase extraction and liquid chromatography-tandem mass spectrometry has been here developed for determination of FAHFAs in serum with the required sensitivity and selectivity. Matrix effects were evaluated by preparation of calibration models in serum and methanol. Recovery factors ranged between 73.8 and 100% in serum. The within-day variability ranged from 7.1 to 13.8%, and the between-days variability varied from 9.3 to 21.6%, which are quite acceptable values taking into account the low concentration levels at which the target analytes are found. The method has been applied to a cohort of human serum samples to estimate the concentrations profiles as a function of the glycaemic state and obesity. Statistical analysis revealed three FAHFAs with levels significantly different depending on the glycaemic state or the body mass index. This automated method could be implemented in high-throughput analysis with minimum user assistance. PMID- 27769382 TI - Development, validation and application of a 96-well enzymatic assay based on LC ESI-MS/MS quantification for the screening of selective inhibitors against Mycobacterium tuberculosis purine nucleoside phosphorylase. AB - Mycobacterium tuberculosis (Mtb) purine nucleoside phosphorylase (PNP, EC 2.4.2.1) has been identified as a target for the development of specific inhibitors with potential antimycobacterial activity. We hereby described the development and validation of a new 96-well LC-ESI-MS/MS method to assess the inhibition activity of nucleoside analogues towards MtbPNP and the human PNP (HsPNP). Enzyme activity was determined by monitoring the phosphorolysis of inosine (Ino) to hypoxanthine (Hpx). The enzymatic assay (v = 0.5 mL, enzyme<0.2 MUg/well, T = 37 degrees C) was performed with an overall time of about 15 min/plate for sample processing and 2 min/sample for LC-MS analysis. Validation of the quantification method met the criteria of the CDER guidance of FDA. Kinetic parameters were in agreement with those reported in literature (HsPNP KM = 0.150 +/- 0.020 mM vs 0.133 +/- 0.015 mM; MtbPNP KM = 0.060 +/- 0.009 mM vs 0.040 +/- 0.003 mM for Ino), thus demonstrating the reliability of the newly developed enzymatic assay. Preliminary inhibition assays confirmed the effects reported for Acyclovir (Acv) and Formycin A (FA) against HsPNP and MtbPNP. The validated enzymatic assay was applied to the evaluation of a set of 8-halo-, 8 amino-, 8-O-alkyl-substituted purine ribonucleosides synthesized on purpose as potential inhibitors against MtbPNP. The assayed 8-substituted ribonucleosides did not exert a significant inhibitory effect against the tested enzymes up to 1 mM. PMID- 27769383 TI - Rapid detection of bacterial endotoxins in ophthalmic viscosurgical device materials by direct analysis in real time mass spectrometry. AB - Bacterial endotoxins are lipopolysaccharides bound to the bacterial cell wall and released when bacteria rupture or disintegrate. Possible contamination of endotoxin in ophthalmic devices can cause a painful eye inflammation or result in toxic anterior segment syndrome after cataract surgery. Measurement of bacterial endotoxin in medical device materials is difficult since endotoxin binds with polymer matrix and some of the materials are very viscous and non-water soluble, where traditional enzyme-based Limulus amebocyte lysate (LAL) assay cannot be applied. Here we propose a rapid and high throughput ambient ionization mass spectrometric (MS) method using direct analysis in real time (DART) for the evaluation of endotoxin contamination in medical device materials. Large and structurally complex endotoxin instantaneously breaks down into low-mass characteristic fragment ions using DART and is detected by MS in both positive and negative ion modes. This method enables the identification and separation of endotoxin from medical materials with a detection limit of 0.03 ng mL-1 endotoxins in aqueous solution. Ophthalmic viscosurgical device materials including sodium hyaluronate (NaHA), non-water soluble perfluoro-n-octane (PFO) and silicone oil (SO) were spiked with different known concentrations of endotoxin and analyzed by DART MS, where the presence of endotoxin was successfully detected and featured small mass fragment ions were generated for NaHA, PFO and SO as well. Current findings showed the feasibility of measuring endotoxin contamination in medical device materials using DART-MS, which can lead to a one-step analysis of endotoxins in different matrices, avoiding any potential contamination during sample pre-treatment steps. PMID- 27769384 TI - A novel enrichment imprinted crystalline colloidal array for the ultratrace detection of chloramphenicol. AB - A novel photonic crystal (PC) for the enrichment and detection of trace chloramphenicol (Cm) was constructed based on the combination of the imprinted crystalline colloidal array (ICCA) and the enrichment effect induced by wettability differences. The enrichment ICCA (E-ICCA) material had a highly ordered opal structure consisted of hydrophilic molecular imprinting polymer (MIP) spheres and the surrounding hydrophobic polydimethylsiloxane (PDMS) matrix, thus showing the desired structural color but also possessing the large hydrophilicity/hydrophobicity (HP) interaction area to enable efficient enrichment of the target Cm molecules from a highly dilute solution to the MIP sphere surface. The sensitive Cm recognition of MIP spheres finally caused the reduced reflection intensity and a red shift of the material due to changes of the periodic structure. Using this sensing platform, the highly sensitive detection of Cm (as low as 1.5*10-9M) with high selectivity was achieved without using label techniques and expensive detection instruments. Furthermore, the developed method successfully used to screen Cm in drinking water samples. Therefore, this approach is extensible to the construction of many sensor systems for the sensitive detection of drugs, diseases, and pollutions of food and the environment. PMID- 27769385 TI - Inkjet-printed CO2 colorimetric indicators. AB - Colorimetric CO2 indicators were prepared by printing pH dyes (M-cresol purple or phenol red, tetrabutylammonium hydroxide, ethylcellulose, 1:2 ethanol:1-butanol solvent), using a commercially available thermal inkjet printer, on either cellulose paper or plastic transparency film. Indicators inks printed on the papers had higher sensitivity to CO2, greater color change, and more producible than those printed on plastic film. Varying the print intensities of the two pH dyes resulted in multiplexed indicators with tunable sensitivity and expanded detection concentration range towards CO2. The ink-jet printing method is simple and highly flexible for the development of indicator to detect CO2 - a gas indicative of product quality in many food products. Further optimization can potentially lead to application of the indicators in intelligent food packaging systems. PMID- 27769386 TI - Simultaneous extraction and determination of phthalate esters in aqueous solution by yolk-shell magnetic mesoporous carbon-molecularly imprinted composites based on solid-phase extraction coupled with gas chromatography-mass spectrometry. AB - A rapid, sensitive and accurate method for the simultaneous extraction and determination of five types of trace phthalate esters (PAEs) in environmental water and beverage samples using magnetic molecularly imprinted solid-phase extraction (MMIP-SPE) coupled with gas chromatography-mass spectrometry (GC-MS) was developed. A novel type of molecularly imprinted polymers on the surface of yolk-shell magnetic mesoporous carbon (Fe3O4@void@C-MIPs) was used as an efficient adsorbent for selective adsorption of phthalate esters based on magnetic solid-phase extraction (MSPE). The real samples were first preconcentrated by Fe3O4@void@C-MIPs, subsequently extracted by eluent and finally determined by GC-MS after magnetic separation. Several variables affecting the extraction efficiency of the analytes, including the type and volume of the elution solvent, amount of adsorbent, extraction time, desorption time and pH of the sample solution, were investigated and optimized. Validation experiments indicated that the developed method presented good linearity (R2>0.9961), satisfactory precision (RSD<6.7%), and high recovery (86.1-103.1%). The limits of detection ranged from 1.6ng/L to 5.2ng/L and the enrichment factor was in the range of 822-1423. The results indicated that the novel method had the advantages of convenience, good sensitivity, and high efficiency, and it could also be successfully applied to the analysis of PAEs in real samples. PMID- 27769387 TI - Analysis of hydroxylated polybrominated diphenyl ethers (OH-BDEs) by supercritical fluid chromatography/mass spectrometry. AB - Hydroxylated polybrominated diphenyl ethers (OH-BDEs), which have anthropogenic and natural origins, have exhibited neurotoxic and endocrine disrupting effects in humans and wildlife. Therefore, there is an increased interest in the analysis of these compounds in biological matrices in order to assess their potential toxicological risks. Analysis of OH-BDEs is conventionally completed using liquid chromatography/mass spectrometry (LC/MS), or by gas chromatography/mass spectrometry (GC/MS) after derivatization. Issues with resolution in separating congeners have limited the analysis of OH-BDEs via LC/MS, with published methods only able to include 13 congeners in the analysis. On the other hand, while GC/MS analysis can analyze more OH-BDE congeners, derivatization of OH-BDEs to convert them to GC amenable compounds adds to sample preparation time and limits the column lifetime due to trace residues of highly reactive derivatization agents entering the column. Herein we report the development of a supercritical fluid chromatography/mass spectrometry (SFC/MS) method for the analysis of 22 OH-BDE congeners. Instrument limits of detection for the developed method ranged from 2 to 106fg injected on column, which is lower than previously optimized LC/MS and GC/MS methods. The developed SFC/MS method was successfully applied towards the analysis of in vitro metabolism samples and human serum samples to demonstrate its applicability with different biological matrices. PMID- 27769388 TI - Combination of visible and mid-infrared spectra for the prediction of chemical parameters of wines. AB - Rapid and environmentally friendly methods for the prediction of chemical compositions have been an interest in the wine industry. The objective of the study was to show the potentials of combined use of visible and mid-infrared (MIR) spectroscopies to improve the prediction of various chemical compounds of wine as opposed to using mid-infrared range only. Wine samples of twelve grape varieties from two harvest years were analyzed. The chemical composition of wine samples was related to MIR and visible spectra using orthogonal partial least square (OPLS) regression technique. The prediction abilities were tested with crossvalidation and independent validation sets. The coefficient of determination of validation (R2val) for anthocyanin compounds of red wines were between 0.76 and 0.90, and that for total phenol content was 0.90. Range of R2val for glycerol, glycerol/ethanol ratio, malic acid, o-coumaric acid and degrees Brix were between 0.77 and 0.96. The spectral ranges that played significant roles in the predictions were also determined. The validations with independent data sets showed that the combination of visible and MIR ranges with multivariate methods improved the prediction of anthocyanin compounds and total phenols; produced comparable results for the rest of the parameters as MIR. This is the first study in the literature that shows the practical use of visible spectra along MIR. The combined use of these spectral ranges with multivariate models can be applied for the rapid, on-line determination of quality parameters and chemical profiles of wines. PMID- 27769389 TI - A novel label-free and sensitive electrochemical biosensor for Hg2+ based on ligase-mediated formation of DNAzyme. AB - A novel label-free electrochemical biosensor for the detection of Hg2+ based on ligase mediated creation of G-quadruplex-hemin DNAzyme has been developed. Firstly, Cp probe was immobilized on the gold electrode surface through Au-SH bond. In the presence of Hg2+, Cp and Ap probes were partly hybridized with the LJ probe respectively through the specific T-Hg2+-T interaction. Then, the adjacent 3'-OH terminal of Cp will link with the 5'-PO4 terminal of Ap to form a G-rich DNA at the function of T4-ligase. After interaction with hemin, the G-rich DNA can form a G-quadruplex-hemin HRP-mimicking DNAzyme. Through measuring the current change caused by DNAzyme-catalyzed oxidation of 3,3',5,5' tetramethylbenzidine(TMB), sensitive detection of Hg2+ can be achieved. The proposed sensor is simple, sensitive and selective, without the need of complicated labeling process, thus holds great potential for routine analysis of Hg2+ in environmental and biological samples. PMID- 27769390 TI - A preconcentration method for indirect determination of acrylamide from chips, crackers and cereal-based baby foods using flame atomic absorption spectrometry. AB - Acrylamide is a toxic species for human health, and is a Maillard reaction product which forms spontaneously in heat treatment process of foods. Therefore, a simple, fast and cost-effective method was developed for the indirect determination of acrylamide in processed foods particularly consumed by children. The method is based on ion-pairing of acrylamide with fluorescein (F2-) in presence of Ni(II) ions at pH 9.0, and then extraction of the formed ternary complex into micellar phase of poly(ethyleneglycol-mono-p-nonylphenylether) (PONPE 7.5) before analysis by flame atomic absorption spectrometry (FAAS). The ultrasonic-assisted cloud point extraction (UA-CPE) has been used for the preconcentration of acrylamide in the samples prior to its FAAS detection. The matrix matched calibration curve is linear in range of 0.3-150ugkg-1 under optimal reagent conditions (1.75mL of 0.1molL-1 ammonia buffer at pH 9.0, 2.2mgL 1 Ni(II), 4.0*10-4molL-1 F2-, 0.4% (w/v) NH4Cl and 0.7% (v/v) PONPE 7.5) with sensitivity enhancement of 160-fold. The proposed method has been validated by assessment of the following parameters; the limits of detection (LOD) and quantification (LOQ) (0.08ugkg-1 and 0.28ugkg-1, respectively) with a relative standard deviation (RSD%) lower than 6.3%, and extractive recovery higher than 95% for acrylamide spiked at levels of 5 and 25ugkg-1. The method was successfully applied to the indirect determination of acrylamide in the processed foods and two CRMs with satisfactory results. PMID- 27769391 TI - Acetamiprid multidetection by disposable electrochemical DNA aptasensor. AB - In this work, we propose an electrochemical DNA aptasensor for sensitive multidetection of acetamiprid based on a competitive format and disposable screen printed arrays. To improve the sensitivity of the aptasensor, polyaniline film and gold nanoparticles were progressively electrodeposited on the graphite screen printed electrode surface by cyclic voltammetry. Gold nanoparticles were then employed as platform for thiol-tethered DNA aptamer immobilization. Different acetamiprid solutions containing a fixed amount of biotinylated complementary oligonucleotide sequence by DNA aptasensor arrays were analyzed. Streptavidin alkaline phosphatase conjugate was then added to trace the affinity reaction. The enzyme catalyzed the hydrolysis of 1-naphthyl phosphate to 1-naphthol. The enzymatic product was detected by differential pulse voltammetry. A decrease of the signal was obtained when the pesticide concentration was increased, making the sensor work as signal off sensor. Under optimized conditions by testing key experimental parameters, a dose-response curve was constructed between 0.25 and 2.0uM acetamiprid concentration range and a limit of detection of 0.086uM was calculated. The selectivity of the aptasensor was also confirmed by the analysis of atrazine pesticide. Finally, preliminary experiments in fruit juice samples spiked with acetamiprid were also performed. PMID- 27769392 TI - Mapping for total surface-enhanced Raman scattering to improve its quantification analysis. AB - Surface-enhanced Raman scattering (SERS) has been applied in a range of fields for its super high sensitivity which can even reach the single molecule level. But the quantification methods based on SERS still have some challenges such as stability, repeatability, and linearity at low concentrations. Here we propose a new quantification approach by using a total mapping scheme, and then add all the spectra together to obtain a final merged spectrum (a total SERS spectrum). The total SERS spectra were used to perform quantification analysis. The results of this approach show that it can improve the signal stability by at least 50% (RSD) and extend the linear quantification range by one order of magnitude. The proposed total SERS mapping quantification strategy is a promising practical working mode to improve its analytical figures of merit. PMID- 27769393 TI - Simultaneous profiling of eicosanoid metabolome in plasma by UPLC-MS/MS method: Application to identify potential makers for rheumatoid arthritis. AB - To evaluate the potential relationship between rheumatoid arthritis and arachidonic acid (AA) metabonomics via cyclooxygenase (COX) and lipoxygenase (LOX) pathways, a UPLC-MS/MS method has been developed and validated for simultaneous and quantitative profiling of eicosanoid metabolome in rat plasma. The analytes were extracted from plasma samples by protein precipitation procedure, and then separated on a Shim-pack XR-ODS column with mobile phase A (0.05% formic acid in water, pH=3.3 adjusted with dilute ammonium hydroxide) and mobile phase B [methanol: acetonitrile (20:80, v/v)]. The detection was performed on UPLC-MS/MS system with an electro spray ion source in the negative ion and multiple reaction-monitoring modes. The developed method was optimized to completely separate all twenty-three analytes and three internal standards in 12min. All standard calibration curves were linear and the calibration regression coefficients were ranged from 0.9903 to 0.9992 for all analytes. The recoveries of analytes were all more than 60%. By means of the method developed, the plasma samples from model rats and normal rats had been successfully determined. Results showed that AA and fifteen kinds of metabolites by LOX and COX pathways in model rat plasma were significant higher than those in normal ones(P<0.05), while 5 HpETE and LTD4 in model rat plasma were significantly lower than those in normal ones(P<0.05). The methods demonstrated the changes of eicosanoid metabolome occurring in plasma from rat subjects with rheumatoid arthritis. It could be a powerful manner to diagnostic and/or prognostic values for rheumatoid arthritis. PMID- 27769394 TI - Field-enhanced sample injection-micelle to solvent stacking in nonaqueous capillary electrophoresis. AB - The low conductivity of separation electrolytes employed in nonaqueous capillary electrophoresis (NACE) limits the use of on-line sample concentration or stacking by field enhancement. Herein, micelle-to-solvent stacking (MSS) was performed by the simple injection of a micellar solution plug prior to electrokinetic injection of sample prepared under field-enhanced stacking conditions (known as field-enhanced sample injection, FESI). The proposed approach allowed a 214-625 fold improvement in peak signals for targeted anticancer drugs (e.g., tamoxifen) and its major metabolites in NACE using 100% methanol-based separation electrolyte that comprised of 7.5mM deoxycholic acid sodium salt, 15mM acetic acid and 1mM 18-crown-6. These improvements yielded tamoxifen and its metabolites with 2-5 times better stacking efficiency as compared to those obtained without micellar solution injection or FESI only. This is comparable to the results typically achieved when FESI is combined with isotachophoresis (electrokinetic supercharging). The FESI-MSS-NACE was tested for the measuring levels of target drugs in plasma. The analytical figures of merit are also reported. PMID- 27769395 TI - Oligonucleotide-templated rapid formation of fluorescent gold nanoclusters and its application for Hg2+ ions sensing. AB - In this work, we developed a simple, rapid and mild strategy for synthesis of DNA templated fluorescent gold nanoclusters (AuNCs) through association of gold ions to DNA templates and reduction with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). After systematical investigation on the formation of fluorescent AuNCs by using different DNA templates, C5 DNA was found as the best template for the formation of fluorescent AuNCs in this system. This process could be completed within 5min after the reaction beginning under ambient conditions. The prepared C5-AuNCs displayed good blue emission and photostability. Furthermore, this C5-AuNCs could be applied to detecting Hg2+ ions specifically based on the specific and strong interaction between Hg2+ and Au+. The C5-AuNCs provided excellent selectivity for Hg2+ ions over other metal ions, and also high sensitivity, with a detection limit of 50nM. As biocompatible, environmentally friendly, and synthesis-rapid, this C5-AuNCs probe appears to be promising candidate for biochemical sensing via simple modification of template DNA. PMID- 27769396 TI - Multielemental speciation analysis by advanced hyphenated technique - HPLC/ICP MS: A review. AB - Speciation analysis has become an invaluable tool in human health risk assessment, environmental monitoring or food quality control. Another step is to develop reliable multielemental speciation methodologies, to reduce costs, waste and time needed for the analysis. Separation and detection of species of several elements in a single analytical run can be accomplished by high performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (HPLC/ICP-MS). Our review assembles articles concerning multielemental speciation determination of: As, Se, Cr, Sb, I, Br, Pb, Hg, V, Mo, Te, Tl, Cd and W in environmental, biological, food and clinical samples analyzed with HPLC/ICP-MS. It addresses the procedures in terms of following issues: sample collection and pretreatment, selection of optimal conditions for elements species separation by HPLC and determination using ICP-MS as well as metrological approach. The presented work is the first review article concerning multielemental speciation analysis by advanced hyphenated technique HPLC/ICP-MS. PMID- 27769397 TI - Highly sensitive and selective lateral flow immunoassay based on magnetic nanoparticles for quantitative detection of carcinoembryonic antigen. AB - Carcinoembryonic antigen (CEA) is an important biomarker in cancer diagnosis. Here, we present an efficient, selective lateral-flow immunoassay (LFIA) based on magnetic nanoparticles (MNPs) for in situ sensitive and accurate point-of-care detection of CEA. Signal amplification mechanism involved linking of detection MNPs with signal MNPs through biotin-modified single-stranded DNA (ssDNA) and streptavidin. To verify the effectiveness of this modified LFIA system, the sensitivity and specificity were evaluated. Sensitivity evaluation showed a broad detection range of 0.25-1000ng/ml for CEA protein by the modified LFIA, and the limit of detection (LOD) of the modified LFIA was 0.25ng/ml, thus producing significant increase in detection threshold compared with the traditional LFIA. The modified LFIA could selectively recognize CEA in presence of several interfering proteins. In addition, this newly developed assay was applied for quantitative detection of CEA in human serum specimens collected from 10 randomly selected patients. The modified LFIA system detected minimum 0.27ng/ml of CEA concentration in serum samples. The results were consistent with the clinical data obtained using commercial electrochemiluminescence immunoassay (ECLIA) (p<0.01). In conclusion, the MNPs based LFIA system not only demonstrated enhanced signal to noise ratio, it also detected CEA with higher sensitivity and selectivity, and thus has great potential to be commercially applied as a sensitive tumor marker filtration system. PMID- 27769398 TI - Photoelectrochemical CaMV35S biosensor for discriminating transgenic from non transgenic soybean based on SiO2@CdTe quantum dots core-shell nanoparticles as signal indicators. AB - A methodology for detection of the Cauliflower Mosaic Virus 35S(CaMV35S) promoter was developed to distinguish transgenic from non-transgenic soybean samples by using photoelectrochemical (PEC) biosensor. In this PEC biosensing system, the as prepared gold nanoparticles-reduced graphene oxide acted as a nanocarrier to immobilize the thiol-functional probe (probe1), and the SiO2@CdTe quantum dots (QDs) core-shell nanoparticles tagged with the amino-functional probe (probe2) acted as signal indicators, respectively. In the presence of target DNA (tDNA) of CaMV35S, the binding of tDNA with probe1 and probe2 through the high specific DNA hybridization led to the fabrication of sandwich structure, and thus the high loading of the signal indicators SiO2@CdTe QDs at the electrode surface, which increased the PEC signal. The increased PEC signal depended on the concentration of tDNA, and a wide linear range from 0.1pM to 0.5nM with low detection limit of 0.05pM was obtained. In addition, the PEC biosensor has been successfully used for discriminating transgenic soybean from non-transgenic samples, which was consistent with the polymerase chain reaction (PCR) results, suggesting the proposed PEC biosensor is a feasible tool for the further daily genetically modified organism detection. PMID- 27769399 TI - Progressing the analysis of Improvised Explosive Devices: Comparative study for trace detection of explosive residues in handprints by Raman spectroscopy and liquid chromatography. AB - Concerning the dreadful global threat of terrorist attacks, the detection of explosive residues in biological traces and marks is a current need in both forensics and homeland security. This study examines the potential of Raman microscopy in comparison to liquid chromatography (ion chromatography (IC) and reversed-phase high performance liquid chromatography (RP-HPLC)) to detect, identify and quantify residues in human handmarks of explosives and energetic salts commonly used to manufacture Improvised Explosive Devices (IEDs) including dynamite, ammonium nitrate, single- and double-smokeless gunpowders and black powder. Dynamite, ammonium nitrate and black powder were detected through the identification of the energetic salts by Raman spectroscopy, their respective anions by IC, and organic components by RP-HPLC. Smokeless gunpowders were not detected, either by Raman spectroscopy or the two liquid chromatography techniques. Several aspects of handprint collection, sample treatment and a critical comparison of the identification of compounds by both techniques are discussed. Raman microscopy and liquid chromatography were shown to be complementary to one another offering more comprehensive information for trace explosives analysis. PMID- 27769401 TI - Sensitive and background-free determination of thiols from wastewater samples by MOF-5 extraction coupled with high-performance liquid chromatography with fluorescence detection using a novel fluorescence probe of carbazole-9-ethyl-2 maleimide. AB - A sensitive and background-free pre-column derivatization method for the determination of thiol compounds using metal-organic framework material (MOF-5) as dispersive solid-phase extraction (DSPE) adsorbent followed by high performance liquid chromatography fluorescence detection (HPLC-FLD) has been developed. In this paper, a novel labeling reagent, carbazole-9-ethyl-2 maleimide(CAEM), was synthesized and reacted with thiols at 40 degrees C for 10min in the presence of PBS buffer (0.02mol/L, pH 7.5). Interestingly, CAEM itself had no fluorescence, while its derivatives exhibited intense fluorescence with an excitation maximum at lambdaex 274nm and an emission maximum at lambdaem 363nm, which greatly reduced the background interference and improved the sensitivity of the method. Furthermore, the MOF-5 was prepared and used as DSPE adsorbent for the selective adsorption of thiols from wastewater sample. Under the optimized experimental conditions, an excellent linearity for all analytes over their concentration ranges of 0.01-1.0MUmol/L (R2>0.9986)were obtained with the limit of detection (LOD) ranging from 8 to 17.1pmol/L for nine tested thiols. The feasibility of this method for the determination of thiols in wastewater samples had been evaluated and satisfactory average recoveries (n=3) were achieved with the range of 86.6-98.5%. PMID- 27769400 TI - A novel Schiff base network-1 nanocomposite coated fiber for solid-phase microextraction of phenols from honey samples. AB - A novel covalent organic framework, Schiff base network-1 (SNW-1), was synthesized and used as a solid-phase microextraction (SPME) fiber coating material. The SNW-1 coated SPME fiber was fabricated by a covalent chemical cross linking between the SNW-1 nanocomposite and a silanol-functionalized stainless steel wire substrate. Scanning electron microscopy and nitrogen isothermal adsorption results indicate that the new fiber coating exhibited a porous, homogenous surface with the Brunauer-Emmett-Teller surface of 668m2g-1. The prepared fiber was explored for the SPME of phenols from honey samples prior to their determination by gas chromatography-mass spectrometry. The developed method had large enrichment factors (136-816), low limits of detection (0.06-0.2ngg-1), good linearity (0.1-100.0ngg-1) and repeatability (<9.7%) for phenols. The recoveries for spiked phenols (1.0ngg-1 and 10.0ngg-1) in Wolfberry, Robinia and Codonopsis honey samples were in the range of 84.2-107.2% with the relative standard deviations ranging from 3.8% to 12.7%. The developed method was suitable for the determination of phenols from honey samples. PMID- 27769402 TI - A simple and sensitive method for determination of tetrahydropalmatine based on a new voltammetric sensor. AB - In this paper, a simple, low cost, highly sensitive voltammetric method for determination of tetrahydropalmatine was described, which was based on a new electrochemical sensor, poly (L-glutamic acid) functionalized electrochemical reduction graphene oxide modified glassy carbon electrode. The electrochemical behavior of tetrahydropalmatine was investigated in detail and some dynamic parameters of electrode process were calculated for the first time. Due to large surface area and good conductivity of proposed sensor, a wider linear range (3.0*10-7-2.0*10-5molL-1) and lower detection limit (1.0*10-7molL-1) were achieved for determination of tetrahydropalmatine. Meanwhile, the proposed method was used in determination of tetrahydropalmatine in Rhizoma Corydalis with well results. PMID- 27769403 TI - In situ quantitative 1H nuclear magnetic resonance spectroscopy discriminates between raw and steam cooked potato strips based on their metabolites. AB - A direct quantitative proton nuclear magnetic resonance spectroscopy method was developed for the measurement of saccharides, organic acids and amino acids in potato (Solanum tuberosum L.) tuber filaments, a complex gel-like food matrix. The method requires minimal sample preparation. It is thus a faster alternative compared to liquid sample matrices, as well as an extension to methods analyzing only selected metabolites in the sample. The samples in this study were either raw or steamed potato strips that were either measured as D2O extracts or directly without extraction or derivatization steps (in situ technique). A total of 22 compounds were identified in extracts and 18 in potato strips. Of these, 20 compounds were quantifiable in potato extracts and 13 compounds in potato strips. The effect of thermal processing was reflected in the profile of analyzed compounds. One example was fumaric acid, which was completely lost in steamed samples in both measurement techniques. Additionally, the content of gamma aminobutyric acid in steamed potato strips was lower. In potato extracts, the contents of additional 7 compounds were statistically different. The raw and steamed samples separated into two groups with multivariate models both in extracts and potato strips, and these groups were linked to changes in aforementioned compounds. These results demonstrated that the in situ quantitative 1H NMR technique is a useful tool to analyze potato metabolites. This technique could be further applied to any gel-like complex matrix, meaning that lengthy sample pretreatment could be skipped. PMID- 27769405 TI - Proof of concept study for different-sized chitosan nanoparticles as carbon dioxide (CO2) indicators in food quality monitoring. AB - The objective of this study was to develop different-sized chitosan nanoparticles as CO2-based food quality indicators. Chitosan nanoparticles were fabricated with different sizes (small, 300nm; medium, 500nm; and large, 1000nm) by ionic gelation. To investigate the performance of chitosan nanoparticles as CO2 indicators, they were suspended in aqueous solution at pH 8.0. Changes in the pH and absorbance of the suspension were measured over time, the absorbance at the transition appearance time being calculated using the inverse-Hill function. The resultant transition appearance times were 11.23, 14.33, and 27.69min for the small, medium, and large-sized chitosan nanoparticles, respectively. Controlling the chitosan nanoparticle size enables the transition appearance time of the CO2 indicator to be adjusted in order to match the change in quality of packaged food. This study suggests that different-sized chitosan nanoparticle-based CO2indicators can be used as food quality indicators. PMID- 27769404 TI - Determination of dopamine, serotonin, biosynthesis precursors and metabolites in rat brain microdialysates by ultrasonic-assisted in situ derivatization dispersive liquid-liquid microextraction coupled with UHPLC-MS/MS. AB - This paper, for the first time, reported a simple, rapid, sensitive and environmental friendly ultrasonic-assisted in situ derivatization-dispersive liquid-liquid microextraction (in situ UAD-DLLME) method followed by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of dopamine (DA), serotonin (5-HT) and their biosynthesis precursors and metabolites in rat brain microdialysates. In this work, a commercial reagent, Lissamine rhodamine B sulfonylchloride (LRSC), was proposed as a derivatization reagent. The ionization efficiency of neurotransmitters was greatly enhanced through the introduction of a permanent charged moiety of LRSC into their derivatives during electrospray ionization MS (ESI-MS) analysis. Parameters of in situ UAD-DLLME and UHPLC-MS/MS conditions were all optimized in detail. The optimum conditions of in situ UAD-DLLME were found to be as follows: a mixture of 150MUL of acetonitrile (dispersant) containing LRSC (derivatization reagents) and 50MUL of low toxic bromobenzene (extractant) was rapidly injected into an aqueous sample containing 30MUL of microdialysate and 800MUL of NaHCO3-Na2CO3 buffer solution (pH 10.5) at 37 degrees C. After ultrasonication for 3min and centrifuging for 2min, the sedimented phase was conveniently injected for UHPLC-MS/MS analysis. Under the optimized conditions, good linearity was observed with the limits of detection (LODs, S/N>3) and limits of quantification (LOQs, S/N>10) in the range of 0.002 0.008 and 0.015-0.040nmol/L, respectively. Meanwhile, it also brought good results of precision (3.2-13.0%, peak area RSDs %), accuracy (86.4-112%), recovery (73.9-105%), matrix effect (86.2-105%), and stability (3.1-8.8%, peak area RSDs %). The developed method was successfully applied for the simultaneous determination of multiple neurotransmitters, their precursors and metabolites in brain microdialysates of normal and L-DOPA induced dyskinesias (LID) rats. PMID- 27769406 TI - Novel "signal-on" electrochemiluminescence biosensor for the detection of PSA based on resonance energy transfer. AB - Here, we propose a simple and novel "signal-on" electrochemiluminescence (ECL) biosensor based on resonance energy transfer (RET) for detection of prostate specific antigen (PSA). The system is composed of Multi-walled carbon nanotubes (MWCNT), polyamidoamine (PAMAM) dendrimer and Au nanoparticles (NPs) film on glassy carbon electrode (GCE) to improve the electron transfer, provide abundant amine group for the immobilization of biomolecules, and amplify the ECL signal. After that, Au nanorods (Au NRs) labeled peptide is modified on electrode surface to serve as ECL-RET acceptor due to the excellent overlap between the ECL emission spectrum of Ru(bpy)32+ and the absorption spectrum of Au NRs, leading to the significant decrement of ECL signal. Upon the sensing cleavage of peptide with PSA, both Au NRs and peptide are released from electrode surface, resulting in the high recovery efficiency of ECL signal. The proposed approach exhibits a wide linear range from 0.1pg/mL to 10ng/mL with a detection limit of 0.03pg/mL. Results revealed that the recoveries were in a range from 95% to 108%, indicating good accuracy of the proposed method for PSA detection. In addition, the proposed biosensor exhibited well specificity for the detection of PSA. PMID- 27769407 TI - Online solid phase extraction and liquid chromatography-mass spectrometric determination of nucleoside drugs in plasma. AB - The bioanalysis and especially the sample preparation of nucleoside drugs in complex media, such as human plasma, has been challenging due to the high polarity and high solubility of these drugs in water. Online solid phase extraction (SPE) offers significant advantages, such as automation and timesaving. Thus, several types of SPE columns have been developed for compounds with different polarities. In this study, SPE was applied to overcome the issue of sample pretreatment of nucleoside drugs in human plasma, with the final aim of establishing a robust analytical platform for drugs with similar structures. A simple, easy-to-use, and efficient method is described for the simultaneous determination of lamivudine, zidovudine, didanosine and emtricitabine in human plasma via online SPE and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Following a simple centrifugation step, a 10MUL plasma sample was injected directly onto the HPLC system. The Oasis MCX cartridge was washed, and the analytes were removed by back-flushing directly onto the analytical column. The analytes were quantified using a triple-quadrupole tandem mass spectrometer in multiple-reaction monitoring mode. Similarly, with the development and application of a Bond Elut phenylboronic acid (PBA) SPE cartridge, a fully automated online SPE-HPLC-MS/MS method was established for the simultaneous determination of ribavirin and taribavirin in human plasma. Linear calibration curves were obtained over the range of 0.5-2000ngmL-1, and the limit of quantification ranged from 0.5ngmL-1 to 10ngmL-1, which is sensitive enough for clinical drug monitoring. The intra- and inter-day precisions were in the range of 0.2-8.9%, and the trueness ranged between 88.9% and 113.1%. Excellent recoveries from plasma were achieved with a range between 86.7% and 105.1%. This procedure is easier to perform and requires less sample handling compared to methods previously described in the literature. This high-throughput method involving the direct injection of plasma samples may provide a practical solution for the analysis of multiple nucleoside drugs in clinical research. The method was tested in plasma samples from some patients and showed good performance. PMID- 27769408 TI - Functionalization of magnetic hollow porous oval shape NiFe2O4 as a highly selective sorbent for the simultaneous determination of five heavy metals in real samples. AB - In this study, a functionalized magnetic hollow porous oval-shape NiFe2O4 (MHPO NiFe2O4) was designed by a facile synthesis procedure, and employed as magnetic solid phase extraction (MSPE) material to extract several heavy metal ions. As prepared MHPO-NiFe2O4 exhibited superior adsorption capacities of 20.17, 16.64, 16.82, 9.69 and 16.58mgg-1, for Cu(II), Cd(II), Cr(III), Co(II) and Zn(II), and was then used to detect these heavy metals elements in real samples by combining with inductively coupled plasma optical emission spectroscopy (ICP-OES). The possible mechanism of the enrichment of heavy metals ions on MHPO-NiFe2O4 was proposed, which involved the dominant adsorption and desorption. The detection limits were as low as 0.015, 0.13, 0.062, 0.035 and 0.46MUgL-1 for Cu(II), Cd(II), Cr(III), Co(II) and Zn(II), respectively. A good repeatability was obtained with the relative standard deviation (RSD) of 3.87%. Moreover, the method was successfully utilized for the analysis of five heavy metals in real samples (cabbage, lettuce, apple, seawater), with satisfactory recoveries in the range of 92-108%. PMID- 27769409 TI - Development and evaluation of an up-converting phosphor technology-based lateral flow assay for rapid and quantitative detection of aflatoxin B1 in crops. AB - Contamination of grains and other crops by aflatoxin B1 (AFB1), a highly toxic aflatoxin produced by Aspergillus flavus and Aspergillus parasiticus, poses a serious threat to human health and is an important food safety issue. In this study, a competitive up-converting phosphor technology-based lateral flow (AFB1 UPT-LF) assay was developed for rapid detection of AFB1. Detection sensitivity of the proposed assay can reach 0.03ngmL-1 for standard AFB1 solutions, with the coefficients of variation (CV) less than 10% (from 1.0 to 9.4%). A good linearity (r=0.9889) was observed for quantification of AFB1 from 0.03 to 1000ngmL-1. Except for aflatoxin M1, no cross-reactivity was found with the abrin, ricin, ochratoxin A, botulinum toxin, shiga toxin 1, shiga toxin 2, and staphylococcal enterotoxin B, even at high concentrations of 100 or 1000ngmL-1. After optimizing the extraction of AFB1, the assay showed good tolerance to various crop samples, with the detection limit (from 0.1 to 5ngg-1) lower than the corresponding maximum residue level (MRL) set in China. The AFB1-UPT-LF assay provides a promising tool for rapid on-site detection of AFB1 because of its high sensitivity, specificity, and sample tolerance. PMID- 27769410 TI - Neural networks applied to characterize blends containing refined and extra virgin olive oils. AB - The identification and quantification of binary blends of refined olive oil with four different extra virgin olive oil (EVOO) varietals (Picual, Cornicabra, Hojiblanca and Arbequina) was carried out with a simple method based on combining visible spectroscopy and non-linear artificial neural networks (ANNs). The data obtained from the spectroscopic analysis was treated and prepared to be used as independent variables for a multilayer perceptron (MLP) model. The model was able to perfectly classify the EVOO varietal (100% identification rate), whereas the error for the quantification of EVOO in the mixtures containing between 0% and 20% of refined olive oil, in terms of the mean prediction error (MPE), was 2.14%. These results turn visible spectroscopy and MLP models into a trustworthy, user friendly, low-cost technique which can be implemented on-line to characterize olive oil mixtures containing refined olive oil and EVOOs. PMID- 27769411 TI - Simultaneous bioimaging recognition of Al3+ and Cu2+ in living-cell, and further detection of F- and S2- by a simple fluorogenic benzimidazole-based chemosensor. AB - A simple Schiff base (BMSA) prepared from salicylaldehyde and 2-(1H benzo[d]imidazol-2-yl)aniline was evaluated as an efficient fluorescent chemosensor for the selective recognition of Al3+and Cu2+ over other common metal ions. This sensor could detect Al3+ in CH3OH/PBS with distinct emission red-shift (the detection limit 0.31MUM)and Cu2+in CH3OH/Tris-HCL (the detection limit 0.54MUM) with obvious fluorescence quenching. The obtained BMSA-Al3+ and BMSA Cu2+ complexes could act as cascade sensors for detecting F- and S2-, respectively. The recognizing behavior of BMSA toward Al3+and Cu2+ has been investigated in detail through Job's Plot, FT-IR NMR, and HRMS analysis. Moreover, this chemosensor was verified to be of low cytotoxicity and good imaging characteristics for the detection of Al3+ and Cu2+, and further for the recognition of F- and S2- in living cells, suggesting that BMSA was proved to be a useful tool for tracking Al3+/Cu2+and F-/S2- ions in vivo. PMID- 27769412 TI - Prediction of fermentation index of cocoa beans (Theobroma cacao L.) based on color measurement and artificial neural networks. AB - Several procedures are currently used to assess fermentation index (FI) of cocoa beans (Theobroma cacao L.) for quality control. However, all of them present several drawbacks. The aim of the present work was to develop and validate a simple image based quantitative procedure, using color measurement and artificial neural network (ANNs). ANN models based on color measurements were tested to predict fermentation index (FI) of fermented cocoa beans. The RGB values were measured from surface and center region of fermented beans in images obtained by camera and desktop scanner. The FI was defined as the ratio of total free amino acids in fermented versus non-fermented samples. The ANN model that included RGB color measurement of fermented cocoa surface and R/G ratio in cocoa bean of alkaline extracts was able to predict FI with no statistical difference compared with the experimental values. Performance of the ANN model was evaluated by the coefficient of determination, Bland-Altman plot and Passing-Bablok regression analyses. Moreover, in fermented beans, total sugar content and titratable acidity showed a similar pattern to the total free amino acid predicted through the color based ANN model. The results of the present work demonstrate that the proposed ANN model can be adopted as a low-cost and in situ procedure to predict FI in fermented cocoa beans through apps developed for mobile device. PMID- 27769413 TI - Discrimination and quantification of two isomeric antineoplastic drugs by rapid and non-invasive analytical control using a handheld Raman spectrometer. AB - Raman spectroscopy is a rapid, non-destructive and non-invasive method that is a promising tool for real-time analytical control of drug concentrations. This study evaluated a handheld Raman device to discriminate and quantify two isomeric drugs used to treat cancer. Doxorubicin (DOXO) and epirubicin (EPIR) samples were analyzed at therapeutic concentrations from 0.1 to 2mg/mL (n=90) and 0.08-2mg/mL (n=90) by non-invasive measurements using a portable Raman spectrometer. The discrimination of these two molecules was demonstrated for all concentrations (n=180) by qualitative analysis using partial least square discriminant analysis (PLS-DA) with 100% classification accuracy, sensitivity and specificity and 0% error rate. For each molecule, quantitative analyses were performed using PLS regression. The validity of the model was evaluated using root mean square error of cross validation (RMSECV) and prediction (RMSEP) that furnished 0.05 and 0.02mg/mL for DOXO and 0.17 and 0.16mg/mL for EPIR after pretreatment optimization. Based on the accuracy profile, the linearity range was from 1.256 to 2.000mg/mL for DOXO (R2=0.9988) and from 0.553 to 2.000mg/Ml for EPIR (R2=0.9240) and repeatability (CV% max of 1.8% for DOXO and 3.2% for EPIR) and intermediate precision (CV% max of 2.8% for DOXO and 4.5% for EPIR) were both acceptable. Despite the narrow validated concentration range for quantitative analysis, this study shows the potential of a handheld Raman spectrometer coupled to chemometric approaches for real-time quantification of cytotoxic drugs, as well for discriminating between two drugs with similar UV absorption profiles. Finally, the use of a handheld spectrometer with the possibility of a direct measurement of substances in containers is a potentially valuable tool for combining patient safety with security of healthcare workers. PMID- 27769414 TI - Speciation analysis of Mn(II)/Mn(VII) using Fe3O4@ionic liquids-beta-cyclodextrin polymer magnetic solid phase extraction coupled with ICP-OES. AB - Ionic liquids-beta-cyclodextrin polymer (ILs-beta-CDCP) was attached on Fe3O4 nanoparticles to prepare magnetic solid phase extraction agent (Fe3O4@ILs-beta CDCP). The properties and morphology of Fe3O4@ILs-beta-CDCP were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction(XRD), size distribution and magnetic analysis. A new method of magnetic solid phase extraction (MSPE) coupled to ICP-OES for the speciation of Mn(II)/Mn(VII) in water samples was established. The results showed that Mn(VII) and total manganese [Mn(II)+Mn(VII)] were quantitatively extracted after adjusting aqueous sample solution to pH 6.0 and 10.0, respectively. Mn(II) was calculated by subtraction of Mn(VII) from total manganese. Fe3O4@ILs-beta-CDCP showed a higher adsorption capacity toward Mn(II) and Mn(VII). Several factors, such as the pH value, extraction temperature and sample volume, were optimized to achieve the best extraction efficiency. Moreover, the adsorption ability of Fe3O4@ILs-beta CDCP would not be significantly lower after reusing of 10 times. The accuracy of the developed method was confirmed by analyzing certified reference materials (GSB 07-1189-2000), and by spiking spring water, city water and lake water samples. PMID- 27769415 TI - Electrochemical sensor based on graphene oxide and ionic liquid for ofloxacin determination at nanomolar levels. AB - New insights into the design of highly sensitive, carbon-based electrochemical sensors are presented in this work by exploring the interesting properties of graphene oxide (GO) and ionic liquids (ILs). An electrochemical sensor based on the carbon paste electrode (CPE) modified with GO and IL was developed for the sensitive detection of ofloxacin using square-wave adsorptive anodic stripping voltammetry (SWAdASV). GO sheets were obtained from the acid treatment of graphene and characterized by scanning and transmission electronic microscopy (SEM and TEM) and selected area electron diffraction (SAED), and the electrochemical behavior of the modified GO-IL/CPE was explored by electrochemical impedance spectroscopy studies. The CPE modification with GO and IL allowed an 8.2 fold increase in the analytical sensitivity for ofloxacin sensing compared to the unmodified CPE. Under the optimized experimental conditions using the SWAdASV technique, the GO-IL/CPE sensor provided an analytical curve for ofloxacin in the concentration range of 7.0*10-9 to 7.0*10 7molL-1, with a sensitivity of 7.7*106MUALmol-1 and limit of detection of 2.8*10 10molL-1 (0.28nmolL-1). The proposed sensor was successfully applied for the ofloxacin determination in human urine and ophthalmic samples, with recoveries near 100%. The results were similar those obtained by a spectrophotometric comparative method. PMID- 27769416 TI - Separation and determination of silver nanoparticle in environmental water and the UV-induced photochemical transformations study of AgNPs by cloud point extraction combined ICP-MS. AB - In this study, cloud point extraction (CPE) combined inductively coupled plasma mass spectrometry (ICP-MS) was used to determinate silver nanoparticles (AgNPs) in environmental water. AgNPs dispersed in water could be extracted into surfactant phase based on optimized CPE parameters which including pH, incubation temperature and equilibration time, the content of nonionic surfactants (Triton X 114, TX-114) and Na2S3O3. Good separation results of AgNPs and ionic silver Ag(I) in aqueous environment was obtained with the addition of Na2S3O3 when the concentration of Ag(I) was lower than ten times of AgNPs. High recoveries of different diameter AgNPs spiked into ultrapure water were obtained. The influence of environmentally relevant matrix on CPE of AgNPs was studied in detail. Our results showed that there were little interference of environmentally relevant ions and five representative engineering nanomaterials (ENMs) on CPE of AgNPs. Moreover high recoveries and good separation were obtained when natural organic matter (NOM) up to 30mg/L mixed with AgNPs in ultrapure water. The detection limit of AgNPs in water using CPE combined ICPMS was 5ng/L. The recoveries of the AgNPs spiked into natural and effluents water with this method were in the range of 79+/-1-123+/-13%. Furthermore CPE-ICPMS and Single particle-ICPMS were used to study the UV induced photochemical transformations of AgNPs suspension at environmental relevant concentrations. PMID- 27769417 TI - Fabrication of cross-linked hydrazone covalent organic frameworks by click chemistry and application to solid phase microextraction. AB - Covalent organic frameworks (COFs) are an emerging class of porous organic frameworks with diverse promising applications. Herein, we presented the first example of cross-linked hydrazone COFs (cross-linked COFs) coating via thiol-ene click chemistry for solid phase microextraction (SPME). Strong covalent bonds and interlayer of the prepared networks ensured the adsorption capacity and durability of the novel SPME fiber. pi-pi conjugated structure existed because of abundant phenyl rings and -C=N groups in the cross-lined COFs. A series of characterizations indicated that the cross-linked COFs possessed large surface areas, high porosities and stabilities as well as hydrophobicities. The fiber was applied to SPME of pesticide residues coupled with gas chromatography with an electron capture detector (GC-ECD). Under the optimum experimental conditions, enhancement factors in the range of 2190-10,998 were obtained, illustrating that the cross-linked COFs possessed remarkable preconcentration ability. The low detection limits of 0.0003-0.0023ngkg-1 were achieved with relative standard deviations (RSDs) in the range of 3.4-7.6% (intra-batch) and 5.7-11.6% (inter batch), respectively. Recovery values in the range of 78.2-107.0% were obtained when the SPME-GC method was applied to the analysis of pesticides in cucumber samples. PMID- 27769418 TI - Calibration of handheld X-ray fluorescence (XRF) equipment for optimum determination of elemental concentrations in sediment samples. AB - Handheld X-ray fluorescence spectrometers (XRFs) represent a more practical, efficient and economic tool to determine the elemental composition of solid inorganic and organic samples than conventional analytical techniques. The objective of this work was to demonstrate that handheld XRFs could be a precise, accurate and reliable tool to analyze up to 27 different elements. This objective was accomplished through the optimization of an empirical calibration curve that, in addition to include certified reference materials (CRM), it also introduced new approaches, such as the use of solid CRM mixtures and combinations of organic and inorganic matrices. These approaches significantly increased the number of calibration points and eliminated hiatuses in the calibration curve. Several factors were evaluated before construction of the calibration curve: incidence time of the X-ray beam, type of film through which the X-ray beams reach the samples, container type, minimum sample volume and sample moisture content. Results show that single elements can be analyzed with variable exposure times or, alternatively, multielemental analyses can be carried out with a constant exposure time (180s). Costs can be reduced by using Ziploc(r) bags as sample containers, but the number of measurable elements drops from 27 to 21, while the possibility of contamination increases. PMID- 27769419 TI - Combined in-situ imaging of structural organization and elemental composition of substantia nigra neurons in the elderly. AB - Human dopaminergic system in general, and substantia nigra (SN) neurons, in particular, are implicated in the pathologies underlying the human brain aging. The interplay between aberrations in the structural organization and elemental composition of SN neuron bodies has recently gained in importance as selected metals: Fe, Cu, Zn, Ca were found to trigger oxidative-stress-mediated aberration in their molecular assembly due to concomitant protein (alpha-synuclein, tau protein) aggregation, gliosis and finally oxidative stress. In the present study, we demonstrate an integrated approach to the analysis of the structural organization, assembly, and metals' accumulation in two distinct areas of SN: in the neuromelanin neurons and neuropil. By using the highly brilliant source of PETRA III and the Kirkpatrick-Baez nano-focus, large area histological brain slices are scanned at the sub-neuronal resolution, taking advantage of continuous motor movement and reduced acquisition time. Elemental analysis with synchrotron radiation based X-ray Fluorescence (SRXRF) is combined with X-ray Phase Contrast Imaging (XPCI) to correct for inherent aberrations in the samples' density and thickness, often referred to as the mass thickness effect. Based on the raw SRXRF spectra, we observed the accumulation of P, S, Cl, K, Ca, Fe, Cu and Zn predominantly in the SN neurons. However, upon the mass thickness correction, the distributions of Cl became significantly more uniform. Simultaneously with the fluorescence signal, the Small Angle X-ray Scattering (SAXS) is recorded by a pixel detector positioned in the far-field, enabling fast online computation of the darkfield and differential phase contrast (DPC). The data has demonstrated the SN neurons and neuropil produces excellent contrast which is due to their different mass density and scattering strength, indicative of differences in local structure and assembly therein. In all, the results show that combined SRXRF-XPCI-SAXS experiments can robustly serve as a unique tool for understanding the interplay between the chemical composition and structural organization that may drive the biochemical age-related processes occurring in the human dopaminergic system. PMID- 27769420 TI - Preparation of a new polymeric ionic liquid-based sorbent for stir cake sorptive extraction of trace antimony in environmental water samples. AB - In this work, a new polymeric ionic liquid (PIL)-based sorbent was prepared by in situ polymerization of 3-(1-ethyl imidazolium-3-yl) propyl-methacrylamido bromide and ethylene dimethacrylate and was used as medium for stir cake sorptive extraction (SCSE) of trace antimony in environmental water samples. The sorbent EPBED was characterized with infrared spectroscopy, elemental analysis, scanning electron microscopy and mercury intrusion porosimetry. A method for determination of trace antimony in water samples was developed based on the combination of SCSE/EPBED and hydride generation atomic fluorescence spectrometry (HG-AFS). Under the optimal extraction conditions, the linear dynamic range of developed method was found to be 0.20-100.0MUg/L with good coefficients of correlation (R2=0.9904) and LOD value as low as 0.084MUg/L. The method showed good reproducibility of results in terms of intra- and inter-day precisions with corresponding relative standard deviations (RSDs) of less than 9%. Recoveries obtained for the determination of antimony in spiked samples ranged from 80.4% to 107% with RSDs below 10% in all cases. PMID- 27769421 TI - Ultrasound-assisted dispersive micro solid-phase extraction with nano-TiO2 as adsorbent for the determination of mercury species. AB - The combination of ultrasound-assisted dispersive micro solid-phase extraction (USA DMSPE), with the use of TiO2 nanoparticles (NPs) as adsorbent, with cold vapor atomic absorption spectrometry (CV AAS) is proposed for preconcentration and determination of mercury species (Hgtotal, Hg2+ and CH3Hg+) in biological, geological and water samples. The experimental parameters including the amount of TiO2 NPs, pH of sample solution, ultrasonication and centrifugation time, TiO2 slurry solution preparation before injection to CV AAS were investigated. Effective preconcentration of trace mercury with 10mg of TiO2 was achieved in pH 7.5. After extraction, adsorbent with analytes was mixed with 500MUL of 1molL-1 HNO3 to prepare slurry solution. The concentration limit of detection was 0.004ngmL-1 for Hg2+. The achieved preconcentration factor was 35. The relative standard deviations (RSDs, %) for mercury species in real samples were 4-20%. The accuracy of this method was evaluated by analyses of certified reference materials: DOLT-2 (Dogfish Liver), IAEA-085 (Human hair), SRM 2709 (San Joaquin Soil), SRM 2711 (Montana Soil) and SRM 2704 (Buffalo River Sediment). The measured mercury species contents in reference materials were in satisfactory agreement with the added amounts (according to the t-test for a 95% confidence level). The presented method has been successfully applied for the determination of mercury species in real water samples (lake and river water). PMID- 27769422 TI - Separation of inositol phosphate isomers in environmental samples by ion-exchange chromatography coupled with electrospray ionization tandem mass spectrometry. AB - A method for isomeric separation of inositol phosphates (InsPn) in environmental samples originating from different sources such as soil, manure/compost, and aquatic sediments has been developed. The method includes a single NaOH-EDTA extraction step, centrifugation and direct injection of a particle free solution into an ion chromatographic column. Isomeric liquid chromatographic separation was achieved with an ammonium carbonate gradient compatible with electrospray ionization tandem mass spectrometric detection (LC-ESI-MS/MS). The detection limits of the LC-ESI-MS/MS method were between 0.03-0.16uM for the different InsPn, corresponding to 37-99ng P/g sample DW. The method has shown to be able to analyze more than 200 samples from soil, manure and sediment without any severe matrix effects. This will allow future studies of the fate of inositol phosphates in the environment. PMID- 27769423 TI - Ion-pair vortex assisted liquid-liquid microextraction with back extraction coupled with high performance liquid chromatography-UV for the determination of metformin in plasma. AB - A new sample preparation method, ion-pair vortex assisted liquid-liquid microextraction (VALLME-BE), for the determination of a highly polar anti diabetic drug (metformin) in plasma sample was developed. The VALLME-BE was performed by diluting the plasma in borate buffer and extracted to 150uL 1 octanol containing 0.2M di-(2-ethylhexyl)phosphoric acid as intermediate phase. The drug was next back-extracted into 20uL of 0.075M HCl solution. The effects of pH, ion-pair concentration, type of organic solvent, volume of extraction phases, ionic strength, vortexing and centrifugation times on the extraction efficiency were investigated. The optimum conditions were at pH 9.3, 60s vortexing and 2min centrifugation. The microextract, contained metformin and buformin (internal standard), was directly injected into a HPLC unit using C1 column (250mm*4.6mm*10um) and detected at 235nm. The method was validated and calibration curve was linear with r2>0.99 over the range of 20-2000ugL-1. The limits of detection and quantitation were 1.4 and 4.1ugL-1, respectively. The accuracy was within 94.8-108% of the nominal concentration. The relative standard deviation for inter- and intra-day precision was less than 10.8%. The method was conveniently applied for the determination of metformin in plasma samples. PMID- 27769424 TI - An effective method for pesticide residues determination in tobacco by GC-MS/MS and UHPLC-MS/MS employing acetonitrile extraction with low-temperature precipitation and d-SPE clean-up. AB - An effective method has been developed and validated for the determination of residues of 55 pesticides in tobacco. The proposed sample preparation method is based on acetonitrile extraction, low-temperature precipitation (LTP) and dispersive solid phase extraction (d-SPE) clean-up. Gas chromatography and ultra high performance liquid chromatography analysis, both coupled to tandem mass spectrometry (GC-MS/MS and UHPLC-MS/MS), were used for determination. LTP is easy to perform and was crucial to obtain a clean extract. Method quantification limit for the pesticides were between 25 and 75ugkg-1. Extraction recoveries obtained for blank samples spiked at 25, 75, 125 and 250ugkg-1 levels ranged from 63 to 161% with relative standard deviations (RSD)<=20%. The method was successfully applied to the analysis of thirteen different tobacco samples, providing to be a robust procedure for routine analysis. The compounds pirimiphos methyl and isofenphos presented residues in the range of 35-51ugkg-1. PMID- 27769425 TI - In situ calibration of three passive samplers for the monitoring of steroid hormones in wastewater. AB - In situ extraction of steroid hormones from waste water using adsorption-based integrative passive samplers represents a promising approach for their monitoring in water at ultra-trace concentrations. Three passive samplers, namely a POCIS, a Chemcatcher fitted with an Empore SDB-RPS disk, and an Empore SDB-RPS disk-based sampler with enhanced water flow, were calibrated in situ in treated municipal wastewater for the purpose of monitoring five estrogens (17-beta-estradiol, 17 alpha-estradiol, 17-alpha-ethinylestradiol, estrone and estriol) at sub ng per litre concentrations. Uptake of steroids to samplers during 14-day exposure in wastewater was compared with steroid concentrations in daily collected composite water samples. Sampling rates were obtained from a numerical solution of first order uptake kinetics equations describing the uptake of compounds into a passive sampler over time. Mass transfer of steroids in the Chemcatcher fitted with naked Empore disks was more than two times faster than in the POCIS sampler. The uptake capacity of the applied Empore disk was not sufficient for integrative uptake of all tested steroids during the entire 14-day exposure. Time-weighted average concentrations of steroids estimated at concentrations in units of ngL-1 using the in situ-calibrated samplers were within a factor of two from values obtained using composite water samples. PMID- 27769426 TI - Facile preparation of molecularly imprinted polypyrrole-graphene-multiwalled carbon nanotubes composite film modified electrode for rutin sensing. AB - In this paper, a novel molecularly imprinted composite film modified electrode was presented for rutin (RT) detection. The modified electrode was fabricated by electropolymerization of pyrrole on a graphene-multiwalled carbon nanotubes composite (G-MWCNTs) coated glassy carbon electrode in the presence of RT. The netlike G-MWCNTs composite, prepared by in situ hydrothermal process, had high conductivity and electrocatalytic activity. At the resulting MIP/G-MWCNTs/GCE electrode RT could produce a sensitive anodic peak in pH 1.87 Britton-Robinson buffer solution. The factors affecting the electrochemical behavior and response of RT on the modified electrode were carefully investigated and optimized. Under the selected conditions, the linear response range of RT was 0.01-1.0MUmolL-1 and the detection limit (S/N=3) was 5.0nmolL-1. The electrode was successfully applied to the determination of RT in buckwheat tea and orange juice samples, and the recoveries for standards added were 93.4-105%. PMID- 27769427 TI - Development of an ATP and hydrogen ion image sensor using a patterned apyrase immobilized membrane. AB - A bio-image sensor using a patterned apyrase-immobilized membrane was developed to visualize the activities of adenosine triphosphate (ATP) and H+ ion in real time. An enzymatic membrane patterning technique was suggested to immobilize apyrase on a specific sensing area of a charge coupled device (CCD)-type image sensor. It was able to observe the spatiotemporal information of ATP and H+ ion. The smallest size of a patterned membrane is 250*250um2. The fabrication parameters of the patterned membrane, such as its thickness and the intensity of the incident light used for photolithography, were optimized experimentally. The sensing area under the patterned apyrase-immobilized membrane revealed a linear response up to 0.6mM of ATP concentration with a sensitivity of 37.8mV/mM. Meanwhile, another sensing area without the patterned membrane measured the diffused H+ ion from nearby membranes. This diffusion characteristics were analyzed to determine a measurement time that can minimize the undesirable impact of the diffused ions. In addition, the newly developed bio-image sensor successfully reconstructed ATP and H+ ion dynamics into sequential 2-dimensional images. PMID- 27769428 TI - Selectivity mapping of the binding sites of (E)-resveratrol imprinted polymers using structurally diverse polyphenolic compounds present in Pinot noir grape skins. AB - This investigation describes a general procedure for the selectivity mapping of molecularly imprinted polymers, using (E)-resveratrol-imprinted polymers as the exemplar, and polyphenolic compounds present in Pinot noir grape skin extracts as the test compounds. The procedure is based on the analysis of samples generated before and after solid-phase extraction of (E)-resveratrol and other polyphenols contained within the Pinot noir grape skins using (E)-resveratrol-imprinted polymers. Capillary reversed-phase high-performance liquid chromatography (RP HPLC) and electrospray ionisation tandem mass spectrometry (ESI MS/MS) was then employed for compound analysis and identification. Under optimised solid-phase extraction conditions, the (E)-resveratrol-imprinted polymer showed high binding affinity and selectivity towards (E)-resveratrol, whilst no resveratrol was bound by the corresponding non-imprinted polymer. In addition, quercetin-3-O glucuronide and a dimer of catechin-methyl-5-furfuraldehyde, which share some structural features with (E)-resveratrol, were also bound by the (E)-resveratrol imprinted polymer. Polyphenols that were non-specifically retained by both the imprinted and non-imprinted polymer were (+)-catechin, a B-type procyanidin and ( )-epicatechin. The compounds that did not bind to the (E)-resveratrol molecularly imprinted polymer had at least one of the following molecular characteristics in comparison to the (E)-resveratrol template: (i) different spatial arrangements of their phenolic hydroxyl groups, (ii) less than three or more than four phenolic hydroxyl groups, or (iii) contained a bulky substituent moiety. The results show that capillary RP-HPLC in conjunction with ESI MS/MS represent very useful techniques for mapping the selectivity of the binding sites of imprinted polymer. Moreover, this procedure permits performance monitoring of the characteristics of molecularly imprinted polymers intended for solid-phase extraction of bioactive and nutraceutical molecules from diverse agricultural waste sources. PMID- 27769429 TI - An ATMND/SGI based label-free and fluorescence ratiometric aptasensor for rapid and highly sensitive detection of cocaine in biofluids. AB - A label-free ratiometric fluorescence aptasensor has been developed for the rapid and sensitive detection of cocaine in complex biofluids. The fluorescent aptasensor is composed of a non-labeled GC-38 cocaine aptamer which serves as a basic sensing unit and two fluorophores, 2-amino-5,6,7-trimethyl-1,8 naphthyridine (ATMND) and SYBR Green I (SGI) which serves as a signal reporter and a build-in reference, respectively. The detection principle is based on a specific cocaine mediated ATMND displacement reaction and the corresponding change in the fluorescence ratio of ATMND to SGI. Due to the high affinity of the non-labeled aptamer, the good precision originated from the ratiometric method, and the good fluorescence quantum yield of the fluorophore, the aptasensor shows good analytical performance with respect to cocaine detection. Under optimal conditions, the aptasensor shows a linear range of 0.10-10MUM and a low limit of detection of 56nM, with a fast response of 20s. The low limit of detection is comparable to most of the fluorescent aptasensors with signal amplification strategies and much lower than all of the unamplified cocaine aptasensors. Practical sample analysis in a series of complex biofluids, including urine, saliva and serum, also indicates the good precision, stability, and high sensitivity of the aptasensor, which may have great potential for the point-of care screening of cocaine in complex biofluids. PMID- 27769430 TI - Simultaneous capture and sequential detection of two malarial biomarkers on magnetic microparticles. AB - We have developed a rapid magnetic microparticle-based detection strategy for malarial biomarkers Plasmodium lactate dehydrogenase (pLDH) and Plasmodium falciparum histidine-rich protein II (PfHRPII). In this assay, magnetic particles functionalized with antibodies specific for pLDH and PfHRPII as well as detection antibodies with distinct enzymes for each biomarker are added to parasitized lysed blood samples. Sandwich complexes for pLDH and PfHRPII form on the surface of the magnetic beads, which are washed and sequentially re-suspended in detection enzyme substrate for each antigen. The developed simultaneous capture and sequential detection (SCSD) assay detects both biomarkers in samples as low as 2.0parasites/ul, an order of magnitude below commercially available ELISA kits, has a total incubation time of 35min, and was found to be reproducible between users over time. This assay provides a simple and efficient alternative to traditional 96-well plate ELISAs, which take 5-8h to complete and are limited to one analyte. Further, the modularity of the magnetic bead-based SCSD ELISA format could serve as a platform for application to other diseases for which multi-biomarker detection is advantageous. PMID- 27769431 TI - Inorganic arsenic speciation in water samples by miniaturized solid phase microextraction using a new polystyrene polydimethyl siloxane polymer in micropipette tip of syringe system. AB - The polymer, polystyrene polydimethyl siloxane was loaded into the micropipette tip of the syringe system as an adsorbent to developed miniaturized solid phase microextraction. Standard solutions of arsenate and arsenite were passed through the adsorbent loaded in micropipette tip to check the adsorption behaviors. It was observed that arsenate adsorbed on the polystyrene polydimethyl siloxane in the pH rang of 6-8, while arsenite was directly passed through the micropipette tip of syringe system. The adsorbed arsenate in micropipette tip of syringe system were eluted by 1.0M hydrochloric acid. The total inorganic arsenic contents were obtained by the addition of oxidizing agent potassium permanganate into the studied samples before passing to the micropipette tip of syringe system. Arsenite concentration in water samples were measured by subtracting arsenate from total inorganic arsenic concentration. Different characteristics which effect the determination of arsenate specie like amount of adsorbent, adsorption capacity, pH, pulled and pushed cycles for adsorption and desorption, volume of sample, eluent type and it volume were also studied in detail. Enrichment factor and detection limit of arsenate by desired method were 218 and 6.9ngL-1 respectively. The relative standard deviation was 4.1% (n=10, C=0.12ugL 1). Accuracy of the desired technique was confirmed by analysis of the CRMs (Lake Ontario Water TM-28.3 and Riverine Water NRCC-SLRS-4). Desired technique was significantly useful for determination of the total arsenic, arsenate, and arsenite contents in different natural water samples. PMID- 27769432 TI - Potential of ion imprinted polymers synthesized by trapping approach for selective solid phase extraction of lanthanides. AB - Ion imprinted polymers (IIPs) specific to lanthanides were synthesized using neodymium ions (Nd3+) as template ions. Nd3+ ions form binary complex ions with 5,7-dichloroquinoline-8-ol (DCQ) or vinylpyridine (VP), or ternary complex ions with both DCQ and VP in 2-methoxyethanol, before copolymerization in the presence of styrene and divinylbenzene as monomer and cross-linker, respectively. DCQ was expected to be trapped in the synthesized polymers pores. The template ion removal was then optimized. For the first time, the DCQ leakage was determined by HPLC-UV during the template removal and the sedimentation steps before solid phase extraction (SPE) packing. It was observed that the trapped DCQ was unfortunately lost in significant amounts, up to 51%, and that this amount varied from one synthesis to another. The grinded and sieved polymers were next packed in SPE cartridges. The study of the SPE profiles obtained with the IIPs synthesized either with the binary or the ternary complex confirmed the prominent role of DCQ on the selectivity of an IIP by comparison with a non-imprinted polymer (NIP), i.e. a polymer synthesized under the same conditions as those of the IIP but without template ions. The influence of the porogenic solvent on the selectivity was also investigated by replacing 2-methoxyethanol by acetonitrile or dimethylsulfoxyde (DMSO). The polymers synthesized in DMSO led to the most repeatable results when elution solutions with a gradual decrease in pH were percolated through the cartridge. This is why DMSO was used to optimize the SPE protocol in order to maximize the difference of extraction yield between the IIP and the NIP, i.e. promoting a selective retention on the IIP. A value of about 30% was obtained for La3+, Ce3+, Nd3+, and Sm3+. Nevertheless, with the optimized SPE protocol, IIPs from different syntheses did not have the same SPE behavior, which may result from different random leakages of DCQ. This demonstrates for the first time the main limitation of the IIPs synthesized in bulk with the trapping approach for their use in SPE. PMID- 27769433 TI - Highly sensitive detection of acid phosphatase by using a graphene quantum dots based forster resonance energy transfer. AB - A novel and effective fluorescence strategy was developed for sensitive and selective detection of acid phosphatase (ACP). A forster resonance energy transfer (FRET) biosensor was established by attaching nile red (NR) to graphene quantum dots (GQDs) via lecithin/beta-Cyclodextrin (lecithin/beta-CD) complex as the linker. The introduction of lecithin/beta-CD would brought GQDs-NR pair close enough through both electrostatic interaction and hydrophobic interaction, thereby making the FRET occur and thus resulting in the fluorescence quenching of GQDs (donor) and meanwhile the fluorescence enhancement of NR (acceptor). The presence of ACP in the sensing system would catalyze the hydrolysis of lecithin into two parts, resulting in the GQDs-NR pair separation. Meanwhile, considerable fluorescence recovery of GQDs and decreasing of NR was observed due to the inhibition of FRET progress. In this method, the limit of detection (LOD) is 28uUmL-1 which was considerably low for ACP detection. Using the GQDs-based fluorescence biosensor, we successfully performed in vitro imaging of human prostate cancer cells. PMID- 27769434 TI - A bright carbon-dot-based fluorescent probe for selective and sensitive detection of mercury ions. AB - In this work, we demonstrated a convenient and green strategy for the synthesis of bright and water-soluble carbon dots (CDs) by carbonizing sodium citrate and glutathione together in a hydrothermal method for the first time. Without post surface modification, the as-synthesized CDs display fluorescence quantum yield (QY) as high as 21.03% and show superior stability not only in concentrated salt solutions but also in neutral and alkaline media. The probe exhibits selective and sensitive recognition capability towards mercury ion (Hg2+) in aqueous solution. The fluorescence of CDs can be quenched by Hg2+ through an effective electron energy transfer process. It displays a linear quenching effect toward mercury ion in the concentration range of 0-15MUM with a correlation coefficient (R2) of 0.99. The limit of detection is determined to be 25nM at the signal to noise ratio of 3. These attractive merits would enable the extensive applications of this probe in environmental science and analytical chemistry in the future. PMID- 27769435 TI - A label-free, PCR-free and signal-on electrochemical DNA biosensor for Leishmania major based on gold nanoleaves. AB - Detection of leishmaniasis is important in clinical diagnoses. In the present study, identification of Leishmania parasites was performed by a label-free, PCR free and signal-on ultrasensitive electrochemical DNA biosensor. Gold nanoleaves were firstly electrodeposited by an electrodeposition method using spermidine as a shape directing agent. The biosensor was fabricated by immobilization of a Leishmania major specific DNA probe onto gold nanoleaves, and methylene blue was employed as a marker. Hybridization of the complementary single stranded DNA sequence with the biosensor under the selected conditions was then investigated. The biosensor could detect a synthetic DNA target in a range of 1.0*10-10 to 1.0*10-19molL-1 with a limit of detection of 1.8*10-20molL-1, and genomic DNA in a range of 0.5-20ngMUL-1 with a limit of detection of 0.07ngMUL-1. The biosensor could distinguish Leishmania major from a non-complementary-sequence oligonucleotide and the tropica species with a high selectivity. The biosensor was applicable to detect Leishmania major in patient samples. PMID- 27769436 TI - Sensitive and selective turn off-on fluorescence detection of heparin based on the energy transfer platform using the BSA-stabilized Au nanoclusters/amino functionalized graphene oxide hybrids. AB - An ultra-sensitive and selective turn off-on fluorescence detection of heparin based on the energy transfer in the BSA-stabilized gold nanoclusters/amino functionalized graphene oxide (BSA-AuNCs/NH2-GO) hybrids was successfully realized. The BSA-AuNCs containing amounts of carboxyl groups could be absorbed on the surface of NH2-GO through the electrostatic interaction, which resulted in the fluorescence quenching of BSA-AuNCs with high efficiency. However, heparin, possessing high density of negative charge, could compete with BSA-AuNCs to bind NH2-GO and block the energy transfer from BSA-AuNCs to NH2-GO. The fluorescence recovery of BSA-AuNCs was closely related to the amount of heparin and there was a good linear relationship between fluorescence recovery of BSA-AuNCs and heparin over the range of 100ng/mL to 30MUg/mL with a detection limit of 40ng/mL. What's more, the fluorescence assay was successfully applied for heparin sensing in human serums and intracellular imaging. PMID- 27769437 TI - Novel bead-based platform for direct detection of unlabelled nucleic acids through Single Nucleobase Labelling. AB - Over the last decade, circulating microRNAs have received attention as diagnostic and prognostic biomarkers. In particular, microRNA122 has been demonstrated to be an early and more sensitive indicator of drug-induced liver injury than the widely used biomarkers such as alanine aminotransferase and aspartate aminotransferase. Recently, microRNA122 has been used in vitro to assess the cellular toxicity of new drugs and as a biomarker for the development of a rapid test for drug overdose/liver damage. In this proof-of-concept study, we report a PCR-free and label-free detection method that has a limit of detection (3 standard deviations) of 15 fmoles of microRNA122, by integrating a dynamic chemical approach for "Single Nucleobase Labelling" with a bead-based platform (Luminex(r)) thereby, in principle, demonstrating the exciting prospect of rapid and accurate profiling of any microRNAs related to diseases and toxicology. PMID- 27769438 TI - Sorbents with non-covalently immobilized beta-diketones for preconcentration of rare earth elements. AB - A comparison of the efficiency of sorbents obtained by different methods of non covalent immobilization of beta-diketones on some low-polar matrices with respect to extraction of rare earth elements (REEs) was carried out. It was shown that sorbents containing reagent amounts of 1-8mmol/g can be obtained by sorption of reagents on low-polar matrices from aqueous and aqueous-organic solutions, and the value for the maximum capacity of the sorbent correlates with the specific surface of the matrix. Similar sorbents were also prepared by impregnating the matrix with reagent. It was found out that, under the chosen conditions, sorbents modified by extracting reagent from the aqueous solutions are more stable and extract lanthanum with higher distribution coefficients than those obtained by impregnation. We have found conditions for quantitative extraction of REEs from seawater in the proposed preconcentration systems (pH 4.0, minicolumn dimensions 2*10mm, v=4ml/min). It was shown that all REE may be quantitatively recovered in both ways: on modified sorbents and as complexes with reagents on unmodified matrices. We have proposed a sorbent for lanthanum preconcentration from large volumes of water samples (500ml). The sorbent is stable in dynamic conditions and is based on hyper cross-linked polystyrene modified with 1-phenyl-3-methyl-4 benzoylpyrazol-5-one (PMBP). Desorption could be carried out with 1-2M HNO3. REEs were determined by ICP-MS, LODs achieved were in ng/l range. PMID- 27769440 TI - Gelatin-modified gold nanoparticles for direct detection of urinary total gelatinase activity: Diagnostic value in bladder cancer. AB - Matrix metalloproteinases (MMPs), in particularly gelatinases (MMP-2 and MMP-9) were reported as urinary markers of bladder cancer. In this work, we developed a simple colorimetric gold nanoparticle (AuNP) assay for rapid and sensitive detection of urinary total gelatinase activity based on the surface plasmon resonance (SPR) property of AuNPs. Gelatin-modified AuNPs were stably suspended in solution even upon addition of an aggregation inducer as 6-mercaptohexan-1-ol (6-MCH). Gelatinases digest gelatin capping. Subsequently, addition of 6-MCH leads to AuNPs aggregation with red to blue color shift. In a pilot study, results of the developed AuNP assay were consistent with zymography for qualitative detection of urinary total gelatinase activity. The sensitivity and specificity of both assays were 80% and 90.9% respectively. The absorption ratios, A625/A530 of the reacted AuNP solutions were used to quantify the total gelatinase concentration. The best cut off value was 0.01895ng/MUg protein, at which the sensitivity was 87.5% and the specificity was 86.4%. The developed AuNP assay is simple, low-cost and can aid non-invasive diagnosis of bladder cancer. PMID- 27769439 TI - Prediction of total antioxidant activity of Prunella L. species by automatic partial least square regression applied to 2-way liquid chromatographic UV spectral images. AB - Four different data representations were evaluated for the determination of the total antioxidant activities of four different Prunella L. species, which are Prunella vulgaris, Prunella grandiflora, Prunella laciniata, and Prunella orientalis Bornm. Three different antioxidant assays, 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABST), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Folin-Ciocalteu (FC) reagent measured the total antioxidant activity and phenolic content of the four Prunella L. species that were extracted with 12 different solvent systems. The data set of 48 Prunella L. extracts was collected by high-performance liquid chromatography (HPLC) with ultraviolet diode array detection. The prediction of total antioxidant activity of Prunella L. species by super partial least square (sPLS) regression was obtained using four different representations of the data; the entire two-way chromatographic-spectral images, the average UV spectra, the total absorbance chromatogram, the lambda max (lambdamax) chromatogram. The coefficients of determination (R2) for the entire two-way chromatographic-spectral images (the ABST (0.943+/-0.008), the DPPH (0.91+/-0.01), and the FC (0.963+/-0.006)) indicated good accuracy for predicting antioxidant activities. The three different wet chemical assays are known to yield different values so it is advantageous to estimate the three separate values with a single LC measurement. The entire two-way chromatographic-spectral images have been used to the first time for calibration. Acidic hexane, as an extraction solvent, gave the least root mean square error of prediction (RMSEP) for the two-way chromatographic-spectral images, so it would be the best solvent for modeling antioxidant activities. PMID- 27769441 TI - Colorimetric sensor for cysteine in human urine based on novel gold nanoparticles. AB - Herein, a novel, high sensitive, and specific colorimetric sensor for cysteine (Cys) based on pectinase protected gold nanoparticles (P@AuNPs) has been demonstrated for the first time. The P@AuNPs were synthesized by "MW-assisted heat method" and were characterized by UV-vis, TEM, FT-IR and zeta potential techniques. Cys could cause the aggregation of P@AuNPs due to formation of the strong covalent Au-S bond and electrostatic binding. As the Cys concentration increased, the color of the solutions gradually changed from wine-red to blue as well as the large absorption band shifted from 523 to 650nm upon P@AuNPs aggregation. In addition, various experimental parameters such as pH, the amount of P@AuNPs and incubation time were investigated for the optimum sensing conditions. The concentration of Cys could be determined by monitoring with the naked eye or a UV-vis spectrometer. The proposed colorimetric sensor showed an extreme selectivity toward the determination of Cys in the presence of 20-fold all other different interferents. Under optimum conditions, this method exhibited two good linear ranges from 4.85*10-9 to 3.02*10-4M (R2=0.996) and 3.25*10-3 to 1.03*10-2M (R2=0.999), with a low detection limit of 4.6*10-9M. Moreover, this colorimetric sensor was successfully applied to the detection of Cys in human urine samples, demonstrating its great value for practical application in biological systems. PMID- 27769442 TI - Accurate and visual discrimination of single-base mismatch by utilization of binary DNA probes in gold nanoparticles-based biosensing strategy. AB - Herein we report a colorimetric biosensing strategy to discriminate single nucleotide mutation in DNA with high selectivity using unmodified gold nanoparticles (AuNPs) as indicators. In the AuNPs-based colorimetric strategy, binary DNA probes were produced by splitting a long DNA probe in the middle for sensitive differentiation of single-base mismatch. The detection limit of this method toward target DNA was 5nM. The developed system has superior advantages of utilization of inexpensive materials, simplicity and visualization. Moreover, binary DNA probes not only can distinguish single-base mutation in the target DNA very well, as compared to long DNA probe, but also can construct "AND" logic gate using two distinct target DNAs as inputs, which holds great potential for increasing the accuracy of disease diagnosis in clinical applications. PMID- 27769443 TI - Label-free, turn-on fluorescent sensor for trypsin activity assay and inhibitor screening. AB - The development of new detection methods for proteases activity assay is important in clinical diagnostics and drug development. In this work, a simple, label-free, and turn-on fluorescent sensor was fabricated for trypsin, a protease produced in the pancreas. Cytochrome c, a natural substance of trypsin, could be selectively cleaved by trypsin into heme-peptide fragment. The produced heme peptide fragment exhibited an intensive catalytic role on the H2O2-mediated the oxidation of thiamine to form strong fluorescent thiochrome. The fluorescence intensity was closely dependent on the amount of trypsin presented. The procedure allowed the measurement of trypsin over the range of 0.5-20.0MUg/mL with a detection limit of 0.125MUg/mL. The sensor showed better precision with a relative standard deviation of 1.6% for the measurement of 1.0MUg/mL trypsin solution (n=11). This sensing system was applied to screen the inhibitor of trypsin, the IC50 values were calculated to be 12.71ng/mL for the trypsin inhibitor from soybean and 2.0MUg/mL for benzamidine hydrochloride, respectively, demonstrating its potential application in drug development and related diseases treatment. PMID- 27769444 TI - Improving the biocompatibility of carbon nanodots for cell imaging. AB - In the practice of in vivo imaging with carbon nanodots (CNDs) as probe, the volume of CNDs solution introduced into living body should be kept at minimum, and a higher concentration is needed to ensure sufficient quantity of the probe for obtaining bright image. Therefore, the improvement on biocompatibility of the CNDs is among the most important and critical issues. We report herein the improvement on the biocompatibility of CNDs with modification by ionic liquid. Amide group functionalization of carbon nanodots is first conducted through microwave irradiation, followed by coupling the ionic liquid 1-carboxymethyl-3 methyl imidazolium bromide on the surface of the Amide-CNDs via covalent conjunction to produce the modified carbon nanodots (IL-CNDs). This modification process significantly improved the biocompatibility of CNDs, as demonstrated by cell imaging at a higher concentration of CNDs. Both Amide-CNDs and IL-CNDs exhibit abundant surface functional groups, resulting in tunable fluorescent emission feature and potential applications in two-color cell imaging. PMID- 27769445 TI - Ionic liquid-based method for direct proteome characterization of velvet antler cartilage. AB - The cartilage zone of the velvet antler is richly vascularized, this being a major difference to the classical cartilage, in which there are no blood vessels. Angiogenesis and rapid growth of vasculature in velvet antler cartilage (VAC) make it an ideal model for discovering the novel angiogenic regulatory factors. However, the proteomic analysis of VAC is challenging due to the serious interference of proteoglycans (PGs) and collagens. To achieve a comprehensive proteome characterization of VAC, herein, we developed an ionic liquid-based method using 1-dodecyl-3-methylimidazolium chloride ([C12-mim]Cl) for selective extraction of cellular proteins from VAC. Compared with the previous cetylpyridinium chloride (CPC)-based method, the developed [C12-mim]Cl-based method takes much less processing time, shows facile preparation procedure and good compatibility towards downstream proteomic analysis, leading to the identification of more protein groups (1543 vs 753), membrane proteins (663 vs 279) and transmembrane proteins (217 vs 58). PMID- 27769446 TI - Effect of different precursors on generation of reference spectra for structural molecular background correction by solid sampling high-resolution continuum source graphite furnace atomic absorption spectrometry: Determination of antimony in cosmetics. AB - Different precursors were evaluated for the generation of reference spectra and correction of the background caused by SiO molecules in the determination of Sb in facial cosmetics by high-resolution continuum source graphite furnace atomic absorption spectrometry employing direct solid sample analysis. Zeolite and mica were the most effective precursors for background correction during Sb determination using the 217.581nm and 231.147nm lines. Full 23 factorial design and central composite design were used to optimize the atomizer temperature program. The optimum pyrolysis and atomization temperatures were 1500 and 2100 degrees C, respectively. A Pd(NO3)2/Mg(NO3)2 mixture was employed as the chemical modifier, and calibration was performed at 217.581nm with aqueous standards containing Sb in the range 0.5-2.25ng, resulting in a correlation coefficient of 0.9995 and a slope of 0.1548s ng-1. The sample mass was in the range 0.15-0.25mg. The accuracy of the method was determined by analysis of Montana Soil (II) certified reference material, together with addition/recovery tests. The Sb concentration found was in agreement with the certified value, at a 95% confidence level (paired t-test). Recoveries of Sb added to the samples were in the range 82-108%. The limit of quantification was 0.9mgkg-1 and the relative standard deviation (n=3) ranged from 0.5% to 7.1%. From thirteen analyzed samples, Sb was not detected in ten samples (blush, eye shadow and compact powder); three samples (two blush and one eye shadow) presented Sb concentration in the 9.1-14.5mgkg-1 range. PMID- 27769447 TI - Rapid and sensitive analysis of N-glycans by MALDI-MS using permanent charge derivatization and methylamidation. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has become an important technology for glycan analysis due to its ease of operation, short analysis time and impurity tolerance. However, the low ionization efficiency of N-glycans led to the difficulty in analyzing glycans of low abundance in complex biological samples due to the lack of basic site for protonation. Therefore, highly sensitive method for the glycans analysis is in urgent demand. Here we report a new strategy to introduce a permanent charge at the reducing end of N-linked glycans by a one pot reaction, where glycosylamines that were obtained by rapid deglycosylation within 5min were labeled with N succinimidyloxycarbonylmethyl tris (2,4,6- trimethoxyphenyl) phosphonium bromide (TMPP-Ac-OSu). With TMPP-Ac labeling, more than 50 fold enhancement in the sensitivity of method was achieved for neutral glycans from ribonuclease B (RNase B) in comparison to their native counterparts. In combination with methylamidation of sialic acid residues, this novel developed strategy could also be used for sialylated glycans analysis from sialoglycoproteins and complex serum sample. As a result, more than 50 glycans were detected with only 25nL human serum sample. PMID- 27769448 TI - Electrochemical RNA genosensors for toxic algal species: enhancing selectivity and sensitivity. AB - Harmful algal blooms (HABs) are becoming more frequent as climate changes, with tropical species moving northward. Monitoring programs detecting the presence of toxic algae before they bloom are of paramount importance to protect aquatic ecosystems, aquaculture, human health and local economies. Rapid and reliable species identification methods using molecular barcodes coupled to biosensor detection tools have received increasing attention over the past decade as an alternative to the impractical standard microscopic counting-based techniques. This work reports on a PCR amplification-free electrochemical genosensor for the enhanced selective and sensitive detection of RNA from multiple Mediterranean toxic algal species. For a sandwich hybridization (SHA), we designed longer capture and signal probes for more specific target discrimination against a single base-pair mismatch from closely related species and for reproducible signals. We optimized experimental conditions, viz., minimal probe concentration in the SHA on a screen-printed gold electrode and selected the best electrochemical mediator. Probes from 13 Mediterranean dinoflagellate species were tested under optimized conditions and the format further tested for quantification of RNA from environmental samples. We not only enhanced the selectivity and sensitivity of the state-of-the-art toxic algal genosensors but also increased the repertoire of toxic algal biosensors in the Mediterranean, towards an integral and automatic monitoring system. PMID- 27769449 TI - A highly selective electrochemical sensor for chloramphenicol based on three dimensional reduced graphene oxide architectures. AB - Chloramphenicol (CAP), as a broad-spectrum antibiotic, has been worldwide banned for using in the food producing animals due to its overuse may cause severe threats to public health. It is therefore highly desirable to develop facile, selective and sensitive biosensor for CAP detection and monitoring in drug and foodstuff samples. In this work, three-dimensional reduced graphene oxide (3DRGO) architectures were prepared through a green and template-free approach and used as active electrode materials to develop a highly selective electrochemical sensor for CAP detection. The spontaneous reduction and assembly of graphene oxide via zinc foil was completed at room temperature, followed by washing with diluted hydrogen chloride solution, to produce 3DRGO. The as-prepared 3DRGO were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy. An electrochemical biosensor for CAP was constructed based on 3DRGO-modified glass carbon electrode (3DRGO/GCE). It was revealed that the present 3DRGO/GCE sensor exhibited a remarkable performance with a detection range of 1-113MUmolL-1 and a detection limit of 0.15MUmolL-1 at physiological pH 7.4. Moreover, the sensor showed an excellent selectivity, stability, reproducibility, and satisfying recovery result for CAP detection in real samples. PMID- 27769450 TI - A simple method using two-step hot embossing technique with shrinking for fabrication of cross microchannels on PMMA substrate and its application to electrophoretic separation of amino acids in functional drinks. AB - This work presents a simple hot embossing method with a shrinking procedure to produce cross-shape microchannels on poly(methyl methacrylate) (PMMA) substrate for the fabrication of an electrophoresis chip. The proposed method employed a simple two-step hot embossing technique, carried out consecutively on the same piece of substrate to make the crossing channels. Studies of embossing conditions, i.e. temperature, pressure and time, were carried out to investigate their effects on the dimension of the microchannels. Applying a simple shrinking procedure reduced the size of the channels from 700+/-20um wide*150+/-5um deep to 250+/-10um wide*30+/-2um deep, i.e. 80% and 64% reduction in the depth and width, respectively. Thermal fusion was employed to bond the PMMA substrate with a PMMA cover plate to produce the microfluidic device. Replication of microchip was achieved by precise control of conditions in the fabrication process (pressure, temperature and time), resulting in lower than 7% RSD of channel dimension, width and depth (n =10 devices). The method was simple and robust without the use of expensive equipment to construct the microstructure on a thermoplastic substrate. The PMMA microchip was used for demonstration of amine functionalization on the PMMA surface, measurement of electroosmotic flow and for electrophoretic separation of amino acids in functional drink samples. The precision of migration time and peak area of the amino acids, Lys, Ile and Phe at 125MUM to 500MUM, were in the range 3.2-4.2% RSD (n=9 devices) and 4.5-5.3% RSD (n=9 devices), respectively. PMID- 27769451 TI - Signal-on CoA-dependent electrochemical biosensor for highly sensitive and label free detection of Citrate synthase activity. AB - We report here a label-free and sensitive electrochemical method for probing Citrate synthase (CS) activity based on detailed investigations into the nucleic acid-mimicking coordination polymer (CP) formed from the coenzyme A (CoA)-Ag(I) repeat units. Our biosensing approach provides an especial and significant detection mechanism: CS can catalyze the essential condensation reaction between acetyl-coenzyme A (Ac-CoA) and oxaloacetate (OAA) to form citrate and CoA; then, in the presence of Ag(I), CoA-Ag(I) CP can be in situ formed because of the strong complexation ability of thiol groups of CoA toward Ag(I). The generated CoA-Ag(I) CP attaches to graphene-modified glassy carbon electrode surface by multiple adenine bases deriving from CoA and acting as the side groups along the polymeric backbone, which displays efficient H2O2-electrocatalyzing activity. More importantly, by using the formed polymer as signal output, the process is implemented to quantitatively analyze the activity of CS. Under the optimal conditions, CS with a detection limit as low as 0.00165U/uL could be sensitively probed with a wide linear range from 0.0033 to 0.264U/uL. Furthermore, with the character of label-free detection, high sensitivity and excellent selectivity, this strategy offers a convenient and specific method for CS activity detection and relevant inhibitors screening, which holds a promising potential in the practical application of CS-based biochemical research, disease diagnosis and drug discovery. PMID- 27769452 TI - A cyanine-based near-infrared fluorescent probe for highly sensitive and selective detection of hypochlorous acid and bioimaging. AB - Hypochlorous acid (HOCl) is a kind of reactive oxygen species which plays an important role in biological process. HOCl detection is of great importance in disease prevention and treatment. Herein, a cyanine-based near-infrared (NIR) fluorescent probe for HOCl has been designed and synthesized. This probe can react with HOCl in a dose-response manner along with the fluorescence of the probe quenched, the reaction through an electrophilic addition to the double bond and subsequent oxidation reaction. Experiments indicate that the probe can be acted as a selective and sensitive indicator for HOCl and the limit of detection for HOCl is estimated to be 22nM. What's more, this probe shows a low toxicity to cells and can be applied to visualize HOCl molecules in living cells. Therefore, the proposed method may make a significant contribution to HOCl detection. PMID- 27769453 TI - Highly sensitive and well reproducible Surface-enhanced Raman spectroscopy from silver triangular platelets. AB - Recently, considerable efforts have been made to prepare Surface-enhanced Raman scattering (SERS) nanostructures with high sensitivity and good reproducibility, which are always difficult and costly. In this article, we provide a simple route on the synthesis of silver particles with a novel single {111} plane and triangular morphology by reducing silver nitrate with poly(vinyl pyrrolidone) (PVP) in N,N-dimethylformamide (DMF) solutions. The results show that the Raman intensities of rhodamine 6G (R6G) decrease with decreasing the loading concentration and that R6G loading follows the first-order adsorption kinetics. Even at a low concentration of 10-12M, the signatures of R6G in Raman spectrum are still clearly observed. It indicates that the silver triangular platelets (i.e. AgTP) can offer sufficient active sites to efficiently capture the R6G molecules from the loading solution, and exhibit high SERS sensitivity. In addition, the relative standard deviation (RSD) of band at 1650cm-1 is calculated to be 13.7%, 12.7%, 15.7%, 15.1%, 13.3%, and 13.1%, respectively, corresponding with the concentration of R6G from 10-6M to 10-12M, which reveals the nanometer scale AgTP can provide abundant hot spots and exhibit excellent reproducibility. This method offers an easy and low-cost way to prepare AgTP substrates and makes SERS detection more practicable. PMID- 27769454 TI - Exploiting multispectral imaging for non-invasive contamination assessment and mapping of meat samples. AB - Recently, imaging and machine vision are gaining attention to food stakeholders since these are considered to be the emerging tools for food safety and quality assessment throughout the whole food chain. Herein, multispectral imaging, a surface chemistry sensor type, has been evaluated in terms of monitoring aerobically packaged beef filet spoilage at different storage temperatures (2, 8, and 15 degrees C) and storage time. Spectral data acquired from the surface of meat samples (with/without background flora; +BF/-BF respectively) along with microbiological analysis. Qualitative analysis was employed for the discrimination of meat samples in two microbiological quality classes based on the values of total viable counts (TVC<2log10CFU/g and TVC>2log10CFU/g). Furthermore, a Support Vector Regression model was developed to provide quantitative estimations of microbial counts during storage. Results exhibit good performance with overall correct classification rate for the two quality classes ranging from 89.2% to 80.8% for model validation. The calculated regression results to an R-square of 0.98. PMID- 27769455 TI - Anneal-shrinked Cu2O dendrites grown on porous Cu foam as a robust interface for high-performance nonenzymatic glucose sensing. AB - Enzyme-free electrochemical detection of glucose in alkaline media with favorable properties has been acquired by fabricating a robust and large-surface sensing platform, which is composed of anneal-shrinked Cu2O dendrites grown on porous Cu foam. On the one hand, the good compatibility of electrodeposited Cu2O architectures and Cu foam substrate, together with a post-deposition anneal at 200 degrees C, offers a mechanically stable interface for glucose determination. On the other hand, the macropores of Cu foam that is decorated with unique Cu2O dendrites provide large active surface for electrocatalytic reaction and mass transport. As a result, selective sensing of glucose in the linear concentration range of 0.001-1.4mM was achieved on the fabricated sensor, with a sensitivity of as high as 5.04mAcm-2mM-1 and a detection limit of 0.13MUM. Desired long-term performance stability was obtained, partially due to the strong adhesion of Cu2O microstructures to the Cu foam support after annealing. Practical monitoring of glucose in serum samples was also demonstrated on the proposed sensor. PMID- 27769456 TI - Model study of modern oil-based paint media by triacylglycerol profiling in positive and negative ionization modes. AB - Lipid binders have traditionally been determined in paintings by using gas chromatography/mass spectrometry (GC/MS) to identify the characteristic profiles and ratios of fatty acids . However, the presence of mixtures in contemporary and modern oil paints makes the GC/MS determination of fatty acids insufficient to fully characterize the lipid binding media. In this study we prove that triacylglycerol (TAG) profiling by high-performance liquid chromatography with high-resolution tandem mass spectrometry, using ESI in positive and negative ionization modes is highly effective. We exploited this analytical approach to study the curing and degradation processes undergone by six plant oils used in the formulation of media in modern paints, using both natural and artificial ageing experiments. We believe that is the first time that a negative ionization mode has been applied for this purpose and that a survey with HPLC-ESI-Q-ToF has been carried out to study the ageing kinetics of plant oils. TAG profiling enabled us to study the evolution over time of the constituents of modern oils, with respect to curing and ageing. The data analyzed in this study demonstrate that our approach is efficient to study the oxidation of TAGs during ageing. The data also improve current knowledge on the properties of vegetable oils, which could lead to the development of new paint materials and conservation treatments for modern and contemporary works of art. PMID- 27769457 TI - Highly selective direct determination of chlorate ions by using a newly developed potentiometric electrode based on modified smectite. AB - A novel polyvinyl chloride membrane chlorate (ClO3-) selective electrode based on modified smectite was developed for the direct determination of chlorate ions and the potentiometric performance characteristics of its were examined. The best selectivity and sensitivity for chlorate ions were obtained for the electrode membrane containing ionophore/polyvinylchloride/o-nitrophenyloctylether in composition of 12/28/60 (w/w%). The proposed electrode showed a Nernstian response toward chlorate ions at pH=7 in the concentration range of 1*10-7-1*10 1M and the limit of detection was calculated as 9*10-8M from the constructed response plot. The linear slope of the electrode was -61+/-1mVdecade-1 for chlorate activity in the mentioned linear working range. The selectivity coefficients were calculated according to both the matched potential method and the separate solution method. The calculated selectivity coefficients showed that the electrode performed excellent selectivity for chlorate ions. The potentiometric response of electrode toward chlorate ions was found to be highly reproducible. The electrode potential was stable between pH=4-10 and it had a dynamic response time of <5s. The potentiometric behavior of the electrode in partial non-aqueous medium was also investigated and the obtained results (up to 5% (v/v) alcohol) were satisfactory. The proposed electrode was used during 15 weeks without any significant change in its potential response. Additionally, the electrode was very useful in water analysis studies such as dam water, river water, tap water, and swimming pool water where the direct determination of chlorate ions was required. PMID- 27769459 TI - Selective and sensitive speciation analysis of Cr(VI) and Cr(III), at sub-MUgL-1 levels in water samples by electrothermal atomic absorption spectrometry after electromembrane extraction. AB - In this work, electromembrane extraction in combination with electrothermal atomic absorption spectrometry (ET-AAS) was investigated for speciation, preconcentration and quantification of Cr(VI) and Cr(III) in water samples through the selective complexation of Cr(VI) with 1,5-diphenylcarbazide (DPC) as a complexing agent. DPC reduces Cr(VI) to Cr(III) ions and then Cr(III) species are extracted based on electrokinetic migration of their cationic complex (Cr(III)-DPC) toward the negative electrode placed in the hollow fiber. Also, once oxidized to Cr(VI), Cr(III) ions in initial sample were determined by this procedure. The influence of extraction parameters such as pH, type of organic solvent, chelating agent concentration, stirring rate, extraction time and applied voltage were evaluated following a one-at-a-time optimization approach. Under optimized conditions, the extracted analyte was quantified by ETAAS, with an acceptable linearity in the range of 0.05-5ngmL-1 (R2 value=0.996), and a repeatability (%RSD) between 3.7% and 12.2% (n=4) for 5.0 and 1.0ngmL-1 of Cr(VI), respectively. Also, we obtained an enrichment factor of 110 that corresponded to the recovery of 66%. The detection limit (S/N ratio of 3:1) was 0.02ngmL-1. Finally, this new method was successfully employed to determine Cr(III) and Cr(VI) species in real water samples. PMID- 27769458 TI - Indoor and outdoor determination of pesticides in air by ion mobility spectrometry. AB - The use of ion mobility spectrometry (IMS) has been evaluated as analytical methodology to detect and evaluate the occupational exposure to pesticides. The developed IMS methodology was used, in positive and negative modes, to determine the presence of pesticides in air and to evaluate possible inhalation exposures of workers and users based on active sampling on Teflon membranes and direct thermal desorption IMS. The negative IMS mode was used to determine bensulfuron, clorpyrifos, diniconazole, diuron, flutolanil and imidacloprid, while the positive mode was employed to evaluate formetanate, metalaxyl, metamitrone, metribuzin, paclobutrazol and pirimicarb. The IMS measurements provided limits of detection from 8pg to 600pg. Indoor air samples, from phytosanitary plants, and outdoor samples, obtained from pesticide treatments in a local farm, were analysed providing pesticide air concentrations in the range of 0.04 to>0.25mgm 3. Occupational exposure of workers and pesticide users were evaluated and compared with values recommended by the authorities, providing useful information to improve the prevention programs in the phytosanitary field. PMID- 27769460 TI - Selective extraction of endogenous peptides from human serum with magnetic mesoporous carbon composites. AB - Highly sensitive and selective enrichment of endogenous peptides or proteins from complex bio-system takes a significant important place to the proteomic. In this work, a unique Fe3O4@2SiO2@mSiO2-C nanomaterial was synthesized, contributing to the separation and enrichment of low concentration peptides from complex mixture. The highly ordered mesoporous carbon structure render the nanospheres with unique properties of strongly connected pore channels, strong hydrophobic properties, high specific surface area (254.90m2/g), uniform pore size (3.61nm). Which made it a promising candidates for the efficient enrichment of peptides through hydrophobic-hydrophobic interaction with low detection limit (0.2fmol), superb size-exclusion of high molecular weight proteins, highly selectivity for BSA digest (molar ratio of BSA tryptic digests/BSA, 1:400), ideal peptides recovery (about 87.5%), wonderful repeatability (RSD less than 25%). Moreover, the as prepared Fe3O4@2SiO2@mSiO2-C nanoparticles were successfully enriched 2198 endogenous peptides from human serum, which fully indicated that the mesoporous carbon nanoparticles was a promising candidate for isolating proteins or peptides from complex biologicals. PMID- 27769462 TI - Green synthesis of mesoporous molecular sieve incorporated monoliths using room temperature ionic liquid and deep eutectic solvents. AB - A hybrid monolith incorporated with mesoporous molecular sieve MCM-41 of uniform pore structure and high surface area was prepared with binary green porogens in the first time. With a mixture of room temperature ionic liquids and deep eutectic solvents as porogens, MCM-41 was modified with 3-(trimethoxysilyl) propyl methacrylate (gamma-MPS) and the resulting MCM-41-MPS was incorporated into poly (BMA-co-EDMA) monoliths covalently. Because of good dispersibility of MCM-41-MPS in the green solvent-based polymerization system, high permeability and homogeneity for the resultant hybrid monolithic columns was achieved. The MCM 41-MPS grafted monolith was characterized by scanning electron microscopy, energy dispersive spectrometer area scanning, transmission electron microscopy, FT-IR spectra and nitrogen adsorption tests. Chromatographic performance of MCM-41-MPS grafted monolith was characterized by separating small molecules in capillary electrochromatography, including phenol series, naphthyl substitutes, aniline series and alkyl benzenes. The maximum column efficiency of MCM-41-MPS grafted monolith reached 209,000 plates/m, which was twice higher than the corresponding MCM-41-MPS free monolith. Moreover, successful separation of non-steroidal anti inflammatory drugs and polycyclic aromatic hydrocarbons demonstrated the capacity in broad-spectrum application of the MCM-41-MPS incorporated monolith. The results indicated that green synthesis using room temperature ionic liquid and deep eutectic solvents is an effective method to prepare molecular sieve incorporated monolithic column. PMID- 27769461 TI - Quantitative analysis of solid samples using modified specular reflectance accessory. AB - Diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS) is a fast, reliable and cost effective analytical method, requiring minimal or no sample preparation. It is commonly used in the course of qualitative and quantitative analysis of pharmaceutical ingredients and food. We demonstrate that simpler and cheaper specular reflectance (SR) accessory working in a DRIFTS like mode (SR-DL) can be an alternative for DIRFTS attachment. An application of a modified SR accessory for quantitative analysis of solids samples is presented. As a case study the concentration of cinnarizine in commercial tablets has been determined from DRIFTS and SR-DL infrared (IR) and near-infrared (NIR) spectra recorded using DTGS (deuterated triglicine sulphate) detector in the IR and NIR regions and InGaAs (indium-gallium arsenide) detector in the NIR range. Based on these spectra Partial Least Squares (PLS) models were constructed and relative standard errors of prediction (RSEP) were calculated for the calibration, validation and analysed data sets. They amounted to 2.4-2.5%, 2.1-2.7% and 2.0-2.6% for the DRIFTS attachment while 2.1-2.2%, 2.0-2.3% and 1.9-2.6%, respectively, for the modified SR accessory. Obtained error values indicate that modified SR accessory can be effectively used for quantification of solid pharmaceutical samples in the mid- and near-infrared regions. PMID- 27769463 TI - Effect of cobalt doping level of ferrites in enhancing sensitivity of analytical performances of carbon paste electrode for simultaneous determination of catechol and hydroquinone. AB - This work presents the simultaneous determination of catechol (CC) and hydroquinone (HQ), employing a modified carbon paste electrode (CPE) with ferrite nanomaterial. Ferrite nanomaterial was doped with different amount of cobalt and this was investigated toward simultaneous oxidation of CC and HQ. It was shown that this modification strongly increases electrochemical characteristics of the CPE. Also, electrocatalytic activity of such materials strongly depends on the level of substituted Co in the ferrite nanoparticles. The modified electrodes, labeled as CoFerrite/CPE, showed two pairs of well-defined redox peaks for the electrochemical processes of catechol and hydroquinone. Involving of ferrite material in the structure of CPE, cause increase in the potentials differences between redox couples of the investigated compounds, accompanied with increases in peaks currents. Several important parameters were optimized and calibration curves, with limits of detection (LOD) of 0.15 and 0.3uM for catechol and hydroquinone, respectively, were constructed by employing amperometric detection. Effect of possible interfering compounds was also studied, and proposed method was successfully applied for CC and HQ quantification in real samples. PMID- 27769464 TI - High temperature diaphragm valve-based comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry. AB - A high temperature diaphragm valve-based two-dimensional (2D) gas chromatography (GC*GC) with time-of-flight mass spectrometry (TOFMS) instrument, with the valve mounted directly in the GC oven, is demonstrated with separations up to 325 degrees C. Use of the diaphragm valve allowed for the use of uncoupled carrier gas flows for 1D (first column dimension) and 2D (second column dimension), with a 1D flow rate of 1ml/min, and a 2D flow rate 3ml/min. The 3ml/min flow rate on 2D was selected to ensure compatibility with most TOFMS detectors. For valve based modulation, a 5ul sample loop coupled with a 60ms pulse width was selected, providing sufficient sensitivity concurrent with an acceptable 2D peak capacity. A 44-component mixture of alkanes, alcohols, and polyaromatic hydrocarbons (including n-alkanes of heptane to triacontane) whose boiling points range from 98 degrees C to 450 degrees C was used to initially study instrument performance. For a 120min separation and a modulation period PM of 2s, average peak widths-at base of 10s and 94ms were achieved for the alkanes on the 1D and 2D dimensions, respectively. Hence, the 1D peak capacity is 1nc~700, and the 2D peak capacity can in principle be 2nc~20. Thus the ideal 2D peak capacity could in principle approach nc,2D~14,000 using the 120min 1D run time. The limit of detection (LOD) for docosane, a representative analyte, was determined to be 1.5ppm injected concentration when 2ul of liquid sample was injected with a 20:1 split. A separation of diesel fuel demonstrated the practical utility of the instrument with this complex sample using a relatively fast run time of 20min and a short modulation period PM of 1s. Average peak widths-at-base of 5.4s and 166ms were achieved on the 1D and 2D dimensions, respectively. This yielded a 1nc~220 and a 2nc~ 6. Therefore, the 2D peak capacity is nc,2D~1320 with the 20min diesel separation. PMID- 27769465 TI - Efficient enrichment of glycopeptides with sulfonic acid-functionalized mesoporous silica. AB - This work presents an efficient and selective enrichment method for glycoprotein/glycopeptides with sulfonic acid-functionalized mesoporous silica (SBA-15-SO3H), which is synthesized via simple oxidation of -SH groups with H2O2. The functionalized SBA-15 shows large surface area and accessible pores, and can selectively adsorb glycopeptides via hydrogen bond and hydrophilic interaction. Upon the selective enrichment prior to the mass spectrometric (MS) analysis, the signals of glycopeptides are significantly enhanced, which leads to the identifiable signals of 21 glycopeptides from the digest of HRP, 16 glycopeptides from the digest of human IgG, and 16 glycopeptides from the digest of chicken avidin. The SBA-15-SO3H gives significant selectivity for glycopeptides even at a low molar ratio of glycopeptides to nonglycopeptides with an enrichment time of 15min. Therefore, this work provides a powerful material for selective enrichment and identification of low abundant glycopeptides in glycoproteomic analysis. PMID- 27769466 TI - Metal organic frameworks (MOFs) for magnetic solid-phase extraction of pyrazole/pyrrole pesticides in environmental water samples followed by HPLC-DAD determination. AB - Magnetic metal-organic frameworks (MOFs, [MIL-101]) were prepared and used as magnetic solid-phase extraction (MSPE) adsorbents for preconcentration of four kinds of pyrazole/pyrrole pesticides (flusilazole, fipronil, chlorfenapyr, and fenpyroximate) in environmental water samples, followed by high-performance liquid chromatography-diode-array detector (HPLC-DAD) determination. Several variables affecting MSPE efficiency were systematically investigated, including amount of MIL-101, extraction time, sample pH, salt concentration, type of desorption solvent and desorption number of times. Under optimized conditions, excellent linearity was achieved in the range of 5.0-200.0MUg/L for flusilazole and fipronil, and 2.0-200.0MUg/L for chlorfenapyr and fenpyroximate, with correlation coefficients r>0.9911. Limits of detection and quantification were 0.3-1.5MUg/L and 1.0-5.0MUg/L, respectively. The intra-day and inter-day precision (relative standard deviation, n=6, %) at three spiked levels were 1.1 5.4% and 3.9-7.8% in terms of peak area, respectively. The method recoveries at three fortified concentration levels ranged from 81.8% to 107.5% for reservoir water samples, 81.0-99.5% for river water samples, and 80.2-106.5% for seawater samples. The developed MOFs based MSPE coupled with HPLC method proved to be a convenient, rapid and eco-friendly alternative to the sensitive determination of pyrazole/pyrrole pesticides with high repeatability and excellent practical applicability. PMID- 27769467 TI - Online monitoring of trace chlorinated benzenes in flue gas of municipal solid waste incinerator by windowless VUV lamp single photon ionization TOFMS coupled with automatic enrichment system. AB - Chlorinated benzenes are typical precursors and indicators for polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) emissions from waste incinerators. Online and real-time monitoring of chlorobenzenes is a challenge due to their low concentration and complex nature of the flue gas. In this work, a continuous online monitoring system was built for detection of trace chlorinated benzenes based on a time-of-flight mass spectrometer (TOFMS). A single photon ionization (SPI) source based on a radiofrequency-excited windowless vacuum ultraviolet (VUV) lamp was developed for the first time to eliminate the signal attenuation resulting from the contamination of magnesium fluoride windows and to avoid the fragment ions. An automatic enrichment system including three parallel Tenax TA adsorption tubes was designed and coupled to the TOFMS to achieve the required ultrahigh sensitivity. The limits of quantitation at 7.65, 5.37 and 6.77pptv were obtained for monochlorobenzene (MCBz), dichlorobenzene (DCBz) and trichlorobenzene (TrCBz), respectively, within a 29-min analytical period. Moreover, this apparatus was applied to continuously online monitor the actual flue gas from a waste incinerator for three months. During this period, the concentrations of MCBz, DCBz and TrCBz detected in the flue gas were in the range of 100-1200, 50-800 and 50-300pptv, respectively. The relative standard deviation (RSD) of the sensitivity for the windowless VUV lamp ion source was 9.71% evaluated by the internal standard benzene over the 3-months flue gas monitoring. These results demonstrated the capability of this method in long-term analysis of the trace chlorinated benzenes in the flue gas. PMID- 27769468 TI - A simple method for the determination of glyphosate and aminomethylphosphonic acid in seawater matrix with high performance liquid chromatography and fluorescence detection. AB - Glyphosate (GLYP) is an important herbicide which is also used as the phosphorus source for marine organisms. The wide applications of GLYP can lead to its accumulation in oceans and coastal waters, thus creating environmental issues. However, there is limited methods for detection of GLYP and its degradation product, aminomethylphosphonic acid (AMPA) in saline samples. Therefore, a simple and fast method for the quantification of GLYP and AMPA in seawater matrix has been developed based on the derivatization with 9-fluorenylmethylchloroformate (FMOC-Cl), separation with high performance liquid chromatography (HPLC) and detection with fluorescence detector (FLD). In order to maximize sensitivity, the derivatization procedure was carefully optimized regarding concentration of FMOC Cl, volume of borate buffer, pH of borate buffer, mixing and derivatization time. The derivatization reaction could be completed within 30min in seawater samples without any additional clean-up or desalting steps. Under the optimized conditions, the developed HPLC method showed a wide linear response (up to several mg/L, R2>0.99). The limits of detection were 0.60MUg/L and 0.30MUg/L for GLYP and AMPA in seawater matrix, respectively. The relative standard deviation was 14.0% for GLYP (1.00mg/L) and 3.1% for AMPA (100MUg/L) in saline samples with three different operators (n=24). This method was applied to determine the concentration of GLYP and AMPA in seawater culture media and the recovery data indicated minimal matrix interference. Due to its simplicity, high reproducibility and successful application in seawater culture media analysis, this method is a potentially useful analytical technique for both marine research and environmental science. PMID- 27769469 TI - Evaluation of calcium alginate beads for Ce, La and Nd preconcentration from groundwater prior to ICP OES analysis. AB - Analytical methods for the determination of rare earth elements (REE) in natural waters by plasma spectrochemical techniques often require sample preparation procedures for analytes preconcentration as well as for removing matrix constituents, that may interfere on the analytical measurements. In the present work, calcium alginate (CA) beads were used for the first time aiming at Ce, La and Nd preconcentration from groundwater samples for further determination by inductively coupled plasma optical emission spectrometry (ICP OES). Test samples were analyzed in batch mode by transferring a 40mL test portion (pH=5+/-0.2) into a 50mL polyethylene flask containing 125mg CA beads. After 15min contact, the analytes were quantitatively extracted from the loaded CA beads with 2.0mL of 1.0molL-1 HCl solution for further determination by ICP OES, using Ce (II) 456.236, La (II) 379.478 and Nd (II) 430.358nm emission lines. The proposed approach is a reliable alternative for REE single-stage preconcentration from aqueous samples, as it provided accurate results based on the addition and recovery analysis of groundwater. The results obtained by the proposed method were also compared with those from reference method based on inductively coupled plasma mass spectrometry (ICP-MS) and no significant differences were observed after applying the Student's t-test at 95% confidence level. PMID- 27769471 TI - Au-Pt bimetallic nanoparticles supported on functionalized nitrogen-doped graphene for sensitive detection of nitrite. AB - In this work, we report a novel Au-Pt bimetallic nanoparticles (Au-PtNPs) decorated on the surface of nitrogen-doped graphene (NG) functionalized with 1, 3, 6, 8-pyrene tetra sulfonic acid sodium salt (PyTS) by direct electrodeposition method. The results of scanning electron microscopy (SEM), energy dispersive X ray spectroscopy (EDS) and electrochemical impendence spectrum (EIS) reveal that the Au-PtNPs were successfully anchored on the surface of NG sheets with a diameter of 20-40nm. Further, the prepared Au-PtNPs/PyTS-NG nanocomposite exhibits superior catalytic activity for the oxidation of nitrite. Under optimal experimental conditions, an amperometric sensor with a linear range of 0.5 1621MUM and a detection limit of 0.19MUM (S/N=3) for the detection of nitrite was set up and applied to real samples. PMID- 27769470 TI - A validated 1H NMR method for quantitative analysis of alpha-bisabolol in essential oils of Eremanthus erythropappus. AB - alpha-Bisabolol is a natural terpene produced by Eremanthus erythropappus and is widely used in cosmetics and pharmaceuticals due to its anti-inflammatory, antibacterial and antimycotic properties. Due to these applications, a control of composition and authenticity of commercial oils rich in this terpene is required, resulting in a demand for new methodologies for quality control. In this work a rapid and efficient method for quantification of alpha-bisabolol in the essential oil of E. erythropappus (candeia) using 1H NMR was developed, validated and compared to gas chromatography (GC) method. The quantification of alpha-bisabolol by 1H NMR was successfully achieved for most of the essential oil samples of E. erythropappus evaluated, except for those with a more complex composition. To circumvent this limitation a 2D NMR COSY contour map was used. This method proved to be a fast and efficient alternative, providing results with standard deviations SD<0.3%. All evaluated parameters (selectivity, linearity, accuracy/precision, repeatability, robustness and stability of analyte and internal standard in solution) gave satisfactory results. Using the 1H NMR signals at 5.36 and 5.13ppm, the limit of detection (LOD) and limit of quantification (LOQ) were 0.26 and 2.59mg, respectively. The results obtained by the 1H NMR method presented SD=0.59%, smaller than the value found for GC (SD=1.18%). Tukey tests have shown that the results obtained by 1H NMR and COSY methodology are similar to the obtained by the traditional GC-FID technique using external and internal standardization and normalization with 95% confidence. PMID- 27769472 TI - The synthesis of surface-glycosylated porous monolithic column via aqueous two phase graft copolymerization and its application in capillary-liquid chromatography. AB - A facile, flexible process was developed for the preparation of surface glycosylated porous monolithic columns via aqueous two-phase graft copolymerization of polyethylene glycol diacrylate (PEGDA) and water-soluble dextran (dextran sulfate). The formation of poly(PEGDA) porous skeletons and surface glycosylation were achieved via a one-step process without pre modification of the dextran. The synthesis conditions were thoroughly optimized. The optimal monolithic column exhibited a large dry state surface area (greater than 400m2/g), and it was evaluated as a hydrophilic liquid chromatography (HILIC) stationary phase. A typical HILIC mechanism was observed at high organic solvent content (>=65% acetonitrile). In addition, the resulting monolithic column demonstrated the potential use in analysis of complex biological sample and enviroment water. PMID- 27769473 TI - Dynamic single-interface hollow fiber liquid phase microextraction of Cr(VI) using ionic liquid containing supported liquid membrane. AB - The concept of dynamic single-interface hollow fiber membrane liquid-phase microextraction (HF-LPME), where the target analyte was extracted on-line and eluted inside the lumen of the HF membrane, was explored. An ionic liquid containing supported liquid membrane was used for the trace determination of Cr(VI) as a model compound. Since the extraction took place on-line inside the hollow fiber membrane, the mass transfer behavior was described and discussed in comparison with the conventional HF-LPME. The extraction efficiency was improved by a recirculation configuration of the sample solution at relatively high sampling flow rates as a result of the increased effective contact area. The positive pressure observed to be built up during extraction was overcome by a flow-balancing pressure design. The dynamic single-interface HF-LPME method with an enrichment factor of 41, a detection limit of 1.2ugL-1 and determination limit of 4.0ugL-1 was successfully applied to the reliable determination of Cr(VI) from environmental water samples. The quantification limit is below the maximum contaminant level in drinking water, set at 10ugL-1 of hexavalent chromium by the California Environmental Protection Agency. PMID- 27769474 TI - Determination of 8-Hydroxydeoxyguanosine: A potential biomarker of oxidative stress, using carbon-allotropic nanomaterials modified glassy carbon sensor. AB - A voltammetric sensor for the determination of 8-Hydroxydeoxyguanosine (8-OHdG); an important, sensitive and integral biomarker of oxidative stress and related pathological conditions like carcinogenesis, renal disorders, mental retardations, diabetes etc. has been fabricated. The synergistic behavior of two allotropic forms of carbon, which are electrochemically reduced graphene oxide (ErGO) and multiwalled carbon nanotubes (MWCNTs), has been exploited for the surface modification. The resulting modified surface has been characterized using Field Emission Scanning Electron Microscopy, X-ray diffraction, Electrochemical Impedance Spectroscopy and voltammetric behavior. The fabricated sensor exhibited excellent electrocatalytic effect towards oxidation of 8-OHdG and also showed substantial increment in sensitivity. The modified sensor showed a sensitivity of 0.1965uA/uM in the linear range of 3-75uM, whereas, a slope of 0.0046uA/uM was obtained for unmodified GCE. A limit of detection as low as 35nM has been obtained using the glassy carbon surface modified sensor. The proposed method was also successfully applied for the quantification of 8-OHdG in the presence of common interfering biomolecules like ascorbic acid, uric acid, xanthine, hypoxanthine etc. and also in human urine samples. PMID- 27769475 TI - Detection of physiological potassium ions level in human serum by Raman scattering spectroscopy. AB - Potassium ions play pivotal roles in biological systems. A simple and effective Raman scattering-based protocol for the detection of physiological potassium ions level in human serum has been developed. We employed sodium cobaltinitrite, which can react with potassium to form potassium-sodium cobaltinitrite. Combining hydrophobic surface and the Raman scattering for potassium detection, highly reproducible Raman spectra of the potassium-sodium cobaltinitrite can be obtained with highly sensitivity. The characteristic Raman peak of potassium-sodium cobaltinitrite was used to distinguish it from other kinds of matter, and its intensity was used to monitor the amounts of potassium ions in human serum. Because of the contribution of the hydrophobic surface aggregation to the Raman, this protocol has great potential for practical detection of the potassium in human serum and has extended the measuring potential use in the detection of potassium in human serum by spectrum method. PMID- 27769476 TI - Salting-out homogenous extraction followed by ionic liquid/ionic liquid liquid liquid micro-extraction for determination of sulfonamides in blood by high performance liquid chromatography. AB - Salting-out homogenous extraction followed by ionic liquid/ionic liquid dispersive liquid-liquid micro-extraction system was developed and applied to the extraction of sulfonamides in blood. High-performance liquid chromatography was applied to the determination of the analytes. The blood sample was centrifuged to obtain the serum. After the proteins in the serum were removed in the presence of acetonitrile, ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, dipotassium hydrogen phosphate, ionic liquid 1-Hexyl-3-methylimidazolium hexafluorophosphate were added into the resulting solution. After the resulting mixture was ultrasonically shaken and centrifuged, the precipitate was separated. The acetonitrile was added in the precipitate and the analytes were extracted into the acetonitrile phase. The parameters affecting the extraction efficiency, such as volume of ionic liquid, amount of dipotassium hydrogen phosphate, volume of dispersant, extraction time and temperature were investigated. The limits of detection of sulfamethizole (STZ), sulfachlorpyridazine (SCP), sulfamethoxazole (SMX) and Sulfisoxazole (SSZ) were 4.78, 3.99, 5.21 and 3.77MUgL-1, respectively. When the present method was applied to the analysis of real blood samples, the recoveries of analytes ranged from 90.0% to 113.0% and relative standard deviations were lower than 7.2%. PMID- 27769477 TI - Optical non-contact pH measurement in cell culture with sterilizable, modular parts. AB - A non-contact real time pH measurement using fully modular optical parts is described for phenol-red medium cell cultures. The modular parts can be sterilized, and once the measurement is started at the beginning of culture, no recalibration or maintenance is needed till the end of the culture. Measurements can be carried out without any special manual attention. The modular assembly of LED and sensor cassettes is unique, robust, reusable and reproducible. pH is measured in an intact closed flow system, without wasting any culture medium. A special pump encapsulation enables the system to be effortlessly functional in extremely humid incubator environments. This avoids lengthy sample tubings in and out of the incubator, associated large temperature changes and CO2 buffering issues. A new correction model to compensate errors caused e.g. by biolayers in spectrometric pH measurement is put-forward, which improves the accuracy of pH estimation significantly. The method provides resolution down to 0.1 pH unit in physiological pH range with mean absolute error 0.02. PMID- 27769478 TI - Simultaneous separation of polar and non-polar mixtures by capillary HPLC based on an ostadecylsilane and taurine derivatized silica continuously packed column. AB - A capillary column was prepared by continuously packing ostadecylsilane (ODS) and taurine derivatized silica (TDS) in one column without interface. This continuously packing chromatography (CPC) column is easy to operate, has good stability and shows simultaneously separation of both polar and non-polar compounds. The simultaneous separation of a series of complex samples with highly hydrophobic components (benzene, toluene, ethylbenzene, and PAHs) and highly hydrophilic components (biogenic amines, bases and nucleosides) using this CPC method was investigated. The relative parameters such as the volume fraction of acetonitrile and length of the ODS and the TDS phases were investigated and optimized. The experimental results show that this column combines the advantages of both ODS and TDS stationary phases, and exhibits a reversed phase liquid chromatography (RPLC) mode followed by a hydrophilic interaction liquid chromatography (HILIC) mode when 80% of acetonitrile was used in the mobile phase. The satisfactory results indicate that the CPC method provides an easy way to simultaneously separate polar and non-polar compounds. PMID- 27769479 TI - Fluorimetric evaluation of glutathione reductase activity and its inhibitors using carbon quantum dots. AB - A highly sensitive fluorimetric assay has been developed for the evaluation of glutathione reductase (GR) activity and the screening of its inhibitors by using carbon quantum dots (CQDs) as the signal reporter. The detection mechanism is based on the following facts: (1) the fluorescence of CQDs can be quenched by Hg(II) through the strong CQDs-Hg(II) coordination; (2) GR can catalyze the reduction of oxidized glutathione (GSSG) into reduced glutathione (GSH), so that the fluorescence recovery of CQDs would take place resulting from the strong GSH Hg(II) interaction; (3) GR can lose its catalytic reduction of GSSG in the presence of its inhibitors, which will inhibit the recovery of the quenched fluorescence of CQDs. The developed CQDs-based fluorimetric method can facilitate the sensitive evaluation of GR activity in the range of 0.10-2.0mUmL-1 with a detection limit of 0.050 mUmL-1. In addition, other kinds of enzymes like myoglobin, thrombin, alcohol dehyrogenase, amylase, pepsin, and trypsin could show no significant effects on the evaluation of GR activity. This work may expand the biological applications of CQDs as the fluorescent probes with low cost, easy preparation, and high photostability. PMID- 27769480 TI - Decoration of multi-walled carbon nanotubes with metal nanoparticles in supercritical carbon dioxide medium as a novel approach for the modification of screen-printed electrodes. AB - A supercritical carbon dioxide medium was used for the decoration of functionalized multi-walled carbon nanotubes (MWCNTs) with metallic nanoparticles. This procedure allowed the rapid and simple decoration of carbon nanotubes with the selected metallic nanoparticles. The prepared nanomaterials were used to modify screen-printed electrodes, improving their electrochemical properties and allowing to obtain a wide range of working electrodes based on carbon nanotubes. These electrodes were applied to the amperometric determination of vitamin B6 in food and pharmaceutical samples as an example of the analytical potentiality of the electrodes thus prepared. Using Ru-nanoparticles-MWCNTs as the working electrode, a linear dynamic range between 2.6*10-6 and 2*10-4molL-1 and a limit of detection of 0.8*10-6molL-1 were obtained. These parameters represented a minimum 3-fold increase in sensitivity compared to the use of bare MWCNTs or other carbon-based working electrodes. PMID- 27769481 TI - Towards the development of solid-state platform optical sensors: aggregation of gold nanoparticles on polyurethane foam. AB - In this paper, we report on a novel type of nanocomposites based on gold nanoparticles (AuNPs) and polyurethane foam (PUF), which represents an ability of AuNP aggregation on solid polymer matrix with the strongly different selectivity in comparison with aggregation of the same AuNPs in solution. This may indicate that a new type of aggregation takes place, which can be called solid-phase aggregation. A systematic study using diffuse reflectance spectroscopy revealed features of the solid-phase aggregation. The PUF-AuNPs nanocomposites can be synthesized by a simple and low cost procedure based on adsorption of different type AuNPs from aqueous solution onto PUF. Prospects of obtained composite materials for sensing some organic compounds using diffuse reflectance spectroscopy or colorimetry are shown. This nanocomposites have the increased selectivity to thiols allowing for their determination with limits of detection of 0.01-0.05MUgmL-1 and relative standard deviations of 3-5%. Charged species that affect AuNPs in solution do not influence them on PUF. PMID- 27769482 TI - Polypeptide with electroactive endgroups as sensing platform for the abused drug 'methamphetamine' by bioelectrochemical method. AB - Affinity-type sensors have emerged as outstanding platforms in the detection of diagnostic protein markers, nucleic acids and drugs. Thus, these novel platforms containing antibodies could be integrated into the monitoring systems for abused drugs. Herein, we established a novel detection platform for the analysis of a common illicit drug; methamphetamine (METH). Initially, a fluorescent-labeled polypeptide (EDOT-BTDA-Pala), derived from L-alanine N-carboxyanhydride (L-Ala NCA) via ring-opening polymerization using 4,7-bis(2,3-dihydrothieno[3,4 b][1,4]dioxin-5-yl)benzo[c][1,2,5]thiadiazole-5,6-diamine (EDOT-NH2-BTDA) as initiator, was employed as a glassy carbon electrode (GCE) covering host, in order to immobilize the METH-selective antibody. Prior to the examination of analytical features, GCE/EDOT-BTDA-Pala/Antibody surface was successfully characterized in the way of electrochemical (cyclic voltammetry and electrochemical impedance spectroscopy) and microscopic techniques (scanning electron microscopy and fluorescence microscopy). As for the analytical characterization, linearity and limit of detection (LOD) were found as 10 100ug/mL with an equation of y=0.0429x-0.2347, (R2=0.996) and 13.07ug/mL, respectively. Moreover, sample application using artificial urine, saliva and serum samples spiked with METH (10, 25, 50ug/mL) were performed and LC-MS/MS system was used for further confirmation. The described platform can be adapted to monitor the other types of abused drugs by using suitably selected biorecognition elements. PMID- 27769483 TI - Surface plasmon resonance sensor for antibiotics detection based on photo initiated polymerization molecularly imprinted array. AB - A surface plasmon resonance (SPR) sensor combined with nanoscale molecularly imprinted polymer (MIP) film as recognition element was developed for selective detection of the antibiotic ciprofloxacin (CIP). The MIP film on SPR sensor chip was prepared by in situ photo-initiated polymerization method which has the advantages of short polymerization time, controllable thickness and good uniformity. The surface wettability and thickness of MIP film on SPR sensor chip were characterized by static contact angle measurement and stylus profiler. The MIP-SPR sensor exhibited high selectivity, sensitivity and good stability for ciprofloxacin. The imprinting factors of the MIP-SPR sensor to ciprofloxacin and its structural analogue ofloxacin were 2.63 and 3.80, which is much higher than those to azithromycin, dopamine and penicillin. The SPR response had good linear relation with CIP concentration over the range 10-11-10-7molL-1. The MIP-SPR sensor also showed good repeatability and stability during cyclic detections. On the basis of the photo-initiated polymerization method, a surface plasmon resonance imaging (SPRi) chip modified with three types of MIP sensing spots was fabricated. The MIPs-SPRi sensor shows different response patterns to ciprofloxacin and azithromycin, revealing the ability to recognize different antibiotic molecules. PMID- 27769484 TI - Capillary electrochromatography coupled with dispersive liquid-liquid microextraction for the analysis of benzimidazole residues in water samples. AB - A novel method for the analysis of benzimidazole residues in water samples by capillary electrochromatography-UV detection (290nm), using laboratory-made packed columns is presented. Capillaries (25cm packed length*75um inner diameter, 34cm total length, 25.5cm effective capillary length) were packed with C18 particles (5um, non-encapped) following a high pressure packing procedure and using a compact steel unit designed for packing capillary columns. Acetone was employed as solvent to carry the particles through the capillary and pack it under a pressure of 42MPa. Outlet and inlet frits were made by sintering the particles of the stationary phase by heating the packed material with a nichrome ribbon connected to a 7V AC power supply. With the aim of achieving a good analytical performance, the variables that affected the separation were studied, using a mobile phase composition of 60:40 (v/v) acetonitrile/water containing ammonium acetate (1mM, pH 6.5), a separation voltage of 25kV and a temperature of 25 degrees C. In addition, a combined hydrodynamic-electrokinetic injection mode was considered and samples were injected for 75s under a voltage of 12.5kV and a pressure of 11.5bar. Finally, the determination of benzimidazoles in water samples was accomplished by capillary electrochromatography using dispersive liquid-liquid microextraction as sample treatment. Variables affecting the extraction efficiency were optimized, using chloroform and ethanol as extraction and disperser solvents, respectively. This method was applied to different water samples, obtaining satisfactory results in terms of linearity (R2>=0.990), repeatability (RSD<=1.2%), reproducibility (RSD<=2.2%) and trueness (R>=87.7%). Detection and quantification limits were lower than 2.8ugL-1 and 9.3ugL-1, respectively. PMID- 27769485 TI - FT-Raman and NIR spectroscopy data fusion strategy for multivariate qualitative analysis of food fraud. AB - Two data fusion strategies (high- and mid-level) combined with a multivariate classification approach (Soft Independent Modelling of Class Analogy, SIMCA) have been applied to take advantage of the synergistic effect of the information obtained from two spectroscopic techniques: FT-Raman and NIR. Mid-level data fusion consists of merging some of the previous selected variables from the spectra obtained from each spectroscopic technique and then applying the classification technique. High-level data fusion combines the SIMCA classification results obtained individually from each spectroscopic technique. Of the possible ways to make the necessary combinations, we decided to use fuzzy aggregation connective operators. As a case study, we considered the possible adulteration of hazelnut paste with almond. Using the two-class SIMCA approach, class 1 consisted of unadulterated hazelnut samples and class 2 of samples adulterated with almond. Models performance was also studied with samples adulterated with chickpea. The results show that data fusion is an effective strategy since the performance parameters are better than the individual ones: sensitivity and specificity values between 75% and 100% for the individual techniques and between 96-100% and 88-100% for the mid- and high-level data fusion strategies, respectively. PMID- 27769486 TI - A microchip for integrated single-cell genotoxicity assay. AB - With the development of large-scale biologic databases, precision medicine is becoming a frontier in biomedical research. As a main focus of precision medicine study, cancer has been widely accepted as a disease born out of inherited genetic variations or accumulating genomic damage. At the single-cell level, microfluidics or lab-on-a-chip technology for cancer study is an emerging tool for improving risk assessment, diagnostic categories and therapeutic strategies. This work presents a multi-layer microchip for single-cell gene expression profiling. Treated by three drug reagents (i.e. methyl methanesulfonate, docetaxel and colchicine) with varied concentrations and time lengths, individual human breast cancer cells (MCF-7) are then lysed on-chip, and the released mRNA templates are captured and reversely transcribed into cDNA on microbead surface. Three genes (GAPDH, CDKN1A, AURKA) are amplified and quantified simultaneously through triplex real-time polymerase chain reactions (qPCR). Readout per run is set to be eighteen, and can be further improved following same approach. The microchip is able to integrate all steps of single-cell gene expression profiling, and provide precision study of drug induced genotoxicity with reduced reagents consumption per reaction and instrumental cost. PMID- 27769487 TI - Slurry micro-sampling technique for use in argon-helium microwave induced plasma optical emission spectrometry. AB - The Flow Focusing Pneumatic Nebulizer (FFPN) working at low liquid flow rates was evaluated for the elemental analysis in slurried samples by argon-helium microwave induced plasma optical emission spectrometry (MIP-OES). The obtained results achieved were compared with commercially available V-groove Babington type nebulizer (VBPN). A univariate approach and the simplex optimization procedure were used to achieve optimized conditions and derive analytical figures of merit. Analytical performance of the micro nebulization system was characterized by a determination of the limits of detection (LODs), the precision (RSDs) and the wash-out times for Ba, Ca, Cd, Cu, Fe, Mg, Mn, Pb and Sr. The experimental concentration detection limits for simultaneous determination, calculated as the concentration giving a signal equal to three times of the standard deviation of the blank (LOD, 3sigmablank criterion, peak height) were 0.9, 0.2, 0.3, 0.2, 0.3, 0.1, 0.2, 0.4, 0.4 and 0.3ngmL-1 for Ba, Ca, Cd, Cu, Fe, Mg, Mn, Pb and Sr, respectively. The method offers relatively good precision (RSD ranged from 5% to 8%) for micro-slurry sampling analysis. Analyses of the certified reference materials (NRCC DOLT-2, GBW 07302 and SRM 2710) were performed in order to determine the accuracy available with the presented nebulization systems. The measured contents of elements in the reference materials were in satisfactory agreement with the certified values. In addition, these elements were determined in two real samples. Slurry concentration up to 3% m/v (particles <20MUm), prepared in 10% m/v HCl through the application of ultrasonic agitation, was used with calibration by the standard addition technique. An ultrasonic probe was used to homogenize the slurry in the polypropylene bottle just before its introduction into the nebulizer. The nebulizers exhibited no clogging problems. PMID- 27769488 TI - Colorimetric detection of Cr (VI) based on the leaching of gold nanoparticles using a paper-based sensor. AB - Herein, we have developed a simple, sensitive and paper-based colorimetric sensor for the selective detection of Chromium (VI) ions (Cr (VI)). Silanization titanium dioxide modified filter paper (STCP) was used to trap bovine serum albumin capped gold nanoparticles (BSA-Au NPs), leading to the fabrication of BSA Au NPs decorated membrane (BSA-Au NPs/STCP). The BSA-Au NPs/STCP operated on the principle that BSA-Au NPs anchored on the STCP were gradually etched by Cr (VI) as the leaching process of gold in the presence of hydrobromic acid (HBr) and hence induced a visible color change. Under optimum conditions, the paper-based colorimetric sensor showed clear color change after reaction with Cr (VI) as well as with favorable selectivity to a variety of possible interfering counterparts. The amount-dependent colorimetric response was linearly correlated with the Cr (VI) concentrations ranging from 0.5uM to 50.0uM with a detection limit down to 280nM. Moreover, the developed cost-effective colorimetric sensor has been successfully applied to real environmental samples which demonstrated the potential for field applications. PMID- 27769489 TI - Inductively coupled plasma mass spectrometry and standard dilution analysis applied to concentrated acids. AB - This work describes a procedure using the recently proposed standard dilution analysis (SDA) calibration method for the determination of As, Cr and Ni in concentrated HNO3 and HCl by inductively coupled plasma tandem mass spectrometry (ICP-MS/MS). Because of the low contaminant levels, and consequently low limits of detection required for these reagents (commonly used in trace element analysis and the semiconductor industry), samples were minimally diluted. The analysis of concentrated acids can result in matrix/transport effects, which may compromise accuracy in ICP-MS determinations. High-chlorine content samples are also challenging for As and Cr determination due to the formation of polyatomic species such as 40Ar35Cl+ and 35Cl16OH+, which overlap the only As isotope, 75As+, and the main Cr isotope, 52Cr+, respectively. The combination of SDA and ICP-MS/MS was evaluated to overcome matrix, transport and spectral interferences in order to increase accuracy, precision and sample throughput. The performance of SDA was compared with the traditional methods of external standard calibration (EC), internal standardization (IS), and standard additions (SA). The limits of detection for SDA were calculated as 6, 10, and 30ngL-1 for As, Cr, and Ni, respectively. Recoveries for spike experiments using the new method were in the 90-114% range for all analytes. The procedure described here provides similar or even better analytical performance in comparison with EC, IS and SA. PMID- 27769490 TI - Development of molecularly imprinted column-on line-two dimensional liquid chromatography for rapidly and selectively monitoring estradiol in cosmetics. AB - Nowadays, the illegal use of estradiol in cosmetics has caused a series of events which endangering public health seriously. Therefore, it is imperative to establish a simple, fast and specific method for monitoring the illegal use of estradiol in cosmetics. In current study, we developed a molecular imprinted monolithic column two dimensional liquid chromatography method (MIMC-2D-LC) for rapid and selective determination of estradiol in various cosmetic samples. The best polymerization, morphology, structure property, surface groups, and the adsorption performance of the prepared material were investigated. The MIMC-2D-LC was validated and successfully used for detecting estradiol in cosmetic samples with good selectivity, sensitivity, efficiency and reproducibility. The linear range of the MIMC-2D-LC for estradiol was 0.5-50MUgg-1 with the limit of detection of 0.08MUgg-1. Finally, six batches of cosmetic samples obtained from local markets were tested by the proposed method. The test results showed that the illegal use of estradiol still existed in the commercially available samples. PMID- 27769491 TI - Highly sensitive determination of esculetin on TiO2-NPs-coated poly(diallyldimethylammonium chloride)-functionalized graphene modified electrode. AB - The nanocomposites of titanium dioxide nanoparticles decorated poly(diallyldimethylammonium chloride)-functionalized graphene (TiO2-PDDA-Gr) were successfully synthesized via a facile and green strategy. The prepared nanocomposites were characterized by X-ray diffraction (XRD), UV-visible spectrophotometry (UV-vis), Fourier Transform infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). By combining the merits of the PDDA-Gr and TiO2 NPs, a highly sensitive electrochemical sensor was erected to detect esculetin based on the TiO2-PDDA-Gr nanocomposites. Under the optimized conditions, a lower detection limit of 4*10-9molL-1 (S/N=3) and a wide linear detection range from 1*10-8 to 3.5*10-6molL-1 were achieved by differential pulse voltammetry (DPV). Additionally, the proposed electroanalytical methodology was applied in Chinese herb Viola yedoensis Makino and Cortex Fraxini with satisfactory results, showing that fabricated sensor has potential to be applied. PMID- 27769492 TI - A fast-responsive fluorescent probe based on BODIPY dye for sensitive detection of hypochlorite and its application in real water samples. AB - Hypochlorite serves as a powerful antimicrobial agent in human immune system, the detection of which is of great significance. Herein a novel fluorescent probe based on BODIPY dye and diaminomaleonitrile has been synthesized and characterized to sense hypochlorite. The fluorescence of the system is dramatically enhanced by ClO- due to the removal of C=N isomerization effect in physiological pH condition. The complete reaction only needs a few seconds, which enables the probe to facilitate real-time detection. This probe also has satisfactory selectivity for ClO- even in the presence of other interferential ions and shows high sensitivity with a detection limit of 19.8nM. Furthermore, Probe 1 has been successfully applied to detect ClO- in real water samples. PMID- 27769493 TI - A capillary electrophoretic method for separation and characterization of carbon dots and carbon dot-antibody bioconjugates. AB - Capillary electrophoresis (CE) coupled with UV absorbance detection has been applied as an analysis tool for carbon dots (C-dots), which were hydrothermally synthesized from precursors citric acid (CA) and ethylene diamine (EDA). An alkaline working buffer (100mM tris acetate, pH 8.4) was found to be optimal for rapid and reliable analysis of C-dots. A calibration curve was established over a broad concentration range (0.5-10mg/mL) with excellent linearity (R2=0.9989). The CE method was also applied to enhance understanding of and facilitate optimization of ensuing C-dot biolabeling reactions. The novel CE method was used to confirm and quantify production of C-dot labeled antibodies. The optimum concentration of antibody for use in the labeling reaction was determined. PMID- 27769494 TI - Synthesis and evaluation of sulfobetaine zwitterionic polymer bonded stationary phase. AB - Zwitterionic polymer stationary phases have attracted increasing attention in hydrophilic interaction chromatography (HILIC). In this work, a zwitterionic sulfobetaine functionalized polyacrylamide stationary phase (named TENS) based on porous silica particles was prepared via controlled surface initiated reversible addition-fragmentation transfer (RAFT) polymerization. Instead of traditional methacrylate type sulfobetaine monomer, acrylamide type sulfobetaine monomer, which has higher chemical stability and hydrophicility, was employed in this work. The characterization of elemental analysis and solid-state 13C cross polarization/magic-angle-spinning nuclear magnetic resonance indicated the successful preparation of TENS stationary phase. Meanwhile, scanning electron microscope (SEM), nitrogen adsorption experiment and study of size exclusion performance were conducted, revealing that the surface initiated polymerization was well controlled. For better understanding of TENS material under HILIC mode, chromatographic evaluation of TENS material was performed, among which, TENS material exhibited good hydrophilicity and chemical stability. To further study the applicability of TENS material, saccharides which were considered as challenging targets in HILIC, were chosen as tested analytes. Various saccharide samples, including fructooligosaccharide, trisaccharide isomers and ginsenosides, were well separated on TENS material. Moreover, TENS material displayed good selectivity for the enrichment of glycopeptides. These results demonstrated the capability of TENS as a promising material in glycomics and glycoproteomics. PMID- 27769495 TI - An electrochemical aptasensor for multiplex antibiotics detection based on metal ions doped nanoscale MOFs as signal tracers and RecJf exonuclease-assisted targets recycling amplification. AB - An ultrasensitive electrochemical aptasensor for simultaneous detection of oxytetracycline (OTC) and kanamycin (KAN) has been developed based on metal ions doped metal organic frame materials (MOFs) as signal tracers and RecJf exonuclease-catalyzed targets recycling amplification. The aptasensor consists of capture beads (the anti-single-stranded DNA Antibody, as anti-ssDNA Ab, labeled on Dynabeads) and nanoscale MOF (NMOF) based signal tracers (simplified as Apts MNM, the NMOF labeled with metal ions and the aptamers). Particularly, the MOF (UiO-66-NH2), with large internal surface areas, ultrahigh porosity and abundant amine groups in the pores, was employed as substrates to carry plenty of metal ions (Pb2+ or Cd2+) and label aptamers of OTC or KAN. Thus, the aptasensor is formed by the specific recognition between anti-ssDNA Ab and aptamers. In the presence of targets (OTC and KAN), aptamers prefer to form targets-Apts-MNM complexes in lieu of anti-ssDNA Ab-aptamer complexes, which results in the dissociation of Apts-MNM from capture beads. With the employment of RecJf exonuclease, targets-Apts-MNM in supernatant was digested into mononucleotides and liberated the target, which can further participate in the next reaction cycling to produce more signal tracers. After magnetic separation, the enhanced square wave voltammetry (SWV) signals were produced from signal tracers. The aptasensor exhibited a linear correlation in the range from 0.5pM to 50nM, with detection limits of 0.18pM and 0.15pM (S/N=3) toward OTC and KAN respectively. This strategy provides specificity and sensitive approach for multiplex antibiotics detection and has promising applications in food analysis. PMID- 27769496 TI - NaEuF4/Au@Ag2S nanoparticles-based fluorescence resonant transfer DNA sensor for ultrasensitive detection of DNA energy. AB - The work investigates a new fluorescence resonance energy transfer (FRET) system using NaEuF4 nanoparticles (NPs) and Au@Ag2S NPs as the energy donor-acceptor pair for the first time. The NaEuF4/Au@Ag2S NPs-based FRET DNA sensor was constructed with NaEuF4 NPs as the fluorescence (FL) donor and Au@Ag2S core-shell NPs as FL acceptor. In order to find the matching energy acceptor, the amount of AgNO3 and Na2S were controlled in the synthesis process to overlap the absorption spectrum of energy acceptor with the emission spectrum of energy donors. The sensitivity of FRET-based DNA sensor can be enhanced and the self-absorption of ligand as well as the background of signals can be decreased because of Eu3+ which owns large Stokes shifts and narrow emission bands due to f-f electronic transitions of 4f shell. We obtained the efficient FRET system by studying suitable distance between the donor and acceptor. Then the FRET-based DNA sensor was used for the design of specific and sensitive detection of target DNA and the quenching efficiency (DeltaFL/F0, DeltaFL=F-F0) of FL was logarithmically related to the concentration of the target DNA, ranging from 100aM to 100pM. We can realize an ultrasensitive detection of target DNA with a detection limit of 32 aM. This proposed method was feasible to analyse target DNA in real samples with satisfactory results. PMID- 27769497 TI - Highly selective and sensitive detection of 2,4,6-trinitrophenol by using newly developed blue-green photoluminescent carbon nanodots. AB - Though many methods of detecting 2,4,6-trinitrophenol (TNP) mainly have been developed recent years, quantification of TNP in environmental matrixes still faces up to great challenges because all the nitroaromatic explosives reveal highly similar chemical structure. In the present work, we have developed a selective and sensitive method for detection of TNP by amorphous photoluminescent carbon nanodots (CNDs), which are prepared through a simple hydrothermal route using spermine and m-phenylenediamine (MPD) as precursors. The as-prepared CNDs are found to show blue-green photoluminescence, excitation-wavelength independence, and excellent chemical and optical stability. Owing to the strong characteristic absorption of TNP at 356nm (epsilon=1.048*104cm-1M-1), which has a good spectral overlap with the excitation band of CNDs, the fluorescence intensity of CNDs at 490nm is linearly quenched with the adding concentration of TNP in the range of 0.1-100MUM. The developing assay based on inner filter effect (IFE) mechanism for the detection of TNP is selective and convenient, showing that the as-prepared CNDs have applicable prospect in the concept of simplicity and specificity in analytical chemistry. PMID- 27769498 TI - A novel electroanalytical approach based on the use of a room temperature ionic liquid for the determination of olive oil acidity. AB - In this paper, a novel voltammetric/amperometric approach for the direct determination of free acidity (FFA, expressed as mass percentage of free oleic acid) in olive oil samples is presented. The method is based on the reduction processes occurring at a platinum microdisk electrode involving the free fatty acids present in the matrices. To overcome problems related to the low conductivity of the samples investigated, olive oils were mixed with suitable amounts of the room temperature ionic liquid (RTIL), tri hexyl(tetradecyl)phosphonium bis (trifluoromethylsulfonyl) imide ([P14,6,6,6]+[NTf2]-), which acted as a supporting electrolyte. Conditions for a reliable quantification of the acids were preliminarily investigated by performing voltammetric and chronoamperometric measurements in RTIL solutions containing oleic acid at different concentrations. Oleic acid (OA) was chosen as a model compound as it is the main component of the FFA content in olive oils. In order to establish the effect of oxygen on the electroanalytical responses, the reduction process of OA was investigated under both deoxygenated and oxygenated conditions. It was found that, in both situations, the current arising from the electrode process of OA depended linearly on the OA concentration over a wide range varying from 0.1% to 8% OA (w/w). This range includes FFA values which can be found on all categories of commercially available oil samples, including extra virgin, virgin and lampante oils. Voltammetric and chronoamperometric experiments were also performed in oil/RTIL samples artificially acidified (extra-virgin olive oils with known addition of oleic acid) and in natural olive oils from some commercial categories. The results obtained indicated that the electrochemical procedure developed was satisfactory in terms of both sensitivity and detection limits. The reliability of the proposed approach for the detection of FFA was finally assessed by comparison of the voltammetric/chronoamperometric values with those obtained by the official method for quantification of olive oil acidity, which is an acid/base volumetric titration. PMID- 27769499 TI - Novel mitochondria-targeted, nitrogen mustard-based DNA alkylation agents with near infrared fluorescence emission. AB - In this report, the design of two novel nitrogen mustard-based DNA cross-linking agents with fluorophores incorporated into the structure (TN-A and TN-B) is disclosed. The results indicate that TN-A and TN-B can serve directly as both reporting and imaging agents for flow cytometry and gel electrophoresis without the necessity of another fluorescent tagging agents. TN-A and TN-B both selectively locate in the mitochondria and exhibit good antitumor activity. Notably, TN-A is the first DNA crosslinking agent with near infrared fluorescence emission properties. PMID- 27769500 TI - Recent trends in electrochemical sensors for multianalyte detection - A review. AB - Voltammetric methods for screening compounds of varied interests are reviewed on the basis of the types of electrodes and analytical strategies. The scope of conventional voltammetric method has been considerably expanded in the last years due to the development of a plethora of modified electrodes, in particular, those involving nanocomposites. Voltammetric methods have distinct advantages over other existing methods regarding sensitivity, minimum detectability, applicability to biological samples without any pretreatment and time saving. Simultaneous determination of compounds by voltammetry offers the advantages of being economical and less time consuming as more than one analyte can be detected easily on the fabricated sensor at the same time. Present review article focuses on the simultaneous voltammetric detection of various compounds reported during the last five years. PMID- 27769501 TI - Simultaneous Determination of Methionine and Homocysteine by on-column derivatization with o-phtaldialdehyde. AB - A fast and simple HPLC-based assay has been developed for the simultaneous determination of homocysteine (Hcy) and methionine (Met) in plasma and urine samples, utilizing as small volume of sample as 10MUL. The assay uses on-column derivatization with o-phthaldialdehyde. The separation of Hcy and Met was achieved in 14min on a reversed phase C-18 column, followed by fluorescence detection (excitation at 348nm and emission at 438nm for Met; excitation at 370nm and emission at 480nm for Hcy). Linearity of the detector response was observed in the range of 2-60 MUmol L-1 for Met and 2-40 MUmol L-1 for Hcy. The method was successfully applied for Met and Hcy quantification in human and mouse plasma and urine samples from cystathionine beta-synthase deficient and unaffected individuals. PMID- 27769502 TI - Dendrimer-assisted hydrophilic magnetic nanoparticles as sensitive substrates for rapid recognition and enhanced isolation of target tumor cells. AB - Capture and detection of targeted tumor cells provide a significant meaning in the early diagnosis and therapy of cancer. Nowadays, the development of advanced nanomaterials for cell capture is outstanding, however there still remain great challenges and extensible space. Herein we report a novel and cushy method to synthesize the epidermal growth factor receptor antibody (anti-EGFR) functionalized dendrimer-assisted hydrophilic magnetic nanoparticles as sensitive substrates, which possess excellent capability of rapid targeting and highly efficient capturing of tumor cells. The introduction of dendrimers immensely improves the hydrophilicity and modification sites of substrates, which not only accelerates the procedure of cell capture, but also improves the amount of antibodies conjugated with the magnetic nanoparticles (MNPs). Thus, the newly synthesized substrates not only cut down the recognition time but also realize highly selective capture of target tumor cells. Moreover, the characteristics of MNPs lead to the rapid contact between substrates and cells and quick separation from the reaction solution. As a result, the functional MNPs can capture 86%+/-5% of tumor cells and isolate rare number of tumor cells from spiked whole blood samples in only 15min without the damage of cell viability. These results suggest that our method is reliable and has great potential in the application of cell isolation. PMID- 27769504 TI - Krawtchouk image moment method for the simultaneous determination of three drugs in human plasma based on fluorescence three-dimensional spectra. AB - The interference signals and overlapped peaks are common phenomena in fluorescence determination, which seriously influence the accuracy and reliability of analytical results. In this paper, Krawtchouk image moment method was introduced to the analysis of fluorescence three-dimensional (3D) spectra and applied to the quantitative analysis of three drugs including nicotinic acid, metoprolol and amlodipine in human plasma. Without any pretreatment to the obtained spectra, Krawtchouk moments were directly calculated on the grayscale images of 3D spectra, and the quantitative linear models for the three drugs were established by stepwise regression, respectively. The determination coefficients (R) were more than 0.9906. The correlation coefficients of leave-one-out cross validation (Rcv) were more than 0.9256. The precisions (RSD, %) of inter-day and intra-day variations were less than 8.4% and 3.1%, separately. The recovery was from 101.84% to 107.88%. The limit of quantification and the limit of detection were 0.12MUgmL-1 and 0.43MUgmL-1, respectively. All the statistical parameters supported that the obtained models performed well and the proposed method was accurate and reliable. Our study indicates that Krawtchouk image moments with the powerful abilities of multi-resolution and extracting local information can be applied to the simultaneous determination of multi-target compounds in plasma based on fluorescence 3D spectra. PMID- 27769503 TI - A highly selective and sensitive nanosensor for the detection of glyphosate. AB - A turn-off fluorescence sensor synthesized by combining copper (II) oxide and multiwall carbon nanotubes (MWCNTs) were used for measuring glyphosate based on the inhibiting the catalytic activity of the CuO/MWCNTs. This sensor was synthesized by precipitating copper ions onto the acidic MWCNTs under basic conditions; the resulting material was characterized by the transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy to confirm its structure. The CuO/MWCNTs nanomaterial was found to exhibit high peroxidase-like catalytic activity toward the reduction of H2O2 to H2O and the oxidation of Amplex Red to resorufin, with a corresponding color change from pink to red and the fluorescence enhancement. However, this activity was inhibited and the fluorescence diminished when glyphosate was added to the system. Using this strategy, we applied this sensor to detect glyphosate. The results indicated that this sensor is not only highly sensitive, with a detection limit of 0.67 ppb and a linear range from 0.002 to 0.01ppm, but also exhibits good selectivity for glyphosate. When this sensor was assessed for detecting glyphosate in real water samples, recoveries of 96-107% were attained. This proposed material and method are a promising approach for rapid screening of glyphosate. PMID- 27769505 TI - Context- and Tissue-Specific Regulation of Immunity and Tolerance by Regulatory T Cells. AB - The immune system has evolved to defend the organism against an almost infinite number of pathogens in a locally confined and antigen-specific manner while at the same time preserving tolerance to harmless antigens and self. Regulatory T (Treg) cells essentially contribute to an immunoregulatory network preventing excessive immune responses and immunopathology. There is emerging evidence that Treg cells not only operate in secondary lymphoid tissue but also regulate immune responses directly at the site of inflammation. Hence, the classification of Treg cells might need to be further extended by Treg cell subsets that are functionally and phenotypically polarized by their residency. In this review, we discuss recent findings on these tissue-resident Treg cell subsets and how these cells may operate in a tissue- and context-dependent manner. PMID- 27769506 TI - Pleiotropic Roles of Type 1 Interferons in Antiviral Immune Responses. AB - Since Isaac's and Lindenmann's seminal experiments over 50 years ago demonstrating a soluble factor generated from heat killed virus-stimulated chicken embryos could inhibit live influenza virus replication, the term interferon has been synonymous with inhibition of virus replication. While the antiviral properties of type 1 interferon (IFN-I) are undeniable, recent studies have reported expanding and somewhat unexpected roles of IFN-I signaling during both acute and persistent viral infections. IFN-I signaling can promote morbidity and mortality through induction of aberrant inflammatory responses and recruitment of inflammatory innate immune cell populations during acute respiratory viral infections. During persistent viral infection, IFN-I signaling promotes containment of early viral replication/dissemination, however, also initiates and maintains immune suppression, lymphoid tissue disorganization, and CD4 T cell dysfunction through modulation of multiple immune cell populations. Finally, new data are emerging illuminating how specific IFN-I species regulate immune pathology and suppression during acute and persistent viral infections, respectively. Systematic characterization of the cellular populations that produce IFN-I, how the timing of IFN-I induction and intricacies of subtype specific IFN-I signaling promote pathology or immune suppression during acute and persistent viral infections should inform the development of treatments and modalities to control viral associated pathologies. PMID- 27769508 TI - B-Lymphopoiesis in Fetal Liver, Guided by Chemokines. AB - Early in embryonic development of mice, from day 12.5 after conception, myeloid lymphoid bipotent progenitors, expressing receptors both for IL7 and CSF-1, migrate from embryonic blood into developing fetal liver. These progenitors also express multiple chemokine receptors, i.e., CCR7, CXCR3, CXCR4, and CXCR5, all on one cell. Their migration through LYVE-1+ vascular endothelium is guided by CCR7, recognizing the chemokine CCL19, and by CXCR3, recognizing CXCL10/11, chemokines which are both produced by the endothelium. Once inside fetal liver, the progenitors are attracted by the chemokine CXCL12 to ALCAM+ liver mesenchyme, which produces not only this chemokine, but also the myeloid differentiation inducing cytokine CSF-1 and the lymphoid differentiation-inducing cytokine IL7. In this mesenchymal environment B-lymphocyte lineage progenitors are then induced by IL7 to enter differentiation and Ig gene rearrangements. Within 3-4 days surface IgM+ immature B-cells develop, which are destined to enter the B1-cell compartments in the peripheral lymphoid organs. PMID- 27769507 TI - Endogenous Retroelements and the Host Innate Immune Sensors. AB - The ability to distinguish between self and nonself is the fundamental basis of the immune system in all organisms. The conceptual distinction between self and nonself, however, breaks down when it comes to endogenous retroviruses and other retroelements. While some retroelements retain the virus-like features including the capacity to replicate and reinvade the host genome, most have become inactive through mutations or host epigenetic silencing. And yet, accumulating evidence suggests that endogenous retroelements, both active and inactive, play important roles not only in pathogenesis of immune disorders, but also in proper functioning of the immune system. This review discusses the recent development in our understanding of the interaction between retroelements and the host innate immune system. In particular, it focuses on the impact of retroelement transcripts on the viral RNA sensors such as Toll-like receptors, RIG-I-like receptors, protein kinase R, and the inflammasomes. PMID- 27769509 TI - The Roles of the Secreted Phospholipase A2 Gene Family in Immunology. AB - Within the phospholipase A2 (PLA2) family that hydrolyzes phospholipids to yield fatty acids and lysophospholipids, secreted PLA2 (sPLA2) enzymes comprise the largest group containing 11 isoforms in mammals. Individual sPLA2s exhibit unique tissue or cellular distributions and enzymatic properties, suggesting their distinct biological roles. Although PLA2 enzymes, particularly cytosolic PLA2 (cPLA2alpha), have long been implicated in inflammation by driving arachidonic acid metabolism, the precise biological roles of sPLA2s have remained a mystery over the last few decades. Recent studies employing mice gene-manipulated for individual sPLA2s, in combination with mass spectrometric lipidomics to identify their target substrates and products in vivo, have revealed their roles in diverse biological events, including immunity and associated disorders, through lipid mediator-dependent or -independent processes in given microenvironments. In this review, we summarize our current knowledge of the roles of sPLA2s in various immune responses and associated diseases. PMID- 27769510 TI - Omentin-1, epicardial fat and coronary artery disease. PMID- 27769512 TI - Prognostic Significance of Right Ventricular Dysfunction in Patients With Functional Mitral Regurgitation Undergoing MitraClip. AB - Functional mitral regurgitation (MR) is common in patients with heart failure and left ventricular (LV) dysfunction. MitraClip (MC) is a novel therapeutic option for patients with high-risk MR. Similar to LV dysfunction, right ventricular dysfunction (RVD) is an important predictor of patients with heart failure. We aimed to clarify the effect of RVD on outcomes of functional MR and LV dysfunction after MC implantation. We examined 117 patients with severe functional MR and reduced LV ejection fraction (<=40%) treated with MC. RVD was defined as tricuspid annular plane systolic excursion <15 mm and was observed in 41 patients (35%). Mean age and gender were similar between patients with and without RVD. Atrial fibrillation was more common in patients with RVD. MR grades at baseline and discharge and LV ejection fraction were not different between the groups. Six months after MC implantation, responders to the N-terminal pro-B-type natriuretic peptide were less common in patients with RVD than those without (29% vs 65%, p = 0.005). Kaplan-Meier curves showed that survival rates of patients with RVD were significantly lower than those without (36.2% vs 69.6%, p = 0.008). After adjusting for covariates, RVD was still associated with all-cause mortality (hazard ratio 1.975, p = 0.042). The present study's results suggest that RVD is associated with worse survival of functional MR and LV dysfunction in patients undergoing MC in association with no response to N-terminal pro-B-type natriuretic peptide. The indication for MC should be carefully considered in functional MR patients with RVD. PMID- 27769511 TI - Antiplatelet Effect Durability of a Novel, 24-Hour, Extended-Release Prescription Formulation of Acetylsalicylic Acid in Patients With Type 2 Diabetes Mellitus. AB - High platelet reactivity and high platelet turnover have been implicated in incomplete platelet inhibition during immediate-release acetylsalicylic acid therapy in patients with type 2 diabetes mellitus (DM). An extended-release acetylsalicylic acid (ER-ASA; Durlaza) formulation was developed to provide 24 hour antithrombotic effects with once-daily dosing. The objective of the study was to evaluate the antiplatelet effects of ER-ASA in patients with DM. In this open-label, single-center study, patients with DM (n = 40) and multiple cardiovascular risk factors received ER-ASA 162.5 mg/day for 14 +/- 4 days. Multiple platelet function tests, serum and urinary thromboxane B2 metabolites, prostacyclin metabolite, and high-sensitive C-reactive protein levels were assessed at 1, 12, 16, and 24 hours post-dose. Patients with high platelet turnover and/or high platelet reactivity were treated with ER-ASA 325 mg/day for 14 +/- 4 days, and laboratory analyses were repeated. All patients responded to ER-ASA 162.5 mg/day as measured by arachidonic acid-induced aggregation, and there was no loss of the platelet inhibitory effect of ER-ASA 162.5 mg/day over 24 hours post-dose (p = not significant). The antiplatelet effect was sustained over 24 hours for all platelet function measurements. Mean 1- to 24-hour serum thromboxane B2 levels were low with both doses and were lower with ER-ASA 325 mg/day compared with 162.5 mg/day therapy (p = 0.002). In conclusion, ER-ASA 162.5 mg daily dose provided sustained antiplatelet effects over 24 hours in patients with type 2 DM and multiple cardiovascular risk factors and had a favorable tolerability profile. PMID- 27769513 TI - [Surgical management of ovarian cancer: Trends in clinical practice]. AB - Surgery has evolved as a mainstay of the management of ovarian cancer since evidence of the major benefit of complete surgery, i.e. achieving complete resection of the disease without visible macroscopic residue in a comprehensively explored abdominal cavity, has been made available. This objective may be difficult to complete in case of advanced ovarian cancer, as it requires the use of advanced techniques of peritoneal and visceral surgery, in the setting of adapted perioperative care, generally in institutions where the caseload is sufficient to ensure an appropriate surgical experience, and where specifically trained surgeons are available. In this paper using the data from the French national database PMSI, evidence of an evolution of the proportion of patients managed in centers where more than 20 patients a year are operated is shown. However, the recommendations of the governmental Plans Cancers are far from universally implemented. PMID- 27769514 TI - Characterizing fluoroscopy based kinematic accuracy as a function of pulse width and velocity. AB - Fluoroscopic imaging has become increasingly popular to investigate total knee arthroplasty kinematics non-invasively - 3D implant models are aligned with 2D image projections, and optimized via an edge-contour alignment technique. Previous studies have quantified the accuracy of this approach, however they do not always adequately address the impact of image collection parameters. A particularly sensitive parameter is the pulse width, or exposure time per frame. At longer pulse widths, more motion is captured in a single frame; this can lead to image blur and subsequent degradation to image edge quality. Therefore, the comparative accuracy of relative joint kinematics as a function of pulse width and joint velocity needs to be defined. A limits of agreement approach was taken to define the mean differences between optoelectric kinematic measures (gold standard) and fluoroscopic methods at various pulse widths (1, 8 and 16ms) and knee velocities (50, 100 and 225 degrees /s). The mean absolute differences between the optoelectric and fluoroscopic methods for 1ms pulse width were less than 1.5 degrees and 0.9mm. Comparable rotational differences (1.3 degrees ) were observed for the 8ms pulse width but had larger translational differences (1.4mm). The 16ms pulse width yielded the greatest mean differences (2.0 degrees and 1.6mm), which increased with knee flexion velocity. The importance of pulse width and velocity should not be overlooked for future studies - this parameter has proven to be a sensitive metric in the quantification of joint motion via fluoroscopy and must be identified and reported in future studies. PMID- 27769515 TI - [Clinical pharmacy: Evaluation of physician's satisfactions and expectations in a French regional hospital]. AB - INTRODUCTION: The purpose of the study was to evaluate physician's satisfaction with the clinical pharmacy activities in a French regional hospital. METHODS: Data were collected by face-to-face interviews carried out by a public health intern with physicians from 14 different departments of medicine and surgery. A specifically designed questionnaire was used for this study. This contained 18 closed-ended questions, 3 open-ended questions and 6 questions relating to the multidisciplinary analysis of prescriptions of elderly patients. RESULTS: The questionnaire was proposed to 78 physicians, of which 62 replied (participation rate of 79%). Thirty-seven percent were interns (23/62), 19% were assistants (12/62) and 44% were senior physicians (27/62). Clinical pharmacy satisfaction levels were generally very high. In regard to clinical skills, 87% of the physicians were satisfied with pharmacists' competencies and 91% by the pertinence of transmitted information. Ninety-five percent of the physicians were also satisfied by the logistical aspect and the relationship with pharmacists (reactivity, availability and communication). Analysis of the open-ended questions showed that physicians were in favour of the increased presence of clinical pharmacists on the wards. CONCLUSIONS: This study shows a high level of physician satisfaction in relation to the clinical pharmacy activities in our hospital, and should be viewed as a strong endorsement of the work of the clinical pharmacy. This study highlights some areas of improvement such as increase presence of the clinical pharmacists on the wards. In order to assess periodically our activity, this study must be repeated in the future. PMID- 27769516 TI - Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on colorectal cancer. PMID- 27769517 TI - Recommendations on Fecal Immunochemical Testing to Screen for Colorectal Neoplasia: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AB - The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed. PMID- 27769518 TI - Comparison of fracture strength and failure mode of different ceramic implant abutments. AB - STATEMENT OF PROBLEM: The whitish color of zirconia (ZrO2) abutments offers favorable esthetics compared with the grayish color of titanium (Ti) abutments. Nonetheless, ZrO2 has greater opacity, making it difficult to achieve natural tooth color. Therefore, lithium disilicate (LaT) abutments have been suggested to replace metal abutments. PURPOSE: The purpose of this in vitro study was to evaluate the fracture strength and failure mode of single-tooth implant restorations using ZrO2 and LaT abutments, and to compare them with titanium (Ti) abutments. MATERIAL AND METHODS: Five different types of abutments, Ti; ZrO2 with no metal base; ZrO2 with a metal base (ZrT); LaT; and LaT combination abutment and crown (LcT) were assembled on 40 Ti implants and restored with LaT crowns. Specimens were subjected to quasistatic loading using a universal testing machine, until the implant-abutment connection failed. As bending of the metal would be considered a clinical failure, the values of force (N) at which the plastic deformation of the metal occurred were calculated, and the rate of deformation was analyzed. Statistical analysis was done using the Mann-Whitney U test (alpha=.05). RESULTS: Group ZrO2 revealed the lowest resistance to failure with a mean of 202 +/-33 N. Groups ZrT, LaT, and LaC withstood higher forces without fracture or debonding of the ceramic suprastructure, and failure was due to deformation of metal bases, with no statistically significant differences between these groups regarding the bending behavior. CONCLUSIONS: Within the limitations of this in vitro study, it was concluded that LaT abutments have the potential to withstand the physiological occlusal forces that occur in the anterior region and that ZrO2 abutments combined with Ti inserts have much higher fracture strength than pure ZrO2 abutments. PMID- 27769519 TI - Mechanical Properties and Tableting Behavior of Amorphous Solid Dispersions. AB - Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (Tg) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and Tg of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs. PMID- 27769522 TI - RETRACTED: Efficacy and Safety of Induction Dosing of Vedolizumab for Reducing Biliary Inflammation in Primary Sclerosing Cholangitis (Psc) in Individuals with Inflammatory Bowel Disease. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The abstract authors and presenters of PS124 - EFFICACY AND SAFETY OF INDUCTION DOSING OF VEDOLIZUMAB FOR REDUCING BILIARY INFLAMMATION IN PRIMARY SCLEROSING CHOLANGITIS (PSC) IN INDIVIDUALS WITH INFLAMMATORY BOWEL DISEASE submitted and presented at ILC 2016 have raised concerns that the source data in some cases are inconsistent and requires further evaluation to determine the true magnitude of effect. Hence given the potential impact of this study in PSC at the authors request this abstract, until such time the data can be more completely presented in manuscript form, is being retracted. PMID- 27769520 TI - Combined Local Pulmonary and Systemic Delivery of AT2R Gene by Modified TAT Peptide Nanoparticles Attenuates Both Murine and Human Lung Carcinoma Xenografts in Mice. AB - To evaluate the potential of cell-penetrating peptide-based delivery of apoptosis inducer gene in cancer therapy, a modified HIV-1 TAT peptide (dimerized TAT peptide, dTAT) was studied. The dTAT and plasmid DNA (pDNA) complexes (dTAT-pDNA) were condensed using calcium chloride (dTAT-pDNA-Ca2+). This simple nonviral formulation approach showed high levels of gene expression in vitro without any cytotoxicity. In mouse studies, a single intratracheal (IT) aerosol spray or 2 intravenous (IV) injections of the dTAT, apoptosis-inducer gene, angiotensin II type 2 receptor (AT2R), and Ca2+ complexes (dTAT-pAT2R-Ca2+) significantly attenuated the acutely growing mouse Lewis lung carcinoma allografts in mouse lungs. Furthermore, single IT (p = 0.054) and the combination of IT and IV (p < 0.05) administrations of dTAT-pAT2R-Ca2+ markedly attenuated slowly growing and relatively large-sized H358 human bronchioloalveolar carcinoma xenografts in mouse lungs. These results indicate that the dTAT-pDNA-Ca2+ effectively delivered the gene to cancer cells by either IT or IV administration although the local pulmonary delivery of the dTAT-pAT2R-Ca2+ showed more effective growth inhibition of orthotopic lung cancer grafts. Thus, the present study offers preclinical proof of concept that a dTAT-based nonviral gene delivery method via IT administration may be an effective lung cancer gene therapy. PMID- 27769523 TI - Intercellular communication for innate immunity. AB - An effective innate immune response relies on the detection of pathogen associated molecular patterns (PAMPs) by various host pattern recognition receptors (PRRs) that result in the production of pro-inflammatory cytokines and chemokines. Viruses and bacteria have co-evolved with the immune system and developed multiple strategies to usurp or circumvent host machinery and blunt the innate immune response in infected cells. Recently, it has become apparent that infected or dying cells can transmit PAMPs and host PRR signalling proteins to uninfected bystander cells to thereby bypass pathogen evasion strategies, and potentiate innate immune signalling. This bystander activation of innate immunity represents an alternative method by which the host can control infections via cell-to-cell communication. In this review, we discuss what is currently known about the intercellular transfer of pathogen- or host-derived RNA, DNA and proteins from infected cells to neighbouring cells and how this impacts on host innate immunity. PMID- 27769524 TI - Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease. AB - Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI CaFe), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell-cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system. PMID- 27769525 TI - Can chemotherapy boost the survival benefit of adjuvant radiotherapy in early stage cervical cancer with intermediate risk factors? A population based study. AB - PURPOSE: The Gynecologic Oncology group (GOG) 0263 trial is currently exploring whether adding chemotherapy to adjuvant radiotherapy improves recurrence-free and/or overall survival in stage IB-IIA cervical cancer patients with pathologic intermediate-risk factors. Using the National Cancer Data Base, we evaluated the benefit of adjuvant chemoradiotherapy over adjuvant radiotherapy alone in the community practice setting. MATERIALS: The analysis included 869 stage IB-IIA cervical cancer patients who underwent radical hysterectomy retrieving intermediate-risk factors justifying adjuvant therapy. Adjuvant chemoradiotherapy and adjuvant radiotherapy were delivered in 440 and 429 patients, respectively. Chi-square test assessed the distribution of variables in each group and the overall survival was estimated using the Kaplan-Meier method. Proportional hazard models were performed to evaluate the impact of the different prognostic factors on survival and propensity score analysis adjusted variables imbalanced distribution. RESULTS: Adding chemotherapy to ART did not show a survival benefit at 48months median follow-up; the 5-year overall survival was 87% and 81% (p=0.6) in the adjuvant chemoradiotherapy and adjuvant radiotherapy groups, respectively. On univariate analysis, age older than 60, a higher comorbidity score, and stage IIA were significantly associated with worse survival, while none of the other covariates were significant prognosticator on multivariate analysis. The same findings held after propensity score analysis. CONCLUSION: Our analysis could not detect a significant survival benefit for adjuvant chemoradiotherapy over adjuvant radiotherapy in women with intermediate-risk factors. Until GOG 0263 results become available, the benefits of adjuvant chemoradiotherapy should be considered on an individual basis within a multidisciplinary approach. PMID- 27769526 TI - Minimally invasive versus standard laparotomic interval debulking surgery in ovarian neoplasm: A single-institution retrospective case-control study. AB - OBJECTIVE: To further investigate the role of MIS comparing patients submitted to MI-IDS with a balanced population treated by standard laparotomy. METHODS: The investigational arm (Cases) includes 30 AEOC patients treated with MI-IDS. The Control arm included a consecutive series of 65 AEOC patients submitted to laparotomic IDS. Inclusion criteria were: age>18years, histologically proven EOC, clinical complete/partial response after NACT, and ECOG PS <2. Preoperative clinical data, perioperative and oncological outcomes were analyzed. General Well Being Schedule (GWBS) was administered to evaluate quality of life before and after surgery. RESULTS: Both groups were well-balanced. A higher percentage of women among Cases received bevacizumab-containing NACT compared with Controls. No statistical differences were registered in terms of surgical procedures and residual tumor. A significantly longer median OT in Cases was counterbalanced by more favorable EBL and median length of stay and TTC. No statistically significant differences were registered in terms of postoperative complications. Cases showed a 6months longer PFS compared to Controls. However, in multivariate analysis only the administration of Bevacizumab and a shorter TTC were independently associated with a longer PFS. Regarding QoL, no statistically significant differences were registered in Cases between pre- and postoperative GWBS score. Differently from Controls where this difference was statistically significant and a more intense distress were recorded. CONCLUSIONS: Minimally invasive approach could represent an advantageous alternative surgical way to perform interval debulking surgery in this specific subset of patients, with no impact on PFS. Based on these findings a randomized clinical trial is now under evaluation in our Institution. PMID- 27769527 TI - Spatial variability of soft-bottom macrobenthic communities in northern Sicily (Western Mediterranean): Contrasting trawled vs. untrawled areas. AB - This study examines the impact of bottom trawl fishing on the macrobenthic communities inhabiting the coastal terrigenous mud off the northern coast of Sicily (Western Mediterranean). Two intensely trawled gulfs were compared with two gulfs from which trawling has been excluded for 15 years. The results show a significant effect of trawling on the faunal assemblage and when comparing the mean biomass and the whole isotopic composition of the benthic communities. A similar pattern, although not significant, was found for total abundance, biomass, production/biomass ratio and diversity. Higher abundance and lower biomass were found in the untrawled areas, attributable to the presence of more numerous yet smaller individuals, possibly a consequence of more abundant larger predators that are not removed by trawling, and consequent higher predatory pressure on the benthic macrofauna. The SIMPER analysis evidenced a dominance of burrowing deposit feeding worms (Paraonidae and Cossuridae) in trawled areas, as a result of increased mechanical alteration and hence more organic matter available as food. In contrast, the response to trawling as drawn by the use of trophic markers (i.e., stable isotopes) was less clear. While delta15N of benthic taxa did not vary significantly between untrawled and trawled areas, delta13C was higher in trawled areas possibly due to high sediment resuspension and consequent intense microbial activity. Mixing models confirmed higher reliance to a detritus based food web for benthic organisms in the trawled areas. Standard Ellipse Areas (SEAc) as a measure of community niche width were slightly larger in trawled areas, likely due to higher generalism triggered by alteration/removal of the original benthic community. PMID- 27769528 TI - Letter to the Editor. PMID- 27769529 TI - Ten years of PCV2 vaccines and vaccination: Is eradication a possibility? AB - More than two decades after its emergence, porcine circovirus type 2 (PCV2) remains an economically important swine pathogen. Commercial vaccines which were first introduced to the U.S in 2006, have been highly effective in reducing clinical signs and improving production. Recent studies have indicated a declining level of PCV2 prevalence and viremia in the field. However, reports on the emergence of new viral variants have also continued to increase. This article reviews topics of current interest in the field of PCV2 vaccines; including the comparative efficacy of the available commercial products, efficacy of current vaccines against new and emerging strains, findings on the differences between immunity in natural infection versus vaccination, limitations of current experimental models for PCV2 vaccine studies, and new developments in novel experimental vaccines. The discussion is framed in the context of attempts for the possible eradication of PCV2 in the future. PMID- 27769530 TI - Inactivation of p120 catenin in mice disturbs intrahepatic bile duct development and aggravates liver carcinogenesis. AB - p120 catenin (p120ctn) is required for the stability of classic cadherins at the cell surface and is thought to play a central role in modulating cell-cell adhesion. Cytoplasmic p120ctn promotes cell motility, and probably other activities, by modulating the activities of RhoA, Rac and Cdc42. E-cadherin is expressed in periportal but not in perivenous hepatocytes. In contrast, all hepatocytes of normal mouse liver express N-cadherin. Cholangiocytes express exclusively E-cadherin. Mice with p120ctn ablation in hepatocytes and cholangiocytes (p120LiKO mice) were generated by Cre-loxP technology. Livers were examined by histological, immunohistochemical, ultrastructural and serum analysis to determine the effect of the p120ctn ablation on liver structure and function. Mouse hepatocyte differentiation and homeostasis were not impaired. However, hepatoblasts differentiated abnormally into hybrid hepato-biliary cells, ductal plate structures were irregular in p120LiKO newborns, and further development of intrahepatic bile ducts was severely impaired. In adults, enrichment of ductular structures was accompanied by portal inflammation and fibrosis. p120LiKO mice did not spontaneously develop hepatocellular carcinoma but initiation of hepatocarcinogenesis by diethylnitrosamine was accelerated. In summary: p120ctn has a critical role in biliary differentiation and is a potent suppressor of liver tumor growth. PMID- 27769531 TI - Comprehensive chemical profiling of Pinellia species tuber and processed Pinellia tuber by gas chromatography-mass spectrometry and liquid chromatography atmospheric pressure chemical ionization-tandem mass spectrometry. AB - A comprehensive profiling method was established for the determination of various chemicals in Pinellia (P.) ternata and pedatisecta species. The profiling method comprises a fast ultrasonic extraction with various solvents, followed by GC-MS and LC-APCI-MS analysis. A total of 73 polar components as trimethylsilyl (TMS) derivatives were detected in methanol extract by GC-MS. The main components of the P. species were profiled as several kinds of fatty acids, amino acids, nucleic acids, carbohydrates, and phenolic compounds. The hexane extract was analyzed by LC-APCI-MS for the lipid profiling. A total of 35 lipid constituents [fatty acids and their esters, mono-, di-, and tri-acylglycerols] and four phytosterols were observed and tentatively characterized by LC-APCI-MS/MS. Among the phytochemicals detected in the hexane extract, triacylglycerols (TAGs) as the major component were identified by LC-APCI-MS and MS/MS. Based on the identified components, a significant difference in the chemical compositions of P. species tuber and processed P. ternata was found that the complete disappearance of TAGs and a considerable decrement of sucrose were observed in processed P. ternata. Furthermore, the degradation mechanism for TAGs in the presence of alum solution is suggested to occur during the processing P. ternata. Malic acid was found to be a characteristic compound for the classification of P. ternata and pedatisecta with different geographic origins. Based on the validated GC/MS method, twenty four P. ternata, processed P. ternata and P. pedatisecta samples were profiled to measure the overall abundance of specific groups of compound and to identify diagnostic compounds. In addition, principal component analysis (PCA) on the GC/MS profiling data revealed a clear classification of P. species samples. In this study, the full chemical complement was for the first time reported for quality evaluation of P. species. The method can be usefully applied for phytochemical analysis of related herbal medicines. PMID- 27769532 TI - Validation of thermally assisted hydrolysis and methylation-gas chromatography for rapid and direct compositional analysis of poly(3-hydroxybutyrate-co-3 hydroxyhexanoate) in whole bacterial cells. AB - Thermally assisted hydrolysis and methylation-gas chromatography (THM-GC) in the presence of an organic alkali was validated for the compositional analysis of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) [P(3HB-co-3HHx)] accumulated in whole bacterial cells. Recombinant Cupriavidus necator Re2058/pCB113 was grown in a batch fermentation with different concentration of palm oil and fructose in order to control the molar fraction of 3HHx in P(3HB-co-3HHx) produced in the cells. Trace amounts (30MUg) of freeze-dried cells were directly subjected to THM GC in the presence of tetramethylammonium hydroxide (TMAH) at 400 degrees C. The obtained chromatograms clearly showed nine characteristic peaks, attributed to the THM products from 3HB and 3HHx units in the polymer chains, without any appreciable interference by the bacterial matrix components. Based on these peak intensities, the copolymer compositions were determined rapidly without using any cumbersome and lengthy sample pretreatment as in conventional GC method. Moreover, the compositions thus obtained were strongly correlated with those by NMR and conventional GC involving solvent extraction. PMID- 27769533 TI - Protein adsorption in polyelectrolyte brush type cation-exchangers. AB - Ion exchange chromatography materials functionalized with polyelectrolyte brushes (PEB) are becoming an integral part of many protein purification steps. Adsorption onto these materials is different than that onto traditional materials, due to the 3D partitioning of proteins into the polyelectrolyte brushes. Despite this mechanistic difference, many works have described the chromatographic behavior of proteins on polyelectrolyte brush type ion exchangers with much of the same methods as used for traditional materials. In this work, unconventional chromatographic behavior on polyelectrolyte brush type materials is observed for several proteins: the peaks shapes reveal first anti-Langmuirian and then Langmuirian types of interactions, with increasing injection volumes. An experimental and model based description of these materials is carried out in order to explain this behavior. The reason for this behavior is shown to be the 3D partitioning of proteins into the polyelectrolyte brushes: proteins that fully and readily utilize the 3D structure of the PEB phase during adsorption show this behavior, whereas those that do not show traditional ion exchange behavior. PMID- 27769534 TI - Rapid screening and quantification of residual pesticides and illegal adulterants in red wine by direct analysis in real time mass spectrometry. AB - A rapid method to screen and quantify multi-class analytic targets in red wine has been developed by direct analysis in real time (DART) coupled with triple quadruple tandem mass spectrometry (QqQ-MS). A modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) procedure was used for increasing analytical speed and reducing matrix effect, and the multiple reaction monitoring (MRM) in DART-MS/MS ensured accurate analysis. One bottle of wine containing 50 pesticides and 12 adulterants, i.e., preservatives, antioxidant, sweeteners, and azo dyes, could be totally determined less than 12min. This method exhibited proper linearity (R2>=0.99) in the range of 1-1000ng/mL for pesticides and 10-5000ng/mL for adulterants. The limits of detection (LODs) were obtained in a 0.5-50ng/mL range for pesticides and 5-50ng/mL range for adulterants, and the limits of quantification (LOQs) were in a 1-100ng/mL range for pesticides and 10-250ng/mL range for adulterants. Three spiked levels for each analyte in wine were evaluated, and the recoveries were in a scope of 75-120%. The results demonstrated DART-MS/MS was a rapid and simple method, and could be applied to rapid analyze residual pesticides and illegal adulterants in a large quantities of red wine. PMID- 27769535 TI - Chondrosarcoma of the hyoid bone - Report of a case and a literature review of the suitable treatment strategy. AB - Chondrosarcoma is a rare malignant tumor occurring in the trunk and long bones. We present an extremely rare case of chondrosarcoma of the hyoid bone with clinical and pathological correlation and a literature review. We searched all cases of the hyoid chondrosarcoma in PubMed (MEDLINE) between 1990 and 2015. Eighteen cases were analyzed, including the present case. Most of them were low grade type. In 12 cases where intraoperative findings were recorded, no adhesion to the surrounding tissue was observed. Chondrosarcoma of the hyoid bone is usually low grade type, and there may be no invasion to the adjacent structures even if invasion is suspected by imaging findings. In order to preserve swallowing and laryngeal function, total hyoidectomy without laryngectomy should be indicated according to the intraoperative findings. Needle biopsy is an effective diagnostic technique, but open biopsy should be avoided to prevent the dissemination. To the best of our knowledge, this is the first presentation of hyoid bone chondrosarcoma with the investigation of intraoperative findings and pre-operative diagnostic modality. PMID- 27769536 TI - Identification of the most abundant proteins in equine amniotic fluid by a proteomic approach. AB - Characterisation of the physiologic equine amniotic fluid (AF) proteome is a prerequisite to study its changes during diseases and discover new biomarkers. The aim of this study was to identify by a proteomic approach the most abundant proteins of equine AF. AF samples were collected at parturition from 24 healthy mares that delivered healthy foals. All samples were subjected to sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) on 4-12% gels. A pool of the 24 samples, after SDS-PAGE, was cut in 25 slices, trypsin-digested and analysed by mass spectrometry (MS) for protein identification. Mean AF protein concentration was 1.96+/-1.12g/L. Thirty-four proteins were successfully identified by MS and subsequently categorised according to Gene Ontology (GO). Twelve proteins (e.g. fibronectin, lumican, thrombospondin and fibulin) belonged to or interacted with the extracellular matrix (ECM) playing an important role in the development of foetal tissues. Most of the remaining proteins were classified as transport (e.g. albumin, major allergen Equ c1 and alpha-fetoprotein) delivering nutrients, ions and lipids essential for foetal growth and development. Among these proteins, major allergen Equ c1 is widely studied in human medicine because it induces Ig-E mediated type I allergic reaction. The absence of immunoglobulins in equine AF was also confirmed. PMID- 27769537 TI - Why Join the Ibero-Latin American College of Dermatology? PMID- 27769538 TI - Electrochemotherapy for the Treatment of Unresectable Locoregionally Advanced Cutaneous Melanoma: A Systematic Review. AB - Electrochemotherapy is a therapeutic option for the treatment of cutaneous and subcutaneous metastases from melanoma and other tumors. The procedure consists of the administration of anticancer drugs followed by locally applied electrical impulses to achieve an effect known as electroporation, which facilitates entry into the cytosol of drugs that cannot cross the cell membrane. The aim of this review is to evaluate the evidence that supports the use of electrochemotherapy as a therapeutic strategy in melanoma. We conducted a qualitative systematic review of the literature using advanced searches of bibliographic databases and full text reviews. Seven studies (3 systematic reviews and 4 cases series) were selected. The quality of the evidence was not good, but the coincidence of results for certain variables supports their consistency. Results of the meta analyses favored electrochemotherapy over chemotherapy. Electrochemotherapy appears to be an effective procedure for the local treatment of malignant tumor nodules (evidence of intermediate or low quality). This inexpensive method is simple to apply, well tolerated, and achieves objective responses under certain circumstances. There is no evidence that electrochemotherapy alters the natural course of the disease and it should therefore be considered a palliative treatment. With an evidence level of 1- (minus), electrochemotherapy can be recommended for the palliative treatment of unresectable, locoregionally advanced melanoma (grade B recommendation). PMID- 27769539 TI - Reply letter. PMID- 27769540 TI - Thyroglobulin antibodies may serve as predictive marker for papillary thyroid carcinoma in indeterminate cytology: Acceptable or not? PMID- 27769541 TI - Empirical validation of the Operative Entrustability Assessment using resident performance in autologous breast reconstruction and hand surgery. AB - BACKGROUND: In 2013, we developed the Operative Entrustability Assessment (OEA) to facilitate evaluation and documentation of resident operative skills. This web based tool provides real-time, transparent feedback to residents on operative performance. This study evaluated the construct validity of the OEA, assessing its association with operative time. METHODS: We used simple and multiple linear regression to estimate associations between OEA scores and operative time in selected procedures performed. RESULTS: OEAs were completed for 93 autologous breast reconstructions and 185 hand procedures. Self-assessed OEA was associated with shorter operative time in breast (p = 0.008) and hand (p = 0.036) cases. Evaluator OEA was associated with shorter operative time in breast (p = 0.018), but not hand cases (p = 0.377). Post-graduate year was not associated. CONCLUSIONS: The OEA demonstrates construct validity: increasing scores are associated with shorter operative time and are better predictors of operative time than post-graduate year, making it an option for documenting competence prior to graduation. PMID- 27769542 TI - Clinical relevance of the routine daily chest X-Ray in the surgical intensive care unit. AB - INTRODUCTION: A daily Chest X-ray (CXR) is obtained in many surgical intensive care units (SICU). This study implemented a selective CXR protocol in a high volume, academic SICU and evaluated its impact on clinical outcomes. METHODS: All SICU patients admitted in 2/2010 were compared with patients admitted in 2/2012. Between the time periods, a protocol eliminating the routine daily CXRs was instituted. RESULTS: In 02/2010 and 02/2012, 107 and 90 patients were admitted to the SICU, respectively, for a total of 1384 patient days. CXRs decreased from 365 (57.1% of patient-days) in 2010 to 299 (40.9% of patient days; p < 0.001) in 2012. A greater proportion of Physician Directed CXRs (PDCXRs) had new findings (80.8%) compared to Automatic Daily CXRs (ADCXRs) (23.5%, p < 0.001). There was no difference in overall or SICU length of stay, ventilator-free days, morbidity or mortality. CONCLUSION: Eliminating ADCXRs decreased the number of CXRs performed, without affecting LOS, mechanical ventilation, morbidity or mortality. Physician-directed ordering of CXRs increased the diagnostic value of the CXR and decreased the number of clinically irrelevant CXRs performed. PMID- 27769543 TI - Randomized trial of a short course of preoperative potassium iodide in patients undergoing thyroidectomy for Graves' disease. AB - BACKGROUND: A short course of potassium iodide (SSKI) has been traditionally used to prepare patients with Graves' disease for thyroidectomy. The rationale for this treatment has evolved over time; from control of hyperthyroidism to facilitating surgery by making the gland less friable and bloody. METHODS: Randomized trial of preoperative SSKI vs no SSKI to test whether that is true. RESULTS: Mean estimated blood loss in the SSKI group (62 mL) was less than in the control group (162 mL) as was the median estimated blood loss (50 vs 140 mL). Mean (142 vs 162 minutes) and median (138 vs 150 minutes) operative times were also less in the SSKI arm. Subjective difficulty of operation was similar. Multivariable comparisons of groups with analysis of covariance showed the SSKI group suffered a mean blood loss 35% of the no treatment group (P = .036), the 9.2% decrease in Operating Room (OR) time between the SSKI group and the no treatment group was not statistically different (P = .464). CONCLUSIONS: SSKI given before operation in patients with Graves' disease reduces blood loss during thyroidectomy. PMID- 27769544 TI - A risk model and cost analysis of post-operative incisional hernia following 2,145 open hysterectomies-Defining indications and opportunities for risk reduction. AB - BACKGROUND: Incisional hernia (IH) is a complication following open abdominal hysterectomy. This study addresses the incidence and health care cost of IH repair after open hysterectomy, and identify perioperative risk factors to create predictive risk models. METHODS: We conduct a retrospective review of patients who underwent open hysterectomy between 2005 and 2013 at the University of Pennsylvania. The primary outcome was post-hysterectomy IH. Univariate/multivariate cox proportional hazard analyses identified perioperative risk factors. We performed cox hazard regression modeling with bootstrapped validation, risk stratification, and assessment of model performance. RESULTS: 2145 patients underwent open hysterectomy during the study period. 76 patients developed IH, and all underwent repair. 31.3% underwent reoperation, generating higher costs ($71,559 vs. $23,313, p < 0.001). 8 risk factors were included in the model, the strongest being presence of a vertical incision (HR = 3.73 [2.01 6.92]). Extreme-risk patients experienced the highest incidence of IH (22%) vs. low-risk patients (0.8%) [C-statistic = 0.82]. CONCLUSIONS: We identify perioperative risk factors for IH and provide a risk prediction instrument to accurately stratify patients in effort to offer risk reductive techniques. SUMMARY: Open hysterectomies account for a magnitude of surgical procedures worldwide. This study presents an internally validated risk model of IH in patients undergoing open hysterectomy after a review of 2145 cases. With an increasing emphasis on prevention in healthcare, we create a risk model to improve outcomes after open hysterectomies in effort to identify high-risk patients, facilitate preoperative risk counseling, and implement evidence-based strategies to improve outcomes. PMID- 27769545 TI - V-Y fasciocutaneous flap closure technique is a safe and efficacious alternative to primary closure of the perineal wound following abdominoperineal resection. AB - BACKGROUND: The aim of this study was to compare wound complications from V-Y flap vs primary closure in the setting of abdominoperineal resection. METHODS: This was a single institution retrospective review (1999-2014). The main outcome measures were any wound complication, hospital length of stay, and unplanned readmissions. RESULTS: Among 80 patients included, 21 (26%) received reconstruction with V-Y flap. Compared with those who received primary closure, patients who underwent V-Y flap reconstruction had lower rates of overall wound complications (14.3% vs 64%, P = .002), superficial surgical site infection (6% vs 32%, P = .05), and wound dehiscence (4.5% vs 14%, P = .251 statistical significance not met). CONCLUSIONS: Reconstruction of perineal defect following abdominoperineal resection using a V-Y fasciocutaneous flap is a safe and efficacious alternative to traditional simple primary closure and is associated with reduced postoperative morbidity. Further comparative effectiveness studies should be undertaken to evaluate long-term and quality-of-life outcomes. PMID- 27769546 TI - Demographics, disparities, and outcomes in substernal goiters in the United States. PMID- 27769547 TI - Predictive factors and outcomes of negative appendectomy. AB - BACKGROUND: The aim of this study was to assess predictive factors for negative appendectomy and to evaluate the outcomes of negative appendectomy. METHODS: A retrospective chart review of 4,878 patients who underwent appendectomy at our institution from January 2008 to December 2014 was performed. RESULTS: Younger age (<=15 years), normal white blood cell count, appendix diameter of less than 6 mm on computed tomography (CT), and CT grade less than 3 were found to be independent predictive factors for negative appendectomy. When complications were investigated according to the results of pathologic diagnosis, negative appendectomy had more complications than appendectomy for nonperforated appendicitis, and this was statistically significant. CONCLUSIONS: When CT findings are equivocal, in deciding to operate for acute appendicitis, additional ultrasonography can be performed. Furthermore, if the patient is younger than 15 years and the white blood cell count is normal, it is recommended to monitor changes in symptoms a little longer rather than operating hastily. PMID- 27769548 TI - Characteristics and treatment of human epidermal growth factor receptor 2 positive breast cancer: 43,485 cases from the National Cancer Database treated in 2010 and 2011. AB - BACKGROUND: Although identification of human epidermal growth factor receptor 2 (Her2) positive breast cancer represents one of the greatest advances over the past 3 decades, it has not been studied extensively on a national level. METHODS: The National Cancer Database is a joint project of the American Cancer Society and the American College of Surgeons and contains data on about 70% of the cancer cases in the United States. Data on Her2 have been collected since 2010 and was used for this study. RESULTS: Of 298,937 cases of invasive breast cancer with known Her2 status diagnosed in 2010 and 2011, 43,485 (14.5%) were Her2 positive. Her2 positivity was greatest in Asian/Pacific Islanders and least in non-Hispanic Whites and was markedly more common in younger women. The incidence of Her2 positive tumors ranged from a low of 13.9% in the Mountain West region to a high of 16.0% in the West South Central region (P < .001). Compared with Her2 negative tumors, Her2 positive tumors were larger (2.6 vs 2.2 cm, P < .001), more likely to have positive nodes (39% vs 31% P < .001), have lymphovascular invasion (30% vs 20%, P < .001), and be high grade (56% vs 29%, P < .001). There were also differences by histology: invasive ductal 16.4%, invasive lobular 5.5%, tubular 2.3%, inflammatory 36%, and Paget's with invasion 59%. When adjusted for age, race, tumor size, and nodal status Her2 positive tumors were much more likely to receive chemotherapy (odds ratio = 5.5, confidence interval = 5.2 to 6.0) and somewhat less likely to undergo breast preservation (odds ratio = .78, confidence interval = .76 to .80). CONCLUSIONS: Her2 positive tumors have distinct epidemiologic, clinical, and treatment characteristics. PMID- 27769549 TI - Association between Postdischarge Oral Corticosteroid Prescription Fills and Readmission in Children with Asthma. AB - OBJECTIVES: To assess the relationships between postdischarge emergency department visits, oral corticosteroid (OCS) use, and 15- to 90-day asthma readmission in children. STUDY DESIGN: Retrospective study of 9288 children from 12 states in the Truven MarketScan Database, ages 2-18 years, hospitalized between January 1, 2009, and June 30, 2011, with asthma, and continuously enrolled in Medicaid for 6 months prior and 3 months after hospitalization. The primary outcome was 15- to 90-day readmission for asthma. Secondary outcomes were postdischarge emergency department visits (within 28 days) and outpatient OCS prescription fills (6-28 days postdischarge or earlier if coinciding with an outpatient asthma visit). Logistic regression was used to assess the relationship of hospital readmission with patient characteristics and asthma health services surrounding the index admission. RESULTS: Median age at index admission was 6 years (IQR, 3-9); 62% were male and 49% were black; 2.8% had a 15- to 90-day readmission (median, 50 days; IQR, 32-70). After index discharge, 4% had an emergency department visit (median, 17 days; IQR, 12-24) and 11% had an outpatient OCS fill (median, 14 days; IQR, 6-21). In multivariable analysis, children with a postdischarge outpatient OCS fill (OR, 3.2; 95% CI, 2.4-4.6) or hospitalization within 6 months preceding the index admission (OR, 2.9; 95% CI, 2.0-4.0) had the greatest likelihood for hospital readmission. CONCLUSIONS: OCS fill within 28 days of hospital discharge was most strongly associated with 15- to 90-day hospital readmission. This finding may inform evolving strategies to reduce asthma readmissions in children. PMID- 27769550 TI - Reversible Cerebral Vasoconstriction Syndrome during Chemotherapy for Acute Lymphoblastic Leukemia. PMID- 27769551 TI - The Effect of a Significant Patent Ductus Arteriosus on Doppler Flow Patterns of Preductal Vessels: An Assessment of the Brachiocephalic Artery. AB - Systemic hypoperfusion secondary to a patent ductus arteriosus (PDA) is thought to only affect post-ductal vessels. In a prospective observational study of 51 preterm infants, we demonstrated that a persistent PDA by day 5-7 is associated with reversed diastolic flow in the brachiocephalic artery when compared with those without a PDA. PMID- 27769552 TI - Early Life Characteristics Associated with Appetite-Related Eating Behaviors in 7 Year-Old Children. AB - OBJECTIVE: To assess early life characteristics associated with appetite-related eating behaviors in 7-year-old children. STUDY DESIGN: The participants are children from the population-based birth cohort Generation XXI. Data on sociodemographics, health, and lifestyles and anthropometrics were collected at birth, and 4- and 7-year-old evaluations. A Portuguese version of the Children's Eating Behavior Questionnaire was completed by mothers (n = 3562 children) with children aged 7 years old. A 2-factor solution was identified: factor 1-appetite restraint and factor 2-appetite disinhibition. Associations were estimated through generalized linear models adjusted for maternal age, education, body mass index (BMI) before birth, family structure, number of siblings, and child's sex (beta regression coefficients and 95% CIs). RESULTS: Higher appetite restraint at 7 years old was associated with higher maternal age and educational level, families with both parents (1- vs 2-parent: beta = -0.074, 95% CI -0.140, -0.007) and no siblings (>=2 vs 0: beta = -0.152, 95% CI -0.224, -0.081), and more sedentary lifestyles at 4 years old. It was also associated with lower child and maternal BMI and waist circumference at 4 years old. In contrast, higher appetite disinhibition was associated with lower maternal educational background, having a 1-parent family, more sedentary behaviors (>=120 vs <120 min/d of media: beta = 0.055, 95% CI 0.018, 0.093), and higher BMI and waist circumference at 4 years old. CONCLUSIONS: Higher maternal age and education, and a family with both parents at 4 years old seem to influence higher appetite restraint, but less appetite disinhibition at 7 years old. More sedentary lifestyles at 4 years old were associated with higher appetite restraint and appetite disinhibition scores later in childhood. These results can be useful for the development of prevention guidelines and educational strategies aimed at improving healthy eating behaviors. PMID- 27769553 TI - Commentary on J-P. Michaud, G. Moreau, Predicting the visitation of carcasses by carrion-related insects under different rates of degree-day accumulation, Forensic Sci. Int. 185 (2009) 78-83. PMID- 27769554 TI - Spontaneous closure of a blue laser induced full thickness macular hole. AB - CASE REPORT: A 14 year-old boy attended our clinic complaining of a scotoma after an accidental exposure to a 10W, 450nm laser beam from a blue-light handheld laser device. Optical coherence tomography confirmed a full thickness macular hole. As visual acuity (VA) remained 20/20 Snellen, observation was decided. Spontaneous closure was confirmed after one month. DISCUSSION: Reckless use of high-power handheld laser devices may induce severe retinal lesions, including full thickness macular holes. Observation is a sensible treatment option in this type of macular hole, especially when VA is preserved. The pathophysiology of these cases differs from senile full thickness macular holes. PMID- 27769555 TI - Coral benchmarks in the center of biodiversity. AB - There is an urgent need to quantify coral reef benchmarks that assess changes and recovery rates through time and serve as goals for management. Yet, few studies have identified benchmarks for hard coral cover and diversity in the center of marine diversity. In this study, we estimated coral cover and generic diversity benchmarks on the Tubbataha reefs, the largest and best-enforced no-take marine protected area in the Philippines. The shallow (2-6m) reef slopes of Tubbataha were monitored annually, from 2012 to 2015, using hierarchical sampling. Mean coral cover was 34% (sigma+/-1.7) and generic diversity was 18 (sigma+/-0.9) per 75m by 25m station. The southeastern leeward slopes supported on average 56% coral cover, whereas the northeastern windward slopes supported 30%, and the western slopes supported 18% coral cover. Generic diversity was more spatially homogeneous than coral cover. PMID- 27769556 TI - Bioaccumulation of trace element concentrations in common dolphins (Delphinus delphis) from Portugal. AB - The common dolphin (Delphinus delphis) is one of the most abundant species in Atlantic Iberia, representing a potentially important tool to assess the bioaccumulation of trace elements in the Iberian marine ecosystem. Nine elements (As, Cd, Cu, Hg, Mn, Ni, Pb, Se and Zn) were evaluated in 36 dolphins stranded in continental Portugal. Dolphins had increasing Hg concentrations (16.72MUg.g-1 ww, liver) compared with previous studies in Atlantic Iberia, whereas Cd concentrations (2.26MUg.g-1 ww, kidney) fell within reported ranges. The concentrations of some trace elements (including Cd and Hg) presented positive relationships with dolphin length, presence of parasites and gross pathologies. Common dolphins may help biomonitoring more offshore Atlantic Iberian areas in future studies, which would otherwise be difficult to assess. PMID- 27769557 TI - Nowhere safe? Exploring the influence of urbanization across mainland and insular seashores in continental Portugal and the Azorean Archipelago. AB - Differences in the structure and functioning of intensively urbanized vs. less human-affected systems are reported, but such evidence is available for a much larger extent in terrestrial than in marine systems. We examined the hypotheses that (i) urbanization was associated to different patterns of variation of intertidal assemblages between urban and extra-urban environments; (ii) such patterns were consistent across mainland and insular systems, spatial scales from 10scm to 100skm, and a three months period. Several trends emerged: (i) a more homogeneous distribution of most algal groups in the urban compared to the extra urban condition and the opposite pattern of most invertebrates; (ii) smaller/larger variances of most organisms where these were, respectively, less/more abundant; (iii) largest variability of most response variables at small scale; (iv) no facilitation of invasive species by urbanization and larger cover of canopy-forming algae in the insular extra-urban condition. Present findings confirm the acknowledged notion that future management strategies will require to include representative assemblages and their relevant scales of variation associated to urbanization gradients on both the mainland and the islands. PMID- 27769558 TI - Vorinostat in Combination With Lenalidomide and Dexamethasone in Lenalidomide Refractory Multiple Myeloma. AB - BACKGROUND: This is a retrospective chart review to evaluate the efficacy of the addition of vorinostat to lenalidomide and dexamethasone in patients with multiple myeloma relapsed/refractory to lenalidomide and dexamethasone. METHODS: Charts from 26 consecutive patients able to obtain commercial vorinostat were analyzed for response and safety data. RESULTS: The overall response rate was 31%, and the clinical beneficial rate was 50%. The median duration of response was 3 months, and the median overall survival was 28.5 months. The most common grade 3 and 4 toxicities were hematologic and metabolic, including neutropenia (44%), thrombocytopenia (53%), and transaminase elevations (aspartate aminotransferase 9% and alanine aminotransferase 6%). No thromboembolic events or febrile neutropenia were observed. CONCLUSION: These observations demonstrate that the addition of vorinostat to patients with lenalidomide- and dexamethasone refractory multiple myeloma was associated with moderate response and was well tolerated, warranting further assessment in a larger prospective study. PMID- 27769559 TI - Increased Bone Marrow Iron Scores Are Strongly Correlated With Elevated Serum Ferritin Levels and Poorer Survival in Patients With Iron Overload That Underwent Allogeneic Hematopoietic Stem Cell Transplantation: A Single Center Experience. AB - BACKGROUND: Iron overload is one of the most significant problems as a leading cause of death in patients with leukemia and those who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). METHODS: In the current study, we retrospectively evaluated the bone marrow iron scores (BMIS) in patients who underwent alloHSCT (n = 125). The first available bone marrow biopsy specimens prior to the alloHSCT procedure or date of hospitalization (control group) were assessed in a blinded fashion using a standardized scoring system. RESULTS: A total of 125 patients were enrolled in the study. Seventy-six (60.8%) of the patients were male, and 49 (39.2%) were female. The median level of pre transplant serum ferritin was 1023.00 ng/mL (range, 393.80-1627.50 ng/mL). The majority of the patients were diagnosed with acute leukemia (83; 66.4%) and lymphomas (20; 16.0%). The median time for neutrophil engraftment was 14.00 days (range, 13.00-16.00 days) and 11.00 days (range, 10.00-14.00 days) for platelet engraftment. The peri-transplant mortality was similar to international mortality rates (3; 2.4%). The overall survival and disease-free survival were strongly correlated with the degree of BMIS, and both were significantly poorer in patients with high bone marrow iron content (P < .001 and P = .012, respectively). CONCLUSION: The validation of BMIS for risk stratification in patients who undergo alloHSCT may predict posttransplant outcomes. PMID- 27769560 TI - Developmental milestones in type I spinal muscular atrophy. AB - The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials. PMID- 27769561 TI - Towards effective empirical treatment for Helicobacter pylori eradication. PMID- 27769563 TI - Comparison of a novel porous titanium construct (Regenerex(r)) to a well proven porous coated tibial surface in cementless total knee arthroplasty - A prospective randomized RSA study with two-year follow-up. AB - BACKGROUND: Regenerex is a novel porous titanium construct with a three dimensional porous structure and biomechanical characteristics close to that of normal trabecular bone. The aim of this study was to compare this novel construct to a well-proven porous plasma sprayed tibial (PPS) implant after total knee arthroplasty. METHODS: Sixty-one patients scheduled for an uncemented TKA were randomized to receive either a novel highly porous titanium construct Regenerex or the PPS tibial component. Radiostereometric analysis of the tibial components was performed postoperatively and at three, six, 12, and 24months with measurements of migration (segment motion and maximum total point motion (MTPM)). RESULTS: Knee and function scores improved significantly from preoperatively to two-year follow-up. For both the Regenerex and the PPS the majority of migration appeared during the first three months and then stabilized. No statistically significant differences in MTPM were found in any follow-up between three and 24months. The Regenerex group had a lower migration rate between 12 and 24months compared with the PPS implants (p=0.03) but the PPS group had an initial significantly lower subsidence (p=0.04). CONCLUSION: In conclusion the Regenerex implant could prove an effective scaffold material for coating of uncemented implants but did no better than the PPS component at 24months of follow-up. ClinicalTrials.gov identifier: NCT01936415. PMID- 27769562 TI - Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. AB - BACKGROUND: Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori. METHODS: In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive 13C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01906879. FINDINGS: Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90.4% (488/540 [95% CI 87.6-92.6]) for 10-day bismuth quadruple therapy, 85.9% (464/540 [82.7-88.6]) for 10-day concomitant therapy, and 83.7% (452/540 [80.4-86.6]) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14 day triple therapy (difference 6.7% [95% CI 2.7-10.7, p=0.001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10 day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy. INTERPRETATION: Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered. FUNDING: National Taiwan University Hospital and Ministry of Science and Technology of Taiwan. PMID- 27769564 TI - In vivo anti-inflammatory activities of novel cytokine IL-38 in Murphy Roths Large (MRL)/lpr mice. AB - The newly named interleukin (IL)-36 subfamily member IL-38 has been shown to exert anti-inflammatory activity. However, the in vivo immunomodulatory activity of IL-38 was poorly investigated in systemic lupus erythematosus (SLE). We have investigated the expression of CD4+IL-17+ Th17, CD4+IFN-gamma+ Th1 and CD3+CD4 CD8- double negative (DN) T cells and the related immunopathological mechanisms in female MRL/lpr mice model of spontaneous lupus-like disease, with or without IL-38 treatment. Intravenous administration of murine recombinant IL-38 into MRL/lpr mice can ameliorate the lupus-like clinical symptoms including proteinuria, leukocyteuria and skin lesions. A remission of histopathology characteristics of skin and nephritis was also observed upon IL-38 treatment. Accordingly, IL-38 receptor was expressed on the cell surface of both CD4+ Th and CD19+ B lymphocytes. The splenic Th17 and DN T lymphocytes, the average mRNA level of epigenetically regulated gene expression of Th17 cells, and serum concentrations of IL-17 and IL-22 were significantly decreased upon the treatment of IL-38 (all p<0.05). The in vivo results suggest that IL-38 can ameliorate skin inflammation and nephritis in SLE mice probably via suppressing the formation of inflammatory cytokines such as IL-17 and IL-22, and pathogenic DN T cells. These findings may provide a biochemical basis for further investigation of the therapeutic mechanisms of IL-38 for the treatment of autoimmune-mediated inflammation. PMID- 27769565 TI - [Thrombotic skin gangrene: A rare extra-intestinal manifestation of ulcerative colitis]. AB - BACKGROUND: Thrombotic cutaneous gangrene is a rare extra-intestinal manifestation of ulcerative colitis with a severe prognosis. CASE REPORT: A 35 year-old woman with a 7-year history of ulcerative colitis presented with extensive ecchymotic lesions that began a few hours earlier. On examination, she was febrile with multiple necrotic lesions. Skin biopsy showed multiple microthrombi in the dermal vessels. A diagnosis of thrombotic cutaneous gangrene was established. The patient was treated with heparin and systemic corticosteroids. The majority of cutaneous lesions showed improvement after 1 month. Thrombophlebitis of the left lower limb occurred subsequently. CONCLUSION: Thrombotic cutaneous gangrene is attributed to microvascular thrombosis, which arises from the hypercoagulability observed in ulcerative colitis. Complete blood and coagulation tests must be performed and early anticoagulation with heparin must be considered in order to prevent the progression of cutaneous infarction. PMID- 27769566 TI - A novel nasal endoscopic approach for removing displaced dental implants from the maxillary sinus. AB - INTRODUCTION: Over the last 30years, dental implants have become widespread all over the world. Though the implantation procedure is standardized and safe, the displacement of implants into the maxillary sinus can occur. The aim of the study has been to describe a novel combined nasal endoscopic approach through the middle and lower meatus for managing dental implants displaced into the maxillary sinus. METHODS/RESULTS: A 40-year-old man was examined for a titanium osteo integrated implant displaced within the alveolar recess of the left maxillary sinus. The indications and procedure are reported in detail. The pros and cons of this approach are compared with those of other standard surgical methods. CONCLUSIONS: The main strength of the technique described here lies in the ample view and ideal control of the displaced dental implant achieved by fashioning a second window at the lower meatus that enables enlargement of the natural ostium to be minimized, thereby ensuring an anatomically and functionally better result. PMID- 27769567 TI - Genome-wide DNA Methylation Changes in a Mouse Model of Infection-Mediated Neurodevelopmental Disorders. AB - BACKGROUND: Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution. METHODS: Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring (n = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of flight mass spectrometry and quantitative real-time polymerase chain reaction analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. Gene ontology term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation. RESULTS: Adult offspring of immune challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for gamma-aminobutyric acidergic differentiation and signaling (e.g., Dlx1, Lhx5, Lhx8), Wnt signaling (Wnt3, Wnt8a, Wnt7b), and neural development (e.g., Efnb3, Mid1, Nlgn1, Nrxn2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring's age and were markedly influenced by the precise timing of prenatal immune activation. CONCLUSIONS: Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories. PMID- 27769569 TI - The quality of the reported sample size calculations in randomized controlled trials indexed in PubMed. AB - BACKGROUND: There are limited data on the quality of reporting of information essential for replication of the calculation as well as the accuracy of the sample size calculation. We examine the current quality of reporting of the sample size calculation in randomized controlled trials (RCTs) published in PubMed and to examine the variation in reporting across study design, study characteristics, and journal impact factor. We also reviewed the targeted sample size reported in trial registries. METHODS: We reviewed and analyzed all RCTs published in December 2014 with journals indexed in PubMed. The 2014 Impact Factors for the journals were used as proxies for their quality. RESULTS: Of the 451 analyzed papers, 58.1% reported an a priori sample size calculation. Nearly all papers provided the level of significance (97.7%) and desired power (96.6%), and most of the papers reported the minimum clinically important effect size (73.3%). The median (inter-quartile range) of the percentage difference of the reported and calculated sample size calculation was 0.0% (IQR -4.6%;3.0%). The accuracy of the reported sample size was better for studies published in journals that endorsed the CONSORT statement and journals with an impact factor. A total of 98 papers had provided targeted sample size on trial registries and about two third of these papers (n=62) reported sample size calculation, but only 25 (40.3%) had no discrepancy with the reported number in the trial registries. CONCLUSIONS: The reporting of the sample size calculation in RCTs published in PubMed-indexed journals and trial registries were poor. The CONSORT statement should be more widely endorsed. PMID- 27769570 TI - Use of the citizen's electronic health record by doctors and patients in a mature application throughout a district of the national health system of Italy. PMID- 27769568 TI - Specific Frontostriatal Circuits for Impaired Cognitive Flexibility and Goal Directed Planning in Obsessive-Compulsive Disorder: Evidence From Resting-State Functional Connectivity. AB - BACKGROUND: A recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity. METHODS: Multiecho resting state acquisition, combined with micromovement correction by blood oxygen level dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects. We measured cognitive flexibility (attentional set-shifting) and goal directed performance (planning of sequential response sequences) by means of well validated, standardized behavioral cognitive paradigms. Functional connectivity strength of striatal seed regions was related to cognitive flexibility and goal directed performance. To gain insights into fundamental network alterations, graph theoretical models of brain networks were derived. RESULTS: Reduced functional connectivity between the caudate and the ventrolateral prefrontal cortex was selectively associated with reduced cognitive flexibility. In contrast, goal-directed performance was selectively related to reduced functional connectivity between the putamen and the dorsolateral prefrontal cortex in OCD patients, as well as to symptom severity. Whole-brain data-driven graph theoretical analysis disclosed that striatal regions constitute a cohesive module of the community structure of the functional connectome in OCD patients as nodes within the basal ganglia and cerebellum were more strongly connected to one another than in healthy control subjects. CONCLUSIONS: These data extend major neuropsychological models of OCD by providing a direct link between intrinsically abnormal functional connectivity within dissociable frontostriatal circuits and those cognitive processes underlying OCD symptoms. PMID- 27769571 TI - Complications associated with radiofrequency ablation of pulmonary veins. AB - OBJECTIVE: Radiofrequency ablation is an efficacious alternative in patients with symptomatic atrial fibrillation who do not respond to or are intolerant to at least one class I or class III antiarrhythmic drug. Although radiofrequency ablation is a safe procedure, complications can occur. Depending on the location, these complications can be classified into those that affect the pulmonary veins themselves, cardiac complications, extracardiac intrathoracic complications, remote complications, and those that result from vascular access. The most common complications are hematomas, arteriovenous fistulas, and pseudoaneurysms at the puncture site. Some complications are benign and transient, such as gastroparesis or diaphragmatic elevation, whereas others are potentially fatal, such as cardiac tamponade. CONCLUSION: Radiologists must be familiar with the complications that can occur secondary to pulmonary vein ablation to ensure early diagnosis and treatment. PMID- 27769572 TI - Susceptibility to penicillin derivatives among third-generation cephalosporin resistant Enterobacteriaceae recovered on hospital admission. AB - As part of the multicenter Antibiotic Therapy Optimisation Study-the largest study on the prevalence of third-generation cephalosporin-resistant Enterobacteriaceae carriage upon hospital admission-minimum inhibitory concentration values were generated for ampicillin/sulbactam, amoxicillin/clavulanic acid, piperacillin/tazobactam, mecillinam, mecillinam/clavulanic acid, and temocillin against third-generation cephalosporin resistant Escherichia coli, Klebsiella species and Enterobacter species. PMID- 27769573 TI - Relationships between mitochondrial DNA content, mitochondrial activity, and boar sperm motility. AB - Energy produced by mitochondria via oxidative phosphorylation (OXPHOS) is essential for mammalian sperm motility. Mammalian mitochondrial DNA (mtDNA) encoded proteins are subunits of the OXPHOS system. Paradoxically, there are less mitochondrial and mtDNA contents in motile sperm than less motile sperm. Here, mature boar sperm was used as a model to investigate the relationships between mtDNA content, mitochondrial activity, and sperm motility. Motile and less motile sperm were separated by centrifugation on a discontinuous percoll density gradient. The contents and expression of mtDNA as well as mitochondrial activity and biosynthesis were determined to reveal possible mechanisms. Motile sperm showed less mitochondrial (P < 0.01) and mtDNA (P < 0.05) contents as compared to less motile sperm. Higher mitochondrial activity in motile sperm indicated by mitochondrial ultrastructure, higher mitochondrial transmembrane potential (P < 0.01), as well as higher mitochondrial respiratory chain complex I activity (P < 0.05). Moreover, more mitochondrial reactive oxygen species (P < 0.01) suggested higher mitochondrial biosynthesis in motile sperm. Although less mtDNA contents in motile sperm, accompanied by the higher expression of transcription factors, the level of mtDNA-encoded protein (cytochrome c oxidase subunit 1) which play pivotal role in OXPHOS was higher in motile sperm. The results are helpful to interpret why mtDNA-less sperm have higher mitochondrial activity and better motility. PMID- 27769574 TI - Carnitine supplementation decreases capacitation-like changes of frozen-thawed buffalo spermatozoa. AB - The aim of this study was to evaluate the effect of carnitine supplementation of semen extender on fertility parameters of frozen-thawed buffalo sperm. Buffalo semen was cryopreserved in BioXcell containing 0 (control group), 2.5 and 7.5-mM carnitine. After thawing, viability, motility, membrane integrity and capacitation status (assessed by localization of phosphotyrosine-containing proteins and chlortetracycline, chlortetracycline assay) were evaluated. Furthermore, total antioxidant capacity, reactive oxygen species (ROS) and lipid peroxidation levels, as well as adenosine triphosphate (ATP) content and phospholipids concentration were assessed. Finally, in vitro-fertilizing ability was evaluated after heterologous IVF. An increased post-thawing sperm motility and membrane integrity were recorded in both treated groups compared with the control (44.4 +/- 3.5, 53.1 +/- 3.9, and 52.5 +/- 3.6%; P < 0.05 and 48.44 +/- 0.69, 55.19 +/- 0.54, 59.63 +/- 0.30%; P < 0.01 with 0, 2.5-mM, and 7.5-mM carnitine, respectively). Supplementation of carnitine to the freezing extender decreased (P < 0.01) the percentage of sperm displaying fluorescence at both equatorial and anterior acrosomal regions (pattern EA), corresponding to high capacitation level, compared with the control (30.3 +/- 3.8, 18.8 +/- 2.8, and 7.2 +/- 2.9%, respectively, with 0, 2.5-mM, and 7.5-mM carnitine). In agreement with this, carnitine also decreased (P < 0.01) the percentage of sperm displaying chlortetracycline pattern B (capacitated sperm) (63.8 +/- 1.8, 46.8 +/- 2.2, and 37.2 +/- 1.8%, respectively with 0, 2.5-, and 7.5-mM carnitine). Interestingly, carnitine increased total antioxidant capacity and ATP content of buffalo frozen thawed sperm (1.32 +/- 0.02, 1.34 +/- 0.01, 1.37 +/- 0.01 mM/L and 4.1 +/- 0.1, 5.3 +/- 0.1 and 8.2 +/- 0.4 nM * 108 sperm; P < 0.01, respectively, with 0, 2.5- and 7.5-mM carnitine). Intracellular ROS decreased in carnitine-treated sperm compared with the control, as indicated by dihydroethidium (DHE) values (0.22 +/- 0.01, 0.18 +/- 0.01, and 0.14 +/- 0.0 MUM/100 MUL dihydroethidium, respectively, with 0, 2.5-, and 7.5-mM carnitine; P < 0.01), whereas lipid peroxidation levels (on average 30.5 +/- 0.3 nmol/mL MDA) and phospholipids concentration (on average 0.14 +/- 0.00 MUg/120 * 106 sperm) were unaffected. Despite the improved sperm quality, the percentage of normospermic penetration after IVF was not influenced (on average 53.5 +/- 1.8). In conclusion, enrichment of extender with carnitine improved buffalo sperm quality by increasing ATP generation and modulating ROS production, without affecting in vitro fertilizing ability. PMID- 27769575 TI - Characterization of interferon alpha and beta receptor IFNAR1 and IFNAR2 expression and regulation in the uterine endometrium during the estrous cycle and pregnancy in pigs. AB - Type I interferons (IFNs) bind to the heterodimeric receptor composed of IFN alpha/beta receptor 1 (IFNAR1) and IFN-alpha and beta receptor 2 (IFNAR2) to transmit signals into the cell. It is well known that IFN-delta (IFND), a type I IFN, is secreted by the conceptus during early pregnancy in pigs. However, expression and regulation of IFNAR1 and IFNAR2 in the porcine uterine endometrium are not well understood. Thus, we analyzed the expression and regulation of IFNAR1 and IFNAR2 in the uterine endometrium during the estrous cycle and pregnancy and conceptus and chorioallantoic tissues during pregnancy in pigs. The IFNAR1 and IFNAR2 mRNAs were expressed in the uterine endometrium, and their levels on Day 12 of pregnancy were higher than those on Day 12 of the estrous cycle and highest during pregnancy. The IFNAR1 and IFNAR2 mRNAs were also expressed in conceptuses during early pregnancy, in chorioallantoic tissues during mid-to-term pregnancy, and in endometrial epithelial cells and chorionic membrane during mid-to-late pregnancy. The abundance of IFNAR1 and IFNAR2 mRNAs was increased by interleukin-1beta (IL1B), and the abundance of IFNAR2 was increased by estradiol in endometrial tissue explants. Thus, IFNAR1 and IFNAR2 mRNAs were expressed in the uterine endometrium during the estrous cycle and pregnancy in a pregnancy status- and stage-specific manner, and their expression was affected by estradiol and/or IL1B. These results suggest that endometrial and conceptus IFNAR1 and IFNAR2 may mediate the action of type I IFNs during the implantation period for the establishment and maintenance of pregnancy in pigs. PMID- 27769576 TI - Survey of temperature, reaction time and ultrasound irradiation power on sonochemical synthesis of two new nanostructured lead(II) coordination supramolecule compounds. AB - Nanoparticles of two new 0D, lead(II) coordination supramolecular compounds, [Pb(L)2(I)2] (1) and [Pb(L)(L/)(H2O)].3H2O (2), (L=1,10-phenanthroline monohydrate, L/=2,6-pyridinedicarboxlic acid), have been synthesized by a sonochemical process and characterized by scanning electron microscopy (SEM), field emission scanning electron microscopy (FE-SEM), X-ray powder diffraction (XRPD), FT-IR spectroscopy and elemental analyses. The single crystal X-ray data of compounds show that the Pb ion is six coordinated in both 1 and 2. The thermal stability of compound 1 and 2 has been studied by thermal gravimetric (TG) and differential thermal analyses (DTA). The role of temperature, reaction time and ultrasound irradiation power on the size and morphology of the nano-structured compound obtained from 1 and 2, have been investigated. Results indicate that an increase of temperature and sonication power and a decrease in time reaction led to a decrease of particle size. Topological analysis shows that the compound 1 and 2 are new topology for net: 1,4M5-1 and nch, respectively. PMID- 27769577 TI - Improving the hydrolysis efficiency of soy sauce residue using ultrasonic probe assisted enzymolysis technology. AB - Ultrasonic probe-assisted enzymolysis technology was developed to improve the hydrolysis efficiency of soy sauce residue (SSR). The effects of enzyme type and enzymatic hydrolysis parameters on the hydrolysis degree of SSR were studied firstly to obtain the optimal enzymatic hydrolysis conditions. Then the effects of ultrasound on protease activity and structure of SSR were investigated to elucidate the acting mechanism of ultrasound. Finally, the ultrasonic-assisted enzymatic hydrolysis modes were designed and compared, and the hydrolysates from SSR were characterized to evaluate their further application. The results showed that a hydrolysis degree of 15.53% could be obtained under the optimum enzymolysis conditions: enzyme amount 6000U/g, pH 7.8, temperature 50 degrees C, the ratio of substrate to water phase 1:20, hydrolysis time 4h. Increasing ultrasound treatment time or power could reduce substrate size and consequently enhance the catalytic surface area. Prolonging ultrasound treatment time had a negative influence on enzyme activity, but low ultrasound power was helpful for increasing the enzyme activity. Ultrasound pretreatment of SSR followed by enzymatic hydrolysis increased the hydrolysis degree by 47.6%. When the ultrasound was applied directly to enzymolysis process, the hydrolysis degree of SSR exhibited an increase of 33.0%. The hydrolysates from SSR exhibited good antioxidant activities, and had a potential use as a functional ingredient in food or feed industry. PMID- 27769578 TI - Corrigendum to "A clinical trial designed to evaluate the safety and effectiveness of a thermosensitive hydrogel-type cultured epidermal allograft for deep second-degree burns" [Burns 40 (December (8)) (2014) 1642-1649]. PMID- 27769579 TI - Molecular structure and differential function of choline kinases CHKalpha and CHKbeta in musculoskeletal system and cancer. AB - Choline, a hydrophilic cation, has versatile physiological roles throughout the body, including cholinergic neurotransmission, memory consolidation and membrane biosynthesis and metabolism. Choline kinases possess enzyme activity that catalyses the conversion of choline to phosphocholine, which is further converted to cytidine diphosphate-coline (CDP-choline) in the biosynthesis of phosphatidylcholine (PC). PC is a major constituent of the phospholipid bilayer which constitutes the eukaryotic cell membrane, and regulates cell signal transduction. Choline Kinase consists of three isoforms, CHKalpha1, CHKalpha2 and CHKbeta, encoded by two separate genes (CHKA(Human)/Chka(Mouse) and CHKB(Human)/Chkb(Mouse)). Both isoforms have similar structures and enzyme activity, but display some distinct molecular structural domains and differential tissue expression patterns. Whilst Choline Kinase was discovered in early 1950, its pivotal role in the development of muscular dystrophy, bone deformities, and cancer has only recently been identified. CHKalpha has been proposed as a cancer biomarker and its inhibition as an anti-cancer therapy. In contrast, restoration of CHKbeta deficiency through CDP-choline supplements like citicoline may be beneficial for the treatment of muscular dystrophy, bone metabolic diseases, and cognitive conditions. The molecular structure and expression pattern of Choline Kinase, the differential roles of Choline Kinase isoforms and their potential as novel therapeutic targets for muscular dystrophy, bone deformities, cognitive conditions and cancer are discussed. PMID- 27769580 TI - Reproducibility of single-pass donor DSAEK tissue preparation with the MORIA single-use microkeratome. AB - PURPOSE: To assess the reproducibility of single-pass cutting for preparation of ultra-thin (<=120MUm) donor cornea grafts in Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: All consecutive patients of DSAEK performed using the MORIA One Use microkeratome (MORIA, Antony, France) in between June 2014 and August 2015. Patient and donor central corneal thickness (CTT), microkeratome head, remaining stromal bed thickness (RSBT), number of cut and graft thickness at 1 month and 6 months postoperatively were recorded in this single-center prospective study. RESULTS: The mean preoperative donor graft CCT was 569.0+/-45.1MUm and the mean donor endothelial graft CCT immediately after the cut was 116.5+/-28.7MUm. At 1 month postoperatively, the mean CCT was 102.8+/ 35.9MUm. At 6 months, the mean CCT was 89.4+/-26.2MUm. In all eyes, the mean CCT decreased from the post-cut (116.5+/-28.7MUm) to the last visit (89.4+/-26.2MUm) (P<0.01) due to in vivo deturgesence of the graft. We obtained 77.5% ultra-thin DSAEK immediately after the cut, 77.5% at 1 month and 89.8% after 6 months. CONCLUSION: Single-pass technique with the MORIA One Use microkeratome offers safe and reproducible DSAEK tissue preparation and allows achieving ultra-thin DSAEK in 89.8% of cases. PMID- 27769581 TI - [Fundus autofluorescence. Has it a place in the management of diabetic macular edema?] AB - PURPOSE: Analyze the characteristics of fundus autofluorescence of diabetic macular edema and study the association between these characteristics and visual function. PATIENTS AND METHODS: Our study included 18 patients (28 eyes) with clinically significant diabetic macular edema. All patients had a complete eye examination with a fundus autofluorescence imaging and optical coherence tomography. The central macular thickness and central macular volume were measured. The integrity of the inner segment-outer segment junction and the integrity of the external limiting membrane were also evaluated in the same area. RESULTS: Among the 28 eyes studied, 8 had normal autofluorescence. The remaining 20 eyes had abnormal autofluorescence: a hyper-cystoid autofluorescence in 5 eyes (25%), hyper-spot autofluorescence in 8 eyes (40%), and hypo-irregular autofluorescence in 5 eyes (25%). Best corrected visual acuity was significantly better in patients with normal autofluorescence and those with hyper-cystoid autofluorescence. There was no significant difference in central macular thickness (P=0.186) and central macular volume (P=0.191) between the four groups. CONCLUSION: The autofluorescence is a simple, fast, and non-invasive technique for the study of diabetic macular edema with good correlation to the visual function as well as to the extent of damage to the retina. It is, therefore, a possible alternative to other invasive imaging techniques in particular in the long term monitoring of diabetic macular edema. PMID- 27769582 TI - [Orbito-palpebral vascular pathology]. AB - Orbito-palpebral vascular pathology represents 10% of all the diseases of this area. The lesion may be discovered during a brain CT scan or MRI, or because it causes clinical symptoms such as orbital mass, visual or oculomotor alteration, pain, proptosis, or acute bleeding due to a complication of the lesion (hemorrhage, thrombosis). We present these lesions using an anatomical, clinical, imaging and therapeutic approach. We distinguish four different entities. Vascular tumors have common imaging characteristics (hypersignal on T2 sequence, contrast enhancement, abnormal vascularization well depicted with ultrasound and Doppler, and possible bleeding). The main lesions are cavernous hemangiomas, the most frequent lesion of that type during adulthood; infantile hemangiomas, the most frequent vascular tumor in children; and more seldomly, hemangioperitcytomas. True vascular malformations are divided according to their flow. Low flow lesions are venous (orbital varix), capillarovenous or lymphatic (lymphangioma). High flow malformations, more rare, are either arteriovenous or arterial malformations (aneurisms). Complex malformations include both low and high flow elements. Lesions leading to modifications of the orbito-palpebral blood flow are mainly due to cavernous sinus abnormalities, either direct carotid cavernous fistula affecting young adults after severe head trauma, or dural fistula, more insidious, found in older adults. The last section is devoted to congenital syndromic vascular malformations (Sturge-Weber, Rendu-Olser...). This classification allows for a better understanding of these pathologies and their specific imaging features. PMID- 27769583 TI - [Unilateral maculopathy in a young male patient: A photic laser injury]. AB - We report the case of a twenty-year-old man with a unilateral maculopathy responsible for an acute visual acuity loss and a sudden absolute central scotoma. His schizoid personality made the medical history fruitless. The patient's best corrected visual acuity was 20/60. Clinical examination revealed a strictly unilateral maculopathy with pigment remodeling and hyper-autofluorescent areas. Through this case report, we describe the characteristics of the lesion and the pathway to the diagnosis: a laser pointer-induced photic injury. PMID- 27769584 TI - Cataract Surgery in Children from Birth to Less than 13 Years of Age: Baseline Characteristics of the Cohort. AB - OBJECTIVE: To describe baseline characteristics, initial postoperative refractive errors, operative complications, and magnitude of the intraocular lens (IOL) prediction error for refractive outcome in children undergoing lensectomy largely in North America. DESIGN: Prospective registry study of children from birth to <13 years of age who underwent lensectomy for any reason within 45 days preceding enrollment. PARTICIPANTS: Total of 1266 eyes of 994 children; 49% female and 59% white. METHODS: Measurement of refractive error, axial length, and complete ophthalmic examination. MAIN OUTCOME MEASURES: Eye and systemic associated conditions, IOL style, refractive error, pseudophakic refraction prediction error, operative and perioperative complications. RESULTS: Mean age at first eligible lens surgery was 4.2 years; 337 (34%) were <1 year of age. Unilateral surgery was performed in 584 children (59%). Additional ocular abnormalities were noted in 301 eyes (24%). An IOL was placed in 35 of 460 eyes (8%) when surgery was performed before 1 year of age, in 70 of 90 eyes (78%) from 1 to <2 years of age, and in 645 of 716 eyes (90%) from 2 to <13 years of age. The odds of IOL implantation were greater in children >=2 years of age than in those <2 years of age (odds ratio = 29.1; P < 0.001; 95% confidence interval: 19.6-43.3). Intraoperative complications were reported for 69 eyes (5%), with the most common being unplanned posterior capsule rupture in 14 eyes, 10 of which had an IOL placed. Prediction error of the implanted IOL was <1.00 diopter in 54% of eyes, but >2.00 diopters in 15% of eyes. CONCLUSIONS: Lensectomy surgery was performed throughout childhood, with about two-thirds of cases performed after 1 year of age. Initial surgery seemed safe, with a low complication rate. IOL placement was nearly universal in children 2 years of age and older. The immediate postoperative refraction was within 1 diopter of the target for about one-half of eyes. PMID- 27769585 TI - Prediction of Postoperative Intraocular Lens Position with Angle-to-Angle Depth Using Anterior Segment Optical Coherence Tomography. AB - PURPOSE: To evaluate the accuracy of a new formula for predicting postoperative anterior chamber depth (ACD) with preoperative angle-to-angle (ATA) depth using anterior segment (AS) optical coherence tomography (OCT) and to compare it with established methods. DESIGN: Retrospective consecutive case series. PARTICIPANTS: Three hundred four eyes (276 patients) implanted with acrylic intraocular lenses (IOLs) were divided randomly into a training set (152 eyes) and a validation set (152 eyes). METHODS: Based on the training set data, the postoperative ACD measured 1 month after surgery was analyzed via multiple linear regression analysis with 5 preoperatively measured variables: ATA depth, ATA width, preoperative ACD measured with AS OCT, axial length (AL), and corneal power. A new regression formula for predicting postoperative ACD was developed using the results of the stepwise analysis. In the validation set data, the coefficients of determination (R2) between the measured postoperative ACD and the predicted postoperative ACD obtained using the new formula were compared with those obtained using the Sanders-Retzlaff-Kraff theoretic (SRK/T) and Haigis formulas. The absolute prediction errors were compared with each formula. MAIN OUTCOME MEASURES: Postoperative ACD, median absolute prediction error of postoperative ACD, and ocular biometric parameters. RESULTS: In the training set, ATA depth yielded the highest standard partial regression coefficient value, indicating that ATA depth is the most effective parameter for predicting postoperative ACD. The new regression formula was developed with 3 variables; ATA depth, preoperative ACD, and AL. In the validation set, the postoperative ACDs of the new formula, the SRK/T formula, and Haigis formula were predicted with R2 of 0.71, 0.36, and 0.55, respectively, and the medians of the absolute prediction errors were 0.10 mm, 0.65 mm, and 0.30 mm, respectively. The absolute prediction error with the new formula was significantly smaller than those obtained with the SRK/T and Haigis formulas (P < 0.0001). CONCLUSIONS: The new formula with 3 preoperative parameters-ATA depth, preoperative ACD, and AL-predicted postoperative ACD more accurately than the SRK/T and Haigis formulas. It may be possible to improve the accuracy of IOL power calculation using an improved postoperative ACD prediction with the ATA depth measured by AS OCT. PMID- 27769586 TI - Clinical and Ultrastructural Studies of Epiretinal Pigmentary Deposits after Retinectomy with Silicone Oil. AB - PURPOSE: Large relaxing retinectomies have become increasingly used in the repair of retinal detachment related to proliferative vitreoretinopathy (PVR). Retinectomies expose the retinal pigment epithelium (RPE) to the vitreous cavity; the direct effects of silicone oil on the RPE are only beginning to be understood. DESIGN: Retrospective case series. PARTICIPANTS: Twelve patients noted to develop pigmented epiretinal deposits at regularly scheduled follow-up visits after repair of complex retinal detachments using silicone oil tamponade and retinectomy. METHODS: Epiretinal pigment deposits were characterized clinically by wide-field color photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography (SD OCT). At the time of silicone oil removal, the pigmented membranes were preserved in fixative and analyzed by light microscopy/immunostaining or electron microscopy for histologic characterization. MAIN OUTCOME MEASURES: Not applicable. RESULTS: We describe the development of diffuse preretinal pigmentary deposits in 12 eyes after surgery for complicated PVR detachments using retinectomies with oil, with an average onset of 3.2 months postoperatively. These pigment clumps produced a striking leopard-spot pattern on fundus autofluorescence imaging. Histopathologic and ultrastructural analysis of these epiretinal proliferations peeled at the time of silicone oil removal revealed RPE cells with intracellular silicone oil droplets, singly dispersed membrane-bound melanin granules, glial tissue (1 case), and a fibrous stroma. CONCLUSIONS: Although in vitro studies have suggested that RPE cells can phagocytose emulsified oil droplets, this report represents the first in vivo documentation by electron microscopy of this phenomenon in patients. These findings underscore that direct contact with silicone oil may affect the behavior of the RPE, which may be clinically relevant in patients who have undergone large relaxing retinectomies with silicone oil tamponade for PVR related retinal detachments. PMID- 27769588 TI - Corrigendum to: "miR-20a mediates temozolomide-resistance in glioblastoma cells via negatively regulating LRIG1 expression" [Biomedicine & Pharmacotherapy (71), (2015) 112-118]. PMID- 27769587 TI - Deep Retinal Layer Microvasculature Dropout Detected by the Optical Coherence Tomography Angiography in Glaucoma. AB - PURPOSE: To investigate factors associated with dropout of the parapapillary deep retinal layer microvasculature assessed by optical coherence tomography angiography (OCTA) in glaucomatous eyes. DESIGN: Cross-sectional study. PARTICIPANTS: Seventy-one eyes from 71 primary open-angle glaucoma (POAG) patients with beta-zone parapapillary atrophy (betaPPA) enrolled in the Diagnostic Innovations in Glaucoma Study. METHODS: Parapapillary deep-layer microvasculature dropout was defined as a complete loss of the microvasculature located within the deep retinal layer of the betaPPA from OCTA-derived optic nerve head vessel density maps by standardized qualitative assessment. Circumpapillary vessel density (cpVD) within the retinal nerve fiber layer (RNFL) also was calculated using OCTA. Choroidal thickness and presence of focal lamina cribrosa (LC) defects were determined using swept-source optical coherence tomography. MAIN OUTCOME MEASURES: Presence of parapapillary deep-layer microvasculature dropout. Parameters including age, systolic and diastolic blood pressure, axial length, intraocular pressure, disc hemorrhage, cpVD, visual field (VF) mean deviation (MD), focal LC defects betaPPA area, and choroidal thickness were analyzed. RESULTS: Parapapillary deep-layer microvasculature dropout was detected in 37 POAG eyes (52.1%). Eyes with microvasculature dropout had a higher prevalence of LC defects (70.3% vs. 32.4%), lower cpVD (52.7% vs. 58.8%), worse VF MD (-9.06 dB vs. -3.83 dB), thinner total choroidal thickness (126.5 MUm vs. 169.1 MUm), longer axial length (24.7 mm vs. 24.0 mm), larger betaPPA (1.2 mm2 vs. 0.76 mm2), and lower diastolic blood pressure (74.7 mmHg vs. 81.7 mmHg) than those without dropout (P < 0.05, respectively). In the multivariate logistic regression analysis, higher prevalence of focal LC defects (odds ratio [OR], 6.27; P = 0.012), reduced cpVD (OR, 1.27; P = 0.002), worse VF MD (OR, 1.27; P = 0.001), thinner choroidal thickness (OR, 1.02; P = 0.014), and lower diastolic blood pressure (OR, 1.16; P = 0.003) were associated significantly with the dropout. CONCLUSIONS: Systemic and ocular factors including focal LC defects more advanced glaucoma, reduced RNFL vessel density, thinner choroidal thickness, and lower diastolic blood pressure were factors associated with the parapapillary deep-layer microvasculature dropout in glaucomatous eyes. Longitudinal studies are required to elucidate the temporal relationship between parapapillary deep layer microvasculature dropout and systemic and ocular factors. PMID- 27769589 TI - Healthcare professionals' assertions and women's responses during labour: A conversation analytic study of data from One born every minute. AB - OBJECTIVE: Communication during labour is consequential for women's experience yet analyses of situated labour-ward interaction are rare. This study demonstrates the value of explicating the interactional practices used to initiate 'decisions' during labour. METHODS: Interactions between 26 labouring women, their birth partners and HCPs were transcribed from the British television programme, One Born Every Minute. Conversation analysis was used to examine how decisions were initiated and accomplished in interaction. FINDINGS: HCPs initiate decision-making using interactional practices that vary the 'optionality' afforded labouring women in the responsive turn. Our focus here is on the minimisation of optionality through 'assertions'. An 'assertive' turn-design (e.g. 'we need to...') conveys strong expectation of agreement. HCPs assert decisions in contexts of risk but also in contexts of routine activities. Labouring women tend to acquiesce to assertions. CONCLUSION: The expectation of agreement set up by an assertive initiating turn can reduce women's opportunities to participate in shared decision-making (SDM). PRACTICE IMPLICATIONS: When decisions are asserted by HCPs there is a possible dissonance between the tenets of SDM in British health policy and what occurs in situ. This highlights an educational need for HCPs in how best to afford labouring women more optionality, particularly in low-risk contexts. PMID- 27769590 TI - The utility of lupus serology in predicting outcomes of renal transplantation in lupus patients: Systematic literature review and analysis of the Toronto lupus cohort. AB - OBJECTIVES: To study the utility of lupus serology as a predictor for kidney graft outcome in (a) a systematic literature review (SLR) and (b) the Toronto lupus cohort (TLC). METHODS: For the SLR, a comprehensive literature search was performed to identify the articles reporting on the serology at renal transplantation (RT) and on the outcome of RT. Studies were critically appraised using the Newcastle Ottawa Scale (NOS). Patients who underwent RT in the TLC were identified and grouped into graft failure and graft survival. The serology in both groups was studied. RESULTS: Of the 749 references, 742 did not have serological status of the patient or were not relevant to the research question. Seven studies in addition to TLC (n = 76) were included in the SLR. The NOS revealed limitations because of small sample size and a short follow-up period. The majority of the grafts survived to at least 1 year regardless of the serology results pre-transplant which is consistent with results of the TLC. Overall, 32 of 1783 patients in the TLC had a RT. In all, 2 patients had a nonfunctional graft, 5 patients had graft failure, and 25 patients had graft survival. Overall, 40% of the graft failures had positive serology compared to 52% in the graft survival, 1 year prior to RT. CONCLUSION: The results of this SLR found that the persistence of serological abnormalities at the time of RT was not associated with graft failure. These results are consistent with the results of the TLC. PMID- 27769591 TI - Pegloticase failure and a possible solution: Immunosuppression to prevent intolerance and inefficacy in patients with gout. AB - INTRODUCTION: Pegloticase is a highly effective therapy for patients with refractory and/or tophaceous gout, but has a high discontinuation rate (30-50%) due to development of anti-drug antibodies causing loss of efficacy and risk of infusion reactions. OBJECTIVE: To describe the use of azathioprine or other immunosuppressive therapies as a pegloticase adjunct to prevent pegloticase immunogenicity when treating gout. METHODS: Case report of azathioprine use in a patient receiving pegloticase therapy for refractory tophaceous gout, and review of the literature for the impact of immunosuppressive agents on development of anti-drug antibodies. RESULTS: A 56-year-old man with severe refractory tophaceous gouty arthritis was placed on low-dose azathioprine (50mg daily) in combination with pegloticase, with successful treatment after 98 weeks illustrated by significant improvement of caliper-measured tophi (77% decrease), resolution of gouty attacks, maintenance of low serum urate (sUA) level, absence of infusion reactions, and good toleration of the treatment by the patient. Two transient increases in sUA (maximal sUA 1.0 and 6.2mg/dL, respectively), were associated with azathioprine non-compliance and resolved with azathioprine reinstitution. Literature review confirmed successful use of DMARDs for prevention of anti-drug antibodies to anti-TNF-alpha therapies in RA, spondyloarthropathies, and inflammatory bowel disease. Additionally, one open label trial of pegloticase for refractory tophaceous gout included 7 organ transplant recipients on immunosuppressive medications (mycophenolate mofetil, cyclosporine, azathioprine, and/or tacrolimus), only one of whom (14%) was noted to experience treatment failure (anti-pegloticase antibodies and loss of urate lowering efficacy without infusion reaction), versus 52% (n =12) of non immunosuppressed subjects (n = 23). CONCLUSIONS: Low doses of oral immunosuppressive therapy may provide a safe, cost-effective adjunct to prevent the development of anti-drug antibodies associated with infusion reactions and high rate of pegloticase failure in patients with refractory gout. Controlled studies to assess an immunosuppressive strategy when using pegloticase are warranted. PMID- 27769593 TI - Viscoelastic properties of orthodontic adhesives used for lingual fixed retainer bonding. AB - OBJECTIVE: To evaluate the viscoelastic properties of two experimental BPA-free and one BisGMA-based orthodontic resin composite adhesives for bonding fixed retainers. METHODS: A commercially available BisGMA-based (TXA: Transbond LR) and two bisphenol A-free experimental adhesives (EXA and EXB) were included in the study. The viscoelastic behavior of the adhesives was evaluated under static and dynamic conditions at dry and wet states and at various temperatures (21, 37, 50 degrees C). The parameters determined were shear modulus (G), Young's modulus (E) under static testing and storage modulus (G1), loss tangent (tandelta) and dynamic viscosity (n*) under dynamic testing. Statistical analysis was performed by 2-way ANOVA and Bonferroni post-hoc tests (alpha=0.05). RESULTS: For static testing, a significant difference was found within material and storage condition variables and a significant interaction between the two independent variables (p<0.001 for G and E). EXA demonstrated the highest G and E values at 21 degrees C/dry group. Dry specimens showed the highest G and E values, but with no significant difference from 21 degrees C/wet specimens, except EXA in G. Wet storage at higher temperatures (37 degrees C and 50 degrees C) adversely affected all the materials to a degree ranging from 40 to 60% (p<0.001). For dynamic testing, a significant difference was also found in material and testing condition groups, with a significant interaction between the two independent variables (p<0.001 for G1 and n*, p<0.01 for tandelta). Reduction in G1, and n* values, and increase in tandelta values were encountered at increased water temperatures. SIGNIFICANCE: The apparent detrimental effect of high temperature on the reduction of properties of adhesives may contribute to the loss of stiffness of the fixed retainer configuration under ordinary clinical conditions with unfavorable effects on tooth position and stability of the orthodontic treatment result. PMID- 27769592 TI - Defining the optimal biological monotherapy in rheumatoid arthritis: A systematic review and meta-analysis of randomised trials. AB - OBJECTIVES: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800. RESULTS: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naive", and 20 "DMARD-Inadequate responder" (DMARD IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068). CONCLUSIONS: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients' preferences and values in the final treatment choice. PMID- 27769594 TI - Financial and Nonfinancial (Allegiance) Conflicts of Interest in Clinical Research. PMID- 27769595 TI - Random Effects: Variance Is the Spice of Life. AB - Covariates in regression analyses allow us to understand how independent variables of interest impact our dependent outcome variable. Often, we consider fixed effects covariates (e.g., gender or diabetes status) for which we examine subjects at each value of the covariate. We examine both men and women and, within each gender, examine both diabetic and nondiabetic patients. Occasionally, however, we consider random effects covariates for which we do not examine subjects at every value. For example, we examine patients from only a sample of hospitals and, within each hospital, examine both diabetic and nondiabetic patients. The random sampling of hospitals is in contrast to the complete coverage of all genders. In this column I explore the differences in meaning and analysis when thinking about fixed and random effects variables. PMID- 27769596 TI - Vaccine development: From concept to early clinical testing. AB - In the 21st century, an array of microbiological and molecular allow antigens for new vaccines to be specifically identified, designed, produced and delivered with the aim of optimising the induction of a protective immune response against a well-defined immunogen. New knowledge about the functioning of the immune system and host pathogen interactions has stimulated the rational design of vaccines. The design toolbox includes vaccines made from whole pathogens, protein subunits, polysaccharides, pathogen-like particles, use of viral/bacterial vectors, plus adjuvants and conjugation technology to increase and broaden the immune response. Processes such as recombinant DNA technology can simplify the complexity of manufacturing and facilitate consistent production of large quantities of antigen. Any new vaccine development is greatly enhanced by, and requires integration of information concerning: 1. Pathogen life-cycle & epidemiology. Knowledge of pathogen structure, route of entry, interaction with cellular receptors, subsequent replication sites and disease-causing mechanisms are all important to identify antigens suitable for disease prevention. The demographics of infection, specific risk groups and age-specific infection rates determine which population to immunise, and at what age. 2. Immune control & escape. Interactions between the host and pathogen are explored, with determination of the relative importance of antibodies, T-cells of different types and innate immunity, immune escape strategies during infection, and possible immune correlates of protection. This information guides identification and selection of antigen and the specific immune response required for protection. 3. Antigen selection & vaccine formulation. The selected antigen is formulated to remain suitably immunogenic and stable over time, induce an immune response that is likely to be protective, plus be amenable to eventual scale-up to commercial production. 4. Vaccine preclinical & clinical testing. The candidate vaccine must be tested for immunogenicity, safety and efficacy in preclinical and appropriately designed clinical trials. This review considers these processes using examples of differing pathogenic challenges, including human papillomavirus, malaria, and ebola. PMID- 27769597 TI - Robot-assisted radical cystoprostatectomy: Analysis of the complications and oncological and functional aspects. AB - OBJECTIVES: To review our experience in robot-assisted radical cystectomy, assessing the complications and oncological and functional results. MATERIALS AND METHODS: From 2007 to 2014, we performed 67 robot-assisted radical cystectomies combined with lymphadenectomy in 61 cases. The operations were performed on 37 patients due to muscle-invasive tumours and on 30 due to high-risk nonmuscle invasive tumours. Urinary diversion was conducted extracorporeally, using a Studer neobladder in 47 cases. RESULTS: The mean blood loss was 300mL. No case required conversion to open surgery. The median number of lymph nodes extracted was 16 (range 3-33). Pathology revealed 16 pT0, 15 pTis,-pT1-pTa and 44 muscle invasive tumours, 8 pN+ and 1 with positive margins. The mean hospital stay was 9 days. With a median follow-up of 16 months, 9 (13%) patients were readmitted after the discharge, most for infections associated with the vesical catheter and other catheters. Forty patients (59.7%) presented complications (most were Clavien grade 1-2). There was recurrence during the follow-up in 4 cases (6%), and 4 (5.9%) patients died from cancer. Nineteen (28.3%) patients had complications after 30 days, most of which were urinary tract infections. Of the 47 patients with a neobladder, 45 (96%) had proper daytime continence and 42 (89%) had proper nighttime continence. Ninety percent and 64% of the patients with previously normal sexual function and reduced sexual function, respectively, were able to preserve sexual function with or without drug treatment. CONCLUSIONS: Robot-assisted radical cystectomy plus lymphadenectomy, with extracorporeal reconstruction of the urinary diversion, offers good oncological and functional results without increasing the number of complications. PMID- 27769599 TI - Traumatic intratumoral hemorrhage of schwannoma of the cauda equina: A report of two cases. PMID- 27769598 TI - Statement on the current treatment of severe obesity in Spain. PMID- 27769600 TI - Lesser tuberosity cysts and their relationship with subscapularis tears and subcoracoid impingement. AB - BACKGROUND: We aimed to evaluate cysts in the lesser tuberosity of humeral head seen on magnetic resonance imaging (MRI) and their relationship with subcoracoid impingement and subscapularis tears evident on arthroscopic surgery videos. Our hypothesis was that the cysts would be more frequent with subscapularis tears and in the case of subcoracoid impingement. METHODS: Patients who underwent shoulder arthroscopy between January 2010 and January 2016 were retrieved to evaluate subscapularis tears on surgery videos and lesser tuberosity cysts (LTC), coracohumeral distances (CHD) on both sagittal oblique and transverse sections of MRI retrospectively. There were 137 patients meeting the study criteria with subscapularis tear evident on surgery video and having preoperatively studied magnetic resonance images. All the tears were classified according to the Lafosse's system. The control group was constituted with 121 patients who underwent shoulder arthroscopy and were diagnosed with no subscapularis tear. Then, any statistically significant relationship between these parameters was investigated by the use of statistics software. RESULTS: The mean age (57), gender distribution (female for 67.1%), and involved shoulder (right for 62.8%) rate of the groups were statistically similar. The existence rate of LTC was 55.5% and 19% for the study and control groups, respectively (P = .000). The study group was then evaluated in two groups regarding the existence of a cyst in the lesser tuberosity. There was no statistical difference between these two groups in terms of coracohumeral distances and tear type (P > .05). The study group was also divided into two depending on the transverse section CHD whether it was under 7 mm or not. There was still no statistical difference between these subgroups in terms of a cyst existence (P > .05). The supraspinatus tear rate and age distribution was also not differing in patients with and without LTC. CONCLUSIONS: The LTCs were significantly associated with subscapularis tears, and could be used as an indicator in the interpretation of MRI scans. However, there was no relationship between the subcoracoid impingement and LTCs. PMID- 27769601 TI - Radiographic evaluation of vessel count and density with quantitative magnetic resonance imaging during external breast expansion in Asian women: A prospective clinical trial. AB - BACKGROUND: Breast augmentation with fat transfer does not bear the risks associated with silicone implantation. The method can potentially be especially useful in Asian women, who often reject augmentation mammoplasty with implants. This prospective clinical trial evaluated the effects of external breast expansion on breast density and vessel count using magnetic resonance imaging. METHODS: Thirty-four enrolled patients were instructed to apply one of two devices, the conventional BRAVA device (used in the AESTES trial) or a novel external expansion device (EVERA) designed for Asian women, continuously for 8 h per day for 12 weeks. For external expansion, the pressure was set to 25 mmHg. Follow-up examinations were performed for 4 weeks after completion of the expansion. The ratio between the fibroglandular and adipose tissues of the breast was measured using T1-weighted MRI, and the number of vessels in the breast tissue was determined before and after the treatment by contrast MRI. Additionally, the volume of the breast was measured by laser scanning before, during, and after the device application. The obtained measurements were compared within and between the groups at different time points. RESULTS: Six patients dropped out, while 28 completed the trial without major side effects or adverse events. External expansion significantly increased breast vessel count in both the EVERA and AESTES groups (p = 0.019, p = 0.022). However, it did not significantly change breast density in either group (p = 0.186, p = 0.638). No significant intergroup differences were noted in vessel count (p = 0.874) or density (p = 0.482). Breast volume increases after 12 weeks of application were statistically significant in both groups, with mean changes of 81 +/- 22 cc (AESTES) and 98 +/- 30 cc (EVERA) (p < 0.001 in both cases). CONCLUSIONS: External expansion resulted in a marked increase in breast vessel count but did not affect breast density. The observed increase in breast volume can be considered substantial for Asian women. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27769602 TI - Corrigendum to "Long-term functional outcome and patient satisfaction after ulnar head resection" [J Plast Reconstr Aesthet Surg 69 (2016), 1417-1423]. PMID- 27769603 TI - Long-term sensory disturbances after orbitozygomatic fractures. AB - BACKGROUND: Orbitozygomatic fractures often lead to infraorbital nerve (ION) injury, and affected sensibility is a common long-term complaint within this patient group. We present a long-term follow-up study where the validated von Frey filament system was used for testing ION sensibility. Furthermore, we examined the incidence of persistent nerve injury and whether more complex fractures led to more pronounced ION sensibility disturbances. METHODS: Patients treated for facial fractures involving the orbitozygomatic complex were included and the follow-up time was 3 years or more. Depending on the location and severity of the fractures, the patients were divided into 4 groups. The patients answered a questionnaire before ION sensibility testing with von Frey filaments. RESULTS: Eighty-one patients were examined: 65 males (80%) and 16 females (20%). Examinations were conducted between 3.0 and 7.6 years (mean 4.9 years) after injury. Sixteen patients (20%) had affected and 6 patients (7.4%) had severely affected ION sensibility according to von Frey testing. No statistically significant differences were found in terms of questionnaire score between the groups. There was also no statistically significant correlation between questionnaire results and log von Frey values. Although the effect of groups could not be statistically verified using the log von Frey values, a larger proportion of patients with complex fractures had higher log von Frey values than the other groups. CONCLUSIONS: Patients with complex fractures report more permanent sensory disturbance of the ION after surgery than those with isolated orbitozygomatic fractures, although this could not be verified statistically with von Frey filament testing at several locations. Hence, a validated method for testing facial sensibility such as von Frey filaments, although sensitive, is inadequate to determine all aspects of sensory malfunction after orbitozygomatic fractures. This suggests that the patient's experience of long-term sensation after trauma may not be correlated with objective measures. PMID- 27769604 TI - A randomised comparison of neurotmesis using scissors or a razor blade for sural nerve graft harvest. PMID- 27769605 TI - Intratissular expansion-mediated, serial fat grafting: A step-by-step working algorithm to achieve 3D biological harmony in autologous breast reconstruction. AB - BACKGROUND: Breast reconstruction involves the use of autologous tissues or implants. Occasionally, microsurgical reconstruction is not an option because of insufficient donor tissues. Fat grafting has become increasingly popular in breast surgery. The challenge with this technique is how to reconstruct a stable and living "scaffold" that resembles a breast. METHODS: Breast reconstruction (n = 7) was performed using intratissular expansion with serial deflation lipofilling sessions. Mean age of the patients was 41 years (22-53). The expander generated a vascularized capsule at 8 weeks, which demarcated a recipient site between the skin and the capsule itself, and functioned as a vascular source for angiogenesis. Serial sessions of deflation and lipofilling were initiated at 8 weeks with removal of the expander at the completion of the treatment. An average of 644 ml (range, 415 ml-950 ml) of lipoaspirate material was injected to reconstruct the breast mound. An average of 4 (range, 3 to 5) fat-grafting sessions with a 3-month interval was needed to achieve symmetry with the contralateral breast. The average follow-up was 14 months (range, 9-29 months). MRI examination was performed at 8 months to analyze tissue survival and the residual volume. RESULTS: MRI examination retained tissue survival and the mean reconstructed breast volume was 386 ml (range, 231 ml-557 ml). An aesthetically pleasant breast mound was created, with a high satisfaction rate. CONCLUSION: We could reconstruct an aesthetically pleasant and stable breast mound in a selected group of patients by using intratissular expansion and fat grafting. PMID- 27769606 TI - Predicting late enophthalmos: Differences between medial and inferior orbital wall fractures. AB - INTRODUCTION: The purpose of this study was to compare the strength of the relationships between predictors and late-onset enophthalmos in medial and inferior orbital wall fractures and to determine the most significant predictive factor of enophthalmos in medial or inferior orbital wall fracture. METHODS: Sixty-three adult patients with unilateral medial or inferior orbital wall fracture who had been left untreated for more than two months were enrolled in this study. Patients who had accompanying multiple orbital wall fractures and those with orbital-zygomatic fractures were excluded. Orbital defect area and herniated muscle and fat volumes were evaluated using computed tomography. The degree of enophthalmos was measured using a Hertel exophthalmometer. RESULTS: Herniated muscle and fat volumes were positively correlated with defect area in the medial orbital wall fracture but showed no positive correlation with inferior orbital wall fracture. In the medial orbital wall fracture group, enophthalmos was positively correlated with defect area and herniated muscle and fat volumes. Defect area was more highly related to enophthalmos than other analyzed metrics. The defect area predictive of enophthalmos was 1.98 cm2. However, enophthalmos was positively correlated only with herniated fat volume in inferior orbital wall fracture. The herniated fat volume predictive of enophthalmos was 343.50 mm3. CONCLUSION: Orbital defect area in medial orbital wall fracture and herniated fat volume in inferior orbital wall fracture were the most significant predictors of late-onset enophthalmos. PMID- 27769607 TI - Determinants of crease width in inherent double eyelid of Asian young women. AB - BACKGROUND: The creation of a superior palpebral crease has been the most popular plastic surgery procedure in Asians for several decades. The most important criterion for judging the success of this procedure is the achievement of the desired size and shape of this crease or the perfect crease width. However, the determinants of crease width remain unclear, which may account for the high rate of unsatisfactory results. METHODS: Standard images were used to study the anatomic parameters, including crease width, crease height, and upper eyelid movement distance (ULMD) at the midpupillary axis, of the inherent double eyelid crease in 32 Chinese women aged 19-26 years. The thickness of the eyelid tissue at 5, 7.5, 10, and 15 mm from the lid margin was measured in the oblique sagittal direction by magnetic resonance imaging (MRI) at the central axis of the optic nerve. Multiple linear regression was used to analyze the relationship between crease width and crease height, ULMD, and eyelid thickness. RESULTS: Multiple linear regression revealed that crease height, crease thickness, and ULMD were significantly associated with crease width (partial regression coefficients: 0.67, -0.33, and -0.29 respectively). The determination coefficient R2 was 0.667 in the regression model, and the result of analysis of variance (ANOVA) showed that the regression model was significant (F = 16.04, p = 0.000). CONCLUSIONS: In performing upper blepharoplasty, it is important to consider eyelid thickness and movement distance of the upper eyelid margin rather than relying on crease height alone. Attention to these factors will help to achieve the desired size and shape of the crease. PMID- 27769608 TI - Variability in Outcome Reporting for Operatively Managed Anterior Glenohumeral Instability: A Systematic Review. AB - PURPOSE: The purpose of this study was to quantify the degree of variability in outcomes assessed after surgery for anterior shoulder instability in recent high impact literature. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, an extensive review of the literature during a 5-year period from January 2011 through December 2015 was performed across 6 orthopaedic journals with high impact factors to identify all studies investigating outcomes after anterior shoulder instability. Studies reporting clinical outcomes for patients with anterior glenohumeral instability after surgical treatment with at least 1-year follow-up were included. Several metrics were collected from each manuscript: (1) range of motion (ROM), (2) quantitative strength, (3) physical examination testing, (4) imaging, (5) patient-reported outcomes (PROs), (6) complications (including recurrent instability), (7) patient satisfaction, and (8) return to preinjury level of activity or sport. Variability in outcome measures was then qualitatively assessed. RESULTS: Sixty-eight studies were included for final analysis ranging from Level I to IV evidence. Fifty-nine percent reported ROM, and 18% measured strength. Other clinical exam maneuvers were assessed in 44%, with 40% assessing apprehension. Imaging was used in 62%, including X-rays, magnetic resonance imaging, and computed tomography scans. On average, 2.25 PROs were assessed. In total, 28 different PROs were used to assess outcomes. The 3 most commonly reported PROs were the Rowe scale at 46%, the Western Ontario Shoulder Instability Index at 31%, and the Constant Shoulder Score at 26%. Twenty-five percent included patient satisfaction in their assessment of outcomes. Recurrence was assessed by 59%, and return to preinjury level of activity was reported by 37% of the studies. CONCLUSIONS: There is substantial variability in outcome reporting for high-impact anterior shoulder instability literature with 28 different outcome tools used, making it difficult to compare outcomes between studies. Agreeing upon a uniform measure to assess outcomes would allow for clearer interpretation of the literature as well as the potential to draw conclusions from pooled data. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies. PMID- 27769609 TI - Sedentary Time, Cardiorespiratory Fitness, and Cardiovascular Risk Factor Clustering in Older Adults--the Generation 100 Study. AB - OBJECTIVE: To determine whether meeting physical activity (PA) recommendations and/or having high age-specific cardiorespiratory fitness (CRF) attenuate the adverse effect of prolonged sedentary time on cardiovascular risk factor (CV-RF) clustering in older adults. PATIENTS AND METHODS: We conducted a cross-sectional study of Norwegian women (495) and men (379) aged 70 to 77 years from August 22, 2012, through June 30, 2013. Sedentary time and PA were assessed by accelerometers and CRF by directly measured peak oxygen uptake (VO2peak). Logistic regression was used to estimate adjusted odds ratios (ORs) and CIs for the association between sedentary time and prevalence of CV-RF clustering (>=3 of the following: hypertension, high blood glucose level, high waist circumference, low high-density lipoprotein cholesterol level, or high triglyceride level) and for the modifying effect of PA and CRF. RESULTS: Overall, 163 of the 495 women (32.9%) and 140 of the 379 men (36.9%) had CV-RF clustering. Each additional hour of sedentary time was associated with 22% (OR, 1.22; 95% CI, 1.02-1.45) and 27% (OR, 1.27; 95% CI, 1.04-1.55) higher likelihood of having CV-RF clustering in women and men, respectively, whereas a 1-metabolic equivalent decrement in VO2peak corresponded to 57% (OR, 1.57; 95% CI, 1.34-1.84) and 67% (OR, 1.67; 95% CI, 1.44-1.95) higher likelihood of CV-RF clustering in women and men, respectively. High CRF (VO2peak >27.5 mL/kg per minute in women and >34.4 mL/kg per minute in men) attenuated the adverse effects of high sedentary time on CV-RF clustering, even among individuals not meeting recommendations for PA. CONCLUSION: High age-specific CRF fully attenuates the adverse effect of prolonged sedentary time on CV-RF clustering, independent of meeting the PA consensus recommendation in older adults. PMID- 27769610 TI - Metabolic Syndrome and the Risk of Ischemic Stroke. AB - BACKGROUND: Metabolic syndrome (MetS) is recently proposed as a predictor for the occurrence of vascular defects causing ischemic stroke. However, details on the association of MetS with stroke are scare in our region. The present study aimed to assess the predictive value of MetS and its components for stoke among the Iranian population. METHODS: A longitudinal population-based study was conducted on adults aged 35 years or older who were living in 3 districts in central part of Iran and followed for 10 years. Stroke was diagnosed using World Health Organization guidelines, and MetS was defined according to the Adult Treatment Panel-III definition. RESULTS: Among the 5398 subjects, 2021 suffered from MetS with an incidence of 37.4%. The incidence rates of stroke in those with and without MetS were 2.6% and 1.1%, respectively, with a higher significance in the former group (P = .026). Compared to the controls, participants with stroke exhibited a higher prevalence of some components of MetS including hyperglycemia and hypertension. On Cox proportional hazard analysis, the hazard ratio for a long-term risk of ischemic stroke was 1.37 overall (95% confidence interval: 1.15 1.63, P < .001) in subjects with MetS. Considering different components of MetS, hyperglycemia (hazard ratio = 1.83, P = .011) and hypertension (1.74, P = .019) could effectively predict occurrence of long-term ischemic stroke. CONCLUSION: MetS and its main components can be potent predictors for long-term ischemic stroke. Thus, the focus should be on identification and appropriate control of MetS components to prevent stroke occurrence. PMID- 27769611 TI - Quantifying the Risk of Spinal Injury in Motor Vehicle Collisions According to Ambulatory Status: A Prospective Analytical Study. AB - BACKGROUND: The association between ambulation at the scene of a motor vehicle collision (MVC) and spinal injury has never been quantified. OBJECTIVE: To evaluate the association between ambulation and spinal injury in patients involved in a MVC. METHODS: Prospective analytical-observational cohort study. Inclusion: patients sustaining traumatic injury in a MVC. Exclusion: < 18 years old, pregnancy. PRIMARY OUTCOME: spinal injury defined as injury to the cervical, thoracic, or lumbar spinal cord, bones, or ligaments. Secondary outcome: Injury resulting in neurological deficit, need for surgery, or death. A generalized linear model was used to evaluate the association between outcome and predictor variables. Risk ratios [RR] were reported with a point estimate and 95% confidence interval (CI). A two-tailed alpha of < 0.05 was the threshold for statistical significance. RESULTS: There were 704 patients analyzed. Nonambulatory patients were 2.29 times more likely to sustain a spinal injury, compared to ambulatory patients (RR 2.29, 95% CI 1.34-3.91). Patients >= 65 years of age were 3.27 times more likely to sustain a spinal injury (RR 3.27, 95% CI 1.66-6.45). Patients with a Glasgow Coma Scale score <= 8 were 4.93 times more likely to sustain a spinal injury (RR 4.93, 95% CI 1.86-13.10). CONCLUSION: In this prospective analytical-observational study evaluating the association between ambulatory status and spinal injury in patients involved in MVCs, we observed that those patients who were nonambulatory were more than two times as likely to have a spinal injury compared to those patients who were ambulatory at the scene. PMID- 27769612 TI - An Unusual Cause of Abdominal Pain. PMID- 27769614 TI - Allergic Reaction to Ketamine as Monotherapy for Procedural Sedation. AB - BACKGROUND: Ketamine is a cyclohexamine derivative that acts as a noncompetitive N-methyl D-aspartate receptor antagonist. Its use for procedural sedation is recommended by national clinical policy. However, its immunogenic potential is not well documented. CASE REPORT: We report a case of allergic reaction associated with the administration of intravenous ketamine for procedural sedation in a 16-year-old male. Minutes after administration, the patient developed a morbilliform, erythematous rash that extended to the upper and lower torso and resolved with intravenous diphenhydramine. It is most likely that this allergic reaction was caused by a ketamine-induced histamine release that has been described in vitro. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This is the first case report in which ketamine was used as monotherapy in the emergency department for the facilitation of procedural sedation that resulted in an allergic reaction. Supportive measures, including advanced airway procedures and hemodynamic support, may be necessary in more severe anaphylactic cases. Providers should be aware of this potential adverse effect when using ketamine for procedural sedation. PMID- 27769613 TI - Synthetic Cannabinoid Abuse Resulting in ST-Segment Elevation Myocardial Infarction Requiring Percutaneous Coronary Intervention. AB - BACKGROUND: Synthetic cannabinoids (SC) are recreational designer drugs intended to mimic delta-9-tetrahydrocannabinol while surreptitiously circumventing classification by the Drug Enforcement Administration. CASE REPORT: A 50-year-old black male arrived in the Emergency Department transported by Emergency Medical Services (EMS) for altered mental status after complaining of chest pain associated with smoking SCs. EMS found the patient with an empty foil pack labeled "Scooby Snax Limited Edition Blueberry Potpourri." The patient was somnolent, but became agitated when stimulated and complained of chest pain. Vital signs were blood pressure 87/52 mm Hg and pulse 52 beats/min. The electrocardiogram demonstrated an inferior wall myocardial infarction. Coronary angiography identified an occluded obtuse marginal second branch that was successfully opened with a drug-eluting stent. The patient recovered uneventfully. Urine drug screen was negative for cocaine, and gas chromatography/mass spectrometry testing of the smoked material identified PB-22 and AMB-FUBINACA as the active ingredients. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians and cardiologists need to be aware that the mechanism of action of synthetic cannabinoids on the endocannabinoid system may result in acute ST-segment elevation myocardial infarction requiring percutaneous coronary intervention. PMID- 27769615 TI - Is a Prehospital Treat and Release Protocol for Opioid Overdose Safe? AB - BACKGROUND: The current standards for domestic emergency medical services suggest that all patients suspected of opioid overdose be transported to the emergency department for evaluation and treatment. This includes patients who improve after naloxone administration in the field because of concerns for rebound toxicity. However, various emergency medical services systems release such patients at the scene after a 15- to 20-min observation period as long as they return to their baseline. OBJECTIVES: We sought to determine if a "treat and release" clinical pathway is safe in prehospital patients with suspected opioid overdose. RESULTS: Five studies were identified and critically appraised. From a pooled total of 3875 patients who refused transport to the emergency department after an opioid overdose, three patient deaths were attributed to rebound toxicity. These results imply that a "treat and release" policy might be safe with rare complications. A close review of these studies reveals several confounding factors that make extrapolation to our population limited. CONCLUSION: The existing literature suggests a "treat and release" policy for suspected prehospital opioid overdose might be safe, but additional research should be conducted in a prospective design. PMID- 27769616 TI - Palliative Care as Life Support for My Career. PMID- 27769617 TI - Shared governance. PMID- 27769618 TI - Novel substituted hydrazono indolo[2,1-b]quinazoline-6,12-dione analogues as cytostatic agents: Synthesis, crystal structure, biological evaluation and molecular docking studies. AB - A series of novel substituted hydrazono indolo[2,1-b]quinazoline-6,12-dione analogues have been synthesized and screened for their in vitro cytotoxic and antimicrobial activities. Among all the target compounds, 3c exhibited the most potent inhibitory activity against three cancer cell lines MCF-7, A549, HeLa with IC50 values 07.14+/-1.285MUM, 09.18+/-0.968MUM and 10.57+/-0.581MUM respectively, while maintaining low toxicity towards non-cancer originated cell line, HEK-293. The detailed studies about molecular interactions with probable target protein indoleamine 2,3-dioxygenase (IDO1) were done by using docking simulations. The results from docking models are in consistent with the experimental in vitro cytotoxic activity conclusions i.e. 3c shows the highest binding energy 11.25kcal/mol. Furthermore, antimicrobial studies revealed that the compound 3e has shown excellent anti bacterial activity against four tested strains and the compounds 3b, 3e and 3f have shown good anti fungal activity against two tested organisms as compared with their standard drugs. PMID- 27769619 TI - Synthesis and cytotoxicity study of novel 3-(triazolyl)coumarins based fluorescent scaffolds. AB - Recently a choice of fluorescent bioimaging probes have been developed as medical diagnostic tools. Herein, we have introduced a series of coumarin-based target specific probes for cancer theranostic application which play a dual role in the field of both diagnosis and therapy. A fluorogenic version of 1,3-dipolar cycloaddition between azides and alkynes (DBCO) has been introduced to develop the triazolylcoumarin based fluorescent scaffolds. These scaffolds were screened for their anticancer activity against breast cancer (MCF7) and human epitheloid cervix carcinoma (HeLa) cell line. It was established that triazolylcoumarins (5c and 5d) are having electronegative substitution in the benzene ring displayed most effective anticancer profile in both the cell lines. Compounds 5a and 5d exhibited maximum quantum yield and strong cellular uptake in the MCF-7 cell line. PMID- 27769620 TI - Synthesis and biological evaluation of ranitidine analogs as multiple-target directed cognitive enhancers for the treatment of Alzheimer's disease. AB - Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and pi-pi interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed. In addition to improving AChE activity and chemical stability, structural modifications allowed determination of binding affinities and selectivities for M1-M4 receptors and butyrylcholinesterase (BuChE). These results as a whole indicate that the 4-nitropyridazine moiety of the JWS-USC-75IX parent ranitidine compound (JWS) can be replaced with other chemotypes while retaining effective AChE inhibition. These studies allowed investigation into multitargeted binding to key receptors and warrant further investigation into 1,8 naphthalimide ranitidine derivatives for the treatment of Alzheimer's disease. PMID- 27769622 TI - Discovery of ursolic acid prodrug (NX-201): Pharmacokinetics and in vivo antitumor effects in PANC-1 pancreatic cancer. AB - The aim of our study was to develop ursolic acid (UA) prodrugs in order to overcome UA's weakness, which has an extremely low bioavailability. UA-medoxomil (NX-201), one of our UA prodrugs, showed an improved bioavailability about 200times better than UA in rodent model. According to in vivo test performed with PANC-1 xenograft SCID mouse model, tumor growth rate decreased dose-dependently and 100mg/kg dose of NX-201 had an anticancer effect comparable to gemcitabine. Most of all the combination of NX-201 (50mg/kg, po, daily) and gemcitabine (40mg/kg, iv, 2timesperweek) even reduced tumor size after three weeks. PMID- 27769621 TI - Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors. AB - High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50 values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication. PMID- 27769623 TI - Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core. AB - A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor. PMID- 27769624 TI - Anticoagulant activity of a sulfated Lachnum polysaccharide in mice with a state of hypercoagulability. AB - A sulfated polysaccharide, designated as SLEP-1, was obtained after sulfation of the exopolysaccharide (LEP-1) which was isolated from Lachnum. The degree of substitution (DS) of sulfate group of SLEP-1 was 1.97. SEM images of SLEP-1 revealed laminated structure in mesh. UV, FT-IR and 13C NMR spectra indicated that the LEP-1 was sulfated successfully. The result of the anticoagulant activity in vitro showed that both of LEP-1 and SLEP-1 could effectively prolong activated partial thromboplastin time (APTT) and thrombin time (TT) of the normal mice plasma, in which SLEP-1 was more effectively than those of LEP-1, and dose effect relationships were found. According to the bleeding time (BT), clotting time (CT), APTT, PT, prothrombin time (TT), fibrinogen (FIB), AT-III activity and FXa concentration of the hypercoagulable mice, it indicated that SLEP-1 (30mg.kg 1 and 90mg.kg-1) had strong inhibitory effect on intrinsic coagulation pathway, which could also enhance fibrinolytic activity. It may constitute an anticoagulant drug of interest in anticoagulant therapy. PMID- 27769625 TI - Effect of genetically modified corn on the jejunal mucosa of adult male albino rat. AB - Genetically modified (GM) plants expressing insecticidal traits offer a new strategy for crop protection. GM-corn contains Bacillus thuringiensis (Bt) genes producing delta endotoxins in the whole plant. Diet can influence the characteristics of the gastrointestinal tract altering its function and structure. The aim of this study was to evaluate the effect of GM-corn on the histological structure of jejunal mucosa of adult male albino rat using different histological, immunohistochemical and morphometrical methods. Twenty adult male albino rats were divided into two equal groups; control and GM-corn fed group administered with 30% GM-corn for 90days. Specimens from the jejunum were processed for light and electron microscopy. Immunohistochemical study was carried out using antibody against proliferating cell nuclear antigen (PCNA). Different morphometrical parameters were assessed. Specimens from GM-corn fed group showed different forms of structural changes. Focal destruction and loss of the villi leaving denuded mucosal surface alternating with stratified areas were observed, while some crypts appeared totally disrupted. Congested blood capillaries and focal infiltration with mononuclear cells were detected. Significant upregulation of PCNA expression, increase in number of goblet cells and a significant increase in both villous height and crypt depth were detected. Marked ultrastructural changes of some enterocytes with focal loss of the microvillous border were observed. Some enterocytes had vacuolated cytoplasm, swollen mitochondria with disrupted cristae and dilated rough endoplasmic reticulum (rER). Some cells had dark irregular nuclei with abnormally clumped chromatin. It could be concluded that consumption of GM-corn profoundly alters the jejunal histological structure. PMID- 27769626 TI - [Diagnosing the hyperactive child who snores]. AB - Attention deficit hyperactivity disorder (ADHD) is a common disorder, often associated with sleep disorders. Patients with primary sleep disorders often present hyperactivity and/or attention deficit symptoms. Indeed, obstructive sleep disorder breathing (snoring, hypoventilation disorder, and obstructive sleep apnea syndrome) with poor sleep quality can mimic ADHD in children. In this case, inattention and hyperactivity behavior are induced by sleep disorders but do not constitute a clinical diagnosis of ADHD. Therefore, it can sometimes be difficult for the clinician to distinguish between a diagnosis of ADHD with comorbid sleep disorder and a sleep disorder that mimics ADHD symptoms. The objective of this article is to review the relations between ADHD and obstructive sleep disorder breathing and propose a decision tree to help diagnosis. PMID- 27769627 TI - [Obstructive sleep apnea-hypopnea syndrome in children: Clinical diagnosis]. AB - The French Society of Research and Sleep Medicine (SFRMS) organized a meeting on obstructive sleep apnea syndrome (OSAS) in children. A multidisciplinary group of specialists (pulmonologist, ENT surgeons, pediatricians, orofacial myofunctional therapists, neurophysiologists, and sleep specialists) reached a consensus on the value of isolated or clustered clinical symptoms and of questionnaires completed by parents in the clinical diagnosis and in assessing the severity of OSAS. Are clinical history with validated questionnaires and a rigorous physical examination sufficient to suspect OSAS, to appreciate its severity, and finally to confirm the diagnosis? Usually, a sleep recording of respiratory parameters remains mandatory for the diagnosis of OSAS to be made. However, clinical symptoms are very useful for estimating the probability of the diagnosis and the severity of the disease, and therefore for classifying which children will benefit form polysomnography and for proposing an adapted follow-up after OSAS therapy. Even if they are not able to ascertain the diagnosis of OSAS in children, clinical history, questionnaires, and physical examination are very important. Finally, we propose a classification of the indications for polysomnography in children suspected of having OSAS. PMID- 27769628 TI - [Obesity and obstructive sleep apnea in children]. AB - Obesity, along with hypertrophy of the adenoids and the tonsils, represents one of the major risk factors for obstructive sleep apnea (OSA) in children. Obesity is associated with an increase in the prevalence and the severity of OSA and is a major factor in the persistence and aggravation of OSA over time. Neurocognitive dysfunction and abnormal behavior are the most important and frequent end-organ morbidities associated with OSA in children. Other deleterious consequences such as cardiovascular stress and metabolic syndrome are less common in children than in adults with OSA. Defining the exact role of obesity in OSA-associated end organ morbidity in children is difficult because of the complex and multidimensional interactions between sleep in general, OSA, obesity, and metabolic dysregulation. This may explain why obesity itself has not been shown to be associated with a significant increase in OSA-associated end-organ morbidity. Obesity is linked to a decreased treatment efficacy and, in particular, of adenotonsillectomy. Peri- and postoperative complications are more common and more severe in obese children as compared with normal-weight controls. Continuous positive airway pressure (CPAP) is frequently needed, but compliance with CPAP is less optimal in obese children than in non-obese children. In conclusion, obesity represents a major public health problem worldwide; its prevention is one of the most efficient tools for decreasing the incidence and the morbidity associated with OSA in children. PMID- 27769629 TI - Letter to the Editor: Tissue factor of endothelial origin: Just another brick in the wall? PMID- 27769630 TI - Letter to Editor response: Endothelial cell tissue factor and coagulation. PMID- 27769631 TI - Evolution of the beta-adrenoreceptors in vertebrates. AB - The study of the evolutionary history of genes related to human disease lies at the interface of evolution and medicine. These studies provide the evolutionary context on which medical researchers should work, and are also useful in providing information to suggest further genetic experiments, especially in model species where genetic manipulations can be made. Here we studied the evolution of the beta-adrenoreceptor gene family in vertebrates with the aim of adding an evolutionary framework to the already abundant physiological information. Our results show that in addition to the three already described vertebrate beta adrenoreceptor genes there is an additional group containing cyclostome sequences. We suggest that beta-adrenoreceptors diversified as a product of the two whole genome duplications that occurred in the ancestor of vertebrates. Gene expression patterns are in general consistent across species, suggesting that expression dynamics were established early in the evolutionary history of vertebrates, and have been maintained since then. Finally, amino acid polymorphisms that are associated to pathological conditions in humans appear to be common in non-human mammals, suggesting that the phenotypic effects of these mutations depend on epistatic interaction with other positions. The evolutionary analysis of the beta-adrenoreceptors delivers new insights about the diversity of these receptors in vertebrates, the evolution of the expression patterns and a comparative perspective regarding the polymorphisms that in humans are linked to pathological conditions. PMID- 27769632 TI - Antioxidant and wound healing activity of Lavandula aspic L. ointment. AB - Lavandula aspic L. is a strongly aromatic shrub plant of the Lamiaceae family and traditionally used in herbal medicine for the treatment of several skin disorders, including wounds, burns, and ulcers. The present study aimed to investigate the composition and in vitro antioxidant activity of lavender essential oil. In addition, it aimed to evaluate the excision wound healing activity and antioxidant property of a Lavandula aspic L. essential oil formulated in ointment using a rat model. The rats were divided into five groups of six animals each. The test groups were topically treated with the vehicle, lavender ointment (4%) and a reference drug, while the control group was left untreated. Wound healing efficiency was determined by monitoring morphological and biochemical parameters and skin histological analysis. Wound contraction and protein synthesis were also determined. Antioxidant activity was assessed by the determination of MDA rates and antioxidant enzymes (GPx, catalase and superoxide dismutase). The treatment with lavender ointment was noted to significantly enhance wound contraction rate (98%) and protein synthesis. Overall, the results provided strong support for the effective wound healing activity of lavender ointment, making it a promising candidate for future application as a therapeutic agent in tissue repairing processes associated with skin injuries. PMID- 27769633 TI - Urine bisphenol A and pubertal development in boys. AB - BACKGROUND: Bisphenol A (BPA) is an environmental endocrine disruptor and is found in many consumer products. Animal studies suggest that BPA may perturb pubertal development in males, although studies in humans are limited. OBJECTIVE: This study investigated the association between BPA exposure and pubertal onset and progression among school-aged boys in Shanghai, China. METHODS: A total of 671 boys aged 9-18 years from three schools (one elementary, one middle, and one high school) in Shanghai were enrolled in a cross-sectional study. Tanner stages for genital and pubic hair development and testicular volume were assessed by a specifically trained physician. Information concerning spermarche was self reported. Urine samples were collected to examine peripubertal BPA exposure levels. Associations between BPA exposure and pubertal development, as indicated by the presence of different milestones in early puberty, mid-puberty and late puberty, were assessed using Poisson multivariate regression to derive adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs). RESULTS: Earlier onset of genital and pubic hair development was observed in boys with moderate BPA exposure compared with those exposed to the least BPA; the adjusted PRs were 1.31 (95%CI:1.03, 1.68) and 1.28 (95%CI:1.02, 1.60) for onset of genital maturation and pubic hair development, respectively. A similar trend was seen for onset of testicular development, although the association was not statistically significant. Conversely, compared with the lowest level of BPA exposure, moderate BPA exposure was associated with delayed presence of the late stage of genital development, with an adjusted PR of 0.78 (95%CI: 0.65, 0.92). A suggestive inverse association was also observed between BPA exposure and late progression of testicular development. CONCLUSIONS: Our findings indicate an association between peripubertal BPA exposure and earlier pubertal onset, but delayed pubertal progression, in boys. Longitudinal studies of male pubertal development with periodic follow-up are needed to verify these results. PMID- 27769634 TI - Upper outer boundaries of the axillary dissection. Result of the SENTIBRAS protocol: Multicentric protocol using axillary reverse mapping in breast cancer patients requiring axillary dissection. AB - BACKGROUND: Two thirds of node-positive breast cancer patients have limited pN1 disease and could benefit from a less extensive axillary lymph node dissection (ALND). METHODS: 172 breast cancers patients requiring an ALND were prospectively enrolled in the Sentibras Protocol of Axillary Reverse Mapping (ARM). Radioisotope was injected in the ipsilateral hand the day before surgery. ALND was standard. Removed lymph nodes were classified into non radioactive nodes and radioactive nodes (ARM nodes). Among ARM nodes, nodes located in the upper outer part of the axilla, above the second intercostal brachial nerve and lateral to the lateral thoracic vein were identified as "zone D ARM nodes". The main objective was: feasibility of identification of the zone D ARM nodes. Secondary objectives were: metastatic involvement and lymphedema rate. RESULTS: 100% of patients had ARM nodes identified. The "zone D ARM nodes" were identified in 92% of cases. The rate of metastatic nodes was 60% in the all cohort, 31% in ARM nodes and 9% in zone D ARM nodes. Among those, metastatic rate was 6% in patients undergoing ALND for a positive sentinel node biopsy, 6% in case of primary ALND versus 14% after neo-adjuvant chemotherapy (p < 0.05). After 34 months of median follow up, 27% of interviewed patients had a lymphedema. CONCLUSION: The ARM technique reliably identifies the "zone D ARM nodes". These nodes can also easily be identified using knowledge of axillary anatomy. In selected patients, a selective ALND sparing the zone D ARM nodes could be performed. PMID- 27769635 TI - Immunotherapy in melanoma: Recent advances and future directions. AB - Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma. Ipilimumab, a monoclonal antibody against the cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as nivolumab and pembrolizumab which target the programmed cell death protein 1 (PD-1) have been shown to prolong overall survival in patients with advanced melanoma. The latter substances seem to have an increased response rate and more tolerable safety profile compared to ipilimumab. The combination of a CTLA-4 and a PD-1 inhibitor seems to be superior to the monotherapies, especially in patients with PD-L1 negative tumours. Checkpoint inhibitors are currently being tested in the adjuvant setting with initial data for ipilimumab suggesting efficacy in this context. Talimogene laherparepvec (TVEC) is the first oncolytic virus approved in the therapy of metastatic melanoma offering a treatment option especially for patients with limited disease. In this review, data on these recently developed and approved immunotherapies are presented. However, further studies are necessary to determine the optimal duration, sequencing and combinations of immunotherapies to further improve the outcome of patients with advanced melanoma. PMID- 27769636 TI - Empowering patients for radiation therapy safety: Results of the EMPATHY study. AB - PURPOSE: With the increase of treatment complexity, enhancing safety is a key concern in radiation oncology. Beyond the involvement of the healthcare professional, patient involvement and empowerment could play a major role in that setting. We explored how patients perceived and fulfilled that role during their radiation treatment. MATERIALS AND METHODS: A voluntary and anonymous questionnaire was administered to all patients treated in our department between November 2013 and May 2014. The following data were collected: sociodemographic profile; information received and initiatives to search for additional information; behavior when an unusual treatment event was perceived; active involvement in the safety of the treatment; nature and perception of their own involvement. A statistical analysis was performed to assess behavioral predictors. RESULTS: A total of 155 patients answered the survey. Most of them were treated for prostate (n=58, 37.4%), lung (n=27, 17.4%), head and neck (n=26, 16.8%) and breast (n=25, 16.1%). Only eight patients (5%) had previously received radiation therapy. Ninety-five percent of the patients estimated they had received enough information about their treatment, but 48% would have wanted more. When patients noticed an unusual event during their treatment session, most of them (61%) reported it to the radiation therapist. CONCLUSION: Patient participation to radiation therapy safety should be encouraged to ensure a cooperative risk management. Healthcare professionals need to inform the patients on the basic technical processes involved in their treatment. Patient empowerment should be added to the verifications made by the radiation therapists and physicians but should not replace them. PMID- 27769638 TI - Importance of homogeneity between groups in the study of therapeutic efficacy. PMID- 27769637 TI - The exciting prospects of new therapies with mesenchymal stromal cells. AB - From the outset, it was apparent that developing new therapies with mesenchymal stem/stromal cells (MSCs) was not a simple or easy task. Among the earliest experiments was administration of MSCs from normal mice to transgenic mice that developed brittle bones because they expressed a mutated gene for type 1 collagen isolated from a patient with osteogenesis imperfecta. The results prompted a clinical trial of MSCs in patients with severe osteogenesis imperfecta. Subsequent work by large numbers of scientists and clinicians has established that, with minor exceptions, MSCs do not engraft or differentiate to a large extent in vivo. Instead the cells produce beneficial effects in a large number of animal models and some clinical trials by secreting paracrine factors and extracellular vesicles in a "hit and run" scenario. The field faces a number of challenges, but the results indicate that we are on the way to effective therapies for millions of patients who suffer from devastating diseases. PMID- 27769639 TI - Platelets and infection. AB - The primary function of platelets is to patrol the vasculature and seal vessel breaches to limit blood loss. However, it is becoming increasingly clear that they also contribute to pathophysiological conditions like thrombosis, atherosclerosis, stroke and infection. Severe sepsis is a devastating disease that claims hundreds of thousands of lives every year in North America and is a major burden to the public health system. Platelet surface receptors like GPIb, alphaIIbbeta3, TLR2 and TLR4 are involved in direct platelet-bacteria interactions. Plasma proteins like fibrinogen and vWF enable indirect interactions. Furthermore, platelet granules contain a plethora of proteins that modulate the immune response as well as microbicidal agents which can directly lyse bacteria. Bacterial toxins are potent platelet activators and can cause intravascular platelet aggregation. Platelets contribute to the antibacterial response of the host involving Kupffer cells, neutrophils and the complement system. In this review we summarize the current knowledge about platelet-bacteria interactions and highlight recent advances in the field. PMID- 27769640 TI - Can a web-based community of practice be established and operated to lead falls prevention activity in residential care? AB - The aims of this study were to evaluate establishing and operating a web-based community of practice (CoP) to lead falls prevention in a residential aged care (RAC) setting. A mixed methods evaluation was conducted in two phases using a survey and transcripts from interactive electronic sources. Nurses and allied health staff (n = 20) with an interest in falls prevention representing 13 sites of an RAC organization participated. In Phase 1, the CoP was developed, and the establishment of its structure and composition was evaluated using determinants of success reported in the literature. In Phase 2, all participants interacted using the web, but frequency of engagement by any participant was low. Participatory barriers, including competing demands from other tasks and low levels of knowledge about information communication technology (ICT) applications, were identified by CoP members. A web-based CoP can be established and operated across multiple RAC sites if RAC management support dedicated time for web-based participation and staff are given web-based training. PMID- 27769641 TI - Inorganic carbon dominates total dissolved carbon concentrations and fluxes in British rivers: Application of the THINCARB model - Thermodynamic modelling of inorganic carbon in freshwaters. AB - River water-quality studies rarely measure dissolved inorganic carbon (DIC) routinely, and there is a gap in our knowledge of the contributions of DIC to aquatic carbon fluxes and cycling processes. Here, we present the THINCARB model (THermodynamic modelling of INorganic CARBon), which uses widely-measured determinands (pH, alkalinity and temperature) to calculate DIC concentrations, speciation (bicarbonate, HCO3-; carbonate, CO32-; and dissolved carbon dioxide, H2CO3*) and excess partial pressures of carbon dioxide (EpCO2) in freshwaters. If calcium concentration measurements are available, THINCARB also calculates calcite saturation. THINCARB was applied to the 39-year Harmonised Monitoring Scheme (HMS) dataset, encompassing all the major British rivers discharging to the coastal zone. Model outputs were combined with the HMS dissolved organic carbon (DOC) datasets, and with spatial land use, geology, digital elevation and hydrological datasets. We provide a first national-scale evaluation of: the spatial and temporal variability in DIC concentrations and fluxes in British rivers; the contributions of DIC and DOC to total dissolved carbon (TDC); and the contributions to DIC from HCO3- and CO32- from weathering sources and H2CO3* from microbial respiration. DIC accounted for >50% of TDC concentrations in 87% of the HMS samples. In the seven largest British rivers, DIC accounted for an average of 80% of the TDC flux (ranging from 57% in the upland River Tay, to 91% in the lowland River Thames). DIC fluxes exceeded DOC fluxes, even under high-flow conditions, including in the Rivers Tay and Tweed, draining upland peaty catchments. Given that particulate organic carbon fluxes from UK rivers are consistently lower than DOC fluxes, DIC fluxes are therefore also the major source of total carbon fluxes to the coastal zone. These results demonstrate the importance of accounting for DIC concentrations and fluxes for quantifying carbon transfers from land, via rivers, to the coastal zone. PMID- 27769643 TI - Gamma knife radiosurgery for residual or recurrent intracranial hemangiopericytomas. AB - Residual or recurrent hemangiopericytoma (HPC) has been treated with radiosurgery; however, its long-term outcome is not well known. This study is to investigate the long-term outcome of gamma knife radiosurgery (GKS) for residual or recurrent HPCs. We conducted a retrospective analysis of 18 patients who underwent gamma knife radiosurgery for residual or recurrent HPCs. Of the 18 patients, 10 patients had high-grade HPCs (27 tumors) and 8 had low-grade HPCs (13 tumors). Median overall survival (OS) after the first GKS was 134.7months and actuarial survival rate at 1, 5, and 10years was 85.6%, 85.6%, and 37.4%, respectively. At the last follow-up, local tumor control was achieved in 32 (80.0%) of the 40 GKS-treated tumors. New lesions developed out of initial GKS target in 8 patients (44.4%). They were also treated with additional GKS. The actuarial local control rate of 40 tumors at 1-, 3-, and 5-years was 89.3%, 60.9%, and 37.5%, respectively. The median local recurrence-free interval of 40 tumors after initial GKS for each lesion was 86.1months for low-grade and 40.5months for high-grade tumors (p=0.010). Extracranial metastases developed in 7 (38.9%) patients with high-grade pathology and became a cause of death in 3 patients. Intracranial tumor control can be achieved over the long term, though additional GKS is frequently necessary. Extracranial metastasis is common in HPC of high-grade pathology. Close surveillance and aggressive treatment is recommended not only for intracranial tumor but also for possible extracranial metastases. PMID- 27769644 TI - Cryptococcosis mimicking lung carcinoma with brain metastases in an immunocompetent patient. AB - Cryptococcosis is a fungal infection caused by Cryptococcus spp. that enters the body via inhalation. This ubiquitous yeast has gained notoriety as an opportunistic pathogen in the immunosuppressed population. The authors report a case of a previously-well adult male presented with left-sided weakness. Imaging demonstrated a pulmonary mass and 2 contrast-enhancing intracranial lesions-all features suggestive of a primary lung carcinoma with brain metastases. However, further investigations confirmed disseminated cryptococcosis, without evidence of malignancy. The patient was successfully treated with a course of antifungals. To the authors' knowledge, this is the first reported case of dissemintated cryptococcosis in an immunocompetent adult male, simulating as primary lung carcinoma with brain metastases. PMID- 27769642 TI - COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings. PMID- 27769645 TI - Nosocomial spread of Klebsiella pneumoniae isolates producing blaGES-4 carbapenemase at a Japanese hospital. AB - Six Klebsiella pneumoniae clinical isolates resistant to various cephalosporins and cephamycins were identified in a Japanese general hospital, a tertiary care hospital, between November 2009 and April 2010. All K. pneumoniae isolates carried blaGES-4 and blaSHV-1, while 2 K. pneumoniae isolates also harbored blaCTX-M-15. The pulsed-field gel electrophoresis patterns revealed that these 6 K. pneumoniae isolates were almost identical, suggesting their clonal relatedness. Plasmid profiles and conjugation assays revealed that these blaGES-4 genes were located on similar conjugative plasmids. These data indicate that nosocomial spread caused by K. pneumoniae isolates producing blaGES-4 carbapenemase occurred at a Japanese general hospital. K. pneumoniae isolate harboring blaGES-4 is rarely reported in Japan, and, to the best of our knowledge, this is the second report of K. pneumoniae isolates harboring blaGES-4 that occurred nosocomial spread in Japan. PMID- 27769646 TI - Non-molecular detection of carbapenemases in Enterobacteriaceae clinical isolates. AB - Infections caused by carbapenemase-producing bacteria are becoming a major clinical and public health concern. Detection of carbapenemase producing strains is often challenging, since susceptibility to carbapenems may vary significantly among carbapenemase producers. Some carbapenemases have shown to exhibit weak activity against carbapenems leading to minimum inhibitory concentrations of carbapenems below the breakpoint for defining clinical resistance and even below the proposed screening breakpoint. Thus, reliable and rapid detection of carbapenemase-activity is needed for an appropriate patient management and a rapid implementation of infection prevention and control measures. Over the last years, an increasing number of non-molecular assays for prompt detection of carbapenemase activity have been described and developed. However, none of the currently available phenotypic methods have proved to be full specific and sensitive. Selection of the appropriate methodological approach will depend on each situation. Factors to be considered include the epidemiological status, laboratory resources and availability of other confirmation tests. In this review, we provide an overview of the currently available non-molecular methods for detection of carbapenemase activity. PMID- 27769647 TI - Benefits of a hungry mind: When hungry, exposure to food facilitates proactive interference resolution. AB - Hunger is an everyday motivational state, which biases cognition to detect food. Although evidence exists on how hunger affects basic attentional and mnemonic processes, less is known about how motivational drive for food modulates higher cognition. We aimed to investigate the effects of food deprivation on proactive interference resolution, in the presence and absence of food. Normal-weight participants performed a recency probes paradigm providing an experimental block with food and object stimuli as well as a control block with object stimuli only, in a fasted and a sated state. Results showed that the interaction of shifts in nutritional state with the perception of food cues evoked an altered resolution of proactive interference. Satiety led to impaired performance, whereas a hungry state resulted in strengthened resistance to proactive interference and lying in between, the control block presenting neutral objects remained unaffected by nutritional state manipulation. Additionally, a further increase in proactive interference resolution occurred when the conflicting probe depicted food compared to non-food objects. We conclude that when exposed to food, hunger initiates biased competition of active memory representations in favor of prioritized source information at cost of familiar, but irrelevant information. The implications of these findings are discussed in terms of an arousal-biased competition in working memory. PMID- 27769648 TI - Reduced MIBG accumulation of the parotid and submandibular glands in idiopathic Parkinson's disease. AB - INTRODUCTION: Alpha-synuclein pathology (ASP) is a characteristic histopathological finding in idiopathic Parkinson's disease (PD). The ASP involves not only the brain but also extracranial structures. In the present study we utilized MIBG scintigraphy to measure the sympathetic innervation of the major salivary glands. We were interested in whether MIBG uptake in the major salivary glands represents a potential biomarker for ASP in PD. METHODS: We investigated 77 PD patients (age 61 +/- 10 years, mean +/- SD), while 15 non-PD patients (age 58 +/- 15 years) with arterial hypertension, who underwent MIBG scintigraphy to exclude pheochromocytoma, served as age-matched controls. The MIBG uptake of the parotid glands and the submandibular glands was quantified by means of a region of interest technique. The sublingual glands were too small for an exact measurement. We applied Generalized Estimating Equations (GEE) to identify and remove factors which may bias the statistical correlation analysis. RESULTS: The PD patients showed a significantly lower MIBG uptake in the parotid and submandibular glands than the controls (p < 0.0001). MIBG uptake in the PD patients did not correlate with clinical severity (Hoehn and Yahr stage, motor part of the UPDRS) or disease duration. CONCLUSION: MIBG uptake in the parotid and submandibular glands might be a candidate biomarker for PD. The missing correlation between MIBG uptake and clinical PD parameters suggests that ASP of the extracranial sympathetic superior cervical ganglion, which innervates the major salivary glands, develops independently from the cerebral dopaminergic nigrostriatal ASP. PMID- 27769650 TI - Process Window for Direct Recycling of Acrylonitrile-Butadiene-Styrene and High Impact Polystyrene from Electrical and Electronic Equipment Waste. AB - The aim of this paper is to assess recycling process window of ABS (Acrylonitrile Butadiene-Styrene) and HIPS (High impact Polystyrene) from WEEE (waste from electrical and electronic equipment) through a final properties/structure screening study on their blends. Main motivation is to evaluate which amount of one plastic WEEE can be included into the other at least keeping their properties. In this sense, a wider margin of error during sorting could be admitted to obtain recycling materials with similar technological application of recycled ABS and HIPS by themselves. Results are discussed in terms of final blend structure, focusing in the interaction, within blends, of copolymers phases and fillers presents in WEEE. The comparative analysis of mechanical performance and morphology of HIPS/ABS blends indicates that the addition of 50wt% HIPS to ABS even improves 50% the elongation at break maintaining the strength. On the opposite, HIPS maintains its properties with 20wt% of ABS added. This study allows enlarging composition process window of recycling plastic WEEE for similar applications. This could be a sustainable way to improve benefit of e-scrap with low costs and easy processability. In consequence, social interest in the recycling of this kind of plastic scrap could be encourage from either ecological or economical points of view. PMID- 27769652 TI - A proposal to improve e-waste collection efficiency in urban mining: Container loading and vehicle routing problems - A case study of Poland. AB - Waste electrical and electronic equipment (WEEE), also known as e-waste, is one of the most important waste streams with high recycling potential. Materials used in these products are valuable, but some of them are hazardous. The urban mining approach attempts to recycle as many materials as possible, so efficiency in collection is vital. There are two main methods used to collect WEEE: stationary and mobile, each with different variants. The responsibility of WEEE organizations and waste collection companies is to assure all resources required for these activities - bins, containers, collection vehicles and staff - are available, taking into account cost minimization. Therefore, it is necessary to correctly determine the capacity of containers and number of collection vehicles for an area where WEEE need to be collected. There are two main problems encountered in collection, storage and transportation of WEEE: container loading problems and vehicle routing problems. In this study, an adaptation of these two models for packing and collecting WEEE is proposed, along with a practical implementation plan designed to be useful for collection companies' guidelines for container loading and route optimization. The solutions are presented in the case studies of real-world conditions for WEEE collection companies in Poland. PMID- 27769651 TI - Between hype and veracity; privatization of municipal solid waste management and its impacts on the informal waste sector. AB - The informal waste recycling sector has been an indispensable but ironically invisible part of the waste management systems in developing countries as India, often completely disregarded and overlooked by decision makers and policy frameworks. The turn towards liberalization of economy since 1991 in India opened the doors for privatization of urban services and the waste sector found favor with private companies facilitated by the local governments. In joining the privatization bandwagon, the local governments aim to create an image of a progressive city demonstrated most visibly through apt management of municipal solid waste. Resultantly, the long important stakeholder, the informal sector has been sidelined and left to face the adverse impacts of privatization. There is hardly any recognition of its contributions or any attempt to integrate it within the formal waste management systems. The study investigates the impacts of privatization on the waste pickers in waste recycling operations. Highlighting the other dimension of waste collection and management in urban India the study focuses on the waste pickers and small time informal scrap dealers and this is done by taking the case study of Amritsar city, which is an important historic centre and a metropolitan city in the state of Punjab, India. The paper develops an analytical framework, drawing from literature review to analyze the impacts. In conclusion, it supports the case for involving informal waste sector towards achieving sustainable waste management in the city. PMID- 27769653 TI - Comparison of different approaches for the estimation of odour emissions from landfill surfaces. AB - The aim of this study is related to the assessment of odour emissions from landfill surfaces. Up to now, there is not a widely accepted method to quantify odour emissions from this particular kind of source. Five different methods were developed and investigated. These methods can be considered as based on three distinct approaches, both experimental and computational. The first approach provides to use models for the estimation the landfill gas production, whereby the second and the third approach are based on direct measurement campaigns on the landfill surface: for the determination of the methane concentration or for the direct measurement of the odour concentration, respectively. The methods were then compared in terms of specific odour emission rates by referring to other literature data. Finally, dispersion modelling was applied in order to allow a further comparison of the resulting odour impacts with other olfactometric data from independent monitoring campaigns on the studied site. PMID- 27769649 TI - Knowledge gaps and research recommendations for essential tremor. AB - Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families. PMID- 27769654 TI - Hydrolysis and acidification of agricultural waste in a non-airtight system: Effect of solid content, temperature, and mixing mode. AB - A two-phase digestion system for treating agricultural waste is beneficial for methane production. This study explored the effect of solid content, temperature, and mixing mode on the process of hydrolysis and acidification using rice straw and cow dung launched in non-airtight acidogenic system. The results showed that the substrate could be hydrolyzed efficiently in the initial stage, the hydrolysis coefficient (k) of maximum cellulose and hemicellulose can be increased by 217.9% and 290.5%, respectively, compared with those of middle and last stages. High solid content played a leading role in promoting hydrolysis, resulted in hydrolysate content (sCOD) that was significantly higher than in treatments with low solid content (P<0.01), and led to organic acids accumulation up to 5.8 and 6.7g/L at mesophilic and thermophilic temperatures. Thermophilic temperature stimulated the hydrolysis and acidification of low solid content (P<0.05), and improved organic acid accumulation of high solid content only during the middle stage (P<0.01). Mixing mode was not a major factor, but increasing the mixing time was necessary for organic acid accumulation during the last stage (P<0.05). In addition, the study comprehensively analyzed a series of corresponding relationships among each operating parameter during the whole treatment process using canonical correspondence analysis. PMID- 27769655 TI - Microorganisms in ticks (Acari: Ixodidae) collected on marsupials and rodents from Santa Catarina, Parana and Mato Grosso do Sul states, Brazil. AB - Information about tick fauna and monitoring of pathogen prevalences in ticks (Acari: Ixodidae) in various habitat types can enhance knowledge about the epidemiology of tick-borne pathogens in Brazil. This work shows the results of a study of tick parasitism of wild rodents and marsupials collected in seven localities in the southern part of Brazil, within Atlantic Forest and Cerrado biomes. A total of 61 ticks were collected from small mammals, and after identification to the species level, the ticks were individually tested for the presence of bacteria of the genera Rickettsia, Borrelia, family Anaplasmataceae, and protozoa of the genus Babesia. The following species of ticks were found: Amblyomma ovale Koch, 1844, Amblyomma dubitatum Neumann, 1899, Amblyomma fuscum Neumann, 1907, Ixodes aragaoi Fonseca, 1935, Ixodes fuscipes Koch, 1844, Ixodes loricatus Neumann, 1899, and Ixodes schulzei Aragao and Fonseca, 1951. Among tested ticks, no DNA of Borrelia, Babesia or Anaplasmataceae was detected. Two nymphs of A. ovale were found infected with Rickettsia bellii and four nymphs of I. aragaoi with Rickettsia sp., genetically close to Rickettsia monacensis, Rickettsia tamurae and the endosymbiont Rickettsia spp., previously found in various Ixodidae. In one nymph of A. fuscum, DNA of a novel Hepatozoon sp. was found. Additionally we provide novel tick-host associations. PMID- 27769656 TI - Putative RNA viral sequences detected in an Ixodes scapularis-derived cell line. AB - Ticks harbour various microorganisms, some of which act as pathogens of humans and animals. The recent advancement of genome sequencing technologies revealed that a wide range of previously unrecognised microorganisms exist in ticks. Continuous cell lines established from ticks could play a key role in the isolation of such microorganisms; however, tick cells themselves have been known to harbour symbiotic microorganisms. The present study aimed to characterise putative RNA viral sequences detected in the culture supernatant of one of the most frequently used tick cell lines, ISE6, which was derived from embryos of the blacklegged tick Ixodes scapularis. Viral particles purified from the culture supernatant were used for RNA extraction, followed by Illumina sequencing. The reads were de novo assembled and the resulting contigs were annotated by tBLASTx search. The results suggested that there were at least five putative viral sequences of four phylogenetically distinct lineages in ISE6 cells. The predominant viral sequence found in ISE6 cells, designated I. scapularis iflavirus, was a member of the family Iflaviridae, which is an arthropod infecting virus group. We also identified L and M segments of the family Bunyaviridae, which could not be classified into any of the five known genera, and a potential capsid protein related to Drosophila A virus. In addition to these previously unrecognised viruses, ISE6 was revealed to harbour a putative genome sequence of I. scapularis-associated virus-1, which was reported in a recent metagenomic study of I. scapularis itself. All the five putative viral sequences were detected by RT-PCR in both ISE6 cells and the culture supernatant. Electron microscopic analysis showed the existence of spherical virions with a varying diameter of 50-70nm in the culture supernatant of ISE6 cells. Further studies are required to investigate the potential roles of ISE6-associated viruses in ticks. PMID- 27769657 TI - Implant-supported mandibular removable partial dentures; patient-based outcome measures in relation to implant position. AB - OBJECTIVES: To assess the benefits of implant support to Removable Partial Dentures (RPD) in patients with a bilateral free-ending situation in the mandible and to determine the most favorable implant position: the premolar (PM) or the molar (M) region. METHODS: Thirty subjects with a bilateral unbounded posterior saddle received 2 PM and 2M implants. A new RPD was placed. Implant support was provided 3 months later. Two PM implants supported the RPD. After 3 months the 2M implants were used or vice versa. Outcome measures included oral health related quality of life (OHIP-NL49), general health status (SF-36), contentment assessed on a Visual Analogue Scale (VAS) and the number of hours that the RPD was worn. Data were collected prior to treatment, 3 months after having functioned with a new RPD and after 3 and 6 months with implant support. Finally, patients expressed their preferred implant position. RESULTS: The general health status (SF-36) was not influenced. OHIP-NL49 values and mean wearing-time were statistical significantly more favorable for ISRPD's, regardless of the implant position. Per day, the ISRPD's were worn 2-3h more than the unsupported new RPD. Patients' expectations were met as the VAS-scores of anticipated and realized contentment did not reach a statistical significant level (p>0.05). VAS scores for ISRPD's with M implant support were higher than for PM implant support. Finally, 56.7% of subjects preferred the M implant support, 13.3% expressed no preference and 30% opted for PM implant support. CONCLUSIONS: Mandibular implant support favorably influences oral health related patient-based outcome measures in patients with a bilateral free-ending situation. The majority of patients prefer the implant support to be in the molar region. CLINICAL SIGNIFICANCE: Patients with a bilateral free-ending situation in the mandible opposed by a maxillary denture benefit from implant support to their mandibular removable partial denture. Most patients prefer this support to be in the molar region. PMID- 27769658 TI - Assuring survival of safety-net surgical patients. AB - BACKGROUND: Survival of surgical inpatients is a key quality metric. Patient, surgeon, and system factors all contribute to inpatient mortality, and sophisticated risk adjustment is required to assess outcomes. When the mortality of general surgery patients was determined to be high at a safety-net hospital, a comprehensive approach was undertaken to improve patient survival. METHODS: General surgical service line mortality was measured in the database of the University HealthSystem Consortium from January 2013 through June 2015. Ten best practices were implemented sequentially to decrease observed and/or increase expected mortality. University HealthSystem Consortium mortality rank, observed, expected, and observed/expected index as well as early deaths were compared with control charts for 30 months. RESULTS: University HealthSystem Consortium general surgery mortality improved from the bottom decile to the top quartile, while Case Mix Index increased from 2.48 to 2.82 (P < .05). Observed mortality decreased from 3.39 to 2.35%. Expected mortality increased from 1.40 to 2.73% (P < .05). The observed/expected mortality index decreased from 2.43 to 0.86 (P < .05). Early deaths decreased from 0.52 to 0% (P < .05). CONCLUSION: Risk-adjusted mortality and early deaths decreased significantly over 30 months in general surgery patients. Systematic implementation of quality best practices was associated with improved survival of general surgery patients at a safety-net medical center. PMID- 27769659 TI - Multiple postoperative complications: Making sense of the trajectories. AB - BACKGROUND: Many studies have evaluated predictors of postoperative complications, yet little is known about the development of multiple complications. The goal of this study was to assess complication timing in cascades of multiple complications and the risk of future complications given a patient's first complication. METHODS: This study includes 30-day, postoperative complications from the American College of Surgeons National Surgical Quality Improvement Program for all patients who underwent major inpatient and outpatient operative procedures from 2005-2013. The timing and sequencing of complications were evaluated using chi2 analysis and pairwise comparisons. RESULTS: More severe postoperative complications (cardiac arrest or myocardial infarction, renal insufficiency or failure, stroke, intubation, septic shock, coma) had the greatest impact on the risk for developing further complications, increasing the relative risk of developing future, specific, severe complications by more than 40-fold. These more severe complications occur within a few days of other complications (whether as a preceding factor or an outcome), while less severe complications, such as surgical site infection and urinary tract infection, are linked less tightly to complication cascades. CONCLUSION: This analysis highlights both the risk for secondary complications after an initial complication and when those future complications are likely to occur. Physicians can use this information to target interventions to prevent high-risk complications. PMID- 27769660 TI - Rates of secondary hyperparathyroidism after bypass operation for super-morbid obesity: An overlooked phenomenon. AB - BACKGROUND: With over 110,000 bariatric operations performed in the United States annually, it is important to understand the biochemical abnormalities causing endocrine dysfunction associated with these procedures. Here we compare 2 malabsorptive procedures, duodenal switch and Roux-en-Y gastric bypass, to determine the role malabsorption plays in secondary hyperparathyroidism in this population. METHODS: Data from all super-obese patients undergoing duodenal switch or Roux-en-Y gastric bypass between August 2002 and October 2005 were prospectively collected. Postoperatively, all patients received 1,200 mg of calcium citrate and 1,000 IU vitamin D3 per American Society for Metabolic and Bariatric Surgery guidelines. Beginning in 2007, duodenal switch patients were instructed to add daily vitamin D3 10,000 IU. Statistical analyses included Student t test, multivariate, and univariate logistic regression. RESULTS: Of 283 patients with a body mass index >=50, 170 (60.1%) underwent duodenal switch, while 113 (39.9%) underwent Roux-en-Y gastric bypass. Of 132 (46.6%) patients with secondary hyperparathyroidism, 101 (59.4%) had undergone duodenal switch and 31 (27.4%) had undergone Roux-en-Y gastric bypass. Symptoms were more common in the duodenal switch group (33 patients [19.4%]) than Roux-en-Y gastric bypass (11 patients [9.7%]). Multivariate logistic regression demonstrated that the extent of bypass and duration of follow-up were the only 2 independent predictive risk factors for developing secondary hyperparathyroidism. Although vitamin D levels improved with increased vitamin D3 supplementation in 2007, rates of secondary hyperparathyroidism increased. CONCLUSION: Despite routine postoperative calcium and vitamin D3 supplementation, secondary hyperparathyroidism is common after Roux-en-Y gastric bypass and duodenal switch. The degree of iatrogenic malabsorption correlates with the incidence of secondary hyperparathyroidism. These rates suggest current supplementation guidelines are not sufficient in preventing secondary hyperparathyroidism. Further work is needed to better define the sequelae of long-term hyperparathyroidism. PMID- 27769661 TI - Comparable liver function and volume increase after portal vein embolization in rabbits and humans. AB - BACKGROUND: Portal vein embolization is the gold standard approach to preoperatively enhance the future liver remnant before liver resection. Portal vein embolization is studied in several experimental animal models; however, clinical translation of results is often difficult. We aimed to examine the translational value of the portal vein embolization response in a standardized rabbit model by comparing the volume and function increase with the response seen in patients. METHODS: Six rabbits were subjected to embolization of the cranial liver lobes, and the hypertrophy response of the caudal liver lobe was studied using computed tomography volumetry and Technetium-99m-labeled-mebrofenin hepatobiliary scintigraphy. Results were compared to those from patients who underwent portal vein embolization between 2005 and 2014. All patients were subjected to computed tomography volumetry and hepatobiliary scintigraphy before and after portal vein embolization. RESULTS: The increase in liver function of the caudal liver lobe in rabbits was faster compared to the increase in liver volume. There was no decrease in total liver function after portal vein embolization. Results in patients were similar to rabbits, with a faster increase in liver function compared to patients and no decrease in total liver function after portal vein embolization. CONCLUSION: The portal vein embolization response in terms of liver volume and function is similar between rabbits and humans. Accordingly, the rabbit model is a suitable tool to study portal vein embolization-related parameters that cannot be investigated in patients. PMID- 27769662 TI - Pre-hepatectomy carcinoembryonic antigen (CEA) levels among patients undergoing resection of colorectal liver metastases: do CEA levels still have prognostic implications? AB - BACKGROUND: The impact of prehepatectomy carcinoembryonic antigen (CEA) levels in the era of modern chemotherapy and expanded surgical indications for colorectal liver metastasis (CRLM) remains not well defined. METHODS: 484 patients were identified and divided into two groups by surgical time period (group 1: 2000 2007 vs. group 2: 2008-2015). The prognostic significance of pre-hepatectomy CEA was determined by assessing the HRs associated with various cut-off levels ranging from 5 to 200 ng/mL. RESULTS: Median CRLM number was comparable in both groups (group 1: 2 vs. group 2: 2, P = 0.504). Bilobar disease was more frequent in group 2 (30.1% vs. 42.5%, P = 0.006). The administration of modern chemotherapy and/or biologic agents increased over time (49.5% vs. 67.9%, P < 0.001). Preoperative CEA independently predicted OS in group 1, even with a cut off as low as >5 ng/mL. However, in group 2 it predicted recurrence and survival only after exceeding 70 and 50 ng/mL, respectively. Of note, in group 2, CEA was strongly associated with survival when CEA levels exceeded 70 ng/mL (HR 4.84). CONCLUSIONS: While pre-hepatectomy CEA level may still have prognostic utility in CRLM resection, the optimal cut-off value has increased in the era of modern chemotherapy. PMID- 27769663 TI - Influence of Adaptive Statistical Iterative Reconstruction on coronary plaque analysis in coronary computed tomography angiography. AB - PURPOSE: The purpose of this study was to study the effect of iterative reconstruction (IR) software on quantitative plaque measurements in coronary computed tomography angiography (CCTA). METHODS: Thirty patients with a three clinical risk factors for coronary artery disease (CAD) had one CCTA performed. Images were reconstructed using FBP, 30% and 60% adaptive statistical IR (ASIR). Coronary plaque analysis was performed as per patient and per vessel (LM, LAD, CX and RCA) measurements. Lumen and vessel volumes and plaque burden measurements were based on automatic detected contours in each reconstruction. Lumen and plaque intensity measurements and HU based plaque characterization were based on corrected contours copied to each reconstruction. RESULTS: No significant changes between FBP and 30% ASIR were found except for lumen- (-2.53 HU) and plaque intensities (-1.28 HU). Between FBP and 60% ASIR the change in total volume showed an increase of 0.94%, 4.36% and 2.01% for lumen, plaque and vessel, respectively. The change in total plaque burden between FBP and 60% ASIR was 0.76%. Lumen and plaque intensities decreased between FBP and 60% ASIR with -9.90 HU and -1.97 HU, respectively. The total plaque component volume changes were all small with a maximum change of -1.13% of necrotic core between FBP and 60% ASIR. CONCLUSIONS: Quantitative plaque measurements only showed modest differences between FBP and the 60% ASIR level. Differences were increased lumen-, vessel- and plaque volumes, decreased lumen- and plaque intensities and a small percentage change in the individual plaque component volumes. PMID- 27769665 TI - Ischemia-modified albumin as a predictor of the severity of acute appendicitis. AB - BACKGROUND: The early prediction of gangrenous/perforated appendicitis is of great importance for the surgical planning, further treatments, and predicting the course of disease. Ischemia-modified albumin (IMA) was previously reported as a biomarker of various ischemia-based diseases. Our aim is to determine the predictive value of serum IMA in the severity of acute appendicitis. METHODS: Sixty-two patients who underwent urgent appendectomy were included in the study. Plasma level of IMA was measured after diagnosis and before treatment. All patients were classified as noncomplicated (acute) appendicitis and complicated (gangrenous/perforated) appendicitis according to histopathological findings, and comparisons were made between the groups. RESULTS: The data of 62 patients with a mean age of 30.1 years were statistically evaluated. The pathological diagnoses were acute appendicitis in 33 (53.2%), and gangrenous/perforated appendicitis in 29 (46.8%) patients. There were significant differences in computed tomography (CT) findings (P = .031) and IMA (P = .012) levels between the groups. A strong positive correlation between IMA levels and CT findings was also found (Spearman rho = +0.688, P = .003). CONCLUSIONS: The IMA can be considered as a novel and useful marker to distinguish gangrenous/perforated appendicitis from noncomplicated appendicitis. The correlation of IMA with CT findings also enhances the predictive value of IMA. PMID- 27769664 TI - Obsessive-compulsive symptoms and negative affect during tobacco withdrawal in a non-clinical sample of African American smokers. AB - The association between obsessive-compulsive (OC) symptomatology and smoking is poorly understood, particularly in African Americans-a group subject to smoking- and OC-related health disparities. In a non-clinical sample of 253 African American smokers, we tested the negative reinforcement model of OC-smoking comorbidity, purporting that smokers with higher OC symptoms experience greater negative affect (NA) and urge to smoke for NA suppression upon acute tobacco abstinence. Following a baseline visit involving OC assessment, participants completed two counterbalanced experimental visits (non-abstinent vs. 16-h tobacco abstinence) involving affect, smoking urge, and nicotine withdrawal assessment. OC symptom severity predicted larger abstinence-provoked increases in overall NA, anger, anxiety, depression, fatigue, urge to smoke to suppress NA, and composite nicotine withdrawal symptom index. African American smokers with elevated OC symptoms appear to be vulnerable to negative reinforcement-mediated smoking motivation and may benefit from cessation treatments that diminish NA or the urge to quell NA via smoking. PMID- 27769666 TI - Predictive validity of different versions of the Triage Risk Screening Tool. PMID- 27769667 TI - Space dynamics and stochastic features of evolutionary game dynamics: Comment on: "Evolutionary game theory using agent-based methods" by Christoph Adami, Jory Schossau and Arend Hintze. PMID- 27769668 TI - The synthesis and biological evaluation of alkyl and benzyl naphthyridinium analogs of eupolauridine as potential antimicrobial and cytotoxic agents. AB - Eupolauridine, an indenonaphthyridine alkaloid, has been previously reported by us to exhibit antifungal activity. This study describes the synthesis of new alkyl and benzyl naphthyridinium/pyridinium analogs of eupolauridine as potential antifungal agents. A majority of the analogs exhibited antifungal activity against opportunistic pathogens such as Candida albicans and Cryptococcus neoformans. Several of them were also effective against bacteria (Staphylococcus aureus, MRS, Pseudomonas and Mycobacterium) and the malaria parasite (Plasmodium falciparum) to variable extents. A number of analogs were also cytotoxic to human cancer cell lines. PMID- 27769669 TI - Folic acid conjugates with photosensitizers for cancer targeting in photodynamic therapy: Synthesis and photophysical properties. AB - Recent researches in photodynamic therapy have focused on novel techniques to enhance tumour targeting of anticancer drugs and photosensitizers. Coupling a photosensitizer with folic acid could allow more effective targeting of folate receptors which are over-expressed on the surface of many tumour cells. In this study, different folic acid-OEG-conjugated photosensitizers were synthesized, characterized and their photophysical properties were evaluated. The introduction of an OEG does not significantly improve the hydrophilicity of the FA-porphyrin. All the FA-targeted photosensitizers present good to very good photophysical properties. The best one appears to be Ce6. Molar extinction coefficient, fluorescence and singlet oxygen quantum yields were determined and were compared to the corresponding photosensitizer alone. PMID- 27769670 TI - Bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones: New classes of antibacterial/antifungal agents. AB - The emergence of multidrug-resistant bacterial and fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicrobial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N' aryl-bishydrazones for their antibacterial and antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi step resistance-selection method, explored their potential to induce the production of reactive oxygen species, and assessed their toxicity. In summary, we found that these compounds exhibited broad-spectrum antibacterial and antifungal activities against most of the tested strains with minimum inhibitory concentration (MIC) values ranging from <0.5 to >500MUM against bacteria and 1.0 to >31.3MUg/mL against fungi; and in most cases, they exhibited either superior or similar antimicrobial activity compared to those of the standard drugs used in the clinic. We also observed minimal emergence of drug resistance to these newly synthesized compounds by bacteria and fungi even after 15 passages, and we found weak to moderate inhibition of the human Ether-a-go-go-related gene (hERG) channel with acceptable IC50 values ranging from 1.12 to 3.29MUM. Overall, these studies show that bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones are potentially promising scaffolds for the discovery of novel antibacterial and antifungal agents. PMID- 27769671 TI - Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy. AB - By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a-l contained 4-anilinoquinazolines with C-6 triazole linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild type EGFR, HDAC1, and HDAC6 with IC50 values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50 values between 0.49 and 8.76MUM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC. PMID- 27769672 TI - Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties. AB - Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3MUM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development. PMID- 27769674 TI - Saving Single-rooted Teeth with Combined Endodontic-periodontal Lesions. AB - INTRODUCTION: Teeth affected by combined endodontic-periodontal lesions are usually considered by all prognosis classifications as hopeless teeth. The development of new biomaterials combined with modern endodontic and periodontal regeneration techniques may improve dental prognosis and maintain the affected teeth. Moreover, 1 of the replacement options for those teeth, dental implants, has shown an increasing number of biological and technical complications. METHODS: Five patients were included in this case series study. Full periodontal and radiographic examination revealed generalized chronic periodontitis. Moreover, endodontic-periodontal lesions affecting single-rooted teeth were detected in those patients with tissue destruction beyond the apex. After splinting those teeth, conventional endodontic and nonsurgical periodontal treatment was performed. Three months later, periodontal regeneration was applied at those teeth in order to reconstruct supporting tissues and to improve dental prognosis. RESULTS: After a follow-up period ranging from 14 months to 17 years, it was observed that all teeth remain asymptomatic and in normal function. No signs of apical pathosis were observed, and the periodontium was stable. All patients were included in a strict maintenance program to check the periodontal and apical status. CONCLUSIONS: This case series shows that it is possible to change the prognosis of teeth affected by combined endodontic-periodontal lesions, even if the periodontal support is destroyed beyond the apex. PMID- 27769675 TI - Pain Reduction in Untreated Symptomatic Irreversible Pulpitis Using Liposomal Bupivacaine (Exparel): A Prospective, Randomized, Double-blind Trial. AB - INTRODUCTION: In the treatment of patients with symptomatic irreversible pulpitis, endodontic debridement is a predictable method to relieve pain. However, there are clinical situations in which emergency care cannot be provided immediately. An unexplored treatment option in these cases may be the use of a long-acting anesthetic to reduce pain in untreated irreversible pulpitis. Some medical studies have shown potential for infiltrations of liposomal bupivacaine (Exparel; Pacira Pharmaceuticals, San Diego, CA) to prolong pain relief and reduce opioid use postoperatively. The Food and Drug Administration has approved Exparel only for infiltrations; therefore, the purpose of this study was to compare an infiltration of liposomal bupivacaine versus bupivacaine for pain control in untreated, symptomatic irreversible pulpitis. METHODS: Ninety-five emergency patients received 2% lidocaine with 1:100,000 epinephrine via infiltration or an inferior alveolar nerve block to relieve their initial presenting pain. Patients then randomly received either 4 mL liposomal bupivacaine (13.3 mg/mL) or 4 mL 0.5% bupivacaine with 1:200,000 epinephrine by infiltration. Patients received a diary for the day of the appointment and 3 days postinjection to record soft tissue numbness, pain levels, and analgesic (non narcotic and narcotic) use. RESULTS: No significant differences (P < .05) were found between the 2 anesthetic formulations for pain or the use of pain medications. A statistically higher level of soft tissue numbness was found on days 1 to 3 for the liposomal bupivacaine group. CONCLUSIONS: Although liposomal bupivacaine had some effect on soft tissue anesthesia, it did not reduce pain to manageable clinical levels in patients presenting with untreated, symptomatic irreversible pulpitis. PMID- 27769676 TI - Material Properties of a Tricalcium Silicate-containing, a Mineral Trioxide Aggregate-containing, and an Epoxy Resin-based Root Canal Sealer. AB - INTRODUCTION: The aim was to compare the solubility, radiopacity, and setting times of a tricalcium silicate-containing (BioRoot RCS; Septodont, St Maur-des Fosses, France) and a mineral trioxide aggregate-containing sealer (MTA Fillapex; Angelus, Londrina, Brazil) with an epoxy resin-based sealer (AH Plus; Dentsply DeTrey, Konstanz, Germany). METHODS: Solubility in distilled water, radiopacity, and setting time were evaluated in accordance with ISO 6876:2012. The solubility was also measured after soaking the materials in phosphate-buffered saline buffer (PBS). All data were analyzed using 1-way analysis of variance and the Student Newman-Keuls test. RESULTS: After immersion for 1 minute in distilled water, BioRoot RCS was significantly less soluble than AH Plus and MTA Fillapex (P < .05). At all other exposure times, AH Plus was significantly less soluble than BioRoot RCS, whereas BioRoot RCS was significantly more soluble than the other 2 sealers (P < .05). All sealers had the same solubility in PBS and distilled water, except for BioRoot RCS after 28 days. At this exposure time, BioRoot RCS was significantly less soluble in PBS than in distilled water and less soluble than MTA Fillapex (P < .05). All BioRoot RCS specimens immersed in PBS had a surface precipitate after 14 and 28 days. The radiopacity of all sealers was greater than 3 mm aluminum with no statistical significant difference between the sealers (P > .05). The final setting time was 324 (+/-1) minutes for BioRoot RCS and 612 (+/-4) minutes for AH Plus. The difference was statistically significant (P < .05). MTA Fillapex did not set completely even after 1 week. CONCLUSIONS: The solubility and radiopacity of the sealers were in accordance with ISO 6876:2012. PBS decreased the solubility of BioRoot RCS. PMID- 27769678 TI - Serine-rich Repeat Adhesin Gordonii Surface Protein B is Important for Streptococcus gordonii Biofilm Formation. AB - INTRODUCTION: Streptococcus gordonii is a predominant member of the oral microflora and has been isolated from root canals of teeth with refractory apical periodontitis. Biofilm formation is important for various dental diseases, and S. gordonii is involved in dental biofilm formation as an early colonizer. Although serine-rich repeat (SRR) adhesins of S. gordonii such as gordonii surface protein B (GspB) are associated with bacterial colonization, the role of GspB in biofilm formation is not clearly understood. In the present study, we investigated the effect of S. gordonii GspB on biofilm formation using wild-type and GspB deficient mutant S. gordonii strains. METHODS: Confocal microscopy and crystal violet assay were used to determine biofilm formation. Bacterial growth was examined by measuring optical density with spectrometry. Bacterial adherence and biofilm on the culture plate and human dentin slices were visualized with a scanning electron microscope. RESULTS: The GspB-deficient S. gordonii mutant strain was less potent than the wild-type strain in biofilm formation. Of note, there was no difference in the bacterial growth rate between the mutant and wild type strains. Differences in biofilm-forming ability between the wild-type and mutant strains were more distinct in the sucrose-supplemented media. Furthermore, the GspB-deficient mutant exhibited attenuated formation of aggregates on the surface of the culture plate and human dentin slices. CONCLUSIONS: These results suggest that GspB is important for S. gordonii biofilm formation, which may contribute to the development of dental biofilm-associated diseases. PMID- 27769677 TI - Bond Strength of Self-adhesive Resin Cement to Different Root Perforation Materials. AB - INTRODUCTION: Different materials have been used for intervening in root perforations. These materials are often in contact with resin cements used for cementation of intraradicular retainers. The aim of this study was to evaluate the bond strength of self-adhesive resin cement to different materials used to treat root perforations (mineral trioxide aggregate [MTA], Portland cement [PORT], and glass ionomer cement [GIC]). METHODS: Four discs (10 * 1 mm) of each material (the MTA, PORT, and GIC groups) were embedded into polyvinyl chloride tubes using acrylic resin, ground, and polished until a flat surface was exposed. Afterward, 4 silicone molds were used to prepare self-adhesive resin cement cylinders (0.7 * 1 mm) on each disc surface (N = 16). The specimens were stored in deionized water at 37 degrees C for 24 hours and subjected to a microshear test. Then, the failure modes were examined. Data were submitted to statistical analysis (alpha = 0.05). RESULTS: The MTA and GIC groups showed significantly higher microshear bond strength values (3.36 +/- 1.56 and 2.90 +/- 1.49 MPa, respectively) than the PORT group (1.39 +/- 0.77 MPa) (P < .05). Only adhesive failure modes were observed. CONCLUSIONS: When PORT was used as a root perforation material, GIC should be used as a base over it to improve shear bond strength with self-adhesive resin cement. PMID- 27769679 TI - Maxillary Sinus Impaction of a Core Carrier Causing Sustained Apical Periodontitis, Sinusitis, and Nasal Stenosis: A 3-year Follow-up. AB - INTRODUCTION: The aim was to present a case report of a full-length extrusion of an obturator's core carrier into the maxillary sinus, causing clinical symptoms from the nose region with differential diagnostics aspects, which, in turn, led to several surgical treatments of the nostrils before diagnosis and correct endodontic retreatment of a maxillary right first molar. A 36-year-old man presented in 2012 with complaints from the right nostril region. Medical treatment with antibiotics and surgical procedures because of nasal stenosis resulted only in partial improvement. Five years earlier, a root canal treatment was performed on the maxillary right first molar. Intraoral radiographs revealed 10-mm overfilling of root filling material into the maxillary sinus from the palatal root of tooth #3. METHODS: Before surgical removal of the excess root filling material, orthograde revision was performed. Cone-beam computed tomographic imaging was used to localize the position of the root filling material, which protruded through the maxillary sinus and reached the inferior nasal wall. RESULTS: Surgical removal from the palatal aspect revealed that the root filling material was a core carrier of an obturator. Scanning electron microscopy and transmission electron microscopy showed evidence of microbial biofilm on the core carrier as well as remnants of sinus mucosa. At the long-term follow-ups, the tooth had healed apically, and symptoms of nasal stenosis were markedly reduced. CONCLUSIONS: This case report represents a challenging differential diagnostic topic urging the importance of a medical and dental interdisciplinary dialogue. The use of cone-beam computed tomographic imaging was crucial for the surgical retreatment. PMID- 27769680 TI - Evaluation of Root Canal Dentin Erosion after Different Irrigation Methods Using Energy-dispersive X-ray Spectroscopy. AB - INTRODUCTION: The purpose of this study was to examine the level of erosion in root dentin caused by different irrigation methods and protocols. METHODS: Thirty five extracted upper molar teeth were instrumented and divided into 7 groups to undergo treatment by different methods: negative control, GentleWave System (Sonendo Inc, Laguna Hills, CA), and syringe needle irrigation following different protocols. The teeth were instrumented to size #25/.08 or #30/.09 for needle irrigation groups and to ProTaper size S1 for the GentleWave group under 5% sodium hypochlorite (NaOCl). The needle irrigation groups were subjected to final rinses of 2 minutes of 3% NaOCl + 2 minutes of 8% EDTA (3% N2 + 8% E2), 2 minutes of 3% NaOCl + 2 minutes of 8% EDTA + 1 minute of 3% NaOCl (3% N2 + 8% E2 + 3% N1), 2 minutes of 5% NaOCl + 2 minutes of 17% EDTA (5% N2 + 17% E2), 2 minutes of 5% NaOCl + 2 minutes of 17% EDTA + 1 minute of 5% NaOCl (5% N2 + 17% E2 + 5% N1), and 5 minutes of 5% NaOCl + 5 minutes of 17% EDTA + 5 minutes of 5% NaOCl (5% N5 + 17% E5 + 5% N5), respectively. The root canal surface was observed by scanning electron microscopy, and the dentin composition was analyzed by continuous line scanning for 300 MUm into dentin using energy-dispersive X-ray spectroscopy. RESULTS: A slight but statistically significant decrease of calcium and an increase of carbon was measured in the 5% N2 + 17% E2 group in comparison with the control; no significant difference was found among GentleWave, 3% N2 + 8% E2, and 5% N2 + 17% E2 (P > .05). A final 1-minute rinse with 3% or 5% NaOCl reduced calcium and phosphorus to a significantly lower level than in groups without a 1-minute final rinse (P < .05). Final irrigation with 5% NaOCl for 5 minutes removed almost all calcium and phosphorus. Scanning electron microscopy showed canal wall erosion when an additional final irrigation with NaOCl was done. CONCLUSIONS: NaOCl followed by final EDTA irrigation performed either by syringe needle or the GentleWave System caused minimal dentin erosion. Erosion was measured as increased loss of calcium and phosphorus in samples in which additional final irrigation was performed using NaOCl after EDTA. PMID- 27769681 TI - Evaluation of a commercial multiplex PCR (Unyvero i60(r)) designed for the diagnosis of bone and joint infections using prosthetic-joint sonication. AB - BACKGROUND: The development of sonication protocols over the last few years has improved the sensitivity of conventional cultures for the diagnosis of prosthetic joint infection (PJI). However, the development of a new, specifically designed kit for the molecular diagnosis of PJI could provide a major improvement in this field. METHODS: Prostheses retrieved from patients who underwent implant removal from May 2014 to May 2015 were sent for culture, and processed according to a previously defined protocol that included sonication. Furthermore, 180 microlitres of sonication fluid were used to carry out the multiplex PCR test (Unyvero i60 system(r)). A comparison of the sensitivity, specificity, positive (PPV) and negative (NPV) predictive value, was performed. The study was approved by the Clinical Research Ethics Committee. RESULTS: The analysis included 88 prostheses from 68 patients (1.29 prostheses/patient). The type of prostheses studied were knee (n=55), total hip (n=26), partial hip (n=5), and shoulder (n=2). Twenty-nine patients were diagnosed with a PJI (15 delayed, 12 acute, and 2 haematogenous infections). In 24 cases, the result of the PCR was positive, all but 1 corresponding to patients with clinical criteria of PJI. Nine resistance mechanisms were detected from 5 samples. The Unyvero i60 system(r) showed slightly better results than traditional culture in terms of specificity and PPV. CONCLUSIONS: The Unyvero i60 system(r) may play a role in rapid diagnosis of PJI, due to its high specificity and PPV. However, despite these results, cultures have to be performed to detect organisms not detected by the system. PMID- 27769673 TI - Not just an antibiotic target: Exploring the role of type I signal peptidase in bacterial virulence. AB - The looming antibiotic crisis has prompted the development of new strategies towards fighting infection. Traditional antibiotics target bacterial processes essential for viability, whereas proposed antivirulence approaches rely on the inhibition of factors that are required only for the initiation and propagation of infection within a host. Although antivirulence compounds have yet to prove their efficacy in the clinic, bacterial signal peptidase I (SPase) represents an attractive target in that SPase inhibitors exhibit broad-spectrum antibiotic activity, but even at sub-MIC doses also impair the secretion of essential virulence factors. The potential consequences of SPase inhibition on bacterial virulence have not been thoroughly examined, and are explored within this review. In addition, we review growing evidence that SPase has relevant biological functions outside of mediating secretion, and discuss how the inhibition of these functions may be clinically significant. PMID- 27769682 TI - Vaccination coverage against pertussis in pregnant women of Catalonia in the first year of implementation of the immunisation program. AB - INTRODUCTION: The re-emergence of pertussis and the severity of its complications in infants younger than 3 months, were determining factors for starting a vaccination program for pregnant women in the third trimester of gestation in Catalonia in February 2014. This was the first autonomous community to introduce it in Spain. The aim of the study was to estimate the coverage of the program in its first year of implementation. METHODS: A retrospective analysis was performed on the data from the Primary Care Centre computerised medical records of pregnant women attending Sexual and Reproductive Health Care centres of the Metropolitan Nord area of the province of Barcelona, part of the Catalan Institute of Health. The overall coverage was estimated, as well as the sociodemographic variables of Tdap vaccination of women who had registered a delivery of a live birth between August 2014 and August 2015. RESULTS: A total of 6,697 deliveries of live births were recorded, and 1,713 pregnant women were vaccinated, which represented an overall coverage of 25.6% (95% CI; 24.1-26.1). Vaccination coverage was higher in pregnant women under 18 years and Spanish women (P=.018 and P=.036, respectively). CONCLUSION: The estimation of vaccine coverage against pertussis in pregnant women in the third trimester of pregnancy, after the first year of implementation of the program in a health area of Catalonia was lower than the objective set. Strategies need to be designed in order to improve program coverage. PMID- 27769683 TI - Low prevalence of mcr-1 positive Enterobacteriaceae isolates in a health area. PMID- 27769684 TI - [Delayed adverse reactions to blood donation: From haemovigilance data to specific studies]. AB - OBJECTIVES: Delayed adverse reactions to blood donation occur after the donor left donation site. Their intrinsic gravity and possible complications can be increased by the fact the donor is alone. This can also increase bad memories, leading to a donation giving up. Blood transfusion centre is only aware in case of donor feedback, hence an event underrating. We choose to compare our data upon delayed adverse donor reactions with those we could find in past studies. METHODS: A first data level comes from French haemovigilance data while serious adverse reactions declaration is mandatory. But a second level can be reached using blood transfusion centre computerized data because all the donation reactions are saved whatever the gravity is. In both cases, delayed reactions are only those reported by donors. We try to make an exhaustive search of specific studies upon the real delayed reactions incidence so as to compare with our data. RESULTS: There were 1957 serious adverse reactions declared in our regional haemovigilance database between 2011 and 2015: 49 % occurring during donation, 40 % after it but before donor departure, and 11 % delayed events. There were 16,050 adverse reactions recorded during the first trimester of 2016 in mainland France, with 2.7 % delayed ones. Proportion of delayed events rises when gravity rises, until 27.6 % for the most serious ones. It varies between 2.2 % and 2.7 % for vasovagal reactions, haematomas, and other local reactions, and reaches 16.2 % for other general reactions. Data found in other studies with a spontaneous donor notification are of the same kind. But four studies soliciting specifically donor notification give a dramatically higher delayed reactions incidence, with an understatement greater than three out of four. Moreover, these studies found a majority of delayed reactions, which are not included in haemovigilance like fatigue or bruising. CONCLUSIONS: Occurrence of a delayed donor reaction is clearly underrated in standard haemovigilance. It remains to be seen whether it have the same impact on donor return as immediate reactions. Considering that delayed reactions are much larger, it might be interesting to take them into account in the evaluation of strategies dedicated to lower immediate reactions. PMID- 27769685 TI - Granuloma formation in leishmaniasis: A mathematical model. AB - Leishmaniasis is a disease caused by the Leishmania parasites. The two common forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is the more severe of the two and, if untreated, may become fatal. The hallmark of VL is the formation of granuloma in the liver or the spleen. In this paper, we develop a mathematical model of the evolution of granuloma in the liver. The model is represented by a system of partial differential equations and it includes migration of cells from the adaptive immune system into the granuloma; the rate of the influx is determined by the strength of the immune response of the infected individual. It is shown that parasite load decreases as the strength of the immune system increases. Furthermore, the efficacy of a commonly used drug, which increases T cells proliferation, increases in an individual with stronger immune response. The model also provides an explanation why, in contrast to humans, mice recover naturally from VL in the liver. PMID- 27769686 TI - Mathematical model of transmission dynamics and optimal control strategies for 2009 A/H1N1 influenza in the Republic of Korea. AB - A mathematical model for the transmission dynamics of the 2009 A/H1N1 influenza epidemic in the Republic of Korea is developed. The simulation period is separated into three consecutive periods based on the government's intervention strategies: the nonpharmaceutical strategy is used during Period 1. The nonpharmaceutical and antiviral strategies are executed during Period 2 and the vaccine strategy is added during Period 3. During Period 1, we estimate the reduction in the transmission rate due to the government's intervention policies as a difference between the data-fitted and uncontrolled transmission rate that is derived from the basic reproductive number, R0, of the model without intervention. This quantified reduced transmission rate is used as an upperbound of the nonpharmaceutical control for studying optimal control strategies, which is a new approach for determining the realistic upperbound of control. In this study, we also explore the real-time prediction of incidence using the mathematical model during the early stage of the epidemic. We investigate the impact of vaccination coverage and timing with respect to the cumulative incidence. The result implies that early vaccination plays a significant role for preventing the epidemic. PMID- 27769687 TI - A cross-validation study of the TGMD-2: The case of an adolescent population. AB - OBJECTIVES: This study proposes an extension of a widely used test evaluating fundamental movement skills proficiency to an adolescent population, with a specific emphasis on validity and reliability for this older age group. DESIGN: Cross-sectional observational study. METHODS: A total of 844 participants (n=456 male, 12.03+/-0.49) participated in this study. The 12 fundamental movement skills of the TGMD-2 were assessed. Inter-rater reliability was examined to ensure a minimum of 95% consistency between coders. Confirmatory factor analysis was undertaken with a one-factor model (all 12 skills) and two-factor model (6 locomotor skills and 6 object-control skills) as proposed by Ulrich et al. (2000). The model fit was examined using chi2, TLI, CFI and RMSEA. Test-retest reliability was carried out with a subsample of 35 participants. RESULTS: The test-retest reliability reached Intraclass Correlation Coefficient of 0.78 (locomotor), 0.76 (object related) and 0.91 (gross motor skill proficiency). The confirmatory factor analysis did not display a good fit for either the one-factor or two-factor model due to a really low contribution of several skills. A reduction in the number of skills to just seven (run, gallop, hop, horizontal jump, bounce, kick and roll) revealed an overall good fit by TLI, CFI and RMSEA measures. CONCLUSIONS: The proposed new model offers the possibility of longitudinal studies to track the maturation of fundamental movement skills across the child and adolescent spectrum, while also giving researchers a valid assessment to tool to evaluate adolescent fundamental movement skills proficiency level. PMID- 27769688 TI - Rate of Oophorectomy for Benign Indications in a Children's Hospital: Influence of a Gynecologist. AB - STUDY OBJECTIVE: To compare the rates of oophorectomy performed by pediatric surgeons for benign indications before and after the addition of a gynecologist to the surgical staff of a children's hospital. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We used a retrospective chart review of patients ages 5-21 years who underwent surgical management by pediatric surgeons for benign adnexal indications at a tertiary care children's hospital. Patient characteristics and clinical outcomes were recorded. Rates of oophorectomy for patients managed before the addition of a gynecologist (1998-2004) were compared with those managed after a gynecologist joined the surgical staff (2005-2013). Logistic regression analysis was conducted to compare the likelihood of oophorectomy before and after the addition of a gynecologist to the surgical staff. RESULTS: One hundred sixty-five cases were included in the final analysis. Pediatric surgeons were 8 times more likely to perform an oophorectomy for benign indications before the addition of a gynecologist to the surgical staff (odds ratio, 8.3; 95% confidence interval, 3.76-18.16). Oophorectomy was performed in 45% (25/56) of cases from 1998 to 2004 compared with 11% (12/109) of cases from 2005 to 2013. Younger age (P = .009), ischemic-appearing adnexa (P < .0001), presence of torsion (P = .017), and mature teratoma (P = .041) were associated with higher likelihood of oophorectomy. CONCLUSION: There was a higher rate of ovarian preservation for benign indications performed by pediatric surgeons after the addition of a gynecologist to the surgical staff. Younger patients, those with a mature teratoma, and ovarian torsion continue to be at higher risk for oophorectomy. PMID- 27769689 TI - Fetiform Teratoma in the Ovary of a 7-Year-Old Girl: A Case Report. AB - BACKGROUND: Fetiform teratoma, a highly differentiated mature cystic teratoma resembling a fetus, is rare and typically found in the ovaries of women of reproductive age. In this report we describe, to our knowledge, the youngest case of ovarian fetiform teratoma. CASE: A 7-year-old girl presented with acute abdominal pain. Radiological examinations revealed a 5.2-cm ovarian complex cystic mass with fetal-like components in favor of fetus in fetu and teratoma. After surgical removal, the mass resembled a fetus consisting of a head, two eye slits, two small upper limb projections, and hair. Pathology indicated mature cystic teratoma supporting the diagnosis of fetiform teratoma. SUMMARY AND CONCLUSION: Although not commonly found in children, fetiform teratoma must be considered in the diagnosis of a child who presents with an adnexal mass resembling a fetus. PMID- 27769691 TI - The rising zebrafish research in China: Meeting report of the 3rd Chinese Zebrafish Principal Investigator Meeting & the Inaugural Meeting of China Zebrafish Society. PMID- 27769690 TI - Dietary Lactobacillus acidophilus modulated skin mucus protein profile, immune and appetite genes expression in gold fish (Carassius auratus gibelio). AB - The objective of the present study was to investigate the effect of dietary Lactobacillus acidophilus on skin mucus protein pattern, immune and appetite related genes expression as well as growth performance in gold fish (Carassius auratus gibelio). Three hundred healthy gold fish (2.5 +/- 0.05) juveniles were randomly distributed in 12 glass aquariums (400-L; 25 fish per aquaria) and fed experimental diets contain different levels of L. acidophilus (0, 1.5 * 108, 3 * 108 and 6 * 108) for 8 weeks. SDS-PAGE analysis of skin mucus protein profile at the end of the feeding trial revealed differences in protein profile of probiotic fed fish and control group; even three new bands were observed in L. acidophilus treated groups. Furthermore, fish fed 6 * 108 CFU g-1 supplemented diet showed up regulation of both TNF-1alpha and TNF-2alpha gene expression (P < 0.05). Evaluation of appetite related gene expression showed down-regulation of ghrelin in probiotic fed fish compared those of control treatment (P < 0.05). However, administration of different levels of L. acidophilus had no significant effects on growth performance (P > 0.05). These results demonstrated that while no beneficial effects on growth performance, dietary L. acidophilus affects immune and appetite related genes expression as well as skin mucus protein profile. PMID- 27769692 TI - Rehabilitation of right (personal) neglect by prism adaptation: A case report. PMID- 27769693 TI - Cdc42 regulates LPS-induced proliferation of primary pulmonary microvascular endothelial cells via ERK pathway. AB - BACKGROUND: After stimulation due to injury, cell division cycle protein 42 (Cdc42) restores and enhances barrier functions by strengthening intercellular adherens junctions; however, its influence on cell proliferation after injury remains unknown. OBJECTIVE: In this study, we sought to investigate the effect of stimulation using small doses of lipopolysaccharide (LPS) on the proliferation of pulmonary microvascular endothelial cells (PMVECs). METHODS: We stimulated PMVECs with different doses of LPS and evaluated the effects on cell proliferation. We also constructed a primary gene-knockout cell line lacking Cdc42 to verify the role of Cdc42 in regulating the proliferation of PMVECs that were stimulated using LPS and to explore related signaling pathways. RESULTS: Stimulating PMVECs with small doses of LPS increased proliferation. Cdc42 is involved in regulating this process, which was mediated by the extracellular regulated protein kinase (ERK) pathway. CONCLUSIONS: Cdc42 plays a role in regulating the proliferation of PMVECs stimulated with small doses of LPS, and this regulation involves the ERK pathway. PMID- 27769694 TI - Cuff pressure monitoring by manual palpation in intubated patients: How accurate is it? A manikin simulation study. AB - BACKGROUND: Endotracheal intubation (ETI) for mechanical ventilation has a central role in the Intensive Care Unit (ICU). ETI is one of the main risk factors for the development of ventilator-associated pneumonia (VAP) as its presence reduces the natural defences of the upper airway and allows the micro suction of secretions in the airways. In order to minimise such complications, it is fundamental to maintain a suitable pressure inside the tube cuff. AIM AND SCOPE: The main objective of the present study is to evaluate the effectiveness and reliability of palpation method, performed with the operators fingers, for detecting the tube cuff pressure. RESULTS: The study was performed using a manikin to test the pressure of the ETT cuff, on a sample constituted by nurses employed in three Italian ICU from two different Umbrian hospitals. From a total of 68 participants, detection by palpation method revealed to be not correct in 68% of cases; in particular, only 10% of respondents can correctly detect a pressure in the recommended range (20-30cmH2O) using palpation. Moreover it was possible to highlight that the participation in emergency courses has a positive effect on the correct measurement of cuff pressure using the palpation method (V=0.501). CONCLUSIONS: The study, in agreement with the literature, confirms the thesis that the palpation method is inadequate to determine an estimate of the pressure existing inside the cuff. PMID- 27769695 TI - A surprise during ultrasound-guided catheterization of the internal yugular vein: Aberrant common carotid artery. PMID- 27769696 TI - Relationship Between Acoustic Voice Onset and Offset and Selected Instances of Oscillatory Onset and Offset in Young Healthy Men and Women. AB - OBJECTIVE: This study aimed to investigate the relationship between (1) onset of the acoustic signal (X1a) and prephonatory phases associated with oscillatory onset and (2) offset of the acoustic signal (X2a) with the postphonatory events associated with oscillatory offset across vocally healthy adults. SUBJECTS AND METHODS: High-speed videoendoscopy was captured simultaneously with the acoustic signal during repeated production of /hi.hi.hi/ at typical pitch and loudness from 56 vocally healthy adults (aged 20-42 years; 21 men, 35 women). The relationships between the acoustic sound pressure signal and oscillatory onset and offset events from the glottal area waveforms (GAWs) were statistically investigated using a multivariate linear regression analysis. RESULTS: The X1a is a significant predictor of the onset of first oscillatory motion (X1g) and onset of sustained oscillations (X2g). X1a as well as gender are significant predictors of the first medial contact of the vocal folds (X1.5g). The X2a is a significant predictor of the first instance of oscillatory offset (X3g), first instance of incomplete glottal closure (X3.5g), and complete cessation of (vocal fold) oscillatory motion (X4g). CONCLUSIONS: The acoustic signal onset is closely related to the X1.5g, but the latency between these events is longer for women compared to men. The X2a occurs immediately after incomplete glottal adduction. The emerging normative group latencies between the onset and offset of the acoustic and the GAW from this study appear promising for future investigations. PMID- 27769697 TI - Efficacy of Water Resistance Therapy in Subjects Diagnosed With Behavioral Dysphonia: A Randomized Controlled Trial. AB - PURPOSE: The purpose of the present study was to determine the efficacy of water resistance therapy (WRT) in a long-term period of voice treatment in subjects diagnosed with voice disorders. METHODS: Twenty participants, with behavioral dysphonia, were randomly assigned to one of two treatment groups: (1) voice treatment with WRT, and (2) voice treatment with tube phonation with the distal end in air (TPA). Before and after voice therapy, participants underwent aerodynamic, electroglottographic, acoustic, and auditory-perceptual assessments. The Voice Handicap Index and self-assessment of resonant voice quality were also performed. The treatment included eight voice therapy sessions. For the WRT group, the exercises consisted of a sequence of five phonatory tasks performed with a drinking straw submerged 5 cm into water. For the TPA, the exercises consisted of the same phonatory tasks, and all of them were performed into the same straw but the distal end was in air. RESULTS: Wilcoxon test showed significant improvements for both groups for Voice Handicap Index (decrease), subglottic pressure (decrease), phonation threshold pressure (decrease), and self perception of resonant voice quality (increase). Improvement in auditory perceptual assessment was found only for the TPA group. No significant differences were found for any acoustic or electroglottographic variables. No significant differences were found between WRT and TPA groups for any variable. CONCLUSIONS: WRT and TPA may improve voice function and self-perceived voice quality in individuals with behavioral dysphonia. No differences between these therapy protocols should be expected. PMID- 27769698 TI - Shape of Thyroid Cartilage Influences Outcome of Montgomery Medialization Thyroplasty: A Gender Issue. AB - OBJECTIVE: This study aimed to determine whether the shape of the thyroid cartilage and gender influence voice outcomes after a Montgomery thyroplasty implant system (MTIS). METHODS: A retrospective cohort study was performed on 20 consecutive patients who underwent MTIS. Voice outcome variables were the relative decrease in Voice Handicap Index (%) and the absolute increase in maximum phonation time (MPT) (in seconds). Material variables were the angle between the thyroid cartilage laminae (alpha-angle), the size of the prosthesis, and a combination of both (the alpha-ratio). Continuous variables were analyzed using medians and were compared between groups using the Mann-Whitney U test. Factors associated with the outcome variables were assessed by multivariable linear regression. A Pearson coefficient was calculated between material variables. RESULTS: The absolute increase in MPT between the pre- and postoperative period was significantly different between men and women, with a median absolute increase of 11.0 seconds for men and of 1.3 seconds for women (P < 0.001). A strong inverse correlation between the alpha-ratio and the absolute increase in MPT is observed in all patients, with a Pearson correlation coefficient R = -0.769 (P < 0.001). No factors were significantly associated with the relative Voice Handicap Index decrease in univariable or multivariable analyses. A better Pearson coefficient between the alpha-angle and the prosthesis size was found for females (0.8 vs 0.71). CONCLUSION: The MTIS is a good thyroplasty modality for male patients, but inadequate design of MTIS female implants leads to poor MPT outcomes. This represents a gender issue that needs to be further studied and eventually tackled. PMID- 27769699 TI - Status of private rheumatology in Spain. AB - INTRODUCTION: Rheumatologic care is offered by the National Health System in Spain. However, more than a quarter of health spending is carried out in private medicine. Currently, there are no data about the number of rheumatologists with private activity in Spain. OBJECTIVES: To evaluate the number of rheumatologists with private activity in Spain and to describe the profile and location of these professionals. MATERIAL AND METHODS: A survey was developed and sent from the SER Commission on Private Practice to all SER active members. Data collection ends in December 2014. A descriptive statistical analysis and comparison of results was done. RESULTS: 759 answers from a total of 980 surveys sent (77.45%) were obtained; 38% of Spanish rheumatologists have private activity; 13% exclusively private practice and 25% private practice shared with his or her public activity. The private practice rheumatologist profile is: male, 49 years old with 19 years of experience after finishing the specialty and with a working day of 42hours per week. There is a clear predominance of private practice in the Autonomous Community of Catalonia with 28% of the total, followed by Madrid 18%, Andalusia 12% and Valencia 8%. CONCLUSIONS: 38% of Spanish rheumatologists are working in private practice. The profile of professionals working in private practice is different from that of those who work exclusively in public health. Private rheumatology is located in all regions, although most private rheumatologists are located in the regions of Catalonia, Madrid, Valencia and Andalusia, representing more than 50% of the total. PMID- 27769700 TI - Effects of thyroid hormones on aortic tissue after myocardial infarction in rats. AB - Studies have shown a cardioprotective role of thyroid hormones (THs) in cardiac remodeling after acute myocardial infarction (MI). However, there is no data in the literature examining the influence of TH administration on the aortic tissue in an animal model of MI. This study aimed to evaluate the effects of thyroid hormones on the aorta after MI. Male Wistar rats were divided into a sham group (SHAM), infarcted group (AMI), sham+TH (SHAMT) and AMI+TH (AMIT). After MI, the animals received T3 and T4 (2 and 8MUg/100g/day, respectively) by oral gavage for 12 days. Later, the animals underwent echocardiography and euthanasia and the aorta was collected for molecular and biochemical analysis. T3 and T4 administration increased the expression of the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1alpha (HIF-1alpha) in the aorta of AMIT rats when compared with AMI. With respect to TH receptors, AMI rats presented a decrease in TRbeta levels, which was prevented by the hormonal administration. In AMIT rats, both TRalpha and TRbeta levels were increased when compared with the AMI group. Reactive oxygen species levels and NADPH oxidase activity were decreased in both treated groups when compared with the non-treated animals. TH administration after MI may improve angiogenic signaling in the aorta as well as the responsiveness of this vessel to T3 and T4. These positive effects in the aorta may result in additional protection for the cardiovascular system in the context of cardiac ischaemic injury. PMID- 27769702 TI - Efficacy of ethanol in hand hygiene against adenoviruses. PMID- 27769701 TI - Pain-depression dyad induced by reserpine is relieved by p,p'-methoxyl-diphenyl diselenide in rats. AB - Depression and pain comorbidity represent a neuropsychiatric condition with substantial socioeconomic impact to society. The commonly used antidepressants and analgesics to treat this comorbidity have shown restricted clinical efficacy. In this way, the aim of this study was to investigate the behavioral, biochemical and neurochemical effects of a p,p'-methoxyl-diphenyl diselenide (OMePhSe)2 supplemented diet on pain-depression dyad induced by reserpine in rats. Adult Wistar rats were fed with 10mg (MeOPhSe)2 per kg of rat chow supplemented diet for 30 days. Pain-depression dyad was induced by daily subcutaneous reserpine injection (0.5mg/kg for three consecutive days) from 22 to 24 day of (MeOPhSe)2 supplementation. The results showed that the reserpine injected rats had behavior phenotypes typical of depression-pain dyad and the (MeOPhSe)2-supplemented diet protected against these modifications. Furthermore, the (MeOPhSe)2 dietary supplementation was effective against the increase in the prefrontal cortical MDA levels caused by reserpine. (MeOPhSe)2-supplemented diet triggered a per se augmentation of Nrf-2 levels. The [3H] serotonin uptake, [3H] glutamate uptake and release and MAO activity were not altered in the prefrontal cortices of rats from any experimental group. Therefore, the results indicate that protective effects of a (MeOPhSe)2-supplemented diet can be mediated, at least in part, by its antioxidant property. PMID- 27769703 TI - The practice of disinfection of high-speed handpieces with 70% w/v alcohol: An evaluation. AB - A high-speed handpiece is used in several dental procedures and the official recommendation for safe decontamination consists of rinsing with water, washing with detergent, mechanical friction, and sterilization; however, many professionals only apply 70% w/v alcohol without also cleaning the tool between patients. We performed an analysis of high-speed handpieces reprocessed only with 70% w/v alcohol and found that the methods used in clinical practice are not safe. PMID- 27769704 TI - An alternative to singing "Happy Birthday": Healthcare provider's rhyme for handwashing time. PMID- 27769705 TI - Glove perforation and contamination in fracture fixation surgeries. AB - The aim of the present study was to investigate glove contamination and perforation rate during traumatic orthopedic surgeries and evaluate the factors affecting glove contamination and perforation. There were significant differences in glove contamination among different surgery stages. In terms of contamination and perforation, there were significant differences between surgeons and assistants (ie, scrub-nurses). PMID- 27769706 TI - Risk factors for high death and loss-to-follow-up rates among patients with multidrug-resistant tuberculosis at a programmatic management unit. AB - Among 186 retrospectively evaluated patients with multidrug-resistant tuberculosis, 33.9% were cured, 6.6% completed treatment, 25% died, 18.3% were lost to follow-up, 2.2% failed treatment, and 13.8% were still undergoing treatment by the end of the study period. Rural residence was a risk factor for loss to follow-up (odds ratio [OR], 3.315; P = .016), whereas baseline body weight <40 kg (OR, 2.175; P = .042) and resistance to ofloxacin (OR, 2.889; P = .025) were risk factors for death. Despite programmatic management, treatment outcomes of the current cohort were distressing. PMID- 27769707 TI - Neglected disease in mentally ill patients: Major tuberculosis outbreak in a psychiatric hospital. AB - As tuberculosis incidence decreases, the possibility of overlooking the disease increases, especially in vulnerable populations. We describe here a major tuberculosis outbreak among mentally ill patients in Croatia, focusing on 1 regional hospital where most patients were hospitalized. The outbreak emphasizes the vulnerability of mentally ill patients to tuberculosis infection and the complexity of infection control measures in psychiatric institutions. The awareness of tuberculosis in these settings should be maintained to interrupt prolonged exposure and avoid unnecessary infection. PMID- 27769708 TI - Beyond extensively drug-resistant tuberculosis in Lisbon, Portugal: a case of linezolid resistance acquisition presenting as an iliopsoas abscess. PMID- 27769709 TI - Therapeutic drug management of linezolid: a missed opportunity for clinicians? AB - Some studies have shown that adjustments to the linezolid dose guided by therapeutic drug monitoring (TDM) can reduce interindividual variability in drug exposure and improve linezolid tolerability. In this study, 6 years of linezolid TDM, a diagnostic service for our hospital and others in the Milan (Italy) area, is described. Samples were collected immediately before the morning dose intake (trough concentrations) in steady-state conditions. Linezolid concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method. Four hundred linezolid trough concentrations from 220 patients were collected. A 20-fold variability in linezolid levels was observed. Positive and significant correlations between linezolid trough concentrations and patient age (r = 0.325, P <0.01) or serum creatinine (r = 0.511, P <0.01) were found. A progressive increase in linezolid concentrations with time was observed in a subgroup of patients with more than one TDM assessment. Elderly patients, especially those aged >80 years and with impaired renal function, are at a higher risk of overexposure to linezolid. Despite the observed progressive increase in linezolid concentrations over time, most physicians did not change the drug dose according to the TDM results, even in the presence of frank overexposure to linezolid. PMID- 27769710 TI - Elevated urinary levels of 8-oxo-2'-deoxyguanosine, (5'R)- and (5'S)-8,5'-cyclo 2'-deoxyadenosines, and 8-iso-prostaglandin F2alpha as potential biomarkers of oxidative stress in patients with prediabetes. AB - Prediabetes is the preclinical stage of type 2 diabetes mellitus (T2DM) with intermediate state of hyperglycemia. Hyperglycemia results in a state of oxidative stress, which may contribute to the production of insulin resistance, beta-cell dysfunction and long-term complications of diabetes. Novel approaches are required for prevention and treatment of diabetes. New biomarkers that can be used in risk stratification and therapy control as supplementary to current parameters are needed. These biomarkers may facilitate a more individualized and sufficient treatment of diabetes. Therefore, the aim of this study was to investigate the levels of oxidatively induced DNA damage products, 8-oxo-2' deoxyguanosine (8-oxo-dG) (also known as 8-OH-dG), (5'R)- and (5'S)-8,5'-cyclo-2' deoxyadenosines (R-cdA and S-cdA), and the lipid peroxidation product 8-iso prostaglandin F2alpha (8-iso-PGF2alpha) as reliable oxidative stress markers in patients with prediabetes or T2DM in comparison with healthy volunteers. Urine samples were collected from these subjects. Absolute quantification of 8-oxo-dG, R-cdA, S-cdA and 8-iso-PGF2alpha was achieved by liquid chromatography-isotope dilution tandem mass spectrometry. The levels of 8-oxo-dG, S-cdA and 8-iso PGF2alpha were significantly greater in prediabetes patients than those in healthy volunteers. T2DM patients also had higher levels of 8-oxo-dG than healthy volunteers. No statistically significant difference was observed for R-cdA levels. 8-Oxo-dG levels positively correlated with R-cdA and S-cdA levels for prediabetes and newly diagnosed T2DM. S-cdA levels and HbA1c were found negatively correlated in prediabetes patients. Also 8-iso-PGF2alpha levels and HbA1c were found negatively correlated in prediabetes patients. These results indicate that oxidatively induced macromolecular damage appears before the establishment of T2DM. Thus, our data suggest that oxidatively induced DNA damage and lipid peroxidation products that were found to be elevated in prediabetic stage may be used as early disease markers in patients at risk for T2DM. PMID- 27769711 TI - Esculetin prevents non-alcoholic fatty liver in diabetic mice fed high-fat diet. AB - This study investigated the effects and mechanism of esculetin (6,7 dihydroxycoumarin) on non-alcoholic fatty liver in diabetic mice fed high-fat diet (HFD). The diabetic mice model was induced by injection of streptozotocin, after which they were fed HFD diet with or without esculetin for 11 weeks. Non diabetic mice were provided a normal diet. Diabetes induced hepatic hypertrophy, lipid accumulation and droplets; however, esculetin reversed these changes. Esculetin treatment in diabetic mice fed HFD significantly down-regulated expression of lipid synthesis genes (Fasn, Dgat2 and Plpp2) and inflammation genes (Tlr4, Myd88, Nfkb, Tnfalpha and Il6). Moreover, the activities of hepatic lipid synthesis enzymes (fatty acid synthase and phosphatidate phosphohydrolase) and gluconeogenesis enzyme (glucose-6-phosphatase) in the esculetin group were decreased compared with the diabetic group. In addition, esculetin significantly reduced blood HbA1c, serum cytokines (TNF-alpha and IL-6) and chemokine (MCP-1) levels compared with the diabetic group without changing the insulin content in serum and the pancreas. Hepatic SOD activity was lower and lipid peroxidation level was higher in the diabetic group than in the normal group; however, esculetin attenuates these differences. Overall, these results demonstrated that esculetin supplementation could protect against development of non-alcoholic fatty liver in diabetes via regulation of lipids, glucose and inflammation. PMID- 27769712 TI - CWF-145, a novel synthetic quinolone derivative exerts potent antimitotic activity against human prostate cancer: Rapamycin enhances antimitotic drug induced apoptosis through the inhibition of Akt/mTOR pathway. AB - CWF-145, a synthetic 2-phenyl-4-quinolone derivative exerted potent cytotoxicity against prostate cancer. CWF-145 inhibited prostate cancer cell lines PC-3, DU 145 and LNCap. It had a very low IC50 about 200 nM against castrate-resistant prostate cancer (CRPC) PC-3. We found that CWF-145 had a similar effect to clinical trial antimitotic agents in cancer cells and normal cells. CWF-145 arrested cell cycle at G2/M phase by binding to the beta-tubulin at the colchicine-binding site then disrupted microtubule polymerization. Furthermore, the damaged microtubule affected the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our data showed that CWF-145 activated Akt and mTOR expression to increase emi1 accumulation and inhibit APC. The increased cyclin B1 and securin arrested cell cycle at G2/M phase. Moreover, we showed that Akt activation markedly increased resistance to microtubule-directed agents, including CWF-145, colchicine, and paclitaxel. Interestingly, rapamycin inhibited Akt-mediated therapeutic resistance, indicating that these effects were dependent on mTOR. Taken together, these observations suggest that activation of the Akt/mTOR signaling pathway can promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data may provide insight into potentially synergistic combinations of anticancer therapies. PMID- 27769713 TI - Androgens modify Wnt agonists/antagonists expression balance in dermal papilla cells preventing hair follicle stem cell differentiation in androgenetic alopecia. AB - In androgenetic alopecia, androgens impair dermal papilla-induced hair follicle stem cell (HFSC) differentiation inhibiting Wnt signaling. Wnt agonists/antagonists balance was analyzed after dihydrotestosterone (DHT) stimulation in androgen-sensitive dermal papilla cells (DPC) cultured as spheroids or monolayer. In both culture conditions, DHT stimulation downregulated Wnt5a and Wnt10b mRNA while the Wnt antagonist Dkk-1 was upregulated. Notably, tissue architecture of DPC-spheroids lowers Dkk-1 and enhances Wnt agonists' basal expression; probably contributing to DPC inductivity. The role of Wnt agonists/antagonists as mediators of androgen inhibition of DPC-induced HFSC differentiation was evaluated. Inductive DPC-conditioned medium supplemented with DKK-1 impaired HFSC differentiation mimicking androgens' action. This effect was associated with inactivation of Wnt/beta-catenin pathway in differentiating HFSC by both DPC-conditioned media. Moreover, addition of WNT10b to DPC-medium conditioned with DHT, overcame androgen inhibition of HFSC differentiation. Our results identify DKK1 and WNT10b as paracrine factors which modulate the HFSC differentiation inhibition involved in androgen-driven balding. PMID- 27769715 TI - Re: Jaimin R. Bhatt, Patrick O. Richard, Nicole S. Kim, et al. Natural History of Renal Angiomyolipoma (AML): Most Patients with Large AMLs >4cm Can Be Offered Active Surveillance as an Initial Management Strategy. Eur Urol 2016;70:85-90. PMID- 27769716 TI - Visual search performance in infants associates with later ASD diagnosis. AB - An enhanced ability to detect visual targets amongst distractors, known as visual search (VS), has often been documented in Autism Spectrum Disorders (ASD). Yet, it is unclear when this behaviour emerges in development and if it is specific to ASD. We followed up infants at high and low familial risk for ASD to investigate how early VS abilities links to later ASD diagnosis, the potential underlying mechanisms of this association and the specificity of superior VS to ASD. Clinical diagnosis of ASD as well as dimensional measures of ASD, attention deficit/hyperactivity disorder (ADHD) and anxiety symptoms were ascertained at 3 years. At 9 and 15 months, but not at age 2 years, high-risk children who later met clinical criteria for ASD (HR-ASD) had better VS performance than those without later diagnosis and low-risk controls. Although HR-ASD children were also more attentive to the task at 9 months, this did not explain search performance. Superior VS specifically predicted 3 year-old ASD but not ADHD or anxiety symptoms. Our results demonstrate that atypical perception and core ASD symptoms of social interaction and communication are closely and selectively associated during early development, and suggest causal links between perceptual and social features of ASD. PMID- 27769714 TI - Ultradian glucocorticoid exposure directs gene-dependent and tissue-specific mRNA expression patterns in vivo. AB - In this paper we report differential decoding of the ultradian corticosterone signal by glucocorticoid target tissues. Pulsatile corticosterone replacement in adrenalectomised rats resulted in different dynamics of Sgk1 mRNA production, with a distinct pulsatile mRNA induction profile observed in the pituitary in contrast to a non-pulsatile induction in the prefrontal cortex (PFC). We further report the first evidence for pulsatile transcriptional repression of a glucocorticoid-target gene in vivo, with pulsatile regulation of Pomc transcription in pituitary. We have explored a potential mechanism for differences in the induction dynamics of the same transcript (Sgk1) between the PFC and pituitary. Glucocorticoid receptor (GR) activation profiles were strikingly different in pituitary and prefrontal cortex, with a significantly greater dynamic range and shorter duration of GR activity detected in the pituitary, consistent with the more pronounced gene pulsing effect observed. In the prefrontal cortex, expression of Gilz mRNA was also non-pulsatile and exhibited a significantly delayed timecourse of increase and decrease when compared to Sgk1, additionally highlighting gene-specific regulatory dynamics during ultradian glucocorticoid treatment. PMID- 27769717 TI - Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition. AB - Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1-5days postinfusion) and late (16 43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1-2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4-5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu?s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process. PMID- 27769719 TI - Analysis of the Cleavage Mechanism by Protein-Only RNase P Using Precursor tRNA Substrates with Modifications at the Cleavage Site. AB - Ribonuclease P (RNase P) is the enzyme that endonucleolytically removes 5' precursor sequences from tRNA transcripts in all domains of life. RNase P activities are either ribonucleoprotein (RNP) or protein-only RNase P (PRORP) enzymes, raising the question about the mechanistic strategies utilized by these architecturally different enzyme classes to catalyze the same type of reaction. Here, we analyzed the kinetics and cleavage-site selection by PRORP3 from Arabidopsis thaliana (AtPRORP3) using precursor tRNAs (pre-tRNAs) with individual modifications at the canonical cleavage site, with either Rp- or Sp phosphorothioate, or 2'-deoxy, 2'-fluoro, 2'-amino, or 2'-O-methyl substitutions. We observed a small but robust rescue effect of Sp-phosphorothioate-modified pre tRNA in the presence of thiophilic Cd2+ ions, consistent with metal-ion coordination to the (pro-)Sp-oxygen during catalysis. Sp-phosphorothioate, 2' deoxy, 2'-amino, and 2'-O-methyl modification redirected the cleavage mainly to the next unmodified phosphodiester in the 5'-direction. Our findings are in line with the 2'-OH substituent at nucleotide -1 being involved in an H-bonding acceptor function. In contrast to bacterial RNase P, AtPRORP3 was found to be able to utilize the canonical and upstream cleavage site with similar efficiency (corresponding to reduced cleavage fidelity), and the two cleavage pathways appear less interdependent than in the bacterial RNA-based system. PMID- 27769720 TI - Molecular analyses reveal two geographic and genetic lineages for tapeworms, Taenia solium and Taenia saginata, from Ecuador using mitochondrial DNA. AB - Tapeworms Taenia solium and Taenia saginata are the causative agents of taeniasis/cysticercosis. These are diseases with high medical and veterinary importance due to their impact on public health and rural economy in tropical countries. The re-emergence of T. solium as a result of human migration, the economic burden affecting livestock industry, and the large variability of symptoms in several human cysticercosis, encourage studies on genetic diversity, and the identification of these parasites with molecular phylogenetic tools. Samples collected from the Ecuadorian provinces: Loja, Guayas, Manabi, Tungurahua (South), and Imbabura, Pichincha (North) from 2000 to 2012 were performed under Maximum Parsimony analyses and haplotype networks using partial sequences of mitochondrial DNA, cytochrome oxidase subunit I (COI) and NADH subunit I (NDI), from Genbank and own sequences of Taenia solium and Taenia saginata from Ecuador. Both species have shown reciprocal monophyly, which confirms its molecular taxonomic identity. The COI and NDI genes results suggest phylogenetic structure for both parasite species from south and north of Ecuador. In T. solium, both genes gene revealed greater geographic structure, whereas in T. saginata, the variability for both genes was low. In conclusion, COI haplotype networks of T. solium suggest two geographical events in the introduction of this species in Ecuador (African and Asian lineages) and occurring sympatric, probably through the most common routes of maritime trade between the XV-XIX centuries. Moreover, the evidence of two NDI geographical lineages in T. solium from the north (province of Imbabura) and the south (province of Loja) of Ecuador derivate from a common Indian ancestor open new approaches for studies on genetic populations and eco-epidemiology. PMID- 27769722 TI - The use of patient-specific implants in orthognathic surgery: A series of 32 maxillary osteotomy patients. AB - The use of virtual surgery, patient-specific saw and drill guides, and custom made osteosynthesis plates is rapidly spreading from deformity surgery to orthognathic surgery. Most of the commercially available systems are using computer-aided design/computer-aided manufacture (CAD/CAM) wafers to produce patient-specific saw guides. However, most plate systems provided are still the conventional "in stock" mini plates that can be individually designed by pre bending according to the stereolithographic model of the patient. Custom made three-dimensional (3D) printed implants have earlier been demonstrated to be an ideal solution in deformity surgery and in reconstruction of complex posttraumatic cases. In this study, we report the novel use of patient-specific saw and drill guides combined with patient-specific 3D titanium alloy implants as a fixation system in maxillary movement after Le Fort I and bimaxillary osteotomies (n = 32). The implants were individually designed for each patient to follow anatomical structures and to provide exact positioning and stability of the repositioned maxilla. PMID- 27769718 TI - Choose Your Own Adventure: The Role of Histone Modifications in Yeast Cell Fate. AB - When yeast cells are challenged by a fluctuating environment, signaling networks activate differentiation programs that promote their individual or collective survival. These programs include the initiation of meiotic sporulation, the formation of filamentous growth structures, and the activation of programmed cell death pathways. The establishment and maintenance of these distinct cell fates are driven by massive gene expression programs that promote the necessary changes in morphology and physiology. While these genomic reprogramming events depend on a specialized network of transcription factors, a diverse set of chromatin regulators, including histone-modifying enzymes, chromatin remodelers, and histone variants, also play essential roles. Here, we review the broad functions of histone modifications in initiating cell fate transitions, with particular focus on their contribution to the control of expression of key genes required for the differentiation programs and chromatin reorganization that accompanies these cell fates. PMID- 27769721 TI - Intraosseous stability of dental implants in free revascularized fibula and iliac crest bone flaps. AB - The aim of this study was to investigate the influence of two different microvascular reanastomized bone transplants on primary (PS) and secondary stability (SS) of dental implants. Totally 96 implants (Bone Level, Institut Straumann AG, Basel, Switzerland) were inserted in fibula (n = 50) and iliac crest (n = 46) in mean of 97.7 SD 75.6 weeks after performing reconstructive surgery. For measuring PS and SS the resonance frequency (RFA) analysis was used in mesiodistal and vestibulo-oral direction to quantify the implant stability quotient (ISQ). Mean values (ISQ) for PS in fibula was about 79.48 SD 2.41 and in iliac crest 61.10 SD 3.34 as well as SS in fibula was about 75.59 SD 5.10 and in iliac crest 73.63 SD 5.34. Statistically significant differences between both flaps were found for PS in mesiodistal and vestibulooral direction (p < 0.001). Between the primary and SS a significant decrease was recognized in fibula flap (p < 0.01) as well as an increase in iliac crest flap (p < 0.001). Statistically no difference was found between both bone flaps for SS (p = 0.076). The implant stability in fibula and iliac crest flap after osseointegration is similar to each other. Therefore, it is not important for choosing the suitable donor side. PMID- 27769723 TI - An extended transcaruncular approach for naso-orbito-ethmoid and Le Fort II fracture repair. AB - BACKGROUND: Recent advancements in computed tomography have enabled the diagnosis of naso-orbito-ethmoid (NOE) fractures to be made in much greater detail. Surgical access to the upper nasofrontal buttress in NOE fractures, however, has remained unchanged over the past decades. All approaches to these fractures using skin incisions have individual drawbacks. The transcaruncular approach is free of the drawbacks of the cutaneous approaches. We further extended the transcaruncular approach for the treatment of NOE and Le Fort II fractures. METHODS: Eight patients; six with Markowitz's Type I NOE fractures and two with Le Fort II fractures, underwent fracture repair using an extended transcaruncular approach to access the upper nasofrontal buttress. RESULTS: In all but one case, which required an additional small skin incision on the glabella, the fracture on the upper nasofrontal buttress was repaired through an extended transcaruncular approach without making any skin incisions. All showed excellent fracture re alignment on post-surgical CT. Complications happened in three cases; those in two cases were attributed to the extended transcaruncular approach, whereas those in the other were not. CONCLUSIONS: The extended transcaruncular approach is a promising alternative to current conventional approaches for NOE and Le Fort II fractures, achieving accurate repair without the need for skin incision. PMID- 27769724 TI - Living under the influence: normalisation of alcohol consumption in our cities. AB - Harmful use of alcohol is one of the world's leading health risks. A positive association between certain characteristics of the urban environment and individual alcohol consumption has been documented in previous research. When developing a tool characterising the urban environment of alcohol in the cities of Barcelona and Madrid we observed that alcohol is ever present in our cities. Urban residents are constantly exposed to a wide variety of alcohol products, marketing and promotion and signs of alcohol consumption. In this field note, we reflect the normalisation of alcohol in urban environments. We highlight the need for further research to better understand attitudes and practices in relation to alcohol consumption. This type of urban studies is necessary to support policy interventions to prevent and control harmful alcohol use. PMID- 27769725 TI - Structural and molecular pathology of the atrium in boxer arrhythmogenic right ventricular cardiomyopathy. AB - OBJECTIVE: To investigate the expression and distribution of desmosomal and gap junction proteins of the intercalated disc in the atria of boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC). ANIMALS: Nineteen control dogs and 13 boxers with histopathologically confirmed ARVC. METHODS: Right and left atrial samples were examined using immunofluorescence and Western blots. The intercalated disc proteins investigated included total and phosphorylated connexin43 (Cx43 and pCx43), connexin45, connexin40, plakoglobin, plakophilin-2, desmoplakin, and N-cadherin. RESULTS: Histopathological changes characteristic of ARVC were present in the left or right atrium of 12 out of 13 boxers and were absent in all control dogs. When compared to the 19 control dogs, immunofluorescence analysis revealed a decrease in signal intensity for pCx43 and plakoglobin in the left (p = 0.03 and p = 0.014, respectively) and right atrium (p = 0.015 and p = 0.002, respectively) of affected boxers. Connexin43 and pCx43 Western blot band density was significantly decreased in the left (p = 0.025 and p = 0.027, respectively) and right atrium (p = 0.001 and p = 0.044, respectively) of affected boxers. CONCLUSION: Altered intercalated disc and gap junction proteins were identified in atrial myocardium of ARVC boxers, supporting atrial involvement as part of this disorder. Reduction in pCx43 in conjunction with histological changes could represent the substrate for atrial arrhythmias associated with ARVC. Furthermore, these findings detected in boxer dogs, lend support for the broader term, arrhythmogenic cardiomyopathy, as preferred nomenclature used to describe this disease in humans. PMID- 27769726 TI - Issues or Identity? Cognitive Foundations of Voter Choice. AB - Voter choice is one of the most important problems in political science. The most common models assume that voting is a rational choice based on policy positions (e.g., key issues) and nonpolicy information (e.g., social identity, personality). Though such models explain macroscopic features of elections, they also reveal important anomalies that have been resistant to explanation. We argue for a new approach that builds upon recent research in cognitive science and neuroscience; specifically, we contend that policy positions and social identities do not combine in merely an additive manner, but compete to determine voter preferences. This model not only explains several key anomalies in voter choice, but also suggests new directions for research in both political science and cognitive science. PMID- 27769728 TI - A 12-Year-Old Girl With Encephalopathy and Acute Flaccid Paralysis: A Neuropathological Correlation and Cohort Review. PMID- 27769729 TI - Willingness to Pay for a Newborn Screening Test for Spinal Muscular Atrophy. AB - OBJECTIVES: The current US mandatory newborn screening panel does not include spinal muscular atrophy, the most common fatal genetic disease among children. We assessed population preferences for newborn screening for spinal muscular atrophy, and how test preferences varied depending on immediate treatment implications. METHODS: We conducted an online willingness-to-pay survey of US adults (n = 982). Respondents were asked to imagine being parents of a newborn. Each respondent was presented with two hypothetical scenarios following the spinal muscular atrophy screening test: current standard of care (no treatment available) and one of three randomly assigned scenarios (new treatment available to improve functioning, survival, or both). We used a bidding game to elicit willingness to pay for the spinal muscular atrophy test, and performed a two-part model to estimate median and mean willingness-to-pay values. RESULTS: Most respondents (79% to 87%) would prefer screening their newborns for spinal muscular atrophy. People expressed a willingness to pay for spinal muscular atrophy screening even without an available therapy (median: $142; mean: $253). Willingness to pay increased with treatment availability (median: $161 to $182; mean: $270 to $297) and respondent income. Most respondents considered test accuracy, treatment availability, and treatment effectiveness very important or important factors in deciding willingness to pay. CONCLUSIONS: Most people would prefer and would be willing to pay for testing their newborn for spinal muscular atrophy, even in the absence of direct treatment. People perceive the spinal muscular atrophy test more valuable if treatment were available to improve the newborn's functioning and survival. Despite preferences for the test information, adding spinal muscular atrophy to newborn screening programs remains controversial. Future studies are needed to determine how early detection may impact long-term patient outcomes. PMID- 27769727 TI - Making Sense of Real-World Scenes. AB - To interact with the world, we have to make sense of the continuous sensory input conveying information about our environment. A recent surge of studies has investigated the processes enabling scene understanding, using increasingly complex stimuli and sophisticated analyses to highlight the visual features and brain regions involved. However, there are two major challenges to producing a comprehensive framework for scene understanding. First, scene perception is highly dynamic, subserving multiple behavioral goals. Second, a multitude of different visual properties co-occur across scenes and may be correlated or independent. We synthesize the recent literature and argue that for a complete view of scene understanding, it is necessary to account for both differing observer goals and the contribution of diverse scene properties. PMID- 27769730 TI - Thrombectomy for Acute Stroke in Childhood: A Case Report, Literature Review, and Recommendations. AB - The updated American Heart Association/American Stroke Association guidelines include recommendation for thrombectomy in certain adult stroke cases. The safety and efficacy of thrombectomy in children are unknown. An 8-year-old girl experienced acute stroke symptoms on two occasions while therapeutically anticoagulated on Novalung. Computed tomography scans showed proximal vessel thrombi, which were retrieved using a Trevo device without hemorrhagic complications. Postprocedural assessment found respective decreases in the National Institutes of Health Stroke Scale score from 10 to 4 and 12 to 7. The indications for treatment and early benefits observed in our case are consistent with other pediatric thrombectomy cases reported. However, publication bias and the heterogeneity of reported cases prevent drawing conclusions about the safety and efficacy of thrombectomy in children. Anticipating that updates to adult stroke guidelines would likely incite stroke providers to consider thrombectomy in children, our institution developed guidelines for thrombectomy before the index patient. Establishing institutional guidelines before considering thrombectomy in children may optimize patient safety. PMID- 27769731 TI - Procoagulant imbalance in patients with non-alcoholic fatty liver disease. PMID- 27769732 TI - Reply to: "Are we still searching for the fifth element of MELD?" PMID- 27769733 TI - Reply to: "Procoagulant imbalance in patients with non-alcoholic fatty liver disease". PMID- 27769734 TI - Systems Mapping of Sexually Transmitted Infection Services at Three Clinical Sentinel Surveillance Sites in South Africa: Opportunities for Integrated Care. AB - Sexually transmitted infection (STI) service delivery in the context of integrated care and the South African HIV epidemic is complex. We aimed to document STI care and HIV testing processes in public health clinics in South Africa, revealing bottlenecks to patient flow and identifying opportunities for improvement. Clinic mapping, with semi-structured interviews and clinic observation, was conducted with facility representatives at three clinical sentinel surveillance sites. Facility surveys assessed patient volume and staffing. Identified challenges were associated with staffing allocations, and disruptions in patient flow resulted from poor clinic layout, inadequate lighting, and limited allocation of space for HIV testing and physical examination. Recommendations include staffing adjustments, reorganization of space to allow for designated service and waiting areas, sufficient supplies, and improved lighting. The facility reorganization component of South Africa's Ideal Clinic initiative provides a key opportunity for enacting many of these recommendations. PMID- 27769736 TI - Cleft relapse and oronasal fistula after Furlow palatoplasty in infants with cleft palate: incidence and risk factors. AB - This study was performed to investigate the incidence of and risk factors for postoperative cleft relapse and oronasal fistula after Furlow palatoplasty in infants. Sixty-two infants with cleft palate, aged 6-12 months (mean 8.25 months), who underwent cleft repair by Furlow double opposing Z-plasty between March 2012 and August 2014, were enrolled in the study. Risk factors for postoperative cleft relapse and oronasal fistula after Furlow palatoplasty were identified by logistic regression analysis. The incidence rates of cleft relapse at 1 week and oronasal fistula at 3 months after surgery were 24.2% (15/62) and 9.7% (6/62), respectively. Among all of the variables screened, only the width of the cleft was significantly associated with the incidence of postoperative cleft relapse (P=0.001) and oronasal fistula (P=0.011); the incidence rates were positively correlated with the width of the cleft when it exceeded 6.8mm and 7.5mm, respectively. Based on these findings, in order to reduce the incidence of postoperative cleft relapse and oronasal fistula, Furlow repair is not recommended for patients with wide clefts. An appropriate angle between the Z flap incision and the central axis, use of a bilateral relaxation incision, and postoperative nursing care can help reduce the incidence of postoperative cleft relapse. PMID- 27769735 TI - Treatment Engagement Moderates the Effect of Neurocognitive Impairment on Antiretroviral Therapy Adherence in HIV-Infected Drug Users in Treatment. AB - Neurocognitive impairment (NCI) and treatment engagement (TE) have been shown to significantly predict antiretroviral therapy (ART) adherence, but no studies have explored the ways and the extent to which similar outcomes might occur when these factors operate together, particularly for people who use drugs (PWUDs). We sought to discover whether TE moderated the effect of NCI on adherence to ART in HIV-infected individuals. One hundred sixteen HIV-infected, methadone-maintained people who reported HIV risk behaviors were enrolled in the study. Variables of interest (NCI, ART adherence, TE) were assessed using audio computer-assisted self-interview. Results revealed a significant interactive effect of NCI and TE on ART adherence, which supported the moderation effect. Findings from post hoc analyses showed that NCI was negatively associated with adherence to ART at low levels of TE. Findings suggest the need to accommodate individual NCI and improve TE as a means to enhance ART adherence in HIV-infected PWUDs. PMID- 27769737 TI - Parent satisfaction with primary repair of paediatric cleft lip in Southwest China. AB - The purpose of this study was to investigate the key factors in relation to parent satisfaction with the primary repair of paediatric cleft lip. One hundred and ninety-five children born with cleft lip and/or palate aged between 3 months and 1 year were recruited, along with their caregivers. All patients underwent primary cleft lip repair, and a telephone interview was held with their main caregivers at 3 months postoperative. The level of satisfaction with each item included in a simplified Cleft Evaluation Profile was ascertained and recorded. Patient clinical data were obtained from the medical records. One hundred and thirty-eight (71%) parents reported satisfaction with the general outcome of surgery. Parents were satisfied with the appearance of the lip and profile of the face, but were dissatisfied with the appearance of the nose and teeth. Mothers of patients showed lower satisfaction levels than fathers and grandparents. Parental satisfaction with the appearance of the lip was lower for patients without a cleft palate than for those with a cleft palate. The results of this study suggest that most Chinese parents of children who undergo primary cleft lip repair express satisfaction with the surgical outcomes. Satisfaction with the appearance of the nose and teeth is low and this needs to be improved. Other factors are likely to influence expressions of satisfaction. PMID- 27769738 TI - Salivary gland tumours in a northern Chinese population: a 50-year retrospective study of 7190 cases. AB - The aims of this study were to investigate the epidemiological and clinical characteristics of epithelial salivary gland tumours in a northern Chinese population and to evaluate the current TNM classification system. A demographic and descriptive analysis of 7190 epithelial salivary gland tumours was performed. There were 4654 benign tumours and 2536 malignant tumours. The percentage of tumours located in the parotid, submandibular, sublingual, and minor salivary glands was 62.66%, 9.92%, 2.57%, and 24.85%, respectively; 22.26%, 35.76%, 92.97%, and 61.89% of the tumours, respectively, were malignant. Over 90% in the tongue and maxillary sinus were malignant. Warthin tumour, salivary duct carcinoma, and squamous cell carcinoma were predominant in males, while basal cell adenoma, myoepithelioma, and pleomorphic adenoma were predominant in females. Further, 2.55% of the tumours were in children and adolescents: 44.81% of the tumours were malignant, as opposed to 35.02% in adults. According to the 7th TNM classification, the percentages of T3 and stage III tumours were approximately 10%. Salivary gland tumours show distribution patterns according to histological type, location, and patient age and sex. The limitations of the current TNM classification of salivary gland carcinoma should be considered and revisions made. PMID- 27769739 TI - Open surgery assisted with arthroscopy to treat synovial chondromatosis of the temporomandibular joint. AB - Open surgery and arthroscopy for the treatment of synovial chondromatosis (SC) of the temporomandibular joint (TMJ) have their advantages and disadvantages. The aim of this study was to report the application and results of the combined use of these two methods in the treatment of SC and the indications for use. A total of 36 patients with magnetic resonance imaging (MRI) confirmation of SC, treated from 2010 to 2015, were included. Patients with tumours in the upper articular cavity and with the extended margin of the medial groove still in-between the medial crest of the condyle and infratemporal space on coronal MRI were selected to undergo open surgery with the assistance of arthroscopy to clear the loose bodies and affected synovium. All 36 patients first went through open surgery. Subsequent arthroscopy examinations indicated the presence of loose bodies in the medial groove in 14 patients (in the anterior or posterior recess), which were removed using a cup-shaped clamp. Thirty-three of the patients were followed up for an average of 33.3 months; there was no recurrence in these patients. This technique has the benefits of the complete elimination of diseased tissues with a minimal osteotomy and a short surgical duration. PMID- 27769740 TI - EPICO 3.0. Management of non-neutropenic patients in medical wards. AB - BACKGROUND: Although the management of invasive fungal infection (IFI) has improved, a number of controversies persist regarding the approach to invasive fungal infection in non-neutropenic medical ward patients. AIMS: To identify the essential clinical knowledge to elaborate a set of recommendations with a high level of consensus necessary for the management of IFI in non-neutropenic medical ward patients. METHODS: A prospective, Spanish questionnaire, which measures consensus through the Delphi technique, was anonymously answered and e-mailed by 30 multidisciplinary national experts, all specialists (intensivists, anesthesiologists, microbiologists, pharmacologists and specialists in infectious diseases) in IFI and belonging to six scientific national societies. They responded to five questions prepared by the coordination group after a thorough review of the literature published in the last few years. For a category to be selected, the level of agreement among the experts in each category had to be equal to or greater than 70%. In a second round, 73 specialists attended a face to-face meeting held after extracting the recommendations from the chosen topics, and validated the pre-selected recommendations and derived algorithm. RESULTS: The following recommendations were validated and included in the algorithm: 1. several elements were identified as risk factors for invasive candidiasis (IC) in non-hematologic medical patients; 2. no agreement on the use of the colonization index to decide whether prescribing an early antifungal treatment to stable patients (no shock), with sepsis and no other evident focus and IC risk factors; 3. agreement on the use of the Candida Score to decide whether prescribing early antifungal treatment to stable patients (no shock) with sepsis and no other evident focus and IC risk factors; 4. agreement on initiating early antifungal treatment in stable patients (no shock) with a colonization index>0.4, sepsis with no other evident focus and IC risk factors; 5. agreement on the performance of additional procedures in stable patients (no shock) with sepsis and no other evident focus, IC risk factors, without colonization index>0.4, but with a high degree of suspicion. CONCLUSIONS: Based on the expert's recommendations, an algorithm for the management of non-neutropenic medical patients was constructed and validated. This algorithm may be useful to support bedside prescription. PMID- 27769741 TI - Three-dimensional printing with polylactic acid (PLA) thermoplastic offers new opportunities for cryobiology. AB - Development of devices through design, prototyping, testing, and fabrication is especially necessary for enhancement of research and eventual application in cryobiology. The advent of 3-dimensional printing offers unique opportunities for this process, given that the materials involved are suitable for use in cryogenic temperatures. We report herein that 3-D printing with polylactic acid (PLA) thermoplastic is ideally suited for cryobiology device development. Devices that are designed and standardized in open-source fashion can be electronically distributed and created locally on increasingly affordable 3-D printers, and can accelerate cryobiology findings and improve reproducibility of results. PMID- 27769742 TI - All-trans retinoic acid promotes wound healing of primary amniocytes through the induction of LOXL4, a member of the lysyl oxidase family. AB - Thirty percent of preterm births directly result from preterm premature rupture of fetal membranes (PPROM). Clinical management currently proposes using a collagen plug to mechanically stop loss of amniotic fluid. Vitamin A and its active metabolite (retinoic acid) have well-known pro-healing properties and could thus make good candidates as a proposable adjuvant to this mechanical approach. Here we investigate the molecular mechanisms involved in the pro healing properties of all-trans retinoic acid (atRA) in fetal membranes via an approach using an in vitro primary amniocyte wound model and transcriptomics. The results demonstrate that atRA promotes migration in primary amniocytes, improving wound healing in vitro by up to 90%. This effect is mediated by the induction of LOXL4, which plays a crucial role in the dynamics of the extracellular matrix by regulating collagen reticulation. This new insight into how atRA exerts its pro healing properties prompts us to propose using atRA as a candidate strategy to help prevent future PPROM. PMID- 27769743 TI - Sensorimotor tests unmask a phenotype in the DYT1 knock-in mouse model of dystonia. AB - Hereditary generalized dystonia is often caused by a GAG deletion in TOR1A (DYT1) that encodes for the protein torsinA. Although mutation carriers show alterations in neuronal connectivity and sensorimotor deficits, only 30% develop dystonia. Uncovering the factors triggering the dystonic symptoms and underlying pathophysiology would greatly benefit the development of more effective therapies. In DYT1 knock-in (KI) mice, the expression of torsinA mutant alters the connectivity of neurons and the function of striatal cholinergic interneurons. We aimed to determine if heterozygous DYT1 KI mice exhibit deficits in behavioural tests that explore the connectivity of the sensory and motor system. DYT1 KI mice were tested in cognitive tests and challenging motor paradigms, followed by the adhesive removal test and the adaptive rotating beam test which both require sensorimotor integration. DYT1 KI mice did not exhibit cognitive deficits and were able to perform similarly to wild type mice even in challenging motor tests with relatively stable sensory input. Conversely, DYT1 KI mice spent more time on sensing and removing an adhesive sticker from the back of the nose; they exhibited difficulty to traverse rotating rods, especially if the surface was smooth and the diameter small. Our observations further support a role of sensorimotor integration in manifestation of this movement disorder. Future studies in DYT1 KI mice will explore the involved neurocircuitry and underlying molecular mechanisms. PMID- 27769744 TI - Sleep-wakefulness cycle and behavior in pannexin1 knockout mice. AB - Pannexins are membrane channel proteins that play a role in a number of critical biological processes (Panchin et al., 2000; Shestopalov, Panchin, 2008). Among other cellular functions, pannexin hemichannels serve as purine nucleoside conduits providing ATP efflux into the extracellular space (Dahl, 2015), where it is rapidly degraded to adenosine. Pannexin1 (Panx1) is abundantly expressed in the brain and has been shown to contribute to adenosine signaling in nervous system tissues (Prochnow et al., 2012). We hypothesized that pannexin1 may contribute to sleep-wake cycle regulation through extracellular adenosine, a well established paracrine factor in slow wave sleep. To investigate this link, EEG and movement activity throughout the light/dark cycle were compared in Panx1-/- and Panx1+/+ mice. We found a significant increase in waking and a correspondent decrease in slow wave sleep percentages in the Panx1-/- animals. These changes were especially pronounced during the dark period. Furthermore, we found a significant increase in movement activity of Panx1-/- mice. These findings are consistent with the hypothesis that extracellular adenosine is relatively depleted in Panx1-/- animals due to the absence of the ATP-permeable hemichannels. At the same time, sleep rebound after a 6-h sleep deprivation remained unchanged in Panx1-/- mice as compared to the control animals. Behavioral tests revealed that Panx1-/- mice were significantly faster during their descent along the vertical pole but more sluggish during their run through the horizontal pole as compared to the control mice. PMID- 27769746 TI - Proximal signaling responses in peripheral T cells from colorectal cancer patients are affected by high concentrations of circulating prostaglandin E2. AB - Patients with colorectal cancer (CRC) have been shown to have elevated levels of circulating prostaglandin E2 (PGE2) which promotes cancer progression and suppresses T cell immune responses. In this study we evaluated whether signaling responses in T lymphocytes obtained from peripheral blood of CRC patients were affected by the sustained exposure to increased levels of PGE2. The phosphorylation status of an extended panel of proteins involved in downstream signaling cascades in T cells was profiled at a single cell level both in naive and antigen-experienced cells after triggering T cell-, prostaglandin- and interleukin-2 receptors. Peripheral T cells from patients with elevated PGE2 levels displayed aberrant T cell signaling responses downstream of the T cell receptor (assessed by reduced phosphorylation of CD3zeta and SLP76), and after triggering the IL-2 receptor (assessed by reduced phosphorylation of STAT5) when compared to T cells from CRC patients with lower levels of PGE2 and T cells from healthy blood donors. This signaling study of circulating T cells from CRC patients indicates that increased systemic PGE2 levels affect proximal T cell responses and confirms phospho-specific flow cytometry to be a valuable tool for revealing signaling signatures in immunological disorders. PMID- 27769745 TI - Determination of mercury in hair: Comparison between gold amalgamation-atomic absorption spectrometry and mass spectrometry. AB - Mercury is a heavy metal that causes serious health problems in exposed subjects. The most toxic form, i.e., methylmercury (MeHg), is mostly excreted through human hair. Numerous analytical methods are available for total Hg analysis in human hair, including cold vapour atomic fluorescence spectrometry (CV-AFS), inductively coupled plasma mass spectrometry (ICP-MS) and thermal decomposition amalgamation atomic absorption spectrometry (TDA-AAS). The aim of the study was to compare the TDA-AAS with the ICP-MS in the Hg quantification in human hair. After the washing procedure to minimize the external contamination, from each hair sample two aliquots were taken; the first was used for direct analysis of Hg by TDA-AAS and the second was digested for Hg determination by the ICP-MS. Results indicated that the two data sets were fully comparable (median; TDA-AAS, 475ngg-1; ICP-MS, 437ngg-1) and were not statistically different (Mann-Whitney test; p=0.44). The two techniques presented results with a good coefficient of correlation (r=0.94) despite different operative ranges and method limits. Both techniques satisfied internal performance requirements and the parameters for method validation resulting sensitive, precise and reliable. Finally, the use of the TDA-AAS can be considered instead of the ICP-MS in hair analysis in order to reduce sample manipulation with minor risk of contamination, less time consuming due to the absence of the digestion step and cheaper analyses. PMID- 27769747 TI - HLA-A, -B and -DRB1 genotyping and haplotype frequencies of 3892 cord blood units in the Hong Kong Chinese Cord Blood Registry. AB - HLA-A, -B and -DRB1 gene and haplotype frequencies have been calculated from 3892 southern Chinese unrelated cord blood units in a Hong Kong Cord Blood Registry. This is the first large-scale paper to report the distribution of A-B-DRB1 alleles in Hong Kong Chinese Cord Blood Units. This information is important for estimating the optimal and economically cost-effective donor size and likelihood of obtaining appropriately matched cord blood units for Chinese patients awaiting haematopoietic stem cell transplantation. The data are available in the Allele Frequencies Net Database under the population name ''Hong Kong Chinese Cord Blood Registry'' and the identifier (AFND003358). PMID- 27769748 TI - HLA-A, -B, -C, and -DRB1 genotyping and haplotype frequencies for a Hong Kong Chinese population of 7595 individuals. AB - HLA-A, -B, -C and -DRB1 gene and haplotype frequencies have been calculated from 7595 southern Chinese unrelated donors in a Hong Kong Bone Marrow Donor Registry. This is the first large-scale paper to report the distribution of A-C-B-DRB1 alleles in Hong Kong Chinese. This information is important for phylogenetic, comparative studies and estimating the optimal and cost-effective donor size and likelihood of obtaining appropriately matched donors for Chinese patients awaiting haematopoietic stem cell transplantation. The allele and haplotype data are available in the Allele Frequencies Net Database under the population name ''Hong Kong Chinese BMDR'' and the identifier (AFND003357). PMID- 27769749 TI - Genetic algorithm to estimate the input parameters of Klatt and HLSyn formant based speech synthesizers. AB - Voice imitation basically consists in estimating a synthesizer's input parameters to mimic a target speech signal. This is a difficult inverse problem because the mapping is time-varying, non-linear and from many to one. It typically requires considerable amount of time to be done manually. This work presents the evolution of a system based on a genetic algorithm (GA) to automatically estimate the input parameters of the Klatt and HLSyn formant synthesizers using an analysis-by synthesis process. Results are presented for natural (human-generated) speech for three male speakers. The results obtained with the GA-based system outperform those obtained with the baseline Winsnoori with respect to four objective figures of merit and a subjective test. The GA with Klatt synthesizer generated similar voices to the target and the subjective tests indicate an improvement in the quality of the synthetic voices when compared to the ones produced by the baseline. PMID- 27769750 TI - Predicting changes of reaction networks with partial kinetic information. AB - We wish to predict changes of reaction networks with partial kinetic information that lead to target changes of their steady states. The changes may be either increases or decreases of influxes, reaction knockouts, or multiple changes of these two kinds. Our prime applications are knockout prediction tasks for metabolic and regulation networks. In a first step, we propose a formal modeling language for reaction networks with partial kinetic information. The modeling language has a graphical syntax reminiscent to Petri nets. Each reaction in a model comes with a partial description of its kinetics, based on a similarity relation on kinetic functions that we introduce. Such partial descriptions are able to model the regulation of existing metabolic networks for which precise kinetic knowledge is usually not available. In a second step, we develop prediction algorithms that can be applied to any reaction network modeled in our language. These algorithms perform qualitative reasoning based on abstract interpretation, by which the kinetic unknowns are abstracted away. Given a reaction network, abstract interpretation produces a finite domain constraint in a novel class. We show how to solve these finite domain constraints with an existing finite domain constraint solver, and how to interpret the solution sets as predictions of multiple reaction knockouts that lead to a desired change of the steady states. We have implemented the prediction algorithm and integrated it into a prediction tool. This journal article extends the two conference papers John et al. (2013) and Niehren et al. (2015) while adding a new prediction algorithm for multiple gene knockouts. An application to single gene knockout prediction for surfactin overproduction was presented in Coutte et al. (2015). It illustrates the adequacy of the model-based predictions made by our algorithm in the wet lab. PMID- 27769751 TI - Fine-Tuning Development Through Antagonistic Peptides: An Emerging Theme. AB - Peptide ligand-receptor kinase interactions have emerged as a key component of plant growth and development. Now, highly related small signaling peptides have been shown to act antagonistically on the same receptor kinase, providing new insights into how plants optimize developmental processes using competitive peptides. PMID- 27769752 TI - Cortical bone thickening in Type A posterior atlas arch defects: experimental report. AB - BACKGROUND CONTEXT: To date, no information about the cortical bone microstructural properties in atlas vertebrae with posterior arch defects has been reported. PURPOSE: To test if there is an increased cortical bone thickening in atlases with Type A posterior atlas arch defects in an experimental model. STUDY DESIGN: Micro-computed tomography (CT) study on cadaveric atlas vertebrae. METHODS: We analyzed the cortical bone thickness, the cortical volume, and the medullary volume (SkyScan 1172 Bruker micro-CT NV, Kontich, Belgium) in cadaveric dry vertebrae with a Type A atlas arch defect and normal control vertebrae. RESULTS: The micro-CT study revealed significant differences in cortical bone thickness (p=.005), cortical volume (p=.003), and medullary volume (p=.009) values between the normal and the Type A vertebrae. CONCLUSIONS: Type A congenital atlas arch defects present a cortical bone thickening that may play a protective role against atlas fractures. PMID- 27769753 TI - Efficacy and Safety of Statins for Pulmonary Hypertension: A Meta-Analysis of Randomised Controlled Trials. AB - BACKGROUND: Pulmonary hypertension (PH) is a serious disease, and treatment is a continuing challenge. Some in vitro and in vivo studies identified that statins were effective for PH. However, results of some randomised controlled trials (RCTs) have been controversial. The objective of our study was to clarify whether statins are effective and safe for pulmonary hypertension. METHODS: We systematically searched for eligible RCTs from PubMed, EMBASE, Web of Science, and the Cochrane Library during January 2016. Two reviewers independently extracted data. Standard mean differences (SMDs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were estimated for continuous data (exercise capacity cardiac, pulmonary arterial pressure (PAP), cardiac index, and low-density lipoprotein (LDL)). Risk ratios (RRs) were estimated for dichotomous data (adverse events and clinical deterioration). RESULTS: A total of 496 patients from six RCTs were included. Low-density lipoprotein in the statin group decreased significantly compared with the placebo group (WMD = -22.79; 95% CI: 34.33 ~ -11.24). However, we did not find a statistically significant effect on exercise capacity (SMD = 0.18; 95% CI: -0.34 - 0.71), PAP (WMD = -3.01; 95% CI: 8.68 - 2.65), or CI (WMD = -0.04; 95% CI: -0.15 - 0.23). Additionally, there was no difference between statins and placebo with respect to hepatic injury (RR: 1.12; 95% CI: 0.43 - 2.92), myalgia (RR: 0.81; 95% CI: 0.32 - 2.03), or clinical deterioration (RR: 0.98; 95% CI: 0.58 - 1.67). CONCLUSIONS: Statin treatment appears to be safe but may have no effect on PH. PMID- 27769755 TI - Noninvasive Regional Aortic Stiffness for Monitoring the Early Stage of Abdominal Aortic Aneurysm in Mice. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) affects more than 5% of the population in developed countries. To study the formation and progression of AAA, we developed a non-invasive method to analyse regional aortic stiffness to monitor the formation and progression of AAA. METHODS: Saline or Angiotensin II (AngII) was subcutaneously infused in apolipoprotein E knockout (ApoE-/-) mice for 28 days; a high-resolution imaging system was used to identify changes in arterial stiffness measured by pulse-wave velocity (PWV) and aortic lumen diameter in the suprarenal aorta. RESULTS: Both regional PWV and luminal diameter in the suprarenal aorta did not change significantly in saline-treated ApoE-/- mice for 28 days. In contrast, AngII treatment for 28 days rapidly increased both regional PWV and luminal diameter. The difference in luminal diameter could be identified at 14 days. However, regional PWV significantly increased within the first 7 days after AngII perfusion as compared with saline treatment. However, in ApoE-/- diabetic mice, both regional PWV and aortic diameter did not differ between AngII and saline treatment at 7 or 28 days. CONCLUSIONS: Regional PWV may be used to monitor AAA development and was improved after AngII infusion in ApoE /- mice. PMID- 27769754 TI - Long Term Prognostic Value of a Negative Work-Up for Acute Coronary Disease in Emergency Department Chest Pain Patients Without Known Coronary Artery Disease: A Cohort Study. AB - BACKGROUND: To determine the rate of all cause and cardiac death, new myocardial infarction (MI) or coronary revascularisation at over three years from index visit in emergency department chest pain patients without known coronary artery disease (CAD) at index presentation who had a negative electrocardiogram (ECG) and biomarker workup for acute coronary syndrome (ACS). METHODS: An unplanned sub study of a prospective observational study of consecutive adult patients presenting to the ED with atraumatic chest pain (or equivalents). The primary outcome of interest was the predictive performance of a negative ECG and biomarker work-up for ACS for all cause and cardiac mortality over more than three years' follow-up in patients not known to have pre-existing CAD presenting to the ED with chest pain. Secondary outcomes were rate of new MI or revascularisation not related to the index visit. RESULTS: 237 patients were studied. Median age was 52 years (IQR 42 - 62) and 55.3% were male. Median follow up was 48 months. There were seven deaths (3%, 95% CI 1.4 - 6%), one of which was potentially cardiac in origin with cause of death given as pulmonary hypertension and cardiac failure (0.4%, 95% CI 0.02 - 2.3%). There was one confirmed MI (0.6%, 95% CI 0.03 - 3.8%). The rate of revascularisation not related to the index visit was 3.1% (95% CI 1.1 - 7.4%). CONCLUSION: Patients who present to ED with potentially cardiac chest pain but who do not have known CAD, and have non ischaemic ECGs and troponin assays below the 99th percentile are at low risk of cardiac death or MI in long-term follow-up. This challenges the recommendation for routine functional or anatomic testing. PMID- 27769756 TI - Intra-Atrial Excision of the Left Atrial Appendage: A Simple and Easy Technique. AB - In patients with atrial fibrillation, closure of the left atrial appendage (LAA) is recommended to prevent thromboembolic events, however, conventional exclusion or excision techniques have potential drawbacks such as persistent blood flow into the appendage and a residual stump. We propose a simple and easy technique for LAA closure consisting of intra-atrial excision of the LAA, which is invaginated into the left atrium (LA), and direct suture closure of the orifice from inside the LA. In this technique, complete elimination of the LAA was achieved without leaving a residual stump because the LAA was excised at the orifice and was closed at the base of the LAA. PMID- 27769757 TI - Atrioventricular Nodal Non Re-Entrant Tachycardia (AVNNT). PMID- 27769758 TI - Enablers and barriers of men with Duchenne muscular dystrophy transitioning from an adult clinic within a pediatric hospital. AB - BACKGROUND: Young men with Duchenne muscular dystrophy (DMD) live into adulthood and need specialized care. However, services for adults are fragmented. We know little about young men's experiences, their parents, and clinicians who support them as they transition to adult care. OBJECTIVE: To explore the enablers and barriers of clinicians, young men, and parents as they transition from an adult DMD clinic within a pediatric hospital to an adult health facility. METHODS: We conducted semi-structured, in-depth interviews with 16 participants (7 clinicians, 5 parents, 4 youth). We used an open-coding, thematic approach to analyze the data. RESULTS: Clinicians, youth and their parents experienced several enablers and barriers in transitioning to an adult health care center. Clinicians reported that structural factors including leadership and advocacy supported the transition. Clinicians and parents found that the availability and continuity of care both enabled and hindered the transition. Parents and youth conveyed the difficulties of adjusting to the different model of adult care and also accessing resources. All participants described how relational factors (i.e., effective communication and family involvement) enabled the transition. On an individual level, clinicians, parents and youth viewed transition readiness and other life skill supports as an enabler and a barrier to transitioning. All participants reported the difficulties of maintaining mental health for youth with DMD transitioning to adult health care. CONCLUSIONS: Clinicians, youth, and parents experienced several enablers and barriers in transitioning to adult health care. Further work is needed to understand the complex transition needs of youth with DMD. PMID- 27769759 TI - Sleep duration, life satisfaction and disability. AB - BACKGROUND: Although sleep is considered an essential part of individuals' lives, there are no previous studies analysing how sleep duration affects the levels of life satisfaction reported by males and females with disabilities. OBJECTIVE/HYPOTHESIS: To analyse and compare the impact of hours of sleep on life satisfaction scores reported by people without and with disabilities (stratified by sex) in Germany. METHODS: Using data taken from the German Socio-Economic Panel for the period 2008-2013, we estimate life satisfaction equations for males and females (running a fixed-effects model) which include a set of variables measuring the number of sleep hours on workdays and weekends. RESULTS: A higher number of sleep hours on workdays increase life satisfaction for all males and females. However, the contribution of each hour of sleep on workdays is greater for males with disabilities in terms of life satisfaction, whereas for females no significant differences by disability status have been found. Although sleep hours on weekends also increase life satisfaction, the magnitude of the coefficients is relatively higher than that found for the corresponding hours of sleep on workdays, but only for the male sample (disabled or not). CONCLUSIONS: The participation and commitment of policymakers, governments, trade unions, employers, and health care professionals are key aspects for developing and formulating new guidelines and specific measures that promote a healthy lifestyle and increase sleep duration. Such guidelines and measures are of essence for people with disabilities who are employed (e.g. using brief sleep opportunities during prolonged work periods, which can contribute to reducing fatigue, stress and anxiety). PMID- 27769760 TI - Neonatal estradiol exposure to female rats changes GABAA receptor expression and function, and spatial learning during adulthood. AB - Exposure of female rats to estradiol during the perinatal period has profound effects on GABAergic neurotransmission that are crucial to establish sexually dimorphic brain characteristics. We previously showed that neonatal beta estradiol 3-benzoate (EB) treatment decreases brain concentrations of the neurosteroid allopregnanolone, a potent positive modulator of extrasynaptic GABAA receptors (GABAAR). We thus evaluated whether neonatal EB treatment affects GABAAR expression and function in the hippocampus of adult female rats. Neonatal EB administration increased the expression of extrasynaptic alpha4/delta subunit containing GABAARs and the modulatory action of THIP on tonic currents mediated by these receptors. The same treatment decreased the expression of synaptic alpha1/alpha4/gamma2 subunit-containing receptors, as well as phasic currents. These effects of neonatal EB treatment are not related to ambient allopregnanolone concentrations per se, given that vehicle-treated rats in diestrus, which have opposite neurosteroid levels than EB-treated rats, show similar changes in GABAARs. Rather, these changes may represent a compensatory mechanism to counteract the long-term reduction in allopregnanolone concentrations, induced by neonatal EB. Given that both alpha4/delta receptors and allopregnanolone are involved in memory consolidation, we evaluated whether neonatal EB treatment alters performance in the Morris water maze test during adulthood. Neonatal EB treatment decreased the latency and the cumulative search error to reach the platform, as well as thigmotaxis, suggesting improved learning, and also enhanced memory performance during the probe trial. These enduring changes in GABAAR plasticity may be relevant for the regulation of neuronal excitability in the hippocampus and for the etiology of psychiatric disorders that originate in development and show sex differences. PMID- 27769761 TI - The Prospective Association Between Sleep and Initiation of Substance Use in Young Adolescents. AB - PURPOSE: This study aimed to determine the unique utility of poor sleep health in predicting the onset of substance use in adolescents. METHODS: Middle school students (N = 829, mean (M)age = 12.6 years, 52% female, 73% white) who participated in an ongoing prospective study of alcohol onset and progression completed a set of Web-based health behavior surveys over a 4-year period, with recruitment beginning in 2009. Surveys included assessments of alcohol, cigarette, and marijuana use as well as sleep duration, bedtime delay (from weekdays to weekends), and daytime sleepiness. Data were analyzed using discrete time Cox Proportional hazard's regression. RESULTS: Controlling for participant age at sleep assessment, gender, and internalizing and externalizing behaviors, shorter sleep duration and greater daytime sleepiness in year 1 were associated with increased odds of having had a full drink of alcohol, having engaged in heavy episodic drinking, and having experienced alcohol-related consequences by year 4. Shorter sleep duration was also associated with increased odds of marijuana use by year 4. No sleep parameter was uniquely associated with increased odds of cigarette use (first puff or first full cigarette). Effects were evident for both males and females. Age at sleep assessment did not moderate effects. CONCLUSIONS: Sleep health is a prospective predictor of the onset of alcohol and marijuana use among adolescents. Increased efforts to prevent and intervene in sleep problems among adolescents are warranted. PMID- 27769763 TI - Fast and automatic identification of particle tilt pairs based on Delaunay triangulation. AB - Random conical tilt (RCT) and orthogonal tilt reconstruction (OTR) are two remarkable methods for reconstructing the three-dimensional structure of macromolecules at low resolution. These techniques use two images at two different sample tilts. One of the most demanding steps in these methods at the image processing level is to identify corresponding particles on both micrographs, and manual or semiautomatic matching methods are usually used. Here we present an approach to solve this bottleneck with a fully automatic method for assigning particle tilt pairs. This new algorithm behaves correctly with a variety of samples, covering the range from small to large macromolecules and from sparse to densely populated fields of view. It is also more rapid than previous approaches. The roots of the method lie in a Delaunay triangulation of the set of independently picked coordinates on both the untilted and tilted micrographs. These triangulations are then used to search an affine transformation between the untilted and tilted triangles. The affine transformation that maximizes the number of correspondences between the two micrographs defines the coordinate matching. PMID- 27769762 TI - Intimacy, Substance Use, and Communication Needs During Cancer Therapy: A Report From the "Resilience in Adolescents and Young Adults" Study. AB - PURPOSE: The prevalence of intimacy and substance use among adolescents and young adults during cancer therapy has not been well described. METHODS: The "Resilience in Adolescents and Young Adults with Cancer" study was a prospective, multicenter, mixed-methods cohort study. English-speaking patients 14-25 years old with newly diagnosed cancer were invited to complete a comprehensive survey at the time of enrollment (T1) and 3-6 months later (T2). Intimate relationships and health behaviors were assessed with questions adapted from the Guidelines for Adolescent Preventative Services assessment. Descriptive statistics characterized the prevalence of sexual and substance-related behaviors at each time point. RESULTS: Of 42 eligible and enrolled participants, 35 (83%) and 25 (59%) completed T1 and T2 surveys, respectively. Their mean age was 17.6 years (standard deviation 2.3), 57% were male, and the most common diagnoses were sarcoma and acute leukemia. Over a third of participants reported dating at each time point; 26% were sexually active at T1, and 32% at T2. Of those endorsing sexual activity, fewer than half reported consistent birth control or condom use and 4 reported their first sexual intercourse during our observation. In addition, 46% (T1) and 44% (T2) reported alcohol use and 23% (T1) and 26% (T2) reported illicit drug use. Despite these activities, fewer than 10% endorsed a worry or need to discuss these behaviors with oncology providers. CONCLUSIONS: Intimacy and substance use among adolescents and young adults are common during cancer therapy. Clinical and research implications include the identification of optimal communication and patient-centered supports. PMID- 27769764 TI - Persistent Thrombocytopenia. PMID- 27769765 TI - Vocal Cord Paralysis After Cardiac Surgery and Interventions: A Review of Possible Etiologies. PMID- 27769766 TI - Prescribing of cyproterone acetate/ethinylestradiol in UK general practice: a retrospective descriptive study using The Health Improvement Network. AB - OBJECTIVE: To investigate prescribing patterns of cyproterone acetate/ethinylestradiol (CPA/EE) in the United Kingdom before and after the 2013 prescribing guidance. STUDY DESIGN: We conducted a retrospective descriptive study in UK general practice. The study population included women with a first prescription (index date) for CPA/EE in The Health Improvement Network in 2011 (N=2760), 2012 (N=2923) and 2014 (N=2341). We evaluated the proportion of new CPA/EE users with (i) a diagnosis of a hyperandrogenic condition, menstrual problem, consultation for contraception management, and other acne treatment, in the year before the index date; and (ii) proportion of new CPA/EE users with concomitant use of another hormonal contraceptive (HC). RESULTS: The percentage of CPA/EE new users with a record of a hyperandrogenic condition was 61% in 2011, 62% in 2012 and 63% in 2014. Corresponding percentages for acne were 51%, 54% and 55%, respectively. When manually reviewing patient records for a sample of CPA/EE new users (n=200), the acne was recorded in 77% of women, hirsutism in 9.5% and polycystic ovary syndrome in 9.5%. Majority of CPA/EE users had a prior acne diagnosis and/or treatment, 76% (n=2091) in 2011, 79% (n=2296) in 2012 and 78% (n=1834) in 2014. Concomitant use of CPA/EE and another HC was rare, 1% of CPA/EE users in 2011 and fewer than 0.5% of CPA/EE users in both 2012 and 2014. CONCLUSIONS: Before and after 2013, the majority of UK women starting treatment with CPA/EE had a condition in line with its approved indication and had received prior acne treatment as per guidance. PMID- 27769768 TI - Corrections. PMID- 27769767 TI - "I don't know what I would have done." Women's experiences acquiring ulipristal acetate emergency contraception online from 2011 to 2015. AB - OBJECTIVES: This study describes women's reasons for seeking ulipristal acetate (UPA) for emergency contraception (EC) through the only authorized online retailer for UPA EC in the US. STUDY DESIGN: Women aged 14 to 59 years, living in states that allow prescription medications to be shipped from out-of-state, accessed the KwikMed online pharmacy between January 2011 and December 2015. After completing a medical eligibility screener, women answered optional multiple choice questions. To obtain UPA through KwikMed, individuals must be female, 50 years of age or younger, not currently pregnant or breastfeeding and not attempting to order UPA more than once within 30 days or more than four times per year. RESULTS: Over the 5-year period, KwikMed provided 8019 prescriptions for UPA, and the number of women using this service more than tripled over time. Among women who responded to the survey questions (n=7133; response rate = 89%), most sought EC because of a condom failure (45.3%) or because they did not use regular contraception (41.2%). More than half (53.5%) of women reported that they chose UPA because of its effectiveness compared to levonorgestrel EC pills, and 58.9% preferred ordering UPA online because they found it easier than getting it from a doctor, clinic or pharmacy. CONCLUSIONS: This study documents the importance of providing confidential services for acquiring EC online. Benefits of online access include convenience, less embarrassment, avoiding situations in which a provider might refuse to provide EC because of their own ideological belief and more reliable availability for this time-sensitive contraceptive. IMPLICATIONS: Though physical, logistical and societal barriers can restrict women's access to EC, this study demonstrates that providing access to UPA online empowers women to obtain EC when they need it. PMID- 27769769 TI - Repeated conservation threats across the Americas: High levels of blood and bone lead in the Andean Condor widen the problem to a continental scale. AB - Wildlife lead exposure is an increasing conservation threat that is being widely investigated. However, for some areas of the world (e.g., South America) and certain species, research on this subject is still scarce or only local information is available. We analyzed the extent and intensity of lead exposure for a widely distributed threatened species, the Andean Condor (Vultur gryphus). We conducted the study at two different scales: 1) sampling of birds received for rehabilitation or necropsy in Argentina, and 2) bibliographic review and extensive survey considering exposure event for the species' distribution in South America. Wild condors from Argentina (n = 76) presented high lead levels consistent with both recent and previous exposure (up to 104 MUg/dL blood level, mean 15.47 +/- 21.21 MUg/dL and up to 148.20 ppm bone level, mean 23.08 +/- 31.39 ppm). In contrast, captive bred individuals -not exposed to lead contamination- had much lower lead levels (mean blood level 5.63 +/- 3.08 MUg/dL, and mean bone level 2.76 +/- 3.06 ppm). Condors were exposed to lead throughout their entire range in continental Argentina, which represents almost sixty percent (>4000 km) of their geographical distribution. We also present evidence of lead exposure events in Chile, Ecuador, and Peru. Lead poisoning is a widespread major conservation threat for the Andean Condor, and probably other sympatric carnivores from South America. The high number and wide range of Andean Condors with lead values complement the results for the California Condor and other scavengers in North America suggesting lead poisoning is a continental threat. Urgent actions are needed to reduce this poison in the wild. PMID- 27769770 TI - Microplastics and potentially toxic elements in coastal sediments of Iran's main oil terminal (Khark Island). AB - Marine pollutants are becoming a growing concern due to their ecological consequences. This study investigates the potential risk posed by microplastics and toxic elements in coastal sediments of Khark Island, the main oil export hub of Iran. Principal component biplots exhibited a significant positive correlation between microplastic quantities (ranging in shape and color) and concentration of heavy metals with industrial activity. Source identification of the heavy metals indicated both natural and anthropogenic origin. Quality and risk assessment of the sediments revealed low to moderate pollution of Zn, Mo, Pb, Cu, Cd and As in some stations. Results of metal fractionation in sediments demonstrated that Cd, Mn, Zn, As and Pb are capable of posing a serious ecological risk due to potential bioavailability. Microplastics, mostly fragments and fibers, were detected in all sediment samples (ranging from 59 to 217 items/200 g dry sediment). A relatively good significant linear relationship exists between microplastic quantities and potentially toxic element/polycyclic aromatic hydrocarbon concentrations in coastal sediments. The results of this study confirmed the key role of microplastics as a "potential contaminant vector" for other types of pollutants. PMID- 27769771 TI - Temporal and spatial characteristics of lead emissions from the lead-acid battery manufacturing industry in China. AB - An inventory of lead emissions was established for the lead-acid battery (LAB) manufacturing industry in China from 2000 to 2014. The lead emissions from the LAB manufacturing industry increased from 133 t in 2000 to a peak at 281 t in 2010 with the rapid development of LAB industry. Since 2011, a mandatory national clean action on LAB industry and a series of retrofitting measures have been implemented in China. As a result, more than 80% of small and low-efficient LAB manufacturers were closed, and technical-environmental performance of the industry has been improved significantly. Thus the lead emissions from the industry declined to 113 t in 2014. Geographically, lead emissions were attributed to several provinces with intensive LAB manufacturers, including Zhejiang, Guangdong, Jiangsu, Shandong, and Hebei Province. Spatial transfer of the LAB manufacturing industry from developed areas to developing areas in China was manifest due to strict environmental regulation, posing potential environmental risks to the areas undertaking the industry transfer. In light of the effectiveness of the national clean action, the LAB manufacturing industry will reduce lead emissions further by implementing the entry criteria strictly, adopting policy of total lead emissions control, and establishing a long-term regulatory mechanism for LAB manufacturers. The local authorities in some developing areas should improve abilities of environmental supervision and environmental risk prevention to deal with the spillover of lead emissions. PMID- 27769772 TI - The short term burden of ambient particulate matters on non-accidental mortality and years of life lost: A ten-year multi-district study in Tianjin, China. AB - Years of life lost (YLL) is a more informative and accurate indicator than daily death counts for assessing air pollution related premature death. However, there is limited evidence available about the relationship of air pollution with YLL, especially in China. We conducted a ten-year (from January 1st, 2001 to December 31st, 2010) multi-district time-series study to estimate the effects of ambient particulate matter with an aerodynamic diameter of less than 10 MUm in size (PM10) on daily non-accidental deaths and YLL in six districts of Tianjin, China. Meta-analysis was used to merge the results of the six districts. We found that the increase of PM10 was significantly associated with daily death and YLL in the six districts, except with the YLL in Heping district. 10 MUg/m3 increases in PM10 were associated with the maximum increases in excess risk (ER) of death counts of 0.33% (95% confidence interval [CI]: 0.25%, 0.41%) at lag01 and in YLL of 0.80 (95%CI: 0.47, 1.13) person year at lag01 for the combined effects of six districts, respectively. Moreover, the associations of PM10 on daily death counts and YLL were stronger in the elder people (>=65 years) than those in the younger ones (<65 years). These findings may help to shed light on the policy-making of PM-control in China and provide useful information for the protection of susceptible population. PMID- 27769773 TI - Antibacterial activity of oxytetracycline photoproducts in marine aquaculture's water. AB - Oxytetracycline (OTC) is one of the most used antibiotics in aquaculture. The main concern related to its use is the bacterial resistance, when ineffective treatments are applied for its removal or inactivation. OTC photo-degradation has been suggested as an efficient complementary process to conventional methods used in intensive fish production (e.g.: ozonation). Despite this, and knowing that the complete mineralization of OTC is difficult, few studies have examined the antibacterial activity of OTC photoproducts. Thus, the main aim of this work is to assess whether the OTC photoproducts retain the antibacterial activity of its parent compound (OTC) after its irradiation, using simulated sunlight. For that, three Gram-negative bacteria (Escherichia coli, Vibrio sp. and Aeromonas sp.) and different synthetic and natural aqueous matrices (phosphate buffered solutions at different salinities, 0 and 210/00, and three different samples from marine aquaculture industries) were tested. The microbiological assays were made using the well-diffusion method before and after OTC has been exposed to sunlight. The results revealed a clear effect of simulated sunlight, resulting on the decrease or elimination of the antibacterial activity for all strains and in all aqueous matrices due to OTC photo-degradation. For E. coli, it was also observed that the antibacterial activity of OTC is lower in the presence of sea-salts, as demonstrated by comparison of halos in aqueous matrices containing or not sea salts. PMID- 27769774 TI - Exposure and health impact evaluation based on simultaneous measurement of indoor and ambient PM2.5 in Haidian, Beijing. AB - Because people spend most of their time indoors, the characterization of indoor air quality is important for exposure assessment. Unfortunately, indoor air data are scarce, leading to a major data gap in risk assessment. In this study, PM2.5 concentrations in both indoor and outdoor air were simultaneously measured using on-line particulate counters in 13 households in Haidian, Beijing for both heating and non-heating seasons. A bimodal distribution of PM2.5 concentrations suggests rapid transitions between polluted and non-polluted situations. The PM2.5 concentrations in indoor and outdoor air varied synchronously, with the indoor variation lagging. The lag time in the heating season was longer than that in the non-heating season. The particle sizes in indoor air were smaller than those in ambient air in the heating season and vice versa in the non-heating season. PM2.5 concentrations in indoor air were generally lower than those in ambient air except when ambient concentrations dropped sharply to very low levels or there were internal emissions from cooking or other activities. The effectiveness of an air cleaner to reduce indoor PM2.5 concentrations was demonstrated. Non-linear regression models were developed to predict indoor air PM2.5 concentrations based on ambient data with lag time incorporated. The models were applied to estimate the overall population exposure to PM2.5 and the health consequences in Haidian. The health impacts would be significantly overestimated without the indoor exposure being taken into consideration, and this bias would increase as the ambient air quality improved in the future. PMID- 27769775 TI - Stylet Use Does Not Improve Diagnostic Outcomes in Endobronchial Ultrasonographic Transbronchial Needle Aspiration: A Randomized Clinical Trial. AB - BACKGROUND: Endobronchial ultrasonographically guided transbronchial needle aspiration (EBUS-TBNA) of thoracic structures is a commonly performed tissue sampling technique. The use of an inner-stylet in the EBUS needle has never been rigorously evaluated and may be unnecessary. METHODS: In a prospective randomized single-blind controlled clinical trial, patients with a clinical indication for EBUS-TBNA underwent lymph node sampling using both with-stylet and without-stylet techniques. Sample adequacy, diagnostic yield, and various cytologic quality measures were compared. RESULTS: One hundred twenty-one patients were enrolled, with 194 lymph nodes sampled, each using both with-stylet and without-stylet techniques. There was no significant difference in sample adequacy or diagnostic yield between techniques. The without-stylet technique resulted in adequate samples in 87% of the 194 study lymph nodes, which was no different from the with stylet adequacy rate (82%; P = .371). The with-stylet technique resulted in a diagnosis in 50 of 194 samples (25.7%), which was similar to the without-stylet group (49 of 194 [25.2%]; P = .740). There was a high degree of concordance in the determination of adequacy (84.0%; 95% CI, 78.1-88.9) and diagnostic sample generation (95.4%; 95% CI, 91.2-97.9) between the two techniques. A similar qualitative number of lymphocytes, malignant cells, and bronchial respiratory epithelia were recovered using each technique. CONCLUSIONS: Omitting stylet use during EBUS-TBNA does not affect diagnostic outcomes and reduces procedural complexity. TRIAL REGISTRY: ClinicalTrials.Gov: No. NCT 02201654; URL:www.clinicaltrials.gov. PMID- 27769776 TI - Immunotherapy for Lung Malignancies: From Gene Sequencing to Novel Therapies. AB - Harnessing the immune system to fight cancer is an exciting advancement in lung cancer therapy. Antitumor immunity can be augmented by checkpoint blockade therapy, which removes the inhibition/brakes imposed on the immune system by the tumor. Checkpoint blockade therapy with anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death ligand 1 (anti-PDL-1) antibodies causes tumor regression in about 25% of patients with lung cancer. In another approach, the immune system is forced or accelerated to attack the tumor through augmentation of the antitumor response against mutations carried by each lung tumor. This latter approach has become feasible since the advent of next-generation sequencing technology, which allows identification of the specific mutations that each individual lung tumor bears. Indeed lung cancers are now known to have high mutation rates, making them logical targets for mutation-directed immune therapies. We review how sequencing of lung cancer mutations leads to better understanding of how the immune system recognizes tumors, providing improved opportunities to track antitumor immunity and ultimately leading to the development of personalized vaccine strategies aimed at unleashing the host immune system to attack mutations in the tumor. PMID- 27769777 TI - Improvised Cricothyrotomy on a Mountain Using Hiking Gear. AB - We present a case of a 57-year-old man who fell while climbing a mountain in California and sustained severe facial trauma. Three firefighters and 2 emergency physicians witnessed the fall and resuscitated the patient. The patient ultimately required a surgical cricothyrotomy performed with a pocket knife and Platypus hydration pack. The physicians made a makeshift positive pressure airway device using the Platypus hydration pack. We believe this is the first case report describing an improvised cricothyrotomy performed in the wilderness using only hiking gear. This report also discusses indications for cricothyrotomy, the challenges of resuscitation in a low-resource environment, and special considerations in a high-altitude setting. PMID- 27769778 TI - A bioinformatics approach reveals seven nearly-complete RNA-virus genomes in bivalve RNA-seq data. AB - Viral metagenomics (viromics) can provide a great contribution in expanding the knowledge of viruses and the relationship with their hosts. Viromic studies on marine organisms are still at a very early stage and only little efforts have been spent in the identification of viruses associated to marine invertebrates to date, leaving the complexity of marine viromes associated to bivalve hosts almost completely unexplored. However, the potential use of viromic approaches in the management of viral diseases affecting aquacultured species has been recently evidenced by the flourishing of studies on the Ostreid herpesvirus type-1, which has been associated with bivalve mortality events. Herein we discuss an effective pipeline to retrieve and reconstruct nearly complete and previously unreported viral genomes from existing host RNA-seq data. As a case study, we report the identification of seven RNA-virus genomes within the frame of a highly diversified viral community that characterizes both Crassostrea gigas and Mytilus galloprovincialis samples collected from the lagoon of Goro (Italy). PMID- 27769779 TI - Synergistic inhibitory effects of Celecoxib and Plumbagin on melanoma tumor growth. AB - Melanoma is a highly drug resistant cancer. To circumvent this problem, a class of synergistically acting drug combinations, which inhibit multiple key pathways in melanoma cells, could be used as one approach for long-term treatment of this deadly disease. A screen has been undertaken on cell lines to identify those that could be combined to synergistically kill melanoma cells. Plumbagin and Celecoxib are two agents that were identified to synergistically kill melanoma cells by inhibiting the COX-2 and STAT3 pathways, which are constitutively activated in up to 70% of melanomas. The combination of these two drugs was more effective at killing melanoma cells than normal cells and decreased cellular proliferation as well as induced apoptosis of cultured cells. The drug combination inhibited development of xenograft melanoma tumors by up to 63% without affecting animal weight or blood biomarkers of organ function, suggesting negligible toxicity. Mechanistically, combination of Celecoxib and Plumbagin decreased melanoma cell proliferation and retarded vascular development of tumors mediated by inhibition of COX-2 and STAT3 leading to decreased levels of key cyclins key on which melanoma cell were dependent for survival. PMID- 27769780 TI - Sec8 modulates TGF-beta induced EMT by controlling N-cadherin via regulation of Smad3/4. AB - Sec8 is one of the subunits of the exocyst, which is an evolutionarily conserved complex of eight proteins, comprising Sec3 (EXOC1), Sec5 (EXOC2), Sec6 (EXOC3), Sec8 (EXOC4), Sec10 (EXOC5), Sec15 (EXOC6), Exo70 (EXOC7), and Exo84 (EXOC8) subunits. Sec8 knockout mice embryos initiate gastrulation but are unable to progress beyond the primitive streak stage and die shortly. During embryonic development, the first epithelial-mesenchymal transition (EMT) event occurs at gastrulation. Sec8 may be involved in the early embryonic development through EMT. However, the function of Sec8 in EMT remains unclear. In the present study, it was found that Sec8 regulates N-cadherin expression by controlling Smad3 and Smad4 expression at the basal transcriptional level, thereby modulating cell migration and adhesion. Furthermore, Sec8 knockdown decreased CREB binding protein (CBP) expression at mRNA and protein levels. However, CBP knockdown did not affect Sec8 expression. These results indicated that Sec8 regulates N cadherin expression by controlling Smad3 and Smad4 expression through CBP, thereby mediating the EMT. PMID- 27769782 TI - Defining malnutrition: A plea to rethink. AB - In a recent consensus report in Clinical Nutrition the undernourished category of malnutrition was proposed to be defined and diagnosed on the basis of a low BMI or unintentional weight loss combined with low BMI or FFMI with certain cut off points. The definition was endorsed by ESPEN despite recent endorsement of a very different definition. The approach aims to assess whether nutritional intake is sufficient but is imprecise because a low BMI does not always indicate malnutrition and individuals with increasing BMI's may have decreasing FFM's. The pathophysiology of individuals, considered to be malnourished in rich countries and in areas with endemic malnutrition, results predominantly from deficient nutrition combined with infection/inflammation. Both elements jointly determine body composition and function and consequently outcome of disease, trauma or treatment. When following the consensus statement only an imprecise estimate is acquired of nutritional intake without knowing the impact of inflammation. Most importantly, functional abilities are not assessed. Consequently it will remain uncertain how well the individual can overcome stressful events, what the causes are of dysfunction, how to set priorities for treatment and how to predict the effect of nutritional support. We therefore advise to consider the pathophysiology of malnourished individuals leading to inclusion of the following elements in the definition of malnutrition: a disordered nutritional state resulting from a combination of inflammation and a negative nutrient balance, leading to changes in body composition, function and outcome. A precise diagnosis of malnutrition should be based on assessment of these elements. PMID- 27769781 TI - Adherence to a Mediterranean diet is associated with lower prevalence of osteoarthritis: Data from the osteoarthritis initiative. AB - BACKGROUND & AIMS: The Mediterranean diet appears to be beneficial for several medical conditions, but data regarding osteoarthritis (OA) are not available. The aim of this study was to investigate if adherence to the Mediterranean diet is associated with a lower prevalence of OA of the knee in a large cohort from North America. METHODS: 4358 community-dwelling participants (2527 females; mean age: 61.2 years) from the Osteoarthritis Initiative were included. Adherence to the Mediterranean diet was evaluated through a validated Mediterranean diet score (aMED) categorized into quartiles (Q). Knee OA was diagnosed both clinically and radiologically. The strength of the association between aMED (divided in quartiles) and knee OA was investigated through a logistic regression analysis and reported as odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for potential confounders. RESULTS: Participants with a higher adherence to Mediterranean diet had a significantly lower prevalence of knee OA compared to those with lower adherence (Q4: 25.2% vs. Q1: 33.8%; p < 0.0001). Using a logistic regression analysis, adjusting for 10 potential confounders with those in the lowest quartile of aMED as reference, participants with the highest aMED had a significant reduction in presence of knee OA (OR, 0.83; 95% CIs: 0.69-0.99, p = 0.04). Among the individual components of Mediterranean diet, only higher use of cereals was associated with lower odds of having knee OA (OR: 0.76; 95%CI: 0.60-0.98; p = 0.03). CONCLUSIONS: Higher adherence to a Mediterranean diet is associated with lower prevalence of knee OA. This remained when adjusting for potential confounders. PMID- 27769783 TI - Dietary fat composition, total body fat and regional body fat distribution in two Caucasian populations of middle-aged and older adult women. AB - OBJECTIVE: We aimed to study whether dietary fat composition (n-3 and n-6 polyunsaturated fatty acids ratio (PUFAs) and PUFAs and saturated fatty acids (SFAs) ratio) is associated with total body fat (TF) and body fat distribution and whether this association was modified by the presence of chronic disease in middle-aged and elderly women in two population-based cohorts in the Netherlands and Australia. METHODS: The study was performed in the Rotterdam Study (RS), a prospective cohort study among subjects aged 55 years and older (N = 1182 women) and the Calcium Intake Fracture Outcome Study (CAIFOS), a 5-year randomized controlled trial among women age 70+ (N = 891). At baseline, diet (i.e. PUFAs and SFAs) was measured by validated food frequency questionnaires. TF was assessed using Dual-energy X-ray absorptiometry in both studies and android abdominal fat (AF), gynoid fat (GF) and the android/gynoid ratio (A/G ratio) in the RS but not the CAIFOS. Chronic disease was defined as the presence of cardiovascular disease, diabetes mellitus and cancer. RESULTS: No association was found between dietary n-3/n-6 PUFAs ratio or SFA/PUFAs ratio with TF in both cohorts. In the RS, a high n-3/n-6 PUFAs ratio was associated with a higher AF (3rd vs. 2nd tertile (reference): beta: 0.15; 95% CI: 0.05, 0.24) but not with the A/G ratio. A low SFA/PUFA ratio was associated with a lower AF (1st vs. 2nd tertile (reference): beta: -0.12; 95% CI: -0.22, -0.06) but not with the A/G ratio. Presence of chronic disease was found to be a significant effect modifier in both cohorts with regard to n-3/n-6 PUFAs and TF (P < 0.05). In participants without chronic disease, a higher n-3/n-6 PUFAs ratio was associated with a higher TF in the RS cohort (3rd vs. 2nd tertile (reference): beta: 0.94; 95% CI: 0.12, 1.76), but this was not replicated in CAIFOS. CONCLUSION: These findings do not support the hypothesis that dietary fat composition is consistently associated with TF and body fat distribution in women. Future studies should clarify to what extent these findings may be influenced by the presence of chronic disease. PMID- 27769784 TI - Vitamin D3 supplementation among adult patients with cystic fibrosis. AB - BACKGROUND & AIMS: Vitamin D (Vit D) deficiency in cystic fibrosis (CF) is partially secondary to exocrine pancreatic insufficiency. Our aim was to establish a Vit D3 supplementation protocol that will increase 25(OH)D to the recommended level (30 ng/mL). METHODS: Retrospective study of 200 patients (>=18 years) conducted from February 2007 to June 2014 at the CF clinic of the Centre Hospitalier de l'Universite de Montreal. Vit D3 supplementation protocol was 1600 IU/day or 10,000 IU/week during the summer (May 1st to October 31st) and 3200 IU/day or 20,000 IU/week during the winter (November 1st to April 30th), in addition to the 1200 IU/day included in multivitamins. RESULTS: Significant increase in serum 25(OH)D levels from baseline (25.9 +/- 10.3 ng/mL) to follow-up (37.0 +/- 11.4 ng/mL) (P <= 0.001). At follow-up, increased doses during the winter improved serum 25(OH)D levels to a degree comparable to the summer. CONCLUSIONS: This supplementation protocol is efficient and needs to be tested in other CF adult cohorts and correlated to potential health benefit measurements. PMID- 27769785 TI - Dornase alfa for cystic fibrosis. PMID- 27769786 TI - Common and distinct brain regions in both parietal and frontal cortex support symbolic and nonsymbolic number processing in humans: A functional neuroimaging meta-analysis. AB - In recent years, there has been substantial growth in neuroimaging studies investigating neural correlates of symbolic (e.g. Arabic numerals) and non symbolic (e.g. dot arrays) number processing. At present it remains contested whether number is represented abstractly, or if number representations in the brain are format-dependent. In order to quantitatively evaluate the available neuroimaging evidence, we used activation likelihood estimation (ALE) to conduct quantitative meta-analyses of the results reported in 57 neuroimaging papers. Consistent with the existence of an abstract representation of number in the brain, conjunction analyses revealed overlapping activation for symbolic and nonsymbolic numbers in frontal and parietal lobes. Consistent with the notion of format-dependent activation, contrast analyses demonstrated anatomically distinct fronto-parietal activation for symbolic and non-symbolic processing. Therefore, symbolic and non-symbolic numbers are subserved by format-dependent and abstract neural systems. Moreover, the present results suggest that regions across the parietal cortex, not just the intraparietal sulcus, are engaged in both symbolic and non-symbolic number processing, challenging the notion that the intraparietal sulcus is the key region for number processing. Additionally, our analyses indicate that regions in the frontal cortex subserve magnitude representations rather than non-numerical cognitive processes associated with number tasks, thereby highlighting the importance of considering both frontal and parietal regions as important for number processing. PMID- 27769787 TI - Neuroprotection of Cilostazol against ischemia/reperfusion-induced cognitive deficits through inhibiting JNK3/caspase-3 by enhancing Akt1. AB - Cilostazol(CTL) is a phosphodiesterase inhibitor, which has been widely used as anti-platelet agent. It also has preventive effects on various central nervous system (CNS) diseases, including ischemic stroke, Parkinson's disease and Alzheimer disease. However, the molecular mechanism underlying the protective effects of CTL is still unclear, and whether CTL can prevent I/R induced cognitive deficit has not been reported. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The open field tasks and Morris water maze were used to assess the effect of CTL on anxiety-like behavioral and cognitive impairment after I/R. Western blotting were performed to examine the expression of related proteins, and HE-staining was used to detect the percentage of neuronal death in the hippocampal CA1 region. Here we found that CTL significantly improved cognitive deficits and the behavior of rats in Morris water maze and open field tasks (P<0.05). HE staining results showed that CTL could significantly protect CA1 neurons against cerebral I/R (P<0.05). Additionally, Akt1 phosphorylation levels were evidently up-regulated (P<0.05), while the activation of JNK3, which is an important contributor to I/R-induced neuron apoptosis, was reduced by CTL after I/R (P<0.05), and caspase-3 levels were also decreased by CTL treatment. Furthermore, all of CTL's protective effects were reversed by LY294002, which is a PI3K/Akt1 inhibitor. Taken together, our results suggest that CTL could protect hippocampal neurons and ameliorate the impairment of learning/memory abilities and locomotor/ exploratory activities in ischemic stroke via a PI3K-Akt1/JNK3/caspase-3 dependent mechanism. PMID- 27769788 TI - Cannabinoid receptor 2 activation restricts fibrosis and alleviates hydrocephalus after intraventricular hemorrhage. AB - Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH). The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases. However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model. Autologous non-anticoagulative blood injection model was induced to mimic ventricular extension of hemorrhage in adult Sprague-Dawley rats. Rats were randomized to receive JWH-133(CB2 agonist), SR144528 (CB2 antagonist) or saline. The lateral ventricular volumes, fibrosis in the subarachnoid space and ventricular wall, transforming growth factor-beta 1(TGF-beta1) in cerebrospinal fluid and brain tissue, and animal neurological scores were measured to evaluate the effects of CB2 in hydrocephalus following IVH. CB2 agonist JWH-133 significantly decreased the lateral ventricular volumes, improved the associated neurological deficits, down-regulated TGF-beta1 expression, and alleviated fibrosis in the subarachnoid space and ventricular wall after IVH. All of these effects were reversed by SR144528. In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-beta1. PMID- 27769789 TI - Protective effect of resveratrol against nigrostriatal pathway injury in striatum via JNK pathway. AB - Nigrostriatal pathway injury is one of the traumatic brain injury models that usually lead to neurological dysfunction or neuron necrosis. Resveratrol-induced benefits have recently been demonstrated in several models of neuronal degeneration diseases. However, the protective properties of resveratrol against neurodegeneration have not been explored definitely. Thus, we employ the nigrostriatal pathway injury model to mimic the insults on the brain. Resveratrol decreased the p-ERK expression and increased the p-JNK expression compared to the DMSO group, but not alter the p38 MAPK proteins around the lesion site by Western blot. Prior to the injury, mice were infused with resveratrol intracerebroventricularly with or without JNK-IN-8, a specific c-JNK pathway inhibitor for JNK1, JNK2 and JNK4. The study assessed modified improved neurological function score (mNSS) and beam/walking test, the level of inflammatory cytokines IL-1beta, IL-6 and TNF-alpha, and striatal expression of Bax and Bcl-2 proteins associated with neuronal apoptosis. The results revealed that resveratrol exerted a neuroprotective effect as shown by the improved mNSS and beam latency, anti-inflammatory effects as indicated by the decreased level of IL-1beta, TNF-alpha and IL-6. Furthermore, resveratrol up-regulated the protein expression of p-JNK and Bcl-2, down-regulated the expression of Bax and the number of Fluoro-Jade C (FJC) positive neurons. However, these advantages of resveratrol were abolished by JNK-IN-8 treatment. Overall, we demonstrated that resveratrol treatment attenuates the nigrostriatal pathway injury-induced neuronal apoptosis and inflammation via activation of c-JNK signaling. PMID- 27769790 TI - Isoflurane neurotoxicity involves activation of hypoxia inducible factor-1alpha via intracellular calcium in neonatal rodents. AB - OBJECTIVE: Previously, we found that the inhaled anesthetic isoflurane up regulated the transcriptional factor hypoxia inducible factor (HIF)-1alpha protein levels during induction of neurodegeneration in the brain of neonatal rats. Here, we investigated the role of HIF-1alpha and the underlying signaling pathway in the neurodegenration induced by isoflurane in rodent developing brain. METHODS: Primary hippocampal neurons were exposed to isoflurane (0.4mM) for 12h. Neuron injury was analyzed by 3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetra zolium bromide (MTT) test and quantification of lactate dehydrogenaserelease. HIF 1alpha gene expression and transcriptional activity, cleaved caspase-3 and phosphoinositide phospholipase C (PLC)-gamma gene expression were quantified. Cytosolic calcium concentration was measured by calcium imagining. The role of HIF-1alpha on juvenile learning and memory impairment induced by isoflurane was studied by fear conditioning and extinction test and Morris water maze test. RESULTS: Isoflurane induced HIF-1alpha gene expression and transcriptional activity in vitro. Furthermore, pharmacological inhibition of HIF-1alpha or knockdown of HIF-1alpha by shRNA counteracted the neurotoxicity of isoflurane. Ca2+ signaling pathways involving PLC-gamma activation are required for isoflurane-evoked HIF-1alpha accumulation. Finally, partial deficiency of HIF 1alpha attenuated isoflurane-induced neurodegeneration in developing brain, and alleviated juvenile learning and memory impairment induced by isoflurane. CONCLUSION: HIF-1alpha activation via cytosolic Ca2+ signaling pathway play a role in the mechanism of isoflurane-induced neurodegeneration in neonatal rodents, suggesting HIF-1alpha as a potential therapeutic target for the prevention of the deleterious effects of prolonged exposures to anesthetics. PMID- 27769791 TI - Liver and Cardiovascular Disease: What Cardiologists Need to Know About Ultrasound Findings. PMID- 27769792 TI - Cardiovascular Disease and Gross Domestic Product in Spain: Correlation Analysis by Autonomous Communities. PMID- 27769793 TI - Impella CP-Assisted High-risk Coronary Percutaneous Intervention: First Experience in Spain. PMID- 27769795 TI - Comparison of nerve combing and percutaneous radiofrequency thermocoagulation in the treatment for idiopathic trigeminal neuralgia. PMID- 27769794 TI - The potential role of amlodipine on experimentally induced bacterial rhinosinusitis. AB - INTRODUCTION: Antibiotics are frequently used for the treatment of rhinosinusitis. Concerns have been raised regarding the adverse effects of antibiotics and growing resistance. The lack of development of new antibiotic compounds has increased the necessity for exploration of non-antibiotic compounds that have antibacterial activity. Amlodipine is a non-antibiotic compound with anti-inflammatory activity. OBJECTIVE: In this study we aimed to investigate the potential role of amlodipine in the treatment of rhinosinusitis by evaluating its effects on tissue oxidative status, mucosal histology and inflammation. METHODS: Fifteen adult albino guinea pigs were inoculated with Staphylococcus aureus and treated with saline, cefazolin sodium, or amlodipine for 7 days. The control group was composed by five healthy guinea pigs. Animals were sacrificed after the treatment. Histopathological changes were identified using Hematoxylin-Eosin staining. Inflammation was assessed by Polymorphonuclear Leukocyte infiltration density. Tissue levels of antioxidants (superoxide dismutase, glutathione) and an oxidative product (malondialdehyde) were determined. RESULTS: In rhinosinusitis induced animals, amlodipine reduced loss of cilia, lamina propria edema and collagen deposition compared to placebo (saline) and although not superior to cefazolin, amlodipine decreased polymorphonuclear leukocyte infiltration. The superoxide dismutase activity and glutathione levels were reduced, whereas the malondialdehyde levels were increased significantly in all three-treatment groups compared to the control group. Amlodipine treated group showed significantly increased superoxide dismutase and glutathione levels and decreased malondialdehyde levels compared to all treatment groups. CONCLUSION: The non antibiotic compound amlodipine may have a role in acute rhinosinusitis treatment through tissue protective, antioxidant and anti-inflammatory mechanisms. PMID- 27769796 TI - Coughing up - Small cell carcinoma lung with gingival metastasis. AB - Small cell lung cancer (SCLC) is known for its metastatic potential. The most common sites are liver, adrenal, bone and brain. We report a case of a 37year old female patient, diagnosed with SCLC, presenting with gingival metastasis, an unusual metastatic site. Radiation therapy to the metastatic lesion to a dose of 20 Gray in 5 fractions over 5days was delivered which achieved haemostasis and good palliation. However, the patient expired in 2months owing to systemic metastasis. PMID- 27769797 TI - Learning by observing: the effect of multiple sessions of action-observation training on the spontaneous movement tempo and motor resonance. AB - The present study was designed to explore the changes in motor performance and motor resonance after multiple sessions of action observation (AO) training. Subjects were exposed to the observation of a video showing finger tapping movements executed at 3Hz, a frequency higher than the spontaneous one (2Hz) for four consecutive days. Motor performance and motor resonance were tested before the AO training on the first day, and on the last day. Results showed that multiple sessions of AO training induced a shift of the speed of execution of finger tapping movements toward the observed one and a change in motor resonance. Before the 3Hz-AO training cortical excitability was highest during the observation of the 2Hz video. This motor resonance effect was lost after one single session of 3Hz-AO training whereas after multiple sessions of 3Hz-AO training cortical excitability was highest during the observation of the 3Hz video. Our study shows for the first time that multiple sessions of AO training are able not only to induce performance gains but also to change the way by which the observer's motor system recognizes a certain movement as belonging to the individual motor repertoire. These results may encourage the development of novel rehabilitative protocols based on multiple sessions of action observation aimed to regain a correct movement when its spontaneous speed is modified by pathologies or to modify the innate temporal properties of certain movements. PMID- 27769798 TI - Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards. AB - Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient centred cancer care. However, the various ways these measures are analysed and interpreted make it difficult to compare results across trials, and hinders the application of research findings to inform publications, product labelling, clinical guidelines, and health policy. To address these problems, the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative has been established. This consortium, directed by the European Organisation for Research and Treatment of Cancer (EORTC), was convened to provide recommendations on how to standardise the analysis of HRQOL and other patient-reported outcomes data in cancer randomised trials. This Personal View discusses the reasons why this project was initiated, the rationale for the planned work, and the expected benefits to cancer research, patient and provider decision making, care delivery, and policy making. PMID- 27769799 TI - Genetic variations of the NPC1L1 gene associated with hepatitis C virus (HCV) infection and biochemical characteristics of HCV patients in China. AB - OBJECTIVES: About 2% of the world population is infected with hepatitis C virus (HCV), a leading cause of hepatic cirrhosis and hepatocellular carcinoma. The Niemann-Pick C1-like 1 cholesterol absorption receptor (NPC1L1) was recently identified to be an important factor for HCV entry into host cells. Whether genetic variations of the NPC1L1 gene are associated with HCV infection is unknown. METHODS: In this study, five single nucleotide polymorphisms (SNPs) of the NPC1L1 gene were analyzed in 261 HCV-infected individuals and 265 general controls from Yunnan Province, China. RESULTS: No significant differences were identified in genotypes or alleles of the SNPs between the two groups. After constructing haplotypes based on the five SNPs, a significant difference between HCV-infected individuals and general controls was shown for two haplotypes. Haplotype GCCTT appeared to be a protective factor and haplotype GCCCT was a risk factor for HCV-infected individuals. Genotypes of four SNPs correlated with biochemical characteristics of HCV-infected persons. Genotypes of SNPs rs799444 and rs2070607 were correlated with total bilirubin. Genotype TT of rs917098 was a risk factor for the gamma-glutamyltransferase level. Furthermore, HCV-infected individuals carrying genotype GG of rs41279633 showed statistically higher gamma glutamyltransferase levels than HCV-infected persons with GT and TT. CONCLUSION: The results of this study identified the association between genetic susceptibility of the NPC1L1 gene and HCV infection, as well as biochemical characteristics of HCV-infected persons in Yunnan, China. PMID- 27769800 TI - The association of cumulative discrimination on quality of care, patient-centered care, and dissatisfaction with care in adults with type 2 diabetes. AB - AIMS: Discrimination is linked to negative health outcomes, but little research has investigated how the cumulative effect of discrimination impacts perceptions of care. This study investigated the influence of cumulative perceived discrimination on quality of care, patient-centeredness, and dissatisfaction with care in adults with type 2 diabetes. METHODS: Six hundred two patients from two primary care clinics in Charleston, SC. Linear regression models assessed associations between perceived discrimination and quality of care, patient centered care, and dissatisfaction with care. The models control for race, site, age, gender, marital status, duration of diabetes, education, hours worked weekly, income, and health status. RESULTS: The mean age was 61.5years, with 66.3% non-Hispanic blacks, and 41.9% earning less than $20,000 annually. In final adjusted analyses, lower patient-centered care was associated with a higher discrimination score (beta=-0.28; p=0.006), reporting at least 1 category of discrimination (beta=-1.47; p=0.002), and reporting at least 2 categories of discrimination (beta=-1.34; p=0.004). Dissatisfaction with care was associated with at least 2 categories of discrimination (beta=0.45; p=0.002). No significant associations were seen with quality of care indicators. CONCLUSIONS: Increased cumulative discrimination was associated with decreased feeling of patient centeredness and increased dissatisfaction with care. However, these perceptions of discrimination were not significantly associated with quality indicators. PMID- 27769801 TI - Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment. AB - AIMS/HYPOTHESIS: Management of diabetic nephropathy includes reduction of albuminuria, blood pressure and weight. The GLP-1 receptor agonist liraglutide may possess these pleiotropic effects in addition to the glucose lowering effect. We aimed to elucidate the individual liraglutide treatment response by determining if high responders (highest reduction) in each risk factor also had high response in other renal risk factors (cross-dependency). METHODS: Open-label study: 31 type 2 diabetics treated with liraglutide for 7weeks. After 3weeks washout 23 re-started treatment and were followed for 1year. HbA1c, weight, systolic blood pressure (SBP), urinary albumin excretion rate (UAER) and mGFR (51Cr-EDTA) were evaluated. Changes in high (Q4) vs. low responders (Q1-Q3) were compared for each renal risk factor. The effects of treatment/off treatment/re treatment (off-on/off-on effect) were evaluated to account for random effects. RESULTS: After 7weeks HbA1c was reduced 6(95% CI: 3;9)mmol/mol, weight 2.5(1.8;3.2)kg, SBP 4(-1;9)mmHg, UAER 30(12;44)% and mGFR 11(7;14)ml/min per 1.73m2. mGFR high responders had a significant reduction in weight compared to low responders (4.3 vs. 1.9kg; p=0.002). SBP high responders had a tendency of a higher reduction in UAER compared to low responders (47 vs. 23%, p=0.14). No cross-dependency was observed in any of the other renal risk factors (p>=0.16). Treatment response did not differ after 7weeks and 1year (p>=0.12). CONCLUSIONS/INTERPRETATION: Liraglutide possesses pleiotropic effects on renal risk factors. On patient level, effect on the individual risk factor cannot be anticipated based on response in other risk factors. Response when re-starting treatment did not differ, indicating that our primary findings were not random. PMID- 27769802 TI - Challenges of up-scaling lentivirus production and processing. AB - Lentiviruses are becoming an increasingly popular choice of gene transfer vehicle for use in the treatment of a variety of genetic and acquired human diseases. As research progresses from basic studies into pre-clinical and clinical phases, there is a growing demand for large volumes of high purity, concentrated vector, and accordingly, the means to produce such quantities. Unlike other viral vectors, lentiviruses are difficult to produce using stable cell lines, therefore transient transfection of adherent cell lines is conventionally used, and this method has proven challenging to up-scale. Furthermore, with the required increases in the volume of vector needed for larger animal and human use, comes the need for more efficient and sophisticated supernatant purification and concentration techniques. This review presents the challenges of up-scaling lentivirus production and processing approaches, novel systems for overcoming these issues, and the quality assessments recommended for producing a clinical grade lentiviral gene therapy product. PMID- 27769804 TI - The effects of swimming fatigue on shoulder strength, range of motion, joint control, and performance in swimmers. AB - PURPOSE: To investigate the effects of training induced fatigue on shoulder strength, ROM, joint position sense, and stroke length in elite competitive swimmers. METHODS: Seventeen national level swimmers performed maximum isometric strength (internal and external rotation), ROM, and joint position sense tests before and after a fatiguing 8 * 100 m training set. Stroke length, heart rate, blood lactate and blood glucose levels were recorded throughout. RESULTS: Peak blood lactate, blood glucose levels, and heart rate increased significantly (P < 0.001) post-training confirming fatigue. Reductions were observed in stroke length of both arms (P < 0.001), external rotation range of motion (P < 0.001, 5.29 degrees , Right shoulder; P = 0.04, -3.18 degrees , Left shoulder) and joint position sense in their dominant (breathing side) arm (P = 0.03). CONCLUSIONS: This investigation revealed a reduction in stroke length across both arms and also an arm bias in swimming whereby a greater reduction in both external rotation range and joint position sense was observed in the dominant arm when fatigued. This has highlighted a relationship between fatigue and potential mechanism of shoulder pathology in swimmers. PMID- 27769805 TI - Bodybuilding-induced Mondor's disease of the chest wall. AB - OBJECTIVE: To describe the association of bodybuilding abdominal exercise with the development of superficial sclerosing thrombophlebitis of the anterolateral thoracoabdominal wall. DESIGN: A single case study. SETTING: University affiliated regional community hospital. CASE DESCRIPTION: A 54-year-old man presented with an otherwise unremarkable past medical history 4 weeks after the start of left-sided chest discomfort. He had undergone orthopedic surgery of the right shoulder three months earlier. Two months after surgery, he had re-started bodybuilding with thoracoabdominal training. Soon thereafter, he noted a painful induration at the left side of his trunk. Doppler and duplex sonography revealed complete venous occlusion compatible with sclerosing thrombophlebitis leading to a palpable, subcutaneous, cord-like lesion on the left side of his trunk. Physical examination and routine laboratory findings were normal. The lesion spontaneously resolved over a course of 3 months. CONCLUSIONS: Mondor's disease of the subcutaneous veins of the chest wall which has been associated with breast or axillary surgery, malignant and systemic diseases can also appear in subjects performing intense thoracoabdominal exercise training. Although it requires only symptomatic therapy, physicians and therapists must be aware of the existence of this disease because, although benign and self-limiting, malignant and systemic diseases need to be ruled out. PMID- 27769803 TI - Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T regulatory Cell Function and Promotes Antitumor Immunity. AB - Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3+ Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy. PMID- 27769806 TI - The bacterial cell envelope as delimiter of anti-infective bioavailability - An in vitro permeation model of the Gram-negative bacterial inner membrane. AB - Gram-negative bacteria possess a unique and complex cell envelope, composed of an inner and outer membrane separated by an intermediate cell wall-containing periplasm. This tripartite structure acts intrinsically as a significant biological barrier, often limiting the permeation of anti-infectives, and so preventing such drugs from reaching their target. Furthermore, identification of the specific permeation-limiting envelope component proves difficult in the case of many anti-infectives, due to the challenges associated with isolation of individual cell envelope structures in bacterial culture. The development of an in vitro permeation model of the Gram-negative inner membrane, prepared by repeated coating of physiologically-relevant phospholipids on Transwell(r) filter inserts, is therefore reported, as a first step in the development of an overall cell envelope model. Characterization and permeability investigations of model compounds as well as anti-infectives confirmed the suitability of the model for quantitative and kinetically-resolved permeability assessment, and additionally confirmed the importance of employing bacteria-specific base materials for more accurate mimicking of the inner membrane lipid composition - both advantages compared to the majority of existing in vitro approaches. Additional incorporation of further elements of the Gram-negative bacterial cell envelope could ultimately facilitate model application as a screening tool in anti infective drug discovery or formulation development. PMID- 27769807 TI - Cytokine profiles in Opisthorchis viverrini stimulated peripheral blood mononuclear cells from cholangiocarcinoma patients. AB - The carcinogenic liver fluke Opisthorchis viverrini causes chronic inflammation in the bile duct and resulting in unremitting tissue damage that lead to hepatobiliary diseases, including cholangiocarcinoma (CCA). Despite inflammatory cytokine expression having been studied in the animal model, so far no studies have been carried out on cytokines in human CCA cases. Here we report the profile of cytokine production in peripheral blood mononuclear cells (PBMCs) collected from O. viverrini-associated human CCA and uninfected normal controls after stimulation with O. viverrini-excretory secretory (ES) product. Eleven cytokine profiles including IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL 12p70, TNF-alpha and LT-alpha measured by flow cytometry revealed both pro inflammatory and anti-inflammatory cytokines were increased in the O. viverrini associated CCA compared to uninfected normal controls. Specifically, net production levels of IFN-gamma, IL-10, and LT-alpha were 40 to >320 times higher in CCA than those of controls. These results suggest dysregulation of the immune response in the liver fluke associated CCA. PMID- 27769808 TI - Genome wide features, distribution and correlations of NF-Y binding sites. AB - NF-Y is a trimeric transcription factor that binds on DNA the CCAAT-box motif. In this article we reviewed and complemented with additional bioinformatic analysis existing data on genome-wide NF-Y binding characterization in human, reaching the following main conclusions: (1) about half of NF-Y binding sites are located at promoters, about 60-80 base pairs from transcription start sites; NF-Y binding to distal genomic regions takes place at inactive chromatin loci and/or DNA repetitive elements more often than active enhancers; (2) on almost half of its binding sites, regardless of their genomic localization (promoters or distal regions), NF-Y finds on DNA more than one CCAAT-box, and most of those multiple CCAAT binding loci present precise spacing and organization of the elements composing them; (3) there exists a well defined class of transcription factors that show genome-wide co-localization with NF-Y. Some of them lack their canonical binding site in binding regions overlapping with NF-Y, hence hinting at NF-Y mediated recruitment, while others show a precise positioning on DNA of their binding sites with respect to the CCAAT box bound by NF-Y. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani. PMID- 27769809 TI - Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease. AB - The management of the pregnant patient with inflammatory bowel disease is complicated by multiple providers, misinformation, and a disease entity that, particularly when active, can adversely affect pregnancy outcomes. This article seeks to frame the debate on medication safety in pregnancy and lactation using the US Food and Drug Administration's new Pregnancy and Lactation Labeling Rule and the most up-to-date safety information to discuss the risks and benefits of using each class of inflammatory bowel disease medication. PMID- 27769813 TI - Current progress toward vaccine and passive immunization approaches for Strongyloides spp. AB - Strongyloides stercoralis is a helminth parasite that can infect millions of people worldwide, particularly in tropical, subtropical and temperate regions with poor sanitation. Several aspects of epidemiology, biology and host-parasite interactions of S. stercoralis have been studied, and substantial knowledge has been acquired; however, very few studies on immunotherapeutic control strategies to prevent infection and disease in humans have been conducted. Therefore, this article reviews the current progress and targets toward vaccine and passive immunization approaches for Strongyloides spp. PMID- 27769812 TI - Comorbid Chronic Pain and Depression: Patient Perspectives on Empathy. AB - Clinician empathy is a well-documented component of effective patient/provider communication. Evidence surrounding the association between patient perspectives on clinician empathy and perception of pain management is currently limited, particularly among patients with chronic pain and depression. The aim of this study was to analyze patients' perspectives on the emergent theme of empathy and describe how patients construct their experiences and expectations surrounding empathic interactions. A secondary analysis of focus group data was designed using grounded theory methodology. Veterans Affairs (VA) and University Primary Care Clinics. Respondents with chronic pain and comorbid depression (N = 18) were 27 to 84 years old (mean 54.8 years), 61% women, 22% black, and 74% white. Study participants highly valued empathy and two types of empathic interactions: empathic listening and empathic action. Patients who provided examples of empathic interactions claimed that others understood, valued, and cared for them. In contrast, patients who perceived a lack of empathy and empathic interactions felt frustrated and uncared for by others (including their physicians) physically and emotionally. Patients with chronic pain and depression claimed that empathy helped them feel understood, believed, taken seriously, and that their needs were met. In demonstrating empathy and engaging in empathic interactions with patients, providers relate better to patients, better understand their life experience, and provide patient-centered care that is meaningful for patients, providers, and the health care systems within which they interact. Future research is needed to purposefully study the effects of empathic interactions on outcomes for patients with chronic pain and comorbid depression. PMID- 27769811 TI - Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis. AB - BACKGROUND & AIMS: Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP. METHODS: We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4+ T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses. RESULTS: Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I alpha1 chain, but not alpha2 smooth muscle actin or transforming growth factor-beta. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers. CONCLUSIONS: AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease. PMID- 27769810 TI - Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. AB - Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment. PMID- 27769815 TI - Parasporins 1 and 2: Their structure and activity. AB - Parasporins are novel protein toxins preferentially cytotoxic against human cancer cells. They are obtained from parasporal inclusions of Bacillus thuringiensis and, accordingly, are considered congeners of the insecticidal Cry toxins. Two types of parasporins have been identified: the three-domain Cry toxin type and the beta-pore-forming-toxin (beta-PFT) type. Crystal structures of representative members of the two types, PS1Aa1 and PS2Aa1, have been determined and compared with those of well-studied toxins. PS1Aa1 has a typical architecture characteristic of the three-domain insecticidal Cry toxins, though it is cleaved into two polypeptides. It has an extra N-terminal segment found only in the inactive form of the Cry toxins and, hence, it is presumed to act through another mechanism as an activator in the apoptotic signaling pathway rather than a pore forming toxin. PS2Aa1 shows a remarkable structural similarity to the aerolysin type beta-PFTs, which is much greater than expected from its limited sequence identity to those toxins. This strongly suggests that a pore-forming mechanism similar to that of beta-PFTs is involved in the action of this type of parasporin. The structural comparison of PS2Aa1 to other aerolysin-type beta-PFTs indicates conserved oligomerization and pore-forming structures in domains 2 and 3, and highly diverse putative receptor binding region structures in domain 1, likely accounting for enhanced cancer cell cytotoxicity as compared to normal control cells. The structural implications for the mechanism of action and cellular specificity of both Cry and beta-PFT type parasporins will be enhanced by further experimental validation. PMID- 27769814 TI - Bile acid synthesis precursors in subjects with genetic hypercholesterolemia negative for LDLR/APOB/PCSK9/APOE mutations. Association with lipids and carotid atherosclerosis. AB - Some oxysterols are precursors of bile acid synthesis and play an important role in cholesterol homeostasis. However, if they are involved in the pathogeny of genetic hypercholesterolemia has not been previously explored. We have studied non-cholesterol sterol markers of cholesterol synthesis (lanosterol and desmosterol) and oxysterols (7alpha-hydroxy-4-cholesten-3-one, 24S hydroxycholesterol and 27-hydroxycholesterol) in 200 affected subjects with primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH) and 100 normolipemic controls. All studied oxysterols and cholesterol synthesis markers were significantly higher in affected subjects than controls (P<0.001). Ratios of oxysterols to total cholesterol were higher in non-FH GH than in controls, although only 24S hydroxycholesterol showed statistical significance (P<0.001). Cholesterol synthesis markers had a positive correlation with BMI, triglycerides, cholesterol and apoB in control population. However, these correlations disappeared in non-FH GH with the exception of a weak positive correlation for non-HDL cholesterol and apoB. The same pattern was observed for oxysterols with high positive correlation in controls and absence of correlation for non-FH GH, except non-HDL cholesterol for 24S-hydroxycholesterol and 27-hydroxycholesterol and apoB for 27 hydroxycholesterol. All non-cholesterol sterols had positive correlation among them in patients and in controls. A total of 65 (32.5%) and 35 (17.5%) affected subjects presented values of oxysterols ratios to total cholesterol above the 95th percentile of the normal distribution (24S-hydroxycholesterol and 27 hydroxycholesterol, respectively). Those patients with the highest levels of 24S hydroxycholesterol associated an increase in the carotid intima media thickness. These results suggest that bile acid metabolism is affected in some patients with primary hypercholesterolemia of genetic origin, negative for mutations in the candidate genes, and may confer a higher cardiovascular risk. Our results confirm that cholesterol synthesis overproduction is a primary defect in non-HF GH and suggest that subjects with non-FH GH show high levels of oxysterols in response to hepatic overproduction of cholesterol. PMID- 27769817 TI - Non-invasive method for airway clearance in a patient with excessive dynamic airway collapse: A case study. PMID- 27769816 TI - Arsenic trioxide induces cell cycle arrest and alters DNA methylation patterns of cell cycle regulatory genes in colorectal cancer cells. AB - AIMS: Cell cycle dysregulation is important in tumorigenesis. Transcriptional silencing of cell cycle regulatory genes, due to DNA methylation, is a common epigenetic event in malignancies. As2O3 has been shown to induce cell cycle arrest and also to be a potential hypomethylating agent. Our study aimed to investigate DNA methylation patterns of cell cycle regulatory genes promoters, the effects of Arsenic trioxide (As2O3) on the methylated genes and cell cycle distribution in colorectal cancer (CRC) cell lines. MAIN METHODS: The methylation specific PCR (MSP) and/or restriction enzyme-based methods were used to study the promoter methylation patterns of 24 cell cycle regulatory genes in CRC cell lines. Gene expression level and cell cycle distribution were determined by Real time PCR and flow cytometric analyses, respectively. KEY FINDINGS: Our methylation analysis indicated that only promoters of RBL1 (p107), CHFR and p16 genes were aberrantly methylated in three cell lines. As2O3 significantly decreased DNA methylation in promoter regions of these genes and restored their expression. We found that As2O3 significantly reduced the expression of DNA methyltransferase 1 (DNMT1) and increased arsenic methyltransferase (AS3MT). Furthermore, As2O3 altered transcriptional activity of several unmethylated cell cycle regulatory genes including cyclin B1, E1, D1, GADD45A and p21. Cell cycle flow cytometry analysis showed As2O3 induced G2/M arrest in all three cell lines. SIGNIFICANCE: These data suggest that demethylation and alteration in the expression level of the cell cycle-related genes may be possible mechanisms in As2O3-induced cell cycle arrest in colorectal cancer cells. PMID- 27769818 TI - Peak cough flow measurement with a pneumotacograph and a portable peak flow meter in patients with neuromuscular diseases. PMID- 27769819 TI - Flavonoid dimers from the total phenolic extract of Chinese dragon's blood, the red resin of Dracaena cochinchinensis. AB - Eight new flavonoid dimers, named cochinchinenins I-M (1-5), including three pairs of enantiomers (1a/1b-3a/3b) and two optically pure flavonoid dimers (4-5), along with a known analogue (6), were isolated from total phenolic extract of the red resin of Dracaena cochinchinensis (Chinese dragon's blood). The planar structures of 1-5 were elucidated by extensive spectroscopic analysis including HRESIMS and 1D/2D NMR. Their absolute configurations were determined on the basis of experimental and calculated electronic circular dichroism (ECD) data. Compounds 4 and 5 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 value of 4.9+/-0.4 and 5.4+/-0.6MUM, respectively. PMID- 27769820 TI - Five new Lycopodium alkaloids from the aerial parts of Phlegmariurus henryi. AB - A series of new Lycopodium alkaloids, namely 1-epi-malycorin A (1), 1-epi-17S hydroxymalycorin A (2), 6alpha-hydroxyphlegmariurine A (3), 2S,4R dihydroxyfawcettimine (4), and 16-hydroxylycodine (5), together with 24 known ones, have been isolated from the club moss Phlegmariurus henryi. The structures of the new compounds were determined by extensive spectroscopic analysis, including 1D and 2D NMR, as well as X-ray crystallographic analysis. Among them, the absolute configurations of 1, 2, and 4 and the structure of 3 were confirmed on the basis of the single-crystal X-ray diffraction analysis. 1-Epi-17S hydroxymalycorin A (2) was a unique C19N-type Lycopodium alkaloid consisting of a serratinine skeleton with 1,2-propanediol unit. 2S,4R-dihydroxyfawcettimine (4) was a 2,4-dihydroxy derivative of fawcettimine. 16-Hydroxylycodine (5) was the oxidative product of lycodine with an unusual hydroxymethyl group at C-15. All new compounds were evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity and cytotoxicity against four human cancer cell lines. PMID- 27769821 TI - Practical Implications for an Effective Radiology Residency Quality Improvement Program for Milestone Assessment. AB - Utilization of a radiology resident-specific quality improvement (QI) program and curriculum based on the Accreditation Council for Graduate Medical Education (ACGME) milestones can enable a program's assessment of the systems-based practice component and prepare residents for QI implementation post graduation. This article outlines the development process, curriculum, QI committee formation, and resident QI project requirements of one institution's designated radiology resident QI program. A method of mapping the curriculum to the ACGME milestones and assessment of resident competence by postgraduate year level is provided. Sample projects, challenges to success, and lessons learned are also described. Survey data of current trainees and alumni about the program reveal that the majority of residents and alumni responders valued the QI curriculum and felt comfortable with principles and understanding of QI. The most highly valued aspect of the program was the utilization of a resident education committee. The majority of alumni responders felt the residency quality curriculum improved understanding of QI, assisted with preparation for the American Board of Radiology examination, and prepared them for QI in their careers. In addition to the survey results, outcomes of resident project completion and resident scholarly activity in QI are evidence of the success of this program. It is hoped that this description of our experiences with a radiology resident QI program, in accordance with the ACGME milestones, may facilitate the development of successful QI programs in other diagnostic radiology residencies. PMID- 27769822 TI - Variability of CT Attenuation Measurements in Virtual Unenhanced Images Generated Using Multimaterial Decomposition from Fast Kilovoltage-switching Dual-energy CT. AB - RATIONALE AND OBJECTIVES: To compare Hounsfield unit (HU) data obtained from true unenhanced (TUE) and virtual-unenhanced (VUE) imaging obtained with a fast kv switching dual-energy computed tomography (CT) scanner using multimaterial decomposition algorithm. MATERIALS AND METHODS: In this Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant, retrospective cohort study, CT scans of 19 patients undergoing multiphasic renal protocol abdominal CT on a fast kv-switching dual-energy CT scanner were reviewed. CT numbers were measured on the matched TUE and VUE generated using a multimaterial decomposition algorithm with selective iodine suppression, and postcontrast images at predefined locations in seven organs. Six hundred sixty regions of interest were placed at 132 locations. Agreement was assessed with paired t test, Pearson's correlation, and Bland-Altman analysis. RESULTS: Mean TUE and VUE measurements were not significantly different in the corticomedullary (P = 0.25) or nephrographic (P = 0.10) phases. There was a strong correlation between TUE and VUE CT numbers (corticomedullary: r = 0.90, nephrographic: r = 0.90, each P < 0.001). Discrepancies >=5 HU occurred 46 times (35%, 46 of 132) in the corticomedullary phase and 44 times (33%, 44 of 132) in the nephrographic phase. Discrepancies >=10 HU occurred in 7% (9 of 132 in both corticomedullary and nephrographic phases). Interphase, intrasubject VUE CT numbers were strongly correlated (r = 0.93, P < 0.001), but discrepancies >=5 HU (22% [29 of 132]) and >=10 HU (2% [3 of 132]) occurred. There was no significant correlation between the true postcontrast CT number and the magnitude of VUE-TUE discrepancy (r = 0.04, P = 0.6). CONCLUSION: CT numbers on VUE images generated from fast kv switching dual-energy CT scans strongly correlate with TUE CT numbers on a population basis, but commonly vary 5-9 HU on a per-patient basis. PMID- 27769823 TI - Radiology Workflow Dynamics: How Workflow Patterns Impact Radiologist Perceptions of Workplace Satisfaction. AB - RATIONALE AND OBJECTIVES: The study aimed to assess perceptions of reading room workflow and the impact separating image-interpretive and nonimage-interpretive task workflows can have on radiologist perceptions of workplace disruptions, workload, and overall satisfaction. MATERIALS AND METHODS: A 14-question survey instrument was developed to measure radiologist perceptions of workplace interruptions, satisfaction, and workload prior to and following implementation of separate image-interpretive and nonimage-interpretive reading room workflows. The results were collected over 2 weeks preceding the intervention and 2 weeks following the end of the intervention. The results were anonymized and analyzed using univariate analysis. RESULTS: A total of 18 people responded to the preintervention survey: 6 neuroradiology fellows and 12 attending neuroradiologists. Fifteen people who were then present for the 1-month intervention period responded to the postintervention survey. Perceptions of workplace disruptions, image interpretation, quality of trainee education, ability to perform nonimage-interpretive tasks, and quality of consultations (P < 0.0001) all improved following the intervention. Mental effort and workload also improved across all assessment domains, as did satisfaction with quality of image interpretation and consultative work. CONCLUSION: Implementation of parallel dedicated image-interpretive and nonimage-interpretive workflows may improve markers of radiologist perceptions of workplace satisfaction. PMID- 27769825 TI - First study of the evolution of the SeDeM expert system parameters based on percolation theory: Monitoring of their critical behavior. AB - The deep understanding of products and processes has become a requirement for pharmaceutical industries to follow the Quality by Design principles promoted by the regulatory authorities. With this aim, SeDeM expert system was developed as a useful preformulation tool to predict the likelihood to process drugs and excipients through direct compression. SeDeM system is a step forward in the rational development of a formulation, allowing the normalisation of the rheological parameters and the identification of the weaknesses and strengths of a powder or a powder blend. However, this method is based on the assumption of a linear behavior of disordered systems. As percolation theory has demonstrated, powder blends behave as non-linear systems that can suffer abrupt changes in their properties near to geometrical phase transitions of the components. The aim of this paper was to analyze for the first time the evolution of the SeDeM parameters in drug/excipient powder blends from the point of view of the percolation theory and to compare the changes predicted by SeDeM with the predictions of Percolation theory. For this purpose, powder blends of lactose and theophylline with varying concentrations of the model drug have been prepared and the SeDeM analysis has been applied to each blend in order to monitor the evolution of their properties. On the other hand, percolation thresholds have been estimated for these powder blends where critical points have been found for important rheological parameters as the powder flow. Finally, the predictions of percolation theory and SeDeM have been compared concluding that percolation theory can complement the SeDeM method for a more accurate estimation of the Design Space. PMID- 27769824 TI - A Study of the Feasibility of FDG-PET/CT to Systematically Detect and Quantify Differential Metabolic Effects of Chronic Tobacco Use in Organs of the Whole Body A Prospective Pilot Study. AB - RATIONALE AND OBJECTIVES: The aim of this study was to assess the feasibility of 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) to systematically detect and quantify differential effects of chronic tobacco use in organs of the whole body. MATERIALS AND METHODS: Twenty healthy male subjects (10 nonsmokers and 10 chronic heavy smokers) were enrolled. Subjects underwent whole-body FDG-PET/CT, diagnostic unenhanced chest CT, mini mental state examination, urine testing for oxidative stress, and serum testing. The organs of interest (thyroid, skin, skeletal muscle, aorta, heart, lung, adipose tissue, liver, spleen, brain, lumbar spinal bone marrow, and testis) were analyzed on FDG-PET/CT images to determine their metabolic activities using standardized uptake value (SUV) or metabolic volumetric product (MVP). Measurements were compared between subject groups using two-sample t tests or Wilcoxon rank-sum tests as determined by tests for normality. Correlational analyses were also performed. RESULTS: FDG-PET/CT revealed significantly decreased metabolic activity of lumbar spinal bone marrow (MVPmean: 29.8 +/- 9.7 cc vs 40.8 +/- 11.6 cc, P = 0.03) and liver (SUVmean: 1.8 +/- 0.2 vs 2.0 +/- 0.2, P = 0.049) and increased metabolic activity of visceral adipose tissue (SUVmean: 0.35 +/- 0.10 vs 0.26 +/- 0.06, P = 0.02) in chronic smokers compared to nonsmokers. Normalized visceral adipose tissue volume was also significantly decreased (P = 0.04) in chronic smokers. There were no statistically significant differences in the metabolic activity of other assessed organs. CONCLUSIONS: Subclinical organ effects of chronic tobacco use are detectable and quantifiable on FDG-PET/CT. FDG-PET/CT may, therefore, play a major role in the study of systemic toxic effects of tobacco use in organs of the whole body for clinical or research purposes. PMID- 27769826 TI - Effects of antiseptic mouthwash on resting metabolic rate: A randomized, double blind, crossover study. AB - The nitrate-nitrite-nitric oxide pathway has emerged as a significant source of nitric oxide (NO) bioactivity. Dietary intake of inorganic nitrate has a number of cardiovascular effects as well as a decrease in oxygen cost during exercise and a reduction in resting metabolic rate (RMR). Oral bacteria have a key role in bioactivation of inorganic nitrate since they catalyse the conversion of salivary nitrate to the more reactive nitrite anion. Recent studies demonstrate that blood pressure increases with the use of an antiseptic mouthwash, indicating that endogenous, NO-synthase derived nitrate is recycled into nitrite and NO, sufficiently to modulate cardiovascular function. Here we tested if also RMR would be affected by an antiseptic mouthwash. Seventeen healthy normotensive female subjects (23 +/- 4 y) participated in this randomized, double-blinded, crossover study. During two 3-day periods separated by 28 days the subjects consumed a diet low in nitrate combined with rinsing their mouth three times daily with a chlorhexidine-containing mouthwash (mouthwash) or placebo mouthwash (placebo) with similar taste but no antiseptic properties. Resting metabolic rate (RMR) was measured by indirect calorimetry and 24 h ambulatory blood pressure recordings were obtained after each intervention together with blood, saliva and urine samples. Treatment with chlorhexidine-containing mouthwash effectively reduced oral conversion of nitrate to nitrite but had no effect on plasma levels of these anions or plasma cGMP. RMR and 24 h ambulatory blood pressure were unaffected by the intervention. We conclude that in young healthy females an antiseptic mouthwash was effective in disrupting oral bacterial nitrate conversion to nitrite, but this was not associated with changes in plasma nitrite, RMR or blood pressure. PMID- 27769827 TI - Role of chronic toxicology studies in revealing new toxicities. AB - Chronic (>3 months) preclinical toxicology studies are conducted to support the safe conduct of clinical trials exceeding 3 months in duration. We have conducted a review of 32 chronic toxicology studies in non-rodents (22 studies in dogs and 10 in non-human primates) and 27 chronic toxicology studies in rats dosed with Merck compounds to determine the frequency at which additional target organ toxicities are observed in chronic toxicology studies as compared to subchronic studies of 3 months in duration. Our review shows that majority of the findings are observed in the subchronic studies since additional target organs were not observed in 24 chronic non rodent studies and in 21 chronic rodent studies. However, 6 studies in non rodents and 6 studies in rodents yielded new findings that were not seen in studies of 3-month or shorter duration. For 3 compounds the new safety findings did contribute to termination of clinical development plans. Although the incidence of compound termination associated with chronic toxicology study observations is low (~10%), the observations made in these studies can be important for evaluating human safety risk. PMID- 27769828 TI - A randomised, parallel group study to evaluate the safety profile of an electronic vapour product over 12 weeks. AB - A randomised, parallel group clinical study was performed to evaluate the safety profile of an e-vapour product (EVP; 2.0% nicotine) in smokers of conventional cigarettes (CCs) switching to use the EVP for 12 weeks. During the study, no clinically significant product-related findings were observed in terms of vital signs, electrocardiogram, lung function tests and standard clinical laboratory parameters. Adverse events (AEs) reported by EVP subjects were more frequent during the first week after switching to the EVP. The frequency of AEs reduced thereafter and out of a total of 1515 reported AEs, 495 were judged as being related to nicotine withdrawal symptoms. The most frequently stated AEs were headache, sore throat, desire to smoke and cough reported by 47.4, 27.8, 27.5 and 17.0% of subjects, respectively. Only 6% of AEs were judged as probably or definitely related to the EVP. Additional observations in EVP subjects included a decrease in the level of urine nicotine equivalents by up to 33.8%, and decreases in the level of three biomarkers of exposure to toxicants known to be present in CC smoke (benzene, acrolein and 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone). The decrease in nicotine equivalents coincided with an increase in nicotine withdrawal symptoms, measured by a questionnaire, which subsided after two weeks. The data presented here shows the potential EVPs may offer smokers looking for an alternative to CCs. PMID- 27769829 TI - Graphical display of histopathology data from toxicology studies for drug discovery and development: An industry perspective. AB - Histopathology data comprise a critical component of pharmaceutical toxicology studies and are typically presented as finding incidence counts and severity scores per organ, and tabulated on multiple pages which can be challenging for review and aggregation of results. However, the SEND (Standard for Exchange of Nonclinical Data) standard provides a means for collecting and managing histopathology data in a uniform fashion which can allow informatics systems to archive, display and analyze data in novel ways. Various software applications have become available to convert histopathology data into graphical displays for analyses. A subgroup of the FDA-PhUSE Nonclinical Working Group conducted intra industry surveys regarding the use of graphical displays of histopathology data. Visual cues, use-cases, the value of cross-domain and cross-study visualizations, and limitations were topics for discussion in the context of the surveys. The subgroup came to the following conclusions. Graphical displays appear advantageous as a communication tool to both pathologists and non-pathologists, and provide an efficient means for communicating pathology findings to project teams. Graphics can support hypothesis-generation which could include cross domain interactive visualizations and/-or aggregating large datasets from multiple studies to observe and/or display patterns and trends. Incorporation of the SEND standard will provide a platform by which visualization tools will be able to aggregate, select and display information from complex and disparate datasets. PMID- 27769830 TI - Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management. AB - Recent studies on gonadal histology have improved the understanding of germ cell malignancy risk in patients with disorders of sex development (DSD), and evidence based gonadal management strategies are gradually emerging. Especially in 46,XY DSD and 45,X/46,XY DSD, which are characterized by gonadal dysgenesis, the risk of germ cell malignancy is significantly increased. This paper summarized the progress over the past 10 years in malignancy risk assessment in patients with DSD, and its implications for optimal surgical handling of the involved gonads. PMID- 27769831 TI - Corrigendum to 'The Right Angular Gyrus Combines Perceptual and Response-Related Expectancies in Visual Search: TMS-EEG Evidence' Brain Stimulation 8 (2015) 816 22. PMID- 27769832 TI - Structural and functional analogies and differences between histidine decarboxylase and aromatic l-amino acid decarboxylase molecular networks: Biomedical implications. AB - Human histidine decarboxylase (HDC) and dopa decarboxilase (DDC) are highly homologous enzymes responsible for the synthesis of biogenic amines (BA) like histamine, and serotonin and dopamine, respectively. The enzymes share many structural and functional analogies, while their product metabolisms also follow similar patterns that are confluent in some metabolic steps. They are involved in common physiological functions, such as neurotransmission, gastrointestinal track function, immunity, cell growth and cell differentiation. As a consequence, metabolic elements of both BA subfamilies are also co-participants in a long list of human diseases. This review summarizes the analogies and differences in their origin (HDC and DDC) as well as their common pathophysiological scenarios. The major gaps of information are also underlined, as they delay the possibility of holistic approaches that would help personalized medicine and pharmacological initiatives for prevalent and rare diseases. PMID- 27769833 TI - Agonism at delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. PMID- 27769834 TI - Perspective: Serum Anticholinergic Drug Level Determinations after 30 Years. PMID- 27769835 TI - Older Age Associated with Mental Health Resiliency in Sexual Minority US Veterans. AB - OBJECTIVES: Objectives were to: (a) identify the mental health needs of older and younger sexual minority and heterosexual U.S. veterans and (b) examine whether sexual minority status confers vulnerability or resiliency in older adulthood. Support and trauma exposure were examined as potential mechanisms for age by sexual orientation differences. METHODS: Participants were a nationally representative sample of 3,095 U.S. veterans (ages 21 to 96 years). Measures included demographics, military characteristics, sexual orientation (lesbian, gay, or bisexual; LGB), social support, trauma, and mental health indicators (lifetime and present depression and post-traumatic stress disorder (PTSD); lifetime anxiety and suicidal ideation). RESULTS: Younger LGB veterans were most likely to report lifetime depression and/or PTSD and current depression compared with older LGB and younger and older heterosexual veterans. Older LGB veterans had low levels of mental health problems, but they reported the smallest social support networks. CONCLUSIONS: Older and younger LGB veterans have different mental health challenges. Younger LGB veterans are more vulnerable to mental health problems than their older LGB peers. Older LGB veterans are resilient, but they may be at greater risk of social isolation than their younger LGB peers. PMID- 27769836 TI - Smoking intensity (pack/day) is a better measure than pack-years or smoking status for modeling cardiovascular disease outcomes. AB - OBJECTIVES: Smoking as an epidemiological exposure can be quantified in many ways including duration, intensity, pack-years, recency, and age at initiation. However, it is not clear which of these are most important for cardiovascular disease (CVD) and how they should be modeled. STUDY DESIGN AND SETTING: Using the Multi-Ethnic Study of Atherosclerosis, Cox models for time to incident CVD adjusted for age, sex, race/ethnicity, education category, and income category were compared which included various characterizations of smoking history. RESULTS: Duration, age at starting, time since quitting, and noncigarette forms of smoking were not independently associated with CVD, whereas baseline current intensity was associated with CVD [e.g., hard CVD hazard ratio 1 pack/d of 1.85 95% confidence interval (1.33, 2.57)]. Former smokers, regardless of duration, intensity, or recency, were not at increased risk, suggesting that risk may risk may drop precipitously from the time of quitting. For CVD events, representing smoking exposure as baseline smoking intensity produced better model fit as measured by Akaike information criterion than models using smoking status or pack years. CONCLUSION: The association of smoking with incident CVD events was well captured by including a simple term for baseline smoking intensity. PMID- 27769837 TI - Ligand binding phenomena that pertain to the metabolic function of renalase. AB - Renalase catalyzes the oxidation of isomers of beta-NAD(P)H that carry the hydride in the 2 or 6 positions of the nicotinamide base to form beta-NAD(P)+. This activity is thought to alleviate inhibition of multiple beta-NAD(P) dependent enzymes of primary and secondary metabolism by these isomers. Here we present evidence for a variety of ligand binding phenomena relevant to the function of renalase. We offer evidence of the potential for primary metabolism inhibition with structures of malate dehydrogenase and lactate dehydrogenase bound to the 6-dihydroNAD isomer. The previously observed preference of renalase from Pseudomonas for NAD-derived substrates over those derived from NADP is accounted for by the structure of the enzyme in complex with NADPH. We also show that nicotinamide nucleosides and mononucleotides reduced in the 2- and 6 positions are renalase substrates, but bind weakly. A seven-fold enhancement of acquisition (kred/Kd) for 6-dihydronicotinamide riboside was observed for human renalase in the presence of ADP. However, generally the addition of complement ligands, AMP for mononucleotide or ADP for nucleoside substrates, did not enhance the reductive half-reaction. Non-substrate nicotinamide nucleosides or nucleotides bind weakly suggesting that only beta-NADH and beta-NADPH compete with dinucleotide substrates for access to the active site. PMID- 27769838 TI - Keap1 as the redox sensor of the antioxidant response. AB - Reactive oxygen species (ROS) and products of their reactions with cellular macromolecules such as unsaturated fatty acids have been implicated to be important regulators of signalling processes via oxidation or alkylation of redox active thiol residues in target proteins. One of key redox-sensitive signalling proteins mediating the response to oxidant stress is Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1), which is a negative regulator of transcription factor Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and the central hub for sensing endogenous and environmental oxidative and electrophilic stress. In this review, we provide an overview of the mechanisms by which Keap1 orchestrates the antioxidant response and how the system can be targeted for therapy. PMID- 27769839 TI - Responsiveness of the active wrist joint position sense test after distal radius fracture intervention. AB - STUDY DESIGN: Prospective cohort study. INTRODUCTION: The active wrist joint position sense (JPS) test has been determined to be a clinically useful test for assessing wrist sensorimotor (SM) status after distal radius fracture (DRF). Its responsiveness is yet to be determined. PURPOSE OF THE STUDY: Primary study aim was to determine the active wrist JPS test responsiveness to detect change in wrist SM status at 8 and 12 weeks after DRF treatment intervention. Secondary aims were to compare group (nonsurgical, surgical, high, and low pain) test responsiveness; compare pain-level group participants test scores; determine the relationship between test minimal clinically important difference (MCID) value and function; compare functional outcomes across assessment times; and determine the Patient Global Impression of Change Scale intrarater reliability. METHODS: A total of 33 male and female participants were tested at baseline, 8, and 12 weeks after nonsurgical (n = 13) and surgical (n = 20) DRF treatment interventions. Distribution-based analysis encompassed both group- (ie, effect size, standardized response mean) and individual-based (ie, minimum detectable change) statistical indices. Anchor-based analysis determined the MCID value by linking test scores to the Patient Global Impression of Change Scale. RESULTS: The active wrist JPS test is highly responsive based on effect size (8 weeks = 1.53 and 12 weeks = 2.36) and standardized response mean (8 weeks = 1.57 and 12 weeks = 2.14). Statistically significant minimum detectable change values were 4.28 degrees and 4.94 degrees at 8 and 12 weeks, respectively. Clinically meaningful MCID values were 5.00 degrees and 7.09 degrees at 8 and 12 weeks, respectively. Between treatment type and pain-level group responsiveness levels were not significantly different. High-pain participants demonstrated significantly greater JPS deficit. Test MCID values and function were significantly associated. DISCUSSION: This is the first study to determine the active wrist JPS test responsiveness as reflected by its group- and individual-based statistical indices following DRF surgical and non-surgical interventions among low- and high pain level participants. The statistical analysis approach, which was used to determine the aforementioned variables of the active wrist JPS test, is consistent with current research. This study's strengths included its design, methodology, and statistical approach. The study findings must be interpreted, however, within the content of several methodological limitations. CONCLUSIONS: The active wrist JPS test was determined to be highly responsive to detect wrist SM status change at 8 and 12 weeks regardless of treatment type or pain level. Clinicians can use this test with confidence to measure clinically meaningful SM impairment after DRF treatment. LEVEL OF EVIDENCE: 2b. PMID- 27769840 TI - A randomized controlled trial of the effect of 2-step orthosis treatment for a mallet finger of tendinous origin. AB - STUDY DESIGN: A randomized clinical trial, with patients treated either by new 2 step orthosis or by the figure-eight-type orthosis with the distal interphalangeal (DIP) joint extended. PURPOSE OF THE STUDY: To report on our new orthosis and to evaluate the treatment efficacy of using a 2-step orthosis for the treatment of a mallet finger of tendinous origin compared with a conventional orthosis. METHODS: Forty-four patients were randomized into the 2-step or conventional orthosis groups. Primary outcomes were active DIP joint flexion and extensor lag, pain, and the Abouna-Brown criteria. RESULTS: The 2-step orthosis was associated with a smaller active DIP extensor lag, compared with the conventional orthosis (-7.5 +/- 4.5 degrees vs -16.4 +/- 6.9 degrees , P = .001), combined with a significantly higher Abouna-Brown criteria (chi2 = 14.57, P = .01). No other between-group differences were identified. CONCLUSION: The therapeutic effectiveness of the 2-step orthosis, over a conventional orthosis, was supported by a large effect size of the treatment in improving residual active extensor lag at the DIP and overall Abouna-Brown criteria. Our study thus suggested that the initial immobilization involved in new 2-step orthosis and is thus a good immobilization technique. LEVEL OF EVIDENCE: Ib. PMID- 27769841 TI - Cross-cultural adaptation and validation of the Patient-Rated Tennis Elbow Evaluation Questionnaire on lateral elbow tendinopathy for French-speaking patients. AB - STUDY DESIGN: Translation and validation of algo-functional questionnaire. INTRODUCTION: The lateral elbow tendinopathy is a common injury in tennis players and physical workers. The Patient-Rated Tennis Elbow Evaluation (PRTEE) Questionnaire was specifically designed to measure pain and functional limitations in patients with lateral epicondylitis (tennis elbow). First developed in English, this questionnaire has since been translated into several languages. PURPOSE OF THE STUDY: The aims of the study were to translate and cross-culturally adapt the PRTEE questionnaire into French and to evaluate the reliability and validity of this translated version of the questionnaire (PRTEE F). METHODS: The PRTEE was translated and cross-culturally adapted into French according to international guidelines. To assess the reliability and validity of the PRTEE-F, 115 participants were asked twice to fill in the PRTEE-F, and once the Disabilities of Arm, Shoulder and Hand Questionnaire (DASH) and the Short Form Health Survey (SF-36). Internal consistency (using Cronbach's alpha), test retest reliability (using intraclass correlation coefficient (ICC), standard error of measurement and minimal detectable change), and convergent and divergent validity (using the Spearman's correlation coefficients respectively with the DASH and with some subscales of the SF-36) were assessed. RESULTS: The PRTEE was translated into French without any problems. PRTEE-F showed a good test-retest reliability for the overall score (ICC 0.86) and for each item (ICC 0.8-0.96) and a high internal consistency (Cronbach's alpha = 0.98). The correlation analyses revealed high correlation coefficients between PRTEE-F and DASH (convergent validity) and, as expected, a low or moderate correlation with the divergent subscales of the SF-36 (discriminant validity). There was no floor or ceiling effect. DISCUSSION AND CONCLUSIONS: The PRTEE questionnaire was successfully cross-culturally adapted into French. The PRTEE-F is reliable and valid for evaluating French-speaking patients with lateral elbow tendinopathy. PMID- 27769842 TI - Isoforce: A new outrigger system for static progressive orthotic interventions of the proximal interphalangeal joint with constant force transmission-Results of a biomechanical study. AB - STUDY DESIGN: Bench research-biomechanical study. INTRODUCTION: Static progressive orthotic devices are efficient in treating contractures. However, current outriggers are unable to keep force transmission and the force application angle (FAA) constant. PURPOSE OF THE STUDY: To evaluate the biomechanical performance of the Isoforce outrigger, a novel extension orthosis. METHODS: A hand model was used to measure the required force at the outrigger and FAA, while simulating resolution of different contracture angles. We also tested feasibility in a small patient series. RESULTS: The force required with the Isoforce device never exceeded 2.4 N, and the FAA did not change more than 6 degrees . Corresponding figures for the reference devices exceeded 16 N and 20 degrees . The 7 patients testing the Isoforce extension device showed an extension deficit that decreased from 40 degrees at baseline to 25 degrees at 6 weeks. They rated the device as very comfortable to wear. CONCLUSIONS: Isoforce maintains constant force transmission and FAA throughout the full range of motion, promotes the lengthening of contracted structures, and is comfortable to wear. LEVEL OF EVIDENCE: Not applicable. PMID- 27769843 TI - Effects of a stretching protocol for the pectoralis minor on muscle length, function, and scapular kinematics in individuals with and without shoulder pain. AB - STUDY DESIGN: Parallel-group intervention with repeated measures. INTRODUCTION: Shortening of the pectoralis minor (PM) may contribute to alterations in scapular kinematics. PURPOSE OF THE STUDY: To evaluate the effects of a stretching protocol on function, muscle length, and scapular kinematics in subjects with and without shoulder pain. METHODS: A sample of 25 patients with shoulder pain and 25 healthy subjects with PM tightness performed a daily stretching protocol for 6 weeks. Outcome measures included Disabilities of the Arm, Shoulder, and Hand questionnaire, PM length, and scapular kinematics. RESULTS: Disabilities of the Arm, Shoulder, and Hand scores decreased (P < .05) in the patient group at post intervention. No differences (P > .05) were found for PM length in both groups. Scapular anterior tilt increased (P < .05) at 90 degrees of flexion in the healthy group. DISCUSSION: This study demonstrated that a daily home stretching protocol significantly decreases pain and improves function in subjects with shoulder pain. The mechanism responsible for these improvements does not appear directly related to PM muscle length or scapula kinematics, suggesting that other neuromuscular mechanisms are involved. CONCLUSION: The PM stretching protocol did not change the PM length or scapular kinematics in subjects with or without shoulder pain. However, pain and function of the upper limbs improved in patients with shoulder pain. LEVEL OF EVIDENCE: 2b. PMID- 27769844 TI - Modifying Kinect placement to improve upper limb joint angle measurement accuracy. AB - STUDY DESIGN: Repeated measures. INTRODUCTION: The Kinect (Microsoft, Redmond, WA) is widely used for telerehabilitation applications including rehabilitation games and assessment. PURPOSE OF THE STUDY: To determine effects of the Kinect location relative to a person on measurement accuracy of upper limb joint angles. METHODS: Kinect error was computed as difference in the upper limb joint range of motion (ROM) during target reaching motion, from the Kinect vs 3D Investigator Motion Capture System (NDI, Waterloo, Ontario, Canada), and compared across 9 Kinect locations. RESULTS: The ROM error was the least when the Kinect was elevated 45 degrees in front of the subject, tilted toward the subject. This error was 54% less than the conventional location in front of a person without elevation and tilting. The ROM error was the largest when the Kinect was located 60 degrees contralateral to the moving arm, at the shoulder height, facing the subject. The ROM error was the least for the shoulder elevation and largest for the wrist angle. DISCUSSION: Accuracy of the Kinect sensor for detecting upper limb joint ROM depends on its location relative to a person. CONCLUSION: This information facilitates implementation of Kinect-based upper limb rehabilitation applications with adequate accuracy. LEVEL OF EVIDENCE: 3b. PMID- 27769846 TI - A PLEC Isoform Identified in Skin, Muscle, and Heart. PMID- 27769845 TI - Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis. AB - Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations. PMID- 27769847 TI - Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis. AB - Atopic dermatitis (AD) is a common inflammatory skin disorder. Chronic AD lesions present hyperkeratosis, indicating a disturbed desquamation process. KLK7 is a serine protease involved in the proteolysis of extracellular corneodesmosome components, including desmocollin 1 and corneodesmosin, which leads to desquamation. KLK7 is secreted by lamellar granules and upregulated in AD lesional skin. However, despite increased KLK7 protein levels, immunostaining and electron microscopy indicated numerous corneodesmosomes remaining in the uppermost layer of the stratum corneum from AD lesions. We aimed to clarify the discrepancy between KLK7 overexpression and retention of corneodesmosomes on AD corneocytes. Western blot analysis indicated abnormal corneodesmosin degradation patterns in stratum corneum from AD lesions. The KLK activity of tape-stripped corneocytes from AD lesions was not significantly elevated in in situ zymography, which was our new attempt to detect the protease activity more precisely than conventional assays. This ineffective KLK activation was associated with impaired KLK7 secretion from lamellar granules and increased expression of LEKTI in AD. Such imbalances in protease-protease inhibitor interactions could lead to abnormal proteolysis of corneodesmosomes and compact hyperkeratosis. Upregulated expression of LEKTI might be a compensatory mechanism to prevent further barrier dysfunction in AD. PMID- 27769848 TI - TREMs in Alzheimer's disease: Genetic and clinical investigations. AB - Triggering receptor expressed on myeloid cells (TREMs) receptors constitute a family modulators in human innate immunity system that encode by a gene cluster. Rare variants in TREM2 were reported to be associated with significant Alzheimer's disease (AD) risk. However, inconsistent results were also reported in some studies of Non-European descents. Recently, the other TREM family members are also considered to involve in AD and cerebrospinal fluid (CSF) soluble form of TREM2 (sTREM2) levels has also been associated with respond to progression of disease. In this review, we converged the data of genetic and clinical investigations to identify the clearer role of TREMs in AD. Here, comprehensively analyze of multidisciplinary fields highlights the contribution of TREMs locus to AD development. PMID- 27769849 TI - Dose-response assessment of the dermal toxicity of Virginia cedarwood oil in F344/N rats and B6C3F1/N mice. AB - Virginia cedarwood oil is widely used as a fragrance material in household and personal products and as a naturally derived pesticide alternative. Due to conflicting literature on dermal exposures in animals and humans, concern for safe levels of human exposure remains. The present study evaluated the toxicity of cedarwood oil applied dermally to F344/N rats and B6C3F1/N mice for 13 weeks. Groups of 10 male and female rats and mice received no treatment (untreated control) or were administered cedarwood oil in 95% aqueous ethanol dermally at concentrations ranging from 0% (vehicle control), 6.25%, 12.5%, 25%, 50%, and 100% (undiluted). Rats and mice developed extensive skin lesions at the site of application. Benchmark dose modeling (BMD) was performed for the significantly increased skin lesions observed in the rat, to provide perspective for risk assessment applications. Benchmark dose modeling levels (BMDL) of 0.65 to 2.1% and 1.2 to 4.4% (equivalent to 13 to 42 mg/kg and 24 to 48 mg/kg, respectively) cedarwood oil were calculated for the most sensitive endpoint of epidermal hyperplasia in female rats and chronic active inflammation in male rats, respectively. These BMDL levels coincide with reported use levels in cosmetics and pesticides, raising the concern for human exposure. PMID- 27769850 TI - Integrated exposure and risk characterization of bisphenol-A in Europe. AB - The current study aims at a comprehensive risk characterization of bisphenol A (BPA) supported by an integrated exposure modelling framework that comprises far field and near field exposure modelling coupled to a dynamic lifetime PBTK model. Exposure analysis was done on European data of BPA food residues and human biomonitoring (HBM). The latter were further assimilated through an advanced exposure reconstruction modelling framework to estimate the corresponding external and internal systemic dose of BPA and its metabolites. Special attention was paid on the assessment of exposure to BPA during critical developmental stages such as gestation by modelling the mother-fetus toxicokinetic interaction. Our findings showed that current exposure levels in Europe are below the temporary Tolerable Daily Intake (t-TDI) of 4 MUg/kg_bw/d proposed by the European Food Safety Authority. Taking into account age-dependent bioavailability differences, internal exposure of premature neonates hosted in intensive care units was reckoned close to the biologically effective dose (BED) resulting from translating the EFSA temporary total daily intake (t-TDI) into equivalent internal dose. Use of the ToxCast21 Biological Pathway Altering Dose (BPAD) as an alternative internal exposure reference value, resulted in increased margins of safety compared to the conventional exposure/risk characterization scheme. PMID- 27769851 TI - Effects of continuous positive airway pressure on energy intake in obstructive sleep apnea: A pilot sham-controlled study. AB - Obesity is among the leading risk factors for obstructive sleep apnea (OSA). A reciprocal relationship between obesity and OSA has been proposed, which may be due to excessive food intake. We conducted a pilot study to test the effects of continuous positive airway pressure (CPAP) on energy intake (EI) in OSA patients using a sham-controlled crossover design. In-laboratory total daily EI was assessed after 2mo of active and sham CPAP. Four men were enrolled (age+/-SEM: 51.8+/-2.1y; body mass index: 31.5+/-1.5kg/m2). All received active treatment first. Meals (breakfast, lunch, dinner, snack) were served in excess portions at fixed times and additional palatable snacks were freely available throughout the day. Total EI was lower after active (3744+/-511kcal/d) vs. sham (4030+/ 456kcal/d) CPAP but this difference was not significant (p=0.51) due to variability in the free snack intake. When only fixed eating occasions were considered, daily EI was significantly lower in the active (3105+/-513kcal/d) vs. sham (3559+/-420kcal/d) condition (p=0.006). This small pilot and feasibility study is the first to utilize a sham-controlled design to investigate the effects of CPAP treatment on objective measures of EI. Findings suggest that CPAP may cause a reduction in fixed meal intake. In demonstrating feasibility of study methodology, our study also suggests a larger randomized sham-controlled trial be conducted to fully characterize the effects of CPAP treatment on EI and energy balance overall. PMID- 27769852 TI - Regulation of AKT activity prevents autonomic nervous system imbalance. AB - Autonomic nervous system (ANS) imbalances are involved in the etiology of cancer, allergy, and collagen diseases. Previously, we hypothesized that FoxO and HSF-1 limit autonomic stress responses via negative feedback on the ANS. Here, we evaluated the role of AKT, a negative regulator of FoxO, during activation of the ANS by loneliness stress in mice. Spontaneous motility was increased during loneliness stress and decreased after release from stress. The AKT activator SC79 attenuated stress-induced spontaneous motility, whereas the AKT inhibitor API-2 prevented decreases in motility after stress release. Our results show that AKT activity regulates ANS responses to loneliness stress. PMID- 27769853 TI - Atrioesophageal fistula formation with cryoballoon ablation is most commonly related to the left inferior pulmonary vein. AB - BACKGROUND: Collateral damage has been reported with use of the cryoballoon for pulmonary vein isolation. OBJECTIVE: The purpose of this study was to determine the incidence and characteristics associated with atrioesophageal fistula (AEF) after cryoballoon use. METHODS: Cases of AEF reported with use of the cryoballoon since 2011 were collected from the Manufacturer and User Facility Device Experience (MAUDE) database, publications, and the manufacturer's database. Lowest balloon temperatures were compared with matched control patients undergoing cryoballoon ablation without AEF formation. Location of AEF was compared with AEF associated with radiofrequency ablation. RESULTS: A total of 11 cases of AEF were identified from a worldwide experience that exceed 120,000 cases. Mean age was 60 (range 31-78 years), and 80% of patients were male. Although mean lowest balloon temperatures were no different between patients with AEF and those with no AEF (-58.5 degrees C +/- 7.2 degrees C vs -56 degrees C +/- 2.6 degrees C, P = NS), balloon inflation times were longer in patients with AEF (238.8 +/- 54.8 seconds vs 178.1 +/- 37.5 seconds in the non-AEF group, P <=.001) All cases of AEF for which location was identified occurred in relation to the left pulmonary veins. The left inferior pulmonary vein (LIPV) was involved in 8 of 10 patients with cryoballoon compared to 0 of 11 patients in the radiofrequency group (P <.05). Mortality for cryoballoon-associated AEF was 64%. CONCLUSION: AEF after cryoballoon use is rare (<1 in 10,000) and most commonly was identified near the LIPV. Proximity of the esophagus to the LIPV and evidence of esophageal luminal cooling should be considered indications to limit cryoablation at this vein. PMID- 27769854 TI - Type-7 metabotropic glutamate receptors negatively regulate alpha1-adrenergic receptor signalling. AB - We studied the interaction between mGlu7 and alpha1-adrenergic receptors in heterologous expression systems, brain slices, and living animals. L-2-Amino-4 phosphonobutanoate (L-AP4), and l-serine-O-phosphate (L-SOP), which activate group III mGlu receptors, restrained the stimulation of polyphosphoinositide (PI) hydrolysis induced by the alpha1-adrenergic receptor agonist, phenylephrine, in HEK 293 cells co-expressing alpha1-adrenergic and mGlu7 receptors. The inibitory action of L-AP4 was abrogated by (i) the mGlu7 receptor antagonist, XAP044; (ii) the C-terminal portion of type-2 G protein coupled receptor kinase; and (iii) the MAP kinase inhibitors, UO126 and PD98059. This suggests that the functional interaction between mGlu7 and alpha1-adrenergic receptors was mediated by the betagamma-subunits of the Gi protein and required the activation of the MAP kinase pathway. Remarkably, activation of neither mGlu2 nor mGlu4 receptors reduced alpha1-adrenergic receptor-mediated PI hydrolysis. In mouse cortical slices, both L-AP4 and L-SOP were able to attenuate norepinephrine- and phenylephrine-stimulated PI hydrolysis at concentrations consistent with the activation of mGlu7 receptors. L-AP4 failed to affect norepinephrine-stimulated PI hydrolysis in cortical slices from mGlu7-/- mice, but retained its inhibitory activity in slices from mGlu4-/- mice. At behavioural level, i.c.v. injection of phenylephrine produced antidepressant-like effects in the forced swim test. The action of phenylephrine was attenuated by L-SOP, which was inactive per se. Finally, both phenylephrine and L-SOP increased corticosterone levels in mice, but the increase was halved when the two drugs were administered in combination. Our data demonstrate that alpha1-adrenergic and mGlu7 receptors functionally interact and suggest that this interaction might be targeted in the treatment of stress-related disorders. PMID- 27769856 TI - The impact of helipad designation on meeting the best practice tariff for fractured neck of femur cases in a major trauma centre. AB - Hip fractures represent a significant burden to the NHS: the cost for all UK hip fractures is approximately L2 billion and in 2013, 64 838 people were admitted to hospital with a fractured neck of femur (FNOF). In April 2010 St George's NHS Hospital was designated one of four Major Trauma Centres (MTC) in London. Following MTC designation, in April 2014 St George's Hospital opened a helipad. This study aimed to assess the impact of the helipad designation on the Trust's ability to meet the Best Practice Tariff (BPT) criteria for FNOF patients. Two samples were analysed: 'pre-helipad' (from October 2013 to March 2014) during which 125 patients presented with FNOF, and 'post-helipad' (from April 2014 to September 2014) during which 122 patients presented with FNOF. The percentage of cases receiving surgery within 36 h, receiving joint care of a consultant geriatrician and a consultant orthopaedic surgeon, and receiving assessment by a geriatrician in the perioperative period were found not to have been negatively impacted by the helipad. However, completion of routine recommended assessments including admission using the agreed assessment protocol (96.6% vs. 50%, p < 0.05) and completion of two Abbreviated Mental Test (AMT) scores (74.7% vs. 58%, p = 0.007) were found to have been compromised. PMID- 27769855 TI - Acute Intermittent Porphyria in children: A case report and review of the literature. AB - Acute Intermittent Porphyria (AIP), an autosomal dominant inborn error of heme metabolism, typically presents in adulthood, most often in women in the reproductive age group. There are limited reports on the clinical presentation in children, and in contrast to the adults, most of the reported pediatric cases are male. While acute abdominal pain is the most common presenting symptom in children, seizures are commonly seen and may precede the diagnosis of AIP. As an example, we report a 9year old developmentally normal pre-pubertal boy who presented with acute abdominal pain, vomiting and constipation followed by hyponatremia, seizures, weakness and neuropathy. After a diagnostic odyssey, his urine porphobilinogen was found to be significantly elevated and genetic testing showed a previously unreported consensus splice-site mutation IVS4-1G>A in the HMBS gene confirming the diagnosis of AIP. Here, we discuss the clinical presentation in this case, and 15 reported pediatric cases since the last review 30years ago and discuss the differential diagnosis and challenges in making the diagnosis in children. We review the childhood-onset cases reported in the Longitudinal Study of the Porphyrias Consortium. Of these, genetically and biochemically confirmed patients, 11 of 204 (5%) reported onset of attacks in childhood. Most of these patients (91%) reported recurrent attacks following the initial presentation. Thus, AIP should be considered in the differential diagnosis of children presenting with unexplained abdominal pain, seizures, weakness and neuropathy. PMID- 27769857 TI - Staurosporine as an agonist for induction of GLUT4 translocation, identified by a pH-sensitive fluorescent IRAP-mOrange2 probe. AB - Insulin-stimulated GLUT4 translocation from GLUT4 storage vesicles (GSVs) to the plasma membrane (PM) constitutes a key process for blood glucose control. Therefore, compounds that could promote GLUT4 translocation into the PM represent potential drugs for the treatment of diabetes. In this research, we screened for agonists that induce GLUT4 translocation by using a novel pH-sensitive fluorescent probe, insulin-regulated aminopeptidase (IRAP)-mOrange2. We identified as well as validated one agonist, staurosporine, from a 64,000 compound library. Staurosporine promotes GSVs translocation into the PM and increases glucose uptake through the AMP-activated protein kinase (AMPK) pathway, serving as an effective insulin additive analogue in L6 cells. Our work highlights the convenience and efficiency of this novel pH-sensitive fluorescent probe and reveals the new biological activity of staurosporine as an agonist for GLUT4 translocation and as an effective insulin additive analogue. PMID- 27769858 TI - CC2D1A and CC2D1B regulate degradation and signaling of EGFR and TLR4. AB - Signaling through many transmembrane receptors is terminated by their sorting to the intraluminal vesicles (ILVs) of multivescular bodies (MVBs) and subsequent lysosomal degradation. ILV formation requires the endosomal sorting complex required for transport (ESCRT) machinery. CC2D1A and CC2D1B interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex, however, their roles in receptor degradation and signaling are poorly defined. Here, we report that CC2D1A binds to CHMP4B polymers formed on endosomes to regulate the endosomal sorting pathway. We show that depletion of CC2D1A and B accelerates degradation of EGFR and elicits rapid termination of its downstream signaling through ERK1 and 2. Depletion of CC2D1A and B promotes sorting of EGFR to ILV leading to its rapid lysosomal degradation. In addition, we show that knockdown of CC2D1A and B has similar effects on degradation and downstream signaling of another membrane receptor, TLR4. Thus, these findings suggest that CC2D1A and B may have broad effects on transmembrane receptors by preventing premature ILV sorting and termination of signaling. PMID- 27769859 TI - CHOP deficiency inhibits methylglyoxal-induced endothelial dysfunction. AB - Epidemiological studies suggested that diabetic patients are susceptible to develop cardiovascular complications along with having endothelial dysfunction. It has been suggested that methylglyoxal (MGO), a glycolytic metabolite, has more detrimental effects on endothelial dysfunction rather than glucose itself. Here, we investigated the molecular mechanism by which MGO induces endothelial dysfunction via the regulation of ER stress. Biochemical data showed that 4-PBA significantly inhibited MGO-induced protein cleavages of PARP-1 and caspase-3. In addition, it was found that high glucose-induced endothelial apoptosis was enhanced in the presence of GLO1 inhibitor, suggesting the role of endogenous MGO in high glucose-induced endothelial dysfunction. MGO-induced endothelial apoptosis was significantly diminished by the depletion of CHOP with si-RNA against human CHOP, but not by SP600125, a specific inhibitor of JNK. The physiological relevance of this signaling pathway was demonstrated in CHOP deficiency mouse model, in which instillation of osmotic pump containing MGO led to aortic endothelial dysfunction. Notably, the aortic endothelial dysfunction response to MGO infusion was significantly improved in CHOP deficiency mice compared to littermate control. Taken together, these findings indicate that MGO specifically induces endothelial dysfunction in a CHOP-dependent manner, suggesting the therapeutic potential of CHOP inhibition in diabetic cardiovascular complications. PMID- 27769860 TI - microRNA-146a inhibits proliferation, migration and invasion of human cervical and colorectal cancer cells. AB - microRNAs (miRNAs) play significant roles in diverse biological processes and their deregulation is implicated in carcinogenesis. miR-146a executes tumour suppressive or oncogenic functions depending on the cancer type, but its effect on human cervical (CaCx) and colorectal (CRC) cancers have not been examined thus far. In this study, miR-146a exhibited high expression in CaCx but poor expression in CRC, in comparison to corresponding normal tissues. Nevertheless, ectopic expression of miR-146a inhibited proliferation in both CaCx and CRC cells and curbed their migration and invasion. When the expression of endogenous miR 146a was suppressed, proliferative, migratory and invasive capacities of CaCx and CRC cells increased, suggesting an anti-tumourigenic function for miR-146a. Re expression of miR-146a down-regulated the expression of crucial signalling intermediates: CTNNB1, STAT3, RELA, CCND1 and SNAI1, and enhanced TP53 and CDH1 expression. Thus, the present study reveals a hitherto unknown tumour suppressive role for miR-146a providing a plausible mechanistic basis for it. PMID- 27769861 TI - Activin A/Smads signaling pathway negatively regulates Oxygen Glucose Deprivation induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells. AB - Activin A (Act A), a member of the transforming growth factor-beta (TGF-beta), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD) induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells. In addition, we found that c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways are involved in the OGD-induced autophagy. The activation of JNK and p38 MAPK pathways in OGD treated PC12 cells was suppressed by exogenous Act A and enhanced by ActRIIA-Ab. Together, our results suggest that Act A/Smads signaling pathway negatively regulates OGD-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells. PMID- 27769862 TI - miR-543 is up-regulated in gefitinib-resistant non-small cell lung cancer and promotes cell proliferation and invasion via phosphatase and tensin homolog. AB - MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. Here, we identified that miR-543 is up-regulated in gefitinib-resistant non-small cell lung cancer (NSCLC) patients comparing gefitinib-sensitive ones. It promotes NSCLC cell proliferation by negatively regulates its target gene PTEN. In NSCLC cell lines, CCK-8 proliferation assay indicated that the cell proliferation is promoted by miR-543 mimics. Transwell assay showed that miR-543 mimics promotes the invasion and migration of NSCLC cells. Luciferase assays confirmed that miR 543 directly binds to the 3'untranslated region of PTEN, and western blotting showed that miR-543 suppresses the expression of PTEN at the protein level. This study indicates that miR-543 promotes proliferation and invasion of NSCLC cell lines by PTEN. The miR-543 may represent a potential therapeutic target for gefitinib-resistant NSCLC intervention. PMID- 27769863 TI - Autocrine Semaphorin3A signaling is essential for the maintenance of stem-like cells in lung cancer. AB - Cancer stem-like cells (CSCs) exist in tumor tissues composed of heterogeneous cell population and are characterized by their self-renewal capacity and tumorigenicity. Many studies demonstrate that eradication of CSCs prevents development and recurrences of tumor; yet, molecules critical for the maintenance of CSCs have not been completely understood. We previously reported that Semaphorin3A (Sema3a) knockdown suppressed the tumorigenicity and proliferative capacity of Lewis lung carcinoma (LLC) cells. Therefore, we identified Sema3a as an essential factor for the establishment or maintenance of CSCs derived from LLC (LLC-stem cell). shRNA against Sema3a was introduced into LLC cells to establish a LLC-stem cell line and its effects on tumorigenesis, sphere formation, and mTORC1 activity were tested. Sema3a knockdown completely abolished tumorigenicity and the sphere-formation and self-renewal ability of LLC-stem cells. The Sema3a knockdown was also associated with decreased expression of mRNA for stem cell markers. The self-renewal ability abolished by Sema3a knockdown could not be recovered by exogenous addition of recombinant SEMA3A. In addition, the activity of mammalian target of rapamycin complex 1 (mTORC1) and the expression of its substrate p70S6K1 were also decreased. These results demonstrate that Sema3a is a potential therapeutic target in eradication of CSCs. PMID- 27769864 TI - HMGB1 induces human non-small cell lung cancer cell motility by activating integrin alphavbeta3/FAK through TLR4/NF-kappaB signaling pathway. AB - High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein with multi functions and plays an important role in tumorigenesis and metastasis in various human cancers. In the present study, we found that HMGB1 induced migration of in human non-small cell lung cancer (NSCLC) cells by up-regulating integrin alphavbeta3 expression. Further investigation evidenced that HMGB1 activated Toll like receptor 4 (TLR4) and NF-kappaB, which was responsible for alphavbeta3 up regulation. Furthermore, HMGB1-induced integrin alphavbeta3 expression led to focal adhesion kinase (FAK) phosphorylation and increased paxillin and talin mRNA expression. Knockdown HMGB1 inhibited xenograft tumor metastasis in athymic mice. Taken together, our findings suggested that HMGB1 enhances tumor cell migration ability by activating alphavbeta3/FAK through TLR4/NF-kappaB signaling, leading to metastasis of NSCLC. PMID- 27769865 TI - Mixing of thawed coagulation samples prior to testing: Is any technique better than another? AB - OBJECTIVE: Thus study was aimed to investigate whether the mixing technique could influence the results of routine and specialized clotting tests on post-thawed specimens. METHODS: The sample population consisted of 13 healthy volunteers. Venous blood was collected by evacuated system into three 3.5mL tubes containing 0.109mmol/L buffered sodium citrate. The three blood tubes of each subject were pooled immediately after collection inside a Falcon 15mL tube, then mixed by 6 gentle end-over-end inversions, and centrifuged at 1500g for 15min. Plasma-pool of each subject was then divided in 4 identical aliquots. All aliquots were thawed after 2-day freezing -70 degrees C. Immediately afterwards, the plasma of the four paired aliquots were treated using four different techniques: (a) reference procedure, entailing 6 gentle end-over-end inversions; (b) placing the sample on a blood tube rocker (i.e., rotor mixing) for 5min to induce agitation and mixing; (c) use of a vortex mixer for 20s to induce agitation and mixing; and (d) no mixing. The significance of differences against the reference technique for mixing thawed plasma specimens (i.e., 6 gentle end-over-end inversions) were assessed with paired Student's t-test. The statistical significance was set at p<0.05. RESULTS AND CONCLUSION: As compared to the reference 6-time gentle inversion technique, statistically significant differences were only observed for fibrinogen, and factor VIII in plasma mixed on tube rocker. Some trends were observed in the remaining other cases, but the bias did not achieve statistical significance. We hence suggest that each laboratory should standardize the procedures for mixing of thawed plasma according to a single technique. PMID- 27769866 TI - Effect of carbon pulsing on the redox household of Lactobacillus diolivorans in order to enhance 1,3-propanediol production. AB - This study investigates potential limitations of 1,3-propanediol formation by Lactobacillus diolivorans. Particular focus is given to enhanced glycerol utilization as well as the elimination of by-product formation. The key aspect is a modulation of the redox household by process engineering through the application of carbon pulses. A shift in the product pattern of C3 products was achieved, improving the ratio of 1,3-propanediol versus 3-hydroxypropionic acid up to a level of 20:1. Moreover, in combination with alternative feeding strategies this ratio was enhanced up to 45:1 and the maximum observed productivity of 1,3-propanediol could be significantly increased to 1.7g/Lh. PMID- 27769868 TI - Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease. AB - Oxidative stress reflects an imbalance between the overproduction and incorporation of free radicals and the dynamic ability of a biosystem to detoxify reactive intermediates. Free radicals produced by oxidative stress are one of the common features in several experimental models of diseases. Free radicals affect both the structure and function of neural cells, and contribute to a wide range of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Although the precise mechanisms that result in the degeneration of neurons and the relevant pathological changes remain unclear, the crucial role of oxidative stress in the pathogenesis of neurodegenerative diseases is associated with several proteins (such as alpha-synuclein, DJ-1, Amyloid beta and tau protein) and some signaling pathways (such as extracellular regulated protein kinases, phosphoinositide 3-kinase/Protein Kinase B pathway and extracellular signal-regulated kinases 1/2) that are tightly associated with the neural damage. In this review, we present evidence, gathered over the last decade, concerning a variety of pathogenic proteins, their important signaling pathways and pathogenic mechanisms associated with oxidative stress in Parkinson's disease and Alzheimer's disease. Proper control and regulation of these proteins' functions and the related signaling pathways may be a promising therapeutic approach to the patients. We also emphasizes antioxidative options, including some new neuroprotective agents that eliminate excess reactive oxygen species efficiently and have a certain therapeutic effect; however, controversy surrounds some of them in terms of the dose and length of therapy. These agents require further investigation by clinical application in patients suffering Parkinson's disease and Alzheimer's disease. PMID- 27769867 TI - Factors Associated with Sedentary Behavior in Patients with Intermittent Claudication. AB - OBJECTIVES: Time spent in sedentary behavior has been associated with cardio metabolic risk factors in the general population and in patients with symptomatic peripheral artery disease (PAD). Given the association of sedentary behavior and poor health outcomes, it is important to identify factors associated with sedentary behavior in these patients. The aim of this study was to identify factors associated with the sedentary time in patients with symptomatic PAD. METHODS: The sample included 297 patients with symptomatic PAD. Sedentary behavior was assessed using a step activity monitor and the patients were divided into tertiles. Demographic data, body mass index, comorbid conditions, and measures of severity of PAD (ankle brachial index, ischemic window, claudication measurements, peak oxygen uptake and walking economy) were obtained. RESULTS: Patients in the highest tertile (i.e. more sedentary) had a higher body mass index and a higher prevalence of diabetes mellitus, metabolic syndrome, and obesity than patients in the lowest tertile, whereas their peak walking time, peak oxygen uptake, and walking economy were lower (p < .05 for all). Using multiple regression procedures, the factors associated with the sedentary time were male sex (b = .217, R2 = .180, p = .001), body mass index (b = .154, R2 = .059, p = .013), peak walking time (b = -.360, R2 = .066, p <= .001), and walking economy (b = -.187, R2 = .142, p = .004). CONCLUSION: In patients with symptomatic PAD, greater time spent in sedentary behavior was found in men, and in patients with higher body mass index, lower peak walking time, and lower walking economy. PMID- 27769869 TI - Alterations in mRNA and protein expression of glutamate transporters in rat hippocampus after paraoxon exposure. AB - Organophosphates affect brain function through a variety of mechanisms beyond their shared role as cholinesterase inhibitors. The aim of the current study was to investigate the changes in the expression of glial (GLAST and GLT-1) and neuronal (EAAC1) glutamate transporters at mRNA and protein levels in paraoxon treated rat hippocampus. Adult male Wistar rats were intraperitoneally treated with either vehicle (corn oil) or one of three dosages of paraoxon (0.3, 0.7 or 1mg/kg). After 4 or 18h, both hippocampi of each rat were collected to detect mRNA and protein expression of glutamate transporters using the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting, respectively. Animals treated with 0.3mg/kg paraoxon showed no difference in mRNA and protein levels of the glutamate transporters when compared with control group. At 4h after exposure with 0.7 and 1mg/kg paraoxon, the expression of GLAST and GLT-1 increased at mRNA and protein levels and remained elevated after 18h. No difference in the expression of EAAC1 at mRNA and protein levels was observed in any paraoxon-treated groups compared with the control group. This study showed an increased expression of glial (GLAST and GLT-1), but not neuronal (EAAC1) glutamate transporters, in adult rat hippocampus following administration of convulsive dosages of paraoxon. These suggest a protective and compensatory adaptation for effective uptake of glutamate in hippocampus induced by paraoxon and thus attenuating seizure activity. PMID- 27769870 TI - BRAF exon 15 mutations in pediatric renal stromal tumors: prevalence in metanephric stromal tumors. AB - Metanephric stromal tumors (MSTs) are rare renal stromal tumors that predominantly affect children. They belong to the metanephric family of tumors, along with metanephric adenofibroma and metanephric adenoma. The previous documentation of BRAF exon 15 mutations in 88% of metanephric adenomas and in isolated cases of metanephric adenofibroma prompted us to investigate the prevalence of these mutations in MSTs and in other pediatric renal stromal tumors. In this study, 17 MSTs, 22 congenital mesoblastic nephromas, and 6 ossifying renal tumors of infancy were selected for BRAF exon 15 testing. Tumor genomic DNA was extracted from formalin-fixed paraffin-embedded tissue, followed by polymerase chain reaction amplification and Sanger dideoxy sequencing with primers flanking the BRAF exon 15 gene. BRAF exon 15 mutations were found in 11 (65%) of the 17 cases of MST, all corresponding to a thymidine-to-adenine substitution at codon 600 (BRAF V600E). All other renal stromal tumors tested were negative for BRAF exon 15 mutations. In conclusion, BRAF V600E mutations are encountered in most MSTs, supporting a link with other metanephric tumors and suggesting a clonal event possibly affecting primordial renal cells. In addition, BRAF V600E mutations have been associated with oncogene-induced senescence in other benign tumors, providing clues to the pathogenesis of metanephric neoplasms in keeping with their overall benign behavior. Our results also suggest a potential diagnostic use for BRAF exon 15 mutations in differentiating MSTs from other pediatric renal stromal tumors, particularly in limited samples. PMID- 27769871 TI - Reevaluation of MAML2 fusion-negative mucoepidermoid carcinoma: a subgroup being actually hyalinizing clear cell carcinoma of the salivary gland with EWSR1 translocation. AB - Hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland tumor with a specific EWSR1-ATF1 fusion gene and can have mucin production. Mucoepidermoid carcinoma (MEC) with a clear cell component is its morphologic mimic. Using MAML2 fluorescence in situ hybridization (FISH), a total of 49 MEC cases were separated into MAML2 fusion-positive (32 cases) and MAML2 fusion-negative groups (17 cases). This study used EWSR1 FISH to investigate MAML2 fusion-negative cases to identify previously unrecognized HCCC. Among 17 MAML2 fusion-negative cases, 3 had rearrangement of the EWSR1 gene and were reclassified as HCCC. Including 5 previously diagnosed HCCC cases, these 8 HCCC cases had a male-to-female ratio of 1:7, and most (7/8) tumors arose from oral minor salivary glands in the oral cavity (tongue base and palate). EWSR1-ATF1 fusion was confirmed by FISH in all 8 HCCC cases. The histologic features between genetically confirmed HCCC and MEC were compared. HCCC was significantly associated with minor salivary gland involvement, a discrepancy between low-grade cytology and intermediate- to high grade histology using the MEC grading system, and absence of both epidermoid cells with abundant cytoplasm and goblet cells lining cysts or forming clusters. Clear cells and a hyalinized stroma were not specific for HCCC. HCCC may be erroneously classified as MEC because clear cells may be a minor histologic component and mucin production is not uncommon. Previously diagnosed MEC cases should be reevaluated, especially those arising from minor salivary glands or without MAML2 fusion. Careful histologic evaluation with supporting molecular testing can facilitate pathologic diagnoses. PMID- 27769872 TI - Primary epithelioid sarcoma of the kidney and adrenal gland: report of 2 cases with immunohistochemical and molecular cytogenetic studies. AB - Epithelioid sarcoma (ES) is a malignant mesenchymal neoplasm with some morphologic or immunophenotypic evidence of epithelial differentiation. The "classic" subtype occurs in younger patients, often in distal extremities as compared with the "proximal" type. Tumors of the proximal type primarily arising in solid organs are rare with only few case reports in the literature. We report 2 cases of primary ES in the kidney of a 27-year-old woman and the adrenal gland of a 73-year-old man. Clinical examination and imaging, including computed tomography and positron-emission tomography, did not reveal tumor elsewhere in both cases. Histologic features were those of ES, proximal type with epithelioid/rhabdoid phenotype. Immunohistochemical study in both cases showed strong, diffuse expression of epithelial markers, CD34, and CD31. Nuclear expression of SMARCB1 protein was lost, but fluorescence in situ hybridization analysis was negative for SMARCB1 deletion. We believe that these are the first reports of primary kidney and adrenal gland ES. PMID- 27769873 TI - Mitochondrial proteomic alterations caused by long-term low-dose copper exposure in mouse cortex. AB - Mitochondrial dysfunction is involved in neurotoxicity caused by exposure of various chemicals such as copper. However, the effects of long-term low-dose copper exposure on mitochondrial proteome remain unclear. In this study, we found the treatment of copper (0.13ppm copper sulfate in drinking water) for 12 months caused abnormal expression of a total of 13 mitochondrial proteins (7 up regulated and 6 down-regulated) as revealed by two-dimensional electrophoresis coupled with mass spectrometry in mouse cortex. Protein functional analysis revealed that these differentially expressed proteins mainly included apoptosis associated proteins, axon guidance-associated proteins, axonogenesis-associated proteins and mitochondrial respiratory chain complex. Among these differentially expressed mitochondrial proteins, GRP75 (75kDa glucose-regulated protein) and GRP78 (78kDa glucose-regulated protein) were found to be significantly down regulated as confirmed by Western-blot analysis. The down-regulation of GRP75 was shown to promote apoptosis. The down-regulation of GRP78/BiP could up-regulate endoplasmic reticulum (ER) stress mediators and thus cause apoptosis. Our study suggested that these differentially expressed mitochondrial proteins such as GRP75 and GRP78 could be involved in neurotoxicity caused by long-term low-dose copper exposure and serve as potential molecular targets for the treatment of copper neurotoxicity. PMID- 27769875 TI - One Health and its practical implications for surveillance of endemic zoonotic diseases in resource limited settings. AB - Surveillance of zoonotic disease requires special attention because the animal and human health sectors are involved. A proliferation of scholarly literature and technical guidelines exist for early detection of exotic and re-emerging diseases and to demonstrate freedom from disease as part of international trade agreements. In contrast, literature focussing on surveillance of endemic zoonotic diseases is relatively rare. In this article, we describe and discuss the main aspects to consider when planning a surveillance system for endemic zoonotic diseases in a resource-limited country. We describe advantages and disadvantages of different active and passive surveillance systems and explore how risk-based sampling might improve efficiency and reduce costs, and which tools are available to identify high-risk populations. PMID- 27769874 TI - Preventive effects of blueberry extract on behavioral and biochemical dysfunctions in rats submitted to a model of manic behavior induced by ketamine. AB - The aim of the present study was to evaluate the protective effects of blueberry extract on oxidative stress and inflammatory parameters in a model of mania induced by ketamine administration in rats. Male rats were pretreated with blueberry extract (200mg/kg, once a day for 14days), lithium chloride (45mg/kg, mood stabilizer used as a positive control, twice a day for 14days), or vehicle. Between the 8th and 14th days, rats also received an injection of ketamine (25mg/kg) or vehicle. In the 15th day, thirty minutes after ketamine administration the hyperlocomotion of the animals was assessed in the open - field apparatus. Immediately after the behavioral analysis brain and blood were collected for biochemical determinations. ketamine treatment induced hyperlocomotion and oxidative damage in cerebral cortex, hippocampus and striatum such as an increase in lipid peroxidation and a decrease in the antioxidant enzymes activities (superoxide dismutase, catalase e glutatione peroxidase). Ketamine administration also increased the IL-6 levels in serum in rats. Pretreatment of rats with blueberry extract or lithium prevented the hyperlocomotion, pro - oxidant effects and inflammation induced by ketamine. Our findings suggest that blueberry consumption has a neuroprotective potential against behavioral and biochemical dysfunctions induced in a preclinical model that mimic some aspects of the manic behavior. PMID- 27769876 TI - Seizure-specific wavelet (Seizlet) design for epileptic seizure detection using CorrEntropy ellipse features based on seizure modulus maximas patterns. AB - BACKGROUND: EEG signal analysis of pediatric patients plays vital role for making a decision to intervene in presurgical stages. NEW METHOD: In this paper, an offline seizure detection algorithm based on definition of a seizure-specific wavelet (Seizlet) is presented. After designing the Seizlet, by forming cone of influence map of the EEG signal, four types of layouts are analytically designed that are called Seizure Modulus Maximas Patterns (SMMP). By mapping CorrEntropy Induced Metric (CIM) series, four structural features based on least square estimation of fitted non-tilt conic ellipse are extracted that are called CorrEntropy Ellipse Features (CEF). The parameters of the SMMP and CEF are tuned by employing a hybrid optimization algorithm based on honeybee hive optimization in combination with Las Vegas randomized algorithm and Elman recurrent classifier. Eventually, the optimal features by AdaBoost classifiers in a cascade structure are classified into the seizure and non-seizure signals. RESULTS: The proposed algorithm is evaluated on 844h signals with 163 seizure events recorded from 23 patients with intractable seizure disorder and accuracy rate of 91.44% and false detection rate of 0.014 per hour are obtained by 7-channel EEG signals. COMPARISON WITH EXISTING METHOD(S): To overcome the restrictions of general kernels and wavelet coefficient-based features, we designed the Seizlet as an exclusive kernel of seizure signal for first time. Also, the Seizlet-based patterns of EEG signals have been modeled to extract the seizure. CONCLUSIONS: The reported results demonstrate that our proposed Seizlet is effectiveness to extract the patterns of the epileptic seizure. PMID- 27769877 TI - Clinical effectiveness and cost savings in diabetes care, supported by pharmacist counselling. AB - OBJECTIVE: To determine the effectiveness and cost savings of a real-world, continuous, pharmacist-delivered service with an employed patient population with diabetes over a 5-year period. SETTING: The Patients, Pharmacists Partnerships (P3 Program) was offered as an "opt-in" benefit to employees of 6 public and private self-insured employers in Maryland and Virginia. Care was provided in ZIP code-matched locations and at 2 employers' worksites. PRACTICE DESCRIPTION: Six hundred two enrolled patients with type 1 and 2 diabetes were studied between July 2006 and May 2012 with an average follow-up of 2.5 years per patient. Of these patients, 162 had health plan cost and utilization data. A network of 50 trained pharmacists provided chronic disease management to patients with diabetes using a common process of care. Communications were provided to patients and physicians. PRACTICE INNOVATION: Employers provided incentives for patients who opted in, including waived medication copayments and free diabetes self monitoring supplies. The service was provided at no cost to the patient. A Web based, electronic medical record that complied with the Health Insurance Portability and Accountability Act helped to standardize care. Quality assurance was conducted to ensure the standard of care. EVALUATION: Glycosylated hemoglobin (A1c), blood pressure, and total health care costs (before and after enrollment). RESULTS: Statistically significant improvements were shown by mean decreases in A1c (-0.41%, P <0.001), low-density lipoprotein levels (-4.7 mg/dL, P = 0.003), systolic blood pressure (-2.3 mm Hg, P = 0.001), and diastolic blood pressure ( 2.4 mm Hg, P <0.001). Total annual health care costs to employers declined by $1031 per beneficiary after the cost of the program was deducted. This 66-month real-world study confirms earlier findings. Employers netted savings through improved clinical outcomes and reduced emergency and hospital utilization when comparing costs 12 months before and after enrollment. CONCLUSION: The P3 program had positive clinical outcomes and economic outcomes. Pharmacist-provided comprehensive medication therapy management services should be included as a required element of insurance offered by employers and health insurance exchanges. PMID- 27769878 TI - ERP Reliability Analysis (ERA) Toolbox: An open-source toolbox for analyzing the reliability of event-related brain potentials. AB - Generalizability theory (G theory) provides a flexible, multifaceted approach to estimating score reliability. G theory's approach to estimating score reliability has important advantages over classical test theory that are relevant for research using event-related brain potentials (ERPs). For example, G theory does not require parallel forms (i.e., equal means, variances, and covariances), can handle unbalanced designs, and provides a single reliability estimate for designs with multiple sources of error. This monograph provides a detailed description of the conceptual framework of G theory using examples relevant to ERP researchers, presents the algorithms needed to estimate ERP score reliability, and provides a detailed walkthrough of newly-developed software, the ERP Reliability Analysis (ERA) Toolbox, that calculates score reliability using G theory. The ERA Toolbox is open-source, Matlab software that uses G theory to estimate the contribution of the number of trials retained for averaging, group, and/or event types on ERP score reliability. The toolbox facilitates the rigorous evaluation of psychometric properties of ERP scores recommended elsewhere in this special issue. PMID- 27769880 TI - Links between autonomic activity and implicit learning. AB - The somatic marker hypothesis posits that autonomic activity occurring in response to specific stimuli aids in implicit learning, the learning of information without explicit awareness of what has been learned. This study investigated whether respiratory sinus arrhythmia (RSA), a measure of autonomic nervous system activity, predicted changes in implicit learning. The interaction of resting RSA and RSA reactivity (change in RSA during the implicit learning task) was associated with changes in implicit learning, with those who had higher resting RSA and greater RSA withdrawal during the task performing better. These findings contribute to a better understanding of the autonomic processes that may underlie implicit learning and are discussed in relation to potential links between autonomic activity, implicit learning, and decision making. PMID- 27769879 TI - Individuals with tension and migraine headaches exhibit increased heart rate variability during post-stress mindfulness meditation practice but a decrease during a post-stress control condition - A randomized, controlled experiment. AB - BACKGROUND: Current research suggests that associations between headache conditions (migraine, tension) and imbalances in the autonomic nervous system (ANS) are due to stress-related dysregulation in the activity of the parasympathetic-sympathetic branches. Mindfulness meditation has demonstrated effectiveness in reducing pain-related distress, and in enhancing heart rate variability-a vagal-mediated marker of ANS balance. This study examined HRV during cognitive stress and mindfulness meditation in individuals with migraine and tension headaches. METHODS: Undergraduate students with tension and migraine headaches (n=36) and headache-free students (n=39) were recruited for an experiment involving HRV measurement during baseline, cognitive stress-induction, and after randomization to post-stress conditions of audio-guided mindfulness meditation practice (MMP) or mindfulness meditation description (MMD). HRV was derived using electrocardiograms as the absolute power in the high frequency bandwidth (ms2). A three-way ANOVA tested the effects of Group (headache vs. headache-free), Phase (baseline, stress, & post-stress), and Condition (MMP vs. MMD) on HRV. RESULTS: ANOVA revealed a significant three-way interaction. Simple effects tests indicated: 1) HRV increased significantly from stress to MMP for headache and headache-free groups (p<0.001), 2) significantly greater HRV for headache (p<0.001) and headache-free (p<0.05) groups during MMP compared to MMD, and 3) significantly lower HRV in the headache vs. headache-free group during the post-stress MMD condition (p<0.05). DISCUSSION: Results suggest mindfulness practice can promote effective heart rate regulation, and thereby promote effective recovery after a stressful event for individuals with headache conditions. Moreover, headache conditions may be associated with dysregulated stress recovery, thus more research is needed on the cardiovascular health and stress resilience of headache sufferers. PMID- 27769881 TI - Characterization of ethoxyresorufin O-deethylase activity (EROD) in oyster Crassostrea brasiliana. AB - Cytochrome P450 family 1 (CYP1) is involved in polycyclic aromatic hydrocarbons (PAHs) biotransformation. PAHs can induce CYP1 protein expression and enzyme activity, the latter being usually quantified as 7-ethoxyresorufin O-deethylase activity (EROD). The aim of this study was to characterize EROD activity in the bivalve mollusk Crassostrea brasiliana. EROD activity was evaluated in cytosolic and microsomal fractions of gills, digestive gland and mantle of C. brasiliana. No EROD activity was detected in mantle, but it was present in microsomal fraction of gills and digestive gland with NADPH as coenzyme. Optima temperature and pH for EROD assay were 30 degrees C and 7.4, respectively. EROD apparent Km (Kmapp) was 4.32MUM for gills and 5.56MUM for digestive gland. EROD Vmax was 337.3fmol.min-1.mg of protein-1 in gills and 297.7fmol.min-1.mg of protein-1 in digestive gland. Compared to other bivalves, a higher Kmapp and a lower Vmax was found in oyster which may suggest that oyster CYP1-like enzyme has lower affinity for substrate 7-ethoxyresorufin (7-ER) than those species. CYP1 inhibitor ellipticine (ELP) inhibited EROD activity in all tested concentrations in both tissues. The higher ELP concentration, 100MUM, inhibited 78% of EROD activity in gills and 47% in digestive gland. The CYP1 inhibitors alpha-naphthoflavone and furafylline did not inhibited EROD activity in microsomes of both tissues. In conclusion, EROD activity can be used to determine CYP1-like activity in oysters and possibly a CYP1A1/A2-like enzyme is responsible for this catalysis. PMID- 27769882 TI - Selection, isolation, and identification of fungi for bioherbicide production. AB - Production of a bioherbicide for biological control of weeds requires a series of steps, from selection of a suitable microbial strain to final formulation. Thus, this study aimed to select fungi for production of secondary metabolites with herbicidal activity using biological resources of the Brazilian Pampa biome. Phytopathogenic fungi were isolated from infected tissues of weeds in the Pampa biome. A liquid synthetic culture medium was used for production of metabolites. The phytotoxicity of fungal metabolites was assessed via biological tests using the plant Cucumis sativus L., and the most promising strain was identified by molecular analysis. Thirty-nine fungi were isolated, and 28 presented some phytotoxic symptoms against the target plant. Fungus VP51 belonging to the genus Diaporthe showed the most pronounced herbicidal activity. The Brazilian Pampa biome is a potential resource for the development of new and sustainable chemical compounds for modern agriculture. PMID- 27769884 TI - Coprophilous Mucorales (ex Zygomycota) from three areas in the semi-arid of Pernambuco, Brazil. AB - Mucorales comprises fungi commonly isolated as saprobes from soil, dung, stored grains and plants. Although these fungi have been studied in several countries, there are relatively a few reports of them in semi-arid areas. Therefore, the aims of the present study were to assess and compare the Mucorales communities in dung from different species and breeds of herbivores in the semi-arid of Pernambuco, based on the frequency of occurrence and species richness of these fungi. Samples of dung collected in the cities of Arcoverde, Serra Talhada and Sertania were incubated in moist chambers in triplicate. Altogether, 24 taxa of Mucorales distributed in the genera Absidia, Circinella, Cunninghamella, Lichtheimia, Mucor, Pilobolus, Rhizopus and Syncephalastrum were identified. The highest species richness was found in sheep excrement. Mucor circinelloides f. griseo-cyanus was the most common taxon, followed by M. ramosissimus. The similarity of the composition of Mucorales species was greatest between the excrements of Guzera and Sindi breeds (bovine). All mucoralean species isolated are being cited for the first time from animal dung found in Caatinga and a new species of Mucor was recorded. An identification key for species of Mucorales from dung in the semi-arid region of Brazil is provided. PMID- 27769885 TI - Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier. AB - The blood brain barrier (BBB) is a major obstacle to drug delivery for diseases of the central nervous system (CNS). This brief review highlights the current invasive and non-invasive technologies available to address this problem. In particular, nanomedicine has shown much promise as a non-invasive strategy due to its drug loading capabilities, ease of targeting to the BBB, and small size. The versatility of this technology in terms of type of drug and imaging agent, carrier material, and targeting mechanism is highlighted in this review. The recent inclusion of imaging agents in the nanocarriers has important consequences for the field of theranostics. PMID- 27769883 TI - Brazilian borreliosis with special emphasis on humans and horses. AB - Borreliosis caused by Borrelia burgdorferi sensu lato is a cosmopolitan zoonosis studied worldwide; it is called Lyme disease in many countries of the Northern Hemisphere and Lyme-like or Baggio-Yoshinari Syndrome in Brazil. However, despite the increasing number of suspect cases, this disease is still neglected in Brazil by the medical and veterinary communities. Brazilian Lyme-like borreliosis likely involves capybaras as reservoirs and Amblyomma and Rhipicephalus ticks as vectors. Thus, domestic animals can serve as key carriers in pathogen dissemination. This zoonosis has been little studied in horses in Brazil. The first survey was performed in the state of Rio de Janeiro, and this Brazilian Borreliosis exhibits many differences from the disease widely described in the Northern Hemisphere. The etiological agent shows different morphological and genetic characteristics, the disease has a higher recurrence rate after treatment with antibiotics, and the pathogen stimulates intense symptoms such as a broader immune response in humans. Additionally, the Brazilian zoonosis is not transmitted by the Ixodes ricinus complex. With respect to clinical manifestations, Baggio-Yoshinari Syndrome has been reported to cause neurological, cardiac, ophthalmic, muscle, and joint alterations in humans. These symptoms can possibly occur in horses. Here, we present a current panel of studies involving the disease in humans and equines, particularly in Brazil. PMID- 27769887 TI - A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin. AB - A major problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulate multi-drug resistance proteins such as P-glycoprotein (P-gp). However, the lack of overexpressed surface biomarkers has limited the targeted therapy of drug-resistant cancers. Here we report a drug-delivery carrier decorated with a targeting ligand for a surface marker protein extra-domain B(EDB) specific to drug-resistant breast cancer cells as a new therapeutic option for the aggressive cancers. We constructed EDB specific aptide (APTEDB)-conjugated liposome to simultaneously deliver siRNA(siMDR1) and Dox to drug-resistant breast cancer cells. APTEDB LS(Dox,siMDR1) led to enhanced delivery of payloads into MCF7/ADR cells and showed significantly higher accumulation and retention in the tumors. While either APTEDB-LS(Dox) or APTEDB-LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APTEDB-LS(Dox,siMDR1) treatment resulted in significant reduction of the drug-resistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy. PMID- 27769886 TI - Bovine bone matrix/poly(l-lactic-co-epsilon-caprolactone)/gelatin hybrid scaffold (SmartBone(r)) for maxillary sinus augmentation: A histologic study on bone regeneration. AB - The ideal scaffold for bone regeneration is required to be highly porous, non immunogenic, biostable until the new tissue formation, bioresorbable and osteoconductive. This study aimed at investigating the process of new bone formation in patients treated with granular SmartBone(r) for sinus augmentation, providing an extensive histologic analysis. Five biopsies were collected at 4-9 months post SmartBone(r) implantation and processed for histochemistry and immunohistochemistry. Histomorphometric analysis was performed. Bone-particle conductivity index (BPCi) was used to assess SmartBone(r) osteoconductivity. At 4 months, SmartBone(r) (12%) and new bone (43.9%) were both present and surrounded by vascularized connective tissue (37.2%). New bone was grown on SmartBone(r) (BPCi=0.22). At 6 months, SmartBone(r) was almost completely resorbed (0.5%) and new bone was massively present (80.8%). At 7 and 9 months, new bone accounted for a large volume fraction (79.3% and 67.4%, respectively) and SmartBone(r) was resorbed (0.5% and 0%, respectively). Well-oriented lamellae and bone scars, typical of mature bone, were observed. In all the biopsies, bone matrix biomolecules and active osteoblasts were visible. The absence of inflammatory cells confirmed SmartBone(r) biocompatibility and non-immunogenicity. These data indicate that SmartBone(r) is osteoconductive, promotes fast bone regeneration, leading to mature bone formation in about 7 months. PMID- 27769888 TI - Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Abeta peptide. AB - Aggregation of amyloid-beta peptide (Abeta) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH2) on the aggregation and toxicity of Abeta. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Abeta oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Abeta. PINPs also bound to Abeta with high affinity (Kd=13.2-50 nM), rescued SHSY-5Y cells from the toxic effect of pre aggregated Abeta, crossed an in vitro blood-brain barrier model (hCMEC/D3 cell monolayer), entered the brains of C57 BL/6 mice, and protected against memory loss in APPSWE transgenic mice in a novel object recognition test. As the most potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD. PMID- 27769889 TI - Ambient intelligence for health environments. PMID- 27769890 TI - Concept and implementation of a study dashboard module for a continuous monitoring of trial recruitment and documentation. AB - BACKGROUND: The difficulty of managing patient recruitment and documentation for clinical trials prompts a demand for instruments for closely monitoring these critical but unpredictable processes. Increasingly adopted Electronic Data Capture (EDC) applications provide novel opportunities to reutilize stored information for an efficient management of traceable trial workflows. In related clinical and administrative settings, so-called digital dashboards that continuously visualize time-dependent parameters have recently met a growing acceptance. To investigate the technical feasibility of a study dashboard for monitoring the progress of patient recruitment and trial documentation, we set out to develop a propositional prototype in the form of a separate software module. METHODS: After narrowing down functional requirements in semi-structured interviews with study coordinators, we analyzed available interfaces of a locally deployed EDC application, and designed the prototypical study dashboard based on previous findings. The module thereby leveraged a standardized export format in order to extract and import relevant trial data into a clinical data warehouse. Web-based reporting tools then facilitated the definition of diverse views, including diagrams of the progress of patient accrual and form completion at different granularity levels. To estimate the utility of the dashboard and its compatibility with current workflows, we interviewed study coordinators after a demonstration of sample outputs from ongoing trials. RESULTS: The employed tools promoted a rapid development. Displays of the implemented dashboard are organized around an entry page that integrates key metrics for available studies, and which links to more detailed information such as study-specific enrollment per center. The interviewed experts commented that the included graphical summaries appeared suitable for detecting that something was generally amiss, although practical remedies would mostly depend on additional information such as access to the original patient-specific data. The dependency on a separate application was seen as a downside. Interestingly, the prospective users warned that in some situations knowledge of specific accrual statistics might undermine blinding in a subtle yet intricate fashion, so ignorance of certain patient features was seen as sometimes preferable for reproducibility. DISCUSSION: Our proposed study dashboard graphically recaps key progress indicators of patient accrual and trial documentation. The modular implementation illustrates the technical feasibility of the approach. The use of a study dashboard might introduce certain technical requirements as well as subtle interpretative complexities, which may have to be weighed against potential efficiency gains. PMID- 27769891 TI - Neuroticism related differences in the functional neuroanatomical correlates of multitasking. An fMRI study. AB - It is known that neuroticism impairs cognitive performance mostly in difficult tasks, but not so much in easier tasks. One pervasive situation of this type is multitasking, in which the combination of two simple tasks creates a highly demanding dual-task, and consequently high neurotics show higher dual-task costs than low neurotics. However, the functional neuroanatomical correlates of these additional performance impairments in high neurotics are unknown. To test for this, we assessed brain activity by means of functional magnetic resonance imaging (fMRI) in 17 low and 15 high neurotics while they were performing a demanding dual-task and the less demanding component tasks as single-tasks. Behavioural results showed that performance (response times and error rates) was lower in the dual-task than in the single-tasks (dual-task costs), and that these dual-task costs were significantly higher in high neurotics. Imaging data showed that high neurotics showed less dual-task specific activation in lateral (mainly middle frontal gyrus) and medial prefrontal cortices. We conclude that high levels of neuroticism impair behavioural performance in demanding tasks, and that this impairment is accompanied by reduced activation of the task-associated brain areas. PMID- 27769892 TI - Bimodal modulation of store-operated Ca2+ channels by clozapine in astrocytes. AB - Clozapine (Clz) and olanzapine (Olz) are second generation (atypical) antipsychotics, used widely for treating schizophrenia and bipolar disorder. These drugs share multiple sites of actions, however their mechanisms remain incompletely understood. Here, we analyzed the effects of these drugs on primary cultures of rat cortical astrocytes and C6 glioma cells using fura-2-based Ca2+ imaging. C6 cells, but not cortical astrocytes, express the serotonin 2A receptor subtype, which couples to phospholipase C. Clz (1MUM) significantly blocked serotonin-induced Ca2+ transients in C6 cells, consistent with known antagonistic actions of Clz. Interestingly, at higher concentrations (>10MUM), Clz but not Olz increased intracellular Ca2+ concentrations in both cortical astrocytes and C6 cells. This Clz-induced Ca2+ increase was concentration-dependent and completely blocked by removal of extracellular Ca2+ using ethylene glycol tetraacetic acid (EGTA). Furthermore, 2-aminoethyl diphenylborinate or SKF-96365, blockers for store-operated Ca2+ channels, significantly inhibited the Clz-induced Ca2+ increase. Therefore, we analyzed the effects of Clz and Olz during Ca2+ re-entry through store-operated Ca2+ channels, which was maximized following depletion of internal Ca2+ stores by thapsigargin and EGTA. The results demonstrated that Clz decreased Ca2+ re-entry through store-operated Ca2+ channels in cortical astrocytes and C6 cells whereas Olz failed to modulate the Ca2+ re-entry. These results suggest Clz-specific bimodal actions via store-operated Ca2+ channels in astrocytic cells. Since intracellular Ca2+ homeostasis in astrocytes is an important determinant for neighboring synaptic signal transmission, our results may explain Clz-specific adverse effects or differential actions between Clz and Olz reported in the treatment of psychiatric disorders. PMID- 27769893 TI - Phenylethanolamine N-methyltransferase gene expression in adrenergic neurons of spontaneously hypertensive rats. AB - Epinephrine is synthesised by the catecholamine biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT), primarily in chromaffin cells of the adrenal medulla and secondarily in brainstem adrenergic neurons of the medulla oblongata. Epinephrine is an important neurotransmitter/neurohormone involved in cardiovascular regulation; however, overproduction is detrimental with negative outcomes such as cellular damage, cardiovascular dysfunction, and hypertension. Genetic mapping studies have linked elevated expression of PNMT to hypertension. Adrenergic neurons are responsible for blood pressure regulation and are the only PNMT containing neurons in the brainstem. The purpose of the current study was to determine whether elevated blood pressure found in adult spontaneously hypertensive rats (SHR) is associated with altered regulation of the PNMT gene in catecholaminergic neurons. C1, C2, and C3 adrenergic regions of 16 week old Wistar Kyoto (WKY) and SHR rats were excised using micropunch microdissection for mRNA expression analyses. Results from the current study confirm high PNMT mRNA expression in all three brainstem adrenergic regions (C1: 2.96-fold; C2: 2.17-fold; C3 1.20-fold) of the SHR compared to normotensive WKY rats. Furthermore, the immediate early gene transcription factor (Egr-1) mRNA was elevated in the C1 (1.84-fold), C2 (8.57-fold) and C3 (2.41-fold) regions in the brainstem of the SHR. Low mRNA expression for transcription factors Sp1 and GR was observed, while no change was observed for AP-2. The findings presented propose that alterations in the PNMT gene regulation in the brainstem contribute to enhanced PNMT production and epinephrine synthesis in the SHR, a genetic model of hypertension. PMID- 27769894 TI - Preparation, isolation and identification of non-conjugated C18:2 fatty acid isomers. AB - Non-conjugated geometric/positional isomers of linoleic acid (c9,c12-18:2) are often present in processed foods and oils. The following work presents a simple addition/elimination reaction for preparation of non-conjugated 18:2 fatty acid isomers. A mixture containing positional and geometric isomers of C18:2 fatty acids was produced by addition of hydrobromic acid to the fatty acid double bonds, followed by its elimination with a strong sterically hindered base. Pure 8,12-, 8,13-, 9,12-, and 9,13-18:2 fatty acid methyl esters were isolated from the synthetic mixture by a combination of sub-ambient RP-HPLC and Ag+-HPLC. The determination of the double bond position was achieved by GC-MS using picolinyl esters derivatives. The determination of the fatty acid double bond geometric configuration was obtained by partial hydrogenation of the isolated isomer with hydrazine, followed by the GC-FID analysis. PMID- 27769896 TI - Reproduction in Leishmania: A focus on genetic exchange. AB - One key process of the life cycle of pathogens is their mode of reproduction. Indeed, this fundamental biological process conditions the multiplication and the transmission of genes and thus the propagation of diseases in the environment. Reproductive strategies of protozoan parasites have been a subject of debate for many years, principally due to the difficulty in making direct observations of sexual reproduction (i.e. genetic recombination). Traditionally, these parasites were considered as characterized by a preeminent clonal structure. Nevertheless, with the development of elaborate culture experiments, population genetics and evolutionary and population genomics, several studies suggested that most of these pathogens were also characterized by constitutive genetic recombination events. In this opinion, we focused on Leishmania parasites, pathogens responsible of leishmaniases, a major public health issue. We first discuss the evolutionary advantages of a mixed mating reproductive strategy, then we review the evidence of genetic exchange, and finally we detail available tools to detect naturally occurring genetic recombination in Leishmania parasites and more generally in protozoan parasites. PMID- 27769895 TI - Prevalence and Risk Factors for Refractive Error in Adult Chinese Americans: The Chinese American Eye Study. AB - PURPOSE: To estimate the prevalence of refractive errors in adult Chinese Americans, and to evaluate factors associated with myopia and high myopia. DESIGN: A population-based, cross-sectional study. METHODS: Chinese Americans 50 years and older residing in Monterey Park, California, were recruited. Noncycloplegic automated refraction with supplemental subjective refraction was performed. Myopia, high myopia, hyperopia, and high hyperopia were defined as a spherical equivalent of <-0.5 diopter (D), <-5.0 D, >+0.5 D, and >=+3.0 D, respectively. Astigmatism and high astigmatism were defined as a cylinder of >0.5 D and >2.25 D, respectively. Risk factor assessment was guided by a conceptual model. RESULTS: Data from 4144 participants were analyzed. The overall prevalence of myopia, high myopia, hyperopia, high hyperopia, astigmatism, and high astigmatism in the right eye was 35.1% (95% confidence interval, 33.6%-36.6%), 7.4% (6.6%-8.3%), 40.2% (38.7%-41.8%), 2.7% (2.2%-3.3%), 45.6% (44.1%-47.2%), and 3.7% (3.1%-4.3%), respectively. The prevalence of myopia and high myopia was lower among older individuals (P < .05). Reversed age trends were observed for the other refractive errors (P < .05). There was no sex difference in the prevalence of refractive errors, except for a higher prevalence of hyperopia among female subjects (P = .010). Age, acculturation, education, income, marital status, birth country, history of ocular disease, nonocular comorbidities, and recent eye examination were associated with prevalence of myopia. All of these factors, except for acculturation, were also associated with high myopia. CONCLUSIONS: Our data present the first population-based estimates of the prevalence of refractive errors among adult Chinese Americans. Compared with whites, Hispanics, and blacks, Chinese Americans have a higher burden of myopia, high myopia, and astigmatism. PMID- 27769897 TI - Evaluating a novel health system intervention for chronic kidney disease care using the RE-AIM framework: Insights after two years. AB - INTRODUCTION: Using a quasi-experimental design, we implemented the Patient Centered Medical Home for Kidney Disease (PCMH-KD), a comprehensive, multidisciplinary care team to improve quality of life and healthcare coordination for adult chronic hemodialysis (CHD) patients. This paper highlights our experience in the first two years of the study. We focus on the process dimensions of Reach, Adoption, and Implementation within the context of the RE AIM framework. MATERIALS AND METHODS: We established a new PCMH-KD model at two outpatient dialysis centers. During the intervention phase, adult patients were recruited for participation and data collection. We monitored RE-AIM measures to identify areas for potential adaptation of the care model. RESULTS: During the start-up phase, we engaged patients and stakeholders in planning the intervention, established the new PCMH-KD team, and trained new and continuing clinicians and staff at two dialysis centers. In the intervention phase we recruited 155 patients to participate. Patients had individual visits with the PCP (40%) and the CHWs (92%) (Reach). Patient feedback informed procedures for appointment scheduling (Adoption). The new PCMH-KD team members were consistent in their roles. With staff changes, some responsibilities were adapted for cross coverage (Implementation). IMPLICATIONS: After one year of start-up and one year of intervention, active monitoring of Reach, Implementation and Adoption measures have facilitated necessary adaptions in the planned intervention to accommodate scheduling demands and patient feedback in the PCMH-KD model. Insights from this trial may inform care of CHD patients more broadly. PMID- 27769898 TI - "Off-On"switching electrochemiluminescence biosensor for mercury(II) detection based on molecular recognition technology. AB - A novel "off-On" electrogenerated chemiluminescence (ECL) biosensor has been developed for the detection of mercury(II) based on molecular recognition technology. The ECL mercury(II) biosensor comprises two main parts: an ECL substrate and an ECL intensity switch. The ECL substrate was made by modifying the complex of Ruthenium(II) tris-(bipyridine)(Ru(bpy)32+)/Cyclodextrins-Au nanoparticles(CD-AuNps)/Nafion on the surface of glass carbon electrode (GCE), and the ECL intensity switch is the single hairpin DNA probe designed according to the "molecular recognition" strategy which was functionalized with ferrocene tag at one end and attached to Cyclodextrins (CD) on modified GCE through supramolecular noncovalent interaction. We demonstrated that, in the absence of Hg(II) ion, the probe keeps single hairpin structure and resulted in a quenching of ECL of Ru(bpy)32+. Whereas, in the presence of Hg(II) ion, the probe prefers to form the T-Hg(II)-T complex and lead to an obvious recovery of ECL of Ru(bpy)32+, which provided a sensing platform for the detection of Hg(II) ion. Using this sensing platform, a simple, rapid and selective "off-On" ECL biosensor for the detection of mercury(II) with a detection limit of 0.1 nM has been developed. PMID- 27769899 TI - AKT-dependent phosphorylation of the SAM domain induces oligomerization and activation of the scaffold protein CNK1. AB - Scaffold proteins are hubs for the coordination of intracellular signaling networks. The scaffold protein CNK1 promotes several signal transduction pathway. Here we demonstrate that sterile motif alpha (SAM) domain-dependent oligomerization of CNK1 stimulates CNK1-mediated signaling in growth factor stimulated cells. We identified Ser22 located within the SAM domain as AKT dependent phosphorylation site triggering CNK1 oligomerization. Oligomeric CNK1 increased the affinity for active AKT indicating a positive AKT feedback mechanism. A CNK1 mutant lacking the SAM domain and the phosphorylation-defective mutant CNK1S22A antagonizes oligomerization and prevents CNK1-driven cell proliferation and matrix metalloproteinase 14 promoter activation. The phosphomimetic mutant CNK1S22D constitutively oligomerizes and stimulates CNK1 downstream signaling. Searching the COSMIC database revealed Ser22 as putative target for oncogenic activation of CNK1. Like the phosphomimetic mutant CNK1S22D, the oncogenic mutant CNK1S22F forms clusters in serum-starved cells comparable to clusters of CNK1 in growth factor-stimulated cells. CNK1 clusters induced by activating Ser22 mutants correlate with enhanced cell invasion and binding to and activation of ADP ribosylation factor 1 associated with tumor formation. Mutational analysis indicate that EGF-triggered phosphorylation of Thr8 within the SAM domain prevents AKT binding and antagonizes CNK1-mediated AKT signaling. Our findings reveal SAM domain-dependent oligomerization by AKT as switch for CNK1 activation. PMID- 27769900 TI - Extended-spectrum beta-lactamase-producing Enterobacteriaceae colonisation in long-term overseas business travellers. AB - BACKGROUND: International travel is considered a risk for colonisation with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). To our knowledge, no studies to date have focused on ESBL-PE colonisation among long term business travellers. Therefore this study aimed to clarify the characteristics associated with ESBL-PE colonisation in Japanese long-term business travellers. METHODS: Japanese business travellers planning to stay abroad for >=6 months were enrolled. Of the 192 travellers, 135 provided only post-travel stool samples and 57 provided both pre- and post-travel stool samples. Additionally, microbiological analyses of ESBL-PE strains, including susceptibility tests and polymerase chain reaction amplification of CTX-M genes and their sequencing were performed. RESULTS: A post-travel survey showed that of the 55 travellers (40.7%) who tested positive for ESBL-PE after travel, the highest proportion was travellers returning from East and Central Asia. CTX-M gene analyses showed that CTX-M-15 was the most frequently observed (55.0%). A pre- and post-travel survey showed that of the 22 travellers (44.9%) acquired ESBL-PE during their travel, with acquisition most frequently observed in travellers returning from South Asia. CONCLUSION: Risk-based evaluations of ESBL PE colonisation should be performed not only for regular tourists but also for long-term business travellers. PMID- 27769901 TI - Phylogenetic position of the white-cheeked macaque (Macaca leucogenys), a newly described primate from southeastern Tibet. AB - The white-cheeked macaque Macaca leucogenys is a recently described species that was only diagnosed based on photos, without any specimen measurements or molecular genetic diagnosis. Using DNA extracted from four newly collected skin specimens, we studied the genetic diversity and phylogenetic position of M. leucogenys using multilocus sequence data, including mitochondrial and Y chromosomal genes. Skin measurements of four individuals showed that the white cheeked macaque is robust and larger than M. assamensis but is similar in body size to M. thibetana. Although the holotype male of M. leucogenys was observed to have a round glans penis in three photos and a 15-s video, the current phylogenetic analysis placed this species in the sinica group, which has a sagittate glans penis. Our results confirm full species status of M. leucogenys and indicate that this species might have diverged from its closest relatives c. 2.5million years ago. The mitochondrial gene tree showed that M. leucogenys is phylogenetically close to M. munzala and M. radiata within the sinica group; however, their relationships were unresolved by Y chromosomal phylogenies, which indicates possible historical episode of male introgression. Further studies using an integrative approach that combines morphological and ecological characterizations and population-based genome-wide analysis are needed to investigate divergence and reproductive isolation, which are very likely to elucidate mechanisms underlying these Asian macaque radiations. PMID- 27769902 TI - From Alaska to Antarctica: Species boundaries and genetic diversity of Prasiola (Trebouxiophyceae), a foliose chlorophyte associated with the bipolar lichen forming fungus Mastodia tessellata. AB - Symbiotic associations between green algae (Chlorophyta) and fungi give rise to morphologically and eco-physiologically distinct entities, or so-called, lichens. In one of the most peculiar of these associations, the partners are species of the macroscopic genus Prasiola (Trebouxiophyceae) and the ascomycete Mastodia tessellata (Verrucariaceae). This is the only known case of a lichen symbiosis involving a foliose green alga. Despite intense research targeted at understanding the biology of this particular association, little is known about the genetic variability of its symbionts. This study focuses on the photobiont partner of this lichen and was designed to explore and compare its genetic diversity along a latitudinal axis from Alaska to Antarctica. Molecular sequence data were generated for three loci: two nuclear markers (nrITS, RPL10A) and one plastid-encoded marker (tufA). The usefulness of the Prasiola nrITS and RPL10A data was examined at the species and intraspecific levels. We used the population assignment tests implemented in BAPS and STRUCTURE and two algorithmic species delimitation procedures (ABGD, GMYC) to generate species boundary discovery hypotheses, which were subsequently tested using Bayes factors. Population genetic differentiation and structure were also assessed through fixation indices, polymorphism statistics and haplotype networks. Based on the results of the species validation method, we propose that at least two species of Prasiola associate with the lichen-forming fungus Mastodia tessellata. Of these, P. borealis is broadly distributed in Alaska, Tierra del Fuego and the Antarctic Peninsula, whereas the second, undescribed, species is restricted to the Antarctic Peninsula. We detected significant phylogeographic substructure in P. borealis, including greater haplotype diversity in the Tierra del Fuego populations. Our findings provide new data that will be useful to unravel the cryptic diversity and phylogeographic patterns of the green alga partners of lichens. PMID- 27769903 TI - Pre-existing risk factors for in-hospital death among older patients could be used to initiate end-of-life discussions rather than Rapid Response System calls: A case-control study. AB - AIM: To investigate associations between clinical parameters - beyond the evident physiological deterioration and limitations of medical treatment - with in hospital death for patients receiving Rapid Response System (RRS) attendances. METHODS: Retrospective case-control analysis of clinical parameters for 328 patients aged 60 years and above at their last RRS call during admission to a single teaching hospital in the 2012-2013 calendar years. Generalised estimating equation modelling was used to compare the deceased with a randomly selected sample of those who had RRS calls and survived admission (controls), matched by age group, sex, and hospital ward. RESULTS: In addition to a pre-existing order for limitation of treatment or cardiac arrest (OR 6.92; 95%CI 4.61-10.27), nursing home residence, proteinuria, advanced malignancy, acute myocardial infarction, chronic kidney disease, cognitive impairment and frailty were associated with high risk of death. After adjusting for all the clinical indicators investigated, the strongest risk factors for in-hospital death for patients with a RRS call were advanced malignancy (OR 3.95; 95%CI 2.16-7.21) and new myocardial infarction (OR 2.79; 95%CI 1.86-4.20). Patients with cognitive impairment, frailty indicator or chronic kidney disease were twice as likely to die as patients without those risk factors. CONCLUSION: In a sample of older deteriorated patients requiring a RRS attendance, multiple indicators of chronic illness, cognitive impairment and frailty were significantly associated with high risk of death. These clinical features beyond the evident orders for limitation of medical treatment should signal the need for clinicians to initiate end-of life discussions that may prevent futile interventions. PMID- 27769904 TI - Learned helplessness activates hippocampal microglia in rats: A potential target for the antidepressant imipramine. AB - An accumulating body of evidence has demonstrated that inflammation is associated with the pathology of depression. We recently found that psychological stress induces inflammation in the hippocampus of the rat brain through the inflammasome, a component of the innate immune system. Microglia, the resident macrophages in the brain, play a central role in the innate immune system and express inflammasomes; thus, we hypothesized that hippocampal microglia would be key mediators in the development of depression via stress-induced inflammation. To test this hypothesis and to determine how antidepressants modulate microglial function, we used immunohistochemistry to examine the morphological changes that occur in the hippocampal microglia of rats exposed to the learned helplessness (LH) paradigm. We noted significantly increased numbers of activated microglia in the granule cell layer, hilus, CA1, and CA3 regions of the hippocampi of LH rats. Conversely, administering imipramine to LH rats for 7days produced a significant decrease in the number of activated microglia in the hilus, but not in the other examined regions. Nonetheless, there were no significant differences in the combined number of activated and non-activated microglia either in LH or LH+imipramine rats relative to control rats. In addition, treating the naive rats with imipramine or fluvoxamine produced no discernible microglial changes. These data suggest that stress activates hippocampal microglia, while certain antidepressants decrease the number of activated microglia in the hilus, but not in other hippocampal regions. Therefore, the hilus represents a candidate target region for the antidepressant imipramine. PMID- 27769905 TI - Improved method for effective screening of ACC (1-aminocyclopropane-1 carboxylate) deaminase producing microorganisms. AB - Aminocyclopropane-1-carboxylate deaminase (ACCD) producing microorganisms support plant growth under a variety of biotic and abiotic stress conditions such as drought, soil salinity, flooding, heavy metal pollution and phyto-pathogen attack. Available screening methods for ACCD give idea only about its primary microbial ACCD activity than the actual potential. In the present investigation, we have simply improved screening method by incorporating pH indicator dyes (phenol red and bromothymol blue) in ACC containing medium. This modification is based on the basic principle that ACCD action releases ammonia which can be detected by color change and zone around the bacterial colony. High color intensity and zone around the colony indicates most potent producer, colony showing only a color change indicates moderate potential and no change in colony color indicates least efficiency. Enzymatic bioassays as well as root elongation studies revealed that ACC-deaminase activity of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Bacillus subtilis clearly corresponds to their growth on dye incorporated ACC medium. This method could be used to complement the existing screening methods and to speed up the targeted isolation of agriculturally important microorganisms. PMID- 27769907 TI - Growing Relevance of Cardiac Rehabilitation for an Older Population With Heart Failure. AB - Cardiac rehabilitation (CR) is a comprehensive lifestyle program that can have particular benefit for older patients with heart failure (HF). Prevalence of HF is increasingly common among older adults. Mounting effects of cardiovascular risk factors in older age as well as the added effects of geriatric syndromes such as multimorbidity, frailty, and sedentariness contribute to the high incidence of HF as well as to management difficulty. CR can play a decisive role in improving function, quality of life, symptoms, morbidity, and mortality, and also address the idiosyncratic complexities of care that often arise in old age. Unfortunately, the current policies and practices regarding CR for patients with HF are limited to HF with reduced ejection fraction and do not extend to HF with preserved ejection fraction, which is likely undercutting its full potential to improve care for today's aging population. Despite the strong rationale for CR on important clinical outcomes, it remains underused, particularly among older patients with HF. In this review, we discuss both the potential and the limitations of contemporary CR for older adults with HF. PMID- 27769908 TI - Prognostic Impact of Living in Temporary Housing in Fukushima After the Great East Japan Earthquake. PMID- 27769906 TI - Transthyretin Cardiac Amyloidosis in Older Americans. AB - Wild-type transthyretin cardiac amyloidosis (ATTRwt), formerly called senile cardiac amyloidosis (SCA), is almost exclusively a disorder of older adults. As the population ages, the diagnosis of ATTRwt will increase, making it the most common form of cardiac amyloidosis. An important precondition to reduce underdiagnosis and misdiagnosis is to maintain a high index of suspicion for cardiac amyloidosis. Several clues can be gleaned from the clinical history, physical exam, electrocardiography, and noninvasive imaging techniques. Nuclear scintigraphy agents using 99mTc-phosphate derivatives combined with assessment for monoclonal proteins are eliminating the need for tissue confirmation in ATTR. Morbidity and mortality from ATTRwt cardiac amyloid is high and the emergence of numerous therapies based on a biologic understanding of the pathophysiology of this condition, including drugs to inhibit the synthesis of TTR, stabilize TTR, and degrade or extract amyloid, provides new hope for those afflicted. This review briefly covers the epidemiology, pathophysiology, and clinical manifestations, as well as diagnostic strategies and treatment, of ATTR in older adults. PMID- 27769909 TI - Skilled Nursing Facility Care for Patients With Heart Failure: Can We Make It "Heart Failure Ready?" AB - Skilled nursing facilities (SNFs) have emerged as an integral component of care for older adults with heart failure (HF). Despite their prominent role, poor clinical outcomes for the medically complex patients with HF managed in SNFs are common. Barriers to providing quality care include poor transitional care during hospital-to-SNF and SNF-to-community discharges, lack of HF training among SNF staff, and a lack of a standardized care process among SNF facilities. Although no evidence-based practice standards have been established, various measures and tools designed to improve HF management in SNFs are being investigated. In this review, we discuss the challenges of HF care in SNFs as well as potential targets and recommendations that can help improve care with respect to transitions, HF management within SNFs, and modifiable factors within facilities. Policy considerations that might help catalyze improvements in SNF-based HF management are also discussed. PMID- 27769910 TI - Is complex allometry in field metabolic rates of mammals a statistical artifact? AB - Recent reports indicate that field metabolic rates (FMRs) of mammals conform to a pattern of complex allometry in which the exponent in a simple, two-parameter power equation increases steadily as a dependent function of body mass. The reports were based, however, on indirect analyses performed on logarithmic transformations of the original data. I re-examined values for FMR and body mass for 114 species of mammal by the conventional approach to allometric analysis (to illustrate why the approach is unreliable) and by linear and nonlinear regression on untransformed variables (to illustrate the power and versatility of newer analytical methods). The best of the regression models fitted directly to untransformed observations is a three-parameter power equation with multiplicative, lognormal, heteroscedastic error and an allometric exponent of 0.82. The mean function is a good fit to data in graphical display. The significant intercept in the model may simply have gone undetected in prior analyses because conventional allometry assumes implicitly that the intercept is zero; or the intercept may be a spurious finding resulting from bias introduced by the haphazard sampling that underlies "exploratory" analyses like the one reported here. The aforementioned issues can be resolved only by gathering new data specifically intended to address the question of scaling of FMR with body mass in mammals. However, there is no support for the concept of complex allometry in the relationship between FMR and body size in mammals. PMID- 27769911 TI - Calcium-induced apoptosis of developing cerebellar granule neurons depends causally on NGFI-B. AB - Immediate early gene nerve growth factor-induced clone B (NGFI-B), a nuclear receptor important for differentiation and apoptosis, is expressed in mice and rat cerebellum from an early stage of postnatal development. Following apoptotic stimuli NGFI-B translocates to mitochondria to initiate cell death processes. Controlled cell death is critical for correct cerebellar development. Immunohistochemical analysis of NGFI-B in sections of mice cerebella showed NGFI B to be expressed in granule neurons in vivo at a time (P8-11) when apoptosis is known to occur. The importance of NGFI-B for apoptosis of cultured rat cerebellar granule neurons was investigated by inducing apoptosis with calcium ionophore A23187 (CaI, 0.1MUM). Imaging studies of gfp-tagged NGFI-B confirmed that mitochondrial translocation of NGFI-B occurred following treatment with CaI and was reduced by addition of 9-cis-retinoic acid (1MUM), a retinoid X receptor (RXR) agonist that prevents dimerization of RXR and NGFI-B that is known to occur before translocation. Consequently, 9-cis-retinoic acid partly reduced cell death. To address the causality of NGFI-B in apoptosis further, knock-down by siRNA was performed and it removed 85% of the NGFI-B protein. This resulted in a complete inhibition of apoptosis after CaI exposure. Together these findings suggest that NGFI-B plays a role in controlling correct cerebellar development. PMID- 27769912 TI - Expression of fibrosis-related molecules in the oral mucosa of six animal species: A reference for selecting animal models. AB - Several animal models have been used in studies associated with oral submucous fibrosis (OSF); however, an appropriate model based on the histopathological characteristics of OSF is still needed. This study aimed to provide histological references for selecting a potential model. The expression intensities of collagen type I (Col I), type III (Col III), type IV (Col IV), fibronectin (FN), transforming growth factors beta (TGF-beta), and connective tissue growth factor (CCN2) in the oral mucosa of the human and six non-human animal species were measured by immunohistochemistry. There was little variation in the expression intensity of Col I while the expression of Col III, Col IV, and FN showed differences. The expression intensities of TGF-beta in dog, rat, sheep, and pig oral mucosae, and those of CCN2 in dog, minipig, rat, and buffalo oral mucosae were equivalent to the expression intensities in human mucosa. The expression of fibrosis-related molecules in the dog oral mucosa optimally mimics the human condition, suggesting its suitability with regard to histopathology as an animal model for the study of OSF. PMID- 27769913 TI - Semi-synthesis and PDT activities of a new amphiphilic chlorin derivative. AB - An amphiphilic chlorin derivative (CHL-T) was prepared from methylpheophorbide a (CHL) and 2-Amino-2-(hydroxymethyl)-1,3-propanediol (TRISMA(r)). The new chlorin was compared to other dyes (CHL and Hypericin) in relation to photophysical and photobiological activities in tumor and non-tumor cell lines. Cytotoxicity and cell death target were determined to evaluate the CHL-T efficiency, comparing to the precursor CHL and to the well-known dye hypericin (HY). All of the studied compounds exhibited absorption bands in the therapeutic window and presented a small fluorescence quantum yield compared to the reference dye (rhodamine B). CHL T was about three times more efficient on singlet oxygen generation than the others photosensitizers. The lipophilicity order of the photosensitizers was CHL>HY>CHL-T. The tumoral HeLa cells presented improved accumulation for CHL and CHL-T compared to HY. The phototoxicity presented by the CHL-T was about ten times higher than by CHL, as demonstrated by the MTT assay. CHL-T showed more cytotoxicity to tumoral cell, comparing to non-tumoral cell in short incubation time. The cell death rises proportionally with increasing PSs concentrations, mainly by necrosis. These findings suggest that CHL-T is a potential new photosensitizer for PDT. PMID- 27769914 TI - The efficacy of photodynamic and photothermal therapy on biofilm formation of Streptococcus mutans: An in vitro study. AB - BACKGROUND: The alternative antibacterial treatments of photodynamic therapy (PDT) and photothermal therapy (PTT) significantly affect microbiota inactivation. The aim of the present research was the assessment of the antimicrobial and anti-biofilm effects of PDT with toluidine blue O (TBO) and PTT with indocyanine green (ICG) on Streptococcus mutans as a cariogenic bacterium. MATERIALS AND METHODS: The S. mutans ATCC 35668 strain was treated with final concentrations of 0.1mg/mL TBO and 1mg/mL ICG with energy densities of 17.18 and 15.62J/cm2, respectively. Cell viability was evaluated after culturing and anti biofilm potential was analyzed using crystal violet assay and scanning electron microscopy. RESULTS: The number of S. mutans colony forming unit (CFU)/mL was significantly lower in the groups submitted to PDT (12.5-100MUg/mL TBO) and PTT (62.5-1000MUg/mL) compared to the control (untreated group). 0.1mg/mL TBO-PDT and 1mg/mL ICG-PTT showed stronger inhibitory effects on biofilm formation in S. mutans than other concentration levels, with a reduction of 63.87% and 67.3%, respectively. CONCLUSION: Photo-elimination by high concentrations of TBO-PDT and ICG-PTT exhibited significantly stronger inhibitory effects on biofilm formation and cell viability in S. mutans. PMID- 27769915 TI - Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming. AB - Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1alpha and ROS/HIF-1alpha signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1+/- mice after treatment with MPTP, a rodent model of Parkinson's disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1+/- DA cells to MPP+, the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1+/- mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD. PMID- 27769916 TI - Increased fibrinogen responses to psychophysiological stress predict future endothelial dysfunction implications for cardiovascular disease? AB - Stress influences the risk of cardiovascular disease. Acute mental stress can induce both low-grade inflammation and endothelial dysfunction. The relationship between inflammatory responses to stress and future endothelial function is unexplored. Knowledge on the impact of other cardiovascular risk factors, such as dyslipidaemia, on such relationships is also limited We investigated the relationship between inflammatory responses to an acute mental stress challenge and endothelial function plus the influence of dyslipidaemia on the associations. Interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha) and fibrinogen were assessed at baseline, immediately following standardized behavioural tasks and 45 min post-task in 158 participants. Blood pressure and heart rate responses were measured. Flow-mediated dilatation (FMD) was measured 3years later. Fibrinogen and IL-6 increased post-stress (p?0.001 & 0.003) but TNFalpha was unchanged (p=0.09). An independent negative association between FMD and change in fibrinogen at 45 min (beta=-0.047 p=0.016) remained after multiple adjustment (baseline fibrinogen, baseline diameter, reactive hyperaemia, age, gender and other cardiovascular risk factors). There was no association between FMD and change in IL-6 or TNFalpha. There were no differences in the responses to stress between those with and without dyslipidaemia. However, there was an interaction between the presence of dyslipidaemia and immediate change in fibrinogen with stress which was associated with FMD. Those participants with dyslipidaemia who had a greater change in fibrinogen had lower FMD. We conclude that elevated fibrinogen responses to stress are associated with future endothelial dysfunction which may reflect increased cardiovascular risk. PMID- 27769917 TI - Challenges in the Diagnosis of Urothelial Carcinoma Variants: Can Emerging Molecular Data Complement Pathology Review? AB - Urothelial carcinoma can exhibit a wide variety of histopathologic phenotypes or variant morphologies, classifications of which have recently been revised in the 2016 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. Many of these variants not only present diagnostic challenges, but also have clinical implications that affect patient prognosis and treatment strategies. This review will discuss these variant morphologies and their relationship to current understanding of the underlying biology of urothelial carcinoma and molecular classification paradigms. PMID- 27769918 TI - Extraordinarily Large Renal Cell Carcinoma With Metasynchronous Neuroendocrine Tumor of the Ileocecal Valve: A Rare Presentation of Disease. AB - A 71-year-old female presented with a large, protuberant abdominal mass, and was found to have both a left renal mass and a biopsy-proven neuroendocrine tumor of the ileocecal valve. Ultimately, right hemicolectomy revealed a well differentiated and low-grade neuroendocrine tumor of the ileocecal valve, whereas left radical nephrectomy revealed a 23 cm * 22 cm * 15 cm renal cell carcinoma, chromophobe-type (RCC-CT) weighing 3564 g. RCC-CT represents a small portion of diagnosed RCC, and generally portends a more favorable prognosis than other variants. Modern reports of renal tumors exceeding 20 cm are exceedingly rare. In spite of massive size, favorable histology may allow for surgical cure. PMID- 27769920 TI - Allopurinol attenuates rhabdomyolysis-associated acute kidney injury: Renal and muscular protection. AB - BACKGROUND: Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI. METHODS: Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol. RESULTS: Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF2a (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade. CONCLUSIONS: Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication. PMID- 27769919 TI - Preoperative Levels of Catecholamines and Metanephrines and Intraoperative Hemodynamics of Patients Undergoing Pheochromocytoma and Paraganglioma Resection. AB - OBJECTIVE: To determine whether, despite pharmacologic adrenergic receptor blockade, higher preoperative levels of catecholamines and metanephrines (adrenergic activity) are associated with increased intraoperative complications. MATERIALS AND METHODS: Records of patients undergoing paraganglioma and pheochromocytoma (PGL-PCC) resection from January 1, 2000, to June 30, 2015, were reviewed for preoperative levels of adrenergic activity, intraoperative variability in blood pressure and heart rate (range), and postoperative outcomes (hypotension requiring treatment). Patients were categorized by maximum preoperative adrenergic activity by greater degree of abnormality, categorized as normal (<=100%) or 101%-200%, 201%-500%, 501%-1000%, and >=1001% of upper limit of normal. RESULTS: In total, 258 patients underwent intrathoracic or intra abdominal PGL-PCC resection, of whom 240 received pretreatment with nonselective alpha1,2-blockers and 7 received pretreatment with selective alpha1-blockers. Intraoperative hemodynamic variability was greater with higher preoperative levels of adrenergic activity (P <.001). However, substantial variability was observed even with adrenergic activity levels within the normal range: systolic blood pressure (median [interquartile range], 75 [63-83] mm Hg) and heart rate (34 [26-43] beats per minute). Among patients with preoperative levels of adrenergic activity <=500% vs >=501% of the upper limit of normal, higher levels were associated with greater likelihood of postoperative diagnosis of volume overload (8% vs 2%, P = .04) and greater requirement for vasopressor infusions for hypotension (5% vs 1%, P = .01). CONCLUSION: Substantial intraoperative hemodynamic instability was encountered in patients with PGL-PCC resection, regardless of preoperative hormonal activity level; therefore, universal preoperative adrenergic receptor blockade should be recommended. Postoperative hypotension was rare and more prevalent in those with higher preoperative hormonal activity. PMID- 27769921 TI - Oral nitrite circumvents antiseptic mouthwash-induced disruption of enterosalivary circuit of nitrate and promotes nitrosation and blood pressure lowering effect. AB - The nitric oxide (NO*) metabolites nitrite and nitrate exert antihypertensive effects by mechanisms that involve gastric formation of S-nitrosothiols. However, while the use of antiseptic mouthwash (AM) is known to attenuate the responses to nitrate by disrupting its enterosalivary cycle, there is little information about whether AM attenuates the effects of orally administered nitrite. We hypothesized that the antihypertensive effects of orally administered nitrite would not be prevented by AM because, in contrast to oral nitrate, oral nitrite could promote S-nitrosothiols formation in the stomach without intereference by AM. Chronic effects of oral nitrite or nitrate were studied in two-kidney, one-clip (2K1C) hypertensive rats (and normotensive controls) treated with AM (or vehicle) once/day. We found that orally administered nitrite exerts antihypertensive effects that were not affected by AM. This finding contrasts with lack of antihypertensive responses to oral nitrate in 2K1C hypertensive rats treated with AM. Nitrite and nitrate treatments increased plasma nitrites, nitrates, and S nitrosothiols concentrations. However, while treatment with AM attenuated the increases in plasma nitrite concentrations after both nitrite and nitrate treatments, AM attenuated the increases in S-nitrosothiols in nitrate-treated rats, but not in nitrite-treated rats. Moreover, AM attenuated vascular S nitrosylation (detected by the SNO-RAC method) after nitrate, but not after nitrite treatment. Significant correlations were found between the hypotensive responses and S-nitrosothiols, and vascular S-nitrosylation levels. These results show for the first time that oral nitrite exerts antihypertensive effects notwithstanding the fact that antiseptic mouthwash disrupts the enterosalivary circulation of nitrate. Our results support a major role for S-nitrosothiols formation resulting in vascular S-nitrosylation as a key mechanism for the antihypertensive effects of both oral nitrite and nitrate. PMID- 27769922 TI - Styrene enhances the noise induced oxidative stress in the cochlea and affects differently mechanosensory and supporting cells. AB - Experimental and human investigations have raised the level of concern about the potential ototoxicity of organic solvents and their interaction with noise. The main objective of this study was to characterize the effects of the combined noise and styrene exposure on hearing focusing on the mechanism of damage on the sensorineural cells and supporting cells of the organ of Corti and neurons of the ganglion of Corti. The impact of single and combined exposures on hearing was evaluated by auditory functional testing and histological analyses of cochlear specimens. The mechanism of damage was studied by analyzing superoxide anion and lipid peroxidation expression and by computational analyses of immunofluorescence data to evaluate and compare the oxidative stress pattern in outer hair cells versus the supporting epithelial cells of the organ of Corti. The oxidative stress hypothesis was further analyzed by evaluating the protective effect of a Coenzyme Q10 analogue, the water soluble Qter, molecule known to have protective antioxidant properties against noise induced hearing loss and by the analysis of the expression of the endogenous defense enzymes. This study provides evidence of a reciprocal noise-styrene synergism based on a redox imbalance mechanism affecting, although with a different intensity of damage, the outer hair cell (OHC) sensory epithelium. Moreover, these two damaging agents address preferentially different cochlear targets: noise mainly the sensory epithelium, styrene the supporting epithelial cells. Namely, the increase pattern of lipid peroxidation in the organ of Corti matched the cell damage distribution, involving predominantly OHC layer in noise exposed cochleae and both OHC and Deiters' cell layers in the styrene or combined exposed cochleae. The antioxidant treatment reduced the lipid peroxidation increase, potentiated the endogenous antioxidant defense system at OHC level in both exposures but it failed to ameliorate the oxidative imbalance and cell death of Deiters' cells in the styrene and combined exposures. Current antioxidant therapeutic approaches to preventing sensory loss focus on hair cells alone. It remains to be seen whether targeting supporting cells, in addition to hair cells, might be an effective approach to protecting exposed subjects. PMID- 27769923 TI - Electric fish genomics: Progress, prospects, and new tools for neuroethology. AB - Electric fish have served as a model system in biology since the 18th century, providing deep insight into the nature of bioelectrogenesis, the molecular structure of the synapse, and brain circuitry underlying complex behavior. Neuroethologists have collected extensive phenotypic data that span biological levels of analysis from molecules to ecosystems. This phenotypic data, together with genomic resources obtained over the past decades, have motivated new and exciting hypotheses that position the weakly electric fish model to address fundamental 21st century biological questions. This review article considers the molecular data collected for weakly electric fish over the past three decades, and the insights that data of this nature has motivated. For readers relatively new to molecular genetics techniques, we also provide a table of terminology aimed at clarifying the numerous acronyms and techniques that accompany this field. Next, we pose a research agenda for expanding genomic resources for electric fish research over the next 10years. We conclude by considering some of the exciting research prospects for neuroethology that electric fish genomics may offer over the coming decades, if the electric fish community is successful in these endeavors. PMID- 27769924 TI - Evolution of electric communication signals in the South American ghost knifefishes (Gymnotiformes: Apteronotidae): A phylogenetic comparative study using a sequence-based phylogeny. AB - The electric communication signals of weakly electric ghost knifefishes (Gymnotiformes: Apteronotidae) provide a valuable model system for understanding the evolution and physiology of behavior. Apteronotids produce continuous wave type electric organ discharges (EODs) that are used for electrolocation and communication. The frequency and waveform of EODs, as well as the structure of transient EOD modulations (chirps), vary substantially across species. Understanding how these signals have evolved, however, has been hampered by the lack of a well-supported phylogeny for this family. We constructed a molecular phylogeny for the Apteronotidae by using sequence data from three genes (cytochrome c oxidase subunit 1, recombination activating gene 2, and cytochrome oxidase B) in 32 species representing 13 apteronotid genera. This phylogeny and an extensive database of apteronotid signals allowed us to examine signal evolution by using ancestral state reconstruction (ASR) and phylogenetic generalized least squares (PGLS) models. Our molecular phylogeny largely agrees with another recent sequence-based phylogeny and identified five robust apteronotid clades: (i) Sternarchorhamphus+Orthosternarchus, (ii) Adontosternarchus, (iii) Apteronotus+Parapteronotus, (iv) Sternarchorhynchus, and (v) a large clade including Porotergus, 'Apteronotus', Compsaraia, Sternarchogiton, Sternarchella, and Magosternarchus. We analyzed novel chirp recordings from two apteronotid species (Orthosternarchus tamandua and Sternarchorhynchus mormyrus), and combined data from these species with that from previously recorded species in our phylogenetic analyses. Some signal parameters in O. tamandua were plesiomorphic (e.g., low frequency EODs and chirps with little frequency modulation that nevertheless interrupt the EOD), suggesting that ultra-high frequency EODs and "big" chirps evolved after apteronotids diverged from other gymnotiforms. In contrast to previous studies, our PGLS analyses using the new phylogeny indicated the presence of phylogenetic signals in the relationships between some EOD and chirp parameters. The ASR demonstrated that most EOD and chirp parameters are evolutionarily labile and have often diversified even among closely related species. PMID- 27769925 TI - Lugol's iodine in Graves' disease - Revisited. PMID- 27769926 TI - Molecular investigation on the interaction of spermine with proteinase K by multispectroscopic techniques and molecular simulation studies. AB - The alteration in structure, function and stability of proteinase K in the presence of spermine was investigated using spectroscopic methods and simulation techniques. The stability and enzyme activity of proteinase K-spermine complex were significantly enhanced as compared to that of the pure enzyme. The increase in the value of Vmax and the catalytic efficiency of Proteinase K in presence of spermine confirmed that the polyamine could bring the enzyme hyperactivation. UV vis spectroscopy, intrinsic fluorescence and circular dichroism methods demonstrated that the binding of spermine changed the microenvironment and structure of proteinase K. The fluorescence studies, showing that spermine quenched the intensity of proteinase K with static mechanism. Thermodynamic parameters analysis suggested that hydrogen bond and van der Waals forces play a key role in complex stability which is in agreement with modeling studies. The CD spectra represented the secondary structure alteration of proteinase K with an increase in alpha-helicity and a decrease in beta-sheet of proteinase K upon spermine conjugation. The molecular simulation results proposed that spermine could interact with proteinase K spontaneously at single binding site, which is in agreement with spectroscopic results. This agreement between experimental and theoretical results may be a worth method for protein-ligand complex studies. PMID- 27769927 TI - Structure, molecular conformation, and immunomodulatory activity of four polysaccharide fractions from Lignosus rhinocerotis sclerotia. AB - Four polysaccharide fractions, LRP-1, LRP-2, LRP-3 and LRP-4 were extracted stepwise from Lignosus rhinocerotis sclerotia with distilled water at 25, 95, 120 degrees C and 1.0M NaOH solution at 4 degrees C. Their structure, molecular size and chain conformation were clarified using SEC-MALLS-RI, GC, FT-IR and UV-vis. Furthermore, their immunomodulatory activities were evaluated by the model of cyclophosphamide (Cy)-induced immunosuppression. The LRP-1 and LRP-2 were polysaccharide-protein complexes (46-68% beta-d-glucan and 27-48% protein), while LRP-3 and LRP-4 were absolutely composed of beta-d-glucose. The LRP-4 with low polydispersity had much higher molecular weight (Mw, 5.86*106g/mol) and intrinsic viscosity ([eta], 202.6ml/g) than other LRP fractions. Based on Mw, radius of gyration (z1/2) and [eta] data with the exponent beta of z1/2-Mw and its U-shaped curve, all four LRP fractions were highly branched macromolecules and LRP-3 showed a more compact sphere-like conformation than LRP-2 in aqueous solution. Additionally, all four LRP fractions exhibited protective effects against Cy-induced immunosuppression in mice by improving immune organs as well as stimulating the release of major cytokines TNF-alpha and INF-gamma. This work provides a theoretical basis for the application of polysaccharides and their protein complexes from Lignosus rhinocerotis sclerotia in food- or drug-based therapies. PMID- 27769928 TI - Binding studies and structure determination of the recombinantly produced type-II 3-dehydroquinate dehydratase from Acinetobacter baumannii. AB - Dehydroquinase (3-dehydroquinate dehydratase, DHQD, EC 4.2.1.10) catalyzes the conversion of dehydroquinate to dehydroshikimate. DHQD from Acinetobacter baumannii (AbDHQD) was cloned, expressed and purified to homogeneity. The binding studies showed that two compounds quinic acid and citrazinic acid bound to AbDHQD at micromolar concentrations. AbDHQD was crystallized using 30% PEG-3350, 50mM tris-HCl and 1.0M MgSO4 at pH 8.0. Crystals of AbDHQD were stabilized with 25% glycerol for data collection at 100K. The X-ray intensity data were collected to 2.0A resolution. Crystals belonged to monoclinic space group P21 with cell dimensions, a=82.3, b=95.3, c=132.3A and beta=95.7 degrees . The structure was solved with molecular replacement method and refined to values of 0.200 and 0.232 for Rcryst and Rfree factors. The structures of 12 crystallographically independent molecules in the asymmetry unit were identical with r.m.s shifts for the Calpha atoms ranging from 0.3A to 0.8A. They formed a dodecamer with four trimers arranged in a tetrahedral manner. The classical lid adopted an open conformation although a sulfate ion was observed in the substrate binding site. As a result of which, the compounds quinic acid and citrazinic acid could not bind to AbDHQD. PMID- 27769929 TI - Polyethylenimine/silk fibroin multilayers deposited nanofibrics for cell culture. AB - Scaffold with good three-dimensional (3D) structure and appropriate surface modification is essential to tissue regeneration in the treatment of tissue or organ failure. Silk fibroin (SF) is a promising scaffolding material with high biocompatibility, cytocompatibility, biodegradability and flexibility. In this study, positively charged polyethylenimine (PEI) and negatively charged SF assembled alternately onto cellulose nanofibrous substrates hydrolyzed from electrospun cellulose acetate nanofibrous mats. The obtained nanofibrous membranes modified with multiple layers of PEI/SF were characterized by field emission scanning electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy and thermogravimetric analysis. L929 cells were applied to examine the cytocompatibility of PEI/SF coated membranes. The results demonstrated that the nanofibrous membranes after modification with multiple layers of PEI/SF maintained 3D nanofibrous structure, and cells cultured on them showed good adherence and spreading on them as well, which indicated that PEI/SF coated membranes had potential application in tissue engineering. PMID- 27769930 TI - Synthesis and physico-chemical characterization of modified starches from banana (Musa AAB) and its biological activities in diabetic rats. AB - This study describes a simple method of preparation and physico-chemical properties of modified starches (type-3 resistant starches) from banana (Musa AAB), and the modified starches investigated as functional food with a beneficial effect on type-2 diabetes. RS3 was prepared using a method combined with debranching modification and physical modification; native and modifies starches were characterized by scanning electron microscope (SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and rapid visco analyzer (RVA). Use of the enzymatic and physical modification methodology, improved the yield of RS (26.62%) from Musa AAB. A reduced viscosity and swelling power; increased transition temperatures, water absorption capacity and solubility index with B-type crystalline pattern and loss of granular appearance were observed during the debranching modification and physical modification. The modified starches exhibited beneficial health effects in diabetic and HFD rats who consumed it. These results recommend that dietary feeding of RS3 was effective in the regulation of glucose and lipid profile in serum and suppressing the oxidative stress in rats under diabetic and HFD condition. This current study provides new bioactive starches, with potential applications in the food and non food industries. PMID- 27769931 TI - Development of repaglinide microspheres using novel acetylated starches of bitter and Chinese yams as polymers. AB - Tropical starches from Dioscorea dumetorum (bitter) and Dioscorea oppositifolia (Chinese) yams were acetylated with acetic anhydride in pyridine medium and utilized as polymers for the delivery of repaglinide in microsphere formulations in comparison to ethyl cellulose. Acetylated starches of bitter and Chinese yams with degrees of substitution of 2.56 and 2.70 respectively were obtained. Acetylation was confirmed by FTIR, 1H NMR spectroscopy. A 32 factorial experimental design was performed using polymer type and drug-polymer ratio as independent variables. Particle size, swelling, entrapment and time for 50% drug release (t50) were dependent variables. Contour plots showed the relationship between the independent factors and the response variables. All variables except swelling increased with drug: polymer ratio. Entrapment efficiency was generally in the rank of Bitter yam>Ethyl cellulose>Chinese yam. Repaglinide microspheres had size 50+/-4.00 to 350+/-18.10MUm, entrapment efficiency 75.30+/-3.03 to 93.10+/-2.75% and t50 3.20+/-0.42 to 7.20+/-0.55h. Bitter yam starch gave longer dissolution times than Chinese yam starch at all drug-polymer ratios. Drug release fitted Korsmeyer-Peppas and Hopfenberg models. Acetylated bitter and Chinese yam starches were found suitable as polymers to prolong release of repaglinide in microsphere formulations. PMID- 27769932 TI - Purification and characterization of chondroitinase ABC from Acinetobacter sp. C26. AB - An extracellular chondroitinase ABC (ChSase ABC, EC 4.2.2.4) produced by cultivating Acinetobacter sp. C26, was purified to homogeneity from the supernatant by ammonium sulfate fractionation, Q-Sepharose Fast Flow and Sephadex G-100 chromatography. The 76kDa enzyme was purified 48.09-fold to homogeneity with specific activity of 348.64U/mg, Using the chondroitin sulfate A (CS-A) as substrate, the maximal reaction rate (Vmax) and Michaelis-Menten constant (Km) of ChSase ABC were found to be 10.471MUmol/min/ml and 0.105mg/ml, respectively. The enzyme showed the highest activity at the optimal conditions of pH 6.0 and 42 ?C, respectively. This enzyme was stable at pH 5-10, 5-9 and 5-7 at 4 degrees C, 37 degrees C and 42 degrees C, respectively. Investigation about thermal stability of ChSase ABC displayed that it was stable at 37 degrees C. ChSase ABC activity was increased in presence of Na+, K+, Mn2+, 1,10-phenanthrolin and strongly inhibited by Cu2+, Hg2+, Al3+and SDS. These properties suggested that ChSase ABC from Acinetobacter sp. C26 bring promising prospects in medical and industry applications. PMID- 27769933 TI - The impact of germination time on the some selected parameters through malting process. AB - In the present study, the impacts of germination time on the enzymes activity attributed in malting and some polysaccharides contents of the malt prepared from the Joseph barley variety have been screened using a completely random design with three levels of germination time(3, 5 and 7days). The archived outcomes revealed that the highest quantity of starch has been observed in the malt resulted from 3days germination, and an enhancement in the germination period from 3 to 7days decreased the quantity of available starch. An enhancement in the germination period presented a reduction in the beta-glucan quantity in the malting seeds. The malt produced 7days after germination had the highest enzymatic activity(253U.kg-1). The comparison of data average using Duncan test showed that the minimum and maximum value of alpha-Amylase enzyme activity and diastatic power were recorded in the malts produced 3 and 7days after germination, respectively. Increasing in the germination time led to a reduction in malting efficiency, however the efficiency of the hot water extraction showed enhancement. The outcomes of the correlation between the studied parameters showed that the beta-glucan and starch quantities are negatively affected by the activities of beta-Glucanase and alpha-Amylase. PMID- 27769934 TI - Polyphenolic glycoconjugates from medical plants of Rosaceae/Asteraceae family protect human lymphocytes against gamma-radiation-induced damage. AB - Radioprotective effects of the water-soluble polyphenolic glycoconjugates, isolated from flowers of Sanguisorba officinalis L.(SO) and Erigeron canadensis L.(EC), and from leaves of Fragaria vesca L. (FV) and Rubus plicatus Whe. Et N. E. (RP), against gamma-radiation-induced toxicity in human peripheral blood lymphocytes were investigated. Cell treatment with glycoconjugates (1, 5 and 25MUg/mL) prior exposure to 10/15Gy radiation resulted in concentration-dependent reduction of DNA damage including oxidative DNA lesions (comet assay), substantial inhibition of lipid peroxidation (TBARS) and restoration of superoxide dismutase and S-glutathione transferase activities. Glycoconjugates isolated from SO and EC ensured better protection versus these from RP and FV, with the SO product potential comparable to that of the reference quercetin. Strong antioxidant/radioprotective activity of the SO and EC glycoconjugates could be attributed to high abundance of syringol-type and ferulic acid units in their matrices, respectively. Moreover, polyphenolic glycoconjugates (25MUg/mL), including RP and FV products, significantly decreased DNA damage when applied post-radiation suggesting their modulating effects on DNA repair pathways. Preliminary data on the glycoconjugate phenolic structural units, based on GLC/MS of the products of pyrolysis and in situ methylation, in relation to application of plant products as potential radioprotectors is promising and deserves further investigation. PMID- 27769935 TI - The matrikine N-acetylated proline-glycine-proline induces premature senescence of nucleus pulposus cells via CXCR1-dependent ROS accumulation and DNA damage and reinforces the destructive effect of these cells on homeostasis of intervertebral discs. AB - Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1. N-Ac PGP induced DNA damage and reactive oxygen species accumulation in NP cells, which resulted in activation of the p53-p21-Rb and p16-Rb pathways. Moreover, the RT2 profiler PCR array showed that N-Ac-PGP down-regulates the expression of antioxidant genes in NP cells, suggesting a decline in the antioxidants of NP cells. On the other hand, N-Ac-PGP up-regulated the expression of matrix catabolic genes and inflammatory genes in NP cells. Concomitantly, N-Ac-PGP reinforced the destructive effects of senescent NP cells on the homeostasis of the IVDs in vivo. Our study suggests that N-Ac-PGP plays critical roles in the pathogenesis of IDD through the induction of premature senescence of disc cells and via the activation of catabolic and inflammatory cascades in disc cells. N-Ac PGP also deteriorates the redox environment of disc cells. Hence, N-Ac-PGP is a new potential therapeutic target for IDD. PMID- 27769936 TI - Leucine 208 in human histamine N-methyltransferase emerges as a hotspot for protein stability rationalizing the role of the L208P variant in intellectual disability. AB - The degradation of histamine catalyzed by the SAM-dependent histamine N methyltransferase (HNMT) is critically important for the maintenance of neurological processes. Recently, two mutations in the encoding human gene were reported to give rise to dysfunctional protein variants (G60D and L208P) leading to intellectual disability. In the present study, we have expressed eight L208 variants with either apolar (L208F and L208V), polar (L208N and L208T) or charged (L208D, L208H, L208K and L208R) amino acids to define the impact of side chain variations on protein structure and function. We found that the variants L208N, L208T, L208D and L208H were severely compromised in their stability. The other four variants were obtained in lower amounts in the order wild-type HNMT>L208F=L208V>L208K=L208R. Biochemical characterization of the two variants L208F and L208V exhibited similar Michaelis-Menten parameters for SAM and histamine while the enzymatic activity was reduced to 21% and 48%, respectively. A substantial loss of enzymatic activity and binding affinity for histamine was seen for the L208K and L208R variants. Similarly the thermal stability for the latter variants was reduced by 8 and 13 degrees C, respectively. These findings demonstrate that position 208 is extremely sensitive to side chain variations and even conservative replacements affect enzymatic function. Molecular dynamics simulations showed that amino acid replacements in position 208 perturb the helical character and disrupt interactions with the adjacent beta-strand, which is involved in the binding and correct positioning of histamine. This finding rationalizes the gradual loss of enzymatic activity observed in the L208 variants. PMID- 27769937 TI - Secretome profiling of highly virulent Mycobacterium bovis 04-303 strain reveals higher abundance of virulence-associated proteins. AB - Mycobacterium bovis is the causative agent of tuberculosis in farms, wildlife and causes sporadic disease in humans. Despite the high similitude in genome sequence between M. bovis strains, some strains like the wild boar 04-303 isolate show a highly virulent phenotype in animal models. Comparative studies will contribute to link protein expression with the virulence phenotype. In vitro, the 04-303 strain was more phagocytized by J774A.1 macrophages in comparison with 444 strain (a cow isolate with the same genotype) and BCG. The secretome of these strains showed a significant proportion of shared proteins (368 spots). Among the proteins only visualized in the secretome of the 04-303 strain, we identify the nine most abundant proteins by LC-MS/MS. The most relevant were EsxA and EsxB proteins, which are encoded in the RD1 region, deleted in BCG strains. These proteins are the major virulence factor of M. tuberculosis. The other proteins identified belong to functional categories of virulence, detoxification, and adaptation; lipid metabolism; and cell wall and cell processes. The relatively high proportion of proteins involved in the cell wall and cell process is consistent with the previously described variation among M. bovis genomes. PMID- 27769938 TI - A bioactivity guided study on the antibacterial activity of Hertia cheirifolia L. extracts. AB - This study was carried out with the objective to investigate the antibacterial activity of Hertia cheirifolia L. extracts against Gram-positive and Gram negative strains including Staphylococcus aureus (ATCC 6538), Bacillus subtilis (ATCC 6633), Bacillus licheniformis, Esherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), Salmonella enterica (CIP 8039) and Salmonella typhimirium. The results of this antibacterial screening showed that the ethyl acetate (EtOAc) extracts had the best activity against the tested microorganisms. A bioassay-oriented fractionation approach for the more active extract (roots ethyl acetate extract) led to the obtaining five sub-fractions. Furthermore, these sub-fractions were also tested for antimicrobial activity and the best results were obtained for the roots EtOAc sub-fraction (C) with MICs values between 0.039 and 0.156 mg/mL. Reversed-phase high performance liquid chromatography (RP-HPLC) analysis indicated that the major phenolic components of active (EtOAc) extracts and sub-fraction (C) are fisetin hydrate (82.06%), trans cinnamic acid (63.66%), gallic acid (38.97%) and myricetin (20.92%). These results may help to improve these natural antibacterial substances that could serve as selective agents for bacterial diseases. PMID- 27769940 TI - Human-derived extracellular matrix from Wharton's jelly: An untapped substrate to build up a standardized and homogeneous coating for vascular engineering. AB - : One of the outstanding goals in tissue engineering is to develop a natural coating surface which is easy to manipulate, effective for cell adhesion and fully biocompatible. The ideal surface would be derived from human tissue, perfectly controllable, and pathogen-free, thereby satisfying all of the standards of the health authorities. This paper reports an innovative approach to coating surfaces using a natural extracellular matrix (ECM) extracted from the Wharton's jelly (WJ) of the umbilical cord (referred to as WJ-ECM). We have shown by atomic force microscopy (AFM), that the deposition of WJ-ECM on surfaces is homogenous with a controllable thickness, and that this easily-prepared coating is appropriate for both the adhesion and proliferation of human mesenchymal stem cells and mature endothelial cells. Furthermore, under physiological shear stress conditions, a larger number of cells remained adhered to WJ-ECM than to a conventional coating such as collagen - a result supported by the higher expression of both integrins alpha2 and beta1 in cells cultured on WJ-ECM. Our data clearly show that Wharton's jelly is a highly promising coating for the design of human biocompatible surfaces in tissue engineering as well as in regenerative medicine. STATEMENT OF SIGNIFICANCE: Discovery and design of biomaterial surface are a hot spot in the tissue engineering field. Natural matrix is preferred to mimic native cell microenvironment but its use is limited due to poor resource availability. Moreover, current studies often use single or several components of natural polymers, which is not the case in human body. This paper reports a natural extracellular matrix with full components derived from healthy human tissue: Wharton's jelly of umbilical cord. Reconstituting this matrix as a culture surface, our easily-prepared coating provides superior biocompatibility for stem and mature cells. Furthermore, we observed improved cell performance on this coating under both static and dynamic condition. This novel human derived ECM would be a promising choice for regenerative medicine. PMID- 27769939 TI - Immunopurification and Mass Spectrometry Identifies Protein Phosphatase 2A (PP2A) and BIN2/GSK3 as Regulators of AKS Transcription Factors in Arabidopsis. PMID- 27769941 TI - Enzyme-mediated stiffening hydrogels for probing activation of pancreatic stellate cells. AB - : The complex network of biochemical and biophysical cues in the pancreatic desmoplasia not only presents challenges to the fundamental understanding of tumor progression, but also hinders the development of therapeutic strategies against pancreatic cancer. Residing in the desmoplasia, pancreatic stellate cells (PSCs) are the major stromal cells affecting the growth and metastasis of pancreatic cancer cells by means of paracrine effects and extracellular matrix protein deposition. PSCs remain in a quiescent/dormant state until they are 'activated' by various environmental cues. While the mechanisms of PSC activation are increasingly being described in literature, the influence of matrix stiffness on PSC activation is largely unexplored. To test the hypothesis that matrix stiffness affects myofibroblastic activation of PSCs, we have prepared cell-laden hydrogels capable of being dynamically stiffened through an enzymatic reaction. The stiffening of the microenvironment was created by using a peptide linker with additional tyrosine residues, which were susceptible to tyrosinase-mediated crosslinking. Tyrosinase catalyzes the oxidation of tyrosine into dihydroxyphenylalanine (DOPA), DOPA quinone, and finally into DOPA dimer. The formation of DOPA dimer led to additional crosslinks and thus stiffening the cell laden hydrogel. In addition to systematically studying the various parameters relevant to the enzymatic reaction and hydrogel stiffening, we also designed experiments to probe the influence of dynamic matrix stiffening on cell fate. Protease-sensitive peptides were used to crosslink hydrogels, whereas integrin binding ligands (e.g., RGD motif) were immobilized in the network to afford cell matrix interaction. PSC-laden hydrogels were placed in media containing tyrosinase for 6h to achieve in situ gel stiffening. We found that PSCs encapsulated and cultured in a stiffened matrix expressed higher levels of alphaSMA and hypoxia-inducible factor 1alpha (HIF-1alpha), suggestive of a myofibroblastic phenotype. This hydrogel platform offers a facile means of in situ stiffening of cell-laden matrices and should be valuable for probing cell fate process dictated by dynamic matrix stiffness. STATEMENT OF SIGNIFICANCE: Hydrogels with spatial-temporal controls over crosslinking kinetics (i.e., dynamic hydrogel) are increasingly being developed for studying mechanobiology in 3D. The general principle of designing dynamic hydrogel is to perform cell encapsulation within a hydrogel network that allows for postgelation modification in gel crosslinking density. The enzyme-mediated in situ gel stiffening is innovative because of the specificity and efficiency of enzymatic reaction. Although tyrosinase has been used for hydrogel crosslinking and in situ cell encapsulation, to the best of our knowledge tyrosinase-mediated DOPA formation has not been explored for in situ stiffening of cell-laden hydrogels. Furthermore, the current work provides a gradual matrix stiffening strategy that may more closely mimic the process of tumor development. PMID- 27769942 TI - Carbon nanotube-composite hydrogels promote intercalated disc assembly in engineered cardiac tissues through beta1-integrin mediated FAK and RhoA pathway. AB - : Carbon nanotube (CNT)-based hydrogels have been shown to support cardiomyocyte growth and function. However, their role in cellular integrity among cardiomyocytes has not been studied in detail and the mechanisms underlying this process remain unclear. Here, single walled CNTs incorporated into gelatin with methacrylate anhydride (CNT/GelMA) hydrogels were utilized to construct cardiac tissues, which enhanced cardiomyocyte adhesion and maturation. Furthermore, through the use of immunohistochemical staining, transmission electron microscopy and intracellular calcium transient measurement, the incorporation of CNTs into the scaffolds was observed to markedly enhance the assembly and formation in the cardiac constructs. Importantly, we further explored the underlying mechanism behind these effects through the use of immunohistochemical staining and western blotting. The beta1-integrin-mediated FAK and RhoA signaling pathways were found to be responsible for CNT-induced upregulation of electrical and mechanical junction proteins respectively. Together, our study provides new insights into the facilitative effects of CNTs on ID formation, which has important significance for improving the quality of engineered cardiac tissue and applying them to cardiac regenerative therapies. STATEMENT OF SIGNIFICANCE: Currently, the bottleneck to engineering cardiac tissues (ECTs) for cardiac regeneration is the lack of efficient cellular integrity among adjacent cells, especially the insufficient remodeling of intercalated discs (IDs) in ECTs. Recently, carbon nanotube (CNT) hydrogels provide an advantageous supporting microenvironment and therefore benefit greatly the functional performance of ECTs. Although their beneficial effect in modulating ECT performance is evident, the influence of CNTs on structural integrity of ECTs has not been studied in detail, and the mechanisms underlying the process remain to be determined. Here, we utilized carbon nanotube incorporated into gelatin with methacrylate anhydride (CNT/GelMA) hydrogels to construct cardiac tissues, determined the influence of CNTs on intercalated discs (IDs) assembly and formation and explored the underlying mechanisms. PMID- 27769944 TI - Functional improvement of hemostatic dressing by addition of recombinant batroxobin. AB - : Although a number of natural materials have been used as hemostatic agents, many substances do not act quickly enough. Here, we created a novel dressings using collagen and chitosan with recombinant batroxobin (r-Bat) to promote faster and more effective hemostasis. We hypothesized that r-Bat would promote synergetic blood coagulation because it contains a blood coagulation active site different than those of collagen and chitosan. Our results suggest that each substances can maintain hemostatic properties while in the mixed dressings and that our novel hemostatic dressings promotes potent control of bleeding, as demonstrated by a whole blood assay and rat hemorrhage model. In a rat femoral artery model, the scaffold with a high r-Bat concentration more rapidly controlled excessive bleeding. This novel dressings has enormous possible for rapidly controlling bleeding and it improves upon the effect of collagen and chitosan used alone. Our novel r-Bat dressings is a possible candidate for improving preoperative care and displays promising properties as an absorbable agent in hemostasis. STATEMENT OF SIGNIFICANCE: Despite the excellent hemostatic properties of collagen and chitosan pads, they reported to brittle behavior and lack sufficient hemostatic effect within relevant time. Therefore, we created a novel pad using collagen and chitosan with recombinant batroxobin (r-Bat). r-Bat acts as a thrombin-like enzyme in the coagulation cascade. Specifically, r-Bat, in contrast to thrombin, only splits fibrinopeptide A off and does not influence other hemostatic factors or cells, which makes it clinically useful as a stable hemostatic agent. Also the materials in the pad have synergetic effect because they have different hemostatic mechanisms in the coagulation cascade. This report propose the novel hemostatic pad isreasonable that a great potential for excessive bleeding injury and improve effects of natural substance hemostatic pad. PMID- 27769943 TI - Mucoadhesive chitosan hydrogels as rectal drug delivery vessels to treat ulcerative colitis. AB - : Mucoadhesive drug delivery systems stick to mucosal tissues and prolong the local retention time of drugs. Since the colon is covered by a mucosal layer, mucoadhesive rectal formulations may improve treatment of such diseases as hypertension or colon cancer. Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation of the colonic mucosa. It is commonly treated with sulfasalazine (SSZ), which is metabolized by the intestinal flora into the therapeutic 5-aminosalicylic acid (5-ASA) and a toxic by-product sulfapyridine (SP). SSZ can be administered orally or rectally. The latter route avoids unintended absorption of the drug or its degradation products in the upper gastrointestinal tract, but often fails due to limited retention time. Here, we propose a mucoadhesive hydrogel to improve the efficacy of rectal SSZ administration. The gel is made of catechol modified-chitosan (Cat-CS) crosslinked by genipin. After loading the gel with SSZ, we evaluated its efficacy in a mouse model of UC. Compared to oral SSZ treatment, rectal SSZ/Cat-CS delivery was more therapeutic, showed equivalent histological scores, and induced a lower plasma concentration of the potentially toxic SP by-product. These results show SSZ/Cat-CS rectal hydrogels are more effective and safer formulations for UC treatment than oral SSZ. STATEMENT OF SIGNIFICANCE: Ulcerative colitis affects the colon by causing chronic inflammation on the mucosa. One of the most common drugs to treat mild to moderate UC is sulfasalazine, which can be administrated both orally and rectally. Rectal formulations are preferable, since their therapeutic effect happens topically, and they prevent side effects related to absorption of the drug in the small intestine. However, the efficacy of rectal sulfasalazine formulations is decreased by their limited colon residence time. Here we propose a chitosan catechol mucoadhesive gel that allows delivering sulfasalazine more effectively and safely than oral administration. Our results bring new insights into the field of mussel-inspired catechol hydrogels, showing their potential as drug delivery systems to treat a widespread disease such as ulcerative colitis. PMID- 27769945 TI - Akt activation by Evodiae Fructus extract protects ovary against 4 vinylcyclohexene diepoxide-induced ovotoxicity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Evodiae Fructus (EF) is the dried, unripe fruit of Evodia rutaecarpa Benth., and one of the main components of traditional herbal prescriptions issued for the treatment of sterility caused by irregular menstruation in Korea. However, scientific evidence regarding the efficacy and action mechanism of EF is lacking. AIM OF THE STUDY: In this study, the authors established an in vitro screening tool to identify promising new drug candidates in herbal medicines for the prevention and treatment of premature ovarian failure. The protective effects of EF extracts against 4-vinylcyclohexene diepoxide (VCD)-induced ovotoxicity were investigated and the molecular mechanism responsible was sought. MATERIAL AND METHODS: EF extract was prepared by boiling EF in water and its quality was confirmed by high performance liquid chromatography. CHO-K1 (Chinese hamster ovary cells) and COV434 (human ovarian granulosa cells) cells were plated, pretreated with EF extract for 2h and then treated with 1.5mM or 0.5mM VCD for 24h, respectively. Cell viabilities were measured using an MTT assay, and protein levels were determined by western blotting. RESULTS: VCD significantly suppressed the viability of both CHO-K1 and COV434 cells in a dose-dependent manner and induced the apoptosis of CHO-K1 cells at 1.5mM. EF extract dose-dependently blocked the ovotoxicity induced by treatment with VCD. Furthermore, EF extract significantly activated Akt and downstream effectors such as mTOR and GSK-3beta in CHO-K1 cells. The ability of EF extract to prevent cytotoxicity by VCD was antagonized by pretreatment of LY294002, a PI3K/Akt inhibitor. CONCLUSION: EF has the ability to protect ovary cells against VCD-induced ovotoxicity, probably via Akt activation. These results suggest that the beneficial effects of EF might be useful for preventing premature ovarian failure or unexplained infertility caused by environmental factors. PMID- 27769946 TI - New antibacterial hydrophobic assay reveals Abies balsamea oleoresin activity against Staphylococcus aureus and MRSA. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Oleoresin of Abies balsamea (L.) Mill. was used by Native Americans of the boreal forest of Canada and French Canadians to treat various infections, suggesting that oleoresin has antibacterial properties. AIM OF THE STUDY: In this study, the antibacterial activity of whole oleoresin from A. balsamea was investigated against E. coli, S. aureus and two methicillin resistant S. aureus (MRSA) strains using a new sensitive assay developed to evaluate hydrophobic matrix and compounds. MATERIALS AND METHODS: Antibacterial activity of oleoresin was first investigated using dilution and disk diffusion methods against E. coli and S. aureus, and compared to a new sensitive assay for hydrophobic matrix. Moreover, whole oleoresin was analyzed by GC-MS to characterize the composition and to identify the compounds responsible of the antibacterial activity. RESULTS: The results showed that whole oleoresin was inactive against Gram-negative E. coli (MIC90 >90ug/ml) but active against Gram positive S. aureus and MRSA with MIC90 ranging from 18.2 to 30ug/ml. The oleoresin is mainly composed of monoterpene (28%), sesquiterpenes (2%), and diterpenes (45%). Resin acids were found, in part, responsible for the antibacterial activity of whole oleoresin. Isopimaric acid and levopimaric acid are the most active with a MIC90 of respectively 9.7ug/ml and 10ug/ml. CONCLUSION: This study supports the use of oleoresin of A. balsamea by the Native Americans and French Canadians to treat bacterial infections due to S. aureus. PMID- 27769947 TI - Chemical composition, antibacterial activity and related mechanism of the essential oil from the leaves of Juniperus rigida Sieb. et Zucc against Klebsiella pneumoniae. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Juniperus rigida is used as Tibetan and Mongolian medicine in China for the treatment of rheumatoid arthritis, nephritis, brucellosis and other various inflammatory diseases. AIM OF THE STUDY: To evaluate antibacterial potential of essential oils from J. rigida leaves against Klebsiella pneumoniae and to examine its possible related mechanisms. The study was undertaken in order to scientifically validate the traditional use of J. rigida. MATERIALS AND METHODS: The essential oil was extracted from the leaves of J. rigida by supercritical CO2 fluid extraction technology. Chemical composition of essential oils was analyzed by gas chromatography-mass spectrometry (GC-MS). The antibacterial activity was evaluated against 10 bacteria by the paper disc diffusion method. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of the essential oil were estimated by agar dilution method. The antibacterial mechanism was evaluated by growth curve, the integrity of cell membrane, the SDS-PAGE of protein patterns and scanning electron microscope (SEM). RESULTS: 61 components were identified from the essential oil. Caryophyllene (13.11%) and alpha-Caryophyllene (11.72%) were found to be the major components. The antibacterial activities of the essential oil were screened and compared against 10 bacteria. The essential oil showed good antibacterial activity against K. pneumoniae, with the biggest diameters of inhibition zones (DIZ) (16.00+/-0.25mm) and the lowest MIC and MBC values of 3.125mg/mL. The increase in proteins, 260nm absorbing materials of bacterial cells suspension indicated that the cytoplasmic membranes were broken by the essential oil. The SDS-PAGE of bacterial proteins demonstrated that the essential oil could damage bacterial cells through the destruction of cellular proteins. Scanning electron microscopy (SEM) showed that the essential oil damaged the morphology of cell wall and membrane. CONCLUSIONS: The essential oil of J. rigida has potential antibacterial activities against K. pneumoniae. The antibacterial mechanism is the essential oil causing the irreversible damage to the cell wall and membrane, leading to the leakage of proteins and 260nm absorbing materials (DNA and RNA). Further phytochemical and pharmacological studies are required for proper scientific validation of the folk use of this plant species. PMID- 27769948 TI - Protein tyrosine phosphatase 1B and alpha-glucosidase inhibitory activities of Pueraria lobata root and its constituents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pueraria lobata root was used to treat wasting thirst regarded as diabetes mellitus and was included in the composition of Okcheonsan, which is prescribed for thirst-waste in traditional Chinese medicine. AIM OF THE STUDY: The objective of this study was to evaluate the anti-diabetic potential of the root of Pueraria lobata and its constituents via protein tyrosine phosphatase 1B (PTP1B) and alpha-glucosidase inhibitory activities. MATERIALS AND METHODS: In this study, anti-diabetic activities of the 70% ethanolic (EtOH) extract from P. lobata roots and its solvent soluble fractions with the isolated compounds were investigated by evaluating in vitro PTP1B and alpha-glucosidase inhibitory activities. We also examined the potentials of active compounds as PTP1B and alpha-glucosidase inhibitors via enzyme kinetics and in silico molecular docking simulation between the enzymes and active compounds. RESULTS: Triterpenoids lupeol and lupenone were potent PTP1B inhibitors with IC50 values of 38.89+/-0.17 and 15.11+/-1.23MUM. Kinetic study using the Lineweaver-Burk and Dixon plots demonstrated that these compounds showed a noncompetitive-type inhibition against PTP1B with respective Ki values of 13.88MUM and 21.24MUM. In addition, molecular docking simulation showed lupeol and lupenone has negative binding energy values of -8.03 and -8.56kcal/mol. Considering the alpha-glucosidase inhibitory potential, daidzein, genistein, and calycosin exhibited the most potent alpha-glucosidase inhibition with IC50 values of 8.58+/-0.94, 2.37+/-0.52 and 6.84+/-1.58MUM, respectively. Kinetic study demonstrated that these 3 compounds showed a noncompetitive-type inhibition against alpha-glucosidase with respective Ki values of 17.64MUM, 5.03MUM and 13.83MUM. Moreover, molecular docking simulation showed daidzein, genistein and calycosin has more lower binding energy (-7.16kcal/mol, -7.42kcal/mol and 7.31kcal/mol) with higher binding affinity and tight binding capacity in the molecular docking studies than standard ligand alpha-D-glucose (-6.74kcal/mol). CONCLUSION: Our results of the present study clearly demonstrate the potential of P. lobata extract and its constituents to inhibit PTP1B and alpha-glucosidase, contributing to the development of therapeutic or preventive agents that can be used in the treatment of diabetes. PMID- 27769949 TI - Rathke Cleft Cyst with Entirely Ossified Cyst Wall and Partially Solid Cyst Content: A Case Report and Literature Review. AB - BACKGROUND: In Rathke cleft cysts (RCCs), inflammation by the cyst contents infrequently spreads to the surrounding structures. Calcification, which is regarded as a result of chronic inflammation of the cyst wall, can rarely be found in RCCs. Moreover, ossification is extremely rare. CASE DESCRIPTION: A 60 year-old woman experienced headaches, fatigue, and weight loss owing to pan hypopituitarism. Magnetic resonance imaging revealed a mass lesion in the sellar region, which was composed of two different parts, with hypointensity anteriorly and hyperintensity posteriorly on T1-weighted image, and the rim with significant hypointensity entirely on T2-weighted image. During the transsphenoidal surgery, the cyst wall was so rigid that it was difficult to cut and remove it. The cyst contained mucinous fluid with both old and new hemorrhages, and a yellowish, elastic hard, solid nodule. Postoperative histologic diagnosis was RCC with unusual lymphocyte infiltration, massive granulation, and mature bone formation. Six months later, the fluid in the cyst reaccumulated, and the patient complained of headaches. Removal of the entire cyst wall and the aspiration of the cyst content were performed to collapse the cyst cavity and, consequently, to prevent further recurrence. Postoperatively, panhypopituitarism was unchanged and the symptoms were treated with hormonal replacement. The cyst has not recurred for 2 years after the second surgery. CONCLUSIONS: Persistent, long-term inflammation induced by the RCC content, mucin-containing fluid, and several phases of hemorrhage presumably promoted the formation of mature bone on the cyst wall and of the elastically solid nodule within the cyst. PMID- 27769950 TI - Trepanation in Ancient China. AB - Trepanation, the process of making a burr hole in the skull to access the brain, is an ancient form of a primitive craniotomy. There is widespread evidence of contributions made to this practice by ancient civilizations in Europe, Africa, and South America, where archaeologists have unearthed thousands of trepanned skulls dating back to the Neolithic period. Little is known about trepanation in China, and it is commonly believed that the Chinese used only traditional Chinese medicine and nonsurgical methods for treating brain injuries. However, a thorough analysis of the available archeological and literary evidence reveals that trepanation was widely practiced throughout China thousands of years ago. A significant number of trepanned Chinese skulls have been unearthed showing signs of healing and suggesting that patients survived after surgery. Trepanation was likely performed for therapeutic and spiritual reasons. Medical and historical works from Chinese literature contain descriptions of primitive neurosurgical procedures, including stories of surgeons, such as the legendary Hua Tuo, and surgical techniques used for the treatment of brain pathologies. The lack of translation of Chinese reports into the English language and the lack of publications on this topic in the English language may have contributed to the misconception that ancient China was devoid of trepanation. This article summarizes the available evidence attesting to the performance of successful primitive cranial surgery in ancient China. PMID- 27769951 TI - Rapid and Minimally Traumatic Replacement of Stimulator Extension Cables: Technical Note on a Novel Use for Sternal Wire. AB - BACKGROUND: Troubleshooting of deep brain stimulators (DBSs, Activa SC/PC/RC Medtronic PLC, Minneapolis, Minnesota, USA) sometimes results in a decision to replace a tunneled stretch-coil extension cable. We present a simple technique to accomplish this atraumatically without a tunneling tool. OBJECTIVES: In the treatment of patients with a DBS, complication avoidance and efficiency of operative time are paramount. We sought to find the safest, most effective, and fastest method of performing the conceptually simple yet technically nuanced act of replacing lead extension cables. METHODS: We connected #6 (8.0 metric) surgical steel 18" (45-cm) monofilament (Ethicon US, LLC, Somerville, New Jersey, USA), also known as #6 sternal wire, in line with DBS extension cables (Medtronic DBS Extension 37086-60) in novel fashion to overcome intraprocedural hurdles encountered during the past decade in a busy functional neurosurgery service. RESULTS: Patients tolerate the procedure well and return home shortly after recovery with no complications. CONCLUSIONS: A less expensive and faster technique for passing pulse generator extension cables may be the use of a sternal wire. Using the described technique, pulse generators may be quickly and safely adjusted from side to side and site to site as the clinical situation dictates. PMID- 27769952 TI - Changes in energy metabolism due to acute rotenone-induced mitochondrial complex I dysfunction - An in vivo large animal model. AB - Metabolic crisis is a clinical condition primarily affecting patients with inherent mitochondrial dysfunction in situations of augmented energy demand. To model this, ten pigs received an infusion of rotenone, a mitochondrial complex I inhibitor, or vehicle. Clinical parameters, blood gases, continuous indirect calorimetry, in vivo muscle oxygen tension, ex vivo mitochondrial respiration and metabolomics were assessed. Rotenone induced a progressive increase in blood lactate which was paralleled by an increase in oxygen tension in venous blood and skeletal muscle. There was an initial decrease in whole body oxygen utilization, and there was a trend towards inhibited mitochondrial respiration in platelets. While levels of succinate were decreased, other intermediates of glycolysis and the TCA cycle were increased. This model may be suited for evaluating pharmaceutical interventions aimed at counteracting metabolic changes due to complex I dysfunction. PMID- 27769953 TI - Evaluating the Effect of Web-Based Iranian Diabetic Personal Health Record App on Self-Care Status and Clinical Indicators: Randomized Controlled Trial. AB - BACKGROUND: There are 4 main types of chronic or noncommunicable diseases. Of these, diabetes is one of the major therapeutic concerns globally. Moreover, Iran is among the countries with the highest incidence of diabetic patients. Furthermore, library-based studies by researchers have shown that thus far no study has been carried out to evaluate the relationship between Web-based diabetic personal health records (DPHR) and self-care indicators in Iran. OBJECTIVE: The objective of this study is to examine the effect of Web-based DPHR on self-care status of diabetic patients in an intervention group as compared with a control group. METHODS: The effect of DPHR on self-care was assessed by using a randomized controlled trial (RCT) protocol for a 2-arm parallel group with a 1:1 allocation ratio. During a 4-month trial period, the control group benefited from the routine care; the intervention group additionally had access to the Web-based DPHR app besides routine care. During the trial, 2 time points at baseline and postintervention were used to evaluate the impact of the DPHR app. A sample size of 72 people was randomly and equally assigned to both the control and intervention groups. The primary outcome measure was the self-care status of the participants. RESULTS: Test results showed that the self-care status in the intervention group in comparison with the control group had a significant difference. In addition, the dimensions of self-care, including normal values, changes trend, the last measured value, and the last time measured values had a significant difference while other dimensions had no significant difference. Furthermore, we found no correlation between Web-based DPHR system and covariates, including scores of weight, glycated hemoglobin (HbA1c), serum creatinine, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and planned visit adherence, as well as the change trend of mean for blood glucose and blood pressure. CONCLUSIONS: We found that as a result of the Web-based DPHR app, the self-care scores in the intervention group were significantly higher than those of the control group. In total, we found no correlation between the Web-based DPHR app and covariates, including planned visit adherence, HbA1c, serum creatinine, HDL, LDL, total cholesterol, weight, and the change trend of mean for blood glucose and blood pressure. CLINICALTRIAL: Iranian Registry of Clinical Trials (IRCT): 2013082914522N1; http://www.irct.ir/searchresult.php?id= 14522&number=1 (Archived by WebCite at http://www.webcitation.org/6cC4PCcau). PMID- 27769954 TI - Online Health Information Regarding Male Infertility: An Evaluation of Readability, Suitability, and Quality. AB - BACKGROUND: Many men lack knowledge about male infertility, and this may have consequences for their reproductive and general health. Men may prefer to seek health information online, but these sources of information vary in quality. OBJECTIVE: The objective of this study is to determine if online sources of information regarding male infertility are readable, suitable, and of appropriate quality for Internet users in the general population. METHODS: This study used a cross-sectional design to evaluate online sources resulting from search engine queries. The following categories of websites were considered: (1) Canadian fertility clinics, (2) North American organizations related to fertility, and (3) the first 20 results of Google searches using the terms "male infertility" and "male fertility preservation" set to the search locations worldwide, English Canada, and French Canada. Websites that met inclusion criteria (N=85) were assessed using readability indices, the Suitability Assessment of Materials (SAM), and the DISCERN tool. The associations between website affiliation (government, university/medical, non-profit organization, commercial/corporate, private practice) and Google placement to readability, suitability, and quality were also examined. RESULTS: None of the sampled websites met recommended levels of readability. Across all websites, the mean SAM score for suitability was 45.37% (SD 11.21), or "adequate", while the DISCERN mean score for quality was 43.19 (SD 10.46) or "fair". Websites that placed higher in Google obtained a higher overall score for quality with an r (58) value of -.328 and a P value of .012, but this position was not related to readability or suitability. In addition, 20% of fertility clinic websites did not include fertility information for men. CONCLUSIONS: There is a lack of high quality online sources of information on male fertility. Many websites target their information to women, or fail to meet established readability criteria for the general population. Since men may prefer to seek health information online, it is important that health care professionals develop high quality sources of information on male fertility for the general population. PMID- 27769955 TI - Do Web-Based Interventions Improve Well-Being in Type 2 Diabetes? A Systematic Review and Meta-Analysis. AB - BACKGROUND: Poor diabetes self-care can have a negative impact on psychological well-being and quality of life. Given the scarcity of traditional psychological support and the barriers to uptake of and attendance at face-to-face education programs, Web-based interventions are becoming a popular approach to provide an additional platform for psychological support in long-term conditions. However, there is limited evidence to assess the effect of Web-based psychological support in people with type 2 diabetes. OBJECTIVE: This systematic review is the first review to critically appraise and quantify the evidence on the effect of Web based interventions that aim to improve well-being in people with type 2 diabetes. METHODS: Searches were carried out in the following electronic databases: MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Library. Reference lists were hand-searched. A meta-analysis was conducted for depression and distress outcomes. RESULTS: A total of 16 randomized controlled studies met the inclusion criteria for the systematic review and 9 were included in the meta analyses. Theories were applied to the majority of the interventions. The most common behavior change techniques were "General information" and "Tracking/monitoring." Interventions with a duration of 2-6 months providing professional-led support with asynchronous and synchronous communication appeared to be associated with significant well-being outcomes. The pooled mean (95% confidence interval) difference between the intervention and control arms at follow-up on depression score was -0.31 (-0.73 to 0.11). The pooled mean difference on distress scores at follow-up was -0.11 (-0.38 to 0.16). No significant improvements in depression (P=.15) or distress (P=.43) were found following meta-analyses. CONCLUSIONS: While the meta-analyses demonstrated nonsignificant results for depression and distress scores, this review has shown that there is a potential for Web-based interventions to improve well-being outcomes in type 2 diabetes. Further research is required to confirm the findings of this review. PMID- 27769956 TI - Data-Driven Iterative Refinement of Bone Marrow Testing Protocols Leads to Progressive Improvement in Cytogenetic and Molecular Test Utilization. AB - Objectives: To determine the effect of iterative refinement of standard ordering protocols on test utilization and results for bone marrow biopsy specimens. Methods: Eighteen months of test utilization and result data were used to revise the protocols that determine cytogenetic and molecular test selection on bone marrow specimens and then compared with data obtained following protocol revision. Results: Revision of protocols resulted in reduction in total tests and associated charges, due to a decrease in tests both concordant and discordant with the protocols. These reductions only occurred in diseases for which revisions were made and were limited to cases in which reflex testing was performed. There was an increase in the fraction of positive tests, which was also limited to reflex testing. Conclusions: Data-driven iterative revision of protocols further improves test utilization and performance, while reducing cost. Analysis of testing data can be used to continuously improve test ordering decisions. PMID- 27769957 TI - Atorvastatin enhances endothelial cell function in posttransplant poor graft function. AB - Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Murine studies suggest that endothelial progenitor cells (EPCs) are preferential supporting cells for hematopoietic stem cells in the bone marrow (BM) microenvironment. Our previous work found that a reduced number of BM EPCs was an independent risk factor for the occurrence of PGF after allo-HSCT. However, little is known about the functional role of BM EPCs and how to improve impaired BM EPCs in PGF. In the current study, we evaluated the function of BM EPCs in subjects with PGF postallotransplant. Moreover, we investigated whether atorvastatin could enhance the number and function of BM EPCs derived from subjects with PGF in vitro. Dysfunctional BM EPCs, which were characterized by impaired proliferation, migration, angiogenesis, and higher levels of reactive oxygen species and apoptosis, were revealed in subjects with PGF. Activation of p38 and its downstream transcription factor cyclic adenosine monophosphate-responsive element binding protein were detected in BM EPCs from subjects with PGF. Furthermore, the number and function of BM EPCs derived from subjects with PGF were enhanced by atorvastatin treatment in vitro through downregulation of the p38 MAPK pathway. In summary, dysfunctional BM EPCs were observed in subjects with PGF. Atorvastatin treatment in vitro quantitatively and functionally improved BM EPCs derived from subjects with PGF through downregulation of the p38 MAPK pathway. These data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in subjects with PGF postallotransplant. PMID- 27769958 TI - Age-related effects on osteoclastic activities after orthodontic tooth movement. AB - OBJECTIVES: To elucidate the effects of age on the expression levels of the receptor activator of the nuclear factor-kappaB ligand (RANKL) and osteoclasts in the periodontal ligament during orthodontic mechanical loading and post orthodontic retention. MATERIALS AND METHODS: The study included 20 male Sprague Dawley rats, ten in the young group (aged four to five weeks) and ten in the adult group (aged 18 to 20 weeks). In each rat, the upper-left first molar was subjected to a seven-day orthodontic force loading followed by a seven-day retention period. The upper-right first molar served as a control. The amount of orthodontic tooth movement was measured after seven-day force application and seven-day post-orthodontic retention. The expression levels of RANKL and the tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts were evaluated on day 7 (end of mechanical force loading) and day 14 (after seven days of post orthodontic retention). Statistical analysis was performed using the t-test, and significance was set at p < 0.05. RESULTS: There was no significant difference between the amount of tooth movement in the young group (0.96, standard deviation (sd) 0.30mm) and that in the adult group (0.80mm, sd 0.28) (p > 0.05) after the seven-day force application. On the compression side, the expression of RANKL and TRAP-positive osteoclasts in both the young and the adult groups increased after the application of force for seven days, and then decreased at the end of the seven-day retention period. However, by the end of the period, the expression of RANKL on the compression side dropped to the control level in the young group (p > 0.05), while it was still higher than that on the control side in the adult group (p < 0.05). The expression of RANKL on the compression side did not show significant difference between the young and the adult groups after seven-day force application (p > 0.05), but it was significantly higher in the adult group than that in the young group after seven-day post-orthodontic retention (p < 0.05). Similarly, the decreasing trend of TRAP-positive osteoclasts during the retention period in the adult group was less obvious than that in the young group. CONCLUSIONS: The bone-resorptive activity in the young rats was more dynamic than that in the adult rats. The expression of RANKL and the number of osteoclasts in adult rats did not drop to the control level during the post orthodontic retention period while RANKL expression and the number of osteoclasts in young rats had returned to the baseline.Cite this article: X. Li, M. Li, J. Lu, Y. Hu, L. Cui, D. Zhang, Y. Yang. Age-related effects on osteoclastic activities after orthodontic tooth movement. Bone Joint Res 2016;5:492-499. DOI: 10.1302/2046-3758.510.BJR-2016-0004.R2. PMID- 27769959 TI - More men with low risk prostate cancer are opting for active surveillance, study finds. PMID- 27769961 TI - Medicare data highlight extent of pharmacists' prescribing. PMID- 27769962 TI - For Schweitzer, shifts in perspective help pharmacy move forward. PMID- 27769960 TI - Response to: 'Monocyte type I interferon signature in antiphospholipid syndrome is related to pro-inflammatory monocyte subsets, hydroxychloroquine and statin use' by van den Hoogen et al. PMID- 27769963 TI - Pittsburgh project takes novel approach in fighting opioid epidemic. PMID- 27769965 TI - Eteplirsen approved for Duchenne muscular dystrophy. PMID- 27769966 TI - Implications of ASHP's Phase II Match process. PMID- 27769967 TI - Alumni survey as a quality-improvement tool for defining residency success. PMID- 27769968 TI - Preparing for an international pharmacy practice experience. PMID- 27769969 TI - Management of neuroendocrine tumors. AB - PURPOSE: Current strategies for managing neuroendocrine tumors (NETs) in adult patients are reviewed, with a focus on medication safety concerns. SUMMARY: NETs usually originate in the gastrointestinal or bronchopulmonary tract. Symptoms due to hormonal hypersecretion often occur in patients with foregut or midgut NETs or liver metastases. Surgical resection is recommended for most localized NETs, while systemic cytotoxic chemotherapy is typically used for high-grade and pancreatic tumors. The standard of care for metastatic NETs is somatostatin analog therapy with octreotide (available in both short- and long-acting formulations) or a depot formulation of lanreotide. Everolimus and sunitinib are targeted therapies with approved indications for use in treating advanced pancreatic NETs. Some patients with liver-predominant disease or liver metastases may undergo regional chemoembolization procedures. Pharmacists should be cognizant of differences between newer and older chemoembolization agents and procedures, as well as differences between somatostatin analog products used as medications and the radiolabelled forms used in diagnostic scintigraphy. Other medication safety issues in NET management arise during perioperative supportive care, patient education, compliance counseling, and management of adverse effects of targeted therapies and chemotherapy, including stomatitis, hyperthyroidism, and hand-foot skin reaction. CONCLUSION: Somatostatin analog therapy is the mainstay for management of locally advanced or metastatic NETs. Liver-directed therapy is an option for localized unresectable disease; platinum-based chemotherapy is the first-line treatment for poorly differentiated tumors. Optimal sequencing of these treatments and targeted therapies such as everolimus and tyrosine kinase inhibitors remains to be elucidated. PMID- 27769970 TI - Evolving therapies for the management of chronic and acute decompensated heart failure. AB - PURPOSE: The pharmacology, clinical efficacy, and safety profiles of evolving therapies for the management of chronic heart failure (HF) and acute decompensated heart failure (ADHF) are described. SUMMARY: HF confers a significant financial burden despite the widespread use of traditional guideline directed medical therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone receptor antagonists, and the rates of HF-related mortality and hospitalization have remained unacceptably high. In response to a demand for novel pharmacologic agents, several therapeutic compounds have recently gained approval or are currently under review by the Food and Drug Administration. Sacubitril-valsartan has demonstrated benefit in reducing cardiovascular mortality and HF-related hospitalizations in clinical trials, while ivabradine and ferric carboxymaltose have proven efficacious in reducing HF-related hospitalizations. Lastly, the role of serelaxin in ADHF is currently under investigation in an ongoing Phase III study. While large, outcome-driven clinical trials are fundamental in informing the clinical application of these therapeutic agents, careful patient selection is imperative to ensuring similar outcomes postmarketing. In addition, optimization of current guideline-directed medical therapy remains essential as new therapies emerge and are incorporated into guideline recommendations. Additional therapeutic agents currently undergoing investigation include bucindolol hydrochloride, cimaglermin alfa, nitroxyl, omecamtiv mecarbil, TRV027, and ularitide. Clinical practitioners should remain abreast of emerging literature so that new therapeutic entities are optimally applied and positive patient outcomes are achieved. CONCLUSION: Recently introduced agents for the treatment of patients with HF include sacubitril-valsartan, ivabradine, and ferric carboxymaltose. Additional agents worthy of attention include serelaxin and other therapies currently under investigation. PMID- 27769972 TI - Physical compatibility of tedizolid phosphate with selected i.v. drugs during simulated Y-site administration. AB - PURPOSE: The physical compatibility of commonly used agents that could be coadministered in the clinical setting with tedizolid phosphate during Y-site administration was evaluated. METHODS: Tedizolid phosphate vials were reconstituted to a final concentration of 0.8 mg/mL. All other drugs were prepared according to manufacturers' recommendations and diluted with 0.9% sodium chloride injection (where applicable) to the highest standard concentrations used clinically. Y-site conditions were simulated in culture tubes by mixing 5 mL of tedizolid phosphate solution with 5 mL of the test drug solutions. The physical characteristics, turbidity, and pH of all admixtures were examined immediately after mixing and at 15, 60, and 120 minutes. Incompatibility was defined as gross precipitation, a positive Tyndall beam test, color changes, or increases in turbidity. RESULTS: With simulated Y-site administration, tedizolid phosphate was compatible with 69 of 86 drugs in 0.9% sodium chloride injection, including 24 of 31 antimicrobial agents. Of note, incompatibility was observed immediately after mixing except with ceftaroline and diphenhydramine, whose incompatibility with tedizolid phosphate was apparent after 15 and 60 minutes, respectively. Among the drug classes tested, tedizolid phosphate was compatible only with 1 aminoglycoside (amikacin) and incompatible with 1 echinocandin (caspofungin) and 1 cephalosporin (ceftaroline). In addition, tedizolid phosphate was incompatible with divalent cations (calcium chloride, calcium gluconate, and magnesium sulfate), probably due to precipitation with the phosphate component. A pH change of >1 unit occurred only with epinephrine (at 120 minutes). CONCLUSION: Tedizolid phosphate 0.8 mg/mL in 0.9% sodium chloride injection was physically compatible with 69 of 86 study drugs during simulated Y-site administration. PMID- 27769971 TI - Role of topical tranexamic acid in the management of idiopathic anterior epistaxis in adult patients in the emergency department. AB - PURPOSE: The role of topical tranexamic acid in the management of anterior epistaxis in adult patients in the emergency department (ED) is examined. SUMMARY: The use of alternative agents for the treatment of epistaxis before the use of nasal packing may be reasonable due to patient discomfort, potential complications, and the need for follow-up with a healthcare provider for packing removal. One such agent is tranexamic acid. Two published studies evaluated the off-label use of topical tranexamic acid for the treatment of epistaxis. The first trial compared the efficacy of a topical gel containing 10% tranexamic acid with a placebo gel containing glycerin for the treatment of epistaxis. The percentage of patients whose bleeding ceased within 30 minutes of the intervention did not significantly differ between the tranexamic acid and placebo groups (p = 0.16). The second trial compared the efficacy of cotton pledgets soaked in the i.v. formulation of tranexamic acid inserted into the bleeding naris with standard nasal packing therapy. Bleeding cessation occurred within 10 minutes in 71% of the tranexamic acid group versus 31.2% of the standard treatment group (odds ratio, 2.28; 95% confidence interval, 1.68-3.09; p < 0.001). Additional information is necessary to fully evaluate the role of topical tranexamic acid in treatment algorithms; however, the use of topical tranexamic acid may be beneficial in select populations. CONCLUSION: Topical tranexamic acid may have a role in the treatment of anterior epistaxis in select ED patients, though additional studies are needed to confirm its role in treatment algorithms. PMID- 27769973 TI - Using ASHP fellowship criteria as a template for continuous professional development. PMID- 27769974 TI - ASHP Guidelines on Pharmacy Services in Correctional Facilities. PMID- 27769975 TI - European drug agency launches website giving open access to trial data. PMID- 27769976 TI - Total recovery of optic nerve sheath meningioma. AB - We reported the case of a 43-year-old woman with a rapid progressive visual loss. The diagnosis of primary optic nerve sheath meningioma was made thanks to atypia evolution, clinical and radiological findings. The patient was treated with an intensity-modulated radiotherapy of 50.4 Gy in 28 fractions 2 months after the diagnosis. Visual acuity and visual field were completely recovered after 2 years of follow-up. No late side effects of irradiation were recorded. PMID- 27769977 TI - Rare cause of massive haemoptysis in pulmonary tuberculosis: Rasmussen's aneurysm. PMID- 27769978 TI - Rare case of type I hypersensitivity reaction to sodium hypochlorite solution in a healthcare setting. AB - Sodium hypochlorite is a clear yellowish solution with a characteristic odour of chlorine and is commonly used as a disinfectant and a bleaching agent. It is used in various healthcare settings for its fast-acting and broad-spectrum antimicrobial activity. It is a known irritant and there are some reports that it can also cause allergic contact dermatitis of type IV hypersensitivity. We report a case of work-related type I hypersensitivity to sodium hypochlorite, presenting with recurrent urticarial rash and a positive prick test reaction to this chemical. He was subsequently excused from further exposure with no further recurrences of the urticarial rash. To the best of our knowledge, this is the first such reported case due to work in the healthcare setting. PMID- 27769979 TI - Mediastinal osteosarcoma metastasis causing right heart failure due to pulmonary trunk compression. PMID- 27769980 TI - Two tunnels for one peritoneal dialysis catheter: a case for caution. PMID- 27769981 TI - Rare case of T-cell lymphoma presenting as acute myelopathy. AB - Acute myelopathy is a rare presentation of systemic T-cell lymphoma. We present the case of a man aged 68 years with a diffuse erythematous maculopapular rash, followed by lower extremity paresthesias and progressive lower extremity weakness. Spinal MRI showed longitudinally extensive T2 hyperintensity with diffuse contrast enhancement. An atypical clonal T-lymphocyte population was identified in cerebrospinal fluid, peripheral blood and bone marrow aspirate, indicating a malignant T-cell lymphoproliferative disorder. The patient was treated with intrathecal and systemic chemotherapy. Unfortunately, he was not responsive to chemotherapy. PMID- 27769983 TI - UK must act quickly to become world leader in regenerative medicine, MPs hear. PMID- 27769982 TI - BMJ Awards South Asia 2016: how to find the best in South Asian healthcare. PMID- 27769984 TI - Young women who are obese are often unaware of risks to fetus, experts warn. PMID- 27769985 TI - Obama urges Republicans to help improve health reform law. PMID- 27769986 TI - Many women with diabetes are unprepared for pregnancy complications, audit finds. PMID- 27769987 TI - Human Microbiome Fusobacterium Nucleatum in Esophageal Cancer Tissue Is Associated with Prognosis. AB - PURPOSE: Fusobacterium nucleatum (F. nucleatum) is a component of the human microbiome that primarily inhabits the oral cavity. It causes periodontal disease and has also been implicated in the development of human cancers. Although there are several reports of the relationship between F. nucleatum and the clinical outcome in human cancers, its prognostic significance in esophageal cancer remains unclear. EXPERIMENTAL DESIGN: We quantified F. nucleatum DNA in 325 resected esophageal cancer specimens by qPCR. Significant pathways in F. nucleatum-positive esophageal cancer tissues were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using microarray data. RESULTS: Esophageal cancer tissues contained significantly more F. nucleatum DNA than matched normal esophageal mucosa (P = 0.021; n = 60). F. nucleatum DNA was detected in 74 of 325 cases (23%). F. nucleatum DNA positivity was significantly associated with tumor stage, but not with sex, age, performance status, tobacco use, alcohol use, histology, tumor location, or preoperative treatment. F. nucleatum DNA positivity was also significantly associated with cancer-specific survival [log-rank P = 0.0039; univariate HR = 2.01; 95% confidence interval (CI), 1.22-3.23; P = 0.0068; multivariate HR = 1.78; 95% CI, 1.06-2.94; P = 0.031]. The top-ranked KEGG pathway in F. nucleatum-positive tissues was "cytokine-cytokine receptor interaction." A significant relationship between F. nucleatum and the chemokine CCL20 was validated by IHC. CONCLUSIONS: F. nucleatum in esophageal cancer tissues was associated with shorter survival, suggesting a potential role as a prognostic biomarker. F. nucleatum might also contribute to aggressive tumor behavior through activation of chemokines, such as CCL20. Clin Cancer Res; 22(22); 5574-81. (c)2016 AACR. PMID- 27769988 TI - Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases. AB - PURPOSE: Bone marrow-derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. EXPERIMENTAL DESIGN: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. RESULTS: Seventy five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). CONCLUSIONS: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666-76. (c)2016 AACR. PMID- 27769989 TI - Statistical Methods for Unusual Count Data: Examples From Studies of Microchimerism. AB - Natural acquisition of small amounts of foreign cells or DNA, referred to as microchimerism, occurs primarily through maternal-fetal exchange during pregnancy. Microchimerism can persist long-term and has been associated with both beneficial and adverse human health outcomes. Quantitative microchimerism data present challenges for statistical analysis, including a skewed distribution, excess zero values, and occasional large values. Methods for comparing microchimerism levels across groups while controlling for covariates are not well established. We compared statistical models for quantitative microchimerism values, applied to simulated data sets and 2 observed data sets, to make recommendations for analytic practice. Modeling the level of quantitative microchimerism as a rate via Poisson or negative binomial model with the rate of detection defined as a count of microchimerism genome equivalents per total cell equivalents tested utilizes all available data and facilitates a comparison of rates between groups. We found that both the marginalized zero-inflated Poisson model and the negative binomial model can provide unbiased and consistent estimates of the overall association of exposure or study group with microchimerism detection rates. The negative binomial model remains the more accessible of these 2 approaches; thus, we conclude that the negative binomial model may be most appropriate for analyzing quantitative microchimerism data. PMID- 27769990 TI - Comparison of Standardization Methods for the Harmonization of Phenotype Data: An Application to Cognitive Measures. AB - Standardization procedures are commonly used to combine phenotype data that were measured using different instruments, but there is little information on how the choice of standardization method influences pooled estimates and heterogeneity. Heterogeneity is of key importance in meta-analyses of observational studies because it affects the statistical models used and the decision of whether or not it is appropriate to calculate a pooled estimate of effect. Using 2-stage individual participant data analyses, we compared 2 common methods of standardization, T-scores and category-centered scores, to create combinable memory scores using cross-sectional data from 3 Canadian population-based studies (the Canadian Study on Health and Aging (1991-1992), the Canadian Community Health Survey on Healthy Aging (2008-2009), and the Quebec Longitudinal Study on Nutrition and Aging (2004-2005)). A simulation was then conducted to assess the influence of varying the following items across population-based studies: 1) effect size, 2) distribution of confounders, and 3) the relationship between confounders and the outcome. We found that pooled estimates based on the unadjusted category-centered scores tended to be larger than those based on the T scores, although the differences were negligible when adjusted scores were used, and that most individual participant data meta-analyses identified significant heterogeneity. The results of the simulation suggested that in terms of heterogeneity, the method of standardization played a smaller role than did different effect sizes across populations and differential confounding of the outcome measure across studies. Although there was general consistency between the 2 types of standardization methods, the simulations identified a number of sources of heterogeneity, some of which are not the usual sources considered by researchers. PMID- 27769992 TI - An empirical likelihood ratio test robust to individual heterogeneity for differential expression analysis of RNA-seq. AB - The individual sample heterogeneity is one of the biggest obstacles in biomarker identification for complex diseases such as cancers. Current statistical models to identify differentially expressed genes between disease and control groups often overlook the substantial human sample heterogeneity. Meanwhile, traditional nonparametric tests lose detailed data information and sacrifice the analysis power, although they are distribution free and robust to heterogeneity. Here, we propose an empirical likelihood ratio test with a mean-variance relationship constraint (ELTSeq) for the differential expression analysis of RNA sequencing (RNA-seq). As a distribution-free nonparametric model, ELTSeq handles individual heterogeneity by estimating an empirical probability for each observation without making any assumption about read-count distribution. It also incorporates a constraint for the read-count overdispersion, which is widely observed in RNA-seq data. ELTSeq demonstrates a significant improvement over existing methods such as edgeR, DESeq, t-tests, Wilcoxon tests and the classic empirical likelihood-ratio test when handling heterogeneous groups. It will significantly advance the transcriptomics studies of cancers and other complex disease. PMID- 27769993 TI - Transferring entropy to the realm of GxG interactions. AB - Genome-wide association studies are moving to genome-wide interaction studies, as the genetic background of many diseases appears to be more complex than previously supposed. Thus, many statistical approaches have been proposed to detect gene-gene (GxG) interactions, among them numerous information theory-based methods, inspired by the concept of entropy. These are suggested as particularly powerful and, because of their nonlinearity, as better able to capture nonlinear relationships between genetic variants and/or variables. However, the introduced entropy-based estimators differ to a surprising extent in their construction and even with respect to the basic definition of interactions. Also, not every entropy-based measure for interaction is accompanied by a proper statistical test. To shed light on this, a systematic review of the literature is presented answering the following questions: (1) How are GxG interactions defined within the framework of information theory? (2) Which entropy-based test statistics are available? (3) Which underlying distribution do the test statistics follow? (4) What are the given strengths and limitations of these test statistics? PMID- 27769994 TI - Hunt denies that NHS efficiencies mean inevitable rationing. PMID- 27769991 TI - Computational pan-genomics: status, promises and challenges. AB - Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains. PMID- 27769995 TI - Parental vitamin D deficiency during pregnancy is associated with increased blood pressure in offspring via Panx1 hypermethylation. AB - Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Maternal vitamin D deficiency is associated with increased susceptibility to hypertension in offspring, but the reasons for this remain unknown. The aim of this study was to determine if parental vitamin D deficiency leads to altered DNA methylation in offspring that may relate to hypertension. Male and female Sprague-Dawley rats were fed a standard or vitamin D-depleted diet. After 10 wk, nonsibling rats were mated. The conceived pups received standard chow. We observed an increased systolic and diastolic blood pressure in the offspring from depleted parents (F1-depl). Genome-wide methylation analyses in offspring identified hypermethylation of the promoter region of the Pannexin-1 (Panx1) gene in F1-depl rats. Panx1 encodes a hemichannel known to be involved in endothelial-dependent relaxation, and we demonstrated that in F1-depl rats the increase in blood pressure was associated with impaired endothelial relaxation of the large vessels, suggesting an underlying biological mechanism of increased blood pressure in children from parents with vitamin deficiency. Parental vitamin D deficiency is associated with epigenetic changes and increased blood pressure levels in offspring. PMID- 27769996 TI - Estrogen receptor antagonism exacerbates cardiac structural and functional remodeling in female rats. AB - : We have previously demonstrated the cardioprotective effects of ovarian hormones against adverse ventricular remodeling imposed by chronic volume overload. Here, we assess the estrogen receptor dependence of this cardioprotection. Four groups of female rats were studied: sham-operated (Sham), volume overloaded [aortocaval fistula (ACF)], Sham treated with estrogen receptor antagonist ICI 182,780 (Sham + ICI), and ACF treated with ICI. Cardiac function was assessed temporally using echocardiogram, and tissue samples were collected at 5 days and 6 wk postsurgery. All rats with volume overload had significantly increased cardiac output (96 +/- 32 ml/min for ACF and 108 +/- 11 ml/min for ACF + ICI vs. 31 +/- 2 for Sham, P < 0.05). At 6 wk, volume overload induced significant left ventricular (LV) hypertrophy in both untreated and treated ACF groups. Both ACF groups developed significantly increased LV end-diastolic diameter (LVEDD), indicating LV dilatation, with the ACF + ICI group having the greatest increase (340%, relative to Sham). Ejection fraction was significantly reduced in the ACF + ICI group (23% reduction) at 6 wk postsurgery compared with untreated ACF (P < 0.05). Interstitial collagen staining was significantly reduced by volume overload, with estrogen receptor antagonism causing greater collagen loss at both 5 days and 6 wk postsurgery. Furthermore, volume overload induced a significant increase in LV wall stress only in rats treated with estrogen antagonist. These data indicate that estrogen receptor signaling is essential for sex hormone-dependent cardioprotection against adverse remodeling. The maintenance of myocardial extracellular matrix collagen appears to play a key role in this cardioprotection. NEW & NOTEWORTHY: We assessed the estrogen receptor (ER) dependence of female-specific cardioprotection using a rat model of chronic volume-overload stress. ER antagonism worsened ventricular wall stress, ventricular dilation, and cardiac dysfunction induced by volume overload. Further, blocking ERs resulted in cardiac remodeling and functional changes similar to that previously found in ovariectomized rats. PMID- 27769997 TI - Exaggerated coronary vasoconstriction limits muscle metaboreflex-induced increases in ventricular performance in hypertension. AB - : Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise likely occurs via the action of and interaction among activation of skeletal muscle afferents, central command, and resetting of the arterial baroreflex. As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction in canines during mild treadmill exercise with muscle metaboreflex activation (MMA; elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance. Experiments were repeated after alpha1-adrenergic blockade (prazosin; 75 ug/kg) and in the same animals following induction of HTN (modified Goldblatt 2K1C model). HTN increased mean arterial pressure from 97.1 +/- 2.6 to 132.1 +/- 5.6 mmHg at rest and MMA-induced increases in CBF, left ventricular dP/dtmax, and cardiac output were markedly reduced to only 32 +/- 13, 26 +/- 11, and 28 +/- 12% of the changes observed in control. In HTN, alpha1-adrenergic blockade restored the coronary vasodilation and increased in ventricular function to the levels observed when normotensive. We conclude that exaggerated MMA-induced increases in SNA functionally vasoconstrict the coronary vasculature impairing increases in CBF, which limits oxygen delivery and ventricular performance in HTN. NEW & NOTEWORTHY: We found that metaboreflex-induced increases in coronary blood flow and ventricular contractility are attenuated in hypertension. alpha1-Adrenergic blockade restored these parameters toward normal levels. These findings indicate that the primary mechanism mediating impaired metaboreflex-induced increases in ventricular function in hypertension is accentuated coronary vasoconstriction. PMID- 27770000 TI - Left and right ventricular hemodynamic forces in healthy volunteers and elite athletes assessed with 4D flow magnetic resonance imaging. AB - Intracardiac blood flow is driven by hemodynamic forces that are exchanged between the blood and myocardium. Previous studies have been limited to 2D measurements or investigated only left ventricular (LV) forces. Right ventricular (RV) forces and their mechanistic contribution to asymmetric redirection of flow in the RV have not been measured. We therefore aimed to quantify 3D hemodynamic forces in both ventricles in a cohort of healthy subjects, using magnetic resonance imaging 4D flow measurements. Twenty five controls, 14 elite endurance athletes, and 2 patients with LV dyssynchrony were included. 4D flow data were used as input for the Navier-Stokes equations to compute hemodynamic forces over the entire cardiac cycle. Hemodynamic forces were found in a qualitatively consistent pattern in all healthy subjects, with variations in amplitude. LV forces were mainly aligned along the apical-basal longitudinal axis, with an additional component aimed toward the aortic valve during systole. Conversely, RV forces were found in both longitudinal and short-axis planes, with a systolic force component driving a slingshot-like acceleration that explains the mechanism behind the redirection of blood flow toward the pulmonary valve. No differences were found between controls and athletes when indexing forces to ventricular volumes, indicating that cardiac force expenditures are tuned to accelerate blood similarly in small and large hearts. Patients' forces differed from controls in both timing and amplitude. Normal cardiac pumping is associated with specific force patterns for both ventricles, and deviation from these forces may be a sensitive marker of ventricular dysfunction. Reference values are provided for future studies.NEW & NOTEWORTHY Biventricular hemodynamic forces were quantified for the first time in healthy controls and elite athletes (n = 39). Hemodynamic forces constitute a slingshot-like mechanism in the right ventricle, redirecting blood flow toward the pulmonary circulation. Force patterns were similar between healthy subjects and athletes, indicating potential utility as a cardiac function biomarker. PMID- 27769998 TI - Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation. AB - We have reported that the Toll-like receptor 9 (TLR9) signaling pathway plays an important role in the development of pressure overload-induced inflammatory responses and heart failure. However, its role in cardiac remodeling after myocardial infarction has not been elucidated. TLR9-deficient and control C57Bl/6 wild-type mice were subjected to left coronary artery ligation. The survival rate 14 days postoperation was significantly lower in TLR9-deficient mice than that in wild-type mice with evidence of cardiac rupture in all dead mice. Cardiac magnetic resonance imaging showed no difference in infarct size and left ventricular wall thickness and function between TLR9-deficient and wild-type mice. There were no differences in the number of infiltrating inflammatory cells and the levels of inflammatory cytokine mRNA in infarct hearts between TLR9 deficient and wild-type mice. The number of alpha-smooth muscle actin (alphaSMA) positive myofibroblasts and alphaSMA/Ki67-double-positive proliferative myofibroblasts was increased in the infarct and border areas in infarct hearts compared with those in sham-operated hearts in wild-type mice, but not in TLR9 deficient mice. The class B CpG oligonucleotide increased the phosphorylation level of NF-kappaB and the number of alphaSMA-positive and alphaSMA/Ki67-double positive cells and these increases were attenuated by BAY1-7082, an NF-kappaB inhibitor, in cardiac fibroblasts isolated from wild-type hearts. The CpG oligonucleotide showed no effect on NF-kappaB activation or the number of alphaSMA-positive and alphaSMA/Ki67-double-positive cells in cardiac fibroblasts from TLR9-deficient hearts. Although the TLR9 signaling pathway is not involved in the acute inflammatory response in infarct hearts, it ameliorates cardiac rupture possibly by promoting proliferation and differentiation of cardiac fibroblasts. PMID- 27769999 TI - Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in alpha- and beta-myosin heavy chain fibers. AB - : The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation A28V in cardiac troponin T (TnT). The A28V mutation is located within the NH2 terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how alpha- and beta-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH2 terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by alpha- and beta-MHC isoforms. Recombinant wild-type mouse TnT (TnTWT) and the mouse equivalent of the human A28V mutation (TnTA30V) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (alpha-MHC) and transgenic (beta-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnTA30V decreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges (ER) by 30% in alpha-MHC fibers. In sharp contrast, TnTA30V increased ER by 55% in beta-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in ER in TnTA30V + alpha-MHC and TnTA30V + beta MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnTA30V-mediated effects on Ca2+ activated maximal tension and instantaneous muscle fiber stiffness (ED) were also divergently affected by alpha- and beta-MHC. Our study demonstrates that TnTA30V + alpha-MHC and TnTA30V + beta-MHC fibers show contrasting contractile phenotypes; however, only the observations from beta-MHC fibers are consistent with the clinical data for A28V in humans. NEW & NOTEWORTHY: The differential impact of alpha- and beta-myosin heavy chain (MHC) on contractile dynamics causes a mutant cardiac troponin T (TnTA30V) to differently modulate cardiac contractile function. TnTA30V attenuated Ca2+-activated maximal tension and length-mediated cross-bridge recruitment against alpha-MHC but augmented these parameters against beta-MHC, suggesting divergent contractile phenotypes. PMID- 27770001 TI - Aortic Cross-Sectional Area/Height Ratio and Outcomes in Patients With a Trileaflet Aortic Valve and a Dilated Aorta. AB - BACKGROUND: In patients with a dilated proximal ascending aorta and trileaflet aortic valve, we aimed to assess (1) factors independently associated with increased long-term mortality and (2) the incremental prognostic utility of indexing aortic root to patient height. METHODS: We studied consecutive patients with a dilated aortic root (>=4 cm) that underwent echocardiography and gated contrast-enhanced thoracic aortic computed tomography or magnetic resonance angiography between 2003 and 2007. A ratio of aortic root area over height was calculated (cm2/m) on tomography, and a cutoff of 10 cm2/m was chosen as abnormal, on the basis of previous reports. All-cause death was recorded. RESULTS: The cohort comprised 771 patients (63 years [interquartile range, 53 71], 87% men, 85% hypertension, 51% hyperlipidemia, 56% smokers). Inherited aortopathies, moderate to severe aortic regurgitation, and severe aortic stenosis were seen in 7%, 18%, and 2%, whereas 91% and 54% were on beta-blockers and angiotensin-converting enzyme inhibitors, respectively. Aortic root area/height ratio was >=10 cm2/m in 24%. The Society of Thoracic Surgeons score and right ventricular systolic pressure were 3.3+/-3 and 31+/-7 mm Hg, respectively. At 7.8 years (interquartile range, 6.6-8.9), 280 (36%) patients underwent aortic surgery (76% within 1 year) and 130 (17%) died (1% in-hospital postoperative mortality). A lower proportion of patients in the surgical (versus nonsurgical) group died (13% versus 19%, P<0.01). On multivariable Cox proportional hazard analysis, aortic root area/height ratio (hazard ratio, 4.04; 95% confidence interval [CI], 2.69-6.231) was associated with death, whereas aortic surgery (hazard ratio, 0.47; 95% CI, 0.27-0.81) was associated with improved survival (both P<0.01). For longer-term mortality, the addition of aortic root area/height ratio >=10 cm2/m to a clinical model (Society of Thoracic Surgeons score, inherited aortopathies, hypertension, hyperlipidemia, medications, aortic regurgitation, and right ventricular systolic pressure), increased the c-statistic from 0.57 (95% CI, 0.35 0.77) to 0.65 (95% CI, 0.52-0.73) and net reclassification index from 0.17 (95% CI, 0.02-0.31) to 0.23 (95% CI, 0.04-0.34), both P<0.01. Of the 327 patients with aortic root diameter between 4.5 and 5.5 cm, 44% had an abnormal aortic root area/height ratio, of which 78% died. CONCLUSIONS: In patients with dilated aortic root and trileaflet aortic valve, a ratio of aortic root area to height provides independent and improved stratification for prediction of death. PMID- 27770002 TI - Triple Therapy Improves Colorectal Cancer Response. AB - Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors. PMID- 27770008 TI - Evaluation of Buccal Cell Samples for Studies of Oral Microbiota. AB - BACKGROUND: The human microbiota is postulated to affect cancer risk, but collecting microbiota specimens with prospective follow-up for diseases will take time. Buccal cell samples have been obtained from mouthwash for the study of human genomic DNA in many cohort studies. Here, we evaluate the feasibility of using buccal cell samples to examine associations of human microbiota and disease risk. METHODS: We obtained buccal cells from mouthwash in 41 healthy participants using a protocol that is widely employed to obtain buccal cells for the study of human DNA. We compared oral microbiota from buccal cells with that from eight other oral sample types collected by following the protocols of the Human Microbiome Project. Microbiota profiles were determined by sequencing 16S rRNA gene V3-V4 region. RESULTS: Compared with each of the eight other oral samples, the buccal cell samples had significantly more observed species (P < 0.002) and higher alpha diversity (Shannon index, P < 0.02). The microbial communities were more similar (smaller beta diversity) among buccal cells samples than in the other samples (P < 0.001 for 12 of 16 weighted and unweighted UniFrac distance comparisons). Buccal cell microbial profiles closely resembled saliva but were distinct from dental plaque and tongue dorsum. CONCLUSIONS: Stored buccal cell samples in prospective cohort studies are a promising resource to study associations of oral microbiota with disease. IMPACT: The feasibility of using existing buccal cell collections in large prospective cohorts allows investigations of the role of oral microbiota in chronic disease etiology in large population studies possible today. Cancer Epidemiol Biomarkers Prev; 26(2); 249-53. (c)2016 AACR. PMID- 27770009 TI - David Oliver: Let's argue about statistics. PMID- 27770011 TI - Nobel Yeast Research. PMID- 27770010 TI - Six3 dosage mediates the pathogenesis of holoprosencephaly. AB - Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE. PMID- 27770012 TI - Life expectancy in patients with pituitary adenoma receiving growth hormone replacement. AB - OBJECTIVE: Hypopituitarism has been associated with increased mortality. The excess mortality may be due to untreated growth hormone (GH) deficiency but also due to various underlying disorders. We therefore analysed mortality in patients with only one underlying disorder, non-functioning pituitary adenoma (NFPA), with and without GH replacement therapy (GHRT). DESIGN AND METHOD: Patients with NFPA in the western region of Sweden, 1997-2011, were identified through the National Patient Registry and cross-referenced with several National Health Registries. All patient records were reviewed. Standardised mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated using the general population as reference. Cox-regression models were performed to identify predictors of mortality. RESULTS: A total of 426 NFPA patients with 4599 patient-years were included, of whom 207 had used GHRT and 219 had not received GHRT. Median (range) follow-up in patients with and without GHRT was 12.2 (0-25) and 8.2 (0-27) years, respectively. Other pituitary hormone deficiencies were more frequent in the GHRT group than those in the non-GHRT group. SMR was 0.65 (95% CI, 0.44-0.94; P = 0.018) for the GHRT group and 1.16 (0.94-1.42; P = 0.17) for the non-GHRT group. Direct comparison between the groups showed reduced mortality among those who were GH replaced (P = 0.0063). The SMR for malignant tumours was reduced in the GHRT-group (0.29; 0.08-0.73; P = 0.004) but not in untreated patients. CONCLUSIONS: Selection bias explaining some of the results cannot be excluded. However, NFPA patients with GHRT had reduced overall mortality compared with the general population, and death due to malignancy was not increased. This suggests that long-term GHRT is safe in adult patients selected for treatment. PMID- 27770013 TI - Correction. PMID- 27770014 TI - The Central Apparatus of Cilia and Eukaryotic Flagella. AB - The motile cilium is a complex organelle that is typically comprised of a 9+2 microtubule skeleton; nine doublet microtubules surrounding a pair of central singlet microtubules. Like the doublet microtubules, the central microtubules form a scaffold for the assembly of protein complexes forming an intricate network of interconnected projections. The central microtubules and associated structures are collectively referred to as the central apparatus (CA). Studies using a variety of experimental approaches and model organisms have led to the discovery of a number of highly conserved protein complexes, unprecedented high resolution views of projection structure, and new insights into regulation of dynein-driven microtubule sliding. Here, we review recent progress in defining mechanisms for the assembly and function of the CA and include possible implications for the importance of the CA in human health. PMID- 27770016 TI - Association of chronic obstructive pulmonary disease and postresection lung cancer survival: a systematic review and meta-analysis. AB - Patients with lung cancer often have chronic obstructive pulmonary disease (COPD), but the impact of COPD on postresection survival of patients with lung cancer is unclear. This study evaluated the impact of COPD on survival of patients with lung cancer following pulmonary resection. Databases searched included PubMed, Cochrane, and Embase until March 2016. Study outcomes were overall survival and pulmonary complication rate (pneumonia, bronchial fistula, and prolonged mechanical ventilation). 6 studies with a total of 3761 patients were included. The presence of COPD was associated with lower overall survival, increased frequency of pneumonia, and prolonged mechanical ventilation (p values <=0.001). COPD had no influence on bronchial fistula development (p=0.098). In summary, COPD was associated with poorer survival and an increased frequency of certain adverse events in patients with lung cancer following resection. PMID- 27770017 TI - Poor Little Butterfly. PMID- 27770018 TI - Duration of antibody response following vaccination against feline immunodeficiency virus. AB - Objectives Recently, two point-of-care (PoC) feline immunodeficiency virus (FIV) antibody test kits (Witness and Anigen Rapid) were reported as being able to differentiate FIV-vaccinated from FIV-infected cats at a single time point, irrespective of the gap between testing and last vaccination (0-7 years). The aim of the current study was to investigate systematically anti-FIV antibody production over time in response to the recommended primary FIV vaccination series. Methods First, residual plasma from the original study was tested using a laboratory-based ELISA to determine whether negative results with PoC testing were due to reduced as opposed to absent antibodies to gp40. Second, a prospective study was performed using immunologically naive client-owned kittens and cats given a primary FIV vaccination series using a commercially available inactivated whole cell/inactivated whole virus vaccine (Fel-O-Vax FIV, three subcutaneous injections at 4 week intervals) and tested systematically (up to 11 times) over 6 months, using four commercially available PoC FIV antibody kits (SNAP FIV/FeLV Combo [detects antibodies to p15/p24], Witness FeLV/FIV [gp40], Anigen Rapid FIV/FeLV [p24/gp40] and VetScan FeLV/FIV Rapid [p24]). Results The laboratory-based ELISA showed cats from the original study vaccinated within the previous 0-15 months had detectable levels of antibodies to gp40, despite testing negative with two kits that use gp40 as a capture antigen (Witness and Anigen Rapid kits). The prospective study showed that antibody testing with SNAP Combo and VetScan Rapid was positive in all cats 2 weeks after the second primary FIV vaccination, and remained positive for the duration of the study (12/12 and 10/12 cats positive, respectively). Antibody testing with Witness and Anigen Rapid was also positive in a high proportion of cats 2 weeks after the second primary FIV vaccination (8/12 and 7/12, respectively), but antibody levels declined below the level of detection in most cats (10/12) by 1 month after the third (final) primary FIV vaccination. All cats tested negative using Witness and Anigen Rapid 6 months after the third primary FIV vaccination. Conclusions and relevance This study has shown that a primary course of FIV vaccination does not interfere with FIV antibody testing in cats using Witness and Anigen Rapid, provided primary vaccination has not occurred within the previous 6 months. Consequently, Witness and Anigen Rapid antibody test kits can be used reliably to determine FIV infection status at the time of annual booster FIV vaccination to help detect 'vaccine breakthroughs' and in cats that have not received a primary course of FIV vaccination within the preceding 6 months. The duration of antibody response following annual booster FIV vaccination and the resulting effect on antibody testing using PoC kits needs to be determined by further research. The mechanism(s) for the variation in FIV antibody test kit performance remains unclear. PMID- 27770019 TI - Implementers' Perspectives on Fidelity of Implementation. AB - Fidelity of implementation is an essential factor in realizing outcomes of evidence-based interventions. Yet perspectives vary on the degree to which fidelity is necessary or desirable, implementers may receive limited guidance on fidelity, and research on implementers' understanding and operationalization of fidelity is lacking. We conducted key informant interviews with 20 individuals who implemented an evidence-based teen dating violence prevention curriculum in seven sites. Interviews addressed how implementers defined fidelity and the adaptations they made in implementing the curriculum. Although all implementers reported delivering the curriculum with fidelity, their definitions of fidelity varied. Most defined fidelity in terms of adherence to the published curriculum, although definitions sometimes allowed modifications of pedagogy or adding or subtracting materials. A smaller group of implementers defined fidelity in terms of their perceptions of the curriculum's core messages. All implementers described variations from the published curriculum, which were frequently inconsistent with their own definitions of fidelity. Implementers committed to the value of implementation with fidelity may need support in its definition and application. Developers can support implementers by communicating program theory in terms that implementers will understand, clarifying expectations for fidelity and allowable adaptations, and codifying lessons learned from previous implementation. PMID- 27770015 TI - Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition. AB - Cilia are plasma membrane protrusions that act as cellular propellers or antennae. To perform these functions, cilia must maintain a composition distinct from those of the contiguous cytosol and plasma membrane. The specialized composition of the cilium depends on the ciliary gate, the region at the ciliary base separating the cilium from the rest of the cell. The ciliary gate's main structural features are electron dense struts connecting microtubules to the adjacent membrane. These structures include the transition fibers, which connect the distal basal body to the base of the ciliary membrane, and the Y-links, which connect the proximal axoneme and ciliary membrane within the transition zone. Both transition fibers and Y-links form early during ciliogenesis and play key roles in ciliary assembly and trafficking. Accordingly, many human ciliopathies are caused by mutations that perturb ciliary gate function. PMID- 27770020 TI - Early micronutrient supplementation protects against early stress-induced cognitive impairments. AB - Early-life stress (ES) impairs cognition later in life. Because ES prevention is problematic, intervention is needed, yet the mechanisms that underlie ES remain largely unknown. So far, the role of early nutrition in brain programming has been largely ignored. Here, we demonstrate that essential 1-carbon metabolism associated micronutrients (1-CMAMs; i.e., methionine and B vitamins) early in life are crucial in programming later cognition by ES. ES was induced in male C57Bl/6 mice from postnatal d (P)2-9. 1-CMAM levels were measured centrally and peripherally by using liquid chromatography-mass spectroscopy. Next, we supplemented the maternal diet with 1-CMAM only during the ES period and studied cognitive, neuroendocrine, neurogenic, transcriptional, and epigenetic changes in adult offspring. We demonstrate that ES specifically reduces methionine in offspring plasma and brain. Of note, dietary 1-CMAM enrichment during P2-9 restored methionine levels and rescued ES-induced adult cognitive impairments. Beneficial effects of this early dietary enrichment were associated with prevention of the ES-induced rise in corticosterone and adrenal gland hypertrophy did not involve changes in maternal care, hippocampal volume, neurogenesis, or global/Nr3c1-specific DNA methylation. In summary, nutrition is important in brain programming by ES. A short, early supplementation with essential micronutrients can already prevent lasting effects of ES. This concept opens new avenues for nutritional intervention.-Naninck, E. F. G., Oosterink, J. E., Yam, K.-Y., de Vries, L. P., Schierbeek, H., van Goudoever, J. B., Verkaik-Schakel, R. N., Plantinga, J. A., Plosch, T., Lucassen, P. J., Korosi, A. Early micronutrient supplementation protects against early stress-induced cognitive impairments. PMID- 27770021 TI - In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects. AB - The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D2 (DP)1, DP2, prostaglandin E2 (EP)1, EP4, prostaglandin F2alpha, and thromboxane A2 receptors but not anti-inflammatory EP2, prostaglandin I2, or EP3 receptors. Established rodent models of ocular inflammatory diseases were used to determine therapeutic effects in living animals. The drugs were administered systemically after predetermination of their blood levels to ensure bioavailability at an appropriate dose level. Whereas compounds selective for a single prostanoid receptor typically exhibited modest but statistically significant inhibition, AGN 211377 profoundly inhibited S-antigen-induced uveitis and laser-induced retinal neovascularization. Consistent with previous polypharmacological studies on chemokine/cytokine release from human macrophages, the prostanoid EP1 receptor played a permissive role in suppressing neovascularization and inflammation in vivo Comparing AGN 211377 with a close structural congener lacking EP1 antagonism (AGN 197727), AGN 197727 was much less active than AGN 211377, but pronounced anti-inflammatory and angiostatic effects were achieved by adding the EP1 antagonist compound (SC-51322) to AGN 197727 in the systemic dosing regimen. Further, AGN 211377 produced superior anti-inflammatory activity compared with the nonsteroidal anti-inflammatory agent ketorolac. These results indicate the value of using a polypharmacological approach in the design of novel therapeutic agents in preference to compounds targeting a single receptor or enzyme. A compound such as AGN 211377 may represent more effective therapy than COX inhibitors in treating uveitis and ocular diseases where neovascularization is a significant part of the pathology.-Woodward, D. F., Wang, J. W., Ni, M., Bauer, A., Martos, J. L., Carling, R. W., Poloso, N. J. In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects. PMID- 27770022 TI - Lysyl Oxidase-like-2 Cross-links Collagen IV of Glomerular Basement Membrane. AB - The 7S dodecamer is recognized as an important structural cross-linking domain of collagen IV networks that provide mechanical stability to basement membranes, a specialized form of extracellular matrix essential for the development and maintenance of tissue architecture. Although the 7S dodecamer is stabilized by covalent cross-linking, the molecular mechanism by which such cross-links are formed has not been revealed. Here, we aimed to identify the enzyme(s) that cross links the 7S dodecamer and characterize its expression in the kidney glomerulus. Pharmacological inhibition of candidate extracellular matrix enzymes revealed that lysyl oxidase activity is required for cross-linking of 7S polypeptides. Among all lysyl oxidase family members, lysyl oxidase-like-2 (LOXL2) was identified as the isoform cross-linking collagen IV in mouse embryonal PFHR-9 cells. Biochemical analyses revealed that LOXL2 readily promoted the formation of lysyl-derived cross-links in the 7S dodecamer but not in the NC1 domain. We also established that LOXL2 is the main lysyl oxidase family member present in the glomerular extracellular matrix. Altogether, we demonstrate that LOXL2 is a novel component of the molecular machinery that forms cross-linked collagen IV networks, which are essential for glomerular basement membrane stability and molecular ultrafiltration function. PMID- 27770023 TI - Expression of Cataract-linked gamma-Crystallin Variants in Zebrafish Reveals a Proteostasis Network That Senses Protein Stability. AB - The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were gammaB- and gammaD-crystallin mutants linked to dominant cataracts in mouse models. Although thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone alpha-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different gammaD-crystallin mutants in the zebrafish lens and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins. Unlike mouse models, a strong correlation was observed between the severity and penetrance of the phenotype and the level of destabilization of the mutant. We interpret this result to reflect the presence of a proteostasis network that can "sense" protein stability. In the more destabilized mutants, the capacity of this network is overwhelmed, leading to the observed increase in phenotypic penetrance. Overexpression of alphaA-crystallin had no significant effects on the penetrance of lens defects, suggesting that its chaperone capacity is not limiting. Although consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that alphaA crystallin may not be efficient to inhibit aggregation of lens gamma-crystallin. Furthermore, our work implicates additional inputs/factors in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract. PMID- 27770024 TI - Structural and Biochemical Characterization of Spa47 Provides Mechanistic Insight into Type III Secretion System ATPase Activation and Shigella Virulence Regulation. AB - Like many Gram-negative pathogens, Shigella rely on a complex type III secretion system (T3SS) to inject effector proteins into host cells, take over host functions, and ultimately establish infection. Despite these critical roles, the energetics and regulatory mechanisms controlling the T3SS and pathogen virulence remain largely unclear. In this study, we present a series of high resolution crystal structures of Spa47 and use the structures to model an activated Spa47 oligomer, finding that ATP hydrolysis may be supported by specific side chain contributions from adjacent protomers within the complex. Follow-up mutagenesis experiments targeting the predicted active site residues validate the oligomeric model and determined that each of the tested residues are essential for Spa47 ATPase activity, although they are not directly responsible for stable oligomer formation. Although N-terminal domain truncation was necessary for crystal formation, it resulted in strictly monomeric Spa47 that is unable to hydrolyze ATP, despite maintaining the canonical ATPase core structure and active site residues. Coupled with studies of ATPase inactive full-length Spa47 point mutants, we find that Spa47 oligomerization and ATP hydrolysis are needed for complete T3SS apparatus formation, a proper translocator secretion profile, and Shigella virulence. This work represents the first structure-function characterization of Spa47, uniquely complementing the multitude of included Shigella T3SS phenotype assays and providing a more complete understanding of T3SS ATPase-mediated pathogen virulence. Additionally, these findings provide a strong platform for follow-up studies evaluating regulation of Spa47 oligomerization in vivo as a much needed means of treating and perhaps preventing shigellosis. PMID- 27770025 TI - Robust Transgene Expression from Bicistronic mRNA in the Green Alga Chlamydomonas reinhardtii. AB - The unicellular green alga Chlamydomonas reinhardtii is a model organism that provides an opportunity to understand the evolution and functional biology of the lineage that includes the land plants, as well as aspects of the fundamental core biology conserved throughout the eukaryotic phylogeny. Although many tools are available to facilitate genetic, molecular biological, biochemical, and cell biological studies in Chlamydomonas, expression of unselected transgenes of interest (GOIs) has been challenging. In most methods used previously, the GOI and a selectable marker are expressed from two separate mRNAs, so that their concomitant expression is not guaranteed. In this study, we developed constructs that allow expression of an upstream GOI and downstream selectable marker from a single bicistronic mRNA. Although this approach in other systems has typically required a translation-enhancing element such as an internal ribosome entry site for the downstream marker, we found that a short stretch of unstructured junction sequence was sufficient to obtain adequate expression of the downstream gene, presumably through post-termination reinitiation. With this system, we obtained robust expression of both endogenous and heterologous GOIs, including fluorescent proteins and tagged fusion proteins, in the vast majority of transformants, thus eliminating the need for tedious secondary screening for GOI-expressing transformants. This improved efficiency should greatly facilitate a variety of genetic and cell-biological studies in Chlamydomonas and also enable new applications such as expression-based screens and large-scale production of foreign proteins. PMID- 27770027 TI - The Interaction of Genotype and Environment Determines Variation in the Maize Kernel Ionome. AB - Plants obtain soil-resident elements that support growth and metabolism from the water-flow facilitated by transpiration and active transport processes. The availability of elements in the environment interacts with the genetic capacity of organisms to modulate element uptake through plastic adaptive responses, such as homeostasis. These interactions should cause the elemental contents of plants to vary such that the effects of genetic polymorphisms will be dramatically dependent on the environment in which the plant is grown. To investigate genotype by environment interactions underlying elemental accumulation, we analyzed levels of elements in maize kernels of the Intermated B73 * Mo17 (IBM) recombinant inbred population grown in 10 different environments, spanning a total of six locations and five different years. In analyses conducted separately for each environment, we identified a total of 79 quantitative trait loci (QTL) controlling seed elemental accumulation. While a set of these QTL was found in multiple environments, the majority were specific to a single environment, suggesting the presence of genetic by environment interactions. To specifically identify and quantify QTL by environment interactions (QEIs), we implemented two methods: linear modeling with environmental covariates, and QTL analysis on trait differences between growouts. With these approaches, we found several instances of QEI, indicating that elemental profiles are highly heritable, interrelated, and responsive to the environment. PMID- 27770026 TI - Microenvironmental Gene Expression Plasticity Among Individual Drosophila melanogaster. AB - Differences in phenotype among genetically identical individuals exposed to the same environmental condition are often noted in genetic studies. Despite this commonplace observation, little is known about the causes of this variability, which has been termed microenvironmental plasticity. One possibility is that stochastic or technical sources of variance produce these differences. A second possibility is that this variation has a genetic component. We have explored gene expression robustness in the transcriptomes of 730 individual Drosophila melanogaster of 16 fixed genotypes, nine of which are infected with Wolbachia Three replicates of flies were grown, controlling for food, day/night cycles, humidity, temperature, sex, mating status, social exposure, and circadian timing of RNA extraction. Despite the use of inbred genotypes, and carefully controlled experimental conditions, thousands of genes were differentially expressed, revealing a unique and dynamic transcriptional signature for each individual fly. We found that 23% of the transcriptome was differentially expressed among individuals, and that the variability in gene expression among individuals is influenced by genotype. This transcriptional variation originated from specific gene pathways, suggesting a plastic response to the microenvironment; but there was also evidence of gene expression differences due to stochastic fluctuations. These observations reveal previously unappreciated genetic sources of variability in gene expression among individuals, which has implications for complex trait genetics and precision medicine. PMID- 27770029 TI - Exposure to secondhand smoke and risk of peripheral arterial disease in southern Chinese non-smokers: The Guangzhou Biobank Cohort Study-Cardiovascular Disease Sub-cohort. AB - Objectives We studied the association between secondhand smoke (SHS) exposure and peripheral arterial disease (PAD) in Chinese non-smokers. Methods We conducted a cross-sectional study using baseline data from the Guangzhou Biobank Cohort Study: Cardiovascular Disease Sub-cohort Study (GBCS-CVD). Guangzhou residents aged >= 50 years were recruited between 2003 and 2008. Baseline data included measurement of ankle brachial pressure index (ABPI) and self-reported smoking status and SHS exposure. Univariate and multivariate logistic regression analyses were used to analyze the association between SHS and PAD (defined as ABPI < 0.9). Results Of the 1507 non-smokers, 24 (1.6%) had PAD. Of these, 12 were men and 12 were women. Exposure to SHS at home of >=25 h per week was reported by 16.7% of PAD cases compared with 3.8% of those without PAD (chi2 test, p = 0.003). After adjustment for potential confounders, exposure to >=25 h per week at home was still associated with PAD (adjusted OR 7.86, 95% CI 2.00-30.95, p = 0.003), with suggestion of a dose-response relationship. Conclusions Our results extend the US Surgeon General's 2006 report that SHS exposure is an independent risk factor for PAD. National smoke-free legislation is needed to protect all people from exposure. PMID- 27770030 TI - The correlation of the platelet-to-lymphocyte ratio with the severity of stenosis and stroke in patients with carotid arterial disease. AB - Objectives Platelet-to-lymphocyte ratio is a novel biomarker, recently shown to be correlated with atherosclerotic inflammation. This study investigated the role of platelet-to-lymphocyte ratio in patients with carotid artery stenosis and stroke. Methods Patients, who underwent carotid angiography with Multiple Detector Computed Tomography Angiography at our hospital, were retrospectively screened. Patients enrolled were divided into three groups based on the platelet to-lymphocyte ratio. Patients with a platelet-to-lymphocyte ratio value between 55.0 and 106.71 were assigned to Group I, patients with a platelet-to-lymphocyte ratio value between 106.79 and 160.61 were assigned to Group II and patients with a platelet-to-lymphocyte ratio value between 162.96 and 619.61 were assigned to Group III. The carotid arterial stenosis calculated was classified as per the criteria of North American Symptomatic Carotid Endarterectomy Trial. Results One hundred fifty patients were included in our trial (mean age 61.9 +/- 13.1 with 104 males). The rate of carotid arterial stenosis was detected to be higher in patients with a high platelet-to-lymphocyte ratio value (p = 0.010). Additionally, the platelet-to-lymphocyte ratio was positively correlated with the carotid arterial stenosis percentage (r = 0.250, p = 0.002). In the multi-variate regression analysis, platelet-to-lymphocyte ratio was detected to be an independent variable with respect to stroke (odd's ratio = 1.012, confidence interval = 1.001-1.024, p = 0.031). Conclusions Increased platelet-to-lymphocyte ratio could be a simple and practical marker of the clinical course in patients with carotid arterial stenosis. PMID- 27770028 TI - cdc-25.4, a Caenorhabditis elegans Ortholog of cdc25, Is Required for Male Mating Behavior. AB - Cell division cycle 25 (cdc25) is an evolutionarily conserved phosphatase that promotes cell cycle progression. Among the four cdc25 orthologs in Caenorhabditis elegans, we found that cdc-25.4 mutant males failed to produce outcrossed progeny. This was not caused by defects in sperm development, but by defects in male mating behavior. The cdc-25.4 mutant males showed various defects during male mating, including contact response, backing, turning, and vulva location. Aberrant turning behavior was the most prominent defect in the cdc-25.4 mutant males. We also found that cdc-25.4 is expressed in many neuronal cells throughout development. The turning defect in cdc-25.4 mutant males was recovered by cdc 25.4 transgenic expression in neuronal cells, suggesting that cdc-25.4 functions in neurons for male mating. However, the neuronal morphology of cdc-25.4 mutant males appeared to be normal, as examined with several neuronal markers. Also, RNAi depletion of wee-1.3, a C. elegans ortholog of Wee1/Myt1 kinase, failed to suppress the mating defects of cdc-25.4 mutant males. These findings suggest that, for successful male mating, cdc-25.4 does not target cell cycles that are required for neuronal differentiation and development. Rather, cdc-25.4 likely regulates noncanonical substrates in neuronal cells. PMID- 27770031 TI - Effects of Child Sexual Abuse on the Parenting of Male Survivors. AB - Research shows that child sexual abuse (CSA) can have detrimental effects on adult functioning. While much research regarding the effects of CSA on parenting of mothers is available, there is a dearth of information on how CSA impacts fatherhood. This literature review finds that the parenting experiences of male survivors are characterized by self-perceptions as adequate parents, deficient parenting as measured by standardized instruments, conceptualization of parenting as an intergenerational legacy and potential healing experience, fear of becoming an abuser, and physical and emotional distance from their children. These themes are strongly related to social discourses on intergenerational cycle of violence theories. Fatherhood is not exclusively problematic for male survivors and can be a healing experience and a source of strength for some survivors. Based on literature concerning male survivors who are parents, narrative therapy is recommended as a therapeutic model to explore how fathers who are survivors challenge dominant discourses around legacies of family violence, intergenerational parenting deficiencies, and victimization. Restorying fatherhood as a healing opportunity is essential when working with fathers who are male survivors and their families. PMID- 27770032 TI - Deficiency in Outer Dense Fiber 1 Is a Marker and Potential Driver of Idiopathic Male Infertility. AB - Globally, ~1 in 15 men of reproductive age are infertile, yet the precise mechanisms underlying their gamete failure are unknown. Although a semen analysis is performed to determine fertilizing potential, the diagnostic suitability of this analysis has been questioned in several reports, as many men, classified as infertile according to their semen analysis, subsequently turn out to be fertile. Herein, we have used a quantitative (phospho)-proteomic analysis, using enrichment on titanium dioxide followed by ion-trap mass spectrometry (LC-MS/MS), to compare the semen of infertile versus fertile males. One protein, namely outer dense fiber 1 (ODF1), was dramatically reduced in infertile males. Using specific antibodies, we then screened the gametes of a cohort of suspected infertile men and demonstrated a reduction in the amount of ODF1 compared with fertile controls. Stress treatment of sperm deficient in ODF1 caused the head to decapitate, suggesting why these gametes fail to initiate fertilization. Interestingly, electron micrographs of ODF1-deficient spermatozoa revealed an abnormal connecting piece, indicating several developmental defects with both the implantation plate and the thin laminated fibers. In some cases, the implantation plate appeared to be reduced in size or was overburdened by granular material near the connecting piece. Hence, a strong reduction ODF1 is a marker of idiopathic male infertility and a potential driver of this condition. PMID- 27770033 TI - Chromatin Association of Gcn4 Is Limited by Post-translational Modifications Triggered by its DNA-Binding in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae transcription factor Gcn4 is expressed during amino acid starvation, and its abundance is controlled by ubiquitin-mediated proteolysis. Cdk8, a kinase component of the RNA polymerase II Mediator complex, phosphorylates Gcn4, which triggers its ubiquitination/proteolysis, and is thought to link Gcn4 degradation with transcription of target genes. In addition to phosphorylation and ubiquitination, we previously showed that Gcn4 becomes sumoylated in a DNA-binding dependent manner, while a nonsumoylatable form of Gcn4 showed increased chromatin occupancy, but only if Cdk8 was present. To further investigate how the association of Gcn4 with chromatin is regulated, here we examine determinants for Gcn4 sumoylation, and how its post-translational modifications are coordinated. Remarkably, artificially targeting Gcn4 that lacks its DNA binding domain to a heterologous DNA site restores sumoylation at its natural modification sites, indicating that DNA binding is sufficient for the modification to occur in vivo Indeed, we find that neither transcription of target genes nor phosphorylation are required for Gcn4 sumoylation, but blocking its sumoylation alters its phosphorylation and ubiquitination patterns, placing Gcn4 sumoylation upstream of these Cdk8-mediated modifications. Strongly supporting a role for sumoylation in limiting its association with chromatin, a hyper-sumoylated form of Gcn4 shows dramatically reduced DNA occupancy and expression of target genes. Importantly, we find that Cdk8 is at least partly responsible for clearing hyper-sumoylated Gcn4 from DNA, further implicating sumoylation as a stimulus for Cdk8-mediated phosphorylation and degradation. These results support a novel function for SUMO in marking the DNA-bound form of a transcription factor, which triggers downstream processes that limit its association with chromatin, thus preventing uncontrolled expression of target genes. PMID- 27770034 TI - Stochasticity in the Genotype-Phenotype Map: Implications for the Robustness and Persistence of Bet-Hedging. AB - Nongenetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance in both bacterial infections and cancers. Here, we study how bet-hedging emerges in genotype-phenotype (GP) mapping through a simple interaction model: a molecular switch. We use simple chemical reaction networks to implement stochastic switches that map gene products to phenotypes, and investigate the impact of structurally distinct mappings on the evolution of phenotypic heterogeneity. Bet-hedging naturally emerges within this model, and is robust to evolutionary loss through mutations to both the expression of individual genes, and to the network itself. This robustness explains an apparent paradox of bet-hedging-why does it persist in environments where natural selection necessarily acts to remove it? The structure of the underlying molecular mechanism, itself subject to selection, can slow the evolutionary loss of bet-hedging to ensure a survival mechanism against environmental catastrophes even when they are rare. Critically, these properties, taken together, have profound implications for the use of treatment-holidays to combat bet-hedging driven resistant disease, as the efficacy of breaks from treatment will ultimately be determined by the structure of the GP mapping. PMID- 27770035 TI - Replication Errors Made During Oogenesis Lead to Detectable De Novo mtDNA Mutations in Zebrafish Oocytes with a Low mtDNA Copy Number. AB - Of all pathogenic mitochondrial DNA (mtDNA) mutations in humans, ~25% is de novo, although the occurrence in oocytes has never been directly assessed. We used next generation sequencing to detect point mutations directly in the mtDNA of 3-15 individual mature oocytes and three somatic tissues from eight zebrafish females. Various statistical and biological filters allowed reliable detection of de novo variants with heteroplasmy >=1.5%. In total, we detected 38 de novo base substitutions, but no insertions or deletions. These 38 de novo mutations were present in 19 of 103 mature oocytes, indicating that ~20% of the mature oocytes carry at least one de novo mutation with heteroplasmy >=1.5%. This frequency of de novo mutations is close to that deducted from the reported error rate of polymerase gamma, the mitochondrial replication enzyme, implying that mtDNA replication errors made during oogenesis are a likely explanation. Substantial variation in the mutation prevalence among mature oocytes can be explained by the highly variable mtDNA copy number, since we previously reported that ~20% of the primordial germ cells have a mtDNA copy number of <=73 and would lead to detectable mutation loads. In conclusion, replication errors made during oogenesis are an important source of de novo mtDNA base substitutions and their location and heteroplasmy level determine their significance. PMID- 27770036 TI - Efficient and Accurate Multiple-Phenotype Regression Method for High Dimensional Data Considering Population Structure. AB - A typical genome-wide association study tests correlation between a single phenotype and each genotype one at a time. However, single-phenotype analysis might miss unmeasured aspects of complex biological networks. Analyzing many phenotypes simultaneously may increase the power to capture these unmeasured aspects and detect more variants. Several multivariate approaches aim to detect variants related to more than one phenotype, but these current approaches do not consider the effects of population structure. As a result, these approaches may result in a significant amount of false positive identifications. Here, we introduce a new methodology, referred to as GAMMA for generalized analysis of molecular variance for mixed-model analysis, which is capable of simultaneously analyzing many phenotypes and correcting for population structure. In a simulated study using data implanted with true genetic effects, GAMMA accurately identifies these true effects without producing false positives induced by population structure. In simulations with this data, GAMMA is an improvement over other methods which either fail to detect true effects or produce many false positive identifications. We further apply our method to genetic studies of yeast and gut microbiome from mice and show that GAMMA identifies several variants that are likely to have true biological mechanisms. PMID- 27770037 TI - The Nonstationary Dynamics of Fitness Distributions: Asexual Model with Epistasis and Standing Variation. AB - Various models describe asexual evolution by mutation, selection, and drift. Some focus directly on fitness, typically modeling drift but ignoring or simplifying both epistasis and the distribution of mutation effects (traveling wave models). Others follow the dynamics of quantitative traits determining fitness (Fisher's geometric model), imposing a complex but fixed form of mutation effects and epistasis, and often ignoring drift. In all cases, predictions are typically obtained in high or low mutation rate limits and for long-term stationary regimes, thus losing information on transient behaviors and the effect of initial conditions. Here, we connect fitness-based and trait-based models into a single framework, and seek explicit solutions even away from stationarity. The expected fitness distribution is followed over time via its cumulant generating function, using a deterministic approximation that neglects drift. In several cases, explicit trajectories for the full fitness distribution are obtained for arbitrary mutation rates and standing variance. For nonepistatic mutations, especially with beneficial mutations, this approximation fails over the long term but captures the early dynamics, thus complementing stationary stochastic predictions. The approximation also handles several diminishing returns epistasis models (e.g., with an optimal genotype); it can be applied at and away from equilibrium. General results arise at equilibrium, where fitness distributions display a "phase transition" with mutation rate. Beyond this phase transition, in Fisher's geometric model, the full trajectory of fitness and trait distributions takes a simple form; robust to the details of the mutant phenotype distribution. Analytical arguments are explored regarding why and when the deterministic approximation applies. PMID- 27770038 TI - Early angiographic signs of acute thrombus formation following cerebral aneurysm treatment with the Pipeline embolization device. AB - BACKGROUND AND OBJECTIVE: Acute thrombus formation following aneurysm treatment with the Pipeline embolization device (PED) is a potentially devastating complication that may result in significant thromboembolic sequelae if not promptly treated. We therefore evaluated PED cases complicated by acute thrombus formation at our institution, with an emphasis on identifying early angiographic signs that may portend this event. MATERIALS AND METHODS: We retrospectively identified cases of acute thrombosis following PED placement in 100 consecutive procedures performed at our institution from a prospectively maintained clinical database. Angiographic findings were analyzed for early signs of acute thrombus formation. We also evaluated the efficacy of treatment of this complication with a glycoprotein IIb/IIIa inhibitor (abciximab), as well as the results of pre procedure platelet inhibition testing. RESULTS: Acute thrombus formation was encountered in five patients following PED placement (5%). Early angiographic signs were present in all cases and included progressive stagnation of blood flow in covered side branches, occlusion of covered side branches, excessive stagnation of blood flow in the target aneurysm, as well as occlusion of the target aneurysm. These sequelae completely resolved following abciximab treatment in all five cases, with no permanent neurological morbidity or mortality. Four of the five patients had a pre-procedure P2Y12 value >200 (range 201-227). CONCLUSIONS: Progressive stagnation or occlusion of covered side branches or target aneurysm are early angiographic signs of acute thrombus formation following PED placement and should prompt immediate treatment with a glycoprotein IIb/IIIa inhibitor. Platelet inhibition testing may help identify those patients who are at an increased risk for this complication. PMID- 27770039 TI - A Critical Role for Extracellular DNA in Dental Plaque Formation. AB - Extracellular DNA (eDNA) has been identified in the matrix of many different monospecies biofilms in vitro, including some of those produced by oral bacteria. In many cases, eDNA stabilizes the structure of monospecies biofilms. Here, the authors aimed to determine whether eDNA is an important component of natural, mixed-species oral biofilms, such as plaque on natural teeth or dental implants. To visualize eDNA in oral biofilms, approaches for fluorescently stained eDNA with either anti-DNA antibodies or an ultrasensitive cell-impermeant dye, YOYO-1, were first developed using Enterococcus faecalis, an organism that has previously been shown to produce extensive eDNA structures within biofilms. Oral biofilms were modelled as in vitro "microcosms" on glass coverslips inoculated with the natural microbial population of human saliva and cultured statically in artificial saliva medium. Using antibodies and YOYO-1, eDNA was found to be distributed throughout microcosm biofilms, and was particularly abundant in the immediate vicinity of cells. Similar arrangements of eDNA were detected in biofilms on crowns and overdenture abutments of dental implants that had been recovered from patients during the restorative phase of treatment, and in subgingival dental plaque of periodontitis patients, indicating that eDNA is a common component of natural oral biofilms. In model oral biofilms, treatment with a DNA-degrading enzyme, NucB from Bacillus licheniformis, strongly inhibited the accumulation of biofilms. The bacterial species diversity was significantly reduced by treatment with NucB and particularly strong reductions were observed in the abundance of anaerobic, proteolytic bacteria such as Peptostreptococcus, Porphyromonas and Prevotella. Preformed biofilms were not significantly reduced by NucB treatment, indicating that eDNA is more important or more exposed during the early stages of biofilm formation. Overall, these data demonstrate that dental plaque eDNA is potentially an important target for oral biofilm control. PMID- 27770040 TI - Classic Spotlight: Genetics of Escherichia coli Chemotaxis. PMID- 27770041 TI - Classic Spotlight: Journal of Bacteriology Minireviews Illuminate Bacterial Translocation Systems. PMID- 27770043 TI - A USE1ful Biomarker and Molecular Target in Lung Cancer? PMID- 27770045 TI - De Novo TUBB2A Variant Presenting With Anterior Temporal Pachygyria. AB - TUBB2A is a gene that has recently been reported in association with structural brain abnormalities. Only 3 cases have been reported to date with disparate brain morphologic abnormalities, although all patients have presented with developmental delay and infantile-onset epilepsy. We report a fourth patient with a de novo variant in TUBB2A that is predicted to be pathogenic, presenting with developmental delay, spastic diplegia, exaggerated startle, and anterior temporal pachygyria in the absence of epilepsy. This report serves to further delineate the phenotype of the TUBB2A-related disorders. Focal anterior temporal pachygyria may facilitate recognition of additional cases of this tubulinopathy. PMID- 27770046 TI - Broadband Optical Properties of Milk. AB - Dairy products play an important role in our daily nutrition. As a turbid scattering medium with different kinds of particles and droplets, each alteration of these components changes the scattering properties of milk. The goal of this work is the determination of the amount of main scattering components, the fat droplets and the casein micelles, by understanding the light propagation in homogenized milk and in raw milk. To provide the absolute impact of these milk components, the geometrical and optical properties such as the size distribution and the refractive index (RI) of the components have to be examined. We determined the reduced scattering coefficient [Formula: see text] and the absorption coefficient [Formula: see text] from integrating sphere measurements. By use of a collimated transmission setup, the scattering coefficient [Formula: see text] was measured. Size measurements were performed to validate the influence of the fat droplet size on the results of the scattering properties; also, the RI of both components was determined by the said coefficients. These results were used to determine the absolute impact of the milk components on the scattering behavior. By fitting Mie theory calculations on scattering spectra [Formula: see text] and [Formula: see text] from different raw milk samples, it was possible to get reliable values for the concentrations of fat and casein and for the size of the fat droplets. By destroying the casein micelles, it was possible to separate the influence of the different scattering components on scattering behavior. PMID- 27770044 TI - Methotrexate impact on radiographic progression in biologic-treated rheumatoid arthritis under clinical remission: A case report on monozygotic Caucasian twins. AB - We describe Caucasian monozygotic twin brothers with rheumatoid arthritis (RA) and discuss influence of predictors to methotrexate (MTX) outcome treatment. Single nucleotide polymorphisms (SNPs) of the MTX metabolic pathways were genotyped. Twins have multiple mutations: a CC mutation of SNP 1298A>C in methylenetetrahydrofolate reductase (MTHFR) gene, CC mutations of three SNPs in the adenosine receptor gene ADORA2A (rs3761422_4217241T>C, rs2267076_4221164T>C, rs2236624_4226593T>C), and a heterozygous genotype in SNPs ATIC_rs2372536_347C>G, MTHFD1_rs2236225_1958G>A. These mutations are known to predict a worse outcome of MTX treatment. The twins had different lifestyles (alcohol drinking and smoking in Twin 1, regular coffee consumption in Twin 2), but a very similar clinical presentation of the outset of RA, radiographic scoring according to the Sharp/van der Heijde method with an almost identical antibodies presentation. The period of the patients before anti-TNFalpha treatment was characterized by unsuccessful per oral MTX pharmacotherapy in both cases (a low effect of MTX in Twin 1; an early discontinuation of MTX due to an adverse event in Twin 2). In both twins, the outcome of well-controlled anti-TNFalpha treatment (co-medication with MTX in Twin 1) for 10 years was expressed as low disease activity measured using composite index DAS28. It is interesting that Twin 2 had an unfavorable radiographic scoring after a 10-year follow-up than Twin 1 in spite of the comparable DAS28 in Twin 2 and smoking in Twin 1. In conclusion, co-medication of MTX with biologics may impact on RA radiographic progression despite predicted bad MTX outcome based on pharmacogenetic analysis. PMID- 27770047 TI - Action research healthcare: Focus on patients, improve quality, drive down costs. AB - We discuss action research healthcare as a transformative approach that continuously innovates in healthcare, attending to the "quadruple" aim. This article is shaped around a decade of evidence in Sweden. At the heart of healthcare action research is the endeavour to "learn by doing" with the participation of key stakeholders, including the patient. Experience suggests that an action research approach is particularly relevant when treating patients with chronic diseases and complex care needs. This inclusion is itself a social learning process and is key to realizing the improved outcomes. Insights from objective quantitative studies are balanced with personal and inter-subjective dialogue that aligns different parts of a system in a movement towards improvement. Close-up non-defensive self-inquiry in the company of colleagues, with trust dynamics building over time, may be a key point of leverage for such systemic improvement activities. PMID- 27770048 TI - Designated specialized units: How Ontario's long-term care homes fill a gap in care. AB - Ontario has eight designated Specialized Units (SUs) located in Long-Term Care (LTC) homes. Each unit serves a well-defined group of residents whose needs go beyond what regular LTC homes can offer but do not require the complexity and range of care provided in hospitals. An applied qualitative research project looked at the realities of designated SUs, explored their role in health system capacity planning, and created a tool kit to help stakeholders navigate the designation process. Results outline the benefits and challenges experienced by the existing SUs that provide care to clients with severe responsive behaviours or dialysis needs and the units' potential to address current and future healthcare system gaps. More systematic data collection, robust evaluations, and cost-benefit analyses are needed to fully understand how effectively and efficiently the SUs fulfill the outcomes desired by residents and their families, as well as how they contribute to health system efficiencies. PMID- 27770049 TI - Treatment decision, death and the value of life. PMID- 27770050 TI - Topics in death and dying. PMID- 27770051 TI - Social Death. PMID- 27770054 TI - Ubiquitous and ambient-assisted living eHealth platforms for Down's syndrome and palliative care in the Republic of Panama: A systematic review. AB - In this work, the authors present two eHealth platforms that are examples of how health systems are migrating from client-server architecture to the web-based and ubiquitous paradigm. These two platforms were modeled, designed, developed and implemented with positive results. First, using ambient-assisted living and ubiquitous computing, the authors enhance how palliative care is being provided to the elderly patients and patients with terminal illness, making the work of doctors, nurses and other health actors easier. Second, applying machine learning methods and a data-centered, ubiquitous, patient's results' repository, the authors intent to improve the Down's syndrome risk estimation process with more accurate predictions based on local woman patients' parameters. These two eHealth platforms can improve the quality of life, not only physically but also psychologically, of the patients and their families in the country of Panama. PMID- 27770052 TI - Nutrition Deficiencies in Mini Gastric Bypass Patients. PMID- 27770055 TI - 'Heading up a blind alley'? Scottish psychiatric hospitals in the era of deinstitutionalization. AB - This article examines Scottish provision of psychiatric care in the 1960s and 1970s. It demonstrates that institutional services did not rapidly disappear across the UK following the Ministry of Health's decision to shut down psychiatric hospitals in 1961, and highlights Scotland's distinctive trajectory. Furthermore, it contends that psychiatric hospitals developed new approaches to assist patients in this era, thereby contributing towards the transformation of post-war psychiatric practice. Connecting a discussion of policy with an analysis of provision, it examines the Department of Health for Scotland's cautious response to the Ministry's embrace of deinstitutionalization, before analysing Glasgow's psychiatric provision in the 1970s. At this point the city boasted virtually no community-based services, and relied heavily on its under-resourced and overburdened hospitals. Closer analysis dispels any impression of stagnation, revealing how ideologies of deinstitutionalization transformed institutional care. PMID- 27770056 TI - What is Intuitive Taxonomic Practice? AB - Scotland and Steel (2015) recently explored the idea of character compatibility, examining the issue from the perspective of a particular model, "a simple and extreme model in which each character either fits perfectly on some tree, or is entirely random $?ldots$,." (Scotland and Steel 2015, p. 492, abstract). They suggested that character compatibility, when formalized as a phylogenetic method, captured what they believed was the "intuitive taxonomic practice of recognizing taxa based on conserved nonhomoplastic characters" (Scotland and Steel 2015, p. 493). Although we agree that there is much to be said for compatibility analysis, and "it has largely been set aside, initially in favour of maximum parsimony, and, more recently, by model-based methods for inferring phylogeny from DNA sequence data" (Scotland and Steel 2015, p. 493), their use of the expression "intuitive taxonomic practice" attracted our attention. Below we discuss in more detail what "intuitive taxonomic practice" might be and relate that understanding to recent progress in the history of biology, specifically the history of systematics (taxonomy), and finally sketch out a proposal that might satisfy those of us who retain an interest in capturing in a more rigorous way what "intuitive taxonomic practice" might have been. [Compatibility methods; monothetic taxa; polythetic taxa."History is what we have to struggle to remember even when legend [myth] is more pleasing" (Adam Gopnik, The New Yorker, 23 November 2015). PMID- 27770057 TI - Plasma apelin-12 levels may predict in-hospital major adverse cardiac events in ST-elevation myocardial infarction and the relationship between apelin-12 and the neutrophil/lymphocyte ratio in patients undergoing primary coronary intervention. AB - OBJECTIVE: We aimed to investigate the compliance of plasma apelin-12 levels to show angiographic properties and hospital MACE in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). MATERIAL AND METHODS: The association of apelin-12 levels with the N/L ratio on admission was assessed in 170 consecutive patients with primary STEMI undergoing primary PCI. All patient SYNTAX scores and thrombolysis in myocardial infarction (TIMI) flow grades were also assessed. Patients were divided into two groups according to their TIMI flow grade. Patients with a TIMI 0-2 flow and TIMI 3 flow with grade 0/1 myocardial blush grade (MBG) score were defined as the no-reflow group and patients with TIMI grade 3 flow with ?2 MBG were considered as the normal flow group. RESULTS: Baseline apelin-12 levels were significantly lower in the no-reflow group than in the normal flow group (3.3+/ 1.81 vs 6.2+/-1.74, p<0.001). In-hospital events, including death, myocardial infarction (MI) and re-infarction were significantly higher in patients in the no reflow group than normal flow group (23% vs 7%, p<0.001). Apelin-12 level was negative correlated with the N/L ratio (r= -0.352, p<0.001), Hs-Crp (r=-0.272, p=0.01) and SYNTAX score (r= -0.246, p=0.029). In the multivariate regression analysis, apelin-12, presence of no-reflow and the SYNTAX score were independent predictors of in-hospital MACE (odds ratio [OR] 1.41, 95% confidence interval (CI) [1.27 to 1.67], p=0.001 for apelin-12, OR 1.085, [0.981 to 1.203], p<0.001 for no-reflow and OR 0.201, 95% CI [0.05 to 0.47], p= 0.004 for SYNTAX score). CONCLUSION: We have shown that lower apelin-12 level on admission is associated with higher SYNTAX scores and no-reflow phenomenon and may be used as a prognostic marker for hospital MACE in patients with STEMI. PMID- 27770058 TI - From Power to Inaction. AB - Research has shown that people who feel powerful are more likely to act than those who feel powerless, whereas people who feel ambivalent are less likely to act than those whose reactions are univalent (entirely positive or entirely negative). But what happens when powerful people also are ambivalent? On the basis of the self-validation theory of judgment, we hypothesized that power and ambivalence would interact to predict individuals' action. Because power can validate individuals' reactions, we reasoned that feeling powerful strengthens whatever reactions people have during a decision. It can strengthen univalent reactions and increase action orientation, as shown in past research. Among people who hold an ambivalent judgment, however, those who feel powerful would be less action oriented than those who feel powerless. Two experiments provide evidence for this hypothesized interactive effect of power and ambivalence on individuals' action tendencies during both positive decisions (promoting an employee; Experiment 1) and negative decisions (firing an employee; Experiment 2). In summary, when individuals' reactions are ambivalent, power increases the likelihood of inaction. PMID- 27770059 TI - Bayesian Models of Individual Differences. AB - According to Bayesian models, perception and cognition depend on the optimal combination of noisy incoming evidence with prior knowledge of the world. Individual differences in perception should therefore be jointly determined by a person's sensitivity to incoming evidence and his or her prior expectations. It has been proposed that individuals with autism have flatter prior distributions than do nonautistic individuals, which suggests that prior variance is linked to the degree of autistic traits in the general population. We tested this idea by studying how perceived speed changes during pursuit eye movement and at low contrast. We found that individual differences in these two motion phenomena were predicted by differences in thresholds and autistic traits when combined in a quantitative Bayesian model. Our findings therefore support the flatter-prior hypothesis and suggest that individual differences in prior expectations are more systematic than previously thought. In order to be revealed, however, individual differences in sensitivity must also be taken into account. PMID- 27770062 TI - At the Grave We Make Our Song: A Palliative Care Study in Rural Guatemala. AB - PURPOSE: We sought to understand decision making, family involvement, and cultural factors that influence palliative care for Guatemalans. DESIGN: A qualitative descriptive study was conducted in Guatemala to explore palliative care experiences among seven participants. FINDINGS: The overarching theme was Relief from Suffering, reinforced by three support systems: the family, community rezadora, and priest. The family made decisions and provided physical care. The rezadora sang prayers and prepared the home altar. The priest provided traditional sacraments. DISCUSSION: The role of the rezadora should be considered in providing palliative care to Guatemalans. Some Guatemalans are unfamiliar with or have difficulty understanding the role of the nurse in palliative and end-of life care. IMPLICATIONS: We suggest training opportunities using international resources to enhance the role for Guatemalan nurses in end-of-life care. Palliative care nurses in the United States may benefit from incorporating the rezadora into strategies that extend these services to Guatemalans. PMID- 27770061 TI - Spectacular Oscillations in Plant Isoprene Emission under Transient Conditions Explain the Enigmatic CO2 Response. AB - Plant isoprene emissions respond to light and temperature similarly to photosynthesis, but CO2 dependencies of isoprene emission and photosynthesis are profoundly different, with photosynthesis increasing and isoprene emission decreasing with increasing CO2 concentration due to reasons not yet understood. We studied isoprene emission, net assimilation rate, and chlorophyll fluorescence under different CO2 and O2 concentrations in the strong isoprene emitter hybrid aspen (Populus tremula * Populus tremuloides), and used rapid changes in ambient CO2 or O2 concentrations or light level to induce oscillations. As isoprene emitting species support very high steady-state chloroplastic pool sizes of the primary isoprene substrate, dimethylallyl diphosphate (DMADP), which can mask the effects of oscillatory dynamics on isoprene emission, the size of the DMADP pool was experimentally reduced by either partial inhibition of isoprenoid synthesis pathway by fosmidomycin-feeding or by changes in ambient gas concentrations leading to DMADP pool depletion in intact leaves. In feedback-limited conditions observed at low O2 and/or high CO2 concentration under which the rate of photosynthesis is governed by the limited rate of ATP and NADPH formation due to low chloroplastic phosphate levels, oscillations in photosynthesis and isoprene emission were repeatedly induced by rapid environmental modifications in both partly fosmidomycin-inhibited leaves and in intact leaves with in vivo reduced DMADP pools. The oscillations in net assimilation rate and isoprene emission in feedback-inhibited leaves were in the same phase, and relative changes in the pools of photosynthetic metabolites and DMADP estimated by in vivo kinetic methods were directly proportional through all oscillations induced by different environmental perturbations. We conclude that the oscillations in isoprene emission provide direct experimental evidence demonstrating that the response of isoprene emission to changes in ambient gas concentrations is controlled by the chloroplastic reductant supply. PMID- 27770060 TI - Cell-Type-Specific H+-ATPase Activity in Root Tissues Enables K+ Retention and Mediates Acclimation of Barley (Hordeum vulgare) to Salinity Stress. AB - While the importance of cell type specificity in plant adaptive responses is widely accepted, only a limited number of studies have addressed this issue at the functional level. We have combined electrophysiological, imaging, and biochemical techniques to reveal the physiological mechanisms conferring higher sensitivity of apical root cells to salinity in barley (Hordeum vulgare). We show that salinity application to the root apex arrests root growth in a highly tissue and treatment-specific manner. Although salinity-induced transient net Na+ uptake was about 4-fold higher in the root apex compared with the mature zone, mature root cells accumulated more cytosolic and vacuolar Na+, suggesting that the higher sensitivity of apical cells to salt is not related to either enhanced Na+ exclusion or sequestration inside the root. Rather, the above differential sensitivity between the two zones originates from a 10-fold difference in K+ efflux between the mature zone and the apical region (much poorer in the root apex) of the root. Major factors contributing to this poor K+ retention ability are (1) an intrinsically lower H+-ATPase activity in the root apex, (2) greater salt-induced membrane depolarization, and (3) a higher reactive oxygen species production under NaCl and a larger density of reactive oxygen species-activated cation currents in the apex. Salinity treatment increased (2- to 5-fold) the content of 10 (out of 25 detected) amino acids in the root apex but not in the mature zone and changed the organic acid and sugar contents. The causal link between the observed changes in the root metabolic profile and the regulation of transporter activity is discussed. PMID- 27770063 TI - Gait Analysis of Foot Compensation After Arthrodesis of the First Metatarsophalangeal Joint. AB - BACKGROUND: Arthrodesis of the first metatarsophalangeal (MTP1) joint is an intervention often used in patients with severe MTP1 joint osteoarthritis and relieves pain in approximately 80% of these patients. The kinematic effects and compensatory mechanism of the foot for restoring a more normal gait pattern after this intervention are unknown. The aim of this study was to clarify this compensatory mechanism, in which it was hypothesized that the hindfoot and forefoot would be responsible for compensation after an arthrodesis of the MTP1 joint. METHODS: Gait properties were evaluated in 10 feet of 8 patients with MTP1 arthrodesis and were compared with 21 feet of 12 healthy subjects. Plantar pressures and intersegmental range of motion were measured during gait by using the multisegment Oxford Foot Model. Pre- and postoperative X-rays of the foot and ankle were also evaluated. RESULTS: The MTP1 arthrodesis caused decreased eversion of the hindfoot during midstance, followed by an increased internal rotation of the hindfoot during terminal stance, and ultimately more supination and less adduction of the forefoot during preswing. In addition, MTP1 arthrodesis resulted in a lower pressure time integral beneath the hallux and higher peak pressures beneath the lesser metatarsals. A mean dorsiflexion fusion angle of 30 +/- 5.4 degrees was observed in postoperative radiographs. CONCLUSION: This study demonstrated that the hindfoot and forefoot compensated for the loss of motion of the MTP1 joint after arthrodesis in order to restore a more normal gait pattern. This resulted in a gait in which the rigid hallux was less loaded while the lesser metatarsals endured higher peak pressures. Further studies are needed to investigate whether this observed transfer of load or a preexistent decreased compensatory mechanism of the foot can possibly explain the disappointing results in the minority of the patients who experience persistent complaints after a MTP1 arthrodesis. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 27770064 TI - Predicting mobility outcome in lower limb amputees with motor ability tests used in early rehabilitation. AB - STUDY DESIGN: Retrospective cohort study. BACKGROUND: Persons with a lower limb amputation can regain mobility using a prosthetic device. For fast and adequate prescription of prosthetic components, it is necessary to predict the mobility outcome early in rehabilitation. Currently, prosthetic prescription is primarily based on empirical knowledge of rehabilitation professionals. OBJECTIVE: In this study, we explored motor ability tests, to be completed without a prosthetic device, which have predictive value for mobility outcome at the end of rehabilitation. METHODS: For this study, data of 82 patients with a lower limb amputation were included. The Single-limb standing balance test (Balance test), the Lower-Extremity Motor Coordination Test and the Amputee Mobility Predictor Assessment Tool (AMPnoPRO) were used as measures for motor ability. Mobility outcome was measured using the Timed Up and Go Test, the Two-Minute Walking Test and K levels were used. RESULTS: The explained variance of the Balance test, the Lower-Extremity Motor Coordination Test and the AMPnoPRO was, respectively, 0.603, 0.534 and 0.649 on the Two-Minute Walking Test (linear regression); 0.597, 0.431 and 0.624 on the Timed Up and Go Test (linear regression); and 0.432, 0.420 and 0.526 on the K levels (logistic regression). CONCLUSION: The AMPnoPRO predicted mobility outcome statistically (largest amount of explained variance). Clinical relevance This study explored the possibility of statistically predicting mobility outcome in lower limb amputees at the end of rehabilitation, using motor ability tests conducted in early rehabilitation. This study suggests the use of the AMPnoPRO to predict mobility outcome in lower limb amputees. PMID- 27770065 TI - Increased risk for clinical onset of myasthenia gravis during the postpartum period. AB - OBJECTIVE: To study the risk of clinical onset of myasthenia gravis (MG) in pregnancy and during the first 6 months postpartum because an association between pregnancy or the postpartum period and the onset of autoimmune MG is widely assumed but not proven. METHODS: The design was a cross-sectional population based cohort study of 2 MG cohorts (Norway and the Netherlands) with 1,038 healthy controls from Norway. Data were obtained on 246 women with MG (age at onset 15-45 years). Data on pregnancy, hormonal factors, and clinical symptoms were collected by a previously validated environmental MG questionnaire. Relative risk of MG onset before, during, and after pregnancy was calculated by multinomial logistic regression for Norwegian women reaching 45 years of age, adjusted for the observed distribution of person-years in the corresponding control group. RESULTS: Of the included women with MG, 13 (11.5%) of the Dutch and 24 (18.0%) of the Norwegian patients had their first myasthenia symptoms during the pregnancy or postpartum period. The postpartum period was confirmed to be significantly associated with the onset of symptoms of MG in Norwegian women with MG (relative risk 5.5, 95% confidence interval 2.6-11.6). The risk was highest after the first childbirth. CONCLUSIONS: Women have a high-risk period for the onset of clinical symptoms of MG in the postpartum period, in particular after the first childbirth. Future studies should aim at elucidating the role of the hormonal-immunological-genetic interaction in the pathogenesis of MG. PMID- 27770066 TI - Refining duration and frequency thresholds of restless legs syndrome diagnosis criteria. AB - OBJECTIVE: This study assesses the prevalence of restless legs syndrome (RLS) using DSM-5 criteria and determines what is the most appropriate threshold for the frequency and duration of RLS symptoms. METHODS: The Sleep-EVAL knowledge base system queried the interviewed subjects on life, sleeping habits, and health. Questions on sleep and mental and organic disorders (DSM-5, ICD-10) were also asked. A representative sample of 19,136 noninstitutionalized individuals older than 18 years living in the United States was interviewed through a cross sectional telephone survey. The participation rate was 83.2%. RESULTS: The prevalence of the 4 leg symptoms describing RLS occurring at least 1 d/wk varied between 5.7% and 12.3%. When the frequency was set to at least 3 d/wk, the prevalence dropped and varied between 1.8% and 4.5% for the 4 leg symptoms. Higher frequency of leg symptoms was associated with greater distress and impairment with a marked increase at 3 d/wk. Symptoms were mostly chronic, lasting for more than 3 months in about 97% of the cases. The prevalence of RLS according to DSM-5 was 1.6% (95% confidence interval 1.4%-1.8%) when frequency was set at 3 d/wk. Stricter criteria for frequency of restless legs symptoms resulted in a reduction of prevalence of the disorder. The prevalence was further reduced when clinical impact was taken into consideration. CONCLUSIONS: In order to avoid inflation of case rates and to identify patients in whom treatment is truly warranted, using a more conservative threshold of 3 times or greater per week appears the most appropriate. PMID- 27770067 TI - Objective, computerized video-based rating of blepharospasm severity. AB - OBJECTIVE: To compare clinical rating scales of blepharospasm severity with involuntary eye closures measured automatically from patient videos with contemporary facial expression software. METHODS: We evaluated video recordings of a standardized clinical examination from 50 patients with blepharospasm in the Dystonia Coalition's Natural History and Biorepository study. Eye closures were measured on a frame-by-frame basis with software known as the Computer Expression Recognition Toolbox (CERT). The proportion of eye closure time was compared with 3 commonly used clinical rating scales: the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale. RESULTS: CERT was reliably able to find the face, and its eye closure measure was correlated with all of the clinical severity ratings (Spearman rho = 0.56, 0.52, and 0.56 for the Burke-Fahn-Marsden Dystonia Rating Scale, Global Dystonia Rating Scale, and Jankovic Rating Scale, respectively, all p < 0.0001). CONCLUSIONS: The results demonstrate that CERT has convergent validity with conventional clinical rating scales and can be used with video recordings to measure blepharospasm symptom severity automatically and objectively. Unlike EMG and kinematics, CERT requires only conventional video recordings and can therefore be more easily adopted for use in the clinic. PMID- 27770069 TI - Electromyographic decoding of response to command in disorders of consciousness. AB - OBJECTIVE: To propose a new methodology based on single-trial analysis for detecting residual response to command with EMG in patients with disorders of consciousness (DOC), overcoming the issue of trial dependency and decreasing the influence of a patient's fluctuation of vigilance or arousal over time on diagnostic accuracy. METHODS: Forty-five patients with DOC (18 with vegetative/unresponsive wakefulness syndrome [VS/UWS], 22 in a minimally conscious state [MCS], 3 who emerged from MCS [EMCS], and 2 with locked-in syndrome [LIS]) and 20 healthy controls were included in the study. Patients were randomly instructed to either move their left or right hand or listen to a control command ("It is a sunny day") while EMG activity was recorded on both arms. RESULTS: Differential EMG activity was detected in all MCS cases displaying reproducible response to command at bedside on multiple assessments, even though only 6 of the 14 individuals presented a behavioral response to command on the day of the EMG assessment. An EMG response was also detected in all EMCS and LIS patients, and 2 MCS patients showing nonreflexive movements without command following at the bedside. None of the VS/UWS presented a response to command with this method. CONCLUSIONS: This method allowed us to reliably distinguish between different levels of consciousness and could potentially help decrease diagnostic errors in patients with motor impairment but presenting residual motor activity. PMID- 27770068 TI - Death with dignity in Washington patients with amyotrophic lateral sclerosis. AB - OBJECTIVES: To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. METHODS: Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. RESULTS: In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46-86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. CONCLUSIONS: Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients' goals without complications. PMID- 27770070 TI - Evaluation of dysphagia by novel real-time MRI. AB - OBJECTIVE: To assess safety and feasibility of real-time (RT) MRI for evaluation of dysphagia and to compare this technique to standard assessment by flexible endoscopic evaluation of swallowing (FEES) and videofluoroscopy (VF) in a cohort of patients with inclusion body myositis (IBM). METHODS: Using RT-MRI, FEES, and VF, an unselected cohort of 20 patients with IBM was studied as index disease with a uniform dysphagia. Symptoms of IBM and dysphagia were explored by standardized tools including Swallowing-Related Quality of Life Questionnaire (SWAL-QoL), IBM Functional Rating Scale, Patient-Reported Functional Assessment, and Medical Research Council Scale. RESULTS: Dysphagia was noted in 80% of the patients and SWAL-QoL was impaired in patients with IBM compared to published reference values of healthy elderly. Swallowing in a supine position during RT MRI was well-tolerated by all patients. RT-MRI equally revealed dysphagia compared to VF and FEES and correlated well with the SWAL-QoL. Only RT-MRI allowed precise time measurements and identification of the respective tissue morphology. The pharyngeal transit times were 2-fold longer compared to published reference values and significantly correlated with morphologic abnormalities. CONCLUSIONS: RT-MRI is safe and equally capable as VF to identify the cause of dysphagia in IBM. Advantages of RT-MRI include visualization of soft tissue, more reliable timing analysis, and lack of X-ray exposure. RT-MRI may become a routine diagnostic tool for detailed assessment of the esophagus and other moving parts of the body, facilitating longitudinal evaluations in daily practice and clinical trials. PMID- 27770071 TI - Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. AB - OBJECTIVE: To investigate seizure outcomes and their relationships to genotype and functional abilities in individuals with the cyclin-dependent kinase-like-5 (CDKL5) disorder. METHODS: Using the International CDKL5 Disorder Database, we identified 172 cases with a pathogenic CDKL5 mutation. We categorized individual mutations into 4 groups based on predicted structural and functional consequences. Negative binomial regression was used to model the linear association between current seizure rate and mutation group, current level of assistance required to walk 10 steps, and the highest level of expressive communication used to convey refusal or request. RESULTS: All but 3 (169/172) patients had a history of epilepsy. The median age at seizure onset was 6 weeks (range 1 week-1.5 years) and the median seizure rate at ascertainment was 2 per day (range 0-20 per day). After adjusting for walking ability and confounders including use or otherwise of polytherapy, seizure rate was lower in those with truncating mutations between aa172 and aa781 compared to those with no functional protein (incidence rate ratio [IRR] 0.57; 95% confidence interval [CI] 0.35 0.93). Ability to walk and use of spoken language were associated with lower rates of current seizures when compared to those with the least ability after adjusting for genotype (walking: IRR 0.62; 95% CI 0.39-0.99, communication: IRR 0.48; 95% CI 0.23-1.02). At a median age at questionnaire completion of 5 years, those previously treated with corticosteroids had more frequent seizures than those who have never been treated, whether or not there was a history of infantile spasms. CONCLUSIONS: Epilepsy is pervasive but not mandatory for the CDKL5 disorder. Genotype and functional abilities were related to seizure frequency, which appears refractory to antiepileptic drugs. PMID- 27770072 TI - Formal faculty observation and assessment of bedside skills for 3rd-year neurology clerks. AB - OBJECTIVE: To evaluate the feasibility and utility of instituting a formalized bedside skills evaluation (BSE) for 3rd-year medical students on the neurology clerkship. METHODS: A neurologic BSE was developed for 3rd-year neurology clerks at the University of Rochester for the 2012-2014 academic years. Faculty directly observed 189 students completing a full history and neurologic examination on real inpatients. Mock grades were calculated utilizing the BSE in the final grade, and number of students with a grade difference was determined when compared to true grade. Correlation was explored between the BSE and clinical scores, National Board of Medical Examiners (NBME) scores, case complexity, and true final grades. A survey was administered to students to assess their clinical skills exposure and the usefulness of the BSE. RESULTS: Faculty completed and submitted a BSE form for 88.3% of students. There was a mock final grade change for 13.2% of students. Correlation coefficients between BSE score and clinical score/NBME score were 0.36 and 0.35, respectively. A statistically significant effect of BSE was found on final clerkship grade (F2,186 = 31.9, p < 0.0001). There was no statistical difference between BSE score and differing case complexities. CONCLUSIONS: Incorporating a formal faculty-observed BSE into the 3rd year neurology clerkship was feasible. Low correlation between BSE score and other evaluations indicated a unique measurement to contribute to student grade. Using real patients with differing case complexity did not alter the grade. PMID- 27770073 TI - Mediodorsal nucleus and its multiple cognitive functions. PMID- 27770076 TI - IV tPA for acute ischemic stroke: Times are changing. PMID- 27770074 TI - Stable incidence but declining case-fatality rates of subarachnoid hemorrhage in a population. AB - OBJECTIVE: To characterize temporal trends in subarachnoid hemorrhage (SAH) incidence and outcomes over 5 time periods in a large population-based stroke study in the United States. METHODS: All SAHs among residents of the Greater Cincinnati/Northern Kentucky region at least 20 years of age were identified and verified via study physician review in 5 distinct year-long study periods between 1988 and 2010. We abstracted demographics, care patterns, and outcomes, and we compared incidence and case-fatality rates across the study periods. RESULTS: The incidence of SAH in the 5 study periods (age-, race-, and sex-adjusted to the 2000 US population) was 8.8 (95% confidence interval 6.8-10.7), 9.2 (7.2-11.2), 10.0 (8.0-12.0), 9.0 (7.1-10.9), and 7.7 (6.0-9.4) per 100,000, respectively; the trend in incidence rates from 1988 to 2010 was not statistically significant (p = 0.22). Advanced neurovascular imaging, endovascular coiling, and neurologic intensive care unit availability increased significantly over time. All-cause 5 day (32%-18%, p = 0.01; for trend), 30-day (46%-25%, p = 0.001), and 90-day (49% 29%, p = 0.001) case-fatality rates declined from 1988 to 2010. When we included only proven or highly likely aneurysmal SAH, the declines in case-fatality were no longer statistically significant. CONCLUSIONS: Although the incidence of SAH remained stable in this population-based region, 5-day, 30-day, and 90-day case fatality rates declined significantly. Advances in surgical and medical management, along with systems-based changes such as the emergence of neurocritical care units, are potential explanations for the reduced case fatality. PMID- 27770077 TI - Where There Is a (Collective) Will, There Are (Effective) Ways: Integrating Individual- and Group-Level Factors in Explaining Humanitarian Collective Action. AB - The 21st century has borne witness to catastrophic natural and human-induced tragedies. These disasters necessitate humanitarian responses; however, the individual and collective bases of support are not well understood. Drawing on Duncan's motivational model of collective action, we focus on how individual differences position a person to adopt group memberships and develop a "group consciousness" that provides the basis for humanitarian action. Longitudinal mediation analyses involving supporters of international humanitarian action (N = 384) sampled annually for 3 years provided support for the hypothesized model, with some twists. The results revealed that within time point, a set of individual differences (together, the "pro-social orientation") promoted a humanitarian group consciousness that, in turn, facilitated collective action. However, longitudinally, there was evidence that a more general pro-social orientation undermined subsequent identification with, and engagement in, the humanitarian cause. Results are discussed in terms of understanding the interplay between individual and group in collective actions. PMID- 27770075 TI - Emerging temporal trends in tissue plasminogen activator use: Results from the BASIC project. AB - OBJECTIVE: To explore temporal trends in tissue plasminogen activator (tPA) administration for acute ischemic stroke (AIS) in a biethnic community without an academic medical center and variation in trends by age, sex, ethnicity, and stroke severity. METHODS: Cases of AIS were identified from 7 hospitals in the Brain Attack Surveillance in Corpus Christi (BASIC) project, a population-based surveillance study between January 1, 2000, and June 30, 2012. tPA, demographics, and stroke severity as assessed by the NIH Stroke Scale (NIHSS) were ascertained from medical records. Temporal trends were explored using generalized estimating equations, and adjustment made for age, sex, ethnicity, and NIHSS. Interaction terms were included to test for effect modification. RESULTS: There were 5,277 AIS cases identified from 4,589 unique individuals. tPA use was steady at 2% and began increasing in 2006, reaching 11% in subsequent years. Stroke severity modified temporal trends (p = 0.003) such that cases in the highest severity quartile (NIHSS > 8) had larger increases in tPA use than those in lower severity quartiles. Although ethnicity did not modify the temporal trend, Mexican Americans (MAs) were less likely to receive tPA than non-Hispanic whites (NHWs) due to emerging ethnic differences in later years. CONCLUSIONS: Dramatic increases in tPA use were apparent in this community without an academic medical center. Primary stroke center certification likely contributed to this rise. Results suggest that increases in tPA use were greater in higher severity patients compared to lower severity patients, and a gap between MAs and NHWs in tPA administration may be emerging. PMID- 27770079 TI - Naked Aggression: The Meaning and Practice of Ejaculation on a Woman's Face. AB - Based on in-depth interviews with 16 heterosexual men, this study focuses on participants' meaning-making surrounding a common and controversial sexual act in pornography: ejaculation on a woman's face (EOWF). We analyze the ways that male consumers decoded EOWF and the ways that EOWF, as a sexual script, was included in the men's accounts of their sexual desires and practices. The majority of the men decoded EOWF through the preferred (encoded) meaning as an act of male dominance and sexual aggression and that they wanted to engage in it despite their general belief that women would not be interested in it. PMID- 27770078 TI - Naturally Biased Associations Between Music and Poetry. AB - The study analyzes the existence of naturally biased associations in the general population between a series of musical selections and a series of quatrains. Differently from other studies in the field, the association is tested between complex stimuli involving literary texts, which increases the load of the semantic factors. The stimuli were eight quatrains taken from the same poem and eight musical clips taken from a classical musical version of the poem. The experiment was conducted in two phases. First, the participants were asked to rate 10 couples of opposite adjectives on a continuous bipolar scale when reading a quatrain or when listening to a musical clip; then they were asked to associate a given clip directly with the quatrains in decreasing order. The results showed the existence of significant associations between the semantics of the quatrains and the musical selections. They also confirmed the correspondences experienced by the composer when writing the musical version of the poem. Connotative dimensions such as rough or smooth, distressing or serene, turbid or clear, and gloomy or bright, characterizing both the semantic and the auditory stimuli, may have played a role in the associations. The results also shed light on the accomplishment of the two diverse methodologies adopted in the two different phases of the test. Finally, the role of specific musical components and their combinations is likely to have played an important role in the associations, an aspect that shall be addressed in further studies. PMID- 27770081 TI - Thoracic Outlet Syndrome in a Volleyball Player Due to Nonunion of the First Rib Fracture. AB - Fracture of the first rib with ensuing callus formation is a rare cause of thoracic outlet syndrome. We report a case of a 17-year-old female volleyball player who presented with months of chronic arm pain. Radiographic imaging demonstrated nonunion fracture of the first rib. Physical therapy had been unsuccessful in relieving the pain, and surgical management was performed with resection of the first rib through a transaxillary approach with complete resolution of symptoms. Inflammation surrounding such fractures may destroy tissue planes, making dissection more technically difficult. PMID- 27770080 TI - Lower Extremity Revascularization in End-Stage Renal Disease. AB - Patients with end-stage renal disease (ESRD) who present with critical limb ischemia (CLI) have become an increasingly common and complex treatment problem for vascular surgeons. Dialysis patients have high short-term mortality rates regardless of whether revascularization is pursued. ESRD patients with CLI can be managed with: local wound care, endovascular or surgical revascularization, or amputation. Some patients may heal small foot wounds with local wound care alone, even if distal perfusion is marginal, as long as any infectious process has been controlled. Surgical revascularization has a mortality rate of 5-10% but has a high chance of limb salvage. However, overall 5-year survival may be as low as 28%. Endovascular therapy also carries a high perioperative mortality risk in this population with similar limb salvage rates. Amputation is indicated in patients with advanced stage CLI, as described by the Society for Vascular Surgery's Wound, Ischemia and foot Infection (WIfI) system. Statistical models predict that endovascular or surgical revascularization strategies are less costly and more functionally beneficial to patients than primary amputation alone. Decisions on how to manage ESRD patients with CLI are complex but revascularization can often result in limb salvage, despite limited overall survival. Dialysis patients with good life expectancy and good quality conduit may benefit most from surgical bypass. PMID- 27770084 TI - RCVS and BVA highlight concerns about Brexit. PMID- 27770082 TI - Endovascular Reconstruction of Extrahepatic Portal Vein in Noncirrhotic and Nonmalignant Chronic Portal Vein Thrombosis Secondary to an Iatrogenic Stenotic Lesion. AB - Portal vein (PV) thrombosis (PVT) in the absence of liver disease or thrombophilia is rare. We report a 57-year-old male with a history of stage 3 chronic kidney disease who presented at the emergency department 18 months after abdominal surgery with progressive abdominal pain and distention. Computed tomography revealed PVT with multiple collaterals and moderate ascites. He had undergone partial gastrectomy and gastrojejunal anastomosis at an outside facility for gastrointestinal stromal tumors that caused an iatrogenic stenotic lesion in the PV. The patient underwent balloon angioplasty and endovascular deployment of an 8 mm * 100 mm Viabahn covered stent (W. L. Gore and Associates, Flagstaff, Arizona) in the extrahepatic PV via a transhepatic approach; the device allowed complete restoration of prograde portal flow with clinical improvement. At 6 months from the intervention, he remains symptom-free with normal liver function tests and patent endoprosthesis on antiplatelet therapy. PMID- 27770086 TI - Wales to adopt a regional approach to bovine TB. PMID- 27770087 TI - 'Outstanding' practices recognised. PMID- 27770085 TI - Equine antibiotic recalled. PMID- 27770091 TI - Brexit: BVA Council agrees key principles for the profession. AB - ? Principles to underpin the profession's lobbying position during Brexit negotiations? Policy priorities for 2016/17? Update on BVA's strategic planThese were among matters discussed by the BVA Council at its meeting during BVA Members' Day on September 22. The then BVA President, Sean Wensley, chaired the meeting, which was held at the At-Bristol Science Centre in Bristol. PMID- 27770090 TI - Support for equine vets juggling practice and parenthood. AB - This year's BEVA congress saw the launch of MumsVet, an online support network for working parents. Set up by four working vet mums, including the new BEVA president, Vicki Nicholls, the network - for dads as well - aims to help vets balance work and parenthood. Gill Harris reports. PMID- 27770092 TI - Lamb deaths associated with administration of oral minerals. AB - Deaths in preweaned lambs associated with administering oral minerals containing copperCongenital malformations in calvesIdiopathic necrotising enteritis in calvesAbomasal obstruction due to trichobezoars in suckled calvesRadial neuropathy (kangaroo gait) in a ewe These are among matters discussed in the disease surveillance report for July 2016 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 27770093 TI - Why aren't more veterinary practices owned or led by women? PMID- 27770094 TI - One Welfare - a platform for improving human and animal welfare. AB - Adopting the concept of One Welfare could help to improve animal welfare and human wellbeing worldwide, argue Rebeca Garcia Pinillos, Michael Appleby, Xavier Manteca, Freda Scott-Park, Charles Smith and Antonio Velarde. PMID- 27770095 TI - Importation of a Hyalomma lusitanicum tick into the UK on a dog. PMID- 27770096 TI - Treatment of contagious ovine digital dermatitis. PMID- 27770105 TI - Ups and downs of life as a PhD student. AB - Myfanwy Hill reflects on her coping strategies and recognises her limitations. She has learnt why it is important to relax and recharge. PMID- 27770097 TI - Treatment of contagious ovine digital dermatitis. PMID- 27770106 TI - Ten-minute chat. AB - TV vet Steve Leonard is a patron of the Painted Dog Conservation UK charity. From time to time he leads conservation safaris to the charity's centre in Hwange National Park in Zimbabwe. PMID- 27770107 TI - Is It Adverse, Nonadverse, Adaptive, or Artifact? AB - One of the principal challenges facing a toxicologic pathologist is to determine and differentiate a true adverse effect from a nonadverse or an adaptive response. Recent publications from the Society of Toxicologic Pathology (STP) and the European STP provide guidance for determining and communicating adversity in nonclinical toxicology studies. In order to provide a forum to inform and engage in a discussion on this important topic, a continuing education (CE) course was held during the 2016 STP Annual meeting in San Diego, CA. The lectures at this course provided guidance on determining and communicating adversity using case studies involving both clinical pathology and anatomic pathology. In addition, one talk also focused on data quality, study design, and interpretation of artifacts that could hinder the determination of adversity. The CE course ended with a talk on understanding adversity in preclinical studies and engaging the regulatory agencies in the decision-making process. This manuscript is designed to provide brief summaries of all the talks in this well-received CE course. PMID- 27770108 TI - Histological Development of Male Reproductive Organs in Microminipigs. AB - Microminipigs are becoming increasingly attractive alternatives for various experimental applications, such as general toxicology studies, owing to their manageable size. However, there are limited studies on the male reproductive organs of microminipigs, particularly on the histological aspects of sexual maturity. To clarify the development of male reproductive organs, 35 male microminipigs, aged 0 to 12 months, were used in this study. Histological and histomorphological evaluation was performed based on spermatogenic development, measurement of tubular structure in testes and epididymides, and histological progress of accessory glands. In addition, spontaneous testicular changes were quantitatively assessed. Histologically, male microminipigs sexually matured around 4.5 months of age, when spermatogenesis in testes and structural development in genital organs were completed. Spontaneous testicular changes occurred in all the animals investigated. Multinucleated giant cell was most commonly observed, followed by hypospermatogenesis and tubular atrophy/hypoplasia. However, the number of affected tubules was less than 1% in testes after 4.5 months of age, suggesting that the influence of these changes on evaluation of toxicity studies may be minimal. It is preferable to use sexually mature animals in toxicology studies; therefore, the information obtained by the present study will be helpful for future toxicity evaluations in microminipigs. PMID- 27770110 TI - The Microbiome. AB - The microbiome is increasingly recognized as a critical component in human development, health, and disease. Its relevance to toxicology and pharmacology involves challenges to current concepts related to absorption, metabolism, gene:environment, and pathways of response. Framing testable hypotheses for experimental and epidemiological studies will require attention to study designs, biosampling, data analysis, and attention to confounders. PMID- 27770109 TI - The Application of Paraphenylenediamine Staining for Assessment of Phospholipidosis. AB - Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies in cells exposed to xenobiotics. Demonstration of the lamellar bodies by transmission electron microscopy (TEM) is the hallmark for a definitive diagnosis of phospholipidosis. However, the preparation of tissue samples for TEM and their ultrastructural evaluation are technically challenging and time consuming. Paraphenylenediamine (PPD) is essentially a fat stain, and the staining mechanism is based upon the osmication of unsaturated lipids. Thus, the application of PPD staining to osmicated tissue samples is considered an optimal way to identify lipids. We evaluated the potential of PPD staining to localize phospholipid accumulations on osmium-fixed semi-thin tissue sections of the lung, kidney, and liver, which were affected with phospholipidosis, under a light microscope. PPD staining revealed the presence of PPD positive dark fine granular material in the cytoplasm for all affected tissues examined, which correlated ultrastructurally with lamellar bodies as well as a light microscopic finding of cytoplasmic vacuolation. The great advantage of PPD is that it can be incorporated into the protocol for standard TEM tissue preparation and significantly improve the efficiency of TEM work. In conclusion, PPD provides a simple, sensitive, and reliable method for visualizing phospholipid accumulation on light microscopy and represents an easy tool to study drug-induced phospholipidosis. PMID- 27770111 TI - Correction: Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle. PMID- 27770112 TI - Measles-Mumps-Rubella vaccine for children with egg allergy: Is admission for inpatient vaccination necessary? AB - INTRODUCTION: Children who develop any hypersensitivity reaction to eggs are routinely referred to hospital for Measles-Mumps-Rubella (MMR) vaccination as inpatients to prevent anaphylaxis. We aimed to study the association between hypersensitivity reactions after egg exposure and similar reactions after MMR immunisation; and examine the necessity of hospital admission for vaccination. METHODS: A prospective observational study was conducted in Paediatric Department in Bukit Mertajam Hospital, Penang, between March and December 2014. Children referred from local polyclinics for inpatient MMR vaccination because of a history of egg allergy were recruited. The children were observed in the ward for post vaccination allergic reactions. Concurrently, a group of children without egg allergy was recruited from those admitted for other illnesses but had recent MMR vaccination at polyclinics. Parents of these children were interviewed and asked if they had observed any reactions post vaccination. In both groups, sociodemographics, medical history and family history of atopy were collected. RESULTS: Eighty-seven subjects were recruited in this study. Fifty-four infants with egg allergy had previous mild allergic reactions after exposure to eggs or egg-related products. They were associated with a family history of egg hypersensitivity, personal history of acute gastroenteritis and upper respiratory tract infections. Two of them developed cutaneous rashes post vaccination during observation, but none developed anaphylactic or anaphylactoid reactions. Two infants among those without egg allergy had post vaccination fever. There was no association between egg allergy and hypersensitivity reactions to MMR vaccine (p=0.632). CONCLUSIONS: MMR vaccine can be safely administered to children with mild egg allergy, hence admission for vaccination in the hospital is not warranted. Risk stratification is required to ensure only infants with severe reactions will be admitted for vaccination. PMID- 27770113 TI - Jellyfish stings on Langkawi Island, Malaysia. AB - INTRODUCTION: Jellyfish stings are the most frequently reported marine animal envenomation worldwide. However, data on jellyfish sting from Malaysia remains obscure due to inadequate research. METHODS: We investigated the epidemiology, clinical features and treatment of patients presenting at the emergency department of Langkawi Hospital between January 2012 and December 2014. Secondary data on the nature of the incident, patient demographics, clinical presentation, and treatment were retrieved from the patients' medical records. Descriptive statistics were presented for all patient variables. RESULTS: A total of 759 patients presented with jellyfish stings during the 3-year study period, with highest number of visits in July, October, November, and December. The mean patient age was 26.7 years (SD: 12.14), 59.4% were men, 68.1% were foreigners or international tourists, and 40.4% were stung between 12.00 p.m. and 6:59 p.m. At least 90 patients presented with mild Irukandji or Irukandji-like syndromes. Most of the jellyfish stings occurred at Chenang Beach (590 reported cases), followed by Tengah Beach and Kok Beach. Most patients were treated symptomatically, and no deaths following a jellyfish sting was reported during the study period. CONCLUSION: There is a need for public health interventions for both local and international tourists who visit Langkawi Island. Preventive steps and education on initial treatment at the incident site could elevate public awareness and decrease the adverse effects of jellyfish stings. PMID- 27770114 TI - The effect of prophylactic phenylephrine on systemic hypotension during induction of anaesthesia with propofol in patients over 55 years old. AB - BACKGROUND: Induction of anaesthesia with propofol is often associated with a significant decrease in arterial pressure, especially in the older population. The aim of this study is to determine the efficacy of phenylephrine in two different doses i.e. 100mcg and 200mcg, given during induction to counteract the anticipated hypotensive effect of propofol in older patients aged over 55 years. METHODS: Seventy-two ASA physical status I - II patients aged 55 years or older were randomly allocated to group 1 (received propofol mixed with normal saline), group 2 (propofol mixed with 100mcg of phenylephrine) or group 3 (propofol mixed with 200mcg of pheynylphrine). Anaesthesia was induced with fentanyl 1.5mcg/kg and propofol 2mg/kg (mixed with the study drug). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and heart rate (HR) were recorded at 1 minute intervals for up to 5 minutes after induction. RESULTS: SBP, MAP and DBP decreased significantly after induction in the control group and group 2 (phenylephrine 100mcg). In contrast, SBP was maintained to near baseline for the first two minutes after induction using phenylephrine 200mcg in group 3, and similar trends were seen with MAP and DBP at a lesser magnitude. CONCLUSION: Phenylephrine 200mcg is more effective than 100mcg in attenuating propofol induced hypotension, especially during the first two minutes after induction, in patients aged 55 years and above. PMID- 27770115 TI - Clinico-epidemiological profile, including body mass index of Malaysian children with psoriasis. AB - BACKGROUND: Limited information exists regarding paediatric psoriasis and its association with body mass index (bMI) in Asia. OBJECTIVES: to determine the clinico-epidemiological profile and to compare the bMI of children with and without psoriasis. METHODS: A case-control study of 92 children with psoriasis versus 59 with atopic eczema and 56 with non-inflammatory skin conditions. RESULTS: Psoriasis was more common in Malay and Indian children when compared to Chinese with odds ratios (Or) of 4.30 (95% CI, 1.85-9.99) and 3.00 (95% CI, 1.02 8.81) respectively. Prevalence of psoriasis was similar between Malay and Indian children (Or 1.43, 95% CI, 0.63-3.25). Male:female ratio was 1:1.09. the mean onset age of psoriasis was 7.9 years. Median onset age was earlier in males (6.5 years versus 9.0 years in females, p=0.05). Plaque psoriasis was the most common phenotype (89.1%) and 94.5% had scalp lesions. Arthritis was seen in 4.3%. Odds of excess adiposity, defined as bMI <=85th percentile, was higher in children with psoriasis versus noninflammatory controls (Or 2.35, 95% CI 0.99-5.56, p= 0.052). No increased risk of adiposity was noted between children with psoriasis and eczema (Or 1.14, 95% CI 0.5-2.62, p=0.753). More children with psoriasis (17.4%) and eczema (20.3%) were underweight (bMI <5th percentile) compared to non inflammatory controls (10.7%). CONCLUSION: Malays and Indians are three to four times more likely than Chinese to have psoriasis in multi-ethnic Malaysia. Plaque psoriasis is the most common phenotype. Odds of excess adiposity is about two times higher in children with psoriasis compared to non-inflammatory controls although this observation just missed conventional statistical significance. PMID- 27770116 TI - DiabCare 2013: A cross-sectional study of hospital based diabetes care delivery and prevention of diabetes related complications in Malaysia. AB - AIMS: The aim of the study was to re-evaluate the relationship between hospital based diabetes care delivery and prevention of complications. METHODS: DiabCare is an observational, non-interventional, cross-sectional study of hospital-based outpatient diabetes care. RESULTS: A total of 1668 patients participated in the study: mean age 57.8 +/- 11.0 years, duration of diabetes 13.0 +/- 8.6 years, and duration of insulin treatment 5.6 +/- 5.5 years. Mean weight was 74.3 +/- 16.6 kg (BMI 29.1 +/- 5.8 kg/m2). The majority of patients were female (53.6%) and the largest ethnic group was Malay (51.3%), followed by Indian (21.9%) and Chinese (20.1%). The percentage of patients with HbA1c < 6.5% (< 42 mmol/mol) and < 7.0% (< 53 mmol/mol) was 12.2% and 23.8%, respectively (mean HbA1c 8.52 +/- 2.01% [70 +/- 22 mmol/mol]). The proportion of patients using insulin was 65% at a total daily dose of 60 +/- 37 IU. One or more episodes of hypoglycaemia were reported by 39% (n=658) of patients within the previous three months. The risk of any hypoglycaemia was associated with the use of insulin (odds ratio [OR 3.26, 95% CI 2.59-4.09]), and total daily insulin dose (OR 1.04, 95% CI 1.01-1.07 per 10 IU increase). Mean HbA1c had not changed significantly between DiabCare cohorts 2008 and 2013 (p=0.08). CONCLUSIONS: Despite evidence of improving processes of diabetes care, glycaemic control and the prevalence of many diabetes related complications were unchanged. PMID- 27770117 TI - Parental preferences with regards to disclosure following adverse events occurring in relation to medication use or diagnosis in the care of their children - perspectives from Malaysia. AB - INTRODUCTION: Open disclosure is poorly understood in Malaysia but is an ethical and professional responsibility. The objectives of this study were to determine: (1) the perception of parents regarding the severity of medical error in relation to medication use or diagnosis; (2) the preference of parents for information following the medical error and its relation to severity; and (3) the preference of parents with regards to disciplinary action, reporting, and legal action. METHODS: We translated and contextualised a questionnaire developed from a previous study. The questionnaire consisted of four case vignettes that described the following: medication error with a lifelong complication; diagnostic error with a lifelong complication; diagnostic error without lifelong effect; and medication error without lifelong effect. Each case vignette was followed by a series of questions examining the subject's perception on the above areas. We also determined the content validity of the questionnaire. We invited parents of Malaysian children admitted to the paediatric wards of Tuanku Jaafar Hospital to participate in the study. RESULTS: One hundred and twenty-three parents participated in the study. The majority of parents wanted to be told regarding the event. As the severity of the case vignettes increased, the desire for information, remedial action, acknowledgement of responsibility, compensation, punishment, legal action, and reporting to a higher agency also increased. The findings did not have strong evidence of a relationship with subject's demographics. CONCLUSION: This study gives insights into previously unexplored perspectives and preferences of parents in Malaysia regarding open disclosure. It also highlights the opportunity for more research in this area with potentially broad applications. PMID- 27770118 TI - Diagnostic performance of contrast-enhanced ultrasound in the evaluation of renal masses in patients with renal impairment. AB - OBJECTIVE: To evaluate the performance of contrastenhanced ultrasound (CEUS) in the risk stratification of indeterminate renal lesions picked up incidentally on abdominal imaging, in patients with renal impairment. METHODS: A retrospective study was performed of nonconsecutive patients who underwent CEUS at our tertiary care centre for indeterminate renal lesions between March 2010 and September 2014. A total of 63 patients with 74 nodules were assessed with CEUS and stratified into either benign (Bosniak I, II, IIF) or suspicious for malignancy (Bosniak III, IV or hypervascular solid lesions). Diagnostic accuracy was determined by comparing these findings to subsequent histological diagnoses, temporal change after at least 20 months follow-up or after a diagnostic computer tomography / magnetic resonance imaging study. RESULTS: CEUS correctly identified 49/52 (94.2%) of benign lesions and 21/22 (95.5%) of malignant lesions, resulting in a sensitivity of 95.5% (95% CI 77.2-99.9%), specificity of 94.2% (95% CI 84.1 98.8%), positive predictive value (PPV) 87.5% (95% CI 67.6-97.3) and negative predictive value (NPV) 98.0% (95% CI 89.4-100%). CONCLUSION: CEUS has high diagnostic performance in predicting the benignity of a renal lesion in patients with renal impairment, showing sensitivity and NPV approaching 100%. PMID- 27770119 TI - You can never have too many accessories - a case of two accessory muscles of the ankle. AB - Accessory muscles are relatively rare anatomic duplications of muscles that may appear anywhere in the muscular system. Though a wide array of accessory and supernumery muscles involving the ankle have been described in the literature, this is the first reported case we are aware of that features two accessory muscles. Accessory muscles are typically asymptomatic and often picked up as incidental findings but are important to be identified in the presence of chronic persistent ankle pain and the absence of other more common aetiologies. PMID- 27770120 TI - A dedifferentiated large posterior mediastinal liposarcoma - An incidental finding successfully resected. AB - This is a case of a posterior mediastinal mass in an asymptomatic gentleman, which was resected successfully and he has been disease free for more than a year of follow up. The histopathology findings happen to be a rare occurrence. PMID- 27770121 TI - A curious case of Meckel's diverticulum. AB - Meckel's diverticulitis or Meckel's associated pathology frequently presents in childhood with gastrointestinal bleeding. It is rarely seen in adults. It is a congenital abnormality that commonly goes undetected. We present a case of a perforated Meckel's diverticulum due to fishbone ingestion in an elderly gentleman. The aim of this case report is to highlight the rare presentation of a perforation in a Meckel's diverticulum due to an extrinsic pathology and to outline diagnostic and management options in cases of Meckel's diverticulum. PMID- 27770122 TI - Discrepancy in blood pressure between the left and right arms - importance of clinical diagnosis and role of radiological imaging. AB - INTRODUCTION: Differences in systolic blood pressure reading between arms are common but could signal trouble if the discrepancy is significant. Early detection of aortic dissection could invariably determine patient's survivability. Hence, a high index of suspicion with prompt diagnostic imaging is vital for accurate diagnosis. CASE PRESENTATION: A previously healthy 35-year-old lady was referred from district hospital for hypertensive cardiomyopathy complicated by acute pulmonary oedema. After being admitted to the Intensive Care Unit, the mean arterial pressure on the left arm was noted to be significant higher. On physical examination, both lower limbs were dusky in appearance because of poor perfusion. INVESTIGATIONS: Computed Tomography Angiography showed extensive arch and abdominal aorta dissection extending to the proximal common carotid artery. There was distal abdominal aorta thrombosis with partial left renal infarction. Echocardiogram showed global hypokinesia, presence of intimal flap, aortic regurgitation and mild pericardial effusion. Supine chest X-ray showed apparent cardiomegaly. TREATMENT: Repair of the ascending aortic dissection and suspension of the aortic valve by the cardiothoracic team on Day 2 of admission. The vascular team did bilateral high above knee amputation on Day 9 of admission. OUTCOME: Patient passed away on Day 10 of admission. DISCUSSION: With the absence of classical features of aortic dissection, establishing the diagnosis can be challenging and requires both good clinical judgment and prompt radiological imaging, such that early treatment can be initiated. CONCLUSION: A high index of suspicion and good clinical judgment is needed in cases of significant blood pressure discrepancy between arms. PMID- 27770123 TI - Rituximab-induced lung disease. AB - Pulmonary toxicity is a rare complication of Rituximab therapy. Although Rituximab is relatively safe and can be administered in an outpatient setting, Rituximab-associated lung disease has been reported and may cause mortality despite early detection. Typically the pulmonary toxicity occurs at around the fourth cycle of Rituximab. High index of suspicion is crucial and other concurrent pathology such as infective causes should be excluded. Radiological imaging and histological confirmation should be obtained and early treatment with corticosteroid should be initiated. Patients should receive counselling regarding respiratory symptoms and possible pulmonary toxicity. PMID- 27770124 TI - Multiple magnet ingestion: The attractive hazardst. AB - Foreign body ingestion among children is common and most usually pass through the gastrointestinal tract without requiring any intervention. Magnets, however, pose a greater threat especially when more than one are ingested. We report a case of multiple bowel perforation secondary to ingestion of magnetic beads in a 3-year old. PMID- 27770125 TI - A case report of aluminium phosphide poisoning. AB - Aluminium phosphide (ALP) is highly toxic and poisoning can result in high mortality rates. A 26-year-old female who allegedly ingested a toxic dose of ALP presented with vomiting and diarrhoea. She developed cardiac arrest with refractory pulseless ventricular tachycardia. Despite aggressive resuscitation, she succumbed to death seven hours following ingestion. In cases like this, a better outcome can be achieved with early arrival, prompt diagnosis, aggressive resuscitation and intensive monitoring. PMID- 27770126 TI - Gastrointestinal bleeding caused by epitheloid sarcoma: A case report. AB - Epithelioid sarcoma (ES) of the small bowel is a rare gastrointestinal tumour. We report a case of gastrointestinal bleeding secondary to small bowel ES in a 55 year-old gentleman. After gastroscopy and colonoscopy failed to identify the source of bleeding, we proceeded with computed tomography angiogram of the mesentery, which revealed intraluminal blood clot in the distal jejunum with features of obstruction. This is a rare cause of obscure gastrointestinal bleeding and emphasises the need for additional evaluation in the presence of negative endoscopic findings. PMID- 27770127 TI - Late presentation of ALCAPA syndrome in an elderly Asian lady. AB - Coronary artery anomalies are often discovered incidentally during cardiac catheterization or computed tomography coronary angiography and may involve the affected coronary artery origin and its course. Coronary artery anomalies are associated with congenital heart disease. The affected coronary arteries may have an unusual high take off origin, origin from contralateral or non-coronary sinus, origin from the pulmonary artery, single coronary system or coronary artery fistula. PMID- 27770128 TI - Traumatic right proximal subclavian artery pseudoaneurysm treated with a hybrid procedure: A case report. AB - Blunt trauma to the right proximal subclavian artery is uncommon and tends to be associated with pseudoaneurysm formation. We report a patient with right proximal subclavian artery pseudoaneurysm after blunt chest trauma following a motor vehicle accident. The condition was successfully treated with a combined insertion of a covered stent and carotid-carotid bypass as a hybrid procedure. Duplex scans at 6 month and 1 year follow-up documented good stent-graft positioning and no pseudoaneurysm recurrence. PMID- 27770131 TI - Incarceration of the Gravid Uterus. AB - Objective: The aim of this review was to describe the risk factors, clinical and radiographic criteria, and management of this rare complication of pregnancy. Methods: A PubMed, Web of Science, and CINAHL search was undertaken with no limitations on the number of years searched. Results: There were 60 articles identified, with 53 articles being the basis of this review. Multiple risk factors have been suggested in the literature including retroverted uterus in the first trimester, deep sacral concavity with an overlying sacral promontory, endometriosis, previous abdominal or pelvic surgery, pelvic or uterine adhesions, ovarian cysts, leiomyomas, multifetal gestation, uterine anomalies, uterine prolapse, and uterine incarceration in a prior pregnancy. The diagnosis is difficult to make owing to the nonspecific presenting symptoms. The diagnosis is clinical and confirmed by imaging. Magnetic resonance imaging is superior to ultrasound to accurately diagnose and elucidate the distorted maternal anatomy. Treatment is dictated by gestational age at diagnosis based on risks and benefits. The recommended route of delivery is cesarean delivery when uterine polarity cannot be corrected. Conclusions: Incarceration of the gravid uterus is a rare but serious complication of pregnancy. The diagnosis is clinical and confirmed with imaging, with magnetic resonance imaging being superior to delineate the distorted maternal anatomy. Reduction of the incarcerated uterus should be attempted to restore polarity and avoid unnecessary cesarean delivery. PMID- 27770130 TI - Why Do Women Not Use Preconception Care? A Systematic Review On Barriers And Facilitators. AB - Importance: Preconception care (PCC) has the potential to optimize pregnancy outcomes. However, awareness of PCC among the target population is generally limited, and the use of PCC remains low. Importance: The objective of this study was to review the literature on women's perceptions regarding barriers and facilitators for the use of PCC. Evidence Acquisition: A systematic search was conducted in MEDLINE, Embase, CINAHL, and PsycINFO for published studies until February 2015. Original qualitative and quantitative peer-reviewed studies from Western countries in English, holding women's perceptions regarding barriers and facilitators for the use of PCC. Data extraction and analysis were performed using NVivo version 10 software. A coding frame was derived from the findings and applied by 2 authors. Thematic analysis was used to identify key topics and themes. Results: Twenty-one good-quality articles were included, of which 10 qualitative and 11 quantitative studies. Seven main themes were identified: preconditions, emotions and beliefs, perceived need, knowledge and experience, social structure, accessibility, and provider characteristics. "Not (fully) planning pregnancy", "perceived absence of risks", "lack of awareness", and "pregnancy experiences" were the most frequently identified barriers and "believing in the benefits" and "availability of PCC" the most frequently identified facilitators for PCC use. Conclusions and Relevance: Women perceive more barriers than facilitators related to PCC uptake, which explains why the use of PCC remains low. Our results provide a starting point to refocus interventions and strategies, aiming on enlarging the awareness, perceived importance, and accessibility of PCC to improve its uptake. PMID- 27770129 TI - MicroRNA-16 Alleviates Inflammatory Pain by Targeting Ras-Related Protein 23 (RAB23) and Inhibiting p38 MAPK Activation. AB - BACKGROUND The purpose of our study was to determine the functional role of microRNA (miR)-16 in chronic inflammatory pain and to disclose its underlying molecular mechanism. MATERIAL AND METHODS Inflammatory pain was induced by injection of complete Freund's adjuvant (CFA) to Wistar rats. The pWPXL-miR-16, PcDNA3.1- Ras-related protein (RAB23), and/or SB203580 were delivered intrathecally to the rats. Behavioral tests were detected at 0 h, 4 h, 1 d, 4 d, 7 d, and 14 d after CFA injection. After behavioral tests, L4-L6 dorsal spinal cord were obtained and the levels of miR-16, RAB23, and phosphorylation of p38 (p p38) were evaluated by quantitative real-time PCR (qRT-PCR). In addition, luciferase reporter assay was performed to explore whether RAB23 was a target of miR-16, and qRT-PCR and Western blotting were used to confirm the regulation between RAB23 and miR-16. RESULTS The level of miR-16 was significantly decreased in the CFA-induced inflammatory pain. Intrathecal injection of miR-16 alleviates pain response and raised pain threshold. The level of RAB23 was significantly increased in the pain model, and intrathecal injection of RAB23 aggravated pain response. Luciferase reporter assay confirmed that RAB23 was a direct target of miR-16, and RAB23 was negatively regulated by miR-16. In addition, we found that simultaneous administration of SB203580 and miR-16 further alleviates pain response compared to only administration of miR-16. CONCLUSIONS Our findings suggest that miR-16 relieves chronic inflammatory pain by targeting RAB23 and inhibiting p38 MAPK activation. PMID- 27770132 TI - Induction of Labor Using a Foley Catheter or Misoprostol: A Systematic Review and Meta-analysis. AB - Importance: Induction of labor is a widely used obstetric intervention, occurring in one in four pregnancies. When the cervix is unfavorable, still many different induction methods are used. Objective: We compared Foley catheter alone to different misoprostol dosages and administration routes, and the combination of Foley catheter with misoprostol. Evidence acquisition: We reviewed the literature on the best induction method regarding their safety and effectiveness, using the outcome measures hyperstimulation, fetal distress, neonatal morbidity and mortality as well as cesarean delivery, vaginal instrumental delivery, and maternal morbidity. We searched Pubmed, Cochrane, and Web of Science from January 1, 1980 to February 12, 2016. Twenty-two randomized controlled trials (RCTs) were included, comparing Foley catheter with or without misoprostol to misoprostol alone (both vaginal and oral) for induction of labor (5,015 women). Results: Most included studies were underpowered to detect differences in safety outcomes, as the majority are powered for time to delivery or cesarean delivery. Meta-analysis of these studies does not allow assessment of the safety profile of Foley catheter compared to misoprostol (any dose, any administration route) with sufficient power. For the safety outcomes of the total group of Foley catheter versus misoprostol (any dose, any administration route) (17 studies, 4,234 women) we found that Foley catheter results in less hyperstimulation compared to misoprostol (2% versus 4%; risk ratio [RR], 0.54; 95% confidence interval [CI], 0.37-0.79) and fewer cesarean deliveries for nonreassuring fetal heart rate, 5% vs 7%; RR, 0.72; 95% CI, 0.55-0.95; while there were no statistically significant differences in neonatal outcomes. The total number of cesarean deliveries was 26% versus 22% (RR, 1.16; 95% CI, 1.00-1.34). There were fewer vaginal instrumental deliveries with a Foley catheter compared to misoprostol (10% vs 14%; RR, 0.74; 95% CI, 0.60-0.91). Foley catheter with misoprostol compared to misoprostol alone (any dose, any administration route) (7 studies, 1,073 women) resulted in less hyperstimulation than misoprostol alone (17% vs 23%; RR, 0.71; 95% CI, 0.52 0.97). Cesarean deliveries for nonreassuring fetal heart rate were comparable (7% vs 9%; RR, 0.79; 95% CI, 0.51-1.22). Neonatal outcomes were infrequently reported. The total number of cesarean deliveries was 34% versus 34% (RR, 1.01; 95% CI, 0.86-1.19). Conclusion: In women with an unripe cervix at term, Foley catheter seems to have a better safety profile than misoprostol (any dose, any administration route) for induction of labor. Larger studies are needed to investigate the safety profile of a Foley catheter compared to separate dosing and administration regimens of misoprostol. PMID- 27770134 TI - Reports of the EASD Study Groups 1989/1990. PMID- 27770133 TI - [Epidermal barrier disorders in dermatoses]. AB - The permeability barrier plays an important role in numerous skin diseases. Particularly well known is the importance of this barrier in eczema. In irritative-toxic contact dermatitis, the first step in the pathogenesis is the disturbance of the permeability barrier by irritative-toxic noxious substances. Only after damage to the barrier is achieved can irritants and allergens penetrate into the living epidermis. In atopic eczema due to an impaired barrier, allergens penetrate from the environment into the skin and cause or worsen the eczema. In psoriasis-the other common chronic inflammatory dermatosis-the role of the permeability barrier is only partly understood. In exanthema, infectious agents or drugs cause systemic inflammation, whereby the inflammation of the skin is followed by a barrier disorder. In principle, disturbed permeability of the skin barrier is present in all inflammatory diseases. PMID- 27770136 TI - Agenda for the 26th General Assembly of the European Association for the study of diabetes to be held in Copenhagen, Bella Center 12th September, 1990 from 16.30 17.00 hours. PMID- 27770135 TI - Minutes of the 25th General Assembly of the European Association for the study of diabetes : Held in Hall A of the Lisbon International Fair, Lisbon, Portugal on Friday, 22 September, 1989 at 10.30 hours. PMID- 27770140 TI - [Weaknesses of studies in surgery must not be overlooked]. PMID- 27770141 TI - [Inguinal and femoral hernia surgery : Open mesh procedure. Video article]. AB - There are several techniques for repair of symptomatic inguinal and femoral hernias. There is an increased acceptance and tendency favoring minimally invasive procedures, such as plug or transinguinal preperitoneal mesh prosthesis (TIPP) and endoscopic procedures, such as totally extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) repair. In the present review the classical techniques of Irving L. Lichtenstein (1986) and Jean Rives (1965), two indispensable procedures, are presented and the results from the literature are discussed. The videos show the repair of three interesting and complex cases. The surgical techniques are demonstrated in detail with the help of a video of the operation and which is available online. It is essential that each hernia surgeon should have proficiency in performing both procedures in order to be able to counsel patients and tailor the procedure according to the clinical findings. PMID- 27770142 TI - [Management of acute appendicitis : Evidence for prompt surgical treatment?] AB - BACKGROUND: Acute appendicitis is a common disease which requires immediate surgical treatment of the focus of inflammation. So far there are no reliable data on how much time can pass between hospitalization, indications for surgery and initiating surgery without an increased risk of morbidity and mortality for the patient. OBJECTIVE: The aim of this study was to investigate how much time can lapse between admission and initiation of surgery for acute appendicitis while still providing patient safety and no increase in complication rates. MATERIAL AND METHODS: This retrospective analysis investigated the management of all patients who underwent appendectomy under the suspicion of acute appendicitis. Besides the time span between hospital admittance and beginning of the operation (admission to incision time, AIT), anamnestic, diagnostic, technical and perioperative data were assessed and statistically analyzed (mean +/- SD). RESULTS: From January 2008 to April 2013 a total of 655 patients underwent appendectomy. The mean AIT was 7 h and the rate of negative appendectomy was 9.8 %. The mean hospitalization period was 5.9 +/- 8.7 days with a postoperative stay of 5.2 +/- 7.1 days. A comparison of the subgroups stratified by increasing AIT showed that there was no increased probability for perforation or postoperative complications with an AIT of up to 8 h. DISCUSSION: This retrospective cohort study showed that appendectomy should be performed within the first 8 h after hospitalization of the patient. PMID- 27770143 TI - 1H nuclear magnetic resonance (NMR)-based serum metabolomics of human gallbladder inflammation. AB - OBJECTIVE AND DESIGN: We present in this article 1H nuclear magnetic resonance (NMR)-based metabolic approach to screen the serum metabolic alterations in human gallbladder inflammation with chronic cholecystitis (CC). MATERIAL/METHODS: Total of 71 human serum samples was divided into two groups, (n = 41, CC) and (n = 30 control). 1H NMR metabolic profiling was carried out for investigation of metabolic alterations. Multivariate statistical analysis was applied for pattern recognition and identification of metabolites playing crucial role in gallbladder inflammation. Receiver operating curve (ROC) and pathway analysis on NMR data were also carried out to validate the findings. RESULTS: Serum metabolites such as glutamine, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), alanine, branch chained amino acids (BCAA), histidine and tyrosine were found to be depleted whereas formate, lactate, 1,2-propanediol were found to be elevated in CC. Metabolic pathways associated with metabolite alteration have also been reported. CONCLUSIONS: NMR has been established for disease diagnosis along with identification of metabolic pattern recognition in biofluids. Gallstones cause inflammation of the gallbladder in the form of CC. Inflammation plays a major role in causation of gall bladder cancer and leads the way to malignancy. Metabolic analysis of CC may lead to early diagnosis of disease and its progression to gallbladder cancer. PMID- 27770144 TI - The importance of protein binding for the in vitro-in vivo extrapolation (IVIVE) example of ibuprofen, a highly protein-bound substance. AB - A physiologically based human kinetic model (PBHKM) was used to predict the in vivo ibuprofen dose leading to the same concentration-time profile as measured in cultured human hepatic cells (Truisi et al. in Toxicol Lett 233(2):172-186, 2015). We parameterized the PBHKM with data from an in vivo study. Tissue partition coefficients were calculated by an algorithm and also derived from the experimental in vitro data for the liver. The predicted concentration-time profile in plasma was in excellent agreement with human experimental data when the liver partition coefficient was calculated by the algorithm (3.01) demonstrating values in line with findings obtained from human postmortem tissues. The results were less adequate when the liver partition coefficient was based on the experimental in vitro data (11.1). The in vivo doses necessary to reach the in vitro concentrations in the liver cells were 3610 mg using the best fitting model with a liver partition coefficient of 3.01 compared to 2840 mg with the in vitro liver partition coefficient of 11.1. We found that this difference is possibly attributable to the difference between protein binding in vivo (99.9 %) and in vitro (nearly zero) as the partition coefficient is highly dependent on protein binding. Hence, the fraction freely diffusible in the liver tissue is several times higher in vitro than in vivo. In consequence, when extrapolating from in vitro to in vivo liver toxicity, it is important to consider non-intended in vitro/in vivo differences in the tissue concentration which may occur due to a low protein content of the medium. PMID- 27770146 TI - [Vascular pathologies and vascular anatomical variants of the posterior cranial fossa]. AB - CLINICAL/METHODICAL ISSUE: The posterior fossa is the location of some specific vascular pathologies and vascular anatomical variants that are important for radiologists to know and recognize. Vascular malformations that are also found in the supratentorial region have some divergent characteristics in the posterior fossa. PRACTICAL RECOMMENDATIONS: Knowledge of the vascular anatomy of the posterior fossa and its variants is important for an understanding of vascular pathologies. PMID- 27770148 TI - [Technique and efficiency of ultrasound-guided injections in the sacroiliac joint for pediatric treatment of sacroiliitis]. PMID- 27770147 TI - [Imaging in urinary tract infections in childhood]. AB - Diagnostic strategies for extended morphological and functional clarification after symptomatic urinary tract infections in children are changing. Improved knowledge of the causes for development of renal scarring and a changing view on the importance of vesicoureteral reflux have led to a change in paradigm in recent years. The purpose of this article is to present the ongoing discussions of the causes and outcome of childhood urinary tract infections, competing diagnostic imaging methods and different diagnostic algorithms. PMID- 27770145 TI - Phase I/II trials of 186Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival. AB - PURPOSE: To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit. METHODS: Clinical data from 57 patients who received 2.5-5.1 GBq of 186Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses. RESULTS: A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (+/-6) Gy and the mean of the whole-body absorbed dose was 0.33 (+/-0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of 186Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004). CONCLUSION: This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose-response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient specific imaging and dosimetry. PMID- 27770151 TI - Concentrations of Heavy Metals in Commercially Important Oysters from Goa, Central-West Coast of India. AB - The major beds of oyster along the central-west coast of India are exposed to different anthropogenic activities and are severely exploited for human consumption. In this viewpoint, tissues of oyster Crassostrea madrasensis, C. gryphoides and Saccostrea cucullata were analyzed for Cu, Ni, Cd and Pb concentrations (dry weight) from Chicalim Bay, Nerul Creek and Chapora Bay in pre monsoon, monsoon and post-monsoon seasons. A higher concentration of Cu (134.4 2167.9 mg kg-1) and Cd (7.1-88.5 mg kg-1) was found, which is greater than the recommended limits in all the three species (and sites). Moreover, significant (p < 0.05) variations were observed for all the metals concentrations among the species, seasons and sites. The high concentrations of Cd and Cu in tissues of edible oyster pose a threat to human health. Therefore, continuous monitoring, people awareness and a stringent government policy should be implemented to mitigate the metal pollution along the studied sites. PMID- 27770152 TI - vanA Gene Harboring Enterococcal and Non-enterococcal Isolates Expressing High Level Vancomycin and Teicoplanin Resistance Reservoired in Surface Waters. AB - Untreated wastewaters and treated effluents even after final disinfection contain antibiotic resistant bacteria and resistance genes before they are released into surface waters. A correlation between resistant bacteria and antibiotics in surface waters has been found, as have antibiotic resistance genes. Of particular interest are vancomycin-resistant enterococci harboring vanA gene that confers high level of resistance to glycopeptide antibiotics including teicoplanin. Therefore, in this study, river water samples were analysed to investigate vancomycin- and teicoplanin-resistant bacterial isolates harboring vanA gene. Out of 290, 15 surface water isolates displayed resistance to both antibiotics. These glycopeptide resistant enterococcal and non-enterococcal isolates, identified by 16S rRNA sequencing, were found to harbor vanA gene with sequence similarities of 50 % to 100 %. The presence of D-alanine-D-lactate ligase encoded by vanA gene was also shown for all vancomycin- and teicoplanin-resistant isolates through western blot analysis. Due to reuse of treated wastewater and release of untreated wastewaters to water bodies, antibiotic resistant bacteria and resistance genes are being introduced into surface waters and present human health risks. Therefore, surface waters are not only hot spots for vanA harboring enterococcal isolates but also non-enterococcal isolates due to gene dissemination and require special scientific consideration. PMID- 27770149 TI - Development of the cardiac pacemaker. AB - The sinoatrial node (SAN) is the dominant pacemaker of the heart. Abnormalities in SAN formation and function can cause sinus arrhythmia, including sick sinus syndrome and sudden death. A better understanding of genes and signaling pathways that regulate SAN development and function is essential to develop more effective treatment to sinus arrhythmia, including biological pacemakers. In this review, we briefly summarize the key processes of SAN morphogenesis during development, and focus on the transcriptional network that drives SAN development. PMID- 27770150 TI - Upper airway changes following single-step or stepwise advancement using the Functional Mandibular Advancer. AB - OBJECTIVES: Purpose of the present study was to determine and compare possible changes in the dimensions of the pharyngeal airway, morphology of the soft palate, and position of the tongue and hyoid bone after single-step or stepwise mandibular advancement using the Functional Mandibular Advancer (FMA). PATIENTS AND METHODS: The sample included 51 peak-pubertal Class II subjects. In all, 34 patients were allocated to two groups using matched randomization: a single-step mandibular advancement group (SSG) and a stepwise mandibular advancement group (SWG). Both groups were treated with FMA followed by fixed appliance therapy; the remaining 17 subjects who underwent only fixed appliance therapy constituted the control group (CG). The study was conducted using pre- and posttreatment lateral cephalometric radiographs. Data were analyzed by paired t test, one-way analysis of variance, and Pearson's correlation coefficient. RESULT: In the SWG and SSG, although increases in nasopharyngeal airway dimensions were not significant compared with those in the CG, enlargements in the oropharyngeal airway dimensions at the level of the soft palate tip and behind the tongue, and decreases in soft palate angulation, were significant. Tongue height increased significantly only in the SWG. Compared with the CG, while forward movement of the hyoid was more prominent in SSG and SWG, the change in the vertical movement of the hyoid was not significant. No significant difference between SWG and SSG was observed in pharyngeal airway, soft palate, tongue or hyoid measurements. CONCLUSIONS: The mode of mandibular advancement in FMA treatment did not significantly affect changes in the pharyngeal airway, soft palate, tongue, and hyoid bone. PMID- 27770154 TI - ? PMID- 27770153 TI - Traumatic diaphragmatic rupture in pediatric age: review of the literature. AB - PURPOSE: Traumatic diaphragm rupture (TDR) is a rare complication of trauma in pediatric age and may be easily missed by the severity of associated injuries so that delayed emergent presentation can occur with increased rate of morbidity and mortality. No review has been available to guide clinicians through the pitfalls and the initial diagnostic approach to pediatric TDR. METHODS: A Medline thorough search on TDR was conducted using different queries. English language citations were identified during the period of January 2000 through December 2014 limiting the search to pediatric age (0-18 years). Abstracts were reviewed to determine eligibility and texts were obtained for further review. Differences were resolved by consensus and only reliable data were included. RESULTS: Most frequently reported presenting symptoms of TDR are respiratory and abdominal. While respiratory symptoms are among the most frequently described at the onset in pediatric and adult series, abdominal symptoms result to be more frequent in adult than pediatric patients. Chest X-ray (CXR) is the first-line imaging exam which is reported to show pathognomonic or suspect findings in 85 %. CT was the second main radiological technique used, in particular to confirm the suspicion of TDR. CONCLUSIONS: A high clinical index of suspicion is needed to diagnose and effectively manage diaphragmatic rupture. TDR should be kept in mind while dealing with patients assessed for abdominal or respiratory symptoms whenever there is history of trauma or blunt injury especially in children as the increasing of non-operative management of blunt abdominal trauma could result in missing important injuries as TDR. PMID- 27770155 TI - Addition of a fracture risk assessment to a coordinator's role improved treatment rates within 6 months of screening in a fragility fracture screening program. AB - : We evaluated the impact of a more intensive version of an existing post fracture coordinator-based fracture prevention program and found that the addition of a full-risk assessment improved treatment rates. These findings provide additional support for more intensive programs aimed at reducing the risk of re-fractures. INTRODUCTION: Evidence-based guidelines support coordinator based programs to improve post-fracture osteoporosis guideline uptake, with more intensive programs including bone mineral density (BMD) testing and/or treatment being associated with better patient outcomes. The purpose of this study was to evaluate the impact of a more intensive version (BMD "fast track") of an existing provincial coordinator-based program. METHODS: We compared two versions of the program that screened treatment naive fragility fracture patients (>50 years). Cases came from the BMD fast track program that included full fracture risk assessment and communication of relevant guidelines to the primary care provider (PCP). Matched controls were selected from the usual care program matching according to age, sex, fracture type, and date. Two matching techniques were used: traditional (hard) matching (TM) and propensity score matching (PS). The outcomes were treatment initiation with bone sparing medication, BMD testing rate, and the rate of returning to discuss the test results with a PCP. RESULTS: The program improvements led to a significant improvement in treatment initiation within 6 months from 16 % (controls based on PS) or 21 % (controls based on TM) to 32 % (cases). Ninety percent of patients in the BMD fast track program returned to their PCP to discuss bone health in the cases versus 60 % of the controls (for TM and PS). BMD testing occurred in 96 % of cases compared to the 66 (TM) or 65 % (PS) of the matched controls. CONCLUSIONS: Addition of a full risk assessment to a coordinator-based program significantly improved treatment rates within 6 months of screening. PMID- 27770156 TI - [Arthroscopic refixation of acute proximal anterior cruciate ligament rupture using suture anchors]. AB - OBJECTIVE: Arthroscopic assisted suture anchor refixation combined with microfracturing of the femoral ACL insertion zone in cases of acute proximal anterior cruciate ligament (ACL) rupture to restore anatomical and biomechanical properties of the native ACL. INDICATIONS: Acute proximal ACL rupture/avulsion, multiligament injury of the knee CONTRAINDICATIONS: Chronic (>6 weeks) proximal ACL rupture, intraligamentary rupture, as well as previous ACL surgery. SURGICAL TECHNIQUE: Arthroscopic examination of the knee joint, debridement of the femoral insertion zone, examination of the ligament quality by a probe, insertion of a curved lasso through the ACL to place the sutures and use of a drill guide to place the anchor in the middle of the femoral ACL insertion. Microfracturing holes around the femoral footprint were made by an awl to enhance healing properties of the ACL. POSTOPERATIVE MANAGEMENT: Partial weight bearing was permitted and crutches were used for 6 weeks, knee brace limited for the first 2 weeks 0-0-0 degrees , then 0-0-90 degrees for the following 4 weeks. RESULTS: A total of 20 patients who underwent acute proximal ACL suture anchor refixation were evaluated after a mean follow-up of 28 months. Regarding stability, mean values of the KT-1000 arthrometer indicated stable results (<3 mm), 3 patients had a 1+ Lachman and 4 patients had a 1+ pivot shift. IKDC (International Knee Documentation Committee) score indicated that 17 cases were very good to good (12A, 4B) and in 3 cases the results were satisfactory (3C). Magnetic resonance imaging showed that the ALC was found to be intact in 17 cases. The total rate of revision was 15 % (3/20) because of recurrent instability. PMID- 27770157 TI - Behavior of perineum during delivery before fetal head expulsion. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to describe perineum deformation during the final part of delivery and suggest a modification of the episiotomy cut to increase accuracy for obtaining a suitable angle (45 degrees ) for surgical wound suture. METHODS: This prospective study enrolled 45 primiparous women. The perineum at rest was marked with five lines (0 degrees , 30 degrees , 45 degrees , 60 degrees , 90 degrees ), and each line was marked with two dots (point A-B: to 2-3 cm from initial point in fourchette, respectively). Two digital pictures were taken: one with the women at rest and the second during fetal head crowning; displacements were calculated for each point and angle. RESULTS: When the perineum is distending, the initial point of every line in the posterior fourchette moves laterally in introitus (only the 0 degrees line remains at midline). The angle and the distance to points A and B of each line drawn do not change significantly from at rest to crowning. However, comparing original line configuration with an imaginary line from the fourchette to points A and B before expulsion, the angle and the distance is increased statistically significantly. CONCLUSIONS: Perineal distension at the moment of fetal head crowning causes a linear displacement of the perineum, which causes the difference in angle between the incision and episiotomy suture. Therefore, to obtain an episiotomy suture from fourchette with an angle of 45 degrees , theoretically, we would have several angle incision options (between 45 degrees and 60 degrees ), with a less acute angle when the introitus cut is closer to the fourchette (45 degrees to 6 mm and ~60 degrees in the fourchette) and a sharper angle with a longer episiotomy. PMID- 27770158 TI - Recurrent pyogenic cholangitis: a review of imaging findings and clinical management. AB - Recurrent pyogenic cholangitis (RPC) is an infective process involving the biliary tree typified by pigmented intraductal calculi with dilatation of the intra- and extrahepatic biliary tree. Previously endemic to South-east Asia, RPC can now be seen in Western countries with the increasing access to international travel and immigration. Affected patients are often plagued by recurrent bouts of cholangitis, and commonly suffer from complications such as abscess formation and biliary strictures. In severe cases, cirrhosis with portal hypertension may develop. The disease is also a known risk factor for cholangiocarcinoma, and can be seen in up to 5% of affected patients. Its exact etiology is unknown, but parasitic infections such as Clonorchis sinensis and Ascaris lumbricoides, ascending bacterial infection with gut flora (Escherichia coli) and low socioeconomic status have been associated strongly with it. This paper reviews the imaging features of the disease, as well as the roles of interventional radiology and surgery with respect to management of the condition. PMID- 27770159 TI - MDCT assessment of resectability in hilar cholangiocarcinoma. AB - PURPOSE: The purpose of this study is to investigate the value of multidetector computed tomography (MDCT) assessment of resectability in hilar cholangiocarcinoma, and to identify the factors associated with unresectability and accurate evaluation of resectability. METHODS: From January 2007 to June 2015, a total of 77 consecutive patients were included. All patients had preoperative MDCT (with MPR and MinIP) and surgical treatment, and were pathologically proven with hilar cholangiocarcinoma. The MDCT images were reviewed retrospectively by two senior radiologists and one hepatobiliary surgeon. The surgical findings and pathologic results were considered to be the gold standard. The Chi square test was used to identify factors associated with unresectability and accurate evaluation of resectability. RESULTS: The sensitivity, specificity, and overall accuracy of MDCT assessment were 83.3 %, 75.9 %, and 80.5 %, respectively. The main causes of inaccuracy were incorrect evaluation of N2 lymph node metastasis (4/15) and distant metastasis (4/15). Bismuth type IV tumor, main or bilateral hepatic artery involvement, and main or bilateral portal vein involvement were highly associated with unresectability (P < 0.001). Patients without biliary drainage had higher accuracy of MDCT evaluation of resectability compared to those with biliary drainage (P < 0.001). CONCLUSION: MDCT is reliable for preoperative assessment of resectability in hilar cholangiocarcinoma. Bismuth type IV tumor and main or bilateral vascular involvement highly suggest the unresectability of hilar cholangiocarcinoma. Patients without biliary drainage have a more accurate MDCT evaluation of resectability. We suggest MDCT should be performed before biliary drainage to achieve an accurate evaluation of resectability in hilar cholangiocarcinoma. PMID- 27770161 TI - Texture analysis in radiology: Does the emperor have no clothes? AB - Texture analysis is more and more frequently used in radiology research. Is this a new technology, and if not, what has changed? Is texture analysis the great diagnostic and prognostic tool we have been searching for in radiology? This commentary answers these questions and places texture analysis into its proper perspective. PMID- 27770160 TI - Current clinical status of 18F-FLT PET or PET/CT in digestive and abdominal organ oncology. AB - Positron emission tomography (PET) or PET/computed tomography (CT) using 18F-3' fluoro-3'-deoxythymidine (18F-FLT) offers noninvasive assessment of cell proliferation in human cancers in vivo. The present review discusses the current status on clinical applications of 18F-FLT-PET (or PET/CT) in digestive and abdominal oncology by comparing with 18F-fluorodeoxyglucose (18F-FDG)-PET (or PET/CT). The results of this review show that although 18F-FLT uptake is lower in most cases of digestive and abdominal malignancies compared with 18F-FDG uptake, 18F-FLT-PET can be used to detect primary tumors. 18F-FLT-PET has shown greater specificity for N staging than 18F-FDG-PET which can show false-positive uptake in areas of inflammation. However, because of the high background uptake in the liver and bone marrow, it has a limited role of assessing liver and bone metastases. Instead, 18F-FLT-PET will be a powerful tool for monitoring response to treatment and provide prognostic information in digestive and abdominal oncology. PMID- 27770162 TI - Multiple arterial phase MRI of arterial hypervascular hepatic lesions: improved arterial phase capture and lesion enhancement. AB - PURPOSE: To establish if triple-phase arterial imaging improves the detection of arterial phase hyperintense lesions based on arterial phase capture, motion artifact degradation, and lesion enhancement when compared to single-phase imaging. MATERIALS AND METHODS: Patients at risk for hepatocellular carcinoma were imaged at 3.0T. Seventy-three consecutive patients with a standard single phase MRI and eighty-five consecutive patients were imaged using extracellular contrast with triple arterial phase MRI using three sequential accelerated acquisitions of 8 s. Arterial phase capture and image quality were qualitatively categorized. Forty single-phase and forty-four triple-phase studies contained arterially enhancing lesions > 1 cm with washout appearance. The contrast-to noise ratio (CNR) of the lesions was calculated. We compared the differences in means with Student t-tests and those in arterial phase capture with a Chi squared test with Yates correction. RESULTS: The triple-phase acquisitions captured the early or late arterial phases more frequently than did the single-phase acquisition (99% vs 86%; P value = 0.006). Triple-phase also provided greater number of patients with early or late arterial phase imaging without motion artifact (92% vs 79%, P-value = 0.05). The lesion analysis revealed increased maximum CNR in the triple-phase imaging (704.4) vs. single-phase imaging (517.2), P-value < 0.001. CONCLUSION: Triple-phase acquisition provides more robust arterial phase imaging for hepatic lesions, with increased lesion CNR, compared to standard single-phase arterial phase imaging. PMID- 27770163 TI - Biliary and pancreatic ductal dilation in patients on methadone maintenance therapy. AB - PURPOSE: To determine whether the diameter of intrahepatic and extrahepatic bile ducts and pancreatic ducts in patients on methadone maintenance therapy is increased when compared with control subjects. METHODS: Between January 1, 2000 and March 15, 2013, a total of 97 patients (mean age 49.9, range 22-79, 65 male, 32 female) were identified who were receiving chronic methadone maintenance therapy (MMT) when they underwent imaging with abdominal MRI or a contrast enhanced abdominopelvic CT. A group of 97 consecutive non-MMT control patients (mean age 51.4, range 21-86, 45 male, 52 female) who underwent imaging with abdominal MRI or contrast-enhanced abdominopelvic CT were identified. Patients with known pancreaticobiliary pathology that may confound biliary ductal measurements were excluded. Blinded interpretation was performed, documenting the diameters of the intrahepatic and extrahepatic bile ducts and pancreatic ducts. Descriptive statistics were performed. RESULTS: Patients on MMT demonstrated increased bile duct diameter, with an average increase in duct diameter of 2.39 mm for the common bile duct (p < 0.001; 95% CI 1.88-2.90 mm), 1.43 mm for the intrahepatic bile ducts (p < 0.001; 95% CI 1.12-1.74 mm), and 0.90 mm for the pancreatic duct (p < 0.001; 95% CI 0.64-1.16 mm). No statistically significant correlation was found between ductal diameters and the daily dose of methadone. CONCLUSION: Patients on methadone maintenance therapy demonstrate significantly increased intra- and extrahepatic bile duct and pancreatic duct diameter when compared with controls. There was no correlation between the dose of methadone and ductal diameter. PMID- 27770164 TI - Diffusion-weighted endorectal MR imaging at 3T for prostate cancer: correlation with tumor cell density and percentage Gleason pattern on whole mount pathology. AB - OBJECTIVE: To determine if tumor cell density and percentage of Gleason pattern within an outlined volumetric tumor region of interest (TROI) on whole-mount pathology (WMP) correlate with apparent diffusion coefficient (ADC) values on corresponding TROIs outlined on pre-operative MRI. METHODS: Men with biopsy proven prostate adenocarcinoma undergoing multiparametric MRI (mpMRI) prior to prostatectomy were consented to this prospective study. WMP and mpMRI images were viewed using 3D Slicer and each TROI from WMP was contoured on the high b-value ADC maps (b0, 1400). For each TROI outlined on WMP, TCD (tumor cell density) and the percentage of Gleason pattern 3, 4, and 5 were recorded. The ADCmean, ADC10th percentile, ADC90th percentile, and ADCratio were also calculated in each case from the ADC maps using 3D Slicer. RESULTS: Nineteen patients with 21 tumors were included in this study. ADCmean values for TROIs were 944.8 +/- 327.4 vs. 1329.9 +/- 201.6 mm2/s for adjacent non-neoplastic prostate tissue (p < 0.001). ADCmean, ADC10th percentile, and ADCratio values for higher grade tumors were lower than those of lower grade tumors (mean 809.71 and 1176.34 mm2/s, p = 0.014; 10th percentile 613.83 and 1018.14 mm2/s, p = 0.009; ratio 0.60 and 0.94, p = 0.005). TCD and ADCmean (rho = -0.61, p = 0.005) and TCD and ADC10th percentile (rho = 0.56, p = 0.01) were negatively correlated. No correlation was observed between percentage of Gleason pattern and ADC values. CONCLUSION: DWI MRI can characterize focal prostate cancer using ADCratio, ADC10th percentile, and ADCmean, which correlate with pathological tumor cell density. PMID- 27770166 TI - [New regulations for inpatient treatment of the statutory accident insurance: From the perspective of a university medical center]. AB - BACKGROUND: New regulations of the German statutory accident insurance for inpatient treatment have been introduced. The aims of the new regulations are to improve cost-effectiveness and the quality of medical care. The introduction of the injury type catalogue and the severe injuries type procedure (SAV) has led to a concentration of resources. The purpose of these innovations is an increase in the quality of treatment of patients with complex injuries. CONCLUSION: The introduction of the new regulations resulted in a centralization of medical care in order to optimize the quality of treatment of complex injuries from occupational accidents. Hence, the high demands concerning infrastructure and human resources expected of a level one university medical center are taken into account. PMID- 27770165 TI - Beyond deficit or compensation: new insights on postural control after long-term total visual loss. AB - Loss of vision is well known to affect postural control in blind subjects. This effect has classically been framed in terms of deficit or compensation depending on whether body sway increases or decreases in comparison with that of sighted subjects with the eyes open. However, studies have shown that postural responses can be modulated by the context and that changes in postural sway may not necessarily mean a worsened or improved postural control. The goal of our study was to test whether balance is affected by the context in blind subjects. Additional to the quantification of center of pressure (COP) displacement, measurements of body motion (COG) and the correspondent net neuromuscular response (COP-COG) were evaluated in anterior-posterior and medial-lateral directions. Thirty-eight completely blind and thirty-two sighted subjects participated of this study. The volunteers were asked to stand barefoot on a force platform for 60 s in two different conditions: feet apart and feet together. Sighted participants performed the tests with both the eyes open and eyes closed. Results showed that the COP-COG displacements in the blind group were greater than those of the sighted group with eyes open in almost all conditions tested, but not in eyes closed condition. However, the COP and COG results confirmed that the postural responses were context dependent. Together these results suggest that total visual loss does not just lead to a balance deficit or compensation, but to a specific postural signature that might imply in enhancing COP, COG and/or COP-COG in specific postural conditions. PMID- 27770167 TI - [Surgical treatment of a complex adolescent carpal fracture : A rare injury to the growing skeleton]. AB - We report the case of a 15-year-old boy with combined fractures of the scaphoid, capitate, and hamate that represents a rare variation of the well-known Fenton's syndrome. Fixation was performed for the unstable fractures of the scaphoid and capitate with the use of cannulated Herbert screws and K-wires respectively. K wires were removed after 6 months, with subsequent physiotherapy. After 6 months, CT confirmed complete consolidation of the two surgically treated carpal fractures and the conservatively treated fracture of the hamate. Regarding function, the patient is able to incorporate the hand into his school-related activities and has a good range of motion, with strong closure of the fist. PMID- 27770168 TI - [Traumatic hip dislocation in a 6-year-old male child: Seldom but demanding]. AB - Traumatic hip dislocations in children are not frequent but constitute true emergencies. They require urgent reduction because of the risk of consecutive avascular necrosis of the femoral head. We report a 6-year-old boy with traumatic posterior hip dislocation on a vacation abroad. After closed reduction the day of the accident, a hip spica cast was applied and the patient was transferred home. Once home, X-ray and CT diagnostics were completed by MRI. In future, long-term clinical and radiological investigations for avascular necrosis and growth disorders, as well as thoroughly informing the parents, should be mandatory. PMID- 27770169 TI - [The rotationally stable screw-anchor with trochanteric stabilizing plate (RoSA/TSP) : First results in unstable trochanteric femur fractures]. AB - BACKGROUND: In unstable trochanteric fractures, the extramedullary rotationally stable screw-anchor (RoSA) combines the benefits of the load and rotational stability of the blade with the advantages of the screw (pull-out resistance, compression capability) in a single load carrier, and was designed to prevent femoral neck shortening by using an additional locked trochanteric stabilizing plate (TSP). OBJECTIVES: The aim of the current prospective cohort study was the clinical evaluation of the RoSA/TSP system regarding the mechanical re-operation rate and the amount of postoperative femoral neck shortening. METHODS: From September 2011 to January 2014 80 patients with unstable trochanteric fractures underwent internal extramedullary fixation with the RoSA/TSP (Konigsee Implantate GmbH, Allendorf, Germany). Due to fracture stability and after induction of compression, additional long locked antitelescoping screws (AT, n = 1-4) were placed reaching the femoral head. Radiological (femoral neck shortening) and clinical re-examination of patients (n = 61) was performed 6-10 weeks and 6-10 months later. RESULTS: In the 61 re-examined patients (76 %) femoral neck shortening was very low with 2 mm 6-10 months after operation. Re-operations occurred in 8 % (n = 6) and in 4 % (n = 3) as prophylactic surgical intervention. Whereas one-third (4 %) of re-operations occurred due to iatrogenic surgical problems from the first operation two-thirds of patients (8 %) had a re-operation due to delay of bone union (3* nonunion, 3 planned removals of AT-screws to improve healing). The in-hospital mortality was 3 % (n = 2). CONCLUSIONS: The fixation of unstable trochanteric femur fractures using the RoSA/TSP in a first clinical setting led to a great primary stability, with significant advantages with regard to limited femoral neck shortening. However, the rigidity of the construct with its consequences regarding bone healing can be challenging for the surgeon. Nevertheless, in some cases of revision it could be beneficial for stability. PMID- 27770170 TI - Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies. AB - INTRODUCTION: Infiltration of non-small-cell lung cancer (NSCLC) by CD8+ T lymphocytes predicts improved patient survival; however, heterogeneity of intratumoral localization complicates this assessment. Strategies for tumor sampling may not accurately represent the whole tumor. We hypothesized that sampling strategies may alter the identification of tumors with high CD8 density and affect the prognostic significance. PATIENTS AND METHODS: Twenty-three primary NSCLC tumors were immunohistochemically stained for CD8 and were assessed using automated software with eight different sampling strategies or the whole tumor. Results of all sampling strategies were compared to the whole tumor counts (paired t tests, Pearson's r). Associations between CD8 densities and overall survival were assessed (log-rank test). RESULTS: Counts from all eight sampling strategies significantly correlated with whole tumor counts (p <= 0.001). However, the magnitude of CD8+ cell counts and categorization into high vs low infiltrate groups were affected by the sampling strategy. The most concordant values were derived from random sampling of 20 % of the tumor, a simulated core biopsy, or from sampling the tumor center. TIL infiltration was associated with survival when sampling the center (p = 0.038), but not the invasive margin (p > 0.2) or other strategies. CONCLUSION: Different tumor sampling strategies may yield discordant TIL density results and different stratification for risk assessment. Small biopsies may be particularly unrepresentative. Random sampling of larger tumor areas is recommended. Enumerating CD8+ T cells in the tumor center may have prognostic value. PMID- 27770172 TI - Focus on acute circulatory failure. PMID- 27770171 TI - Should we take into account ESBLs in empirical antibiotic treatment? PMID- 27770174 TI - Posttraumatic stress disorder (PTSD) symptoms mediate the relationship between substance misuse and violent offending among female prisoners. AB - PURPOSE: Despite empirical evidence suggesting complex associations between psychological trauma, substance misuse, and violent offending, there is a dearth of research investigating these associations in the female prison population. METHODS: A cross-sectional, interview-format questionnaire study was undertaken with a sample of 89 female prisoners. History of traumatic events, DSM-5 PTSD, drug use, and offending behaviour were assessed. RESULTS: Traumatic experiences had occurred in 97.8 % of the sample, while 60.5 % met criteria for a PTSD diagnosis. The majority of the sample (70.8 %) reported using illicit drugs, and 59.6 % had committed at least one violent offence. History of drug use was significantly correlated with trauma, PTSD status, and violent offending. A mediation analysis identified an indirect effect of PTSD symptoms on the relationship between history of drug use and violent offending. CONCLUSIONS: The result of our mediation analysis further highlights the importance of addressing PTSD symptoms and substance misuse, among female offenders, to help prevent violent offending. PMID- 27770173 TI - Veterans are not the only ones suffering from posttraumatic stress symptoms: what do we know about dependents' secondary traumatic stress? AB - PURPOSE: Previous research has mainly focused on veterans' mental health problems, especially on posttraumatic stress disorder (PTSD). Less is known about the impact that the veteran's experienced potentially traumatic events (PTEs) might have on their significant others. Therefore, we reviewed the scientific literature to find out what is known about the prevalence of secondary traumatic stress (STS) in significant others of veterans. METHODS: We systematically searched Pubmed, PsycINFO, Embase, Cochrane Library and PILOTS for relevant articles. This search resulted in 3100 records from which we included 48 articles. RESULTS: Two studies that reported on parental PTSD did not find evidence that parents were affected by their offspring's experience. Nine studies that reported on PTSD in mainly adult children of veterans found only scant evidence that children were affected by their parent's experienced PTE. Twenty seven studies investigated PTSD symptoms in partners of veterans. Here results varied largely between studies with PTSD rates between 0 and 51 %. CONCLUSIONS: Overall, we found the strongest evidence of STS in partners of help-seeking veterans with PTSD. The lack of clarity provided by the currently available evidence suggests a pressing need for further work to examine this subject in more detail. PMID- 27770175 TI - Measuring Accelerated Rates of Insertions and Deletions Independent of Rates of Nucleotide Substitution. AB - Evolutionary constraint for insertions and deletions (indels) is not necessarily equal to constraint for nucleotide substitutions for any given region of a genome. Knowing the variation in indel-specific evolutionary rates across the sequence will aid our understanding of evolutionary constraints on indels, and help us infer how indels have contributed to the evolution of the sequence. However, unlike for nucleotide substitutions, there has been no phylogenetic method that can statistically infer significantly different rates of indels across the sequence space independent of substitution rates. Here, we have developed a software that will find sites with accelerated evolutionary rates specific to indels, by introducing a scaling parameter that only applies to the indel rates and not to the nucleotide substitution rates. Using the software, we show that we can find regions of accelerated rates of indels in the protein alignments of primate genomes. We also confirm that the sites that have high rates of indels are different from the sites that have high rates of nucleotide substitutions within the protein sequences. By identifying regions with accelerated rates of indels independent of nucleotide substitutions, we will be able to better understand the impact of indel mutations on protein sequence evolution. PMID- 27770176 TI - Development of engineered yeast for biosorption of beer haze-active polyphenols. AB - Compared to most other alcoholic beverages, the shelf life of beer is much more limited due to its instability in the bottle. That instability is most likely to appear as turbidity (haze), even sedimentation, during storage. The haze in beer is mostly caused by colloidal particles formed by interactions between proteins and polyphenols within the beer. Therefore, beers are usually stabilized by removing at least one of these components. We developed and constructed a Saccharomyces cerevisiae strain with a proline-rich QPF peptide attached to the cell wall, using the C-terminal anchoring domain of alpha-agglutinin. The QPF peptide served to bind polyphenols during fermentation and, thus, to decrease their concentration. Strains displaying QPF were able to bind about twice as much catechin and epicatechin as a control strain displaying only the anchoring domain. All these experiments were done with model solutions. Depending on the concentration of yeast, uptake of polyphenols was 1.7-2.5 times higher. Similarly, the uptake of proanthocyanidins was increased by about 20 %. Since the modification of yeasts with QPF did not affect their fermentation performance under laboratory conditions, the display of QPF appears to be an approach to increase the stability of beer. PMID- 27770177 TI - Geographic and environmental sources of variation in bacterial community composition in a large-scale municipal landfill site in China. AB - Little is known regarding how bacterial communities assemble at landfill, as well as how the environment shapes the composition of bacterial community. In this study, up to 42 refuse samples from a large-scale landfill in China were physicochemically and phylogenetically investigated. 16S ribosomal RNA (rRNA) gene-based Illumina MiSeq sequencing (nine samples) revealed that representatives of Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Firmicutes, and Bacteroidetes were dominant in the refuse samples, which was similar to a previous study on landfill leachate by using 454 pyrosequencing. Although 741 operational taxonomic units (OTUs) were detected across all nine samples, 6 of these OTUs were detected in all of the data sets, suggesting difference between bacterial community structures. Geographical differences between the samples, irrespective of depths, were revealed by a principal component analysis (PCA) based on the terminal restriction fragment length polymorphism (TRFLP) profiles of 42 refuse samples. Redundancy analysis (RDA) suggested that environmental heterogeneity (pH, landfilling ages, and depths) and the abundance of bacteria (represented by 16S rRNA gene copy numbers) were the main drivers shaping the bacterial community structure. PMID- 27770178 TI - The temperate Burkholderia phage AP3 of the Peduovirinae shows efficient antimicrobial activity against B. cenocepacia of the IIIA lineage. AB - Burkholderia phage AP3 (vB_BceM_AP3) is a temperate virus of the Myoviridae and the Peduovirinae subfamily (P2likevirus genus). This phage specifically infects multidrug-resistant clinical Burkholderia cenocepacia lineage IIIA strains commonly isolated from cystic fibrosis patients. AP3 exhibits high pairwise nucleotide identity (61.7 %) to Burkholderia phage KS5, specific to the same B. cenocepacia host, and has 46.7-49.5 % identity to phages infecting other species of Burkholderia. The lysis cassette of these related phages has a similar organization (putative antiholin, putative holin, endolysin, and spanins) and shows 29-98 % homology between specific lysis genes, in contrast to Enterobacteria phage P2, the hallmark phage of this genus. The AP3 and KS5 lysis genes have conserved locations and high amino acid sequence similarity. The AP3 bacteriophage particles remain infective up to 5 h at pH 4-10 and are stable at 60 degrees C for 30 min, but are sensitive to chloroform, with no remaining infective particles after 24 h of treatment. AP3 lysogeny can occur by stable genomic integration and by pseudo-lysogeny. The lysogenic bacterial mutants did not exhibit any significant changes in virulence compared to wild-type host strain when tested in the Galleria mellonella moth wax model. Moreover, AP3 treatment of larvae infected with B. cenocepacia revealed a significant increase (P < 0.0001) in larvae survival in comparison to AP3-untreated infected larvae. AP3 showed robust lytic activity, as evidenced by its broad host range, the absence of increased virulence in lysogenic isolates, the lack of bacterial gene disruption conditioned by bacterial tRNA downstream integration site, and the absence of detected toxin sequences. These data suggest that the AP3 phage is a promising potent agent against bacteria belonging to the most common B. cenocepacia IIIA lineage strains. PMID- 27770179 TI - High stability and low competitive inhibition of thermophilic Thermopolyspora flexuosa GH10 xylanase in biomass-dissolving ionic liquids. AB - Thermophilic Thermopolyspora flexuosa GH10 xylanase (TfXYN10A) was studied in the presence of biomass-dissolving hydrophilic ionic liquids (ILs) [EMIM]OAc, [EMIM]DMP and [DBNH]OAc. The temperature optimum of TfXYN10A with insoluble xylan in the pulp was at 65-70 degrees C, with solubilised 1 % xylan at 70-75 degrees C and with 3 % xylan at 75-80 degrees C. Therefore, the amount of soluble substrate affects the enzyme activity at high temperatures. The experiments with ILs were done with 1 % substrate. TfXYN10A can partially hydrolyse soluble xylan even in the presence of 40 % (v/v) ILs. Although ILs decrease the apparent temperature optimum, a surprising finding was that at the inactivating temperatures (80-90 degrees C), especially [EMIM]OAc increases the stability of TfXYN10A indicating that the binding of IL molecules strengthens the protein structure. Earlier kinetic studies showed an increased K m with ILs, indicating that ILs function as competitive inhibitors. TfXYN10A showed low increase of K m, which was 2-, 3- and 4-fold with 15 % [EMIM]OAc, [DBNH]OAc and [EMIM]DMP, respectively. One reason for the low competitive inhibition could be the high affinity to the substrate (low K m). Xylanases with low K m (~1 mg/mL) appear to show higher tolerance to ILs than xylanases with higher K m (~2 mg/mL). Capillary electrophoresis showed that TfXYN10A hydrolyses xylan to the end-products in 15 35 % ILs practically as completely as without IL, also indicating good binding of the short substrate molecules by TfXYN10A despite of major apparent IL binding sites above the catalytic residues. Substrate binding interactions in the active site appear to explain the high tolerance of TfXYN10A to ILs. PMID- 27770181 TI - Agenda for the 40th General Assembly of the European Association for the Study of Diabetes to be held in Munich, Germany on 8th September 2004 at 18:00 hours. PMID- 27770182 TI - Minutes of the 39th General Assembly of the European Association for the Study of Diabetes held in Le Palais des Congres, Mezzanine Level 3.5, Salles 322, 323 on Thursday 28th August 2003 at 17:30. PMID- 27770184 TI - Agenda for the 35th General Assembly of the European Association for the Study of Diabetes to be held in Brussels, Belgium, in the Auditorium 2000 of the Brussels Exhibition Centre, Heysel, on Friday, 1st October 1999 from 17:30-18:30 h. PMID- 27770185 TI - Minutes of the 34th General Assembly of the European Association for the Study of Diabetes. PMID- 27770187 TI - [Categorization of uterine cervix tumors : What's new in the 2014 WHO classification]. AB - In the 2014 WHO classification, squamous cell precursor lesions are classified as low-grade and high-grade intraepithelial lesions. LSIL corresponds to CIN1, HSIL includes CIN2 and CIN3. Only adenocarcinoma in situ (AIS) is accepted as precursor of adenocarcinoma and includes the stratified mucin-producing intraepithelial lesion (SMILE). Although relatively rare, adenocarcinoma and squamous cell carcinoma can be mixed with a poorly differentiated neuroendocrine carcinoma. Most cervical adenocarcinomas are low grade and of endocervical type. Mucinous carcinomas show marked intra- and extracellular mucin production. Almost all squamous cell carcinomas, the vast majority of adenocarcinomas, and many rare carcinoma types are HPV related. For low grade endocervical adenocarcinomas, the pattern-based classification according to Silva should be reported. Neuroendocrine tumors are rare and are classified into low-grade and high-grade, whereby the term carcinoid is still used. PMID- 27770186 TI - Fusion rate and clinical outcome in anterior lumbar interbody fusion with beta tricalcium phosphate and bone marrow aspirate as a bone graft substitute. A prospective clinical study in fifty patients. AB - PURPOSE: Bone graft substitutes have been successfully used in posterolateral lumbar fusion, anterior cervical fusion and animal studies. This study has been conducted to assess the safety and efficacy of beta-tricalcium phosphate (beta TCP) in instrumented anterior lumbar interbody fusion (ALIF) procedure. METHODS: In a prospective clinical study, ALIF cages were prefilled with beta-TCP and additionally fixated with posterior pedicle screw. Computed tomography (CT) and X rays were performed one year after surgery. Fusion was assessed and functional status was evaluated before and one year after surgery. RESULTS: X-ray evaluation showed a definite fusion in 85.48 % of treated levels. CT assessment showed anterior and posterior intersegemental bone bridging in 77.78 % of treated levels. CONCLUSIONS: The X-ray fusion rate presented is comparable with those published for ALIF procedures with bone graft. Fusion rates beta-TCP are similar to autologous bone. ALIF with beta-TCP and additional posterior fixation is a safe and effective procedure. PMID- 27770189 TI - Identification of urinary metabolites with potential blood pressure-lowering effects in lentil-fed spontaneously hypertensive rats. AB - PURPOSE: Urine samples were obtained from a previously completed study that showed lentil consumption attenuates the increase in blood pressure that occurs over time in spontaneously hypertensive rats (SHRs). The objective of the present study was to compare the metabolite profile of the urine samples from control and lentil-fed SHR in relation to the compounds present in lentils but not in other pulses. METHODS: The urine samples were from 17-week-old, male SHR fed semi purified diet prepared with powder (30 %, w/w) from cooked whole pulses or a pulse-free control diet (n = 8/group) for 4 weeks. Pulse powders, control diet and urine samples were extracted using acetonitrile and analyzed by a high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (LC QTOF-MS). RESULTS: Twenty-seven metabolites were significantly different in urine samples from lentil-fed SHR compared to SHR fed control diet, but only 7 were not present in the urine of SHR fed other pulses. Of these metabolites, only citrulline is linked to blood pressure regulation via production of the vasodilator nitric oxide (NO). Several arginine-related compounds that are NO synthase substrates or inhibitors were detected in lentils but not the control diet or other pulse powders. CONCLUSIONS: Consumption of lentils increases the availability of arginine and several related compounds that could potentially elevate production of NO and contribute to the blood pressure-lowering effects of lentil-rich diets. PMID- 27770193 TI - Variation of some arteries of the vertebrobasilar system: case report. AB - A specificity of the vertebrobasilar system (VBS) is a convergent junction of paired vertebral arteries (VAs) in the basilar artery (BA) usually at the level of bulbopontine sulcus on the ventral side of the rhombencephalon. We revealed multiple VBS variations (a high junction of both VAs, absence of posterior inferior cerebellar arteries, short and ectatic BA, hypoplasia and initial duplication of the left anterior inferior cerebellar artery, and bilateral common trunks of the posterior cerebral and superior cerebellar arteries) in a 52-year old male that routinely autopsied at the Institute of Forensic Medicine. Embryological base and morphological status of presented VBS variations is highlighted according to the literature data. Summarized variations of VBS can be classified as morphological rarity, and may be of clinical importance during angiographic studies or neurosurgical procedures. PMID- 27770194 TI - [Imaging of the lamina cribrosa for early detection of glaucoma : Latest trends from the annual ARVO meeting 2016]. AB - Studying the lamina cribrosa (LC) is relevant to understand the mechanisms of retinal ganglion cell degeneration in glaucoma and develop new diagnostic and therapeutic strategies. We would like to present some of the emerging trends and hot topics in imaging of the lamina cribrosa in glaucoma from the 2016 ARVO (The Association of Research in Vision and Ophthalmology) annual meeting, which was held in Seattle, WA, USA. Presentation of the path of ganglion cells through the pores of the lamina cribrosa as well as changes to the shape of the lamina cribrosa with increase of the intraocular and intracerebral pressure have been of great international interest. PMID- 27770197 TI - The endogenous development and pathogenicity of Eimeria anseris (Kotlan, 1932) in domestic goslings. AB - Twenty-one, 25-day-old, artificially reared, coccidia-free goslings (Anser cygnoides var. domestica) were inoculated orally with 0.5 * 104, 1 * 104, or 100 * 104 sporulated oocysts of Eimeria anseris and sacrificed at intervals from 24 to 216 h post-inoculation (HPI). Nine uninfected goslings served as negative controls. Parts of the visceral organs from goslings, including the intestines, kidneys, and liver, were fixed, sectioned, and observed microscopically. The results revealed that two generations of meronts occurred in the life cycle of E. anseris. The first generation of meronts developed at 24-96 HPI and the second generation at 90-128 HPI. Each meront contained 4-10 merozoites. Development of gamonts began at 128 HPI and mature oocysts appeared at 168 HPI. Developmental stages presented mainly in the epithelial cells of crypts and lamina propria in the posterior parts of the jejunum and ileum. Parasites localized mostly in the cytoplasm and occasionally in the nuclei of host cells. Histological lesions were pronounced in the jejunum and ileum. Desquamation and necrosis of the epithelium of intestine and crypts, infiltration of inflammatory cells, and hemorrhage and mucosal edema were associated with aggregates of endogenous stages. The infected goslings mainly showed severe diarrhea, depression, anorexia, and emaciation, suggesting that E. anseris is highly pathogenic in goslings. PMID- 27770191 TI - Rhizobium albus sp. nov., Isolated from Lake Water in Xiamen, Fujian Province of China. AB - A Gram-stain-negative, aerobic bacterial strain, designated Y21T, was isolated from surface lake water in Xiamen, Fujian Province of China. Growth was observed at temperatures from 4 to 37 degrees C, at salinities from 0 to 7.0 % and at pH from 6.0 to 10.0. Optimum growth was observed at 28 degrees C, at pH 7.0 and with 1.5-2.0 % (w/v) NaCl. The highest similarity of 16S rRNA gene sequence between strain Y21T and the other strains was 96.9 %. Phylogenetic analysis based on 16S rRNA gene sequencing revealed that the strain was a member of the genus Rhizobium, forming a distinct lineage with R. subbaraonis KCTC 23614T. The dominant fatty acids were summed feature 8 (comprising C18:1 omega7c and/or C18:1 omega6c), C18:1 omega7c 11-methyl, which accounted for 78.1 %. The G+C content of the chromosomal DNA was 60.9 mol%. The predominant respiratory quinone was ubiquinone-10. The polar lipids of strain Y21T were found to consist of five unidentified phospholipids and three unidentified aminolipids. According to its morphology, physiology, fatty acid composition and 16S rRNA sequence data, strain Y21T should be regarded as a new species of the genus Rhizobium, for which Rhizobium albus sp. nov. is proposed (type strain Y21T = MCCC 1F01210T = KCTC 42252T). PMID- 27770195 TI - Early outcomes in re-do operation after acute type A aortic dissection: results from the multicenter REAAD database. AB - This study provides early results of re-operations after the prior surgical treatment of acute type A aortic dissection (AAD) and identifies risk factors for mortality. Between May 2003 and January 2014, 117 aortic re-operations after an initial operation for AAD (a mean time from the first procedure was 3.98 years, with a range of 0.1-20.87 years) were performed in 110 patients (a mean age of 59.8 +/- 12.6 years) in seven European institutions. The re-operation was indicated due to a proximal aortic pathology in ninety cases: twenty aortic root aneurysms, seventeen root re-dissections, twenty-seven aortic valve insufficiencies and twenty-six proximal anastomotic pseudoaneurysms. In fifty eight cases, repetitive surgical treatment was subscripted because of distal aortic pathology: eighteen arch re-dissections, fifteen arch dilation and twenty five anastomotic pseudoaneurysms. Surgical procedures comprised a total of seventy-one isolated proximals, thirty-one isolated distals and fifteen combined interventions. In-hospital mortality was 19.6 % (twenty-three patients); 11.1 % in patients with elective/urgent indication and 66.6 % in emergency cases. Mortality rates for isolated proximal, distal and combined operations regardless of the emergency setting were 14.1 % (10 pts.), 25.8 % (8 pts.) and 33.3 % (5 pts.), respectively. The causes of death were cardiac in eight, neurological in three, MOF in five, sepsis in two, bleeding in three and lung failure in two patients. A multivariate logistic regression analysis revealed that risk factors for mortality included previous distal procedure (p = 0.04), new distal procedure (p = 0.018) and emergency operation (p < 0.001). New proximal procedures were not found to be risk factors for early mortality (p = 0.15). This multicenter experience shows that the outcome of REAAD is highly dependent on the localization and extension of aortic pathology and the need for emergency treatment. Surgery in an emergency setting and distal re-do operations after previous AAD remain a surgical challenge, while proximal aortic re-operations show a lower mortality rate. Foresighted decision-making is needed in cases of AAD repair, as the results are essential preconditions for further surgical interventions. PMID- 27770196 TI - Is congenital pulmonary airway malformation really a rare disease? Result of a prospective registry with universal antenatal screening program. AB - BACKGROUND: Congenital pulmonary airway malformation (CPAM) is an increasingly recognized disease with potential mortality. Owing to limited published studies, the true incidence is yet to be determined. We carried out this prospective study with the aim to estimate its true incidence on a population basis. METHODS: An antenatal ultrasonography program was implemented since 2009. Fetuses with suspected intra-thoracic lesions were monitored by regular follow-ups. Antenatal course, postnatal outcomes, and other demographics were compared to those of patients with CPAM in the previous decades (1989-2008). The incidence of CPAM was calculated in different periods. RESULTS: 66 CPAM patients were identified between 2009 and 2014 with 62 patients being detected by antenatal scan. In contrast, 45 patients were identified between 1989 and 2008 with 27 patients being detected antenatally. The incidence rate during the past and recent period was estimated as ~1 in 27,400 and ~1 in 7200 live births, respectively (p = 0.024). CONCLUSION: With increasing awareness of clinicians and the universal use of latest ultrasound technology, it is likely that more CPAM cases will be detected in the future. Here, we presented our best estimated incidence rate of CPAM, yet only a larger scale study can reveal its true incidence. PMID- 27770188 TI - Dietary fat and carbohydrate quality have independent effects on postprandial glucose and lipid responses. AB - PURPOSE: The magnitude of postprandial lipemia is influenced not only by the amount but also the type of fat and carbohydrate consumed. The aim of this study was to evaluate differences in postprandial glucose and lipid responses after a mixed meal containing low- or high-glycemic-index (GI) carbohydrate and three different types of fat varying in the degree of saturation in healthy subjects. METHODS: A randomized, controlled, single-blinded crossover study was conducted in 20 healthy Chinese men. Subjects consumed in random order six experimental isocaloric meals that differed in carbohydrate and fat quality, and contained 40 g of either saturated fat (SFA, butter), monounsaturated fat (MUFA, olive oil) or polyunsaturated fat (PUFA, grapeseed oil), and 50 g of either low-GI (basmati rice) or high-GI (jasmine rice) carbohydrate. Glucose, insulin, c-peptide, triglycerides (TG) and non-esterified fatty acids (NEFA) were measured over 4 h. RESULTS: For all substrates evaluated, there were no significant interactions between fat and carbohydrate. The incremental area under the curve (iAUC) for TG was significantly lower after the SFA and PUFA meals compared with the MUFA meal, irrespective of GI. No significant difference was found for NEFA iAUC in all treatments. Glucose, insulin and c-peptide iAUCs were significantly lower after ingestion of low-GI than high-GI meals, independent of the type of fat. CONCLUSIONS: A carbohydrate-rich meal (of either low or high GI) that contains butter or grapeseed oil results in lower postprandial TG concentrations relative to olive oil in healthy Chinese males. Glucose, insulin and c-peptide responses, however, are directly dependent on the GI of the meal and not on the degree of saturation of dietary fat. The trial was registered at clinicaltrials.gov as NCT02585427. PMID- 27770190 TI - A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats. AB - British shorthair (BSH) kittens in multiple litters died as a result of a severe non-neoplastic lymphoproliferative disease that showed many similarities with human autoimmune lymphoproliferative syndrome (ALPS). Human ALPS is caused by inherited defects in FAS-mediated lymphocyte apoptosis and the possibility of similar defects was investigated in BSH cats. The whole genomes of two affected kittens were sequenced and compared to 82 existing cat genomes. Both BSH kittens had homozygous insertions of an adenine within exon 3 of the FAS-ligand gene. The resultant frameshift and premature stop codon were predicted to result in a severely truncated protein that is unlikely to be able to activate FAS. Three additional affected BSH kittens were homozygous for the variant, while 11 of 16 unaffected, but closely related, BSH cats were heterozygous for the variant. All BSH cats in the study were from a population with significant inbreeding. The variant was not identified in a further survey of 510 non-BSH cats. Identification of a genetic defect in the FAS-mediated apoptosis pathway confirms that the lymphoproliferative disease in BSH cats fulfills the diagnostic criteria for ALPS in humans. These results will enable the development of a genetic test to detect BSH carrier animals. PMID- 27770198 TI - Production and characterization of a monoclonal antibody specific to 16 kDa antigen of Paramphistomum gracile. AB - A number of monoclonal antibodies (MoAbs) against the 16 kDa antigen of Paramphistomum gracile (16 kDaAgPg) were produced in vitro by hybridoma technique. Reactivity and specificity of these MoAbs were evaluated by ELISA and immunoblotting assays. Seven MoAb clones were selected from the stable hybridoma clones, namely 1D10, 2D7, 3B10, 3D9, 4F1, 4G4, and 5G12. It was found to be IgM and kappa light chain isotypes. By immunoblotting and ELISA, all MoAbs reacted with purified 16 kDaAgPg at molecular weight (MW) of 16 kDa and with the native 16 kDa antigen at MW of 16 kDa in the whole body (WB) and excretory-secretory (ES) fractions, but not with tegumental antigens (TA) of adult fluke. All of these MoAbs showed no cross-reactions with antigens of other parasites commonly found in ruminants, including Eurytrema pancreaticum, Gigantocotyle explanatum, Schistosoma spindale, Moniezia benedeni, Avitellina centripunctata, Haemonchus placei, Trichuris sp., and Setaria labiato-papillosa. Localization and distribution of the native 16 kDaAg in adult P. gracile by immunohistochemistry, using MoAbs as probes, showed that the native 16 kDaAg was present in high concentration in the cytoplasm of vitelline cells, eggshell globules, and the shells of eggs, but not in the tegument, muscle, parenchymal cells, and cecum of adult fluke. This finding indicated that the 16 kDaAg is a copiously expressed parasite protein that is released into the ES; thus, 16 kDaAg and its MoAb could be a good candidate for immunodiagnosis of paramphistomosis in ruminants. PMID- 27770199 TI - Genetic regulation of maize flower development and sex determination. AB - MAIN CONCLUSION: The determining process of pistil fate are central to maize sex determination, mainly regulated by a genetic network in which the sex-determining genes SILKLESS 1 , TASSEL SEED 1 , TASSEL SEED 2 and the paramutagenic locus Required to maintain repression 6 play pivotal roles. Maize silks, which emerge from the ear shoot and derived from the pistil, are the functional stigmas of female flowers and play a pivotal role in pollination. Previous studies on sex related mutants have revealed that sex-determining genes and phytohormones play an important role in the regulation of flower organogenesis. The processes determining pistil fate are central to flower development, where a silk identified gene SILKLESS 1 (SK1) is required to protect pistil primordia from a cell death signal produced by two commonly known genes, TASSEL SEED 1 (TS1) and TASSEL SEED 2 (TS2). In this review, maize flower developmental process is presented together with a focus on important sex-determining mutants and hormonal signaling affecting pistil development. The role of sex-determining genes, microRNAs, phytohormones, and the paramutagenic locus Required to maintain repression 6 (Rmr6), in forming a regulatory network that determines pistil fate, is discussed. Cloning SK1 and clarifying its function were crucial in understanding the regulation network of sex determination. The signaling mechanisms of phytohormones in sex determination are also an important research focus. PMID- 27770192 TI - Reconstruction of totally degloved fingers: a novel application of the bilobed spiraled innervated radial artery superficial palmar branch perforator flap design provides for primary donor-site closure. AB - INTRODUCTION: To investigate the results of resurfacing completely degloved digits using bilobed innervated radial artery superficial palmar branch (RASPB) perforator flap in a spiral fashion. METHODS: A detailed anatomic study on 30 adult fresh frozen cadavers preinjected with silicone rubber compound to demarcate arterial anatomy documented locations, numbers, and diameters of arteries and skin perforators with surrounding nerves. The flap-raising procedure was performed using four fresh cadaver specimen. We reviewed the reconstruction of 12 digits by using a bilobed spiraled innervated RASPB free perforator flap after non-replantable degloving injury. Two skin paddles were marked out using standard points of reference. At least two separate cutaneous perforator vessels were identified using a hand-held Doppler and were dissected back to the RASPB in retrograde fashion. The skin paddles were then divided between the two cutaneous perforators to provide two separate paddles with a common vascular supply. The skin paddles were stacked in a spiral fashion on the flap inset, effectively increasing the width of the flap to cover the totally degloved finger while still allowing closure of the primary donor-site. RESULTS: The RASPB was present within the flap in all cadavers. The direct perforator and the musculocutaneous perforator were available in 93.33 and 76.67 %, respectively, with neither of them in 6.67 % of the cases. The constantly present two perforators allowed the design of a new bilobed spiraled innervated radial artery superficial palmar branch perforator flap. We used the proposed flap to reconstruct completely degloved digits in 12 patients (mean age 28.6 years; range 17-35 years). With our proposed flap, no flap failure or re-exploration occurred and the donor site was closed primarily in all cases. All the flaps survived uneventfully. Total active motion ranged from 92 degrees to 140 degrees and 111 degrees to 155 degrees in the cases with and without metacarpophalangeal joint involvement, respectively. The static 2 point discrimination test varied from 6 to 11 mm. All the patients were satisfied with the overall results. CONCLUSION: The bilobed flap is large enough to cover totally degloved finger defects and contain direct skin perforators, provides a bespoke cover for complex soft tissue defects of completely degloved digits while also improving morbidity and cosmesis of the donor site. LEVEL OF EVIDENCE: Level IV, retrospective series. PMID- 27770201 TI - Histopathological and immunological changes during the acute and recovery phase in Henoch-Schonlein purpura rabbit model. AB - Henoch-Schonlein purpura (HSP) is a systemic vasculitis mediated by autologous immune complex. Animal models of HSP are scarce. Here, we describe the characteristics of HSP rabbit model in the acute and recovery phase. First, we constructed the HSP rabbit models, and then assessed immunologic indicators of models by enzyme-linked immunosorbent assay and immunoturbidimetry. Histomorphological characteristics were analyzed by haematoxylin-eosin, immunofluorescence and special staining. In the acute stage (24 h) after antigen challenge, the model group rabbits featured skin ecchymosis and abnormal laboratory examination results. Three weeks following the allergic reaction, purple spots improved markedly, and edema and blood seeping decreased, but obvious inflammation was present in the skin, kidneys, joints, gastrointestinal, lung and liver. Serological results of CD4, CD/CD8, IL-2, IL-4, and TNF-alpha, IgA, IgG, TropI, Alb and T were still abnormal. IgA and C3 expressed in skin and kidney and eosinophils expressed in skin and lungs were increased. The rabbit model can mimic human HSP lesions in symptoms, pathology, and immunology and may provide valuable insight into the pathogenesis of HSP and serve as a tool for future therapeutic development targeting HSP. PMID- 27770200 TI - Arabidopsis AtNAP functions as a negative regulator via repression of AREB1 in salt stress response. AB - MAIN CONCLUSION: AtNAP , an Arabidopsis NAC transcription factor family gene, functions as a negative regulator via transcriptional repression of AREB1 in salt stress response. AtNAP is an NAC family transcription factor in Arabidopsis and is known to be a positive regulator of senescence. However, its exact function and underlying molecular mechanism in stress responses are not well known. Here, we investigated functional roles of AtNAP in salt stress response. AtNAP expression significantly increased at the seedling stage, with higher expression in both shoots and roots under NaCl, mannitol, and ABA treatments. T-DNA insertional loss-of-function mutants of AtNAP were more tolerant to salt stress than wild type (WT), whereas AtNAP-overexpressing transgenic plants (OXs) were more sensitive to salt stress than WT during germination, seedling development, and mature plant stage. Transcript levels of stress-responsive genes in the ABA dependent pathway, such as AREB1, RD20, and RD29B, were significantly higher and lower in atnap mutants and AtNAP OXs, respectively, than in WT under salt stress conditions, suggesting that AtNAP might negatively regulate the expression of those genes under salt stress conditions. Indeed, AtNAP repressed the promoter activity of AREB1 under normal and salt stress conditions. These results indicate that AtNAP functions as a negative regulator in the salt stress response. Our results, together with previous studies, suggest that AtNAP functions as a negative regulator in osmotic stress responses, whereas it functions as a positive regulator in senescence. PMID- 27770202 TI - Operational aspects of SO2 removal and microbial population in an integrated bioreactor with two bioreaction zones. AB - An integrated-bioreactor, which consisted of a suspended zone and an immobilized zone, was applied to treat gases containing SO2. The removal of SO2 in suspended zone differed slightly from that in immobilized zone. The influences of operational aspects such as SO2 load, temperature, and pH on integrated bioreactor performance and bacterial community composition were investigated. The synergistic action of the two zones led to effective reduction of SO2, and the total removal efficiencies with the inlet concentration of 91-117 mg/m3, were over 85 % in steady state. Paenibacillus sp. and Lysinibacillus sp. dominated both zones as desulfurization bacteria. Results of polymerase chain reaction denaturing gradient gel electrophoresis followed by clone library analysis indicated that temporal shifts in bacterial community composition in both zones developed differently. Differences in the concentration of introduced SO2 and supported mode of microorganisms for survival, confirmed that bacterial community composition and abundance significantly differed among individual zones. PMID- 27770204 TI - Overnight Changes in Lung Function of Obese Patients with Obstructive Sleep Apnoea. AB - PURPOSE: Obstructive sleep apnoea (OSA) is a prevalent disorder, characterised by collapse of the upper airways during sleep. The impact of sleep-disordered breathing on pulmonary function indices is however currently not well described. The aim of the study was to evaluate diurnal change in lung function indices in a cohort of patients with OSA and relate pulmonary function changes to disease severity. METHODS: 42 patients with OSA and 73 healthy control subjects participated in the study. Asthma and COPD were excluded in all volunteers following a clinical and spirometric assessment. Spirometry was then performed in all subjects in the evening and the morning following a polysomnography study. RESULTS: There was no difference in evening or morning FEV1 or FVC between patients and control subjects (p > 0.05). Neither FEV1 nor FVC changed in control subjects overnight (p > 0.05). In contrast, FEV1 significantly increased from evening (2.18/1.54-4.46/L) to morning measurement (2.26/1.42-4.63/L) in OSA without any change in FVC. The FEV1 increase in OSA was related to male gender, obesity and the lack of treatment with statins or beta-blockers (all p < 0.05). A tendency for a direct correlation was apparent between overnight FEV1 change and RDI (p = 0.05, r = 0.30). CONCLUSIONS: Diurnal variations in spirometric indices occur in patients with OSA and FEV1 appears to increase in subjects with OSA overnight. These changes occur in the absence of change in FVC and are directly related to the severity of OSA. These findings dictate a need to consider time of lung function measurement. PMID- 27770206 TI - The Enhancing Connections-Telephone study: a pilot feasibility test of a cancer parenting program. AB - PURPOSE: The purposes of the study were to (1) test the short-term impact of a telephone-delivered cancer parenting education program, the Enhancing Connections Telephone (EC-T) Program, on maternal anxiety, depressed mood, parenting competencies, and child behavioral-emotional adjustment and (2) compare those outcomes with outcomes achieved from an in-person delivery of the same program (EC). METHODS: Thirty-two mothers comprised the sample for the within-group design and 77 mothers for the between-group design. Mothers were eligible if they had one or more dependent children and were recently diagnosed with stages 0-III breast cancer. Mothers in both groups received five intervention sessions at 2 week intervals from a patient educator using a fully scripted intervention manual. RESULTS: Outcomes from the within-group analysis revealed significant improvements on maternal anxiety, parenting competencies, and the child's behavioral-emotional functioning. Outcomes from the between-group analysis showed the EC-T did as well or better than EC in positively affecting maternal anxiety, depressed mood, parenting competencies, and the child's behavioral-emotional adjustment. Furthermore, the EC-T had a significantly greater impact than the EC on maternal confidence in helping their family and themselves manage the cancer's impact and in staying calm during emotionally charged conversations about the breast cancer with their child. CONCLUSIONS: Regardless of the channel of delivery, the Enhancing Connections Program has the potential to positively affect parenting competencies and behavioral-emotional adjustment in mothers and dependent children in the first year of stages 0-III maternal breast cancer. Its positive impact from telephone delivery holds promise for sustainability. PMID- 27770205 TI - Comparison of symptom clusters associated with fatigue in older and younger survivors of colorectal cancer. AB - PURPOSE: Cancer-related fatigue (CRF) is one of the most frequently reported symptoms in cancer survivors. To be able to optimally treat CRF, knowledge of symptoms that interact with CRF is helpful. During aging, changes occur in body composition with progressive deterioration in physiological functions and metabolic processes causing a decline of adaptive capacity. Therefore, symptoms caused by cancer and its treatment might coexist in different symptom clusters in older cancer survivors, compared to younger survivors. The purpose of this analysis was to identify and compare symptom clusters that include CRF between older and younger survivors of colorectal cancer (CRC). METHODS: Data were drawn from a cross-sectional study from the Netherlands Cancer Registry. In total, 1698 stage I and II CRC survivors diagnosed from 2000 to 2009 completed questionnaires on fatigue and psychological distress. Survivors were categorized in two groups based on age (<=65 versus >65 years) Symptom clusters were assessed using principal component analysis. A sensitivity analysis was performed on the results with categorical principal component analysis. RESULTS: In both age groups, three components including two symptom clusters were identified: an emotional symptom cluster containing anxiety, fatigue, and depression; a pain symptom cluster containing pain and insomnia; and a third component containing dyspnea only. CONCLUSIONS: Symptom clusters in survivors of CRC appear to be independent of age. In treating CRC survivors for fatigue, regardless of age, it is advisable to assess depression and anxiety and, if necessary, refer for further diagnosis and treatment. PMID- 27770207 TI - Gait disorders in adults and the elderly : A clinical guide. AB - Human gait depends on a complex interplay of major parts of the nervous, musculoskeletal and cardiorespiratory systems. The individual gait pattern is influenced by age, personality, mood and sociocultural factors. The preferred walking speed in older adults is a sensitive marker of general health and survival. Safe walking requires intact cognition and executive control. Gait disorders lead to a loss of personal freedom, falls and injuries and result in a marked reduction in the quality of life. Acute onset of a gait disorder may indicate a cerebrovascular or other acute lesion in the nervous system but also systemic diseases or adverse effects of medication, in particular polypharmacy including sedatives. The prevalence of gait disorders increases from 10 % in people aged 60-69 years to more than 60 % in community dwelling subjects aged over 80 years. Sensory ataxia due to polyneuropathy, parkinsonism and frontal gait disorders due to subcortical vascular encephalopathy or disorders associated with dementia are among the most common neurological causes. Hip and knee osteoarthritis are common non-neurological causes of gait disorders. With advancing age the proportion of patients with multiple causes or combinations of neurological and non-neurological gait disorders increases. Thorough clinical observation of gait, taking a focused patient history and physical, neurological and orthopedic examinations are basic steps in the categorization of gait disorders and serve as a guide for ancillary investigations and therapeutic interventions. This clinically oriented review provides an overview on the phenotypic spectrum, work-up and treatment of gait disorders. PMID- 27770209 TI - Current status of prophylactic surgical treatment for familial adenomatous polyposis in Japan. AB - PURPOSE: We conducted this study to clarify the current clinical practice of prophylactic colectomy for patients with familial adenomatous polyposis (FAP) in Japan. METHODS: This retrospective multi-center cohort study involved 23 specialized institutions for colorectal disease in Japan. We analyzed the records of 147 patients who underwent prophylactic surgical treatment between 2000 and 2012. Patients were divided into Group 1 (2000-2006) and Group 2 (2007-2012) based on their date of surgery. RESULTS: Age at the time of prophylactic surgery was 27 and 31 years in Groups 1 and 2, respectively. The proportion of attenuated FAP was significantly lower in Group 2 than in Group 1 (1.0 vs. 13 %, respectively). Pathological examination revealed an increased incidence of malignant polyps in the resected specimens from Group 2 patients (10 vs. 23 %, respectively; P = 0.034). Laparoscopic surgery was more frequent in Group 2 than in Group 1 (61 vs. 40 %, respectively). There was no surgical mortality in either group. CONCLUSION: Prophylactic surgery for FAP results in good short-term surgical outcomes in Japan. The current surgical approach is characterized by limited surgical indications for patients with attenuated FAP, delayed timing of colectomy, and the increasing standardization of laparoscopic surgery. PMID- 27770208 TI - The short-term outcomes of laparoscopic multivisceral resection for locally advanced colorectal cancer: our experience of 39 cases. AB - PURPOSE: Laparoscopic surgery for locally advanced colorectal cancer suspected of direct invasion to adjacent organs or structures remains controversial because of its high conversion rate, inadequate oncologic clearance and surgical outcomes. This study retrospectively evaluated the short-term outcomes of laparoscopic multivisceral resection for colorectal cancer and investigated the factors influencing conversion to open surgery. METHODS: Between 2010 and 2015, 39 patients who underwent laparoscopic multivisceral resection for colorectal cancer intraoperatively suspected of direct invasion to adjacent organs or structures were included. The conversion rate, resection margin status, surgical results, and morbidity and mortality rates were evaluated. We also investigated the factors influencing conversion. RESULTS: The conversion rate was 28 %. The resection margin was negative in all cases. The median operative time was 247 min, and the median blood loss was 80 ml. The postoperative mortality rate was 0 %, and the morbidity rate was 28 %; complications of Grade 3 or more were observed in 2 patients (5 %). The factors influencing conversion were >=2 adherent organs (p = 0.028) and clinical suspicion of direct invasion to adjacent organs (cT4b) (p = 0.076). CONCLUSION: Laparoscopic multivisceral resection for colorectal cancer intraoperatively suspected of direct invasion to adjacent organs or structures is feasible in selected patients. Conversion is more likely with >=2 adherent organs and cT4b. PMID- 27770210 TI - Characteristics of cases with postoperative vitreous hemorrhage after 25-gauge vitrectomy for repair of proliferative diabetic retinopathy. AB - PURPOSE: The purpose of this study was to compare ocular and systemic parameters between proliferative diabetic retinopathy (PDR) cases with postoperative vitreous hemorrhage (PVH) and those without PVH after 25-gauge vitrectomy, and to investigate the predictors of PVH. METHODS: The medical records of 106 eyes of 78 consecutive patients who underwent primary 25-gauge vitrectomy were reviewed. RESULTS: The incidences of early and late PVH were found to be 18.9 % (20/106 eyes) and 17.9 % (19/106 eyes) respectively. On multiple logistic regression analysis, intraoperative bleeding from new vessels on the disc was identified as the most important factor, with the greatest odds ratio, for the development of early PVH (odds ratio = 3.395, P = 0.134), while the HbA1c level was identified as the most important significant factor, with the greatest odds ratio, for the development of late PVH (odds ratio = 1.403, P = 0.014). CONCLUSIONS: Early PVH tends to occur in severe PDR cases, while late PVH tends to occur in cases with poor diabetic control. PMID- 27770211 TI - RETRACTED ARTICLE: Neural auditory intensity discrimination during naturalistic listening: a brain decoding study. PMID- 27770212 TI - Erratum to: Remifentanil for labor analgesia: a comprehensive review. PMID- 27770213 TI - Multiscale modeling of growth plate cartilage mechanobiology. AB - Growth plate chondrocytes are responsible for bone growth through proliferation and differentiation. However, the way they experience physiological loads and regulate bone formation, especially during the later developmental phase in the mature growth plate, is still under active investigation. In this study, a previously developed multiscale finite element model of the growth plate is utilized to study the stress and strain distributions within the cartilage at the cellular level when rapidly compressed to 20 %. Detailed structures of the chondron are included in the model to examine the hypothesis that the same combination of mechanoregulatory signals shown to maintain cartilage or stimulate osteogenesis or fibrogenesis in the cartilage anlage or fracture callus also performs the same function at the cell level within the chondrons of growth plate cartilage. Our cell-level results are qualitatively and quantitatively in agreement with tissue-level theories when both hydrostatic cellular stress and strain are considered simultaneously in a mechanoregulatory phase diagram similar to that proposed at the tissue level by Claes and Heigele for fracture healing. Chondrocytes near the reserve/proliferative zone border are subjected to combinations of high compressive hydrostatic stresses ([Formula: see text] MPa), and cell height and width strains of [Formula: see text] to [Formula: see text] respectively, that maintain cartilage and keep chondrocytes from differentiating and provide conditions favorable for cell division, whereas chondrocytes closer to the hypertrophic/calcified zone undergo combinations of lower compressive hydrostatic stress ([Formula: see text] MPa) and cell height and width strains as low as [Formula: see text] to +4 %, respectively, that promote cell differentiation toward osteogenesis; cells near the outer periphery of the growth plate structure experience a combination of low compressive hydrostatic stress (0 to [Formula: see text] MPa) and high maximum principal strain (20-29 %) that stimulate cell differentiation toward fibrocartilage or fibrous tissue. PMID- 27770214 TI - Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy. AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease. PMID- 27770216 TI - The genome sequence of Dioscorea bacilliform TR virus, a member of the genus Badnavirus infecting Dioscorea spp., sheds light on the possible function of endogenous Dioscorea bacilliform viruses. AB - The complete genome sequence of Dioscorea bacilliform TR virus (DBTRV) was determined. The closest relatives of DBTRV are Dioscorea bacilliform AL virus (DBALV) and Dioscorea bacilliform RT virus 1 (DBRTV1). Specific primers were designed and used to determine the prevalence of DBTRV in a yam germplasm collection. It was found that this virus infects Dioscorea alata and D. trifida plants in Guadeloupe and French Guyana. DTRBV was not detected in any of the tested D. cayenensis-rotundata accessions. In silico analysis provided evidence for the presence of DBTRV-like endogenous sequences in the genome of D. cayenensis-rotundata, pointing to a possible role of these sequences in antiviral defense. PMID- 27770215 TI - Preferences for Long-Acting Pre-exposure Prophylaxis (PrEP), Daily Oral PrEP, or Condoms for HIV Prevention Among U.S. Men Who Have Sex with Men. AB - HIV prevention method preferences were evaluated among 512 U.S. men who have sex with men (MSM; median age: 22 years). Approximately 90 % consistently preferred one option across pairwise comparisons of condoms, daily oral pre-exposure prophylaxis (PrEP), and long-acting PrEP delivered via either an injectable or one of two types of PrEP implants differing in visibility. Condoms were most frequently preferred (33.8 %), followed by non-visible implants (21.5 %), and oral PrEP (17.0 %); HIV risk was reported by more choosing implants. In a follow up question comparing the four PrEP options only, daily oral pills and non visible implants were most frequently preferred (35.5 and 34.3 %, respectively), followed by injections (25.2 %) and visible implants (4.3 %). An inductive, open coding approach determined that convenience, duration of protection, and privacy were the most commonly cited reasons for a PrEP method choice, and associated with self-report of HIV risk. Tailoring PrEP product development to privacy and other concerns important to those at highest HIV risk may improve HIV prevention. PMID- 27770218 TI - 3D Cell Culturing and Possibilities for Myometrial Tissue Engineering. AB - Research insights into uterine function and the mechanisms of labour have been hindered by the lack of suitable animal and cellular models. The use of traditional culturing methods limits the exploration of complex uterine functions, such as cell interactions, connectivity and contractile behaviour, as it fails to mimic the three-dimensional (3D) nature of uterine cell interactions in vivo. Animal models are an option, however, use of these models is constrained by ethical considerations as well as translational limitations to humans. Evidence indicates that these limitations can be overcome by using 3D culture systems, or 3D Bioprinters, to model the in vivo cytological architecture of the tissue in an in vitro environment. 3D cultured or 3D printed cells can be used to form an artificial tissue. This artificial tissue can not only be used as an appropriate model in which to study cellular function and organisation, but could also be used for regenerative medicine purposes including organ or tissue transplantation, organ donation and obstetric care. The current review describes recent developments in cell culture that can facilitate the development of myometrial 3D structures and tissue engineering applications. PMID- 27770219 TI - Computational and Experimental Analysis of Fluid Transport Through Three Dimensional Collagen-Matrigel Hydrogels. AB - A preclinical testing model for cancer therapeutics that replicates in vivo physiology is needed to accurately describe drug delivery and efficacy prior to clinical trials. To develop an in vitro model of breast cancer that mimics in vivo drug/nutrient delivery as well as physiological size and bio-composition, it is essential to describe the mass transport quantitatively. The objective of the present study was to develop in vitro and computational models to measure mass transport from a perfusion system into a 3D extracellular matrix (ECM). A perfusion-flow bioreactor system was used to control and quantify the mass transport of a macromolecule within an ECM hydrogel with embedded through channels. The material properties, fluid mechanics, and structure of the construct quantified in the in vitro model were input into, and served as validation of, the computational fluid dynamics (CFD) simulation. Results showed that advection and diffusion played a complementary role in mass transport. As the CFD simulation becomes more complex with embedded blood vessels and cancer cells, it will become more recapitulative of in vivo breast cancers. This study is a step toward development of a preclinical testing platform that will be more predictive of patient response to therapeutics than two-dimensional cell culture. PMID- 27770217 TI - Partial Adenosine A1 Agonist in Heart Failure. AB - Adenosine exerts a variety of physiological effects by binding to cell surface G protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting. PMID- 27770220 TI - Pseudoruegeria marinistellae sp. nov., isolated from an unidentified starfish in Sanya, China. AB - A taxonomic study was carried out on a Gram-stain negative, rod-shaped, non flagellated, and facultatively anaerobic bacterial strain designated as strain SF 16T, which was isolated from an unidentified starfish in Sanya, China. Strain SF 16T was found to be 5.0-7.0 MUm long, and oxidase and catalase positive. Cell growth was observed at pH 6.0-8.5 (optimum, 7.0-8.0), temperatures of 10-41 degrees C (optimum, 25-30 degrees C), and salinities of 0-12 % (optimum, 3.0-6.0 %). The predominant fatty acids (>20 %) were found to be C18:1 omega7c and/or C18:1 omega6c (summed feature 8). Ubiquinone 10 was identified as the predominant quinone for strain SF-16T. The polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids, two unidentified lipids, and three unidentified phospholipids. The DNA G+C content of the genomic DNA of strain SF-16T was determined to be 63.0 mol%. Phylogenetic analysis based on the 16S rRNA gene showed that strain SF-16T belongs to the genus Pseudoruegeria and is closely related to Pseudoruegeria sabulilitoris GJMS-35T (98.42 % similarity). The ANI value between strain SF-16T and P. sabulilitoris GJMS-35T was found to be 74.98 %, and DNA-DNA hybridization value was 21.1 +/- 2.3 % in silico and 57 % in vitro. Based on the low level of the genetic relatedness, phylogenetic and phenotypic data, a novel species Pseudoruegeria marinistellae sp. nov. is proposed. The type strain is SF-16T (=MCCC 1K01155T = KCTC 42910T). PMID- 27770221 TI - One-year follow-up results of intradiscal diode laser, radiofrequency, and pulsed radiofrequency therapies: a retrospective study. AB - This study aims to investigate the efficacy of three different percutaneous intradiscal therapies in patients with chronic low back pain (CLBP) due to lumbar disc herniation (LDH). Medical files of a total of 120 patients who received percutaneous intradiscal therapy were retrospectively analyzed. All patients were divided into three groups: group L: diode laser (n = 40), group R: radiofrequency (RF) (n = 40), and group P: pulsed radiofrequency (PRF) (n = 40). The visual analogue scale (VAS) and Oswestry Disability Index (ODI) scores were calculated at 1, 3, 6, and 12 months for all patients. One-year follow-up results were as follows: group L: pre-treatment (PreT) VAS 5.6 +/- -1, ODI 37.6 +/- -4.7, post treatment 12th month (PT12) VAS 2.8 +/- -1.4, ODI 14.1 +/- -7.1; group P: PreT VAS 6.0 +/- 1, ODI 37.5 +/- 5.9, PT12 VAS 3.1 +/- 1.3, ODI 20.3 +/- 17.0; and group R: PreT VAS 5.6 +/- 1.0, ODI 37.9 +/- 4.7, PT12 VAS 3.3 +/- 1.4, ODI 27.2 +/- 14.1. In each of the three groups, there was a statistically significant reduction in the VAS and ODI scores at 1, 3, 6, and 12 months, compared to the baseline values (p < 0.05). The highest reduction in the VAS and ODI scores was observed in group L, whereas the lowest reduction was in group R. We consider that in groups with patient selection criteria at our study; diode laser, RF, and PRF, which are administered using the percutaneous intradiscal route for CLBP patients diagnosed with LDH, may be used as an alternative treatment option. PMID- 27770223 TI - Benson Earl Ginsburg 1918-2016: A Pioneer in Behavior Genetics. PMID- 27770222 TI - Combined effects of electromagnetic field and low-level laser increase proliferation and alter the morphology of human adipose tissue-derived mesenchymal stem cells. AB - In recent years, electromagnetic field (EMF) and low-level laser (LLL) have been found to affect various biological processes, the growth and proliferation of cells, and especially that of stem cells. The aim of this study was to investigate the effects of EMF and LLL on proliferation of human adipose tissue derived mesenchymal stem cells (hAT-MSCs) and thus to examine the impact of these therapeutic physical modalities on stem cell engraftment. hAT-MSCs were isolated from subcutaneous adipose tissue of six persons ranging in age from 21 to 56 years. EMF was applied for a period of 7 days, once a day for 30 min, via a magnetic cushion surface at a frequency of 50 Hz and an intensity of 3 mT. LLL was applied also for 7 days, once a day for 5 min, at radiation energies of 3 J/cm2, with a wavelength of 808 nm, power output of 200 mW, and power density of 0.2 W/cm2. Nonexposed cells (control) were cultivated under the same culture conditions. Seven days after treatment, the cells were examined for cell viability, proliferation, and morphology. We found that after 7 days, the number of EMF-treated hAT-MSCs was significantly higher than the number of the untreated cells, LLL-treated hAT-MSCs were more numerous than EMF-treated cells, and hAT MSCs that were treated with the combination of EMF and LLL were the most numerous. EMF and/or LLL treatment did not significantly affect hAT-MSC viability by itself. Changes in cell morphology were also observed, in terms of an increase in cell surface area and fractal dimension in hAT-MSCs treated with EMF and the combination of EMF and LLL. In conclusion, EMF and/or LLL treatment accelerated the proliferation of hAT-MSCs without compromising their viability, and therefore, they may be used in stem cell tissue engineering. PMID- 27770225 TI - Measurement of Common Mental Health Conditions in VHA Co-located, Collaborative Care. AB - The VA has integrated psychologists and other licensed mental health providers, known collectively as co-located collaborative care (CCC) providers, into patients' primary care medical homes to improve mental health services for veterans. However, it is unclear if CCC providers are routinely using mental health measures as part of evidence-based, coordinated care. This study aimed to determine the prevalence and predictors of CCC provider utilization of brief, validated measures. A retrospective review of VA electronic medical records from 8403 veterans diagnosed with depression, posttraumatic stress disorder, or anxiety disorder was conducted. Results indicated that 23 % of the sample had a screening or brief symptom measure documented by a CCC provider. Likelihood of measurement was predicted by primary diagnosis, length of care episode, CCC provider credential, and clinic setting. Future research should address factors impacting measurement practices of CCC providers in order to develop implementation strategies for advancing measurement-based mental health care. PMID- 27770224 TI - Regulation of crucial enzymes and transcription factors on 2-phenylethanol biosynthesis via Ehrlich pathway in Saccharomyces cerevisiae. AB - 2-Phenylethanol (2-PE) is widely used in food, perfume and pharmaceutical industry, but lower production in microbes and less known regulatory mechanisms of 2-PE make further study necessary. In this study, crucial genes like ARO8 and ARO10 of Ehrlich pathway for 2-PE synthesis and key transcription factor ARO80 in Saccharomyces cerevisiae were re-regulated using constitutive promoter; in the meantime, the effect of nitrogen source in synthetic complete (SC) medium with L phenylalanine (L-Phe) on Aro8/Aro9 and Aro10 was investigated. The results showed that aromatic aminotransferase activities of ARO8 over-expressing strains were seriously inhibited by ammonia sulfate in SC + Phe medium. Flask fermentation test demonstrated that over-expressing ARO8 or ARO10 led to about 42 % increase in 2-PE production when compared with the control strain. Furthermore, influence of transcription factors Cat8 and Mig1 on 2-PE biosynthesis was explored. CAT8 over-expression or MIG1 deletion increased in the transcription of ARO9 and ARO10. 2-PE production of CAT8 over-expressing strain was 62 % higher than that of control strain. Deletion of MIG1 also led to 2-PE biosynthesis enhancement. The strain of CAT8 over-expression and MIG1 deletion was most effective in regulating expression of ARO9 and ARO10. Analysis of mRNA levels and enzyme activities indicates that transaminase in Ehrlich pathway is the crucial target of Nitrogen Catabolize Repression (NCR). Among the engineering strains, the higher 3.73 g/L 2-PE production in CAT8 over-expressing strain without in situ product recovery suggests that the robust strain has potentiality for commercial exploitation. PMID- 27770226 TI - Posterior reversible encephalopathy syndrome in Henoch-Schonlein purpura. PMID- 27770227 TI - Prevalence of comorbidities and management of gout in a tropical city in Australia. AB - To examine the management of gout in general practice in Townsville, Australia, and to explore comorbid conditions in patients with gout. Study will also explore how closely guidelines are being followed in managing gout. Retrospective chart review was conducted from May to November 2014 in three general practices in Townsville. Registers for patients were established by searching "gout" and "gouty arthritis". Three hundred and twenty-one patients were included in the study after excluding inactive patients, patients below age of 18 and patients with cancer. Main outcome measures were prevalence of comorbidities in gout patients, gout medications and adequate serum urate control (<=0.36 mmol/l). Multivariate logistic regression was used to study the relationship between serum urate level, comorbid conditions and lifestyle factors. Hypertension was the most common comorbid condition with 60.8 % of patients followed by obesity and dyslipidaemia. In terms of medication, 46.7 % of patients were on allopurinol, 12.8 % on indomethacin and 13.4 % on diuretics. Eighty-six percentage of patients had serum urate level (sUA) recorded in the previous year. Of these, 32.2 % had a serum urate level below or equal to 0.36 mmol/l. Moreover, 17.4 % of patients had lifestyle advice documented in chart. Male gender was the most influential factor in having poor uric acid control (p < 0.01), followed by not being on allopurinol (p < 0.01) and patients older than 50 years (p = 0.02). Management of gout in this study sample was not entirely concordant with guidelines. The study also suggests a need for possible tighter monitoring and allopurinol dosing regime in older, male patients. PMID- 27770229 TI - Whole brain analysis of postmortem density changes of grey and white matter on computed tomography by statistical parametric mapping. AB - OBJECTIVES: This study examined the usefulness of statistical parametric mapping (SPM) for investigating postmortem changes on brain computed tomography (CT). METHODS: This retrospective study included 128 patients (23 - 100 years old) without cerebral abnormalities who underwent unenhanced brain CT before and after death. The antemortem CT (AMCT) scans and postmortem CT (PMCT) scans were spatially normalized using our original brain CT template, and postmortem changes of CT values (in Hounsfield units; HU) were analysed by the SPM technique. RESULTS: Compared with AMCT scans, 58.6 % and 98.4 % of PMCT scans showed loss of the cerebral sulci and an unclear grey matter (GM)-white matter (WM) interface, respectively. SPM analysis revealed a significant decrease in cortical GM density within 70 min after death on PMCT scans, suggesting cytotoxic brain oedema. Furthermore, there was a significant increase in the density of the WM, lenticular nucleus and thalamus more than 120 min after death. CONCLUSIONS: The SPM technique demonstrated typical postmortem changes on brain CT scans, and revealed that the unclear GM-WM interface on early PMCT scans is caused by a rapid decrease in cortical GM density combined with a delayed increase in WM density. SPM may be useful for assessment of whole brain postmortem changes. KEY POINTS: * The original brain CT template achieved successful normalization of brain morphology. * Postmortem changes in the brain were independent of sex. * Cortical GM density decreased rapidly after death. * WM and deep GM densities increased following cortical GM density change. * SPM could be useful for assessment of whole brain postmortem changes. PMID- 27770228 TI - ESUR recommendations for MR imaging of the sonographically indeterminate adnexal mass: an update. AB - : An update of the 2010 published ESUR recommendations of MRI of the sonographically indeterminate adnexal mass integrating functional techniques is provided. An algorithmic approach using sagittal T2 and a set of transaxial T1 and T2WI allows categorization of adnexal masses in one of the following three types according to its predominant signal characteristics. T1 'bright' masses due to fat or blood content can be simply and effectively determined using a combination of T1W, T2W and FST1W imaging. When there is concern for a solid component within such a mass, it requires additional assessment as for a complex cystic or cystic-solid mass. For low T2 solid adnexal masses, DWI is now recommended. Such masses with low DWI signal on high b value image (e.g. > b 1000 s/mm2) can be regarded as benign. Any other solid adnexal mass, displaying intermediate or high DWI signal, requires further assessment by contrast-enhanced (CE)T1W imaging, ideally with DCE MR, where a type 3 curve is highly predictive of malignancy. For complex cystic or cystic-solid masses, both DWI and CET1W preferably DCE MRI-is recommended. Characteristic enhancement curves of solid components can discriminate between lesions that are highly likely malignant and highly likely benign. KEY POINTS: * MRI is a useful complementary imaging technique for assessing sonographically indeterminate masses. * Categorization allows confident diagnosis in the majority of adnexal masses. * Type 3 contrast enhancement curve is a strong indicator of malignancy. * In sonographically indeterminate masses, complementary MRI assists in triaging patient management. PMID- 27770230 TI - Added value of smooth hypointense rim in the hepatobiliary phase of gadoxetic acid-enhanced MRI in identifying tumour capsule and diagnosing hepatocellular carcinoma. AB - OBJECTIVES: To examine the added value of considering smooth hypointense rim in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI as capsule appearance for diagnosing tumour capsules and hepatocellular carcinoma (HCC). METHODS: A total of 377 hepatic lesions (330 HCCs, 35 non-HCC malignancies and 12 benign) were included from 345 patients who underwent resection after MRI between January 2008 and December 2011. Two radiologists assessed the presence or absence of conventional capsule appearance and smooth hypointense rim in the HBP, and categorized each hepatic lesion according to the Liver Imaging Reporting and Data System. Difference in diagnostic performance was evaluated using the generalized estimating equation method. RESULTS: For identifying capsule, the sensitivity and accuracy of HBP hypointense rim were significantly higher than those of conventional capsule appearance (81.5 % vs. 57.8 % and 76.1 % vs. 59.4 %, respectively; P < 0.001). For diagnosing HCC, the sensitivity and accuracy of LR 5 or LR-5 V were significantly higher when the HBP hypointense rim was also considered capsule appearance (83 % vs. 72.7 % and 84.1 % vs. 75.1 %, respectively; P < 0.001), with the same specificity (91.5 %). CONCLUSIONS: Regarding smooth hypointense rim in the HBP as capsule appearance could improve the detection of tumour capsule and the diagnosis of HCC. KEY POINTS: * Identifying tumour capsule is important for diagnosis of hepatocellular carcinoma (HCC). * Gadoxetic acid-enhanced MRI provides hepatobiliary phase (HBP) images. * Smooth hypointense rim seen in HBP may represent tumour capsule. * Regarding smooth hypointense rim as capsule appearance may improve HCC diagnosis. PMID- 27770232 TI - The Parenting Anxious Kids Ratings Scale-Parent Report (PAKRS-PR): Initial Scale Development and Psychometric Properties. AB - Developmental models of pediatric anxiety posit multiple, maladaptive parenting behaviors as potential risk factors. Despite this, a standardized means of assessing multiple of these practices (i.e., anxiogenic parenting) in a comprehensive and efficient manner are lacking. In Study 1531 parents of children 7-17 years old completed an online survey via Amazon Mechanical Turk. In Study 2, a separate community sample (N = 109; 9-17 years old) was recruited and completed a comprehensive assessment battery as part of a larger study. All parents (Study 1 and 2 samples) completed the Parenting Anxious Kids Ratings Scale-Parent Report (PAKRS-PR), a measurement tool designed to assess anxiogenic parenting. Factor analysis conducted as part of Study 1 revealed a 32-item scale consisting of five factors: conflict, overinvolvement, accommodation/beliefs, modeling, and emotional warmth/support. Four of these factors were significantly correlated with parent-report of anxiety severity. Within Study 2, the parents of children diagnosed with an anxiety or related disorder reported significantly higher levels of anxiogenic parenting practices as compared to the parents of healthy controls. The PAKRS-PR and respective subscales demonstrated acceptable reliability and validity in both the internet (Study 1) and community (Study 2) samples. The PAKRS-PR may be a beneficial multidimensional parenting scale for use among anxious youths. PMID- 27770231 TI - The targeting of starch binding domains from starch synthase III to the cell wall alters cell wall composition and properties. AB - KEY MESSAGE: Starch binding domains of starch synthase III from Arabidopsis thaliana (SBD123) binds preferentially to cell wall polysaccharides rather than to starch in vitro. Transgenic plants overexpressing SBD123 in the cell wall are larger than wild type. Cell wall components are altered in transgenic plants. Transgenic plants are more susceptible to digestion than wild type and present higher released glucose content. Our results suggest that the transgenic plants have an advantage for the production of bioethanol in terms of saccharification of essential substrates. The plant cell wall, which represents a major source of biomass for biofuel production, is composed of cellulose, hemicelluloses, pectins and lignin. A potential biotechnological target for improving the production of biofuels is the modification of plant cell walls. This modification is achieved via several strategies, including, among others, altering biosynthetic pathways and modifying the associations and structures of various cell wall components. In this study, we modified the cell wall of A. thaliana by targeting the starch binding domains of A. thaliana starch synthase III to this structure. The resulting transgenic plants (E8-SDB123) showed an increased biomass, higher levels of both fermentable sugars and hydrolyzed cellulose and altered cell wall properties such as higher laxity and degradability, which are valuable characteristics for the second-generation biofuels industry. The increased biomass and degradability phenotype of E8-SBD123 plants could be explained by the putative cell-wall loosening effect of the in tandem starch binding domains. Based on these results, our approach represents a promising biotechnological tool for reducing of biomass recalcitrance and therefore, the need for pretreatments. PMID- 27770233 TI - Effects of Chrysosporum (Aphanizomenon) ovalisporum extracts containing cylindrospermopsin on growth, photosynthetic capacity, and mineral content of carrots (Daucus carota). AB - Natural toxins produced by freshwater cyanobacteria, such as cylindrospermopsin, have been regarded as an emergent environmental threat. Despite the risks for food safety, the impact of these water contaminants in agriculture is not yet fully understood. Carrots (Daucus carota) are root vegetables, extensively consumed worldwide with great importance for human nourishment and economy. It is, therefore, important to evaluate the possible effects of using water contaminated with cyanotoxins on carrot cultivation. The aim of this work was to investigate cylindrospermopsin effects on D. carota grown in soil and irrigated for 30 days, with a Chrysosporum ovalisporum extract containing environmentally relevant concentrations of cylindrospermopsin (10 and 50 MUg/L). The parameters evaluated were plant growth, photosynthetic capacity, and nutritional value (mineral content) in roots of carrots, as these are the edible parts of this plant crop. The results show that, exposure to cylindrospermopsin did not have a clear negative effect on growth or photosynthesis of D. carota, even leading to an increase of both parameters. However, alterations in mineral contents were detected after exposure to crude extracts of C. ovalisporum containing cylindrospermopsin. A general decline was observed for most minerals (Ca, Mg, Na, Fe, Mn, Zn, Mo, and P), although an increase was shown in the case of K and Cu, pointing to a possible interference of the cyanobacterial extract in mineral uptake. This study is the first to evaluate the effects of C. ovalisporum extracts on a root vegetable, however, more research is necessary to understand the effects of this toxin in environmentally relevant scenarios. PMID- 27770234 TI - Soluble pre-fibrillar tau and beta-amyloid species emerge in early human Alzheimer's disease and track disease progression and cognitive decline. AB - Post-mortem investigations of human Alzheimer's disease (AD) have largely failed to provide unequivocal evidence in support of the original amyloid cascade hypothesis, which postulated deposition of beta-amyloid (Abeta) aggregates to be the cause of a demented state as well as inductive to tau neurofibrillary tangles (NFTs). Conflicting evidence suggests, however, that Abeta plaques and NFTs, albeit to a lesser extent, are present in a substantial subset of non-demented individuals. Hence, a range of soluble tau and Abeta species has more recently been implicated as the disease-relevant toxic entities. Despite the incorporation of soluble proteins into a revised amyloid cascade hypothesis, a detailed characterization of these species in the context of human AD onset, progression and cognitive decline has been lacking. Here, lateral temporal lobe samples (Brodmann area 21) of 46 human cases were profiled via tau and Abeta Western blot and native state dot blot protocols. Elevations in phospho-tau (antibodies: CP13, AT8 and PHF-1), pathological tau conformations (MC-1) and oligomeric tau (TOC1) agreed with medical diagnosis (non-AD cf. AD) and Braak stage classification (low, intermediate and high), alongside elevations in soluble Abeta species (MOAB 2 and pyro-glu Abeta) and a decline in levels of the amyloid precursor protein. Strong correlations were observed between individual Braak stages and multiple cognitive measures with all tau markers as well as total soluble Abeta. In contrast to previous reports, SDS-stable Abeta oligomers (*56) were not found to be reliable for all classifications and appeared likely to be a technical artefact. Critically, the robust predictive value of total soluble Abeta was dependent on native state quantification. Elevations in tau and Abeta within soluble fractions (Braak stage 2-3 cf. 0) were evident earlier than previously established in fibril-focused disease progression scales. Together, these data provide strong evidence that soluble forms of tau and Abeta co-localise early in AD and are closely linked to disease progression and cognitive decline. PMID- 27770236 TI - Notch pathway plays a novel and critical role in regulating responses of T and antigen-presenting cells in aGVHD. AB - Graft-versus-host disease (GVHD) induced by host antigen-presenting cells (APCs) and donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). Notch signaling pathway is a highly conserved cell cell communication that is important in T cell development. Recently, Notch signaling pathway is reported to be involved in regulating GVHD. To investigate the role of Notch inhibition in modulating GVHD, we established MHC-mismatched murine allo-BMT model. We found that inhibition of Notch signaling pathway by gamma-secretase inhibitor in vivo could reduce aGVHD, which was shown by the onset time of aGVHD, body weight, clinical aGVHD scores, pathology aGVHD scores, and survival. Inhibition of Notch signaling pathway by DAPT ex vivo only reduced pathology aGVHD scores in the liver and intestine and had no impact on the onset time and clinical aGVHD scores. We investigated the possible mechanism by analyzing the phenotype of host APCs and donor-derived T cells. Notch signaling pathway had a broad effect on both host APCs and donor-derived T cells. The expressions of CD11c, CD40, and CD86 as the markers of activated dendritic cells (DCs) were decreased. The proliferative response of CD8+ T cell decreased, while CD4+ Notch-deprived T cells had preserved expansion with increased expressions of CD25 and Foxp3 as markers of regulatory T cells (Tregs). In conclusion, Notch inhibition may minimize aGVHD by decreasing proliferation and activation of DCs and CD8+ T cells while preserving Tregs expansion. PMID- 27770235 TI - Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis. AB - Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuVJL5) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuVJL5 associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis was only possible by deep sequencing of the brain biopsy. Sequence comparison of the vaccine batch to the MuVJL5 isolated from brain identified biased hypermutation, particularly in the matrix gene, similar to those found in measles from cases of SSPE. The findings provide unique insights into the pathogenesis of paramyxovirus brain infections. PMID- 27770237 TI - EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases. AB - PURPOSE: Central nervous system (CNS) is the prevalent site for metastases in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-relapsed NSCLC patients. To understand the EGFR mutation status in paired cerebrospinal fluid (CSF) and plasma samples after EGFR-TKI treatment failure might be useful to guide the treatment of intra- and extracranial tumors in those patients. METHODS: Paired CSF and plasma samples were collected from seven NSCLC patients with CNS metastases after EGFR-TKI failure. EGFR mutations were tested by amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) methods. Gefitinib concentrations were evaluated by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). RESULTS: EGFR mutations were detected in all seven CSF samples, including three of E19-Del, three of L858R and one of E19-Del&T790M by both methods. On the other hand, majority of the matched plasma samples (5/7) were negative for EGFR mutations by both methods. The other two plasma samples were positive for E19-Del&T790M by ddPCR, and one of them had undetectable T790M by ARMS. Gefitinib concentration in CSF was much lower than that in plasma (mean CSF/plasma ratio: 1.8 %). CONCLUSIONS: After EGFR-TKI failure, majority of the NSCLC patients with CNS metastases remained positive detection of EGFR sensitive mutations in CSF, but much less detection in the matched plasma. Significantly low exposure of gefitinib in CSF might explain the intracranial protection of the EGFR sensitive mutation positive tumor cells. PMID- 27770238 TI - Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a "European Pediatric Oncology Off-patents Medicines Consortium" trial. AB - PURPOSE: Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. METHODS: We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m2. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children >=3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity. RESULTS: Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 +/- 5.8 l/h/m2) than older children (26.6 +/- 6.7 l/h/m2) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics. CONCLUSION: In the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses. PMID- 27770239 TI - Irinotecan-induced mucositis: the interactions and potential role of GLP-2 analogues. AB - PURPOSE: A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. METHODS: This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. RESULTS: Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. CONCLUSION: This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis. PMID- 27770240 TI - Does the internal inguinal ring need closure during laparoscopic orchiopexy with Prentiss manoeuvre? AB - BACKGROUND: Undescended testis is a common problem, which is prevalent in 3 % of male infants. This study aimed to determine the effect of leaving the deep inguinal ring (DIR) without closure during laparoscopic orchiopexy (LO), with regard to post-operative hernia formation and other outcomes. METHODS: From 2012 to 2014, 63 testicular units were managed with laparoscopy for non-palpable testis (NPT). Diagnostic laparoscopy was performed for all NPTs, and when they were intra-abdominal (42 testicular units), the DIR was left open after mobilization of the testis into the scrotum medial to the inferior epigastric vessels (Prentiss manoeuvre). We followed up these cases to check for hernia formation. RESULTS: The ages ranged from 10 months to 11 years with mean age at 3.7 years. Clinically, no cases presented with hernia, hydrocele or any other complications during a mean follow-up period of 34.4 months. CONCLUSION: Closing the peritoneum over the DIR might be omitted in LO with Prentiss manoeuvre, saving operative time and effort. By doing so, there is no risk of hernia formation. PMID- 27770241 TI - The complete mitochondrial genome of Trabala vishnou guttata (Lepidoptera: Lasiocampidae) and the related phylogenetic analyses. AB - The bluish yellow lappet moth, Trabala vishnou guttata is an extraordinarily important pest in China. The complete mitochondrial genome is sequenced and determined firstly, which is based on traditional PCR amplification and primer walking methods with a length of 15,281 bp, including 13 protein-coding (PCG) genes, 22 transfer RNA (rRNA) genes, two ribosomal RNA (tRNA) genes, and an A + T rich region. The gene order and orientation of the T. vishnou guttata mitogenome were identical to the other sequenced Lasiocampidae species. The overall nucleotide composition of T. vishnou guttata is A (40.27 %), T (40.59 %), C (11.58 %) and G (7.56 %), respectively. All the PCGs initiate with the three orthodox start codons ATN except for coxI with CGA start codon. Three PCGs (coxI, coxII and nad4) used incomplete stop codon T, while the other 10 PCGs terminate with complete stop codon TAA. All tRNA genes have a typical clover-leaf structure except for the absence of a dihydrouridine arm in trnS (AGN). The length of A + T rich region is 383 bp. Phylogeny is established to reveal the genetic relationship between T. vishnou guttata and other lepidopteran species based on 13 PCGs nucleotide sequences of the sequenced species (32 taxa) by Maximum likelihood and Bayesian methods. Phylogenetic analyses presents that T. vishnou guttata and its closely related species (Dendrolimus taxa) are clustered on Lasiocampidae group. It is a sister clade relationship between Lasiocampidae and other families in Bombycoidea with a bootstrap value of 83 % and a posterior probability of 0.75. This study supports that Lasiocampidae may be independent from Bombycoidea. PMID- 27770242 TI - The Relation Between Catastrophizing and Occupational Disability in Individuals with Major Depression: Concurrent and Prospective Associations. AB - Background Catastrophic thinking has been associated with occupational disability in individuals with debilitating pain conditions. The relation between catastrophic thinking and occupational disability has not been previously examined in individuals with debilitating mental health conditions. The present study examined the relation between catastrophic thinking and occupational disability in individuals with major depression. Methods The study sample consisted of 80 work-disabled individuals with major depressive disorder (MDD) who were referred to an occupational rehabilitation service. Participants completed measures of depressive symptom severity, catastrophic thinking and occupational disability at admission and termination of a rehabilitation intervention. Return-to-work outcomes were assessed 1 month following the termination of the rehabilitation intervention. Results Cross-sectional analyses of admission data revealed that catastrophic thinking contributed significant variance to the prediction of self-reported occupational disability, beyond the variance accounted for by depressive symptom severity. Prospective analyses revealed that reductions in catastrophic thinking predicted successful return to work following the rehabilitation intervention, beyond the variance accounted for by reductions in depressive symptom severity. Conclusions The findings suggest that catastrophic thinking is a determinant of occupational disability in individuals with major depressive disorder. The findings further suggest that interventions designed to reduce catastrophic thinking might promote occupational re-integration in individuals with debilitating mental health conditions. PMID- 27770243 TI - Abstracts from Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene) vol. 71, no. 3. PMID- 27770244 TI - Higher hair nicotine level in children compared to mother living with smoking father in Malaysia. AB - OBJECTIVES: The objectives of this study are to determine parental and children's hair nicotine levels, their relationships as well as to investigate the association of smoking status of the fathers with mothers' and children's hair nicotine. METHODS: A cross-sectional study design was conducted among 124 families who were participants of the Universiti Sains Malaysia Pregnancy Cohort Study. Both parents with their 2 years old children joined this study. A total of 92 hair samples of fathers, 124 hair samples of mothers and 111 hair samples of children were collected and analyzed by gas chromatography-mass spectrometry. RESULTS: Of total, 52.4 % of the fathers reported smoking. None of the mothers were smokers. Hair nicotine levels of fathers were found to be significantly correlated with mothers (r = 0.233, p = 0.026) and children (r = 0.508, p < 0.001). Children living with smoking fathers had significantly higher median hair nicotine level compared to the children of non-smoking fathers (6.08 vs 0.22 ng/mg, p = 0.046). However, this association was not seen in the mothers. Quantile regression showed significant association between fathers' and children's hair nicotine. CONCLUSION: There is a positive relationship between fathers' hair nicotine with mother's and children's hair nicotine. Living with smoking fathers can contribute to higher hair nicotine levels in children but not in mothers. PMID- 27770245 TI - New adverse obstetrics outcomes associated with endometriosis: a retrospective cohort study. AB - PURPOSE: The main aim of this study was to evaluate the incidence of endometriosis and intrahepatic cholestasis (ICP) and induction of labor in pregnant women with endometriosis compared with women without endometriosis. The secondary aim was to confirm increased incidence of already known endometriosis related pregnancy complications in these patients. METHODS: This is a retrospective cohort study performed at a tertiary hospital between January 2009 and December 2014 to compare obstetrics outcome between women with endometriosis and women without endometriosis. Pregnant patients with endometriosis were included in the study group. Patients were divided in the following subgroups: patients with deep infiltrating endometriosis (DIE subgroup) and patients without deep infiltrating endometriosis (non-DIE subgroup); patients with singleton pregnancy and spontaneous conception (subgroup A) and patients with multiple pregnancy and/or patients who underwent assisted reproductive technology (subgroup B). To form a control group, for each patient with endometriosis, two patients without endometriosis were selected as the control group by means of matched sample. RESULTS: The study population included 262 pregnant women with endometriosis and 524 controls. Patients of the study population had significantly increased risks of placenta praevia (p < 0.05), ICP (p < 0.01), induction of labor (p < 0.01) and preterm birth (p < 0.01). DIE patients had a significantly higher percentage only of preterm birth (p < 0.01), while in non DIE group all complications had a higher incidence except for placenta praevia, which did not differ with control. Subgroup A had a statistically higher incidence of placenta praevia (p < 0.01), ICP (p < 0.01), induction of labor (p < 0.01) and preterm birth (p < 0.01) compared to its control subgroup. There was no difference in distribution of pregnancy complications between subgroup B and control subgroup. CONCLUSIONS: Our results showed for the first time that women with endometriosis are at higher risk of developing ICP and experiencing an induced labor. Further studies are warranted to clarify whether the history of endometriosis might be taken into account in the antenatal care of these patients. PMID- 27770246 TI - Incidence of adhesions and maternal and neonatal morbidity after repeat cesarean section. AB - PURPOSE OF INVESTIGATION: We investigated the effect of repeat cesarean sections (CSs) and intra-abdominal adhesions on neonatal and maternal morbidity. MATERIALS AND METHODS: We analyzed intra-abdominal adhesions of 672 patients. RESULTS: Among the patients, 173, 206, 151, and 142 underwent CS for the first, second, third, and fourth time or more, respectively. There were adhesions in 393 (58.5 %) patients. Among first CSs, there were no adhesions, the rate of maternal morbidity [Morales et al. (Am J Obstet Gynecol 196(5):461, 2007)] was 26 %, and the rate of neonatal morbidity (NM) was 35 %. Among women who have history of two CSs, the adhesion rate was 66.3 %, the adhesion score was 2.05, MM was 14 %, and NM was 21 %. Among third CSs, these values were 82.1, 2.82, 23, and 14 %, respectively. Among women who have history of four or more CSs, these values were 92.2, 4.72, 31.7, and 18 %, respectively. Adhesion sites and dense fibrous adhesions increased parallel to the number of subsequent CSs. Increased adhesion score was associated with 1.175-fold higher odds of NM and 1.29-fold higher odds of MM. The rate of NM was eightfold higher in emergency-delivered newborns (emergency: 39.4, 40 %; elective: 4.9 %). MM was 20 and 26 % for elective and emergency CSs, respectively. CONCLUSIONS: Emergency operations and adhesions increased complications. PMID- 27770247 TI - Urogenital function in robotic vs laparoscopic rectal cancer surgery: a comparative study. AB - PURPOSE: Urological and sexual dysfunction are recognised risks of rectal cancer surgery; however, there is limited evidence regarding urogenital function comparing robotic to laparoscopic techniques. The aim of this study was to assess the urogenital functional outcomes of patients undergoing laparoscopic and robotic rectal cancer surgery. METHODS: Urological and sexual functions were assessed using gender-specific validated standardised questionnaires. Questionnaires were sent a minimum of 6 months after surgery, and patients were asked to report their urogenital function pre- and post-operatively, allowing changes in urogenital function to be identified. Questionnaires were sent to 158 patients (89 laparoscopy, 69 robotic) of whom 126 (80 %) responded. Seventy-eight (49 male, 29 female) of the responders underwent laparoscopic and 48 (35 male, 13 female) robotic surgery. RESULTS: Male patients in the robotic group deteriorated less across all components of sexual function and in five components of urological function. Composite male urological and sexual function score changes from baseline were better in the robotic cohort (p < 0.001). In females, there was no difference between the two groups in any of the components of urological or sexual function. However, composite female urological function score change from baseline was better in the robotic group (p = 0.003). CONCLUSION: Robotic rectal cancer surgery might offer better post-operative urological and sexual outcomes compared to laparoscopic surgery in male patients and better urological outcomes in females. Larger scale, prospective randomised control studies including urodynamic assessment of urogenital function are required to validate these results. PMID- 27770248 TI - A trial of radiofrequency ablation for anal intraepithelial neoplasia. AB - PURPOSE: Radiofrequency ablation (RFA) effectively treats esophageal high-grade dysplasia, but its efficacy in treating anal canal high-grade squamous intraepithelial lesions (HSILs) is unsubstantiated. This prospective study assessed the safety and efficacy of applying hemi-circumferential RFA to anal canal HSIL. METHODS: Twenty-one HIV-negative participants with HSIL occupying <= half the anal canal circumference were treated with hemi-circumferential anal canal RFA. Participants were assessed every 3 months for 12 months with high resolution anoscopy; recurrence in the treatment zone was re-treated with focal RFA. RESULTS: Twenty-one participants with a mean of 1.7 lesions (range 1-4) enrolled and completed the trial. Six (29 %) participants had recurrent HSIL within the treated hemi-circumference within 1 year. Four participants (19 %) had persistence of an index lesion at 3 months. One (2.9 %) index HSIL persisted again at 12 months. No participants had more than two RFA treatments. KM curve predicted HSIL-free survival within the treatment zone at 1 year was 76 % (95 % CI 52-89 %). Comparing the first 7 and last 14 participants, the predicted 1-year HSIL-free survivals are 43 % (95 % CI 10-73 %) and 93 % (95 % CI 59-99 %), respectively (p = 0.008), suggesting a learning curve with the treating physician. Multivariable analysis showed decreased recurrence in the last 14 participants (HR 0.02; 95 % CI 0.001-0.63) while increasing BMI increased recurrence (HR 1.43, 95 % CI 1.01-2.01). No participants had device or procedure related serious adverse events, anal stricture, or heavy bleeding. CONCLUSIONS: Hemi-circumferential RFA yielded a high rate of anal HSIL eradication in HIV negative patients at 1 year with minimal adverse events. Lesion persistence was probably related to incomplete initial ablation. PMID- 27770249 TI - Enhanced recovery ERAS for elderly: a safe and beneficial pathway in colorectal surgery. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) pathway includes recovery goals requiring active participation of the patients; this may be perceived as "aggressive" care in older patients. The aim of the present study was to assess whether ERAS was feasible and beneficial in older patients. METHODS: Since June 2011, all consecutive colorectal patients were included in an ERAS pathway and documented in a dedicated prospective database. This retrospective analysis included 513 patients, 311 younger patients (<70 years) and 202 older patients (>=70 years). Outcomes were adherence to the ERAS pathway, functional recovery, postoperative complications, and hospital stay. RESULTS: Older patients had significantly more diabetes, malignancies, cardiac, and respiratory co morbidities; both groups underwent similar surgical procedures. Overall adherence to the ERAS pathway was in median 78 % in younger and 74 % in older patients (P = 0.86). In older patients, urinary drains were kept longer (P = 0.001), and oral fluid intake was reduced from day 0 to day 3 (P < 0.001). There were no differences in mobilization and intake of nutritional supplements. Postoperative complications were similar for both comparative groups (51.5 vs. 46.6 %, P = 0.32). Median length of stay was 7 days (IQR 5-13) in older patients vs. 6 days (IQR 4-10) in the younger group (P = 0.001). CONCLUSION: Adherence to the ERAS pathway was equally high in older patients. Despite more co-morbidities, older patients did not experience more complications. Recovery was similar and hospital stay was only 1 day longer than in younger patients. ERAS pathway is of value for all patients and does not need any adaptation for the elderly. PMID- 27770250 TI - Preoperative anaemia and perioperative red blood cell transfusion as prognostic factors for recurrence and mortality in colorectal cancer-a Swedish cohort study. AB - PURPOSE: The hypothesis in this study was that anaemia prior to surgery and perioperative red blood cell transfusion increases the risk for recurrence and overall mortality in patients with stages I-III colorectal cancer after abdominal resection with curative intent. METHODS: This is a Swedish single centre retrospective cohort study. Data on 496 consecutive radical abdominal resections stages I-III colorectal cancer performed at the Karolinska University Hospital 2007-2010 were extracted from the Swedish Colorectal Cancer Registry. Data were linked to local laboratory and transfusion databases to identify preoperative anaemia and perioperative transfusion. Disease recurrence was validated by scrutiny of patient records. A total of 496 stages I-III colorectal cancer patients were included in the analysis. Multivariate Cox regression analysis adjusted for tumour and patient characteristics were performed to assess risk for recurrence and overall mortality. RESULTS: Anaemia prior to surgery was associated with increased risk for overall mortality (HR 2.1, 95% CI 1.4-3.2). There was no association between anaemia and risk for recurrence (HR 1.6, 95% CI 0.97-2.6). Transfusion was not associated with increased risk of recurrence (HR 0.7, 95% CI 0.4-1.3) or overall mortality (HR 1.04, 95% CI 0.7-1.6). CONCLUSIONS: Anaemia prior to colorectal cancer surgery was associated with increased risk for overall mortality while a no increased risk was seen for recurrence. Previous findings indicating an association between blood transfusion and increased risk for recurrence could not be confirmed. PMID- 27770252 TI - Simulation-based camera navigation training in laparoscopy-a randomized trial. AB - BACKGROUND: Inexperienced operating assistants are often tasked with the important role of handling camera navigation during laparoscopic surgery. Incorrect handling can lead to poor visualization, increased operating time, and frustration for the operating surgeon-all of which can compromise patient safety. The objectives of this trial were to examine how to train laparoscopic camera navigation and to explore the transfer of skills to the operating room. MATERIALS AND METHODS: A randomized, single-center superiority trial with three groups: The first group practiced simulation-based camera navigation tasks (camera group), the second group practiced performing a simulation-based cholecystectomy (procedure group), and the third group received no training (control group). Participants were surgical novices without prior laparoscopic experience. The primary outcome was assessment of camera navigation skills during a laparoscopic cholecystectomy. The secondary outcome was technical skills after training, using a previously developed model for testing camera navigational skills. The exploratory outcome measured participants' motivation toward the task as an operating assistant. RESULTS: Thirty-six participants were randomized. No significant difference was found in the primary outcome between the three groups (p = 0.279). The secondary outcome showed no significant difference between the interventions groups, total time 167 s (95% CI, 118-217) and 194 s (95% CI, 152 236) for the camera group and the procedure group, respectively (p = 0.369). Both interventions groups were significantly faster than the control group, 307 s (95% CI, 202-412), p = 0.018 and p = 0.045, respectively. On the exploratory outcome, the control group for two dimensions, interest/enjoyment (p = 0.030) and perceived choice (p = 0.033), had a higher score. CONCLUSIONS: Simulation-based training improves the technical skills required for camera navigation, regardless of practicing camera navigation or the procedure itself. Transfer to the clinical setting could, however, not be demonstrated. The control group demonstrated higher interest/enjoyment and perceived choice than the camera group. PMID- 27770251 TI - The role of endobronchial ultrasonography for mediastinal lymphadenopathy in cases with extrathoracic malignancy. AB - INTRODUCTION: Many extrathoracic malignancies can metastasize to lungs and mediastinal lymph nodes. Whether mediastinal lesions are metastasis in these patients changes staging, prognosis, and treatment strategy. In this study, we aimed to find out the contribution of EBUS-TBNA to the diagnosis in cases with extrathoracic malignancy. MATERIALS AND METHODS: Patients who had been previously diagnosed as extrapulmonary solid organ malignancy and in whom mediastinal or hilar lymphadenopathy developed during their follow-up and EBUS-TBNA was applied for diagnostic purposes were retrospectively included in this study. RESULTS: A total of 91 patients consisting of 35 females (38.5 %) and 56 males (61.5 %) were included in the study. The mean age of the patients was 60.5 (+/-11.4). Malignancy was not observed in 54 (59.3 %) patients; primary malignancy metastasis was detected in 33 (36.3 %) patients, and primary lung cancer was detected in 4 (4.4 %) patients with EBUS-TBNA. The sensitivity of EBUS-TBNA in extrathoracic malignancies was determined as 90.2 %; its specificity was determined as 100 %, its negative predictive value as 92.5 %, its positive predictive value as 100 %, and its diagnostic accuracy as 95.6 %. The highest rate was determined in the left lower paratracheal lymph node when they were examined in terms of malignancy detection rate in lymph node stations. CONCLUSION: EBUS-TBNA is a minimally invasive method with quite a low complication rate that does not require general anesthesia. It should be the first step method to be used in the diagnosis of mediastinal and hilar lymphadenopathies seen in extrathoracic malignancies since it has high diagnostic accuracy, sensitivity, and specificity. EBUS-TBNA significantly reduces the need for surgical intervention. Further surgical interventions can be planned in patients in whom diagnostic competence is not ensured. PMID- 27770254 TI - Updating metacognitive control in response to expected retention intervals. AB - In five experiments, we investigated whether expected retention intervals affect subjects' encoding strategies. In the first four experiments, our subjects studied paired associates consisting of words from the Graduate Record Exam and a synonym. They were told to expect a test on a word pair after either a short or a longer interval. Subjects were tested on most pairs after the expected retention interval. For some pairs, however, subjects were tested after the other retention interval, allowing for a comparison of performance at a given retention interval conditional upon the expected retention interval. No effect of the expected retention interval was found for 1 min versus 4 min (Exp. 1), 30 s versus 3 min (Exp. 2), and 30 s versus 10 min (Exps. 3 and 4), even when subjects were given complete control over the pacing of study items (Exp. 4). However, when the difference between the expected retention intervals was increased massively (10 min vs. 24 h; Exp. 5), subjects remembered more items that they expected to be tested sooner, an effect consistent with the idea that they traded off efforts to remember items for the later test versus items that were about to be tested. Overall, this set of results accords with much of the test-expectancy literature, revealing that subjects are often reluctant to adjust encoding strategies on an item-by-item basis, and when they do, they usually make quantitative, rather than qualitative, adjustments. PMID- 27770253 TI - Experts' memory superiority for domain-specific random material generalizes across fields of expertise: A meta-analysis. AB - Experts' remarkable ability to recall meaningful domain-specific material is a classic result in cognitive psychology. Influential explanations for this ability have focused on the acquisition of high-level structures (e.g., schemata) or experts' capability to process information holistically. However, research on chess players suggests that experts maintain some reliable memory advantage over novices when random stimuli (e.g., shuffled chess positions) are presented. This skill effect cannot be explained by theories emphasizing high-level memory structures or holistic processing of stimuli, because random material does not contain large structures nor wholes. By contrast, theories hypothesizing the presence of small memory structures-such as chunks-predict this outcome, because some chunks still occur by chance in the stimuli, even after randomization. The current meta-analysis assessed the correlation between level of expertise and recall of random material in diverse domains. The overall correlation was moderate but statistically significant ([Formula: see text]), and the effect was observed in nearly every study. This outcome suggests that experts partly base their superiority on a vaster amount of small memory structures, in addition to high-level structures or holistic processing. PMID- 27770255 TI - Characterisation of vitamin D-related molecules and calcium-sensing receptor in human Fallopian tube during the menstrual cycle and in ectopic pregnancy. AB - This is a prospective observational study that measures the expression of vitamin D (VD) metabolising and signalling molecules and Ca2+ sensing receptor (CaSR) in human Fallopian tube (FT) during the menstrual cycle and ectopic pregnancy (EP). Fresh FTs were obtained during total abdominal hysterectomy at the follicular (n = 16) and midluteal (n = 16) phases. Specimens from remote and implantation sites as well as trophoblastic tissues were also freshly collected from each FT with EP (n = 10). All women had normal serum VD and ionised Ca2+. The expression of VD synthesising (CYP27B1) and catalysing (CYP24A1) enzymes, binding protein (VDBP), receptor (VDR), retinoid X receptor (RXR) and CaSR was measured by immunohistochemistry and quantitative RT-PCR. All molecules, except VDBP, were significantly increased (P < 0.05) in midluteal compared with follicular samples. Remote EP sites showed significantly (P < 0.05) lower expression of CYP27B1, CYP24A1, VDR and RXR and a higher expression of VDBP and CaSR (P < 0.05) compared with midluteal samples. Significant differences were observed by immunohistochemistry between implantation and remote sites from EP for all molecules, which were also localised in the trophoblastic tissues. In conclusion, VD and calcium are under cycle-dependent regulations within human FT and they appear to play a role in tubal biology through paracrine/autocrine mode of signalling. Furthermore, EP was associated with alterations in the expression of all the studied molecules by the tubal epithelium. Further studies are needed to explore the roles of VD in tubal biology and pathogenesis of EP. PMID- 27770256 TI - Cell-based therapies for neonatal lung disease. AB - Preterm birth occurs in approximately 11 % of all births worldwide. Advances in perinatal care have enabled the survival of preterm infants born as early as 23 24 weeks of gestation. However, many are affected by bronchopulmonary dysplasia (BPD)-a common respiratory complication of preterm birth, which has life-long consequences for lung health. Currently, there is no specific treatment for BPD. Recent advances in stem cell research have opened new therapeutic avenues for prevention/repair of lung damage. This review summarizes recent pre-clinical data and early clinical translation of cell-based therapies for BPD. PMID- 27770257 TI - Chondrogenesis of embryonic limb bud cells in micromass culture progresses rapidly to hypertrophy and is modulated by hydrostatic pressure. AB - Chondrogenesis in vivo is precisely controlled in time and space. The entire limb skeleton forms from cells at the core of the early limb bud that condense and undergo chondrogenic differentiation. Whether they form stable cartilage at the articular surface of the joint or transient cartilage that progresses to hypertrophy as endochondral bone, replacing the cartilage template of the skeletal rudiment, is spatially controlled over several days in the embryo. Here, we follow the differentiation of cells taken from the early limb bud (embryonic day 11.5), grown in high-density micromass culture and show that a self organising pattern of evenly spaced cartilage nodules occurs spontaneously in growth medium. Although chondrogenesis is enhanced by addition of BMP6 to the medium, the spatial pattern of nodule formation is disrupted. We show rapid progression of the entire nodule to hypertrophy in culture and therefore loss of the local signals required to direct formation of stable cartilage. Dynamic hydrostatic pressure, which we have previously predicted to be a feature of the forming embryonic joint region, had a stabilising effect on chondrogenesis, reducing expression of hypertrophic marker genes. This demonstrates the use of micromass culture as a relatively simple assay to compare the effect of both biophysical and molecular signals on spatial and temporal control of chondrogenesis that could be used to examine the response of different types of progenitor cell, both adult- and embryo-derived. PMID- 27770258 TI - Kidney transplantation fails to provide adequate growth in children with chronic kidney disease born small for gestational age. AB - BACKGROUND: Children with chronic kidney disease are frequently born small for gestational age (SGA) and prone to disproportionately short stature. It is unclear how SGA affects growth after kidney transplantation (KTx). METHODS: Linear growth (height, sitting height, and leg length) was prospectively investigated in a cohort of 322 pediatric KTx recipients, with a mean follow-up of 4.9 years. Sitting height index (ratio of sitting height to total body height) was used to assess body proportions. Predictors of growth outcome in KTx patients with (n = 94) and without (n = 228) an SGA history were evaluated by the use of linear mixed-effects models. RESULTS: Mean z-scores for all linear body dimensions were lower in SGA compared with non-SGA patients (p < 0.001). SGA patients presented with higher target height deficit and degree of body disproportion (p < 0.001). The latter was mainly due to reduced leg growth during childhood. Pubertal trunk growth was diminished in SGA patients, and the pubertal growth spurt of legs was delayed in both groups, resulting in further impairment of adult height, which was more frequently reduced in SGA than in non-SGA patients (50 % vs 18 %, p < 0.001). Use of growth hormone treatment in the pre transplant period, preemptive KTx, transplant function, and control of metabolic acidosis were the only potentially modifiable correlates of post-transplant growth in SGA groups. By contrast, living related KTx, steroid exposure, and degree of anemia proved to be correlates in non-SGA only. CONCLUSIONS: In children born SGA, growth outcome after KTx is significantly more impaired and affected by different clinical parameters compared with non-SGA patients. PMID- 27770259 TI - New insights from an old mutant: SPADIX4 governs fruiting body development but not hyphal fusion in Sordaria macrospora. AB - During the sexual life cycle of filamentous fungi, multicellular fruiting bodies are generated for the dispersal of spores. The filamentous ascomycete Sordaria macrospora has a long history as a model system for studying fruiting body formation, and two collections of sterile mutants have been generated. However, for most of these mutants, the underlying genetic defect remains unknown. Here, we investigated the mutant spadix (spd) that was generated by X-ray mutagenesis in the 1950s and terminates sexual development after the formation of pre fruiting bodies (protoperithecia). We sequenced the spd genome and found a 22 kb deletion affecting four genes, which we termed spd1-4. Generation of deletion strains revealed that only spd4 is required for fruiting body formation. Although sterility in S. macrospora is often coupled with a vegetative hyphal fusion defect, Deltaspd4 was still capable of fusion. This feature distinguishes SPD4 from many other regulators of sexual development. Remarkably, GFP-tagged SPD4 accumulated in the nuclei of vegetative hyphae and fruiting body initials, the ascogonial coils, but not in sterile tissue from the developing protoperithecium. Our results point to SPD4 as a specific determinant of fruiting body formation. Research on SPD4 will, therefore, contribute to understanding cellular reprogramming during initiation of sexual development in fungi. PMID- 27770260 TI - Reply to the letter to the editor concerning: 'Inlay butterfly cartilage tympanoplasty in the treatment of dry central perforated chronic otitis media as an effective and time-saving procedure' by Haksever et al. PMID- 27770261 TI - Epidemiology and Recurrence Rates of Clostridium difficile Infections in Germany: A Secondary Data Analysis. AB - INTRODUCTION: Clostridium difficile infection (CDI) is the most common cause of health-care-associated infectious diarrhea. Recurrence rates are as high as 20 30% after standard treatment with metronidazole or vancomycin, and appear to be reduced for patients treated with fidaxomicin. According to the literature, the risk of CDI recurrence increases after the second relapse to 30-65%. Accurate data for Germany are not yet available. METHODS: Based on the research database of arvato health analytics (Munich, Germany), a secondary data analysis for the incidence, treatment characteristics and course of CDI was performed. The database included high granular accounting information of about 1.46 million medically insured patients covering the period 2006-2013, being representative for Germany. The analysis was based on new-onset CDI in 2012 in patients which either received outpatient antibiotic therapy for CDI or were hospitalized. RESULTS: The ICD-10 coded incidence of CDI in 2012 was 83 cases per 100,000 population. Overall mortality rates within the follow-up period of 1 year were 13.5% in inpatients with primary diagnosis of CDI, compared to 24.3% in inpatients with secondary diagnosis of CDI (P < 0.001), and 7.1% in outpatients (P < 0.001). In the median, patients with secondary diagnosis of CDI remained significantly longer hospitalized (24 vs. 9 days, P < 0.001). First recurrence of CDI was observed in 18.2% of cases with index events. There was a significantly increased risk to suffer a second and third recurrence, reaching 28.4% (P < 0.001), and 30.2% (P = 0.017), respectively. Antibiotic therapy of CDI in outpatients was performed mainly with metronidazole (in 90.8% of index events, 60.0% of first recurrences, and 43.5% of second recurrences). CONCLUSION: The reported incidence of CDI in Germany is higher than noted previously. The recurrence rates do increase with the number of relapses, but are lower than reported in the literature, despite dominance of metronidazole treatment in outpatients. FUNDING: MSD Sharp & Dohme GmbH, Haar, Germany. PMID- 27770262 TI - Prior Bariatric Surgery Is Linked to Improved Colorectal Cancer Surgery Outcomes and Costs: A Propensity-Matched Analysis. AB - BACKGROUND: Morbid obesity is associated with worse colorectal cancer (CRC) perioperative outcomes. The impact of bariatric surgery on these outcomes is unknown. METHODS: The National Inpatient Sample Database (2006-2012) was used to identify adults with prior bariatric surgery (divided into BMI <=35 kg/m2 and BMI >35 kg/m2) or morbid obesity that underwent CRC surgery. Main outcomes were mortality, surgical complications and health care utilization. RESULTS: There were 1813 patients with prior bariatric surgery and 22,552 morbidly obese patients that underwent CRC surgery between 2006 and 2012. Prior bariatric surgery patients were younger, with fewer comorbidities, and had less emergency CRC surgery admissions (p < 0.05). Multivariate analyses revealed no adverse association (OR 0.54, 95 % CI = 0.16 to 1.79) between prior bariatric surgery and CRC perioperative mortality. Notably, multivariate analysis revealed that bariatric surgery patients undergoing CRC surgery had fewer accidental surgical lacerations (OR 0.38, 95 % CI = 0.15 to 0.93), shorter hospitalizations (-1.85 days, 95 % CI = 2.03 to 1.67), decreased total hospital costs (US$-5374, 95 % CI = -5935 to -4813) and lower disposition to short-term rehabilitation facilities (OR 0.65, 95 % CI = -0.43 to 0.97). Propensity score matched analysis validated these reductions in surgical complications and health care utilization in bariatric surgery patients, which were further more pronounced when bariatric surgery patients were restricted to BMI <=35 kg/m2. CONCLUSIONS: Analysis of national-level data demonstrates that prior bariatric surgery is associated with fewer colorectal cancer surgical complications and improved health care resource utilization compared to morbidly obese patients. These findings emphasize and extend the therapeutic effect of bariatric surgery to the colorectal cancer perioperative setting. PMID- 27770264 TI - The benefits of utilising geo-mapping for visualising the vitamin D status of Dublin city and the surrounding urban districts. AB - CONTEXT: There have been few published reports of visualising vitamin D status at a micro level, i.e., within large individual urban centres of countries. OBJECTIVE: To produce a visual map of the vitamin D status [25-hydroxy vitamin D 25(OH)D] of a large urban centre (n > 350,000) incorporating the regions of Dublin city that constitute the general practitioner catchment area of a large academic teaching adult hospital. DESIGN, SETTING AND PARTICIPANTS: An observational investigation of 5287 free living Irish adults (>18 years). RESULTS: Approximately, 15.2 % of those sampled in the winter period (October February) were vitamin D deficient (<30 nmol/L) compared with 10.8 % of those sampled in the summer period (March-September). Vitamin D tests requested from the most social economically deprived urban locations (Dublin 8 and Lucan postal districts) had the highest rates of deficiency (23.5 and 20.4 %, respectively, both seasons). On average, females had a significantly higher 25(OH)D concentration compared with males (57.9 vs 52.3 nmol/L, respectively), while the younger participants (18-50 years) mean 25(OH)D concentration was 27 % lower in winter and 20.7 % lower in summer in comparison with the older participants (>50 years) (P < 0.0001). CONCLUSIONS: For the first time in Ireland, a visual depiction of data can be used to aid in the rapid identification of vitamin D status trends within a major urban area. These findings provide useful data to help inform public health policy regarding endemic vitamin D insufficiency to help target the population groups and resident location areas most at risk. PMID- 27770263 TI - Factors predicting the outcome following surgical treatment of mesial temporal epilepsy due to mesial temporal sclerosis. AB - BACKGROUND: Mesial temporal sclerosis (MTS) is the most common disease found in an epilepsy surgery series. Early age of onset, a history of febrile convulsions, epileptiform discharges on EEG, duration of epilepsy, number of generalized seizures and severity of psychiatric disorders are possible prognostic factors in patients with MTS. OBJECTIVE: The aim of this study is to review the clinical, semiotic, psychological, electrophysiological and neuroradiological researches and relate their findings to the prognosis of patients with MTS who underwent anteromedial temporal lobectomy (ATL). METHODS: Of 1,214 patients evaluated for surgery in the epilepsy Center of Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), a tertiary Brazilian epilepsy center, 400 underwent ATL for MTS. Examinations and clinical data were analyzed and compared with the Engel Outcome Classification. RESULTS: Of all the items analyzed, the MRI showed the greatest influence on patient outcome. As for the clinical evaluation and pathological antecedents, age at surgery, epilepsy duration, perinatal insults, family history of epilepsy, febrile seizures, neuropsychological abnormalities and presence of generalized tonic-clonic seizure all had statistical significance. CONCLUSION: In order to identify the most appropriate candidates for ATL, it is very important to consider the prognostic factors associated with a favorable outcome for counseling patients in daily practice. PMID- 27770265 TI - Hadrontherapy from the Italian Radiation Oncologist point of view: face the reality. The Italian Society of Oncological Radiotherapy (AIRO) survey. AB - Hadrontherapy has been in constant progress in the past decades. Due to the increasing interest in this field and the spreading of the technique in Italy and worldwide, the Italian Society of Radiation Oncology surveyed (by an online survey) its members regarding their perception of hadrontherapy. The survey outline addressed different items all related to hadrontherapy, such as: demographics (3 items), personal knowledge (5 items), actual use in clinical practice (5 items), and future perspectives and development (5 items). The survey was filled in by 224 radiation oncologists (RO). Among them, 74.6 % were RO with more than 5 years of clinical practice, and only 10.4 % RO in training. Median age was 46 years (range 27-77). 32.24 % admitted average knowledge about heavy particles radiobiology rationale and 32.42 % about the ongoing particle therapy clinical trials. Radioresistant tumors are perceived as-principal indications for carbon ions in 39.3 % of responders, and pediatric malignancies for protons in 37 %. Re-irradiation is highly recommended for 52.2 %. Strikingly, 38.8 % of participating ROs reported that, in the daily clinical practice, approximately less than 1 out of 10 patients asks to be referred for hadrontherapy. On the other side, 35.7 % claimed need for at least 3 up to 5 particle therapy centers in Italy. Overall, the results of the present survey highlight the interest of the Italian RO community for particle therapy among the other radiotherapy technique. Analysis of our results might picture the clinical attitude of the RO community towards hadrontherapy in Italy, and help in promoting targeted initiatives to spread clinical results and knowledge about technical innovations in this field. PMID- 27770267 TI - 2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway. AB - Apoptosis is a representative form of programmed cell death, which has been assumed to be critical for cancer prevention. Thus, any agent that can induce apoptosis may be useful for cancer treatment and apoptosis induction is arguably the most potent defense against cancer promotion. In our previous studies, 2-aryl benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity and one of the new molecule (2f) was considered as a potential lead. This lead molecule showed significant antiproliferative activity against human breast cancer cell line, MCF-7. The results of the present study revealed that this compound arrested the cell cycle at G2/M phase. Topoisomerase II inhibition assay and Western blot analysis suggested that this compound effectively inhibits topoisomerase II activity which leads to apoptotic cell death. Apoptosis induction in MCF-7 cells was further confirmed by loss of mitochondrial membrane potential (?Psim), release of cytochrome c from mitochondria, an increase in the level of apoptosis inducing factor (AIF), generation of reactive oxygen species (ROS), up regulation of proapoptotic protein Bax and down regulation of anti apoptotic protein Bcl-2. Apoptosis assay using Annexin V-FITC assay also suggested that this compound induced cell death by apoptosis. However, compound 2f induced apoptosis could not be reversed by Z VAD-FMK (a pan-caspase inhibitor) demonstrated that the 2f induced apoptosis was caspase independent. Further, 2f treatment did not activate caspase-7 and caspase 9 activity, suggesting that this compound induced apoptosis in breast cancer cells via a caspase independent pathway. Most importantly, this compound was less toxic towards non-tumorigenic breast epithelial cells, MCF-10A. Furthermore, docking studies also support the potentiality of this molecule to bind to the DNA topoisomerase II. PMID- 27770266 TI - First application of a protein-based approach for time since death estimation. AB - Awareness of postmortem degradation processes in a human body is fundamental to develop methods for forensic time since death estimation (TDE). Currently, applied approaches are all more or less limited to certain postmortem phases, or have restrictions on behalf of circumstances of death. Novel techniques, however, rarely exceed basic research phases due to various reasons. We report the first application of a novel method, based on decay of muscle proteins, in a recent case of murder-suicide, where other TDE methods failed to obtain data. We detected considerably different protein degradation profiles in both individuals involved and compared the data to our presently available database. We obtained statistical evidence for un-simultaneous death and therefore received valuable information to trace the progression of events based on protein degradation. Although we could not sensibly convert the data to respective times of death, this case highlights the potential for future application and elucidates the necessary further steps to develop a viable TDE method. PMID- 27770268 TI - Sensitizing effect of juglone is mediated by down regulation of Notch1 signaling pathway in trastuzumab-resistant SKBR3 cells. AB - Trastuzumab (Herceptin) monoclonal antibody directed against HER2 receptor has been administered as a treatment for metastatic HER2 positive breast cancer. The problematic issue in treatment of HER2 positive breast cancer cells is commonly the induction of resistance to trastuzumab which might be due to modulation of some vital signaling elements such as Notch1 and Pin1. In this study, we were aimed to investigate whether the cross talk between pin1 and Notch1 has a role in this event. Our results indicated that the expression level of Pin1 in resistant SKBR3 cells increased by about twofold relative to sensitive SKBR3 cells. Besides, Pin1 inhibition via juglone reduced the extent of proliferation, colony formation and migration capacity of resistant SKBR3 cells. In addition, despite a feed forward loop between Notch1 and Pin1 in sensitive SKBR3 cells, inhibition of Notch1 cleavage in resistant SKBR3 cells did not affect pin1 level whereas pin1 inhibition by juglone reduced the level of Hes1, p-Akt and increased the cellular content of Numb. Therefore, we concluded that pin1 inhibition could be considered as a promising sensitizing strategy to weaken trastuzumab resistance. PMID- 27770271 TI - Scientific Reviewers. PMID- 27770269 TI - Coenzyme Q10 protects renal proximal tubule cells against nicotine-induced apoptosis through induction of p66shc-dependent antioxidant responses. AB - Chronic nicotine exposure (via smoking, E-cigarettes) increases oxidative stress in the kidney that sensitizes it to additional injury in experimental models and in the renal patient. The pro-apoptotic p66shc protein-via serine36 phosphorylation that facilitates its mitochondrial translocation and therein cytochrome c binding-generates oxidative stress that leads to injury of renal proximal tubule cells during chronic nicotine exposure. Coenzyme Q10-a clinically safe antioxidant-has been used against nicotine/smoke extract-associated oxidative stress in various non-renal cells. This study explored the anti oxidant/anti-apoptotic effect of Coenzyme Q10 on nicotine-induced oxidative stress and its impact on p66shc in cultured rat renal proximal tubule cells (NRK52E). We studied the anti-oxidant effect of 10 uM Coenzyme Q10 using various mutants of the p66shc gene and also determined the induction of selected anti oxidant entities (antioxidant response element, promoter of the manganese superoxide dismutase gene) in reporter luciferase assay during oxidative stress induced by 200 uM nicotine. Our studies revealed that Coenzyme Q10 strongly inhibits nicotine-mediated production of reactive oxygen species and consequent apoptosis that requires serine36 phosphorylation but not mitochondrial translocation/cytochrome c binding of p66shc. While both nicotine and Coenzyme Q10 stimulates the p66shc promoter, only nicotine exposure results in mitochondrial translocation of p66shc. In contrast, the Coenzyme Q10-stimulated and non-mitochondrial p66shc activates the anti-oxidant manganese superoxide dismutase promoter via the antioxidant response elements and hence, rescues cells from nicotine-induced oxidative stress and consequent apoptosis. PMID- 27770270 TI - Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure. AB - The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd3+ ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd3+ treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO2), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gd3+ concentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gd3+ ions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood-brain barrier damages. PMID- 27770272 TI - Sexual headache from view point of Avicenna and traditional Persian medicine. AB - One of the best remaining manuscripts is the "Canon of Medicine" fathered by Avicenna in the Islamic Golden Age [ninth to twelfth century AD]. Considering Avicenna's role in the development of medical science in the Islamic Golden Age, we reviewed Avicenna's point of view on sexual headache based on his famous book "Canon of Medicine". This historical review discusses the clinical approaches applied to diagnose, classify, and treat sexual headache-specifically herbal therapy-from the viewpoint of Avicenna and Traditional Persian Medicine. The accurate observations of Avicenna give a comprehensive classified etiology of the sexual headache. The efficacy of some medicinal herbs used by him for sexual headache treatments, such as the analgesic effect of lavender, chamomile, and jasmine has been proved by current medicine; however, the knowledge of medieval physicians should be scientifically investigated even further to extend new remedial options for sexual headache. PMID- 27770274 TI - Let's cut it short: Italian standardization of the MMSPE (Mini-Mental State Pediatric Examination), a brief cognitive screening tool for school-age children. AB - A pediatric cognitive screening tool has been shaped in three versions according to school class to assess spatial and temporal orientation, language, reading, writing, drawing, number knowledge, memory, praxis and executive functions in children aged 6-13. It has been standardized on an Italian sample of 807 children. Raw scores were adjusted for critical variables (child's age and parents' education) and a cut-off for the resulting global cognitive score was made available for clinical practice. In line with previous research, adapting the Mini-Mental State Examination to pediatric neuropsychological assessment turned out to be useful in estimating global cognitive functioning in children. PMID- 27770273 TI - Pure alexia in a patient with multiple sclerosis. PMID- 27770275 TI - Prevalence of rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease: a meta and meta-regression analysis. AB - Rapid eye movement sleep behavior disorder (RBD) is thought to be one of the most frequent preceding symptoms of Parkinson's disease (PD). However, the prevalence of RBD in PD stated in the published studies is still inconsistent. We conducted a meta and meta-regression analysis in this paper to estimate the pooled prevalence. We searched the electronic databases of PubMed, ScienceDirect, EMBASE and EBSCO up to June 2016 for related articles. STATA 12.0 statistics software was used to calculate the available data from each research. The prevalence of RBD in PD patients in each study was combined to a pooled prevalence with a 95 % confidence interval (CI). Subgroup analysis and meta-regression analysis were performed to search for the causes of the heterogeneity. A total of 28 studies with 6869 PD cases were deemed eligible and included in our meta-analysis based on the inclusion and exclusion criteria. The pooled prevalence of RBD in PD was 42.3 % (95 % CI 37.4-47.1 %). In subgroup analysis and meta-regression analysis, we found that the important causes of heterogeneity were the diagnosis criteria of RBD and age of PD patients (P = 0.016, P = 0.019, respectively). The results indicate that nearly half of the PD patients are suffering from RBD. Older age and longer duration are risk factors for RBD in PD. We can use the minimal diagnosis criteria for RBD according to the International Classification of Sleep Disorders to diagnose RBD patients in our daily work if polysomnography is not necessary. PMID- 27770277 TI - Erratum to: Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors. PMID- 27770276 TI - Prevalence of hepatitis E virus antibodies in workers occupationally exposed to swine in Portugal. AB - The concept of zoonotic hepatitis E in industrialized countries has emerged with the discovery of swine strains of hepatitis E virus (HEV) genotype 3, closely related to human HEV. Different routes of zoonotic HEV transmission have been recognized, including contact with infected pigs. Workers occupationally exposed to swine (WOES) have been considered a risk group for HEV infection, but contradictory results have been reported. In the present study, we searched for anti-HEV IgG in WOES (butchers, slaughterhouse workers, veterinarians and pig farmers; n = 114) and in the general population (n = 804) in order to investigate the potential occupational risk of zoonotic HEV infection in this work group. A significantly higher (p = 0.008) anti-HEV IgG seroprevalence was found in WOES (30.7 %) when compared with the general population (19.9 %). Multivariate analysis showed that having professions with exposure to pigs for more than 16.5 years was a risk factor for being positive for anti-HEV IgG (aOR of 5.4, 95 % CI 1.9-15.6, p = 0.002). To our knowledge, this is the first study on the prevalence of anti-HEV IgG in WOES in Portugal, also showing increased probability for infection in this group. PMID- 27770278 TI - Comprehensive proteome profiling of glioblastoma-derived extracellular vesicles identifies markers for more aggressive disease. AB - Extracellular vesicles (EVs) play key roles in glioblastoma (GBM) biology and represent novel sources of biomarkers that are detectable in the peripheral circulation. Despite this notionally non-invasive approach to assess GBM tumours in situ, a comprehensive GBM EV protein signature has not been described. Here, EVs secreted by six GBM cell lines were isolated and analysed by quantitative high-resolution mass spectrometry. Overall, 844 proteins were identified in the GBM EV proteome, of which 145 proteins were common to EVs secreted by all cell lines examined; included in the curated EV compendium (Vesiclepedia_559; http://microvesicles.org ). Levels of 14 EV proteins significantly correlated with cell invasion (invadopodia production; r2 > 0.5, p < 0.05), including several proteins that interact with molecules responsible for regulating invadopodia formation. Invadopodia, actin-rich membrane protrusions with proteolytic activity, are associated with more aggressive disease and are sites of EV release. Gene levels corresponding to invasion-related EV proteins showed that five genes (annexin A1, actin-related protein 3, integrin-beta1, insulin like growth factor 2 receptor and programmed cell death 6-interacting protein) were significantly higher in GBM tumours compared to normal brain in silico, with common functions relating to actin polymerisation and endosomal sorting. We also show that Cavitron Ultrasonic Surgical Aspirator (CUSA) washings are a novel source of brain tumour-derived EVs, demonstrated by particle tracking analysis, TEM and proteome profiling. Quantitative proteomics corroborated the high levels of proposed invasion-related proteins in EVs enriched from a GBM compared to low grade astrocytoma tumour. Large-scale clinical follow-up of putative biomarkers, particularly the proposed survival marker annexin A1, is warranted. PMID- 27770279 TI - NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma. AB - Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age >=18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75-100 mg/m2 day 1-21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of >=35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage. PMID- 27770280 TI - Comparative effectiveness of radiotherapy with vs. without temozolomide in older patients with glioblastoma. AB - It is unknown whether the addition of temozolomide (TMZ) to radiotherapy (RT) is associated with improved overall survival (OS) among older glioblastoma patients. We performed a retrospective cohort SEER-Medicare analysis of 1652 patients aged >=65 years with glioblastoma who received >=10 fractions of RT from 2005 to 2009, or from 1995 to 1999 before TMZ was available. Three cohorts were assembled based on diagnosis year and treatment initiated within 60 days of diagnosis: (1) 2005 2009 and TMZ/RT, (2) 2005-2009 and RT only, or (3) 1995-1999 and RT only. Associations with OS were estimated using Cox proportional hazards models and propensity score analyses; OS was calculated starting 60 days after diagnosis. Pre-specified sensitivity analyses were performed among patients who received long-course RT (>=27 fractions). Median survival estimates were 7.4 (IQR, 3.3 14.7) months for TMZ/RT, 5.9 (IQR, 2.6-12.1) months for RT alone in 2005-2009, and 5.6 (IQR, 2.7-9.6) months for RT alone in 1995-1999. OS at 2 years was 10.1 % for TMZ/RT, 7.1 % for RT in 2005-2009, and 4.7 % for RT in 1995-1999. Adjusted models suggested decreased mortality risk for TMZ/RT compared to RT in 2005-2009 (AHR, 0.86; 95 % CI, 0.76-0.98) and RT in 1995-1999 (AHR, 0.71; 95 % CI, 0.57 0.90). Among patients from 2005 to 2009 who received long-course RT, however, the addition of TMZ did not significantly improve survival (AHR, 0.91; 95 % CI, 0.80 1.04). In summary, among a large cohort of older glioblastoma patients treated in a real-world setting, the addition of TMZ to RT was associated with a small survival gain. PMID- 27770282 TI - Platinum salts in advanced breast cancer: a systematic review and meta-analysis of randomized clinical trials. AB - BACKGROUND: The interest in platinum salts in breast cancer (BC) therapy has been recently renewed as inhibition of DNA damage response may enhance the effects of DNA-damaging agents in BC tumors with high genomic instability. The present systematic review and meta-analysis of randomized trials were performed to assess the efficacy and safety of therapy with platinum salts in patients with locally advanced or metastatic (hereinafter advanced) BC. METHODS: We searched PubMed, EMBASE, SCOPUS, Web of Science, the Cochrane Library, and CINAHL for phase II/III clinical trials that assessed efficacy of platinum-based therapy in patients with advanced BC. Pooled estimates of overall response rate (RR), median progression free survival (PFS) and overall survival (OS) were computed using random or fixed effects models. RESULTS: Data on 4625 patients from 23 phase II and III trials (11 with cisplatin, 11 with carboplatin, and 1 with either agents respectively) were analyzed. Estimates for RR, PFS, and OS were obtained from 23, 13, and 15 studies, respectively. Although at the cost of significantly increased fatigue, hematological and gastrointestinal toxicity, compared with non-platinum schemas, cisplatin, and carboplatin prolonged OS (HR 0.91; 95 % CI 0.83-1.00, p = 0.04), PFS (HR 0.84; 95 % CI 0.73-0.97, p = 0.01), and RR (HR 1.27; 95 % CI 1.03-1.57, p = 0.03). CONCLUSIONS: Despite some limitations of the studies examined, including partial information on hormonal receptor and HER2 status, the use of platinum salts significantly prolonged OS, and PFS of patients with advanced BC with no unexpected toxicity. PMID- 27770281 TI - Long-term safety of growth hormone replacement therapy after childhood medulloblastoma and PNET: it is time to set aside old concerns. AB - To assess the long-term safety of administering growth hormone (GH) in patients with GH deficiency due to treatment for childhood medulloblastoma and primitive neuroectodermal tumor (PNET). Data were retrospectively retrieved on children receiving GH supplementation, assessing their disease-free and overall survival outcomes and risk of secondary malignancies using Kaplan-Meier and Cox models. Overall 65 children were consecutively collected from May 1981 to April 2013. All patients had undergone craniospinal irradiation (total dose 18-39 Gy), and subsequently received GH for a median (interquartile range, IQR) of 81 (50.6 114.9) months. At a median (IQR) of 122.4 months (74.4-149.5) after the end of their adjuvant cancer treatment, two patients (3 %) experienced recurrent disease and 8 (12.3 %) developed secondary malignancies, all but one of them (an osteosarcoma) related to radiation exposure and occurring within the radiation fields. There was no apparent correlation between the administration of GH replacement therapy (or its duration) and primary tumor relapse or the onset of secondary malignancies [HR: 1.01 (95 % CI: 0.98, 1.03) for every additional 12 months of GH supplementation; p = 0.36). At univariate analysis, the large cell or anaplastic medulloblastoma subtype, metastases and myeloablative chemotherapy correlated with a higher risk of secondary malignancies (p < 0.1), but multivariate analysis failed to identify any factors independently associated with this risk. Our data supports once more the safety of long-term GH replacement therapy in children treated for medulloblastoma/PNET, previously reported in larger data sets. The neurooncology community now need to warrant large-scale meta-analyses or international prospective trials in order to consolidate our knowledge of factors other than GH, such as genetic predisposition, high-grade/metastatic disease, high-dose chemotherapy and era of treatment, in promoting the occurrence of secondary malignancies. PMID- 27770283 TI - Accounting for individualized competing mortality risks in estimating postmenopausal breast cancer risk. AB - PURPOSE: Accurate risk assessment is necessary for decision-making around breast cancer prevention. We aimed to develop a breast cancer prediction model for postmenopausal women that would take into account their individualized competing risk of non-breast cancer death. METHODS: We included 73,066 women who completed the 2004 Nurses' Health Study (NHS) questionnaire (all >=57 years) and followed participants until May 2014. We considered 17 breast cancer risk factors (health behaviors, demographics, family history, reproductive factors) and 7 risk factors for non-breast cancer death (comorbidities, functional dependency) and mammography use. We used competing risk regression to identify factors independently associated with breast cancer. We validated the final model by examining calibration (expected-to-observed ratio of breast cancer incidence, E/O) and discrimination (c-statistic) using 74,887 subjects from the Women's Health Initiative Extension Study (WHI-ES; all were >=55 years and followed for 5 years). RESULTS: Within 5 years, 1.8 % of NHS participants were diagnosed with breast cancer (vs. 2.0 % in WHI-ES, p = 0.02), and 6.6 % experienced non-breast cancer death (vs. 5.2 % in WHI-ES, p < 0.001). Using a model selection procedure which incorporated the Akaike Information Criterion, c-statistic, statistical significance, and clinical judgement, our final model included 9 breast cancer risk factors, 5 comorbidities, functional dependency, and mammography use. The model's c-statistic was 0.61 (95 % CI [0.60-0.63]) in NHS and 0.57 (0.55-0.58) in WHI-ES. On average, our model under predicted breast cancer in WHI-ES (E/O 0.92 [0.88-0.97]). CONCLUSIONS: We developed a novel prediction model that factors in postmenopausal women's individualized competing risks of non-breast cancer death when estimating breast cancer risk. PMID- 27770285 TI - Anterior tibial tubercle osteotomy using cerclage wire fixation in total knee replacement: a modification of the usual technique. AB - Anterior tibial tubercle (ATT) osteotomy facilitates exposure in knee arthroplasty. However, it is not without complications. We have introduced some technical modifications that reduce the surgical aggression by designing a short osteotomy that does not invade the intramedullary canal, and synthesizing it with three cerclage wires with a particular layout that increases the solidity of the system. A retrospective review was performed on the surgical revision of total knee replacement cases intervened in our center that required an ATT osteotomy from February 2014 to February 2015, and who had a minimum clinical follow-up of 12 months. In all cases, there was an average proximal increase in ATT of 5 mm and, however, did not result in any loss of knee extension. All the osteotomies achieved complete bone consolidation at 3 months. There were no other complications. Our technique may be a valid option as it shows satisfactory results and demonstrates that a small increase in ATT does not affect the final clinical outcome. PMID- 27770286 TI - Dietary oxidized tyrosine (O-Tyr) stimulates TGF-beta1-induced extracellular matrix production via the JNK/p38 signaling pathway in rat kidneys. AB - Oxidized tyrosine (O-Tyr) products have been detected in commercial food and have been demonstrated to induce liver injury in our previous study, but the precise mechanisms of the impact induced by dietary O-Tyr are still unclear. Kidney plays an important role in the metabolism of protein. Accumulation of O-Tyr products, especially the dityrosine (Dityr) and advanced oxidation protein products (AOPPs), in vivo was shown to be associated with many kidney diseases. Therefore, this study determined whether chronic exposure to dietary O-Tyr impaired renal function in rats. After O-Tyr treatment for 24 weeks, rats exhibited oxidative stress and protein oxidation in the kidneys, accompanied with inflammatory reaction and renal dysfunction. Elevated extracellular matrix (ECM) contents and the histological examination (HE and Masson stain) results indicated renal fibrosis. The Real-time PCR and Western blotting assay showed that O-Tyr activated phosphorylation of JNK/p38 and up-regulated the expression of transforming growth factor-beta1 (TGF-beta1) and Smad 2/3. These results suggest that dietary O-Tyr could induce oxidative stress, inflammation and renal fibrosis through JNK/p38/TGF-beta1 signaling pathway. Dityr (accounting for 22 % of the total O-Tyr material) may be responsible for the O-Tyr-induced injury. This study also provides a modified procedure for separation and purification of Dityr, the main oxidized product in O-Tyr. PMID- 27770284 TI - Aberrant activity and connectivity of the posterior superior temporal sulcus during social cognition in schizophrenia. AB - Schizophrenia is associated with significant impairments in social cognition. These impairments have been shown to go along with altered activation of the posterior superior temporal sulcus (pSTS). However, studies that investigate connectivity of pSTS during social cognition in schizophrenia are sparse. Twenty two patients with schizophrenia and 22 matched healthy controls completed a social-cognitive task for functional magnetic resonance imaging that allows the investigation of affective Theory of Mind (ToM), emotion recognition and the processing of neutral facial expressions. Moreover, a resting-state measurement was taken. Patients with schizophrenia performed worse in the social-cognitive task (main effect of group). In addition, a group by social-cognitive processing interaction was revealed for activity, as well as for connectivity during the social-cognitive task, i.e., patients with schizophrenia showed hyperactivity of right pSTS during neutral face processing, but hypoactivity during emotion recognition and affective ToM. In addition, hypoconnectivity between right and left pSTS was revealed for affective ToM, but not for neutral face processing or emotion recognition. No group differences in connectivity from right to left pSTS occurred during resting state. This pattern of aberrant activity and connectivity of the right pSTS during social cognition might form the basis of false-positive perceptions of emotions and intentions and could contribute to the emergence and sustainment of delusions. PMID- 27770288 TI - Buried Barrett Metaplasia After Endoluminal Ablation: a Ticking Time Bomb or Much Ado About Nothing? PMID- 27770287 TI - Cue-target contingencies modulate voluntary orienting of spatial attention: dissociable effects for speed and accuracy. AB - Voluntary orienting of spatial attention is typically investigated by visually presented directional cues, which are called predictive when they indicate where the target is more likely to appear. In this study, we investigated the nature of the potential link between cue predictivity (the proportion of valid trials) and the strength of the resulting covert orienting of attention. Participants judged the orientation of a unilateral Gabor grating preceded by a centrally presented, non-directional, color cue, arbitrarily prompting a leftwards or rightwards shift of attention. Unknown to them, cue predictivity was manipulated across blocks, whereby the cue was only predictive for either the first or the second half of the experiment. Our results show that the cueing effects were strongly influenced by the change in predictivity. This influence differently emerged in response speed and accuracy. The speed difference between valid and invalid trials was significantly larger when cues were predictive, and the amplitude of this effect was modulated at the single trial level by the recent trial history. Complementary to these findings, accuracy revealed a robust effect of block history and also a different time-course compared with speed, as if it mainly mirrored voluntary processes. These findings, obtained with a new manipulation and using arbitrary non-directional cueing, demonstrate that cue-target contingencies strongly modulate the way attention is deployed in space. PMID- 27770289 TI - The Impact of Advancing Age on Recurrence and Survival Following Major Hepatectomy for Colorectal Liver Metastases. AB - INTRODUCTION: This study analysed the effect of age on survival in patients undergoing major hepatectomy (MH) for colorectal liver metastases (CRLM). The effect of adjuvant chemotherapy (AC) with age was also assessed. METHOD: Patients undergoing MH for CRLM between 1996 and 2011 were reviewed. Patients aged <75 or >=75 were compared for disease-free (DFS) and overall survival (OS) as well as impact of AC on survival. RESULTS: Seven hundred twenty-seven patients underwent MH of which 105 (14 %) were aged >=75. Morbidity was greater in the >=75 group (25 versus 34 %, p = 0.048). No difference was noted in mortality. There was no difference in DFS between the two groups at 5 years (16.8 vs 18.9 months (p = 0.570). OS was longer in the <75 group (38.6 vs 32.0 months (p = 0.001). DFS was better in groups receiving AC than those not (<75 24.2 vs 12.2 months (p = <0.001) and >=75 24 vs 12.1 months (p = 0.007)). OS in the >=75 group was improved in the group receiving AC compared to the >=75 group not (41.1 vs 16.6 months, p = 0.005). Age >=75 was not an independent risk factor for reduced DFS on multivariate analysis. CONCLUSION: Well-selected patients aged >=75 should be considered for MH followed by adjuvant chemotherapy. PMID- 27770291 TI - Erratum to: Endemic impact of human T cell leukemia virus type 1 screening in bone allografts. PMID- 27770290 TI - Minimally Invasive Resection of Adrenocortical Carcinoma: a Multi-Institutional Study of 201 Patients. AB - BACKGROUND AND OBJECTIVES: Minimally invasive surgery for adrenocortical carcinoma (ACC) is controversial. We sought to evaluate the perioperative and long-term outcomes following minimally invasive (MIS) and open resection (OA) of ACC in patients treated with curative intent surgery. METHODS: Retrospective data from patients who underwent adrenalectomy for primary ACC at 13 tertiary care cancer centers were analyzed, including demographics, clinicopathological, and operative outcomes. Outcomes following MIS were compared to OA. RESULTS: A total of 201 patients were evaluated including 47 MIS and 154 OA. There was no difference in utilization of MIS approach among institutions (p = 0.24) or 30-day morbidity (29.3 %, MIS, vs. 30.9 %, OA; p = 0.839). The only preoperatively determined predictor for MIS was smaller tumor size (p < 0.001). There was no difference in rates of intraoperative tumor rupture (p = 0.612) or R0 resection (p = 0.953). Only EBL (p = 0.038) and T stage (p = 0.045) were independent prognostic indicators of overall survival after adjusting for significant factors. The surgical approach was not associated with overall or disease-free survival. CONCLUSION: MIS adrenalectomy may be utilized for preoperatively determined ACC <= 10.0 cm; however, OA should be utilized for adrenal masses with either preoperative or intraoperative evidence of local invasion or enlarged lymph nodes, regardless of size. PMID- 27770292 TI - The potential role of perivascular lymphatic vessels in preservation of kidney allograft function. AB - BACKGROUND: Lymphangiogenesis occurs in diseased native kidneys and kidney allografts, and correlates with histological injury; however, the clinical significance of lymphatic vessels in kidney allografts is unclear. METHODS: This study retrospectively reviewed 63 kidney transplant patients who underwent protocol biopsies. Lymphatic vessels were identified by immunohistochemical staining for podoplanin, and were classified according to their location as perivascular or interstitial lymphatic vessels. The associations between perivascular lymphatic density and kidney allograft function and pathological findings were analyzed. RESULTS: There were no significant differences in perivascular lymphatic densities in kidney allograft biopsy specimens obtained at 0 h, 3 months and 12 months. The groups with higher perivascular lymphatic density showed a lower proportion of progression of interstitial fibrosis/tubular atrophy grade from 3 to 12 months (P for trend = 0.039). Perivascular lymphatic density was significantly associated with annual decline of estimated glomerular filtration rate after 12 months (r = -0.31, P = 0.017), even after adjusting for multiple confounders (standardized beta = -0.30, P = 0.019). CONCLUSIONS: High perivascular lymphatic density is associated with favourable kidney allograft function. The perivascular lymphatic network may be involved in inhibition of allograft fibrosis and stabilization of graft function. PMID- 27770293 TI - Randomized Controlled Trial of a Brief Versus Extended Internet Intervention for Problem Drinkers. AB - PURPOSE: Brief Internet interventions have been shown to reduce alcohol consumption. This trial intended to compare the effects of one such brief intervention to an extended Internet intervention for problem drinkers. METHOD: Using online advertising, 490 participants, 18 years or older, were recruited and randomized to receive a brief ( CheckYourDrinking.net ) versus an extended ( AlcoholHelpCentre.net ) Internet intervention and were followed up at 6, 12, and 24 months. The per protocol primary analysis assessed difference between condition at the 12-month follow-up. RESULTS: The follow-up rate at 12 months was 83.3 %. ANCOVAs of the primary (Alcohol Use Disorder Identification Test (AUDIT) C) and secondary outcome variables (drinks in a typical week, highest number of drinks on one occasion-baseline drinking as covariate) revealed no significant (p > 0.05) differences between the interventions. Similarly, combined analyses of the 6-, 12-, and 24-month follow-up revealed no significant differences between interventions at all time points. CONCLUSION: The present study does not provide support for the added benefit of an extended Internet intervention for problem drinkers over a brief Internet intervention. PMID- 27770295 TI - All that glisters is not an endophenotype: rethinking endophenotypes in anorexia nervosa. PMID- 27770294 TI - Do child healthcare professionals and parents recognize social-emotional and behavioral problems in 1-year-old infants? AB - Growing evidence supports the existence of clinically significant social emotional/behavioral (SEB) problems among as young as 1-year-old infants. However, a substantial proportion of early SEB problems remain unidentified during contacts with child healthcare professionals. In this study, child healthcare nurse (CHCN; N = 1008) and parental (N = 518) reports about SEB worries were gathered, along with the maternal and paternal Brief Infant-Toddler Social and Emotional Assessment (BITSEA) ratings, for 12-month-old infants randomly recruited through Finnish child health centers. Only 1.4-1.8 % of CHCNs, 3.9 % of mothers, and 3.2 % of fathers reported of being worried about the assessed child's SEB development. When the CHCNs' and parental reports were combined, 7.7 % (33/428) of the infants assessed each by all three adults had one (7.0 %), two (0.7 %) or three (0 %) worry reports. Even the combination of the CHCN's and parental worry reports identified only 7.0-13.8 % of the infants with the maternal and/or paternal BITSEA Problem or Competence rating in the of concern range. Identified associations across the three informants' worry reports, parental BITSEA ratings and sociodemographic factors are discussed in the paper. Routine and frequent use of developmentally appropriate screening measures, such as the BITSEA, might enhance identification and intervening of early SEB problems in preventive child healthcare by guiding both professionals and parents to pay more attention to substantial aspects of young children's SEB development and encouraging them to discuss possible problems and worries. PMID- 27770297 TI - Early predictors of need for remediation in the Australian general practice training program: a retrospective cohort study. AB - Underperforming trainees requiring remediation may threaten patient safety and are challenging for vocational training programs. Decisions to institute remediation are high-stakes-remediation being resource-intensive and emotionally demanding on trainees. Detection of underperformance requiring remediation is particularly problematic in general (family) practice. We sought to establish early-training assessment instruments predictive of general practice (GP) trainees' subsequently requiring formal remediation. We conducted a retrospective cohort study of trainees from a large Australian regionally-based GP training organization. The outcome factor was requirement for formal remediation. Independent variables were demographic factors and a range of formative assessments conducted immediately prior to or during early-stage training. Analyses employed univariate and multivariate logistic regression of each predictor assessment modality with the outcome, adjusting for potential confounders. Of 248 trainees, 26 (10.5 %) required formal remediation. Performance on the Colleague Feedback Evaluation Tool (entailing feedback from a trainee's clinical colleagues on clinical performance, communication and probity) and External Clinical Teaching Visits (half-day sessions of the trainee's clinical consultations observed directly by an experienced GP), along with non Australian primary medical qualification, were significantly associated with requiring remediation. There was a non-significant trend for association with performance on the Doctors Interpersonal Skills Questionnaire (patient feedback on interpersonal elements of the consultation). There were no significant associations with entry-selection scores or formative exam or assessment scores. Our finding that 'in vivo' assessments of complex behaviour, but not 'in vitro' knowledge-based assessments, predict need for remediation is consistent with theoretical understanding of the nature of remediation decision-making and should inform remediation practice in GP vocational training. PMID- 27770299 TI - Effect of iron ions (Fe2+, Fe3+) on the formation and structure of aerobic granular sludge. AB - Aerobic granulation is a promising technology for wastewater treatment, but problems regarding its formation and stability need to be solved. Divalent metal ions, especially Ca2+, Mg2+ and Mn2+, have been demonstrated to play an important role in the process of aerobic granulation. Here, we studied whether iron ions can affect aerobic granulation. Granular sludge formed without iron ion addition (<0.02 mg Fe2+ L-1) was fluffy and had a finger-type structure and filamentous out-growth. The addition of iron ions to concentrations of 1 and 10 mg Fe2+ L-1 repressed the finger-type structure and filamentous out-growth. The results show that chemical precipitation in the granules with iron ion addition was higher than that in the granules without ferrous addition. The amount of precipitates was higher inside the granules than outside. This study demonstrates that iron ions (Fe2+/Fe3+) increase the size and stability of aerobic granular sludge but do not affect the granulation time, which is the time that the first granular sludge is observed. The study shows that aerobic granular sludge technology can be confidently applied to actual wastewater containing a high concentration of iron compounds. PMID- 27770298 TI - Ko Tangonge Te Wai: Indigenous and Technical Data Come Together in Restoration Efforts. AB - In Aotearoa New Zealand, Maori aspirations around land and water conflict with settler interests. As indigenous people, Maori struggle to enact agency over resources, despite Treaty (Treaty of Waitangi/Te Tiriti o Waitangi is an 1840 agreement between Maori and the crown) settlement processes returning some lands. Returns are complex since changes wrought by dispossession may be extreme, requiring multiple stakeholder engagements. Tangonge, a heavily modified wetland, in northern Aotearoa New Zealand has been the subject of iwi (tribe or tribes) claims since the 1890s. Reparation processes have returned significant areas surrounding Tangonge to key iwi, Te Rarawa and Ngai Takoto, who formed the Tangonge Restoration Group to plan management and restoration. The vision of the iwi is to restore Tangonge as a wetland to rekindle usage by manawhenua (people with demonstrated authority and tribal links to the area in question) and local communities. However, perceived Maori privilege, distrust in Maori praxis and fear of alienation of stakeholders mean the situation presents challenges as well as opportunities. Understanding that various parties view knowledge in particular ways, the Restoration Group sought to juxtapose technical data and manawhenua knowledge about Tangonge. Hydrology findings and local aspirations were aligned to produce ideas for actions that encompassed the broad concerns. This integration of knowledge provides strategic steps for working with administrative authorities who have historical and ongoing interests. PMID- 27770296 TI - Lithium in Bipolar Disorder: Optimizing Therapy Using Prolonged-Release Formulations. AB - Lithium has been a gold standard in the treatment of bipolar disorder (BD) for several decades. Despite a general reduction in the use of lithium over the past several years, it is effective in the management of both manic and depressive episodes in BD and continues to be recommended as a first-line mood stabilizer. This review provides an overview of the pharmacology of lithium and highlights its clinical profile in the management of BD, focusing on the potential advantages of prolonged-release (PR) versus immediate-release (IR) formulations of lithium. A literature search using PubMed was performed to identify articles describing IR and PR lithium in BD using specific search terms like 'lithium', 'prolonged-release', 'sustained-release', 'extended-release', 'bipolar disorder', 'adherence' and 'compliance'. Relevant pharmacodynamic and pharmacokinetic data were also included. Several clinical trials suggested that lithium is effective in the treatment of acute mania and prophylaxis of BD and reduces the risk of suicide in patients with BD; it may also be used in combination with other drugs in the treatment of bipolar depression. Treatment with lithium must be monitored to avoid lithium-associated toxicity. The prolonged PR formulation of lithium has several advantages including consistent serum lithium concentrations, fewer adverse events and improved adherence to therapy. Although direct comparative studies between PR and IR formulations of lithium are primarily limited to pharmacokinetic studies, PR formulation of lithium provides potential advantages over IR formulation and can be effectively used in the management of BD with lesser adverse events. PMID- 27770300 TI - Cultivating Medical Intentionality: The Phenomenology of Diagnostic Virtuosity in East Asian Medicine. AB - This study examines the perceptual basis of diagnostic virtuosity in East Asian medicine, combining Merleau-Ponty's phenomenology and an ethnographic investigation of Korean medicine in South Korea. A novice, being exposed to numerous clinical transactions during apprenticeship, organizes perceptual experience that occurs between him or herself and patients. In the process, the fledgling practitioner's body begins to set up a medically-tinged "intentionality" interconnecting his or her consciousness and medically significant qualities in patients. Diagnostic virtuosity is gained when the practitioner embodies a cultivated medical intentionality. In the process of becoming a practitioner imbued with virtuosity, this study focuses on the East Asian notion of "Image" that maximizes the body's perceptual capacity, and minimizes possible reductions by linguistic re-presentation. "Image" enables the practitioner to somatically conceptualize the core notions of East Asian medicine, such as Yin-Yang, and to use them as an embodied litmus as the practitioner's cultivated body instinctively conjures up medical notions at clinical encounters. In line with anthropological critiques of reductionist frameworks that congeal human existential and perceptual vitality within a "scientific" explanatory model, this article attempts to provide an example of various knowing and caring practices, institutionalized external to the culture of science. PMID- 27770301 TI - Characterization of basidiomycetous yeasts in hypersaline soils of the Urmia Lake National Park, Iran. AB - Urmia Lake, located in northwest Iran, is an oligotrophic and extremely hypersaline habitat that supports diverse forms of life. Owing to its unique biodiversity and special environmental conditions, Urmia Lake National Park has been designated as one of the biosphere reserves by UNESCO. This study was aimed to characterize basidiomycetous yeasts in hypersaline soils surrounding the Urmia Lake National Park using a polyphasic combination of molecular and physiological data. Soil samples were collected from eight sites in Lake Basin and six islands insides the lake. Yeast strains were identified by sequencing the D1/D2 domains of the 26S rRNA gene. When D1/D2 domain sequencing did not resolve the identity of the species, strain identification was obtained by ITS 1 & 2 sequencing. Twenty-one species belonging to the genera Cystobasidium, Holtermanniella, Naganishia, Rhodotorula, Saitozyma, Solicoccozyma, Tausonia, Vanrija, and Vishniacozyma were identified. Solicoccozyma aeria represented the dominant species. The ability of isolates to grow at 10 and 15 % of NaCl was checked; about two-thirds of the strains grew at 10 %, while about 13 % of the isolates grew in medium with 15 % NaCl. this study is the first study on the culturable yeast diversity in hypersaline soils surrounding an Asian lake. PMID- 27770303 TI - Cabazitaxel for Hormone-Relapsed Metastatic Prostate Cancer Previously Treated With a Docetaxel-Containing Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures cabazitaxel (Jevtana(r), Sanofi, UK) to submit evidence for the clinical and cost effectiveness of cabazitaxel for treatment of patients with metastatic hormone relapsed prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the company's submission to NICE. Clinical evidence for cabazitaxel was derived from a multinational randomised open-label phase III trial (TROPIC) of cabazitaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone, which was assumed to represent best supportive care. The NICE final scope identified a further three comparators: abiraterone in combination with prednisone or prednisolone; enzalutamide; and radium-223 dichloride for the subgroup of people with bone metastasis only (no visceral metastasis). The company did not consider radium-223 dichloride to be a relevant comparator. Neither abiraterone nor enzalutamide has been directly compared in a trial with cabazitaxel. Instead, clinical evidence was synthesised within a network meta analysis (NMA). Results from TROPIC showed that cabazitaxel was associated with a statistically significant improvement in both overall survival and progression free survival compared with mitoxantrone. Results from a random-effects NMA, as conducted by the company and updated by the ERG, indicated that there was no statistically significant difference between the three active treatments for both overall survival and progression-free survival. Utility data were not collected as part of the TROPIC trial, and were instead taken from the company's UK early access programme. Evidence on resource use came from the TROPIC trial, supplemented by both expert clinical opinion and a UK clinical audit. List prices were used for mitoxantrone, abiraterone and enzalutamide as directed by NICE, although commercial in-confidence patient-access schemes (PASs) are in place for abiraterone and enzalutamide. The confidential PAS was used for cabazitaxel. Sequential use of the advanced hormonal therapies (abiraterone and enzalutamide) does not usually occur in clinical practice in the UK. Hence, cabazitaxel could be used within two pathways of care: either when an advanced hormonal therapy was used pre-docetaxel, or when one was used post-docetaxel. The company believed that the former pathway was more likely to represent standard National Health Service (NHS) practice, and so their main comparison was between cabazitaxel and mitoxantrone, with effectiveness data from the TROPIC trial. Results of the company's updated cost-effectiveness analysis estimated a probabilistic incremental cost-effectiveness ratio (ICER) of L45,982 per quality-adjusted life year (QALY) gained, which the committee considered to be the most plausible value for this comparison. Cabazitaxel was estimated to be both cheaper and more effective than abiraterone. Cabazitaxel was estimated to be cheaper but less effective than enzalutamide, resulting in an ICER of L212,038 per QALY gained for enzalutamide compared with cabazitaxel. The ERG noted that radium-223 is a valid comparator (for the indicated sub-group), and that it may be used in either of the two care pathways. Hence, its exclusion leads to uncertainty in the cost effectiveness results. In addition, the company assumed that there would be no drug wastage when cabazitaxel was used, with cost-effectiveness results being sensitive to this assumption: modelling drug wastage increased the ICER comparing cabazitaxel with mitoxantrone to over L55,000 per QALY gained. The ERG updated the company's NMA and used a random effects model to perform a fully incremental analysis between cabazitaxel, abiraterone, enzalutamide and best supportive care using PASs for abiraterone and enzalutamide. Results showed that both cabazitaxel and abiraterone were extendedly dominated by the combination of best supportive care and enzalutamide. Preliminary guidance from the committee, which included wastage of cabazitaxel, did not recommend its use. In response, the company provided both a further discount to the confidential PAS for cabazitaxel and confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in pre-prepared intravenous-infusion bags, which would remove the cost of drug wastage. As a result, the committee recommended use of cabazitaxel as a treatment option in people with an Eastern Cooperative Oncology Group performance status of 0 or 1 whose disease had progressed during or after treatment with at least 225 mg/m2 of docetaxel, as long as it was provided at the discount agreed in the PAS and purchased in either pre-prepared intravenous infusion bags or in vials at a reduced price to reflect the average per-patient drug wastage. PMID- 27770302 TI - The utility of bone scintigraphy in the assessment of mandibular metabolism during long-term bisphosphonate administration. AB - The duration of antiresorptive therapy is an important risk factor for medication related osteonecrosis of the jaw. We performed a pilot study using quantitative analysis by bone scintigraphy to test the hypothesis that mandibular metabolism is affected by long-term bisphosphonate (BP) therapy. Our primary objectives were to assess changes in bone metabolism of the mandible in response to long-term BP therapy and compare the bone metabolism changes of the mandible with other bone sites. We compared the metabolic difference at the site in the mandible unaffected by disease, the humerus and the femur between 14 osteoporosis patients who were being treated with BP (BP group) and 14 patients who were not being treated with BP (control group) using a quantitative analysis and bone scintigraphy. Study endpoints were the mean and maximum bone uptake values (BUVs) quantified using bone scintigraphy images of the mandible, humerus and femur. Quantified images of the site in the mandible unaffected by disease had significantly higher mean and maximum BUVs compared to the controls (mean, 0.74 vs. 0.49, p = 0.019; max., 1.29 vs. 0.85, p = 0.009, respectively). The mean and maximum BUV of femur ROIs in the BP group were significantly lower than those in control patients (mean BUV, 0.23 vs. 0.30, p = 0.039; max. BUV, 0.43 vs. 0.53, p = 0.024, respectively). This is the first report of mandible changes in response to long-term BP treatment, using bone scintigraphy. The results using bone scintigraphy demonstrated that the bone metabolism of the intact mandible is affected by a long-term administration of BP. PMID- 27770305 TI - Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening. AB - We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic alpha/beta-hydrolase domain and a beta-propeller domain, and in which the substrate docks at the inter domain interface, suggesting a "jaw opening" gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays. This strategy was successful as all 13 tested molecules suggested from the in silico calculations were found out to be active POPTc80 inhibitors in the micromolar range (lowest K i at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease. PMID- 27770304 TI - Involvement of monoaminergic systems in anxiolytic and antidepressive activities of the standardized extract of Cocos nucifera L. AB - Extracts from the husk fiber of Cocos nucifera are used in folk medicine, but their actions on the central nervous system have not been studied. Here, the anxiolytic and antidepressant effects of the standardized hydroalcoholic extract of C. nucifera husk fiber (HECN) were evaluated. Male Swiss mice were treated with HECN (50, 100, or 200 mg/kg) 60 min before experiments involving the plus maze test, hole-board test, tail suspension test, and forced swimming test (FST). HECN was administered orally (p.o.) in acute and repeated-dose treatments. The forced swimming test was performed with dopaminergic and noradrenergic antagonists, as well as a serotonin release inhibitor. Administration of HECN in the FST after intraperitoneal (i.p.) pretreatment of mice with sulpiride (50 mg/kg), prazosin (1 mg/kg), or p-chlorophenylalanine (PCPA, 100 mg/kg) caused the actions of these three agents to be reversed. However, this effect was not observed after pretreating the animals with SCH23390 (15 ug/kg, i.p.) or yohimbine (1 mg/kg, i.p.) The dose chosen for HECN was 100 mg/kg, p.o., which increased the number of entries as well as the permanence in the open arms of the maze after acute and repeated doses. In both the forced swimming and the tail suspension tests, the same dose decreased the time spent immobile but did not disturb locomotor activity in an open-field test. The anxiolytic effect of HECN appears to be related to the GABAergic system, while its antidepressant effect depends upon its interaction with the serotoninergic, noradrenergic (alpha1 receptors), and dopaminergic (D2 dopamine receptors) systems. PMID- 27770306 TI - Factors Supporting the Employment of Young Adult Peer Providers: Perspectives of Peers and Supervisors. AB - Peer providers are a promising practice for transition-age youth community mental health treatment engagement and support, yet little is known about the experience of being a young adult peer provider or what helps to make an individual in this role successful. Utilizing a capital theory lens, this study uses data from focus groups (two with young adult peer providers and two with their supervisors) to examine facilitators of young adult peer provider success in community mental health treatment settings. Eight factors were identified as critical to young adult peer provider on-the-job success: persistence, job confidence, resilience, job training, skilled communications with colleagues, regular and individualized supervision, support from colleagues, and family support. Findings suggest that young adult peer providers may benefit immensely from an agency level focus on fostering social organizational capital as well as more individualized efforts to increase cultural, social, and psychological capital through training and supervision. PMID- 27770307 TI - Some Remarks on Applications of Tests for Detecting A Change Point to Psychometric Problems. AB - Tests for a change point (e.g., Chen and Gupta, Parametric statistical change point analysis (2nd ed.). Birkhuser, Boston, 2012; Hawkins et al., J Qual Technol 35:355-366, 2003) have recently been brought into the spotlight for their potential uses in psychometrics. They have been successfully applied to detect an unusual change in the mean score of a sequence of administrations of an international language assessment (Lee and von Davier, Psychometrika 78:557-575, 2013) and to detect speededness of examinees (Shao et al., Psychometrika, 2015). The differences in the type of data used, the test statistics, and the manner in which the critical values were obtained in these papers lead to questions such as "what type of psychometric problems can be solved by tests for a change point?" and "what test statistics should be used with tests for a change point in psychometric problems?" This note attempts to answer some of these questions by providing a general overview of tests for a change point with a focus on application to psychometric problems. A discussion is provided on the choice of an appropriate test statistic and on the computation of a corresponding critical value for tests for a change point. Then, three real data examples are provided to demonstrate how tests for a change point can be used to make important inferences in psychometric problems. The examples include some clarifications and remarks on the critical values used in Lee and von Davier (Psychometrika, 78:557 575, 2013) and Shao et al. (Psychometrika, 2015). The overview and the examples provide insight on tests for a change point above and beyond Lee and von Davier (Psychometrika, 78:557-575, 2013) and Shao et al. (Psychometrika, 2015). Thus, this note extends the research of Lee and von Davier (Psychometrika, 78:557-575, 2013) and Shao et al. (Psychometrika, 2015) on tests for a change point. PMID- 27770308 TI - The surgical treatment of acromegaly. AB - PURPOSE: Surgical extraction of as much tumour mass as possible is considered the first step of treatment in acromegaly in many centers. In this article the potential benefits, disadvantages and limitations of operative acromegaly treatment are reviewed. METHODS: Pertinent literature was selected to provide a review covering current indications, techniques and results of operations for acromegaly. RESULTS: The rapid reduction of tumour volume is an asset of surgery. To date, in almost all patients, minimally invasive, transsphenoidal microscopic or endoscopic approaches are employed. Whether a curative approach is feasible or a debulking procedure is planned, can be anticipated on the basis of preoperative magnetic resonance imaging. The radicality of adenoma resection essentially depends on localization, size and invasive character of the tumour. The normalization rates of growth hormone and IGF-1 secretion, respectively, depend on tumour-related factors such as size, extension, the presence or absence of invasion and the magnitude of IGF-1 and growth hormone oversecretion. However, also surgeon-related factors such as experience and patient load of the centers have been shown to strongly affect surgical results and the rate of complications. As compared to most medical treatments, surgery is relatively cheap since the costs occur only once and not repeatedly. There are several new technical gadgets which aid in the surgical procedure: navigation and variants of intraoperative imaging. CONCLUSIONS: For the mentioned reasons, current algorithms of acromegaly management suggest an initial operation, unless the patients are unfit for surgery, refuse an operation or only an unsatisfactory resection is anticipated. A few suggestions are made when a re-operation could be considered. PMID- 27770309 TI - USP9X, a Putative Tumor Suppressor Gene, Exhibits Frameshift Mutations in Colorectal Cancers. PMID- 27770310 TI - Treating Alopecia Areata: Current Practices Versus New Directions. AB - Alopecia areata (AA) is non-scarring hair loss resulting from an autoimmune disorder. Severity varies from patchy hair loss that often spontaneously resolves to severe and chronic cases that can progress to total loss of scalp and body hair. Many treatments are available; however, the efficacy of these treatments has not been confirmed, especially in severe cases, and relapse rates are high. First-line treatment often includes corticosteroids such as intralesional or topical steroids for mild cases and systemic steroids or topical immunotherapy with diphenylcyclopropenone or squaric acid dibutylester in severe cases. Minoxidil and bimatoprost may also be recommended, usually in combination with another treatment. Ongoing research and new insights into mechanisms have led to proposals of innovative therapies. New directions include biologics targeting immune response as well as lasers and autologous platelet-rich plasma therapy. Preliminary data are encouraging, and it is hoped this research will translate into new options for the treatment of AA in the near future. PMID- 27770311 TI - Up-regulation of small nucleolar RNA 78 is correlated with aggressive phenotype and poor prognosis of hepatocellular carcinoma. AB - Small nucleolar RNAs (snoRNAs) as a novel molecular species may have significant and comprehensive influences on the development and progression of hepatocellular carcinoma (HCC). We recently characterized snoRNA transcriptome signatures in HCC tissues by small RNA sequencing and found that small nucleolar RNA 78 (SNORD78) was associated with HCC. However, little is known about the pathological role of SNORD78 in HCC patients. This study aimed to profile SNORD78 expression signature and then to explore the pathogenesis of SNORD78 in HCC. The real-time PCR results showed that SNORD78 was greatly upregulated in HCC tissues than adjacent noncancerous tissues (p = 0.004). Correlation analysis showed that high-level expression of SNORD78 was notably associated with tumor number (single vs. multiply, p = 0.02), stage (I~II vs. III~IV, p = 0.014), and distant metastasis (absent vs. present, p = 0.01) in HCC patients. Univatiate and multivariate analyses showed that SNORD78 was a significant prognostic predictor for overall survival and recurrence-free survival of HCC patients (hazard ratio = 1.375, 95 % CI = 1.125-1.680, p = 0.002; hazard ratio = 1.418, 95 % CI = 1.201-1.675, p < 0.001). Moreover, Kaplan-Meier analysis showed that high-level expression of SNORD78 was associated with short overall survival and recurrence-free survival of HCC patients (p = 0.023, 0.014). Functionally, knockdown of SNORD78 significantly inhibited cellular proliferation, migration, and invasion of SK-Hep 1 via inducing G0/G1 cell cycle arrest and apoptosis. In conclusion, SNORD78 may be associated with aggressive phenotype and poor prognosis of HCC. PMID- 27770312 TI - Dynamics of liquid-crystalline magnetic suspensions in a rotating magnetic field. AB - We theoretically study the dynamics of the orientational structure of a ferronematic liquid crystal with soft planar coupling between the director and the magnetization in a rotating magnetic field. We determine critical parameters characterizing the boundary between synchronous and asynchronous rotation regimes. We show that the magnetic impurity increases the stability threshold of an asynchronous rotation regime. The critical angular velocity, the angles of the director and the magnetization rotation in each regime of orientational structure rotation are found for rigid planar coupling. We obtain that in weak magnetic fields when the main mechanism of the field influence on a ferronematic liquid crystal is associated with the effect on the magnetic particles, the critical angular velocity is linearly dependent on the field strength, while in strong magnetic fields, when the influence of a field is determined by a diamagnetic mechanism, the critical velocity is quadratically dependent on the field strength. PMID- 27770313 TI - Measuring the solubility of solids in non-solvents: case of polystyrene in alkanes. AB - We introduce a simple and sensitive technique for measuring extremely low solubilities with a small sample size and small solvent volume. This technique involves measuring the decrease in the thickness of a supported thin film after exposure to a drop of known volume of solvent and removal of the solution. The feasibility of measuring very small changes in film thickness directly translates to the ability to measure extremely low solubility while at the same time using only MUL of solvent. We apply the technique to the case of polystyrene with Mw values in the range 2500 g/mol to 22200 g/mol in alkane solvents and show that we can easily measure a solubility of 0.1 g/L using only 1[Formula: see text] g of material and 3[Formula: see text] L of solvent for each sample. PMID- 27770314 TI - Dynamics of topological monopoles annihilation on a fibre in a thick and thin nematic layer. AB - We study topological defect annihilation on a glass fibre with homeotropic surface anchoring of nematic liquid crystal molecules. The fibre is set parallel to the nematic director of a planar cell with variable thickness and we create pairs of Saturn ring and Saturn anti-ring using the laser tweezers. In thick cells we observe in the whole region of defect separation a Coulomb-like pair attraction with no background force, [Formula: see text] with [Formula: see text]. In cells with thickness comparable to glass fibre diameter, we observe the Coulomb-like attraction only at small separations of the defect pair. For separations larger than the fibre diameter, the pair interaction force is independent of separation. This string-like force is attributed to the formation of defect lines, connecting both monopoles and are indeed visible only on extremely confined fibre, where the fibre diameter is practically equal to the nematic layer thickness. Numerical simulations confirm the formation of defect lines connecting both rings. PMID- 27770315 TI - Effects of Behavioural Strategy on the Exploitative Competition Dynamics. AB - We investigate a system of two species exploiting a common resource. We consider both abiotic (i.e. with a constant resource supply rate) and biotic (i.e. with resource reproduction and self-limitation) resources. We are interested in the asymmetric competition where a given consumer is the locally superior resource exploiter (LSE) and the other is the locally inferior resource exploiter (LIE). They also interact directly via interference competition in the sense that LIE individuals can use two opposite strategies to compete with LSE individuals: we assume, in the first case, that LIE uses an avoiding strategy, i.e. LIE individuals go to a non-competition patch to avoids competition with LSE individuals, and in the second one, LIE uses an aggressive strategy, i.e. being very aggressive so that LSE individuals have to go to a non-competition patch. We further assume that there is no resource in the non-competition patch so that individuals have to come back to the competition patch for their maintenance, and the migration process acts on a fast time scale in comparison with demography and competition processes. The models show that being aggressive is efficient for LIE's survival and even provoke global extinction of the LSE and this result does not depend on the nature of resource. PMID- 27770317 TI - Basin of Attraction of Solutions with Pattern Formation in Slow-Fast Reaction Diffusion Systems. AB - This article is devoted to the characterization of the basin of attraction of pattern solutions for some slow-fast reaction-diffusion systems with a symmetric property and an underlying oscillatory reaction part. We characterize some subsets of initial conditions that prevent the dynamical system to evolve asymptotically toward solutions which are homogeneous in space. We also perform numerical simulations that illustrate theoretical results and give rise to symmetric and non-symmetric pattern solutions. We obtain these last solutions by choosing particular random initial conditions. PMID- 27770316 TI - Can Fishing Pressure Invert the Outcome of Interspecific Competition? The Case of the Thiof and of the Octopus Along the Senegalese Coast. AB - We present a mathematical model of two competing marine species that are harvested. We consider three models according to different levels of complexity, without and with species refuge and density-independent and density-dependent species movement between fishing area and refuge. We particularly study the effects of the fishing pressure on the outcome of the competition. We focus on conditions that allow an inferior competitor to invade as a result of fishing pressure. The model is discussed in relationship to the case of the thiof and the octopus along the Atlantic West African coast. At the origin, the thiof was abundant and the octopus scarce in that region. Since, the fishing pressure has strongly increased in some fishing areas leading to the depletion of the thiof and the invasion of its competitor, the octopus. PMID- 27770318 TI - Preface. PMID- 27770319 TI - Efficacy of model-based iterative reconstruction technique in non-enhanced CT of the renal tracts for ureteric calculi. AB - The purpose of this study was to assess the efficacy of model-based iterative reconstruction (MBIR), statistical iterative reconstruction (SIR), and filtered back projection (FBP) image reconstruction algorithms in the delineation of ureters and overall image quality on non-enhanced computed tomography of the renal tracts (NECT-KUB). This was a prospective study of 40 adult patients who underwent NECT-KUB for investigation of ureteric colic. Images were reconstructed using FBP, SIR, and MBIR techniques and individually and randomly assessed by two blinded radiologists. Parameters measured were overall image quality, presence of ureteric calculus, presence of hydronephrosis or hydroureters, image quality of each ureteric segment, total length of ureters unable to be visualized, attenuation values of image noise, and retroperitoneal fat content for each patient. There were no diagnostic discrepancies between image reconstruction modalities for urolithiasis. Overall image qualities and for each ureteric segment were superior using MBIR (67.5 % rated as 'Good to Excellent' vs. 25 % in SIR and 2.5 % in FBP). The lengths of non-visualized ureteric segments were shortest using MBIR (55.0 % measured 'less than 5 cm' vs. ASIR 33.8 % and FBP 10 %). MBIR was able to reduce overall image noise by up to 49.36 % over SIR and 71.02 % over FBP. MBIR technique improves overall image quality and visualization of ureters over FBP and SIR. PMID- 27770321 TI - Giant cutaneous hemangioma imitating squamous cell carcinoma. PMID- 27770320 TI - [LDL-cholesterol and cardiovascular events: the lower the better?] AB - For over 30 years, intensive research efforts investigated the role of LDL cholesterol in the pathogenesis of cardiovascular disease. In various settings, large statin trials showed an association between LDL cholesterol levels and cardiovascular event rates. This association is often referred to as the 'LDL cholesterol hypothesis'. More recent trials on agents with totally different modes of action confirmed this association and indicated a causal relationship between lower LDL cholesterol levels and improved cardiovascular outcomes. It has been proposed to term this causal relationship the 'LDL cholesterol principle'. It is to be expected that currently ongoing outcomes trials will further support the assumption of a causal relationship and will finally offer an armamentarium to therapists that will enable individualized treatment of dyslipidemias and their sequelae. PMID- 27770323 TI - Environmental characterisation of sewage sludge/paper ash-based composites in relation to their possible use in civil engineering. AB - The environmental acceptability of geotechnical composites made of treated municipal sewage sludge (SwS) and paper ash (PA) after two different curing periods has been investigated. The mineral composition of such composites, including their content of major oxides, is mainly influenced by the PA. The content of potentially toxic elements (PTEs) in the initial materials and in the composites varies considerably. In the SwS the Ba, Cd, Cr, Cu, Hg, Ni and Zn contents are above the legally permitted limits. The PTE content of PA are lower, but still somewhat above the permitted values for Ba and Cu. Mixing these two materials together resulted in a decrease in the PTE, but the Ba, Cu and Zn contents are still too high for agricultural application. However, leachates from composites that had been cured for 28 days are highly alkaline, and the As, Ba, Cd, Cr, Hg, Mo, Ni, Pb and Zn contents in them are well below the permitted values. The Cu contents (2.4 to 5.4 mg/kg) are above the permitted limit for inert material, but inside the range for non-hazardous material. In a leachate of composite which was prepared with fresh PA and a lower PA to SwS ratio, the Cu content was 1.4 mg/kg, since fresh PA is more reactive and therefore has a higher ability to immobilise Cu. Therefore, such mixtures can be utilised for covers and liners for sanitary landfills. PMID- 27770322 TI - Terra firma-forme dermatosis. AB - Terra firma-forme dermatosis (TFFD) belongs to the group of "dirty dermatoses" and represents a not well-known and surely underestimated vexing skin condition. Firstly described by Duncan, Tschen and Knox in 1987, it accounts for a few case series in the literature and has a still undefined aetiology. The authors present an additional report of TFFD, occurring in a young Caucasian girl, and briefly review the current medical literature on the topic. PMID- 27770324 TI - Investigation on the reaction of phenolic pollutions to mono-rhamnolipid micelles using MEUF. AB - Micellar-enhanced ultrafiltration (MEUF) processes of resorcinol, phenol, and 1 Naphthol with rhamnolipid as an anionic biosurfactant were investigated using polysulfone membrane. The effects of retentate/permeate concentration of phenolic pollutants (C R/C P), distribution coefficient of phenolic pollutions (D), concentration ratios of phenolic pollutions (alpha P) and rhamnolipids (alpha R) and adsorption capacity of the membrane (N m) were studied by operating pressure, pH condition, feed surfactant, and phenolic pollution concentrations. Results showed that C R (with pH) increased and ranked in the following order: resorcinol > phenol > 1-Naphthol, which is same with C R (with pressure), C R (with surfactant), C R/C P (with pollution), alpha,P and D, while C P (with pH), C P (with pressure), and C P (with surfactant) ranked in the reverse order. The operating pressure increased the solubility of phenolic from 0 to 0.1 MPa and then decreased slowly above 0.1 MPa. The concentration ratio of rhamnolipid was nearly at 2.0 and that of phenolic pollution was slightly above 1.0. D of phenolic pollutants reached the maximum at phenolic pollution concentration of 0.1 mM and the feed rhamnolipid concentration at 1 CMC. Moreover, zeta potential in feed stream and retentate stream and membrane adsorption of phenolic pollutions were firstly investigated in this article; the magnitudes of zeta potential with the feed stream of three phenolic pollutions were nearly the same and slightly lower than those with the retentate stream. The adsorption capacity of the membrane (N m) was calculated and compared to the former research, which showed that rhamnolipid significantly decreases the membrane adsorption of phenolic pollutions at a relatively lower concentration. It was implied that rhamnolipid can be substituted for chemical surfactants. PMID- 27770325 TI - Effects of tidal operation on pilot-scale horizontal subsurface flow constructed wetland treating sulfate rich wastewater contaminated by chlorinated hydrocarbons. AB - Three different flow regimes were carried out in a pilot-scale horizontal subsurface flow constructed wetland-treating sulfate rich wastewater contaminated with monochlorobenzene (MCB) and perchloroethene (PCE). The three regimes were continuous flow, 7-day cycle discontinuous flow, and 2.5-day cycle discontinuous flow. The results show that intensifying the tidal regime (2.5-day cycle) significantly enhanced MCB removal before 2 m from the inlet and increasing PCE removal efficiency at 0.5 m. The PCE dechlorination process was promoted with tidal operation, especially under the 2.5-day cycle regime, with significant increases of cis-1,2- dichloroethenes (DCEs), vinyl chloride (VC), and ethene, but trans-1,2-DCE was significantly decreased after tidal operation. Due to the high sulfate concentration in the influent, sulfide was observed in pore water up to 20 and 23 mg L-1 under continuous flow and 7-day cycle regime, respectively. However, sulfide concentrations decreased to less than 4 mg L-1 under intensified tidal operation (2.5-day cycle). The increase of oxygen concentration in pore water through intensified tidal operation resulted in better MCB removal performance and the successful inhibition of sulfate reduction. In conclusion, intensifying tidal operation is an effective approach for the treatment of chlorinated hydrocarbons and inhibiting sulfide accumulation in horizontal subsurface flow constructed wetland. PMID- 27770326 TI - Aspirin and paracetamol removal using a commercial micro-sized TiO2 catalyst in deionized and tap water. AB - Micro-sized TiO2 catalyst was employed to degrade pharmaceutical compounds, i.e. aspirin and paracetamol, two of the most widely used drugs, purchasable without prescription. Their active agents, acetylsalicylic acid and acetaminophen, are characterized by different substituent groups, linked to the aromatic ring, which affect both the photodegradation and mineralization processes. The experimental conditions highlight the relationship between the nature of the pristine molecules, their degradation mechanisms, their mutual interference and the water's role. The research started from model systems with a single pollutant to the mixture of them and finally by moving from deionized water to tap water. PMID- 27770327 TI - Efficacy of indigenous probiotic Lactobacillus strains to reduce cadmium bioaccessibility - An in vitro digestion model. AB - The toxic heavy metal cadmium (Cd) appears as one of the major global threats to human and animal health. Human being and aquatic life are exposed to Cd by breathing, eating, or drinking when industrial effluents released into environment. The study was aimed to identify cadmium-binding Lactobacillus strain to reduce its bioaccessibility in in vitro digestion model. In this context, forty-eight lactobacilli strains isolated and characterized from fermented dairy products and human origin were screened for their Cd biosorption potential using Flame Atomic Absorption Spectroscopy (FAAS). The present study revealed that Cd biosorption potential of 48 lactobacilli strains ranged from 1.0832 +/- 0.012 to 3.562 +/- 0.03 mg Cd g-1 of cells from initial 10 mg L-1 cadmium chloride (CdCl2) aqueous solution. Lactobacillus plantarum strain HD 48 demonstrated highest biosorption of 3.562 +/- 0.03 mg Cd g-1 of cells. Lactobacilli-Cd complex stability indicated its strong stability as even after three washes with Milli-Q water metal desorption was nonsignificant (p < 0.05) and further studies to delineate the influence of Cd (100 mg L-1 CdCl2) on their growth. Moreover, these strains were able to reduce Cd bioaccessibility in the in vitro digestion model in the range of 24.71 to 41.62 %. Transmission electron microscopy (TEM) investigations on Cd bioadsorption also revealed its surface associated bioadsorption phenomenon. These findings depicted that probiotic strain L. plantarum HD 48 was found to be endowed with remarkable Cd biosorption ability as well as reduction in its bioaccessibility. These results suggest that probiotic strain L. plantarum HD 48 has immense potential to sequester Cd from aqueous solution which could be further explored as a potent source to diminish body Cd burden. PMID- 27770328 TI - Quantifying the environmental impact of a Li-rich high-capacity cathode material in electric vehicles via life cycle assessment. AB - A promising Li-rich high-capacity cathode material (xLi2MnO3.(1-x)LiMn0.5Ni0.5O2) has received much attention with regard to improving the performance of lithium ion batteries in electric vehicles. This study presents an environmental impact evaluation of a lithium-ion battery with Li-rich materials used in an electric vehicle throughout the life cycle of the battery. A comparison between this cathode material and a Li-ion cathode material containing cobalt was compiled in this study. The battery use stage was found to play a large role in the total environmental impact and high greenhouse gas emissions. During battery production, cathode material manufacturing has the highest environmental impact due to its complex processing and variety of raw materials. Compared to the cathode with cobalt, the Li-rich material generates fewer impacts in terms of human health and ecosystem quality. Through the life cycle assessment (LCA) results and sensitivity analysis, we found that the electricity mix and energy efficiency significantly influence the environmental impacts of both battery production and battery use. This paper also provides a detailed life cycle inventory, including firsthand data on lithium-ion batteries with Li-rich cathode materials. PMID- 27770329 TI - Mercury toxicity to Eisenia fetida in three different soils. AB - Three different soils were spiked with 12 different concentrations of inorganic mercury (Hg). Sub-chronic Hg toxicity tests were carried out with Eisenia fetida in spiked soils by exposing the worms for 28 days following standard procedures. The toxicity studies revealed that Hg exerted less lethal effect on earthworms in acidic soil with higher organic carbon (S-3 soil) where water soluble Hg recovery was very low compared to the water soluble Hg fractions in soils with less organic carbon and higher pH (S-1 and S-2 soils). The concentrations of total Hg that caused 50 % lethality to E. fetida (LC50) after 28 days of exposure in S-1, S-2 and S-3 soils were 152, 294 and 367 mg kg-1, respectively. The average weight loss of E. fetida in three soils ranged from 5 to 65 %. The worms showed less weight loss in the organic carbon-rich soil (S-3) compared to less organic carbon containing soils (S-1 and S-2). The bioconcentration of Hg in E. fetida increased with increased Hg concentrations. The highest bioaccumulation took place in the acidic soil with higher organic carbon contents with estimated bioaccumulation factors ranging from 2 to 7.7. The findings of this study will be highly useful for deriving a more robust soil ecological guideline value for Hg. PMID- 27770332 TI - Errata corrige. PMID- 27770333 TI - Answer to the Letter to the Editor of F. Sanchez-Mariscal et al. concerning "Risk of revision surgery for adult idiopathic scoliosis: a survival analysis of 517 cases over 25 years" by G. Riouallon et al. (Eur Spine J; 2016;25(8):2527-2534). PMID- 27770330 TI - Education as a predictor of antidepressant and anxiolytic medication use after bereavement: a population-based record linkage study. AB - PURPOSE: Educational attainment has been shown to be positively associated with mental health and a potential buffer to stressful events. One stressful life event likely to affect everyone in their lifetime is bereavement. This paper assesses the effect of educational attainment on mental health post-bereavement. METHODS: By utilising large administrative datasets, linking Census returns to death records and prescribed medication data, we analysed the bereavement exposure of 208,332 individuals aged 25-74 years. Two-level multi-level logistic regression models were constructed to determine the likelihood of antidepressant medication use (a proxy of mental ill health) post-bereavement given level of educational attainment. RESULTS: Individuals who are bereaved have greater antidepressant use than those who are not bereaved, with over a quarter (26.5 %) of those bereaved by suicide in receipt of antidepressant medication compared to just 12.4 % of those not bereaved. Within individuals bereaved by a sudden death, those with a university degree or higher qualifications are 73 % less likely to be in receipt of antidepressant medication compared to those with no qualifications, after full adjustment for demographic, socio-economic and area factors (OR 0.27, 95 % CI 0.09,0.75). Higher educational attainment and no qualifications have an equivalent effect for those bereaved by suicide. CONCLUSIONS: Education may protect against poor mental health, as measured by the use of antidepressant medication, post-bereavement, except in those bereaved by suicide. This is likely due to the improved cognitive, personal and psychological skills gained from time spent in education. PMID- 27770334 TI - Secondary balloon kyphoplasty for new vertebral compression fracture after initial single-level balloon kyphoplasty for osteoporotic vertebral compression fracture. AB - PURPOSE: To explore the efficacy of secondary balloon kyphoplasty (BKP) for new vertebral compression fracture (NVCF) of previously non-fractured, non-treated vertebrae after previous BKP and to compare the therapeutic effect between patients with single-level adjacent NVCF and remote NVCF. METHODS: We retrospectively studied patients with single-level NVCF after initial BKP in our hospital from January 2007 to August 2014. The mean follow-up time from secondary BKP was 13.78 +/- 3.18 (12-24) months. Visual analog scale (VAS) and Oswestry disability index (ODI) scores were assessed prior to the initial BKP, one day after initial BKP, prior to the secondary BKP, one day after the secondary BKP, and at last follow-up. Kyphotic angle and vertebral heights were also compared for secondary BKP. Data were compared between patients with adjacent NVCF and remote NVCF. RESULTS: 36 patients were investigated. Compared with pre-operative value of initial and secondary BKP, patients in both groups gained statistical significant improvements for VAS and ODI after initial and secondary BKP, respectively (P < 0.05), and this improvement maintained at final follow-up. No statistical difference in VAS was found between the 2 groups after initial BKP and prior to the secondary BKP (P > 0.05), but patients in remote NVCF group achieved better VAS score than patients in adjacent NVCF group after the secondary BKP and at the final follow-up (P < 0.05). No statistical differences were detected in ODI between the 2 groups prior to the initial BKP, one day after initial BKP, prior to the secondary BKP and 1 day after the secondary BKP (P > 0.05), but the ODI scores were higher in adjacent NVCF group than in remote NVCF at last follow-up (P < 0.05). Kyphotic angle and vertebral heights were significantly restored and maintained after secondary BKP within groups, respectively. CONCLUSIONS: Secondary BKP is an effective procedure for treating NVCF after initial BKP. Patients with new fracture in remote level gain slightly better pain relief than those in the adjacent level. PMID- 27770335 TI - Health-care costs of conservative management of spine fractures in trauma patients. AB - BACKGROUND AND PURPOSE: There is a lack of evidence on the broad health-care costs of treating spine trauma patients without neurological deficits conservatively. The aim of the present study was to estimate the primary and secondary health-care sector costs associated with conservative treatment of spine fractures as well as their determinants. METHODS: Patients were identified between 1999 and 2008 in the hospital's administrative system based on relevant diagnostic codes. Inclusion criteria were: (1) spine fractures (C1-L5); (2) age >18; and (3) conservative treatment. Exclusion criteria were: (1) neurological involvement and (2) fractures secondary to osteoporosis/malignancy. Health-care utilization and costs were retrieved from national administrative databases covering the entire health-care sector. RESULTS: 201 cervical, 150 thoracic, and 140 lumbar fracture patients were included in the study. The total health cost was estimated at ?18,919 (16,199; 21,756), ?8571 (6062; 11,733), ?5526 (3473; 7465) for cervical, thoracic, and lumbar regions, respectively. Hospital admissions accounted for the vast majority of costs while primary health care accounted for less than 3 % and prescription medication for less than 2 %. The determinants of costs included fracture site (p < 0.001) and concomitant lower limb injuries (p = 0.009). CONCLUSIONS: Spinal fractures, even mild ones, appear to incur substantial health-care utilization and costs. Health-care costs in conjunction with cervical fractures are more than two-fold of those affiliated with thoracic and lumbar fractures. Among the concomitant injuries, lower limb injuries exert a substantial influence over health-care costs. PMID- 27770336 TI - A prospective multi-center study of intramedullary nailing vs casting of stable tibial shaft fractures. AB - BACKGROUND: The purpose of this study was to determine optimal treatment of stable tibial shaft fractures using intramedullary nailing (IMN) or casting. MATERIALS AND METHODS: We performed a multi-center prospective study cohort. Patients with stable tibia shaft fractures meeting Sarmiento's criteria (isolated closed fractures with less than 12 mm of shortening and 10 degrees of angulation) were enrolled prospectively and treated with either a reamed IMN with static interlocking screws or closed reduction followed by long-leg casting. Both groups were weight bearing following surgery. Radiographs were taken until union, and range of motion of knee and ankle joints was assessed. Malalignment (>5 degrees ) and malunion (>10 degrees ) were determined. Functional outcome measures using short musculoskeletal assessment scores (SMFA) and a knee pain score were scheduled at 6 weeks, 3 months and 6 months. RESULTS: At 3 months, differences between the casting and IMN groups were noted in return to work (6/15 vs 3/17, P < 0.05); ankle dorsiflexion (7 degrees vs 12 degrees , P < 0.05); plantar flexion (28 degrees vs 39 degrees , P < 0.05); and SMFA domains of Dysfunction Index, Bother Index, daily activities, emotional status, and arm/hand function (P < 0.05). The SMFA mobility function demonstrated a significant trend (P = 0.065). At 6 months, malalignment was present in 3/15 in the casting group and in 1/17 in the IMN group (P = 0.02). Malunion was present in 1/15 in the cast group. One fracture in the casting group went on to nonunion and required late IMN placement at 7 months and eventually healed. There were no differences in ankle motion, SMFA scores, or return to work. There was no difference in knee pain between the groups as measured by VAS and Court-Brown pain scale at 6 months. CONCLUSIONS: Patients with stable tibia fractures treated with intramedullary nailing have improved clinical and functional outcomes at 3 months compared with those treated with casting, but there are no differences in any other outcome measure. Patients treated in a cast may have a higher incidence of malalignment or malunion. LEVEL OF EVIDENCE: Level-II prognostic. PMID- 27770337 TI - Current concepts for the diagnosis and management of eosinophilic granuloma of bone. AB - This review summarizes current concepts in the diagnosis and management of the patients with eosinophilic granuloma. Given the benign biology, the clinical course, and the pediatric group of patients that this condition more commonly affects, a treatment approach that carries a lower risk of complications while ensuring a successful cure is desirable. Variable treatment options have been reported with satisfactory results and a recurrence rate of less than 20 %. In this setting, symptomatic lesions that are accessible in the spine or the extremities may be treated with intralesional methylprednisolone injection after tissue biopsy for histological diagnosis. PMID- 27770338 TI - Alteration of inflammatory cytokine production in primary total knee arthroplasty using antibiotic-loaded bone cement. AB - BACKGROUND: The aim was to compare serum levels of interleukin-6 (SIL6), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and joint fluid IL 6 (JIL-6) level between total knee arthroplasty (TKA) that used bone cement (BC group) and antibiotic-loaded bone cement (ALBC group). MATERIALS AND METHODS: Thirty-nine patients (40 TKAs) with a mean age of 69.6 years were non-randomly assigned to the BC or ALBC groups. Samples of SIL6, ESR, and CRP were collected at baseline and at 24 h, 72 h, and 4 weeks after surgery. JIL-6 levels were collected intraoperatively before joint arthrotomy, before finishing the procedure and 24 h after surgery. Postoperative mediator levels were compared with baseline levels within the same group and between groups at each time point. Knee Society Score-knee (KSSK) and Knee Society Score-function (KSSF) scores were evaluated. RESULTS: SIL-6, ESR, and CRP levels were significantly elevated at 24 and 72 h, compared to baseline. Only SIL-6 levels at 72 h in the ALBC group showed a significantly lower level than those in the BC group. JIL-6 levels were not different between groups. There were no significant differences in KSSK or KSSF scores between groups at 4 weeks and the most recent follow-up (1.4 +/- 0.6 years) evaluation. No correlations were identified among SIL-6 and JIL-6 levels at 24 and 72 h, and KSSK and KSSF scores at 4 weeks and at the most recent evaluation. CONCLUSIONS: ALBC showed a favorable immunomodulatory effect and lower SIL-6 level at 72 h following TKA compared to BC, although functional benefits require further investigation. LEVEL OF EVIDENCE: OCEBM, Level 3. PMID- 27770339 TI - Co-morbidities Rather than Age Impact Outcomes in Patients Receiving Preoperative Therapy for Gastroesophageal Adenocarcinoma. AB - BACKGROUND: Older patients with localized gastric adenocarcinoma (LGAC) have substantial postoperative morbidity and mortality; however, postoperative outcomes of the patients who receive preoperative chemotherapy and/or chemoradiation have not been reported. We examined the impact of age at baseline on potential predictors of postoperative outcomes. METHODS: Patients with LGAC who were treated with chemotherapy and/or chemoradiation followed by surgery (n = 203) formed two groups: (1) >=65 years old (n = 70) and (2) <65 years old (n = 133). We assessed postoperative morbidity and mortality as well as overall survival (OS) and progression-free survival (PFS). Potential predictors of 90-day postoperative outcomes were identified i) by age groups and ii) other clinical covariates. Descriptive statistics and survival analyses were utilized. RESULTS: 90-day postoperative morbidity was similar in older and younger patients (61 % vs 58 %; P = 0.655). 90-day mortality was similar (3 % vs 0 %; P = 0.118). Major Clavien grade III/IV complications were similar (17 % vs 12 %; P = 0.392). OS and PFS were also similar for both groups (P = 0.863 and P = 0.558, respectively). Other factors, such as Charlson comorbidity index (P < 0.001) and median operative time (P = 0.002) were strongly associated with postoperative complications. CONCLUSION: Our data show that older patients with LGAC generally have similar outcomes as do younger patients after preoperative therapy but comorbidity indices have significant impact on complications and the long-term outcomes rather than age. PMID- 27770340 TI - Increasing the Number of Examined Lymph Nodes is a Prerequisite for Improvement in the Accurate Evaluation of Overall Survival of Node-Negative Gastric Cancer Patients. AB - BACKGROUND: This study aims to elucidate whether increasing the number of examined lymph nodes (NELN) is mandatory for the accurate prognosis of node negative gastric cancer (GC) patients after curative gastrectomy in Eastern countries (China and Japan). METHODS: The clinicopathological data of 2455 GC patients (including 1137 node-negative cases) were included to demonstrate whether a minimum NELN is inevitable for guaranteeing the accurate prognosis of node-negative GC patients after curative gastrectomy. RESULTS: Survival analyses revealed that the NELN significantly positively correlated with overall survival (p < 0.001) and was an independent prognostic predictor (hazard ratio 0.447; p = 0.025) of 1137 node-negative GC patients. Stratum analysis within the Kaplan Meier method showed that sex, tumor size, and extent of lymphadenectomy did not affect the NELN in predicting the prognosis of all node-negative GC patients. Stage migration was mainly detected in the subgroup of node-negative GC Chinese patients who presented considerably lower mean NELN and more advanced staging than patients from Japan. The NELN was identified as the most intensively independent predictor of prognosis of 600 node-negative GC patients from China, with the smallest Akaike information criterion (176.964) and Bayesian information criterion values (194.552). These findings indicate that increasing the NELN is a prerequisite to guaranteeing precise TNM classification. CONCLUSIONS: The NELN should be considered a mandatory requirement for improving the accuracy of prognostic evaluation of GC patients, especially for advanced-stage patients. PMID- 27770342 TI - Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND: The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC). METHODS: The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro. RESULTS: In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells. CONCLUSIONS: Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC. PMID- 27770341 TI - Preoperative Neutrophil-Lymphocyte and Lymphocyte-Monocyte Ratios Reflect Immune Cell Population Rearrangement in Resectable Pancreatic Cancer. AB - BACKGROUND: Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) may serve as a simple index of the immune function. The aim of this study was to investigate the prognostic significance of NLR, PLR, and LMR in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and to verify whether such biomarkers are associated with changes in populations of lymphoid cells. METHODS: The prognostic implications of blood count parameters were evaluated in a retrospective cohort of 442 subjects undergoing pancreatic resections for PDAC. Subpopulations of lymphocytes and monocytes in peripheral blood were identified by FACS in a prospective cohort of 54 patients. RESULTS: In the univariate analysis, NLR < 5 and LMR >= 3 were associated with significantly longer median survival of 25.7 vs 12.6 months and 29.2 vs 13.1 months, respectively. PLR did not influence survival. The Cox proportional hazards model showed that high NLR (HR 1.66, 95 % CI 1.12 to 2.46, P = 0.012) and low LMR (HR 1.65, 95 % CI 1.06 to 2.58, P = 0.026) were independent predictors of poor prognosis. NLR >= 5 and LMR < 3 correlated with an approximately twofold decrease in counts of helper and cytotoxic T cells, B cells, and NK cells. High NLR was also accompanied with increased neutrophil counts, while low LMR showed increased numbers of monocytes, mostly classical. CONCLUSIONS: NLR and LMR may carry important prognostic information for patients with resected PDAC. The unfavorable prognosis likely correlates with reduced numbers of immune cells effective against the tumor and increased populations of cells involved in immune suppression. PMID- 27770343 TI - FAM46C Serves as a Predictor of Hepatic Recurrence in Patients with Resectable Gastric Cancer. AB - BACKGROUND: Gastric cancer (GC) relapse can occur even if curative resection is achieved. Biomarkers predicting recurrence are needed to provide appropriate postoperative surveillance and perioperative therapeutic strategy. METHODS: A global expression profiling was performed using tissues from GC patients with synchronous liver-confined metastasis. Family with sequence similarity 46, member C (FAM46C), was identified as a candidate biomarker. mRNA expression analysis, direct nucleotide sequencing, bisulfite sequencing and copy number assays for FAM46C were performed with eleven GC cell lines. Expression levels of FAM46C in primary GC tissues from 129 patients who underwent curative GC resection were determined and correlated with clinicopathological factors, including postoperative outcome. RESULTS: Levels of FAM46C mRNA differed among GC cell lines. Point mutations in FAM46C were detected in five GC cell lines accompanied with reduced FAM46C transcription. No hypermethylation was found in the promoter region of FAM46C. Copy number alterations were found in six GC cell lines with differing FAM46C transcription levels. Reduced FAM46C mRNA expression levels were detected in 117 (91 %) GC specimens compared with adjacent noncancerous tissues. Low FAM46C expression levels were significantly associated with larger macroscopic GC tumor sizes. The low FAM46C expression group was likely to have shorter disease-free survival than the high group and low FAM46C level was identified as an independent risk factor for recurrence after curative resection. FAM46C expression levels were low in all cases that were later found to have hepatic recurrence. CONCLUSIONS: Reduced GC expression of FAM46C is a potential biomarker to predict hepatic recurrence after curative gastrectomy. PMID- 27770344 TI - When and When Not to Perform a Right Colon Resection with Mucinous Appendiceal Neoplasms. AB - BACKGROUND: Mucinous appendiceal neoplasms (MAN) with peritoneal dissemination is treated as a standard of care using cytoreductive surgery and hyperthermic perioperative chemotherapy. The extent of the resection of peritoneal surfaces and visceral structures is generally well defined. Exception to this consensus regarding structures to be removed are the right colon and adjacent ileocolic lymph nodes. METHODS: From a prospectively maintained database, all patients with a histologic diagnosis of peritoneal mucinous carcinoma (PMCA) who underwent complete cytoreductive surgery were assessed for the presence versus absence of adenocarcinoma in lymph nodes within the appendiceal mesentery and/or in the lymph nodes of the ileocolic group. The histologic grade of the PMCA was correlated with the incidence of lymph node invasion. Also, in those PMCA patients who had no evidence of lymph node invasion, recurrence within the ileocolic lymph nodes was determined by computed tomography or second look. RESULTS: In a database of MAN patients, 299 had a histologic diagnosis of PMCA. In well-differentiated (n = 44), moderately differentiated (n = 107), and poorly differentiated (n = 148) PMCA specimens, there were 6.8, 5.6, and 29 % positive lymph nodes, respectively. None of these 151 patients with well- or moderately differentiated PMCA had a computed tomographic scan or clinical evidence by second-look surgery of recurrence within the ileocolic lymph nodes. CONCLUSIONS: There is a low incidence (6.0 %) of positive lymph nodes in patients with low or moderately differentiated PMCA. With high-grade disease, lymph node invasion increased to 29.0 %. Right colectomy is indicated in patients with high-grade PMCA. PMID- 27770346 TI - Long-Term Outcomes of 98 Surgically Resected Metastatic Tumors in the Pancreas. AB - PURPOSE: The goal of this study was to assess the outcomes and characteristics of patients who underwent pancreatectomy for metastatic disease to the pancreas. METHODS: Patients who underwent surgical resection of metastatic disease to the pancreas from 1988 to 2016 were identified using a prospectively maintained database. Data on clinicopathological features and outcomes of these patients were analyzed. Cox proportional hazard models were employed to identify patient specific risk factors that influence survival. RESULTS: Ninety-seven patients underwent 98 pancreatic metastasectomies from July 1988 through March 2016 for metastatic disease from 13 different primary cancers. Pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 49 (50 %), 37 (38 %), and 12 (12 %) patients, respectively. Postoperative complications occurred in 55 (56 %) patients, while 3 (3 %) perioperative deaths occurred. Median follow-up was 2.0 years, with a median survival of 3.2 years. Multivariate analysis revealed that older patients [hazard ratio (HR) 1.04/year; p = 0.006], non-renal cell carcinomas (HR 5.07; p < 0.001), vascular invasion (HR 3.53; p < 0.001), and positive resection margins (HR 2.62; p = 0.008) were independently associated with an increased risk of mortality. CONCLUSIONS: Pancreatic metastasectomy is safe and feasible in well-selected patients and is associated with acceptable long-term survival. PMID- 27770345 TI - Chemosensitivity and Endocrine Sensitivity in Clinical Luminal Breast Cancer Patients in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST) Predicted by Molecular Subtyping. AB - PURPOSE: Hormone receptor-positive (HR+) tumors have heterogeneous biology and present a challenge for determining optimal treatment. In the Neoadjuvant Breast Registry Symphony Trial (NBRST) patients were classified according to MammaPrint/BluePrint subtyping to provide insight into the response to neoadjuvant endocrine therapy (NET) or neoadjuvant chemotherapy (NCT). OBJECTIVE: The purpose of this predefined substudy was to compare MammaPrint/BluePrint with conventional 'clinical' immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) subtyping in 'clinical luminal' [HR+/human epidermal growth factor receptor 2-negative (HER2-)] breast cancer patients to predict treatment sensitivity. METHODS: NBRST IHC/FISH HR+/HER2- breast cancer patients (n = 474) were classified into four molecular subgroups by MammaPrint/BluePrint subtyping: Luminal A, Luminal B, HER2, and Basal type. Pathological complete response (pCR) rates were compared with conventional IHC/FISH subtype. RESULTS: The overall pCR rate for 'clinical luminal' patients to NCT was 11 %; however, 87 of these 474 patients were reclassified as Basal type by BluePrint, with a high pCR rate of 32 %. The MammaPrint index was highly associated with the likelihood of pCR (p < 0.001). Fifty-three patients with BluePrint Luminal tumors received NET with an aromatase inhibitor and 36 (68 %) had a clinical response. CONCLUSIONS: With BluePrint subtyping, 18 % of clinical 'luminal' patients are classified in a different subgroup, compared with conventional assessment, and these patients have a significantly higher response rate to NCT compared with BluePrint Luminal patients. MammaPrint/BluePrint subtyping can help allocate effective treatment to appropriate patients. In addition, accurate identification of subtype biology is important in the interpretation of neoadjuvant treatment response since lack of pCR in luminal patients does not portend the worse prognosis associated with residual disease in Basal and HER2 subtypes. PMID- 27770347 TI - Sources of errors and uncertainties in the assessment of forest soil carbon stocks at different scales-review and recommendations. AB - Spatially explicit knowledge of recent and past soil organic carbon (SOC) stocks in forests will improve our understanding of the effect of human- and non-human induced changes on forest C fluxes. For SOC accounting, a minimum detectable difference must be defined in order to adequately determine temporal changes and spatial differences in SOC. This requires sufficiently detailed data to predict SOC stocks at appropriate scales within the required accuracy so that only significant changes are accounted for. When designing sampling campaigns, taking into account factors influencing SOC spatial and temporal distribution (such as soil type, topography, climate and vegetation) are needed to optimise sampling depths and numbers of samples, thereby ensuring that samples accurately reflect the distribution of SOC at a site. Furthermore, the appropriate scales related to the research question need to be defined: profile, plot, forests, catchment, national or wider. Scaling up SOC stocks from point sample to landscape unit is challenging, and thus requires reliable baseline data. Knowledge of the associated uncertainties related to SOC measures at each particular scale and how to reduce them is crucial for assessing SOC stocks with the highest possible accuracy at each scale. This review identifies where potential sources of errors and uncertainties related to forest SOC stock estimation occur at five different scales-sample, profile, plot, landscape/regional and European. Recommendations are also provided on how to reduce forest SOC uncertainties and increase efficiency of SOC assessment at each scale. PMID- 27770349 TI - Control of Cortaderia selloana with a glyphosate-based herbicide led to a short term stimulation of soil fungal communities. AB - In the north of Spain, Cortaderia selloana plants have invaded ecosystems of high ecological value. Control of this species is carried out with the application of glyphosate-based formulations. The aim of this work was to determine, under microcosm conditions, the short-term (2 months) effects of the application of a glyphosate-based herbicide (Roundup(r)) on C. selloana rhizosphere microbial communities. To this purpose, before and after the application of Roundup(r), several parameters that provide information on the biomass, activity and diversity of rhizosphere fungal and bacterial communities (enzyme activities, basal and substrate-induced respiration, potentially mineralizable nitrogen, nitrification potential rate, ergosterol content and community-level profiles with BiologTM plates and ARISA) were determined. We observed a stimulation of some microbial parameters, in particular those related to fungal communities. Further research is needed to determine the long-term consequences of this short term fungal stimulation for soil functioning. PMID- 27770348 TI - Mercury and selenium concentrations in marine shrimps of NW Mexico: health risk assessment. AB - We determined total Hg and Se contents of hepatopancreas, exoskeleton, and muscle, and the Se:Hg molar ratios in the muscle of shrimps Farfantepenaeus californiensis and Litopenaeus stylirostris caught in NE Pacific Mexican waters. Total Hg mean values in muscle, hepatopancreas, and exoskeleton were 0.31 +/- 0.26, 0.28 +/- 0.29, and 0.24 +/- 0.06 MUg g-1, and 0.46 +/- 0.46, 0.41 +/- .034, and 0.24 +/- 0.06 MUg g-1 for F. californiensis and L. stylirostris, respectively. In all tissues, the mean concentrations of Se tended to be close to one order of magnitude higher than the respective Hg values. In F. californiensis, the hepatopancreas of the larger commercial size had significantly (p < 0.05) higher Hg content than smaller sizes, but correlations size-Hg concentration calculated for each tissue of either species were not significant. The Hg content of the muscle of all commercial sizes of both species was lower than the permissible limit and their Se:Hg ratios in all sizes were higher than 1, indicating low risk for human consumption. PMID- 27770350 TI - Impact of clinical pharmacy interventions on medication error nodes. AB - Background Pharmacists' involvement in patient care has improved the quality of care and reduced medication errors. However, this has required a lot of work that could not have been accomplished without documentation of interventions. Several means of documenting errors have been proposed in the literature but without a consistent comprehensive process. Recently, the American College of Clinical Pharmacy (ACCP) recognized that pharmacy practice lacks a consistent process for direct patient care and discussed several options for a pharmaceutical care plan, essentially encompassing medication therapy assessment, development and implementation of a pharmaceutical care plan and finally evaluation of the outcome. Therefore, as per the recommendations of ACCP, we sought to retrospectively analyze interventions by grouping them according to medication related problems (MRP) and their nodes such as prescribing; administering; monitoring; documenting and dispensing. Objective The aim of this study is to report interventions according to medication error (ME) nodes and show the impact of pharmacy interventions in reducing MRPs. Setting The study was conducted at the cardiology and infectious diseases services at a teaching hospital located in Beirut, Lebanon. Methods Intervention documentation was completed by pharmacy students on infectious diseases and cardiology rotations then reviewed by clinical pharmacists with respective specialties. Before data analysis, a new pharmacy reporting sheet was developed in order to link interventions according to MRP. Then, MRPs were grouped in the five ME nodes. During the documentation process, whether MRP had reached the patient or not may have not been reported which prevented the classification to the corresponding medication error nodes as ME. Main outcome Reduction in medication related problems across all ME nodes. Results A total of n = 1174 interventions were documented. N = 1091 interventions were classified as MRPs. Interventions were analyzed per 1000 patient days and resulted in 340 medication related problem/1000 patient days. A 72 % reduction in MRP across all ME nodes was seen. The majority of interventions were in the field of cardiology followed by infectious disease related. When interventions per ME nodes were analyzed, a high percentage of intervention acceptance was noted across all nodes especially prescribing (68.30 %) monitoring (77.7 %) and in documenting errors (79.36 %). Conclusion The role of pharmacists in reducing preventable MRPs can be shown when pharmacy interventions are analyzed according to corresponding MRP and ME nodes. PMID- 27770351 TI - The Impact of Shortages on Medication Prices: Implications for Shortage Prevention. AB - BACKGROUND: Medication shortages are frequent and have clinical and financial ramifications; however, their effect on drug prices remains unknown. OBJECTIVE: To examine price progression of medications affected by a shortage. METHODS: We collected prices of medications covered under Medicare Part B, reflective of general market prices, and data on clinically relevant shortages for the period 2005-16. We used linear mixed-effects models to examine the price growth of affected medications. RESULTS: Shortage medications demonstrated a quarterly price growth of -0.5 % (95 % confidence interval [CI] -1.6, 0.6) in the period preceding a shortage, 4.3 % (95 % CI 3.6, 4.5) during a shortage, and 4.1 % (95 % CI 2.6, 5.5) in the post-shortage period. Medications not affected by a shortage had a quarterly price growth of 0.2 % (95 % CI -0.3, 0.6). CONCLUSIONS: Medication shortages are associated with price increases, and these increases are likely reactive to the low profitability of the affected medications and thus, proactive collaboration between the US Food and Drug Administration and industry can serve to identify low-profit drugs and evaluate measures to ensure continued production. PMID- 27770352 TI - Collagenase Clostridium Histolyticum for the Treatment of Peyronie's Disease: A 'Real World' Clinical Perspective. AB - The introduction of collagenase Clostridium histolyticum (CCH) as a treatment option for Peyronie's disease (PD), defined as the abnormal formation of collagen on the tunica albuginea of the penis, has provided patients with a promising new conservative therapy. Studies have shown that CCH improves curvature by an average of 17 degrees , and although patient and sexual partner satisfaction is high, the improvement has arguable clinical implications. Similarly, the efficacy and cost of CCH contrasts strongly with more invasive surgical management, and is further limited by rare, but serious, complications and several contraindications. The future of CCH involves well-designed trials analyzing the effects of CCH on patients who are currently not indicated for therapy, and the optimal amount of treatment for the most efficient treatment possible. CCH provides a promising treatment option for patients who do not desire invasive management, but need further trials to fully elucidate its treatment implications. PMID- 27770354 TI - Chromatin Conformation Capture-Based Analysis of Nuclear Architecture. AB - Nuclear organization and higher-order chromosome structure in interphase nuclei are thought to have important effects on fundamental biological processes, including chromosome condensation, replication, and transcription. Until recently, however, nuclear organization could only be analyzed microscopically. The development of chromatin conformation capture (3C)-based techniques now allows a detailed look at chromosomal architecture from the level of individual loci to the entire genome. Here we provide a robust Hi-C protocol, allowing the analysis of nuclear organization in nuclei from different wild-type and mutant plant tissues. This method is quantitative and provides a highly efficient and comprehensive way to study chromatin organization during plant development, in response to different environmental stimuli, and in mutants disrupting a variety of processes, including epigenetic pathways regulating gene expression. PMID- 27770353 TI - Chromatin Immunoprecipitation Protocol for Histone Modifications and Protein-DNA Binding Analyses in Arabidopsis. AB - Epigenetic control of plant development via histone modifications is involved in different processes ranging from embryonic development, vegetative development, flowering time control, floral organ development, to pollen tube growth. The identification of an increasing number of epigenetically regulated processes was greatly advanced by methods allowing the survey of genome-wide histone modifications and chromatin-protein interactions. However, genome-wide approaches are too broad to access in detail a large number of histone modifications taking place at a single locus. Here, we provide a robust chromatin immunoprecipitation (ChIP) protocol, allowing in vivo analyses of multiple chromatin modifications and binding of histone modifiers in different plant organs and tissues. This method is quantitative and provides a way to study the dynamic state of chromatin during plant development and also in response to different environmental stimuli. PMID- 27770355 TI - Meta-analysis of Genome-Wide Chromatin Data. AB - Genome-wide analyses of chromatin factor-binding sites or histone modification localization generate lists of up to several thousand potential target genes. For many model organisms, large annotation databases are available to help with the characterization and classification of genomic datasets. The term meta-analysis has been coined for this type of multi-database comparison. In this chapter, we describe a workflow to perform a transcriptional and functional analysis of genome-wide target genes. Sources of transcription data and clustering tools to subdivide genes according to their expression pattern are described. For a functional analysis, we focus on the Gene Ontology (GO) vocabulary and methods to uncover over- or underrepresented functions among target genes. Genomic targets of the histone modification H3K27me3 are presented as a case study to demonstrate that meta-analysis can uncover functions that were hidden in genome-wide datasets. PMID- 27770356 TI - Localization of miRNAs by In Situ Hybridization in Plants Using Conventional Oligonucleotide Probes. AB - Among the epigenetic mechanisms studied with a greater interest in the last decade are the microRNAs (miRNAs). These small noncoding RNA sequences that are approximately 17-22 nucleotides in length play an essential role in many biological processes of various organisms, including plants. The analysis of spatiotemporal expression of miRNAs provides a better understanding of the role of these small molecules in plant development, cell differentiation, and other processes; but such analysis is also an important method for the validation of biological functions. In this work, we describe the optimization of an efficient protocol for the spatiotemporal analysis of miRNA by in situ hybridization using different plant tissues embedded in paraffin. Instead of LNA-modified probes that are typically used for this work, we use conventional oligonucleotide probes that yield a high specificity and clean distribution of miRNAs. PMID- 27770357 TI - The Combined Bisulfite Restriction Analysis (COBRA) Assay for the Analysis of Locus-Specific Changes in Methylation Patterns. AB - DNA methylation is a heritable but reversible epigenetic mechanism of control over gene expression. The level of DNA methylation of specific genomic regions correlates with chromatin condensation, the level of gene expression, and in some cases genome stability and the frequency of homologous recombination. Here, we describe the combined bisulfite restriction analysis (COBRA) assay that allows analyzing the methylation status at a specific locus. The protocol consists of the following major steps: bisulfite conversion of non-methylated cytosines to uracils, the locus-specific PCR amplification of converted DNA, restriction digestion, the analysis of restriction patterns on the gel, and the quantification of these restriction patterns using ImageJ or a similar program. PMID- 27770358 TI - Analysis of Global Genome Methylation Using the Cytosine-Extension Assay. AB - DNA methylation is a reversible covalent chemical modification of DNA intended to regulate chromatin structure and gene expression in a cell- and tissue-specific manner and in response to the environment. Cytosine methylation is predominantly occurring in plants, and cytosine nucleotides in plants can be methylated at symmetrical (CpG and CpHpG) and nonsymmetrical sites. Although there exists a number of various methods for the detection of cytosine methylation, most of them are either laborious or expensive or both. Here, we describe a quick inexpensive method for the analysis of global genome methylation using a cytosine-extension assay. The assay can be used for the analysis of the total level of CpG, CpHpG, and CpHpH methylation in a given sample of plant DNA. PMID- 27770359 TI - In Situ Analysis of DNA Methylation in Plants. AB - Epigenetic regulation in the plant genome is associated with the determination of expression patterns of various genes. Methylation of DNA at cytosine residues is one of the mechanisms of epigenetic regulation and has been a subject of various studies. Various techniques have been developed to analyze DNA methylation, most of which involve isolation of chromatin from cells and further in vitro studies. Limited techniques are available for in situ study of DNA methylation in plants. Here, we present such an in situ method for DNA methylation analysis which has high sensitivity and good reproducibility. PMID- 27770360 TI - Analysis of DNA Hydroxymethylation Using Colorimetric Assay. AB - Hydroxymethylcytosine (hmC or 5-hmC) is a nitrogen base occurring as a result of cytosine methylation followed by replacing a methyl group with a hydroxyl group through active oxidation. 5-hmC is considered to be one of the forms of epigenetic modification and is suggested as an intermediate step in a semi-active loss of DNA methylation mark. 5-hmC plays an important role in the epigenetic regulation of gene expression in animals, although its role in plants remains controversial. Here, we present a colorimetric method of quantification of 5-hmC using Brassica rapa DNA. PMID- 27770361 TI - Analysis of DNA Cytosine Methylation Patterns Using Methylation-Sensitive Amplification Polymorphism (MSAP). AB - Different molecular techniques have been developed to study either the global level of methylated cytosines or methylation at specific gene sequences. One of them is the methylation-sensitive amplified polymorphism technique (MSAP) which is a modification of amplified fragment length polymorphism (AFLP). It has been used to study methylation of anonymous CCGG sequences in different fungi, plants, and animal species. The main variation of this technique resides on the use of isoschizomers with different methylation sensitivity (such as HpaII and MspI) as a frequent-cutter restriction enzyme. For each sample, MSAP analysis is performed using both EcoRI/HpaII- and EcoRI/MspI-digested samples. A comparative analysis between EcoRI/HpaII and EcoRI/MspI fragment patterns allows the identification of two types of polymorphisms: (1) methylation-insensitive polymorphisms that show common EcoRI/HpaII and EcoRI/MspI patterns but are detected as polymorphic amplified fragments among samples and (2) methylation-sensitive polymorphisms which are associated with the amplified fragments that differ in their presence or absence or in their intensity between EcoRI/HpaII and EcoRI/MspI patterns. This chapter describes a detailed protocol of this technique and discusses the modifications that can be applied to adjust the technology to different species of interest. PMID- 27770362 TI - Differentially Methylated Region-Representational Difference Analysis (DMR-RDA): A Powerful Method to Identify DMRs in Uncharacterized Genomes. AB - Over the last years, it has become increasingly clear that environmental influences can affect the epigenomic landscape and that some epigenetic variants can have heritable, phenotypic effects. While there are a variety of methods to perform genome-wide analyses of DNA methylation in model organisms, this is still a challenging task for non-model organisms without a reference genome. Differentially methylated region-representational difference analysis (DMR-RDA) is a sensitive and powerful PCR-based technique that isolates DNA fragments that are differentially methylated between two otherwise identical genomes. The technique does not require special equipment and is independent of prior knowledge about the genome. It is even applicable to genomes that have high complexity and a large size, being the method of choice for the analysis of plant non-model systems. PMID- 27770364 TI - Northern Blotting Techniques for Small RNAs. AB - Cells have evolved intricate RNA-directed mechanisms that destroy viruses, silence transposons, and regulate gene expression. These nucleic acid surveillance and gene silencing mechanisms rely upon the selective base-pairing of ~19-25 nt small RNAs to complementary RNA targets. This chapter describes northern blot hybridization techniques for the detection of such small RNAs. Blots spiked with synthetic standards are used to illustrate the detection specificity and sensitivity of DNA oligonucleotide probes. Known endogenous small RNAs are then analyzed in samples prepared from several model plants, including Arabidopsis thaliana, Nicotiana benthamiana, Oryza sativa, Zea mays, and Physcomitrella patens, as well as from the animals Drosophila melanogaster and Mus musculus. Finally, the value of northern blotting for dissecting small RNA biogenesis is shown using an example of virus infection in A. thaliana. PMID- 27770363 TI - Analysis of Small RNA Populations Using Hybridization to DNA Tiling Arrays. AB - Epigenetic response to stress in plants involves changes in DNA methylation, histone modifications, and expression of small noncoding RNAs (sRNA). Here we present the method of analysis of differential expression of sRNA populations using DNA tiling arrays. sRNA extracted from Arabidopsis thaliana plants exposed to pathogen elicitor or control plants were reverse-transcribed into cDNAs, and subsequently hybridized after labeling to a custom-made DNA tiling array covering Arabidopsis chromosome 4. We first designed a control experiment with eight cDNA clones corresponding to sequences located on chromosome 4 and obtained robust and specific hybridization signals. Furthermore, hybridization signals along chromosome 4 were in good agreement with sRNA abundance as previously determined by massive parallel sequence signature (MPSS) in the case of untreated plants, but differed substantially after stress treatment. These results demonstrate the utility of hybridization to DNA tiling arrays to detect major changes in sRNA abundance. PMID- 27770365 TI - Stem-Loop qRT-PCR for the Detection of Plant microRNAs. AB - Plant microRNAs (miRNAs) play important roles in the posttranscriptional regulation of protein-coding genes, and they are essential for a normal development and survival. Mature miRNAs are cleaved from larger precursor RNAs and are typically 21-22 nt long.The small size, the lack of a common feature like a poly(A) tail, 3' end-modifications, and presence of a precursor-all these factors affect the detection and hinder the quantification of miRNAs. The stem loop qRT-PCR method described here is designed to detect and quantify mature miRNAs in a fast, specific, accurate, and reliable manner. Firstly, a miRNA specific stem-loop RT primer is hybridized to miRNA and then reverse transcribed. Next, the RT product is amplified and monitored in real time using a miRNA specific forward primer and a universal reverse primer. This method enables miRNA expression profiling from as little as 10 pg of total RNA, and it is suitable for a relatively high-throughput analysis of miRNA expression. PMID- 27770366 TI - Profiling New Small RNA Sequences. AB - Small RNAs are key molecules in RNA silencing pathways that exert the sequence specific regulation of gene expression and chromatin modifications in many eukaryotes. In plants, endogenous small RNAs, including microRNAs (miRNAs), trans acting short interfering RNAs (tasiRNAs), and heterochromatic siRNAs (hc-siRNAs), play an important role in switching or orchestrating biological processes during the development and at the onset of stress responses. These endogenous and exogenous small RNAs are mainly 20-24 nucleotides in length. In addition, viral genome-derived siRNAs of similar lengths are produced during viral infection, and they exhibit anti-viral defense activity in RNA silencing pathway.Here, we introduce a method to isolate and characterize small RNA molecules possibly applicable to a wide range of plant resources and tissues. After purification from total RNAs, small RNAs were subjected to Illumina sequencing analysis using compatible reagents kits. Following the sample preparation protocol, small RNAs are ligated first at the 3'- and then at the 5'-end to the respective RNA adapters followed by reverse transcription with a set of primers to produce cDNAs with Index sequences at ends. After PCR amplification, cDNAs are subjected (after gel purification) to RNA-seq analysis. This method could be applied to isolate small RNAs from different sources and characterize small RNA profiles to compare different sets of samples, e.g., wild-type and mutant plants, plants under different stress environments, and virus-infected plants because the starting RNA material is free of contaminated starch or similar material which would block further analysis. PMID- 27770368 TI - Bioinformatics Analysis of Small RNA Transcriptomes: The Detailed Workflow. AB - Next-generation sequencing became a method of choice for the investigation of small RNA transcriptomes in plants and animals. Although a technical side of sequencing itself is becoming routine, and experimental costs are affordable, data analysis still remains a challenge, especially for researchers with limited computational experience. Here, we present a detailed description of a computational workflow designed to take raw sequencing reads as input, to obtain small RNA predictions, and to detect the differentially expressed microRNAs as a result. The exact commands and pieces of code are provided and hopefully can be adapted and used by other researchers to facilitate the study of small RNA regulation. PMID- 27770367 TI - Small RNA Library Preparation and Illumina Sequencing in Plants. AB - The discovery of small RNAs in plants and animals almost two decades ago attracted a significant interest towards epigenetic regulation of gene expression and the practical implementation of the gained knowledge in applied studies. New and sometimes unexpected functions have been ascribed to sRNAs almost every couple of years since their discovery, hence indicating that the complete role of sRNAs in plant and animal physiology is still barely understood. Next-generation sequencing technologies allow to generate high-resolution profiles of sRNAs for the consequent analysis and possibly to discover novel functions of sRNAs. In this chapter, we provide brief guidelines for sRNA library preparation in plants and a practical approach that can be implemented to overcome possible difficulties with sequencing library generation. PMID- 27770369 TI - Increasing a Stable Transformation Efficiency of Arabidopsis by Manipulating the Endogenous Gene Expression Using Virus-Induced Gene Silencing. AB - Virus-induced gene silencing (VIGS) is a powerful epigenetic tool that allows in a relatively short period of time to down-regulate the expression of an endogenous gene in infected plants for either monitoring the resulting phenotype or enhancing/modifying a particular trait associated with the gene. Here, we describe the utilization of Tobacco rattle virus (TRV) as a vector for the VIGS technique in Arabidopsis plants. The unique ability of TRV to infect both somatic tissues and gametes allows deciphering the role of genes in these tissues simultaneously. As an example, we demonstrate the utilization of TRV to down regulate the expression of AGO2 and NRPD1a genes in ovules of Arabidopsis plants in order to boost the stable transformation efficiency by floral dip. PMID- 27770370 TI - The Random Oligonucleotide-Primed Synthesis Assay for the Quantification of DNA Strand Breaks. AB - DNA strand breaks arise from normal cellular processes such as replication, transcription, and DNA repair as well as spontaneous DNA damage caused by cell metabolic activities. In addition, strand breaks occur due to direct or indirect DNA damage produced by various abiotic and biotic stresses. Strand breaks are among the most problematic DNA lesions because unrepaired strand breaks may lead to cell cycle arrest, gross chromosome rearrangements, or even cell death. Thus, the measurement of the relative number of strand breaks can provide an informative picture of genome stability of a given cell, tissue, or organism. Here, we describe the use of random oligonucleotide-primed synthesis (ROPS) assay for the detection and quantification of the level of strand breaks in tissue samples. The applications of the assay for a quantitative detection of 3'OH, 3'P, or DNA strand breaks at a cleavage site of the deoxyribose residue are discussed. PMID- 27770371 TI - Profiling Transposable Elements and Their Epigenetic Effects in Non-model Species. AB - Taking transposable elements into consideration in surveys of genetic and epigenetic variation remains challenging in species lacking a high-quality reference genome. Here, molecular techniques reducing genome complexity and specifically targeting restructuring and methylation changes in TE genome fractions are described. In particular, methyl-sensitive transposon display (MSTD) uses isoschizomers and PCR amplifications to assess the methylation environment of TE insertions. MSTD offers reliable insights into genome-wide epigenetic changes associated with TEs, especially when used together with similar techniques tracking random sequences. PMID- 27770372 TI - microRNA-590 suppresses the tumorigenesis and invasiveness of non-small cell lung cancer cells by targeting ADAM9. AB - microRNAs (miRNAs), a family of small non-coding RNA molecules, are implicated in cancer growth and progression. In the present study, we examined the expression and biological roles of miR-590 in non-small cell lung cancer (NSCLC). Compared to normal lung tissues, miR-590 expression was downregulated in primary NSCLCs and, to a greater extent, in corresponding brain metastases. NSCLC cell lines with high metastatic potential had significantly (P < 0.05) lower levels of miR 590 than those with low metastatic potential. Re-expression of miR-590 suppressed NSCLC cell proliferation, colony formation, migration, and invasion in vitro and tumorigenesis in vivo. In contrast, inhibition of miR-590 enhanced the migration and invasion of NSCLC cells. Mechanistic studies revealed that a disintegrin and metalloproteinase 9 (ADAM9) was a direct target of miR-590. Delivery of miR-590 mimic was found to decrease endogenous ADAM9 expression in NSCLC cells. Enforced expression of a miRNA-resistant form of ADAM9 significantly restored the aggressive behaviors in miR-590-overexpressing NSCLC cells. Taken together, our data reveal miR-590 as a tumor suppressor in NSCLC, which is at least partially mediated through targeting of ADAM9. Restoration of miR-590 may provide a promising therapeutic strategy for NSCLC. PMID- 27770373 TI - Extracellular matrix 1 (ECM1) regulates the actin cytoskeletal architecture of aggressive breast cancer cells in part via S100A4 and Rho-family GTPases. AB - ECM1 overexpression is an independent predictor of poor prognosis in primary breast carcinomas, however the mechanisms by which ECM1 affects tumor progression have not been completely elucidated. ECM1 was silenced in the triple-negative breast cancer cell lines Hs578T and MDAMB231 using siRNA and the cells were evaluated for changes in morphology, migration, invasion and adhesion. Actin cytoskeleton alterations were evaluated by fluorescent staining and levels of activated Rho GTPases by pull down assays. ECM1 downregulation led to significantly diminished cell migration (p = 0.0005 for Hs578T and p = 0.02 for MDAMB231) and cell adhesion (p < 0.001 for Hs578T and p = 0.01 for MDAMB231). Cell invasion (matrigel) was reduced only in the Hs578T cells (p < 0.01). Silencing decreased the expression of the prometastatic molecules S100A4 and TGFbetaR2 in both cell lines and CD44 in Hs578T cells. ECM1-silenced cells also exhibited alterations in cell shape and showed bundles of F-actin across the cell (stress fibers) whereas NT-siRNA treated cells showed peripheral membrane ruffling. Downregulation of ECM1 was also associated with an increased F/G actin ratio, when compared to the cells transfected with NT siRNA (p < 0.001 for Hs578T and p < 0.00035 for MDAMB231) and a concomitant decline of activated Rho A in the Hs578T cells. Re-expression of S100A4 in ECM1-silenced cells rescued the phenotype in the Hs578T cells but not the MDAMB231 cells. We conclude that ECM1 is a key player in the metastatic process and regulates the actin cytoskeletal architecture of aggressive breast cancer cells at least in part via alterations in S100A4 and Rho A. PMID- 27770374 TI - Factors Influencing Food Choices Among Older Adults in the Rural Western USA. AB - Nutrition is an essential component in promoting health and quality of life into the older adults years. The purpose of this qualitative research is to explore how the rural food environment influences food choices of older adults. Four focus groups were conducted with 33 older adults (50 years of age and older) residing in rural Montana communities. Four major themes related to factors influencing food choices among rural older adults emerged from this study: perception of the rural community environment, support as a means of increasing food access, personal access to food sources, and dietary factors. The findings from this current study warrant further research and promotion of specifically tailored approaches that influence the food choices of older adults in the rural western USA, including the developing and expanding public transportation systems, increasing availability of local grocers with quality and affordable food options, increasing awareness and decreasing stigma surrounding community food programs, and increasing nutrition education targeting senior health issues. PMID- 27770375 TI - Predictors and Barriers to Hepatitis B Screening in a Midwest Suburban Asian Population. AB - Despite guidelines recommending hepatitis B virus (HBV) screening among the Asian population, not all Asians are screened. We assessed barriers to and factors predicting HBV screening in Michigan. Adults residing in Southeast Michigan self identifying as Asian were surveyed at Asian grocery stores, restaurants, churches, and community events. 404 persons participated in the survey, 54 % were women, median age was 51 years, 63 % were Chinese, and 93.8 % were born outside the U.S. 181 (44.8 %) had not or could not recall having been screened for HBV. Of these, 89 % said their primary care physicians (PCP) had never brought up screening. Unscreened participants were more likely to think HBV is genetically inherited and cannot be treated than those who had been screened. They were also more likely to think they should avoid close contact with others, would bring shame to their families, and lose their job, if found to be infected with HBV. Among 223 (55.2 %) who had been screened, 48 % said their PCP had the greatest influence in their decision to be screened and 70.9 % said they were screened at a doctor's visit. Screened participants were more likely to know someone with HBV, have a PCP, and have health insurance. Logistic regression analysis showed knowing someone with HBV was the only predictor for screening. Despite guidelines for HBV screening, only half of the Asian Americans surveyed had been screened. Increasing awareness among PCPs is needed to increase HBV screening in this population. PMID- 27770377 TI - Global Health Education for Gastroenterologists in the USA: Where to from Here? PMID- 27770376 TI - Endoscopic Submucosal Dissection of Superficial Esophageal Neoplasms Is Feasible and Not Riskier for Patients with Liver Cirrhosis. AB - BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) has rarely been reported for the treatment of cirrhotic patients. AIM: To report the results of ESD treatment of superficial esophageal neoplasms (SENs) for cirrhotic patients. METHODS: Forty patients with 50 consecutive SENs undergoing 46 sessions of ESD were retrospectively reviewed. The cirrhotic group included eight patients (11 SENs) with liver cirrhosis consisting of six patients classified as Child-Pugh class A liver cirrhosis and two patients classified as class B liver cirrhosis. Four patients (6 SENs) had coexisting esophageal varices. Parameters were compared between the cirrhotic patients and the non-cirrhotic controls (32 patients, 39 SENs). RESULTS: Platelet counts of the cirrhotic group were significantly lower, while international normalized ratio was significantly higher. When the cirrhotic group and non-cirrhotic group were compared, the mean tumor length (4 vs. 3.7 cm, p = 0.56) and median procedure time (15.1 vs. 11.5 min/cm2, p = 0.30) were similar. The en bloc resection rates were 81.8 and 89.7 % (p = 0.60). Within the cirrhotic group, both lesions without en bloc resection were patients with esophageal varices. The rates of submucosal disease for the cirrhotic group and non-cirrhotic groups were 54.5 and 25.6 % (p = 0.064), respectively, while the R0 resection rates were 77.8 and 94.3 % (p = 0.16), respectively. The two lesions without R0 resection in cirrhotic group had positive vertical but not horizontal margins due to submucosal invasion. Intraprocedural bleeding occurred more frequently in cirrhotic patients than non cirrhotic patients (18.2 vs. 0 %, p = 0.045). None of the patients suffered from esophageal perforation, postoperative bleeding, or death that was related to the ESD. CONCLUSION: Esophageal ESD seems to be safely and can be effectively performed on cirrhotic patients, particularly those without severe liver dysfunction. PMID- 27770378 TI - Predictors of Suboptimal Bowel Preparation Using 3-l of Polyethylene Glycol for an Outpatient Colonoscopy: A Prospective Observational Study. AB - BACKGROUND: A 3-l polyethylene glycol (PEG) solution provided better bowel cleansing quality than a 2-l solution for outpatient colonoscopy. Predictors of suboptimal preparation using a 3-l PEG have not been previously reported. AIMS: To investigate the possible predictors of suboptimal bowel preparation using 3-l of PEG. METHODS: We analyzed a database of 1404 consecutive colonoscopies during a 27-month period at a community hospital. A split-dose PEG regimen was provided for morning colonoscopies, and a same-day PEG regimen was provided for afternoon colonoscopies. The level of bowel cleansing was prospectively scored according to the Boston Bowel Preparation Scale (BBPS). Possible predictors of suboptimal colon preparation, defined as a BBPS score <7, were analyzed using univariate statistics and multivariate logistic regression models. RESULTS: The mean age of the study population (46.7 % men) was 52.5 years (range 20-80 years, SD 11.1 years), and the majority of patients (77.6 %) underwent morning colonoscopies. A suboptimal bowel preparation was reported in 17.2 % of the observed colonoscopies. In the multivariate regression analysis, constipation (odds ratio [OR] 1.60, 95 % confidence interval [CI] 1.15-2.22), male gender (OR 1.68, 95 % CI 1.25-2.25), obesity (OR 1.76, 95 % CI 1.29-2.41), and inadequate (<80 %) PEG consumption (OR 5.4, 95 % CI 2.67-10.89) were independent predictors of a suboptimal colon preparation. CONCLUSIONS: This prospective study identified that constipation, male gender, obesity, and inadequate intake of PEG were significant risk factors for suboptimal bowel preparation using a 3-l PEG solution for outpatient colonoscopy. Interventions of optimized colonoscopy preparation should be targeted at these patient populations. PMID- 27770379 TI - In defense of succinylcholine. PMID- 27770380 TI - In reply: In defense of succinylcholine. PMID- 27770381 TI - De novo transcriptome analysis of Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) genes in latently infected Se301 cells. AB - Cells of the P8-Se301-C1 strain are Spodoptera exigua cell clones that each harbor a partial version of the S. exigua multiple nucleopolyhedrovirus (SeMNPV) genome and which are resistant to homologous SeMNPV infections. The cells produce no viral progeny, suggesting that the infection is a latent-like viral infection. To investigate the SeMNPV genes harbored in the P8-Se301-C1 cells, the de novo transcriptomes of P8-Se301-C1 cells and S. exigua Se301 cells were analyzed and compared. A total of 54,569,296 reads were obtained from the P8-Se301-C1 cells that yielded 112,565 final unigenes with a mean length of 1,093 nt. A total of 56,865,504 reads were obtained from the Se301 cells that yielded 102,996 final unigenes with a mean length of 1,082 nt. Ten SeMNPV gene transcripts (se5, se7, se8, se12, se43, se45, se89, se90, se124, and se126) were detected in the P8 Se301-C1 cells by RNA-Seq but not in the Se301 cells, which was verified by RTPCR. 5'/3' RACE analyses showed that the 3'- or 5'-end sequences of the viral transcripts are aligned to the host gene sequences in P8-Se301-C1 cells, suggesting that the SeMNPV genes may integrate into and be transcribed with the host genes in the P8-Se301-C1 cells. Furthermore, six additional viral gene transcripts, se11, se42, se44, se88, se91, and se127 (incorporated into chimeric fusion transcripts in the P8-Se301-C1 cells), were detected in the RACE analyses. Taken together, sixteen SeMNPV transcripts were identified in the P8-Se301-C1 cell strain. This study provides information to develop the understanding of baculovirus latent infections and superinfection exclusion. PMID- 27770382 TI - Immune checkpoint inhibitors for cancer treatment. AB - During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development. As a result, anti-CTLA-4 and anti-PD-1 (or anti-PD-L1) antibodies were recently developed as immune checkpoint inhibitors for use in cancer treatments. In this review we describe several receptors that function as immunological checkpoints as well as the pharmaceuticals that target them. PMID- 27770383 TI - Chalcone-templated Hsp90 inhibitors and their effects on gefitinib resistance in non-small cell lung cancer (NSCLC). AB - The molecular chaperone Hsp90 has emerged as an attractive cancer therapeutic target due to its role in cellular homeostasis by modulating the stabilization and maturation of many oncogenic proteins. In this study, we designed and synthesized a series of Hsp90 inhibitors that hybridized NVP-AUY992 (2) and PU3 (3) in the chalcone scaffold using a structure-based approach. Our results indicate that compound 1g inhibited the proliferation of gefitinib-resistant non small cell lung cancer (H1975) cells, downregulated the expression of client proteins of Hsp90 including EGFR, MET, Her2 and Akt, and up-regulated the expression of Hsp70. The compound 1g represents a new class of Hsp90 inhibitors with a chalcone structure. The design, synthesis, and evaluation of 1g are described herein. PMID- 27770384 TI - Nontuberculous mycobacterial disease concomitant with a pulmonary artery occlusion caused by Takayasu's arteritis. AB - We herein describe a surgical case of pulmonary involvement in Takayasu's arteritis with pulmonary infections of nontuberculous mycobacteria. A 24-year-old female was admitted to our hospital because of a recurrent fever, and contrast enhanced computed tomography of the chest revealed the occlusion of the right pulmonary artery and cavitary lesions in the right lower lobe of the lung. A further examination of the neck revealed the occlusion of aortic branches, and the patient was diagnosed with Takayasu's arteritis. The cavitary lesions were diagnosed as nontuberculous mycobacteria disease according to the sputum culture result of Mycobacterium intracellulare. After antibiotic treatment for 6 months, the right pneumonectomy was performed with a good result. We should be aware of Takayasu's arteritis as a disease which can lead to the development of unexplained respiratory symptoms due to pulmonary artery involvement in young adults. PMID- 27770386 TI - Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors. AB - The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor. PMID- 27770385 TI - Defining Team Effort Involved in Patient Care from the Primary Care Physician's Perspective. AB - BACKGROUND: A better understanding of the attributes of patients who require more effort to manage may improve risk adjustment approaches and lead to more efficient resource allocation, improved patient care and health outcomes, and reduced burnout in primary care clinicians. OBJECTIVE: To identify and characterize high-effort patients from the physician's perspective. DESIGN: Cohort study. PARTICIPANTS: Ninety-nine primary care physicians in an academic primary care network. MAIN MEASURES: From a list of 100 randomly selected patients in their panels, PCPs identified patients who required a high level of team-based effort and patients they considered complex. For high-effort patients, PCPs indicated which factors influenced their decision: medical/care coordination, behavioral health, and/or socioeconomic factors. We examined differences in patient characteristics based on PCP-defined effort and complexity. KEY RESULTS: Among 9594 eligible patients, PCPs classified 2277 (23.7 %) as high-effort and 2676 (27.9 %) as complex. Behavioral health issues were the major driver of effort in younger patients, while medical/care coordination issues predominated in older patients. Compared to low-effort patients, high effort patients were significantly (P < 0.01 for all) more likely to have higher rates of medical (e.g. 23.2 % vs. 6.3 % for diabetes) and behavioral health problems (e.g. 9.8 % vs. 2.9 % for substance use disorder), more frequent primary care visits (10.9 vs. 6.0 visits), and higher acute care utilization rates (25.8 % vs. 7.7 % for emergency department [ED] visits and 15.0 % vs. 3.9 % for hospitalization). Almost one in five (18 %) patients who were considered high effort were not deemed complex by the same PCPs. CONCLUSIONS: Patients defined as high-effort by their primary care physicians, not all of whom were medically complex, appear to have a high burden of psychosocial issues that may not be accounted for in current chronic disease-focused risk adjustment approaches. PMID- 27770387 TI - Primary cilium is required for the stimulating effect of icaritin on osteogenic differentiation and mineralization of osteoblasts in vitro. AB - OBJECTIVE: Icaritin, one effective metabolite of Herba Epimedii-derived flavonoid icariin, has a strong osteogenic activity. However, its action mechanism remains unclear. Since primary cilia have been shown to play a pivotal role in regulating the osteogenesis, we hypothesized primary cilia are indispensable in mediating icaritin osteogenic effect. MATERIALS AND METHODS: Primary rat calvarial osteoblasts were transfected with siRNA1 targeting intraflagellar transport protein 88 (IFT88), a protein required for ciliogenesis, to prevent formation of primary cilium and were treated with 10-6 M icaritin. RESULTS: Alkaline phosphatase (ALP) activity was significantly increased after 3 days in cells transfected with scrambled siRNA control and treated by icaritin (SC+I group) compared to cells transfected with scrambled siRNA control only (SC group). ALP activity after IFT88 siRNA1 transfection and icaritin treatment (siRNA1+I group) was significantly lower than that of SC+I group. Formation of ALP positively stained colonies after 6 days, osteocalcin secretion after 9 days and formation of calcified nodules after 12 days displayed a similar tendency among the three groups. mRNA expression of osteogenesis-related genes ALP, BMP-2, COL1alpha, RUNX 2 and OSX after 24 h was significantly increased in SC+I group, but was not different with SC group in siRNA1+I group. Protein levels of BMP-2, COL1alpha, RUNX-2 and OSX after 48 h showed the similar tendency with gene expression. CONCLUSION: Primary cilia are important in mediating icaritin-stimulated osteogenic differentiation and may be a novel target for pharmacological therapies for bone loss. PMID- 27770388 TI - Risk of malignant neoplasms in acromegaly: a case-control study. AB - PURPOSE: Acromegaly is a chronic disease resulting from pathological oversecretion of growth hormone and subsequently insulin growth factor-1. Several complications of the disease have been reported, including cardiovascular diseases, respiratory disorders but also increased risk of benign and malignant neoplasms. The aim of the study was to evaluate the risk of malignant neoplasms in the patients with acromegaly in comparison with the control group. PATIENTS AND METHODS: Medical documentation of acromegalic patients treated in one medical center between 2005 and 2016 has been analyzed. Results were compared with sex- and age-matched group of subjects with prolactinomas and hormonally inactive pituitary lesions hospitalized in the same department. RESULTS: Two hundred patients with acromegaly were included. Control group was composed of 145 patients. Any malignant neoplasm in anamnesis was present in 27 (13.5 %) patients with acromegaly and six (4.1 %) subjects from control group (p = 0.003). Thyroid cancer was present in 14 (7.0 %) patients with acromegaly and two (1.4 %) in control group (p = 0.02). Breast cancer was present in seven women (5.4 % of women) in acromegaly group but none of subjects in control group (p = 0.02). Colon cancer-4 (2.0 %) patients in acromegaly group and 0 in control group (p = 0.14). CONCLUSIONS: Malignant neoplasms are significantly more common in patients with acromegaly. Particularly, risk of thyroid cancer was increased over fivefold. Systematic screening for neoplastic diseases should be important part of follow-up in these patients. Further case-control studies are strongly indicated to evaluate which neoplasms are more common in acromegalic patients and what is the exact risk of malignancy. PMID- 27770390 TI - Repeatability of ocular biometry with IOLMaster 700 in subjects with clear lens. AB - PURPOSE: The purpose of the study was to assess the reproducibility of ocular biometry using the IOLMaster-700 in a healthy population. METHODS: This is a prospective, cross-sectional, observational reproducibility study. Ocular biometry was performed three times on each of 45 studied eyes. Flattest meridian (Kf) and the steepest meridian (Ks), central corneal thickness, axial length, anterior chamber depth, aqueous depth, lens thickness, and white-to-white distances were recorded. Reproducibility was evaluated using the coefficient of variation (CV), the within subject standard deviation, and the intraclass correlation coefficient (ICC). RESULTS: There was a high reproducibility in all parameters; CV was between 0.3 and 1 %, and the ICC was higher than 0.87 in all measurements. CONCLUSIONS: IOLMaster-700 showed high reproducibility for ocular biometry. PMID- 27770389 TI - Illumina Miseq platform analysis caecum bacterial communities of rex rabbits fed with different antibiotics. AB - Antibiotics have been widely used for the prevention and the treatment of diseases to humans and animals, and they have fed additives for agricultural animals to promote growth. However, there is a growing concern over the practice due to its side effects on intestinal microbial communities which plays a vital role in animals' health. To investigate the effect of antibiotics on the bacterial population of the caecum in rex rabbits, 80 rex rabbits were randomly divided into four groups: control group (B, basal diet), chlortetracycline group (C, 50 mg/kg), colistin sulfate group (S, 20 mg/kg) and zinc bacitracin group (Z, 40 mg/kg). Caecum microbial communities of rex rabbits from the four groups were analyzed through Illumina Miseq platform after being fed 28 days. The results showed that most obtained sequences belongs to Firmicutes followed by Bacteroidetes, and the ratio of Bacteroidetes/Firmicutes in C group (42.31 %) was higher than that in Z group (21.84 %). Zinc bacitracin supplementation caused a significant decreased of the Proteobacteria phylum and Lactobacillus spp. (P < 0.05), while the Lactobacillus spp. significantly increased in S group (P < 0.05). In addition, Ruminococcus spp., especially Ruminococcus albus were the predominant bacterial species found in both S and Z groups. The proportion of Coprococcus spp. significantly increased in Z group (P < 0.05). These findings suggested that the antibiotics used may cause significant changes in the caecum microbiota of rex rabbits, and we also found C group had a similarity caecum bacteria structure with B group which was probably due to the high levels of chlortetracycline resistance. PMID- 27770391 TI - The effectiveness of disc synoptoscope on patients with abnormal binocular vision: a prospective cohort study. AB - PURPOSE: We performed a prospective cohort study to evaluate the effectiveness of disc synoptoscope on binocularity in patients with abnormal binocular vision. METHODS: 39 eligible subjects were recruited for visual therapy with disc synoptoscope in treatment group and 38 were just observed as control. RESULTS: Simultaneous perception in treatment group was better than controls at 6-month visit (p < 0.05). Fusional amplitude improved in treatment group but decreased in control group at 3- and 6-months visits (p < 0.001). Near and distance stereopsis in treatment group were better than controls at 3- and 6-months (p < 0.05). The improvements of monocular and binocular acuity in treatment group were better than controls at 3- and 6-months (p < 0.05). Postoperative recurrence rate in treatment group was lower than controls (p < 0.05). CONCLUSION: Visual therapy with disc synoptoscope is effective in improving short-term binocular vision for the patients with abnormal binocular vision; disc synoptoscope could serve as an effective home-based visual therapy instrument. PMID- 27770392 TI - Evaluation of retinal nerve fiber layer, ganglion cell layer and macular changes in patients with migraine. AB - The aim of this study was to investigate retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) thickness, macular changes (central subfield thickness (CST), cube average thickness (CAT), cube volume (CV) in patients with migraine using spectral-domain optical coherence tomography (OCT) and to assess if there was any correlation with white matter lesions (WML). In this prospective case control study, RNFL, GCL thickness and macular changes of 19 migraine patients with aura (MA), 41 migraine without aura (MO) and 60 age- and gender-matched healthy subjects were measured using OCT device. OCT measurements were taken at the same time of the day to minimize the effects of diurnal variation. The average, inferior and superior quadrant RNFL thickness were significantly thinner in patients with migraine (p = 0.017, p = 0.010, p = 0.048). There was also a significant difference between patients with and without aura in the mean and superior quadrant RNFL thickness (p = 0.02, p = 0.043).While there was a significant thinning in CST and CAT in patients with migraine (p = 0.020), there were no significant difference in GCL measurements (p = 0.184). When the groups were compared to the control group, there were significant differences between MA and the control group regarding average, superior and inferior quadrant RNLF thickness (p < 0.001, p = 0.025, p < 0.001). On the other hand, there were significant differences between MO and the control group regarding average and inferior faces (p = 0.037, p = 0.04). When OCT measurements were evaluated according to the frequency of attacks, CST and GCL thickness were significantly thinner in patients who had more than four attacks a month (p = 0.024, p = 0.014). In patients with WML, only CV measurements were significantly thinner than migraine patients without WML (p = 0.014). The decreased RNFL, CST, CAT and CV of the migraine patients might be related to the vascular pathology of the disease. Because WML was not correlated with the same measurements except CV, we think that further studies are needed to evaluate the etiopathologic relationship between OCT measurements and WML in migraine patients. PMID- 27770393 TI - Poly(Vinylidene Fluoride-Trifluorethylene)/barium titanate membrane promotes de novo bone formation and may modulate gene expression in osteoporotic rat model. AB - Osteoporosis is a chronic disease that impairs proper bone remodeling. Guided bone regeneration is a surgical technique that improves bone defect in a particular region through new bone formation, using barrier materials (e.g. membranes) to protect the space adjacent to the bone defect. The polytetrafluorethylene membrane is widely used in guided bone regeneration, however, new membranes are being investigated. The purpose of this study was to evaluate the effect of P(VDFTrFE)/BT [poly(vinylidene fluoride trifluoroethylene)/barium titanate] membrane on in vivo bone formation. Twenty three Wistar rats were submitted to bilateral ovariectomy. Five animals were subjected to sham surgery. After 150 days, bone defects were created and filled with P(VDF-TrFE)/BT membrane or PTFE membrane (except for the sham and OVX groups). After 4 weeks, the animals were euthanized and calvaria samples were subjected to histomorphometric and computed microtomography analysis (microCT), besides real time polymerase chain reaction (real time PCR) to evaluate gene expression. The histomorphometric analysis showed that the animals that received the P(VDF-TrFE)/BT membrane presented morphometric parameters similar or even better compared to the animals that received the PTFE membrane. The comparison between groups showed that gene expression of RUNX2, BSP, OPN, OSX and RANKL were lower on P(VDF-TrFE)/BT membrane; the gene expression of ALP, OC, RANK and CTSK were similar and the gene expression of OPG, CALCR and MMP9 were higher when compared to PTFE. The results showed that the P(VDF-TrFE)/BT membrane favors bone formation, and therefore, may be considered a promising biomaterial to support bone repair in a situation of osteoporosis. PMID- 27770394 TI - Effect of enzymatic degradation of chitosan in polyhydroxybutyrate/chitosan/calcium phosphate composites on in vitro osteoblast response. AB - Polyhydroxybutyrate/chitosan/calcium phosphate composites are interesting biomaterials for utilization in regenerative medicine and they may by applied in reconstruction of deeper subchondral defects. Insufficient informations were found in recent papers about the influence of lysozyme degradation of chitosan in calcium phosphate/chitosan based composites on in vitro cytotoxicity and proliferation activity of osteoblasts. The effect of enzymatic chitosan degradation on osteoblasts proliferation was studied on composite films in which the porosity of origin 3D scaffolds was eliminated and the surface texture was modified. The significantly enhanced proliferation activity with faster population growth of osteoblasts were found on enzymatically degraded biopolymer composite films with alpha-tricalcium phosphate and nanohydroxyapatite. No cytotoxicity of composite films prepared from lysozyme degraded scaffolds containing a large fraction of low molecular weight chitosans (LMWC), was revealed after 10 days of cultivation. Contrary to above in the higher cytotoxicity origin untreated nanohydroxyapatite films and porous composite scaffolds. The results showed that the synergistic effect of surface distribution, morphology of nanohydroxyapatite particles, microtopography and the presence of LMWC due to chitosan degradation in composite films were responsible for compensation of the cytotoxicity of nanohydroxyapatite composite films or porous composite scaffolds. PMID- 27770395 TI - Large Deletion of MAGT1 Gene in a Patient with Classic Kaposi Sarcoma, CD4 Lymphopenia, and EBV Infection. PMID- 27770396 TI - Insulin resistance elicited in postpubertal primate offspring deprived of estrogen in utero. AB - We recently demonstrated that offspring delivered to baboons deprived of estrogen during the second half of gestation exhibited insulin resistance prior to onset of puberty. Because gonadal hormones have a profound effect on insulin action and secretion in adults, we determined whether insulin resistance is retained after initiation of gonadal secretion of testosterone and estradiol. Glucose tolerance tests were performed in postpubertal baboon offspring of untreated and letrozole treated animals (serum estradiol reduced >95 %). Basal fasting levels of insulin (P < 0.05) and peak 1 min and 1 + 3 + 5 min levels of glucose after glucose tolerance tests challenge (P < 0.03) were greater in offspring delivered to letrozole-treated, estrogen-deprived baboons than untreated animals. Moreover, the value for the HOMA-IR, an accepted index of insulin resistance, was 2-fold greater (P < 0.05) in offspring delivered to baboons treated with letrozole than in untreated animals. Collectively these results support the proposal that estrogen normally has an important role in programming mechanisms in utero within the developing fetus that lead to insulin sensitivity after birth. PMID- 27770398 TI - Well begun is half done. PMID- 27770397 TI - Intermittent versus continuous androgen deprivation therapy to biochemical recurrence after external beam radiotherapy: a phase 3 GICOR study. AB - PURPOSE: We compared biochemical control and quality of life with intermittent (6 months) versus continuous (36 months) androgen deprivation therapy (ADT) in a non inferiority randomized phase 3 trial in patients with biochemical failure (BF) after external beam radical radiotherapy (EBRT). MATERIALS AND METHODS: Patients were stratified according to the Gleason score (GS) and were classified as low risk with a GS < 6 and 7 (3 + 4) and high risk with a GS of 7 (4 + 3) and >7. Patients were followed with PSA determinations and quality-of-life assessments (QLQ C-30 and QLQ PR-25) every 6 months for a period of 3 years. BF after radiation was defined as a PSA level of nadir +2 ng/ml. Disease progression (DP) after ADT was defined as PSA >=4 ng/ml (BF) and/or metastases. RESULTS: Seventy seven patients were included in this multicenter phase 3 trial from 2005 to 2009. Thirty-eight and 39 patients were included in the intermittent and continuous groups, respectively. The median follow-up for both groups was 48 months (40-68). DP after ADT in the intermittent group was seen in three patients (distant metastases in one patient) versus 0 in the continuous group. The QLQ-C30 and QLQ PR-25 scores did not show any statistically difference between the two ADT groups. CONCLUSIONS: No significant differences were seen in DP and QLQ between intermittent (6 months) and continuous (36 months) ADT in patients with BF after EBRT. PMID- 27770400 TI - New diagnosis of von Hippel-Lindau on CT. PMID- 27770399 TI - Papillary Thyroid Carcinoma Cervical Lymph Node Metastasis with Cystic Change Differentiated from Congenital Cystic Lesions with the Assistance of Immunohistochemistry: A Case Study. AB - Diagnosis of cystic papillary thyroid carcinoma (PTC) lymph node metastasis at head neck region can be a challenge in the absence of known PTC history. The congenital cystic lesions of head neck, especially thyroglossal duct cyst (TGDC) and branchial cleft cyst (BCC), are major differential diagnoses in this clinicopathological scenario. The location of cyst and morphology of lining epithelium are critical clues for reaching correct diagnosis. However it is not uncommon that the flattened bland epithelial lining can be seen in both cystic metastases and congenital cystic lesions. Given that Pax8 and TTF-1 are common markers in thyroid follicular epithelium; we applied immunohistochemical stains of those two markers on aforementioned cystic lesions. Here we reported a case of cystic PTC metastasis to lymph node without prior malignancy history and cases of TGDC and BCC. Both Pax8 and TTF-1 stainings highlighted the cyst lining in PTC metastatic lymph node, while they were negative in the lining of TGDC and BCC. Collectively, Pax8 and TTF-1 immunohistochemical studies are very helpful tools for making correct diagnosis of head neck cystic lesions in the challenging clinical cases. PMID- 27770401 TI - Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAFV600E In Vivo. AB - PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF V600E , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[18F]fluoroglutamine (4-[18F]F-GLN) positron emission tomography (PET) to predict response to BRAFV600E-targeted therapy in preclinical models of colon cancer. PROCEDURES: Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[18F]F-GLN PET was evaluated in mouse models of human BRAF V600E -expressing and BRAF wild-type CRC. RESULTS: Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [18F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[18F]F GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF V600E -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAFV600E-targeted therapies are ineffective. CONCLUSIONS: 4-[18F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[18F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation. PMID- 27770402 TI - A Novel Framework for Automated Segmentation and Labeling of Homogeneous Versus Heterogeneous Lung Tumors in [18F]FDG-PET Imaging. AB - PURPOSE: Determination of intra-tumor high-uptake area using 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) imaging is an important consideration for dose painting in radiation treatment applications. The aim of our study was to develop a framework towards automated segmentation and labeling of homogeneous vs. heterogeneous tumors in clinical lung [18F]FDG PET with the capability of intra-tumor high-uptake region delineation. PROCEDURES: We utilized and extended a fuzzy random walk PET tumor segmentation algorithm to delineate intra-tumor high-uptake areas. Tumor textural feature (TF) analysis was used to find a relationship between tumor type and TF values. Segmentation accuracy was evaluated quantitatively utilizing 70 clinical [18F]FDG PET lung images of patients with a total of 150 solid tumors. For volumetric analysis, the Dice similarity coefficient (DSC) and Hausdorff distance (HD) measures were extracted with respect to gold-standard manual segmentation. A multi-linear regression model was also proposed for automated tumor labeling based on TFs, including cross-validation analysis. RESULTS: Two-tailed t test analysis of TFs between homogeneous and heterogeneous tumors revealed significant statistical difference for size-zone variability (SZV), intensity variability (IV), zone percentage (ZP), proposed parameters II and III, entropy and tumor volume (p < 0.001), dissimilarity, high intensity emphasis (HIE), and SUVmin (p < 0.01). Lower statistical differences were observed for proposed parameter I (p = 0.02), and no significant differences were observed for SUVmax and SUVmean. Furthermore, the Spearman rank analysis between visual tumor labeling and TF analysis depicted a significant correlation for SZV, IV, entropy, parameters II and III, and tumor volume (0.68 <= rho <= 0.84) and moderate correlation for ZP, HIE, homogeneity, dissimilarity, parameter I, and SUVmin (0.22 <= rho <= 0.52), while no correlations were observed for SUVmax and SUVmean (rho < 0.08). The multi-linear regression model for automated tumor labeling process resulted in R 2 and RMSE values of 0.93 and 0.14, respectively (p < 0.001), and generated tumor labeling sensitivity and specificity of 0.93 and 0.89. With respect to baseline random walk segmentation, the results showed significant (p < 0.001) mean DSC, HD, and SUVmean error improvements of 21.4 +/- 11.5 %, 1.4 +/- 0.8 mm, and 16.8 +/- 8.1 % in homogeneous tumors and 7.4 +/- 4.4 %, 1.5 +/- 0.6 mm, and 7.9 +/- 2.7 % in heterogeneous lesions. In addition, significant (p < 0.001) mean DSC, HD, and SUVmean error improvements were observed for tumor sub-volume delineations, namely 5 +/- 2 %, 1.5 +/- 0.6 mm, and 7 +/- 3 % for the proposed Fuzzy RW method compared to RW segmentation. CONCLUSION: We proposed and demonstrated an automatic framework for significantly improved segmentation and labeling of homogeneous vs. heterogeneous tumors in lung [18F]FDG-PET images. PMID- 27770403 TI - Characterising the premonitory stage of migraine in children: a clinic-based study of 100 patients in a specialist headache service. AB - BACKGROUND: The premonitory stage of migraine attacks, when symptomatology outside of pain can manifest hours to days before the onset of the headache, is well recognised. Such symptoms have been reported in adults in a number of studies, and have value in predicting an impending headache. These symptoms have not been extensively studied in children. We aimed to characterise which, if any, of these symptoms are reported in children seen within a Specialist Headache Service. METHODS: We reviewed clinic letters from the initial consultation of children and adolescents seen within the Specialist Headache Service at Great Ormond Street Hospital between 1999 and 2015 with migraine in whom we had prospectively assessed clinical phenotype data. We randomly selected 100 cases with at least one premonitory symptom recorded in the letter. For these patients, the age at headache onset, presence of family history of headache, headache diagnosis, presence of episodic syndromes which may be associated with headache, developmental milestones, gestation at birth, mode of delivery and presence of premonitory symptoms occurring before or during headache were recorded. RESULTS: Of the 100 patients selected, 65 % were female. The age range of the patients was 18 months to 15 years at the time of headache onset. The most common diagnosis was chronic migraine in 58 %, followed by episodic migraine (29 %), New Daily Persistent Headache with migrainous features (8 %) and hemiplegic migraine (5 %). A history of infantile colic was noted in 31 % and was the most common childhood episodic syndrome associated with migraine. The most common premonitory symptoms recorded were fatigue, mood change and neck stiffness. The commonest number of reported premonitory symptoms was two. CONCLUSION: Premonitory symptoms associated with migraine are reported in children as young as 18 months, with an overall clinical phenotype comparable to adults. Better documentation of this stage will aid parents and clinicians to better understand the phenotype of attacks, better recognise migraine and thus initiate appropriate management. Larger studies with a broader base are warranted to understand the extent and implications of these symptoms for childhood and adolescent migraine. PMID- 27770404 TI - Side-locked headaches: an algorithm-based approach. AB - The differential diagnosis of strictly unilateral hemicranial pain includes a large number of primary and secondary headaches and cranial neuropathies. It may arise from both intracranial and extracranial structures such as cranium, neck, vessels, eyes, ears, nose, sinuses, teeth, mouth, and the other facial or cervical structure. Available data suggest that about two-third patients with side-locked headache visiting neurology or headache clinics have primary headaches. Other one-third will have either secondary headaches or neuralgias. Many of these hemicranial pain syndromes have overlapping presentations. Primary headache disorders may spread to involve the face and / or neck. Even various intracranial and extracranial pathologies may have similar overlapping presentations. Patients may present to a variety of clinicians, including headache experts, dentists, otolaryngologists, ophthalmologist, psychiatrists, and physiotherapists. Unfortunately, there is not uniform approach for such patients and diagnostic ambiguity is frequently encountered in clinical practice.Herein, we review the differential diagnoses of side-locked headaches and provide an algorithm based approach for patients presenting with side-locked headaches. Side-locked headache is itself a red flag. So, the first priority should be to rule out secondary headaches. A comprehensive history and thorough examinations will help one to formulate an algorithm to rule out or confirm secondary side-locked headaches. The diagnoses of most secondary side-locked headaches are largely investigations dependent. Therefore, each suspected secondary headache should be subjected for appropriate investigations or referral. The diagnostic approach of primary side-locked headache starts once one rule out all the possible secondary headaches. We have discussed an algorithmic approach for both secondary and primary side-locked headaches. PMID- 27770405 TI - Pharmacology of reflex blinks in the rat: a novel model for headache research. AB - BACKGROUND: Migraineurs are highly sensitive to the nitric oxide donor glyceryl trinitrate which triggers attacks in many sufferers. In animal studies, glyceryl trinitrate increases neuronal activity in the trigeminovascular pathway and elevates neurotransmitter levels in the brainstem. Many migraineurs also display alterations in blink reflexes, known to involve brainstem circuits. We investigated the effect of GTN on evoked blinks in the anaesthetised rat to determine whether such reflexes may prove useful as the basis for a novel animal model to evaluate potential anti-migraine therapeutic agents. METHOD: In anaesthetised rats the electromyogram associated with the reflex blink evoked by corneal airpuff was recorded. Rats were infused with glyceryl trinitrate, sumatriptan plus glyceryl trinitrate or vehicle control. Changes in the magnitude of the reflex blink-associated electromyogram following these treatments were measured. RESULTS: Glyceryl trinitrate potentiated the evoked reflex blink associated EMG response from 2 h after infusion. That effect was abolished by simultaneous infusion of sumatriptan with glyceryl trinitrate. CONCLUSIONS: These results show that simple skin surface measurements of evoked electromyographic activity in the rat can reliably detect the evoked blink reflex that can be potentiated by nitric oxide donors. This novel model may be an effective tool for evaluating putative anti-migraine therapeutic agents. PMID- 27770407 TI - Recent Perioperative Pharmacological Prevention of Acute Kidney Injury after Cardiac Surgery: A Narrative Review. AB - Acute kidney injury (AKI) is a common and severe complication of cardiac surgery, and related rates of both hospitalization and long-term mortality are increasing. A number of studies have explored the preventive effects of perioperative pharmacological therapy on AKI after cardiac surgery. However, the mechanisms of AKI are multifaceted, and no universal treatment has been confirmed as beneficial. We review and analyze several current perioperative pharmacological therapies for AKI after cardiac surgery to identify promising preventive strategies. PMID- 27770406 TI - Prevalence of restless legs syndrome in migraine patients with and without aura: a cross-sectional, case-controlled study. AB - BACKGROUND: Although the comorbidity of migraine and restless legs syndrome (RLS) has been well-documented, the association between RLS and migraine frequency has yet to be elucidated. The present study aims to evaluate the prevalence of RLS among individuals who experience low-frequency, high-frequency, or chronic migraine presenting with and without aura. METHODS: We conducted a cross sectional, case-controlled study involving 505 participants receiving outpatient headache treatment. Standardized questionnaires were administered to collect information on experiences of migraine, RLS, sleep quality, anxiety, depression, and demographics. Participants were categorized into low-frequency (1-8/month), high-frequency (9-14/month), and chronic (>=15/month) headache groups. RLS was diagnosed according to the criteria outlined by the International RLS Study Group (IRLSSG). The Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality and identify symptoms of anxiety and depression. Associations between migraine frequency and RLS prevalence were investigated using multivariate linear and logistic regression. RESULTS: Univariate analysis revealed an effect of migraine frequency on RLS prevalence (p = 0.026), though this effect did not persist following adjustment for baseline characteristics (p = 0.256). The trend was robust in patients whose migraines presented with auras (p univariate = 0.002; p multivariate = 0.043) but not in those without auras (p univariate and p multivariate > 0.05). Higher anxiety [odds ratio (OR) = 1.18, p = 0.019] and sleep disturbance (OR = 1.17, p = 0.023) scores were associated with higher RLS prevalence. CONCLUSIONS: Higher migraine frequency correlates with a higher prevalence of RLS, particularly among patients with auras. PMID- 27770408 TI - A case of atypical type A thymoma variant. AB - BACKGROUND: An atypical type A thymoma variant was newly added to the WHO classification of type A thymoma family in 2015. CASE PRESENTATION: A 72-year-old female was present a large round mass in the anterior mediastinum. The radiological examination led to a preoperative diagnosis of non-invasive thymoma. Tumor resection was undertaken via median sternotomy. Complete removal of the mediastinal tumor was achieved. Pathological examination revealed that the tumor cells were spindle- and oval-shaped with atypia. Immunohistochemical work-up revealed that the tumor was type A thymoma. On the basis of these findings, the tumor was finally diagnosed to be an atypical type A thymoma variant. CONCLUSIONS: Preoperative diagnosis as atypical type A thymoma variant based on radiological examination is difficult. In case of atypical type A thymoma variant, a careful postoperative systemic follow-up should be done. PMID- 27770409 TI - Introduction to the Field of Enzyme Immobilization and Stabilization. AB - Enzyme stabilization is important for many biomedical or industrial application of enzymes (i.e., cell-free biotransformations and biosensors). In many applications, the goal is to provide extended active lifetime at normal environmental conditions with traditional substrates at low concentrations in buffered solutions. However, as enzymes are used for more and more applications, there is a desire to use them in extreme environmental conditions (i.e., high temperatures), in high substrate concentration or high ionic strength, and in nontraditional solvent systems. This chapter introduces the topic enzyme stabilization and the methods used for enzyme stabilization including enzyme immobilization. PMID- 27770410 TI - Stabilization of Enzymes Through Encapsulation in Liposomes. AB - Phospholipid vesicle (liposome) offers an aqueous compartment surrounded by lipid bilayer membranes. Various enzyme molecules have been reported to be encapsulated in liposomes. The liposomal enzyme shows peculiar catalytic activity and selectivity to the substrate in the bulk liquid, which are predominantly derived from the substrate permeation resistance through the membrane. We reported that the quaternary structure of bovine liver catalase and alcohol dehydrogenase was stabilized in liposomes through their interaction with lipid membranes. The method and condition for preparing the enzyme-containing liposomes with well defined size, lipid composition, and enzyme content are of particular importance, because these properties dominate the catalytic performance and stability of the liposomal enzymes. PMID- 27770411 TI - Micellar Enzymology for Thermal, pH, and Solvent Stability. AB - This chapter describes methods for enzyme stabilization using micellar solutions. Micellar solutions have been shown to increase the thermal stability, as well as the pH and solvent tolerance of enzymes. This field is traditionally referred to as micellar enzymology. This chapter details the use of ionic and nonionic micelles for the stabilization of polyphenol oxidase, lipase, and catalase, although this method could be used with any enzymatic system or enzyme cascade system. PMID- 27770412 TI - Lipase Activation and Stabilization in Room-Temperature Ionic Liquids. AB - Widespread interest in the use of room-temperature ionic liquids (RTILs) as solvents in anhydrous biocatalytic reactions has largely been met with underwhelming results. Enzymes are frequently inactivated in RTILs as a result of the influence of solvent on the enzyme's microenvironment, be it through interacting with the enzyme or enzyme-bound water molecules. The purpose of this chapter is to present a rational approach to mediate RTIL-enzyme interactions, which is essential if we are to realize the advantages of RTILs over conventional solvents for biocatalysis in full. The underlying premise for this approach is the stabilization of enzyme structure via multipoint covalent immobilization within a polyurethane foam matrix. Additionally, the approach entails the use of salt hydrates to control the level of hydration of the immobilized enzyme, which is critical to the activation of enzymes in nonaqueous media. Although lipase is used as a model enzyme, this approach may be effective in activating and stabilizing virtually any enzyme in RTILs. PMID- 27770413 TI - Nanoporous Gold for Enzyme Immobilization. AB - Nanoporous gold (NPG) is a material of emerging interest for immobilization of biomolecules, especially enzymes. The material provides a high surface area form of gold that is suitable for physisorption or for covalent modification by self assembled monolayers. The material can be used as a high surface area electrode and with immobilized enzymes can be used for amperometric detection schemes. NPG can be prepared in a variety of formats from alloys containing between 20 and 50 % atomic composition of gold and less noble element(s) by dealloying procedures. Materials resembling NPG can be prepared by hydrothermal and electrodeposition methods. Related high surface area gold structures have been prepared using templating approaches. Covalent enzyme immobilization can be achieved by first forming a self-assembled monolayer on NPG bearing a terminal reactive functional group followed by conjugation to the enzyme through amide linkages to lysine residues. Enzymes can also be entrapped by physisorption or immobilized by electrostatic interactions. PMID- 27770414 TI - Enzyme Stabilization via Bio-Templated Silicification Reactions. AB - Effective entrapment of enzymes in solid phase materials is critical to their practical application. The entrapment generally stabilizes biological activity compared to soluble molecules and the material simplifies catalyst integration compared to other methods. A silica sol-gel process based upon biological mechanisms of inorganic material formation (biomineralization) supports protein immobilization reactions within minutes. The material has high protein binding capacity and the catalytic activity of the enzyme is retained. We have demonstrated that both oligopeptides and selected proteins will mediate the biomineralization of silica and allow effective co-encapsulation of other proteins present in the reaction mixture. The detailed methods described here provide a simple and effective approach for molecular biologists, biochemists and bioengineers to create stable, solid phase biocatalysts that may be integrated within sensors, synthetic processes, reactive barriers, energy conversion, and other biotechnology concepts. PMID- 27770415 TI - Covalent Immobilization of Enzymes on Eupergit(r) Supports: Effect of the Immobilization Protocol. AB - A selection of best combination of adequate immobilization support and efficient immobilization method is still a key requirement for successful application of immobilized enzymes on an industrial level. Eupergit(r) supports exhibit good mechanical and chemical properties and allow establishment of satisfactory hydrodynamic regime in enzyme reactors. This is advantageous for their wide application in enzyme immobilization after finding the most favorable immobilization method. Methods for enzyme immobilization that have been previously reported as efficient considering the obtained activity of immobilized enzyme are presented: direct binding to polymers via their epoxy groups, binding to polymers via a spacer made from ethylene diamine/glutaraldehyde, and coupling the periodate-oxidized sugar moieties of the enzymes to the polymer beads. The modification of the conventionally immobilized enzyme with ethylenediamine via the carbodiimide route seems to be a powerful tool to improve its stability and catalytic activity. PMID- 27770416 TI - Micellar Polymer Encapsulation of Enzymes. AB - Although enzymes are highly efficient and selective catalysts, there have been problems incorporating them into fuel cells. Early enzyme-based fuel cells contained enzymes in solution rather than immobilized on the electrode surface. One problem utilizing an enzyme in solution is an issue of transport associated with long diffusion lengths between the site of bioelectrocatalysis and the electrode. This issue drastically decreases the theoretical overall power output due to the poor electron conductivity. On the other hand, enzymes immobilized at the electrode surface have eliminated the issue of poor electron conduction due to close proximity of electron transfer between electrode and the biocatalyst. Another problem is inefficient and short term stability of catalytic activity within the enzyme that is suspended in free flowing solution. Enzymes in solutions are only stable for hours to days, whereas immobilized enzymes can be stable for weeks to months and now even years. Over the last decade, there has been substantial research on immobilizing enzymes at electrode surfaces for biofuel cell and sensor applications. The most commonly used techniques are sandwich or wired. Sandwich techniques are powerful and successful for enzyme immobilization; however, the enzymes optimal activity is not retained due to the physical distress applied by the polymer limiting its applications as well as the non-uniform distribution of the enzyme and the diffusion of analyte through the polymer is slowed significantly. Wired techniques have shown to extend the lifetime of an enzyme at the electrode surface; however, this technique is very hard to master due to specific covalent bonding of enzyme and polymer which changes the three-dimensional configuration of enzyme and with that decreases the optimal catalytic activity. This chapter details encapsulation techniques where an enzyme will be immobilized within the pores/pockets of the hydrophobically modified micellar polymers such as Nafion(r) and chitosan. This strategy has been shown to safely immobilize enzymes at electrode surfaces with storage and continuous operation lifetime of more than 2 years. PMID- 27770417 TI - Cross-Linked Enzyme Aggregates for Applications in Aqueous and Nonaqueous Media. AB - Extensive cross-linking of a precipitate of a protein by a cross-linking reagent (glutaraldehyde has been most commonly used) creates an insoluble enzyme preparation called cross-linked enzyme aggregates (CLEAs). CLEAs show high stability and performance in conventional aqueous as well as nonaqueous media. These are also stable at fairly high temperatures. CLEAs with more than one kind of enzyme activity can be prepared, and such CLEAs are called combi-CLEAs or multipurpose CLEAs. Extent of cross-linking often influences their morphology, stability, activity, and enantioselectivity. PMID- 27770419 TI - Macroporous Poly(GMA-co-EGDMA) for Enzyme Stabilization. AB - One of the most used procedures for enzyme stabilization is immobilization. Although immobilization on solid supports has been pursued since the 1950s, there are no general rules for selecting the best support for a giving application. A macroporous copolymer of ethylene glycol dimethacrylate and glycidyl methacrylate (poly (GMA-co-EGDMA)) is a carrier consisting of macroporous beads for immobilizing enzymes of industrial potential for the production of fine chemicals and pharmaceuticals. PMID- 27770418 TI - Protein-Coated Microcrystals, Combi-Protein-Coated Microcrystals, and Cross Linked Protein-Coated Microcrystals of Enzymes for Use in Low-Water Media. AB - Protein-coated microcrystals (PCMC) are a high-activity preparation of enzymes for use in low-water media. The protocols for the preparation of PCMCs of Subtilisin Carlsberg and Candida antarctica lipase B (CAL B) are described. The combi-PCMC concept is useful both for cascade and non-cascade reactions. It can also be beneficial to combine two different specificities of a lipase when the substrate requires it. Combi-PCMC of CALB and Palatase used for the conversion of coffee oil present in spent coffee grounds to biodiesel is described. Cross linked protein-coated microcrystals (CL-PCMC) in some cases can give better results than PCMC. Protocols for the CLPCMC of Subtilisin Carlsberg and Candida antarctica lipase B (CAL B) are described. A discussion of their applications is also provided. PMID- 27770420 TI - Cytochrome c Stabilization and Immobilization in Aerogels. AB - Sol-gel-derived aerogels are three-dimensional, nanoscale materials that combine large surface area with high porosity. These traits make them useful for any rate critical chemical process, particularly sensing or electrochemical applications, once physical or chemical moieties are incorporated into the gels to add their functionality to the ultraporous scaffold. Incorporating biomolecules into aerogels, other than such rugged species as lipases or cellulose, has been challenging due to the inability of most biomolecules to remain structurally intact within the gels during the necessary supercritical fluid (SCF) processing. However, the heme protein cytochrome c (cyt.c) forms self-organized superstructures around gold (or silver) nanoparticles in buffer that can be encapsulated into wet gels as the sol undergoes gelation. The guest-host wet gel can then be processed to form composite aerogels in which cyt.c retains its characteristic visible absorption. The gold (or silver) nanoparticle-nucleated superstructures protect the majority of the protein from the harsh physicochemical conditions necessary to form an aerogel. The Au~cyt.c superstructures exhibit rapid gas-phase recognition of nitric oxide (NO) within the bioaerogel matrix, as facilitated by the high-quality pore structure of the aerogel, while remaining viable for weeks at room temperature. More recently, careful control of synthetic parameters (e.g., buffer concentration, protein concentration, SCF extraction rate) have allowed for the preparation of cyt.c silica aerogels, sans nucleating nanoparticles; these bioaerogels also exhibit rapid gas-phase sensing while retaining protein structural stability. PMID- 27770421 TI - Enzyme Immobilization and Mediation with Osmium Redox Polymers. AB - Enzymatic electrodes are becoming increasingly common for energy production and sensing applications. Research over the past several decades has addressed a major issue that can occur when using these biocatalysts, i.e., slow heterogeneous electron transfer, by incorporation of a redox active species to act as an electron shuttle. There are several advantages to immobilizing both the enzyme and mediator at the enzyme surface, including increased electron transfer rates, decreased enzyme leaching, and minimized diffusion limitations. Redox polymers consisting of a redox active center attached to a polymer backbone are a particularly attractive option because they have high self-exchange rates for electron transfer and tunable redox potential. Osmium (Os) polymers are the most well studied of this type of polymer for bioelectrocatalysis. Here, we describe the methods to synthesize one of the most common Os redox polymers and how it can be used to fabricate glucose oxidase electrodes. Procedures are also outlined for evaluating the enzymatic electrodes. PMID- 27770422 TI - Ferrocene-Modified Linear Poly(ethylenimine) for Enzymatic Immobilization and Electron Mediation. AB - Enzymatic glucose biosensors and biofuel cells make use of the electrochemical transduction between an oxidoreductase enzyme, such as glucose oxidase (GOx), and an electrode to either quantify the amount of glucose in a solution or generate electrical energy. However, many enzymes including GOx are not able to electrochemically interact with an electrode surface directly, but require an external electrochemical relay to shuttle electrons to the electrode. Ferrocene modified linear poly(ethylenimine) (Fc-LPEI) redox polymers have been designed to simultaneously immobilize glucose oxidase (GOx) at an electrode and mediate electron transfer from their flavin adenine dinucleotide (FAD) active site to the electrode surface. Cross-linked films of Fc-LPEI create hydrogel networks that allow for rapid transport of glucose, while the covalently bound ferrocene moieties are able to facilitate rapid electron transfer due to the ability of ferrocene to exchange electrons between adjacent ferrocene residues. For these reasons, Fc-LPEI films have been widely used in the development of high current density bioanode materials. This chapter describes the synthesis of a commonly used dimethylferrocene-modified linear poly(ethylenimine), as well as the subsequent preparation and electrochemical characterization of a GOx bioanode film utilizing the synthesized polymer. PMID- 27770423 TI - FAD-Dependent Glucose Dehydrogenase Immobilization and Mediation Within a Naphthoquinone Redox Polymer. AB - Electrochemically-active polymers (redox polymers) are useful tools for simultaneous immobilization and electron transfer of enzymes at electrode surfaces, which also serve to increase the localized concentration of the biocatalyst. The properties of the employed redox couple must be compatible with the target biocatalyst from both an electrochemical (potential) and biochemical standpoint. This chapter details the synthesis of a naphthoquinone-functionalized redox polymer (NQ-LPEI) that is used to immobilize and electronically communicate with flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH), yielding an enzymatic bioanode that is able to deliver large catalytic current densities for glucose oxidation at a relatively low associated potential. PMID- 27770425 TI - Kinetic Measurements for Enzyme Immobilization. AB - Enzyme kinetics is the study of the chemical reactions that are catalyzed by enzymes, with a focus on their reaction rates. The study of an enzyme's kinetics considers the various stages of activity, reveals the catalytic mechanism of this enzyme, correlates its value to assay conditions, and describes how a drug or a poison might inhibit the enzyme. Victor Henri initially reported that enzyme reactions were initiated by a bond between the enzyme and the substrate. By 1910, Michaelis and Menten were advancing their work by studying the kinetics of an enzyme saccharase which catalyzes the hydrolysis of sucrose into glucose and fructose. They published their analysis and ever since the Michaelis-Menten equation has been used as the standard to describe the kinetics of many enzymes. Unfortunately, soluble enzymes must generally be immobilized to be reused for long times in industrial reactors. In addition, other critical enzyme properties have to be improved like stability, activity, inhibition by reaction products, and selectivity towards nonnatural substrates. Immobilization is by far the chosen process to achieve these goals.Although the Michaelis-Menten approach has been regularly adapted to the analysis of immobilized enzyme activity, its applicability to the immobilized state is limited by the barriers the immobilization matrix places upon the measurement of compounds that are used to model enzyme kinetics. That being said, the estimated value of the Michaelis Menten coefficients (e.g., V max, K M) can be used to evaluate effects of immobilization on enzyme activity in the immobilized state when applied in a controlled manner. In this review enzyme activity and kinetics are discussed in the context of the immobilized state, and a few novel protocols are presented that address some of the unique constraints imposed by the immobilization barrier. PMID- 27770424 TI - Layer-by-Layer Assembly of Glucose Oxidase on Carbon Nanotube Modified Electrodes. AB - The use of enzymatically modified electrodes for the detection of glucose or other non-electrochemically active analytes is becoming increasingly common. Direct heterogeneous electron transfer to glucose oxidase has been shown to be kinetically difficult, which is why electron transfer mediators or indirect detection is usually used for monitoring glucose with electrochemical sensors. It has been found, however, that electrodes modified with single or multi-walled carbon nanotubes (CNTs) demonstrate fast heterogeneous electron transfer kinetics as compared to that found for traditional electrodes. Incorporating CNTs into the assembly of electrochemical glucose sensors, therefore, affords the possibility of facile electron transfer to glucose oxidase, and a more direct determination of glucose. This chapter describes the methods used to use CNTs in a layer-by layer structure along with glucose oxidase to produce an enzymatically modified electrode with high turnover rates, increased stability and shelf-life. PMID- 27770427 TI - Discrimination in Seeking Medical Care for Female Child from Birth to Adolescence - A Retrospective Study: Correspondence. PMID- 27770426 TI - The Sensing Properties of Single Y-Doped SnO2 Nanobelt Device to Acetone. AB - Pure SnO2 and Y-doped SnO2 nanobelts were prepared by thermal evaporation at 1350 degrees C in the presence of Ar carrier gas (30 sccm). The samples were characterized by scanning electron microscope (SEM), X-ray diffraction (XRD), energy dispersion spectrometer (EDS), X-ray photoelectron spectrometer (XPS), UV Vis absorption spectroscopy, Raman spectroscopy, and Fourier transform infrared spectrum (FTIR). The sensing properties of the devices based on a single SnO2 nanobelt and Y-doped SnO2 nanobelt were explored to acetone, ethanol, and ethanediol. It reveals that the sensitivity of single Y-doped SnO2 nanobelt device is 11.4 to 100 ppm of acetone at 210 degrees C, which is the highest response among the three tested VOC gases. Y3+ ions improve the sensitivity of SnO2 sensor and have an influence on the optical properties of Y-doped SnO2 nanobelts. PMID- 27770428 TI - Long Segment Bony Spur in Split Cord Malformation Type 1. PMID- 27770429 TI - Radiation dosimetry of the alpha4beta2 nicotinic receptor ligand (+) [18F]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results. AB - BACKGROUND: Both enantiomers of [18F]flubatine are new radioligands for neuroimaging of alpha4beta2 nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[18F]flubatine compared to (-)-[18F]flubatine was its higher binding affinity suggesting that (+)-[18F]flubatine might be able to detect also slight reductions of alpha4beta2 nAChRs and could be more sensitive than (-)-[18F]flubatine in early stages of Alzheimer's disease. To support the clinical translation, we investigated a fully image-based internal dosimetry approach for (+)-[18F]flubatine, comparing mouse data collected on a preclinical PET/MRI system to piglet and first-in-human data acquired on a clinical PET/CT system. Time-activity curves (TACs) were obtained from the three species, the animal data extrapolated to human scale, exponentially fitted and the organ doses (OD), and effective dose (ED) calculated with OLINDA. RESULTS: The excreting organs (urinary bladder, kidneys, and liver) receive the highest organ doses in all species. Hence, a renal/hepatobiliary excretion pathway can be assumed. In addition, the ED conversion factors of 12.1 MUSv/MBq (mice), 14.3 MUSv/MBq (piglets), and 23.0 MUSv/MBq (humans) were calculated which are well within the order of magnitude as known from other 18F-labeled radiotracers. CONCLUSIONS: Although both enantiomers of [18F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[18F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the tolerability of the radiation risk of (+)-[18F]flubatine imaging which is well within the range as caused by other 18F-labeled tracers. However, as shown in previous studies, the ED in humans is underestimated by up to 50 % using preclinical imaging for internal dosimetry. This fact needs to be considered when applying for first-in-human studies based on preclinical biokinetic data scaled to human anatomy. PMID- 27770430 TI - Physiologically based pharmacokinetic modeling in regulatory decision-making at the European Medicines Agency. AB - Physiologically based pharmacokinetic (PBPK) modeling is a valuable tool in drug development and regulatory assessment, as it offers the opportunity to simulate the pharmacokinetics of a compound, with a mechanistic understanding, in a variety of populations and situations. This work reviews the use and impact of such modeling in selected regulatory procedures submitted to the European Medicines Agency (EMA) before the end of 2015, together with its subsequent reflection in public documents relating to the assessment of these procedures. It is apparent that the reference to PBPK modeling in regulatory public documents underrepresents its use. A positive trend over time of the number of PBPK models submitted is shown, and in a number of cases the results of these may impact the decision-making process or lead to recommendations in the product labeling. These results confirm the need for regulatory guidance in this field, which is currently under development by the EMA. PMID- 27770431 TI - Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury. AB - Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making. PMID- 27770432 TI - Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia. AB - Inflammation-induced FGF10 protein deficiency is associated with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants characterized by arrested alveolar development. So far, experimental evidence for a direct role of FGF10 in lung disease is lacking. Using the hyperoxia-induced neonatal lung injury as a mouse model of BPD, the impact of Fgf10 deficiency in Fgf10+/- versus Fgf10+/+ pups was investigated. In normoxia, no lethality of Fgf10+/+ or Fgf10+/- pups was observed. By contrast, all Fgf10+/- pups died within 8 days of hyperoxic injury, with lethality starting at day 5, whereas Fgf10+/+ pups were all alive. Lungs of pups from the two genotypes were collected on postnatal day 3 following normoxia or hyperoxia exposure for further analysis. In hyperoxia, Fgf10+/- lungs exhibited increased hypoalveolarization. Analysis by FACS of the Fgf10+/- versus control lungs in normoxia revealed a decreased ratio of alveolar epithelial type II (AECII) cells over total Epcam-positive cells. In addition, gene array analysis indicated reduced AECII and increased AECI transcriptome signatures in isolated AECII cells from Fgf10+/- lungs. Such an imbalance in differentiation is also seen in hyperoxia and is associated with reduced mature surfactant protein B and C expression. Attenuation of the activity of Fgfr2b ligands postnatally in the context of hyperoxia also led to increased lethality with decreased surfactant expression. In summary, decreased Fgf10 mRNA levels lead to congenital lung defects, which are compatible with postnatal survival, but which compromise the ability of the lungs to cope with sub-lethal hyperoxic injury. Fgf10 deficiency affects quantitatively and qualitatively the formation of AECII cells. In addition, Fgfr2b ligands are also important for repair after hyperoxia exposure in neonates. Deficient AECII cells could be an additional complication for patients with BPD. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27770435 TI - A scoping review of root canal revascularization: relevant aspects for clinical success and tissue formation. AB - The aim of this scoping study was to evaluate the survival rate and nature of tissue formed inside root canals of human immature permanent teeth with necrotic pulps (NIPT) under root canal revascularization (RCR). The search was performed in SciVerse Scopus(r), PubMed/MEDLINE, Web of Science(r), BIREME and in the grey literature up to November 2015. The keywords were selected using MeSH terms and DECs. Two independent reviewers scrutinized the records obtained considering specific inclusion criteria. The included studies were evaluated in accordance with a modified Arksey and O' Malley's framework. From 375 studies that were evaluated, 75 were included. A total of 367 NIPT were submitted to RCR, from which only 21 needed further endodontic treatment. The weighted mean follow-up time was 17.6 months. The data were derived mainly from case reports (69%) or small case series (15%). NaOCl [0.5-6%] was applied as the disinfecting solution in almost all studies. Triple antibiotic paste was as effective as Ca(OH)2 as on intracanal medicament. De novo tissue was cementum and poorly mineralized bone positive to bone sialoprotein (BSP) but negative to dentine sialoprotein (DSP). Failures were associated mainly with reinfection of the root canal. The majority of included studies reported a significant increase in both root length and width. However, as most of these data came from case reports, they must be interpreted with care, as most were focused on treatment successes (not failures). Therefore, well-designed randomized controlled trials comparing RCR with available apexification treatments are needed to address this gap in the literature. PMID- 27770434 TI - Prediagnostic circulating inflammation markers and endometrial cancer risk in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. AB - Inflammation is proposed to increase risk of developing endometrial cancer, but few prospective epidemiologic studies have investigated the relationship between circulating inflammation markers and endometrial cancer risk. In a nested case control study within the PLCO Screening Trial we measured serum levels of 64 inflammation-related biomarkers in 284 incident endometrial cancer cases and 284 matched controls. Using multivariable logistic regression inflammation markers were evaluated individually and combined into a cross-validated inflammation score. Of 64 markers, 22 were associated with endometrial cancer risk at p < 0.05 and 17 of 22 markers remained associated after multiple testing corrections. After adjusting for BMI and estradiol, SERPINE1 [quartile(Q)4 vs. Q1 odds ratio (OR) (95% confidence interval (CI)), p trend = 2.43 (0.94-6.29), 0.03] and VEGFA [2.56 (1.52-4.30), 0.0002] were positively associated with endometrial cancer risk, while CCL3 [0.46 (0.27-0.77), 0.01], IL13 [0.55 (0.33-0.93), 0.01], IL21 [0.52 (0.31-0.87), 0.01], IL1B [0.51 (0.30-0.86), 0.01] and IL23 [0.60 (0.35 1.03), 0.02] were inversely associated with risk. We observed large differences in ORs across BMI-inflammation score categories. Endometrial cancer risk was most pronounced among obese women with the highest inflammation score tertile (T) [10.25 (3.56-29.55) vs. normal BMI/T1]. Several inflammation markers were prospectively associated with endometrial cancer, including adipokines, pro- and anti-inflammatory cytokines, angiogenic factors and acute phase proteins. Inverse associations with anti-inflammatory markers (IL13, IL21), other inflammation markers/mediators (CCL3, IL1B, IL23), and a robust positive association between VEGFA and endometrial cancer risk were independent of BMI and estradiol, suggesting that these factors may influence risk through other mechanisms. PMID- 27770433 TI - Interleukin-6-mediated signaling in adrenal medullary chromaffin cells. AB - The pro-inflammatory cytokines, tumor necrosis factor-alpha, and interleukin 1beta/alpha modulate catecholamine secretion, and long-term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin-6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Consistent with ERK1/2 activation, IL6 rapidly increased tyrosine hydroxylase phosphorylation (serine-31) and activity, as well as up regulated genes, encoding secreted proteins including galanin, vasoactive intestinal peptide, gastrin-releasing peptide, and parathyroid hormone-like hormone. The effects of IL6 on the entire bovine chromaffin cell transcriptome were compared to those generated by G-protein-coupled receptor (GPCR) agonists (histamine and pituitary adenylate cyclase-activating polypeptide) and the cytokine receptor agonists (interferon-alpha and tumor necrosis factor-alpha). Of 90 genes up-regulated by IL6, only 16 are known targets of IL6 in the immune system. Those remaining likely represent a combination of novel IL6/STAT3 targets, ERK1/2 targets and, potentially, IL6-dependent genes activated by IL6 induced transcription factors, such as hypoxia-inducible factor 1alpha. Notably, genes induced by IL6 include both neuroendocrine-specific genes activated by GPCR agonists, and transcripts also activated by the cytokines. These results suggest an integrative role for IL6 in the fine-tuning of the chromaffin cell response to a wide range of physiological and paraphysiological stressors, particularly when immune and endocrine stimuli converge. PMID- 27770436 TI - Effect of sodium hypochlorite and saline on cyclic fatigue resistance of WaveOne Gold and Reciproc reciprocating instruments. AB - AIM: To compare the cyclic fatigue resistance of WaveOne Gold (Dentsply Tulsa Dental Specialties, Tulsa, OK, USA) and Reciproc (VDW, Munich, Germany) reciprocating instruments during immersion in sodium hypochlorite (NaOCl) and saline solutions at body temperature. METHODOLOGY: A total of 180 new WaveOne Gold primary size 25, .07 taper, and Reciproc size 25, .08 taper were randomly divided into three groups: group 1: no immersion (control, air); group 2: immersion in saline at 37 +/- 1 degrees C; and group 3: immersion in 5% NaOCl at 37 +/- 1 degrees C. The instruments were reciprocated in the test solution until fracture, and the number of cycles to failure was recorded. The data were analysed statistically using t-tests and one-way analysis of variance (anova) with the significance level set at P < 0.05. A Weibull analysis was performed on number of cycles to failure data. RESULTS: WaveOne Gold instruments had significantly greater number of cycles to failure than Reciproc instruments in all groups (P < 0.001). Fatigue resistance for both instruments tested in air was significantly higher than that in saline and NaOCl solutions (P < 0.001). For both instruments, there was no significant difference in the fatigue resistance between saline and NaOCl solutions (P > 0.05). The Weibull analysis showed that the predicted cycles of WaveOne Gold in air was 1027 cycles for 99% survival. However, Reciproc instruments tested in NaOCl solution had the lowest predicted cycles (613 cycles) among the groups. CONCLUSIONS: Immersion of WaveOne Gold and Reciproc reciprocating instruments in saline and NaOCl solutions decreased considerably their cyclic fatigue resistance. The fatigue resistance of WaveOne Gold instruments was higher than that of Reciproc instruments. PMID- 27770437 TI - Death in the clinic: women's perceptions and experiences of discarding supernumerary IVF embryos. AB - Perspectives on the status of human embryos and whether they should be discarded differ globally. Some countries protect embryos in law while in other countries embryos 'die' or 'succumb' in assisted reproductive technology clinics on a daily basis. This study analyses interview data drawn from a larger qualitative study conducted in South Australia from 2004-2007. 21 women and 12 of 21 partners were interviewed about the decision they made to discard their embryos. The analysis reported here sought to examine the ways in which women constructed and experienced the decision to discard embryos. The article highlights the ways in which embryo discard is a contested discursive space. Embryo death is sequestered through their confinement in the laboratory and their invisibility to the naked eye. The clinic treated embryo discard as disposal of biological waste and failed to acknowledge the meaning of the event. By contrast women experienced emotional bereavement described as similar to early pregnancy loss, and described experiences of attachment and grief. For sensitive and compassionate care these differences in perceptions of embryo discard need to be addressed. PMID- 27770438 TI - Fifty percent of anaesthetists are worse than average at understanding statistics and risk. PMID- 27770440 TI - To what extent does diagnosis matter? Dementia diagnosis, trouble interpretation and caregiving network dynamics. AB - Contemporary research into health and mental health treats diagnosis as a central step in understanding illness management and trajectory; consequently, in the last two decades, sociology of diagnosis has attained increasing influence within medical sociology. Deeply embedded in social constructionism, the set of research divides between those who focus on the social and historical construction of diagnoses as categories, and those who see diagnosis as a process. Regarding the latter, this approach explores the constitution of the medical production, highlighting how it constitutes a starting point for entering a 'sick role', for being labelled, for naming one's problem and by extension, for framing one's illness narrative. PMID- 27770439 TI - Non-proton ligand-sensing domain of acid-sensing ion channel 3 is required for itch sensation. AB - Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. However, the molecular mechanisms of itch are unclear. Acid-sensing ion channel 3 (ASIC3) is a sensor of acidic and primary inflammatory pain. The whole-cell patch clamp technique was used to determine the effect of chloroquine (CQ) on ASICs currents in primary sensory neurons or the Chinese hamster ovary cells transfected with rat ASIC1a or ASIC3. Site-directed mutagenesis of plasmid was performed. Scratching behavior was evaluated by measuring the number of bouts during 30 min after injection. CQ, an anti-malarial drug defined as a histamine-independent pruritogen, selectively enhanced the sustained phase of ASIC3 current in a concentration-dependent manner either in ASIC3-transfected Chinese hamster ovary cells or in primary cultured rat dorsal root ganglion neurons. Further studies revealed that the effect of CQ on ASIC3 channels depends on the newly identified non-proton ligand-sensing domain. Importantly, CQ-evoked scratching behavior was largely alleviated by APETx2, a selective ASIC3 channel blocker. Like CQ, other compounds such as amiloride, 2-guanidine-4-methylquinazoline and neuropeptide FF, which have been previously reported to be non-proton ligands that activate ASIC3, undoubtedly evoked the scratching response. In conclusion, ASIC3, a proton-gated ion channel critical for pain sensation, also functions as an essential component of itch transduction. PMID- 27770441 TI - Effect of static magnetic field on pain level and expression of P2X3 receptors in the trigeminal ganglion in mice following experimental tooth movement. AB - Recent research has demonstrated that static magnetic fields (SMF) can generate an analgesic effect in different conditions. The present study explored effects of SMF on pain levels and expressions of P2X3 receptors in trigeminal ganglion (TG) in mice after experimental tooth movement (tooth movement induced by springs between teeth). Experiments were performed in male mice (body mass: 25-30 g) and divided into SMF + force group, force group, and no force group. Exposure time was over 22 h per day. Mouse Grimace Scale was used for evaluating orofacial pain levels during experimental tooth movement at 4 h and 1, 3, 7, and 14 days. Meanwhile, expression levels of P2X3 receptors in the TG were evaluated by immunohistochemistry and western blotting at same time points. We finally found that during experimental tooth movement, pain levels of mice peaked at 3 days, and then decreased. While pain levels of mice were reduced in the SMF environment at 4 h, 1 and 3 days, there was a significant difference at 1 and 3 days. Meanwhile, under the action of SMF, expression levels of P2X3 receptors in TG were significantly lower at 4 h, 3 and 7 days. These results suggest that SMF can reduce pain levels in mice, and down-regulate P2X3 receptors in TG. Bioelectromagnetics. 38:22-30, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27770442 TI - Association between apical periodontitis and cardiovascular diseases: a systematic review of the literature. AB - A systematic review was conducted to assess the association between apical periodontitis (AP) and cardiovascular disease (CVD). Studies published from the earliest date available until September 2015 were retrieved from the Medline, PubMed and Embase databases. The included studies reported the results from observational studies and assessed the link between AP and CVD as confirmed by one of the following criteria: diagnosed coronary artery disease, angina pectoris, acute myocardial infarction, stroke or mortality caused by cardiac pathology. The study characteristics were abstracted by independent researchers following the PRISMA standard protocol. NOS criteria were used to rate the quality of the studies, and the GRADE was used for level of evidence evaluation. Nineteen epidemiological studies fulfilled the predetermined inclusion criteria: 10 case-control studies, five cross-sectional studies and four cohort studies. There was considerable heterogeneity amongst the included studies in terms of their study design, population, outcomes of interest and AP evaluation methods. Considering the limited availability and the heterogeneity amongst the studies, meta-analysis was not attempted. Thirteen of the 19 included studies found a significant positive association between apical periodontitis and cardiovascular disease, although in two of them, the significance was present only in univariate analysis. Five studies failed to reveal positive significance, and one study reported a negative association. In conclusion, although most of the published studies found a positive association between apical periodontitis and cardiovascular disease, the quality of the existing evidence is moderate-low and a causal relationship cannot be established. PMID- 27770443 TI - Studying the effect of microwave heating on the digestion process and identification of proteins. AB - The impact of microwave irradiation on the in-solution digestion processes and the detection limit of proteins are systematically studied. Kinetic processes of many peptides produced through the trypsin digestion of various proteins under microwave heating at 50 degrees C were investigated with MALDI-MS. This study also examines the detection limits and digestion completeness of individual proteins under microwave heating at 50 degrees C and at different time intervals (1, 5 and 30 min) using LC-MS. We conclude that if the peptides without missed cleavage dictate the detection limit, conventional digestion will lead to a better detection limit. The detection limit may not differ between the microwave and conventional heating if the peptides with missed cleavage sites and strong intensity are formed at the very early stage (i.e., less than 1 min) and are not further digested throughout the entire digestion process. The digestion of Escherichia coli lysate was compared under conventional and short time (microwave) conditions. The number of proteins identified under conventional heating exceeded that obtained from microwave heating over heating periods less than 5 min. The overall results show that the microwave-assisted digestion is not complete. Although the sequence coverage might be better, the detection limit might be worse than that under conventional heating. PMID- 27770444 TI - Application of response surface methodology for optimization of trace amount of diazinon preconcentration in natural waters and biological samples by carbon mesoporous CMK-3. AB - Preconcentration of trace amounts of diazinon by carbon mesoporous CMK-3 in water and biological samples and measurement by high-performance liquid chromatography were investigated. CMK-3 was prepared using hexagonal SBA-15 as the template. The synthesized materials were characterized by X-Ray diffraction (XRD), Fourier transform infrared spectroscopy, Brunaur-Emmet-Teller, transmission electron microscopy and Boehm titration method. The preconcentration procedure was optimized using a multivariate optimization approach following a two-stage process. The effect of analytical parameters including the amount of the CMK-3 as an adsorbent, pH, type and volume of eluent and flow rate of eluent and sample were studied by a screening project, then the effective parameters were optimized by response surface methodology based on central composite design. The average extraction efficiency of diazinon under optimal conditions (CMK-3 dosage = 25 mg, sample flow rate = 2.5 mL min-1 , eluent flow rate = 1.25 mL min-1 , volume of methanol as an eluent =3.5 mL and initial pH = 6) was 97.11%, which agrees well with the predicted response value (97.93%). The linearity of the method was in the range of 0.5-100 MUg L-1 with a correlation coefficient of 0.997. Enrichment factor, limit of detection and limit of quantification were 285.7, 0.09 and 0.23 MUg L-1 , respectively. The relative standard deviation (RSD) under optimum conditions was 2.21% (n = 5). The proposed method was applied to determine diazinon in real water and biological samples. Recovery of diazinon from real samples was between 95.80 and 104.94% with an RSD of 0.19-4.65%. Thus, this method is suitable for the preconcentration and determination of diazinon in real water and biological samples. PMID- 27770445 TI - Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy. AB - The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. Accumulating evidence is underscoring the fundamental importance of epigenetic regulation in tumour immune evasion. Following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies ('epimutations'), there is also a growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells towards an immunosuppressive state. Pharmacological inhibition of DNA methylation and histone modifications can augment the efficiency of immune checkpoint blockage, and unleash anti-tumour T-cell responses. However, these non-specific agents also represent a 'double-edged sword', as they can also reactivate gene transcription of checkpoint molecules, interrupting immune surveillance programmes. By understanding the impact of epigenetic control on the tumour microenvironment, rational combinatorial epigenetic and checkpoint blockage therapies have the potential to harness the immune system for the treatment of cancer. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27770448 TI - Impact of spinal anaesthesia vs. general anaesthesia on peri-operative outcome in lumbar spine surgery: a systematic review and meta-analysis of randomised, controlled trials. AB - Lumbar spinal surgery is most commonly performed under general anaesthesia. However, spinal anaesthesia has also been used. We aimed to systematically review the comparative evidence. We only included randomised, controlled trials in this meta-analysis and calculated the risk ratio or standardised mean difference for haemodynamics, blood loss, surgical time, analgesic requirement, nausea and/or vomiting, and length of hospital stay. Eight studies with a total of 625 patients were included. These were considered to be at high risk of bias. Compared with general anaesthesia, the risk ratio (95% CI) with spinal anaesthesia for intra operative hypertension was 0.31 (0.15-0.64), I2 = 0% (p = 0.002); for intra operative tachycardia 0.51 (0.30-0.84), I2 = 0% (p = 0.009); for analgesic requirement in the postanaesthesia care unit 0.32 (0.24-0.43), I2 = 0% (p < 0.0001); and for nausea/vomiting within 24 h postoperatively 0.29 (0.18-0.46), I2 = 12% (p < 0.00001). The standardised mean difference (95% CI) for hospital stay was -1.15 (-1.98 to -0.31), I2 = 89% (p = 0.007). There was no evidence of a difference in intra-operative hypotension and bradycardia, blood loss, surgical time, analgesic requirement within 24 h postoperatively, and nausea/vomiting in the postanaesthesia care unit. We conclude that spinal anaesthesia appears to offer advantages over general anaesthesia for lumbar spine surgery. PMID- 27770447 TI - Secular trends of physical growth and abdominal adiposity of school children and adolescents living at a moderate altitude in Peru. AB - OBJECTIVE: Identify changes in physical growth and abdominal adiposity at an interval of 14 years in children and adolescents living at a moderate altitude in Peru. MATERIALS AND METHODS: The data comes from two cross-sectional studies carried out in the city of Arequipa, Peru, located at a moderate altitude of 2,320 meters. In 2001, 473 males and 482 females were assessed, and in 2015, 432 males and 403 females between 6.0 and 12.9 years old were evaluated. Data were collected in public state schools and measured using the anthropometric variables for weight, height, and waist circumference. Body mass index (BMI) was calculated according to age and sex. RESULTS: Positive trends for weight were identified for both males and females at all ages (p < .001). For height, significant increases were observed in males for all ages. No significant increases (p > .05) occurred in height for females between the ages of 6 and 8 years. However, commencing at age 9 until 12 years, females showed positive and significant increases (p < .001) in height. In 2015, BMI and waist circumference increased significantly for both sexes at all ages. DISCUSSION: Between 2001 and 2015, positive trends in physical growth and abdominal adiposity were identified for children and adolescents living in Arequipa, Peru. These changes may be associated with the rapid economic development in the country. PMID- 27770446 TI - The role of genetics in pulmonary arterial hypertension. AB - Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH) is a rare disease characterized by proliferation and occlusion of small pulmonary arterioles, leading to progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, and right ventricular failure. Historically, it has been associated with a high mortality rate, although, over the last decade, treatment has improved survival. PAH includes idiopathic PAH (IPAH), heritable PAH (HPAH), and PAH associated with certain medical conditions. The aetiology of PAH is heterogeneous, and genetics play an important role in some cases. Mutations in BMPR2, encoding bone morphogenetic protein receptor 2, a member of the transforming growth factor-beta superfamily of receptors, have been identified in 70% of cases of HPAH, and in 10-40% of cases of IPAH. Other genetic causes of PAH include mutations in the genes encoding activin receptor-like type 1, endoglin, SMAD9, caveolin 1, and potassium two-pore-domain channel subfamily K member 3. Mutations in the gene encoding T-box 4 have been identified in 10-30% of paediatric PAH patients, but rarely in adults with PAH. PAH in children is much more heterogeneous than in adults, and can be associated with several genetic syndromes, congenital heart disease, pulmonary disease, and vascular disease. In addition to rare mutations as a monogenic cause of HPAH, common variants in the gene encoding cerebellin 2 increase the risk of PAH by approximately two-fold. A PAH panel of genes is available for clinical testing, and should be considered for use in clinical management, especially for patients with a family history of PAH. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27770450 TI - Enabling and controlling parenthood in publicly provided maternity healthcare: becoming a parent in Finland. AB - This article discusses practices of parental support in the maternity healthcare provided by the welfare state. Drawing on ethnographic material from clinics in Finland, I discuss maternity healthcare practices and processes as the specific contexts of subjectification to parenthood in the Nordic welfare state. The analysis shows that in both nurses' (work) experience-based knowledge and population-statistical knowledge, parental competence is achieved largely through the 'natural' process of experiencing pregnant life. Care practices can be seen as enabling parenthood through respect for this process. Clinics encourage parents-to-be to self-reflect and be self-reliant. Emphasis on self-reflection and self-reliance has previously been interpreted as the state adoption of therapy culture, and as a response to market demands for the welfare state to offer to and require of its citizens more autonomy and choice. I argue, however, that the parental subject emerging from the practices of this welfare service cannot be reduced to a neoliberal reflexive individual for whom parenthood is an individual project and who is to blame for individual shortcomings. Equally, they are no mere disciplined product of governmentality being pushed to conform to an idealised parent figure derived from collective ideas of good parenthood. PMID- 27770449 TI - Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies. AB - Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 * 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 * 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage. PMID- 27770451 TI - Frequency of fetal karyotype abnormalities in women undergoing invasive testing in the absence of ultrasound and other high-risk indications. AB - OBJECTIVES: No previous studies have reported the frequencies of individual chromosomal anomalies in normal-appearing fetuses stratified by maternal age (MA) and gestational age (GA). We therefore sought to (1) characterize the frequency of all fetal karyotype anomalies in sonographically normal appearing fetuses without pretest risk factors, and (2) assess MA and GA impact on the proportion of anomalies targeted by screening and consequent impact on residual risk following a negative result. METHODS: Fetal karyotypes from samples without prior risk assessment or ultrasound anomalies were analyzed. We calculated, per single year MA and in two GA intervals, the predicted frequency of each cytogenetic defect. RESULTS: A total of 129 263 karyotypes were analyzed. The risk for significant, cytogenetically visible chromosomal anomalies, at 15 to 20 weeks GA, varies between 1/301 at MA of 18 years, and 1/9 at MA of 48 years. The proportion of clinically significant anomalies not addressed by current screening methods is 47% at MA of 18 years and 5% at MA of 48 years. CONCLUSIONS: By determining frequencies for individual karyotype anomalies stratified by MA and GA, in the setting of normal-appearing fetuses, a more personalized risk assessment, including the residual risk after a normal fetal aneuploidy screening result, can be provided. (c) 2016 John Wiley & Sons, Ltd. PMID- 27770453 TI - Capillary electrophoresis with contactless conductivity detection for the quantification of fluoride in lithium ion battery electrolytes and in ionic liquids-A comparison to the results gained with a fluoride ion-selective electrode. AB - In this study, an optimized method using capillary electrophoresis (CE) with a direct contactless conductivity detector (C4 D) for a new application field is presented for the quantification of fluoride in common used lithium ion battery (LIB) electrolyte using LiPF6 in organic carbonate solvents and in ionic liquids (ILs) after contacted to Li metal. The method development for finding the right buffer and the suitable CE conditions for the quantification of fluoride was investigated. The results of the concentration of fluoride in different LIB electrolyte samples were compared to the results from the ion-selective electrode (ISE). The relative standard deviations (RSDs) and recovery rates for fluoride were obtained with a very high accuracy in both methods. The results of the fluoride concentration in the LIB electrolytes were in very good agreement for both methods. In addition, the limit of detection (LOD) and limit of quantification (LOQ) values were determined for the CE method. The CE method has been applied also for the quantification of fluoride in ILs. In the fresh IL sample, the concentration of fluoride was under the LOD. Another sample of the IL mixed with Li metal has been investigated as well. It was possible to quantify the fluoride concentration in this sample. PMID- 27770452 TI - Cuticle hydrolysis in four medically important fly species by enzymes of the entomopathogenic fungus Conidiobolus coronatus. AB - Entomopathogenic fungi infect insects via penetration through the cuticle, which varies remarkably in chemical composition across species and life stages. Fungal infection involves the production of enzymes that hydrolyse cuticular proteins, chitin and lipids. Host specificity is associated with fungus-cuticle interactions related to substrate utilization and resistance to host-specific inhibitors. The soil fungus Conidiobolus coronatus (Constantin) (Entomophthorales: Ancylistaceae) shows virulence against susceptible species. The larvae and pupae of Calliphora vicina (Robineau-Desvoidy) (Diptera: Calliphoridae), Calliphora vomitoria (Linnaeus), Lucilia sericata (Meigen) (Diptera: Calliphoridae) and Musca domestica (Linnaeus) (Diptera: Muscidae) are resistant, but adults exposed to C. coronatus quickly perish. Fungus was cultivated for 3 weeks in a minimal medium. Cell-free filtrate, for which activity of elastase, N-acetylglucosaminidase, chitobiosidase and lipase was determined, was used for in vitro hydrolysis of the cuticle from larvae, puparia and adults. Amounts of amino acids, N-glucosamine and fatty acids released were measured after 8 h of incubation. The effectiveness of fungal enzymes was correlated with concentrations of compounds detected in the cuticles of tested insects. Positive correlations suggest compounds used by the fungus as nutrients, whereas negative correlations may indicate compounds responsible for insect resistance. Adult deaths result from the ingestion of conidia or fungal excretions. PMID- 27770454 TI - Oncological and functional outcomes of postoperative total parenteral nutrition after radical cystectomy in bladder cancer patients: A single-center randomized trial. AB - OBJECTIVES: To prospectively evaluate the long-term oncological and functional outcomes of postoperative total parenteral nutrition after radical cystectomy. METHODS: A total of 157 consecutive patients (<=cT3, cN0, cM0) who underwent extended pelvic lymph node dissection, radical cystectomy and ileal urinary diversion from September 2008 to March 2011 at a single center were randomized to receive either postoperative total parenteral nutrition (group A; n = 74) or oral nutrition alone (group B; n = 83). All but two patients in group B (who were thus excluded from further analysis) had regular postoperative follow up at the Department of Urology, University of Bern, Switzerland. Computed tomography and bone scan were carried out to assess local recurrences and distal metastases. We used validated questionnaires to evaluate bowel function, sexual function and quality of life, and an institutional questionnaire to evaluate neobladder function. RESULTS: The median follow up was 50 months (IQR 21-62). The rate of local recurrences (4/74 [5.4%] in group A; 4/81 [4.9%] in group B; P = 0.9) and the rate of distant metastases (23/74 [31%] in group A; 23/81 [28%] in group B; P = 0.72) did not differ between the two groups. There was no difference in cancer specific (P = 0.86) and overall survival (P = 0.85). Group B patients had significantly better bowel function at 3 months (P = 0.03) and 12 months (P = 0.01). There was no difference in terms of quality of life, and sexual and neobladder function. CONCLUSIONS: The administration of total parenteral nutrition after radical cystectomy does not impair long-term oncological outcomes. It does, however, negatively influence long-term bowel function. PMID- 27770455 TI - The Laterosensory Canal System in Epigean and Subterranean Ituglanis (Siluriformes: Trichomycteridae), With Comments About Troglomorphism and the Phylogeny of the Genus. AB - The laterosensory system is a mechanosensory modality involved in many aspects of fish biology and behavior. Laterosensory perception may be crucial for individual survival, especially in habitats where other sensory modalities are generally useless, such as the permanently aphotic subterranean environment. In the present study, we describe the laterosensory canal system of epigean and subterranean species of the genus Ituglanis (Siluriformes: Trichomycteridae). With seven independent colonizations of the subterranean environment in a limited geographical range coupled with a high diversity of epigean forms, the genus is an excellent model for the study of morphological specialization to hypogean life. The comparison between epigean and subterranean species reveals a trend toward reduction of the laterosensory canal system in the subterranean species, coupled with higher intraspecific variability and asymmetry. This trend is mirrored in other subterranean fishes and in species living in different confined spaces, like the interstitial environment. Therefore, we propose that the reduction of the laterosensory canal system should be regarded as a troglomorphic (= cave-related) character for subterranean fishes. We also comment about the patterns of the laterosensory canal system in trichomycterids and use the diversity of this system among species of Ituglanis to infer phylogenetic relationships within the genus. J. Morphol. 278:4-28, 2017. (c)(c) 2016 Wiley Periodicals,Inc. PMID- 27770456 TI - Control of asthma by omalizumab: the role of CD4+ Foxp3+ regulatory T cells. PMID- 27770457 TI - Autocalibrated wave-CAIPI reconstruction; Joint optimization of k-space trajectory and parallel imaging reconstruction. AB - PURPOSE: Fast MRI acquisitions often rely on efficient traversal of k-space and hardware limitations, or other physical effects can cause the k-space trajectory to deviate from a theoretical path in a manner dependent on the image prescription and protocol parameters. Additional measurements or generalized calibrations are typically needed to characterize the discrepancies. We propose an autocalibrated technique to determine these discrepancies. METHODS: A joint optimization is used to estimate the trajectory simultaneously with the parallel imaging reconstruction, without the need for additional measurements. Model reduction is introduced to make this optimization computationally efficient, and to ensure final image quality. RESULTS: We demonstrate our approach for the wave CAIPI fast acquisition method that uses a corkscrew k-space path to efficiently encode k-space and spread the voxel aliasing. Model reduction allows for the 3D trajectory to be automatically calculated in fewer than 30 s on standard vendor hardware. The method achieves equivalent accuracy to full-gradient calibration scans. CONCLUSIONS: The proposed method allows for high-quality wave-CAIPI reconstruction across wide ranges of protocol parameters, such as field of view (FOV) location/orientation, bandwidth, echo time (TE), resolution, and sinusoidal amplitude/frequency. Our framework should allow for the autocalibration of gradient trajectories from many other fast MRI techniques in clinically relevant time. Magn Reson Med 78:1093-1099, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27770459 TI - Experimental evolution of rhizobia may lead to either extra- or intracellular symbiotic adaptation depending on the selection regime. AB - Experimental evolution is a powerful approach to study the process of adaptation to new environments, including the colonization of eukaryotic hosts. Facultative endosymbionts, including pathogens and mutualists, face changing and spatially structured environments during the symbiotic process, which impose diverse selection pressures. Here, we provide evidence that different selection regimes, involving different times spent in the plant environment, can result in either intra- or extracellular symbiotic adaptations. In previous work, we introduced the symbiotic plasmid of Cupriavidus taiwanensis, the rhizobial symbiont of Mimosa pudica, into the phytopathogen Ralstonia solanacearum and selected three variants able to form root nodules on M. pudica, two (CBM212 and CBM349) being able to rudimentarily infect nodule cells and the third one (CBM356) only capable of extracellular infection of nodules. Each nodulating ancestor was further challenged to evolve using serial ex planta-in planta cycles of either 21 (three short-cycle lineages) or 42 days (three long-cycle lineages). In this study, we compared the phenotype of the 18 final evolved clones. Evolution through short and long cycles resulted in similar adaptive paths on lineages deriving from the two intracellularly infectious ancestors, CBM212 and CBM349. In contrast, only short cycles allowed a stable acquisition of intracellular infection in lineages deriving from the extracellularly infecting ancestor, CBM356. Long cycles, instead, favoured improvement of extracellular infection. Our work highlights the importance of the selection regime in shaping desired traits during host-mediated selection experiments. PMID- 27770460 TI - Alcohol hyper-responsiveness in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: An important percentage of subjects diagnosed with chronic upper airway disease report alcohol-induced worsening of their symptoms. The prevalence and characteristics of respiratory reactions provoked by alcohol-containing drinks have not been fully investigated yet. OBJECTIVE: The aim of this study was to estimate the prevalence and characteristics of alcohol hyper-responsiveness in patients with chronic airway disease and healthy controls. Furthermore, nasal inflammation was evaluated in nasal polyp patients with and without hyper responsiveness. METHODS: We evaluated the prevalence and characteristics of alcohol-induced respiratory complaints in 1281 subjects. Chronic rhinosinusitis with nasal polyps (CRSwNP) patients with and without NSAID exacerbated respiratory disease (NERD), chronic rhinosinusitis patients without nasal polyps (CRSsNP), allergic rhinitis (AR) patients and healthy controls were approached by means of a questionnaire. Inflammatory markers (eosinophilic cationic protein (ECP), IL-5, IgE, SAE-specific IgE, IL-17, TNFalpha and IFNgamma) in tissue were then compared between alcohol hyper-responsive and non-hyper-responsive CRSwNP patients. RESULTS: The highest prevalence of nasal and bronchial alcohol hyper responsiveness was observed in patients with NERD, followed by CRSwNP, and less frequent in CRSsNP, AR and healthy controls. Alcohol hyper-responsiveness is significantly more prevalent in CRSwNP patients suffering from recurrent disease and in patients with severe symptomatology. In nasal tissue of the hyper responsive CRSwNP group, we observed significantly higher nasal levels of the eosinophilic biomarker ECP. CONCLUSION AND CLINICAL RELEVANCE: Nasal hyper responsiveness to alcohol is significantly more prevalent in severe eosinophilic upper airway disease. PMID- 27770458 TI - Spectrally selective three-dimensional dynamic balanced steady-state free precession for hyperpolarized C-13 metabolic imaging with spectrally selective radiofrequency pulses. AB - PURPOSE: Balanced steady-state free precession (bSSFP) sequences can provide superior signal-to-noise ratio efficiency for hyperpolarized (HP) carbon-13 (13 C) magnetic resonance imaging by efficiently utilizing the nonrecoverable magnetization, but managing their spectral response is challenging in the context of metabolic imaging. A new spectrally selective bSSFP sequence was developed for fast imaging of multiple HP 13 C metabolites with high spatiotemporal resolution. THEORY AND METHODS: This novel approach for bSSFP spectral selectivity incorporates optimized short-duration spectrally selective radiofrequency pulses within a bSSFP pulse train and a carefully chosen repetition time to avoid banding artifacts. RESULTS: The sequence enabled subsecond 3D dynamic spectrally selective imaging of 13 C metabolites of copolarized [1-13 C]pyruvate and [13 C]urea at 2-mm isotropic resolution, with excellent spectral selectivity (~100:1). The sequence was successfully tested in phantom studies and in vivo studies with normal mice. CONCLUSION: This sequence is expected to benefit applications requiring dynamic volumetric imaging of metabolically active 13 C compounds at high spatiotemporal resolution, including preclinical studies at high field and, potentially, clinical studies. Magn Reson Med 78:963-975, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27770461 TI - Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum. AB - : Tissue-resident macrophages and bone marrow (BM)-derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte-specific Cflar-deficient (CflarHep-low ) mice. Cellular FLICE inhibitory protein expression was down-regulated in Cflar-deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor-induced apoptosis. CflarHep-low mice developed acute hepatitis and recovered with clearance of apoptotic hepatocytes at 24 hours after injection of low doses of tumor necrosis factor alpha (TNFalpha), which could not induce hepatitis in wild type (WT) mice. Depletion of Kupffer cells (KCs) by clodronate liposomes did not impair clearance of dying hepatocytes or exacerbate hepatitis in CflarHep-low mice. To elucidate the roles of BM-derived monocytes and neutrophils in clearance of apoptotic hepatocytes, we examined the effect of depletion of these cells on TNFalpha-induced hepatitis in CflarHep-low mice. We reconstituted CflarHep-low mice with BM cells from transgenic mice in which human diphtheria toxin receptor (DTR) was expressed under control of the lysozyme M (LysM) promoter. TNFalpha induced infiltration of myeloid cells, including monocytes and neutrophils, was completely ablated in LysM-DTR BM-reconstituted CflarHep-low mice pretreated with diphtheria toxin, whereas KCs remained present in the livers. Under these experimental conditions, LysM-DTR BM-reconstituted CflarHep-low mice rapidly developed severe hepatitis and succumbed within several hours of TNFalpha injection. We found that serum interleukin-6 (IL-6), TNFalpha, and histone H3 were aberrantly increased in LysM-DTR BM-reconstituted, but not in WT BM reconstituted, CflarHep-low mice following TNFalpha injection. CONCLUSION: These findings indicate an unexpected role of myeloid cells in decreasing serum IL-6, TNFalpha, and histone H3 levels via the suppression of TNFalpha-induced hepatocyte apoptosis. (Hepatology 2017;65:237-252). PMID- 27770463 TI - Associations between postpartum depressive symptoms and childhood asthma diminish with child age. AB - BACKGROUND: Affecting 19% of women, postpartum depression is a major concern to the immediate health of mothers and infants. In the long-term, it has been linked to the development of early-onset asthma at school entry, but only if the depression persists beyond the postnatal period. No studies have tested whether associations with postpartum depressive symptoms and early-onset asthma phenotypes persist into later school age. OBJECTIVE: To determine associations between maternal postpartum depressive symptoms and childhood asthma between the ages of 5-10 by using a nested longitudinal design. METHODS: Data were drawn from the 1994-2004 administrations of the Canadian National Longitudinal Survey of Children and Youth, which tracks the health of a nationally representative sample of children in Canada. Child asthma was diagnosed by a health professional, and maternal depressive symptoms were assessed by the Centre for Epidemiological Studies Depression scale. Analyses were conducted by using a multilevel modelling approach, in which longitudinal assessments of asthma in 1696 children were nested within the exposure of postpartum depression. RESULTS: Postpartum depressive symptoms had a 1.5-fold significant association with childhood asthma between the ages 6-8. This was independent of male sex, maternal asthma, non immigrant status, low household socioeconomic status, being firstborn, low birthweight, low family functioning and urban-rural residence, of which the first 4 covariates elevated the risk of asthma. Statistical significance was lost at age 8 when maternal prenatal smoking replaced urban-rural residence as a covariate. At ages 9-10, an association was no longer evident. CONCLUSIONS AND CLINICAL RELEVANCE: Women affected by postpartum depressive symptoms are concerned about long-term health effects of their illness on their infants. Although postpartum depressive symptoms were associated with school-age asthma at ages 6 and 7, this association diminished later. Both home and school life stress should be considered in future studies on asthma development later in childhood. PMID- 27770462 TI - IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. AB - : Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway. Whereas IL-6 classic signaling is important for innate and acquired immunity, IL-6 trans signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA-damage-induced hepatocyte apoptosis through suppression of p53 and enhances beta-catenin activation and tumor proliferation. Second, IL-6 trans-signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL-6 trans-signaling are largely protected from tumor formation in a diethylnitrosamine/3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene model of HCC. CONCLUSION: IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103). PMID- 27770464 TI - In Vivo Pig-a gene mutation assay: Guidance for 3Rs-friendly implementation. AB - The rodent Pig-a assay is an in vivo method for the detection of gene mutation, where lack of glycosylphosphatidylinositol-anchored proteins on the surface of circulating red blood cells (RBCs) serves as a reporter for Pig-a gene mutation. In the case of rats, the frequency of mutant phenotype RBCs is measured via fluorescent anti-CD59 antibodies and flow cytometry. The Pig-a assay meets the growing expectations for novel approaches in animal experimentation not only focusing on the scientific value of the assay but also on animal welfare aspects (3Rs principles), for example, amenable to integration into pivotal rodent 28-day general toxicology studies. However, as recommended in the Organisation for Economic Co-operation and Development Test Guidelines for genotoxicity testing, laboratories are expected to demonstrate their proficiency. While this has historically involved the extensive use of animals, here we describe an alternative approach based on a series of blood dilutions covering a range of mutant frequencies. The experiments described herein utilized either non fluorescent anti-CD59 antibodies to provide elevated numbers of mutant-like cells, or a low volume blood sample from a single N-ethyl-N-nitrosourea treated animal. Results from these so-called reconstruction experiments from four independent laboratories showed good overall precision (correlation coefficients: 0.9979-0.9999) and accuracy (estimated slope: 0.71-1.09) of mutant cell scoring, which was further confirmed by Bland-Altman analysis. These data strongly support the use of reconstruction experiments for training purposes and demonstrating laboratory proficiency with very few animals, an ideal situation given the typically conflicting goals of demonstrating laboratory proficiency and reducing the use of animals. Environ. Mol. Mutagen. 57:678-686, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27770465 TI - Perception of Impossible Scenes Reveals Differential Hippocampal and Parahippocampal Place Area Contributions to Spatial Coherency. AB - Surprisingly little is known about how the brain combines spatial elements to form a coherent percept. Regions that may underlie this process include the hippocampus (HC) and parahippocampal place area (PPA), regions central to spatial perception but whose role in spatial coherency has not been explored. Participants were scanned with functional MRI while they judged whether Escher like scenes were possible or impossible. Univariate analyses revealed differential HC and PPA involvement, with greater HC activity during spatial incoherency detection and more PPA activity during spatial coherency detection. Recognition and eye-tracking data ruled out long- or short-term memory confounds. Multivariate statistics demonstrated spatial coherency-dependent functional connectivity for the HC, but not PPA, with greater HC connectivity to various brain regions including lateral occipital complex during spatial incoherency detection. We suggest the PPA is preferentially involved during the perception of spatially coherent scenes, whereas the HC binds distinct features to create coherent representations. (c) 2016 Wiley Periodicals, Inc. PMID- 27770466 TI - Developmental effects of visual environment on species-assortative mating preferences in Lake Victoria cichlid fish. AB - Local adaptation can be a potent force in speciation, with environmental heterogeneity leading to niche specialization and population divergence. However, local adaption often requires nonrandom mating to generate reproductive isolation. Population divergence in sensory properties can be particularly consequential in speciation, affecting both ecological adaptation and sexual communication. Pundamilia pundamila and Pundamilia nyererei are two closely related African cichlid species that differ in male coloration, blue vs. red. They co-occur at rocky islands in southern Lake Victoria, but inhabit different depth ranges with different light environments. The species differ in colour vision properties, and females exert species-specific preferences for blue vs. red males. Here, we investigated the mechanistic link between colour vision and preference, which could provide a rapid route to reproductive isolation. We tested the behavioural components of this link by experimentally manipulating colour perception - we raised both species and their hybrids under light conditions mimicking shallow and deep habitats - and tested female preference for blue and red males under both conditions. We found that rearing light significantly affected female preference: shallow-reared females responded more strongly to P. pundamilia males and deep-reared females favoured P. nyererei males - implying that visual development causally affects mate choice. These results are consistent with sensory drive predictions, suggesting that the visual environment is key to behavioural isolation of these species. However, the observed plasticity could also make the species barrier vulnerable to environmental change: species-assortative preferences were weaker in females that were reared in the other species' light condition. PMID- 27770467 TI - Pre- and probiotics for allergy prevention: time to revisit recommendations? AB - Reduced intensity and diversity of microbial exposure is considered a major factor driving abnormal postnatal immune maturation and increasing allergy prevalence, particularly in more affluent regions. Quantitatively, the largest important source of early immune-microbial interaction, the gut microbiota, is of particular interest in this context, with variations in composition and diversity in the first months of life associated with subsequent allergy development. Attempting to restore the health consequences of the 'dysbiotic drift' in modern society, interventions modulating gut microbiota for allergy prevention have been evaluated in several randomized placebo-controlled trials. In this review, we provide an overview of these trials and discuss recommendations from international expert bodies regarding prebiotic, probiotic and synbiotic interventions. Recent guidelines from the World Allergy Organization recommend the use of probiotics for the primary prevention of eczema in pregnant and breastfeeding mothers of infants at high risk for developing allergy and in high risk infants. It is however stressed that these recommendations are conditional, based on very low-quality evidence and great heterogeneity between studies, which also impedes specific and practical advice to consumers on the most effective regimens. We discuss how the choice of probiotic strains, timing and duration of administration can critically influence the outcome due to different effects on immune modulation and gut microbiota composition. Furthermore, we propose strategies to potentially improve allergy-preventive effects and enable future evidence-based implementation. PMID- 27770468 TI - Impact of biomaterial microtopography on bone regeneration: comparison of three hydroxyapatites. AB - AIMS: The primary objective of this study was to compare the in vivo performance, namely in terms of quantity of newly formed bone and bone-to-material contact (osteoconductivity), of three hydroxyapatite-based biomaterials (HA) of different origins (natural or synthetic) or manufacturing process in a sinus lift model in rabbits. The secondary objective was to correlate the findings with the physical and topographical characteristics of the biomaterials. MATERIALS AND METHODS: Two bovine HA manufactured with different processes (bovine hydroxyapatites [BHA] and cuttlebone hydroxyapatite [CBHA]) and a synthetic hydroxyapatite (SHA) sintered at high temperature were characterised with scanning electronic microscopy (SEM) and the measurement of specific surface area (BET). The materials were implanted in a sinus lift model in rabbits; histological and histomorphometric evaluation using non-decalcified sections was performed at 1, 5 and 12 weeks after implantation. RESULTS: The studied biomaterials displayed a different surface topography. The two natural HA displayed significantly higher bone quantities (P = 0.0017; BHA vs. SHA, P = 0.0018 and CBHA vs. SHA, P = 0.033) at 5 and 12 weeks compared to the synthetic one (SHA). Moreover, the osteoconductivity (bone-to material contact) was significantly higher in the BHA group compared to the two other groups (P = 0.014; BHA vs. SHA, P = 0.023 and BHA vs. CBHA, P = 0.033). CONCLUSION: HA-based biomaterials from diverse origins and manufacturing processes displayed different topographical characteristics. This may have influenced different regenerated bone architecture observed; more bone was found with natural HA compared to the synthetic one, and significantly higher bone-to material contacts were found with BHA. PMID- 27770469 TI - Toward imaging the body at 10.5 tesla. AB - PURPOSE: To explore the potential of performing body imaging at 10.5 Tesla (T) compared with 7.0T through evaluating the transmit/receive performance of similarly configured dipole antenna arrays. METHODS: Fractionated dipole antenna elements for 10.5T body imaging were designed and evaluated using numerical simulations. Transmit performance of antenna arrays inside the prostate, kidneys and heart were investigated and compared with those at 7.0T using both phase-only radiofrequency (RF) shimming and multi-spoke pulses. Signal-to-noise ratio (SNR) comparisons were also performed. A 10-channel antenna array was constructed to image the abdomen of a swine at 10.5T. Numerical methods were validated with phantom studies at both field strengths. RESULTS: Similar power efficiencies were observed inside target organs with phase-only shimming, but RF nonuniformity was significantly higher at 10.5T. Spokes RF pulses allowed similar transmit performance with accompanying local specific absorption rate increases of 25-90% compared with 7.0T. Relative SNR gains inside the target anatomies were calculated to be >two-fold higher at 10.5T, and 2.2-fold SNR gain was measured in a phantom. Gradient echo and fast spin echo imaging demonstrated the feasibility of body imaging at 10.5T with the designed array. CONCLUSION: While comparable power efficiencies can be achieved using dipole antenna arrays with static shimming at 10.5T; increasing RF nonuniformities underscore the need for efficient, robust, and safe parallel transmission methods. Magn Reson Med 77:434 443, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27770471 TI - Empowering women: Perspective from a hepatologist. PMID- 27770470 TI - Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET. AB - Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BPND ) in patients with ADHD and to assess associations of SERT BPND between the brain regions. 25 medication-free patients with ADHD (age +/- SD; 32.39 +/- 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 +/- 10.20) were measured once with PET and the highly selective and specific radioligand [11 C]DASB. SERT BPND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BPND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BPND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R2 = 0.284, R2 = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27770472 TI - WhatsApp is an effective tool for obtaining second opinion in oral pathology practice. AB - BACKGROUND: The aim of this study was to find out the efficacy of WhatsApp application for obtaining second opinion on histopathological diagnosis in oral pathology practice. METHODS: A total of 247 cases comprising of 34 different oral pathologies were photomicrographed using smartphone cameras through compound microscopes and sent for second opinion diagnosis (SOD) to 20 different oral pathologists using WhatsApp. RESULTS: Of 4795 (97.06%) total second opinion received, correct SOD were received for 4710 (98.22%) cases. Hundred percent times correct SOD was received for lesions including adenomatoid odontogenic tumor, keratinizing cystic odontogenic tumor, odontome, and dentigerous cyst. Lesions such as myoepithelial carcinoma, osteosarcoma, fibrosarcoma, and intravascular papillary endothelial hyperplasia received less percentage of correct SOD (85.71-75.75%). Correct SOD was obtained for variants of ameloblastoma (99.01%), grading of epithelial dysplasia (87.54%), and squamous cell carcinoma (95.26%). A positive correlation was observed between correct SOD and age (P = 0.0143) and experience (P = 0.0189) of the pathologist. The time taken for giving second opinion by the pathologists ranged from 81.98 +/- 32.89 to 90.72 +/- 38.88 min. CONCLUSION: Smartphone camera is a handy and efficient tool in capturing photomicrographs from the compound microscope. Transfer of such photomicrograph via WhatsApp is an effective and convenient approach in procuring second opinion on histopathological diagnosis of oral pathologies. PMID- 27770473 TI - Single-shot spiral imaging enabled by an expanded encoding model: Demonstration in diffusion MRI. AB - PURPOSE: The purpose of this work was to improve the quality of single-shot spiral MRI and demonstrate its application for diffusion-weighted imaging. METHODS: Image formation is based on an expanded encoding model that accounts for dynamic magnetic fields up to third order in space, nonuniform static B0 , and coil sensitivity encoding. The encoding model is determined by B0 mapping, sensitivity mapping, and concurrent field monitoring. Reconstruction is performed by iterative inversion of the expanded signal equations. Diffusion-tensor imaging with single-shot spiral readouts is performed in a phantom and in vivo, using a clinical 3T instrument. Image quality is assessed in terms of artefact levels, image congruence, and the influence of the different encoding factors. RESULTS: Using the full encoding model, diffusion-weighted single-shot spiral imaging of high quality is accomplished both in vitro and in vivo. Accounting for actual field dynamics, including higher orders, is found to be critical to suppress blurring, aliasing, and distortion. Enhanced image congruence permitted data fusion and diffusion tensor analysis without coregistration. CONCLUSION: Use of an expanded signal model largely overcomes the traditional vulnerability of spiral imaging with long readouts. It renders single-shot spirals competitive with echo-planar readouts and thus deploys shorter echo times and superior readout efficiency for diffusion imaging and further prospective applications. Magn Reson Med 77:83-91, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27770474 TI - Getting care of older people right: the need for appropriate frailty assessment? PMID- 27770475 TI - Long-term outcomes in patients with multiple endocrine neoplasia type 1 and pancreaticoduodenal neuroendocrine tumours. AB - BACKGROUND: In patients with multiple endocrine neoplasia type 1 (MEN-1), pancreaticoduodenal (PD) neuroendocrine tumours (NETs) are associated with early mortality, yet the best treatment strategy remains uncertain. AIM: To assess patient important outcomes (mortality and metastasis) of PD-NETs and predictors of outcomes in patients with MEN-1. METHODS: Retrospective cohort of patients with MEN-1 who attended the Mayo Clinic, Rochester, MN from 1997 to 2014. RESULTS: We identified 287 patients with MEN-1; 199 (69%) patients had 217 PD NETs. Among those with a PD-NETs, 129 (65%) had surgery of which 90 (70%) had their primary surgery performed at Mayo Clinic. The median postoperative follow up was 8 years during which 13 (14%) patients died. The mean (+/-standard deviation) age of death was 51 (+/-9) years. Tumour size, metastasis at surgery or tumour type were not predictive of mortality, but for every year older at surgery, the odds of metastasis increased by 6%. Surgery was not performed in 70 (35%) patients. Among those who were observed/medically managed without known metastatic disease, mean tumour growth was 0.02 cm/year (range, -0.13-0.4 cm/year). Four patients (7%) died at a median age of 77 (range, 51-89) years. CONCLUSION: PD-NETs are common in patients with MEN-1 and are associated with early mortality even after surgical intervention. Active surveillance is a viable option in nonaggressive PD-NETs, although definitive factors identifying such patients are lacking. Therefore, counselling regarding risks and benefits of current treatment options remains integral to the care of patients with MEN-1. PMID- 27770476 TI - Familiarity expands space and contracts time. AB - When humans draw maps, or make judgments about travel-time, their responses are rarely accurate and are often systematically distorted. Distortion effects on estimating time to arrival and the scale of sketch-maps reveal the nature of mental representation of time and space. Inspired by data from rodent entorhinal grid cells, we predicted that familiarity to an environment would distort representations of the space by expanding the size of it. We also hypothesized that travel-time estimation would be distorted in the same direction as space size, if time and space rely on the same cognitive map. We asked international students, who had lived at a college in London for 9 months, to sketch a south-up map of their college district, estimate travel-time to destinations within the area, and mark their everyday walking routes. We found that while estimates for sketched space were expanded with familiarity, estimates of the time to travel through the space were contracted with familiarity. Thus, we found dissociable responses to familiarity in representations of time and space. (c) 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID- 27770477 TI - IgE and allergen-specific immunotherapy-induced IgG4 recognize similar epitopes of Bet v 1, the major allergen of birch pollen. AB - BACKGROUND: Allergen-specific immunotherapy (AIT) with birch pollen generates Bet v 1-specific immunoglobulin (Ig)G4 which blocks IgE-mediated hypersensitivity mechanisms. Whether IgG4 specific for Bet v 1a competes with IgE for identical epitopes or whether novel epitope specificities of IgG4 antibodies are developed is under debate. OBJECTIVE: We sought to analyze the epitope specificities of IgE and IgG4 antibodies from sera of patients who received AIT. METHODS: 15 sera of patients (13/15 received AIT) with Bet v 1a-specific IgE and IgG4 were analyzed. The structural arrangements of recombinant (r)Bet v 1a and rBet v 1a_11x , modified in five potential epitopes, were analyzed by circular dichroism and nuclear magnetic resonance spectroscopy. IgE binding to Bet v 1 was assessed by ELISA and mediator release assays. Competitive binding of monoclonal antibodies specific for Bet v 1a and serum IgE/IgG4 to rBet v 1a and serum antibody binding to a non-allergenic Bet v 1-type model protein presenting an individual epitope for IgE was analyzed in ELISA and western blot. RESULTS: rBet v 1a_11x had a Bet v 1a - similar secondary and tertiary structure. Monomeric dispersion of rBet v 1a_11x was concentration and buffer-dependent. Up to 1500-fold increase in the EC50 for IgE-mediated mediator release induced by rBet v 1a_11x was determined. The reduction of IgE and IgG4 binding to rBet v 1a_11x was comparable in 67% (10/15) of sera. Bet v 1a-specific monoclonal antibodies inhibited binding of serum IgE and IgG4 to 66.1% and 64.9%, respectively. Serum IgE and IgG4 bound specifically to an individual epitope presented by our model protein in 33% (5/15) of sera. CONCLUSION AND CLINICAL RELEVANCE: Patients receiving AIT develop Bet v 1a-specific IgG4 which competes with IgE for partly identical or largely overlapping epitopes. The similarities of epitopes for IgE and IgG4 might stimulate the development of epitope-specific diagnostics and therapeutics. PMID- 27770479 TI - Hidden mechanisms beyond the pupillary block in acute angle closure: ultrasound biomicroscopic study. AB - BACKGROUND: To evaluate the mechanisms of acute angle closure (AAC) other than the pupillary block using ultrasound biomicroscopy. DESIGN: Retrospective chart review. PARTICIPANTS: All patients who were diagnosed with AAC in Ramathibodi Hospital, Bangkok, Thailand, between June 2011 and February 2015 were enrolled. METHODS: Seventy-two patients who were diagnosed with AAC underwent a detailed ocular examination. The diagnosed mechanism of AAC was confirmed by UBM and ocular biometry. MAIN OUTCOME MEASURES: Primary mechanism responsible for acute angle closure. RESULTS: In 72 patients, the mean age was 62.33 +/- 10.4 years, 18 (25%) patients were male and 54 (75%) patients were female. The primary mechanism of AAC was iridolenticular wrapping (crowded-angle (CR) plus anterior lens subluxation (LS)) in 49 eyes (68.1%), pupillary block (PB) in 17 (23.6%) eyes, and plateau iris (PL) in 6 (8.3%) eyes. Thirty (41.7%) out of 72 eyes without previous iridotomy before UBM examination were analyzed. The most common primary mechanism in this group was iridolenticular wrapping (20 eyes, 66.7%). There were seven (23.3%) eyes that had a pupillary block, and only three (10.0%) eyes had plateau iris syndrome as the primary mechanism of AAC. There was a single mechanism in 14 (46.7%) eyes, and there were combined mechanisms in 16 (53.3%) eyes. CONCLUSIONS: The most common mechanism contributing to AAC development in this Thai population was iridolenticular wrapping. From this study, we suggest that iridolenticular wrapping was the most common hidden mechanism beyond pupillary block among Thai patients. PMID- 27770478 TI - Deriving frequency-dependent spatial patterns in MEG-derived resting state sensorimotor network: A novel multiband ICA technique. AB - Recently, independent components analysis (ICA) of resting state magnetoencephalography (MEG) recordings has revealed resting state networks (RSNs) that exhibit fluctuations of band-limited power envelopes. Most of the work in this area has concentrated on networks derived from the power envelope of beta bandpass-filtered data. Although research has demonstrated that most networks show maximal correlation in the beta band, little is known about how spatial patterns of correlations may differ across frequencies. This study analyzed MEG data from 18 healthy subjects to determine if the spatial patterns of RSNs differed between delta, theta, alpha, beta, gamma, and high gamma frequency bands. To validate our method, we focused on the sensorimotor network, which is well-characterized and robust in both MEG and functional magnetic resonance imaging (fMRI) resting state data. Synthetic aperture magnetometry (SAM) was used to project signals into anatomical source space separately in each band before a group temporal ICA was performed over all subjects and bands. This method preserved the inherent correlation structure of the data and reflected connectivity derived from single-band ICA, but also allowed identification of spatial spectral modes that are consistent across subjects. The implications of these results on our understanding of sensorimotor function are discussed, as are the potential applications of this technique. Hum Brain Mapp 38:779-791, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27770480 TI - Agreement between quantitative and qualitative sensory testing of changes in oro facial somatosensory sensitivity. AB - Qualitative somatosensory testing (QualST) is a simple chairside test. It can be used to roughly assess the presence or absence of altered somatosensory function. To use QualST clinically, it is important to assess its agreement with quantitative sensory testing (QST). The aims of this study were to assess the agreement between QST and QualST when testing the modulation of facial sensitivity by capsaicin in healthy participants and to explore the agreement between QST and QualST in assessing the intraoral sensory function in clinical atypical odontalgia (AO) patients. Eighteen healthy pain-free adults and data from 27 AO patients were included in the study. Thirteen QST and three QualST parameters were evaluated at each site. Z-scores were computed for healthy participants, and Loss-Gain scores were created. The agreement observed between QST and QualST in participants with no alterations in facial sensation (placebo) was good, that is ranging from 89% to 94%. A poorer agreement was seen after capsaicin application in all test modalities with agreement ranging from 50% to 72%. The commonest misclassification observed was participants classified as normal according to QST, but hyper- or hyposensitive according to QualST after capsaicin application, especially for cold and pinprick. A similar trend was observed in AO patients where patients classified as normal using QST were misclassified as hypersensitive and in few patients as hyposensitive by QualST. In conclusion, the study showed that QualST may be used as a screening tool in the clinical setting, especially to show that subjects have normal sensory function. PMID- 27770481 TI - Biocidal Compounds from Mentha sp. Essential Oils and Their Structure-Activity Relationships. AB - Essential oils from Greek Mentha species showed different chemical compositions for two populations of M. pulegium, characterized by piperitone and pulegone. Mentha spicata essential oil was characterized by endocyclic piperitenone epoxide, piperitone epoxide, and carvone. The bioactivities of these essential oils and their components have been tested against insect pests (Leptinotarsa decemlineata, Spodoptera littoralis and Myzus persicae), root-knot nematodes (Meloydogine javanica) and plants (Lactuca sativa, Lolium perenne, Solanum lycopersicum). The structure-activity relationships of these compounds have been studied including semi-synthetic endocyclic trans-carvone epoxide, exocyclic carvone epoxide, a new exocyclic piperitenone epoxide and trans-pulegone epoxide. Leptinotarsa decemlineata feeding was affected by piperitenone and piperitone epoxide. Spodoptera littoralis was affected by piperitone epoxide and pulegone. The strongest nematicidal agent was piperitenone epoxide, followed by piperitone epoxide, piperitenone and carvone. Germination of S. lycopersicum and L. perenne was significantly affected by piperitenone epoxide. This compound and carvone epoxide inhibited L. perenne root and leaf growth. Piperitenone epoxide also inhibited the root growth of S. lycopersicum. The presence of a C(1) epoxide resulted in strong antifeedant, nematicidal and phytotoxic compounds regardless of the C(4) substituent. New natural crop protectants could be developed through appropriate structural modifications in the p-menthane skeleton. PMID- 27770482 TI - A glycoprotein alpha-amylase inhibitor from Withania somnifera differentially inhibits various alpha-amylases and affects the growth and development of Tribolium castaneum. AB - BACKGROUND: Identification and characterisation of plant defensive molecules enrich our resources to design crop protection strategies. In particular, plant derived proteinaceous inhibitor(s) of insect digestive enzymes appear to be a safe, sustainable and attractive option. RESULTS: A glycoprotein having non competitive alpha-amylase inhibitory activity with a molecular weight of 8.3 kDa was isolated and purified from seeds of Withania somnifera alpha-amylase inhibitor (WSAI). Its mass spectrometry analysis revealed 59% sequence coverage with Wrightide II-type alpha-amylase inhibitor from Wrightia religiosa. A dose dependent inhibition of alpha-amylases from Aspergillus oryzae, Bacillus subtilis, Helicoverpa armigera and Tribolium castaneum was recorded. Interestingly, WSAI did not inhibit human salivary alpha-amylase significantly. When adults of T. castaneum were fed with WSAI (1.6 mg g-1 ), decrease in consumption, growth and efficiency of conversion of ingested food was evident, along with over fourfold increases in feeding deterrence index. A decline in larval residual alpha-amylase activity after feeding of WSAI resulted in a reduction in longevity of T. castaneum. CONCLUSION: The study reflects the significance of WSAI in affecting the overall growth and development of T. castaneum. Pre- and post-harvest pest resistive capability makes WSAI a potential candidate for insect pest management. Further, the effectiveness of this inhibitor could be explored either in formulations or through a transgenic approach. (c) 2016 Society of Chemical Industry. PMID- 27770483 TI - An economic evaluation of planned immediate versus delayed birth for preterm prelabour rupture of membranes: findings from the PPROMT randomised controlled trial. AB - OBJECTIVE: This study is an economic evaluation of immediate birth compared with expectant management in women with preterm prelabour rupture of the membranes near term (PPROMT). DESIGN: A cost-effectiveness analysis alongside the PPROMT randomised controlled trial. SETTING: Obstetric departments in 65 hospitals across 11 countries. POPULATION: Women with a singleton pregnancy with ruptured membranes between 34+0 and 36+6 weeks gestation. METHODS: Women were randomly allocated to immediate birth or expectant management. Costs to the health system were identified and valued. National hospital costing data from both the UK and Australia were used. Average cost per recruit in each arm was calculated and 95% confidence intervals were estimated using bootstrap re-sampling. Averages costs during antenatal care, delivery and postnatal care, and by country were estimated. MAIN OUTCOMES MEASURES: Total mean cost difference between immediate birth and expectant management arms of the trial. RESULTS: From 11 countries 923 women were randomised to immediate birth and 912 were randomised to expectant management. Total mean costs per recruit were L8852 for immediate birth and L8740 for expectant delivery resulting in a mean difference in costs of L112 (95% CI: 431 to 662). The expectant management arm had significantly higher antenatal costs, whereas the immediate birth arm had significantly higher delivery and neonatal costs. There was large variation between total mean costs by country. CONCLUSION: This economic evaluation found no evidence that expectant management was more or less costly than immediate birth. Outpatient management may offer opportunities for cost savings for those women with delayed delivery. TWEETABLE ABSTRACT: For women with preterm prelabour rupture of the membranes, the relative benefits and harms of immediate and expectant management should inform counselling as costs are similar. PMID- 27770485 TI - 3,5-diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. AB - AIM: Thyroid hormones regulate metabolic response. While triiodothyronine (T3) is usually considered to be the active form of thyroid hormone, one form of diiodothyronine (3,5-T2) exerts T3-like effects on energy consumption and lipid metabolism. 3,5-T2 also improves glucose tolerance in rats and 3,5-T2 levels correlate with fasting glucose in humans. Presently, however, little is known about mechanisms of 3,5-T2 effects on glucose metabolism. Here, we set out to compare effects of T3, 3,5-T2 and another form of T2 (3,3-T2) in a mouse model of diet-induced obesity and determined effects of T3 and 3,5-T2 on markers of classical insulin sensitization to understand how diiodothyronines influence blood glucose. METHODS: Cell- and protein-based assays of thyroid hormone action. Assays of metabolic parameters in mice. Analysis of transcript and protein levels in different tissues by qRT-PCR and Western blot. RESULTS: T3 and 3,5-T2 both reduce body weight, adiposity and body temperature despite increased food intake. 3,3'-T2 lacks these effects. T3 and 3,5-T2 reduce blood glucose levels, whereas 3,3'-T2 worsens glucose tolerance. Neither T3 nor 3,5-T2 affects markers of insulin sensitization in skeletal muscle or white adipose tissue (WAT), but both reduce hepatic GLUT2 glucose transporter levels and glucose output. T3 and 3,5-T2 also induce expression of mitochondrial uncoupling proteins (UCPs) 3 and 1 in skeletal muscle and WAT respectively. CONCLUSIONS: 3,5-T2 influences glucose metabolism in a manner that is distinct from insulin sensitization and involves reductions in hepatic glucose output and changes in energy utilization. PMID- 27770484 TI - Medical therapies for heavy menstrual bleeding in women with uterine fibroids: a retrospective analysis of a large commercially insured population in the USA. AB - OBJECTIVES: To report patterns and patient characteristics associated with initiation of and persistence with medical therapies for uterine fibroid-related heavy menstrual bleeding. DESIGN: Retrospective cohort study. SETTING: US commercial insurance claims database. POPULATION: 41 561 women aged 18-54 years with uterine fibroids and heavy menstrual bleeding who initiated medical therapies from January 2000 through December 2013. METHOD: Multinomial logistic regression was used to assess patient characteristics associated with initiation and persistence. Cox proportional hazards regression was used on propensity score matched cohorts to examine change from index medication. MAIN OUTCOMES MEASURES: Initiation of and persistence with four first-line medical therapies: short- and long-acting reversible contraceptive steroids, leuprolide acetate, and tranexamic acid. RESULTS: Most women (79.4%) took short-acting reversible contraceptive steroids as first-line therapy (index medication), whereas 9.5%, 8.5%, and 2.7% used long-acting reversible contraceptive steroids, leuprolide acetate, and tranexamic acid, respectively. During follow-up, 16 594 women (39.9%) switched to nonindex medication (18.4%) or procedural treatment (81.6%). In comparison with women taking short-acting steroids, those receiving long-acting steroids were less likely to switch [hazard ratio (HR) 0.84, 95% CI 0.79-0.91], whereas women taking leuprolide acetate (HR 2.44, 95% CI 2.27-2.62) or tranexamic acid (HR 1.44, 95% CI 1.26-1.65) were more likely to switch. Older age, emergency department visits, anaemia, and inflammatory disease diagnoses at baseline were associated with increased probability of discontinuing the index medication or switching to another therapy. CONCLUSIONS: Women with uterine fibroid-related heavy menstrual bleeding were more likely to persist with their initial therapy of long-acting reversible contraceptive steroid compared with other medical options. TWEETABLE ABSTRACT: 80% women with fibroid-related heavy menstrual bleeding use SARC, but LARC users are more persistent. PMID- 27770486 TI - Nutritional status and weakness following pediatric hematopoietic cell transplantation. AB - Survivorship after pediatric HCT has increased over the past decade. Focus on long-term care and well-being remains critical due to risk of poor dietary habits and exaggerated sedentary behavior, which can lead to muscle weakness, increased risk for obesity, and cardiometabolic disorders. Nutrition and physical activity are key factors in survivorship; however, data are limited. Comprehensive nutritional assessments, including nutrition-focused physical examination, grip strength, and food/activity surveys, were completed in 36 pediatric HCT survivors (aged 2-25 years). Patients were divided into undernutrition, normal-nutrition, and overnutrition categories. Fifty percent of participants were classified as normal nutrition, 22% undernutrition, and 28% overnutrition. Few patients met the U.S. Dietary Guidelines recommended intake for vegetables, fiber, saturated fat, and So FAS. Patients in the undernutrition group demonstrated significantly lower grip strength than those in the normal- and overnutrition groups. When grip strength was normalized to body mass, patients in the overnutrition group had the highest prevalence of weakness. Using NHANES reference data, maximum grip strength and NGS cutoffs were identified that could significantly distinguish the nutrition groups. Comprehensive nutritional assessments and grip strength measurements are feasible, non-invasive, easy to perform, and inform both under- and overnutrition in pediatric HCT survivors. PMID- 27770487 TI - Medial Ganglionic Eminence Cells Freshly Obtained or Expanded as Neurospheres Show Distinct Cellular and Molecular Properties in Reducing Epileptic Seizures. AB - AIMS: Medial ganglionic eminence (MGE) progenitors give rise to inhibitory interneurons and may serve as an alternative cell source for large-scale cell transplantation for epilepsy after in vitro expansion. We investigated whether modifications in the culture medium of MGE neurospheres affect neuronal differentiation and expression of MGE-specific genes. In vivo, we compared anticonvulsant effects and cell differentiation pattern among neurospheres grown in different culture media and compared them with freshly harvested MGE cells. METHODS: We used four variations of cell culture: standard, containing growth factors (EGF/FGF-2) (GF); addition of retinoic acid (GF-RA); withdrawal of EGF/FGF-2 (WD); and addition of retinoic acid and withdrawal of EGF/FGF-2 (WD RA). Based on in vitro results neurosphere-grown (WD-RA or GF conditions) or fresh MGE cells were transplanted into the hippocampus. RESULTS: In vitro WD-RA showed increased neuronal population and higher expression of Dlx1, Nkx2.1, and Lhx6 genes in comparison with GF culture condition. After transplantation, fresh MGE cells and neurospheres (GF) showed anticonvulsant effects. However, fresh MGE cells differentiated preferentially into inhibitory neurons, while GF gave rise to glial cells. CONCLUSION: We conclude that freshly isolated and neurosphere grown MGE cells reduced seizures by different mechanisms (inhibitory interneurons vs. astrocytes). Fresh MGE cells appear more appropriate for cell therapies targeting inhibitory interneurons for conferring anticonvulsant outcomes. PMID- 27770488 TI - State of the Science: Tools and Measurement for Shared Decision Making. AB - Shared decision making (SDM) has been advocated as an approach to selecting medical tests and treatments for many situations. The goal of SDM is to ensure that patients are well informed, are meaningfully involved in decisions, and receive treatments that meet their goals and preferences. There is considerable evidence about the tools used to promote SDM, called patient decision aids, and many different measures have been developed to assess the impact of SDM. However, fairly little is known about the applicability of the tools and measures in the emergency department (ED) setting. This article builds on insights from two keynote lectures presented at the 2016 Academic Emergency Medicine Consensus Conference discussing the state of the science for measurement of SDM and the design of patient decision aids to promote SDM conversations and highlights some key areas for further research to advance SDM in the ED. PMID- 27770489 TI - Comparison of gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer. AB - AIM: It remains unclear whether capecitabine combined with cisplatin would show similar effects compared with standard therapy using gemcitabine and cisplatin in advanced biliary tract cancer (BTC). METHODS: Patients with advanced BTC who were treated with first-line chemotherapy at Asan Medical Center were retrospectively analyzed. All patients received either cisplatin followed by gemcitabine on days 1 and 8 every 3 weeks (GP group), or capecitabine on days 1-14 with cisplatin on day 1 every 3 weeks (XP group). RESULTS: Of the 134 patients who met the inclusion criteria, 78 received XP and 56 were treated with GP. After a median follow-up of 26.2 months, the progression-free survival was 5.7 months for XP versus 4.1 months for GP (hazard ratio [HR] = 0.81, P = 0.31). The overall survival (OS) was 11.0 months for XP versus 9.8 months for GP (HR = 0.84, P = 0.36). In the multivariate analysis, there were no significant differences in PFS and OS between the two groups. CONCLUSION: XP seems to be as effective as GP in patients with advanced BTC. The XP regimen is feasible and might offer increased convenience regarding the schedule of drug administration. PMID- 27770490 TI - Point-of-care Ultrasound for Diagnosis of Abscess in Skin and Soft Tissue Infections. AB - BACKGROUND: Traditionally, emergency department (ED) physicians rely on their clinical examination to differentiate between cellulitis and abscess when evaluating skin and soft tissue infections (SSTI). Management of an abscess requires incision and drainage, whereas cellulitis generally requires a course of antibiotics. Misdiagnosis often results in unnecessary invasive procedures, sedations (for incision and drainage in pediatric patients), or a return ED visit for failed antibiotic therapy. OBJECTIVE: The objective was to describe the operating characteristics of point-of-care ultrasound (POCUS) compared to clinical examination in identifying abscesses in ED patients with SSTI. METHODS: We systematically searched Medline, Web of Science, EMBASE, CINAHL, and Cochrane Library databases from inception until May 2015. Trials comparing POCUS with clinical examination to identify abscesses when evaluating SSTI in the ED were included. Trials that included intraoral abscesses or abscess drainage in the operating room were excluded. The presence of an abscess was defined by drainage of pus. The absence of an abscess was defined as no pus drainage upon incision and drainage or resolution of SSTI without pus drainage at follow-up. Quality of trials was assessed using the QUADAS-2 tool. Operating characteristics were reported as sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-), with their respective 95% confidence intervals (CI). Summary measures were calculated by generating a hierarchical summary receiver operating characteristic (HSROC) model. RESULTS: Of 3,203 references identified, six observational studies (four pediatric trials and two adult trials) with a total of 800 patients were included. Two trials compared clinical examination with clinical examination plus POCUS. The other four trials directly compared clinical examination to POCUS. The POCUS HSROC revealed a sensitivity of 97% (95% CI = 94% to 98%), specificity of 83% (95% CI = 75% to 88%), LR+ of 5.5 (95% CI = 3.7 to 8.2), and LR- of 0.04 (95% CI = 0.02 to 0.08). CONCLUSION: Existing evidence indicates that POCUS is useful in identifying abscess in ED patients with SSTI. In cases where physical examination is equivocal, POCUS can assist physicians to distinguish abscess from cellulitis. PMID- 27770491 TI - An efficacy and safety of nanofractional radiofrequency for the treatment of striae alba. AB - BACKGROUND: Striae distensae (SD) is a form of dermal scar. A number of treatments have been proposed, but they usually have unsatisfactory result especially in striae alba. Recently, nanofractional RF has been developed. Its mechanism of action is to stimulate dermal remodeling and epidermal re epithelization. AIM: To evaluate the efficacy and safety of nanofractional RF in the treatment of striae alba. PATIENTS/METHODS: This is an experimental, assessor blinded, before-after study. Thirty-three subjects, with striae alba on their thighs, abdomen, or buttocks (11 subjects each) were enrolled. Treatments with nanofractional RF were undergone for a total of three sessions at 4-week intervals. Clinical outcomes were assessed, by comparing pre- and post-treatment measurement of total lesional surface area (using digital PictzarTM software), and length and width of lesions. Histopathological evaluation was also performed. RESULTS: At 4 weeks after the last treatment, the total surface area, and the width and the length of striae alba significantly decreased from the baseline (P < 0.001). Postinflammatory hyperpigmentation was reported in six subjects. Regarding histopathology, the average mean number of collagen and elastin bundles was significantly increased (P = 0.005 and 0.012, respectively). CONCLUSION: Nanofractional RF is highly effective with a good safety profile for the treatment of striae alba. PMID- 27770492 TI - The need for organization of laparoscopic liver resection. AB - In this article, we present the rationale for creating a new society aiming at organizing laparoscopic liver surgery. It has been named International Laparoscopic Liver Society (ILLS). Its main mission is to facilitate the diffusion and education of laparoscopic liver resection for meaningful improvements in patient care. This will include organization of a biannual congress dedicated to laparoscopic liver resection, coordination of international registries, helping in the education of surgeons wishing to learn these techniques including travel grants, provide a website serving as a forum supporting collaboration between surgeons interested in the advancement of laparoscopic liver resection techniques (http://www.ills.global/). ILLS aims at working in collaboration with existing HPB societies. PMID- 27770493 TI - No Evidence of Hendra Virus Infection in the Australian Flying-fox Ectoparasite Genus Cyclopodia. AB - Hendra virus (HeV) causes potentially fatal respiratory and/or neurological disease in both horses and humans. Although Australian flying-foxes of the genus Pteropus have been identified as reservoir hosts, the precise mechanism of HeV transmission has yet to be elucidated. To date, there has been limited investigation into the role of haematophagous insects as vectors of HeV. This mode of transmission is particularly relevant because Australian flying-foxes host the bat-specific blood-feeding ectoparasites of the genus Cyclopodia (Diptera: Nycteribiidae), also known as bat flies. Using molecular detection methods, we screened for HeV RNA in 183 bat flies collected from flying-foxes inhabiting a roost in Boonah, Queensland, Australia. It was subsequently demonstrated that during the study period, Pteropus alecto in this roost had a HeV RNA prevalence between 2 and 15% (95% CI [1, 6] to [8, 26], respectively). We found no evidence of HeV in any bat flies tested, including 10 bat flies collected from P. alecto in which we detected HeV RNA. Our negative findings are consistent with previous findings and provide additional evidence that bat flies do not play a primary role in HeV transmission. PMID- 27770494 TI - Paternal age and psychiatric disorders: A review. AB - We review the hypotheses concerning the association between the paternal age at childbearing and childhood psychiatric disorders (autism spectrum- and attention deficit/hyperactive disorder) and adult disorders (schizophrenia, bipolar-, obsessive-compulsive-, and major depressive disorder) based on epidemiological studies. Several hypotheses have been proposed to explain the paternal age effect. We discuss the four main-not mutually exclusive-hypotheses. These are the de novo mutation hypothesis, the hypothesis concerning epigenetic alterations, the selection into late fatherhood hypothesis, and the environmental resource hypothesis. Advanced paternal age in relation to autism spectrum disorders and schizophrenia provided the most robust epidemiological evidence for an association, with some studies reporting a monotonic risk increase over age, and others reporting a marked increase at a given age threshold. Although there is evidence for the de novo mutation hypothesis and the selection into late fatherhood hypothesis, the mechanism(s) underlying the association between advanced paternal age and psychiatric illness in offspring remains to be further clarified. (c) 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID- 27770495 TI - Advanced maternal age increases the risk of very preterm birth, irrespective of parity: a population-based register study. AB - OBJECTIVE: To investigate whether advanced maternal age is associated with preterm birth, irrespective of parity. DESIGN: Population-based registry study. SETTING: Swedish Medical Birth Register. POPULATION: First, second, and third live singleton births to women aged 20 years or older in Sweden, from 1990 to 2011 (n = 2 009 068). METHODS: Logistic regression analysis was used in each parity group to estimate risks of very and moderately preterm births to women at 20-24, 25-29, 30-34, 35-39, and 40 years or older, using 25-29 years as the reference group. Odds ratios (ORs) were adjusted for year of birth, education, country of birth, smoking, body mass index, and history of preterm birth. Age related risks of spontaneous and medically indicated preterm births were also investigated. MAIN OUTCOME MEASURES: Very preterm (22-31 weeks of gestation) and moderately preterm (32-36 weeks) births. RESULTS: Risks of very preterm birth increased with maternal age, irrespective of parity: adjusted ORs in first, second, and third births ranged from 1.18 to 1.28 at 30-34 years, from 1.59 to 1.70 at 35-39 years, and from 1.97 to 2.40 at >=40 years. In moderately preterm births, age-related associations were weaker, but were statistically significant from 35-39 years in all parity groups. Advanced maternal age increased the risks of both spontaneous and medically indicated preterm births. CONCLUSIONS: Advanced maternal age is associated with an increased risk of preterm birth, irrespective of parity, especially very preterm birth. Women aged 35 years and older, expecting their first, second, or third births, should be regarded as a risk group for very preterm birth. TWEETABLE ABSTRACT: Women aged 35 years and older should be regarded as a risk group for very preterm birth, irrespective of parity. PMID- 27770496 TI - "Frank" presentations as a novel research construct and element of diagnostic decision-making in autism spectrum disorder. AB - Many individuals with ASD have a distinctive behavioral presentation that is recognizable within moments, a phenomenon we call "frank" ASD. This phenomenon has been discussed informally for decades, perhaps as "classic" ASD; however, there is no unitary "classic" presentation, and classic autism does not seem to correspond to level of functioning. Thus, neither "frank" nor "classic" autism has been delineated or studied as a research construct. To initiate the empirical study of frank ASD, we surveyed 151 clinicians, from a range of disciplines that diagnose ASD, about this phenomenon. Respondents completed a 13-item questionnaire about frank ASD, which was analyzed using a mixed-methods approach. Ninety-seven percentage of respondents were familiar with the phenomenon. Respondents estimated that 40% of the ASD population has a frank presentation. Respondents reported the most highly specific behaviors associated with frank presentations were a general sense of impaired reciprocity, quality of eye contact, atypical vocal prosody, presence of motor mannerisms, and atypical gait or posture. In general, respondents reported detecting frank features rapidly, with the majority forming their impressions within the first ten minutes of interaction or observation. Although unstudied empirically, "frank" presentations of ASD are familiar to diagnosing clinicians, and appear to be based on behaviors both central to ASD diagnostic criteria (e.g., impaired reciprocity), and absent from diagnostic criteria (e.g., atypical gait or posture). We discuss these findings within the context of diagnostic decision-making and behavioral phenotyping of ASD. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 653-662. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27770497 TI - Hospital-wide implementation of an electronic-workflow solution aiming to make surgical practice improvement easy. AB - BACKGROUND: In measuring quality of health-care delivery, digital infrastructure is essential. The aim at this tertiary centre was to create a hospital-wide workflow system that collected data prospectively as part of daily practice. METHODS: In moving towards an electronic health record, a hospital-wide integrated workflow system was introduced in 2013, which electronically managed the perioperative patient journey while simultaneously facilitating surgical audit. Analysis of its implementation was carried out presenting early outcomes using general surgery as an example. RESULTS: Theatre-bookings (44 953) were made with compliance approaching 90% for all services. Of 7179 general surgical operations over 24 months, 5785 (80%) had an operation note created using the new system. Cumulative summation of uptake of synoptic operative reporting (SOR) for laparoscopic cholecystectomy (LC) was 81% with documentation being superior in terms of antibiotic use and steps to safe cholecystectomy (P < 0.001). A LC SOR took 4 min to complete (interquartile ranges 2-5 min, n = 425) and was immediately available on the day of surgery compared to narrative operative reports taking 2 days (interquartile ranges 1-5 days, n = 174) (P < 0.001). From July 2014 to November 2015, 557 (10%) complications were recorded for 5749 general surgical operations with 99% of complications being reviewed. CONCLUSION: The rapid and sustained uptake of both theatre-bookings and SOR likely reflect high end-user satisfaction with the system. Service metrics indicate a significant improvement in the time of delivery. The ability to seamlessly complete the audit cycle at an individual, department and hospital level has been achieved. PMID- 27770499 TI - Genetic factors in neurodegenerative diseases. PMID- 27770498 TI - Acute physical exercise and long-term individual shear rate therapy increase telomerase activity in human peripheral blood mononuclear cells. AB - AIM: Physical activity is a potent way to impede vascular ageing. However, patients who suffer from peripheral artery disease (PAD) are often unable to exercise adequately. For those patients, we have developed individual shear rate therapy (ISRT), which is an adaptation of external counterpulsation and enhances endovascular fluid shear stress to increase collateral growth (arteriogenesis). To evaluate the effects of physical exercise and ISRT on the telomere biology of peripheral blood mononuclear cells (PBMCs), we conducted two clinical trials. METHODS: In the ISRT-1 study, we assessed PBMC telomerase activity in 26 young healthy volunteers upon a single (short-term) ISRT session and a single treadmill running session. In the ISRT-2 study, we investigated PBMC telomere biology of 14 elderly patients with PAD, who underwent 30 h of (long-term) ISRT within a 5-week period. RESULTS: We demonstrate that telomerase activity significantly increased from 39.84 Total Product Generated (TPG) Units +/- 6.15 to 58.10 TPG +/- 10.46 upon a single treadmill running session in healthy volunteers. In the ISRT-2 trial, PBMC telomerase activity and the mRNA expression of the telomere protective factor TRF2 increased from 40.87 TPG +/- 4.45 to 60.98 TPG +/- 6.83 and 2.10-fold +/- 0.40, respectively, upon long-term ISRT in elderly patients with PAD. CONCLUSION: In summary, we show that acute exercise and long-term ISRT positively affect PBMC telomerase activity, which is indicative for an improved regenerative potential of immune cells and vascular tissues. Long-term ISRT also enhances the gene expression of the telomere-protective factor TRF2. PMID- 27770500 TI - Pathogenic factors in Candida biofilm-related infectious diseases. AB - Candida albicans is a commonly found member of the human microflora and is a major human opportunistic fungal pathogen. A perturbation of the microbiome can lead to infectious diseases caused by various micro-organisms, including C. albicans. Moreover, the interactions between C. albicans and bacteria are considered to play critical roles in human health. The major biological feature of C. albicans, which impacts human health, resides in its ability to form biofilms. In particular, the extracellular matrix (ECM) of Candida biofilm plays a multifaceted role and therefore may be considered as a highly attractive target to combat biofilm-related infectious diseases. In addition, extracellular DNA (eDNA) also plays a crucial role in Candida biofilm formation and its structural integrity and induces the morphological transition from yeast to the hyphal growth form during C. albicans biofilm development. This review focuses on pathogenic factors such as eDNA in Candida biofilm formation and its ECM production and provides meaningful information for future studies to develop a novel strategy to battle infectious diseases elicited by Candida-formed biofilm. PMID- 27770504 TI - Threshold loss of discontinuous permafrost and landscape evolution. AB - This study demonstrates linkages between the 1997/1998 El Nino/Southern Oscillation index and a threshold shift to increased permafrost loss within a southern Taiga Plains watershed, Northwest Territories, Canada. Three-dimensional contraction of permafrost plateaus and changes in vegetation structural characteristics are determined from multitemporal airborne Light Detection And Ranging (LiDAR) surveys in 2008, 2011 and 2015. Morphological changes in permafrost cover are compared with optical image analogues from 1970, 1977, 2000 and 2008 and time-series hydro-climate data. Results demonstrate that significant changes in air temperature, precipitation, runoff and a shortening of the snow covered season by 35 days (1998-2014) and 50 days (1998 only) occurred after 1997. The albedo reduction associated with 35 and 50 days less snow cover leads to increases in shortwave energy receipt during the active thaw period of ~12% (3% annually) and ~16% (5% annually), respectively. From 2000 to 2015, sporadic permafrost loss accelerated from 0.19% (of total basin area) per year between 1970 and 2000 to 0.58% per year from 2000 to 2015, with a projected total loss of permafrost by ~2044. From ~1997 to 2011, we observe a corresponding shift to increased runoff ratio. However, observed increases in the proportion of snow precipitation and the volumetric contribution of permafrost loss to runoff post 1997 (0.6-6.4% per year) cannot fully explain this shift. This suggests increases in drainage efficiency and possible losses from long-term groundwater storage as a result of subtle terrain morphological and soil zone hydraulic conductivity changes. These hydrological changes appear coincident with high vegetation mortality at plateau margins combined with succession-related canopy growth in some bog and fen areas, which are presumed to be drying. Similar changes in runoff response were observed at adjacent Birch, Trout and Jean Marie River watersheds indicating that observations are representative of northern Boreal sporadic permafrost/wetland watersheds in the Taiga Plains. PMID- 27770505 TI - Sensitivity of Direct Culture, Enrichment and PCR for Detection of Campylobacter jejuni and C. coli in Broiler Flocks at Slaughter. AB - Broiler chicken flocks are a significant source of Campylobacter jejuni and Campylobacter coli that result in the major public health problem of campylobacteriosis. Accurate estimates of the prevalence of both C. coli and C. jejuni in flocks would enhance epidemiological understanding, risk assessment and control options. This study combined results from a panel of 10 detection tests (direct culture, enrichment and PCR) on caecal samples from flocks at slaughter. A parallel interpretation approach was used to determine the presence of Campylobacter spp. and for C. jejuni and C. coli individually. The sample was considered positive if at least one method detected the target and this interpretation was taken to represent a 'proxy gold standard' for detection in the absence of a gold standard reference test. The sensitivity of each individual method to detect Campylobacter spp., C. jejuni and C. coli was then estimated relative to the proxy gold standard. Enrichment in adapted Exeter broth (deficient in polymyxin B) with a resuscitation step was 100% sensitive, whilst direct culture on modified charcoal cefoperazone deoxycholate agar (mCCDA) was highly sensitive (97.9%). Enrichment methods using Preston broth and Bolton broth were significantly less sensitive. Enrichment in Exeter broth promoted the recovery of C. jejuni, whilst enrichment in Bolton broth favoured C. coli. A RT PCR detection test could identify 80% of flocks that were co-colonised with both species. This study found that 76.3% (n = 127) of flocks were colonised with Campylobacter spp. The majority (95.9%) of Campylobacter-positive flocks were colonised with C. jejuni; however, approximately one-third of positive flocks were simultaneously colonised with both C. jejuni and C. coli. The findings highlight the impact of different detection methodologies on the accuracy of the estimated incidence of both C. jejuni and C. coli entering the abattoir within broiler flocks and the associated public health risks. PMID- 27770503 TI - Survivin isoform expression in arsenic trioxide-treated acute promyelocytic leukemia cell line and patients: The odd expression pattern of survivin-2alpha. AB - AIM: Survivin, an inhibitor of apoptosis protein, is overexpressed in most cancers and is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival. Several survivin splice variants have been described, and none of their expressions have been defined in acute promyelocytic leukemia (APL). METHODS: Expression of the survivin gene isoforms (survivin, -2alpha, -2B, -DeltaEpsilonx3 and -3B) were analyzed in 50 peripheral blood and 19 bone marrow samples that were collected at different phases of the disease (diagnostic, remission and relapse) in APL patients treated with arsenic trioxide (ATO) as a front-line therapy. In addition, the human APL-derived cell line (NB4) was analyzed for the expression of survivin isoforms and capsase-3 in response to the ATO. RESULTS: Survivin and its variants were overexpressed significantly in patient's bone marrow samples compared to peripheral blood or normal samples. Their expression was decreased after ATO treatment in both NB4 cells (except survivin-2alpha) and APL patients along with PML-RARalpha copy number reduction. Downregulation of survivin isoforms was associated with an increase in both caspase-3 gene expression and its enzymatic activity levels. In a patient who did not respond to ATO treatment, expression of survivin isoforms (except survivin-2alpha) were highly increased during the induction therapy. CONCLUSION: Survivin isoforms are upregulated in APL patients, and their expression is diminished during the ATO treatment. In addition, overexpression of survivin and its variants (except survivin-2alpha) are associated with unfavorable results, suggesting that they may play an important role in mechanisms underlying the resistance of APL cells to ATO. PMID- 27770501 TI - KymoAnalyzer: a software tool for the quantitative analysis of intracellular transport in neurons. AB - In axons, proper localization of proteins, vesicles, organelles, and other cargoes is accomplished by the highly regulated coordination of kinesins and dyneins, molecular motors that bind to cargoes and translocate them along microtubule (MT) tracks. Impairment of axonal transport is implicated in the pathogenesis of multiple neurodegenerative disorders including Alzheimer's and Huntington's diseases. To understand how MT-based cargo motility is regulated and to delineate its role in neurodegeneration, it is critical to analyze the detailed dynamics of moving cargoes inside axons. Here, we present KymoAnalyzer, a software tool that facilitates the robust analysis of axonal transport from time-lapse live-imaging sequences. KymoAnalyzer is an open-source software that automatically classifies particle trajectories and systematically calculates velocities, run lengths, pauses, and a wealth of other parameters that are characteristic of motor-based transport. We anticipate that laboratories will easily use this package to unveil previously uncovered intracellular transport details of individually-moving cargoes inside neurons. PMID- 27770506 TI - Spermatogonia, Germline Cells, and Testicular Organization in the Characiform Prochilodus lineatus Studied Using Histological, Stereological, and Morphometric Approaches. AB - Prochilodus lineatus is an important representative of the order Characiformes and a species that offers great advantages to fish farming. Therefore, detailed knowledge of its reproductive biology can be applied to various fields of production and biotechnology. In this study, we have identified testicular germ cells during spermatogenesis and have evaluated the volumetric proportion of the testes occupied by structures of the tubular and intertubular compartments. In addition, the individual volume of type A spermatogonia was measured and used to estimate the mean number of these cells per testis. Gonads of adult P. lineatus males were extracted and fixed. Light and transmission electron microscopy were applied to fragments of three testicular regions. Histological, stereological, and morphometric analyses were performed. The stereological data suggest that components of the tubular and intertubular compartments of the P. lineatus testes present a uniform distribution in all three regions and therefore reflect regions with similar distributions of cell types. In addition, P. lineatus testes showed ~0.6% of type A spermatogonia, as well as a predominance of cysts of primary spermatocytes and spermatids during the reproductive phase evaluated. The results from this study provide a better understanding of the morphology and structure of the testis and of the characterization of the type A spermatogonia in P. lineatus. The nuclear diameter of germ cells also decreases significantly during spermatogenesis. The data presented herein are the first of its kind for the order Characiformes and may be useful for future biotechnology studies on fish reproduction. Anat Rec, 300:589-599, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27770507 TI - Integrated population modeling reveals the impact of climate on the survival of juvenile emperor penguins. AB - Early-life demographic traits are poorly known, impeding our understanding of population processes and sensitivity to climate change. Survival of immature individuals is a critical component of population dynamics and recruitment in particular. However, obtaining reliable estimates of juvenile survival (i.e., from independence to first year) remains challenging, as immatures are often difficult to observe and to monitor individually in the field. This is particularly acute for seabirds, in which juveniles stay at sea and remain undetectable for several years. In this work, we developed a Bayesian integrated population model to estimate the juvenile survival of emperor penguins (Aptenodytes forsteri), and other demographic parameters including adult survival and fecundity of the species. Using this statistical method, we simultaneously analyzed capture-recapture data of adults, the annual number of breeding females, and the number of fledglings of emperor penguins collected at Dumont d'Urville, Antarctica, for the period 1971-1998. We also assessed how climate covariates known to affect the species foraging habitats and prey [southern annular mode (SAM), sea ice concentration (SIC)] affect juvenile survival. Our analyses revealed that there was a strong evidence for the positive effect of SAM during the rearing period (SAMR) on juvenile survival. Our findings suggest that this large-scale climate index affects juvenile emperor penguins body condition and survival through its influence on wind patterns, fast ice extent, and distance to open water. Estimating the influence of environmental covariates on juvenile survival is of major importance to understand the impacts of climate variability and change on the population dynamics of emperor penguins and seabirds in general and to make robust predictions on the impact of climate change on marine predators. PMID- 27770508 TI - NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma. AB - Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28-87% of the cases. NRG1 fusions were recently discovered in KRAS-negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed. In the IMA samples remaining negative for these driver oncogenes, an NRG1 rearrangement detection was performed by FISH. A driver oncogene was identified in 14/25 IMA, namely 12 KRAS mutations (48%), one ROS1 rearrangement (4%), and one ALK rearrangement (4%). The detection of NRG1 rearrangement by FISH was conducted in the 11 pan-negative IMA. One sample was NRG1FISH-positive and 100% of the tumor nuclei analyzed were positive. This NRG1-positive patient was a 61-year-old nonsmoking woman of Vietnamese ethnicity and was the sole patient of Asian ethnicity of the cohort. She died 6 months after the diagnosis with a pulmonary multifocal disease. NRG1FISH detection should be considered in patients with IMA pan-negative for known driver oncogenes. These results might suggest that NRG1 fusion is more frequent in IMA from Asian patient. Larger studies are needed. PMID- 27770509 TI - Comparison of Tube, Gel, and Immunochromatographic Strip Methods for Evaluation of Blood Transfusion Compatibility in Horses. AB - BACKGROUND: Assessment of blood compatibility, typically by tube agglutination (TUBE) and hemolysis crossmatch or, less commonly, by blood typing and alloantibody screening, often is performed before blood transfusion in horses. In contrast, gel column (GEL) and immunochromatographic strip (STRIP) techniques are preferred for compatibility testing in dogs and cats. OBJECTIVE: To determine the accuracy of novel and standard crossmatch and typing methods. ANIMALS: Thirty eight healthy horses, previously blood typed and alloantibody screened. METHODS: TUBE and GEL crossmatches were performed on 146 different recipient-donor pairs with 56 incompatible TUBE crossmatches. Crossmatches were compared by nonparametric area under the curve of receiver operating characteristic (AUC-ROC) analyses. Horses also were blood typed by the novel immunochromatographic Ca typing STRIP. RESULTS: Compared to TUBE crossmatch, GEL had excellent accuracy for agglutination (AUC-ROC = 0.903), but marginal accuracy for hemolysis (AUC-ROC = 0.639). Compared to macroscopic TUBE, microscopic TUBE had excellent accuracy for agglutination (AUC-ROC = 0.912). The predicted crossmatch compatibility based on blood type and alloantibody assay showed excellent accuracy compared to TUBE and GEL (AUC-ROC = 0.843 and 0.897, respectively). However, there were more recipient-donor pairs identified as incompatible by both TUBE and GEL than predicted by blood type and antibody screen, suggesting the presence of unidentified alloantibodies. A Ca typing STRIP exhibited 100% sensitivity and specificity for the 35 Ca+ and 3 Ca- horses tested. CONCLUSIONS AND CLINICAL RELEVANCE: Gel column crossmatch and Ca typing immunochromatographic strip are simple and accurate methods to evaluate clinical blood compatibility. PMID- 27770510 TI - Isomeric discrimination of synthetic cannabinoids by GC-EI-MS: 1-adamantyl and 2 adamantyl isomers of N-adamantyl carboxamides. AB - N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA) and N-(1-adamantyl) 1-pentyl-1H-indole-3-carboxamide (APICA) are carboxamide-type synthetic cannabinoids comprising indazole/indole-3-carboxylic acid and adamantan-1-amine moieties. However, in the case of compounds like APINACA or APICA, adamantyl positional isomers exist, wherein either adamantan-1-amine or adamantan-2-amine is present. These adamantyl positional isomers have not been reported in previous studies, and no analytical data are available. To avoid misidentification of adamantyl carboxamide-type synthetic cannabinoids, it is important to develop methods to discriminate these adamantyl positional isomers. In this study, we report the analytical characterization by gas chromatography-electron ionization mass spectrometry (GC-EI-MS). For providing analytical standards, we synthesized eight carboxamide-type synthetic cannabinoids (APINACA 2-adamantyl isomer, APICA 2-adamantyl isomer, 5 F-APINACA 2-adamantyl isomer, 5 F-APICA 2-adamantyl isomer, 5Cl-APINACA, 5Cl-APINACA 2-adamantyl isomer, adamantyl-THPINACA, 2-adamantyl THPINACA) and purchased four 1-adamantyl derivatives (APINACA, APICA, 5 F APINACA, 5 F-APICA). Although the retention times of the isomers are similar, 1 adamantyl carboxamides can be clearly discriminated from their 2-adamantyl isomers based on their different fragmentation patterns in the EI-MS spectra. Specifically, EI-MS spectra for adamantylindazole carboxamides showed remarkable differences between the 1-adamantyl and 2-adamantyl isomers. On the other hand, EI-MS spectra for adamantylindole carboxamides were similar, but the diagnostic ions of the 2-adamantyl isomers were observed. The method described herein was applicable to all compounds tested in this study and is expected to be of use for isomeric differentiation between other untested adamantyl carboxamide-type synthetic cannabinoids. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27770511 TI - Epidermal growth factor receptor and notch signaling in non-small-cell lung cancer. AB - Lung cancer is the most common reason of cancer deaths and about 85% of these are non-small-cell lung cancer. Currently, lung cancer therapy is mainly based on the tumor node metastasis (TNM) disease staging and tumor histological classification. Despite therapeutic innovations, the prognosis for lung cancer patients has not significantly changed in the last years. Therefore, a proper understanding of cell signaling pathways involved in cancer pathogenesis seems to be essential for improvement in cancer therapy field. The knowledge of crosstalk between epidermal growth factor receptor (EGFR) and Notch pathway can lead to enhanced screening for the expression of these genes allowing patients to optimize treatment options and predict potential treatment resistance. This review focuses on recent advances related to the mechanisms of EGFR and Notch signaling in non-small-cell lung cancer and the effectiveness of current Notch- and EGFR-targeted therapies. PMID- 27770512 TI - Serious maternal complications in relation to severe pre-eclampsia: a retrospective cohort study of the impact of hospital volume. AB - OBJECTIVE: We examined rates of serious maternal complications in relation to severe pre-eclampsia based on the delivering hospital's annualised volume. DESIGN: Retrospective cohort study. POPULATION AND SETTING: Singleton deliveries (n = 25 782 235) in 439 hospitals in the USA. METHODS: Annualised hospital volume was categorised as 25-500, 501-1000, 1001-2000 and >2000. MAIN OUTCOME MEASURES: Rates of in-hospital maternal death and serious maternal complications, including puerperal cerebrovascular disorders, pulmonary oedema, disseminated intravascular coagulation, acute renal, heart and liver failure, sepsis, haemorrhage and intubation in relation to severe pre-eclampsia. We derived adjusted risk ratio (RR) and 95% confidence interval (CI), from hierarchical Poisson regression models. RESULTS: Severe pre-eclampsia was associated with an 8.7-fold (95% CI 7.6, 10.1) risk of composite maternal complications, with similar RRs across levels of hospital volumes. However, compared with hospitals with low annual volume (<2000), maternal mortality rates in relation to severe pre-eclampsia were lower in high volume hospitals. The rates of serious maternal complications were 410.7 per 10 000 to women who delivered in hospitals with a high rate of severe pre-eclampsia (>=2.12%) and 584.8 per 10 000 to women who delivered in hospitals with low severe pre-eclampsia rates (<=0.41; RR 1.75, 95% CI 1.24, 2.45). CONCLUSIONS: While the risks of serious maternal complications in relation to severe pre-eclampsia was similar across hospital delivery volume categories, deaths showed lower rates in large delivery volume hospitals than in smaller volume hospitals. The risk of complications was increased in hospitals with low compared with high severe pre-eclampsia rates. TWEETABLE ABSTRACT: Hospital volume had little impact on the association between severe pre-eclampsia and maternal complications. PMID- 27770513 TI - Cytology diagnosis of metastatic clear cell renal cell carcinoma, synchronous to pancreas, and metachronous to thyroid and contralateral adrenal: Report of a case and literature review. AB - Renal cell carcinoma metastases to pancreas, thyroid, and contralateral adrenal gland are decidedly uncommon. Clear cell renal cell carcinoma (CCRCC) is the most frequent subtype. Cytology diagnosis may be challenging. A 74-year-old male with remote history of vocal cord malignancy and hypertension presented with abdominal pain. Computed tomography (CT) revealed 8.4 cm left renal mass highly suspicious for renal cell carcinoma, a 1.8 cm mass within vessels near left adrenal and a 2.5 cm mass in pancreatic tail. Right pulmonary middle lobe showed two small nodules. Metastatic CCRCC was diagnosed on preoperative transgastric, endoscopic ultrasound guided fine-needle aspiration cytology of pancreatic tail mass. Left radical nephrectomy and distal pancreatectomy and splenectomy confirmed CCRCC (pT3bNxM1), with metastases in adrenal and pancreatic tail. The 3p deletion identification in pancreatic tumor suggested CCRCC origin. Follow-up positron emission tomography-CT (PET-CT) scan revealed left thyroid lower pole mass. Thyroid ultrasound showed three clustered 6 mm nodules in left mid pole. Ultrasound-guided fine needle aspiration (US-FNA) biopsies, 4-month post nephrectomy, were consistent with metastatic renal cell carcinoma in lower, and atypia of undetermined significance in mid poles respectively. Left lobectomy and isthmus and pyramidal lobe resections confirmed metastatic renal cell carcinoma. One year post-radical nephrectomy, contralateral adrenal lesion noted on PET-CT was interpreted as metastatic CCRCC on CT-guided core biopsy with touch imprints. Rapid on-site evaluation was implemented, and immunoprofile typical of CCRCC substantiated cytomorphology at all three sites. Previously reported cases of renal cell carcinoma metastases to organs as in the described case are reviewed as well. Diagn. Cytopathol. 2017;45:161-167. (c) 2016 Wiley Periodicals, Inc. PMID- 27770514 TI - What Is Shared Decision Making? (and What It Is Not). PMID- 27770515 TI - Managing and characterizing monoclonal antibody glycosylation. PMID- 27770516 TI - History and current status of peste des petits ruminants virus in Tanzania. AB - Peste des petits ruminants virus (PPRV) causes the acute, highly contagious disease peste des petits ruminants (PPR) that affects small domestic and wild ruminants. PPR is of importance in the small livestock-keeping industry in Tanzania, especially in rural areas as it is an important source of livelihood. Morbidity and case fatality rate can be as high as 80-100% in naive herds; however, in endemic areas, morbidity and case fatality range between 10 and 100% where previous immunity, age, and species of infected animal determine severity of outcome. PPR was officially confirmed in domestic animals in the Ngorongoro district of Tanzania in 2008. It is now considered to be endemic in the domestic sheep and goat populations throughout Tanzania, but restricted to one or more areas in the small ruminant wildlife population. In this article, we review the history and the current status of PPR in Tanzania and neighboring countries. To control and eradicate PPR in the region, a joint effort between these countries needs to be undertaken. The effort must also secure genuine engagement from the animal holders to succeed. PMID- 27770518 TI - ? PMID- 27770519 TI - ROTAVIRUS VACCINE IMPLEMENTATION IN GEORGIA - IMPACT OF KNOWLEDGE, APPROACH, AND PRACTICES OF HEALTH CARE WORKERS. AB - Rotavirus (RV) is the most common cause of severe gastroenteritis in infants and young children worldwide. RV causes approximately half a million deaths each year among children aged <5 years. According to WHO estimates for 2008, there were approximately 10 to 50 deaths annually in young children due to rotavirus diarrhea in Georgia. The purpose of this study was to assess the knowledge, attitudes, and practices related to rotavirus diarrhea and the rotavirus vaccine among health care workers (HCWs). The National Center for Disease Control and Public Health (NCDC) conducted a cross-sectional survey of HCWs involved in the expanded program of immunization (EPI). The HCWs were selected by simple random sampling using employee lists, and questionnaires were hand-delivered to selected HCWs during working hours. The majority of HCWs (67.9%) recognized diarrhea as a frequent health-related problem in children under 2 years of age. However, 53.9% partially disagreed with the statement that rotavirus is the most common cause of all forms of diarrhea. Multivariable analysis revealed that the following perceptions among HCWs more than doubled the likelihood that they would not support adoption of the RV vaccine: no perception of need for this vaccine in Georgia specifically (OR=2.54, CI: 1.46-4.42), no perception of need to address burden of disease in developing countries (OR=2.75, CI: 1.59-4.75), and concerns about the vaccine's safety (OR=2.51, CI: 1.56-4.02). Concerns about vaccine safety, low awareness about the RV disease burden and the effectiveness of the RV vaccine, combined with a lack of communication skills represented the main predictors of RV vaccine uptake among HCWs. Intensive vaccine promotion interventions that focus on the epidemiology of disease and vaccine effectiveness are urgently needed. PMID- 27770520 TI - CHANGES OF ENDOTHELIN-1 CONTENT AND BLOOD RHEOLOGICAL PROPERTIES IN CRUSH SYNDROME. AB - This study describes hematocrit values and quantitative changes in plasma endothelin-1 (ET-1) levels according to the severity of crush syndrome (CS) compression and decompression periods. The experiments were carried out on 50 randomly selected 200-250 gr mass Wistar rats with the use of the standard crush syndrome modeling method. The plasma level of ET-1 was determined by the immuneenzyme method with the use of ELISA REDEAR URIT 660. Hematocrit was determined using the standard method and measured according to tube column divisions. Our data show that ET-1 and hematocrit values rise commensurate with an increased duration of compression, and especially decompression periods. In CS, elevation of ET-1 concentrations and hematocrit values leads to significant microcirculation disturbances in parallel with longer and more severe compression and decompression periods. Specifically, the ET-1 concentration was significantly elevated, possibly in response to activation of surface endothelial V (ET-B) receptors located in the vessel endothelium. These receptors, in turn, have a vasodilative effect due to nitrogen oxide synthesis induction and vascular smooth muscle relaxation. The rise in hematocrit values during crush syndrome is associated with plasmorrhagia induced by trauma and toxic (rhabdomyolysis) shock. PMID- 27770521 TI - TONIC INFLUENCE OF NEOCORTEX ON HIPPOCAMPAL SEIZURES. AB - The interaction between different brain structures could be crucial to predicting seizure occurrence, threshold and spread. Moreover, the sleep-wake cycle and electrical activity of brain structures in different phases of sleep could significantly affect the pattern and extent of seizure spread, and therefore the characteristics of epileptic activity. In this animal model using 15 Wistar rats, we show that the duration of hippocampal seizures, induced by electrical stimulation of the hippocampus, is significantly increased during slow sleep. Moreover, decreasing the electrical activity of the neocortex by cooling of the cortical surface or induction of cortical spreading depression also caused an increase in hippocampal seizure duration. Conversely, warming the cortical surface triggered a remission in spreading depression, in turn restoring the duration of epileptic episodes. Our data suggest that the neocortex probably exerts a tonic inhibitory influence on hippocampal seizures. Thus, cortico hippocampal interaction could be an important component in the manifestation and generalization of limbic seizures. PMID- 27770517 TI - Microbiological and bioinformatics analysis of primary Sjogren's syndrome patients with normal salivation. AB - BACKGROUND: Reduced salivation is considered a major clinical feature of most but not all cases of primary Sjogren's syndrome (pSS). Reduced saliva flow may lead to changes in the salivary microbiota. These changes have mainly been studied with culture that typically recovers only 65% of the bacteria present. OBJECTIVE: This study was to use high throughput sequencing, covering both cultivated and not-yet-cultivated bacteria, to assess the bacterial microbiota of whole saliva in pSS patients with normal salivation. METHODS: Bacteria of whole unstimulated saliva from nine pSS patients with normal salivation flow and from nine healthy controls were examined by high throughput sequencing of the hypervariable region V1V2 of 16S rRNA using the 454 GS Junior system. Raw sequence reads were subjected to a species-level, reference-based taxonomy assignment pipeline specially designed for studying the human oral microbial community. Each of the sequence reads was BLASTN-searched against a database consisting of reference sequences representing 1,156 oral and 12,013 non-oral species. Unassigned reads were then screened for high-quality non-chimeras and subjected to de novo species level operational taxonomy unit (OTU) calling for potential novel species. Downstream analyses, including alpha and beta diversities, were analyzed using the Quantitative Insights into Microbial Ecology (QIIME) pipeline. To reveal significant differences between the microbiota of control saliva and Sjogren's saliva, a statistical method introduced in Metastats www.metastats.cbcb.umd.edu was used. RESULTS: Saliva of pSS patients with normal salivation had a significantly higher frequency of Firmicutes compared with controls (p=0.004). Two other major phyla, Synergistetes and Spirochaetes, were significantly depleted in pSS (p=0.001 for both). In addition, we saw a nearly 17% decrease in the number of genera in pSS (25 vs. 30). While Prevotella was almost equally abundant in both groups (25% in pSS and 22% in controls), about a twofold increase in pSS of Streptococcus (28% vs. 17%) and Veillonella (26% vs. 12%) was detected. Prevotella melaninogenica was the major species in controls (13%) while Veillonella atypica and the Veillonella parvula groups dominated in patient samples (14 and 14%). The scarcity in bacterial species in pSS compared with controls was also demonstrated by alpha and beta diversity analyses, as well as read abundance depicted in a phylogenetic tree. CONCLUSIONS: While Firmicutes was significantly higher in pSS patients than in controls, Synergistetes and Spirochaetes were significantly lower. The number of bacterial genera and species was also lower. These data showed that microbial dysbiosis is another key characteristic of pSS whole saliva which can occur independent of hyposalivation. PMID- 27770522 TI - FACTORS ASSOCIATED WITH DEPRESSIVE EPISODE IN PATIENTS HOSPITALIZED WITH ACUTE CORONARY EVENTS. AB - Severe infarction or its consequences are considered as triggering factors of incidental depression. The aim of our study was to reveal factors associated with depressive episode in patients hospitalized with acute coronary syndrome (acute myocardial infarction, unstable angina). The Beck Depression inventory (BDI) was used for assessment of depressive symptoms in patients with coronary disease in Emergency Cardiology Clinic Tbilisi, Georgia. The study sample included 84 patients. The clinical Information was collected from hospital recordings. The chi-square test was used for assessment the difference between groups. Independent t-test was used to compare means for numerical variable "age". A binary logistic regression was applied in order to assess a relationship between disease severity factors (ejection fraction and revascularization) and depressive episode. Study sample included 79% of men and 21% of women with a mean age 59 years. Coronary obstruction as well as cardiac risk factors was revealed in majority of participants. The mean depression score was 13.0, while BDI score > 16 was revealed in 28.6% of patients. In the binary regression model ejection fraction was inversely associated with depressive episode even after adjustment to the age, gender and coronary risk factors. When disease severity markers (ejection fraction, revascularization) together with classic risk factors were included into the model, they explained only 42% of depressive episodes. It may be concluded that disease severity markers together with classic cardiac risk factors explain only partially depressive episode in patients, hospitalized for acute coronary events. A multidisciplinary approach is needed in order to provide optimal care and improve prognosis of patients with acute coronary syndrome (ACS). PMID- 27770523 TI - POSSIBLE MECHANISM OF DEVELOPMENT OF SALT SENSITIVE ESSENTIAL HYPERTENSION. AB - It has been known that salt-sensitivity of blood pressure is defined genetically as well as can be developed secondary to either decreased renal function or by influence of other environmental factors. The aim of the study was to evaluate the possible mechanism for the development of salt-sensitive essential hypertension in the population of Georgia. The Case-Control study included 185 subjects, 94 cases with Essential Hypertension stage I (JNC7) without prior antihypertensive treatment, and 91 controls. Salt-sensitivity test was used to divide both case and control groups into salt-sensitive (n=112) and salt resistant (n=73) subgroups. Endogenous cardiotonic steroids, sodium and PRA were measured in blood and urine samples at the different sodium conditions. Determinations of circulating levels of endogenous sodium pump inhibitors and PRA were carried out using the ELISA and RIA methods. Descriptive statistics were used to analyze the data. Differences in variables between sodium conditions were assessed using paired t-tests. Salt-sensitivity was found in 60.5% of total population investigated, with higher frequency in females. Salt-sensitivity positively correlated with age in females (r=0.262, p<0.01). Statistically significant positive correlation was found between 24 hour urine sodium concentration changes and salt-sensitivity r=0.334, p<0.01. Significant negative correlation was found between salt-sensitivity and PRA. Since no significant correlations were found between BMI and salt-sensitivity, we assume that BMI and salt-sensitivity should be discussed as different independent risk factors for the development of Essential Hypertension. Significant correlation was found between changes in GFR in salt-sensitive cases and controls p<0.01. This can be explained with comparable hyperfiltration of the kidneys at high sodium load and discussed as early sign of hypertensive nephropathy in salt-sensitive individuals. At the high sodium condition Endogenous MBG and OU were high in salt sensitive subjects compared to salt-resistant. These compounds decreased after low salt diet in salt-sensitive cases as well as controls but remained within the same level in salt-resistant individuals. MBG and OU levels positively correlated with SBP in salt-sensitive individuals but salt-resistant subjects didn't show any changes. Our results support the idea that chronic high sodium loading (>200 mmol) which is typical in traditional Georgian as well as other diets switch those humoral and pathophysiological mechanisms that can lead to the development of certain type of hypertension in salt-sensitive individuals. Salt intake reduction can prevent development of hypertension in salt-sensitive subjects, although hypertension develops in the salt-resistant individuals but by other mechanism such as RAAS. PMID- 27770524 TI - ASSOSIATION OF ENDOGENOUS CARDIOTONIC STEROIDS WITH SALT-SENSITIVITY OF BLOOD PRESSURE IN GEORGIAN POPULATION. AB - This investigation differentiates types of essential hypertension in a Georgian population as well as describes endogenous cardiotonic steroids in salt-sensitive and salt-resistant subjects. This case control study included 185 subjects: 94 cases with stage 1 essential hypertension (JNC7) naive to antihypertensive treatment, and 91 controls. A salt-sensitivity test was used to dichotomize case and control groups into salt-sensitive and salt-resistant subgroups. Blood and urine samples were obtained to categorize participants as consuming high and low salt diets. Endogenous cardiotonic steroids, sodium and plasma-renin activity (PRA) were measured in both samples at the different sodium conditions. Determinants of circulating levels of endogenous sodium pump inhibitors were carried out using the ELISA and RIA methods; PRA was assessed by radioimmunoassay. Descriptive statistics were used to analyze the data. Differences in variables between sodium conditions were assessed using paired t tests. Salt-sensitivity was found in 60.5% of the total population investigated, with a higher proportion in females. A statistically significant positive correlation was found between salt-sensitivity and age in females (r=0.262, p<0.01), and with 24-hour urine sodium concentration changes (r=0.334, p<0.01). A significant negative correlation was found between salt-sensitivity and PRA. At the high sodium condition, endogenous MBG and OU were high in salt-sensitive subjects compared to those who were salt-resistant. These compounds decreased with a low-salt diet in both salt-sensitive cases and controls but remained the same in salt-resistant individuals. The MBG and OU levels positively correlated with systolic blood pressure in salt-sensitive individuals but no variability was evident among salt-resistant subjects. Our results show that MBG and OU levels start to increase at the normotensive stage and sustained high concentrations can lead to elevated systolic blood pressure, a risk factor for arterial hypertension in salt-sensitive subjects. PMID- 27770525 TI - EPIDEMIOLOGY OF CLINICALLY MANIFESTED ACUTE HEPATITIS C CASES IN GEORGIA. AB - Hepatitis C virus is responsible for the majority of persistent viral infections of the liver, chronic hepatitis, liver cirrhosis and/ or hepatocellular carcinoma. Two strategies are important to curtailing the rising prevalence of disease: efficient diagnosis of acute hepatitis and identification of the likely mode of transmission. The aim of this study was to identify the clinical and epidemiological hallmarks of acute hepatitis C. During 2013-2015, 31 patients were hospitalized with a diagnosis of acute C hepatitis. According to epidemiological data, the primary mode of transmission is during medical procedures, responsible for 14 (45.16%) of cases, followed by injection drug use 3 (9.7%) of cases and sexual transmission - 2 (6.43%) of cases. However, in 12 (38.71%) of cases the infected individual was unable identify the likely source of infection. Given that nearly half of all cases arise from nosocomial infection, it is imperative that infection control practices be reviewed and resources provided to prepare a sterile environment for patients and health care providers. PMID- 27770526 TI - GENOTYPIC DISTRIBUTION OF HPV AMONG WOMEN OF REPRODUCTIVE AGE IN GEORGIA. AB - Of the 100 types of human papillomaviruses (HPV), approximately 35 infect the genital tract. The viruses are categorized as "high risk" and "low risk" depending on whether they are known to cause cancer or not. Cervical cancer is an important cause of cancer mortality in Georgia, and worldwide. Only limited and incomplete data are available about the epidemiology of HPV infection and related molecular and cellular changes in Georgia. Objectives of our study included the estimation of the prevalence and the distribution of HPV genotypes among women in Georgia. The study participants were women (~2000) aged 18-49 years randomly selected during a clinic appointment with a gynecologist for a regular check-up at one of the women's consultation centers (WCC) participating in the study. Venous blood (5 ml) was drawn and the prevalence of HPV evaluated by the detection of the HPV DNA. For genotyping, HPV DNA were extracted from the cervical samples, amplified first by consensus and then by primer-specific PCR, followed by a detection step on agarose gel. Of the total samples, 250 were positive for HPV DNA; these were further tested to identify the specific HPV genotype. The genotype distribution was as follows: type 6, 98 women (39.2 %); type 16, 64 (25.6%); type 18, 47 (18.8%); type 33, 23 (9.2%); type 11, 27 (10.8%); type 45, 19 (7.6%); and type 66, 9 (3.6%). In 37 women (14.8%), we found coexistence of several different HPV genotypes. The HPV genotypic profile among Georgian women is similar to data generated from studies conducted among the populations in other European countries. Presence of the subset of HPV genotypes not covered by quadrivalent anti-HPV vaccine (types 33, 45 and 66) was demonstrated among Georgian women. PMID- 27770527 TI - ROLE OF VIRAL PATHOGENS IN INFANTS WITH SYSTEMIC INFECTION AT THE NEWBORN INTENSIVE CARE UNITS IN GEORGIA. AB - In Georgia, causative agents among infants with systemic infections are generally not identified and "neonatal sepsis" is usually diagnosed and treated without determining the etiology. The objective of this study was to estimate the role of viral pathogens (Herpesviridae and Enteroviruses) among neonates with generalized infections. A cross-sectional study was performed among neonates younger than <8 weeks admitted to a neonatal intensive care unit (NICU) at the two largest pediatric hospitals in Tbilisi, Georgia. Laboratory tests were performed by consensus and then by type-specific PCR methods. A total of 187 infants were recruited from the NICUs; most participants (74.9%) were of normal birth weight at admission to the NICU and half (51.3%) were younger than 7 days of age. Almost all babies (91.4%) were treated with a broad-spectrum antibiotic despite a lack of microbe identification. While the overall mortality rate of infants with a systemic infection was 21.9 %, neonatal outcomes were more favorable when the infection was due to enteroviruses (2.9% mortality rate) compared to a herpesvirus infection (16.1% mortality rate). Multivariate analyses identified independent predictors associated with neonatal mortality. These included etiology of infection, APGAR score and the type of delivery. Our investigation suggests that viral pathogens play a substantial role in systemic infections among NICU infants. Utilizing molecular-based testing in these cases could improve both the clinical management and outcomes of neonates with generalized infections. PMID- 27770528 TI - BACTERIOLOGICAL EXAMINATION OF THE ABDOMINAL EFFUSION IN BACTERIAL PERITONITIS. AB - This study provides a contemporary epidemiology of aspirates taken during surgery from the abdominal cavity among patients with bacterial peritonitis to identify the isolates and study their sensitivity to antibiotics. Our bacteriology investigations included isolation of poor cultures, and detection of microbes was conducted using a rapid identification system (API20E, API Staph, API Strep, API Ana, BioMerieux). Rapid tests for detection of oxidase and catalase activity were also used. Susceptibility of microorganisms to antibiotics was defined by the disc-diffusion method using standard discs (EUCAST guidelines 2015) according to Clinical Laboratory Standard Institute (CLSI) protocols (ATB strips: ATB G, ATB Staph, ATBANA, ATBPse, ATBStrep. BioMerieux). The recovery rate from the clinical samples was good, likely because our protocol immediately inoculated study material into the thioglycollate broth which is an appropriate medium both for aerobic and anaerobic bacteria. Among the 36 patients with monomicrobial growth by bacteriological investigation, Gram-negative bacteria prevailed; Escherichia coli was recovered in 14 patients and Enterobacter cloacae in 9 patients. Among the Gram-positive bacteria, D-group Streptococci were prevalent, Enterococcus faecalis was found in six patients, Staphylococcus aureus in three patients, Candida albicans in two patients. In one patient, we observed dual colonization of two Gram-negative anaerobes Bacteroides fragilis and Fusobacterium spp. Polymicrobial growth was evident in three cases in the following combinations: Candida albicans and Escherichia coli, Enterobacter cloacae and Candida albicans, Escherichia coli and Bacteroides fragilis. Antibiotic susceptibility testing indicated that 12% of Gram-negative bacteria were resistant to quinolones and 19% to third-generation cephalosporins. No evidence of methicillin-resistant Staphylococcus aureus was found in Gram-positive specimens. The timely identification of microbes and administration of appropriate therapy based on antibiotic sensitivity profiles is important to optimizing clinical outcomes in bacterial peritonitis. PMID- 27770529 TI - DETECTION OF CTX-M GENE ANTIBIOTICS RESISTANCE IN KLEBSIELLA PNEUMONIA ISOLATES OF HOSPITALS IN ADJARA (GEORGIA). AB - Research describing the epidemiology of antibiotic resistant microbes is vital to the proactive development of new antimicrobial agents. In the last years, CTX-M extended-spectrum beta-lactamases (ESBLs) have emerged worldwide and have replaced classical TEM and SHV-type ESBLs in many countries. CTX-M-15 is currently the most frequent, with a pandemic distribution, and its rapid spread is facilitated by incorporation of resistance genes in mobile genetic elements. The ESBL is efficacious in Gram-negative bacteria and thus closely associated with nosocomial environments, often colonizing the intestines, particularly in older and dependent patients. Little is known about the CTX-M ESBLs among Klebsiella pneumonia in Adjara. Our paper describes the detected and characterized ESBLs among Klebsiella pneumonia isolates from patients in two different hospitals in Adjara. PMID- 27770530 TI - SOME CLINICALLY IMPORTANT ERYTHROCYTE BLOOD GROUP ANTIGENS IN DONORS. AB - The distribution of erythrocyte blood group antigens was evaluated among 656 donors; samples were provided by the diagnostic laboratory "Medina" Ltd Health Centre of Batumi. Lab analysis of the sample was conducted by the immunogenetics laboratory at Batumi Shota Rustaveli State University. The frequency of the ABO allele system in donors was as follows: r (0.70), q (0.23), p (0.07). The distribution of Rhesus (Rh) factor in the donor population was as follows: Rh(-) was found among 16.3+/-1.43% of investigated donors; the Rh(+) phenotype was found in 83.7+/-1.43% of donors. Additionally, the CcDee phenotype frequency was 29.9+/-1.78%; CCD-ee was 17.2+/-1.47%; ccddee was 14.9+/-1.38%; and CcD-Ee was 13.9+/-1.34%; ccD-Ee phenotype was 11.1+/-1.22%; ccD-ee was 5.5+/-0.88%; same phenotype indicators -2.1+/-0.55 were observed for CcD-EE and ccD-EE; CCD-Ee was 1.4+/-0.45%, CCD-EE was 0.4+/-0.26%; and finally, the frequency of Ccddee phenotype amounts was 1.1+/-0.40%, ccddEe and CCddee phenotypes were both 0.2+/ 0.17%. The analysis of the Kell system allele revealed a low frequency for the p allele at 0.05, whereas the frequency of the q allele was 0.95. This large epidemiologic analysis of donor blood provides valuable information for hematological and transfusion centers to inform the preparation of blood components for transfusion. PMID- 27770531 TI - SMOKING INCLINED GROUPS ACCORDING TO THE PHENOTYPE OF THE PTC GENE. AB - The ability to sense phenylthiocarbamide (PTC) bitterness represents a well-known and convenient genetic marker for human populations and biomedical studies. Two basic phenotypes can be dichotomized by PTC sensitivity: PTC-sensitive or "tester" and PTC-insensitive or "non-tester". The majority of the population (approximately 70%) belong to the PTC-sensitive phenotype, while the remaining 30% are PTC-insensitive. The distribution of PTC sensitivities varies by consumption of alcohol, bitter coffee and cigarettes. This study was conducted among randomly selected 90 cigarette smokers living in the Ajara Region of Georgia. Our results indicate that PTC-insensitive phenotypes are correlated with cigarette consumption and should be considered as an important genetic proxy for cigarette use. This marker may prove very useful for identifying adolescents who might benefit from a focused smoking prevention intervention. PMID- 27770532 TI - IMPACT OF SOME ENVIRONMENTAL FACTORS ON HUMAN HEALTH. AB - This paper presents statistical data of 2012-2015 on the diseases caused by the atmospheric air and water pollutions in Ajara region. The research on the content of dust, sulfur dioxide and nitrogen dioxide as well as carbon monoxide in the atmospheric air was held together with the National Environment Agency Ajara Monitoring Service. The results of the research have shown that the average content of the dust reached its maximum in 2012 (0.60 mg/m3) and it dropped to the minimum in 2015 (0.441 mg/m3). As for average content of carbon monoxide the maximum was observed in 2013 (3.1 mg/m3) and minimum in 2015 (2.1 mg/m3). Average content of the sulfur dioxide was at maximum in 2015 (0.159 mg/m3) and at minimum in 2012 (0.07 mg/m3). The average content of nitrogen dioxide reached its maximum in 2015 (0.153 mg/m3) and was found to be at its minimum in 2012 (0.13 mg/m3). In parallel statistical research of the registered diseases (chronic and undetermined bronchitis, asthma, allergic rhinitis and trachea/bronchi/lung malignant cancer) in Ajara during 2012-2015 has been performed. These diseases were especially common among the population over the age of 40. It may be concluded that in 2015 the cases of diseases caused by the atmospheric air pollution in Ajara have become more frequent compared to the previous years. Therefore, it is evident that monitoring of atmosphere air should be improved and corresponding preventive measures should be undertaken. PMID- 27770533 TI - KNOWLEDGE, ATTITUDE TOWARD DISEASE AND PRACTICE SURVEY ON DIABETES IN GARDABANI DISTRICT. AB - In 2014-2016, the Georgia Red Cross Society (GRCS) implemented a project to improve diabetes prevention, detection and care in rural Georgia, namely in the Gardabani district. The KAP survey was conducted to determine current levels of knowledge, attitudes and practices regarding diabetes among the general population in the Gardabani district. We compared current findings with baseline results from a 2014 survey to identify trends. A cross sectional study design with multi-stage random sampling was used to select participants. Data were collected at households through face-to-face individual interviews using a specially designed questionnaire. In total, 716 individuals were surveyed, the majority of whom (98.9%) were aware of diabetes. Most respondents (85.3%) believed that diabetes can be prevented and correctly identified measures of diabetes prevention. Compared to the previous survey, the level of knowledge regarding risk factors, symptoms and complication of diabetes had improved significantly. Knowledge of diabetes prevention correlated positively with individuals having a higher education level (62.6% vs. 50.8%; p=0.05), higher family income (62.2% vs. 53.5%; p=0.03) and residing in rural settlements (58.6% vs. 25%; p<0.001). Knowledge of diabetes management was significantly associated with type of residence (rural 50.3% vs. urban 28.4%; p<0.001) and family income (high family income 52.3% vs. low family income 45.5%; p=0.05). Respondents identifying GRCS as a source of information tended to have a higher awareness of diabetes prevention and management. Knowledge of diabetes has significantly improved among the general population of the Garabani district from 2014 to 2016. The development and implementation of similar public health programs to increase the level of awareness and knowledge about diabetes is required in other parts of Georgia to improve control and management of the disease throughout the country. PMID- 27770534 TI - CLOSTRIDIAL PARAPROCTITIS WITH GAS GANGRENE OF FRONT-LATERAL ABDOMINAL WALLS AND NECROTIC FASCIO-MYOSITIS (CASE REPORT). AB - Anaerobic clostridial infection is the most severe form of paraproctitis. The incubation period is very short, from 3 to 6 hours, sometimes lasting for 1-2 days. Clostridial infection spreads rapidly and induces gas gangrene, causes destruction of cells and other intermediate substances, and impedes blood circulation. This paper presents a case study of an extremely severe form of anaerobic infection with spontaneous gas gangrene, cellulitis, fasciomyositic necrosis, severe intoxication and septic shock on the abdominal front and lateral surfaces. This patient presented as infected with Clostridium septicum, a rare and highly toxic Gram-positive, spore-forming, obligate anaerobic bacillus that progresses and migrates rapidly, affecting all soft tissues (muscle, fascia), and produces four toxins which cause gas gangrene, intravascular hemolysis, tissue necrosis, and septic shock. The mortality rate is typically 80%. In this case study, a positive clinical outcome was achieved by aggressive identification of the microbe, appropriate and immediate therapy, and vigorous surgical intervention. Specifically, immediate surgery was conducted to ensure a wide excision of damaged tissues, necrectomy, curettage, wide drainage, readjustment, oxygenation through drainages, further additional surgical corrections through CT control with wide bandages in the operating area. Further, the diagnostic workup was thorough, identifying the microbe through a properly constructed diagnostic algorithm, ultrasound and CT studies, infectious agent assessments, and bacteriological monitoring carried out on the 1st-2nd-5th-7th-12th-15th-21st-25th days. Rational antibiotic therapy with permanent susceptibility testing informed the selection of an appropriate agent. Finally, markers for the evaluation of severity (Apache scale) were assessed, as they were for stage of infection (prokalcitonin), inflammation (CRP) and other indicators. PMID- 27770535 TI - CONFLICT IN EASTERN UKRAINE: STRATEGY FOR TUBERCULOSIS. AB - This root cause analysis concerns the conflict in the Eastern Ukraine and its impact on healthcare delivery in the context of treating internally displaced persons (IDPs). Inadequate treatment of tuberculosis (TB) was selected as a major topic for intervention planning in conflict areas in Ukraine. With respect to treating TB among IDPs, rapid diagnosis and adequate nutrition and shelter are important components of care and disease control. The DOT, supported by trained primary healthcare providers equipped with rapid MDR TB diagnostic capacities, need to provide appropriate shelter and nutrition to IDPs. In addition to active disease management, this paper discusses the important role of ongoing project monitoring and communicating evaluation findings with all the major stakeholders shaping the national TB strategy in Ukraine. A comprehensive strategy is essential for successful transitioning and re-structuring of TB healthcare delivery both during after conflict resolution. PMID- 27770536 TI - IMPORTANT ASPECT OF HEALTH CARE ASSOCIATED INFECTIONS IN GEORGIA WITH THE FOCUS ON VENTILATOR-ASSOCIATED PNEUMONIA (REVIEW). AB - Health care associated infections are the most frequent adverse event accompanying healthcare delivery worldwide. Of these, respiratory tract infections, including ventilator-associated pneumonia (VAP), have been recognized as the most common infections in acute hospitals. Sparse anecdotal and epidemiologic data from intensive care units (ICU) and infectious diseases physicians, as well as several publications in this field, suggest that the etiology of VAP in Georgia is most likely Klebsiella pneumoniae. This review article discusses the challenges of infection control in the Georgian health care system, with a focus on VAP. We present the most significant risk factors as well as potential strategies to remediate infection control practices and reduce the prevalence of VAP. PMID- 27770537 TI - IMMUNOGENETIC FACTORS INFLUENCING CLINICAL COURSE OF HCV INFECTION (REVIEW). AB - Hepatitis C virus (HCV) infection remains one of the most important blood-borne diseases worldwide with about 130-170 million people chronically infected with hepatitis C virus, and more than 350 000 people die from hepatitis C-related liver diseases each year. Infection with HCV becomes chronic in approximately 80% of cases, while in up to 20% of cases hepatitis C virus is cleared from the human organism. Chronic infections of hepatitis C often leads to the end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The clinical course and the outcome of the HCV infection is determined by the complex interplay between the viral replication and the host defense mechanisms. Several recent studies have shown that MHC class I and class II as well as natural killer (NK) cell's immunoglobulin-like receptors (KIR) loci can be associated with the HCV protection and clearance as well as with disease progression and responsiveness to antiviral treatment. Current status of our knowledge about the influence of immunogenetic factors on the clinical course of HCV infection is presented in the paper. Plans to investigate these factors among HCV infected patients enrolled in the HCV Elimination Program (launched in April 2015 in Georgia) are discussed. PMID- 27770538 TI - RAPID IDENTIFICATION OF THE ETIOLOGICAL FACTORS CAUSING DIARRHEAL DISEASES. AB - The main objective of this investigation was to develop and pilot a real-time Polymerase Chain Reaction (rt-PCR) diagnostic system for rapid and simultaneous identification of pathogens with a particular emphasis on diarrheal disease diagnostics. The diarrheal diseases were selected as a target for the pilot because they constitute a primary public health priority in Georgia and worldwide. The product developed by our research team "Neo_PCR_Diagnostics" represents an original system for the identification of pathogens associated with gastrointestinal tract infections and diarrhea. The advantages of the proposed technology over existing conventional methods include the ability of simultaneous identification of multiple pathogens and the detection of pathogenic agents directly from the fecal samples. For the evaluation of the new diagnostic system, stool samples were collected at collaborating hospitals and clinics and analyzed by real-time PCR using the Neo_PCR_Diagnostic system. The selection of the pathogens for detection was based on their epidemiological and clinical importance. The following bacterial pathogens were targets for detection: Salmonella spp., Campylobacter spp., Shigella spp., Clostridium difficile (Toxin A/B), Escherichia coli (ETEC, STEC and O157), Yersinia enterocolitica and Vibrio cholerae. The following viral pathogens were studied: adenoviruses, rotaviruses and noroviruses. Genetic material (DNA) of the following parasites were targets in our study: Giardia lamblia, Entamoeba histolitica and Cryptosporidium spp. We also compared the results obtained by our molecular technology with the conventional methods - bacterial culture (for bacterial growth) and ELISA (for bacterial toxins). For viral and parasitic pathogens, comparison tests were performed with immunochromatographic assays for direct detection of antigens in the stool samples or with the data obtained by use of home-made end-point PCR (where available). Advantages of the proposed technology over existing conventional technologies include the ability of simultaneous identification of diarrheal infections by multiple pathogens. The proposed test system allows the detection of pathogenic agents directly from the fecal samples and can be completed within one working day. In general, the spectrum of pathogens detected by our approach was wider than those detected by the conventional methods used in the clinical setting, taking into consideration the list of pathogenic agents requisitioned by physicians within the framework of the routine clinical visit. Given these promising results, Neo_PCR_Diagnostics test performance and accuracy may be sufficient for use in molecular microbiological diagnostics in clinical and/or research settings. PMID- 27770539 TI - Inhibiting MicroRNA-503 and MicroRNA-181d with Losartan Ameliorates Diabetic Nephropathy in KKAy Mice. AB - BACKGROUND Diabetic nephropathy (DN) is the most lethal diabetic microvascular complication; it is a major cause of renal failure, and an increasingly globally prominent healthcare problem. MATERIAL AND METHODS To identify susceptible microRNAs for the pathogenesis of DN and the targets of losartan treatment, microRNA arrays were employed to survey the glomerular microRNA expression profiles of KKAy mice treated with or without losartan. KKAy mice were assigned to either a losartan-treated group or a non-treatment group, with C57BL/6 mice used as a normal control. Twelve weeks after treatment, glomeruli from the mice were isolated. MicroRNA expression profiles were analyzed using microRNA arrays. Real-time PCR was used to confirm the results. RESULTS Losartan treatment improved albuminuria and the pathological lesions of KKAy mice. The expression of 10 microRNAs was higher, and the expression of 12 microRNAs was lower in the glomeruli of the KKAy untreated mice than that of the CL57BL/6 mice. The expression of 4 microRNAs was down-regulated in the glomeruli of the KKAy losartan-treated mice compared to that of the untreated mice. The expression of miRNA-503 and miRNA-181d was apparently higher in the glomeruli of the KKAy untreated mice, and was inhibited by losartan treatment. CONCLUSIONS The over expression of miR-503 and miR-181d in glomeruli of KKAy mice may be responsible for the pathogenesis of DN and are potential therapeutic targets for DN. PMID- 27770540 TI - A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia. AB - MicroRNA-9-1(miR-9-1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR-9-1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR-9-1 downregulation and the RUNX1-RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1-RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1-RUNX1T1-containing transcription factor complex. In this study, we demonstrate that miR-9-1 expression increases significantly after the treatment of RUNX1-RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1-RUNX1T1 triggers the heterochromatic silencing of miR-9-1 by binding to RUNX1-binding sites in the promoter region of miR-9-1 and recruiting chromatin-remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR-9-1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1-RUNX1T1 are all regulated by miR-9-1, the silencing of miR-9-1 enhances the oncogenic activity of these genes. Besides, overexpression of miR-9-1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR-9-1 and RUNX1-RUNX1T1, contributing to leukemogenesis in RUNX1-RUNX1T1 (+) AML cell lines. PMID- 27770541 TI - Feasibility and preliminary effects of a screening, brief intervention and referral to treatment model to address gender-based violence among women who use drugs in Kyrgyzstan: Project WINGS (Women Initiating New Goals of Safety). AB - INTRODUCTION AND AIMS: Intimate partner violence (IPV) and other forms of gender based violence (GBV) are serious public health threats among women who use drugs or engage in binge drinking in Kyrgyzstan. This study aimed to evaluate the feasibility and preliminary effects of a two-session IPV and GBV screening, brief intervention and referral to treatment model (WINGS) with HIV counselling and testing for women who use drugs or engage in binge drinking in Kyrgyzstan, using a pre/post-design. DESIGN AND METHODS: We screened 109 women from harm reduction non-government organisations in Kyrgyzstan, of whom 78 were eligible, 73 participated in the intervention study, and 66 completed a 3-month post intervention follow-up. To assess the effects of the intervention, we used random effect Poisson and Logistic regression analyses for continuous and dichotomous outcomes respectively. RESULTS: At baseline, 73% reported any physical or sexual IPV victimisation, and 60% reported any physical or sexual GBV victimisation in the past year. At the 3-month follow-up, participants reported experiencing 59% fewer physical IPV incidents in the prior 90 days than at baseline (P < 0.001) and 27% fewer physical GBV incidents than at baseline (P < 0.01). From baseline to the 3-month follow-up, participants also reported a 65% reduction in the odds of using any illicit drugs (P < 0.05) and were more likely to report receiving GBV-related services (P < 0.001). DISCUSSION AND CONCLUSION: The high rates of participation, attendance and retention and significant reductions in IPV and GBV victimisation and drug use from baseline to the 3-month follow-up suggest the feasibility and promising effects of this brief intervention. [Gilbert L, Jiwatram-Negron T, Nikitin D, Rychkova O, McCrimmon T, Ermolaeva I, Sharonova N, Mukambetov A, Hunt T. Feasibility and preliminary effects of a screening, brief intervention and referral to treatment model to address gender-based violence among women who use drugs in Kyrgyzstan: Project WINGS (Women Initiating New Goals of Safety). Drug Alcohol Rev 2017;36:125-133]. PMID- 27770544 TI - Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized Exocyclic C=C Bonds. AB - An iridium-catalyzed asymmetric hydrogenation of unfunctionalized exocyclic C=C bonds was performed by using an axially flexible chiral phosphine-oxazoline ligand, providing the desired chiral 1-benzyl-2,3-dihydro-1H-indene products with up to 98 % ee (enantiomeric excess). This represents the first general hydrogenation of unfunctionalized exocyclic olefins with high selectivity reported thus far. The additive acetate ion plays an important role in the reaction's high enantioselectivity. The chiral product can be further transformed into key intermediates required for the synthesis of an important insecticide and a drug compound. PMID- 27770542 TI - Sertraline use in the first trimester and risk of congenital anomalies: a systemic review and meta-analysis of cohort studies. AB - AIM: To perform a meta-analysis of available cohort studies on the association between sertraline use by pregnant women in the first trimester and the findings of congenital anomalies in infants. METHODS: A comprehensive search of articles published from the index date up to 31st December 2015 investigating the aforementioned associations was conducted on PubMed and Web of Science. Mesh headings used included the terms "serotonin reuptake inhibitor," "sertraline," "congenital anomalies" and "obstetrical outcome." RESULTS: Twelve cohort studies that involved 6 468 241 pregnant women were identified. We summarized odds ratios (ORs) and 95% confidence intervals (CIs) of congenital anomalies using the random effects model. Pregnant women who used sertraline in the first trimester had a statistically significant increased risk of infant cardiovascular-related malformations (OR = 1.36; 95% CI = 1.06-1.74; I2 = 64.4%; n = 12) as well as atrial and/or ventricular septal defects (OR = 1.36, 95% CI = 1.06-1.76; I2 = 62.2%; n = 8). Additionally, positive but nonsignificant associations between sertraline use and congenital anomalies of the nervous system (OR = 1.39; 95% CI = 0.83-2.32; I2 = 0%; n = 5), digestive system (OR = 1.23; 95% CI = 0.76-1.98; I2 = 0%; n = 5), eye, ear, face and neck (OR = 1.08; 95% CI = 0.33-3.55; I2 = 32.1%; n = 3), urogenital system (OR = 1.03; 95% CI = 0.73-1.46; I2 = 0%; n = 5), and musculoskeletal system (OR = 0.97; 95% CI = 0.69-1.36; I2 = 0%; n = 5) were observed. CONCLUSION: This meta-analysis suggested that the use of sertraline use by pregnant women in the first trimester had an increased risk of cardiovascular-related malformations as well as atrial and/or ventricular septal defects in infants. Meanwhile, nonsignificant associations between sertraline use and other congenital anomalies were found. More cohort studies are warranted to provide detailed results of other congenital anomalies. PMID- 27770543 TI - Uptake of hepatitis C screening, characteristics of patients tested, and intervention costs in the BEST-C study. AB - : From December 2012 to March 2014, three randomized trials, each implementing a unique intervention in primary care settings (repeated mailing, an electronic health record best practice alert [BPA], and patient solicitation), evaluated hepatitis C virus (HCV) antibody testing, diagnosis, and costs for each of the interventions compared with standard-of-care testing. Multilevel multivariable models were used to estimate the adjusted risk ratio (aRR) for receiving an HCV antibody test, and costs were estimated using activity-based costing. The goal of this study was to estimate the effects of interventions conducted as part of the Birth-Cohort Evaluation to Advance Screening and Testing for Hepatitis C study on HCV testing and costs among persons of the 1945-1965 birth cohort (BC). Intervention resulted in substantially higher HCV testing rates compared with standard-of-care testing (26.9% versus 1.4% for repeated mailing, 30.9% versus 3.6% for BPA, and 63.5% versus 2.0% for patient solicitation) and significantly higher aRR for testing after controlling for sex, birth year, race, insurance type, and median household income (19.2 [95% confidence interval (CI), 9.7-38.2] for repeated mailing, 13.2 [95% CI, 3.6-48.6] for BPA, and 32.9 [95% CI, 19.3 56.1] for patient solicitation). The BPA intervention had the lowest incremental cost per completed test ($24 with fixed startup costs, $3 without) and also the lowest incremental cost per new case identified after omitting fixed startup costs ($1691). CONCLUSION: HCV testing interventions resulted in an increase in BC testing compared with standard-of-care testing but also increased costs. The effect size and incremental costs of BPA intervention (excluding startup costs) support more widespread adoption compared with the other interventions. (Hepatology 2017;65:44-53). PMID- 27770545 TI - Template-based modeling and ab initio refinement of protein oligomer structures using GALAXY in CAPRI round 30. AB - Many proteins function as homo- or hetero-oligomers; therefore, attempts to understand and regulate protein functions require knowledge of protein oligomer structures. The number of available experimental protein structures is increasing, and oligomer structures can be predicted using the experimental structures of related proteins as templates. However, template-based models may have errors due to sequence differences between the target and template proteins, which can lead to functional differences. Such structural differences may be predicted by loop modeling of local regions or refinement of the overall structure. In CAPRI (Critical Assessment of PRotein Interactions) round 30, we used recently developed features of the GALAXY protein modeling package, including template-based structure prediction, loop modeling, model refinement, and protein-protein docking to predict protein complex structures from amino acid sequences. Out of the 25 CAPRI targets, medium and acceptable quality models were obtained for 14 and 1 target(s), respectively, for which proper oligomer or monomer templates could be detected. Symmetric interface loop modeling on oligomer model structures successfully improved model quality, while loop modeling on monomer model structures failed. Overall refinement of the predicted oligomer structures consistently improved the model quality, in particular in interface contacts. Proteins 2017; 85:399-407. (c) 2016 Wiley Periodicals, Inc. PMID- 27770547 TI - Visible-Light Promoted Distereodivergent Intramolecular Oxyamidation of Alkenes. AB - The visible-light-promoted diastereodivergent intramolecular oxyamination of alkenes is described to construct oxazolindinones, pyrrolidinones and imidazolidones via mild generation of primary amidyl radicals from functionalized hydroxylamines. A unique phenomenon of highly diastereoselective ring-opening of aziridines controlled by electron sacrifices was observed. Highly diastereoselective amino alcohols derivatives were obtained efficiently through this protocol in gram scales. The mechanistic studies suggested the isolatable anti-aziridine intermediates were generated quickly from primary amidyl radicals and the diastereoselectivities were controlled by pKa values of the electron sacrifices. PMID- 27770546 TI - Skeletal muscle patch engineering on synthetic and acellular human skeletal muscle originated scaffolds. AB - The reconstruction of skeletal muscle tissue is currently performed by transplanting a muscle tissue graft from local or distant sites of the patient's body, but this practice leads to donor site morbidity in case of large defects. With the aim of providing an alternative treatment approach, skeletal muscle tissue formation potential of human myoblasts and human menstrual blood derived mesenchymal stem cells (hMB-MSCs) on synthetic [poly(l-lactide-co-caprolactone), 70:30] scaffolds with oriented microfibers, human muscle extracellular matrix (ECM), and their hybrids was investigated in this study. The reactive muscle ECM pieces were chemically crosslinked to the synthetic scaffolds to produce the hybrids. Cell proliferation assay WST-1, scanning electron microscopy (SEM), and immunostaining were carried out after culturing the cells on the scaffolds. The ECM and the synthetic scaffolds were effective in promoting spontaneous myotube formation from human myoblasts. Anisotropic muscle patch formation was more successful when human myoblasts were grown on the synthetic scaffolds. Nonetheless, spontaneous differentiation could not be induced in hMB-MSCs on any type of the scaffolds. Human myoblast-synthetic scaffold combination is promising as a skeletal muscle patch, and can be improved further to serve as a fast integrating functional patch by introducing vascular and neuronal networks to the structure. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 879 890, 2017. PMID- 27770548 TI - Identification of Small-Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor. AB - The prolyl hydroxylase domain (PHD) protein:hypoxia inducible factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as erythropoietin (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N terminal MYND-type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-alpha hydroxylation. Targeting this motif could provide a means of specifically inhibiting this PHD isoform. Here, we screened a library of chemical compounds for their capacity to inhibit the zinc finger of PHD2. We identified compounds that, in vitro, can inhibit PHD2 binding to a PXLE-containing peptide and induce activation of HIF. Injection of one of these compounds into mice induces an increase in hematocrit. This study offers proof of principle that inhibition of the zinc finger of PHD2 can provide a means of selectively targeting PHD2 to activate the HIF pathway. PMID- 27770551 TI - Implantable chemotherapy-loaded silk protein materials for neuroblastoma treatment. AB - Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multicycle chemotherapies, resulting in short- and long-term toxicities. Here, we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment. The intratumoral drug concentration was significantly higher with intratumoral delivery versus IV. Furthermore, intratumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a "small-round-blue cell" (SBRC) to predominantly "large cell" neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor recurrence and developing more effective treatment strategies for recurrent tumors. PMID- 27770550 TI - An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female anorectal dysfunction. AB - INTRODUCTION: The terminology for anorectal dysfunction in women has long been in need of a specific clinically-based Consensus Report. METHODS: This Report combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted on Committee by experts in their fields to form a Joint IUGA/ICS Working Group on Female Anorectal Terminology. Appropriate core clinical categories and sub classifications were developed to give an alphanumeric coding to each definition. An extensive process of twenty rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for anorectal dysfunction, encompassing over 130 separate definitions, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Female-specific anorectal investigations and imaging (ultrasound, radiology and MRI) has been included whilst appropriate figures have been included to supplement and help clarify the text. Interval review (5-10 years) is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based Terminology Report for female anorectal dysfunction terminology has been produced aimed at being a significant aid to clinical practice and a stimulus for research. Neurourol. Urodynam. 36:10-34, 2017. (c) 2016 Wiley Periodicals, Inc., and The International Urogynecological Association. PMID- 27770552 TI - Ultrafast Photogenerated Hole Extraction/Transport Behavior in a CH3 NH3 PbI3 /Carbon Nanocomposite and Its Application in a Metal-Electrode-Free Solar Cell. AB - Aligned and flexible electrospun carbon nanomaterials are used to synthesize carbon/perovskite nanocomposites. The free-electron diffusion length in the CH3 NH3 PbI3 phase of the CH3 NH3 PbI3 /carbon nanocomposite is almost twice that of bare CH3 NH3 PbI3 , and nearly 95 % of the photogenerated free holes can be injected from the CH3 NH3 PbI3 phase into the carbon nanomaterial. The exciton binding energy of the composite is estimated to be 23 meV by utilizing temperature-dependent optical absorption spectroscopy. The calculated free carriers increase with increasing total photoexcitation density, and this broadens the potential of this material for a broad range of optoelectronics applications. A metal-electrode-free perovskite solar cell (power conversion efficiency: 13.0 %) is fabricated with this perovskite/carbon composite, which shows great potential for the fabrication of efficient, large-scale, low-cost, and metal-electrode-free perovskite solar cells. PMID- 27770549 TI - Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay. AB - : Bile acids (BAs) play critical physiological functions in cholesterol homeostasis, and deregulation of BA metabolism causes cholestatic liver injury. The long noncoding RNA maternally expressed gene 3 (MEG3) was recently shown as a potential tumor suppressor; however, its basic hepatic function remains elusive. Using RNA pull-down with biotin-labeled sense or anti-sense MEG 3RNA followed by mass spectrometry, we identified RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) as a MEG3 interacting protein and validated their interaction by RNA immunoprecipitation (RIP). Bioinformatics analysis revealed putative binding sites for PTBP1 within the coding region (CDS) of small heterodimer partner (SHP), a key repressor of BA biosynthesis. Forced expression of MEG3 in hepatocellular carcinoma cells guided and facilitated PTBP1 binding to the Shp CDS, resulting in Shp mRNA decay. Transient overexpression of MEG3 RNA in vivo in mouse liver caused rapid Shp mRNA degradation and cholestatic liver injury, which was accompanied by the disruption of BA homeostasis, elevation of liver enzymes, as well as dysregulation of BA synthetic enzymes and metabolic genes. Interestingly, RNA sequencing coupled with quantitative PCR (qPCR) revealed a drastic induction of MEG3 RNA in Shp-/- liver. SHP inhibited MEG3 gene transcription by repressing cAMP response element-binding protein (CREB) transactivation of the MEG3 promoter. In addition, the expression of MEG3 and PTBP1 was activated in human fibrotic and cirrhotic livers. CONCLUSION: MEG3 causes cholestasis by serving as a guide RNA scaffold to recruit PTBP1 to destabilize Shp mRNA. SHP in turn represses CREB-mediated activation of MEG3 expression in a feedback-regulatory fashion. (Hepatology 2017;65:604-615). PMID- 27770553 TI - Antiviral treatment and liver-related complications in hepatitis delta. AB - : Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG-IFNalpha) is effective in only 25%-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow-up, 5.2 years; range, 0.6-18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty-nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNalpha)-based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death developed in 55 patients (40%). Patients who received IFNalpha-based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNalpha therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07 0.9). Loss of HDV RNA during follow-up was more frequent in IFNalpha-treated patients and strongly linked with a lower likelihood to experience liver-related complications. CONCLUSION: IFNalpha-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425). PMID- 27770554 TI - Human liver sinusoidal endothelial cells promote intracellular crawling of lymphocytes during recruitment: A new step in migration. AB - : The recruitment of lymphocytes via the hepatic sinusoidal channels and positioning within liver tissue is a critical event in the development and persistence of chronic inflammatory liver diseases. The hepatic sinusoid is a unique vascular bed lined by hepatic sinusoidal endothelial cells (HSECs), a functionally and phenotypically distinct subpopulation of endothelial cells. Using flow-based adhesion assays to study the migration of lymphocytes across primary human HSECs, we found that lymphocytes enter into HSECs, confirmed by electron microscopy demonstrating clear intracellular localization of lymphocytes in vitro and by studies in human liver tissues. Stimulation by interferon-gamma increased intracellular localization of lymphocytes within HSECs. Furthermore, using confocal imaging and time-lapse recordings, we demonstrated "intracellular crawling" of lymphocytes entering into one endothelial cell from another. This required the expression of intracellular adhesion molecule-1 and stabilin-1 and was facilitated by the junctional complexes between HSECs. CONCLUSION: Lymphocyte migration is facilitated by the unique structure of HSECs. Intracellular crawling may contribute to optimal lymphocyte positioning in liver tissue during chronic hepatitis. (Hepatology 2017;65:294-309). PMID- 27770555 TI - Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer. AB - Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD = 9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD = 3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85, 95% CI = 0.82-0.88) but among men with T2DM, those on metformin had no decrease (HR = 0.96, 95% CI = 0.77-1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73, 95% CI = 0.55-0.98), compared to men with T2DM not on anti-diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR = 1.11, 95% CI = 0.95-1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk. PMID- 27770556 TI - Survival and cost-effectiveness of sorafenib therapy in advanced hepatocellular carcinoma: An analysis of the SEER-Medicare database. AB - : Sorafenib is the only chemotherapeutic approved for treatment of advanced hepatocellular carcinoma (HCC). However, its effectiveness in patients with Child Pugh class B cirrhosis and any moderating effects of health system characteristics are unclear. We examined the survival and cost-effectiveness associated with sorafenib in elderly patients with advanced HCC. We performed an analysis of Medicare beneficiaries with HCC diagnoses from 2007 to 2009. We compared advanced stage patients with HCC (American Joint Committee on Cancer stage III/IV) who received sorafenib within 6 months of diagnosis (and were otherwise untreated) to advanced stage patients with HCC who received no therapy (control). We performed univariate and multivariate analyses to identify predictors of survival. Incremental cost-effectiveness ratios (ICERs) were calculated for sorafenib-treated and control patients. We included 228 sorafenib treated patients and 870 control patients. The median survival of the sorafenib treated patients was 150.5 days versus 62 days for control patients. On multivariate analysis, significant predictors of improved survival were treatment with sorafenib (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57 0.77), being seen at a National Cancer Institute-designated cancer center (HR, 0.77; 95% CI, 0.62-0.97), and being seen at a transplantation center (HR, 0.77; 95% CI, 0.65-0.93). Predictors of worse survival included stage IV disease (HR, 1.40; 95% CI, 1.24-1.58), decompensated cirrhosis (HR, 1.49; 95% CI, 1.30-1.70), and treatment in an urban setting (HR, 1.45; 95% CI, 1.21-1.73.) Although sorafenib use was associated with a survival benefit (HR, 0.61; 95% CI, 0.47 0.79) among patients with decompensated cirrhosis, the median survival benefit was 31 days, and it was not cost-effective (ICER, $224,914 per life year gained). CONCLUSION: Sorafenib is associated with improved survival in elderly patients with advanced HCC; however, it is not cost-effective among those with hepatic decompensation. (Hepatology 2017;65:122-133). PMID- 27770557 TI - Aligning, analyzing, and visualizing sequences for antibody engineering: Automated recognition of immunoglobulin variable region features. AB - The analysis and comparison of large numbers of immunoglobulin (Ig) sequences that arise during an antibody selection campaign can be time-consuming and tedious. Typically, the identification and annotation of framework as well as complementarity-determining regions (CDRs) is based on multiple sequence alignments using standardized numbering schemes, which allow identification of equivalent residues among different family members but often necessitate expert knowledge and manual intervention. Moreover, due to the enormous length variability of some CDRs the benefit of conventional Ig numbering schemes is limited and the calculation of correct sequence alignments can become challenging. Whereas, in principle, a well established set of rules permits the assignment of CDRs from the amino acid sequence alone, no currently available sequence alignment editor provides an algorithm to annotate new Ig sequences accordingly. Here we present a unique pattern matching method implemented into our recently developed ANTICALIgN editor that automatically identifies all hypervariable and framework regions in experimentally elucidated antibody sequences using so-called "regular expressions." By combination of this widely supported software syntax with the unique capabilities of real-time aligning, editing and analyzing extended sets of amino acid and/or nucleotide sequences simultaneously on a local workstation, ANTICALIgN provides a powerful utility for antibody engineering. Proteins 2016; 85:65-71. (c) 2016 Wiley Periodicals, Inc. PMID- 27770558 TI - Expression of scavenger receptor-AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis. AB - : The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mphi) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mphi in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this report, we demonstrate that expression of C-type lectin receptor scavenger receptor-AI (SR-AI) is crucial for promoting M2-like Mphi activation and polarization during hepatic inflammation. Liver Mphi uniquely up regulated SR-AI during hepatotropic viral infection and displayed increased expression of alternative Mphi activation markers, such as YM-1, arginase-1, and interleukin-10 by activation of mer receptor tyrosine kinase associated with inhibition of mammalian target of rapamycin. Expression of these molecules was reduced on Mphi obtained from livers of infected mice deficient for the gene encoding SR-AI (msr1). Furthermore, in vitro studies using an SR-AI-deficient Mphi cell line revealed impeded M2 polarization and decreased phagocytic capacity. Direct stimulation with virus was sufficient to activate M2 gene expression in the wild-type (WT) cell line, but not in the knockdown cell line. Importantly, tissue damage and fibrosis were exacerbated in SR-AI-/- mice following hepatic infection and adoptive transfer of WT bone-marrow-derived Mphi conferred protection against fibrosis in these mice. CONCLUSION: SR-AI expression on liver Mphi promotes recovery from infection-induced tissue damage by mediating a switch to a proresolving Mphi polarization state. (Hepatology 2017;65:32-43). PMID- 27770559 TI - Fluorescent quantification of melanin. AB - Melanin quantification is reportedly performed by absorption spectroscopy, commonly at 405 nm. Here, we propose the implementation of fluorescence spectroscopy for melanin assessment. In a typical in vitro assay to assess melanin production in response to an external stimulus, absorption spectroscopy clearly overvalues melanin content. This method is also incapable of distinguishing non-melanotic/amelanotic control cells from those that are actually capable of performing melanogenesis. Therefore, fluorescence spectroscopy is the best method for melanin quantification as it proved to be highly specific and accurate, detecting even small variations in the synthesis of melanin. This method can also be applied to the quantification of melanin in more complex biological matrices like zebrafish embryos and human hair. PMID- 27770560 TI - Clathrin regulates blue light-triggered lateral auxin distribution and hypocotyl phototropism in Arabidopsis. AB - Phototropism is the process by which plants grow towards light in order to maximize the capture of light for photosynthesis, which is particularly important for germinating seedlings. In Arabidopsis, hypocotyl phototropism is predominantly triggered by blue light (BL), which has a profound effect on the establishment of asymmetric auxin distribution, essential for hypocotyl phototropism. Two auxin efflux transporters ATP-binding cassette B19 (ABCB19) and PIN-formed 3 (PIN3) are known to mediate the effect of BL on auxin distribution in the hypocotyl, but the details for how BL triggers PIN3 lateralization remain poorly understood. Here, we report a critical role for clathrin in BL-triggered, PIN3-mediated asymmetric auxin distribution in hypocotyl phototropism. We show that unilateral BL induces relocalization of clathrin in the hypocotyl. Loss of clathrin light chain 2 (CLC2) and CLC3 affects endocytosis and lateral distribution of PIN3 thereby impairing BL-triggered establishment of asymmetric auxin distribution and consequently, phototropic bending. Conversely, auxin efflux inhibitors N-1-naphthylphthalamic acid and 2,3,5-triiodobenzoic acid affect BL-induced relocalization of clathrin, endocytosis and lateralization of PIN3 as well as asymmetric distribution of auxin. These results together demonstrate an important interplay between auxin and clathrin function that dynamically regulates BL-triggered hypocotyl phototropism in Arabidopsis. PMID- 27770561 TI - Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: A randomized trial. AB - : Direct-acting antiviral agents (DAAs) represent the standard of care for patients with hepatitis C virus (HCV) infection. Combining DAAs with different mechanisms may allow for shorter treatment durations that are effective across multiple genotypes. The aim of the C-SWIFT study was to identify the minimum effective treatment duration across multiple genotypes. C-SWIFT was an open label, single-center trial in treatment-naive patients with chronic HCV genotype (GT)1 or 3 infection. All patients received elbasvir (EBR) 50 mg/grazoprevir (GZR) 100 mg with sofosbuvir (SOF) 400 mg for 4-12 weeks. Patients with GT1 infection who failed therapy were eligible for retreatment with EBR/GZR+SOF and ribavirin for 12 weeks. The primary efficacy endpoint was sustained virological response [SVR]12 (SVR of HCV RNA <15 IU/mL 12 weeks after the end of therapy). Rates of SVR12 were 32% (10 of 31) and 87% (26 of 30) in patients without cirrhosis with GT1 infection treated for 4 and 6 weeks and 80% (16 of 20) and 81% (17 of 21) in GT1-infected patients with cirrhosis treated for 6 and 8 weeks. Among GT3-infected patients without cirrhosis, SVR12 was 93% (14 of 15) and 100% (14 of 14) after 8 and 12 weeks. SVR12 in GT3-infected patients with cirrhosis was 83% (10 of 12) after 12 weeks of treatment. Twenty-three GT1-infected patients who relapsed following initial treatment completed retreatment; all achieved SVR12. In the initial treatment phase, there was one serious adverse event of pneumonia, which led to treatment discontinuation, and during retreatment, 1 patient discontinued ribavirin because of pruritus. CONCLUSION: Data from this study support the use of 8-week treatment regimens that maintain high efficacy, even for patients with HCV GT3 infection. Retreatment of patients who failed short-duration therapy was achieved through extended treatment duration and addition of ribavirin. (Hepatology 2017;65:439-450). PMID- 27770562 TI - Effect of matrix metalloproteinase-mediated matrix degradation on glioblastoma cell behavior in 3D PEG-based hydrogels. AB - Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor with median survival of 12 months. To improve clinical outcomes, it is critical to develop in vitro models that support GBM proliferation and invasion for deciphering tumor progression and screening drug candidates. A key hallmark of GBM cells is their extreme invasiveness, a process mediated by matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix. We recently reported the development of a MMP-degradable, poly(ethylene-glycol) based hydrogel platform for culturing GBM cells. In the present study, we modulated the percentage of MMP-degradable crosslinks in 3D hydrogels to analyze the effects of MMP-degradability on GBM fates. Using an immortalized GBM cell line (U87) as a model cell type, our results showed that MMP-degradability was not required for supporting GBM proliferation. All hydrogel formulations supported robust GBM proliferation, up to 10 fold after 14 days. However, MMP degradability was essential for facilitating tumor spreading, and 50% MMP degradable hydrogels were sufficient to enable both robust tumor cell proliferation and spreading in 3D. The findings of this study highlight the importance of modulating MMP-degradability in engineering 3D in vitro brain cancer models and may be applied for engineering in vitro models for other cancer types. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 770-778, 2017. PMID- 27770563 TI - Biocompatibility and toxicology effects of graphene oxide in cancer, normal, and primary immune cells. AB - Graphene oxide (GO) has received enormous attention regarding its possible applications in medical areas including cancer treatment. Nevertheless, graphene biocompatibility and its interactions with cancer, normal and immune system cells still remain a major issue. In the current study, we focused on the immunological impact of GO in the oxidative burst by GO produced in fresh isolated primary human neutrophils, the most abundant leukocyte of immune system. We also studied the GO cytotoxicity, cell uptake, and genotoxicity in fresh isolated primary human monocyte, neutrophil, human carcinoma cervical (HeLa) and L929 cells. GO biocompatibility was also analyzed in human red blood cell (hemocompatibility) and in primary human T lymphocytes (T cell). We observed that GO can interact with HeLa in vitro and immune system cells, but in major extension with cancer cells. The latter opened the way for further studies on the effects of GO on immune system pathways and treatments for human cancer at lower concentrations. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 728-736, 2017. PMID- 27770564 TI - Lung inflammation caused by long-term exposure to titanium dioxide in mice involving in NF-kappaB signaling pathway. AB - Titanium dioxide nanoparticles (TiO2 NPs) are used in many fields, such as paints, medicine additives, food additives, sunscreens, and agriculture. The aim of this study was to investigate the mechanism behind the formation of inflammation induced by TiO2 NPs. ICR mice were exposed to TiO2 NPs through intragastric administration at 2.5, 5, and 10 mg/kg body weight every day for 90 consecutive days. The experiment suggested that long-term exposure to TiO2 NPs resulted in an obvious inflammatory response in mice lung tissues, which led to a thickened alveoli septum, lung hyperemia, and titanium accumulation. Furthermore, our results show that TiO2 NPs exposure remarkably altered the expression of inflammation-related cytokines, with increases in proinflammatory cytokines-such as nucleic factor-kappaB, interferon-alpha, interferon-beta, interleukin-1beta, interleukin-6, cyclo-oxygen-ase, interleukin-8, interferon-inducible protein-10, and platelet-derived growth factor AB-and decreases in anti-inflammatory cytokines-such as inhibitor of NF-kappaB suppressor of cytokine signaling 1, endothelin 1, peroxisome proliferators-activated receptors-gamma, and peroxisome proliferators-activated receptors coactivator-1alpha. This finding indicated that TiO2 NPs cause lung inflammation in mice after intragastric administration, primarily through the NF-kappaB signaling pathways. Therefore, more attention should be placed on the application of TiO2 NPs and their potential long-term effects, especially in human beings. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 720-727, 2017. PMID- 27770565 TI - The effect of particle size on the genotoxicity of gold nanoparticles. AB - Despite the increasing biomedical applications of gold nanoparticles (AuNPs), their toxicological effects need to be thoroughly understood. In the present study, the genotoxic potential of commercially available AuNPs with varying size (5, 20, and 50 nm) were assessed using a battery of in vitro and in vivo genotoxicity assays. In the comet assay, 20 and 50 nm AuNPs did not induce obvious DNA damage in HepG2 cells at the tested concentrations, whereas 5 nm NPs induced a dose-dependent increment in DNA damage after 24-h exposure. Furthermore, 5 nm AuNPs induced cell cycle arrest in G1 phase in response to DNA damage, and promoted the production of reactive oxygen species (ROS). In the chromosomal aberration test, AuNPs exposure did not increase in the frequency of chromosomal aberrations in Chinese hamster lung (CHL) cells. In the standard in vivo micronucleus test, no obvious increase in the frequency of micronucleus formation was found in mice after 4 day exposure of AuNPs. However, when the exposure period was extended to 14 days, 5 nm AuNPs presented significant clastogenic damage, with a dose-dependent increase of micronuclei frequencies. This finding suggests that particle size plays an important role in determining the genotoxicity of AuNPs. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 710-719, 2017. PMID- 27770566 TI - Differential magnesium implant corrosion coat formation and contribution to bone bonding. AB - Magnesium alloys are presently under investigation as promising biodegradable implant materials with osteoconductive properties. To study the molecular mechanisms involved, the potential contribution of soluble magnesium corrosion products to the stimulation of osteoblastic cell differentiation was examined. However, no evidence for the stimulation of osteoblast differentiation could be obtained when cultured mesenchymal precursor cells were differentiated in the presence of metallic magnesium or in cell culture medium containing elevated magnesium ion levels. Similarly, in soft tissue no bone induction by metallic magnesium or by the corrosion product magnesium hydroxide could be observed in a mouse model. Motivated by the comparatively rapid accumulation solid corrosion products physicochemical processes were examined as an alternative mechanism to explain the stimulation of bone growth by magnesium-based implants. During exposure to physiological solutions a structured corrosion coat formed on magnesium whereby the elements calcium and phosphate were enriched in the outermost layer which could play a role in the established biocompatible behavior of magnesium implants. When magnesium pins were inserted into avital bones, corrosion lead to increases in the pull out force, suggesting that the expanding corrosion layer was interlocking with the surrounding bone. Since mechanical stress is a well-established inducer of bone growth, volume increases caused by the rapid accumulation of corrosion products and the resulting force development could be a key mechanism and provide an explanation for the observed stimulatory effects of magnesium-based implants in hard tissue. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 697-709, 2017. PMID- 27770567 TI - A computational interactome and functional annotation for the human proteome. AB - We present a database, PrePPI (Predicting Protein-Protein Interactions), of more than 1.35 million predicted protein-protein interactions (PPIs). Of these at least 127,000 are expected to constitute direct physical interactions although the actual number may be much larger (~500,000). The current PrePPI, which contains predicted interactions for about 85% of the human proteome, is related to an earlier version but is based on additional sources of interaction evidence and is far larger in scope. The use of structural relationships allows PrePPI to infer numerous previously unreported interactions. PrePPI has been subjected to a series of validation tests including reproducing known interactions, recapitulating multi-protein complexes, analysis of disease associated SNPs, and identifying functional relationships between interacting proteins. We show, using Gene Set Enrichment Analysis (GSEA), that predicted interaction partners can be used to annotate a protein's function. We provide annotations for most human proteins, including many annotated as having unknown function. PMID- 27770568 TI - Sub-synaptic, multiplexed analysis of proteins reveals Fragile X related protein 2 is mislocalized in Fmr1 KO synapses. AB - The distribution of proteins within sub-synaptic compartments is an essential aspect of their neurological function. Current methodologies, such as electron microscopy (EM) and super-resolution imaging techniques, can provide the precise localization of proteins, but are often limited to a small number of one-time observations with narrow spatial and molecular coverage. The diversity of synaptic proteins and synapse types demands synapse analysis on a scale that is prohibitive with current methods. Here, we demonstrate SubSynMAP, a fast, multiplexed sub-synaptic protein analysis method using wide-field data from deconvolution array tomography (ATD). SubSynMAP generates probability distributions for that reveal the functional range of proteins within the averaged synapse of a particular class. This enables the differentiation of closely juxtaposed proteins. Using this method, we analyzed 15 synaptic proteins in normal and Fragile X mental retardation syndrome (FXS) model mouse cortex, and revealed disease-specific modifications of sub-synaptic protein distributions across synapse classes and cortical layers. PMID- 27770571 TI - Silencing of genes responsible for polyQ diseases using chemically modified single-stranded siRNAs. AB - Polyglutamine (polyQ) diseases comprise a group of nine genetic disorders that are caused by the expansion of the CAG triplet repeat, which encodes glutamine, in unrelated single genes. Various oligonucleotide (ON)-based therapeutic approaches have been considered for polyQ diseases. The very attractive CAG repeat-targeting strategy offers selective silencing of the mutant allele by directly targeting the mutation site. CAG repeat-targeting miRNA-like siRNAs have been shown to specifically inhibit the mutant gene expression, and their characteristic feature is the formation of mismatches in their interactions with the target site. Here, we designed novel single-stranded siRNAs that contain base substitutions and chemical modifications, in order to develop improved therapeutic tools with universal properties for several polyQ diseases. We tested these ONs in cellular models of Huntington's disease (HD), spinocerebellar ataxia type 3 (SCA3) and dentatorubral-pallidoluysian atrophy (DRPLA). Selected siRNAs caused the efficient and selective downregulation of the mutant huntingtin, ataxin-3 and atrophin-1 levels in cultured human fibroblasts. We also prove the efficiency of novel ONs, with chemical modification pattern mainly containing 2' fluoro (2'F), in HD mouse striatal cells. PMID- 27770570 TI - Characterization of human translesion DNA synthesis across a UV-induced DNA lesion. AB - Translesion DNA synthesis (TLS) during S-phase uses specialized TLS DNA polymerases to replicate a DNA lesion, allowing stringent DNA synthesis to resume beyond the offending damage. Human TLS involves the conjugation of ubiquitin to PCNA clamps encircling damaged DNA and the role of this post-translational modification is under scrutiny. A widely-accepted model purports that ubiquitinated PCNA recruits TLS polymerases such as pol eta to sites of DNA damage where they may also displace a blocked replicative polymerase. We provide extensive quantitative evidence that the binding of pol eta to PCNA and the ensuing TLS are both independent of PCNA ubiquitination. Rather, the unique properties of pols eta and delta are attuned to promote an efficient and passive exchange of polymerases during TLS on the lagging strand. PMID- 27770572 TI - Biological functions of natural antisense transcripts. AB - Natural antisense transcripts (NATs) are RNA molecules that originate from opposite DNA strands of the same genomic locus (cis-NAT) or unlinked genomic loci (trans-NAT). NATs may play various regulatory functions at the transcriptional level via transcriptional interference. NATs may also regulate gene expression levels post-transcriptionally via induction of epigenetic changes or double stranded RNA formation, which may lead to endogenous RNA interference, RNA editing or RNA masking. The true biological significance of the natural antisense transcripts remains controversial despite many years of research. Here, we summarize the current state of knowledge and discuss the sense-antisense overlap regulatory mechanisms and their potential. PMID- 27770569 TI - Internal states drive nutrient homeostasis by modulating exploration-exploitation trade-off. AB - Internal states can profoundly alter the behavior of animals. A quantitative understanding of the behavioral changes upon metabolic challenges is key to a mechanistic dissection of how animals maintain nutritional homeostasis. We used an automated video tracking setup to characterize how amino acid and reproductive states interact to shape exploitation and exploration decisions taken by adult Drosophila melanogaster. We find that these two states have specific effects on the decisions to stop at and leave proteinaceous food patches. Furthermore, the internal nutrient state defines the exploration-exploitation trade-off: nutrient deprived flies focus on specific patches while satiated flies explore more globally. Finally, we show that olfaction mediates the efficient recognition of yeast as an appropriate protein source in mated females and that octopamine is specifically required to mediate homeostatic postmating responses without affecting internal nutrient sensing. Internal states therefore modulate specific aspects of exploitation and exploration to change nutrient selection. PMID- 27770573 TI - Barley primary microRNA expression pattern is affected by soil water availability. AB - MicroRNAs are short molecules of 21-24 nt in length. They are present in all eukaryotic organisms and regulate gene expression by guiding posttranscriptional silencing of mRNAs. In plants, they are key players in signal transduction, growth and development, and in response to abiotic and biotic stresses. Barley (Hordeum vulgare) is an economically important monocotyledonous crop plant. Drought is the world's main cause of loss in cereal production. We have constructed a high-throughput Real-Time RT-qPCR platform for parallel determination of 159 barley primary microRNAs' levels. The platform was tested for two drought-and-rehydration-treated barley genotypes (Rolap and Sebastian). We have determined changes in the expression of primary microRNAs responding to mild drought, severe drought, and rehydration. Based on the results obtained, we conclude that alteration in the primary microRNA expression is relative to the stress's intensity. Mild drought and rehydration mostly decrease the pri-miRNA levels in both of the tested genotypes. Severe drought mainly induces the primary microRNA expression. The main difference between the genotypes tested was a much stronger induction of pri-miRNAs in Rolap encountering severe drought. The primary microRNAs respond dynamically to mild drought, severe drought, and rehydration treatments. We propose that some of the individual pri-miRNAs could be used as drought stress or rehydration markers. The usage of the platform in biotechnology is also postulated. PMID- 27770574 TI - Risks, consequences, and prevention of falls of older people in oral healthcare centers. AB - One-third of community-dwelling people older than 65 years of age fall each year, and half of them fall at least twice a year. Older care home residents are approximately three times more likely to fall when compared to community-dwelling older people. Risk indicators for falls are related to the older people's body, environment, behavior, and activities. An important health risk indicator is (orthostatic or postprandial) hypotension, which may induce cerebral hypoperfusion. Although the majority of falls remain without major consequences, 10% to 25% of falls in care homes result in bodily trauma. Prevalent fall-related injuries are brain injury, lower extremity fracture including hip fracture and forearm/wrist fracture, facial fracture, humeral fracture, and rib/scapular fracture. As fall accidents by older people can have severe consequences, prevention of falls is of paramount importance. Healthcare providers, including oral healthcare providers, should inform older people on risks of falling and draw attention to potentially hazardous arrangements. PMID- 27770575 TI - Direct cutaneous lateral thoracic artery perforator misdiagnosed as second thoracodorsal artery perforator. PMID- 27770576 TI - Improved pocket control in immediate microsurgical breast reconstruction with simultaneous implant placement through the use of mesh. AB - BACKGROUND: Autologous breast reconstruction is associated with long-term patient satisfaction that is superior to implant-based approaches. Occasionally, however, patients who desire autologous reconstruction present with inadequate donor-site volume. A hybrid approach, combining free flap reconstruction with simultaneous implant placement, is a solution. We present our experience with the use of mesh for improved pocket control using this reconstructive modality. METHODS: A retrospective analysis of a prospectively maintained database of patients undergoing autologous breast reconstruction was performed. Patients who underwent bilateral immediate breast reconstruction with free microsurgical abdominal tissue transfer with simultaneous implant placement were included for analysis. RESULTS: A total of 19 patients (38 breasts) with a mean age of 42.7 years (range, 31-57 years) and mean BMI of 26.3 (range, 23.6-30.8) were included in the study. No flap loss or implant-related complications were encountered during a mean follow-up of 14.2 months. The most common implant volume was 150 cc (N = 15; [78.9%]). No patient requested an implant change due to malposition or insufficient volume. Secondary fat grafting was performed in 5 patients (26.3%), 4 of which had undergone adjuvant radiotherapy. Three cases of red breast syndrome were observed following acellular dermal matrix placement. This prompted a transition to using polyglactin mesh thereafter without any untoward sequelae. CONCLUSIONS: Abdominal flap transfer with simultaneous implant placement is a safe reconstructive option in select patients. Improved implant pocket control is achieved through the use of mesh, thus, minimizing problems related to implant malposition. Adjuvant radiotherapy does not appear to put the reconstruction at risk with the occasional flap volume loss being easily remedied by secondary fat grafting. PMID- 27770578 TI - RNA interference and dietary inhibitors induce a similar compensation response in Tribolium castaneum larvae. AB - Tribolium castaneum is a major agriculture pest damaging stored grains and cereal products. The T. castaneum genome contains 26 cysteine peptidase genes, mostly cathepsins L and B, and seven have a major role in digestion. We targeted the expression of the most highly expressed cathepsin L gene on chromosome 10, TC011001, by RNA interference (RNAi), using double-stranded RNA (dsRNA) constructs of different regions of the gene (3', middle, 5' and entire coding regions). RNA sequencing and quantitation (RNA-seq) was used to evaluate knockdown and specificity amongst the treatments. Overall, target gene expression decreased in all treatment groups, but was more severe and specific in dsRNA targeting the 3' and entire coding regions, encoding the proteolytic active site in the enzyme. Additional cysteine cathepsin genes also were down-regulated (off target effects), but some were up-regulated in response to RNAi treatment. Notably, some serine peptidase genes were increased in expression, especially in dsRNA targeting 5' and middle regions, and the response was similar to the effects of dietary cysteine protease inhibitors. We manually annotated these serine peptidase genes to gain insight into function and relevance to the RNAi study. The data indicate that T. castaneum larvae compensate for the loss of digestive peptidase activity in the larval gut, regardless of the mechanism of disruption. PMID- 27770577 TI - Metabotropic and ionotropic glutamate receptors mediate the modulation of acetylcholine release at the frog neuromuscular junction. AB - There is some evidence that glutamate (Glu) acts as a signaling molecule at vertebrate neuromuscular junctions where acetylcholine (ACh) serves as a neurotransmitter. In this study, performed on the cutaneous pectoris muscle of the frog Rana ridibunda, Glu receptor mechanisms that modulate ACh release processes were analyzed. Electrophysiological experiments showed that Glu reduces both spontaneous and evoked quantal secretion of ACh and synchronizes its release in response to electrical stimulation. Quisqualate, an agonist of ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors and metabotropic Group I mGlu receptors, also exerted Glu-like inhibitory effects on the secretion of ACh but had no effect on the kinetics of quantal release. Quisqualate's inhibitory effect did not occur when a blocker of Group I mGlu receptors (LY 367385) or an inhibitor of phospholipase C (U73122) was present. An increase in the degree of synchrony of ACh quantal release, such as that produced by Glu, was obtained after application of N-methyl-D-aspartic acid (NMDA). The presence of Group I mGlu and NMDA receptors in the neuromuscular synapse was confirmed by immunocytochemistry. Thus, the data suggest that both metabotropic Group I mGlu receptors and ionotropic NMDA receptors are present at the neuromuscular synapse of amphibians, and that the activation of these receptors initiates different mechanisms for the regulation of ACh release from motor nerve terminals. (c) 2016 Wiley Periodicals, Inc. PMID- 27770580 TI - BCL2L10 inhibits growth and metastasis of hepatocellular carcinoma both in vitro and in vivo. AB - BCL2L10 is an apoptosis-related member of the BCL-2 protein family. The role of BCL2L10 in the pathogenesis of hepatocellular carcinoma (HCC) is poorly understood. This study was aimed to investigate the function and underlying mechanisms of BCL2L10 in HCC. BCL2L10 expression in human HCC and corresponding adjacent normal tissues was investigated by quantitative real-time PCR and Western blot. The biological functions of BCL2L10 in HCC cell lines were determined by cell viability, colony formation, cell apoptosis, cell cycle, and cell metastasis assays, and in vivo by tumorigenicity and lung metastasis assays in nude mice. Human cancer pathway PCR array was employed to explore the genes regulated by BCL2L10 in HCC. BCL2L10 was down-regulated in human HCC tissues compared to their adjacent non-tumor tissues. Ectopic expression of BCL2L10 in HepG2 and Huh7 cells suppressed cell growth as evidenced by cell viability and colony formation assay, and induced cell apoptosis. HCC cells transfected with BCL2L10 revealed an increased cell proportion arrested at G2/M phase, concomitant with a reduction in the cell proportion in S-phase as compared with control cells. Additional, BCL2L10 repressed cell migration and angiogenesis. Over expression of BCL2L10 also restrained the tumorigenecity and lung metastasis capacity in nude mice. The activation of JAK-STAT3 signaling was suppressed by BCL2L10 in HCC. BCL2L10 was down-regulated in human HCC tissues compared to adjacent normal tissues. BCL2L10 suppressed HCC progression through inhibiting cell growth and metastasis. Thus, BCL2L10 functions as a tumor-suppressor in HCC. (c) 2016 Wiley Periodicals, Inc. PMID- 27770579 TI - Febrile infection-related epilepsy syndrome treated with anakinra. AB - Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945. PMID- 27770581 TI - A pharmacotherapy review of the novel, oral antithrombotics. AB - Coagulation disorders account for a high incidence of death in the U.S. due to stroke, myocardial infarction, and venous thromboembolism. In the past few years, numerous agents have been brought to market for the treatment of thromboembolism or prevention of thromboembolism. Similar to warfarin, these agents can cause bleeding disorders, which may exacerbate dental care treatment plans. This literature review examines the newer agents for the treatment of thromboembolism disorders, common side effects and drug interactions, the specific medical conditions each agent treats, and the dental perspective on how to medically management patients prescribed these medications. PMID- 27770582 TI - RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia. AB - Despite the introduction of newer technologies and improved insulin formulations, recurrent hypoglycaemia continues to affect the lives of many people with Type 1 and Type 2 diabetes. Developing strategies or therapies designed to prevent or minimize hypoglycaemia risk is of utmost importance to help individuals safely achieve glycaemic targets. Novel, educational or behavioural approaches need to be based on a clear understanding of the mechanisms underpinning both the detection of hypoglycaemia and why repeated exposure to hypoglycaemia leads to the development of a clinical syndrome referred to as impaired awareness of hypoglycaemia. In the present review, I propose that impaired awareness of hypoglycaemia may represent a form of learning called habituation, a response that, at a cellular level, represents a biological adaptation designed to protect the organism from future exposure to that stressor. In diabetes, this survival response to low glucose is, however, overwhelmed by high systemic insulin levels resulting from exogenous insulin therapy, leading to progressively more severe hypoglycaemia. A recognition of the underlying mechanism means that the development of impaired awareness of hypoglycaemia can perhaps be better understood and explained to individuals with diabetes, and novel therapeutic approaches such as dishabituation or cognitive behavioural therapies can be considered. PMID- 27770584 TI - Linked color imaging enhances gastric cancer in gastric intestinal metaplasia. PMID- 27770583 TI - A population-based study of chronic myeloid leukemia patients treated with imatinib in first line. AB - Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second line. Older age (>=70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27770585 TI - Comparison of a Virtual Older Driver Assessment with an On-Road Driving Test. AB - OBJECTIVES: To design a low-cost simulator-based driving assessment for older adults and to compare its validity with that of an on-road driving assessment and other measures of older driver risk. DESIGN: Cross-sectional observational study. SETTING: Canberra, Australia. PARTICIPANTS: Older adult drivers (N = 47; aged 65 88, mean age 75.2). MEASUREMENTS: Error rate on a simulated drive with environment and scoring procedure matched to those of an on-road test. Other measures included participant age, simulator sickness severity, neuropsychological measures, and driver screening measures. Outcome variables included occupational therapist (OT)-rated on-road errors, on-road safety rating, and safety category. RESULTS: Participants' error rate on the simulated drive was significantly correlated with their OT-rated driving safety (correlation coefficient (r) = -0.398, P = .006), even after adjustment for age and simulator sickness (P = .009). The simulator error rate was a significant predictor of categorization as unsafe on the road (P = .02, sensitivity 69.2%, specificity 100%), with 13 (27%) drivers assessed as unsafe. Simulator error was also associated with other older driver safety screening measures such as useful field of view (r = 0.341, P = .02), DriveSafe (r = -0.455, P < .01), and visual motion sensitivity (r = 0.368, P = .01) but was not associated with memory (delayed word recall) or global cognition (Mini-Mental State Examination). Drivers made twice as many errors on the simulated assessment as during the on-road assessment (P < .001), with significant differences in the rate and type of errors between the two mediums. CONCLUSION: A low-cost simulator-based assessment is valid as a screening instrument for identifying at-risk older drivers but not as an alternative to on-road evaluation when accurate data on competence or pattern of impairment is required for licensing decisions and training programs. PMID- 27770586 TI - Assessing the role of endophytic bacteria in the halophyte Arthrocnemum macrostachyum salt tolerance. AB - There is an increasing interest to use halophytes for revegetation of salt affected ecosystems, as well as in understanding their mechanisms of salt tolerance. We hypothesized that bacteria from the phyllosphere of these plants might play a key role in its high tolerance to excessive salinity. Eight endophytic bacteria belonging to Bacillus and closely related genera were isolated from phyllosphere of the halophyte Arthrocnemum macrostachyum growing in salty agricultural soils. The presence of plant-growth promoting (PGP) properties, enzymatic activities and tolerance towards NaCl was determined. Effects of inoculation on seeds germination and adult plant growth under experimental NaCl treatments (0, 510 and 1030 mM NaCl) were studied. Inoculation with a consortium including the best performing bacteria improved considerably the kinetics of germination and the final germination percentage of A. macrostachyum seeds. At high NaCl concentrations (1030 mM), inoculation of plants mitigated the effects of high salinity on plant growth and physiological performance and, in addition, this consortium appears to have increased the potential of A. macrostachyum to accumulate Na+ in its shoots, thus improving sodium phytoextraction capacity. Bacteria isolated from A. macrostachyum phyllosphere seem to play an important role in plant salt tolerance under stressing salt concentrations. The combined use of A. macrostachyum and its microbiome can be an adequate tool to enhance plant adaptation and sodium phytoextraction during restoration of salt degraded soils. PMID- 27770587 TI - Pollination of Campomanesia phaea (Myrtaceae) by night-active bees: a new nocturnal pollination system mediated by floral scent. AB - Bees are the most important diurnal pollinators of angiosperms. In several groups of bees a nocturnal/crepuscular habit developed, yet little is known about their role in pollination and whether some plants are adapted specifically to these bees. We used a multidisciplinary approach to investigate the reproductive biology and to understand the role of nocturnal/crepuscular bees in pollination of Campomanesia phaea (Myrtaceae), popularly named cambuci. We studied the floral biology and breeding system of C. phaea. We collected the floral visitors and tested the pollinators' effectiveness. We also determined the floral scents released at night and during daytime, and studied behavioural responses of crepuscular/nocturnal bees towards these scents. The flowers of cambuci were self incompatible and had pollen as the only resource for flower visitors. Anthesis lasted around 14 h, beginning at 04:30 h at night. The flowers released 14 volatile compounds, mainly aliphatic and aromatic compounds. We collected 52 species of floral visitors, mainly bees. Nocturnal and crepuscular bees (four species) were among the most frequent species and the only effective pollinators. In field bioassays performed at night, nocturnal/crepuscular bees were attracted by a synthetic scent blend consisting of the six most abundant compounds. This study describes the first scent-mediated pollination system between a plant and its nocturnal bee pollinators. Further, C. phaea has several floral traits that do not allow classification into other nocturnal pollination syndromes (e.g. pollinator attraction already before sunrise, with pollen as the only reward), instead it is a plant specifically adapted to nocturnal bees. PMID- 27770588 TI - Health Care for Older Adults in Uganda: Lessons for the Developing World. AB - Approximately two-thirds of the world's older adults live in developing nations. By 2050, as many as 80% of such older people will live in low- and middle-income countries. In sub-Saharan Africa alone, the number of individuals aged 60 and older is projected to reach 163 million. Despite this demographic wave, the majority of Africa has limited access to qualified geriatric health care.3 Although foreign aid and capacity-building efforts can help to close this gap over time, it is likely that failure to understand the unique context of Africa's older adults, many of whom are marginalized, will lead to inadequacies in service delivery and poor health outcomes.4 As the need for culturally competent care of older adults gains recognition in the developed world, research in geriatric care in developing countries should progress in tandem.4 By examining the multidimensional challenges that an older woman with the human immunodeficiency virus (HIV) in rural Uganda faces, this article makes contextualized policy recommendations for older adults in Africa and provides lessons for the developing world. PMID- 27770589 TI - Factors affecting the benefit of insulin dose intensification in people with Type 2 diabetes: an analysis from the OpT2mise randomized trial. PMID- 27770590 TI - Higher skin autofluorescence in young people with Type 1 diabetes and microvascular complications. AB - AIM: To test the hypothesis that non-invasive skin autofluorescence, a measure of advanced glycation end products, would provide a surrogate measure of long-term glycaemia and be associated with early markers of microvascular complications in adolescents with Type 1 diabetes. METHODS: Forearm skin autofluorescence (arbitrary units) was measured in a cross-sectional study of 135 adolescents with Type 1 diabetes [mean +/- sd age 15.6 +/- 2.1 years, diabetes duration 8.7 +/- 3.5 years, HbA1c 72 +/- 16 mmol/mol (8.7 +/- 1.5%)]. Retinopathy, assessed using seven-field stereoscopic fundal photography, was defined as >=1 microaneurysm or haemorrhage. Cardiac autonomic function was measured by standard deviation of consecutive RR intervals on a 10-min continuous electrocardiogram recording, as a measure of heart rate variability. RESULTS: Skin autofluorescence was significantly associated with age (R2 = 0.15; P < 0.001). Age- and gender adjusted skin autofluorescence was associated with concurrent HbA1c (R2 = 0.32; P < 0.001) and HbA1c over the previous 2.5-10 years (R2 = 0.34-0.43; P < 0.002). Age- and gender-adjusted mean skin autofluorescence was higher in adolescents with retinopathy vs those without retinopathy [mean 1.38 (95% CI 1.29, 1.48) vs 1.22 (95% CI 1.17, 1.26) arbitrary units; P = 0.002]. In multivariable analysis, retinopathy was significantly associated with skin autofluorescence, adjusted for duration (R2 = 0.19; P = 0.03). Cardiac autonomic dysfunction was also independently associated with skin autofluorescence (R2 = 0.11; P = 0.006). CONCLUSIONS: Higher skin autofluorescence is associated with retinopathy and cardiac autonomic dysfunction in adolescents with Type 1 diabetes. The relationship between skin autofluorescence and previous glycaemia may provide insight into metabolic memory. Longitudinal studies will determine the utility of skin autofluorescence as a non-invasive screening tool to predict future microvascular complications. PMID- 27770591 TI - Economic evaluation of chronic disease self-management for people with diabetes: a systematic review. AB - AIMS: To systematically review the evidence on the costs and cost-effectiveness of self-management support interventions for people with diabetes. BACKGROUND: Self-management support is the provision of education and supportive interventions to increase patients' skills and confidence in managing their health problems, potentially leading to improvements in HbA1c levels in people with diabetes. METHODS: Randomized controlled trials, observational studies or economic modelling studies were eligible for inclusion in the review. The target population was adults with diabetes. Interventions had to have a substantial component of self-management support and be compared with routine care. Study quality was evaluated using the Consensus on Health Economic Criteria and International Society of Pharmacoeconomic Outcomes Research questionnaires. A narrative review approach was used. RESULTS: A total of 16 costing and 21 cost effectiveness studies of a range of self-management support interventions were identified. There was reasonably consistent evidence across 22 studies evaluating education self-management support programmes suggesting these interventions are cost-effective or superior to usual care. Telemedicine-type interventions were more expensive than usual care and potentially not cost-effective. There was insufficient evidence regarding the other types of self-management interventions, including pharmacist-led and behavioural interventions. The identified studies were predominantly of poor quality, with outcomes based on short-term follow-up data and study designs at high risk of bias. CONCLUSIONS: Self-management support education programmes may be cost-effective. There was limited evidence regarding other formats of self-management support interventions. The poor quality of many of the studies undermines the evidence base regarding the economic efficiency of self-management support interventions for people with diabetes. PMID- 27770593 TI - Brazil's worst mining disaster: Corporations must be compelled to pay the actual environmental costs. AB - In November 2015, a large mine-tailing dam owned by Samarco Corporation collapsed in Brazil, generating a massive wave of toxic mud that spread down the Doce River, killing 20 people and affecting biodiversity across hundreds of kilometers of river, riparian lands, and Atlantic coast. Besides the disaster's serious human and socioeconomic tolls, we estimate the regional loss of environmental services to be ~US$521 million per year. Although our estimate is conservative, it is still six times higher than the fine imposed on Samarco by Brazilian environmental authorities. To reduce such disparities between estimated damages and levied fines, we advocate for an environmental bond policy that considers potential risks and environmental services that could possibly be impacted by irresponsible mining activity. Environmental bonds and insurance are commonly used policy instruments in many countries, but there are no clear environmental bond policies in Brazil. Environmental bonds are likely to be more effective at securing environmental restitution than post-disaster fines, which generally are inadequate and often unpaid. We estimate that at least 126 mining dams in Brazil are vulnerable to failure in the forthcoming years. Any such event could have severe social-environmental consequences, underscoring the need for effective disaster-management strategies for large-scale mining operations. PMID- 27770592 TI - Circulating adiponectin concentration is inversely associated with glucose tolerance and insulin secretion in people with newly diagnosed diabetes. AB - AIMS: To examine the hypothesis that changes in serum adiponectin concentration inversely relate to changes in glucose tolerance and beta-cell function already during the early stage of disease progression in recently diagnosed Type 1 and Type 2 diabetes mellitus. METHODS: Participants in the prospective observational German Diabetes Study (Type 2 diabetes, n = 94; Type 1 diabetes, n = 42) underwent i.v. glucose tolerance and glucagon stimulation testing to assess pre hepatic beta-cell function, glucose tolerance index and C-peptide secretion within the first year of diabetes diagnosis and 2 years later. Associations of changes in serum concentrations of total adiponectin, high-molecular-weight adiponectin and their ratio with changes in the aforementioned metabolic variables were calculated using linear regression. RESULTS: Among people with Type 2 diabetes, 2-year increases in high-molecular-weight adiponectin and in high-molecular-weight/total adiponectin ratio were associated with decreases in glucose tolerance index of 0.1%/min (P = 0.020) and 0.8%/min (P = 0.013), respectively. Increases in high-molecular-weight/total adiponectin ratio were related to decreases in acute C-peptide secretion of 54.6% (P = 0.020). Among people with Type 1 diabetes, 2-year increases in total adiponectin were associated with 2-year decreases in acute C-peptide secretion of 56.2% (P = 0.035). CONCLUSIONS: Increases in adiponectin concentrations in the first 2 years after diagnosis were related to a worsening of acute insulin secretion and glucose tolerance index in Type 1 and Type 2 diabetes. (Clinical Trials Registry no.: NCT01055093). PMID- 27770594 TI - Pollination biology of the hexaploid self-compatible species Turnera velutina (Passifloraceae). AB - The evolution of monomorphisms from heterostylous ancestors has been related to the presence of homostyly and the loss of self-incompatibility, allowing the occurrence of selfing, which could be advantageous under pollinator limitation. However, flowers of some monomorphic species show herkogamy, attraction and rewarding traits that presumably favour cross-pollination and/or a mixed mating system. This study evaluated the contributions of pollinators, breeding system and floral traits to the reproduction of Turnera velutina, a herkogamous monomorphic species. Floral visitors and frequency of visits were recorded, controlled hand cross-pollinations were conducted under greenhouse and natural conditions, and individual variation in floral traits was characterised to determine their contribution to seed production. Apis mellifera was the most frequent floral visitor. Flowers presented approach herkogamy, high variation in nectar features, and a positive correlation of floral length with nectar volume and sugar concentration. Seed production did not differ between manual self- and cross-pollinations, controls or open cross-pollinations, but autonomous self pollination produced, on average, 82.74% fewer seeds than the other forms, irrespective of the level of herkogamy. Differences in seed production among autonomous self-pollination and other treatments showed that T. velutina flowers depend on insect pollination for reproduction, and that approach herkogamy drastically reduced seed production in the absence of pollen vectors. The lack of differences in seed production from manual cross- and self-pollinations suggests the possible presence of a mixed mating system in the studied population. Overall, this species was possibly derived from a distylous ancestor but appears fully capable of outcrossing despite being monomorphic. PMID- 27770595 TI - Microtubule binding protein PACRG plays a role in regulating specific ciliary dyneins during microtubule sliding. AB - The complex waveforms characteristic of motile eukaryotic cilia and flagella are produced by the temporally and spatially regulated action of multiple dynein subforms generating sliding between subsets of axonemal microtubules. Multiple protein complexes have been identified that are associated with the doublet microtubules and that mediate regulatory signals between key axonemal structures, such as the radial spokes and central apparatus, and the dynein arm motors; these complexes include the N-DRC, MIA, and CSC complexes. Previous studies have shown that PACRG (parkin co-regulated gene) forms a complex that is anchored to the axonemal doublet microtubules. Loss of PACRG causes defects in ciliary motility and cilia related diseases. Here, we use an in vitro microtubule sliding assay to demonstrate that PACRG and its interactors are part of a signaling pathway that includes the central apparatus, radial spokes and specific inner dynein arm subforms to control dynein-driven microtubule sliding. Using a biochemical approach, our studies also indicate that PACRG interacts with the radial spokes. (c) 2016 Wiley Periodicals, Inc. PMID- 27770596 TI - Modeling of Large Pharmacokinetic Data Using Nonlinear Mixed-Effects: A Paradigm Shift in Veterinary Pharmacology. A Case Study With Robenacoxib in Cats. AB - The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed-effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first-order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (Ka = 0.68 h-1 ) was lower than beta (median, 1.08 h-1 ), unveiling flip-flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population. PMID- 27770597 TI - Assessing the Impact of Tissue Target Concentration Data on Uncertainty in In Vivo Target Coverage Predictions. AB - Understanding pharmacological target coverage is fundamental in drug discovery and development as it helps establish a sequence of research activities, from laboratory objectives to clinical doses. To this end, we evaluated the impact of tissue target concentration data on the level of confidence in tissue coverage predictions using a site of action (SoA) model for antibodies. By fitting the model to increasing amounts of synthetic tissue data and comparing the uncertainty in SoA coverage predictions, we confirmed that, in general, uncertainty decreases with longitudinal tissue data. Furthermore, a global sensitivity analysis showed that coverage is sensitive to experimentally identifiable parameters, such as baseline target concentration in plasma and target turnover half-life and fixing them reduces uncertainty in coverage predictions. Overall, our computational analysis indicates that measurement of baseline tissue target concentration reduces the uncertainty in coverage predictions and identifies target-related parameters that greatly impact the confidence in coverage predictions. PMID- 27770598 TI - Development of the Japanese Version of the Leeds Assessment of the Neuropathic Symptoms and Signs Pain Scale: Diagnostic Utility in a Clinical Setting. AB - OBJECTIVE: We aimed to assess the diagnostic utility of the linguistically validated Japanese version of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (LANSS-J) as a screening tool for neuropathic pain in the clinical setting. METHODS: Patients with neuropathic pain or nociceptive pain who were 20 to 85 years of age were included. Sensitivity and specificity using the original cutoff value of 12 were assessed to evaluate the diagnostic utility of the LANSS-J. Sensitivity and specificity with possible cutoff values were calculated, along with area under the receiver operating characteristic curve. We then evaluated agreement regarding assessment of the LANSS-J by two investigators. We used the intraclass correlation coefficient (ICC) for the total score and Cohen's kappa coefficient for each item. RESULTS: Data for patients with neuropathic pain (n = 30) and those with nociceptive pain (n = 29) were analyzed. With a cutoff of 12, the sensitivity was 63.3% (19/30) and the specificity 93.1% (27/29). Sensitivity improved substantially with a cutoff of <= 11 (>= 83.3%, 25/30). High specificity (93.1%, 27/29) was sustained with a cutoff of 9 to 12. The ICC for the total score was 0.85, indicating sufficient agreement. Kappa coefficients ranged from 0.68 to 0.84. CONCLUSIONS: The LANSS-J is a valid screening tool for detecting neuropathic pain. Our results suggest that employing the original cutoff value provides high specificity, although a lower cutoff value of 10 or 11 (with its high specificity maintained) may be more beneficial when pain attributed to neuropathic mechanisms is suspected in Japanese patients. PMID- 27770599 TI - High-Frequency Spinal Cord Stimulation in a Patient with an Implanted Cardiac Device. AB - BACKGROUND: New advances in spinal cord stimulation have led to improved treatment of patients suffering from chronic pain. While the overall safety of newer stimulation devices has been established, no published reports exist regarding safety considerations when these devices are implanted in patients with a preexisting cardiac device. CASE REPORT: An 83-year-old man with a history of out-of-hospital cardiac arrest secondary to an episode of ventricular fibrillation underwent automated implantable cardiac defibrillator placement. Concomitantly, he suffered from intractable chronic low axial back pain and was deemed a candidate for high-frequency (10 kHz) spinal cord stimulation (SCS). Cardiac monitoring during SCS trial and implantation was performed with no interference noted. Following high-frequency SCS implantation, the patient was observed to have significant pain relief with functional improvement. DISCUSSION: While others have reported safety during traditional SCS in patients with implanted cardiac devices, this is the first case report to describe safe and effective use of high-frequency SCS in a patient with an implanted cardiac device. PMID- 27770601 TI - Portuguese Version of the Pain Beliefs and Perceptions Inventory: A Multicenter Validation Study. AB - BACKGROUND: We aimed to perform the translation, cultural adaptation, and validation of the Pain Beliefs and Perceptions Inventory (PBPI) for the European Portuguese language and chronic pain population. METHODS: This is a longitudinal multicenter validation study. A Portuguese version of the PBPI (PBPI-P) was created through a process of translation, back translation, and expert panel evaluation. The PBPI-P was administered to a total of 122 patients from 13 chronic pain clinics in Portugal, at baseline and after 7 days. Internal consistency and test-retest reliability were assessed by Cronbach's alpha (alpha) and intraclass correlation coefficient (ICC). Construct (convergent and discriminant) validity was assessed based on a set of previously developed theoretical hypotheses about interrelations between the PBPI-P and other measures. Exploratory and confirmatory factor analyses were performed to test the theoretical structure of the PBPI-P. RESULTS: The internal consistency and test retest reliability coefficients for each respective subscale were alpha = 0.620 and ICC = 0.801 for mystery; alpha = 0.744 and ICC = 0.841 for permanence; alpha = 0.778 and ICC = 0.791 for constancy; and alpha = 0.764 and ICC = 0.881 for self blame. Exploratory and confirmatory factor analysis revealed a four-factor structure (performance, constancy, self-blame, and mystery) that explained 63% of the variance. The construct validity of the PBPI-P was shown to be adequate, with more than 90% of the previously defined hypotheses regarding interrelations with other measures confirmed. CONCLUSION: The PBPI-P has been shown to be adequate and to have excellent reliability, internal consistency, and validity. It may contribute to a better pain assessment and is suitable for research and clinical use. PMID- 27770600 TI - INF2- and FHOD-related formins promote ovulation in the somatic gonad of C. elegans. AB - Formins are regulators of actin filament dynamics. We demonstrate here that two formins, FHOD-1 and EXC-6, are important in the nematode Caenorhabditis elegans for ovulation, during which actomyosin contractions push a maturing oocyte from the gonad arm into a distensible bag-like organ, the spermatheca. EXC-6, a homolog of the disease-associated mammalian formin INF2, is highly expressed in the spermatheca, where it localizes to cell-cell junctions and to circumferential actin filament bundles. Loss of EXC-6 does not noticeably affect the organization the actin filament bundles, and causes only a very modest increase in the population of junction-associated actin filaments. Despite absence of a strong cytoskeletal phenotype, approximately half of ovulations in exc-6 mutants exhibit extreme defects, including failure of the oocyte to enter the spermatheca, or breakage of the oocyte as the distal spermatheca entrance constricts during ovulation. Loss of FHOD-1 alone has little effect, and we cannot detect FHOD-1 in the spermatheca. However, combined loss of these formins in double fhod-1;exc-6 mutants results in profound ovulation defects, with significant slowing of the entry of oocytes into the spermatheca, and failure of nearly 80% of ovulations. We suggest that EXC-6 plays a role directly in the spermatheca, perhaps by modulating the ability of the spermatheca wall to rapidly accommodate an incoming oocyte, while FHOD-1 may play an indirect role relating to its known importance in the growth and function of the egg-laying muscles. (c) 2016 The Authors. Cytoskeleton Published by Wiley Periodicals, Inc. PMID- 27770602 TI - Rapid diagnostic test for G6PD deficiency in Plasmodium vivax-infected men: a budget impact analysis based in Brazilian Amazon. AB - OBJECTIVE: The aim of this study was to estimate the incremental budget impact (IBI) of a rapid diagnostic test to detect G6PDd in male patients infected with Plasmodium vivax in the Brazilian Amazon, as compared with the routine protocol recommended in Brazil which does not include G6PDd testing. METHODS: The budget impact analysis was performed from the perspective of the Brazilian health system, in the Brazilian Amazon for the years 2013, 2014 and 2015. The analysis used a decision model to compare two scenarios: the first consisting of the routine recommended in Brazil which does not include prior diagnosis of dG6PD, and the second based on the use of RDT CareStartTM G6PD (CS-G6PD) in all male subjects diagnosed with vivax malaria. The expected implementation of the diagnostic test was 30% in the first year, 70% the second year and 100% in the third year. RESULTS: The analysis identified negative IBIs which were progressively smaller in the 3 years evaluated. The sensitivity analysis showed that the uncertainties associated with the analytical model did not significantly affect the results. CONCLUSION: A strategy based on the use of CS-G6PD would result in better use of public resources in the Brazilian Amazon. PMID- 27770604 TI - Cropping history trumps fallow duration in long-term soil and vegetation dynamics of shifting cultivation systems. AB - In the study of shifting cultivation systems, fallow duration is seen as the key determinant of vegetation and soil dynamics: long fallows renew soil fertility, biomass, and biodiversity. However, long fallow systems are increasingly replaced around the world with short-medium fallow systems, and awareness is growing of the need to look across multiple (not just single) crop-fallow cycles to accurately understand observed soil and vegetation patterns. In a study from Peru that builds on 50+ years of field-level land-use histories, we found that, over multiple crop-fallow cycles, farmers' cropping practices mattered more than fallow duration for biodiversity and soil fertility. After initial clearing of primary forest, a precipitous decline occurred in tree species richness of fallows (>50%) with gradual but continued loss thereafter (~0.5 species/yr), which resulted in shifts in species composition over time. For soils, the decline in fertility was more gradual with each additional cycle of cropping resulting in lowered soil organic matter, available phosphorus, and exchangeable sodium levels, even in fields with long fallow durations. In the most intensively used sites, soils experienced a 16% decline of soil organic matter over 4+ cycles. In contrast to previous studies, biomass accumulation and carbon stocks were not related to cropping history or to the number and duration of cycles observed. This suggests that biodiversity-soils-biomass dynamics may not necessarily "move together" in these systems. These results point to the importance of the number of crop-fallow cycles over fallow duration in driving soil fertility and vegetation dynamics under shifting cultivation in the Peruvian Amazon. Overtime shifting cultivation may erode soil fertility and biodiversity levels even if long fallows persist. As the decline in soils appears slow, it may be possible to address this effect with the use of amendments, however biodiversity declines and species compositional changes may be much harder to reverse. PMID- 27770603 TI - Prevalence and oral health-related quality of life of self-reported orofacial conditions in Sweden. AB - OBJECTIVES: To (i) determine the prevalences of self-report in a Swedish adult population, of temporomandibular disorders, burning mouth syndrome, dry mouth, and bad breath and (ii) determine oral health-related quality-of-life impairment in subjects reporting these conditions. SUBJECTS AND METHODS: A cross-sectional, randomized sample of the adult Swedish population (response rate: 46%, N = 1309 subjects) self-reported their condition from the preceding month to assess prevalences of self-report for the studied conditions together with comorbidity group of subjects who reported more than one condition. The 49-item Oral Health Impact Profile (OHIP) used to assess oral health-related quality of life. RESULTS: The most prevalent condition was bad breath (39%), followed by dry mouth (22%), temporomandibular disorders (18%) and burning mouth syndrome (4%). High comorbidity of conditions occurred in 27% of the population. Quality-of-life impairment increased with the number of comorbid conditions. Among individual conditions, burning mouth syndrome and temporomandibular disorders (57% and 40% OHIP points) presented higher impairment than dry mouth and bad breath (32% and 26% OHIP points). CONCLUSIONS: Orofacial conditions were common and often coexist. The comorbidity group experienced the highest impact on oral health related quality of life: the more the comorbid conditions, the greater the negative impact. PMID- 27770605 TI - NMR reassignment of stictic acid isolated from a Sumatran lichen Stereocaulon montagneanum (Stereocaulaceae) with superoxide anion scavenging activities. AB - The phytochemical study of Stereocaulon montagneanum harvested in Sumatra (Indonesia) led to the isolation of 11 known compounds including two metabolites not previously described in the genus Stereocaulon, peristictic acid (8) and menegazziaic acid (10). The complete 1H and 13C NMR spectral assignments of stictic acid derivatives are reported with some revisions. Five depsidones belonging to the stictic acid chemosyndrome were superoxide anion scavengers as potent as ascorbic acid and with no toxicity on two human cell lines. PMID- 27770606 TI - Simultaneous formulation of terbinafine and salvia monoterpenes into chitosan hydrogel with testing biological activity of corresponding dialysates against C. albicans yeast. AB - This work was aimed at a progressive formulation of drugs into chitosan hydrogels. It was taken into consideration that a therapeutic effect of the drugs could be enhanced by a combination of natural compounds with chemical (synthetic) drugs. In this work, sage essential oil (SEO) bicyclic monoterpenes with antiflogistic, antiseptic, and antimycotic properties were combined with terbinafine (TB) having a strong antimycotic activity. Detail optimization of the hydrogel-drugs composition (SEO monoterpenes, TB, chitosan, and polysorbate 80 concentrations), based on permeation experiment and UV absorption/GC-MS analysis of permeated species (eucalyptol, camphor, borneol, thujone, TB) in dialysates, was made. Concerning the active drugs formulation, an optimum concentration of TB was set at the level providing maximum release of the SEO monoterpenes. In vitro activity of the dialysates from the optimized hydrogel was tested against Candida albicans showing that a minimum inhibition concentration was significantly exceeded. The experimental results revealed that the chitosan hydrogel was suitable for the simultaneous formulation of the natural drugs (SEO) with chemical drug (TB) resulting in the preparation with acceptable stability, required gel properties, and significant biological activity. Such preparation should be effective in an antimycotic dermal use. PMID- 27770607 TI - The Association Between the Genetic Variants of the NOTCH3 Gene and Ischemic Stroke Risk. AB - BACKGROUND Ischemic stroke (IS) is a leading cause of disability and death and NOTCH3 as a gene related with cardiac-cerebral vascular disease plays a vital role in IS development. However, the reports about the effect of genetic variants in NOTCH3 gene on IS are still few. MATERIAL AND METHODS In order to explore the association between NOTCH3 polymorphisms and IS, 134 patients with IS and 115 controls were enrolled in this case-control study. Polymerase chain reaction was used to do the genotyping of polymorphisms. The chi2 test was performed to evaluate Hardy-Weinberg equilibrium (HWE) in the control group and calculate odds ratio (OR) with corresponding 95% confidence interval (CI) which represented the association intensity of NOTCH3 gene polymorphisms and IS risk. RESULTS The genotype frequencies in the control group all confirmed to HWE. TT genotype of 381C>T was associated significantly with IS risk (OR=2.441, 95%CI=1.021-5.837). TC, CC mutant genotypes of 1735T>C had higher frequencies in cases than controls and the difference was significant (P=0.013, 0.041); further, its C allele also increased 0.722 times risk in the case group than controls (OR=1.722, 95%CI=1.166 2.541). CONCLUSIONS NOTCH3 381C>T and 1735T>C polymorphisms were associated with IS and might be the risk factors for IS development, but not NOTCH3 605C>T polymorphism. PMID- 27770608 TI - Non-canonical expression patterns and evolutionary rates of sex-biased genes in a seasonal fish. AB - Sex determination is a highly variable process that utilizes many different mechanisms to initiate the cascade of differentiation processes. The molecular pathways controlling sexual development are less conserved than previously assumed, and appear to require active maintenance in some species; indeed, the developmental decision of gonad phenotype in gonochoristic species is not fixed at an early developmental stage. Much of the knowledge about sex determination mechanisms was derived from research on gonochoristic, non-seasonal breeders. In this study, the transcriptome of resting adult gonads of a seasonal breeder, the endangered Iberian cyprinid fish Squalius pyrenaicus, was analyzed to assess the expression patterns and evolutionary rates of sex-biased genes that could be involved in maintenance of gonad identity as well as in sex determination. Remarkably, some crucial female genes-such as aromatase cyp19a1a, estrogen receptor esr1a, and foxl2-were expressed more abundantly in S. pyrenaicus testis than in ovaries. Moreover, contrary to the higher evolutionary rate changes observed in male-biased genes, higher dN /dS ratios were observed for female biased genes than for male-biased genes in S. pyrenaicus. These results help unravel the impact of seasonality in sex determination mechanisms and the evolution of genes, and highlight the need to study fish at different gonadal maturation states to understand the function of sex-biased genes. Mol. Reprod. Dev. 83: 1102-1115, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27770609 TI - In vivo six-degree-of-freedom knee-joint kinematics in overground and treadmill walking following total knee arthroplasty. AB - No data are available to describe six-degree-of-freedom (6-DOF) knee-joint kinematics for one complete cycle of overground walking following total knee arthroplasty (TKA). The aims of this study were firstly, to measure 6-DOF knee joint kinematics and condylar motion for overground walking following TKA; and secondly, to determine whether such data differed between overground and treadmill gait when participants walked at the same speed during both tasks. A unique mobile biplane X-ray imaging system enabled accurate measurement of 6-DOF TKA knee kinematics during overground walking by simultaneously tracking and imaging the joint. The largest rotations occurred for flexion-extension and internal-external rotation whereas the largest translations were associated with joint distraction and anterior-posterior drawer. Strong associations were found between flexion-extension and adduction-abduction (R2 = 0.92), joint distraction (R2 = 1.00), and anterior-posterior translation (R2 = 0.77), providing evidence of kinematic coupling in the TKA knee. Although the measured kinematic profiles for overground walking were grossly similar to those for treadmill walking, several statistically significant differences were observed between the two conditions with respect to temporo-spatial parameters, 6-DOF knee-joint kinematics, and condylar contact locations and sliding. Thus, caution is advised when making recommendations regarding knee implant performance based on treadmill measured knee-joint kinematic data. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1634-1643, 2017. PMID- 27770610 TI - In vivo evaluation of stem cell aggregates on osteochondral regeneration. AB - To date, many osteochondral regenerative approaches have utilized varied combinations of biocompatible materials and cells to engineer cartilage. Even in cell-based approaches, to date, no study has utilized stem cell aggregates alone for regenerating articular cartilage. Thus, the purpose of this study was to evaluate the performance of a novel stem cell-based aggregate approach in a fibrin carrier to regenerate osteochondral defects in the Sprague-Dawley rat trochlear groove model. Two different densities of rat bone marrow mesenchymal stem cell (rBMSC) aggregates were fabricated by the hanging drop technique. At 8 weeks, the cell aggregates supported the defects and served as a catalyst for neo cartilage synthesis, and the experimental groups may have been beneficial for bone and cartilage regeneration compared to the fibrin-only control and sham groups, as evidenced by histological assessment. The cell density of rBMSC aggregates may thus directly impact chondrogenesis. The usage of cell aggregates with fibrin as a cell-based technology is a promising and translational new treatment strategy for repair of cartilage defects. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1606-1616, 2017. PMID- 27770611 TI - CREB activity is required for luteinizing hormone-induced the expression of EGF like factors. AB - A surge of luteinizing hormone (LH) from the pituitary gland induces the expression of the epidermal growth factor (EGF)-like factors, which triggers oocyte maturation, cumulus expansion, and ovulation. How LH induces EGF-like factor expression is unclear. In the present study, a rapid increase of phosphorylated cAMP response element binding protein (CREB) was observed after the activation of LH receptor by human chorionic gonadotropin. Large antral follicles from equine chorionic gonadotropin-primed mice were cultured in medium with LH to stimulate the expression of EGF-like factors. CREB phosphorylation was increased in granulosa cells; conversely KG-501, a CREB functional inhibitor, significantly reduced LH-induced gene expression of EGF-like factors, oocyte meiotic resumption, and cumulus cell expansion. Reduction of CREB expression by Creb siRNA also repressed LH-induced expression of EGF-like factors in cultured granulosa cells. Inactivation of mitogen-activated protein kinase (MAPK3/1) by U0126 inhibited LH-induced CREB phosphorylation and EGF-like factors gene expression, whereas the activation of LH receptor increased Akt/protein kinase B phosphorylation, which is involved in LH-induced CREB phosphorylation and the expression of EGF-like factors. Thus, LH induces MAPK3/1 and Akt activation, both of which are required for the CREB-promoted expression of EGF-like factors in granulosa cells. Mol. Reprod. Dev. 83: 1116-1127, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27770612 TI - Let-7i-Induced Atg4B Suppression Is Essential for Autophagy of Placental Trophoblast in Preeclampsia. AB - Autophagy, identified as type II programmed cell death, has already been known to be involved in the pathophysiology of preeclampsia (PE), which is a gestational disease with high morbidity. The present study aims to investigate the functional role of let-7i, a miRNA, in trophoblastic autophagy. Placental tissue used in this study was collected from patients with severe preeclampsia (SPE) or normal pregnant women. A decreased level of let-7i was found in placenta of SPE. In addition, autophagic vacuoles were observed in SPE and the expression of microtubule associated protein 1 light chain 3 (LC3) II/I was elevated. In vitro, let-7i mimics suppressed the autophagic activities in human HTR-8/SVneo trophoblast cell line (HTR-8) and human placental choriocarcinoma cell line JEG 3, whereas let-7i inhibitor enhanced the activities. As a potential target of let 7i, autophagy-related 4B cysteine peptidase (Atg4B) had an increased expression level in SPE. As expected, the increased expression of Atg4B was negatively regulated by let-7i using dual luciferase reporter assay. Furthermore, these trophoblast-like cells transfected with the let-7i mimic or inhibitors resulted in a significant change of Atg4B in both mRNA and protein level. More importantly, Atg4B overexpression could partly reverse let-7i mimic-reduced LC3II/I levels; whereas Atg4B silencing partly attenuated let-7i inhibitor induced the level of LC3II/I expression. Taken together, these findings suggest that let-7i is able to regulate autophagic activity via regulating Atg4B expression, which might contribute to the pathogenesis of PE. J. Cell. Physiol. 232: 2581-2589, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27770614 TI - Lysosomal Storage of Subunit c of Mitochondrial ATP Synthase in Brain-Specific Atp13a2-Deficient Mice. AB - Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of early-onset parkinsonism linked to the PARK9 locus. The causative gene for KRS is Atp13a2, which encodes a lysosomal type 5 P-type ATPase. We recently showed that KRS/PARK9 linked mutations lead to several lysosomal alterations, including reduced proteolytic processing of cathepsin D in vitro. However, it remains unknown how deficiency of Atp13a2 is connected to lysosomal impairments. To address this issue, we analyzed brain tissues of Atp13a2 conditional-knockout mice, which exhibited characteristic features of neuronal ceroid lipofuscinosis, including accumulation of lipofuscin positive for subunit c of mitochondrial ATP synthase, suggesting that a common pathogenic mechanism underlies both neuronal ceroid lipofuscinosis and Parkinson disease. PMID- 27770613 TI - Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling. AB - Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODC-overexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN. PMID- 27770616 TI - Antiproliferative and anti-inflammatory furostanol saponins from the rhizomes of Tupistra chinensis. AB - Phytochemical investigations of the rhizome of Tupistra chinensis led to the isolation of ten new furostanol saponins along with fourteen known spirostanols. Their chemical structures were elucidated on the basis of spectroscopic and chemical methods, including IR, NMR, MS, and GC analyses. The antiproliferative effects against FaDu and Detroit 562 cell lines and inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in a macrophage cell line RAW 264.7 were assayed for all the isolated compounds. Compound 14 exhibited significant antiproliferative effects against FaDu and Detroit 562 cells with IC50 values of 1.1+/-0.1 and 1.2+/-0.1MUM, respectively. Compounds 1, 2, 6, 13, 16, 19 and 24 exhibited inhibitory effects on NO production with IC50 values ranging from 15.7 to 46.2MUM. PMID- 27770615 TI - Plesiomonas shigelloides exports a lethal cytotoxic-enterotoxin (LCE) by membrane vesicles. AB - Plesiomonas shigelloides isolated from water in Brazil was previously described as a hemorrhagic heat-labile cytotoxic-enterotoxin producer. We purified this toxin from culture supernatants using ion metallic affinity chromatography (IMAC) followed by molecular exclusion chromatography. The pure toxin presented molecular mass of 50kDa and isoelectric point (pI) around 6.9 by 2D electrophoresis. When injected intravenously, the purified cytotoxic-enterotoxin induced also severe spasms followed by sudden death of mice. Hence, we entitled it as lethal cytotoxic-enterotoxin (LCE). The presence of membrane vesicles (MVs) on cell surfaces of P. shigelloides was observed by scan electron microscopy (SEM). From these MVs the LCE toxin was extracted and confirmed by biological and serological assays. These data suggest that P. shigelloides also exports this cytotoxic-enterotoxin by membrane vesicles, a different mechanism of delivering extra cellular virulence factors, so far not described in this bacterium. PMID- 27770617 TI - Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells. AB - A series of methotrexate-diosgenin conjugates was designed and synthesized to enhance the passive internalization of methotrexate (MTX) into transport resistant cells. The inhibitory effects of these conjugates on dihydrofolate reductase (DHFR), and their anti-proliferation behaviors against a transport resistant breast cancer cell line, MDA-MB-231, were investigated. All of the synthesized conjugates retained an ability to inhibit DHFR after the diosgenin substitution. The MTX conjugates were much more potent against methotrexate resistant MDA-MB-231 cells than MTX. Conjugate 18, containing a disulfide bond, exhibited the most potent anti-proliferative and DHFR inhibitory effects (IC50=4.1MUM and 17.21nM, respectively). Anti-proliferative activity was higher in the conjugate with a longer space linker (conjugate 21) than those with shorter linkers (conjugates 19 and 20). These results suggest that diosgenin conjugation of MTX may be an effective way to overcome its transport resistance in cancer cells. PMID- 27770618 TI - Diabetic ketoacidosis in a pediatric intensive care unit. AB - OBJECTIVE: To describe the characteristics of children aged 0-14 years diagnosed with diabetic ketoacidosis and compare the following outcomes between children with prior diagnosis of type 1 diabetes mellitus and children without prior diagnosis of type 1 diabetes mellitus length of hospital stay, severity on admission, insulin dosage, time of continuous insulin use, volume of fluids infused during treatment, and complications. METHODS: A retrospective descriptive study with review of medical records of patients admitted to the pediatric intensive care unit of a referral hospital from June 2013 to July 2015. The following data regarding 52 admissions were analyzed: age, sex, weight, body surface area, signs, symptoms and severity on admission, blood gas, blood glucose, glycated hemoglobin, serum osmolarity, and index of mortality. The insulin dosage, time of continuous insulin use, volume administered in the expansion phase and in the first 24h, length of stay, and complications such as electrolyte disturbances, hypoglycemia, cerebral edema, and death were compared between the two groups. RESULTS: Patients without a previous diagnosis of DM1 were younger at admission, with mean age of 8.4 years (p<0.01), reported more nausea or vomiting, polydipsia and polyuria, and showed more weight loss (p<0.01). This study also observed a higher prevalence of hypokalemia (p<0.01) and longer hospital stay in this group. CONCLUSIONS: No differences in severity between groups were observed. The study showed that children without prior diagnosis of type 1 diabetes mellitus were younger at admission, had more hypokalemia during the course of treatment, and had greater length of hospital stay. PMID- 27770620 TI - Performance in noise: Impact of reduced speech intelligibility on Sailor performance in a Navy command and control environment. AB - Noise, hearing loss, and electronic signal distortion, which are common problems in military environments, can impair speech intelligibility and thereby jeopardize mission success. The current study investigated the impact that impaired communication has on operational performance in a command and control environment by parametrically degrading speech intelligibility in a simulated shipborne Combat Information Center. Experienced U.S. Navy personnel served as the study participants and were required to monitor information from multiple sources and respond appropriately to communications initiated by investigators playing the roles of other personnel involved in a realistic Naval scenario. In each block of the scenario, an adaptive intelligibility modification system employing automatic gain control was used to adjust the signal-to-noise ratio to achieve one of four speech intelligibility levels on a Modified Rhyme Test: No Loss, 80%, 60%, or 40%. Objective and subjective measures of operational performance suggested that performance systematically degraded with decreasing speech intelligibility, with the largest drop occurring between 80% and 60%. These results confirm the importance of noise reduction, good communication design, and effective hearing conservation programs to maximize the operational effectiveness of military personnel. PMID- 27770621 TI - The influence of memory and attention on the ear advantage in dichotic listening. AB - The role of memory retention and attentional control on hemispheric asymmetry was investigated using a verbal dichotic listening paradigm, with the consonant-vowel syllables (/ba/,/da/,/ga/,/ka/,/pa/and/ta/), while manipulating the focus of attention and the time interval between stimulus and response. Attention was manipulated using three conditions: non-forced (NF), forced left (FL) and forced right (FR) attention. Memory involvement was varied using four delays (0, 1, 3 and 4 s) between stimulus presentation and response. Results showed a significant right ear advantage (REA) in the NF condition and an increased REA in the FR condition. A left ear advantage (LEA) was found in FL condition. The REA increased significantly in the NF attention condition at the 3-s compared to the 0-s delay and in the FR condition at the 1-s compared to the 0-s delay. No modulation of the left ear advantage was observed in the FL condition. These results are discussed in terms of an interaction between attentional processes and memory retention. PMID- 27770619 TI - Coenzyme Q10 and pro-inflammatory markers in children with Down syndrome: clinical and biochemical aspects. AB - OBJECTIVE: Evidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 and selected pro-inflammatory markers such as interleukin 6 and tumor necrosis factor alpha in children with Down syndrome. METHODS: Eighty-six children (5-8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of interleukin 6, tumor necrosis factor alpha, coenzyme Q10, fasting blood glucose, and intelligence quotient were measured. RESULTS: Forty-three young Down syndrome children and forty-three controls were included over a period of eight months (January-August 2014). Compared with the control group, the Down syndrome patients showed significant increase in interleukin 6 and tumor necrosis factor alpha (p=0.002), while coenzyme Q10 was significantly decreased (p=0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between coenzyme Q10 and intelligence quotient levels, as well as between interleukin 6 and tumor necrosis factor alpha. CONCLUSION: Interleukin 6 and tumor necrosis factor alpha levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms. PMID- 27770622 TI - Category selectivity of the N170 and the role of expertise in deaf signers. AB - Deafness is known to affect processing of visual motion and information in the visual periphery, as well as the neural substrates for these domains. This study was designed to characterize the effects of early deafness and lifelong sign language use on visual category sensitivity of the N170 event-related potential. Images from nine categories of visual forms including upright faces, inverted faces, and hands were presented to twelve typically hearing adults and twelve adult congenitally deaf signers. Classic N170 category sensitivity was observed in both participant groups, whereby faces elicited larger amplitudes than all other visual categories, and inverted faces elicited larger amplitudes and slower latencies than upright faces. In hearing adults, hands elicited a right hemispheric asymmetry while in deaf signers this category elicited a left hemispheric asymmetry. Pilot data from five hearing native signers suggests that this effect is due to lifelong use of American Sign Language rather than auditory deprivation itself. PMID- 27770623 TI - Musicians' edge: A comparison of auditory processing, cognitive abilities and statistical learning. AB - It has been hypothesized that musical expertise is associated with enhanced auditory processing and cognitive abilities. Recent research has examined the relationship between musicians' advantage and implicit statistical learning skills. In the present study, we assessed a variety of auditory processing skills, cognitive processing skills, and statistical learning (auditory and visual forms) in age-matched musicians (N = 17) and non-musicians (N = 18). Musicians had significantly better performance than non-musicians on frequency discrimination, and backward digit span. A key finding was that musicians had better auditory, but not visual, statistical learning than non-musicians. Performance on the statistical learning tasks was not correlated with performance on auditory and cognitive measures. Musicians' superior performance on auditory (but not visual) statistical learning suggests that musical expertise is associated with an enhanced ability to detect statistical regularities in auditory stimuli. PMID- 27770624 TI - Spatial and temporal disparity in signals and maskers affects signal detection in non-human primates. AB - Detection thresholds for auditory stimuli (signals) increase in the presence of maskers. Natural environments contain maskers/distractors that can have a wide range of spatiotemporal properties relative to the signal. While these parameters have been well explored psychophysically in humans, they have not been well explored in animal models, and their neuronal underpinnings are not well understood. As a precursor to the neuronal measurements, we report the effects of systematically varying the spatial and temporal relationship between signals and noise in macaque monkeys (Macaca mulatta and Macaca radiata). Macaques detected tones masked by noise in a Go/No-Go task in which the spatiotemporal relationships between the tone and noise were systematically varied. Masked thresholds were higher when the masker was continuous or gated on and off simultaneously with the signal, and lower when the continuous masker was turned off during the signal. A burst of noise caused higher masked thresholds if it completely temporally overlapped with the signal, whereas partial overlap resulted in lower thresholds. Noise durations needed to be at least 100 ms before significant masking could be observed. Thresholds for short duration tones were significantly higher when the onsets of signal and masker coincided compared to when the signal was presented during the steady state portion of the noise (overshoot). When signal and masker were separated in space, masked signal detection thresholds decreased relative to when the masker and signal were co located (spatial release from masking). Masking release was larger for azimuthal separations than for elevation separations. These results in macaques are similar to those observed in humans, suggesting that the specific spatiotemporal relationship between signal and masker determine threshold in natural environments for macaques in a manner similar to humans. These results form the basis for future investigations of neuronal correlates and mechanisms of masking. PMID- 27770626 TI - Corrigendum to "Neuroprotective and anti-inflammatory properties of a novel non thiazolidinedione PPARgamma agonist in vitro and in MPTP-treated mice" [Neuroscience 302 (2015) 23-35]. PMID- 27770625 TI - Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging. AB - Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control. PMID- 27770627 TI - Phylogenetic and functional analyses of a plant protein related to human B-cell receptor-associated proteins. AB - Human B-cell receptor-associated protein BAP31 (HsBAP31) is the endoplasmic reticulum-resident protein involved in protein sorting and transport as well as pro-apoptotic signaling. Plant orthologs of HsBAP31 termed 'plant BAP-like proteins' (PBL proteins) have thus far remained unstudied. Recently, the PBL protein from Nicotiana tabacum (NtPBL) was identified as an interactor of Nt-4/1, a plant protein known to interact with plant virus movement proteins and affect the long-distance transport of potato spindle tuber viroid (PSTVd) via the phloem. Here, we have compared the sequences of PBL proteins and studied the biochemical properties of NtPBL. Analysis of a number of fully sequenced plant genomes revealed that PBL-encoding genes represent a small multigene family with up to six members per genome. Two conserved motifs were identified in the C terminal region of PBL proteins. The NtPBL C-terminal hydrophilic region (NtPBL C) was expressed in bacterial cells, purified, and used for analysis of its RNA binding properties in vitro. In gel shift experiments, NtPBL-C was found to bind several tested RNAs, showing the most efficient binding to microRNA precursors (pre-miRNA) and less efficient interaction with PSTVd. Mutational analysis suggested that NtPBL-C has a composite RNA-binding site, with two conserved lysine residues in the most C-terminal protein region being involved in binding of pre-miRNA but not PSTVd RNA. Virus-mediated transient expression of NtPBL-C in plants resulted in stunting and leaf malformation, developmental abnormalities similar to those described previously for blockage of miRNA biogenesis/function. We hypothesize that the NtPBL protein represents a previously undiscovered component of the miRNA pathway. PMID- 27770629 TI - Recurrent Retinoblastoma With Mandibular Metastasis: A Case Report. AB - Retinoblastoma (RB) is an aggressive intraocular tumor arising from cells of the retina. Infrequently, distant metastasis occurs in advanced stages of the disease. This case report describes the metastasis of the tumor to the mandible, an extremely rare phenomenon. This condition was observed for a recurrent tumor in a patient who initially underwent chemotherapy, making this case report unique and providing new insights into the behavior of this tumor. An overview of the management of a metastatic RB also is discussed. PMID- 27770628 TI - Analgesic Effect of Perioperative Systemic Dexamethasone on Blowout Fracture Surgery. AB - PURPOSE: To clarify the effect of systemic dexamethasone (DXM) on pain and postoperative opioid (oxycodone) consumption after blowout fracture surgery. MATERIALS AND METHODS: A prospective randomized observer-blinded trial of 20 patients who had a blowout fracture requiring surgical intervention was conducted. Patients were randomly assigned to receive a total dose of intravenous DXM 30 mg perioperatively or no DXM (controls). Pain was assessed postoperatively using a 10-cm visual analog scale (VAS) each time analgesics (acetaminophen every 6 hours or oxycodone upon request) were administered. The VAS area under the curve (VAS AUC) for 24 hours postoperatively represented the outcome. Data were analyzed using chi2 test, Student t test, 2-tailed Mann-Whitney U test, and linear regression, with a P value less than .05 indicating significance. RESULTS: Patients with blowout fracture receiving perioperative systemic DXM exhibited a significantly lower average VAS AUC (P = .04). After controlling for other confounding variables, this result remained significant (P = .03). CONCLUSIONS: DXM appears to decrease postoperative pain and thus is recommended as a pre emptive analgesic in blowout fracture surgery. PMID- 27770630 TI - 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. AB - Stem cell therapy is a promising therapeutic method for the treatment of ischemic heart diseases; however, some challenges prohibit the efficacy after cell delivery due to hostile microenvironment of the injured myocardium. 3D printed pre-vascularized stem cell patch can enhance the therapeutic efficacy for cardiac repair through promotion of rapid vascularization after patch transplantation. In this study, stem cell-laden decellularized extracellular matrix bioinks are used in 3D printing of pre-vascularized and functional multi-material structures. The printed structure composed of spatial patterning of dual stem cells improves cell to-cell interactions and differentiation capability and promotes functionality for tissue regeneration. The developed stem cell patch promoted strong vascularization and tissue matrix formation in vivo. The patterned patch exhibited enhanced cardiac functions, reduced cardiac hypertrophy and fibrosis, increased migration from patch to the infarct area, neo-muscle and capillary formation along with improvements in cardiac functions. Therefore, pre vascularized stem cell patch provides cardiac niche-like microenvironment, resulting in beneficial effects on cardiac repair. PMID- 27770631 TI - Click chemistry improved wet adhesion strength of mussel-inspired citrate-based antimicrobial bioadhesives. AB - For the first time, a convenient copper-catalyzed azide-alkyne cycloaddition (CuAAC, click chemistry) was successfully introduced into injectable citrate based mussel-inspired bioadhesives (iCMBAs, iCs) to improve both cohesive and wet adhesive strengths and elongate the degradation time, providing numerous advantages in surgical applications. The major challenge in developing such adhesives was the mutual inhibition effect between the oxidant used for crosslinking catechol groups and the Cu(II) reductant used for CuAAC, which was successfully minimized by adding a biocompatible buffering agent typically used in cell culture, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), as a copper chelating agent. Among the investigated formulations, the highest adhesion strength achieved (223.11 +/- 15.94 kPa) was around 13 times higher than that of a commercially available fibrin glue (15.4 +/- 2.8 kPa). In addition, dual crosslinked (i.e. click crosslinking and mussel-inspired crosslinking) iCMBAs still preserved considerable antibacterial and antifungal capabilities that are beneficial for the bioadhesives used as hemostatic adhesives or sealants for wound management. PMID- 27770632 TI - Current status on clinical applications of magnesium-based orthopaedic implants: A review from clinical translational perspective. AB - As a new generation of medical metallic material, magnesium (Mg) and its alloys with or without surface coating have attracted a great deal of attention due to its biodegradability and potential for avoiding a removal operation after the implant has fulfilled its function for surgical fixation of injured musculoskeletal tissues. Although a few clinical cases on Mg-based orthopaedic implants were reported more than a century ago, it was not until recently that clinical trials using these implants with improved physicochemical properties were carried out in Germany, China and Korea for bone fracture fixation. The promising results so far suggest a bright future for biodegradable Mg-based orthopaedic implants and would warrant large scale phase II/III studies. Given the increasing interest on this emerging biomaterials and intense effort to improve its properties for various clinical applications, this review covers the evolution, current strategies, and future perspectives in the development of Mg based orthopaedic implants. We also highlight a few clinical cases performed in China that may be unfamiliar to the general orthopaedic community. PMID- 27770634 TI - Repair of bone defects in vivo using tissue engineered hypertrophic cartilage grafts produced from nasal chondrocytes. AB - The regeneration of large bone defects remains clinically challenging. The aim of our study was to use a rat model to use nasal chondrocytes to engineer a hypertrophic cartilage tissue which could be remodelled into bone in vivo by endochondral ossification. Primary adult rat nasal chondrocytes were isolated from the nasal septum, the cell numbers expanded in monolayer culture and the cells cultured in vitro on polyglycolic acid scaffolds in chondrogenic medium for culture periods of 5-10 weeks. Hypertrophic differentiation was assessed by determining the temporal expression of key marker genes and proteins involved in hypertrophic cartilage formation. The temporal changes in the genes measured reflected the temporal changes observed in the growth plate. Collagen II gene expression increased 6 fold by day 7 and was then significantly downregulated from day 14 onwards. Conversely, collagen X gene expression was detectable by day 14 and increased 100-fold by day 35. The temporal increase in collagen X expression was mirrored by increases in alkaline phosphatase gene expression which also was detectable by day 14 with a 30-fold increase in gene expression by day 35. Histological and immunohistochemical analysis of the engineered constructs showed increased chondrocyte cell volume (31-45 MUm), deposition of collagen X in the extracellular matrix and expression of alkaline phosphatase activity. However, no cartilage mineralisation was observed in in vitro culture of up to 10 weeks. On subcutaneous implantation of the hypertrophic engineered constructs, the grafts became vascularised, cartilage mineralisation occurred and loss of the proteoglycan in the matrix was observed. Implantation of the hypertrophic engineered constructs into a rat cranial defect resulted in angiogenesis, mineralisation and remodelling of the cartilage tissue into bone. Micro-CT analysis indicated that defects which received the engineered hypertrophic constructs showed 38.48% in bone volume compared to 7.01% in the control defects. Development of tissue engineered hypertrophic cartilage to use as a bone graft substitute is an exciting development in regenerative medicine. This is a proof of principal study demonstrating the potential of nasal chondrocytes to engineer hypertrophic cartilage which will remodel into bone on in vivo transplantation. This approach to making engineered hypertrophic cartilage grafts could form the basis of a new potential future clinical treatment for maxillofacial reconstruction. PMID- 27770633 TI - Polymer fiber-based models of connective tissue repair and healing. AB - Physiologically relevant models of wound healing are essential for understanding the biology of connective tissue repair and healing. They can also be used to identify key cellular processes and matrix characteristics critical for the design of soft tissue grafts. Modeling the various stages of repair post tendon injury, polymer meshes of varying fiber diameter (nano-1 (390 nm) < nano-2 (740 nm) < micro (1420 nm)) were produced. Alignment was also introduced in the nano-2 group to model matrix undergoing biological healing rather than scar formation. The response of human tendon fibroblasts on these model substrates were evaluated over time as a function of fiber diameter and alignment. It was observed that the repair models of unaligned nanoscale fibers enhanced cell growth and collagen synthesis, while these outcomes were significantly reduced in the mature repair model consisting of unaligned micron-sized fibers. Organization of paxillin and actin on unaligned meshes was enhanced on micro- compared to nano-sized fibers, while the expression and activity of RhoA and Rac1 were greater on nanofibers. In contrast, aligned nanofibers promoted early cell organization, while reducing excessive cell growth and collagen production in the long term. These results show that the early-stage repair model of unaligned nanoscale fibers elicits a response characteristic of the proliferative phase of wound repair, while the more mature model consisting of unaligned micron-sized fibers is more representative of the remodeling phase by supporting cell organization while suppressing growth and biosynthesis. Interestingly, introduction of fiber alignment in the nanofiber model alters fibroblast response from repair to healing, implicating matrix alignment as a critical design factor for circumventing scar formation and promoting biological healing of soft tissue injuries. PMID- 27770635 TI - Hemodynamic and serum cardiac markers and risk of cognitive impairment and dementia. AB - INTRODUCTION: Cardiac function is a key player in maintaining energy homeostasis in the brain. Heart failure is closely related to higher risk of neurocognitive disorders. Recent evidence shows that this relationship might not be limited to patients with advanced heart failure, and even suboptimal cardiac functioning is associated with accelerated brain aging. Hence, hemodynamic and serum cardiac markers may provide valuable information about the risk of dementia. METHODS: We provide an overview on the link between cardiac markers and cognitive function by a systematic search in five databases. Furthermore, we discuss the pathophysiological aspects of this link and highlight the pertinent clinical and public health implications. RESULTS: Increasing evidence supports the associations of hemodynamic and serum cardiac markers with accelerated cognitive decline. DISCUSSION: Hemodynamic and serum cardiac markers are closely linked with risk of cognitive impairment. This highlights the significance of the heart brain connection in reducing the burden of dementia. PMID- 27770637 TI - The efficacy of intraoperative autologous platelet gel in total knee arthroplasty: A meta-analysis. AB - PURPOSE: Autologous platelet gel, developed from fresh autologous blood, is a breakthrough in the promotion and acceleration of soft tissue and bone repair. The application of autologous platelet gel has been reported to improve haemostasis and promote function recovery. We screened the randomized controlled trials and controlled clinical trials of high quality to investigate whether autologous platelet gel makes a better performance for postoperative bleeding and functional recovery in patients after total knee arthroplasty. METHOD: The Web of Science, the Cochrane Library, EMBASE, and PubMed databases were comprehensively searched. A total of 1234 patients with 1333 knees were included in the twelve studies. The PRISMA guidelines and Cochrane Handbook were applied to appraise the results published in all included studies. Review Manager 5.3 for Windows was used to analyse the extracted data. RESULTS: Compared with the placebo group, the autologous platelet gel group showed a significant decrease in visual analogue scale. No significant differences were found in the drop of haemoglobin, knee society score, Western ontario mcmaster osteoarthritis index, length of hospital stay, postoperative narcotics, and range of motion during post-operative follow up. CONCLUSIONS: Compared with placebo, APG offers superior pain control after total knee arthroplasties. However, APG has no advantage in blood loss, functional recovery, postoperative narcotics and length of stay. The use of autologous platelet gel is not worthy of being recommended as a bioactive autologous material to improve the clinical outcomes in total knee arthroplasty patients. PMID- 27770638 TI - Evaluation of the surgical outcome and complications of total laparoscopic hysterectomy in patients with enlarged uteruses. AB - OBJECTIVE: The aim of this study was to investigate whether uterine weight has a deleterious effect on the operation time, complication rates, length of hospital stay and incidence of intraoperative haemorrhage during total laparoscopic hysterectomy operation. METHODS: A total of 282 patients who underwent total laparoscopic hysterectomy for benign gynaecologic indications were retrospectively analyzed. The median operation time of 70 min was accepted as an index number, and a cut-off point of >=300 g was calculated for uterine weight by using reciever operator characteristics (ROC) curve analysis. RESULTS: There was no statistically significant relationship between the uterine weight and haemoglobin drop rate (1.27 +/- 0.89 vs 1.21 +/- 0.88, p = 0.905), complication rate (10.83% vs 9.26%, p = 0.062) and length of hospital stay (3.27 +/- 1.23 vs 3.37 +/- 1.35 days, p = 0.505) based on this cut. Lee-Huang point was preferred for abdominal entry in cases with uteruses reached the level of umbilicus -2 cm in physical examination. CONCLUSIONS: Uterine weight was not effected the complication rate, estimated blood loss and length of hospital stay in total laparoscopic hysterectomy operation. A cut-off value of 300 g could be used for an increased operation time. PMID- 27770636 TI - Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. AB - INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 * 10-8), upstream of COBL, and rs16961023 (P = 4.6 * 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS. PMID- 27770640 TI - Potential of the small cyclopoid copepod Paracyclopina nana as an invertebrate model for ecotoxicity testing. AB - Aquatic invertebrates contribute significantly to environmental impact assessment of contaminants in aquatic ecosystems. Much effort has been made to identify viable and ecologically relevant invertebrate test organisms to meet rigorous regulatory requirements. Copepods, which are ecologically important and widely distributed in aquatic organisms, offer a huge opportunity as test organisms for aquatic toxicity testing. They have a major role not only in the transfer of energy in aquatic food chains, but also as a medium of transfer of aquatic pollutants across the tropic levels. In this regard, a supratidal and benthic harpacticoid copepod Tigriopus japonicus Mori (order Harpacticoida) has shown promising characteristics as a test organism in the field of ecotoxicology. Because there is a need to standardize a battery of test organisms from species in different phylogenetic and critical ecosystem positions, it is important to identify another unrelated planktonic species for wider application and comparison. In this regard, the cyclopoid copepod Paracyclopina nana Smirnov (order Cyclopoida) has emerged as a potential test organism to meet such requirements. Like T. japonicus, it has a number of features that make it a candidate worth consideration in such efforts. Recently, the genomics of P. nana has been unraveled. Data on biochemical and molecular responses of P. nana against exposure to environmental chemicals and other stressors have been collected. Recently, sequences and expression profiles of a number of genes in P. nana encoding for heat shock proteins, xenobiotic-metabolizing enzymes, and antioxidants have been reported. These genes serve as potential biomarkers in biomonitoring of environmental pollutants. Moreover, the application of gene expression techniques and the use of its whole transcriptome have allowed evaluation of transcriptional changes in P. nana with the ultimate aim of understanding the mechanisms of action of environmental stressors. Whole-animal bioassays and gene expression studies indicate that P. nana may serve as an excellent tool to evaluate the impact of diverse disturbances in the marine environment. With a better understanding of toxicological mechanisms, ecotoxicologists will be able to understand defense mechanisms against toxicants in copepods. In this review, we illustrate the potential of P. nana as an alternative as well as a complementary invertebrate model organism for risk assessment of aquatic pollutants. PMID- 27770641 TI - Stress and its role in the dentin hypersensitivity in rats. AB - INTRODUCTION: The perception of pain varies individually. Chronic stress leads to analgesia. The use of animal chronic mild stress model to mimic human condition was previously developed and now applied in the evaluation of pain perception in rats with dentin hypersensitivity (DH). AIMS: Using DH model induced by dentin erosion (DE) mediated by acidic solution, the present study aimed the evaluation of the interaction of chronic stress and pain induced by DH in rats with DE. METHODS: DH was induced by ad libitum 30-day intake of acidic solution. Stress was induced by the New York subway model. Body weight was weekly taken, during treatment. Groups WO (water, no stress), WS (water and stress), EO (acidic solution, no stress) and ES (acidic solution, stress) were submitted to treatments. RESULTS: After 30 days, all groups were submitted to DH test assessed by cold water stimuli in the labial surface of molars, for 5s, and the rats responses were scored as grades 0, 0.5, 1, 2, or 3. After euthanasia, blood was taken to obtain the levels of corticosterone, stomachs were observed in fresh preparations, kidneys and livers were submitted to histological evaluation. Open field model supported stress evaluation, as did corticosterone analysis. Stressed animals showed significant increase in pain perception and a decrease in locomotion frequency, tending to be more frequent in the periphery of the arena, corroborating stressed behavior and the need of protection as a pain relief. Corticosterone levels were increased in the stressed rats with dentin erosion and also corroborate present findings. Finally, reduction in weight gain was impaired in stressed group with dentin erosion. CONCLUSION: The animal model enabled the evaluation of how chronic mild stress interfered in DH pain perception. PMID- 27770639 TI - Preferred reporting of case series in surgery; the PROCESS guidelines. AB - INTRODUCTION: Case series have been a long held tradition within the surgical literature and are still frequently published. Reporting guidelines can improve transparency and reporting quality. No guideline exists for reporting case series, and our recent systematic review highlights the fact that key data are being missed from such reports. Our objective was to develop reporting guidelines for surgical case series. METHODS: A Delphi consensus exercise was conducted to determine items to include in the reporting guideline. Items included those identified from a previous systematic review on case series and those included in the SCARE Guidelines for case reports. The Delphi questionnaire was administered via Google Forms and conducted using standard Delphi methodology. Surgeons and others with expertise in the reporting of case series were invited to participate. In round one, participants voted to define case series and also what elements should be included in them. In round two, participants voted on what items to include in the PROCESS guideline using a nine-point Likert scale to assess agreement as proposed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) working group. RESULTS: In round one, there was a 49% (29/59) response rate. Following adjustment of the guideline with incorporation of recommended changes, round two commenced and there was an 81% (48/59) response rate. All but one of the items were approved by the participants and Likert scores 7-9 were awarded by >70% of respondents. The final guideline consists of an eight item checklist. CONCLUSION: We present the PROCESS Guideline, consisting of an eight item checklist that will improve the reporting quality of surgical case series. We encourage authors, reviewers, editors, journals, publishers and the wider surgical and scholarly community to adopt these. PMID- 27770643 TI - 1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder. AB - BACKGROUND: Previous studies of patients with bipolar disorder (BD) using magnetic resonance spectroscopy (MRS) have shown neurophysiological abnormalities related to the glutamate (Glu)-glutamine (Gln) cycle, membrane turnover, and neuronal integrity, although the results were neither consistent nor conclusive. Recently it has been reported the Gln/Glu ratio is the most useful index, quantifying neuronal-glial interactions and the balance of glutamatergic metabolites In this MRS study, we elucidated the abnormalities of metabolites in a larger sample of patients with BD with a high-field MRI system. METHODS: Sixty two subjects (31 patients with BD and 31 healthy controls [HC]) underwent 3T proton MRS (1H-MRS) of the anterior cingulate cortex (ACC) and left basal ganglia (ltBG) using a stimulated echo acquisition mode (STEAM) sequence. RESULTS: After verifying the data quality, 20 patients with BD and 23 age- and gender-matched HCs were compared using repeated-measures analysis of covariance (ANCOVA). Compared to the HC group, the BD group showed increased levels of Gln, creatine (Cr), N-acetyl aspartate (NAA), choline (Cho), and an increased ratio of Gln to Glu in the ACC, and increased Gln and Cho in the ltBG. These findings remained after the participants with BD were limited to only euthymic patients. After removing the influence of lithium (Li) and sodium valproate (VPA), we observed activated glutamatergic neurotransmission in the ACC but not in the ltBG. LIMITATIONS: The present findings are cross-sectional and metabolites were measured in only two regions. CONCLUSIONS: Our results support a wide range of metabolite changes in patients with BD involved in glutamatergic neurotransmission, membrane turnover, and neuronal integrity. Moreover, the elevation of Gln/Glu ratio suggested that hyperactivity of glutamatergic neurotransmission in the ACC is a disease marker for BD. PMID- 27770642 TI - DEFB1 polymorphisms and salivary hBD-1 concentration in Oral Lichen Planus patients and healthy subjects. AB - OBJECTIVES: The aetiology of Oral Lichen Planus (OLP), a chronic inflammatory disease of oral mucosa, is not yet well understood. Since innate immunity may be hypothesized as involved in the susceptibility to OLP, we studied human beta defensin 1 (hBD-1) an antimicrobial peptide constitutively expressed in the saliva, looking at functional genetic variants possibly able to diminish hBD-1 production an consequently conferring major susceptibility to OLP. DESIGN: We analysed three DEFB1 polymorphisms at 5' UTR, -52G>A (rs1799946), -44C>G (rs1800972), -20G>A (rs11362) and two DEFB1 polymorphisms at 3'UTR, c*5G>A (rs1047031), c*87A>G (rs1800971), with the aim of correlating these genetic variants and hBD-1 salivary level in a group of OLP patients and in healthy subjects. We also evaluated hBD-1 salivary concentrations, using ELISA, in OLP and healthy controls. RESULTS: We compared hBD-1 concentrations in OLP and healthy subjects: hBD-1 concentration was significantly higher in OLP patients respect to control. When considering the correlation between DEFB1 polymorphisms genotypes and hBD-1 expression levels, significant results were obtained for SNPs -52G>A (p=0.03 both in OLP patients and healthy individuals) and -44C>G (p=0.02 in OLP patients). CONCLUSIONS: hBD-1 production was different between OLP and healthy subjects (not age-matched with OLP). DEFB1 gene polymorphisms, -52G>A and -44C>G, correlated with hBD-1 salivary concentrations. PMID- 27770644 TI - Reliability and validity of the Japanese version of the Emotion Regulation Skills Questionnaire. AB - BACKGROUND: The Emotion Regulation Skills Questionnaire (ERSQ) comprehensively assesses nine aspects of emotion regulation skills: awareness, clarity, sensation, understanding, compassionate self-support, modification, acceptance, tolerance, and readiness to confront. However, it is unknown about the levels of emotion regulation skills in various mental disorders, and its cross-cultural validity. We developed a Japanese version of the ERSQ, then examined its validity and reliability in clinical and non-clinical populations. METHODS: In an Internet based survey, 2684 participants (406 with MDD, 198 with PD, 116 with SAD, 66 with OCD, 636 with comorbid MDD and >=1 anxiety disorder, and 99 with comorbid anxiety disorders; 1163 non-clinical sample) answered the ERSQ, diagnostic status, and measures of mindfulness, emotion regulation, behavioral activation, psychological distress, and life satisfaction. RESULTS: Confirmatory factor analysis (CFA) replicated the theoretical nine-factor structure of the original ERSQ. Higher order factor analysis model assuming two second-order factors and nine first order factors also showed adequate fit to the data, suggesting the factorial validity of the scale. Analyses of multi-group CFA indicated the equivalence of factor loadings across clinical and non-clinical subsamples. The levels of internal consistency and time stability were sufficient. Convergent validity of the scale was also confirmed for most of external criteria. Character on the emotion regulation skills for each diagnostic group was depicted. LIMITATIONS: Internet survey of samples with limited disorders, with self-reported diagnoses, may limit generalizability. CONCLUSIONS: The Japanese version of the ERSQ showed adequate reliability and validity. PMID- 27770646 TI - Trans-generational influences of sulfamethoxazole on lifespan, reproduction and population growth of Caenorhabditis elegans. AB - Trans-generational effects are increasingly used to indicate long-term influences of environmental pollutants. However, such studies can be complex and yield inconclusive results. In this study, the trans-generational effects of sulfamethoxazole (SMX) on Caenorhabditis elegans on lifespan, reproduction and population growth were tested for 7 consecutive generations, which included gestating generation (F0), embryo-exposed generation (F1), germline-exposed generation (F2), the first non-exposed generation (F3) and the three following generations (F4-F6). Results showed that lifespan was significantly affected by embryo exposure (F1) at 400um SMX with a value as low as 47% of the control. The reproduction (a total brood size as 49% of the control) and population growth (81% of the control) were significantly affected in germline exposure (F2). Lifespan and reproduction were severely inhibited in non-exposed generations, confirming the real trans-generational effects. Notably, initial reproduction and reproduction duration showed opposite generation-related changes, indicating their interplay in the overall brood size. The population growth rate was well correlated with median lethal time, brood size and initial reproduction, which indicated that the population would increase when the nematodes lived longer and reproduced more offspring within shorter duration. PMID- 27770645 TI - Insomnia and suicide-related behaviors: A multi-study investigation of thwarted belongingness as a distinct explanatory factor. AB - BACKGROUND: Insomnia is a robust correlate of suicidal ideation and behavior. Preliminary research has identified thwarted belongingness (c.f. social disconnection) as an explanatory link between insomnia and suicidal ideation. OBJECTIVES: This study replicates and extends previous findings using both cross sectional and longitudinal designs in four demographically diverse samples. Additionally, the specificity of thwarted belongingness was evaluated by testing anxiety as a rival mediator. METHOD: Self-report measures of insomnia symptoms, thwarted belongingness, suicidal ideation and behavior, and anxiety were administered in four adult samples: 469 undergraduate students, 352 psychiatric outpatients, 858 firefighters, and 217 primary care patients. RESULTS: More severe insomnia was associated with more severe thwarted belongingness and suicidality. Thwarted belongingness significantly accounted for the association between insomnia and suicidality, cross-sectionally and longitudinally, beyond anxiety. Notably, findings supported the specificity of thwarted belongingness: anxiety did not significantly mediate the association between insomnia and suicidality, and insomnia did not mediate the relation between thwarted belongingness and suicidality. LIMITATIONS: This study relied solely on self report measures. Future studies incorporating objective sleep measurements are needed. CONCLUSION: Findings underscore the utility of assessing and addressing sleep disturbances and social disconnection to reduce suicide risk. PMID- 27770647 TI - Histopathological analysis of tilapia gills (Oreochromis niloticus Linnaeus, 1758) exposed to sugarcane vinasse. AB - Sugarcane vinasse is one of the main residues generated by the transformation of cane into ethanol. Because of the high organic content (COD), high biochemical oxygen demand (BOD), low pH, the large amount that this residue is generated (15l for every liter of ethanol produced) and their use as fertilizer on the sugarcane crop, this residue is potentially polluting to the soil ecossystem and by percolation to water ecossystem too. Thus, this study aimed to assess the toxicity of vinasse by analyzing Oreochromis niloticus gills exposed to different dilutions (1%, 2.5%, 5% and 10%) in two bioassays. The gills were collected, fixed and analyzed using ultra morphological, histological, and histochemical techniques. After exposure to the vinasse, a statistically significant reduction of the ridges present on the surface of pavimentous cells was observed in one of the bioassays; such structures are responsible for mucus retention, which helps to protect the tissue. In addition, an intumescence of the cells was observed in the treatments with vinasse as well as an increase in the amount of chloridric cells. Some striking tissue changes detected in the treatments were epithelial detachment and loss of integrity of secondary lamellae, causing their rupture and consequent hemorrhage. In the first bioassay, the amount of these changes was statistically significant at the 5% dilution, and the focus of hemorrhage was significant at all dilution ratios. In the second bioassay, the epithelial disorganization was statistically significant only at the 2.5% dilution of vinasse. Moreover, for both bioassays performed, a significant increase in mucous cells was observed when compared with the control. Our results demonstrate the toxic action of sugarcane vinasse, which caused histopathological changes in the exposed animals at all four dilution tested. This highlights the need for caution in the disposal of sugarcane vinasse on the soil, especially due to its capacity for being leached or percolated into water resources, which could seriously damage aquatic fauna. PMID- 27770649 TI - Variation in toxicity during the biodegradation of various heterocyclic and homocyclic aromatic hydrocarbons in single and multi-substrate systems. AB - In the present study, an attempt was made to understand the variation in the toxicity during the biodegradation of aromatic hydrocarbons in single and multi substrate system. The bacterial bioassay based on the inhibition of dehydrogenase enzyme activity of two different bacterial sp. E.coli and Pseudomonas fluorescens was used for toxicity assessment. Amongst the chosen pollutants, the highest acute toxicity was observed for benzothiophene followed by benzofuran having EC50 value of 16.60mg/L and 19.30mg/L respectively. Maximum residual toxicity of 30.8% was observed at the end during the degradation of benzothiophene. Due to the accumulation of transitory metabolites in both single and multisubstrate systems, reduction in toxicity was not proportional to the decrease in pollutant concentration. In multi-substrate system involving mixture of heterocyclic hydrocarbons, maximum residual toxicity of 39.5% was observed at the end of biodegradation. Enhanced degradation of benzofuran, benzothiophene and their metabolic intermediates were observed in the presence of naphthalene resulting in significant reduction in residual toxicity. 2 (1H) - quinolinone, an intermediate metabolite of quinoline was observed having significant eco-toxicity amongst all other intermediates investigated. PMID- 27770648 TI - Accumulation of lead (Pb) in brown trout (Salmo trutta) from a lake downstream a former shooting range. AB - An environmental survey was performed in Lake Kyrtjonn, a small lake within an abandoned shooting range in the south of Norway. In Lake Kyrtjonn the total water concentrations of Pb (14ug/L), Cu (6.1ug/L) and Sb (1.3ug/L) were elevated compared to the nearby reference Lake Stitjonn, where the total concentrations of Pb, Cu and Sb were 0.76, 1.8 and 0.12ug/L, respectively. Brown trout (Salmo trutta) from Lake Kyrtjonn had very high levels of Pb in bone (104mg/kg w.w.), kidney (161mg/kg w.w.) and the gills (137mg/kg d.w), and a strong inhibition of the ALA-D enzyme activity were observed in the blood (24% of control). Dry fertilized brown trout eggs were placed in the small outlet streams from Lake Kyrtjonn and the reference lake for 6 months, and the concentrations of Pb and Cu in eggs from the Lake Kyrtjonn stream were significantly higher than in eggs from the reference. More than 90% of Pb accumulated in the egg shell, whereas more than 80% of the Cu and Zn accumulated in the egg interior. Pb in the lake sediments was elevated in the upper 2-5cm layer (410-2700mg/kg d.w), and was predominantly associated with redox sensitive fractions (e.g., organic materials, hydroxides) indicating low potential mobility and bioavailability of the deposited Pb. Only minor amounts of Cu and Sb were deposited in the sediments. The present work showed that the adult brown trout, as well as fertilized eggs and alevins, may be subjected to increased stress due to chronic exposure to Pb, whereas exposure to Cu, Zn and Sb were of less importance. PMID- 27770650 TI - Mimicking natural systems: Changes in behavior as a result of dynamic exposure to naproxen. AB - Animals living in aquatic habitats regularly encounter anthropogenic chemical pollution. Typically, the toxicity of a chemical toxicant is determined by the median lethal concentration (LC50) through a static exposure test. However, LC50 values and static tests do not provide an accurate representation of exposure to pollutants within natural stream systems. In their native habitats, animals experience exposure as a fluctuating concentration due to turbulent mixing, temporal variations of contamination (seasonal inputs), and contaminant input type (point vs. non-point). Research has shown that turbulent environments produce exposures with a high degree of fluctuation in frequency, duration, and intensity. In order to more effectively evaluate the effects of pollutants, we created a dynamic exposure paradigm, utilizing both flow and substrate within a small mesocosm. A commonly used pharmaceutical, naproxen, was used as the toxicant and female crayfish (Orconectes virilis) as the target organism to investigate changes in fighting behavior as a result of dynamic exposure. Crayfish underwent either a 23h long static or a dynamic exposure to naproxen. Following exposure, the target crayfish and an unexposed size matched opponent underwent a 15min fight trial. These fight trials were recorded and later analyzed using a standard ethogram. Results indicate that exposure to sublethal concentrations of naproxen, in both static and flowing conditions, negatively impact aggressive behavior. Results also indicate that a dynamic exposure paradigm has a greater negative impact on behavior than a static exposure. Turbulence and habitat structure play important roles in shaping chemical exposure. Future research should incorporate features of dynamic chemical exposure in order to form a more comprehensive image of chemical exposure and predict the resulting sublethal effects from exposure. Possible techniques for assessment include utilizing flow-through experimental set-ups in tandem with behavioral or physiological endpoints as opposed to acute toxicity. Other possibilities of assessment could involve utilizing fine-scale chemical measurements of pollutants to determine the actual concentrations animals encounter during an exposure event. PMID- 27770651 TI - The thermodynamic efficiency of ATP synthesis in oxidative phosphorylation. AB - As the chief energy source of eukaryotic cells, it is important to determine the thermodynamic efficiency of ATP synthesis in oxidative phosphorylation (OX PHOS). Previous estimates of the thermodynamic efficiency of this vital process have ranged from Lehninger's original back-of-the-envelope calculation of 38% to the often quoted value of 55-60% in current textbooks of biochemistry, to high values of 90% from recent information theoretic considerations, and reports of realizations of close to ideal 100% efficiencies by single molecule experiments. Hence this problem has been reinvestigated from first principles. The overall thermodynamic efficiency of ATP synthesis in the mitochondrial energy transduction OX PHOS process has been found to lie between 40 and 41% from four different approaches based on a) estimation using structural and biochemical data, b) fundamental nonequilibrium thermodynamic analysis, c) novel insights arising from Nath's torsional mechanism of energy transduction and ATP synthesis, and d) the overall balance of cellular energetics. The torsional mechanism also offers an explanation for the observation of a thermodynamic efficiency approaching 100% in some experiments. Applications of the unique, molecular machine mode of functioning of F1FO-ATP synthase involving direct inter conversion of chemical and mechanical energies in the design and fabrication of novel, man-made mechanochemical devices have been envisaged, and some new ways to exorcise Maxwell's demon have been proposed. It is hoped that analysis of the fundamental problem of energy transduction in OX PHOS from a fresh perspective will catalyze new avenues of research in this interdisciplinary field. PMID- 27770652 TI - Methanol carbonylation over copper-modified mordenite zeolite: A solid-state NMR study. AB - The carbonylation of methanol with carbon monoxide to generate methyl acetate over Cu-H-MOR and H-MOR zeolites is studied using solid-state NMR spectroscopy. It is found that the catalytic activity of Cu-H-MOR zeolite is much higher than that of H-MOR zeolite. The presence of Cu+ species enables the stabilization of dimethyl ether, which efficiently suppresses the hydrocarbon formation during carbonylation process over Cu-H-MOR zeolite. In addition, the carbon monoxide adsorbed on Cu+ site is not an active species to produce either methyl acetate or acetic acid. PMID- 27770653 TI - Abscisic acid content and the expression of genes related to its metabolism during maturation of triticale grains of cultivars differing in pre-harvest sprouting susceptibility. AB - Abscisic acid (ABA) is a plant hormone that plays a predominant role in the onset and maintenance of primary dormancy. Peak ABA accumulation in embryos of triticale grains was observed before any significant loss of water and was higher in Fredro, a cultivar less susceptible to pre-harvest sprouting (PHS), than in Leontino, a cultivar more sensitive to PHS. At full maturity, embryonic ABA content in Fredro was twice as high as in Leontino. Two full-length cDNAs of 9 cis-epoxycarotenoid dioxygenase (TsNCED1, TsNCED2), an enzyme involved in ABA biosynthesis, and two full-length cDNAs of ABA 8'-hydroxylase (TsABA8'OH1 and TsABA8'OH2), an enzyme involved in ABA catabolism, were identified in triticale grains and characterized. The maximum transcript level of both TsNCED1 and TsNCED2 preceded the peak of ABA accumulation, suggesting that both TsNCEDs contribute to reach this peak, although the expression of TsNCED1 was significantly higher in Fredro than in Leontino. High expression of TsABA8'OH2 and TsABA8'OH1 was observed long before and at the end of the ABA accumulation peak, respectively, but no differences were observed between cultivars. The obtained results suggest that mainly TsNCED1 might be related to the higher ABA content and higher resistance of Fredro to PHS. However, Fredro embryos not only have higher ABA content, but also exhibit greater sensitivity to ABA, which may also have a significant effect on grain dormancy and lower susceptibility to PHS for grains of this cultivar. PMID- 27770654 TI - Optimal perioperative management of antithrombotic agents in patients with chronic subdural hematoma. AB - OBJECTIVE: The use of antithrombotic agents such as anticoagulants and antiplatelet agents is widespread, and the opportunities to treat patients with chronic subdural hematoma (CSDH) under antithrombotic therapy are growing. However, whether antithrombotic therapy contributes to postoperative complications and recurrences of CSDH and how these agents should be managed in the surgical treatment of CSDH remains unclear. METHODS: We retrospectively analyzed 150 consecutive patients with CSDH who underwent neurosurgical interventions at Kyushu Rosai Hospital from 2011 to 2015 and followed them for more than 3 months. RESULTS: Of the 150 study patients, 44 received antithrombotic therapy. All anticoagulants and 76% of the antiplatelet agents were discontinued before surgical treatment of CSDH and resumed within 1 week except in 4 patients whose treatment was terminated and 7 patients who developed postoperative complications or underwent reoperations before resumption of these agents. Postoperative hemorrhagic complications associated with surgical treatment of CSDH occurred in 8 patients (5.3%), and there was no significant difference in the incidence of these complications between patients with and without antithrombotic therapy (6.8% vs. 4.7%, respectively; p=0.90). Postoperative thromboembolic complications occurred in 5 patients (5.4%), including 4 patients with antithrombotic therapy; these complications developed before resumption of antithrombotic agents in 2 patients. There was a significant difference in the incidence of postoperative thromboembolic complications between patients with and without antithrombotic therapy (9.1% vs. 0.9%, respectively; p=0.04). There were no significant differences in the incidence of radiographic deterioration or reoperation of ipsilateral or contralateral hematomas between patients with and without antithrombotic therapy after surgical treatment of unilateral CSDH. CONCLUSION: A history of antithrombotic therapy was significantly correlated with the incidence of postoperative thromboembolic complications in patients with CSDH. Antithrombotic agents should be resumed as soon as possible when no hemorrhagic complication is confirmed after neurosurgical intervention for CSDH. PMID- 27770655 TI - Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice. AB - Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS). Low plus intermediate Sokal score correlated to optimal imatinib responses, as well as OS at 8-years, thus confirming the established role of Sokal score as a prognostic factor in CML patients. Low ABCB1 and high OCT1 mRNA levels were associated with an optimal molecular response, while the inverse levels were associated with non-responders (warning and failure) patients. Our results suggest that ABCB1 and OCT1 mRNA expressions may present biological relevance to identify responder and non-responder patients to imatinib treatment. PMID- 27770656 TI - Laser-induced fluorescence in fish scales to evaluate the environmental integrity of ecosystems. AB - The aim of this study was to evaluate the fluorescence of Astyanax lacustris fish scales when excited in the UV-A and blue regions for use as a bioindicator of aquatic ecosystems. This species was firstly defined as Astyanax altiparanae, popularly known as "lambari-do-rabo-amarelo". Currently, abiotic/biotic environmental integrity is generally assessed using limnological and physicochemical parameters related to biological indicators in streams or rivers, which are not sufficient to evaluate the real environmental conditions: in some cases, these parameters can be strongly dependent on local weather conditions. In this study, after the fish scales were excited with UV-A (360nm) and blue (405nm) photons, a strong and broad visible fluorescence band (from blue to red) could be observed that was mainly related to collagen and hydroxyapatite, independent of whether the excitation was applied to the inside or outside of the scale. Selected emission wavelengths were used as variables and the fluorescence intensities were interpreted using multivariate discriminant statistical analysis to compare streams with known different levels of integrity. The fluorescence data showed strong correlation with the electrical conductivity of the water, indicating that the scales of A. lacustris could be employed as bioindicators of environmental integrity on water chemistry monitoring programs. PMID- 27770658 TI - Combined effects of low levels of palmitate on toxicity of ZnO nanoparticles to THP-1 macrophages. AB - We have recently proposed that the interaction between food components and nanoparticles (NPs) should be considered when evaluating the toxicity of NPs. In the present study, we used THP-1 differentiated macrophages as a model for immune cells and investigated the combined toxicity of low levels of palmitate (PA; 10 or 50MUM) and ZnO NPs. The results showed that PA especially at 50MUM changed the size, Zeta potential and UV-vis spectra of ZnO NPs, indicating a possible coating effect. Up to 32MUg/mL ZnO NPs did not significantly affect mitochondrial activity, intracellular reactive oxygen species (ROS) or release of interleukin 6 (IL-6), but significantly impaired lysosomal function as assessed by neutral red uptake assay and acridine orange staining. The presence of 50MUM PA, but not 10MUM PA, further promoted the toxic effects of ZnO NPs to lysosomes but did not significantly affect other endpoints. In addition, ZnO NPs dose-dependently increased intracellular Zn ions in THP-1 macrophages, which was not significantly affected by PA. Taken together, the results of the present study showed a combined toxicity of low levels of PA and ZnO NPs especially to lysosomes in THP 1 macrophages. PMID- 27770659 TI - Biosynthesis of reduced graphene oxide nanosheets and their in vitro cytotoxicity against cardiac cell lines of Catla catla. AB - This work reports a one-step simple synthesis method for functionalized reduced graphene oxide (RGO) nanosheets by a Platanus orientalis leaf extract polyphenol mediated deoxygenation of graphene oxide (GO). Microscopic and spectroscopic characterization revealed the successful deoxygenation of GO and subsequent stabilization by oxidized polyphenols of plant extract. X-ray photoelectron spectroscopy, Raman spectroscopy, and X-ray diffraction analyses were used to examine the reduction of GO. Fourier-transform infrared spectroscopy results revealed capping of RGO with oxidized polyphenols of Platanus orientalis extract, which prevented aggregation of graphene sheets. Transmission electron microscopy and atomic force microscopy images revealed the formation of thin, transparent, sheet-like graphene. The in vitro cytotoxicity of synthesized RGO exhibited a dose-dependent toxicity against cardiac cell lines of Catla catla. Further, this work opens up a green synthesis route for the development of new graphene-based technologies. PMID- 27770657 TI - Prevalence and correlates of "Vaping" as a route of cannabis administration in medical cannabis patients. AB - PURPOSE: To examine the prevalence and correlates of vaporization (i.e., "vaping") as a route of cannabis administration in a sample of medical cannabis patients. PROCEDURES: Adults ages 21 and older (N=1485M age=45.1) who were seeking medical cannabis certification (either for the first time or as a renewal) at medical cannabis clinics in southern Michigan completed a screening assessment. Participants completed measures of route of cannabis administration, cannabis use, alcohol and other substance use. FINDINGS: An estimated 39% (n=511) of the sample reported past-month cannabis vaping, but vaping as the sole route of cannabis administration was rare. Specifically, only 30 participants (2.3% of the full sample and 5.9% of those who reported any vaping) indicated vaping as the sole route of cannabis administration. The majority (87.3%) of those who reported vaping also reported smoking (combustion) as a route of cannabis administration. Being younger than age 44, having more than a high school education, engaging in nonmedical stimulant use, being a returning medical cannabis patient, and greater frequency of cannabis use were associated with higher odds of vaping at the bivariate level and with all variables considered simultaneously. CONCLUSIONS: Vaping appears to be relatively common among medical cannabis patients, but is seldom used as the sole route of cannabis administration. RESULTS: highlight the importance of monitoring trends in vaping and other substance use behaviors in this population and underscore the need for longitudinal research into the motives, correlates, and consequences of cannabis vaping in medical cannabis patients. PMID- 27770660 TI - Coniferaldehyde inhibits LPS-induced apoptosis through the PKC alpha/beta II/Nrf 2/HO-1 dependent pathway in RAW264.7 macrophage cells. AB - Coniferaldehyde (CA) exerts anti-inflammatory properties by inducing heme oxygenase-1 (HO-1). To define the regulation mechanism by which CA induces a cytoprotective function and HO-1 expression, the up-stream regulations involved in the activation of nuclear transcription factor-erythroid 2-related factor (Nrf)-2/HO-1 pathway were investigated. CA dramatically increased the Nrf-2 nuclear translocation and HO-1 expression. Lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and cell death were down-regulated by CA, which were reversed by inhibition of HO 1 activity. Furthermore, CA specifically enhanced the phosphorylation of protein kinase C (PKC) alpha/beta II. Selective inhibition of PKC alpha/beta II using Go6976 or siRNA abolished the CA-induced Nrf-2/HO-1 signaling, and consequently suppressed the cytoprotective activity of CA on the LPS-induced cell death. Together, our results elucidate the regulatory mechanism of PKC alpha/beta II as the upstream molecule of Nrf-2 required for HO-1 expression during CA-induced anti-inflammatory cytoprotective function in LPS stimulated macrophages. PMID- 27770661 TI - Pim-2 protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced apoptosis via downregulation of Bim expression. AB - We know that silencing Bim, a pro-apoptosis protein, significantly attenuates glucose and oxygen-deprived induced apoptosis in cardiomyocytes. However, the mechanisms underlying the regulation of the Bim activation in the heart have remained unknown. Pim-2 is one of three Pim serine/threonine kinase family members thought to be involved in cell survival and proliferation. H9c2 cardiomyocytes were subjected to a hypoxia/reoxygenation (H/R) condition in vitro, mimicking ischemic/reperfusion injury in vivo. H/R augmented the expression of Bim, Cyt C, and Pim-2 and induced H9c2 cell apoptosis. Overexpression of Pim-2 attenuated apoptosis which induced by H/R in H9c2 cells, via downregulation of Bim and Cyt C expression. Silencing of Pim-2 promoted H/R induced apoptosis via upregulation of Bim and Cyt C expression. Co-IP revealed the interaction between Pim-2 and Bim protein, with Bim Ser65 phosphorylated by Pim-2. Furthermore, blocking proteasome activity by MG132 prevented Bim degradation, and Bim S65A mutation could reverse the anti-apoptotic role of Pim-2 which induced by H/R. These data demonstrated that Pim-2 is a novel Bim interacting protein, which negatively regulates Bim degradation and protects H9c2 cardiomyocytes from H/R-induced apoptosis. PMID- 27770662 TI - Menstrual cycle-related variation in autonomic nervous system functioning in women in the early menopausal transition with and without insomnia disorder. AB - Insomnia is considered a hyperarousal disorder, in which several psychophysiological domains including the autonomic nervous system (ANS) are over activated, potentially contributing to increased risk for cardiovascular (CV) disease. Here, we aimed to determine whether insomnia that develops in the context of the transition to menopause (menopausal transition insomnia, MTI) is similarly characterized by autonomic arousal. We also took into account modulation of the ANS by the hormonal changes of the menstrual cycle, a factor that has not previously been considered in studies on insomnia. Twenty one women with insomnia (49.0+/-3y) and 25 controls (48.8+/-2.6 y), also in the menopausal transition, had overnight laboratory-based polysomnographic recordings, including electrocardiograph, during the follicular and/or luteal (progesterone>=3ngml-1) phases of the menstrual cycle, with 21 women having recordings in both phases. Nocturnal time and frequency-domain heart rate variability (HRV) measures were calculated. Heart rate (HR) was significantly elevated (by ~4bpm) in MTI compared to controls in both follicular and luteal phases, across hours of the night, including during undisturbed periods of NREM and REM sleep (p<0.05). A higher HR tended to be associated with lower frequency- and time-domain vagal HRV indices in MTI compared with controls. In both groups, HR was significantly higher and total and high frequency HRV measures were lower in the luteal phase compared to the follicular phase (p<0.05). In addition, REM compared to NREM sleep was characterized by increased HR coupled with decreased vagal modulation and increased sympathovagal balance (p<0.01). Insomnia in the menopausal transition is characterized by nocturnal autonomic hyperarousal during both follicular and luteal phases of the menstrual cycle, which could be a factor in the etiology of MTI as well as a potential CV risk factor. PMID- 27770663 TI - Low protein Z plasma level is a risk factor for acute myocardial infarction in coronary atherosclerosis disease patients. AB - OBJECTIVES: To examine plasma protein Z (PZ) levels in acute myocardial infarction (AMI) and chronic coronary atherosclerosis disease (CCAD) patients without history of AMI and explore its potential clinical significance. METHODS: Plasma PZ concentrations were measured in 90 AMI patients (Group A), 87 CCAD patients without AMI history who remained free of major clinical events at least one year (Group B), and 88 clinically healthy controls (Group C). RESULTS: PZ was found to be significantly lower (P<0.001) in Group A (1508.5+/-486.2ng/mL) compared with Group B (1823.0+/-607.8ng/mL) and C (2001.7+/-733.0ng/mL) and in Group A+B compared with Group C (Group A+B 1663.1+/-570.0 ng/mL, P<0.001). No statistically significant difference was reached between Group B and C (P=0.081). PZ level was significantly correlated with concentration of creatine kinase MB, high sensitive-cardiac troponin T, high sensitive C reactive protein, D-dimer and coagulation factor II and may be a useful predictor for AMI (OR: 1.38, 95% CI: 1.13-1.77, P=0.03). Subgroup analysis showed PZ concentration below the lowest tertile (<1398ng/mL) had a significantly increased risk for AMI and CCAD (OR: 3.39; 95% CI: 1.12-10.31; P=0.03 and OR: 7.39; 95% CI: 2.62-20.79; P<0.001 respectively). CONCLUSIONS: PZ deficiency is found in AMI patients and could potentially reflect the myocardium injury, local coagulation activation and inflammation response during the acute phase of coronary atherosclerosis disease. PMID- 27770664 TI - Clinical implications of the detection of antibodies directed against domain 1 of beta2-glycoprotein 1 in thrombotic antiphospholipid syndrome. AB - INTRODUCTION: Antibodies directed against domain 1 of beta2 glycoprotein 1 (abeta2GP1-Dm1) have been involved in the immunopathogenesis of antiphospholipid syndrome (APS). However, the clinical relevance of abeta2GP1-Dm1 in thrombotic APS has not yet been fully explored. OBJECTIVES: To determine the frequency of abeta2GP1-Dm1 in a cohort of patients with thrombotic APS, and to evaluate whether testing for abeta2GP1-Dm1 could have a clinical impact upon the risk assessment of the disease. METHODS: Patients were tested for abeta2GP1-Dm1 antibodies by chemiluminescence (BioFlash/AcuStar(r), ES). The presence of abeta2GP1-Dm1 was evaluated in different clinical presentations of the disease. RESULTS: Eight-four patients with a history of venous or arterial thrombosis were included. Forty-five (54%) patients had abeta2GP1 antibodies and 40% of them were positive for abeta2GP1-Dm1. Levels of abeta2GP1-Dm1 were higher in patients with systemic autoimmune disease (AUC=0.665; 95% CI=0.544-0.786; P=0.01), positive antinuclear antibody (AUC=0.654; 95% CI=0.535-0.772; P=0.01), triple antiphospholipid antibody (aPL) positivity (AUC=0.680; 95% CI=0.534-0.825; P=0.02) and positive lupus anticoagulant (AUC=0.639; 95% CI=0.502-0.776; P=0.07). In this cohort, abeta2GP1-Dm1 antibodies were not associated with the site of the first thrombosis (OR=0,62, 95% CI=0.20-1.94, P=0.42), thrombosis recurrence (OR=1.0, 95% CI=0.37-2.71, P=1.0) or pregnancy morbidity (OR=1.5, 95% CI=0.33 7.34, P=0.58). In multivariate analysis, positivity for abeta2GP1-Dm1 antibodies was associated with the diagnosis of systemic autoimmune disease (OR=4.01, 95% CI=1.14-14.2; P=0.03) and triple aPL positivity (OR=3.59, 95% CI=0.87-14.85; P=0.07). CONCLUSIONS: In the present cohort of thrombotic-APS patients, abeta2GP1 Dm1 antibodies were related to the diagnosis of systemic autoimmunity and complex serological profile of the disease, as triple aPL positivity and positive antinuclear antibody. Thus, our results suggest that testing for abeta2GP1-Dm1 antibodies may be useful for improving APS risk assessment. PMID- 27770665 TI - Current view and outcome of ITI therapy - A change over time? AB - INTRODUCTION: Inhibitor development in people with haemophilia is a serious complication that may require intensive and costly interventions. The goal of inhibitor management should be permanent inhibitor eradication through immune tolerance induction (ITI), but well-designed studies are lacking and the management of patients is therefore defined by the experience and views of the clinician. OBJECTIVES: To explore the current clinical practice and outcome of ITI therapy in Europe and how this may have changed over the last decade, as well as to provide consensus recommendations to guide clinicians in their clinical practice. METHODS: A survey was conducted among 16 European haemophilia comprehensive care centres to evaluate current ITI treatment regimens and success rates in severe and mild/moderate haemophilia A and haemophilia B. In addition, an updated literature review was performed as guidance for providing recommendations. RESULTS: We demonstrated successful inhibitor treatment in 86% of severe haemophilia A patients with low responding (LR) and 59% of patients with high responding (HR) inhibitors. Some new trends in the management of patients with inhibitors were identified, including a tendency to use low-dose regimens (<50IU/kg/d) in both children and adults with HR inhibitors possibly based on similar success rates demonstrated in the I-ITI study compared to a high dose protocol. Data on ITI therapy in mild and moderate haemophilia as well as haemophilia B were limited. CONCLUSIONS: The outcome of ITI therapy seems to be stable over time, and treatment regimens remain heterogeneous. The use of low dose regimens however is considered more frequently. PMID- 27770666 TI - Modeling of nonlinear interactions between guided waves and fatigue cracks using local interaction simulation approach. AB - This article presents a parallel algorithm to model the nonlinear dynamic interactions between ultrasonic guided waves and fatigue cracks. The Local Interaction Simulation Approach (LISA) is further developed to capture the contact-impact clapping phenomena during the wave crack interactions based on the penalty method. Initial opening and closure distributions are considered to approximate the 3-D rough crack microscopic features. A Coulomb friction model is integrated to capture the stick-slip contact motions between the crack surfaces. The LISA procedure is parallelized via the Compute Unified Device Architecture (CUDA), which enables parallel computing on powerful graphic cards. The explicit contact formulation, the parallel algorithm, as well as the GPU-based implementation facilitate LISA's high computational efficiency over the conventional finite element method (FEM). This article starts with the theoretical formulation and numerical implementation of the proposed algorithm, followed by the solution behavior study and numerical verification against a commercial finite element code. Numerical case studies are conducted on Lamb wave interactions with fatigue cracks. Several nonlinear ultrasonic phenomena are addressed. The classical nonlinear higher harmonic and DC response are successfully captured. The nonlinear mode conversion at a through-thickness and a half-thickness fatigue crack is investigated. Threshold behaviors, induced by initial openings and closures of rough crack surfaces, are depicted by the proposed contact LISA model. PMID- 27770667 TI - Altered cortical processing of motor inhibition in schizophrenia. AB - Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient gamma-aminobutyric acid (GABA) ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task related modulation of SICI was higher in subjects who showed less inhibition related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia. PMID- 27770668 TI - The impact of neighborhood social capital on life satisfaction and self-rated health: A possible pathway for health promotion? AB - Neighborhood social capital has repeatedly been linked to favorable health outcomes and life satisfaction. However, it has been questioned whether it's impact on health has been over-rated. We aim to investigate relationships between neighborhood social capital and self-rated health (SRH) and life satisfaction (LS) respectively, both directly and indirectly mediated via Sense of Coherence and self-esteem. Based on a cross-sectional population-survey (N=865) in a medium size Norwegian municipality, we specified a structural equation model (SEM) including the above-listed variables, while controlling for gender, age, education, income, and employment status. The applied model explains more variance in LS (46%) than in SRH (23%). Social capital has a stronger impact on life satisfaction than on health. The indirect pathway via SOC had the highest impact on life satisfaction, but no significant relationship to SRH. Self-rated health was more tightly linked to personal background variables. Enhancing social capital in the neighborhood might be a beneficial strategy to promote life satisfaction, as well as strengthening sense of coherence even in healthy communities. PMID- 27770183 TI - 35th Annual Meeting of the European Association for the Study of Diabetes : Brussels, Belgium, 28 September-2 October 1999. PMID- 27770670 TI - Three modes of power operation: Understanding doctor-patient conflicts in China's hospital therapeutic landscapes. AB - Doctor-patient conflicts in contemporary China are increasing in numbers and severity. This health geographic study shows how hospitals as a type of therapeutic landscape can shape doctor-patient relationships. First, the comprehensive nature of therapeutic landscapes with an emphasis on power operation within symbolic environments is provided as a framework for this study. Second, the results from participant observation and interviews with patients and doctors previously involved in conflicts are reported from Internal Medicine and Surgery Departments, within four hospitals in Anhui Province, Eastern China. The study finds that the spatial and temporal arrangements of spaces, the inside decorations and the different modes of discourses can build or ruin harmonious doctor-patient relations. The research concludes that adaptations to current hospital therapeutic landscapes can improve trust between patients and doctors, resulting in fewer conflicts and better health outcomes in China. PMID- 27770669 TI - E-cigarette use among students and e-cigarette specialty retailer presence near schools. AB - OBJECTIVE: This study examined the association between presence of e-cigarette specialty retailers near schools and e-cigarette use among middle and high school students in Orange County (OC), CA. METHODS: The OC subsample of the 2013-2014 California Healthy Kids Survey (N=67,701) was combined with geocoded e-cigarette retailers to determine whether a retailer was present within one-quarter mile of each public school in OC. Multilevel logistic regression models evaluated individual-level and school-level e-cigarette use correlates among middle and high school students. RESULTS: Among middle school students, the presence of an e cigarette retailer within one-quarter mile of their school predicted lifetime e cigarette use (OR=1.70, 95% CI=1.02, 2.83), controlling for confounders but no effect for current use. No significant effect was found for high school students. CONCLUSIONS: E-cigarette specialty retailers clustered around schools may be an environmental influence on student e-cigarette experimentation. PMID- 27770674 TI - Evaluation of alkaline electrolyzed water to replace traditional phosphate enhancement solutions: Effects on water holding capacity, tenderness, and sensory characteristics. AB - Sixty-four pork loins were randomly assigned to one of four treatments to evaluate the use of alkaline electrolyzed reduced water as a replacement for traditional enhancement solutions. Treatments included: alkaline electrolyzed reduced water (EOH; pH~11.5), EOH plus 2.5% potassium-lactate (EOK), industry standard (IS; 0.35% sodium tri-polyphosphate, 0.14% sodium chloride, 2.5% potassium-lactate), and no enhancement (CON). After enhancement (targeting 110%) and rest period, chops were cut (2.54-cm) to test treatment effects on water holding capacity, Warner-Bratzler shear force (WBSF), and sensory attributes. Despite its alkaline nature EOH chops exuded more water (P<0.05) than EOK, IS, or CON chops. Control chops were similar (P>0.05) to EOK, however CON and EOK both lost more moisture (P<0.05) than IS. The use of alkaline electrolyzed reduced water did not improve WBSF or sensory characteristics compared to IS treated chops. As a stand-alone enhancement solution alkaline electrolyzed reduced water was not a suitable replacement for industry standard solutions. PMID- 27770672 TI - Population-based analysis of breast cancer treatment by intrinsic sub-type in Manitoba, Canada. AB - BACKGROUND: Few descriptive epidemiological studies on the incidence, treatment and survival can accurately reflect a whole population. Manitoba, Canada has an accurate cancer registry, a drug information program network and a breast screening program since 1995. This combined with a stable population provides true population data that can accurately describe the region. METHODS: Using a retrospective cohort design all Breast Cancer cases were obtained from 2004-2010 (N=5399) and grouped by Intrinsic sub-type. Identifiable co-morbidities, prescribed endocrine therapy, staging, surgery, treatment and overall and disease free survival by intrinsic sub-type were evaluated. RESULTS: Prevalence of Luminal A (41.7%), Luminal B HER2- (15.6%), Luminal B HER2+ (8.9%), Basal like(10.8%), and HER2+ non-luminal (5.1%) were consistent with other descriptive studies in Canada and Spain. Over this time period the number of lumpectomies increased 1.7% per year (P=0.007). There was a steady increase of 3.4% per year in the use of aromatase inhibitors (P=0.005). Pre-menopausal patients had an increased proportion of HER2+ and Basal-like sub-types. The 7year overall/disease free survival percentages for Luminal A, Luminal B HER2-, Luminal B HER2+, Basal like, and HER2+ non-luminal were 88.7%/83.6, 78.2%/73.0, 81.5%/73.3%, 67.7%/63.2%, 70.4%/65.6% respectively. CONCLUSIONS: Reasons for variability in the prevalence of intrinsic sub-type by region is not fully understood. Manitoba is unique due the stability of the population, completeness of the registry and length of breast cancer screening program. Few true population-based studies grouped by intrinsic sub-type are available. IMPACT: Descriptive epidemiological studies guide future research by identifying factors that can affect treatment, recurrence, and survival. PMID- 27770673 TI - Effects of attention-deficit/hyperactivity disorder on child abuse and neglect. AB - It is known that children with mental and developmental problems are at risk of abuse and neglect. Attention-deficit/hyperactivity disorder is one of the most frequent neurodevelopmental disorders in children and adolescents. The purpose of this study is to examine whether children diagnosed with ADHD are under more risk in terms of child abuse and neglect compared to controls. In this case-control study, 104 children, who applied to Child and Adolescent Psychiatry Unit of Bursa Yuksek Ihtisas Training and Research Hospital between January and June 2015, were diagnosed with ADHD, and had no other psychiatric comorbidity except for disruptive behavior disorders, and 104 healthy children were compared. Abuse Assessment Questionnaire was applied to children after approval of the families was received. It was determined that the children diagnosed with ADHD were exposed to more physical (96.2%) and emotional abuse (87.5%) in a statistically significant way compared to controls (46.2%; 34.6%), they were exposed to physical and emotional neglect (5.8%) at a lower rate compared to healthy children (24.0%), and there was no difference between them and healthy children in terms of witnessing family violence (56.7%; 47.1%) and being exposed to sexual abuse (5.8%; 1.9%). The children diagnosed with ADHD were exposed to physical and emotional abuse at a higher rate; further studies should emphasize the role of parents in this topic and how parental education and treatment programs change the results. PMID- 27770675 TI - Two step transfer entropy - An estimator of delayed directional couplings between multivariate EEG time series. AB - Quantifying delayed directional couplings between electroencephalographic (EEG) time series requires an efficient method of causal network inference. This is especially due to the limited knowledge about the underlying dynamics of the brain activity. Recent methods based on information theoretic measures such as Transfer Entropy (TE) made significant progress on this issue by providing a model-free framework for causality detection. However, TE estimation from observed data is not a trivial task, especially when the number of variables is large which is the case in a highly complex system like human brain. Here we propose a computationally efficient procedure for TE estimation based on using sets of the Most Informative Variables that effectively contribute to resolving the uncertainty of the destination. In the first step of this method, some conditioning sets are determined through a nonlinear state space reconstruction; then in the second step, optimal estimation of TE is done based on these sets. Validation of the proposed method using synthetic data and neurophysiological signals demonstrates computational efficiency in quantifying delayed directional couplings compared with the common TE analysis. PMID- 27770676 TI - The complexity of electrodermal activity is altered in mental cognitive stressors. AB - The aim of this study was to evaluate potential changes in the electrodermal activity (EDA) to enable the detection of variations in the sympathetic nervous system during mental load and recovery period. Several EDA parameters were used: SCA (skin conductance amplitude), frequency of NS-EDR (nonspecific electrodermal responses), SIE (symbolic information entropy), and ApEn (approximate entropy). The cohort consisted of 50 healthy students (average age: 23.33+/-0.24yr., 25 women). The stress profile consisted of five phases: baseline (P1), Stroop test (P2), recovery (P3), mental arithmetic test (P4), and recovery (P5). All phases of the stress profile lasted six minutes. The results indicate that the three EDA indices have sufficient sensitivity to detect changes in the sympathetic nervous system. The SCA, SIE and ApEn were significantly increased during mental loads and decreased during recovery periods. However, SCA remained significantly elevated during recovery periods versus baseline, and SIE and ApEn decreased significantly during recovery versus baseline. The frequency of NS-EDR had no significant changes during stress. The EDA is a sensitive marker for evaluation of changes during the activation of sympathetic nervous system under the influence of a load. Detailed knowledge of EDA regulatory mechanisms associated with stress could provide important information associated with autonomic dysregulation. PMID- 27770677 TI - Automated retina identification based on multiscale elastic registration. AB - In this work we propose a novel method for identifying individuals based on retinal fundus image matching. The method is based on the image registration of retina blood vessels, since it is known that the retina vasculature of an individual is a signature, i.e., a distinctive pattern of the individual. The proposed image registration consists of a multiscale affine registration followed by a multiscale elastic registration. The major advantage of this particular two step image registration procedure is that it is able to account for both rigid and non-rigid deformations either inherent to the retina tissues or as a result of the imaging process itself. Afterwards a decision identification measure, relying on a suitable normalized function, is defined to decide whether or not the pair of images belongs to the same individual. The method is tested on a data set of 21721 real pairs generated from a total of 946 retinal fundus images of 339 different individuals, consisting of patients followed in the context of different retinal diseases and also healthy patients. The evaluation of its performance reveals that it achieves a very low false rejection rate (FRR) at zero FAR (the false acceptance rate), equal to 0.084, as well as a low equal error rate (EER), equal to 0.053. Moreover, the tests performed by using only the multiscale affine registration, and discarding the multiscale elastic registration, clearly show the advantage of the proposed approach. The outcome of this study also indicates that the proposed method is reliable and competitive with other existing retinal identification methods, and forecasts its future appropriateness and applicability in real-life applications. PMID- 27770671 TI - Structural inequalities drive late HIV diagnosis: The role of black racial concentration, income inequality, socioeconomic deprivation, and HIV testing. AB - In the United States, research is limited on the mechanisms that link socioeconomic and structural factors to HIV diagnosis outcomes. We tested whether neighborhood income inequality, socioeconomic deprivation, and black racial concentration were associated with gender-specific rates of HIV in the advanced stages of AIDS (i.e., late HIV diagnosis). We then examined whether HIV testing prevalence and accessibility mediated any of the associations above. Neighborhoods with highest (relative to lowest) black racial concentration had higher relative risk of late HIV diagnosis among men (RR=1.86; 95%CI=1.15, 3.00) and women (RR=5.37; 95%CI=3.16, 10.43) independent of income inequality and socioeconomic deprivation. HIV testing prevalence and accessibility did not significantly mediate the associations above. Research should focus on mechanisms that link black racial concentration to HIV diagnosis outcomes. PMID- 27770678 TI - A new age-related model for blood stroke volume. AB - BACKGROUND: A new computer model for systolic pulse waves within the cardiovascular system is presented. The emphasis was made on blood stroke volume (BS). The new waveform for pulse wave demands the re-computing of the BS. The authors showed the applicability of suggested model for arterial aging problem. METHODS: Suggested model is based on the well-known Korteweg-de Vries (KdV) equation. Instead of the common accepted solitary wave, the periodical cnoidal wave is used. Both waves are exact solutions of the KdV equation. The cnoidal waves are described by the Jacobi elliptic functions. Depending on a specific parameter called the elliptic module, m (0<=m<=1), these functions can be either harmonic or hyperbolic type. RESULTS: The explicit expression for the dimensionless BS was obtained. The dimensionless BS depends, as was found, on the elliptic module only. Dimensional analysis demonstrates the dimensionless BS has limited range of variation. This allows the direct estimation of elliptic module that turns out to be close but not exact equal to one. It is shown, that correct calculations of BS can not be done at m=1 (corresponds to simpler soliton model), and the periodicity of pulse waves has to be taken into consideration. CONCLUSIONS: Only the cnoidal model with the limited wavelength provides the correct computing of the BS. The natural bounds of dimensionless BS were found for the first time. PMID- 27770679 TI - T2-adjusted computed diffusion-weighted imaging: A novel method to enhance tumour visualisation. AB - PURPOSE: To introduce T2-adjusted computed DWI (T2-cDWI), a method that provides synthetic images at arbitrary b-values and echo times (TEs) that improve tissue contrast by removing or increasing T2 contrast in diffusion-weighted images. MATERIALS AND METHODS: In addition to the standard DWI acquisition protocol T2 weighted echo-planar images at multiple (>=2) echo times were acquired. This allows voxelwise estimation of apparent diffusion coefficient (ADC) and T2 values, permitting synthetic images to be generated at any chosen b-value and echo time. An analytical model is derived for the noise properties in T2-cDWI, and validated using a diffusion test-object. Furthermore, we present T2-cDWI in two example clinical case studies: (i) a patient with mesothelioma demonstrating multiple disease tissue compartments and (ii) a patient with primary ovarian cancer demonstrating solid and cystic disease compartments. RESULTS: Measured image noise in T2-cDWI from phantom experiments conformed to the analytical model and demonstrated that T2-cDWI at high computed b-value/TE combinations achieves lower noise compared with conventional DWI. In patients, T2-cDWI with low b-value and long TE enhanced fluid signal while suppressing solid tumour components. Conversely, large b-values and short TEs overcome T2 shine-through effects and increase the contrast between tumour and fluid compared with conventional high-b value DW images. CONCLUSION: T2-cDWI is a promising clinical tool for improving image signal-to-noise, image contrast, and tumour detection through suppression of T2 shine-through effects. PMID- 27770680 TI - Correcting waveform bias using principal component analysis: Applications in multicentre motion analysis studies. AB - Multicentre studies are rare in three dimensional motion analyses due to challenges associated with combining waveform data from different centres. Principal component analysis (PCA) is a statistical technique that can be used to quantify variability in waveform data and identify group differences. A correction technique based on PCA is proposed that can be used in post processing to remove nuisance variation introduced by the differences between centres. Using this technique, the waveform bias that exists between the two datasets is corrected such that the means agree. No information is lost in the individual datasets, but the overall variability in the combined data is reduced. The correction is demonstrated on gait kinematics with synthesized crosstalk and on gait data from knee arthroplasty patients collected in two centres. The induced crosstalk was successfully removed from the knee joint angle data. In the second example, the removal of the nuisance variation due to the multicentre data collection allowed significant differences in implant type to be identified. This PCA-based technique can be used to correct for differences between waveform datasets in post processing and has the potential to enable multicentre motion analysis studies. PMID- 27770681 TI - The importance of parkinsonian signs for gait and balance in patients with Alzheimer's disease of mild degree. AB - Parkinsonian signs are common in patients with Alzheimer's disease (AD) of mild degree and predict functional decline, but their relationship with gait speed and balance is unclear. The aims of this study were to describe characteristics of patients with parkinsonian signs among 98 patients with AD of mild degree (with no comorbid Parkinson's disease), and to examine associations between parkinsonian signs with gait speed and balance. A cross sectional study at a memory clinic was conducted. Presence of each parkinsonian sign (bradykinesia, rigidity and tremor) was derived from the UPDRS, regular gait speed was recorded over 10m and balance were assessed using the Mini-Balance Evaluation Systems Test (Mini-BESTest). Bradykinesia was present in 30.6% of the sample, rigidity in 13.3% and tremor only in one patient. Patients with bradykinesia were older, had worse cognitive impairment and worse gait and balance performance than those without bradykinesia. More men than women had rigidity. Bradykinesia was significantly associated with mini-BESTest after adjusting for demographic factors (p<0.001, explaining 13.3% of the variance), but was not significantly associated with gait speed. Rigidity was not associated with either gait speed or balance. We conclude that assessment of bradykinesia should be included in examination of balance control in patients with AD of mild degree. PMID- 27770682 TI - Activity of essential oil-based microemulsions against Staphylococcus aureus biofilms developed on stainless steel surface in different culture media and growth conditions. AB - Food safety is a fundamental concern for both consumers and the food industry, especially as the numbers of reported cases of food-associated infections continue to increase. Industrial surfaces can provide a suitable substrate for the development and persistence of bacterial organized in biofilms that represent a potential source of food contamination. The negative consumer perception of chemical disinfectants has shifted the attention to natural substances, such as plant extracts. The aim of this study was to investigate the possibility of using the essential oils (EOs) in the fight against S. aureus biofilms. First, the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Minimum Biofilm Inhibitory Concentration (MBIC), Minimum Biofilm Eradication Concentration (MBEC) of eleven EOs against S. aureus were determined. Cinnamomum cassia and Salvia officinalis EOs showed the greatest antibacterial properties with 1.25% MIC and MBC, 1.25% MBIC and 2.5% MBEC respectively. Gas Chromatography/Mass Spectrometry analysis revealed cinnamaldehyde (82.66%) and methoxy cinnamaldehyde (10.12%) as the most abundant substances of C. cassia, while cis-thujone (23.90%), camphor (19.22%) and 1.8-cineole (10.62%) of S. officinalis. Three different microemulsions, formulated with C. cassia, S. officinalis or both, were finally tested against S. aureus biofilms in different culture media and growth conditions, causing a >3 logarithmic reductions in S. aureus 24h-old biofilms and desiccated biofilms, and up to 68% of biofilm removal after 90min of exposure. The obtained data suggest the potential use of EOs, alone or in combination, for the formulation of sanitizers as alternative or in support in the disinfection of contaminated surfaces. PMID- 27770683 TI - Effect of nanomaterial and media physicochemical properties on Ag NM aggregation kinetics. AB - Nanomaterial (NM) aggregation is a key process determining their environmental, fate behavior and effects. Nanomaterials are typically engineered to remain kinetically stable; however, in environmental and toxicological media, NMs are prone to aggregation. The aggregation kinetics of NM is typically quantified by measuring their attachment efficiency (alpha) and critical coagulation concentration (CCC). Several studies measured alpha and CCC for Ag NMs with a major focus on investigating the effects of ionic strength, ion valency and natural organic matter, with few studies investigating other environmental factors such as light and dissolved oxygen and none investigating the effect of particle size, buffer type and concentration, or surface coverage by capping agent. A survey of recent research articles reporting CCC values for Ag NMs reveals substantial variation in experimental conditions and particle stability with CCC values of monovalent and divalent counterions covering a wide range (ca. 25 to infinity for monovalent counterions and 1.6 to infinity for divalent counterions). Here, we rationalize the differences in the CCC values for Ag NMs based on the variability in the experimental conditions, which includes NM and medium physicochemical properties. Capping agents determines NM stability mechanism with citrate, sodium dodecyl sulfate (SDS), and alginate stabilizing NM by electrostatic mechanism; whereas polyvinylpyrrolidone (PVP), casein, dextrin, tween, branched polyethyleneimine (BPEI), and Gum Arabic stabilizing NMs by steric mechanisms. The CCC values for Ag NMs with different capping agents follow the order citrate~alginate~SDS8ng/mL, cirrhosis, HCC, tumor size>5cm, and Barcelona Clinic Liver Cancer-C stage. These results suggested that the plasma visfatin level is associated with the presence of HCC, and that a higher plasma visfatin level may be important in the pathogenesis of HCC. Visfatin may act as both a protective and pro-inflammatory factor. Plasma visfatin concentration may serve as an additional tool to identify patients with more advanced necroinflammation. PMID- 27770716 TI - Mechanisms of change in psychotherapy for depression: An empirical update and evaluation of research aimed at identifying psychological mediators. AB - We present a systematic empirical update and critical evaluation of the current status of research aimed at identifying a variety of psychological mediators in various forms of psychotherapy for depression. We summarize study characteristics and results of 35 relevant studies, and discuss the extent to which these studies meet several important requirements for mechanism research. Our review indicates that in spite of increased attention for the topic, advances in theoretical consensus about necessities for mechanism research, and sophistication of study designs, research in this field is still heterogeneous and unsatisfactory in methodological respect. Probably the biggest challenge in the field is demonstrating the causal relation between change in the mediator and change in depressive symptoms. The field would benefit from a further refinement of research methods to identify processes of therapeutic change. Recommendations for future research are discussed. However, even in the most optimal research designs, explaining psychotherapeutic change remains a challenge. Psychotherapy is a multi-dimensional phenomenon that might work through interplay of multiple mechanisms at several levels. As a result, it might be too complex to be explained in relatively simple causal models of psychological change. PMID- 27770717 TI - Quantitative UPLC-MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency. AB - Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary disorder that leads to excessive urinary excretion of 2,8-dihydroxyadenine (DHA), causing nephrolithiasis and chronic kidney disease. Treatment with allopurinol or febuxostat reduces DHA production and attenuates the renal manifestations. Assessment of DHA crystalluria by urine microscopy is used for therapeutic monitoring, but lacks sensitivity. We report a high-throughput assay based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC MS/MS) for quantification of urinary DHA. The UPLC-MS/MS assay was optimized by a chemometric approach for absolute quantification of DHA, utilizing isotopically labeled DHA as an internal standard. Experimental screening was conducted with D optimal design and optimization of the DHA response was performed with central composite face design and related to the peak area of DHA using partial least square regression. Acceptable precision and accuracy of the DHA concentration were obtained over a calibration range of 100 to 5000ng/mL on three different days. The intra- and inter-day accuracy and precision coefficients of variation were well within +/-15% for quality control samples analyzed in replicates of six at three concentration levels. Absolute quantification of DHA in urine samples from patients with APRT deficiency was achieved wihtin 6.5min. Measurement of DHA in 24h urine samples from three patients with APRT deficiency, diluted 1:15 (v/v) with 10mM ammonium hydroxide (NH4OH), yielded a concentration of 3021, 5860 and 10563ng/mL and 24h excretion of 816, 1327 and 1649mg, respectively. A rapid and robust UPLC-MS/MS assay for absolute quantification of DHA in urine was successfully developed. We believe this method will greatly facilitate diagnosis and management of patients with APRT deficiency. PMID- 27770718 TI - A framework for combining a motion atlas with non-motion information to learn clinically useful biomarkers: Application to cardiac resynchronisation therapy response prediction. AB - We present a framework for combining a cardiac motion atlas with non-motion data. The atlas represents cardiac cycle motion across a number of subjects in a common space based on rich motion descriptors capturing 3D displacement, velocity, strain and strain rate. The non-motion data are derived from a variety of sources such as imaging, electrocardiogram (ECG) and clinical reports. Once in the atlas space, we apply a novel supervised learning approach based on random projections and ensemble learning to learn the relationship between the atlas data and some desired clinical output. We apply our framework to the problem of predicting response to Cardiac Resynchronisation Therapy (CRT). Using a cohort of 34 patients selected for CRT using conventional criteria, results show that the combination of motion and non-motion data enables CRT response to be predicted with 91.2% accuracy (100% sensitivity and 62.5% specificity), which compares favourably with the current state-of-the-art in CRT response prediction. PMID- 27770719 TI - Epilepsy with myoclonic absences: Electroclinical characteristics in a distinctive pediatric epilepsy phenotype. AB - PURPOSE: The purpose of this article was to study the electroclinical characteristics and seizure outcome of children with epilepsy with myoclonic absences (EMA). METHOD: In this descriptive cohort study, we reviewed clinical records of patients who met the criteria for EMA. Each patient's demographic data, birth/developmental history, seizure semiology/pattern, antiepileptic drugs (AED), clinical examination, video-electroencephalography (VEEG), and neuroimaging data were reviewed. Response to AED and change in seizure frequency/pattern on follow-up were noted. Responders were defined by seizure freedom/>50% reduction in seizure frequency on follow-up. RESULT: Twelve children were diagnosed with EMA between 2008 and 2013 [50% male; mean age of onset: 3.5years]. Main seizure types were the characteristic myoclonic absences (100%) and generalized tonic-clonic seizures (42%). Ictal correlate on VEEG was 3- to 3.5-Hz spike-and-wave discharges (82%) and fast recruiting bifrontal rhythm (25%). One patient had specific MRI abnormalities. Mean duration of follow-up was 23.9months. Seizure frequency had significantly improved on follow-up (p=0.005), and at last follow-up, nine patients were in the responder group: four seizure free for at least 1year, two with >90%, and three with >50% reduction in seizure frequency. The number of AED reduced significantly between initial visit and last follow-up among responders. Two patients on follow-up developed different seizure patterns, with generalized tonic and complex partial seizures. One responder expired because of unprovoked generalized convulsive status epilepticus. CONCLUSION: This cohort, the largest from the Indian subcontinent on the rare syndrome of EMA, suggests mild heterogeneity in a seemingly homogenous electroclinical phenotype. Clinical semiology while unique may demonstrate focality and variable ictal patterns. Most patients respond to either valproate monotherapy or valproate-lamotrigine combination; however, the prognosis remains guarded. The seizures of a minority of patients remain drug-refractory and may evolve into tonic or complex partial seizures. PMID- 27770721 TI - Forensic age estimation of living persons from the knee: Comparison of MRI with radiographs. AB - To perform a study to clarify how strong the chronological age relates to ossification of the knee in Chinese on X-rays and the MRI when a similar four stage grading system was used. 322 individuals with conventional radiographs and MRI were collected from routine medical investigations and evaluated retrospectively. Bland Altman plots were performed to reveal the agreement of grading of MRI and radiograph. Regression analysis was conducted to establish a mathematical model for age estimation. The ossification process of the knee occurs earlier in females than in males for about 1-2 years. The process on X-ray grading is consistently higher than that of MRI. The chronological age is well correlated with both grading of MRI and radiograph (all p values were less than 0.001). By comparison, the R-square of grading of MRI were relatively higher than that of radiograph. Finally, the chronological age is well correlated with the ossification of the knee when both grading of MRI and radiograph were used, with the R-square for MRI were relatively higher than that of radiograph. Furthermore, the use of MRI will reduce exposure to X-ray radiation as much as possible. PMID- 27770720 TI - Inhibitory effects of flavonoids extracted from Nepalese propolis on the LPS signaling pathway. AB - Flavonoids, particularly those derived from plants, harbor biological effects such as anti-inflammation and the inhibition of cancer progression. In the present study, we investigated the effects of 10 kinds of flavonoids isolated from Nepalese propolis on the LPS signaling pathway in order to clarify their anti-inflammatory activities. Five types of flavonoids: isoliquiritigenin, chrysin, 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, and cearoin, markedly inhibited inflammatory responses including LPS-induced NO production by suppressing the expression of iNOS mRNA and LPS-induced mRNA expression of TNFalpha and CCL2. Their inhibitory effects on LPS-induced inflammatory responses correlated with the intensities of these flavonoids to suppress the LPS-induced activation of nuclear factor kappaB (NF-kappaB), an essential transcription factor for the mRNA expression of iNOS, TNFalpha, and CCL2. Among these flavonoids, 3',4'-dihydroxy-4-methoxydalbergione and 4-methoxydalbergion markedly inhibited the LPS-induced activation of IKK, thereby abrogating the degradation of IkappaBalpha and nuclear localization of NF-kappaB. On the other hand, isoliquiritigenin, chrysin, and cearoin failed to inhibit these signaling steps, but suppressed the transcriptional activity of NF-kappaB, which caused their anti inflammatory effects. The results of the present study revealed that these five kinds of flavonoids are the components of Nepalese propolis that exhibit anti inflammatory activities with a different regulatory mechanism for the activation of NF-kappaB. PMID- 27770722 TI - Aquatic toxicity testing of liquid hydrophobic chemicals - Passive dosing exactly at the saturation limit. AB - The aims of the present study were (1) to develop a passive dosing approach for aquatic toxicity testing of liquid substances with very high Kow values and (2) to apply this approach to the model substance dodecylbenzene (DDB, Log Kow = 8.65). The first step was to design a new passive dosing format for testing DDB exactly at its saturation limit. Silicone O-rings were saturated by direct immersion in pure liquid DDB, which resulted in swelling of >14%. These saturated O-rings were used to establish and maintain DDB exposure exactly at the saturation limit throughout 72-h algal growth inhibition tests with green algae Raphidocelis subcapitata. Growth rate inhibition at DDB solubility was 13 +/- 5% (95% CI) in a first and 8 +/- 3% (95% CI) in a repeated test, which demonstrated that improved exposure control can lead to good precision and repeatability of toxicity tests. This moderate toxicity at chemical activity of unity was higher than expected relative to a reported hydrophobicity cut-off in toxicity, but lower than expected relative to a reported chemical activity range for baseline toxicity. The present study introduces a new effective approach for toxicity testing of an important group of challenging chemicals, while providing a basis for investigating toxicity cut-off theories. PMID- 27770723 TI - Occurrence and formation of haloacetamides from chlorination at water purification plants across Japan. AB - The occurrence of six haloacetamides (HAcAms), which are a group of emerging nitrogenous disinfection byproducts, was investigated in drinking water across Japan in September 2015 and February 2016. At least one of the six HAcAms were found in all of the drinking water samples and their total concentrations ranged from 0.3 to 3.8 MUg/L. The detection frequencies and concentrations of 2,2 dichloroacetamide (DCAcAm) and 2-bromo-2-chloroacetamide (BCAcAm) were the largest among the targeted HAcAm species. The total HAcAm concentrations in the raw water after chlorination ranged from 0.8 to 11 MUg/L. The bromine incorporation factors (BIFs) of the targeted dihalogenated HAcAms (di-HAcAms) (DCAcAm, BCAcAm, and 2,2-dibromoacetamide) in the drinking water samples correlated well with those in the raw water after chlorination. The total HAcAm concentrations and the BIF of the di-HAcAms in the raw water after chlorination correlated with trihalomethane concentrations. HAcAm concentrations after chlorination increased with chlorination time. While the formation of di-HAcAms after chlorination was higher at higher pH, that of 2,2,2-trichloroacetamide remained unaffected by pH. PMID- 27770724 TI - Comprehensive structure-selective characterization of dissolved organic matter by reducing molecular complexity and increasing analytical dimensions. AB - Deciphering the molecular codes of dissolved organic matter (DOM) improves our understanding of its role in the global element cycles and its active involvement in ecosystem services. This study demonstrates comprehensive characterization of DOM by an initial polarity-based stepwise solid phase extraction (SPE) with single methanol elution of the cartridges, but separate collection of equal aliquots of eluate. The reduction of molecular complexity in the individual DOM fractions attenuates intermolecular interactions and substantially increases the disposable resolution of any structure selective characterization. Suwannee River DOM (SR DOM) was used to collect five distinct SPE fractions with overall 91% DOC recovery. Optical spectroscopy (UV and fluorescence spectroscopy), high-field Fourier transform ion cyclotron mass spectrometry (FTICR MS) and nuclear magnetic resonance (NMR) spectroscopy showed analogous hierarchical clustering among the five eluates corroborating the robustness of this approach. Two abundant moderately hydrophobic fractions contained most of the SR DOM compounds, with substantial proportions of aliphatics, carboxylic-rich alicyclic molecules, carbohydrates and aromatics. A minor early eluting hydrophilic fraction was highly aliphatic and presented a large diversity of alicyclic carboxylic acids, whereas the two late eluting, minor hydrophobic fractions appeared as a largely defunctionalized mixture of aliphatic molecules. Comparative mass analysis showed that fractionation of SR DOM was governed by multiple molecular interactions depending on O/C ratio, molecular weight and aromaticity. The traditional optical indices SUVA254 and fluorescence index (FI) indicated the relative aromaticity in agreement with FTICR mass and NMR spectra; the classical fluorescent peaks A and C were observed in all four latter eluates. This versatile approach can be easily expanded to preparative scale under field conditions, and transferred to different DOM sources and SPE conditions. PMID- 27770725 TI - Transformation and products of captopril with humic constituents during laccase catalyzed oxidation: Role of reactive intermediates. AB - The transformation of captopril (CAP), a widely-used thiol drug, was studied with the presence of dissolved model humic constituents (HCs) in a laccase-catalyzed system. Reaction products were analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry and condensed fukui function computation. CAP reacted with different model HCs in the enzymatic system for 1 h, ranging from 75% (syringic acid) to 96% (p-coumaric acid). In the absence of HCs, only 15% of CAP was removed through self-coupling. The presence of HCs apparently changed the transformation of CAP in aqueous environment, and the HC reactive intermediates played an important role. First, during laccase catalysis, HCs with different structures were oxidized to produce reactive intermediates, including phenoxyl radical cation, ortho-, and para-quinone intermediates. Second, these intermediates were readily attacked by CAP via nucleophilic reactions, forming C-S-C covalent conjugates. More importantly, the standard reduction potential of these intermediates is a critical parameter, as PCA showed the highest reactivity to the nucleophilic addition reaction with CAP by forming phenoxy radical cations. While SYR showed the least reactivity due to the formation of para-quinone intermediates. Therefore, the functional groups on HCs could greatly influence the cross-coupling with CAP, as well as the type and stability of the coupling products. This work clearly demonstrated the transformation of CAP and other thiol drugs with the presence of HCs in aqueous environment, which is similar to the natural humification process. PMID- 27770726 TI - Photomineralization of aqueous salicylic acids. Photoproducts characterization and formation of light induced secondary OH precursors (LIS-OH). AB - The photolysis of aqueous 5-chlorosalicylic acid (ClSA) and dihydroxybenzoic acid (DHBA), its main photoproduct, was studied to determine the extent of degradation caused by simulated solar light. Photoproducts identification was achieved using high resolution LC-MS and GC-MS. About 40 photoproducts from C19 to C1 were characterized, including a dihydroxycyclopentadienic acid, a ring contraction photoproduct, and numerous carbonyls and carboxylic acid derivatives that were detected thanks to derivatization. UV-visible spectral monitoring of the reactions revealed that ClSA and DHBA underwent photobleaching after developing a temporarily featureless absorbance between 300 and 500 nm. Measurement of OH radicals using terephtalic acid as a probe showed that OH radicals were generated with an average rate of 7 * 10-9 M s-1 and a total cumulated concentration of 10 3 M, corresponding to ~ 5-fold the initial concentration of DHBA. Furthermore, TOC analysis indicated that significant mineralization (51-90%) occurred. These findings are consistent with the formation of light induced secondary OH (LIS-OH) precursors such as featureless long wavelength absorbing compounds as well as non absorbing hydroperoxides. The formation of LIS-OH illustrated here may also take place in the aqueous photodegradation of other substituted phenols likely present in dissolved organic matter and humic substructures, it deserves to be studied in more details. PMID- 27770727 TI - Sulfate radical-based oxidation of fluoroquinolone antibiotics: Kinetics, mechanisms and effects of natural water matrices. AB - Widespread occurrence of fluoroquinolone antibiotics (FQs) in surface water, groundwater, soil and sediment has been reported and their remediation is essentially needed. Sulfate radical (SO4-) based advanced oxidation processes (SR AOPs) are promising technologies for soil and groundwater remediation. In this study, the degradation kinetics, mechanisms, and effects of natural water matrices on heat-activated persulfate (PS) oxidation of FQs were systematically investigated. Experimental results clearly demonstrated that 92% of CIP was removed within 180 min (pH = 7, 60 degrees C). Higher temperature and lower pH facilitated the degradation of ciprofloxacin (CIP). The piperazine moiety of CIP was identified as the reactive site for SO4- attack by comparison with substructural analogs, flumequine (FLU) and 1-(2-fluorophenyl) piperazine (FPP). A comparison of the degradation of CIP, norfloxacin (NOR), enrofloxacin (ENR) and ofloxacin (OFL) confirmed that the presence of cyclopropane ring also influence the degradation of FQs. Water matrix significantly influenced the degradation of CIP and ENR, and the degradation rate followed the order of Milli-Q water (pH = 7) > groundwater > artificial seawater > artificial surface water > lake water. Degradation products of CIP in different water matrix were enriched by solid phase extraction (SPE) and then analyzed by liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (LC-ESI-MS/MS). Detailed transformation pathways of CIP were proposed and were compared with respect to different water matrices. Four transformation pathways including stepwise piperazine ring oxidation, OH/F substitution, hydroxylation, and cyclopropane ring cleavage were proposed for CIP degradation. Results clearly show that the water matrix influenced the degradation of FQs appreciably, a phenomenon that should be taken into consideration when applying SR-AOPs for remediation of soil and groundwater contaminated by FQs. PMID- 27770728 TI - Effects of the residual ammonium concentration on NOB repression during partial nitritation with granular sludge. AB - Partial nitritation was stably achieved in a bench-scale airlift reactor (1.5L) containing granular sludge. Continuous operation at 20 degrees C treating low strength synthetic wastewater (50 mg N-NH4+/L and no COD) achieved nitrogen loading rates of 0.8 g N-NH4+/(L.d) during partial nitritation. The switch between nitrite-oxidizing bacteria (NOB) repression and NOB proliferation was observed when ammonium concentrations in the reactor were below 2-5 mg N-NH4+/L for DO concentrations lower than 4 mg O2/L at 20 degrees C. Nitrospira spp. were detected to be the dominant NOB population during the entire reactor operation, whereas Nitrobacter spp. were found to be increasing in numbers over time. Stratification of the granule structure, with ammonia-oxidizing bacteria (AOB) occupying the outer shell, was found to be highly important in the repression of NOB in the long term. The pH gradient in the granule, containing a pH difference of ca. 0.4 between the granule surface and the granule centre, creates a decreasing gradient of ammonia towards the centre of the granule. Higher residual ammonium concentration enhances the ammonium oxidation rate of those cells located further away from the granule surface, where the competition for oxygen between AOB and NOB is more important, and it contributes to the stratification of both populations in the biofilm. PMID- 27770729 TI - Surfactant removal with multiwalled carbon nanotubes. AB - The ability of multiwalled carbon nanotubes (MWCNTs) to remove a non-ionic surfactant, Triton X-100 (TX100), an anionic surfactant, sodium dodecylbenzenesulonate (SDBS), and a cationic surfactant, hexadecyltrimethylammonium bromide (CTAB) from the aqueous phase was investigated. Untreated, OH-, and COOH-functionalized MWCNTs with different outer diameters and chemical composition were examined and compared. As both the concentrations of surfactants and MWCNTs initially added may affect removal efficiency of surfactants, a relationship between the initial concentration ratio of surfactants and MWCNTs (Rc) and the removal efficiency (E) was established. The results showed that for a given Rc (e.g., 0.8), removal efficiency of the tested surfactants by a specific MWCNT (e.g., the untreated one with outer diameter <8 nm) decreased in the following order: TX100 (52.3%) > SDBS (26.2%) > CTAB (3.8%). TX100 was more readily removed by MWCNTs than SDBS and CTAB, due to its longer aliphatic chain compared to SDBS and CTAB thus higher hydrophobicity, and stronger pi-pi interactions with the aromatic structure of the surfaces of graphite sheets relative to CTAB. Based upon the established relationship between Rc and E of surfactants by MWCNTs, the maximum removal efficiency and the most appropriate Rc of TX100 and SDBS by two MWCNTs (UT8 and OH8) were derived. It was interesting to notice that, except for the case to remove TX100 using UT8, even though a large quantity of UT8 or OH8 was added to the TX100 or SDBS removal systems, they cannot be completely removed, with the maximum removal efficiency in the range of 55.88-87.17%. This mostly resulted from strong aggregation of MWCNTs thus reducing their readily accessible surface area and porosity for sorption. PMID- 27770730 TI - Socioeconomic outcome of epilepsy surgery: A controlled national study. AB - PURPOSE: Epilepsy surgery has been a standard treatment for refractory epilepsies that cannot be controlled by standard medical treatment. We aimed to evaluate the health and social consequences of resective surgery relative to controls from a study of national data. METHODS: Using the Danish National Patient Registry we identified all subjects with an epilepsy diagnosis between 1996 and 2009 and compared them with a group of patients with an epilepsy diagnosis who had had neither epilepsy surgery nor a vagus stimulation diagnosis by the index date, and who were matched by gender, index year for epilepsy diagnosis, and index year for epilepsy surgery. We considered all the health and social information available in the Danish health, medication and social registers. The duration of follow-up was three years. RESULTS: 254 epilepsy patients and 989 controls were analyzed. Surgery patients were more severely affected by their disease as indicated by health care use and social impact before the surgical procedure. Patients who underwent epilepsy surgery had a significantly lower costs associated with the use of medication, outpatient services, inpatient admissions, and accident and emergency visits after surgery. The surgical intervention had no significant effects on social status in terms of occupation and educational level. CONCLUSION: Although epilepsy surgery was followed by a reduction in inpatient and outpatient health care use, medication and use of accident and emergency facilities, suggesting a positive effect on the epileptic disease, there was no significant effect on social outcome measures. PMID- 27770731 TI - Exploring the risk factors of suicidal ideation among the seniors in Shandong, China: A path analysis. AB - BACKGROUND: Suicide is a global public health problem that has a significant negative influence on individuals, families and the society. The objective of this study is to explore the risk factors associated with suicidal ideation among the elderly in Shandong Province, China. METHOD: A total of 3313 participants (60+) of Shandong Province, China were included in this study. Suicidal ideation was assessed by using questions from the NCS (National Comorbidity Survey). Multiple logistic regression analysis was performed to examine the factors associated with suicidal ideation. Path analysis was conducted to test the direct and indirect association between factors and suicidal ideation. RESULTS: The prevalence of suicidal ideation among the seniors in Shandong, China was 4.2%. Depression had the strongest direct (beta=0.303, p-value<0.05) and total effect (beta=0.303), life satisfaction (beta=-0.103, p-value<0.05; beta=-0.136, p value<0.05), economic status (beta=-0.046, p-value<0.05; beta=-0.040, p value<0.05) had both direct and indirect impacts on suicidal ideation. Social support (beta=-0.040, p-value<0.05) had indirect influence on suicidal ideation. Depression was a mediator between life satisfaction, economic status, social support and suicidal ideation. LIMITATIONS: The data used in this study was cross sectional, and the relationship between identified factors and suicidal ideation cannot be interpreted as cause-effect. CONCLUSIONS: Depression was the strongest influencing factor of suicidal ideation among the elderly, followed by life satisfaction, economic status. Active intervention measures focusing on the depression screening and treatment both in urban and rural communities should be taken to prevent suicide. PMID- 27770732 TI - The effect of depressive symptoms on social support one year following traumatic injury. AB - BACKGROUND: Depression is a common mental health outcome after traumatic injury, negatively impacting physical outcomes and increasing the cost of care. Research shows that the presence and quality of support is a leading protective factor against depression post-injury; however, research is vague on the directional effects of both factors over the course of recovery. METHODS: 130 patients admitted to a Level I Trauma Center were recruited to a prospective study examining overall outcomes one-year after injury. Effects of social support and depression at baseline and 12-months post-injury were examined using correlational and cross-lagged path model analyses. Additional follow-up analyses were conducted for depression on specific types of social support. RESULTS: Findings replicated previous research suggesting depression and social support were inversely related. Initial depression at time of traumatic injury was predictive of social support 12-months after their injury, but initial social support levels did not significantly predict depression at 12-months. Additionally, initial depression significantly predicted attachment, social integration, reassurance of worth, and guidance 12-months later. LIMITATIONS: Findings of the analyses are limited by lack of experimentation and inability to control for other related variables. CONCLUSIONS: Findings of the present study support the notion that initial depression predicts poorer social support in recovery, in lieu of prevailing theory (i.e., initial support buffers against later depression) in a sample of trauma patients. These findings highlight the need for medical staff to target specific factors during inpatient stay, such as addressing depressive symptoms and preparing family members and caregivers prior to discharge. PMID- 27770733 TI - Neurocognition and psychosocial functioning in adolescents with bipolar disorder. AB - BACKGROUND: Adults with bipolar disorder demonstrate significantly poorer psychosocial functioning and neurocognition compared to controls. In adult bipolar disorder neurocognition predicts a substantial portion of variance in functioning. Adolescents with bipolar disorder have reducedpsychosocial functioning, but less is known about neurocognitive impairments, and no studies have examined the relationship between neurocognition and functioning in an adolescent sample. METHODS: 38 adolescents with bipolar disorder and 49 healthy controls under 20 years of age completed assessments of psychosocial functioning, neurocognitive ability, and psychiatric symptoms. RESULTS: Adolescents with bipolar disorder had significantly poorer psychosocial functioning in domains of daily activities, social functioning, and satisfaction with functioning, ps<.006, compared to healthy controls. They also had poorer general neurocognitive functioning than controls, p=.004, with the greatest impairment on a test of sustained attention. Neurocognition was not a significant predictor of psychosocial functioning in this sample, but depressive symptoms significantly predicted functioning in all domains, p<.033. LIMITATIONS: Limited sample size did not allow for complex statistical analyses. Differences in demographic characteristics of the clinical and control groups may limit generalization of these results. CONCLUSIONS: This adolescent sample with bipolar disorder experiences significantly poorer neurocognitive and psychosocial functioning compared to controls; however, psychosocial functioning appears to be more strongly related to mood symptoms than to neurocognition. Future work is needed to delineate the time course of neurocognitive functioning and its relation to psychosocial functioning across the course of illness. Adolescence may provide an ideal time for cognitive enhancement and intensive psychosocial intervention. PMID- 27770734 TI - Downregulated endogenous sulfur dioxide/aspartate aminotransferase pathway is involved in angiotensin II-stimulated cardiomyocyte autophagy and myocardial hypertrophy in mice. AB - BACKGROUND: The study was designed to investigate if endogenous sulfur dioxide (SO2) was involved in cardiomyocyte autophagy and myocardial hypertrophy stimulated by angiotensin II (Ang II). METHODS: Thirty-two C57 mice were randomly divided into control, SO2, Ang II and Ang II+SO2 groups. Human myocardial cell line H9c2 was divided into four groups including control, SO2, Ang II and Ang II+SO2 groups. Blood pressure and myocardial hypertrophy of the mice were measured two weeks after Ang II administration. LC3 II/I ratio, and Beclin1, Atg4B and p62 expressions were determined both in vivo and in vitro. Autophagosome was observed in H9c2 cells with confocal microscope. Endogenous SO2 generation and aspartate aminotransferase (AAT) expression were measured. RESULTS: In animal studies, hypertension and myocardial hypertrophy developed two weeks after Ang II administration. LC3 II/I ratio and Beclin1 and Atg4B expressions were markedly elevated (P all <0.05), but p62 expression was lowered (P<0.05) both in vivo and in vitro. Compared with control group, endogenous SO2 levels, AAT activity and AAT2 expression were obviously down-regulated (P all <0.05). However, SO2 donor significantly reduced Ang II-induced myocardial hypertrophy in mice. LC3 II/I ratio and Beclin1 and Atg4B expressions were down regulated (P all <0.05) but p62 expression was significantly increased (P<0.05) in the presence of SO2 both in vivo and in vitro. CONCLUSION: Down-regulated endogenous SO2/AAT2 pathway might be involved in the pathogenesis of myocardial hypertrophy. SO2 prevented Ang II -induced myocardial hypertrophy accompanied by down-regulating cardiomyocyte autophagy. PMID- 27770736 TI - Synthesis and evaluation of in vitro antiproliferative activity of new ethyl 3 (arylethynyl)quinoxaline-2-carboxylate and pyrido[4,3-b]quinoxalin-1(2H)-one derivatives. AB - We report a novel series of quinoxaline derivatives from which agents with antiproliferative activity have been identified. Two ethyl 3 (arylethynyl)quinoxaline-2-carboxylates demonstrated substantial antiproliferative activity against both human non-small cell lung carcinoma (A549) and glioblastoma (U87-MG) cell lines. Pyrido[4,3-b]quinoxalin-1(2H)-ones demonstrated poor activity against A549 and U87-MG cell lines. Three of the derivatives in ethyl 3-(arylethynyl)quinoxaline-2-carboxylate series demonstrated substantial antiproliferative activity. The arylethynyl derivative 2a and 2d proved to be the most cytotoxic with an IC50 value of 3.3 MUM for both A549 and U87-MG cell lines. PMID- 27770735 TI - Analogue based drug design, synthesis, molecular docking and anticancer evaluation of novel chromene sulfonamide hybrids as aromatase inhibitors and apoptosis enhancers. AB - Twenty novel chromene derivatives carrying different sulfonamide moieties (3-22) were designed and synthesized. All the newly prepared compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (T47D). Most of the synthesized compounds showed good to moderate activity (IC50 = 8.8 108.9 MUM), where compound 16 (IC50 = 8.8 MUM) exhibited higher activity compared to doxorubicin (IC50 = 9.8 MUM). In order to determine the mechanism of the anticancer activity in T47D cells, the effect of the most potent compounds (5-8, 11-14, and 16-18) on the aromatase activity was tested. Most of the selected compounds showed significant inhibitory effect on the aromatase activity, with compound 18 showing IC50 = 4.66 MUM. Furthermore, apoptosis studies were conducted on two of the most potent compounds (8 & 16) to estimate the proapoptotic potential of our compounds. Both induced the levels of active caspase 3, caspase 8 and caspase 9. Moreover, they surprisingly boosted the Bax/Bcl2 ratio 5936 & 33,000 folds, respectively compared to the control. Moreover, they showed mild cytotoxic effect (IC50 = 183.8 MUM & 172.04 MUM, respectively) in normal breast cells 184A1. Finally, a molecular docking study was performed to investigate the probable interaction with the aromatase enzyme. PMID- 27770737 TI - Surgical sponge forgotten for nine years in the abdomen: A case report. AB - INTRODUCTION: Retained surgical sponge or other items in patients' bodies happens more frequently than is reported. Healthcare personnel can forget to remove textile material or instruments during complicated, extended, or emergency surgery. In addition, changes in the operating team can influence the occurrence of such errors. PRESENTATION OF CASE: We present a case with a symptomatic gossypiboma nine years after a previous cesarean section. A 34-year-old woman was admitted to the emergency room having experienced abdominal pain and fever for the previous month. An abdominal computed tomography revealed an abscess in the lower abdomen. A laparotomy was performed, and a resection and block were carried out. A surgical sponge was extracted from an omental abscess. DISCUSSION: Surgical sponges are the most common foreign materials retained (70%) in the abdominal cavity because of their frequent usage and small size. Moreover, a blood-soaked sponge in a hemorrhagic abdomen can be difficult to distinguish from blood. CONCLUSION: Whenever the accounting for material depends on humans, mistakes will continue to be committed. A falsely correct sponge count was reported in 71.42% of cases [14]; therefore, a new count system must be developed for post-surgical situations. PMID- 27770738 TI - Scrotal dartos-fascio-myo-cutaneous flaps for penis elongation after catastrophic iatrogenic skin shaft sub-amputation: A case of recovery using an extremely adaptable flap. AB - INTRODUCTION: Genitalia are linked to self-esteem and male sexual identity, especially among young men, who sometimes require a surgical procedure to acquire more confidence. Among the surgical procedures requested for aesthetical purposes, circumcision is one of the most popular. Although it can be considered to be a simple surgical practice, it may cause severe complications such as penile skin necrosis. PRESENTATION OF CASE: We report a case of a catastrophic situation after a circumcision performed on a 27-year-old HIV positive man resulted in a drastic reduction in the length of the penile shaft due to extensive skin loss; this was subsequently restored using dartos-fascio-myo cutaneous flaps. Primary healing occurred in 10days. No infection, dehiscence or flap ischemia were reported. Donor site morbidity was minimal. An adequate aesthetical appearance and satisfactory functional results were obtained. DISCUSSION AND CONCLUSION: Various techniques are available for penile skin covering, such as skin grafts or cutaneous flaps. The skin of the scrotum seems to be the most suitable tissue to be used to reconstruct the skin covering of the shaft as it is the most similar. Dartos-fascio-myo-cutaneous flap is a single stage procedure that is easy and safe to perform. It can provide satisfactory cosmetic and functional results, offering a large amount of tissue, with minimal donor site morbidity. PMID- 27770739 TI - Schistosomal appendicitis in Kuwait A5-year study. AB - BACKGROUND: Appendicular schistosomiasis is an unusual etiology of acute appendicitis, which has been reported in countries endemic in schistosomiasis, such as sub-saharan Africa and South America. Nowadays, due to globalization, this disease has been diagnosed in non-endemic countries. Kuwait is a country possessing a larger percentage of foreigners than national citizens. Therefore, several cases of schistosomal appendicitis were found. METHOD: The clinicopathological records of all patients that underwent appendectomy during January 2007 and December 2011 were recorded from the archives of Al-Adan Hospital in Kuwait. All cases of schistosomal appendicitis were retrieved and the histopathologic slides reconfirmed by the histopathologist. RESULTS: During the 5 year study period, 3012 appendectomies were performed and 8 schistosomal appendicitis were found. They were all Egyptian males that were admitted for a clinical suspicion of acute appendicitis. The age ranged between 24 and 42 years, with a mean age of 32.75 years. All cases showed histological features of acute or acute suppurative inflammation, with ova seen in the vasculature of all layers of appendicular wall. CONCLUSION: Although schistosomiasis is a rare causative agent of acute appendicitis, this however can't be confirmed until histological evaluation. Therefore, adequate follow up postoperatively is necessary to insure eradication of the disease and to prevent further serious consequences. PMID- 27770740 TI - Escitalopram but not placebo modulates brain rhythmic oscillatory activity in the first week of treatment of Major Depressive Disorder. AB - Serotonin modulates brain oscillatory activity, and serotonergic projections to the thalamus and cortex modulate the frequency of prefrontal rhythmic oscillations. Changes in serotonergic tone have been reported to shift oscillations between the combined delta-theta (2.5-8 Hz) and the alpha (8-12 Hz) frequency ranges. Such frequency shifts may constitute a useful biomarker for the effects of selective serotonin reuptake inhibitor (SSRI) medications in Major Depressive Disorder (MDD). We utilized quantitative electroencephalography (qEEG) to measure shifts in prefrontal rhythmic oscillations early in treatment with either the SSRI escitalopram or placebo, and examined the relationship between these changes and remission of depressive symptoms. Prefrontal delta-theta and alpha power were calculated for 194 subjects with moderate MDD prior to and one week after start of treatment. Changes at one week in delta-theta and alpha power, as well as the delta-theta/alpha ratio, were examined in three cohorts: initial (N = 70) and replication (N = 76) cohorts treated with escitalopram, and a cohort treated with placebo (N = 48). Mean delta-theta power significantly increased and alpha power decreased after one week of escitalopram treatment, but did not significantly change with placebo treatment. The delta-theta/alpha ratio change was a specific predictor of the likelihood of remission after seven weeks of medication treatment: a large increase in this ratio was associated with non remission in escitalopram-treated subjects, but not placebo-treated subjects. Escitalopram and placebo treatment have differential effects on delta-theta and alpha frequency oscillations. Early increase in delta-theta/alpha may constitute a replicable biomarker for non-remission during SSRI treatment of MDD. PMID- 27770741 TI - Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder. AB - Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged. PMID- 27770742 TI - Drivers' psychiatric disorders and fatal motor vehicle accidents in Finland. AB - Relatively little is known about fatal motor vehicle accidents (FMVA) involving drivers with psychiatric disorders. In this study of all drivers killed in FMVAs in Finland between 1990 and 2011, we aimed to study drivers' death rate trends in FMVAs, with special focus on drivers with a history of psychiatric disorders. Prevalence of drivers' hospital treated psychiatric disorders, and characteristics of drivers with psychiatric disorders were also studied. For the purpose of this study, three national registers were accessed. Drivers' hospital treated psychiatric disorders were screened in a five-year period prior to death. Drivers with (n = 425) and without (n = 3856) psychiatric disorders were compared, female and male drivers separately. The main outcome measure was any psychiatric disorder in drivers within the five-year timescale. Socio-demographic factors, use of intoxicants and medication at the time of death, recent adverse life events, and drivers' physical and emotional states were used as covariates in the statistical analyses. During the study period, death rates increased for females with psychiatric disorders, and decreased for females without psychiatric disorders. Death rates for males with psychiatric disorders decreased between the years 1990-2000 and 2007-2011, and increased between the years 2000-2007. Death rates decreased over the whole study period in males without psychiatric disorders. Alcohol related disorders and affective disorders were the most prevalent hospital treated psychiatric disorders among drivers involved in FMVAs. Use of medications at the time of death, and committing suicide in traffic both associated with being a driver with psychiatric disorders involved in FMVAs for both genders. As FMVAs involving drivers with psychiatric disorders have increased, a more focused and detailed evaluation of the driving performance of drivers with psychiatric disorders is recommended. These evaluations should also be extended to drivers with non-psychotic disorders. PMID- 27770743 TI - Abnormalities in the structural covariance of emotion regulation networks in major depressive disorder. AB - Major depressive disorder (MDD) is a common psychiatric disorder that is characterized by cognitive deficits and affective symptoms. To date, an increasing number of neuroimaging studies have focused on emotion regulation and have consistently shown that emotion dysregulation is one of the central features and underlying mechanisms of MDD. Although gray matter morphological abnormalities in regions within emotion regulation networks have been identified in MDD, the interactions and relationships between these gray matter structures remain largely unknown. Thus, in this study, we adopted a structural covariance method based on gray matter volume to investigate the brain morphological abnormalities within the emotion regulation networks in a large cohort of 65 MDD patients and 65 age- and gender-matched healthy controls. A permutation test with p < 0.05 was used to identify the significant changes in covariance connectivity strengths between MDD patients and healthy controls. The structural covariance analysis revealed an increased correlation strength of gray matter volume between the left angular gyrus and the left amygdala and between the right angular gyrus and the right amygdala, as well as a decreased correlation strength of the gray matter volume between the right angular gyrus and the posterior cingulate cortex in MDD. Our findings support the notion that emotion dysregulation is an underlying mechanism of MDD by revealing disrupted structural covariance patterns in the emotion regulation network. PMID- 27770744 TI - Computational modelling and protein-ligand interaction studies of SMlipA lipase cloned from forest metagenome. AB - The understanding of the 3-dimensional enzyme structure is important for the point of protein engineering and applications. Computer-based molecular modelling is a vital tool for theoretical predication of enzyme activities and finding their substrates and inhibitors. SMlipA lipase was cloned from forest soil metagenome and characterized as broad spectrum enzyme with high stability in various organic solvents. In the present study, to understand the mechanism of SMlipA lipase and to identify the key residues involved in enzyme-substrate interaction, three dimensional-computational model of SMlipA has been generated and validated for stereo-chemical and amino-acid environment quality using appropriate programs, and further validation of the active-site architecture was achieved by performing docking studies with different ligand. The three dimensional structure created here provide a new understanding of the ligand preferences and their interaction with protein. PMID- 27770745 TI - Computational insights into the protonation states of catalytic dyad in BACE1 acyl guanidine based inhibitor complex. AB - Developing small compound based drugs targeting the beta-secretase (BACE) enzyme is one of the most promising strategies in treatment of the Alzheimer's disease. As the enzyme shows the activity based on the acid-base reaction at a very narrow pH range, the protonation state of aspartic acids with the residue number 32 and 228 (Asp32 and Asp228), which forms the active site dyad, along with the protonation state of the ligand (substrate or inhibitor) play very critical role in interactions between the ligand and enzyme. Thus, understanding the nature of the protonation state of both enzyme's active site dyad and ligand is crucial for drug design in Alzheimer's disease field. Here we have investigated the protonation state of the Asp32 and Asp228 residues in the presence of a highly potent beta secretase inhibitor, containing acyl guanidine warhead that have recently been devised but not extensively studied. Our Quantum Mechanical, Molecular Dynamics and Docking studies on all the possible protonation states have suggested that the dyad residues are in di-deprotonated states in the presence of protonated inhibitor. PMID- 27770746 TI - Binding affinity models for Falcipain inhibition based on the Linear Interaction Energy method. AB - The high rate of drug resistance as well as the complex biochemical process of the parasite reproduction cycle makes development of new drugs for malaria a very important but challenging task. Falcipain 2 (FL2) and Falcipain 3 (FL3) are the major cysteine protease enzymes that play a central role in providing essential amino acids for the parasite's protein biosynthesis through the hemoglobin hydrolysis process. Selective inhibition of these enzymes is considered as a promising chemotherapeutic target. In the present investigation, the highly efficient linear interaction energy (LIE) method has been parameterized for binding affinity predictions and assessed with a set of 244 compounds for FL2 and FL3 inhibition. The results revealed that the van der Waals energy is very important for ligands binding to Falcipain proteins and that, overall, the electrostatic energy contribution is minor. The best models obtained for FL2 and FL3 give root mean square errors (RMSE) of 1.82 and 1.33kcal/mol respectively, for the test set. In this study, we also investigate how the choice of initial protein-ligand confirmation (pose) impacts the overall quality of the LIE models. Moreover, the transferability of LIE parameters is further discussed. PMID- 27770747 TI - Effect of polyelectrolyte size on multilayer conformation and dynamics at different temperatures and salt concentrations. AB - Polyelectrolyte bilayers, which consist of poly-l-lysine (PLL) and hyaluronic acid (HA) were simulated with lipid membranes at different temperatures and ion concentrations. Starting with the sequential deposition of PLL and HA above the membrane surface, PLL and HA become completely mixed, leading to the formation of stable bilayers. PLL/HA bilayers are thicker at higher salt concentration because of weakened electrostatic interactions between PLLs and membrane lipids, in agreement with experiments. This salt effect decreases as PLL size increases. Also, bilayers become thinner at higher temperature because of the increased surface area of membrane. In particular, regardless of temperature and salt concentration, larger PLLs induce thicker bilayers, although larger PLLs have lower diffusivities than do smaller ones. Bilayers with larger PLLs show larger vacancy (more water) inside the bilayer, indicating that larger PLLs are less densely stacked on membrane surface than do smaller ones and thus form the thicker bilayer. These findings show the lower diffusivity of larger polyelectrolytes, which supports the experimental observation regarding the restricted diffusion of large polymers, and also imply the dependence of bilayer thickness on the polymer size. PMID- 27770748 TI - Trauma-related self-defining memories and future goals in Dissociative Identity Disorder. AB - This study examined the content of self-defining autobiographical memories in different identities in patients with Dissociative Identity Disorder (DID) and comparison groups of patients with PTSD, healthy controls, and DID simulators. Consistent with the DID trauma model, analyses of objective ratings showed that DID patients in trauma identities retrieved more negative and trauma-related self defining memories than DID patients in avoidant identities. Inconsistent with the DID trauma model, DID patients' self-rated trauma-relatedness of self-defining memories and future life goals did not differ between trauma identities and trauma avoidant identities. That is, the DID patients did not seem to be "shut off" from their trauma while in their avoidant identity. Furthermore, DID patients in both identities reported a higher proportion of avoidance goals compared to PTSD patients, with the latter group scoring comparably to healthy controls. The simulators behaved according to the instructions to respond differently in each identity (i.e., to report memories and goals consistent with the identity tested). The discrepant task behavior by DID patients and simulators indicated that DID patients did not seem to intentionally produce the hypothesized differences in performance between identities. In conclusion, for patients with DID (i.e., in both identities) and patients with PTSD, trauma played a central role in the retrieval of self-defining memories and in the formulation of life goals. PMID- 27770749 TI - Marital history and survival after a heart attack. AB - Heart disease is the leading cause of death in the United States and nearly one million Americans will have a heart attack this year. Although the risks associated with a heart attack are well established, we know surprisingly little about how marital factors contribute to survival in adults afflicted with heart disease. This study uses a life course perspective and longitudinal data from the Health and Retirement Study to examine how various dimensions of marital life influence survival in U.S. older adults who suffered a heart attack (n = 2197). We found that adults who were never married (odds ratio [OR] = 1.73), currently divorced (OR = 1.70), or widowed (OR = 1.34) were at significantly greater risk of dying after a heart attack than adults who were continuously married; and the risks were not uniform over time. We also found that the risk of dying increased by 12% for every additional marital loss and decreased by 7% for every one-tenth increase in the proportion of years married. After accounting for more than a dozen socioeconomic, psychosocial, behavioral, and physiological factors, we found that current marital status remained the most robust indicator of survival following a heart attack. The implications of the findings are discussed in the context of life course inequalities in chronic disease and directions for future research. PMID- 27770750 TI - Oxidative defense metabolites induced by salinity stress in roots of Salicornia herbacea. AB - High salinity is a major abiotic stress that affects the growth and development of plants. This type of stress can influence flowering, the production of crops, defense mechanisms and other physiological processes. Previous studies have attempted to elucidate salt-tolerance mechanisms to improve plant growth and productivity in the presence of sodium chloride. One such plant that has been studied in detail is Salicornia, a well-known halophyte, which has adapted to grow in the presence of high salt. To further the understanding of how Salicornia grows and develops under high saline conditions, Salicornia herbacea (S. herbacea) was grown under varying saline concentrations (0, 50, 100, 200, 300, and 400mM), and the resulting phenotype, ion levels, and metabolites were investigated. The optimal condition for the growth of S. herbacea was determined to be 100mM NaCl, and increased salt concentrations directly decreased the internal concentrations of other inorganic ions including Ca2+, K+, and Mg2+. Metabolomics were performed on the roots of the plant as a systematic metabolomics study has not yet been reported for Salicornia roots. Using ethylacetate and methanol extraction followed by high resolution ultra performance liquid chromatography coupled with mass spectrometry (UPLC-MS), 1793 metabolites were identified at different NaCl levels. Structural and functional analyses demonstrated that the concentration of 53 metabolites increased as the concentration of NaCl increased. These metabolites have been linked to stress responses, primarily oxidative stress responses, which increase under saline stress. Most metabolites can be classified as polyols, alkaloids, and steroids. Functional studies of these metabolites show that shikimic acid, vitamin K1, and indole-3-carboxylic acid are generated as a result of defense mechanisms, including the shikimate pathway, to protect against reactive oxygen species (ROS) generated by salt stress. This metabolite profiling provides valuable information on the salt-tolerance mechanisms of S. herbacea and may be applied to bioengineer plants with improved salt tolerance. PMID- 27770752 TI - Data-driven outbreak forecasting with a simple nonlinear growth model. AB - Recent events have thrown the spotlight on infectious disease outbreak response. We developed a data-driven method, EpiGro, which can be applied to cumulative case reports to estimate the order of magnitude of the duration, peak and ultimate size of an ongoing outbreak. It is based on a surprisingly simple mathematical property of many epidemiological data sets, does not require knowledge or estimation of disease transmission parameters, is robust to noise and to small data sets, and runs quickly due to its mathematical simplicity. Using data from historic and ongoing epidemics, we present the model. We also provide modeling considerations that justify this approach and discuss its limitations. In the absence of other information or in conjunction with other models, EpiGro may be useful to public health responders. PMID- 27770753 TI - Do rheumatologists have a role in health promotion among elderly? PMID- 27770180 TI - 40th EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004. PMID- 27770754 TI - 2016 update of the Portuguese recommendations for the use of biological therapies in children and adolescents with Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To provide evidence-based guidance for the rational and safe prescription of biological therapies in children and adolescents with juvenile idiopathic arthritis (JIAs) considering the latest available evidence and the new licensed biologics. METHODS: Rheumatologists and Pediatricians with expertise in Pediatric Rheumatology updated the recommendations endorsed by the Portuguese Society of Rheumatology and the Portuguese Society of Pediatrics based on published evidence and expert opinion. The level of agreement with final propositions was voted using an online survey. RESULTS: In total, 20 recommendations to guide the use of biological therapy in children and adolescents with JIAs are issued, comprising 4 general principles and 16 specific recommendations. A consensus was achieved regarding the eligibility and response criteria, maintenance of biological therapy, and procedures in case of non response, for each JIA category. Specific recommendations concerning safety procedures were also updated. CONCLUSIONS: These recommendations take into account the specificities of each JIA category and are intended to continuously improve the management of JIA patients. PMID- 27770756 TI - Exosomes in the context of Toxoplasma gondii - host communication AB - Extracellular vesicles - EV's, including exosomes, are known to be essential tools of intercellular communication, enabling the exchange of information without direct contact between cells. Exosomes are secreted both in vitro and in vivo by single- and multi-cellular organisms, regardless of their type, and play an essential role in cell-to-cell communication. EV's may carry various materials and ongoing studies have provided a new insight into their potential participation in various critical biological processes, including carcinogenesis, protein trafficking, immunostimulation and pathogenesis of infectious diseases. Although knowledge of the contribution of exosomes in Toxoplasma invasion is still very limited, the present article discusses aspects of their involvement in the interactions between host and T. gondii. PMID- 27770755 TI - African Swine Fever Virus: a new old enemy of Europe AB - African swine fever (ASF) is a highly contagious viral disease of swine with a mortality rate approaching 100 percent. African Swine Fever Virus (ASFV) is a double-stranded DNA virus with a complex molecular structure. Its large genome, encoding multiple virulence factors, allows for efficient replication, which takes place predominantly in the cytoplasm of monocytes and macrophages. Also, ASFV has the ability to interfere with cell signalling pathways, which leads to various modulations in the synthesis profiles of interferon and other cytokines. Sustained viremia favours the persistence of virions in blood and tissues of the convalescents, and the extended circulation of ASFV within the herd. ASFV has been spreading in the Caucasus since 2007, and in 2014 reached the eastern territory of the European Union. Outbreaks pose an economical threat to native pig rearing, especially since a single point source may easily develop into an epizootic event. There is currently no effective vaccine nor treatment for ASF, and eradication is possible only by prevention or the slaughter of diseased animals. This review paper summarizes the current state of knowledge about ASFV. PMID- 27770751 TI - Effects of a novel beta-lapachone derivative on Trypanosoma cruzi: Parasite death involving apoptosis, autophagy and necrosis. AB - Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel beta-lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 beta-lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72 treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72 treated parasites suffered necrosis within 24 h. The present data indicate that the beta-lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis. PMID- 27770757 TI - The mycobiome - a friendly cross-talk between fungal colonizers and their host AB - The organisms colonizing a living host create together with their host a holobiome. The holobioms are networks of mutualistic interactions between host's cells and microorganisms communities. The fungi are among these microorganisms and have been also well known to infect human and animals. These organisms are associated with a wide range of diseases as superficial or systemic mycoses. Fungi as colonizers can also modify host physiology and metabolism, energy acquisition, vitamin-cofactor availability, development and function of immune system, and even host behavior. The objective of this review is to familiarize with recent data concerning the role of fungi creating mammalian mycobiome in the maintenance of the host health status PMID- 27770762 TI - Virulence of geographically different Cryptosporidium parvum isolates in experimental animal model AB - Cryptosporidium parvum is a coccidian parasite which causes gastrointestinal disease in humans and a variety of other mammalian species. Several studies have reported different degrees of pathogenicity and virulence among Cryptosporidium species and isolates of the same species as well as evidence of variation in host susceptibility to infection. The study aimed to investigate infectivity and virulence of two Cryptosporidium parvum "Iowa isolate" (CpI) and a "local water isolate" (CpW). Thirty-three Swiss albino mice have been divided into three groups: Negative control Group (C), the CpI group infected with "Iowa isolate "and the CpW group infected with C. parvum oocysts isolated from a local water supply. Infectivity and virulence have been measured by evaluating clinical, parasitological and histological aspects of infection. Significant differences were detected regarding oocysts shedding rate, clinical outcomes, and the histopathological picture of the intestine, lung, and brain. It was concluded that the local water isolate is significantly more virulent than the exported one. PMID- 27770758 TI - The role of ticks in transmission cycle of Toxoplasma gondii AB - Toxoplasmosis is globally distributed, water- and food borne zoonosis caused by the single protozoan Toxoplasma gondii and probably one-third of the world's human population is infected with this pathogen. Domestic and wild felids are definitive hosts of this pathogen and intermediate hosts for great variety of other homoeothermic animals. Human as other of the intermediate hosts may become infected in the main route of infection; it is the ingestion of parasite oocysts in contaminated water or soil and undercooked meat. However, the mechanism which this parasite uses to so large spread is not fully understood, because oral transmission does not explain the common event of this parasite in a variety of hosts, such as herbivorous animals or rodents and birds, as well as routes of spread to domestic hosts. Such a wide circle of hosts suggests a possibility of other paths of transmission and a role of ticks, the bloodseeking arthropods was considered in the transmission of T. gondii. PMID- 27770761 TI - Pre-exposure to faeces or saliva of Triatoma dimidiata decreases parasitemia in mice challenged with Trypanosoma cruzi: a description of the inflammatory reaction at the inoculation site AB - Under natural conditions, Trypanosoma cruzi infection is transmitted to mammals when faeces contaminated with metacyclic trypomastigotes gain access through skin lesions, mucosa or bite wounds. Natural infection of bugs with T. cruzi can vary greatly from less than 1% up to 70%, depending on triatomine species: in the case of Triatoma dimidiata, the percentage of infection is around 30%. In this work uses biological fluids (saliva and faeces) from Triatoma dimidiata to inoculate experimental animals once or multiple times, before inoculation with faeces contaminated with metacyclic trypomastigotes discrete type unit Ia (TcI). The site of infection was analyzed for histological changes based on hematoxile eosine technique and toluide blue stain for mast cells. Inoculation with saliva led to the recruitment of eosinophils and mononuclear cells at the inoculation site, whereas inoculation with faeces led to the recruitment of neutrophils. Mice inoculated multiple times exhibited a strong inflammatory reaction from the first hour. Mono- or multi-exposure to T. dimidiata fluids before inoculation with metacyclic trypomastigotes helped to control the level of parasitemia. Previous contact with saliva or faeces of T. dimidiata reduces parasitemia in T. cruzi I infected mice. PMID- 27770763 TI - Comparative assessment of selected intraoral microorganisms - potential factors for peri-surgical management complications AB - In this research, a comparative analysis of results of investigations involving different human populations, in terms of a relation between the oral cavity health and the species composition of mouth microbiota is reported. The purpose of this analysis was to identify and assess microorganisms that could cause health complications in patients with neoplasm requiring dental problem-related surgical management. The patients with the oral cancer surgically treated and those without neoplasm were assessed for their oral health: status of teeth, gingiva, periodontium, and occurrence of inflammatory processes. From each patient, microorganisms isolated of periodontium, dental plaque, and dental pocket swabs were identified in wet and stained microscopic preparations; standard microbiology in vitro techniques were also applied to determine the fungal and bacterial strains. The comparative analysis of results of direct microscopic examinations and in vitro cultures assessment indicated significant differences in prevalences of fungi, parasitic oral protozoans and bacteriae in particular patient's groups. Yeast-like fungi belonging to Candida genus, mostly of C. albicans group, were identified in 93.75% patients with the oral cancer, while in 25% of individuals assessed without neoplasm. E. gingivalis amoebae were only found in 12.5% patients with the serious disease; no trichomonads were detected in all patients analyzed. Among bacteria species, potentially pathogenic Enterobacteriaceae were found in the patients with oral cancer. The pronounced shift in the microbiota species composition in the patients who needed prolonged treatment due to oral cavity cancer, compared to other generally healthy persons has been showed in this analysis. PMID- 27770760 TI - The hydrolytic enzymes produced by fungi strains isolated from the sand and soil of recreational areas AB - The pathogenicity of fungi depends on, inter alia, the secretion of hydrolytic enzymes. The aim of this study was to determine the enzymatic activity of yeasts and yeast-like fungi isolated from children's recreation areas, and compare the results with literature data of strains obtained from patients with mycoses. The enzymatic activity of 96 strains was assessed using an API ZYM kit (bioMerieux, France) and their biotypes were established. The fungal species were found to produce from 16 to 19 hydrolases: the most active were: leucine arylamidase (e5), acid phosphatase (e10), alkaline phosphatase (e1), naphthol-AS-BI phosphohydrolase (e11), esterase - C4 (e2), beta-galac - tosidase (e13) and beta glucosidase (e16). In addition, 13 biotypes characteristic of particular species of fungi were defined. Most strains could be categorized as biotypes C2 - 39.5% and A - 26%. The examined fungal strains isolated from recreational areas have selected biochemical characteristics i.e. production of hydrolases, which demonstrate their pathogenicity. They produce a number of enzymes which are also present in strains isolated from patients with mycoses, including: leucine arylamidase (e5), acid phosphatase (e10), naphthol-AS-BI-phosphohydrolase (e11) and alkaline phosphatase (e1). The biotypes identified in the course of this study (A, B3, B4, C1, C6 and D3) have been also reported in cases of fungal infection. Therefore, the fungi present in the sand and soil of recreational have pathogenic properties and are possible factors of fungal infection among children. PMID- 27770764 TI - Cryptosporidium meleagridis infection: the first report in Poland of its occurrence in an HIV-positive woman AB - Cryptosporidium is an opportunistic protozoan parasite that can cause severe diarrhoea in immunocompromised patients. The transmission of this pathogen in humans and animals is not fully understood. C. meleagridis, originally described in birds, is the only Cryptosporidium species known to naturally infect mammalian and avian species. This study documents the first detection of C. meleagridis in an HIV-infected woman in Poland. PMID- 27770765 TI - Treatment of scabies, comparing the different medications PMID- 27770759 TI - Subtype analysis of Blastocystis sp. isolates from asymptomatic individuals in an urban community in the Philippines AB - Blastocystis sp. is a commonly reported enteric protistan parasite in faecal specimens with a worldwide distribution afflicting both humans and a wide range of animals. The aim of this study is to characterize the subtypes (STs) of Blastocystis sp. isolates from asymptomatic individuals in an urban community in Pateros, Metro Manila, Philippines. The 600-bp small subunit ribosomal RNA (SSU rRNA) barcoding region of Blastocystis sp. isolates was amplified and sequenced using the primers RD5 and BhRDr. Subtypes were identified by uploading the sequences onto the Basic Local Alignment and Search Tool (BLAST) websites, the Blastocystis Subtype (18S) and Sequence Typing (MLST) Database and by construction of a phylogenetic tree. Twenty-nine (29) out of 35 individuals were detected positive for Blastocystis sp. ST3 is the most common among the three STs detected (65.5%), followed by ST1 (31.0%) and ST4 (3.44%). This study showed that DNA barcoding can serve as a helpful tool to investigate the diversity of Blastocystis sp. in the Philippines. PMID- 27770766 TI - Professor Barbara Machnicka-Rowinska DVM PhD (1932-2016) PMID- 27770767 TI - MICAL-like Regulates Fasciclin II Membrane Cycling and Synaptic Development. AB - Fasciclin II (FasII), the Drosophila ortholog of neural cell adhesion molecule (NCAM), plays a critical role in synaptic stabilization and plasticity. Although this molecule undergoes constitutive cycling at the synaptic membrane, how its membrane trafficking is regulated to ensure proper synaptic development remains poorly understood. In a genetic screen, we recovered a mutation in Drosophila mical-like that displays an increase in bouton numbers and a decrease in FasII levels at the neuromuscular junction (NMJ). Similar phenotypes were induced by presynaptic, but not postsynaptic, knockdown of mical-like expression. FasII trafficking assays revealed that the recycling of internalized FasII molecules to the cell surface was significantly impaired in mical-like-knockdown cells. Importantly, this defect correlated with an enhancement of endosomal sorting of FasII to the lysosomal degradation pathway. Similarly, synaptic vesicle exocytosis was also impaired in mical-like mutants. Together, our results identify Mical-like as a novel regulator of synaptic growth and FasII endocytic recycling. PMID- 27770768 TI - Phage Therapy: A New Horizon in the Antibacterial Treatment of Oral Pathogens. AB - Dental diseases are perhaps the most prevalent infection-related diseases in humans. Biofilm is involved in almost every infectious disease compromising oral health, notably caries, periodontal disease, gingivitis, endodontic infections and peri-implantitis. Current therapies of biofilm-derived oral infections lack sensitivity; they are not species-specific and kill pathogenic species as well as commensal species, which are protective against the formation of pathogenic biofilms. Moreover, antibiotics have a limited effect on biofilm and are almost unused in oral diseases. A promising alternative approach is bacteriophage (phage) therapy. Phages play a key role in the natural balance in a predator-prey relationship with bacteria and thus have the potential to be efficient anti bacterial agents. Phages are highly efficient against biofilm, strain specific and easy to isolate and manipulate. Thus, like in many other medicinal fields, phage therapy offers new horizons to dentistry, both therapeutics and research. The present review presents the etiology of common oral diseases, characterization of the infection and the treatment challenges of phage therapy in dentistry. Recent findings and development in the use of phages for prevention, control, and treatment of oral infections as well as possibilities of engineering the oral microbiome are discussed. PMID- 27770769 TI - Open data models for smart health interconnected applications: the example of openEHR. AB - BACKGROUND: Smart Health is known as a concept that enhances networking, intelligent data processing and combining patient data with other parameters. Open data models can play an important role in creating a framework for providing interoperable data services that support the development of innovative Smart Health applications profiting from data fusion and sharing. METHODS: This article describes a model-driven engineering approach based on standardized clinical information models and explores its application for the development of interoperable electronic health record systems. The following possible model driven procedures were considered: provision of data schemes for data exchange, automated generation of artefacts for application development and native platforms that directly execute the models. The applicability of the approach in practice was examined using the openEHR framework as an example. RESULTS: A comprehensive infrastructure for model-driven engineering of electronic health records is presented using the example of the openEHR framework. It is shown that data schema definitions to be used in common practice software development processes can be derived from domain models. The capabilities for automatic creation of implementation artefacts (e.g., data entry forms) are demonstrated. Complementary programming libraries and frameworks that foster the use of open data models are introduced. Several compatible health data platforms are listed. They provide standard based interfaces for interconnecting with further applications. CONCLUSION: Open data models help build a framework for interoperable data services that support the development of innovative Smart Health applications. Related tools for model-driven application development foster semantic interoperability and interconnected innovative applications. PMID- 27770770 TI - Sociodemographic factors associated with IgG and IgM seroprevalence for human cytomegalovirus infection in adult populations of Pakistan: a seroprevalence survey. AB - BACKGROUND: The seroprevalence of human cytomegalovirus (HCMV) infection ranges from 30 to 90 % in developed countries. Reliable estimates of HCMV seroprevalence are not available for Pakistan. This study determined the seroprevalence and sociodemographic factors associated with HCMV infection in adult populations of Karachi, Pakistan. METHODS: A seroprevalence survey was conducted on 1000 adults, including residents of two semi-urban communities, and visitors to a government and a private hospital. Questionnaire-based interviews were conducted. Sera were analysed for HCMV-specific IgG and IgM. Chi-square or Fisher's exact test was used for comparing sociodemographic variables against seropositivity of HCMV-IgG or IgM. Multiple logistic regression modeling was performed for IgG seroprevalence and adjusted odds ratios were computed. RESULTS: The seroprevalence of HCMV-IgG and IgM was 93.2 and 4.3 % respectively. 95.3 % of individuals who were IgM seropositive were also seropositive for IgG. Around 6 % (15/250) of women of childbearing age remained uninfected and were therefore susceptible to primary infection. HCMV-IgG seroprevalence was associated with being female (p = 0.001), increasing age (p = 0.002) and crowding index (p = 0.003) and also with lower levels of both education (p < 0.001) and income (p = 0.008). Seroprevalence also differed significantly by marital status (p = 0.008) and sampling location (p < 0.001). A logistic regression model for HCMV-IgG seroprevalence showed associations with being female (OR = 1.89; 95 % CI: 1.10 3.25), increasing age (OR = 3.95; 95 % CI: 1.79-8.71) and decreasing income (OR = 0.72; 95 % CI: 0.54-0.96). A strong association was observed between increased seroprevalence of HCMV-IgM and decreasing household size (p = 0.008). CONCLUSIONS: Seroprevalence of HCMV is very high in Pakistan, although 6 % of women of childbearing age remain at risk of primary infection. The IgM seropositivity observed in some individuals living in small household size (1-3 individuals) with persistent HCMV infection could have resulted from a recurrent HCMV infection. Future longitudinal research in pregnant women and neonates is required to study the trends in HCMV seroprevalence over time in Pakistan for the development of a potential HCMV prevention and vaccination programme. PMID- 27770771 TI - Evaluation of efficacy, safety and tolerability of Ambrisentan in Chinese adults with pulmonary arterial hypertension: a prospective open label cohort study. AB - BACKGROUND: Although several new drugs have been approved in recent years, pulmonary arterial hypertension (PAH) remains a rapidly progressive disease with a poor prognosis. Ambrisentan, a selective endothelin type A antagonist, has been approved for treatment of PAH. This open label study assessed the efficacy and safety of ambrisentan in Chinese subjects with PAH. METHODS: Eligible patients with PAH (World Health Organisation [WHO] functional class [FC] II orIII) were enrolled and received Ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period (dose titration to 10 mgallowed). Endpoints included: change from baseline in 6-Minute Walk Distance (6 MWD), N-Terminal Pro B-Type Natriuretic Peptide (NT-pro-BNP), WHO FC, Borg Dyspnoea Index (BDI), clinical worsening of PAH and incidences of adverse events (AE). RESULTS: One hundred thirty-three subjects (85 % women, mean age: 36 years) with PAH (WHOFC II or III) were enrolled and received ambrisentan (5 mg) once daily for a 12-week preliminary evaluation period, and a 12-week dose-adjustment period. Mean (SD) duration of drug exposure was 161.7 (27.13) days. Ambrisentan (average daily dose of 6.27 mg) significantly improved exercise capacity (6MWD) from baseline (mean: 377.1 m [m]) at week 12 (+53.6 m, p < 0.001) (primary endpoint). Improvement in exercise capacity was noted as early as week 4, and was sustained up to week 24 (+ 64.4 m, p < 0.001). NT-pro-BNP plasma levels decreased significantly (p < 0.001) at week 12 (-861.4 ng/L) and week 24 (-806 ng/L) from baseline (mean: 1600.7 ng/L). The WHO FC showed improvements for 44 subjects at week 12 and 51 subjects at week 24. BDI scores decreased significantly at week 12 (-0.3, p < 0.001) and week 24 (-0.2, p = 0.003) from baseline (mean: 2.5). Four patients died during the study (sudden cardiac death [n = 2], cerebral haemorrhage [n = 1], cardiac failure [n = 1]). Drug related adverse events occurred in 34.3 % of subjects; peripheral oedema (11.2 %) and flushing (8.2 %) occurred most frequently. CONCLUSION: Ambrisentan (5 and 10 mg, orally) significantly improved the exercise capacity in Chinese PAH subjects with a safety profile similar to that observed in global studies. TRIAL REGISTRATION: NCT No. (ClinicalTrials.gov): NCT01808313 ; Registration date (first time): February 28, 2013. PMID- 27770772 TI - Frequency of satisfaction and dissatisfaction with practice among rural-based, group-employed physicians and non-physician practitioners. AB - BACKGROUND: Widespread dissatisfaction among United States (U.S.) clinicians could endanger ongoing reforms. Practitioners in rural/underserved areas withstand stressors that are unique to or accentuated in those settings. Medical professionals employed by integrating delivery systems are often distressed by the cacophony of organizational change(s) that such consolidation portends. We investigated the factors associated with dis/satisfaction with rural practice among doctors/non-physician practitioners employed by an integrated healthcare delivery network serving 9 counties of upstate New York, during a time of organizational transition. METHODS: We linked administrative data about practice units with cross-sectional data from a self-administered multi-dimensional questionnaire that contained practitioner demographics plus valid scales assessing autonomy/relatedness needs, risk aversion, tolerance for uncertainty/ambiguity, meaningfulness of patient care, and workload. We targeted medical professionals on the institutional payroll for inclusion. We excluded those who retired, resigned or were fired during the study launch, plus members of the advisory board and research team. Fixed-effects beta regressions were performed to test univariate associations between each factor and the percent of time a provider was dis/satisfied. Factors that manifested significant fixed effects were entered into multivariate, inflated beta regression models of the proportion of time that practitioners were dis/satisfied, incorporating clustering by practice unit as a random effect. RESULTS: Of the 473 eligible participants. 308 (65.1 %) completed the questionnaire. 59.1 % of respondents were doctoral-level; 40.9 % mid-level practitioners. Practitioners with heavier workloads and/or greater uncertainty intolerance were less likely to enjoy top quintile satisfaction; those deriving greater meaning from practice were more likely. Higher meaningfulness and gratified relational needs increased one's likelihood of being in the lowest quintile of dissatisfaction; heavier workload and greater intolerance of uncertainty reduced that likelihood. Practitioner demographics and most practice unit characteristics did not manifest any independent effect. CONCLUSIONS: Mutable factors, such as workload, work meaningfulness, relational needs, uncertainty/ambiguity tolerance, and risk taking attitudes displayed the strongest association with practitioner satisfaction/dissatisfaction, independent of demographics and practice unit characteristics. Organizational efforts should be dedicated to a redesign of group-employment models, including more equitable division of clinical labor, building supportive peer networks, and uncertainty/risk tolerance coaching, to improve the quality of work life among rural practitioners. PMID- 27770773 TI - Antinociceptive effect of methanol extract of Celosia cristata Linn. in mice. AB - BACKGROUND: Celosia cristata Linn. (Amaranthaceae) is used in traditional medicine for the treatment of headache, sores, ulcers, eye inflammations, skin eruption, painful menstruation and carpal tunnel syndrome. This study was performed to evaluate the antinociceptive activity of methanol extract of the whole plant of C. cristata (MECC). METHODS: The evaluation of the antinociceptive effect of MECC was performed using thermal (hot plate, tail immersion test) and chemical (acetic acid, formalin, and glutamate-induced nociception test) pain models in mice at four different doses (50, 100, 200, 400 mg/kg; p.o.). Involvement of opioid receptors mediated central antinociceptive mechanism of MECC was evaluated using naloxone. Furthermore, the association of ATP-sensitive K+ channel and cGMP pathway were evaluated using glibenclamide and methylene blue respectively. RESULTS: Oral treatment of MECC produced significant, strong and dose-dependent central and peripheral antinociceptive effect in experimental pain models. MECC significantly increased the latency time of thermal threshold in both hot plate and tail immersion test. The inhibition of writhing syndrome by the extract in the acetic acid-induced writhing test was remarkable. MECC significantly reduced the formalin-induced neurogenic and inflammatory pain. In addition, the inhibition of glutamate-induced paw licking and edema by MECC was significant. The antinociceptive effect was significantly reversed by naloxone and glibenclamide, suggesting the association of opioid and ATP-sensitive K+ channel system respectively. In addition, MECC also demonstrated the involvement of cGMP pathway in the antinociceptive action. CONCLUSION: The study suggests that C. cristata possess significant antinociceptive effect which is associated with both central and peripheral mechanisms and provides a rationale for its extensive use at different painful conditions in traditional medicine. PMID- 27770774 TI - Combination of intramedullary rod, wrapping bone grafting and Ilizarov's fixator for the treatment of Crawford type IV congenital pseudarthrosis of the tibia: mid term follow up of 56 cases. AB - BACKGROUND: The purpose of this study was to investigate the initial union rate, refracture rate and residual deformities of congenital pseudarthrosis of the tibia (CPT), using combined surgery including pseudarthrosis resection, intramedullary rodding, autogenous iliac bone grafting and Ilizarov's fixator, with a mean 5.2 years follow-up. METHODS: We retrospectively reviewed the records and diagrams of patients with Crawford type IV congenital pseudarthrosis of the tibia between February 2007 and March 2010. Patients managed by pseudarthrosis resection, intramedullary rod of the tibia, wrapping autogenous iliac bone grafting and Ilizarov's fixator were enrolled. We evaluated the bone union rate, tibial alignment, limb length discrepancy (LLD), valgus deformity of the ankle and the frequencies of refracture during period of follow-up. RESULTS: There were 56 cases enrolled in the study, with a mean follow-up 5.2 years (range, 3 to 6.7 years). The mean age of the patients at surgery was 3.5 years (range, 1.5 to 12.4 years). Fifty (89.2 %) of the 56 patients had primary bone union at site of pseudarthrosis, while 5 obtained union after second surgery and 1 failed. The average time spent to obtain pseudarthrosis initial union was 4.5 months (range, 3.0 to 10.0 months) and mean duration of Ilizarov treatment was 4.7 months (range, 3.2 to 10.4 months). Eleven (19.6 %) patients had proximal tibial valgus with a mean angle of 9.5 degrees (range, 5 to 24 degrees ), while 10 (17.9 %) patients had ankle valgus deformities with a mean of 12.3 degrees (range, 6 to 21 degrees ). Sixteen (28.6 %) patients had an average 2.2 cm LLD (range, 1.5-4.2 cm). Of the 50 cases who obtained initial bone union of pseudarthrosis, 13 (26.0 %) had refracture which need cast immobilization or secondary surgery. CONCLUSIONS: This combined surgery obtained initial union rate of 89.2 % at primary surgery while the refracture rate is 26.0 %. However, residual deformities such as proximal tibial valgus, LLD and ankle valgus were also existed which should be pay more attention to and dealt with. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov under the name "The Effect of Combined Surgery in Management of Congenital Pseudarthrosis of Tibia" ( NCT02640040 ), which was released on August 31, 2015. PMID- 27770775 TI - HIV risk perception and testing behaviours among men having sex with men (MSM) reporting potential transmission risks in the previous 12 months from a large online sample of MSM living in Germany. AB - BACKGROUND: HIV testing and serostatus awareness are essential to implement biomedical strategies (treatment as prevention; oral chemoprophylaxis), and for effective serostatus-based behaviours (HIV serosorting; strategic positioning). The analysis focuses on the associations between reported sexual risks, the perceived risk for HIV infection, and HIV testing behaviour in order to identify the most relevant barriers for HIV test uptake among MSM living in Germany. METHODS: MSM were recruited to a nationwide anonymous online-survey in 2013 on MSM social networking/dating sites. Questions covered testing behaviours, reasons for testing decisions, and HIV risk perception (5-point scale). Additional questions addressed arguments in favour of home/ home collection testing (HT). Using descriptive statistics and logistic regression we compared men reporting recent HIV testing (RT; previous 12 month) with men never tested (NT) in a subsample not previously diagnosed with HIV and reporting >=2 episodes of condomless anal intercourse (CLAI) with a non-steady partner of unknown HIV serostatus in the previous 12 months. RESULTS: The subsample consisted of 775 RT (13 % of RT) and 396 NT (7 % of NT). The number of CLAI episodes in the last 12 months with non-steady partners of unknown HIV status did not differ significantly between the groups, but RT reported significantly higher numbers of partners (>5 AI partners: 65 vs. 44 %). While perceived risks regarding last AI were comparable between the groups, 49vs. 30 % NT were <30 years, lived more often in towns/villages <100,000 residents (60 vs. 39 %), were less out particularly towards care providers-about being attracted to men (aOR 10.1; 6.9 14.8), more often identified as bisexual (aOR 3.5; 2.5-4.8), and reported lower testing intentions (aOR 0.08; 0.06-0.11). Perceived risks (67 %) and routine testing (49 %) were the most common testing reasons for RT, while the strong belief not to be infected (59 %) and various worries (41 %) and fears of testing positive (35 %) were predominant reasons of NT. Greater anonymity (aOR 3.2; 2.4 4.4), less embarrassment, (aOR 2.8; 1.9-4.1), and avoiding discussions on sexual behaviour (aOR 1.6; 1.1-2.2) were emphasized in favour of HT by NT. CONCLUSIONS: Perceived partner knowledge and reasons reflecting perceived gay- and HIV-related stigma predicted testing decisions rather than risk perception. Access barriers for testing should be further lowered, e.g. by making affordable HT available, addressing structural barriers (stigma), and emphasizing beneficial aspects of serostatus awareness. PMID- 27770776 TI - The phylogenetic significance of leaf anatomical traits of southern African Oxalis. AB - BACKGROUND: The southern African Oxalis radiation is extremely morphologically variable. Despite recent progress in the phylogenetics of the genus, there are few morphological synapomorphies supporting DNA-based clades. Leaflet anatomy can provide an understudied and potentially valuable source of information on the evolutionary history and systematics of this lineage. Fifty-nine leaflet anatomical traits of 109 southern African Oxalis species were assessed in search of phylogenetically significant characters that delineate clades. RESULTS: A combination of 6 leaflet anatomical traits (stomatal position, adaxial epidermal cells, abaxial epidermal cells, mesophyll, sheath around vascular tissue, degree of leaflet conduplication) clearly support various clades defined by previous DNA based phylogenetic work. Other, mostly continuous leaflet anatomical traits were highly variable and showed less phylogenetic pattern. CONCLUSIONS: Major and unexpected findings include the transition from ancestral hypostomatic leaflets to adaxially-located stomata in the vast majority of southern African Oxalis, the loss of semi-swollen AB epidermal cells and the gain of swollen adaxial and abaxial epidermal cells in selected clades, and multiple changes from ancestral bifacial mesophyll to isobilateral or homogenous mesophyll types. The information gathered in this study will aid in the taxonomic revision of this speciose member of the Greater Cape Floristic Region and provide a basis for future hypotheses regarding its radiation. PMID- 27770777 TI - Multi-locus sequence data illuminate demographic drivers of Pleistocene speciation in semi-arid southern Australian birds (Cinclosoma spp.). AB - BACKGROUND: During the Pleistocene, shifts of species distributions and their isolation in disjunct refugia led to varied outcomes in how taxa diversified. Some species diverged, others did not. Here, we begin to address another facet of the role of the Pleistocene in generating today's diversity. We ask which processes contributed to divergence in semi-arid southern Australian birds. We isolated 11 autosomal nuclear loci and one mitochondrial locus from a total of 29 specimens of the sister species pair, Chestnut Quail-thrush Cinclosoma castanotum and Copperback Quail-thrush C. clarum. RESULTS: A population clustering analysis confirmed the location of the current species boundary as a well-known biogeographical barrier in southern Australia, the Eyrean Barrier. Coalescent based analyses placed the time of species divergence to the Middle Pleistocene. Gene flow between the species since divergence has been low. The analyses suggest the effective population size of the ancestor was 54 to 178 times smaller than populations since divergence. This contrasts with recent multi-locus studies in some other Australian birds (butcherbirds, ducks) where a lack of phenotypic divergence was accompanied by larger historical population sizes. Post-divergence population size histories of C. clarum and C. castanotum were inferred using the extended Bayesian skyline model. The population size of C. clarum increased substantially during the late Pleistocene and continued to increase through the Last Glacial Maximum and Holocene. The timing of this expansion across its vast range is broadly concordant with that documented in several other Australian birds. In contrast, effective population size of C. castanotum was much more constrained and may reflect its smaller range and more restricted habitat east of the Eyrean Barrier compared with that available to C. clarum to the west. CONCLUSIONS: Our results contribute to awareness of increased population sizes, following significant contractions, as having been important in shaping diversity in Australian arid and semi-arid zones. Further, we improve knowledge of the role of Pleistocene climatic shifts in areas of the planet that were not glaciated at that time but which still experienced that period's cyclical climatic fluctuations. PMID- 27770778 TI - Observational study on patterns of neuromuscular blockade reversal. AB - BACKGROUND: Using electronic health record data, we hypothesized that larger reversal doses are used for patients with deeper levels of neuromuscular blockade (NMB) as evidenced by the last recorded TOF measurement. We also examined if dosing regimens reflect current practice guidelines of using ideal body weight (IBW) for NMB agents and total body weight (TBW) for neostigmine. METHODS: This is a retrospective observational study of adult, ASA 1-4 patients who underwent general anaesthesia and received non-depolarizing NMB agents between 01/01/2004 and 12/31/2013. For the primary outcome, percentages of cases receiving neostigmine and median doses administered for each subjective train-of-four (TOF) category were calculated. Secondary analyses evaluated associations between NMB dosing and neostigmine administration based on Body Mass Index (BMI) categories. RESULTS: A total of 135,633 cases met inclusion criteria for the study. There was no clinically significant difference in median neostigmine dosing based on last TOF count prior to reversal administration: 37.5 mcg/kg for TOF of 4/4 vs. 37.9 mcg/kg for TOF of 0/4 for the total neostigmine dose. Significantly higher number of patients with lower TOF counts received additional neostigmine administration: 5.7 % for 0/4 vs. 1.5 % for 4/4 TOF counts. The median times to extubation following neostigmine administration were clinically similar across TOF count categories. The median doses for neostigmine based on TBW decreased with higher BMI categories and were significantly different between the lowest and highest categories: 42.8 mcg/kg vs 30.8 mcg/kg for total doses (p < .0001) respectively. The percentages of cases requiring reversal in addition to the initial dose increased with increasing BMI categories and were 2.1 % for BMI < 18 vs. 3.3 % for BMI >= 40. The total median dose of NMB agents in ED95 equivalents per IBW increased from 2.9 in the Underweight category to 4.2 in the Class III Obese category. The majority of patients in the pancuronium subgroup received very low ED95 equivalent dose of 0.1 and did not require reversal. Patients receiving cisatracurium were given significantly higher median ED95 equivalent dose of 5.6 vs 2.8-3.9 compared to other intermediate acting NMB agents, while receiving clinically similar doses of neostigmine. CONCLUSIONS: Neither neostigmine dosing nor times to extubation were affected by the depth of the neuromuscular blockade prior to reversal. The need for additional reversal, or rescue, correlated strongly with the depth of NMB. There was significant variability in neostigmine dosing across the BMI categories. Underweight patients received relatively lower NMB doses while simultaneously receiving relatively higher reversal doses, and the opposite was true for patients with BMI >40. PMID- 27770779 TI - Eugenia aurata and Eugenia punicifolia HBK inhibit inflammatory response by reducing neutrophil adhesion, degranulation and NET release. AB - BACKGROUND: Eugenia spp. are used in popular medicine in the treatment of pain, diabetes, intestinal disorders and cough. The aim of the work is to evaluate, ex vivo and in vivo, the anti-inflammatory activity of the hydroethanolic extracts of the leaves of Eugenia aurata (EA) and Eugenia punicifolia HBK (EP) upon neutrophils. METHODS: Ex vivo, isolated human neutrophils were sensitized by Eugenia extracts (0.1-1000 MUg/mL) and stimulated by PMA. In these conditions, different neutrophil activities related to inflammatory process were measured: adhesion, degranulation and NET release. Neutrophil viability and tumor line cells were monitored. In vivo, neutrophil influx was evaluated by peritonitis model performed in mice pretreated with different concentrations of Eugenia extracts. Phytochemical profile was assessed by mass spectrometry. RESULTS: Ex vivo, EA and EP (1000 MUg/mL) reduced cell adhesion and degranulation, respectively. NET release was inhibited by EA and EP. Anti-inflammatory activities occurred in the absence of cytotoxicity. In vivo, both EA as EP inhibited neutrophil migration. The phytochemical profile revealed that EA contains myricitrin, rutin, quinic acid and quercetin derivatives. EP presents gallic acid, quercetin derivatives, syringic acid, ellagic acid, monogalloyl glucose, glycosyringic acid, mudanoside B, HHDP glucose isomer and digalloylglucose isomer. EA and EP inhibit neutrophil migration by different pathways. CONCLUSION: Different chemical compositions may explain the anti inflammatory effects described herein for EA and EP. Both extracts inhibit NET release but only EA reduces cell adhesion whereas EP decreases elastase secretion. This work contributes to the elucidation of cellular mechanisms related to the anti-inflammatory activity for leaves of E. aurata and E. punicifolia HBK. PMID- 27770780 TI - Seeking consent for research with indigenous communities: a systematic review. AB - BACKGROUND: When conducting research with Indigenous populations consent should be sought from both individual participants and the local community. We aimed to search and summarise the literature about methods for seeking consent for research with Indigenous populations. METHODS: A systematic literature search was conducted for articles that describe or evaluate the process of seeking informed consent for research with Indigenous participants. Guidelines for ethical research and for seeking consent with Indigenous people are also included in our review. RESULTS: Of 1447 articles found 1391 were excluded (duplicates, irrelevant, not in English); 56 were relevant and included. Articles were categorised into original research that evaluated the consent process (n = 5) or publications detailing the process of seeking consent (n = 13) and guidelines for ethical research (n = 38). Guidelines were categorised into international (n = 8); national (n = 20) and state/regional/local guidelines (n = 10). In five studies based in Australia, Canada and The United States of America the consent process with Indigenous people was objectively evaluated. In 13 other studies interpreters, voice recording, videos, pictures, flipcharts and "plain language" forms were used to assist in seeking consent but these processes were not evaluated. Some Indigenous organisations provide examples of community-designed resources for seeking consent and describe methods of community engagement, but none are evaluated. International, national and local ethical guidelines stress the importance of upholding Indigenous values but fail to specify methods for engaging communities or obtaining individual consent. In the 'Grey literature' concerns about the consent process are identified but no solutions are offered. CONCLUSION: Consultation with Indigenous communities is needed to determine how consent should be sought from the community and the individual, and how to evaluate this process. PMID- 27770781 TI - Racial disparities in adult all-cause and cause-specific mortality among us adults: mediating and moderating factors. AB - BACKGROUND: Studies uncovering factors beyond socio-economic status (SES) that would explain racial and ethnic disparities in mortality are scarce. METHODS: Using prospective cohort data from the Third National Health and Nutrition Examination Survey (NHANES III), we examined all-cause and cause-specific mortality disparities by race, mediation through key factors and moderation by age (20-49 vs. 50+), sex and poverty status. Cox proportional hazards, discrete time hazards and competing risk regression models were conducted (N = 16,573 participants, n = 4207 deaths, Median time = 170 months (1-217 months)). RESULTS: Age, sex and poverty income ratio-adjusted hazard rates were higher among Non Hispanic Blacks (NHBs) vs. Non-Hispanic Whites (NHW). Within the above-poverty young men stratum where this association was the strongest, the socio-demographic adjusted HR = 2.59, p < 0.001 was only partially attenuated by SES and other factors (full model HR = 2.08, p = 0.003). Income, education, diet quality, allostatic load and self-rated health, were among key mediators explaining NHB vs. NHW disparity in mortality. The Hispanic paradox was observed consistently among women above poverty (young and old). NHBs had higher CVD-related mortality risk compared to NHW which was explained by factors beyond SES. Those factors did not explain excess risk among NHB for neoplasm-related death (fully adjusted HR = 1.41, 95 % CI: 1.02-2.75, p = 0.044). Moreover, those factors explained the lower risk of neoplasm-related death among MA compared to NHW, while CVD-related mortality risk became lower among MA compared to NHW upon multivariate adjustment. CONCLUSIONS: In sum, racial/ethnic disparities in all-cause and cause specific mortality (particularly cardiovascular and neoplasms) were partly explained by socio-demographic, SES, health-related and dietary factors, and differentially by age, sex and poverty strata. PMID- 27770783 TI - A statistical approach to detection of copy number variations in PCR-enriched targeted sequencing data. AB - BACKGROUND: Multiplex polymerase chain reaction (PCR) is a common enrichment technique for targeted massive parallel sequencing (MPS) protocols. MPS is widely used in biomedical research and clinical diagnostics as the fast and accurate tool for the detection of short genetic variations. However, identification of larger variations such as structure variants and copy number variations (CNV) is still being a challenge for targeted MPS. Some approaches and tools for structural variants detection were proposed, but they have limitations and often require datasets of certain type, size and expected number of amplicons affected by CNVs. In the paper, we describe novel algorithm for high-resolution germinal CNV detection in the PCR-enriched targeted sequencing data and present accompanying tool. RESULTS: We have developed a machine learning algorithm for the detection of large duplications and deletions in the targeted sequencing data generated with PCR-based enrichment step. We have performed verification studies and established the algorithm's sensitivity and specificity. We have compared developed tool with other available methods applicable for the described data and revealed its higher performance. CONCLUSION: We showed that our method has high specificity and sensitivity for high-resolution copy number detection in targeted sequencing data using large cohort of samples. PMID- 27770782 TI - Triple negative breast cancer in North of Morocco: clinicopathologic and prognostic features. AB - BACKGROUND: Triple Negative Breast Cancer (TNBC) is defined by a lack of estrogen and progesterone receptor gene expression and by the absence of overexpression on HER2. It is associated to a poor prognosis. We propose to analyze the clinicopathologic and prognostic characteristics of this breast cancer subtype in a Mediterranean population originated or resident in the North of Morocco. METHODS: We conducted a retrospective study of 279 patients diagnosed with breast cancer between January 2010 and January 2015. Clinicopathologic and prognostic features have been analyzed. Disease-Free Survival (DFS) and Overall Survival (OS) have been estimated. RESULTS: Of all cases, forty-nine (17.6 %) were identified as having triple negative breast cancer with a median age of 46 years. The average tumor size was 3.6 cm. The majority of patients have had invasive ductal carcinoma (91.8 %) and 40.4 % of them were grade III SBR. Nodal metastasis was detected in 38.9 % of the patients and vascular invasion was found in 36.6 % of them. About half of the patients had an early disease (53.1 %) and 46.9 % were diagnosed at an advanced stage. Patients with operable tumors (61.2 %) underwent primary surgery and adjuvant chemotherapy. Patients with no operable tumors (26.5 %) received neoadjuvant chemotherapy followed by surgery, and patients with metastatic disease (12.2 %) were treated by palliative chemotherapy. DFS and OS at 5 years were respectively 83.7 and 71.4 %. Among 49, twelve had recurrences, found either when diagnosing them or after a follow-up. Local relapse was 6.1 %. Lung and liver metastases accounted consecutively for 8.2 and 10.2 %. Bone metastases were found in 4.1 % and brain metastases in 2.1 % of the cases. CONCLUSION: Our results are in accordance with literature data, particularly what concerning young age and poor prognosis among TNBC phenotype. Therefore, the identification of BRCA mutations in our population seems to be essential in order to better adapt management options for this aggressive form of breast cancer. PMID- 27770785 TI - Bogijetong decoction and its active herbal components protect the peripheral nerve from damage caused by taxol or nerve crush. AB - BACKGROUND: Bogijetong decoction (BGJTD) is a herbal drug formulation used in the traditional Asian medicine to treat neuropathic insults associated with diabetes and anticancer therapy. To understand the biological basis of BGJTD on protective effects against neuropathy, we investigated physiological and biochemical responses of the sciatic nerves deranged by taxol injection or crush injury in the rats. METHODS: Dissociated Schwann cells and neurons were prepared from the sciatic nerve and dorsal root ganglia (DRG) respectively and were treated with taxol and BGJTD. The sciatic nerve in the rat was injected with taxol or given crush injury. Animals were then administered orally with BGJTD. Effects of BGJTD treatment on cultured cells and in vivo sciatic nerves and DRG tissues were examined by immunofluorescence staining and western blot analysis. Sciatic nerve regeneration was assessed by histological observation using retrograde tracing technique and by behavioral hot plate test. Eighteen different herbal components of BGJTD were divided into 4 subgroups and were used to select herbal drugs that enhanced neurite outgrowth in cultured neurons. RESULTS: Morphological abnormalities in the sciatic nerve axons and DRG tissue caused by taxol injection were largely improved by BGJTD treatment. BGJTD treatment enhanced neurite outgrowth in cultured DRG neurons and improved Schwann cell survival. Phospho Erk1/2 levels were elevated by BGJTD administration in the injured- or taxol injected sciatic nerves. Vimentin phosphorylation catalyzed by cell division cycle 2 (Cdc2) kinase was induced from Schwann cells in the sciatic nerves after taxol injection and crush injury, and phospho-vimentin levels were further upregulated by BGJTD treatment. Retrograde tracing of DiI-labeled DRG sensory neurons revealed growth-promoting activity of BGJTD on axonal regeneration. A drug group (Be) composed of 4 active herbal components which were selected by neurite growth-enhancing activity was as effective as BGJDT for the recovery of thermal sensitivity of the hind paws which had been suppressed by taxol administration. CONCLUSIONS: These data suggest that BGJTD and its active herbal components may protects the peripheral nerve from damage caused by taxol injection and nerve crush. PMID- 27770784 TI - Effects of two neuromuscular training programs on running biomechanics with load carriage: a study protocol for a randomised controlled trial. AB - BACKGROUND: In recent years, athletes have ventured into ultra-endurance and adventure racing events, which tests their ability to race, navigate, and survive. These events often require race participants to carry some form of load, to bear equipment for navigation and survival purposes. Previous studies have reported specific alterations in biomechanics when running with load which potentially influence running performance and injury risk. We hypothesize that a biomechanically informed neuromuscular training program would optimize running mechanics during load carriage to a greater extent than a generic strength training program. METHODS: This will be a two group, parallel randomized controlled trial design, with single assessor blinding. Thirty healthy runners will be recruited to participate in a six weeks neuromuscular training program. Participants will be randomized into either a generic training group, or a biomechanically informed training group. Primary outcomes include self-determined running velocity with a 20 % body weight load, jump power, hopping leg stiffness, knee extensor and triceps-surae strength. Secondary outcomes include running kinetics and kinematics. Assessments will occur at baseline and post-training. DISCUSSION: To our knowledge, no training programs are available that specifically targets a runner's ability to carry load while running. This will provide sport scientists and coaches with a foundation to base their exercise prescription on. TRIAL REGISTRATION: ANZCTR ( ACTRN12616000023459 ) (14 Jan 2016). PMID- 27770786 TI - Subcellular protein expression models for microsatellite instability in colorectal adenocarcinoma tissue images. AB - BACKGROUND: New bioimaging techniques capable of visualising the co-location of numerous proteins within individual cells have been proposed to study tumour heterogeneity of neighbouring cells within the same tissue specimen. These techniques have highlighted the need to better understand the interplay between proteins in terms of their colocalisation. RESULTS: We recently proposed a cellular-level model of the healthy and cancerous colonic crypt microenvironments. Here, we extend the model to include detailed models of protein expression to generate synthetic multiplex fluorescence data. As a first step, we present models for various cell organelles learned from real immunofluorescence data from the Human Protein Atlas. Comparison between the distribution of various features obtained from the real and synthetic organelles has shown very good agreement. This has included both features that have been used as part of the model input and ones that have not been explicitly considered. We then develop models for six proteins which are important colorectal cancer biomarkers and are associated with microsatellite instability, namely MLH1, PMS2, MSH2, MSH6, P53 and PTEN. The protein models include their complex expression patterns and which cell phenotypes express them. The models have been validated by comparing distributions of real and synthesised parameters and by application of frameworks for analysing multiplex immunofluorescence image data. CONCLUSIONS: The six proteins have been chosen as a case study to illustrate how the model can be used to generate synthetic multiplex immunofluorescence data. Further proteins could be included within the model in a similar manner to enable the study of a larger set of proteins of interest and their interactions. To the best of our knowledge, this is the first model for expression of multiple proteins in anatomically intact tissue, rather than within cells in culture. PMID- 27770787 TI - The NUTRAOLEOUM Study, a randomized controlled trial, for achieving nutritional added value for olive oils. AB - BACKGROUND: Virgin olive oil, a recognized healthy food, cannot be consumed in great quantities. We aim to assess in humans whether an optimized virgin olive oil with high phenolic content (OVOO, 429 mg/Kg) and a functional one (FOO), both rich in phenolic compounds (429 mg/Kg) and triterpenic acids (389 mg/kg), could provide health benefits additional to those supplied a by a standard virgin olive oil (VOO). METHODS/DESIGN: A randomized, double-blind, crossover, controlled study will be conducted. Healthy volunteers (aged 20 to 50) will be randomized into one of three groups of daily raw olive oil consumption: VOO, OVOO, and FOO (30 mL/d). Olive oils will be administered over 3-week periods preceded by 2-week washout ones. The main outcomes will be markers of lipid and DNA oxidation, inflammation, and vascular damage. A bioavailability and dose-response study will be nested within this sustained- consumption one. It will be made up of 18 volunteers and be performed at two stages after a single dose of each olive oil. Endothelial function and nitric oxide will be assessed at baseline and at 4 h and 6 h after olive oil single dose ingestion. DISCUSSION: For the first time the NUTRAOLEUM Study will provide first level evidence on the health benefits in vivo in humans of olive oil triterpenes (oleanolic and maslinic acid) in addition to their bioavailability and disposition. TRIAL REGISTRATION: The Trial has been registered in ClinicalTrials.gov ID: NCT02520739 . PMID- 27770788 TI - Bioelectrical Impedance Analysis (BIA) of the association of the Japanese Kampo concept "Suidoku" (fluid disturbance) and the body composition of women. AB - BACKGROUND: In Japanese Kampo medical practice, suidoku (fluid disturbance) is one of the most important concepts for selecting the proper medication. Suidoku is an excessive or uneven distribution of fluid that is indicated by splashing sounds and pitting edema. However, few objective reports about suidoku have been published. Bioelectrical impedance analysis (BIA) uses resistance values obtained from weak electrical currents to estimate body composition, including intracellular and extracellular water and muscle and fat mass. In this study, we used BIA to search for objective factors that can discriminate the various types of suidoku. METHODS: Two hundred twenty-nine patients who visited the Kampo Medicine Clinic of Kyushu University Hospital from June 2010 to August 2015 were divided into non-suidoku (n = 180, 80 male and 100 female), splashing sound (n = 32, 8 male and 24 female) and edema groups (n = 17, 5 male and 12 female). Body composition values were taken from the electronic medical records of InBody730 (a vertical, segmental, multi-frequency analyzer by InBody, Tokyo Japan) testing done at the initial visit. Various parameters of the body composition values of female in the non-suidoku and suidoku groups (splashing sound and edema groups) were compared: there were too few male patients to provide significance. RESULTS: The age and body weight were significantly lower in the splashing sound group than in the non-suidoku group (p < 0.05). In contrast, the body weight of the edema group was significantly heavier than that of the non-suidoku group (p < 0.05). In ROC analysis, the percent Body Fat <= 27.8 %, Muscle Mass Index of the Trunk <= 6.5 kg/m2, VFA (Visceral fat area) <= 5.4 and BMI <= 19.2 kg/m2 were associated with splashing sound, and Muscle Mass Index of Legs >= 4.8 kg/m2 and BMI >= 21.4 kg/m2 were associated with edema. CONCLUSION: Our data suggest that the use of this type of BIA to estimate body composition would be a useful tool for the diagnosis of suidoku for women. PMID- 27770789 TI - A DNA vaccine targeting TcdA and TcdB induces protective immunity against Clostridium difficile. AB - BACKGROUND: Clostridium difficile-associated disease (CDAD) constitutes a great majority of hospital diarrhea cases in industrialized countries and is induced by two types of large toxin molecules: toxin A (TcdA) and toxin B (TcdB). Development of immunotherapeutic approaches, either active or passive, has seen a resurgence in recent years. Studies have described vaccine plasmids that express either TcdA and/or TcdB receptor binding domain (RBD). However, the effectiveness of one vector encoding both toxin RBDs against CDAD has not been evaluated. METHODS: In the study, we constructed highly optimized plasmids to express the receptor binding domains of both TcdA and TcdB from a single vector. The DNA vaccine was evaluated in two animal models for its immunogenicity and protective effects. RESULTS: The DNA vaccine induced high levels of serum antibodies to toxin A and/or B and demonstrated neutralizing activity in both in vitro and in vivo systems. In a C. difficile hamster infection model, immunization with the DNA vaccine reduced infection severity and conferred significant protection against a lethal C. difficile strain. CONCLUSIONS: This study has demonstrated a single plasmid encoding the RBD domains of C. difficile TcdA and TcdB as a DNA vaccine that could provide protection from C. difficile disease. PMID- 27770790 TI - Reduced mRNA expression levels of NFE2L2 are associated with poor outcome in breast cancer patients. AB - BACKGROUND: The transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2; previously known as NRF2) is a crucial regulator of the intracellular antioxidant response. It controls the expression of genes involved in the detoxification and elimination of reactive oxidants and electrophilic agents. The role of NFE2L2 in cancer is subject of controversial discussion, as it has been reported to have both pro-and anti-tumourigenic functions. To shed some light on this paradox, we analysed the NFE2L2 mRNA expression levels in breast cancer and its association with clinicopathological features and survival. METHODS: We retrospectively evaluated the NFE2L2 mRNA expression levels in tumour tissue of two independent breast cancer patient cohorts. In the training set we analysed data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). In the test set we measured the NFE2L2 mRNA expression levels in 176 breast tumour tissues by quantitative real-time reverse transcription PCR (qRT PCR). Group differences were analysed using Mann-Whitney U-test, and associations between NFE2L2 mRNA expression levels and clinicopathological features were examined by means of univariate and multivariate survival analyses. Furthermore, we compared NFE2L2 mRNA expression levels between tumour and normal breast tissue samples by means of 108 paired samples from the The Cancer Genome Atlas (TCGA) dataset. RESULTS: In the training set we identified an independent predictive value for high NFE2L2 mRNA expression levels [HRdisease specific death 0.8 (0.6 1.0), P = 0.041; HRdeath 0.8 (0.6-1.0), P = 0.023] especially in the subgroup of oestrogen receptor (ER) positive tumours [HRdisease specific death 0.6 (0.4-0.9), P = 0.008; HRdeath 0.6 (0.4-0.8), P = 0.001]. Similarly, we found this association also in the test set [HRrelapse 0.4 (0.2-0.9), P = 0.031] and again, more pronounced in patients with ER positive tumours [HRrelapse 0.2 (0.1-0.7), P = 0.012]. In addition, we observed generally lower NFE2L2 expression levels in tumour tissues than in normal breast tissues. CONCLUSION: We concluded that reduced NFE2L2 mRNA expression in tumour tissues is an independent predictor of shortened survival in breast cancer patients. PMID- 27770791 TI - Prognosis of patients with severe hyponatraemia is related not only to hyponatraemia but also to comorbidities and to medical management: results of an observational retrospective study. AB - BACKGROUND: The true cause of death in severe hyponatraemic patients remains controversial. The present study aimed to analyse the relationship between comorbidity, medical management and prognosis in severe hyponatraemic patients. METHODS: Medical records of all patients hospitalised in our institution in 2012 with a plasma sodium <=120 mmol/l were retrospectively analysed. RESULTS: One hundred forty-seven of 64 723 adult patients (0.2 %) were identified with severe hyponatraemia. In-hospital mortality rate was 24.5 and 50.3 % after a median follow-up of 431 days. Patients with plasma sodium <110 mmol/l had less comorbidity (Charlson Comorbidity Index 2.2 +/- 1.9 vs. 4.0 +/- 3.1 (plasma sodium 110-115 mmol/l) and 4.2 +/- 3.1 (plasma sodium 116-120 mmol/l); P = .02)) and a small trend for less mortality, respectively 40.0, 51.2 and 52.3 % (P = .64). At discharge, nonsurvivors and survivors had similar plasma sodium with 58.3 % of nonsurvivors being normonatraemic. Urine analysis was performed in 74.2 % of cases and associated with lower in-hospital mortality (20.2 % vs. 36.8 %, P = .05). In multivariate Cox analysis, mortality was significantly associated with plasma sodium normalisation (HR 0.35, P < 0.001), urine analysis (HR 0.48, P = .01), Charlson Comorbidity Index (HR 1.23, P < .001) and serum albumin (HR 0.88, P < .001). CONCLUSION: Mortality in severe hyponatraemia appears mainly due to comorbidities although the latter are potentiated by hyponatraemia itself and its management thereby exacerbating the risk of death. PMID- 27770792 TI - More frequent, more costly? Health economic modelling aspects of monitoring glaucoma patients in England. AB - BACKGROUND: Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. METHODS: Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. RESULTS: An ICER of L21,392 per QALY was derived for proposed practice improving to a value of L11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > L60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. CONCLUSION: Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment. PMID- 27770793 TI - Long term evolution of endothelial function during kidney transplantation. AB - BACKGROUND: Endothelial dysfunction is an important precursor to the development of atherosclerosis, and has been suggested to play a role in the increased cardiovascular risk in patients with end stage renal disease. Endothelial function improves rapidly following post kidney transplantation, but the long term change remains unclear. Hypothesizing that endothelial function would remain improved long term post kidney transplantation, we evaluated the longitudinal change of endothelial function, measured by flow-mediated dilation (FMD) of the brachial artery, from months 1 to 24 post transplantation. Given the previously reported association of fibroblast growth factor 23 (FGF-23) with endothelial dysfunction, we also examined changes in the association between FGF-23 levels and the change in FMD following kidney transplantation. METHODS: We performed a prospective cohort study of 149 kidney transplant recipients, measuring endothelial function by FMD at months 1, 12, and 24 post-transplant. FGF-23 levels were measured at months 1 and 24 post-transplant. Linear mixed effects models were used to assess both the unadjusted and adjusted outcomes. RESULTS: The cohort (mean age 49 +/- 13 years) was 74 % male and 75 % white. The median FMD was 6.3 % (IQR: 3.4, 10.2), 5.4 % (IQR: 3.1, 8.5), and 5.6 % (IQR: 3.5, 9.1) at 1, 12, and 24 months, respectively. After adjustment for covariates, compared to month 1, no change occurred in FMD at 12 months (-0.66 %; 95 % CI: -1.81 %, 0.49 %; P = 0.262) or 24 months (-0.25 %; 95%CI: -1.76 %, 1.26 %; P = 0.746). FGF 23 decreased significantly over time (P = 0.024), but there was no significant association between FGF-23 and FMD (P = 0.799). CONCLUSION: Endothelial function remained stable at 12 and 24 months from 1 month post-kidney transplant, indicating that the improved endothelial function seen with transplant is maintained up to 2 years post transplantation. There was also no significant association between FGF-23 and endothelial function following kidney transplantation. PMID- 27770794 TI - National ethics guidance in Sub-Saharan Africa on the collection and use of human biological specimens: a systematic review. AB - BACKGROUND: Ethical and regulatory guidance on the collection and use of human biospecimens (HBS) for research forms an essential component of national health systems in Sub-Saharan Africa (SSA), where rapid advances in genetic- and genomic based technologies are fueling clinical trials involving HBS and the establishment of large-scale biobanks. METHODS: An extensive multi-level search for publicly available ethics regulatory guidance was conducted for each SSA country. A second review documented active trials listed in the WHO International Clinical Trials Registry Platform as of January 2015 in which HBS collection was specified in the protocol. Findings were combined to determine the extent to which countries that are study sites for HBS-related research are supported by regulatory guidance language on the collection, use, ownership and storage of biospecimens. RESULTS: Of the 49 SSA countries, 29 had some form of national ethics guidance, yet only 17 provided language relating to HBS-related research, with specific guidance on consent (14), ownership (6), reuse (10), storage (9), and export/import/transfer (13). Ten countries accounted for 84 % of the active clinical trials involving the collection of HBS in SSA. All except one of these countries were found to have some national guidance in the form of regulations, codes of ethics, and/or standard operating procedures; however, only seven of the ten offered any language specific to HBS. CONCLUSIONS: Despite the fact that the bulk of registered clinical trials in SSA involving HBS, as well as existing and proposed sites for biorepositories under the H3Africa Initiative, are currently situated in countries with the most complete ethics and regulatory guidance, variability in the regulations themselves may create challenges for planned and future pan-African collaborations and may require legislative action at the national level to revise. Countries in SSA that still lack regulatory guidance on HBS will require extensive health system strengthening in ethics governance before they can be full participants in the modern research enterprise. PMID- 27770795 TI - Replacement of carbohydrate binding modules improves acetyl xylan esterase activity and its synergistic hydrolysis of different substrates with xylanase. AB - BACKGROUND: Acetylation of the xylan backbone was a major obstacle to enzymatic decomposition. Removal of acetyl groups by acetyl xylan esterases (AXEs) is essential for completely enzymatic hydrolysis of xylan. Appended carbohydrate binding modules (CBMs) can promote the enzymatic deconstruction of plant cell walls by targeting and proximity effects. Fungal acetyl xylan esterases are strictly appended to cellulose-specific CBM1. It is still unclear whether xylan specific CBMs have a greater advantage than CBM1 in potentiating the activity of fungal deacetylating enzymes and its synergistic hydrolysis of different substrates with xylanase. RESULTS: Three recombinant AXE1s fused with different xylan-specific CBMs, together with wild-type AXE1 with CBM1 and CBM1-deleted mutant AXE1dC, were constructed in this study. The optimal temperature and pH of recombinant AXE1s was 50 degrees C and 8.0 (except AXE1dC-CBM6), respectively. Cellulose-specific CBM1 in AXE1 obviously contributed to its catalytic action against substrates compared with AXE1dC. However, replacement of CBM1 with xylan specific CBM4-2 significantly enhanced AXE1 thermostability and catalytic activity against soluble substrate 4-methylumbelliferyl acetate. Whereas replacements with xylan-specific CBM6 and CBM22-2 were more effective in enzymatic release of acetic acid from destarched wheat bran, NaClO2-treated wheat straw, and water-insoluble wheat arabinoxylan compared to AXE1. Moreover, replacement with CBM6 and CBM22-2 also resulted in higher degree releases of reducing sugar and acetic acid from different substrates when simultaneous hydrolysis with xylanase. A good linear relationship exists between the acetic acid and reducing sugar release. CONCLUSIONS: Our findings suggested that the replacement with CBM6 and CBM22-2 not only significantly improved the catalysis efficiency of AXE1, but also increased its synergistic hydrolysis of different substrates with xylanase, indicating the significance of targeting effect in AXE1 catalysis mediated by xylan-specific CBMs. PMID- 27770797 TI - Towards comprehensive early abortion service delivery in high income countries: insights for improving universal access to abortion in Australia. AB - BACKGROUND: Improving access to safe abortion is an essential strategy in the provision of universal access to reproductive health care. Australians are largely supportive of the provision of abortion and its decriminalization. However, the lack of data and the complex legal and service delivery situation impacts upon access for women seeking an early termination of pregnancy. There are no systematic reviews from a health services perspective to help direct health planners and policy makers to improve access comprehensive medical and early surgical abortion in high income countries. This review therefore aims to identify quality studies of abortion services to provide insight into how access to services can be improved in Australia. METHODS: We undertook a structured search of six bibliographic databases and hand-searching to ascertain peer reviewed primary research in English between 2005 and 2015. Qualitative and quantitative study designs were deemed suitable for inclusion. A deductive content analysis methodology was employed to analyse selected manuscripts based upon a framework we developed to examine access to early abortion services. RESULTS: This review identified the dimensions of access to surgical and medical abortion at clinic or hospital-outpatient based abortion services, as well as new service delivery approaches utilising a remote telemedicine approach. A range of factors, mostly from studies in the United Kingdom and United States of America were found to facilitate improved access to abortion, in particular, flexible service delivery approaches that provide women with cost effective options and technology based services. Standards, recommendations and targets were also identified that provided services and providers with guidance regarding the quality of abortion care. CONCLUSIONS: Key insights for service delivery in Australia include the: establishment of standards, provision of choice of procedure, improved provider education and training and the expansion of telemedicine for medical abortion. However, to implement such directives leadership is required from Australian medical, nursing, midwifery and pharmacy practitioners, academic faculties and their associated professional associations. In addition, political will is needed to nationally decriminalise abortion and ensure dedicated public provision that is based on comprehensive models tailored for all populations. PMID- 27770796 TI - A cluster of KPC-2 and VIM-2-producing Klebsiella pneumoniae ST833 isolates from the pediatric service of a Venezuelan Hospital. AB - BACKGROUND: Klebsiella pneumoniae is a bacterial pathogen that has developed resistance to multiple antibiotics and is a major cause of nosocomial infections worldwide. Carbapenemase-producing Klebsiella pneumoniae have been isolated in many hospitals in Venezuela, but they have not been well-studied. The aim of this study was to characterize carbapenem-resistant Klebsiella pneumoniae isolates from the pediatric service of a hospital located in Anzoategui State, in the eastern part of Venezuela. METHODS: Nineteen Klebsiella pneumoniae strains isolated in the hospital from April to July 2014 were evaluated phenotypically and molecularly for the presence of carbapenemases blaKPC, blaIMP and blaVIM. Molecular epidemiology was performed with Repetitive Extragenic Palindromic-PCR (REP-PCR) and Multilocus Sequence Typing (MLST). They were also studied for phenotypic and molecular resistance to a quaternary ammonium compound (QAC) disinfectant. RESULTS: All 19 isolates contained both bla VIM-2 and bla KPC-2 genes, and the bla KPC-2 gene was associated with Tn4401b. All isolates were phenotypically sensitive to QACs and contained qacDeltaE and addA2 genes typical of class 1 integrons. Analysis by REP-PCR and MLST showed that all isolates had identical profiles characteristic of sequence type ST833. CONCLUSION: All 19 strains are bla VIM-2 and bla KPC-2-producing ST833 K. pneumoniae sensitive to QACs. This analysis may help to understand the routes of dissemination and confirms that QAC disinfectants can be used to help control their spread. PMID- 27770798 TI - Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats. AB - BACKGROUND: Saffron is the dried stigma of Crocus sativus L. flower which commonly used as a natural remedy to enhance health and even fights disease in the Middle-East and Southeast Asian countries. METHODS: This study was aimed to investigate protective effect of saffron extract and crocin in fatty liver tissue of high-fat diet induced obese rats. A total of 36 healthy male Sprague Dawley rats were divided into six groups. Two groups served as controls, a normal diet (ND) and a high-fat diet (HFD). The other four groups were each supplemented with saffron extract and crocin at concentrations of 40 and 80 mg/kg body weight/day for 8 weeks. All groups except ND were fed with HFD until end of the study. At baseline, blood sample was collected for determination of levels of hepatic marker enzymes, including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatise and albumin. Liver sample was collected, weighed and stained with haematoxylin and eosin for further histopathological examination. RESULTS: Saffron extract and crocin at concentrations of 40 and 80 mg/kg had dose dependently alleviated levels of liver enzymes and histopathological changes in diet-induced obese rat model compared to control (HFD group). CONCLUSION: This study suggested that saffron extract and crocin supplements have hepatoprotective effect against non-alcoholic fatty liver disease and HFD-induced liver damage. PMID- 27770800 TI - Does cognitive/physical screening in an outpatient setting predict institutionalization after hip fracture? AB - BACKGROUND: Institutionalization after hip fracture is a socio-economical burden. We examined the predictive value of Instrumental Activities of Daily Living (IADL) and Mini Mental State Examination (MMSE) for institutionalization after hip fracture to identify patients at risk for institutionalization. METHODS: Fragility hip fracture patients >=65 years of age (n = 584) were comprehensively examined at a geriatric outpatient clinic 4 to 6 months after surgery and followed 1 year postoperatively. A telephone interview with a structured inquiry was performed at 1, 4, and 12 months after hip fracture. RESULTS: Age-adjusted univariate logistic regression analysis revealed that IADL and MMSE scores measured at the outpatient clinic were significantly associated with living arrangements 1 year after hip fracture. Multivariate logistic regression analysis established that institutionalization 1 year after hip fracture was significantly predicted by institutionalization at 4 months (odds ratio [OR] 16.26, 95 % confidence interval [CI] 7.37-35.86), IADL <5 (OR 12.96, 95 % CI 1.62-103.9), and MMSE <20 (OR 4.19, 95 % CI 1.82-9.66). A cut-off value of 5 was established for IADL with 100 % (95 % CI 96 %-100 %) sensitivity and 38 % (95 % CI 33 %-43 %) specificity and for MMSE, a cut-off value of 20 had 83 % (95 % CI 74 %-91 %) sensitivity and 65 % (95 % CI 60 %-70 %) specificity for institutionalization. During the time period from 4 to 12 months, 66 (11 %) patients changed living arrangements, and 36 (55 %) of these patients required more supportive accommodations. CONCLUSION: IADL and MMSE scores obtained 4 to 6 months after hospital discharge may be applicable for predicting institutionalization among fragility hip fracture patients >=65 years of age at 1 year after hip fracture. An IADL score of >=5 predicted the ability to remain in the community. Changes in living arrangements also often occur after 4 months. PMID- 27770799 TI - Correction of metabolic acidosis improves insulin resistance in chronic kidney disease. AB - BACKGROUND: Correction of metabolic acidosis (MA) with nutritional therapy or bicarbonate administration is widely used in chronic kidney disease (CKD) patients. However, it is unknown whether these interventions reduce insulin resistance (IR) in diabetic patients with CKD. We sought to evaluate the effect of MA correction on endogenous insulin action in diabetic type 2 (DM2) CKD patients. METHODS: A total of 145 CKD subjects (83 men e 62 women) with DM2 treated with oral antidiabetic drugs were included in the study and followed up to 1 year. All patients were randomly assigned 1:1 to either open-label (A) oral bicarbonate to achieve serum bicarbonate levels of 24-28 mmol/L (treatment group) or (B) no treatment (control group). The Homeostatic model assessment (HOMA) index was used to evaluate IR at study inception and conclusion. Parametric and non-parametric tests as well as linear regression were used. RESULTS: At baseline no differences in demographic and clinical characteristics between the two groups was observed. Average dose of bicarbonate in the treatment group was 0.7 +/- 0.2 mmol/kg. Treated patients showed a better metabolic control as confirmed by lower insulin levels (13.4 +/- 5.2 vs 19.9 +/- 6.3; for treated and control subjects respectively; p < 0.001), Homa-IR (5.9[5.0-7.0] vs 6.3[5.3-8.2]; p = 0.01) and need for oral antidiabetic drugs. The serum bicarbonate and HOMA-IR relationship was non-linear and the largest HOMA-IR reduction was noted for serum bicarbonate levels between 24 and 28 mmol/l. Adjustment for confounders, suggests that serum bicarbonate rather than treatment drives the effect on HOMA-IR. CONCLUSIONS: Serum bicarbonate is related to IR and the largest HOMA-IR reduction is noted for serum bicarbonate between 24 and 28 mmol/l. Treatment with bicarbonate influences IR. However, changes in serum bicarbonate explains the effect of treatment on HOMA index. Future efforts are required to validate these results in diabetic and non-diabetic CKD patients. TRIAL REGISTRATION: The trial was registered at www.clinicaltrial.gov (Use of Bicarbonate in Chronic Renal Insufficiency (UBI) study - NCT01640119 ). PMID- 27770801 TI - Balance chiropractic therapy for cervical spondylotic radiculopathy: study protocol for a randomized controlled trial. AB - BACKGROUND: Cervical spondylosis is a very common disorder and cervical spondylotic radiculopathy (CSR) is the most common form of spinal degenerative disease. Its clinical manifestations focus on pain and numbness of the neck and arm as well as restricted movement of the neck, which greatly affect the patient's life and work. The orthopedic of traditional Chinese medicine (TCM) theory holds that the basic pathologic change in spinal degenerative diseases is the imbalance between the dynamic system and the static system of the cervical spine. Based on this theory, some Chinese physicians have developed a balance chiropractic therapy (BCT) to treat CSR, which has been clinically examined for more than 50 years to effectively cure CSR. The purpose of this study is to evaluate the therapeutic effect and safety of BCT on CSR and to investigate the mechanism by which the efficacy is achieved. METHODS/DESIGN: We propose a multicenter, parallel-group, randomized controlled trial to evaluate the efficacy and safety of BCT for CSR. Participants aged 18 to 65 years, who are in conformity with the diagnostic criteria of CSR and whose pain score on a Visual Analog Scale (VAS) is more than 4 points and less than 8 points, will be included and randomly allocated into two groups: a treatment group and a control group. Participants in the treatment group will be treated with BCT, while the control group will receive traction therapy (TT). The primary outcome is pain severity (measured with a VAS). Secondary outcomes will include cervical curvature (measured by the Borden Index), a composite of functional status (measured by the Neck Disability Index, NDI), patient health status (evaluated by the SF-36 health survey) and adverse events (AEs) as reported in the trial. DISCUSSION: If BCT can relieve neck pain without adverse effects, it may be a novel strategy for the treatment of CSR. Furthermore, the mechanism of BCT for CSR will be partially elucidated. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT02705131 . Registered on 9 March 2016. PMID- 27770802 TI - The emerging role of apolipoprotein C-III: beyond effects on triglyceride metabolism. AB - Apolipoprotein C-III has been referred to as an important participant in the metabolism of triglyceride-rich lipoproteins, leading to hypertriglyceridemia and thereafter cardiovascular disease. Accumulating evidence indicates that apolipoprotein C-III is a multifaceted protein which not only regulates triglyceride metabolism, but also participates in the atherosclerotic lesion formation and several other pathological processes involved in atherosclerosis. Based on data from experiments and clinical trials, some novel therapies such as antisense technology emerge. PMID- 27770803 TI - The response of mute swans (Cygnus olor, Gm. 1789) to vaccination against avian influenza with an inactivated H5N2 vaccine. AB - BACKGROUND: Recent epidemics of highly pathogenic avian influenza (HPAI) produced an unprecedented number of cases in mute swans (Cygnus olor) in European countries, which indicates that these birds are very sensitive to the H5N1 virus. The HPAI outbreaks stirred a debate on the controversial stamping-out policy in populations of protected bird species. After preventive vaccination had been approved in the European Union, several countries have introduced vaccination schemes to protect poultry, captive wild birds or exotic birds in zoos against HPAI. The aim of this study was to investigate the immune response of wild mute swans to immunization with an inactivated AI H5N2 vaccine approved for use in poultry. The serological responses of mute swans were assessed by comparison with racing pigeons (Columba livia), a species which is characterized by different susceptibility to infection with the H5N1 HPAI virus and plays a questionable role in the ecology of influenza (H5N1) viruses. RESULTS: Swans were vaccinated once or twice at an interval of 4 weeks. The humoral immune response was evaluated by hemagglutination inhibition (HI) and NP-ELISA. The lymphocyte blast transformation test was used to determine the cell-mediated immune response. Higher values of the geometric mean titer (GMT) and 100 % seroconversion (HI >=32) were noted in double vaccinated swans (1448.2) than in single vaccinated swans (128.0) or in double vaccinated pigeons (215.3). Significant differences in HI titers were observed between swans and pigeons, but no variations in ELISA scores were noted after the booster dose. Immunization of swans had no effect on the proliferative activity of lymphocytes. CONCLUSIONS: The inactivated H5N2 vaccine was safe and immunogenic for mute swans and pigeons. Vaccination may have practical implications for swans kept in zoos, wildlife parks or rehabilitation centers. However, challenge studies are needed to prove the efficacy of the H5N2 AI vaccine. PMID- 27770804 TI - Proteases and oxidant stress control organic dust induction of inflammatory gene expression in lung epithelial cells. AB - BACKGROUND: Persistant inflammatory responses to infectious agents and other components in organic dust underlie lung injury and development of respiratory diseases. Organic dust components responsible for eliciting inflammation and the mechanisms by which they cause lung inflammation are not fully understood. We studied the mechanisms by which protease activities in poultry dust extracts and intracellular oxidant stress induce inflammatory gene expression in A549 and Beas2B lung epithelial cells. METHODS: The effects of dust extracts on inflammatory gene expression were analyzed by quantitative polymerase chain reaction (qPCR), enzyme linked immunosorbent (ELISA) and western blot assays. Oxidant stress was probed by dihydroethidium (DHE) labeling, and immunostaining for 4-hydroxynonenal (4-HNE). Effects on interleukin-8 (IL-8) promoter regulation were determined by transient transfection assay. RESULTS: Dust extracts contained trypsin and elastase activities, and activated protease activated receptor (PAR) 1 and -2. Serine protease inhibitors and PAR-1 or PAR-2 knockdown suppressed inflammatory gene induction. Dust extract induction of IL-8 gene expression was associated with increased DHE-fluorescence and 4-HNE staining, and antioxidants suppressed inflammatory gene induction. Protease inhibitors and antioxidants suppressed protein kinase C and NF-kappaB activation and induction of IL-8 promoter activity in cells exposed to dust extract. CONCLUSIONS: Our studies demonstrate that proteases and intracellular oxidants control organic dust induction of inflammatory gene expression in lung epithelial cells. Targeting proteases and oxidant stress may serve as novel approaches for the treatment of organic dust induced lung diseases. This is the first report on the involvement of oxidant stress in the induction of inflammatory gene expression by organic dust. PMID- 27770806 TI - Rapid growth of mitotically active cellular fibroma of the ovary: a case report and review of the literature. AB - BACKGROUND: Mitotically active cellular fibroma (MACF) of the ovary, characterized by relatively high mitotic activity without severe atypia, represents a relatively new disease entity. MACF is categorized as a benign ovarian tumor. However, due to a limited number of case reports, its clinical and pathological features and optimum management remains largely undetermined. Herein, we report on a rare case of MACF that grew rapidly in size and was diagnosed on detailed pathological examination. CASE PRESENTATION: A 44-year-old Japanese woman, who detected a myoma-like lesion 1-year earlier, was referred to our hospital when the follow-up examination demonstrated that the mass had increased in size. Magnetic resonance imaging revealed a T1 isointense and T2 hyperintense tumor (11 cm in diameter) in the right pelvic cavity. Laparoscopy confirmed the presence of a right ovarian tumor and laparoscopic right adnexectomy was performed. The tumor cells consisted of dense cellular proliferations of spindle fibroblast-like cells without significant cytological atypia. The mitotic activity index was estimated at >15 mitotic figures per 10 high-power fields. Reticulin staining and FOXL2 mutation analysis excluded the possibility of an adult granulosa cell tumor, and the patient was diagnosed with a MACF of the ovary. CONCLUSIONS: To the best of our knowledge, we are the first to report on a case of rapid growth of a MACF of the ovary during follow-up. When an increase in the size of a solid ovarian mass is detected, a MACF should be considered as a differential diagnosis. PMID- 27770805 TI - A disease spectrum for ITPA variation: advances in biochemical and clinical research. AB - Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5'-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA related disease. Recent biochemical studies have aimed to provide rationale for clinical observations, better understand substrate selectivity and provide a platform for modulation of ITPase activity. PMID- 27770807 TI - Barriers and enablers to guideline implementation strategies to improve obstetric care practice in low- and middle-income countries: a systematic review of qualitative evidence. AB - BACKGROUND: Maternal mortality remains a major international health problem in low- and middle-income countries (LMIC), and most could have been prevented by quality improvement interventions already demonstrated to be effective, such as clinical guideline implementation strategies. The aim of this systematic review was to synthesise qualitative evidence on guideline implementation strategies to improve obstetric care practice in LMIC in order to identify barriers and enablers to their successful implementation. METHODS: We searched MEDLINE and CINAHL databases for articles reporting research findings on barriers and enablers to guideline implementation strategies in obstetric care practice in LMIC. We conducted a "best fit" framework synthesis of the included studies. We used an organisational "stages of change" model as our a priori framework for the synthesis. RESULTS: Nine studies were included: all were based in Sub-Saharan Africa and in hospital health care facilities. The majority of studies (seven) evaluated one particular guideline implementation strategy: clinical audit and feedback (both criterion-based audit and maternal death reviews), and a minority (two) evaluated educational interventions. A range of barriers and enablers to successful guideline implementation was identified. A key finding of the framework synthesis was that "high" and "low" intrinsic health care professional motivation are overall enablers and barriers, respectively, of successful guideline implementation. We developed a modified "stages of change" model to take account of these findings. CONCLUSION: We have identified a number of quality improvement processes that are amenable to change at limited or no additional cost, although some identified barriers may be difficult to address without increased resources. We note the pathways to implementation may be complex and require further research to develop our understanding of individual and organisational behaviours and motivation in LMIC settings. TRIAL REGISTRATION: PROSPERO CRD42015016062. PMID- 27770808 TI - p14 expression differences in ovarian benign, borderline and malignant epithelial tumors. AB - BACKGROUND: Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian epithelial carcinogenesis, p16 and p53 show higher immunohistochemical staining frequencies in malignant tumors and are associated with poor prognoses. p14 was only analyzed in carcinomas, with conflicting results. There are no reports on its expression in benign and borderline tumors. This study aims to determine p14, p16 and p53 expression frequencies in ovarian benign, borderline and malignant tumors and their associations with clinical parameters. METHODS: A cross-sectional study utilizing immunohistochemistry was performed on paraffin-embedded ovarian epithelial tumor samples. Clinical data were collected from medical records. Fisher's exact test and the Bonferroni correction were performed for frequency associations. Survival comparisons utilized Kaplan-Meier and log rank testing. Associations were considered significant when p < 0.05. RESULTS: p14 absent expression was associated with malignant tumors (60 % positive) (p = 0.000), while 93 % and 94 % of benign and borderline tumors, respectively, were positive. p16 was positive in 94.6 % of carcinomas, 75 % of borderline and 45.7 % of benign tumors (p = 0.000). p53 negative staining was associated with benign tumors (2.9 % positive) (p = 0.016) but no difference was observed between borderline (16.7 %) and malignant tumors (29.7 %) (p = 0.560). No associations were found between expression rates, disease-free survival times or clinical variables. Carcinoma subtypes showed no difference in expression. CONCLUSIONS: This is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate that p14 abnormalities occur later in carcinogenesis. p16 and p53 frequencies increase from benign to borderline and malignant tumors, similarly to previous reports, possibly reflecting the accumulation of inactive mutant protein. The small sample size may have prevented statistically significant survival analyses and clinical correlations. Future studies should investigate genetic abnormalities in p14 coding sequences and include all types of ovarian epithelial tumors. Bigger sample sizes may be needed for significant associations. PMID- 27770810 TI - Systematic assessment of HER2/neu in gynecologic neoplasms, an institutional experience. AB - BACKGROUND: HER2/neu overexpression and/or amplification has been widely studied in a number of solid tumors, primarily in the breast. In gynecologic neoplasms, determination of HER2/neu status has not been well studied as a predictive biomarker in anti-HER2/neu treatment. METHODS: We systematically evaluated the HER2/neu reactions by immunohistochemistry and fluorescent in situ hybridization in malignant gynecologic neoplasms as experienced in our institution. RESULTS: The HER2/neu overexpression or amplification occurred in 8 % of the cancers of the gynecological organs in our series. Majority of the HER2/neu overexpression and/or amplification occurred in clear cell (27 %) and serous (11 %) carcinomas. HER2/neu positivity was also seen in undifferentiated as well as in mixed clear cell and serous carcinomas. Discordant IHC and FISH results (positive by FISH but not IHC) was seen in 2 cases. Majority of the HER2/neu overexpression and/or amplification occurs in the endometrium rather than the ovary. Heterogeneity of the HER2/neu by IHC staining was in < 2 % of the tumors in our series. CONCLUSIONS: We recommend the HER2/neu studies on Mullerian carcinomas of clear cell, serous, and undifferentiated types, particularly when they arise in the endometrium. Since there are some discordant IHC/FISH results, we also propose performing the HER2/neu testing by FISH when the IHC score is less than 3 + . PMID- 27770809 TI - Is low-dose amitriptyline effective in the management of chronic low back pain? Study protocol for a randomised controlled trial. AB - BACKGROUND: Low back pain is a major clinical and public health problem, with limited evidence-based treatments. Low-dose antidepressants are commonly used to treat pain in chronic low back pain. However, their efficacy is unproven. The aim of this pragmatic, double-blind, randomised, placebo-controlled trial is to determine whether low-dose amitriptyline (an antidepressant) is more effective than placebo in reducing pain in individuals with chronic low back pain. METHODS/DESIGN: One hundred and fifty individuals with chronic low back pain will be recruited through hospital and private medical and allied health clinics, advertising in local media and posting of flyers in community locations. They will be randomly allocated to receive either low-dose amitriptyline (25 mg) or an active placebo (benztropine mesylate, 1 mg) for 6 months. The primary outcome measure of pain intensity will be assessed at baseline, 3 and 6 months using validated questionnaires. Secondary measures of self-reported low back disability, work absence and hindrance in the performance of paid/unpaid work will also be examined. Intention-to-treat analyses will be performed. DISCUSSION: This pragmatic, double-blind, randomised, placebo-controlled trial will provide evidence regarding the effectiveness of low-dose antidepressants compared with placebo in reducing pain, disability, work absenteeism and hindrance in work performance in individuals with chronic low back pain. This trial has major public health and clinical importance as it has the potential to provide an effective approach to the management of chronic low back pain. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12612000131853 ; registered on 30 January 2012. PMID- 27770811 TI - Long range personalized cancer treatment strategies incorporating evolutionary dynamics. AB - BACKGROUND: Current cancer precision medicine strategies match therapies to static consensus molecular properties of an individual's cancer, thus determining the next therapeutic maneuver. These strategies typically maintain a constant treatment while the cancer is not worsening. However, cancers feature complicated sub-clonal structure and dynamic evolution. We have recently shown, in a comprehensive simulation of two non-cross resistant therapies across a broad parameter space representing realistic tumors, that substantial improvement in cure rates and median survival can be obtained utilizing dynamic precision medicine strategies. These dynamic strategies explicitly consider intratumoral heterogeneity and evolutionary dynamics, including predicted future drug resistance states, and reevaluate optimal therapy every 45 days. However, the optimization is performed in single 45 day steps ("single-step optimization"). RESULTS: Herein we evaluate analogous strategies that think multiple therapeutic maneuvers ahead, considering potential outcomes at 5 steps ahead ("multi-step optimization") or 40 steps ahead ("adaptive long term optimization (ALTO)") when recommending the optimal therapy in each 45 day block, in simulations involving both 2 and 3 non-cross resistant therapies. We also evaluate an ALTO approach for situations where simultaneous combination therapy is not feasible ("Adaptive long term optimization: serial monotherapy only (ALTO-SMO)"). Simulations utilize populations of 764,000 and 1,700,000 virtual patients for 2 and 3 drug cases, respectively. Each virtual patient represents a unique clinical presentation including sizes of major and minor tumor subclones, growth rates, evolution rates, and drug sensitivities. While multi-step optimization and ALTO provide no significant average survival benefit, cure rates are significantly increased by ALTO. Furthermore, in the subset of individual virtual patients demonstrating clinically significant difference in outcome between approaches, by far the majority show an advantage of multi-step or ALTO over single-step optimization. ALTO-SMO delivers cure rates superior or equal to those of single- or multi-step optimization, in 2 and 3 drug cases respectively. CONCLUSION: In selected virtual patients incurable by dynamic precision medicine using single-step optimization, analogous strategies that "think ahead" can deliver long-term survival and cure without any disadvantage for non-responders. When therapies require dose reduction in combination (due to toxicity), optimal strategies feature complex patterns involving rapidly interleaved pulses of combinations and high dose monotherapy. REVIEWERS: This article was reviewed by Wendy Cornell, Marek Kimmel, and Andrzej Swierniak. Wendy Cornell and Andrzej Swierniak are external reviewers (not members of the Biology Direct editorial board). Andrzej Swierniak was nominated by Marek Kimmel. PMID- 27770812 TI - Combining laboratory and mathematical models to infer mechanisms underlying kinetic changes in macrophage susceptibility to an RNA virus. AB - BACKGROUND: Macrophages are essential to innate immunity against many pathogens, but some pathogens also target macrophages as routes to infection. The Porcine Reproductive and Respiratory Syndrome virus (PRRSV) is an RNA virus that infects porcine alveolar macrophages (PAMs) causing devastating impact on global pig production. Identifying the cellular mechanisms that mediate PAM susceptibility to the virus is crucial for developing effective interventions. Previous evidence suggests that the scavenger receptor CD163 is essential for productive infection of PAMs with PRRSV. Here we use an integrative in-vitro-in-silico modelling approach to determine whether and how PAM susceptibility to PRRSV changes over time, to assess the role of CD163 expression on such changes, and to infer other potential causative mechanisms altering cell susceptibility. RESULTS: Our in vitro experiment showed that PAM susceptibility to PRRSV changed considerably over incubation time. Moreover, an increasing proportion of PAMs apparently lacking CD163 were found susceptible to PRRSV at the later incubation stages, thus conflicting with current understanding that CD163 is essential for productive infection of PAMs with PRRSV. We developed process based dynamic mathematical models and fitted these to the data to assess alternative hypotheses regarding potential underlying mechanisms for the observed susceptibility and biomarker trends. The models informed by our data support the hypothesis that although CD163 may have enhanced cell susceptibility, it was not essential for productive infection in our study. Instead the models promote the existence of a reversible cellular state, such as macrophage polarization, mediated in a density dependent manner by autocrine factors, to be responsible for the observed kinetics in cell susceptibility. CONCLUSIONS: Our dynamic model-inference approach provides strong support that PAM susceptibility to the PRRS virus is transient, reversible and can be mediated by compounds produced by the target cells themselves, and that these can render PAMs lacking the CD163 receptor susceptible to PRRSV. The results have implications for the development of therapeutics aiming to boost target cell resistance and prompt future investigation of dynamic changes in macrophage susceptibility to PRRSV and other viruses. PMID- 27770813 TI - Childhood-onset granulomatosis with polyangiitis and microscopic polyangiitis: systematic review and meta-analysis. AB - BACKGROUND: The data from cohorts of childhood-onset granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) remain scarce and heterogeneous. We aimed to analyse the features at presentation, therapeutic approaches and the disease course of these rare diseases. METHODS: Electronic searches of Medline and the Cochrane Central Register of Controlled trials database were conducted. We also checked the reference lists of the studies included and other systematic reviews, to identify additional reports. We included all cohorts, cross-sectional studies or registries reporting features at presentation or outcomes in patients with a diagnosis of childhood-onset GPA or MPA (age <18 years). The pooled prevalence of clinical manifestations at presentation, ANCA and induction therapies for GPA and MPA was calculated. RESULTS: We reviewed 570 full texts and identified 14 studies on GPA and 8 on MPA. Childhood-onset GPA and MPA occurred predominantly in female subjects during adolescence. For GPA, ear-nose-throat (ENT) disease (pooled prevalence 82 % [95 % CI 78-87]), constitutional symptoms (73 % [95 % CI 55-88]), renal (65 % [95 % CI 49-79]), and lower respiratory tract (61 % [95 % CI 48-74]) manifestations were the most frequently reported at presentation. Renal disease was a hallmark of MPA (94 % [95 % CI 89-97]). ANCA were detected in >90 % of children with GPA or MPA. Combined corticosteroids and cyclophosphamide was the most frequently used first remission-inducing treatment for GPA (76 % [95 % CI 69-82]) and MPA (62 % [95 % CI 20-96]). Relapses occurred more frequently in GPA (67-100 %) than in MPA (25 50 %). The leading causes of death were the disease itself, and infections. CONCLUSIONS: Childhood-onset MPA and GPA remain severe diseases with frequent relapses and a high cumulative morbidity. Survival and disease-free survival need to be improved. PMID- 27770814 TI - External validation of a multivariable claims-based rule for predicting in hospital mortality and 30-day post-pulmonary embolism complications. AB - BACKGROUND: Low-risk pulmonary embolism (PE) patients may be candidates for outpatient treatment or abbreviated hospital stay. There is a need for a claims based prediction rule that payers/hospitals can use to risk stratify PE patients. We sought to validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule for in-hospital and 30-day outcomes. METHODS: We used the Optum Research Database from 1/2008-3/2015 and included adults hospitalized for PE (415.1x in the primary position or secondary position when accompanied by a primary code for a PE complication) and having continuous medical and prescription coverage for >=6-months prior and 3-months post inclusion or until death. In-hospital and 30-day mortality and 30-day complications (recurrent venous thromboembolism, rehospitalization or death) were assessed and prognostic accuracies of IMPACT with 95 % confidence intervals (CIs) were calculated. RESULTS: In total, 47,531 PE patients were included. In-hospital and 30-day mortality occurred in 7.9 and 9.4 % of patients and 20.8 % experienced any complication within 30-days. Of the 19.5 % of patients classified as low-risk by IMPACT, 2.0 % died in-hospital, resulting in a sensitivity and specificity of 95.2 % (95 % CI, 94.4-95.8) and 20.7 % (95 % CI, 20.4-21.1). Only 1 additional low-risk patient died within 30-days of admission and 12.2 % experienced a complication, translating into a sensitivity and specificity of 95.9 % (95 % CI, 95.3-96.5) and 21.1 % (95 % CI, 20.7-21.5) for mortality and 88.5 % (95 % CI, 87.9-89.2) and 21.6 % (95 % CI, 21.2-22.0) for any complication. CONCLUSION: IMPACT had acceptable sensitivity for predicting in-hospital and 30-day mortality or complications and may be valuable for retrospective risk stratification of PE patients. PMID- 27770816 TI - Apparent diffusion coefficient histogram shape analysis for monitoring early response in patients with advanced cervical cancers undergoing concurrent chemo radiotherapy. AB - BACKGROUND: To explore the role of apparent diffusion coefficient (ADC) histogram shape related parameters in early assessment of treatment response during the concurrent chemo-radiotherapy (CCRT) course of advanced cervical cancers. METHODS: This prospective study was approved by the local ethics committee and informed consent was obtained from all patients. Thirty-two patients with advanced cervical squamous cell carcinomas underwent diffusion weighted magnetic resonance imaging (b values, 0 and 800 s/mm2) before CCRT, at the end of 2nd and 4th week during CCRT and immediately after CCRT completion. Whole lesion ADC histogram analysis generated several histogram shape related parameters including skewness, kurtosis, s-sDav, width, standard deviation, as well as first-order entropy and second-order entropies. The averaged ADC histograms of 32 patients were generated to visually observe dynamic changes of the histogram shape following CCRT. RESULTS: All parameters except width and standard deviation showed significant changes during CCRT (all P < 0.05), and their variation trends fell into four different patterns. Skewness and kurtosis both showed high early decline rate (43.10 %, 48.29 %) at the end of 2nd week of CCRT. All entropies kept decreasing significantly since 2 weeks after CCRT initiated. The shape of averaged ADC histogram also changed obviously following CCRT. CONCLUSIONS: ADC histogram shape analysis held the potential in monitoring early tumor response in patients with advanced cervical cancers undergoing CCRT. PMID- 27770815 TI - Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice. AB - BACKGROUND: The endometrial regenerative cell (ERC) is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4)-induced acute liver injury (ALI). METHODS: An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse) into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. RESULTS: ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G) was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA) was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs) was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26 labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1beta, IL-6, and TNF alpha but higher level of IL-10 in both serum and liver. CONCLUSIONS: Human ERCs protect the liver from acute injury in mice through hepatocyte proliferation promotion, as well as through anti-inflammatory and immunoregulatory effects. PMID- 27770817 TI - Human cytomegalovirus reactivation from latency: validation of a "switch" model in vitro. AB - BACKGROUND: Human cytomegalovirus (HCMV) is an opportunistic pathogen leading to severe and even fatal diseases in 'at-risk' categories of individuals upon primary infection or the symptomatic reactivation of the endogenous virus. The mechanisms which make the virus able to reactivate from latency are still matter of intense study. However, the very low number of peripheral blood monocytes (an important latent virus reservoir) harbouring HCMV DNA makes it very difficult to obtain adequate viral quantities to use in such studies. Thus, the aim of the present study was to demonstrate the usefulness of human THP-1 monocytes, mostly employed as HCMV latent or lytic infection system, as a reactivation model. METHODS: THP-1 monocytes were infected with HCMV TB40E strain (latency model) at multiplicities of infection (MOI) of 0.5, 0.25 or 0.125. After infection, THP-1 aliquots were differentiated into macrophages (reactivation model). Infections were carried out for 30 h, 4, 6 and 7 days. Viral DNA evaluation was performed with viable and UV-inactivated virus by q-Real-Time PCR. RNA extracted from latency and reactivation models at 7 days post-infection (p.i.) was subjected to RT-PCR to analyse viral latency and lytic transcripts. To perform viral progeny analysis and titration, the culture medium from infected THP-1 latency and reactivation models (7 days p.i.) was used to infect human fibroblasts; it was also checked for the presence of exosomes. For viral progeny analysis experiments, the Towne strain was also used. RESULTS: Our results showed that, while comparable TB40E DNA amounts were present in both latent and reactivation models at 30 h p.i., gradually increased quantities of viral DNA were only evident in the latter model at 4, 6, 7 days p.i.. The completion of the lytic cycle upon reactivation was also proved by the presence of HCMV lytic transcripts and an infectious viral yield at 7 days p.i. CONCLUSIONS: Our data demonstrate the effectiveness of THP-1 cells as a "switch" model for studying the mechanisms that regulate HCMV reactivation from latency. This system is able to provide adequate quantities of cells harbouring latent/reactivated virus, thereby overcoming the intrinsic difficulties connected to the ex vivo system. PMID- 27770819 TI - Implementing school nursing strategies to reduce LGBTQ adolescent suicide: a randomized cluster trial study protocol. AB - BACKGROUND: Reducing youth suicide in the United States (U.S.) is a national public health priority, and lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) youth are at elevated risk. The Centers for Disease Control and Prevention (CDC) endorses six evidence-based (EB) strategies that center on meeting the needs of LGBTQ youth in schools; however, fewer than 6 % of U.S. schools implement all of them. The proposed intervention model, "RLAS" (Implementing School Nursing Strategies to Reduce LGBTQ Adolescent Suicide), builds on the Exploration, Preparation, Implementation, and Sustainment (EPIS) conceptual framework and the Dynamic Adaptation Process (DAP) to implement EB strategies in U.S. high schools. The DAP accounts for the multilevel context of school settings and uses Implementation Resource Teams (IRTs) to facilitate appropriate expertise, advise on acceptable adaptations, and provide data feedback to make schools implementation ready and prepared to sustain changes. METHODS/DESIGN: Mixed methods will be used to examine individual, school, and community factors influencing both implementation process and youth outcomes. A cluster randomized controlled trial will assess whether LGBTQ students and their peers in RLAS intervention schools (n = 20) report reductions in suicidality, depression, substance use, bullying, and truancy related to safety concerns compared to those in usual care schools (n = 20). Implementation progress and fidelity for each EB strategy in RLAS intervention schools will be examined using a modified version of the Stages of Implementation Completion checklist. During the implementation and sustainment phases, annual focus groups will be conducted with the 20 IRTs to document their experiences identifying and advancing adaptation supports to facilitate use of EB strategies and their perceptions of the DAP. DISCUSSION: The DAP represents a data-informed, collaborative, multiple stakeholder approach to progress from exploration to sustainment and obtain fidelity during the implementation of EB strategies in school settings. This study is designed to address the real-world implications of enabling the use of EB strategies by school nurses with the goal of decreasing suicide and youth risk behaviors among LGBTQ youth. Through its participatory processes to refine and sustain EB strategies in high schools, the RLAS represents a novel contribution to implementation science. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02875535. PMID- 27770818 TI - Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling. AB - BACKGROUND: Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues. RESULTS: Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice. CONCLUSION: We infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery. PMID- 27770820 TI - A randomised controlled trial of the clinical and cost-effectiveness of a contingency management intervention compared to treatment as usual for reduction of cannabis use and of relapse in early psychosis (CIRCLE): a study protocol for a randomised controlled trial. AB - BACKGROUND: Around 35-45 % of people in contact with services for a first episode of psychosis are using cannabis. Cannabis use is associated with delays in remission, poorer clinical outcomes, significant increases in the risk of relapse, and lower engagement in work or education. While there is a clear need for effective interventions, so far only very limited benefits have been achieved from psychological interventions. Contingency management (CM) is a behavioural intervention in which specified desired behavioural change is reinforced through financial rewards. CM is now recognised to have a substantial evidence base in some contexts and its adoption in the UK is advocated by the National Institute for Health and Care Excellence (NICE) guidance as a treatment for substance or alcohol misuse. However, there is currently little published data testing its effectiveness for reducing cannabis use in early psychosis. METHODS: CIRCLE is a two-arm, rater-blinded randomised controlled trial (RCT) investigating the clinical and cost-effectiveness of a CM intervention for reducing cannabis use among young people receiving treatment from UK Early Intervention in Psychosis (EIP) services. EIP service users (n = 544) with a recent history of cannabis use will be recruited. The experimental group will receive 12 once-weekly CM sessions, and a voucher reward if urinalysis shows that they have not used cannabis in the previous week. Both the experimental and the control groups will be offered an Optimised Treatment as Usual (OTAU) psychoeducational package targeting cannabis use. Assessment interviews will be performed at consent, at 3 months, and at 18 months. The primary outcome is time to relapse, defined as admission to an acute mental health service. Secondary outcomes include proportion of cannabis-free urine samples during the intervention period, severity of positive psychotic symptoms, quality-adjusted life years, and engagement in work or education. DISCUSSION: CIRCLE is a RCT of CM for cannabis use in young people with a recent history of psychosis (EIP service users) and recent cannabis use. It is designed to investigate whether the intervention is a clinically and cost-effective treatment for cannabis use. It is intended to inform future treatment delivery, particularly in EIP settings. TRIAL REGISTRATION: ISRCTN33576045 : doi 10.1186/ISRCTN33576045 , registered on 28 November 2011. PMID- 27770821 TI - The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells. AB - BACKGROUND: Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-kappaB signaling pathway. Synthetic structural modification yielded the derivative 3 ((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms. METHODS: U87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFkappaB pathway by western blotting technique. RESULTS: Here, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFkappaB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFkappaB pathway. CONCLUSIONS: RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFkappaB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets. PMID- 27770822 TI - ApCPEB4, a non-prion domain containing homolog of ApCPEB, is involved in the initiation of long-term facilitation. AB - Two pharmacologically distinct types of local protein synthesis are required for synapse- specific long-term synaptic facilitation (LTF) in Aplysia: one for initiation and the other for maintenance. ApCPEB, a rapamycin sensitive prion like molecule regulates a form of local protein synthesis that is specifically required for the maintenance of the LTF. However, the molecular component of the local protein synthesis that is required for the initiation of LTF and that is sensitive to emetine is not known. Here, we identify a homolog of ApCPEB responsible for the initiation of LTF. ApCPEB4 which we have named after its mammalian CPEB4-like homolog lacks a prion-like domain, is responsive to 5 hydroxytryptamine, and is translated (but not transcribed) in an emetine sensitive, rapamycin-insensitive, and PKA-dependent manner. The ApCPEB4 binds to different target RNAs than does ApCPEB. Knock-down of ApCPEB4 blocked the induction of LTF, whereas overexpression of ApCPEB4 reduces the threshold of the formation of LTF. Thus, our findings suggest that the two different forms of CPEBs play distinct roles in LTF; ApCPEB is required for maintenance of LTF, whereas the ApCPEB4, which lacks a prion-like domain, is required for the initiation of LTF. PMID- 27770824 TI - Childhood hospitalisation with infections and later development of ankylosing spondylitis: a national case-control study. AB - BACKGROUND: The role of environmental exposures in the pathogenesis of ankylosing spondylitis (AS) remains unclear. In particular, two types of exposures have been suspected to play a role: mechanical stress and infections. The objective of this case-control study was to determine if childhood infections are associated with later development of AS. METHODS: The cases with AS were identified through the Swedish national outpatient specialised-care register, based on having been given at least one AS diagnosis in the register between 2001 and 2010. Five controls per case were identified in the Swedish population register, matched at the time point of the index case's first spondyloarthritis diagnosis on sex, birth year, and county. All cases/controls matched prior to the age of 17 years were excluded, as well as all cases/controls given a diagnosis of reactive arthritis or juvenile arthritis at any time point, or any other diagnosis of a rheumatic disease, psoriasis, iridocyclitis, or inflammatory bowel disease before the time point of matching. All events of hospitalisation with an infection before the age of 17 years were retrieved from the register, and categorised according to the focus of the infection. Odds ratios (ORs) and confidence intervals (CIs) were determined through conditional logistic regression analyses. RESULTS: Of the 2453 cases with AS and 10,257 controls, 17.4 % of the cases and 16.3 % of the controls had been hospitalised with an infection before the age of 17 years (OR 1.08, 95 % CI 0.96-1.22). Appendicitis (1.5 % cases; 2.5 % controls; OR 0.59, 95 % CI 0.41 0.83), respiratory tract infections (cases 11.2 %; controls 9.2 %; OR 1.24, 95 % CI 1.07-1.44) and, in particular, tonsillitis (cases 3.7 %; controls 2.8 %; OR 1.31, 95 % CI 1.03-1.67) were associated with AS. There were no associations between AS and any other type of infection, and the point estimates were similar in several sensitivity analyses. CONCLUSIONS: Childhood appendicitis was associated with a decreased risk, whereas respiratory tract infections were associated with an increased risk for later development of AS. These findings support a possible relationship between childhood infections and later development of AS, although the study is limited to infections resulting in inpatient care. PMID- 27770823 TI - Body mass index and extent of MRI-detected inflammation: opposite effects in rheumatoid arthritis versus other arthritides and asymptomatic persons. AB - BACKGROUND: In the population a high body mass index (BMI) has been associated with slightly increased inflammatory markers. Within rheumatoid arthritis (RA), however, a high BMI has been associated with less radiographic progression; this phenomenon is unexplained. We hypothesized that the phenomenon is caused by an inverse relationship between BMI and inflammation in hand and foot joints with RA. To explore this hypothesis, local inflammation was measured using magnetic resonance imaging (MRI) in early arthritis patients presenting with RA or other arthritides and in asymptomatic volunteers. METHODS: A total of 195 RA patients, 159 patients with other inflammatory arthritides included in the Leiden Early Arthritis Clinic, and 193 asymptomatic volunteers underwent a unilateral contrast enhanced 1.5 T MRI scan of metacarpophalangeal, wrist, and metatarsophalangeal joints. Each MRI scan was scored by two readers on synovitis, bone marrow edema (BME), and tenosynovitis; the sum yielded the total MRI inflammation score. Linear regression on log-transformed MRI data was used. RESULTS: A higher BMI was associated with higher MRI inflammation scores in arthritides other than RA (beta = 1.082, p < 0.001) and in asymptomatic volunteers (beta = 1.029, p = 0.040), whereas it was associated with lower MRI inflammation scores in RA (beta = 0.97, p = 0.005). Evaluating the different types of inflammation, a higher BMI was associated with higher synovitis, BME, and tenosynovitis scores in arthritides other than RA (respectively beta = 1.084, p < 0.001, beta = 1.021, p = 0.24, and beta = 1.054, p = 0.003), but with lower synovitis and BME scores in RA (respectively beta = 0.98, p = 0.047 and beta = 0.95, p = 0.002). CONCLUSIONS: Increased BMI is correlated with less severe MRI-detected synovitis and BME in RA. This might explain the paradox in RA where obesity correlates with less severe radiographic progression. PMID- 27770825 TI - Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan. AB - BACKGROUND: Since the precise mechanism for the pathogenesis of systemic lupus erythematosus (SLE) is unknown, no targeted therapies in addition to immunosuppression are available so far. We recently demonstrated that administration of the topoisomerase I (topo I) inhibitor irinotecan at extremely low concentrations reversed established lupus nephritis in NZB/NZW mice. While profound immunosuppression was absent, we proposed changes in DNA relaxation and anti-double-stranded (ds)DNA antibody binding as the underlying mechanism. To exclude that these effects were restricted to NZB/NZW mice, irinotecan was used in a genetically different strain of lupus-prone mice. METHODS: MRL/lpr mice were treated with high- and low-dose irinotecan beginning at 8 weeks of age. Treatment was repeated every fourth week. In vitro, DNA was relaxed by recombinant topo I, and altered anti-dsDNA antibody binding was measured by enzyme-linked immunosorbent assay. RESULTS: Administration of both high- and low-dose irinotecan prevented proteinuria and prolonged survival in MRL/lpr mice. Moreover, both concentrations of irinotecan significantly improved histopathology of the skin at 18 weeks of age. While only high-dose irinotecan diminished the numbers of plasmablasts and double-negative T cells, no changes in IgG-secreting cells or anti-dsDNA IgG were observed. In vitro, relaxation of DNA by topo I increased the binding of anti-dsDNA IgG but not the binding of anti-dsDNA IgM derived from the plasma of MRL/lpr mice. CONCLUSION: The beneficial effects of topo I inhibition in a second, genetically different strain of lupus-prone mice strongly implicate irinotecan as a new therapeutic option for human SLE. PMID- 27770826 TI - Plasma, urine and ligament tissue metabolite profiling reveals potential biomarkers of ankylosing spondylitis using NMR-based metabolic profiles. AB - BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune rheumatic disease mostly affecting the axial skeleton. Currently, anti-tumour necrosis factor alpha (anti TNF-alpha) represents an effective treatment for AS that may delay the progression of the disease and alleviate the symptoms if the diagnosis can be made early. Unfortunately, effective diagnostic biomarkers for AS are still lacking; therefore, most patients with AS do not receive timely and effective treatment. The intent of this study was to determine several key metabolites as potential biomarkers of AS using metabolomic methods to facilitate the early diagnosis of AS. METHODS: First, we collected samples of plasma, urine, and ligament tissue around the hip joint from AS and control groups. The samples were examined by nuclear magnetic resonance spectrometry, and multivariate data analysis was performed to find metabolites that differed between the groups. Subsequently, according to the correlation coefficients, variable importance for the projection (VIP) and P values of the metabolites obtained in the multivariate data analysis, the most crucial metabolites were selected as potential biomarkers of AS. Finally, metabolic pathways involving the potential biomarkers were determined using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the metabolic pathway map was drawn. RESULTS: Forty-four patients with AS agreed to provide plasma and urine samples, and 30 provided ligament tissue samples. An equal number of volunteers were recruited for the control group. Multidimensional statistical analysis suggested significant differences between the patients with AS and control subjects, and the models exhibited good discrimination and predictive ability. A total of 20 different metabolites ultimately met the requirements for potential biomarkers. According to KEGG analysis, these marker metabolites were primarily related to fat metabolism, intestinal microbial metabolism, glucose metabolism and choline metabolism pathways, and they were also probably associated with immune regulation. CONCLUSIONS: Our work demonstrates that the potential biomarkers that were identified appeared to have diagnostic value for AS and deserve to be further investigated. In addition, this work also suggests that the metabolomic profiling approach is a promising screening tool for the diagnosis of patients with AS. PMID- 27770827 TI - Power Doppler ultrasonographic assessment of the joint-draining lymph node complex in rheumatoid arthritis: a prospective, proof-of-concept study on treatment with tumor necrosis factor inhibitors. AB - BACKGROUND: Emerging research on the mechanisms of disease chronicity in experimental arthritis has included a new focus on the draining lymph node (LN). Here, we combined clinical-serological analyses and power Doppler ultrasound (PDUS) imaging to delineate noninvasively the reciprocal relationship in vivo between the joint and the draining LN in patients with rheumatoid arthritis (RA). METHODS: Forty consecutive patients refractory to conventional synthetic disease modifying anti-rheumatic drugs were examined through parallel PDUS of the hand wrist joints and axillary LNs and compared with 20 healthy subjects. A semiquantitative score for LN gray-scale (GS) parameters (nodal hypertrophy and cortical structure) and LN PD signal was developed. A 6-month follow-up study with serial sonographic assessments was then performed on initiation of tumor necrosis factor (TNF) inhibitors. RESULTS: PDUS analysis of RA axillary LNs revealed the existence of marked inter-individual heterogeneity and of quantitative differences compared with healthy individuals in both GS and PD characteristics. RA LN changes were plastic, responsive to anti-TNF treatment, and displayed a degree of concordance with synovitis activity in peripheral joints. However, low LN PD signal at baseline despite active arthritis was strongly associated with a poor clinical response to TNF blockade. CONCLUSIONS: PDUS analysis of the draining LN in RA allows capture of measurable inter individual differences and dynamic changes linked to the underlying pathologic process. LN and joint sonographic assessments are nonredundant approaches that may provide independent perspectives on peripheral disease and its evolution over time. PMID- 27770829 TI - A review of the mosquito species (Diptera: Culicidae) of Bangladesh. AB - BACKGROUND: Diseases caused by mosquito-borne pathogens remain an important source of morbidity and mortality in Bangladesh. To better control the vectors that transmit the agents of disease, and hence the diseases they cause, and to appreciate the diversity of the family Culicidae, it is important to have an up to-date list of the species present in the country. Original records were collected from a literature review to compile a list of the species recorded in Bangladesh. RESULTS: Records for 123 species were collected, although some species had only a single record. This is an increase of ten species over the most recent complete list, compiled nearly 30 years ago. Collection records of three additional species are included here: Anopheles pseudowillmori, Armigeres malayi and Mimomyia luzonensis. CONCLUSIONS: While this work constitutes the most complete list of mosquito species collected in Bangladesh, further work is needed to refine this list and understand the distributions of those species within the country. Improved morphological and molecular methods of identification will allow the refinement of this list in years to come. PMID- 27770830 TI - The association of low complement with disease activity in systemic sclerosis: a prospective cohort study. AB - BACKGROUND: In some rheumatic diseases such as systemic lupus erythematosus (SLE), low serum complement ('hypocomplementaemia') is a feature of active disease. However, the role of hypocomplementaemia in systemic sclerosis (SSc) is unknown. We sought to determine the frequency, clinical associations and relationship to disease activity of hypocomplementaemia in SSc. METHODS: The study included 1140 patients fulfilling the 2013 American College of Rheumatology criteria for SSc. Demographic, serological and clinical data, obtained prospectively through annual review, were analysed using univariable methods. Linear and logistic regression, together with generalised estimating equations, were used to determine the independent correlates of hypocomplementaemia ever, and at each visit, respectively. RESULTS: At least one episode of hypocomplementaemia (low C3 and/or low C4) occurred in 24.1 % of patients over 1893 visits; these patients were more likely to be seropositive for anti ribonucleoprotein (OR = 3.8, p = 0.002), anti-Ro (OR = 2.2, p = 0.002), anti Smith (OR = 6.3, p = 0.035) and anti-phospholipid antibodies (OR = 1.4, p = 0.021) and were more likely to display features of overlap connective tissue disease, in particular polymyositis (OR = 16.0, p = 0.012). However, no association was found between hypocomplementaemia and either the European Scleroderma Study Group disease activity score or any of its component variables (including erythrocyte sedimentation rate) in univariate analysis. Among patients with SSc overlap disease features, those who were hypocomplementaemic were more likely to have digital ulcers (OR = 1.6, p = 0.034), tendon friction rubs (OR = 2.4, p = 0.037), forced vital capacity <80 % predicted (OR = 2.9, p = 0.008) and lower body mass index (BMI) (OR for BMI = 0.9, p < 0.0005) at that visit, all of which are features associated with SSc disease activity and/or severity. CONCLUSIONS: While hypocomplementaemia is not associated with disease activity in patients with non-overlap SSc, it is associated with some features of increased SSc disease activity in patients with overlap disease features. PMID- 27770831 TI - Association of anti-peptidyl arginine deiminase antibodies with radiographic severity of rheumatoid arthritis in African Americans. AB - BACKGROUND: Evidence suggests that the presence of peptidyl arginine deiminase type 4 (PAD4) antibodies is associated with radiographic-severity rheumatoid arthritis (RA) among Caucasian patients. The presence of anti-PAD4 antibodies that were cross-reactivity against PAD3 was associated with more aggressive erosive disease (compared with the presence of anti-PAD4 antibodies without anti PAD3 crossreactivity) in Caucasian RA patients. The objectives of this study were to determine the prevalence of serum anti-PAD4 and anti-PAD4/PAD3 cross-reactive autoantibodies in African Americans with RA and whether these antibodies associate with radiographic severity and radiographic progression. METHODS: Serum anti-PAD4 and anti-PAD4/PAD3 antibodies were measured by immunoprecipitation, and the temporal trends in titers were analyzed. We compared total radiographic scores among anti-PAD4-positive, anti-PAD4/PAD3-positive, and anti-PAD4-negative patients and used a zero-inflated negative binomial model to determine associations between radiographic severity and antibody status. Logistic regression was used to analyze radiographic progression. RESULTS: Of 192 African American patients with RA, 73 % were anti-citrullinated peptide/protein antibody (ACPA)-positive, 46 out of 192 (24 %) of whom had serum anti-PAD4 antibodies. Median (interquartile range) total Sharp van der Heijde radiographic scores were 2 (1-97.5) in ACPA-positive patients and 0 (0-3) in ACPA-negative patients (P < 0.001). Of the 46 anti-PAD4-positive patients, 20 had anti-PAD4 antibodies that cross-reacted with PAD3. In patients with early RA, anti-PAD4 and anti-PAD4/PAD3 antibody titers increased over time (P = 0.006, P = 0.001, respectively). Median (interquartile range) total radiographic scores were higher for anti-PAD4 positive than for anti-PAD4-negative patients (3 (1-115) versus 2 (0-11), respectively; P = 0.005). Median (interquartile range) total radiographic score for anti-PAD4/PAD3-positive patients was 76 (3-117) (P < 0.001) versus anti-PAD4 negative patients. Only anti-PAD4/PAD3 antibodies associated with radiographic severity (incidence rate ratio = 2.81; 95 % confidence interval 1.23, 6.43). CONCLUSION: This analysis suggests that autoantibodies against PAD4 and PAD3 proteins may serve as biomarkers for identifying African-American patients with RA and higher radiographic severity. PMID- 27770833 TI - Handling missing items in the Hospital Anxiety and Depression Scale (HADS): a simulation study. AB - BACKGROUND: The Hospital Anxiety and Depression Scale (HADS) is a widely used questionnaire in health research, but there is little guidance on how to handle missing items. We aimed to investigate approaches to handling item non-response, varying sample size, proportion of subjects with missing items, proportion of missing items per subject, and the missingness mechanism. METHODS: We performed a simulation study based on anxiety and depression data among cancer survivors and patients. Item level data were deleted according to random, demographic, and subscale dependent missingness mechanisms. Seven methods for handling missing items were assessed for bias and imprecision. Imputation, imputation conditional on the number of non-missing items, and complete case approaches were used. One thousand datasets were simulated for each parameter combination. RESULTS: All methods were most sensitive when missingness was dependent on the subscale (i.e., higher values of depression leads to higher levels of missingness). The worst performing approach was to analyze only individuals with complete data. The best performing imputation methods depended on whether inference was targeted at the individual or at the population. CONCLUSIONS: We recommend the 'half rule' using individual subscale means when using the HADS scores at the individual level (e.g. screening). For population inference, we recommend relaxing the requirement that at least half the items be answered to minimize missing scores. PMID- 27770832 TI - Contralateral migration of oculomotor neurons is regulated by Slit/Robo signaling. AB - BACKGROUND: Oculomotor neurons develop initially like typical motor neurons, projecting axons out of the ventral midbrain to their ipsilateral targets, the extraocular muscles. However, in all vertebrates, after the oculomotor nerve (nIII) has reached the extraocular muscle primordia, the cell bodies that innervate the superior rectus migrate to join the contralateral nucleus. This motor neuron migration represents a unique strategy to form a contralateral motor projection. Whether migration is guided by diffusible cues remains unknown. METHODS: We examined the role of Slit chemorepellent signals in contralateral oculomotor migration by analyzing mutant mouse embryos. RESULTS: We found that the ventral midbrain expresses high levels of both Slit1 and 2, and that oculomotor neurons express the repellent Slit receptors Robo1 and Robo2. Therefore, Slit signals are in a position to influence the migration of oculomotor neurons. In Slit 1/2 or Robo1/2 double mutant embryos, motor neuron cell bodies migrated into the ventral midbrain on E10.5, three days prior to normal migration. These early migrating neurons had leading projections into and across the floor plate. In contrast to the double mutants, embryos which were mutant for single Slit or Robo genes did not have premature migration or outgrowth on E10.5, demonstrating a cooperative requirement of Slit1 and 2, as well as Robo1 and 2. To test how Slit/Robo midline repulsion is modulated, we found that the normal migration did not require the receptors Robo3 and CXCR4, or the chemoattractant, Netrin 1. The signal to initiate contralateral migration is likely autonomous to the midbrain because oculomotor neurons migrate in embryos that lack either nerve outgrowth or extraocular muscles, or in cultured midbrains that lacked peripheral tissue. CONCLUSION: Overall, our results demonstrate that a migratory subset of motor neurons respond to floor plate-derived Slit repulsion to properly control the timing of contralateral migration. PMID- 27770834 TI - Preclinical study of mouse pluripotent parthenogenetic embryonic stem cell derivatives for the construction of tissue-engineered skin equivalent. AB - BACKGROUND: Embryonic stem cell (ESC) derivatives hold great promise for the construction of tissue-engineered skin equivalents (TESE). However, harvesting of ESCs destroys viable embryos and may lead to political and ethical concerns over their application. In the current study, we directed mouse parthenogenetic embryonic stem cells (pESCs) to differentiate into fibroblasts, constructed TESE, and evaluated its function in vivo. METHODS: The stemness marker expression and the pluripotent differentiation ability of pESCs were tested. After embryoid body (EB) formation and adherence culture, mesenchymal stem cells (MSCs) were enriched and directed to differentiate into fibroblastic lineage. Characteristics of derived fibroblasts were assessed by quantitative real-time PCR and ELISA. Functional ability of the constructed TESE was tested by a mouse skin defects repair model. RESULTS: Mouse pESCs expressed stemness marker and could form teratoma containing three germ layers. MSCs could be enriched from outgrowths of EBs and directed to differentiate into fibroblastic lineage. These cells express a high level of growth factors including FGF, EGF, VEGF, TGF, PDGF, and IGF1, similar to those of ESC-derived fibroblasts and mouse fibroblasts. Seeded into collagen gels, the fibroblasts derived from pESCs could form TESE. Mouse skin defects could be successfully repaired 15 days after transplantation of TESE constructed by fibroblasts derived from pESCs. CONCLUSIONS: pESCs could be induced to differentiate into fibroblastic lineage, which could be applied to the construction of TESE and skin defect repair. Particularly, pESC derivatives avoid the limitations of political and ethical concerns, and provide a promising source for regenerative medicine. PMID- 27770836 TI - The influence of front-of-pack nutrition information on consumers' portion size perceptions. AB - Issue addressed Portion size guidance strategies have been suggested as an important component of weight management; therefore, the Health Star Rating (HSR) front-of-pack labels could influence consumers' portion-size decisions. However, this has not been investigated to date. This study aims to evaluate whether presenting energy content information and HSRs influences portion size self selection of specific foods and meals. Methods Adults were randomly assigned to one of three experimental groups in this randomised controlled experiment. Each participant was given either a kJ/100g food label or a HSR label, or was given no information on nutrient composition. They were then asked to serve themselves an adequate portion of breakfast cereal (Kellogg's Nutri-Grain), fruit salad and chocolate, plus a three-component meal (chicken, fries and mixed vegetables). Portion serves and meal weights were compared between each experimental group using ANOVA and the discretionary foods were also compared with the Australian Guide to Healthy Eating (AGHE). Results Neither the kilojoule nor HSR information influenced the self-served portion size of foods or meal components. Mean self served portion size of the discretionary foods were significantly greater than the standard serving sizes as specified in the AGHE. Conclusion Although food labels have the potential to assist consumers in making product choices, this study indicates that presenting nutrition information does not affect portion size decisions in young adults. So what? Strategies that assist consumers to choose appropriate portion sizes should be developed as a weight management tool. PMID- 27770835 TI - Localization of human adipose-derived stem cells and their effect in repair of diabetic foot ulcers in rats. AB - BACKGROUND: Diabetic foot ulcer (DFU) is an intractable diabetic complication. Patients suffering from diabetes mellitus (DM) frequently present with infected DFUs. In this study, a wound healing model on diabetic rat foot was established to mimic the pathophysiology of clinical patients who suffer from DFUs. Our study aimed to explore the localization of human adipose-derived stem cells (hADSCs) and the role of these cells in the repair of foot ulcerated tissue in diabetic rats, and thus to estimate the possibilities of adipose-derived stem cells for diabetic wound therapy. METHOD: Sprague-Dawley rats were used to establish diabetic models by streptozotocin injection. A full-thickness foot dorsal skin wound was created by a 5 mm skin biopsy punch and a Westcott scissor. These rats were randomly divided into two groups: the hADSC-treated group and the phosphate buffered saline (PBS) control group. The hADSC or PBS treatment was delivered through the left femoral vein of rats. We evaluated the localization of hADSCs with fluorescence immunohistochemistry and the ulcer area and ulcerative histology were detected dynamically. RESULT: The hADSCs had a positive effect on the full-thickness foot dorsal skin wound in diabetic rats with a significantly reduced ulcer area at day 15. More granulation tissue formation, angiogenesis, cellular proliferation, and higher levels of growth factors expression were also detected in wound beds. CONCLUSIONS: Our data suggest that hADSC transplantation has the potential to promote foot wound healing in diabetic rats, and transplantation of exogenous stem cells may be suitable for clinical application in the treatment of DFU. PMID- 27770838 TI - Thyroid Gland Metastasis from Cancer of the Uterine Cervix: An Extremely Rare Case Report. AB - The thyroid gland is a relatively uncommon site for a metastatic disease, although it is richly supplied with blood. The metastases may originate from various primary sites, mainly kidney, lung, head and neck, and breast. Thyroid metastasis from cervical carcinomas is extremely rare; and only a few cases have been previously reported in the literature. In patient with thyroid nodules and an oncological history, the possibility of thyroid metastasis should be seriously considered. Despite the rarity of the metastasis of cervical carcinoma to the thyroid, it is difficult to say appropriate treatment approach for these lesions. When managing such patients, decision-making should balance the possibility of gaining long-term survival against estimation of the aggressiveness of the disease and its possible complications. Here, a case of thyroid metastasis from a squamous cell carcinoma of the uterine cervix presenting with cervical mass and difficulty in swallowing and its treatment is reported. PMID- 27770837 TI - Effect of Riboflavin/UVA Collagen Cross-linking on Central Cornea, Limbus and Intraocular Pressure. Experimental Study in Rabbit Eyes. AB - The Purpose of present study was to investigate the effect of riboflavin/ultraviolet-A-induced collagen cross-linking (CXL) on central cornea, limbus and intraocular pressure (IOP). This was an animal experimental study. The right corneas of 10 rabbits were ultraviolet-A irradiated (3 mW/cm2 for 30 minutes) after de-epithelialization and instillation of 0.1% riboflavin / 20% Dextran drops. Left corneas served as controls. Samples were examined histologically one month postoperatively. Before and after treatment, IOP measurements were recorded bilaterally. At central cornea of eyes underwent CXL keratocyte repopulation, normal arrangement of collagen fibres and a statistically significant change in fibres diameter were detected, compared to controls. At limbus area, there were not any significant histological differences after CXL. There was no statistically significant difference between pre- and postoperative IOP in all eyes. PMID- 27770839 TI - Anomalous Medial Branch of Radial Artery: A Rare Variant. AB - Radial artery is an important consistent vessel of the upper limb. It is a useful vascular access site for coronary procedures and its reliable anatomy has resulted in an elevation of radial forearm flaps for reconstructive surgeries of head and neck. Technical failures, in both the procedures, are mainly due to anatomical variations, such as radial loops, ectopic radial arteries or tortuosity in the vessel. We present a rare and a unique anomalous medial branch of the radial artery spiraling around the flexor carpi radialis muscle in the forearm with a high rising superficial palmar branch of radial artery. Developmentally it probably is a remanent of the normal pattern of capillary vessel maintenance and regression. Such a case is of importance for reconstructive surgeons and coronary interventionists, especially in view of its unique medial and deep course. PMID- 27770840 TI - Pain in the ICU - The fifth sign, not the fifth element. PMID- 27770841 TI - [Improvement in cardiovascular prognosis of type 2 diabetes mellitus, is it a reality?] PMID- 27770842 TI - Negative Secular Trends in Medicine: High Hospital Profits. PMID- 27770828 TI - Delay in diagnosis of influenza A (H1N1)pdm09 virus infection in critically ill patients and impact on clinical outcome. AB - BACKGROUND: Patients infected with influenza A (H1N1)pdm09 virus requiring admission to the ICU remain an important source of mortality during the influenza season. The objective of the study was to assess the impact of a delay in diagnosis of community-acquired influenza A (H1N1)pdm09 virus infection on clinical outcome in critically ill patients admitted to the ICU. METHODS: A prospective multicenter observational cohort study was based on data from the GETGAG/SEMICYUC registry (2009-2015) collected by 148 Spanish ICUs. All patients admitted to the ICU in which diagnosis of influenza A (H1N1)pdm09 virus infection had been established within the first week of hospitalization were included. Patients were classified into two groups according to the time at which the diagnosis was made: early (within the first 2 days of hospital admission) and late (between the 3rd and 7th day of hospital admission). Factors associated with a delay in diagnosis were assessed by logistic regression analysis. RESULTS: In 2059 ICU patients diagnosed with influenza A (H1N1)pdm09 virus infection within the first 7 days of hospitalization, the diagnosis was established early in 1314 (63.8 %) patients and late in the remaining 745 (36.2 %). Independent variables related to a late diagnosis were: age (odds ratio (OR) = 1.02, 95 % confidence interval (CI) 1.01-1.03, P < 0.001); first seasonal period (2009-2012) (OR = 2.08, 95 % CI 1.64-2.63, P < 0.001); days of hospital stay before ICU admission (OR = 1.26, 95 % CI 1.17-1.35, P < 0.001); mechanical ventilation (OR = 1.58, 95 % CI 1.17-2.13, P = 0.002); and continuous venovenous hemofiltration (OR = 1.54, 95 % CI 1.08-2.18, P = 0.016). The intra-ICU mortality was significantly higher among patients with late diagnosis as compared with early diagnosis (26.9 % vs 17.1 %, P < 0.001). Diagnostic delay was one independent risk factor for mortality (OR = 1.36, 95 % CI 1.03-1.81, P < 0.001). CONCLUSIONS: Late diagnosis of community-acquired influenza A (H1N1)pdm09 virus infection is associated with a delay in ICU admission, greater possibilities of respiratory and renal failure, and higher mortality rate. Delay in diagnosis of flu is an independent variable related to death. PMID- 27770843 TI - Zika Virus in Returning Travelers. PMID- 27770844 TI - No, Mindfulness Meditation-Based Analgesia Is Not Mediated by Endogenous Opioids. PMID- 27770845 TI - Better to Avoid Grapefruit with Certain Statins. PMID- 27770846 TI - The Reply. PMID- 27770847 TI - Propensity Approach? PMID- 27770848 TI - The Reply. PMID- 27770849 TI - The Reply. PMID- 27770850 TI - Accuracy and Reliability of Neck and Shoulder Examination. PMID- 27770851 TI - Emerging and Future Applications of Matrix-Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry in the Clinical Microbiology Laboratory: A Report of the Association for Molecular Pathology. AB - The performance of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MS) for routine bacterial and yeast identification as well as direct-from-blood culture bottle identification has been thoroughly evaluated in the peer-reviewed literature. Microbiologists are now moving beyond these methods to apply MS to other areas of the diagnostic process. This review discusses the emergence of advanced matrix-assisted laser desorption ionization time-of-flight MS applications, including the identification of filamentous fungi and mycobacteria and the current and future state of antimicrobial resistance testing. PMID- 27770852 TI - Comparison of Next-Generation Sequencing Panels and Platforms for Detection and Verification of Somatic Tumor Variants for Clinical Diagnostics. AB - Use of next-generation sequencing to detect somatic variants in DNA extracted from formalin-fixed, paraffin-embedded tumor tissues poses a challenge for clinical molecular diagnostic laboratories because of variable DNA quality and quantity, and the potential to detect low allele frequency somatic variants difficult to verify by non-next-generation sequencing methods. We evaluated somatic variant detection performance of the MiSeq and Ion Proton benchtop sequencers using two commercially available panels, the TruSeq Amplicon Cancer Panel and the AmpliSeq Cancer Hotspot Panel Version 2. Both the MiSeq-TruSeq Amplicon Cancer Panel and Ion Proton-AmpliSeq Cancer Hotspot Panel Version 2 were comparable in terms of detection of somatic variants and allele frequency determination using DNA extracted from tumor tissue. Concordance was 100% between the panels for detection of somatic variants in genomic regions tested by both panels, including 27 variants present at low somatic allele frequency (<15%). Use of both the MiSeq and Ion Proton platforms in a combined workflow enabled detection of potentially actionable variants with importance for patient diagnosis, prognosis, or treatment in 49% (305/621) of cases. Overall, a combined workflow using both platforms enabled successful molecular profiling of 96% (621/644) of tumor samples, and provided an approach for verification of somatic variants not amenable to verification by Sanger sequencing (<15% variant allele frequency). PMID- 27770853 TI - External Mechanical Devices and Vascular Surgery for Erectile Dysfunction. AB - INTRODUCTION: The field of sexual medicine is continuously advancing, with novel outcomes reported on a regular basis. Given the rapid evolution, updated guidelines are essential to inform practicing clinicians on best practices. AIM: To summarize the current literature and provide clinical guidelines on penile traction therapy, vacuum erection devices, and penile revascularization. METHODS: A consensus panel was held with leading sexual medicine experts during the 2015 International Consultation on Sexual Medicine (ICSM). Relevant literature was reviewed and graded based on Oxford criteria to develop evidence-based guideline and consensus statements. MAIN OUTCOME MEASURES: The development of clinically relevant guidelines. RESULTS: Penile traction therapy is a viable therapy to modestly improve penile length as a primary therapy, before penile prosthesis placement in men with decreased penile length or after surgery for Peyronie's disease. It also might have a role in the acute phase of Peyronie's disease but has inconsistent outcomes in the long-term phase. Vacuum erection devices are effective in creating an erection satisfactory for intercourse, even in difficult to-treat populations. They also might be used in the post-prostatectomy setting to maintain penile length but have insufficient evidence as a penile rehabilitation therapy. For vasculogenic erectile dysfunction, men with suspected arterial insufficiency can be evaluated with penile Duplex Doppler ultrasonography and confirmatory angiography. Penile revascularization procedures have consistently demonstrated benefits in very select patient populations; however, inadequate data exists to suggest the superiority of one technique. Men with vascular risk factors are likely poor candidates for penile revascularization, although veno-occlusive dysfunction and age are less significant. Therapies for treating primary veno-occlusive dysfunction are not recommended and should be reserved for clinical trials. CONCLUSIONS: Since the prior ICSM meeting, multiple developments have occurred in external mechanical devices and penile revascularization for the treatment of erectile and sexual dysfunction. Sexual medicine clinicians are encouraged to review and incorporate recommendations as applicable to their scope of practice. PMID- 27770855 TI - Predictors of Sexual Distress in Women With Desire and Arousal Difficulties: Distinguishing Between Personal, Partner, and Interpersonal Distress. AB - INTRODUCTION: Although impaired sexual function is relatively common, not all sexual impairments are associated with distress. To date, most studies on protective and risk factors for sexual distress have asked about distress in a more general manner and have failed to distinguish different dimensions of sexual distress. AIM: To examine the association of several intra- and interpersonal factors with personal, perceived partner, and interpersonal distress due to an impairment in sexual functioning in women. METHODS: This study is a cross sectional representative population-based survey with a two-level random selection of Flemish women 14 to 80 years old from the Belgian National Register. The data of 520 sexually active heterosexual women with a partner (weighted N) and impairment in sexual desire (n = 291) and/or sexual arousal (n = 273) were used for analysis. MAIN OUTCOME MEASURES: Demographic information was obtained, and the five-item Mental Health Inventory, the Marital Adjustment subscale of the Maudsley Marital Questionnaire, and the four-item Dyadic Sexual Communication Questionnaire were used. Presence and severity of sexual impairments and associated sexual distress were assessed using the Sexual Functioning Scale. RESULTS: Severity and number of sexual impairments were predictive of all types of sexual distress. Also, for desire and arousal impairments, lower mental well being predicted personal distress, and lower relationship satisfaction predicted perceived partner distress. For desire impairments, lower relationship satisfaction and less communication about sexual needs were predictive of interpersonal distress. For impairments in sexual arousal, lower mental well being and lower relationship satisfaction were predictive of interpersonal distress. CONCLUSION: Personal, perceived partner, and interpersonal distress due to sexual impairments have different types of predictors. Clinical assessment and treatment could benefit from differentiating between different types of distress and the intra- and interpersonal factors that are associated with them. PMID- 27770854 TI - Effectiveness of Intracavernous Delivery of Recombinant Human Hepatocyte Growth Factor on Erectile Function in the Streptozotocin-Induced Diabetic Mouse. AB - INTRODUCTION: Diabetic erectile dysfunction is a disease mostly of vascular origin and men with diabetic erectile dysfunction respond poorly to oral phosphodiesterase-5 inhibitors. Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an essential role in the regulation of cell proliferation, survival, and angiogenesis. AIM: To determine the effectiveness of recombinant human (rh)-HGF in restoring erectile function in diabetic mice. METHODS: Four groups of mice were used: control non-diabetic mice and streptozotocin-induced diabetic mice receiving two successive intracavernous injections of phosphate buffered saline (days -3 and 0), a single intracavernous injection of rh-HGF (day 0), or two successive intracavernous injections of rh-HGF (days -3 and 0). We also examined the effect of rh-HGF in primary cultured mouse cavernous endothelial cells and in major pelvic ganglion culture in vitro, which was incubated under a normal-glucose (5 mmol/L) or a high-glucose (30 mmol/L) condition. MAIN OUTCOME MEASURES: Two weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve and the penis was harvested for histologic studies. RESULTS: Repeated intracavernous injections of rh-HGF protein induced significant restoration of erectile function in diabetic mice (89-100% of control values), whereas a single intracavernous injection of rh HGF protein elicited modest improvement. Rh-HGF significantly induced phosphorylation of its receptor c-Met, increased the content of endothelial cells and smooth muscle cells, and decreased the generation of reactive oxygen species (superoxide anion and peroxynitrite) and extravasation of oxidized low-density lipoprotein in diabetic mice. Under the high-glucose condition, rh-HGF protein also promoted tube formation in mouse cavernous endothelial cells and enhanced neurite sprouting in major pelvic ganglion culture in vitro. CONCLUSION: The dual angiogenic and neurotrophic effects of HGF could open a new avenue through which diabetic erectile dysfunction can be treated. PMID- 27770856 TI - Longitudinal and Horizontal Load Testing of Inflatable Penile Implant Cylinders of Two Manufacturers: An Ex Vivo Demonstration of Inflated Rigidity. AB - INTRODUCTION: Since the inception of the inflatable penile prosthesis, a new era has been ushered in for the management of erectile dysfunction. Despite multiple innovations to improve function and reliability, there are no current data comparing the biomechanical properties of these devices. AIM: To compare the resistance of the Coloplast Titan (Minneapolis, MN, USA) with that of the AMS 700 LGX (Minnetonka, MN, USA) penile prosthesis cylinders to longitudinal (penetration) and horizontal (gravity) forces. METHODS: We compared two cylinder sizes from each company: the Coloplast Titan (18 and 22 cm) and the AMS 700 LGX (18 and 21 cm). To evaluate axial rigidity, which simulates forces during penetration, we performed a longitudinal load compression test to determine the load required to cause the cylinder to kink. To test horizontal rigidity, which simulates the horizontal forces exerted by gravity, we performed a modified cantilever test and measured the degrees of bend for each device. All devices were tested at 10, 15, and 20 PSI to simulate in vivo pressures. MAIN OUTCOME MEASURES: The main outcome measurement for the longitudinal load test (penetration) was the force required for the inflated cylinder to bend, thereby affecting its rigidity. The main outcome for the horizontal rigidity test (gravity) was the angle of displacement, in which a smaller angle represents a more horizontally rigid device. RESULTS: Longitudinal column testing (penetration) demonstrated that less force was required for the AMS device to kink compared with the Coloplast implant across all three fill pressures tested. The Coloplast Titan also had a smaller angle of displacement at the modified cantilever test (gravity) compared with the AMS implant across all fill pressures. CONCLUSION: The Coloplast Titan demonstrated greater resistance to longitudinal (penetration) and horizontal (gravity) forces in this study. The AMS device was very sensitive to fill pressures. In contrast, the Coloplast Titan's ability to resist these forces was less dependent on the device fill pressure. PMID- 27770857 TI - Marine Microorganism: An Underexplored Source of l-Asparaginase. AB - l-Asparaginase (EC 3.5.1.1) is an enzyme that catalyzes the hydrolysis of l asparagine to l-aspartic acid. This enzyme has an important role in medicine and food. l-Asparaginase is a potential drug in cancer therapy. Furthermore, it is also applied for reducing acrylamide, a carcinogenic compound in baked and fried foods. Until now, approved l-asparaginases for both applications are few due to their lack of appropriate properties. As a result, researchers have been enthusiastically seeking new sources of enzyme with better performance. A great number of terrestrial l-asparaginase-producing microorganisms have been reported but unfortunately, almost all failed to meet criteria for cancer therapy and acrylamide reducing agent. As a largest area than Earth, marine environment, by contrast, has not been optimally explored yet. So far, a great challenge facing an exploration of marine microorganisms is mainly due to their harsh, mysterious, and dangerous environment. It is clear that marine environment, a gigantic potential source for marine natural products is scantily revealed, although several approaches and technologies have been developed. This chapter presents the historical of l-asparaginase discovery and applications. It is also discussed, how the marine environment, even though offering a great potency but is still one of the less explored area for l-asparaginase-producing microorganisms. PMID- 27770858 TI - Mechanism and Aquaculture Application of Teleost Enzymes Adapted at Low Temperature. AB - Environment temperature highly influences the physiological condition of poikilothermic teleost. There are different physiological and biochemical responses between fish in different habitats. In order to take profit of fish adapted to different temperatures, some important enzymes have been isolated, assayed, and analyzed. Enzyme expression patterns and properties were evaluated in lactate dehydrogenase, creatine kinase, and stearoyl-CoA desaturase studies. In this chapter, we try to identify the mechanisms of enzyme activity at low temperature by comparing different studies on enzyme kinetics and regulation. The protein-protein interaction between monomers, protein-solvent interaction, and protein substrate correlation are discussed. Studying fish enzymes could accumulate the understanding of marine organism's enzyme function during adaptation in different temperature zones. Based on these mechanisms, the application of cold-adapted enzymes in aquaculture system is illustrated. Furthermore, this information may create a possible explanation of fish physiological and biochemical evolution route and construct an appropriate strategy to overcome the climate change. PMID- 27770859 TI - Usefulness of Alginate Lyases Derived from Marine Organisms for the Preparation of Alginate Oligomers with Various Bioactivities. AB - Alginate-degrading enzyme, alginate lyase, catalyzes the cleavage of glycosidic 1 4 O-linkages between uronic acid residues of alginate by a beta-elimination reaction leaving a 4-deoxy-l-erythro-hex-4-ene pyranosyluronate as nonreducing terminal end. The enzymes from a wide variety of sources such as marine molluscs, seaweeds, and marine bacteria have been discovered and studied not only from a point of view of enzymological interest of enzyme itself but also for elucidation of fine chemical structure of alginate, structure-activity relationship of alginate, and biological activities and physicochemical features of the enzymatic digestion products. Based on the substrate specificities, alginate lyases are classified into three groups: poly(beta-d-mannuronate) lyase, poly(alpha-l guluronate) lyase, and bifunctional alginate lyase, which are specific to mannuronate, guluronate, and both uronic acid residues, respectively. We have studied enzymological aspects of these three types of alginate lyases, and bioactivities of enzymatically digested alginate oligomers. In this chapter, we described the purification and characterization of three types of alginate lyases from different marine origins and overviewed the bioactivities of alginate oligomers. PMID- 27770860 TI - Marine Microbial Amylases: Properties and Applications. AB - Amylases are crucial enzymes which hydrolyze internal glycosidic linkages in starch and produce as primary products dextrins and oligosaccharides. Amylases are classified into alpha-amylase, beta-amylase, and glucoamylase based on their three-dimensional structures, reaction mechanisms, and amino acid sequences. Amylases have innumerable applications in clinical, medical, and analytical chemistries as well as in food, detergent, textile, brewing, and distilling industries. Amylases can be produced from plants, animals, and microbial sources. Due to the advantages in microbial production, it meets commercial needs. The pervasive nature, easy production, and wide range of applications make amylase an industrially pivotal enzyme. This chapter will focus on amylases found in marine microorganisms, their potential industrial applications, and how these enzymes can be improved to the required bioprocessing conditions. PMID- 27770861 TI - Enzyme Immobilization: An Overview on Methods, Support Material, and Applications of Immobilized Enzymes. AB - Immobilized enzymes can be used in a wide range of processes. In recent years, a variety of new approaches have emerged for the immobilization of enzymes that have greater efficiency and wider usage. During the course of the last two decades, this area has rapidly expanded into a multidisciplinary field. This current study is a comprehensive review of a variety of literature produced on the different enzymes that have been immobilized on various supporting materials. These immobilized enzymes have a wide range of applications. These include applications in the sugar, fish, and wine industries, where they are used for removing organic compounds from waste water. This study also reviews their use in sophisticated biosensors for metabolite control and in situ measurements of environmental pollutants. Immobilized enzymes also find significant application in drug metabolism, biodiesel and antibiotic production, bioremediation, and the food industry. The widespread usage of immobilized enzymes is largely due to the fact that they are cheaper, environment friendly, and much easier to use when compared to equivalent technologies. PMID- 27770862 TI - Marine Microbes as a Potential Source of Cellulolytic Enzymes. AB - Marine environment hosts the wide range of habitats with remarkably high and diverse microbial populations. The ability of marine microorganisms to survive in extreme temperature, salinity, and pressure depends on the function of multivarious enzyme systems that in turn provide vast potential for biotechnological exploration studies. Therefore, the enzymes from marine microorganism represent novel bio catalytic potential with stable and reliable properties. Microbial cellulases constitute a major group of industrial enzymes that find applications in various industries. Majority of cellulases are of terrestrial origin, and very limited research has been carried out to explore marine microbes as a source of cellulases. This chapter presents an overview about the types of marine polysaccharases, classification and potential applications of cellulases, different sources of marine cellulases, and their future perspectives. PMID- 27770863 TI - Extremozymes from Marine Actinobacteria. AB - Marine microorganisms that have the possibility to survive in diverse conditions such as extreme temperature, pH, pressure, and salinity are known as extremophiles. They produce biocatalysts so named as extremozymes that are active and stable at extreme conditions. These enzymes have numerous industrial applications due to its distinct properties. Till now, only a fraction of microorganisms on Earth have been exploited for screening of extremozymes. Novel techniques used for the cultivation and production of extremophiles, as well as cloning and overexpression of their genes in various expression systems, will pave the way to use these enzymes for chemical, food, pharmaceutical, and other industrial applications. PMID- 27770864 TI - Enzymes From Rare Actinobacterial Strains. AB - Actinobacteria constitute rich sources of novel biocatalysts and novel natural products for medical and industrial utilization. Although actinobacteria are potential source of economically important enzymes, the isolation and culturing are somewhat tough because of its extreme habitats. But now-a-days, the rate of discovery of novel compounds producing actinomycetes from soil, freshwater, and marine ecosystem has increased much through the developed culturing and genetic engineering techniques. Actinobacteria are well-known source of their bioactive compounds and they are the promising source of broad range of industrially important enzymes. The bacteria have the capability to degrade a range of pesticides, hydrocarbons, aromatic, and aliphatic compounds (Sambasiva Rao, Tripathy, Mahalaxmi, & Prakasham, 2012). Most of the enzymes are mainly derived from microorganisms because of their easy of growth, minimal nutritional requirements, and low-cost for downstream processing. The focus of this review is about the new, commercially useful enzymes from rare actinobacterial strains. Industrial requirements are now fulfilled by the novel actinobacterial enzymes which assist the effective production. Oxidative enzymes, lignocellulolytic enzymes, extremozymes, and clinically useful enzymes are often utilized in many industrial processes because of their ability to catalyze numerous reactions. Novel, extremophilic, oxidative, lignocellulolytic, and industrially important enzymes from rare Actinobacterial population are discussed in this chapter. PMID- 27770865 TI - Bioprospects of Microbial Enzymes from Mangrove-Associated Fungi and Bacteria. AB - Mangroves ecosystem provides the unique habitat for the colonization of fungi and bacteria. Interestingly, the enzymes derived from mangroves associated microorganisms have enormous economic value in industries of agriculture, pulp, paper, medicine, sewage treatments, etc. Microbial enzyme activity is required for the metabolism of plants and animals. In addition, the enzymes are also involved in aquatic animal food cycle and degradation of mangroves detritus. However, the understanding of current status of mangroves associated microorganism-derived enzymes and its application is required to improve the future omics studies. Therefore, this chapter is summarizing the current reports and application on enzymes derived from mangroves associated bacteria and fungi. PMID- 27770866 TI - Preface. PMID- 27770867 TI - Stability of (-)-epigallocatechin gallate and its activity in liquid formulations and delivery systems. AB - (-)-Epigallocatechin gallate (EGCG) has become a popular disease-preventive supplement worldwide because it may aid in slowing down the onset of age-related diseases such as cancer, diabetes and tissue degeneration. As largely demonstrated in cell culture studies, EGCG possesses antioxidant properties and exhibits favorable effects on gene expression, signal transduction and other cell functions. However, only limited effects have been observed in experimental animals and human epidemiological studies. The inconsistency between the biological activity of EGCG in cell cultures and in vivo can be attributed to its low stability, which not only decreases its bioavailability but also leads to the formation of degradation products and prooxidant molecules with possible side effects. Understanding EGCG degradation kinetics in solution and in vivo is crucial for its successful clinical application. Ambient conditions (pH, temperature, oxygen) can either enhance or decrease the stability of EGCG, thus influencing its biological activity. Usage of stabilizers and/or encapsulation of EGCG into particulate systems such as nanoparticles or microparticles can significantly increase its stability. In this review, the effects of ambient conditions, stabilizers and encapsulation systems on EGCG stability, activity and degradation rate are illustrated. PMID- 27770868 TI - Laser fabrication of Ag-HA nanocomposites on Ti6Al4V implant for enhancing bioactivity and antibacterial capability. AB - For titanium alloy implants, both surface bioactivity and antibacterial infection are the two critical factors in determining the success of clinical implantation of these metallic implants. In the present work, a novel nanocomposite layer of nano-silver-containing hydroxyapatite (Ag-HA) was prepared on the surface of biomedical Ti6Al4V by laser processing. Analysis using SEM, EDS and XRD shows the formation of an Ag-HA layer of about 200MUm fusion bonded to the substrate. Mineralization tests in simulated body fluid (SBF) showed that laser fabricated Ag-HA nanocomposite layer favors the deposition of apatite on the surface of the implants. Antibacterial tests confirmed that all Ag-HA nanocomposite layers can kill bacteria while a higher Ag content would lower the cytocompatibility of these coatings. Cell viability decreases when the Ag content reaches 5% in these coatings, due to the larger amount of Ag leached out, as confirmed by ion release evaluation. Our results reveal that laser fabricated Ag-HA nanocomposite coatings containing 2% Ag show both excellent cytocompatibility and antibacterial capability. PMID- 27770869 TI - A new bi-layered scaffold for osteochondral tissue regeneration: In vitro and in vivo preclinical investigations. AB - Current treatments for acute or degenerative chondral and osteochondral lesions are in need of improvement, as these types of injuries lead to disability and worsen the quality of life in a high percentage of patients. The aim of this study was to develop a new bi-layered scaffold for osteochondral tissue regeneration through a "biomimetic" and "bioinspired" approach. For chondral regeneration, the scaffold was realized with an organic compound (type I collagen), while for the regeneration of the subchondral layer, bioactive magnesium-doped hydroxyapatite (Mg/HA) crystals were co-precipitated with the organic component of the scaffold. The entire scaffold structure was stabilized with a cross-linking agent, highly reactive bis-epoxyde (1,4-butanediol diglycidyl ether - BDDGE 1wt%). The developed scaffold was then characterized for its physico-chemical characteristics. Its structure and adhesion strength between the integrated layers were investigated. At the same time, in vitro cell culture studies were carried out to examine the ability of chondral and bone scaffold layers to separately support adhesion, proliferation and differentiation of human mesenchymal stem cells (hMSCs) into chondrocytes and osteoblasts, respectively. Moreover, an in vivo study with nude mice, transplanted with osteochondral scaffolds plain or engineered with undifferentiated hMSCs, was also set up with 4 and 8-week time points. The results showed that chondral and bone scaffold layers represented biocompatible scaffolds able to sustain hMSCs attachment and proliferation. Moreover, the association of scaffold stimuli and differentiation medium, induced hMSCs chondrogenic and osteogenic differentiation and deposition of extracellular matrix (ECM). The ectopic implantation of the engineered osteochondral scaffolds indicated that hMSCs were able to colonize the osteochondral scaffold in depth. The scaffold appeared permissive to tissue growth and penetration, ensuring the diffusion of nutrients and oxygen, as also suggested by the presence of a neo-angiogenesis process, especially at 4weeks. Moreover, the in vivo results further confirmed the great potential of the scaffold in tissue engineering, as it was able to support the initial formation of new bone and chondral tissue, confirming the importance of combined and innovative strategies to improve the available therapeutic strategies for chondral and osteochondral regeneration. PMID- 27770870 TI - In vitro degradation of ZnO flowered coated Zn-Mg alloys in simulated physiological conditions. AB - Flowered coatings composed by ZnO crystals were successfully electrodeposited on Zn-Mg alloys. The distinct coatings morphologies were found to be dependent upon the solid interfaces distribution, with the smaller number of bigger flowers (o 46MUm) obtained on Zn-Mg alloy containing 1wt.% Mg (Zn-1Mg) contrasting with the higher number of smaller flowers (o 38MUm) achieved on Zn-Mg alloy with 2wt.% Mg (Zn-2Mg). To assess the in vitro behaviour of these novel resorbable materials, a detailed evaluation of the degradation behaviour, in simulated physiological conditions, was performed by electrochemical impedance spectroscopy (EIS). The opposite behaviours observed in the corrosion resistances resulted in the build up of distinct corrosion layers. The products forming these layers, preferentially detected at the flowers, were identified and their spatial distribution disclosed by EDS and Raman spectroscopy techniques. The presence of smithsonite, simonkolleite, hydrozincite, skorpionite and hydroxyapatite were assigned to both corrosion layers. However the distinct spatial distributions depicted may impact the biocompatibility of these resorbable materials, with the bone analogue compounds (hydroxyapatite and skorpionite) depicted in-between the ZnO crystals and on the top corrosion layer of Zn-1Mg flowers clearly contrasting with the hindered layer formed at the interface of the substrate with the flowers on Zn-2Mg. PMID- 27770871 TI - On the biological performance of graphene oxide-modified chitosan/polyvinyl pyrrolidone nanocomposite membranes: In vitro and in vivo effects of graphene oxide. AB - Nanofibrous structures that mimic the native extracellular matrix and promote cell adhesion have attracted considerable interest for biomedical applications. In this study, GO-modified nanofibrous biopolymers (GO) were prepared by electrospinning blended solutions of chitosan (80vol%), polyvinyl pyrrolidone (15vol%), polyethylene oxide (5vol%) containing GO nanosheets (0-2wt%). It is shown that GO nanosheets significantly change the conductivity and viscosity of highly concentrated chitosan solutions, so that ultrafine and uniform fibers with an average diameter of 60nm are spinnable. The GO-reinforced nanofibers with controlled pore structure exhibit enhanced elastic modulus and tensile strength (150-300%) with a controllable water permeability to meet the required properties of natural skins. Potential use of the GO-modified biocomposites for tissue engineering is demonstrated in mesenchymal stem cell lines extracted from rat's bone marrow. The biocompatibility assay and SEM imaging reveal that the nanofibrous structure promotes the attachment and maintained characteristic cell morphology and viability up to 72h. In-vivo evaluations in rats show that a faster and more efficient wound closure rate (about 33%) are attained for the 1.5% GO nanofibrous membrane as compared with control (sterile gauze sponges). PMID- 27770872 TI - Synthesis and characterization of mesoporous magnetic nanocomposites wrapped with chitosan gatekeepers for pH-sensitive controlled release of doxorubicin. AB - Multifunctional nanocarriers based on the Fe3O4 nanoparticles core and mesoporous silica shell (mSiO2) were synthesized for controlled drug release through magnetic targeting and pH-sensitive performances. The developed Fe3O4@mSiO2 nanocarriers exhibited a suitable size (63nm) and good magnetic responsibility, doxorubicin (DOX) could be successfully loaded into the mesoporous of Fe3O4@mSiO2 via electrostatic interaction, and the drug loading content and loading efficiency are 29.3% and 93.6%, respectively. The chitosan (CS) was employed to wrap the Fe3O4@mSiO2-DOX as the blocking agent to inhibit premature drug release, and the final CS/Fe3O4@mSiO2-DOX exhibited excellent pH-sensitivity, 86.1% DOX was released within 48h at pH4.0. Furthermore, all the release behaviors fit the Higuchi model very well and a purely diffusion-controlled process played a major role on DOX release from CS/Fe3O4@mSiO2-DOX. In addition, MTT assays in human liver hepatocellular carcinoma cells (HepG2) demonstrated that the CS/Fe3O4@mSiO2 DOX had high anti-tumor activity, while the Fe3O4@mSiO2 nanocarriers were practically non-toxic. Thus, our results revealed that the CS/Fe3O4@mSiO2-DOX could play an important role in the development of intracellular delivery nanodevices for cancer therapy. PMID- 27770873 TI - Mechanical and degradation properties of biodegradable Mg strengthened poly lactic acid composite through plastic injection molding. AB - Full biodegradable magnesium alloy (AZ31) strengthened poly-lactic acid (PLA) composite rods for potential application for bone fracture fixation were prepared by plastic injection process in this work. Their surface/interfacial morphologies, mechanical properties and vitro degradation were studied. In comparison with untreated Mg rod, porous MgO ceramic coating on Mg surface formed by Anodizing (AO) and micro-arc-oxidation (MAO)treatment can significantly improve the interfacial binding between outer PLA cladding and inner Mg rod due to the micro-anchoring action, leading to better mechanical properties and degradation performance of the composite rods.With prolonging immersion time in simulated body fluid (SBF) solution until 8weeks, the MgO porous coating were corroded gradually, along with the disappearance of original pores and the formation of a relatively smooth surface. This resulted in a rapidly reduction in mechanical properties for corresponding composite rods owing to the weakening of interfacial binding capacity. The present results indicated that this new PLA clad Mg composite rods show good potential biomedical applications for implants and instruments of orthopedic inner fixation. PMID- 27770874 TI - Silk fibroin membrane used for guided bone tissue regeneration. AB - With the aim to develop a novel membrane with an appropriate mechanical property and degradation rate for guided bone tissue regeneration, lyophilized and densified silk fibroin membrane was fabricated and its mechanical behavior as well as biodegradation property were investigated. The osteoconductive potency of the silk fibroin membranes were evaluated in a defect rabbit calvarial model. Silk fibroin membrane showed the modulated biodegradable and mechanical properties via ethanol treatment with different concentration. The membrane could prevent soft tissue invasion from normal tissue healing, and the amounts of new bone and defect closure with silk fibroin membrane were similar to those of commercially available collagen membrane. PMID- 27770875 TI - Nanostructured screen-printed electrodes based on titanate nanowires for biosensing applications. AB - This work demonstrates the successful modification of screen-printed electrodes using functionalized titanate nanowires for producing a peroxide biosensor. Titanate nanowires were synthesized by the hydrothermal method and characterized using physico-chemical techniques. The surface of the nanowires was modified with (3-aminopropyl)trimethoxysilane and glutaraldehyde to immobilize horseradish peroxidase through covalent bound, obtaining a surface coverage of 1.62mg of enzyme/m2. The surface of screen-printed carbon electrodes was modified with peroxidase-containing nanowires. Cyclic voltammetry and chronoamperometry were employed to study the electrochemical properties of the nanostructured electrode. A low hydrogen peroxide reduction potential around -0.98V (vs Ag, pH7.0) was observed, with linear response in the range of 40 to 560MUmolL-1, detection limit of 10.7MUmolL-1 and good stability. Reproducibility relative standard deviation was as low as 4.7%. For repeatability, deviation was 3.3%. PMID- 27770876 TI - Combined effect of magnesia and zirconia on the bioactivity of calcium silicate ceramics at C?S ratio less than unity. AB - This paper describes the effect of magnesia in the presence of zirconia on the bioactivity, microstructure and physico-mechanical properties of calcium silicate composition adjusted at calcia/silica ratio(C/S) of 0.5. A mixture from calcium carbonate and silica was conducted at C/S of 0.5. 20wt.% of magnesia and 5-25wt.% of ZrO2 were added. Each mixture was mixed with ethanol in a planetary ball mill, dried, formed and fired at a temperature of 1325+/-5 degrees C. Phase composition, FE-SEM, and physico-mechanical properties of the fired specimens were determined and explained. The in vitro bioactivities of these specimens were investigated by analysis of their abilities to form apatite in the simulated body fluid (SBF) for a short time (7days) using SEM-EDS. The findings indicated that the surface of the specimens containing 5 and 15wt.% ZrO2 were completely covered by single and multilayered hydroxyapatite (HA) precipitate typical to "cauliflower" morphology, respectively. The surface of the specimen containing 25wt.% ZrO2 did not cover, but there are some scattered HA precipitate. The differences among the results were rationalized based on the phase composition. Vickers hardness and fracture toughness of the specimens of highly promised bioactivity were 2.32-2.57GPa and 1.80-1.50MPa. m1/2, respectively. The properties of these specimens are similar to the properties of human cortical bone. Consequently, these composites might be used as bone implant materials. PMID- 27770877 TI - Intracellular uptake of magnetite nanoparticles: A focus on physico-chemical characterization and interpretation of in vitro data. AB - Comprehensive characterization of nanoparticles associated with investigation of their cellular uptake creates the basis on which fundamental in vitro and in vivo studies can be built. In this work, a complex analysis of various surface modified magnetite nanoparticles in biologically relevant environment is reported and the promotion of incorrect characterization into the results obtained from model biological experiments leading to false conclusions is demonstrated. Via a bottom-up approach from particle characterization by DLS towards interpretation of biological data based on cellular uptake, this work draws attention to the systematic propagation of errors stemming from inaccurate determination of input parameters for DLS, improper selection of particle size distribution, inadequate sampling, unknown colloidal behavior and the omission of fraction of particles complying with the internalization threshold. In addition, cellular uptake depending on the number of treated cells is shown. The definition of cellular uptake efficacy reflecting the size distribution of particles beside their absolute internalization is postulated. PMID- 27770878 TI - Cationic cyclodextrin/alginate chitosan nanoflowers as 5-fluorouracil drug delivery system. AB - Cyclodextrins (CDs) have widely been used as component of drug delivery systems. However unmodified cyclodextrins are associated with cytotoxicity and poor water solubility thus limiting their use in pharmaceutical industry. The cationic-beta cyclodextrin (Cat-beta-CD) polymer cores were synthesized using beta-CD, epichlorohydrin and choline chloride via a one-step polycondensation process. The main aim of this study was to synthesize hierarchical nanoflowers composed of cationic-beta-CD as polymeric core along with alginate and chitosan "petals" (Cat beta-CD/Alg-Chi nanoflowers) as carriers for oral delivery of 5-Fluorouracil (5 FU) via an ionic-gelation technique. The drug loading capacity, particle size, zeta potential and surface morphology of the synthesized nanoflowers were determined. The prepared nanoflowers were formed with an average size of 300nm and a zeta potential of +9.90mV with good encapsulation efficiency of up to 77.3%. In vitro release of 5-FU from the loaded nanoflowers showed controlled and sustained release compared to the inclusion complex alone. Cat-beta-CD/Alg-Chi nanoflowers were assessed against L929 cells and found to be effectively inhibiting the growth of L929 cells in a concentration dependent manner. PMID- 27770879 TI - Iron doped SnO2/Co3O4 nanocomposites synthesized by sol-gel and precipitation method for metronidazole antibiotic degradation. AB - Sol-gel and precipitation reaction methods were used to synthesize Un-doped and Fe-doped SnO2/Co3O4 nanocomposites under UV light; the synthesized nanocomposites were applied for the photocatalytic degradation of metronidazole antibiotic. The developed photo catalyst was well characterized using energy dispersive X-ray spectrometer (EDX), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), field emission scanning electron microscopy (FE-SEM), UV-Visible and photoluminescence (PL) spectroscopy. Effective parameters such as pH, photocatalyst dose and contact time was optimized and well investigated. From the obtained facts it is clear that the 98.3% of MTZ was degraded with in 15min, pH6 and 0.1g catalyst when the Fe molar ratio was 1:1 at %. As compared to results obtained from un-doped SnO2/Co3O4 nanocomposites Fe doped SnO2/Co3O4 nanocomposites possess greater photocatalytic efficiency. PMID- 27770880 TI - A treatise on benzimidazole based Schiff base metal(II) complexes accentuating their biological efficacy: Spectroscopic evaluation of DNA interactions, DNA cleavage and antimicrobial screening. AB - Two novel imidazole derived Schiff bases, (Z)-1-(1H-benzo[d]imidazol-2-yl)-N benzylidenemethanamine (L1) and 1-(1H-benzo[d]imidazol-2-yl)-N-(4 nitrobenzylidene) methanamine, and a series of their transition metal complexes of the types [M(L1)2]Cl2 and [M(L2)2]Cl2 where, M=Cu(II), Ni(II), Co(II) and Zn(II) have been designed and synthesized. These compounds were characterized by various spectral and physicochemical data. UV-Vis, magnetic susceptibility and molar conductivity data indicate that all the complexes adopt square planar geometry. The EPR spectral data of the Cu(II) complexes have provided supportive evidence to the conclusion derived on the basis of electronic absorption and magnetic moment values. Moreover, the interaction of complexes with DNA via intercalation has been explored by absorption, fluorescence spectroscopy, cyclic voltammetry, viscosity and circular dichroism. Agarose gel electrophoresis technique reveals that the complexes are good metallonucleases. All the compounds have relatively high antibacterial and antifungal potencies. Among the metal complexes, Cu(II) complexes exhibit higher efficacy against all the pathogens. PMID- 27770881 TI - Effect of electrolyte composition and deposition current for Fe/Fe-P electroformed bilayers for biodegradable metallic medical applications. AB - With its proven biocompatibility and excellent mechanical properties, iron is an excellent source material for clinical cardiac and vascular applications. However, its relatively low degradation rate limits its use for the healing and remodeling of diseased blood vessels. To address these issues, a multi-purpose fabrication process to develop a bilayer alloy composed of electroformed iron (E Fe) and iron-phosphorus (Fe-P) was employed. Bilayers of Fe/Fe-P were produced in an electrolytic bath. The effects of electrolyte chemical composition and deposition current density (idep) on layer structure and chemical composition were assessed by scanning electron microscopy, electron probe microanalysis, X ray diffraction and X-ray photoelectron spectroscopy. The corrosion rate was determined by potentiodynamic polarization tests. The bilayers showed an increasing amount of P with increasing NaH2PO4.H2O in the electrolyte. Fe-P structure became finer for higher P amounts. Potentiodynamic polarization tests revealed that the corrosion rate was strongly influenced by deposition conditions. For a P amount of ~2 wt.%, the corrosion rate was 1.46mm/year, which confirms the potential of this material to demonstrate high mechanical properties and a suitable corrosion rate for biomedical applications. PMID- 27770882 TI - Surface properties of Ti-6Al-4V alloy part I: Surface roughness and apparent surface free energy. AB - Titanium (Ti) and its alloys are the most often used implants material in dental treatment and orthopedics. Topography and wettability of its surface play important role in film formation, protein adhesion, following osseointegration and even duration of inserted implant. In this paper, we prepared Ti-6Al-4V alloy samples using different smoothing and polishing materials as well the air plasma treatment, on which contact angles of water, formamide and diiodomethane were measured. Then the apparent surface free energy was calculated using four different approaches (CAH, LWAB, O-W and Neumann's Equation of State). From LWAB approach the components of surface free energy were obtained, which shed more light on the wetting properties of samples surface. The surface roughness of the prepared samples was investigated with the help of optical profilometer and AFM. It was interesting whether the surface roughness affects the apparent surface free energy. It was found that both polar interactions the electron donor parameter of the energy and the work of water adhesion increased with decreasing roughness of the surfaces. Moreover, short time plasma treatment (1min) caused decrease in the surface hydrophilic character, while longer time (10min) treatment caused significant increase in the polar interactions and the work of water adhesion. Although Ti-6Al-4V alloy has been investigated many times, to our knowledge, so far no paper has been published in which surface roughness and changes in the surface free energy of the alloy were compared in the quantitative way in such large extent. This novel approach deliver better knowledge about the surface properties of differently smoothed and polished samples which may be helpful to facilitate cell adhesion, proliferation and mineralization. Therefore the results obtained present also potentially practical meaning. PMID- 27770883 TI - Multifunctional magnetic nanostructured hardystonite scaffold for hyperthermia, drug delivery and tissue engineering applications. AB - Hyperthermia and local drug delivery have been proposed as potential therapeutic approaches for killing cancer cells. The development of bioactive materials such as Hardystonite (HT) with magnetic and drug delivery properties can potentially meet this target. This new class of magnetic bioceramic can replace the widely used magnetic iron oxide nanoparticles, whose long-term biocompatibility is not clear. Magnetic HT can be potentially employed to develop new ceramic scaffolds for bone surgery and anticancer therapies. With this in mind, a synthesis procedure was developed to prepare multifunctional bioactive scaffold for tissue engineering, hyperthermia and drug delivery applications. To this end, iron (Fe3+)-containing HT scaffolds were prepared. The effect of Fe on biological, magnetic and drug delivery properties of HT scaffolds were investigated. The results showed that obtained Fe-HT is bioactive and magnetic with no magnetite or maghemite as secondary phases. The Fe-HT scaffolds obtained also possessed high specific surface areas and demonstrated sustained drug delivery. These results potentially open new aspects for biomaterials aimed at regeneration of large-bone defects caused by malignant bone tumors through a combination of hyperthermia, local drug delivery and osteoconductivity. PMID- 27770884 TI - Bis-naphthalimides self-assembly organogel formation and application in detection of p-phenylenediamine. AB - Two new gelators containing bis-naphthalimides group were designed and synthesized. The gelator 1b could form gels in DMF and mixed solvent of DMSO/H2O (10/1, v/v). The self-assembly processes of 1b in two kinds of solvents were detailedly investigated by UV-vis, fluorescence, infrared spectroscopy, field emission scanning electron microscope (FE-SEM), X-ray diffraction and contact angle experiments. The experiment results showed the hydrogen bonding was the main force for the gel formation. The gel 1b formed in mixed solvent of DMSO/H2O (10/1, v/v) possessed of the ability of distinguishing of o-phenylenediamine, m phenylenediamine and p-phenylenediamine. At the same time, the gelator 1b could selectively and sensitively detect p-phenylenediamine in solution with the detection limit of 8.961*10-8ML-1. The detection experiment was also confirmed by DFT theoretical calculations. This research would expand the supramolecular self assembly materials application in sensor field and offer a new detection method for organic amines. PMID- 27770885 TI - Horseradish peroxidase and toluidine blue covalently immobilized leak-free sol gel composite biosensor for hydrogen peroxide. AB - The enzyme horseradish peroxidase and the water-soluble mediator toluidine blue were covalently immobilized to 3-aminopropyl trimethoxy silane precursor through glutaraldehyde crosslinker. A rigid ceramic composite electrode was fabricated from this modified silane along with graphite powder, which resulted in an amperometric biosensor for H2O2. The electrochemical behaviour of the modified biosensor was monitored using cyclic voltammetry in the potential range of 0.2V to -0.4V vs SCE. The biosensor exhibited a stable voltammogram with cathodic peak at -0.234V and anodic peak at -0.172V, with a formal potential of -0.203V. Various factors influencing the performance of the biosensor such as buffer solution, pH, temperature and potential were examined for optimizing the working conditions. The modified biosensor exhibited a good catalytic behaviour for the reduction of H2O2 at a lower potential of -0.25V without any barrier from possible interferents. The analytical working range was found to be 0.429MUM to 0.455mM of H2O2 with a detection limit of 0.171MUM. The fabricated biosensor is robust for long-term usage in addition to the high sensitivity, rapid response and having an advantage of surface renewability by simple mechanical polishing. PMID- 27770886 TI - Characterization of human adipose tissue-derived stem cells in vitro culture and in vivo differentiation in a temperature-sensitive chitosan/beta- glycerophosphate/collagen hybrid hydrogel. AB - In this study, the interaction of human adipose tissue-derived stem cells (ADSCs) with chitosan/beta-glycerophosphate/collagen (C/GP/Co) hybrid hydrogel was test, followed by investigating the capability of engineered adipose tissue formation using this ADSCs seeded hydrogel. The ADSCs were harvested and mixed with a C/GP/Co hydrogel followed by a gelation at 37 degrees C and an in vitro culture. The results showed that the ADSCs within C/GP/Co hydrogels achieved a 30% of expansion over 7days in culture medium and encapsulated cell in C/GP/Co hydrogel demonstrated a characteristic morphology with high viability over 5days. C/GP/Co hydrogel were subcutaneous injected into SD-rats to assess the biocompatibility. The induced ADSCs-C/GP/Co hydrogel and non-induced ADSCs-C/GP/Co hydrogel were subcutaneously injected into nude mice for detecting potential of adipogenic differentiation. It has shown that C/GP/Co hydrogel were well tolerated in SD rats where they had persisted over 4weeks post implantation. Histology analysis indicated that induced ADSCs-C/GP/Co hydrogel has a greater number of adipocytes and vascularized adipose tissues compared with non-induced ADSCs-C/GP/Co hydrogel. PMID- 27770887 TI - Electrodeposited reduced graphene oxide incorporating polymerization of l-lysine on electrode surface and its application in simultaneous electrochemical determination of ascorbic acid, dopamine and uric acid. AB - This paper demonstrates a novel strategy for the construction of a graphene hybrid composites film, which was fabricated by electrodeposited reduced graphene oxide (ERGO) incorporating polymerization of l-lysine (PLL) onto glassy carbon electrode (GCE). Here we show that graphene films can be prepared on electrodes directly from GO dispersions by one-step electrodeposition technique based on electropolymerized PLL as a positively charged polymer interface to adsorb negatively charged GO nanosheets through electrostatic attraction. The thickness of graphene film can be easily controlled by using the electrodeposition technique, a distinct advantage over previously developed methods. The electrochemically reduced process of GO and electropolymerization of l-lysine were investigated by cyclic voltammetry with a wide potential range. The surface morphology of the modified electrode was characterized by scanning electron microscopy. The ERGO/PLL/GCE shows conducive to electron transfer kinetics for Fe(CN)63-/Fe(CN)64- redox probes, compared with bare GCE, PLL/GCE and ERGO/GCE. The electrochemical behaviors of ascorbic acid (AA), dopamine (DA) and uric acid (UA) at ERGO/PLL/GCE were investigated by cyclic voltammetry, and the results suggest that the modified electrode exhibits enhanced electrocatalytic activity toward these important molecules. Under physiological condition and in the co existence system of AA, DA and UA, the ERGO/PLL/GCE showed linear voltammetric responses in the concentration of 100MUM-1200MUM for AA, 2.0MUM-60MUM for DA and 20MUM-200MUM for UA, and with the detection limits (S/N=3) of 2.0MUM, 0.10MUM and 0.15MUM for AA, DA and UA, respectively. The developed method has been applied to simultaneous determination of AA, DA and UA in human urine with satisfactory recoveries of 104.2%, 95.4% and 99.9%, respectively. This work demonstrates that the attractive features of ERGO/PLL provide promising applications in simultaneous determination of AA, DA and UA in physiological and pathological studies. PMID- 27770888 TI - Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs. AB - Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, EthocelTM (EC) and Kollicoat(r) SR 30D associated with Opadry(r) II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat(r) SR 30D and Opadry(r) II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs. PMID- 27770889 TI - Self-organized double-wall oxide nanotube layers on glass-forming Ti-Zr-Si(-Nb) alloys. AB - In this work, we report for the first time on the use of melt spun glass-forming alloys - Ti75Zr10Si15 (TZS) and Ti60Zr10Si15Nb15 (TZSN) - as substrates for the growth of anodic oxide nanotube layers. Upon their anodization in ethylene glycol based electrolytes, highly ordered nanotube layers were achieved. In comparison to TiO2 nanotube layers grown on Ti foils, under the same conditions for reference, smaller diameter nanotubes (~116nm for TZS and ~90nm for TZSN) and shorter nanotubes (~11.5MUm and ~6.5MUm for TZS and TZSN, respectively) were obtained for both amorphous alloys. Furthermore, TEM and STEM studies, coupled with EDX analysis, revealed a double-wall structure of the as-grown amorphous oxide nanotubes with Ti species being enriched in the inner wall, and Si species in the outer wall, whereby Zr and Nb species were homogeneously distributed. PMID- 27770890 TI - Osseointegration is improved by coating titanium implants with a nanostructured thin film with titanium carbide and titanium oxides clustered around graphitic carbon. AB - Titanium implants coated with a 500nm nanostructured layer, deposited by the Ion Plating Plasma Assisted (IPPA) technology, composed of 60% graphitic carbon, 25% titanium oxides and 15% titanium carbide were implanted into rabbit femurs whilst into the controlateral femurs uncoated titanium implants were inserted as control. At four time points the animals were injected with calcein green, xylenol orange, oxytetracycline and alizarin. After 2, 4 and 8weeks femurs were removed and processed for histology and static and dynamic histomorphometry for undecalcified bone processing into methylmethacrylate, sectioned, thinned, polished and stained with Toluidine blue and Fast green. The overall bone-implant contacts rate (percentage of bone-implant contacts/weeks) of the TiC coated implant was 1.6 fold than that of the uncoated titanium implant. The histomorphometric analyses confirmed the histological evaluations. More precisely, higher Mineral Apposition Rate (MAR, MUm/day) (p<0.005) and Bone Formation Rate (BFR, MUm2/MUm/day) (p<0.0005) as well as Bone Implant Contact (Bic) and Bone Ingrowth values (p<0.0005) were observed for the TiC coated implants compared to uncoated implants. In conclusion the hard nanostructured TiC layer protects the bulk titanium implant against the harsh conditions of biological tissues and in the same time, stimulating adhesion, proliferation and activity of osteoblasts, induces a better bone-implant contacts of the implant compared to the uncoated titanium implant. PMID- 27770891 TI - Concentrated polymer brush-modified silica particle coating confers biofouling resistance on modified materials. AB - Biofouling, an undesired adsorption of biological material to otherwise inert surfaces, is detrimental in medical, pharmaceutical, and other sectors. Concentrated polymer brushes (CPB) confer non-biofouling properties on modified surfaces but are cumbersome to fabricate. Here, a simple and versatile method of fabricating non-biofouling coatings for various substrates was developed using CPB-modified silica nanoparticles (SiPs). Concentrated poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA) brushes were grafted on SiPs by surface initiated atom transfer radical polymerization. CPB-SiPs were spin-coated onto silicon wafers or quartz crystal microbalance (QCM) sensor chips with phenyl azido cross-linkers. SiP cross-linking was then performed by ultra violet irradiation for 20s, or by heating at 120 degrees C for 12h. Protein adsorption to coatings was studied by QCM approach and human umbilical vein endothelial cell adhesion to coatings was examined. SiP to cross-linker weight ratios were varied from 2.0/0.5 to 9.0/0.5 (wt/wt%) and the coatings almost completely suppressed protein adsorption and cell adhesion to treated surfaces. The coating was also applied to polymeric films, rendering these materials biofouling-resistant. PMID- 27770892 TI - Preparation of chitosan-based multifunctional nanocarriers overcoming multiple barriers for oral delivery of insulin. AB - To overcome multiple barriers for oral delivery of insulin, the chitosan-based multifunctional nanocarriers modified by L-valine (LV, used as a target ligand to facilitate the absorption of the small intestine) and phenylboronic acid (PBA, used as a glucose-responsive unit) have been designed and evaluated in this study. The resultant nanocarriers exhibited low cytotoxicity against HT-29 cells and excellent stability against protein solution. The insulin release behaviors were evaluated triggered by pH and glucose in vitro. The chemical stability of loaded insulin against digestive enzyme were established in presence of simulated gastric fluid (SGF) containing pepsin and simulated intestinal fluid (SIF) containing pancreatin, respectively. The uptake behavior of HT-29 cells was evaluated by confocal laser scanning microscope. After oral administration to the diabetic rats, an effective hypoglycemic effect was obtained compared with subcutaneous injection of insulin. This work suggests that L-valine modified chitosan-based multifunctional nanocarriers may be a promising drug delivery carrier for oral administration of insulin. PMID- 27770893 TI - Covalently antibacterial alginate-chitosan hydrogel dressing integrated gelatin microspheres containing tetracycline hydrochloride for wound healing. AB - An antibacterial and biodegradable composite hydrogel dressing integrated with microspheres is developed for drug delivery and wound healing. The mechanism of gelation is attributed to the Schiff-base reaction between aldehyde and amino groups of oxidized alginate (OAlg) and carboxymethyl chitosan (CMCS). To enhance antibacterial and mechanical properties, tetracycline hydrochloride (TH) loaded gelatin microspheres (GMs) were fabricated by an emulsion cross-linking method, followed by integrating into the OAlg-CMCS hydrogel to produce a composite gel dressing. In vitro gelation time, swelling, degradation, compressive modulus and rheological properties of the gel dressing were investigated as the function of microsphere ratios. With increasing ratios of microspheres from 10 to 40mg/mL, the composite dressing manifested shorter gelation time and lower swelling ratios, as well as higher mechanical strength. Comparing to other formulations, the gel dressing with 30mg/mL microspheres showed more suitable stabilities and mechanical properties for wound healing. Also, in vitro drug release results showed that the loaded TH could be sustained release from the composite gel dressing by contrast with pure hydrogels and microspheres. Furthermore, powerful bacteria growth inhibition effects against Escherichia coli and Staphylococcus aureus suggested that the composite gel dressing, especially the one with 30mg/mL GMs containing TH, has a promising future in treatment of bacterial infection. PMID- 27770894 TI - Sepiolite as a promising nanoclay for nano-biocomposites based on starch and biodegradable polyester. AB - The effects of sepiolite addition (0, 1, 3 and 5wt%) were evaluated on dynamic mechanical behaviour, water uptake, thermal and optical properties of thermoplastic starch (TPS)/poly (butylene adipate-co-terephthalate) (PBAT) nano biocomposites, with different TPS/PBAT (w/w) ratios and nanofiller contents. The results highlighted the improvement of the dynamic-mechanical behaviour with the addition of sepiolite, producing high performance materials. An increase of 25 degrees C in the Tg of TPS was recorded by DMTA analysis at sepiolite content of 5wt%. The sepiolite influenced the crystallisation of nano-biocomposites, without causing interference in the crystal organisation, evidenced by DSC analysis. The addition of sepiolite nanoclay decreased the water adsorption rate and water adsorption capacity of the corresponding nano-biocomposites. For such multiphase systems, the successful use of natural sepiolite brought a clear benefit, without the need of any modifications or additional processes to produce advanced nano biocomposites. PMID- 27770895 TI - Effects of halloysite nanotubes on physical properties and cytocompatibility of alginate composite hydrogels. AB - Sodium alginate (SA)/halloysite nanotubes (HNTs) composite hydrogels were successfully prepared by solution blending and cross-linking with calcium ions. HNTs can improve the physical properties and cytocompatibility of composite hydrogels. The static and shear viscosity of SA/HNTs solution increase by the addition of HNTs. FTIR suggests the presence of hydrogen bond interactions between HNTs and SA. The crystal structure of HNTs is retained in the composites as showed by the X-ray diffraction result. A porous structure with pore size of 100-250MUm is found in the hydrogels, which can provide a space for cell growth and migration. The compressive mechanical properties of composite hydrogels significantly increase compared to the pure SA hydrogel. The SA/HNTs composite hydrogels with 80% HNTs loading exhibit the compressive stress at 80% strain of 2.99MPa, while the stress at 80% strain of pure SA hydrogel is only 0.8MPa. The dynamic storage modulus of composite hydrogels also markedly increases with HNTs concentration. The differential scanning calorimetry endothermic peak area and swelling ratios in NaCl solution of the composite hydrogels decrease by the addition of HNTs. Preosteoblast (MC3T3-E1) culture results reveal that the SA/HNTs composites especially at relatively low HNTs loading show a significant increase in cells adhesion and proliferation compared to the pure SA hydrogel. All the results demonstrate that the SA/HNTs composite hydrogels show a promising application in bone tissue engineering. PMID- 27770896 TI - Light-induced antibacterial activity of electrospun chitosan-based material containing photosensitizer. AB - Increasing antimicrobial resistance requires the development of novel materials and approaches for treatment of various infections. Utilization of photodynamic therapy represents an advanced alternative to antibiotics and metal-based agents. Here, we report the fabrication of electrospun material that possesses benefits of both topical antimicrobial and photodynamic therapies. This material combines chitosan, as a biocompatible polymer, and a second generation photosensitizer. The incorporation of photosensitizer doesn't affect the material morphology and its nearly uniform distribution in fibers structure was observed by confocal Raman microscopy. Owing to photosensitizer the prepared material exhibits the light-induced and spatially limited antimicrobial activity that was demonstrated against Staphylococcus aureus, an important etiological infectious agent. Such material can be potentially used in antibacterial therapy of chronic wounds, infections of diabetic ulcers, and burns, as well as rapidly spreading and intractable soft-tissue infections caused by resistant bacteria. PMID- 27770897 TI - P(TA) macro-, micro-, nanoparticle-embedded super porous p(HEMA) cryogels as wound dressing material. AB - Super porous poly(2-hydroxy ethyl methacrylate) (p(HEMA)) cryogel was successfully synthesized by using polyethylene glycol diacrylate (p(EGDA)) crosslinker under cryogenic conditions. Poly(Tannic acid) (p(TA)) macro-, micro-, and nanoparticles prepared from a natural polyphenol, tannic acid (TA), were embedded into p(HEMA) cryogel networks to obtain composite p(TA) particle embedded p(HEMA) cryogel. Different size ranges of spherical p(TA) particles, 2000-500MUm, 500-200MUm, 200-20MUm, and 20-0.5MUm size, were included in the cryogel network and illustrated by digital camera, optic microscope, and SEM images of the microgel-cryogel network. The swelling properties and moisture content of p(TA) microgel-embedded p(HEMA) cryogel were investigated at wound healing pH conditions such as pH5.4, 7.4, and 9 at 37.5 degrees C, and the highest swelling capacity was found at pH9 with 972+/-2% swelling in 30s. Higher amounts of DI water were quickly absorbed by p(HEMA)-based cryogel, and moisture retention within the cryogel structure for a longer time period at room temperature is due to existence of p(TA) particles. Degradation profiles of p(TA) particle-embedded p(HEMA) cryogel were shown to be controlled by different pH conditions, and a linear release profile was found with total cumulative release of 5.8+/-0.8mg/g TA up to 12days at pH7.4 and 37.5 degrees C. The antioxidant behavior of degraded p(TA) particles from p(HEMA) cryogel were found as 46+/ 1MUgmL-1 gallic acid equivalent and 165+/-18mMtroloxequivalentg-1. The p(TA) particle-embedded p(HEMA) cryogel has high hemocompatibility with 0.0158+/ 0.0126% hemolysis ratio, and effective hemostatic properties with 8.1+/-0.9 blood clotting index. PMID- 27770898 TI - Comparative assessment of physico-chemical characteristics and fibril formation capacity of thermostable carp scales collagen. AB - Collagen and collagen fibers have been widely documented as a potential and competitive biomaterial for medical applications. However, the searches for safe and realistic new collagen sources are still underway. Currently, fishery by products (scales), a promising collagen source are usually discarded. In the present study, in vitro fibril-forming ability of the extracted fish scale collagen is reported. The aim of the investigation was to evaluate the concomitant comparison of fibril-forming abilities and characteristics of acid and pepsin soluble collagens from the scales of Indian major carp catla (Catla catla) and rohu (Labeo rohita). The extracted collagens were characterized as type I, with a total yield of 2.80-4.11% (w/w). Denaturation temperature determined for all collagens were between 35.9 and 37.7 degrees C. All collagens exhibited high solubility in acidic pH and low NaCl concentrations. SEM clarified the lyophilized collagens and their fibril-forming capacity. Amino acid content and radical scavenging efficacy were also analyzed for the extracted collagen. The results revealed that extracted scale collagen from a renewable biological source could be used as biomaterials in various sectors. It might be suitable for preparing collagen gel for biomedical devices or as a scaffold for cell culture because of its high stability and fibril formation capacity. PMID- 27770899 TI - Nanoparticle formulation having ability to control the release of protein for drug delivery application. AB - Controlled release of therapeutic protein is desirable for protein delivery applications. This study discuss about a unique nanomaterial which is capable to provide the protein release in controlled manner. The nanomaterial has been synthesized from folic acid molecules and bovine serum albumin (BSA1) is loaded in these nanoparticles as a model protein. The size distribution of the synthesized folic acid nanoparticles was observed between 200 and 300nm. The release study using high performance liquid chromatography suggests that more than 90% of BSA can be encapsulated in the nanoparticles having BSA loaded up to 19.29mg (57% of folic acid loaded). Release study also reveals that more than 95% of the total folic acid and BSA were released in phosphate buffer saline solution within 48h. Investigation of folic acid release along with BSA release reveals that the particles are formed through folic acid-protein complex. Salt concentration in the release medium and crosslinked cations in the nanoparticles are found to be the key parameters to control the release rate. Thus, folic acid nanoparticles are efficient carrier for protein encapsulation and release in the controlled manner with minimum drug loss. PMID- 27770900 TI - PLD prepared bioactive BaTiO3 films on TiNb implants. AB - BaTiO3 (BTO) layers were deposited by pulsed laser deposition (PLD) on TiNb, Pt/TiNb, Si (100), and fused silica substrates using various deposition conditions. Polycrystalline BTO with sizes of crystallites in the range from 90nm to 160nm was obtained at elevated substrate temperatures of (600 degrees C-700 degrees C). With increasing deposition temperature above 700 degrees C the formation of unwanted rutile phase prevented the growth of perovskite ferroelectric BTO. Concurrently, with decreasing substrate temperature below 500 degrees C, amorphous films were formed. Post-deposition annealing of the amorphous deposits allowed obtaining perovskite BTO. Using a very thin Pt interlayer between the BTO films and TiNb substrate enabled high-temperature growth of preferentially oriented BTO. Raman spectroscopy and electrical characterization indicated polar ferroelectric behaviour of the BTO films. PMID- 27770901 TI - Enhanced near-infrared photoacoustic imaging of silica-coated rare-earth doped nanoparticles. AB - Near-infrared photoacoustic (PA) imaging is an emerging diagnostic technology that utilizes the tissue transparent window to achieve improved contrast and spatial resolution for deep tissue imaging. In this study, we investigated the enhancement effect of the SiO2 shell on the PA property of our core/shell rare earth nanoparticles (REs) consisting of an active rare-earth doped core of NaYF4:Yb,Er (REDNPs) and an undoped NaYF4 shell. We observed that the PA signal amplitude increased with SiO2 shell thickness. Although the SiO2 shell caused an observed decrease in the integrated fluorescence intensity due to the dilution effect, fluorescence quenching of the rare earth emitting ions within the REDNPs cores was successfully prevented by the undoped NaYF4 shell. Therefore, our multilayer structure consisting of an active core with successive functional layers was demonstrated to be an effective design for dual-modal fluorescence and PA imaging probes with improved PA property. The result from this work addresses a critical need for the development of dual-modal contrast agent that advances deep tissue imaging with high resolution and signal-to-noise ratio. PMID- 27770902 TI - Dual responsive zein hydrogel membrane with selective protein adsorption and sustained release property. AB - Drug-loaded hydrogels have been paid increasing attentions in biomedical fields. As a sort of natural plant protein, zein generally cannot form hydrogel with high water retention because of its predominant hydrophobicity, which will limit its application as biomaterial. In this paper, zein electrospun fibrous membranes (ZEFM) are fabricated through a chemical modification of zein using citric acid and acetic anhydride. The resulting ZEFM can be totally soluble in neutral phosphate buffer solution. After being crosslinked by sodium hexametaphosphate, the ZEFM can form a hydrogel membrane and displays stimuli-responsive behavior towards pH and ionic strength. The hydrogel membrane exhibits better protein adsorption, selectivity and sustained release profile for positively-charged proteins such as cytochrome C, compared with those unmodified ones, and also shows fast biodegradation behavior and qualified cytotoxicity, which all make it favourable for biomedical use. PMID- 27770903 TI - Development of LiCl-containing calcium aluminate cement for bone repair and remodeling applications. AB - The effect of LiCl additions on the in vitro bioactivity, hemolysis, cytotoxicity, compressive strength and setting time of calcium aluminate cements was studied. Calcium aluminate clinker (AC) was obtained via solid state reaction from reagent grade chemicals of CaCO3 and Al2O3. Calcium aluminate cements (CAC) were prepared by mixing the clinker with water or aqueous LiCl solutions (0.01, 0.0125 or 0.015M (M)) using a w/c ratio of 0.4. After 21days of immersion in a simulated body fluid (SBF) at physiological conditions of temperature and pH, a Ca-P rich layer, identified as hydroxyapatite (HA), was formed on the cement without LiCl and on the cement prepared with 0.01M of LiCl solution. This indicates the high bioactivity of these cements. The cements setting times were significantly reduced using LiCl. The measured hemolysis percentages, all of them lower than 5%, indicated that the cements were not hemolytic. The compressive strength of the cements was not negatively affected by the LiCl additions. The obtained cement when a solution of LiCl 0.010M was added, presented high compressive strength, appropriated bioactivity, no cytotoxicity and low setting time, making this material a potentially bone cement. PMID- 27770904 TI - Comparative evaluation of electrical conductivity of hydroxyapatite ceramics densified through ramp and hold, spark plasma and post sinter Hot Isostatic Pressing routes. AB - Hydroxyapatite ceramics synthesized through sonochemical route were processed and densified through ramp & hold (R&H) and Spark Plasma Sintering (SPS) routes. The effect of processing route on the relative density and electrical conductivity were studied. Further, the samples were Hot Isostatically Pressed (HIP) under argon pressure at elevated temperature to further densify the sample. All these samples processed under different conditions were characterized by X-ray diffraction, Scanning Electron Microscopy and AC Conductivity. The samples have exhibited hydroxyapatite phase; however, microstructures exhibited distinctly different grain morphologies and grain sizes. AC impedance spectroscopic measurement was carried out on hydroxyapatite samples processed through different routes and the corresponding spectra were analyzed by the analogy to equivalent circuit involving resistors and capacitors. SPS sintered sample after HIPing has exhibited the highest conductivity. This can be attributed to the higher density in combination with finer grain sizes. Activation energy based on Arrhenius equation is calculated and the prominent conduction mechanism is proposed. PMID- 27770905 TI - Effect of gelatin sponge with colloid silver on bone healing in infected cranial defects. AB - Oral infectious diseases may lead to bone loss, which makes it difficult to achieve satisfactory restoration. The rise of multidrug resistant bacteria has put forward severe challenges to the use of antibiotics. Silver (Ag) has long been known as a strong antibacterial agent. In clinic, gelatin sponge with colloid silver is used to reduce tooth extraction complication. To investigate how this material affect infected bone defects, methicillin-resistant Staphylococcus aureus (MRSA) infected 3-mm-diameter cranial defects were created in adult female Sprague-Dawley rats. One week after infection, the defects were debrided of all nonviable tissue and then implanted with gelatin sponge with colloid silver (gelatin/Ag group) or gelatin alone (gelatin group). At 2 and 3days after debridement, significantly lower mRNA expression levels of IL-6 and TNF-alpha and lower plate colony count value were detected in gelatin/Ag group than control. Micro-CT analysis showed a significant increase of newly formed bone volume fraction (BV/TV) in gelatin/Ag treated defects. The HE stained cranium sections also showed a faster rate of defect closure in gelatin/Ag group than control. These findings demonstrated that gelatin sponge with colloid silver can effectively reduce the infection caused by MRSA in cranial defects and accelerate bone healing process. PMID- 27770906 TI - Preparation of collagen peptide functionalized chitosan nanoparticles by ionic gelation method: An effective carrier system for encapsulation and release of doxorubicin for cancer drug delivery. AB - In recent years, nanoparticles (NPs) based on biopolymers or peptides are gaining popularity for the encapsulation and release of drug molecules, especially for cancer therapy, due to their ability for targeted and controlled release. The use of collagen peptide (CP) for the preparation of chitosan (CN) NPs is especially interesting as it results in NPs that are stable under physiological conditions. In this work, mono-dispersed pH responsive CPCN NPs of about 100nm were prepared via ionic gelation method by simple and mild co-precipitation of CN and CP. Investigation of NPs with Fourier transform infra-red (FTIR) spectroscopy and dynamic light scattering (DLS) measurements reveals that hydrogen bonding and electrostatic interactions are believed to be major driving forces for NP formation and drug encapsulation, respectively. Scanning electron microscopic (SEM) investigations show that hard and fine CPCN NPs transform to soft and bigger gel like particles as a function of collagen concentration. The unique "polymeric gel" structure of NPs showed high encapsulation efficiency towards doxorubicin hydrochloride (DOX) as well as pH controlled release. Anti proliferative and cell viability analysis revealed that DOX loaded NPs showed excellent anti-proliferative characteristics against HeLa cells with favorable biocompatibility against normal cells. Such NPs have high potential for use as smart drug delivery carriers in advanced cancer therapy. PMID- 27770907 TI - Reduced bacteria adhesion on octenidine loaded mesoporous silica nanoparticles coating on titanium substrates. AB - Bacterial infection is one of the most severe postoperative complications leading to implantation failure. The early bacterial stage (4-6h) was proved to be the "decisive period" for long-term bacteria-related infection. Thus, to endow potential early antibacterial capacity for a titanium (Ti) based implant, an effective antiseptic agent of octenidine dihydrochloride (OCT) was effectively loaded on the mesoporous silica nanoparticles (MSNs)-incorporated titania coating which was fabricated by an electrophoretic-enhanced micro-arc oxidation technique. The surface characteristic of the coatings were characterized by various methods (SEM, AFM, XPS, XRD, etc.), and its corrosion resistance was also examined by the potentiodynamic polarization curves. The composite coating without OCT loading not only displayed good cytocompatibility but also exhibited certain anti-bacterial property. After loading with OCT, its antibacterial efficiency of the titanium substrates with composite coating was greatly enhanced without compromising their cytocompatibility. The study provides an approach for the fabrication of anti-bacterial Ti implant for potential orthopedic application. PMID- 27770908 TI - Factors influencing the stability and type of hydroxyapatite stabilized Pickering emulsion. AB - Hydroxyapatite (HAp) nanoparticle stabilized Pickering emulsion was fabricated with poly(l-lactic acid) dissolved in dichloromethane (CH2Cl2) solution as oil phase and HAp aqueous dispersion as aqueous phase. Pickering emulsion was cured via in situ solvent evaporation method. Effect of PLLA concentrations, pH value, HAp concentrations, oil-water ratio, emulsification rates and times were studied on emulsion stability and emulsion type, etc. The results indicated emulsion stability increased with the increase of HAp concentration, emulsification rate and time; it is very stable when pH value of aqueous phase was adjusted to 10. Stable W/O and O/W emulsions were fabricated successfully using as-received HAp particles as stabilizer by adjusting the fabricating parameters. The interaction between HAp and PLLA played an important role to stabilize Pickering emulsions. SEM results indicated that both microsphere and porous materials were fabricated using emulsion stabilized by unmodified HAp nanoparticles, implying that both W/O and O/W emulsion type were obtained. PMID- 27770909 TI - On the texture, phase and tensile properties of commercially pure Ti produced via selective laser melting assisted by static magnetic field. AB - Tensile strength and ductility of Selective Laser Melting (SLM) processed commercially pure Ti (CP-Ti) were simultaneous enhanced by preforming the melting/solidification processes under Static Magnetic Field (SMF). The effects of SMF on microstructure and tensile properties were examined. The SMF-SLMed CP Ti sample presents a microstructure of fine acicular martensitic alpha'-Ti and lath-shaped alpha-Ti. Meanwhile, the texture structure of SLMed CP-Ti was eliminated after adding a SMF. The SMF-SLM process offers new avenues to ameliorate the microstructure and improve the mechanical properties of SLMed sample. PMID- 27770911 TI - Rapid, efficient and selective preconcentration of benzo[a]pyrene (BaP) by molecularly imprinted composite cartridge and HPLC. AB - In this study, cryogel-based molecularly imprinted composite cartridges were designed for the rapid, efficient, and selective preconcentration of benzo[a]pyrene (BaP) from water samples. First, a BaP-imprinted poly(2 hydroxyethyl methacrylate-N-methacryloyl-(L)-phenylalanine) composite cartridge was synthesized under semi-frozen conditions and characterized by scanning electron microscopy, elemental analysis, Fourier transform infrared spectroscopy, and swelling tests. After the optimization of preconcentration parameters, i.e., pH and initial BaP concentration, the selectivity and preconcentration efficiency, and reusability of these cartridges were also evaluated. In selectivity experiments, BaP imprinted composite cartridge exhibited binding capacities 3.09, 9.52, 8.87, and 8.77-fold higher than that of the non-imprinted composite cartridge in the presence of competitors, such as benzo[b]fluoranthene (BbF), benzo[k]fluoranthene (BkF), indeno[1,2,3-cd]pyrene (IcdP), and 1-naphthol, respectively. The method detection limit (MDL), relative standard deviation (RSD) and preconcentration efficiency (PE) of the synthesized composite cartridge were calculated as 24.86MUg/L, 1.60%, and 349.6%, respectively. PMID- 27770910 TI - Mg substituted apatite coating from alkali conversion of acidic calcium phosphate. AB - In this work, two solutions were developed: the first, rich in Ca2+, PO43- ions and the second, rich in Ca2+, PO43- and Mg2+, defined as Mg-modified precursor solution. For each Mg-modified precursor solution, the concentrations of Mg2+ ions were progressively increased by 5%, 10% and 15%wt. The aims of this research were to investigate the influence of magnesium ions substitution in calcium phosphate coatings on titanium surface and to evaluate these coatings by bioactivity assay in McCoy culture medium. The obtained coatings were characterized by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analysis, and the presence of Mg ions was confirmed by the inductively coupled plasma atomic emission spectroscopy (ICP) analysis. In vitro bioactivity assay in McCoy culture medium showed bioactivity after 14days in incubation for the HA and 10% Mg-monetite coatings. The high chemical stability of Mg-HA coatings was verified by the bioactivity assays, and no bone-like apatite deposition, characteristic of bioactivity, was observed for Mg-HA coatings, for the time period used in this study. PMID- 27770913 TI - Synthesis of tremella-like CoS and its application in sensing of hydrogen peroxide and glucose. AB - Different phases of cobalt sulfides have been fabricated by one-pot hydrothermal method. Comparing all of the prepared materials, and the results revealed that CoS was the most conductive and could accelerate electron transfer. The CoS presented tremella-like and excellent catalytic activities towards hydrogen peroxide and glucose. The sensor based on CoS performed amperometric sensing of hydrogen peroxide in a linear range between 5.00MUM and 14.82mM. Meanwhile, sensing of glucose with double-linear range, one is between 5.00MUM and 1.10mM, the other is between 1.20mM and 10.20mM. These due to the fact that more and more intermediate species absorb onto electrode surface with increasing the concentration of glucose, which limit the following glucose oxidation. Furthermore, the hydrogen peroxide and glucose sensors based on tremella-like CoS also exhibited excellent selectivity, stability, and reproducibility. Thus, the sensor showed potential utilities in hydrogen peroxide and glucose detection. PMID- 27770912 TI - Biocompatible cationic pullulan-g-desoxycholic acid-g-PEI micelles used to co deliver drug and gene for cancer therapy. AB - The greatest crux in the combination of chemotherapy and gene therapy is the construction of a feasible and biocompatible carrier for loading the therapeutic drug and gene simultaneously. Here, a new amphiphilic bifunctional pullulan derivative (named as PDP) synthesized by grafting lipophilic desoxycholic acid and low-molecular weight (1kDa) branched polyethylenimine onto the backbone of pullulan was evaluated as a nano-carrier for the co-delivery of drug and gene for potential cancer therapy. PDP exhibited good blood compatibility and low cytotoxicity in the hemolysis and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays, respectively. By self-assembly process, the amphiphilic PDP polymer formed cationic core-shell nanomicelles in aqueous solution with an average diameter of 160.8nm and a zeta potential of approximate 28mV. The PDP micelles had relative higher drug encapsulation efficiency (84.05%) and loading capacity (7.64%) for doxorubicin (DOX), an effective anti-tumor drug, demonstrating sustained drug release profile and good DNA-binding ability. The flow cytometry and confocal laser scanning microscopy showed that PDP/DOX micelles could be successfully internalized by MCF-7 cells, and presenting higher cytotoxicity against MCF-7 cells than that of free DOX. Furthermore, PDP micelles could efficiently transport tumor suppressor gene p53 into MCF-7 cells, and the expressed exogenous p53 protein induced MCF-7 cells to die. More excitedly, in comparison with single DOX or p53 delivery, the co-delivery of DOX and gene p53 using PDP micelles displayed higher cytotoxicity, induced higher apoptosis rate of tumor cells and blocked more effectively the migration of cancer cells in vitro. In tumor-bearing mice, co-delivery of DOX and p53 also exhibited enhanced antitumor efficacy as compared with single delivery of DOX or p53 alone. In summary, these results demonstrated that it is highly promising to use cationic PDP micelles for effectively co-delivering functional gene and chemotherapeutic agent, and thus improving antitumor efficacy and systemic toxicity. PMID- 27770914 TI - Corrosion resistance and biocompatibility of magnesium alloy modified by alkali heating treatment followed by the immobilization of poly (ethylene glycol), fibronectin and heparin. AB - In recent years, magnesium alloys are attracting more and more attention as a kind of biodegradable metallic biomaterials, however, their uncontrollable biodegradation speed in vivo and the limited surface biocompatibility hinder their clinical applications. In the present study, with the aim of improving the corrosion resistance and biocompatibility, the magnesium alloy (AZ31B) surface was modified by alkali heating treatment followed by the self-assembly of 3 aminopropyltrimethoxysilane (APTMS). Subsequently, poly (ethylene glycol) (PEG) and fibronectin or fibronectin/heparin complex were sequentially immobilized on the modified surface. The results of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed that the above molecules were successfully immobilized on the magnesium alloy surface. An excellent hydrophilic surface was obtained after the alkali heating treatment while the hydrophilicity decreased to some degree after the self-assembly of APTMS, the surface hydrophilicity was gradually improved again after the immobilization of PEG, fibronectin or fibronectin/heparin complex. The corrosion resistance of the control magnesium alloy was significantly improved by the alkali heating treatment. The self-assembly of APTMS and the following immobilization of PEG further enhanced the corrosion resistance of the substrates, however, the grafting of fibronectin or fibronectin/heparin complex slightly lowered the corrosion resistance. As compared to the pristine magnesium alloy, the samples modified by the immobilization of PEG and fibronectin/heparin complex presented better blood compatibility according to the results of hemolysis assay and platelet adhesion as well as the activated partial thromboplastin time (APTT). In addition, the modified substrates had better cytocompatibility to endothelial cells due to the improved anticorrosion and the introduction of fibronectin. The substrates modified by fibronectin or fibronectin/heparin complex can significantly promote endothelial cell adhesion and proliferation. Taking all these results into consideration, the method of the present study can be used for the surface modification of the magnesium alloy to simultaneously impart it better corrosion resistance, favorable blood compatibility and good cytocompatibility to endothelial cells. PMID- 27770915 TI - Histological structure affects recellularization of decellularized arteries. AB - Decellularized arteries were prepared to evaluate the in vivo recellularization of biological material after implantation. Porcine aortas and radial arteries were decellularized using high-hydrostatic pressure to form materials with histologically-different structures. Successful removal of cells from decellularized arteries was evaluated by hematoxylin-eosin staining and measurement of residual DNA. Cell remnants were eliminated completely from the decellularized arteries, and histological structures were preserved. Cells adhered to all decellularized artery samples, but infiltration of cells was observed only from the adventitial side of the decellularized radial artery. Rats were implanted subcutaneously with a decellularized aorta or radial artery to evaluate in vivo performance. Decellularized aortic tissue prevented cell infiltration better than that of the decellularized radial artery, suggesting that the elastin lamina in decellularized tissues prevents cell infiltration and suppresses recellularization. PMID- 27770916 TI - Biofilm behavior on sulfonated poly(ether-ether-ketone) (sPEEK). AB - Poly(ether-ether-ketone) (PEEK) has also shown to be very attractive for incorporating therapeutic compounds thanks to a sulfonation process which modifies the material structure resulting in a sulfonated-PEEK (sPEEK). Concerning biomedical applications, the objective of this work was to evaluate the influence of different sulfonation degree of sPEEK on the biofilm growth. PEEK samples were functionalized by using sulphuric acid (98%) and then dissolved into dimethyl-sulfoxide. A dip coating technique was used to synthesize sPEEK thin films. The sulfonation degree of the materials was analyzed by FT-IR, H NMR, TG and IEC. The surfaces were characterized by scanning electron microscopy, profilometry and contact angle analyses. Subsequently, the biofilm formation on sulfonated-PEEK based on Streptococcus mutans and Enterococcus faecalis was measured by spectrophotometry, colony forming units (CFUmL-1) and SEM. Results obtained from thermal and chemical analyses showed an intensification in sulfonation degree for sPEEK at 2 and 2.5h. The E. faecalis or S. mutans biofilm growth revealed statistically significant differences (p<0.05) between 2 and 3h sulfonation groups. A significant decrease (p<0.05) in CFUmL-1 was recorded for S. mutans or E. faecalis biofilm grown on 2.5 or 3h sPEEK. Regarding the thermal chemical and microbiologic analyses, the sulfonation degree of sPEEK ranging from 2 up to 3h was successful capable to decrease the biofilm growth. That revealed an alternative strategy to embed anti-biofilm and therapeutic compounds into PEEK avoiding infections in biomedical applications. PMID- 27770917 TI - Development of a custom biological scaffold for investigating ultrasound-mediated intracellular delivery. AB - In vitro investigations of ultrasound mediated, intracellular drug and gene delivery (i.e. sonoporation) are typically carried out in cells cultured in standard plastic well plates. This creates conditions that poorly resemble in vivo conditions, as well as generating unwanted ultrasound phenomena that may confound the interpretation of results. Here, we present our results in the development of a biological scaffold for sonoporation studies. The scaffolds were comprised of cellulose fibers coated with chitosan and gelatin. Scaffold formulation was optimized for adherence and proliferation of mouse fibroblasts in terms of the ratio and relative concentration of the two constituents. The scaffolds were also shown to significantly reduce ultrasound reflections compared to the plastic well plates. A custom treatment chamber was designed and built, and the occurrence of acoustic cavitation in the chamber during the ultrasound treatments was detected; a requirement for the process of sonoporation. Finally, experiments were carried out to optimize the ultrasound exposures to minimize cellular damage. Ultrasound exposure was then shown to enable the uptake of 100nm fluorescently labeled polystyrene nanoparticles in suspension into the cells seeded on scaffolds, compared to incubation of cell-seeded scaffolds with nanoparticles alone. These preliminary results set the basis for further development of this platform. They also provide motivation for the development of similar platforms for the controlled investigation of other ultrasound mediated cell and tissue therapies. PMID- 27770918 TI - Characterisation, in vitro release study, and antibacterial activity of montmorillonite-gentamicin complex material. AB - The present paper concerns the potential use of montmorillonite as a drug carrier and focusses on the intercalation of the studied clay with gentamicin (an aminoglycoside antibiotic) at various temperatures (20, 50 and 80 degrees C). The experiments were performed to identify the temperature required for the optimum intercalation of gentamicin into the interlayer of montmorillonite. The structural and microstructural properties of gentamicin and the potential for introducing it between smectite clay layers were investigated by means of X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopic techniques, and SEM with EDS analysis. Additionally, the in vitro drug release behaviour of the montmorillonite-gentamicin complex and its antibacterial activity against Escherichia coli (E. coli) bacteria was investigated. Based on these studies, the impact of temperature on the intercalation of the drug between layers of smectite was evaluated. It was found that an intercalation temperature of 50 degrees C resulted in the highest shift in the position of principle peak d(001) as measured by XRD, suggesting, that the greatest amount of gentamicin had been introduced into the interlayer space of montmorillonite at this temperature. Subsequently, the montmorillonite-gentamicin complex material obtained at 50 degrees C revealed the greatest capacity for killing E. coli bacteria during an in vitro test. PMID- 27770919 TI - Cytotoxicity of Pd nanostructures supported on PEN: Influence of sterilization on Pd/PEN interface. AB - Non-conventional antimicrobial agents, such as palladium nanostructures, have been increasingly used in the medicinal technology. However, experiences uncovering their harmful and damaging effects to human health have begun to appear. In this study, we have focused on in vitro cytotoxicity assessment of Pd nanostructures supported on a biocompatible polymer. Pd nanolayers of variable thicknesses (ranging from 1.1 to 22.4nm) were sputtered on polyethylene naphthalate (PEN). These nanolayers were transformed by low-temperature post deposition annealing into discrete nanoislands. Samples were characterized by AFM, XPS, ICP-MS and electrokinetic analysis before and after annealing. Sterilization of samples prior to cytotoxicity testing was done by UV irradiation, autoclave and/or ethanol. Among the listed sterilization techniques, we have chosen the gentlest one which had minimal impact on sample morphology, Pd dissolution and overall Pd/PEN interface quality. Cytotoxic response of Pd nanostructures was determined by WST-1 cell viability assay in vitro using three model cell lines: mouse macrophages (RAW 264.7) and two types of mouse embryonic fibroblasts (L929 and NIH 3T3). Finally, cell morphology in response to Pd/PEN was evaluated by means of fluorescence microscopy. PMID- 27770920 TI - Crystallisation of hydroxyapatite in phosphorylated poly(vinyl alcohol) as a synthetic route to tough mechanical hybrid materials. AB - Partially phosphorylated poly(vinyl alcohol) was prepared by treating poly(vinyl alcohol) with 100% phosphoric acid, and 5, 10 and 20% of the hydroxyl groups were converted to phosphoric acid ester. Addition of Ca2+ to an aqueous solution of phosphorylated poly(vinyl alcohol) gave a transparent gel. Five cycles of alternate soaking of the gel in aqueous CaCl2 and aqueous (NH4)2HPO4 were carried out to crystallise hydroxyapatite (HAP) in the phosphorylated poly(vinyl alcohol) matrix. The X-ray diffraction peaks of HAP formed in 5% phosphorylated PVA were sharp, while those of HAP formed in 20% phosphorylated PVA were broad. The contents of inorganic phase in the hybrid powder were increased from 58 to 76wt% as the fraction of phosphate groups in the gel was decreased from 20% to 5%. The hybrid powder was first subjected to uniaxial pressing, followed by cold isostatic pressing (CIP) and warm isostatic pressing (WIP) at 120 degrees C at pressures of 300-980MPa, to obtain the specimens for three-point bending test. These hybrid specimens showed bending strengths of 15-53MPa. The hybrid compacts prepared from 10% phosphorylated poly(vinyl alcohol) showed the smallest Young's modulus, the largest displacement at break, and the largest fracture energy, showing that it has the highest toughness among the hybrid materials prepared from poly(vinyl alcohol) with varying degrees of phosphorylation. PMID- 27770921 TI - Computational simulation of static/cyclic cell stimulations to investigate mechanical modulation of an individual mesenchymal stem cell using confocal microscopy. AB - It has been found that cells react to mechanical stimuli, while the type and magnitude of these cells are different in various physiological and pathological conditions. These stimuli may affect cell behaviors via mechanotransduction mechanisms. The aim of this study is to evaluate mechanical responses of a mesenchymal stem cell (MSC) to a pressure loading using finite elements method (FEM) to clarify procedures of MSC mechanotransduction. The model is constructed based on an experimental set up in which statics and cyclic compressive loads are implemented on a model constructed from a confocal microscopy 3D image of a stem cell. Both of the applied compressive loads are considered in the physiological loading regimes. Moreover, a viscohyperelastic material model was assumed for the cell through which the finite elements simulation anticipates cell behavior based on strain and stress distributions in its components. As a result, high strain and stress values were captured from the viscohyperelastic model because of fluidic behavior of cytosol when compared with the obtained results through the hyperelastic models. It can be concluded that the generated strain produced by cyclic pressure is almost 8% higher than that caused by the static load and the von Mises stress distribution is significantly increased to about 150kPa through the cyclic loading. In total, the results does not only trace the efficacy of an individual 3D model of MSC using biomechanical experiments of cell modulation, but these results provide knowledge in interpretations from cell geometry. The current study was performed to determine a realistic aspect of cell behavior. PMID- 27770922 TI - PLGA nano/microparticles loaded with cresyl violet as a tracer for drug delivery: Characterization and in-situ hyperspectral fluorescence and 2-photon localization. AB - Here we present the production, characterization and in-vivo assessment of cresyl violet-loaded biodegradable PLGA nano/microparticles (CV-NP and CV-MP). We demonstrate that the beneficial spectral characteristics of cresyl violet make it suitable as a tracer for particle-based drug delivery using both hyperspectral wide field and two-photon excited fluorescence microscopy. Particles were prepared using a cosolvent method, after which the physicochemical properties such as morphology, particle size, drug entrapment efficiency, drug loading and in vitro drug release behavior were measured in addition to spectroscopic properties, such as absorption, fluorescence and infrared spectra. The particles were then tested in an in vivo mouse model to assess their biodistribution characteristics. The location and integrity of particles after injection was determined using both hyperspectral fluorescence and two-photon microscopy within intact organs in situ. Our results show that cresyl violet is efficiently entrapped into PLGA particles, and that the particles are spherical in shape, ranging from 300 to 5070nm in diameter. Particle biodistribution in the mouse was found to depend on particle size, as expected. Cresyl violet is shown to be an ideal tracer to assess the properties PLGA particle-based drug delivery in combination with our novel multi-scale optical imaging techniques for in-situ particle localization. PMID- 27770923 TI - In-situ synthesis of magnetic iron-oxide nanoparticle-nanofibre composites using electrospinning. AB - We demonstrate a facile, one-step process to form polymer scaffolds composed of magnetic iron oxide nanoparticles (MNPs) contained within electrospun nano- and micro-fibres of two biocompatible polymers, Poly(ethylene oxide) (PEO) and Poly(vinyl pyrrolidone) (PVP). This was achieved with both needle and free surface electrospinning systems demonstrating the scalability of the composite fibre manufacture; a 228 fold increase in fibre fabrication was observed for the free-surface system. In all cases the nanoparticle-nanofibre composite scaffolds displayed morphological properties as good as or better than those previously described and fabricated using complex multi-stage techniques. Fibres produced had an average diameter (Needle-spun: 125+/-18nm (PEO) and 1.58+/-0.28MUm (PVP); Free-surface electrospun: 155+/-31nm (PEO)) similar to that reported previously, were smooth with no bead defects. Nanoparticle-nanofibre composites were characterised using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), dynamic light scattering (DLS) (Nanoparticle average diameter ranging from 8+/-3nm to 27+/-5nm), XRD (Phase of iron oxide nanoparticles identified as magnetite) and nuclear magnetic resonance relaxation measurements (NMR) (T1/T2: 32.44 for PEO fibres containing MNPs) were used to verify the magnetic behaviour of MNPs. This study represents a significant step forward for production rates of magnetic nanoparticle-nanofibre composite scaffolds by the electrospinning technique. PMID- 27770924 TI - Development of highly porous biodegradable gamma-Fe2O3/polyvinyl alcohol nanofiber mats using electrospinning process for biomedical application. AB - The use of electrospinning process in fabricating tissue engineering scaffolds has received great attention in recent years due to its simplicity. The nanofibers produced via electrospinning possessed morphological characteristics similar to extracellular matrix of most tissue components. Porosity plays a vital role in developing tissue engineering scaffolds because it influences the biocompatibility performance of the scaffolds. In this study, maghemite (gamma Fe2O3) was mixed with polyvinyl alcohol (PVA) and subsequently electrospun to produce nanofibers. Five factors; nanoparticles content, voltage, flow rate, spinning distance, and rotating speed were varied to produce the electrospun nanofibrous mats with high porosity value. Empirical model was developed using response surface methodology to analyze the effect of these factors to the porosity. The results revealed that the optimum porosity (90.85%) was obtained using 5% w/v nanoparticle content, 35kV of voltage, 1.1ml/h volume flow rate of solution, 8cm spinning distance and 2455rpm of rotating speed. The empirical model was verified successfully by performing confirmation experiments. The properties of optimum PVA/gamma-Fe2O3 nanofiber mats such as fiber diameter, mechanical properties, and contact angle were investigated. In addition, cytocompatibility test, in vitro degradation rate, and MTT assay were also performed. Results revealed that high porosity biodegradable gamma Fe2O3/polyvinyl alcohol nanofiber mats have low mechanical properties but good degradation rates and cytocompatibility properties. Thus, they are suitable for low load bearing biomedical application or soft tissue engineering scaffold. PMID- 27770925 TI - Polydiacetylene/triblock copolymer nanosensor for the detection of native and free bovine serum albumin. AB - Bovine serum albumin (BSA) has been recognized as a marker of the cow's health, milk quality, an allergenic protein and as a carrier. Its detection is important in the food, pharmaceutical and medical industries. However, traditional techniques used to detect BSA are often time-consuming, expensive, and show limited sensitivity. This paper describes properties of polydiacetylene-triblock copolymer (L64) nanosensors, synthesized to easily detect BSA. Sensor efficiency was studied as a function of nanosensor composition, polydiacetylene chemical structures, BSA conformation and hydrophobic domain availability, using spectroscopic, calorimetric, light scattering, and electrokinetic analyses. Nanosensors were sensitive to detect the average BSA concentration of milk and dairy products and discriminated between native and denatured protein through naked-eye detectable blue-to-red transition. The standard Gibbs free energy ( 10.4411 times. The association constant for the BSA/Ab-AFB1/nBi2O3/ITO immunosensor was determined as 7.318ng/dL. PMID- 27770930 TI - A polyamidoamne dendrimer functionalized graphene oxide for DOX and MMP-9 shRNA plasmid co-delivery. AB - It is a promising way to treat the multi drug resistance (MDR) of tumor cells in both of drug and gene methods. A polyamidoamne dendrimer functionalized graphene oxide (GO-PAMAM) was designed, which could load doxorubicin (DOX) and MMP-9 shRNA plasmid at the same time in order to achieve effective treatment to breast cancer. GO-PAMAM has a high loading capacity to DOX and pH-controlled DOX release. Besides, it has efficient gene transfer ability, the transfection efficiency is significantly better than PEI-25k in the presence of serum, and it can significantly inhibit the expression of MMP-9 protein in MCF-7 cells. The effect of DOX and MMP-9 shRNA plasmid co-delivery was more significant than that of the single drug. Moreover, GO-PAMAM exhibited lower cytotoxicity compared to PEI-25k in CCK-8 assays, and also showed a good biocompatibility in vivo. Therefore, GO-PAMAM will have broad prospects for drug and gene co-delivery. PMID- 27770931 TI - Development of 3D PCL microsphere/TiO2 nanotube composite scaffolds for bone tissue engineering. AB - In this research, the three dimensional porous scaffolds made of a polycaprolactone (PCL) microsphere/TiO2 nanotube (TNT) composite was fabricated and evaluated for potential bone substitute applications. We used a microsphere sintering method to produce three dimensional PCL microsphere/TNT composite scaffolds. The mechanical properties of composite scaffolds were regulated by varying parameters, such as sintering time, microsphere diameter range size and PCL/TNT ratio. The obtained results ascertained that the PCL/TNT (0.5wt%) scaffold sintered at 60 degrees C for 90min had the most optimal mechanical properties and an appropriate pore structure for bone tissue engineering applications. The average pore size and total porosity percentage increased after increasing the microsphere diameter range for PCL and PCL/TNT (0.5wt%) scaffolds. The degradation rate was relatively high in PCL/TNT (0.5wt%) composites compared to pure PCL when the samples were placed in the simulated body fluid (SBF) for 6weeks. Also, the compressive strength and modulus of PCL and PCL/TNT (0.5wt%) composite scaffolds decreased during the 6weeks of storage in SBF. MTT (3-(4,5 Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay and alkaline phosphates (ALP) activity results demonstrated that a generally increasing trend in cell viability was observed for PCL/TNT (0.5wt%) scaffold sintered at 60 degrees C for 90min compared to the control group. Eventually, the quantitative RT-PCR data provided the evidence that the PCL scaffold containing TiO2 nanotube constitutes a good substrate for cell differentiation leading to ECM mineralization. PMID- 27770932 TI - In vitro and in vivo assessment of chitosan modified urocanic acid as gene carrier. AB - Chitosan nanoparticles modified with 10 and 30% urocanic acid (CUA) via carbodiimide crosslinking were examined for an efficient gene delivery carrier. The CUA gene carrier was characterized by FTIR, TEM, SEM and the in vitro transfection efficiency CUA polyplex was tested with HeLa and 3T3 cells. The loading efficiency of CUA complexes with DNA was assessed at different N/P ratio of 1, 2, 4, 6, 8, and 10. The DNA loading efficiency was found be to >85% for chitosan, CUA10 and CUA30% and the DNA protection ability of CUA10 and CUA30 nanoparticle complexes was confirmed upon incubation with NheI and HindIII. The cell toxicity and cell viability results have supported the non-toxic nature of CUA10 and CUA30 nanoparticles. In vitro transfection efficiency of CUA10 and CUA30 polyplex was tested for EGFP expression in 3T3 and HeLa cells and a relative maximum % transfection of about 10% was confirmed by CUA10 and CUA30 after 96h transfection. The feasibility and biocompatibility of CUA gene carrier in transgenic chickens was also demonstrated. The in vitro transfection and in vivo embryonic viability studies further confirmed the CUA as promising gene carrier because of the improved biocompatibility and DNA protection ability. PMID- 27770933 TI - Fully glutathione degradable waterborne polyurethane nanocarriers: Preparation, redox-sensitivity, and triggered intracellular drug release. AB - Polyurethanes are important class of biomaterials that are extensively used in medical devices. In spite of their easy synthesis, polyurethanes that are fully degradable in response to the intracellular reducing environment are less explored for controlled drug delivery. Herein, a novel glutathione degradable waterborne polyurethane (WPU) nanocarrier for redox triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX) is reported. The WPU was prepared from polyaddition reaction of isophorone diisocyanate (IPDI) and a novel linear polyester polyol involving disulfide linkage, disulfide labeled chain extender, dimethylolpropionic acid (DMPA) using dibutyltin dilaurate (DBTDL) as a catalyst. The resulting polyurethane self-assembles into nanocarrier in water. The dynamic light scattering (DLS) measurements and scanning electron microscope (SEM) revealed fast swelling and disruption of nanocarriers under an intracellular reduction-mimicking environment. The in vitro release studies showed that DOX was released in a controlled and redox-dependent manner. MTT assays showed that DOX-loaded WPU had a high in vitro antitumor activity in both HDF noncancer cells and MCF- 7 cancer cells. In addition, it is found that the blank WPU nanocarriers are nontoxic to HDF and MCF-7 cells even at a high concentration of 2mg/mL. Hence, nanocarriers based on disulfide labeled WPU have appeared as a new class of biocompatible and redox-degradable nanovehicle for efficient intracellular drug delivery. PMID- 27770934 TI - Structural and rheological characterizations of nanoparticles of environment sensitive hydrophobic alginate in aqueous solution. AB - Amphiphilic polymers that form self-assembled structures in aqueous media have been investigated and used for the diagnosis and therapy of various diseases, including cancer. In our work, a series of environment-sensitive hydrophobic alginates (Ugi-Alg) with various weight-average molecular mass values (Mw~6.7*105 6.7*104g/mol) were synthesized via Ugi reaction. The structure of Ugi-Alg was characterized by 1HNMR spectrometer. The electrostatic self-assembly of different molecular weight (Mw) and composition (M/G ratio) of Ugi-Alg chain under various Na+ concentrations, was investigated by dynamic light scattering, electron spin resonance experiments, and transmission electron microscopy. Result showed that by comparing to other Ugi-Alg, the mid-Mw Ugi-Alg (Mw~2.8*105g/mol) could form stable and homogeneous nanoparticles in low Na+ concentration solution. However, G/M values exerted no obvious effect on nanoparticles structure. Additionally, steady-shear flow, thixotropy and dynamical viscoelasticity tests were performed to characterize the rheological behavior of Ugi-Alg aqueous solutions as influenced by Mw and M/G ratio. All of the samples exhibited a non-Newtonian shear-thinning behavior above a critical shear rate (gammac2). The greater the Mw, the more sensitive the temperature-dependent behavior will be. The upward downward rheograms showed that all of the systems evaluated in this study displayed a hysteresis loop, indicating a strong thixotropic behavior, and the thixotropic of mid-Mw Ugi-Alg was the strongest. The dynamical viscoelastic properties were characterized by oscillatory frequency sweep, revealing the gel like viscoelastic behavior of mid-low Ugi-Alg and the fluid-like viscoelastic behavior of high-Mw Ugi-Alg. PMID- 27770935 TI - Acellular dermal matrix loading with bFGF achieves similar acceleration of bone regeneration to BMP-2 via differential effects on recruitment, proliferation and sustained osteodifferentiation of mesenchymal stem cells. AB - New generation of barrier membranes has been developed, which not only act as barriers but also as delivery devices to release specific growth factors. This study observed biological behaviors of bone morrow mesenchymal stem cells (BMMSCs) pretreated by bFGF or BMP-2 in vitro and evaluated differential bone regeneration process induced by bFGF and BMP-2 loaded acellular dermal matrix (ADM) membrane using critical-size rat calvarial defect model in vivo. The results showed that the proliferation capability of BMMSCs pretreated by bFGF was stronger than that by BMP-2, while there was temporally differential effect of bFGF and BMP-2 pretreatment on MSC osteogenic differentiation potentials. During healing process of rat calvarial defects, 2-fold more CD34-/CD90+ MSCs in group of bFGF-ADM was observed than in any other treatment group at 2weeks. However, there were similar amount of new bone formation and expression of osteopotin in newly-formed bone tissue in groups of bFGF- and BMP-2-ADM at 8weeks, which were more than those in ADM alone and blank control. Taken together, bFGF-ADM guided similar bone regeneration to BMP-2 through more efficient recruitment of MSCs, and moreover, BMMSCs pretreated by bFGF showed stronger proliferation at 1-5days and osteogenic differentiation potentials at 14days compared with BMP-2 pretreatment. PMID- 27770936 TI - A novel electrochemical sensor based on FeS anchored reduced graphene oxide nanosheets for simultaneous determination of dopamine and acetaminophen. AB - In this paper, FeS nanoparticles anchored on reduced graphene oxide (rGO) nanosheets are synthesized via a facile direct-precipitation method. For the first time, a novel electrochemical sensor is developed based on FeS/rGO nanosheets modified glassy carbon electrode (GCE). It has been proved that the resultant FeS/rGO/GCE sensor is very suitable for the individual and simultaneous measurement of dopamine (DA) and acetaminophen (AC) and delivers excellent anti interference ability to ascorbic acid (AA) and uric acid (UA). Under optimum conditions with differential pulse voltammetry method, a broad linear response versus the concentrations of DA and AC has been observed in the ranges of 2.0 to 250.0MUM and 5.0 to 300.0MUM, respectively. The detection limits for DA and AC are 0.098MUM and 0.18MUM, respectively. Furthermore, the as-obtained sensor has been successfully utilized in real samples and satisfactory results have been achieved. Consequently, by virtue of its outstanding electrocatalytic activity, excellent sensitivity, and long time stability, the as-obtained FeS/rGO modified electrode can be considered as a new promising DA and AC sensor. PMID- 27770937 TI - Evaluation of the potential of rhTGF- beta3 encapsulated P(LLA-CL)/collagen nanofibers for tracheal cartilage regeneration using mesenchymal stems cells derived from Wharton's jelly of human umbilical cord. AB - Tracheal injuries are one of major challenging issues in clinical medicine because of the poor intrinsic ability of tracheal cartilage for repair. Tissue engineering provides an alternative method for the treatment of tracheal defects by generating replacement tracheal structures. In this study, core-shell nanofibrous scaffold was fabricated to encapsulate bovine serum albumin & rhTGF beta3 (recombinant human transforming growth factor-beta3) into the core of the nanofibers for tracheal cartilage regeneration. Characterization of the core shell nanofibrous scaffold was carried out by scanning electron microscope (SEM), transmission electron microscope (TEM), laser scanning confocal microscopy (LSCM), and tensile mechanical test. The rhTGF-beta3 released from the scaffolds in a sustained and stable manner for about 2months. The bioactivity of released rhTGF-beta3 was evaluated by its effect on the synthesis of type II collagen (COL2) and glycosaminoglycans (GAGs) by chondrocytes. The results suggested that its bioactivity was retained during release process. The proliferation and morphology analyses of mesenchymal stems cells derived from Wharton's jelly of human umbilical cord (WMSCs) indicated the good biocompatibility of the fabricated nanofibrous scaffold. Meanwhile, the chondrogenic differentiation of WMSCs cultured on core-shell nanofibrous scaffold was evaluated by real-time qPCR and histological staining. The results suggested that the core-shell nanofibrous scaffold with rhTGF-beta3 could promote the chondrogenic differentiation ability of WMSCs. Therefore, WMSCs could be a promising seed cells in the construction of tissue-engineered tracheal cartilage. Overall, the core-shell nanofibrous scaffold could be an effective delivery system for rhTGF-beta3 and served as a promising tissue engineered scaffold for tracheal cartilage regeneration. PMID- 27770938 TI - Biological and mechanical characterization of carbon fiber frameworks for dental implant applications. AB - OBJECTIVES: The aim of the present study was to investigate the biocompatibility and mechanical characteristics of dental implant frameworks made of carbon fiber composite. METHODS: The biocompatibility of intact samples and fragments was evaluated by cell count and MTT test according to EN-ISO 10993-5:2009 directions. Destructive and non-destructive mechanical tests were performed in order to evaluate: porosity, static and dynamic elastic modulus of carbon fiber samples. These tests were conducted on different batches of samples manufactured by different dental technicians. The samples were evaluated by optical microscope and by SEM. A compression test was performed to compare complete implant supported fixed dentures, provided with a metal or carbon fiber framework. RESULTS: Carbon fiber intact and fragmented samples showed optimal biocompatibility. Manufacture technique strongly influenced the mechanical characteristics of fiber-reinforced composite materials. The implant-supported full-arch fixed denture provided with a carbon fiber framework, showed a yield strength comparable to the implant-supported full-arch fixed denture, provided with a metal framework. SIGNIFICANCE: Carbon fiber-reinforced composites demonstrated optimal biocompatibility and mechanical characteristics. They appear suitable for the fabrication of frameworks for implant-supported full-arch dentures. Great attention must be paid to manufacture technique as it strongly affects the material mechanical characteristics. PMID- 27770940 TI - New strategy for design and fabrication of polymer hydrogel with tunable porosity as artificial corneal skirt. AB - In order to obtain an ideal material using for artificial corneal skirt, a porous polymer hydrogel containing 2-hydroxyethyl methacrylate (HEMA), trimethylolpropane triacrylate (TMPTA) and butyl acrylate was prepared through one-step radical polymerization method and the usage of CaCO3 whisker as porogen. The physical-chemical properties of the fabricated polymer hydrogel can be adjusted by CaCO3 whisker content, such as pore size, porosity, water content of materials and surface topography. Then a series of cell biology experiments of human corneal fibroblasts (HCFs) were carried out to evaluate its properties as an artificial corneal skirt, such as the adhesion of cells on the materials with different pore size and porosity, the apoptosis on materials with different characteristics, the distribution of the cells on the material surface. The results revealed that high porosity not only could improve water content of hydrogel, but also strengthen the adhesion of HCFs on hydrogel. In addition, high porosity hydrogel with the whisker shape of pores showed much elongate spindle like morphology than those low porosity hydrogels. MTT assay certified that the resulted polymer hydrogel material possessed excellent biocompatibility and was suitable for HCFs growing, making it promising for being developed as artificial corneal skirt. PMID- 27770939 TI - Synthesis, characterization of Ag-Au core-shell bimetal nanoparticles and its application for electrocatalytic oxidation/sensing of l-methionine. AB - The Ag-Au core-shell bimetal nanoparticles (BNPs) was prepared using chemical reduction method. The prepared Ag-Au core-shell BNPs were characterized by UV Visible (UV-Vis) spectroscopy, field emission scanning electron microscopy (FE SEM), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HR-TEM), X-ray diffraction (XRD), atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) pattern. These results showed the Ag-Au BNPs exhibited core-shell shape. The Ag-Au core-shell BNPs was examined towards electrocatalytic oxidation of l-methionine (l-Met) by cyclic voltammetry (CV), linear sweep voltammetry (LSV) and chronoamperometry. According to the results, l-Met is determined with detection limit of 30MUM. Interference studies in biological buffer was also studied. PMID- 27770941 TI - Bioactivity characterization of 45S5 bioglass using TL, OSL and EPR: Comparison with the case of 58S sol-gel bioactive glass. AB - The current work exploits the effective application of thermoluminescence (TL), optically stimulated luminescence (OSL) and the possibility of applying Electron Paramagnetic Resonance (EPR) for the discrimination between different bioactive responses in the case of the 45S5 bioactive glass (SiO2 45, Na2O 24.5, CaO 24.5, P2O5 6 in wt%), which was synthesized through melting process. These techniques are suggested mainly due to their low spectroscopic detection thresholds. The original 45S5 in grain size range of 20-40MUm was immersed in the Simulated Body Fluid (SBF) for various different immersion times ranging over one week. In this work the 110 degrees C TL peak, a specific OSL component and the EPR signal at g=2.013 ascribed to oxygen hole center (OHC) are used due to their sensitivity to the different bioactive responses. For all luminescence and EPR components, the intensity plot versus immersion time yields sharp discontinuities, resulting in effective probes regarding the timescale for both the beginning as well as the end of the procedure of the crystalline HCAp formation respectively. On the contrary to the smooth decreasing pattern of both luminescence entities, the peak to peak amplitude of the EPR signal indicates an initial increase for the initial 16min of immersion, followed by a further decrease throughout the immersion time duration. The discontinuities monitored for both sensitivity of TL, OSL and EPR, in conjunction with the discontinuities monitored for the sensitization of TL and OSL, when plotted versus immersion time, provide an individual time scale for each one of the chemical reactions involved in the five steps of the aforementioned procedure. According to the authors' best knowledge, scarce characterization techniques could provide this time scale frame, while it is the first time that such an application of OSL and EPR is attempted. Finally, the bioactive response of the 45S5 bioglass was compared with that of the 58S sol-gel bioactive glass, in terms of the timescale of these five stages required for the final formation of the HCAp. The techniques of luminescence and EPR which take advantage of trapped charges are proposed as alternative cheap and prompt effective techniques towards discrimination between different bioactive responses in bioactive glasses. PMID- 27770942 TI - An electrical bio-chip to transfer and detect electromagnetic stimulation on the cells based on vertically aligned carbon nanotubes. AB - A highly sensitive impedimetric bio-chip based on vertically aligned multiwall carbon nanotubes (VAMWCNTs), was applied in direct interaction with lung cancer cells. Our tool provided both inducing and monitoring the bioelectrical changes in the cells initiated by electromagnetic (EM) wave stimulation. EM wave of 940MHz frequency with different intensities was used. Here, wave ablation might accumulate electrical charge on the tips of nanotubes penetrated into cell's membrane. The charge might induce ionic exchanges into the cell and cause alterations in electrical states of the membrane. Transmembrane electrostatic/dynamic states would be strongly affected due to such exchanges. Our novel modality was that, the cells' vitality changes caused by charge inductions were electrically detected with the same nanotubes in the architecture of electrodes for impedance measurement. The responses of the sensor were confirmed by electron and florescent microscopy images as well as biological assays. In summation, our method provided an effective biochip for enhancing and detecting external EM stimulation on the cells useful for future diagnostic and therapeutic applications, such as wave-guided drug-resistance breakage. PMID- 27770943 TI - Insight into the collagen assembly in the presence of lysine and glutamic acid: An in vitro study. AB - The aim of this study is to evaluate the effects of two different charged amino acids in collagen chains, lysine and glutamic acid, on the fibrillogenesis process of collagen molecules. The turbidity, zeta potential, and fiber diameter analysis suggest that introducing the positively charged lysine into collagen might improve the sizes or amounts of the self-assembled collagen fibrils significantly. Conversely, the negatively charged glutamic acid might restrict the self-assembly of collagen building blocks into a higher order structure. Meanwhile, the optimal fibrillogenesis condition is achieved when the concentration of lysine reaches to 1mM. Both scanning electron microscopy (SEM) and atomic force microscope (AFM) analysis indicates that compared to pure collagen fibrils, the reconstructed collagen-lysine co-fibrils exhibit a higher degree of inter-fiber entanglements with more straight and longer fibrils. Noted that the specific D-period patterns of the reconstructed collagen fibrils could be clearly discernible and the width of D-banding increases steadily after introducing lysine. Besides, the kinetic and thermodynamic collagen self-assembly analysis confirms that the rate constants of both the first and second assembly phase decrease after introducing lysine, and lysine could promote the process of collagen fibrillogenesis obeying the laws of thermodynamics. PMID- 27770944 TI - Deferoxamine immobilized poly(D,L-lactide) membrane via polydopamine adhesive coating: The influence on mouse embryo osteoblast precursor cells and human umbilical vein endothelial cells. AB - Osteogenesis and angiogenesis play the prominent role in the bone regeneration. In this study, deferoxamine (DFO), an induced agent for osteogenesis and angiogenesis, was modified onto the surface of poly(D,L-lactide) (PDLLA) membrane via a facile and convenient approach based on the self-polymerization of dopamine (DOPA). The surface composition, morphology, hydrophilicity and surface energy of the original and modified PDLLA membranes were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), scanning electronic microscopy (SEM), atomic force microscopy (AFM) and contact angle measurement. The surface roughness and hydrophilicity of the PDLLA membrane were obviously increased by introducing either the single polydopamine (PDOPA) or the dual layers of PDOPA and DFO. In vitro cells culture experiments indicated that both the PDLLA/PDOPA and PDLLA/PDOPA-DFO composite membranes were more beneficial to the attachment, proliferation and spreading of MC3T3-E1 cells and HUVECs compared to the original PDLLA membrane. The PDLLA/PDOPA-DFO membrane was supportive for the proliferation of both MC3T3-E1 cells and HUVECs, and especially for HUVECs. The results suggested that the as-prepared PDLLA/PDOPA-DFO composite can be expected to be used as a promising bone regenerative material with promoted angiogenesis. PMID- 27770945 TI - Bioactive carbon-PEEK composites prepared by chemical surface treatment. AB - Polyetheretherketone (PEEK) has attracted much attention as an artificial intervertebral spacer for spinal reconstruction. Furthermore, PEEK plastic reinforced with carbon fiber has twice the bending strength of pure PEEK. However, the PEEK-based materials do not show ability for direct bone bonding, i.e., bioactivity. Although several trials have been conducted for enabling PEEK with bioactivity, few studies have reported on bioactive surface modification of carbon-PEEK composites. In the present study, we attempted the preparation of bioactive carbon-PEEK composites by chemical treatments with H2SO4 and CaCl2. Bioactivity was evaluated by in vitro apatite formation in simulated body fluid (SBF). The apatite formation on the carbon-PEEK composite was compared with that of pure PEEK. Both pure PEEK and carbon-PEEK composite formed the apatite in SBF when they were treated with H2SO4 and CaCl2; the latter showed higher apatite forming ability than the former. It is conjectured that many functional groups able to induce the apatite nucleation, such as sulfo and carboxyl groups, are incorporated into the dispersed carbon phase in the carbon-PEEK composites. PMID- 27770946 TI - Natural collagenic skeleton of marine sponges in pharmaceutics: Innovative biomaterial for topical drug delivery. AB - The growing interest in the use of recyclable and biodegradable natural materials has become a relevant topic in pharmaceutics. In this work, we suggest the use and valorization of natural horny skeleton of marine sponges (Porifera, Dictyoceratida) as bio-based dressing for topical drug delivery. Biomaterial characterization focusing on morpho-functional traits, swelling behavior, fluid uptake performances, glycosaminoglycans content and composition and microbiological quality assessment was carried out to investigate the collagenic skeleton properties. After grinding and sieving processes, l-cysteine hydrochloride-loaded formulations were designed in form of powder or polymeric film by testing various drug concentrations and different drying parameters. Drug content, SEM analyses and in vitro permeation studies were performed to test the suitability of skeleton-based formulations. To this respect, drying time and temperature are key parameters for skeleton-mediated drug crystallization. Consequently, this behavior seems to influence drug loading and permeation profiles of formulations. The high percentages of drug are found after absorption into sponge powder and in vitro permeation studies demonstrate that cysteine is released more slowly than the pure drug within 1h. Such a system is attractive because it combines the known healing properties of cysteine with the advantageous potentials of the collagen/proteoglycan network, which can act as biocompatible carrier able to absorb the excess of the wound exudate while releasing the drug. Furthermore, due to its glycosaminoglycans content, natural sponge skeletal scaffold might act as bioactive-biomimetic carrier regulating the wound healing processes. PMID- 27770947 TI - Molecular level interactions in brushite-aminoacids composites. AB - The interaction of aminoacids (Glycine, Proline, Lysine) with brushite based bone cements has been investigated by several techniques (FTIR spectroscopy, Thermogravimetry-TG, Scanning Electron Microscopy-SEM, mechanical properties studies), with the aim to elucidate the properties of the resulting composite materials and the interaction occurring at molecular level between the inorganic matrix and the organic moieties. Brushite phase is predominantly obtained also in the presence of aminoacids added during preparation of the bone cement. Focusing on Glycine incorporation, the presence of a fraction of bulk Glycine, weakly interacting with the inorganic matrix, together with Glycine specifically interacting with adsorption sites can be envisaged, as pointed out by FT IR and thermogravimetric data. In detail, FT-IR data evidenced changes in shape and position of bands associated to stretching modes of the carboxylic groups in Glycine structure, which can be explained by the coordination of these functional groups with the Ca ions in the matrix. Heating this composite at controlled temperature results in the detection of a condensation products, either cyclic condensation product, either dipeptide. Diffuse and not specific H-bonding seems to be the main form of interaction of Proline and Lysine with brushite. Due to the coordination with Ca ions here described, Glycine can act as retardant during brushite preparation, allowing good workability of the resulting composite. PMID- 27770948 TI - In vitro and in vivo insulin amyloid degradation mediated by Serratiopeptidase. AB - A transition of amyloidogenic protein by alternative folding pathway under certain conditions leads to the formation of protease resistant amyloid fibrils, having predominantly cross beta structure. These amyloids are related to various neurodegenerative diseases and clearance of such amyloids may be a therapeutic approach for amyloid-related diseases. Insulin, that can form amyloids, is widely used as a model amyloidogenic protein for the study of various amyloid related diseases. In this study, insulin amyloids were formed in vitro and the potential of Serratiopeptidase (SP), a fibrinolytic-like serine protease, towards the dissociation of insulin amyloids was explored. The dissociation of the amyloids was demonstrated using in vitro and in vivo using zebrafish model. The amyloid dissociation property was compared with a standard amyloid dissociating enzyme nattokinase (NK). SP shows better amyloid dissociation ability than NK and therefore, SP can be considered as amyloid dissociating agent with potential as a drug candidate for different amyloid related disorders. PMID- 27770949 TI - Super-paramagnetic responsive silk fibroin/chitosan/magnetite scaffolds with tunable pore structures for bone tissue engineering applications. AB - Tissue engineering is a promising approach in repairing damaged tissues. During the last few years, magnetic nanoparticles have been of great interest in this field of study due to their controlled responsive characteristics in specific external magnetic fields. In this study, after synthesizing iron oxide (magnetite) nanoparticles through a reverse coprecipitation method, silk fibroin/chitosan-based magnetic scaffolds were prepared using different amounts of magnetite nanoparticles (0, 0.5, 1 and 2%) by freeze-casting method. The physicochemical activity of the scaffolds was monitored in phosphate-buffered saline (PBS) solution to determine the biodegradation and swelling behaviors. The stability of the magnetite nanoparticles in the fabricated scaffolds was determined by atomic absorption spectroscopy (AAS). Moreover, the cellular activity of the magnetic scaffolds was examined under a static magnetic field. The results showed that the lamellar structured scaffolds having MNPs in the walls could not affect the final structure and deteriorate the biological characteristics of the scaffolds, while the ability of magnetic responsivity was added to the scaffolds. This study warrants further pre-clinical and clinical evaluations. PMID- 27770950 TI - Physico-chemical and mechanical characterization of in-situ forming xyloglucan gels incorporating a growth factor to promote cartilage reconstruction. AB - The development of growth factors is very promising in the field of tissue regeneration but specifically designed formulations have to be developed in order to enable such new biological entities (NBEs). In particular, the range of therapeutic concentrations is usually very low compared to other active proteins and the confinement in the target site can be of crucial importance. In-situ forming scaffolds are very promising solutions for minimally invasive intervention in cartilage reconstruction and targeting of NBEs. In this work injectable, in-situ forming gels of a temperature responsive partially degalactosylated xyloglucan (Deg-XG) incorporating the growth factor FGF-18 are formulated and characterized. In particular, injectability and shear viscosity at room temperature, time-to-gel at body temperature, morphology and mechanical properties of gels are investigated. The highly hydrophobic growth factor is favorably incorporated and retained by the gel. Gels undergo a slow erosion process when immersed in PBS at 37 degrees C that opens up their porous structure. The prolonged hydrothermal treatment leads to structural rearrangements towards tougher networks with increased dynamic shear modulus. Preliminary biological evaluations confirm absence of cytotoxicity and the ability of these scaffolds to host cells and promote their proliferation. PMID- 27770952 TI - Nanoscale upconversion for oxygen sensing. AB - Optical oxygen sensors have many promising qualities but rely on excitation by violet or blue wavelengths that suffer from high levels of scattering and absorption in biological tissues. Here we demonstrate an alternative method using 980nm near-infrared light to initially stimulate ceramic upconverting nanoparticles (UCNPs) contained within a novel form, electrospun core-shell fibers. The emission of the UCNPs excites a molecular optical oxygen sensor, the subsequent phosphorescent emission being dynamically quenched by the presence of molecular oxygen. The potential for use of such an energy transfer within electrospun fibers widely used in biological applications is promising. However, current knowledge of such 'handshake' interactions is limited. Fiber-based carriers enabling such optical conversions provide unique opportunities for biosensing as they recapitulate the topography of the extracellular matrix. This creates a wide array of potential theranostic, fiber-based applications in disease diagnosis/imaging, drug delivery and monitoring of therapeutic response. Using a fiber-based vehicle, we observed gaseous oxygen sensing capabilities and a linear Stern-Volmer response allowing highly accurate calibration. Configurational aspects were also studied to determine how to maximize the efficiency of this 'handshake' interaction. PMID- 27770951 TI - Application of quercetin and its bio-inspired nanoparticles as anti-adhesive agents against Bacillus subtilis attachment to surface. AB - The aim of this study was directed to reveal the repulsive effect of coated glass slides by quercetin and its bio-inspired titanium oxide and tungsten oxide nanoparticles on physical surface attachment of Bacillus subtilis as an ab-initio step of biofilm formation. Nanoparticles were successfully synthesized using sol gel and acid precipitation methods for titanium oxide and tungsten oxide, respectively (in the absence or presence of quercetin). The anti-adhesive impact of the coated-slides was tested through the physical attachment of B. subtilis after 24h using Confocal Laser Scanning Microscopy (CLSM). Here, quercetin was presented as a bio-route for the synthesis of tungsten mixed oxides nano-plates at room temperature. In addition, quercetin had an impact on zeta potential and adsorption capacity of both bio-inspired amorphous titanium oxide and tungsten oxide nano-plates. Interestingly, our experiments indicated a contrary effect of quercetin as an anti-adhesive agent than previously reported. However, its bio inspired metal oxide proved their repulsive efficiency. In addition, quercetin mediated nano-tungsten and quercetin-mediated amorphous titanium showed anti adhesive activity against B. subtilis biofilm. PMID- 27770953 TI - Superparamagnetic iron oxide nanoparticles conjugated with folic acid for dual target-specific drug delivery and MRI in cancer theranostics. AB - Monodispersed SPIONs (superparamagnetic iron oxide nanoparticles) co-coated with PEG and PEI polymers were prepared by an improved polyol method. To accomplish cancer-specific targeting properties, FA (folic acid) was then modified on the SPIONs via EDC/NHS method (FA-SPIONs). Doxorubicin (DOX) as an example anticancer drug was loaded within FA-SPIONs (DOX@FA-SPIONs), the DOX release rate of DOX@FA SPIONs was much high in low pH PBS. The SPIONs, FA-SPIONs and DOX@FA-SPIONs with mean hydrodynamic diameters of 23, 40 and 67nm, respectively, performed excellent colloidal stability in PBS. Confocal laser scanning microscope (CLSM) study implicates that the DOX@FA-SPIONs target MCF-7 cells efficiently through the FA receptor-mediated endocytosis. DOX@FA-SPIONs were tested in nude mice with xenograft MCF-7 breast tumor though tail intravenous injection and were found inhibiting tumor growth more efficiently. The application of a magnetic field (MF) greatly improved the growth inhibiting efficiencies of DOX@FA-SPIONs on MCF 7 cells in vitro and on xenograft MCF-7 breast tumor of nude mice in vivo. The aggregation of SPIONs in tumor was monitored by magnetic resonance imaging (MRI) as the DOX@FA-SPIONs exhibited high r2 relaxivity (81.77mM-1S-1). Histology on liver, Lung, kidney and heart in mice showed no significant toxicity of DOX@FA SPIONs on mice organs after 35-day treatment. The FA-SPIONs are a high efficient drug delivery nanoplatform for advanced cancer theranostics. PMID- 27770954 TI - Modeling of a biological material nacre: Waviness stiffness model. AB - Nacre is a tough yet stiff natural composite composed of microscopic mineral polygonal tablets bonded by a tough biopolymer. The high stiffness of nacre is known to be due to its high mineral content. However, the remarkable toughness of nacre is explained by its ability to deform past a yield point and develop large inelastic strain over a large volume around defects and cracks. The high strain is mainly due to sliding and waviness of the tablets. Mimicking nacre's remarkable properties, to date, is still a challenge due in part to fabrication challenges as well as a lack of models that can predict its properties or properties of a bulk material given specific constituent materials and material structure. Previous attempts to create analytical models for nacre include tablet sliding but don't account for the waviness of the tablets. In this work, a mathematical model is proposed to account for the waviness of the tablet. Using this model, a better prediction of the elastic modulus is obtained that agrees with experimental values found in the literature. In addition, the waviness angle can be predicted which is within the recommended range. Having a good representative model aids in designing a bio-mimicked nacre. PMID- 27770955 TI - Intermolecular interactions between B. mori silk fibroin and poly(l-lactic acid) in electrospun composite nanofibrous scaffolds. AB - In this study, composite nanofibrous scaffolds were obtained by electrospinning a trifluoroacetic acid solution containing B. mori silk fibroin (SF) and poly(l lactic acid) (PLLA) in a 1:1 weight ratio. SF, PLLA and SF/PLLA nanofibres were prepared with average diameter sizes of 360+/-90nm, 470+/-240nm and 580+/-220nm, respectively, as assessed by SEM analysis. Vibrational and thermal analyses showed that upon blending in the SF/PLLA nanofibres, the crystallisation of PLLA was hindered by the presence of SF, which crystallized preferentially and underwent conformational changes that did not significantly change its prevailing beta-sheet structure. The two components were thermodynamically compatible and the intermolecular interactions between them were revealed for the first time. Human keratinocytes were cultured on nanofibres and their viability and proliferation were determined. Preliminary in vitro tests showed that the incorporation of SF into the PLLA component enhanced cell adhesion and proliferation with respect to the unfunctionalised material. SF has been successfully used to modify the biomaterial properties and confirmed to be an efficient bioactive protein to mediate cell-biomaterial interaction. PMID- 27770956 TI - Simple and versatile method for creation of non-leaching antimicrobial surfaces based on cross-linked alkylated polyethyleneimine derivatives. AB - Novel quaternized polyethyleneimine and cross-linked polyethyleneimine derivatives have been synthesized using both traditional and microwave-assisted techniques to create antimicrobial coatings, with octyl, dodecyl, or hexadecyl bromides as alkylating agent and various bifunctional electrophiles as cross linkers. Quaternization has been performed using methyl iodide or dimethyl sulfate; it has been shown that methyl iodide has no advantages over dimethyl sulfate. Antimicrobial activity of the polymers against Gram-positive (S. aureus) and Gram-negative (P. aeruginosa) bacteria has been evaluated. Antimicrobial activity declines with increase in the alkylating agent chain length. Equimolar ratio of the alkylating agent and the primary amino groups in polyethyleneimine is optimal. Although cross-linking decreases the antimicrobial activity of quaternized polyethyleneimines, it improves their "non-leaching" properties (i.e. minimizes undesirable water washout of the polymeric coatings). PMID- 27770957 TI - Novel route for rapid sol-gel synthesis of hydroxyapatite, avoiding ageing and using fast drying with a 50-fold to 200-fold reduction in process time. AB - We have developed an innovative, rapid sol-gel method of producing hydroxyapatite nanopowders that avoids the conventional lengthy ageing and drying processes (over a week), being 200 times quicker in comparison to conventional aqueous sol gel preparation, and 50 times quicker than ethanol based sol-gel synthesis. Two different sets of experimental conditions, in terms of pH value (5.5 and 7.5), synthesis temperature (45 and 90 degrees C), drying temperature (60 and 80 degrees C) and calcination temperature (400 and 700 degrees C) were explored. The products were characterised by X-ray diffraction (XRD) Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and specific surface area (SSA) measurements. Pure hydroxyapatite (Ca10(PO4)6(OH)2, HAp) was obtained for the powders synthesised at pH7.5 and calcined at 400 degrees C, while biphasic mixtures of HAp/beta-tricalcium phosphate (beta-Ca3(PO4)2, TCP) were produced at pH5.5 and (pH7.5 at elevated temperature). The novel rapid drying was up to 200 times faster than conventional drying, only needing 1h with no prior ageing step, and favoured the formation of smaller/finer nanopowders, while producing pure HAp or phase mixtures virtually identical to those obtained from the slow conventional drying method, despite the absence of a slow ageing process. The products of this novel rapid process were actually shown to have smaller crystallite sizes and larger SSA, which should result in increased bioactivity. PMID- 27770958 TI - Preparation and properties of in-situ growth of carbon nanotubes reinforced hydroxyapatite coating for carbon/carbon composites. AB - Carbon nanotubes (CNTs) possess excellent mechanical properties for their role playing in reinforcement as imparting strength to brittle hydroxyapatite (HA) bioceramic coating. However, there are few reports relating to the in-situ grown carbon nanotubes reinforced hydroxyapatite (CNTs-HA) coating. Here we demonstrate the potential application in reinforcing biomaterials by an attempt to use in situ grown of CNTs strengthen HA coating, using a combined method composited of injection chemical vapor deposition (ICVD) and pulsed electrodeposition. The microstructure, phases and chemical compositions of CNTs-HA coatings were characterized by various advanced methods. The scanning electron microscopy (SEM) images indicated that CNTs-HA coatings avoided the inhomogeneous dispersion of CNTs inside HA coating. The result show that the interfacial shear strength between CNTs-HA coating and the C/C composite matrix reaches to 12.86+/-1.43MPa. Potenitodynamic polarization and electrochemical impedance spectroscopy (EIS) studies show that the content of CNTs affects the corrosion resistance of CNTs-HA coating. Cell culturing and simulated body fluid test elicit the biocompatibility with living cells and bioactivity of CNTs-HA coatings, respectively. PMID- 27770959 TI - Microstructure and compression properties of 3D powder printed Ti-6Al-4V scaffolds with designed porosity: Experimental and computational analysis. AB - The osseointegration of metallic implants depends on an effective balance among designed porosity to facilitate angiogenesis, tissue in-growth and bone-mimicking elastic modulus with good strength properties. While addressing such twin requirements, the present study demonstrates a low temperature additive manufacturing based processing strategy to fabricate Ti-6Al-4V scaffolds with designed porosity using inkjet-based 3D powder printing (3DPP). A novel starch based aqueous binder was prepared and the physico-chemical parameters such as pH, viscosity, and surface tension were optimized for drop-on-demand (DOD) based thermal inkjet printing. Micro-computed tomography (micro-CT) of sintered scaffolds revealed a 57% total porosity in homogeneously porous scaffold and 45% in the gradient porous scaffold with 99% interconnectivity among the micropores. Under uniaxial compression testing, the strength of homogeneously porous and gradient porous scaffolds were ~47MPa and ~90MPa, respectively. The progressive failure in homogeneously porous scaffold was recorded. In parallel to experimental measurements, finite element (FE) analyses have been performed to study the stress distribution globally and also locally around the designed pores. Consistent with FE analyses, a higher elastic modulus was recorded with gradient porous scaffolds (~3GPa) than the homogenously porous scaffolds (~2GPa). While comparing with the existing literature reports, the present work, for the first time, establishes 'direct powder printing methodology' of Ti-6Al-4V porous scaffolds with biomedically relevant microstructural and mechanical properties. Also, a new FE analysis approach, based on the critical understanding of the porous architecture using micro-CT results, is presented to realistically predict the compression response of porous scaffolds. PMID- 27770960 TI - The effect of the type of HA on the degradation of PLGA/HA composites. AB - The aim of this study is to explore the importance of the potentially competing effects of buffering effects of the calcium phosphate filler and particle mediated water sorption on the degradation products of poly(d,l lactide-co glycolide (50:50))(PLGA)/hydroxyapatite(HA) composites. Further the influence of type of HA on the mechanical properties of the composites was investigated. Phase pure HA was synthesised via a reaction between aqueous solutions of calcium hydroxide and orthophosphoric acid. The powder produced was either used as produced (uncalcined) or calcined in air or calcined in a humidified argon atmosphere. An in-vitro degradation study was carried out in phosphate buffered saline (PBS). The results obtained indicated that the degradation rate of the composite might be better understood if both the buffering effects and the rate of water sorption by the composites are considered. PMID- 27770962 TI - Mechanical properties of PNIPAM based hydrogels: A review. AB - Materials which adjust their properties in response to environmental factors such as temperature, pH and ionic strength are rapidly evolving and known as smart materials. Hydrogels formed by smart polymers have various applications. Among the smart polymers, thermoresponsive polymer poly(N-isopropylacrylamide)(PNIPAM) is very important because of its well defined structure and property specially its temperature response is closed to human body and can be finetuned as well. Mechanical properties are critical for the performance of stimuli responsive hydrogels in diverse applications. However, native PNIPAM hydrogels are very fragile and hardly useful for any practical purpose. Intense researches have been done in recent decade to enhance the mechanical features of PNIPAM hydrogel. In this review, several strategies including interpenetrating polymer network (IPN), double network (DN), nanocomposite (NC) and slide ring (SR) hydrogels are discussed in the context of PNIPAM hydrogel. PMID- 27770961 TI - Corrosion resistance characteristics of a Ti-6Al-4V alloy scaffold that is fabricated by electron beam melting and selective laser melting for implantation in vivo. AB - The purpose of this study is to determine the corrosion resistance of Ti-6Al-4V alloy fabricated with electron beam melting and selective laser melting for implantation in vivo. Ti-6Al-4V alloy specimens were fabricated with electron beam melting (EBM) and selective laser melting (SLM). A wrought form of Ti-6Al-4V alloy was used as a control. Surface morphology observation, component analysis, corrosion resistance experimental results, electrochemical impedance spectroscopy, crevice corrosion resistance experimental results, immersion test and metal ions precipitation analysis were processed, respectively. The thermal stability of EBM specimen was the worst, based on the result of open circuit potential (OCP) result. The result of electrochemical impedance spectroscopy indicated that the corrosion resistance of the SLM specimen was the best under the low electric potential. The result of potentiodynamic polarization suggested that the corrosion resistance of the SLM specimen was the best under the low electric potential (<1.5V) and EBM specimen was the best under the high electric potential (>1.5V).The crevice corrosion resistance of the EBM specimen was the best. The corrosion resistance of SLM specimen was the best, based on the result of immersion test. The content of Ti, Al and V ions of EBM, SLM and wrought specimens was very low. In general, the scaffolds that were fabricated with EBM and SLM had good corrosion resistance, and were suitable for implantation in vivo. PMID- 27770963 TI - Development of biodegradable metaloxide/polymer nanocomposite films based on poly epsilon-caprolactone and terephthalic acid. AB - The present investigation describes the development of metal-oxide polymer nanocomposite films from biodegradable poly-epsilon-caprolactone, disposed poly(ethylene terephthalate) oil bottles monomer and zinc oxide-copper oxide nanoparticles. The terephthalic acid and zinc oxide-copper oxide nanoparticles were synthesized by using a temperature-dependent precipitation technique and double precipitation method, respectively. The terephthalic acid synthesized was confirmed by FTIR analysis and furthermore, it was characterized by thermal analysis. The as-prepared CuO-ZnO nanoparticles structure was confirmed by XRD analysis and its morphology was analyzed by SEM/EDS and TEM. Furthermore, the metal-oxide polymer nanocomposite films have excellent mechanical properties, with tensile strength and modulus better than pure films. The metal-oxide polymer nanocomposite films that were successfully developed show a relatively brighter colour when compared to CuO film. These new metal-oxide polymer nanocomposite films can replace many non-degradable plastics. The new metal-oxide polymer nanocomposite films developed are envisaged to be suitable for use in industrial and domestic packaging applications. PMID- 27770964 TI - Strategies for delivering bone morphogenetic protein for bone healing. AB - Bone morphogenetic proteins (BMPs) are the most significant growth factors that belong to the Transforming Growth Factor Beta (TGF-beta) super-family. Though more than twenty members of this family have been identified so far in humans, Food and Drug Administration (FDA) approved two growth factors: BMP-2 and BMP-7 for treatments of spinal fusion and long-bone fractures with collagen carriers. Currently BMPs are clinically used in spinal fusion, oral and maxillofacial surgery and also in the repair of long bone defects. The efficiency of BMPs depends a lot on the selection of suitable carriers. At present, different types of carrier materials are used: natural and synthetic polymers, calcium phosphate and ceramic-polymer composite materials. Number of research articles has been published on the minute intricacies of the loading process and release kinetics of BMPs. Despite the significant evidence of its potential for bone healing demonstrated in animal models, future clinical investigations are needed to define dose, scaffold and route of administration. The efficacy and application of BMPs in various levels with a proper carrier and dose is yet to be established. The present article collates various aspects of success and limitation and identifies the prospects and challenges associated with the use of BMPs in orthopaedic surgery. PMID- 27770965 TI - Resorbable bone fixation alloys, forming, and post-fabrication treatments. AB - Metallic alloys have been introduced as biodegradable metals for various biomedical applications over the last decade owing to their gradual corrosion in the body, biocompatibility and superior strength compared to biodegradable polymers. Mg alloys possess advantageous properties that make them the most extensively studied biodegradable metallic material for orthopedic applications such as their low density, modulus of elasticity, close to that of the bone, and resorbability. Early resorption (i.e., <3months) and relatively inadequate strength are the main challenges that hinder the use of Mg alloys for bone fixation applications. The development of resorbable Mg-based bone fixation hardware with superior mechanical and corrosion performance requires a thorough understanding of the physical and mechanical properties of Mg alloys. This paper discusses the characteristics of successful Mg-based skeletal fixation hardware and the possible ways to improve its properties using different methods such as mechanical and heat treatment processes. We also review the most recent work pertaining to Mg alloys and surface coatings. To this end, this paper covers (i) the properties and development of Mg alloys and coatings with an emphasis on the Mg-Zn-Ca-based alloys; (ii) Mg alloys fabrication techniques; and (iii) strategies towards achieving Mg-based, resorbable, skeletal fixation devices. PMID- 27770966 TI - Preferential binding of positive nanoparticles on cell membranes is due to electrostatic interactions: A too simplistic explanation that does not take into account the nanoparticle protein corona. AB - The internalization of nanoparticles by cells (and more broadly the nanoparticle/cell interaction) is a crucial issue both for biomedical applications (for the design of nanocarriers with enhanced cellular uptake to reach their intracellular therapeutic targets) and in a nanosafety context (as the internalized dose is one of the key factors in cytotoxicity). Many parameters can influence the nanoparticle/cell interaction, among them, the nanoparticle physico-chemical features, and especially the surface charge. It is generally admitted that positive nanoparticles are more uptaken by cells than neutral or negative nanoparticles. It is supposedly due to favorable electrostatic interactions with negatively charged cell membrane. However, this theory seems too simplistic as it does not consider a fundamental element: the nanoparticle protein corona. Indeed, once introduced in a biological medium nanoparticles adsorb proteins at their surface, forming a new interface defining the nanoparticle "biological identity". This adds a new level of complexity in the interactions with biological systems that cannot be any more limited to electrostatic binding. These interactions will then influence cell behavior. Based on a literature review and on an example of our own experience the parameters involved in the nanoparticle protein corona formation as well as in the nanoparticle/cell interactions are discussed. PMID- 27770967 TI - A comprehensive study on the fabrication and properties of biocomposites of poly(lactic acid)/ceramics for bone tissue engineering. AB - The fabrication of a suitable scaffold material is one of the major challenges for bone tissue engineering. Poly(lactic acid) (PLA) is one of the most favorable matrix materials in bone tissue engineering owing to its biocompatibility and biodegradability. However, PLA suffers from some shortcomings including low degradation rate, low cell adhesion caused by its hydrophobic property, and inflammatory reactions in vivo due to its degradation product, lactic acid. Therefore, the incorporation of bioactive reinforcements is considered as a powerful method to improve the properties of PLA. This review presents a comprehensive study on recent advances in the synthesis of PLA-based biocomposites containing ceramic reinforcements, including various methods of production and the evaluation of the scaffolds in terms of porosity, mechanical properties, in vitro and in vivo biocompatibility and bioactivity for bone tissue engineering applications. The production routes range from traditional approaches such as the use of porogens to provide porosity in the scaffolds to novel methods such as solid free-form techniques. PMID- 27770968 TI - Manipulation of novel nano-prodrug composed of organic pigment-based hybrid network and its optical uses. AB - Here we developed the first case of pyropheophorbide-a-loaded PEGylated-hybrid carbon nanohorns (CNH-Pyro) to study tumor targeting therapy. During incubation with living cells, CNH-Pyro exhibited very intense red emissions. The intracellular imaging results were carried out by flow cytometry based on four different kinds of cell lines (including three adherent cell lines and one suspension cell line). Compared with free pyropheophorbide-a, CNH-Pyro demonstrated enhanced photodynamic tumor ablation efficiency during in vitro experiments due to improved biocompatibility of the hybrid nanomaterial and the photothermal therapy effect derived from carbon-network structure. Trypan blue staining experiments supported that the cell fate was dependent on the synergistic effects of both CNH-Pyro and laser irradiations. These results indicated that the chlorin-entrapped carbon nanohorns could provide powerful delivery vehicles for increasing photodynamic efficacy and possess early identification of the disease. PMID- 27770971 TI - Corrigendum to "Development of new radiopaque glass fiber posts" [Mater. Sci. Eng. C 2016; 59(1), 855-862]. PMID- 27770970 TI - Letter to the Editor re "Characterization of alginate-brushite in-situ hydrogel composites". PMID- 27770969 TI - A current overview of materials and strategies for potential use in maxillofacial tissue regeneration. AB - Tissue regeneration is rapidly evolving to treat anomalies in the entire human body. The production of biodegradable, customizable scaffolds to achieve this clinical aim is dependent on the interdisciplinary collaboration among clinicians, bioengineers and materials scientists. While bone grafts and varying reconstructive procedures have been traditionally used for maxillofacial defects, the goal of this review is to provide insight on all materials involved in the progressing utilization of the tissue engineering approach to yield successful treatment outcomes for both hard and soft tissues. In vitro and in vivo studies that have demonstrated the restoration of bone and cartilage tissue with different scaffold material types, stem cells and growth factors show promise in regenerative treatment interventions for maxillofacial defects. The repair of the temporomandibular joint (TMJ) disc and mandibular bone were discussed extensively in the report, supported by evidence of regeneration of the same tissue types in different medical capacities. Furthermore, in addition to the thorough explanation of polymeric, ceramic, and composite scaffolds, this review includes the application of biodegradable metallic scaffolds for regeneration of hard tissue. The purpose of compiling all the relevant information in this review is to lay the foundation for future investigation in materials used in scaffold synthesis in the realm of oral and maxillofacial surgery. PMID- 27770972 TI - A novel multistep method for chondroitin sulphate immobilization and its interaction with fibroblast cells. AB - Polymeric biomaterials are widely used in medical applications owing to their low cost, processability and sufficient toughness. Surface modification by creating a thin film of bioactive agents is promising technique to enhance cellular interactions, regulate the protein adsorption and/or avoid bacterial infections. Polyethylene is one of the most used polymeric biomaterial but its hydrophobic nature impedes its further chemical modifications. Plasma treatment is unique method to increase its hydrophilicity by incorporating hydrophilic oxidative functional groups and tailoring the surface by physical etching. Furthermore, grafting of polymer brushes of amine group containing monomers onto the functionalized surface lead to strongly immobilized bioactive agents at the final step. Chondroitin sulphate is natural polysaccharide mainly found in connective cartilage tissue which used as a bioactive agent to immobilize onto polyethylene surface by multistep method in this study. PMID- 27770973 TI - Checkpoint Inhibitors in Lung Cancer Are Not Immune from Cost-Effectiveness Analysis. PMID- 27770974 TI - Trimodality Approach to Stage IIIA-N2 NSCLC: As Good as It Gets? PMID- 27770975 TI - BRCA1-Associated Protein 1 Testing in Cancer. PMID- 27770976 TI - Expanding Tumor Lymphocytic Infiltration as a Prognostic Tool to Patients with NSCLC Who Are Treated with Radiotherapy? PMID- 27770977 TI - PD-L1 as a Companion Biomarker for Immune Checkpoint Inhibitors in NSCLC: Should RNA ISH (RISH) Be Considered? PMID- 27770978 TI - Adjuvant Chemotherapy, Retrospective Cohorts, and the Immortal Time Bias. PMID- 27770980 TI - Current methods to unravel ROS biology. PMID- 27770979 TI - It's All in the "Swerve of the Curve". PMID- 27770981 TI - Marine Mammals in the Mediterranean Sea: An Overview. AB - Despite being a small part of the world's oceans, the Mediterranean Sea hosts a diverse marine mammal fauna, with a total of 28 different species known to occur, or to have occurred, in the region. Species currently recognised as regular in the Mediterranean-the Mediterranean monk seal (Monachus monachus) and 11 cetaceans (fin whale, Balaenoptera physalus; sperm whale, Physeter macrocephalus; Cuvier's beaked whale, Ziphius cavirostris; short-beaked common dolphin, Delphinus delphis; long-finned pilot whale, Globicephala melas; Risso's dolphin, Grampus griseus; killer whale, Orcinus orca; striped dolphin, Stenella coeruleoalba; rough-toothed dolphin, Steno bredanensis; common bottlenose dolphin, Tursiops truncatus; harbour porpoise, Phocoena phocoena relicta) have adapted well to the region's environmental conditions, but their coexistence with humans is problematic. All the regular species are represented in the Mediterranean by populations genetically distinct from their North Atlantic relatives. Seventeen other species (three pinnipeds and 14 cetaceans) occur or have occurred in the Mediterranean as vagrants from adjacent regions. Impacts on the conservation status of marine mammals in the region deriving from a variety of threats include: (a) mortality caused by deliberate killing (to a large extent resulting from fisheries interactions), naval sonar, ship strikes, epizootics, fisheries bycatch, chemical pollution and ingestion of solid debris; (b) short term redistribution caused by naval sonar, seismic surveys, vessel disturbance and vessel noise; and (c) long-term redistribution caused by fishery-induced food depletion, coastal development and possibly climate change. Accordingly, seven of the 12 marine mammals regular in the Mediterranean region are listed as Threatened on IUCN's Red List; regrettably, three are Data Deficient and two remain unassessed. PMID- 27770982 TI - Cuvier's Beaked Whale, Ziphius cavirostris, Distribution and Occurrence in the Mediterranean Sea: High-Use Areas and Conservation Threats. AB - Cuvier's beaked whale (Ziphius cavirostris G. Cuvier, 1823) is the only beaked whale species commonly found in the Mediterranean Sea. Until recently, species presence in this area was only inferred from stranding events. Dedicated cetacean surveys have increased our knowledge of the distribution of Cuvier's beaked whales, even though many areas still remain unexplored. Here, we present an updated analysis of available sighting and stranding data, focusing on the atypical mass strandings that have occurred in the Mediterranean Sea since 1963. We describe in detail the five more recent events (2006-14), highlighting their relationship with naval exercises that used mid-frequency active sonar. The distribution of the species is apparently characterized by areas of high density where animals seem to be relatively abundant, including the Alboran Sea, Ligurian Sea, Central Tyrrhenian Sea, southern Adriatic Sea and the Hellenic Trench, but other such areas may exist where little or no survey work has been conducted. Population size has been estimated for the Alboran and Ligurian seas. Habitat modelling studies for those areas, confirmed the species preference for the continental slope and its particular association with submarine canyons, as has also been found to be the case in other areas of the world. The application of results from habitat modelling to areas different from their calibration sites is proposed as a management tool for minimizing the potential impacts of human activities at sea. Military sonar is known worldwide as a threat for this species and is suggested to be a major threat for Cuvier's beaked whale in the Mediterranean Sea. PMID- 27770983 TI - Conservation Status of Killer Whales, Orcinus orca, in the Strait of Gibraltar. AB - Killer whales (Orcinus orca) in the Mediterranean Sea are currently restricted to the Strait of Gibraltar and surrounding waters. Thirty-nine individuals were present in 2011, with a well-differentiated social structure, organized into five pods. Killer whale occurrence in the Strait is apparently related to the migration of their main prey, Atlantic bluefin tuna (Thunnus thynnus). In spring, whale distribution was restricted to shallow waters off the western coast of the Strait where all pods were observed actively hunting tuna. In summer, the whales were observed in the shallow central waters of the Strait. A relatively new feeding strategy has been observed among two of the five pods. These two pods interact with an artisanal drop-line fishery. Pods depredating the fishery had access to larger tuna in comparison with pods that were actively hunting. The Strait of Gibraltar killer whales are socially and ecologically different from individuals in the Canary Islands. Molecular genetic research has indicated that there is little or no female-mediated gene migration between these areas. Conservation threats include small population size, prey depletion, vessel traffic, and contaminants. We propose the declaration of the Strait of Gibraltar killer whales as an endangered subpopulation. A conservation plan to protect the Strait of Gibraltar killer whales is urgently needed, and we recommend implementation of a seasonal management area where activities producing underwater noise are restricted, and the promotion of bluefin tuna conservation. PMID- 27770984 TI - Conservation Status of Long-Finned Pilot Whales, Globicephala melas, in the Mediterranean Sea. AB - Mediterranean Sea long-finned pilot whales (Globicephala melas) are currently classified as Data Deficient on the International Union for the Conservation of Nature (IUCN) Red List. Multiple lines of evidence, including molecular genetic and photo-identification mark-recapture analyses, indicate that the Strait of Gibraltar population (distributed from 5.8 degrees W longitude to west of Djibouti Bank and Alboran Dorsal in the Alboran Sea) is differentiated from the Mediterranean Sea population (east of Djibouti Bank and the Alboran Dorsal up to the Ligurian Sea). There is low genetic diversity within the Mediterranean population, and recent gene flow with the Strait of Gibraltar population is restricted. Current total abundance estimates are lacking for the species in the Mediterranean. Pilot whales in the Alboran Sea region were negatively affected by a morbillivirus epizootic from 2006 to 2007, and recovery may be difficult. The Strait of Gibraltar population, currently estimated to be fewer than 250 individuals, decreased by 26.2% over 5 years after the morbillivirus epizootic. Population viability analyses predicted an 85% probability of extinction for this population over the next 100 years. Increasing maritime traffic, increased contaminant burdens, and occasional fisheries interactions may severely impair the capacity of the Strait of Gibraltar population to recover after the decline due to the pathogen. PMID- 27770985 TI - Risso's Dolphin, Grampus griseus, in the Western Ligurian Sea: Trends in Population Size and Habitat Use. AB - This paper provides a summary of 25 years of research on Risso's dolphins (Grampus griseus) in the western Ligurian Sea. Seasonal variations in abundance, distribution and habitat use were observed. Photographic mark-recapture methods provided a population size estimate for the period from 1998 to 2012, of about 100 individuals (95% CI of 60-220 individuals). The same methods detected a decline in population size from an average of about 120-150 from 2000 to 2005, to an average of 70-100 during 2010 to 2014. Species occurrence appeared to be significantly decreasing in coastal and continental slope areas, while it seemed to be stable in the most pelagic area. In addition, a dramatic change was observed in the local primary production, which was analysed based on time series of sea surface temperature and chlorophyll data from 1990 to 2014. Based on fisheries landings, there may have been a general decrease in fishery productivity, both in the western Ligurian Sea and in adjacent regions. Environmental variability, depletion of resources by fisheries and possibly interspecies competition may all have contributed to cause changes in Risso's dolphin habitat use and occurrence in the western Ligurian Sea. PMID- 27770986 TI - The Rough-Toothed Dolphin, Steno bredanensis, in the Eastern Mediterranean Sea: A Relict Population? AB - Only recently included among the cetacean species thought to regularly occur in the Mediterranean, the rough-toothed dolphin (Steno bredanensis) is an obscure and enigmatic member of this ensemble. Preliminary genetic evidence strongly indicates an Atlantic origin, yet the Mediterranean distribution for this species is conspicuously detached from the Atlantic, with all authenticated records during the last three decades being east of the Sicilian Channel and most within the bounds of the Levantine Basin. These dolphins are apparently a small, relict population, probably the remnant of a larger one, contiguous with that in the Atlantic and nowadays entrapped in the easternmost and warmest province. Abundance data are lacking for the species in the Mediterranean. Configuring acoustic detection software to recognise the apparently idiosyncratic vocalisations of rough-toothed dolphins in past and future acoustic recordings may prove useful for potential acoustic monitoring. Evidence accumulated so far, though scant, points to seasonal occupation of shallow coastal waters. Vulnerability to entanglement in gill-nets, contaminants in the region, and the occurrence of mass strandings (possibly in response to anthropogenic noise), are major conservation concerns for the population in the Mediterranean Sea. PMID- 27770987 TI - The Gulf of Ambracia's Common Bottlenose Dolphins, Tursiops truncatus: A Highly Dense and yet Threatened Population. AB - The common bottlenose dolphin (Tursiops truncatus) is the only cetacean present in the semiclosed waters of the Gulf of Ambracia, Western Greece. This increasingly degraded coastal ecosystem hosts one of the highest observed densities in the Mediterranean Sea for this species. Photo-identification data and tissue samples collected through skin-swabbing and remote biopsy sampling techniques during boat-based surveys conducted between 2006 and 2015 in the Gulf, were used to examine bottlenose dolphin abundance, population trends, site fidelity, genetic differentiation and toxicological status. Bottlenose dolphins showed high levels of year-round site fidelity throughout the 10-year study period. Dolphin population estimates mostly fell between 130 and 170 with CVs averaging about 10%; a trend in population size over the 10 years was a decline of 1.6% per year (but this was not significant). Genetic differentiation between the bottlenose dolphins of the Gulf and their conspecifics from neighbouring populations was detected, and low genetic diversity was found among individuals sampled. In addition, pesticides where identified as factors posing a real toxicological problem for local bottlenose dolphins. Therefore, in the Gulf of Ambracia, high dolphin density does not seem to be indicative of favourable conservation status or pristine habitat. PMID- 27770988 TI - Dolphins in a Scaled-Down Mediterranean: The Gulf of Corinth's Odontocetes. AB - The Gulf of Corinth is a 2400-km2 semi-enclosed inland system (a mediterraneus) in central Greece. Its continental shelf areas, steep bottom relief, and waters up to 500-900m deep offer suitable habitat to neritic and pelagic species. We used photographic capture-recapture, distribution modelling, and direct observations to investigate the abundance, status, habitat preferences, movements, and group size of four odontocete species regularly observed in the Gulf, based on five years (2011-2015) of survey effort from small boats. Striped dolphins (Stenella coeruleoalba) are more abundant (1324 individuals, 95%CI 1158 1515) than was determined from previous estimates. Striped dolphins appear to be confined to the Gulf, where they favour deep and oligotrophic waters, and were encountered in single-species and mixed-species groups. Short-beaked common dolphins (Delphinus delphis) (22 individuals, 95%CI 16-31), individuals with intermediate pigmentation (possibly striped/common dolphin hybrids) (55, 95%CI 36 83), and a single Risso's dolphin (Grampus griseus) were only encountered in mixed-species groups with striped dolphins. Short-beaked common dolphins constitute a discrete conservation unit (subpopulation), and based on the current estimate, would qualify as Critically Endangered according to International Union for the Conservation of Nature (IUCN) Red List criteria. Common bottlenose dolphins (Tursiops truncatus) (39 animals, 95%CI 33-47) occur in single-species groups; they prefer continental shelf waters and areas near fish farms in the northern sector, and several animals appear to move into and out of the Gulf. Additionally, we contribute records of marine fauna and an assessment of the fishing fleet operating in the Gulf. Our study shows that the importance of this vulnerable marine environment has been underestimated, and management action must be taken to mitigate human impact and ensure long-term protection. PMID- 27770989 TI - Harbour Porpoises, Phocoena phocoena, in the Mediterranean Sea and Adjacent Regions: Biogeographic Relicts of the Last Glacial Period. AB - The harbour porpoise, Phocoena phocoena, is one of the best studied cetacean species owing to its common distribution along the coastal waters of the Northern Hemisphere. In European waters, strandings are common and bycatch mortalities in commercial fisheries reach alarming numbers. Lethal interactions resulting from human activities together with ongoing environmental changes raise serious concerns about population viability throughout the species' range. These concerns foster the need to fill critical gaps in knowledge of harbour porpoise biology, including population structure, feeding ecology, habitat preference and evolutionary history, that are critical information for planning effective management and conservation efforts. While the species is distributed fairly continuously in the North Atlantic Ocean, it becomes fragmented in the south eastern part with isolated populations occurring along the Atlantic coasts of the Iberian Peninsula, Northwest Africa and the Black Sea. The latter population is separated from Atlantic populations by the Mediterranean Sea, where the species is almost entirely absent. Understanding the evolutionary history of these populations occurring in marginal habitats holds the potential to reveal fundamental aspects of the species' biology such as the factors determining its distribution, ecological niche, and how past and recent environmental variation have shaped the current population structure. This information can be critical for understanding the future evolution of the species in consideration of ongoing environmental changes. This chapter summarizes the recent advances in our knowledge regarding the populations bordering the Mediterranean Sea with a special emphasis on their ecological and evolutionary history, which has recently been reconstructed from genetic analyses. PMID- 27770990 TI - Are Mediterranean Monk Seals, Monachus monachus, Being Left to Save Themselves from Extinction? AB - Mediterranean monk seals (Monachus monachus), amongst the most endangered marine mammals, are showing localised signs of recovery warranting their recent down listing, from Critically Endangered to Endangered, on the International Union for the Conservation of Nature (IUCN) Red List. This, however, cannot be taken as a reason for complacency, as the species' condition is still very critical, having been extirpated from most of its historical range. Monk seals within the Mediterranean, a 'unit to conserve' separate from Atlantic conspecifics, were once widely distributed throughout the Mediterranean Sea, with their range also extending into the Sea of Marmara and the Black Sea. Today breeding nuclei persist only in the northeastern portion of the region, in Greek, Turkish and Cypriot waters. The main reasons for their decline include deliberate killing and human encroachment of their critical habitat. Past conservation efforts have mostly failed due to the inability of implementing institutional commitments, lack of coordination and continuity of efforts and insufficient consideration of the socioeconomic implications of conserving monk seals. Yet the small reversal of the species' decline that has been observed in Greece may have resulted from conservation efforts by civil society, combined with ongoing societal change within the local communities coexisting with the seals. The inaccessibility of large portions of monk seal habitat in the Eastern Mediterranean Sea may also have contributed, by offering to the monk seals a refuge from persecution and encroachment. Despite continued threats to monk seals, conservation activities at the local scale that utilise lessons learned from previous failures and successes could secure the survival of the largest Mediterranean colony of monk seals, while also providing a model to support the species' recovery in other portions of its former range. PMID- 27770991 TI - Mediterranean Sperm Whales, Physeter macrocephalus: The Precarious State of a Lost Tribe. AB - First observed in the classical era, a population of sperm whales (Physeter macrocephalus) persists to this day in the deep waters of the Mediterranean Sea. Genetic and observational evidence support the notion that this is an isolated population, separated from its Atlantic neighbours. These whales depend on mesopelagic squid for food, and appear to occupy a very similar ecological niche to sperm whales in the open oceans. Recent evidence proving that individuals can pass between the eastern and western deep water basins confirms that this is a single population, not isolated into western and eastern stocks. We lack robust information on their population status, but they could number in the hundreds rather than thousands, and current densities appear to be much lower than those reported in the 1950s, suggesting that we should be very concerned about the conservation status of this population. This makes it vitally important to address the serious threats posed by ship strikes and entanglement in fishing nets, especially driftnets, and to carefully monitor other potential sources of anthropogenic impact. A step change in funding to collect better data and a clear shift in policy priorities are needed if we are to be serious about conserving this population. PMID- 27770993 TI - Fin Whales, Balaenoptera physalus: At Home in a Changing Mediterranean Sea? PMID- 27770992 TI - The International Legal Framework for Marine Mammal Conservation in the Mediterranean Sea. AB - The paper reviews the international treaties that are today applicable for the protection of marine mammals in the Mediterranean Sea. They include instruments applicable at the world or the regional level. Emphasis is put on the International Whaling Commission, which is today affected by a confrontation between the two opposing groups of nonwhaling and whaling parties, the Agreement on the Conservation of Cetaceans of the Black Sea, Mediterranean Sea and Contiguous Atlantic Area (ACCOBAMS) and its implementation through the resolutions adopted by the Meeting of the Parties, as well as the subregional Agreement between France, Italy and Monaco for the establishment of a sanctuary for the protection of marine mammals (Pelagos Sanctuary). While several treaty provisions are in place to ensure the protection of marine mammals in the Mediterranean, specific mandatory provisions are still lacking for certain subjects, such as underwater noise, collisions with ships, by catch in fishing gear and ingestion of plastic litter. PMID- 27770994 TI - Preface. PMID- 27770995 TI - [Localized prostate cancer: Changes are still expected]. PMID- 27770996 TI - Spray-dried microparticles of glutathione and S-nitrosoglutathione based on Eudragit(r) FS 30D polymer. AB - OBJECTIVE: In recent years, S-nitrosoglutathione has been proposed for the treatment of Crohn's disease to prevent mucosal barrier failure. In this paper, we report the formulation of spray dried microparticles of glutathione and S nitrosoglutathione based on Eudragit(r) FS 30D polymer (i.e. colon-specific delivery system). MATERIAL AND METHODS: The influence of several spray-drying parameters (inlet temperature 80-150 degrees C, solvent flow 5-10mL/min) was studied. The parameters that yielded the best formulations (inlet temperature 120 degrees C, outlet temperature 47 degrees C, solvent flow 5mL/min and air flow 100%) were selected for further studies. RESULTS: Scanning electron microscopy revealed that the resulting microparticles were spherical in shape. The powder X ray diffraction patterns of pure GSH and GSNO showed sharp peaks that were not present in the microparticles, confirming a molecular dispersion of the drugs by the polymer. The stability of the drugs in the microparticles was confirmed by Fourier transform infrared spectroscopy. Release studies in phosphate buffer solutions showed fast release at basic pH 7.4, sustained release at pH 6.8, but practically no release at the acidic pHs of 1.2, 3 and 6 for the pH-sensitive microparticles. The microparticles prevented the release of drugs at acidic pH while demonstrating fast release at basic pH 7.4; this suggests the suitability of these microparticles to be evaluated for specific colon targeting. CONCLUSION: Using Eudragit(r) FS 30D as a gastro-resistant rate-controlling polymer, S nitrosoglutathion could be targeted to the colon for further studies in the treatment of inflammatory bowel diseases including Crohn's disease. PMID- 27770997 TI - Update on Merkel Cell Carcinoma: Epidemiology, Etiopathogenesis, Clinical Features, Diagnosis, and Staging. AB - Merkel cell carcinoma (MCC) is a rare, highly aggressive tumor, and local or regional disease recurrence is common, as is metastasis. MCC usually develops in sun-exposed skin in patients of advanced age. Its incidence has risen 4-fold in recent decades as the population has aged and immunohistochemical techniques have led to more diagnoses. The pathogenesis of MCC remains unclear but UV radiation, immunosuppression, and the presence of Merkel cell polyomavirus in the tumor genome seem to play key roles. This review seeks to update our understanding of the epidemiology, etiology, pathogenesis, and clinical features of MCC. We also review histologic and immunohistochemical features required for diagnosis. MCC staging is discussed, given its great importance in establishing a prognosis for these patients. PMID- 27770998 TI - Formation of alloy nanoparticles by laser ablation of Au/Fe multilayer films in liquid environment. AB - Laser ablation in liquids (LAL) emerged as a powerful technique for the synthesis of multielement nanoparticles (NPs) such as metal alloys with thermodynamically forbidden composition. Consequently, there is a great interest in expanding the current knowledge about NPs formation during LAL, in order to improve the control on product structure and to extend the range of compositions accessible by this technique. Here we performed a systematic investigation on alloy NPs formation by nanosecond LAL of Au/Fe/glass multilayers with different thickness and order of deposition. The experiments were carried out in ethanol and water, which have, respectively, favourable and unfavourable effects on alloy formation. Results were analyzed with optical absorption spectroscopy, transmission electron microscopy and Mie theory for simple and core-shell spheres. Since alloy NPs were obtained in all cases, our findings provide the evidence that the two metals are mixed during particles formation. Besides, our results suggest that the probability of interaction between ablated matter and solution species is higher for the topmost layer of the target, i.e. the one closer to the solid/liquid interface. This provides useful insight for the synthesis of nanoalloys with new compositions, that are of interest in several fields, from catalysis to photonics and nanomedicine. PMID- 27770999 TI - The generic modeling fallacy: Average biomechanical models often produce non average results! AB - Computational biomechanics models constructed using nominal or average input parameters are often assumed to produce average results that are representative of a target population of interest. To investigate this assumption a stochastic Monte Carlo analysis of two common biomechanical models was conducted. Consistent discrepancies were found between the behavior of average models and the average behavior of the population from which the average models' input parameters were derived. More interestingly, broadly distributed sets of non-average input parameters were found to produce average or near average model behaviors. In other words, average models did not produce average results, and models that did produce average results possessed non-average input parameters. These findings have implications on the prevalent practice of employing average input parameters in computational models. To facilitate further discussion on the topic, the authors have termed this phenomenon the "Generic Modeling Fallacy". The mathematical explanation of the Generic Modeling Fallacy is presented and suggestions for avoiding it are provided. Analytical and empirical examples of the Generic Modeling Fallacy are also given. PMID- 27771000 TI - A swelling of the lateral portion of the hard palate. PMID- 27771001 TI - Esthetic perception of changes in facial profile resulting from orthodontic treatment with extraction of premolars: A systematic review. AB - BACKGROUND: The authors conducted a systematic review to assess changes in patients' facial profiles resulting from orthodontic treatment with and without extraction of 4 premolars and to identify cephalometric parameters that can assist decision making in borderline cases. TYPES OF STUDIES REVIEWED: The authors conducted a systematic review of randomized clinical trials and observational studies comparing the 2 types of treatment (with and without premolar extraction) in terms of the changes in facial profile. The authors conducted an electronic search of the databases the Cochrane Library, PubMed MEDLINE, Embase, and Latin-American and Caribbean Health Sciences Literature. RESULTS: The authors identified 1 clinical trial with 26 participants and 5 observational cohort studies, collectively involving 362 participants. The authors assessed cephalometric parameters and esthetic outcomes. Four studies used linear regression analysis to investigate esthetic interaction between treatment strategy and initial lower lip protrusion. The 4 studies determined that if the initial lip protrusion was beyond a determined point, esthetic preferences favored extraction, and if the initial lip protrusion was not to that point, esthetic preferences favored conservative treatment. CONCLUSIONS AND PRACTICAL IMPLICATIONS: The results of the authors' systematic review found no significant differences between the groups in terms of the esthetic outcomes. The cephalometric parameter of initial lip protrusion can help with decision making in borderline cases. PMID- 27771002 TI - Effectiveness and Safety of an Independently Run Nurse Practitioner Outpatient Cardioversion Program (2009 to 2014). AB - Sustained growth in the arrhythmia population at Stanford Health Care led to an independent nurse practitioner-run outpatient direct current cardioversion (DCCV) program in 2012. DCCVs performed by a medical doctor, a nurse practitioner under supervision, or nurse practitioners from 2009 to 2014 were compared for safety and efficacy. A retrospective review of the electronic medical records system (Epic) was performed on biodemographic data, cardiovascular risk factors, medication history, procedural data, and DCCV outcomes. A total of 869 DCCVs were performed on 557 outpatients. Subjects were largely men with an average age of 65 years; 1/3 were obese; most had atrial fibrillation; and majority of subjects were on warfarin. The success rate of the DCCVs was 93.4% (812 of 869) with no differences among the groups. There were no short-term complications: stroke, myocardial infarction, or death. The length of stay was shortest in the NP group compared to the other groups (p <0.001). In conclusion, the success rate of DCCV in all groups was extremely high, and there were no complications in any of the DCCV groups. PMID- 27771003 TI - Effect of Diffuse Subendocardial Hypoperfusion on Left Ventricular Cavity Size by 13N-Ammonia Perfusion PET in Patients With Hypertrophic Cardiomyopathy. AB - Vasodilator-induced transient left ventricular (LV) cavity dilation by positron emission tomography (PET) is common in patients with hypertrophic cardiomyopathy (HC). Because most patients with PET-LV cavity dilation lack obstructive epicardial coronary artery disease, we hypothesized that vasodilator-induced subendocardial hypoperfusion resulting from microvascular dysfunction underlies this result. To test this hypothesis, we quantified myocardial blood flow (MBF) (subepicardial, subendocardial, and global MBF) and left ventricular ejection fraction (LVEF) in 104 patients with HC without significant coronary artery disease, using 13NH3-PET. Patients with HC were divided into 2 groups, based on the presence/absence of LV cavity dilation (LVvolumestress/LVvolumerest >1.13). Transient PET-LV cavity dilation was evident in 52% of patients with HC. LV mass, stress left ventricular outflow tract gradient, mitral E/E', late gadolinium enhancement, and prevalence of ischemic ST-T changes after vasodilator were significantly higher in patients with HC with LV cavity dilation. Baseline LVEF was similar in the 2 groups, but LV cavity dilation+ patients had lower stress LVEF (43 +/- 11 vs 53 +/- 10; p <0.001), lower stress-MBF in the subendocardial region (1.6 +/- 0.7 vs 2.3 +/- 1.0 ml/min/g; p <0.001), and greater regional perfusion abnormalities (summed difference score: 7.0 +/- 6.1 vs 3.9 +/- 4.3; p = 0.004). The transmural perfusion gradient, an indicator of subendocardial perfusion, was similar at rest in the 2 groups. Notably, LV cavity dilation+ patients had lower stress-transmural perfusion gradients (0.85 +/- 0.22, LV cavity dilation+ vs 1.09 +/- 0.39, LV cavity dilation-; p <0.001), indicating vasodilator-induced subendocardial hypoperfusion. The stress-transmural perfusion gradient, global myocardial flow reserve, and stress-LVEF were associated with LV cavity dilation. In conclusion, diffuse subendocardial hypoperfusion and myocardial ischemia resulting from microvascular dysfunction contribute to development of transient LV cavity dilation in HC. PMID- 27771005 TI - Reply to letter to the editor. PMID- 27771004 TI - Prenatal exposure to low-level methylmercury alters the child's fine motor skills at the age of 18 months. AB - OBJECTIVES: To compare motor, cognitive and language characteristics in children aged 18 months who were prenatally exposed to low-level methyl-mercury (MeHg), and to analyze the eventual differences in these characteristics in relation to cord blood THg concentration. PATIENTS AND METHODS: The total number of 205 child mother pairs was included in the study, and total cord blood mercury was measured in 198 of them. Out of the 198 already measured samples, 47 of them have also been tested for methyl-mercury in cord blood. Data regarding the 47 samples of MeHg levels has been used for calculating the correlation between cord blood THg and cord blood MeHg. MeHg and THg showed a significant correlation (r=0.95, p<0.05). One month after the delivery, mothers were asked to complete the questionnaire regarding socioeconomic factors, breastfeeding of their infants, and dietary habits during pregnancy. Neurodevelopmental assessment of motor, cognitive and language skills were conducted on 168 children using The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Regarding the cord blood THg concentration, 135 children were divided in 4 quartile groups. Their neurodevelopmental characteristics have been compared. RESULTS: The cord blood THg concentration median and inter-quartile range was 2.98ng/g (1.41 5.61ng/g). There was a negative correlation between cord blood THg concentration and fine motor skills (rho=-0.22, p=0.01). It is evident that children grouped in 2nd ,3rd and 4th quartile had statistically significant lower fine motor skills assessment related to those grouped in 1st quartile (2nd quartile -1.24, p=0.03; 3rd quartile -1.28, p=0.03; 4th quartile -1.45, p=0.01). The differences in fine motor skills assessments between children in 2nd and 3rd and 3rd and 4th quartile were not statistically significant. CONCLUSION: Intrauterine exposure to low level THg (MeHg) is associated with alterations in fine motor skills at the age of 18 months. PMID- 27771006 TI - Epidemiologic Characteristics of Children with Blood Lead Levels >=45 MUg/dL. AB - OBJECTIVES: To identify risk factors and describe outcomes for children newly identified with blood lead levels (BLLs) >=45 ug/dL in New York City (NYC) during 2004-2010 to promote timely identification as well as inform clinical practice and public health policy. STUDY DESIGN: Inclusion criteria were residence in NYC and an elevated confirmatory venous test within 2 weeks of the initial BLL >=45 ug/dL. Data collected during case coordination of these children were linked with blood testing data and home inspection reports. Children with BLLs >=45 ug/dL also were compared with the general population of children younger than 18 years of age in NYC. RESULTS: A total of 145 children <18 years of age were newly identified with BLLs >=45 ug/dL. The mean age was 3.83 years, and the median time for BLL to decline below 10 ug/dL was 3.26 years. Major reported risk factors were eating paint (36%), spending time outside the US (34%), having a developmental delay (27%), using imported products (26%), being foreign born (14%), being of Pakistani descent (12%), eating soil (5%), and having sickle cell disease (4%). Compared with the age-standardized NYC population, cases were more likely to be Asian or black and live in housing built before 1940. CONCLUSIONS: Although the incidence of lead poisoning has declined in the US, severe cases still occur. Physicians should be especially vigilant in certain at-risk populations including children who eat paint chips or soil, spend time outside the US (particularly in Pakistan), use imported products, or have developmental delays or sickle cell disease. PMID- 27771007 TI - Development of a checklist (I-SEAVD) for public health nutrition programmes related to cardiovascular disease in Southeast Asia. PMID- 27771008 TI - Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation at high risk of bleeding and normal kidney function. AB - INTRODUCTION: The comparative cost-effectiveness of all oral anticoagulants approved up to date has not been evaluated from the US perspective. The objective of this study was to compare the cost-effectiveness of edoxaban 60mg, apixaban 5mg, dabigatran 150mg, dabigatran 110mg, rivaroxaban 20mg and warfarin in stroke prevention in atrial fibrillation patients at high-risk of bleeding (defined as HAS-BLED score>=3). MATERIALS AND METHODS: We constructed a Markov state transition model to evaluate lifetime costs and quality-adjusted life years (QALYs) with each of the six treatments from the perspective of US third-party payers. Probabilities of clinical events were obtained from the RE-LY, ROCKET-AF, ARISTOTLE and ENGAGE AF-TIMI trials; costs were derived from the Healthcare Cost and Utilization Project, and other studies. Because edoxaban is only indicated in patients with creatinine clearance <=95ml/min, we re-ran our analyses after excluding edoxaban from the analysis. RESULTS: Treatment with edoxaban 60mg cost $77,565/QALY gained compared to warfarin, and apixaban 5mg cost $108,631/QALY gained compared to edoxaban 60mg. When edoxaban was not included in the analysis, treatment with apixaban 5mg cost $84,128/QALY gained, compared to warfarin. Dabigatran 150mg, dabigatran 110mg and rivaroxaban 20mg were dominated strategies. CONCLUSIONS: For patients with creatinine clearance between 50 and 95ml/min, apixaban 5mg was the most cost-effective treatment for willingness-to pay thresholds (WTP) above $115,000/QALY gained, and edoxaban 60mg was cost effective when the WTP was between $75,000 and $115,000/QALY gained. For patients with creatinine clearance >95ml/min, apixaban 5mg was the most cost-effective treatment for WTP thresholds above $80,000/QALY gained. PMID- 27771009 TI - Molecular and biochemical characterization of a benzenoid/phenylpropanoid meta/para-O-methyltransferase from Rauwolfia serpentina roots. AB - The monoterpenoid indole alkaloids, reserpine and rescinnamine contain 3, 4, 5 trimethoxybenzoate or 3, 4, 5-trimethoxycinnamate, respectively, within their structures and they accumulate in different plant organs and particularly within roots of Rauwolfia serpentina. This plant also accumulates acylated sugars substituted with 3, 4, 5-trimethoxybenzoate and 3, 4, 5-trimethoxycinnamate. In the present study, transcriptome and metabolome analyses of R. serpentina roots allowed the identification of 7 candidate O-methytransferase (OMT) genes that might be associated with the formation of 3, 4, 5-trimethoxybenzoate and 3, 4, 5 trimethoxycinnamate and led to the molecular cloning of 4 genes for functional expression and analysis. Two candidate genes were expressed in E. coli and were shown to use different phenolics as methyl acceptors. RsOMT1, a member of the caffeoyl CoA-OMT-like family of genes, converted 3, 5 dimethoxy-4 hydroxycinnamic, caffeic and 3, 4, 5 trihydroxybenzoic acids to trimethoxycinnamic-, ferulic/isoferulic- and 3-methoxy, 4, 5 dihydroxybenzoic or 4-methoxy, 3, 5 dihydroxybenzoic acids, respectively, when supplied with these substrates. RsOMT3, a member of the caffeic acid-OMT-like family of genes, only converted caffeic acid to ferulic acid. Both enzymes showed considerable promiscuity with respect to various flavonoid substrates that they accepted. The para-O-methylation activity of RsOMT1 is quite rare and unusual for plant OMTs. The involvement of RsOMT1 and RsOMT3 in the assembly of trimethoxybenzoic and trimethoxycinnamic acids is discussed. PMID- 27771010 TI - Gendered pathways from child sexual abuse to sexual aggression victimization and perpetration in adolescence and young adulthood. AB - This study aimed to examine the pathways from child sexual abuse to sexual assault victimization and perpetration in adolescence and early adulthood, considering risky sexual behavior and lowered sexual self-esteem as mediator variables. In a two-wave longitudinal study with 2251 college students in Germany, male and female participants provided reports of sexual aggression victimization and perpetration since age 14 (T1) and again a year later (T2), covering the last 12 months. In addition, child sexual abuse (CSA; before the age of 14), risky sexual behavior, and sexual self-esteem were assessed at T1, and risky sexual behavior and sexual-self-esteem were assessed again at T2. Experience of CSA was significantly associated with greater likelihood of sexual aggression victimization and perpetration, lower sexual self-esteem, and more risky sexual behavior in both gender groups at T1 and was directly related to victimization at T2 among male participants. In both gender groups, CSA indirectly contributed to a higher probability of sexual victimization at T2 via its impact on victimization T1. In males, the indirect path from CSA to T2 perpetration via T1 perpetration was also significant. Through its negative impact on sexual self-esteem, CSA indirectly increased the probability of sexual victimization among women and the probability of sexual aggression perpetration among men. Risky sexual behavior mediated the pathway from CSA to sexual victimization at T2 for men and women and the pathway from CSA to sexual aggression perpetration for women. The findings contribute to the understanding of gendered effects of CSA on revictimization and the victim-to-perpetrator cycle. PMID- 27771011 TI - The contribution of evaluations to the discourse quality of newspaper content. AB - This research shows how the use of evaluations in newspaper articles contributes to the quality of public media discourse prior to direct-democratic votes. Data from Swiss direct-democratic campaigns on school policy between 2000 and 2012 are used to compare newspaper articles that contain evaluations with those that do not refer to evaluations. Results show that those newspaper articles containing evaluations exhibit higher levels of justification, reciprocity and respect, tend to argue in terms of the common good, and contain less storytelling than newspaper articles that do not refer to evaluations. Implications for public deliberation and evaluation practice are discussed. PMID- 27771012 TI - Concept mapping as an approach for expert-guided model building: The example of health literacy. AB - Concept mapping served as the starting point for the aim of capturing the comprehensive structure of the construct of 'health literacy.' Ideas about health literacy were generated by 99 experts and resulted in 105 statements that were subsequently organized by 27 experts in an unstructured card sorting. Multidimensional scaling was applied to the sorting data and a two and three dimensional solution was computed. The three dimensional solution was used in subsequent cluster analysis and resulted in a concept map of nine "clusters": (1) self-regulation, (2) self-perception, (3) proactive approach to health, (4) basic literacy and numeracy skills, (5) information appraisal, (6) information search, (7) health care system knowledge and acting, (8) communication and cooperation, and (9) beneficial personality traits. Subsequently, this concept map served as a starting point for developing a "qualitative" structural model of health literacy and a questionnaire for the measurement of health literacy. On the basis of questionnaire data, a "quantitative" structural model was created by first applying exploratory factor analyses (EFA) and then cross-validating the model with confirmatory factor analyses (CFA). Concept mapping proved to be a highly valuable tool for the process of model building up to translational research in the "real world". PMID- 27771013 TI - When is a theory a theory? A case example. AB - This discussion comments on the approximately 20years history of writings on the prescriptive theory called Empowerment Evaluation. To do so, involves examining how "Empowerment Evaluation Theory" has been defined at various points of time (particularly 1996 and now in 2015). Defining a theory is different from judging the success of a theory. This latter topic has been addressed elsewhere by Michael Scriven, Michael Patton, and Brad Cousins. I am initially guided by the work of Robin Miller (2010) who has written on the issue of how to judge the success of a theory. In doing so, she provided potential standards for judging the adequacy of theories. My task is not judging the adequacy or success of the Empowerment Evaluation prescriptive theory in practice, but determining how well the theory is delineated. That is, to what extent do the writings qualify as a prescriptive theory. PMID- 27771014 TI - Reponse to J. Finsterer and S. Zarrouk-Mahjoub. PMID- 27771015 TI - Preventing violent extremism: the role of doctors. PMID- 27771016 TI - False dichotomies in global health: the need for integrative thinking. PMID- 27771017 TI - Subcutaneous lymphoid follicular hyperplasia secondary to vaccination: correlation of ultrasound findings with clinical and histological findings. AB - In recent years, the use of vaccines has been standardized within vaccination programs. Adverse effects at the puncture site are usually mild and transient. Nevertheless, in some cases, persistence subcutaneous nodules can develop; these are often underdiagnosed because they are so rare and because of the long time that can transpire between the vaccination and their appearance. Histologically, they consist of a lymphoid follicular hyperplasia that occurs as a reaction to the aluminum particles usually used as an adjuvant in some vaccines. We were unable to find any reference in the radiological literature to these soft-tissue nodules secondary to vaccination. We report the characteristic ultrasound findings that will enable radiologists to identify or strongly suspect these lesions and thereby avoid unnecessary imaging tests that might lead to confusion and inadequate management of these patients. PMID- 27771019 TI - Predatory Publishing: A Sinister, Brave New World. PMID- 27771018 TI - Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis. AB - Protective effects of pregnancy during MS have led to clinical trials of estriol, the pregnancy estrogen, in MS. Since estriol binds to estrogen receptor (ER) beta, ER beta ligand could represent a "next generation estriol" treatment. Here, ER beta ligand treatment was protective in EAE in both sexes and across genetic backgrounds. Neuroprotection was shown in spinal cord, sparing myelin and axons, and in brain, sparing neurons and synapses. Longitudinal in vivo MRIs showed decreased brain atrophy in cerebral cortex gray matter and cerebellum during EAE. Investigation of ER beta ligand as a neuroprotective treatment for MS is warranted. PMID- 27771021 TI - Corrigendum to "A randomised, controlled, double-blind crossover study on the effects of isovolumetric and isoeffective infusions of colloid versus crystalloid on blood volume, cardiac output and renal blood flow" [Clin Nutr 35 (2016) S22]. PMID- 27771020 TI - Effects of inulin-type fructans, galacto-oligosaccharides and related synbiotics on inflammatory markers in adult patients with overweight or obesity: A systematic review. AB - BACKGROUND & AIMS: Studies in humans with overweight or obesity have reported that some prebiotics and synbiotics have beneficial effects on metabolic endotoxaemia and immune function. However, to date, no systematic review of controlled clinical trials assessed this topic. The aim of this study was to evaluate the effects of inulin-type fructans, galacto-oligosaccharides and related synbiotics on inflammatory markers in adults with overweight or obesity. METHODS: A systematic review of the literature was performed until November 6, 2015 in four electronic databases and reference lists of all included articles and relevant reviews in the field, without using any filter. RESULTS: Ten trials (six prebiotic and four synbiotic trials) representing 534 overweight/obese adults were included. All trials evaluated C-reactive protein or high-sensitivity C-reactive protein, four trials evaluated cytokines (two prebiotic and two synbiotic trials) and five trials evaluated endotoxin (four prebiotic and one synbiotic trials). Six trials (two with galacto-oligosaccharide, one with inulin and three with different synbiotics) showed a reduction on high-sensitivity C reactive protein. Four trials (one with oligofructose-enriched inulin, one with inulin and two with different synbiotics) showed a reduction on interleukin-6 and/or tumor necrosis factor. Four trials (one with galacto-oligosaccharide, one with oligofructose-enriched inulin, one with inulin and one with synbiotic) showed a reduction on endotoxin. CONCLUSIONS: Some prebiotics and synbiotics may have immunomodulatory action, however, more randomized controlled trials are needed to support the clinical use of inulin-type fructans, galacto oligosaccharides or related synbiotics for the treatment of metabolic endotoxaemia or low-grade inflammation in overweight/obese people. PMID- 27771022 TI - Bilateral posterior cortical diffusion restriction due to electrocution. PMID- 27771023 TI - Geomagnetic disturbance: A new field in multiple sclerosis research. PMID- 27771024 TI - Skin nodules in a liver transplant recipient. PMID- 27771025 TI - No Rush to Motherhood: The Lived Experience of African American Never Pregnant Sexually Active Female Teens. AB - PURPOSE: The aim of this study was to gain a deeper understanding of the lived experiences of underserved minority sexually active teenaged girls' successful avoidance of unwanted pregnancy. DESIGN AND METHOD: Merleau-Ponty's methodology and van Manen's method of doing phenomenological research guided and facilitated the process of the study. 7 participants were eligible and all of them were interviewed for this study. RESULTS: Six main themes were identified: sense of emotional safety; sense of being free from a potential pregnancy; feeling supported by family and friends; connections built on trust and communication; regard for self through self-esteem and self-confidence; and sense of having life goals. CONCLUSION: The interpretive statement of 'these teen-agers experienced a sense of emotional safety, support by family and friends, trust and connection with family, friends and healthcare providers, and self-confidence resulting in the opportunity to develop life goals and feel strongly motivated to be free from pregnancy' was developed after further reflection upon the study themes. PRACTICE IMPLICATIONS: Healthcare providers, primarily nurses, can use the findings of this study to improve their interactions with sexually active never pregnant female teens. PMID- 27771028 TI - Giant saphenous vein graft aneurysm compressing the lingular bronchus. PMID- 27771026 TI - Impact of the implementation of a Sepsis Code hospital protocol in antibiotic prescription and clinical outcomes in an intensive care unit. AB - INTRODUCTION: A study was performed to analyze the impact of an in-hospital Sepsis Code (SC) program on use of antibiotic and clinical outcomes. DESIGN: Quasi-experimental observational retrospective study. SETTING: Polyvalent 11 beds ICU belonging to a tertiary Universitary hospital. PATIENTS: Patients admitted consecutively to the ICU with diagnosis of severe sepsis or septic shock. INTERVENTIONS: A post intervention group (POST-SC) (September 2012-August 2013) was compared with a historical group (PRE-SC) used as control (January-December 2010). VARIABLES: Antibiotic treatment, therapeutic antibiotic strategy, mortality and length of stay. Antibiotic consumption was expressed as defined daily doses (DDD)/ 100 stays. RESULTS: 42 patients with SS/SS in POST-SC group and 50 patients in PRE-SC group were consecutively recluted and further analyzed. Total antibiotic consumption (DDD) was similar in both groups. Rate of de escalation therapy was significantly higher in POST-SC group (75% vs 30,8%, p<0,005) while prescription of restricted antibiotics was significantly lower (74% vs 52%, p=0,031). Finally POST-SC patients showed a significantly decrease in hospital and 28 days mortality rates [23% vs 44%, (p=0,035) and 31% vs 56% (p=0,014) respectively] as well as a reduction in ICU length of stay compared to PRE-SC cohort (5 days vs 10,5 days, p=0,05). CONCLUSION: The implementation of a Sepsis Code-hospital protocol is associated to an improvement in the management of antibiotic therapy with a significant increase in de-escalation therapy and lesser utilization of restricted use antibiotics, as well as a significant reduction in mortality, and a tendency towards shorter ICU length stay. PMID- 27771029 TI - Implanted pedicled autologous pericardium mimics vasculature tissue: Case report. PMID- 27771030 TI - Endothelial dysfunction of internal thoracic artery graft in patients with chronic kidney disease. AB - OBJECTIVES: The present study was designed to evaluate the association between chronic kidney disease and the endothelial function of internal thoracic artery (ITA) grafts in patients undergoing coronary bypass surgery. An isometric tension study was performed in ITA strips obtained during surgery. Concentration-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed in ITA strips partially precontracted with phenylephrine under the inhibition of cyclooxygenase. The integrity of the endothelium was verified histologically by en-face staining of the luminal surface with the use of silver nitrate solution. RESULTS: In endothelium-intact ITA strips, ACh produced a concentration-dependent relaxation in patients with glomerular filtration rate (GFR, mL/min/1.73 m2) > 60. A concentration-dependent relaxation response also was observed in patients with GFR 30 to 60, but it was reduced significantly compared with those with GFR > 60. In both groups, removal of endothelium or treatment with nitric oxide (NO) synthase inhibitors almost abolished the ACh-induced relaxation. On the other hand, in patients with GFR < 30, mild contraction rather than relaxation was induced at a high concentration of ACh, which was modified neither by treatment with NO synthase inhibitors nor by removal of the endothelium. Vasodilator responses to sodium nitroprusside were comparable among the 3 groups. The relaxation of endothelium-intact strips to a peak ACh concentration correlated positively with GFR. This relationship held true in a multiple linear regression model, and interaction terms between GFR and other risk factors were not statistically significant. CONCLUSIONS: Endothelial function of ITA grafts to release NO is impaired at the time of surgery in patients with chronic kidney disease. PMID- 27771031 TI - The role of lateral neck ultrasound in detecting single or multiple lymph nodes in papillary thyroid cancer. AB - BACKGROUND: Lateral neck dissection (LND) for papillary thyroid cancer (PTC) transitioned from isolated lymphadenectomy or "berry picking" based on clinical examination to multicompartment lymphadenectomy. We aimed to assess ultrasound (US) as a predictor of solitary (SLN) or multiple lymph node (MLN) metastases. METHODS: Demographics, US findings, extent of LND, and pathology were collected in patients with PTC who underwent LND. US sensitivity and specificity were calculated, and accuracy was correlated with US findings and patient characteristics. RESULTS: A total of 462 patients underwent 590 LNDs. US showed an SLN in 179 patients (30%) and MLNs in 411 patients (70%). Sensitivity, positive predictive value, and accuracy were 61%, 43%, and 75% for US detected SLN and 78%, 89%, and 75% for US detected MLNs. US accuracy for MLNs increased as node size increased (<10 mm, 63%; 10 to 20 mm, 71%; >20 mm, 89%; P < .0001). CONCLUSIONS: US has limited accuracy in the detection SLN metastasis in the lateral neck. Care should be taken when considering a focused compartment dissection. PMID- 27771033 TI - Factors associated With burnout among French digestive surgeons in training: results of a national survey on 328 residents and fellows. AB - BACKGROUND: Digestive surgery training is notoriously difficult and medical students choose this path less and less often leading to a veritable demographic crisis for this specialty in France. The aim of this study was to evaluate the working conditions to measure the prevalence of burnout syndrome (BOS) and to identify potential risk factors to implement preventive measures and appropriate support. METHODS: This was a multicenter, cross-sectional study. An anonymous questionnaire was sent by e-mail to 500 French digestive surgeons in training (residents and fellows). RESULTS: The response rate was 65.6%. The mean working week was 75.7 hours (+/-12) and the mean number of night shifts was 5.3 (+/ 1.6)/month. Sixty-seven percent of respondents had trouble sleeping and 12% reported suicidal thoughts. High-emotional exhaustion, depersonalization, and personal accomplishment low scores were observed respectively in 24.7%, 44.6%, and 47%, corresponding to a high score of BOS in 52%. CONCLUSIONS: This study showed a high rate of BOS in French digestive surgeons in training and a worrying rate of suicide ideation. PMID- 27771032 TI - Complications and surgical outcomes after interhospital transfer vs direct admission in colorectal surgery: A National Surgical Quality Improvement Program analysis. AB - BACKGROUND: Interhospital transfer is common among patients undergoing colorectal surgery. The purpose of this study was to determine surgical outcomes after transfer vs direct admission in patients undergoing colorectal surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database from 2010 to 2012 was used. Colorectal operations were selected, including both emergency and nonemergency cases. Transfers were compared with direct admissions using a complex comorbidity analysis model. Primary outcomes of interest were mortality, extended hospital length of stay, and complication rates. RESULTS: The study included 121,040 admissions. After adjusting for multiple patient factors and comorbidities, nonemergency transfers still had higher mortality rates (RR = 1.20; P < .05), longer length of hospital stay (RR = 1.24; P < .05), and higher complication rates (RR = 1.18; P < .05). CONCLUSIONS: Preoperative hospital transfer is common among patients requiring colorectal surgery. Despite extensive propensity score matching, nonemergency transfers have higher rates of mortality, longer length of hospital stay, and higher overall complication rates compared with direct admissions. Transfer status is an important variable in hospital performance models and should be taken into consideration when analyzing hospital outcomes. PMID- 27771034 TI - Efficacy of retroperitoneal triple neurectomy for refractory neuropathic inguinodynia. AB - BACKGROUND: Refractory neuropathic inguinodynia following inguinal herniorrhaphy is a common and debilitating complication. This prospective study evaluated long term outcomes associated with laparoscopic retroperitoneal triple neurectomy. METHODS: Sixty-two consecutive patients (51 male; mean age, 47); all failing pain management; prior reoperation in 35, prior neurectomy in 26; average follow-up 681 days (range: 90 days to 3 years). Measured outcomes include numeric pain ratings, dermatomal mapping, histologic confirmation, quantitative sensory testing, complications, narcotic usage, and activity level. RESULTS: Mean numerical pain scores were significantly decreased (baseline, 8.6) at all postoperative time points (POD 1, 3.6; P < .001: POD 90, 2.3, P < .001) with durable efficacy from POD 90 to 3 years (P < .001). Quantitative sensory testing showed marked group-level increases of sensory thresholds. Narcotic dependence decreased in 57/62 and was eliminated in 44/62 and activity level improved in 58/62. CONCLUSIONS: Retroperitoneal triple neurectomy is an effective and durable treatment for refractory neuropathic inguinodynia. PMID- 27771035 TI - Ethnic and economic disparities effect on management of hyperparathyroidism. AB - BACKGROUND: Successful parathyroidectomy requires advanced surgeon experience. We aim to examine population characteristics at risk of being managed by low-volume surgeons. METHODS: A cross-sectional study was performed utilizing the Nationwide Inpatient Sample database, 2004 to 2009. The study population included adult inpatients who underwent parathyroidectomy for primary hyperparathyroidism. RESULTS: A total of 3,503 discharge records were included. Men, Hispanics, and those with Medicaid/Medicare health coverage were more likely to be managed by low-volume surgeons (P < .05 each). Low-volume surgeons were more likely to operate in rural (odds ratio [OR], 3.99; 95% confidence interval [CI], 1.95 to 8.16; P < .001) or nonteaching hospitals (OR, 2.15; 95% CI, 1.42 to 3.27; P < .001). Southern region of the United States had a high prevalence of low-volume surgeons compared with other regions (Southern: 51.3%, Northeast: 24.3%, Midwest: 25.6%, and West: 27.6%, P < .001). Operations by the low-volume surgeons associated with a higher risk of postoperative complications (OR, 1.81; 95% CI, 1.11 to 2.97) and a hospital stay more than 2 days (OR, 7.12; 95% CI, 3.75 to 13.45; P < .001). CONCLUSIONS: Certain populations are at risk of management by low-volume surgeons based on their demographic and economic characteristics. PMID- 27771036 TI - A pilot study examining experiential learning vs didactic education of abdominal compartment syndrome. AB - BACKGROUND: Current surgical education relies on simulated educational experiences or didactic sessions to teach low-frequency clinical events such as abdominal compartment syndrome (ACS). The purpose of this pilot study was to evaluate if simulation would improve performance and knowledge retention of ACS better than a didactic lecture. METHODS: Nineteen general surgery residents were block randomized by postgraduate year level to a didactic or a simulation session. After 3 months, all residents completed a knowledge assessment before participating in an additional simulation. Two independent reviewers assessed resident performance via audio-video recordings. RESULTS: No baseline differences in ACS experience were noted between groups. The observational evaluation demonstrated a significant difference in performance between the didactic and simulation groups: 9.9 vs 12.5, P = .037 (effect size = 1.15). Knowledge retention was equivalent between groups. CONCLUSIONS: This pilot study suggests that simulation-based education may be more effective for teaching the basic concepts of ACS. PMID- 27771037 TI - Nonoperative management of adhesive small bowel obstruction: what is the break point? AB - BACKGROUND: The current management paradigm for recurrent adhesive small bowel obstruction (SBO) is nonoperative. Rates of recurrence differ based on time interval between and number of previous occurrences. Optimal time to intervene has not been determined. METHODS: We constructed a Markov model to evaluate costs and quality of life on a hypothetical cohort of 40-year-old patients after their first episode of medical management for postoperative SBO. We estimated a relative risk reduction of .55 with surgical intervention and a relative risk increase of 2.1, 2.9, and 5.7 after the medical management of the 2nd, 3rd, and 4th SBO. RESULTS: Surgery performed after earlier episodes of SBO was more costly but also more effective. The cost difference between surgery after the 1st SBO recurrence vs the 2nd SBO recurrence was $1,643, with an increase of .135 quality adjusted life years (QALYs), the incremental cost-effectiveness ratio was $12,170 per QALY. CONCLUSIONS: Surgery after the first episode of SBO provides a small increase in QALY at a small cost since surgical intervention lowers the risk of recurrence. PMID- 27771038 TI - Demographic and socioeconomic factors influencing disparities in prevalence of alcohol-related injury among underserved trauma patients in a safety-net hospital. AB - BACKGROUND: Alcohol-related trauma remains high among underserved patients despite ongoing preventive measures. Geographic variability in prevalence of alcohol-related injury has prompted reexamination of this burden across different regions. We sought to elucidate demographic and socioeconomic factors influencing the prevalence of alcohol-related trauma among underserved patients and determine alcohol effects on selected outcomes. METHODS: A retrospective analysis examined whether patients admitted to a suburban trauma center differed according to their blood alcohol concentration (BAC) on admission. Patients were stratified based on their BAC into four categories (undetectable BAC, BAC 1-99mg/dL, BAC 100 199mg/dL, and BAC >= 200mg/dL). T-tests and X2 tests were used to detect differences between BAC categories in terms of patient demographics and clinical outcomes. Multivariate linear and logistic regressions were used to investigate the association between patient variables and selected outcomes while controlling for confounders. RESULTS: One third of 738 patients analyzed were BAC-positive, mean (SD) BAC was 211.4 (118.9) mg/dL, 80% of BAC-positive patients had levels >= 100mg/dL. After risk adjustments, the following patient characteristics were predictive of having highly elevated BAC (>=200mg/dL) upon admission to the Trauma Center; Hispanic patients (adjusted odds ratio (OR)=1.91, 95% confidence interval (CI): 1.14-3.21), unemployment (OR=1.74, 95% CI: 1.09-2.78), Medicaid beneficiaries (OR=3.59, 95% CI: 1.96-6.59), and uninsured patients (OR=2.86, 95% CI: 1.60-5.13). Patients with BAC of 100-199mg/dL were likely to be more severely injured (P=0.016) compared to undetectable-BAC patients. There was no association between being intoxicated, and being ICU-admitted or having differences in length of ICU or hospital stay. CONCLUSION: Demographic and socioeconomic factors underlie disparities in the prevalence of alcohol-related trauma among underserved patients. These findings may guide targeted interventions toward specific populations to help reduce the burden of alcohol-related injury. PMID- 27771039 TI - Prevalence of injuries among high school students in Eastern and Western parts of Cairo, Egypt. AB - BACKGROUND: Injury is the leading cause of death and long term disability and a significant contributor to healthcare costs among children worldwide especially those aged 15-19 years. OBJECTIVES: To determine the prevalence of injuries among secondary school students in Cairo, Egypt and to explore the associated risk factors for sustaining injury. METHODOLOGY: A Cross-sectional study was conducted on secondary school students in eastern and western part of Cairo; self administered questionnaire was used for assessing injuries sustained in previous 12 months and the associated risk factors for injury. RESULTS: The overall prevalence of injuries was 68.5%. Unintentional injuries were the most common injuries falls (50%) and burns (38.6%). Significant factors associated with sustaining injury were truancy, smoking, alcohol use, quarreling behavior, carrying weapon, threatened by weapon and verbal bullying. CONCLUSION: This study showed a high prevalence of injuries among high school students in Egypt which necessitates raising public awareness about the magnitude and burden of injuries among adolescents. PMID- 27771040 TI - Fate of subchondral fatigue fractures of femoral head in young adults differs from general outcome of fracture healing. AB - PURPOSE: The purpose of this study is to report the clinical course of fatigue type subchondral fractures of the femoral head in young healthy adults. MATERIALS/METHODS: We retrospectively reviewed 28 consecutive patients (34 hips) who had a clear history of a sudden increase in physical activity without trauma on the hip and pelvis, and were diagnosed as having a fatigue-type subchondral fracture of the femoral head. The diagnosis was made primarily on the basis of sequential plain radiographs and magnetic resonance images. RESULTS: Of the 34 hips, 19 hips with no bony collapse experienced gradual disappearance of subjective pain a few months after onset, and there were no recurrences. Other 2 hips that showed bony collapse, but preserved the articular margin, also experienced no definite deterioration of collapse or arthritic change and did not need surgical intervention. In the remaining13 hips with bony collapse and destroyed articular margin or arthritic change, hip pain gradually worsened necessitating surgery. CONCLUSIONS: The current findings suggest that a subchondral fatigue fracture of the femoral head could show a different severity of subchondral injury over time. In the collapsed subchondral fatigue fractures, especially when combined with head incongruency, the hip pain was aggravated enough to require surgical intervention. PMID- 27771041 TI - One versus two venous anastomoses in microvascular lower extremity reconstruction using gracilis muscle or anterolateral thigh flaps. AB - INTRODUCTION: Free tissue transfers are a highly reliable procedure routinely performed for reconstruction of a wide range of defects. Main complication in free flap surgery is usually venous thrombosis. Many technical controversies exist regarding the technical details of the microvascular anastomosis in order to prevent occurrence of thrombosis and optimize outcomes. We therefore evaluated our results regarding the execution of one versus two venous anastomoses in a variety of free flaps (fasciocutaneous- or muscle free flap) utilized for lower limb reconstruction. PATIENTS AND METHODS: Between 2009 and 2015, 354 patients underwent 386 free ALT- or gracilis flaps for lower limb defect reconstruction after trauma, infection, or malignancies at our institution. The data was retrospectively screened for patients' demographics, perioperative details, flap survival, and surgical complications. The cases were divided into two groups regarding the number of microsurgically performed venous anastomosis: one versus two veins. RESULTS: Regarding the preoperative evaluation, there were no significant differences regarding comorbidities between the two groups. Overall, there was no significant difference regarding the rate of major (1 vein: 20.38% versus 2 veins: 18.78%, p>0.05) and minor (1 vein: 1.27% versus 2 veins: 2.18%, p>0.05) surgical complications during our 3-months follow-up period. Major complications included total flap losses of 5.73% (1 vein) versus 8.78% (2 veins). CONCLUSION: This study analyzed a large series of microsurgical reconstructions, with a focus on the impact of the number of venous anastomosis. The findings suggest that successful free tissue transfer for lower limb reconstruction can be achieved independent of the number of venous anastomoses, however two should be performed when technically feasible. PMID- 27771042 TI - The sensitivity of ct scans in diagnosing occult femoral neck fractures. AB - Non-displaced hip fractures can be difficult to diagnose on plain film radiographs. When there is ongoing clinical suspicion of an occult fracture, further imaging is obtained. We investigated the sensitivity of computed tomography (CT) scans in detecting these fractures and the delays to surgery that three-dimensional imaging causes. We identified 78 CT scans performed for possible hip fractures over the past 3 years with the presence and absence of a fracture recorded. Based on subsequent imaging, the accuracy of CT scans was determined. CT scanning yielded sensitivity was 86% and specificity 98% for occult hip fracture (OHF). The median delay to definitive diagnosis was 37h. Our results demonstrate that CT scan does not bear sufficient sensitivity to detect all OHFs. We therefore recommend that MRI should be offered when a fracture is suspected. CT scans should be reserved for when MRI is not available, but a negative scan should be confirmed with subsequent MRI. PMID- 27771043 TI - Tracking the development of agrammatic aphasia: A tensor-based morphometry study. AB - Agrammatic aphasia can be observed in neurodegenerative disorders and has been traditionally linked with damage to Broca's area, although there have been disagreements concerning whether damage to Broca's area is necessary or sufficient for the development of agrammatism. We aimed to investigate the neuroanatomical correlates of the emergence of agrammatic aphasia utilizing a unique cohort of patients with primary progressive apraxia of speech (PPAOS) that did not have agrammatism at baseline but developed agrammatic aphasia over time. Twenty PPAOS patients were recruited and underwent detailed speech/language assessments and 3T MRI at two visits, approximately two years apart. None of the patients showed evidence of agrammatism in writing or speech at baseline. Eight patients developed aphasia at follow-up (progressors) and 12 did not (non progressors). Tensor-based morphometry utilizing symmetric normalization (SyN) was used to assess patterns of grey matter atrophy and voxel-based morphometry was used to assess patterns of grey matter loss at baseline. The progressors were younger at onset and more likely to show distorted sound substitutions or additions compared to non-progressors. Both groups showed change over time in premotor and motor cortices, posterior frontal lobe, basal ganglia, thalamus and midbrain, but the progressors showed greater rates of atrophy in left pars triangularis, thalamus and putamen compared to non-progressors. The progressors also showed greater grey matter loss in pars triangularis and putamen at baseline. This cohort provided a unique opportunity to assess the anatomical changes that accompany the development of agrammatic aphasia. The results suggest that damage to a network of regions including Broca's area, thalamus and basal ganglia are responsible for the development of agrammatic aphasia in PPAOS. Clinical and neuroimaging abnormalities were also present before the onset of agrammatism that could help improve prognosis in these subjects. PMID- 27771045 TI - Evaluation of a Self-Instructional CPR Program for Parents With Children Enrolled in Community Swim Lessons. AB - INTRODUCTION: This project evaluated an evidence-based self-instructional program aimed at improving cardiopulmonary resuscitation (CPR) knowledge and confidence in parents with children in swim lessons. METHOD: A prospective, repeated measures design evaluated the CPR Anytime Child program. Twenty-nine parents completed questionnaires before, immediately after, and 1 month after the program. RESULTS: Knowledge and confidence scores improved significantly over time. Compared with a baseline knowledge mean score of 47.3%, mean score immediately after the program was 93.5% (t = -12.176, p < .01) and at 1 month was 80.9% (t = -8.459, p < .01). Confidence in determining CPR need increased from a baseline of 2.52 to 3.18 points immediately after the program (t = -2.88, p = .013) and 3.20 at 1 month (t = 4.759, p < .01). Confidence in performing CPR increased from a baseline of 2.14 to 3.18 immediately after the program (t = 4.759, p < .01) and 2.73 at 1 month (t = -2.88, p = .013). DISCUSSION: The CPR Anytime Child program had a significant sustained effect on improving knowledge and confidence in parents of children in swim lessons. The simplicity of this program makes it replicable and sustainable in this setting. PMID- 27771046 TI - Improving national standards of child protection skeletal surveys: the value of College guidance. AB - AIM: To re-assess the content and quality of skeletal surveys performed in the investigation of non-accidental injury following the publication of nationally agreed guidelines produced jointly by the Royal College of Radiologists and the Royal College of Paediatrics and Child Health in 2008. MATERIALS AND METHODS: One hundred consecutive skeletal surveys performed in England, which were sent to a tertiary paediatric hospital for a second opinion, were reviewed for their content and quality. The number and type of view was assessed with reference to the 21 recommended views as set out in the College guidance. The quality of each view was assessed and given a score up to a maximum of 10. RESULTS: A total of 2,294 radiographic views were acquired, with an average of 22.9 per survey (range 12-21). Fifty-one of the surveys contained all 21 recommended views (previously 15%). The average quality score per view was 9.7/10 (97%), previously 9.7/11 (88%). The commonest cause of reduced quality was the presence of an artefact on the image. CONCLUSION: There has been an improvement in the content of skeletal surveys performed in England, which in part may be due to the publication of the national joint Royal College guidance; however, there remain areas for continued development in order to improve practice further. PMID- 27771044 TI - The self-reference effect in dementia: Differential involvement of cortical midline structures in Alzheimer's disease and behavioural-variant frontotemporal dementia. AB - Encoding information in reference to the self enhances subsequent memory for the source of this information. In healthy adults, self-referential processing has been proposed to be mediated by the cortical midline structures (CMS), with functional differentiation between anterior-ventral, anterior-dorsal and posterior regions. While both Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD) patients show source memory impairment, it remains unclear whether they show a typical memory advantage for self-referenced materials. We also sought to identify the neural correlates of this so-called 'self-reference effect' (SRE) in these patient groups. The SRE paradigm was tested in AD (n = 16) and bvFTD (n = 22) patients and age-matched healthy controls (n = 17). In this task, participants studied pictures of common objects paired with one of two background scenes (sources) under self-reference or other reference encoding instructions, followed by an item and source recognition memory test. Voxel-based morphometry was used to investigate correlations between SRE measures and regions of grey matter atrophy in the CMS. The behavioural results indicated that self-referential encoding did not ameliorate the significant source memory impairments in AD and bvFTD patients. Furthermore, the reduced benefit of self-referential relative to other-referential encoding was not related to general episodic memory deficits. Our imaging findings revealed that reductions in the SRE were associated with atrophy in the anterior-dorsal CMS across both patient groups, with additional involvement of the posterior CMS in AD and anterior-ventral CMS in bvFTD. These findings suggest that although the SRE is comparably reduced in AD and bvFTD, this arises due to impairments in different subcomponents of self-referential processing. PMID- 27771049 TI - Application of In-line Focused Beam Reflectance Measurement to Brivanib Alaninate Wet Granulation Process to Enable Scale-up and Attribute-based Monitoring and Control Strategies. AB - Application of in-line real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design development of a drug product and enable attribute-based monitoring and control strategies. In this study, an in-line laser focused beam reflectance measurement (FBRM) C35 probe was used to investigate the effect of formulation and process parameters on the granule growth profile over time during the high shear wet granulation of a high drug load formulation of brivanib alaninate. The probe quantitatively captured changes in the granule chord length distribution (CLD) with the progress of granulation and delineated the impact of water concentration used during granulation. The results correlated well with offline particle size distribution measured by nested sieve analyses. An end point indication algorithm was developed that was able to successfully track the process time needed to reach the target CLD. Testing of the brivanib alaninate granulation through 25-fold scale-up of the batch process indicated that the FBRM CLD profile can provide a scale-independent granule attribute-based process fingerprint. These studies highlight the ability of FBRM to quantitate a granule attribute of interest during wet granulation that can be used as an attribute-based scale-up and process monitoring and control parameter. PMID- 27771047 TI - Diffusion-weighted magnetic resonance neurography for the diagnosis of carpal tunnel syndrome: a pilot study. AB - AIM: To investigate the applicability of diffusion-weighted magnetic resonance neurography (DW-MRN) in the diagnosis of carpal tunnel syndrome (CTS). MATERIALS AND METHODS: In total, 47 patients with CTS (69 wrists) and 19 normal participants (38 wrists) was included in this study. Cross-sectional area (CSA) and apparent diffusion coefficient (ADC) values of the median nerves in the carpal tunnel were determined using DW-MRN. Receiver operating characteristic (ROC) analysis was performed. RESULTS: No significant differences in age or body mass index (BMI) were observed between the control and CTS groups. DW-MRN imaging showed obvious hyperintensity in the lesions in CTS wrists, while other nerve regions were related to slight hyperintensity. Interobserver variability analysis indicated excellent agreement regarding both the CSA and ADC measurements for the control and CTS groups. Both the mean CSA and ADC values of the median nerves in carpal tunnel in the CTS group were significantly higher than the control group. According to the ROC analysis, the CSA cut-off value was 11.7 mm2, and sensitivity and specificity were 66.7% and 89.5%, respectively. Conversely, the median nerve ADC cut-off value was 1.047*10-3 mm2/s. The sensitivity and specificity were 91.3% and 76.3.9%, respectively. CONCLUSION: DW-MRN represents a highly reproducible diagnostic technique for CTS. The ADC value of median nerves in the carpal tunnel is significantly higher in CTS patients, which provides a potential powerful tool for the disease diagnosis. PMID- 27771050 TI - Past, Present, and Future Drug Delivery Systems for Antiretrovirals. AB - The human immunodeficiency virus has infected millions of people and the epidemic continues to grow rapidly in some parts of the world. Antiretroviral (ARV) therapy has provided improved treatment and prolonged the life expectancy of patients. Moreover, there is growing interest in using ARVs to protect against new infections. Hence, ARVs have emerged as our primary strategy in combating the virus. Unfortunately, several challenges limit the optimal performance of these drugs. First, ARVs often require life-long use and complex dosing regimens. This results in low patient adherence and periods of lapsed treatment manifesting in drug resistance. This has prompted the development of alternate dosage forms such as vaginal rings and long-acting injectables that stand to improve patient adherence. Another problem central to therapeutic failure is the inadequate penetration of drugs into infected tissues. This can lead to incomplete treatment, development of resistance, and viral rebound. Several strategies have been developed to improve drug penetration into these drug-free sanctuaries. These include encapsulation of drugs in nanoparticles, use of pharmacokinetic enhancers, and cell-based drug delivery platforms. In this review, we discuss issues surrounding ARV therapy and their impact on drug efficacy. We also describe various drug delivery-based approaches developed to overcome these issues. PMID- 27771048 TI - Increasing Comorbidities Suggest that Atopic Dermatitis Is a Systemic Disorder. AB - Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies. Given the possibility of atopic dermatitis-related systemic immune activation, future investigations of new interventions should concurrently examine the impact on these comorbidities. PMID- 27771052 TI - Effects of 2 Polyoxyethylene Alkyl Ethers on the Function of Intestinal P glycoprotein and Their Inhibitory Mechanisms. AB - The purpose of this study was to investigate the effects of polyoxyethylene 10 oleyl ether and polyoxyethylene 9-lauryl ether, 2 polyoxyethylene alkyl ethers, on the transport and absorption of 2 P-glycoprotein (P-gp) substrates, quinidine and prednisolone, across the intestinal membrane and to elucidate the inhibitory mechanisms of intestinal P-gp by these polyoxyethylene alkyl ethers. For in vitro studies, we used a diffusion chamber method and the Caco-2 cell model. An in situ closed-loop method was used for in vivo study. The 2 polyoxyethylene alkyl ethers, nonionic surfactants, increased the intestinal absorptive transport of quinidine and prednisolone in the diffusion chamber studies, and absorptive permeability was enhanced in the in vitro Caco-2 cell study. Furthermore, these surfactants enhanced the rat intestinal absorption of prednisolone, and we observed no intestinal membrane damage in the presence of these surfactants. Furthermore, these surfactants increased membrane fluidity in intestinal brush border membranes and inhibited P-gp ATPase activity. For in vitro and in vivo studies, these surfactants enhanced the intestinal absorption of quinidine and prednisolone, 2 P-gp substrates. The alteration in intestinal membrane fluidity and the inhibition of P-gp ATPase activity by these 2 polyoxyethylene alkyl ethers may be confirmed as mechanisms of P-gp inhibition. PMID- 27771051 TI - Enhanced Oral Delivery of Bisphosphonate by Novel Absorption Enhancers: Improvement of Intestinal Absorption of Alendronate by N-Acyl Amino Acids and N Acyl Taurates and Their Absorption-Enhancing Mechanisms. AB - Bisphosphonates (BPs) are carbon-substituted pyrophosphate analogs that exhibit a high affinity to hydroxyapatite and specifically inhibit bone resorption. Alendronate sodium (sodium 4-amino-1-hydroxybutylidene-1,1-bisphosphonate trihydrate) is a typical BP compound in clinical use. BPs have very low bioavailability, typically <1% after their oral administration, and their intestinal absorption is further reduced by co-administered drugs or food. In this study, we examined the effects of N-acyl amino acids and N-acyl taurates on the small intestinal absorption of alendronate. All N-acyl amino acids and N-acyl taurates increased the small intestinal absorption of alendronate, especially 1% (wt/vol) sodium palmitoyl sarcosinate (PN), which elicited a 14-fold increase. In addition, the absorption-enhancing effects of these enhancers were reversible and they may not cause continuous and irreversible membrane toxicity in the rat small intestine. Furthermore, we examined the absorption-promoting mechanisms of PN and found that it increased the membrane fluidity of the lipid bilayers. In addition, it was found that PN may open the tight junctions by reducing the expression level of claudin-4, which is a major tight junction protein. These findings indicate that these enhancers are useful for promoting the intestinal absorption of alendronate. PMID- 27771053 TI - Corrigendum to "Isoleucine 61 in PLO is important for the hemolytic activity of PLO of Trueperella pyogenes" [Vet. Microbiol. 182 (2016) 196-201]. PMID- 27771054 TI - Feral pigeons: A reservoir of zoonotic Salmonella Enteritidis strains? AB - Salmonella enterica infections in pigeons are generally associated with pigeon adapted strains of serovar Typhimurium that are of little public health concern. Here, we isolated Salmonella Enteritidis phage type 4 (PT4), an important human pathogen, from a population of feral pigeons in Brussels, which was further characterized by Pulsed-Field Gel Electrophoresis. All pigeon isolates belonged to the same pulsotype, which has been present in Belgian pigeons at least since 2001 and is associated with poultry and disease in humans. A high prevalence of 33% of Salmonella Enteritidis in Brussels combined with dense pigeon populations suggest that feral pigeons may constitute a significant, but unrevealed reservoir for contracting salmonellosis in the urban environment. PMID- 27771055 TI - Induction of functional interferon alpha and gamma responses during acute infection of cattle with non-cytopathic bovine viral diarrhea virus. AB - As a part of their pathogenic mechanism, many pathogens causing persistent infections, including bovine viral diarrhea virus (BVDV), immunosuppress their hosts, often by limiting the ability to either produce, or respond to, interferon. The objective of this study was to quantify the extent to which an acute infection of cattle with a non-cytopathic strain of BVDV induces interferon responses and to establish the functionality of these responses. Functionality of responses was investigated using a bovine specific peptide array to monitor kinase-mediated signal transduction activity within peripheral blood mononuclear cells (PBMCs) at time points corresponding to the interferon gamma (IFN-gamma) and alpha (IFN-alpha) responsive phases of acute BVDV infection. Further, with an appreciation of diverse mechanisms and levels at which pathogens modulate host cell defences, patterns of expression of IFN-gamma and -alpha responsive genes were also quantified within PBMCs. Infection of cows with ncpBVDV2-1373 induced significant increases in levels of serum IFN-gamma and IFN-alpha. Within the PBMCs of the infected animals, distinct patterns of kinase-mediated signal transduction activity, in particular with respect to activation of classic IFN activated signalling pathways, such as Jak-Stat, as well as induced expression of IFN-gamma and IFN-alpha regulated genes, support the functionality of the host interferon response. PMID- 27771056 TI - Enteropathogen infections in canine puppies: (Co-)occurrence, clinical relevance and risk factors. AB - Laboratory confirmation of the causative agent(s) of diarrhoea in puppies may allow for appropriate treatment. The presence of potential pathogens however, does not prove a causal relationship with diarrhoea. The aim of this study was to identify specific enteropathogens in <=12 month old puppies with and without acute diarrhoea and to assess their associations with clinical signs, putative risk factors and pathogen co-occurrence. Faecal samples from puppies with (n=113) and without (n=56) acute diarrhoea were collected and screened for Canine Parvovirus (CPV), Canine Coronavirus (CCoV), Salmonella spp., Campylobacter spp., Clostridium perfringens, Clostridium difficile, beta-hemolytic Eschericha coli (hEC), Giardia spp., Toxocara spp., Cystoisospora spp., and Cyniclomyces guttulatus. One or more pathogens were detected in 86.5% of diarrhoeic puppies and in 77.8% of asymptomatic puppies. Significant positive associations were found between CPV and CCoV, CPV and Cystoisospora spp., Toxocara spp. and hEC, Giardia spp. and C. guttulatus. Only CPV and CCoV were significantly associated with diarrhoea, hEC with a subset of puppies that had diarrhoea and severe clinical signs. CPV was more prevalent in puppies under 3 months of age. Puppies from high-volume dog breeders were significantly at increased risk for CPV (OR 4.20), CCoV (OR 4.50) and Cystoisospora spp. (OR 3.60). CCoV occurred significantly more often in winter (OR 3.35), and CPV in winter (OR 3.78) and spring (OR 4.72) as compared to summer. We conclude that routine screening for CPV, CCoV and hEC is recommended in puppies with acute diarrhoea, especially if they are under 3 months of age and originate from high-volume dog breeders. Routine screening for other pathogens may lead to less conclusive results. PMID- 27771057 TI - Outer membrane vesicles of Gallibacterium anatis induce protective immunity in egg-laying hens. AB - Gallibacterium anatis causes infections in the reproductive tract of egg-laying hens and induce increased mortality and decreased egg production. New prophylactic measures are needed in order to improve animal welfare and production efficiency. Bacterial outer membrane vesicles (OMVs) have previously shown promising results in protection against infections and we hypothesized that OMVs could serve as an immunogen to protect egg-laying hens against G. anatis. To investigate the immunogenic potential of G. anatis OMVs, two in vivo studies in egg-laying hens were made. The trials assessedthe degree of protection provided by immunization with G. anatis OMV against challenge and the IgY responses in serum after immunization and challenge, respectively. A total of 64 egg-laying hens were included in the trials. OMVs for immunization were produced and purified from a high-producing G. anatis DeltatolR mutant. Challenge was done with G. anatis 12656-12 and evaluated by scoring lesions and bacterial re isolation rates from peritoneum. Finally, levels of OMV-specific IgY in sera were assayed by ELISA. Immunization with OMVs decreased the lesions scores significantly, while the bacterial re-isolation remained unchanged. Furthermore, a high OMV-specific IgY response was induced by immunization and subsequent challenge of the hens. The results strongly indicate that immunization with G. anatis OMVs provides significant protection against G. anatis challenge and induces specific antibody responses with high titers of OMV-specific IgY in serum. The results therefore show great promise for OMV based vaccines aiming at providing protecting against G. anatis in egg-laying hens. PMID- 27771058 TI - Involvement of NF-kappaB in regulation of Actinobacillus pleuropneumoniae exotoxin ApxI-induced proinflammatory cytokine production in porcine alveolar macrophages. AB - Actinobacillus pleuropneumoniae is a crucial respiratory pathogen that causes fibrinous, hemorrhagic, necrotizing pleuropneumonia in pigs. A. pleuropneumoniae exotoxins (ApxI to IV) are the major virulence factors contributing to A. pleuropneumoniae pathogenesis. Previously, we demonstrated that ApxI induces the expression of proinflammatory cytokines in porcine alveolar macrophages (PAMs) via the mitogen-activated protein kinases (MAPKs) p38 and cJun NH2-terminal kinase (JNK). Nonetheless, the role of nuclear factor (NF)-kappaB-a transcription factor widely implicated in immune and inflammatory responses-in ApxI-elicited cytokine production has yet to be defined. In the present study, we examined the involvement of NF-kappaB in ApxI-elicited production of interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha in PAMs and investigated the correlation between NF-kappaB and MAPK (p38 and JNK) pathways in this event. The results of Western blot analysis, confocal microscopy, and a DNA binding activity assay revealed that the classical NF-kappaB pathway was activated by ApxI, as evidenced by the decreased levels of IkappaB and subsequent NF-kappaB translocation and activation in ApxI-stimulated PAMs. Moreover, the blocking of ApxI-induced NF-kappaB activation significantly attenuated the levels of mRNA and protein secretion of IL-1beta, IL-8, and TNF-alpha in PAMs. Notably, the attenuation of JNK activation by a specific inhibitor (SP600125) reduced ApxI induced NF-kappaB activation, whereas a p38 blocker (SB203580) had no effect on the NF-kappaB pathway. Further examination revealed that the level of phosphorylation at serine 536 on the NF-kappaB p65 subunit was dependent on JNK activity. Collectively, this study, for the first time, demonstrates a pivotal role of NF-kappaB in ApxI-induced IL-1beta, IL-8, and TNF-alpha production; JNK, but not p38, may positively affect the activation of the classical NF-kappaB pathway. PMID- 27771059 TI - Experimental infection of New Zealand Merino sheep with a suspension of Mycobacterium avium subspecies paratuberculosis (Map) strain Telford: Kinetics of the immune response, histopathology and Map culture. AB - A long-term study was undertaken to monitor immune responses, faecal cultures and clinical disease in sheep experimentally infected with Mycobacterium avium subspecies paratuberculosis (Map) strain Telford. New Zealand Merino lambs (N=56) were challenged with three oral doses of Map suspension. The lambs were weighed and faecal and blood samples obtained at different time-points. At 63 weeks post challenge, surviving sheep were euthanised and samples of liver, ileo-caecal valve and mesenteric lymph node were collected for histopathology and Map culture. High IFN-gamma and antibody responses were evident as early as 8 weeks post-C1 which persisted until the end of the trial. Approximately 92% of the sheep shed Map in faeces at 36 weeks post-challenge, with the prevalence decreasing to around 40% at the end of the trial. Thirteen sheep progressively lost weight and were euthanised between weeks 32 and 58 post-challenge. Nearly 58% of surviving sheep exhibited histo-pathological lesions in at least one of the three tissues sampled, while 42% showed acid-fast bacilli in at least one tissue. A positive Map culture in at least one tissue was obtained from approximately 85% of sheep. These results indicate that the three doses of Map challenge were highly effective in establishing Johne's disease in NZ Merino lambs. PMID- 27771061 TI - Clinical aspects and weight gain reduction in swine infected with porcine circovirus type 2 and torque teno sus virus in Brazil. AB - Simultaneous Porcine circovirus type 2 (PCV-2) and Torque teno sus virus (TTSuV) infections have been reported around the world, generally linked to severe infections. In the present study, 257 swine plasma samples from 31 swine herds located in Brazil, were PCR screened for PCV-2 and TTSuV-1/2 and correlated with clinical data. PCV-2 was detected in 25%, followed by 38.1% and 42.4% of TTSuV-1 and TTSuV-2, respectively. Co-infections of two or three viruses were found in 32.3% of samples. PCV-2 was more frequently detected in the growing (p=0.030) and finishing phases (p=0.0005) while TTSuV-2 in the nursery (p=0.009). Only TTSuV-1 was statistically associated to clinical disease (multiple signs), in combination or not with PCV-2 or TTSuV-2 (p=0.015). PCV-2/TTSuV co-infections were more frequently related to weight gain reduction in comparison to mono-infections (p=0.049) and no-infections (p=0.027), and also in animals with (p=0.011) or without (p=0.037) clinical signs, being the nursery the most affected phase (p=0.025). Our results uphold the pathogenic potential of TTSuV in naturally infected pigs and the clinical/economical impact of this agent, especially in co infections. Studies addressing the physiopathological mechanisms of simultaneous infections are needed. PMID- 27771063 TI - Corrigendum to: "In vitro antimicrobial activity of gallium maltolate against virulent Rhodococcus equi " [Veterinary Microbiology 146 (2010) 175-178]. PMID- 27771060 TI - The efficacy of alcelaphine herpesvirus-1 (AlHV-1) immunization with the adjuvants Emulsigen(r) and the monomeric TLR5 ligand FliC in zebu cattle against AlHV-1 malignant catarrhal fever induced by experimental virus challenge. AB - Malignant catarrhal fever (MCF) is a fatal disease of cattle that, in East Africa, follows contact with wildebeest excreting alcelaphine herpesvirus 1 (AlHV 1). Recently an attenuated vaccine (atAlHV-1) was tested under experimental challenge on Friesian-Holstein (FH) cattle and gave a vaccine efficacy (VE) of approximately 90%. However testing under field conditions on an East African breed, the shorthorn zebu cross (SZC), gave a VE of 56% suggesting that FH and SZC cattle may respond differently to the vaccine. To investigate, a challenge trial was carried out using SZC. Additionally three adjuvant combinations were tested: (i) Emulsigen(r), (ii) bacterial flagellin (FliC) and (iii) Emulsigen(r)+bacterial flagellin. We report 100% seroconversion in all immunized cattle. The group inoculated with atAlHV-1+Emulsigen(r) had significantly higher antibody titres than groups inoculated with FliC, the smallest number of animals that became infected and the fewest fatalities, suggesting this was the most effective combination. A larger study is required to more accurately determine the protective effect of this regime in SZC. There was an apparent inhibition of the antibody response in cattle inoculated with atAlHV-1+FliC, suggesting FliC might induce an immune suppressive mechanism. The VE in SZC (50-60%) was less than that in FH (80-90%). We speculate that this might be due to increased risk of disease in vaccinated SZC (suggesting that the vaccine may be less effective at stimulating an appropriate immune response in this breed) and/or increased survival in unvaccinated SZC (suggesting that these cattle may have a degree of prior immunity against infection with AlHV-1). PMID- 27771062 TI - Selective medium for culture of Mycoplasma hyopneumoniae. AB - The fastidious porcine respiratory pathogen Mycoplasma hyopneumoniae has proven difficult to culture since it was first isolated in 1965. A reliable solid medium has been particularly challenging. Moreover, clinical and pathological samples often contain the fast-growing M. hyorhinis which contaminates and overgrows M. hyopneumoniae in primary culture. The aim of this study was to optimise the culture medium for recovery of M. hyopneumoniae and to devise a medium for selection of M. hyopneumoniae from clinical samples also containing M. hyorhinis. The solid medium devised by Niels Friis was improved by use of Purified agar and incorporation of DEAE-dextran. Addition of glucose or neutralization of acidity in liquid medium with NaOH did not improve the final yield of viable organisms or alter the timing of peak viability. Analysis of the relative susceptibility of M. hyopneumoniae and M. hyorhinis strains to four antimicrobials showed that M. hyopneumoniae is less susceptible than M. hyorhinis to kanamycin. This was consistent in all UK and Danish strains tested. A concentration of 2MUg/ml of kanamycin selectively inhibited the growth of all M. hyorhinis tested, while M. hyopneumoniae was able to grow. This forms the basis of an effective selective culture medium for M. hyopneumoniae. PMID- 27771064 TI - A Pasteurella multocida strain affecting nulliparous heifers and calves in different ways. AB - Pasteurella multocida isolates from dairy cattle on a farm in Spain were associated with pneumonia of calves (six isolates) and mastitis of heifers (five isolates). The objective was to determine if the P. multocida isolates retrieved from both disease scenarios were the same strain or whether more than one strain was present. The isolates were identified by a species-specific polymerase chain (PCR) assay, serotyped by the Heddleston scheme and then typed by a number of molecular genotyping assays including multi-locus sequence typing (MLST). The 11 isolates were confirmed as P. multocida but failed to react with any of the 16 Heddleston antisera. The PCR targeting the genes associated with the lipopolysaccharide outer core biosynthesis locus assigned all the isolates to L3 the type that contains Heddleston serovars 3 and 4. The MLST analysis showed all isolates belonging to ST 79 within the clonal complex of ST13. Only one of the isolates showed a slight different profile by the repetitive extragenic palindromic PCR. The conclusion was that the same strain was associated with pneumonia in calves and mastitis in heifers. PMID- 27771065 TI - Development of multilocus sequence typing (MLST) assay for Mycoplasma iowae. AB - Mycoplasma iowae (MI) infection is an economically and commercially important disease of turkeys. There are no sequence typing assays available for MI strain identification, the only available molecular tools for this purpose, are DNA fingerprinting assays. In addition to their low reproducibility, fingerprinting assays require isolation of the microorganism in pure culture, which is difficult for avian mycoplasma. Therefore, we propose a multilocus sequence typing (MLST) assay as the first genotyping assay for identification of MI. Based on the two available MI genomes on GenBank, 26 loci of housekeeping genes were identified and studied in a diverse sample set. Finally, six genes were selected for the newly developed MLST assay. The final sequence analysis of the six loci (total of 5019bp) (dppC, ulaA, valS, rpoC, leuS, kdpA) allowed the differentiation of 47 MI samples into 23 unique sequence types. Moreover, when only 4 loci were used to type the same set of samples, they resulted in 20 unique sequence types. Analysis of phylogenetic trees and clonal groups generated by MLST displayed a high degree of agreement with geographical and temporal information of the tested samples. MLST is a highly reproducible molecular epidemiology assay that can be used to identify positive clinical cases directly from DNA samples. Therefore, it provides a useful tool allowing for better identification, control and eradication efforts. PMID- 27771066 TI - 'Candidatus Mycoplasma haemobos': Transplacental transmission in dairy cows (Bos taurus). AB - 'Candidatus Mycoplasma haemobos' is a haemotropic mycoplasma that can produce various clinical signs in cattle, but abortive potential of the parasite is unknown, as well as the frequency of transplacental transmission in cattle. Thus, the objective of this work was to evaluate the frequency of detection of 'C. M. haemobos' in aborted fetuses and the blood of dairy cows. Blood samples of 22 dairy cows that aborted and pool tissues (brain, lung, heart and liver) of their respective aborted fetuses were tested by conventional PCR. The occurrence of 'C. M. haemobos' DNA in adult animals was 40.9% (9/22) and in the fetuses was 18.2% (4/22). Two fetuses that contained 'C. M. haemobos' DNA were derived from cows which were PCR negative. When stratifying by breed, it was observed that Jersey cows had a higher proportion of positive animals (8/11; 72.7%) as compared to Holstein (1/9; 11.1% P<0.01). The results of this study suggest that this parasite can be transferred via the placenta, but it is not certain if the abortions were due to 'C. M. haemobos'. PMID- 27771067 TI - Circulation of multiple genotypes of H1N2 viruses in a swine farm in Italy over a two-month period. AB - In August 2012 repeated respiratory outbreaks caused by swine influenza A virus (swIAV) were registered for a whole year in a breeding farm in northeast Italy that supplied piglets for fattening. The virus, initially characterized in the farm, was a reassortant Eurasian avian-like H1N1 (H1avN1) genotype, containing a haemagglutinin segment derived from the pandemic H1N1 (A(H1N1)pdm09) lineage. To control infection, a vaccination program using vaccines against the A(H1N1)pdm09, human-like H1N2 (H1huN2), human-like H3N2 (H3N2), and H1avN1 viruses was implemented in sows in November 2013. Vaccine efficacy was assessed by sampling nasal swabs for two months in 35-75 day-old piglets born from vaccinated sows. Complete genome sequencing of eight swIAV-positive nasal swabs collected longitudinally from piglets after the implementation of the vaccination program was conducted to investigate the virus characteristics. Over the two-month period, two different genotypes involving multiple reassortment events were detected. The unexpected circulation of multiple reassortant genotypes in such a short time highlights the complexity of the genetic diversity of swIAV and the need for a better surveillance plan, based on the combination of clinical signs, epidemiological data and whole genome characterization. PMID- 27771068 TI - Molecular and epidemiological population-based integrative analysis of human and animal Mycobacterium bovis infections in a low-prevalence setting. AB - Human Mycobacterium bovis infections are considered to be due to reactivations, when involve elderly people, or to recent transmissions, when exposure is occupational. We determined the cause of M. bovis infections by genotyping M. bovis isolates in a population-based study integrating human and animal databases. Among the 1,586 tuberculosis (TB) cases in Asturias, Northern Spain (1,080,000 inhabitants), 1,567 corresponded to M. tuberculosis and 19 to M. bovis. The number of human isolates sharing genotype with cattle isolates was higher than expected (47%) for a setting with low prevalence of bovine TB and efficient control programs in cattle. The risk of exposure to infected animals was probable/possible in most of these matched cases (77.7%). Recent transmission was the likely explanation of most M. bovis infections in elderly people. A potential human-to-human transmission was found. Our study illustrates a model of collaboration between human and animal health professionals to provide a precise snapshot of the transmission of M. bovis in the human-animal interface. PMID- 27771069 TI - Whole genomic analysis of bovine group A rotavirus strains A5-10 and A5-13 provides evidence for close evolutionary relationship with human rotaviruses. AB - Bovine group A rotavirus (RVA) is an important cause of acute diarrhea in calves worldwide. In order to obtain precise information on the origin and evolutionary dynamics of bovine RVA strains, we determined and analyzed the complete nucleotide sequences of the whole genomes of six archival bovine RVA strains; four Thai strains (RVA/Cow-tc/THA/A5-10/1988/G8P[1], RVA/Cow-tc/THA/A5 13/1988/G8P[1], RVA/Cow-tc/THA/61A/1989/G10P[5], and RVA/Cow tc/THA/A44/1989/G10P[11]), one American strain (RVA/Cow tc/USA/B223/1983/G10P[11]), and one Japanese strain (RVA/Cow tc/JPN/KK3/1983/G10P[11]). On whole genomic analysis, the 11 gene segments of strains A5-10, A5-13, 61A, A44, B223, and KK3 were found to be considerably genetically diverse, but to share a conserved non-G/P genotype constellation except for the NSP1 gene (I2-R2-C2-M2-(A3/11/13/14)-N2-T6-E2-H3), which is commonly found in RVA strains from artiodactyls such as cattle. Furthermore, phylogenetic analysis revealed that most genes of the six strains were genetically related to bovine and bovine-like strains. Of note is that the VP1, VP3, and NSP2 genes of strains A5-10 and A5-13 exhibited a closer relationship with the cognate genes of human DS-1-like strains than those of other RVA strains. Furthermore, the VP6 genes of strains A5-10 and A5-13 appeared to be equally related to both human DS-1-like and bovine strains. Thus, strains A5-10 and A5-13 were suggested to be derived from the same evolutionary origin as human DS-1-like strains, and were assumed to be examples of bovine RVA strains that provide direct evidence for a close evolutionary relationship between bovine and human DS-1-like strains. Our findings will provide important insights into the origin of bovine RVA strains, and into evolutionary links between bovine and human RVA strains. PMID- 27771070 TI - Corrigendum to "In vivo virulence of viral haemorrhagic septicaemia virus (VHSV) in rainbow trout Oncorhynchus mykiss correlates inversely with in vitro Mx gene expression" [Vet. Microbiol. 187 (2016) 31-40]. PMID- 27771071 TI - Differential expression of putative adhesin genes of Actinobacillus suis grown in in vivo-like conditions. AB - Actinobacillus suis is an opportunistic pathogen that resides in the tonsils of the soft palate of swine. Unknown stimuli can cause this organism to invade the host, resulting in septicaemia and sequelae including death. To better understand its pathogenesis, the expression of several adhesin genes was evaluated by semi quantitative real-time PCR in A. suis grown in conditions that mimic the host environment, including different nutrient and oxygen levels, exponential and stationary phases of growth, and in the presence of the stress hormone epinephrine. Fifty micromolar epinephrine did not affect the growth rate or expression of A. suis adhesin genes, but there was a significant growth phase effect for many genes. Most adhesin genes were also differentially expressed during anoxic static growth or aerobic growth, and in this study, all genes were differentially expressed in either exponential or stationary phase. Based on the time*treatment interactions observed in the anoxic study, a model of persistence of A. suis in the host environment in biofilm and planktonic states is proposed. Biofilm dynamics were further studied using wild type and isogenic mutants of the type IVb pilin (Delta flp1), the OmpA outer membrane protein (DeltaompA), and the fibronectin-binding (DeltacomE1) genes. Disruption of these adhesin genes affected the early stages of biofilm formation, but in most cases, biofilm formation of the mutant strains was similar to that of the wild type by 24h of incubation. We postulate that other adhesins may have overlapping functions that can compensate for those of the missing adhesins. PMID- 27771072 TI - Mouse model for the Rift Valley fever virus MP12 strain infection. AB - Rift Valley fever virus (RVFV), a Category A pathogen and select agent, is the causative agent of Rift Valley fever. To date, no fully licensed vaccine is available in the U.S. for human or animal use and effective antiviral drugs have not been identified. The RVFV MP12 strain is conditionally licensed for use for veterinary purposes in the U.S. which was excluded from the select agent rule of Health and Human Services and the U.S. Department of Agriculture. The MP12 vaccine strain is commonly used in BSL-2 laboratories that is generally not virulent in mice. To establish a small animal model that can be used in a BSL-2 facility for antiviral drug development, we investigated susceptibility of six mouse strains (129S6/SvEv, STAT-1 KO, 129S1/SvlmJ, C57BL/6J, NZW/LacJ, BALB/c) to the MP12 virus infection via an intranasal inoculation route. Severe weight loss, obvious clinical and neurologic signs, and 50% mortality was observed in the STAT 1 KO mice, whereas the other 5 mouse strains did not display obvious and/or severe disease. Virus replication and histopathological lesions were detected in brain and liver of MP12-infected STAT-1 KO mice that developed the acute-onset hepatitis and delayed-onset encephalitis. In conclusion, the STAT-1 KO mouse strain is susceptible to MP12 virus infection, indicating that it can be used to investigate RVFV antivirals in a BSL-2 environment. PMID- 27771073 TI - Identification of recombination among VP1 gene of Muscovy duck parvovirus from the Mainland of China. PMID- 27771074 TI - Caveolin-1-mediated endocytic pathway is involved in classical swine fever virus Shimen infection of porcine alveolar macrophages. AB - Macrophages are at the frontline of defense against pathogenic microorganisms. However, very little is known about the cell invasion mechanism of classical swine fever virus (CSFV) Shimen strain. To elucidate the infective mechanism of this important pathogen, we screened deep-sequencing data derived from macrophages infected with CSFV Shimen and uninfected macrophages, and identified a role of caveolin-1 (CAV1). Digital gene expression profiling showed that CAV1 was differentially expressed in CSFV Shimen-infected macrophages. Quantitative polymerase chain reaction and western blot analyses showed that the transcription and translation of CAV1 were significantly up-regulated in CSFV Shimen-infected macrophages. In addition, immunofluorescent confocal microscopy analysis suggested that CAV1 was temporally colocalized with CSFV E2 throughout the course of the infection. Through the overexpression of recombinant CAV1 or the silencing of CAV1 expression using small interfering RNA in macrophages, we demonstrated that CAV1 expression is beneficial for the replication of CSFV Shimen. However, RNA silencing of CAV1 did not prevent viral replication, which may indicate that CSFV can also enter macrophages by other mechanisms. Our findings suggest that CAV1-mediated endocytosis is advantageous for productive CSFV Shimen infection in macrophages, providing a new insight into the mechanisms of evasion of host immunity for successful viral infection. PMID- 27771075 TI - Autophagy and apoptosis induced by Chinese giant salamander (Andrias davidianus) iridovirus (CGSIV). AB - The outbreak of Chinese Giant Salamander (Andrias davidianus, CGS) Iridovirus (CGSIV) caused massive death of CGSs. However, some CGSs with low level of CGSIV usually could survive. In our study, major capsid protein (MCP) DNA replicates of CGSIV in shedding skin were employed to assess the relative content of CGSIV in the living CGSs by qPCR. Furthermore, the examinations of autophagy and apoptosis in CGSs in vivo and in the primary renal cells in vitro were performed, respectively. The results showed that the relative contents of CGSIV in the shedding skin could reflect those in liver, spleen, and kidney of the CGSs. In these tissues of the CGSs with low-level replicates of CGSIV, there were not obviously macroscopic lesions. But the irregularly-shaped vesicles perhaps involving in autophagosome were observed by transmission electron microscopy (TEM). The LC3B protein displayed uneven distribution by Immunohistochemistry and the level mRNA of Atg5 was higher in these tissues than that in the tissues of healthy CGSs using qRT-PCR. Meanwhile, the apoptosis also appeared in these tissues by TUNEL staining and higher level mRNA of type I IFN were detected in these tissues using qRT-PCR. Further, both the expression level of LC3B II protein and Atg5 mRNA increased significantly at 2h after the virus infected the primary renal cells from the health CGSs in vitro. In addition, apoptosis and type I IFN mRNA began to increase significantly at 4h after the virus infected the renal cells. It was suggested that autophagy may be a pivotal role for survival of CGSIV in the CGSs during early infection and the rapid proliferation of CGSIV could be inhibited by innate immune response and apoptosis. PMID- 27771076 TI - A longitudinal study of the Mycobacterium avium subspecies paratuberculosis infection status in young goats and their mothers. AB - The dynamics between Mycobacterium avium subspecies paratuberculosis (MAP) infection and the immune response of goats naturally exposed to MAP were studied in a herd where the clinical expression of paratuberculosis had been observed. Four generations of goats were observed over a 33-month period: mothers of three different generations (G1, G2, G3) and their daughters, generation 4 (G4). A MAP infection status was defined according to the combined results of an IFN-gamma assay, antibody response, faecal culture and post-mortem examination. Goats were defined as non-infected (NI), infected and non-shedder (INS), infected and shedder (IS) or atypical (A). Twenty-nine percent of goats were NI, 66% were infected and either shedding (14%) or not shedding (52%) MAP, and 5% were atypical. IFN-gamma responses were detected first, followed by faecal shedding and antibody responses. The results showed that in goats naturally exposed to MAP, IFN-gamma responses were regularly detected earlier in non-shedders than in young infected shedder goats and were stronger in shedder than in non-shedder goats. They were also higher in the mother goats than in their daughters. Goats shedding MAP or with positive antibody response at the beginning of their pregnancy are more likely to have an infected daughter positive to an IFN-gamma assay by the age of 15 months. PMID- 27771077 TI - Felis catus papillomavirus type 2 E6 oncogene enhances mitogen-activated protein kinases and Akt activation but not EGFR expression in an in vitro feline model of viral pathogenesis. AB - A possible causative role of Felis catus papillomavirus type 2 (FcaPV2) in the development of feline oral and cutaneous squamous cell carcinomas (SCC) has been recently suggested by demonstrating viral gene expression in vivo and transforming properties by its putative oncogenes E6 and E7 in vitro. The activated molecules MEK (pMEK), ERK (pERK) and Akt (pAkt) are signaling transduction effectors regulating cell proliferation and inhibition of apoptosis, which are critical steps towards tumour formation. Here, we show by Western blotting (WB) that expression of FcaPV2 E6 in feline epithelial cells enhances pMEK, pERK and pAkt levels compared to control cells. Additionally, we demonstrated by real-time quantitative PCR on epidermal growth factor receptor (EGFR) transcripts and WB that activation of these signaling routes is independent from EGFR differential gene expression, total protein levels or phosphorylation, unlike in human papillomavirus associated tumours. This study contributes to define the molecular scenario underlying FcaPV2-triggered pathogenesis of feline SCC. PMID- 27771078 TI - Establishment and application of milk fingerprint by gel filtration chromatography. AB - Raw milk adulteration frequently occurs in undeveloped countries. It not only reduces the nutritional value of milk, but it is also harmful to consumers. In this paper, we focused on investigating an efficient method for the quality control of raw milk protein. A gel filtration chromatography (GFC) fingerprint method combined with chemometrics was developed for fingerprint analysis of raw milk. To optimize the GFC conditions, milk fat was removed by centrifugation, and GFC analysis was performed on a Superdex 75 10/300GL column (Just Scientific, Shanghai, China) with 0.2 M NaH2PO4-Na2HPO4 buffer (pH 7.0) as the mobile phase. The flow rate was 0.5mL/min, and the detection wavelength was set at 280 nm. Ten batches of 120 raw milk samples were analyzed to establish the GFC fingerprint under optimal conditions. Six major peaks common to the chromatogram of each raw milk sample were selected for fingerprint analysis, and the characteristic peaks were used to establish a standard chromatographic fingerprint. Principal component analysis was then applied to classify GFC information of adulterated milk and raw milk, allowing adulterated samples to be effectively screened out from the raw milk in principal component analysis scores plot. The fingerprint method demonstrates promising features in detecting milk protein adulteration. PMID- 27771079 TI - Choline absorption and evaluation of bioavailability markers when supplementing choline to lactating dairy cows. AB - The metabolites of choline have a central role in many mammalian biological processes, and choline supplementation to the periparturient dairy cow improves hepatic lipid metabolism. However, variability in responses to choline supplementation has highlighted a lack of understanding of choline absorption in the lactating dairy cow. Our objective was to determine net choline absorption by measuring net portal fluxes of choline and choline metabolites in cows receiving either dietary supplements of rumen-protected choline (RPC) or abomasal delivery of choline (ADC). We also evaluated markers for choline bioavailability by examining relationships between net portal absorption of choline and choline metabolites in plasma and milk. Five late-lactation Holstein cows were used in a 5*5 Latin square design, with 5-d treatment periods and a 2-d interval between periods. Treatments were (1) control (0g/d of choline), (2) 12.5g/d of choline fed as RPC, (3) 25g/d of choline fed as RPC, (4) 12.5g/d of choline provided as ADC, and (5) 25g/d of choline provided as ADC. At the end of each 5-d period, milk was sampled and 9 blood samples were collected simultaneously from an artery and portal vein at 30-min intervals. Plasma, milk, and feed ingredient concentrations of acetylcholine, betaine, free choline, glycerophosphocholine, lysophosphatidylcholine, phosphatidylcholine, phosphocholine, and sphingomyelin were quantified by hydrophilic interaction liquid chromatography-tandem mass spectrometry. With an increasing dose of ADC, the net portal flux of free choline increased and regression analysis indicated 61% net absorption of the infused dose. Among the choline metabolites, only concentrations of betaine, free choline, and phosphocholine increased in both arterial plasma (3.9, 1.9, and 0.4 times, respectively) and milk (2.5, 1.4, and 1.0 times, respectively) with 25g/d of ADC relative to the control. For RPC, the net portal flux of free choline was low relative to ADC (13%), which was similar to the relative difference observed in the concentrations and yields of milk free choline and betaine (averaged 21%). When evaluating markers for choline bioavailability, betaine was the leading candidate. Betaine in plasma and milk (alone or in combination with phosphocholine) was strongly associated with net free choline portal flux (coefficient of determination ranging from 0.64 to 0.79). In summary, free choline supply to the lactating dairy cow increases only specific choline metabolites in plasma and milk, which can be potential markers for choline bioavailability. PMID- 27771080 TI - Proteomics method to quantify the percentage of cow, goat, and sheep milks in raw materials for dairy products. AB - Fraud in milk and dairy products occurs when cow milk is added to sheep and goat milk for economic reasons. No reliable, selective, and sensitive method exists for quantifying the milk percentage of different species. This work reports the development and validation of a proteomics-based method for the qualitative detection and quantitative determination of cow, sheep, and goat milks in the raw materials used for dairy products. beta-Lactoglobulin was selected as the protein marker because it is a major protein in milk and whey powder. The tryptic peptides LSFNPTQLEEQCHI and LAFNPTQLEGQCHV were used as signature peptides for cow milk and for sheep and goat milks, respectively. The winged peptides LKALPMHIRLSFNPTQL*EEQCHI* and LKALPMHIRLAFNPTQL*EGQCHV* were designed and synthesized as internal standards. Validation of the method showed that it has good sensitivity, specificity, reproducibility, precision, and accuracy. This method is easily applicable in routine laboratory analysis without intensive proteomics background. PMID- 27771081 TI - Goat whey ameliorates intestinal inflammation on acetic acid-induced colitis in rats. AB - Complementary or alternative medicine is of great interest for the treatment of inflammatory bowel disease, with the aim of ameliorating the side effects of the drugs commonly used or improving their efficacy. In this study, we evaluated the ability of goat whey to prevent intestinal inflammation in the experimental model of acetic acid-induced rats and compared it to sulfasalazine. Pretreatment with goat whey (1, 2, and 4g/kg) and sulfasalazine (250mg/kg) on colitic rats improved colonic inflammatory markers, including myeloperoxidase activity, leukotriene B4 levels, as well as the production of proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha. Furthermore, the administration of goat whey significantly reduced the colonic oxidative stress by reducing malondialdehyde levels and increased total glutathione content, a potent antioxidant peptide. The histological evaluation of the colonic specimens from colitic rats confirmed these beneficial effects, as goat whey preserved the colonic tissue, especially in those rats treated with the highest dose of goat whey or with sulfasalazine. The immunohistochemistry analysis of the colonic tissue evaluation also revealed a reduction in the expression of cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinase-9, together with an increased expression of suppressor of cytokine signaling-1. These results suggest that goat whey exerted a preventive effect against the intestinal damage induced by acetic acid, showing a similar efficacy to that shown by sulfasalazine, therefore making it a potential treatment for human inflammatory bowel disease. PMID- 27771082 TI - Application of propidium monoazide quantitative real-time PCR to quantify the viability of Lactobacillus delbrueckii ssp. bulgaricus. AB - In this study, a combination of propidium monoazide (PMA) and quantitative real time PCR (qPCR) was used to develop a method to determine the viability of cells of Lactobacillus delbrueckii ssp. bulgaricus ND02 (L. bulgaricus) that may have entered into a viable but nonculturable state. This can happen due to its susceptibility to cold shock during lyophilization and storage. Propidium monoazide concentration, PMA incubation time, and light exposure time were optimized to fully exploit the PMA-qPCR approach to accurately assess the total number of living L. bulgaricus ND02. Although PMA has little influence on living cells, when concentrations of PMA were higher than 30MUg/mL the number of PCR positive living bacteria decreased from 106 to 105 cfu/mL in comparison with qPCR enumeration. Mixtures of living and dead cells were used as method verification samples for enumeration by PMA-qPCR, demonstrating that this method was feasible and effective for distinguishing living cells of L. bulgaricus when mixed with a known number of dead cells. We suggest that several conditions need to be studied further before PMA-qPCR methods can be accurately used to distinguish living from dead cells for enumeration under more realistic sampling situations. However, this research provides a rapid way to enumerate living cells of L. bulgaricus and could be used to optimize selection of cryoprotectants in the lyophilization process and develop technologies for high cell density cultivation and optimal freeze-drying processes. PMID- 27771083 TI - Bioavailability of aflatoxin B1 and ochratoxin A, but not fumonisin B1 or deoxynivalenol, is increased in starch-induced low ruminal pH in nonlactating dairy cows. AB - High-production dairy and beef systems require diets rich in starch. This practice may induce ruminal acidosis and also increase exposure to mycotoxins because starches in starch-rich diets are the main vehicles of mycotoxin contamination. The aim of this study was to investigate the effects of low ruminal pH on the bioavailability of 4 major mycotoxins [i.e., aflatoxin B1 (AFB1), ochratoxin A (OTA), deoxynivalenol (DON), and fumonisin B1 (FB1)]. Eight nonlactating dairy cows fitted with rumen cannulas were used in a double crossover experiment. The trial was divided into 4 periods with 2 periods per crossover. Cows were divided into 2 groups receiving a low (15% dry matter basis) and high-starch diet (30.8%) with and without live yeast supplementation (1*1010 cfu per cow) in the first and second crossover, respectively. At the end of each period, cows received a single dose of mycotoxin-contaminated feed containing 0.05, 0.2, 0.24, and 0.56mg of AFB1, OTA, DON, and FB1 per kg of feed, respectively. The fecal and urinary excretion of mycotoxins and their metabolites was monitored for up to 48h postdosing. As expected, ruminal pH decreased in cows fed the high-starch diet. The high-starch diet increased the bioavailability of OTA and AFB1. Urinary excretion of OTA 24h after mycotoxin administration increased 3-fold in the high-starch diet, correlated with lower fecal excretion. Similarly, a decrease in fecal excretion of AFB1 was accompanied by an increase in urinary excretion of its major metabolite, aflatoxin M1, 48h after mycotoxin administration. In contrast to AFB1 and OTA, the bioavailability of DON and FB1 remained unchanged. Yeast supplementation had no effect on the excretion balance of these 2 mycotoxins. In conclusion, these results show that high-starch diets increased the bioavailability of OTA and AFB1, most probably through the lowering effect on ruminal pH. This greater bioavailability potentially increases the toxic effects of these mycotoxins. PMID- 27771084 TI - Immune-modulating properties of horse milk administered to mice sensitized to cow milk. AB - The aim of this study was to examine immune adaptive changes, the expression of innate biomarkers and variations in intestinal microbiota composition after horse milk administration in BALB/c mice, which were sensitized intraperitoneally using cow beta-lactoglobulin and alpha-casein with aluminum adjuvant. We measured serum antibody IgE levels and the expression of MCP-1, IL-4, and TNF-alpha in duodenal samples. Changes in immune cell populations in peripheral blood were quantified using flow cytometry, and intestinal microbiota composition was assessed using real-time PCR. We found that horse-milk administration decreased serum IgE levels in sensitized mice. The groups that received horse milk showed an increased population of regulatory T cells (CD4+Foxp3+). Horse-milk administration decreased the mRNA levels of IL-4 and resulted in higher transcripts of TLR-4 in all treatment groups; however, the levels of MCP-1, TNF-alpha, and TLR-2 were unaltered. After horse-milk treatment, we observed a positive effect, with increased numbers of intestinal Bifidobacterium spp. We observed immune modulating properties of horse milk, but future studies should focus on testing horse-milk processing, such as fermentation and destroying most allergenic epitopes to continue research under clinical conditions. PMID- 27771085 TI - Condensed milk storage and evaporation affect the flavor of nonfat dry milk. AB - Unit operations in nonfat dry milk (NFDM) manufacture influence sensory properties, and consequently, its use and acceptance in ingredient applications. Condensed skim milk may be stored at refrigeration temperatures for extended periods before spray drying due to shipping or lack of drying capacity. Currently, NFDM processors have 2 options for milk concentration up to 30% solids: evaporation (E) or reverse osmosis (RO). The objective of this study was to determine the effect of condensed milk storage and milk concentration method (E vs. RO) on the flavor of NFDM and investigate mechanisms behind flavor differences. For experiment 1, skim milk was pasteurized and concentrated to 30% solids by E or RO and then either stored for 24h at 4 degrees C or concentrated to 50% solids by E and spray dried immediately. To investigate mechanisms behind the results from experiment 1, experiment 2 was constructed. In experiment 2, pasteurized skim milk was subjected to 1 of 4 treatments: control (no E), heated in the evaporator without vacuum, E concentration to 30% solids, or E concentration to 40% solids. The milks were then diluted to the same solids content and evaluated. Volatile compounds were also measured during concentration in the vapor separator of the evaporator. Sensory properties were evaluated by descriptive sensory analysis and instrumental volatile compound analysis was conducted to evaluate volatile compounds. Interaction effects between storage and method of concentration were investigated. In experiment 1, E decreased sweet aromatic flavor and many characteristic milk flavor compounds and increased cardboard and cooked flavors in NFDM compared with RO. Liquid storage increased cardboard flavor and hexanal and octanal and decreased sweet aromatic flavors and vanillin concentration. Results from experiment 2 indicated that the characteristic milk flavors and their associated volatile compounds were removed by the vapor separator in the evaporator due to the heat and vacuum applied during concentration. These results demonstrate that off-flavors are significantly reduced when RO is used in place of E and storage of condensed milk is avoided. PMID- 27771086 TI - Quality characteristics, chemical composition, and sensory properties of butter from cows on pasture versus indoor feeding systems. AB - This study evaluated the effects of 3 widely practiced cow feeding systems in the United States, Europe, and Southern Hemisphere regions on the characteristics, quality, and consumer perception of sweet cream butter. Fifty-four multiparous and primiparous Friesian cows were divided into 3 groups (n=18) for an entire lactation. Group 1 was housed indoors and fed a total mixed ration diet (TMR) of grass silage, maize silage, and concentrates; group 2 was maintained outdoors on perennial ryegrass-only pasture (GRS); and group 3 was maintained outdoors on a perennial ryegrass/white clover pasture (CLV). Mid-lactation butter was manufactured in triplicate with milk from each group in June 2015 (137+/-7d in milk) and was analyzed over a 6-mo storage period at 5 degrees C for textural and thermal properties, fatty acid composition, sensory properties, and volatile compounds. The nutritional value of butters was improved by pasture feeding, and butter from pasture-fed cows had significantly lower thrombogenicity index scores compared with butters from TMR-fed cows. In line with these results, pasture derived milks (GRS and CLV) produced butter with significantly higher concentrations of conjugated linoleic acid (cis-9,trans-11) and trans-beta carotene than TMR butter. Alterations in the fatty acid composition of butter contributed to significant differences in textural and thermal properties of the butters. Total mixed ration-derived butters had significantly higher hardness scores at room temperature than those of GRS and CLV. Onset of crystallization for TMR butters also occurred at significantly higher temperatures compared with pasture butters. Volatile analysis of butter by gas chromatography-mass spectrometry identified 25 compounds present in each of the butters, 5 of which differed significantly based on feeding system, including acetone, 2-butanone, 1 pentenol, toluene, and beta-pinene. Toluene was very significantly correlated with pasture-derived butter. Sensory analysis revealed significantly higher scores for GRS-derived butter in several attributes including "liking" of appearance, flavor, and color over those of TMR butter. Partial least square regression plots of fatty acid profiles showed clear separation of butter derived from grazed pasture-based perennial ryegrass or perennial rye/white clover diets from that of a TMR system, offering further insight into the ability of fatty acid profiling to verify such pasture-derived dairy products. PMID- 27771087 TI - A new application of a sodium deoxycholate-propidium monoazide-quantitative PCR assay for rapid and sensitive detection of viable Cronobacter sakazakii in powdered infant formula. AB - A rapid, reliable, and sensitive method for the detection of Cronobacter sakazakii, a common foodborne pathogen that may cause serious neonatal disease, has been developed. In this study, a rapid real-time quantitative PCR (qPCR) assay combined with sodium deoxycholate (SD) and propidium monoazide (PMA) was developed to detect C. sakazakii contamination in powdered infant formula (PIF). This method could eliminate the interference from dead or injured bacteria. Optimization studies indicated that SD and PMA at 0.08% (wt/vol) and 5ug/mL, respectively, were the most appropriate. In addition, qPCR, PMA-qPCR, SD-PMA qPCR, and plate count assays were used to account for the number of viable bacteria in cell suspensions that were exposed to a 55 degrees C water bath at different length of time. As a result, the viable number by PMA-qPCR showed significantly higher than of the number from SD-PMA-qPCR or plate counts. The number of viable bacteria was consistent between SD-PMA-qPCR and traditional plate counts, which indicated that SD treatment could eliminate the interference from dead or injured cells. Using the optimized parameters, the limit of detection with the SD-PMA-qPCR assay was 3.3*102 cfu/mL and 4.4*102 cfu/g in pure culture and in spiked PIF, respectively. A similar detection limit of 5.6*102 cfu/g was obtained in the presence of the Staphylococcus aureus (107 cfu/mL). The combined SD-PMA-qPCR assay holds promise for the rapid detection of viable C. sakazakii in PIF. PMID- 27771088 TI - Variability in chemical and microbiological profiles of long-ripened Caciocavallo cheeses. AB - Five protected designation of origin (PDO) Caciocavallo Silano and 6 non-PDO Caciocavallo cheeses, ripened for 6mo and collected in the 5 Italian regions of the PDO area (Apulia, Basilicata, Calabria, Campania, and Molise, Italy), were studied to assess their physico-chemical (pH, acidity, moisture, fat, ash, protein, and free amino acid composition) and microbiological profiles. Analyses evidenced a certain fluctuation of previous parameters among samples regardless of the kind of cheese evaluated (PDO and non-PDO). The PCR-denaturing gradient gel electrophoresis analysis performed on the DNA directly extracted from cheeses gave different results, but a low number of bands was always observed. Only one band, corresponding to the species Streptococcus thermophilus, was detectable in 1 PDO and in 2 non-PDO cheese samples, whose free amino acid content was the lowest. Analyses were repeated on experimental Caciocavallo cheeses. Specifically, 2 productions were made, one mimicking the industrial technology (pasteurized milk and selected starter culture) and one the artisanal technology (raw milk and natural whey starter). Results obtained on experimental cheeses at 6mo of ripening showed that industrial samples had lower amounts of total free amino acids then the artisanal ones (1,188.2 vs. 7,523.67mg/100 g of dry matter). Moreover, the PCR-denaturing gradient gel electrophoresis analysis evidenced the sole presence of S. thermophilus in the case of the industrial technology. These data sustain the hypothesis that, out of 11 cheeses analyzed previously, 1 PDO Caciocavallo Silano and 2 non-PDO Caciocavallo cheeses were obtained with the industrial technology. These results could be of help in the discrimination of PDO products, taking into account that the PDO production regulation does not allow the milk pasteurization, nor the use of selected starters. PMID- 27771089 TI - Short communication: Hypolipidemic and antiinflammatory effects of fermented Maillard reaction products by Lactobacillus fermentum H9 in an animal model. AB - This study examined the effects of Maillard reaction products reacted by casein and lactose (cMRP) and of cMRP fermented by Lactobacillus fermentum H9 (F-cMRP) on hypolipidemic and antiinflammatory effects in rats fed a high-fat and high cholesterol diet (HD). The HD-fed rats had significantly increased hepatic triglyceride concentrations compared with the rats fed a normal diet. It was shown that treatment with simvastatin, L. fermentum H9 (H9), cMRP, and F-cMRP decreased total triglycerides in the liver compared with the HD group. On histological analysis, a reduction of lipid accumulation in the liver and aortic tissues was observed in the cMRP, F-cMRP, and H9-fed rats. Also, F-cMRP and cMRP reduced intima-media thickness in the HD group. In addition, the H9, cMRP, and F cMRP treatments significantly reduced the expression levels of ICAM-1 and VCAM-1, but not of MCP-1. In particular, the expressions of ICAM-1 and VCAM-1 were significantly decreased in the F-cMRP group compared with the HD group. These results of the present study suggest that cMRP and F-cMRP in dairy foods could potentially be used to prevent or treat cardiovascular diseases, especially atherosclerosis. PMID- 27771090 TI - Effects of nutrient intake level on mammary parenchyma growth and gene expression in crossbred (Holstein * Gyr) prepubertal heifers. AB - This study investigated the effects of increased nutrient intake levels on prepubertal mammary parenchyma development in crossbreed (Holstein * Gyr) dairy heifers. Eighteen heifers age 3 to 4 mo were fed 1 of 3 nutrient intake levels (n=6 per treatment) designed to sustain an average daily gain of 0.0kg/d (maintenance, MA), 0.5kg/d (low gain, LG), or 1.0kg/d (high gain, HG). Serum blood samples collected on d 42 and 84 after a 12-h fast were analyzed for triglycerides, leptin, insulin, and insulin-like growth factor 1 (IGF-1). Liver and mammary parenchyma were biopsied on d 42 and harvested on d 84 for gene expression analysis. Parenchyma samples were also used for biochemical and histological analysis. Mammary parenchyma weight was lower in HG than in MA or LG heifers, but mammary extraparenchymal fat was greater in HG heifers than in other groups. Heifers fed the HG diet had a greater fraction of ether extract in their parenchyma than the others and a smaller fraction of crude protein in their parenchyma than MA heifers. Moreover, the HG and LG heifers had greater body fat mass than MA heifers. Nutrient intake level had no effect on the number of intraparenchymal adipocytes. Heifers fed the HG diet had greater serum IGF-1 than the others, and serum insulin was lower in the MA than the HG or LG heifers. Liver GHR, IGF1, and IGFBP3 mRNA expression was higher, but IGFBP2 mRNA was lower in HG heifers than in others. The parenchyma mRNA expression of lipogenic markers, such as CD36, ACCA, FASN, and ADIPOR1, was upregulated by nutrient intake level. Significant nutrient intake * time interactions for lipogenic genes during the experimental period indicated variable gene expression depending on the time point of prepubertal mammary gland development. Overall, our data suggest that enhancing nutrient intake increased body fat accumulation and lipogenesis in the mammary gland to the detriment of parenchyma growth. Moreover, increased lipogenesis in the parenchyma of HG heifers may indicate that fat accumulation occurred because of adipocyte hypertrophy and not differences in adipogenesis. The implications of these results for milk yield needs to be elucidated. PMID- 27771091 TI - Availability of zinc from infant formula by in vitro methods (solubility and dialyzability) and size-exclusion chromatography coupled to inductively coupled plasma-mass spectrometry. AB - Zinc bioaccessibility from infant formula was estimated by in vitro methods (solubility and dialyzability) and size-exclusion chromatography (SEC) coupled to inductively coupled plasma-mass spectrometry (ICP-MS). Infant formula samples were first characterized in terms of Zn bound to lipids and proteins and Zn distribution in the aqueous soluble protein fraction. We found that Zn is not incorporated into the lipid fraction of the samples, being mainly associated with the protein fraction (around 100%). Fractionation of Zn-containing proteins in the soluble protein fraction was achieved by SEC-ICP-MS after performing protein extraction with a solution of 100mM (pH 6.8) Tris-HCl. The percentages of zinc in the soluble protein fraction in the soy-based and lactose-free infant formula were very low, around 7 and 24%, respectively, whereas the content of Zn in the soluble protein fraction of milk-based formula was around 90%. By SEC-ICP-MS, we found that Zn is associated with low-molecular weight compounds (around 10kDa) in all the infant formulas tested. The percentages of Zn estimated in the in vitro gastrointestinal digests of the infant formula ranged from 30 to 70% and from 1 to 10% for solubility and dialyzability assays, respectively. The dialyzability test resulted in lower than expected scores, as SEC-ICP-MS analysis of the gastrointestinal extracts revealed that Zn is bound to biomolecules with a molecular weight ranging from 1 to 7kDa, which suggests that dialysis data should be interpreted with caution. Speciation studies are a valuable tool for establishing availability of nutrients and for validating data from dialyzable in vitro methods. PMID- 27771092 TI - Antimicrobial susceptibility, virulence genes, and randomly amplified polymorphic DNA analysis of Staphylococcus aureus recovered from bovine mastitis in Ningxia, China. AB - Staphylococcus aureusis the leading pathogen involved inbovine mastitis, but knowledgeabout antimicrobial resistance, virulence factors, and genotypes of Staphylococcus aureus resulting in bovine mastitis in Ningxia, China, is limited. Therefore, antimicrobial susceptibility, virulence gene, and randomly amplified polymorphic DNA (RAPD) analyses of Staph. aureus were carried out. A total of 327 milk samples from cows with clinical and subclinical mastitis in 4 regions of Ningxia were used for the isolation and identification of pathogens according to phenotypic and molecular characteristics. Antimicrobial susceptibility against 22 antimicrobial agents was determined by disk diffusion. The presence of 8 virulence genes in Staph. aureus isolates was tested by PCR. Genotypes of isolates were investigated based on RAPD. Results showed that 35 isolates obtained from mastitis milk samples were identified as Staph. aureus. The isolates were resistant to sulfamethoxazole (100%), penicillin G (94.3%), ampicillin (94.3%), erythromycin (68.6%), azithromycin (68.6%), clindamycin (25.7%), amoxicillin (11.4%), and tetracycline (5.7%). All of the isolates contained one or more virulence genes with average (standard deviation) of 6.6+/ 1.6. The most prevalent virulence genes were hlb (97.1%), followed by fnbpA, hla, coa (94.3% each), nuc (85.7%), fnbpB (80%), clfA (77.1%), and tsst-1 (40%). Nine different gene patterns were found and 3 of them were the dominant gene combinations (77.1%). Staphylococcus aureus isolates (n=35) were divided into 6 genotypes by RAPD tying, the genotypes III and VI were the most prevalent genotypes. There was greatvariation in genotypes of Staph. aureus isolates, not only among different farms, but also within the same herd in Ningxia province. The study showed a high incidence of Staph. aureus with genomic variation of resistance genes, which is matter of great concern in public and animal health in Ningxia province of China. PMID- 27771093 TI - Normothermic ex vivo liver perfusion from donors after type 2 cardiac arrest. PMID- 27771094 TI - "Fast track" and intestinal surgery for Crohn's disease: Factors associated with prolonged hospital stay. AB - OBJECTIVE: The aim of this study was to determine factors associated with a prolonged postoperative stay (PS) in patients operated on with bowel resection for Crohn's disease (CD) included in an enhanced recovery program (ERP). METHODS: We included patients operated on for CD between January 2013 and December 2015. ERP was organized following an 8-point protocol. Variables studied were: age, sex, PS, ASA, location and type of CD, presence of perianal disease, Harvey Bradshaw index, previous resection, type of surgery (minimally invasive vs. laparotomy) and Clavien Dindo. An inferential study was performed to identify factors related with a PS> 6 days and multivariate analysis. RESULTS: A total of 52 patients were operated on. The median PS was 8 days (IR: 5-11). In the univariate analysis, location (L1 vs. L2-3), type (B2 vs. B3), presence of perianal disease, prior surgery, type of surgery performed, Harvey-Bradshaw index and Clavien-Dindo were associated with a PS>or< than 6 days. The model that best adjusts to predict a PS> 6days contained the variable Harvey-Bradshaw (OR: 6,49; 95% CI: 1,46-28,8) and the type of surgery (OR: 0,23; 95%CI: 0,05-0,95). CONCLUSION: A prolonged postoperative stay after bowel resection for CD is more related to the type or severity of the disease and the type of surgery performed, than with other patient factors. Patients with CD need good coordination between prehabilitation, ERP and postoperative management. PMID- 27771095 TI - Transanal hemorrhoid dearterialization is a safe and effective outpatient procedure for the treatment of hemorrhoidal disease. AB - INTRODUCTION: This prospective, observational study evaluated transanal dearterialization (THD) efficacy and safety in grade 2-4 hemorrhoids (HD). METHODS: THD was performed under sedation-locoregional anesthesia in 402 outpatients. Patients had follow-up evaluation 3 days, 2 weeks, 1, 6 and 12 months postoperatively. Postoperative complications and recurrence of symptoms at 12 months were analyzed. The relationship between the learning curve and the number of postoperative complications was studied. RESULTS: Mean patient age was 46.4 (range 20-85) years. A total of 268 patients (66.6%) were male. Sixteen patients (4.0%) had grade 2 HD, 210 (52.2%) had grade 3 and 176 (43.8%) had grade 4 HD. Surgery lasted 23 (17-34) min. A total of 67 patients had complications: bleeding in 10 patients (2.5%), hemorrhoidal thromboses in 10 (2.5%), perianal fistulas in 5 (1.2%), fissures in 14 (3.5%), urinary retention in 3 (0.8%), residual prolapse in 19 (4.7%), severe anal pain in 3 (0.8%), and perianal abscess in 3 patients (0.8%). Recurrent HD occurred in 6.3% (1/16) of grade 2 HD patients, 5.8% (12/210) of grade 3 patients and 9.7% (17/176) of grade 4 patients. Twelve months after THD, bleeding was controlled in 363 patients (90.5%), prolapse was controlled in 391 (97.3%) and pain markedly improved in 390 patients (97%). CONCLUSION: THD appears safe and effective for grade 2-4 HD, and the number of complications decreased with increasing surgeon experience. THD advantages include mild pain, fast recovery, early return to daily activities and low incidence of complications. PMID- 27771096 TI - Low plastic ingestion rate in Atlantic cod (Gadus morhua) from Newfoundland destined for human consumption collected through citizen science methods. AB - Marine microplastics are a contaminant of concern because their small size allows ingestion by a wide range of marine life. Using citizen science during the Newfoundland recreational cod fishery, we sampled 205 Atlantic cod (Gadus morhua) destined for human consumption and found that 5 had eaten plastic, an ingestion prevalence rate of 2.4%. This ingestion rate for Atlantic cod is the second lowest recorded rate in the reviewed published literature (the lowest is 1.4%), and the lowest for any fish in the North Atlantic. This is the first report for plastic ingestion in fish in Newfoundland, Canada, a province dependent on fish for sustenance and livelihoods. PMID- 27771097 TI - Sea surface microplastics in Slovenian part of the Northern Adriatic. AB - Plastics are the most common material of marine litter and have become a global pollution concern. They are persistent in the environment where they gradually degrade into increasingly smaller particles-microplastics (MP). Our study presents results of sea-surface monitoring for MP in the Slovenian part of the Trieste Bay in the Northern Adriatic Sea. In 17 trawls conducted over a 20-month period we found a high average concentration of 406*103MPparticles/km2. Over 80% of the particles were identified as polyethylene. The significant variability of MP concentrations obtained on different sampling dates is explained by use of surface current maps and a recently developed Markov chain marine litter distribution model for the Adriatic Sea. PMID- 27771098 TI - Seasonal variations of phytoplankton assemblages and its relation to environmental variables in a scallop culture sea area of Bohai Bay, China. AB - Seasonal variations of phytoplankton assemblages were examined in a scallop culture sea area of Bohai Bay (China) with regard to some major physical and chemical variables. Samples were collected at three stations from July 2011 to September 2013. A total of 134 species belong to 4 phyla were identified, of which 104 were diatoms, 27 were dinoflagellates, 1 was euglenophyte and 2 were chrysophytes. The cells abundance in autumn (55.44*103cells/L) was higher than that in summer (6.99*103cells/L), spring (3.46*103cells/L) and winter (2.69*103cells/L). The Shannon-Wiener diversity index was higher in summer (3.06), followed by spring (3.02) and winter (2.91), and low in autumn (1.40). Results of canonical correspondence analysis showed that phosphate, salinity, temperature, silicate and DIN/SiO2 ratio were the most important environmental factors influencing the variation of phytoplankton community structure. It is suggested that eutrophication resulted from scallop culture would cause a potential red tide risk. PMID- 27771099 TI - Escherichia coli in marine water: Comparison of methods for the assessment of recreational bathing water samples. AB - Bathing Water Directive (2006/7/EC) specifies two reference methods for Escherichia coli detection: ISO 9308-1 and 9308-3. The revised ISO 9308-1 is recommended only for waters with a low bacterial background flora. Considering the extended time needed for analysis and, generally, the lack of experience in using ISO 9308-3 in the Mediterranean, the suitability of ISO 9308-1 for the examination of E. coli in bathing water was evaluated. The present study was aimed at a comparison of data obtained by the reference method in seawater samples (110 beaches, N=477) with data received from six alternative methods. Results show that recently used TSA/TBA method may overestimate E. coli numbers in marine waters. The temperature modified ISO 9308-1 (44 degrees C) did not significantly alter the results, but outperformed the antibiotic supplemented agar at reducing non-E. coli bacteria on the plates, allowing the use of the respective method for monitoring coastal water. PMID- 27771100 TI - Centrifuge-less dispersive liquid-liquid microextraction base on the solidification of switchable solvent for rapid on-site extraction of four pyrethroid insecticides in water samples. AB - An on-site dispersive liquid liquid microextraction base on the solidification of switchable solvent has been developed as a simple, rapid and eco-friendly sample extraction method for the fast determination of pyrethroid insecticides in aqueous samples using high-performance liquid chromatography with ultraviolet detection. In this extraction method, medium-chain saturated fatty acids (n>=10), which can rapidly solidify at low temperatures (<20 degrees C), were investigated as switchable hydrophilic solvents. The fatty acids were converted into the hydrophilic form by adding sodium hydroxide. Microdroplets of the fatty acids were generated when injected into an acidic sample that had been pretreated by the addition of sulfuric acid. The formed cloudy solution was cooled to a low temperature to turn the fatty acids into a solid, which was then separated by filtration, thus avoiding the time-consuming step of centrifugation. The microextraction process was performed in a 10mL syringe and the pretreatment process could thus be finished in 5min. No external energy resources were required in this method, which makes it a potential method for on-site extraction. The optimal experimental parameters were as follows: 350MUL of decanoic acid (1mol/L) was used as the extraction solvent, 150MUL of sulfuric acid (2mol/L) was used to decrease the pH of the samples, no salt was added, and the temperature of the samples was in the range of 20-40 degrees C. Finally, the sample was cooled in an ice bath for three minutes. Under these optimal conditions, good responses for four pyrethroid insecticides were obtained in the concentration ranges of 1-500MUg/L, with coefficients of determination greater than 0.9993. The recoveries of the four pyrethroid insecticides ranged from 84.7 to 95.3%, with relative standard deviations ranging from 1.6 to 4.6%. The limits of detection based on a signal-to-noise ratio of 3 were in the range of 0.24 0.68MUg/L, and the enrichment factors were in the range of 121-136. The results demonstrate that this method was successfully applied to determine pyrethroid insecticides in real water samples. No centrifugation or any special apparatus are required, make this a promising method for rapid field-sampling procedures. PMID- 27771101 TI - Synthesis of thermo-responsive polymers recycling aqueous two-phase systems and phase formation mechanism with partition of epsilon-polylysine. AB - Aqueous two-phase systems (ATPS) have the potential application in bioseparation and biocatalysis engineering. In this paper, a recyclable ATPS was developed by two thermo-responsive copolymers, PVBAm and PN. Copolymer PVBAm was copolymerized using N-vinylcaprolactam, Butyl methacrylate and Acrylamide as monomers, and PN was synthesized by N-isopropylacrylamide. The lower critical solution temperature (LCST) of PVBAm and PN were 45.0 degrees C and 33.5 degrees C, respectively. The recoveries of both polymers could achieve over 95.0%. The phase behavior and formation mechanism of PVBAm/PN ATPS was studied. Low-field nuclear magnetic resonance (LF-NMR) was applied in the phase-forming mechanism study in ATPS. In addition, combining the analysis results of surface tension, transmission electron microscopy and dynamic light scattering, the phase-forming of the PVBAm/PN ATPS was proved. The application was performed by partition of epsilon polylysine in the 2% PVBAm/2% PN (w/w) ATPS. The results demonstrated that epsilon-polylysine was extracted into the PN-rich phase, the maximal partition coefficient (1/K) and extraction recovery of pure epsilon-polylysine were 6.87 and 96.36%, respectively, and 7.41 partition coefficient and 97.85% extraction recovery for epsilon-polylysine fermentation broth were obtained in the presence of 50mM (NH4)2SO4 at room temperature. And this method can effectively remove the most impurities from fermentation broth when (NH4)2SO4 exists in the ATPS. It is believed that the thermo-responsive recycling ATPS has a good application prospect in the field of bio-separation. PMID- 27771102 TI - Integrating targeted glycomics and untargeted metabolomics to investigate the processing chemistry of herbal medicines, a case study on Rehmanniae Radix. AB - It is well-recognized that multiple components, the majority of which are secondary metabolites and carbohydrates, collectively contribute to the therapeutic effects of herbal medicines. The chemical characterization of herbal medicines has focused extensively on secondary metabolites but has largely overlooked carbohydrates. Here, we proposed an integrated chromatographic technique based targeted glycomics and untargeted metabolomics strategy simultaneously determining carbohydrates and secondary metabolites for the overall chemical profiling of herbal medicines; this strategy was successfully exemplified in an investigation of processing chemistry of Rehmanniae Radix (RR), a Chinese medicinal herb. It was demonstrated that the integrated strategy holistically illuminated the variations in the glycome and metabolome of RR samples processed by the traditionally-adopted nine cycles of steaming and drying, and further elucidated the processing-induced chemical transformation mechanisms of carbohydrates and secondary metabolites, and thereby revealed the inherent chemical connections between carbohydrates and secondary metabolites. The result suggested that the proposed strategy meets the technical demands for the overall chemical characterization of herbal medicines, and therefore could serve as a powerful tool for deciphering the scientific basis of herbal medicines. PMID- 27771103 TI - Development and validation of a selective and effective pressurized liquid extraction followed by liquid chromatography-mass spectrometry method for the determination of fructosazine analogues in the ammonia treated extract of Eugenia jambolana Lamarck seeds. AB - This study describes a selective and effective pressurized liquid extraction (PLE) coupled with HPLC-DAD-ESI/MS method for the identification and quantification of three fructosazine analogues (FZAs), fructosazine, 2,6- and 2,5 deoxyfructosazine in Madeglucyl(r) (MG) which is an ammonia treated extract of Eugenia jambolana Lamarck seeds, and is the world's first anti-diabetic phytodrug. FZAs were extracted from MG by PLE using methanol as extraction solvent. The PLE extract was then analyzed directly by HPLC-DAD-ESI/MS without cleanup step. Chromatographic separation of these highly related structures was achieved on a porous graphic carbon (PGC) column. The identification of the target FZAs was confirmed by the similar retention time, similar UV and MS spectra to the corresponding pure standards. The quantification was performed by using an electrospray positive ionization mass spectrometry in the selected ion monitoring (SIM) mode. The PLE procedure was optimized and overall method was validated in terms of sensitivity, linearity, selectivity and matrix effect, precision, accuracy and recovery, and stability of the target FZAs in the aqueous solution and in the PLE extracts solution of MG. The developed method was proved to be selective, sensitive, precise, accurate for the quantification of FZAs in MG. PMID- 27771104 TI - [Therapeutic drug monitoring of clozapine]. AB - Clozapine is a prototypical atypical antipsychotic used to treat severe schizophrenia and for which a therapeutic drug monitoring (TDM) is quite commonly proposed. Clozapine is rapidly absorbed (maximum concentration reached within 1 to 4hours), and is extensively metabolized in the liver by CYP1A2 to an active metabolite (and to a lesser extent, to inactive metabolites via other enzymes). Its half-life is 8 to 16h. A therapeutic range has been proposed for clozapine as some studies have reported both a relationship between low plasmatic concentrations and resistance to treatment (threshold level is likely between 250 and 400MUg/L), and a relationship between high plasmatic concentrations and an increase in the occurrence of toxicity (alert level=1000MUg/L). Given the data obtained in different studies, the TDM was evaluated for this molecule, to recommended. PMID- 27771105 TI - [Which psychoactives substances are found in used syringes?] AB - OBJECTIVE: The aim of this study is to analyze the residual content of used syringes. METHODS: Used syringes were collected in March 2014 at 9 sites in Marseille (automatic injection kit dispensers, streets, drug-user risk reduction centers [Centres d'accueil et d'accompagnement a la reduction de risques pour usagers de drogues [CAARUD]). Several substances (n=28) were investigated using liquid chromatography and mass spectrometry method. RESULTS: On average, 2+/-1 substances in each syringe were found among 254 syringes analyzed. The most detected substances were cocaine, buprenorphine, methylphenidate and cathinones (in 57 %, 56 %, 39 % and 19 % of the syringes respectively). Heroin and morphine were found in 10 % of the syringes. DISCUSSION-CONCLUSION: This study helps define the main substances consumed by injection drugs users. It highlighted differencies in used substances according to neighborhood and site of collection and thus help to adjust prevention and harm reduction strategies. PMID- 27771106 TI - [Interaction between amoxicillin clavulanic acid and fluindione: Two case reports]. PMID- 27771107 TI - [Hypertriglyceridemia, discovered on a pseudohyponatremia, induced by l asparaginase in the treatment of B acute lymphoblastic leukemia in child]. PMID- 27771108 TI - Multiple drug intolerance syndrome in an epileptic woman. PMID- 27771109 TI - Cerebellopontine angle gangliogliomas: Report of two cases. AB - BACKGROUND: Gangliogliomas are rare tumors of the central nervous system. We report two unusual cases of gangliogliomas located in the cerebellopontine angle (CPA). POPULATION AND METHODS: The first patient was a 57-year-old woman, who presented with dizziness and harbored a non-enhanced heterogeneous mass located in the cisternal space of the CPA. A partial microsurgical removal was performed, and the pathological examination concluded a grade I ganglioglioma according to the WHO Classification. The postoperative course was uneventful without any adjuvant treatment and the 5-year imaging follow-up indicated a stable remnant tumor. The second patient was a 35-year-old male who presented with acute vertigo and imbalance associated with recent prominent headaches; MR imaging showed a large heterogeneous and post-contrast enhanced tumor mass located in the CPA cistern with a mass effect on the brain. An optimal subtotal surgical resection was performed. The pathologists concluded a WHO grade III ganglioglioma. In spite of adjuvant radiotherapy and chemotherapy, the evolution proved unfavorable and patient died from cancer complications within a 2-year period. In both cases, the precise origin of the tumor could not be clearly identified even if the major component was present in the cisternal space. CONCLUSION: Gangliogliomas growing into the cisternal spaces are exceedingly rare particularly in the CPA. Due to its infiltrating behavior and major difficulties to identify the tumor margins, total resection is not routinely feasible. The histological grading is the most important predictor for oncological prognosis. PMID- 27771110 TI - Image-guided transoral approach in severe craniovertebral junction malformations at the golden age of endoscopy: Regarding 2 cases. AB - INTRODUCTION: The image-guided transoral approach (IGTOA) provides a safe exposure to skull base midline lesions and the ventral aspect of the craniovertebral junction (CVJ). The IGTOA has several advantages: the head being placed in the extended position, it decreases the brainstem angulation during surgery; the approach being done through the avascular median pharyngeal raphe, not only lowers the bleeding risk but also provides a direct access to the bony pathology and granulation tissue accessible only via the ventral route. Wide field exposure and maneuverability are necessary to deal with the entire ventral brainstem compression in case of severe CVJ malformation to safely perform partial clivectomy and odontoidectomy. PRESENTATION OF TWO CASES: We illustrate the cases of two patients, 52-year-old and 42-year-old males, who presented with an impressive craniovertebral junction malformation, confirmed on CT and MRI images. They first underwent surgery by IGTOA, later completed by occipitocervical fixation. For the two patients, outcomes were assessed respectively at 4 and 5 years and showed satisfactory results both clinically and radiologically. CONCLUSION: In patients with marked ventral compression, the IGTOA provides direct and guided access to the anterior aspect of the CVJ and effective means for odontoidectomy and clivectomy. This approach is more easily maneuverable compared to the endonasal endoscopic approach. The IGTOA approach is quite a complex technique, requiring multidisciplinary skills, but it should primarily be used in difficult situations. We suggest that endonasal endoscopy is over-utilized. We consider that endoscopy should not be routinely performed and kept only for well-selected cases. PMID- 27771111 TI - Ziconotide intrathecal delivery as treatment for secondary therapeutic failure of motor cortex stimulation after 6 years. AB - INTRODUCTION: Motor cortex stimulation is a well-known treatment modality for refractory neuropathic pain. Nevertheless, some cases of therapeutic failure have been described but alternative therapies for these cases are rarely reported. CASE REPORT: The patient presented with neuropathic pain in his right arm due to a cervical syrinx which was surgically treated by a shunt in 2003 with no clinical improvement. As alternative therapy, after an evaluation by repetitive magnetic transcranial stimulation with significant benefit, motor cortex stimulation was successfully implanted in 2004. In 2010, a similar pain occurred in the same territory. Local mean pain visual analogical scale (VAS) increased to 82/100. A newer generation stimulation device was then implanted and, within a period of 8months, different stimulation parameter settings were tested, without any pain relief. An intrathecal drug delivery pump was then implanted in 2011, and the upper extremity catheter was located at the cervicothoracic junction. There was no postoperative complication. A bitherapy was initiated at a daily dosage of 0.2mg morphine and 1.3MUg ziconotide, not modified since August 2013. At 43months follow-up, mean VAS was 21/100 with improvement of daily life and spare-time activities, anxiety and depression, quality of life (as measured by the SF-36 survey and EQ5D-3L questionnaire). DISCUSSION: Refractory neuropathic pain treated by motor cortex stimulation may be considered in palliative situations, and secondary therapeutic failure offers only a few perspectives. Intrathecal ziconotide, indicated as a first-line drug in non-cancer pain, could be proposed in such cases. CONCLUSION: Intrathecal drug delivery including ziconotide in refractory neuropathic pain represents a reasonable option with a good clinical tolerance. PMID- 27771112 TI - Hemiparkinsonism secondary to sphenoid wing meningioma. AB - We describe the case of a 41 year-old woman who presented with a slight slowness of the right hand movement, which began four months prior to admission. Neurological examination showed slight rest tremor of the right hand, moderate bradykinesia and rigidity. She had been taking medication for Parkinson's disease, but without any benefit. The patient underwent a gadolinium-enhanced brain MRI, which showed a large left sphenoid wing meningioma with surrounding edema compressing the basal ganglia. Total excision of tumor was performed. The right hemiparkinsonian signs were completely resolved. This rare case underlines the significance of neuroimaging in patients presenting with Parkinson's disease especially in those patients with a relatively younger age at onset or unresponsive to medication. PMID- 27771113 TI - [Cerebral primitive osteosarcoma, a radiological and histological atypia]. AB - INTRODUCTION: Osteosarcoma is a malignant mesenchymal tumor including cells that present an osteoblastic differentiation. On the skull, it has often extra-axial development associated with bone reaction. We report an atypical and rare case of intracranial or cerebral osteosarcoma underline the radiological and pathological diagnostic difficulties. CASE REPORT: Our case concerns a primary osteosarcoma without bone involvement in a 10-year old boy who was admitted for intracranial hypertension with progressive worsening and brachial monoparesis. Subtotal resection was performed but the postoperative course was not favorable. The child died five months after the initial surgery. Its radiological aspect prompted us evoke several diagnoses including glioma or meningioma. On the histological level, osteosarcoma, especially with poorly differentiated cells, can be deceiving with other processes, including a gliosarcoma that was revealed by simple microscopic reading before being confirmed by an immunohistochemical study. CONCLUSION: In the absence of any bone reaction or known extra-cranial location, it can be difficult to suggest the diagnosis of osteosarcoma based on imagery alone. Immunohistochemistry is essential for an accurate diagnosis. PMID- 27771114 TI - Ovarian dysfunction associated with zona pellucida-based immunocontraceptive vaccines. AB - Despite more than 40 years of research into zona pellucida (ZP)-based vaccines, relatively little is known about their mechanism of action. Early research demonstrated precipitation of ZP glycoproteins by antiovarian antiserum, rendering oocytes resistant to sperm binding in vitro. Subsequent work showed significantly decreased fertilization rates following passive immunization, sparking interest in anti-ZP immunocontraception for human and animal use. The primary mechanism of action of ZP vaccines is generally considered to be an antibody-mediated interference with sperm-oocyte binding and/or fertilization. However, this mechanism of action excludes the potential for ovarian dysfunction associated with anti-ZP treatment in some species. A review of relevant literature in pertinent model, domestic and wildlife species reveals a variety of previous and current hypotheses for ovarian effects following ZP-based immunization. Ovarian dysfunction has been suggested to be a species-specific response. In addition, cytotoxic T-lymphocytes and the use of Freund's adjuvants have been suggested to play a role. Finally, the type and extent of glycosylation of ZP antigens have been proposed to influence ovarian effects. The validity of these hypotheses is re-examined in the light of current knowledge. Further investigation of ovarian function in species believed to be resistant to the ovarian effects of anti-ZP vaccines is warranted. To this end, anti-Mullerian hormone may provide a novel tool for the assessment of ovarian function during ZP based immunocontraception, particularly in wildlife species not amenable to frequent clinical examination. PMID- 27771115 TI - Comparing strategies to synchronize estrus before fixed-time artificial insemination in primiparous 2-year-old beef cows. AB - Two experiments evaluated controlled internal drug release (CIDR)-based protocols to synchronize estrus in primiparous 2-year-old beef cows. In each experiment, treatments were balanced according to body condition score and days postpartum. Experiment 1 compared the 14-day CIDR-PG (14-d) and 7-day CO-Synch + CIDR (7-d) protocols on the basis of estrous response, pregnancy rates after fixed-time artificial insemination (FTAI), and final pregnancy rate. Cows assigned to 14-d (n = 355) received a CIDR insert on Day 0 with removal on Day 14. Cows assigned to 7-d (n = 349) received gonadotropin releasing hormone (GnRH) and a CIDR insert on Day 23. On Day 30, CIDRs were removed from 7-d cows, and PGF2alpha was administered to all cows in each treatment. On Day 33, GnRH was administered concurrent with FTAI at 66 and 72 hours after PGF2alpha for 7-d and 14-d treated cows, respectively. Estrous response before FTAI was higher for 7-d compared with 14-d cows (74% vs. 43%, respectively; P < 0.0001); however, pregnancy rates resulting from FTAI were similar (14-d 63%; 7-d 64%; P = 0.52). Ovarian follicular dynamics and serum estradiol-17beta concentrations were evaluated among a subset of cows assigned to each protocol. Dominant follicle diameter was smaller at PGF2alpha (P = 0.04) and FTAI (P = 0.002) among 14-d cows compared with 7-d cows; however, estradiol-17beta at PGF2alpha (P = 0.06) and FTAI (P = 0.001) was greater for 14-d versus 7-d treated cows. Experiment 2 compared estrous response and pregnancy rates in 2-year-old beef cows after FTAI- or split time artificial insemination (STAI) following synchronization of estrus with the 14-day protocol. Cows assigned to FTAI (n = 266) were inseminated at a fixed time concurrent with GnRH at 72 hours after PGF2alpha regardless of estrus expression, whereas cows assigned to STAI (n = 257) were inseminated based on estrus expression as determined by activation of an estrus detection aid. Cows assigned to STAI that exhibited estrus by 72 hours were inseminated; however, AI was delayed until 24 hours after GnRH (96 hours after PGF2alpha) for nonestrous cows. Total estrous response was increased for STAI- versus FTAI-treated cows (STAI 64%; FTAI 42%; P < 0.0001); pregnancy rates resulting from AI were similar (STAI 55%; FTAI 56%; P = 0.60). In summary, the 14-day CIDR-PG and 7-day CO-Synch + CIDR protocols can be used effectively to synchronize estrus before FTAI in primiparous 2-year-old beef cows. Although expression of estrus was increased using STAI in conjunction with the 14-day protocol, this approach did not increase pregnancy rates compared with FTAI. PMID- 27771116 TI - Coxiella burnetii detected in three species of endangered North African gazelles that recently aborted. AB - Coxiella (C.) burnetii is the etiological agent of the zoonotic disease known a Q fever. This agent can infect multiple hosts although its pathogenic potential in wild ruminants has been poorly studied. The polymerase chain reaction and the serological test detected the presence of C. burnetii in a population of North African gazelles (n = 355), comprising dorcas gazelle (Gazella dorcas neglecta), dama gazelle (Nanger dama mhorr) and Cuvier's gazelle (Gazella cuvieri) which, some of them, they recently aborted. Serological tests for Brucella spp., C. burnetii, Chlamydophila abortus, border disease pestivirus, and Toxoplasma spp. were performed together with specific cultures to detect Salmonella spp., Listeria spp., and Campylobacter spp. and a polymerase chain reaction for C. burnetii on serum and vaginal swabs samples collected from a representative number of animals (n = 65). These tests only detected the presence of C. burnetii in 18 specimens (27.3%). C. burnetii was the only pathogen detected, with eight animals testing positive on the polymerase chain reaction, 15 on the serological test, and five on both the tests. This article reveals the presence of C. burnetii during a medium and late-stage abortions occurred in a population of North African gazelles. The presence of C. burnetii as causal agent of abortions in Cuvier's gazelles has never been reported. The consequences of the findings are discussed here, showing the need to adopt urgent control measures to prevent the spread of C. burnetii in captive populations that are essential for the conservation of these endangered species. PMID- 27771117 TI - Cellular thermotolerance is inheritable from Holstein cattle cloned with ooplasts of Taiwan native yellow cattle. AB - We have previously demonstrated that the somatic cells from cattle cloned with Holstein (H) donor cells and Taiwan native yellow cattle (Y) ooplasm (Yo-Hd) had better thermotolerance than those from cattle cloned with both Holstein donor cells and ooplasm (Ho-Hd). The present study aimed to investigate whether the cellular thermotolerance of these cloned cattle is transmissible to their offspring (Ho-Hd-F1 and Yo-Hd-F1). Thermotolerance of ear fibroblasts derived from these cloned cattle and their offspring were analyzed. Polymorphisms in mitochondrial DNA (mtDNA) D-loop of ear fibroblasts derived from Yo-Hd and Yo-Hd F1 indicated that the cytoplasm is originated from Bos indicus (Y). After heat shock, the apoptotic rates, B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 ratios, and relative expression levels of cysteine-aspartic proteases (caspases)-3, -8, and -9 of ear fibroblasts with Y-originated cytoplasm (including Y, Yo-Hd, and Yo-Hd-F1) were lower (P < 0.05) than those of ear fibroblasts with H-originated cytoplasm (including H, Ho-Hd, and Ho-Hd-F1). In contrast, the relative level of HSP-70 was higher (P < 0.05) in ear fibroblasts with Y-originated cytoplasm than that of with H-originated cytoplasm. Based on our results, thermotolerance of ear fibroblasts derived from Yo-Hd and Yo-Hd-F1 cattle is better and can be transmitted, at least at the cellular level, to their offspring. PMID- 27771118 TI - Puerarin ameliorates heat stress-induced oxidative damage and apoptosis in bovine Sertoli cells by suppressing ROS production and upregulating Hsp72 expression. AB - Puerarin, a bioactive isoflavone glucoside extracted from radix Puerariae, has been proven to possess many biological activities. However, the role of puerarin in protecting bovine Sertoli cells (bSCs) under heat stress conditions remains to be clarified. The present study aimed to explore the possible protective mechanism of puerarin for primary cultured bSCs subjected to heat stress. Bovine Sertoli cells were treated with 15 MUM of puerarin before they were exposed to 42 degrees C for 1 hour. The dose of puerarin (15 MUM) was determined on the basis of cell viability. The results showed that puerarin treatment suppressed the production of reactive oxygen species and decreased the oxidative damage of the bSCs subjected to heat stress, as indicated by changes in superoxide dismutase, catalase, and glutathione peroxidase activities and malondialdehyde content. Moreover, puerarin treatment also suppressed the initiation of mitochondria dependent apoptotic pathway, as revealed by changes in Bax to Bcl-2 ratio, mitochondrial membrane potential, cytochrome C release, caspase-3 activation, and apoptotic rate compared with the heat stress group. In addition, puerarin treatment increased Hsp72 expression in the bSCs with no apparent cellular cytotoxicity compared with the control group. Furthermore, increased Hsp72 was detected in the heat stress plus puerarin group compared with the heat stress group. In conclusion, puerarin attenuates heat stress-induced oxidative damage and apoptosis of bSCs by suppressing reactive oxygen species production and upregulating Hsp72 expression. PMID- 27771119 TI - [Multiple and recurring pyogenic granulomas treated with topical timolol]. PMID- 27771120 TI - [Retrospective study of hypertensive leg ulcers at Reims University Hospital: Epidemiological, clinical, disease progression data, effects of vitamin K antagonists]. AB - BACKGROUND: Hypertensive leg ulcers (HLU) are a form of necrotic leg ulcer. Their physiopathology is not well known and in these patients, no venous or arterial insufficiency is detected. The primary objective of this study was to evaluate the association between HLU severity and the presence or absence of concomitant vitamin K antagonist (VKA) medication. We furthermore aimed to describe the epidemiology of this entity and the prevalence of thrombophilia factors in this population. PATIENTS AND METHODS: This was a retrospective study in 54 patients hospitalized in the dermatology department of Reims University Hospital between 01/01/2007 and 31/12/2013: 23 patients were included in the "without VKA" group, and 30 were included in the "with VKA" group. Clinical and laboratory data were collected. RESULTS: The average HLU surface was higher in the "with VKA" group i.e. 35.00cm2 (min: 3.0; max: 220.0) versus 23.00cm2 (min: 5.0; max: 300.0) (P=0.05). No significant difference was found in terms of time to healing, mean hospitalization duration, HLU treatment by skin grafting, or time to recurrence after healing. Mean patient age was 74.2+/-9.3 years; 100% of patients had arterial hypertension, 50.9% had diabetes, and 20.8% were active smokers. Abnormal but non-significant values for thrombophilia factors were observed. CONCLUSION: Our study shows no obvious differences between patients with HLU with or without VKA medication. A prospective, comparative study is necessary to further evaluate this hypothesis, with particular emphasis on routine thrombophilia factor analysis. PMID- 27771121 TI - [Muir-Torre syndrome associated with Waldenstrom's macroglobulinemia]. AB - BACKGROUND: Muir-Torre syndrome (MTS), a cutaneous variant of Lynch syndrome, consists of hereditary predisposition to cutaneous tumours and gastrointestinal and gynaecological neoplasms, with autosomal dominant transmission. It is associated with mutations in genes coding for proteins in the DNA mismatch repair system. PATIENTS AND METHODS: Herein, we report a case of a male patient presenting Waldenstrom's macroglobulinemia since the age of 50 and which, after the age of 65 years, developed into sebaceous tumours (5 sebaceous adenomas, 1 sebaceoma, 1 sebaceous carcinoma) and colonic lesions (4 adenomas). The clinical phenotype was consistent with MTS. Somatic analysis carried out on one sebaceous tumour showed instability of the microsatellites with loss of expression of MSH2 and MSH6 although constitutional genetic analysis showed no germline mutations known to be harmful. DISCUSSION: This noteworthy case raises a number of questions, including the possibility of association between STM and Waldenstrom's macroglobulinemia, which is discussed herein. PMID- 27771122 TI - [Vaccination status in psoriasis patients on immunosuppressant therapy (including biologics)]. AB - OBJECTIVES: To evaluate the vaccine coverage of psoriasis patients prior to initiating or changing immunosuppressant therapy, and to verify that the prescribed vaccines have been administered. PATIENTS AND METHODS: We conducted a bi-centre, observational, cross-sectional study over 9 months. Psoriasis patients in whom immunosuppressant therapy (comprising cyclosporine, methotrexate, etanercept, infliximab, adalimumab or ustekinumab) was indicated were included. Medical history, previous treatments, vaccination status, viral serology results (for hepatitis B, measles, and chickenpox), and reasons for non-vaccination were assessed via questionnaire. RESULTS: Sixty-eight patients were included. One third brought their immunization records. Overall, 54.4% had already received immunosuppressant therapy; of these, 9 were up to date for influenza and 3 were up to date for pneumococcus. Only one patient was up to date for all of the recommended vaccinations. A total of 61% of patients were seronegative for hepatitis B. The following vaccines were updated: DTP (in 2 patients), DTP pertussis (12), influenza (22), pneumococcus (45), and hepatitis B (6). None of the three patients with plans to travel to yellow fever-endemic countries had been vaccinated. In all, 53 (78%) stated that they had already had chickenpox and 43 (63.2%) stated that they had had one of the following three diseases: measles, rubella, or mumps. Fifty-two patients were serologically tested for chickenpox, and 98% were immunized. The most common reasons for not updating the immunization schedule were the absence of any notification or proposal by the patient's doctor and oversight. CONCLUSION: This study should help raise awareness among patients and health professionals concerning the new vaccination recommendations for a population particularly at risk of infection. PMID- 27771123 TI - [Circumscribed palmar hypokeratosis (CPM): The diagnostic value of dermoscopy]. AB - BACKGROUND: Circumscribed palmar hypokeratosis (CPH) is a rare skin disease, first described in 2002, associated with sudden localized reduction of the corneal layer. In most cases, it presents as an isolated rounded erythematous palmar lesion on the thenar eminence. We describe the dermoscopic semiology of CPH in 3 cases. PATIENTS AND METHODS: Three patients between the ages of 59 and 72 presented very limited erythematous lesions suggestive of CPH. Dermoscopic examination of these lesions provided similar findings. Biopsy, which was performed in one patient, confirmed the diagnosis of CPH. RESULTS: Two dermoscopic elements of CPH are characteristic: (1) the sides of the lesion have a "stair step" or "geological strata" type of configuration, and the thickness of the different strata varies; (2) the centre of the lesion showed a homogeneous erythematous area with a vascular pattern composed of dotted vessels of the superficial dermis and sometime vascular loops. DISCUSSION: These dermoscopic aspects are characteristic and enable CPH to be differentiated from Bowen's disease or porokeratosis of Mibelli. In Bowen's disease, there is no stair step like aspect to the sides of lesions; further, the centre of the lesion shows glomerular vessels (coiled vessels) and/or globular vessels (small red clods). In porokeratosis, peripheral keratotic "white track" structures comprise a single pigmented channel or a double white line. There is no "stair step" or central vascular pattern. CONCLUSION: The dermoscopic semiology of CPH is highly characteristic and enables differentiation from Bowen's disease and porokeratosis. PMID- 27771124 TI - [Genital herpes]. PMID- 27771125 TI - [Nested melanoma]. AB - BACKGROUND: Nested melanoma in elderly subjects is an entity that has been reported in the literature only since 2012. In this paper, we describe its distinctive clinical, dermatoscopic and histopathological features and compare them to previous published cases, with the aim of highlighting certain specific criteria of this melanoma subtype. CASE REPORT: A 52-year-old man was referred for the presence on his chest of a large suspicious pigmented lesion of irregular shape and colour. Dermatoscopically, the lesion was chaotic and characterized by a black, structureless, eccentric area with some peripheral globules as well as some segmental radial lines. Histopathological examination revealed the presence of an asymmetric lesion with large junctional melanocytic nests showing a focal tendency to gathering and some cytological atypia. A diagnosis of nested melanoma was ultimately made. DISCUSSION: Nested melanoma of the elderly represents a distinct anatomoclinical variant of superficial spreading melanoma. Clinically, the lesion is usually large and occurs in photodamaged skin. We would stress that the "elderly" criterion is not mandatory given the numerous cases reported in people under 60 years. The main dermatoscopic feature is a globular pattern, but several features characteristic of superficial spreading melanoma may also be present. Histological diagnosis may be difficult because of the mainly nested pattern, and the condition may be confused histologically with a benign junctional nevus. But these large junctional nests of different sizes, with bridging and cytonuclear atypias, together with asymmetry of the lesions are the hallmark of this special kind of melanoma. PMID- 27771127 TI - Should we Refrain from Performing Oophorectomy in Conjunction with Radical Cystectomy for Bladder Cancer? AB - Radical cystectomy with neoadjuvant chemotherapy is the gold standard for treating muscle-invasive bladder cancer. Women subjected to radical cystectomy are frequently postmenopausal, and the median age for bladder cancer diagnosis in women in Sweden is currently 73 yr (Swedish National Bladder Cancer Register). Traditionally, most women treated with radical cystectomy have undergone simultaneous bilateral oophorectomy and hysterosalpingectomy to diminish the risk of later ovarian disease and ovarian bladder cancer recurrence, but also the belief that there is no impact on health or health-related quality of life associated with oophorectomy and the fact that it might be easier surgery to take the ovarian pedicles, rather than sparing the ovaries. However, pelvic organ preservation is considered in some younger women to diminish postoperative functional impairment. Based on recent literature in several areas related to oophorectomy, we question the rationale and arguments for performing oophorectomy in women in conjunction with radical cystectomy for bladder cancer. PMID- 27771128 TI - Obesity and Prostate Cancer: A Focused Update on Active Surveillance, Race, and Molecular Subtyping. AB - CONTEXT: In 2012, we published a detailed review on obesity and prostate cancer. Since then, new studies have brought further understanding regarding the role of obesity in selecting active surveillance candidates, and differing associations between obesity and prostate cancer as a function of race and molecular subtype of prostate cancer. OBJECTIVE: To review new manuscripts on these new concepts for which there were limited data before 2012. EVIDENCE ACQUISITION: A PubMed search from July 2012 to March 2016 was performed using the terms "prostate cancer" and "obesity". Of 450 articles, we included 15 related to these three topics. EVIDENCE SYNTHESIS: Among men on active surveillance or candidates for active surveillance, multiple studies suggest that the risk of upgrading is higher for obese men. No study has shown long-term oncologic differences, and the risk of prostate cancer mortality remains low. One study suggested that the link between obesity and prostate cancer risk is stronger among black men; however, other studies found that obesity is correlated with aggressive disease regardless of race. Two studies found that the associations between obesity and prostate cancer (ie, fewer low-grade cancers and yet more aggressive cancers) was limited to men with TMPRSS2-ERG-positive tumors. CONCLUSIONS: The past 4 yr has seen much new work on the obesity-prostate cancer link. If confirmed in other studies, these findings provide novel insights into not only the link between obesity and prostate cancer but also prostate cancer biology in general. PATIENT SUMMARY: While their outcomes may be slightly worse, obese men with localized prostate cancer should not be discouraged from active surveillance. Early studies suggest there may be subtypes of patients in whom obesity is more strongly linked to aggressive disease. PMID- 27771129 TI - Are dust mite allergens more abundant and/or more stable than other Dermatophagoides pteronyssinus proteins? PMID- 27771130 TI - Radionuclide concentration variations in the fuel and residues of oil shale-fired power plants: Estimations of the radiological characteristics over a 2-year period. AB - Several multi-day samplings were conducted over a 2-year period from an oil shale fired power plant operating with pulverized fuel type of boilers that were equipped with either novel integrated desulphurization system and bag filters or with electrostatic precipitators. Oil shale, bottom ash and fly ash samples were collected and radionuclides from the 238U and 232Th series as well as 40K were determined. The work aimed at determining possible variations in the concentrations of naturally occurring radionuclides within the collected samples and detect the sources of these fluctuations. During the continuous multi-day samplings, various boiler parameters were recorded as well. With couple of exceptions, no statistically significant differences were detected (significance level 0.05) between the measured radionuclide mean values in various ash samples within the same sampling. When comparing the results between multiple years and samplings, no statistically significant variations were observed between 238U and 226Ra values. However, there were significant differences between the values in the fly ashes when comparing 210Pb, 40K, 228Ra and 232Th values between the various samplings. In all cases the radionuclide activity concentrations in the specific fly ash remained under 100 Bq kg-1, posing no radiological concerns when using this material as an additive in construction or building materials. Correlation analysis between the registered boiler parameters and measured radionuclide activity concentrations showed weak or no correlation. The obtained results suggest that the main sources of variations are due to the characteristics of the used fuel. The changes in the radionuclide activity concentrations between multiple years were in general rather modest. The radionuclide activity concentrations varied dominantly between 4% and 15% from the measured mean within the same sampling. The relative standard deviation was however within the same range as the relative measurement uncertainty, suggesting that the main component of fluctuations is derived from the measurement method and approach. The obtained results indicate that representativeness of the data over a longer time period is valid only when a fuel with a similar composition is used and when the combustion boilers operate with a uniform setup (same boiler type and purification system). The results and the accompanying statistical analysis clearly demonstrated that in order to obtain data with higher reliability, a repeated multi-day sampling should be organized and combined with the registered boiler technical and operational parameters. PMID- 27771126 TI - Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category. AB - BACKGROUND: We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response. OBJECTIVE: To assess outcomes of 2L according to type of therapy and change in IMDC prognostic category. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of the IMDC database for mRCC patients who received first line (1L) VEGF inhibitors (VEGFi) and then 2L with VEGFi or mTOR inhibitors (mTORi). IMDC prognostic categories were defined before each line of therapy (favorable, F; intermediate, I; poor, P). Data were analyzed for 1516 patients, of whom 89% had clear cell histology. INTERVENTION: All included patients received targeted therapy for mRCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), time to treatment failure, and response to 2L were analyzed using Cox or logistic regression. RESULTS AND LIMITATIONS: At start of 2L, 60% of patients remained in the same prognostic category; 9.0% improved (3% I -> F; 6% P -> I); 31% deteriorated (15% F -> I or P; 16% I -> P). Patients with the same or better IMDC prognostic category had a longer time to treatment failure if they remained on VEGFi compared to those who switched to mTORi (adjusted hazard ratio [AHR] ranging from 0.33 to 0.78, adjusted p<0.05). Patients who deteriorated from F to I appeared more likely to benefit from switching to mTORi (median OS 16.5 mo, 95% confidence interval [CI] 12.0-19.0 for VEGFi; 20.2 mo, 95% CI 14.3-26.1 for mTORi; AHR 1.53, 95% CI 1.04-2.24; adjusted p=0.03). CONCLUSIONS: Changes in IMDC prognostic category predict the subsequent clinical course for patients with mRCC and provide a rational basis for selection of subsequent therapy. PATIENT SUMMARY: The pattern of treatment failure might help to predict what the next treatment should be for patients with metastatic renal cell carcinoma. PMID- 27771131 TI - Radiological investigation of phosphate fertilizers: Leaching studies. AB - The raw materials of the phosphate fertilizer industry are the various apatite minerals. Some of these have high levels of natural radionuclides, and thus phosphate fertilizers contain significant amounts of U-238, K-40 and Ra-226. These can leach out of the fertilizers used in large quantities for resupplying essential nutrients in the soil and can then enter the food chain through plants, thereby increasing the internal dose of the affected population. In the current study, the radiological risk of eight commercially available phosphate fertilizers (superphosphate, NPK, PK) and their leaching behaviours were investigated using different techniques (gamma and alpha spectrometry), and the dose contributions of using these fertilizers were estimated. To characterize the leaching behaviour, two leaching procedures were applied and compared -the MSZ 21470-50 (Hungarian standard) and the Tessier five-step sequential extraction method. Based on the evaluation of the gamma-spectra, it is found that the level of Th-232 in the samples was low (max.7 +/- 6 Bq kg-1), the average Ra-226 activity concentration was 309 +/- 39 Bq kg-1 (min. 10 +/- 8 Bq kg-1, max. 570 +/ 46 Bq kg-1), while the K-40 concentrations (average 3139 +/- 188 Bq kg-1, min. 51 +/- 36 Bq kg-1) could be as high as 7057 +/- 427 Bq kg-1. The high K-40 can be explained by reference to the composition of the investigated fertilizers (NPK, PK). U concentrations were between 15 and 361 Bq kg-1, with the average of 254 Bq kg-1, measured using alpha spectrometry. The good correlation between P2O5 content and radioactivity reported previously is not found in our data. The leaching studies reveal that the mobility of the fertilizer's uranium content is greatly influenced by the parameters of the leaching methods. The availability of U to water ranged between 3 and 28 m/m%, while the Lakanen-Ervio solution mobilized between 10 and 100% of the U content. PMID- 27771132 TI - Biomarkers of aortic valve stenosis: Should we rely on a single one? PMID- 27771133 TI - An initial waitlist-controlled trial of the unified protocol for the treatment of emotional disorders in adolescents. AB - A substantial proportion of adolescents are non-responders to well-established treatments for anxiety and depression, and many existent approaches do not adequately address comorbidity. There is a need to develop and evaluate unified treatments for adolescents that flexibly address higher order factors shared among internalizing or emotional disorders. The Unified Protocol for the Treatment of Emotional Disorders in Adolescents (UP-A) is a transdiagnostic treatment that targets shared vulnerability and maintenance factors in a flexible format. This study examined initial outcomes of a randomized, waitlist-controlled trial of the UP-A. The UP-A outperformed waitlist at mid-treatment with respect to disorder severity and functional impairment, and there was a significant treatment effect in favor of the UP-A on all outcome measures at post-treatment. Within-subjects analyses collapsing across participants revealed significant improvements on outcome measures over time. Results support further study of the UP-A and its potential efficacy in treating adolescent anxiety and depression. PMID- 27771134 TI - The Role of Urban Environment, Social and Health Determinants in the Tracking of Leisure-Time Physical Activity Throughout Adolescence. AB - PURPOSE: Adolescence may be a period particularly relevant for acquisition of lifelong habits of physical activity (PA). We investigated the tracking of leisure-time PA from 13 to 17 years old and the influence of urban environment and other determinants. METHODS: As part of the EPITeen cohort (Portugal), we evaluated 969 adolescents living in the city of Porto. Participants were assembled in public and private schools at 13 years and reevaluated at 17 years. Leisure-time PA was evaluated by self-reported questionnaires. The shortest routes from residence to urban green spaces and open sports spaces were calculated using the street network within a Geographical Information System. Odds ratio (OR) and 95% confidence intervals were calculated by multinomial logistic regression. RESULTS: Among sedentary girls at 13 years, 33.1% were still sedentary at 17 years, 39.8% changed to low, 22.3% to moderate, and only 4.6% changed to vigorous PA. In boys, the respective values were 32.3%, 17.3%, 36.2%, and 14.2%. High PA levels were maintained by 19.5% of the girls and by 41.1% of the boys. After adjustment for parental education and body image at 13 years, practice of sports at 13 years was strongly associated with stable high PA at 17 years: in girls OR = 3.96 (2.21, 7.12); in boys OR = 6.81 (3.30, 14.07). Distance to urban green spaces or to open sports spaces was not associated to changes in leisure-time PA. CONCLUSION: Practice of sports in early adolescence may be important to promote maintenance of high PA. Urban environment in the vicinity of residence did not affect changes in the practice of leisure-time PA. PMID- 27771135 TI - Novel thin layer flow-cell screen-printed graphene electrode for enzymatic sensors. AB - A new Screen-printed electrodes (SPE) integrated in one channel flow-cell was developed. The one channel flow-cell is attached and directly changeable with electrode. In the new flow-cell the injection is done through an "in-line luer injection port" which can be less aggressive than wall-jet flow cell for a biological recognition element immobilized on the surface of the electrode. The sample volume can be easily controlled by the operator through a syringe. In this novel thin layer flow-cell screen-printed electrodes, the working electrode was modified with graphene materials, and an enhancement of electroactive area to 388% over a standard electrode was found. This new configuration was applied to study the entrapped cellobiose dehydrogenase from the ascomycete Corynascus thermophilus (CtCDH) in a photocrosslinkable PVA-based polymer. The calibration curve of lactose using optimized parameters shows a wide linear measurement ranges between 0.25 and 5mM. A good operational stability of the CtCDH-PVA modified graphene electrode is obtained, which keeps the same initial activity during 8h and exhibits a good storage stability with a decrease of only 9% in analytical response after 3 months storage at 4?C. PMID- 27771136 TI - New approach for monitoring fish stress: A novel enzyme-functionalized label-free immunosensor system for detecting cortisol levels in fish. AB - Fishes display a wide variation in their physiological responses to stress, which is clearly evident in the plasma corticosteroid changes, chiefly cortisol levels in fish. As a well-known indicator of fish stress, a simple and rapid method for detecting cortisol changes especially sudden increases is desired. In this study, we describe an enzyme-functionalized label-free immunosensor system for detecting fish cortisol levels. Detection of cortisol using amperometry was achieved by immobilizing both anti-cortisol antibody (selective detection of cortisol) and glucose oxidase (signal amplification and non-toxic measurement) on an Au electrode surface with a self-assembled monolayer. This system is based on the maximum glucose oxidation output current change induced by the generation of a non-conductive antigen-antibody complex, which depends on the levels of cortisol in the sample. The immunosensor responded to cortisol levels with a linear decrease in the current in the range of 1.25-200ngml-1 (R=0.964). Since the dynamic range of the sensor can cover the normal range of plasma cortisol in fish, the samples obtained from the fish did not need to be diluted. Further, electrochemical measurement of one sample required only ~30min. The sensor system was applied to determine the cortisol levels in plasma sampled from Nile tilapia (Oreochromis niloticus), which were then compared with levels of the same samples determined using the conventional method (ELISA). Values determined using both methods were well correlated. These findings suggest that the proposed label-free immunosensor could be useful for rapid and convenient analysis of cortisol levels in fish without sample dilution. We also believe that the proposed system could be integrated in a miniaturized potentiostat for point-of-care cortisol detection and useful as a portable diagnostic in fish farms in the future. PMID- 27771137 TI - Recent advances in 2D bioelectronics. PMID- 27771138 TI - Hesperidin interaction to collagen detected by physico-chemical techniques. AB - OBJECTIVE: Dentin collagen can be modified by some plant-derived flavonoids to improve properties of dentin organic matrix. Hesperidin (HPN), a hesperetin-7-O rutinoside flavonoid, has a potential of dentin modification for being based on evidence that a treatment with HPN may resist collagenase degradation and arrest demineralization of human dentin. In this study, biophysical and molecular-level information on the interaction of HPN and collagen was investigated. METHODS: HPN is extracted from citrus fruits. Sample collagenous solution was prepared using atelocollagen (ATCL) as a triple-helical peptide model. We have performed circular dichroism spectroscopic analysis, sedimentation velocity measurement by ultracentrifuge and saturation transfer difference measurement (STD) by NMR on HPN-collagen in solution state. RESULTS: The circular dichroism and sedimentation velocity measurement showed the evidence for the molecular interaction between ATCL and HPN, while HPN did not induce any conformational change of ATCL. The STD NMR study further confirmed this interaction and suggested that HPN interacted with ATCL through its aromatic part, not through its disaccharide moiety. SIGNIFICANCE: These findings indicated that HPN is weakly bound to ATCL not causing structural modification of collagen. This interaction may contribute to the preservation of collagen by protecting from collagenase degradation. PMID- 27771139 TI - Correlative analysis of cement-dentin interfaces using an interfacial fracture toughness and micro-tensile bond strength approach. AB - OBJECTIVES: To determine the interfacial fracture toughness (iFT) and micro tensile strength (MUTBS) of composite cements bonded to dentin. METHODS: Fifty feldspar ceramic blocks (Vita Mark II, Vita Zahnfabrik) were luted onto dentin using two self-adhesive (G-CEM LinkAce, GC; SpeedCEM, Ivoclar Vivadent), two self etch (Multilink Primer & Multilink Automix, Ivoclar Vivadent; Scotchbond Universal & RelyX Ultimate, 3 M ESPE), and one etch-and-rinse (Excite F DSC & Variolink II, Ivoclar Vivadent) composite cement (n=10). After 48h in 100% relative humidity at 37 degrees C, one half of each tooth was sectioned in sticks with a chevron notch at the cement-dentin interface and tested in a 4-point bending test setup (iFT). The remaining half of the tooth was sectioned in micro specimens and stressed in tension until failure (MUTBS). The mode of failure was determined with a stereomicroscope at 50* magnification. Data were submitted to Weibull analysis and Pearson's correlation (alpha=0.05). RESULTS: At 10% probability of failure, no significant differences could be found using iFT, while the etch-and-rinse composite cement Variolink II presented a significantly higher MUTBS at this level. At 63.2% probability of failure, the self-adhesive composite cement G-CEM LinkAce revealed a significantly lower MUTBS and iFT, and the self-etch cement Multilink Automix also revealed a significantly lower MUTBS than all other cements. The correlation found between iFT and MUTBS was moderate and not significant (r2=0.618, p=0.11). SIGNIFICANCE: Overall, the etch-and-rinse and 'universal' self-etch composite cements performed best. The micro-tensile bond strength and interfacial fracture toughness tests did not correlate well. PMID- 27771141 TI - Polarization and asymmetry in T cell metabolism. AB - T cell activation results in a rapidly proliferating T cell endowed with a metabolic phenotype necessary for growth and division. However, before the cell can proceed towards this burst of cell division a phase of quiescence occurs, during which the basic mechanisms governing regulation of metabolic reprograming are established. This review focuses on key cellular processes controlling early metabolic regulation and how these circuits of metabolic control dictate distinct cellular fates upon the first asymmetric division. PMID- 27771140 TI - Integrating immunometabolism and macrophage diversity. AB - Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in cellular metabolism are important determinants of macrophage function and phenotype. At the same time, our appreciation of macrophage diversity in vivo has also been increasing. Factors such as cell origin and tissue localization are now recognized as important variables that influence macrophage biology. Whether different macrophage populations also have unique metabolic phenotypes has not been extensively explored. In this article, we will discuss the importance of understanding how macrophage origin can modulate metabolic programming and influence inflammatory responses. PMID- 27771142 TI - Errors in causal inference: an organizational schema for systematic error and random error. AB - PURPOSE: To provide an organizational schema for systematic error and random error in estimating causal measures, aimed at clarifying the concept of errors from the perspective of causal inference. METHODS: We propose to divide systematic error into structural error and analytic error. With regard to random error, our schema shows its four major sources: nondeterministic counterfactuals, sampling variability, a mechanism that generates exposure events and measurement variability. RESULTS: Structural error is defined from the perspective of counterfactual reasoning and divided into nonexchangeability bias (which comprises confounding bias and selection bias) and measurement bias. Directed acyclic graphs are useful to illustrate this kind of error. Nonexchangeability bias implies a lack of "exchangeability" between the selected exposed and unexposed groups. A lack of exchangeability is not a primary concern of measurement bias, justifying its separation from confounding bias and selection bias. Many forms of analytic errors result from the small-sample properties of the estimator used and vanish asymptotically. Analytic error also results from wrong (misspecified) statistical models and inappropriate statistical methods. CONCLUSIONS: Our organizational schema is helpful for understanding the relationship between systematic error and random error from a previously less investigated aspect, enabling us to better understand the relationship between accuracy, validity, and precision. PMID- 27771143 TI - Managing Research Environments: Heterarchies in Academia. A Response to Cumming. PMID- 27771144 TI - Corrigendum to "Migraine and neuropeptides" [Neuropeptides (2015) 19-30]. PMID- 27771145 TI - The Cerebellar Mossy Fiber Synapse as a Model for High-Frequency Transmission in the Mammalian CNS. AB - The speed of neuronal information processing depends on neuronal firing frequency. Here, we describe the evolutionary advantages and ubiquitous occurrence of high-frequency firing within the mammalian nervous system in general. The highest firing frequencies so far have been observed at the cerebellar mossy fiber to granule cell synapse. The mechanisms enabling high frequency transmission at this synapse are reviewed and compared with other synapses. Finally, information coding of high-frequency signals at the mossy fiber synapse is discussed. The exceptionally high firing frequencies and amenability to high-resolution technical approaches both in vitro and in vivo establish the cerebellar mossy fiber synapse as an attractive model to investigate high-frequency signaling from the molecular up to the network level. PMID- 27771146 TI - Heritability of Choroidal Thickness in the Amish. AB - PURPOSE: To evaluate the heritability of choroidal thickness and its relationship to age-related macular degeneration (AMD). DESIGN: Cohort study. PARTICIPANTS: Six hundred eighty-nine individuals from Amish families with early or intermediate AMD. METHODS: Ocular coherence tomography was used to quantify choroidal thickness, and fundus photography was used to classify eyes into categories using a modified Clinical Age-Related Maculopathy Staging (CARMS) system. Repeatability and heritability of choroidal thickness and its phenotypic and genetic correlations with the AMD phenotype (CARMS category) were estimated using a generalized linear mixed model (GLMM) approach that accounted for relatedness, repeated measures (left and right eyes), and the effects of age, gender, and refraction. MAIN OUTCOME MEASURES: Heritability of choroidal thickness and its phenotypic and genetic correlation with the AMD phenotype (CARMS category). RESULTS: Phenotypic correlation between choroidal thickness and CARMS category was moderate (Spearman's rank correlation, rs = -0.24; n = 1313 eyes) and significant (GLMM posterior mean, -4.27; 95% credible interval [CI], 7.88 to -0.79; P = 0.02) after controlling for relatedness, age, gender, and refraction. Eyes with advanced AMD had thinner choroids than eyes without AMD (posterior mean, -73.8; 95% CI, -94.7 to -54.6; P < 0.001; n = 1178 eyes). Choroidal thickness was highly repeatable within individuals (repeatability, 0.78; 95% CI, 0.68 to 0.89) and moderately heritable (heritability, 0.40; 95% CI, 0.14 to 0.51), but did not show significant genetic correlation with CARMS category, although the effect size was moderate (genetic correlation, -0.18; 95% CI, -0.49 to 0.16). Choroidal thickness also varied with age, gender, and refraction. The CARMS category showed moderate heritability (heritability, 0.49; 95% CI, 0.26 to 0.72). CONCLUSIONS: We quantify the heritability of choroidal thickness for the first time, highlighting a heritable, quantitative trait that is measurable in all individuals regardless of AMD affection status, and moderately phenotypically correlated with AMD severity. Choroidal thickness therefore may capture variation not captured by the CARMS system. However, because the genetic correlation between choroidal thickness and AMD severity was not significant in our data set, genes associated with the 2 traits may not overlap substantially. Future studies should therefore test for genetic variation associated with choroidal thickness to determine the overlap in genetic basis with AMD. PMID- 27771147 TI - A technique for minimizing subgingival residual cement by using rubber dam for cement-retained implant crowns. PMID- 27771148 TI - Corrigendum to 'Efficacy of a standard meticillin-resistant Staphylococcus aureus decolonisation protocol in routine clinical practice' [Journal of Hospital Infection (2010) 93-98]. PMID- 27771149 TI - ESBL-producing Gram-negative organisms in the healthcare environment as a source of genetic material for resistance in human infections. AB - BACKGROUND: The increasing prevalence of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in the healthcare setting and in the community despite established infection control guidelines indicates that these microorganisms may possess survival strategies that allow them to persist in the environment. AIMS: To determine the extent and variation in endemic ESBL-carrying species in different ward environments, and to investigate the potential for cephalosporin resistance to be transferred from environmental isolates to human pathogens. METHODS: Conventional microbiological methods were used to sample 1436 environmental surfaces for ESBL-producing bacteria. Transconjugation assays (broth mating experiments) were performed using environmental ESBL-producing isolates as donors and streptomycin-resistant Escherichia coli (NCTC 50237) as the recipient. FINDINGS: The prevalence of ESBL-producing bacteria on surfaces in a non-outbreak setting was low (45/1436; 3.1%). The sites most likely to be contaminated were the drains of handwash basins (28/105; 26.7%) and floors (14/160; 8.8%). Fifty-nine ESBL-carrying organisms were isolated. Of these, Klebsiella spp. (33.9%), Enterobacter spp. (20.3%), Pantoea spp. (15.3%) and Citrobacter spp. (13.6%) were the most common isolates. ESBL determinants were transferred successfully from three representative environmental isolates (Pantoea calida, Klebsiella oxytoca, Raoultella ornithinolytica) to the human pathogen E. coli. CONCLUSION: ESBL-producing Gram-negative isolates were recovered from the hospital environment in the absence of any ESBL infection on the wards. The drains of handwash basins should be considered potential long-term reservoirs of multi-drug-resistant bacteria and drug resistance genes. These genes can reside in various genera of hardy environmental organisms and be a potential source of ESBL for more common human pathogens. PMID- 27771150 TI - [Unusual cause of thoracic pain]. PMID- 27771151 TI - The colourful history of malachite green: from ancient Egypt to modern surgery. PMID- 27771152 TI - Grade of sclerosis in the contralateral mandibular area in osteonecrosis of the jaws. AB - The objective of this study was to compare the grade of radiographic sclerosis between the area of osteonecrosis and the at-risk contralateral mandibular area without osteonecrosis. Three groups were studied: group 1 comprised 30 cases of medication-related osteonecrosis of the jaws (MRONJ); group 2 was the healthy contralateral area without osteonecrosis of the group 1 cases; group 3 comprised 30 healthy controls. ImageJ software was used to analyze the computed tomography images, and the grade of bone sclerosis was compared between the three groups. The grade of sclerosis was significantly higher in group 1 than in the other groups (P<0.05); the difference between groups 2 and 3 was not significant. Sclerosis was significantly greater in the area of bone necrosis than in the contralateral mandibular area in patients with MRONJ. No significant differences were found in the grade of sclerosis between the contralateral non-affected mandibular area of patients with MRONJ and the control patients. PMID- 27771153 TI - Work-Related Asthma: the Dawn of Knowledge? PMID- 27771156 TI - Vertigo and deafness: The sole presenting feature of multiple myeloma. PMID- 27771154 TI - Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway. AB - AIMS: Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP 4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated. METHODS: The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n=71) and non-diabetic patients (n=52), and through in vitro experiments on endothelial cell (EC). RESULTS: Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non diabetic patients, along with higher oxidative stress, tumor necrosis factor alpha (TNF-alpha), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25mM) and GLP-1 (100nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone. CONCLUSIONS: Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM. PMID- 27771155 TI - Final oocyte maturation with two different GnRH agonists in antagonist co-treated cycles at risk of ovarian hyperstimulation syndrome. AB - Triptorelin 0.2 mg and leuprolide 1 mg subcutaneous injections for triggering final follicular maturation were compared in patients with a high risk for ovarian hyperstimulation syndrome (OHSS). Infertile patients treated with GnRH antagonist protocol between January 2014 and March 2016 were recruited. Patients with high serum oestradiol levels on HCG day (>3000 pg/ml) indicating a risk of OHSS consisted of the study groups (A and B). Patients with serum oestradiol levels less than 3000 pg/ml consisted of the control group (C). A single injection of 0.2 mg triptorelin, 1 mg leuprolide and 10000 IU HCG were administered for final oocyte triggering in groups A (n = 63), B (n = 74) and C (n = 131), respectively. Demographic parameters were comparable between the groups. No cases of severe or moderate OHSS occurred in any group. The clinical pregnancy rates were 31.7%, 37.8% and 32.8% in groups A, B and C, respectively. Both injections had comparable efficacy in clinical outcome and OHSS risk. Regardless of preferred drug, GnRH agonist trigger for final oocyte maturation seems to be safe for patients with high OHSS risk, and can be safely used in fresh embryo transfer cycles. PMID- 27771157 TI - The diagnostic value of soluble urokinase plasminogen activator receptor (suPAR) compared to C-reactive protein (CRP) and procalcitonin (PCT) in children with systemic inflammatory response syndrome (SIRS). AB - BACKGROUND: The aim of the present study was to determine the diagnostic and prognostic values of suPAR and to compare them to CRP and PCT in pediatric patients with systemic inflammatory response syndrome (SIRS). MATERIAL-METHODS: A prospective case-control study was performed.The study was performed in a tertiary university hospital which has a 649-bed capacity. Patients included 27 children with SIRS and 27 control subjects without any infection or immunosuppressive condition. Blood samples were obtained on the day of admission and on the 4-7th days of the hospital stay. RESULTS: The median (min-max) serum levels of suPAR obtained on the first day of the admission were 10.06 (2.7-57.46) and 2.22 (1.08-5.13) ng/Ml for the SIRS group and control group, respectively. The median serum levels of suPAR in the SIRS group was significantly higher than that in the control group (p < 0.05). The serum suPAR levels was significantly higher in nonsurvivors than in survivors in SIRS group (p < 0.05). In the SIRS group, the area under the receiver operating characteristics curve (AUCROC) for suPAR revealed an optimum cut-off value, sensitivity, specificity, NPV and PPV of 0.978, 3.8 ng/mL, 96%, 96%, 96%, and 96%, respectively. CONCLUSIONS: We conclude that suPAR does have diagnostic value in children with SIRS. Additionally, persistent high serum suPAR level predicts mortality in SIRS in children. PMID- 27771158 TI - Incidence and risk factors of hepatocellular carcinoma after orthotopic liver transplantation. AB - BACKGROUND: The incidence of hepatocellular carcinoma has doubled over the past 2 decades, becoming the fifth most common cancer worldwide. Orthotopic liver transplant is the gold standard treatment for those with hepatocellular carcinoma meeting eligibility criteria, although recurrence rates of hepatocellular carcinoma after orthotopic liver transplant still remain an understudied obstacle. METHODS: We performed a single-center, retrospective, longitudinal study with the aim of determining the predominant baseline and follow-up variables associated with hepatocellular carcinoma recurrence. We gathered pre- and post-transplant data and conducted univariate and multivariate analysis to assess variables predicting hepatocellular carcinoma recurrence after orthotopic liver transplant. RESULTS: Between 2003 and 2015, 141 patients underwent orthotopic liver transplant for hepatocellular carcinoma. We identified 9 (6.4%) cases of documented hepatocellular carcinoma recurrence. Univariate analysis indicated that the difference in serum alpha-fetoprotein levels (most recent prior to transplant subtracted from maximum level) was lower in the hepatocellular carcinoma recurrence group (median 3 ng/mL vs 0 ng/mL, P = .052) as well as the pretransplant serum cholesterol level (median 158 mg/dL vs 113 mg/dL, P = .019) and days between hepatocellular carcinoma neoadjuvant treatment initiation and transplantation (median 122 vs 0, P = .045). Multivariate analysis revealed that a low pretransplant serum cholesterol level (<100 mg/dL) was independently associated with hepatocellular carcinoma recurrence (hazard ratio 11.0, P = .004). CONCLUSION: The risk of hepatocellular carcinoma recurrence after orthotopic liver transplant was low, at 6.4%, in this cohort. Low pretransplant serum cholesterol was the strongest predictor of recurrence and may help clinicians risk stratify patients for appropriate post-transplant monitoring and follow-up. PMID- 27771159 TI - Inhibition of Fgf signaling in short bowel syndrome increases weight loss and epithelial proliferation. AB - BACKGROUND: Signaling by fibroblast growth factor is critical for epithelial proliferation, differentiation, and the development of many organs, including the intestine. Fibroblast growth factor 10 and fibroblast growth factor 2c are upregulated after massive bowel resection during intestinal adaptation. This pathway is conserved highly. We hypothesized that inhibition of fibroblast growth factor signaling would impair intestinal adaptation in the zebrafish model of short bowel syndrome and allow insight into the negative regulation of this pathway. METHODS: Short bowel syndrome equivalent to a high jejunostomy was generated in adult male hsp70:dnfgfr1-GFP zebrafish, wildtype fish exposed to tyrosine-kinase inhibitor, and wildtype fish in absence of tyrosine-kinase inhibitor. Heat shock in hsp70:dnfgfr1-GFP fish decreases fgf 1 expression. Parameters including weight, proliferation, and differentiation were evaluated after harvest in experimental and control groups. RESULTS: Although short bowel syndrome zebrafish lost more weight relative to sham zebrafish in both groups, heat shock fish with short bowel syndrome lost more weight compared with non-heat shock fish with short bowel syndrome. In the non-heat shock controls, the villus epithelial perimeter increased in short bowel syndrome compared with sham fish, but this did not occur in heat shock fish. Non-heat shock fish with short bowel syndrome fish had significantly increased Bromodeoxyuridine(+) proliferative cells per hemivillus compared with non-heat shock-sham, while heat shock-short bowel syndrome had a more substantial increase in Bromodeoxyuridine(+) cells compared with HS-sham. Non-heat shock-short bowel syndrome demonstrated a significantly increased percentage of Alcian blue(+) goblet cells per hemivillus compared with non-heat shock-sham, while the heat shock-short bowel syndrome demonstrated decreased Alcian blue(+) cells compared with non-heat shock-short bowel syndrome. In contrast, SU5402 inhibited epithelial proliferation while increasing weight loss. CONCLUSION: Inhibition of fibroblast growth factor-1 signaling in short bowel syndrome decreases epithelial adaptation, increases Bromodeoxyuridine-labeled cells at 2 weeks, and exacerbates weight loss while decreasing epithelial goblet cells. PMID- 27771160 TI - Evaluating cumulative and annual surgeon volume in laparoscopic cholecystectomy. AB - BACKGROUND: Although there is a large body of published data demonstrating improved outcomes for complex operations when performed by high-volume surgeons at high-volume hospitals, the literature is mixed regarding whether this same relationship applies in less complex and more common surgeries such as laparoscopic cholecystectomy. METHODS: This study utilized the New York State Department of Health Statewide Planning and Research Cooperative System database to identify patients undergoing laparoscopic cholecystectomy for acute and chronic biliary pathology. Rates of perioperative outcomes were compared among 4 distinct categories of surgeons based on surgeon annual and cumulative volume: low cumulative/low annual, low cumulative/high annual, high cumulative/low annual, and high cumulative/high annual. RESULTS: A total of 150,938 patients undergoing operation by 3,306 surgeons at 250 hospitals across New York state were included for analysis from 2000-2014. There was no difference in adjusted 30 day in-hospital mortality, major events, procedural complications, bile duct injury, or reintervention rates between the 4 groups of surgeons. However, patients undergoing operation by high cumulative/high annual volume surgeons were less likely to experience 30-day readmission, prolonged duration of stay, and high charges when compared with low cumulative/low annual volume surgeons. CONCLUSION: In New York state, increased surgeon annual and cumulative volume predicts lower rates of 30-day readmission, prolonged duration of stay, and high charges in laparoscopic cholecystectomy, but has no effect on in-hospital mortality, major events, bile duct injury, procedural complications, or reintervention. There is no evidence to support regionalization of this procedure as operative outcomes are comparable even in less experienced hands. PMID- 27771161 TI - The effectiveness of patient navigation to improve healthcare utilization outcomes: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: To determine the effects of patient navigation (PN) on healthcare utilization outcomes using meta-analysis and the quality of evidence. METHODS: Medical and social science databases were searched for randomized controlled trials published in English between 1989 and May 2015. The review process was guided by PRISMA. Included studies were assessed for quality using the Downs and Black tool. Data were extracted to assess the effect of navigation on: health screening rates, diagnostic resolution, cancer care follow-up treatment adherence, and attendance of care events. Random-effects models were used to compute risk ratios and I2 statistics determined the impact of heterogeneity. RESULTS: Of 3985 articles screened, 25 articles met inclusion criteria. Compared to usual care, patients who received PN were significantly more likely to access health screening (OR 2.48, 95% CI, 1.93-3.18, P<0.00001) and attend a recommended care event (OR 2.55, 95% CI, 1.27-5.10, P<0.01). PN was favoured to increase adherence to cancer care follow-up treatment and obtain diagnoses. Most studies involved trained lay navigators (n=12) compared to health professionals (n=9). CONCLUSION: PN is effective to increase screening rates and complete care events. PRACTICE IMPLICATIONS: PN is an effective intervention for use in healthcare. PMID- 27771162 TI - Multi locus sequence analysis and symbiotic characterization of novel Ensifer strains nodulating Tephrosia spp. in the Indian Thar Desert. AB - Phylogenetically diverse Ensifer strains associated with five species of Tephrosia growing in alkaline soils of semi-arid regions of the Thar Desert were characterized using multi locus sequence analysis. Based on 16S rRNA and four protein-coding housekeeping gene (recA, atpD, glnII and dnaK) sequences, the Tephrosia-Ensifer strains were genetically different from the type strains of Ensifer saheli, Ensifer kostiensis, Ensifer terangae (African origin) and Ensifer psoraleae (Asiatic origin). One strain, Ensifer sp. TL4, showed maximum similarity (99%) to Ensifer adhaerens LMG 20216T and formed a separate lineage close to it. Phylogenetic incongruence between sym and housekeeping genes was observed. The monophyletic origin of symbiotic genes from Asia in the Tephrosia Ensifer strains from the Thar Desert suggests that they might have been acquired from a common ancestor and horizontally transferred. These novel strains are promiscuous, cross-nodulating some papilionoid crop species, mimosoid trees and the caesalpinioid Chamaecrista pumila. This study improves understanding of the distribution of Ensifer in unexplored and threatened alkaline arid regions of the Thar Desert and how this relates to other similar regions in the world. PMID- 27771163 TI - Influence of secondary wound healing after mandibular third molar coronectomy. AB - Our aim was to describe the postoperative morbidity related to secondary wound healing after coronectomy. Ten of 116 patients treated by coronectomy healed by second intention as a result of failed sutures. We made a retrospective analysis after two years to evaluate the postoperative morbidity related to secondary wound healing. The complete closure of the alveolus of the 10 surgical sites was recorded three months after coronectomy. No patients had postoperative infections, dry socket, or pulpitis. All patients were free of symptoms, the retained roots were completely included, and were not detectable with a periodontal probe. The importance of primary wound closure after coronectomy has been stressed as a critical point to avoid postoperative infection of the root. We found that secondary wound healing after coronectomy was not associated with a high postoperative infection rate, but further randomised clinical studies are necessary to confirm the need for primary closure and its relations to the long term success of the coronectomy. PMID- 27771164 TI - Transparent, resin-based, three-dimensional model to help visualise intraosseous tumours. PMID- 27771165 TI - Endoplasmic reticulum stress in complex atypical hyperplasia as a possible predictor of occult carcinoma and progestin response. AB - : Glucose-regulated protein (GRP)-78, the key regulator of endoplasmic reticulum (ER) stress, is associated with endometrial cancer (EC) development and progression. However, its role in the continuum from complex atypical hyperplasia (CAH) to EC is unknown and the focus of this study. METHODS: 252 formalin-fixed, paraffin-embedded endometrial biopsies from patients with CAH diagnosed between 2003 and 2011 were evaluated for GRP78 expression by immunohistochemistry. Expression was also evaluated in subsequent biopsies from those patients treated with progestins. Differences in GRP78 expression were assessed using standard statistical methods. RESULTS: GRP78 expression was undetectable in 45(18%) patients with CAH, while 120(48%) CAH cases showed moderate/strong expression. Among women who ultimately underwent hysterectomy for CAH (n=134), 54(40%) had occult EC while 57(43%) had persistent CAH. Those with occult EC upon hysterectomy had significantly stronger GRP78 expression than those who did not have occult EC (p=0.007). Greater GRP78 expression within CAH remained independently associated with the presence of an occult EC (p=0.017). Thirty-four of 54 (63%) patients with occult EC had moderate/strong GRP78 expression compared to 36 of 80 (45%) patients with persistent CAH, benign or non-atypical hyperplastic endometrium. In those treated with progestins, samples with persistent CAH and EC were more likely to have high levels of GRP78 expression in the initial biopsies than those who responded (p=0.014). CONCLUSIONS: Increased GRP78 expression in untreated CAH correlates with the presence of an occult EC. In addition, CAH specimens with greater GRP78 expression may identify patients who are less likely to respond to progestin therapy. PMID- 27771166 TI - Survival of women with Mullerian adenosarcoma: A National Cancer Data Base study. AB - OBJECTIVE: To determine overall survival (OS) and factors associated with OS of women with Mullerian adenosarcoma. METHODS: Women with adenosarcoma of the uterus, cervix or ovary (n=2205) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. A subset analysis of women with uterine adenosarcoma was also performed. Analyzed confounders included age, insurance status, income, race, surgical margin status, nodal and distant metastasis, surgical procedure type, and treatment with radiation and/or chemotherapy. RESULTS: Primary sites were uterus (n=1884), cervix (n=229) and ovary (n=92), representing 0.43% of uterine, 0.16% of cervical, and 0.04% of ovarian cancers in the NCDB. Only 36/1176 (3.1%) and 2.5% (33/1,342) had nodal and/or distant metastasis, respectively, at diagnosis. Distant metastasis, positive surgical margin, increased age, higher composite comorbidity score and adjuvant radiotherapy were independently associated with decreased OS. Primary site, lymph node status, surgical procedure, chemotherapy use, race, insurance status and income quartiles were not significantly associated with OS. Each 1cm increase in tumor size was associated with increased hazard for death (HR (95% CI) 1.06 (1.01-1.12), p=0.018) among women with uterine adenosarcoma. CONCLUSION: Complete surgical resection remains the only treatment with well-evidenced OS benefit among women with Mullerian adenosarcoma. Early surgical resection may increase survival of Mullerian adenosarcoma. PMID- 27771167 TI - Treatment preferences of advanced ovarian cancer patients for adding bevacizumab to first-line therapy. AB - BACKGROUND: The GOG-218 and ICON-7 studies recently showed that adding bevacizumab to first-line therapy for patients with advanced ovarian cancer increased progression-free survival. However, the high cost and long treatment duration prevents the incorporation of bevacizumab in practice. The aim of this study was to explore and quantify patients' preferences for adding bevacizumab to first-line therapy. METHODS: A discrete choice experiment (DCE) and trade-off question were designed and distributed to 102 ovarian cancer patients. Participants were asked to choose between two hypothetical first-line therapies that differed in terms of effectiveness, safety, and the financial burden. A trade-off technique varying the cost of bevacizumab was used to quantify a willingness-to-pay threshold for selecting bevacizumab. RESULTS: All attributes of the DCE had a statistically significant impact on respondents' preferences and the financial burden was the most important attribute. The results of the trade off question showed that more than half of patients would prefer to add bevacizumab to standard chemotherapy when the cost of the drug was reduced to 17% (1/6) of the baseline cost. CONCLUSION: Patients' preferences for bevacizumab in the adjuvant treatment of ovarian cancer depend primarily on drug costs. Our results suggest that the current cost of bevacizumab is sufficiently high that the majority of ovarian cancer patients are not willing to pay to accept a small increase in progression-free survival. PMID- 27771169 TI - Editorial Comment. PMID- 27771170 TI - Integrating Social Media and Anterior Cruciate Ligament Surgery: An Analysis of Patient, Surgeon, and Hospital Use. AB - PURPOSE: The purpose of this observational study of social media in sports medicine was to investigate and analyze the presence and shared content of anterior cruciate ligament (ACL) patients, sports surgeons, and top orthopaedic hospitals on popular social media streams. METHODS: A search of 2 public domains (Instagram and Twitter) was performed over a 6-month period. ACL surgery ("#aclsurgery") was selected for the Instagram-based patient analysis after exclusion of veterinary ACL operations. A binary scoring system was used for media format, time (preoperatively or postoperatively), perioperative period (within 1 week of surgery), tone (positive or negative), return-to-work reference, return-to-play reference, rehabilitation reference, surgical-site reference, satisfaction reference, and dissatisfaction reference; perspective of the media was noted as well. A sample of 97 National Football League team surgeons was used for analysis of physician use in social media outlets and quantified by the number of posts. Hospital analysis categorized a sample of the top 50 orthopaedic hospitals by average number of posts and monthly posting rates with regard to orthopaedics, research, education, and personnel focus. RESULTS: In the patient analysis, 3,145 public posts of human subjects were shared on Instagram. Of these, 92% were personal recovery stories, with an emphasis on postoperative photographs (93%) with a positive tone (88%) more than 1 week after surgery (73%). Posts focused on surgical site (25%), return to play (30%), and postoperative rehabilitation (37%). Of the physicians, 16% had Twitter accounts, with an average of 94 posts per surgeon; none had Instagram accounts. Of the hospitals, 96% had Twitter accounts and 32% had Instagram accounts. Most of the hospital-based Instagram content in the sample was centered on patients or celebrities. CONCLUSIONS: Orthopaedic surgery has a large social media presence. Patients emphasize wound appearance, the rehabilitation process, and return to play. Ninety-six percent of hospitals are represented in social media outlets, whereas physicians are relatively under-represented. CLINICAL RELEVANCE: Social media offers a unique window into what truly matters to patients after surgery and may help us better manage expectations, enhance health care delivery, and improve marketing strategies. PMID- 27771168 TI - The association between timing of initiation of adjuvant therapy and the survival of early stage ovarian cancer patients - An analysis of NRG Oncology/Gynecologic Oncology Group trials. AB - OBJECTIVES: To determine the association between timing of adjuvant therapy initiation and survival of early stage ovarian cancer patients. METHODS: Data were obtained from women who underwent primary surgical staging followed by adjuvant therapy from two Gynecologic Oncology Group trials (protocols # 95 and 157). Kaplan-Meier estimates and Cox proportional hazards model adjusted for covariates were used for analyses. RESULTS: Of 497 stage I-II epithelial ovarian cancer patients, the median time between surgery and initiation of adjuvant therapy was 23days (25th-75th%: 12-33days). The time interval from surgery to initiation of adjuvant therapy was categorized into three groups: <2weeks, 2 4weeks, and >4weeks. The corresponding 5-year recurrence-free survival rates were 72.8%, 73.9%, and 79.5% (p=0.62). The 5-year overall survival rates were 79.4%, 81.9%, and 82.8%, respectively (p=0.51; p=0.33 - global test). As compared to <2weeks, the hazard ratio for recurrence-free survival was 0.90 (95%CI=0.59-1.37) for 2-4weeks and 0.72 (95%CI=0.46-1.13) for >4weeks. Age, stage, grade, and cytology were important prognostic factors. CONCLUSIONS: Timing of adjuvant therapy initiation was not associated with survival in early stage epithelial ovarian cancer patients. PMID- 27771171 TI - Inter- and Intrarater Reliability of the Femoral Tunnel Clock-Face Grading System During Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To determine the inter- and intrarater reliability of the clock-face grading system as used by 3 fellowship-trained sports medicine surgeons. METHODS: Arthroscopic video was taken of the femoral tunnel placement during 20 consecutive anterior cruciate ligament (ACL) reconstructions performed by 2 surgeons. All femoral tunnels were created using a medial portal technique. The video was taken using a 30 degrees arthroscope placed in the lateral portal and showed the femoral tunnel as well as the remainder of the femoral notch, the posterior cruciate ligament, and the menisci for orientation. Three fellowship trained sports medicine surgeons were asked to review the videos and assign an o'clock position to the femoral tunnel from the 9 to the 3 o'clock positions in "half-hour" increments. They were also asked to review the videos again 6 months later to determine intrarater reliability. Inter-rater reliability was evaluated using the intraclass correlation coefficient (ICC) 2-way mixed effect model with absolute agreement. The Spearman rank-order correlation coefficient (r) was applied to evaluate intrarater reliability. RESULTS: The inter-rater reliability as measured by the ICC revealed poor agreement between the 3 surgeons (ICC = 0.204, 95% confidence interval = -0.015 to 0.491, F = 2.8, P = .004). The intrarater reliability at a 6-month interval was found to be moderate (r's = .43, P = .004). CONCLUSIONS: The inter-rater reliability of the clock-face femoral tunnel grading system was found to be poor among fellowship-trained sports medicine surgeons whereas the intrarater reliability was found to be moderate. The utility of the femoral tunnel clock-face grading system may be compromised by suboptimal inter- and intrarater reliability, making it less useful as a tool of communication between surgeons. LEVEL OF EVIDENCE: Level IV, case series with poor reference standard. PMID- 27771172 TI - Resveratrol improves treatment outcome and laboratory parameters in patients with Takayasu arteritis: A randomized double-blind and placebo-controlled trial. AB - Tumor necrosis factor (TNF) inhibitors have exhibited certain clinical efficacy in treating refractory Takayasu arteritis (TA), albeit with severe adverse effects. We aimed to explore the anti-TNF function of resveratrol, a natural compound, in the treatment of TA. A total of 271 patients diagnosed of acute TA were enrolled in this clinical trial, who were then randomized to be administered 250mg resveratrol or placebo on a daily basis for a period of 3 months, and revisited biweekly to assess treatment outcomes. Primary treatment outcome was defined as the disease activity, determined using the Birmingham Vascular Activity Score (BVAS). Secondary outcome was defined by laboratory parameters, including erythrocyte sedimentation rate (ESR), plasma levels of C-reactive protein (CRP) and TNF-alpha. BVAS score and laboratory parameters of patients receiving resveratrol treatment exhibited a steady decline throughout the study. In contrast, outcomes remained practically unchanged in placebo-treated patients. Strong linear correlations were also observed between TNF-alpha with BVAS scores, ESR and plasma levels of CRP. Resveratrol could greatly improve treatment outcome and laboratory parameters in acute TA patients, likely due to its anti-TNF property. PMID- 27771173 TI - Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies. AB - BACKGROUND: The secondary forms of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (secondary TMA) emerge as complications of coexisting diseases. OBJECTIVES: We hypothesized that secondary TMA could be characterized by the presence of relative ADAMTS13 deficiency and complement activation, and this relationship may have a prognostic value for outcome. PATIENTS AND METHODS: Fifty-three patients with thrombotic microangiopathy (TMA) and coexisting disease (such as malignancies, sepsis, heart surgery with extracorporeal circulation, solid organ transplantation, systemic autoimmune disorders), 41 patient controls, and 34 healthy controls were enrolled in our case-control study with 30days follow-up. Complement profile (from serum) and activation products, von Willebrand factor (VWF, from EDTA plasma), and ADAMTS13 activity were determined. RESULTS: ADAMTS13 activity was reduced, while VWF level was elevated in secondary TMA patients. The activity of the classical, lectin and alternative pathways, as well as the levels of C3, C4, and Factor H were significantly lower in secondary TMA patients, and were accompanied by high activation product levels (C3a and sC5b-9). Factor H concentration correlated to relative ADAMTS13 deficiency (i.e. VWF/ADAMTS13 ratio (r=-0.368, p=0.019)). 28/53 patients (53%) died during the follow-up period. Increased sC5b-9, C3a, and C reactive protein levels were all associated with a poor patient outcome. CONCLUSIONS: Our results indicate that the secondary TMA syndrome and its poor outcome is characterized by relative ADAMTS13 deficiency, inflammation, and complement activation with consumption via the classical and alternative pathways. It is yet to be determined whether complement inhibition could be a possible therapeutic option for patients with secondary TMA. PMID- 27771174 TI - Down-regulation of Na+/H+ exchanger 1 by Toll-like receptor stimulation in macrophages. AB - The role of Na+/H+ exchanger 1 (NHE1) in various cell types, including inflammatory cells, has been extensively studied. However, regulation of NHE1 protein level in activated inflammatory cells is yet to be characterized. In this study, we investigated whether Toll-like receptor (TLR) ligands can regulate NHE1 protein level in the mouse macrophage-like RAW 264 cell line. We found that lipopolysaccharide (LPS), a TLR4 ligand, lowered NHE1 level and activity in RAW 264 cells and in primary murine macrophages. Other TLR ligands, such as zymosan A and poly(I:C), also displayed reduced NHE1 level. LPS promoted NHE1 ubiquitination and reduced the expression of calcineurin homologous protein 1 (CHP1), a regulator of NHE1 activity and stability. These responses were inhibited by c-Jun N-terminal kinase (JNK) inhibitor SP600125 and dexamethasone. A proteasome inhibitor, but not caspase-3 or lysosomal inhibitors, blocked the LPS-induced NHE1 down-regulation. These results suggested that LPS promotes the degranulation of NHE1 mediated by the ubiquitin-proteasome system and CHP1 downregulation resulting from activation of JNK. PMID- 27771175 TI - Abnormal serotonin transporter availability in the brains of adults with conduct disorder. AB - BACKGROUND/PURPOSE: The aims of the current study were to determine whether patients with conduct disorder (CD) showed an abnormal availability of serotonin reuptake transporter (SERT), and if their hyperkinetic symptoms, impulsivity, and quality of life were correlated with the availability of SERT. METHODS: We recruited 14 drug-naive patients with CD and eight age-matched healthy controls (HCs). The adult attention-deficit/hyperactivity disorder (ADHD) self-report scale (ASRS), Barrett impulsivity scale (BIS), and the World Health Organization quality of life-brief version (WHOQOL-BREF) scale were administered. Positron emission tomography (PET) of the brain with 4-[18F]-ADAM was arranged for SERT imaging. RESULTS: SERT availability was significantly reduced in the striatum and midbrain of patients with CD. Quality of life and inattention symptoms were also significantly correlated with the availability of SERT in the prefrontal cortex. CONCLUSION: The study suggested that a reduction in the availability of SERT might be associated with CD and could potentially predict poor quality of life or symptoms of inattention for these patients. The implications of our results might be limited to individuals with CD; a future study with a larger sample to validate our preliminary results is warranted. PMID- 27771177 TI - Cost-effectiveness Analysis of Treatment Sequence Initiating With Etanercept Compared With Leflunomide in Rheumatoid Arthritis: Impact of Reduced Etanercept Cost With Patent Expiration in South Korea. AB - PURPOSE: In south Korea, the price of biologics has been decreasing owing to patent expiration and the availability of biosimilars. This study evaluated the cost-effectiveness of a treatment strategy initiated with etanercept (ETN) compared with leflunomide (LFN) after a 30% reduction in the medication cost of ETN in patients with active rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR). METHODS: A cohort-based Markov model was designed to evaluate the lifetime cost-effectiveness of treatment sequence initiated with ETN (A) compared with 2 sequences initiated with LFN: LFN-ETN sequence (B) and LFN sequence (C). Patients transited through the treatment sequences, which consisted of sequential biologics and palliative therapy, based on American College of Rheumatology (ACR) responses and the probability of discontinuation. A systematic literature review and a network meta-analysis were conducted to estimate ACR responses to ETN and LFN. Utility was estimated by mapping an equation for converting the Health Assessment Questionnaire-Disability Index score to utility weight. The costs comprised medications, outpatient visits, administration, dispensing, monitoring, palliative therapy, and treatment for adverse events. A subanalysis was conducted to identify the influence of the ETN price reduction compared with the unreduced price, and sensitivity analyses explored the uncertainty of model parameters and assumptions. FINDINGS: The ETN sequence (A) was associated with higher costs and a gain in quality-adjusted life years (QALYs) compared with both sequences initiated with LFN (B, C) throughout the lifetime of patients with RA and MTX-IR. The incremental cost-effectiveness ratio (ICER) for strategy A versus B was ?13,965,825 (US$1726) per QALY and that for strategy A versus C was ?9,587,983 (US$8050) per QALY. The results indicated that strategy A was cost-effective based on the commonly cited ICER threshold of ?20,000,000 (US$16,793) per QALY in South Korea. The robustness of the base-case analysis was confirmed using sensitivity analyses. When the unreduced medication cost of ETN was applied in a subanalysis, the ICER for strategy A versus B was ?20,909,572 (US$17,556) per QALY and that for strategy A versus C was ?22,334,713 (US$18,753) per QALY. IMPLICATIONS: This study indicated that a treatment strategy initiated with ETN was more cost-effective in patients with active RA and MTX-IR than 2 sequences initiated with LFN. The results also indicate that the reduced price of ETN affected the cost-effectiveness associated with its earlier use. PMID- 27771176 TI - Vancomycin-resistant Enterococcal Bloodstream Infections in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancies: Impact of Daptomycin MICs of 3 to 4 mg/L. AB - PURPOSE: Case reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated. METHODS: We performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest. FINDINGS: Forty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio = 1.79, 95% CI, 0.52-6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3-4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3-4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant (P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all cause 30-day mortality approached statistical significance (P = 0.06). IMPLICATIONS: Duration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30 day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L. PMID- 27771178 TI - Gross motor function in children with spastic Cerebral Palsy and Cerebral Visual Impairment: A comparison between outcomes of the original and the Cerebral Visual Impairment adapted Gross Motor Function Measure-88 (GMFM-88-CVI). AB - PURPOSE: To investigate whether the adapted version of the Gross Motor Function Measure-88 (GMFM-88) for children with Cerebral Palsy (CP) and Cerebral Visual Impairment (CVI) results in higher scores. This is most likely to be a reflection of their gross motor function, however it may be the result of a better comprehension of the instruction of the adapted version. METHOD: The scores of the original and adapted GMFM-88 were compared in the same group of children (n=21 boys and n=16 girls), mean (SD) age 113 (30) months with CP and CVI, within a time span of two weeks. A paediatric physical therapist familiar with the child assessed both tests in random order. The GMFCS level, mental development and age at testing were also collected. The Wilcoxon signed-rank test was used to compare two different measurements (the original and adapted GMFM-88) on a single sample, (the same child with CP and CVI; p<0.05). RESULTS: The comparison between scores on the original and adapted GMFM-88 in all children with CP and CVI showed a positive difference in percentage score on at least one of the five dimensions and positive percentage scores for the two versions differed on all five dimensions for fourteen children. For six children a difference was seen in four dimensions and in 10 children difference was present in three dimensions (GMFM dimension A, B& C or C, D & E) (p<0.001). CONCLUSION: The adapted GMFM-88 provides a better estimate of gross motor function per se in children with CP and CVI that is not adversely impacted bytheir visual problems. On the basis of these findings, we recommend using the adapted GMFM-88 to measure gross motor functioning in children with CP and CVI. PMID- 27771179 TI - A Qualitative Description of HIV-Infected African American Women's Experiences of Psychological Distress and Their Coping Strategies. AB - HIV-infected individuals are at risk for psychological distress, including depression, sadness, and suicidality. The purpose of this qualitative descriptive study was to examine 22 HIV-infected African American women's experiences of psychological distress and use of coping strategies. Data were collected through in-person one-on-one interviews until conceptual saturation was reached. Data were analyzed using inductive content analysis. Four themes were found: (a) psychoemotional suffering, (b) contextual factors negatively influence the everydayness of living with HIV infection, (c) HIV-related stigma perpetuates isolation and loneliness, and (d) creating a safe haven. Implications for nurses and other health care providers include (a) holistic assessment to include evaluation of emotional and mental state, and (b) coping strategies. Integration of spiritual practices into plan of care is also important. Development and evaluation of individualized coping interventions that address stigma and psychological distress through holistic modalities is warranted. PMID- 27771180 TI - Identification of 4-(2-furanyl)pyrimidin-2-amines as Janus kinase 2 inhibitors. AB - Janus kinases inhibitor is considered to have therapeutic potential for the treatment of oncology and immune-inflammatory diseases. Two series of 4-(2 benzofuranyl)pyrimidin-2-amine and 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2 yl)pyrimidin-2-amine derivatives have been designed and synthesized. Primary SAR studies resulted in the discovery of a novel class of 4,5,6,7-tetrahydrofuro[3,2 c]pyridine based JAK2 inhibitors with higher potency (IC50 of 0.7nM) and selectivity (>30 fold) to JAK3 kinase than tofacitinib. PMID- 27771181 TI - Measuring polio immunity to plan immunization activities. AB - The Global Polio Eradication Initiative is closer than ever to achieving a polio free world. Immunization activities must still be carried out in non-endemic countries to maintain population immunity at levels which will stop poliovirus from spreading if it is re-introduced from still-infected areas. In areas where there is no active transmission of poliovirus, programs must rely on surrogate indicators of population immunity to determine the appropriate immunization activities, typically caregiver-reported vaccination history obtained from non polio acute flaccid paralysis patients identified through polio surveillance. We used regression models to examine the relationship between polio vaccination campaigns and caregiver-reported polio vaccination history. We find that in many countries, vaccination campaigns have a surprisingly weak impact on these commonly used indicators. We conclude that alternative criteria and data, such as routine immunization indicators from vaccination records or household surveys, should be considered for planning polio vaccination campaigns, and that validation of such surrogate indicators is necessary if they are to be used as the basis for program planning and risk assessment. We recommend that the GPEI and similar organizations consider or continue devoting additional resources to rigorously study population immunity and campaign effectiveness in at-risk countries. PMID- 27771182 TI - A novel inactivated enterovirus 71 vaccine can elicit cross-protective immunity against coxsackievirus A16 in mice. AB - Hand, foot, and mouth disease (HFMD) is a highly contagious disease that mainly affects infants and children. Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major pathogens of HFMD. Two EV71 vaccines were recently licensed in China and the administration of the EV71 vaccines is believed to significantly reduce the number of HFMD-related severe or fatal cases. However, a monovalent EV71 vaccine cannot cross-protect against CA16 infection, this may result in that it cannot effectively control the overall HFMD epidemic. In this study, a chimeric EV71, whose VP1/210-225 epitope was replaced by that of CA16, was constructed using a reverse genetics technique to produce a candidate EV71/CA16 bivalent vaccine strain. The chimeric EV71 was infectious and showed similar growth characteristics as its parental strain. The replacement of the VP1/210-225 epitope did not significantly affect the antigenicity and immunogenicity of EV71. More importantly, the chimeric EV71 could induce protective immunity against both EV71 and CA16, and protect neonatal mice against either EV71 or CA16 lethal infections, the chimeric EV71 constructed in this study was shown to be a feasible and promising candidate bivalent vaccine against both EV71 and CA16. The construction of a chimeric enterovirus also provides an alternative platform for broad-spectrum HFMD vaccines development. PMID- 27771183 TI - Manufacturing costs of HPV vaccines for developing countries. AB - BACKGROUND: Nearly all of the 500,000 new cases of cervical cancer and 270,000 deaths occur in middle or lower income countries. Yet the two most prevalent HPV vaccines are unaffordable to most. Even prices to Gavi, the Vaccine Alliance, are unaffordable to graduating countries, once they lose Gavi subsidies. Merck and Glaxosmithkline (GSK) claim their prices to Gavi equal their manufacturing costs; but these costs remain undisclosed. We undertook this investigation to estimate those costs. METHODS: Searches in published and commercial literature for information about the manufacturing of these vaccines. Interviews with experts in vaccine manufacturing. FINDINGS: This detailed sensitivity analysis, based on the best available evidence, finds that after a first set of batches for affluent markets, manufacturing costs of Gardasil for developing countries range between $0.48 and $0.59 a dose, a fraction of its alleged costs of $4.50. Because volume of Cervarix is low, its per unit costs are much higher, though at comparable volumes, its costs would be similar. INTERPRETATION: Given the recovery of fixed and annual costs from sales in affluent markets, Merck's break-even price to Gavi could be $0.50-$0.60, not $4.50. These savings could support Gavi programs to strengthen delivery and increase coverage. Outside Gavi, prices to lower- and middle-income countries, with profit, could also be lowered and made available to millions more adolescents at risk. These estimates and their policy implications deserve further discussion. PMID- 27771184 TI - Brucella abortus S19 vaccine protects dairy cattle against natural infection with Brucella melitensis. AB - Brucellosis is a zoonotic disease that can cause severe illness in humans and considerable economic loss in the livestock industry. Although small ruminants are the preferential host for Brucella melitensis, this pathogen has emerged as a cause for Brucella outbreaks in cattle. S19 vaccination is implemented in many countries where B. abortus is endemic but its effectiveness against B. melitensis has not been validated. Here we show that vaccine effectiveness in preventing disease transmission between vaccinated and unvaccinated cohorts, as determined by seroconversion, was 87.2% (95% CI 69.5-94.6%). Furthermore, vaccination was associated with a reduced risk for abortion. Together, our data emphasize the role S19 vaccination could play in preventing B. melitensis outbreaks in areas where this pathogen is prevalent in small ruminant populations. PMID- 27771185 TI - Role of antibodies and IL17-mediated immunity in protection against pneumococcal otitis media. AB - Widespread vaccination against Streptococcus pneumoniae (the pneumococcus) has significantly reduced pneumococcal disease caused by vaccine serotypes. Despite vaccination, overall pneumococcal colonization rates in children have not reduced and otitis media (OM) by non-vaccine serotypes remains one of the most common childhood infections. Pneumococcal surface protein A (PspA) has been shown to be a promising protein antigen to induce broad protection against pneumococcal colonization. However, its ability to protect against OM remains unclear. Using our previously established mouse model of influenza-virus induced pneumococcal OM, we here show that intranasal vaccination of mice with PspA together with the mucosal adjuvant CTB results in a decrease in pneumococcal load in the middle ears. This decrease correlated with the induction of PspA-specific IgA, a balanced IgG1:IgG2a antibody response and the induction of a mucosal Th17 response. Our data suggests that the IL-17 response to PspA is more important for protection against OM, whilst the presence of antibodies may be less important, as determined in mice deficient in IL-17 signaling or antibody production. Together, these results suggest that mucosal vaccination with PspA may not only protect against colonization, but also against the development of virus-induced pneumococcal OM. PMID- 27771186 TI - Incidence of rotavirus gastroenteritis hospitalizations and genotypes, before and five years after introducing universal immunization in Israel. AB - BACKGROUND: Uncertainty exists about the sustainability of the reduction in rotavirus gastroenteritis (RVGE) following the introduction of rotavirus vaccines into national immunization programs, and on its potential impact on circulating genotypes. RotaTeq was introduced into the Israeli national immunization program in December 2010, and vaccination coverage is around 80%. AIMS: To examine the change in incidence of RVGE hospitalization and rotavirus genotypes, during the five years after introduction of RotaTeq into the Israeli national immunization program. METHODS: Data were obtained prospectively on hospitalization of children aged 0-59months due to acute gastroenteritis (N=7346) from three hospitals in northern Israel. Stool samples were tested for rotavirus by immunochromatography. Rotavirus was genotyped (N=506) by RT-PCR and/or sequencing. RESULTS: The average incidence of RVGE hospitalization declined by 61.0% (95% CI 49.0-73.4%), from 5.6 per 1000 (95% CI 5.0-6.2) in the pre-universal immunization period (2008-2010) to 2.2 per 1000 (95% CI 1.8-2.5) during the universal immunization period (2012 2015), but yearly fluctuations were still observed. The most common genotypes in the pre-universal immunization period were G1P[8] (35.3%) followed by G2P[4] (15.5%), G3P[8] (8.8%), G4P[8] (4.3%) and G9P[8] (4.3%), and 19.5% were mixed infections. The dominance of G1P[8] continued into the universal immunization period (48.6%), followed by G3P[8] (21.5%), G9P[8] (15.9%) and G12P[8] (4.7%), while mixed rotavirus infections were no longer detected. CONCLUSIONS: Universal immunization with RotaTeq in Israel was associated a sustained reduction in RVGE hospitalization. It is unclear whether changes in the circulating rotavirus genotypes are due to vaccine-induced selective pressure. Assessment of the long term impact of rotavirus vaccination on the incidence of rotavirus gastroenteritis and continued strain surveillance is warranted. PMID- 27771187 TI - Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis. AB - Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine samples as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration-time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CLCr) and patient weight, respectively. Patient ethnicity was not supported as a covariate in the final model. Significant differences were observed for meropenem clearance between the Indigenous and Caucasian groups [median 11.0 (range 3.0-14.1) L/h vs. 17.4 (4.3 30.3) L/h, respectively; P <0.01]. Standard dosing regimens (1 g intravenous every 8 h as a 30-min infusion) consistently achieved target exposures at the minimum inhibitory concentration breakpoint in the absence of augmented renal clearance. No significant interethnic differences in meropenem pharmacokinetics between the Indigenous and Caucasian groups were detected and CLCr was found to be the strongest determinant of appropriate dosing regimens. PMID- 27771188 TI - First case of OXA-24-producing Acinetobacter baumannii in cattle from Reunion Island, France. PMID- 27771189 TI - Evaluation of the accuracy of extraoral laboratory scanners with a single-tooth abutment model: A 3D analysis. AB - PURPOSE: The aim of this study was to compare the accuracy of different laboratory scanners using a calibrated coordinate measuring machine as reference. METHODS: A sand blasted titanium reference model (RM) was scanned with an industrial 3D scanner in order to obtain a reference digital model (dRM) that was saved in the standard tessellation format (.stl). RM was scanned ten times with each one of the tested scanners (GC Europe Aadva, Zfx Evolution, 3Shape D640, 3Shape D700, NobilMetal Sinergia, EGS DScan3, Open Technologies Concept Scan Top) and all the scans were exported in .stl format for the comparison. All files were imported in a dedicated software (Geomagic Qualify 2013). Accuracy was evaluated calculating trueness and precision. RESULTS: Trueness values (MUm [95% confidence interval]) were: Aadva 7,7 [6,8-8,5]; Zfx Evolution 9,2 [8,6-9,8]; D640 18,1 [12,2-24,0]; D700 12,8 [12,4-13,3]; Sinergia 31,1 [26,3-35,9]; DScan3 15,6 [11,5 19,7]; Concept Scan Top 28,6 [25,6-31,6]. Differences between scanners were statistically significant (p<.0005). Precision values (MUm [95% CI]) were: Aadva 4,0 [3,8-4,2]; Zfx Evolution 5,1 [4,4-5,9]; D640 12,7 [12,4-13,1]; D700 11,0 [10,7-11,3]; Sinergia 16,3 [15,0-17,5]; DScan3 9,5 [8,3-10,6]; Concept Scan Top 19,5 [19,1-19,8]. Differences between scanners were statistically significant (p<.0005). CONCLUSIONS: The use a standardized scanning procedure fabricating a titanium reference model is useful to compare trueness and precision of different laboratory scanners; two laboratory scanners (Aadva, Zfx Evolution) were significantly better that other tested scanners. PMID- 27771191 TI - Covert Recording by Patients of Encounters With Gastroenterology Providers: Path to Empowerment or Breach of Trust? PMID- 27771192 TI - [Access to kidney transplantation's waiting list: Setting up a clinical pathway]. AB - Early information about the kidney transplant is recommended to begin quickly the process of registration on the kidney transplantation waiting list, even for the patients not dialyzed at stage V of the renal insufficiency. It is a strategic choice for the patient care. From the arrival of all the patients in our center of dialysis, a systematic evaluation of the access to the kidney transplant waiting list is organized thanks to a clinical pathway. The impact of this new organization was estimated at 18 months with regard to the information about the kidney transplant transmitted to the patient, of the time required for the assessment of pre-kidney transplant evaluation, and of putting in contraindication. On 78 incident patients, 64 received the information concerning the kidney transplant. After 18 months, 50 clinical pathways are finalized at the time of the analysis among which 25 with a period lower than 6 days and 25 with a median of 169 days. A significant difference of age exists between both groups. The main causes of definitive medical contraindications were estimated. Twenty two percent of the clinical pathway finalized is awaiting lifting of temporary contraindication. The management of the patient is improved, due to motivation of all the medical teams and a considerable work of coordination between the secretarial department and the department of transplantation in teaching hospital. PMID- 27771193 TI - [Care characteristics of the foreigner population in the emergency department at the University Hospital of Torrevieja, Alicante (Spain): differences with the native population]. PMID- 27771194 TI - [Adapting the service portfolio of a public health organisation to shrinking resources]. AB - This paper describes the review process of the Agency of Public Health of Barcelona's service portfolio in response to the budget cuts introduced since 2010 in the public administrations in Spain. A working group reviewed the different business activities, taking into account their costs and generated revenue and their justification, assessing factors such as the existence of legal constraints, tied funding, explicit demands from the founding administrations and other actors that may be capable of undertaking particular activities. The changes and their consequences are described. The new service portfolio has been consolidated and is considered ratified by the Agency board, which was renewed after political changes. We conclude that this is because it was based on professional consensus and management criteria, which are key for the smooth operation of a public autonomous executive organisation. PMID- 27771195 TI - The Effectiveness of Repetitive Transcranial Magnetic Stimulation for Poststroke Apathy Is Associated with Improved Interhemispheric Functional Connectivity. AB - Poststroke apathy is relatively common and has negative effects on the functional recovery of the patient; however, few reports have demonstrated the existence of effective treatments for poststroke apathy. Here, we describe a case of poststroke apathy that was successfully treated with repetitive transcranial magnetic stimulation (rTMS). Using resting-state functional magnetic resonance imaging, we detected improved interhemispheric functional connectivity that was correlated with the patient's recovery from poststroke apathy. Our case suggests that rTMS can improve the transfer of information through the corpus callosum, which is crucial for helping patients recover from poststroke apathy. PMID- 27771196 TI - Fluid-Attenuated Inversion Recovery Hyperintensity Is Associated with Hemorrhagic Transformation following Reperfusion Therapy. AB - BACKGROUND: It is still controversial whether early fluid-attenuated inversion recovery (FLAIR) hyperintensity within acute ischemic lesions carries the risk of hemorrhagic transformation (HT) after reperfusion therapy. Furthermore, the association between the location of FLAIR hyperintensity and HT has not been investigated. METHODS: We retrospectively reviewed patients who underwent reperfusion therapy within 6 hours of stroke onset and magnetic resonance imaging including a FLAIR sequence before completing reperfusion therapy. FLAIR hyperintensity within the diffusion-weighted imaging (DWI) lesion was rated qualitatively, and HT was assessed on follow-up gradient echo imaging. The location of the FLAIR change and HT was classified as subcortical, cortical, or cortico-subcortical. RESULTS: Of 134 patients with acute ischemic stroke included in this study, early FLAIR changes within DWI lesions were identified in 56 (41.8%) patients, and HT was noted in 51 (38.1%) patients. FLAIR change was independently associated with HT (odds ratio: 4.37, 95% confidence interval: 1.72 11.12). Geographically, 48.2% of the patients with a FLAIR change developed a matched HT (restricted to the region with the FLAIR change), and the risk of HT was further increased in patients with a FLAIR change in the cortico-subcortical region (68.8%). CONCLUSIONS: In patients in the acute stage of stroke, an early FLAIR change is associated with the risk of HT following reperfusion therapy with a highly matched geographic relationship and common risk factors. Thus, identification of FLAIR change may be a useful surrogate marker to assess the likelihood of subsequent HT in patients treated with reperfusion therapy. PMID- 27771197 TI - Deficient prepulse inhibition of blink reflex in migraine and its relation to allodynia. AB - OBJECTIVE: Prepulse inhibition (PPI) of the blink reflex (BR) is a reduction in BR excitability due to a conditioning stimulus, reflecting sensory gating by brainstem structures. We aimed to analyze PPI changes during a painful episode in chronic or episodic migraine and its relation to allodynia, since abnormal brainstem filtering has been hypothesized in migraine pathophysiology. METHODS: We included 20 patients with migraine during headache episode, and age- and gender-matched 22 healthy subjects. We recorded BR after unconditioned and conditioned supraorbital stimuli. For conditioned stimuli, we applied preceding subthreshold stimulus to the median nerve at wrist. The presence of PPI was compared between the two groups, as well as the specific BR parameters (latency, amplitude or area of R1 and R2 components) in unconditioned (test) and conditioned (PPI) paradigms. RESULTS: In the patient group, seven (35%) patients did not have R2-PPI whereas all healthy subjects had R2-PPI (P=0.003). Healthy subjects displayed significantly increased R1 amplitude and reduced R2 amplitude and area after conditioned stimuli. In migraine patients, we observed significant reduction only in R2 amplitude. Logistic regression demonstrated that allodynia was independently related with the presence of PPI (beta: -0.535, P=0.021). CONCLUSIONS: Our study provides evidence for sensory gating impairment at brainstem level in migraine headache, related to the presence of allodynia. PMID- 27771198 TI - Yield of repeated intermittent EEG for seizure detection in critically ill adults. AB - INTRODUCTION: Seizures are common in critically ill patients and prevalence can exceed 30% in the neuro-intensive care unit (ICU). Continuous EEG monitoring (cEEG) is the gold standard for seizure detection in critically ill patients. OBJECTIVES: To determine the yield of intermittent EEG (iEEG) to detect critically ill adult patients with seizures and to identify the factors that affect this yield. METHODS: We retrospectively analyzed cEEG data and medical records from 977 consecutive critically ill patients undergoing cEEG. We included those presenting at least one electrographic seizure during the first 24hours of cEEG. Patients with hypoxic-ischemic encephalopathy were excluded. For seizure detection, we reviewed six 30-minute epochs on cEEG selected at H0, H3, H6, H12, H18 and H24. RESULTS: Seizures occurred in 10.75% (105/977) of patients. Level of consciousness was impaired in 79 (75%) of patients, with 42 (40%) in coma. Review of the H0 epoch on cEEG permitted to detect seizures in 61 (58%) patients. These figures increased to 70 (67%), 75 (71%), 91 (87%) and 97 (92%) patients for a sampling every 24, 12, 6 and 3hours, respectively (P=0.02). Frequency of seizures on cEEG was the only factor significantly affecting the probability of seizure detection. Sampling every 6hours revealed seizures in all patients with more than six seizures per 24hours. CONCLUSIONS: iEEG repeated every 6hours can accurately detect patients presenting seizures, especially when seizure frequency is greater than six per 24hours. These findings have practical implications for electrographic seizure detection in critically ill patients in settings lacking cEEG. PMID- 27771199 TI - [Erratum in "Regional Study of Patient Safety Incidents (ERIDA) in the Emergency Services"]. PMID- 27771200 TI - Assessment of by-products of bioenergy systems (anaerobic digestion and gasification) as potential crop nutrient. AB - Alternative fertilizer resources have drawn attention in recent times in order to cope up with ever increasing demand for fertilizer. By-products of bioenergy system are considered favourable as organic fertilizer due to their ability to recycle plant nutrients. Present study evaluates fertilizer suitability of by products of two bioenergy systems viz. 3 types of anaerobic digestion by-products (digestate) from local surplus biomass such as cowdung, Ipomoea carnea:cowdung (60:40) and ricestraw:green gram stover:cowdung (30:30:40) and one gasification by-product (biochar) from rice husk. Digestates were assessed considering 4 different application options of each viz. whole, solid, liquid and ash from solid digestates. Digestate characteristics (organic matter, macronutrients, micronutrients and heavy metal content) were found to be a function of feedstock and processing (solid liquid separation and ashing). Ipomoea carnea based digestates in all application options showed comparatively higher N, P, K, NH4+ N, Ca, Mg, S and micro nutrient content than other digestates. Separation concentrated plant nutrients and organic matter in solid digestates, making these suitable both as organic amendments and fertilizer. Separated liquid digestate shared larger fraction of ammonium nitrogen (61-91% of total content), indicating their suitability as readily available N source. However, fertilizer application of liquid digestate may not match crop requirements due to lower total nutrient concentration. Higher electrical conductivity of the liquid digestates (3.4 9.3mScm-1) than solid digestates (1.5-2mScm-1) may impart phyto-toxic effect upon fertilization due to salinity. In case of by-products with unstable organic fraction i.e. whole and solid digestates of rice straw:green gram stover:cowdung digestates (Humification index 0.7), further processing (stabilization, composting) may be required to maximize their fertilizer benefit. Heavy metal contents of the by-products were found to be within the permitted range specified for organic fertilizer (vermicompost) in India. However, higher Al content of the digestates in whole, solid and ash phase (0.06-16.97gkg-1 fresh matter) can be a concern in acid soil which may cause Al toxicity. Understanding on agrochemical characteristics of bioenergy by-products with varying feedstock and application option is expected to promote their valorization opportunities considering user specific requirements. In the context of agriculturally dominant but energy deficient rural Indian scenario, integrated production of bioenergy and by product based fertilizer could be very significant to meet the critical additional requirement of both energy and fertilizer. PMID- 27771201 TI - Validation of the tablet-administered Brief Assessment of Cognition (BAC App). AB - Computerized tests benefit from automated scoring procedures and standardized administration instructions. These methods can reduce the potential for rater error. However, especially in patients with severe mental illnesses, the equivalency of traditional and tablet-based tests cannot be assumed. The Brief Assessment of Cognition in Schizophrenia (BACS) is a pen-and-paper cognitive assessment tool that has been used in hundreds of research studies and clinical trials, and has normative data available for generating age- and gender-corrected standardized scores. A tablet-based version of the BACS called the BAC App has been developed. This study compared performance on the BACS and the BAC App in patients with schizophrenia and healthy controls. Test equivalency was assessed, and the applicability of paper-based normative data was evaluated. Results demonstrated the distributions of standardized composite scores for the tablet based BAC App and the pen-and-paper BACS were indistinguishable, and the between methods mean differences were not statistically significant. The discrimination between patients and controls was similarly robust. The between-methods correlations for individual measures in patients were r>0.70 for most subtests. When data from the Token Motor Test was omitted, the between-methods correlation of composite scores was r=0.88 (df=48; p<0.001) in healthy controls and r=0.89 (df=46; p<0.001) in patients, consistent with the test-retest reliability of each measure. Taken together, results indicate that the tablet-based BAC App generates results consistent with the traditional pen-and-paper BACS, and support the notion that the BAC App is appropriate for use in clinical trials and clinical practice. PMID- 27771202 TI - [In case of fetal macrosomia, the best strategy is the induction of labor at 38 weeks of gestation]. AB - Macrosomic fetuses are at increased risk of obstetric complications, and notably shoulder dystocia, responsible for a severe neonatal morbidity. In case of fetal macrosomia, three options are: (i) the elective cesarean delivery, but this is recommended only when the estimated fetal weight is>=4500g for diabetic women and 5000g for non-diabetic women; (ii) the expectative management, but children with birth weight>=4500 had significantly increased risk of perinatal mortality, neonatal asphyxia, trauma, and cesarean delivery; (iii) the induction of labor which, reducing the possibility of fetal growth, reduce the risk of cesarean delivery for cephalopelvic disproportion and shoulder dystocia. As 2 former trials did not show maternal or neonatal benefit with induction of labor for fetal macrosomia, it was therefore not recommended. However, these 2 studies had small sample size (273 and 40 women) and a methodology limiting their ability to show a difference, justifying to achieve a large multicentre randomized controlled trial. This trial was performed by Boulvain et al. and the results published in 2015 in the Lancet. Inclusion criteria were: a singleton pregnancy in cephalic presentation and a suspected fetal macrosomia defined by an ultrasound estimated weight>95th percentile between 36 and 38 weeks. Women were randomly assigned to receive induction of labor within 3 days between 37+0 and 38+6 weeks of gestation, or expectant management. Expectant management continued until either spontaneous labour or diagnosis of a condition necessitating induction. The primary outcome was a composite of clinically significant shoulder dystocia, fracture of the clavicle, brachial plexus injury, intracranial haemorrhage, or death. Baseline characteristics were similar between groups. The mean birth weight (+/-SD) was 3831 (+/-324) g in the induction group 4118 (+/ 392) g in the expectant group. Induction of labor significantly reduced the risk of shoulder dystocia or associated morbidity (8/407; 2 %) compared with expectant management (25/411; 6 %); P=0.004. The number needed to treat was 25 (95 % CI: 15 70). The incidence of caesarean section and operative vaginal delivery did not differ significantly between the groups. The likelihood of spontaneous vaginal delivery increased significantly in the induction of labor group (59 % vs. 52 %, RR: 1.14; 95 % CI: 1.01-1.29). In all, the results of the Boulvain et al. trial justify to propose an induction of labor in cases of suspected macrosomia>95th percentile: the induction of labor reduced the risk of severe shoulder dystocia, and does not increase the risk of cesarean section. It even increases the likelihood of spontaneous vaginal delivery. PMID- 27771203 TI - [Molecular diagnosis of human papillomaviruses (HPV): What test(s) in clinical practice?] AB - Prescription of an HPV test in practice will enable the clinician to optimize the monitoring and the management of patients, especially in the context of cervical cancer screening. Numerous HPV tests are available that present different analytical and clinical sensitivity and specificity. International recommendations on clinical performance of HPV tests used for cervical cancer screening have been published by a group of experts, and tests that meet these performance criteria should be used. Apart from the HPV detection kit, the whole circuit from sampling to report of the results must be considered. This implies that the pre-analytical (sampling, quality of sample collection medium, storage condition and sample transportation...) and post-analytical steps (quality of result reporting, providing expert advices...) are also standardized. For this purpose, medical-biology laboratories are subjected to a COFRAC certification, as defined by the international standard ISO 15189 providing quality criteria for any clinical laboratory test and HPV test in particular. PMID- 27771204 TI - [CME MMC: Evaluation of a continuous medical education tool by e-learning from the morbi-mortality conferences of the Burgundy]. AB - OBJECTIVES: The objective of this study was to validate a continuing medical education e-learning tool. METHODS: The CME MMC was for all health professionals maternity Burgundy and concerned regional morbidity and mortality conferences. It was divided into steps: a pre-test for an assessment of initial knowledge, an access to the recommendations of each RMM and a post-test to assess the progress of participants. A satisfaction questionnaire was proposed after the test. The primary endpoint was the comparison of the post-test scores than the pre-test. RESULTS: CME MMC was opened 3 months and recorded 156 participants among 598 health professionals in Burgundy, a rate 2.4 times higher than the average participation rate at MMC the past two years. A statistically significant increase was demonstrated individually by comparing the post-test scores than the pre-test (P<0.00001). The increase was significantly higher for midwives and professionals absents at the RMM. Finally, 96.2% of participants have been satisfied by this formation. CONCLUSION: This prospective multicenter study validates our tool. CME MMC is accessible, without geographic or time restrictions, not expensive, and efficient because it proves that it can update our knowledge in obstetrics and perinatology. PMID- 27771205 TI - Lung transplantation after prior cardiothoracic surgery: To transplant or not to transplant. PMID- 27771206 TI - How food insecurity contributes to poor HIV health outcomes: Qualitative evidence from the San Francisco Bay Area. AB - RATIONALE: Food-insecure people living with HIV/AIDS (PLHIV) consistently exhibit worse clinical outcomes than their food-secure counterparts. This relationship is mediated in part through non-adherence to antiretroviral therapy (ART), sub optimal engagement in HIV care, and poor mental health. An in-depth understanding of how these pathways operate in resource-rich settings, however, remains elusive. OBJECTIVE: We aimed to understand the relationship between food insecurity and HIV health among low-income individuals in the San Francisco Bay Area using qualitative methods. METHODS: Semi-structured in-depth interviews were conducted with 34 low-income PLHIV receiving food assistance from a non-profit organization. Interviews explored experiences with food insecurity and its perceived effects on HIV-related health, mental health, and health behaviors including taking ART and attending clinics. Thematic content analysis of transcripts followed an integrative inductive-deductive approach. RESULTS: Food insecurity was reported to contribute to poor ART adherence and missing scheduled clinic visits through various mechanisms, including exacerbated ART side effects in the absence of food, physical feelings of hunger and fatigue, and HIV stigma at public free-meal sites. Food insecurity led to depressive symptoms among participants by producing physical feelings of hunger, aggravating pre-existing struggles with depression, and nurturing a chronic self-perception of social failure. Participants further explained how food insecurity, depression, and ART non-adherence could reinforce each other in complex interactions. CONCLUSION: Our study demonstrates how food insecurity detrimentally shapes HIV health behavior and outcomes through complex and interacting mechanisms, acting via multiple socio-ecological levels of influence in this setting. The findings emphasize the need for broad, multisectoral approaches to tackling food insecurity among urban poor PLHIV in the United States. PMID- 27771208 TI - Comparative evaluation of the FilmArray meningitis/encephalitis molecular panel in a pediatric population. AB - We compared an FDA cleared molecular meningitis/encephalitis panel to lab developed viral PCRs and bacterial culture. Of the 67 viral PCR or bacterial culture-positive samples, 92.5% were positive for the same target by the panel. Of the 66 negative samples tested, no targets were detected by the panel, for an agreement of 96.2%. PMID- 27771207 TI - Determining the cause of recurrent Clostridium difficile infection using whole genome sequencing. AB - Understanding the contribution of relapse and reinfection to recurrent Clostridium difficile infection (CDI) has implications for therapy and infection prevention, respectively. We used whole genome sequencing to determine the relation of C. difficile strains isolated from patients with recurrent CDI at an academic medical center in the United States. Thirty-five toxigenic C. difficile isolates from 16 patients with 19 recurrent CDI episodes with median time of 53.5days (range, 13-362) between episodes were whole genome sequenced on the Illumina MiSeq platform. In 84% (16) of recurrences, the cause of recurrence was relapse with prior strain of C. difficile. In 16% (3) of recurrent episodes, reinfection with a new strain of C. difficile was the cause. In conclusion, the majority of CDI recurrences at our institution were due to infection with the same strain rather than infection with a new strain. PMID- 27771209 TI - Characterization of a novel blaIMP gene, blaIMP-58, using whole genome sequencing in a Pseudomonas putida isolate detected in Denmark. AB - A multidrug-resistant strain of Pseudomonas putida was isolated from the urine of a 65-year-old women hospitalized for serious clinical conditions. Using whole genome sequencing a novel blaIMP gene, blaIMP-58 was discovered and characterized. PMID- 27771211 TI - Response to "Parents' emotional status, ADHD symptoms and sleep problems in children with epilepsy". PMID- 27771210 TI - Pulmonary metastasectomy - A retrospective comparison of surgical outcomes after laser-assisted and conventional resection. AB - INTRODUCTION: Indications and surgical techniques for pulmonary metastasectomy (PME) are controversially discussed issues. Laser-assisted surgery (LAS) is a recent innovation that has been advocated especially in patients with multiple pulmonary metastases (PM). However, there are hardly any studies comparing surgical outcomes after laser-assisted and conventional resection. The aim of the current study was to evaluate the value of LAS in a larger study population. MATERIALS & METHODS: A retrospective analysis was completed on 178 consecutive patients undergoing 236 PMEs at a single center between 2010 and 2015. The main endpoint was survival. Statistical analysis was performed using the Kaplan-Meier method and survival rates were compared with the log rank test. Follow-up was done with special attention to the development of recurrent PM. Local relapse was defined as a recurrent metastasis in direct relation to the previously resected area according to CT scan comparisons. RESULTS: LAS was performed on 256 metastases in 99 patients, non-laser-assisted surgery (NLAS) on 127 metastases in 79 patients. 5-year-survival rates were 69.3% in all patients, 65.7% after LAS and 73.6% after NLAS. There was no statistically significant survival difference after LAS or NLAS (p = 0.41). The rate of local relapse was 0.8% after LAS vs 3.1% after NLAS (p = 0.073). CONCLUSION: Despite a larger number of negative predictors for survival in LAS patients, overall survival (OS) was similar in the compared groups. There was also a trend for a lower risk of local relapses after LAS. Therefore, LAS should be considered a promising method for PME. PMID- 27771212 TI - Adult onset Rasmussen's encephalitis associated with reflex language induced seizures responsive to Rituximab therapy. PMID- 27771213 TI - Senescence and quiescence in adipose-derived stromal cells: Effects of human platelet lysate, fetal bovine serum and hypoxia. AB - BACKGROUND AIMS: Adipose-derived stromal cells (ASCs) are attractive sources for cell-based therapies. The hypoxic niche of ASCs in vivo implies that cells will benefit from hypoxia during in vitro expansion. Human platelet lysate (hPL) enhances ASC proliferation rates, compared with fetal bovine serum (FBS) at normoxia. However, the low proliferation rates of FBS-expanded ASCs could be signs of senescence or quiescence. We aimed to determine the effects of hypoxia and hPL on the expansion of ASCs and whether FBS-expanded ASCs are senescent or quiescent. METHODS: ASCs expanded in FBS or hPL at normoxia or hypoxia until passage 7 (P7), or in FBS until P5 followed by culture in hPL until P7, were evaluated by proliferation rates, cell cycle analyses, gene expression and beta galactosidase activity. RESULTS: hPL at normoxia and hypoxia enhanced proliferation rates and expression of cyclins, and decreased G0/G1 fractions and expression of p21 and p27, compared with FBS. The shift from FBS to hPL enhanced cyclin levels, decreased p21 and p27 levels and tended to decrease G0/G1 fractions. CONCLUSION: Hypoxia does not add to the effect of hPL during ASC expansion with regard to proliferation, cell cycle regulation and expression of cyclins, p21 and p27. hPL rejuvenates FBS-expanded ASCs with regard to cell cycle regulation and expression of cyclins, p21 and p27. This indicates a reversible arrest. Therefore, we conclude that ASCs expanded until P7 are not senescent regardless of culture conditions. PMID- 27771215 TI - Zinc deficiency presenting as diarrhea and diffuse erythroderma. PMID- 27771214 TI - Orthotic use for CMC osteoarthritis: Variations among different health professionals in Brazil. AB - STUDY DESIGN: Cross-sectional descriptive study. INTRODUCTION: Osteoarthritis (OA) is the most prevalent musculoskeletal disease in the adult and older adult populations. The use of orthoses to stabilize the thumb's articular complex is one of the most common conservative management strategies. Despite substantial research about this topic, there is insufficient evidence about the optimal use of orthoses to inform clinical practice, contributing to practice variations within and across health professionals. PURPOSE OF THE STUDY: To identify the prescription patterns, design preferences, and barriers for the use of orthotic devices among Brazilian health care professionals involved in the treatment of patients with OA of the basal thumb joint. METHODS: An electronic questionnaire was sent to occupational therapists, physiotherapists, and rheumatologists across Brazil through professional association mailing lists. Survey included questions about orthosis design, materials, and barriers to the use of orthotic interventions. Respondents indicated their use based on photographs of 25 orthoses models that were selected through bibliographic review and expert consultation. Descriptive statistics, the chi-square test for independence, and the Fisher exact test were used to compare differences among orthotic prescription preferences, barriers, and challenges observed amidst the 3 participants' professional classes. RESULTS: There was no consensus about orthotic prescription among 275 professionals who answered the survey. About 69% of participants reported the use of multiple orthosis during treatment of patients with thumb OA. Results suggest significant variations in the number of joints included and stabilization strategies adopted, with a preference for orthotics made in rigid materials and involving the wrist, carpometacarpal, and metacarpophalangeal joints (P < .001). The lack of knowledge about orthotic options, institutional regulations, and policies were the major barriers reported by respondents (P < .01). CONCLUSION: A plentiful variety of different orthoses designs were observed in this study, and the prescriptions made by 3 professional classes showed differences regarding types of stabilization, joint involvement, and positioning. Despite the existence of clinical trials suggesting benefits for specific custom-made design models, our results indicated widespread clinical variation in practices and preferences. LEVEL OF EVIDENCE: Not applicable. PMID- 27771216 TI - Prevalence of sessile serrated adenoma/polyp in hyperplastic-appearing diminutive rectosigmoid polyps. AB - BACKGROUND AND AIMS: The American Society for Gastrointestinal Endoscopy recommends that distal colon hyperplastic lesions can be left in place without resection if adenomatous histology can be excluded with >90% negative predictive value. However, some lesions could be sessile serrated adenomas/polyps (SSA/Ps), which is also precancerous. The aim of this study was to describe the prevalence of SSA/Ps in hyperplastic-appearing diminutive rectosigmoid polyps. METHODS: We prospectively placed 513 consecutive diminutive rectosigmoid polyps that appeared hyperplastic to an expert endoscopist in individual bottles for pathologic. Each polyp was examined by 3 expert GI pathologists. RESULTS: The prevalence of SSA/P in the study polyps ranged from .6% to 2.1%. The lowest negative predictive value found by the endoscopist for the combination of adenomas plus SSA/Ps was 96.7%. CONCLUSIONS: The prevalence of SSA/Ps in diminutive rectosigmoid hyperplastic appearing polyps is very low. These results support the safety and feasibility of a "do not resect" policy for diminutive hyperplastic-appearing rectosigmoid polyps. PMID- 27771219 TI - [Give up the spirit? Fine, but whose? As Gainsbourg used to say]. PMID- 27771217 TI - Prevalence and reasons for delaying and foregoing necessary care by the presence and type of disability among working-age adults. AB - BACKGROUND: While it is commonly accepted that disparities in unmet need for care vary by age, race/ethnicity, income, education, and access to care, literature documenting unmet needs experienced by adults with different types of disabilities is developing. OBJECTIVE: The main objective was to determine whether subgroups of people with disabilities are more likely than people without disabilities to delay/forgo necessary care, in general and among the insured. METHODS: We used pooled Medical Expenditure Panel Survey data (2004-2010) to examine delaying or forgoing medical, dental, and pharmacy care among five disability subgroups (physical, cognitive, visual, hearing, multiple) and the non disabled population. Logistic regression was conducted to examine delayed/forgone care, controlling for sociodemographic, health, and health care factors. RESULTS: Over 13% of all working-age adults delayed/forwent necessary care; lack of insurance was the strongest predictor of unmet needs. Among the insured, disability subgroups were greater than two times more likely to report delayed/forgone care than adults without disabilities. Insured working-age adults with multiple chronic conditions and those with ADL/IADL assistance needs had higher odds of delayed or forgone care than their peers without these characteristics. Reasons related to affordability were most often listed as leading to unmet needs, regardless of disability. CONCLUSION: Although insurance status most strongly predicted unmet needs for care, many people with insurance delayed/forewent necessary care. Even among the insured, all disability subgroups had significantly greater likelihood of having to delay/forgo care than those without disabilities. Differences also existed between the disability subgroups. Cost was most frequently cited reason for unmet needs. PMID- 27771218 TI - Structure, supramolecular organization and phase behavior of N-acyl-beta alanines: Structural homologues of mammalian brain constituents N-acylglycine and N-acyl-GABA. AB - N-Acyl-beta-alanines (NABAs) are structural homologues of N-acylglycines (NAGs) and N-acyl-gamma-aminobutyric acids (NAGABAs), and achiral isomers of N acylalanines, which are all present in mammalian brain and other tissues and modulate activity of biological receptors with various functions. In the present study, we synthesized and characterized a homologous series of NABAs bearing saturated acyl chains (n=8-20) and investigated their supramolecular organization and thermotropic phase behavior. In differential scanning calorimetric (DSC) studies, most of the NABAs gave one or two minor transitions before the main chain-melting phase transition in the dry state as well as upon hydration with water, but gave only a single transition when hydrated with buffer (pH7.6). Transition enthalpies (DeltaHt) and entropies (DeltaSt), obtained from the DSC studies showed linear dependence on the chain length in the dry state and upon hydration with buffer, whereas odd-even alteration was observed when hydrated with water. The crystal structures of N-lauroyl-beta-alanine (NLBA) and N myristoyl-beta-alanine (NMBA) were solved in monoclinic system in the P21/c space group. Both NLBA and NMBA were packed in tilted bilayers with head-to-head (and tail-to-tail) arrangement with tilt angles of 33.28 degrees and 34.42 degrees , respectively. Strong hydrogen bonding interactions between COOH groups of the molecules from opposite leaflets as well as NH?O hydrogen bonds between the amide groups from adjacent molecules in the same leaflet as well as dispersion interactions between the acyl chains stabilize the bilayer structure. The d spacings calculated from powder X-ray diffraction studies showed odd-even alteration with odd-chain length compounds exhibiting higher values as compared to the even-chain length ones and the tilt angles calculated from the PXRD data are higher for the even chain NABAs. These observations are relevant to developing structure-activity relationships for these amphiphiles and understand how NABAs differ from their homologues and isomers, namely NAGs, NAGABAs, and N acylalanines. PMID- 27771220 TI - ? PMID- 27771221 TI - Impact of the educational program on outcomes among patients with sepsis hospitalized from the ED. PMID- 27771222 TI - Analyses of demographical and injury characteristics of adult and pediatric patients injured in Syrian civil war. AB - PURPOSE: Aimed to analyze demographical data and injury characteristics of patients who were injured in the Syrian Civil War (SCW) and to define differences in injury characteristics between adult and pediatric patients. METHODOLOGY: Patients who were injured in the SCW and transferred to our emergency department were retrospectively analyzed in this study during the 15-month period between July 2013 and October 2014. RESULTS: During the study period, 1591 patients who were the victims of the SCW and admitted to our emergency department due to war injury enrolled in the study. Of these patients, 285 were children (18%). The median of the injury severity score was 16 (interquartile range [IQR]: 9-25) in all patients. The most frequent mechanism of injury was blunt trauma (899 cases, 55%), and the most frequently-injured region of the body was the head (676 cases, 42.5%). Head injury rates among the children's group were higher than those of the adult group (P < .001). In contrast, injury rates for the abdomen and extremities in the children's group were lower than those in the adult group (P < .001, P < .001). CONCLUSION: The majority of patients were adults, and the most frequent mechanism of injury was blunt trauma. Similarly, the children were substantially affected by war. Although the injury severity score values and mortality rates of the child and adult groups were similar, it was determined that the number of head injuries was higher, but the number of abdomen and extremity injuries was lower in the children's group than in the adult group. PMID- 27771224 TI - Effects of age on the outcome of peritoneal dialysis-associated peritonitis. PMID- 27771223 TI - Effects of Plasma-lyte A, lactated Ringer's, and normal saline on acid-base status and intestine injury in the initial treatment of hemorrhagic shock. AB - BACKGROUND: Several kinds of crystalloid solutions have been used in the treatment of hemorrhagic shock (HS). Clinicians are faced with how to select the resuscitation fluids. The aim of the present study is to compare the effects of 3 crystalloid solutions, such as normal saline (NS), lactated Ringer's (LR), and Plasma-lyte A (PA), on acid-base status and intestine injury in rats subjected to HS. METHODS: Thirty Wistar rats were divided into 4 groups. The sham group had no blood withdrawal. The other groups were subjected to severe HS and then injected with NS, LR, or PA. All treatments were followed with an infusion of red blood cell suspension. The mean arterial pressure was monitored throughout the experiment. The arterial blood gas, malonaldehyde, and myeloperoxidase levels in the small intestine were assayed 120 minutes after resuscitation. RESULTS: Plasma lyte A treatment could restore the pH, base excess (BE), HCO3-, Pao2, and Paco2. Comparing with sham group, NS failed to correct the decreased pH, BE, and HCO3- (P < .05), whereas LR treatment showed the decreased BE and HCO3- (P < .05) and increased Pao2 (P < .05). There were no significant differences in malonaldehyde among the 4 groups (P > .05). Both PA and LR were more effective than NS in decreasing the myeloperoxidase level in the small intestine (P < .01). CONCLUSIONS: Although the 3 crystalloid solutions play different roles, PA is better at correcting the acid-base balance and improving intestine injury during HS than NS and LR. PMID- 27771225 TI - The impact of recommended percutaneous coronary intervention care on hospital outcomes for interhospital-transferred STEMI patients. AB - BACKGROUND: Timely transfer and percutaneous coronary intervention (PCI) with or without thrombolysis are recommended by the American Heart Association (AHA) to care for ST-segment elevation myocardial infarction (STEMI) patients who present first to a non-PCI-capable hospital. This study was to evaluate the impact on in hospital mortality of the compliance with guidelines regarding to the time of PCI for patients with STEMI who were transferred to a capable PCI hospital. METHODS: We used the CArdioVAscular disease Surveillance data from November 2007 to December 2012 for this study. Adult patients who were diagnosed with STEMI and transferred from a primary hospital for PCI were included. Patients who underwent PCI or coronary artery bypass graft surgery in the primary hospital and patients with an unknown emergency department disposition were excluded. The main exposure was the AHA recommendation for reperfusion therapy. We tested the association between compliance with AHA and hospital mortality. RESULTS: A total of 2078 patients were analyzed, 30.0% of whom were treated in compliance with the guidelines, whereas the remaining 70.0% were not. Thrombolysis was performed in 7.9% and 0.8% (P value < .01) and hospital mortality was 5.0% and 6.8% (P value = .11) in the compliant and violence groups, respectively. The adjusted odds ratios (95% confidence intervals) of the compliant group for hospital mortality were 0.75 (0.46-1.21), respectively. A sensitivity analysis of symptom onset to arrival time was a trend for a beneficial effect in the compliant group. CONCLUSIONS: Among the patients who were transferred for STEMI care, undergoing PCI as recommended by the AHA was not associated with a mortality benefit, but the patients whose symptom onset to hospital arrival time was within 30 minutes showed an association between compliance and lower mortality. PMID- 27771226 TI - A novel bimanual lip extraction and backward, upward, rightward pressure combination for improved laryngoscopy. PMID- 27771227 TI - Diagnostic Accuracy of Noninvasive 64-row Computed Tomographic Coronary Angiography (CCTA) Compared with Myocardial Perfusion Imaging (MPI): The PICTURE Study, A Prospective Multicenter Trial. AB - RATIONALE AND OBJECTIVES: Although multiple studies have shown excellent accuracy statistics for noninvasive angiography by coronary computed tomographic angiography (CCTA), most studies comparing nuclear imaging to CCTA were performed on patients already referred for cardiac catheterization, introducing referral and selection bias. This prospective trial evaluated the diagnostic accuracy of 64-row CCTA to detect obstructive coronary stenosis compared to myocardial perfusion imaging (MPI), using quantitative coronary angiography (QCA) as a reference standard. MATERIALS AND METHODS: Twelve sites prospectively enrolled 230 patients (49% male, 57.8 years) with chest pain. All patients underwent MPI and CCTA (Lightspeed VCT/Visipaque 320, GE Healthcare, Milwaukee, WI, USA) prior to invasive coronary angiography (ICA). All patients were evaluated, and those found to have either an abnormal MPI or CCTA were clinically referred for ICA. CCTAs were graded on a 15-segment American Heart Association model by three blinded readers for presence of obstructive stenosis (>50% or >70%); MPI was graded by two blinded readers using a 17-segment model for estimation of the % myocardium ischemic or with stress defects. ICAs were independently graded for % stenosis by QCA. The efficacies of MPI and CCTA were assessed including all vessel segments for per-patient and per-vessel analyses. RESULTS: The prevalence of stenosis >=50% by ICA was 52.1% (25 of 48). The sensitivity of CCTA was significantly higher than nuclear imaging (92.0% vs 54.5%, P < 0.001), with similar specificity (87.0% vs 78.3%) when obstructive disease was defined as >=50%. CCTA provided superior sensitivity (92.6% vs 59.3%, P < 0.001) and similar specificity (88.9% vs 81.5%) using QCA stenosis >=70%. For >=50% stenosis, the computed tomographic angiography odds ratio for ICA disease was 51.75 (95% CI = 8.50-314.94, P < 0.001). For summed stress score >=5%, the odds ratio for ICA CAD was 12.73 (95% CI = 2.43-66.55, P < 0.001). Using receiver operating characteristic curve analysis, CCTA was better at classifying obstructive coronary artery disease when compared to MPI (area = 0.85 vs 0.71, P < 0.0001). CONCLUSIONS: This study represents one of the first prospective multicenter, controlled clinical trials comparing 64-row CCTA to MPI in the same patients, demonstrating superior diagnostic accuracy of CCTA over myocardial perfusion single photon emission computed tomography (MPS) to reliably detect >50% and >70% stenosis in stable chest pain patients. PMID- 27771228 TI - DYT2 screening in early-onset isolated dystonia. AB - BACKGROUND: Mutations in HPCA, a gene implicated in calcium signaling in the striatum, have been recently described in recessive dystonia cases previously grouped under the term "DYT2 dystonia". Positive patients reported so far show focal onset during childhood with subsequent generalization and a slowly progressive course to adulthood. METHODS: 73 patients with isolated dystonia of various distribution, manifesting within 21 years of age, were enrolled in this Italian study and underwent a mutational screening of HPCA gene by means of Sanger sequencing. RESULTS/CONCLUSIONS: Mean age at onset was 10.2 (+/-5.1) years and mean age at the time of genetic testing was 33 (+/-14.2) years. Mean disease duration at the time of enrollment was 22.7 (+/-12.8) years. None of the patients enrolled was found to carry HPCA mutations, rising suspicion that these probably represent a very rare cause of dystonia in childhood-adolescence. Larger studies will help determining the real mutational frequency of this gene also in different ethnic groups. PMID- 27771230 TI - Sox9 facilitates proliferation, differentiation and lipogenesis in primary cultured human sebocytes. AB - BACKGROUND: The transcription factor Sox9 is pivotal in the morphogenesis of hair follicles, but its role in sebocytes is poorly understood. OBJECTIVE: We investigated the effect of Sox9 on human sebocyte proliferation, differentiation and lipogenesis. METHODS: Sox9 expression was detected by immunohistochemistry in normal skin and acne lesion. Primary cultured human sebocytes were transfected with adenovirus expressing GFP-Sox9 or Sox9 microRNA. Sox9 and peroxisome proliferator-activated receptor (PPAR)gamma expression in sebocytes was detected by quantitative real-time PCR, Western blot and immunocytofluorescence; cell proliferation was measured by MTS and [3H]-thymidine incorporation assays; cell cycle distribution and apoptosis were evaluated by propidium iodide staining based flow cytometry; and intracellular lipid levels were assessed by Oil Red O stain. RESULTS: Sox9 immunostaining was increased in mature sebocytes of acne lesion compared with normal skin. Expression of Sox9 mRNA and protein and PPARgamma protein was elevated with cell confluent levels in sebocytes. Sox9 overexpression enhanced proliferation, differentiation, proportion of S and G2/M cells, lipogenesis and PPARgamma expression in sebocytes, while Sox9 silencing caused inhibition of differentiation, lipogenesis and PPARgamma expression, and increase of G1 and sub-G1 (apoptotic) cell fraction. The suppression of Sox9 knockdown on sebocyte growth was observed using [3H]-thymidine incorporation but not MTS assay. CONCLUSION: These results demonstrate that Sox9 can reinforce sebocyte proliferation, differentiation and lipogenesis. The G1/S transition arrest and apoptotic induction might contribute to inhibitory effect of Sox9 silencing on sebocyte proliferation. PMID- 27771229 TI - Comparative study on driver mutations in primary and metastatic melanomas at a single Japanese institute: A clue for intra- and inter-tumor heterogeneity. AB - BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared. RESULTS: Of 77 tissue samples, BRAF V600E was detected in 21 samples (27%), CDK4 R24C in 7, EPHB6 G404S in 6, BRAF V600K in 2, NEK10 E379K in 2, and CDK4 R24H, NRAS Q61K, NRAS Q61R, KRAS G12A, KIT L576P, KIT V559A, ERBB4 E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAF V600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases. CONCLUSIONS: BRAF V600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity). PMID- 27771232 TI - Are we shifting attrition downstream in the HIV cascade? PMID- 27771233 TI - The emergent role of exosomes in glioma. AB - Extracellular vesicles (EVs) are known mediators of intercellular communication for both normal and tumour cells. With the capability to transfer nucleic acids, proteins and lipids, EVs are able to influence numerous functional and pathological aspects of both donor and recipient cells. The tumour microenvironment possesses a high level of complex heterogeneity, particularly within the most prominent brain malignancy, glioblastoma multiforme (GBM). This complexity relies on a network-based communication between many different components of the local niche, including the various cell types, stroma, blood vessels, secreted factors and surrounding matrix. Exosomes are one type of EV which facilitates this intercellular communication and cross-talk within the tumour microenvironment. Exosomes secreted by tumour cells are increasingly recognized in a number of processes underlying tumour progression including facilitating the transport of receptors, signalling molecules, oncogenic genes and miRNA. They are emerging as a key component in the biogenesis of glioma, in addition to contributing to the modification of the surrounding microenvironment to support tumour progression. In this review we describe advancements in the understanding of the biology of exosomes, as well as their roles in tumour progression, as a tumour biomarker for tracking cancer progression, and as a potential therapeutic target/delivery system, with a contextual emphasis on GBM. PMID- 27771231 TI - Evaluating strategies to improve HIV care outcomes in Kenya: a modelling study. AB - BACKGROUND: With expanded access to antiretroviral therapy (ART) in sub-Saharan Africa, HIV mortality has decreased, yet life-years are still lost to AIDS. Strengthening of treatment programmes is a priority. We examined the state of an HIV care programme in Kenya and assessed interventions to improve the impact of ART programmes on population health. METHODS: We created an individual-based mathematical model to describe the HIV epidemic and the experiences of care among adults infected with HIV in Kenya. We calibrated the model to a longitudinal dataset from the Academic Model Providing Access To Healthcare (known as AMPATH) programme describing the routes into care, losses from care, and clinical outcomes. We simulated the cost and effect of interventions at different stages of HIV care, including improvements to diagnosis, linkage to care, retention and adherence of ART, immediate ART eligibility, and a universal test-and-treat strategy. FINDINGS: We estimate that, of people dying from AIDS between 2010 and 2030, most will have initiated treatment (61%), but many will never have been diagnosed (25%) or will have been diagnosed but never started ART (14%). Many interventions targeting a single stage of the health-care cascade were likely to be cost-effective, but any individual intervention averted only a small percentage of deaths because the effect is attenuated by other weaknesses in care. However, a combination of five interventions (including improved linkage, point-of-care CD4 testing, voluntary counselling and testing with point-of-care CD4, and outreach to improve retention in pre-ART care and on-ART) would have a much larger impact, averting 1.10 million disability-adjusted life-years (DALYs) and 25% of expected new infections and would probably be cost-effective (US$571 per DALY averted). This strategy would improve health more efficiently than a universal test-and-treat intervention if there were no accompanying improvements to care ($1760 per DALY averted). INTERPRETATION: When resources are limited, combinations of interventions to improve care should be prioritised over high cost strategies such as universal test-and-treat strategy, especially if this is not accompanied by improvements to the care cascade. International guidance on ART should reflect alternative routes to programme strengthening and encourage country programmes to evaluate the costs and population-health impact in addition to the clinical benefits of immediate initiation. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, National Institutes of Health. PMID- 27771234 TI - Comparison of Conscious Sedation and Asleep-Awake-Asleep Techniques for Awake Craniotomy. AB - Since awake craniotomy (AC) has become a standard of care for supratentorial tumour resection, especially in the motor and language cortex, determining the most appropriate anaesthetic protocol is very important. The aim of this retrospective study is to compare the effectiveness of conscious sedation (CS) to "awake-asleep-awake" (AAA) techniques for supratentorial tumour resection. Forty two patients undergoing CS and 22 patients undergoing AAA were included in the study. The primary endpoint was to compare the CS and AAA techniques with respect to intraoperative pain and agitation in patients undergoing supratentorial tumour resection. The secondary endpoint was comparison of the other intraoperative complications. This study results show that the incidence of intraoperative agitation and seizure were lower in the AAA group than in the CS group. Intraoperative blood pressures were significantly higher in the CS group than in the AAA group during the pinning and incision, but the level of blood pressures did not need antihypertensive treatment. Otherwise, blood pressures were significantly higher in the AAA group than in the CS group during the neurological examination and the severity of hypertension needed statistically significant more antihypertensive treatment in the AAA group. As a result of hypertension, the amount of intraoperative bleeding was higher in the AAA group than in the CS group. In conclusion, the AAA technique may provide better results with respect to agitation and seizure, but intraoperative hypertension needed a vigilant follow-up especially in the wake-up period. PMID- 27771235 TI - Relationship Between Diabetic Variables and Outcomes After Coronary Artery Bypass Grafting in Diabetic Patients. AB - BACKGROUND: Nearly half of the patients undergoing coronary artery bypass grafting (CABG) have diabetes. There is mixed data as to whether preoperative (haemoglobin A1c{HbA1c}) and/or perioperative diabetes control is associated with mortality and morbidity after CABG. We reviewed the characteristics and outcomes of diabetic patients undergoing CABG with a focus on HbA1c, perioperative glucose levels and diabetic treatment regimens. METHODS: Diabetic patients undergoing CABG during July 2010 to June 2012 were studied (n=306). The last preoperative HbA1c levels, and perioperative glucose levels (mean and coefficient of variation {CV}) were retrospectively recorded, as well as the pre-existing and perioperative diabetes treatment regimens for analyses. RESULTS: Mean HbA1c was 7.7+/-1.6%, and 11.1% (34), 56.2% (172), and 32.7% (100) of patients were managed preoperatively with diet only, oral diabetic medications and insulin respectively. For operative mortality which occurred in 2.0%, C-statistics (95% confidence interval) was only significant for HbA1c, 0.855 (0.757-0.975), and glucose CV on the day of surgery, 0.722 (0.567-0.877). HbA1c also detected postoperative renal failure, C-statistic 0.617 (0.504-0.730), but not other complications or mortality during follow-up. In multivariate analysis, HbA1c was the only diabetes-related independent predictor of operative mortality, hazards ratio 4.13 (1.04-16.4), and none of the diabetes-related variables predicted mortality during follow-up or other postoperative complications. CONCLUSION: Preoperative HbA1c was the only diabetic variable to independently predict operative mortality after CABG, suggesting medium-term preoperative diabetes control is more important and prognostic of operative outcomes than perioperative diabetes control. PMID- 27771236 TI - Mesenchymal Stem Cells Expressing eNOS and a Cav1 Mutant Inhibit Vascular Smooth Muscle Cell Proliferation in a Rat Model of Pulmonary Hypertension. AB - BACKGROUND: This study aimed to investigate the effect of bone marrow derived mesenchymal stem cells (rBMSCs) transduced with lentiviral vectors expressing endothelial nitric oxide synthase (eNOS) and/or a mutant caveolin-1(F92A-Cav1), on the pulmonary haemodynamics and structure in a rat model of pulmonary arterial hypertension (PAH). METHODS: Pulmonary arterial hypertension was induced with monocrotaline (MCT) in 60 adult male Wistar rats prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1, eNOS and/or F92A-Cav1. Changes in pulmonary haemodynamics, right ventricular hypertrophy index (RVHI), and serum nitric oxide (NO) were evaluated. Ultrastructure changes in lung tissues were observed by transmission electron microscopy. Expression of Kruppel-like factor 4 (KLF4), p53, P21, eNOS, and alpha-smooth muscle actin were evaluated by real time PCR, western blotting or immunohistochemistry. RESULTS: Treatment of PAH rats with gene modified rBMSCs (eNOS +/- Cav1 F92A) decreased right ventricular systolic pressure and improved pulmonary haemodynamics. The protein of alpha smooth muscle actin expression was decreased whilst KLF4, p53, P21, eNOS expression, and serum NO concentration was elevated. The survival rate of rats in the treatment groups was also improved, after 35 days of observation. CONCLUSION: Intravenous delivery of rBMSCs expressing eNOS/F92A-Cav1 to PAH rats inhibits pulmonary vascular smooth muscle cell proliferation, and improves pulmonary haemodynamics, vascular remodelling and short-term survival. Activation of KLF4 p53 signalling pathway may be involved in these beneficial effects. PMID- 27771237 TI - Editiorial Commentary: Genomics and drug discovery: The next frontier in precision medicine. PMID- 27771238 TI - Editorial commentary: Simulation training in cardiovascular medicine: Problematic, utopian or necessary? PMID- 27771239 TI - Nutrition in CF - Two new important guidelines. PMID- 27771240 TI - Letter response: Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer. PMID- 27771241 TI - Botulinum toxin for treatment of restrictive strabismus. AB - PURPOSE: To study the types of acquired restrictive strabismus treated in a tertiary hospital and the outcome of treatment with botulinum toxin. METHODS: We performed a 10-year retrospective study of patients with restrictive strabismus aged >=18 years who were treated with botulinum toxin. Treatment was considered successful if the final vertical deviation was <=5 PD, horizontal deviation <=10 PD, with no head turn or diplopia. RESULTS: We included 27 cases (mean age, 61.9 years). Horizontal strabismus was diagnosed in 11.1%, vertical in 51.9%, and mixed in 37%. Strabismus was secondary to cataract surgery in 6 cases, high myopia in 6, orbital fractures in 5, retinal surgery in 5, Graves ophthalmopathy in 4, and repair of conjunctival injury in 1 case. Diplopia was diagnosed in all patients, head turn in 33.3%. The initial deviation was 14 PD (range, 2-40), the mean number of injections per patient was 1.6 (range, 1-3), and the mean dose was 9.5 IU (range, 2.5-22.5). At the end of follow-up, diplopia was recorded in 59.3%, head turn in 18.5%, surgical treatment in 51.9%, and need for prism glasses in 14.8%. Outcome was successful in 37% of patients (4 high myopia, 3 orbital fractures, 2 post-surgical retinal detachment, and 1 post-cataract surgery). Mean follow-up was 3+/-1.8 years. CONCLUSION: Vertical deviation was observed in half of the sample. The most frequent deviation was secondary to cataract surgery and high myopia. Treatment with botulinum toxin was successful in one-third of the patients at the end of follow-up. PMID- 27771242 TI - Incorporating three-dimensional ultrasound into permanent breast seed implant brachytherapy treatment planning. AB - PURPOSE: Planning permanent breast seed implant (PBSI) brachytherapy using CT alone may reduce treatment accuracy because of differences in seroma visualization compared with ultrasound (US). This study evaluates dosimetric effects of seroma delineation in PBSI and the potential impact of incorporating three-dimensional (3D) US into PBSI treatment planning. METHODS AND MATERIALS: Spatially coregistered CT and 3D US images from 10 patients were retrospectively analyzed to simulate the PBSI procedure. Seromas contoured on CT and US defined clinical target volumes, CTVCT and CTVUS, which were expanded to create planning target volumes (PTVs). PBSI plans were generated using PTVCT alone, and the resulting coverage to PTVUS was evaluated. To assess the potential impact of transferring to an US-guided procedure, the CT-based plans were centered on CTVUS. The volume encompassed by both PTVs was used to evaluate how 3D US can affect the planning procedure. RESULTS: Median (range) PTVCTV100 was 95.6% (93.3 97.3%), resulting in PTVUS coverage of 91.5% (80.5-97.9%). Centering plans on CTVUS decreased PTVCTV100 by a mean of 10 +/- 8%, and increased PTVUSV100 by 5 +/ 4%. The combined PTVs were a mean 9+/-6% larger than PTVCT. Acceptable dosimetry to the combined PTVs resulted in sufficient coverage to individual PTVs but with a mean 11 +/- 24% increase to skin dose and 6 +/- 8% increase in breast V200. CONCLUSIONS: Differences in seroma visualization have dosimetric effects in PBSI. CT-based plans can underdose US-defined volumes and may not adequately translate to an US-guided procedure. Implementing 3D US into planning can potentially compensate for differences in delineation. PMID- 27771243 TI - American Brachytherapy Society Task Group Report: Combination of brachytherapy and external beam radiation for high-risk prostate cancer. AB - PURPOSE: To review outcomes for high-risk prostate cancer treated with combined modality radiation therapy (CMRT) utilizing external beam radiation therapy (EBRT) with a brachytherapy boost. METHODS AND MATERIALS: The available literature for high-risk prostate cancer treated with combined modality radiation therapy was reviewed and summarized. RESULTS: At this time, the literature suggests that the majority of high-risk cancers are curable with multimodal treatment. Several large retrospective studies and three prospective randomized trials comparing CMRT to dose-escalated EBRT have demonstrated superior biochemical control with CMRT. Longer followup of the randomized trials will be required to determine if this will translate to a benefit in metastasis-free survival, disease-specific survival, and overall survival. Although greater toxicity has been associated with CMRT compared to EBRT, recent studies suggest that technological advances that allow better definition and sparing of critical adjacent structures as well as increasing experience with brachytherapy have improved implant quality and the toxicity profile of brachytherapy. The role of androgen deprivation therapy is well established in the external beam literature for high-risk disease, but there is controversy regarding the applicability of these data in the setting of dose escalation. At this time, there is not sufficient evidence for the omission of androgen deprivation therapy with dose escalation in this population. Comparisons with surgery remain limited by differences in patient selection, but the evidence would suggest better disease control with CMRT compared to surgery alone. CONCLUSIONS: Due to a series of technological advances, modern combination series have demonstrated unparalleled rates of disease control in the high-risk population. Given the evidence from recent randomized trials, combination therapy may become the standard of care for high-risk cancers. PMID- 27771244 TI - A Study of Combination Bicalutamide and Raloxifene for Patients With Castration Resistant Prostate Cancer. AB - BACKGROUND: Prostate tissue expresses 2 estrogen receptor (ER) isoforms, ER-alpha and ER-beta, and estrogen-based therapies have shown activity in preclinical studies. Raloxifene, a selective ER modulator, has inhibited the growth of prostate cancer xenograft models and was tested in a phase II trial of castration resistant prostate cancer (CRPC), with some patients achieving stable disease. However, no studies have examined the safety of the combination of bicalutamide plus raloxifene for CRPC. Therefore, we investigated the safety of treatment with bicalutamide plus raloxifene in patients with CRPC in an initial study. MATERIALS AND METHODS: We conducted a study to evaluate the toxicity (primary endpoint) of the combination of bicalutamide (50 mg) and raloxifene (60 mg) in 28-day cycles (maximum, 6 cycles) in men with progressive CRPC. The secondary endpoint, quality of life (QOL), was assessed by patients using a 6-item linear analog self assessment or hormonal domain scale of the Expanded Prostate Cancer Index Composite. RESULTS: We enrolled 18 patients with CRPC in the study to evaluate the safety of, and patient assessment of QOL (mental, physical, social, emotional, and spiritual) with, bicalutamide plus raloxifene therapy. No grade 3 or 4 adverse events occurred. None of the 18 patients required dose reductions. The patient assessment of QOL showed no statistically significant changes after 2 treatment cycles. The median progression-free survival with bicalutamide plus raloxifene was 1.9 months (95% confidence interval, 1.8-2.8 months). CONCLUSION: The results of the present study have shown that bicalutamide/raloxifene treatment is well tolerated. However, limited clinical activity occurred in men with CRPC who had previously undergone secondary hormonal therapy or chemotherapy. PMID- 27771246 TI - Protective effects of estrogen against vascular calcification via estrogen receptor alpha-dependent growth arrest-specific gene 6 transactivation. AB - Vascular calcification is one of the major complications of cardiovascular disease and is an independent risk factor for myocardial infarction and cardiac death. Postmenopausal women have a higher prevalence of vascular calcification compared with premenopausal women, suggesting protective effects of estrogen (E2). However, the underlying mechanisms of its beneficial effects remain unclear. In the present study, we examined the inhibitory effects of E2 on vascular smooth muscle cell (VSMC) calcification, and found that growth arrest specific gene 6 (Gas6), a crucial molecule in vascular calcification, is transactivated by estrogen receptor alpha (ERalpha) in response to E2. In human aortic smooth muscle cells, physiological levels of E2 inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner. This inhibitory effect was significantly abolished by MPP, an ERalpha-selective antagonist, and ERalpha siRNA, but not by PHTPP, an ERbeta-selective antagonist, and ERbeta siRNA, implicating an ERalpha-dependent action. Apoptosis, an essential process for Pi-induced VSMC calcification, was inhibited by E2 in a concentration-dependent manner and further, MPP abolished this inhibition. Mechanistically, E2 restored the inhibited expression of Gas6 and phospho-Akt in Pi-induced apoptosis through ERalpha. Furthermore, E2 significantly activated Gas6 transcription, and MPP abrogated this E2-dependent Gas6 transactivation. E2 BSA failed to activate Gas6 transcription and to inhibit Ca deposition in VSMC, suggesting beneficial actions of genomic signaling by E2/nuclear ERalpha. Taken together, these results indicate that E2 exerts inhibitory effects on VSMC apoptosis and calcification through ERalpha-mediated Gas6 transactivation. These findings indicate a potential therapeutic strategy for the prevention of vascular calcification, especially in postmenopausal women. PMID- 27771245 TI - Early- and Late-Onset Depression in Late Life: A Prospective Study on Clinical and Structural Brain Characteristics and Response to Electroconvulsive Therapy. AB - OBJECTIVE: The clinical profile of late-life depression (LLD) is frequently associated with cognitive impairment, aging-related brain changes, and somatic comorbidity. This two-site naturalistic longitudinal study aimed to explore differences in clinical and brain characteristics and response to electroconvulsive therapy (ECT) in early- (EOD) versus late-onset (LOD) late-life depression (respectively onset <55 and >=55 years). METHODS: Between January 2011 and December 2013, 110 patients aged 55 years and older with ECT-treated unipolar depression were included in The Mood Disorders in Elderly treated with ECT study. Clinical profile and somatic health were assessed. Magnetic resonance imaging (MRI) scans were performed before the first ECT and visually rated. RESULTS: Response rate was 78.2% and similar between the two sites but significantly higher in LOD compared with EOD (86.9 versus 67.3%). Clinical, somatic, and brain characteristics were not different between EOD and LOD. Response to ECT was associated with late age at onset and presence of psychotic symptoms and not with structural MRI characteristics. In EOD only, the odds for a higher response were associated with a shorter index episode. CONCLUSION: The clinical profile, somatic comorbidities, and brain characteristics in LLD were similar in EOD and LOD. Nevertheless, patients with LOD showed a superior response to ECT compared with patients with EOD. Our results indicate that ECT is very effective in LLD, even in vascular burdened patients. PMID- 27771247 TI - An inhibitor of apoptosis protein antagonist T-3256336 potentiates the antitumor efficacy of the Nedd8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924). AB - Inhibitors of apoptosis proteins (IAPs) are antiapoptotic regulators that block cell death, and are frequently overexpressed in several human cancers, where they facilitate evasion of apoptosis and promote cell survival. IAP antagonists are also known as second mitochondria-derived activator of caspase (SMAC)-mimetics, and have recently been considered as novel therapeutic agents for inducing apoptosis, alone and in combination with other anticancer drugs. In this study, we showed that T-3256336, the orally available IAP antagonist has synergistically enhances the antiproliferative effects of the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924), and these effects were attenuated by a TNFalpha-neutralizing antibody. In the present mechanistic analyses, pevonedistat induced TNFalpha mRNA and triggered IAP antagonist-dependent extrinsic apoptotic cell death in cancer cell lines. Furthermore, synergistic effects of the combination of T-3256336 and pevonedistat were demonstrated in a HL-60 mouse xenograft model. Our findings provide mechanistic evidence of the effects of IAP antagonists in combination with NAE inhibitors, and demonstrate the potential of a new combination therapy for cancer. PMID- 27771248 TI - Dynamin2 GTPase contributes to invadopodia formation in invasive bladder cancer cells. AB - Cancer cell invasion is mediated by actin-based membrane protrusions termed invadopodia. Invadopodia consist of "core" F-actin bundles associated with adhesive and proteolytic machineries promoting cell invasion by degrading extracellular matrix (ECM). Formation of the F-actin core in invadopodia is regulated by various actin-binding proteins including Arp2/3 complex and cortactin. Dynamin GTPase localizes to the invadopodia and is implicated in cancer cell invasion, but its precise role at the invadopodia remained elusive. In this study, we examined the roles of dynamin at the invadopodia of bladder cancer cells. Although all three dynamin isoforms (dynamin1, 2 and 3) are expressed in human bladder cancer cell line T24, only dynamin2 localizes to the invadopodia. Inhibition of dynamin2 function, using either RNA interference (RNAi) or the dynamin specific inhibitor Dynasore, caused defects in invadopodia formation and suppressed invasive activity of T24 bladder cancer cells. Structure function analysis using dynamin2 deletion fragments identified the proline/arginine-rich domain (PRD) of dynamin2 as indispensable for invadopodia formation and invasiveness of T24 cells. Thus, dynamin2 contributes to bladder cancer invasion by controlling invadopodia formation in bladder cancer cells and may prove a valuable therapeutic target. PMID- 27771249 TI - Chromosome mapping, molecular cloning and expression analysis of a novel gene response for leaf width in rice. AB - Genetic analysis revealed that narrow leaf, small panicle, thin and slender stems as well as low fertility rate of an Indica rice variety were recessive traits and controlled by a single gene. Applying map-based cloning strategy, a novel narrow leaf gene, which was named nal11 was delimited to an interval of 58.3 kb between the InDel markers N10 and InD5016. There are 9 genes in the mapping interval, and only a heat shock DNAJ protein encode gene (Os07g09450) has a specific G to T SNP, which was occurred at the last base of the second exon of Os07g09450 in ZYX. 5' and 3' RACE result shown that there were two transcripts in NAL11, and the SNP in nal11 leads to a variable shear of mRNA. In addition, this type of mRNA alternative splicing together with a stop codon closely followed the SNP which caused termination of translation destroyed the DNAJ domain of nal11's product. These results suggested that the heat shock DNAJ gene was most likely to be the candidate gene of nal11. The results of RT-PCR and real-time PCR further verified that the SNP in the ZYX-nal11 gene affects mRNA splicing pattern. Phenotype of ZYX may be caused by a statistically significant reduction in the total number of small veins in leaf, size and number of small vascular bundles and cells in stems, similar to several previous reported mutations. The basic molecular information we provide here will be useful for further investigations of the physiological function of the heat shock DNAJ gene, which will be helpful in better understanding the role of the DNAJ family in regulation of plant type traits such as leaf width of rice. PMID- 27771250 TI - Characterization and evolutionary analysis of ent-kaurene synthase like genes from the wild rice species Oryza rufipogon. AB - Cultivated rice (Oryza sativa) possesses various labdane-related diterpene synthase genes, homologs of ent-copalyl diphosphate synthase (CPS) and ent kaurene synthase (KS) that are responsible for the biosynthesis of phytohormone gibberellins. The CPS homologs and KS like (KSL) homologs successively converted geranylgeranyl diphosphate to cyclic diterpene hydrocarbons via ent-copalyl diphosphate or syn-copalyl diphosphate in O. sativa. Consequently, a variety of labdane-related diterpenoids, including phytoalexin phytocassanes, momilactones and oryzalexins, have been identified from cultivated rice. Our previous report indicated that the biosynthesis of phytocassanes and momilactones is conserved in Oryza rufipogon, the progenitor of Asian cultivated rice. Moreover, their biosynthetic gene clusters, containing OsCPS2 and OsKSL7 for phytocassane biosynthesis and OsCPS4 and OsKSL4 for momilactone biosynthesis, are also present in the O. rufipogon genome. We herein characterized O. rufipogon homologs of OsKSL5, OsKSL6, OsKSL8 responsible for oryzalexin S biosynthesis, and OsKSL10 responsible for oryzalexins A-F biosynthesis, to obtain more evolutionary insight into diterpenoid biosynthesis in O. sativa. Our phytoalexin analyses showed that no accumulation of oryzalexins was detected in extracts from O. rufipogon leaf blades. In vitro functional analyses indicated that unlike OsKSL10, O. rufipogon KSL10 functions as an ent-miltiradiene synthase, which explains the lack of accumulation of oryzalexins A-F in O. rufipogon. The different functions of KSL5 and KSL8 in O. sativa japonica to those in indica are conserved in each type of O. rufipogon, while KSL6 functions (ent-isokaurene synthases) are well conserved. Our study suggests that O. sativa japonica has evolved distinct specialized diterpenoid metabolism, including the biosynthesis of oryzalexins. PMID- 27771251 TI - Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. AB - Glioblastoma is one of the most vascular brain tumour and highly resistant to current therapy. Targeting both glioblastoma cells and angiogenesis may present an effective therapeutic strategy for glioblastoma. In our work, we show that an anthelmintic drug, ivermectin, is active against glioblastoma cells in vitro and in vivo, and also targets angiogenesis. Ivermectin significantly inhibits growth and anchorage-independent colony formation in U87 and T98G glioblastoma cells. It induces apoptosis in these cells through a caspase-dependent manner. Ivermectin significantly suppresses the growth of two independent glioblastoma xenograft mouse models. In addition, ivermectin effectively targets angiogenesis through inhibiting capillary network formation, proliferation and survival in human brain microvascular endothelial cell (HBMEC). Mechanistically, ivermectin decreases mitochondrial respiration, membrane potential, ATP levels and increases mitochondrial superoxide in U87, T98G and HBMEC cells exposed to ivermectin. The inhibitory effects of ivermectin are significantly reversed in mitochondria deficient cells or cells treated with antioxidants, further confirming that ivermectin acts through mitochondrial respiration inhibition and induction of oxidative stress. Importantly, we show that ivermectin suppresses phosphorylation of Akt, mTOR and ribosomal S6 in glioblastoma and HBMEC cells, suggesting its inhibitory role in deactivating Akt/mTOR pathway. Altogether, our work demonstrates that ivermectin is a useful addition to the treatment armamentarium for glioblastoma. Our work also highlights the therapeutic value of targeting mitochondrial metabolism in glioblastoma. PMID- 27771252 TI - On the thickness and nanomechanical properties of salivary pellicle formed on tooth enamel. AB - OBJECTIVE: To determine the thickness and nanomechanical properties of salivary pellicle formed on tooth enamel. METHODS: In vitro adsorption experiments were conducted by immersing enamel samples in centrifuged saliva for 1min, and then the nanomechanical properties of the salivary pellicle/tooth enamel system were measured firstly using nanoindentation based on a continuous stiffness measurement technique. Finally, a model was proposed to obtain the thickness and the intrinsic nanohardness of this biofilm. RESULTS: The composite nanohardness of salivary pellicle/tooth enamel system varied with indentation depth. The model can describe the experimental date at both shallow and deep indentation depths very well. The fitted average thickness of salivary pellicle was about 17nm, which was in good accord with the scanning probe microscopy experimental results. The intrinsic hardness of salivary pellicle and tooth enamel was about 0.52Gpa and 4.88Gpa respectively, which was consistent with previous studies. CONCLUSIONS: It was convenient to extract intrinsic hardness and thickness of salivary pellicle from the indentation curve according to the model. Moreover, this model was applicable to plasticity-dominated behaviour of the soft film/hard substrate system. CLINICAL SIGNIFICANCE: The research results may be helpful to extend the understanding of our lubricating and anti-caries behaviours of salivary pellicle and to the oral hygiene industry for diagnose oral diseases. PMID- 27771253 TI - Replication and shedding kinetics of infectious hematopoietic necrosis virus in juvenile rainbow trout. AB - Viral replication and shedding are key components of transmission and fitness, the kinetics of which are heavily dependent on virus, host, and environmental factors. To date, no studies have quantified the shedding kinetics of infectious hematopoietic necrosis virus (IHNV) in rainbow trout (Oncorhynchus mykiss), or how they are associated with replication, making it difficult to ascertain the transmission dynamics of this pathogen of high agricultural and conservation importance. Here, the replication and shedding kinetics of two M genogroup IHNV genotypes were examined in their naturally co-evolved rainbow trout host. Within host virus replication began rapidly, approaching maximum values by day 3 post infection, after which viral load was maintained or gradually dropped through day 7. Host innate immune response measured as stimulation of Mx-1 gene expression generally followed within host viral loads. Shedding also began very quickly and peaked within 2days, defining a generally uniform early peak period of shedding from 1 to 4days after exposure to virus. This was followed by a post-peak period where shedding declined, such that the majority of fish were no longer shedding by day 12 post-infection. Despite similar kinetics, the average shedding rate over the course of infection was significantly lower in mixed compared to single genotype infections, suggesting a competition effect, however, this did not significantly impact the total amount of virus shed. The data also indicated that the duration of shedding, rather than peak amount of virus shed, was correlated with fish mortality. Generally, the majority of virus produced during infection appeared to be shed into the environment rather than maintained in the host, although there was more retention of within host virus during the post-peak period. Viral virulence was correlated with shedding, such that the more virulent of the two genotypes shed more total virus. This fundamental understanding of IHNV shedding kinetics and variation at the individual fish level could assist with management decisions about how to respond to disease outbreaks when they occur. PMID- 27771254 TI - CD4+ Foxp3+ T-cells contribute to myocardial ischemia-reperfusion injury. AB - OBJECTIVE: The present study analyzed the effect of CD4+ Forkhead box protein 3 negative (Foxp3-) T-cells and Foxp3+ CD4+ T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. APPROACH AND RESULTS: We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30minutes of coronary ligation followed by 24hours of reperfusion. CD4+ T cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5+/-4.7% in MHCII KO versus 59.4+/-4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9+/ 2.8% in MHC II KO versus 39.0+/-4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24hours of reperfusion. Also CD4+ T cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4+ T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4+ T-cell activation in heart draining lymph nodes in response to 24hours of ischemia-reperfusion. Adoptive transfer of CD4+ T-cells in CD4 KO mice increased the infarct size only when including the Foxp3+ CD25+ subset. Depletion of CD4+ Foxp3+ T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. CONCLUSIONS: CD4+ Foxp3+ T-cells enhance myocardial ischemia-reperfusion injury. CD4+ T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition. PMID- 27771256 TI - Climate-driven longitudinal trends in pasture-borne helminth infections of dairy cattle. AB - Helminth parasites of grazing ruminants are highly prevalent globally and impact negatively on animal productivity and food security. There is a growing concern that climate change increases helminth disease frequency and intensity. In Europe, these concerns stem from case reports and theoretical life cycle models assessing the effects of climate change scenarios on helminth epidemiology. We believe this study is the first to investigate climate-driven trends in helminth infections of cattle on a cohort of randomly selected farms. One thousand, six hundred and eighty dairy farms were monitored over an 8year period for the two major helminth infections in temperate climate regions and climate-driven trends were investigated by multivariable linear mixed models. The general levels of exposure to Fasciola hepatica decreased over the study period while those to Ostertagia ostertagi increased, and this could at least be partially explained by meteorological factors (i.e. the number of rainy (precipitation >1mm) and warm days (average daily temperature >10 degrees C) in a year). The longitudinal trends varied according to the altitude and the agricultural region of the farm. This study shows that longitudinal epidemiological data from sentinel farms combined with meteorological datasets can significantly contribute to understanding the effects of climate on infectious disease dynamics. When local environmental conditions are taken into account, the effects of climate change on disease dynamics can also be understood at more local scales. We recommend setting up a longitudinal sampling strategy across Europe in order to monitor climate-driven changes in helminth disease risk to inform adaptation strategies to promote animal health and productivity. PMID- 27771255 TI - Pb exposure prolongs the time period for postnatal transient uptake of 5-HT by murine LSO neurons. AB - Pb exposure is associated with cognitive deficits including Attention Deficit Hyperactivity Disorder (ADHD) in children and alters auditory temporal processing in humans and animals. Serotonin has been implicated in auditory temporal processing and previous studies from our laboratory have demonstrated that developmental Pb decreases expression of serotonin (5-HT) in the adult murine lateral superior olive (LSO). During development, certain non-serotonergic sensory neurons, including auditory LSO neurons, transiently take up 5-HT through the serotonin reuptake transporter (SERT). The uptake of 5-HT is important for development of sensory systems. This study examines the effect of Pb on the serotonergic system in the LSO of the early postnatal mouse. Mice were exposed to moderate Pb (0.01mM) or high Pb (0.1mM) throughout gestation and postnatal day 4 (P4) and P8. We found that Pb exposure prolongs the normal developmental expression of 5-HT by LSO neurons and this is correlated with expression of SERT on LSO cell bodies. The prolonged expression of 5-HT by postnatal LSO neurons is correlated with decreased synaptic immunolabeling within the LSO. This Pb associated decrease in synaptic density within the LSO could contribute to the auditory temporal processing deficits and cognitive deficits associated with developmental Pb exposure. PMID- 27771257 TI - Excretory/secretory products in the Echinococcus granulosus metacestode: is the intermediate host complacent with infection caused by the larval form of the parasite? AB - The genus Echinococcus consists of parasites that have a life cycle with two mammalian hosts. Their larval stage, called the hydatid cyst, develops predominantly in the liver and lungs of intermediate hosts. The hydatid cyst is the causative agent of cystic hydatid disease and the species Echinococcus granulosus, G1 haplotype, is responsible for the vast majority of cases in humans, cattle and sheep. Protein characterization in hydatid cysts is essential for better understanding of the host-parasite relationship and the fertility process of Echinococcus. The aims of this work were the identification and quantitative comparison of proteins found in hydatid fluid from fertile and infertile cysts from E. granulosus, in order to highlight possible mechanisms involved in cyst fertility or infertility. Hydatid fluid samples containing proteins from both E. granulosus and Bos taurus were analysed by LC-MS/MS. Our proteomic analysis of fertile and infertile cysts allowed identification of a total of 498 proteins, of which 153 proteins were exclusively identified in the fertile cyst, 271 in the infertile cyst, and 74 in both. Functional in silico analysis allowed us to highlight some important aspects: (i) clues about the possible existence of an "arms race" involving parasite and host responses in fertile and infertile cysts; (ii) a number of proteins in hydatid fluid without functional annotation or with possible alternative functions; (iii) the presence of extracellular vesicles such as exosomes, which was confirmed by transmission electron microscopy. PMID- 27771258 TI - Development and validation of a sensitive and selective LC-MS/MS method for determination of tacrolimus in oral fluids. AB - Tacrolimus is a commonly used immunosuppressive agent in organ transplant recipients. Therapeutic drug monitoring (TDM) of tacrolimus is essential to adjust the dose and achieve optimal immunosuppression level. Routine TDM is practiced using whole blood samples obtained through venipuncture. However, tacrolimus concentration that is present in oral fluid (OF) can theoretically represent the free or pharmacologically active form of tacrolimus. In this study, we report the development and validation of a rapid, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of tacrolimus in OF. Chromatographic separation were achieved on an Acquity UPLC BEH C18 column by a gradient elution using 2mM ammonium acetate/0.1% (v/v) formic acid in water (mobile phase A) and in methanol (mobile phase B) with a 2.2min chromatographic run time. Tacrolimus was extracted from OF with acetonitrile as the precipitating solvent. Both extraction and chromatography was optimized to provide optimal sample cleanness, negligible matrix effect, and optimal specificity. The lower limit of quantification (LLOQ) for the assay was set at 10pg/mL using a 50MUL aliquot of OF obtained by passive drool. The method demonstrated adequate accuracy and precision with accuracy between 94.5-103.6%, and coefficient of variation ranging from 4 to 9.8%. Tacrolimus was stable in OF for up to one month at -80 degrees C and the extracted matrix was stable up to 48h in auto-sampler at 20 degrees C. The method showed high reproducibility as confirmed by incurred sample reanalysis test. This assay was employed in several clinical pharmacokinetic studies and could successfully measure the concentration of tacrolimus in OF. PMID- 27771259 TI - Implementation of national body contouring surgery guidelines following massive weight loss: A national cross-sectional survey of commissioning in England. AB - INTRODUCTION: National guidelines for commissioning of body contouring surgery (BCS) following massive weight loss (MWL) in England were published in 2014. Nearly three-quarters of patients who have MWL seek BCS; however, access is known to vary according to the region. The aim of national guidelines was to standardise access. The purpose of this study was to determine implementation of the national guidelines by clinical commissioning groups (CCGs) in England. MATERIALS AND METHODS: A cross-sectional, web-based survey was sent to all CCG chairs in England. RESULTS: Of 211 potential respondents, 108 completed the survey or provided funding guidelines (response rate = 52%). Eight CCGs (7%) had implemented the guidelines. A total of 69 CCGs were aware of the new guidelines (64%), and 66 CCGs stated that they fund BCS after MWL (61%). A total of 81 CCGs (75%) identified local funding guidelines, while 15 CCGs (14%) cited individual funding requests (IFRs) as the means of accessing funding. To improve patient access to BCS; 58 of 65 respondents (89%) stated cost-effectiveness, whereas 56 of 75 respondents (75%) thought patient-reported outcome measures were key. Qualitative data to improve access included an integrated pathway from bariatric surgery to BCS, an improved evidence base and greater CCG finances. One CCG stated that it cannot afford to fund cosmetic procedures. CONCLUSIONS: The purpose of national guidelines was to simplify the pathway to BCS after MWL and create fair distribution of funds across the country to needy patients; however, their uptake has been poor. Access to funding for BCS across England varies according to the location. PMID- 27771260 TI - Upper lip lift with a "T"-shaped resection of the orbicularis oris muscle for Asian perioral rejuvenation: A report of 84 patients. AB - BACKGROUND: An overlong upper lip or philtrum indicates aging. In the current study, a procedure for upper lip lift to alleviate this defect is illustrated and assessed for its esthetic effects and risks. METHODS: A total of 84 Chinese patients with overlong upper lip underwent surgery for upper lip lift from 2012 to 2014. Skin excision height was designed on the basis of the golden proportion of the lower region of the face. The incision was made at the subnasal (inferior border of the columella-nostril-alar) region. After undermining the tissue between the subcutis and orbicularis oris, a "T"-shaped region of the muscle was resected. Both sides of the muscular flaps were developed and suspended upward to the columella base to lift the upper lip. The incision was then sutured delicately. RESULTS: Of the 76 patients who were effectively followed up, recovery period, lift effect, visibility of the scar, vermilion shape, surgery associated effects, any complications, and overall rejuvenation, among other outcomes, were evaluated at 1 week, 1 month, and 3-24 months postoperation. Assessment was performed by both objective measurements and subjective satisfaction: significant efficiency was achieved and high satisfaction, satisfaction, and dissatisfaction ratings were reported by 55 (72.4%), 18 (23.7%), and 3 (3.9%) patients, respectively. CONCLUSIONS: Upper lip lift yields a significant esthetic effect with few complications. This surgical intervention merits further clinical development and application. PMID- 27771261 TI - Effectiveness of the extended surgical approach to visualize the axillary nerve in the blind zone in an arthroscopic axillary nerve injury model. AB - INTRODUCTION: The aims of this study were to create a model of axillary nerve (AN) injury during an arthroscopic capsular plication to analyze the site for potential nerve injury and to determine the AN length that can be visualized through standard and extended anterior, axillary, and posterior approaches. MATERIAL AND METHODS: Six arthroscopic inferior capsular plications were performed in 3 human adult frozen cadavers. A nonabsorbable suture was used to plicate the inferior capsule aiming at capturing the AN (at a location closest to the joint capsule). We then attempted to explore the AN through 3 different surgical approaches (each approach was performed in 2 shoulders): a standard and an extended anterior, axillary, and posterior approach. Surgical clips were used to mark the AN length that was visualized through each approach. RESULTS: The AN injury was located in a range from 5.4 to 7.8 cm from its origin from the posterior cord. This location corresponds with the previously described AN injury zone B (blind) and zone C (circumflex). Compared to the standard approaches, the extended anterior, axillary, and posterior approaches improved the visualization of the AN by 3.6, 1.5, and 2.8 cm, respectively. None of these approaches independently was sufficient to expose the entire course of the AN. CONCLUSIONS: The blind zone is a potential location for AN injury after inferior capsular plication. On the basis of this study, a combination of a standard and an extended surgical approach may lead to better exposure of most of the AN length. PMID- 27771262 TI - Outcome after urgent microvascular revision of free DIEP, SIEA and SGAP flaps for autologous breast reconstruction. AB - INTRODUCTION: Microvascular complications after free flap breast reconstruction are devastating, and revision of a compromised breast reconstruction is very challenging. The aim of this study was to review the different characteristics of urgent microvascular revision in DIEP, SIEA and SGAP flaps and to evaluate the final outcome after revision. MATERIALS AND METHODS: A retrospective chart review was performed for all patients who underwent an autologous breast reconstruction with a DIEP, SIEA or SGAP flap at the University Hospitals of Leuven between August 1997 and December 2013. The number of revisions, time to revision, reason for revision, and outcome after microvascular free flap revision were analysed. RESULTS: A total of 1562 free flaps were evaluated during the study period, of which 4.42% required urgent exploration. DIEP flaps (3.38%) had a statistically significant lower revision rate than SIEA flaps (11.76%) and SGAP flaps (8.42%). Venous insufficiency was the main reason for revision of DIEP flaps (86.7%) and SGAP flaps (62.5%). SIEA flaps mostly failed because of an arterial problem (62.5%). SIEA flaps (62.5%) had a higher revision failure rate than DIEP flaps (37.8%) and SGAP flaps (12.5%). We found a statistically significant difference (p < 0.001) in the outcome of revision in DIEP flaps in correlation to the time to revision. Our overall flap failure rate was 1.79% (DIEP 1.28%; SIEA 7.35%; SGAP 1.05%). CONCLUSIONS: The DIEP flap remains the most reliable flap for microvascular breast reconstructions. SIEA flaps are only performed when no suitable perforator for a DIEP flap is present. Multiple revisions are no longer performed, as the outcome after more than one revision is very disappointing. The difference in reason for revision between the different flaps led to the introduction of some technical refinements. PMID- 27771263 TI - Clinical efficacy of hydrodistention with joint manipulation under interscalene block compared with intra-articular corticosteroid injection for frozen shoulder: a prospective randomized controlled study. AB - BACKGROUND: Hydrodistention is known to be an effective method of treatment for frozen shoulder. However, hydrodistention is accompanied by severe pain during the procedure. An interscalene block may relieve the severe pain associated with the procedure of hydrodistention. This study compared the clinical efficacy of hydrodistention with joint manipulation under an interscalene block with that of intra-articular corticosteroid injection. METHODS: This prospective randomized controlled study included 121 patients presenting with frozen shoulder. Patients were randomized into 2 groups; those in group A (60 patients) were treated by hydrodistention with joint manipulation under an interscalene block, and those in group B (61 patients) were managed with intra-articular corticosteroid injection. Pain intensity and patient satisfaction were assessed by the visual analog scale. Functional outcomes were assessed by the Constant score and the range of shoulder motion. RESULTS: Group A demonstrated better patient satisfaction and earlier restoration of range of motion than group B at 6 weeks (P <= .001). At 12 weeks, the pain score was lower and the Constant score was better in group A than in group B. However, at 12 months after treatment, pain score (P = .717), patient satisfaction (P = .832), range of motion (P > .05), and Constant score (P = .480) were similar in the 2 groups. CONCLUSION: Hydrodistention combined with joint manipulation under an interscalene block provided earlier pain relief and restoration of shoulder range of motion and function compared with single intra articular corticosteroid injection in patients with primary frozen shoulder. PMID- 27771264 TI - CFD study of the flow pattern in an ultrasonic horn reactor: Introducing a realistic vibrating boundary condition. AB - Recently, great attention has been paid to predict the acoustic streaming field distribution inside the sonoreactors, induced by high-power ultrasonic wave generator. The focus of this paper is to model an ultrasonic vibrating horn and study the induced flow pattern with a newly developed moving boundary condition. The numerical simulation utilizes the modified cavitation model along with the "mixture" model for turbulent flow (RNG, k-epsilon), and a moving boundary condition with an oscillating parabolic-logarithmic profile, applied to the horn tip. This moving-boundary provides the situation in which the center of the horn tip vibrates stronger than that of the peripheral regions. The velocity field obtained by computational fluid dynamic was in a reasonably good agreement with the PIV results. The moving boundary model is more accurate since it better approximates the movement of the horn tip in the ultrasonic assisted process. From an optimizing point of view, the model with the new moving boundary is more suitable than the conventional models for design purposes because the displacement magnitude of the horn tip is the only fitting parameter. After developing and validating the numerical model, the model was utilized to predict various quantities such as cavitation zone, pressure field and stream function that are not experimentally feasible to measure. PMID- 27771265 TI - Recent developments on ultrasound-assisted one-pot multicomponent synthesis of biologically relevant heterocycles. AB - Heterocycles are the backbone of organic compounds. Specially, N- &O-containing heterocycles represent privileged structural subunits well distributed in naturally occurring compounds with immense biological activities. Multicomponent reactions (MCRs) are becoming valuable tool for synthesizing structurally diverse molecular entities. On the other hand, the last decade has seen a tremendous outburst in modifying chemical processes to make them sustainable for the betterment of our environment. The application of ultrasound in organic synthesis is fulfilling some of the goals of 'green and sustainable chemistry' as it has some advantages over the traditional thermal methods in terms of reaction rates, yields, purity of the products, product selectivity, etc. Therefore the synthesis of biologically relevant heterocycles using one-pot multi-component technique coupled with the application of ultrasound is one of the thrusting areas in the 21st Century among the organic chemists. The present review deals with the "up to date" developments on ultrasound assisted one-pot multi-component synthesis of biologically relevant heterocycles reported so far. PMID- 27771266 TI - Recent developments on ultrasound assisted catalyst-free organic synthesis. AB - Mother Nature needs to be protected from ever increasing chemical pollutions associated with synthetic organic processes. The fundamental challenge for today's methodologists is to make their protocols more environmentally benign and sustainable by avoiding the extensive use of hazardous reagents and solvents, harsh reaction conditions, and toxic metal catalysts. However, the people of the twenty-first century are well aware about the side effects of those hazardous substances used and generated by the chemical processes. As a result, the last decade has seen a tremendous outburst in modifying chemical processes to make them 'sustainable' for the betterment of our environment. Catalysts play a crucial role in organic synthesis and thus they find huge applications and uses. Scientists' continuously trying to modify the catalysts to reduce their toxicity level, but the most benign way is to design an organic reaction without catalyst(s), if possible. It is worthy to mention that the involvement of ultrasound in organic synthesis is sometimes fulfilling this goal. In many occasions the applications of ultrasound can avoid the use of catalysts in organic reactions. Such beneficial features as a whole have motivated the organic chemists to apply ultrasonic irradiation in more heights and as a results, in recent past, there were immense applications of ultrasound in organic reactions for the synthesis of diverse organic scaffolds under catalyst-free condition. The present review summarizes the latest developments on ultrasound assisted catalyst free organic synthesis reported so far. PMID- 27771267 TI - Sonochemical zinc oxide and layered hydroxy zinc acetate synthesis in fenton-like reactions. AB - Zinc acetate solution is sonicated at high power in water and in ethanol in the absence and presence of various peroxides. In the absence of peroxides, the products are zinc oxide and layered hydroxy zinc acetate in water and in ethanol, respectively. Layered basic zinc acetate are prepared for the first time using sonochemical methods. The addition of peroxides alters the reaction mechanisms. In water, insoluble peroxides produce zinc oxides while the water soluble peroxide, i.e. hydrogen peroxide, completely destroyed the structure and casted a doubt on the accepted peroxide initiated mechanism of reactions. In ethanol, peroxide addition caused the reaction mechanism to change and some oxide formation is observed. The reaction mechanism is sensitive to water/ethanol amounts as well as the peroxide to zinc ion mole ratio. Thin zinc oxide wafers (ca. 30nm) with band gaps of 3.24eV were obtained. PMID- 27771268 TI - Perturbation of a radially oscillating single-bubble by a micron-sized object. AB - A single bubble oscillating in a levitation cell is acoustically monitored by a piezo-ceramics microphone glued on the cell external wall. The correlation of the filtered signal recorded over distant cycles on one hand, and its harmonic content on the other hand, are shown to carry rich information on the bubble stability and existence. For example, the harmonic content of the signal is shown to increase drastically once air is fully dissociated in the bubble, and the resulting pure argon bubble enters into the upper branch of the sonoluminescence regime. As a consequence, the bubble disappearance can be unambiguously detected by a net drop in the harmonic content. On the other hand, we perturb a stable sonoluminescing bubble by approaching a micron-sized fiber. The bubble remains unperturbed until the fiber tip is approached within a critical distance, below which the bubble becomes unstable and disappears. This distance can be easily measured by image treatment, and is shown to scale roughly with 3-4 times the bubble maximal radius. The bubble disappearance is well detected by the drop of the microphone harmonic content, but several thousands of periods after the bubble actually disappeared. The delay is attributed to the slow extinction of higher modes of the levitation cell, excited by the bubble oscillation. The acoustic detection method should however allow the early detection and imaging of non-predictable perturbations of the bubble by foreign micron-sized objects, such as crystals or droplets. PMID- 27771269 TI - A survey on the effects of ultrasonic irradiation, reaction time and concentration of initial reagents on formation of kinetically or thermodynamically stable copper(I) metal-organic nanomaterials. AB - In order to evaluation the effects of ultrasonic irradiations, concentration of initial reagents and reaction time on formation [Cu4(MBT)4] or [Cu6(MBT)6] copper(I) metal-organic nanomaterials, [HMBT=2-Mercaptobenzothiazole], we designed some experiments and synthesized six samples under different conditions. These nanostructures were characterized by IR spectroscopy, X-ray powder diffraction (XRD) and Scanning Electron Microscopy (SEM). It seems that the tetranuclear cluster of [Cu4(MBT)4] (2) is the kinetically stable product which is formed at the initial time of the reaction and as the time went, it converts to thermodynamically stable product of [Cu6(MBT)6] (1) with hexanuclear cluster unit. In the samples which synthesized with low concentration of initial reagents, against to those synthesized with high concentration of initial reagents, the ultrasonic irradiation does not have any effect on formation of any special morphology. PMID- 27771270 TI - Use of the ultrasonic cavitation in wool dyeing process: Effect of the dye-bath temperature. AB - The present work aims to study the effect of the liquid temperature on the performance of ultrasounds (US) in a dyeing process. The approach was both theoretical and experimental. In the theoretical part the simplified model of a single bubble implosion is used to demonstrate that the "maximum implosion pressure" calculated with the well known Rayleigh-Plesset equation for a single bubble can be correlated with the cavitation intensity experimentally measured with an Ultrasonic Energy Meter (by PPB Megasonics). In particular the model was used to study the influence of the fluid temperature on the cavitation intensity. The "relative" theoretical data calculated from the implosion pressure were satisfactorily correlated with the experimental ones and evidence a zone, between 50 and 60 degrees C, were the cavitation intensity is almost constant and still sufficiently high. Hence an experimental part of wool dyeing was carried out both to validate the previous results and to verify the dyeing quality at low temperatures (40-70 degrees C) in presence of US. A prototype dyeing equipment able to treat textile samples with US system of 600W power, was used. The dyeing performances in the presence and absence of US were verified by measuring DeltaE (colour variation), Re,% (reflectance percentage), K/S (colour strength) and colour fastness. The US tests performed in the temperature range of 40-70 degrees C were compared with the conventional wool dyeing at 98 degrees C. The obtained results show that a temperature close to 60 degrees C should be chosen as the recommended US dyeing condition, being a compromise between the cavitation intensity and the kinetics which rules the dyestuff diffusion within the fibres. PMID- 27771271 TI - Associations between gestational diabetes mellitus and elevated HbA1c early postpartum in a multi-ethnic population. AB - AIMS: To investigate the prevalence of elevated HbA1c 14 weeks postpartum in different ethnic groups and in women with and without gestational diabetes mellitus (GDM) in the index pregnancy and to explore demographic and biological factors from early pregnancy associated with elevated HbA1c (HbA1c >=5.7% (>=39mmol/mol)) postpartum. METHODS: From a cohort study in Oslo, Norway, we included 570 pregnant women, examined in gestational week 15, 28, and 14 weeks postpartum. The association between elevated HbA1c and demographic and biological factors were assessed by logistic regression analyses. RESULTS: The prevalence of elevated HbA1c postpartum was 23% in the total population, 15% among Western Europeans and 28% among women with ethnic minority background (p<0.01). In ethnic minorities elevated HbA1c was found in 39% of women with recent GDM diagnosed by the World Health Organization 2013 criteria and in 21% of women without GDM (p<0.01), compared to 22% and 13% in Western Europeans (p=0.11). We found independent associations between elevated HbA1c and ethnic minority background (OR 2.0, 95% CI 1.27, 3.18), and GDM (OR 2.04, 95% CI 1.35, 3.10) (p<0.01). CONCLUSIONS: The prevalence of elevated HbA1c postpartum was 23%, and significantly higher among women with ethnic minority background irrespective of GDM. PMID- 27771272 TI - Stress, anxiety and depression in heart disease patients: A major challenge for cardiac rehabilitation. AB - Cardiovascular events and emotional disorders share a common epidemiology, thus suggesting fundamental pathways linking these different diseases. Growing evidence in the literature highlights the influence of psychological determinants in somatic diseases. A patient's socio-economic aspects, personality traits, health behavior and even biological pathways may contribute to the course of cardiovascular disease. Cardiac events often occur suddenly and the episode can be traumatic for people not prepared for such an event. In this review of the literature, the authors tackle the question of psychobiological mechanisms of stress, in a pathophysiological approach to fundamental pathways linking the brain to the heart. Various psychological, biological and genetic arguments are presented in support of the hypothesis that various etiological mechanisms may be involved. The authors finally deal with biological and psychological strategies in a context of cardiovascular disease. Indeed, in this context, cardiac rehabilitation, with its global approach, seems to be a good time to diagnose emotional disorders like anxiety and depression, and to help people to cope with stressful events. In this field, cardiac rehabilitation seems to be a crucial step in order to improve patients' outcomes, by helping them to understand the influence of psychobiological risk factors, and to build strategies in order to manage daily stress. PMID- 27771273 TI - In-Hospital and Long-Term Mortality in 35,173 Chinese Patients Undergoing Coronary Artery Bypass Grafting in Beijing: Impact of Sex, Age, Myocardial Infarction, and Cardiopulmonary Bypass. AB - OBJECTIVE: The purpose of this study was to investigate the independent risk factors for mortality, the correlation between female sex and mortality, and the effects of cardiopulmonary bypass on prognosis in Chinese patients undergoing coronary artery bypass grafting (CABG). SETTING: A retrospective, observational study. PARTICIPANTS: The study included 26,926 (76.6%) men and 8,247 (23.4%) women. INTERVENTIONS: Patients undergoing isolated CABG were included in this study. MEASUREMENTS AND MAIN RESULTS: The medical records of patients undergoing CABG between January 1, 2006, and December 31, 2011, in Beijing were reviewed. Multivariate logistic regression and propensity score-matched analyses were performed to analyze the independent risk factors for in-hospital and long-term mortality. A total of 35,173 patients (76.6% men) were included in this study. Women were significantly older than men, and the proportions of women presenting with hypertension and unstable angina at hospital admission were significantly higher than those of men (all p<0.05). Women showed significantly higher in hospital mortality (1.62% v 1.30%, p = 0.0248) and long-term mortality (3-year mortality, 10.2% v 7.3%, p<0.0001) than did men. Multivariate logistic regression analyses on the total patients and the propensity score-matched group revealed that female sex was not an independent risk factor for in-hospital mortality, whereas age and off-pump CABG were associated significantly with mortality (all p<0.0001). Age, a history of myocardial infarction before CABG, and on-pump CABG were independent risk factors for long-term mortality (all p<0.0001), but female sex was not. CONCLUSIONS: These findings suggested that advancing age but not female sex, appeared to be an independent risk factor for post-CABG in-hospital and long-term mortality, and off-pump CABG may be associated with worse in hospital mortality and better long-term survival compared with on-pump CABG. PMID- 27771274 TI - Continuous Positive Airway Pressure Versus Oxygen Therapy in the Cardiac Surgical Ward: A Randomized Trial. AB - BACKGROUND: Noninvasive ventilation (NIV) is a common technique to manage patients with acute respiratory failure in the intensive care unit. However, use of NIV in general wards is less well described. The authors' aim was to demonstrate efficacy of NIV, applied in a cardiac surgery ward, in improving oxygenation in patients who developed hypoxemic acute respiratory failure after being discharged from the intensive care unit. DESIGN: Randomized, open-label trial. SETTING: University hospital. PARTICIPANTS: Sixty-four patients with hypoxemia (PaO2/FIO2 ratio between 100 and 250) admitted to the main ward after cardiac surgery. INTERVENTIONS: Patients were randomized to receive standard treatment (oxygen, early mobilization, a program of breathing exercises and diuretics) or continuous positive airway pressure in addition to standard treatment. Continuous positive airway pressure was administered 3 times a day for 2 consecutive days. Every cycle lasted 1 to 3 hours. All patients completed their 1-year follow-up. Data were analyzed according to the intention-to-treat principle. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the number of patients with PaO2/FIO2<200 48 hours after randomization. Continuous positive airway pressure use was associated with a statistically significant reduction in the number of patients with PaO2/FIO2<200 (4/33 [12%] v 14/31 [45%], p = 0.003). One patient in the control group died at the 30-day follow-up. CONCLUSIONS: Among patients with acute respiratory failure following cardiac surgery, administration of continuous positive airway pressure in the main ward was associated with improved respiratory outcome. This was the first study that was performed in the main ward of post-surgical patients with acute respiratory failure. PMID- 27771275 TI - Towards high-resolution spatial modeling of infectious disease dynamics: Comment on "Pattern transitions in spatial epidemics: Mechanisms and emergent properties" by Gui-Quan Sun et al. PMID- 27771276 TI - Randomized Trial of Plaque-Identifying Toothpaste: Decreasing Plaque and Inflammation. AB - BACKGROUND: Randomized data are sparse about whether a plaque-identifying toothpaste reduces dental plaque and nonexistent for inflammation. Inflammation is intimately involved in the pathogenesis of atherosclerosis and is accurately measured by high-sensitivity C-reactive protein (hs-CRP), a sensitive marker for cardiovascular disease. The hypotheses that Plaque HD (TJA Health LLC, Joliet, Ill), a plaque-identifying toothpaste, produces statistically significant reductions in dental plaque and hs-CRP were tested in this randomized trial. METHODS: Sixty-one apparently healthy subjects aged 19 to 44 years were assigned at random to this plaque-identifying (n = 31) or placebo toothpaste (n = 30) for 60 days. Changes from baseline to follow-up in dental plaque and hs-CRP were assessed. RESULTS: In an intention-to-treat analysis, the plaque-identifying toothpaste reduced mean plaque score by 49%, compared with a 24% reduction in placebo (P = .001). In a prespecified subgroup analysis of 38 subjects with baseline levels >0.5 mg/L, the plaque-identifying toothpaste reduced hs-CRP by 29%, compared with a 25% increase in placebo toothpaste (P = .041). CONCLUSION: This plaque-identifying toothpaste produced statistically significant reductions in dental plaque and hs-CRP. The observed reduction in dental plaque confirms and extends a previous observation. The observed reduction in inflammation supports the hypothesis of a reduction in risks of cardiovascular disease. The direct test of this hypothesis requires a large-scale randomized trial of sufficient size and duration designed a priori to do so. Such a finding would have major clinical and public health implications. PMID- 27771277 TI - Can a Toothpaste Reduce Heart Attacks and Strokes? PMID- 27771278 TI - Efficient liver segmentation in CT images based on graph cuts and bottleneck detection. AB - Liver segmentation from abdominal computed tomography (CT) volumes is extremely important for computer-aided liver disease diagnosis and surgical planning of liver transplantation. Due to ambiguous edges, tissue adhesion, and variation in liver intensity and shape across patients, accurate liver segmentation is a challenging task. In this paper, we present an efficient semi-automatic method using intensity, local context, and spatial correlation of adjacent slices for the segmentation of healthy liver regions in CT volumes. An intensity model is combined with a principal component analysis (PCA) based appearance model to exclude complex background and highlight liver region. They are then integrated with location information from neighboring slices into graph cuts to segment the liver in each slice automatically. Finally, a boundary refinement method based on bottleneck detection is used to increase the segmentation accuracy. Our method does not require heavy training process or statistical model construction, and is capable of dealing with complicated shape and intensity variations. We apply the proposed method on XHCSU14 and SLIVER07 databases, and evaluate it by MICCAI criteria and Dice similarity coefficient. Experimental results show our method outperforms several existing methods on liver segmentation. PMID- 27771279 TI - Cell-free and circulating tumor cell-based biomarkers in men with metastatic prostate cancer: Tools for real-time precision medicine? AB - The recent expansion of therapeutic options for the treatment of metastatic prostate cancer highlights the need for precision medicine approaches to enable the rational selection of appropriate therapies for individual patients. In this context, circulating biomarkers in the peripheral blood are attractive as readily accessible tools for predicting and monitoring therapeutic response. In the case of circulating tumor cells and circulating tumor DNA, they may also serve as a noninvasive means of assessing molecular aberrations in tumors at multiple time points before and during therapy. These so-called "liquid biopsies" can provide a snapshot view of tumor molecular architecture and may enable clinicians to monitor the molecular status of tumors as they evolve during treatment, thus allowing for individualized precision therapeutic decisions for patients over time. In this review, we outline recent progress in the field of circulating biomarkers in metastatic prostate cancer and evaluate their potential for enabling this vision of real-time precision medicine. PMID- 27771281 TI - The surgeon-anesthesiologist relationship in the era of enhanced recovery. PMID- 27771282 TI - Phytochemical mediated-modulation of the expression and transporter function of breast cancer resistance protein at the blood-brain barrier: An in-vitro study. AB - Clinical translation of BCRP inhibitors have failed due to neurotoxicity and novel approaches are required to identify suitable modulators of BCRP to enhance CNS drug delivery. In this study we examine 18 compounds, primarily phytochemicals, as potential novel modulators of AhR-mediated regulation of BCRP expression and function in immortalised and primary porcine brain microvascular endothelial cells as a mechanism to enhance CNS drug delivery. The majority of modulators possessed a cellular viability IC50 >100um in both cell systems. BCRP activity, when exposed to modulators for 1h, was diminished for most modulators through significant increases in H33342 accumulation at <10um with 2,6,4 trimethoflavone increasing H33342 intracellular accumulation by 3.7-6.6 fold over 1-100um. Western blotting and qPCR identified two inducers of BCRP (quercetin and naringin) and two down-regulators (17-beta-estradiol and curcumin) with associated changes in BCRP efflux transport function further confirmed in both cell lines. siRNA downregulation of AhR resulted in a 1.75+/-0.08 fold change in BCRP expression, confirming the role of AhR in the regulation of BCRP. These findings establish the regulatory role AhR of in controlling BCRP expression at the BBB and confirm quercetin, naringin, 17-beta-estradiol, and curcumin as novel inducers and down-regulators of BCRP gene, protein expression and functional transporter activity and hence potential novel target sites and candidates for enhancing CNS drug delivery. PMID- 27771280 TI - Longer average blood storage duration is associated with increased risk of infection and overall morbidity following radical cystectomy. AB - BACKGROUND: Patients with bladder cancer undergoing radical cystectomy (RC) experience high rates of perioperative blood transfusions (PBTs) and morbidity. The aim of this study was to evaluate the effect of blood storage duration on the risk of adverse perioperative outcomes in this high-risk patient population. MATERIALS AND METHODS: In a retrospective review of RC patients from 2010 to 2014 who received PBTs, the average storage duration for all units transfused was used to classify patients as receiving older blood using 3 different definitions (>=21 days,>=28 days, and>=35 days). Multivariable Poisson regression models were used to determine the adjusted relative risk of perioperative infections and overall morbidity in those given older blood compared to fresher blood. RESULTS: Of the 451 patients undergoing RC, 205 (45%) received nonirradiated PBTs. In multivariable modeling, increasing average blood storage duration, as a continuous variable, was associated with an increased risk of infections (risk ratio [RR] = 1.08 per day, 95% CI: 1.01-1.17) and overall morbidity (RR = 1.08 per day, 95% CI: 1.01-1.15). Furthermore, >=28-day blood storage (vs.<28) was associated with increased infections (RR = 2.69, 95% CI: 1.18-6.14) and morbidity (RR = 2.54, 95% CI: 1.31-4.95), and >=35-day blood storage (vs.<35) was also associated with increased infections (RR = 2.83, 95% CI: 1.42-5.66) and morbidity (RR = 3.35, 95% CI: 1.95-5.77). CONCLUSIONS: Although blood is stored up to 42 days, storage>=28 days may expose RC patients to increased perioperative infections and overall morbidity compared with storage<28 days. Prospective cohort studies are warranted in cystectomy and other high-risk surgical oncology patients to better determine the effect of blood storage duration. PMID- 27771283 TI - Rhythmic Bdnf and TrkB expression patterns in the prefrontal cortex are lost in aged rats. AB - Aging brain undergoes several changes leading to a decline in cognitive functions. Memory and learning-related genes such as Creb, Bdnf and its receptor TrkB, are expressed in different brain regions including prefrontal cortex. Those genes' proteins regulate a wide range of functions such as synaptic plasticity and long-term potentiation. In this work, our objectives were: 1) to investigate whether Creb1, Bdnf and TrkB genes display endogenous circadian expression rhythms, in the prefrontal cortex of rats maintained under constant darkness conditions; 2) to study the synchronization of those temporal patterns to the local cellular clock and 3) to evaluate the aging consequences on both cognition related genes and activating clock transcription factor, BMAL1, rhythms. A bioinformatics analysis revealed clock-responsive (E-box) sites in regulatory regions of Creb1, Bdnf and TrkB genes. Additionally, cAMP response elements (CRE) were found in Bdnf and TrkB promoters. We observed those key cognition-related factors expression oscillates in the rat prefrontal cortex. Creb1 and TrkB mRNAs display a circadian rhythm with their highest levels occurring at the second half of the 24h period. Interestingly, the cosinor analysis revealed a 12-h rhythm of Bdnf transcript levels, with peaks occurring at the second half of the subjective day and night, respectively. As expected, the BMAL1 rhythm's acrophase precedes Creb1 and first Bdnf expression peaks. Noteworthy, Creb1, Bdnf and TrkB expression rhythms are lost in the prefrontal cortex of aged rats, probably, as consequence of the loss of BMAL1 protein circadian rhythm and altered function of the local cellular clock. PMID- 27771285 TI - End of the beginning for supported accommodation? PMID- 27771284 TI - Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. AB - The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse. PMID- 27771286 TI - Quality of life, autonomy, satisfaction, and costs associated with mental health supported accommodation services in England: a national survey. AB - BACKGROUND: Little research has been done into the effectiveness of mental health supported accommodation services. We did a national survey to investigate provision and costs of services and assess service user quality of life and outcomes across England. METHODS: We randomly sampled three types of services from 14 nationally representative regions-residential care, supported housing, and floating outreach-and recruited up to ten service users per service. Service quality and costs and service users' quality of life, autonomy, and satisfaction with care were assessed in a standardised manner with validated tools and compared by multilevel modelling. FINDINGS: 619 service users were recruited from 22 residential care, 35 supported housing, and 30 floating outreach services. Those in residential care and supported housing had more severe mental health problems than those in floating outreach. 348 (57%) were assessed as being at risk of severe self-neglect and 229 (37%) as being vulnerable to exploitation in the previous 2 years. Residential care was most expensive but provided for people with the greatest needs. The mean annual budget was L466 687 for residential care (range L276 000-777 920), compared with L365 452 for supported housing (L174 877 818 000), and L172 114 for floating outreach (L17 126-491 692). Quality of care was best in supported housing. People in supported housing and floating outreach were more socially included but experienced more crime than those in residential care. After adjustment for service quality and service user sociodemographic and clinical factors, quality of life was similar for service users in residential care and supported housing (mean difference -0.138, 95% CI -0.402 to 0.126, p=0.306) and lower for those in floating outreach than in residential care ( 0.424, -0.734 to -0.114, p=0.007). However, autonomy was greater for those in supported housing than for those in residential care (0.145, 0.010 to 0.279, p=0.035). Satisfaction with care was similar across services. INTERPRETATION: Supported housing might be cost-effective, but the benefits need to be weighed against the risks associated with increased autonomy. FUNDING: National Institute for Health Research. PMID- 27771287 TI - Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients. AB - BACKGROUND: The effects of deep brain stimulation of the subthalamic nucleus (DBS STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood. OBJECTIVES: By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients. METHODS: PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group. RESULTS: STN-DBS enhanced early global TMS-evoked activity (~45-80ms) and high-alpha TMS-evoked oscillations (11-13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (~80-130ms) and beta TMS-evoked oscillations (13-30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values. CONCLUSIONS: Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity. PMID- 27771288 TI - Claudin tight junction proteins in rainbow trout (Oncorhynchus mykiss) skin: Spatial response to elevated cortisol levels. AB - This study examined regional distribution and corticosteroid-induced alterations of claudin (cldn) transcript abundance in teleost fish skin. Regional comparison of mRNA encoding 20 Cldns indicated that 12 exhibit differences in abundance along the dorsoventral axis of skin. However, relative abundance of cldns (i.e. most to least abundant) remained similar in different skin regions. Several cldns appear to be present in the epidermis and dermal vasculature whereas others are present only in the epidermis. Increased circulating cortisol levels significantly altered mRNA abundance of 10 cldns in a region specific manner, as well as corticosteroid receptors and 11beta-hydroxysteroid dehydrogenase (type 2). Epidermis and epidermal mucous cell morphometrics also altered in response to cortisol, exhibiting changes that appear to enhance skin barrier properties. Taken together, data provide a first look at spatial variation in the molecular physiology of the teleost fish integument TJ complex and region-specific sensitivity to an endocrine factor. PMID- 27771289 TI - A novel UPLC-MS/MS based method to determine the activity of N-acetylglutamate synthase in liver tissue. AB - BACKGROUND: N-acetylglutamate synthase (NAGS) plays a key role in the removal of ammonia via the urea cycle by catalyzing the synthesis of N-acetylglutamate (NAG), the obligatory cofactor in the carbamyl phosphate synthetase 1 reaction. Enzymatic analysis of NAGS in liver homogenates has remained insensitive and inaccurate, which prompted the development of a novel method. METHODS: UPLC-MS/MS was used in conjunction with stable isotope (N-acetylglutamic-2,3,3,4,4-d5 acid) dilution for the quantitative detection of NAG produced by the NAGS enzyme. The assay conditions were optimized using purified human NAGS and the optimized enzyme conditions were used to measure the activity in mouse liver homogenates. RESULTS: A low signal-to-noise ratio in liver tissue samples was observed due to non-enzymatic formation of N-acetylglutamate and low specific activity, which interfered with quantitative analysis. Quenching of acetyl-CoA immediately after the incubation circumvented this analytical difficulty and allowed accurate and sensitive determination of mammalian NAGS activity. The specificity of the assay was validated by demonstrating a complete deficiency of NAGS in liver homogenates from Nags -/- mice. CONCLUSION: The novel NAGS enzyme assay reported herein can be used for the diagnosis of inherited NAGS deficiency and may also be of value in the study of secondary hyperammonemia present in various inborn errors of metabolism as well as drug treatment. PMID- 27771290 TI - Integrating Genomics in Myelodysplastic Syndrome to Predict Outcomes After Allogeneic Hematopoietic Cell Transplantation. AB - Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic neoplastic disorders most commonly occurring in the elderly population; MDS has a tendency to progress to acute leukemia. Although epigenetic therapies have improved the outcomes of MDS patients, allogeneic hematopoietic cell transplantation remains the only curative option. Molecular characterization of MDS using next-generation sequencing has expanded not only the knowledge on MDS but also the depth of understanding of evolution and contribution of recurrent somatic mutations in precursor conditions. Rapidly evolving genomic information on MDS may provide clinicians with better risk stratification tools and may also aid in supplying useful information to allow comprehensive therapeutic decision making for MDS patients. In this concise review, we summarize the current knowledge and understanding of recurrent somatic mutations in MDS and discuss salient genomic information predicting response and influencing therapeutic outcomes in the context of allogeneic hematopoietic cell transplantation, as well as the potential application of these findings into future clinical practice. PMID- 27771291 TI - Survival Analyses and Prognosis of Plasma-Cell Myeloma and Plasmacytoma-Like Posttransplantation Lymphoproliferative Disorders. AB - BACKGROUND: Multiple myeloma/plasmacytoma-like posttransplantation lymphoproliferative disorder (PTLD-MM) is a rare complication of solid organ transplantation. Case series have shown variable outcomes, and survival data in the modern era are lacking. PATIENTS AND METHODS: A cohort of 212 PTLD-MM patients was identified in the Scientific Registry of Transplant Recipients between 1999 and 2011. Overall survival (OS) was estimated by the Kaplan-Meier method, and the effects of treatment and patient characteristics on OS were evaluated by Cox proportional hazards models. OS in 185 PTLD-MM patients was compared to 4048 matched controls with multiple myeloma (SEER-MM) derived from Surveillance, Epidemiology, and End Results (SEER) data. RESULTS: Men comprised 71% of patients; extramedullary disease was noted in 58%. Novel therapeutic agents were used in 19% of patients (more commonly during 2007-2011 vs. 1999 2006; P = .01), reduced immunosuppression in 55%, and chemotherapy in 32%. Median OS was 2.4 years and improved in the later time period (adjusted hazard ratio [aHR], 0.64, P = .05). Advanced age, creatinine > 2 g/dL, white race, and use of OKT3 were associated with inferior OS in multivariable analysis. OS of PTLD-MM patients is significantly inferior to SEER-MM patients (aHR, 1.6, P < .001). Improvements in OS over time differed between PTLD-MM and SEER-MM. Median OS of patients diagnosed from 2000 to 2005 was shorter for PTLD-MM than SEER-MM patients (18 vs. 47 months, P < .001). There was no difference among those diagnosed from 2006 to 2010 (44 months vs. median not reached, P = .5; interaction P = .08). CONCLUSION: Age at diagnosis, elevated creatinine, white race, and OKT3 were associated with inferior survival in patients with PTLD-MM. Survival of PTLD-MM is inferior to SEER-MM, although significant improvements in survival have been documented. PMID- 27771292 TI - Ceramidases, roles in sphingolipid metabolism and in health and disease. AB - Over the past three decades, extensive research has been able to determine the biologic functions for the main bioactive sphingolipids, namely ceramide, sphingosine, and sphingosine 1-phosphate (S1P) (Hannun, 1996; Hannun et al., 1986; Okazaki et al., 1989). These studies have managed to define the metabolism, regulation, and function of these bioactive sphingolipids. This emerging body of literature has also implicated bioactive sphingolipids, particularly S1P and ceramide, as key regulators of cellular homeostasis. Ceramidases have the important role of cleaving fatty acid from ceramide and producing sphingosine, thereby controlling the interconversion of these two lipids. Thus far, five human ceramidases encoded by five different genes have been identified: acid ceramidase (AC), neutral ceramidase (NC), alkaline ceramidase 1 (ACER1), alkaline ceramidase 2 (ACER2), and alkaline ceramidase 3 (ACER3). These ceramidases are classified according to their optimal pH for catalytic activity. AC, which is localized to the lysosomal compartment, has been associated with Farber's disease and is involved in the regulation of cell viability. Neutral ceramidase, which is localized to the plasma membrane and primarily expressed in the small intestine and colon, is involved in digestion, and has been implicated in colon carcinogenesis. ACER1 which can be found in the endoplasmic reticulum and is highly expressed in the skin, plays an important role in keratinocyte differentiation. ACER2, localized to the Golgi complex and highly expressed in the placenta, is involved in programed cell death in response to DNA damage. ACER3, also localized to the endoplasmic reticulum and the Golgi complex, is ubiquitously expressed, and is involved in motor coordination-associated Purkinje cell degeneration. This review seeks to consolidate the current knowledge regarding these key cellular players. PMID- 27771294 TI - Virus-host interactions under hypoxia. AB - Oxygen tension can exert a significant effect on viral propagation in vitro and possibly in vivo. In general, hypoxia restricts the replication of viruses that naturally infect tissues exposed to ambient oxygen and induces the growth of viruses that naturally target tissues exposed to low oxygen. Some viruses can reprogram cell bioenergetics towards lowering cellular respiration and therefore oxygen consumption in order to support their replication. Aim of this review is to summarize findings on the interplay between viral infection and oxygen levels, highlighting the implicated oxygen tension-sensitive elements and metabolic determinants and concluding with possible therapeutic approaches targeting these mediators. PMID- 27771295 TI - C/EBP homologous protein promotes NSAID-activated gene 1-linked pro-inflammatory signals and enterocyte invasion by enteropathogenic Escherichia coli. AB - NSAID-activated Gene 1 (NAG-1) is a prognostic indicator of chronic inflammatory diseases and aggressive tumors. Among the stress sentinels in response to infection by enteropathogenic Escherichia coli (EPEC) or other pathogenic E. coli, C/EBP homologous protein (CHOP), a representative stress-regulated transcription factor, was prominently increased and assessed for its involvement in NAG-1-mediated pathogenic cellular responses. NAG-1 expression was transcriptionally upregulated by CHOP, which promoted chemokine production through sustained NF-kappaB activation. Mechanistically, NF-kappaB activation by NAG-1 was due to TGFbeta-activated kinase 1 (TAK-1)-mediated pathway rather than SMAD-associated signals. Moreover, CHOP and subsequent TAK-1-linked signals were also involved in bacterial invasion into human cells. Therefore, CHOP as an infection-induced sentinel played crucial roles in induction of NAG-1 and subsequent prolonged activation of pro-inflammatory responses to EPEC infection or related chronic pathogenic states. PMID- 27771296 TI - Mild hypothermia protects rat neuronal injury after intracerebral hemorrhage via attenuating endoplasmic reticulum response induced neuron apoptosis. AB - BACKGROUND AND PURPOSE: Mild hypothermia has been proved to reduce global and focal cerebral ischemic injury in rodents by preventing cellular apoptosis through several pathways. However, whether hypothermia will be beneficial for intracerebral hemorrhage (ICH) and its underlying mechanisms haven't reached a consensus. It has been implicated that endoplasmic reticulum (ER) stress plays a role in the secondary injury after ICH in rats. In this study, we aimed to investigate whether mild hypothermia would attenuate ICH induced neuronal injury via regulating ER stress. METHODS: The model of ICH was induced by injecting autologous blood (120MUl) into the rat striatum. Rats were divided into sham, normothermic (NT) and hypothermic (HT) groups. HT group were subjected to mild hypothermia (33 degrees C-35 degrees C) for 2days starting from 6h after ICH. Neurological deficits were evaluated. The ER stress related proteins (GRP78, CHOP and p-eIF2alpha) and the apoptosis associated indicators (cleaved caspase3, Bcl-2 and Bim) around hematoma were assessed by western blot, qRT-PCR (quantificational real-time polymerase chain reaction), immunofluorescence and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assay. RESULTS: Neurological deficits following ICH were reduced in HT group compared to NT group. Protein levels of GRP78, CHOP and p-eIF2alpha significantly increased after ICH in both NT and HT group compared to sham group, which was consistent with the trend of cleaved-caspase3 at protein level, and Bim, Bcl-2 at gene level. In comparison to NT group, GRP78, CHOP, p-eIF2alpha, cleaved caspase-3 and Bim all decreased, while Bcl-2 increased in HT group. Additionally, apoptotic cells detected by TUNEL staining significantly decreased in the HT group. CONCLUSION: Mild hypothermia could attenuate ICH caused neuron injury by decreasing ER response-induced neuron apoptosis. PMID- 27771293 TI - Utilizing the planarian voltage-gated ion channel transcriptome to resolve a role for a Ca2+ channel in neuromuscular function and regeneration. AB - The robust regenerative capacity of planarian flatworms depends on the orchestration of signaling events from early wounding responses through the stem cell enacted differentiative outcomes that restore appropriate tissue types. Acute signaling events in excitable cells play an important role in determining regenerative polarity, rationalized by the discovery that sub-epidermal muscle cells express critical patterning genes known to control regenerative outcomes. These data imply a dual conductive (neuromuscular signaling) and instructive (anterior-posterior patterning) role for Ca2+ signaling in planarian regeneration. Here, to facilitate study of acute signaling events in the excitable cell niche, we provide a de novo transcriptome assembly from the planarian Dugesia japonica allowing characterization of the diverse ionotropic portfolio of this model organism. We demonstrate the utility of this resource by proceeding to characterize the individual role of each of the planarian voltage operated Ca2+ channels during regeneration, and demonstrate that knockdown of a specific voltage operated Ca2+ channel (Cav1B) that impairs muscle function uniquely creates an environment permissive for anteriorization. Provision of the full transcriptomic dataset should facilitate further investigations of molecules within the planarian voltage-gated channel portfolio to explore the role of excitable cell physiology on regenerative outcomes. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 27771297 TI - Laterality of proprioception in the orofacial muscles and temporomandibular joint. AB - Laterality of function in the orofacial musculature suggests there may be side-to side asymmetry of proprioceptive acuity in lip movement compared to the temporomandibular joint (TMJ). In the present work, 14 young adults were tested for acuity of lip and TMJ closure movements onto plugs varying from 5 to 8mm without visual feedback. Testing was conducted on both left and right sides, using the same psychophysical task and stimuli. Results showed superior proprioceptive acuity at the lips, with no significant side effect. However, there was side-to-side asymmetry in the correlations between proprioceptive performance for the two anatomical structures, with performance on the right side strongly correlated but not on the left. This is consistent with the need for coordination between structures during chewing. When acuity at different points in the stimulus range was examined, the right side lips were better with small stimuli. Overall, results support enhanced use-specific proprioception. PMID- 27771298 TI - The effect of atmosphere temperature on out-of-hospital cardiac arrest outcomes. AB - BACKGROUND: It is unclear whether the atmosphere temperature is associated with outcomes after out-of-hospital cardiac arrest (OHCA). METHODS: This is a nationwide observational study using the national OHCA registry merged with a geographical and weather database. Adult patients with a cardiac etiology that occurred from 2006 to 2013 were included, excluding patients with unknown outcome or unknown weather information. The main exposure was the hourly measured temperature matched to the OHCA event time. The covariates were age, gender, metropolis, place, and weather factors (wind speed and humidity). The primary outcome was good cerebral performance scale (CPC) 1 or 2. Patients were classified with three temperature groups by quartile range: Cold (<4 degrees C), Intermediate (4-21 degrees C), and Hot (>=22 degrees C). We tested the associations between the atmosphere temperature (by 1 degrees C and by temperature group) and outcomes using multivariable logistic regression analysis. RESULTS: Of 17,3051 OHCAs, a total of 115,578 cases were matched to weather database. A total of 78,717 OHCAs were analyzed. The proportion of good CPC 1 or 2 was 1.7% in the Cold group, 1.8% in the Intermediate group, and 2.3% in the Hot group. As the temperature at the event of OHCA increased by 1 degrees C, AORs (95% CIs) were 1.006 (1.002-1.009) for good CPC. The AORs (95% CIs) for good CPC in Cold and Hot group comparing with Intermediate group for good CPC were 0.964 (0.845-1.100) and 1.246 (1.096-1.416), respectively. CONCLUSION: The temperature at the time of the OHCA event was associated with outcomes after OHCA in a nationwide observational study in Korea. PMID- 27771299 TI - Sodium nitroprusside enhanced cardiopulmonary resuscitation improves short term survival in a porcine model of ischemic refractory ventricular fibrillation. AB - INTRODUCTION: Sodium nitroprusside (SNP) enhanced CPR (SNPeCPR) demonstrates increased vital organ blood flow and survival in multiple porcine models. We developed a new, coronary occlusion/ischemia model of prolonged resuscitation, mimicking the majority of out-of-hospital cardiac arrests presenting with shockable rhythms. HYPOTHESIS: SNPeCPR will increase short term (4-h) survival compared to standard 2015 Advanced Cardiac Life Support (ACLS) guidelines in an ischemic refractory ventricular fibrillation (VF), prolonged CPR model. METHODS: Sixteen anesthetized pigs had the ostial left anterior descending artery occluded leading to ischemic VF arrest. VF was untreated for 5min. Basic life support was performed for 10min. At minute 10 (EMS arrival), animals received either SNPeCPR (n=8) or standard ACLS (n=8). Defibrillation (200J) occurred every 3min. CPR continued for a total of 45min, then the balloon was deflated simulating revascularization. CPR continued until return of spontaneous circulation (ROSC) or a total of 60min, if unsuccessful. SNPeCPR animals received 2mg of SNP at minute 10 followed by 1mg every 5min until ROSC. Standard ACLS animals received 0.5mg epinephrine every 5min until ROSC. Primary endpoints were ROSC and 4-h survival. RESULTS: All SNPeCPR animals (8/8) achieved sustained ROSC versus 2/8 standard ACLS animals within one hour of resuscitation (p=0.04). The 4-h survival was significantly improved with SNPeCPR compared to standard ACLS, 7/8 versus 1/8 respectively, p=0.0019. CONCLUSION: SNPeCPR significantly improved ROSC and 4-h survival compared with standard ACLS CPR in a porcine model of prolonged ischemic, refractory VF cardiac arrest. PMID- 27771301 TI - Extracranial metastasis of multiforme glioblastoma detected by 11C-methionine brain PET/CT. PMID- 27771300 TI - An insight into fusion technology aiding efficient recombinant protein production for functional proteomics. AB - Advancements in peptide fusion technologies to maximize the protein production has taken a big leap to fulfill the demands of post-genomics era targeting elucidation of structure/function of the proteome and its therapeutic applications, by over-expression in heterologous expression systems. Despite being most preferred protein expression system armed with variety of cardinal fusion tags, expression of the functionally active recombinant protein in E. coli remains plagued. The present review critically analyses the aptness of well characterized fusion tags utilized for over-expression of recombinant proteins with improved solubility and their compatibility with downstream purification procedures. The combinatorial tandem affinity strategies have shown to provide more versatile options. Solubility decreasing fusion tags have proved to facilitate the overproduction of antimicrobial peptides. Efficient removal of fusion tags prior to final usage is of utmost importance and has been summarized discussing the efficiency of various enzymatic and chemical methods of tag removal. Unfortunately, no single fusion tag works as a magic bullet to completely fulfill the requirements of protein expression and purification in active form. The information provided might help in selection and development of a successful protocol for efficient recombinant protein production for functional proteomics. PMID- 27771302 TI - Blurred Lines: Dysbiosis and Probiotics in the ICU. AB - Clinicians have traditionally dichotomized bacteria as friendly commensals or harmful pathogens. However, the line separating the two has become blurred with the recognition that the intestinal microbiome is a complex entity in which species can shift sides-from friend to foe and back again-based on crucial factors in their local environment. Significant disruptions in the homeostasis of the microbiome, a phenomenon called dysbiosis, is increasingly associated with a host of untoward effects. Patients in the ICU are at high risk for dysbiosis given the high rate of antibiotic use, acute changes in diet, and the stress of critical illness. Probiotics are living microbes of human origin that when ingested in sufficient quantities, can colonize sites such as the oropharynx and GI tract and provide benefits to the host. In recent years, we have increasingly explored the utility of using probiotics to reverse the intestinal dysbiosis associated with critical illness, thereby reducing select ICU complications associated with increased morbidity and mortality. Although these preliminary efforts have demonstrated varying degrees of success, our present studies suffer from a host of limitations that hinder the strength of their conclusions and the generalizability of their results. Probiotic investigations have been further hobbled by current regulatory requirements, which were designed to serve as the framework for pharmaceutical research. Although such measures are intended to ensure patient safety, they inadvertently impose barriers that stifle innovation regarding nutraceuticals. This review strives to summarize the current evidence regarding the efficacy and safety of probiotics in the ICU as well as to provide an overview of the obstacles probiotic researchers face going forward. PMID- 27771303 TI - Dietary Habits and Risk of Kidney Function Decline in an Urban Population. AB - OBJECTIVE: Explore the association between following a Dietary Approaches to Stop Hypertension (DASH)-accordant diet and kidney end points among urban adults. DESIGN: Prospective cohort study. SETTING: Healthy Aging in Neighborhoods of Diversity across the Life Span study. SUBJECTS: A total of 1,534 urban dwelling participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span study with a baseline estimated glomerular filtration rate (eGFR) >=60 mL/minute/1.73 m2. INTERVENTION: DASH diet accordance determined via a score based on nine target nutrients. MAIN OUTCOME MEASURE: Rapid kidney function decline (eGFR decline >3 mL/minute/1.73 m2 per year), incident chronic kidney disease (CKD) (follow-up eGFR <60 mL/minute/1.73 m2), and eGFR decline >25%. RESULTS: Participants' mean age was 48 years, and 59% were African-American. Median DASH score was 1.5 (range, 0-8). Over a median of 5 years, 13.4% experienced rapid eGFR decline, including 15.2% among participants not following a DASH-accordant diet (score <=1) and 12.0% with higher accordance (score >1) (P = .08). Outcomes varied by hypertension status. In multinomial logistic regression models, following adjustment for sociodemographic and clinical factors, including total energy intake, low DASH diet accordance was associated with rapid eGFR decline among participants with hypertension (risk ratio, 1.68; 95% confidence interval: 1.17-2.42) but not among those without hypertension (risk ratio, 0.83; 95% confidence interval: 0.56-1.24; P interaction .001). There was no statistically significant association between DASH diet accordance and incident CKD or eGFR decline >25%. Results were similar when DASH diet accordance was analyzed in tertiles. CONCLUSIONS: Among urban adults, low accordance to a DASH-type diet was not associated with incident CKD, but was associated with higher risk of rapid eGFR decline among those with hypertension, yet not among those without hypertension. Further study of dietary patterns as a potential target for improving kidney outcomes among high-risk populations is warranted. PMID- 27771304 TI - Additional Contribution of the Malnutrition-Inflammation Score to Predict Mortality and Patient-Reported Outcomes as Compared With Its Components in a Cohort of African Descent Hemodialysis Patients. AB - OBJECTIVE: The malnutrition-inflammation score (MIS) combines ten components to assess nutritional status. Higher MIS has been associated with higher mortality and poorer health-related quality of life (HRQOL) in maintenance hemodialysis (MHD) patients. It is interesting to investigate associations of each component with mortality and patient-reported outcomes (PROs), that is, HRQOL and depression symptoms, and if MIS associations are generalizable for diverse populations. This study assessed associations of MIS and its components with mortality and PROs in an African descent MHD population. DESIGN: Prospective cohort for mortality and cross-sectional design for PROs using data of the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO). SUBJECTS: A total of 632 MHD patients (92% black or mixed race) treated in Salvador, Brazil. PREDICTORS: MIS (range: 0-30, higher worse) and each of its ten components (range: 0-4, higher worse). MAIN OUTCOME MEASURES: Mortality, HRQOL using the KDQOL-SF, and depression symptoms using the 20-item Center for Epidemiological Studies Depression Scale. STATISTICAL ANALYSIS: Linear regression for comparing scores and Cox regression for mortality. RESULTS: After extensive adjustments, MIS >=6 was associated with 52% higher mortality (hazard ratio = 1.52; 95% confidence interval = 1.13-2.05), higher depression symptoms, and poorer HRQOL, including physical, mental, and kidney disease-targeted HRQOL measures. Weight change, comorbidity, muscle wasting, and albumin were the MIS components indicating associations between poor nutrition and higher mortality. By contrast, gastrointestinal symptoms and functional capacity were the MIS components denoting detrimental associations of poorer nutritional status with PROs. LIMITATION: Causal conclusions are not possible. CONCLUSIONS: The PROHEMO results indicate that MIS components associated with mortality are not the same associated with PROs. However, the MIS showed consistent associations with mortality and PROs. These results in a population that were not the target of previous investigations, add support for using tools combining nutritional components, such as MIS, to predict outcomes in MHD populations. PMID- 27771305 TI - High-throughput mutation, selection, and phenotype screening of mutant methanogenic archaea. AB - Bacterial and archaeal genomes can contain 30% or more hypothetical genes with no predicted function. Phylogenetically deep-branching microbes, such as methane producing archaea (methanogens), contain up to 50% genes with unknown function. In order to formulate hypotheses about the function of hypothetical gene functions in the strict anaerobe, Methanosarcina acetivorans, we have developed high-throughput anaerobic techniques to UV mutagenize, screen, and select for mutant strains in 96-well plates. Using these approaches we have isolated 10 mutant strains that exhibit a variety of physiological changes including increased or decreased growth rate relative to the parent strain when cells use methanol and/or acetate as carbon and energy sources. This method provides an avenue for the first step in identifying new gene functions: associating a genetic mutation with a reproducible phenotype. Mutations in bona fide methanogenesis genes such as corrinoid methyltransferases and proton translocating F420H2:methanophenazine oxidoreductase (Fpo) were also generated, opening the door to in vivo functional complementation experiments. Irradiation based mutagenesis such as from ultraviolet (UV) light, combined with modern genome sequencing, is a useful procedure to discern systems-level gene function in prokaryote taxa that can be axenically cultured but which may be resistant to chemical mutagens. PMID- 27771306 TI - Overexpression of HMGB1 A-box reduced IL-1beta-induced MMP expression and the production of inflammatory mediators in human chondrocytes. AB - The pro-inflammatory cytokine interleukin-1 beta (IL-1beta) plays a crucial role in the pathogenesis of osteoarthritis (OA) by stimulating several mediators that contribute to cartilage degradation. The aim of this study was to investigate the effects and mechanism of high mobility group box 1 (HMGB1) inhibitors HMGB1 A-box on the expression of matrix metalloproteinase (MMP) and the production of inflammatory mediators in human osteoarthritis chondrocytes after activation by IL-1beta. We found that the overexpression of HMGB1 A-box significantly decreased the IL-1beta-stimulated the production of MMP-1, MMP-3 and MMP-9, and also reduced the elevated levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) associated with the inhibition of prostaglandin E2 (PGE2) and nitric oxide (NO) production in IL-1beta-stimulated chondrocytes. In addition, overexpression of the HMGB1 A-box significantly inhibited the up regulation of ADAMTS-4, ADAMTS-5 and HMGB1 caused by IL-1beta in chondrocytes. Moreover, the overexpression of HMGB1 A-box markedly suppressed the IL-1beta mediated activation of the Toll-like receptor 4 (TRL4)/NF-kappaB pathway. Our observations indicated that the HMGB1 A-box can play a protective role by suppressing the IL-1beta-induced expression of MMPs and that the production of inflammatory mediators in chondrocytes was associated with suppression of the HMGB1/TLR4/NF-kappaB pathway. In conclusion, HMGB1 A-box relieves the development of OA that may be associated with regulating the HMGB1/TLR4/NF-kappaB pathway. PMID- 27771307 TI - Nerve excitability in the rat forelimb: a technique to improve translational utility. AB - BACKGROUND: Nerve excitability testing by threshold-tracking is the only available method to study axonal ion channel function and membrane potential in the clinical setting. The measures are, however, indirect and the interpretation of neuropathic changes remains challenging. The same multiple measures of axonal excitability were adapted to further explore the pathophysiological changes in rodent disease models under pharmacologic and genetic manipulations. These studies are typically limited to the investigation of the "long nerves" such as the tail or the tibial nerves. NEW METHOD: We introduce a novel setup to explore the ulnar nerve excitability in rodents. We provide normative ulnar data in 11 adult female Long Evans rats under anaesthesia by comparison with tibial and caudal nerves. Additionally, these measures were repeated weekly on 3 occasions to determine the repeatability of these tests. RESULTS: Nerve excitability assessment of ulnar nerve proved to be a longitudinally repeatable measure of axonal function mature in rats, as were measures in tibial and caudal nerves. Comparison with existing method: Ulnar nerve motor excitability measures were different from the caudal and tibial excitability measures. Most notably, ulnar nerve showed the largest threshold changes during both depolarizing and hyperpolarizing threshold electrotonus. CONCLUSIONS: Ulnar nerves demonstrate a distinct nerve excitability profile than the caudal and tibial nerves which could have functional and pathological implications. PMID- 27771308 TI - Discharge medication complexity and 30-day heart failure readmissions. AB - BACKGROUND: Limited research exists regarding Medication Regimen Complexity Index (MRCI) and its utility in identifying patients at risk for hospital readmission. OBJECTIVE: This study evaluates the association between discharge MRCI and 30-day rehospitalization in patients with heart failure (HF) after discharge. METHODS: The study involved a retrospective, cohort study at a large tertiary teaching facility from the University HealthSystem Consortium. The consortium database was used to identify HF patients hospitalized from January 2011 to December 2013. A 30-day readmission was defined as being readmitted to the same hospital within 30 days of discharge with a principal discharge diagnosis of HF. Index hospitalizations was defined as the first hospitalization, and readmission was the subsequent hospitalization for HF. A pilot analysis was conducted to compare manual MRCI collection tool and a computerized scoring MRCI system. Multivariable logistic regression was used to examine the association of computerized MRCI (>=15) and 30-day rehospitalization after controlling for other variables. RESULTS: A total of 1,452 patients were included in the study with 81 patients (5.9%) readmitted within 30 days of discharge. The manual and computerized MRCIs were correlated with an R of 0.74 and R2 of 0.55. The multivariate logistic regression analysis found computerized MRCI >=15 (OR: 1.62; 95% CI: 1.01-2.59) was associated with 30-day rehospitalization after controlling for other factors. Patients prescribed angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, were less likely (OR: 0.54; CI: 0.33-0.89) to be readmitted 30 days after discharge, and patients with coronary artery disease were more likely (OR: 1.76; CI: 1.03-3.00) to be readmitted 30 days after discharge. CONCLUSIONS: The computerized MRCI score was moderately correlated with manual MRCI score. A significant association was found between computerized MRCI and 30-day HF readmission. Such predictive tools may allow pharmacists to prioritize patient care and optimize patient outcomes through medication therapy management. PMID- 27771309 TI - Comment on: Assessing national provision of care: variability in bariatric clinical care pathways. PMID- 27771310 TI - Surgical management of obesity in a patient with situs ambiguous. PMID- 27771311 TI - Robotic-assisted revision of gastrojejunostomy for gastrogastric fistula takedown after gastric bypass: a video case report. PMID- 27771312 TI - Long-term outcomes of gastric band removal without additional bariatric surgery. AB - OBJECTIVE: The outcomes of patients undergoing band removal alone without an additional bariatric procedure after laparoscopic gastric banding are not well reported. We seek to close this gap in the literature. SETTING: Cantonal Hospital & University Teaching Hospital, Switzerland METHODS: In this retrospective study, we investigated 21 patients who underwent band removal with a mean follow-up of 63 months. Weight regain, co-morbidities, and quality of life were assessed. RESULTS: The laparoscopic gastric bandings were implanted at a mean initial body mass index (BMI) of 44.6 kg/m2. The bands remained in situ for an average of 87.7 months (range: 14-185 mo). The reasons for band removal included band slippage in 9 cases (42.9%), band penetration in 6 cases (28.6%), leakage, port infection, and patient request in 2 cases (9.5% each). The average BMI at the time of band removal was 34.9 kg/m2. At 62.9 months after band removal, patients regained an average of 17.3 kg and attained a mean BMI of 41.0 kg/m2. Co-morbidities such as type 2 diabetes, arterial hypertension, obstructive sleep apnea, and psychiatric disorders worsened during the follow-up period. Thirteen of 21 patients rated their quality of life as bad, 5 as mediocre, and only 3 as good. Only 2 patients said they would undergo a gastric banding procedure again. The patients achieved an average of-.6 points on the Moorehead-Ardelt quality of life score, which indicates a fair quality of life. CONCLUSION: This study finds that reversal of gastric banding procedures with removal of the banding system alone leads to weight regain, deterioration of physical and psychiatric co-morbidities, and low quality of life scores. PMID- 27771313 TI - Food cravings and food consumption after Roux-en-Y gastric bypass versus cholecystectomy. AB - BACKGROUND: Food cravings and consumption of craved foods after Roux-en-Y gastric bypass (RYGB) are poorly understood. Food cravings after bariatric surgery may explain why some patients fail to change eating behaviors after RYGB, and understanding these cravings may provide better information for nutritional counseling to either enhance weight loss or prevent weight regain. OBJECTIVES: To study cravings in RYGB patients and compare them with cholecystectomy (CC) control patients. SETTING: This study took place in a university hospital. METHODS: RYGB patients (n = 50) and CC control patients (n = 38) completed a validated food craving inventory before surgery and at 2 and 6 weeks postoperatively. In addition, RYGB patients completed the food craving inventory at 12, 24, 36, and 52 weeks postoperatively. A linear mixed-effect model with a first-order autoregressive structure for correlations was used to evaluate changes in food consumption and food cravings between visits. Correlations between food cravings and body mass index (BMI) or weight changes before and after RYGB were assessed with Spearman correlation coefficients. P<.05 was considered statistically significant. RESULTS: After RYGB, food consumption decreased significantly compared with CC control patients and was lowest at 2 weeks. Consumption progressively increased over time in the first year but remained significantly less than that from presurgery. In addition, a higher preoperative BMI was found to correlate moderately with higher preoperative cravings of the total of all 4 food groups studied (r = .3, P = .04); high-fat foods (r = .3, P = .04); and sweets (r = .3, P = .03). However, with the exception of preoperative cravings for high-fat foods, these scores were not predictive of changes in BMI after surgery. Overall, RYGB did not significantly affect food cravings after surgery compared with CC control patients. CONCLUSION: These findings indicate that RYGB may limit food consumption but does not affect the drive to consume certain types of food. Because food cravings are high in patients with obesity before surgery and remain high after surgery, these findings suggest a possible reason for noncompliance with dietary recommendations after RYGB. PMID- 27771314 TI - Acute pain management in morbid obesity - an evidence based clinical update. AB - Increasing numbers of patients with morbid obesity are presenting for surgery and their acute pain management requires an evidence-based clinical update. The objective of this study was to complete a literature review for acute pain management in morbid obesity and provide an evidence-based clinical update with recommendations. Using standardized search terms, in March 2015, we completed a literature search to determine evidence for different acute pain pharmacological modalities in morbid obesity. For each modality the highest level of evidence was ascertained and recommendations for each pharmacological modality are presented. Though overall evidence is limited to few well conducted clinical trials, mostly related to weight loss surgery, multimodal analgesia with step-wise, severity based, opioid-sparing approach appears to improve acute pain management in morbid obesity. The perioperative use of non-opioid adjuvants appears to offer further improvements in patient safety and outcomes. Further research into standardization of pain assessments and implementation of acute pain management protocols is required. PMID- 27771315 TI - Associations between psychological test results and failure to proceed with bariatric surgery. AB - BACKGROUND: The reasons why some patients who begin the presurgical process for bariatric surgery fail to complete the procedure are understudied. Previous research implies that psychological factors play a role. OBJECTIVES: To examine whether scores from baseline psychological testing incrementally predict failure to proceed with bariatric surgery beyond demographic information in patients' medical charts and data derived from a clinical interview. SETTING: Cleveland Clinic Bariatric and Metabolic Institute. METHODS: The sample (n = 1160) was mainly female (72.41%), middle aged (mean age = 46.07 yr, SD = 11.70) and of Caucasian descent (65.76%). Hierarchical logistic regressions were conducted to test the incremental validity of baseline Minnesota Multiphasic Personality Inventory-2 Restructured Form scores after controlling for information gathered from the psychological interview and medical charts. Relative risk ratios were calculated to reflect the clinical utility of the results. RESULTS: In total, 27.16% of patients failed to proceed with bariatric surgery after 1 year or more after a recommendation for surgery from their psychological evaluations. Psychological test scores were substantially associated with failure to proceed with surgery and significantly accounted for up to 6% of additional variance after controlling for psychological interview variables and medical chart data. Elevated scores on Minnesota Multiphasic Personality Inventory-2 Restructured Form scales, such as anxiety and substance use, identify patients at up to 2.5 times greater risk for failing to proceed with bariatric surgery. CONCLUSIONS: Objective psychological test data-notably, scale scores assessing for substance abuse, anxiety, and demoralization-add to information obtained from a clinical interview and medical records in identifying patients at risk for failing to proceed with bariatric surgery. PMID- 27771316 TI - Changes in physical activity after bariatric surgery: using objective and self reported measures. AB - BACKGROUND: Many studies using self-reported physical activity (PA) assessment tools have suggested there is an increase in PA after bariatric surgery. OBJECTIVES: Our aim was to assess PA and sedentary behavior before bariatric surgery and at 6 months after, using subjective and objective tools. SETTING: Bariatric surgery candidates were recruited from a single center. METHODS: Demographic data, medical history, current medications, and anthropometric measurements were recorded. Participants were asked to complete a PA and lifestyle questionnaire and to wear an accelerometer on their nondominant wrist. Data were collected before and at 6 months after surgery. RESULTS: Twenty-two participants were included (17 gastric bypass; 4 sleeve gastrectomy; 1 intragastric balloon). Mean age was 46 years and the majority were female (72%). At a median of 6.3 months follow-up, there were significant reductions in measures of body fatness with a mean reduction of 27 kg in weight. The majority of daytime (12.5+/-1.1 out of 16 h) was spent in sedentary behavior presurgery with little change postsurgery (12.2+/-1.2; P = .186). Objectively measured mean moderate-vigorous PA did not change significantly from pre- to postsurgery (mean 11.5+/-13.9 and 11.6+/-13.1 min/d, respectively; P = .971). Self-reported total nonoccupational PA did not change significantly (P = .390). CONCLUSIONS: The majority of bariatric surgery candidates were physically inactive presurgery, and there was no significant change in either subjectively or objectively measured PA at follow-up. This patient group may benefit from objective PA assessment and interventions aimed at increasing PA. PMID- 27771317 TI - Commentary on "Computational Study of Anatomical Risk Factors in Idealized Models of Type B Aortic Dissection". PMID- 27771319 TI - Commentary on 'Retrievable Inferior Cava Filters in Trauma Patients: Prevalence and Management of Thrombus Within the Filter'. PMID- 27771318 TI - Diagnosis of Aortic Graft Infection: A Case Definition by the Management of Aortic Graft Infection Collaboration (MAGIC). AB - OBJECTIVE/BACKGROUND: The management of aortic graft infection (AGI) is highly complex and in the absence of a universally accepted case definition and evidence based guidelines, clinical approaches and outcomes vary widely. The objective was to define precise criteria for diagnosing AGI. METHODS: A process of expert review and consensus, involving formal collaboration between vascular surgeons, infection specialists, and radiologists from several English National Health Service hospital Trusts with large vascular services (Management of Aortic Graft Infection Collaboration [MAGIC]), produced the definition. RESULTS: Diagnostic criteria from three categories were classified as major or minor. It is proposed that AGI should be suspected if a single major criterion or two or more minor criteria from different categories are present. AGI is diagnosed if there is one major plus any criterion (major or minor) from another category. (i) Clinical/surgical major criteria comprise intraoperative identification of pus around a graft and situations where direct communication between the prosthesis and a nonsterile site exists, including fistulae, exposed grafts in open wounds, and deployment of an endovascular stent-graft into an infected field (e.g., mycotic aneurysm); minor criteria are localized AGI features or fever >=38 degrees C, where AGI is the most likely cause. (ii) Radiological major criteria comprise increasing perigraft gas volume on serial computed tomography (CT) imaging or perigraft gas or fluid (>=7 weeks and >=3 months, respectively) postimplantation; minor criteria include other CT features or evidence from alternative imaging techniques. (iii) Laboratory major criteria comprise isolation of microorganisms from percutaneous aspirates of perigraft fluid, explanted grafts, and other intraoperative specimens; minor criteria are positive blood cultures or elevated inflammatory indices with no alternative source. CONCLUSION: This AGI definition potentially offers a practical and consistent diagnostic standard, essential for comparing clinical management strategies, trial design, and developing evidence-based guidelines. It requires validation that is planned in a multicenter, clinical service database supported by the Vascular Society of Great Britain & Ireland. PMID- 27771320 TI - "No pain, no gain": The experience of women using sterile water injections. AB - PROBLEM/BACKGROUND: Sterile water injections (SWI) are gaining popularity amongst women and midwives for the relief of back pain in labour. However the brief but intense pain associated with the injection has been cited as a deterrent to use and may negatively affect the birth experience. AIM: To explore women's experiences of using sterile water injections as analgesia for back pain in labour. DESIGN: A qualitative study, which generated data through individual semi structured interviews with postnatal women. Data were analysed thematically. SETTING: Two metropolitan maternity units in Queensland, Australia. PARTICIPANTS: Nine postnatal women who had participated in a randomised controlled trial investigating the use of sterile water injections for back pain in labour FINDINGS: Three major themes were identified including sterile water injections as a non-pharmacological injection; balancing injection pain against expectations of pain relief; the analgesic effect of sterile water injections. KEY CONCLUSIONS: Women in this study largely viewed sterile water injections as an effective analgesia with few side effects. The pain associated with the injection of sterile water was weighed against the likelihood of rapid, effective pain relief. Women used the period of analgesia to support their objectives, be this a period of respite during the labour or to enhance the ability to focus on the birth experience. Information on SWI provided by health professionals should also balance realistic descriptions of the injection pain with prospect of analgesia. PMID- 27771321 TI - Australian midwives' experiences of their workplace culture. AB - BACKGROUND: A number of adverse events in Australia and overseas have highlighted the need to examine the workplace culture in the maternity environment. Little attention has been paid to the midwifery workplace culture in Australia. AIM: The study aimed to explore the midwifery workplace culture from the perspective of midwives themselves. METHODS: A qualitative descriptive design was used. Group and individual interviews were undertaken of urban, regional and rural-based midwives in Australia. Data were analysed thematically. FINDINGS: The study showed that both new and experienced midwives felt frustrated by organisational environments and attitudes, and expressed strategies to cope with this. Five themes were identified from the data. These were: Bullying and resilience, Fatigued and powerless midwives, Being 'hampered by the environment', and The importance of support for midwifery. DISCUSSION: The study discusses the themes in depth. In particular, discussion focusses on how midwifery practise was affected by midwives' workplace culture and model of care, and the importance of supportive relationships from peers and managers. CONCLUSION: This study illuminated both positive and negative aspects of the midwifery workplace culture in Australia. One way to ensure the wellbeing and satisfaction of midwives in order to maintain the midwifery workforce and provide quality care to women and their families is to provide positive workplace cultures. PMID- 27771322 TI - Adult atopic dermatitis and the risk of type 2 diabetes. PMID- 27771323 TI - Cross-talk between human mast cells and epithelial cells by IgE-mediated periostin production in eosinophilic nasal polyps. PMID- 27771324 TI - Aspirin-exacerbated respiratory disease: Mediators and mechanisms of a clinical disease. PMID- 27771326 TI - Identification of a TSPY co-expression network associated with DNA hypomethylation and tumor gene expression in somatic cancers. AB - Testis specific protein Y-encoded (TSPY) is a Y-located proto-oncogene predominantly expressed in normal male germ cells and various types of germ cell tumor. Significantly, TSPY is frequently expressed in somatic cancers including liver cancer but not in adjacent normal tissues, suggesting that ectopic TSPY expression could be associated with oncogenesis in non-germ cell cancers. Various studies demonstrated that TSPY expression promotes growth and proliferation in cancer cells; however, its relationship to other oncogenic events in TSPY positive cancers remains unknown. The present study seeks to correlate TSPY expression with other molecular features in clinical cancer samples, by analyses of RNA-seq transcriptome and DNA methylation data in the Cancer Genome Atlas (TCGA) database. A total of 53 genes, including oncogenic lineage protein 28 homolog B (LIN28B) gene and RNA-binding motif protein Y-linked (RBMY) gene, are identified to be consistently co-expressed with TSPY, and have been collectively designated as the TSPY co-expression network (TCN). TCN genes were simultaneously activated in subsets of liver hepatocellular carcinoma (30%) and lung adenocarcinoma (10%) regardless of pathological stage, but only minimally in other cancer types. Further analysis revealed that the DNA methylation level was globally lower in the TCN-active than TCN-silent cancers. The specific expression and methylation patterns of TCN genes suggest that they could be useful as biomarkers for the diagnosis, prognosis and clinical management of cancers, especially those for liver and lung cancers, associated with TSPY co-expression network genes. PMID- 27771325 TI - Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts. AB - BACKGROUND: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. OBJECTIVE: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). METHODS: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. RESULTS: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. CONCLUSIONS: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. PMID- 27771328 TI - Holocrine Secretion of Sebum Is a Unique DNase2-Dependent Mode of Programmed Cell Death. AB - Sebaceous glands produce sebum via holocrine secretion, a largely uncharacterized mode of programmed cell death that contributes to the homeostasis and barrier function of the skin. To determine the mechanism of DNA degradation during sebocyte cell death, we have inactivated candidate DNA-degrading enzymes by targeted gene deletions in mice. DNase1 and DNase1-like 2 were dispensable for nuclear DNA degradation in sebocytes. By contrast, epithelial cell-specific deletion of lysosomal DNase2 blocked DNA degradation in these cells. DNA breakdown during sebocyte differentiation coincided with the loss of LAMP1 and was accelerated by the abrogation of autophagy, the central cellular program of lysosome-dependent catabolism. Suppression of DNA degradation by the deletion of DNase2 resulted in aberrantly increased concentrations of residual DNA and decreased amounts of the DNA metabolite uric acid in secreted sebum. These results define holocrine secretion as a DNase2-mediated form of programmed cell death and suggest that autophagy-dependent metabolism, DNA degradation, and the molecular composition of sebum are mechanistically linked. PMID- 27771329 TI - TLN-58, an Additional hCAP18 Processing Form, Found in the Lesion Vesicle of Palmoplantar Pustulosis in the Skin. AB - We previously reported that the early vesicle of the palmoplantar pustulosis (PPP) vesicle originated from eccrine sweat in the acrosyringium and that the PPP vesicle contains the antimicrobial peptide human cathelicidin-18/LL-37. The concentration of LL-37 was sufficient to induce the subsequent inflammation in lesions and human keratinocytes, and the PPP vesicles contained additional small fragments of human cathelicidin-18, of approximately 7 kDa, which have not been identified. The aim of the present study was to clarify the additional processed forms found in PPP vesicles and their physiological effects on normal keratinocytes and sweat gland cells. Lesional PPP vesicles were collected from PPP patients, and endogenous human cathelicidin-18/LL-37 was depleted using a LL 37 antibody affinity column. A designed recombinant human cathelicidin-18 peptide was prepared and incubated with the depleted PPP vesicle fluid to confirm the additional processed form. In-gel digestion analysis and protein sequencing confirmed the additional form as TLN-58. TLN-58 up-regulated IL-17C, IL-8, IL-23, IL-1alpha, and IL-1beta mRNA and protein expression in normal human keratinocytes and also showed antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, and group A Streptococcus species, similar to LL-37. This additional form could be involved in the continued inflammation in PPP lesions. PMID- 27771330 TI - Influence of initial fixation position in scene viewing. AB - During scene perception our eyes generate complex sequences of fixations. Predictors of fixation locations are bottom-up factors such as luminance contrast, top-down factors like viewing instruction, and systematic biases, e.g., the tendency to place fixations near the center of an image. However, comparatively little is known about the dynamics of scanpaths after experimental manipulation of specific fixation locations. Here we investigate the influence of initial fixation position on subsequent eye-movement behavior on an image. We presented 64 colored photographs to participants who started their scanpaths from one of two experimentally controlled positions in the right or left part of an image. Additionally, we used computational models to predict the images' fixation locations and classified them as balanced images or images with high conspicuity on either the left or right side of a picture. The manipulation of the starting position influenced viewing behavior for several seconds and produced a tendency to overshoot to the image side opposite to the starting position. Possible mechanisms for the generation of this overshoot were investigated using numerical simulations of statistical and dynamical models. Our model comparisons show that inhibitory tagging is a viable mechanism for dynamical planning of scanpaths. PMID- 27771331 TI - Dynamic disorder can explain non-exponential kinetics of fast protein mechanical unfolding. AB - Protein unfolding often does not obey a simple two-state behavior. Previous single molecule force spectroscopy studies demonstrated stretched exponential kinetics of protein unfolding under a constant pulling force, the molecular origin of which remains subject to debate. We here set out to extensively sample the mechanical unfolding of ubiquitin and NuG2 by Molecular Dynamics (MD) simulations. Both proteins show kinetics best fit by stretched exponentials, with stretching exponents similar to those found in experiments, even though static disorder is absent in our short MD simulations. Instead, we can ascribe non exponential kinetics to dynamic disorder, due to conformational fluctuations on the nanosecond timescale. Our study highlights the general role of dynamic disorder in protein kinetics on a broad range of time scales even including those probed in MD simulations. PMID- 27771333 TI - Ixodid ticks in the megapolis of Kyiv, Ukraine. AB - The Ixodidae include the most common tick species encountered in Europe. The ticks transmit a variety of bacterial and protozoan agents of medical and veterinary significance. The aim of the current work was to investigate distribution of Ixodes ricinus and Dermacentor reticulatus ticks in Kyiv, the largest and most densely populated megapolis of Ukraine. Ticks were collected at various recreational areas by flagging during May, the month that showed the highest tick abundance in the past. Sex distribution among I. ricinus ticks was relatively equal, whereas females were collected in higher numbers for D. reticulatus. As opposed to western and central Europe where nymphal ticks had been more abundant, the nymph:adult ratio for I. ricinus was reversed. Also, this report documents detection of Rhipicephalus sanguineus sensu lato (s.l.) in Kyiv region, well outside of its historically documented distribution area. Previously thought to be restricted to the southern Ukraine, a single male specimen of R. sanguineus s.l. was collected just outside the city limits. Data on tick diversity over the past 30 years, however, indicates that this finding may only be incidental. PMID- 27771334 TI - Exposure and preventive behaviours toward ticks and Lyme disease in Canada: Results from a first national survey. AB - Lyme disease (LD) risk is increasing in Canada. In 2014, the government of Canada launched a national communication campaign to raise awareness and promote the adoption of individual preventive behaviours toward ticks and LD. The objectives of this study were to evaluate and compare the adoption of LD preventive behaviours and the exposure to tick bites of Canadians in the five main targeted regions (British Columbia, Prairie provinces, Ontario, Quebec and the Atlantic provinces). A national survey was conducted in December 2014 (n=2876) to collect data on LD awareness, behaviours and risk factors. Overall, the proportion of respondents reporting tick exposure was high (20%). The results suggest that even though LD awareness was found to be high (with only 12% of the respondents reporting that they never heard about LD), less than half of the Canadians who heard about it have adopted specific preventive behaviours toward tick bites, such as regular tick checks (reported by 52%), protective clothing (50%), using tick repellent (41%) or shower or bath (41%) after visiting a wooded area in a LD risk area. Moreover, significant differences were found between regions, gender, age groups and dog ownership status, regarding preventive behaviours and factors of exposure. A high level of knowledge of Lyme disease, living in the Prairie region, as well as having found a tick on oneself or a relative, were found to be associated with the adoption of preventive behaviours. This study underlines the importance to take into account specific regional characteristics of risk and to maintain public health communication efforts through time in order to increase the adoption of preventive behaviours of Canadians. PMID- 27771332 TI - Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases. AB - Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid levels. Although LPL expression and activity modulation is observed as a pleiotropic action of some the commonly used lipid lowering drugs, the deliberate development of drugs targeting LPL has not occurred yet. In this review, we present the biology of LPL, highlight the LPL modulation property of currently used drugs and review the novel emerging approaches to target LPL. PMID- 27771335 TI - Response letter to the Editor: In reference to the recent Letter to the Editor by Caneiro et al., 2016, regarding 'Low back pain misdiagnosis or missed diagnosis: Core principles'. PMID- 27771336 TI - The predictive value of plasma catestatin for all-cause and cardiac deaths in chronic heart failure patients. AB - Catestatin (CST) is a proteolytic fragment of Chromogranin A with a broad spectrum of activities in the cardiovascular system. The level of plasma CST increases in chronic heart failure patients, but its potential relationship to patient prognosis is unknown. In this study, we measured plasma CST levels in 202 chronic heart failure patients and followed them for a median of 52.5 months. The plasma CST level was higher in patients with all-cause death and cardiac death than in survivors. According to univariate COX regression, higher plasma CST levels predicted increased risk of all-cause and cardiac death. After adjustment for other confounding factors, plasma CST was an independent risk factor for both outcomes, and the hazard ratios (HRs) were 1.84 (95% CI: 1.02-3.32, p=0.042) and 2.41 (95% CI: 1.26-4.62, p=0.008) for all-cause death and cardiac death, respectively. The new risk-predictive model considering CST was superior to the previous model for both outcomes by ANOVA and likelihood ratio tests (p=0.040 and p=0.008, respectively). Concurrent increases in plasma BNP (B-type natriuretic peptide) and CST levels predicted the highest risk for both all-cause and cardiac deaths [HR=5.18 (95% CI: 1.94-13.87, p=0.001) and HR=9.19 (95% CI: 2.75-30.78, p<0.001), respectively]. Large-scale studies are needed to further assess the value of plasma CST in predicting heart failure prognosis. PMID- 27771337 TI - Changing of the Guard. PMID- 27771338 TI - Tools for Assessment of Communication Skills of Hospital Action Teams: A Systematic Review. AB - BACKGROUND: Hospital action teams comprise interdisciplinary health care providers working simultaneously to treat critically ill patients. Assessments designed to evaluate communication effectiveness or "nontechnical" performance of these teams are essential to minimize medical errors and improve team productivity. Although multiple communication tools are available, the characteristics and psychometric validity of these instruments have yet to be systematically compared. OBJECTIVE: To identify assessments used to evaluate the communication or "nontechnical" performance of hospital action teams and summarize evidence to develop and validate these instruments. METHOD: A literature search was conducted using MEDLINE/PubMed database to identify original articles related to assessment of communication skills in teams working in acute care medicine not exclusive to emergency room, operating room, prehospital air and ground transport, or code blue/rapid response resuscitations. RESULTS: Ten communication assessment tools were identified. Six tools (60%) were designed to measure communication performance of the whole team, whereas 4 tools (40%) were created to assess individual team member's communication skills. Regardless of the type of analysis, the most commonly assessed behavior domains were Leadership, Teamwork, Communication, and Situation awareness. Only 1 of 16 articles describing a particular communication assessment tool reported all the validation criteria, other authors underreported efforts to validate their instruments. CONCLUSION: A number of tools designed to measure the communication or "nontechnical" performance of hospital action teams are available. Unfortunately, limited reported validity evidence may hamper the utility of these tools in actual clinical practice until further validation studies are performed. PMID- 27771327 TI - In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease. AB - In vivo confocal microscopy (IVCM) is becoming an indispensable tool for studying corneal physiology and disease. Enabling the dissection of corneal architecture at a cellular level, this technique offers fast and noninvasive in vivo imaging of the cornea with images comparable to those of ex vivo histochemical techniques. Corneal nerves bear substantial relevance to clinicians and scientists alike, given their pivotal roles in regulation of corneal sensation, maintenance of epithelial integrity, as well as proliferation and promotion of wound healing. Thus, IVCM offers a unique method to study corneal nerve alterations in a myriad of conditions, such as ocular and systemic diseases and following corneal surgery, without altering the tissue microenvironment. Of particular interest has been the correlation of corneal subbasal nerves to their function, which has been studied in normal eyes, contact lens wearers, and patients with keratoconus, infectious keratitis, corneal dystrophies, and neurotrophic keratopathy. Longitudinal studies have applied IVCM to investigate the effects of corneal surgery on nerves, demonstrating their regenerative capacity. IVCM is increasingly important in the diagnosis and management of systemic conditions such as peripheral diabetic neuropathy and, more recently, in ocular diseases. In this review, we outline the principles and applications of IVCM in the study of corneal nerves in various ocular and systemic diseases. PMID- 27771339 TI - The Value of Clinical Practice in Cadaveric Dissection: Lessons Learned From a Course in Eye and Orbital Anatomy. AB - OBJECTIVE: To test the hypothesis that there is greater benefit in a dissection based anatomy course among those participants with clinical experience in the relevant field, and those without. DESIGN: A retrospective comparative study. SETTING: Brighton and Sussex Medical School Anatomy Department: an educational facility that provides undergraduate and postgraduate anatomy teaching using cadaveric specimens. PARTICIPANTS: All attendees (n = 40) to a postgraduate course in eye and orbital anatomy completed course evaluation forms. The course has been attended by delegates from around the country, with experience ranging from that of final year medical students to clinical fellows who have completed their specialist training in ophthalmology. RESULTS: Those participants who were practicing ophthalmology tended to be older than those who were not, with a greater amount of time spent on prior learning. Participants scored both the prosection-led and dissection-led sessions highly, with a mean combined evaluation of 8.9 (out of 10) for dissection-led learning and 9.2 for prosection led learning. Prosection-led learning was regarded equally by those participants currently practicing in ophthalmology, and those who are not. In contrast, dissection-led learning was scored higher by those participants who were practicing ophthalmology (9.4), when compared with those not in ophthalmic practice (8.5; p = 0.018). CONCLUSIONS: The present study supports the hypothesis that the benefits of cadaveric dissection could be maximized during postgraduate surgical training. This has important implications given the trend away from cadaveric dissection in the undergraduate curriculum. PMID- 27771340 TI - Apoptotic forces in tissue morphogenesis. AB - It is now well established that apoptosis is induced in response to mechanical strain. Indeed, increasing compressive forces induces apoptosis in confined spheroids of tumour cells, whereas releasing stress reduces apoptosis in spheroids cultivated in free suspension (Cheng et al., 2009). Apoptosis can also be induced by applying a 100 to 250MPa pressure, as shown in different cultured cells (for review, see (Frey et al., 2008)). During epithelium development, the pressure caused by a fast-growing clone can trigger apoptosis at the vicinity of the clone, mediating mechanical cell competition (Levayer et al., 2016). While the effect of strain has long been known for its role in apoptosis induction, the reciprocal mechanism has only recently been highlighted. First demonstrated at the cellular level, the effect of an apoptotic cell on its direct neighbours has been analysed in different kinds of monolayer epithelium (Gu et al., 2011; Rosenblatt et al., 2001; Kuipers et al., 2014; Lubkov & Bar-Sagi, 2014). More recently, the concept of a broader impact of apoptotic cell behaviours on tissue mechanical strain has emerged from the characterisation of tissue remodelling during Drosophila development (Toyama et al., 2008; Monier et al., 2015). In the present review, we summarize our current knowledge on the mechanical impact of apoptosis during tissue remodelling. PMID- 27771341 TI - Identification and characteristic of three members of the C1q/TNF-related proteins (CTRPs) superfamily in Eudontomyzon morii. AB - C1q is the target recognition protein of the classical complement pathway and a major connecting link between innate and acquired immunity. C1q and the multifunctional tumor necrosis factor (TNF) ligand family is of similar crystal structures, are designated the C1q/TNF-related proteins (CTRPs) superfamily. They are involved in processes as diverse as host defense, inflammation, apoptosis, autoimmunity, cell differentiation, organogenesis, hibernation and insulinresistant obesity. In this study, three members of the CTRPs superfamily were isolated and characterized in Yalu River lampreys (Eudontomyzon morii), and are respectively named LaC1qC, LaCTRP1, LaCTRP9. The full-length cDNAs of C1qC like (LaC1qAL), CTRP1-like (LaCTRP1), and CTRP9-like (LaCTRP9) consist of 723, 762 and 825 bp of nucleotide sequence encoding polypeptides of 241, 254 and 275 amino acids, respectively. All-three proteins share three common domains: a signal peptide at the N terminus, a collagenous domain (characteristic Gly-X-Y repeats), and a C-terminal globular domain. In addition, the higher expression level of the three proteins in heart by RT-PCR and real-time PCR tissue profiling implied that they might involve in immune response or injury repair of the heart in lamprey. PMID- 27771342 TI - The need for transparency and reproducibility in documenting values for regulatory decision making and evaluating causality: The example of formaldehyde. AB - Reproducibility and transparency in scientific reporting is paramount to advancing science and providing the foundation required for sound regulation. Recent examples demonstrate that pivotal scientific findings cannot be replicated, due to poor documentation or methodological bias, sparking debate across scientific and regulatory communities. However, there is general agreement that improvements in communicating and documenting research and risk assessment methods are needed. In the case of formaldehyde, the peer-review conducted by a National Academy of Sciences (NAS) Committee questioned the approaches used by the Integrated Risk Information System (IRIS) in developing draft unit risk values. Using the original data from the key study (Beane Freeman et al., 2009) and documentation provided in the draft IRIS profile, we attempted to duplicate the reported inhalation unit risk values and address the NAS Committee's questions regarding application of the appropriate dose-response model. Overall, documentation of the methods lacked sufficient detail to allow for replication of the unit risk estimates, specifically for Hodgkin lymphoma and leukemias, the key systemic endpoints selected by IRIS. The lack of apparent exposure-response relationships for selected endpoints raises the question whether quantitative analyses are appropriate for these endpoints, and if so, how results are to be interpreted. PMID- 27771343 TI - Re-engineering laboratory diagnostics for preventing preanalytical errors. PMID- 27771344 TI - Comparison of predictive equations of resting energy expenditure in older adults with chronic obstructive pulmonary disease. PMID- 27771345 TI - The association between vitamin D receptor polymorphisms and serum 25 hydroxyvitamin D levels with ulcerative colitis in Chinese Han population. AB - There is now growing evidence suggesting that Vitamin D is playing a critical role in modulating the innate and adaptive immune responses. Several polymorphisms have been identified in the vitamin D receptor (VDR) gene but their association with ulcerative colitis (UC) susceptibility remained controversy. In the current study, we examined the association between VDR polymorphisms and serum level of 25-hydroxyvitamin D [25(OH)D] with UC in Chinese Han population. Polymorphisms of FokI (rs2228570)/BsmI (rs1544410)/ApaI (rs7975232)/TaqI (rs731236) in the VDR gene were assessed in a case-control study comprising 404 UC patients and 612 controls. Moreover, 25(OH)D levels were measured by electro chemiluminescence immunoassay in 75 UC patients and 120 controls. Our results suggested that BsmI polymorphism frequency was significantly lower in UC patients (P=0.028), and the frequency of AAC haplotype formed by BsmI, ApaI and TaqI was also significantly lower in UC patients (P=0.012). Moreover, FokI polymorphism was more frequently observed in patients with mild and moderate UC as compared to those with severe UC (P=0.001, P<0.001, respectively). Average 25(OH)D level was lower in UC patients than in controls (19.3+/-6.8 vs. 21.8+/-7.3ng/mL, P=0.017), and was significantly correlated with hemoglobin (beta=0.49, P<0.001), C-reactive protein (beta=-0.36, P<0.001), severity of UC (beta=-0.21, P=0.025) and FokI polymorphism (beta=-0.20, P=0.031) in UC patients. Interestingly, there was a significant correlation between FokI polymorphism and vitamin D deficiency (<20ng/mL) in UC patients (P=0.006). Together, these results supported that VDR polymorphisms and 25(OH)D level were significantly correlated with UC risk and severity in Chinese Han population. PMID- 27771346 TI - Commonality of neural representations of sentences across languages: Predicting brain activation during Portuguese sentence comprehension using an English-based model of brain function. AB - The aim of the study was to test the cross-language generative capability of a model that predicts neural activation patterns evoked by sentence reading, based on a semantic characterization of the sentence. In a previous study on English monolingual speakers (Wang et al., submitted), a computational model performed a mapping from a set of 42 concept-level semantic features (Neurally Plausible Semantic Features, NPSFs) as well as 6 thematic role markers to neural activation patterns (assessed with fMRI), to predict activation levels in a network of brain locations. The model used two types of information gained from the English-based fMRI data to predict the activation for individual sentences in Portuguese. First, it used the mapping weights from NPSFs to voxel activation levels derived from the model for English reading. Second, the brain locations for which the activation levels were predicted were derived from a factor analysis of the brain activation patterns during English reading. These meta-language locations were defined by the clusters of voxels with high loadings on each of the four main dimensions (factors), namely people, places, actions and feelings, underlying the neural representations of the stimulus sentences. This cross-language model succeeded in predicting the brain activation patterns associated with the reading of 60 individual Portuguese sentences that were entirely new to the model, attaining accuracies reliably above chance level. The prediction accuracy was not affected by whether the Portuguese speaker was monolingual or Portuguese-English bilingual. The model's confusion errors indicated an accurate capture of the events or states described in the sentence at a conceptual level. Overall, the cross-language predictive capability of the model demonstrates the neural commonality between speakers of different languages in the representations of everyday events and states, and provides an initial characterization of the common meta-language neural basis. PMID- 27771347 TI - Analysing concurrent transcranial magnetic stimulation and electroencephalographic data: A review and introduction to the open-source TESA software. AB - The concurrent use of transcranial magnetic stimulation with electroencephalography (TMS-EEG) is growing in popularity as a method for assessing various cortical properties such as excitability, oscillations and connectivity. However, this combination of methods is technically challenging, resulting in artifacts both during recording and following typical EEG analysis methods, which can distort the underlying neural signal. In this article, we review the causes of artifacts in EEG recordings resulting from TMS, as well as artifacts introduced during analysis (e.g. as the result of filtering over high frequency, large amplitude artifacts). We then discuss methods for removing artifacts, and ways of designing pipelines to minimise analysis-related artifacts. Finally, we introduce the TMS-EEG signal analyser (TESA), an open source extension for EEGLAB, which includes functions that are specific for TMS EEG analysis, such as removing and interpolating the TMS pulse artifact, removing and minimising TMS-evoked muscle activity, and analysing TMS-evoked potentials. The aims of TESA are to provide users with easy access to current TMS-EEG analysis methods and to encourage direct comparisons of these methods and pipelines. It is hoped that providing open-source functions will aid in both improving and standardising analysis across the field of TMS-EEG research. PMID- 27771348 TI - Coordinative task difficulty and behavioural errors are associated with increased long-range beta band synchronization. AB - The neural network and the task-dependence of (local) activity changes involved in bimanual coordination are well documented. However, much less is known about the functional connectivity within this neural network and its modulation according to manipulations of task complexity. Here, we assessed neural activity via high-density electroencephalography, focussing on changes of activity in the beta frequency band (~15-30Hz) across the motor network in 26 young adult participants (19-29 years old). We investigated how network connectivity was modulated with task difficulty and errors of performance during a bimanual visuomotor movement consisting of dial rotation according to three different ratios of speed: an isofrequency movement (1:1), a non-isofrequency movement with the right hand keeping the fast pace (1:3), and the converse ratio with the left hand keeping the fast pace (3:1). To quantify functional coupling, we determined neural synchronization which might be key for the timing of the activity within brain regions during task execution. Individual source activity with realistic head models was reconstructed at seven regions of interest including frontal and parietal areas, among which we estimated phase-based connectivity. Partial least squares analysis revealed a significant modulation of connectivity with task difficulty, and significant correlations between connectivity and errors in performance, in particular between sensorimotor cortices. Our findings suggest that modulation of long-range synchronization is instrumental for coping with increasing task demands in bimanual coordination. PMID- 27771349 TI - Standardization: Recent achievements of the IFCC Scientific Division. PMID- 27771350 TI - Synaptotagmin 7 and SYNCRIP proteins are ubiquitously expressed in the rat brain and co-localize in Purkinje neurons. AB - Synaptotagmin 7 (SYT7) is ubiquitously expressed calcium sensor, involved in neuronal membrane trafficking. Immunoprecipitation experiments demonstrated that SYT7 interacts with Synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP). SYNCRIP is a component of mRNA granules, which are transported to dendrites and are prerequisite for synaptic plasticity. Given the potential significance of SYT7 regulation in processes of neurodegeneration, which are characterized by high level of synaptic vulnerability, we aimed to analyse and compare the distribution of SYT7 and SYNCRIP proteins in the adult rat striatum, hippocampus, cerebral and cerebellar cortex. We investigated the degree of SYT7 SYNCRIP co-localization in order to examine possible functional interaction of these two proteins. We found that SYT7 is abundantly distributed in neuropil of all examined anatomical areas of the brain, most prominently in axons. On the contrary, SYNCRIP had cytoplasmic somatodendritic pattern of expression, which was most prominent in the hippocampus and cerebellum. In the striatum, hippocampus and cerebral cortex SYT7 and SYNCRIP immunofluorescent signals were mutually excluded, thus diminishing the probability for their physiological interaction. In somata of Purkinje neurons in the cerebellar cortex, both SYT7 and SYNCRIP were expressed and partially co-localized suggesting possible functional connection between SYT7 and SYNCRIP proteins in Purkinje neurons. PMID- 27771351 TI - The ontogenetic development of neurons containing calcium-binding proteins in the septum of the guinea pig: Late onset of parvalbumin immunoreactivity versus calbindin and calretinin. AB - The study describes the immunoreactivity of calbindin (CB), calretinin (CR) and parvalbumin (PV), their distribution pattern and the co-distribution of CB and CR as well as CB and PV in the septum of the guinea pig during development. Immunohistochemistry was conducted on embryonic (E40, E50, E60), newborn (P0) and postnatal (P5, P10, P20, P40, P100) guinea pig brains. The presence of both CB and CR was detected at E40, while PV began to be observed at E60. Immunoreactivity for CB was constant throughout ontogeny. In contrast to CR immunoreactivity, PV immunoreactivity was higher in the postnatal stages than in the prenatal and newborn stages. Double immunostaining showed that CB co localized with CR from E40 onwards, while with PV from P5 onwards, suggesting that CB co-operates with these proteins in the guinea pig septum during different periods of ontogeny. Our results also indicate that among the studied CaBPs, CB exhibited the highest immunoreactivity during both embryonic and postnatal development. PMID- 27771352 TI - Functional alterations of the dopaminergic and glutamatergic systems in spontaneous alpha-synuclein overexpressing rats. AB - The presence of alpha-synuclein (alpha-syn) in Lewy bodies and Lewy neurites is an important characteristic of the neurodegenerative processes of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons in Parkinson's disease (PD) and other synucleinopathies. Here we report that Berlin-Druckrey rats carrying a spontaneous mutation in the 3' untranslated region of alpha-syn mRNA (m/m rats) display a marked accumulation of alpha-syn in the mesencephalic area, striatum and frontal cortex, accompanied to severe dysfunctions in the dorsolateral striatum. Despite a small reduction in the number of SNpc and ventral tegmental area DAergic cells, the surviving dopaminergic neurons of the m/m rats do not show clear-cut alterations of the spontaneous and evoked firing activity, DA responses and somatic amphetamine-induced firing inhibition. Interestingly, mutant DAergic neurons display diminished whole-cell Ih conductance and a reduced frequency of spontaneous excitatory synaptic currents. By contrast, m/m rats show a severe impairment of DA and glutamate release in the dorsolateral striatum, as revealed by amperometric measure of DA currents and by electrophysiological recordings of glutamatergic synaptic events in striatal medium spiny neurons. These functional impairments are paralleled by a decreased expression of the DA transporter and VGluT1 proteins in the same area. Thus, together with alpha-syn overload in the mesencephalic region, striatum and frontal cortex, the main functional alterations occur in the DAergic and glutamatergic terminals in the dorsal striatum of the m/m rats. PMID- 27771353 TI - G-CSF treatment promotes apoptosis of autoreactive T cells to restrict the inflammatory cascade and accelerate recovery in experimental allergic encephalomyelitis. AB - G-CSF is a hematopoietic growth factor that regulates the proliferation, differentiation and survival of myeloid lineage cells, which has protective effects in autoimmune neuroinflammatory diseases such as EAE. Here we use EAE model treated by G-CSF to address the hypothesis that G-CSF inhibits the proliferative response of splenic T cells via the enhancement of apoptosis, and this priming effect of G-CSF depends on the cell cycle. Our results show that G CSF administration reduced EAE frequency and severity of attacks. The inflammatory cells and demyelination areas were decreased in the CNS of G-CSF treated mice. G-CSF treatment altered cytokine profiles in vivo to inhibit the productions of IFN-gamma, IL-1beta, IL-2, TNF-alpha, IL-17 and NO, while the secretions of IL-4 and IL-10 were increased. Splenic T cells from G-CSF-treated mice showed significantly lower proliferative response to specific antigen MOG35 55 stimulation. G-CSF enhanced the percentage of a CD4+CD25+ T cell subset in spleen T cells. Moreover, G-CSF promoted the G0/G1 to S phase transition of MOG35 55 autoreactive T cells inducing apoptosis and elevating Bax gene expression of apoptosis marker. These findings indicate that G-CSF treatment induces the apoptosis of MOG35-55 autoreactive T cells, which decreases the production of pro inflammatory cytokines and NO, suppresses the proliferation of autoreactive T cells and elevates a CD4+CD25+ T cell subset to inhibit inflammatory infiltration and demyelination within CNS of EAE. The conclusions of G-CSF treatment in EAE mice suggest that G-CSF is clinically applicable and may be considered for future use in therapeutic measures for multiple sclerosis treatment. PMID- 27771354 TI - Paradoxical lower sensitivity of Locus Coeruleus than Substantia Nigra pars compacta neurons to acute actions of rotenone. AB - Parkinson's disease (PD) is not only associated with degeneration of dopaminergic (DAergic) neurons in the Substantia Nigra, but also with profound loss of noradrenergic neurons in the Locus Coeruleus (LC). Remarkably, LC degeneration may exceed, or even precede the loss of nigral DAergic neurons, suggesting that LC neurons may be more susceptible to damage by various insults. Using a combination of electrophysiology, fluorescence imaging and electrochemistry, we directly compared the responses of LC, nigral DAergic and nigral non-dopaminergic (non-DAergic) neurons in rat brain slices to acute application of rotenone, a mitochondrial toxin used to create animal and in vitro models of PD. Rotenone (0.01-5.0MUM) dose-dependently inhibited the firing of all three groups of neurons, primarily by activating KATP channels. The toxin also depolarised mitochondrial potential (Psim) and released reactive oxygen species (H2O2). When KATP channels were blocked, rotenone (1MUM) increased the firing of LC neurons by activating an inward current associated with dose-dependent increase of cytosolic free Ca2+ ([Ca2+]i). This effect was attenuated by blocking oxidative stress sensitive TRPM2 channels, and by pre-treatment of slices with anti-oxidants. These results demonstrate that rotenone inhibits the activity of LC neurons mainly by activating KATP channels, and increases [Ca2+]ivia TRPM2 channels. Since the responses of LC neurons were smaller than those of nigral DAergic neurons, our study shows that LC neurons are paradoxically less sensitive to acute effects of this parkinsonian toxin. PMID- 27771356 TI - Latin American Clinical Epidemiology Network Series - Paper 6: The influence of alcohol in traffic accidents and health care costs of it in Bogota-Colombia. AB - OBJECTIVES: In Colombia, some studies have estimated medical costs associated to traffic accidents. It is required to assess results by city or region and determine the influence of variables such as alcohol consumption. The main objective of this study was to identify health care costs associated to traffic accidents in Bogota and determine whether alcohol consumption can increase them. STUDY DESIGN AND SETTING: Cross-sectional costs study conducted in patients over 18 years treated in the emergency rooms of six different hospitals in Bogota, Colombia. RESULTS: The average total cost of medical care per patient was 628 USD, in Bogota-Colombia. The average cost per accident was estimated at 1,349 USD. On average, the total cost for health care for patients with positive blood alcohol level was 1.8 times higher than those who did not consume alcohol. The indirect costs were on average 115.3 USD per injured person. Numbers are expressed in 2011 U.S. dollars. CONCLUSION: Alcohol consumption increases the risk of traffic accidents and direct medical health costs. PMID- 27771355 TI - Ovarian aging and the activation of the primordial follicle reserve in the long lived Ames dwarf and the short-lived bGH transgenic mice. AB - The aim of this study was to evaluate the effect of growth hormone (GH) in the maintenance of the ovarian primordial follicle reserve. Ovaries from 16 mo old GH deficient Ames Dwarf (df/df) and Normal (N/df) mice were used. A subgroup of df/df and N mice received GH or saline injections for six weeks starting at 14 mo of age. In addition, ovaries from 12 mo old mice overexpressing bovine GH (bGH) and controls were used. df/df mice had higher number of primordial and total follicles than N/df mice (p < 0.05), while GH treatment decreased follicle counts in both genotypes (p < 0.05). In addition, bGH mice had lower number of primordial and total follicles than the controls (p < 0.05). pFoxO3a levels were higher in mice treated with GH and in bGH mice (p < 0.05) when comparing with age match controls. These results indicate that increased circulating GH is associated with a reduced ovarian primordial follicle reserve and increased pFoxO3a content in oocytes. PMID- 27771357 TI - A pseudo-random patient sampling method evaluated. AB - OBJECTIVES: To compare two human immunodeficiency virus (HIV) cohorts to determine whether a pseudo-random sample can represent the entire study population. STUDY DESIGN AND SETTING: HIV-positive patients receiving care at eight sites in seven Asian countries. The TREAT Asia HIV Observational database (TAHOD) pseudo-randomly selected a patient sample, while TREAT Asia HIV Observational database-Low Intensity Transfer (TAHOD-LITE) included all patients. We compared patient demographics, CD4 count, and HIV viral load testing for each cohort. Risk factors associated with CD4 count response, HIV viral load suppression (<400 copies/mL), and survival were determined for each cohort. RESULTS: There were 2,318 TAHOD patients and 14,714 TAHOD-LITE patients. Patient demographics, CD4 count, and HIV viral load testing rates were broadly similar between the cohorts. CD4 count response and all-cause mortality were consistent among the cohorts with similar risk factors. HIV viral load response appeared to be superior in TAHOD and many risk factors differed, possibly due to viral load being tested on a subset of patients. CONCLUSION: Our study gives the first empirical evidence that analysis of risk factors for completely ascertained end points from our pseudo-randomly selected patient sample may be generalized to our larger, complete population of HIV-positive patients. However, results can significantly vary when analyzing smaller or pseudo-random samples, particularly if some patient data are not completely missing at random, such as viral load results. PMID- 27771358 TI - Latin American Clinical Epidemiology Network Series - Paper 5: Years of life lost due to premature death in traffic accidents in Bogota, Colombia. AB - OBJECTIVE: This study aimed to quantify the number of years of life lost in traffic accidents in Bogota, Colombia. STUDY DESIGN AND SETTING: The years of life lost were calculated using the 'age-standardized expected years of life lost' method, the table of Japanese adjusted life expectancy and the database of the Institute of Legal Medicine and Forensic Science between September 2012 and August 2013. RESULTS: During a period of 1 year, 430 people died and 10,056.3 years of life were lost in Bogota due to traffic accidents. CONCLUSION: The mortality burden of traffic accidents in Bogota is high. Further studies are required in order to characterize the accidents and develop effective policy decisions. PMID- 27771359 TI - Is Interferential Current Before Pilates Exercises More Effective Than Placebo in Patients With Chronic Nonspecific Low Back Pain?: A Randomized Controlled Trial. AB - OBJECTIVE: To determine whether interferential current (IFC) before Pilates exercises is more effective than placebo in patients with chronic nonspecific low back pain. DESIGN: Two-arm randomized controlled trial, with a blinded assessor, and 6 months follow-up. SETTING: Clinic of a school of physical therapy. PARTICIPANTS: The random sample consisted of patients (N=148) of both sexes, with age between 18 and 80 years and chronic nonspecific low back pain. In addition, participants were recruited by disclosure of the treatment in the media. INTERVENTIONS: Patients were allocated into 2 groups: active IFC + Pilates or placebo IFC + Pilates. In the first 2 weeks, patients were treated for 30 minutes with active or placebo IFC. In the following 4 weeks, 40 minutes of Pilates exercises were added after the application of the active or placebo IFC. A total of 18 sessions were offered during 6 weeks. MAIN OUTCOME MEASURES: The primary outcome measures were pain intensity, pressure pain threshold, and disability measured at 6 weeks after randomization. RESULTS: No significant differences were found between the groups for pain (0.1 points; 95% confidence interval, -0.9 to 1.0 points), pressure pain threshold (25.3kPa; 95% confidence interval, -4.4 to 55.0kPa), and disability (0.4 points; 95% confidence interval, -1.3 to 2.2). However, there was a significant difference between baseline and 6-week and 6 month follow-ups in the intragroup analysis for all outcomes (P<.05), except pressure pain threshold in the placebo IFC + Pilates group. CONCLUSIONS: These findings suggest that active IFC before Pilates exercise is not more effective than placebo IFC with respect to the outcomes assessed in patients with chronic nonspecific low back pain. PMID- 27771360 TI - Sensorimotor Control in Individuals With Idiopathic Neck Pain and Healthy Individuals: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: (1) To identify reported tests used to assess sensorimotor control in individuals with idiopathic neck pain and (2) to investigate whether these tests can quantify differences between individuals with idiopathic neck pain and healthy individuals. DATA SOURCES: Allied and Complementary Medicine Database, CINAHL, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Physiotherapy Evidence Database, Scopus, and SPORTDiscus. STUDY SELECTION: Studies reporting sensorimotor outcomes in individuals with idiopathic neck pain or healthy individuals were identified. There were 1,677 records screened independently by 2 researchers for eligibility: 43 studies were included in the review, with 30 of these studies included in the meta-analysis. DATA EXTRACTION: Methodologic quality was determined using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data were extracted using a standardized extraction table. DATA SYNTHESIS: Sensorimotor control was most commonly assessed by joint position error and postural sway. Pooled means for joint position error after cervical rotation in individuals with neck pain (range, 2.2 degrees -9.8 degrees ) differed significantly (P=.04) compared with healthy individuals (range, 1.66 degrees -5.1 degrees ). Postural sway with eyes open ranged from 4.85 to 10.5cm2 (neck pain) and 3.5 to 6.6cm2 (healthy) (P=.16), and postural sway with eyes closed ranged from 2.51 to 16.6cm2 (neck pain) and 2.74 to 10.9cm2 (healthy) (P=.30). Individual studies, but not meta-analysis, demonstrated differences between neck pain and healthy groups for postural sway. Other test conditions and other tests were not sufficiently investigated to enable pooling of data. CONCLUSIONS: The findings from this review suggest sensorimotor control testing may be clinically useful in individuals with idiopathic neck pain. However, results should be interpreted with caution because clinical differences were small; therefore, further cross-sectional research with larger samples is needed to determine the magnitude of the relation between sensorimotor control and pain and to assess any potential clinical significance. PMID- 27771361 TI - Accuracy of McMurray and Joint Line Tenderness Tests in the Diagnosis of Chronic Meniscal Tears: An Ad Hoc Receiver Operator Characteristic Analysis Approach. AB - OBJECTIVE: To determine the overall diagnostic accuracy of the McMurray and joint line tenderness (JLT) tests for the detection of meniscal lesions. DESIGN: Secondary analysis of a prospective observational study. SETTING: Orthopedics outpatient clinic, university hospital. PARTICIPANTS: Patients (N=56) with suspected nonacute meniscal lesions who underwent knee arthroscopy. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Diagnostic accuracy of the McMurray and JLT tests as determined by receiver operator characteristic analysis. RESULTS: The McMurray test showed higher accuracy (area under the curve [AUC], .69; SE, .079) than the JLT test (AUC, .58; SE, .084). CONCLUSIONS: The McMurray test, although presenting a higher diagnostic accuracy than the JLT test, does not suffice as a standalone diagnostic procedure for chronic meniscal lesions. The test may still be valuable to guide the diagnosis in cases with highly suspected meniscal tears. PMID- 27771363 TI - Articular cartilage and joint development from embryogenesis to adulthood. AB - Within each synovial joint, the articular cartilage is uniquely adapted to bear dynamic compressive loads and shear forces throughout the joint's range of motion. Injury and age-related degeneration of the articular cartilage often lead to significant pain and disability, as the intrinsic repair capability of the tissue is extremely limited. Current surgical and biological treatment options have been unable to restore cartilage de novo. Before successful clinical cartilage restoration strategies can be developed, a better understanding of how the cartilage forms during normal development is essential. This review focuses on recent progress made towards addressing key questions about articular cartilage morphogenesis, including the origin of synovial joint progenitor cells, postnatal development and growth of the tissue. These advances have provided novel insight into fundamental questions about the developmental biology of articular cartilage, as well as potential cell sources that may participate in joint response to injury. PMID- 27771362 TI - Transcriptional control of chondrocyte specification and differentiation. AB - A milestone in the evolutionary emergence of vertebrates was the invention of cartilage, a tissue that has key roles in modeling, protecting and complementing the bony skeleton. Cartilage is elaborated and maintained by chondrocytes. These cells derive from multipotent skeletal progenitors and they perform highly specialized functions as they proceed through sequential lineage commitment and differentiation steps. They form cartilage primordia, the primary skeleton of the embryo. They then transform these primordia either into cartilage growth plates, temporary drivers of skeletal elongation and endochondral ossification, or into permanent tissues, namely articular cartilage. Chondrocyte fate decisions and differentiated activities are controlled by numerous extrinsic and intrinsic cues, and they are implemented at the gene expression level by transcription factors. The latter are the focus of this review. Meritorious efforts from many research groups have led over the last two decades to the identification of dozens of key chondrogenic transcription factors. These regulators belong to all types of transcription factor families. Some have master roles at one or several differentiation steps. They include SOX9 and RUNX2/3. Others decisively assist or antagonize the activities of these masters. They include TWIST1, SOX5/6, and MEF2C/D. Many more have tissue-patterning roles and regulate cell survival, proliferation and the pace of cell differentiation. They include, but are not limited to, homeodomain-containing proteins and growth factor signaling mediators. We here review current knowledge of all these factors, one superclass, class, and family at a time. We then compile all knowledge into transcriptional networks. We also identify remaining gaps in knowledge and directions for future research to fill these gaps and thereby provide novel insights into cartilage disease mechanisms and treatment options. PMID- 27771365 TI - Conjugated Alpha-Alumina nanoparticle with vasoactive intestinal peptide as a Nano-drug in treatment of allergic asthma in mice. AB - Asthma is a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, airway hyperresponsiveness and recurring attacks of impaired breathing. Vasoactive intestinal peptide (VIP) has been proposed as a novel anti asthma drug due to its effects on airway smooth muscle relaxation, bronchodilation and vasodilation along with its immunomodulatory and anti inflammatory properties. In the current study, we investigated the therapeutic effects of VIP when conjugated with alpha-alumina nanoparticle (alpha-AN) to prevent enzymatic degradation of VIP in the respiratory tract. VIP was conjugated with alpha-AN. Balb/c mice were sensitized and challenges with ovalbumin (OVA) or PBS and were divided in four groups; VIP-treated, alpha-AN-treated, alpha-AN-VIP treated and beclomethasone-treated as a positive control group. Specific and total IgE level, airway hyperresponsiveness (AHR), bronchial cytokine expression and lung histology were measured. alpha-AN-VIP significantly reduced the number of eosinophils (Eos), serum IgE level, Th2 cytokines and AHR. These effects of alpha-AN-VIP were more pronounced than that seen with beclomethasone or VIP alone (P<0.05). The current data indicate that alpha-AN-VIP can be considered as an effective nano-drug for the treatment of asthma. PMID- 27771364 TI - Reaction kinetic analysis of the 3-hydroxypropionate/4-hydroxybutyrate CO2 fixation cycle in extremely thermoacidophilic archaea. AB - The 3-hydroxypropionate/4-hydroxybutyrate (3HP/4HB) cycle fixes CO2 in extremely thermoacidophilic archaea and holds promise for metabolic engineering because of its thermostability and potentially rapid pathway kinetics. A reaction kinetics model was developed to examine the biological and biotechnological attributes of the 3HP/4HB cycle as it operates in Metallosphaera sedula, based on previous information as well as on kinetic parameters determined here for recombinant versions of five of the cycle enzymes (malonyl-CoA/succinyl-CoA reductase, 3 hydroxypropionyl-CoA synthetase, 3-hydroxypropionyl-CoA dehydratase, acryloyl-CoA reductase, and succinic semialdehyde reductase). The model correctly predicted previously observed features of the cycle: the 35-65% split of carbon flux through the acetyl-CoA and succinate branches, the high abundance and relative ratio of acetyl-CoA/propionyl-CoA carboxylase (ACC) and MCR, and the significance of ACC and hydroxybutyryl-CoA synthetase (HBCS) as regulated control points for the cycle. The model was then used to assess metabolic engineering strategies for incorporating CO2 into chemical intermediates and products of biotechnological importance: acetyl-CoA, succinate, and 3-hydroxypropionate. PMID- 27771366 TI - Molecular targeting of hypoxia in radiotherapy. AB - Hypoxia (low O2) is an essential microenvironmental driver of phenotypic diversity in human solid cancers. Hypoxic cancer cells hijack evolutionarily conserved, O2- sensitive pathways eliciting molecular adaptations that impact responses to radiotherapy, tumor recurrence and patient survival. In this review, we summarize the radiobiological, genetic, epigenetic and metabolic mechanisms orchestrating oncogenic responses to hypoxia. In addition, we outline emerging hypoxia- targeting strategies that hold promise for individualized cancer therapy in the context of radiotherapy and drug delivery. PMID- 27771367 TI - IN.PACTTM AdmiralTM drug-coated balloon: Durable, consistent and safe treatment for femoropopliteal peripheral artery disease. AB - Endovascular management of peripheral artery disease was until recently limited to percutaneous balloon angioplasty, atherectomy, stent grafts, and bare-metal stents. These therapies have been valuable, but plagued by high restenosis and revascularization rates. Important progress has been made with the introduction of combination devices, including drug-eluting stents and drug-coated balloons (DCB), designed to combat restenosis by locally delivering anti-proliferative drugs. In particular, promising clinical performance has been seen with the Medtronic IN.PACTTM AdmiralTM DCB, with durable, consistent and safe results. Rigorous, randomized controlled trials have directly compared this and other drug delivering devices to their non-drug-coated counterparts with data available through two years. Additionally, trials are ongoing to assess use of drug-coated technologies in combination with traditional therapies in hope of synergistic effects. This review gathers data from currently published clinical trials with the IN.PACT Admiral DCB for the treatment of femoropopliteal peripheral artery disease and explores the possible impact on continuing clinical practice. PMID- 27771368 TI - Paraoxonase and atherosclerosis-related cardiovascular diseases. AB - In humans, three paraoxonase (PON1, PON2, and PON3) genes are clustered on chromosome 7 at a locus that spans a distance around 170 kb. These genes are highly homologous to each other and have a similar protein structural organization. PON2 is the intracellular enzyme, which is expressed in many tissues and organs, while two other members of PON gene family are produced by liver and associate with high density lipoprotein (HDL). The lactonase activity is the ancestral. Besides lactones and organic phosphates, PONs can hydrolyze and therefore detoxify oxidized low density lipoprotein and homocysteine thiolactone, i.e. two cytotoxic compounds with a strong proatherogenic action. Indeed, PONs possess numerous atheroprotective properties, which include antioxidant activity, anti-inflammatory action, preserving HDL function, stimulation of cholesterol efflux, anti-apoptosis, anti-thrombosis, and anti-adhesion. PON genetic polymorphisms contribute to susceptibility/protection from atherosclerosis related diseases. The bright antiatherogenic activity of the PON cluster makes it a promising target for the development of new therapeutic strategies. PMID- 27771369 TI - Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain. AB - Human pendrin (SLC26A4) is an anion transporter mostly expressed in the inner ear, thyroid and kidney. SLC26A4 gene mutations are associated with a broad phenotypic spectrum, including Pendred Syndrome and non-syndromic hearing loss with enlarged vestibular aqueduct (ns-EVA). No experimental structure of pendrin is currently available, making phenotype-genotype correlations difficult as predictions of transmembrane (TM) segments vary in number. Here, we propose a novel three-dimensional (3D) pendrin transmembrane domain model based on the SLC26Dg transporter. The resulting 14 TM topology was found to include two non canonical transmembrane segments crucial for pendrin activity. Mutation mapping of 147 clinically validated pathological mutations shows that most affect two previously undescribed TM regions. PMID- 27771371 TI - REM sleep disorder following general anesthesia in rats. AB - Postoperative sleep disorders, particularly the REM sleep disorder, may have a significant deleterious impact on postoperative outcomes and may contribute to the genesis of certain delayed postoperative complications. We have followed the effect of distinct anesthesia regimens (ketamine/diazepam vs. pentobarbital) over 6days following the induction of a stable anesthetized state in adult male Wistar rats, chronically instrumented for sleep recording. In order to compare the effect of both anesthetics in the physiological controls vs. the rats with impaired pedunculopontine tegmental nucleus (PPT) cholinergic innervation, during the operative procedure for the implantation of EEG and EMG electrodes, the bilateral PPT lesion was conducted using ibotenic acid (IBO). We have followed in particular post-anesthesia REM sleep. Our results show the distinct EEG microstructure of the motor cortex during the different stable anesthetized states, and their distinct impact on post-anesthesia REM sleep. In contrast to pentobarbital anesthesia, the ketamine/diazepam anesthesia potentiated the long lasting post-anesthesia REM statewith higher muscle tone (REM1) vs. REM state with atonia (REM2). Whereas both anesthesias prolonged the post-anesthesia REM sleep duration, the long-term prolongation of the REM1 state was demonstrated only after the ketamine/diazepam anesthesia, first due to the increased number of REM1 episodes, and then due to the prolonged REM1 episodes duration. On the other hand, whereas both anesthetic regimens abolished the prolonged post-anesthesia REM/REM1 sleep and the EEG microstructure disorder during REM sleep, only the pentobarbital abolished the increased NREM/REM/NREM transitions, caused by the PPT lesion. In addition, in the PPT lesioned rats, the ketamine/diazepam anesthesia decreased the Wake/NREM/Wake transitions while the pentobarbital anesthesia decreased the Wake/REM/Wake transitions. Our present study suggests pentobarbital anesthesia as being highly beneficial for post-anesthesia REM sleep in the physiological condition as well as during PPT cholinergic neuropathology. PMID- 27771370 TI - Novel non-beta-lactam inhibitor of beta-lactamase TEM-171 based on acylated phenoxyaniline. AB - The microbial resistance to antibiotics is a genuine global threat. Consequently, a search of new inhibitors remains of acute importance due to the increasing spread of multidrug resistance. Here we present a new type of non-beta-lactam beta-lactamase inhibitor PA-34 based on natural phenoxyaniline, identified using computer-assisted screening of scaffolds related to those of known low-affinity inhibitors. The compound displays reversible competitive inhibition of bacterial beta-lactamase TEM-171, with a Ki of 88 MUM. Using enzyme kinetics, infra-red spectroscopy, fluorescence quenching and computer docking, we propose that the inhibitor binds at the entrance to the enzyme active site. This is a novel inhibition mechanism compared to binding covalently to the catalytic serine in the active site or non-covalently to the allosteric site. The residues involved in binding the inhibitor are conserved among molecular class A beta-lactamases. The identified compound and its proposed binding mode may have a potential for a regulation of the catalytic activity of a wide range of class A beta-lactamases. We also hypothesise that the presented route for finding non-beta-lactam compounds may be an effective and durable approach for combating bacterial antibiotic resistance. PMID- 27771372 TI - Pseudomonas aeruginosa develops Ciprofloxacin resistance from low to high level with distinctive proteome changes. AB - : Pseudomonas aeruginosa infection is difficult to treat because of its drug resistance, but how it develops drug resistance remains largely unknown. In this study we investigated Ciprofloxacin resistance development in P. aeruginosa. Different Ciprofloxacin concentrations selected different low level resistant mutants, and high level resistant mutants emerged from low level resistant mutants if stressed further by Ciprofloxacin. A deep quantitative proteomic study of the Ciprofloxacin resistant mutants uncovered the cellular pathways that supported such resistances. The two low level resistant mutants had different molecular mechanisms. One was mainly due to switching to anaerobic respiration and overexpression of catalase and peroxidase, and the other was probably due to iron and polyamine uptake and DNA repair. High level of resistance involved the mexCD-oprJ efflux pump and the downregulation of PQS quorum sensing. Other pathways might also have contributed to high level resistance, like the arginine deiminase pathway, catalase, peroxidase, protein degradation and DNA repair. The intracellular Ciprofloxacin concentration assay indicated that only the mexCD oprJ overexpressed mutants had low drug accumulation. This study provided a comprehensive overview of the proteomic landscape in the evolution of Ciprofloxacin resistance in P. aeruginosa, and might have implications in diagnosis and treatment of Ciprofloxacin resistant P. aeruginosa. Data are available via ProteomeXchange with identifier PXD004560. BIOLOGICAL SIGNIFICANCE: Pseudomonas aeruginosa infection is difficult to treat because of its drug resistance, but how it develops drug resistance remains largely unknown. In this study we investigated Ciprofloxacin resistance development in P. aeruginosa. We found that Ciprofloxacin resistance developed from low to high level. Two different low levels resistant molecular mechanisms were discovered from different mutants selected by different Ciprofloxacin concentrations, one was mainly due to switching to anaerobic respiration and overexpression of catalase and peroxidase, the other was probably due to iron, polyamine, and DNA repair. High level of Ciprofloxacin resistance all involved the efflux pump, mexCD-oprJ, and the downregulation of quorum sensing. The findings of this study provided insights into the evolution of Ciprofloxacin resistance in P. aeruginosa and should have implications in diagnosis and treatment of Ciprofloxacin resistant P. aeruginosa. PMID- 27771373 TI - Expression of cathepsins V and S in thymic epithelial tumors. AB - Cathepsins are a group of proteolytic enzymes of the endosomal/lysosomal pathway involved in the thymic development of T cells restricted by major histocompatibility complex class II molecules. In the normal thymus, cathepsin V (CTV) and cathepsin S (CTS) are expressed in cortical and medullary epithelial cells, respectively. To investigate whether cathepsins could serve as a diagnostic marker, we performed immunohistochemical analysis for CTV and CTS in 77 cases of thymic epithelial tumors. Almost all cases (59/60) of thymoma expressed CTV, whereas 28 of 60 cases of thymoma expressed CTS. Notably, CTS was expressed in most cases of type A and type AB thymomas, but not in type B thymoma. The expression of cathepsins in type AB thymoma showed a clear correlation with histologic features; CTV was found predominantly in the type B component, and CTS was frequently expressed in the type A component. In thymic carcinoma, CTV was expressed in less than half cases (7/17), and the ratio of CTS positive cases was equivalent to that of thymoma (8/17). Cases of CTV-negative thymic carcinoma tended to have a higher incidence of recurrence than did CTV positive cases. Although further studies with a larger number of cases are required to confirm the utility of cathepsin immunostaining, CTV and CTS appear to serve as auxiliary diagnostic and/or prognostic markers in thymic epithelial tumors. PMID- 27771374 TI - BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma. AB - BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis. PMID- 27771375 TI - Spleen histology in children with sickle cell disease and hereditary spherocytosis: hints on the disease pathophysiology. AB - Hereditary spherocytosis (HS) and sickle cell disease (SCD) are associated with splenomegaly and spleen dysfunction in pediatric patients. Scant data exist on possible correlations between spleen morphology and function in HS and SCD. This study aimed to assess the histologic and morphometric features of HS and SCD spleens, to get possible correlations with disease pathophysiology. In a large series of spleens from SCD, HS, and control patients, the following parameters were considered: (i) macroscopic features, (ii) lymphoid follicle (LF) density, (iii) presence of perifollicular marginal zones, (iv) presence of Gamna-Gandy bodies, (v) density of CD8-positive sinusoids, (vi) density of CD34-positive microvessels, (vii) presence/distribution of fibrosis and smooth muscle actin (SMA)-positive myoid cells, and (viii) density of CD68-positive macrophages. SCD and HS spleens had similar macroscopic features. SCD spleens had lower LF density and fewer marginal zones than did HS spleens and controls. SCD also showed lower CD8-positive sinusoid density, increased CD34-positive microvessel density and SMA-positive myoid cells, and higher prevalence of fibrosis and Gamna-Gandy bodies. HS had lower LF and CD8-positive sinusoid density than did controls. No significant differences were noted in red pulp macrophages. By multivariate analysis, most HS spleens clustered with controls, whereas SCD grouped separately. A multiparametric score could predict the degree of spleen changes irrespective of the underlying disease. In conclusion, SCD spleens display greater histologic effacement than HS, and SCD-related changes suggest impaired function due to vascular damage. These observations may contribute to guide the clinical management of patients. PMID- 27771376 TI - Clinicopathological characteristics of invasive gastric Helicobacter pylori. AB - Helicobacter pylori organisms have been observed deep within the stomach mucosa with an "intracellular" appearance, although the clinicopathological characteristics of such cases remain poorly understood. We analyzed 18 cases of deep mucosal H pylori and associated clinical (sex, age, history of H pylori infection, or proton pump inhibitor [PPI] use, medications, smoking, alcohol use, comorbidities, treatment response) and pathological (presence of lymphoid aggregates, intestinal metaplasia, PPI effect, active and/or chronic inflammation, quantity of invasive versus surface H pylori) characteristics. Electron microscopy was performed on 6 cases with the highest burden of invasive H pylori. Within our sample, 3 of 16 had a history of H pylori infection, 10 of 15 were receiving PPIs at the time of biopsy, and 12 of 13 had a negative posttreatment follow-up. Histology revealed that invasive H pylori were more commonly associated with chronic inflammation, in both the antrum (15/15 chronic, 8/15 acute) and fundus (17/18 chronic, 8/18 acute). Electron microscopy showed organisms within intercellular and luminal spaces, but no intracellular organisms. Deep mucosal H pylori often have an intracellular appearance but are contained within intercellular and luminal spaces and are responsive to standard therapy. PMID- 27771377 TI - Malignant transformation of polyostotic fibrous dysplasia with aberrant keratin expression. AB - Malignant transformation of fibrous dysplasia (FD) is exceedingly rare, occurring in less than 1% of all FD cases, and has been described in both monostotic and polyostotic forms of this entity. We report a case of a large proximal femur mass arising in a 45-year-old man. The biopsy revealed a high-grade pleomorphic malignancy that focally expressed multiple keratins. Based on the presence of keratin immunoreactivity, the morphologic differential diagnosis included metastatic sarcomatoid carcinoma. However, review of the clinical information revealed a history of polyostotic FD, and imaging findings were compatible with malignant transformation of FD. The resected neoplasm was biphasic and composed of areas of conventional FD admixed with a high-grade pleomorphic malignancy. Activating GNAS mutations were identified in both components. To the best of our knowledge, this is the first description of keratin expression in malignant transformation of FD. PMID- 27771378 TI - 15-Deoxy-Delta12,14-prostaglandin J2 induced neurotoxicity via suppressing phosphoinositide 3-kinase. AB - 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) induces neuronal cell death via apoptosis independently of its receptors. 15d-PGJ2 inhibits growth factor-induced cell proliferation of primary astrocytes via down-regulating phosphoinositide 3 kinase (PI3K)-Akt pathway. Although 15d-PGJ2-reduced cell viability is accompanied with attenuation of the PI3K signaling in neuroblastoma, it has not been sufficiently clarified how 15d-PGJ2 induces cell death in primary neurons. Here, we found that 15d-PGJ2 exhibited neurotoxicity via inhibiting the PI3K signaling in the primary culture of rat cortical neurons. A PI3K inhibitor induced neuronal cell death regardless serum throughout maturation, confirming that PI3K is required for neuronal cell survival. The inhibitor disrupted neuronal cell bodies, shortened neurites thinly, damaged plasma membranes and activated caspase-3 similarly to 15d-PGJ2. Little additive or synergistic neurotoxicity was detected between 15d-PGJ2 and the PI3K inhibitor. A PI3K activator prevented neurons from undergoing the 15d-PGJ2-induced cell death in vitro. In vivo, the PI3K signaling is required for contextual memory retrieval, which was impaired by bilateral injection of 15d-PGJ2 into hippocampus. The activator suppressed the 15d-PGJ2-impaired memory retrieval significantly. In neurons as well as primary astrocytes and neuroblastomas, 15d-PGJ2 exhibited cytotoxicity via suppressing the PI3K-Akt pathway in vivo and in vitro. PMID- 27771380 TI - The social determinants of polio in Pakistan. PMID- 27771379 TI - Novel, highly potent and in vivo active inhibitor of GABA transporter subtype 1 with anticonvulsant, anxiolytic, antidepressant and antinociceptive properties. AB - BACKGROUND AND PURPOSE: Since GABAergic dysfunction underlies a variety of neurological and psychiatric disorders, numerous strategies leading to the augmentation of GABAergic neurotransmission have been introduced. One of them is the inhibition of GABA reuptake from the synaptic cleft mediated by four plasma membrane GABA transporters (GAT1-4). GAT1 which is exclusively expressed in the brain is an interesting target for centrally acting drugs. In this research, pharmacological properties of a novel, highly potent and selective inhibitor of GAT1, the guvacine derivative named DDPM-2571, were assessed in vivo. EXPERIMENTAL APPROACH: Pharmacological effects and pharmacokinetics of intraperitoneally administered DDPM-2571 were assessed in CD-1 mice. KEY RESULTS: DDPM-2571 was quickly distributed into the brain and was highly effective in the prevention of chemically-induced seizures (pentylenetetrazole and pilocarpine models) and 6-Hz convulsions. It demonstrated significant anxiolytic-like and antidepressant-like properties. DDPM-2571 had antinociceptive properties, both in the hot plate test and in the second phase of the formalin test. Within the dose range tested, it did not impair animals' motor skills, but it impaired cognition and potentiated scopolamine-induced cognitive deficits in the passive avoidance task. CONCLUSIONS AND IMPLICATIONS: Due to GAT1 inhibition, DDPM-2571 is effective in mouse models of chemically-induced seizures, anxiety, depression, acute and tonic pain. At biologically active doses, it does not impair animals' motor skills, but it might induce memory deficits. Taken together, DDPM-2571 can be regarded as a promising lead structure in the search for new centrally acting drugs and a potent pharmacological tool to study the biological role of GAT1. PMID- 27771381 TI - Niacin and its metabolites as master regulators of macrophage activation. AB - Niacin is a broad-spectrum lipid-regulating drug used for clinical therapy of chronic high-grade inflammatory diseases. However, the mechanisms by which either niacin or the byproducts of its catabolism ameliorate these inflammatory diseases are not clear yet. Human circulating monocytes and mature macrophages were used to analyze the effects of niacin and its metabolites (NAM, NUA and 2-Pyr) on oxidative stress, plasticity and inflammatory response by using biochemical, flow cytometry, quantitative real-time PCR and Western blot technologies. Niacin, NAM and 2-Pyr significantly decreased ROS, NO and NOS2 expression in LPS-treated human mature macrophages. Niacin and NAM skewed macrophage polarization toward antiinflammatory M2 macrophage whereas a trend toward proinflammatory M1 macrophage was noted following treatment with NUA. Niacin and NAM also reduced the inflammatory competence of LPS-treated human mature macrophages and promoted bias toward antiinflammatory CD14+CD16++ nonclassical human primary monocytes. This study reveals for the first time that niacin and its metabolites possess antioxidant, reprogramming and antiinflammatory properties on human primary monocytes and monocyte-derived macrophages. Our findings imply a new understanding of the mechanisms by which niacin and its metabolites favor a continuous and gradual plasticity process in the human monocyte/macrophage system. PMID- 27771382 TI - Transcriptional control of Sost in bone. AB - Sclerostin is an osteocyte derived negative regulator of bone formation. A highly specific expression pattern and the exclusive bone phenotype have made Sclerostin an attractive target for therapeutic intervention in treating metabolic bone diseases such as osteoporosis and in facilitating fracture repair. Understanding the molecular mechanisms that regulate Sclerostin transcription is of great interest as it may unveil new avenues for therapeutic approaches. Such studies may also elucidate how various signaling pathways intersect to modulate bone metabolism. Here we review the current understanding of the upstream molecular mechanisms that regulate Sost/SOST transcription, in bone. PMID- 27771383 TI - Maternal separation exacerbates Alzheimer's disease-like behavioral and pathological changes in adult APPswe/PS1dE9 mice. AB - Alzheimer's disease (AD), the most common neurodegenerative disorder that gradually destroys memory and cognitive abilities in the elderly, makes a huge emotional and economic burden on the patients and their families. The presence of senile plaques and the loss of cholinergic neurons in the brain are two neuropathological hallmarks of AD. Maternal separation (MS) is an animal paradigm designed to make early life stress. Studies on wild type rodents showed that MS could induce AD-like cognitive deficit and pathological changes. However, the effects of MS on AD susceptible population or AD animal models are still unclear. In the present study, male APPswe/PS1dE9 transgenic mice were separated from dam and pups 3h per day from postnatal day 2 to day 21. After weaning, all animals were housed under normal conditions (4 mice per cage). At 9-month age, MWM tests were performed to evaluate the learning and memory abilities. Then the pathological changes in the brain were measured by histology staining. The results showed MS mice had more severe deficit of learning and memory. Compared to the control, there were more senile plaques in cortex and hippocampus, fewer cholinergic neurons in nucleus basalis of Meynert in MS mice. These results indicate that MS exacerbates Alzheimer's disease-like behavioral and pathological changes in APPswe/PS1dE9 mice. PMID- 27771384 TI - The new kidney allocation system does not equally advantage all very high cPRA candidates - A single center analysis. AB - The new UNOS kidney allocation system awards very high points to candidates with cPRA 99% and 100%, and allows for national sharing for cPRA 100% candidates. We sought to determine the effect of this new kidney allocation system on candidates who are very highly sensitized (90-98% cPRA) but not eligible for very high points or national sharing by examining offers to these candidates for 5months pre-implementation and two consecutive 5month periods post-implementation and comparing them to cPRA?99% candidates. We found that the cPRA?99% candidates received significantly more offers and transplants after implementation, while offers and transplants to the 90-98% candidates decreased. A slight adjustment to the allocation system may be needed to provide more equitable distribution of kidneys to all high cPRA candidates. PMID- 27771385 TI - Should epitope-based HLA compatibility be used in the kidney allocation system? AB - The new kidney allocation system (KAS) still applies donor-recipient HLA compatibility mostly at the antigen level and although some four-digit alleles have been included. This system is used to record unacceptable mismatches for sensitized transplant candidates with serum HLA antibodies. Since the reactivities of such antibodies are specifically associated with epitopes rather than HLA antigens, a more scientifically accurate assessment of mismatch acceptability could be based on epitopes. HLA class I and class II epitope specificity analyses can now be readily performed with serum antibody assays with single allele panels. This report describes an epitope-based HLA compatibility system for KAS and involves recipient and donor HLA typing at the four-digit allele level. It focuses on sensitized patients who have serum antibodies specific for HLA epitopes that can be entered as unacceptable mismatches in the transplant candidate database. Newly developed software programs could readily identify compatible HLA types. PMID- 27771386 TI - Kinetic aspects of enzyme-mediated repair of DNA single-strand breaks. AB - In cells and bacteria, DNA can be damaged in different ways. The efficient damage repair, mediated by various enzymes, is crucial for their survival. Most frequently, the damage is reduced to single-strand breaks. In human cells, according to the experiments, the repair of such breaks can mechanistically be divided into four steps including (i) the break detection, (ii) processing of damaged ends, (iii) gap filling, and (iv) ligation of unbound ends of the broken strand. The first and second steps run in parallel while the third and fourth steps are sequential. The author proposes a kinetic model describing these steps. It allows one to understand the likely dependence of the number of breaks in different states on enzyme concentrations. The dependence of these concentrations on the rate of the formation of breaks can be understood as well. In addition, the likely role of unzipping and zipping of the fragments of broken ends of the strand in the ligation step has been scrutinized taking the specifics of binding of DNA stands into account. PMID- 27771387 TI - HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes. AB - Hepatitis D virus (HDV) super-infection of Hepatitis B virus (HBV)-infected patients is the most aggressive form of viral hepatitis. HDV infection is not susceptible to direct anti-HBV drugs, and only suboptimal antiviral responses are obtained with interferon (IFN)-alpha-based therapy. To get insights on HDV replication and interplay with HBV in physiologically relevant hepatocytes, differentiated HepaRG (dHepaRG) cells, previously infected or not with HBV, were infected with HDV, and viral markers were extensively analyzed. Innate and IFN responses to HDV were monitored by measuring pro-inflammatory and interferon stimulated gene (ISG) expression. Both mono- and super-infected dHepaRG cells supported a strong HDV intracellular replication, which was accompanied by a strong secretion of infectious HDV virions only in the super-infection setting and despite the low number of co-infected cells. Upon HDV super-infection, HBV replication markers including HBeAg, total HBV-DNA and pregenomic RNA were significantly decreased, confirming the interference of HDV on HBV. Yet, no decrease of circular covalently closed HBV DNA (cccDNA) and HBsAg levels was evidenced. At the peak of HDV-RNA accumulation and onset of interference on HBV replication, a strong type-I IFN response was observed, with interferon stimulated genes, RSAD2 (Viperin) and IFI78 (MxA) being highly induced. We established a cellular model to characterize in more detail the direct interference of HBV and HDV, and the indirect interplay between the two viruses via innate immune responses. This model will be instrumental to assess molecular and immunological mechanisms of this viral interference. PMID- 27771388 TI - Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice. AB - Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and young children. There are no licensed RSV vaccines available, and the few treatment options for high-risk individuals are either extremely costly or cause severe side effects and toxicity. Immunomodulation mediated by a novel formulation consisting of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene (P-I-P) was evaluated in the context of lethal infection with pneumonia virus of mice (PVM). Intranasal delivery of a single dose of P-I-P protected adult mice against PVM when given 24 h prior to challenge. These animals experienced minimal weight loss, no clinical disease, 100% survival, and reduced lung pathology. Similar clinical outcomes were observed in mice treated up to 3 days prior to infection. P-I-P pre-treatment induced early mRNA and protein expression of key chemokine and cytokine genes, reduced the recruitment of neutrophils and eosinophils, decreased virus titers in the lungs, and modulated the delayed exacerbated nature of PVM disease without any short-term side effects. On day 14 post-infection, P-I-P-treated mice were confirmed to be PVM-free. These results demonstrate the capacity of this formulation to prevent PVM and possibly other viral respiratory infections. PMID- 27771390 TI - Activities of JNJ63623872 and oseltamivir against influenza A H1N1pdm and H3N2 virus infections in mice. AB - JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the cap-snatching activity of the virus that is essential for virus replication. Previously published work has documented antiviral activity of JNJ63623872 in cell culture and mouse infection studies. In this report, we extend the in vivo observations by comparing the efficacies of JNJ63623872 and oseltamivir in mice infected with influenza A/California/04/2009 (H1N1pdm) and A/Victoria/3/75 (H3N2) viruses. Animals received JNJ63623872 or oseltamivir orally twice daily for 10 days starting 2 h pre-infection. JNJ63623872 (2, 6, and 20 mg/kg/day) and oseltamivir (20 mg/kg/day) completely prevented death in the H1N1pdm virus infection. Weight loss at nadir was only 12% in mice receiving 2 mg/kg/day of JNJ63623872 compared to 23% and 32%, respectively, in oseltamivir treated (20 mg/kg/day) and placebo groups. Lung hemorrhage scores, lung weights, and lung virus titers on day 6 were reduced in a dose-responsive manner by JNJ63623872 treatments, whereas oseltamivir treatments were not as effective. JNJ63623872 was less active against H3N2 virus infection, with more body weight loss occurring and only 30% survival at the 2-mg/kg/day dose. Lung scores, lung weights, and H3N2 viral titers in lungs of mice were reduced less by JNJ63623872 treatments compared to the H1N1pdm infection. Nevertheless, the 20-mg/kg/day dose of JNJ63623872 was more effective than oseltamivir (20 mg/kg/day) in improving body weight and reducing the severity of lung infection. JNJ63623872 appears to be an important new drug candidate to treat influenza A H1N1pdm and H3N2 virus infections. PMID- 27771389 TI - Lassa and Ebola virus inhibitors identified using minigenome and recombinant virus reporter systems. AB - Lassa virus (LASV) and Ebola virus (EBOV) infections are important global health issues resulting in significant morbidity and mortality. While several promising drug and vaccine trials for EBOV are ongoing, options for LASV infection are currently limited to ribavirin treatment. A major factor impeding the development of antiviral compounds to treat these infections is the need to manipulate the virus under BSL-4 containment, limiting research to a few institutes worldwide. Here we describe the development of a novel LASV minigenome assay based on the ambisense LASV S segment genome, with authentic terminal untranslated regions flanking a ZsGreen (ZsG) fluorescent reporter protein and a Gaussia princeps luciferase (gLuc) reporter gene. This assay, along with a similar previously established EBOV minigenome, was optimized for high-throughput screening (HTS) of potential antiviral compounds under BSL-2 containment. In addition, we rescued a recombinant LASV expressing ZsG, which, in conjunction with a recombinant EBOV reporter virus, was used to confirm any potential antiviral hits in vitro. Combining an initial screen to identify potential antiviral compounds at BSL-2 containment before progressing to HTS with infectious virus will reduce the amount of expensive and technically challenging BSL-4 containment research. Using these assays, we identified 6-azauridine as having anti-LASV activity, and demonstrated its anti-EBOV activity in human cells. We further identified 2' deoxy-2'-fluorocytidine as having potent anti-LASV activity, with an EC50 value 10 times lower than that of ribavirin. PMID- 27771392 TI - High-throughput purification of recombinant proteins using self-cleaving intein tags. AB - High throughput methods for recombinant protein production using E. coli typically involve the use of affinity tags for simple purification of the protein of interest. One drawback of these techniques is the occasional need for tag removal before study, which can be hard to predict. In this work, we demonstrate two high throughput purification methods for untagged protein targets based on simple and cost-effective self-cleaving intein tags. Two model proteins, E. coli beta-galactosidase (betaGal) and superfolder green fluorescent protein (sfGFP), were purified using self-cleaving versions of the conventional chitin-binding domain (CBD) affinity tag and the nonchromatographic elastin-like-polypeptide (ELP) precipitation tag in a 96-well filter plate format. Initial tests with shake flask cultures confirmed that the intein purification scheme could be scaled down, with >90% pure product generated in a single step using both methods. The scheme was then validated in a high throughput expression platform using 24-well plate cultures followed by purification in 96-well plates. For both tags and with both target proteins, the purified product was consistently obtained in a single-step, with low well-to-well and plate-to-plate variability. This simple method thus allows the reproducible production of highly pure untagged recombinant proteins in a convenient microtiter plate format. PMID- 27771393 TI - Comparison of simple sucrose and percoll based methodologies for synaptosome enrichment. AB - Synaptosomes are isolated nerve terminals. They represent an extremely attractive in vitro model system to study synaptic physiology since they preserve morphological and functional characteristics of the synapse. As such they have been used to investigate synaptic dysfunctions associated with neuropathologies like Alzheimer's disease. In the present work two simple methodologies for isolating synaptosomal-enriched fractions were compared for the first time. The starting points of both protocols were rat cortical or hippocampal homogenized tissues that underwent several differential centrifugation steps followed by a final purification of synaptosomal-enriched fractions using either a Percoll gradient or a Sucrose gradient. Comparison of the fractions obtained was carried out, using both biochemical and electron microscopy approaches. In the biochemical analysis the protein levels of pre-synaptic, post-synaptic, nuclear and mitochondrial markers were evaluated. Additional characterization of the synaptosomal-enriched fractions was performed using transmission electron microscopy. In summary, the results indicate that under the conditions tested the Sucrose based protocol is more efficient for the isolation of synaptosomal enriched fractions from both neuronal tissues, being particularly efficient for hippocampus that is a less abundant brain tissue. Further, the sucrose protocol apparently results in a higher yield of viable synaptosomes suitable for further assays, including structural and functional studies of synapses; making this an attractive procedure to study processes associated with neuropathologies. PMID- 27771391 TI - Gaussian and linear deconvolution of LC-MS/MS chromatograms of the eight aminobutyric acid isomers. AB - Isomeric molecules present a challenge for analytical resolution and quantification, even with MS-based detection. The eight aminobutyric acid (ABA) isomers are of interest for their various biological activities, particularly gamma-aminobutyric acid (GABA) and the d- and l-isomers of beta-aminoisobutyric acid (beta-AIBA; BAIBA). This study aimed to investigate LC-MS/MS-based resolution of these ABA isomers as their Marfey's (Mar) reagent derivatives. HPLC was able to separate three Mar-ABA isomers l-beta-ABA (l-BABA), and l- and d alpha-ABA (AABA) completely, with three isomers (GABA, and d/l-BAIBA) in one chromatographic cluster, and two isomers (alpha-AIBA (AAIBA) and d-BABA) in a second cluster. Partially separated cluster components were deconvoluted using Gaussian peak fitting except for GABA and d-BAIBA. MS/MS detection of Marfey's derivatized ABA isomers provided six MS/MS fragments, with substantially different intensity profiles between structural isomers. This allowed linear deconvolution of ABA isomer peaks. Combining HPLC separation with linear and Gaussian deconvolution allowed resolution of all eight ABA isomers. Application to human serum found a substantial level of l-AABA (13 MUM), an intermediate level of l-BAIBA (0.8 MUM), and low but detectable levels (<0.2 MUM) of GABA, l BABA, AAIBA, d-BAIBA, and d-AABA. This approach should be useful for LC-MS/MS deconvolution of other challenging groups of isomeric molecules. PMID- 27771394 TI - Bacteroides pyogenes causing serious human wound infection from animal bites. AB - Bacteroides pyogenes is part of the normal oral flora of domestic animals. There is one previous report of human infection, with B. pyogenes bacteremia following a cat bite (Madsen 2011). We report seven severe human infections where B. pyogenes was identified by Bruker matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDTI-TOF MS), but not by VITEK MS and was misidentified by VITEK ANC card. PMID- 27771395 TI - Individual consistency and context dependence in group-size preference of Eurasian perch. AB - Many fish spend a large part of their life in groups. The size of the group influences potential costs and benefits of group living, and depending on context a fish may prefer different group sizes. Group-size preference may also depend on personality, with social individuals expected to prefer larger groups than asocial fish. This study investigates context-dependent group size preference in two populations of a highly social fish, young of the year Eurasian perch. The perch were given a choice between a group of two and a group of eight conspecifics under three different situations: the small group was feeding, the small group had access to shelter, and a control treatment with no extra stimuli. In general, the perch associated more with the large group, but significantly less so during the food treatment. Perceived access to shelter did not affect group size preference compared to the control treatment. Consistent individual differences in social attraction were found within each context, but not among all contexts. Also, an individual's sociability did not correlate with its degree of boldness, indicating a lack of a behavioural syndrome between the two personality traits in the studied populations. The results highlight the importance of considering environmental context when studying social behaviour in obligate social fish, and show the complexity of the concept of sociability as a personality trait by demonstrating context dependence in individual consistency in social behaviour. PMID- 27771396 TI - Electroacupuncture pretreatment with different waveforms prevents brain injury in rats subjected to cecal ligation and puncture via inhibiting microglial activation, and attenuating inflammation, oxidative stress and apoptosis. AB - Sepsis is associated with high morbidity and mortality. This study was to investigate the protective effects of electroacupuncture (EA) pretreatment with different waveforms on septic brain injury in rats and its mechanism. Male Sprague-Dawley rats were pretreated by EA with different waveforms (continuous wave, dilatational wave, or intermittent wave) at Baihui (GV20) and Tsusanli (ST36) acupoints for 30min, and underwent cecal ligation and puncture (CLP) or sham operation. The results showed that EA pretreatment with different waveforms improved survival rate, attenuated encephaledema, brain injury, neuronal apoptosis and cognitive dysfunction, and preserved blood-brain barrier (BBB). EA pretreatment decreased the production of tumor necrosis factor(TNF)-alpha, interleukin(IL)-6, malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and catalase (CAT) in serum and hippocampus at 48h after sham or CLP operation. Additionally, EA pretreatment downregulated the expressions of toll-like receptor-4 (TLR-4), nuclear factor-kappa B (NF-kappaB) and ionized calcium binding adaptor molecule 1(Iba 1). The effect of dilatational wave was the most significant, followed by intermittent wave, and continuous wave was relatively poor. In conclusion, our results demonstrate that EA pretreatment with three waveforms alleviates sepsis-induced brain injury by inhibition of microglial activation and attenuation of inflammation, oxidative stress and apoptosis. These findings suggest that EA pretreatment with dilatational wave at Baihui and Tsusanli acupoints might be a promising therapeutic strategy for relieving septic brain injury. PMID- 27771397 TI - From Recognized to Novel Quantitative CMR Biomarkers of LV Recovery: A Paradigm Shift in Acute Myocardial Infarction Imaging. PMID- 27771398 TI - Myocardial Extracellular Volume Estimation by CMR Predicts Functional Recovery Following Acute MI. AB - OBJECTIVES: In the setting of reperfused acute myocardial infarction (AMI), the authors sought to compare prediction of contractile recovery by infarct extracellular volume (ECV), as measured by T1-mapping cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) transmural extent. BACKGROUND: The transmural extent of myocardial infarction as assessed by LGE CMR is a strong predictor of functional recovery, but accuracy of the technique may be reduced in AMI. ECV mapping by CMR can provide a continuous measure associated with the severity of tissue damage within infarcted myocardium. METHODS: Thirty-nine patients underwent acute (day 2) and convalescent (3 months) CMR scans following AMI. Cine imaging, tissue tagging, T2-weighted imaging, modified Look-Locker inversion T1 mapping natively and 15 min post-gadolinium-contrast administration, and LGE imaging were performed. The ability of acute infarct ECV and acute transmural extent of LGE to predict convalescent wall motion, ejection fraction (EF), and strain were compared per-segment and per-patient. RESULTS: Per-segment, acute ECV and LGE transmural extent were associated with convalescent wall motion score (p < 0.01; p < 0.01, respectively). ECV had higher accuracy than LGE extent to predict improved wall motion (area under receiver-operating characteristics curve 0.77 vs. 0.66; p = 0.02). Infarct ECV <=0.5 had sensitivity 81% and specificity 65% for prediction of improvement in segmental function; LGE transmural extent <=0.5 had sensitivity 61% and specificity 71%. Per-patient, ECV and LGE correlated with convalescent wall motion score (r = 0.45; p < 0.01; r = 0.41; p = 0.02, respectively) and convalescent EF (p < 0.01; p = 0.04). ECV and LGE extent were not significantly correlated (r = 0.34; p = 0.07). In multivariable linear regression analysis, acute infarct ECV was independently associated with convalescent infarct strain and EF (p = 0.03; p = 0.04), whereas LGE was not (p = 0.29; p = 0.24). CONCLUSIONS: Acute infarct ECV in reperfused AMI can complement LGE assessment as an additional predictor of regional and global LV functional recovery that is independent of transmural extent of infarction. PMID- 27771400 TI - Primary and Secondary Prevention, or Subclinical and Clinical Atherosclerosis. PMID- 27771399 TI - Noninvasive CT-Derived FFR Based on Structural and Fluid Analysis: A Comparison With Invasive FFR for Detection of Functionally Significant Stenosis. AB - OBJECTIVES: This study describes the feasibility and accuracy of a novel computed tomography (CT) fractional flow reserve (FFR) technique based on alternative boundary conditions. BACKGROUND: Techniques used to compute FFR based on images acquired from coronary computed tomography angiography (CTA) are described. Boundary conditions were typically determined by allometric scaling laws and assumptions regarding microvascular resistance. Alternatively, boundary conditions can be derived from the structural deformation of coronary lumen and aorta, although its accuracy remains unknown. METHODS: Forty-two patients (78 vessels) in a single institution prospectively underwent 320-detector coronary CTA and FFR. Deformation of coronary cross-sectional lumen and aorta, computed from coronary CTA images acquired over diastole, was used to determine the boundary conditions based on hierarchical Bayes modeling. CT-FFR was derived using a reduced order model performed using a standard desktop computer and dedicated software. First, 12 patients (20 vessels) formed the derivation cohort to determine optimal CT-FFR threshold with which to detect functional stenosis, defined as FFR of <=0.8, which was validated in the subsequent 30 patients (58 vessels). RESULTS: Derivation cohort results demonstrated optimal threshold for CT-FFR was 0.8 with 67% sensitivity and 91% specificity. In the validation cohort, CT-FFR was successfully computed in 56 of 58 vessels (97%). Compared with coronary CTA, CT-FFR at <=0.8 demonstrated a higher specificity (87% vs. 74%, respectively) and positive predictive value (74% vs. 60%, respectively), with comparable sensitivity (78% vs. 79%, respectively), negative predictive value (89% vs. 88%, respectively), and accuracy (area under the curve: 0.88 vs. 0.77, respectively; p = 0.22). Based on Bland-Altman analysis, mean intraobserver and interobserver variability values for CT-FFR were, respectively, -0.02 +/- 0.05 (95% limits of agreement: -0.12 to 0.08) and 0.03 +/- 0.06 (95% limits: 0.07 to 0.19). Mean time per patient for CT-FFR analysis was 27.07 +/- 7.54 min. CONCLUSIONS: CT-FFR based on alternative boundary conditions and reduced-order fluid model is feasible, highly reproducible, and may be accurate in detecting FFR <= 0.8. It requires a short processing time and can be completed at point-of care. Further validation is required in large prospective multicenter settings. PMID- 27771401 TI - Combination of ECG and Echocardiography for Identification of Arrhythmic Events in Early ARVC. AB - OBJECTIVES: The aim of this study was to investigate early markers of arrhythmic events (AEs) and improve risk stratification in early arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: AEs are frequent in patients with ARVC, but risk stratification in subjects with early ARVC is challenging. METHODS: Early ARVC disease was defined as possible or borderline ARVC diagnosis according to the ARVC Task Force Criteria 2010. We performed resting and signal averaged electrocardiogram (ECG). Using echocardiography, we assessed right ventricular (RV) outflow tract diameter and right ventricular basal diameter (RV diameter). Global longitudinal strain and mechanical dispersion (MD) from strain echocardiography were assessed in both the right and left ventricle. AEs were defined as documented ventricular tachycardia, cardiac syncope, or aborted cardiac arrest. RESULTS: Of 162 included subjects with ARVC (41 +/- 16 years of age, 47% female), 73 had early ARVC, including mutation positive family members not fulfilling definite ARVC diagnosis. AEs occurred in 15 (21%) subjects with early ARVC. Those with AEs in early disease had larger RV diameter (40 +/- 4 mm vs. 37 +/- 5 mm), more pronounced RVMD (39 +/- 15 ms vs. 26 +/- 11 ms), and more pathological signal averaged ECGs compared with those without AEs (all p <= 0.05). Adding measurements of RV diameter and RVMD to electrical parameters improved identification of subjects with AEs compared with electrical parameters alone (p = 0.05). CONCLUSIONS: ECG parameters, RV diameter, and RVMD were markers of previous arrhythmic events in patients with early ARVC. A combination of electrical and echocardiographic parameters improved identification of subjects with AEs in early ARVC disease. PMID- 27771402 TI - Moving From Multimodality Diagnostic Tests Toward Multimodality Risk Stratification in ARVC. PMID- 27771403 TI - The New Era of Computational Fluid Dynamics in CT Angiography: Far Beyond the FFR Number. PMID- 27771404 TI - Impact of Intensive LDL Cholesterol Lowering on Coronary Artery Atherosclerosis Progression: A Serial CT Angiography Study. AB - OBJECTIVES: The aim of this study was to explore the relationship between temporal changes in coronary plaque volume and the intensity of lipid-lowering treatments, utilizing coronary computed tomography angiography (CTA). BACKGROUND: Coronary CTA has acceptable accuracy in terms of quantitative measurement of plaque volume. Although, coronary CTA is perhaps capable of identifying the differences in plaque volume progression according to the intensity of lipid lowering treatment, to date, few studies have examined this notion. METHODS: In this multicenter, observational study, the authors reviewed 467 patients who underwent serial coronary CTA with a scan period of more than 2 years (median 3.2 years [2.4 to 4.8]) apart, and whose laboratory data were available within 1 month of both the baseline and follow-up coronary CTA. Among them, 147 patients (comprising 336 vessels) with visible plaque were enrolled in this study. The authors performed quantitative assessment of coronary plaque in both. Patients who achieved a low-density lipoprotein cholesterol (LDL-C) with a cut off value below 70 mg/dl at follow-up were compared with those who did not. RESULTS: Patients with LDL-C below 70 mg/dl displayed a significant attenuation in plaque progression as compared with those with follow-up LDL-C levels >=70 mg/dl (12.7 +/- 38.2 mm3 vs. 44.2 +/- 73.6 mm3, respectively; p = 0.014). In multivariate analysis, factors influencing plaque progression per year was follow-up LDL-C levels >=70 mg/dl (beta 0.193; p = 0.021). CONCLUSIONS: Strict LDL-C control appeared to significantly attenuate plaque volume progression based on noninvasive quantitative assessment by coronary CTA. PMID- 27771406 TI - Covalent immobilization of tyrosinase onto cyanuric chloride crosslinked amine functionalized superparamagnetic nanoparticles: Synthesis and characterization of the recyclable nanobiocatalyst. AB - Magnetic nanoparticles (MNPs) were synthesized using the chemical co precipitation method. Then the nanoparticles were coated with silica via hydrolysis of tetraethyl orthosilicate using the sol-gel process. The silica coated magnetic nanoparticles were amine-functionalized with 3 aminopropyltriethoxysilane/ethanol solution. Subsequently, the nanoparticles were added to a solution of cyanuric chloride in tetrahydrofuran to synthesize cyanuric chloride-functionalized magnetic nanoparticles (Cy-MNPs). For covalent immobilization of tyrosinase, Cy-MNPs were added to a freshly prepared tyrosinase solution and the mixture was shaken. The FTIR spectra, as well as EDX, analysis proved the covalent immobilization of tyrosinase on the nanoparticles. The magnetic properties of tyrosinase-immobilized magnetic nanoparticles (tyrosinase MNPs) were specified by VSM analysis. TEM images indicated that the most of the tyrosinase-MNPs had a semi-spherical shape with an average size of 17nm. The synthesized nanoparticles had a high loading capacity of 194mg tyrosinase/g nanoparticles with an immobilization yield of 69%. The optimum condition for both free and immobilized tyrosinase was found at pH 7.0 and 35 degrees C. The immobilized enzyme was active after treatment of the particles at various pHs and temperatures for 100min. In addition, reusability of the immobilized enzyme was investigated and it was proved its suitability to be used for more than 7 cycles. Also, tyrosinase-MNPs remained about 70% of its initial activity after storing at 4 degrees C for 40days. This nanobiocatalyst with interesting properties is promising for practical application in wastewater treatment and biosensor development. PMID- 27771405 TI - Cadmium modulates hematopoietic stem and progenitor cells and skews toward myelopoiesis in mice. AB - The heavy metal cadmium (Cd) is known to modulate immunity and cause osteoporosis. However, how Cd influences on hematopoiesis remain largely unknown. Herein, we show that wild-type C57BL/6 (B6) mice exposed to Cd for 3months had expanded bone marrow (BM) populations of long-term hematopoietic stem cells (LT HSCs), common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs), while having reduced populations of multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). A competitive mixed BM transplantation assay indicates that BM from Cd-treated mice had impaired LT-HSC ability to differentiate into mature cells. In accordance with increased myeloid progenitors and decreased lymphoid progenitors, the BM and spleens of Cd-treated mice had more monocytes and/or neutrophils and fewer B cells and T cells. Cd impaired the ability of the non-hematopoietic system to support LT-HSCs, in that lethally irradiated Cd-treated recipients transplanted with normal BM cells had reduced LT HSCs after the hematopoietic system was fully reconstituted. This is consistent with reduced osteoblasts, a known critical component for HSC niche, observed in Cd-treated mice. Conversely, lethally irradiated control recipients transplanted with BM cells from Cd-treated mice had normal LT-HSC reconstitution. Furthermore, both control mice and Cd-treated mice that received Alendronate, a clinical drug used for treating osteoporosis, had BM increases of LT-HSCs. Thus, the results suggest Cd increase of LT-HSCs is due to effects on HSCs and not on osteoblasts, although, Cd causes osteoblast reduction and impaired niche function for maintaining HSCs. Furthermore, Cd skews HSCs toward myelopoiesis. PMID- 27771407 TI - Role of alginate in antibacterial finishing of textiles. AB - Antibacterial finishing of textiles has been introduced as a necessary process for various purposes especially creating a fabric with antimicrobial activities. Currently, the textile industry continues to look for textiles antimicrobial finishing process based on sustainable biopolymers from the viewpoints of environmental friendliness, industrialization, and economic concerns. This paper reviews the role of alginate, a sustainable biopolymer, in the development of antimicrobial textiles, including both basic physicochemical properties of alginate such as preparation, chemical structure, molecular weight, solubility, viscosity, and sol-gel transformation property. Then different processing routes (e.g. nanocomposite coating, ionic cross-linking coating, and Layer-by-Layer coating) for the antibacterial finishing of textiles by using alginate are revised in some detail. The achievements in this area have increased our knowledge of alginate application in the field of textile industry and promoted the development of green textile finishing. PMID- 27771408 TI - Activity of a peptidase secreted by Phanerochaete chrysosporium depends on lysine to subsite S'1. AB - Peptidases are enzymes that catalyze the rupture of peptide bonds. Catalytic specificity studies of these enzymes have illuminated their modes of action and preferred hydrolysis targets. We describe the biochemical characteristics and catalytic specificity of a lysine-dependent peptidase secreted by the basidiomycete fungus Phanerochaete chrysosporium. We attained 5.7-fold purification of a ~23-kDa neutral peptidase using size-exclusion (Sephadex G-50 resin) and ion-exchange (Source 15S resin) chromatography. Using the Fluorescence Resonance Energy Transfer substrate Abz-KLRSSKQ-EDDnp, we detected maximal activity at pH 7.0 and 45-55 degrees C. The peptidase retained ~80% of its enzymatic activity for a wide range of conditions (pH 4-9; temperatures up to 50 degrees C for 1h). The peptidase activity was lowered by the ionic surfactants, sodium dodecyl sulfate and cetyltrimethylammonium bromide; the reducing agent, dithiothreitol; the chaotrope, guanidine; copper (II) ion; and the cysteine peptidase-specific inhibitors, iodoacetic acid and N-ethylmaleimide. The peptidase preferred the basic amino acids K and R and high selectivity on S'1 subsite, exhibiting a condition of lysine-dependence to catalysis on anchoring of this subsite. PMID- 27771409 TI - A new TRAF-like protein from B. oleracea ssp. botrytis with lectin activity and its effect on macrophages. AB - Lectins are involved in a wide range of biological mechanisms, like immunomodulatory agent able to activate the innate immunity. In this study, we purified and characterized a new lectin from cauliflower (Brassica oleracea ssp. botrytis - BOL) by three sequential chromatographic steps and confirmed the purity by SDS-PAGE. Additionally, we evaluated the role of the lectin in innate immunity by a phagocytosis assay, production of H2O2 and NO. BOL was characterized like a non-glycosylated protein that showed a molecular mass of ~34kDa in SDS-PAGE. Its N-terminal sequence (ETRAFREERPSSKIVTIAG) did not reveal any similarity to the other lectins; nevertheless, it showed 100% homology to a putative TRAF-like protein from Brassica rapa and Brassica napus. This is a first report of the TRAF-protein with lectinic activity. The BOL retained its complete hemagglutination activity from 4 degrees C up to 60 degrees C, with stability being more apparent between pH 7.0 and 8.0. Moreover, the lectin was able to stimulate phagocytosis and induce the production of H2O2 and NO. Therefore, BOL can be explored as an immunomodulatory agent by being able to activate the innate immunity and favor antigen removal. PMID- 27771410 TI - Use of Plantago major seed mucilage as a novel edible coating incorporated with Anethum graveolens essential oil on shelf life extension of beef in refrigerated storage. AB - In this study, Plantago major seed mucilage (PMSM) was extracted from whole seeds using hot-water extraction (HWE). The dill (D) essential oil components were identified through gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS) and its antioxidant properties were examined through the methods of 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant potential (FRAP) and beta-carotene-linoleic acid assay (B-CL). Total phenolic content (TPC) was characterized through the Folin-Ciocalteu method and the antimicrobial effect was evaluated on 10 pathogenic microorganisms. PMSM edible coating incorporated were prepared in four different concentrations of essential oils, including 0, 0.5, 1 and 1.5% (w/w). The control and the coated beef samples were analyzed periodically for microbiological (total viable count, psychrotrophic count, Escherichia coli, Staphylococcus aureus and fungi), chemical (thiobarbituric acid, peroxide value and pH), and sensory characteristics. The IC50, FRAP, B-CL and TPC of the dill essential oil were equal to 11.44MUg/ml, 9.45mmol/g, 82.86 and 162.65MUg/ml GAE, respectively. PMSM extended the microbial shelf life of beef by 3days, whereas the PMSM+0.5%D, PMSM+1%D and PMSM+1.5%D resulted in a significant shelf life extension of the beef by 6, 9 and 9days, respectively, as compared to the control samples. PMID- 27771411 TI - Da-KGM based GO-reinforced FMBO-loaded aerogels for efficient arsenic removal in aqueous solution. AB - Composites based on deacetylated konjac glucomannan (Da-KGM) and graphene oxide (GO) aerogels with iron and manganese oxides (FMBO) for effective removal of arsenic from contaminated water. Da-KGM, which was used as supporting composite matrix here, were firstly treated with GO and loaded FMBO. The obtained Da KGM/GO/FMBO composite aerogels were characterized by compression test, thermo gravimetric analysis (TGA), X-ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). The characteristic results showed that addition of GO exhibited enhanced mechanical properties towards Da-KGM aerogels. What's more, results of FTIR indicated the strong intermolecular hydrogen bond interaction between KGM and GO. Batch adsorption tests were used to evaluate arsenic removal capacity. Da-KGM/GO loaded FMBO composite aerogels exhibited high adsorption ability for arsenite [As(III)] and arsenate [As(V)]. The adsorption results showed that the arsenic for both arsenite [As(III)] and arsenate [As(V)] removal process followed a pseudo-second order rate equation and Langmuir monolayer adsorption. The maximum As(III) and As(V) uptake capacity of Da-KGM/GO(10%)/FMBO composite aerogels reached 30.21mgg 1 and 12.08mgg-1 respectively according to Langmuir isotherm at pH 7 and 323K. PMID- 27771413 TI - A direct detection of human papillomavirus 16 genomic DNA using gold nanoprobes. AB - Nanoparticles have been investigated as flagging tests for the sensitive DNA recognition that can be utilized as a part of field applications to defeat restrictions. Gold nanoparticles (AuNPs) have been widely utilized due to its optical property and capacity to get functionalized with a mixed bag of biomolecules. This study exhibits the utilization of AuNPs functionalized with single-stranded oligonucleotide (AuNP-oligo test) for fast the identification of Human Papillomavirus (HPV). This test is displayed on interdigitated electrode sensor and supported by colorimetric assay. DNA conjugated AuNP has optical property that can be controlled for the applications in diagnostics. With its identification abilities, this methodology incorporates minimal effort, strong reagents and basic identification of HPV. PMID- 27771412 TI - Co-precipitation synthesis and characterization of Co doped SnO2 NPs, HSA interaction via various spectroscopic techniques and their antimicrobial and photocatalytic activities. AB - Sn1-xCoxO2 (x=0.00, 0.01, 0.03, 0.05) nanoparticles (NPs) of average size ~30 40nm were synthesized by co-precipitation method. The interaction of Co doped SnO2 NPs with human serum albumin (HSA) and their photocatalytic and antimicrobial properties were studied. The structural analysis and morphology of Co doped SnO2 NPs were analysed via X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), high resolution transmission electron microscopy (HRTEM) and Fourier transform infrared spectroscopy (FT-IR). Besides the structural and morphological analysis, the interaction of Co doped SnO2 NPs with HSA were studied by UV-vis, Circular dichroism (CD) and fluorescence spectroscopy. Fluorescence quenching results suggest that Co doped SnO2 NPs interact with an HSA molecule through static mechanism. CD indicates that alpha-helicity of HSA increases due to the interaction of Co doped SnO2 NPs. The photocatalytic activities of the NPs with increased doping concentration were evaluated through a degradation process in the presence of methylene-blue (MB) dye under UV light irradiation, which exhibited that the surface area of NPs with increased doping concentration plays a major role in improving the photocatalytic activity. The antimicrobial effect of undoped and Co-doped SnO2 NPs was determined using agar-well diffusion method and analyzed against gram-positive bacteria (Bacillus Cereus MC 2434). In our results, we have found that as the doping concentration increases into NPs, zone of inhibition increases, which could be ascribed to the production of ROS and large surface area of the NPs. PMID- 27771414 TI - Determination of the distributions of degrees of acetylation of chitosan. AB - Chitosan is often characterized by its average degree of acetylation. To increase chitosan's use in various industries, a more thorough characterization is necessary as the acetylation of chitosan affects properties such as dissolution and mechanical properties of chitosan films. Despite the poor solubility of chitosan, free solution capillary electrophoresis (CE) allows a robust separation of chitosan by the degree of acetylation. The distribution of degrees of acetylation of various chitosan samples was characterized through their distributions of electrophoretic mobilities. These distributions can be obtained easily and with high precision. The heterogeneity of the chitosan chains in terms of acetylation was characterized through the dispersity of the electrophoretic mobility distributions obtained. The relationship between the number-average degree of acetylation obtained by solid-state NMR spectroscopy and the weight average electrophoretic mobilities was established. The distribution of degrees of acetylation was determined using capillary electrophoresis in the critical conditions (CE-CC). PMID- 27771415 TI - Structural transition of kidney cystatin induced by silicon dioxide nanoparticles: An implication for renal diseases. AB - Nanotechnology is one of the fastest growing fields of science owing to use of nanomaterials in industries and medicine across the globe. Currently silicon dioxide nanoparticles (SiO2 NPs) are one of the most popular nanomaterials owing to their inert toxicity profile and hence exposure to SiO2 nanoparticles is on the increase. Cystatins are thiol proteinase inhibitors (TPIs) ubiquitously distributed in plants and animals and they are now at the heed of a number of normal and pathological conditions and shouldn't be regarded solely as TPIs. Up till now many studies have targeted the potential toxicity of NPs on pulmonary target; although little focus is given to kidney which is a secondary target organ. The objective of this work is to study the structural changes in buffalo kidney cystatin (BKC) induced by SiO2 NPs. UV and Fluorescence spectroscopy shows BKC transformation from native to non-native form evident by decreased absorbance and increased fluorescence. FTIR and CD spectroscopy further confirmed secondary structure disruption of BKC. Isothermal titration calorimetry (ITC) and microscopy were resorted to visualize interaction between SiO2 NPs and BKC. Comet assay and MTT assay were utilized to perceive the toxicity of SiO2 NPs incubated BKC; decreased cell viability clearly suggesting toxicity of SiO2 NPs incubated BKC. Our work suggests that SiO2 NPs have a deteriorating effect on BKC thereby causing a decrease in its ability to inhibit papain and hence less functionality. This study also shows that BKC transforms to a toxic non-native form in presence of SiO2 NPs. PMID- 27771416 TI - Candidate gene analysis of the fibrinogen phenotype reveals the importance of polygenic co-regulation. AB - Fibrinogen and its functional aspects have been linked to cardiovascular disease. There is vast discrepancy between the heritability of fibrinogen concentrations observed in twin studies and the heritability uncovered by genome wide association studies. We postulate that some of the missing heritability might be explained by the pleiotropic and polygenic co-regulation of fibrinogen through multiple targeted genes, apart from the fibrinogen genes themselves. To this end we investigated single nucleotide polymorphisms (SNPs) in genes coding for phenotypes associated with total and gamma' fibrinogen concentrations and clot properties. Their individual and accumulative associations with the fibrinogen variables were explored together with possible co-regulatory processes as a result of the gain and loss of transcription factor binding sites (TFBS). Seventy eight SNPs spanning the APOB, APOE, CBS, CRP, F13A1, FGA, FGB, FGG, LDL-R, MTHFR, MTR, PCSK-9 and SERPINE-1 genes were included in the final analysis. A novel PCSK 9 SNP (rs369066144) was identified in this population, which associated significantly (p=0.04) with clot lysis time (CLT). Apart from SNPs in the fibrinogen (FGA, FGB and FGG) and FXIII (F13A1) genes, the fibrinogen phenotypes were also associated with SNPs in genes playing a role in lipid homeostasis (LDL R, PCSK-9) together with CBS and CRP polymorphisms (particularly, CRP-rs3093068). The genetic risk scores, presenting accumulative genetic risk, were significantly associated (p<=0.007) with total and gamma' fibrinogen concentrations, lag time, slope and CLT, highlighting the importance of a polygenetic approach in determining complex phenotypes. SNPs significantly associated with the fibrinogen phenotypes, resulted in a total of 75 TFBS changes, of which 35 resulted in a loss and 40 in a gain of TFBS. In terms of co-regulation, V$IRF4.02, V$E2FF and V$HIFF were of particular importance. The investigation into TFBS provided valuable insight as to how sequence divergences in seemingly unrelated genes can result in transcriptional co-regulation of the fibrinogen phenotypes. The observed associations between the identified SNPs and the fibrinogen phenotypes therefore do not imply direct effects on cardiovascular disease outcomes, but may prove useful in explaining more of the genetic regulation of the investigated fibrinogen phenotypes. PMID- 27771417 TI - The role of exhaled nitric oxide in patients with chronic obstructive pulmonary disease undergoing laparotomy surgery - The noxious study. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) has been associated with major perioperative morbidities or mortalities, especially in surgical patients receiving general anesthesia. The severity of the COPD and the degree of bronchial hyperreactivity can determine the perioperative anesthetic risk; therefore they have to be assessed by a thorough preoperative evaluation in order to give the rationale on which to decide for optimum anesthetic management. OBJECTIVE: Aim of the study was to assess the predictive applicability of exhaled Nitric Oxide (NO) in smoking surgical population with COPD, on the basis of morbidity and mortality. METHODS: A prospective, observational study was undertaken in 70 smoking patients diagnosed with COPD scheduled for laparotomy surgery under general anesthesia COPD was evaluated with the GOLD Classification of Air Flow Limitation, the Modified MRC Dyspnoea Scale (mMRC), the BODE Index score and the 6 Minutes Walk Distance (6MWD) using spirometry parameters. All patients were observed for presenting perioperative and postoperative respiratory complications. A cut off value of 19 ppb was determined for fractional exhaled nitric oxide measured at expiratory flow of 50 mL/s (FENO50) to differentiate patients poor prognosis from those with favorable outcome. RESULTS: Patients with severe COPD had high BODE index score as well as FENO50. Elevated FENO50 is significantly related to multiple complications (p = 0.004) and postoperative cough (p < 0.001). Patients from the high FENO50 group that were not treated with steroids had a statistically significant higher incidence of extra hospital care need (p < 0.001). Increased FENO50 and ABCD classification are both related with the presentation of multiple complications (Odds ratio = 2.5, 95% CI 1.1 to 5.7, p = 0.028 for ABCD and Odds ratio = 6.39, 95% CI 1.33 to 30.5, p = 0.020 for FENO50). Increased FENO50 and ABCD are related with extra hospital care (p = 0.001 and p = 0.002 respectively) and combined with corticosteroid administration could predict the necessity for extra hospital care (Odds ratio 4.09, 95% CI 1.1 to 15.3, p = 0.036 for corticosteroid treatment, odds ratio 2.4, 95% CI 1.1 to 5.1, p = 0.029 for ABCD and odds ratio 7.93, 95% CI 1.7 to 35.3, p = 0.007 for FENO50). CONCLUSION: The FENO50 may identify high risk smoking surgical patients with COPD receiving general anesthesia. Perioperative and postoperative complications in COPD smoking patients undergoing abdominal surgery can be predicted using not only ABCD GOLD 2011 classification but also the FENO50 as a preoperative marker. PMID- 27771418 TI - How unlicensed drug vendors in rural Uganda perceive their role in the management of childhood malaria. AB - BACKGROUND: A large number of caregivers in Uganda rely on the private drug delivery sector to manage childhood illnesses such as malaria. In rural settings where the formal private sector is scarce, unlicensed retail drug outlets are an important initial source of care for households. Despite their abundance, little is known about them. This study explores unlicensed retail drug outlet vendors' perceptions of their practice and social environment in one rural district of Uganda. MATERIALS AND METHODS: A qualitative design using semi-structured interviews was conducted with vendors from unlicensed retail drug outlets across all 10 sub-counties of Butaleja District. The study was conducted over a six-week period in 2011. Open-ended questions were used to gain insight into participants' perspectives, and data were analyzed using acceptable qualitative research protocols. RESULTS: Interviews were carried out with 75 vendors by trained local research assistants. Most vendors operated out of drug shops, just over half were both owners and shop attendants, and only 14% had qualifications to apply for operating a licensed drug shop. Vendors' experiences with managing malaria in children aged five and under in their community revealed five major themes, their perceptions of: 1) their role in the community, 2) their ability to manage uncomplicated malaria in young children, 3) the challenges of day-to-day operations, 4) the effect of regulatory policies on their ability to serve their communities, and 5) the prospect of future training programs. While the literature has raised concerns regarding the quality of care provided at such unlicensed outlets, most vendors in this study had a limited awareness of their deficiencies. CONCLUSIONS: There was a general sentiment among vendors that the public health system within Butaleja was failing the community and their presence was filling an important vacuum. Given the dominance of unlicensed retail drug outlets over their formal (licensed) counterparts in many rural settings, further deliberations and research is critical to determine how best to fit in and create value from the unlicensed sector within the formal health system. PMID- 27771419 TI - Aedes (Stegomyia) albopictus' dynamics influenced by spatiotemporal characteristics in a Brazilian dengue-endemic risk city. AB - Brazil reported the majority of the dengue cases in Americas during the last two decades, where the occurrence of human dengue cases is exclusively attributed to the Aedes (Stegomyia) aegypti (Linnaeus). Nowadays, other recognized Dengue virus (DENV) vector in Asian countries, Aedes (Stegomyia) albopictus (Skuse), has been detected in more than half of the 5565 Brazilian municipalities. Therefore, the aim of the present study was to investigate the presence of, and determine the Ae. albopictus' dynamics influenced by spatiotemporal characteristics in a dengue endemic risk city of Belo Horizonte, Minas Gerais State's capital. Aedes albopictus were collected across four consecutive DENV transmission seasons from 2010 to 2014. These mosquitoes were caught in three selected districts, which had been reported in the previous ten years as having high mosquito densities and an elevated concentration of human dengue cases during epidemic seasons. All field caught Ae. albopictus was individually processed by real-time RT-PCR, to research the DENV presence. The third season (p<0.05) and the Pampulha district (p<0.05) had the highest proportions of field-caught Ae. albopictus, respectively. The second season had the highest proportion of DENV-infected field-caught females (p<0.05), but there was no difference among the proportions of DENV-infected Ae. albopictus when comparing the collection in the three districts (p=0.98). Minimum (p=0.004) and maximum (p<0.0001) temperature were correlated with the field caught Ae. albopictus in four different periods and districts. In the generalized linear model of Poisson, the field-caught DENV-infected Ae. albopictus (p=0.005), East district (p=0.003), minimum temperature (p<0.0001) and relative humidity (p=0.001) remained associated with the total number of human dengue cases. Our study demonstrated that the number of field-caught DENV-infected Ae. albopictus was inversed correlated with the number of human dengue cases. Our study raises the possibility that the DENV circulating in mosquitoes Ae. albopictus is happening in non-epidemic periods, showing that this species may be keeping only the presence of the virus in nature. Further long-term studies are necessary to better understand the role of Ae. albopictus in DENV transmission and or its vectorial competence in Belo Horizonte and in other endemic cities in Brazil and in the New World countries. PMID- 27771420 TI - Alterations in serum paraoxonase-1 activity and lipid profile in chronic alcoholic patients infected with Strongyloides stercoralis. AB - The objective of this study was to investigate paraoxonase-1 (PON1) activity, cortisol levels, and the lipid profile in the sera of alcoholic and non-alcoholic Strongyloides stercoralis-infected and uninfected individuals in a sample of 276 individuals attended at the National Health System in Salvador, Bahia, Brazil. The activity of PON1 was measured by the Beltowski method, serum lipids, and cortisol levels using commercial kits. PON1 activity was low in both alcoholic and non-alcoholic individuals infected with S. stercoralis. A positive correlation was observed between PON1 activity and cortisol concentration in alcoholic individuals who were not infected with S. stercoralis; whereas a negative correlation occurred in S. stercoralis-infected nonalcoholic individuals. The levels of triglycerides, LDL-C, and VLDL-C in S. stercoralis infected alcoholic individuals were significantly lower than in uninfected alcoholic individuals. The high level of HDL-C and the low level of LDL-C, VLDL, triglycerides and PON1 activity in alcoholic patients infected with S. stercoralis evidenced an anti-atherogenic pattern. PMID- 27771421 TI - Habitat preference and seasonal dynamics of Phlebotomus orientalis in urban and semi-urban areas of kala-azar endemic district of Kafta Humera, northwest Ethiopia. AB - Visceral leishmaniasis is a significant public health problem in northwest Ethiopia, particularly in Kafta Humera district. The study was designed to determine the species composition and population dynamics of sand flies in five villages representing urban and semi-urban areas of Kafta Humera district namely, Setit Humera, Mykadra, Rawyan, Bereket and Adebay. Sand flies were collected for two to three nights monthly from May 2011 to April 2012 using CDC light-traps and sticky traps. Traps were placed in villages, at periphery of villages and farm fields. Sticky traps were also used for sampling indoor active sand flies. In total, 13,097 sand fly specimens of eight Phlebotomus species and 91,949 Sergentomyia specimens were collected. Among the Phlebotomus, P. orientalis was the predominant species (58.1%) followed by P. papatasi (29.6%), P. lesleyae (5.6%), P. bergeroti (3.8%), P. duboscqi (2.1%), P. alexandri (0.4%), P. heischi (0.2%) and P. rodhaini (0.2%). Significantly, higher number of P. orientalis was caught in Adebay village and the least in Setit Humera town. Seasonal abundance of P. orientalis increased during the dry season (January-May) and dropped drastically in the wet season (late June-September). Significant positive correlation was found between monthly abundance of P. orientalis and the monthly average air and surface soil temperature, while a negative correlation was found with monthly average rainfall and relative humidity. Higher number of P. orientalis was collected outdoors, especially in the farm fields followed by periphery of villages. Thus, various observations strongly suggested P. orientalis to be the principal vector in the study areas, where farm lands and periphery of villages were identified as the most risky habitats, whereas the indoors were the least ones. Appropriate control methods should be designed and implemented according to the knowledge of P. orientalis habitat preferences and seasonal dynamics in the district. PMID- 27771422 TI - Phlegmasia Alba Dolens Caused by a Distended Bladder. AB - We describe the case of a 64-year-old patient with a deep venous thrombosis unusually caused by the obstruction of a severely distended atonic bladder as a result of an iatrogenic injury. Distention of the urinary bladder has previously been described to elevate pressure in the iliac veins, but has seldom been linked to the development of deep venous thrombosis. Through this case, we want to attract attention to this major complication of bladder distention, and we emphasize the importance of proper physical examination. PMID- 27771423 TI - Short-term Complications After Pyeloplasty in Children With Lower Urinary Tract Anomalies. AB - OBJECTIVE: To investigate whether children with lower urinary tract (LUT) anomalies are at greater risk for postoperative complications after laparoscopic pyeloplasty stented with a double-J catheter (JJC). MATERIALS AND METHODS: Prospectively collected data of laparoscopic pyeloplasty (LP) performed between 2006 and 2015 were analyzed. Inclusion criteria are (1) toilet-trained child and (2) unilateral dismembered pyeloplasty stented with a JJC done by the same surgeon. Our pyeloplasty protocol includes cystoscopy and retrograde pyelography. JJC is left in for 3weeks. Asymptomatic patients with infravesical LUT anomalies (a-LUTA) and those with history of LUT symptoms (LUTS) were identified. Any short term complication was classified according to Clavien-Dindo. Fisher's exact test was used for statistical analysis. RESULTS: Fifty-four children (mean 9.8 years) were included. Ten of 54 patients had LUTS. In 4 of those 10, anatomical infravesical anomaly was found during cystoscopy. Accidental urethral anomaly was found in 11 patients (a-LUTA). The control group (CG) consisted of 33 patients. Postoperative hospital stay ranged from 1 to 8 days (mean 2 days). Overall complication rate was 8 of 54 (14%). Grade 1 complications occurred in 3 patients in the CG. Five patients had grade 3 complications (2 needed replacement of bladder catheter, and 3 had diversion of the upper tract). Those problems occurred in 1 of 10 patients with LUTS and 3 of 11 patients with a-LUTA compared to 1 of 33 in the CG. This difference was statistically significant (P < .05). CONCLUSION: Careful history should be taken in toilet-trained children before pyeloplasty. If any infravesical abnormality is discovered, internal diversion should probably be avoided. Special attention must be paid to bladder function in the postoperative period. PMID- 27771424 TI - Impact of Minimally Invasive Benign Prostatic Hyperplasia Therapies on 30- and 90 Day Postoperative Office Encounters. AB - OBJECTIVE: To compare the frequency of postoperative encounters in the 30-day and 90-day postoperative periods for various bladder outlet obstruction surgical therapies. MATERIALS AND METHODS: All patients who underwent transurethral resection of the prostate (TURP), GreenLight laser photovaporization of the prostate (GL-PVP) (American Medical Systems Inc.), and holmium laser enucleation of the prostate (HoLEP) from January 1, 2012 to December 31, 2014 were followed for 6 months postoperatively. All postoperative encounters such as patient calls or questions, catheter exchanges or removals, and hospital-based readmissions or emergency department visits were recorded in the electronic medical record. RESULTS: Two hundred and ninety-one consecutive patients underwent outlet procedures during the study period: TURP (N = 199; mean age, 71 years; mean body mass index [BMI], 28.5), HoLEP (N = 60; mean age, 68 years; mean BMI, 28.1), or GL-PVP (N = 32; mean age, 72 years; mean BMI, 29.3). No statistically significant difference was observed for age, BMI, preoperative American Urological Association symptom score, or preoperative maximum flow velocity between the 3 groups. Thirty-day postoperative encounters differed significantly between the 3 surgery types (P < .001). Specifically, there were fewer encounters within 30 days of surgery for TURP compared to both HoLEP (>=1 encounter: TURP = 48.7%, HoLEP = 66.7%; P = .006) and GL-PVP (>=1 encounter: TURP = 48.7%, GL-PVP = 93.7%; P < .001). The number of encounters within 90 days postoperatively was also significantly lower for TURP patients (P < .001). CONCLUSION: TURP results in fewer postoperative encounters in both the 30-day and 90-day postoperative periods compared to HoLEP and GL-PVP. Laser prostate therapies may place increased burden on clinic staff during the 30-day and 90-day postoperative periods. PMID- 27771426 TI - Editorial introduction: Special issue on plasticity following hearing loss and deafness. PMID- 27771425 TI - Short-Term Preoperative High-Intensity Interval Training in Patients Awaiting Lung Cancer Surgery: A Randomized Controlled Trial. AB - INTRODUCTION: Impairment in aerobic fitness is a potential modifiable risk factor for postoperative complications. In this randomized controlled trial, we hypothesized that a high-intensity interval training (HIIT) program enhances cardiorespiratory fitness before lung cancer surgery and therefore reduces the risk of postoperative complications. METHODS: Patients with operable lung cancer were randomly assigned to usual care (UC) (n = 77) or preoperative rehabilitation based on HIIT (Rehab) (n = 74). Maximal cardiopulmonary exercise testing and the 6-minute walk test were performed twice before surgery. The primary outcome measure was a composite of death and in-hospital postoperative complications. RESULTS: The groups were well balanced in terms of patient characteristics. During the preoperative waiting period (median 25 days), the peak oxygen consumption and the 6-minute walking distance increased (median +15%, interquartile range, 25th to 75 percentile [IQR25%-75%, %] = +9% to +22%, p = 0.003 and +15%, IQR25%-75% = +8% to +28%, p < 0.001, respectively) in the Rehab group, whereas peak oxygen consumption declined in the UC group (median -8%, IQR25%-75% = -16% to 0%], p = 0.005). The primary end point did not differ significantly between the two groups: at least one postoperative complication developed in 27 of the 74 patients (35.5%) in the Rehab group and 39 of 77 patients (50.6%) in the UC group (p = 0.080). Notably, the incidence of pulmonary complications was lower in the Rehab compared with in the UC group (23% versus 44%, p = 0.018), owing to a significant reduction in atelectasis (12.2% versus 36.4%, p < 0.001), and this decrease was accompanied by a shorter length of stay in the postanesthesia care unit (median -7 hours, IQR25%-75% = -4 to -10). CONCLUSIONS: In this randomized controlled trial, preoperative HIIT resulted in significant improvement in aerobic performances but failed to reduce early complications after lung cancer resection. PMID- 27771427 TI - Comparison between total disc replacement and hybrid construct at two lumbar levels with minimum follow-up of two years. AB - INTRODUCTION: Lower back pain due to degenerative disc disease is a therapeutic challenge in young patients. Although arthrodesis is currently the gold standard for surgical treatment, improvement in total disc replacement techniques makes it possible to preserve segmental mobility with good results in one-level surgery. Nevertheless, the French National Health Authority does not recommend total disc replacement for multilevel surgery. Thus, hybrid constructs that combine one level disc replacement with arthrodesis have been developed for multilevel indications. HYPOTHESIS: The outcome of two-level lumbar disc arthroplasty does not differ from hybrid constructs. METHODS: The clinical and radiographic outcomes of disc arthroplasty were compared to hybrid constructs for two-level degenerative disc disease in 72 patients after a continuous follow-up of at least 2 years. The patients were divided into two groups that were similar for the indication and type of implants. RESULTS: There was no statistical difference in pain relief (-3.9 points versus -3.5 points for lumbar VAS) or reduction in ODI ( 29.5% versus -27.0%) between TDR and hybrid constructs, respectively. There was no statistical difference in range of motion at the level of arthroplasty (8.4 degrees versus 7.6 degrees ) and no kinematic dysfunction was identified. The re operation rate at two years for persistent lumbar pain was respectively 6.7% for two-level disc arthroplasty and 4.3% for hybrid constructs. The complication rate was 4.8% and 8.7% respectively. DISCUSSION: No difference was found in this comparison of two homogeneous series between two-level disc arthroplasty and hybrid constructs for the treatment of degenerative disc disease after two years of follow-up. Two-level disc arthroplasty may be an alternative for young patients depending on an evaluation of long-term results. LEVEL OF EVIDENCE: Cohort observational study level III. PMID- 27771428 TI - Preliminary clinical outcomes of Latarjet-Patte coracoid transfer by arthroscopy vs. open surgery: Prospective multicentre study of 390 cases. AB - BACKGROUND: The Latarjet-Patte procedure consisting in transfer and screw fixation of the coracoid process to the anterior glenoid is a treatment of reference for anterior shoulder instability. Over time, surgical innovations translated into a number of improvements and, in late 2003, an arthroscopically assisted variant of the procedure was described. OBJECTIVE: To evaluate and compare clinical outcomes of the modified Latarjet-Patte procedure performed by open surgery, arthroscopy with screw fixation, or arthroscopy with endobutton fixation. MATERIAL AND METHOD: A total of 390 patients who underwent surgery to treat anterior shoulder instability between March 2013 and June 2014 were included and divided into three groups depending on whether they were managed using open surgery with screw fixation, arthroscopy with screw fixation, or arthroscopy with endobutton fixation. Clinical findings were recorded pre operatively then 6 months post-operatively and at last follow-up (mean, 27.7 months). Range of motion and apprehension test (arm in external rotation at 0 degrees , 90 degrees , and 140 degrees of abduction) were assessed and the Walch Duplay and modified Rowe scores were determined. RESULTS: Motion range restriction was minimal with all three techniques, and motion range continued to improve throughout follow-up. Apprehension in external rotation was noted at 90 degrees of abduction in 11% of cases and at 140 degrees of abduction in 4% of cases. The mean total Walch-Duplay score improved from 46 pre-operatively to 90.6 and the mean total modified Rowe score from 46 pre-operatively to 91.1. By statistical analysis, external rotation at 90 degrees of abduction and internal rotation at 0 degrees of abduction were better after open surgery, but the differences were of limited clinical significance. Recurrence was noted in 3.3% of cases, nerve injury in 0.8%, and infection in 1.5%. CONCLUSION: In this study, the three techniques produced similar clinical outcomes, with a stable shoulder and no joint stiffness. PMID- 27771429 TI - Total knee implant posterior stabilised by a third condyle: Design evolution and post-operative complications. AB - BACKGROUND: Despite excellent long-term outcomes, posterior stabilisation by a third condyle continues to receive unwarranted criticism regarding patellar complications and instability. HYPOTHESIS: Complication rates with a tri-condylar posterior-stabilised implant are similar to those with other posterior-stabilised prostheses and have diminished over time due to improvements in prosthesis design. MATERIAL AND METHODS: Post-operative complications and revision rates were assessed retrospectively in a prospective cohort of 4189 consecutive patients who had primary total knee arthroplasty (TKA) using a tri-condylar posterior-stabilised implant (Wright-Tornier) and were then followed-up for at least 24 months. The analysis included 2844 knees. The prosthesis generations were HLS1(r), n=20; HLS2(r), n=220; HLS Evolution(r), n=636; HLS Noetos(r), n=1373; and HLS KneeTec(r), n=595. Complications were compared across generations by applying Fisher's exact test, and survival was compared using the Kaplan-Meier method. RESULTS: At last follow-up, there had been 341 (12%) post-operative complications in 306 (10.8%) knees, including 168 (5.9%) related to the implant, 41 (1.4%) infections, and 132 (4.6%) secondary complications unrelated to the implant. Re-operation was required for 200 complications (7%), including 87 (3.1%) consisting in revision of the prosthesis. Implant-related complications were stiffness (n=67, 2.4%), patellar fracture (n=34, 1.2%), patellar clunk syndrome (n=25, 0.9%), patellar loosening (n=3, 0.1%), tibial/femoral loosening (n=15, 0.5%), polyethylene wear (n=3, 0.1%), and implant rupture (n=1, 0.04%). Significant differences across generations were found for stiffness (P<0.0001), patellar fracture (P=0.03), clunk syndrome (P=0.03), and polyethylene wear (P=0.004), whose frequencies declined from one generation to the next. Overall 10 year survival was 92% with no significant difference across generations (P=0.1). DISCUSSION: Outcomes of tri-condylar posterior-stabilised TKA are similar to those obtained using other posterior-stabilised implants. Neither patellar complications nor instability are more common, and improvements in implant design have contributed to correct early flaws. LEVEL OF EVIDENCE: IV, historical cohort, retrospective assessment of prospectively collected data. PMID- 27771431 TI - Nanoscale imaging and characterization of Caenorhabditis elegans epicuticle using atomic force microscopy. AB - Here we introduce PeakForce Tapping non-resonance atomic force microscopy for imaging and nanomechanical mapping of Caenorhabditis elegans nematodes. The animals were imaged both in air and water at nanoscale resolution. Layer-by-layer glass surface modification was employed to secure the worms for imaging in water. Microtopography of head region, annuli, furrows, lateral alae and tail region was visualized. Analysis of nanoscale surface features obtained during AFM imaging of three larval and adult hermaphrodite nematodes in natural environment allowed for numerical evaluation of annuli periodicity, furrows depth and annuli roughness. Nanomechanical mapping of surface deformation, Young modulus and adhesion confirms that the mechanical properties of the nematode cuticle are non-uniform. Overall, PeakForce Tapping AFM is a robust and simple approach applicable for nanoscale three-dimensional imaging and characterization of C. elegans nematodes. PMID- 27771430 TI - Neuronal protection against oxidative insult by polyanhydride nanoparticle-based mitochondria-targeted antioxidant therapy. AB - A progressive loss of neuronal structure and function is a signature of many neurodegenerative conditions including chronic traumatic encephalopathy, Parkinson's, Huntington's and Alzheimer's diseases. Mitochondrial dysfunction and oxidative and nitrative stress have been implicated as key pathological mechanisms underlying the neurodegenerative processes. However, current therapeutic approaches targeting oxidative damage are ineffective in preventing the progression of neurodegeneration. Mitochondria-targeted antioxidants were recently shown to alleviate oxidative damage. In this work, we investigated the delivery of biodegradable polyanhydride nanoparticles containing the mitochondria targeted antioxidant apocynin to neuronal cells and the ability of the nano formulation to protect cells against oxidative stress. The nano-formulated mitochondria-targeted apocynin provided excellent protection against oxidative stress-induced mitochondrial dysfunction and neuronal damage in a dopaminergic neuronal cell line, mouse primary cortical neurons, and a human mesencephalic cell line. Collectively, our results demonstrate that nano-formulated mitochondria-targeted apocynin may offer improved efficacy of mitochondria targeted antioxidants to treat neurodegenerative disease. PMID- 27771432 TI - Fullerene nanoparticle in dermatological and cosmetic applications. AB - Nanoparticles are equipped with exceptional properties which make them well suitable for diverse and novel applications. Fullerene is one of the nanomaterials that has valuable applications in the field of biomedicine. It possesses exceptional antioxidant capacity which has made it a promising core ingredient in many dermatological and skin care products. However, fullerene has the potentials to display a range of activities resulting in cell death or dysfunction. This review outlines the achievements made so far by reporting studies that have focused on incorporating fullerene in skin care products and cosmetics and assessed their beneficial effects. We have also documented reports that have assessed toxicity of this novel carbon allotrope toward skin cells and discussed its possible dermal reactions. Aside from pointing out the recent developments, areas that can benefit from further researches are identified. PMID- 27771433 TI - Cells redox environment modulates BRCA1 expression and DNA homologous recombination repair. AB - Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS. However, increase in oxidative DNA lesions does not always lead to malignancy. Hence, additional ROS-dependent, pro-carcinogenic mechanisms must be important. Our recent study demonstrated that Tyr nitration of PP2A stimulates its activity and leads to downregulation of BRCA1 expression. This provides a mechanism for chromosomal instability essential for tumor progression. In the present work, we demonstrated that inhibition of ROS production by generating mitochondrial electron-transport-deficient cell lines (rho0 cells) or by inhibition of NOX activity with a selective peptide inhibitor significantly reduced PP2A Tyr nitration and its activity in different cancer cell lines. As a result of the decreased PP2A activity, BRCA1 expression was restored along with a significantly enhanced level of DNA HRR. We used TCGA database to analyze the correlation between expressions of the NOX regulatory subunits, NOS isoforms, and BRCA1 in the 3 cancer research studies: breast invasive carcinoma, ovarian cystadenocarcinoma, and lung adenocarcinoma. TCGA database analysis demonstrated that the high expression levels of most of the NOX regulatory subunits responsible for stimulation of NOX1-NOX4 were associated with significant downregulation of BRCA1 expression. PMID- 27771435 TI - New therapeutic opportunities for 5-HT2 receptor ligands. AB - Serotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. Serotonin (5-hydroxytryptamine, 5-HT) mediates numerous physiological functions in the brain and the periphery by activating a variety of receptors. 5 HT receptors are divided into four classes, three of which belong to the G protein-coupled receptor family. This review provides an overview of the recent pharmacological developments involving the Gq-coupled 5-HT2 receptor subfamily as well as the pathological implications of this receptor subfamily with regard to fibrosis, the central nervous system, cardiovascular disorders, and cancer. The final section highlights new therapeutic opportunities and emerging research revealing unexplored medical opportunities for this class of 5-HT receptors. The development of biased 5-HT2 receptor ligands appears to be an interesting topic in various areas. In light of recent discoveries, the need for the development of new and safer drugs should take into account the risk of cardiovascular side effects such as pulmonary hypertension and heart valve disease. PMID- 27771436 TI - Clinical potential of oligonucleotide-based therapeutics in the respiratory system. AB - The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition. PMID- 27771437 TI - Specific histone modifications play critical roles in the control of encystation and antigenic variation in the early-branching eukaryote Giardia lamblia. AB - During evolution, parasitic microorganisms have faced the challenges of adapting to different environments to colonize a variety of hosts. Giardia lamblia, a common cause of intestinal disease, has developed fascinating strategies to adapt both outside and inside its host's intestine, such as trophozoite differentiation into cyst and the switching of its major surface antigens. How gene expression is regulated during these adaptive processes remains undefined. Giardia lacks some typical eukaryotic features, like canonical transcription factors, linker histone H1, and complex promoter regions; suggesting that post-transcriptional and translational control of gene expression is essential for parasite survival. However, epigenetic factors may also play critical roles at the transcriptional level. Here, we describe the most common post-translational histone modifications; characterize enzymes involved in these reactions, and analyze their association with the Giardia's differentiation processes. We present evidence that NAD+-dependent and NAD+-independent histone deacetylases regulate encystation; however, a unique NAD+-independent histone deacetylase modulate antigenic switching. The rates of acetylation of H4K8 and H4K16 are critical for encystation, whereas a decrease in acetylation of H4K8 and methylation of H3K9 occur preferentially during antigenic variation. These results show the complexity of the mechanisms regulating gene expression in this minimalistic protozoan parasite. PMID- 27771438 TI - Stem cells and matrix. PMID- 27771434 TI - Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. AB - Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects. PMID- 27771441 TI - Label-free monitoring of DNA polymerase activity based on a thrombin-binding aptamer G-quadruplex. AB - We have developed a label-free assay for the detection of DNA polymerase activity based on a thrombin-binding aptamer (TBA) G-quadruplex. In the presence of DNA polymerase, the 3'-OH termini of the hairpin substrate are immediately elongated to replace the TBA, which can be recognized quickly by the ThT dye and results in an increase of fluorescence. This method is highly sensitive with a detection limit of 0.1 U/mL. It is simple and cost-effective without any requirement of labeling with a fluorophore-quencher pair. Furthermore, the proposed method can also be applied to analyze the inhibition of DNA polymerase, which clearly indicates that the proposed method can be applied for screening of potential DNA polymerase inhibitors. PMID- 27771440 TI - Heterologous mitochondrial targeting sequences can deliver functional proteins into mitochondria. AB - Mitochondrial Targeting Sequences (MTSs) are responsible for trafficking nuclear encoded proteins into mitochondria. Once entering the mitochondria, the MTS is recognized and cleaved off. Some MTSs are long and undergo two-step processing, as in the case of the human frataxin (FXN) protein (80aa), implicated in Friedreich's ataxia (FA). Therefore, we chose the FXN protein to examine whether nuclear-encoded mitochondrial proteins can efficiently be targeted via a heterologous MTS (hMTS) and deliver a functional protein into mitochondria. We examined three hMTSs; that of citrate synthase (cs), lipoamide deydrogenase (LAD) and C6ORF66 (ORF), as classically MTS sequences, known to be removed by one-step processing, to deliver FXN into mitochondria, in the form of fusion proteins. We demonstrate that using hMTSs for delivering FXN results in the production of 4-5 fold larger amounts of the fusion proteins, and at 4-5-fold higher concentrations. Moreover, hMTSs delivered a functional FXN protein into the mitochondria even more efficiently than the native MTSfxn, as evidenced by the rescue of FA patients' cells from oxidative stress; demonstrating a 18%-54% increase in cell survival; and a 13%-33% increase in ATP levels, as compared to the fusion protein carrying the native MTS. One fusion protein with MTScs increased aconitase activity within patients' cells, by 400-fold. The implications form our studies are of vast importance for both basic and translational research of mitochondrial proteins as any mitochondrial protein can be delivered efficiently by an hMTS. Moreover, effective targeting of functional proteins is important for restoration of mitochondrial function and treatment of related disorders. PMID- 27771442 TI - Serum based fluorescent assay for evaluating dipeptidyl peptidase I activity in collagen induced arthritis rat model. AB - Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease and derived from immune granule cells. It has been suggested playing an important role in the development of rheumatoid arthritis. In this study, a coumarin based fluorescent probe (GF-AFC) was designed and synthesized to evaluate DPPI activity in serum or tissue homogenates of collagen-induced arthritis (CIA) rats, an inflammatory arthropathy model. It was revealed that the fluorescent intensity was significantly increased in a very short time after specific substrate GF-AFC reacted with the DPPI. The fluorophore (AFC) was released to shine after the cleavage reaction which was examined by 19F NMR spectroscopy. It has been shown that DPPI hydrolyzed the GF-AFC in a robust, linear, and time dependent manner at a significant high rate. A serum-based DPPI activity assay was validated by spiking and gradient dilution methods, there were no interferences or auto fluorescence observed. The Coefficient of Variance calculated for serum-based DPPI activity assays indicates the good reproducibility. The good correlation has been seen between serum DPPI levels and the severity of arthritis during RA development in CIA rats. Our study has demonstrated a new serum based diagnostic assay for detecting DPPI activity using coumarin conjugated fluorescent (GF-AFC) as a substrate. The successful implementation of the case would provide beneficial experience in rheumatoid arthritis research. PMID- 27771439 TI - Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments. AB - Normal epithelium exists within a dynamic extracellular matrix (ECM) that is tuned to regulate tissue specific epithelial cell function. As such, ECM contributes to tissue homeostasis, differentiation, and disease, including cancer. Though it is now recognized that the functional unit of normal and transformed epithelium is the epithelial cell and its adjacent ECM, we lack a basic understanding of tissue-specific ECM composition and abundance, as well as how physiologic changes in ECM impact cancer risk and outcomes. While traditional proteomic techniques have advanced to robustly identify ECM proteins within tissues, methods to determine absolute abundance have lagged. Here, with a focus on tissues relevant to breast cancer, we utilize mass spectrometry methods optimized for absolute quantitative ECM analysis. Employing an extensive protein extraction and digestion method, combined with stable isotope labeled Quantitative conCATamer (QconCAT) peptides that serve as internal standards for absolute quantification of protein, we quantify 98 ECM, ECM-associated, and cellular proteins in a single analytical run. In rodent models, we applied this approach to the primary site of breast cancer, the normal mammary gland, as well as a common and particularly deadly site of breast cancer metastasis, the liver. We find that mammary gland and liver have distinct ECM abundance and relative composition. Further, we show mammary gland ECM abundance and relative compositions differ across the reproductive cycle, with the most dramatic changes occurring during the pro-tumorigenic window of weaning-induced involution. Combined, this work suggests ECM candidates for investigation of breast cancer progression and metastasis, particularly in postpartum breast cancers that are characterized by high metastatic rates. Finally, we suggest that with use of absolute quantitative ECM proteomics to characterize tissues of interest, it will be possible to reconstruct more relevant in vitro models to investigate tumor-ECM dynamics at higher resolution. PMID- 27771444 TI - Acid resistant zirconium phosphate for the long term application of 68Ge/68Ga generator system. AB - The 68Ge/68Ga generator system is an excellent source for producing ready-to-use Ga-68 in clinical Positron Emission Tomography (PET) applications. The column adsorbent is the key component for the 68Ge/68Ga generator system. Therefore, several studies have been conducted to identify column materials with a stable and superior elution yield in an acidic eluent (0.1 N HCl solution). In this study, four different zirconium phosphates were synthesized with a particle size of 200-800nm, pore-size of 55~190A and surface area of 0.72-268m2g-1. Synthesized and studied amorphous zirconium phosphate (ZrP-1) exhibited excellent acid resistant properties for the 0.1 N HCl eluent and a large surface area of 268m2g 1. Amorphous ZrP-1 showed a good Ga-68 elution yield of 74% in 0.1 N HCl eluent accompanying extraordinary low breakthrough of Ge-68 (0.007%). PMID- 27771443 TI - The interaction between physical activity and obesity gene variants in association with BMI: Does the obesogenic environment matter? AB - Little is known about how obesity susceptibility single nucleotide polymorphisms (SNPs) interact with moderate to vigorous physical activity (MVPA) in relation to BMI during adolescence, once obesogenic neighborhood factors are accounted for. In race stratified models, including European (EA; N=4977), African (AA; N=1726), and Hispanic Americans (HA; N=1270) from the National Longitudinal Study of Adolescent to Adult Health (1996; ages 12-21), we assessed the evidence for a SNPxMVPA interaction with BMI-for-age Z score, once accounting for obesogenic neighborhood factors including physical activity amenities, transportation and recreation infrastructure, poverty and crime. Eight SNPxMVPA interactions with suggestive significance (p<0.10; three in each EA, and AA, two in HA) were observed showing attenuation on BMI-for-age Z score in adolescents with >=5 versus <5 bouts/week MVPA, except for rs10146997 (near NRXN3). Findings were robust to the inclusion of neighborhood-level variables as covariates. These findings suggest that any attenuation from MVPA on a genetic susceptibility to obesity during adolescence is likely not operating through obesogenic neighborhood factors. PMID- 27771445 TI - Spot-welding solid targets for high current cyclotron irradiation. AB - Zirconium-89 finds broad application for use in positron emission tomography. Its cyclotron production has been limited by the heat transfer from yttrium targets at high beam currents. A spot welding technique allows a three-fold increase in beam current, without affecting 89Zr quality. An yttrium foil, welded to a jet cooled tantalum support base accommodates a 50uA proton beam degraded to 14MeV. The resulting activity yield of 48+/-4 MBq/(MUA?hr) now extends the outreach of 89Zr for a broader distribution. PMID- 27771446 TI - Cherenkov light production from the alpha-emitting decay chains of 223Ra, 212Pb, and 149Tb for Cherenkov Luminescence Imaging. AB - Cherenkov Luminescence Imaging (CLI) is a new method to image radioactive therapeutic and diagnostic agents, primarily in preclinical studies. This study used Geant4 and Python to generate the predicted Cherenkov light production as a function of time for a set of isotopic chains of interest for targeted alpha therapy: 223Ra, 212Pb, and 149Tb. All are shown to produce substantial Cherenkov light, though time delays between initial decays and the production of Cherenkov light requires caution in interpreting CLI. PMID- 27771447 TI - Production and modeling of radioactive gold nanoparticles in Tehran research reactor. AB - Gold has two medically useful radioactive isotopes, 198Au and 199Au, for locally irradiating and killing tumor cells. 198Au radionuclide has been produced through the irradiation of the pure gold via 197Au(n,gamma)198Au reaction in the Tehran Research Reactor at a thermal neutron flux of 4.5*1013ncm-2s-1 for the different irradiation times. In this paper, the activity of 198Au radionuclide has been determined using MCNPX-2.6 and TALYS-1.6 codes and also the theoretical approach. The calculated results were compared with the corresponding experimental values. The calculated results were in good agreement with the experimental data, thus the used codes can be used as a powerful tool to predict and optimize production conditions in reactor. PMID- 27771448 TI - Distinct gene networks drive differential response to abrupt or gradual water deficit in potato. AB - Water-limiting conditions affect dramatically plant growth and development and, ultimately, yield of potato plants (Solanum tuberosum L.). Therefore, understanding the mechanisms underlying the response to water deficit is of paramount interest to obtain drought tolerant potato varieties. Herein, potato 10K cDNA array slides were used to profile transcriptomic changes of two potato cell populations under abrupt (shocked cells) or gradual exposure (adapted cells) to polyethylene glycol (PEG)-mediated water stress. Data analysis identified >1000 differentially expressed genes (DEGs) in our experimental conditions. Noteworthy, our microarray study also suggests that distinct gene networks underlie the cellular response to shock or gradual water stress. On the basis of our experimental findings, it is possible to speculate that DEGs identified in shocked cells participate in early protective and sensing mechanisms to environmental insults, while the genes whose expression was modulated in adapted cells are directly involved in the acquisition of a new cellular homeostasis to cope with water stress conditions. To validate microarray data obtained for potato cells, the expression analysis of 21 selected genes of interest was performed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). Intriguingly, the expression levels of these transcripts in 4-week old potato plants exposed to long-term water-deficit. qRT-PCR analysis showed that several genes were regulated similarly in potato cells cultures and tissues exposed to drought, thus confirming the efficacy of our simple experimental system to capture important genes involved in osmotic stress response. Highlighting the differences in gene expression between shock-like and adaptive response, our findings could contribute to the discussion on the biological function of distinct gene networks involved in the response to abrupt and gradual adaptation to water deficit. PMID- 27771449 TI - The nuclear higher-order structure defined by the set of topological relationships between DNA and the nuclear matrix is species-specific in hepatocytes. AB - During the interphase the nuclear DNA of metazoan cells is organized in supercoiled loops anchored to constituents of a nuclear substructure or compartment known as the nuclear matrix. The stable interactions between DNA and the nuclear matrix (NM) correspond to a set of topological relationships that define a nuclear higher-order structure (NHOS). Current evidence suggests that the NHOS is cell-type-specific. Biophysical evidence and theoretical models suggest that thermodynamic and structural constraints drive the actualization of DNA-NM interactions. However, if the topological relationships between DNA and the NM were the subject of any biological constraint with functional significance then they must be adaptive and thus be positively selected by natural selection and they should be reasonably conserved, at least within closely related species. We carried out a coarse-grained, comparative evaluation of the DNA-NM topological relationships in primary hepatocytes from two closely related mammals: rat and mouse, by determining the relative position to the NM of a limited set of target sequences corresponding to highly-conserved genomic regions that also represent a sample of distinct chromosome territories within the interphase nucleus. Our results indicate that the pattern of topological relationships between DNA and the NM is not conserved between the hepatocytes of the two closely related species, suggesting that the NHOS, like the karyotype, is species-specific. PMID- 27771450 TI - Expression patterns of NLRC5 and key genes in the STAT1 pathway following infection with Salmonella pullorum. AB - NLRC5, a protein belonging to the NOD-like receptor protein family (NLRs), is highly expressed in immune tissues and cells. NLRC5 plays an important role in the immune response of humans, where its regulatory mechanism has been elucidated. However, the function and regulation of NLRC5 in chickens remains unclear. In this study, temporal expression characteristics of NLRC5 and associated genes in the STAT1 pathway in chickens following infection with Salmonella pullorum were investigated using quantitative real-time polymerase chain reaction and hierarchical cluster analyses. The role of transcription factor STAT1 in NLRC5 promoter activity was studied via point mutation of the STAT1-binding cis-element and dual-luciferase assays. Our results showed a strong correlation between NLRC5 and NF-kappaB. In addition, STAT1 played a crucial role in NLRC5 promoter activity, and may be activated via the interferon pathway. There was also a close relationship between CD80 and NF-kappaB, and CD80 may up regulate NF-kappaB expression and enhance its protein activity in chickens. These findings reveal the temporal characteristics of chicken NLRC5 and STAT1 genes during S. pullorum infection, and highlight the role of STAT1 in NLRC5 promoter activity. This information aids our understanding of the regulatory mechanisms of NLRC5 and associated genes, and will help elucidate their function in the immune response of chickens. PMID- 27771452 TI - Are we still searching for the fifth element of MELD? PMID- 27771451 TI - Two mammalian homologs of yeast Rad23, HR23A and HR23B, as multifunctional proteins. AB - Mammalian cells express two homologs of yeast Rad23, the so-called homolog of Rad23 (HR23) proteins. The HR23 proteins were identified more than two decades ago as factors involved in initiation of global genome nucleotide excision repair (GG-NER) along with their interacting partner, xeroderma pigmentosum group C (XPC) protein. Because the HR23 genes encode proteins harboring ubiquitin-like (UBL) domains at their N-termini and two ubiquitin-associated (UBA) domains in their central- and C-terminal regions, the link between HR23 proteins and proteolytic degradation has been widely explored by several methods, including yeast two-hybrid screening and co-affinity purification. To date, various HR23 protein partners have been identified, and these proteins are involved not only in DNA repair, but also in ubiquitin-dependent protein degradation, transcriptional regulation, and cell cycle control. In addition, establishment of mouse strains lacking the HR23 genes and RNA silencing of these genes in human cells demonstrated their significance in animal development and cell growth. Through these studies, the functional differences between the two HR23 proteins have been gradually revealed. Furthermore, recent comprehensive proteomic analyses will help to elucidate the functional protein-protein networks involving the HR23 proteins. PMID- 27771453 TI - Battlefield against hepatitis B infection and HCC in Africa. AB - Despite effective and safe hepatitis B virus (HBV) vaccine and antiviral therapies, HBV-related hepatocellular carcinoma (HCC) remains a major cause of deaths in young adults in Africa. There are multiple barriers to control the burden of HBV infection and HCC. In comparison to other major infectious diseases, HBV infection and liver diseases have received remarkably little attention from the global health community. There is an urgent need to improve birth dose vaccine coverage and implementing screening and treatment interventions. This requires a dramatic simplification of the management of chronic hepatitis B in Africa, with access to reliable, robust and inexpensive diagnostic tools and strong support from the local governments and the international health community. This review analyses 1) the characteristics of HBV hepatitis and HCC epidemics in Africa and 2) the barriers and potential solutions to control it. PMID- 27771454 TI - Hedgehog pathway mediates early acceleration of liver regeneration induced by a novel two-staged hepatectomy in mice. AB - BACKGROUND & AIMS: ALPPS, a novel two-staged approach for the surgical removal of large/multiple liver tumors, combines portal vein ligation (PVL) with parenchymal transection. This causes acceleration of compensatory liver growth, enabling faster and more extensive tumor removal. We sought to identify the plasma factors thought to mediate the regenerative acceleration following ALPPS. METHODS: We compared a mouse model of ALPPS against PVL and additional control surgeries (n=6 per group). RNA deep sequencing was performed to identify candidate molecules unique to ALPPS liver (n=3 per group). Recombinant protein and a neutralizing antibody combined with appropriate surgeries were used to explore candidate functions in ALPPS (n=6 per group). Indian hedgehog (IHH/Ihh) levels were assessed in human ALPPS patient plasma (n=6). RESULTS: ALPPS in mouse confirmed significant acceleration of liver regeneration relative to PVL (p<0.001). Ihh mRNA, coding for a secreted ligand inducing hedgehog signaling, was uniquely upregulated in ALPPS liver (p<0.001). Ihh plasma levels rose 4h after surgery (p<0.01), along with hedgehog pathway activation and subsequent cyclin D1 induction in the liver. When combined with PVL, Ihh alone was sufficient to induce ALPPS-like acceleration of liver growth. Conversely, blocking Ihh markedly inhibited the accelerating effects of ALPPS. In the small cohort of ALPPS patients, IHH tended to be elevated early after surgery. CONCLUSIONS: Ihh and hedgehog pathway activation provide the first mechanistic insight into the acceleration of liver regeneration triggered by ALPPS surgery. The accelerating potency of recombinant Ihh, and its potential effect in human ALPPS may lead to a clinical role for this protein. LAY SUMMARY: ALPPS, a novel two-staged hepatectomy, accelerates liver regeneration, thereby helping to treat patients with otherwise unresectable liver tumors. The molecular mechanisms behind this accelerated regeneration are unknown. Here, we elucidate that Indian hedgehog, a secreted ligand important for fetal development, is a crucial mediator of the regenerative acceleration triggered by ALPPS surgery. PMID- 27771455 TI - Enhanced axonal regeneration of the injured sciatic nerve by administration of Buyang Huanwu decoction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu decoction (BYHWD) has been used in the traditional Chinese medicine for the treatment of cardiovascular and neurological symptoms, and recent experimental studies have begun to provide evidence showing its protective effects on neural cells. Yet, its function for the regenerative responses of axons in the peripheral nerve after injury is not known. AIM OF THE STUDY: The primary objective of the present study was to explore that BYHWD is involved in growth-promoting activity of the peripheral nerve axons after injury. We further examined whether the effect of BYHWD exerted directly on regrowing axons or Schwann cells. MATERIALS AND METHODS: Sciatic nerves in rats were given crush injury, and BYHWD was injected by oral administration. Sciatic nerves or DRG tissues were prepared for immunofluorescence staining and western blot analysis. Levels of axonal regeneration were quantified by retrograde tracing technique. Cultured DRG sensory neurons and Schwann cells were prepared from rats and used to examine the effects of BYHWD on the neurite outgrowth. Behavioral analysis on functional recovery after nerve injury was assessed in mice by pin prick test, adhesive removal test, and toe-spreading reflex. RESULTS: Immunofluorescence and retrograde tracing analyses showed that the distal extension of the sciatic nerve axons was significantly improved by BYHWD treatment. Levels of axonal growth associated protein GAP-43 were upregulated by BYHWD treatment in the sciatic nerve after injury and in the neurites of cultured DRG neurons. In vivo administration of BYHWD in rats upregulated the induction level of cell division cycle 2 (Cdc2) and its phosphorylation of vimentin in Schwann cells from injured sciatic nerve. Coculture of DRG neurons with Schwann cells prepared from preinjured sciatic nerves in animals administered with BYHWD led to the enhancement in neurite outgrowth. Behavioral tests in mice given sciatic nerve injury showed a significant improvement in sensorimotor activity by BYHWD administration. CONCLUSIONS: Our results suggest that BYHWD administration into animals given sciatic nerve injury facilitates axonal regeneration by acting on both the axons undergoing regeneration and neighboring Schwann cells and improves functional recovery. PMID- 27771456 TI - Lotus leaf alkaloid fraction can strongly inhibit CYP2D6 isoenzyme activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine He-Ye, the leaves of the lotus (Nelumbo nucifera) plant, is traditionally used in China for the treatment of sunstroke, thirst, diarrhea, and fever. Currently, the leaf is used not only as an herbal tea to reduce lipid level and control body weight, but also as a major ingredient in some lipid-lowering Chinese patented medicines. Our previous study demonstrated that the alkaloid fraction (AF) of the herb has a strong inhibitory effect on CYP2D6 isoenzyme activity in vitro. The present study aims to further verify this activity using the in vivo rat model and to explore the inhibitory mechanism on CYP2D6 using human liver microsomes (HLMs). MATERIALS AND METHODS: After a continuous 7-d oral dose of AF (50mg/kg) or a vehicle, Sprague Dawley rats received a single intravenous dose of dextromethorphan or metoprolol. Blood samples were collected at various time points, and the plasma concentrations of the relevant metabolites dextrorphan and hydroxymetoprolol were assayed by LC-MS/MS for evaluating the effect of AF on their pharmacokinetics and CYP2D6 activity. Dextromethorphan as a probe at different concentrations was incubated with HLMs in an incubation buffer system, in the presence or absence of AF at different concentrations. After incubation, the produced metabolite was assayed. RESULTS: After being pretreated with AF in rats, the plasma concentrations of dextrorphan and hydroxymetoprolol significantly decreased, with Cmax going from 79.44 to 29.96 and 151.18 to 83.39hng/mL (P<0.05), AUCall from 167.27 to 62.25 and 347.68 to 223.24hng/mL (P<0.05), and AUCinf from 183.39 to 84.76 and 350.59 to 234.57hng/mL (P<0.05), respectively, in comparison with those of untreated rats. The t1/2 of hydroxymetoprolol significantly increased from 1.14 to 1.99h (P<0.05). The in vitro incubation test showed that AF competitively inhibited the CYP2D6, with apparent Ki value of 0.64ug/mL. CONCLUSIONS: AF can strongly inhibit the activity of CYP2D6 enzyme, as confirmed by in vivo and in vitro models. Possible drug interactions may occur between AF and other medications metabolized by CYP2D6. Thus, caution should be paid when the lotus leaf and its preparations are concurrently administered with conventional medicines. PMID- 27771457 TI - Identification of NF-kappaB inhibitors following Shenfu injection and bioactivity integrated UPLC/Q-TOF-MS and screening for related anti-inflammatory targets in vitro and in silico. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu injection (SFI) is a commercial medicinal product approved by the China Food and Drug Administration that is widely used in the treatment of stroke and coronary heart disease. However, the material basis and the mechanism of SFI are not fully understood. AIM OF THE STUDY: With network pharmacology analysis, our research committed to identify the anti-inflammatory ingredients and mechanism of SFI by combining high-throughput screening. MATERIALS AND METHODS: We developed a bioactivity-based UPLC/Q-TOF-MS method followed by network pharmacology and identified the anti-inflammatory active ingredients of SFI from two different perspectives of network computing and high throughput screening. Then we verified the anti-inflammatory effect of SFI in vitro with endothelial cells. After detecting the cell viability, the expression of interleukin-6 (IL-6), inhibitor of nuclear factor kappa-B kinase (IKK), phosphorylated IKK, phosphorylated NF-kappaB and phosphorylated IkappaB-alpha from the supernatant were determined. RESULTS: SFI could significantly suppress inflammatory responses, and the mechanism may be via an NF-kappaB-dependent pathway. The results of high throughput screening (HTS) revealed that protopanaxadiol glycosides (ginsenosides Rb1, Rb2, Rb3, Rc and Rd), protopanaxatriol glycosides (ginsenosides Rg1, Rg2, Re, Rf and F1), diester-type alkaloids (fuziline and neoline) and aconine derivatives (mesaconine and benzoyl mesaconine) have anti-NF-kappaB activity. The three compounds (including benzoyl mesaconine, fuziline and neoline) are the first reported SFI compounds to have NF kappaB inhibitor activity. CONCLUSIONS: SFI may play a critical role in counteracting inflammation through the NF-kappaB signaling pathway. The active ingredients are protopanaxadiol glycosides, protopanaxatriol glycosides, diester type alkaloids and aconine derivatives. PMID- 27771458 TI - Gene expression kinetics of renal transporters induced by ochratoxin A in male and female F344 rats. AB - Ochratoxin A (OTA) is a mycotoxin that contaminates foodstuffs. The most relevant concern is its high kidney carcinogenicity in male rats and its unclear mechanism of action. It has been hypothesized that variations in transport mechanisms in kidney cells may be the reason of different sex-dependent sensitivities towards OTA. The aim of this study was to analyze, by RT- qPCR, renal transporters expression in 15-week-old male (M) and female (F) F344 rats at basal level and after single oral OTA administration (0.50 mg/kg bw). Temporal profiles (24h, 48h, 72h, 96h, 1 and 2 months) were studied per sex and transporter. The reference gene for all comparisons was Ppia. At basal level, sex differences were confirmed for Oatp1, Bcrp (M>F) and Oat2 (F>M). OTA tended to inhibit the expression of almost all transporters in both sexes, but clearly induced the expression of Oat2 in males. Regarding time profiles, the highest sex differences involved Oat (Slc22) transporters: Oat2, Oat3 and Oat5 expression showed a significant increase in males (24h) while Oat1, Oat2 and Oat5 level decreased in females (48h). Overall, basal sex differences in F344 rats and the specific sex dependent response to OTA of Oat2 might contribute to high kidney damage in male rats. PMID- 27771459 TI - RIFM fragrance ingredient safety assessment, Isopropylphenylbutanal, CAS Registry Number 125109-85-5. PMID- 27771460 TI - Molecular characterization and phylogenetic analysis of Fasciola gigantica from Nigeria. AB - Fasciola gigantica is considered the major pathogen causing fasciolosis in Africa; however, molecular characterization of this fluke has not been adequately elucidated. It is important to scientifically elucidate the dispersal history of F. gigantica by analyzing its genetic diversity. Fasciola flukes from Nigeria were analyzed using nuclear and mitochondrial DNA markers. A total of 172 Fasciola flukes collected from cattle were identified as F. gigantica because they displayed the F. gigantica fragment pattern in multiplex PCR for the nuclear marker, phosphoenolpyruvate carboxykinase (pepck). In total, 70 haplotypes were detected from Nigerian F. gigantica on the basis of the concatenated sequence of mitochondrial NADH dehydrogenase subunit 1 (nad1) and cytochrome c oxidase 1 (cox1). The index of neutrality (Fu's Fs) suggests rapid expansion of the Nigerian F. gigantica population. Although four haplogroups, Nigeria 1A, 1B, 2A, and 2B, were detected from Nigerian F. gigantica, a climate-specific genetic structure was not observed among F. gigantica populations from three agro climatic regions (Sahel, Savannah, and Forest). This is probably because of the frequent transportation of livestock from one part of the country to the other. Nigeria 1A and 1B had close relationships with the Egyptian population of F. gigantica, whereas Nigeria 2A and 2B were comparatively related to the Zambian population. No haplotype was shared among the three countries, and it therefore is difficult to estimate the dispersal route of F. gigantica within the African continent. PMID- 27771461 TI - An integrated phylogenetic analysis on ascaridoid nematodes (Anisakidae, Raphidascarididae), including further description and intraspecific variations of Raphidascaris (Sprentascaris) lanfrediae in freshwater fishes from Brazil. AB - Genetic and morphological variations in two component populations of Raphidascaris (Sprentascaris) lanfrediae collected in the intestine of Geophagus argyrosticus and G. proximus (Cichlidae) from States of Para and Amapa, Brazil, respectively, were explored for the first time. A phylogenetic study including two genes (18S and 28S of the rDNA) plus morphological and life history traits of "anisakid-related" nematodes (Anisakidae, Raphidascarididae) was also performed in order to clarify taxonomic and systematic issues related to these taxa. Gene alignments were subjected to maximum likelihood (ML) and Bayesian Inference (BI), and combined data of the genetic and morphological datasets was subjected to maximum parsimony (MP) analysis. Despite of the subtle differences in the morphology (mainly in male caudal papillae) and morphometry between specimens of R. (S.) lanfrediae from the two different hosts and from the type material of the species, no genetic variation was found among representatives of the newly collected material. This find may represent an example of gene-environment interactions, similar to that recently observed for Raphidascaroides brasiliensis. Phylogenetic reconstructions indicated the paraphyly of Anisakidae represented by two subfamilies, i.e., Anisakinae and Contracaecinae and the monophyly of Raphidascarididae. Analysis of the combined datasets revealed that some morphological traits may represent apomorphic characters of Raphidascarididae and Anisakidae, whereas others are highly homoplastic and some may be interpreted with careful to avoid errors. The results support the premise that taxonomists should consider Anisakidae and Raphidascarididae as separate families, and only two subfamilies of Anisakidae, i.e., Anisakinae and Contracaecinae. PMID- 27771462 TI - Novel synthetic compounds with endoperoxide structure damage juvenile stage of Schistosoma mansoni by targeting lysosome-like organelles. AB - The new synthetic compound 1,2,6,7-tetraoxaspiro[7.11]nonadecan (N-89), a novel anti-malaria drug candidate, is also a promising drug candidate against schistosomiasis with killing effects against juvenile stage of S. mansoni. In order to investigate how N-89 kills schistosomes, we used a derivative of N-89, 6 (1,2,6,7-tetraoxaspiro[7.11] nonadec-4-yl)hexan-1-ol (N-251), which enables us to conjugate with fluorescent reagents. Firstly, N-251 showed strong killing effects to larvae of S. mansoni in vitro. Ultrastructural analysis showed the disruptions of the lysosome-like organelles or the acetabular glands, followed by cytoplasmic lysis inside the worm body in N-251-treated group under electron microscopy. For rhodamine-conjugated N-251 and organelle markers, we observed that N-251 accumulated in acidic organelle. In addition, LysoTracker signals in these acidic organelles disappeared in N-251-treated group over time. Finally, we observed that the activity of cathepsin B, a lysosome-specific enzyme, was also decreased together with alternation of acidic organelle marker signal by N-251-treated group. These results suggested that our synthesized compounds induced the dysfunction or the disruption of acidic lysosome-like organelles and finally led to worm death. PMID- 27771463 TI - Upregulation of MKP-7 in response to rosiglitazone treatment ameliorates lipopolysaccharide-induced destabilization of SIRT1 by inactivating JNK. AB - Silent mating type information regulation 2 homolog 1 (SIRT1), a NAD-dependent deacetylase, mediates cellular processes involved in gene silencing and aging. The regulation of lifespan by SIRT1 has been extensively investigated, but less is known about the mechanisms associated with its cellular turnover during inflammatory responses. In this study, we found that peroxisome proliferator activated receptor (PPAR) gamma is associated with SIRT1 stability in murine macrophage RAW 264.7 cells exposed to lipopolysaccharide (LPS). Activation of PPARgamma by rosiglitazone, a specific ligand of PPARgamma, rescues LPS-induced destabilization of SIRT1, with a concomitant decrease in phosphorylation of residue Ser-46, which is targeted by JNK-1 to promote proteasome-mediated degradation of SIRT1. The rosiglitazone-mediated increase in SIRT1 stability is accompanied by upregulation of mitogen-activated protein kinase phosphatase (MKP) 7, a JNK-specific phosphatase. These effects are significantly influenced by ablation or ectopic expression of PPARgamma, indicating that PPARgamma is directly involved in the regulation of SIRT1 stability. Furthermore, gain of MKP 7 function mimicked the effect of rosiglitazone on LPS-induced destabilization and ubiquitination of SIRT1. These results indicate that PPARgamma-dependent upregulation of MKP-7 improves the stability of SIRT1 by inactivating JNK during inflammatory responses of LPS-activated macrophages. PMID- 27771464 TI - Nanoparticles for cancer gene therapy: Recent advances, challenges, and strategies. AB - Compared to conventional treatments, gene therapy offers a variety of advantages for cancer treatment including high potency and specificity, low off-target toxicity, and delivery of multiple genes that concurrently target cancer tumorigenesis, recurrence, and drug resistance. In the past decades, gene therapy has undergone remarkable progress, and is now poised to become a first line therapy for cancer. Among various gene delivery systems, nanoparticles have attracted much attention because of their desirable characteristics including low toxicity profiles, well-controlled and high gene delivery efficiency, and multi functionalities. This review provides an overview on gene therapeutics and gene delivery technologies, and highlight recent advances, challenges and insights into the design and the utility of nanoparticles in gene therapy for cancer treatment. PMID- 27771465 TI - Focused ultrasound induced hyperthermia accelerates and increases the uptake of anti-HER-2 antibodies in a xenograft model. AB - Image guided drug delivery has gained significant attention during the last few years. Labelling nanoparticles or macromolecules and monitoring their fate in the body provides information that can be used to modulate their biodistribution and improve their pharmacokinetics. In this study we label antibodies and monitor their distribution in the tumours post intravenous injection. Using Focused Ultrasound (FUS, a non-invasive method of hyperthermia) we increase the tumour temperature to 42 degrees C for a short period of time (3-5min) and we observe an increased accumulation of labelled antibody. Repetition of focused ultrasound induced hyperthermic treatment increased still further the accumulation of the antibodies in the tumour. This treatment also augmented the accumulation of other macromolecules non-specific to the tumour, such as IgG and albumin. These effects may be used to enhance the therapeutic efficiency of antibodies and/or targeted nanoparticles. PMID- 27771466 TI - Gender-related differences in pulmonary arterial hypertension targeted drugs administration. AB - During the last 15 years, a real "paradigm-shift" occurred, due to the development of PAH-targeted drugs, leading to crucial improvements in symptoms, exercise capacity, hemodynamics and outcome of PAH patients. In order to describe differences regarding epidemiology and therapy in PAH according to gender, we performed a review of the available literature in "PubMed" and "Web of Science" databases. In order to find relevant articles, we combined each of the following the keywords "pulmonary arterial hypertension", "gender", "sex", "men", "woman", "male", "female", "phosphodiesterase inhibitors", "endothelin receptor antagonists", "prostanoids". While there is a substantial agreement among epidemiological studies in reporting an increased prevalence of pulmonary arterial hypertension (PAH) among women, male PAH patients are affected by a higher impairment of the right ventricular function and consequently experience poorer outcomes. With regards to PAH-targeted drug administration, endothelin receptor antagonists (ERAs) and prostacyclin analogues (PC) show better treatment results in female PAH patients, while phosphodiesterase-5 inhibitors (PD5-I) seem to exert a more beneficial effect on male patients. However, to date no clear consensus could be formed by the available literature, which is constituted mainly by retrospective studies. Females with PAH are more prone to develop PAH, while males experience poorer outcomes. Females PAH might benefit more from ERAs and PC, while males seem to have more beneficial effects from PD5-I administration. However, more research is warranted in order to assess the most effective treatment for PAH patients according to gender. PMID- 27771467 TI - Investigating kinship of Neolithic post-LBK human remains from Krusza Zamkowa, Poland using ancient DNA. AB - We applied an interdisciplinary approach to investigate kinship patterns and funerary practices during the middle Neolithic. Genetic studies, radiocarbon dating, and taphonomic analyses were used to examine two grave clusters from Krusza Zamkowa, Poland. To reconstruct kinship and determine biological sex, we extracted DNA from bones and teeth, analyzed mitochondrial genomes and nuclear SNPs using the HID-Ion AmpliSeqTM Identity panel generated on Illumina and Ion Torrent platforms, respectively. We further dated the material (AMS 14C) and to exclude aquatic radiocarbon reservoir effects, measures of carbon and nitrogen stable isotopes for diet reconstruction were used. We found distinct mitochondrial genomes belonging to haplogroups U5b2a1a, K1c and H3d in the first grave cluster, and excluded maternal kin patterns among the three analyzed individuals. In the second grave cluster one individual belonged to K1a4. However, we could not affiliate the second individual to a certain haplogroup due to the fragmented state of the mitochondrial genome. Although the individuals from the second grave cluster differ at position 6643, we believe that more data is needed to fully resolve this issue. We retrieved between 26 and 77 autosomal SNPs from three of the individuals. Based on kinship estimations, taking into account the allelic dropout distribution, we could not exclude first degree kin relation between the two individuals from the second grave cluster. We could, however, exclude a first degree kinship between these two individuals and an individual from the first grave cluster. Presumably, not only biological kinship, but also social relations played an important role in the funerary practice during this time period. We further conclude that the HID-Ion AmpliSeqTM Identity Panel may prove useful for first degree kin relation studies for samples with good DNA preservation, and that mitochondrial genome capture enrichment is a powerful tool for excluding direct maternal relationship in ancient individuals. PMID- 27771468 TI - Phytomonas (Euglenozoa: Trypanosomatidae): Phylogenetic analyses support infrageneric lineages and a new species transmitted to Solanaceae fruits by a pentatomid hemipteran. AB - The genus Phytomonas includes trypanosomatids transmitted to the fruits, latex, and phloem of vascular plants by hemipterans. We inferred the phylogenetic relationships of plant and insect isolates assigned to the previously defined genetic groups A-F and H of Phytomonas, particularly those from groups A, C and E comprising flagellates of Solanaceae fruits. Phylogenetic analyses using glycosomal Glyceraldehyde Phosphate Dehydrogenase (gGAPDH) and Small Subunit rRNA (SSU rRNA) genes strongly supported the monophyly of the genus Phytomonas and its division into seven main infrageneric phylogenetic lineages (Phy clades). Isolates from fruit or latex do not constitute monophyletic assemblages but disperse through more than one lineages. In this study, fruit flagellates were distributed in three clades: PhyA, formed by isolates from Solanaceae and phytophagous hemipterans; PhyC comprising flagellates from four plant families; and PhyE, which contains 15 fruit isolates from seven species of Solanaceae. The flagellates of PhyE are described as Phytomonas dolleti n. sp. according to their positioning in phylogenetic trees, complemented by data about their life cycle, and developmental and morphological characteristics in cultures, fruits of Solanum spp., and salivary glands of the vector, the phytophagous hemipteran Arvelius albopunctatus (Pentatomidae). PMID- 27771469 TI - The association between functional HLA-G 14bp insertion/deletion and +3142 C>G polymorphisms and susceptibility to multiple sclerosis. AB - We aimed to investigate two main polymorphisms in the 3' untranslated region (3'UTR) of the HLA-G gene [14bp insertion/deletion (INS/DEL) and +3142 C>G] and to assess their impact on the soluble HLA-G (sHLA-G) production in patients with multiple sclerosis (MS). This study included 60 patients with relasping-remitting (RR) MS and 112 healthy donors (HD). Mutations were identified by PCR and PCR RFLP, and serum sHLA-G quantification was performed by ELISA. For the 14bp INS/DEL polymorphism, variants frequencies were similar in patients and controls, whereas a significant increased frequency of the +3142 G allele was found in MS patients compared to HD (63.4% vs 52.3%, p=0.04; OR=1.58, 95%CI=1.003-2.48). In addition, an association was found between MS susceptibility and the haplotypes regrouping both studied polymorphisms. Indeed, the 14bp DEL/+3142 G haplotype frequency was significantly increased in MS patients compared to HD (20.8% vs 12.5%, p=0.04, OR=1.84). On the other hand, no associations were detected between both polymorphisms and clinical parameters, except the lower age of disease onset (ADO) in patients with the +3142 C/C genotype. Moreover, our study doesn't show any significant variation of sHLA-G serum levels between patients and controls. Our findings showed that the +3142 C>G, but not the 14bp INS/DEL, polymorphism may constitute a genetic susceptibility factor to MS in the Tunisian population. However, no association was found between the two polymorphisms and sHLA-G serum levels. PMID- 27771471 TI - A case of Finegoldia magna (formerly Peptostreptococcus magnus) infection mimicking disseminated malignancy. AB - A 44-year-old alcoholic (and therefore immunocompromised) hospital cleaner presented with general malaise, weight loss, and erythematous skin nodules. Computed tomography scanning revealed a neck mass invading the thyroid gland, pulmonary infiltrates, liver lesions, and deposits on the anterior abdominal wall, consistent with disseminated malignancy. However, tissue diagnosis showed a necro-inflammatory process with no evidence of malignancy. Microscopy and culture of samples failed to detect any infectious pathogen, but after an extended incubation period, Finegoldia magna was isolated. This case study illustrates the importance of tissue diagnosis in suspected disseminated malignancy and raises the risk of acquiring the rarer bacteria amongst hospital staff. PMID- 27771470 TI - Factors associated with the over-treatment and under-treatment of gonorrhea and chlamydia in adolescents presenting to a public hospital emergency department. AB - OBJECTIVES: The purpose of this study was to measure the prevalence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) and the rates and factors associated with their over-treatment (OT) and under-treatment (UT). METHODS: A retrospective chart review was performed of patients aged 13-24 years who were screened for GC/CT in the emergency department (ED) of a public hospital. Descriptive statistics were obtained for all variables, and multivariate log binomial regression was performed to ascertain the factors associated with OT and UT. RESULTS: Seven hundred and ninety-seven adolescents and young adults were screened for GC/CT. The overall sexually transmitted infection (STI) positivity rate was 21.6%; 136 (21.6%) subjects were over-treated and 74 (43.4%) subjects were under-treated. Patients presenting with STI exposure or genito-urinary symptoms were more likely to be OT. Additionally, females aged 18-19 years or with a prior history of STIs were more likely to be OT. Females (83.6%) were more likely to be UT, while STI exposure, genito-urinary symptoms, and a prior history of STI were protective of UT . CONCLUSION: Adolescents and young adults screened for STIs have a high prevalence of GC/CT. A significant proportion of these patients end up over-treated and an even higher proportion are under-treated. PMID- 27771472 TI - Haplotype analysis of alpha-thalassemia chromosomes reveals heterogeneity and multiple founders in Ashkenazi Jews. AB - alpha-Thalassemia (alpha-thal) is among the world's most common single gene disorders, generally attributed to a selective advantage of heterozygotes against malaria mortality. A high frequency of -alpha3.7 deletion heterozygosity has been previously reported in Ashkenazi Jews despite lack of obvious malarial selection pressure in this population. Using haplotype and -alpha3.7 subtype analysis we analyzed a subset of -alpha3.7 homozygotes from various Israeli ethnic groups. We found a high frequency of the common Ia haplotype in Yemenite Jews and Arabs (54% and 13% respectively). Ashkenazi Jews exhibited a high frequency of IIIb alleles (67%) previously reported only in Aboriginal Australians and not found in other Israeli ethnicities. Both Yemenites and Ashkenazim carried the rare IIh alleles (18% and 15% respectively). These results may suggest multiple founder effects in Ashkenazi Jews as well a common founder for both Yemenite and Ashkenazi Jews. PMID- 27771473 TI - Williams syndrome and mature B-Leukemia: A random association? AB - Williams syndrome (WBS) is a rare neurodevelopmental disorder with specific phenotypic characteristics and cardiac abnormalities, but is not considered as a cancer predisposing condition. However, in rare cases, malignancies have been described in patients with WBS, with hematologic cancer (mainly Burkitt Lymphoma and Acute Lymphoblastic Leukemia) as the most represented. We report here the case of a boy with WS and B-NHL. This is the unique case within the large cohort of patients (n = 117) followed in our institution for long time (mean clinical follow-up, 13 years). We herewith propose that the BCL7B gene, located in the chromosomal region commonly deleted in Williams syndrome, could potentially have a role in this particular association. PMID- 27771474 TI - Sex differences in the prevalence and incidence of mild cognitive impairment: A meta-analysis. AB - OBJECTIVE: More women have Alzheimer's disease (AD) than men. Understanding sex differences in mild cognitive impairment (MCI) may further knowledge of AD etiology and prevention. We conducted a meta-analysis to examine sex differences in the prevalence and incidence of MCI, which included amnestic and non-amnestic subtypes. METHOD: Systematic searches were performed in July 2015 using MEDLINE/PubMed, Scopus, and PsycINFO for population-or community-based studies with MCI data for men and women. Random-effects model were used. RESULTS: Fifty six studies were included. There were no statistically significant sex differences in prevalence or incidence of amnestic MCI. There was a significantly higher prevalence (p=0.038), but not incidence, of non-amnestic MCI among women. There were no sex differences in studies that combined both subtypes of MCI. CONCLUSION: The only statistically significant finding emerging from this study was that women have a higher prevalence of non-amnestic MCI. To better understand sex differences in the preclinical stages of dementia, studies must better characterize the etiology of the cognitive impairment. PMID- 27771475 TI - The safety of intrauterine devices among young women: a systematic review. AB - OBJECTIVE: The objective was to determine the association between use of intrauterine devices (IUDs) by young women and risk of adverse outcomes. METHODS: We searched Pubmed, CINAHL, Embase, Popline and the Cochrane Library for articles from inception of database through December 2015. For outcomes specific to IUD use (IUD expulsion and perforation), we examined effect measures for IUD users generally aged 25 years or younger compared with older IUD users. For outcomes of pregnancy, infection, pelvic inflammatory disease (PID), and heavy bleeding or anemia, we examined young IUD users compared with young users of other contraceptive methods or no method. RESULTS: We identified 3169 articles of which 16 articles from 14 studies met our inclusion criteria. Six studies (Level II-2, good to poor) reported increased risk of expulsion among younger age groups compared with older age groups using copper-bearing (Cu-) IUDs. Two studies (Level II-2, fair) examined risks of expulsion among younger compared with older women using levonorgestrel-releasing (LNG-) IUDs; one reported no difference in expulsion, while the other reported increased odds for younger women. Four studies (Level II-2, good to poor) examined risk of expulsion among Cu- and LNG IUD users combined and reported no significant differences between younger and older women. For perforation, four studies (Level II-2, fair to poor) found very low perforation rates (range, 0%-0.1%), with no significant differences between younger and older women. Pregnancies were generally rare among young IUD users in nine studies (Level I to II-2, fair to poor), and no differences were reported for young IUD users compared with young combined oral contraceptive (COC) or etonogestrel (ENG) implant users. PID was rare among young IUD users; one study reported no cases among COC or IUD users, and one reported no difference in PID among LNG-IUD users compared with ENG implant users from nationwide insurance claims data (Level I to II-2, fair). One study reported decreased odds of bleeding with LNG-IUD compared with COC use among young women, while one study of young women reported decreased odds of removal for bleeding with LNG-IUD compared with ENG implant (Level I to II-2, fair). CONCLUSION: Overall evidence suggests that the risk of adverse outcomes related to pregnancy, perforation, infection, heavy bleeding or removals for bleeding among young IUD users is low and may not be clinically meaningful. However, the risk of expulsion, especially for Cu-IUDs, is higher for younger women compared with older women. If IUD expulsion occurs, a young woman is exposed to an increased risk of unintended pregnancy if replacement contraception is not initiated. IUDs are safe for young women and provide highly effective reversible contraception. PMID- 27771476 TI - Nonoral combined hormonal contraceptives and thromboembolism: a systematic review. AB - BACKGROUND: Combined hormonal contraceptives (CHCs), containing estrogen and progestin, are associated with an increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) compared with nonuse. Few studies have examined whether nonoral formulations (including the combined hormonal patch, combined vaginal ring and combined injectable contraceptives) increase the risk of thrombosis compared with combined oral contraceptives (COCs). OBJECTIVES: The objectives were to examine the risk of VTE and ATE among women using nonoral CHCs compared to women using COCs. METHODS: We searched the PubMed database for all English language articles published from database inception through May 2016. We included primary research studies that examined women using the patch, ring or combined injectables compared with women using levonorgestrel-containing or norgestimate-containing COCs. Outcomes of interest included VTE (deep venous thrombosis or pulmonary embolism) or ATE (acute myocardial infarction or ischemic stroke). We assessed the quality of each individual piece of evidence using the system developed by the United States Preventive Services Task Force. RESULTS: Eight studies were identified that met inclusion criteria. Of seven analyses from six studies examining VTE among patch users compared with levonorgestrel- or norgestimate-containing COC users, two found a statistically significantly elevated risk among patch users (risk estimates 2.2-2.3), one found an elevated risk that did not meet statistical significance (risk estimate 2.0), and four found no increased risk. Of three studies examining VTE among ring users compared with levonorgestrel COC users, one found a statistically significantly elevated risk among patch users (risk estimate 1.9) and two did not. Two studies did not find an increased risk for ATE among women using the patch compared with norgestimate COCs. We did not identify any studies examining combined injectable contraceptives. CONCLUSION: Limited Level II-2 good to fair evidence demonstrated conflicting results on whether women using the patch or the ring have a higher risk of VTE than women using COCs. Evidence did not demonstrate an increased risk of ATE among women using the patch. Overall, any potential elevated risk likely represents a small number of events on a population level. Additional studies with standard methodology are needed to further clarify any associations and better understand mechanisms of hormone-induced thrombosis among users of nonoral combined hormonal contraception. PMID- 27771477 TI - Unique Venous Drainage of a Sphenoid Wing Dural Arteriovenous Fistula with Ocular Symptoms. AB - BACKGROUND: Dural arteriovenous fistulas (DAVFs) presenting with ocular symptoms, such as exophthalmos and chemosis, are commonly situated in the cavernous sinus (CS). DAVFs at the sphenoid wing with a drainage route into the superior orbital vein (SOV) should be considered as one of the differential diagnoses of ocular symptoms. CASE DESCRIPTION: A 41-year-old woman presented with progressive left sided chemosis and proptosis after left pulsating tinnitus that disappeared spontaneously. Cerebral angiography showed that the fistula was situated along the inferior edge of the superior orbital fissure on the greater sphenoid wing and drained solely into the SOV without flowing into the CS that caused ocular symptoms. Transvenous selective catheterization was performed via the facial vein and SOV. The fistula was then embolized using detachable coils. CONCLUSIONS: After embolization, the ocular symptoms resolved, and the patient was discharged without neurologic deficit. Herein, we discuss the developmental mechanism of the unique drainage pattern, including the clinical symptoms and anatomic features of greater sphenoid wing DAVFs. PMID- 27771478 TI - Comparison of the Surgical Outcome of Pterional and Frontotemporal Orbitozygomatic Approaches and Determination of Predictors of Recurrence for Sphenoid Wing Meningiomas. AB - OBJECTIVE: The pterional/frontotemporal orbitozygomatic (FTOZ) approaches are the 2 most widely used procedures for resection of sphenoid wing meningiomas; however, a comparison of outcomes and complications of these 2 approaches has not been well described yet. Here, we investigated the outcomes, complications, and predictors of favorable outcomes of these 2 approaches. METHODS: Data of 90 consecutive cases with sphenoid wing meningiomas between 1995 and 2015 was reviewed retrospectively. A Kaplan-Meier survival analysis and Cox proportional hazards regression model was used to determine the recurrence-free (RFS) survival and independent predictor of RFS. RESULTS: In this study, the overall recurrence rate after tumor excision with pterional and FTOZ approaches was 36.5% and 12.2% respectively (P = 0.001). Based on surgical approach, the median RFS of the patients with sphenoid wing meningiomas also varied significantly (pterional, 114 months vs. FTOZ, 145 months, P = 0.03). The median RFS for patients with sphenoid wing meningiomas also varied according to the extent of resection (gross total resection [GTR], 146 months vs. subtotal resection, 52 months, P = 0.009). In Cox regression analysis, the FTOZ approach (P = 0.041), GTR (P = 0.047), and Karnofsky performance score >70 (P = 0.04) were revealed as significant predictors of favorable outcome after resection of sphenoid wing meningiomas. CONCLUSIONS: In summary, sphenoid wing meningiomas undergoing extensive skull base approach (FTOZ) and GTR had a low recurrence rate and greater RFS. Even though FTOZ with GTR is preferable to resect the sphenoid wing meningiomas, the procedure should be tailored to each patient depending on the risks and surgical morbidity. PMID- 27771479 TI - Surgical Management for Destructive Atlantoaxial Spondyloarthropathy in Long-Term Hemodialysis Patients. AB - BACKGROUND: Atlantoaxial spondyloarthropathy most often results from rheumatoid arthritis, cancer metastasis, or basilar invagination. Dialysis-related spondyloarthropathy is a rare cause of spinal deformity and cervical myelopathy at the atlantoaxial joint. We report 2 patients on long-term hemodialysis who presented with atlantoaxial spondyloarthropathy. CASE DESCRIPTION: Two patients with end-stage renal failure presented with a history of progressively worsening neck pain, motion limitation, and gait disturbance. In both patients, radiologic findings showed a bone-destroying soft tissue mass lateral to C1 and C2, compressing the spinal cord and causing atlantoaxial instability. We performed a C1 laminectomy and C12 transarticular screw fixation and biopsied the osteolytic mass. The neck pain, hand numbness, and gait disturbance improved. CONCLUSIONS: Although the surgical management of these patients involves many challenges, appropriate decompression and fusion surgery is an effective treatment option. PMID- 27771480 TI - Identification of a GUAAY Pentaloop Sequence Involved in a Novel RNA Loop-Helix Interaction. AB - Large RNAs often utilize GNRA tetraloops as structural elements to stabilize the overall tertiary fold. These tetraloop-receptor (TR) interactions have a conserved geometry in which the tetraloop docks into the receptor at an angle of ~15 degrees from the helix containing the receptor. Here, we show that the conserved GUAAY pentaloop found in domain III of group IIB1 introns participates in a novel class of RNA tertiary interaction with a geometry and mode of binding that are significantly different from that found in GNRA TR interactions. This pentaloop is highly conserved within the IIB1 class and interacts with the minor groove of the catalytic domain V. The base planes of the loop and receptor nucleotides are not coplanar and greatly deviate from standard A-minor motifs. The helical axis of the GUAAY stem loop diverges ~70 degrees from the angle of insertion found in a typical GNRA TR interaction. Therefore, the loop architecture and insertion orientation are distinctive, with in vitro splicing data indicating that a GNRA tetraloop is incompatible at this position. The GUAAY pentaloop-receptor motif is also found in the structure of the eukaryotic thiamine pyrophosphate riboswitch in the context of a hexanucleotide loop sequence. We therefore propose, based on phylogenetic, structural, and biochemical data, that the GUAAY pentaloop-receptor interaction represents a novel structural motif that is present in multiple structured RNAs. PMID- 27771481 TI - SimGen: A General Simulation Method for Large Systems. AB - SimGen is a stand-alone computer program that reads a script of commands to represent complex macromolecules, including proteins and nucleic acids, in a structural hierarchy that can then be viewed using an integral graphical viewer or animated through a high-level application programming interface in C++. Structural levels in the hierarchy range from alpha-carbon or phosphate backbones through secondary structure to domains, molecules, and multimers with each level represented in an identical data structure that can be manipulated using the application programming interface. Unlike most coarse-grained simulation approaches, the higher-level objects represented in SimGen can be soft, allowing the lower-level objects that they contain to interact directly. The default motion simulated by SimGen is a Brownian-like diffusion that can be set to occur across all levels of representation in the hierarchy. Links can also be defined between objects, which, when combined with large high-level random movements, result in an effective search strategy for constraint satisfaction, including structure prediction from predicted pairwise distances. The implementation of SimGen makes use of the hierarchic data structure to avoid unnecessary calculation, especially for collision detection, allowing it to be simultaneously run and viewed on a laptop computer while simulating large systems of over 20,000 objects. It has been used previously to model complex molecular interactions including the motion of a myosin-V dimer "walking" on an actin fibre, RNA stem loop packing, and the simulation of cell motion and aggregation. Several extensions to this original functionality are described. PMID- 27771483 TI - Senataxin: Genome Guardian at the Interface of Transcription and Neurodegeneration. AB - R-loops comprise an RNA/DNA hybrid and a displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia and fragile X syndrome), and cancer. Currently, it is unclear which mechanisms cause R-loop structures to become pathogenic. The RNA/DNA helicase senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4). SETX is known to play a role in transcription, neurogenesis, and antiviral response. Here, we review the causes of R-loop dysregulation in neurodegenerative diseases and how these structures contribute to pathomechanisms. We will discuss the importance of SETX as a genome guardian in suppressing aberrant R-loop formation and analyse how SETX mutations can lead to neurodegeneration in AOA2/ALS4. Finally, we will discuss the implications for other R-loop-associated neurodegenerative diseases and point to future therapeutic approaches to treat these disorders. PMID- 27771484 TI - In vivo skin penetration of macromolecules in irritant contact dermatitis. AB - Recently, a selective preferential accumulation of polymeric nanoparticles (in the size range around 100nm) has been observed in the follicular system of dermatitis skin. The present investigation aimed at clearly investigating the effect of irritant contact dermatitis on the barrier permeability for colloidal systems below this size range, namely quantum dots and hydrophilic macromolecules. Irritant dermatitis was induced in mice and the penetrability of quantum dots (5nm) and hydrophilic dextran molecules has been tracked in both healthy and inflamed skin using confocal laser scanning microscopy. The selective accumulation of the quantum dots was clearly observed in inflamed skin while hydrophilic dextran behaved similarly in both healthy and inflamed skin. The therapeutic potential for the transdermal delivery of peptide drugs through inflamed skin has been also tested in rats. Results revealed that the transdermal permeation of insulin and calcitonin was not significantly enhanced in dermatitis compared to healthy skin. On the other side, permeation through stripped skin was significantly higher. However, the effect was limited and shorter compared to the SC injection where tmin was 0.5h and 2h with a 70% and 46% reduction in blood glucose levels for the stripped skin and the SC injection respectively. Similarly, tmin was 4h and 8h with area under the curve of 161+/-65% and 350+/ 97% for the stripped skin and the SC injection respectively. In conclusion, the changes in skin permeability accompanied with skin inflammation did not affect its permeability to peptide drugs. Our findings also underline that experiments with the tape stripped skin model as a surrogate for inflamed skin can risk misleading conclusions due to significant difference of skin permeability between the tape stripped skin and inflamed skin. PMID- 27771482 TI - ClusPro-DC: Dimer Classification by the Cluspro Server for Protein-Protein Docking. AB - ClusPro-DC (https://cluspro.bu.edu/) implements a straightforward approach to the discrimination between crystallographic and biological dimers by docking the two subunits to exhaustively sample the interaction energy landscape. If a substantial number of low energy docked poses cluster in a narrow vicinity of the native structure of the dimer, then one can assume that there is a well-defined free energy well around the native state, which makes the interaction stable. In contrast, if the interaction sites in the docked poses do not form a large enough cluster around the native structure, then it is unlikely that the subunits form a stable biological dimer. The number of near-native structures is used to estimate the probability of a dimer being biological. Currently, the server examines only the stability of a given interface rather than generating all putative quaternary structures as accomplished by PISA or EPPIC, but it complements the information provided by these methods. PMID- 27771485 TI - Co amorphous systems: A product development perspective. AB - Solubility is one of the major problems associated with most of the new chemical entities that can be reasonably addressed by drug amorphization. However, being a high-energy form, it usually tends to re-crystallize, necessitating new formulation strategies to stabilize amorphous drugs. Polymeric amorphous solid dispersion (PASD) is one of the widely investigated strategies to stabilize amorphous drug, with major limitations like limited polymer solubility and hygroscopicity. Co amorphous system (CAM), a new entrant in amorphous arena is a promising alternative to PASD. CAMs are multi component single phase amorphous solid systems made up of two or more small molecules that may be a combination of drugs or drug and excipients. Excipients explored for CAM preparation include amino acids, carboxylic acids, nicotinamide and saccharine. Advantages offered by CAM include improved aqueous solubility and physical stability of amorphous drug, with a potential to improve therapeutic efficacy. This review attempts to address different aspects in the development of CAM as drug products. Criterion for co former selection, various methods involved in CAM preparation, characterization tools, stability, scale up and regulatory requirements for the CAM product development are discussed. PMID- 27771487 TI - Miktoarm star copolymers from D-(-)-salicin core aggregated into dandelion-like structures as anticancer drug delivery systems: synthesis, self-assembly and drug release. AB - The beta-glucoside-based heterofunctional initiator was used in the synthesis of well-defined eight-armed miktopolymers by sequential ring opening polymerization (ROP) of epsilon-caprolactone (CL) and atom transfer radical (co)polymerization (ATRP) of methyl methacrylate (MMA) and/or tert-butyl methacrylate (tBMA). Consequently, methacrylic acid (MAA) repeating units were introduced via selective cleavage of pendant tert-butyl protecting groups. Both the amphiphilic copolymers and miktoarm copolymers were self-assembled at 37 degrees C and pH 7.4. The aggregates of miktoarm polymers were larger than that formed by polymethacrylate homoarm stars (>=250nm vs <=200nm). The critical aggregation concentrations (CAC) of (mikto)stars were relatively low (0.006-0.411mg/mL) and decreased with the increase in MAA fraction content. Both MAA-based mikto- and homoarmed (co)polymers with shorter arms exhibited lower doxorubicin (DOX) loading capacity, whereas camptothecin (CPT) was encapsulated preferably by miktostars. The kinetic profiles of drug release showed that the rate of release was higher at acidic environment (pH 5.0) than in neutral pH. In the most cases the studied miktopolymer systems demonstrated the well-controlled delivery of the model anticancer drugs, which can be adjusted by structural parameters of polymeric carriers. PMID- 27771486 TI - Delivery system for berberine chloride based on the nanocarrier ZnAl-layered double hydroxide: Physicochemical characterization, release behavior and evaluation of anti-bacterial potential. AB - Layered double hydroxide (LDH) has attracted major interest as one of the most versatile drug delivery systems especially for adsorption capacity and/or controlled delivery property of bioactive agents owing to their combining features of biohybrid. ZnAl synthesized layered double hydroxide can offer a platform to immobilize various types of bioactive compounds, particularly berberine chloride (BBC). However, the immobilization reaction of berberine chloride into ZnAl-LDH was performed by direct co-precipitation method at different ratios of BBC/LDH. BBC-ZnAl-LDH biohybrids were characterized in terms of structure, surface morphology, in vitro drug release profile and antibacterial assay against various bacterial cells. The BBC biomolecules were attached by coordinate bond. Structural and microstructural characterization confirms that interaction of BBC with ZnAl-LDH occurs by adsorption rather than intercalation of BBC within LDH layers. The BBC release profiles from BBC-ZnAl-LDH had a longer release duration compared to the physical mixture, and the drug release seemed faster with the low ratio of BBC/LDH. BBC-ZnAl-LDH can be internalized into bacterial cells. In vitro experiments in PBS medium showed that BBC-ZnAl-LDH biohybrid had higher cytotoxicity and inhibitory effects against three pathogenic bacteria; Staphylococcus aureus CIP 543154, Pseudomonas aeruginosa A22 and Bacillus subtilus ILP 1428B upon the drug release profiles and its destructive potential depends on the loading BBC on the LDH layers. Nonetheless these results prove that the prepared BBC-ZnAl-LDH biohybrids retain the anti-bacterial character of the BBC molecules and are therefore potential modified drug delivery system (DDS). PMID- 27771490 TI - Heart Failure in Older Adults-More Than Just Age. PMID- 27771488 TI - Preformulation of cysteamine gels for treatment of the ophthalmic complications in cystinosis. AB - Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised lysosomal levels of cystine in the cells of all organs. It is treated by regular administration of the aminothiol, cysteamine. Corneal crystal deposition is one of the most troublesome complications affecting patients and requires the hourly administration of cysteamine eye drops. In an attempt to reduce this frequency and improve the treatment, the preformulation and evaluation of cysteamine containing gels is reported. Suitability for ophthalmic delivery was determined by analysis of rheology, bioadhesion, dissolution and stability. The results demonstrated that three polymers were suitable for ophthalmic delivery of cysteamine; namely sodium hyaluronate, hydroxyethyl cellulose and carbomer 934. Sodium hyaluronate displayed optimum performance in the preformulation tests, being pseudoplastic (reduction in apparent viscosity under increasing shear rate), bioadhesive, releasing cysteamine over 40min and displaying stability over time. In conclusion these results offer the possibility to formulate cysteamine in an ocular applicable gel formulation. PMID- 27771489 TI - Tailoring biomaterial scaffolds for osteochondral repair. AB - Articular cartilage is a mechanically and structurally complex, lubricious tissue that permits load-bearing and frictionless movement of our joints upon articulation. Unfortunately, cartilage is unable to properly self-heal as a result of acute trauma or damage, resulting in many cases in significant pain, reduction in physical activity and quality of life for the patient. Due to the inability of resident cells to repair damaged osteochondral tissue, researchers have focused on utilizing endogenously or exogenously sourced cells (chondrocytes or tissue-derived mesenchymal stem cells), with or without scaffolds, to encourage the secretion of extracellular matrix (ECM) that replicates this highly anisotropic osteochondral tissue, in which the phenotype of the cells and the composition and orientation of the ECM varies along its depth. Important advances have been achieved towards the development of scaffolds with macroscopically relevant structures, however, articular cartilage and bone tissue contain complex, hierarchical structures that provide cells with biophysical and biochemical cues spanning multiple length scales, presenting researchers with some substantial challenges. This review summarizes the latest advances in mechanical, biochemical and topographical engineering of biomaterials to drive requisite biological responses, such as cell differentiation and matrix deposition, in an effort to achieve functional repair of osteochondral defects. PMID- 27771491 TI - Longitudinal evolution of true protein, amino acids and bioactive proteins in breast milk: a developmental perspective. AB - The protein content of breast milk provides a foundation for estimating protein requirements of infants. Because it serves as a guideline for regulatory agencies issuing regulations for infant formula composition, it is critical that information on the protein content of breast milk is reliable. We have therefore carried out a meta-analysis of the protein and amino acid contents of breast milk and how they evolve during lactation. As several bioactive proteins are not completely digested in the infant and therefore represent "non-utilizable" protein, we evaluated the quantity, mechanism of action and digestive fate of several major breast milk proteins. A better knowledge of the development of the protein contents of breast milk and to what extent protein utilization changes with age of the infant will help improve understanding of protein needs in infancy. It is also essential when designing the composition of infant formulas, particularly when the formula uses a "staging" approach in which the composition of the formula is modified in stages to reflect changes in breast milk and changing requirements as the infant ages. PMID- 27771492 TI - What is the status of food literacy in Australian high schools? Perceptions of home economics teachers. AB - The high school setting has been identified as an ideal setting to teach adolescents about healthy dietary behaviours. This study explored home economics teachers' (HETs) views on the role of high schools in enhancing adolescents' food literacy and promoting healthy dietary behaviours. Semi-structured interviews with 22 HETs were conducted. The interview questions focused on the perceived strengths/opportunities and the limitations/barriers in enhancing adolescents' food literacy and healthy dietary behaviours in Australian high schools. Thematic data analysis was used to identify five key themes from the interview transcripts: (1) the standing of food-related life skills; (2) food literacy in the Australian school curriculum; (3) emphasis on resources; (4) learning through school canteens; and (5) building a school to home and community nexus. Overall, HETs reported that home economics was regarded by parents and other school staff to be less important than Maths or English for adolescents to learn in Australian high schools. Some teachers indicated that their schools offered one year compulsory teaching of food related studies which is typically delivered in the leaning areas of Technologies or Health and Physical Education (HPE). However, HETs stated that the time was insufficient to develop sustainable food-related life skills and introduce broader concepts of food literacy such as environmental sustainability. The lack of financial resources and non-supportive school food environments, including school canteens, were reportedly major factors that prevented food literacy education and healthy dietary behaviours of adolescents. Increasing the status of food literacy education in schools would support adolescents to develop food-related life skills and mobilise them as agents of dietary behaviour change in the home setting. PMID- 27771493 TI - Penetration of mucoadhesive chitosan-dextran sulfate nanoparticles into the porcine cornea. AB - Topical application of drugs to the eyes suffers from poor bioavailability at the ocular surface and in the anterior chamber. This is due to rapid clearance of the drug because of tear secretion and outflow. This study has investigated mucoadhesive and penetration characteristics of chitosan-dextran sulfate nanoparticles (CDNs), prepared by polyelectrolyte complexation technique, following topical administration to the ocular surface. Topical FITC-labeled CDNs (FCDNs; mean size of 400nm and a surface charge of +48mV) were retained on the porcine ocular surface for more than 4h. Topical FCDNs were partially endocytosed into porcine corneal epithelial cells via a clathrin-dependent pathway. After 6h of topical FCDNs, particles accumulated in the corneal epithelium but not found in the corneal stroma. When epithelium was removed, FCDNs penetrated the stroma. Thus, CDNs are potentially useful for drug/gene delivery to the ocular surface and to stroma when epithelium is damaged. PMID- 27771494 TI - Drug induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences. AB - Several commonly used medications impair mitochondrial function resulting in adverse effects or toxicities. Drug induced mitochondrial dysfunction may be a consequence of increased production of reactive oxygen species, altered mitochondrial permeability transition, impaired mitochondrial respiration, mitochondrial DNA damage or inhibition of beta-oxidation of fatty acids. The clinical manifestation depends on the specific drug and its effect on mitochondria. Given the ubiquitous presence of mitochondria and its central role in cellular metabolism, drug-mitochondrial interactions may manifest clinically as hepatotoxicity, enteropathy, myelosuppression, lipodystrophy syndrome or neuropsychiatric adverse effects, to name a few. The current review focuses on specific drug groups which adversely affect mitochondria, the mechanisms involved and the clinical consequences based on the data available from experimental and clinical studies. Knowledge of these adverse drug-mitochondrial interactions may help the clinicians foresee potential issues in individual patients, prevent adverse drug reactions or alter drug regimens to enhance patient safety. PMID- 27771495 TI - A severe pediatric infection with a novel enterovirus A71 strain, Thuringia, Germany. AB - Infection by Enterovirus A71 (EV-A71) is an important cause of hand, foot, and mouth disease (HFMD). Outbreaks including severe cases with neurological and cardiopulmonary complications have been reported particularly from Southeast Asia. In Europe, the epidemiology of EV-A71 is not well understood. In summer 2015, a two-year-old girl from Thuringia, Germany, presented with rhombencephalitis/brainstem encephalitis associated with severe neurological and cardiopulmonary complications. EV-A71 was detected in stool and almost the entire viral genome was amplified and sequenced. While the capsid protein VP1-encoding region belongs to the EV-A71 subgenogroup C1, the 3D polymerase encoding region represents a unique lineage. Thus, the data suggest that the Thuringian EV-A71 sequence likely represents a recombinant. The case underlines the importance of intensified EV-A71 surveillance in Germany and Europe including analysis of full genome data. PMID- 27771496 TI - Phase II Study of Yttrium-90-Ibritumomab Tiuxetan as Part of Reduced-Intensity Conditioning (with Melphalan, Fludarabine +/- Thiotepa) for Allogeneic Transplantation in Relapsed or Refractory Aggressive B Cell Lymphoma: A GELTAMO Trial. AB - We designed a phase II clinical trial including Y-90 ibritumomab-tiuxetan as part of a reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (Clinical Trials Identifier: NCT00644371). Eligible patients had high-risk relapsed/refractory aggressive lymphoma. The conditioning regimen consisted of rituximab 250 mg (days -21 and 14), Y-90 ibritumomab IV (.4 m Ci/kg, day -14), fludarabine 30 mg/m2 i.v. (days 3 and -2) plus melphalan 70 mg/m2 i.v. (days -3 and -2) or 1 dose of melphalan and thiotepa 5 mg/kg (day -8). Donors were related. Eighteen patients were evaluable. At the time of transplantation, responses were complete remission (CR) (n = 7, 39%), partial remission (n = 6, 33%) or refractory disease (n = 4, 28%). Y-90-ibritumomab infusions were well tolerated, with no adverse reactions. Nonrelapse mortality at 1 year was 28%. Median follow-up was 46 (range, 39 to 55) months. Estimated 1-year progression-free survival (PFS) was 50%, and 4-year overall survival (OS) and PFS were both 44.4%. CR at the moment of AlloSCT had significant impact on PFS (71% versus 27%, P = .046) and OS (71% versus 27%, P = .047). Our results show that Y-90-ibritumomab-tiuxetan as a component of RIC for AlloSCT is feasible in patients with high-risk B cell lymphoma. Development of phase III clinical trials is needed to clarify the contribution of radioimmunotherapy to RIC AlloSCT. PMID- 27771497 TI - Negative effects of retinoic acid on stem cell niche of mouse incisor. AB - The continuous growth of mouse incisors depends on epithelial stem cells (SCs) residing in the SC niche, called labial cervical loop (LaCL). The homeostasis of the SCs is subtly regulated by complex signaling networks. In this study, we focus on retinoic acid (RA), a derivative of Vitamin A and a known pivotal signaling molecule in controlling the functions of stem cells (SCs). We analyzed the expression profiles of several key molecules of the RA signaling pathway in cultured incisor explants upon exogenous RA treatment. The expression patterns of these molecules suggested a negative feedback regulation of RA signaling in the developing incisor. We demonstrated that exogenous RA had negative effects on incisor SCs and that this was accompanied by downregulation of Fgf10, a mesenchymally expressed SC survival factor in the mouse incisor. Supplement of Fgf10 in incisor cultures completely blocked RA effects by antagonizing apoptosis and increasing proliferation in LaCL epithelial SCs. In addition, Fgf10 obviously antagonized RA-induced downregulation of the SC marker Sox2 in incisor epithelial SCs. Our findings suggest that the negative effects of RA on incisor SCs result from inhibition of mesenchymal Fgf10. PMID- 27771498 TI - EphrinB3 restricts endogenous neural stem cell migration after traumatic brain injury. AB - Traumatic brain injury (TBI) leads to a series of pathological events that can have profound influences on motor, sensory and cognitive functions. Conversely, TBI can also stimulate neural stem/progenitor cell proliferation leading to increased numbers of neuroblasts migrating outside their restrictive neurogenic zone to areas of damage in support of tissue integrity. Unfortunately, the factors that regulate migration are poorly understood. Here, we examine whether ephrinB3 functions to restrict neuroblasts from migrating outside the subventricular zone (SVZ) and rostral migratory stream (RMS). We have previously shown that ephrinB3 is expressed in tissues surrounding these regions, including the overlying corpus callosum (CC), and is reduced after controlled cortical impact (CCI) injury. Our current study takes advantage of ephrinB3 knockout mice to examine the influences of ephrinB3 on neuroblast migration into CC and cortex tissues after CCI injury. Both injury and/or ephrinB3 deficiency led to increased neuroblast numbers and enhanced migration outside the SVZ/RMS zones. Application of soluble ephrinB3-Fc molecules reduced neuroblast migration into the CC after injury and limited neuroblast chain migration in cultured SVZ explants. Our findings suggest that ephrinB3 expression in tissues surrounding neurogenic regions functions to restrict neuroblast migration outside the RMS by limiting chain migration. PMID- 27771499 TI - Breast cancer in women aging 35 years old and younger: The Egyptian National Cancer Institute (NCI) experience. AB - OBJECTIVE: The aim is to identify the epidemiological and clinicopathological features associated with young breast cancer (BC) patients and to discuss factors affecting tumor recurrence and DFS. PATIENTS & METHODS: A retrospective analysis was conducted based on medical records from young females patients aged <=35 years with pathologically confirmed primary breast cancer treated during 2008 2010 at NCI. Cases with non invasive cancer and non carcinoma histology are excluded. RESULTS: Of the 5408 cases diagnosed with breast cancer, 554 were young. Four hundred & fifty eight patients representing 9.2% were within our inclusion criteria. Almost half of the patients (45.9%) presented with stage III. Axillary nodes involvement was in 63.9%, 83.3% were grade 2. More than one quarter of tumors was hormone receptors negative (28.8%) & Her2 was over expressed in 30%. Mastectomy was offered in 72% while conservative breast surgery in 26%, 69.2% received chemotherapy either adjuvant, neoadjuvant or both, 82.5% received adjuvant radiotherapy, 68.6% received hormonal therapy. Metastatic disease developed in 51.3%, with 31% having more than one site of metastases. After a median follow up period of 66 months, the median DFS of patients was 60 months. The median DFS was significantly shorter among patients with positive lymph nodes (P < 0.0001), ER negative disease (P = 0.045) and stage III disease (P < 0.0001). CONCLUSION: Breast cancer in young women is aggressive from the time of diagnosis. Our results provide baseline data of young BC in the Middle East & North Africa region; thus, contributing to future epidemiological and hospital-based researches. PMID- 27771500 TI - Bisphenol A and its analogs: Do their metabolites have endocrine activity? AB - Structural analogs of bisphenol A are commonly used as its alternatives in industrial and commercial applications. Nevertheless, the question arises whether the use of other bisphenols is justified as replacements for bisphenol A in mass production of plastic materials. To evaluate the influence of metabolic reactions on endocrine activities of bisphenols, we conducted a systematic review of the literature. Knowledge about the metabolic pathways and enzymes involved in metabolic biotransformations is essential for understanding and predicting mechanisms of toxicity. Bisphenols are metabolized predominantly by the glucuronidation reaction, which is considered their most important detoxification pathway, as based on current knowledge, glucuronides do not have activity on endocrine receptors. In contrast, several oxidative metabolites of bisphenols with enhanced endocrine activities are presented, and these findings indicate that oxidative metabolites of bisphenols can still have endocrine activities in humans. PMID- 27771501 TI - Applications in environmental risk assessment of biochemical analysis on the Indian fresh water fish, Labeo rohita exposed to monocrotophos pesticide. AB - Pesticides are widely used in modern agriculture to aid in the production of high quality food. However, some pesticides have the potential to cause serious health and environmental damage. Repeated exposure to sub-lethal doses of pesticides can cause physiological and behavioral changes in fish that reduce populations such as abandonment of nests and broods, decreased immunity to disease and increased failure to avoid predators. Monocrotophos is one of the organophosphorus pesticide used in this study. The median lethal concentration (LC50) of Monocrotophos to fish L. rohita for 96h was found to be 45.1ppm. In sublethal concentration (1/10th of LC50 96h value, 4.51ppm) fishes were exposed for 24, 48, 72, 96h and 10, 20 and 30days. Organs of fishes were sacrificed and tested for biochemical analysis. A significant decrease in protein, carbohydrate and lipids were observed throughout the study period when compared to the control. It is essential for assessing the ecological risk of these pesticides. PMID- 27771502 TI - The roles of cysteine proteases and phytocystatins in development and germination of cereal seeds. AB - Proteolysis is an important process for development and germination of cereal seeds. Among the many types of proteases identified in plants are the cysteine proteases (CPs) of the papain and legumain families, which play a crucial role in hydrolysing storage proteins during seed germination as well as in processing the precursors of these proteins and the inactive forms of other proteases. Moreover, all of the tissues of cereal seeds undergo progressive degradation via programed cell death, which is integral to their growth. In view of the important roles played by proteases, their uncontrolled activity could be harmful to the development of seeds and young seedlings. Thus, the activities of these enzymes are regulated by intracellular inhibitors called phytocystatins (PhyCys). The phytocystatins inhibit the activity of proteases of the papain family, and the presence of an additional motif in their C-termini allows them to also regulate the activity of members of the legumain family. A balance between the levels of cysteine proteases and phytocystatins is necessary for proper cereal seed development, and this is maintained through the antagonistic activities of gibberellins (GAs) and abscisic acid (ABA), which regulate the expression of the corresponding genes. Transcriptional regulation of cysteine proteases and phytocystatins is determined by cis-acting elements located in the promoters of these genes and by the expression of their corresponding transcription factors (TFs) and the interactions between different TFs. PMID- 27771503 TI - Effect of moderate high temperature on the vegetative growth and potassium allocation in olive plants. AB - There is little information about the prolonged effect of a moderately high temperature on the growth of olive (Olea europaea L.). It has been suggested that when the temperature of the air rises above 35 degrees C the shoot growth of olive is inhibited while there is any reference on how growth is affected when the soil is warmed. In order to examine these effects, mist-cuttings and young plants generated from seeds were grown under moderate high temperature (37 degrees C) for 64 and 42days respectively. In our study, plant dry matter accumulation was reduced when the temperature of both the air and the root medium was moderately high. However, when the temperature of the root medium was 25 degrees C, the inhibitory effect of air high temperature on plant growth was not observed. The exposure of both the aerial part and the root to moderate high temperature also reduced the accumulation of K+ in the stem and the root, the water use efficiency and leaf relative water content. However, when only the aerial part was exposed to moderate high temperature, the accumulation of K+ in the stem, the water use efficiency and leaf relative water content were not modified. The results from this study suggest that the olive is very efficient in regulating the water and potassium transport through the plant when only the atmosphere surrounding the aerial part is warmed up. However, an increase in the soil temperature decrease root K+ uptake and its transport to the aerial parts resulting in a reduction in shoot water status and growth. PMID- 27771504 TI - Changes in the levels of l-carnitine, acetyl-l-carnitine and propionyl-l carnitine are involved in perfluorooctanoic acid induced developmental cardiotoxicity in chicken embryo. AB - Perfluorooctanoic acid (PFOA), a persistent organic pollutant, is associated with developmental toxicity. This study investigated the mechanism of PFOA-induced developmental cardiotoxicity in chicken embryo, focusing on the interactions between developmental exposure to PFOA and the levels of l-carnitine (LC), acetyl l-carnitine (ALC) and propionyl-l-carnitine (PLC) in the heart. To evaluate the developmental cardiotoxicity, fertile chicken eggs were exposed to 0.1, 0.5, 1, 2 or 5mg/kg PFOA via air cell injection. Furthermore, exposure to 2mg/kg PFOA, with or without 100mg/kg LC were applied to investigate the effects of LC supplement. The results of functional and morphological assessments confirmed PFOA induced developmental cardiotoxicity in chicken embryo, which could be alleviated by co exposure to LC. LC-MS/MS results also revealed remarkable decrease in LC, ALC and PLC levels in embryonic day six (ED6) chicken embryo hearts as well as LC level in embryonic day fifteen (ED15) chicken embryo hearts following developmental exposure to 2mg/kg PFOA. Meanwhile, co-exposure to 100mg/kg LC significantly elevated the levels of LC, ALC and PLC in chicken embryo hearts. Significantly elevated expression level of carnitine acetyltransferase (CRAT) in PFOA-exposed ED6 chicken embryo hearts was observed via western blotting, while LC co-exposure counteracted such changes. In conclusion, changes in the levels of LC, ALC and PLC in early embryonic stages are associated with PFOA induced developmental cardiotoxicity in chicken embryos. PMID- 27771505 TI - The suppressive effects of aluminum chloride on the osteoblasts function. AB - Aluminum (Al) exposure impairs bone formation, and bone formation is mediated by the osteoblasts. But effects of Al on the osteoblasts function remain elusive. The osteoblasts were exposed to 0, 0.0252, 0.126, 0.252mg/mL AlCl3.6H2O for 24h. The osteoblasts viability, TGF-beta1, BMP-2, IGF-I and Cbfalpha1 mRNA expressions, and GSH-Px and SOD activities, ROS concentration were determined. The osteoblasts ultrastructural features were also observed. The results showed that AlCl3 suppressed the osteoblasts viability, TGF-beta1, BMP-2, IGF-I and Cbfalpha1 mRNA expressions, GSH-Px and SOD activities, and elevated ROS concentration compared with the CG. The ultrastructural features of osteoblasts in the HG showed mitochondrial swelling, foam-like structure, uneven distribution of chromatin, incomplete cell membrane and cytoplasm spillover compared with the CG. It indicates that AlCl3 inhibits osteoblasts viability, growth regulation factors mRNA expressions, anti-oxidative function, and damaged the osteoblasts histology structure, impairing the osteoblasts function. PMID- 27771506 TI - Contribution of oxidative stress to TiO2 nanoparticle-induced toxicity. AB - With the rapid development of nanotechnology, titanium dioxide nanoparticles (TNPs) are widely used in many fields. People in such workplaces or researchers in laboratories are at a higher risk of being exposed to TNPs, so are the consumers. Moreover, increasing evidence revealed that the concentrations of TNPs are elevated in animal organs after systematic exposure and such accumulated TNPs could induce organ dysfunction. Although cellular responses such as oxidative stress, inflammatory response, apoptosis, autophagy, signaling pathways, and genotoxic effects contribute to the toxicity of TNPs, the interrelationship among them remains obscure. Given the pivotal role of oxidative stress, we summarized relevant articles covering the involvement of oxidative stress in TNPs' toxicity and found that TNP-induced oxidative stress might play a central role in toxic mechanisms. However, available data are far from being conclusive and more investigations should be performed to further confirm whether the toxicity of TNPs might be attributed in part to the cascades of oxidative stress. Tackling this uncertain issue may help us to comprehensively understand the interrelationship among toxic cellular responses induced by TNPs and might shed some light on methods to alleviate toxicity of TNPs. PMID- 27771507 TI - Zearalenone as an endocrine disruptor in humans. AB - Zearalenone (ZEA), a fungal mycotoxin, is present in a wide range of human foods. Many animal studies have found ZEA to possess a disruptive effect on the hormonal balance, mainly due to its similarity to naturally-occurring estrogens. With increasing consciousness of the adverse effects of endocrine disruptors on human health, it is becoming more important to monitor ZEA concentrations in food and identify its potential effects on human health. Based on a review of recent studies on animal models and molecular pathways in which ZEA is reported to have an influence on humans, we postulate that ZEA might act as an endocrine disruptor in humans in a similar way to animals. Moreover, its endocrine-disrupting effect might be also a causative factor in carcinogenesis. This review article summarizes the latest knowledge about the influence of ZEA on the human hormonal balance. PMID- 27771508 TI - Tyrosine hydroxylase haploinsufficiency prevents age-associated arterial pressure elevation and increases half-life in mice. AB - Catecholamines are essential for the maintenance of physiological homeostasis under basal and stress conditions. We aim to determine the impact of deletion of a single allele of the tyrosine hydroxylase (Th) gene might have on aging arterial pressure and life-span. We found that Th haploinsufficiency prevents age associated increase of arterial pressure (AP) in mature adult mice, and it results in the extension of the half-life of Th-heterozygous (TH-HET) mice respect to their wild-type (WT) littermates. Heart performance was similar in both genotypes. To further investigate the lack of increase in AP with age in TH HET mice, we measured the AP response to intra-peritoneal administration of substances involved in AP regulation. The response to acetylcholine and the basal sympathetic tone were similar in both genotypes, while norepinephrine had a greater pressor effect in TH-HET mice, which correlated with altered adrenoreceptor expression in blood vessels and the heart. Furthermore, sympatho adrenomedular response to stress was attenuated in TH-HET mice. Plasma catecholamine levels and urine glucose increased markedly in WT but not in TH-HET mice after stress. Our results showed that TH-HET mice are resistant to age associated hypertension, present a reduction in the sympathetic response to stress and display an extended half-life. PMID- 27771509 TI - A mouse model of aniridia reveals the in vivo downstream targets of Pax6 driving iris and ciliary body development in the eye. AB - The Pax6 transcription factor is essential for development of the brain, eye, olfactory and endocrine systems. Haploinsufficiency of PAX6 in humans and mice causes the congenital condition aniridia, with defects in each of these organs and systems. Identification of the PAX6 transcription networks driving normal development is therefore critical in understanding the pathophysiology observed with loss-of-function defects. Here we have focused on identification of the downstream targets for Pax6 in the developing iris and ciliary body, where we used laser capture microdissection in mouse eyes from E12.5-E16.5, followed by chromatin immunoprecipitation, promoter-reporter assays and immunohistochemistry. We identified 6 differentially expressed genes between wildtype and Pax6 heterozygous mouse tissues and demonstrated that Bmp4, Tgfbeta2, and Foxc1 were direct downstream targets of Pax6 in developing iris/ciliary body. These results improve our understanding of how mutations in Bmp4, Tgfbeta2, and Foxc1 result in phenocopies of the aniridic eye disease and provide possible targets for therapeutic intervention. PMID- 27771510 TI - Methionine synthase and methionine synthase reductase interact with MMACHC and with MMADHC. AB - An increasing number of studies indicate that each step of the intracellular processing of vitamin B12 or cobalamin (Cbl) involves protein-protein interactions. We have previously described a novel interaction between methionine synthase (MS) and MMACHC and its effect on the regulation of MMACHC activity. Our goal is to further characterize the interactions of MS with other potential partners in a so-called MS interactome. We dissected the interactions and their alterations by co-immunoprecipitation and DuoLink proximity ligation assays in fibroblasts with cblG, cblE, and cblC genetic defects affecting respectively the expression of MS, methionine synthase reductase (MSR) and MMACHC and in HepG2 cells transfected with corresponding siRNAs. We observed the known interactions of MS with MSR and with MMACHC as well as MMADHC with MMACHC, but we also observed novel interactions for MSR with MMACHC and with MMADHC and MS with MMADHC. Furthermore, we show that the absence of MS or MMACHC expression disrupts the interactions between the other interactome members, in cblC and cblG fibroblasts and in HepG2 cells transfected with siRNAs. Our data show that the processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least MS, MSR, MMACHC and MMADHC, which could contribute to shuttle safely and efficiently Cbl towards MS. Our data suggest that defective protein-protein interactions among key players of this pathway could contribute to the molecular mechanisms of the cblC, cblG and cblE genetic defects and provide novel insights into our understanding of the pathophysiology of inherited disorders of Cbl metabolism. PMID- 27771511 TI - High fat diet induces brain insulin resistance and cognitive impairment in mice. AB - High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Six week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS 1. These changes were accompanied by inflammatory (NFkappaB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice. PMID- 27771513 TI - pH-Sensitive mesoporous silica nanoparticles anticancer prodrugs for sustained release of ursolic acid and the enhanced anti-cancer efficacy for hepatocellular carcinoma cancer. AB - Ursolic acid (UA) as a nature product exhibits good anti-cancer activity, low toxicity, and good liver protection features. However, the low-solubility and poor bioavailability restrict its further clinical application. To overcome this problem, a pH-sensitive prodrug delivery system (UA@MSN-UA) that incorporated acid-sensitive linkage between drug and silica-based mesoporous nanosphere (MSN) was successfully designed and synthesized. The physicochemical properties of the UA@MSN-UA nanoparticles were investigated for shape, particle size, zeta potential, nitrogen adsorption-desorption and infrared (IR) spectroscopy. The nanoparticles were further evaluated for in vitro cytotoxicity, including proliferation inhibition, cell cycle distribution and apoptotic effects against human hepatocellular carcinoma HepG2 cells. The TEM image showed that the size of synthesized MSN nanoparticle was a near-spherical shape with ~100nm diameter. In vitro cytotoxicity testing demonstrated that UA@MSN-UA nanoparticles prodrug exhibited higher proliferation inhibition, cell cycle arrest at the G2/M phase and significantly caused the early and late apoptosis in HepG2 cells, which would be contributed to high loading capacity, high cellular uptake and sustained release of UA. Overall, the UA-modified MSN prodrug delivery system can be a promising drug carrier for improving the bioavailability of UA, and further enhance its anti-cancer efficacy. PMID- 27771514 TI - KeepEX, a simple dilution protocol for improving extracellular vesicle yields from urine. AB - Urinary extracellular vesicles (EVs) are a promising source of biomarkers, which can be obtained in a non-invasive manner. However, the yield of EVs from urine samples may be insufficient for various analyses due to the entrapment of EVs by the Tamm-Horsfall protein (THP) meshwork. Here, we developed a simple dilution protocol to increase the urinary EV yield by disrupting the interaction between THP filaments and EVs with the help of alkaline pH and lowered ionic concentration. The integrity of the EVs and THP was assessed by electron microscopy. The effect of the protocol on the EV yield was quantified against an undiluted control by western blotting of four EV markers, nanoparticle tracking analysis and measuring of the RNA/miRNA concentration of the EV samples. The average EV yield from the dilution protocol was 2-7 fold the yield from the undiluted control i.e. increased by 130-624% as measured by western blotting and NTA. The yield increased most from samples with a high THP to EV ratio. The morphology and size range of the EVs were unaltered by the protocol. However, RNA/miRNA yields were the same as from the undiluted control and THP filaments could still be detected in EV samples. The dilution protocol, that we named KeepEX, provides a simple and efficient way to prevent loss of EVs thus increasing their yield from urine. Since KeepEX does not require individual adjustment of sample pH nor extra centrifugation steps, it could be used on its own or in combination with other EV purification protocols to improve EV isolation particularly from small urine volumes. PMID- 27771512 TI - Positive Feedback Amplifies the Response of Mitochondrial Membrane Potential to Glucose Concentration in Clonal Pancreatic Beta Cells. AB - Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1 832/13 pancreatic beta-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (DeltapsiM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry. In these cells the sensitive response of DeltapsiM to extracellular glucose concentration drives glucose-stimulated insulin secretion. Using metabolic control analysis we identified the control properties that generate this sensitive response. Force-flux relationships between DeltapsiM and respiration were used to calculate kinetic responses to DeltapsiM of processes both upstream (glucose oxidation) and downstream (proton leak and ATP turnover) of DeltapsiM. The analysis revealed that glucose-evoked DeltapsiM hyperpolarization is amplified by increased glucose oxidation activity caused by factors downstream of DeltapsiM. At high glucose, the hyperpolarized DeltapsiM is stabilized almost completely by the action of glucose oxidation, whereas proton leak also contributes to the homeostatic control of DeltapsiM at low glucose. These findings suggest a strong positive feedback loop in the regulation of beta-cell energetics, and a possible regulatory role of proton leak in the fasting state. Analysis of islet bioenergetics from published cases of type 2 diabetes suggests that disruption of this feedback can explain the damaged bioenergetic response of beta-cells to glucose. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy. PMID- 27771515 TI - Metabolically active extracellular vesicles released from hepatocytes under drug induced liver-damaging conditions modify serum metabolome and might affect different pathophysiological processes. AB - Hepatocytes are involved in the endogenous and drug metabolism; many of the enzymes involved in those processes are incorporated into extracellular vesicles and secreted into the bloodstream. Liver-damaging conditions modify the molecular cargo of those vesicles significantly. However, no information about the effect of these hepatic vesicles on the extracellular environment is available. Drug induced liver damage increases the number of circulating extracellular vesicles and affects the release and content of hepatocyte-derived vesicles. In this work, we evaluated the metabolic effect of these vesicles on the composition of the serum. We performed a targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics analysis of serum samples. The samples had been first incubated with hepatic extracellular vesicles from hepatocytes challenged with acetaminophen or diclofenac. The incubation affected the serum levels of 67 metabolites, such as amino acids and different species of lipids. The metabolites included various species of phosphatidylcholines and phosphatidylethanolamines. These compounds are the components of biological membranes; our observations suggest that the vesicles might take part in remodelling and maintenance of the membranes. Alterations in the levels of some other serum metabolites might have deleterious consequences, for example, the tetracosanoic acid with its cardiovascular effects. However, some of the metabolites whose levels were increased, including alpha-linoleic and tauroursodeoxycholic acids, have been reported to have a protective effect. Our targeted metabolomics analysis indicated that the hepatic extracellular vesicles act as nano-metabolic machines supplying the extracellular environment with the means to integrate diverse tissue responses. In conclusion, we show that the hepatic extracellular vesicles are metabolically active and might play a role in the physiopathological response to hepatic insults, including drug-induced liver injury. PMID- 27771516 TI - Formulation, functional evaluation and ex vivo performance of thermoresponsive soluble gels - A platform for therapeutic delivery to mucosal sinus tissue. AB - Mucoadhesive in situ gelling systems (soluble gels) have received considerable attention recently as effective stimuli-transforming vectors for a range of drug delivery applications. Considering this fact, the present work involves systematic formulation development, optimization, functional evaluation and ex vivo performance of thermosensitive soluble gels containing dexamethasone 21 phosphate disodium salt (DXN) as the model therapeutic. A series of in situ gel forming systems comprising the thermoreversible polymer poloxamer-407 (P407), along with hydroxypropyl methyl cellulose (HPMC) and chitosan were first formulated. The optimized soluble gels were evaluated for their potential to promote greater retention at the mucosal surface, for improved therapeutic efficacy, compared to existing solution/suspension-based steroid formulations used clinically. Optimized soluble gels demonstrated a desirable gelation temperature with Newtonian fluid behaviour observed under storage conditions (4-8 degrees C), and pseudoplastic fluid behaviour recorded at nasal cavity/sinus temperature (~34 degrees C). The in vitro characterization of formulations including rheological evaluation, textural analysis and mucoadhesion studies of the gel form were investigated. Considerable improvement in mechanical properties and mucoadhesion was observed with incorporation of HPMC and chitosan into the gelling systems. The lead poloxamer-based soluble gels, PGHC4 and PGHC7, which were carried through to ex vivo permeation studies displayed extended drug release profiles in conditions mimicking the human nasal cavity, which indicates their suitability for treating a range of conditions affecting the nasal cavity/sinuses. PMID- 27771517 TI - Chikungunya: an unexpected emergence in Europe. AB - Since the first outbreak of chikungunya in Italy in 2007, Europe has been facing an increase in local transmission of arboviral diseases. Dengue virus (DENV) and chikungunya virus (CHIKV) are both transmitted by the mosquito Aedes albopictus present in 20 European countries. CHIKV emergence in Europe was mainly associated with the East-Central-South African (ECSA) genotype, recently exemplified by the 11 CHIKV cases in southern France in 2014. Despite hundreds of travelers returning from the Americas where the Asian CHIKV genotype was responsible for more than one million cases, no autochthonous transmission associated with the Asian genotype was reported in Europe. Thus the pattern of transmission can be significantly different depending on the mosquito population, the virus genotype and environmental factors such as temperature. PMID- 27771518 TI - The effect of methylenetetrahydrofolate reductase polymorphisms on susceptibility to human papilloma virus infection and cervical cancer. AB - Cervical cancer is the third most common cancer among women worldwide. Several factors lead to cervical cancer, among which human papilloma virus (HPV) infection has a prominent role. Methylenetetrahydrofolate reductase (MTHFR) is crucial in folate metabolic pathway and plays an important role in DNA synthesis and DNA methylation. MTHFR gene polymorphisms, including C677T and A1298C, lead to reduced enzyme activity. This case-control study aims to illustrate the association between MTHFR gene polymorphisms and the risk of cervical cancer. This study was conducted on 196 samples, which included 96 cervical biopsy samples compared to 100 Pap smear samples of normal healthy women without HPV infection. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for the MTHFR polymorphism detection, followed by fluorescent amplification-based specific hybridization PCR method to detect HPV16 and HPV18. The results show that the MTHFR 677TT genotype plays a protective role in cervical cancer (P=0.0030) (OR=0.21, 95% confidence interval [CI]: 0.07-0.59). Furthermore, there was a strong significant association between MTHFR 1298CC genotype and the risk of cervical cancer (OR=10.69; 95% CI: 4.28-26.71, P=0.0001). It can be concluded that A1298C polymorphism is a genetic risk factor for cervical cancer in the assessed Iranian population group. It seems that MTHFR 1298CC genotype is more susceptible to HPV 16 infection. Combination analysis of MTHFR C677T and A1298C polymorphisms revealed that combined MTHFR 677CC and 1298CC are strongly associated with a risk of cervical cancer. PMID- 27771519 TI - "Genetic regulation of Mycobacterium tuberculosis in a lipid-rich environment". AB - Tuberculosis (TB) remains as one of the leading causes of morbidity and mortality among infectious diseases worldwide. Although lipids (mainly fatty acids and cholesterol) have been reported to play an important role during active and latent infection of M. tuberculosis, there are other molecular aspects of bacterial response to those substrates that are not fully understood, involving gene regulation background. This review highlights recent insights on pathogen gene expression: regulation during its active growth, during survival in presence of lipids and under variable hostile host microenvironments. We also propose several application options of this knowledge that may contribute for improved TB control. PMID- 27771520 TI - Multiple-locus variable number of tandem repeat analysis as a tool for molecular epidemiology of botulism: The Italian experience. AB - Clostridium botulinum is the bacterial agent of botulism, a rare but severe neuro paralytic disease. Because of its high impact, in Italy botulism is monitored by an ad hoc surveillance system. The National Reference Centre for Botulism, as part of this system, collects and analyzes all demographic, epidemiologic, microbiological, and molecular data recovered during cases and/or outbreaks occurred in Italy. A panel of 312 C. botulinum strains belonging to group I were submitted to MLVA sub-typing. Strains, isolated from clinical specimens, food and environmental samples collected during the surveillance activities, were representative of all forms of botulism from all Italian regions. Through clustering analysis isolates were grouped into 12 main clusters. No regional or temporal clustering was detected, demonstrating the high heterogeneity of strains circulating in Italy. This study confirmed that MLVA is capable of sub-typing C. botulinum strains. Moreover, MLVA is effective at tracing and tracking the source of contamination and is helpful for the surveillance system in terms of planning and upgrading of procedures, activities and data collection forms. PMID- 27771521 TI - Clinical value of the neutrophil/lymphocyte ratio in diagnosing adult strangulated inguinal hernia. AB - BACKGROUND: Diagnosis of incarcerated inguinal hernia (IIH) is not difficult, but currently, there are no diagnostic criteria that can be used to differentiate it from strangulated inguinal hernia (SIH). This research aimed to evaluate the clinical value of the neutrophil/lymphocyte ratio (NLR) in diagnosing SIH. METHODS: We retrospectively analyzed 263 patients with IIH who had undergone emergency operation. The patients were divided into two groups according to IIH severity: group A, patients with pure IIH validated during operation as having no bowel ischemia; group B, patients with SIH validated during operation as having obvious bowel ischemia, including bowel necrosis. We statistically evaluated the relation between several clinical features and SIH. The accuracy of different indices was then evaluated and compared using receiver operating characteristic (ROC) curve analyses, and the corresponding cutoff values were calculated. RESULT: Univariate analysis showed eight clinical features that were significantly different between the two groups. They were then subjected to multivariate analysis, which showed that the NLR, type of hernia, and incarcerated organ were significantly related to SIH. ROC curve analysis showed that the NLR had the largest area under the ROC curve. CONCLUSION: Among the different clinical features, the NLR appears to be the best index in diagnosing SIH. PMID- 27771522 TI - Bariatric surgery and pregnancy: What outcomes? PMID- 27771523 TI - It isn't all just fun and games: Collegiate participation in extracurricular activities and risk for generalized and sexual harassment, psychological distress, and alcohol use. AB - Collegiate extracurricular activities, despite their benefits, may place students at an increased risk for experiencing harassment. This study utilizes multiple waves of data from an online longitudinal survey to examine how participation in college activities (intramural sports, fraternities/sororities, school clubs) relates to experiences of sexual and generalized harassment and outcomes (psychological distress, heavy alcohol use) among undergraduates (N = 1852, 58.6% female, 57.4% White) in the Midwestern United States. Activity participation was related to harassment, but the pattern depended on the activity, harassment type, and sex. Fraternity/sorority involvement was associated with generalized harassment, whereas school club involvement was linked to both generalized and sexual harassment. Female intramural athletes were at an increased risk to experience both harassment types. In addition to direct relations, activity participation was indirectly linked to future psychological distress (depression, anxiety) and heavy alcohol use via harassment. Implications for intervention with this college student population are discussed. PMID- 27771524 TI - Injecting drug use in India and the need for policy and program change. PMID- 27771525 TI - Role of steel slags on biomass/carbon dioxide gasification integrated with recovery of high temperature heat. AB - Disposal of biomass in the agriculture and steel slags in the steel industry provides a significant solution toward sustainability in China. Herein these two sectors were creatively combined as a novel method, i.e., biomass/CO2 gasification using waste heat from hot slags where the influence of chemical compositions of steel slags, characterized as iron oxide content and basicity, on gasification thermodynamics, was systemically reported for the first time. Both the target gases of CO, H2 and CH4 and the polluted gases of NH3, NO and NO2 were considered. It was first found that an increasing iron content and slag basicity continuously improved the CO yield at 600-1000 degrees C and 800-1000 degrees C, respectively; while the effect on polluted gas releases was limited. Moreover, the solid wastes after gasification could be utilized to provide nutrients and improve the soil in the agriculture, starting from which an integrated modern system was proposed herein. PMID- 27771526 TI - Effect of pyrolysis temperature on characteristics and aromatic contaminants adsorption behavior of magnetic biochar derived from pyrolysis oil distillation residue. AB - The magnetic biochars were easily fabricated by thermal pyrolysis of Fe(NO3)3 and distillation residue derived from rice straw pyrolysis oil at 400, 600 and 800 degrees C. The effects of pyrolysis temperature on characteristics of magnetic biochars as well as adsorption capacity for aromatic contaminants (i.e., anisole, phenol and guaiacol) were investigated carefully. The degree of carbonization of magnetic biochars become higher as pyrolysis temperature increasing. The magnetic biochar reached the largest surface area and pore volume at the pyrolysis temperature of 600 degrees C due to pores blocking in biochar during pyrolysis at 800 degrees C. Based on batch adsorption experiments, the used adsorbent could be magnetically separated and the adsorption capacity of anisole on magnetic biochars was stronger than that of phenol and guaiacol. The properties of magnetic biochar, including surface area, pore volume, aromaticity, grapheme-like structure and iron oxide (gamma-Fe2O3) particles, showed pronounced effects on the adsorption performance of aromatic contaminants. PMID- 27771527 TI - Effect of bisulfite treatment on composition, structure, enzymatic hydrolysis and cellulase adsorption profiles of sugarcane bagasse. AB - The effect of sulfite pretreatment to overcome recalcitrance of lignocellulose (SPORL) on composition, structure, enzymatic hydrolysis and cellulase adsorption profiles of sugarcane bagasse (SCB) was investigated. SPORL gave a higher SCB hydrolysis yield (85.33%) compared to dilute acid pretreatment (DA) (64.39%). The SEM pictures showed that SPORL SCB structure became more disordered and looser, suggesting SPORL SCB was more accessible to cellulase. The zeta potential of SPORL SCB suspension (-21.89mV) was significantly different from that of DA SCB ( 12.87mV), which demonstrated the lignin in SPORL SCB was more hydrophilic. With regard to cellulase adsorption profiles, SPORL SCB had a lower non-productive adsorption (14.87mg/glignin) and a higher productive adsorption (37.67 mg/gcarbohydrate) compared with DA SCB (17.05mg/glignin; 25.79mg/gcarbohydrate). These results indicated that SPORL SCB had better accessibility to cellulase and the higher productive cellulase adsorption of SPORL SCB had improved hydrolysis. PMID- 27771528 TI - Strategy for dual production of bioethanol and d-psicose as value-added products from cruciferous vegetable residue. AB - In this study, fermentable sugars and d-fructose were produced from cruciferous vegetable residue by enzymatic method without the use of either chemical or mechanical mechanisms. Production of d-psicose was effectively converted from hydrolyzed d-fructose in cabbage residue by d-psicose-3 epimerase; the presence of the borate increased the conversion rate by about two fold, and ethanol production yield was 85.7% of the theoretical yield. Both products, bioethanol and d-psicose, were successfully separated and purified by pervaporation and cation exchange chromatography, and their recovery yields were approximately 87% and 86.2%, respectively. PMID- 27771529 TI - The effect of oral contraception on cardiometabolic risk factors in women with elevated androgen levels. AB - BACKGROUND: In unselected reproductive-aged women, use of combined estrogen progestin oral contraceptive pills has been linked with an increased risk of vascular disease. The aim of this study was to investigate the effect of oral contraception on cardiometabolic risk factors in a population of women with hyperandrogenism. METHODS: The study included 16 untreated women with elevated testosterone levels and 15 matched healthy women who were then treated with oral contraceptive pills containing ethinyl estradiol (30MUg) and drospirenone (3mg). Plasma lipids, glucose homeostasis markers, circulating levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, as well as urinary albumin-to-creatinine ratio (UACR) were assessed at baseline and after 12 weeks of treatment. RESULTS: Compared to healthy women, women with elevated androgen levels showed increased plasma levels of hsCRP, fibrinogen and homocysteine, as well as a higher value of UACR. Oral contraception reduced androgen levels only in hyperandrogenic women. In healthy women, ethinyl estradiol plus drospirenone increased plasma levels of insulin, hsCRP, fibrinogen and homocysteine, while in women with elevated androgen levels their effect was limited only to a small increase in hsCRP. CONCLUSIONS: Our results suggest that a deteriorating effect of oral contraceptive pills containing ethinyl estradiol and drospirenone in hyperandrogenic women is weaker than in healthy young women and that ethinyl estradiol/drospirenone combination therapy may be safely used in the former group of patients. PMID- 27771530 TI - Thrombin and protein C pathway in peripheral nerve Schwann cells. AB - Thrombin and activated protein C (aPC) bound to the endothelial protein C receptor (EPCR) both activate protease-activated receptor 1 (PAR1) generating either harmful or protective signaling respectively. In the present study we examined the localization of PAR-1 and EPCR and thrombin activity in Schwann glial cells of normal and crushed peripheral nerve and in Schwannoma cell lines. In the sciatic crush model nerves were excised 1h, 1, 4, and 7days after the injury. Schwannoma cell lines produced high levels of prothrombin which is converted to active thrombin and expressed both EPCR and PAR-1 which co localized. In the injured sciatic nerve thrombin levels were elevated as early as 1h after injury, reached their peak 1day after injury which was significantly higher (24.4+/-4.1mU/ml) compared to contralateral uninjured nerves (2.6+/ 7mU/ml, t-test p<0.001) and declined linearly reaching baseline levels by day 7. EPCR was found to be located at the microvilli of Schwann cells at the node of Ranvier and in cytoplasm surrounding the nucleus. Four days after sciatic injury, EPCR levels increased significantly (57,785+/-16602AU versus 4790+/-1294AU in the contralateral uninjured nerves, p<0.001 by t-test) mainly distal to the site of injury, where axon degeneration is followed by proliferation of Schwann cells which are diffusely stained for EPCR. EPCR seems to be located to cytoplasmic component of Schwann cells and not to compact myelin component, and is highly increased following injury. PMID- 27771532 TI - Intrastriatal injection of ionomycin profoundly changes motor response to l-DOPA and its underlying molecular mechanisms. AB - Long-term l-DOPA treatment of Parkinson's disease is accompanied with fluctuations of motor responses and l-DOPA-induced dyskinesia (LID). Phosphorylation of the dopamine and c-AMP regulated phosphoprotein of 32kDa (DARPP-32) plays a role in the pathogenesis of LID, and thus dephosphorylation of this protein by activated calcineurin may help reduce LID. One important activator of calcineurin is the Ca2+ ionophore ionomycin. Here, we investigated whether intrastriatal injection of ionomycin to hemiparkinsonian rats produced changes in l-DOPA responses including LID. We also analyzed the effects of ionomycin on key molecular mediators of LID. Results confirmed our hypothesis that ionomycin could downregulate the phosphorylation of DARPP32 at Thr-34 and reduce LID. Besides, ionomycin decreased two established molecular markers of LID, FosB/DeltaFosB and phosphorylated ERK1/2. Ionomycin also decreased the phosphorylation of three main subunits of the NMDA receptor, NR1 phosphorylated at ser896, NR2A phosphorylated at Tyr-1325, and NR2B phosphorylated at Tyr-1472. Furthermore, the anti-LID effect of striatally injected ionomycin was not accompanied by reduction of the antiparkinsonian action of l-DOPA. These data indicate that ionomycin largely interacts with striatal mechanisms that are critical to the l-DOPA motor response highlighting the role of protein dephosphorylation by calcineurin. PMID- 27771531 TI - Involvement of CB1 and TRPV1 receptors located in the ventral medial prefrontal cortex in the modulation of stress coping behavior. AB - Cannabinoid type-1 (CB1) and transient receptor potential vanilloid type-1 (TRPV1) receptors may have opposite roles in modulating neural activity and, consequently, in regulating the stress response. These receptors are widely expressed in several brain structures, including the ventral medial prefrontal cortex (vmPFC). The functional consequences of the interaction between CB1 and TRPV1, however, have scarcely been explored. Therefore, we investigated if CB1 and TRPV1 receptors located in the vmPFC would be involved in the behavioral changes induced by the stress of the forced swim test (FST). Rats with cannulae implanted into the vmPFC were given the dual blocker of TRPV1 receptors and fatty acid amide hydrolase (FAAH), Arachidonyl serotonin (AA-5HT, 0.125/0.25/0.5nmol), TRPV1 antagonist, SB366791 (0.5/1/10nmol), FAAH inhibitor, URB597 (0.001/0.01/0.1/1nmol), or vehicle and were submitted to the FST, or to the open field test. Another group received intra-vmPFC injection of SB366791 or vehicle, followed by a second injection of URB597 or vehicle, and was submitted to the FST. Lastly, a group received intra-vmPFC injection of a CB1 antagonist, in sub effective dose or vehicle, followed by AA-5HT, SB366791 or vehicle. The results showed that AA-5HT, SB366791 and URB597 significantly reduced the immobility time without changing the locomotor activity. Furthermore, the co-administration of URB597 and SB366791 in sub-effective doses induced an antidepressant-like effect in the FST. Additionally, the antidepressant-like effect of AA-5HT was prevented by the CB1 antagonist. Together, these results suggest that both, CB1 and TRPV1 receptors located in the vmPFC are involved in the behavioral responses to stress, although in opposite ways. PMID- 27771533 TI - High-resolution SNP genotyping platform identified recurrent and novel CNVs in autism multiplex families. AB - Single nucleotide polymorphisms (SNPs)-based genotyping using microarray platform is now frequently used to detect copy number variants (CNVs) in the human genome. Here, we report CNVs identified using Illumina Human Omni 2.5M oligonucleotide microarrays in 11 multiplex families with autism spectrum disorder (ASD) referred to Autism Research and Treatment Center (ART) and Madinah Maternity and Children Hospital (MMCH). Of the 11 families, 22 patients with ASD (all males) and their parents, were recruited for the present study. In total, 43 individuals were genotyped with high-resolution array. Abnormal microarray results were seen in all 22 patients with ASD. A total of 17 shared CNVs were selected for further analysis. Out of these 17 CNVs, we discovered one novel CNV, previously not described, and 16 recurrent CNVs that overlap with the genomic imbalances defined in the autism database, autism chromosome rearrangement database and database of genomic variants. Recurrent CNVs include 11 common and 5 rare CNVs. All rare CNVs are duplications except a 16-kb deletion on chr2q36.3. Rare gain of copy numbers includes a 2-kb duplication on chr9q21.13, overlapping duplications of 107kb and 181kb on chrXp22.33 in 2 different families and a 10-kb duplication on chr18q21.13. A novel loss of copy number on chr3q23 was found in four ASD cases. This CNV results in deletion of intron 2 of calsyntenin 2 (CLSTN2) encoding synaptic protein calsyntenin 2. CLSTN2 is expressed exclusively in the brain, with high levels occurring in cortical gamma-aminobutyric acid (GABA)ergic interneurons and in medial temporal lobe regions. These results verify the diagnostic relevance of genome-wide small common and rare CNVs and provide further evidence of the high diagnostic yield of microarray for genetic testing in children with ASD. PMID- 27771534 TI - Neural mechanisms and functional correlates of altered postural responses to perturbed standing balance with chronic low back pain. AB - This study sought to determine the effects of chronic low back pain (LBP) on the cortical evoked potentials, muscle activation, and kinematics of postural responses to perturbations of standing balance. Thirteen subjects with chronic, recurrent, non-specific LBP and 13 subjects without LBP participated. The subjects responded to unpredictably timed postural perturbations while standing on a platform that randomly rotated either "toes up" or "toes down". Electroencephalography (EEG) was used to calculate the negative peak (N1) and subsequent positive peak (P2) amplitudes of the perturbation-evoked cortical potentials. Passive-marker motion capture was used to calculate joint and center of-mass (CoM) displacements. Surface electromyography was used to record muscle onset latencies. Questionnaires assessed pain, interference with activity, fear of activity, and pain catastrophizing. Results demonstrated that subjects with LBP exhibited significantly larger P2 potentials, delayed erector spinae, rectus abdominae, and external oblique onset latencies, as well as smaller trunk extension yet larger trunk flexion, knee flexion, and ankle dorsiflexion displacements compared to subjects without LBP. For the subjects with LBP, CoM displacements significantly and positively correlated with knee displacements as well as activity interference and fear scores. The P2 potentials significantly and negatively correlated with CoM displacements as well as activity interference, catastrophizing, and fear scores. These results demonstrate that people with LBP exhibit altered late-phase cortical processing of postural perturbations concomitant with altered kinematic and muscle responses, and these cortical and postural response characteristics correlate with each other as well as with clinical reports of pain-related fears and activity interference. PMID- 27771535 TI - Protective effects of a herbal extract combination of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica against MPTP-induced neurotoxicity via regulation of nuclear receptor-related 1 protein. AB - Parkinson's disease (PD) is one of the progressive neurodegenerative diseases of whose condition is characterized by dopaminergic neuronal cell loss and dysfunction in the substantia nigra pars compacta (SNpc) and the striatum. Recent studies have demonstrated that the nuclear receptor-related 1 protein (Nurr1) is critical of dopaminergic phenotype induction in mesencephalic dopaminergic neurons. Further, Nurr1 engages in synthesizing and storing dopamine through regulating levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). The aim of this study was to investigate the protective effects of a herbal extract combination, consisting of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica (MABH), on 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like symptoms and to elucidate possible mechanisms of action focusing on Nurr1. In a subacute mouse model of MPTP-induced PD, MABH treatment resulted in recovery from movement impairments. MABH prevented dopamine depletion and protected against dopaminergic neuronal degradation induced by MPTP. Additionally, MABH increased Nurr1 expression in the SNpc of mice. To evaluate the effects of MABH on Nurr1 expression, we measured the protein levels of Nurr1 and its regulating factors using Western blot analysis in PC12 cells. MABH treatment induced the phosphorylation of extracellular signal-regulated kinase protein via increasing the protein expression levels of Nurr1 and ultimately the levels of TH, VMAT2, and DAT. These results indicate that MABH has protective effects on dopaminergic neurons in a mouse model of PD by regulating Nurr1. PMID- 27771537 TI - Temporal distortion in the perception of actions and events. AB - In everyday life, actions and sensory events occur in complex sequences, with events triggering actions that in turn give rise to additional events and so on. Earlier work has shown that a sensory event that is triggered by a voluntary action is perceived to have occurred earlier in time than an identical event that is not triggered by an action. In other words, events that are believed to be caused by our actions are drawn forward in time towards our actions. Similarly, when a sensory event triggers an action, that event is again drawn in time towards the action and is thus perceived to have occurred later than it really did. This alteration in time perception serves to bind together events and actions that are causally linked. It is not clear, however, whether or not the perceived timing of a sensory event embedded within a longer series of actions and sensory events is also temporally bound to the actions in that sequence. In the current study, we measured the temporal binding in sequences consisting of two simple dyads of event-action and action-event in a series of manual action tasks: an event-action-event triad (Experiment 1) and an action-event-action triad (Experiment 2). Auditory tones either triggered an action or were presented 250ms after an action was performed. To reduce the influence of sensory events other than the tone, such as a noise associated with pressing a key on a keyboard, we used an optical sensor to detect hand movements where no contact was made with a surface. In Experiment 1, there appeared to be no change in the perceived onset of an auditory tone when the onset of that tone followed a hand movement and then the tone triggered a second hand movement. It was as if the temporal binding between the action and the tone and then the tone and the subsequent action summed algebraically and cancelled each other out. In Experiment 2, both the perceived onset of an initial tone which triggered an action and the perceived onset of a second tone which was presented 250ms after the action were temporally bound to the action. Taken together, the present study suggests that the temporal binding between our actions and sensory events occur separately in each dyad within a longer sequence of actions and events. PMID- 27771536 TI - Internalizing symptoms and conduct problems: Redundant, incremental, or interactive risk factors for adolescent substance use during the first year of high school? AB - AIM: The complex interplay of externalizing and internalizing problems in substance use risk is not well understood. This study tested whether the relationship of conduct problems and several internalizing disorders with future substance use is redundant, incremental, or interactive in adolescents. METHODS: Two semiannual waves of data from the Happiness and Health Study were used, which included 3383 adolescents (M age=14.1years old; 53% females) in Los Angeles who were beginning high school at baseline. Logistic regression models tested the likelihood of past six-month alcohol, tobacco, marijuana, and any substance use at follow-up conditional on baseline conduct problems, symptoms of one of several internalizing disorders (i.e., Social Phobia and Major Depressive, Generalized Anxiety, Panic, and Obsessive-Compulsive Disorder), and their interaction adjusting for baseline use and other covariates. FINDINGS: Conduct problems were a robust and consistent risk factor of each substance use outcome at follow-up. When adjusting for the internalizing-conduct comorbidity, depressive symptoms were the only internalizing problem whose risk for alcohol, tobacco, and any substance use was incremental to conduct problems. With the exception of social phobia, antagonistic interactive relationships between each internalizing disorder and conduct problems were found when predicting any substance use; internalizing symptoms was a more robust risk factor for substance use in teens with low (vs. high) conduct problems. CONCLUSIONS: Although internalizing and externalizing problems both generally increase risk of substance use, a closer look reveals important nuances in these risk pathways, particularly among teens with comorbid externalizing and internalizing problems. PMID- 27771538 TI - Successful communication does not drive language development: Evidence from adult homesign. AB - Constructivist accounts of language acquisition maintain that the language learner aims to match a target provided by mature users. Communicative problem solving in the context of social interaction and matching a linguistic target or model are presented as primary mechanisms driving the language development process. However, research on the development of homesign gesture systems by deaf individuals who have no access to a linguistic model suggests that aspects of language can develop even when typical input is unavailable. In four studies, we examined the role of communication in the genesis of homesign systems by assessing how well homesigners' family members comprehend homesign productions. In Study 1, homesigners' mothers showed poorer comprehension of homesign descriptions produced by their now-adult deaf child than of spoken Spanish descriptions of the same events produced by one of their adult hearing children. Study 2 found that the younger a family member was when they first interacted with their deaf relative, the better they understood the homesigner. Despite this, no family member comprehended homesign productions at levels that would be expected if family members co-generated homesign systems with their deaf relative via communicative interactions. Study 3 found that mothers' poor or incomplete comprehension of homesign was not a result of incomplete homesign descriptions. In Study 4 we demonstrated that Deaf native users of American Sign Language, who had no previous experience with the homesigners or their homesign systems, nevertheless comprehended homesign productions out of context better than the homesigners' mothers. This suggests that homesign has comprehensible structure, to which mothers and other family members are not fully sensitive. Taken together, these studies show that communicative problem solving is not responsible for the development of structure in homesign systems. The role of this mechanism must therefore be re-evaluated in constructivist theories of language development. PMID- 27771539 TI - Disfluency effects on lexical selection. AB - Recent research has suggested that introducing a disfluency in the context of written composition (i.e., typing with one hand) can increase lexical sophistication. In the current study, we provide a strong test between two accounts of this phenomenon, one that attributes it to the delay caused by the disfluency and one that attributes it to the disruption of typical finger-to letter mappings caused by the disfluency. To test between these accounts, we slowed down participants' typewriting by introducing a small delay between keystrokes while individuals wrote essays. Critically, this manipulation did not disrupt typical finger-to-letter mappings. Consistent with the delay-based account, our results demonstrate that the essays written in this less fluent condition were more lexically diverse and used less frequent words. Implications for the temporal dynamics of lexical selection in complex cognitive tasks are discussed. PMID- 27771540 TI - Description and experience: How experimental investors learn about booms and busts affects their financial risk taking. AB - A few years ago, the world experienced the most severe economic crisis since the Great Depression. According to the depression baby hypothesis, people who live through such macroeconomic shocks take less financial risk in their future lives (e.g., lower stock market participation). This hypothesis has previously been tested against survey data. Here, we tested it in a simulated experimental stock market (based on the Spanish stock index, IBEX-35), varying both the length of historical data available to participants (including or excluding a macroeconomic shock) and the mode of learning about macroeconomic events (through sequential experience or symbolic descriptions). Investors who learned about the market from personal experience took less financial risk than did those who learned from graphs, thus echoing the description-experience gap observed in risky choice. In a second experiment, we reversed the market, turning the crisis into a boom. The description-experience gap persisted, with investors who experienced the boom taking more risk than those who did not. The results of a third experiment suggest that the observed gap is not driven by a wealth effect, and modeling suggests that the description-experience gap is explained by the fact that participants who learn from experience are more risk averse after a negative shock. Our findings highlight the crucial role of the mode of learning for financial risk taking and, by extension, in the legally required provision of financial advice. PMID- 27771542 TI - Advancing student nurse knowledge of the biomedical sciences: A mixed methods study. AB - BACKGROUND: Nursing students' ability to learn, integrate and apply bioscience knowledge to their clinical practice remains a concern. OBJECTIVES: To evaluate the implementation, influence, and student perspective of a team-teaching workshop to integrate bioscience theory with clinical nursing practice. DESIGN: The team-teaching workshop was offered prior to commencement of the university semester as a refresher course at an Australian university. This study employed a sequential explanatory mixed methods design incorporating both quantitative and qualitative items. METHODS: An evaluation survey with quantitative and qualitative items and a focus group were employed. The qualitative data were analysed using a thematic approach. The quantitative data was combined with the emergent themes in the qualitative data. PARTICIPANTS: Participants were final year nursing students. Nine students attended the workshop. All students completed the evaluation (N=9) and 44.4% (N=4) attended the focus group. RESULTS: The results revealed six themes: (1) lectures are an inadequate teaching strategy for bioscience; (2) teaching strategies which incorporate active learning engage students; (3) the team-teaching workshop provides an effective learning environment; (4) the workshop content should be expanded; (5) pharmacology should relate to bioscience, and bioscience should relate to nursing; and (6) team teaching was effective in integrating pharmacology with bioscience, and then translating this into nursing practice. Students had felt there was disjointedness between pharmacology and bioscience, and between bioscience and nursing care within their undergraduate studies. The workshop that was based on team-teaching bridged those gaps, utilised active learning strategies and provided an effective learning environment. CONCLUSION: Team-teaching that employs active learning strategies is an effective approach to assist nursing students to integrate bioscience knowledge into their nursing practice. PMID- 27771541 TI - Comparison of different advanced treatment processes in removing endocrine disruption effects from municipal wastewater secondary effluent. AB - In this study, secondary effluent from the Wulongkou (WLK) municipal wastewater plant (Zhengzhou, China) was tested for its toxicity effects before and after five advanced treatment processes (ATPs, i.e. coagulation sedimentation, nan da magnetic polyacrylic anion exchange resin (NDMP) resin adsorption, activated carbon adsorption, ozonation and electro-adsorption). Results showed that estrogen disruption effects (EDEs) were particularly significant for the raw secondary effluent among the studied dioxin-like toxicity effect, androgenic/anti androgenic response effect, EDEs, and genotoxicity effect. And E1, E2, and EE2 were the main endocrine disruption chemicals (EDCs) contributing to EDEs. Except coagulation sedimentation, all the other four ATPs were efficient in removing the steroid estrogens (i.e. E1, E2, and EE2), but were inefficient in the artificial EDC (i.e. DBP, OP and BPA) removal. In the ATPs treated samples, vitellogenin (VTG) in zebrafish were largely removed. However, they were still significant in comparison with the control, probably due to artificial EDCs. Therefore, finding ways to thoroughly remove EDEs and EDCs from the secondary effluent will be a new research direction in the future. PMID- 27771545 TI - Insurance coverage and socioeconomic differences in patient choice between private and public health care providers in China. AB - The private health care sector has become an increasingly important complement to China's health care system. During the health care reform in 2009, China's central government established multiple initiatives to relax constraints on the growth of the private health care sector. However, private health services have not been growing as rapidly as private health care facilities. Using data from the China Health and Retirement Longitudinal Study collected between 2011 and 2013, this study investigated patient choice between private and public providers for outpatient care and estimated its relationship with health insurance and socioeconomic status (SES). The Heckman sample selection model was applied to address the problem of selection bias caused by a lack of awareness of provider ownership. We found that 82.1% of the outpatient care users were aware of their provider's ownership, and 23.8% chose private health care providers. Although patients with health insurance and higher SES were more likely to be aware of their provider's ownership, they preferred public providers over private providers. For example, having Urban Employee Basic Medical Insurance was associated with a 16.5% lower probability of choosing private providers than no health insurance. Respondents with the highest level of household expenditure had a 7.5% lower probability of choosing private providers than those with the lowest level of expenditure. The probability of choosing private providers were significantly lower by 4.0% among respondents with an education level of junior high school and above than those with no formal education. For private providers to play an effective role in the health care system, policies that have constrained the growth of the private sector should be changed, and more effort should be directed toward equalizing health insurance coverage for both types of providers. PMID- 27771543 TI - Protein folding, binding, and droplet formation in cell-like conditions. AB - The many bystander macromolecules in the crowded cellular environments present both steric repulsion and weak attraction to proteins undergoing folding or binding and hence impact the thermodynamic and kinetic properties of these processes. The weak but nonrandom binding with bystander macromolecules may facilitate subcellular localization and biological function. Weak binding also leads to the emergence of a protein-rich droplet phase, which has been implicated in regulating a variety of cellular functions. All these important problems can now be addressed by realistic modeling of intermolecular interactions. Configurational sampling of concentrated protein solutions is an ongoing challenge. PMID- 27771544 TI - Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy. AB - Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after >=18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%-66.3%) and 66.7% (95% CI, 51.0%-80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874. PMID- 27771546 TI - Intersystem return on investment in public mental health: Positive externality of public mental health expenditure for the jail system in the U.S. AB - This study examines the extent to which increased public mental health expenditures lead to a reduction in jail populations and computes the associated intersystem return on investment (ROI). We analyze unique panel data on 44 U.S. states and D.C. for years 2001-2009. To isolate the intersystem spillover effect, we exploit variations across states and over time within states in per capita public mental health expenditures and average daily jail inmates. Regression models control for a comprehensive set of determinants of jail incarcerations as well as unobserved determinants specific to state and year. Findings show a positive spillover benefit of increased public mental health spending on the jail system: a 10% increase in per capita public inpatient mental health expenditure on average leads to a 1.5% reduction in jail inmates. We also find that the positive intersystem externality of increased public inpatient mental health expenditure is greater when the level of community mental health spending is lower. Similarly, the intersystem spillover effect of community mental health expenditure is larger when inpatient mental health spending is lower. We compute that overall an extra dollar in public inpatient mental health expenditure by a state would yield an intersystem ROI of a quarter dollar for the jail system. There is significant cross-state variation in the intersystem ROI in both public inpatient and community mental health expenditures, and the ROI overall is greater for inpatient mental health spending than for community mental health spending. PMID- 27771547 TI - Polyoxovanadate fabricated gold nanoparticles: Application in SERS. AB - This article reports a surface modification of gold nanoparticles with water soluble polyoxometalate, V10O286- (decavanadate, V10). Two sizes of citrate capped gold nanoparticles AuNP-Citrate-S (~11nm) and AuNP-Citrate-L (~46nm) were modified with V10 in aqueous media to form AuNP-V10-S and AuNP-V10-L, respectively. Both AuNP-V10-S and AuNP-V10-L were found to be significantly better than their citrate counterparts in strengthening Raman vibrational signals of analyte molecule. All the nanoparticles were characterized by UV-visible and Fourier transform infrared (FTIR) spectroscopies, dynamic light scattering (DLS), transmission electron microscopy (TEM) and energy dispersive X-ray (EDX) line analysis. We demonstrate that AuNP-V10-L is excellent surface-enhanced Raman scattering (SERS) substrate for a Raman-active analyte molecule at nanomolar concentrations. PMID- 27771548 TI - Stepwise thinning dynamics of a foam film formed from an anionic micellar solution. AB - Liquid films formed from a surfactant micellar solution thin in a stepwise fashion (stratify): the film thickness decreases layer-by-layer and dark spots appear (areas of the film with one micellar layer less than their surroundings). In a recent paper [Langmuir2016, 32, 4837-4847], we presented a two-dimensional diffusion model to explain the expansion of the dark spots inside the foam film formed from a nonionic surfactant micellar solution. Here, we apply the model to explain the dark spot expansion in the foam film formed from an anionic surfactant micellar solution of sodium dodecyl sulfate. We also apply this model to explain the expansion rate of the dark spot that makes contact with the meniscus. Our model adequately predicts the experimental measurements. PMID- 27771549 TI - Facile synthesis and enhanced catalytic performance of reduced graphene oxide decorated with hexagonal structure Ni nanoparticles. AB - In this study, reduced graphene oxide (RGO) supported Ni nanoparticles were synthesized by a facile in-situ refluxing approach using triethylene glycol as both reductive and dispersing agent. The as-synthesized RGO/Ni nanocomposites were characterized by X-ray diffraction, Raman spectroscopy and transmission electron microscopy, which revealed that Ni nanoparticles with hexagonal close packed structure were homogeneously dispersed on the surface of RGO sheets. The catalytic activity and electrochemical properties of the RGO/Ni nanocomposites were investigated. It is found that the RGO/Ni nanocomposites exhibit markedly enhanced catalytic activity toward the reduction of p-nitrophenol by NaBH4, which is comparable to noble metal catalyst. The RGO/Ni nanocomposites also exhibited excellent electrocatalytic response to glucose. The linear range, detection limit and sensitivity were estimated to be 0.01-3.0mM (R2=0.997), 2.8MUM and 535.258MUAmM-1cm-2, respectively. It is expected that this facile method presented here could be extended to synthesize other RGO/metal nanocomposites with various functions. PMID- 27771550 TI - Tunable porosity and polarity of polar post-cross-linked resins and selective adsorption. AB - Herein we synthesized three polar post-cross-linked resins by adjusting the initial cross-linking degree of the precursor copolymers, and found that the porosity and polarity of these resins could be effectively tuned. The polar post cross-linked resin with the initial cross-linking degree of 10% (abbreviated as PVE_10%_pc) possessed a much greater BET surface area and almost all micro/mesopores, but lower content of ester groups, while that with the initial cross-linking degree of 60% (named as PVE_60%_pc) had a much less BET surface area, less micro/mesopores and considerable macropores, but higher content of ester groups. The different porosity and polarity of these resins endowed them with different selectivity for the adsorption of aromatic compounds. PVE_10%_pc owned the largest equilibrium capacity to phenol whilst PVE_40%_pc was the most efficient for adsorption of benzoic acid, and hydrogen bonding, hydrophobic interaction and pi-pi stacking were the main driving forces for the adsorption. PMID- 27771551 TI - Childhood disclosure of sexual abuse: Necessary but not necessarily sufficient. AB - Prevention programs often encourage sexually abused children to disclose without fully considering the potential for adverse consequences. This study examined the impact of disclosure on abuse cessation and later adult symptomatology. A clinical sample of 301 adult survivors completed the Impact of Event Scale (IES/IES-R), and the Beck Depression Inventory (BDI-II). Participants were divided into 3 groups: Nondisclosure (n=221), Disclosure/Abuse Ended (n=25), and Disclosure/Abuse Continued (n=55). Multivariate analyses of covariance, adjusting for abuse characteristics (age of onset, penetration, and number of perpetrators) and other trauma exposure, revealed significant differences in psychiatric symptom severity among the three groups, Wilks' lambda=0. 95, F (6, 584)=2.69, p=0.014, etap2=0.03. Specifically, those in the Disclosure/Abuse Continued group scored significantly higher on the IES/IES-R Intrusion subscale (p=0.04) and the BDI-II (p=0.01), as compared to the Nondisclosure group. The Disclosure/Abuse Ended group did not differ significantly from the other groups. Results suggest that disclosure may be detrimental unless adequate steps are taken to ensure abuse cessation and appropriate treatment. PMID- 27771552 TI - Use of non-warfarin oral anticoagulants instead of warfarin during left atrial appendage closure with the Watchman device. AB - BACKGROUND: In the stroke prevention trials of left atrial appendage closure with the Watchman device (Boston Scientific), a postimplantation antithrombotic regimen of 6 weeks of warfarin was used. OBJECTIVE: Given the clinical complexity of warfarin use, the purpose of this study was to study the relative feasibility and safety of using non-warfarin oral anticoagulants (NOACs) instead of warfarin during the peri- and initial postimplantation periods after Watchman implantation. METHODS: This was a retrospective multicenter study of consecutive patients undergoing Watchman implantation and receiving peri- and postprocedural NOACs or warfarin. Transesophageal echocardiography or chest computed tomography was performed between 6 weeks and 4 months postimplant to assess for device related thrombosis. Bleeding and thromboembolic events also were evaluated at the time of follow-up. RESULTS: In 5 centers, 214 patients received NOACs (46% apixaban, 46% rivaroxaban, 7% dabigatran, and 1% edoxaban) in either an uninterrupted (82%) or a single-held-dose (16%) fashion. Compared to a control group receiving uninterrupted warfarin (n = 212), the rates of periprocedural complications, including bleeding events, were similar (2.8% vs 2.4%, P = 1). At follow-up, the rates of device-related thrombosis (0.9% vs 0.5%, P = 1), composite of thromboembolism or device-related thrombosis (1.4% vs 0.9%, P = 1), and postprocedure bleeding events (0.5% vs 0.9%, P = .6) also were comparable between the NOAC and warfarin groups. CONCLUSION: NOACs proved to be a feasible peri- and postprocedural alternative regimen to warfarin for preventing device related thrombosis and thromboembolic complications expected early after appendage closure with the Watchman device, without increasing the risk of bleeding. PMID- 27771554 TI - [18F]-FDG PET neuroimaging in rats with quinpirole-induced checking behavior as a model for obsessive compulsive disorder. PMID- 27771553 TI - Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure. AB - BACKGROUND: Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR). OBJECTIVE: The purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca2+ leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure. METHODS: Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle. RESULTS: TAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca2+ spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca2+ transients in TAC cells during and after 1-5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM. CONCLUSION: Several disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca2+ leakage, delayed afterdepolarization, triggered activity, Ca2+ spark frequency, spontaneous Ca2+ transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2. PMID- 27771555 TI - SREBF-2 polymorphism influences white matter microstructure in bipolar disorder. AB - The aim of the study is to investigate if gene polymorphisms in sterol regulatory element binding protein transcriptional factors SREBF-1 and SREBF-2, which regulate lipid and cholesterol metabolism, could affect white matter (WM) microstructure, the most recognized structural biomarker of bipolar disorder (BD). In a sample of 93 patients affected by BD, we investigated the effect of SREBF-1 rs11868035, and SREBF-2 rs1052717, on WM microstructure, using diffusion tensor imaging and tract-based spatial statistics. We observed increased radial diffusivity in the rs1052717 A/A genotype compared to A/G and G/G, and reduced fractional anisotropy (FA) in the rs1052717 A/A genotype compared to G carriers in cingulum, corpus callosum, superior and inferior longitudinal fasciculi, and anterior thalamic radiation. These results seem to suggest an involvement of SREBF-2 in the integrity of white matter tracts in BD and therefore a possible role of SREBP pathway in CNS myelination processes. PMID- 27771557 TI - Deficits in social cognition in first episode psychosis: A review of the literature. AB - OBJECTIVE: Individuals with chronic schizophrenia (SCZ) consistently show impairments in social cognition (SC) that are associated with functional decline, and work suggests that similar associations exist in first-episode psychosis (FEP). The goal of the current article is to review and synthesize the current body of work examining SC in FEP. Secondary aims are to examine the relationship between SC and symptoms, and change in SC over time in FEP. DESIGN: Literature is reviewed from four key SC domains: emotion processing (EP), theory of mind (ToM), social perception (SP), and attributional style (AS). Targeted searches of PsycINFO and Google Scholar were conducted to identify relevant manuscripts. RESULTS: Data from 48 relevant studies (6 longitudinal) were reviewed and integrated. CONCLUSIONS: (1) FEP individuals show consistent deficits in SC compared to healthy controls, most consistently in EP (particularly, fear and sadness recognition) and ToM compared to SP and AS, (2) individuals with FEP and SCZ show comparable SC deficits, (3) some evidence indicates SC deficits in FEP are associated with negative and positive symptoms, and (4) SC appears to be stable over time in FEP. PMID- 27771556 TI - Weighted edge based clustering to identify protein complexes in protein-protein interaction networks incorporating gene expression profile. AB - : Protein complex detection from protein-protein interaction (PPI) network has received a lot of focus in recent years. A number of methods identify protein complexes as dense sub-graphs using network information while several other methods detect protein complexes based on topological information. While the methods based on identifying dense sub-graphs are more effective in identifying protein complexes, not all protein complexes have high density. Moreover, existing methods focus more on static PPI networks and usually overlook the dynamic nature of protein complexes. Here, we propose a new method, Weighted Edge based Clustering (WEC), to identify protein complexes based on the weight of the edge between two interacting proteins, where the weight is defined by the edge clustering coefficient and the gene expression correlation between the interacting proteins. Our WEC method is capable of detecting highly inter connected and co-expressed protein complexes. The experimental results of WEC on three real life data shows that our method can detect protein complexes effectively in comparison with other highly cited existing methods. AVAILABILITY: The WEC tool is available at http://agnigarh.tezu.ernet.in/~rosy8/shared.html. PMID- 27771558 TI - Speckle tracking and speckle content based composite strain imaging for solid and fluid filled lesions. AB - Strain imaging though for solid lesions provides an effective way for determining their pathologic condition by displaying the tissue stiffness contrast, for fluid filled lesions such an imaging is yet an open problem. In this paper, we propose a novel speckle content based strain imaging technique for visualization and classification of fluid filled lesions in elastography after automatic identification of the presence of fluid filled lesions. Speckle content based strain, defined as a function of speckle density based on the relationship between strain and speckle density, gives an indirect strain value for fluid filled lesions. To measure the speckle density of the fluid filled lesions, two new criteria based on oscillation count of the windowed radio frequency signal and local variance of the normalized B-mode image are used. An improved speckle tracking technique is also proposed for strain imaging of the solid lesions and background. A wavelet-based integration technique is then proposed for combining the strain images from these two techniques for visualizing both the solid and fluid filled lesions from a common framework. The final output of our algorithm is a high quality composite strain image which can effectively visualize both solid and fluid filled breast lesions in addition to the speckle content of the fluid filled lesions for their discrimination. The performance of our algorithm is evaluated using the in vivo patient data and compared with recently reported techniques. The results show that both the solid and fluid filled lesions can be better visualized using our technique and the fluid filled lesions can be classified with good accuracy. PMID- 27771559 TI - A neural mechanism of cognitive control for resolving conflict between abstract task rules. AB - Conflict between multiple sensory stimuli or potential motor responses is thought to be resolved via bias signals from prefrontal cortex (PFC). However, population codes in the PFC also represent abstract information, such as task rules. How is conflict between active abstract representations resolved? We used functional neuroimaging to investigate the mechanism responsible for resolving conflict between abstract representations of task rules. Participants performed two different tasks based on a cue. We manipulated the degree of conflict at the task rule level by training participants to associate the color and shape dimensions of the cue with either the same task rule (congruent cues) or different ones (incongruent cues). Phonological and semantic tasks were used in which performance depended on learned, abstract representations of information, rather than sensory features of the target stimulus or on any habituated stimulus response associations. In addition, these tasks activate distinct regions that allowed us to measure magnitude of conflict between tasks. We found that incongruent cues were associated with increased activity in several cognitive control areas, including the inferior frontal gyrus, inferior parietal lobule, insula, and subcortical regions. Conflict between abstract representations appears to be resolved by rule-specific activity in the inferior frontal gyrus that is correlated with enhanced activity related to the relevant information. Furthermore, multi-voxel pattern analysis of the activity in the inferior frontal gyrus was shown to carry information about both the currently relevant rule (semantic/phonological) and the currently relevant cue context (color/shape). Similar to models of attentional selection of conflicting sensory or motor representations, the current findings indicate part of the frontal cortex provides a bias signal, representing task rules, that enhances task-relevant information. However, the frontal cortex can also be the target of these bias signals in order to enhance abstract representations that are independent of particular stimuli or motor responses. PMID- 27771560 TI - In vitro exposure system for study of aerosolized influenza virus. AB - Infection of adherent cell monolayers using a liquid inoculum represents an established method to reliably and quantitatively study virus infection, but poorly recapitulates the exposure and infection of cells in the respiratory tract that occurs during infection with aerosolized pathogens. To better simulate natural infection in vitro, we adapted a system that generates viral aerosols similar to those exhaled by infected humans to the inoculation of epithelial cell monolayers. Procedures for cellular infection and calculation of exposure dose were developed and tested using viruses characterized by distinct transmission and pathogenicity phenotypes: an HPAI H5N1, an LPAI H7N9, and a seasonal H3N2 virus. While all three aerosolized viruses were highly infectious in a human bronchial epithelial cell line (Calu-3) cultured submerged in media, differences between the viruses were observed in primary human alveolar epithelial cells and in Calu-3 cells cultured at air-liquid interface. This system provides a novel enhancement to traditional in vitro experiments, particularly those focused on the early stages of infection. PMID- 27771562 TI - Detection of ORF6 protein associated with latent KHV infection. AB - Koi herpesvirus (KHV) is highly pathogenic to Cyprinus carpio. KHV can also become latent in recovered fish and reactivate from latency under stressful conditions. Understanding KHV latency is important for development of strategies against herpesvirus latent infection. Our previous studies found KHV ORF6 mRNA is detectable during latent infection. In this study, ORF6 protein expression was investigated by a polyclonal antibody specific to ORF6 peptide. Positive staining by an immunofluorescence assay was observed in both KHV infected CCB (common carp brain) cells and IgM+ white blood cells (WBCs) from recovered KHV+ koi. Proteins at the expected size, 68kDa, and several different sizes can be detected during productive infection. Five potential sumoylation sites were identified in the ORF6 protein. Our study demonstrated that ORF6 protein is expressed in both productive infection and latent infection and may have different post translational modifications during productive infection. PMID- 27771561 TI - Proteomic analysis of the gamma human papillomavirus type 197 E6 and E7 associated cellular proteins. AB - Gamma HPV197 was the most frequently identified HPV when human skin cancer specimens were analyzed by deep sequencing (Arroyo Muhr et al., Int. J. Cancer 136: 2546-55, 2015). To gain insight into the biological activities of HPV197, we investigated the cellular interactomes of HPV197 E6 and E7. HPV197 E6 protein interacts with a broad spectrum of cellular LXXLL domain proteins, including UBE3A and MAML1. HPV197 E6 also binds and inhibits the TP53 tumor suppressor and interacts with the CCR4-NOT ubiquitin ligase and deadenylation complex. Despite lacking a canonical retinoblastoma (RB1) tumor suppressor binding site, HPV197 E7 binds RB1 and activates E2F transcription. Hence, HPV197 E6 and E7 proteins interact with a similar set of cellular proteins as E6 and E7 proteins encoded by HPVs that have been linked to human carcinogenesis and/or have transforming activities in vitro. PMID- 27771563 TI - The Modular Assessment of Risk for Imminent Suicide (MARIS): A proof of concept for a multi-informant tool for evaluation of short-term suicide risk. AB - BACKGROUND: To date, no diagnostic tool has demonstrated clinical value for the assessment of short-term suicide risk among high-risk individuals. To this end we have developed the Modular Assessment of Risk for Imminent Suicide (MARIS), a modular patient and clinician informed risk evaluation instrument. Here we assess its predictive validity for suicidal behavior (SB) in psychiatric patients following discharge from an inpatient unit. METHODS: The MARIS and a psychological test battery were administered to 136 adult psychiatric patients hospitalized for high risk of suicide. Eighty-six participants had complete data at discharge and 59 (69.8%) were reached for follow-up. Logistic regressions were used to assess the predictive validity of the MARIS for SB over the 4-8weeks following hospital discharge and its incremental predictive validity over standard risk factors. RESULTS: Patients who exhibited SB in the period between initial assessment and follow-up had significantly higher MARIS scores. ROC analysis indicated good sensitivity and specificity of MARIS in identifying risk (OR=19). Further, MARIS total score significantly improved predictive validity by the standard risk factors when added to a model comprising global depression severity, hopelessness, and lifetime number of suicide attempts, and was the only factor that approached independent significance. CONCLUSION: The MARIS appears to be a practical and effective tool for detecting short-term suicide risk following hospital discharge, supporting the validity of modular multi-informant approach to suicide risk evaluation. Replication of these findings and further investigation of the applications of such an approach are warranted. PMID- 27771564 TI - Human exposure to environmental pollutants after a tire landfill fire in Spain: Health risks. AB - In May 2016, a fire occurred in one of the largest landfills in Europe (Sesena, Toledo, Spain), where 70,000-90,000tons of tires had been illegally accumulated for >15years. Because of the proximity of population nuclei and the duration of the episode (>20days), we conducted a preliminary human health risk assessment study just after the tire fire. Samples of air and soil were collected in 3 areas surrounding the landfill (El Quinon, at only 500m, and Sesena Nuevo and Sesena Viejo, both at 4km), as well as in background sites. In addition, samples of crops (barley, wheat, cabbage and lettuce) were also obtained from local farmers. The concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and a number of trace elements (As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Sb, Sn, Tl, and V) were analyzed in all the samples. The concentrations of all the target pollutants, excepting PAHs, were relatively similar at the different sampling zones, irrespective of the distance to the landfill. In turn, a significant increase of PAHs was noted near the tire landfill, with air levels up to 6-times higher than those found at 4km (134 vs. 19.5-22.7ng/m3). Similarly, PAH concentrations in lettuce were relatively higher than those typically found in monitoring programs of food safety. Because of the increase of airborne PAHs, cancer risks due to exposure to environmental pollutants for the population living at El Quinon, near the landfill, were between 3- and 5-times higher than those estimated for the inhabitants of Sesena. After this preliminary study, further investigations, focused only on PAHs, but more extensive in terms of number of samples, should be conducted to assure that PAHs have been progressively degraded through time. PMID- 27771565 TI - Testing the ecological validity of the Trier Social Stress Test: Association with real-life exam stress. AB - The Trier Social Stress Test (TSST) is the most widely used laboratory stress protocol in psychoneuroendocrinology. Despite its popularity, surprisingly few attempts have been made to explore the ecological validity of the TSST. In the present study, 31 young healthy subjects (24 females) were exposed to the TSST about 4 weeks before completing an oral exam on a separate day. Salivary cortisol levels increased significantly in response to both stimuli (TSST: F(2.21, 66.33)=5.73, p=0.004; oral exam: F(1.98, 59.28)=4.38, p=0.017) with similar mean response curves and significant correlations between cortisol increases and areas under the response curves (increase: r=0.67; AUC: r=0.56; both p<=0.01). Correspondingly, changes in positive and negative affect did also show significant correlations between conditions (increase: positive affect: r=0.36; negative affect: r=0.50; both: p<=0.05; AUC: positive affect: r=0.81; negative affect: r=0.70; both p<=0.01) while mean time course dynamics were significantly different (positive affect: F(2.55, 76.60)=10.15, p=0.001; negative affect: F(1.56, 46.82)=23.32, p=0.001), indicating that the oral exam had a more pronounced impact on affect than the TSST. Our findings provide new evidence for the view that cortisol as well as subjective stress responses to the TSST are indeed significantly associated with acute stress responses in real life. PMID- 27771567 TI - Chronic toxicity effects of ZnSO4 and ZnO nanoparticles in Daphnia magna. AB - The chronic toxicity of ZnSO4 and ZnO nanoparticles has been studied in Daphnia magna also considering the life cycle parameters beyond the standard 21-day exposure time. Specimens have been individually followed until the natural end of their life, and some of them sampled for microscopic analyses at 48h, 9 and 21 days. Despite the low level of exposure (0.3mg Zn/L), ultrastructural analyses of the midgut epithelial cells revealed efficient internalization of nanoparticles between 48h and 9d, and translocation to other tissues as well. At 21d, the most affected fields have been recorded for both compounds; in particular samples exposed to ZnO nanoparticles showed swelling of mitochondria, while those exposed to ZnSO4 had a great number of autophagy vacuoles. The life cycle parameters resulted altered as well, with a significant inhibition of reproduction in both groups, when compared to controls. After the 21-day exposure, some interesting results were obtained: animals, previously exposed to nanoZnO at low concentrations, showed a complete recovery of the full reproduction potential, while those previously exposed to ZnSO4 presented a dose-dependent and compound specific reduction in lifespan. Based on the results from the present research and the effects of the same chemicals at higher doses, it can be concluded that the soluble form plays a key role in ZnO nanoparticle cytotoxicity, and that the nanoparticulate form is able to locally increase the amount of Zn inside the cell, even within the ovary. It's worth noting that ZnO nanoparticles have been internalized despite the very low concentration used: this raises concern about the possible environmental implications which may derive from their use, and which in turn must be carefully considered. PMID- 27771566 TI - Prenatal maternal cortisol concentrations predict neurodevelopment in middle childhood. AB - Glucocorticoids (cortisol in humans) are the end product of the hypothalamic pituitary-adrenocortical (HPA) axis and are proposed as a key mechanism for programming fetal brain development. The present prospective longitudinal study evaluates the association between prenatal maternal cortisol concentrations and child neurodevelopment. Participants included a low risk sample of 91 mother child pairs. Prenatal maternal plasma cortisol concentrations were measured at 19 and 31 gestational weeks. Brain development and cognitive functioning were assessed when children were 6-9 years of age. Structural magnetic resonance imaging scans were acquired and cortical thickness was determined. Child cognitive functioning was evaluated using standardized measures (Wechsler Intelligence Scale for Children IV and Expressive Vocabulary Test, Second Edition). Higher maternal cortisol concentrations during the third trimester were associated with greater child cortical thickness primarily in frontal regions. No significant associations were observed between prenatal maternal cortisol concentrations and child cortical thinning. Elevated third trimester maternal cortisol additionally was associated with enhanced child cognitive performance. Findings in this normative sample of typically developing children suggest that elevated maternal cortisol during late gestation exert lasting benefits for brain development and cognitive functioning 6-9 years later. The benefits of fetal exposure to higher maternal cortisol during the third trimester for child neurodevelopment are consistent with the role cortisol plays in maturation of the human fetus. It is plausible that more extreme elevations in maternal cortisol concentrations late in gestation, as well as exposure to pharmacological levels of synthetic glucocorticoids, may have neurotoxic effects on the developing fetal brain. PMID- 27771568 TI - Effect of surfactant in mitigating cadmium oxide nanoparticle toxicity: Implications for mitigating cadmium toxicity in environment. AB - Cadmium (Cd), classified as human carcinogen, is an extremely toxic heavy metal pollutant, and there is an increasing environmental concern for cadmium exposure through anthropogenic sources including cigarette smoke. Though Cd based nanoparticles such as cadmium oxide (CdO) are being widely used in a variety of clinical and industrial applications, the toxicity of CdO nanoparticles has not been well characterized. Herein we report the toxicity of CdO nanoparticles employing zebrafish as a model. Two different CdO nanoparticles were prepared, calcination of Cd(OH)2 without any organic molecule (CdO-1) and calcination of Cd citrate coordination polymer (CdO-2), to evaluate and compare the toxicity of these two different CdO nanoparticles. Results show that zebrafish exposed to CdO 2 nanoparticles expressed reduced toxicity as judged by lower oxidative stress levels, rescue of liver carboxylesterases and reduction in metallothionein activity compared to CdO-1 nanoparticles. Histopathological observations also support our contention that CdO-1 nanoparticles showed higher toxicity relative to CdO-2 nanoparticles. The organic unit of Cd-citrate coordination polymer might have converted into carbon during calcination that might have covered the surface of CdO nanoparticles. This carbon surface coverage can control the release of Cd2+ ions in CdO-2 compared to non-covered CdO-1 nanoparticles and hence mitigate the toxicity in the case of CdO-2. This was supported by atomic absorption spectrophotometer analyses of Cd2+ ions release from CdO-1 and CdO-2 nanoparticles. Thus the present study clearly demonstrates the toxicity of CdO nanoparticles in an aquatic animal and also indicates that the toxicity could be substantially reduced by carbon coverage. This could have important implications in terms of anthropogenic release and environmental pollution caused by Cd and human exposure to Cd2+ from sources such as cigarette smoke. PMID- 27771569 TI - Lead ingestion as a potential contributing factor to the decline in vulture populations in southern Africa. AB - Vulture populations in southern Africa have been on the decline for years, which unlike the Asian vulture crisis, has no one specific cause. Reasons attributable are deliberate and secondary poisonings, drowning, power line injuries, electrocutions, traditional medicine ("muti" trade) and calcium deficiencies. However, lead toxicity as a potential causal factor is hardly mentioned. The potential for lead toxicity needs to be considered as substantial game hunting occurs in the region with little regulatory control on bullet types. In this study, we determined the whole blood lead concentrations of captive and wild vulture populations in South Africa and Namibia (n=185). Results were compared to previous published ranges indicative of background exposure (<10MUg/dL), non toxic point exposure based upon the range established from captive birds and subclinical exposure. In general, whole blood lead concentrations were higher for wild African White-backed vultures (Gyps africanus)(AWBV) than Cape vultures (G. coprotheres)(CGV) at 15.54+/-12.63MUg/dL vs 12.53+/-8.88MUg/dL (non-significantly different), while in the Bearded vultures (Gypaetus barbatus) no indication of exposure was evident. Very similar exposures resulted irrespective of the birds being in captivity or under wild, free-roaming conditions. A proportion of wild birds did, however, appear to be exposed to another source of lead than purely environmental (+/-12% and 30.6% for AWBV and CGV respectively). One bird, which had a whole blood concentration of 100MUg/dL, died soon after capture. To find the relationship between whole blood lead concentration and likely exposure factors, birds were compared by their rural/urban location, vicinity to mines and surrounding soil lead concentrations. With no relationship being present for the latter factors, we believe that this is evidence that the portion of southern African vultures being exposed to unknown source of lead, which we suggest arises from leaded ammunition remaining from hunting. PMID- 27771570 TI - Circulating levels of perfluoroalkyl substances (PFASs) and carotid artery atherosclerosis. AB - BACKGROUND AND OBJECTIVE: During recent years, some persistent organic pollutants (POPs) have been linked to atherosclerosis. One group of POPs, the poly- and perfluoroalkyl substances (PFASs) have not been investigated with regard to atherosclerotic plaques. METHODS: Carotid artery atherosclerosis was assessed by ultrasound in 1016 subjects aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants' plasma by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant linear associations were observed between the PFASs and intima-media thickness (IMT), or the echogenicity in the intima-media complex (IM-GSM, a marker of lipid infiltration in the artery) when men and women were analyzed together. Neither was occurrence of carotid plaques related to PFASs levels. However, highly significant interactions were observed between some PFASs and sex regarding both IM-GSM and plaque prevalence. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), were all related to IM-GSM in a positive fashion in women (p=0.002-0.003), while these relationships were negative in men. The levels of PFUnDA were significantly related to carotid plaque in women (OR 1.59, 95%CI 1.03-2.43, p=0.03), but not in men (OR 0.93, 95%CI 0.62-1.42, p=0.75). CONCLUSIONS: In this cross-sectional study, a pronounced gender difference was observed regarding associations between some PFASs, especially the long-chain PFUnDA, and markers of atherosclerosis, with more pronounced relationships found in women. These findings suggest a sex specific role for PFASs in atherosclerosis. PMID- 27771571 TI - Environmental exposure to human carcinogens in teenagers and the association with DNA damage. AB - BACKGROUND: We investigated whether human environmental exposure to chemicals that are labeled as (potential) carcinogens leads to increased (oxidative) damage to DNA in adolescents. MATERIAL AND METHODS: Six hundred 14-15-year-old youngsters were recruited all over Flanders (Belgium) and in two areas with important industrial activities. DNA damage was assessed by alkaline and formamidopyrimidine DNA glycosylase (Fpg) modified comet assays in peripheral blood cells and analysis of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Personal exposure to potentially carcinogenic compounds was measured in urine, namely: chromium, cadmium, nickel, 1-hydroxypyrene as a proxy for exposure to other carcinogenic polycyclic aromatic hydrocarbons (PAHs), t,t-muconic acid as a metabolite of benzene, 2,5-dichlorophenol (2,5-DCP), organophosphate pesticide metabolites, and di(2-ethylhexyl) phthalate (DEHP) metabolites. In blood, arsenic, polychlorinated biphenyl (PCB) congeners 118 and 156, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and perfluorooctanoic acid (PFOA) were analyzed. Levels of methylmercury (MeHg) were measured in hair. Multiple linear regression models were used to establish exposure-response relationships. RESULTS: Biomarkers of exposure to PAHs and urinary chromium were associated with higher levels of both 8-OHdG in urine and DNA damage detected by the alkaline comet assay. Concentrations of 8-OHdG in urine increased in relation with increasing concentrations of urinary t,t-muconic acid, cadmium, nickel, 2,5-DCP, and DEHP metabolites. Increased concentrations of PFOA in blood were associated with higher levels of DNA damage measured by the alkaline comet assay, whereas DDT was associated in the same direction with the Fpg-modified comet assay. Inverse associations were observed between blood arsenic, hair MeHg, PCB 156 and HCB, and urinary 8-OHdG. The latter exposure biomarkers were also associated with higher fish intake. Urinary nickel and t,t-muconic acid were inversely associated with the alkaline comet assay. CONCLUSION: This cross-sectional study found associations between current environmental exposure to (potential) human carcinogens in 14-15-year-old Flemish adolescents and short-term (oxidative) damage to DNA. Prospective follow-up will be required to investigate whether long term effects may occur due to complex environmental exposures. PMID- 27771572 TI - d-Cycloserine does not enhance the effects of in vivo exposure among young people with broad-based anxiety disorders. AB - Use of the partial NMDA receptor agonist d-Cycloserine (DCS) to increase extinction to feared cues among anxious adults has shown mixed, although overall positive effects. Few studies have extended this effect to youth and none have addressed young people with broad-based anxiety such as separation anxiety, social anxiety, or generalised anxiety. In the current trial 51 children and adolescents with diagnosed anxiety disorders, aged 7-14 years received four sessions of graduated, experimenter-led, in vivo exposure to a hierarchy of feared cues relevant to their primary fear. They were randomly allocated to receive either 50 mg of DCS or a matched placebo capsule in a fully double-blind design. Both groups showed large reductions across sessions in their primary fear according to both parent and child report, but there were no significant differences between conditions at any session. The results are consistent with most studies to date of DCS-augmented exposure in young people. PMID- 27771573 TI - Disulfide bond characterization of human factor Xa by mass spectrometry through protein-level partial reduction. AB - Protein-level partial reduction was investigated as a novel sample preparation technique to characterize proteins with cystine knots or complex disulfide linkages. Human Factor Xa containing twelve disulfide bonds was selected as a model protein to demonstrate this methodology. Five in twelve disulfide linkages were characterized through conventional non-reduced samples while the other seven disulfide linkages containing cystine knots were successfully characterized though partially reduced samples. Each disulfide linkage was confirmed through product ions generated by an UPLC-ESI QTOF MS system equipped with data independent collision-induced dissociation (CID) acquisition. Free cysteines in the sample were also determined in this study. PMID- 27771574 TI - In silico identification and computational analysis of the nucleotide binding site in the C-terminal domain of Hsp90. AB - Hsp90 contains two distinct Nucleotide Binding Sites (NBS), in its N-terminal domain (NTD) and C-terminal domain (CTD), respectively. The NTD site belongs to the GHKL super-family of ATPases and has been the subject of extensive characterization. However, a structure of the nucleotide-bound form of CTD is still unavailable. In this study molecular modeling was employed to incorporate experimental data using partial constructs of the CTD, from work published by many research groups, onto existing structural models of its apo- form. Our attempts to locate potential nucleotide ligand-binding sites or cavities yielded one major candidate-a structurally unconventional site-exhibiting the requisite shape and volume for accommodation of tri-phosphate nucleotides. Its structure was refined by molecular dynamics (MD)-based techniques. We reproducibly docked the Mg2+ complexed form of ATP, GTP, CTP, TTP and UTP to this putative NBS. These docking simulations and calculated ligand-binding scores are in general agreement with published data about experimentally measured binding to the CTD. The overall pattern of interactions between residues lining the site and docked nucleotides is conserved and broadly similar to that of other nucleotide-binding sites. Our docking simulations suggest that nucleotide binding stabilizes the only structurally labile region, thereby providing a rationale for the increased resistance to thermal denaturation and proteolysis. The docked nucleotides do not intrude onto the surface of residues involved in dimerization or chaperoning. Our molecular modeling permitted recognition of larger structural changes in the nucleotide-bound CTD dimer, including stabilization of helix-2 in both chains and intra- and inter- chain interactions between three residues (I613, Q617, R620). PMID- 27771575 TI - Ensemble docking-based virtual screening yields novel spirocyclic JAK1 inhibitors. AB - Small molecule inhibition of Janus kinases (JAKs) has been demonstrated as a viable strategy for the treatment of various inflammatory conditions and continues to emerge in cancer-related indications. In this study, a large supplier database was screened to identify novel chemistry starting points for JAK1. The docking-based screening was followed up by testing ten hit compounds experimentally, out of which five have displayed single-digit micromolar and submicromolar IC50 values on JAK1. Thus, the study was concluded with the discovery of five novel JAK inhibitors from a tiny screening deck with a remarkable hitrate of 50%. The results have highlighted spirocyclic pyrrolopyrimidines with submicromolar JAK1 IC50 values and a preference for JAK1 over JAK2 as potential starting points in developing a novel class of JAK1 inhibitors. PMID- 27771576 TI - Conductometric titration to determine total volatile basic nitrogen (TVB-N) for post-mortem interval (PMI). AB - Precise measurement of cadaver decomposition rate is the basis to accurate post mortem interval (PMI) estimation. There are many approaches explored in recent years, however, it is still unsolved completely. Total volatile basic nitrogen (TVB-N), which is an important index to predict meat freshness and shelf life in food science, could serve as an indicator for measuring PMI associated decomposition rate of cadavers. The aim of this work was to establish a practical method to determine TVB-N in cadaver soft tissues (mainly skeletal muscle) for measuring decomposition rate. Determination of TVB-N in the simulation and animal experiments was conducted by steam distillation and conductometric titration using Kjeldahl distillation unit and conductivity meter. In simulation, standard concentrations of ammonium were used as TVB analogies, TVB-N contents were determined and the recovery rates of nitrogen were calculated. In animal experiment, TVB-N in skeletal muscle of forty-two rats was determined at different PMIs for 312 h at 24 degrees C +/- 1 degrees C. The relationship between PMI and TVB-N was investigated also. The method showed high precision with 99%-100% recovery rates. TVB-N in skeletal muscle changed significantly with PMI especially after 24 h, and the data fit well to y = 3.35 E-5x3-2.17 E 2x2+6.13x-85.82 (adj. R2 = 0.985). ECi (initial electrical conductivity in the samples just before titration) had positive linear relationship to final measured TVB-N values, y = 1.98x+16.16 (adj. R2 = 0.985). The overall results demonstrated that the method is accurate, rapid and flexible, which could be expected as a basic technique for measuring decomposition rate in later PMI-estimation researches. Further studies are needed to validate our findings. PMID- 27771577 TI - How fear-relevant illusory correlations might develop and persist in anxiety disorders: A model of contributing factors. AB - Fear-relevant illusory correlations (ICs) are defined as the overestimation of the relationship between a fear-relevant stimulus and aversive consequences. ICs reflect biased cognitions affecting the learning and unlearning of fear in anxiety disorders, and a deeper understanding might help to improve treatment. A model for the maintenance of ICs is proposed that highlights the importance of amplified aversiveness and salience of fear-relevant outcomes, impaired executive contingency monitoring and an availability heuristic. The model explains why ICs are enhanced in high fearful individuals and allows for some implications that might be applied to augment the effectiveness of cognitive behavior therapy, such as emotion regulation and the direction of attention to non-aversive experiences. Finally, we suggest possible future research directions and an alternative measure of ICs. PMID- 27771578 TI - Alcohol and its contributory role in fatal drowning in Australian rivers, 2002 2012. AB - OBJECTIVE: Examine the prevalence of alcohol and its contributory role in unintentional fatal river drowning in Australia to inform strategies for prevention. METHODS: Cases of unintentional fatal river drowning in Australia, 1 July-2002 to 30-June-2012, were extracted from the National Coronial Information System. Cases with positive alcohol readings found through autopsy or toxicology reports were retained for analysis. Discrete analysis was conducted on cases with a Blood Alcohol Content (BAC) of >=0.05% (0.05grams of alcohol in every 100 millilitres of blood). RESULTS: Alcohol was known to be involved in 314 cases (40.8%), 279 recorded a positive BAC, 196 (70.3%) recorded a BAC of >=0.05%. 40.3% of adult victims had a BAC of >=0.20%. Known alcohol involvement was found to be more likely for victims who drowned as a result of jumping in (chi2=7.8; p<0.01), identify as Aboriginal and Torres Strait Islander (chi2=8.9; p<0.01) and drowned in the evening (chi2=7.8; p<0.01) and early morning (chi2=16.1; p<0.01) hours. DISCUSSION: The number of people who drown with alcohol in their bloodstream is concerning and challenging for prevention. To assist with the prevention of alcohol related river drowning improved data quality, as well as a greater understanding of alcohol's contribution and consumption patterns at rivers (especially those <18 years of age) is required. CONCLUSION: Alcohol contributes to fatal unintentional drowning in Australian rivers. Although prevention is challenging, better data and exposure studies are the next step to enhance prevention efforts. PMID- 27771579 TI - Functional diversity within the Penicillium roqueforti species. AB - Penicillium roqueforti is used as a ripening culture for blue cheeses and largely contributes to their organoleptic quality and typical characteristics. Different types of blue cheeses are manufactured and consumed worldwide and have distinct aspects, textures, flavors and colors. These features are well accepted to be due to the different manufacturing methods but also to the specific P. roqueforti strains used. Indeed, inoculated P. roqueforti strains, via their proteolytic and lipolytic activities, have an effect on both blue cheese texture and flavor. In particular, P. roqueforti produces a wide range of flavor compounds and variations in their proportions influence the flavor profiles of this type of cheese. Moreover, P. roqueforti is also characterized by substantial morphological and genetic diversity thus raising the question about the functional diversity of this species. In this context, 55 representative strains were screened for key metabolic properties including proteolytic activity (by determining free NH2 amino groups) and secondary metabolite production (aroma compounds using HS-Trap GC-MS and mycotoxins via LC-MS/Q-TOF). Mini model cheeses were used for aroma production and proteolysis analyses, whereas Yeast Extract Sucrose (YES) agar medium was used for mycotoxin production. Overall, this study highlighted high functional diversity among isolates. Noteworthy, when only P. roqueforti strains isolated from Protected Designation of Origin (PDO) or Protected Geographical Indication (PGI) blue cheeses were considered, a clear relationship between genetic diversity, population structure and the assessed functional traits was shown. PMID- 27771580 TI - An RRM-containing mei2-like MCT1 plays a negative role in the seed germination and seedling growth of Arabidopsis thaliana in the presence of ABA. AB - Despite an increasing understanding of the essential role of the Mei2 gene encoding an RNA-binding protein (RBP) in premeiotic DNA synthesis and meiosis in yeasts and animals, the functional roles of the mei2-like genes in plant growth and development are largely unknown. Contrary to other mei2-like RBPs that contain three RNA-recognition motifs (RRMs), the mei2 C-terminal RRM only (MCT) is unique in that it harbors only the last C-terminal RRM. Although MCTs have been implicated to play important roles in plants, their functional roles in stress responses as well as plant growth and development are still unknown. Here, we investigated the expression and functional role of MCT1 (At1g37140) in plant response to abscisic acid (ABA). Confocal analysis of MCT1-GFP-expressing plants revealed that MCT1 is localized to the nucleus. The transcript level of MCT1 was markedly increased upon ABA treatment. Analysis of MCT1-overexpressing transgenic Arabidopsis plants and artificial miRNA-mediated mct1 knockdown mutants demonstrated that MCT1 inhibited seed germination and cotyledon greening of Arabidopsis plants under ABA. The transcript levels of ABA signaling-related genes, such as ABI3, ABI4, and ABI5, were markedly increased in the MCT1 overexpressing transgenic plant. Collectively, these results suggest that ABA upregulated MCT1 plays a negative role in Arabidopsis seed germination and seedling growth under ABA by modulating the expression of ABA signaling-related genes. PMID- 27771581 TI - Variation in waterlogging-triggered stomatal behavior contributes to changes in the cold acclimation process in prehardened Lolium perenne and Festuca pratensis. AB - According to predicted changes in climate, waterlogging events may occur more frequently in the future during autumn and winter at high latitudes of the Northern Hemisphere. If excess soil water coincides with the process of cold acclimation for plants, winter survival may potentially be affected. The effects of waterlogging during cold acclimation on stomatal aperture, relative water content, photochemical activity of photosystem II, freezing tolerance and plant regrowth after freezing were compared for two prehardened overwintering forage grasses, Lolium perenne and Festuca pratensis. The experiment was performed to test the hypothesis that changes in photochemical activity initiated by waterlogging-triggered modifications in the stomatal aperture contribute to changes in freezing tolerance. Principal component analysis showed that waterlogging activated different adaptive strategies in the two species studied. The increased freezing tolerance of F. pratensis was associated with increased photochemical activity connected with stomatal opening, whereas freezing tolerance of L. perenne was associated with a decrease in stomatal aperture. In conclusion, waterlogging-triggered stomatal behavior contributed to the efficiency of the cold acclimation process in L. perenne and F. pratensis. PMID- 27771582 TI - Hydrogen sulfide and proline cooperate to alleviate cadmium stress in foxtail millet seedlings. AB - Hydrogen sulfide (H2S) and some functional amino acids in crops have been involved in the defense system against heavy-metal pollution. Here we report the relationships and functions of H2S and proline to cadmium (Cd) stress. Sodium hydrosulfide (NaHS) pretreatment decreased the electrolytic leakage and the malondialdehyde and hydrogen peroxide contents while enhancing photosynthesis in Cd-treated seedlings. Furthermore, pretreatment with NaHS markedly exacerbated Cd induced alterations in proline content, the activities of proline-5-carboxylate reductase (P5CR) and proline dehydrogenase (PDH), and the transcript levels of P5CR and PDH. When endogenous H2S was scavenged or inhibited by various H2S modulators, the Cd-induced increase in endogenous proline was weakened. Combined pretreatment with H2S and proline was moderately higher in the Cd-stressed growth status, stomata movements and oxidative damage of seedlings compared to a single treatment with H2S or proline. These results suggest that H2S and proline cooperate to alleviate Cd-damage in foxtail millet. PMID- 27771583 TI - The characterization of the adaptive responses of durum wheat to different Fe availability highlights an optimum Fe requirement threshold. AB - Plant mechanisms responding to iron (Fe) deficiency have been widely described; it is well known that Strategy II plants, as durum wheat, cope with this stress by increasing both the synthesis and secretion of phytosiderophores (PS). The important contribution of the sulfate assimilatory pathway has been also demonstrated to improve Fe use efficiency in several grasses, such as maize, barley and wheat, most likely because PS are produced from nicotianamine, whose precursor is methionine. Here, the physiological response of durum wheat (T. durum L.) plants - in terms of plant ionome, PS release, thiols content and S pathway-related enzymes - was investigated by gradually decreasing Fe availability that allowed the identification of three specific limit Fe concentrations: 75 MUM, 25 MUM and 0 MUM Fe, i.e. the complete Fe deprivation. At each limit, plants begin to induce different and specific adaptive responses to improve Fe acquisition or to reduce the damage resulting from limited Fe availability. The identification of the Fe availability level below which durum wheat plants start an expensive metabolic reorganization of S and several other elements, could be of benefit not only for an effective cultivation of the crop but also for the grain quality. PMID- 27771584 TI - Expression levels of the receptor activator of NF-kappaB ligand and osteoprotegerin and the number of gram-negative bacteria in symptomatic and asymptomatic periapical lesions. AB - OBJECTIVE: The study aimed to verify the potential correlation between the detected amount of gram-negative bacteria and the radiographic sizes of the lesions in patients with symptomatic and asymptomatic apical periodontitis. Furthermore, to evaluate whether the expression of receptor activator of NF kappaB ligand (RANKL) and osteoprotegerin (OPG) and the RANKL/OPG ratio are differentially regulated in both groups. DESIGN: Twenty patients with periapical lesions were divided into two groups: symptomatic (SYM) n=10 and asymptomatic (ASYM) n=10. After periapical surgery, the lesions were collected and processed for histological examination, and immunohistochemistry. The percentage of RANKL- and OPG-immunopositive areas relative to the total area of the microscopic field was calculated. For gram staining, the number of gram-negative cells per microscopic field was assessed. The radiographs of each patient were processed and measured. The Student's t-test and the Pearson correlation coefficient were performed. RESULTS: The SYM group showed a significantly higher number of gram negative cells (p=0.007) when compared to the ASYM group. A higher number of gram negative bacteria occurred more frequently in larger periapical lesions and the SYM group (p=0.03). The expression for RANKL and OPG and the RANKL/OPG ratio were not significantly different between the groups. There was a significant positive correlation between the number of bacteria and OPG levels in the SYM group (p=0.01). CONCLUSION: The number of bacteria seems to influence the symptoms and the radiographic size of a periapical lesion. Gram-negative bacteria may play an important role in OPG activity in the SYM group. PMID- 27771585 TI - Efficacy of freeze-dried platelet-rich plasma in bone engineering. AB - OBJECTIVE: Platelet-rich plasma (PRP) is typically isolated and applied immediately after preparation, making it both a time- and labor-intensive addition to the operative procedure. Thus, it would be convenient if PRP could be preserved. We evaluated the efficacy of freeze-dried PRP (FD-PRP), as compared with freshly isolated PRP (f-PRP) for bone engineering. DESIGN: FD-PRP was prepared by lyophilization of f-PRP and was subsequently preserved at -20 degrees C for one month. It was then rehydrated with an equal or 1/3 amount of distilled water (*1FD-PRP, *3FD-PRP, respectively), and we assessed its gelation properties and the release of growth factors (PDGF-BB, TGF-beta1, and VEGF). We also examined the bone forming ability with onlay-grafting on mice calvaria using beta TCP granules as a scaffold. RESULTS: FD-PRP showed comparable gelation as f-PRP. In terms of growth factor release,*1FD-PRP released identical concentrations of PDGF-BB and TGF-beta1 to f-PRP, while *3FD-PRP released approximately 3-fold concentrations when compared with f-PRP. In vivo, *1FD-PRP promoted identical levels of the bone formation as f-PRP, and *3FD-PRP induced more abundant bone formation. CONCLUSIONS: These results suggest that f-PRP can be stored without functional loss by freeze-drying and the concentration of PRP may improve its efficacy in bone engineering. PMID- 27771586 TI - Antifungal activity, mode of action and anti-biofilm effects of Laurus nobilis Linnaeus essential oil against Candida spp. AB - OBJECTIVE: The present study demonstrated the antifungal potential of the chemically characterized essential oil (EO) of Laurus nobilis L. (bay laurel) against Candida spp. biofilm adhesion and formation, and further established its mode of action on C. albicans. METHODS: L. nobilis EO was obtained and tested for its minimum inhibitory and fungicidal concentrations (MIC/MFC) against Candida spp., as well as for interaction with cell wall biosynthesis and membrane ionic permeability. Then we evaluated its effects on the adhesion, formation, and reduction of 48hC. albicans biofilms. The EO phytochemical profile was determined by gas chromatography coupled to mass spectrometry (GC/MS). RESULTS: The MIC and MFC values of the EO ranged from (250 to 500) MUg/mL. The MIC values increased in the presence of sorbitol (osmotic protector) and ergosterol, which indicates that the EO may affect cell wall biosynthesis and membrane ionic permeability, respectively. At 2 MIC the EO disrupted initial adhesion of C. albicans biofilms (p<0.05) and affected biofilm formation with no difference compared to nystatin (p>0.05). When applied for 1min, every 8h, for 24h and 48h, the EO reduced the amount of C. albicans mature biofilm with no difference in relation to nystatin (p>0.05). The phytochemical analysis identified isoeugenol as the major compound (53.49%) in the sample. CONCLUSIONS: L. nobilis EO has antifungal activity probably due to monoterpenes and sesquiterpenes in its composition. This EO may affect cell wall biosynthesis and membrane permeability, and showed deleterious effects against C. albicans biofilms. PMID- 27771587 TI - Study on the effects of gradient mechanical pressures on the proliferation, apoptosis, chondrogenesis and hypertrophy of mandibular condylar chondrocytes in vitro. AB - OBJECTIVE: To investigate the effects of gradient mechanical pressure on chondrocyte proliferation, apoptosis, and the expression of markers of chondrogenesis and chondrocyte hypertrophy. METHODS: Mandibular condylar chondrocytes from 5 rabbits were cultured in vitro, and pressed with static pressures of 50kPa, 100kPa, 150kPa and 200kPa for 3h, respectively. The chondrocytes cultured without pressure (0kPa) were used as control. Cell proliferation, apoptosis, and the expression of aggrecan (AGG), collagen II (COL2), collagen X (COL10), alkaline phosphatase (ALP) were investigated. Ultrastructures of the pressurized chondrocytes under transmission electron microscopy (TEM) were observed. RESULTS: Chondrocyte proliferation increased at 100kPa and decreased at 200kPa. Chondrocyte apoptosis increased with peak pressure at 200kPa in a dose-dependent manner. Chondrocyte necrosis increased at 200kPa. The expression of AGG increased at 200kPa. The expression of COL2 decreased at 50kPa and increased at 150kPa. The expression of COL10 and ALP increased at 150kPa. Ultrastructure of the pressurized chondrocytes under TEM showed: at 100kPa, cells were enlarged with less cellular microvillus and a bigger nucleus; at 200kPa, cells shrank with the sign of apoptosis, and apoptosis cells were found. CONCLUSIONS: The mechanical loading of 150kPa is the moderate pressure for chondrocyte: cell proliferation and apoptosis is balanced, necrosis is reduced, and chondrogenesis and chondrocyte hypertrophy are promoted. When the pressure is lower, chondrogenesis and chondrocyte hypertrophy are inhibited. At 200kPa, degeneration of cartilage is implied. PMID- 27771588 TI - Age-related periodontitis and alveolar bone loss in rice rats. AB - OBJECTIVE: To characterize in rice rats: (a) periodontitis (PD) progress with feeding of standard laboratory rat chow (STD) during ages 4-80 weeks; and (b) PD progress with feeding of a high sucrose-casein (H-SC) diet during young adulthood. METHODS: One group (N=12) was euthanized at age 4 weeks (Baseline). Four groups (N=8-16) consumed a STD diet from baseline and were necropsied at ages 22, 30, 52, and 80 weeks. Three groups (N=10-16) consumed an H-SC diet from baseline. Two were necropsied at ages 22 and 30 weeks, respectively. The third switched to the STD diet at age 22 weeks and was necropsied at age 30 weeks. All mandibles/maxillae were assessed by histometry for degree of periodontal inflammation (PD Score), alveolar crest height (ACH, mm), and horizontal alveolar bone height (hABH, mm2). RESULTS: In STD diet rats aged >=30 weeks, all endpoints were worse (P<0.05) than at Baseline. In H-SC diet rats aged >=22 weeks, all endpoints were worse than at Baseline (P<0.05). At age 22 weeks, all endpoints were worse in the H-SC group than in the STD group (P<0.05). By age 30 weeks, the STD and H-SC groups did not differ. CONCLUSIONS: 1) STD diet fed rice rats develop moderate/severe PD by age 30 weeks; 2) an H-SC diet accelerates moderate/severe PD development; and 3) switching to a STD diet does not halt/reverse PD that was accelerated by an H-SC diet. These data further clarify use of the rice rat as a PD model. PMID- 27771589 TI - Urine metabolic profiling for the pathogenesis research of erosive oral lichen planus. AB - OBJECTIVE: Oral lichen planus (OLP) is a relatively common chronic immune pathological and inflammatory disease and potentially oral precancerous lesion. Erosive OLP patients show the higher rate of malignant transformation than patients with non-erosive OLP. Identifying the potential biomarkers related to erosive OLP may help to understand the pathogenesis of the diseases. METHODS: Metabolic profiles were compared in control and patient subjects with erosive OLP by using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods An integrative analysis was used to identify the perturbed metabolic pathways and pathological processes that may be associated with the disease. RESULTS: In total, 12 modulated metabolites were identified and considered as the potential biomarkers of erosive OLP. Multiple metabolic pathways and pathological processes were involved in erosive OLP. CONCLUSION: The dysregulations of these metabolites could be used to explain the pathogenesis of the disease, which could also be the potential therapeutic targets for the disease. PMID- 27771590 TI - Decreased resting state metabolic activity in frontopolar and parietal brain regions is associated with suicide plans in depressed individuals. AB - Suicide plans are a major risk factor for suicide, which is a devastating outcome of depression. While structural and functional brain changes have been demonstrated in relation to suicidal thoughts and behaviour, brain mechanisms underlying suicide plans have not yet been studied. Here, we studied changes in regional cerebral metabolic activity in association with suicide plans in depressed individuals. Using 18FDG-PET, a comparative study of regional cerebral glucose metabolism (rCMRglu) was carried out in depressed individuals with suicidal thoughts and suicide plans, depressed individuals with only suicidal thoughts, depressed individuals without suicide thoughts and plans, and healthy controls. When compared to the other groups, depressed individuals with suicide plans showed relative hypometabolism in the right middle frontal gyrus and the right inferior parietal lobe (Brodmann areas 10 and 39). Suicide plans in depressed individuals appear to be associated with reduced activity in brain areas that are involved in decision-making and choice, more particularly in exploratory behaviour. PMID- 27771591 TI - Using the Theory of Planned Behavior to predict pregnant women's intention to engage in regular exercise. AB - OBJECTIVE: the objectives of this study were to use the Theory of Planned Behavior (TPB) in order to determine to what degree pregnant women intended to exercise regularly during pregnancy, and then to evaluate the TPB model fit. DESIGN: this study was based on a cross-sectional survey with a tool which was developed specifically for this study. SETTING: we identified and invited pregnant women from two medical center hospitals and one certified prenatal center in northern Taiwan to participate. PARTICIPANTS: using purposive sampling, we selected participants who were in at least the 12th week of gestation and did not have a high-risk pregnancy. 621 completed the instrument, their mean age was 31.76 (SD=3.87). METHODS: a self-administered instrument was used to determine the firmness of participants' intention to engage in regular exercise during pregnancy. The data were analyzed using SPSS 19.0 software and LISREL 8.72 software. FINDINGS: of the pregnant women in our study, 64.2% were found to be likely to exercise regularly up until delivery. The TPB was used to arrive at specific findings with regard to "intention to exercise regularly during pregnancy." Our participants demonstrated a positive intention to exercise regularly, a positive attitude (ATT), positive subjective norms (SN) and positive perceived behavioral controls (PBC) during pregnancy. The most influential factor in determining the participants' positive intention to exercise was found to be PBC (beta=0.68, p<0.01), followed by the SN (beta=0.12, p<0.01). The participants' ATT did not significantly influence their intention. Overall, the final model explained 59% of the variation in "intention to exercise regularly." KEY CONCLUSION AND IMPLICATION FOR PRACTICE: the most important factor in determining the participants' intention to exercise regularly was PBC, followed by the SN. Medical staff members should be able to help pregnant women overcome obstacles to regular exercise, for example, by assisting in providing appropriate resources. PMID- 27771592 TI - Breast feeding basic competence in primary care: Development and validation of the CAPA questionnaire. AB - BACKGROUND: validated and reliable tools measuring the level of competence about breastfeeding amongst health professionals who attend mothers in primary care are scarce. OBJECTIVE: to develop and validate a self-administered online questionnaire to assess basic competence about breastfeeding in the full range of health professionals attending lactating mothers in primary care. DESIGN: methodological study. SETTINGS: the study was conducted in 33 primary care centers administered by the Catalan Health Institute (Institut Catala de la Salut) in the Girona Region (northeast Spain). PARTICIPANTS: the questionnaire was sent to 398 health professionals who were likely to be in contact with breast feeding mothers. We included midwives, general practitioners, pediatric nurses (who provide care for children from birth to 14 years old), non-pediatric nurses (who provide care for patients older than 14 year), pediatricians, and gynecologists. The random sampling was stratified by discipline to ensure representativeness. METHODS: the development and validation of the self administered online questionnaire had five phases: (1) literature review, preparation of a draft for evaluation by an expert panel and pilot study; (2) design of a questionnaire based on observations from Phase 1; (3) questionnaire administration to a random sample of 398 health professionals, stratified by discipline; (4) re-testing after four weeks; and (5) assessment of construct validity using factor analysis and hypothesis-testing, comparing scores between professional groups and estimating effect size. Internal consistency was assessed by Cronbach alpha and reproducibility by the intraclass correlation coefficient. FINDINGS: The response rate was 69.3%. The final version of the questionnaire has 24 items. The uni-dimensionality of the questionnaire was confirmed by the factor analysis. The score differed significantly between professional groups (F=12.904; p<0.001), among whom midwives achieved the highest score (129+/-10 points) and non-pediatric nurses the lowest (111+/-14 points).The effect sized values ranged from 0.6 and 1.5. Cronbach alpha was 0.870 (95% CI: 0.847, 0.891) and intraclass correlation coefficient was 0.856 (95%CI: 0.817, 0.888). CONCLUSIONS: this is a valid and reliable questionnaire to assess a basic level of competence about breast feeding among primary care professionals involved in supporting breast feeding mothers. This questionnaire may help to identify health professionals who require support to improve their capability to manage women who are breast feeding. PMID- 27771593 TI - Mercury and drought along the lower Carson River, Nevada: IV. Snowy egret post fledging dispersal, timing of migration and survival, 2002-2004. AB - This telemetry study is an extension of our 1997-2006 research on historical mercury contamination on snowy egrets (Egretta thula) up to ~ 20 days of age. Findings from initial studies at the mercury-contaminated Carson River colony at Lahontan Reservoir (LR) and a similar-sized reference (REF) colony on the Humboldt River included mercury-related physiological, biochemical, histopathological and reproductive effects up to ~20 days of age; with poor water years (2000-04), i.e., reduced prey availability, exacerbating effects. Herein, we compare timing of dispersal and migration at LR vs. REF, but the primary question now addressed is "whether survival of young mercury-exposed snowy egrets from LR would be further compromised beyond ~20 days of age? " Based upon telemetry signals until 90-110 days of age (including dead bird counts and survival rate estimates), we conclude that mercury did not further compromise survival. Dead bird counts and survival rate estimates included time in the colony when fed by adults, plus the critical period when young dispersed from the colony to forage independently. The extended drought during this 3-year study was most critical in 2002 when production of ~20d old egrets at LR was only 0.24 young/nest. In 2002, survival rates were low at both colonies and we documented the highest counts of dead egrets for both colonies. We suggest the losses in 2002 beyond 20 days of age were more a function of prey availability influenced by drought than exposure to mercury, especially at LR, because higher mercury concentrations, higher survival rates and fewer dead birds were documented at LR in 2003 when water conditions improved. Furthermore, total mercury (THg) in blood in 2003 was more than double 2002 (geometric mean, 3.39 vs 1.47ug/g wet weight (ww). This higher THg exposure at LR in 2003 was associated with a redistribution of parent and post-dispersal feeding activities upstream (where there was higher mercury from historic mining) related to slightly improved water levels. When comparing the 3-year telemetry findings based upon ~20d old young at LR (blood THg, geo. means 1.47, 3.39 and 1.89ug/g ww), we found no evidence that age at dispersal, Julian date at dispersal, timing of migration, or pre-migration survival (~20 to ~100 days post-hatch) were adversely affected by elevated mercury. PMID- 27771595 TI - Using a chewing simulator for fatigue testing of metal ceramic crowns. AB - OBJECTIVE: Dynamic loading is a more important predictor for the clinical longevity of ceramic crowns than static loading. However, dynamic loading machines are costly and mostly have only one test station. The SD Mechatronik Chewing Simulator (formerly Willytec) may be a cost-effective alternative to evaluate the fatigue resistance of metal ceramic crowns. METHOD: Four metal ceramic materials were tested on lower first molar crowns: GC InitiaI, Creation (Willy Geller), IPS InLine (Ivoclar Vivadent) and the new low-fusion IPS Style Ceram (Ivoclar Vivadent). The ceramic material was manually layered on frames made of the nickel-chromium alloy 4all (Ivoclar Vivadent) by using a silicone mould. The crowns were adhesively luted to PMMA dies. Dynamic loading was carried out with a SD Mechatronik Chewing Simulator using additional bars with weights. A steel antagonist (O 4mm) with 40mm/s downward speed hit the disto-buccal cusp of the crown with minimal impulse while sliding for a distance of 0.7mm. The starting load was 250N. The forces at each load level had been verified with a 3D force sensor (Kistler). Four crowns per group and load were submitted to four decreasing load levels for 200,000 cycles with a resulting simulation frequency of 0.9Hz and simultaneous thermocycling (5 degrees C/55 degrees C) until all four crowns no longer showed chippings. Statistical analyses had been carried out using an exponential, a Weibull and a lognormal model. The fatigue resistance was defined as the maximal load for which one would observe less than 1% failure after 200,000 cycles. In addition to the fatigue testing of the molar crowns, simulations of finite element method (FEM) were conducted in order to investigate the influence of the mismatch of the thermal expansion coefficient (CTE) between the PMMA die and the molar crown on the fatigue resistance. RESULTS: The 3D-force measurements revealed that the summarised forces were very similar to the force of the dead weights that were put on the bars. The failure modes consisted of cracks and small and big chippings. Chi-square test and Gamma revealed no statistically significant differences between the four test materials in relation to the failure mode. At 250N all materials showed chippings within the ceramic or down to the metal frame, while at lower loads there were differences. The estimated fatigue resistance was 68N for GC Initial, 88N for Creation, 96N for IPS Style Ceram, and 105N for IPS InLine, when using a Weibull model and considering all possible events. Furthermore, FEM simulations revealed that the maximum values of the maximum principal stress were 90 MPa for the thermocycling and 225 MPa for the external load. CONCLUSION: The SD Mechatronik Chewing Simulator is an adequate and cost-effective tool to test layered PFM crowns for fatigue resistance. The test method and the chewing simulator can be used for ceramic on metal, ceramic on zirconia and monolithic ceramic materials. PMID- 27771594 TI - Exoenzyme activity in contaminated soils before and after soil washing: beta glucosidase activity as a biological indicator of soil health. AB - It is essential to remediate or amend soils contaminated with various heavy metals or pollutants so that the soils may be used again safely. Verifying that the remediated or amended soils meet soil quality standards is an important part of the process. We estimated the activity levels of eight soil exoenzymes (acid phosphatase, arylsulfatase, catalase, dehydrogenase, fluorescein diacetate hydrolase, protease, urease, and beta-glucosidase) in contaminated and remediated soils from two sites near a non-ferrous metal smelter, using colorimetric and titrimetric determination methods. Our results provided the levels of activity of soil exoenzymes that indicate soil health. Most enzymes showed lower activity levels in remediated soils than in contaminated soils, with the exception of protease and urease, which showed higher activity after remediation in some soils, perhaps due to the limited nutrients available in remediated soils. Soil exoenzymes showed significantly higher activity in soils from one of the sites than from the other, due to improper conditions at the second site, including high pH, poor nutrient levels, and a high proportion of sand in the latter soil. Principal component analysis revealed that beta-glucosidase was the best indicator of soil ecosystem health, among the enzymes evaluated. We recommend using beta-glucosidase enzyme activity as a prior indicator in estimating soil ecosystem health. PMID- 27771596 TI - CTX-M-14 production by a clinical isolate of the European clone of Salmonella enterica 4,[5],12:i. PMID- 27771597 TI - The prevalence of bipolar disorder in China: A meta-analysis. AB - OBJECTIVE: This is a meta-analysis of the prevalence of bipolar disorders (BD) in the general population of China. METHODS: A systematic literature search was conducted via the following databases: PubMed, EMBASE, PsycINFO, China National Knowledge Infrastructure (CNKI), WanFang and SinoMed. Studies on the prevalence of BD in the general population in China were identified. Statistical analyses were performed using the Comprehensive Meta-Analysis program. RESULTS: Altogether 32 studies conducted between 1984 and 2013 with 470,411 participants met the inclusion criteria for the analysis; the median age was 44.6 years and 49.6% of participants were female. The estimated point, 12-month and lifetime prevalence of BD in China were 0.09% (95% Confidence interval [CI]: 0.06-0.12%), 0.17% (95% CI: 0.10-0.29%) and 0.11% (95% CI: 0.07-0.17%), respectively. For BD-I, the estimated point, 12-month and lifetime prevalence rates were 0.06% (95% CI: 0.04 0.10%), 0.08% (95% CI: 0.02-0.30%) and 0.09% (95% CI: 0.05-0.16%), respectively. For BD-II, the estimated point and lifetime prevalence rates were 0.04% (95% CI: 0.02-0.06%) and 0.04% (95% CI: 0.02-0.09%), respectively. The 12-month prevalence of BD before the year 2010 was significantly lower than that after 2010 (0.12% vs. 0.26%, P=0.04). Meta-regression analysis revealed that younger age was significantly associated with higher 12-month prevalence of BD (coefficient=0.096, 95% CI: 0.027, 0.164, P=0.006). CONCLUSION: This first meta analysis of the pooled prevalence of BD in China found that rates are generally lower than those reported in Western countries. Future studies with more rigorous and refined methodology are needed. PMID- 27771598 TI - Absolute lactate value vs relative reduction as a predictor of mortality in severe sepsis and septic shock. AB - PURPOSE: Lactate reduction, a common method of risk stratification, has been variably defined. Among patients with an initial lactate >4mmol/L, we compared mortality prediction between a subsequent lactate >=4mmol/L to a <10% and <20% decrease between initial and subsequent lactate values. MATERIALS AND METHODS: We performed a single-center retrospective study of patients presenting to the emergency department with an initial lactate >=4mmol/L and suspected infection. Patients were stratified by lactate reduction using 3 previously identified definitions (subsequent lactate >=4mmol/L, and <10% and <20% relative decrease in lactate) and compared using multivariable logistic regression. Sensitivity and specificity were compared using McNemar test. RESULTS: A subsequent lactate >=4mmol/L and a lactate reduction <20% were associated with increased in-hospital mortality (odds ratio [OR], 3.18; 95% confidence interval [CI], 1.24-8.16; P=.02 and OR, 3.11; 95% CI, 1.39-6.96; P=.006, respectively), whereas a lactate reduction <10% was not (OR, 1.13; 95% CI, 0.94-1.34; P=.11). A subsequent lactate >=4mmol/L and a lactate reduction <20% were more sensitive than a lactate reduction <10% (72% vs 41%, P=.002 and 62% vs 41%, P=.008, respectively) but less specific (57% vs 76%, P<.001 and 67% vs 76%, P=.002, respectively). CONCLUSIONS: A subsequent lactate >=4mmol/L and lactate reduction <20% were associated with increased in-hospital mortality, whereas a lactate reduction <10% was not. Sensitivity and specificity are different between these parameters. PMID- 27771600 TI - Deep venous thrombosis as the single sign of unexpected metastatic urinary tract cancer in a patient with a history of cutaneous melanoma: A case report. AB - INTRODUCTION: Cancer is a recognized risk factor of venous thromboembolism (VTE) as it induces a prothrombotic state through various mechanisms of activation of coagulation. Recognizing occult cancer as a risk factor is equally important. In patients with no known thromboembolic risk factors, utilizing PET/CT as a screening tool may be considered in order to reveal occult malignancy associated with otherwise unexplainable VTE. METHODS: This case report has been reported in line with the SCARE criteria. PRESENTATION OF CASE: We describe a case of deep venous thrombosis of the lower leg as the single sign of metastatic urinary tract cancer. The patient had a history of cutaneous melanoma but no thromboembolic risk factors. Following treatment for deep venous thrombosis, the patient was referred directly to the plastic surgery department for further examination including PET/CT due to suspicion of metastatic melanoma. DISCUSSION: Screening for occult cancer in patients with unprovoked VTE has so far not been shown to benefit survival. As new treatments emerge, significant improvement in prognosis might be expected with early diagnosis of occult cancer and initiation of treatment. Thus an open mind should be kept towards utilizing advanced diagnostic tools such as PET/CT to screen for occult cancer in patients presenting with unprovoked VTE. CONCLUSION: This case highlights the importance of considering all possible causes and utilizing targeted diagnostic tools when assessing a patient with seemingly unprovoked deep venous thrombosis. A whole-body PET/CT scan ultimately proved significant in revealing occult metastatic cancer of a completely different origin than expected. PMID- 27771599 TI - Design, synthesis and biological evaluation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives possessing a hydrazone moiety as antiproliferative agents. AB - A series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC50 values of 0.85 MUM against MGC-803 and 56.17 MUM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 MUM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1. PMID- 27771601 TI - R gas under diaphragm. AB - INTRODUCTION: The most common cause of gas under diaphragm is hollow viscous perforation. In 10% of cases it can be due to rare causes, both abdominal and extra-abdominal, one of them being intra abdominal infection by gas forming organisms. PRESENTATION OF THE CASE: A 51 year old male patient, a poorly controlled diabetic, presented with a second episode of severe pain abdomen and abdominal distention, with lower abdominal tenderness. Plain Xray of the abdomen in erect posture showed gas under the right dome of diaphragm and ultrasound abdomen confirmed gross pneumoperitoneum. On emergency laparotomy, a pancreatic abscess was discovered, which had ruptured through the inferior leaf of the transverse mesocolon. DISCUSSION: There are many obscure causes for extra intestinal and extra abdominal sources for gas under diaphragm which contribute to 10% of the etiology for the same.These are as follows: post laparotomy status, ruptured liver abscess, retroperitoneal air, biliary-enteric fistula, gall stone ileus, incompetent sphincter of Oddi, focal biliary lipomatosis, post scuba diving, post adeno-tonsillectomy, post dental extraction, following arthroscopy of the knee, intra abdominal sepsis by gas forming organisms and pneumatosis coli to name a few. In this case, Klebsiella was responsible for producing gas under the diaphragm. CONCLUSION: Pancreatic abscess, in particular, as a extraintestinal source for gas under diaphragm has not been reported in English literature. PMID- 27771602 TI - Primary leiomyosarcoma of the greater omentum: a case report. AB - INTRODUCTION: Greater omentum leiomyosarcomas are rare tumors with only a few cases reported in literature. PRESENTATION OF CASE: We report the case of a 68 year-old man who consulted complaining of diffuse abdominal pain without a palpable mass at physical examination. Imaging studies revealed a solid-cystic lesion in the right lower quadrant. Surgical resection was performed and the tumor was diagnosed as a leiomyoscarcoma by histological and immunohistochemical examinations. DISCUSSION: Surgical resection of all lesions seems to be a reasonable therapeutic approach if resection is feasible. Chemotherapy may be used in selected cases. CONCLUSION: More cases are needed to define the best treatment approach of this disease. PMID- 27771603 TI - Atraumatic diplaced bilateral femoral neck fracture in a patient with hypophosphatemic rickets in postpartum period: A missed diagnosis. AB - INTRODUCTION: Simultaneous bilateral femoral neck fracture is an uncommon condition. There are very few cases reported in the literature and most of these cases have underlying bone pathologies such as renal osteodystrophy and osteomalacia. In some cases bilateral femoral neck fractures occur due to generalized seizures or high-energy trauma. PRESENTATION OF CASE: In this case report "atraumatic bilateral femoral neck fracture in a 26year old woman in postpartum period with hypophosphatemic rickets disease" is presented. DISCUSSION: Femoral neck fractures are more frequently seen in elderly because of the reduction of bone quality and developing osteoporosis. In the literature generalized epilepsy, osteomalacia, hypovitaminosis D and chronic renal failure are shown as facilitating causes of bilateral femoral neck fractures. In patients without any additional pathology electric shock, electroconvulsive therapy, and high-energy trauma can lead to femoral neck fractures. In our patient there was also an underlying pathology, she has been followed due to autosomal recessive hypophosphatemic rickets disease since she was one year old. In the treatment of bilateral femoral neck fractures open/closed reduction internal fixation or hip arthroplasty are applied. CONCLUSION: For patients with bone metabolic diseases and/or the patients in pregnancy and postpartum period, preventive measures should be increased to reduce the risk of pathologic fracture. Admitting to the hospital physicians must be more careful about detecting fractures in these patients. PMID- 27771604 TI - Microalgae recycling improves biomass recovery from wastewater treatment high rate algal ponds. AB - Microalgal biomass harvesting by inducing spontaneous flocculation (bioflocculation) sets an attractive approach, since neither chemicals nor energy are needed. Indeed, bioflocculation may be promoted by recycling part of the harvested microalgal biomass to the photobioreactor in order to increase the predominance of rapidly settling microalgae species. The aim of the present study was to improve the recovery of microalgal biomass produced in wastewater treatment high rate algal ponds (HRAPs) by recycling part of the harvested microalgal biomass. The recirculation of 2% and 10% (dry weight) of the HRAPs microalgal biomass was tested over one year in an experimental HRAP treating real urban wastewater. Results indicated that biomass recycling had a positive effect on the harvesting efficiency, obtaining higher biomass recovery in the HRAP with recycling (R-HRAP) (92-94%) than in the control HRAP without recycling (C-HRAP) (75-89%). Microalgal biomass production was similar in both systems, ranging between 3.3 and 25.8 g TSS/m2d, depending on the weather conditions. Concerning the microalgae species, Chlorella sp. was dominant overall the experimental period in both HRAPs (abundance >60%). However, when the recycling rate was increased to 10%, Chlorella sp. dominance decreased from 97.6 to 88.1%; while increasing the abundance of rapidly settling species such as Stigeoclonium sp. (16.8%, only present in the HRAP with biomass recycling) and diatoms (from 0.7 to 7.3%). Concerning the secondary treatment of the HRAPs, high removals of COD (80%) and N-NH4+ (97%) were found in both HRAPs. Moreover, by increasing the biomass recovery in the R-HRAP the effluent total suspended solids (TSS) concentration was decreased to less than 35 mg/L, meeting effluent quality requirements for discharge. This study shows that microalgal biomass recycling (10% dry weight) increases biomass recovery up to 94% by selecting the most rapidly settling microalgae species without compromising the biomass production and improving the wastewater treatment in terms of TSS removal. PMID- 27771606 TI - The in situ force in the calcaneofibular ligament and the contribution of this ligament to ankle joint stability. AB - BACKGROUND: Numerous biomechanical studies of the lateral ankle ligaments have been reported; however, the isolated function of the calcaneofibular ligament has not been clarified. We hypothesize that the calcaneofibular ligament would stabilize the ankle joint complex under multidirectional loading, and that the in situ force in the calcaneofibular ligament would change in each flexed position. METHODS: Using seven fresh frozen cadaveric lower extremities, the motions and forces of the intact ankle under multidirectional loading were recorded using a 6 degree-of-freedom robotic system. On repeating these intact ankle joint complex motions after the calcaneofibular ligament transection, the in situ force in the calcaneofibular ligament and the contribution of the calcaneofibular ligament to ankle joint complex stability were calculated. Finally, the motions of the calcaneofibular ligament-transected ankle joint complex were recorded. FINDINGS: Under an inversion load, significant increases of inversion angle were observed in all the flexed positions following calcaneofibular ligament transection, and the calcaneofibular ligament accounted for 50%-70% of ankle joint complex stability during inversion. The in situ forces in the calcaneofibular ligament under an anterior force, inversion moment, and external rotation moment were larger in the dorsiflexed position than in the plantarflexed position. INTERPRETATION: The calcaneofibular ligament plays a role in stabilizing the ankle joint complex to multidirectional loads and the role differs with load directions. The in situ force of the calcaneofibular ligament is larger at the dorsiflexed position. This ligament provides the primary restraint to the inversion ankle stability. PMID- 27771605 TI - Biodegradability of DBP precursors after drinking water ozonation. AB - Ozonation is known to generate biodegradable organic matter, which is typically reduced by biological filtration to avoid bacterial regrowth in distribution systems. Post-chlorination generates halogenated disinfection byproducts (DBPs) but little is known about the biodegradability of their precursors. This study determined the effect of ozonation and biofiltration conditions, specifically ozone exposure and empty bed contact time (EBCT), on the control of DBP formation potentials in drinking water. Ozone exposure was varied through addition of H2O2 during ozonation at 1 mgO3/mgDOC followed by biological filtration using either activated carbon (BAC) or anthracite. Ozonation led to a 10% decrease in dissolved organic carbon (DOC), without further improvement from H2O2 addition. Raising H2O2 concentrations from 0 to 2 mmol/mmolO3 resulted in increased DBP formation potentials during post-chlorination of the ozonated water (target Cl2 residual after 24 h = 1-2 mg/L) as follows: 4 trihalomethanes (THM4, 37%), 8 haloacetic acids (HAA8, 44%), chloral hydrate (CH, 107%), 2 haloketones (HK2, 97%), 4 haloacetonitriles (HAN4, 33%), trichloroacetamide (TCAM, 43%), and adsorbable organic halogen (AOX, 27%), but a decrease in the concentrations of 2 trihalonitromethanes (THNM2, 43%). Coupling ozonation with biofiltration prior to chlorination effectively lowered the formation potentials of all DBPs including CH, HK2, and THNM2, all of which increased after ozonation. The dynamics of DBP formation potentials during BAC filtration at different EBCTs followed first order reaction kinetics. Minimum steady-state concentrations were attained at an EBCT of about 10-20 min, depending on the DBP species. The rate of reduction in DBP formation potentials varied among individual species before reaching their minimum concentrations. CH, HK2, and THNM2 had the highest rate constants of between 0.5 and 0.6 min-1 followed by HAN4 (0.4 min-1), THM4 (0.3 min-1), HAA8 (0.2 min-1), and AOX (0.1 min-1). At an EBCT of 15 min, the reduction in formation potential for most DBPs was less than 50% but was higher than 70% for CH, HK2, and THNM2. The formation of bromine-containing DBPs increased with increasing EBCT, most likely due to an increase in Br-/DOC ratio. Overall, this study demonstrated that the combination of ozonation and biofiltration is an effective approach to mitigate DBP formation during drinking water treatment. PMID- 27771607 TI - Recent advances in liquid and gas chromatography methodology for extending coverage of the metabolome. AB - The metabolome is the complete complement of metabolites (small organic biomolecules). In order to comprehensively understand the effect of stimuli on a biological system, it is important to detect as many of the metabolites within that system as possible. This review briefly describes some new advances in liquid and gas chromatography to improve coverage of the metabolome, including the serial combination of two columns in tandem, column switching and different variations of two-dimensional chromatography. Supercritical fluid chromatography could provide complimentary data to liquid and gas chromatography. Although there have been many recent advancements in the field of metabolomics, it is evident that a combination, rather than a single method, is required to approach full coverage of the metabolome. PMID- 27771608 TI - Advertising on Social Media: The Plastic Surgeon's Prerogative. PMID- 27771609 TI - Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer. AB - Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry. Associations between pevonedistat sensitivity and CRC molecular features were assessed by Student's t test. A 184 gene transcriptional predictor was generated in cell lines and applied to 87 metastatic CRC samples for which patient-derived xenografts (PDXs) were available. In vivo reponse to pevonedistat was assessed in PDX models (>=5 mice per group). All statistical tests were two-sided. Results: Sixteen (13.1%) cell lines displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block, and increased apoptosis. Pevonedistat sensitivity did not statistically significantly correlate with microsatellite instability or mutations in KRAS or BRAF and was functionally associated with low EGFR pathway activity. While ineffective on predicted resistant PDXs, in vivo administration of pevonedistat statistically significantly impaired growth of five out of six predicted sensitive models (P < .01). In samples from CRC patients, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery (hazard ratio [HR] = 2.49, 95% confidence interval [CI] = 1.34 to 4.62, P = .003) and early progression under cetuximab treatment (HR = 3.59, 95% CI = 1.60 to 8.04, P < .001). Histological and immunohistochemical analyses revealed that the pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma. Conclusions: These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated, clinically aggressive CRC. PMID- 27771611 TI - Identification of a FGFR3-TACC3 fusion in esophageal cancer. PMID- 27771612 TI - Oncology drug costs-the imaginary crisis? PMID- 27771610 TI - A phase II study of tivozanib in patients with metastatic and nonresectable soft tissue sarcomas. AB - Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRalpha/beta and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8 3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRalpha/beta or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number: NCT01782313. PMID- 27771613 TI - Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials?. AB - Background: Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. Patients and methods: We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Results: Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0 36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P = 0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P = 0.033). This association varied significantly with cancer types (P < 0.001) and approval status (P = 0.012) for SAEs but no evidence of heterogeneity was found for FAEs. Conclusions: This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making. PMID- 27771614 TI - Same map, different direction - Exploring new opportunities that dementia care mappingTM can offer to acute mental health admission wards for older people - Innovative practice. AB - Dementia Care MappingTM is widely acknowledged as the gold standard observational method that can support the introduction of person centred care into a variety of settings (http://www.bradford.ac.uk/health/dementia/dementia-care-mapping/). It encourages care staff to think about how the person with dementia is experiencing the care provided and the care setting. It has been shown to raise care staff awareness sufficiently to bring about improvements in care. In this paper, we describe a programme of work in North Wales that seeks to find innovative ways to use Dementia Care MappingTM, in acute mental health admission wards for people affected by dementia, and we set out some of those innovations. PMID- 27771615 TI - "Here everyone is the same" - A qualitative evaluation of participating in a Boccia (indoor bowling) group: Innovative practice. AB - This qualitative study explored the impact of a Boccia (modified indoor bowls) group on the lives of people with dementia and their carers. Semi-structured interviews with people with dementia (N = 6), carers (N = 10) and the group organisers (N = 6) analysed using thematic analysis revealed four main themes. 'The struggle of being a carer' was relieved by participating in the group and benefitting from the caring support and social aspects of "This group is a family". "The unique nature of Boccia" helped it to provide physical and mental stimulation as well as being an inclusive and enjoyable group. These aspects contributed to many participants describing the group as a Dementia friendly environment where "Here everyone is the same": treated as equals, without feeling hindered or defined by dementia. Boccia appears an exciting initiative but further research is needed to see if these findings can be replicated with other groups. PMID- 27771616 TI - Bidirectional Associations Between Disordered Eating and Health-Related Quality of Life in Elementary School-Age Youth. AB - Objective: To examine longitudinal, bidirectional associations between disordered eating and physical/psychosocial health-related quality of life (HRQOL) in a nonclinical community sample of elementary school-age youth. Methods: Participants included 130 children between the ages of 7 and 10 years ( M age = 8.62). Disordered eating and physical/psychosocial HRQOL were assessed using self report measures at three time points. The potential bidirectional associations were examined using a longitudinal panel model. Results: Higher disordered eating predicted lower psychosocial HRQOL during a 6-month period within the same academic year, and lower HRQOL predicted higher disordered eating during a 6 month period across academic years. Conclusion: The current study found longitudinal, bidirectional associations between disordered eating and psychosocial, but not physical, HRQOL. The results provide evidence for psychosocial HRQOL as a potential predictor and consequence of disordered eating attitudes. Limitations, future directions, and implications of this research are discussed. PMID- 27771617 TI - Supervising for Home Safety Program: A Randomized Controlled Trial (RCT) Testing Community-Based Group Delivery. AB - Objective: The individually delivered Supervising for Home Safety (SHS) program improves caregivers' injury-related beliefs and supervision practices. The current randomized controlled trial used a group delivery in a community setting and assessed program impact, feasibility, and acceptance. Methods: Caregivers of 2-5-year-olds were randomized to receive either the SHS or an attention-matched control program. Results: In the SHS group only, there were increases from baseline to postintervention in the following: beliefs about children's vulnerability to injury, caregiver preventability of injuries, and self-efficacy to do so; readiness for change in supervision; and watchful supervision. Face-to face recruitment by staff at community organizations proved most successful. Caregivers' satisfaction ratings were high, as was caregiver engagement (95% completed at least seven of the nine sessions). Conclusion: The SHS program can be delivered to groups of caregivers in community settings, is positively received by caregivers, and produces desirable changes that can be expected to improve caregivers' home safety practices. PMID- 27771618 TI - Juvenile systemic lupus erythematosus in Nigeria. AB - Juvenile systemic lupus erythematosus (JSLE) is a complex multisystemic autoimmune disorder of unknown cause. It accounts for about one in five cases of SLE. The tendency for SLE to run a fulminant course when it starts in childhood has made JSLE a potentially more severe disease than adult SLE. Reports of JSLE from sub-Saharan Africa are scanty in spite of the increasing reports of adult SLE. We conducted a 4-year retrospective study of JSLE cases seen at the Lagos State University Teaching Hospital between January 2010 and December 2014. Out of the 12 patients studied, eight were girls and four were boys. All patients had positive antinuclear antibody and extractable nuclear antibody tests. Anti-dsDNA antibody was positive in 10 patients. Eight patients had renal disease while four patients had neuropsychiatric manifestations. Haematological abnormalities and constitutional symptoms were present in all patients. Patients were treated with pulse methylprednisolone, oral prednisolone, hydroxychloroquine and azathioprine. Three patients also received rituximab. In conclusion, JSLE exists in Nigeria and exhibits clinical and immunological characteristics similar to its pattern in other parts of the world. It is, however, diagnosed late and is possibly being underdiagnosed as there is no paediatric rheumatologist in the country. PMID- 27771619 TI - Corrigendum. PMID- 27771620 TI - A Survey of Knowledge and Practices of Transfusion Medicine Among Post Intern Doctors in Specialized Hospital in Sri Lanka. AB - BACKGROUND: Knowledge of transfusion medicine is the key element of better transfusion practices. This deficit observed at the blood bank end on daily basis exposing the patients for redundant risk. We assessed the knowledge of transfusion medicine among post intern doctors. OBJECTIVE: To assess the knowledge of transfusion medicine among post intern doctors in working in our hospital. METHODS: Self administrated questionnaire was used. 45 questions of transfusion medicine included in the questioner. A total 57 post internship doctors participated in the survey. Statistical analysis was done using SPSS. RESULTS: In overall survey average score was 41.45%. Lowest score 19.8% was for the area of lab result interpretation. Highest score 56.63% obtained for the administration of blood component. Differences among the medical officers of various specialties were not statistically significant. CONCLUSIONS: Transfusion medicine knowledge among post internship doctors in our hospital need to be upgraded. PMID- 27771621 TI - Comparison of protein-chip array analysis and traditional ELISAs for biomarker detection of diabetic limb arterial stenosis. AB - The aim of this study was to screen the biomarkers of diabetic limb arterial stenosis. Fasting blood samples of 40 patients with diabetic limb arterial stenosis (experimental group), 40 diabetes patients (diabetic control group), and 40 healthy individuals (healthy control group) were collected. Protein-chip assay analysis and ELISA were used to detect tumor necrosis factor alpha, interleukin 6, endothelin-1, calcitonin gene-related peptide and high-sensitivity C-reactive protein in the three groups. Protein-chip array analysis and ELISA found consistent results that endothelin-1, tumor necrosis factor alpha, interleukin-6 and high-sensitivity C-reactive protein in the experimental group were significantly up-regulated while the expression of calcitonin gene-related peptide was down-regulated compared with the healthy control group ( P < 0.01). When compared with the diabetic control group, only markedly increased calcitonin gene-related peptide and interleukin-6 were observed in the experimental group ( P < 0.01). The study suggests that high-throughput protein-chip may be a reliable method to screen biomarkers of diabetic limb arterial stenosis. Calcitonin gene related peptide and interleukin-6 might be promising biomarkers for diabetic limb arterial stenosis. PMID- 27771622 TI - Refractory sporotrichosis due to Sporothrix brasiliensis in humans appears to be unrelated to in vivo resistance. AB - Sporotrichosis is a subacute to chronic infection caused by members of the Sporothrix schenckii complex. Itraconazole is the first choice antifungal drug for treating this infection, with terbinafine and potassium iodide as alternatives and amphotericin B used in cases of severe infections. Correlation of antifungal susceptibility data with the clinical outcome of the patients is scarce. The aim of this study was to correlate clinical and mycological data in patients with refractory sporotrichosis. In this work, antifungal susceptibilities, determined according to the reference M38-A2 CLSI protocol, of 25 Sporothrix strains, isolated from seven human cases of sporotrichosis with adversities in the treatment, are presented. Tested drugs included itraconazole, ketoconazole, posaconazole, voriconazole, terbinafine, and amphotericin B. Fungi were identified using the T3B PCR fingerprinting. This method identified all strains as Sporothrix brasiliensis and also demonstrated a high degree of similarity between the strains. In general, voriconazole was ineffective against all strains, and elevated minimal inhibitory concentrations (MICs) were observed for amphotericin B. High itraconazole and terbinafine MICs were not observed in S. brasiliensis isolates from patients of this study. Moreover, a significant increase in itraconazole and terbinafine MIC values from strains isolated from the same patient in different periods was not observed. The results suggest that the antifungal susceptibility to terbinafine and itraconazole determined by the reference method does not play an important role in therapeutic failure of sporotrichosis and that acquisition of resistance during prolonged antifungal treatment is not likely to occur in S. brasiliensis. PMID- 27771623 TI - Malignancies in Children with Human Immunodeficiency Virus Infection - Our Experience at Chandigarh, North India. AB - Background: With improved survival in children living with human immunodeficiency virus (HIV) infection (CLHIV), malignancies are being increasingly recognized. Patients and methods: Among the CLHIV registered at our institute from January 1994 to March 2015, children with malignancy were analysed in detail. Results: In total, 734 children affected by HIV were registered. Out of these, 11 children (9 boys, 2 girls) were diagnosed to have malignancy. Malignancy was the presenting feature of HIV infection in 4 children. High-grade non-Hodgkin lymphoma (NHL) was the most common malignancy noted in 9 of 11 (81%) children, whereas the remaining 2 children had Hodgkin's lymphoma. Survival in our cohort was 80% among children in whom chemotherapy was initiated, and overall survival was 36% (4 of 11 children). Conclusion: NHL was the most common malignancy in CLHIV in our cohort. Low-conditioning chemotherapy protocols along with initiation of anti-retroviral therapy resulted in improved outcomes in CLHIV with malignancy. PMID- 27771624 TI - Non-androgen secreting adrenocortical carcinoma in preadolescence: a case report and literature review. AB - Adrenocortical carcinoma (ACC) is a rare malignancy in childhood. Affected children with ACC mostly present with virilization, but not the pure form of Cushing's syndrome. A 9-year-old Japanese girl was hospitalized, because of the unstable emotions and excessive weight gain. She was diagnosed as having Cushing's syndrome and a left adrenal tumor. The adrenalectomy led to the pathological diagnosis of ACC without metastasis. There was no mutation of PRKACA in the tumor-derived DNA, or p53 in peripheral blood-derived DNA. Testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels were normal throughout the clinical course. On the other hand, these levels were elevated in all five reported cases of preadolescent ACC children with isolated Cushing's syndrome. The exceptional secretory behavior of ACC gave a diagnostic precaution of the rare pediatric cancer. PMID- 27771625 TI - Puberty - genes, environment and clinical issues. PMID- 27771626 TI - Pregnancy outcomes regarding maternal serum AFP value in second trimester screening. AB - AIM: The aim of this study was to evaluate the predictive value of alpha fetoprotein in maternal serum (MS-AFP) as a marker for diverse pregnancy outcomes. METHODS: The study was based on pregnancy and delivery data from 5520 women between 1999 and 2014 at University Hospital of Zurich (UHZ). INCLUSION CRITERIA: both MS-AFP and pregnancy outcome were known for the same pregnancy. Pregnancy outcomes and characteristics such as fetal malformation, intrauterine fetal death (IUFD) and intrauterine growth retardation as well as maternal age, weight before pregnancy, gestational age (GA) at delivery, newborn weight, length and head circumference were analyzed with respect to the MS-AFP value. MS-AFP value was categorized into three groups: elevated MS-AFP>2.5 multiples of the median (MoM), normal 0.5-2.49 MoM and decreased <0.5 MoM. RESULTS: Newborn weight (g) and length (cm) were significantly lower in the elevated MS-AFP (P<0.001) group, and infants had 1 week lower GA at delivery (P<0.05). In the group of elevated MS-AFP (n=46), 26.1% of pregnancies were significantly related to adverse pregnancy outcomes, such as fetal malformations, fetuses small for gestational age (SGA) and IUFD. Adverse pregnancy outcomes of 5.6% were registered in the group of normal MS-AFP and 7.3% in the group of low MS-AFP (P<0.05). CONCLUSION: MS-AFP level in the second trimester is still an important indicator of fetal surface malformations; however, ultrasound still outweighs as a screening method. Nevertheless, pregnant women with elevated MS-AFP values and with no sonographically detected fetal malformations should additionally receive the third trimester ultrasound examination to exclude other possible complications of pregnancy. PMID- 27771627 TI - Anti-inflammatory activity of highly oxygenated terpenoids from Achillea biebersteinii Afan. AB - In continuation of our chemical investigation on some medicinal plants of the genus Achillea, chromatographic investigation of the methylene chloride/methanol (1:1) extract of the air-dried aerial part of Achillea biebersteinii Afan. (family Asteraceae) afforded a new natural monoterpene (2), in addition to two known sesquiterpenes (3 and 4). Compound 1 was isolated as light needle crystals. Structures were established on the basis of MS and NMR spectroscopic (1H, 13C, 1H 1H correlation spectroscopy, heteronuclear multiple-quantum coherence and heteronuclear multiple-bond correlation) data and in case of compound 1 were confirmed by X-ray analysis. All isolated compounds were examined for their anti inflammatory activity to inhibit lipopolysaccharide-induced NO production in RAW264.7 macrophage cells. Compounds 3 and 4 produced a promising anti inflammatory effect (76% and 80% inhibition, respectively). However, compounds 1 and 2 produced moderate inhibition of NO release recording a 41% and 36% inhibition of NO production, respectively. PMID- 27771628 TI - The development of a novel medical education elective for fourth-year medical students. PMID- 27771630 TI - Development, improvement and funding of the emergency medicine cases open-access podcast. PMID- 27771629 TI - Participating in university entrance exam despite repeated failure: a qualitative study of participants' experiences. AB - Objectives: To explore the experiences of general practitioners who continue to sit a highly-competitive residency entrance examination, despite repeated failure. Methods: This qualitative, exploratory study employed semi-structured, in-depth interviews with 35 candidates of a residency entrance exam who had failed the examination at least twice and were preparing to sit it again. Interview questions addressed the challenges they faced and how they managed these challenges. Interview data were audiotaped, transcribed, and analysed to identify themes. Results: The results demonstrated that more than 50% (n=19) of candidates struggled continuously and internally with different aspects of the exam. These include being under a great deal of pressure to succeed, failing to prioritize study materials, inefficient review during the final days of preparation, and sitting the exam with an afflicted body. Furthermore, during the examination, they frequently used inefficient strategies to answer questions. Afterwards, they experienced feelings of freedom associated with having finished the exam. Conclusions: Participation in a highly-competitive examination exerts a considerable amount pressure on low-performing candidates. This climate not only results in burn out of participants, but it also influences their learning styles and identities as future physicians. It is therefore necessary to design a syllabus for both test candidates and policy makers, in order better to manage this environment. Candidates also should be aware of their individual weaknesses in order to improve their studying skills. PMID- 27771631 TI - Celebrating Indias Achievements Towards Polio Eradication. PMID- 27771633 TI - The Estimated Health and Economic Benefits of Three Decades of Polio Elimination Efforts in India. AB - OBJECTIVE: In March 2014, India, the country with historically the highest burden of polio, was declared polio free, with no reported cases since January 2011. We estimate the health and economic benefits of polio elimination in India with the oral polio vaccine (OPV) during 1982-2012. METHODS: Based on a pre-vaccine incidence rate, we estimate the counterfactual burden of polio in the hypothetical absence of the national polio elimination program in India. We attribute differences in outcomes between the actual (adjusted for under reporting) and hypothetical counterfactual scenarios in our model to the national polio program. We measure health benefits as averted polio incidence, deaths, and disability adjusted life years (DALYs). We consider two methods to measure economic benefits: the value of statistical life approach, and equating one DALY to the Gross National Income (GNI) per capita. RESULTS: We estimate that the National Program against Polio averted 3.94 million (95% confidence interval [CI]: 3.89-3.99 million) paralytic polio cases, 393,918 polio deaths (95% CI: 388,897- 398,939), and 1.48 billion DALYs (95% CI: 1.46-1.50 billion). We also estimate that the program contributed to a $1.71 trillion (INR 76.91 trillion) gain (95% CI: $1.69-$1.73 trillion [INR 75.93-77.89 trillion]) in economic productivity between 1982 and 2012 in our base case analysis. Using the GNI and DALY method, the economic gain from the program is estimated to be $1.11 trillion (INR 50.13 trillion) (95% CI: $1.10-$1.13 trillion [INR 49.50-50.76 trillion]) over the same period. CONCLUSION: India accrued large health and economic benefits from investing in polio elimination efforts. Other programs to control/eliminate more vaccine-preventable diseases are likely to contribute to large health and economic benefits in India. PMID- 27771632 TI - The Need and Potential of Inactivated Poliovirus Vaccine. AB - As the polio endgame progresses, the world will increasingly rely on inactivated polio vaccine (IPV) for protection against polio (wild and vaccine-related) and for risk mitigation during the phased removal of oral polio vaccine (OPV). IPV has already been introduced in most countries and strategies are underway to ensure the remaining OPV-only using countries succeed in introducing IPV in light of operational challenges. Questions remain as to the ideal dosing schedule for IPV in developing countries as well as the length of time for IPV to be administered beyond certification of eradication of wild polioviruses and total OPV withdrawal. IPV policies will likely evolve and new technologies will become available to meet unforeseen needs during this historical and unprecedented public health endeavor. Pediatricians in India have a crucial role to play in this global effort by supporting the overall polio eradication strategy and ensuring that all targeted children in India receive IPV. PMID- 27771634 TI - Cross-sectional Serologic Assessment of Immunity to Poliovirus in Differential Risk Areas of India: India Seroprevalence Survey - 2014. AB - OBJECTIVE: To assess the seroprevalence against all three poliovirus serotypes in traditional high risk areas in Bihar, lowest routine immunization coverage areas in Madhya Pradesh and migrant population living in Mumbai urban slums. DESIGN: Cross-sectional Survey. SETTING: Subjects selected by house to house visit (community based) and transported to government health facilities for further study procedures. PARTICIPANTS: 1137 randomly selected healthy infants 6-11 months of age residing in the selected high-risk areas. METHODS: Serum samples from the study site were shipped to Enterovirus Research Centre (ERC), Mumbai to determine the neutralizing antibodies against all three poliovirus serotypes. Children with a reciprocal antibody titer >=1:8 were considered seropositive to the specific poliovirus. RESULTS: Overall, seroprevalence in all the three study areas was 98%, 98% and 91% against poliovirus type-1, type-2 and type-3, respectively. Bihar had a seroprevalence of 99%, 99% and 92% against type-1, type 2 and type-3 respectively. Corresponding figures for Madhya Pradesh and Mumbai were 98%, 99% and 88% and 98%, 97% and 94%, respectively. CONCLUSION: The study found high seroprevalence against all three poliovirus types not only in the traditional high-risk areas for polio in India, but even in the areas known to have low routine immunization coverage and among the migratory clusters living in Mumbai urban slums. Type-2 seroprevalence was found to be high. These findings are reassuring against the threat of emergence of circulating vaccine derived polioviruses (cVDPVs) in the country subsequent to switch from trivalent oral polio vaccine to bivalent oral polio vaccine in the routine immunization schedule from April 2016. PMID- 27771635 TI - A Brief History of Vaccines Against Polio. AB - Poliomyelitis, a dreaded disease of the last century that had already crippled millions of people across the globe, is now on the verge of eradication thanks mainly to two polio vaccines, inactivated polio vaccine (IPV) and oral polio vaccine (OPV). Ever since their development in late 1950s and early 1960s, the journey of their early development process, clinical trials, licensure and ultimately widespread clinical use in different countries provide a fascinating tale of events. Oral polio vaccine has been the mainstay of global polio eradication initiative (GPEI) in most of the countries. With the advent of 'polio endgame', the focus has now shifted back to IPV. However, there are certain issues associated with global cessation of OPV use and universal implementation of IPV in routine immunization schedules across the globe that need to be dealt with some urgency, before proclaiming the global victory over polio. PMID- 27771636 TI - Polio Eradication and Endgame Plan - Victory within Grasp. AB - Since the launch of the Global Polio Eradication Initiative (GPEI) by the World Health Assembly (WHA) in 1988, the number of polio-endemic countries has decreased from 125 to 2 (Afghanistan and Pakistan). To secure the gains and to address the remaining challenges, the GPEI developed the Polio Eradication and Endgame Strategic Plan, 2013-2018 (the Plan), endorsed by all Member States at the WHA in May 2013. One of the major elements that distinguishes this Plan from previous GPEI strategies is the approach to ending all polioviruses, both wild and vaccine-derived. Overall, the Plan outlines four main objectives: (1) to stop all wild poliovirus (WPV) transmission; (2) to introduce inactivated polio vaccine (IPV), withdraw all oral polio vaccines (OPV), and strengthen immunization systems in countries with weak immunization systems and strong polio infrastructure; (3) to certify all regions as polio-free and safely contain all poliovirus stocks; (4) and to mainstream the investment in polio eradication to benefit other priority public health initiatives for years to come. Implementing the Plan and meeting the milestones in a timely manner will help to ensure that that the world remains permanently polio-free. PMID- 27771637 TI - Polio Endgame, Information Gaps Related to Vaccines and Immunity. AB - Evidence generated through research studies has guided programmatic actions and fine-tuned strategies for the Global Polio Eradication Initiative (GPEI). However, many gaps still persist in the understanding of a risk-free implementation of the polio endgame. Immediate concerns relate to the introduction of inactivated polio vaccine (IPV) and switch from trivalent oral polio vaccine (tOPV) to bivalent oral polio vaccine (bOPV) in routine immunization schedule. A comprehensive understanding of mucosal immunity in populations and best response options against circulating vaccine derived poliovirus (cVDPV) outbreaks in post tOPV-bOPV switch is essential to mitigate the risks of wild and vaccine-derived poliovirus importations and emergence of cVDPVs in polio-free countries. A clearer picture is also needed on few operational issues, interference between polio vaccines and other EPI vaccines and products related to polio endgame. It is also extremely important to develop mechanisms to identify and manage long-term poliovirus excretors who may pose a risk of reintroduction into the population after global eradication of poliovirus. PMID- 27771638 TI - India's Research Contributions Towards Polio Eradication (1965-2015). AB - Pioneering research has been conducted in India during the past five decades, comprehensively covering epidemiology of poliovirus infection and of polio, efficacy and effectiveness of oral and inactivated polio vaccines (OPV, IPV) as well as pathogenesis of wild and vaccine polioviruses. It was estimated, based on epidemiology data, that India had a very heavy burden of polio, with average 500 1000 cases per day. Prevention was an urgent need, but OPV showed unacceptably low vaccine efficacy (VE) for poliovirus types 1 and 3. Having learned that response to sequential doses followed arithmetic pattern and not prime-boost principle, multiple doses were tested and found to be a simple intervention to increase VE. Eventually this knowledge became critical for polio eradication. Indian research demonstrated that monovalent OPV (mOPV) had nearly three timed higher VE than trivalent OPV (tOPV). Eventually, mOPV type 1 became essential to interrupt wild type 1 infection in many locations where the VE of tOPV was very low. Indian research pointed to the epidemiologic importance of direct person-to person spread of wild polio viruses and the need and potential of IPV to prevent and control polio. Research on vaccine responses led to the understanding that OPV would become wild-like through back mutations and to the definition of eradication as interrupting transmission of both wild and vaccine-derived polioviruses. By asking and answering the right questions insequence, Indian polio research presaged and guided polio eradication. PMID- 27771639 TI - India's Preparedness for Introduction of IPV and Switch from tOPV to bOPV. AB - Global Polio Eradication and Endgame Strategic Plan 2013-18 calls for the ultimate withdrawal of oral polio vaccines (OPV) from all immunization programs across the world. The phased globally synchronized withdrawal would begin with type 2 serotype in 2016 through a switch from trivalent OPV (tOPV) to bivalent OPV (bOPV) and is associated with small but real risk of Vaccine Derived Polio Virus (VDPV) outbreaks. To mitigate this risk, efforts across the world, including India, are underway that comprise of Inactivated Polio Vaccine (IPV) introduction, containment of type 2 wild and vaccine strains, securing bOPV supplies, and surveillance and response protocols for any outbreaks after switch. Switch implementation in India is particularly challenging as country has one of the largest cold chain system in world with - 27000 cold chain points from where tOPV will be exchanged with bOPV and disposed in short time frame as any use/storage of tOPV beyond switch will jeopardize the global polio eradication. PMID- 27771640 TI - Role of Social Mobilization (Network) in Polio Eradication in India. AB - In 2009, India contributed to over half the global cases of poliomyelitis. Many believed that India would be the last country to be polio free. India proved them wrong and was certified polio free in 2014. In January 2016, India celebrated 5 years of being polio free. One of the major reasons behind the interruption of polio transmission in the Polio endemic states of Uttar Pradesh and Bihar was the deployment of Social Mobilization Network (SMNet). A three tiered structure, the 7300 strong SMNet is now the gold standard in public health communication. It mobilizes communities by spearheading civil society participation; and works at district, block and community levels. The SMNet's social mobilization has evolved into an accelerated approach for achieving results with principles of mobilization at its core. The SMNet targets resistance to polio immunization through a multipronged approach by using local religious leaders, community influencers, interpersonal communication, counseling, mothers meetings, announcements from religious institutions and rallies. The success of the SMNet has been its ability to identify and convert resistant families into advocates for polio immunization. Deeply respected in the community, the SMNet mobilizers (98 percent of whom are women) are themselves models for gender empowerment. The SMNet model shows how mobilization techniques can be harnessed for short term and long term goals and can be replicated in other health programs to achieve the same results as were achieved for Polio. PMID- 27771641 TI - Role of Global Alliance for Vaccines and Immunization (GAVI) in Accelerating Inactivated Polio Vaccine Introduction. AB - Global Alliance for Vaccines and Immunization (GAVI, the Vaccine Alliance) is an international organization built through public-private partnership. GAVI has supported more than 200 vaccine introductions in the last 5 years by financing major proportion of costs of vaccine to 73 low-income countries using a co financing model. GAVI has worked in close co-ordination with Global Polio Eradication Initiative (GPEI) since 2013, to strengthen health systems in countries so as to accelerate introduction of inactivated polio vaccine (IPV). GAVI is involved in many IPV related issues like demand generation, supply, market shaping, communications, country readiness etc. Most of the 73 GAVI eligible countries are also high priority countries for GPEI. GAVI support has helped India to accelerate introduction of IPV in all its states. However, GAVI faces challenges in IPV supply-related issues in the near future. It also needs to play a key role in global polio legacy planning and implementation. PMID- 27771642 TI - Global Polio Eradication,The Journey So Far. AB - The Global Polio Eradication Initiative (GPE I), since its launch in 1988 has achieved more than 99% reduction in polio cases globally, using oral polio vaccine (OPV). Currently only two countries (Pakistan and Afghanistan) have not been able to stop transmission of wild poliovirus (wPV). In this article, we discuss some of the challenges faced by these two countries. The lessons learnt from the tremendous public health success stories of India and Nigeria are also highlighted. Reintroduction of wPV in the polio-free areas remains a valid risk globally and some recent examples are discussed. Inactivated polio vaccine (IPV) is the most accepted risk-mitigation strategy to secure a polio-free world from both wPV and circulating vaccine derived poliomyelitis (VDPV). The challenges related to switch from trivalent to bivalent OPV and introduction of IPV in 156 countries using trivalent OPV, are also highlighted. PMID- 27771643 TI - Rationale of Antibiotic Therapy - Think before you Ink. PMID- 27771644 TI - Spirometry Reference Equations for Indian Children: Create Local or Go Global? PMID- 27771645 TI - Prediction Equations for Spirometry for Children from Northern India. AB - OBJECTIVE: To develop prediction equations for spirometry for children from northern India using current international guidelines for standardization. DESIGN: Re-analysis of cross-sectional data from a single school. PARTICIPANTS: 670 normal children (age 6-17 y; 365 boys) of northern Indian parentage. METHODS: After screening for normal health, we carried out spirometry with recommended quality assurance according to current guidelines. We developed linear and nonlinear prediction equations using multiple regression analysis. We selected the final models on the basis of the highest coefficient of multiple determination (R2) and statistical validity. MAIN OUTCOME MEASURES: Spirometry parameters: FVC, FEV1, PEFR, FEF50, FEF75 and FEF25-75. RESULTS: The equations for the main parameters were as follows: Boys, Ln FVC = -1.687+0.016*height +0.022*age; Ln FEV1 = -1.748+0.015*height+0.031*age. Girls, Ln FVC = -9.989 +(2.018*Ln(height)) + (0.324*Ln(age)); Ln FEV1 = -10.055 +(1.990*Ln(height))+(0.358*Ln(age)). Nonlinear regression yielded substantially greater R2 values compared to linear models except for FEF50 for girls. Height and age were found to be the significant explanatory variables for all parameters on multiple regression with weight making no significant contribution. CONCLUSION: We developed prediction equations for spirometry for children from northern India. Nonlinear equations were superior to linear equations. PMID- 27771646 TI - Improving the Diagnosis of Children with 22q11.2 Deletion Syndrome: A Single center Experience from Serbia. AB - OBJECTIVE: The incidence of the 22q11.2 microdeletion among children who have at least two out of five major clinical criteria for 22q11.2 deletion syndrome. DESIGN: Prospective study. SETTING: University Childrens Hospital in Belgrade, Serbia between 2005 and 2014. PARTICIPANTS: 57 patients with clinical characteristics of 22q11.2 deletion syndrome. METHODS: Standard G-banding cytogenetic analysis was performed in all children, and the 22q11.2 genomic region was examined using fluorescence in situ hybridization (FISH). For patients with no deletion detected by FISH, multiplex ligation-dependent probe amplification (MLPA) analysis was also done in order to detect cryptic deletions of this region and to analyze other genomic loci associated with phenotypes resembling the syndrome. A selected group of patients diagnosed to have 22q11.2 microdeletion by FISH underwent MLPA testing in order to characterize the size and position of deletion. OUTCOME MEASURES: The frequency of 22q11.2 microdeletion among children with at least two of the five major characteristics of 22q11.2 deletion syndrome (heart malformations, facial dysmorphism, T-cell immunodeficiency, palatal clefts and hypocalcemia/hypoparathyroidism). RESULTS: Typical 22q11.2 microdeletion was detected in 42.1% of patients; heart malformation were identified in all of them, facial dysmorphism in 79.2%, immunological problems in 63.6%, hypocalcemia in 62.5% and cleft palate in 8.3%. CONCLUSION: A higher detection rate compared to one-feature criterion is obtained when at least two major features of 22q11.2 deletion syndrome are taking into consideration. The criteria applied in this study could be considered by centers in low-income countries. PMID- 27771647 TI - Cost analysis of Healthcare in a Private sector Neonatal Intensive Care Unit in India. AB - OBJECTIVE: To study the actual cost of care per patient in private-sector level IIIa Neonatal Intensive Care Unit (NICU). METHODS: Prospective cost-analysis study. Cost incurred by the family on the treatment of baby, separately for every newborn for entire length of hospitalization, was calculated. RESULTS: 126 newborns were enrolled; High level of intervention was needed for 25.4% babies. The mean cost of care was US $ 90.7 per patient per day. CONCLUSION: Bulk of the cost of care was the hospital bill. PMID- 27771648 TI - Reporting Statistics in Biomedical Research Literature: The Numbers Say it All. PMID- 27771649 TI - Efficacy of a Mobile based Application on Quality of Care and Perinatal Mortality: Evidence based Medicine Viewpoint. PMID- 27771650 TI - Efficacy of a Mobile-based Application on Quality of Care and Perinatal Mortality: Neonatologists Viewpoint. PMID- 27771651 TI - Efficacy of a Mobile-based Application on Quality of Care and Perinatal Mortality: Public Health Experts Viewpoint. PMID- 27771652 TI - Fanconi Bickel Syndrome with Hypercalciuria due to GLUT 2 Mutation. AB - BACKGROUND: Fanconi Bickel Syndrome is a rare, autosomal recessive, disorder of carbohydrate metabolism. Presence of hypercalciuria is rare. CASE CHARACTERISTICS: 4.5-years-old boy presented with growth failure, hepatomegaly, rickets, fasting hypoglycemia with postprandial hyperglycemia, fanconi syndrome and hypercalciuria. OUTCOME: A rare mutation in GLUT-2 gene suggestive of Fanconi Bickel Syndrome. MESSAGE: Fanconi Bickel Syndrome may present with hypercalciuria with proximal renal tubulopathy along with fasting hypoglycemia and postprandial hyperglycemia. PMID- 27771653 TI - Infantile Achalasia Cardia. AB - BACKGROUND: Achalasia is extremely rare in infants. CASE CHARACTERISTICS: We report three infants of age 9, 7 and 12 months, who presented with recurrent non bilious vomiting, repeated chest infection and severe failure to thrive. Diagnosis of achalasia cardia was confirmed on contrast-swallow study. Hellers cardiomyotomy with fundoplication led to complete symptomatic relief, and weight gain on follow-up. MESSAGE: Achalasia cardia is often misdiagnosed as gastroesophageal reflux disease which leads to significant delay in diagnosis and increased morbidity. PMID- 27771654 TI - Ruptured Hepatocellular Carcinoma in a Child with Budd-Chiari Syndrome. AB - BACKGROUND: Hepatocellular carcinoma is an uncommon complication described in patients with Budd-Chiari syndrome. CASE CHARACTERISTICS: A 12-year-old boy with Budd-Chiari syndrome, who was earlier treated with Transjugular intrahepatic porto-systemic shunt (TIPS), presented with acute onset hemoperitoneum and hypotension. OUTCOME: It was diagnosed to be a case of ruptured hepatocellular carcinoma. MESSAGE: Successful TIPS may not prevent the development of hepatocellular carcinoma, and children with Budd Chiari syndrome should be monitored for the same. PMID- 27771655 TI - Improvement in Neurocognitive Manifestations with Short-term Multidisciplinary Intervention in DiGeorge Syndrome. AB - BACKGROUND: DiGeorge syndrome involves deletion of chromosomal region 22q11.2. CASE CHARACTERISTICS: 3-year-old girl presenting with speech delay showed defiant behaviour and sensory concerns. OUTCOME: Multidisciplinary intervention with parental counselling improved communication and social skills. MESSAGE: Cognitive and behavioral issues in DiGeorge syndrome should be addressed through timely, multidisciplinary intervention. PMID- 27771656 TI - Percutaneously Inserted Central Venous Catheter Tip Position in Preterm Neonates and Complications. PMID- 27771657 TI - Saccharomyces kluyveri Fungemia in an Infant with Severe Combined Immunodeficiency. PMID- 27771658 TI - Long QTc Syndrome and Propionic Acidemia. PMID- 27771659 TI - Serum Phenobarbitone Levels in Neonates with Seizures: Some Clarifications. PMID- 27771660 TI - Neonatal Tetanus: Still a Scourge after Elimination from India. PMID- 27771661 TI - Toilet-training and Constipation. PMID- 27771662 TI - Auricular Blister, A Rare Transfusion Reaction. PMID- 27771663 TI - Leukocytoclastic Vasculitis after Exercise. PMID- 27771664 TI - Necrobiosis Lipoidica. PMID- 27771665 TI - Live Life, Not Just Survive. PMID- 27771666 TI - Moving Beyond a Maternal Perspective to Child Survival. PMID- 27771667 TI - Bacterial Co-infection in Hospitalized Children with Mycoplasma pneumoniae Pneumonia. AB - OBJECTIVE: To describe the frequency and impact of bacterial co-infections in children hospitalized with Mycoplasma pneumoniae pneumonia. DESIGN: Retrospective, descriptive study. SETTING: Tertiary-care hospital in Beijing, China. PARTICIPANTS: 8612 children admitted to Beijing Childrens Hospital from June 2006 to June 2014. METHODS: According to the testing results of etiology we divided the cases into pure M. pneumoniae infection group and mixed bacterial infection group. We analyzed clinical features, hospital expenses and differences between these two groups. RESULTS: 173 (2%) of included children had bacterial coinfection. 56.2% of bacterial pathogens were identified as Streptococcus pneumoniae. CONCLUSION: The most common bacterium causing co-infection in children with M. pneumoniae pneumonia was S. pneumoniae. PMID- 27771668 TI - Injuries in Children With Epilepsy: A Hospital based Study. AB - OBJECTIVE: To study the magnitude and pattern of injuries in children with epilepsy. METHODS: This prospective cohort study enrolled children with epilepsy (CWE) aged 2-16 years on treatment with anti-epileptics for a minimum duration of one-month and compared them with their own siblings (controls). A semi-structured questionnaire was used to enquire about epilepsy and type and frequency of injuries sustained at monthly follow-up visits. Participants were followed up for 12-months for occurrence of injuries. RESULTS: 208 cases and 212 controls were analyzed. 21 cases (10.1%) and 10 controls (4.7%) had sustained injuries (P=0.03) (RR 2.1; 95% CI, 1.0 - 4.4). Seizure-related injuries were present in 4.3% of cases. CONCLUSION: Children with epilepsy are at an increased risk of injuries and hence need supervision. PMID- 27771669 TI - Ultrasonographic Confirmation of Endotracheal Tube Position in Neonates. AB - OBJECTIVE: To compare endotracheal tube tip-to-carina distance obtained by ultrasonography vs. that obtained by chest X-ray in neonates. METHODS: After endotracheal intubation of 40 neonates, chest X-ray and, within one hour, ultrasonography was obtained for each patient for measurement of endotracheal tube tip-to-carina distance. RESULTS: Means of endotracheal tube tip-to-carina distances were not significantly different by both modalities (mean difference 0.157 cm, P= 0.06). In addition, an intraclass correlation was observed between them (r2= 0.61, 95% CI= 0.26, 0.79). CONCLUSION: Ultrasonography and chest X-ray are equally accurate for determination of endotracheal tube tip-to-carina in infants. As ultrasonography is more easily available and is safer than X-ray, it may be a better modality for confirming proper placement of endotracheal tube in neonates. PMID- 27771670 TI - Discussion: The Heart of the Paper. AB - The discussion section explains the meaning of results to the readers, and addresses the implications of the findings emanating from the particular study. Authors should compare their results with previous reports, and attempt to explain similarities and differences. It is useful to outline the limitations and strengths of the study, and suggest a future line of work. A concise, convincing and meticulous discussion with scholarly referencing is the key to a lasting impression. PMID- 27771671 TI - Growth, Nutritional status and Anemia in Indian Adolescents. PMID- 27771672 TI - Tenofovir for Prevention of Mother to Child Transmission of Hepatitis B, Evidence based Medicine Viewpoint. PMID- 27771673 TI - Tenofovir for Prevention of Mother to Child Transmission of Hepatitis B, Obstetricians Viewpoint. PMID- 27771674 TI - Tenofovir for Prevention of Mother to Child Transmission of Hepatitis B,Neonatologists Viewpoint. PMID- 27771675 TI - Hyperinsulinemic Hypoglycemia of Infancy due to Novel HADH Mutation in Two Siblings. AB - BACKGROUND: Hyperinsulinemia is the commonest cause of persistent hypoglycemia in infancy. Inactivating mutations in the genes ABCC8 and KCNJ11 are the commonest cause. Mutation in the HADH gene, which encodes the short-chain-L-3-hydroxyacyl CoA dehydrogenase, is a rare cause. CASE CHARACTERISTICS: Two Indian sisters who presented with hyperinsulinemic hypoglycemia of infancy. OBSERVATION/INTERVENTION: A novel homozygous missense mutation in the HADH gene was identified in both the sisters, while the parents were found to be heterozygous carriers. OUTCOME: Establishment of molecular diagnosis, optimization of therapy and counseling of parents regarding risk of recurrence in future pregnancy. MESSAGE: HADH mutations are rare causes of hypoglycemia and can be mitigated with diazoxide and appropriate dietary therapy if identified early. PMID- 27771676 TI - Ethylmalonic Encephalopathy in an Indian Boy. AB - BACKGROUND: Ethylmalonic encephalopathy is a rare inborn error of metabolism characterized by neurodevelopmental delay / regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. CASE CHARACTERISTICS: 4-year-old boy with developmental regression, chronic diarrhea, petechial spots and acrocyanosis. MRI brain showed T2W/FLAIR hyperintensities in bilateral caudate and putamen. Abnormal acyl-carnitine profile and metabolites on urinary GC-MS analysis suggested the diagnosis. INTERVENTION: Sequencing of ETHE1 gene revealed mutations: c.488G>A and c.375+5G>T (novel). MESSAGE: EE is clinically recognizable disorder with typical clinical features. PMID- 27771677 TI - Cerebrotendinous Xanthomatosis Without Skin Changes: Diagnostic Delay and Confirmation by Genetic Analysis. AB - BACKGROUND: Cerebrotendinous xanthomatosis is an inherited lipid storage disease manifesting with infantile onset diarrhea, cataracts, xanthomas and adult-onset neurological dysfunction with cerebellar signs and neuropathy. CASE CHARACTERISTICS: 10-year-old boy presented with progressive ataxia, neuropathy and cataracts. Over 6 years, he developed dementia, kyphoscoliosis with worsening ataxia, and neuropathy. OUTCOME: Sterol analysis and CYP27A1 sequencing confirmed the diagnosis. MESSAGE: The condition should be considered in childhood onset cerebellar ataxia with cataracts, even in the absence of skin signs. PMID- 27771678 TI - Central or Peripheral Precocious Puberty: Diagnostic Difficulties. AB - BACKGROUND: An underlying identifiable organic cause is present in up to 50% cases of central precocious puberty in male patients. CASE CHARACTERISTICS: A 7 years-8-months-old presented with delayed puberal development. Analytical examinations showed suppressed basal and stimulated levels of testosterone, LH and FSH. Abdominal ultrasound and contrast cranial magnetic resonance results were initially negative. OUTCOME: Germinoma was found on cranial computer tomography. CONCLUSION: There is often a wide time-lapse between symptoms and diagnosis of germinoma, so frequent monitoring is vital. PMID- 27771679 TI - Antibiotic Sensitivity and Clinico- epidemiological Profile of Staphylococcal Infections. AB - This hospital-based study describes the antibiotic sensitivity of 66 S. aureus isolates from the admitted children (age 0-18 y) in a tertiary hospital of Kolkata, India. Methicillin-resistant S. aureus constituted 16.7% (n=11) of the isolates. Clindamycin-resistance was observed in 60% and 82% of methicillin sensitive and methicillin-resistant strains, respectively. PMID- 27771680 TI - Etiology and Short-term Outcome of First Seizure in Hospitalized Infants. AB - We enrolled 75 consecutive infants presenting with history of first seizure at a tertiary care hospital in New Delhi, India. Clinical and biochemical work-up for etiology, and electroencephalography were performed in all infants. Developmental assessment was done 3-month after discharge. 72% had generalized seizures, and fever was the commonest co-morbidity (57.3%). 68% had provoked seizures, mainly due to hypocalcemia (34.3%) or neuro-infections (29.3%). Seven (9.3%) infants died during hospital stay; mostly those with neuro-infections. 13 (20.3%) infants had developmental delay. PMID- 27771681 TI - Ibandronate in the Treatment of Pediatric Osteoporosis. AB - We administered oral ibandronate (once a month) to 7 children (6 boys) with low bone mineral density and prevalent low energy fractures. We observed a significant increase (17%) in bone density after one year and additional 3% increase after second year. No further fractures occurred. PMID- 27771682 TI - Severe Hyponatremia Complicating Urinary Tract Malformation with Pyelonephritis. PMID- 27771683 TI - Masking of the Symptoms of Bilateral Congenital Choanal Atresia by a Coexisting Anomaly of the Upper Lip. PMID- 27771684 TI - Non-operative Management of Spontaneous Splenic Rupture in Hemophilia. PMID- 27771685 TI - Staphylococcus xylosus Meningitis Following Dog bite. PMID- 27771686 TI - Primary Epidural and Paraspinal Rhabdomyosarcoma in a Child. PMID- 27771687 TI - Non-availability of Pediatric Formulations of Antiretroviral Drugs. PMID- 27771688 TI - Bystander Cardio Pulmonary Resuscitation Saves Life in a Patient with Short QT Syndrome. PMID- 27771689 TI - Immune Thrombocytopenia Following Diphtheria Pertussis- Tetanus and Oral Polio Vaccine. PMID- 27771690 TI - Immune Thrombocytopenic Purpura in Typhoid Fever. PMID- 27771691 TI - Aspiration of Rear End of Pen in Children,Management Issues. PMID- 27771692 TI - Staphylococcal Scalded Skin Syndrome. PMID- 27771694 TI - Activation of Tryptophan and Phenylalanine Catabolism in the Remission Phase of Allergic Contact Dermatitis: A Pilot Study. AB - BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory skin disease caused by repeated skin exposure to contact allergens. The severity and duration of this disease are associated with many different factors. Some of these factors may represent markers for monitoring disease activity and the individual response to an intervention. METHODS: We used a targeted metabolomics approach to find such factors in the serum of individuals with ACD. Metabolomics profiles were examined and compared in the acute phase of the disease and also in the absence of disease activity. RESULTS: Our study identified a significant remission phase of ACD-associated systemic biochemical shifts in 2 metabolic pathways: tryptophan kynurenine and phenylalanine-tyrosine. CONCLUSIONS: Although the responsible mechanisms are unclear, these results suggest that the remission phase of ACD is linked to tryptophan metabolism via kynurenine and phenylalanine-tyrosine pathways. However, further replication studies with a larger number of subjects and their subgroups are necessary to validate our results. These studies may provide a new perspective with which to understand the mechanism of and find potential biomarkers of ACD, as well as a new reference for personalized treatment. PMID- 27771693 TI - Kidney Injury Marker 1 and Neutrophil Gelatinase-Associated Lipocalin in Chronic Kidney Disease. AB - The current categorization of chronic kidney disease (CKD) is based on biomarkers of the glomerular function (estimated glomerular filtration rate, eGFR) and injury (urinary albumin creatinine ratio, UACR) and provides information on the risk of death and of progression of kidney disease. However, there are gaps in knowledge regarding the risk stratification of elderly patients with eGFR 45-60 ml/min/1.73 m2 and of younger patients with higher eGFR but physiological albuminuria. In this regard, most of the kidney cell mass is composed of tubules. Recent studies have explored whether biomarkers derived from the acute kidney injury literature, which are mainly tubular injury markers, may improve the information provided by eGFR and UACR. We now review the potential role of kidney injury molecule 1 (KIM-1), hepatitis A virus cellular receptor 1, T-cell immunoglobulin and mucin domain-1 and neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin 2 as biomarkers for kidney or cardiovascular outcomes in CKD patients. In general, neither urinary KIM-1 nor urinary NGAL (uNGAL) outperform or add relevant information to eGFR or UACR. However, promising results were obtained for circulating KIM-1 prediction of renal outcomes in type 1 diabetes. Additionally, uNGAL may have some value in non-proteinuric patients and increased values have been observed in persons at risk for Mesoamerican nephropathy. Further studies are warranted in these niche populations. PMID- 27771695 TI - The Biological Impact of Genomic Diversity in Cervical Cancer Development. AB - Human papillomaviruses (HPVs) are the etiologic agents of cervical cancer, the unique human neoplasia that has one single necessary cause. The diversity of HPVs is well described, with 200 HPV types existing as distinct taxonomic units and each receiving an Arabic number. On a clinical basis, they are usually grouped by their site of occurrence and disease associations. Those types inhabiting the anogenital mucosa are more intensively studied and further divided into cancer associated HPVs, which are termed 'high risk', while those linked to benign proliferative lesions are assigned as 'low risk'. HPV16 is responsible for approximately 50% of all ICC cases, and paradoxically is one of the most prevalent types among healthy women. Longitudinal studies have shown that when an incidental HPV16 infection becomes persistent it will result in an enhanced risk for the development of high-grade lesions. However, it is unknown why some persistent, HPV16 infections (or infections by other HR-HPV types) progress to CIN3+ while most clear spontaneously. Several epidemiological investigations have focused on cofactors, from the most obvious such as cigarette and other carcinogenic exposures, to coinfections by other STDs such as chlamydia, with no significant findings. Thus, the current focus is on genomic variation from both virus and host. Such studies have been potentialized by the enormous technical advances in nucleic acid sequencing, allowing this relationship to be broadly interrogated. Corroborating subgenomic data from decades ago, an association between HPV16 lineages and carcinogenesis is being revealed. However, this effect does not seem to apply across female populations from different continents/ethnicities, again highlighting a role played by HPV16 adaptation and evasion from the host over time. PMID- 27771696 TI - Angelman Syndrome Caused by Chromosomal Rearrangements: A Case Report of 46,XX,+der(13)t(13;15)(q14.1;q12)mat,-15 with an Atypical Phenotype and Review of the Literature. AB - Less than 1% of the cases with Angelman syndrome (AS) are caused by chromosomal rearrangements. This category of AS is not well defined and may manifest atypical phenotypes. Here, we report a girl with AS due to der(13)t(13;15)(q14.1;q12)mat. SNP array detected the precise deletion/duplication points and the parental origin of the 15q deletion. Multicolor FISH confirmed a balanced translocation t(13;15)(q14.1;q12) in her mother. Her facial appearance showed some features of dup(13)(pter->q14). Also, she lacked the most characteristic and unique behavioral symptoms of AS, i.e., frequent laughter, happy demeanor, and easy excitability. A review of the literature indicated that AS cases caused by chromosomal rearrangements can be classified into 2 major categories and 4 groups. The first category is paternal uniparental disomy 15, which is subdivided into isodisomy by de novo rob(15;15) and heterodisomy caused by paternal translocation. The second category is the deletion of the AS locus due to maternal reciprocal translocation, which is subdivided into 2 groups associated with partial monosomy by 3:1 segregation and partial trisomy by adjacent-2 segregation. Classification into these categories facilitates the understanding of the mechanisms of chromosomal rearrangements and helps in accurate diagnosis and genetic counseling of these rare forms of AS. PMID- 27771697 TI - Inhibition by Teriflunomide of Erythrocyte Cell Membrane Scrambling Following Energy Depletion, Oxidative Stress and Ionomycin. AB - BACKGROUND/AIMS: Teriflunomide, an inhibitor of pyrimidine synthesis and thus proliferation of activated T and B lymphocytes, is successfully used for treatment of inflammatory disease. Teriflunomide has further been shown to trigger apoptosis of tumor cells and has thus been considered for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane with translocation of phosphatidylserine to the erythrocyte surface. Triggers of cell membrane scrambling include energy depletion, oxidative stress and increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored whether teriflunomide modifies eryptosis. METHODS: Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, and [Ca2+]i from Fluo3 fluorescence. RESULTS: Oxidative stress (60 min exposure to 0.3 mM tert-butylhydroperoxide), energy depletion (removal of glucose for 48 hours), and exposure to the Ca2+ ionophore ionomycin (1 uM, 60 min) all increased annexin-V-binding, decreased forward scatter and enhanced Fluo3 fluorescence. Teriflunomide (5 ug/ml) did not significantly influence Fluo3 fluorescence, forward scatter and annexin-V-binding under control conditions but significantly blunted the increase of annexin-V binding following oxidative stress, energy depletion and ionomycin exposure. Teriflunomide further blunted the increase of Fluo3 fluorescence following energy depletion, but did not significantly interfere with increase of Fluo3 fluorescence following oxidative stress and ionomycin exposure. CONCLUSION: Teriflunomide is a novel inhibitor of suicidal erythrocyte death. PMID- 27771698 TI - Elder Abuse in Nursing Homes: Do Special Care Units Make a Difference? A Secondary Data Analysis of the Swiss Nursing Homes Human Resources Project. AB - BACKGROUND: In special care units (SCUs) for residents with advanced dementia, both personnel and organizations are adapted to the needs of residents. However, whether these adaptations have a preventive effect on elder abuse has not yet been explored. OBJECTIVE: To describe the prevalence of observed emotional abuse, neglect, and physical abuse in Swiss nursing homes, to compare SCUs with non-SCUs concerning the frequency of observed emotional abuse, neglect, and physical abuse, and to explore how resident-related characteristics, staff outcomes/characteristics, and organizational/environmental factors relate to observed elder abuse. METHODS: This is a secondary data analysis of the Swiss Nursing Homes Human Resources Project (SHURP), a cross-sectional multicenter study. Data were collected from 2012 to 2013 and are based on observed rather than perpetrated elder abuse. We performed multilevel mixed-effects logistic regressions taking into account the hierarchical structure of the data with personnel nested within units and facilities. RESULTS: Of 4,599 care workers in 400 units and 156 facilities, 50.8% observed emotional abuse, 23.7% neglect, and 1.4% physical abuse. There was no significant difference between SCUs and non SCUs regarding observed emotional abuse and neglect. Higher scores for 'workload' and sexual aggression towards care workers were associated with higher rates of emotional abuse and neglect. Verbal and physical resident aggression, however, were only associated with higher rates of emotional abuse. Negative associations were found between 'teamwork and resident safety climate' and both forms of abuse. CONCLUSION: Improving teamwork and the safety climate and reducing work stressors might be promising points of intervention to reduce elder abuse. More specific research about elder abuse in SCUs and the interaction between work climate and elder abuse is required. PMID- 27771700 TI - Early Activation of PINCH/ Glycogen-Synthase Kinase 3beta/ERK Pathway in Obstructive Nephropathy Rat Model. AB - BACKGROUND: Despite a previous study showing that PINCH-1 exerts an important role in regulating TGF-beta1-mediated mesenchymal transition through its interaction with integrin-linked kinase, relatively little is known about the role of PINCH in the obstructive nephropathy. METHODS: To construct a rat model of renal interstitial fibrosis and obstructive nephropathy, unilateral ureteral obstruction (UUO) was used. Hematoxylin and eosin and Masson staining were used in histologic examinations. Quantificational reverse transcription-PCR was used to analyze the mRNA expression level. Western blot and the immunohistochemistry staining were used to detect the protein levels. RESULTS: Histologic examination showed that slight interstitial fibrosis and tubular atrophy existed in the kidney of UUO rats. PINCH, alpha-smooth muscle actin, vascular endothelial growth factor and connective tissue growth factor were markedly induced in the kidney of the UUO rats. However, the expression level of E-cadherin was markedly suppressed in the kidney of the UUO rats. Moreover, both JUN and phosphorylation of JUN proteins were significantly decreased in the kidney of the UUO rats. Conversely, phosphorylation of ERK1/2 and glycogen-synthase kinase 3beta (GSK3beta) were markedly induced in UUO rats compared to that in sham rats. However, ERK1/2 proteins showed no statistically significant difference between UUO and sham groups. CONCLUSIONS: PINCH/GSK3beta/ERK pathway was early molecular responses to obstructed kidney induced by UUO in rat. PMID- 27771699 TI - Cardiac Hepcidin Expression Associates with Injury Independent of Iron. AB - BACKGROUND: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. METHODS: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. RESULTS: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (beta = 0.734, p < 0.001) and connective tissue growth factor (beta = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups. CONCLUSIONS: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure. PMID- 27771701 TI - A Comprehensive Review on Eryptosis. AB - Erythrocytes (RBCs) are extremely sensitive cells, and although they do not have nuclei and mitochondria, are important health indicators. This is particularly true because, during inflammation, whether it is systemic or chronic, the haematological system is constantly exposed to circulating inflammatory mediators. RBCs have a highly specialized and organized membrane structure, which interacts and reacts to inflammatory molecule insults, and undergo programmed cell death, similar to apoptosis, known as eryptosis. Over the past years, eryptosis studies have focussed on determining if membrane changes have occurred, particularly whether a phosphatidylserine (PS) flip, Ca2+ leakage into the cell, changes to ceramide and cell shrinkage have occurred. Mostly, flow cytometry is used, but confocal microscopy and ultrastructural studies also confirm eryptosis. Here, we provide a comprehensive overview of eryptosis, where we revisit the biochemical process of the process, review all literature in PUBMED, that is shown under the search word, "eryptosis", and also discuss current methodologies to determine the presence of eryptosis; included in the discussion of the methodologies, we discuss a pitfalls section for each method. This paper is therefore a comprehensive synopsis of current knowledge of eryptosis and discusses how RBCs may provide an essential in vivo cell model system to study not only inflammation in disease, but also track disease progression and treatment regimes. PMID- 27771703 TI - High Coronary Heart Disease Risk in Hemodialysis Patients with Central Sleep Apnea: A Pilot Study. AB - BACKGROUND: The high prevalence of sleep apnea is reported in hemodialysis patients despite the low prevalence of obesity. The present study compared the occurrence of central sleep apnea (CSA) in hemodialysis patients with that in non hemodialysis patients, and its association with new-onset coronary heart disease (CHD) events. METHODS: Seventy-three hemodialysis and 444 non-hemodialysis patients were examined for CSA and obstructive sleep apnea (OSA) occurrence using polysomnography. Hemodialysis patients were monitored for the occurrence of new onset CHD events. RESULTS: Hemodialysis patients had a significantly higher central apnea-hypopnea index (AHI; 0.7, range 0.2-3.1) than age-, sex- and obstructive AHI-matched non-hemodialysis patients (0.1, range 0-1.0; p < 0.001), in contrast with an insignificant difference for obstructive AHI. Furthermore, the prevalence of CSA was significantly higher in the hemodialysis (21.9%) than in the non-hemodialysis group (9.7%; p = 0.004). A significant and negative association existed between log (central AHI + 1) and Kt/V in hemodialysis patients. In the Kaplan-Meier analysis, hemodialysis patients with CSA had a significantly higher rate of new-onset CHD events than those without CSA. Cox proportional-hazards regression analysis identified CSA prevalence as an independent risk factor for the development of a new-onset CHD event, independent of OSA. CONCLUSIONS: The present study demonstrated that hemodialysis patients had a significantly higher CSA prevalence than non-hemodialysis patients despite similar obstructive AHI, and that hemodialysis patients with CSA had a significantly higher risk for new-onset CHD events than those without CSA independent of obstructive AHI, suggesting CSA as a potential CHD risk specifically in hemodialysis patients. PMID- 27771704 TI - SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition. AB - The serum- and glucocorticoid-regulated kinase (SGK) family consists of three members, SGK1, SGK2 and SGK3, all displaying serine/threonine kinase activity and sharing structural and functional similarities with the AKT family of kinases. SGK1 was originally described as a key enzyme in the hormonal regulation of several ion channels and pumps. Over time, growing and impressive evidence has been accumulated, linking SGK1 to the cell survival, de-differentiation, cell cycle control, regulation of caspases, response to chemical, mechanical and oxidative injury in cancer models as well as to the control of mitotic stability. Much evidence shows that SGK1 is over-expressed in a variety of epithelial tumors. More recently, many contributions to the published literature demonstrate that SGK1 can mediate chemo-and radio-resistance during the treatment of various human tumors, both in vitro and in vivo. SGK1 appears therefore as a dirty player in the stress response to chemical and radio-agents, responsible of a selective advantage that favors the uncontrolled tumor progression and the selection of the most aggressive clones. The purpose of this review is the analysis of the literature describing SGK1 as central node of the cell resistance, and a summary of the possible strategies in the pharmacological targeting of SGK1. PMID- 27771702 TI - Role of the Renal Microcirculation in Progression of Chronic Kidney Injury in Obesity. AB - BACKGROUND: Obesity is largely responsible for the growing incidence and prevalence of diabetes, cardiovascular and renal diseases. Current strategies to prevent and treat obesity and its consequences have been insufficient to reverse the ongoing trends. Lifestyle modification or pharmacological therapies often produce modest weight loss which is not sustained and recurrence of obesity is frequently observed, leading to progression of target organ damage in many obese subjects. Therefore, research efforts have focused not only on the factors that regulate energy balance, but also on understanding mechanisms of target organ injury in obesity. Summary and Key Message: Microvascular (MV) disease plays a pivotal role in progressive kidney injury from different etiologies such as hypertension, diabetes, and atherosclerosis, which are all important consequences of chronic obesity. The MV networks are anatomical units that are closely adapted to specific functions of nutrition and removal of waste in every organ. Damage of the small vessels in several tissues and organs has been reported in obesity and may increase cardio-renal risk. However, the mechanisms by which obesity and its attendant cardiovascular and metabolic consequences interact to cause renal MV injury and chronic kidney disease are still unclear, although substantial progress has been made in recent years. This review addresses potential mechanisms and consequences of obesity-induced renal MV injury as well as current treatments that may provide protection of the renal microcirculation and slow progressive kidney injury in obesity. PMID- 27771706 TI - Magnesium and Kidney Health - More on the 'Forgotten Electrolyte'. PMID- 27771705 TI - Concurrent Hemoperfusion and Hemodialysis in Patients with Acute Pesticide Intoxication. AB - BACKGROUND: Water soluble and insoluble chemicals in the pesticide formulation may be eliminated more effectively in time if hemodialysis (HD) and hemoperfusion (HP) are performed concurrently. AIM: This study is aimed at evaluating the efficacy of concurrent HP and HD in patients with acute pesticide intoxication. METHODS: Between January 2011 and December 2012, we used HP and HD consecutively (HP-HD group, 347 cases), and then during the next 2 years (January 2013 to December 2014), we used concurrent HP and HD (HPD group, 383 cases). We compared the clinical outcomes between the 2 groups. RESULTS: The mortality was higher in the HP-HD group than in the HPD group: (48.1 vs. 20.9%) for the overall mortality and (81.8 vs. 57.9%) for the paraquat (bipyridylium) mortality (p < 0.001). In multiple logistic analyses, age (p = 0.013), ingested volume (p < 0.001), and HP HD (p = 0.014) were significant risk factors for mortality in the paraquat ingested group. CONCLUSION: Concurrent HP and HD would be an effective and safe treatment for patients with acute pesticide intoxication, in particular, paraquat intoxication. PMID- 27771707 TI - Peripheral Immune Cell Counts and Advanced Imaging as Biomarkers of Stroke Outcome. AB - INTRODUCTION: Circulating neutrophil and lymphocyte levels may be modifiable outcome predictors of ischemic stroke. We sought to compare these immune cell parameters with advanced imaging assessment and the 90-day clinical outcome. METHODS: We used a retrospectively collected cohort of consecutive ischemic stroke patients presenting within 4.5 h of symptom onset who had acute CT perfusion and routine blood collection before treatment with intravenous thrombolysis and 24-hour MRI scanning at the John Hunter Hospital. Full blood counts were performed acutely at 24 h and 7 days. Patient outcomes were assed at 90 days after stroke with the modified Rankin Scale (mRS). RESULTS: Overall, 142 patients were assessed during the study period. Patients with a poor outcome (mRS 3-6) had increased neutrophils (44% increase, p = 0.016), decreased lymphocytes (7% decrease, p = 0.491) and an increased lymphocyte-to-neutrophil ratio (196% increase, p < 0.001). Patients with good outcomes (mRS 0-2) did not have significant changes in their full blood counts. There was no relationship between the neutrophil count at 24 h and penumbral volume (r2 = 0.217, p = 0.212), reperfusion (r2 = 0.111, p = 0.085), or core growth (r2 = 0.297, p = 0.107). A backward multivariate analysis containing the 24-hour core volume and 24-hour neutrophil count was strongly related to the 3-month outcome (r2 = 0.477, area under the curve = 0.902, p < 0.001). CONCLUSIONS: Peripheral neutrophils have potential as a biomarker of outcome when used in conjunction with advanced imaging. Peripherally measured neutrophil counts change significantly over time after stroke and may be potential targets for immunomodulatory therapy in patients with a severe stroke or a large infarct volume. PMID- 27771708 TI - Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores. AB - BACKGROUND/AIMS: The purpose of this study was to investigate the implications of protein kinase C-epsilon (PKCepsilon), Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and mitochondrial permeability transition pore (mPTP) in myocardial protection induced by morphine postconditioning (MpostC). METHODS: The isolated rat hearts were randomly assigned into one of eight groups. Hearts in time control (TC) group were constantly perfused for 105min. Hearts in ischemia reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. epsilonV1-2 (an inhibitor of PKCepsilon) and PD (an inhibitor of ERK1/2) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. I/R injury was assessed by functional parameters, creatine kinase-MB (CK-MB) release and infarct size (IS/AAR). Additional hearts were excised at 20 min following reperfusion to detect the membrane-specific translocation of PKCepsilon, ERK1/2 phosphorylation, mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) release. RESULTS: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of epsilonV1-2 or PD. Compared to TC group, the membrane translocation of PKCepsilon, ERK1/2 phosphorylation, mPTP opening, and Cyt-c release were significantly increased in I/R hearts. MpostC further increased the membrane translocation of PKCepsilon and ERK1/2 phosphorylation, and significantly inhibited mPTP opening and Cyt-c release. However, those protective effects induced by MpostC were abolished by epsilonV1-2 or PD, which, used alone, showed no influence on reperfusion injury. CONCLUSIONS: These findings suggest that MpostC protects isolated rat hearts against ischemia reperfusion injury via activating PKCepsilon-ERK1/2 pathway and inhibiting mPTP opening. PMID- 27771710 TI - Bridge Suture for Successful McDonald Emergency Cerclage. AB - OBJECTIVES: To create awareness about a surgical technique termed bridge suture, which is performed as a pretreatment before a McDonald cerclage is performed on an emergency to treat severe cervical insufficiency. METHODS: Procedures for bridge suture were reviewed in detail and outcomes of 16 patients treated with bridge suture followed by McDonald cerclage were evaluated retrospectively. RESULTS: Using the bridge suture, the edges of uterine cervix were temporarily sutured and the external uterine os was closed, while the hourglass-shaped fetal membranes were concomitantly confined within the cervix; subsequently, a McDonald cerclage was performed. Over a 22-year period, 16 patients with a dilated cervix and bulging fetal membranes were treated using the technique of bridge suture followed by an emergency cerclage. The mean gestational age at cerclage was 22.5 weeks; the mean gestational age at delivery was 30.7 weeks; and the mean interval between cerclage and delivery was 8.2 weeks. In 15 out of 16 cases, cerclage was performed without encountering any complications. No maternal complications, including cervical laceration, were observed. The mean body weight of 17 neonates, including that of a twin, was 1,516 g and of them, 15 neonates survived. CONCLUSION: The important outcome of bridge suture is the replacement of fetal membranes back into the uterine cavity before McDonald's cerclage is performed. Pretreatment with bridge suture may facilitate the performance of a successful emergency cerclage and contribute to good maternal and neonatal outcomes. PMID- 27771709 TI - Novel Insights in the Regulation of Phosphatidylserine Exposure in Human Red Blood Cells. AB - BACKGROUND/AIMS: In previous publications we were able to demonstrate the exposure of phosphatidylserine (PS) in the outer membrane leaflet after activation of red blood cells (RBCs) by lysophosphatidic acid (LPA), phorbol-12 myristate-13acetate (PMA), or 4-bromo-A23187 (A23187). It has been concluded that three different mechanisms are responsible for the PS exposure in human RBCs: (i) Ca2+-stimulated scramblase activation (and flippase inhibition) by A23187, LPA, and PMA; (ii) PKCalpha activation by LPA and PMA; and (iii) enhanced lipid flip flop caused by LPA. Further studies aimed to elucidate interconnections between the increased Ca2+ content, scramblase- and PKCalpha-activation. In addition, the role of the Ca2+-activated K+ channel (Gardos channel) activity in the process of PS exposure needs to be investigated. METHODS: The intracellular Ca2+ content and the PS exposure of RBCs have been investigated after treatment with LPA (2.5 uM), PMA (6 uM), or A23187 (2 uM). Fluo-4 and annexin V-FITC has been used to detect intracellular Ca2+ content and PS exposure, respectively. Both parameters (Ca2+ content, PS exposure) were studied using flow cytometry. Inhibitors of the scramblase, the PKCalpha, and the Gardos channel have been applied. RESULTS: The percentage of RBCs showing PS exposure after activation with LPA, PMA, or A23187 is significantly reduced after inhibition of the scramblase using the specific inhibitor R5421 as well as after the inhibition of the PKCalpha using chelerythrine chloride or calphostin C. The inhibitory effect is more pronounced when the scramblase and the PKCalpha are inhibited simultaneously. Additionally, the inhibition of the Gardos channel using charybdotoxin resulted in a significant reduction of the percentage of RBCs showing PS exposure under all conditions measured. Similar results were obtained when the Gardos channel activity was suppressed by increased extracellular K+ content. CONCLUSION: PS exposure is mediated by the Ca2+-dependent scramblase but also by PKCalpha activated by LPA and PMA in a Ca2+-dependent and a Ca2+-independent manner. Furthermore, we hypothesize that a hyperpolarisation of RBCs caused by the opening of the Gardos channel is essential for the scramblase activity as well as for a fraction of the LPA-induced Ca2+ entry. PMID- 27771711 TI - Clinical Therapeutic Effects of Aspirin in Combination with Fufang Danshen Diwan, a Traditional Chinese Medicine Formula, on Coronary Heart Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Coronary heart disease is characterized by vascular stenosis or occlusion resulting in myocardial ischemia, hypoxia and necrosis. In China, the combination of aspirin and Fufang Danshen Diwan (FDD), a traditional Chinese medicine formula, has been suggested in the treatment of coronary heart disease. There have been several studies comparing the effectiveness of aspirin alone and in combination with FDD to treat coronary artery disease; however, it remains unclear whether combined aspirin therapy is superior. This study was thus designed to clarify this issue through a systematic review and meta-analysis. METHODS: Databases including PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) database, Wanfang Data and VIP Information were searched. Papers were reviewed systematically by two researchers and analyzed using Cochrane software Revman 5.1. RESULTS: Fourteen randomized controlled trials enrolling 1367 subjects were included. Meta-analyses revealed that aspirin in combination with FDD was significantly more effective at alleviating angina pectoris and improving electrocardiogram (ECG) results relative to aspirin therapy alone, reflected by the summary effects for the clinical markedly effective (OR = 2.45; 95% CI 1.95-3.08) and the total effective (OR = 3.92; 95% CI 2.87-5.36) rates. In addition, combined aspirin and FDD was significantly more efficacious than aspirin monotherapy at improving blood lipid levels, as indicated by the following outcomes: 1) reduction of TC level (SMD -1.12; 95% CI 1.49 to -0.76); 2) reduction of TG level (SMD -0.94; 95% CI -1.15 to -0.74); 3) reduction of LDL level (SMD -0.68; 95% CI -0.88 to -0.48); and 4) improvement of HDL level (SMD 0.52; 95% CI 0.04 to 0.99 ). No serious adverse events were reported in any of the included trials. CONCLUSION: The present meta-analysis demonstrated that aspirin in combination with FDD was more effective than aspirin alone for treating coronary heart disease. More full-scale randomized clinical trials with reliable designs are recommended to further evaluate the clinical benefits and long-term effectiveness of FDD for the treatment of coronary heart disease. PMID- 27771712 TI - Prognostic Significance of MiRNA in Patients with Diffuse Large B-Cell Lymphoma: a Meta-Analysis. AB - INTRODUCTION: This pooled analysis study aimed to reveal the prognostic relevance of microRNAs (miRNAs) in patients with diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: We examined the impact of miRNAs on clinical outcome. Eligible studies were identified and quality assessed using multiple search strategies. Data were extracted from included studies which correlated survival with expression of miRNAs (serum or tissue). RESULTS: We pooled proper studies, and combined the hazard ratios with 95% confidence intervals to estimate strength of the correlations. There were 18 studies including 1950 patients with DLBCL eligible for pooled analysis. We found significant combined HRs for poor overall survival for high expression of miR-21 and low expression of miR-224 in tumor tissue, but for favorable relapse free survival for high expression of miR-21 in serum. Progression free survival was shortened in patients with low expression of miR-199a/b, miR-146b-5p, miR-224 and high expression of miR-222. CONCLUSION: MiRNAs may act as independent prognostic factors in patients with DLBCL, and useful in risk stratification. PMID- 27771713 TI - Frailty in Chinese Peritoneal Dialysis Patients: Prevalence and Prognostic Significance. AB - BACKGROUND/AIMS: Previous studies showed that frailty is prevalent in both pre dialysis and dialysis patients. However, the prevalence and prognostic implication of frailty in Chinese peritoneal dialysis (PD) patients remain unknown. METHODS: We used a validated questionnaire to determine the Frailty Score of 193 unselected prevalent PD patients. All patients were then followed for 2 years for their need of hospitalization and mortality. RESULTS: Amongst the 193 patients, 134 (69.4%) met the criteria of being frail. Frailty Score significantly correlated with Charlson's comorbidity score (r = 0.40, p < 0.0001), Malnutrition Inflammation Score (r = 0.59, p < 0.0001), and inversely with Subjective Global Assessment score (r = -0.44, p < 0.0001). Frailty was closely associated with the need of hospitalization. Patients with nil, mild, moderate, and severe frailty required 2.4 +/- 6.0, 1.6 +/- 1.6, 2.7 +/- 2.5, 5.2 +/- 4.8 hospital admissions per year, respectively (p < 0.0001), and they stayed in hospital for 6.4 +/- 9.2, 5.3 +/- 6.2, 10.0 +/- 10.4, 12.9 +/- 20.1 days per hospital admission, respectively (p < 0.0001). However, Frailty Score was not an independent predictor of patient or technique survival. CONCLUSIONS: Frailty is prevalent among Chinese PD patients. Frail PD patients have a high risk of requiring hospitalization and their hospital stay tends to be prolonged. Early identification may allow timely intervention to prevent adverse health outcomes in this group of patients. PMID- 27771714 TI - Wnt/beta-Catenin Signaling Exacerbates Keloid Cell Proliferation by Regulating Telomerase. AB - OBJECTIVES: Our goal was to investigate the relationship between keloid and telomerase as well as clarifying the influence of Wnt/beta-catenin signaling on keloid cell proliferation. METHODS: Tissues from 18 keloid patients were collected for further study. Keloid progenitor cells (KPC) and skin progenitor cells (SKP) were both included in this study. Lenti-virus transfection was used to divide cells into different groups in which cells were treated with different substances: negative control (NC) group, wnt10a siRNA group, beta-catenin siRNA group and TERT siRNA group. KPC cells were injected into 20 male BALB/c nude mice in order to build tumor models. Several experiments including immunohistochemistry, western blot and RT-PCR were conducted in order to detect the corresponding protein expressions and relative mRNA levels. MTT assay and flow cytometry were also conducted for assessing cell proliferation and apoptosis status. RESULTS: beta-catenin and telomerase expression levels in keloid tissues were elevated compared to normal tissues (all P < 0.05). KPC cells in keloid exhibited more dynamic telomerase activity than SKP cells (P < 0.05). Luciferase activity assay confirmed that beta-catenin could directly interact with telomerase. After wnt10a/beta-catenin signaling pathway was inhibited, the proliferation of KPC cells was significantly suppressed and the apoptosis rate was remarkably increased (all P < 0.05). Results from tumor models also validated that wnt10a/beta-catenin signaling pathway influenced the activity and length of telomerase. CONCLUSIONS: Wnt/beta-catenin signaling pathway is able to exacerbate keloid cell proliferation and inhibit the apoptosis of keloid cells through its interaction with telomerase. PMID- 27771715 TI - ER Stress via CHOP Pathway is Involved in FK506-Induced Apoptosis in Rat Fibroblasts. AB - BACKGROUND/AIMS: Hypertrophic scars (HS) formation results from reduced apoptosis and increased proliferation of fibroblasts. Therefore, apoptosis of fibroblasts is a key target for the development of novel therapeutic strategies for HS. Previous reports demonstrated that FK506 could attenuate scar formation in vivo and FK506 could also induce endoplasmic reticulum stress (ER stress). However, the effects of FK506 on ER stress-mediated apoptosis in fibroblasts remain unclear. METHODS: Rat skin fibroblasts were used in the study. Cell viability was examined using cell counting Kit-8. Apoptosis was detected by Annexin V/Propidium Iodide Double Staining. Gene silencing was performed using Small Interfering RNAs (siRNAs) or via lentiviral infection. The expression of apoptosis-related proteins was determined via Western blot. Interaction between proteins was explored by co-immunoprecipitation. RESULTS: FK506 significantly reduced cell viability and induced apoptosis in fibroblasts. Interestingly, ER stress was also activated after FK506 treatment. We further demonstrated that FK506-induced apoptosis was mediated by ER stress via activating CHOP, evidenced by decreased apoptosis after inhibition of ER stress using TUDCA or silencing expression of CHOP. Furthermore, Co-immunoprecipitation results indicated that treatment of FK506 induced disassociation of FKBP12.6 from RyR2 and its translocation from ER membrane to cytosol, consequently promoting ER stress-mediated apoptosis. CONCLUSION: FK506-induced fibroblasts apoptosis was mediated by ER stress via CHOP signaling pathway. PMID- 27771716 TI - A Novel Natural Product-Derived Compound, Vestaine A1, Exerts both Pro-Angiogenic and Anti-Permeability Activity via a Different Pathway from VEGF. AB - BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is a key molecule in the regulation of both angiogenesis and vascular permeability. However, it is known that overproduction of VEGF induces abnormal blood vessel formation and these vessels cause several disease pathologies, such as diabetic retinopathy. The purpose of this study was to find novel vasoactive compounds which have different properties from VEGF. METHODS/RESULTS: We screened a natural product library using a co-culture angiogenic assay of endothelial cells and fibroblasts. By focusing on morphological changes of endothelial cells, we isolated the novel compounds vestaine A1 and vestaine B1 from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 63697. Vestaine A1 enhanced tube formation of endothelial cells in Matrigel and suppressed cell death induced by serum deprivation. Vestaine A1 activated both MEK1/2 and PI-3 kinase pathways independently of the VEGF pathway in a dose- and time-dependent fashion. Finally, vestaine A1 potently suppressed VEGF-induced vascular permeability both in vitro and in vivo. CONCLUSION: Vestaine A1 has the potential to exhibit both pro angiogenic and anti-permeability properties, and would therefore be useful for therapeutic treatment for abnormal vascular permeability-related diseases. PMID- 27771717 TI - CO2 and HCO3- Permeability of the Rat Liver Mitochondrial Membrane. AB - BACKGROUND/AIMS: Across the mitochondrial membrane an exceptionally intense exchange of O2 and CO2 occurs. We have asked, 1) whether the CO2 permeability, PM,CO2, of this membrane is also exceptionally high, and 2) whether the mitochondrial membrane is sufficiently permeable to HCO3- to make passage of this ion an alternative pathway for exit of metabolically produced CO2. METHODS: The two permeabilities were measured using the previously published mass spectrometric 18O exchange technique to study suspensions of mitochondria freshly isolated from rat livers. The mitochondria were functionally and morphologically in excellent condition. RESULTS: The intramitochondrial CA activity was exclusively localized in the matrix. PM,CO2 of the inner mitochondrial membrane was 0.33 (SD +/- 0.03) cm/s, which is the highest value reported for any biological membrane, even two times higher than PM,CO2 of the red cell membrane. PM,HCO3- was 2. 10-6 (SD +/- 2. 10-6) cm/s and thus extremely low, almost 3 orders of magnitude lower than PM,HCO3- of the red cell membrane. CONCLUSION: The inner mitochondrial membrane is almost impermeable to HCO3- but extremely permeable to CO2. Since gas channels are absent, this membrane constitutes a unique example of a membrane of very high gas permeability due to its extremely low content of cholesterol. PMID- 27771718 TI - Sodium Butyrate Upregulates miR-203 Expression to Exert Anti-Proliferation Effect on Colorectal Cancer Cells. AB - BACKGROUND: As the end product of the bacterial fermentation of dietary fiber in the colonic lumen, sodium butyrate (NaBt) has been reported to exert antitumor effects on colorectal cancer (CRC). In addition to functioning as a histone deacetylase (HDAC) inhibitor, NaBt also regulates the expression of microRNAs (miRNAs) to inhibit CRC cell proliferation. Yet, the mechanisms involved are not completely understood. Here we investigate whether NaBt regulates miR-203 to inhibit CRC growth and explore the promising target gene of miR-203 in CRC cells. METHODS: We conducted qRT-PCR and Western blotting assays to evaluate the effects of NaBt on the expression of miR-203 and NEDD9 in HT-29 and Caco-2 cell lines. The promising target gene of miR-203 was predicted by miRNA target prediction and dual luciferase reporter assay. CRC Cell proliferation, colony formation, cell apoptosis and cell invasion assays were performed to explore the effect of NaBt, miR-203 and NEDD9 on HT-29 and Caco-2 cell lines. RESULTS: The results showed that NaBt increased the expression of miR-203 to induce CRC cell apoptosis as well as inhibit cell proliferation, colony formation and cell invasion. Moreover, we determined that the NEDD9 was a target gene of miR-203. NEDD9 partially overcame the inhibitory effects of miR-203 on CRC cell colony formation and invasion. CONCLUSIONS: NaBt could induce CRC cell apoptosis, inhibit CRC cell proliferation, colony formation and invasion through miR-203/NEDD9 cascade. The present study may enrich the mechanisms underlying the process that NaBt exerts anti-tumor effects on CRC cells. PMID- 27771719 TI - Toll-Like Receptor 3 Contributes to Wallerian Degeneration after Peripheral Nerve Injury. AB - OBJECTIVE: It is well known that Schwann cells play an important role in Wallerian degeneration after peripheral nerve injury. Previously, we reported that toll-like receptor 3 (TLR3) is expressed on Schwann cells, implicating its role in Schwann cell activation during Wallerian degeneration. In this study, we tested this possibility using TLR3 knock-out mice. METHODS: Sciatic nerve-crush injury was induced in wild-type and TLR3 knock-out mice. Histological sections of the sciatic nerve were analyzed for Wallerian degeneration on days 3 and 7 after injury. The level of macrophage infiltration was measured by real-time RT-PCR, flow cytometry and immunohistochemistry. The macrophage-recruiting chemokine gene expressions in the injured nerve were determined by real-time RT-PCR. RESULTS: In TLR3 knock-out mice, the nerve injury-induced axonal degeneration and subsequent axonal debris clearance were reduced compared to in wild-type mice. In addition, nerve injury-induced macrophage infiltration into injury sites was attenuated in TLR3 knock-out mice and was accompanied by reduced expression of macrophage recruiting chemokines such as CC-chemokine ligands (CCL)2/MCP-1, CCL4/MIP-1beta and CCL5/RANTES. These macrophage-recruiting chemokines were induced in primary Schwann cells upon TLR3 stimulation. Finally, intraneural injection of polyinosinic-polycytidylic acid, a synthetic TLR3 agonist, induced macrophage infiltration into the sciatic nerve in vivo. CONCLUSION: These data show that TLR3 signaling contributes to Wallerian degeneration after peripheral nerve injury by affecting Schwann cell activation and macrophage recruitment to injured nerves. PMID- 27771721 TI - Leptin Regulates Tau Phosphorylation through Wnt Signaling Pathway in PC12 Cells. AB - BACKGROUND/AIMS: Leptin, an adipocytokine produced endogenously in the brain, is decreased in Alzheimer's disease(AD) and has also been shown to reduce Abeta levels in vitro and in vivo. Sets of evidence show that leptin reduces Abeta production and tau phosphorylation in neuronal cells and transgenic mice models of AD. Herein, we investigated the signaling pathway activated by leptin, to better understand its mechanism of action. METHODS: Western blotting was performed to assess the levels of phosphor-tau and Bax, RT-PCR to check the mRNA level of Bax. RESULTS: Leptin treatment significantly blunted Abeta-evoked tau phosphorylation and Bax levels, effects of which could be reversed by antagonist of Wnt signaling. CONCLUSION: The data indicate that Leptin may provide a novel therapeutic approach to AD treatment via wnt signaling. PMID- 27771720 TI - Dietary Magnesium and Kidney Function Decline: The Healthy Aging in Neighborhoods of Diversity across the Life Span Study. AB - BACKGROUND: Prior studies suggest that certain aspects of the diet related to magnesium intake, such as dietary acid load, protein intake and dietary patterns rich in fruits and vegetables, may impact kidney disease risk. We hypothesized that lower dietary magnesium intake would be prospectively associated with more rapid kidney function decline. METHODS: Among participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study with estimated glomerular filtration rate (eGFR) >=60 ml/min/1.73 m2 at baseline (2004-2009), dietary magnesium intake was calculated from two 24-hour dietary recalls. Rapid decline was defined as >=3% eGFR decline per year. RESULTS: Median (25th-75th percentile) dietary magnesium intake was 116 (96-356) mg/1,000 kcal. Among 1,252 participants, those with lower dietary magnesium intake were younger, and were more likely to be African-American men. A total of 177 participants (14.1%) experienced rapid eGFR decline over a median follow-up of 5 years. Lower dietary magnesium intake was significantly associated with a greater odds of rapid eGFR decline (OR for tertile 1 vs. 3: 2.02, 95% CI 1.05-3.86, p value for trend across tertiles = 0.02) in analyses adjusted for sociodemographics (age, sex, race, education level, health insurance status, poverty status), kidney disease risk factors (smoking status, diabetes, hemoglobin A1c, hypertension, body mass index), baseline eGFR and dietary factors (total energy intake; diet quality; dietary intake of fiber, sodium, calcium, potassium and phosphorus). CONCLUSIONS: In this urban population, lower dietary magnesium intake was independently associated with greater odds of rapid kidney function decline. PMID- 27771723 TI - Cortical Responses and Shape Complexity of Stereoscopic Image - A Simultaneous EEG/MEG Study. AB - BACKGROUND/AIMS: In exploring human factors, stereoscopic 3D images have been used to investigate the neural responses associated with excessive depth, texture complexity, and other factors. However, the cortical oscillation associated with the complexity of stereoscopic images has been studied rarely. Here, we demonstrated that the oscillatory responses to three differently shaped 3D images (circle, star, and bat) increase as the complexity of the image increases. METHODS: We recorded simultaneous EEG/MEG for three different stimuli. Spatio temporal and spatio-spectro-temporal features were investigated by non-parametric permutation test. RESULTS: The results showed that N300 and alpha inhibition increased in the ventral area as the shape complexity of the stereoscopic image increased. CONCLUSION: It seems that the relative disparity in complex stereoscopic images may increase cognitive processing (N300) and cortical load (alpha inhibition) in the ventral area. PMID- 27771722 TI - Inhibitory Effects of Antidepressants on Acetylcholine-Induced Contractions in Isolated Guinea Pig Urinary Bladder Smooth Muscle. AB - BACKGROUND/AIMS: To investigate the potential inhibitory effects of 18 clinically available antidepressants on acetylcholine (ACh)-induced contractions in guinea pig urinary bladder smooth muscle (UBSM) in order to predict whether they may induce voiding impairment. METHODS: Concentration-response curves for ACh-induced contractions in guinea pig UBSM strips were obtained in the absence or presence of selected antidepressants. When inhibitory effects indicated competitive antagonism, pA2 values against ACh were calculated and compared to plausible antidepressant blood concentrations. RESULTS: ACh-induced contraction was antagonized competitively within clinical dose ranges by tricyclic antidepressants (imipramine, amitriptyline, trimipramine, clomipramine, nortriptyline, and amoxapine), maprotiline (a tetracyclic antidepressant), and mirtazapine (a noradrenergic and specific serotonergic antidepressant). ACh induced contraction was also significantly inhibited by mianserin (a tetracyclic antidepressant), paroxetine and sertraline (serotonin-selective reuptake inhibitors, SSRIs), and duloxetine (a serotonin noradrenaline (norepinephrine) reuptake inhibitor, SNRI), albeit at concentrations that substantially exceeded clinically achievable blood levels. However, ACh-induced contractions were not significantly affected by fluvoxamine and escitalopram (SSRIs), milnacipran (an SNRI), trazodone (a serotonin 5-HT2A receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), or aripiprazole (a dopamine partial agonist). CONCLUSION: These findings suggest that in addition to tricyclics, some relatively novel antidepressants such as mirtazapine can induce voiding impairment, attributed to diminished UBSM contractility from the inhibition of muscarinic receptors in the UBSM. PMID- 27771725 TI - Erratum. PMID- 27771724 TI - Association between Recreational Physical Activity and the Risk of Upper Urinary Calculi. AB - OBJECTIVE: Upper urinary calculi (UUC) is considered to be a comprehensive disease associated with many risk factors, but the role of physical activity (PA) is undefined. Here, we conducted a cross-sectional study to investigate this relationship in Asian populations. MATERIALS AND METHODS: Patients diagnosed with UUC were the subjects of study and those who participated in a health examination in local medical center were included as controls. Information was collected through the same standard questionnaire. A metabolic equivalent score (METs) was measured for each kind of activity. OR of UUC in categories of PA were determined by logistic regression. RESULTS: A total of 1,782 controls and 1,517 cases were enrolled. People who took higher PA (5-9.9, 10-19.9, 20-29.9 and >30 METs/wk) weekly were associated with lower risks of UUC than those took lower PA (<4.9 METs/wk) after adjusting for age, ethnicity, body mass index, systolic blood pressure, water intake, history of gout, history of diabetes mellitus, history of supplemental calcium use and history of hypertension (adjusted OR 0.11, 0.32, 0.24, 0.34; 95% CI 0.08-0.15, 0.23-0.43, 0.15-0.40, 0.22-0.53, respectively; p value <0.001). CONCLUSIONS: In our cross-sectional study, PA was associated with UUC. PMID- 27771727 TI - Thioester-Containing Protein-4 Regulates the Drosophila Immune Signaling and Function against the Pathogen Photorhabdus. AB - Despite important progress in identifying the molecules that participate in the immune response of Drosophila melanogaster to microbial infections, the involvement of thioester-containing proteins (TEPs) in the antibacterial immunity of the fly is not fully clarified. Previous studies mostly focused on identifying the function of TEP2, TEP3 and TEP6 molecules in the D. melanogaster immune system. Here, we investigated the role of TEP4 in the regulation and function of D. melanogaster host defense against 2 virulent pathogens from the genus Photorhabdus, i.e. the insect pathogenic bacterium Photorhabdus luminescens and the emerging human pathogen P. asymbiotica. We demonstrate that Tep4 is strongly upregulated in adult flies following the injection of Photorhabdus bacteria. We also show that Tep4 loss-of-function mutants are resistant to P. luminescens but not to P. asymbiotica infection. In addition, we find that inactivation of Tep4 results in the upregulation of the Toll and Imd immune pathways, and the downregulation of the Jak/Stat and Jnk pathways upon Photorhabdus infection. We document that loss of Tep4 promotes melanization and phenoloxidase activity in the mutant flies infected with Photorhabdus. Together, these findings generate novel insights into the immune role of TEP4 as a regulator and effector of the D. melanogaster antibacterial immune response. PMID- 27771728 TI - Chronobiology of Aging: A Mini-Review. AB - Aging is generally associated with weakening of the circadian system. The circadian amplitude is reduced and the circadian acrophase becomes more labile, tending to occur earlier with advancing age. As originally noted by Franz Halberg, similar features are observed in the experimental laboratory after bilateral lesioning of the suprachiasmatic nuclei, suggesting the involvement of clock genes in the aging process as they are in various disease conditions. Recent work has been shedding light on underlying pathways involved in the aging process, with the promise of interventions to extend healthy life spans. Caloric restriction, which is consistently and reproducibly associated with prolonging life in different animal models, is associated with an increased circadian amplitude. These results indicate the critical importance of chronobiology in dealing with problems of aging, from the circadian clock machinery orchestrating metabolism to the development of geroprotectors. The quantitative estimation of circadian rhythm characteristics interpreted in the light of time-specified reference values helps (1) to distinguish effects of natural healthy aging from those associated with disease and predisease; (2) to detect alterations in rhythm characteristics as markers of increased risk before there is overt disease; and (3) to individually optimize by timing prophylactic and/or therapeutic interventions aimed at restoring a disturbed circadian system and/or enhancing a healthy life span. Mapping changes in amplitude and/or acrophase that may overshadow any change in average value also avoids drawing spurious conclusions resulting from data collected at a fixed clock hour. Timely risk detection combined with treatment optimization by timing (chronotherapy) is the goal of several ongoing comprehensive community-based studies focusing on the well-being of the elderly, so that longevity is not achieved at the cost of a reduced quality of life. PMID- 27771726 TI - Gram-Negative Pneumonia Alters Large-Vein Cell-Adhesion Molecule Profile and Potentiates Experimental Stasis Venous Thrombosis. AB - BACKGROUND/AIMS: Pneumonia is a significant risk factor for the development of venous thrombosis (VT). Cell-adhesion molecules (CAMs) are linked to the pathogenesis of both pneumonia and VT. We hypothesized that remote infection would confer a prothrombogenic milieu via systemic elevation of CAMs. METHODS: Lung injury was induced in wild-type (C57BL/6) mice by lung contusion or intratracheal inoculation with Klebsiella pneumoniae or saline controls. K. pneumoniae-treated mice and controls additionally underwent inferior vena cava (IVC) ligation to generate VT. RESULTS: Lung-contusion mice demonstrated no increase in E-selectin or P-selectin whereas mice infected with K. pneumoniae demonstrated increased circulating P-selectin, ICAM-1, VCAM-1 and thrombin antithrombin (TAT) complexes. Mice with pneumonia formed VT 3 times larger than controls, demonstrated significantly more upregulation of vein-wall and systemic CAMs, and formed erythrocyte-rich thrombi. CONCLUSION: Elevated CAM expression was identified in mice with pneumonia, but not lung contusion, indicating that the type of inflammatory stimulus and the presence of infection drive the vein wall response. Elevation of CAMs was associated with amplified VT and may represent an alternate mechanism by which to target the prevention of VT. PMID- 27771729 TI - Preoperative 18F-Fluorodeoxyglucose Positron Emission Tomography/CT in Prediction of Uterine Risk Factors and Lymph Node Metastasis: An Analysis of 111 Endometrioid Endometrial Cancer Patients. AB - INTRODUCTION: This study evaluated the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT) in the detection of lymph node metastases and the association between uterine maximum standardized uptake values (SUVmax) and the histopathological features in endometrial cancer patients. MATERIALS AND METHODS: Patients with endometrioid endometrial cancer underwent preoperative 18F-FDG PET/CT imaging and were staged surgically. 18F-FDG PET/CT findings were compared with final pathology reports. Grade 3 histology or grade 2 histology with myometrial invasion >=50% was established as a high risk feature. RESULTS: One hundred and eleven patients were analysed. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 18F-FDG PET/CT in the detection of lymph node metastasis in all patients (n = 111) were 67, 96, 93, 60 and 97%, respectively. In the high-risk group, sensitivity, specificity, accuracy, PPV and NPV of 18F-FDG PET/CT were 75, 92, 91, 60 and 96%, respectively. Uterine SUVmax was found to be associated with myometrial invasion, grade and cervical stromal involvement. CONCLUSIONS: 18F-FDG PET/CT has limited sensitivity and accuracy in detecting lymph node metastasis. Therefore, as of now, it is not accepted as a modality that can replace lymphadenectomy. SUVmax values can predict high-risk factors. PMID- 27771730 TI - Spatiotemporal Development of the Orexinergic (Hypocretinergic) System in the Central Nervous System of Xenopus laevis. AB - The present immunohistochemical study represents a detailed spatiotemporal analysis of the localization of orexin-immunoreactive (OX-ir) cells and fibers throughout development in the brain of the anuran amphibian Xenopus laevis, a model frequently used in developmental studies. Anurans undergo remarkable physiological changes during the early life stages, and very little is known about the ontogeny and the localization of the centers that control functions such as appetite and feed ingestion in the developing brain. We examined the onset of the orexinergic system, demonstrated to be involved in appetite regulation, using antibodies against mammalian orexin-A and orexin-B peptides. Simultaneous detection of orexins with other territorial markers was used to assess the precise location of the orexinergic cells in the hypothalamus, analyzed within a segmental paradigm. Double staining of orexins and tyrosine hydroxylase served to evaluate possible interactions with the catecholaminergic systems. At early embryonic stages, the first OX-ir cells were detected in the hypothalamus and, soon after, long descending projections were observed through the brainstem to the spinal cord. As brain development proceeded, the double staining techniques demonstrated that this OX-ir cell group was located in the suprachiasmatic nucleus within the alar hypothalamus. Throughout larval development, the number of OX-ir cells increased notably and a widespread fiber network that innervated the main areas of the forebrain and brainstem was progressively formed, including innervation in the posterior tubercle and mesencephalon, the locus coeruleus, and the nucleus of the solitary tract where catecholaminergic cells are present. In addition, orexinergic cells were detected in the preoptic area and the tuberal hypothalamus only at late prometamorphic stages. The final distribution pattern, largely similar to that of the adult, was achieved through metamorphic climax. The early expression of orexins in Xenopus suggests important roles in brain development in the embryonic period before feeding, and the progression of the temporal and spatial complexity of the orexinergic system might be correlated to the maturation of appetite control regulation, among other functions. PMID- 27771731 TI - Extra-articular rheumatoid arthritis imaged by [18F]FDG-PET/CT. PMID- 27771732 TI - Class III beta-Tubulin in Colorectal Cancer: Tissue Distribution and Clinical Analysis of Chinese Patients. AB - BACKGROUND Class III beta-tubulin (betaIII-tubulin) has been reported to express at the invasive margin of colorectal cancer. The present study aimed to investigate the clinical implication of betaIII-tubulin expression at the invasive margin of colorectal cancer. MATERIAL AND METHODS We recruited 111 patients with surgically resected colorectal carcinoma for bIII-tubulin expression analysis. The cases with bIII-tubulin-positive tumor cells found only in the invasive front tumor area were assigned to the invasive front group, while the remaining cases were all assigned to the non-invasive front group. Clinical analysis of betaIII-tubulin and other clinical data was performed. RESULTS The positive staining rates and staining intensity of bIII-tubulin were significantly different between the invasive and non-invasive front groups (p=0.001 and p=0.006), and there was a significant difference in tumor differentiation between the 2 groups (p=0.032). In the non-invasive front group, staining intensity of bIII-tubulin was significantly associated with positive staining rates and lymphatic metastasis (p<0.001 and p=0.048). CONCLUSIONS Our data showed the tissue distribution of bIII-tubulin expression at invasive margin or diffuse distribution. Expression of bIII-tubulin was correlated with tumor differentiation and lymphatic metastasis, suggesting a potential role of bIII tubulin in tumor differentiation and metastasis. This study may shed light on bIII-tubulin as a novel potential molecular target for a new anti-cancer drug. PMID- 27771734 TI - Clinicopathological and Prognostic Factors in 106 Prostate Cancer Patients Aged <=55 Years: A Single-Center Study in China. AB - BACKGROUND Early-onset prostate cancer patients (aged <=55 years) from Western countries have been well characterized in previous studies. However, the clinicopathological and prognostic characteristics of early-onset Chinese prostate cancer patients have not yet been assessed. This study aimed to examine the clinicopathological and prognostic factors of prostate cancer patients aged <=55 years in a single Chinese center. MATERIAL AND METHODS One hundred six prostate cancer patients aged <=55 years with complete clinicopathological data who were treated at our hospital between January 2000 and June 2014 were selected for this study. Survival rate was investigated by Kaplan-Meier analysis, and prognostic factors were examined by univariate and multivariate analysis. RESULTS The median time from the onset of symptoms to diagnosis was 3.5 months (range, 2 55 months). The median time after endocrine therapy to development of androgen independent prostate cancer was 10.5 months. A total of 54 patients died (50.9%), of whom 96.2% died from prostate cancer. The 1-, 3-, and 5-year overall survival rates were 88.7%, 66.2%, and 36.0%, respectively. Univariate and multivariate analysis showed that T staging, visceral metastasis, pathological pattern, and Gleason sum were independent prognostic factors in these patients. CONCLUSIONS Prostate cancer patients aged <=55 years are often omitted or misdiagnosed in China. Furthermore, the pathology patterns in this age group were mostly complicated with a high degree of malignancy. Late staging, visceral metastasis, pathological pattern, and high Gleason score were independent prognostic factors in these patients. Comprehensive therapy combined with local therapy is an effective treatment strategy. PMID- 27771733 TI - MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial Mesenchymal Transition (EMT) by Targeting Connective Tissue Growth Factor (CTGF) in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND This study investigated the mechanism of miR-145 in targeting connective tissue growth factor (CTGF), which affects the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells. MATERIAL AND METHODS A total of 50 ESCC tissues and their corresponding normal adjacent esophageal tissue samples were collected. Then, miR-145 expression in both ESCC clinical specimens and cell lines was detected using quantitative real time PCR. CTGF protein was detected using immunohistochemistry. Dual luciferase reporter gene assay was employed to assess the effect of miR-145 on the 3'UTR luciferase activity of CTGF. Eca109 cells were transfected with miR-145 mimics and CTGF siRNA, respectively, and changes in cellular proliferation, migration, and invasion were detected via MTT assay, wound-healing assay, and Transwell assay, respectively. Western blotting assay was used to detect the expression of marker genes related to EMT. RESULTS MiR-145 was significantly down-regulated in ESCC tissues and cell lines compared with normal tissues and cell lines (P<0.05). We found significantly more positively expressed CTGF protein in ESCC tissues was than in normal adjacent esophageal tissues (P<0.01). Dual luciferase reporter gene assay showed that miR-145 can specifically bind with the 3'UTR of CTGF and significantly inhibit the luciferase activity by 55% (P<0.01). Up-regulation of miR-145 or down-regulation of CTGF can suppress the proliferation, migration, invasion, and EMT process of ESCC cells. CONCLUSIONS MiR-145 was significantly down-regulated in ESCC tissues and cell lines, while the protein expression of CTGF exhibited the opposite trend. MiR-145 inhibited the proliferation, migration, invasiveness, and the EMT process of ESCC cells through targeted regulation of CTGF expression. PMID- 27771735 TI - The orthologs of HLA-DQ and -DP genes display abundant levels of variability in macaque species. AB - The human major histocompatibility complex (MHC) region encodes three types of class II molecules designated HLA-DR, -DQ, and -DP. Both the HLA-DQ and -DP gene region comprise a duplicated tandem of A and B genes, whereas in macaques, only one set of genes is present per region. A substantial sequencing project on the DQ and DP genes in various macaque populations resulted in the detection of previously 304 unreported full-length alleles. Phylogenetic studies showed that humans and macaques share trans-species lineages for the DQA1 and DQB1 genes, whereas the DPA1 and DPB1 lineages in macaques appear to be species-specific. Amino acid variability plot analyses revealed that each of the four genes displays more allelic variation in macaques than is encountered in humans. Moreover, the numbers of different amino acids at certain positions in the encoded proteins are higher than in humans. This phenomenon is remarkably prominent at the contact positions of the peptide-binding sites of the deduced macaque DPbeta-chains. These differences in the MHC class II DP regions of macaques and humans suggest separate evolutionary mechanisms in the generation of diversity. PMID- 27771736 TI - Unloading-Induced Degradation of the Anisotropic Arrangement of Collagen/Apatite in Rat Femurs. AB - The specific orientation of collagen and biological apatite (BAp) is an anisotropic feature of bone micro-organization; it is an important determinant of bone mechanical function and performance under anisotropic stress. However, it is poorly understood how this microstructure orientation is altered when the mechanical environment changes. We hypothesized that the preferential orientation of collagen/BAp would change in response to changes in mechanical conditions, similar to the manner in which bone mass and bone shape change. In the present study, we investigated the effect of unloading (removal of anisotropic stress) on the preferential orientation of collagen/BAp using a rat sciatic neurectomy model. Bone tissue that formed under unloaded conditions showed a more disordered collagen/BAp orientation than bone tissue that formed under physiological conditions. Coincidentally, osteocytes in unloaded bone displayed spherical morphology and random alignment. To the best of our knowledge, this study is the first to demonstrate the degradation of preferential collagen/BAp orientation in response to unloading conditions. In summary, we identified alterations in bone material anisotropy as an important aspect of the bone's response to unloading, which had previously been examined with regard to bone loss only. PMID- 27771737 TI - Youth baseball players with elbow and shoulder pain have both low back and knee pain: a cross-sectional study. AB - PURPOSE: Serious arm injuries in youth baseball players have been increasing. Though a breakage in the kinetic chain could affect arm injuries, an association between arm injuries and insufficient support of the trunk and lower extremities is not well understood. The purpose of this study was to investigate the association of low back and knee pain with elbow and/or shoulder complaints among youth baseball players. METHODS: A self-administered questionnaire and document informed consent were mailed to youth athletes belonging to the Miyagi Amateur Sports Association. Multiple logistic regression analysis was used to examine the association of low back and knee pain with elbow and/or shoulder pain at the time of the questionnaire. Variables considered in the models were as follows: sex, age, BMI, years of athletic experience, position, team level, the amount of practice, participating day in team practice and game per week, frequency of participation in games, and practice intensity. RESULTS: The final study population was comprised 1582 youth baseball players (aged 6-15 years old, male 95.6 %) who had responded to the questionnaire. A total of 24.8 % (n = 381) had elbow and/or shoulder pain, whereas 8.5 % (n = 130) had low back pain and 13.1 % (n = 201) had knee pain. The prevalence of elbow and/or shoulder pain with concomitant low back and knee pain was 61.2 % (n = 82) and 51.9 % (n = 108) (p < 0.001), respectively. The presence of low back and knee pain was significantly associated with the prevalence of elbow and/or shoulder pain among youth baseball players [adjusted odds ratio (ORs): 4.31, 95 % confidence interval (95 % CI): 2.86-6.51, p < 0.001, and ORs: 2.92, 95 % CI: 2.09-4.09, p < 0.001, respectively]. For other variables, older age (10- and 11-year old: ORs: 1.73, 95 % CI 1.10-2.73, p = 0.018; 12-15 year old: ORs: 1.62, 95 % CI: 1.18-2.58, p = 0.006), pitcher (ORs: 1.46, 95 % CI: 1.10-1.94, p = 0.009), catcher (ORs: 1.69, 95 % CI: 1.24-2.31, p = 0.001,), and practice intensity (ORs: 1.58, 95 % CI: 1.22 2.06, p = 0.001) were significantly associated with elbow and/or shoulder pain. CONCLUSION: Both low back and knee pain were significantly associated with elbow and/or shoulder pain in youth baseball players. Clinicians should check the complaints of the trunk and lower extremities as well as those of the elbow and shoulder for preventing severe injuries in youth baseball players. Level of Evidence III. PMID- 27771738 TI - Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study. AB - AIMS/HYPOTHESIS: Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes. METHODS: We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose >=7.0 mmol/l or a non-fasting blood glucose >=11.1 mmol/l. RESULTS: During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural log-transformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio. CONCLUSIONS/INTERPRETATION: DHEA serum levels might be an independent marker of type 2 diabetes. PMID- 27771739 TI - Effect of early postextubation high-flow nasal cannula vs conventional oxygen therapy on hypoxaemia in patients after major abdominal surgery: a French multicentre randomised controlled trial (OPERA). AB - PURPOSE: High-flow nasal cannula (HFNC) oxygen therapy is attracting increasing interest in acute medicine as an alternative to standard oxygen therapy; however, its use to prevent hypoxaemia after major abdominal surgery has not been evaluated. Our trial was designed to close this evidence gap. METHODS: A multicentre randomised controlled trial was carried out at three university hospitals in France. Adult patients at moderate to high risk of postoperative pulmonary complications who had undergone major abdominal surgery using lung protective ventilation were randomly assigned using a computer-generated sequence to receive either HFNC oxygen therapy or standard oxygen therapy (low-flow oxygen delivered via nasal prongs or facemask) directly after extubation. The primary endpoint was absolute risk reduction (ARR) for hypoxaemia at 1 h after extubation and after treatment discontinuation. Secondary outcomes included occurrence of postoperative pulmonary complications within 7 days after surgery, the duration of hospital stay, and in-hospital mortality. The analysis was performed on data from the modified intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT01887015). RESULTS: Between 6 November 2013 and 1 March 2015, 220 patients were randomly assigned to receive either HFNC (n = 108) or standard oxygen therapy (n = 112); all of these patients completed follow-up. The median duration of the allocated treatment was 16 h (interquartile range 14-18 h) with standard oxygen therapy and 15 h (interquartile range 12-18) with HFNC therapy. Twenty-three (21 %) of the 108 patients treated with HFNC 1 h after extubation and 29 (27 %) of the 108 patients after treatment discontinuation had postextubation hypoxaemia, compared with 27 (24 %) and 34 (30 %) of the 112 patients treated with standard oxygen (ARR 4, 95 % CI -8 to 15 %; p = 0.57; adjusted relative risk [RR] 0.87, 95 % CI 0.53-1.43; p = 0.58). Over the 7-day postoperative follow-up period, there was no statistically significant difference between the groups in the proportion of patients who remained free of any pulmonary complication (ARR 7, 95 % CI -6 to 20 %; p = 0.40). Other secondary outcomes also did not differ significantly between the two groups. CONCLUSIONS: Among patients undergoing major abdominal surgery, early preventive application of high-flow nasal cannula oxygen therapy after extubation did not result in improved pulmonary outcomes compared with standard oxygen therapy. PMID- 27771740 TI - Dynamic change of surface microbiota with different environmental cleaning methods between two wards in a hospital. AB - Terminal disinfection and daily cleaning have been performed in hospitals in Taiwan for many years to reduce the risks of healthcare-associated infections. However, the effectiveness of these cleaning approaches and dynamic changes of surface microbiota upon cleaning remain unclear. Here, we report the surface changes of bacterial communities with terminal disinfection and daily cleaning in a medical intensive care unit (MICU) and only terminal disinfection in a respiratory care center (RCC) using 16s ribosomal RNA (rRNA) metagenomics. A total of 36 samples, including 9 samples per sampling time, from each ward were analysed. The clinical isolates were recorded during the sampling time. A large amount of microbial diversity was detected, and human skin microbiota (HSM) was predominant in both wards. In addition, the colonization rate of the HSM in the MICU was higher than that in the RCC, especially for Moraxellaceae. A higher alpha-diversity (p = 0.005519) and a lower UniFrac distance was shown in the RCC due to the lack of daily cleaning. Moreover, a significantly higher abundance among Acinetobacter sp., Streptococcus sp. and Pseudomonas sp. was shown in the RCC compared to the MICU using the paired t test. We concluded that cleaning changes might contribute to the difference in diversity between two wards. PMID- 27771742 TI - Pre-engraftment bloodstream infections in acute leukemia patients undergoing unrelated cord blood transplantation following intensified myeloablative conditioning without ATG. AB - The aim of this study is to investigate the impact of pre-engraftment bloodstream infections (BSIs) on the outcomes in acute leukemia patients undergoing myeloablative cord blood transplantation (CBT). A total of 226 acute leukemia patients who received unrelated CBT were enrolled in this study, and all these patients received an intensified myeloablative conditioning without ATG. Pre engraftment BSIs occurred in 72 patients (31.9 %), and the median time of onset was 4.5 days after cord blood infusion, BSIs of gram-negative bacilli, and gram positive cocci comprised of 63.8 and 36.2 %, respectively. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic graft versus host disease (GVHD) were comparable among the non-BSI, gram-negative bacilli BSI, and gram-positive cocci BSI groups. The cumulative incidence of transplant related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) was similar between the non-BSI and the BSI groups. For subgroups analysis, TRM was lower in gram-positive cocci BSI patients compared with that of gram-negative bacilli BSI patients (8.3 vs 39.3 %) (p = 0.01) (HR = 0.39, p = 0.034), and the 5-year OS was higher in gram-positive cocci BSI cohort (79.1 vs 44.2 %) (p = 0.01) (HR = 0.36, p = 0.046). Our study demonstrated that, for acute leukemia patients who received CBT after myeloablative conditioning that omitted ATG, pre-engraftment BSI had no impact on engraftment, GVHD, TRM, relapse, and long-term survival. Due to the fact that gram-negative bacilli BSI was associated with poor outcomes compared with gram-positive cocci BSI, appropriate early empirical antimicrobial management strategies and better supportive care are required to decrease the gram-negative bacilli BSI-related mortality. PMID- 27771741 TI - Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report. AB - INTRODUCTION: The increased availability of immunotherapeutic agents for the treatment of a wide array of cancer in the general oncology practice setting will reveal rare and unique toxicities. MATERIALS AND METHODS: The mechanism of cardiac allograft rejection in the context of PD-1 antibody therapy was explored in a patient with cutaneous squamous cell cancer complicating long-standing cardiac allograft. Immune cell infiltrate in the myocardium and peripheral blood lymphocyte repertoire were assessed using myocardial biopsy and temporal analysis of peripheral blood samples. The efficacy of high-intensity immunosuppression to reverse graft rejection was explored. RESULTS: Endomyocardial biopsy showed acute moderate diffuse cellular rejection with a predominant population of CD3+, CD8+ and CD4+ infiltrating lymphocytes; peripheral blood circulating lymphocytes showed a high frequency of proliferating and activated CD8+ T cells expressing PD 1 compared to a normal control. There was no difference in the activation and proliferation of CD4+ T cells compared to a normal control. Cardiac function improved following high-intensity immunosuppression and patient survived for up to 7 months after discontinuation of nivolumab. CONCLUSIONS: Immune checkpoint inhibitors should be avoided in allograft recipients but high-intensity immunosuppression is effective to salvage allograft rejection induced by these agents. PMID- 27771743 TI - The importance of erythroblast enumeration in myeloid neoplasia. PMID- 27771745 TI - Stress responses of Acinetobacter strain Y during phenol degradation. AB - Quantification of gene expression of Acinetobacter strain Y under 1000 mg/l of phenol was investigated using qPCR and proteomic analyses. The results show that Acinetobacter strain Y utilized 100 % of phenol within 18 h of exposure. The results of qPCR and proteomic analyses demonstrate a sequential expression of phenol-degrading genes of Acinetobacter strain Y via the ortho-pathway followed by the beta-ketoadipate pathway. Many stress-responsive proteins such as chaperones, chaperonins, porins and the enzymes involved in the signal transduction pathway were upregulated especially in the early stage. The stressed bacteria produced more ABC-type transporters, membrane receptors and efflux pumps to mitigate the impacts of phenol stress. The functions of TCA/glyoxylate cycle and oxidative phosphorylation processes were negatively affected. Many enzymes in the gluconeogenesis pathway were upregulated. This study demonstrates bacterial strategies of Acinetobacter strain Y via the energy saving mechanisms and the coordinated control between carbon (C)- and nitrogen (N)-limitations in coping with the stress by scavenging the reactive oxygen species. PMID- 27771744 TI - Mapping of novel powdery mildew resistance gene(s) from Agropyron cristatum chromosome 2P. AB - KEY MESSAGE: A physical map of Agropyron cristatum 2P chromosome was constructed for the first time and the novel powdery mildew resistance gene(s) from chromosome 2P was(were) also mapped. Agropyron cristatum (L.) Gaertn. (2n = 28, PPPP), a wild relative of common wheat, is highly resistant to powdery mildew. Previous studies showed that wheat-A. cristatum 2P disomic addition line II-9-3 displayed high resistance to powdery mildew, and the resistance was attributable to A. cristatum chromosome 2P. To utilize and physically map the powdery mildew resistance gene(s), 15 wheat-A. cristatum 2P translocation lines and three A. cristatum 2P deletion lines with different chromosomal segment sizes, obtained from II-9-3 using 60Co-gamma ray irradiation, were characterized using cytogenetic and molecular marker analysis. A. cristatum 2P chromosomal segments in the translocations were translocated to different wheat chromosomes, including 1A, 4A, 5A, 6A, 7A, 1B, 2B, 3B, 7B, 3D, 4D, and 6D. A physical map of the 2P chromosome was constructed with 82 STS markers, consisting of nine bins with 34 markers on 2PS and eight bins with 48 markers on 2PL. The BC1F2 populations of seven wheat-A. cristatum 2P translocation lines (2PT-3, 2PT-4, 2PT-5, 2PT-6, 2PT 8, 2PT-9, and 2PT-10) were developed by self-pollination, tested with powdery mildew and genotyped with 2P-specific STS markers. From these results, the gene(s) conferring powdery mildew resistance was(were) located on 2PL bin FL 0.66 0.86 and 19 2P-specific markers were identified in this bin. Moreover, two new powdery mildew-resistant translocation lines (2PT-4 and 2PT-5) with small 2PL chromosome segments were obtained. The newly developed wheat lines with powdery mildew resistance and the closely linked molecular markers will be valuable for wheat disease breeding in the future. PMID- 27771746 TI - Identification and functional analysis of the GTPV bidirectional promoter region. AB - The goat pox chick embryo-attenuated virus (GTPV) has been developed as an effective vaccine that can elicit protective immune responses. It possesses a large genome and a robust ability to express exogenous genes. Thus, this virus is an ideal vector for recombinant live vaccines for infectious diseases in ruminant animals. In this study, we identified a novel bidirectional promoter region of GTPV through screening named PbVV(+/-). PbVV(+/-) is located between ETF-l and VITF-3, which are transcribed in opposite directions. A new recombinant goat pox virus (rGTPV) was constructed, in which duplicate PbVV(+) was used as a promoter element to enhance Brucella OMP31 expression, and duplicate PbVV(-) was used as a promoter element to regulate enhanced green fluorescent protein (EGFP) at the same time as the selection marker. PbVV(-) promoter activity was compared to that of the P7.5 promoter of vaccinia virus, as measured by EGFP expression; the fluorescence intensity of EGFP expressed in cells was confirmed by fluorescence microscopy and flow cytometry. PbVV(+) promoter activity was measured by Brucella OMP31 expression. Interaction with the anti-Brucella-OMP31 monoclonal antibody was confirmed by western blotting, and OMP31 mRNA expression was assessed by qRT PCR. The results of this study will be useful for the further study of effective multivalent vaccines based on rGTPV. This study also provides a theoretical basis for overcoming the problem of low expression of exogenous genes. PMID- 27771747 TI - The Daily Readiness Huddle: a process to rapidly identify issues and foster improvement through problem-solving accountability. AB - BACKGROUND: Because of the increasing complexities of providing imaging for pediatric health care services, a more reliable process to manage the daily delivery of care is necessary. Objective We describe our Daily Readiness Huddle and the effects of the process on problem identification and improvement. MATERIALS AND METHODS: Our Daily Readiness Huddle has four elements: metrics review, clinical volume review, daily readiness assessment, and problem accountability. It is attended by radiologists, directors, managers, front-line staff with concerns, representatives from support services (information technology [IT] and biomedical engineering [biomed]), and representatives who join the meeting in a virtual format from off-site locations. Data are visually displayed on erasable whiteboards. The daily readiness assessment uses queues to determine whether anyone has concerns or outlier data in regard to S-MESA (Safety, Methods, Equipment, Supplies or Associates). Through this assessment, problems are identified and categorized as quick hits (will be resolved in 24-48 h, not requiring project management) and complex issues. Complex issues are assigned an owner, quality coach and report-back date. Additionally, projects are defined as improvements that are often strategic, are anticipated to take more than 60 days, and do not necessarily arise out of identified issues during the Daily Readiness Huddle. We tracked and calculated the mean, median and range of days to resolution and completion for complex issues and for projects during the first full year of implementing this process. RESULTS: During the first 12 months, 91 complex issues were identified and resolved, 11 projects were in progress and 33 completed, with 23 other projects active or in planning. Time to resolution of complex issues (in days) was mean 37.5, median 34.0, and range 1 105. For projects, time to completion (in days) was mean 86.0, median 84.0, and range 5-280. CONCLUSION: The Daily Readiness Huddle process has given us a framework to rapidly identify issues, bring accountability to problem-solving, and foster improvement. It has also had a positive effect on team-building and coordination. PMID- 27771750 TI - Health system redesign following sexual violence during the genocide in Rwanda. PMID- 27771749 TI - The 2030 agenda for sustainable development: a golden opportunity for global violence prevention. PMID- 27771748 TI - Pharmacogenetics of stimulant abuse liability: association of CDH13 variant with amphetamine response in a racially-heterogeneous sample of healthy young adults. AB - RATIONALE: A previous genome-wide association study (GWAS) in a predominately Caucasian sample of healthy young adults linked greater amphetamine-induced rewarding effects with the rs3784943 G allele of the cadherin 13 (CDH13; i.e., a cell adhesion molecule implicated in neuronal connectivity) gene. This association has not been subsequently examined, nor has it been studied in Asian populations, which may have greater frequencies of the risk allele. OBJECTIVE: The objective of this study was to examine the association of rs3784943 with amphetamine response in a racially heterogeneous sample (37 % Asian) of healthy young adults. METHODS: Participants (N = 84; 18-35 years old) genotyped for rs3784943 completed counterbalanced sessions involving 20 mg oral d-amphetamine or placebo administration. At both sessions, cardiovascular and subjective drug effects measures were collected. RESULTS: In the combined racially heterogeneous sample, amphetamine (vs. placebo) effects were significantly greater on "Feel Drug" ratings (p < 0.05) and marginally greater on "Feel High" ratings and systolic blood pressure (p < 0.10) in G/A + G/G genotypes than A/A genotypes. The G allele was more common among Asian than other racial groups. Among the subsample of Asian participants (N = 31), drug effects were significantly greater on Feel Drug (p < 0.05) and marginally greater on Feel High and heart rate (p < 0.10) among Asians with G/A + G/G (vs. A/A) genotypes. CONCLUSIONS: In concert with a previous GWAS result, this candidate gene study provides convergent evidence implicating CDH13 rs3784943 variant in d-amphetamine's drug effect profile and suggests generalization to Asian populations. CDH13 and genes coding for other cell adhesion molecules may be worthy of study in the biology of psychostimulant abuse liability. PMID- 27771751 TI - Violence and health: implications of the 2030 Agenda for South-North collaboration. PMID- 27771752 TI - Multiple giant cell tumors of bone arising from multiple fatty tumors. AB - We describe a patient with a history of giant cell tumor who over the course of 18 years developed multiple fat containing osseous lesions in the pelvis and spine. Two of these lesions subsequently evolved into biopsy proven giant cell tumor of bone. To our knowledge, this phenomenon of giant cell tumors evolving from fat containing lesions has not been described. PMID- 27771753 TI - Freehand direct arthrography of the shoulder using near real-time guidance in an open 1.0-T MRI scanner. AB - OBJECTIVE: To assess the technical success and duration of magnetic resonance imaging (MRI)-guided freehand direct shoulder arthrography (FDSA) with near real time imaging implemented in a routine shoulder MRI examination on an open 1.0-T MRI scanner, and to assess the learning curve of residents new to this technique. METHODS: An experienced MRI interventionalist (the expert) performed 125 MRI guided FDSA procedures, and 75 patients were treated by one of three residents without previous experience in MRI-guided FDSA. Technical success rate and duration of MRI-guided FDSA of the expert and the residents were compared. The residents' learning curves were assessed. The occurrence of extra-articular deposition and leakage of contrast media from the puncture site and the subsequent impairment of image interpretation were retrospectively analyzed. RESULTS: Overall technical success was 97.5 %. The expert needed overall fewer puncture needle readjustments and was faster at puncture needle positioning (p < 0.01). The learning curve of the residents, however, was steep. They leveled with the performance of the expert after ~ 15 interventions. With a minimal amount of training all steps of MRI-guided FDSA can be performed in <=10 min. CONCLUSION: Magnetic resonance-guided FDSA in an open 1.0-T MRI scanner can be performed with high technical success in a reasonably short amount of time. Only a short learning curve is necessary to achieve expert level. PMID- 27771754 TI - Long-term outcomes of percutaneous lumbar facet synovial cyst rupture. AB - OBJECTIVE: To evaluate the therapeutic value, safety, and long-term clinical outcomes of percutaneous lumbar facet synovial cyst (LFSC) rupture. MATERIALS AND METHODS: Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant. The study group comprised 71 patients (44 women, mean age: 65 +/- 17 years) who underwent CT- or fluoroscopy-guided percutaneous LFSC rupture. The technical success of LFSC rupture, the long-term clinical outcome, including repeat procedures or surgery, and imaging findings on MRI and CT were recorded. RESULTS: Seventy-nine LFSC ruptures were performed in 71 patients. CT guidance was used in 57 cases and fluoroscopy guidance in 22 cases. LFSC rupture was technically successful in 58 out of 79 cases (73 %). Mean injection volume for cyst rupture was 3.6 +/- 2.2 mL and a combination of steroid and anesthetic was injected in all cases. Over a mean follow-up time of 44 months, 12 % of patients underwent repeat cyst rupture, and 46 % eventually underwent surgery, whereas the majority of patients (55 %) experienced symptomatic relief and did not undergo surgery. There was no significant association between a successful outcome and age, sex, level, or size of LFSC (p > 0.1). LFSCs with T2 hypointensity were more likely to require surgery (p = 0.02). There was one complication, a bacterial skin infection that completely resolved following antibiotic therapy. CONCLUSION: Percutaneous LFSC rupture is an effective and safe nonsurgical treatment option for LFSC. More than half of treated patients were able to avoid subsequent surgery. Therefore, percutaneous LFSC rupture should be considered before surgical intervention. PMID- 27771756 TI - Seasonal Differences in Contaminant Accumulation in Neotropical Migrant and Resident Songbirds. AB - For many years, it has been hypothesized that Neotropical migrants breeding in the United States and Canada accumulate organochlorine pesticides (OCPs) while on their wintering grounds in Latin America. We investigated the seasonal accumulation of persistent organic pollutant (POPs) in migrant and resident passerines in Texas, Yucatan, and Costa Rica collected during the fall, winter, and spring from 2011 to 2013. A total of 153 birds were collected, and all contained detectable levels of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and OCPs with dichlorodiphenyldichloroethylene (DDE) being the most predominant pesticide. OCPs and PCBs were the predominant contaminants, accounting for >=80 % of the total POPs burden, whereas PBDEs accounted for <=16 %. Only spring migrants from Texas had significantly greater DDE concentrations (64.6 ng/g dry weight [dw]) than migrants collected in Costa Rica (23.2 ng/g dw). Resident birds in Texas had significantly greater levels of DDE (121 ng/g dw) and SigmaPBDEs (34.8 ng/g dw) compared with residents in Yucatan and Costa Rica. For SigmaPCBs, resident birds from Costa Rica had significantly lower concentrations (9.60 ng/g dw) compared with their migrant counterparts (43.7 ng/g dw) and residents from Texas (48.3 ng/g dw) and the Yucatan (32.1 ng/g dw). Migrant and resident passerines had similar congener profiles for PCBs and PBDEs suggesting similar exposure and retention of these contaminants. No significant accumulation of DDE was observed in migrants while on their wintering grounds. Relatively high concentrations of PBDEs in resident birds from Costa Rica warrant future studies of PBDE contamination in Latin America. PMID- 27771755 TI - Evaluation of Stage-Dependent Genotoxic Effect of Roundup(r) (Glyphosate) on Caiman latirostris Embryos. AB - The agricultural expansion over the past decades, along with the associated increase in the use of pesticides, represents a high risk for many wild species. Caiman latirostris is a South American caiman with many features that make it highly vulnerable to pesticide exposure. Considering previous finding on the genotoxicity of the glyphosate-based formulation Roundup(r) in this species, the aim of this study was to evaluate the possible stage-dependent effect of this compound on C. latirostris embryos through the Comet assay (CA), micronuclei (MN), and nuclear abnormalities (NA) tests. Caiman eggs were exposed to three effective concentrations of Roundup(r) (750, 1250, 1750 ug/egg) in three different stages of the incubation period (total duration 70 +/- 3 days at 31 +/- 2 degrees C) of approximately 23 days each. A statistically significant difference in DNA damage determined by the CA was found between groups exposed to different concentrations of RU (p < 0.05) and the negative control, but no difference was observed among the three stages of exposure within any treatment (p > 0.05). There was no differences in the MN or NA frequencies between the different groups and the negative control (p > 0.05), nor among the different stages within each treatment. The results obtained in this study indicate that RU produce DNA damage on C. latirostris embryos independently of the developmental stage where the exposure occurs, implying an important risk for the species during all its period of development, when pesticide application is at maximum rate. PMID- 27771760 TI - Anastomosis between accessory middle cerebral artery and middle cerebral artery diagnosed by magnetic resonance angiography. AB - The accessory middle cerebral artery (MCA) is a common variation of the MCA that arises from the anterior cerebral artery. We report a patient with anastomosis of the accessory MCA with the main MCA, an extremely rare variant that we diagnosed by magnetic resonance (MR) angiography. Both partial maximum-intensity-projection and partial volume-rendering MR angiographic images obtained at 3 T are useful to identify such rare vascular variation. PMID- 27771761 TI - Being prepared to work in Gynecology Medicine: evaluation of an intervention to promote junior gynecologists professionalism, mental health and job satisfaction. AB - BACKGROUND: Dealing with work-related stress is highly prevalent for employees in Gynecology Medicine. Junior physicians, in particular, have to face high working demands and challenges while starting their medical career after graduation. Job resources (i.e., social support) and personal resources (coping skills) might reduce job strain. The evidence for supportive and effective mental health interventions for clinicians is limited. Offering psychosocial skill training for entrants in Gynecology Medicine is expected to be highly beneficial. Following this, the present pilot study focused on strengthening physicians' psychosocial skills and analyzed the effects of innovative training for junior gynecologists working in German hospitals. METHODS: Coping skills training for junior gynecologists was offered as group training for 12 weekly sessions over a time period of 3 months. Physicians were randomized to either an intervention group (IG) receiving the training (n = 38) or a control group (CG; n = 40). Training content involved developing and learning coping skills as well as solution focused and cognitive behavioral counselling for junior gynecologists. Study outcomes were (1) perceived occupational stress, (2) emotional exhaustion, (3) resilience coping behavior, (4) emotion regulation skills and (5) job satisfaction. Surveys were distributed at baseline (T0), after the training (T1), after 3 (T2) and 6 months (T3). RESULTS: Junior gynecologists (IG) reported a significant decrease in perceived job stress and emotional exhaustion from baseline to all follow-ups, whereas the control group did not show any comparable results. A clear positive value of the mental health promotion program was also noticeable with regard to job satisfaction and increased coping skills (i.e., emotion regulation). Overall satisfaction with the skill training was high: gynecologists reported high scores for training design, content, received outcome and overall satisfaction with the training. CONCLUSIONS: In this pilot study, participating in a psychosocial skills training course adapted for gynecology clinicians was associated with reductions in perceived job stress, exhaustion and improvements in coping skills and satisfaction. Modified psychosocial skills training may be a time-efficient tool to support gynecologists in their performance and well-being, which may have positive implications for patient care. PMID- 27771763 TI - Maternal warmth and toddler development: support for transactional models in disadvantaged families. AB - Studies support cognitive and social domains of development as entwined in childhood, however, there is a paucity of investigation into the nature of the mother-child relationship within an interdependence framework. Furthermore, the focus on these processes within families from impoverished communities using frequent assessments in early childhood has been limited. Our objectives were to identify (1) the directional associations between toddler's communication ability and social competence, (2) to establish whether the association between toddler's communication ability and social competence is mediated by maternal warmth, and (3) to establish support for transactional models between toddlers' outcomes and maternal warmth in disadvantaged communities in Ireland. Participants included 173 toddlers and their families enrolled in a prenatally commencing prevention programme. Toddler's communication and social competence were assessed at 12, 18, 24 and 36 months and maternal warmth at 6 and 24 months. Cross-lagged models were estimated examining multiple paths of associations simultaneously. Direct and indirect paths of maternal warmth were also examined. Bi-directional associations were found between communication ability and social competence from 12 to 24 months but not thereafter. Maternal warmth did not significantly mediate these associations, however, support of a transactional model was found with social competence. The results support early positive associations between better communication ability and social competence in the first 2 years, however, they suggest that these associations are no longer present by the third year. The role of maternal warmth in fostering social competencies is important for toddlers and equally important is toddler's level of social competence in eliciting increased maternal warmth. PMID- 27771764 TI - Reference intervals for HbA1c partitioned for gender and age: a multicenter study. PMID- 27771762 TI - Brevicoryne brassicae aphids interfere with transcriptome responses of Arabidopsis thaliana to feeding by Plutella xylostella caterpillars in a density dependent manner. AB - Plants are commonly attacked by multiple herbivorous species. Yet, little is known about transcriptional patterns underlying plant responses to multiple insect attackers feeding simultaneously. Here, we assessed transcriptomic responses of Arabidopsis thaliana plants to simultaneous feeding by Plutella xylostella caterpillars and Brevicoryne brassicae aphids in comparison to plants infested by P. xylostella caterpillars alone, using microarray analysis. We particularly investigated how aphid feeding interferes with the transcriptomic response to P. xylostella caterpillars and whether this interference is dependent on aphid density and time since aphid attack. Various JA-responsive genes were up regulated in response to feeding by P. xylostella caterpillars. The additional presence of aphids, both at low and high densities, clearly affected the transcriptional plant response to caterpillars. Interestingly, some important modulators of plant defense signalling, including WRKY transcription factor genes and ABA-dependent genes, were differentially induced in response to simultaneous aphid feeding at low or high density compared with responses to P. xylostella caterpillars feeding alone. Furthermore, aphids affected the P. xylostella induced transcriptomic response in a density-dependent manner, which caused an acceleration in plant response against dual insect attack at high aphid density compared to dual insect attack at low aphid density. In conclusion, our study provides evidence that aphids influence the caterpillar-induced transcriptional response of A. thaliana in a density-dependent manner. It highlights the importance of addressing insect density to understand how plant responses to single attackers interfere with responses to other attackers and thus underlines the importance of the dynamics of transcriptional plant responses to multiple herbivory. PMID- 27771765 TI - Toe amputations with SGLT-2 inhibitors: data from randomized clinical trials. PMID- 27771766 TI - A novel insulin sensitivity index particularly suitable to measure insulin sensitivity during gestation. AB - AIMS: Insulin resistance underlies the etiology of both type 2 diabetes and gestational diabetes. In pregnancy, insulin resistance is also associated with an unfavorable metabolic programming of the fetus, potentially contributing to a higher risk of obesity and type 2 diabetes in the offspring. To assess insulin sensitivity, several methods based on glucose and insulin levels during a 75-g oral glucose tolerance test (OGTT) exist. It is unclear how they perform during pregnancy, where physiologically altered metabolism could introduce a bias. METHODS: In a cohort comprising 476 non-diabetic subjects undergoing OGTT and hyperinsulinemic-euglycemic clamp (HEC), we used cross-validation to develop an insulin sensitivity index also based on non-esterified fatty acids (NEFA) that could be more robust during pregnancy (NEFA-index). We tested commonly used OGTT based indexes and the NEFA-index in a different cohort of 42 women during pregnancy and 1 year after delivery. RESULTS: The Matsuda and OGIS index failed to detect lower insulin sensitivity during pregnancy as compared to the follow-up OGTT 1 year after delivery (p > 0.09). The new NEFA-index incorporating BMI, plasma insulin and NEFA, but not glucose, clearly indicated lower insulin sensitivity during pregnancy (p < 0.0001). In the non-pregnant cohort, this NEFA index correlated well with the gold-standard HEC-based insulin sensitivity index, and outperformed other tested indexes for the prediction of HEC-measured insulin resistance. CONCLUSIONS: This insulin/NEFA-based approach is feasible, robust, and could be consistently used to estimate insulin sensitivity also during pregnancy. PMID- 27771768 TI - Advances in genetic hearing loss: CIB2 gene. AB - Hearing plays a crucial role in human development. Receiving and processing sounds are essential for the advancement of the speech ability during the early childhood and for a proper functioning in the society. Hearing loss is one of the most frequent disabilities that affect human senses. It can be caused by genetic or environmental factors or both of them. Calcium- and integrin-binding protein 2 (CIB2) is one of the recently identified genes, involved in HI pathogenesis. CIB2 is widely expressed in various human and animal tissues, mainly in skeletal muscle, nervous tissue, inner ear, and retina. The CIB2 protein is responsible for maintaining Ca2+ homeostasis in cells and interacting with integrins transmembrane receptors essential for cell adhesion, migration, and activation of signaling pathways. Calcium signaling pathway is crucial for signal transduction in the inner ear, and integrins regulate hair cell differentiation and maturation of the stereocilia. To date, mutations detected in CIB2 are causative for nonsyndromic hearing loss (DFNB48) or Usher syndrome type 1 J. Patients harboring biallelic CIB2 mutations suffer from bilateral, early onset, moderate to profound HI. In the paper, we summarize the current status of the research on CIB2. PMID- 27771767 TI - Nonconventional cation-coupled flagellar motors derived from the alkaliphilic Bacillus and Paenibacillus species. AB - Prior to 2008, all previously studied conventional bacterial flagellar motors appeared to utilize either H+ or Na+ as coupling ions. Membrane-embedded stator complexes support conversion of energy using transmembrane electrochemical ion gradients. The main H+-coupled stators, known as MotAB, differ from Na+-coupled stators, PomAB of marine bacteria, and MotPS of alkaliphilic Bacillus. However, in 2008, a MotAB-type flagellar motor of alkaliphilic Bacillus clausii KSM-K16 was revealed as an exception with the first dual-function motor. This bacterium was identified as the first bacterium with a single stator-rotor that can utilize both H+ and Na+ for ion-coupling at different pH ranges. Subsequently, another exception, a MotPS-type flagellar motor of alkaliphilic Bacillus alcalophilus AV1934, was reported to utilize Na+ plus K+ and Rb+ as coupling ions for flagellar rotation. In addition, the alkaline-tolerant bacterium Paenibacillus sp. TCA20, which can utilize divalent cations such as Ca2+, Mg2+, and Sr2+, was recently isolated from a hot spring in Japan, which contains a high Ca2+ concentration. These findings show that bacterial flagellar motors isolated from unique environments utilize unexpected coupling ions. This suggests that bacteria that grow in different extreme environments adapt to local conditions and evolve their motility machinery. PMID- 27771769 TI - High expression of cytoplasmic polyadenylation element-binding protein 4 correlates with poor prognosis of patients with colorectal cancer. AB - Cytoplasmic polyadenylation element-binding protein 4 (CPEB4), a zinc-finger containing sequence-specific RNA-binding protein, has been associated with tumor proliferation, invasion, and migration. Expression of CPEB4 and its prognostic significance in human colorectal cancer (CRC) have not been studied. The aim of the present study was to investigate expression of CPEB4 and its prognostic significance in CRC. Expression of CPEB4 in CRC tissues from two independent cohorts was examined by immunohistochemistry. Prognostic significance was analyzed using receiver operating characteristic curve analysis, Kaplan-Meier curves, and Cox regression analysis. High expression of CPEB4 was observed in 14.8 % of CRCs in the training cohort and 12.2 % of CRCs in the validation cohort. High expression of CPEB4 was significantly correlated with the pM classification, TNM stage, and poorer overall survival in both cohorts. Through multivariate Cox regression analysis, high expression of CPEB4 was found to be an independent prognostic biomarker for overall survival in CRC patients. High expression of CPEB4 may be an independent and useful biomarker for predicting the poor survival of patients with CRC. PMID- 27771771 TI - Survival after intravenous thrombin prior to cardiopulmonary bypass. AB - We present a case of a patient undergoing aortic valve replacement being inadvertently administered 5000 U of bovine thrombin instead of heparin for anticoagulation for cardiopulmonary bypass. The labeling error was made within the operating room pharmacy. The key to survival of this patient was a rapid diagnosis, administration of antithrombin and heparin, and removal of cardiac and great vessel thrombi. It is recommended that point of care anesthesia providers 'prepare heparin for cardiopulmonary bypass anticoagulation, as thrombin is not used in anesthetic practice and is not contained within anesthesia cabinet medication drawers. PMID- 27771770 TI - Associations between exclusive breastfeeding and physical fitness during childhood. AB - PURPOSE: Exposure to breastfeeding improves the survival, health, and development of children; therefore, breast milk is recommended as the exclusive nutrient source for feeding term infants during the first 6 months. This cross-sectional study aimed to determine the possible association between exposure to exclusive breastfeeding and physical fitness performance in children and, if so, whether this association is influenced by the breastfeeding duration. METHODS: A total of 2853 (52.3 % girls) European children from the IDEFICS study aged 6-11 years with complete data on physical fitness (cardiorespiratory fitness, muscular strength, flexibility, balance, speed) and exclusive breastfeeding duration (never, 1-3, 4 6, 7-12 months) were included in the present study. Multivariate and mixed linear regression models were estimated and adjusted for sex, age, birth weight, diet, physical activity, body mass index, and parental factors (age, body mass index, educational attainment). RESULTS: We found a positive association between exclusive breastfeeding and lower-body explosive strength (beta = 0.034) as well as flexibility (beta = 0.028). We also found a positive association between breastfeeding and balance in boys (beta = 0.039), while this association was negative in girls (beta = -0.029). To improve lower-body explosive strength, 1-3 months of exclusive breastfeeding were enough; a longer duration did not lead to increasing benefit. In contrast, 4-6 months of breastfeeding were necessary to have any benefit on flexibility or balance, although this became nonsignificant after adjustment for body mass index and physical activity. CONCLUSIONS: Exclusive breastfeeding seems a natural way of slightly improving some physical fitness components (mainly lower-body muscle strength) and thus future health. PMID- 27771772 TI - Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy. AB - Microhemorrhages are strongly associated with advanced cerebral amyloid angiopathy (CAA). Although it has been frequently proposed that the deposition of Abeta in the walls of cortical vessels directly causes microhemorrhages, this has not been studied in great detail, mainly because the ruptured vessels are often missed on routine histopathologic examination. Here, we examined histopathological data from studies targeting microhemorrhages with high resolution ex vivo 7 T MRI in nine cases with moderate-to-severe CAA, and assessed the presence of Abeta in the walls of involved vessels. We also assessed the density of Abeta positive cortical vessels in areas surrounding microhemorrhages compared to control areas. In seven out of 19 microhemorrhages, the presumed involved vessel could be identified on the histopathological section. Only one of these vessels was positive for Abeta at the site of rupture. Moreover, the density of Abeta positive cortical vessels was lower (1.0 per mm2) within a range of 315 um surrounding the microhemorrhage, compared to control areas (2.0 per mm2; p < 0.05). These findings question the widely held assumption that the deposition of Abeta in the walls of cortical vessels directly causes microhemorrhages. PMID- 27771774 TI - Usefulness of combination therapy with Daclatasvir plus Asunaprevir in chronic hepatitis C patients with chronic kidney disease. AB - AIM: Combination therapy with Daclatasvir (DCV) plus Asunaprevir (ASV) has been proven effective in patients with chronic hepatitis C virus (HCV) infection. However, little is known as to the effect of this therapy in patients with reduced renal function. Focusing on CKD patients whose renal function has declined, the present trial addresses the efficacy and safety of this combination therapy in CKD patients with reduced estimated glomerular filtration rate (eGFR). MATERIALS AND METHODS: The study design is a single-center, retrospective longitudinal observational study enrolling 106 patients with (n = 29) or without (n = 77) CKD. After the treatment with combined DCV with ASV for chronic HCV genotype 1b, patients were followed for a total of 48 weeks and the comparison was made in clinical parameters between the two groups. RESULTS: (1) The majority of patients in both groups achieved sustained virological response at 24 weeks (90.8 % in the non-CKD group, and 93.1 % in the CKD). (2)The reduction rate in HCV-RNA levels 2 weeks after commencing the treatment was faster in the CKD group than that in the non-CKD group (81.8 vs. 79.2 %, p < 0.01). (3) Three patients in the CKD group and 6 patients in the non-CKD group withdrew from the treatment because of the adverse events. CONCLUSION: Combination therapy with DCV plus ASV for chronic HCV genotype 1b infection is useful and tolerable, not only in patients with normal eGFR, but also in those with CKD with declined eGFR. Viral eradication at an early phase of the treatment appears to be faster in CKD patients. PMID- 27771775 TI - Comprehensive histological and immunological studies reveal a novel glycoprotein hormone and thyrostimulin expressing proto-glycotrope in the sea lamprey pituitary. AB - In the adenohypophysis (anterior pituitary) of all gnathostomes, there are six tropic cell types: corticotropes, melanotropes, somatotropes, lactotropes, gonadotropes and thyrotropes; each cell type produces specific tropic hormones. In contrast, we report in this study that there are only four tropic cell types in the sea lamprey (Petromyzon marinus) adenohypophysis. We specifically focused on the cell types that produce the glycoprotein hormones (GpHs). The gnathostome adenohypophyseal GpHs are follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and thyrostimulin. However, lampreys only have two heterodimeric adenohypophyseal GpHs consisting of unique alpha and beta subunits, lamprey GpH (lGpH) (lGpA2/lGpHbeta) and thyrostimulin (lGpA2/lGpB5). We used an array of histological techniques to determine the (co) localization and (co)-expression of the lGpH and thyrostimulin subunits in the lamprey adenohypophysis at different life stages (larval, parasitic, adult) and to identify their synthesizing cell(s). The thyrostimulin subunits (lGpA2/lGpB5) were co-expressed throughout the adenohypophysis (larval, parasitic, and adult), while the GpH beta-subunit (lGpHbeta) exhibited localized distribution (adult); all three subunits were co-localized and co-expressed, suggesting that both GpHs are synthesized in the same cells, novel proto-glycotropes, in specific adenohypophyseal regions at different life stages. In summary, we provide the first comprehensive study using histology, transmission electron microscopy, in situ hybridization and immunohistochemistry that strongly supports further evidence for four definitive adenohypophyseal cell types in the lamprey, including: corticotropes, somatotropes, melanotropes, and the first identification of a novel proto-glycotrope. In addition, our studies show that there is developmental and region-specific co-localization and co-expression of lGpH and thyrostimulin in the lamprey adenohypophysis. PMID- 27771773 TI - Case-control study of candidate gene methylation and adenomatous polyp formation. AB - PURPOSE: Colorectal cancer (CRC) is one of the most common and preventable forms of cancer but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70-90 % of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation. METHODS: Patients recruited from a local endoscopy clinic provided informed consent and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios (ORs) and 95 % confidence intervals (95% CIs) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders. RESULTS: Complete data were available for 107 participants; 36 % had adenomas (men 40 %, women 31 %). Hypomethylation of the MINT1 locus (OR 5.3, 95% CI 1.0-28.2) and the PER1 (OR 2.9, 95% CI 1.1-7.7) and PER3 (OR 11.6, 95% CI 1.6-78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71 97 %), sensitivity was relatively low (18-45 %). CONCLUSION: Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance. PMID- 27771777 TI - The effects of vitreous on proliferative diabetic retinopathy and the response to pan retinal photocoagulation. PMID- 27771776 TI - Multidisciplinary evaluation at baseline and during treatment improves the rate of compliance and efficacy of deferasirox in elderly myelodysplastic patients. AB - BACKGROUND: Deferasirox (DFX) is used to reduce iron levels in patients with myelodysplastic syndrome (MDS) who develop iron overload after chronic red blood cell infusions. However, DFX can be associated with renal and gastrointestinal toxicities, which may cause treatment interruption or discontinuation. This study aimed to determine the effectiveness and safety of DFX in patients with MDS. METHODS: This multicenter, retrospective, observational study was conducted at two hospitals in Italy. Elderly patients with transfusion-dependent MDS received DFX for up to 12 months and were divided into two groups: group A comprised patients who were not under multidisciplinary assessment; group B comprised patients under multidisciplinary control. Treatment effectiveness was estimated by monitoring the serum ferritin (SF) levels throughout the study. Any treatment related adverse events (AEs), clinically relevant analytical alterations, and reasons for treatment discontinuation were monitored. RESULTS: The study included 44 patients (13 female, 31 male; median age 77.0 years). At 3 months, SF levels decreased by >=20 % in 29 and 31 % of patients in groups A and B, respectively, in 17 and 36 % of patients at 6 months, and in 22 and 58 % at 12 months. The most common AEs were diarrhea and increased serum creatinine, which were more frequent in group A. The discontinuation rate after renal AE was 15 and 5 % in groups A and B, respectively. CONCLUSION: Multidisciplinary evaluation can be an effective strategy for monitoring renal function in patients on DFX therapy, to improve treatment adherence and overall efficacy in elderly patients with MDS. PMID- 27771778 TI - Genome-Wide Analysis of Alternative Splicing Provides Insights into Stress Adaptation of the Pacific Oyster. AB - Alternative splicing (AS) is thought to enhance transcriptome diversity dramatically and play an important role in stress adaptation. While well studied in vertebrates, AS remains poorly understood in invertebrates. Here, we used high throughput RNA-sequencing data to perform a genome-wide survey of AS in the Pacific oyster (Crassostrea gigas), an economically important mollusk that is cultivated worldwide. This analysis identified 8223 AS events corresponding to 4480 genes in the Pacific oyster, suggesting that about 16 % of oyster multiexonic genes undergo AS. We observed that a majority of the identified AS events were related to skipped exons (37.8 %). Then Gene Ontology analysis was conducted to analyze the function of the genes that undergo AS and the genes that produce more than five AS isoforms. After that, the expression of AS isoforms facing temperature, salinity, and air exposure challenge were examined. To validate our bioinformatic-predicted results and examine whether AS affects stress adaptation, we selected heat-shock protein 60 (HSP60) and HSP90 genes, both of which experience AS, for reverse transcription PCR (RT-PCR). We also performed quantitative real-time PCR (qRT-PCR) to determine the relative expression of each AS isoform among different stress adapted populations. Our study indicates that AS events are likely complex in the Pacific oyster and may be related to stress adaptation. These results will complement the predicted gene database of C. gigas and provide an invaluable resource for future functional genomic studies on molluscs. PMID- 27771779 TI - Population attributable burden of Helicobacter pylori-related gastric cancer, coronary heart disease, and ischemic stroke in China. AB - Helicobacter pylori, a risk factor of cancer and chronic diseases, remains highly prevalent in China. This review aims to systematically evaluate the H. pylori attributable burden for gastric cancer (GC), coronary heart disease (CHD), and ischemic stroke (IS) in the Chinese population. Helicobacter pylori prevalence was updated by pooling the results reported in studies across China. The population attributable fraction (PAF) was calculated based on the H. pylori prevalence 10 years ago and relative risks of specific disease by reviewing the prospective studies published from 2000 through 2015. In China, the nationwide average prevalence of H. pylori was estimated to be 42.06 % in the general population during 2009-2013. The fixed effects pooled relative risk (RR) of 1.89 [95 % confidence interval (CI): 1.57-2.26] was obtained for gastric cancer and H. pylori infection. Helicobacter pylori infection was responsible for around 37.38 % of noncardia GC, corresponding to about 105,536 cases in 2012. As for extra gastric disorders, H. pylori infections had higher risk of CHD (RR = 1.55, 95 % CI: 1.37-1.76) and IS (RR = 1.54, 95 % CI: 1.42-1.66). About 23.15 % of CHD and 22.29 % of IS were attributable to H. pylori infection. The estimates of H. pylori-attributable burden reveal a great potential of reducing H. pylori-related chronic disease burden by H. pylori eradication. Large prospective studies are warranted to identify which H. pylori strains, which subtypes of the disease, and which subgroups of the population have the greatest risk of relevant diseases and the effect of H. pylori eradication on the prevention of H. pylori-related diseases. PMID- 27771780 TI - Comprehensive detection and identification of bacterial DNA in the blood of patients with sepsis and healthy volunteers using next-generation sequencing method - the observation of DNAemia. AB - Blood is considered to be a sterile microenvironment, in which bacteria appear only periodically. Previously used methods allowed only for the detection of either viable bacteria with low sensitivity or selected species of bacteria. The Next-Generation Sequencing method (NGS) enables the identification of all bacteria in the sample with their taxonomic classification. We used NGS for the analysis of blood samples from healthy volunteers (n = 23) and patients with sepsis (n = 62) to check whether any bacterial DNA exists in the blood of healthy people and to identify bacterial taxonomic profile in the blood of septic patients. The presence of bacterial DNA was found both in septic and healthy subjects; however, bacterial diversity was significantly different (P = 0.002) between the studied groups. Among healthy volunteers, a significant predominance of anaerobic bacteria (76.2 %), of which most were bacteria of the order Bifidobacteriales (73.0 %), was observed. In sepsis, the majority of detected taxa belonged to aerobic or microaerophilic microorganisms (75.1 %). The most striking difference was seen in the case of Actinobacteria phyla, the abundance of which was decreased in sepsis (P < 0.001) and Proteobacteria phyla which was decreased in the healthy volunteers (P < 0.001). Our research shows that bacterial DNA can be detected in the blood of healthy people and that its taxonomic composition is different from the one seen in septic patients. Detection of bacterial DNA in the blood of healthy people may suggest that bacteria continuously translocate into the blood, but not always cause sepsis; this observation can be called DNAemia. PMID- 27771781 TI - A whole cell biocatalyst for double oxidation of cyclooctane. AB - A novel whole cell cascade for double oxidation of cyclooctane to cyclooctanone was developed. The one-pot oxidation cascade requires only a minimum of reaction components: resting E. coli cells in aqueous buffered medium (=catalyst), the target substrate and oxygen as environmental friendly oxidant. Conversion of cyclooctane was catalysed with high efficiency (50% yield) and excellent selectivity (>94%) to cyclooctanone. The reported oxidation cascade represents a novel whole cell system for double oxidation of non-activated alkanes including an integrated cofactor regeneration. Notably, two alcohol dehydrogenases from Lactobacillus brevis and from Rhodococcus erythropolis with opposite cofactor selectivities and one monooxygenase P450 BM3 were produced in a coexpression system in one single host. The system represents the most efficient route with a TTN of up to 24363 being a promising process in terms of sustainability as well. PMID- 27771782 TI - A systems biology approach to investigate the antimicrobial activity of oleuropein. AB - Oleuropein and its hydrolysis products are olive phenolic compounds that have antimicrobial effects on a variety of pathogens, with the potential to be utilized in food and pharmaceutical products. While the existing research is mainly focused on individual genes or enzymes that are regulated by oleuropein for antimicrobial activities, little work has been done to integrate intracellular genes, enzymes and metabolic reactions for a systematic investigation of antimicrobial mechanism of oleuropein. In this study, the first genome-scale modeling method was developed to predict the system-level changes of intracellular metabolism triggered by oleuropein in Staphylococcus aureus, a common food-borne pathogen. To simulate the antimicrobial effect, an existing S. aureus genome-scale metabolic model was extended by adding the missing nitric oxide reactions, and exchange rates of potassium, phosphate and glutamate were adjusted in the model as suggested by previous research to mimic the stress imposed by oleuropein on S. aureus. The developed modeling approach was able to match S. aureus growth rates with experimental data for five oleuropein concentrations. The reactions with large flux change were identified and the enzymes of fifteen of these reactions were validated by existing research for their important roles in oleuropein metabolism. When compared with experimental data, the up/down gene regulations of 80% of these enzymes were correctly predicted by our modeling approach. This study indicates that the genome-scale modeling approach provides a promising avenue for revealing the intracellular metabolism of oleuropein antimicrobial properties. PMID- 27771783 TI - Accessibility of opioid analgesics and barriers to optimal chronic pain treatment in Poland in 2000-2015. AB - PURPOSE: Based on the international reports, consumption of opioid analgesics in Poland is relatively low. There is limited information on possible impediments to optimal opioid use. This study was aimed to identify possible barriers to access to opioid analgesics and causes of failure to comply with current clinical guidelines. METHODS: Consumption data per capita in 2000-2015 were analyzed in terms of oral morphine equivalents in total, per prescription type, per reimbursement status, to identify the impact of regulations specific for Poland. RESULTS: The consumption of opioid analgesics has been consistently growing from 36.0 in 2000 to 103.4 mg oral morphine equivalents (OME) per capita in 2015, mainly thanks to strong opioid consumption growth. Tramadol is the most commonly used opioid in Poland. Fentanyl and buprenorphine transdermal formulations are the most frequently used strong opioid analgesics in terms of OME. The vast majority (92.8 %) of opioids were distributed upon for outpatient use in 2015, with a almost fourfold growth of consumption of strong opioids and almost threefold of weak opioids between 2000 and 2015. Strong opioids were 41 % of OME used upon prescription in 2015. Acceleration of consumption growth has been observed since 2013. CONCLUSIONS: The prescription pattern does not abide by the current clinical guidelines for pain treatment, and the most often used opioids in Poland are tramadol, buprenorphine, and fentanyl. The use of opioids in Poland grows fast, with acceleration since 2013. The most important legal impediments of optimal opioid analgesics use have been lack of reimbursement, special prescription forms, and complicated prescribing rules. PMID- 27771784 TI - Body weight changes in patients undergoing chemotherapy for ovarian cancer influence progression-free and overall survival. AB - PURPOSE: The aim of this study was to evaluate whether body weight changes in patients undergoing chemotherapy for epithelial ovarian cancer (EOC) influence progression-free survival (PFS) and overall survival (OS). METHODS: An analysis of 190 patients diagnosed with ovarian cancer after first-line chemotherapy was conducted. Changes in body weight were assessed by comparing measurements at baseline to those of the third and sixth cycles of chemotherapy. PFS and OS were calculated with the Kaplan-Meier method and multivariate Cox model. RESULTS: Significant reduction in body weight in advanced EOC was observed with no changes in early EOC. Significant differences in PFS were observed in advanced EOC patients that lost more than 5 % of their body weight (6 months), maintained weight (13 months), or gained more than 5 % of their body weight (15 months). Similarly, significant differences in OS were noted in advanced EOC at the following time points: 24.3, 42.4, and 66.2 months. No effect was reported for early EOC patients. The multivariate Cox analysis showed significant body weight changes from the first to the sixth chemotherapy cycle for PFS (HR = 0.97; 95 % CI 0.95-0.99) and OS (HR = 0.94; 95 % CI 0.91-0.97) as well as from the first to the third chemotherapy cycle for OS (HR = 0.93; 95 % CI 0.88-0.98). CONCLUSIONS: Body weight changes can be recognized as a prognostic factor for PFS and OS in advanced EOC patients undergoing chemotherapy. Weight loss is associated with poorer survival while weight gain improved outcomes. PMID- 27771785 TI - Psychometric properties and measurement equivalence of the English and Chinese versions of the Beck Anxiety Inventory in patients with breast cancer. AB - BACKGROUND: There is a lack of psychometric data for both the English and Chinese versions of Beck Anxiety Inventory (BAI) to support its usage among breast cancer patients. This study examined the psychometric properties and measurement equivalence of the English and Chinese versions of BAI among breast cancer patients in Singapore. METHODS: Patients were recruited from two major cancer centers in Singapore. The criterion and construct validity of BAI was assessed by its correlation strength with (1) the emotional functioning subdomain of EORTC QLQ-C30 and (2) constructs related to anxiety, namely fatigue, dyspnea, and quality of life. The known-group validity was assessed according to the patients' breast cancer stage, religious beliefs, and emotional functioning levels. The internal consistency of the BAI domains was evaluated using Cronbach's alpha coefficient. Regression analysis was performed to compare the BAI total and domain scores between the two language versions. RESULTS: Data from 244 patients (144 English-speaking and 100 Chinese-speaking) were analyzed. For both language versions, the BAI total scores correlated moderately with the EORTC QLQ-C30 emotional functioning subdomain (r = -0.655 and -0.601). Correlations with fatigue, quality of life, and dyspnea were moderate (|r| = 0.456-0.606). Patients with poorer emotional functioning reported higher anxiety levels, establishing known-group validity. All BAI domains demonstrated satisfactory internal consistencies (alpha = 0.74-0.87), except for the panic domain (alpha = 0.57 0.61). Possible measurement equivalence between the language versions was established. CONCLUSION: Both English and Chinese versions of BAI are valid, reliable, and possibly equivalent for future use. PMID- 27771786 TI - Do-not-resuscitate orders in cancer patients: a review of literature. AB - Discussing do-not-resuscitate (DNR) orders is part of daily hospital practice in oncology departments. Several medical factors and patient characteristics are associated with issuing DNR orders in cancer patients. DNR orders are often placed late in the disease process. This may be a cause for disagreements between doctors and between doctors and patients and may cause for unnecessary treatments and admissions. In addition, DNR orders on itself may influence the rest of the medical treatment for patients. We present recommendations for discussing DNR orders and medical futility in practice through shared decision-making. Prospective studies are needed to investigate in which a patient's cardiopulmonary resuscitation (CPR) is futile and whether or not DNR orders influence the medical care of patients. PMID- 27771788 TI - Normative data for parameters of sagittal spinal alignment in healthy subjects: an analysis of gender specific differences and changes with aging in 626 asymptomatic individuals. AB - PURPOSE: This study aims to establish normative data for parameters of spino pelvic and spinal sagittal alignment, gender related differences and age-related changes in asymptomatic subjects. METHODS: A total of 626 asymptomatic volunteers from Japanese population were enrolled in this study, including 50 subjects at least for each gender and each decade from 3rd to 8th. Full length, free-standing spine radiographs were obtained. Cervical lordosis (CL; C3-7), thoracic kyphosis (TK; T1-12), lumbar lordosis (LL; T12-S1), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS) and sagittal vertical axis (SVA) were measured. RESULTS: The average values (degrees) are 4.1 +/- 11.7 for CL, 36.0 +/- 10.1 for TK, 49.7 +/- 11.2 for LL, 53.7 +/- 10.9 for PI, 14.5 +/- 8.4 for PT, and 39.4 +/- 8.0 for SS. Mean SVA is 3.1 +/- 12.6 mm. Advancing age caused an increase in CL, PT and SVA, and a decrease in LL and SS. There was a significant gender difference in CL, TK, LL, PI, PT and SVA. From 7th decade to 8th decade, remarkable decrease of LL & TK and increase of PT were seen. A large increase of SVA was also seen between 60' and 70'. CONCLUSION: Standard values of spino-pelvic sagittal alignment were established in each gender and each decade from 20' to 70'. A remarkable change of spino-pelvic sagittal alignment was seen from 7th decade to 8th decade in asymptomatic subjects. PMID- 27771787 TI - Anterior cervical discectomy and fusion versus cervical arthroplasty for the management of cervical spondylosis: a meta-analysis. AB - PURPOSE: The aim of this study was to compare the efficacy and safety of anterior cervical discectomy and fusion (ACDF) and cervical arthroplasty for patients with cervical spondylosis. METHODS: PubMed, Embase, and Cochrane Library were used to search for relevant articles published prior to April 2016 to identify studies comparing ACDF and cervical arthroplasty involving patients with cervical spondylosis. Relative risks (RR) and mean differences (MD) were used to measure the efficacy and safety of ACDF and cervical arthroplasty using the random effects model. RESULTS: The meta-analysis of 17 studies involved 3122 patients diagnosed with cervical spondylosis. Patients undergoing ACDF showed lower overall success rate (RR 0.84; 95 % CI 0.77-0.92; P < 0.001), higher VAS score (MD 0.36; 95 % CI 0.08-0.64; P = 0.011), and shorter mean surgical duration (MD 1.62; 95 % CI -2.80 to -0.44; P = 0.007) when compared with cervical arthroplasty. However, the association between ACDF therapy and the risk of mean blood loss (MD -0.16; 95 % CI -0.34 to 0.02; P = 0.082), mean hospitalization (MD 0.02; 95 % CI -0.31 to 0.36; P = 0.901), patient satisfaction (RR 0.96; 95 % CI 0.92-1.00; P = 0.066), neck disability index (MD 0.20; 95 % CI -0.05 to 0.44; P = 0.113), reoperation (RR 1.25; 95 % CI 0.64-2.41; P = 0.514), or complication (RR 1.17; 95 % CI 0.90-1.52; P = 0.242) was not statistically significant. CONCLUSIONS: Patients undergoing ACDF therapy tended to exhibit lower overall success rate, higher VAS score, and decreased mean surgical duration when compared with patients treated with cervical arthroplasty. PMID- 27771789 TI - Comparison of outcomes after atlantoaxial fusion with C1 lateral mass-C2 pedicle screws and C1-C2 transarticular screws. AB - PURPOSE: To compare the clinical and radiological outcomes of posterior atlantoaxial fixation and fusion using C1 lateral mass-C2 pedicle screws (screw rod constructs, SRC) with C1-C2 transarticular screws (TAS). METHODS: A retrospective review was conducted of 105 patients with atlantoaxial instability who underwent posterior C1-C2 fixation and fusion by SRC group (60 pt) and TAS group (45 pt). The follow-up period was minimum 2 years. Clinical outcomes measurements included the Numeric Rating Scale (NRS) for pain assessment, the Neck Disability Index (NDI), the Japanese Orthopedic Association (JOA) score and the American Spinal Injury Association (ASIA) impairment scale for the functional and neurological outcomes that were assessed. Radiological outcomes were assessed by evaluating the fusion rate and proper screws position. Both outcomes were evaluated in the early postoperative period, 3, 6, 12 and 24 months after surgery. Operative time, estimated blood loss, complications and length of stay were also reviewed. RESULTS: The majority of cases were caused by trauma and presented with axial neck pain. The improvement of NRS, NDI, JOA score and ASIA impairment scale were not different between the two groups. Proper screw position and fusion rate were also observed similarly between the two groups. Estimated blood loss was lesser and operative time was shorter in TAS group than SRC group (p = 0.047, p = 0.001, respectively). Operative complications and the length of hospital stay were also not different between the two groups. CONCLUSION: Both SRC and TAS produced excellent outcomes for atlantoaxial stabilization. But the volume of bleeding and operation time tended to be better in TAS group compared to SRC group. PMID- 27771790 TI - Population structure and diversity of citrus tristeza virus (CTV) isolates in Hunan province, China. AB - Stem-pitting (SP) is the main type of citrus tristeza virus (CTV) that causes severe damage to citrus trees, especially those of sweet orange, in Hunan province, China. Understanding the local CTV population structure should provide clues for effective mild strain cross-protection (MSCP) of the SP strain of CTV. In this study, markers for the p23 gene, multiple molecular markers (MMMs), and sequence analysis of the three silencing suppressor genes (p20, p23 and p25) were employed to analyze the genetic diversity and genotype composition of the CTV population based on 51 CTV-positive samples collected from 14 citrus orchards scattered around six major citrus-growing areas of Hunan. The results indicated that the CTV population structure was extremely complex and that infection was highly mixed. In total, p23 gene markers resulted in six profiles, and MMMs demonstrated 25 profiles. The severe VT and T3 types appeared to be predominantly associated with SP, while the mild T30 and RB types were related to asymptomatic samples. Based on phylogenetic analysis of the amino acid sequences of p20, p23 and p25, 19 representative CTV samples were classified into seven recently established CTV groups and a potentially novel one. A high level of genetic diversity, as well as potential recombination, was revealed among different CTV isolates. Five pure SP severe and two pure mild strains were identified by genotype composition analysis. Taken together, the results update the genetic diversity of CTV in Hunan with the detection of one possible novel strain, and this information might be applicable for the selection of appropriate mild CTV strains for controlling citrus SP disease through cross-protection. PMID- 27771791 TI - The molecular epidemiological study of bovine leukemia virus infection in Myanmar cattle. AB - Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis, which is the most common neoplastic disease of cattle. BLV infects cattle worldwide and affects both health status and productivity. However, no studies have examined the distribution of BLV in Myanmar, and the genetic characteristics of Myanmar BLV strains are unknown. Therefore, the aim of this study was to detect BLV infection in Myanmar and examine genetic variability. Blood samples were obtained from 66 cattle from different farms in four townships of the Nay Pyi Taw Union Territory of central Myanmar. BLV provirus was detected by nested PCR and real-time PCR targeting BLV long terminal repeats. Results were confirmed by nested PCR targeting the BLV env-gp51 gene and real-time PCR targeting the BLV tax gene. Out of 66 samples, six (9.1 %) were positive for BLV provirus. A phylogenetic tree, constructed using five distinct partial and complete env-gp51 sequences from BLV strains isolated from three different townships, indicated that Myanmar strains were genotype-10. A phylogenetic tree constructed from whole genome sequences obtained by sequencing cloned, overlapping PCR products from two Myanmar strains confirmed the existence of genotype-10 in Myanmar. Comparative analysis of complete genome sequences identified genotype-10-specific amino acid substitutions in both structural and non-structural genes, thereby distinguishing genotype-10 strains from other known genotypes. This study provides information regarding BLV infection levels in Myanmar and confirms that genotype-10 is circulating in Myanmar. PMID- 27771792 TI - Molecular evidence of Orthopoxvirus DNA in capybara (Hydrochoerus hydrochaeris) stool samples. AB - Vaccinia virus (VACV) is responsible for outbreaks in Brazil and has immense potential as an emerging virus. VACV can be found naturally circulating in India, Pakistan and South America, where it causes infections characterised by exanthematic lesions in buffaloes, cattle and humans. The transmission cycle of Brazilian VACV has still not been fully characterised; one of the most important gaps in knowledge being the role of wild animals. Capybaras, which are restricted to the Americas, are the world's largest rodents and have peculiar characteristics that make them possible candidates for being part of a natural VACV reservoir. Here, we developed a method for detecting orthopoxvirus DNA in capybara stool samples, and have described for the first time the detection of orthopoxvirus DNA in capybaras samples from three different regions in Brazil. These findings strongly suggest that capybaras might be involved in the natural transmission cycle of VACV and furthermore represent a public health problem, when associated with Brazilian bovine vaccinia outbreaks. This makes infected animals an important factor to be considered when predicting and managing Brazilian VACV outbreaks. PMID- 27771793 TI - Identification and characterization of a new member of the genus Luteovirus from cherry. AB - The complete genomic sequence of a new virus from cherry trees was determined. Its genome is 5857 nt long and resembles that of members of the genus Luteovirus in its genomic organization and nucleotide sequence. Based on the species demarcation criteria for luteoviruses, the virus represents a new luteovirus species. Furthermore, a 47-nt-long inverted repeat was found at the 3' end of its genome. The virus has been provisionally named cherry-associated luteovirus (ChALV) and is the fourth member of the family Luteoviridae reported to naturally infect woody plants. PMID- 27771794 TI - An integrated approach using orthogonal analytical techniques to characterize heparan sulfate structure. AB - Heparan sulfate (HS), a glycosaminoglycan present on the surface of cells, has been postulated to have important roles in driving both normal and pathological physiologies. The chemical structure and sulfation pattern (domain structure) of HS is believed to determine its biological function, to vary across tissue types, and to be modified in the context of disease. Characterization of HS requires isolation and purification of cell surface HS as a complex mixture. This process may introduce additional chemical modification of the native residues. In this study, we describe an approach towards thorough characterization of bovine kidney heparan sulfate (BKHS) that utilizes a variety of orthogonal analytical techniques (e.g. NMR, IP-RPHPLC, LC-MS). These techniques are applied to characterize this mixture at various levels including composition, fragment level, and overall chain properties. The combination of these techniques in many instances provides orthogonal views into the fine structure of HS, and in other instances provides overlapping / confirmatory information from different perspectives. Specifically, this approach enables quantitative determination of natural and modified saccharide residues in the HS chains, and identifies unusual structures. Analysis of partially digested HS chains allows for a better understanding of the domain structures within this mixture, and yields specific insights into the non-reducing end and reducing end structures of the chains. This approach outlines a useful framework that can be applied to elucidate HS structure and thereby provides means to advance understanding of its biological role and potential involvement in disease progression. In addition, the techniques described here can be applied to characterization of heparin from different sources. PMID- 27771795 TI - Clinicopathological significance of caveolin-1 expression by cancer-associated fibroblasts in lung adenocarcinoma. AB - PURPOSE: Caveolin is an essential constituent of caveolae and has many biological functions. Expression of caveolin-1 in cancer cells was reported to be a prognostic marker in several types of cancers, the prognostic significance of its expression in cancer-associated fibroblasts (CAFs) has not been investigated. This study aimed to evaluate the clinicopathological significance of expression by CAFs in lung adenocarcinoma. METHODS: We examined caveolin-1 expression in both CAFs and cancer cells in stage I invasive lung adenocarcinoma (n = 412) and analyzed the relationship between the expression and clinicopathological factors. RESULTS: Caveolin-1 expression by CAFs and cancer cells was observed in 12.1% and 7.8% of adenocarcinomas, respectively. Tumors with caveolin-1-positive CAFs had vascular and pleural invasion significantly more frequently than those with caveolin-1-negative CAF (p < 0.05). This was also the cases with tumors with caveolin-1-positive cancer cells (p < 0.01). Caveolin-1 expression by CAFs and that by cancer cells were significant predictors of shorter recurrence-free survival (p < 0.001). Caveolin-1 expression by CAFs and cancer cells was found in 25% and 30% of solid predominant subtype, respectively, but only 9.2% and 2.7% of non-solid predominant subtype, respectively. The frequency of cases with caveolin 1-positive CAFs or cancer cells was significantly higher in the solid predominant subtype than in non-solid predominant subtype (p < 0.001). CONCLUSIONS: Our current results highlight the prognostic importance of caveolin-1 expression by CAFs in stage I lung adenocarcinoma and provide new insights into the biological significance of caveolin-1 in the tumor microenvironment, especially in microenvironment of solid predominant adenocarcinoma. PMID- 27771797 TI - Sex Pheromone of the Cotton Mealybug, Phenacoccus solenopsis, with an Unusual Cyclobutane Structure. AB - The cotton mealybug, Phenacoccus solenopsis, the distribution of which was formerly limited to Nearctic and Neotropical regions, recently invaded many countries in various regions including Asia, Africa, and the Pacific. More recently, P. solenopsis was newly recorded in Japan and is currently an emerging pest of agricultural crops. In this study, we determined the structure of a sex pheromone of P. solenopsis in order to develop an effective lure for monitoring this pest. From volatiles emitted by virgin adult females, we isolated a compound attractive to males. By means of coupled gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy, we identified this as (2,2-dimethyl-3 isopropylidenecyclobutyl)methyl 3-methylbut-2-enoate. This compound was synthesized and shown to be attractive to male P. solenopsis. Analysis by gas chromatography using an enantioselective stationary phase and polarimetry analyses of the natural pheromone and synthetic enantiomers showed the natural compound to be the (R)-(-)-enantiomer. This compound is an ester of maconelliol, which has an unusual cyclobutane structure found in sex pheromones of other mealybug species, and senecioic acid, also found in the pheromones of other mealybug species. However, this is the first example of the ester of maconelliol and senecioic acid as a natural product. PMID- 27771796 TI - Bilateral pelvic lymph node dissection for Chinese patients with penile cancer: a multicenter collaboration study. AB - BACKGROUND: Current guidelines recommend pelvic lymphadenectomy (PLND) for patients with pelvic lymph node metastasis and special state. However, these data and recommendations do not distinguish the role of PLND in different patient groups and confirm the final benefits. The aim of this study was to confirm the efficacy of pelvic lymphadenectomy (PLND) for the different groups of patients. METHODS: Data obtained from 7 centers were retrospectively analyzed. Of the patients, 190 pN2-3 penile carcinoma patients confirmed by bilateral inguinal lymph node excision were included in this study. Sixty-nine and 121 of these patients did and did not undergo bilateral PLND, respectively. The baseline differences from the patients were matched by propensity score analysis. RESULTS: In this study, the Kaplan-Meier estimated disease-specific survival (DSS) was not significantly different between the PLND and no-PLND groups (P = 0.796). According to the propensity score matching for T stage, N stage, grade, adjuvant therapies, and lymph node stage (number of inguinal lymph node metastasis and extranodal extension), 48 patients were selected for each group. Among the pN2 patients, the PLND group showed higher DSS rates than the no-surgery group (P = 0.030). However, even after matching, survival did not differ between the PLND and no-PLND patients among all patients (P = 0.609) and pN3 patients (P = 0.417) with comparable DSS. CONCLUSION: Bilateral PLND may improve survival in pN2 patients. Men with pN3 may not benefit from bilateral PLND. PMID- 27771798 TI - Synergism between Enantiomers Creates Species-Specific Pheromone Blends and Minimizes Cross-Attraction for Two Species of Cerambycid Beetles. AB - Research over the last decade has revealed extensive parsimony among pheromones within the large insect family Cerambycidae, with males of many species producing the same, or very similar aggregation pheromones. Among some species in the subfamily Cerambycinae, interspecific attraction is minimized by temporal segregation, and/or by minor pheromone components that synergize attraction of conspecifics or inhibit attraction of heterospecifics. Less is known about pheromone-based mechanisms of reproductive isolation among species in the largest subfamily, the Lamiinae. Here, we present evidence that the pheromone systems of two sympatric lamiine species consist of synergistic blends of enantiomers of (E) 6,10-dimethyl-5,9-undecadien-2-ol (fuscumol) and the structurally related (E) 6,10-dimethyl-5,9-undecadien-2-yl acetate (fuscumol acetate), as a mechanism by which species-specific blends of pheromone components can minimize interspecific attraction. Male Astylidius parvus (LeConte) were found to produce (R)- and (S) fuscumol + (R)-fuscumol acetate + geranylacetone, whereas males of Lepturges angulatus (LeConte) produced (R)- and (S)-fuscumol acetate + geranylacetone. Field experiments confirmed that adult beetles were attracted only by their species-specific blend of the enantiomers of fuscumol and fuscumol acetate, respectively, and not to the individual enantiomers. Because other lamiine species are known to produce single enantiomers or blends of enantiomers of fuscumol and/or fuscumol acetate, synergism between enantiomers, or inhibition by enantiomers, may be a widespread mechanism for forming species-specific pheromone blends in this subfamily. PMID- 27771800 TI - Changes in resting mitogen-activated protein kinases following resistance exercise overreaching and overtraining. AB - PURPOSE: Many physiological maladaptations persist after overreaching and overtraining resistance exercise (RE). However, no studies have investigated changes in mitogen-activated protein kinases (MAPK) after overtraining in humans, despite their critical role regulating exercise-induced muscular adaptations. The purpose of this study was to describe the changes in total and resting phosphorylation status of extracellular signal-regulated kinase 1/2 (ERK1/2), c Jun NH2-terminal kinase (JNK) and p38-MAPK following a period of RE overreaching or overtraining. METHODS: Following 2-4 weeks of normal training (low volume/low intensity), two groups of males performed either a high-power overreaching protocol (HPOR n = 6, mean +/- SD, age 23 +/- 3.4 years, mass 86.5 +/- 17.7 kg, height 1.77 +/- 0.06 m) or high-intensity overtraining protocol (HIOT n = 8, age 19.8 +/- 1.8 years, mass 76.8 +/- 6.7 kg, height 1.8 +/- 0.06 m). Resting muscle biopsies were obtained at baseline (BL; end of normal training period) and 24 h after the final session of stressful training (i.e., HPOR or HIOT programs). Total MAPK and ratio of phosphorylated/total (p-MAPK)- ERK1/2, JNK, and p38-MAPK were analyzed via western blotting. 2 * 2 (group * time) ANOVA determined differences in MAPK between BL and post-training protocols. RESULTS: Compared to BL, total-ERK increased after HPOR, but decreased after HIOT (p <= 0.05). p ERK1/2/total-ERK increased after HIOT (p <= 0.05). The ratio of p-JNK/total-JNK and p-ERK1/2/total-ERK decreased after HPOR (p <= 0.05); however, this result was primarily due to increased total MAPK content. p-p38-MAPK decreased after HPOR (p <= 0.05). CONCLUSION: Total and p-MAPK are differentially expressed after HPOR and HIOT RE. These changes are likely involved in the maladaptation reported in overreaching and overtraining exercise. This is the first study describing altered MAPK in RE overtrained and overreached humans. PMID- 27771799 TI - Salbutamol effects on systemic potassium dynamics during and following intense continuous and intermittent exercise. AB - PURPOSE: Salbutamol inhalation is permissible by WADA in athletic competition for asthma management and affects potassium regulation, which is vital for muscle function. Salbutamol effects on arterial potassium concentration ([K+]a) during and after high-intensity continuous exercise (HIcont) and intermittent exercise comprising repeated, brief sprints (HIint), and on performance during HIint are unknown and were investigated. METHODS: Seven recreationally active men participated in a double-blind, randomised, cross-over design, inhaling 1000 ug salbutamol or placebo. Participants cycled continuously for 5 min at 40 % [Formula: see text]O2peak and 60 % [Formula: see text]O2peak, then HIcont (90 s at 130 % [Formula: see text]O2peak), 20 min recovery, and then HIint (3 sets, 5 * 4 s sprints), with 30 min recovery. RESULTS: Plasma [K+]a increased throughout exercise and subsequently declined below baseline (P < 0.001). Plasma [K+]a was greater during HIcont than HIint (P < 0.001, HIcont 5.94 +/- 0.65 vs HIint set 1, 4.71 +/- 0.40 mM); the change in [K+]a from baseline (Delta[K+]a) was 2.6-fold greater during HIcont than HIint (P < 0.001). The Delta[K+] throughout the trial was less with salbutamol than placebo (P < 0.001, treatment main effect, 0.03 +/- 0.67 vs 0.22 +/- 0.69 mM, respectively); and remained less after correction for fluid shifts (P < 0.001). The Delta[K+] during HIcont was less after salbutamol (P < 0.05), but not during HIint. Blood lactate, plasma pH, and the work output during HIint did not differ between trials. CONCLUSIONS: Inhaled salbutamol modulated the [K+]a rise across the trial, comprising intense continuous and intermittent exercise and recovery, lowering Delta[K+] during HIcont. The limited [K+]a changes during HIint suggest that salbutamol is unlikely to influence systemic [K+] during periods of intense effort in intermittent sports. PMID- 27771801 TI - Characteristics of Autism Spectrum Disorder in Sotos Syndrome. AB - Sotos syndrome is a congenital overgrowth disorder with an incidence of approximately 1 in 14,000. This study investigated behavioural characteristics of ASD within a large cohort of individuals with Sotos syndrome (n = 78). As measured by the Social Responsiveness Scale, second edition (SRS-2), 65 participants (83.33 %) met clinical cut-off (T-score >=60). There was no significant gender difference in symptom severity. There was a significant effect of age, with lower scores observed in early childhood and adulthood, compared to childhood. Furthermore, individuals with Sotos syndrome appear to display a trait profile that is similar to that identified in ASD. Overall, these findings indicate that the majority of individuals with Sotos syndrome display clinically significant behavioural symptomatology associated with ASD. PMID- 27771802 TI - Evaluation of the infectivity and the persistence of Trichinella patagoniensis in muscle tissue of decomposing guinea pig (Cavia porcellus). AB - Trichinella patagoniensis, a new species of Trichinella, is widespread in Argentina. The success of parasite transmission depends, among other factors, on the resistance of L1 larvae present in the muscle tissue (ML) of dead hosts undergoing the decomposition process in different environmental conditions. The aim of the present work was to study the infectivity of T. patagoniensis muscle larvae in Cavia porcellus and the capability of the parasite to survive in decomposed muscle tissue of guinea pigs subjected to different environmental conditions. Thirty-two female Ssi:AL guinea pigs were orally inoculated with 2000 ML of T. patagoniensis (ISS2311). All the animals were sacrificed 42 days post infection. Twenty-six animals were eviscerated, and carcasses were placed on the surface of soil inside plastic boxes that were exposed to environmental conditions in the summer 2014-2015 and autumn of 2015 in Buenos Aires, Argentina. Carcasses from six animals were placed into a plastic box inside the refrigerator at a temperature of 4 degrees C. The muscle tissue samples from the carcasses were examined weekly for the presence of larvae, and the infectivity of recovered ML was tested in BALB/c mice. Our results showed for the first time the ability of T. patagoniensis to complete its life cycle in guinea pigs, thus serving as a potential natural host. Also, larvae of T. patagoniensis remained infective in muscle tissue for several weeks while undergoing decomposition under different environmental conditions. PMID- 27771806 TI - The Moonglow, 1945. PMID- 27771803 TI - Efficacy against nematode infections and safety of afoxolaner plus milbemycin oxime chewable tablets in domestic dogs under field conditions in Europe. AB - Afoxolaner (AFX) plus milbemycin oxime (MO) combination chewable tablets (NexGard Spectra(r), Merial) were evaluated for safety and efficacy against naturally acquired nematode infections in domestic dogs in a multi-centre, positive control, blinded field study using a randomized block design based on the order of presentation for allocation. In total, 408 dogs confirmed positive for naturally acquired infections of intestinal nematodes by pre-treatment faecal examination were studied in ten countries in Europe (Albania, Austria, Bulgaria, France, Germany, Hungary, Italy, Lithuania, Romania and Slovakia). Pre-treatment faecal examination revealed Toxocara, Toxascaris, hookworm, Trichuris and/or Capillaria nematode infections in 134, 30, 223, 155 and 14 dogs, respectively. Dogs were allocated to one of two treatment groups in a ratio of 1, AFX + MO chewables (>=2.5 mg AFX + >=0.5 mg MO per kg body weight, according to dose bands; 207 dogs), and 1, MO plus praziquantel (PRZ) chewables (Milbemax(r), Novartis; >=0.5 mg MO + >=5 mg PRZ per kg body weight, according to the manufacturer's instructions; 201 dogs) and treated once. For evaluation of efficacy based on reduction of faecal nematode egg counts, two faecal samples, one collected prior to treatment and one collected 9 to 21 days after treatment, were examined using modified McMaster techniques. For evaluation of systemic safety, dogs were examined by a veterinarian before treatment administration and at study end, and dog owners observed the health status of their dogs until the end of the study and reported any abnormal observation. For dogs treated with AFX + MO chewables, the efficacy was 99.7, 99.7, 97.2, 99.7 and 99.7 % for Toxocara, Toxascaris, hookworm, Trichuris and Capillaria, respectively; and the efficacy was 99.5, 99.4, 94.3, 99.9 and 98.0 %, respectively, for the MO + PRZ-treated dogs (p <= 0.002 for all nematodes and both treatments). For Toxocara, hookworm and Trichuris, non-inferiority analysis demonstrated that the efficacy of AFX + MO chewable tablets was equal to or better than that of MO + PRZ. In spite that both treatments were >=98 % efficacious against Toxascaris and Capillaria, a hypothesis of non-inferiority for both genera could not be established due to the low number of dogs infected with these parasites. No treatment-related adverse experiences were observed throughout the study. For both treatments, all dogs were given a systemic safety score of 'excellent' apart from one dog in each treatment group which received a score of 'acceptable'. AFX + MO combination chewables were shown to be safe and demonstrated a high level of efficacy when administered once to dogs infected with a broad range of parasitic nematodes under field conditions. PMID- 27771805 TI - A Novel Fluorescent Biosensor for Detection of Silver Ions Based on Upconversion Nanoparticles. AB - In this paper, we report a simple and sensitive fluorescent biosensor for the quantitative analysis of silver ions (Ag+) by using NaYF4:Yb3+, Tm3+ upconversion nanoparticles (UCNPs). Ag+ could oxidize o-phenylenediamine (OPD) to the oxidized OPD (oxOPD) directly. The fluorescence of UCNPs can be significantly quenched by oxOPD through inner filter effects (IFE). Under the optimized conditions, the Ag+ concentration is proportional to the changes of the fluorescence intensity of UCNPs. The proposed method shows high selectivity and Ag+ could be quantitatively detected in the range of 0 to 0.5 mM with a low detection limit of 33 nM for Ag+. The selectivity and sensitivity of the detection can also be satisfactory. More importantly, this method has potential in practical application to detect Ag+ in real samples without interference. PMID- 27771804 TI - Overcoming research barriers in Chagas disease-designing effective implementation science. AB - Chagas disease is a complex tropical parasitic infection. It affects a significant portion of the population in Latin America, especially in areas of poverty and poor access to health care. It also affects immigrants in high-income countries who lack access to health care due to their legal status. Millions of people are at risk of contracting the disease, and approximately 30 % of chronically infected patients will develop cardiomyopathy. The cost of caring for patients that have been infected is substantial. Basic science research has introduced new concepts and knowledge for the parasite and vector biology as well as better understanding of the pathophysiology of the disease. These research findings nevertheless require effective and timely translation into clinical practice. Likewise, the design of new research projects should account for the multiple system-based barriers. Implementation science facilitates the applicability of research findings and identifies barriers to its execution. Creation of implementation science measures to reach and sustain research programs with greater potential to impact Chagas disease are lacking. This point of view proposes opportunities for implementation science in Chagas disease and strategies for researching effective interventions for preventing and treating the disease. PMID- 27771807 TI - Effects of photodynamic therapy, 2 % chlorhexidine, triantibiotic mixture, propolis and ozone on root canals experimentally infected with Enterococcus faecalis: an in vitro study. AB - The aim of this study was to evaluate the antibacterial effect of photodynamic therapy (PDT), 2 % chlorhexidine (CHX). The teeth were contaminated with 0.1 mL Enterococcus faecalis (3 * 108 cell/mL) and randomized into eight treatment groups: Group 1 (2.5 % NaOCl); Group 2 (PDT); Group 3 (2 % CHX); Group 4 (TAM); Group 5 (propolis), Group 6 (ozone), Group 7 (positive control) and Group 8 (negative control). Following treatment, the canal content was sampled. The samples were cultured in triplicate on blood agar plates to determine the number of colony forming units (CFU)/mL. The teeth were analyzed by SEM to determine the percentage of area with contamination and debris. The group with the lowest CFU/mL count was the ozone group, which obtained similar values to the PDT group. SEM images showed that 2.5 % NaOCL group showed the lowest percentage of contaminated area. Applications of PDT, 2 % CHX, TAM, propolis and ozone showed antibacterial potential similar to 2.5 % NaOCL. PMID- 27771809 TI - Identification of a second PAD1 in Brettanomyces bruxellensis LAMAP2480. AB - Volatile phenols are aromatic compounds produced by some yeasts of the genus Brettanomyces as defense against the toxicity of hydroxycinnamic acids (p coumaric acid, ferulic acid and caffeic acid). The origin of these compounds in winemaking involves the sequential action of two enzymes: coumarate decarboxylase and vinylphenol reductase. The first one converts hydroxycinnamic acids into hydroxystyrenes, which are then reduced to ethyl derivatives by vinylphenol reductase. Volatile phenols derived from p-coumaric acid (4-vinylphenol and 4 ethylphenol) have been described as the major contributors to self-defeating aromas associated with stable, gouache, wet mouse, etc., which generates large economic losses in the wine industry. The gene responsible for the production of 4-vinylphenol from p-coumaric acid has been identified as PAD1, which encodes a phenylacrylic acid decarboxylase. PAD1 has been described for many species, among them Candida albicans, Candida dubliniensis, Debaryomyces hansenii and Pichia anomala. In Brettanomyces bruxellensis LAMAP2480, a 666 bp reading frame (DbPAD) encodes a coumarate decarboxylase. Recent studies have reported the existence of a new reading frame belonging to DbPAD called DbPAD2 of 531 bp, which could encode a protein with similar enzymatic activity to PAD1. The present study confirmed that the transformation of Saccharomyces cerevisiae strain BY4722 with reading frame DbPAD2 under the control of the B. bruxellensis ACT1 promoter, encodes an enzyme with coumarate decarboxylase activity. This work has provided deeper insight into the origin of aroma defects in wine due to contamination by Brettanomyces spp. PMID- 27771808 TI - Systematized water content calculation in cartilage using T1-mapping MR estimations: design and validation of a mathematical model. AB - BACKGROUND: Up to 80 % of cartilage is water; the rest is collagen fibers and proteoglycans. Magnetic resonance (MR) T1-weighted measurements can be employed to calculate the water content of a tissue using T1 mapping. In this study, a method that translates T1 values into water content data was tested statistically. MATERIALS AND METHODS: To develop a predictive equation, T1 values were obtained for tissue-mimicking gelatin samples. 1.5 T MRI was performed using inverse angle phase and an inverse sequence at 37 (+/-0.5) degrees C. Regions of interest were manually delineated and the mean T1 value was estimated in arbitrary units. Data were collected and modeled using linear regression. To validate the method, articular cartilage from six healthy pigs was used. The experiment was conducted in accordance with the Danish Animal Experiment Committee. Double measurements were performed for each animal. Ex vivo, all water in the tissue was extracted by lyophilization, thus allowing the volume of water to be measured. This was then compared with the predicted water content via Lin's concordance correlation coefficient at the 95 % confidence level. RESULTS: The mathematical model was highly significant when compared to a null model (p < 0.0001). 97.3 % of the variation in water content can be explained by absolute T1 values. Percentage water content could be predicted as 0.476 + (T1 value) * 0.000193 * 100 %. We found that there was 98 % concordance between the actual and predicted water contents. CONCLUSION: The results of this study demonstrate that MR data can be used to predict percentage water contents of cartilage samples. LEVEL OF EVIDENCE: 3 (case-control study). PMID- 27771810 TI - Investigating the effects of point mutations on the affinity between the cyanobacterial lectin microvirin and high mannose-type glycans present on the HIV envelope glycoprotein. AB - Human immunodeficiency virus (HIV) infections continue to exert an enormous impact on global human health. This led experts to emphasize the importance of new measures for preventing HIV infections, including the development of vaccines and novel drugs. In this context, a promising approach involves the use of lectins that can bind the surface envelope glycoprotein gp120 of HIV with high affinity, preventing viral entry. The cyanobacterial lectin microvirin (MVN) has been proposed as a candidate for development as a topical microbicide because of its ability to bind to high mannose-type glycans, potently inhibiting HIV-1 entry. Thus, the aim of this computational study was to investigate the effects of four point mutations (D53Q, D53E, D53K, and D53W) on the structure and affinity of MVN with di-mannose (MAN). Molecular dynamics simulations followed by binding free energy calculations using MM-GBSA were employed. The calculated binding free energy of ligand-receptor complexation of MVN with MAN was -26.02 kcal mol-1. We identified in the wild-type protein that residues I45, T59, and Q81 have a major contribution to the binding free energy of di-mannose. Among the investigated mutants, the most promising one was the D53W mutation, with a theoretical binding free energy value of -29.16 kcal mol-1. We suggest that this increased stability is due to the introduction of extra rigidity on the hinge region connecting two key structural elements of the MVN binding site. PMID- 27771811 TI - Constitutive description of human femoropopliteal artery aging. AB - Femoropopliteal artery (FPA) mechanics play a paramount role in pathophysiology and the artery's response to therapeutic interventions, but data on FPA mechanical properties are scarce. Our goal was to characterize human FPAs over a wide population to derive a constitutive description of FPA aging to be used for computational modeling. Fresh human FPA specimens ([Formula: see text]) were obtained from [Formula: see text] predominantly male (80 %) donors 54+/-15 years old (range 13-82 years). Morphometric characteristics including radius, wall thickness, opening angle, and longitudinal pre-stretch were recorded. Arteries were subjected to multi-ratio planar biaxial extension to determine constitutive parameters for an invariant-based model accounting for the passive contributions of ground substance, elastin, collagen, and smooth muscle. Nonparametric bootstrapping was used to determine unique sets of material parameters that were used to derive age-group-specific characteristics. Physiologic stress-stretch state was calculated to capture changes with aging. Morphometric and constitutive parameters were derived for seven age groups. Vessel radius, wall thickness, and circumferential opening angle increased with aging, while longitudinal pre stretch decreased ([Formula: see text]). Age-group-specific constitutive parameters portrayed orthotropic FPA stiffening, especially in the longitudinal direction. Structural changes in artery wall elastin were associated with reduction of physiologic longitudinal and circumferential stretches and stresses with age. These data and the constitutive description of FPA aging shed new light on our understanding of peripheral arterial disease pathophysiology and arterial aging. Application of this knowledge might improve patient selection for specific treatment modalities in personalized, precision medicine algorithms and could assist in device development for treatment of peripheral artery disease. PMID- 27771814 TI - Factor Analysis of Therapist-Identified Treatment Targets in Community-Based Children's Mental Health. AB - The present study used exploratory and confirmatory factor analyses to identify underlying latent factors affecting variation in community therapists' endorsement of treatment targets. As part of a statewide practice management program, therapist completed monthly reports of treatment targets (up to 10 per month) for a sample of youth (n = 790) receiving intensive in-home therapy. Nearly 75 % of youth were diagnosed with multiple co-occurring disorders. Five factors emerged: Disinhibition, Societal Rules Evasion, Social Engagement Deficits, Emotional Distress, and Management of Biodevelopmental Outcomes. Using logistic regression, primary diagnosis predicted therapist selection of Disinhibition and Emotional Distress targets. Client age predicted endorsement of Societal Rules Evasion targets. Practice-to-research implications are discussed. PMID- 27771813 TI - A case of multiple gastrointestinal stromal tumors caused by a germline KIT gene mutation (p.Leu576Pro). AB - Multiple gastrointestinal stromal tumors (GISTs) caused by germline KIT gene mutations are an extremely rare autosomal dominant disorder. We report a case of a 21-year-old woman who presented to the emergency department with a 2-week history of asthenia, palpitations and upper gastrointestinal bleeding. After further clinical evaluation one gastric and two small bowel GISTs were diagnosed, which were surgically resected after neoadjuvant therapy with Imatinib. Diffuse hyperplasia of the interstitial cells of Cajal was also seen in the background gastric and small intestinal walls. Somatic mutational analysis of the KIT gene revealed a substitution at codon 576 in exon 11 (p.Leu576Pro) in all tumors and normal ileal mucosa. The germline nature of this mutation was confirmed by mutation analysis in peripheral blood leukocytes. However, she had no familial history of GISTs and her parents did not carry the respective germline mutation. PMID- 27771816 TI - Ending AIDS: All Hands on Deck. PMID- 27771815 TI - Array of translational systems pharmacodynamic models of anti-cancer drugs. AB - Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems. However, reliable mechanistic and systems PK/PD models for anti-cancer agents have been developed and successfully applied to: (1) provide insights into fundamental mechanisms implicated in tumor growth, (2) assist in dose selection for first-in-human phase I studies (e.g., effective dose, escalating doses, and maximal tolerated doses), (3) design and optimize combination drug regimens, (4) design clinical trials, and (5) establish links between drug efficacy and safety and the concentrations of measured biomarkers. In this commentary, classes of relevant mechanism-based and systems PK/PD models of anti-cancer agents that have shown promise in translating preclinical data and enhancing stages of the drug development process are reviewed. Specific features of such models are discussed including their strengths and limitations along with a prospectus of using these models alone or in combination for cancer therapy. PMID- 27771817 TI - Policy Changes and Improvements in Health Insurance Coverage Among MSM: 20 U.S. Cities, 2008-2014. AB - Recent policy changes have improved the ability of gay, bisexual, and other men who have sex with men (MSM) to secure health insurance. We wanted to assess changes over time in self-reported health insurance status among MSM participating in CDC's National HIV Behavioral Surveillance (NHBS) in 2008, 2011, and 2014. We analyzed NHBS data from sexually active MSM interviewed at venues in 20 U.S. cities. To determine if interview year was associated with health insurance status, we used a Poisson model with robust standard errors. Among included MSM, the overall percentage of MSM with health insurance rose 16 % from 2008 (68 %) to 2014 (79 %) (p value for trend < 0.001). The change in coverage over time was greatest in key demographic segments with lower health insurance coverage all three interview years, by age, education, and income. Corresponding with recent policy changes, health insurance improved among MSM participating in NHBS, with greater improvements in historically underinsured demographic segments. Despite these increases, improved coverage is still needed. Improved access to health insurance could lead to a reduction in health disparities among MSM over time. PMID- 27771818 TI - Minority Men Who Have Sex with Men Demonstrate Increased Risk for HIV Transmission. AB - Black and Hispanic (minority) MSM have a higher incidence of HIV than white MSM. Multiple sexual partners, being under the influence of drugs and/or alcohol during sex, having a detectable HIV-1 RNA, and non-condom use are factors associated with HIV transmission. Using data from the Veterans Aging Cohort Study, we consider minority status and sexual orientation jointly to characterize and compare these factors. White non-MSM had the lowest prevalence of these factors (p < 0.001) and were used as the comparator group in calculating odds ratios (OR). Both MSM groups were more likely to report multiple sex partners (white MSM OR 7.50; 95 % CI 5.26, 10.71; minority MSM OR 10.24; 95 % CI 7.44, 14.08), and more likely to be under the influence during sex (white MSM OR 2.15; 95 % CI 1.49, 3.11; minority MSM OR 2.94; 95 % CI 2.16, 4.01). Only minority MSM were more likely to have detectable HIV-1 RNA (OR 1.87; 95 % CI 1.12, 3.11). Both MSM groups were more likely to use condoms than white non-MSM. These analyses suggest that tailored interventions to prevent HIV transmission among minority MSM are needed, with awareness of the potential co-occurrence of risk factors. PMID- 27771819 TI - Ethylene promotes mycelial growth and ganoderic acid biosynthesis in Ganoderma lucidum. AB - OBJECTIVE: To investigate the effects of ethylene, in the form of ethephon (2 chloroethylphosphonic acid), on mycelial growth and ganoderic acid (GA) accumulation in the higher basidiomycete Ganoderma lucidum. RESULTS: Treatment with both 10 and 15 mM ethephon enhanced the growth of G. lucidum on solid CYM plates and in CYM liquid medium. After optimization using response surface methodology, GA reached 33 mg/g dry cell weight (DW), an increase of 90 %, compared with the control. Lanosterol and squalene contents were 31 and 2.4 MUg/g DW, being increased by 1.2- and 0.6-fold, respectively, in response to ethephon. Additionally, the transcriptional levels of hydroxymethylglutaryl-CoA reductase, squalene synthase and oxidosqualene cyclase were up-regulated by 2.6-, 4.3- and 3.8-fold, respectively, compared with the control group. CONCLUSIONS: This approach provides an efficient strategy for improving GA accumulation in G. lucidum, with potential future applications. PMID- 27771820 TI - Meta-analysis of efficacy and safety of apixaban and uninterrupted apixaban therapy compared to vitamin K antagonists in patients undergoing catheter ablation for atrial fibrillation. AB - BACKGROUND: Apixaban is a Factor Xa inhibitor increasingly being used for stroke prevention in atrial fibrillation (AF). Although several studies have been done, the efficacy and safety of apixaban during the peri-procedural period of AF ablation remains unclear. We sought to systematically review pooled data from these various studies to evaluate thromboembolic and bleeding risks in patients undergoing catheter ablation for AF who are treated with apixaban (interrupted and uninterrupted). METHODS: Studies comparing anticoagulation with apixaban or vitamin K antagonists (VKA) in patients undergoing ablation for AF were identified via an electronic search of MEDLINE, EMBASE, clinical trials.gov, and Cochrane Library from inception to January 2016. Study-specific risk ratios were calculated and combined with a fixed-effects model meta-analysis. RESULTS: In the analysis of 2100 pooled patients, thromboembolic complications (TE) occurred in 14/778 (1.80 %) patients in the apixaban group (AG) compared to 20/1322 patients in the VKA group (RR 1.03, 95 % CI 0.55-1.90, p = 0.93, I 2 = 0 %). Major bleeding occurred in 9/778 (1.2 %) of the AG compared to 20/1322 (1.51 %) in the VKA group (RR 1.03, 95 % CI 0.55-1.90, p = 0.93, I 2 = 0 %). In uninterrupted apixaban group (uAG), TE occurred in 4/585 (0.68 %) patients in the uAG compared to 6/910 (0.66 %) in VKA group (RR 0.86, 95 % CI 0.25-2.95, p = 0.81, I 2 = 0 %). Major bleeding occurred in 5/585 (0.85 %) in uAG compared to 7/910 (0.77 %) in the VKA group (RR 1.20, 95 % CI 0.37-3.88, p = 0.76, I 2 = 0 %). CONCLUSION: Our study demonstrates patients treated with apixaban and VKA during the peri procedural period for AF ablation have similar rates of TE and bleeding complications. Interrupted and uninterrupted apixaban strategies were associated with similar outcomes. PMID- 27771821 TI - Potentially harmful elements in house dust from Estarreja, Portugal: characterization and genotoxicity of the bioaccessible fraction. AB - Due to their behavioral characteristics, young children are vulnerable to the ingestion of indoor dust, often contaminated with chemicals that are potentially harmful. Exposure to potentially harmful elements (PHEs) is currently exacerbated by their widespread use in several industrial, agricultural, domestic and technological applications. PHEs cause adverse health effects on immune and nervous systems and can lead to cancer development via genotoxic mechanisms. The present study is an integrated approach that aims at assessing the genotoxicity of bioaccessible PHEs following ingestion of contaminated house dust. A multidisciplinary methodology associating chemical characterization of five house dust samples, extraction of the bioaccessible PHEs in gastric extracts by the unified BARGE method, determination of the bioaccessible fraction and in vitro genotoxicity of gastric extracts in adenocarcinoma gastric human (AGS) cells was developed. The five gastric extracts induced dose-dependent genotoxicity in AGS cells. Copper (bioaccessible concentration up to 111 mg/kg) was probably the prevalent PHE inducing primary DNA damage (up to 5.1-fold increase in tail DNA at 0.53 g/l of gastric extract). Lead (bioaccessible concentration up to 245 mg/kg) was the most prevalent PHE inducing chromosome-damaging effects (r = 0.55; p < 0.001 for micronucleated cells induction). The association of principal component analysis and Spearman's correlations was decisive to understand the chromosome damaging properties of the bioaccessible PHEs in AGS cells. This methodology could be used on a larger-scale study to provide useful information for science based decision-making in regulatory policies, and a better estimation of human exposure and associated health risks. PMID- 27771822 TI - "Life is at a standstill" Quality of life after lower extremity trauma in Malawi. AB - PURPOSE: Low- and middle-income countries face a disproportionate burden of death and disability from injuries, many of which are due to road traffic accidents or falls. Lower extremity injuries in particular have implications not only for physical disabilities affecting work and school performance, but also for quality of life (QOL) of the individual. This qualitative study explores the psychosocial impact and QOL changes due to lower extremity injuries among trauma patients in central Malawi. METHODS: We transcribed and translated interviews with 20 patients who received care for a trauma to the lower extremity at a tertiary hospital in Lilongwe. We used NVivo to organize and thematically analyze the data. RESULTS: Participants reported limitations in physical functioning, activities of daily living, social roles, and vocational and social activities. Limited mobility led to unplanned long-term disruptions in work, personal financial loss, and household economic hardship. As a result, psychological distress, fears and worries about recovery, and poor perceptions of health and QOL were common. Several contextual factors influenced patient outcomes including socioeconomic status, religious beliefs, social networks, local landscape, housing structures, and transportation accessibility. CONCLUSION: Lower extremity trauma led to physical suffering and ongoing social and economic costs among Malawians. Injuries affecting mobility have broad QOL and economic consequences for patients and affected family members. Interventions are needed to improve post-injury recovery and QOL. Better access to trauma surgery and social and welfare support services for people living with disabling conditions are needed to alleviate the consequences of injuries. PMID- 27771823 TI - Effect of nepafenac on the foveal profile of glaucomatous patients undergoing phacoemulsification. AB - PURPOSE: Retrospective, pilot study to determine whether nepafenac treatment pre- and postcataract surgery in glaucoma patients using topical hypotensive agents minimized cystoid macular edema by comparing pre- and postsurgical foveal characteristics, as in some cases these agents cannot be withdrawn and, hypothetically, their inflammatory effect on the fovea could be neutralized by the addition of nepafenac. METHODS: Patients were divided into two subgroups depending on whether or not topical nepafenac was added to the surgical protocol (NEP = nepafenac group and nNEP = non nepafenac group). All had undergone phacoemulsification and data on pre- and postoperative macular status were recorded. RESULTS: In the nNEP group, there was a significant increase in foveal thickness (FT) in the first month postoperative visit with respect to the preoperative status (p = 0.006), and this situation did not change at the third postoperative month (p = 0.9411). In the NEP group, the increase in FT was not significant at the first month after surgery (p = 0.056) nor at the final visit (p = 0.268), in contrast to the nNEP group. CONCLUSION: This study of the possible prophylactic effect of nepafenac on postoperative macular edema supports the results of other studies that confirm subclinical edema post phacoemulsification, and found a significantly lower gradient in the increase in FT in patients treated pre- and postoperatively with nepafenac. PMID- 27771824 TI - Treating Posttraumatic Stress Disorder in Diverse Settings: Recent Advances and Challenges for the Future. AB - Racial and ethnic minorities are at high risk for developing posttraumatic stress disorder (PTSD) after experiencing a traumatic event and are less likely to receive evidence-based treatment for their symptoms. There is a growing body of literature showing that culturally appropriate interventions result in greater uptake, symptom reduction, and sustained treatment gains. This article review explores new findings in the cultural understanding of PTSD among racial and ethnic minorities. We first review recent advances in the understanding of PTSD symptomotology. Next, we provide overview of trials demonstrating efficacy and effectiveness of cognitive processing therapy (CPT), prolonged exposure (PE), and trauma-focused cognitive-behavioral therapy (TF-CBT) in diverse communities. Then, we discuss specific implementation strategies common across intervention trials used to increase feasibility, acceptability, adoption, and sustainability. Last, we discuss areas for future research and dissemination efforts. PMID- 27771825 TI - Mother-Child Relationship in Youths with Attention-Deficit Hyperactivity Disorder and their Siblings. AB - Despite impaired mother-child interactions noted in youth with attention deficit/hyperactivity disorder (ADHD), there is no such information for their siblings. This study aimed to test whether the affected and unaffected siblings, like youth with ADHD, also encountered impaired mothering and mother-child relationships as compared to typically developing youth (TD). The sample consisted of 122 probands (107 males, 87.7 %), aged 10-16, with DSM-IV ADHD, 44 affected (26 males, 59.1 %) and 78 unaffected (28 males, 35.9 %) siblings, and 122 TD youth. Both participants and their mothers received psychiatric interviews (K-SADS-E) about the participants and reported maternal parenting style, mother child interactions and child behavioral problems at home. Based on both reports, probands with ADHD and affected siblings (only youth report) had more impaired relationships, more behavioral problems at home, and less perceived family support than unaffected siblings and TD youth. Probands with ADHD had higher maternal authoritarian control than unaffected siblings. The findings suggest that impaired mothering, mother-child interactions, and family support are related to the presence of ADHD diagnosis in both probands and their affected siblings. PMID- 27771826 TI - The mycobiome of root canal infections is correlated to the bacteriome. AB - OBJECTIVES: Bacterial infection of the root canal system causes apical periodontitis. Less is known about the role of fungi in these infections. This study aimed to assess the fungal prevalence, abundance, and diversity of root canal infections, as well as the relation between fungi and bacteria present in different parts of the root canal. MATERIALS AND METHODS: Twenty-six teeth with primary apical periodontitis were extracted, split in apical and coronal root segments, and cryo-pulverized. Bacteriome profiles of 23 teeth were analyzed based on the V3-V4 hypervariable region of the 16S ribosomal RNA gene. Mycobiome profiles of six teeth were analyzed based on the internal transcribed spacer (ITS) 1 or ITS2 region. Samples were sequenced on the Illumina MiSeq platform. RESULTS: A total of 338 bacterial operational taxonomic units (OTUs), 28 ITS1 OTUs, and 24 ITS2 OTUs were identified. Candida and Malassezia were the most frequently identified fungi. No differences could be found between the bacteriome and mycobiome profiles of the apical and coronal root segments. The bacteriome of fungi-positive root segments contained more Actinomyces, Bifidobacterium, four different Lactobacillus OTUs, Propionibacterium, and Streptococcus. A Spearman correlation matrix between bacteriomes and mycobiomes identified no correlations, but separate clusters could be observed. CONCLUSIONS: A considerable proportion of the root canal infections contain fungi, although fungal diversity is limited. However, when fungi are present, the composition of the bacteriome is clearly different. CLINICAL RELEVANCE: Interaction between bacteria and fungi in root canal infections may complicate the infection and require alternative treatment strategies. PMID- 27771827 TI - Recombinant human bone morphogenetic protein (rhBMP)9 induces osteoblast differentiation when combined with demineralized freeze-dried bone allografts (DFDBAs) or biphasic calcium phosphate (BCP). AB - OBJECTIVES: Recently, recombinant human bone morphogenetic protein 9 (rhBMP9) has been characterized as one of the most osteogenic growth factors among the 15 human BMPs. The aim of the present study was to investigate the effects of rhBMP9 in comparison to the clinically utilized rhBMP2 on in vitro cell behavior when combined with two bone graft materials including demineralized freeze-dried bone allografts (DFDBAs) and biphasic calcium phosphate (BCP). MATERIALS AND METHODS: The absorption and release kinetics of rhBMPs from DFDBA and BCP were investigated by ELISA. Moreover, murine bone stromal ST2 cell behavior was investigated on DFDBA or BCP seeded on (1) graft only, (2) rhBMP2 (10 ng/ml), (3) rhBMP2 (100 ng/ml), (4) rhBMP9 (10 ng/ml), and (5) rhBMP9 (100 ng/ml). The effects of rhBMPs on DFDBA and BCP were assessed for cell adhesion, proliferation, and osteoblast differentiation by alkaline phosphatase (ALP) activity, alizarin red staining, and real-time PCR for genes encoding Runx2, ALP, and bone sialoprotein (BSP). RESULTS: While both BMPs were gradually released from DFDBA and BCP over time, significantly higher adsorption was observed on BCP when compared to DFDBA. Cell attachment and proliferation was higher on BCP with little influence of either rhBMP2/9. Despite rhBMPs having relatively no effect on cell attachment/proliferation, a pronounced and marked effect was observed on osteoblast differentiation for both rhBMP2/9. Interestingly, it was observed that rhBMP9 induced significantly higher ALP activity, alizarin red staining, and messenger RNA (mRNA) levels of ALP and BSP when compared to rhBMP2. Our results also revealed higher differentiation for rhBMP2/9 with BCP when compared to DFDBA most likely as a result of higher growth factor adsorption. CONCLUSION: While both rhBMP2/9 combined with DFDBA or BCP induced osteoblast differentiation, rhBMP9 induced greater osteoblast differentiation when compared to rhBMP2. CLINICAL RELEVANCE: rhBMP9 may be a recombinant growth factor with higher potential to induce new bone formation when compared to rhBMP2. Further in vivo studies are necessary to characterize its regenerative potential in various animal models. PMID- 27771828 TI - Immunoexpression of IGF1, IGF2, and osteopontin in craniofacial bone repair associated with autogenous grafting in rat models treated with alendronate sodium. AB - OBJECTIVES: The aim of this study was to verify the likely influence of presurgical administration of low doses of alendronate sodium in craniofacial bone repair and correlate the histological frame found on reparative tissue to the immunohistochemical presence of IGF1, IGF2, and osteopontin (OP). MATERIALS AND METHODS: In total, 120 rats were randomly allocated into four groups: group C (control), group OA (autogenous bone), group B (bisphosphonates), and group OA-B (autogenous bone + bisphosphonates). Groups B and OA-B received alendronate sodium (ALN) 0.01 mg/kg subcutaneously on alternate days for 4 weeks. Groups C and OA received saline solution. Critical 5-mm defects were created in rat calvaria, which were filled with blood clot in groups C and B and with autogenous bone in groups OA and OA-B. The animals were euthanized at 15 or 30 days postoperatively. Histological analysis and immunohistochemistry of IGF1, IGF2, and OP proteins was performed. Immunohistochemistry evaluated the expression in cells and extracellular matrix. RESULTS: Groups C and B revealed healing predominantly characterized by connective tissue. In groups OA and OA-B, healing of connective tissue and neoformation of compact bone was observed. Expression of IGF1 an OP was present in all specimens. IGF1 expression in cells was more pronounced in groups OA and OA-B 15 days postoperatively. The expression of IGF2 was only observed in groups OA and OA-B, with greater intensity in group OA-B 30 days postoperatively. OP expression was only observed in cells and not in the extracellular matrix and was more pronounced in group OA 15 days postoperatively. CONCLUSIONS: The application of systemic ALN at a dose of 0.01 mg/kg did not improve cranial bone matrix deposition. Nevertheless, the expression of IGF1 and OP and a slight marking of IGF2 were observed especially in groups OA and OA-B in the wound healing process. Future studies should assess higher doses of ALN to verify its influence on bone repair. CLINICAL RELEVANCE: The systemic use of ALN 0.01 mg/kg on alternate days 4 weeks prior to surgery did not interfere with bone repair. PMID- 27771830 TI - Solid-state NMR chemical shift assignments for AL-09 VL immunoglobulin light chain fibrils. AB - Light chain (AL) amyloidosis is a systemic disease characterized by the formation of immunoglobulin light-chain fibrils in critical organs of the body. The light chain protein AL-09 presents one severe case of cardiac AL amyloidosis, which contains seven mutations in the variable domain (VL) relative to its germline counterpart, kappaI O18/O8 VL. Three of these mutations are non-conservative Y87H, N34I, and K42Q-and previous work has shown that they are responsible for significantly reducing the protein's thermodynamic stability, allowing fibril formation to occur with fast kinetics and across a wide-range of pH conditions. Currently, however, there is extremely limited structural information available which explicitly describes the residues that are involved in supporting the misfolded fibril structure. Here, we assign the site-specific 15N and 13C chemical shifts of the rigid residues of AL-09 VL fibrils by solid-state NMR, reporting on the regions of the protein involved in the fibril as well as the extent of secondary structure. PMID- 27771829 TI - A retrospective study of osteomyelitis and osteonecrosis of the jaws and its etiologic implication of bisphosphonate in Asians. AB - OBJECTIVE: The objective of this study were to find the annual case trend of inflammatory jawbone diseases and to investigate the impact of medication-related osteonecrosis of the jaws (MRONJ). MATERIAL AND METHODS: A retrospective study of 372 patients diagnosed with inflammatory jawbone condition except for alveolar osteitis from 2007 to 2015 was initiated. History taking and investigation of etiologic factors MRONJ, osteoradionecrosis (ORN), odontogenic infection, foreign body, and trauma were investigated. A separate analysis showed the number of MRONJ cases in two age groups (under 70 years; 70 years and over) and serum C terminal peptide (s-CTX) values that were found. RESULTS: The results showed that the number of MRONJ cases was significantly larger in the older age group (p < 0.05). Regarding gender and sites of lesions, MRONJ was significantly frequent in the female and the mandible (p < 0.05). The R 2 values for the regression analysis for MRONJ (R 2 = 0.9234) and odontogenic etiology (R 2 = 0.0427) signified linear increase in the number of MRONJ cases, whereas bone lesions due to traditional odontogenic etiology stayed stationary. CONCLUSION: The number of MRONJ has escalated, and most of the patients are elderly people. The current trend of inflammatory conditions of the jaw may have changed since the advent of MRONJ. CLINICAL RELEVANCE: Long-term bisphosphonate therapy became a major risk factor for the osteomyelitis and osteonecrosis of the jaws. Thorough medical history, taking would be essential and communication with prescribing physicians should be emphasized during the dental treatment planning. PMID- 27771831 TI - Validation of a field-friendly extraction and storage method to monitor fecal steroid metabolites in wild orangutans. AB - Measuring hormone metabolites from feces is the most often used method to assess hormonal status in wildlife. Although immediate freezing of fecal samples collected in the field is the best method to minimize the risk of degradation of hormones over time, this is often not possible in remote field sites. Therefore, alternative storage and preservation methods for fecal samples are required in these conditions. We conducted an experiment to investigate if fecal glucocorticoid (FGCM) and progesterone metabolite (pregnanediol-3-glucuronide; PdG) levels measured from samples that were extracted with a simple, field friendly methodology correlate with those generated from frozen samples. We also evaluated whether storing fecal samples in alcohol is a suitable alternative to preserve FGCM and PdG concentrations long-term (i.e. over a 9-month period) at locations where fecal extraction is not feasible. Finally, we tested if the hormone concentrations in unpreserved fecal samples of orangutans change over 14 h when stored at ambient conditions, representing the maximum duration between sample collection and return to the camp. FGCM and PdG levels measured from samples that were extracted with the field-friendly method showed strong correlations with those generated from frozen samples, and mean levels did not differ significantly between these methods. FGCM concentrations showed no significant change compared to control samples when fecal samples were stored for up to 6 months in alcohol at ambient temperature and PdG concentrations even remained stable for up to 9 months of storage. FGCM concentrations of fecal samples kept at ambient temperature for up to 14 h post-defecation did not significantly differ compared to control samples frozen immediately after collection. These results provide the basis for the successful monitoring of the physiological status of orangutans living in remote natural settings, like those included in the Indonesian reintroduction programs. PMID- 27771832 TI - Preliminary findings on social and ecological correlates of a polyspecific association between a golden-headed lion tamarin (Leontopithecus chrysomelas) and Wied's marmosets (Callithrix kuhlii). AB - The advantages of living in a group include feeding benefits and/or predation avoidance, while the disadvantages are typically related to competition. One way to avoid competition while maintaining the benefits of living in a group is to form interspecific associations with species with relatively little dietary overlap. Here we report a stable association between a male golden-headed lion tamarin (GHLT), Leontopithecus chrysomelas, and a group of Wied's black-tufted ear marmosets (WBTMs), Callithrix kuhlii. We collected ecological and behavioral data on a duo of GHLTs from May to August 2008, totaling 62 h of observations. On 19 August 2008, the radio-collared GHLT dispersed alone and was located on 28 August in association with WBTMs. To examine possible changes in GHLT ecology and behavior, we monitored the mixed-species group between September and December 2008, totaling 122 h of observations. We found that the GHLT's home range and daily path length decreased by about ten and three times, respectively, after joining the WBTM group, suggesting adaptations to the WBTMs' use of space. All non-agonistic behaviors recorded in the mixed group were directed from GHLT to the WBMTs, whereas all agonistic interactions were directed from the WBMTs to the GHLT, indicating a subordinate position of GHLT in the mixed group. In golden lion tamarins, reproductive success of subordinate adult males that remain in the group is higher than that of those that disperse and "prospect" for a breeding opportunity. If dispersing individuals are unable to find a mate and defend a territory, they will likely die within a year. The dispersing GHLT in this study assumed a subordinate role in a mixed-species group outside a GHLT territory. Apparently, the benefits of waiting for a dispersing female in a relatively safe situation may exceed the costs of prospecting elsewhere or being a subordinate. PMID- 27771833 TI - Human aging, finite lives and the idealization of clocks. AB - Aging and time are interconnected because aging is basically living seen in a temporal perspective. This makes 'time' an important concept in trying to explain aging. However, throughout modernity time has increasingly been identified as clock time: perfectly fit to measure 'age' as time since birth but failing to explain 'age' as an indicator of aging processes and even less adequate to grasp the lived time of human beings. Moreover, the clock as a cultural idol of instrumentalist perfection has led to approaching human aging in terms of maintenance and repair, inspiring a neglect and depreciation of human vulnerability. The instrumentalist culture of late modern society, including its health cure system, has difficulties to relate to the elusive but inevitable limitations of finite life. This tendency is supported by outspoken approaches in biogerontology indulging in perspectives of infinite human lives; a message that is eagerly consumed by the mass media. Moreover, as most people can be expected to survive into old age, thinking about finitude is easily postponed and reserved for those who are 'really old'. Instead of reducing aging to the opposite or mere continuation of vital adulthood, it should be seen as something with a potentially broad and deep significance: a process of learning to live a finite life. PMID- 27771834 TI - Familial Papillary Thyroid Carcinoma (FPTC): a Retrospective Analysis in a Sample of the Bulgarian Population for a 10-Year Period. AB - In recent years, there are numerous reports indicating the presence of familial papillary carcinoma. Unfortunately, no genetic defect can be linked directly to the disease. In this study, we set the goal to make a retrospective analysis of the cases with papillary carcinoma in the Department of Endocrine Surgery for the past 10 years, to compare the characteristics of sporadic and familial forms of the disease and to find families with hereditary papillary carcinoma. The study included 810 patients treated for thyroid cancer in the Department of Endocrine Surgery, USBALE "Acad. Iv. Penchev" Hospital, between January 1, 2006 and December 31, 2015. We used chi square test to determine statistical significant difference. The data analysis and interpretation was performed on SPSS 20.0. Both groups had similar demographic distribution. We found that 587 patients have sporadic papillary carcinoma, while 147 have a relative with thyroid pathology in the first degree of kinship. In 8 patients, there was a blood relative with thyroid cancer. When we compared the two groups, we found statistically significant difference only in tumor size. There was no significant difference in aggressiveness of the thyroid cancer (multifocality and lymph node metastasis). When analyzing the results, we identified 147 patients with a family history of thyroid disease (20%). In 8 patients (5.44%), we found at least one relative with papillary thyroid carcinoma. However, our study does not demonstrate any difference in the aggressiveness of familial and sporadic papillary thyroid carcinoma. PMID- 27771835 TI - Chromosomal translocation t(1;22)(q21;q11) in a patient with angioimmunoblastic T cell lymphoma. PMID- 27771836 TI - Paradoxical thrombosis in idiopathic thrombocytopenic purpura. PMID- 27771837 TI - Bacteremia during neutropenic episodes in children undergoing hematopoietic stem cell transplantation with ciprofloxacin and penicillin prophylaxis. AB - Bacteremia during neutropenic episodes is a cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). We have used oral ciprofloxacin and penicillin V, from the start of the conditioning regimen until engraftment, for the prophylaxis of bacterial infection. The objective of this study was to retrospectively analyze the prevalence of and risk factors for breakthrough bacteremia during neutropenic episodes in autologous and allogeneic HSCT patients. There were 215 patients enrolled, with a median age of 8.32 years (range 0.51-21.64 years) between 2002 and 2014. The common underlying diseases were thalassemia and acute leukemia. Bacteremia was documented in 33 patients (15.3 %), with 39 microorganisms isolated. Escherichia coli (28.2 %) and Streptococcus viridans (12.8 %) were the most commonly isolated Gram-negative and Gram-positive bacteria, respectively. Multidrug resistant strains were found in 32 and 14.3 % of Gram-negative and Gram-positive bacteria, respectively. Risk factors for bacteremia were receiving anti-thymocyte globulin (ATG) [odds ratio (OR) 2.44, 95 % confidence interval (CI) 1.06-5.65, P = 0.037] and umbilical cord blood as a stem cell graft (OR 6.60, 95 % CI 1.04-41.83, P = 0.045). In conclusion, the prevalence of bacteremia was 15.3 % and the use of ATG and cord blood were risk factors for bacteremia during neutropenic episodes. PMID- 27771838 TI - Central Xanthoma of the Jaw Bones: A Benign Tumor. AB - Extragnathic xanthomas are seen in the bones or as soft tissue masses. They are often associated with hyperlipidemia and are considered as reactive or metabolic lesions. Only 19 cases of xanthomas of the jaws have been reported so far in the English literature. A total of ten cases of central xanthoma of the jaw bones were identified from the Oral and Maxillofacial Pathology biopsy services of the University of Washington and the Tufts University School of Dental Medicine, between the years 2000-2016. The demographic and clinical information on these cases was tabulated logically on the basis of age, gender, location and presence or absence of symptoms, extragnathic lesions and serum hyperlipidemia. Radiographic and histopathological features were also examined. The findings in these cases were correlated with those available from the previously reported cases. Majority of cases are seen in the second and third decades of life. There is no gender predilection. Jaw lesions presented as solitary radiolucencies with a predilection for the posterior mandible. Unlike maxillary lesions, pain and expansion are inconsistent findings in mandibular lesions. Jaw lesions are not associated with extragnathic bone or soft tissue involvement or a hyperlipidemia. The central xanthoma of the jaws is a unique benign tumor. Histopathologically, many other jaw lesions contain variable numbers of foamy histiocytes. Therefore, a diagnosis of a central xanthoma of the jaws must be made after excluding all other such histiocyte containing lesions. This requires correlation of histopathological findings with clinical and radiographic features. PMID- 27771839 TI - Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CA H1047R in HER2/ER-positive breast cancer. AB - PURPOSE: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti estrogen receptor (ER) agents in HER2 or ER positive (HER2+/ER+) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2+/ER+ breast cancer would provide novel insights into elucidating resistance to anti HER2/ER therapies. METHODS: In this study, we systematically investigated the biological consequences of PIK3CA H1047R in HER2+/ER+ breast cancer by uniquely incorporating mRNA transcriptomic data from The Cancer Genome Atlas and proteomic data from reverse-phase protein arrays. RESULTS: Our integrative bioinformatics analyses revealed that several important pathways such as STAT3 and VEGF/hypoxia were selectively altered by PIK3CA H1047R in HER2+/ER+ breast cancer. Protein differential expression analysis indicated that an elevated eIF4G might promote tumor angiogenesis and growth via regulation of the hypoxia-activated switch in HER2+ PIK3CA H1047R breast cancer. We observed hypo-phosphorylation of EGFR in HER2+ PIK3CA H1047R breast cancer versus HER2+PIK3CAwild-type (PIK3CA WT). In addition, ER and PIK3CA H1047R might cooperate to activate STAT3, MAPK, AKT, and Hippo pathways in ER+ PIK3CA H1047R breast cancer. A higher YAPpS127 level was observed in ER+ PIK3CA H1047R patients than that in an ER+ PIK3CA WT subgroup. By examining breast cancer cell lines having both microarray gene expression and drug treatment data from the Genomics of Drug Sensitivity in Cancer and the Stand Up to Cancer datasets, we found that the elevated YAP1 mRNA expression was associated with the resistance of BCL-2 family inhibitors, but with the sensitivity to MEK/MAPK inhibitors in breast cancer cells. CONCLUSIONS: In summary, these findings shed light on the functional consequences of PIK3CA H1047R-driven breast tumorigenesis and resistance to the existing therapeutic agents in HER2+/ER+ breast cancer. PMID- 27771840 TI - Comparing treatment and outcomes of ductal carcinoma in situ among women in Missouri by race. AB - PURPOSE: To investigate whether treatment (surgery, radiation therapy, and endocrine therapy) contributes to racial disparities in outcomes of ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: The analysis included 8184 non Hispanic White and 954 non-Hispanic Black women diagnosed with DCIS between 1996 and 2011 and identified in the Missouri Cancer Registry. Logistic regression models were used to estimate odds ratios (ORs) of treatment for race. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) of ipsilateral breast tumor (IBT) and contralateral breast tumor (CBT) for race. RESULTS: There was no significant difference between Black and White women in utilization of mastectomy (OR 1.16; 95 % CI 0.99-1.35) or endocrine therapy (OR 1.19; 95 % CI 0.94-1.51). Despite no significant difference in underutilization of radiation therapy (OR 1.14; 95 % CI 0.92-1.42), Black women had higher odds of radiation delay, defined as at least 8 weeks between surgery and radiation (OR 1.92; 95 % CI 1.55-2.37). Among 9138 patients, 184 had IBTs and 326 had CBTs. Black women had a higher risk of IBTs (HR 1.69; 95 % CI 1.15-2.50) and a comparable risk of CBTs (HR 1.19; 95 % CI 0.84-1.68), which were independent of pathological features and treatment. CONCLUSION: Racial differences in DCIS treatment and outcomes exist in Missouri. This study could not completely explain the higher risk of IBTs in Black women. Future studies should identify differences in timely initiation and completion of treatment, which may contribute to the racial difference in IBTs after DCIS. PMID- 27771841 TI - Longitudinally collected CTCs and CTC-clusters and clinical outcomes of metastatic breast cancer. AB - PURPOSE: Circulating tumor cell (CTC) is a well-established prognosis predictor for metastatic breast cancer (MBC), and CTC-cluster exhibits significantly higher metastasis-promoting capability than individual CTCs. Because measurement of CTCs and CTC-clusters at a single time point may underestimate their prognostic values, we aimed to analyze longitudinally collected CTCs and CTC-clusters in MBC prognostication. METHODS: CTCs and CTC-clusters were enumerated in 370 longitudinally collected blood samples from 128 MBC patients. The associations between baseline, first follow-up, and longitudinal enumerations of CTCs and CTC clusters with patient progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models. RESULTS: CTC and CTC-cluster counts at both baseline and first follow-up were significantly associated with patient PFS and OS. Time-dependent analysis of longitudinally collected samples confirmed the significantly unfavorable PFS and OS in patients with >=5 CTCs, and further demonstrated the independent prognostic values by CTC-clusters compared to CTC-enumeration alone. Longitudinal analyses also identified a link between the size of CTC-clusters and patient OS: compared to the patients without any CTC, those with 2-cell CTC-clusters and >=3-cell CTC-clusters had a hazard ratio (HR) of 7.96 [95 % confidence level (CI) 2.00-31.61, P = 0.003] and 14.50 (3.98 52.80, P < 0.001), respectively. CONCLUSIONS: In this novel time-dependent analysis of longitudinally collected CTCs and CTC-clusters, we showed that CTC clusters added additional prognostic values to CTC enumeration alone, and a larger-size CTC-cluster conferred a higher risk of death in MBC patients. PMID- 27771842 TI - Central vascular structures as a characteristic finding of regenerative nodules using hepatobiliary phase gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid-enhanced MRI and arterial dominant phase contrast-enhanced US. AB - OBJECTIVE: We investigated the characteristic findings of regenerative nodules (RNs) for differentiating early hepatocellular carcinoma (HCC) from high-grade dysplastic nodules (HGDNs) using magnetic resonance imaging (MRI) with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA; EOB-MRI) and contrast-enhanced ultrasonography (CEUS) in patients with chronic liver disease. SUBJECTS AND METHODS: Pathologically confirmed lesions (100 early HCCs, 7 HGDNs, and 20 RNs with a maximum diameter of more than 1 cm and mean maximal diameters of 15.5, 15.1, and 14.8 mm, respectively) were enrolled in this retrospective study. The signal intensities of these lesions during the hepatobiliary phase of EOB-MRI were investigated, and findings characteristic of RNs using this modality were also evaluated using CEUS. RESULTS: Ninety-eight of the 100 early HCCs that were hypo-intense (n = 95), iso-intense (n = 2), or hyper-intense (n = 1) and the seven HGDNs that were hypo-intense (n = 6) or hyper-intense (n = 1) during the hepatobiliary phase of EOB-MRI exhibited centripetal vessels during the arterial dominant phase of CEUS, although one early HCC that was hypo-intense exhibited both centrifugal and centripetal vessels. Eighteen of the 20 RNs and one early HCC that were hyper-intense with a small central hypo-intensity and the remaining two RNs that were hyper-intense on EOB-MRI exhibited centrifugal vessels during the arterial dominant phase of CEUS. The small central hypo-intense area corresponded to central vascular structures in the lesion, such as the hepatic artery and portal vein running from the center to the periphery, when viewed using CEUS. CONCLUSION: Central vascular structures may be a characteristic finding of RNs when observed during the hepatobiliary phase of EOB-MRI and the arterial dominant phase of CEUS. PMID- 27771844 TI - Accuracy of a smartphone application in estimating sleep in children. AB - PURPOSE: Chronic sleep problems can lead to difficulties for both the individual and society at large, making it important to effectively measure sleep. This study assessed the accuracy of an iPhone application (app) that could potentially be used as a simple, inexpensive means to measure sleep over an extended period of time in the home. METHODS: Twenty-five subjects from the ages of 2-14 who were undergoing overnight polysomnography (PSG) were recruited. The phone was placed on the mattress, near their pillow, and recorded data simultaneously with the PSG. The data were then downloaded and certain parameters were compared between the app and PSG, including total sleep time, sleep latency, and time spent in various defined "stages." RESULTS: Although there seemed to be a visual relationship between the graphs generated by the app and PSG, this was not confirmed on numerical analysis. There was no correlation between total sleep time or sleep latency between the app and PSG. Sleep latency from the PSG and latency to "deep sleep" from the app had a significant relationship (p = 0.03). No combination of PSG sleep stages corresponded with app "stages" in a meaningful way. CONCLUSIONS: The Sleep Cycle App may have value in increasing the user's awareness of sleep issues, but it is not yet accurate enough to be used as a clinical tool. PMID- 27771843 TI - Scale-adaptive supervoxel-based random forests for liver tumor segmentation in dynamic contrast-enhanced CT scans. AB - PURPOSE: Toward an efficient clinical management of hepatocellular carcinoma (HCC), we propose a classification framework dedicated to tumor necrosis rate estimation from dynamic contrast-enhanced CT scans. Based on machine learning, it requires weak interaction efforts to segment healthy, active and necrotic liver tissues. METHODS: Our contributions are two-fold. First, we apply random forest (RF) on supervoxels using multi-phase supervoxel-based features that discriminate tissues based on their dynamic in response to contrast agent injection. Second, we extend this technique in a hierarchical multi-scale fashion to deal with multiple spatial extents and appearance heterogeneity. It translates in an adaptive data sampling scheme combining RF and hierarchical multi-scale tree resulting from recursive supervoxel decomposition. By concatenating multi-phase features across the hierarchical multi-scale tree to describe leaf supervoxels, we enable RF to automatically infer the most informative scales without defining any explicit rules on how to combine them. RESULTS: Assessment on clinical data confirms the benefits of multi-phase information embedded in a multi-scale supervoxel representation for HCC tumor segmentation. CONCLUSION: Dedicated but not limited only to HCC management, both contributions reach further steps toward more accurate multi-label tissue classification. PMID- 27771845 TI - Association of suicidal ideation with poor sleep quality among Ethiopian adults. AB - OBJECTIVE: The objective of this study was to examine the extent to which poor sleep quality is associated with suicidal ideation among Ethiopian adults. METHODS: A cross-sectional study was conducted among 1054 adults attending outpatient clinical facilities in Ethiopia. Standardized questionnaires were utilized to collect data on demographics, sleep quality, lifestyle, and depression status. Depression and suicidal ideation were assessed using the Patient Health Questionnaire-9 (PHQ-9), while the Pittsburgh Sleep Quality Index (PSQI) questionnaire was utilized to assess sleep quality. Multivariate logistic regression models were fit to estimate adjusted odds ratio (AOR) and 95 % confidence intervals (95 % CI). RESULTS: The prevalence of suicidal ideation was 24.3 % while poor sleep quality (PSQI global score of >5 vs. <=5) was endorsed by 60.2 % of participants. After adjustment for confounders including depression, poor sleep quality was associated with more than 3-fold increased odds of suicidal ideation (AOR = 3.59; 95 % CI 2.34-5.51). When assessed as a continuous variable, each 1-unit increase in the global PSQI score resulted in a 20 % increased odds for suicidal ideation, even after adjusting for depression (AOR = 1.20; 95 % CI 1.14-1.27). Participants with both poor sleep quality and depression had much higher odds (AOR = 23.22, 95 % CI 14.10-38.28) of suicidal ideation as compared with those who had good sleep quality and no depression although inferences from this analysis are limited due to the wide 95 % CI. CONCLUSION: Suicidal ideation and poor sleep quality are highly prevalent. Individuals with poor sleep quality have higher odds of suicidal ideation. If confirmed, mental health services need to address sleep disturbances seriously to prevent suicidal episodes. PMID- 27771846 TI - Reciprocal Relationships: the Genetic Counselor-Patient Relationship Following a Life-Limiting Prenatal Diagnosis. AB - Utilizing the tenet, "Relationship is integral to the genetic counseling process" from the Reciprocal Engagement Model (REM) of genetic counseling practice, this study sought to explore the relationship between the genetic counselor and patient following a "life-limiting" prenatal diagnosis that resulted in a major loss (termination, stillbirth/miscarriage, or neonatal death). The specific aims of this study were to: 1) Understand and describe aspects of the genetic counselor-patient relationship in the context of the life-limiting prenatal diagnosis, and identify characteristics and actions of the 2) genetic counselor and 3) patient that influence the relationship. Genetic counselor (GC) participants were recruited via a web-based survey distributed by NSGC and the NSGC Prenatal SIG. Eligible GCs maintained a relationship with a patient beyond the prenatal diagnosis and had a willing patient participant. Individual 60-min audio-recorded telephone interviews were conducted with eight GC and 8 respective patients (n = 16) using parallel interview guides (n = 16). Transcriptions underwent thematic content analysis for systematic coding and identification of emergent themes. The GC-patient relationship was characterized by the evolution of communication and promoted by the supportive needs of the patient, the nature of the diagnosis, and characteristics and supportive actions of the participants. This exploratory study highlights the unique service of support offered by genetic counselors in the context of a life-limiting prenatal diagnosis. PMID- 27771847 TI - Multicenter Randomized Double-Blind Comparison of Nebivolol plus HCTZ and Irbesartan plus HCTZ in the Treatment of Isolated Systolic Hypertension in Elderly Patients: Results of the NEHIS Study. AB - INTRODUCTION: The present study was aimed at comparing the antihypertensive efficacy, tolerability, and side effects profile of nebivolol/hydrochlorothiazide (NH) vs irbesartan/hydrochlorothiazide (IH) combination in elderly patients with isolated systolic hypertension (ISH). METHODS: 124 ISH patients aged 69.1 +/- 5.1 years (mean +/- SD) were enrolled by 13 general practitioners in Netherlands and Belgium and randomized in a double-blind fashion to receive either NH (5/12.5 mg day, n = 62) or IH (150/12.5 mg day, n = 62) for a 12-week period. The primary efficacy endpoint of the study was the comparison of the two combinations in terms of sitting office systolic blood pressure (BP) reduction after 12 weeks of treatment. In addition ambulatory BP, 24-h BP variability, tolerability, and safety profile were also investigated. RESULTS: 122 patients were included in the intention-to-treat analysis. After 12 weeks of treatment the reduction of systolic BP with NH was significantly greater than IH (-25.8 +/- 12 vs -21.2 +/- 14 mm Hg, P < 0.03). Diastolic BP reduction was significantly greater with NH after 4 and 8 weeks of treatment but similar at the end of the study (or after 12 weeks). In contrast, the magnitude of the 24-h, daytime, and nighttime systolic and diastolic BP reduction was almost similar in the two groups, while heart rate reduction induced by NH was significantly (P < 0.001) greater during the 24-h, daytime, and nighttime period than that induced by IH. NH caused a reduction in 24-h BP variability significantly greater than IH (standard deviation -4.4 +/- 2.7 vs -2.2 +/- 5.1 mm Hg, P < 0.02, variation coefficient -2.0 +/- 2.6 vs -0.3 +/- 3.4%, P < 0.01). Both treatment regimens were well tolerated. CONCLUSIONS: These data provide evidence that NH reduces office BP more than IH but has similar effects on 24-h BP. NH reduces 24-h systolic and diastolic BP variability more than IH, suggesting a greater protective effect on a variable known to adversely affect prognosis. TRIAL REGISTRATION: EU clinical Trials Register identifier, 2010-023104-28. FUNDING: Menarini International Operations Luxembourg. PMID- 27771848 TI - Hypouricemic effect of flaccidoside II in rodents. AB - To investigate the effect of flaccidoside II on the serum uric acid levels in hyperuricemic rodents. Both mice and rats were injected intraperitoneally with potassium oxonate to induce hyperuricemia. Different dosages of flaccidoside II were orally administrated to hyperuricemic and normal rodents for 7 days, respectively. Liver xanthine oxidase (XOD) activities in hyperuricemic mice were determined using the colorimetric method. Acute toxicity of flaccidoside II was also evaluated in mice. Allopurinol, as a positive control, was administered under the same treatment scheme. The results showed that flaccidoside II (32, 16 and 8 mg/kg) could significantly lower serum uric acid levels in hyperuricemic mice. Flaccidoside II (24, 12 and 6 mg/kg) could also markedly lower serum uric acid levels in hyperuricemic rats. However, unlike allopurinol, oral administration of flaccidoside II did not produce any observable hypouricemic effect in normal animals. Flaccidoside II at the dose of 32 mg/kg significantly suppressed XOD activities in the liver of hyperuricemic mice, while at doses of 16 and 8 mg/kg flaccidoside II did not show a significant effect on XOD activities. In addition, flaccidoside II (300 mg/kg) has no or less toxicity than allopurinol in mice. These findings demonstrate that flaccidoside II exhibits anti-hyperuricemic activity in hyperuricemic animals. PMID- 27771849 TI - Hypocholesterolemic effect of sericin-derived oligopeptides in high-cholesterol fed rats. AB - The beneficial effect of cholesterol-lowering proteins and/or peptides derived from various dietary sources is continuously reported. A non-dietary protein from silk cocoon, sericin, has also demonstrated cholesterol-lowering activity. A sericin hydrolysate prepared by enzymatic hydrolysis was also expected to posses this effect. The present study was aimed at investigating the cholesterol lowering effect of sericin peptides, so called "sericin-derived oligopeptides" (SDO) both in vivo and in vitro. The results showed that SDO at all three doses tested (10 mg kg-1 day-1, 50 mg kg-1 day-1, and 200 mg kg-1 day-1) suppressed serum total and non-HDL cholesterol levels in rats fed a high-cholesterol diet. Triglyceride and HDL-cholesterol levels were not significantly changed among all groups. The fecal contents of bile acids and cholesterol did not differ among high-cholesterol fed rats. SDO dose-dependently reduced cholesterol solubility in lipid micelles, and inhibited cholesterol uptake in monolayer Caco-2 cells. SDO also effectively bound to all three types of bile salts including taurocholate, deoxytaurocholate, and glycodeoxycholate. Direct interaction with bile acids of SDO may disrupt micellar cholesterol solubility, and subsequently reduce the absorption of dietary cholesterol in intestines. Taking all data together, SDO or sericin peptides exhibit a beneficial effect on blood cholesterol levels and could be potentially used as a health-promoting dietary supplement or nutraceutical product. PMID- 27771850 TI - Robot-assisted complete thymectomy for mediastinal ectopic parathyroid adenomas in primary hyperparathyroidism. AB - One to two percent of ectopic parathyroid adenomas are found in the lower mediastinum and often these are best accessed via a sternotomy or thoracotomy. Video-assisted thoracoscopic surgery (VATS) is an alternative approach with less surgical trauma, decreased morbidity, shorter hospital stays, and superior cosmetic results. Ten years after the first VATS resection of an ectopic mediastinal parathyroid, a robot-assisted thoracoscopic approach was described. Here we describe a series of five robot assisted complete thymectomies in patients with primary hyperparathyroidism due to mediastinal ectopic parathyroid adenomas. A single surgeon, single institution case series of five consecutive robotic-assisted mediastinal parathyroidectomies was performed between March 2013 and September 2015. The patients' ages ranged from 31 to 65, 80 % were female, and all had primary hyperparathyroidism due to an ectopic parathyroid located in the lower mediastinum. Pre-operative imaging workup included Technetium 99 sestimibi parathyroid scan and CT scan of the chest. An ectopic parathyroid adenoma was successfully removed in all five cases, with intraoperative iOPTH decreasing ~50 % from baseline after 10 minutes. A hypercellular parathyroid was confirmed on pathologic exam in all specimens. Post-operative discharge and follow up calcium levels all returned to normal. There were no intraoperative complications, including no recurrent laryngeal nerve injuries, no postoperative morbidity, and no mortalities. This case series demonstrates that a robot assisted complete thymectomy for mediastinal parathyroid adenomas causing primary hyperparathyroidism provides excellent visualization of the mediastinum, is effective at reducing PTH and calcium levels, and is safe with no morbidity or mortality. PMID- 27771851 TI - In-Vitro Refolding and Characterization of Recombinant Laccase (CotA) From Bacillus pumilus MK001 and Its Potential for Phenolics Degradation. AB - Among lignocellulolytic enzymes, laccases are the most versatile, broadly specific, and largely studied enzyme with a wide range of biotechnological potential. Putative laccase (CotA) from Bacillus pumilus MK001 was cloned and expressed in E. coli. In addition to soluble bioactive fraction, inactive inclusion body fraction was also harvested and refolded under optimized conditions resulting in 64 % of refolding efficiency. The enzyme was found to be thermostable exhibiting a half-life of 60 min at 80 degrees C. UV thermal CD spectra also supported the observation as about 9 % increase in beta-sheets was recorded after thermal induction. The 3D CotA structure was constructed through homology modeling and the best selected model was verified through PROCHECK, ERRAT, Verify 3D, and PROSA servers. Final 3D model showed potential binding affinities with ferulic acid, caffeic acid, and vanillin. Results of the docking studies were further validated by HPLC analysis which signified the efficient bioconversion ability of CotA. PMID- 27771852 TI - Threshold and Target for Blood Pressure Lowering in the Elderly. AB - PURPOSE OF REVIEW: Detection of elevated blood pressure values in elderly patients represents a common clinical condition associated with an increased cardiovascular risk. This has been shown to be the case in both systodiastolic and isolated systolic hypertension as well. However, despite the evidence of the benefits of the blood pressure lowering intervention in terms of reduction of cardiovascular morbidity and mortality, at least two issues related to antihypertensive drug treatment in aged individuals are still undefined: (1) the blood pressure threshold at which antihypertensive drug should be initiated and (2) the blood pressure goals of the therapeutic intervention. RECENT FINDINGS: The present paper will critically review the evidence available so far on these two issues as well as the position of current guidelines and consensus statements. Emphasis will be given to the analysis of the new data of the Systolic Blood Pressure Interventional Trial (SPRINT), which have recently demonstrated the benefits, even in individuals aged more than 75 years, of a tight blood pressure reduction to systolic blood pressure to 120 mmHg or less. The potential limitations of the trial will be also critically addressed and the expectations of ongoing clinical studies investigating the issue in elderly patients properly emphasized. Although of interest, the results of the SPRINT trial encompass a number of limitations which limit their applicability to the general elderly hypertensive population. A prudent approach will be to adopt in clinical practice the less intensive and more conservative targets recommended by current guidelines. PMID- 27771853 TI - Failure of Expectations in Vaginal Surgery: Lack of Appropriate Consent, Goals and Expectations of Surgery. AB - INTRODUCTION AND BACKGROUND: Vaginal surgery for the treatment of urinary stress incontinence (USI) and pelvic organ prolapse (POP) using a synthetic polypropylene mesh is going through a time of unprecedented turmoil and debate. This review focuses on vaginal surgery for vaginal prolapse and looks at the current scientific literature on issues surrounding surgery including consent and expectations. SAFETY AND EFFECTIVENESS OF SURGICAL OPTIONS: Synthetic mesh has been used both abdominally and vaginally to improve the effectiveness of POP surgery. The relatively high incidence of mesh complications particularly with vaginal surgery has lead to repeat surgery, disappointment and litigation in some women. The benefits and risks of the various POP procedures are reviewed including native tissue repair, uterine conservation and obliterative vaginal surgery. CONCLUSION: Women with symptomatic pelvic organ prolapse and their doctors have many treatment options. The benefits and risks should be discussed as part of shared decision making. PMID- 27771854 TI - A Complete World Literature Review of Quality of Life (QOL) in Patients with Kidney Stone Disease (KSD). AB - PURPOSE OF REVIEW: The purpose of this study was to review the current evidence for quality of life (QOL) in patients with kidney stone disease (KSD). RECENT FINDINGS: A review of literature from inception to May 2016 for all prospective English language articles on QOL in patients with KSD was done. QOL studies post urological procedures or ureteric stents were excluded. Nine studies (1570 patients) were included of which most (n = 6) used the SF-36 QOL tool. Overall, seven of the nine studies demonstrated a lower QOL in patients with KSD. Bodily pain and general health were significantly lower in patients with KSD compared to their control groups. Patients with KSD have an overall lower QOL with most impact on bodily pain and general health domains. Compared to the scale of patients suffering from KSD, more work needs to be done in measuring QOL both in terms of 'Stone specific' QOL measuring tools and the quality/number of studies in this field. PMID- 27771855 TI - Chloroquine inhibits tumor growth and angiogenesis in malignant pleural effusion. AB - Malignant pleural effusion (MPE) is associated with a poor prognosis in lung cancer. Currently, no effective cure exists for MPE. Chloroquine (CQ) has been demonstrated to induce vascular normalization and inhibit tumor growth. The aim of this study was to assess whether CQ affects MPE. The xenografts mice were divided into normal saline (NS), CQ, or bevacizumab (BE) group. Tumor growth and microvascular density (MVD) were monitored. We explored the effect of CQ on the proliferation, survival, and proangiogenic signaling of tumor cells in vitro. We further evaluated the effects of CQ on the viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). A chicken chorioallantoic membrane (CAM) model was used to elucidate the effects of CQ on angiogenesis. Finally, an MPE mouse model were treated by CQ, BE, or NS. The volume of pleural effusion, tumor foci, and MVD was evaluated. CQ therapy group exhibited decreased tumor volume, tumor weight, and MVD in the mouse xenografts. CQ inhibited the proliferation of the tumor cells. However, the expression of vascular endothelial growth factor was not affected. Additionally, CQ inhibited the proliferation, migration, and tube formation of HUVECs and also restrained angiogenesis in the CAM. Western blot showed that CQ might suppress angiogenesis by downregulating p-Akt, Jagged1, and Ang2 in HUVECs. In MPE mice, the volume of the pleural effusion, the number of pleural tumor foci, and the MVD were significantly reduced in the CQ group. Our work demonstrated that CQ played the role of an efficient treatment for MPE. PMID- 27771856 TI - Conditioning the Heart: Thirty Years of Research and Still Far from Humans. PMID- 27771858 TI - Curvature correction to the mobility of fluid membrane inclusions. AB - Using rigorous low-Reynolds-number hydrodynamic theory on curved surfaces, we provide, via a Stokeslet-type approach, a general and concise expression for the leading-order curvature correction to the canonical, planar, Saffman-Delbruck value of the diffusion constant for a small inclusion embedded in an arbitrarily (albeit weakly) curved fluid membrane. In order to demonstrate the efficacy and utility of this general result, we apply our theory to the specific case of calculating the diffusion coefficient of a locally curvature inducing membrane inclusion. By including both the effects of inclusion and membrane elasticity, as well as their respective thermal shape fluctuations, excellent agreement is found with recently published experimental data on the surface tension dependent mobility of membrane bound inclusions. PMID- 27771857 TI - Brain alterations in low-frequency fluctuations across multiple bands in obsessive compulsive disorder. AB - The extent of functional abnormalities in frontal-subcortical circuits in obsessive-compulsive disorder (OCD) is still unclear. Although neuroimaging studies, in general, and resting-state functional Magnetic Resonance Imaging (rs fMRI), in particular, have provided relevant information regarding such alterations, rs-fMRI studies have been typically limited to the analysis of between-region functional connectivity alterations at low-frequency signal fluctuations (i.e., <0.08 Hz). Conversely, the local attributes of Blood Oxygen Level Dependent (BOLD) signal across different frequency bands have been seldom studied, although they may provide valuable information. Here, we evaluated local alterations in low-frequency fluctuations across different oscillation bands in OCD. Sixty-five OCD patients and 50 healthy controls underwent an rs-fMRI assessment. Alterations in the fractional amplitude of low-frequency fluctuations (fALFF) were evaluated, voxel-wise, across four different bands (from 0.01 Hz to 0.25 Hz). OCD patients showed decreased fALFF values in medial orbitofrontal regions and increased fALFF values in the dorsal-medial prefrontal cortex (DMPFC) at frequency bands <0.08 Hz. This pattern was reversed at higher frequencies, where increased fALFF values also appeared in medial temporal lobe structures and medial thalamus. Clinical variables (i.e., symptom-specific severities) were associated with fALFF values across the different frequency bands. Our findings provide novel evidence about the nature and regional distribution of functional alterations in OCD, which should contribute to refine neurobiological models of the disorder. We suggest that the evaluation of the local attributes of BOLD signal across different frequency bands may be a sensitive approach to further characterize brain functional alterations in psychiatric disorders. PMID- 27771859 TI - Ligand-mediated adhesive mechanics of two static, deformed spheres. AB - A self-consistent model is developed to investigate attachment/detachment kinetics of two static, deformable microspheres with irregular surface and coated with flexible binding ligands. The model highlights how the microscale binding kinetics of these ligands as well as the attractive/repulsive potential of the charged surface affects the macroscale static deformed configuration of the spheres. It is shown that in the limit of smooth, neutrally charged surface (i.e., the dimensionless inverse Debye length, [Formula: see text]), interacting via elastic binders (i.e., the dimensionless stiffness coefficient, [Formula: see text]) the adhesion mechanics approaches the regime of application of the JKR theory, and in this particular limit, the contact radius, Rc, scales with the particle radius, R, according to the scaling law, [Formula: see text]. We show that static, deformed, highly charged, ligand-coated surface of micro-spheres exhibit strong adhesion. Normal stress distribution within the contact area adjusts with the binder stiffness coefficient, from a maximum at the center to a maximum at the periphery of the region. Although reported in some in vitro experiments involving particle adhesion, until now a physical interpretation for this variation of the stress distribution for deformable, charged, ligand-coated microspheres is missing. Surface roughness results in a diminished adhesion with a distinct reduction in the pull-off force, larger separation gap, weaker normal stress and limited area of adhesion. These results are in agreement with the published experimental findings. PMID- 27771860 TI - Can an Imidazole Be Formed from an Alanyl-Seryl-Glycine Tripeptide under Possible Prebiotic Conditions? AB - The five-membered heterocyclic imidazole group, which is an essential component of purines, histidine and many cofactors, has been abiotically synthesized in different model experiments that attempt to simulate the prebiotic environment. The evolutionary significance of imidazoles is highlighted not only by its presence in nucleic acid components and in histidine, but also by experimental reports of its ability to restore the catalytic activity of ribozymes. However, as of today there are no reports of histidine in carbonaceous chondrites, and although the abiotic synthesis of His reported by Shen et al. (1987, 1990a) proceeds via an Amadori rearrangement, like in the biosynthesis of histidine, neither the reactants nor the conditions are truly prebiotic. Based on the autocatalytic biosynthesis of 4-methylidene-imidazole-one (MIO), a cofactor of some members of the amino acid aromatic ammonia-lyases and aminomutases, which occur via the self-condensation of a simple Ala-Ser-Gly motif within the sequence of the enzymes, we propose a possible prebiotic synthesis of an imidazolide. PMID- 27771861 TI - Cooperative Learning Groups and the Evolution of Human Adaptability : (Another Reason) Why Hermits Are Rare in Tonga and Elsewhere. AB - Understanding the prevalence of adaptive culture in part requires understanding the dynamics of learning. Here we explore the adaptive value of social learning in groups and how formal social groups function as effective mediums of information exchange. We discuss the education literature on Cooperative Learning Groups (CLGs), which outlines the potential of group learning for enhancing learning outcomes. Four qualities appear essential for CLGs to enhance learning: (1) extended conversations, (2) regular interactions, (3) gathering of experts, and (4) incentives for sharing knowledge. We analyze these four qualities within the context of a small-scale agricultural society using data we collected in 2010 and 2012. Through an analysis of surveys, interviews, and observations in the Tongan islands, we describe the role CLGs likely plays in facilitating individuals' learning of adaptive information. Our analysis of group affiliation, membership, and topics of conversation suggest that the first three CLG qualities reflect conditions for adaptive learning in groups. We utilize ethnographic anecdotes to suggest the fourth quality is also conducive to adaptive group learning. Using an evolutionary model, we further explore the scope for CLGs outside the Tongan socioecological context. Model analysis shows that environmental volatility and migration rates among human groups mediate the scope for CLGs. We call for wider attention to how group structure facilitates learning in informal settings, which may be key to assessing the contribution of groups to the evolution of complex, adaptive culture. PMID- 27771862 TI - A protocol for the refinement of NMR structures using simultaneously pseudocontact shift restraints from multiple lanthanide ions. AB - The binding of paramagnetic metal ions to proteins produces a number of different effects on the NMR spectra of the system. In particular, when the magnetic susceptibility of the metal ion is anisotropic, pseudocontact shifts (PCSs) arise and can be easily measured. They constitute very useful restraints for the solution structure determination of metal-binding proteins. In this context, there has been great interest in the use of lanthanide(III) ions to induce PCSs in diamagnetic proteins, e.g. through the replacement native calcium(II) ions. By preparing multiple samples in each of which a different ion of the lanthanide series is introduced, it is possible to obtain multiple independent PCS datasets that can be used synergistically to generate protein structure ensembles (typically called bundles). For typical NMR-based determination of protein structure, it is necessary to perform an energetic refinement of such initial bundles to obtain final structures whose geometric quality is suitable for deposition in the PDB. This can be conveniently done by using restrained molecular dynamics simulations (rMD) in explicit solvent. However, there are no available protocols for rMD using multiple PCS datasets as part of the restraints. In this work, we extended the PCS module of the AMBER MD package to handle multiple datasets and tuned a previously developed protocol for NMR structure refinement to achieve consistent convergence with PCS restraints. Test calculations with real experimental data show that this new implementation delivers the expected improvement of protein geometry, resulting in final structures that are of suitable quality for deposition. Furthermore, we observe that also initial structures generated only with traditional restraints can be successfully refined using traditional and PCS restraints simultaneously. PMID- 27771864 TI - Echinocandin Resistance in Candida Species: a Review of Recent Developments. AB - The echinocandins are important agents for the treatment of invasive fungal infections, especially those caused by Candida species. However, as with other antimicrobial agents, microbiologic resistance to this class of antifungal agents has emerged and can result in clinical failure. Several studies have recently reported an increase in echinocandin resistance in Candida glabrata isolates at various medical centers in different geographic regions of the USA. Recent studies have also reported that many of these isolates may also be fluconazole resistant, leaving few treatment options available for clinicians to use in patients with invasive candidiasis caused by this species. Our understanding of the clinical relevance of specific point mutations within the FKS genes that cause echinocandin resistance and risk factors for the development of microbiologic resistance and clinical failure have also increased. The purpose of this review is to discuss echinocandin resistance in Candida species and recent reports that have increased our understanding of this growing clinical problem. PMID- 27771863 TI - Solution NMR structure of the HLTF HIRAN domain: a conserved module in SWI2/SNF2 DNA damage tolerance proteins. AB - HLTF is a SWI2/SNF2-family ATP-dependent chromatin remodeling enzyme that acts in the error-free branch of DNA damage tolerance (DDT), a cellular mechanism that enables replication of damaged DNA while leaving damage repair for a later time. Human HLTF and a closely related protein SHPRH, as well as their yeast homologue Rad5, are multi-functional enzymes that share E3 ubiquitin-ligase activity required for activation of the error-free DDT. HLTF and Rad5 also function as ATP dependent dsDNA translocases and possess replication fork reversal activities. Thus, they can convert Y-shaped replication forks into X-shaped Holliday junction structures that allow error-free replication over DNA lesions. The fork reversal activity of HLTF is dependent on 3'-ssDNA-end binding activity of its N-terminal HIRAN domain. Here we present the solution NMR structure of the human HLTF HIRAN domain, an OB-like fold module found in organisms from bacteria (as a stand-alone domain) to plants, fungi and metazoan (in combination with SWI2/SNF2 helicase like domain). The obtained structure of free HLTF HIRAN is similar to recently reported structures of its DNA bound form, while the NMR analysis also reveals that the DNA binding site of the free domain exhibits conformational heterogeneity. Sequence comparison of N-terminal regions of HLTF, SHPRH and Rad5 aided by knowledge of the HLTF HIRAN structure suggests that the SHPRH N-terminus also includes an uncharacterized structured module, exhibiting weak sequence similarity with HIRAN regions of HLTF and Rad5, and potentially playing a similar functional role. PMID- 27771865 TI - Habitual physical activity is associated with improved anthropometric and androgenic profile in PCOS: a cross-sectional study. AB - PURPOSE: To examine the effect of habitual physical activity (PA) on the metabolic and hormonal profiles of women with polycystic ovary syndrome. MATERIALS AND METHODS: Anthropometric, metabolic and hormonal assessment and determination of habitual PA levels with a digital pedometer were evaluated in 84 women with PCOS and 67 age- and body mass index (BMI)-matched controls. PA status was defined according to number of steps (>=7500 steps, active, or <7500 steps, sedentary). RESULTS: BMI was lower in active women from both groups. Active PCOS women presented lower waist circumference (WC) and lipid accumulation product (LAP) values versus sedentary PCOS women. In the control group, active women also had lower WC, lower values for fasting and 120-min insulin, and lower LAP than sedentary controls. In the PCOS group, androgen levels were lower in active versus sedentary women (p = 0.001). In the control group, free androgen index (FAI) was also lower in active versus sedentary women (p = 0.018). Homeostasis model assessment of insulin resistance and 2000 daily step increments were independent predictors of FAI. Each 2000 daily step increment was associated with a decrease of 1.07 in FAI. CONCLUSIONS: Habitual PA was associated with a better anthropometric and androgenic profile in PCOS. PMID- 27771866 TI - Histopathology of valves in infective endocarditis, diagnostic criteria and treatment considerations. AB - BACKGROUND: Infective endocarditis (IE) is a severe disease. Pathogen isolation is fundamental so as to treat effectively and reduce morbidity and mortality. Blood and valve culture and histopathology (HP) are routinely employed for this purpose. Valve HP is the gold standard for diagnosis. OBJECTIVES: To determine the sensitivity and specificity of clinical criteria for IE (the modified Duke and the St Thomas' minor modifications, STH) of blood and valve culture compared to valve HP, and to evaluate antibiotic treatment duration. METHODS: Prospective case series of patients, from 2006 to 2014 with surgically treated IE. Statistical analysis was done by the R software. RESULTS: There were 136 clinically definite episodes of IE in 133 patients. Mean age +/- SD was 43 +/- 15.6 years and IE was left sided in 81.6 %. HP was definite in 96 valves examined, which were used as gold standard. Sensitivity of blood culture was 61 % (CI 0.51, 0.71) and of valve culture 15 % (CI 0.07, 0.26). The modified Duke criteria were 65 % (CI 0.55, 0.75) sensitive and 33 % specific, while the STH's sensitivity was 72 % (CI 0.61, 0.80) with similar specificity. In multivariate analysis and logistic regression, the only variable with statistical significance was duration of antibiotic therapy postoperatively. CONCLUSIONS: Valve HP had high sensitivity and valve culture low sensitivity in the diagnosis of IE. The STH's criteria were more sensitive than the modified Duke criteria. Valve HP should guide duration of postoperative antibiotic treatment. PMID- 27771867 TI - Plant characterization of genetically modified maize hybrids MON-89O34-3 * MON 88O17-3, MON-89O34-3 * MON-OO6O3-6, and MON-OO6O3-6: alternatives for maize production in Mexico. AB - Environmental risk assessment (ERA) of genetically modified (GM) crops is a process to evaluate whether the biotechnology trait(s) in a GM crop may result in increased pest potential or harm to the environment. In this analysis, two GM insect-resistant (IR) herbicide-tolerant maize hybrids (MON-89O34-3 * MON-88O17-3 and MON-89O34-3 * MON-OO6O3-6) and one herbicide-tolerant GM hybrid (MON-OO6O3-6) were compared with conventional maize hybrids of similar genetic backgrounds. Two sets of studies, Experimental Phase and Pilot Phase, were conducted across five ecological regions (ecoregions) in Mexico during 2009-2013, and data were subject to meta-analysis. Results from the Experimental Phase studies, which were used for ERA, indicated that the three GM hybrids were not different from conventional maize for early stand count, days-to-silking, days-to-anthesis, root lodging, stalk lodging, or final stand count. Statistically significant differences were observed for seedling vigor, ear height, plant height, grain moisture, and grain yield, particularly in the IR hybrids; however, none of these phenotypic differences are expected to contribute to a biological or ecological change that would result in an increased pest potential or ecological risk when cultivating these GM hybrids. Overall, results from the Experimental Phase studies are consistent with those from other world regions, confirming that there are no additional risks compared to conventional maize. Results from Pilot Phase studies indicated that, compared to conventional maize hybrids, no differences were detected for the agronomic and phenotypic characteristics measured on the three GM maize hybrids, with the exception of grain moisture and grain yield in the IR hybrids. Since MON-89O34-3 * MON-88O17-3 and MON-89O34-3 * MON-OO6O3-6 confer resistance to target insect pests, they are an alternative for farmers in Mexico to protect the crop from insect damage. Additionally, the herbicide tolerance conferred by all three GM hybrids enables more cost-effective weed management. PMID- 27771868 TI - Proteome rebalancing in transgenic Camelina occurs within the enlarged proteome induced by beta-carotene accumulation and storage protein suppression. AB - Oilseed crops are global commodities for their oil and protein seed content. We have engineered the oilseed Camelina sativa to exhibit increased protein content with a slight decrease in oil content. The introduction of a phytoene synthase gene with an RNAi cassette directed to suppress the storage protein 2S albumin resulted in seeds with an 11-24 % elevation in overall protein. The phytoene synthase cassette alone produced enhanced beta-carotene content of an average 275 +/- 6.10 MUg/g dry seed and an overall altered seed composition of 11 % less protein and comparable nontransgenic amounts of both oil and carbohydrates. Stacking an RNAi to suppress the major 2S storage protein resulted in seeds that contain elevated protein and slight decrease in oil and carbohydrate amounts showing that Camelina rebalances its proteome within an enlarged protein content genotype. In both beta-carotene enhanced seeds with/without RNAi2S suppression, the seed size was noticeably enlarged compared to nontransgenic counterpart seeds. Metabolic analysis of maturing seeds indicate that the enhanced beta carotene trait had the larger effect than the RNAi2S suppression on the seed metabolome. The use of a GRAS (generally regarded as safe) beta-carotene as a visual marker in a floral dip transformation system, such as Camelina, might eliminate the need for costly regulatory and controversial antibiotic resistance markers. beta-carotene enhanced RNAi2S suppressed Camelina seeds could be further developed as a rapid heterologous protein production platform in a nonfood crop leveraging its enlarged protein content and visual marker. PMID- 27771870 TI - Disseminated nontuberculous mycobacterial infection with multifocal retinitis and vasculitis in an immunocompromised patient with anti-IFN-gamma autoantibodies. AB - BACKGROUND: Nontuberculous mycobacteria (NTM) are found ubiquitously in the environment. Since exposure to NTM is universal, infection likely represents underlying host susceptibility factors. Anti-IFN-gamma autoantibodies have been described previously in patients with NTM. Up to 88 % of patients with disseminated NTM or other opportunistic infections have high-titer anti-IFN-gamma autoantibodies, compared with 2 % of patients with TB and healthy controls. FINDINGS: We report a unique presentation of a patient with anti-IFN-gamma autoantibodies with disseminated NTM infection who presents with panuveitis with multifocal retinitis and vasculitis. Treatment with systemic anti tubercular therapy resulted in complete clinical resolution with good visual recovery. CONCLUSIONS: Patients with anti-IFN-gamma autoantibodies present with a novel syndrome that links autoimmunity and immunodeficiency. This case emphasizes the importance of testing for anti-IFN-gamma autoantibodies in patients with disseminated mycobacterial infection. PMID- 27771869 TI - Prognostic significance of major lipids in patients with acute ischemic stroke. AB - Although dyslipidemia increases the risk for ischemic stroke, previous studies reported conflicting data regarding the association between lipid levels and stroke severity and outcome. To evaluate the predictive value of major lipids in patients with acute ischemic stroke. We prospectively studied 790 consecutive patients who were admitted with acute ischemic stroke (41.0 % males, age 79.4 +/- 6.8 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Moderate/severe stroke was defined as NIHSS >=5. The outcome was assessed with dependency rates at discharge (modified Rankin scale between 2 and 5) and with in-hospital mortality. Independent predictors of moderate/severe stroke were age (relative risk (RR) 1.05, 95 % confidence interval (CI) 1.02-1.08, p < 0.001), atrial fibrillation (RR 1.71, 95 % CI 1.19-2.47, p < 0.005), heart rate (RR 1.02, 95 % CI 1.01-1.04, p < 0.001), log-triglyceride (TG) levels (RR 0.24, 95 % CI 0.08-0.68, p < 0.01) and high density lipoprotein cholesterol (HDL-C) levels (RR 0.97, 95 % CI 0.95-0.98, p < 0.001). Major lipids did not predict dependency at discharge. Independent predictors of in-hospital mortality were atrial fibrillation (RR 2.35, 95 % CI 1.09-5.04, p < 0.05), diastolic blood pressure (RR 1.05, 95 % CI 1.02-1.08, p < 0.001), log-TG levels (RR 0.09, 95 % CI 0.01-0.87, p < 0.05) and NIHSS at admission (RR 1.19, 95 % CI 1.14-1.24, p < 0.001). Low-density lipoprotein cholesterol levels were not associated with stroke severity or outcome. Lower TG and HDL-C levels are associated with more severe stroke. Lower TG levels also appear to predict in-hospital mortality in patients with acute ischemic stroke. PMID- 27771871 TI - Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury. AB - It has been shown that diabetes modifies the myocardial responses to ischemia/reperfusion (I/R) and to cardioprotective agents. In this study, we aimed to investigate the effects of combined treatment with ischemic postconditioning (IPostC) and cyclosporine A (CsA) on inflammation and apoptosis of the diabetic myocardium injured by I/R. Eight weeks after induction of diabetes in Wistar rats, hearts were mounted on a Langendorff apparatus and were subsequently subjected to a 30-min regional ischemia followed by 45-min reperfusion. IPostC was induced at the onset of reperfusion, by 3 cycles of 30-s reperfusion/ischemia (R/I). The concentration of creatine kinase (CK), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined; the levels of total and phosphorylated glycogen synthase kinase 3 beta (p GSK3beta) and B-cell lymphoma 2 (Bcl-2) were quantified by western blotting, and the rate of apoptosis was assessed by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) staining. Administration of either IPostC or CsA alone in nondiabetic animals significantly reduced CK, TNF-alpha, IL-1beta, and IL-6 concentrations, increased the p-GSK3beta and Bcl-2, and decreased the level of apoptosis (P < 0.05) but had no effect on diabetic hearts. However, in diabetic animals, after administration of CsA, the cardioprotective effects of IPostC in increasing the p-GSK3beta and Bcl-2 and decreasing apoptosis and inflammation were restored in comparison with nonpostconditioned diabetic hearts. IPostC or CsA failed to affect apoptosis and inflammation and failed to protect the diabetic myocardium against I/R injury. However, combined administration of IPostC and CsA at reperfusion can protect the diabetic myocardium by decreasing the inflammatory response and apoptosis. PMID- 27771872 TI - Effects of glyphosate at environmentally relevant concentrations on the growth of and microcystin production by Microcystis aeruginosa. AB - The use of glyphosate, which is a well-known sterilant herbicide, has been growing rapidly because the area under the cultivation of genetically modified crops that are tolerant to this herbicide has increased. Glyphosate can enter into aquatic systems through many different ways. However, information on the potential risks of glyphosate at environmentally relevant levels to aquatic systems is still limited. In this study, we selected the cyanobacterium Microcystis aeruginosa FACHB-905 (M. aeruginosa) as a model organism to evaluate the effects of glyphosate at environmentally relevant concentrations on the former's growth and microcystin (MC) production. Our results show that low levels of glyphosate stimulate the growth of M. aeruginosa. Subsequently, there was significant increase in the total MC-LR and intracellular MC-LR, but not in extracellular MC-LR, after exposure to 0.1-2 mg/L of glyphosate. The increase in total MC-LR is mainly due to the effects of glyphosate on the cell density of M. aeruginosa. The data provided here show that low level of glyphosate in a water body is a potential environmental risk factor that stimulates the growth and enhances MC production in M. aeruginosa, which should arouse great concern. PMID- 27771873 TI - Rules versus layers: which side wins the battle of model calibration? AB - Continuous surface of urbanization suitability, as an input to many urban growth models (UGM), has a significant role on a proper calibration process. The present study evaluates and compares the simulation success of the Cellular Automata Markov Chain (CA-MC) model through multiple methods. For this, a series of mapping algorithms are applied ranging from empirical methods such as multi criteria evaluation (MCE) to statistical algorithms without spatially explicit suitability mapping rules such as logistic regression (LR) and multi-layer perceptron (MLP) neural network and finally statistical and spatially explicit rule-based methods such as SLEUTH-Genetic Algorithm (SLEUTH-GA) model. The CA-MC model was calibrated in three study locations including Azadshahr, Gonbad, and Gorgan cities in northeastern Iran. Applying Kappa-based indices (Kappa, K location, K Simulation, and K Transloc) and computing relative error (RE) values of landscape metrics, performance of the model was quantified and compared across the three study sites. The MCE and SLEUTH-GA methods, as the most data-demanding and the most computationally complex methods, respectively, yielded approximately similar results (especially in case of Kappa-based indices) and these methods were less successful compared to LR and MLP models. LR and MLP models were less data-demanding, while they produced approximately equal results. This study concludes that, when historical growth patterns feed an urbanization suitability mapping process, neither rules (SLEUTH-GA) nor layers (MCE) are effectively efficient when applied in a separated manner. Instead, methods with statistical rules and least-correlated input layers (LR and MLP) provide better simulation outputs. In contrast, methods such as MCE are more applicable when a non-path dependent mapping procedure is desired since this method does not require training data (dependent variable) and the provided flexibilities in urbanization suitability mapping under various scenarios can improve the functionality of land use change prediction algorithms into innovative land allocation tools. PMID- 27771874 TI - In Situ Dynamics of F-Specific RNA Bacteriophages in a Small River: New Way to Assess Viral Propagation in Water Quality Studies. AB - The occurrence and propagation of enteric viruses in rivers constitute a major public health issue. However, little information is available on the in situ transport and spread of viruses in surface water. In this study, an original in situ experimental approach using the residence time of the river water mass was developed to accurately follow the propagation of F-specific RNA bacteriophages (FRNAPHs) along a 3-km studied river. Surface water and sediment of 9 sampling campaigns were collected and analyzed using both infectivity and RT-qPCR assays. In parallel, some physico-chemical variables such as flow rate, water temperature, conductivity and total suspended solids were measured to investigate the impact of environmental conditions on phage propagation. For campaigns with low flow rate and high temperature, the results highlight a decrease of infectious phage concentration along the river, which was successfully modelled according to a first-order negative exponential decay. The monitoring of infectious FRNAPHs belonging mainly to the genogroup II was confirmed with direct phage genotyping and total phage particle quantification. Reported k decay coefficients according to exponential models allowed for the determination of the actual in situ distance and time necessary for removing 90 % of infectious phage particles. This present work provides a new way to assess the true in situ viral propagation along a small river. These findings can be highly useful in water quality and risk assessment studies to determine the viral contamination spread from a point contamination source to the nearest recreational areas. PMID- 27771875 TI - Increased default mode network connectivity and increased regional homogeneity in migraineurs without aura. AB - BACKGROUND: The precuneus/posterior cingulate cortex, which has been associated with pain sensitivity, plays a pivotal role in the default mode network. However, information regarding migraine-related alterations in resting-state brain functional connectivity in the default mode network and in local regional spontaneous neuronal activity is not adequate. METHODS: This study used functional magnetic resonance imaging to acquire resting-state scans in 22 migraineurs without aura and in 22 healthy matched controls. Independent component analysis, a data-driven method, was used to calculate the resting-state functional connectivity of the default mode network in the patient and healthy control groups. Regional homogeneity (ReHo) was used to analyse the local features of spontaneous resting-state brain activity in the migraineurs without aura. RESULTS: Compared with the healthy controls, migraineurs without aura showed increased functional connectivity in the left precuneus/posterior cingulate cortex within the default mode network and significant increase in ReHo values in the bilateral precuneus/posterior cingulate cortex, left pons and trigeminal nerve entry zone. In addition, functional connectivity was decreased between the areas with abnormal ReHo (using the peaks in the precuneus/posterior cingulate cortex) and other brain areas. CONCLUSIONS: The abnormalities in the precuneus/posterior cingulate cortex suggest that migraineurs without aura may exhibit information transfer and multimodal integration dysfunction and that pain sensitivity and pian processing may also be affected. PMID- 27771876 TI - HIV and Aging Research in Women: An Overview. AB - This paper reviews some background issues as a foundation to place the ensuing supplement papers of this special issue section in context. The articles in this special supplement issue deepen and expand our understanding of biomedical, neurocognitive, and psychosocial aspects involved in human immunodeficiency virus (HIV) of older women, primarily through the use of the Women's Interagency HIV Study (WIHS) prospective cohort study. As it relates to research on the intersection between HIV and aging in women, we discuss (i) epidemiology as introduction, (ii) the cohort study design featuring the WIHS, (iii) definitions, (iv) models, and (v) section articles. PMID- 27771877 TI - Removal of methylparaben from synthetic aqueous solutions using polyacrylonitrile beads: kinetic and equilibrium studies. AB - The removal of methylparaben (MP), a well-known endocrine disruptor, from aqueous solutions using polyacrylonitrile (PAN) beads has been studied under batch conditions, at room temperature and at different initial MP concentrations. The kinetic and equilibrium results have been analyzed. Kinetic modeling analysis has been carried out with three different types of adsorption models: pseudo-first order, pseudo-second-order, and Elovich model. Kinetic data analysis indicated that the adsorption was a second-order process. The MP adsorption by PAN was also quantitatively evaluated by using the equilibrium adsorption isotherm models of Langmuir, Freundlich, Dubinin-Radushkevich (D-R), and Temkin and the applicability of the respective isotherm equations has been compared through the correlation coefficients. Adsorption data resulted well fitted by the Freundlich isotherm model. Data of MP adsorption have also been used to test different adsorption diffusion models. The diffusion rate equations inside particulate of Dumwald-Wagner and the intraparticle diffusion model have been used to calculate the diffusion rate. The actual rate-controlling step involved in the MB adsorption process was determined. The kinetic expression by Boyd gave the right indications. All together, our results indicate that PAN beads are a useful tool to remediate water bodies polluted by endocrine disruptors. PMID- 27771878 TI - Forest Stewardship Council (FSC) pesticide policy and integrated pest management in certified tropical plantations. AB - The Forest Stewardship Council (FSC) was the first non-governmental organization composed of multi-stakeholders to ensure the social, environmental, and economic sustainability of forest resources. FSC prohibits certain chemicals and active ingredients in certified forest plantations. A company seeking certification must discontinue use of products so listed and many face problems to comply with these constraints. The aim of this study was to assess the impacts of certification on pest management from the perspective of Brazilian private forestry sector. Ninety three percent of Brazilian FSC-certified forest companies rated leaf-cutting ants as "very important" pests. Chemical control was the most important management technique used and considered very important by 82 % of respondents. The main chemical used to control leaf-cutting ants, sulfluramid, is in the derogation process and was classified as very important by 96.5 % of the certified companies. Certified companies were generally satisfied in relation to FSC certification and the integrated management of forest pests, but 27.6 % agreed that the prohibitions of pesticides for leaf-cutting ant and termite control could be considered as a non-tariff barrier on high-productivity Brazilian forest plantations. FSC forest certification has encouraged the implementation of more sustainable techniques and decisions in pest management in forest plantations in Brazil. The prohibition on pesticides like sulfluramid and the use of alternatives without the same efficiency will result in pest mismanagement, production losses, and higher costs. This work has shown that the application of global rules for sustainable forest management needs to adapt to each local reality. PMID- 27771879 TI - Study on each phase characteristics of the whole coal life cycle and their ecological risk assessment-a case of coal in China. AB - The paper divided the whole coal life cycle, explained each phase characteristics, and took coal mine in China as a study case to assess the ecological risk in coal utilization phase. The main conclusions are as follows: (1) the whole coal life cycle is divided into coal mining, processing, transportation, utilization, and waste disposal. (2) The key points of production organization and characteristics in the five phases have great differences. The coal mining phase is characterized by the damage of the key ecological factors (water, soil, atmosphere, vegetation, etc.) damaged while the coal processing phase by discharging waste. The characteristics in coal transportation phase mainly performance as escaping and migration of atmospheric pollutants. In coal utilization phase, the main characteristics are aggravation of greenhouse effect. The main characteristics of waste disposal phase are accumulation of negative ecological effects on the land. (3) The ecological risk of soil heavy metals is serious in coal utilization phase. The potential ecological hazard coefficients of Pb and As in coal, residue and ash are all lower than 40, presenting low environmental impact on soil; the potential ecological risk coefficients of Cd are higher than 60, nearly half of their potential ecological risk coefficients are higher than 160, which presents high environmental pollution impact on soil; Hg's potential ecological risk coefficients are higher than 320, presenting the highest environmental pollution impact on soil; the comprehensive pollution indexes in coal, residue, and ash are relatively high, which means the pollution hazard potential to soil environment is high. (4) The ecological risk of the atmospheric solid suspended matter is relatively strong in coal utilization phase. The ecological risk of Cd and As in primary flue gas is both lower than net flue gas. The geoaccumulation indexes of Cd and Hg in primary flue gas and net flue gas are both higher than 5, presenting the very strong ecological risk; 50 % of the geoaccumulation index values of As are between 3 and 4, which has also presenting a strong ecological risk while Pb does not present the ecological risk characterization. PMID- 27771880 TI - Atmospheric emission of nitric oxide and processes involved in its biogeochemical transformation in terrestrial environment. AB - Nitric oxide (NO) is an intra- and intercellular gaseous signaling molecule with a broad spectrum of regulatory functions in biological system. Its emissions are produced by both natural and anthropogenic sources; however, soils are among the most important sources of NO. Nitric oxide plays a decisive role in environmental atmospheric chemistry by controlling the tropospheric photochemical production of ozone and regulates formation of various oxidizing agents such as hydroxyl radical (OH), which contributes to the formation of acid of precipitates. Consequently, for developing strategies to overcome the deleterious impact of NO on terrestrial ecosystem, it is mandatory to have reliable information about the exact emission mechanism and processes involved in its transformation in soil atmospheric system. Although the formation process of NO is a complex phenomenon and depends on many physicochemical characteristics, such as organic matter, soil pH, soil moisture, soil temperature, etc., this review provides comprehensive updates about the emission characteristics and biogeochemical transformation mechanism of NO. Moreover, this article will also be helpful to understand the processes involved in the consumption of NO in soils. Further studies describing the functions of NO in biological system are also discussed. PMID- 27771881 TI - The occurrence and potential ecological risk assessment of bauxite mine-impacted water and sediments in Kuantan, Pahang,Malaysia. AB - Recent bauxite mining activities in the vicinity of Kuantan, Pahang, have been associated with apparent environmental quality degradation and have raised environmental concerns among the public. This study was carried out to evaluate the overall ecological impacts on water and sediment quality from the bauxite mining activities. Water and sediment samples were collected at seven sampling locations within the bauxite mining areas between June and December 2015. The water samples were analyzed for water quality index (WQI) and distribution of major and trace element geochemistry. Sediment samples were evaluated based on geochemical indices, i.e., the enrichment factor (EF) and geoaccumulation index (I geo). Potential ecological risk index was estimated to assess the degree to which sediments of the mine-impacted areas have been contaminated with heavy metals. The results showed that WQIs of some locations were classified as slightly polluted and contained metal contents exceeding the recommended guideline values. The EFs indicated minimal to moderate enrichment of metals (Pb, Cu, Zn, Mn, As, Cd, Cr, Ni, Co, and Sr) in the sediments. I geo showed slightly to partially polluted sediments with respect to As at some locations. The potential ecological risk index (RI) showed that As posed the highest potential ecological risk with RI of 52.35-60.92 at two locations, while other locations indicated low risk. The findings from this study have demonstrated the impact of recent bauxite mining activities, which might be of importance to the local communities and relevant authorities to initiate immediate rehabilitation phase of the impacted area. PMID- 27771882 TI - Multibiomarker responses in aquatic insect Belostoma elegans (Hemiptera) to organic pollution in freshwater system. AB - The present study analyzes a battery of biomarkers in the water bug Belostoma elegans from a stream polluted with organic matter (OMS), and another one considered as reference site (RS) during spring-summer season (December to March). Biochemical parameters of glucidic, lipidic and oxidative metabolic pathways were analyzed in males and females of this insect. In general, no significant differences were observed in all biomarkers assayed between both sexes, except lactate concentration which was higher in males than in females (p < 0.0006) in the first three months. About carbohydrate metabolism parameters, only pyruvate-kinase showed significant differences between insects collected in both streams (p < 0.05) during December. However, the total lipid content, saturated fatty acid, and mainly triacylglycerol were higher in insects from RS compared to those from OMS (p < 0.002) in all sampled months. Levels of lipoperoxidation, protein oxidation, reduced glutathione and glutathione-S transferase activity showed no differences between insects collected from both streams. Nevertheless, the significant increase observed in superoxide dismutase and catalase activities (p < 0.004) could be due to the elevated oxidative metabolism in insects from RS compared to those from OMS with lower dissolved oxygen. Regarding those responding parameters, males accounted for the differences between the two sites during the study period. In conclusion, our results support that lipidic energetic reserves and antioxidant enzyme activities in B. elegans could be used as biomarkers of environmental pollution by organic matter. PMID- 27771884 TI - Temporal Regulation by Innate Type 2 Cytokines in Food Allergies. AB - PURPOSE OF REVIEW: Food allergies (FAs) are a growing epidemic in western countries with poorly defined etiology. Defined as an adverse immune response to common food allergens, FAs present heterogeneously as a single- or multi-organ response that ranges in severity from localized hives and angioedema to systemic anaphylaxis. RECENT FINDINGS: Current research focusing on epithelial-derived cytokines contends that temporal regulation by these factors impact initial sensitization and persistence of FA responses upon repeated food allergen exposure. Mechanistic understanding of FA draws insight from a myriad of atopic conditions studied in humans and modeled in mice. In this review, we will highlight how epithelial-derived cytokines initiate and then potentiate FAs. We will also review existing evidence of the contribution of other atopic diseases to FA pathogenesis and whether FA symptoms overlap with other atopic diseases. PMID- 27771883 TI - Natural Products: An Alternative to Conventional Therapy for Dermatophytosis? AB - The increased incidence of fungal infections, associated with the widespread use of antifungal drugs, has resulted in the development of resistance, making it necessary to discover new therapeutic alternatives. Among fungal infections, dermatophytoses constitute a serious public health problem, affecting 20-25 % of the world population. Medicinal plants represent an endless source of bioactive molecules, and their volatile and non-volatile extracts are clearly recognized for being the historical basis of therapeutic health care. Because of this, the research on natural products with antifungal activity against dermatophytes has considerably increased in recent years. However, despite the recognized anti dermatophytic potential of natural products, often advantageous face to commercial drugs, there is still a long way to go until their use in therapeutics. This review attempts to summarize the current status of anti dermatophytic natural products, focusing on their mechanism of action, the developed pharmaceutical formulations and their effectiveness in human and animal models of infection. PMID- 27771886 TI - Frameshift Mutations of SMG7 Essential for Nonsense-Mediated mRNA Decay in Gastric and Colorectal Cancers. PMID- 27771885 TI - Capecitabine in Combination with Docetaxel in First Line in HER2-Negative Metastatic Breast Cancer: an Observational Study. AB - Due to the limited experience with capecitabine plus docetaxel (XT) combination in the first-line treatment of metastatic breast cancer in Hungary, the main objective of the study was to analyze the effectiveness and tolerability of XT therapy. A prospective, open-label, non-randomized, single-arm, multicenter, observational study was designed. All female patients were eligible whose metastatic breast cancer could be treated with the XT protocol according to the summary of product characteristics of the drugs. The median progression free survival was 9.9 +/- 3.0 months. Time to treatment failure was 4.6 +/- 5.1 months on average. The overall response rate was 28.9 %, the clinical benefit rate was 73.3 %. The treatment was discontinued in 35.6 % of patients due to disease progression and in 20.0 % due to adverse events (AE). 33 patients with a total of 73 AEs have been reported, and 13 of them had serious adverse events (SAE). The efficacy and the safety profile of XT chemotherapy proven in the study are consistent with the results demonstrated in randomized trials. First-line XT chemotherapy effectively improves the PFS in metastatic breast cancer. PMID- 27771888 TI - Remifentanil patient-controlled analgesia for labour: optimizing drug delivery regimens. AB - PURPOSE: A pilot study was undertaken to compare the efficacy of two regimens of intravenous patient-controlled analgesia (PCA) with remifentanil for labour analgesia. METHODS: Twenty term parturients requesting labour analgesia were randomized to receive one of two regimens of intravenous remifentanil. The initial settings in both groups consisted of an infusion of 0.025 MUg.kg-1.min-1, a PCA bolus of 0.25 MUg.kg-1 and a lockout interval of two minutes. In Group A, the infusion was increased in a stepwise manner from 0.025 to 0.05, 0.075 and 0.1 MUg.kg-1.min-1 as required; the bolus was kept constant at 0.25 MUg.kg-1. In Group B, the bolus was increased from 0.25 to 0.5, 0.75 and 1 MUg.kg-1 as necessary; the infusion was kept constant at 0.025 MUg.kg-1.min-1. Maternal pain, satisfaction and sedation scores, remifentanil requirement, and side effects were recorded. RESULTS: Mean pain and patient satisfaction scores, and cumulative doses of remifentanil were similar in the two groups. The overall incidence of side effects was greater in Group B (P = 0.0007), with drowsiness observed in 100% of patients, as compared to 30% in Group A (P = 0.003). The minimum oxygen saturation levels were 94.3% +/- 2.6% and 92.2% +/- 3.8% in Groups A and B respectively (P = 0.19). CONCLUSIONS: Although pain and satisfaction scores were similar in both groups, the regimen used in Group A was associated with fewer side effects compared to the Group B dosing regimen. This pilot study suggests that remifentanil intravenous PCA is efficacious for labour analgesia as a bolus of 0.25 MUg.kg-1, with a lockout interval of two minutes and continuous infusion of 0.025-0.1 MUg.kg-1.min-1. The potential for respiratory depression mandates close respiratory monitoring. Large-scale trials to evaluate safety issues are warranted. PMID- 27771893 TI - Une cause atypique d'infarctus apres remplacement valvulaire mitral [An atypical cause of my o car dial infarction after mitral valve replacement. PMID- 27771887 TI - Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer. AB - Macrophage migration inhibitory factor (MIF) emerged in recent years as an important inflammation mediator, playing a prominent role in the pathogenesis of various types of malignant neoplasm. MIF is a glycoprotein that presents a wide spectrum of biological activities and exerts a complex interaction with various cellular signaling pathways, causing imbalance of homeostasis. Experimental and clinical studies show that high levels of MIF are found in almost all types of human cancers and are implicated in seemingly all stages of development of the tumors. The production of MIF is triggered through an autocrine signal emitted by tumor cells, and stimulates the production of cytokines, chemokines, and growth as well as angiogenic factors that lead to growth of the tumor, increasing its aggressiveness and metastatic potential. MIF is produced by virtually all types of human body cells, in response to stress caused by different factors, leading to pathological conditions such as chronic inflammation and immunomodulation with suppression of immune surveillance and of immune response against tumors, angiogenesis, and carcinogenesis. In this review, we present recent advances on the biological activity of MIF, the signaling pathways with which it is involved and their role in tumorigenesis. PMID- 27771896 TI - Erratum to: Tauroursodeoxycholic Acid Protects Against Mitochondrial Dysfunction and Cell Death via Mitophagy in Human Neuroblastoma Cells. PMID- 27771897 TI - Profiling of Signaling Proteins in Penumbra After Focal Photothrombotic Infarct in the Rat Brain Cortex. AB - In ischemic stroke, cell damage propagates from infarct core to surrounding tissue. To reveal proteins involved in neurodegeneration and neuroprotection, we explored the protein profile in penumbra surrounding the photothrombotic infarct core induced in rat cerebral cortex by local laser irradiation after Bengal Rose administration. Using antibody microarrays, we studied changes in expression of 224 signaling proteins 1, 4, or 24 h after photothrombotic infarct compared with untreated contralateral cortex. Changes in protein expression were greatest at 4 h after photothrombotic impact. These included over-expression of proteins initiating, regulating, or executing various apoptosis stages (caspases, SMAC/DIABLO, Bcl-10, phosphatidylserine receptor (PSR), prostate apoptosis response 4 (Par4), E2F1, p75, p38, JNK, p53, growth arrest and DNA damage inducible protein 153 (GADD153), glutamate decarboxylases (GAD65/67), NMDAR2a, c myc) and antiapoptotic proteins (Bcl-x, p63, MDM2, p21WAF-1, ERK1/2, ERK5, MAP kinase-activated protein kinase-2 (MAKAPK2), PKCalpha, PKCbeta, PKCMU, RAF1, protein phosphatases 1alpha and MAP kinase phosphatase-1 (MKP-1), neural precursor cell expressed, developmentally down-regulated 8 (NEDD8), estrogen and EGF receptors, calmodulin, CaMKIIalpha, CaMKIV, amyloid precursor protein (APP), nicastrin). Phospholipase Cgamma1, S-100, and S-100beta were down-regulated. Bidirectional changes in levels of adhesion and cytoskeleton proteins were related to destruction and/or remodeling of penumbra. Following proteins regulating actin cytoskeleton were over-expressed: cofilin, actopaxin, p120CTN, alpha-catenin, p35, myosin Va, and pFAK were up-regulated, whereas ezrin, tropomyosin, spectrin (alpha + beta), betaIV-tubulin and polyglutamated beta tubulin, and cytokeratins 7 and 19 were down-regulated. Down-regulation of syntaxin, AP2beta/gamma, and adaptin beta1/2 indicated impairment of vesicular transport and synaptic processes. Down-regulation of cyclin-dependent kinase 6 (Cdk6), cell division cycle 7-related protein kinase (Cdc7 kinase), telomeric repeat-binding factor 1 (Trf1), and topoisomerase-1 showed proliferation suppression. Cytoprotection proteins AOP-1 and chaperons Hsp70 and Hsp90 were down-regulated. These data provide the integral view on penumbra response to photothrombotic infarct. Some of these proteins may be potential targets for antistroke therapy. PMID- 27771898 TI - Trehalose Inhibits Protein Aggregation Caused by Transient Ischemic Insults Through Preservation of Proteasome Activity, Not via Induction of Autophagy. AB - Protein aggregation has been proved to be a pathological basis accounting for neuronal death caused by either transient global ischemia or oxygen glucose deprivation (OGD), and inhibition of protein aggregation is emerging as a potential strategy of preventing brain damage. Trehalose was found to inhibit protein aggregation caused by neurodegenerative diseases via induction of autophagy, whereas its effect is still elusive on ischemia-induced protein aggregation. In this study, we investigated this issue by using rat model of transient global ischemia and SH-SY5Y model of OGD. We found that pretreatment with trehalose inhibited transient global ischemia-induced neuronal death in the hippocampus CA1 neurons and OGD-induced death in SH-SY5Y cells, which was associated with inhibition of the formation of ubiquitin-labeled protein aggregates and preservation of proteasome activity. In vitro study showed that the protection of trehalose against OGD-induced cell death and protein aggregation in SH-SY5Y cells was reversed when proteasome activity was inhibited by MG-132. Further studies revealed that trehalose prevented OGD-induced reduction of proteasome activity via suppression of both oxidative stress and endoplasmic reticulum stress. Particularly, our results showed that trehalose inhibited OGD-induced autophagy. Therefore, we demonstrated that proteasome dysfunction contributed to protein aggregation caused by ischemic insults and trehalose prevented protein aggregation via preservation of proteasome activity, not via induction of autophagy. PMID- 27771901 TI - Impaired Mitochondrial Function and Dynamics in the Pathogenesis of FXTAS. AB - Mitochondrial involvement plays an important role in neurodegenerative diseases. At least one-third of adult carriers of a FMR1 premutation (55-200 CGG repeats) are at risk of presenting an adult-onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). In an attempt to provide new insights into the mechanisms involved in the pathogenesis of FXTAS, we characterized mitochondrial function and dynamics by the assessment of oxidative respiratory chain function, mitochondrial content, oxidative stress levels, and mitochondrial network complexity. Regarding mitochondrial function, we found that mitochondrial respiratory capacity is compromised in skin fibroblasts whereas in blood, no differences were observed between the FXTAS and control groups. Furthermore, fibroblasts from FXTAS patients presented altered mitochondrial architecture, with more circular and less interconnected mitochondria being observed. Mitochondrial function and dynamics deregulation and characteristic of neurological disorders are present in FXTAS patients. These features might be limiting temporal and spatial bioenergetics cells supply and thus contributing to disease pathogenesis. PMID- 27771900 TI - RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation. AB - Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A2 (cPLA2), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10th thoracic (T10) vertebral level. We found that co-administration of TNF-alpha and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA2. Inhibition of RhoA, Rho kinase and cPLA2 significantly reduced TNF alpha/glutamate-induced cell death by 33, 52 and 43 %, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly downregulated cPLA2 activation by 66 and 60 %, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA2. The immunofluorescence staining showed that ROCK1 or ROCK2, two isoforms of Rho kinase, was co-localized with cPLA2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK1 or ROCK2 bonded directly with cPLA2 and phospho-cPLA2. When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA2 activation and expression and reduced injury-induced apoptosis at and close to the lesion site. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA2 activation. PMID- 27771899 TI - Determining the Roles of Inositol Trisphosphate Receptors in Neurodegeneration: Interdisciplinary Perspectives on a Complex Topic. AB - It is well known that calcium (Ca2+) is involved in the triggering of neuronal death. Ca2+ cytosolic levels are regulated by Ca2+ release from internal stores located in organelles, such as the endoplasmic reticulum. Indeed, Ca2+ transit from distinct cell compartments follows complex dynamics that are mediated by specific receptors, notably inositol trisphosphate receptors (IP3Rs). Ca2+ release by IP3Rs plays essential roles in several neurological disorders; however, details of these processes are poorly understood. Moreover, recent studies have shown that subcellular location, molecular identity, and density of IP3Rs profoundly affect Ca2+ transit in neurons. Therefore, regulation of IP3R gene products in specific cellular vicinities seems to be crucial in a wide range of cellular processes from neuroprotection to neurodegeneration. In this regard, microRNAs seem to govern not only IP3Rs translation levels but also subcellular accumulation. Combining new data from molecular cell biology with mathematical modelling, we were able to summarize the state of the art on this topic. In addition to presenting how Ca2+ dynamics mediated by IP3R activation follow a stochastic regimen, we integrated a theoretical approach in an easy-to-apply, cell biology-coherent fashion. Following the presented premises and in contrast to previously tested hypotheses, Ca2+ released by IP3Rs may play different roles in specific neurological diseases, including Alzheimer's disease and Parkinson's disease. PMID- 27771902 TI - Changes in Cell Cycle and Up-Regulation of Neuronal Markers During SH-SY5Y Neurodifferentiation by Retinoic Acid are Mediated by Reactive Species Production and Oxidative Stress. AB - Human neuroblastoma SH-SY5Y cells have been used as an in vitro model for neurodegenerative disorders such as Parkinson's disease and can be induced to a mature neuronal phenotype through retinoic acid (RA) differentiation. However, mechanisms of RA-induced differentiation remain unclear. Here, we investigate the role of reactive species (RS) on SH-SY5Y neuroblastoma cells under RA differentiation, using the antioxidant Trolox(r) as co-treatment. We found that RA treatment for 7 days reduced the cell number and proliferative capacity and induced the expression of adult catecholaminergic/neuronal markers such as tyrosine hydroxylase (TH), beta-III tubulin, and enolase-2. Evaluation of intracellular RS production by DCFH oxidation assay and quantification of cell non-enzymatic antioxidant activity by TRAP demonstrated that RA increases RS production. Furthermore, mitochondrial NADH oxidation showed to be inhibited under differentiation with RA. Cells subjected to co-treatment with antioxidant Trolox(r) demonstrated a remaining proliferative capacity and a decrease in the pro-oxidant state and RS production. Besides, antioxidant treatment restores the mitochondrial NADH oxidation. Importantly, Trolox(r) co-treatment inhibited the appearance of morphological characteristics such as neurite extension and branching, and decreased the expression of TH, beta-III tubulin, and enolase-2 after a seven-day differentiation with RA, indicating that RS production is a necessary step in this process. Trolox(r) also inhibited the phosphorylation of Akt and ERK1/2, which are involved in differentiation and survival, respectively, of these cells. Altogether, these data indicate the presence of a redox-dependent mechanism in SH-SY5Y RA-differentiation process and can be a useful insight to improve understanding of neuronal differentiation signaling. PMID- 27771904 TI - Pilot study: use of gallium-68 PSMA PET for detection of metastatic lesions in patients with renal tumour. AB - BACKGROUND: In this study, we prospectively evaluate the diagnostic potential of a gallium-68 (68Ga) prostate-specific membrane antigen (PSMA)-binding ligand and positron emission tomography (PET) in detecting metastatic lesions in patients with renal tumour. The secondary aim was to determine whether the findings would result in the alteration of patient management. RESULTS: Ten patients with renal lesion and potential metastatic disease on conventional imaging were recruited. Patients underwent PSMA PET in addition to standard imaging. Nine patients underwent nephrectomy and 4 patients underwent additional targeted biopsy to provide specimens for histopathological validation. There were 89 pathological lesions on CT, of which 32 were removed or biopsied for histopathological correlation. With PSMA PET, 86 PET avid lesions were identified with 36 samples being available for analysis. Thirty-five of 36 samples were positive for renal cell carcinoma deposits, whilst 1 sample was inconclusive for diagnosis on biopsy. For the histologically confirmed lesions, there were no false-negative PSMA PET lesions; however, CT was false negative in 11. In two patients, surgical strategies were changed based on PSMA PET findings. CONCLUSIONS: PSMA PET may potentially have a role in the preoperative staging of advanced renal cell carcinoma as PET detected multiple histologically proven metastatic lesions which were false negative on CT scanning, resulting in change in surgical strategies in some patients. We cautiously support a larger study to confirm these results and to assess the longitudinal impact on patient outcomes. TRIAL REGISTRATION: Australia and New Zealand Clinical Trial Registry (ANZCTR), ACTRN12615000854538 . PMID- 27771903 TI - N-Cadherin is Involved in Neuronal Activity-Dependent Regulation of Myelinating Capacity of Zebrafish Individual Oligodendrocytes In Vivo. AB - Stimulating neuronal activity increases myelin sheath formation by individual oligodendrocytes, but how myelination is regulated by neuronal activity in vivo is still not fully understood. While in vitro studies have revealed the important role of N-cadherin in myelination, our understanding in vivo remains quite limited. To obtain the role of N-cadherin during activity-dependent regulation of myelinating capacity of individual oligodendrocytes, we successfully built an in vivo dynamic imaging model of the Mauthner cell at the subcellular structure level in the zebrafish central nervous system. Enhanced green fluorescent protein (EGFP)-tagged N-cadherin was used to visualize the stable accumulations and mobile transports of N-cadherin by single-cell electroporation at the single-cell level. We found that pentylenetetrazol (PTZ) significantly enhanced the accumulation of N-cadherin in Mauthner axons, a response that was paralleled by enhanced sheath number per oligodendrocytes. By offsetting this phenotype using oligopeptide (AHAVD) which blocks the function of N-cadherin, we showed that PTZ regulates myelination in an N-cadherin-dependent manner. What is more, we further suggested that PTZ influences N-cadherin and myelination via a cAMP pathway. Consequently, our data indicated that N-cadherin is involved in neuronal activity dependent regulation of myelinating capacity of zebrafish individual oligodendrocytes in vivo. PMID- 27771905 TI - Is propofol neurotoxic to the developing brain? PMID- 27771906 TI - Propofol induces growth cone collapse and neurite retractions in chick explant culture[Le propofol provoque un collapsus des cones de croissance et des retractions des neurites de poussin embryonnaire en culture]. AB - PURPOSE: Propofol neurotoxicity has been demonstrated in several cell culture systems. This study was undertaken to determine whether propofol has neurotoxic effects on peripheral, retinal, and autonomic neurons, and which neurons are particularly liable to injury by propofol. METHOD: Dorsal root ganglia, retinal ganglion cell layers, and sympathetic ganglion chains were isolated from day eight chick embryos and cultured for 20 hr. Thereafter, propofol was added at various concentrations [5-300 MUM (0.9-53 MUg.mL-1)] to investigate its effects on these three types of neuronal tissue. Morphological changes were examined quantitatively by growth cone collapse assay. Propofol concentrations were measured using high performance liquid chromatography. RESULTS: Propofol induced growth cone collapse and neurite destruction. The three types of neurons tested exhibited significantly different dose-response relationships two hours after the application of propofol (P < 0.001) but not at 24 hr after application. The growth cone-collapsing effect was at least partially reversible in all three types of neurons after exposure to 100 MUM propofol up to six hours, though reversibility was not observed after 24-hr exposure. CONCLUSION: While the clinical safety profile of propofol has been well documented, at high concentrations propofol has potential neurotoxicity on growing neurons in vitro. OBJECTIF: La neurotoxicite du propofol a ete demontree dans plusieurs systemes de culture cellulaire. Notre etude cherche a determiner si le propofol a des effets neurotoxiques sur les neurones peripheriques, retiniens et du systeme autonome, et quels neurones sont particulierement susceptibles de subir des lesions causees par le propofol. MeTHODE: Des ganglions de la racine dorsale, des couches cellulaires de la retine et des chaines sympathiques provenant d'embryons de poussin de huit jours ont ete isoles et mis en culture pendant 20 h. Par la suite, differentes concentrations de propofol ont ete ajoutees [5-300 MUM (0,9-53 MUg.mL-1)] pour etudier ses effets sur les trois types de tissu neuronal. Les changements morphologiques ont ete evalues quantitativement par l'analyse du collapsus des cones de croissance. La chromatographie liquide a haute performance a ete utilisee pour mesurer les concentrations de propofol. ReSULTATS: Le propofol a provoque un collapsus des cones de croissance et la destruction des neurites. Les trois types de neurones testes ont affiche des relations dose reponse significativement differentes, deux heures apres l'application du propofol (P < 0,001) mais non a 24 h apres l'application. L'effet de collapsus des cones de croissance etait au moins partiellement reversible dans les trois types de neurones apres l'exposition a 100 MUM de propofol pendant six heures ou moins, mais la reversibilite n'etait plus observee apres 24 h d'exposition. CONCLUSION: Le profil de securite clinique du propofol est bien connu, mais a concentrations elevees, le propofol possede une neurotoxicite potentielle sur les neurones en developpement in vitro. PMID- 27771907 TI - Documentation on the anesthetic record: correlation with clinically important variables : [Documentation sur le dossier anesthesique : correlation avec les variables cliniques importantes]. AB - PURPOSE: A survey was undertaken at a single Academic Health Sciences Centre to document the opinions of anesthesiologists regarding what variables are important to document on the anesthetic record. A subsequent chart review of anesthetic records was undertaken to determine the extent to which these anesthesiologists record the variables they consider important. METHODS: A survey form was mailed to all practicing staff anesthesiologists at the four adult McGill University affiliated hospitals. Anesthesiologists were asked to rank 23 preoperative and 33 intraoperative variables on a scale from 1-5: (1 = essential; 2 = important; 3 = useful; 4 = not important; 5 = excessive information). All variables considered by consensus <= 2 (important to essential) were then assessed as to whether they were recorded on 60 charts randomly selected from each of the four teaching hospitals. Only anesthetic records completed by staff anesthesiologists were evaluated. RESULTS: Ninety percent (47/52) of survey forms were completed and returned. Preoperative variables considered most important to document included examination of the patient's airway and allergy status. Intraoperative variables considered most important for documentation were the patient's vital signs. The only variable to have been recorded on all the anesthetic records was the anesthesiologist's name. The allergy status was the most recorded preoperative variable (84% of charts). The recording rates of intraoperative variables ranged from 100% (anesthesiologist's name, start time of anesthesia) to 24% (estimated blood loss). CONCLUSION: McGill anesthesiologists consider many preoperative and intraoperative variables to be important to document on the anesthetic record. However, subsequent chart review indicated that many of these variables are recorded inconsistently. The transmission of anesthesia-related medical information might be improved if anesthesiologists recorded more consistently information they consider to be important. OBJECTIF: Une enquete a ete menee a un Centre universitaire de sciences de la sante pour connaitre les opinions des anesthesiologistes sur les variables jugees importantes a inscrire au dossier anesthesique. Une revue subsequente des dossiers anesthesiques a ete realisee pour verifier si les anesthesiologistes enregistrent les variables qu'ils considerent importantes. MeTHODE: Un formulaire d'enquete a ete poste a tous les anesthesiologistes en exercice dans les quatre hopitaux pour adultes affilies a l'universite McGill. On leur a demande de coter 23 variables preoperatoires et 33 peroperatoires sur une echelle de 1-5: (1 = essentielle, 2 = importante, 3 = utile, 4 = non importante et 5 = surinformation). Toutes les variables reconnues par la majorite <= 2 (importante a essentielle) ont ete ensuite verifiees pour savoir si elles etaient enregistrees dans 60 dossiers choisis au hasard dans chacun des quatre hopitaux d'enseignement. Seuls les dossiers anesthesiques remplis par des specialistes en service ont ete evalues. ReSULTATS: Des formulaires envoyes 90 % (47/52) ont ete remplis et retournes. Les variables preoperatoires considerees importantes comprenaient l'examen des voies aeriennes du patient et la presence d'allergie. Les variables peroperatoires prioritaires ont ete les signes vitaux des patients. La seule variable enregistree dans tous les dossiers a ete le nom de l'anesthesiologiste. La presence d'allergie a ete la variable preoperatoire la plus souvent enregistree (84 % des dossiers). Les taux d'enregistrement des variables peroperatoires allait de 100 % (nom de l'anesthesiologiste, heure du debut de l'anesthesie) a 24 % (perte sanguine estimee). CONCLUSION: Les anesthesiologistes de McGill considerent que de nombreuses variables preoperatoires et peroperatoires sont importantes a noter au dossier anesthesique. Une revue subsequente des dossiers a indique que beaucoup de ces variables ne sont pas constamment inscrites. La transmission des informations medicales liees a l'anesthesie serait amelioree si les anesthesiologistes notaient plus regulierement les variables qu'ils jugent les plus importantes. PMID- 27771908 TI - Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration : [Des preparations liposomiques de prilocaine, de lidocaine et de mepivacaine prolongent la duree de l'analgesie]. AB - PURPOSE: A laboratory investigation was undertaken to compare the in vivo antinociceptive effects of 2% liposomal formulations of prilocaine (PLC), lidocaine (LDC) and mepivacaine (MVC) compared to plain solutions of each of these three local anesthetics. METHODS: Large unilamellar vesicles were prepared by extrusion (400 nm), at pH 7.4. The membrane/water partition coefficients were obtained from encapsulation efficiency values, after incorporation of each local anesthetic to the vesicles. The anesthetic effect of each liposomal formulation was compared to the respective local anesthetic solution in water, using the infraorbital nerve-blockade test, in rats. RESULTS: The partition coefficients were: 57 for PLC, 114 for LDC and 93 for MVC. In vivo results showed that local anesthetic-free liposomes, used as control, had no analgesic effect. In contrast, the encapsulated formulations induced increased intensities of total anesthetic effect (35.3%, 26.1 % and 57.1 %) and time for recovery (percentage increases of 30%, 23.1 % and 56%), respectively, for PLC, LDC and MVC when compared to the plain solutions (P < 0.01). CONCLUSIONS: These results indicate that liposomes provide effective drug-delivery systems for intermediate-duration local anesthetics. Mepivacaine was affected to the greatest extent, while LDC benefited least from liposome encapsulation, possibly due to greater vasodilatory properties of LDC. OBJECTIF: Une recherche en laboratoire a ete entreprise pour comparer les effets antinociceptifs in vivo de preparations liposomiques de prilocaine (PLC), de lidocaine (LDC) et de mepivacaine (MVC) a 2 %, a des solutions simples de chacun de ces anesthesiques locaux. MeTHODE: De grandes vesicules unilamellaires ont ete preparees par extrusion (400 nm), a un pH de 7,4. Les coefficients de partage membrane/eau ont ete obtenus des valeurs d'efficacite de l'encapsulation, apres l'introduction de chaque anesthesique local dans les vesicules. L'effet anesthesique de chaque preparation liposomique a ete compare a la solution respective d'anesthesique local dans l'eau par le test de blocage du nerf infra-orbitaire chez des rats. ReSULTATS: Les coefficients de partage ont ete de : 57 pour la PLC, 114 pour la LDC et 93 pour la MVC. Les resultats in vivo ont montre que les liposomes temoins sans anesthesique local n'avaient pas d'effet analgesique. Par contre, les preparations en capsules ont augmente l'intensite anesthesique totale (35,3 %, 26,1 % et 57,1 %) et le temps de recuperation (30 %, 23,1 % et 56 %) respectivement pour la PLC, la LDC et la MVC comparees aux solutions simples (P < 0,01). CONCLUSION: Ces resultats indiquent que les liposomes sont des systemes de vecteurs de medicaments efficaces pour les anesthesiques locaux de duree moyenne. La MVC a surtout beneficie, et la LDC le moins, de l'encapsulation liposomique, peut-etre a cause de ses plus importantes proprietes vasodilatatrices. PMID- 27771909 TI - Compressed air injection technique to standardize block injection pressures : [La technique d'injection d'air comprime pour normaliser les pressions d'injection d'un blocage nerveux]. AB - PURPOSE: Presently, no standardized technique exists to monitor injection pressures during peripheral nerve blocks. Our objective was to determine if a compressed air injection technique, using an in vitro model based on Boyle's law and typical regional anesthesia equipment, could consistently maintain injection pressures below a 1293 mmHg level associated with clinically significant nerve injury. METHODS: Injection pressures for 20 and 30 mL syringes with various needle sizes ( 18G, 20G, 21 G, 22G, and 24G) were measured in a closed system. A set volume of air was aspirated into a saline-filled syringe and then compressed and maintained at various percentages while pressure was measured. The needle was inserted into the injection port of a pressure sensor, which had attached extension tubing with an injection plug clamped "off". Using linear regression with all data points, the pressure value and 99% confidence interval (CI) at 50% air compression was estimated. RESULTS: The linearity of Boyle's law was demonstrated with a high correlation, r = 0.99, and a slope of 0.984 (99% CI: 0.967-1.001). The net pressure generated at 50% compression was estimated as 744.8 mmHg, with the 99% CI between 729.6 and 760.0 mmHg. The various syringe/needle combinations had similar results. CONCLUSION: By creating and maintaining syringe air compression at 50% or less, injection pressures will be substantially below the 1293 mmHg threshold considered to be an associated risk factor for clinically significant nerve injury. This technique may allow simple, real-time and objective monitoring during local anesthetic injections while inherently reducing injection speed. OBJECTIF: Presentement, aucune technique normalisee ne permet de verifier les pressions d'injection pendant les blocages nerveux peripheriques. Nous voulions verifier si une technique d'injection d'air comprime, utilisant un modele in vitro fonde sur la loi de Boyle et du materiel propre a l'anesthesie regionale, pouvait maintenir avec regularite les pressions d'injection sous les 1293 mmHg, pression associee a une lesion nerveuse cliniquement significative. MeTHODE: Les pressions d'injection pour des seringues de 20 et 30 mL et diverses tailles d'aiguilles (18G, 20G, 21G, 22G et 24G) ont ete mesurees dans un systeme ferme. Un volume defini d'air a ete aspire dans une seringue rempli de solution saline, puis comprime et maintenu a des pourcentages varies pendant la mesure de la pression. L'aiguille a ete inseree dans l'ouverture a injection d'un detecteur de pression muni d'une extension avec un bouchon d'injection en position fermee. La valeur de la pression et l'intervalle de confiance de 99 % (IC) pour une compression d'air a 50 % ont ete evalues en utilisant une regression lineaire avec tous les points de donnees. ReSULTATS: La linearite de la loi de Boyle a ete demontree avec une forte correlation, r = 0,99 et une pente de 0,984 (IC de 99 % : 0,967-1,001) La pression nette generee sous une compression de 50% a ete de 744,8 mmHg avec un IC de 99 % entre 729,6 et 760,0 mmHg. Les diverses combinaisons de seringues et d'aiguilles ont presente des resultats similaires. CONCLUSION: En creant et en maintenant dans la seringue une compression d'air a 50% ou moins, les pressions d'injection seront dans l'ensemble sous le seuil des 1293 mmHg associe a un facteur de risque de lesion nerveuse cliniquement significative. Cette technique peut permettre une surveillance simple, objective et en temps reel pendant les injections d'anesthesiques locaux tout en reduisant fondamentalement la vitesse d'injection. PMID- 27771910 TI - Topical lidocaine and oral acetaminophen provide similar analgesia for myringotomy and tube placement in children : [L'application topique de lidocaine et l'administration orale d' acetaminophene procurent une analgesie similaire pour la myringotomie et la pose d'un aerateur tympanique chez les enfants]. AB - PURPOSE: Preoperative oral acetaminophen (30 mg.kg-1) was compared with topical 2% lidocaine ear drops for postoperative analgesia following bilateral myringotomy and tube placement (BMT) in children. METHODS: In a randomized, prospective, double-blind trial, we studied 124 patients, six months to eight years, ASA physical status I or II, undergoing elective BMT under general anesthesia. The patients in Group I received acetaminophen 30 mg.kg-1 orally in a grape flavoured syrup 30 to 60 min before surgery and 0.9% saline drops (placebo) in each ear upon insertion of tympanostomy tube. Patients in Group II received a placebo (grape flavoured syrup) before surgery and 2% lidocaine, 0.5 mL in each ear when ear tubes were inserted. Postoperative pain assessments were recorded every five minutes in the postanesthesia care unit, and every 15 min in the day care surgical unit (DCSU) using the modified Children's Hospital of Eastern Ontario pain scale (mCHEOPS), a ten-point scale. Pain at home was documented by parents using a 0 (no pain) to 10 (worst pain imaginable) scale. RESULTS: The median (range) mCHEOPS scores in the DCSU at 15 and 30 min were similar, i.e., 5 (4-9) in the acetaminophen group and 4 (4-8) in the lidocaine group. The proportion of patients receiving supplemental analgesics in the 24 hr following surgery was similar in both groups (45% and 42% respectively). CONCLUSION: Topical lidocaine and oral acetaminophen in a dose of 30 mg.kg-1 provide similar analgesia following BMT. OBJECTIF: La prise orale preoperatoire d'acetaminophene (30 mg.kg-1) a ete comparee a des gouttes auriculaires de lidocaine a 2 % pour l'analgesie suivant une myringotomie bilaterale et la pose d'un aerateur tympanique (MBA) chez des enfants. MeTHODE: L'etude randomisee, prospective et a double insu a ete realisee aupres de 124 patients de six mois a huit ans, d'etat physique ASA I ou II, devant subir une MBA sous anesthesie generale. Les patients du groupe I ont recu 30 mg.kg-1 d'acetaminophene orale dans un sirop aromatise au raisin, 30 a 60 min avant l'operation, et des gouttes auriculaires de solution salee a 0,9 % (placebo) dans chaque oreille a l'insertion de l'aerateur tympanique. Ceux du groupe II ont eu un placebo (le sirop) preoperatoire, puis de la lidocaine a 2%, 0,5 mL dans chaque oreille a l'insertion des aerateurs. La douleur postoperatoire a ete evaluee toutes les cinq minutes a la salle de reveil, et toutes les 15 min a l'unite de chirurgie d'un jour (UCUJ) avec une echelle de douleur modifiee, en dix points, du Children's Hospital of Eastern Ontario. A domicile, les parents ont utilise une echelle de 0 (aucune douleur) a 10 (la pire douleur imaginable). ReSULTATS: La mediane (limites) des scores de douleur a l'UCUJ a 15 et 30 min ont ete similaires a 5 (4-9) avec l'acetaminophene et a 4 (4-8) avec la lidocaine. Le taux de patients necessitant une analgesie supplementaire au cours des 24 h suivant l'operation a ete semblable dans les deux groupes (respectivement 45 % et 42 %). CONCLUSION: La lidocaine topique et l'acetaminophene orale en dose de 30 mg.kg-1 procurent une analgesie similaire a la suite d'une MBA. PMID- 27771911 TI - Images in Anesthesia : Ex utero intrapartum treatment (exit procedure): fetal airway management. PMID- 27771912 TI - Effects of halothane, sevoflurane and desflurane on the force-frequency relation in the dog heart in vivo. AB - PURPOSE: Frequency potentiation is the increase in force of contraction induced by an increased heart rate (HR). This positive staircase phenomenon has been attributed to changes in Ca2+ entry and loading of intracellular Ca2+ stores. Volatile anesthetics interfere with Ca2+ homeostasis of cardiomyocytes. We hypothesized that frequency potentiation is altered by volatile anesthetics and investigated the influence of halothane (H), sevoflurane (S) and desflurane (D) on the positive staircase phenomenon in dogsin vivo. METHODS: Dogs were chronically instrumented for measurement of left ventricular (LV) pressure and cardiac output. Heart rate was increased by atrial pacing from 120 to 220 beats.min-1 and the LV maximal rate of pressure increase (dP/ dtmax) was determined as an index of myocardial performance. Measurements were performed in conscious dogs and during anesthesia with 1.0 minimal alveolar concentrations of each of the three inhaled anesthetics. RESULTS: Increasing HR from 120 to 220 beats.min-1 increased dP/dtmax from 3394 +/- 786 (mean +/- SD) to 3798 +/- 810 mmHg sec-1 in conscious dogs. All anesthetics reduced dP/dtmax during baseline (at 120 beatss.min-1: H, 1745 +/- 340 mmHgs.sec-1; S, 1882 +/- 418; D, 1928 +/- 454, allP < 0.05vs awake) but did not influence the frequency potentiation of dP/dtmax (at 220 beatss.min-1: H, 1981 +/- 587 mmHgs.sec-1; S, 2187 +/- 787; D, 2307 +/- 691). The slope of the regression line correlating dP/dtmax and HR was not different between awake and anesetized dogs. Increasing HR did not influence cardiac output in awake or anesthetized dogs. CONCLUSION: These results indicate that volatile anesthetics do not alter the force-frequency relation in dogs in vivo. PMID- 27771913 TI - Best evidence in critical care medicine Early antibiotics and survival from septic shock: it's about time. PMID- 27771914 TI - [Respiratory depression after intrathecal injection of tramadol with hyperbaric bupivacaine]. PMID- 27771915 TI - GlideScope(r) videolaryngoscope facilitates nasotracheal intubation. PMID- 27771916 TI - Improved production of Daptomycin in an airlift bioreactor by morphologically modified and immobilized cells of Streptomyces roseosporus. AB - The increased threat of drug resistance has challenged the existence of several conventional and non-conventional antibiotics in the recent times. Daptomycin is a novel cyclic-lipopeptide antibiotic produced by Streptomyces roseosporus that has progressed as a significant anti-MRSA (methicillin-resistant Staphylococcus aureus) antibiotic. But, the economic practicality of this highly valued secondary metabolite is deterred by its poor production and tedious processing methodology. The present study aims at strategic improvement of Daptomycin production through morphological variations of S. roseosporus cells. Free cells, pelletized cells and immobilized cells on ultra porous refractory brick and silk sachets were investigated for the production of Daptomycin in a lab-scale 2.0 l air-lift bioreactor. The effect(s) of nitrogen source, inoculum size and oxygen stress were analyzed for pellet formation of S. roseosporus. Interestingly, free cells produced 750 mg/l of Daptomycin in a single batch. But, the three phase broth viscosity increased due to vigorous growth of free cells which hampered the oxygen transfer rate. The cell degeneration over the time deterred pellet reusability. 1430 mg/l Daptomycin was produced using pellets for 2 batches. On the contrary, mechanical stability, buoyancy and reusability of refractory bricks and silk sachets were beneficial. Daptomycin production was recorded for 6-8 batches. Immobilized cells on refractory bricks and silk sachets led to 4895 mg/l and 3623 mg/l Daptomycin production respectively. Cell immobilization improved the three phase broth rheology and hence, the hydrodynamics within the reactor. Therefore, whole-cell immobilization could contribute to the ameliorated production of this life-saving drug. PMID- 27771917 TI - The remanence ratio in CoFe2O4 nanoparticles with approximate single-domain sizes. AB - Approximately single-domain-sized 9-, 13-, and 16-nm CoFe2O4 nanoparticles are synthesized using the thermal decomposition of a metal-organic salt. By means of dilution and reduction, the concentration, moment, and anisotropy of nanoparticles are changed and their influence on the magnetic properties is investigated. The relation of M r/M s ? 1/lgH dip is observed, where M r/M s is the remanence ratio and H dip is the maximum dipolar field. Especially, such relation is more accurate for the nanoparticle systems with higher concentration and higher moment, i.e., larger H dip. The deviation from M r/M s ? 1/lgH dip appearing at low temperatures can be attributed to the effects of surface spins for the single-phase CoFe2O4 nanoparticles and to the pinning effect of CoFe2O4 on CoFe2 for the slightly reduced nanoparticles. Graphical Abstract Approximately single-domain-sized 9-, 13-, and 16-nm CoFe2O4 nanoparticles were synthesized and then the concentration, moment, and anisotropy of these NPs were changed. The correlation of M r/M s ? 1/lgH dip was observed, independent of the size, concentration, moment, and anisotropy, and especially, such correlation is more accurate for the nanoparticle systems with higher concentration or moment, i.e., stronger dipolar interaction, which has not been reported before as far as we know. PMID- 27771918 TI - Cinnamon and Chronic Diseases. AB - Cinnamon (Cinnamomum zeylanicum and Cinnamon cassia), the eternal tree of tropical medicine, belongs to the Lauraceae family and is one of the most important spices used daily by people all over the world. It contains a lot of manganese, iron, dietary fiber, and calcium. Cinnamon contains derivatives, such as cinnamaldehyde, cinnamic acid, cinnamate, and numerous other components such as polyphenols and antioxidant, anti-inflammatory, antidiabetic, antimicrobial, anticancer effects. Several reports have dealt with the numerous properties of cinnamon in the forms of bark, essential oils, bark powder, and phenolic compounds, and each of these properties can play a key role in human health. Recently, many trials have explored the beneficial effects of cinnamon in Alzheimer's disease, diabetes, arthritis, and arteriosclerosis, but still we need further investigations to provide additional clinical evidence for this spice against cancer and inflammatory, cardioprotective, and neurological disorders. PMID- 27771919 TI - Silymarin and Its Role in Chronic Diseases. AB - Silymarin is the active constituent of Silybum marianum (milk thistle) which is a C-25 containing flavonolignan. Milk thistle has a lot of traditional values, being used as a vegetable, as salad, as bitter tonic, and as galactogogue in nursing mothers and in various ailments such as liver complications, depression, dyspepsia, spleenic congestions, varicose veins, diabetes, amenorrhea, uterine hemorrhage, and menstrual problems. In this present chapter, a comprehensive attempt has been made to discuss the potential of silymarin in chronic disorders. An insight into modulation of cellular signaling by silymarin and its implication in various disorders such as liver disorders, inflammatory disorders, cancer, neurological disorders, skin diseases, and hypercholesterolemia is being provided. PMID- 27771920 TI - Eugenol and Its Role in Chronic Diseases. AB - The active components in cloves are eugenol and isoeugenol. Eugenol has recently become a focus of interest because of its potential role in alleviating and preventing chronic diseases such as cancer, inflammatory reactions, and other conditions. The radical-scavenging and anti-inflammatory activities of eugenol have been shown to modulate chronic diseases in vitro and in vivo, but in humans, the therapeutic use of eugenol still remains to be explored. Based on a review of the recent literature, the antioxidant, anti-proliferative, and anti-inflammatory activities of eugenol and its related compounds are discussed in relation to experimentally determined antioxidant activity (stoichiometric factor n and inhibition rate constant) and theoretical parameters [phenolic O-H bond dissociation enthalpy (BDE), ionization potential (IP according to Koopman's theorem), and electrophilicity (omega)], calculated using a density functional theory method. Dimers of eugenol and its related compounds showed large antioxidant activities and high omega values and also exerted efficient anti inflammatory activities. Eugenol appears to possess multiple antioxidant activities (dimerization, recycling, and chelating effect) in one molecule, thus having the potential to alleviate and prevent chronic diseases. PMID- 27771921 TI - Catechins and Its Role in Chronic Diseases. AB - The mechanisms of action of polyphenols have attracted much attention. Catechins are generally known as tea polyphenols. Researchers have extensively investigated the molecular mechanisms of these substances, especially (-)-epigallocatechin gallate of green tea catechin, and have provided new insights in the prevention and therapy for chronic diseases. This chapter summarizes catechins and their effects on chronic diseases, including metabolic syndromes, cardiovascular diseases, neurodegenerative diseases, and cancer, focusing on the effects of green tea catechins. PMID- 27771923 TI - Diallyl Sulfide and Its Role in Chronic Diseases Prevention. AB - Diallyl sulfide (C6H10S, DAS) is one of the novel natural organosulfur compounds, which is mostly obtained from the genus Allium plants. Numerous studies have revealed several unique properties of DAS in terms of its health-promoting effects. DAS has proved to be anticancer, antimicrobial, anti-angiogenic, and immunomodulatory like unique functions as demonstrated by the multiple investigations. Diallyl sulfide can also impede oxidative stress and chronic inflammation as suggested by the literature. Studies also explored that DAS could thwart the development of chronic diseases like cancer, neuronal, cardiovascular disease through modulating mechanistic pathways involved in pathogenesis. In this book chapter, we have attempted to give the comprehensive view on DAS about the physiochemical and biological properties, and its preventive role in chronic diseases with a mechanistic overview. PMID- 27771922 TI - Capsaicin and Its Role in Chronic Diseases. AB - A significant number of experimental and clinical studies published in peer reviewed journals have demonstrated promising pharmacological properties of capsaicin in relieving signs and symptoms of non-communicable diseases (chronic diseases). This chapter provides an overview made from basic and clinical research studies of the potential therapeutic effects of capsaicin, loaded in different application forms, such as solution and cream, on chronic diseases (e.g. arthritis, chronic pain, functional gastrointestinal disorders and cancer). In addition to the anti-inflammatory and analgesic properties of capsaicin largely recognized via, mainly, interaction with the TRPV1, the effects of capsaicin on different cell signalling pathways will be further discussed here. The analgesic, anti-inflammatory or apoptotic effects of capsaicin show promising results in arthritis, neuropathic pain, gastrointestinal disorders or cancer, since evidence demonstrates that the oral or local application of capsaicin reduce inflammation and pain in rheumatoid arthritis, promotes gastric protection against ulcer and induces apoptosis of the tumour cells. Sadly, these results have been paralleled by conflicting studies, which indicate that high concentrations of capsaicin are likely to evoke deleterious effects, thus suggesting that capsaicin activates different pathways at different concentrations in both human and rodent tissues. Thus, to establish effective capsaicin doses for chronic conditions, which can be benefited from capsaicin therapeutic effects, is a real challenge that must be pursued. PMID- 27771924 TI - Lupeol and Its Role in Chronic Diseases. AB - Lupeol belongs to pentacyclic lupane-type triterpenes and exhibits in edible vegetables, fruits and many plants. Many researches indicated that lupeol possesses many beneficial pharmacological activities including antioxidant, anti inflammatory, anti-hyperglycemic, anti-dyslipidemic and anti-mutagenic effects. From various disease-targeted animal models, these reports indicated that lupeol has anti-diabetic, anti-asthma, anti-arthritic, cardioprotective, hepatoprotective, nephroprotective, neuroprotective and anticancer efficiency under various routes of administration such as topical, oral, subcutaneous, intraperitoneal and intravenous. It is worth mentioning that clinical trials of lupeol were performed to treat canine oral malignant melanoma and human moderate skin acne in Japan and Korea. The detailed mechanism of anti-inflammatory, anti diabetic, hepatoprotective and anticancer activities was further reviewed from published papers. These evidence indicate that lupeol is a multi-target agent to exert diverse pharmacological potency with many potential targeting proteins such as alpha-glucosidase, alpha-amylase, protein tyrosine phosphatase 1B (PTP 1B) and TCA cycle enzymes and targeting pathway such as IL-1 receptor-associated kinase mediated toll-like receptor 4 (IRAK-TLR4), Bcl-2 family, nuclear factor kappa B (NF-kB), phosphatidylinositol-3-kinase (PI3-K)/Akt and Wnt/beta-catenin signaling pathways. This review also provides suggestion that lupeol might be a valuable and potential lead compound to develop as anti-inflammatory, anti-diabetic, hepatoprotective and anticancer drugs. PMID- 27771925 TI - Gingerol and Its Role in Chronic Diseases. AB - Since antiquity, ginger or Zingiber officinale, has been used by humans for medicinal purposes and as spice condiments to enhance flavor in cooking. Ginger contains many phenolic compounds such as gingerol, shogaol and paradol that exhibit antioxidant, anti-tumor and anti-inflammatory properties. The role of ginger and its constituents in ameliorating diseases has been the focus of study in the past two decades by many researchers who provide strong scientific evidence of its health benefit. This review discusses research findings and works devoted to gingerols, the major pungent constituent of ginger, in modulating and targeting signaling pathways with subsequent changes that ameliorate, reverse or prevent chronic diseases in human studies and animal models. The physical, chemical and biological properties of gingerols are also described. The use of ginger and especially gingerols as medicinal food derivative appears to be safe in treating or preventing chronic diseases which will benefit the common population, clinicians, patients, researchers, students and industrialists. PMID- 27771926 TI - Potential Use of Flavopiridol in Treatment of Chronic Diseases. AB - This chapter describes the potential use of flavopiridol, a CDK inhibitor with anti-inflammatory and anti-proliferative activities, in the treatment of various chronic diseases. Flavopiridol arrests cell cycle progression in the G1 or G2 phase by inhibiting the kinase activities of CDK1, CDK2, CDK4/6, and CDK7. Additionally, it binds tightly to CDK9, a component of the P-TEFb complex (CDK9/cyclin T), and interferes with RNA polymerase II activation and associated transcription. This in turn inhibits expression of several pro-survival and anti apoptotic genes, and enhances cytotoxicity in transformed cells or differentiation in growth-arrested cells. Recent studies indicate that flavopiridol elicits anti-inflammatory activity via CDK9 and NFkappaB-dependent signaling. Overall, these effects of flavopiridol potentiate its ability to overcome aberrant cell cycle activation and/or inflammatory stimuli, which are mediators of various chronic diseases. PMID- 27771927 TI - Plumbagin and Its Role in Chronic Diseases. AB - Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a plant-derived naphthoquinones obtained mainly from three families, including Plumbaginaceae, Droseraceae, and Ebenaceae. Plumbagin has exhibited its potential therapeutic benefits on numerous chronic diseases, i.e., breast cancer, non-small cell lung cancer, melanoma, ovarian, squamous cell carcinomas, pancreatic cancer, and prostate cancer. In addition, its anti-inflammatory and antimicrobial activities as well as control of diabetes and cardiovascular diseases have been reported. Thus, plumbagin is a promising agent for development as a new drug for the treatment or control of chronic diseases. Studies on controlled drug release or drug delivery systems have been involved for improvement of its therapeutic efficacy as well as for the reduction of its toxicity. However, most of the recent research information is from in vitro and in vivo studies. Further clinical studies are therefore required for its developments and applications as a novel drug used to treat chronic diseases. PMID- 27771928 TI - Anethole and Its Role in Chronic Diseases. AB - Anethole is the main fragrance and bioactive compound of anise, fennel, and star anise spices and more than other 20 plant species. It is widely used as flavor agent in food industry and other industries, in cosmetics, perfumery, and pharmaceuticals. In the last few years, various studies have revealed multiple beneficial effects of anethole for human health, such as anti-inflammatory, anticarcinogenic and chemopreventive, antidiabetic, immunomodulatory, neuroprotective, or antithrombotic, that are mediated by the modulation of several cell signaling pathways, mainly NF-kB and TNF-alpha signaling, and various ion channels. This chapter aims to review the scientific data and attempts to provide an insight into pharmacological activity of anethole and its therapeutic potential in human chronic diseases. PMID- 27771929 TI - The Role of Indirubins in Inflammation and Associated Tumorigenesis. AB - Indirubin is the major active component of an herbal recipe 'Dangui Luhui Wan' () in traditional Chinese medicine (TCM). It is widely used in China for the treatment of inflammation, cancer, and other chronic diseases and is known for good efficiency and very low side effects. Primary studies on the mechanism of action revealed that indirubin and derivatives are potent ATP-competitive inhibitors of CDKs and GSK3beta achieving IC50 values down to the low nanomolar range. However, the clinical application of indirubins is limited by the extremely poor water solubility (<1 mg/L in general) and consequently the insufficient bioavailability originating from strong binding forces in the crystal lattice. In the last few decades, a lot of efforts had been put into the structure optimization of indirubin derivatives binding selectively to specific kinases. Thus, a number of new indirubins have been developed bearing substituents mainly in the 5- and 3'-position suitable for improved solubility and inhibition against CDKs and GSK3beta, referred to as canonical indirubins. Interestingly, several noncanonical 7- and 7'-indirubin derivatives have been reported, showing a distinct binding model in the ATP-binding pocket and targeting a very different spectrum of protein kinases as seen from kinase profiling. In this chapter, we will review the field of indirubin research from its discovery, synthesis, chemical modification, structure-activity relationship, and mechanism of action to molecular targets comprising recent advantages and new findings in the context of inflammation-associated signaling pathways, in particular in tumorigenesis, including NF-kappaB, STAT3, TGF-beta, and AhR. PMID- 27771930 TI - CDDO and Its Role in Chronic Diseases. AB - There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional Chinese medicine used in hepatitis therapy, was modified by chemical processes to form 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO). This modification increased anti-inflammatory activity significantly and additional functional groups on the CDDO backbone have shown promise in treating conditions ranging from kidney disease to obesity to diabetes. CDDO's therapeutic effect is due to its upregulation of the master antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) through conformational change of Nrf2-repressing, Kelch-like erythroid cell-derived protein with CNC homology associated protein 1 (Keap1) and multiple animal and human studies have verified subsequent activation of Nrf2-controlled antioxidant genes via upstream Antioxidant Response Element (ARE) regions. At the present time, positive results have been obtained in the laboratory and clinical trials with CDDO derivatives treating conditions such as lung injury, inflammation and chronic kidney disease. However, clinical trials for cancer and cardiovascular disease have not shown equally positive results and further exploration of CDDO and its derivatives is needed to put these shortcomings into context for the purpose of future therapeutic modalities. PMID- 27771931 TI - Evodiamine and Its Role in Chronic Diseases. AB - Evodiamine (EVO) is a major alkaloid compound extracted from the dry unripened fruit Evodiae fructus (Evodia rutaecarpa Benth., Rutaceae). EVO has a variety of pharmacological activities, such as anti-obesity, anti-allergenic, analgesic, anti-tumor, anti-ulcerogenic, and neuroprotective activities. EVO has varying efficacies in animal models and humans. Here, the physicochemical properties of EVO are presented, and the EVO's functions and mechanisms of action in various chronic diseases are reviewed. EVO is worth exploring in more depth in the future for its potential use in various chronic diseases. PMID- 27771932 TI - Guggulsterone and Its Role in Chronic Diseases. AB - Guggulsterone is a plant sterol derived from gum resin of Commiphora wightii. The gum resin from guggul plants has been used for thousand years in Ayurveda to treat various disorders, including internal tumors, obesity, liver disorders, malignant sores and ulcers, urinary complaints, intestinal worms, leucoderma, sinuses, edema, and sudden paralytic seizures. Guggulsterone has been identified a bioactive components of this gum resin. This plant steroid has been reported to work as an antagonist of certain nuclear receptors, especially farnesoid X receptor, which regulates bile acids and cholesterol metabolism. Guggulsterone also mediates gene expression through the regulation of transcription factors, including nuclear factor-kappa B and signal transducer and activator of transcription 3, which plays important roles in the development of inflammation and tumorigenesis. Guggulsterone has been shown to downregulate the expression of proteins involved in anti-apoptotic, cell survival, cell proliferation, angiogenic, metastatic, and chemoresistant activities in tumor cells. This review aimed to clarify the cell signal pathways targeted by guggulsterone and the bioactivities of guggulsterone in animal models and humans. PMID- 27771933 TI - Deguelin and Its Role in Chronic Diseases. AB - Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function. Deguelin has also been implicated as a regulator of apoptosis through signaling pathways, such as the (PI3K)/Akt pathway, as well as an initiator of cell cycle arrest. Consequently, this compound has accrued great interest as a potential chemopreventive and chemotherapeutic. Additionally, deguelin exposure has been linked to Parkinson's disease (PD). PD is a neurodegenerative disorder, characterized by a substantial loss of dopaminergic neurons in the substantia nigra, as well the manifestation of symptoms such as bradykinesia, rigidity, and rest tremor. While exploring the genetic impact of PD is imperative, environmental factors, such as exposure to pesticides, herbicides, and insecticides, have also been connected to the development of PD. The etiology and pathogenesis of PD are yet to be fully understood and elucidated, but mitochondrial dysfunction is gaining recognition as a molecular hallmark of PD. In fact, deguelin has been reported to elicit PD-like symptoms (degeneration of the dopaminergic pathway) in rats administered with deguelin (6 mg/kg/day for 6 days), possibly through the inhibition of mitochondrial complex I. Further research investigating the mechanisms by which deguelin inhibits central cellular processes is essential in order to advance any prospective research addressing potential applications and risks of deguelin. PMID- 27771934 TI - Quercetin and Its Role in Chronic Diseases. AB - Quercetin, a member of the flavonoid class of polyphenol, is one of the most abundantly distributed flavonoids found in various food sources such as fruits, vegetables, nuts, wine and seeds. Quercetin and quercetin-rich foods have been reported to have wide range of health promoting effects, especially in the prevention and management of several diseases; however, the subject of its solubility and bioavailability has limited its use. This section will therefore, consider quercetin as a food-rich flavonoid, the various food sources, the limitations in its use and new approaches at improving its solubility and bioavailability. The therapeutic potentials of quercetin at the prevention/management of some degenerative diseases such as diabetes, hypertension and neurodegenerative diseases, as well as the underlying biochemical mechanisms such as free radical scavenging and enzyme inhibition will also be discussed. PMID- 27771935 TI - Eucalyptol and Its Role in Chronic Diseases. AB - Patients with chronic diseases such as cardiovascular diseases, chronic respiratory diseases, and neurological diseases have been shown to benefit from treatments such as aromatherapy in addition to medication. Most chronic diseases are caused by chronic inflammation and oxidative stress as well as harmful factors. Eucalyptol (1,8-cineole), a terpenoid oxide isolated from Eucalyptus species, is a promising compound for treating such conditions as it has been shown to have anti-inflammatory and antioxidant effects in various diseases, including respiratory disease, pancreatitis, colon damage, and cardiovascular and neurodegenerative diseases. Eucalyptol suppresses lipopolysaccharide (LPS) induced proinflammatory cytokine production through the action of NF-kappaB, TNF alpha, IL-1beta, and IL-6 and the extracellular signal-regulated kinase (ERK) pathway, and reduces oxidative stress through the regulation of signaling pathways and radical scavenging. The effects of eucalyptol have been studied in several cell and animal models as well as in patients with chronic diseases. Furthermore, eucalyptol can pass the blood-brain barrier and hence can be used as a carrier to deliver drugs to the brain via a microemulsion system. In summary, the various biological activities of eucalyptol such as its anti-inflammatory and antioxidant properties, as well as its physicochemical characteristics, make this compound a potentially important drug for the treatment of chronic diseases. PMID- 27771936 TI - Auraptene and Its Role in Chronic Diseases. AB - Auraptene (7-geranyloxycoumarin) is the best known and most abundant prenyloxycoumarin present in nature. It is synthesized by various plant species, mainly those of the Rutaceae and Umbeliferae (Apiaceae) families, comprising many edible fruits and vegetables such as lemons, grapefruit and orange. Auraptene has shown a remarkable effect in the prevention of degenerative diseases, in particular it has been reported to be one the most promising known natural chemopreventive agents against several types of cancer. The aim of this chapter is to review the effects of auraptene in the prevention and treatment of different chronic diseases. PMID- 27771937 TI - Lumbar intervertebral disc allograft transplantation: healing and remodelling of the bony structure. AB - Previous human study suggested that fresh-frozen intervertebral disc allograft transplantation can relieve neurological symptoms and restore segmental kinematics. Before wide clinical application, research into the pathophysiology of the postoperative disc allograft is needed. One important question that remains to be answered in disc allografting is the healing process of the host graft interface and the subsequent change of the endplates. With the goat model for lumbar disc allografting, histology, micro-computed tomography analysis, scanning electron microscopy and energy-dispersive X-ray spectroscopy mapping were applied to evaluate the healing of the host-graft interfaces, the remodelling of subchondral bone, and the changes of the bony and cartilaginous endplates after transplantation. It was found that healing of the host-graft interfaces started at 1.5 months and was completed at 6 months by natural remodelling. This bony remodelling was also noted in the subchondral bone area after 6 months. The bony endplate was well preserved initially, but was gradually replaced by trabecular bone afterwards; on the other hand, the cartilaginous endplate became atrophic at 6 months and nearly disappeared at the final follow up. Collectively, after intervertebral disc allograft transplantation, bony healing and remodelling were seen which ensured the stability and mobility of the disc-transplanted segment, but the integrity of bony and cartilaginous endplates was gradually lost and nearly disappeared finally. PMID- 27771938 TI - UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes. AB - OBJECTIVES: The purpose of this study was to examine whether UV exposure alters folate status according to C677T-MTHFR genotype, and to consider the relevance of this to human health and the evolutionary model of skin pigmentation. METHODS: Total Ozone Mapping Spectrometer (TOMS) satellite data were used to examine surface UV-irradiance, as a marker of UV exposure, in a large (n = 649) Australian cross-sectional study population. PCR/RFLP analysis was used to genotype C677T-MTHFR. RESULTS: Overall, cumulative UV-irradiance (42 and 120 days pre-clinic) was significantly negatively related to red cell folate (RCF) levels. When the cohort was stratified by MTHFR-C677T genotype, the relationship between UV-irradiance (42 days pre-clinic) and RCF remained significant only in the cohorts containing carriers of the T allele. Statistically significant z-score statistics and interaction terms from genotype and UV-irradiance (p-interaction) demonstrated that genotype did modify the effect of UV-irradiance on RCF, with the largest effect of UV being demonstrated in the 677TT-MTHFR subjects. CONCLUSIONS: Data provide strong evidence that surface UV-irradiance reduces long term systemic folate levels, and that this is influenced by the C677T-MTHFR gene variant. We speculate this effect may be due to 677TT-MTHFR individuals containing more 5,10CH2 -H4 PteGlu, and that this folate form may be particularly UV labile. Since UV-irradiance lowers RCF in an MTHFR genotype-specific way, there are likely implications for human health and the evolution of skin pigmentation. PMID- 27771939 TI - Expanding the archaellum regulatory network - the eukaryotic protein kinases ArnC and ArnD influence motility of Sulfolobus acidocaldarius. AB - Expression of the archaellum, the archaeal-type IV pilus-like rotating motility structure is upregulated under nutrient limitation. This is controlled by a network of regulators, called the archaellum regulatory network (arn). Several of the components of this network in Sulfolobus acidocaldarius can be phosphorylated, and the deletion of the phosphatase PP2A results in strongly increased motility during starvation, indicating a role for phosphorylation in the regulation of motility. Analysis of the motility of different protein kinase deletion strains revealed that deletion of saci_0965, saci_1181, and saci_1193 resulted in reduced motility, whereas the deletion of saci_1694 resulted in hypermotility. Here ArnC (Saci_1193) and ArnD (Saci_1694) are characterized. Purified ArnC and ArnD phosphorylate serine and threonine residues in the C terminus of the repressor ArnB. arnC is upregulated in starvation medium, whereas arnD is constitutively expressed. However, while differences in the expression and levels of flaB were observed in the DeltaarnD strain during growth under rich conditions, under nutrient limiting conditions the DeltaarnC and DeltaarnD strains showed no large differences in the expression levels of the archaellum or of the studied regulators. This suggests that next to the regulation via the archaellum regulatory network additional regulatory mechanisms of expression and/or activity of the archaellum exist. PMID- 27771941 TI - Analysis on the precision of the dimensions of self-ligating brackets. AB - OBJECTIVE: The present study aimed to evaluate the precision of the torque applied by 0.022" self-ligating brackets of different brands, the precision of parallelism between the inner walls of their slots, and precision of their slot height. Eighty brackets for upper central incisors of eight trademarked models were selected: Abzil, GAC, American Orthodontics, Morelli, Orthometric, Ormco, Forestadent, and Ortho Organizers. Images of the brackets were obtained using a scanning electron microscope (SEM) and these were measured using the AutoCAD 2011 software. The tolerance parameters stated in the ISO 27020 standard were used as references. The results showed that only the Orthometric, Morelli, and Ormco groups showed results inconsistent with the ISO standard. Regarding the parallelism of the internal walls of the slots, most of the models studied had results in line with the ISO prescription, except the Morelli group. In assessing bracket slot height, only the Forestadent, GAC, American Orthodontics, and Ormco groups presented results in accordance with the ISO standard. The GAC, Forestadent, and American Orthodontics groups did not differ in relation to the three factors of the ISO 27020 standard. Great variability of results is observed in relation to all the variables. PMID- 27771940 TI - Synthetic non-peptide low molecular weight agonists of the relaxin receptor 1. AB - : Relaxin is a small heterodimeric peptide hormone of the insulin/relaxin superfamily produced mainly in female and male reproductive organs. It has potent antifibrotic, vasodilatory and angiogenic effects and regulates the normal function of various physiological systems. Preclinical studies and recent clinical trials have shown the promise of recombinant relaxin as a therapeutic agent in the treatment of cardiovascular and fibrotic diseases. However, there are the universal drawbacks of peptide-based pharmacology that apply to relaxin: a short half-life in vivo requires its continuous delivery, and there are high costs of production, storage and treatment, as well as the possibility of immune responses. All these issues can be resolved by the development of low non-peptide MW agonists of the relaxin receptors which are stable, bioavailable, easily synthesized and specific. In this review, we describe the discovery and characterization of the first series of such compounds. The lead compound, ML290, binds to an allosteric site of the relaxin GPCR, RXFP1. ML290 shows high activity and efficacy, measured by cAMP response, in cells expressing endogenous or transfected RXFP1. Relaxin-like effects of ML290 were shown in various functional cellular assays in vitro. ML290 has excellent absorption, distribution, metabolism and excretion properties and in vivo stability. The identified series of low MW agonists does not activate rodent RXFP1 receptors and thus, the production of a RXFP1 humanized mouse model is needed for preclinical studies. The future analysis and clinical perspectives of relaxin receptor agonists are discussed. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 27771942 TI - Maternal transfer of perfluoroalkyl substances in hooded seals. AB - The role of milk in the transfer of perfluoroalkyl substances (PFASs) to offspring is not well known in wildlife. Eight PFASs were quantified in plasma and milk in mother-pup pairs of hooded seals (Cystophora cristata) during the nursing period, and the role of milk in the transfer process was analyzed. Hooded seal was chosen because of its short lactation period (3-4 d), during which the pup feeds only on milk. Placental or lactation transfer would thus be the only source of PFAS in the pup. Of the 8 PFASs analyzed (Sigma8 PFAS), 7 were found in all samples; therefore, milk is a source to PFASs in pups. Perfluorooctane sulfonate was the dominant PFAS in all samples. Mean Sigma8 PFAS concentrations were 6.0 ng/g protein (36 ng/g wet wt) in maternal plasma, 0.77 ng/g protein (3.2 ng/g wet wt) in milk, and 12 ng/g protein (66 ng/g wet wt) in pup plasma. Measured concentrations in plasma were within ranges previously reported from other seal species, below known toxicity thresholds for experimental rodents. Individual PFASs differed in transfer efficiency from mother to pup, depending on carbon chain lengths, with the lowest relative transfer for the intermediate chained PFASs (C9 -C10 ). The results show maternal transfer of PFASs via both milk and the placenta, of which placental transfer is the dominant pathway. Environ Toxicol Chem 2017;36:763-770. (c) 2016 SETAC. PMID- 27771944 TI - Is Gastroesophageal Reflux Disease and Achalasia Coincident or Not? AB - Achalasia and gastroesophageal reflux disease (GERD) are on opposite ends of the spectrum of lower esophageal sphincter dysfunction. Heartburn is the main symptom of GERD. However, heartburn and regurgitation are frequently observed in patients who have achalasia. The diagnosis of achalasia might be delayed because these symptoms are misinterpreted as gastroesophageal reflux. Here, we reviewed the clinical characteristics of patients with the erroneous diagnosis of GERD who actually had untreated achalasia. PMID- 27771943 TI - Synaptic Zn2+ and febrile seizure susceptibility. AB - Zn2+ , the second most prevalent trace element in the body, is essential for supporting a wide range of biological functions. While the majority of Zn2+ in the brain is protein-bound, a significant proportion of free Zn2+ is found co localized with glutamate in synaptic vesicles and is released in an activity dependent manner. Clinical studies have shown Zn2+ levels are significantly lower in blood and cerebrospinal fluid of children that suffer febrile seizures. Likewise, investigations in multiple animal models demonstrate that low levels of brain Zn2+ increase seizure susceptibility. Recent work provides human genetic evidence that disruption of brain Zn2+ homeostasis at the level of the synapse is associated with increased seizure susceptibility. In this review, we have explored the clinical, functional and genetic data supporting the view that low synaptic Zn2+ increases cellular excitability and febrile seizure susceptibility. Finally, the review focuses on the potential of therapeutic Zn2+ supplementation for at risk patients. PMID- 27771946 TI - Precipitation Dominates Interannual Variability of Riverine Nitrogen Loading across the Continental United States. AB - Excessive nitrogen loading to waterways leads to increased eutrophication and associated water quality impacts. An understanding of the regional and interannual variability in nitrogen loading and associated drivers is necessary for the design of effective management strategies. Here we develop a parsimonious empirical model based on net anthropogenic nitrogen input, precipitation, and land use that explains 68% of the observed variability in annual total nitrogen flux (QTN) (76% of ln(QTN)) across 242 catchment years. We use this model to present the first spatially and temporally resolved estimates of QTN for all eight-digit hydrologic unit (HUC8) watersheds within the continental United States (CONUS), focusing on the period 1987-2007. Results reveal high spatial and temporal variability in loading, with spatial variability primarily driven by nitrogen inputs, but with interannual variability and the occurrence of extremes dominated by precipitation across over three-quarters of the CONUS. High interannual variability and its correlation with precipitation persist at large aggregated scales. These findings point to a fundamental challenge in managing regions with high nutrient loading, because these regions also exhibit the strongest interannual variability and because the impact of changes in management practices will be modulated by meteorological variability and climatic trends. PMID- 27771945 TI - Binding and Uptake into Human Hepatocellular Carcinoma Cells of Peptide Functionalized Gold Nanoparticles. AB - One of the most daunting challenges of nanomedicine is the finding of appropriate targeting agents to deliver suitable payloads precisely to cells affected by malignancies. Even more complex is the ability to ensure that the nanosystems enter those cells. Here, we use 2 nm (metal core) gold nanoparticles to target human hepatocellular carcinoma (HepG2) cells stably transfected with the SERPINB3 (SB3) protein. The nanoparticles were coated with a 85:15 mixture of thiols featuring, respectively, a phosphoryl choline (to ensure water solubility and biocompatibility) and a 28-mer peptide corresponding to the amino acid sequence 21-47 of the hepatitis B virus-PreS1 protein (PreS1(21-47)). Conjugation of the peptide was performed via the maleimide-thiol reaction in methanol, allowing the use of a limited amount of the targeting molecule. This is an efficient procedure also in the perspective of selecting libraries of new targeting agents. The rationale behind the selection of the peptide is that SB3, which is undetectable in normal hepatocytes, is overexpressed in hepatocellular carcinoma and in hepatoblastoma and has been proposed as a target of the hepatitis B virus (HBV). For the latter, the key recognition element is the PreS1(21-47) peptide, which is a fragment of one of the proteins composing the viral envelope. The ability of the conjugated nanoparticles to bind the target protein SB3, expressed in liver cancer cells, was investigated by surface plasmon resonance analysis and in vitro via cellular uptake analysis followed by atomic absorption analysis of digested samples. The results showed that the PreS1(21-47) peptide is a suitable targeting agent for cells overexpressing the SB3 protein. Even more important is the evidence that the gold nanoparticles are internalized by the cells. The comparison between the surface plasmon resonance analysis and the cellular uptake studies suggests that the presentation of the protein on the cell surface is critical for efficient recognition. PMID- 27771947 TI - Rapid and Sensitive Detection of 3-Amino-2-oxazolidinone Using a Quantum Dot Based Immunochromatographic Fluorescent Biosensor. AB - To monitor the levels of furazolidone in edible animal tissues, a fluorescent sensor was developed for the determination of 3-amino-2-oxazolidinone (AOZ), the metabolite of furazolidone, featuring an immunochromatographic test strip assay (ITSA) integrated with a quantum dot (QD) label. The optimal QD-based ITSA sensor exhibits good dynamic linear detection for AOZ over the range of 0.1-100 MUg/L, with a 50% inhibitory concentration (IC50) of 1.06 MUg/L. The decision limit and the detection capability were 0.14-0.15 and 0.27-0.33 MUg/kg, respectively, for this analyte using the QD-based ITSA sensor. These values represent an improvement over a previously reported gold nanoparticle-based immunochromatographic assay. The recoveries of AOZ in kinds of animal tissues were between 76.3 and 98.4% at the levels of 1.0, 5.0, and 10.0 MUg/kg. The performance and practicality of our QD-based fluorescent immunosensor were confirmed by commercial ELISA kit and LC-MS/MS. In conclusion, the proposed sensor was a feasible detection method for AOZ analysis on site. PMID- 27771948 TI - Level of Alkenylbenzenes in Parsley and Dill Based Teas and Associated Risk Assessment Using the Margin of Exposure Approach. AB - Risk assessment of parsley and dill based teas that contain alkenylbenzenes was performed. To this end the estimated daily intake (EDI) of alkenylbenzenes resulting from use of the teas was quantified. Since most teas appeared to contain more than one alkenylbenzene, a combined risk assessment was performed based on equal potency of all alkenylbenzenes or using a so-called toxic equivalency (TEQ) approach through defining toxic equivalency factors (TEFs) for the different alkenylbenzenes. The EDI values resulting from consuming one cup of tea a day were 0.2-10.1 MUg/kg bw for the individual alkenylbenzenes, 0.6-13.1 MUg/kg bw for the sum of the alkenylbenzenes, and 0.3-10.7 MUg safrole equiv/kg bw for the sum of alkenylbenzenes when expressed in safrole equivalents. The margin of exposure (MOE) values obtained were generally <10000, indicating a concern if the teas would be consumed on a daily basis over longer periods of time. PMID- 27771949 TI - Enantioselective Total Synthesis of (+)-Hinckdentine A via a Catalytic Dearomatization Approach. AB - Optically pure hinckdentine A was synthesized on a 300 mg scale via an asymmetric catalysis-based strategy. The key steps to the first asymmetric synthesis involved (i) enantioselective dearomative cyclization of an achiral N-acyl indole that allowed for the efficient construction of the key polycyclic indoline intermediate with a crucial tetrasubstituted stereogenic carbon center, (ii) Beckmann fragmentation-mediated ring expansion, (iii) rearrangement-based introduction of an anilinic nitrogen atom, (iv) regioselective tribromination, and (v) final closure of the cyclic amidine moiety. PMID- 27771950 TI - Sediment Monitored Natural Recovery Evidenced by Compound Specific Isotope Analysis and High-Resolution Pore Water Sampling. AB - Monitoring natural recovery of contaminated sediments requires the use of techniques that can provide definitive evidence of in situ contaminant degradation. In this study, a passive diffusion sampler, called "peeper", was combined with Compound Specific Isotope Analysis to determine benzene and monochlorobenzene (MCB) stable carbon isotope values at a fine vertical resolution (3 cm) across the sediment water interface at a contaminated site. Results indicated significant decrease in concentrations of MCB from the bottom to the top layers of the sediment over 25 cm, and a 3.5 0/00 enrichment in delta13C values of MCB over that distance. Benzene was always at lower concentrations than MCB, with consistently more depleted delta13C values than MCB. The redox conditions were dominated by iron reduction along most of the sediment profile. These results provide multiple lines of evidence for in situ reductive dechlorination of MCB to benzene. Stable isotope analysis of contaminants in pore water is a valuable method to demonstrate in situ natural recovery of contaminated sediments. This novel high-resolution approach is critical to deciphering the combined effects of parent contaminant (e.g., MCB) degradation and both production and simultaneous degradation of daughter products, especially benzene. PMID- 27771951 TI - New Insight into the Local Structure of Hydrous Ferric Arsenate Using Full Potential Multiple Scattering Analysis, Density Functional Theory Calculations, and Vibrational Spectroscopy. AB - Hydrous ferric arsenate (HFA) is an important arsenic-bearing precipitate in the mining-impacted environment and hydrometallurgical tailings. However, there is no agreement on its local atomic structure. The local structure of HFA was reprobed by employing a full-potential multiple scattering (FPMS) analysis, density functional theory (DFT) calculations, and vibrational spectroscopy. The FPMS simulations indicated that the coordination number of the As-Fe, Fe-As, or both in HFA was approximately two. The DFT calculations constructed a structure of HFA with the formula of Fe(HAsO4)x(H2AsO4)1-x(OH)y.zH2O. The presence of protonated arsenate in HFA was also evidenced by vibrational spectroscopy. The As and Fe K edge X-ray absorption near-edge structure spectra of HFA were accurately reproduced by FPMS simulations using the chain structure, which was also a reasonable model for extended X-Ray absorption fine structure fitting. The FPMS refinements indicated that the interatomic Fe-Fe distance was approximately 5.2 A, consistent with that obtained by Mikutta et al. (Environ. Sci. Technol. 2013, 47 (7), 3122-3131) using wavelet analysis. All of the results suggested that HFA was more likely to occur as a chain with AsO4 tetrahedra and FeO6 octahedra connecting alternately in an isolated bidentate-type fashion. This finding is of significance for understanding the fate of arsenic and the formation of ferric arsenate minerals in an acidic environment. PMID- 27771952 TI - Using Molecular Architecture to Control the Reactivity of a Triplet Vinylnitrene. AB - Photolysis of 3-azido-1-indenone (1) with a light-emitting diode (LED, lambda = 405 nm) or mercury arc lamp (Pyrex) resulted in the formation of heterodimer 3 in excellent yield, through dimerization of triplet vinylnitrene 32. At ambient temperature, vinylnitrene 32 (lambdamax at 340 and 480 nm) was detected directly with laser flash photolysis of vinyl azide 1. The vinylnitrene intermediate was also characterized directly with IR and ESR spectroscopy in cryogenic matrices. The ESR spectrum of vinylnitrene 32 yielded a zero-field splitting parameter |D/hc| of 0.460 cm-1 and |E/hc| of 0.015 cm-1, which reveals that vinylnitrene 32 has significant 1,3-biradical character. The proposed mechanism for the formation and reactivity of triplet vinylnitrene 32 was supported with density functional theory (DFT) calculations, which highlight that the steric demand of the five membered ring in vinylnitrene 32 prevents intersystem crossing to the corresponding azirine (10). CASSCF and CASPT2 calculations showed that the energy gap between the singlet and triplet configurations of vinylnitrene 2 is only 10 kcal/mol. In spite of this small energy gap, vinylnitrene 32 does not decay by intersystem crossing, but rather by dimerization. Thus, triplet vinylnitrenes can be selectively formed with visible light and used to form new C-N bonds in synthetic applications. PMID- 27771953 TI - Influence of Cholesterol on Phospholipid Bilayer Structure and Dynamics. AB - In this study, the influence of cholesterol on lipid bilayers is investigated by changing phospholipid headgroup, cholesterol concentration, chain saturation, and temperature. Molecular dynamics (MD) simulations were used to characterize bilayers containing phosphatidylcholine (PC) head groups with either fully saturated dimyristoyl (DM) or monounsaturated dioleoyl (DO) acyl chains and cholesterol concentrations ranging from 5 to 50%. To further explore the effects of cholesterol on bilayers with different head groups, we also performed MD simulations of bilayer systems having 15% cholesterol with phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), and phosphatidylserine (PS), each having DM chains and at a temperature above the solid gel phase transition. Additionally, bilayers of DMPA, DMPE, and DMPS with 15% cholesterol were simulated at temperatures below the solid gel phase transition temperatures. Compared to membranes without cholesterol, cholesterol in the model bilayers increases chain order in bilayers with the highest order in the liquid ordered and solid gel phases. Head group properties and acyl chain saturation are also found to critically impact bilayer dynamics, largely through the formation of hydrogen bonds between membrane components. These results provide a better understanding of the basic characteristics on structure and dynamics of cholesterol-containing membranes by revealing molecular details of interactions between cholesterol and phospholipids as well as add to the library of simulation data necessary for the MD community to accurately represent relevant models of atomic-scale systems. PMID- 27771954 TI - Biodegradation of Chlorpyrifos, Malathion, and Dimethoate by Three Strains of Bacteria Isolated from Pesticide-Polluted Soils in Sudan. AB - This study was done to identify pesticide-biodegrading microorganisms and to characterize degradation rates. Bacillus safensis strain FO-36bT, Bacillus subtilis subsp. inaquosorum strain KCTC13429T, and Bacillus cereus strain ATCC14579T were isolated from pesticide-polluted soil in Sudan, separately incubated with each pesticide with periodic samples drawn for GC and GC-MS. Pesticide biodegradation followed a biphasic model. alpha and beta half-lives (days) of chlorpyrifos, malathion, and dimethoate in B. safensis culture were 2.13, 4.76; 2.59, 5.66; and 9.5, 11.0, respectively. Values in B. subtilis and B. cereus cultures were 4.09, 9.45 and 4.33, 9.99 for chlorpyrifos; 2.99, 5.36 and 2.43, 4.71 for malathion; and 9.53, 15.11 and 4.16, 9.27 for dimethoate. No metabolite was detected in B. subtilis cultures, whereas a few were detected from B. safensis and B. cereus cultures. Bacterial efficiency can be ordered as B. safensis > B. subtilis > B. cereus for chlorpyrifos and B. cereus > B. subtilis > B. safensis for malathion and dimethoate. PMID- 27771955 TI - Cation-Hydroxide-Water Coadsorption Inhibits the Alkaline Hydrogen Oxidation Reaction. AB - Rotating disk electrode voltammograms and infrared reflection absorption spectra indicate that the hydrogen oxidation reaction of platinum in 0.1 M tetramethylammonium hydroxide solution is adversely impacted by time-dependent and potential-driven cation-hydroxide-water coadsorption. Impedance analysis suggests that the hydrogen oxidation reaction inhibition is mainly caused by the hydrogen diffusion barrier of the coadsorbed trilayer rather than intuitive catalyst site blocking by the adsorbed cation species. These results give useful insights on how to design ionomeric binders for advanced alkaline membrane fuel cells. PMID- 27771956 TI - Parallel Polyadenine Duplex Formation at Low pH Facilitates DNA Conjugation onto Gold Nanoparticles. AB - DNA-functionalized gold nanoparticles (AuNPs) have been extensively used in sensing, drug delivery, and materials science. A key step is to attach DNA to AuNPs, forming a stable and functional conjugate. Although the traditional salt aging method takes a full day or longer, a recent low-pH method allows DNA conjugation in a few minutes. The effect of low pH was attributed to the protonation of adenine (A) and cytosine (C), resulting in an overall lower negative charge density on DNA. In this work, the effect of DNA conformation at low pH is studied. Using circular dichroism (CD) spectroscopy, the parallel poly A duplex (A-motif) is detected when a poly-A segment is linked to a random DNA, a design typically used for DNA conjugation. A DNA staining dye, thiazole orange, is identified for detecting such A-motifs. The A-motif structure is ideal for DNA conjugation because it exposes the thiol group to directly react with the gold surface while minimizing nonspecific DNA base adsorption. For nonthiolated DNA, the optimal procedure is to incubate DNA and AuNPs followed by lowering the pH. The i-motif formed by poly-C DNA at low pH is less favorable to the conjugation reaction because of its unique way of folding. The stability of poly-A and poly-G DNA at low pH is examined. An excellent stability of poly-A DNA is confirmed, but poly-G has lower stability. This study provides new fundamental insights into a practically useful technique of conjugating DNA to AuNPs. PMID- 27771957 TI - Simultaneous Quantitation of Advanced Glycation End Products in Soy Sauce and Beer by Liquid Chromatography-Tandem Mass Spectrometry without Ion-Pair Reagents and Derivatization. AB - The aim of this study was to develop a simple and sensitive method to analyze several advanced glycation end products (AGEs) simultaneously using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and to apply this method to the quantitation of AGEs in brown-colored foods. The developed method enabled to separate and quantitate simultaneously seven AGEs, and was applied to the determination of free AGEs contained in various kinds of soy sauce and beer. The major AGEs in soy sauce and beer were Nepsilon-carboxymethyllysine (CML), Nepsilon-carboxyethyllysine (CEL), and Ndelta-(5-hydro-5-methyl-4-imidazolon-2 yl)ornithine (MG-H1). Using the developed LC-MS/MS method, recovery test on soy sauce and beer samples showed the recovery values of 85.3-103.9% for CML, 95.9 107.4% for CEL, and 69.5-123.2% for MG-H1. In particular, it is the first report that free CML, CEL, and MG-H1 were present in beer. Furthermore, long-term storage and heating process of soy sauce increased CML and MG-H1. PMID- 27771958 TI - Oxygen- and Lithium-Doped Hybrid Boron-Nitride/Carbon Networks for Hydrogen Storage. AB - Hydrogen storage capacities have been studied on newly designed three-dimensional pillared boron nitride (PBN) and pillared graphene boron nitride (PGBN). We propose these novel materials based on the covalent connection of BNNTs and graphene sheets, which enhance the surface and free volume for storage within the nanomaterial and increase the gravimetric and volumetric hydrogen uptake capacities. Density functional theory and molecular dynamics simulations show that these lithium- and oxygen-doped pillared structures have improved gravimetric and volumetric hydrogen capacities at room temperature, with values on the order of 9.1-11.6 wt % and 40-60 g/L. Our findings demonstrate that the gravimetric uptake of oxygen- and lithium-doped PBN and PGBN has significantly enhanced the hydrogen sorption and desorption. Calculations for O-doped PGBN yield gravimetric hydrogen uptake capacities greater than 11.6 wt % at room temperature. This increased value is attributed to the pillared morphology, which improves the mechanical properties and increases porosity, as well as the high binding energy between oxygen and GBN. Our results suggest that hybrid carbon/BNNT nanostructures are an excellent candidate for hydrogen storage, owing to the combination of the electron mobility of graphene and the polarized nature of BN at heterojunctions, which enhances the uptake capacity, providing ample opportunities to further tune this hybrid material for efficient hydrogen storage. PMID- 27771960 TI - Early onset of type 2 diabetes among visible minority and immigrant populations in Canada. AB - OBJECTIVES: Type 2 diabetes is a chronic condition that affects nearly over three million Canadians, including immigrants. The timing of the first onset of diabetes has been linked to several other severe diseases. Yet, there is a dearth of empirical studies that examine the timing of the first onset of diabetes among Canadians, in general, and among immigrants and ethnic minority populations within Canada, in particular. DESIGN: Applying event history techniques to the 2013 Canadian Community and Health Survey, we address this research void by examining factors that contribute to the first onset of diabetes among immigrant and visible minority populations in Canada (N = 8905). Given the gendered patterns in the epidemiology of diseases and the differences in risk factors for men and women, gender-specific models were estimated. RESULTS: Results showed that South Asian, Black and Filipino women developed diabetes earlier, compared to women from the UK. Similarly, South Asian, Chinese, Filipino, Black, South East Asian and Arab men developed diabetes earlier than men from the UK. A significant and important finding of this analysis was that the risks of developing diabetes vanished completely for Black and Filipino women, after accounting for lifestyle factors. For South Asian women, however, there was significant attenuation in their risks after accounting for lifestyle factors. The findings were strikingly different for immigrant men. Specifically, their risks of developing diabetes increased after accounting for lifestyle factors. CONCLUSIONS: These results suggest the development of gender-specific and lifestyle interventions, targeted at specific immigrant groups with increased risks of developing diabetes earlier in the life course. PMID- 27771959 TI - Future prospects of therapeutic clinical trials in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future. PMID- 27771961 TI - Building a better understanding of the burden of disease in familial chylomicronemia syndrome. PMID- 27771963 TI - Possible influence of the environmental pollutant bisphenol A on the cardiometabolic risk factors. AB - Bisphenol A (BPA) is a ubiquitous environmental pollutant which is often associated with various health issues. In this study 103 healthy female volunteers in reproductive age from Serbian north province Vojvodina were enrolled and examined for the BPA exposure in the urine samples after 12 h of fasting. BPA was found in 35.92 % (37/103) of subjects. Statistically significant increment in waist circumference (p = 0.045) and waist-to-height ratio (p = 0.037) was observed among the BPA positive women in comparison with the women who had the same energetic balance and had not been exposed to BPA. Linear correlation was obtained between the BPA concentration in urine samples and body mass index (r2 = 0.35, p = 0.003) waist circumference (r2 = 0.21, p = 0.02) and waist-to-height ratio (r2 = 0.25, p = 0.01) among the obese. High energetic intake and reduced physical activity additionally pronounced BPA positive association with obesity. No statistically significant difference was observed in triglycerides, HDL and LDL cholesterol levels between the BPA exposed and BPA non exposed female volunteers. PMID- 27771962 TI - Humoral Antibody Responses to HIV Viral Proteins and to CD4 Among HIV Controllers, Rapid and Typical Progressors in an HIV-Positive Patient Cohort. AB - The purpose of this study was to assess humoral antibody responses as a function of disease progression (DP) in a well-defined HIV+ cohort. We quantified antibodies to HIV-1 gp120, Gag, and CD4 receptor by enzyme-linked immunosorbent assay in sera from a cohort of 97 HIV+ subjects at defined stages of DP. We also measured antibody-dependent cellular cytotoxicity (ADCC) as a function of the clinical status of the patients. We purified antibodies to CD4 and gp120 and assessed them for specificity, ability to block gp120 binding to target cells, ability to block virus infection, and ability to facilitate ADCC. All of the HIV+ patient samples were positive for antibodies to HIV gp120 and p24 and 80% showed evidence of hypergammaglobulinemia. Approximately 10% of cohort members were positive for antibodies to CD4, but we noted no significant correlation relevant to DP. There were statistically significant differences between the groups concerning the level of humoral response to gp120 and Gag. However, we observed no distinction in ability of anti-gp120 antibodies purified from each group to neutralize infection. In addition, there was a statistically significant difference in ADCC, with elite controllers exhibiting significantly lower levels of ADCC than the other five groups. We detected IgA anti-gp120 antibodies, but did not correlate their presence with either DP or ADCC levels. The results are consistent with the interpretation that the humoral antibody response to the antigens assessed here represents a signature of the level of viremia but does not correlate with clinical status of HIV infection. PMID- 27771965 TI - Reviewing the diagnostic criteria for acute-on-chronic liver failure. AB - INTRODUCTION: For over 20 years, acute-on-chronic liver failure (ACLF) has taken multiple definitions and/or classifications. The definition outlines the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific time frame. Early and accurate diagnosis is essential as this inflammation of the liver may tilt the balance of liver destruction and regeneration adversely. Various factors such as superadded systemic sepsis, liver reserve, cause of primary chronic liver disease, state of immune system or the state of gut microbial flora might determine the ultimate prognosis. Areas covered: To date, there has been no universally accepted definition of ACLF. In this review, we discuss the strengths and weaknesses, controversies and basis for early identification and accurate diagnosis of ACLF. PubMed and Google scholar database searches were conducted, search terms included 'acute on chronic liver failure,' 'ACLF,' and 'diagnostic criteria.' Expert commentary: With recent advances in the management of advanced cirrhosis, research will gradually shift towards ACLF in the near future, focusing on the pathogenesis, new treatment options and improving survival. Once we improve understanding of this syndrome, newer definitions will evolve, thereby enabling earlier diagnosis and novel therapeutic avenues. PMID- 27771964 TI - Reinventing the political role of health professionals in conflict prevention & reconciliation: the Sudanese model. AB - Given the persistent recurrence of armed conflict, influential actors owe it to the affected communities to take action. The legitimacy of health professionals to mitigate the effects of conflict relates to their ability to save lives and address the physical and mental consequences of armed conflict during which thousands of lives may be lost. Medical professionals have unique and potentially far-reaching skills. These become crucial during wartime and disasters in terms of providing medical services and humanitarian aid. However, they are insufficiently used in one area: involvement in politics as a tool to foster peace. Despite this, Sudanese individuals from medical backgrounds have participated actively in conflict resolution and peace-building processes. In fact, their political actions throughout the last six decades have aimed to prevent conflict at four different levels, which are described by Yusuf et al. in their article on the political involvement of health professionals in prevention. Their stand against President Nimeiri's Sharia laws was primordial prevention of religious conflict at the national level. Their leading role in the second Sudanese Intifada uprising was a key factor in saving the country from civil war, and another example of primary prevention. Sudanese physicians were also involved in secondary prevention by being influentially involved in almost all national peace agreements. Avoiding disputes at the tertiary level represents the weakest link in their repeated efforts. This paper outlines the different roles Sudanese medical personnel have taken in peacemaking. It also critically evaluates them in order to consider new methods of political involvement that suit future challenges. PMID- 27771967 TI - Novel investigational therapies for treating biliary tract carcinoma. AB - INTRODUCTION: Cholangiocarcinoma (CCA) is an epithelial cell malignancy arising from bile ducts and/or peribiliary glands. Even though it is considered as a rare neoplasm, its incidence is raising, particularly in developed countries. Prognosis is generally poor with few patients who present the inclusion criteria for surgery (the mainstay treatment for this tumour). Several genetic alterations potentially driving tumour progression have been described, representing a possible target for new compounds. Areas covered: A clinical trial search in Clinicaltrials.gov encompassing a literature search in PubMed and ASCO/ESMO Websites was undertaken in March 2016. Expert opinion: Notwithstanding a large number of drug tested, results are still disappointing. The main reasons could be the low number of patients enrolled in trials, and the lack of a patient selection based on the biological profile of the tumours. Potential active drugs could have been discharged simply because beneficial in a particular subgroup of patients and not in un unselected population. The future direction of the research should consider biomarker evaluation in order to describe the genetic alteration/s that drive tumour progression and aggressiveness and the mechanisms of drug resistance. Finally, it will be of great interest to consider the results of immunotherapy whenever available. PMID- 27771966 TI - Design, synthesis and molecular docking of novel diarylcyclohexenone and diarylindazole derivatives as tubulin polymerization inhibitors. AB - New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R1) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds 4b, 5e and 5f exhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells. The mechanism of the antitumor activity was investigated through evaluating the tubulin inhibition potential of the active compounds. Compounds 4b, 5e and 5f showed percentage inhibition of tubulin in both cell line homogenates ranging from 79.72% to 89.31%. Cell cycle analysis of compounds 4b, 5e and 5f revealed cell cycle arrest at G2/M phase. Molecular docking revealed the binding mode of these new compounds into the colchicine binding site of tubulin.[Formula: see text]. PMID- 27771968 TI - Application of microemulsions for the removal of synthetic resins from paintings on canvas. AB - Traditional cleaning methods with organic solvents often are not suitable for removal of aged resin so researchers have to find new formulations. In this work, a case study is reported in which new microemulsions were applied on the surface of a painting covered by some aged resin layers used during a previous restoration. Based on the quality of the intervention and the analysis of a sample of the varnish carried out with both MALDI-TOF and ATR-IR spectrometers, it was conjectured that this undesired material could be an acrylic polymer. So it was chosen to use xylene, ethyl acetate and propylene carbonate (XYL and EAPC) microemulsions (O/W oil in water). The first is able to solubilise only acrylic polymers, the second may solve both acrylic and vinyl resins. The first has had the greatest effect allowing complete varnish removal and original artwork restoration. PMID- 27771969 TI - Vinflunine for the treatment of non-small cell lung cancer. AB - INTRODUCTION: Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC). Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included. The review also summarizes clinical studies, including phase I trials involving NSCLC among other tumors as well as phase II/III trials specifically addressing this malignancy. Additionally, the safety profile and the current regulatory status of vinflunine is discussed. Expert opinion: Vinflunine is active as single agent and as part of platinum-based combinations in NSCLC. It results non-inferior to docetaxel in a randomized phase III trial including previously treated NSCLC patients; additionally, its safety profile is generally considered manageable. Ultimately, further studies are needed to confirm the role of vinflunine in NSCLC, in consideration of the evolving evidence regarding targeted therapies and immune check-point inhibitors. PMID- 27771970 TI - A Longitudinal Study of Adjustment Disorder After Trauma Exposure. AB - OBJECTIVE: Adjustment disorder has been recategorized as a trauma- and stressor related disorder in DSM-5. The aim of this study was to determine the prevalence of adjustment disorder in the first 12 months after severe injury; to determine whether adjustment disorder was a less severe disorder compared with other disorders in terms of disability and quality of life; to investigate the trajectory of adjustment disorder; and to examine whether the subtypes described in DSM-5 are distinguishable. METHOD: In a multisite, cohort study, injury patients were assessed during hospitalization and at 3 and 12 months postinjury (N=826). Structured clinical interviews were used to assess affective, anxiety, and substance use disorders, and self-report measures of disability, anxiety, depression, and quality of life were administered. RESULTS: The prevalence of adjustment disorder was 19% at 3 months and 16% at 12 months. Participants with adjustment disorder reported worse outcomes relative to those with no psychiatric diagnosis but better outcomes compared with those diagnosed with other psychiatric disorders. Participants with adjustment disorder at 3 months postinjury were significantly more likely to meet criteria for a psychiatric disorder at 12 months (odds ratio=2.67, 95% CI=1.59-4.49). Latent-profile analysis identified a three-class model that was based on symptom severity, not the subtypes identified by DSM-5. CONCLUSIONS: Recategorization of adjustment disorder into the trauma- and stressor-related disorders is supported by this study. However, further description of the phenomenology of the disorder is required. PMID- 27771971 TI - Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders. AB - OBJECTIVE: Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I-IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. METHOD: NRG3 isoform classes I-IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. RESULTS: NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. CONCLUSIONS: Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development. PMID- 27771972 TI - The Epidemiology of First-Episode Psychosis in Early Intervention in Psychosis Services: Findings From the Social Epidemiology of Psychoses in East Anglia [SEPEA] Study. AB - OBJECTIVE: Few studies have characterized the epidemiology of first-episode psychoses in rural or urban settings since the introduction of early intervention psychosis services. To address this, the authors conducted a naturalistic cohort study in England, where such services are well established. METHOD: All new first episode psychosis cases, 16-35 years old, presenting to early intervention psychosis services in the East of England were identified during 2 million person years follow-up. Presence of ICD-10 F10-33 psychotic disorder was confirmed using OPCRIT [operational criteria for psychotic illness]. Incidence rate ratios were estimated following multivariable Poisson regression, adjusting for age, sex, ethnicity, socioeconomic status, neighborhood-level deprivation, and population density. RESULTS: Of 1,005 referrals, 687 participants (68.4%) fulfilled epidemiological and diagnostic criteria for first-episode psychosis (34.0 new cases per 100,000 person-years; 95% CI=31.5-36.6). Median age at referral was similar for men (22.5 years; interquartile range: 19.5-26.7) and women (23.4 years; interquartile range: 19.5-29.1); incidence rates were highest for men and women before 20 years of age. Rates increased for ethnic minority groups (incidence rate ratio: 1.4; 95% CI=1.1-1.6), as well as with lower socioeconomic status (incidence rate ratio: 1.3; 95% CI=1.2-1.4) and in more urban (incidence rate ratio: 1.4;95%CI=1.0-1.8) and deprived (incidence rate ratio: 2.1; 95% CI=1.3-3.3) neighborhoods, after adjustment for confounders. CONCLUSIONS: Pronounced variation in psychosis incidence, peaking before 20 years old, exists in populations served by early intervention psychosis services. Excess rates were restricted to urban and deprived communities, suggesting that a threshold of socioenvironmental adversity may be necessary to increase incidence. This robust epidemiology can inform service development in various settings about likely population-level need. PMID- 27771974 TI - New treatment strategies for HIV-positive cancer patients undergoing antiblastic chemotherapy. AB - INTRODUCTION: The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the outcome of HIV-infected patients by prolonging their survival. The increase in life expectancy has led to an increased risk of non-AIDS-related mortality and morbidity, including cardiovascular diseases, neurocognitive diseases, neuroendocrine dysfunctions and cancer. Areas covered: The GICAT (Italian Cooperation Group on AIDS and Tumors) has demonstrated that patients who receive a multidisciplinary approach with the combination of anticancer agents (AC) and HAART can achieve better responses and survival rates than patients who receive AC alone. The first obstacle for the oncologist to plan treatment for cancer HIV-patients is the preliminary evaluation of drug-drug interactions between AC and HAART. Recent progress in pharmacogenomics could provide a new approach for personalized treatments. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, to maximize the efficacy of both concomitant therapy and to minimize the risk of DDIs, a currently useful list of pharmacogenomic markers of key metabolic enzymes is provided. Expert opinion: In this scenario, the importance of cooperation between oncologists and other health specialists (i.e., infectivologists, pharmacists, genetics and lab specialists) must not be underestimated in the management of these patients with the aim of planning an individual treatment strategy. PMID- 27771973 TI - Dopaminergic Enhancement of Striatal Response to Reward in Major Depression. AB - OBJECTIVE: Major depressive disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning in depressed individuals. METHOD: In a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy control participants were randomly assigned to receive either placebo or a single low dose (50 mg) of the D2/D3 receptor antagonist amisulpride, which is believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional MRI) and a probabilistic reward learning task were administered at absorption peaks of amisulpride. RESULTS: Depressed participants selected previously rewarded stimuli less frequently than did control participants, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and control participants receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and the midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among control participants receiving placebo. CONCLUSIONS: Acute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals but had no behavioral effects. Taken together, the results suggest that targeted pharmacological treatments may normalize neural correlates of reward processing in depression; despite such acute effects on neural function, behavioral modification may require more chronic exposure. This is consistent with previous reports that antidepressant effects of amisulpride in depression emerged after sustained administration. PMID- 27771975 TI - Does it take a community to raise a plant? A summary of the Canadian Crop Microbiome Workshop. PMID- 27771976 TI - Hepatitis B reactivation during everolimus treatment. PMID- 27771977 TI - Multicenter evaluation of the Luminex(r) ARIES(r) HSV 1&2 Assay for the detection of herpes simplex virus types 1 and 2 in cutaneous and mucocutaneous lesion specimens. AB - INTRODUCTION: The ARIES(r) HSV 1&2 Assay is a new FDA cleared real-time PCR test for detection and differentiation of HSV-1 and HSV-2 DNA from cutaneous and mucocutaneous lesions. The test is performed on the ARIES(r) System, an automated sample to answer real-time PCR instrument that provides a closed system and simple workflow for performing molecular testing. Areas covered: This article reports the clinical performance of the ARIES(r) HSV 1&2 Assay assessed on 1963 prospectively collected specimens. Assay sensitivities were 91.1-95% (cutaneous) and 97-98.5% (mucocutaneous), and specificities were 88.8-94.2% (cutaneous) and 93.2-95.4% (mucocutaneous), as compared to the ELVIS(r) HSV test system. Expert commentary: Detection of HSV DNA by PCR is rapid and more sensitive than traditional culture and immunoassay methods and is being widely adopted in many laboratory settings. Sample to answer molecular platforms like ARIES(r) will enable routine and non-molecular labs to perform sensitive and rapid molecular testing with ease. PMID- 27771978 TI - Challenges and opportunities in the treatment of ventilator-associated pneumonia. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) is a distinct clinical entity characterized by an onset after 48 hours of the application of mechanical ventilation (MV). Protocols exist to aid in the prevention of VAP, but this infection carries a devastating impact on patient morbidity and potentially mortality. Areas covered: In this review we present key concepts from existing guidelines to aid clinicians. Challenges remain in defining this disease and, most importantly appropriate empiric antimicrobial treatment is the main determinant of outcome. We highlight that the selection of initial antibiotics is critical, as VAP can by caused by a broad array of drug resistant organisms (DROs), the appropriate duration of treatment for VAP is an evolving concept, but may, in part, be guided by biomarkers, and provide focus on diagnostic challenges, initial therapies and treatment strategies for VAP. Both traditional and novel antimicrobials are presented, including developments in the modes of delivery. Expert commentary: The clinical approach to VAP continues to evolve. Recent evidence regarding the changes in microbiology, diagnostics approaches, and treatment strategies for VAP are important for clinicians to remain informed of to provide optimal patient care. PMID- 27771979 TI - Recent advances in understanding and treating COPD related to alpha1-antitrypsin deficiency. AB - INTRODUCTION: Alpha-1-antitrypsin deficiency (AATD) is an orphan disease that predisposes individuals to COPD and liver disease. The following is a comprehensive review of AATD from epidemiology to treatment for physicians who treat COPD or asthma. Areas covered: In this comprehensive review of alpha-1 antitrypsin deficiency, we describe the historical perspective, genetics, epidemiology, clinical presentation and symptoms, screening and diagnosis, and treatments of the condition. Expert commentary: The two most important directions for advancing the understanding of AATD involve improving detection of the condition, especially in asymptomatic patients, and advancing knowledge of treatments directed specifically at AATD-related conditions. With regard to treatment for AATD-related conditions, research must continue to explore the implications and importance of augmentation therapy as well as consider new implementations that may prove more successful taking into consideration not only factors of pulmonary function and liver health, but also product availability and financial viability. PMID- 27771981 TI - Blood biomarker discovery in drug-free schizophrenia: the contributionof proteomics and multiplex immunoassays. AB - INTRODUCTION: Recent evidence supports an association between systemic abnormalities and the pathology of psychotic disorders which has led to the search for peripheral blood-based biomarkers. Areas covered: Here, we summarize blood biomarker findings in schizophrenia from the literature identified by two methods currently driving biomarker discovery in the human proteome; mass spectrometry and multiplex immunoassay. From a total of 14 studies in the serum or plasma of drug-free schizophrenia patients; 47 proteins were found to be significantly altered twice or more, in the same direction. Pathway analysis was performed on these proteins, and the resulting pathways discussed in relation to schizophrenia pathology. Future directions are also discussed, with particular emphasis on the potential for high-throughput validation techniques such as data independent analysis for confirmation of biomarker candidates. Expert commentary: We present promising findings that point to a convergence of pathophysiological mechanisms in schizophrenia that involve the acute-phase response, glucocorticoid receptor signalling, coagulation, and lipid and glucose metabolism. PMID- 27771980 TI - The biological fate of decabromodiphenyl ethane following oral, dermal or intravenous administration. AB - 1. It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ether (decaBDE), high potential for environmental persistence and bioaccumulation, and high production volume. 2. In the present study, female Sprague Dawley rats were administered a single dose of [14C]-DBDPE by oral, topical or IV routes. Another set of rats were administered 10 daily oral doses of [14C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose. 3. DBDPE was poorly absorbed following oral dosing, with 95% of administered [14C] radioactivity recovered in the feces unchanged, 1% recovered in the urine and less than 3% in the tissues at 72 h. DBDPE excretion was similar in male mice and female rats. Accumulation of [14C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses to rats. 4. Rat and human skin were used to assess potential dermal uptake of DBDPE. The dermis was a depot for dermally applied DBDPE; conservative estimates predict ~14 +/- 8% of DBDPE may be absorbed into human skin in vivo; ~7 +/- 4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24 h). 5. Following intravenous administration, ~70% of the dose remained in tissues after 72 h, with the highest concentrations found in lung (1223 +/- 723 pmol-eq/g), spleen (1096 +/- 369 pmol-eq/g) and liver (366 +/- 98 pmol-eq/g); 5 +/- 1% of the dose was recovered in urine and 26 +/- 4% in the feces. PMID- 27771982 TI - Systemic cyclosporine treatment in severe childhood psoriasis: A retrospective chart review. AB - BACKGROUND: Data regarding the use of cyclosporine (CYC) in the treatment of childhood psoriasis is meager. MATERIALS AND METHODS: The records of all psoriasis patients aged less than 18 years and treated with systemic CYC at our institute were retrieved. Clinical status of patients was assessed at regular intervals and response to therapy was graded as good (50-75% decrease in PASI) and excellent (>75% decrease). Laboratory investigations to detect CYC-induced toxicity were done at regular intervals. RESULTS: There were total 10 children having psoriasis treated with systemic CYC over this period. Indication for the institution of CYC therapy was severe diseases, viz. extensive recalcitrant plaque type psoriasis in four patients, erythroderma in three and generalized pustular psoriasis in one patient. Response to therapy was excellent (>75% decrease in PASI) in all but three patients with psoriatic erythroderma. The mean time to control the disease, i.e. 50% reduction in PASI was 4.2 weeks. Side effects were mild, observed in two children, which included pain abdomen and an increase in serum creatinine over baseline value. CONCLUSIONS: CYC is an effective and reasonably safe drug to be used as crisis management therapy in severe childhood psoriasis under an expert supervision and laboratory monitoring. PMID- 27771983 TI - Potassium supplementation and long-term outcomes in chronic peritoneal dialysis patients with end-stage renal disease: a propensity score matching study. AB - OBJECTIVE: In this retrospective matched-cohort study, the association between potassium supplementation and long-term outcomes was determined. METHODS: Chronic peritoneal dialysis (PD) patients, aged >= 16 years, being referred to four PD centers in China, with serum potassium levels <= 3.5 mEq/L on three consecutive monthly in Q4 2008 and without receiving oral potassium supplementation in the prior three months were included in this study. Patients were divided into two groups, either to receive (test group) or not (control group) oral potassium supplementation in both Q4 2008 and the subsequent follow-up period, until 31 December 2014. The patients from the test group were matched to those from the control group using a propensity score. The clinical outcomes for all-cause and cardiovascular mortality were estimated by Matched Cox regression models during 61.5 months of median follow-up. All patients were also categorized according to serum potassium correction levels (<3.0, 3.0 to <4.0, 4.0 to <5.0 and >=5.0 mEq/L) after the whole follow-up. The hazard ratios (HRs) were used to assess the relationship between corrected potassium levels and all-cause and cardiovascular mortality in PD patients. Subgroup analysis was used to determine the homogeneity of the associations between potassium supplementation and all-cause mortality. RESULTS: All-cause mortality occurred in 108 patients (605/10,000 person-years) in the test group and 114 patients (677/10,000 person-years) in the control group during 1786- and 1685-year follow-up, respectively [hazard ratio (HR), 0.89; 95% confidence interval (CI), 0.68-1.16; p = 0.38]. Cardiovascular mortality occurred in 97 patients (542/10,000 person-years) in the test group and 101 patients (598/10,000 person-years) in the control group (HR, 0.89; 95% CI, 0.67-1.18; p = 0.43). There were no significant interactions between potassium supplementation and any of the subgroups, except for diabetes mellitus and volume overload. During a median follow-up of 61.5 months, adjusted all-cause mortality hazard ratio (HR) and 95% confidence interval (CI) for corrected serum potassium of <3.0, 3.0 to < 4.0, and >=5.0 mEq/L, compared with 4.0 to < 5.0 mEq/L (reference), were 2.23 (1.17-3.72), 1.35 (0.89-1.81), and 1.74 (1.05-3.72), respectively. CONCLUSION: The use of potassium supplementation in chronic PD patients is not associated with mortality. While it may be necessary for the correction of hypokalemia or the maintenance of normokalemia, and the consequent reduction of hypokalemia-associated mortality. Additionally, use of aldosterone antagonists may be preferable for the handling of hypokalemia in PD patients. PMID- 27771984 TI - The effects of adding ischemic preconditioning during desflurane inhalation anesthesia or propofol total intravenous anesthesia on pneumoperitoneum-induced oxidative stress. AB - BACKGROUND: The aim of the study was to explore the differences in oxidative stress during anesthesia with desflurane/N2O or propofol/remifentanil in patients undergoing laparoscopic cholecystectomy and additionally to evaluate the differential effects of desflurane and propofol on ischemic preconditioning (IP). MATERIALS AND METHODS: One hundred patients were randomly allocated to four groups. For anesthesia maintenance, the inhalation group (Group I) and the inhalation plus IP group (Group IIP) received desflurane at an end-tidal concentration of 4-6 vol% in oxygen/N2O, and the TIVA group (Group T) and TIVA plus IP group (Group TIP) received infusions of propofol and remifentanil. In Groups IIP and TIP, IP was carried out by 10 min of pneumoperitoneum followed by 10 min of deflation. Preoperative and postoperative plasma total antioxidant status (TAS), total oxidant status (TOS), paraoxonase, stimulated paraoxonase, arylesterase, ceruloplasmin, and myeloperoxidase levels were analyzed; oxidative stress index (OSI) was calculated. RESULTS: When oxidative stress parameters were compared between groups, myeloperoxidase values in Group I were statistically significantly lower compared to Group TIP (p = .004 with Bonferroni's correction). There were no differences between preoperative and postoperative TAS, paraoxonase, stimulated paraoxonase, arylesterase, or ceruloplasmin levels (p > .05). In intragroup evaluations, postoperative paraoxonase and stimulated paraoxonase levels were found to be lower than preoperative values in Group TIP (p = .021 and .012, respectively). CONCLUSION: In laparoscopic cholecystectomy lasting less than 60 min, there were no differences in the measured oxidative stress parameters between maintenance of anesthesia by desflurane/N2O and propofol/remifentanil/N2O. The addition of 10 min IP administration during both anesthesia techniques did not result in additional changes in the analyzed oxidative stress. PMID- 27771986 TI - Studying the interaction between three synthesized heterocyclic sulfonamide compounds with hemoglobin by spectroscopy and molecular modeling techniques. AB - The interaction between synthesized heterocyclic benzene sulfonamide compounds, N (7-benzyl-56-biphenyl-2m-tolyl-7H-pyrrolo[23-d]pyrimidine-4-yl)-benzene sulfonamide (HBS1), N-(7-benzyl-56-biphenyl-2-m-tolyl-7H-pyrrolo[23-d] pyrimidine 4-yl)-4-methyl- benzene sulfonamide (HBS2), and N-(7-benzyl-56-biphenyl-2-m-tolyl 7H-pyrrolo[23-d]pyrimidine-4-yl)-4-chloro-benzene sulfonamide (HBS3) with Hb was studied by fluorescence quenching, zeta potentional, circular dichroism, and molecular modeling techniques. The fluorescence spectroscopy experiments were performed in order to study the conformational changes, possibly due to a discrete reorganization of Trp residues during binding between HBS derivatives and Hb. The variation of the KSV value suggested that hydrophobic and electrostatic interactions were the predominant intermolecular forces stabilizing the complex. The KSV1 ans KSV2 values of HBS derivatives with Hb are .6 * 1013 and 3 * 1013 M-1 for Hb-HBS1, 1 * 1013 and 4 * 1013 M-1 for Hb-HBS2, .9 * 1013, and 6 * 1013 M-1 for Hb-HBS3, respectively. The molecular distances between Hb and HBS derivatives in binary and ternary systems were estimated according to Forster's theory of dipole-dipole non-radiation energy transfer. The quantitative analysis data of circular dichroism spectra demonstrated that the binding of the three HBS derivatives to Hb induced conformational changes in Hb. Changes in the zeta potential of the Hb-HBS derivatives complexes demonstrated a hydrophobic adsorption of the anionic ligand onto the surface of Hb as well as both electrostatic and hydrophobic adsorption in the case of the complex. The modeling data thus confirmed the experimental results. This study is expected to provide important insight into the interaction of Hb with three HBS derivatives to use in various toxicological and therapeutic processes. PMID- 27771987 TI - Dammarane-type triterpene extracts of Panax notoginseng root ameliorates hyperglycemia and insulin sensitivity by enhancing glucose uptake in skeletal muscle. AB - Skeletal muscle is an important organ for controlling the development of type 2 diabetes. We discovered Panax notoginseng roots as a candidate to improve hyperglycemia through in vitro muscle cells screening test. Saponins are considered as the active ingredients of ginseng. However, in the body, saponins are converted to dammarane-type triterpenes, which may account for the anti hyperglycemic activity. We developed a method for producing a dammarane-type triterpene extract (DTE) from Panax notoginseng roots and investigated the extract's potential anti-hyperglycemic activity. We found that DTE had stronger suppressive activity on blood glucose levels than the saponin extract (SE) did in KK-Ay mice. Additionally, DTE improved oral glucose tolerance, insulin sensitivity, glucose uptake, and Akt phosphorylation in skeletal muscle. These results suggest that DTE is a promising agent for controlling hyperglycemia by enhancing glucose uptake in skeletal muscle. PMID- 27771988 TI - Evaluation of protein-ligand affinity prediction using steered molecular dynamics simulations. AB - In computational drug design, ranking a series of compound analogs in a manner that is consistent with experimental affinities remains a challenge. In this study, we evaluated the prediction of protein-ligand binding affinities using steered molecular dynamics simulations. First, we investigated the appropriate conditions for accurate predictions in these simulations. A conic harmonic restraint was applied to the system for efficient sampling of work values on the ligand unbinding pathway. We found that pulling velocity significantly influenced affinity predictions, but that the number of collectable trajectories was less influential. We identified the appropriate pulling velocity and collectable trajectories for binding affinity predictions as 1.25 A/ns and 100, respectively, and these parameters were used to evaluate three target proteins (FK506 binding protein, trypsin, and cyclin-dependent kinase 2). For these proteins using our parameters, the accuracy of affinity prediction was higher and more stable when Jarzynski's equality was employed compared with the second-order cumulant expansion equation of Jarzynski's equality. Our results showed that steered molecular dynamics simulations are effective for predicting the rank order of ligands; thus, they are a potential tool for compound selection in hit-to-lead and lead optimization processes. PMID- 27771989 TI - Negative impact on clinical outcome of the mutational co-occurrence of SF3B1 and DNMT3A in refractory anemia with ring sideroblasts (RARS). AB - The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1mutDNMT3Amut). All co mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1mutDNMT3Amut patients showed a higher RBC transfusion dependency (92% versus 48%, p = .007), a shorter overall survival (OS) (median, 30 versus 97 months, p = .034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p = .023) than SF3B1mutDNMT3Awt patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1mut patients with a negative clinical impact. PMID- 27771990 TI - Spectroscopic and molecular modeling approaches to investigate the binding of proton pump inhibitors to human serum albumin. AB - The interaction between two proton pump inhibitors viz., omeprazole (OME) and esomeprazole (EPZ) with human serum albumin (HSA) was studied by fluorescence, absorption, circular dichroism (CD), Fourier transform infrared spectroscopy (FT IR), voltammetry, and molecular modeling approaches. The Stern-Volmer quenching constants (Ksv) for OME-HSA and EPZ-HSA systems obtained at different temperatures revealed that both OME and EPZ quenched the intensity of HSA through dynamic mode of quenching mechanism. The binding constants of OME-HSA and EPZ-HSA increased with temperature, indicating the increased stability of these systems at higher temperatures. Thermodynamic parameters viz., ?H degrees , ?S degrees , and ?G degrees were determined for both systems. These values revealed that both systems were stabilized by hydrophobic forces. The competitive displacement and molecular docking studies suggested that OME/EPZ was bound to Sudlow's site I in subdomain IIA in HSA. The extent of energy transfer from HSA to OME/EPZ and the distance of separation in tryptophan (Trp214) Trp214-OME and Trp214-EPZ was determined based on the theory of fluorescence resonance energy transfer. UV absorption, 3D fluorescence, and CD studies indicated that the binding of OME/EPZ to HSA has induced micro environmental changes around the protein which resulted changes in its secondary structure. PMID- 27771991 TI - Protective effect of amifostine on busulfan induced DNA damage in human hepatoma cells. AB - Busulfan is one of the most effective chemotherapeutic agents used for the treatment of chronic myeloid leukemia. However, as a bifunctional alkylating agent, during clinical use several side effects may occur. In addition, several in vivo and in vitro studies of busulfan have shown a range of genotoxic effects including DNA strand break and inhibition of DNA synthesis. Amifostine, an organic thiophosphate compound, has been shown to exert an important cyto protective effect in many tissues. The aim of this study was to explore whether amifostine protects against busulfan-induced genotoxicity in HepG2 cell line. Our results showed that amifostine reduced the genotoxic effects of busulfan significantly in both type of experiment conditions, as measured via comet assay. Furthermore, amifostine decreased the intracellular ROS generation induced by busulfan and also increased the intracellular GSH levels in HepG2 cells. Altogether, our results suggest a protective action of amifostine against busulfan cytotoxicity and genotoxicity via various pathways. The most protective effect was observed with amifostine when it was administrated 24 h before busulfan treatment. PMID- 27771985 TI - Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting. AB - BACKGROUND: We previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure between patients who underwent coronary artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report the results at 5 years (the end of the trial). METHODS: A total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. RESULTS: There were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-pump CABG, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72) or in the rates of the components of the outcome, including repeat coronary revascularization, which was performed in 2.8% of the patients in the off-pump group and in 2.3% of the patients in the on-pump group (hazard ratio, 1.21; 95% CI, 0.85 to 1.73; P=0.29). The secondary outcome for the overall period of the trial - the mean cost in U.S. dollars per patient - also did not differ significantly between the off-pump group and the on-pump group ($15,107 and $14,992, respectively; between-group difference, $115; 95% CI, -$697 to $927). There were no significant between-group differences in quality-of-life measures. CONCLUSIONS: In our trial, the rate of the composite outcome of death, stroke, myocardial infarction, renal failure, or repeat revascularization at 5 years of follow-up was similar among patients who underwent off-pump CABG and those who underwent on-pump CABG. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .). PMID- 27771992 TI - Castleman's disease of the spleen. AB - INTRODUCTION: Castleman's disease (CD), also known as giant or angiofolicular lymphoid hyperplasia or lymphoid hamartoma, is a group of atypical lymphoproliferative disorders that share common lymph node histological features and may be localized either to a single lymph node (unicentric) or occur systemically (multicentric). PATIENT AND METHOD: Herein, we present a rare case of a of 75-year-old female patient who was referred to our department and after a thorough work-up, underwent splenectomy with synchronous resection of an accessory spleen, splenic artery lymph nodes, and splenic hilar lymph nodes due to splenic involvement in a multicentric CD. RESULTS: The pathology of the specimens led to the conclusion that it was a case of polycentric HHV-8-positive CD, affecting the spleen, the accessory spleen, and the lymph nodes. CONCLUSIONS: Incidence of this rare condition is believed to be approximately 0.001-0.05%. CD has been linked to the human immunodeficiency virus (HIV), human herpes virus 8 (HHV-8), and is associated with malignancies. The pathogenesis mechanism is considered to be a dysregulation and hypersecretion of cytokines, either idiopathic or secondary to a viral infection, with the latter considered the most frequent. Solid organ involvement is very rare as is splenic involvement. PMID- 27771993 TI - Identification, Prokaryote Expression of Medaka gdnfa/b and Their Biological Activity in a Spermatogonial Cell Line. AB - The origin and evolution of molecular mechanisms underlying the self-renewal and differentiation of spermatogonial stem cells (SSCs) are fundamental questions in stem cell biology as well as reproduction medicine. In mammals, glial cell line derived neurotrophic factor (GDNF) is crucial for SSC self-renewal and maintenance. However, in nonmammals, the role of Gdnf in SSCs still remains unknown. In this study, we report that the two GDNF homologs from medaka fish (Oryzias latipes), namely OlGdnfa and OlGdnfb, can promote proliferation activity and retain the spermatogonial property of SG3, a spermatogonial cell line derived from adult medaka showing the intrinsic property of SSCs by self-renewal and differentiation potential during 2 years of culture. Cloning and sequencing led to the identification of two cDNA sequences as Olgdnfa and Olgdnfb, which are 780 nt and 744-nt in length for 253 and 245 amino acid residues, respectively. Both are homologs of mammalian GDNF and share over 45% identity with the other known vertebrate homologs. Importantly, in a well-defined condition, the recombinant proteins, OlGdnfa and OlGdnfb, can significantly promote the proliferative activity of SG3 cells and retain the spermatogonial gene expression pattern and alkaline phosphatase activity. Meanwhile, both of the two recombinant proteins can upregulate the mRNA expression level of bcl6b, one of the prominent GDNF regulated genes involved in SSC self-renewal and maintenance in mammals. Taken together, our findings suggest that just like the mammalian counterpart, the nonmammalian Gdnfs might mediate the self-renewal and maintenance of SSCs; moreover, Bcl6b might be a conserved regulator in SSC self-renewal across vertebrate taxa. This study extends our knowledge of GDNF functions in SSC biology during evolution. PMID- 27771994 TI - Engagement with professional development plans. PMID- 27771995 TI - Peer motivation - assessing and facilitating. PMID- 27771996 TI - How Regenerative Medicine Stakeholders Adapt to Ever-Changing Technology and Regulatory Challenges? Snapshots from the World TERMIS Industry Symposium (September 10, 2015, Boston). AB - Regenerative medicine (RM) is a fascinating area of research and innovation. The huge potential of the field has been fairly underexploited so far. Both TERMIS-AM and TERMIS-EU Industry Committees are committed to mentoring and training young entrepreneurs for more successful commercial translation of upstream research. With this objective in mind, the two entities jointly organized an industry symposium during the past TERMIS World Congress (Boston, September 8-11, 2015) and invited senior managers of the RM industry for lectures and panel discussions. One of the two sessions of the symposium-How to overcome obstacles encountered when bringing products to the commercial phase?-aimed to share the inside, real experiences of leaders from TEI Biosciences (an Integra Company), Vericel (formerly Aastrom; acquirer of Genzyme Regenerative Medicine assets), RegenMedTX (formerly Tengion), Mindset Rx, ViThera Pharmaceuticals, and L'Oreal Research & Innovation. The symposium provided practical recommendations for RM product development, for remaining critical and objective when reviewing progress, for keeping solutions simple, and for remaining relevant and persistent. PMID- 27771999 TI - Independent Nonprofessionals in the Community: A Case History Analysis of a Human Relations Program. PMID- 27772010 TI - Children's Understanding of Their Emotionally Disturbed Peers. PMID- 27771997 TI - Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil. AB - Growth factor-based therapeutics using bone morphogenetic protein 2 (BMP-2) presents a promising strategy to reconstruct craniofacial bone defects such as mandible. However, clinical applications require supraphysiological BMP doses that often increase inappropriate adipogenesis, resulting in well-documented, cyst-like bone formation. Here we reported a novel complementary strategy to enhance osteogenesis and mandibular bone repair by using small-molecule phenamil that has been shown to be a strong activator of BMP signaling. Phenamil synergistically induced osteogenic differentiation of human bone marrow mesenchymal stem cells with BMP-2 while suppressing their adipogenic differentiation induced by BMP-2 in vitro. The observed pro-osteogenic and antiadipogenic activity of phenamil was mediated by expression of tribbles homolog 3 (Trb3) that enhanced BMP-smad signaling and inhibited expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipogenesis. The synergistic effect of BMP-2+phenamil on bone regeneration was further confirmed in a critical-sized rat mandibular bone defect by implanting polymer scaffolds designed to slowly release the therapeutic molecules. These findings indicate a new complementary osteoinductive strategy to improve clinical efficacy and safety of current BMP-based therapeutics. PMID- 27772012 TI - Notes and Comments. PMID- 27772016 TI - Editorial Notes. PMID- 27772015 TI - The Narrative-Emotion Process Coding System 2.0: A multi-methodological approach to identifying and assessing narrative-emotion process markers in psychotherapy. AB - OBJECTIVE: Recent studies suggest that it is not simply the expression of emotion or emotional arousal in session that is important, but rather it is the reflective processing of emergent, adaptive emotions, arising in the context of personal storytelling and/or Emotion-Focused Therapy (EFT) interventions, that is associated with change. METHOD: To enhance narrative-emotion integration specifically in EFT, Angus and Greenberg originally identified a set of eight clinically derived narrative-emotion integration markers were originally identified for the implementation of process-guiding therapeutic responses. Further evaluation and testing by the Angus Narrative-Emotion Marker Lab resulted in the identification of 10 empirically validated Narrative-Emotion Process (N EP) markers that are included in the Narrative-Emotion Process Coding System Version 2.0 (NEPCS 2.0). RESULTS: Based on empirical research findings, individual markers are clustered into Problem (e.g., stuckness in repetitive story patterns, over-controlled or dysregulated emotion, lack of reflectivity), Transition (e.g., reflective, access to adaptive emotions and new emotional plotlines, heightened narrative and emotion integration), and Change (e.g., new story outcomes and self-narrative discovery, and co-construction and re conceptualization) subgroups. To date, research using the NEPCS 2.0 has investigated the proportion and pattern of narrative-emotion markers in Emotion Focused, Client-Centered, and Cognitive Therapy for Major Depression, Motivational Interviewing plus Cognitive Behavioral Therapy for Generalized Anxiety Disorder, and EFT for Complex Trauma. Results have consistently identified significantly higher proportions of N-EP Transition and Change markers, and productive shifts, in mid- and late phase sessions, for clients who achieved recovery by treatment termination. CONCLUSIONS: Recovery is consistently associated with client storytelling that is emotionally engaged, reflective, and evidencing new story outcomes and self-narrative change. Implications for future research, practice and training are discussed. PMID- 27772017 TI - Schizophrenics' Mutual Glance Patterns. PMID- 27772528 TI - Prevalence of Schistosoma mansoni infection and the therapeutic efficacy of praziquantel among school children in Manna District, Jimma Zone, southwest Ethiopia. AB - BACKGROUND: Intestinal schistosomiasis is one of the neglected tropical parasitic diseases caused by Schistosoma mansoni. Currently, the control measures for the disease are mainly based on mass drug administration (MDA) with praziquantel (PZQ) targeting the school-age children. In Ethiopia, the potential foci for schistosomiasis and therapeutic efficacy of PZQ among school-age children remain poorly explored. Therefore, we determined both the prevalence and intensity of S. mansoni infection and the therapeutic efficacy of PZQ among school children in the Manna District (new foci for S. mansoni), Jimma Zone, southwest Ethiopia. METHODS: A cross-sectional study was conducted among the school children aged between 6 and 18 years in three primary schools in Manna district from March to April 2014. For diagnosis of S. mansoni, a single stool sample was obtained from each child and processed using single Kato Katz and examined under light microscopy. A questionnaire was used to collect demographic information of the school children participated in the study. School children excreting eggs of S. mansoni were administered with 40 mg/kg of PZQ and re-examined after three weeks post-treatment. The therapeutic efficacy of PZQ against S. mansoni was evaluated by means of cure rate and egg reduction rate. RESULTS: The overall prevalence of S. mansoni among the school children in the three primary schools in Manna District was 24.0 %. Higher prevalence was recorded for males 25.6 % (61/238) than for females 22.5 % (59/262). Majority (27.5 %) of infection intensity was light with mean faecal egg count (FEC) of 202 eggs per gram (EPG). The therapeutic efficacy of PZQ at a dose of 40 mg/kg was highly efficient (cure rate of 99.1 % and egg reduction rate of 99.9 %) among the school children in the three primary schools in Manna District. CONCLUSIONS: The school children in the three primary schools of Manna District, Jimma Zone were at moderate risk of the morbidity caused by S. mansoni (prevalence > 10 % and < 50 % according to WHO threshold), and hence a biannual MDA with PZQ is required. PZQ available on the local market was found efficient and can be recommended for individual treatment in absence of MDA. The therapeutic efficacy of PZQ at 40 mg/kg against S. mansoni was high in the study area. PMID- 27772529 TI - Does ventilator-associated event surveillance detect ventilator-associated pneumonia in intensive care units? A systematic review and meta-analysis. AB - BACKGROUND: Ventilator-associated event (VAE) is a new surveillance paradigm for monitoring complications in mechanically ventilated patients in intensive care units (ICUs). The National Healthcare Safety Network replaced traditional ventilator-associated pneumonia (VAP) surveillance with VAE surveillance in 2013. The objective of this study was to assess the consistency between VAE surveillance and traditional VAP surveillance. METHODS: We systematically searched electronic reference databases for articles describing VAE and VAP in ICUs. Pooled VAE prevalence, pooled estimates (sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)) of VAE for the detection of VAP, and pooled estimates (weighted mean difference (WMD) and odds ratio ([OR)) of risk factors for VAE compared to VAP were calculated. RESULTS: From 2191 screened titles, 18 articles met our inclusion criteria, representing 61,489 patients receiving mechanical ventilation at ICUs in eight countries. The pooled prevalence rates of ventilator-associated conditions (VAC), infection related VAC (IVAC), possible VAP, probable VAP, and traditional VAP were 13.8 %, 6.4 %, 1.1 %, 0.9 %, and 11.9 %, respectively. Pooled sensitivity and PPV of each VAE type for VAP detection did not exceed 50 %, while pooled specificity and NPV exceeded 80 %. Compared with VAP, pooled ORs of in-hospital death were 1.49 for VAC and 1.76 for IVAC; pooled WMDs of hospital length of stay were -4.27 days for VAC and -5.86 days for IVAC; and pooled WMDs of ventilation duration were -2.79 days for VAC and -2.89 days for IVAC. CONCLUSIONS: VAE surveillance missed many cases of VAP, and the population characteristics identified by the two surveillance paradigms differed. VAE surveillance does not accurately detect cases of traditional VAP in ICUs. PMID- 27772530 TI - Survey of the training and use of echocardiography and lung ultrasound in Australasian intensive care units. PMID- 27772533 TI - Assessing Occupancy and Its Relation to Healthcare-Associated Infections. AB - Occupancy has been associated with risk for healthcare-associated infections, yet its definition varies widely. Occupancy can be modeled as a function of census, acuity of the patient care unit, staffing ratio, or some combination. This article discusses the appropriate parameterization of these measures and how to interpret their impact. Infect Control Hosp Epidemiol 2016:1-3. PMID- 27772531 TI - Association of circulating neuregulin 4 with metabolic syndrome in obese adults: a cross-sectional study. AB - BACKGROUND: Neuregulin 4 (Nrg4) is a secreted adipokine recently identified as playing an important role in modulating systemic energy metabolism and the development of obesity-associated disorders. However, information is not available regarding the association between circulating Nrg4 and risk of metabolic syndrome (MetS) in humans. METHODS: We measured serum Nrg4 in 1212 obese adult subjects (aged 40 years or older), with a waist circumference greater than 90 cm for men or 80 cm for women, recruited from the community. RESULTS: MetS subjects had lower levels of circulating Nrg4 than healthy controls (P < 0.01). The prevalence of MetS was higher in subjects with lower levels of circulating Nrg4 compared to those with higher values (67.3 % vs. 57.4 %, P < 0.05). Likewise, subjects with low levels of circulating Nrg4 had high prevalence of raised fasting glucose and blood pressure, but there was no association with raised triglycerides and reduced HDL-c. In multivariable logistic regression analyses, increased serum Nrg4 was significantly associated with reduced risk of MetS (OR: 0.603; 95 % CI, 0.439-0.828; P = 0.002), adjusting for age, gender, current smoking, alcohol consumption, physical activity, BMI, systolic blood pressure, fasting glucose, triglyceride, HDL-c, HOMA-IR, and body fat mass; however, such associations with serum Nrg4 were not noted for each component of MetS. CONCLUSIONS: These findings indicate that circulating Nrg4 concentrations are inversely associated with risk of MetS in obese Chinese adults, suggesting that circulating Nrg4 concentrations may be a protective factor in the development of MetS. PMID- 27772532 TI - Multidisciplinary Management of Pediatric Sports-Related Concussion. AB - OBJECTIVES: To summarize the clinical characteristics and outcomes of pediatric sports-related concussion (SRC) patients who were evaluated and managed at a multidisciplinary pediatric concussion program and examine the healthcare resources and personnel required to meet the needs of this patient population. METHODS: We conducted a retrospective review of all pediatric SRC patients referred to the Pan Am Concussion Program from September 1st, 2013 to May 25th, 2015. Initial assessments and diagnoses were carried out by a single neurosurgeon. Return-to-Play decision-making was carried out by the multidisciplinary team. RESULTS: 604 patients, including 423 pediatric SRC patients were evaluated at the Pan Am Concussion Program during the study period. The mean age of study patients was 14.30 years (SD: 2.32, range 7-19 years); 252 (59.57%) were males. Hockey (182; 43.03%) and soccer (60; 14.18%) were the most commonly played sports at the time of injury. Overall, 294 (69.50%) of SRC patients met the clinical criteria for concussion recovery, while 75 (17.73%) were lost to follow-up, and 53 (12.53%) remained in active treatment at the end of the study period. The median duration of symptoms among the 261 acute SRC patients with complete follow-up was 23 days (IQR: 15, 36). Overall, 25.30% of pediatric SRC patients underwent at least one diagnostic imaging test and 32.62% received referral to another member of our multidisciplinary clinical team. CONCLUSION: Comprehensive care of pediatric SRC patients requires access to appropriate diagnostic resources and the multidisciplinary collaboration of experts with national and provincially-recognized training in TBI. PMID- 27772534 TI - Glial cells as key elements in the pathophysiology and treatment of bipolar disorder. AB - OBJECTIVE: The exact pathophysiology of bipolar disorder (BD) is not yet fully understood, and there are many questions in this area which should be answered. This review aims to discuss the roles of glial cells in the pathophysiology of BD and their contribution to the mechanism of action of mood-stabilising drugs. METHODS: We critically reviewed the most recent advances regarding glial cell roles in the pathophysiology and treatment of BD and the neuroprotective and neurotrophic effects of these cells. RESULTS: Postmortem studies revealed a decrease in the glial cell number or density in the specific layers of prefrontal and anterior cingulate cortex in the patients with BD, whereas there was no difference in other brain regions, such as entorhinal cortex, amygdala and hippocampus. Astrocytes and oligodendrocytes were the most important glial types that were responsible for the glial reduction, but microglia activation rather than loss may be implicated in BD. The decreased number or density of glial cells may contribute to the pathological changes observed in neurons in the patients with BD. Alteration of specific neurotrophic factors such as glial cell line derived neurotrophic factor and S100B may be an important feature of BD. Glial cells mediate the therapeutic effects of mood-stabilising agents in the treatment of BD. CONCLUSION: Recent studies provide important evidence on the impairment of glial cells in the pathophysiology and treatment of BD. However, future controlled studies are necessary to elucidate different aspects of glial cells contribution to BD, and the mechanism of action of mood-stabilising drugs. PMID- 27772535 TI - 1H magnetic resonance spectroscopy evidence for occipital involvement in treatment-naive paediatric obsessive-compulsive disorder. AB - OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder leading to considerable distress and disability. Therapies are effective in a majority of paediatric patients, however, many only get partial response. It is therefore important to study the underlying pathophysiology of the disorder. METHODS: 1H magnetic resonance spectroscopy (MRS) was used to study the concentration of brain metabolites in four different locations (cingulate gyrus and sulcus, occipital cortex, thalamus and right caudate nucleus). Treatment naive children and adolescents with OCD (13 subjects) were compared with a group of healthy age- and gender-matched subjects (11 subjects). Multivariate analyses were performed on the concentration values. RESULTS: No separation between controls and patients was found. However, a correlation between metabolite concentrations and symptom severity as measured with the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was found. Strongest was the correlation with the CY-BOCS obsession subscore and aspartate and choline in the caudate nucleus (positively correlated with obsessions), lipids at 2 and 0.9 ppm in thalamus, and occipital glutamate+glutamine, N-acetylaspartate and myo-inosytol (negatively correlated with obsessions). CONCLUSIONS: The observed correlations between 1H MRS and CY-BOCS in treatment-naive patients further supports an occipital involvement in OCD. The results are consistent with our previous study on adult OCD patients. The 1H MRS data were not supportive of a separation between the patient and control groups. PMID- 27772536 TI - The adaptive calibration model of stress responsivity: An empirical test in the Tracking Adolescents' Individual Lives Survey study. AB - The adaptive calibration model (ACM) is a theory of developmental programing focusing on calibration of stress response systems and associated life history strategies to local environmental conditions. In this article, we tested some key predictions of the ACM in a longitudinal study of Dutch adolescent males (11-16 years old; N = 351). Measures of sympathetic, parasympathetic, and adrenocortical activation, reactivity to, and recovery from social-evaluative stress validated the four-pattern taxonomy of the ACM via latent profile analysis, though with some deviations from expected patterns. The physiological profiles generally showed predicted associations with antecedent measures of familial and ecological conditions and life stress; as expected, high- and low-responsivity patterns were found under both low-stress and high-stress family conditions. The four patterns were also differentially associated with aggressive/rule-breaking behavior and withdrawn/depressed behavior. This study provides measured support for key predictions of the ACM and highlights important empirical issues and methodological challenges for future research. PMID- 27772537 TI - Music therapy for palliative care: A realist review. AB - OBJECTIVE: Music therapy has experienced a rising demand as an adjunct therapy for symptom management among palliative care patients. We conducted a realist review of the literature to develop a greater understanding of how music therapy might benefit palliative care patients and the contextual mechanisms that promote or inhibit its successful implementation. METHOD: We searched electronic databases (CINAHL, Embase, Medline, and PsychINFO) for literature containing information on music therapy for palliative care. In keeping with the realist approach, we examined all relevant literature to develop theories that could explain how music therapy works. RESULTS: A total of 51 articles were included in the review. Music therapy was found to have a therapeutic effect on the physical, psychological, emotional, and spiritual suffering of palliative care patients. We also identified program mechanisms that help explain music therapy's therapeutic effects, along with facilitating contexts for implementation. SIGNIFICANCE OF RESULTS: Music therapy may be an effective nonpharmacological approach to managing distressing symptoms in palliative care patients. The findings also suggest that group music therapy may be a cost-efficient and effective way to support staff caring for palliative care patients. We encourage others to continue developing the evidence base in order to expand our understanding of how music therapy works, with the aim of informing and improving the provision of music therapy for palliative care patients. PMID- 27772538 TI - Proposing the short Neurological Evaluation Scale. AB - OBJECTIVES: The time required in completing the 26 items of neurological examinations in the standard Neurological Evaluation Scale (NES) may limit its utility in pragmatic clinical situations. We propose the Short Neurological Evaluation Scale (S-NES) for use in busy clinical settings, and in research. METHODS: Using confirmatory factor analyses, we identified 12 items of neurological examination showing significant overlap with previously reported theoretical and empirical categories of neurological soft signs (NSS) in schizophrenia. This provided justification for the development of a shorter version of the NES based on the empirically identified NSS. In the present study, we relied on existing data to present an initial validation of the S-NES against the referent standard 26-item NES. We determined sensitivity, specificity, and likelihood ratios. Posterior-test probability was estimated using a Bayesian nomogram plot. RESULTS: Using data derived from 84 unmedicated or minimally treated patients with first-episode schizophrenia, 12 empirically determined items of neurological examinations showed high agreement with the 26 items in the standard NES battery (sensitivity=96.3%, specificity=100%, and posterior-test probability=100%). CONCLUSIONS: Within limitations of validity estimates derived from existing data, the present results suggest that the design of the S-NES based on empirically identified 12 items of neurological examination is a logical step. If successful, the S-NES will be useful for rapid screening of NSS in busy clinical settings, and also in research. PMID- 27772539 TI - Cyclic patterns in the central European tick-borne encephalitis incidence series. AB - Tick-borne encephalitis (TBE) is peculiar due to its unstable dynamics with profound inter-annual fluctuations in case numbers - a phenomenon not well understood to date. Possible reasons - apart from variable human contact with TBE foci - include external factors, e.g. climatic forcing, autonomous oscillations of the disease system itself, or a combined action of both. Spectral analysis of TBE data from six regions of central Europe (CE) revealed that the ostensibly chaotic dynamics can be explained in terms of four superposed (quasi-)periodical oscillations: a quasi-biennial, triennial, pentennial, and a decadal cycle. These oscillations exhibit a high degree of regularity and synchrony across CE. Nevertheless, some amplitude and phase variations are responsible for regional differences in incidence patterns. In addition, periodic changes occur in the degree of synchrony in the regions: marked in-phase periods alternate with rather off-phase periods. Such a feature in the disease dynamics implies that it arises as basically diverging self-oscillations of local disease systems which, at intervals, receive synchronizing impulses, such as periodic variations in food availability for key hosts driven by external factors. This makes the disease dynamics synchronized over a large area during peaks in the synchronization signal, shifting to asynchrony in the time in between. PMID- 27772542 TI - Training the Next Generation of Innovators in Dermatology. PMID- 27772541 TI - Bone Marrow Stromal Cells Combined With Sodium Ferulate and n-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors After Ischemic Stroke. AB - Being a potential candidate for stroke treatment, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been demonstrated to be able to enhance angiogenesis and proliferation of reactive astrocytes, which subsequently leads to the amelioration of neurological injury. Increasing evidence further indicates that combining BM-MSCs with certain agents, such as simvastatin, may improve therapeutic effects. Sodium ferulate (SF) and n-butylidenephthalide (BP), two main components of Radix Angelica Sinensis, are proven to be important regulators of stem cells in cell migration, differentiation, and pluripotency maintenance. This study aimed to investigate whether combining BM-MSCs with SF and BP had better therapeutic effect in the treatment of stroke, and the underlying molecular basis for the therapeutic effects was also investigated. The results showed that combination treatment notably reduced neurological injury after stroke and increased the expression of astrocyte-derived vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and von Willebrand factor-positive vascular density in the ischemic boundary zone as evaluated by immunofluorescence staining. After treatment with BM-MSCs plus SF and BP, astrocytes showed increased expression of VEGF and BDNF by upregulating protein kinase B/mammalian target of rapamycin (AKT/mTOR) expression in an oxygen and glucose-deprived (OGD) environment. Human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium (CM) derived from OGD astrocytes treated with BM-MSCs plus SF and BP showed significantly increased migration and tube formation compared with those incubated with the CM derived from OGD astrocytes treated with BM-MSCs alone. These results demonstrate that combination treatment enhances the expression of astrocyte-derived VEGF and BDNF, which contribute to angiogenesis after cerebral ischemia, and the underlying mechanism is associated with activation of the astrocytic AKT/mTOR signaling pathway. Our study provides a potential therapeutic approach for ischemic stroke. PMID- 27772543 TI - Stem Cell Therapy for Epidermolysis Bullosa-Does It Work? AB - Epidermolysis bullosa is a group of heritable skin fragility disorders with considerable morbidity and mortality. It is known to be caused by mutations in as many as 18 distinct genes, but there is no specific or effective treatment. Preclinical developments of gene correction, protein replacement, and cell-based approaches for treatment have suggested new therapeutic avenues, and some of them, including bone marrow transplantation and mesenchymal stem cell therapy, have entered into early clinical trials. Hammersen et al. report on two patients with severe generalized junctional epidermolysis bullosa treated with allogeneic stem cell therapy, but with little success. Careful examination of the existing literature suggests that current approaches of cell-based therapies may be helpful in ameliorating some of the clinical features and symptoms in these patients, but advanced strategies, with improved safety profiles, are required for development of durable therapy for these currently intractable disorders. PMID- 27772544 TI - Administrative and Survey Data: Potential and Pitfalls. AB - Today, "big data" often generated by administrative activities or survey are used to inform many commercial, administrative and clinical decisions. Although they provide a broader perspective about disease and care than that available from clinical experience and research studies, inferences from these data need to be made cautiously. PMID- 27772545 TI - In the Red: Deficits in Immune Regulation Underlie Psoriasis Severity. AB - IL-17-driven pathways are active in the skin of patients with psoriasis. Kim et al. examined lesions from mild and moderate to severe psoriasis and found that differences in cutaneous disease severity may be the outcome of lapses in immunoregulatory mechanisms; because as much, if not more, T helper type 17 induced inflammation was seen in mild psoriasis, these patients may also benefit from anti-IL-17-targeted biologics. PMID- 27772546 TI - New Cutaneous Vaccine Adjuvant that STINGs a Little Less. AB - Cutaneous vaccination can be a challenge because the development of local skin inflammation is often unavoidable. Thus, it is important to identify and validate new vaccine adjuvants that enhance immunization without the burden of inflammation. Wang et al. now report on a cyclic GMP-AMP adjuvant, the natural stimulator of interferon genes agonist, providing evidence for potent immune responses without inflammation. PMID- 27772547 TI - Utility and Limitations of Large Population-Based Data for Skin Cancer Outcomes. AB - Large population-based studies are useful for determining cancer outcomes, but interpreting their findings requires understanding their limitations. Youlden et al. highlight the utility of using a large dataset for studying melanoma survival, whereas Gimotty et al. point out the limitations of such datasets in miscoding thickness, a key prognostic variable. Awareness of limitations of population-based registry data can help to inform their interpretations and clinical implications. PMID- 27772549 TI - Erratum. PMID- 27772548 TI - JAK-STAT Signaling Jump Starts the Hair Cycle. AB - Legrand et al show that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in the murine hair cycle. Interestingly, others have shown that JAK inhibition is able to induce telogen-to-anagen transition in wild-type mice. This apparent contradiction highlights the complexity of interactions within the hair follicle, and encourages further discussion on the role of JAK-STAT signaling in the various stem cell niches of the hair follicle. PMID- 27772550 TI - Research Techniques Made Simple: Assessing Risk of Bias in Systematic Reviews. AB - Systematic reviews are increasingly utilized in the medical literature to summarize available evidence on a research question. Like other studies, systematic reviews are at risk for bias from a number of sources. A systematic review should be based on a formal protocol developed and made publicly available before the conduct of the review; deviations from a protocol with selective presentation of data can result in reporting bias. Evidence selection bias occurs when a systematic review does not identify all available data on a topic. This can arise from publication bias, where data from statistically significant studies are more likely to be published than those that are not statistically significant. Systematic reviews are also susceptible to bias that arises in any of the included primary studies, each of which needs to be critically appraised. Finally, competing interests can lead to bias in favor of a particular intervention. Awareness of these sources of bias is important for authors and consumers of the scientific literature as they conduct and read systematic reviews and incorporate their findings into clinical practice and policy making. PMID- 27772553 TI - CAV3 mutation in a patient with transient hyperCKemia and myalgia. AB - Mutations in caveolin-3 (CAV3) can lead to different clinical phenotypes affecting skeletal or cardiac muscles. Here, we describe a patient with Klinefelter syndrome, ulcerative colitis and Sjogren syndrome, who developed transient hyperCKemia, myalgia and mild muscular weakness. Using whole exome sequencing (WES), a missense mutation G169A was found in the CAV3 gene. In addition, we identified a homozygous frameshift deletion in MS4A12 that may contribute to inflammatory bowel disease, further demonstrating usefulness of WES in dual molecular diagnoses. PMID- 27772555 TI - Identifying psychosocial predictors of medication non-adherence following acute coronary syndrome: A systematic review and meta-analysis. AB - OBJECTIVE: Medication non-adherence following acute coronary syndrome (ACS) is associated with poor clinical outcomes. A systematic review and meta-analysis were undertaken to identify psychosocial factors associated with medication adherence in patients with ACS. METHODS: A search of electronic databases (Cochrane Library, Medline, EMBASE, PsycINFO, Web of Science, International Pharmaceutical Abstracts, CINAHL, ASSIA, OpenGrey, EthOS and WorldCat) was undertaken to identify relevant articles published in English between 2000 and 2014. Articles were screened against our inclusion criteria and data on study design, sample characteristics, predictors, outcomes, analyses, key findings and study limitations were abstracted. RESULTS: Our search identified 3609 records, of which 17 articles met our inclusion criteria (15 independent studies). Eight out of ten studies found an association between depression and non-adherence. A meta-analysis revealed that depressed patients were twice as likely to be non adherent compared to patients without depression (OR=2.00, 95% CI 1.57-3.33, p=0.015). Type D personality was found to predict non-adherence in both studies in which it was measured. Three out of three studies reported that treatment beliefs based on the Necessity-Concerns Framework predicted medication non adherence and there was some evidence that social support was associated with better adherence. There was insufficient data to meta-analyse all other psychosocial factors identified. CONCLUSION: There was some evidence that psychosocial factors, particularly depression, were associated with medication adherence following ACS. Targeting depressive symptoms, screening for Type D personality, challenging maladaptive treatment beliefs, and providing better social support for patients may be useful strategies to improve medication adherence. PMID- 27772554 TI - What's 'difficult'? A multi-stage qualitative analysis of secondary care specialists' experiences with medically unexplained symptoms. AB - BACKGROUND: The term 'difficult' is pervasively used in relation to medically unexplained symptoms (MUS) and patients with MUS. This article scrutinises the use of the term by analysing interview data from a study of secondary care specialists' experiences with and attitudes towards patients suffering from MUS. DESIGN: Qualitative design employing semi-structured open-ended interviews systematically analysed in three stages: first, data were analysed according to the principles of content analysis. The analysis subsequently focused on the use of the term 'difficult'. Iterations of the term were extracted by summative analysis and thematic coding revealed its different meanings. Finally, alternative expressions were explored. SETTING: Three NHS trust secondary care hospitals in North-East England. PARTICIPANTS: 17 senior clinicians from seven medical and two surgical specialities. RESULTS: Unsolicited use of the term 'difficult' was common. 'Difficult' was rarely used as a patient characteristic or to describe the therapeutic relationship. Participants used 'difficult' to describe their experience of diagnosing, explaining, communicating and managing these conditions and their own emotional reactions. Health care system deficits and the conceptual basis for MUS were other facets of 'difficult'. Participants also reported experiences that were rewarding and positive. CONCLUSIONS: This study shows that blanket statements such as 'difficult patients' mask the complexity of doctors' experiences in the context of MUS. Our nuanced analysis of the use of 'difficult' challenges preconceived attitudes. This can help counter the unreflexive perpetuation of negative evaluations that stigmatize patients with MUS, encourage greater acknowledgement of doctors' emotions, and lead to more appropriate conceptualizations and management of MUS. PMID- 27772556 TI - Psychometric analysis of the Patient Health Questionnaire in Danish patients with an implantable cardioverter defibrillator (The DEFIB-WOMEN study). AB - OBJECTIVE: To assess the psychometric properties of the Patient Health Questionnaire (PHQ-9), a measure of depressive symptoms, in a large Danish national cohort of patients with heart disease, implanted with an implantable cardioverter defibrillator (ICD), using item response theory. METHODS: A prospective cohort of patients implanted with an ICD (n=1531; 80.4% men) completed the PHQ-9 at the time of implant. Data were analyzed using two item response theory models, the partial credit model and the generalized partial credit model. RESULTS: The analysis showed disordered response thresholds in eight of nine items for the partial credit model and five of nine items for the generalized partial credit model, indicating that respondents have difficulty discriminating between response options. When collapsing response options 2 and 3, the rescored PHQ-9 had a better fit to both models. The unidimensionality and the precision of the rescored PHQ-9 were confirmed. Items did not have any differential functioning (DIF) across educational level, age, indication for ICD implantation, and severity of heart failure that influence depression outcomes in patients with an ICD. One item exhibited DIF by gender. Three items did not fit the partial credit model, but the generalized partial credit model could be fitted to the full item set. CONCLUSION: The unidimensionality and reliability of the Danish version of the PHQ-9 were confirmed. However, the associated consequences of the number of response options (3-point versus 4-point Likert scale) need to be further examined for the PHQ-9 both as a screening tool and outcome measure. PMID- 27772557 TI - Effectiveness of cognitive behavioral therapy for the treatment of fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. AB - BACKGROUND: Fatigue is a frequently occurring symptom of multiple sclerosis (MS) that limits social participation. OBJECTIVE: To systematically determine the short and long-term effects of cognitive behavioral therapy (CBT) for the treatment of MS-related fatigue. DATA SOURCES: Pubmed, Cochrane, EMBASE, Psychology and Behavioral Sciences Collection, ERIC, PsychINFO, Cinahl, PsycARTICLES, and relevant trial registers were searched up to February 2016. In addition, references from retrieved articles were examined. STUDY SELECTION: Studies were included if participants had MS, fatigue was a primary outcome measure, the intervention was CBT, and the design was a randomized controlled trial. The search was performed by two independent reviewers, three CBT experts determined whether interventions were CBT. DATA EXTRACTION: Data on patient and study characteristics and fatigue were systematically extracted using a standardized data extraction form. Two independent reviewers assessed risk of bias using the Cochrane Collaboration risk of bias tool. In the event of disagreement, a third reviewer was consulted. DATA SYNTHESIS: Of the 994 identified studies, 4 studies were included in the meta-analysis, comprising 193 CBT-treated patients and 210 patients who underwent a control treatment. Meta analyses of these studies showed that CBT treatment had a positive short-term effect on fatigue (standardized mean difference [SMD]=-0.47; 95% confidence interval [CI]=-0.88; -0.06; I2=73%). In addition, three studies showed a long term positive effect of CBT (SMD=-0.30; CI -0.51; -0.08; I2=0%). CONCLUSIONS: This review found that the use of CBT for the treatment of fatigue in patients with MS has a moderately positive short-term effect. However, this effect decreases with cessation of treatment. PMID- 27772558 TI - Cost-utility of a specific collaborative group intervention for patients with functional somatic syndromes. AB - BACKGROUND: Collaborative group intervention (CGI) in patients with functional somatic syndromes (FSS) has been shown to improve mental quality of life. OBJECTIVE: To analyse incremental cost-utility of CGI compared to enhanced medical care in patients with FSS. METHODS: An economic evaluation alongside a cluster-randomised controlled trial was performed. 35 general practitioners (GPs) recruited 300 FSS patients. Patients in the CGI arm were offered 10 group sessions within 3months and 2 booster sessions 6 and 12months after baseline. Costs were assessed via questionnaire. Quality adjusted life years (QALYs) were calculated using the SF-6D index, derived from the 36-item short-form health survey (SF-36). We calculated patients' net-monetary-benefit (NMB), estimated the treatment effect via regression, and generated cost-effectiveness acceptability curves. RESULTS: Using intention-to-treat analysis, total costs during the 12 month study period were 5777EUR in the intervention, and 6858EUR in the control group. Controlling for possible confounders, we found a small, but significant positive intervention effect on QALYs (+0.017; p=0.019) and an insignificant cost saving resulting from a cost-increase in the control group (-10.5%; p=0.278). NMB regression showed that the probability of CGI to be cost-effective was 69% for a willingness to pay (WTP) of 0EUR/QALY, increased to 92% for a WTP of 50,000EUR/QALY and reached the level of 95% at a WTP of 70,375EUR/QALY. Subgroup analyses yielded that CGI was only cost-effective in severe somatic symptom severity (PHQ-15>=15). CONCLUSION: CGI has a high probability to be a cost effective treatment for FSS, in particular for patients with severe somatic symptom severity. PMID- 27772559 TI - The overlap of somatic, anxious and depressive syndromes: A population-based analysis. AB - OBJECTIVE: The comorbidity of somatic, anxious and depressive syndromes occurs in half of all primary care cases. As research on this overlap of syndromes in the general population is scarce, the present study investigated the prevalence of the overlapping syndromes and their association with health care use. METHOD: A national general population survey was conducted between June and July 2012. Trained interviewers contacted participants face-to-face, during which, individuals reported their health care use in the previous 12months. Somatic, anxious and depressive syndromes were assessed using the Somatic Symptom Scale-8 (SSS-8), Generalized Anxiety Disorder-2 (GAD-2) and Patient Health Questionnaire 2 (PHQ-2) respectively. RESULTS: Out of 2510 participants, 236 (9.4%) reported somatic (5.9%), anxious (3.4%) or depressive (4.7%) syndromes, which were comorbid in 86 (3.4%) cases. The increase in the number of syndromes was associated with increase in health care visits (no syndrome: 3.18 visits vs. mono syndrome: 5.82 visits vs. multi syndromes: 14.16 visits, (F(2,2507)=149.10, p<0.00001)). Compared to each somatic (semi-partial r2=3.4%), anxious (semi partial r2=0.82%) or depressive (semi-partial r2=0.002%) syndrome, the syndrome overlap (semi-partial r2=6.6%) explained the greatest part of variance of health care use (change_inR2=11.2%, change_inF(3,2499)=112.81, p<0.001.) CONCLUSIONS: The overlap of somatic, anxious and depressive syndromes is frequent in the general population but appears to be less common compared to primary care populations. To estimate health care use in the general population the overlap of somatic, anxious and depressive syndromes should be considered. PMID- 27772560 TI - Psychometric properties of the short form of the Children's Depression Inventory (CDI-S) in young people with physical disabilities. AB - OBJECTIVE: Depression is a significant issue for young people with physical disabilities. Efficient and reliable questionnaires are needed to evaluate and monitor the efficacy of depression treatments in this population. The aim of this study was to evaluate the reliability and validity of the 10-item version of the Children's Depression Inventory (CDI-S) in a sample of young people with physical disabilities. METHODS: A convenience sample of young people with physical disabilities (N=97) was recruited and interviewed. Reliability was evaluated using the Cronbach's alpha and examining the item-total correlations. Validity was evaluated by computing Pearson correlations between scores on the CDI-S and measures of pain and psychological functioning (anxiety and depression). RESULTS: The CDS-I items loaded on a single factor. The internal consistency of the scale was good (Cronbach's alpha=0.84) and the CDI-S showed moderate significant correlations with pain intensity (r=0.29), pain interference (r=0.46) and psychological functioning (r=-0.57). Two of the items, however, did not perform well (i.e., item-total correlations <0.3, and Cronbach's alpha improved when they were deleted). CONCLUSION: The findings support the reliability and validity of the CDI-S scores for use in young people with physical disabilities. The measure's psychometric properties should be studied in larger samples. In addition, there is a new brief version of the CDI (CDI-S 2) that needs to be evaluated in order to determine which of the two scales is better for assessing depression in young people with physical disabilities. PMID- 27772561 TI - Associations between work stress and suicidal ideation: Individual-participant data from six cross-sectional studies. AB - OBJECTIVE: Epidemiological evidence suggests that work stress is associated with suicidal ideation (SI). However, only few studies in this area have drawn on well established theoretical work stress models (i.e., the job-demand-control [JDC] model, the effort-reward-imbalance [ERI] model, and the model of organizational injustice [OJ]). Utilization of such models allows though for theory-based assessments and workplace interventions. Since evidence on those models' relationship with suicide-related outcomes is currently inconclusive (with regard to JDC), markedly sparse (OJ) or lacking (ERI), we aimed to provide additional or initial evidence. METHODS: We drew on original data from six cross-sectional studies, which were conducted in four countries (i.e., South Korea, China, Australia, and Germany). Work stress was measured by established questionnaires and was categorized into tertiles. In each study, SI was assessed by either one or two items taken from validated scales. Associations of work stress with SI were estimated for each study and were pooled across studies using multivariate random-effects logistic modeling. RESULTS: In the pooled analyses (n=12,422) all three work stress models were significantly associated with SI with odds ratios fluctuating around 2. For instance, the pooled odds ratios for highest versus lowest work stress exposure in terms of job strain, OJ, and ERI equalled 1.91 (95% confidence interval [CI]=1.52, 2.41), 1.98 (95% CI=1.48, 2.65), and 2.77 (95% CI=1.57, 4.88), respectively. Patterns of associations were largely consistent across the individual studies. CONCLUSION: Our study provides robust evidence of a positive association between work stress and SI. PMID- 27772563 TI - Depression in survival following acute infection. PMID- 27772562 TI - Is there a relationship between psychological stress or anxiety and chronic nonspecific neck-arm pain in adults? A systematic review and meta-analysis. AB - PURPOSE: To systematically review and analyze the research evidence linking stress or anxiety to chronic nonspecific neck-arm pain (NSNAP) in adults. SUBJECTS AND METHODS: Data were obtained from Pubmed, Scopus, PsycInfo, Web of Science, Physiotherapy Evidence Database (PEDro) and The Cochrane library database from their inception to July 2015. Two authors independently conducted the searches, extracted data, and completed methodological quality assessments. The methodological quality of the cohort and case-control studies was evaluated using the Newcastle-Ottawa scale, whilst the quality of the Randomized Controlled Trial (RCT) was evaluated using the PEDro scale. RESULTS: Twenty-eight studies involving 39,166 participants met the inclusion criteria. Four studies, including 5 pair-wise comparisons, were included in the meta-analysis: Three were cohort studies and 1 was a cross-sectional study. The meta-analysis outcome demonstrated a relationship between chronic NSNAP and psychological stress. The estimate odds ratio for all studies combined was 2.33 (95% CI, 1.04-5.18; p=0.039). A high heterogeneity of the findings appeared (Q=28.94, I2=86% p=0.00). CONCLUSION: This study shows that there is a strong relationship between stress and chronic NSNAP. Despite this finding, we cannot support that stress is a risk factor for chronic NSNAP due to the low quality of the results according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). It was not possible to make a quantitative analysis comparing the relationship between anxiety and chronic NSNAP. However, according to the qualitative analysis there is a strong relationship between anxiety and chronic NSNAP. PMID- 27772564 TI - Attention, vigilance and visuospatial function in hospitalized elderly medical patients: Relationship to neurocognitive diagnosis. AB - OBJECTIVE: Efficient detection of neurocognitive disorders is a key diagnostic challenge. We explored how simple bedside tests of attention, vigilance and visuospatial function might assist in identifying delirium in hospitalized patients. METHODS: Performance on a battery of bedside cognitive tests was compared in elderly medical inpatients with DSM-IV delirium, dementia, comorbid delirium-dementia, and no neurocognitive disorder. RESULTS: 193 patients [mean age 79.9+/-7.3; 97 male] were assessed with delirium (n=45), dementia (n=33), comorbid delirium-dementia (n=65) and no neurocognitive disorder (NNCD) (n=50). The ability to meaningfully engage with the tests varied from 84% (Spatial Span Forwards) to 57% (Vigilance B test), and was especially problematic among the comorbid delirium-dementia group. The NNCD was distinguished from the delirium groups for most tests, and from the dementia group for the Vigilance B test and the Clock Drawing Test. The dementia group differed from delirium groups in respect of the Months Backward Test, Vigilance A and B tests, Global assessment of visuospatial ability and the Interlocking Pentagons Test. Overall, patients with delirium were best identified by three tests - the Months Backward Test, Vigilance A test and the Global Assessment of visuospatial function with failure to correctly complete any two of these predicting delirium status in 80% of cases. CONCLUSION: Simple bedside tests of attention, vigilance and visuospatial ability can help to distinguish neurocognitive disorders, including delirium, from other presentations. There is a need to develop more accurate methods specifically designed to assess patients with neurocognitive disorder who are unable to engage with conventional tests. PMID- 27772566 TI - The associations among vitamin D deficiency, C-reactive protein, and depressive symptoms. AB - OBJECTIVE: Vitamin D deficiency has been reported to be associated with depression, but the underlying mechanisms aren't well understood. Our study aims to investigate the associations among serum vitamin D, C-reactive protein (CRP) level, and depressive symptoms. METHODS: Serum levels of Vitamin D and CRP were measured from 52,228 participants. Depressive symptoms were assessed using a Korean version of the CES-D scale. We used logistic regression to calculate the odds ratio (ORs) of depressive symptoms according to vitamin D and CRP levels. The regressions were adjusted for covariates, and each model was adjusted mutually for vitamin D and CRP levels. RESULTS: A significant difference was found in vitamin D status between depressed and non-depressed participants, but CRP status was not significantly different. The OR for the presence of depressive symptoms was significantly increased in participants with vitamin D deficiency after adjusting for potentially confounding factors (Adjusted OR=1.158, 95% CI=1.003-1.336, p=0.046). The OR of depressive symptoms was not significantly increased in individuals with high (3.01-10mg/L) CRP level compared to individuals with low (<=3mg/L) CRP level (Adjusted OR=1.004, 95% CI=0.821-1.227, p=0.97). There was no significant association between vitamin D and CRP level. Additional adjustment for serum CRP level did not weaken the resulting association between vitamin D deficiency and the presence of depressive symptoms. CONCLUSION: Vitamin D deficiency was associated with depressive symptoms, but elevated serum CRP level was not. The results indicate that CRP level does not account for the association between vitamin D deficiency and the presence of depressive symptoms. PMID- 27772567 TI - Innovation for Life. PMID- 27772565 TI - Validity of the Center for Epidemiological Studies Depression scale in Type 2 diabetes. AB - OBJECTIVE: Depressive symptoms are common among people with Type 2 diabetes mellitus (T2DM). This study aimed to validate the 3-factor structure of the 14 item Center for Epidemiological Studies Depression (CES-D) scale proposed by Carleton et al. (2013) in a T2DM population. METHODS: The CES-D was administered to consecutive patients with T2DM entering a rehabilitation program. Construct validity was assessed using confirmatory factor analysis. Subscale viability, differential item functioning, and associations with clinical characteristics were tested in bifactor models. RESULTS: Among adults with T2DM (n=305, age 56.9+/-11.1, 44.9% male, duration of diabetes 7.8+/-7.9years, HbA1c 0.076+/ 0.014%), the construct validity of Carleton's 3-factor solution (negative affective, positive affective and somatic symptoms) was confirmed, although negative affective and somatic symptoms were highly correlated (r=0.926). The CES D items can be summed to arrive at a total score (omegaH=0.869), but not subscale scores (omegaS>0.7). Differential item functioning was not found based on age or body mass index (BMI), but Item 1 ("I was bothered by things that don't usually bother me") was inflated in women and Item 7 ("I felt that everything I did was an effort") was inflated in those with higher glycosylated haemoglobin (HbA1c). The general depression factor decreased with age (beta=-0.247, p<0.001) and increased with BMI (beta=0.102, p=0.041) but not HbA1c (beta=0.065, p=0.461). Negative affective symptoms (beta=0.743, p=0.001), but not other depressive symptoms, were higher in women. CONCLUSIONS: The 14-item CES-D retained construct validity in adults with T2DM. Depressive symptoms were associated with younger age, female gender and BMI, but not with glycemic control. PMID- 27772568 TI - What is a Cardiothoracic Surgical "Center of Excellence"? PMID- 27772569 TI - Envisioning Excellence. PMID- 27772570 TI - Transhiatal Esophagectomy: How I Teach It. PMID- 27772571 TI - Should Family Presence Be Allowed During Cardiopulmonary Resuscitation? PMID- 27772573 TI - Invited Commentary. PMID- 27772572 TI - The Society of Thoracic Surgeons General Thoracic Surgery Database: 2016 Update on Research. AB - The Society of Thoracic Surgeons General Thoracic Surgery Database has grown to more than 500,000 case records. Clinical research supported by the database is increasingly used to advance patient outcomes. This research review from the General Thoracic Surgery Database in 2014 and 2015 discusses 6 recent publications and an ongoing study on longitudinal outcomes in lung cancer surgery from The Society of Thoracic Surgeons Task Force for Linked Registries and Longitudinal Follow-up. A lack of database variables specific for certain uncommon procedures limits the ability to study these operations; inclusion of clinical descriptors for selected infrequent but clinically important thoracic disorders is suggested. PMID- 27772574 TI - Karl Viktor Hall: From In Situ Vein Bypass to the Tilting Disc Heart Valve Prosthesis. AB - In 1977, Karl Viktor Hall implanted a novel tilting disc heart valve prosthesis at Rikshospitalet in Oslo, Norway. The Medtronic-Hall valve was known for its excellent durability and low thrombogenicity. Hall popularized the use of the great saphenous vein in situ as an arterial shunt in the 1960s, made a metal stripper to lyse vein valves, and introduced electromagnetic flowmeters in vascular surgery. He performed the first coronary artery bypass graft in Scandinavia in 1969. Under his leadership the first heart transplantation and the first heart-lung transplantation were performed in Scandinavia by his successor Tor Froysaker in 1983 and 1986, respectively. PMID- 27772575 TI - High-Dose Statins After Coronary Artery Bypass Grafting: Questions Remain. PMID- 27772576 TI - Reply. PMID- 27772577 TI - Stent Placement in the Management of Esophageal Leaks. PMID- 27772578 TI - Surgical Repair of Pectus Excavatum. PMID- 27772579 TI - Reply. PMID- 27772580 TI - Which Variables Should be Considered as Confounders of p38-Mitogen Activated Protein Kinase Activation Measurements? PMID- 27772581 TI - Reply. PMID- 27772582 TI - Reply. PMID- 27772583 TI - Dr Winslow's Duck: Correction of a Surgical Myth Concerning Tracheobronchial Injury. PMID- 27772585 TI - Correction. PMID- 27772584 TI - Misconceptions About Malignant Metamorphosis in Myxoma. PMID- 27772586 TI - Marjolin's Ulcer of the Pleural Surface Within a Long-Standing Eloesser Flap. AB - Marjolin's ulcers typically result from long-term chronic inflammation of a squamous surface, most often related to burns and other scars. This report describes a squamous cell carcinoma arising from the pleural surface in a patient with a chronically neglected Eloesser flap. PMID- 27772587 TI - Splenic Artery Ligation for Iatrogenic Injury in Esophagectomy Operations. AB - Studies have shown that splenic artery ligation without splenectomy can successfully control hemorrhage and preserve the spleen in splenic trauma. The short gastric arteries and left gastroepiploic arteries may be the most important part of the collateral blood supply to the spleen. Moreover, that the human spleen can also survive even if most of the short gastric arteries have been ligated along with the splenic artery has also been proven. Revascularization of the spleen by collateral vessels from the superior mesenteric, pancreatic, and left inferior phrenic arteries has been demonstrated by celiac angiography. Thus, splenic artery ligation could be also an alternative to splenectomy for iatrogenic spleen injury in esophagectomy operations. PMID- 27772588 TI - Thoracoscopic Pulmonary Sub-Subsegmentectomy Based on Three-Dimensional Images. AB - Thoracoscopic anatomic pulmonary segmentectomy and subsegmentectomy have become sophisticated surgical solutions for complex pulmonary diseases. The rapid development of three-dimensional computed tomographic angiography (3DCTA) has made it possible to provide more refined individualized anatomic details and has consequently enabled subsubsegmentectomy (SSS). In this study, we report two successful thoracoscopic anatomic SSSs of the left S1+2aii and S3aii under the guidance of 3DCTA reconstructed images. To the best of our knowledge, these are the first two cases of SSSs ever detailed reported. The nomenclature of subsubsegments is adopted according to the Japanese Committee on the Nomenclature for Bronchial Branching. PMID- 27772589 TI - Paragonimus kellicotti Presenting With Hemoptysis and a Left Upper Lobe Mass. AB - A 46-year-old man presented to the thoracic surgery clinic with a 6-month history of cough and hemoptysis refractory to treatment. Examination of specimens from repeated biopsies was nondiagnostic, so the patient underwent video-assisted thoracoscopic left upper lobe wedge resection. Pathologic examination revealed Paragonimus organisms, and the patient was prescribed praziquantel, with resolution of his symptoms. Although Paragonimus infections are common in Asia, they are rare in the United States despite P kellicotti being endemic. Clinicians should have a high index of suspicion for patients presenting with unusual lung symptoms in endemic areas to avoid prolonged evaluations with potentially unnecessary diagnostic modalities. PMID- 27772590 TI - A Glomus Tumor With Recurrence and Malignant Transformation in the Chest Wall: A Cautionary Tale of Seeding? AB - Glomus tumors are rare tumors most often occurring in the extremities of the limbs. We report a unique case of a glomus tumor, originally arising in the paraspinal region, which was excised and subsequently recurred in the chest wall with malignant transformation. The recurrence is likely to have been caused by wound seeding. To the best of our knowledge, this is the first report in the English literature of a glomus tumor recurrence secondary to the notion of wound seeding. PMID- 27772591 TI - Resection of a Giant Mediastinal Teratoma. AB - This case report describes the surgical management of a giant mediastinal teratoma. Perioperative considerations and operative approach to effect good outcomes are described. PMID- 27772592 TI - Substernal Colonic Interposition After Previous Coronary Artery Bypass Graft in a Patient With a Patent Left Internal Thoracic Artery Graft: A Surgical Challenge. AB - Esophageal reconstruction by a substernal route with a colonic conduit after previous esophagectomy and end-cervical esophagostomy in the presence of a patent left internal thoracic artery graft to the left anterior descending coronary artery is a technically challenging procedure. In this case report, we describe a safe approach to this difficult problem. With proper planning and careful dissection, substernal esophageal reconstruction after previous sternotomy in patients with a patent left internal thoracic artery graft is feasible and can be safely performed. PMID- 27772593 TI - Extranodal Marginal Zone Endobronchial Lymphoma Associated With Hepatitis C. AB - We describe two patients with hepatitis C and a diagnosis of pulmonary extranodal marginal zone B cell lymphoma. Both patients demonstrated a chronic nonproductive cough without hemoptysis. Diagnosis was obtained after a computed tomographic chest scan and flexible bronchoscopic biopsy. We discuss the staging and prognosis of this disease, its correlation with hepatitis C, and potential benefits of treating the associated hepatitis C. PMID- 27772594 TI - Cerebral Fat Embolism After Video-Assisted Thoracic Surgery. AB - Cerebral fat embolism (CFE) is an uncommon disease occurring mainly after traumatic lower limb long bone fractures. A 64-year-old woman with pneumonia and bilateral pleural effusion underwent video-assisted thoracic surgery (VATS). After 3 days, the patient had an acute decrease in consciousness level followed by the onset of seizures and right hemiparesis. Brain computed tomography and magnetic resonance imaging showed findings suggestive of CFE. CFE occurring after an uncommon nontraumatic cause of fat embolism, such as VATS, is a rare clinical event whose diagnosis could be challenging. Neuroimaging can hasten diagnosis and prevent other unnecessary investigations and treatments. PMID- 27772595 TI - Concomitant Thoracic Aortobifemoral Bypass With Left Ventricular Assist Device Implantation. AB - Improved quality of life for patients after left ventricular assist device (LVAD) implantation can be greatly limited by peripheral vascular disease even if heart failure symptoms are resolved by LVAD support. We present a case of concomitant thoracic aortobifemoral bypass and LVAD implantation in a patient with ischemic cardiomyopathy, severe peripheral vascular disease, and multiple previous failed revascularization attempts. In this patient, we used the LVAD outflow to provide the inflow to the femoral artery bypass graft. This graft has remained patent at a 2-year follow-up, without claudication symptoms. Performing concomitant major vascular operations safely and successfully is feasible in patients with LVADs. Quality of life after ventricular assist device placement can be limited by vascular disease, but it can be markedly improved after vascular surgical intervention. PMID- 27772596 TI - Percutaneous Rescue for Critical Mitral Stenosis Late After Mitral Valve Repair. AB - We report a case of catastrophic hemodynamic compromise secondary to pannus ingrowth and severe mitral stenosis occurring years after repair of a nonrheumatic mitral valve. The initial repair included closure of a posterior leaflet cleft and implantation of an annuloplasty ring. We describe a hybrid treatment strategy for this severely compromised patient, which included initial placement of a right ventricular assist device followed by percutaneous balloon mitral valvuloplasty and, eventually, a definitive mitral valve reoperation. This case report reinforces the importance of routine clinical and echocardiographic follow-up for patients after mitral valve repair, and it includes the description of a novel therapeutic approach. PMID- 27772598 TI - Redo Aortic Valve Implantation After Full Root Replacement Using A Sutureless Valve Prosthesis. AB - We report the case of a 83-year-old man who had undergone a full root replacement with a stentless bioprosthesis 15 years earlier. He was now diagnosed with severe aortic valve regurgitation secondary to leaflet degeneration, moderate mitral regurgitation, and single-vessel coronary artery disease. To reduce cross-clamp time and technical difficulties a sutureless aortic prosthesis was used. His surgery and postoperative course were uneventful. This is the first report of the successful use of a sutureless aortic valve prosthesis in a patient after bioprosthetic full root replacement who required additional mitral repair and coronary artery bypass surgery. PMID- 27772597 TI - Closed Mitral Commissurotomy During Pregnancy in East Africa. AB - Cardiac surgeons traveling to East Africa on humanitarian surgical missions treat a large number of people of all ages with rheumatic heart disease. A patient with severe mitral stenosis with pulmonary edema in the second trimester of pregnancy was treated successfully with closed mitral commissurotomy in a hospital in rural Kenya. An operation from the late 1940s may regain prominence more than 70 years later in areas of the world with a high incidence of rheumatic heart disease and limited cardiology and cardiac surgery resources. PMID- 27772599 TI - Intravenous Lobular Capillary Hemangioma in the Subclavian Vein. AB - We report the case of a 73-year-old man with severe edema of the right upper extremity. Computed tomography, magnetic resonance imaging, and venography revealed an intravenous tumor in the middle portion of the right subclavian vein. The tumor was completely resected, and an accompanying thrombus was also removed using the transmanubrial osteomuscular sparing approach. The patient recovered well without any complications or recurrence. The histopathologic diagnosis was intravenous lobular capillary hemangioma, which is also called pyogenic granuloma. To our knowledge, this is the first reported surgical case involving this type of benign tumor originating in a thoracic vein. PMID- 27772600 TI - Type B Aortic Arch Interruption in an Adult. AB - The presentation and treatment of a patient with a type B interrupted aortic arch with an isolated left subclavian artery is described. PMID- 27772601 TI - Implantation of Transcatheter Aortic Prosthesis in 3 Patients With Mitral Annular Calcification. AB - Mitral annular calcification (MAC) is a chronic degenerative process at the fibrous base of the mitral valve. It is a feared diagnosis in the context of mitral valve operations because of the risk of severe adverse events such as atrioventricular disruption, injury to the circumflex artery during debridement, and difficult placement of annular sutures. We report a series of 3 consecutive female patients with severe circular MAC who underwent successful mitral valve replacement through a lateral minithoracotomy with use of an inverted transcatheter aortic valve. PMID- 27772602 TI - Aortic Valve Stenosis in a Dialysis Patient Waitlisted for Kidney Transplantation. AB - Management of dialysis patients with valvular heart disease waitlisted for kidney transplantation is challenging. Development of severe aortic valve stenosis can lead to the exclusion from the transplant program or even death while on the waiting list. In dialysis patients, surgical aortic valve replacement is associated with a high perioperative risk with increased morbidity and mortality. In contrast, transcatheter aortic valve implantation emerges as a viable option for dialysis patients. Herein, we present the long-term follow-up of successful kidney transplantation after TAVI in a diabetic patient receiving long-term hemodialysis. PMID- 27772603 TI - Isolated Anomalous Origin of Left Pulmonary Artery From the Descending Aorta: An Embryologic Ambiguity. AB - Anomalous origin of a branch pulmonary artery from the aorta is a rare malformation, accounting for 0.12% of all congenital heart defects. Anomalous origin of the left pulmonary artery from the aorta (ALPA) constitutes a small proportion of these cases. ALPA has been reported to arise from the ascending aorta with various embryologic postulates. We report a case of isolated ALPA arising from the descending aorta in association with a patent ductus arteriosus, to emphasize its embryologic ambiguity. PMID- 27772604 TI - Parachute Tricuspid Valve: A Case Treated by Open Heart Surgery. AB - Parachute valve is the malformation of an atrioventricular valve in which the tension apparatus springs from a single papillary muscle or group of muscles. Parachute tricuspid valve is a rare anomaly with no surgically repaired case to date. We describe a case of parachute deformity of the tricuspid valve leading to hemodynamically significant severe tricuspid stenosis. The present case was successfully repaired surgically along with atrial septal defect (ASD) and ventricular septal defect (VSD) closure. PMID- 27772605 TI - Transient Electromechanical Dissociation Caused by a Transesophageal Echocardiography Probe. AB - Intraoperative transesophageal echocardiography is an established modality for confirming the preoperative diagnosis, assess adequacy of surgical repair, identify residual problems, and help improve the outcome after operation. Despite the multitude of advantages, intraoperative transesophageal echocardiography can affect the hemodynamic parameters in small neonates and children. A severe transient electromechanical dissociation caused by the anteflexion of a transesophageal echocardiography probe during a total anomalous pulmonary venous connection repair in an infant is reported. PMID- 27772606 TI - Robotic-Assisted Coil Embolization of Ascending Aortic Pseudoaneurysm. AB - A 62-year-old man with coronary artery disease and ischemic cardiomyopathy after coronary artery bypass grafting and insertion of a HeartMate II (Thoratec, Pleasanton, CA) left ventricular assist device (LVAD) presented with spontaneous incisional bleeding and an ascending aortic pseudoaneurysm. Aortic angiography revealed an anomalous connection between the pseudoaneurysm and the LVAD conduit. We were able to partially embolize the tract with standard techniques, but the patient returned with repeated bleeding. Using the additional stability and control afforded by the Magellan Robotic System (Hansen Medical, Mountain View, CA), a remotely steerable catheter, we were able to cannulate and completely embolize the pseudoaneurysm and occlude the anomalous tract. PMID- 27772607 TI - Catamenial Pneumothorax With Hepatic Herniation. PMID- 27772608 TI - Unusual Solution for a Transcatheter Aortic Valve Embolization: Deployment of an Endovascular Stent Through a Floating Prosthesis. PMID- 27772610 TI - A Giant Left Atrial Thrombus After Radiofrequency Catheter Ablation. PMID- 27772609 TI - Posterior Leaflet Tumor as a Presentation of Mitral Valve Endocarditis. PMID- 27772611 TI - Giant Left Atrial Myxoma. PMID- 27772612 TI - Ultrasound-Guided Video-Assisted Mediastinoscopic Biopsy: A Novel Approach. AB - Video-assisted mediastinoscopy (VAM) is the most commonly used invasive method for the preoperative mediastinal staging of lung cancer and for the diagnosis of other mediastinal diseases. However, VAM has the risk of causing life-threatening bleeding consequent to the specific mediastinal anatomy. We adopted the ultrasonic technique for VAM biopsies that can easily distinguish the lymph nodes from the surrounding great vessels and thus makes the procedure easier and safer. PMID- 27772613 TI - A Novel Technique for Laryngotracheal Reconstruction for Idiopathic Subglottic Stenosis. AB - Idiopathic subglottic stenosis is the most challenging condition in the field of upper airway reconstruction. We describe a successful novel technique for enlarging the airway space at the site of the laryngotracheal anastomosis in very high-level reconstructions. PMID- 27772614 TI - Concomitant Maze IV Ablation Procedure Performed Entirely by Bipolar Clamp Through Right Lateral Minithoracotomy. AB - Atrial fibrillation ablation with bipolar clamp has proved to be effective for patients with valvular atrial fibrillation. However, left pulmonary vein ablation with bipolar clamp through right minithoracotomy was considered difficult or impossible. In this report, we described a novel technique of performing concomitant Maze IV ablation procedure entirely by bipolar clamp through right minithoracotomy. Left pulmonary vein ablation with bipolar clamp was performed through an established channel and a natural space. This technique has proved to be safe and feasible and to have good clinical outcomes that may deserve further use for patients with atrial fibrillation and mitral valve disease. PMID- 27772615 TI - Reoperative Aortic Valve Replacement in a Previous Biologic Composite Valve Graft. AB - Structural valve deterioration with biologic composite valve grafts previously required reoperative aortic root replacement. We present a technique for avoiding repeated root replacement. Exposure is by a transverse incision through the Dacron graft. The valve is disassembled within the graft, and a new prosthesis is implanted. We used this technique in 11 patients with good success. PMID- 27772616 TI - Modified Norwood Procedure for Tricuspid Atresia, Transposition of Great Arteries, and Hypoplastic Right Arch With Complete Vascular Ring. AB - We report a modified Norwood stage I procedure for tricuspid atresia, transposition of great arteries, and hypoplastic right aortic arch with complete vascular ring. In this technique, we applied dual arterial cannulation to avoid circulation arrest during neoaortic reconstruction, and also corrected the arch laterality during the Norwood stage I palliation procedure. Pulmonary flow was supplied by the Blalock-Taussig shunt. Postoperative imaging revealed the patent left neoaortic arch, and the vascular ring was relieved with a patent tracheobronchial tree. PMID- 27772617 TI - STIC-ing with what we know. PMID- 27772618 TI - Introduction: Kidney Transplantation and Viral Infection. PMID- 27772619 TI - alpha Herpes Virus Infections Among Renal Transplant Recipients. AB - The alpha herpes viruses HSV-1, HSV-2, and VZV often reactivate in the setting of immune suppression after solid organ transplantation. Oral or genital mucocutaneous disease is the most common clinical manifestation of HSV disease while VZV manifests as varicella (or chickenpox) or reactivation herpes zoster, characterized by a diffuse rash, or a painful unilateral vesicular eruption in a dermatomal distribution, respectively. The diagnosis of HSV and VZV is primarily based on history and clinical presentation, although diagnostic tests may be necessary for atypical presentations of disease. Treatment usually involves oral or intravenous antiviral therapy, depending on severity of illness. PMID- 27772620 TI - Cytomegalovirus and Other beta-Herpesviruses. AB - Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous beta herpesviruses that can cause opportunistic infection and disease in kidney transplant recipients. Active CMV infection and disease are associated with acute allograft failure and death, and HHV-6 and HHV-7 replication are associated with CMV disease. CMV prevention strategies are used commonly after kidney transplantation, and include prophylaxis with antiviral medications and preemptive treatment upon the detection of asymptomatic viral replication in blood. Both approaches decrease CMV disease and allograft rejection, but CMV prophylaxis is preferred for high-risk patients because it is easy to administer and may be more effective in real-world settings. CMV disease commonly occurs even with current preventive strategies, whereas HHV-6 and HHV-7 diseases are rare. The clinical manifestations of CMV, HHV-6, and HHV-7 are nonspecific, and laboratory confirmation is essential to establishing diagnoses. Although nucleic acid testing has supplanted other diagnostic modalities given its high sensitivity and specificity, histopathologic examination sometimes is necessary to identify disease definitively. Ganciclovir and valganciclovir are the treatments of choice for CMV and HHV-6, and foscarnet can be used to treat HHV-7. Treatment duration should be informed by the initial severity of disease, and subsequent clinical and virologic responses. PMID- 27772621 TI - Oncogenic gamma Herpesviruses EBV and HHV8 in Kidney Transplantation. AB - Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) are gamma herpesviruses associated with post-transplant malignancies in kidney transplant recipients. EBV is associated with post-transplantation lymphoproliferative disorder (PTLD), with increased risk in EBV-seronegative patients on intensified immunosuppression. Human herpesvirus-8 is associated with Kaposi's sarcoma (KS), with an increased risk in certain patient populations. Diagnosis of PTLD and KS relies on tissue biopsy. The mainstay of therapy for both PTLD and Kaposi's sarcoma is a reduction of immunosuppression, and in the case of PTLD, consideration of rituximab. Chemotherapy, radiation therapy, or surgery is provided for disseminated or recalcitrant disease. The prognoses vary depending on the type of malignancy identified and stage of disease. PMID- 27772622 TI - BK and Other Polyomaviruses in Kidney Transplantation. AB - For more than 40 years, polyomaviruses (BK virus and JC virus) have been known to cause disease in human beings. Recently, 11 new polyomaviruses were discovered. However, the majority of these viruses are rare in renal transplant recipients and BK and JC viruses remain the most important polyomaviruses to impact this population. BK virus presents as BK virus nephropathy and has, in rare instances, been associated with hemorrhagic cystitis or ureteral strictures. JC virus can cause progressive multifocal leukoencephalopathy or nephropathy in this population as well, but is uncommon. Antiviral prophylactic and therapeutic interventions for these diseases are lacking to date, although reduction of immunosuppression has been associated with success in treating both BK virus nephropathy and JC virus-induced disease. Risk factors are not well defined and vary across studies. However, the cumulative degree of immunosuppression is regarded universally as an important contributor to BK virus replication. For these reasons, it is recommended to screen all renal transplant recipients prospectively for BK virus infection. Multicenter trials using standardized BK and JC virus screening methods are necessary to define risk factors better, and to determine the effect of prophylaxis and treatments for these polyomaviruses affecting renal transplant recipients. PMID- 27772623 TI - Hepatitis Viruses in Kidney Transplantation. AB - Hepatitis viruses are named for their primary clinical illness, inflammation of the liver. Currently, six types of viruses are designated hepatitis viruses (A, B, C, D, E, and G), although only five of these cause hepatitis. Hepatitis viruses are composed of RNA and DNA viruses from different families and with different virologic properties, some of which typically cause acute hepatitis while others cause acute and chronic hepatitis. In addition to their role in liver disease, members of this group of viruses may cause a variety of pathologic changes in the kidney and other organs, and chronic infection may lead to cirrhosis in addition to raising a variety of important issues in the management of kidney transplant recipients. In this brief report, we review the virologic and clinical properties of each of the hepatitis viruses, and highlight the role of each virus in renal disease and kidney transplantation. PMID- 27772625 TI - Human Immunodeficiency Virus in Kidney Transplantation. AB - Patients infected with human immunodeficiency virus (HIV) are living longer, healthier lives on highly active antiretroviral therapy and, as a result, interest in kidney transplantation for HIV-infected patients with end-stage renal disease has increased. HIV is no longer considered a contraindication to solid organ transplantation and the number of kidney transplants performed in HIV infected patients each year is increasing steadily. HIV-infected kidney transplant recipients have had excellent outcomes overall, but there are still significant challenges, including high rates of acute rejection, drug-drug interactions, and poor outcomes in patients co-infected with hepatitis C virus. The gap between supply and demand for organs remains a challenge but new developments in HIV-positive to HIV-positive kidney transplantation may help bridge this gap. PMID- 27772624 TI - Human Papillomavirus in Kidney Transplant Recipients. AB - Human papillomavirus (HPV) is a common infection in kidney transplant recipients. HPV causes cervical, anal, vulvar, vaginal, penile and head and neck cancers. Kidney transplant recipients have a disproportionate burden of disease given prolonged immunosuppression. Given the long pre-invasive state of precancer lesions such as cervical intraepithelial neoplasia (CIN) and anal intraepithelial neoplasia (AIN) most HPV-cancers are preventable with screening and targeted treatment of disease. Pre-transplant vaccination of age-eligible kidney transplant recipients is otherwise ideal. PMID- 27772626 TI - Respiratory Viruses: Influenza, RSV, and Adenovirus in Kidney Transplantation. AB - Although advances in immunosuppression and antimicrobial prophylaxis have led to improved patient and graft survival, respiratory viruses continue to be a common cause of morbidity and mortality in immunocompromised populations. We describe the clinical manifestations, diagnosis and treatment options for influenza, respiratory syncytial virus and adenovirus infection in the kidney transplant population. PMID- 27772627 TI - Not the Usual Viral Suspects: Parvovirus B19, West Nile Virus, and Human T-Cell Lymphotrophic Virus Infections After Kidney Transplantation. AB - Kidney transplant recipients are at increased risk of developing clinical disease due to uncommon opportunistic viral pathogens. Refractory anemia is classically associated with parvovirus B19 infection. West Nile virus has the propensity to cause fever and neurologic symptoms, while spastic paresis and lymphoma can be triggered by human T cell lymphotrophic virus. In this review article, the epidemiology, clinical manifestations, diagnosis and treatment of less common viruses are discussed in the setting of kidney transplantation. PMID- 27772628 TI - Oral Iron Therapy: After Three Centuries, It Is Time for a Change. PMID- 27772629 TI - Phosphate Binders: The Evidence Gap Persists. PMID- 27772630 TI - Kidney Disease, Income, and Life Expectancy. PMID- 27772631 TI - In Reply to 'C4 Deposition in Glomerular Disease'. PMID- 27772633 TI - C4 Deposition in Glomerular Disease. PMID- 27772632 TI - Abnormality in FGF-23-alpha-Klotho Axis: A Possible Mechanism Underlying Hemodialysis-Related Cognitive Dysfunction? PMID- 27772634 TI - In Reply to 'Abnormality in FGF-23-alpha-Klotho Axis: A Possible Mechanism Underlying Hemodialysis-Related Cognitive Dysfunction?' PMID- 27772635 TI - Quiz Page November 2016: Kidney and Neurologic Complications in the Treatment of a Patient With Hepatic Encephalopathy. PMID- 27772636 TI - AJKD Atlas of Renal Pathology: Anti-Glomerular Basement Membrane Antibody Mediated Glomerulonephritis. PMID- 27772637 TI - AJKD Atlas of Renal Pathology: Pauci-immune Necrotizing Crescentic Glomerulonephritis. PMID- 27772638 TI - Intensive Hemodialysis: Time to Give the Therapy Greater Consideration. PMID- 27772639 TI - Intensive Hemodialysis, Blood Pressure, and Antihypertensive Medication Use. AB - Hypertension is a cardinal feature of end-stage renal disease (ESRD). Hypertensive nephropathy is the primary cause of ESRD for nearly 30% of patients, and the prevalence of hypertension is >85% in new patients with ESRD. In contemporary hemodialysis (HD) patients, mean predialysis systolic blood pressure (SBP) is nearly 150mmHg, and about 70%, 50%, and 40% use beta-blockers, calcium channel blockers, and renin-angiotensin system inhibitors, respectively. Predialysis SBP generally exhibits a U-shaped association with mortality risk. Interdialytic ambulatory SBP is more strongly associated with risk. Hypertension is multifactorial; key causes include persistent hypervolemia and elevated peripheral resistance. With 3 HD sessions per week, blood pressure (BP) climbs during the interdialytic interval, in step with interdialytic weight gain, particularly among elderly patients and those with higher dry weight. Elevated peripheral resistance can be attributed to inappropriate activation of the sympathetic nervous system due to higher plasma norepinephrine concentrations. Multiple randomized clinical trials show that intensive HD reduces BP and the need for oral medications indicated for hypertension. In the first 2 months of the Frequent Hemodialysis Network trial, the short daily schedule reduced predialysis SBP by 7.7mmHg, whereas the nocturnal schedule reduced predialysis SBP by 7.3mmHg, both relative to 3 sessions per week. Improvements were sustained after 12 months. Both schedules reduced antihypertensive medication use relative to 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, the mean number of prescribed antihypertensive agents decreased from 1.7 to 1.0 in 1 year, whereas the percentage of patients not prescribed antihypertensive agents increased from 21% to 47%. Nocturnal HD appears to markedly reduce total peripheral resistance and plasma norepinephrine and restore endothelium-dependent vasodilation. In conclusion, intensive HD reduces BP and the need for antihypertensive medications. PMID- 27772640 TI - Intensive Hemodialysis, Mineral and Bone Disorder, and Phosphate Binder Use. AB - Mineral and bone disorder is a common complication of end-stage renal disease. Notably, hyperphosphatemia likely promotes calcification of the myocardium, valves, and arteries. Hyperphosphatemia is associated with higher risk for cardiovascular mortality and morbidity along a gradient beginning at 5.0mg/dL. Among contemporary hemodialysis (HD) patients, mean serum phosphorus level is 5.2mg/dL, although 25% of patients have serum phosphorus levels of 5.5 to 6.9mg/dL; and 13%, >7.0mg/dL. Treatment of hyperphosphatemia is burdensome. Dialysis patients consume a mean of 19 pills per day, half of which are phosphate binders. Medicare Part D expenditures on binders for dialysis patients approached $700 million in 2013. Phosphorus removal with thrice-weekly HD (4 hours per session) is ~3,000mg/wk. However, clearance is unlikely to counterbalance dietary intake, which varies around a mean of 7,000mg/wk. Dietary restriction and phosphate binders are important interventions, but each has limitations. Dietary control is complicated by limited access to healthy food choices and unclear labeling. Meanwhile, adherence to phosphate binders is poor, especially in younger patients and those with high pill burden. Multiple randomized clinical trials show that intensive HD reduces serum phosphorus levels. In the Frequent Hemodialysis Network (FHN) trial, short daily and nocturnal schedules reduced serum phosphorus levels by 0.6 and 1.6mg/dL, respectively, relative to 3 sessions per week. A similar effect of nocturnal HD was observed in an earlier trial. In the daily arm of the FHN trial, intensive HD significantly lowered estimated phosphate binder dose per day, whereas in the nocturnal arm, intensive HD led to binder discontinuation in 75% of patients. However, intensive HD appears to have no meaningful effects on serum calcium and parathyroid hormone concentrations. In conclusion, intensive HD, especially nocturnal HD, lowers serum phosphorus levels and decreases the need for phosphate binders. PMID- 27772642 TI - Intensive Hemodialysis and Treatment Complications and Tolerability. AB - Hemodialysis (HD) treatment can be difficult to tolerate. Common complications are intradialytic hypotension (IDH) and long time to recovery after an HD session. IDH, as defined by nadir systolic blood pressure < 90mmHg and intradialytic decline > 30mmHg, occurs in almost 8% of HD sessions. IDH may be caused by aggressive ultrafiltration in response to interdialytic weight gain, can lead to myocardial stunning and cardiac arrhythmias, and is associated with increased risk for death. Long recovery time after a treatment session is also common. In DOPPS (Dialysis Outcomes and Practice Patterns Study), recovery time was 2 to 6 hours for 41% of HD patients and longer than 6 hours for 27%; recovery time was linearly associated with increased risks for death and hospitalization. Importantly, both decreases in blood pressure and feeling washed out or drained have been identified by patients as more important outcomes than death or hospitalization. Intensive HD likely reduces the likelihood of IDH. In the Frequent Hemodialysis Network trial, short daily and nocturnal schedules reduced the per-session probability of IDH by 20% and 68%, respectively, relative to 3 sessions per week. Due to lower ultrafiltration volume and/or rate, intensive HD may reduce intradialytic blood pressure variability. In a cross-sectional study, short daily and nocturnal schedules were associated with slower ultrafiltration and less dialysis-induced myocardial stunning than 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, recovery time was reduced after 12 months from 8 hours to 1 hour, according to per-protocol analysis. Recovery time after nocturnal HD may be minutes. In conclusion, intensive HD can improve the tolerability of HD treatment by reducing the risk for IDH and decreasing recovery time after HD. These changes may improve the patient centeredness of end-stage renal disease care. PMID- 27772641 TI - Intensive Hemodialysis and Health-Related Quality of Life. AB - Diminished health-related quality of life (HRQoL) is common in dialysis patients and associated with increased risks for morbidity and mortality. Patients may present limitations in both physical and mental HRQoL. Poor physical HRQoL may be defined by limited physical function, role limitations due to physical health, dissatisfaction with physical ability, and impaired mobility. Sleep disorders such as obstructive sleep apnea, restless legs, and fatigue are typical manifestations of poor physical HRQoL in dialysis patients. Poor mental HRQoL may be defined by depressive thinking, lack of positive affect, anxiety, and feelings of social isolation. The prevalence of depression is high in dialysis patients. Intensive hemodialysis (HD) can positively address HRQoL. In 3 randomized clinical trials, relative to conventional HD, intensive HD increased physical and mental component summary scores from the 36-Item Short-Form Health Survey (SF 36), although individual treatment effects of daily nocturnal HD were not statistically significant. In another large prospective study, initiation of short daily HD therapy was followed after 12 months by improvements in all SF-36 domains, sleep quality, and restless legs symptoms. In a small study of nocturnal HD, apnea and hypopnea episodes per hour decreased by almost 70% after conversion from conventional HD. Intensive HD is also associated with a large reduction in postdialysis recovery time. In contrast, 2 randomized clinical trials failed to demonstrate statistically significant effects of intensive HD on the Beck Depression Inventory score despite a significant decrease in Beck Depression Inventory score in the prospective study of short daily HD. Furthermore, intensive HD may not improve objective physical performance and can increase burden on caregivers in the home setting. In conclusion, intensive HD potentially can address both physical and mental aspects of poor HRQoL relative to conventional HD. However, more studies are needed to understand the effects of intensive HD, including specific schedules, on HRQoL. PMID- 27772643 TI - Intensive Hemodialysis, Left Ventricular Hypertrophy, and Cardiovascular Disease. AB - The prevalence of cardiovascular disease, including cardiac arrhythmia, coronary artery disease, cardiomyopathy, and valvular heart disease, is higher in hemodialysis (HD) patients than in the US resident population. Cardiovascular disease is the leading cause of death in HD patients and the principal discharge diagnosis accompanying 1 in 4 hospital admissions. Furthermore, the rate of hospital admissions for either heart failure or fluid overload is persistently high despite widespread use of beta-blockers and renin-angiotensin system inhibitors and attempts to manage fluid overload with ultrafiltration. An important predictor of cardiovascular mortality and morbidity in dialysis patients is left ventricular hypertrophy (LVH). LVH is an adaptive response to increased cardiac work, typically caused by combined pressure and volume overload, resulting in cardiomyocyte hypertrophy and increased intercellular matrix. In new dialysis patients, the prevalence of LVH is 75%. Regression of LVH may reduce cardiovascular risk, including the incidence of heart failure, complications after myocardial infarction, and sudden arrhythmic death. Multiple randomized clinical trials show that intensive HD reduces left ventricular mass, a measure of LVH. Short daily and nocturnal schedules in the Frequent Hemodialysis Network trial reduced left ventricular mass by 14 (10%) and 11 (8%) g, respectively, relative to 3 sessions per week. Comparable efficacy was observed in an earlier trial of nocturnal HD. Intensive HD also improves cardiac rhythm. Clinical benefits have been reported only in observational studies. Daily home HD is associated with 17% and 16% lower risks for cardiovascular death and hospitalization, respectively; admissions for cerebrovascular disease, heart failure, and hypertensive disease, which collectively constitute around half of cardiovascular hospitalizations, were less likely with daily home HD. Relative to peritoneal dialysis, daily home HD is likewise associated with lower risk for cardiovascular hospitalization. In conclusion, intensive HD likely reduces left ventricular mass and may lead to lower risks for adverse cardiac events. PMID- 27772644 TI - Intensive Hemodialysis and Potential Risks With Increasing Treatment. AB - Although intensive hemodialysis (HD) can address important clinical problems, increasing treatment also introduces risks. In this review, we assess risks pertaining to 6 domains: vascular access complications, infection, mortality, loss of residual kidney function, solute balance, and patient and care partner burden. In the Frequent Hemodialysis Network (FHN) trials, short daily and nocturnal schedules increased the incidence of access complications, although the incidence of access loss was not statistically higher. Observational studies indicate that infection-related hospitalization is an ongoing challenge with short daily HD. Excess risk may be catalyzed by poor infection control practices in the home setting in which intensive HD is typically delivered, but with fixed probability of bacterial contamination per cannulation, greater treatment frequency necessarily increases the risk for infectious complications. Buttonhole cannulation may increase the risk for metastatic infections. However, intensive HD in the home setting is associated with lower risk for infection than peritoneal dialysis. Data regarding mortality are equivocal. With extended follow up of individuals in the FHN trials, short daily HD was associated with lower risk relative to the usual schedule, whereas nocturnal HD was associated with higher risk. In many, but not all, observational studies, short daily HD has been associated with lower risk than both in-center HD and peritoneal dialysis; however, observational studies are subject to unmeasured confounding. Intensive HD can accelerate the loss of residual kidney function in new dialysis patients with substantial urine output and can deplete solutes (eg, phosphorus) to the extent that supplementation is necessary. Finally, intensive HD may increase burden on patients and caregivers, possibly leading to technique failure. Some of these problems might be addressed with careful monitoring, so that relevant interventions (eg, antibiotics, retraining, and respite care) can be delivered. Ultimately, intensive HD is not a panacea for end-stage renal disease. Potential benefits and risks of treatment should be jointly considered. PMID- 27772645 TI - Corneal Cross-linking for Keratoconus: A Look at the Data, the Food and Drug Administration, and the Future. PMID- 27772646 TI - Big Data and Uveitis. PMID- 27772647 TI - Cystic Compound Melanocytic Nevus in a Pediatric Patient. PMID- 27772648 TI - Retinal Macroaneurysm in Long-Standing Hypertension. PMID- 27772649 TI - Scleritis with Devastating Consequences. PMID- 27772651 TI - Corrigendum. PMID- 27772650 TI - Tubular Apocrine Adenoma in Association with an Apocrine Hidrocystoma. PMID- 27772652 TI - Re: Jonas et al.: Cognitive function and subfoveal choroidal thickness: The Beijing Eye Study (Ophthalmology 2016;123:220-2). PMID- 27772653 TI - Reply. PMID- 27772654 TI - Re: Li et al.: Comparative effectiveness of first-line medications for primary open-angle glaucoma: a systematic review and network meta-analysis (Ophthalmology 2016;123:129-40). PMID- 27772655 TI - Re: Sharma et al.: Adjuvant role of amniotic membrane transplantation in acute ocular Stevens-Johnson syndrome: a randomized control trial (Ophthalmology 2016;123:484-91). PMID- 27772656 TI - Reply. PMID- 27772657 TI - Re: Raman et al.: Five-year incidence and visual outcomes in postintravitreal injection endophthalmitis (Ophthalmology 2016;123:1162-4). PMID- 27772658 TI - Reply. PMID- 27772659 TI - Reply. PMID- 27772660 TI - Do We Need More Measures of Bullying? PMID- 27772662 TI - Preventing and Treating Adolescent Obesity: A Position Paper of the Society for Adolescent Health and Medicine. PMID- 27772663 TI - Erratum. PMID- 27772661 TI - Psychological Factors Influencing the Decision of Urban Adolescents With Undiagnosed Asthma to Obtain Medical Care. AB - PURPOSE: Adolescents are low users of medical care. Psychological factors and perceived reasons to not seek routine medical care may increase risk of nonuse by adolescents with undiagnosed asthma. This study tests if psychological factors were associated with seeing a medical provider for asthma-like symptoms; identifies adolescents' perceived reasons for not obtaining care; explores if psychological factors are associated with these perceptions; and explores if asthma severity moderates the relationships with psychological factors. METHODS: We analyzed cross-sectional data from a baseline assessment of 349 urban, primarily ethnic minority adolescents with moderate to severe asthma-like symptoms but no asthma diagnosis who were enrolled in a controlled trial. RESULTS: The odds of seeing a provider for their asthma-like symptoms were significantly higher for those with asthma-related anxiety (odds ratio [OR]: 1.644; 95% confidence interval [CI]: 1.242-2.176) and depressive symptoms (OR: 1.031; 95% CI: 1.004-1.059). The most commonly endorsed reason for noncare included a characterization of symptoms as not serious, past medical visits not diagnosed as asthma, fear of diagnosis, busy lifestyles, and not wanting medication. Psychological factors were not related to the number of reasons or to most of the commonly endorsed reasons. Adolescents with more asthma-related anxiety were less likely to characterize their breathing problems as serious (OR = .0583; 95% CI: .424-.802) and were more likely to report busy lifestyles (OR = 1.593; 95% CI: 1.122-2.261). CONCLUSIONS: Adolescent-perceived reasons for noncare were not pragmatic, but instead highlighted denial. Asthma-related anxiety was the most robust psychological factor associated with the decision to seek medical care. PMID- 27772664 TI - Follow-Up of Electrocardiographic Findings and Arrhythmias in Patients With Anomalously Arising Left Coronary Artery from the Pulmonary Trunk. AB - Follow-up data and correlation of arrhythmias, electrocardiogram (ECG) changes, and cardiac function in anomalous left coronary artery from the pulmonary trunk or artery have not been previously studied. This is a retrospective single-center review of 44 anomalous left coronary artery from the pulmonary trunk or artery patients diagnosed between 1992 and 2014, at a median age of 3 months (3 days to 13 years). Clinical history, ECG, Holter, and echocardiogram data were reviewed. ECGs were reviewed for contiguous Q-or T-wave inversions, hypertrophy, bundle branch block, and axis deviation. High-grade ventricular ectopy, supraventricular tachycardia (SVT), and ventricular tachycardia (VT) were recorded. Patients with <6 months of clinical follow-up were excluded from longitudinal analysis. At diagnosis, 43 (98%) were noted to have electrocardiographic changes. During hospitalization, arrhythmias were seen in 13 patients (30%): 2 (5%) with sustained VT or ventricular fibrillation, 6 (17%) with high-grade ventricular ectopy, and 4 (9%) with SVT. Seven patients (16%) required antiarrhythmic treatment. During outpatient follow-up, arrhythmias were seen in 11 patients. New arrhythmias were documented in 6 without a history of in-hospital arrhythmias. Of 34 patients with at least 6 months follow-up (median 6 years, 0.5 to 20 years), 20 had left ventricular (LV) dysfunction before surgery. Normalization of function occurred in 94% (median 1 year, 5 days to 4 years). Electrocardiographic changes persisted in 94% at the time of LV function recovery. In conclusion, electrocardiographic changes and arrhythmias may persist despite recovery of ventricular function. Therefore, prolonged myocardial remodeling may continue even after resolution of LV dysfunction during which time arrhythmias may occur. PMID- 27772666 TI - Introduction to Special Issue on Bladder Control in Neurological Diseases. PMID- 27772665 TI - [Reconciliating neurology and psychiatry: The prototypical case of frontotemporal dementia]. AB - Frontotemporal degeneration (FTD) in its behavioral variant (bvFTD) is probably one of the conditions that best illustrates the links between psychiatry and neurology. It is indeed admitted that between a third and half of patients with this condition, especially in early-onset forms, receive an initial diagnosis of psychiatric disorder (depression, schizophrenia, bipolar disorder) and are then referred to a psychiatric ward. BvFTD can thus be considered a neurological disorder with a psychiatric presentation. Among psychiatric symptoms reported in this disease, psychotic symptoms (hallucinations, delusions, especially of persecution), which have long been underestimated in bvFTD and are not part of the current diagnostic criteria, are present in about 20% of cases and may be inaugural. They are particularly common in the genetic forms related to a mutation in the C9orf72 gene (up to 50%), and to a lesser extent in the GRN gene (up to 25%). C9orf72 gene mutation is often associated with a family history of dementia or motor neuron disease but also of psychiatric disorders. It has also been described in sporadic presentation forms. Sometimes, the moderate degree of brain atrophy on MRI described in patients carrying this mutation may complicate the differential diagnosis with late-onset psychiatric diseases. In the present article, we underline the importance of considering that psychiatric - especially psychotic - symptoms are not rare in bvFTD, which should lead to a revision of the diagnostic criteria of this disease by taking greater account of this fact. We also propose a diagnostic chart, based on concerted evaluation by neurologists and psychiatrists for cases of atypical psychiatric symptoms (late-onset or pharmacoresistant troubles) leading to consider the possibility of a neurological disorder, in order to shed a new light on these difficult clinical situations. In the field of research, bvFTD may constitute a model to explore the neural basis of certain psychiatric disorders, and a possible molecular link between bvFTD and psychoses, which could eventually lead to new therapeutic approaches, has been recently suggested. Thus, bvFTD illustrates how the links between neurology and psychiatry are close and tend to evolve with the progress of scientific knowledge. It is necessary to strengthen collaboration between the two disciplines both to improve the care - diagnosis and management of these patients - and to promote the emergence of innovative clinical research. PMID- 27772667 TI - Heart, lung, and vascular registries: Evolving goals, successful approaches, and ongoing innovation. PMID- 27772668 TI - The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. PMID- 27772670 TI - The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. PMID- 27772669 TI - The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart-Lung Transplant Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. PMID- 27772671 TI - The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Lung and Heart-Lung Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. PMID- 27772672 TI - Young Man With Severe Abdominal Pain. PMID- 27772673 TI - Male With Pain in His Neck. PMID- 27772675 TI - Commentary. PMID- 27772674 TI - Geolocalization of Influenza Outbreak Within an Acute Care Population: A Layered Surveillance Approach. AB - STUDY OBJECTIVE: We seek to use a novel layered-surveillance approach to localize influenza clusters within an acute care population. The first layer of this system is a syndromic surveillance screen to guide rapid polymerase chain reaction testing. The second layer is geolocalization and cluster analysis of these patients. We posit that any identified clusters could represent at-risk populations who could serve as high-yield targets for preventive medical interventions. METHODS: This was a prospective observational surveillance study. Patients were screened with a previously derived clinical decision guideline that has a 90% sensitivity and 30% specificity for influenza. Patients received points for the following signs and symptoms within the past 7 days: cough (2 points), headache (1 point), subjective fever (1 point), and documented fever at triage (temperature >38 degrees C [100.4 degrees F]) (1 point). Patients scoring 3 points or higher were indicated for influenza testing. Patients were tested with Xpert Flu (Cepheid, Sunnyvale, CA), a rapid polymerase chain reaction test. Positive results were mapped with ArcGIS (ESRI, Redlands, CA) and analyzed with kernel density estimation to create heat maps. RESULTS: There were 1,360 patients tested with Xpert Flu with retrievable addresses within the greater Phoenix metro area. One hundred sixty-seven (12%) of them tested positive for influenza A and 23 (2%) tested positive for influenza B. The influenza A virus exhibited a clear cluster pattern within this patient population. The densest cluster was located in an approximately 1-square-mile region southeast of our hospital. CONCLUSION: Our layered-surveillance approach was effective in localizing a cluster of influenza A outbreak. This region may house a high-yield target population for public health intervention. Further collaborative efforts will be made between our hospital and the Maricopa County Department of Public Health to perform a series of community vaccination events before the next influenza season. We hope these efforts will ultimately serve to reduce the burden of this disease on our patient population, and that this system will serve as a framework for future investigations locating at-risk populations. PMID- 27772676 TI - Just Listen: You Will Truly Be Amazed at All That You Can Hear. PMID- 27772677 TI - Gut Feelings. PMID- 27772678 TI - Would You Like Fries With That? PMID- 27772679 TI - One and Done: Steroids for Adult Asthma: November 2016 Annals of Emergency Medicine Journal Club. PMID- 27772680 TI - Child With Sore Throat. PMID- 27772682 TI - Aortic Dissection! Or Is It? Sigh. PMID- 27772681 TI - Adolescent Athlete With Sudden Groin Pain. PMID- 27772683 TI - The Importance of an Accurate Diagnosis for Renal Colic. PMID- 27772684 TI - In reply. PMID- 27772685 TI - Coronary Computed Tomography Angiography for Low-Risk Chest Pain. PMID- 27772686 TI - Mandatory Electronic Prescriptions Are a Hazard to the Health of Emergency Department Patients. PMID- 27772687 TI - In reply. PMID- 27772688 TI - Elderly Male With Mass on Right Thumb. PMID- 27772689 TI - Young Man With Epigastric Pain. PMID- 27772690 TI - Male With Hypertension. PMID- 27772691 TI - Neonate With a Swollen Thigh. PMID- 27772692 TI - The Letter 'P' and Pediatric Advocacy. PMID- 27772693 TI - Meaningful Research. PMID- 27772694 TI - A Practical Application of Educational Theories in Developing a Boot Camp Program for Pediatric Critical Care Fellows. PMID- 27772695 TI - Quality Improvement in Primary Care for Children: Interest and Desire, but Lack of Action. PMID- 27772696 TI - Ameliorating Maternal Depression and Its Harmful Consequences for Low-Income Families: Primary Care to the Rescue? PMID- 27772697 TI - Editorial. PMID- 27772699 TI - Comparison of ectopic bone formation process induced by four calcium phosphate ceramics in mice. AB - Phase composition played a key role in the biodegradation of calcium phosphate ceramics (CaP), which in turn influences the osteoinductive ability. The in vivo biological mechanism is still poorly understood. In this study, four types of porous CaP ceramics were investigated, namely, hydroxyapatite (HA), beta tricalcium phosphate (TCP), and biphasic calcium phosphates BCP1 and BCP2, with HA to beta-TCP ratios of 70/30 and 30/70, respectively. The four types of ceramics were implanted into thigh muscle of mice for 16weeks. Longitudinal ectopic bone formation process at gene, protein, and tissue level induced by the material was assessed. Histological analysis revealed that BCP2 was the only group that had promoted new bone formation after 16weeks. In micro-CT analysis of biodegradation, the BCP2 group had the least increment of porosity due to the new bone formation, resulting in a significant elevation in material density. Instead of a steady increase, multiple peaks were observed in most of the temporal gene expression patterns. The gene expression results were further confirmed by immunohistochemical staining of the corresponding proteins. Among the target genes, Osterix and type I collagen were activated successively. The osteoinductive BCP2 group showed earlier and significantly higher peaks in BMP2, BMPR1A, and OPG expressions than non-bone forming groups. These findings revealed that the occurrence time and magnitude of these osteogenetic gene expression peaks can be crucial in the osteoinduction process. PMID- 27772700 TI - Fabrication of silver nanowires-loaded polydimethylsiloxane film with antimicrobial activities and cell compatibility. AB - Microbial contamination on various surfaces is one of the greatest health problems worldwide, afflicting millions of peoples annually. Given the advantages of silver nanowires (AgNWs) in forming a percolated network when fabricated into a film, there is significant interest in developing AgNWs loaded polymeric coatings for antimicrobial applications. In this work, AgNWs with high aspect ratio are drop-coated onto a silicon wafer to form a uniform interconnected network. The AgNW network is then embedded into polydimethylsiloxane (PDMS) matrix to fabricate AgNWs/PDMS film. The PDMS loaded with various amounts of AgNWs can efficiently destroy Escherichia coli and Staphylococcus aureus bacteria, and PDMS with 0.2mg of AgNW loading (i.e. 50MUgcm-2) exhibit excellent cell compatibility. Furthermore, AgNWs/PDMS films show a long-term antibacterial effect for at least one month. The utilization of AgNWs in polymeric coatings provides a novel platform to reduce the microorganism infection. PMID- 27772698 TI - Comparison of Ambulatory, High-Dose, Intravenous Diuretic Therapy to Standard Hospitalization and Diuretic Therapy for Treatment of Acute Decompensated Heart Failure. AB - Innovative treatment strategies for decompensated heart failure (HF) are required to achieve cost savings and improvements in outcomes. We developed a decision analytic model from a hospital perspective to compare 2 strategies for the treatment of decompensated HF, ambulatory diuretic infusion therapy, and hospitalization (standard care), with respect to total HF hospitalizations and costs. The ambulatory diuretic therapy strategy included outpatient treatment with high doses of intravenous loop diuretics in a specialized HF unit whereas standard care included hospitalization for intravenous loop diuretic therapy. Model probabilities were derived from the outcomes of patients who were treated for decompensated HF at Brigham and Women's Hospital (Boston, MA). Costs were based on Centers for Medicare and Medicaid reimbursement and the available reports. Based on a sample of patients treated at our institution, the ambulatory diuretic therapy strategy was estimated to achieve a significant reduction in total HF hospitalizations compared with standard care (relative reduction 58.3%). Under the base case assumptions, the total cost of the ambulatory diuretic therapy strategy was $6,078 per decompensation episode per 90 days compared with $12,175 per 90 days with standard care, for a savings of $6,097. The cost savings associated with the ambulatory diuretic strategy were robust against variation up to 50% in costs of ambulatory diuretic therapy and the likelihood of posttreatment hospitalization. An exploratory analysis suggests that ambulatory diuretic therapy is likely to remain cost saving over the long-term. In conclusion, this decision analytic model demonstrates that ambulatory diuretic therapy is likely to be cost saving compared with hospitalization for the treatment of decompensated HF from a hospital perspective. These results suggest that implementation of outpatient HF units that provide ambulatory diuretic therapy to well-selected subgroup of patients may result in significant reductions in health care costs while improving the care of patients across a variety of health care settings. PMID- 27772701 TI - Metal nanostructures for non-enzymatic glucose sensing. AB - This review covers the recent development of metal nanostructures in electrochemical non-enzymatic glucose sensing. It highlights a variety of nanostructured materials including noble metals, other transition metals, bimetallic systems, and their hybrid with carbon-based nanomaterials. Particularly, attention is devoted to numerous approaches that have been implemented for improving the sensors performance by tailoring size, shape, composition, effective surface area, adsorption capability and electron-transfer properties. The correlation of the metal nanostructures to the glucose sensing performance is addressed with respect to the linear concentration range, sensitivity and detection limit. In overall, this review provides important clues from the recent scientific achievements of glucose sensor nanomaterials which will be essentially useful in designing better and more effective electrocatalysts for future electrochemical sensing industry. PMID- 27772702 TI - PEG-based autonomous capillary system with integrated microbead array for immunoassay. AB - Surface-tension-driven capillary systems (CSs) enable self-powered delivery of samples and reagents for bioassays and thus are especially suitable for point-of care applications. Current silicon and polymer based CSs require extensive work in professional cleanroom for the fabrication of either the silicon device itself or the micromold for polymer processing. In this work, we fabricated a PEG-based CS in a one-step photopolymerization process without the requirement of any cleanroom work. Water, buffer and serum can flow autonomously in this CS and the liquid flow rate can be tuned by modification with surfactant solution of different concentrations. We further integrated an antibody-coated microbead array into this CS for the autonomous immunoassay of two tumor markers, prostate specific antigen (PSA) and human chorionic gonadotropin (hCG), in serum samples with a total assay time of less than 10min. The detection limits for the two tumor markers were at sub-nanogram per milliliter range which is lower than their clinical threshold concentrations for cancer diagnosis. Moreover, simultaneous and multiplex detection of the two tumor markers was also achieved by using spatially encoded microbeads. This low cost and easy-fabricated CS enables fast, multiplex and autonomous immunoassay for protein markers and has the potential to be applied for point-of-care diagnostics on real clinical samples. PMID- 27772703 TI - Nanomaterials for delivery of nucleic acid to the central nervous system (CNS). AB - Billions of dollars have been invested in the therapeutic application of nucleic acid-based agents in humans in recent years. There are inspirable data from ongoing clinical trial for different diseases. However, in order to widely apply nucleic acid in prevention, diagnosis and treatment of age-related disease, such as neurodegeneration and disorders, suitable, safe and effective drug delivery nanocarriers have to been developed to overcome the blood brain barrier (BBB), which is the most inflexible barrier in human body. Here, we highlight the structure and function of barriers in the central nervous system (CNS) and summary several types of nanomaterials which can be potentially used in the brain delivery nucleic acid. PMID- 27772704 TI - Construction of surface HA/TiO2 coating on porous titanium scaffolds and its preliminary biological evaluation. AB - A simple approach to fabricating hydroxyxapatite/titanium dioxide (HA/TiO2) coating on porous titanium (Ti) scaffolds was developed in the present study. Surface TiO2 layer was firstly formed on porous Ti scaffolds with multi-scale pores by acid-alkali (AA) treatment. The outer HA layer was then formed on the TiO2 layer by subsequent pulse electrochemical deposition (ED) technique. All the three main process parameters, i.e. deposition times, current density and mass transfer mode affected the properties of the HA coating notably. Under the conditions of 90 deposition cycles, -10mA/cm2 of pulse current density and stirring, a thin layer of homogeneous and nanorod-like HA sediments was formed on the substrate surface of porous Ti scaffolds. The results of protein adsorption and cellular experiments showed that compared to the single TiO2 surface, the HA/TiO2 surface allowed more adsorption of serum proteins and further enhanced the alkaline phosphatase (ALP) activity of MC3T3-E1 osteoblasts. PMID- 27772705 TI - Bio-functionalization of biomedical metals. AB - Bio-functionalization means to endow biomaterials with bio-functions so as to make the materials or devices more suitable for biomedical applications. Traditionally, because of the excellent mechanical properties, the biomedical metals have been widely used in clinic. However, the utilized functions are basically supporting or fixation especially for the implantable devices. Nowadays, some new functions, including bioactivity, anti-tumor, anti-microbial, and so on, are introduced to biomedical metals. To realize those bio-functions on the metallic biomedical materials, surface modification is the most commonly used method. Surface modification, including physical and chemical methods, is an effective way to alter the surface morphology and composition of biomaterials. It can endow the biomedical metals with new surface properties while still retain the good mechanical properties of the bulk material. Having analyzed the ways of realizing the bio-functionalization, this article briefly summarized the bio functionalization concepts of six hot spots in this field. They are bioactivity, bony tissue inducing, anti-microbial, anti-tumor, anticoagulation, and drug loading functions. PMID- 27772706 TI - In vitro studying corrosion behavior of porous titanium coating in dynamic electrolyte. AB - Porous titanium (PT) is considered as a promising biomaterials for orthopedic implants. Besides biocompatibility and mechanical properties, corrosion resistance in physiological environment is the other important factor affecting the long stability of an implant. In order to investigate the corrosion behavior of porous titanium implants in a dynamic physiological environment, a dynamic circle system was designed in this study. Then a titanium-based implant with PT coating was fabricated by plasma spraying. The corrosion resistance of PT samples in flowing 0.9% NaCl solution was evaluated by electrochemical measurements. Commercial pure solid titanium (ST) disc was used as a control. The studies of potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) show that the pores in the PT play a negetive part in corrosion resistance and the flowing electrolyte can increase the corrosive rate of all titanium samples. The results suggest that pore design of titanium implants should pay attention to the effect of dynamic process of a physiological environment on the corrosion behavior of implants. PMID- 27772707 TI - Superparamagnetic nanocomposites based on surface imprinting for biomacromolecular recognition. AB - A combination strategy of moderate self-polymerization and assembly technique was proposed to fabricate superparamagnetic surface imprinted nanocomposites (SSINs) for efficient protein recognition. Homogeneous Fe3O4/Poly (methyl methacrylate) (PMMA)/Poly (dihydroxyphenylacetic acid) (PDOPA) SSINs were obtained via self polymerization of DOPA on the surface of Fe3O4/PMMA nanospheres in the presence of lysozyme (Lyz) as a template. The Lyz-imprinted Fe3O4/PMMA/PDOPA SSINs possessed average diameters of 200nm, high magnetic content, high saturation magnetization, as well as excellent specific recognition capacity toward Lyz template, exhibiting their great potential for biomacromolecular recognition. PMID- 27772708 TI - Microstructure, mechanical properties, bio-corrosion properties and cytotoxicity of as-extruded Mg-Sr alloys. AB - In this study, as-extruded Mg-Sr alloys were studied for orthopedic application, and the microstructure, mechanical properties, bio-corrosion properties and cytotoxicity of as-extruded Mg-Sr alloys were investigated by optical microscopy, scanning electron microscopy with an energy dispersive X-ray spectroscopy, X-ray diffraction, tensile and compressive tests, immersion test, electrochemical test and cytotoxicity test. The results showed that as-extruded Mg-Sr alloys were composed of alpha-Mg and Mg17Sr2 phases, and the content of Mg17Sr2 phases increased with increasing Sr content. As-extruded Mg-Sr alloy with 0.5wt.% Sr was equiaxed grains, while the one with a higher Sr content was long elongated grains and the grain size of the long elongated grains decreased with increasing Sr content. Tensile and compressive tests showed an increase of both tensile and compressive strength and a decrease of elongation with increasing Sr content. Immersion and electrochemical tests showed that as-extruded Mg-0.5Sr alloy exhibited the best anti-corrosion property, and the anti-corrosion property of as extruded Mg-Sr alloys deteriorated with increasing Sr content, which was greatly associated with galvanic couple effect. The cytotoxicity test revealed that as extruded Mg-0.5Sr alloy did not induce toxicity to cells. These results indicated that as-extruded Mg-0.5Sr alloy with suitable mechanical properties, corrosion resistance and good cytocompatibility was potential as a biodegradable implant for orthopedic application. PMID- 27772710 TI - Functionalization of 2D transition metal dichalcogenides for biomedical applications. AB - Recent research has revealed a gamut of interesting properties present in layered two-dimensional (2D) transition metal dichalcogenides (TMDCs) such as photoluminescence, comparatively high electron mobility, flexibility, mechanical strength and relatively low toxicity. The large surface to area ratio inherent in these materials also allows easy functionalization and maximal interaction with the external environment. Due to its unique physical and chemical properties, much work has been done in tailoring TMDCs through chemical functionalization for use in a diverse range of biomedical applications as biosensors, drug delivery carriers or even as therapeutic agents. In this review, current progress on the different types of TMDC functionalization for various biological applications will be presented and its future outlook will be discussed. PMID- 27772709 TI - Electrospinning of poly(glycerol sebacate)-based nanofibers for nerve tissue engineering. AB - Nerve tissue engineering (TE) requires biomimetic scaffolds providing essential chemical and topographical cues for nerve regeneration. Poly(glycerol sebacate) (PGS) is a biodegradable and elastic polymer that has gained great interest as a TE scaffolding biomaterial. However, uncured PGS is difficult to be electrospun into nanofibers. PGS would, therefore, require the addition of electrospinning agents. In this study, we modified PGS by using atom transfer radical polymerization (ATRP) to synthesize PGS-based copolymers with methyl methacrylate (MMA). The synthesized PGS-PMMA copolymer showed a molecular weight of 82kDa and a glass transition temperature of 115 degrees C. More importantly, the PGS-PMMA could be easily electrospun into nanofiber with a fiber diameter of 167+/-33nm. Blending gelatin into PGS-PMMA nanofibers was found to increase its hydrophilicity and biocompatibility. Rat PC12 cells were seeded onto the PGS PMMA/gelatin nanofibers to investigate their potential for nerve regeneration. It was found that gelatin-containing PGS-based nanofibers promoted cell proliferation. The elongated cell morphology observed on such nanofibers indicated that the scaffolds could induce the neurite outgrowth of the nerve stem cells. Overall, our study suggested that the synthesis of PGS-based copolymers might be a promising approach to enhance their processability, and therefore advancing bioscaffold engineering for various TE applications. PMID- 27772711 TI - Reactive blends based on polyhydroxyalkanoates: Preparation and biomedical application. AB - Polyhydroxyalkanoates (PHAs) are a class of natural polyesters as carbon and energy reserves by >300 species of microorganisms. They are fully biodegradable, biocompatible and piezoelectric biopolymers that have attracted much attention recently as the biomaterial of choice for medical applications. However, the toughness, processability and hydrophilicity of PHAs need to tune to expand their applications as tissue engineering scaffolds or drug delivery systems. Reactive polymer blending is one of the most economic and versatile way to produce materials combining the desired properties via forming the compatibilizing agents in situ or inducing the chemico-physical interactions between polymer blends. This review focuses on the PHAs-based reactive blends aiming to present a brief introduction to the mechanism of reactive polymer blending technique, including the formation of H-bonding, branching/crosslinking copolymers, graft copolymers or complex copolymers during polymer blending process. PMID- 27772712 TI - Hydrolytic conversion of amorphous calcium phosphate into apatite accompanied by sustained calcium and orthophosphate ions release. AB - The aim of this study is to investigate the calcium and orthophosphate ions release during the transformation of amorphous calcium phosphate (ACP) to hydroxyapatite (HA) in aqueous solution. The ACP is prepared by a wet chemical method and further immersed in the distilled water for various time points till 14d. The release of calcium and orthophosphate ions is measured with calcium and phosphate colorimetric assay kits, respectively. The transition of ACP towards HA is detected by x-ray diffraction (XRD), transmission electron microscopy (TEM), and fourier transform infrared spectroscopy (FTIR). The results indicate that the morphological conversion of ACP to HA occurs within the first 9h, whereas the calcium and orthophosphate ions releases last for over 7d. Such sustained calcium and orthophosphate ions release is very useful for ACP as a candidate material for hard tissue regeneration. PMID- 27772713 TI - Preparation of polymer/calcium phosphate porous composite as bone tissue scaffolds. AB - Composite scaffolds, especially polymer/calcium phosphate composite scaffolds with porous structures are promising materials for bone tissue engineering. Depositing minerals on the surface of polymer scaffolds is a general method however, attachment between inorganic minerals and organic polymeric is a big challenge, because of the absence of strong interactions between the interfaces. In this work, polymer/calcium phosphate composite scaffolds with good attachment were fabricated through introduction of calcium and alternate mineralization. Calcium methacrylate was polymerized into the polymer scaffold and calcium acted as "ion glue" endowing the polymer/calcium phosphate composite good interfacial interaction. After alternate mineralization, the surface of polymer scaffold with calcium was coated with plate-like minerals which attached to polymer well and composite scaffold preserved the porous morphology. The results demonstrated that the concept of "ion glue" provided an option for the improvement of attachment between inorganic minerals and organic polymer. The results also indicated that the good attachment of minerals with polymer scaffolds enhanced the mechanical properties and improved the cell attachment of the polymer scaffolds. PMID- 27772714 TI - NECL1 coated PLGA as favorable conduits for repair of injured peripheral nerve. AB - Restoration of normal neurological function of transected peripheral nerve challenged regenerative medicine and surgery. Previous studies showed that Nectin like molecule 1 (NECL1) is one of the important adhesion molecules on the axons and Schwann cells is located along the internodes in direct apposition to NECL1. In this study, we fabricated PLGA membrane pre-coated with NECL1, mimicking the natural axons to enhance the adhesion of Schwann cells. Investigation of the cellular response in vitro was performed by detecting cytotoxicity, proliferation, morphology, viability, specific markers and Scanning Electron Microscopy (SEM) of Schwann cells cultured in PLGA. Further, the NECL1-coated PLGA conduits were used for peripheral nerve repair after sciatic nerve defect was constructed. Results showed that PLGA-coated NECL1 enhanced cell proliferation compared with PLGA, as evidenced by MTT analysis, cell viability assay and histological evaluation. RT-PCR results showed that GDNF (glial cell line-derived neurotrophic factor), BDNF (brain-derived neurotrophic factor), CNTF (ciliary neurotrophic factor) and neurotrophic factors of axonal regeneration were highly expressed in PLGA/NECL1 group. S100, which is Schwann cell marker, was also elevated in PLGA-NCEL1 in both mRNA and protein expression as demonstrated by PCR and immunohistochemical examination. Moreover, in vivo study showed that implantation of PLGA/NCEL1 tubes in bridging the nerve defect can significantly improve Schwann cell aggregation and attachment and greatly enhance the functional recovery of nerve regeneration as compared with control and PLGA groups. Therefore, the novel blend of PLGA/NECL1 conduits proved to be promising candidate for tissue engineering scaffold. PMID- 27772715 TI - Sequential coating upconversion NaYF4:Yb,Tm nanocrystals with SiO2 and ZnO layers for NIR-driven photocatalytic and antibacterial applications. AB - ZnO is one of the most promising materials for both photocatalytic and antibacterial applications, but its wide bandgap requires the excitation of UV light which limits their applications under visible and NIR bands. Herein, we demonstrate a facile approach to synthesize core-shell-shell hybrid nanoparticles consisting of hexagonal NaYF4:Yb,Tm, amorphous SiO2 and wurtzite ZnO. The upconversion nanocrystals are used as the core seeds and sequentially coated with an insulting shell and a semiconductor layer. Such hybrid nanoparticles can efficiently utilize the NIR light through the upconverting process, and display notable photocatalytic performance and antibacterial activity under NIR irradiation. The developed NaYF4:Yb,Tm@SiO2@ZnO nanoparticles are characterized with TEM, XRD, EDS, XPS and PL spectra, and their working mechanism is also elucidated. PMID- 27772716 TI - Uniformly-dispersed nanohydroxapatite-reinforced poly(epsilon-caprolactone) composite films for tendon tissue engineering application. AB - Regeneration of injuries at tendon-to-bone interface (TBI) remains a challenging issue due to the complex tissue composition involving both soft tendon tissues and relatively hard bone tissues. Tissue engineering using polymeric/ceramic composites has been of great interest to generate scaffolds for tissue's healing at TBI. Herein, we presented a novel method to blend polymers and bioceramics for tendon tissue engineering application. A homogeneous composite comprising of nanohydroxyapatite (nHA) particles in poly(epsilon-caprolactone) (PCL) matrix was obtained using a combination of solvent and mechanical blending process. X-ray diffraction analysis showed that the as-fabricated PCL/nHA composite film retained phase-pure apatite and semi-crystalline properties of PCL. Infrared spectroscopy spectra confirmed that the PCL/nHA composite film exhibited the characteristics functional groups of PCL and nHA, without alteration to the chemical properties of the composite. The incorporation of nHA resulted in PCL/nHA composite film with improved mechanical properties such as Young's Modulus and ultimate tensile stress, which were comparable to that of the native human rotator tendon. Seeding with human tenocytes, cells attached on the PCL/nHA composite film, and after 14days of culturing, these cells could acquire elongated morphology without induced cytotoxicity. PCL/nHA composite film could also result in increased cell metabolism with prolonged culturing, which was comparable to that of the PCL group and higher than that of the nHA group. All these results demonstrated that the developed technique of combining solvent and mechanical blending could be applied to fabricate composite films with potential for tendon tissue engineering applications. PMID- 27772717 TI - Role of electrostatic complementarity between perylenediimide and porphyrin in highly stabilized GNA. AB - Relatively electron-deficient perylenediimide (PDI) and relatively electron-rich porphyrin (Por) were introduced into the middle of 16-mer glycol nucleic acid (GNA), and up to five consecutive chromophores were arranged in the zipper-like interstrand alternating fashion. Remarkable variation for the CD spectra ascribed to chromophores was observed, and bathochromic shift in the UV/Vis absorption region of chromophores occurred upon duplex formation. Interestingly, zipper-like heteroaggregates of chromophores inside had marvelous positive effects on the stabilization of the duplex, Tm of Por-PDI-Por sandwich-type modified GNA duplex was increased by 24 degrees C in comparison with three A-T base pairs, moreover, Por-PDI-Por-PDI-Por interstrand modified GNA duplex was even stabilized by 25 degrees C in replacement of five A-T base pairs. The specificity of high duplex stability might be driven by the strong hydrophobic electrostatic complementarity between PDI and Por face-centered stacking. PMID- 27772718 TI - Controlling cell adhesion using layer-by-layer approaches for biomedical applications. AB - Controlling the adhesion of mammalian and bacterial cells at the interfaces between synthetic materials and biological environments is a real challenge in the biomedical fields such as tissue engineering, antibacterial coating, implantable biomaterials and biosensors. The surface properties of materials are known to profoundly influence the adhesion processes. To mediate the adhesion processes, polymeric coatings have been used to functionalize surfaces to introduce diverse physicochemical properties. The polyelectrolyte multilayer films built via the layer-by-layer (LbL) method, introduced by Moehwald, Decher, and Lvov 20years ago, has led to significant developments ranging from the fundamental understanding of cellular processes to controlling cell adhesion for biomedical applications. In this review, we focus our attention on the modification of surface physicochemical properties, using the LbL approach, to construct films which can either promote or inhibit mammalian/bacterial cell adhesion. We also discuss the emerging field of multifunctional surfaces capable of responding to specific cellular activity but being inert to the others. PMID- 27772719 TI - Photosensitive semiconducting polymer-incorporated nanofibers for promoting the regeneration of skin wound. AB - Photosensitive semiconducting polymer (SP) combined with light stimulation has shown the capability in promoting the proliferation of human dermal fibroblasts (HDFs). However, the high cytotoxicity of the used SP hindered its further application in bioactive scaffolds. In this contribution, we designed and synthesized a SP, poly (N,N-bis(2-octyldodecyl)-3,6-di(thiophen-2-yl)-2,5 dihydropyrrolo[3,4-c]pyrrole-1,4-dione-alt-thieno[3,2-b]thiophene) (PDBTT) with low cytotoxicity and strong absorbance in red and near-infrared region (600 1200nm). The photosensitive SP was then applied in electrospun poly(epsilon caprolactone) (PCL) nanofibrous scaffold and evaluated its proliferative effect on HDFs under the illumination from red light-emitting diode (LED) with high tissue penetration. After 9days of continuous stimulation, the hybrid electrospun PCL/PDBTT nanofibers with low cytotoxicity showed excellent support for HDFs adhesion, proliferation and collagen secretion than neat PCL nanofibers and HDFs on the stimulated PCL/PDBTT nanofibers gained typical spindle morphology, indicating the well cell spreading on the stimulated PCL/PDBTT nanofibers. The incorporation of functional materials within synthetic biomaterials could be a novel way in improving the performance of engineered tissue constructs by providing multiple cues (e.g. electrical stimulation) to the attached cells. PMID- 27772720 TI - Recent progress of atomic layer deposition on polymeric materials. AB - As a very promising surface coating technology, atomic layer deposition (ALD) can be used to modify the surfaces of polymeric materials for improving their functions and expanding their application areas. Polymeric materials vary in surface functional groups (number and type), surface morphology and internal structure, and thus ALD deposition conditions that typically work on a normal solid surface, usually do not work on a polymeric material surface. To date, a large variety of research has been carried out to investigate ALD deposition on various polymeric materials. This paper aims to provide an in-depth review of ALD deposition on polymeric materials and its applications. Through this review, we will provide a better understanding of surface chemistry and reaction mechanism for controlled surface modification of polymeric materials by ALD. The integrated knowledge can aid in devising an improved way in the reaction between reactant precursors and polymer functional groups/polymer backbones, which will in turn open new opportunities in processing ALD materials for better inorganic/organic film integration and potential applications. PMID- 27772721 TI - An improved polymeric sponge replication method for biomedical porous titanium scaffolds. AB - Biomedical porous titanium (Ti) scaffolds were fabricated by an improved polymeric sponge replication method. The unique formulations and distinct processing techniques, i.e. a mixture of water and ethanol as solvent, multiple coatings with different viscosities of the Ti slurries and centrifugation for removing the extra slurries were used in the present study. The optimized porous Ti scaffolds had uniform porous structure and completely interconnected macropores (~365.1MUm). In addition, two different sizes of micropores (~45.4 and ~6.2MUm) were also formed in the skeleton of the scaffold. The addition of ethanol to the Ti slurry increased the compressive strength of the scaffold by improving the compactness of the skeleton. A compressive strength of 83.6+/ 4.0MPa was achieved for a porous Ti scaffold with a porosity of 66.4+/-1.8%. Our cellular study also revealed that the scaffolds could support the growth and proliferation of mesenchymal stem cells (MSCs). PMID- 27772723 TI - Special issue: Biomedical applications editorial. PMID- 27772722 TI - Preparation of bioactive beta-tricalcium phosphate microspheres as bone graft substitute materials. AB - In this study, beta-tricalcium phosphate (Ca3PO4, beta-TCP) microspheres with different diameters were fabricated via a solid-in-oil-in-water (S/O/W) emulsion method. After soaking in simulated body fluid (SBF), the fabricated beta-TCP microspheres were fully covered with a new bone-like apatite layer; subsequent analysis suggested that the microspheres have excellent bioactivity properties, specifically in inducing apatite deposition. The calcium release profiles of the microspheres were tested in pH7.4 Tris-HCl buffer, and results demonstrated that the Ca2+ continually released from microspheres during the two-week test period. We then co-cultured bone marrow stem cells (BMSCs) in vitro with beta-TCP microspheres, and performed SEM and confocal microscope analyses to find that beta-TCP microspheres efficiently promoted BMSC attachment and bone-related gene expression. The co-cultured BMSCs and microspheres were successfully implanted subcutaneously into nude mice for 8weeks. The H&E neo-tissue staining results showed that abundant new bone-like structures had formed between the beta-TCP microspheres, implying that beta-TCP microspheres used as a cell carrier and bone graft substitute material show highly promising potential application for irregular-shaped bone defect regeneration. PMID- 27772724 TI - Nanodelivery systems for enhancing the immunostimulatory effect of CpG oligodeoxynucleotides. AB - Synthetic oligodeoxynucleotides containing immunostimulatory CpG motif mimic bacterial DNA and are potent activator of innate and adaptive immune responses. Therefore, CpG ODNs have significant potentials as immunotherapeutic agent for treatment of infectious diseases, allergy and cancer. Many clinical trials involving CpG ODNs either used alone or as adjuvant have been initiated. However, delivery of CpG ODNs to target sites still remains a great challenge due to their extreme susceptibility to nuclease degradation in serum and poor cellular uptake. Chemical modification of CpG ODNs backbone can protect them against degradation by nucleases, but have raised concern regarding several severe side effects. Development of efficient CpG ODNs delivery systems to address these issues and enhance their immunostimulatory effect are highly desirable. In recent years, the emergence of nanotechnology has provided unprecedented opportunities to encapsulate CpG ODN into various nanocarriers or synthesize CpG ODNs nanostructures. This review provides an overview of the delivery systems based on nanomaterials and nanostructures newly developed for enhancing the immunostimulatory effect of CpG ODNs, together with a brief discussion on perspectives for future studies in this field. PMID- 27772725 TI - Hierarchical self-assembly of heparin-PEG end-capped porous silica as a redox sensitive nanocarrier for doxorubicin delivery. AB - Porous nanosilica (PNS) has been attracting a great attention in fabrication carriers for drug delivery system (DDS). However, unmodified PNS-based carriers exhibited the initial burst release of loaded bioactive molecules, which may limit their potential clinical application. In this study, the surface of PNS was conjugated with adamantylamine (A) via disulfide bonds (PNS-SS-A) which was functionalized with cyclodextrin-heparin-polyethylene glycol (CD-HPEG) for redox triggered doxorubicin (DOX) delivery. The modified PNS was successfully formed with spherical shape and diameter around 50nm determined by transmission electron microscopy (TEM). DOX was efficiently trapped in the PNS-SS-A@CD-HPEG and slowly released in phosphate buffered saline (PBS) without any initial burst effect. Importantly, the release of DOX was triggered due to the cleavage of the disulfide bonds in the presence of dithiothreitol (DTT). In addition, the MTT assay data showed that PNS-SS-A@CD-HPEG was a biocompatible nanocarrier and reduced the toxicity of DOX. These results demonstrated that PNS-SS-A@CD-HPEG has great potential as a novel nanocarrier for anticancer drug in cancer therapy. PMID- 27772726 TI - Effect of apatite formation of biphasic calcium phosphate ceramic (BCP) on osteoblastogenesis using simulated body fluid (SBF) with or without bovine serum albumin (BSA). AB - Although biphasic calcium phosphate ceramic (BCP) holds promise in therapy of bone defect, surface mineralization prior to implantation may improve the bioactivity to better integrate with the host. Immersion in simulated body fluid (SBF) and bovine serum albumin-simulated body fluid (BSA-SBF) are common methods to form apatite interface layer. This study was intended to investigate the effect of SBF and BSA-SBF treatment on the bioactivity of BCP in vitro. In this study, osteoblasts were grown on BCP with or without treatment of SBF or BSA-SBF, and detected with general observation, scanning electron microscope (SEM), cell proliferation assay, morphology observation, viability assay, alkaline phosphatase (ALP) activity assay, and osteogenic specific gene expression of alkaline phosphatase (ALPL), bone gamma-carboxyglutamate (gla) protein (BGLAP), bone morphogenetic protein 2 (BMP2), bone sialoprotein (BSP), type I collagen (COLI) and runt-related transcription factor 2 (RUNX2) after culture of 2, 5 and 8days. As the results shown, BCP pre-incubated in SBF and BSA-SBF up-regulated ALP activity and osteogenic related genes and proteins, which testified the positive effect of SBF and BSA-SBF. Especially, BSA-SBF enhanced the cell growth significantly. This study indicated that treatment by BSA-SBF is of importance for BCP before clinical application. PMID- 27772727 TI - A scaffold-filter model for studying the chondrogenic differentiation of stem cells in vitro. AB - This study was undertaken to explore the synergistic effect of scaffold materials and a cartilage-like environment on the chondrogenic differentiation of stem cells. Because stem cells encapsulated in a cartilage scaffold will be induced by scaffold molecules as well as permeable molecules from the surroundings, it is impossible to optimize a chondro-inducible scaffold without considering environmental sensitivity. How do we know if a designed scaffold will be sufficient prior to implantation? In this study, bone marrow mesenchymal stem cells (bMSCs) were seeded in various scaffolds, including collagen hydrogel, collage/sodium alginate hydrogel, collagen sponge and silk fibroin sponge. The cell-scaffold complex was encapsulated in a filter pocket to avoid direct contact with co-cultured chondrocytes. Scaffolds differed in the ability to adsorb inducible molecules expressed by chondrocytes, as evidenced by various expressions of cartilage specific proteins and genes. Collagen hydrogel unexpectedly supported chondrogenic differentiation in an environment filled with chondrocytes secretion better than other reinforced scaffolds, which is consistent with the previous experiment in vivo. This result indicated that the environmental sensitivity of a scaffold is important for in vivo chondro induction. This in vitro scaffold-filter model may be useful as a precursor to investigate the chondro-inducing potential of various scaffolds for cartilage repair. PMID- 27772728 TI - Effect of inorganic/organic ratio and chemical coupling on the performance of porous silica/chitosan hybrid scaffolds. AB - Inorganic/organic hybrid scaffolds have great potential for tissue engineering applications due to controllable mechanical properties and tailorable biodegradation. Here, silica/chitosan hybrid scaffolds were fabricated through the sol-gel method with a freeze drying process. 3-Glycidoxypropyl trimethoxysilane (GPTMS) and tetraethylorthosilicate (TEOS) were used as the covalent inorganic/organic coupling agent and the separate inorganic source, respectively. Hybrid scaffolds with various inorganic/organic weight ratios (I/Os) and molar ratios of chitosan and GPTMS (GCs) were examined and compared in this study. FTIR showed that higher GPTMS content resulted in the increased covalent cross-linking of the chitosan and the silica network in hybrids. Compression testing indicated that increasing the GPTMS content greatly improved the compressive strength of scaffold. LIVE/DEAD assay showed that enhanced cytocompatibility was obtained as the silica content increased. Therefore, the results confirmed that the two parameters I/O and GC can largely influence the scaffold performance, which can be used to tailor the hybrid properties. PMID- 27772729 TI - Low-temperature deposition manufacturing: A novel and promising rapid prototyping technology for the fabrication of tissue-engineered scaffold. AB - Developed in recent years, low-temperature deposition manufacturing (LDM) represents one of the most promising rapid prototyping technologies. It is not only based on rapid deposition manufacturing process but also combined with phase separation process. Besides the controlled macropore size, tissue-engineered scaffold fabricated by LDM has inter-connected micropores in the deposited lines. More importantly, it is a green manufacturing process that involves non-heating liquefying of materials. It has been employed to fabricate tissue-engineered scaffolds for bone, cartilage, blood vessel and nerve tissue regenerations. It is a promising technology in the fabrication of tissue-engineered scaffold similar to ideal scaffold and the design of complex organs. In the current paper, this novel LDM technology is introduced, and its control parameters, biomedical applications and challenges are included and discussed as well. PMID- 27772730 TI - Regulation of the secretion of immunoregulatory factors of mesenchymal stem cells (MSCs) by collagen-based scaffolds during chondrogenesis. AB - In the latest decade, mesenchymal stem cells (MSCs) have wildly considered as a source of seeded cells in tissue engineering, not only because of its multi differentiation potentials, but also due to its immunoregulation ability. The main immunoregulatory features of MSCs could be divided into low self immunogenicity and secretion of soluble factors. In this study, we explored how scaffold structures modulated the secretion of soluble immunoregulatory factors in MSCs under an allogeneic cartilage tissue engineering background. MSCs were seeded in four different collagen-based scaffolds. Their proliferation, differentiation, and secretion of various soluble factors associated with the immunosuppressive effects were evaluated. In this study, qRT-PCR, ELISA and immunoregulation results showed a great variability of the factor secretion by MSCs seeded in scaffolds with different structures. Compared with two-dimensional (2D) monolayer culture condition, three-dimensional (3D) groups (hydrogels and sponge) could effectively promote the mRNA expression and the protein production of soluble immune-related factors. Also, the supernatants collected from 3D groups obviously showed inhibition on allogeneic lymphocyte activating. These results suggested that scaffold structures might modulate MSCs' secretion of soluble immunoregulatory factors, and our study might enlighten the scaffold designs for desired tissue regeneration to control the host immune rejection through immune-regulation reaction. PMID- 27772731 TI - Highly lipophilic pluronics-conjugated polyamidoamine dendrimer nanocarriers as potential delivery system for hydrophobic drugs. AB - In the study, four kinds of pluronics (P123, F68, F127 and F108) with varying hydrophilic-lipophilic balance (HLB) values were modified and conjugated on 4th generation of polyamidoamine dendrimer (PAMAM). The obtained results from FT-IR, 1H NMR and GPC showed that the pluronics effectively conjugated on the dendrimer. The molecular weight of four PAMAM G4.0-Pluronics and its morphologies are in range of 200.15-377.14kDa and around 60-180nm in diameter by TEM, respectively. Loading efficiency and release of hydrophobic fluorouracil (5-FU) anticancer drug were evaluated by HPLC; Interesting that the dendrimer nanocarrier was conjugated with the highly lipophilic pluronic P123 (G4.0-P123) exhibiting a higher drug loading efficiency (up to 76.25%) in comparison with another pluronics. Live/dead fibroblast cell staining assay mentioned that all conjugated nanocarriers are highly biocompatible. The drug-loaded nanocarriers also indicated a highly anti proliferative activity against MCF-7 breast cancer cell. The obtained results demonstrated a great potential of the highly lipophilic pluronics-conjugated nanocarriers in hydrophobic drugs delivery for biomedical applications. PMID- 27772732 TI - Corrigendum to "Lower uncarboxylated osteocalcin and higher sclerostin levels are significantly associated with coronary artery disease" [Bone 83 (2016) 178-183]. PMID- 27772733 TI - Corrigendum to FGF23-regulated production of fetuin-A (AHSG) in osteocytes [Bone 83 (2016) 35-47]. PMID- 27772734 TI - Retraction notice to "Are uric acid plasma levels different between unipolar depression with and without adult attention deficit hyperactivity disorder?" [J. Affect. Disord. 177C (2015) 114-117]. PMID- 27772735 TI - Retinal imaging and axonal degeneration in later onset multiple sclerosis. AB - BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS typically affecting younger adults and resulting in neuro-axonal degeneration already at early stages of the disease. Less is known about the effects of a later disease onset (LOMS, onset >50years of age). Analysis of retinal layers by optical coherence tomography (OCT) is a non-invasive method to investigate retinal and neuro-axonal degeneration. We applied OCT to detect differences in retinal damage depending on a later disease manifestation. METHODS: 14 LOMS patients, 14 age- and 14 disease duration-matched normal onset (NOMS) patients with a relapsing remitting disease course and 15 healthy controls (HC) were included. OCT measurement of peripapillary retinal nerve fiber layer (RNFL), total macular volume (TMV), combined ganglion cell/inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer retinal layers (ORL) was conducted. Furthermore, analysis of clinical features and of effects of previous optic neuritis (ON) was performed RESULTS: In a GEE based analysis of age- and disease duration matched NOMS, LOMS patients show no significant differences in retinal layer thickness whereas ON significantly reduced thickness of retinal layers. All MS groups display lower retinal layer thickness as compared to HC independently of type of onset. DISCUSSION: Our LOMS findings are well in line with published OCT data of normal onset MS. As the degree of retinal layer thinning was similar in MS subgroups, retinal neurodegeneration in MS may occur independently of time of disease onset. PMID- 27772737 TI - Impaired arterial smooth muscle cell vasodilatory function in methamphetamine users. AB - OBJECTIVES: Methamphetamine use is a strong risk factor for stroke. This study was designed to evaluate arterial function and structure in methamphetamine users ultrasonographically. METHODS: In a cross-sectional study, 20 methamphetamine users and 21 controls, aged between 20 and 40years, were enrolled. Common carotid artery intima-media thickness (CCA-IMT) marker of early atherogenesis, flow mediated dilatation (FMD) determinants of endothelium-dependent vasodilation, and nitroglycerine-mediated dilatation (NMD) independent marker of vasodilation were measured in two groups. RESULTS: There were no significant differences between the two groups regarding demographic and metabolic characteristics. The mean (+/ SD) CCA-IMT in methamphetamine users was 0.58+/-0.09mm, versus 0.59+/-0.07mm in the controls (p=0.84). Likewise, FMD% was not significantly different between the two groups [7.6+/-6.1% in methamphetamine users vs. 8.2+/-5.1% in the controls; p=0.72], nor were peak flow and shear rate after hyperemia. However, NMD% was considerably decreased in the methamphetamine users [8.5+/-7.8% in methamphetamine users vs. 13.4+/-6.2% in controls; p=0.03]. CONCLUSION: According to our results, NMD is reduced among otherwise healthy methamphetamine users, which represents smooth muscle dysfunction in this group. This may contribute to the high risk of stroke among methamphetamine users. PMID- 27772736 TI - Vitamin D receptor gene polymorphisms and cognitive decline in Parkinson's disease. AB - We and others have suggested that vitamin D receptor gene (VDR) polymorphisms influence susceptibility for Parkinson's disease (PD), Alzheimer's disease (AD), mild cognitive impairment (MCI) or overall cognitive functioning. Here we examine VDR polymorphisms and cognitive decline in patients with PD. Non-Hispanic Caucasian PD patients (n=190) in the Parkinson Environment Gene (PEG) study were successfully genotyped for seven VDR polymorphisms. Cognitive function was assessed with the Mini-Mental State Exam (MMSE) at baseline and at a maximum of three follow-up exams. Using repeated-measures regression we assessed associations between VDR SNP genotypes and change in MMSE longitudinally. PD cases were on average 67.4years old at diagnosis and were followed for an average of 7.1years into disease. Each additional copy of the FokI A allele was associated with a 0.115 decrease in the total MMSE score per year of follow-up (beta=-0.115, SE(beta)=0.05, p=0.03) after adjusting for age, sex, education and PD duration. The effect on MMSE by the FokI A allele was comparable in absolute magnitude to the effect for disease duration in years prior to first interview (beta=-0.129 per year, SE(beta)=0.08, p=0.13), and years of education (beta=0.118 per year, SE(beta)=0.03, p<0.001). When LD/LED use and PD subtype were added to the model, the effect of the FokI A allele on total MMSE score was magnified (beta=-0.141, SE(beta)=0.05, p=0.005). Results point to Fokl, a functional VDR polymorphism, as being associated with cognitive decline in PD. Future studies examining the contributions of the vitamin D metabolic pathway to cognitive dysfunction in PD are needed. PMID- 27772738 TI - Validation of Thwaites Index for diagnosing tuberculous meningitis in a Colombian population. AB - OBJECTIVE: To determine the diagnostic accuracy of Thwaites Index (TI) in a Colombian population to distinguish meningeal tuberculosis (MTB) from bacterial meningitis (BM) and from non-tuberculous meningitis. Exploratory analyses were conducted to assess the TI's validity for patients with human immunodeficiency virus (HIV) and children above six-years-old. METHODS: The study included 527 patients, the TI was calculated and results compared with those of a reference standard established by expert neurologists. Sensitivity, specificity, area under the curve of receiver-operator characteristics (AUC-ROC) and likelihood ratios were calculated. RESULTS: The AUC-ROC to distinguish MTB from non-tuberculous meningitis was 0.72 (95% CI: 0.67-0.77) for HIV negative adults. AUC-ROC was 0.62 (95% CI: 0.50-0.74) for HIV positive adults and 0.83 (95% CI: 0.68-0.97) for children. For distinguishing MTB from BM the AUC-ROC was 0.78 (95% CI: 0.73 0.83); furthermore, the AUC-ROC was 0.57 (95% CI: 0.31-0.83) for HIV positive adults and 0.86 (95% CI: 0.73-0.99) for children. CONCLUSION: The TI was sensitive but not specific when used to distinguish MTB from BM in HIV negative adults. In HIV positive adults the index had low diagnostic accuracy. Moreover, the TI showed discrimination capability for children over 6years; however, research with larger samples is required in these. PMID- 27772739 TI - Retinal nerve fiber layer thickening in ARSACS carriers. AB - PURPOSE: Two Caucasian Belgian families were diagnosed with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The ophthalmological findings in both ARSACS disease and carriers are described. METHODS: In addition to a complete ophthalmological assessment, in both patients and carriers, spectral domain Optical Coherence Tomography scans of the peri-papillary retinal nerve fiber layer were performed. RESULTS: Molecular analysis revealed a missense mutation which has not been reported before. Besides patients with ARSACS, who also presented additional ophthalmological abnormalities i.e. eye movement problems, ARSACS carriers demonstrated thickening of the retinal nerve fiber layer. CONCLUSION: The most conspicuous ophthalmological feature of ARSACS is an increased thickness of the peri-papillary retinal nerve fiber layer. Retinal striation and thickening of the nerve fiber layer on spectral-domain Optical Coherence Tomography appeared also in carriers of the ARSACS-gene. Other ophthalmological features encountered, were gaze-evoked nystagmus and rebound nystagmus. PMID- 27772740 TI - Prolonged-release fampridine treatment improved subject-reported impact of multiple sclerosis: Item-level analysis of the MSIS-29. AB - Prolonged-release (PR) fampridine is approved to treat walking impairment in persons with multiple sclerosis (MS); however, treatment benefits may extend beyond walking. MOBILE was a phase 2, 24-week, double-blind, placebo-controlled exploratory study to assess the impact of 10mg PR-fampridine twice daily versus placebo on several subject-assessed measures. This analysis evaluated the physical and psychological health outcomes of subjects with progressing or relapsing MS from individual items of the Multiple Sclerosis Impact Scale (MSIS 29). PR-fampridine treatment (n=68) resulted in greater improvements from baseline in the MSIS-29 physical (PHYS) and psychological (PSYCH) impact subscales, with differences of 89% and 148% in mean score reduction from baseline (n=64) at week 24 versus placebo, respectively. MSIS-29 item analysis showed that a higher percentage of PR-fampridine subjects had mean improvements in 16/20 PHYS and 6/9 PSYCH items versus placebo after 24weeks. Post hoc analysis of the 12 item Multiple Sclerosis Walking Scale (MSWS-12) improver population (>=8-point mean improvement) demonstrated differences in mean reductions from baseline of 97% and 111% in PR-fampridine MSIS-29 PHYS and PSYCH subscales versus the overall placebo group over 24weeks. A higher percentage of MSWS-12 improvers treated with PR-fampridine showed mean improvements in 20/20 PHYS and 8/9 PSYCH items versus placebo at 24weeks. In conclusion, PR-fampridine resulted in physical and psychological benefits versus placebo, sustained over 24weeks. PMID- 27772741 TI - Decreased risk of cancer in multiple sclerosis patients and analysis of the effect of disease modifying therapies on cancer risk. AB - BACKGROUND: Although dysimmunity is considered an important link between multiple sclerosis (MS), family history and cancer risk, their relationship to the use of disease modifying therapies (DMT) is not fully understood. OBJECTIVE: To assess the observed versus expected number of cancers in MS patients, and family history of cancer, among DMT users and DMT naive patients. METHODS: Cancer, DMT use, and family history of cancer were assessed using the New York State Multiple Sclerosis Consortium (NYSMSC) registry. Self-reported cancers in MS patients were tested for associations with DMT use, family history of cancer and other factors. Expected number of cancer cases was estimated using age- and gender-specific prevalence and incidence rates from the general population. RESULTS: The prevalence of cancer in males and females in the NYSMSC cohort was lower than expected (p<0.001). Patients with cancer were older at MS diagnosis and more likely to be female (p<0.001). MS patients with a personal history of cancer were more likely to report DMT use (p<0.001) and family history of cancer (p<0.001). Multivariable analysis did not support a higher risk of cancer after DMT initiation. CONCLUSIONS: We report a lower than expected number of cancer cases in MS patients compared to the general population. MS patients with a personal history of cancer were more likely to report DMT use suggesting that DMTs may abrogate the lower incidence of cancer in MS. PMID- 27772742 TI - Smart device neuropathy. AB - Compression of the lateral femoral cutaneous nerve (LFCN) in the thigh, commonly referred to as meralgia paresthetica, may be due to obesity, tight clothing and other external factors. We report two cases of meralgia paresthetica due to compression of the LFCN by portable electronic or "smart" devices. PMID- 27772743 TI - Electrophysiological characterization of Nsc-34 cell line using Microelectrode Array. AB - Neurons communicate with each other through intricate network to evolve higher brain functions. The electrical activity of the neurons plays a crucial role in shaping the connectivity. With motor neurons being vulnerable to neurodegenerative diseases, understanding the electrophysiological properties of motor neurons is the need of the hour, in order to comprehend the impairment of connectivity in these diseases. NSC-34 cell line serves as an excellent model to study the properties of motor neurons as they express Choline acetyltransferase (ChAT). Although NSC-34 cell lines have been used to study the effect of various toxicological, neurotrophic and neuroprotective agents, the electrical activity of these cells has not been elucidated. In the current study, we have characterized the electrophysiological properties of NSC-34 cell lines using Micro-Electrode Array (MEA) as a tool. Based on the spike waveform, firing frequency, auto- and cross-correlogram analysis, we demonstrate that NSC-34 cell culture has >2 distinct types of neuronal population: principal excitatory neurons, putative interneurons and unclassified neurons. The presence of interneurons in the NSC-34 culture was characterized by increased expression of GAD-67 markers. Thus, finding an understanding of the electrophysiological properties of different population of neurons in NSC-34 cell line, will have multiple applications in the treatment of neurological disorders. PMID- 27772744 TI - Obesity is associated with better survival and functional outcome after acute intracerebral hemorrhage. AB - OBJECTIVE: To evaluate the association of obesity measured by body mass index (BMI) with mortality and functional outcome in patients with acute intracerebral hemorrhage (ICH). METHODS: Data were from 1571 patients with ICH enrolled in a national, multi-centre, prospective, hospital-based register: the ChinaQUEST (Quality Evaluation of Stroke Care and Treatment) study. The outcomes included all-cause mortality at 12months, and death or high dependency at 3 and 12months. High dependency was defined as a modified Rankin Scale score of 3-5. RESULTS: Of 1571 patients with ICH, 109 were underweight (BMI<18.5kg/m2), 657 were normal weight (BMI 18.5-23kg/m2), 341 were overweight (BMI 23-25kg/m2) and 464 were obese (BMI>=25kg/m2). Compared with normal-weight patients, obese patients had significantly decreased risks of death at 12months (HR: 0.71, 95% CI: 0.56-0.91) and death or high dependency at 3 and 12months (OR: 0.71, 95% CI: 0.53-0.95; OR: 0.69, 95% CI: 0.51-0.94) after adjusting for baseline characteristics. Neither underweight nor overweight was associated with these three outcomes significantly. CONCLUSIONS: In patients with acute ICH, being obese is associated with a decreased mortality and better functional recovery. Further interventional studies are needed to guide the weight management strategy for patients with ICH. PMID- 27772745 TI - Preserved regional cerebral blood flow in the occipital cortices, brainstem, and cerebellum of patients with V180I-129M genetic Creutzfeldt-Jakob disease in serial SPECT studies. AB - Creutzfeldt-Jakob disease (CJD) with a causative point mutation of valine to isoleucine at codon 180 (V180I) is one of the major types of genetic CJD (gCJD) in Japan. V180I gCJD is rarely accompanied by a family history, and its clinical characteristics include late-onset, long disease duration, and edematous cortical hyperintensity in diffusion, fluid attenuate inversion and T2-weighted MRI. We performed serial imaging with single-photon emission computed tomography (SPECT) and MRI in three V180I gCJD cases over long-term observation. All cases were characterized by progressive dementia, parkinsonism, and the absence of cerebellar signs or cortical visual dysfunction in their clinical courses. Moreover, during the end-stage, SPECT findings showed preserved regional cerebral blood flow (rCBF) in the occipital cortices, brainstem, and cerebellum. Similarly, no apparent atrophy or increased signal intensities were observed in MRI images of the occipital and cerebellar regions. In conclusion, we report a decrease in rCBF predominantly in the frontal and temporal cortices during the early-stage, which became more widespread as the disease progressed. Importantly, rCBF was preserved in the occipital cortices, brainstem, and cerebellar regions until the end-stage, which may be distinct to V180I gCJD cases. PMID- 27772746 TI - Diagnostic ability of cerebrospinal fluid tap test for predicting shunt responsiveness in patients with normal pressure hydrocephalus. PMID- 27772748 TI - CSF tap test - Obsolete or appropriate test for predicting shunt responsiveness? A systemic review. PMID- 27772747 TI - IL-6 serum levels are elevated in Parkinson's disease patients with fatigue compared to patients without fatigue. AB - To investigate the influence of interleukin-6 (IL-6) and soluble tumor necrosis factor receptors (sTNFR) in fatigued Parkinson's disease (PD) patients. Forty four PD patients were evaluated, and fatigue was assessed with the Parkinson Fatigue Scale. Logistic regression analysis was used to evaluate the contribution of disease severity scores and cytokine levels on fatigue scores. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of IL-6 in fatigue. Fatigued PD patients had worse cognitive function and depressive symptoms. These patients had worse PD signs and symptoms, displayed more advanced stages of PD, and had greater functional dependence. There was a significant difference in IL-6 serum levels (p=0.026), but there was no difference in sTNFR levels. Total scores on the Unified Parkinson Disease Rating Scale (beta=1.108; p=0.004) and IL-6 levels (beta=12.843; p=0.020) were found to be significant predictors of fatigue scores. A ROC curve revealed that IL-6 concentrations of 1.18pg/ml represented the best cut-off value for detecting fatigue (sensitivity of 0.941 and specificity of 0.704). Fatigued PD patients have poor clinical outcomes and elevated IL-6 serum levels when compared with non fatigued patients. These results suggest that IL-6 may play a role in the pathophysiology of fatigue in PD. PMID- 27772749 TI - Favorable outcome of a pregnancy after fampridine exposition during the first month. PMID- 27772750 TI - Bilateral anteriorly draining dural carotid-cavernous fistulas presenting without orbital signs or symptoms. PMID- 27772751 TI - Predatory journals: Prevention better than cure? PMID- 27772753 TI - Antioxidant and inflammatory biomarkers for the identification of prodromal Parkinson's disease. AB - OBJECTIVES: We explored the role of oxidative stress and inflammatory molecules as potential Parkinson (PD) biomarkers and correlated biological with non-motor abnormalities (olfactory impairment and dysautonomia), in patients with idiopathic REM behavior disorder (iRBD) (prodromal PD) and established PD. METHODS: We recruited 11 iRBD and 15 patients with idiopathic PD (Hohen&Yahr 1-3, on L-DOPA and dopamine agonists combination therapy) and 12 age- and sex-matched controls (CTRL). We measured total olfactory score (TOS), autonomic function [deep breathing (DB), lying to standing (LS) and Valsalva manoeuvre (VM) ratios], blood reduced glutathione (Br-GSH), oxidative stress and inflammatory markers (neopterin). RESULTS: Anosmia was similarly prevalent in iRBD (36%) and PD (33%) patients, but absent in CTRL. Orthostatic hypotension was more common among iRBD (73%) and PD (60%) than in CTRL (25%). By univariable ordinal logistic regression, TOS, Br-GSH, LS and VM ratio worsened from CTRL to iRBD and PD groups. Only reduced Br-GSH levels (p=0.037, OR=0.994; 95%CI 0.988-1.000) were independently associated to PD. TOS correlated with Br-GSH (R=0.34, p=0.037), VM ratio (R=0.43, p=0.015), and neopterin (rho=0.39, p=0.016). CONCLUSIONS: Reduced systemic antioxidant capacity is found in prodromal and overt PD and may represent, in association with olfactory loss and cardiovascular dysautonomia, a useful biomarker for an integrative, early diagnosis of PD. PMID- 27772752 TI - Role of neurodevelopment involved genes in psychiatric comorbidities and modulation of inflammatory processes in Alzheimer's disease. AB - INTRODUCTION: With the increase of the population's average age, Alzheimer's disease (AD) is becoming one of the most disabling diseases worldwide. Recently, neurodevelopment processes have been involved in the AD etiopathogenesis. Genetic studies in this field could contribute to our knowledge and suggest new molecular targets for possible treatments. METHODS: Our primary aim was to investigate the associations among single nucleotide polymorphisms (SNPs) within neurodevelopment related genes (BDNF, ST8SIA2, C15orf32, NCAPG2, ESYT2, WDR60, LOC154822, VIPR2, GSK3B, NR1I2, ZNF804A, SP4) and AD. A number of exploratory analyses was also performed to evaluate the associations with the presence of behavioral and psychiatric symptoms of dementia (BPSD), as well as with variations in hematological parameters. Two independent samples were investigated, one of 228 Greek subjects and one sample of 229 Italian subjects, including 156Alzheimer's Disease patients CE patients and 301 healthy controls. All patients were affected by late onset AD (LOAD). RESULTS: None of the analyzed SNPs was associated with AD in our samples. In the exploratory analyses, several genetic variants were associated with inflammation parameters in the Greek sample and in the merged one, suggesting a relationship among these genes and the modulation of inflammation and the immune response. Other exploratory analyses showed associations among several SNPs and psychiatric symptomatology in the Greek sample, suggesting a possible modulation of these variants on psychiatric comorbidities in AD. CONCLUSIONS: Although we failed to find a direct relationship between AD and the genetic variants investigated, possible connections with inflammation and psychiatric symptoms were suggested. PMID- 27772754 TI - Leukoencephalopathy with cerebral calcification and cysts: Cases report and literature review. AB - BACKGROUND: Leukoencephalopathy with calcifications and cysts (LCC) is a rare disease in which parenchymal cysts and calcifications within a widespread leukoencephalopathy can cause a broad spectrum of neurological symptoms. We present cases with adult LCC and discuss previously described entities in relevant literature. CASE PRESENTATION: Two cases of adult-onset LCC confirmed by clinical presentations, typical neuroimaging and neuropathological findings are reported. LITERATURE REVIEW: A detailed search of all relevant reports published in the English language between 1996 and 2015 via PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was performed, with "Leukoencephalopathy", "cerebral calcifications" and "cysts" as keywords. Including the current cases, we summarized the clinical presentations, neuroimaging features, biopsy features, and genetic features of 38 LCC patients. CONCLUSION: Our findings suggested that LCC could be diagnosed by clinical presentations, neuroimaging and gene detection, and biopsy might not be necessary. Therefore, we propose a diagnostic flow chart for neuroimaging in leukoencephalopathy, cerebral calcifications and cysts. PMID- 27772755 TI - Isolated intermittent bilateral hearing loss revealing a brain hemorrhage. PMID- 27772756 TI - Hypertrophic olivary degeneration: Case series and review of literature. AB - Hypertrophic Olivary Degeneration (HOD) is a rare neurological condition caused by trans-synaptic degeneration in the brainstem and cerebellum, resulting in varied clinical symptoms, classical being palatal tremors, along with characteristic imaging presentation. Large number of pathologic lesions can cause this condition, ranging from ischemic stroke to neoplasm. The most common conditions include hemorrhage, vascular malformations and infarct. Magnetic resonance scan (MRI) is the imaging modality of choice which shows signal changes with hypertrophy of the inferior olivary nucleus, as well as the primary underlying pathology. Through this pictorial essay, we present the imaging and clinical findings in a number of patients with HOD secondary to varied causes and explain the mechanism behind the changes. PMID- 27772757 TI - Recombinant tissue plasminogen activator enhances microparticle release from mouse brain-derived endothelial cells through plasmin. AB - Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is currently the only approved pharmacological strategy for acute ischemic stroke. However, rt PA exhibits vascular toxicity mainly due to endothelial damage. To investigate the mechanisms underlying rt-PA-induced endothelial alterations, we assessed the role of rt-PA in the generation of endothelial microparticles (EMPs), emerging biological markers and effectors of endothelial dysfunction. The mouse brain derived endothelial cell line bEnd.3 was used. Cells were treated with rt-PA at 20, 40 or 80MUg/ml for 15 or 24h, and EMPs were quantified in the culture media using Annexin-V staining coupled with flow cytometry. Rt-PA enhanced EMP release from bEnd.3 cells with a maximal increase at the 40MUg/ml dose for 24h (+78% compared to controls). Using tranexamic acid and aprotinin we demonstrated that plasmin is responsible for rt-PA-induced EMP release. The p38 MAPK inhibitor SB203580 and the poly(ADP-ribose)polymerase (PARP) inhibitor PJ34 also reduced rt PA-induced EMP production, suggesting that p38 MAPK and PARP are downstream intracellular effectors of rt-PA/plasmin. Rt-PA also altered through plasmin the morphology and the confluence of bEnd.3 cells. By contrast, these changes did not implicate p38 MAPK and PARP. This study demonstrates that rt-PA induces the production of microparticles by cerebral endothelial cells, through plasmin, p38 MAPK and PARP pathways. Determining the phenotype of these EMPs to clarify their role on the endothelium in ischemic conditions could thus be of particular interest. PMID- 27772758 TI - Role of 18F-FDG PET in demonstrating disease burden in patients with tuberculous meningitis. AB - OBJECTIVE: To study the role of 18fluoro-deoxy glucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan in documenting the disease burden in patients with tuberculous meningitis (TBM), and compare these findings with conventional imaging and magnetic resonance imaging (MRI). SUBJECTS AND METHODS: Ten patients with definite TBM were prospectively recruited. The severity of TBM was graded into stage I to III. The patients were subjected to whole body 18F-FDG PET/CT imaging and MRI brain. 18F-FDG PET/CT results were compared with the findings of brain MRI and other convectional imaging modalities (ultrasonography of abdomen and chest radiograph). RESULTS: There were ten patients with TBM whose median age was 27 (14-55) years, and the median duration of illness was 4 (0.5-8.0) months. Two patients were in stage I, six in stage II, and two in stage III meningitis. 18F-FDG PET/CT confirmed the cranial MRI findings in six patients, revealed additional brain lesion in one and did not detect the existing MRI lesions in three patients. 18F-FDG PET/CT however detected additional lesions in vertebrae, spinal cord and lymph nodes which were not seen on the conventional imaging. CONCLUSION: 18F-FDG PET/CT has a complementary role to MRI for detection of cranial lesions and is more sensitive in detecting the extra cranial tuberculosis burden in the patients with TBM. PMID- 27772759 TI - Congenital insensitivity to pain and anhidrosis: Case report and review of findings along neuro-immune axis in the disorder. AB - Congenital insensitivity to pain and anhidrosis (CIPA) is one of the hereditary autonomic and sensory neuropathies. Typically presenting in infancy, it manifests as hyperpyrexia from defects in sweating (autonomic) and self-mutilating injuries from pain insensitivity (sensory). CIPA being rare in North America, diagnosis is often missed due to variable presentation. Subsequent management of its complications is therefore delayed. We report an unusual presentation in a 2-year old girl with preexisting diagnosis of CIPA who was evaluated for bilateral upper extremity paresis of insidious onset. MRI revealed a mass compressing her cervical spine as the cause, and work up suggested immune dysfunction as possible etiology. To our knowledge, this complication has not been reported before in association with the disease. We introduce the disease by explaining the molecular pathology behind its presenting features. The neurological findings, documented in association with CIPA, are summarized and serve as a reference for the various presentations of this rare disorder. Since this disease is known to affect the immune system, immune defects in CIPA are discussed with recommendations for surveillance of patient's immune status. PMID- 27772760 TI - Role of Rho-mediated ROCK-Semaphorin3A signaling pathway in the pathogenesis of Parkinson's disease in a mouse model. AB - OBJECTIVE: The present study aims to elucidate the role of Rho-mediated ROCK Semaphorin3A signaling pathway in the pathogenesis of Parkinson's disease (PD) in a mouse model. METHODS: One-hundred twelve eight-week male C57BL/6 mice were selected. The mouse model of PD was constructed by intraperitoneal injection of MPTP. All mice were divided into four groups (28 mice in each group): Blank group, Model group, Rho knockout (Rho+/-) group and ROCK knockout (ROCK+/-) group. Changes of behavior of the mice were studied through automatic moving test and rotarod test. Immunohistochemistry (IHC) was used to detect the expressions of TH, CD11b and GFAP. High performance liquid chromatograph (HPLC) was performed for detection of dopamine and its metabolic product. The mRNA and protein expressions of Rho, ROCK, Sema3A, PlexinA and NRP-1 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: Rho and ROCK knockout improved the damage caused by MPTP on the behavior of mice and protected dopaminergic neurons from injury, along with the increases of dopamine and its metabolic product. The mRNA and protein expressions of Rho, ROCK, Sema3A, PlexinA and NRP-1 were increased in PD mice in the Model group compared with those in the Blank group. Compared to the Model group, the mRNA and protein expressions of Rho, ROCK, Sema3A, PlexinA and NRP-1 were reduced in the Rho+/- and ROCK+/- groups. CONCLUSION: These findings indicate that Rho and ROCK knockout may improve the behavior of mice and prevent MPTP-induced dopaminergic neurons damage by regulating Sema3A, PlexinA and NRP-1 in a mouse model of PD. PMID- 27772761 TI - Corpus callosum microstructural changes associated with Kawashima Nintendo Brain Training in patients with multiple sclerosis. PMID- 27772763 TI - Smoking increases the risk of progression in multiple sclerosis: A cohort study in Queensland, Australia. AB - BACKGROUND: Cigarette smoking has been associated with increased risk of progressive multiple sclerosis (MS). The effect of smoking status on risk and timing of disease progression in patients with MS in Queensland, Australia has not been established. METHODS: A clinical cohort of 646 cases (531 females, 115 males) were followed from first clinic attendance to onset of clinically determined progressive disease. Progression risk was analysed with gender, age, age of onset, exposure to disease modifying therapy, and smoking status as covariates in a Cox proportional hazards analysis. RESULTS: There were significantly higher risks of secondary progressive disease in males (Hazard Ratio, HR 1.83, 95% CI: 1.3-2.7) and in ever smokers (HR 1.4, 95% CI: 1.0-2.0). Progressive disease occurred approximately 4years earlier in ever smokers. Smoking did not affect age of onset of primary progressive disease. CONCLUSIONS: Cigarette smoking was associated with earlier onset of progressive disease in this large clinical cohort. For patients with relapsing-remitting disease, smoking cessation should be encouraged. PMID- 27772762 TI - Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability. AB - BACKGROUND: Neuromyelitis optica (NMO) sometimes coexists with serological marker positive, non-organ-specific autoimmune disorders. We evaluated the prevalence of thyroid dysfunction and anti-thyroid antibodies in patients with NMO spectrum disorder (NMOSD) and investigated the associations between thyroid dysfunction/autoimmunity and clinical features of NMOSD. METHODS: Forty-nine NMOSD patients with anti-aquaporin-4 antibody and 392 age- and sex-matched healthy controls were included. We measured the levels of thyroid hormones and anti-thyroid antibodies. RESULTS: The prevalence of clinical hypothyroidism, subclinical hyperthyroidism, and low T3 syndrome were higher in patients with NMOSD (4.1%, 12.2%, and 20.4%, respectively) compared with healthy controls (0.3%, 2.8%, and 0.5%, respectively; p=0.034, p=0.001, and p<0.001, respectively). However, anti-thyroperoxidase antibody (anti-TPO)-positivity did not significantly differ between NMOSD patients (20.4%) and controls (11.5%). Low T3 syndrome was more prevalent among patients during an attack (N=10/19, 52.6%) than those in remission (N=1/30, 3.3%). In addition, patients with low T 3 syndrome had significantly higher EDSS scores at the last visits as well as at sampling compared to those without low T3 syndrome. T3 levels were inversely correlated with EDSS score at the last visit after adjustment for age, sex, disease duration, clinical status (attack vs. remission), oral prednisolone use, iv methylprednisolone use, other immunosuppressive agents use, and the location of lesion (rho=-0.416, p=0.010). CONCLUSIONS: Our study suggests that thyroid dysfunction is frequent in patients with NMOSD; particularly, serum T3 levels may be a useful indicator of disease activity and disability in NMOSD. PMID- 27772764 TI - Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and cyclophosphamide among patients with neuromyelitis optica spectrum disorder: A prospective cohort study. AB - AIMS: To compare the efficacy and tolerability of azathioprine (AZA), mycophenolate mofetil (MMF), and cyclophosphamide (CTX) in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: We performed a prospective cohort analysis of relapses, disability, and adverse events in NMOSD patients treated with AZA, MMF, or CTX (n=119, 38, and 41, respectively). All the patients were co-treated with oral prednisone. RESULTS: A significant reduction in relapse rate was found in patients taking AZA (p<0.001), MMF (p<0.001) or CTX (p=0.01). MMF was associated with a lower risk of relapse than AZA, but this difference was not statistically significant (p=0.08). AZA and MMF decreased the mean Expanded Disability Status Scale (EDSS) scores significantly (AZA: p=0.02; MMF: p=0.01), whereas CTX did not. Compared with AZA, MMF had a significantly lower risk of treatment discontinuation due to drug-related adverse events (p=0.02), whereas CTX had a comparable risk (p=0.35). CONCLUSIONS: MMF is a good first-line treatment option for NMOSD and AZA remains a valuable first-line drug if its side effects are tolerable while CTX can be a treatment option for patients who cannot tolerate AZA and MMF. PMID- 27772765 TI - Pretreated duloxetine protects hippocampal CA1 pyramidal neurons from ischemia reperfusion injury through decreases of glial activation and oxidative stress. AB - Duloxetine (DXT), a serotonin/norepinephrine reuptake inhibitor, is widely used for the treatment of major depressive disorders. In the present study, we investigated the neuroprotective effect of pre-treated DXT in the hippocampal CA1 region following transient global cerebral ischemia. Pre-treatment with 40mg/kg DXT protected pyramidal neurons in the CA1 region from ischemia-reperfusion injury. In addition, pre-treatment with DXT reduced ischemia-induced activations of microglia and astrocytes in the ischemic CA1 region. On the other hand, we found that pre-treatment with DXT did not increase 4-hydroxy-2-noneal (a marker for lipid peroxidation) and significantly increased the expression of Cu, Zn superoxide dismutase, an antioxidant, in the CA1 pyramidal neurons compared with non-treated those after ischemia-reperfusion. These results indicate that pre treated DXT has neuroprotective effect against transient global cerebral ischemia and suggest that the neuroprotective effect of DXT may be due to the attenuation of ischemia-induced glial activation as well as the decrease of oxidative stress. PMID- 27772767 TI - A non-travel related case of Angiostrongylus cantonensis eosinophilic meningomyelitis acquired in Israel. PMID- 27772766 TI - Retinal and optic nerve abnormalities in neurodegeneration associated with mutations in C19orf12 (MPAN). AB - BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an neurodegeneration with brain iron accumulation (NBIA) subtype with mutation of C19orf12. Optic atrophy is one of the core symptoms in almost all MPAN cases, but the detailed ophthalmologic features of MPAN patients have not yet been described. METHODS: All consecutive symptomatic, gene proven MPAN patients underwent a detailed ophthalmological examination: best corrected visual acuity (BCVA), slit lamp examination, dilated fundus examination, tonometry, optical coherent tomography (OCT) and electrophysiological examinations. The total thickness of the macula (Mth) and the retinal nerve fiber layer (RNFL) were measured separately. RESULTS: Six males aged 18 to 21years were examined. Dilated fundus examination revealed complete optic disc paleness in 5 patients. In all patients, the Mth was normal. The total RNFL was thin in five patients. The latencies of PVEP were prolonged in all patients except one. In all cases, the ERG latencies and amplitudes were normal under both scotopic and photopic conditions. One patient, carrying different mutation and with different disease course, had a normal optic nerve head, normal RNFL thickness and PVEP latencies. CONCLUSIONS: Optic nerve atrophy seems to be genotype-dependent in MPAN patients but is typical for the disease. This phenomenon, together with normal ERG examination, is most distinctive for MPAN. PMID- 27772768 TI - Cognitive impairment after traumatic brain injury: The role of MRI and possible pathological basis. AB - Traumatic brain injury (TBI) is closely related to increased incidence of cognitive impairment from the acute phase to chronic phase. At present, the pathological mechanism leading to cognitive impairment after TBI is still not fully understood. We hypothesize that neuron loss, diffuse axonal injury, microbleed, and blood-brain barrier (BBB) disruption altogether contribute to the development of cognitive impairment. Furthermore, the disruption of structural and functional neural network related to the cognitive function might bring about the final step in the occurrence of cognitive impairment after TBI. In this review, we summarize the role of different MRI techniques in the assessment of the pathological changes related to cognitive impairment after TBI. These MRI techniques include T1-MPRAGE sequence reflecting neuron loss, diffusion tensor imaging reflecting diffuse axonal injury, diffusion kurtosis imaging reflecting diffuse axonal injury and reactive gliosis, susceptibility weighted imaging showing microbleed, arterial spin labeling showing blood flow and dynamic contrast enhanced MRI showing BBB disruption. In the future, correlational study of multi-MRI sequences scan, pathological examination, and cognitive tests will provide valuable information for understanding the mechanism of cognitive impairment after TBI and manage TBI patients. PMID- 27772769 TI - Cardiovascular dysfunction in untreated Parkinson's disease: A multi-modality assessment. AB - BACKGROUND: The clinical presentation of Parkinson's disease (PD) includes a wide spectrum of non-motor features, including cardiovascular autonomic failure. OBJECTIVE: To evaluate cardiovascular autonomic status and cardiac functional capacity in drug-naive PD patients. METHODS: 18 newly-diagnosed PD patients underwent laboratory cardiovascular autonomic function tests using power spectral analysis of the R-R interval, blood pressure (BP) short-term variability and non invasive baroreflex sensitivity (BRS). A two-dimensional (2D) transthoracic echocardiogram, spirometry and cardiopulmonary exercise test (CPET) were also performed. Thirteen patients underwent myocardial scintigraphy with [123I] metaiodobenzylguanidine (MIBG). RESULTS: At rest, total power spectral analysis of heart rate variability was lower in PD patients than in controls. BRS decreased during sympathetic activation in both patients and controls. While echocardiography and spirometry were normal, a mild degree of exercise intolerance was observed at the CPET in PD patients (mean V'O2max: 83% of predicted; mean Wmax: 80% of predicted). The heart-to-mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in 9 patients, one of whom displayed a definite cardiovascular dysautonomic pattern. CONCLUSIONS: Our results confirm that subclinical to overt cardiovascular autonomic failure may occur from the early stages of PD. The less efficient adaptive response to physical stimuli during the CPET and postural changes observed in untreated PD patients possibly reflect cardiac sympathetic denervation, although the involvement of PD-related motor impairment in physical deconditioning cannot be excluded. PMID- 27772770 TI - Lingual protrusion dystonia: Manifestation during "on" periods in Parkinson's disease. PMID- 27772771 TI - Surgical versus non-surgical treatment for pituitary apoplexy: A systematic review and meta-analysis. AB - BACKGROUND: Pituitary apoplexy is a rare disease caused by a sudden hemorrhage into or infarction of the pituitary gland. Its optimal management remains controversial. The aim of this study was to compare the outcomes of surgical and non-surgical treatments for pituitary apoplexy. METHODS: A systematic literature search was performed of MedLine, EmBase, the Cochrane Library, and the Web of Science for articles published between January 1992 and September 2014. Studies of the outcomes in consecutive patients that compared surgical intervention with non-surgical treatment for pituitary apoplexy were included. RESULTS: Six studies met the inclusion criteria. As compared to the non-surgically treated patients, surgically treated patients had a significantly higher rate of recovery of ocular palsy and visual field (both P<0.05). However, there was no significant difference in the recovery of visual acuity and pituitary function (P>0.05) between the two groups. CONCLUSIONS: The findings of our study suggest that surgical intervention should be advocated for pituitary apoplexy patients with visual field defects and ocular palsy. PMID- 27772772 TI - Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray. AB - BACKGROUND: Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex(r)) has been recently approved for the management of treatment resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex(r) on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex(r), at both central and spinal levels, through an extensive neurophysiological battery in patients with MS. METHODS: Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex(r) patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls. RESULTS: A significant reduction of the MAS score after 4weeks of Sativex(r) treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex(r) on different pathways, predominantly of inhibitory type. Sativex(r) treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth. DISCUSSION: Our results confirm the clinical benefit of Sativex(r) on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability. PMID- 27772773 TI - Predictors of health-related quality of life in people with amyotrophic lateral sclerosis. AB - BACKGROUND: Knowledge of factors influencing health-related quality of life (HRQL) in people with amyotrophic lateral sclerosis (ALS) is important because some factors might be amenable to intervention. OBJECTIVES: The aim was to describe and explore the effects of disease severity, fatigue, anxiety, depression, frequency of social and lifestyle activities, coping capacity and mechanical ventilator use on HRQL in people with ALS. METHODS: Sixty people with ALS were enrolled in this cross-sectional study. Data were collected with questionnaires during home visits. The Sickness Impact Profile and the EuroQol Visual Analogue Scale were used to assess HRQL. Multivariate regression analyses explored associations between HRQL and independent factors. RESULTS: Low frequency of social and lifestyle activities, and severe disease, were associated with worse HRQL, explaining 57% of total variance in the Sickness Impact Profile physical score. Severe disease, weak coping capacity and anxiety and/or depression were associated with worse HRQL, explaining 33% of total variance in Sickness Impact Profile psychosocial score. Fatigue and mechanical ventilator use were associated with worse HRQL, explaining 17% of variance in the EuroQol Visual Analogue Scale. CONCLUSION: Knowledge and understanding of how frequency of social and lifestyle activities, disease severity, coping capacity, anxiety and/or depression, fatigue and ventilator use contribute to and predict self rated HRQL can optimize person-centred care and support. PMID- 27772774 TI - Central nervous system involvement in multiple symmetric lipomatosis. PMID- 27772775 TI - Central pontine myelinolysis caused by hypernatremia. PMID- 27772776 TI - Brain activation changes during locomotion in middle-aged to older adults with multiple sclerosis. AB - Mobility and cognitive impairments are common in persons with multiple sclerosis (MS), and are expected to worsen with increasing age. However, no studies, to date, in part due to limitations of conventional neuroimaging methods, have examined changes in brain activation patterns during active locomotion in older patients with MS. This study used functional Near Infrared Spectroscopy (fNIRS) to evaluate real-time neural activation differences in the pre-frontal cortex (PFC) between middle-aged to older adults with MS and healthy controls during single (Normal Walk; NW) and dual-task (Walking While Talking; WWT) locomotion tasks. Eight middle-aged to older adults with MS and eight healthy controls underwent fNIRS recording while performing the NW and WWT tasks with an fNIRS cap consisting of 16 optodes positioned over the forehead. The MS group had greater elevations in PFC oxygenation levels during WWT compared to NW than healthy controls. There was no walking performance difference between groups during locomotion. These findings suggest that middle-aged to older individuals with MS might be able to achieve similar levels of performance through the use of increased brain activation. This study is the first to investigate brain activation changes during the performance of simple and divided-attention locomotion tasks in MS using fNIRS. PMID- 27772777 TI - Status epilepticus in the elderly: Prognostic implications of rhythmic and periodic patterns in electroencephalography and hyperintensities on diffusion weighted imaging. AB - OBJECTIVE: To delineate the clinical characteristics and functional outcome of status epilepticus (SE) in elderly people, and elucidate prognostic implications of SE-associated rhythmic and periodic patterns (RPPs) in electroencephalography and hyperintensities on diffusion-weighted imaging. METHODS: We retrospectively investigated 107 consecutive patients with SE aged>=65years in a comprehensive community hospital. RPPs were classified using the 2012 American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. Poor outcome was defined as an increase in modified Rankin Scale (mRS) score at discharge compared with that at baseline, including death. RESULTS: Median age of patients was 80.0years. Median mRS score at baseline was 3. Thirty-four patients (31.8%) had a previous diagnosis of epilepsy. Cerebrovascular disease and dementia were major etiologies. Poor outcome occurred in 41 (38.3%). In electroencephalography, periodic discharges (PDs) were present in 21.0% (22/105), rhythmic delta activity (RDA) in 10.5% (11/105), and conventional seizure patterns in 9.5% (10/105). Diffusion-weighted hyperintensities associated with SE were observed in 28.0% (26/93). With univariate analysis, poor outcome was significantly associated with no previous diagnosis of epilepsy, etiology, refractory SE, specific electroencephalographic patterns (PDs and conventional seizure patterns, but not RDA), and diffusion-weighted hyperintensities. With multivariate logistic regression analysis, diffusion-weighted hyperintensities (OR 6.13 [95% CI 1.72-21.9]) and refractory SE (OR 5.36 [95% CI 1.28-22.4]) were independently associated with poor outcome. CONCLUSIONS: SE often occurred as the first seizure in already disabled elderly people, further worsening their functional disabilities. Diffusion-weighted hyperintensities and refractory SE, but not RPPs in electroencephalography, were independent functional prognostic factors. PMID- 27772778 TI - A population-based epidemiologic study of adult-onset narcolepsy incidence and associated risk factors, 2004-2013. AB - An increase in narcolepsy incidence was noted after the novel pandemic influenza of 2009, leading to further interest in risk factors associated with this disease. However, there is limited data on the epidemiology of narcolepsy, particularly in the adult population. Therefore, we sought to examine narcolepsy incidence rates in the United States and describe associated characteristics. We performed a population based epidemiologic study of active duty military personnel. All outpatient clinics in the continental United States providing care for active duty military between 2004 through 2013 were included utilizing existing databases. Narcolepsy was defined in 3 ways: (1) 2 diagnoses of narcolepsy within 6months of each other, one made by a sleep expert; (2) 2 diagnoses by any provider followed by a narcolepsy prescription within 14days of last visit; and (3) procedure code for a sleep study followed by a narcolepsy diagnosis by a sleep expert within 6months. There were 1675 narcolepsy cases. Overall incidence of narcolepsy trended from 14.6 to 27.3 cases per 100,000 person-years, with an increase starting after 2005-2006 and peaking during the 2011-2012 influenza season. Higher frequencies were seen among females, non Hispanic blacks, and members living in the south. Narcolepsy incidence rates among active duty military members are higher than previously described. The reason for the steady rise of incidence from 2005 to 2006 through 2011-2012 is unknown; however, these findings require further exploration. We detected risk factors associated with the development of narcolepsy which may aid in future study efforts. PMID- 27772779 TI - Latency to treatment of status epilepticus is associated with mortality and functional status. AB - INTRODUCTION: Status epilepticus (SE) is a life-threatening neurologic emergency. Despite advances in management, in-hospital mortality remains unchanged. This is partly due to the pharmacoresistance which develops the longer that seizures persist. Therefore, rapid antiseizure medication (ASM) administration may represent a beneficial treatment option. The purpose of this study was to determine: 1) whether in-hospital mortality is reduced with shorter latencies to initial treatment of SE with an ASM (LTSE); and 2) the critical time frame during which LTSE is associated with reduced in-hospital mortality. MATERIALS AND METHODS: This was a retrospective, single-center study of adults diagnosed with SE between 1/1/2005 and 10/31/2012. Demographic characteristics included seizure history, etiology, semiology, and duration. Subjects were assigned to LTSE groups at the time frames of 5, 10, 30 and 60min. The primary outcome was in-hospital mortality, with poor functional status (mRS 3-6) as a secondary measure. Pearson's chi-square, Mann-Whitney-U, two-sample-t-tests, and binary logistic regression analysis were used as appropriate, with p<0.05. RESULTS: In unadjusted analysis, LTSE>30min demonstrated increased risk of mortality (OR 2.06, CI 1.01 4.17, p=0.046) and poor functional status (OR 2.48, CI 1.05-5.85, p=0.038) compared to LTSE<=30min. Increased mortality risk remained after adjusting for SE duration (OR 2.07, CI 1.01-4.26, p=0.047) and nonconvulsive seizures (OR 2.28, CI 1.08-4.80, p=0.03). Compared to subjects treated within 60min, those treated after 60min were at increased risk of poor functional status, regardless of the presence of nonconvulsive seizures (OR 2.96, CI 1.14-7.73, p=0.026). In addition, when acute symptomatic SE was stratified by cardiac versus non-cardiac etiologies, subjects with non-cardiac acute symptomatic SE demonstrated worse functional outcome when treated after 60min (OR 7.20, CI 1.13-46.07, p=0.037). CONCLUSIONS: Treatment of SE within 30min of onset is associated with reduced risk of in-hospital mortality and poor functional status, although this may be attenuated by acute symptomatic seizures related to cardiac arrest. This represents a therapeutic option which has the potential to benefit patient outcomes. PMID- 27772781 TI - Congenital insensitivity to pain with anhidrosis: A report of two siblings with a novel mutation in (TrkA) NTRK1 gene in a Saudi family. AB - Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN type IV) is an extremely rare autosomal recessive disorder with an estimated incidence of 1 in 25,000. It was first described in 1963, and since then several case reports and review articles have been published. In this article, we report two brothers with clinical features of CIPA, who presented with recurrent episodes of hyperthermia, anhidrosis, profound loss of pain sensitivity, and unconscious self-mutilation of fingers, lip and tongue. Sanger sequencing analysis confirmed the presence of a novel mutation c.783_785delGAA in the NTRK1 gene in the two affected members of the family. Early diagnosis and management of different systemic complications including orthopedic, visual, and dental may be useful in the reduction of frequency and severity of these complications. PMID- 27772780 TI - Non-alcoholic Korsakoff syndrome in psychiatric patients with a history of undiagnosed Wernicke's encephalopathy. AB - Wernicke's encephalopathy is often undiagnosed, particularly in non-alcoholics. There are very few reports of non-alcoholic patients diagnosed with Korsakoff syndrome in the absence of a prior diagnosis of Wernicke's encephalopathy and no studies of diffusion tensor imaging in non-alcoholic Korsakoff syndrome. We report on three non-alcoholic psychiatric patients (all women) with long-term non progressive memory impairment that developed after malnutrition accompanied by at least one of the three Wernicke's encephalopathy manifestations: ocular abnormalities, ataxia or unsteadiness, and an altered mental state or mild memory impairment. In neuropsychological examination, all patients had memory impairment, including intrusions. One patient had mild cerebellar vermis atrophy in MRI taken after the second episode of Wernicke's encephalopathy. The same patient had mild hypometabolism in the lateral cortex of the temporal lobes. Another patient had mild symmetrical atrophy and hypometabolism of the superior frontal lobes. Two patients were examined with diffusion tensor imaging. Reduced fractional anisotropy values were found in the corona radiata in two patients, and the uncinate fasciculus and the inferior longitudinal fasciculus in one patient. Our results suggest that non-alcoholic Korsakoff syndrome is underdiagnosed. Psychiatric patients with long-term memory impairment may have Korsakoff syndrome and, therefore, they should be evaluated for a history of previously undiagnosed Wernicke's encephalopathy. PMID- 27772783 TI - Idarucizumab elimination of dabigatran minutes before systemic thrombolysis in acute ischemic stroke. PMID- 27772784 TI - Boy with cortical visual impairment and unilateral hemiparesis in Jeff Huntington's "Slip" (2011). AB - Face recognition is strongly associated with the human face and face perception is an important part in identifying health qualities of a person and is an integral part of so called spot diagnosis in clinical neurology. Neurology depends in part on observation, description and interpretation of visual information. Similar skills are required in visual art. Here we report a case of eye cortical visual impairment (CVI) and unilateral facial weakness in a boy depicted by the painter Jeff Huntington (2011). The corollary of this is that art serves medical clinical exercise. Art interpretation helps neurology students to apply the same skills they will use in clinical experience and to develop their observational and interpretive skills in non-clinical settings. Furthermore, the development of an increased awareness of emotional and character expression in the human face may facilitate successful doctor-patient relationships. PMID- 27772782 TI - Involuntary movements and coma as the prognostic marker for acute encephalopathy with biphasic seizures and late reduced diffusion. AB - Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) occurs in children associated with infection. It is characterized by a prolonged febrile seizure in the first phase, and a cluster of seizures, deterioration of consciousness and the white matter lesions with reduced diffusion in the second phase. The patients often have severe neurological sequelae, but the prognostic indicators remain unknown. The present study aimed to clarify the characteristics of AESD patients who subsequently exhibited severe neurological sequelae. We retrospectively analyzed the clinical and laboratory findings along with the brain imaging in patients who had severe (n=8) and non-severe neurodevelopmental outcomes (n=12). Severe group more frequently showed coma (p=0.014) or involuntary movements including dystonia and oral dyskinesia (p=0.018) before the second phase than non-severe group. Severe group exhibited higher levels of serum alanine aminotransferase than non-severe group (p=0.001). Quantitatively assessed MRI in the second phase revealed that severe group had more extensive lesions than non-severe group, in the anterior (p=0.015) and posterior parts (p=0.011) of the cerebrum and basal ganglia (p=0.020). Early appearing involuntary movements or coma might account for the extension of acute brain lesions and the poor neurological outcomes in AESD patients. PMID- 27772785 TI - Oxidative damage to myelin proteins accompanies peripheral nerve motor dysfunction in aging C57BL/6 male mice. AB - Aging is associated with a decline in peripheral nerve function of both motor and sensory nerves. The decline in function of peripheral sensorimotor nerves with aging has been linked to sarcopenia, the age-related decline in muscle mass and function that significantly compromises the quality of life in older humans. In this study, we report a significant increase in oxidized fatty acids and insoluble protein carbonyls in sciatic nerves of aged C57BL/6 male mice (28-30mo) that exhibit a profound decline in motor nerve function and degenerative changes in both axon and myelin structure, compared to young mice (6-8mo). Our data further suggests that this age-related loss of function of peripheral motor nerves is likely precipitated by changes in mechanisms that protect and/or repair oxidative damage. We predict that interventions that target these mechanisms may protect against age-related decline in peripheral sensorimotor nerve function and likely improve the debilitating outcome of sarcopenia in older humans. PMID- 27772787 TI - Neuroacanthocytosis: A case with unusual clinical features & novel response to treatment. PMID- 27772786 TI - Acute disseminated encephalomyelitis secondary to serogroup B meningococcal vaccine. PMID- 27772788 TI - Association of serum uric acid and cardioembolic stroke in patients with acute ischemic stroke. AB - BACKGROUND: Although high uric acid levels have been reported to be a risk factor for cardiovascular disease and stroke, the relationship between serum uric acid (SUA) levels and cardioembolic stroke (CES) has not been fully elucidated. In this study, we sought to investigate the relationship between the risk of CES and SUA levels. We hypothesized that SUA concentrations are associated with CES. METHODS: We retrospectively analyzed 2350 patients with acute ischemic stroke who were admitted to the Seoul National University Hospital between 2002 and 2010. The participants were stratified into five groups according to SUA levels obtained within 24h after stroke onset. The association between SUA levels and CES was evaluated using multivariable logistic regression models. RESULTS: Of the 2350 patients, 412 (27.7%) were classified with CES, and 1077 (72.3%) were classified with non-CES, including LAA (large artery atherosclerosis) and SVO (small vessel occlusion). Among the acute stroke patients, SUA levels were higher in those with atrial fibrillation and other cardiovascular risk factors. Compared with the non-CES patients, the CES patients were more likely to fall in the highest quintile of SUA level. Multivariate analysis revealed that the patients with SUA concentrations in the highest quintile were associated with CES (OR=2.59, 95% CI: 1.35-4.97), test for trend P<0.001. Similar results were obtained for gender-based subgroups by (in men, OR=2.34, 95% CI: 1.06-5.15 and in women OR=3.41, 95% CI: 1.15-10.07), test for trend P<0.01 and P<0.001, respectively. CONCLUSION: SUA level is associated with the risk of CES in acute ischemic stroke patients of both sexes. Further prospective clinical trials of lowering SUA to prevent CES may be worth considering. PMID- 27772790 TI - Whole body and local cryotherapy in restless legs syndrome: A randomized, single blind, controlled parallel group pilot study. AB - OBJECTIVE: Treatment of restless legs syndrome (RLS) is primarily based on drugs. Since many patients report improvement of symptoms due to cooling their legs, we examined the efficacy of cryotherapy in RLS. PATIENTS AND METHODS: 35 patients (28 women, 60.9+/-12.5years) with idiopathic RLS and symptoms starting not later than 6pm were randomized into three groups: cold air chamber at -60 degrees C (n=12); cold air chamber at -10 degrees C (n=12); local cryotherapy at -17 degrees C (n=11). After a two week baseline, the different therapies were applied three minutes daily at 6pm over two weeks, followed by a four week observation period. The patients completed several questionnaires regarding RLS symptoms, sleep, and quality of life on a weekly basis (IRLS, ESS), VAS and sleep/morning protocol were completed daily, MOSS/RLS-QLI were completed once in each period. Additionally, the PLM index was measured by a mobile device at the end of baseline, intervention, and follow-up. The IRLS score was chosen as primary efficacy parameter. RESULTS: At the end of follow-up, significant improvement of RLS symptoms and quality of life could be observed only in the -60 degrees C group as compared to baseline (IRLS: p=0.009; RLS-QLI: p=0.006; ESS: p=0.020). Local cryotherapy led to improvement in quality of life (VAS4: p=0.028; RLS-QLI: p=0.014) and sleep quality (MOSS: p=0.020; MOSS2: p=0.022) but not in IRLS and ESS. In the -10 degrees C group, the only significant effect was shortening of number of wake phases per night. Serious side-effects were not reported. CONCLUSIONS: Whole body cryotherapy at -60 degrees C and, to a less extent, local cryotherapy seem to be a treatment option for RLS in addition to conventional pharmacological treatment. However, the exact mode of cryotherapy needs to be established. PMID- 27772789 TI - Neuropsychiatric characteristics of GBA-associated Parkinson disease. AB - Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n=31) and non-carrier (IPD; n=55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p<0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13-11.8) (p=0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association. PMID- 27772791 TI - Evaluating the morphological changes of intracranial arteries and whole-brain perfusion in undetermined isolated vertigo. AB - PURPOSE: To determine the morphological changes of intracranial arteries and whole-brain perfusion in undetermined isolated vertigo (UIV) patients using 320 detector row computed tomography (CT). METHODS: A total of 150 patients who underwent CT angiography (CTA) and CT perfusion (CTP) imaging were divided into UIV group and benign paroxysmal positional vertigo (BPPV) group. Sixty individuals with sex- and age-matched without vertigo and cerebral diseases served as the control. The morphological changes of intracranial arteries, perfusion parameters and vascular risk factors (VRFs) were analyzed, calculated and compared. RESULTS: In UIV patients, hypertension (HT), hyperlipidemia and number of VRFs>=3 occurred more commonly (P<0.0125, respectively). The incidence of vertebral artery dominance (VAD), vertebral artery stenosis (VAS) and basilar artery curvature (BAC) were significantly higher (P<0.0125, respectively). HT was an independent risk predictor of non-VAD (OR: 5.411, 95%CI: 1.401; 20.900, P=0.014). HT and VAD associated with BAC served as risk predictors (OR: 4.081, 95%CI: 1.056;15.775, P=0.041 and OR: 6.284, 95%CI: 1.848; 21.365, P=0.003, respectively). The absolute difference in relative values of CTP parameters from cerebellum and brainstem were significantly different (P<0.05), and hypoperfusion was found in the territories of the non-VAD side and the BAC cohort (P<0.05, respectively). CONCLUSIONS: On the basis of multiple VRFs, morphological changes of vertebrobasilar artery (VBA) and the unilateral hypoperfusion of the cerebellum and brainstem, that acts as a herald for IV occurrence, which should be paid cautious attention to UIV patients. PMID- 27772792 TI - The homocysteine associated variant rs548987 of SLC17A3 confers susceptibility to ischemic stroke in Chinese population. AB - Ischemic stroke is a common cause of death due to obstructed blood supply of the brain. Despite growing numbers of research, etiology underlying ischemic stroke remains complex and elusive. Elevated plasma homocysteine has been known as a risk factor for ischemic stroke. Recently, a genome-wide association study reported association between rs548987 of SLC17A3 and homocysteine. Given existing relation between homocysteine and ischemic stroke, SLC17A3 was believed to be a promising candidate gene of ischemic stroke. Indeed, its association with ischemic stroke was previously reported in a western population. Herein, we used rs548987 as a candidate genetic variant of ischemic stroke and performed association analysis in a Chinese population with 918 ischemic stroke cases and 979 controls. Although rs548987 failed to show significant association with total ischemic stroke and large vessel disease subtype, the C allele of rs548987 showed significant association with small vessel disease subtype of ischemic stroke (OR=0.68, p=0.004). Our preliminary results suggested different genetic etiology underlying the two most common subtypes of ischemic stroke and provided additional evidence to understand contribution of homocysteine to the disease. PMID- 27772793 TI - Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia. AB - BACKGROUND: The abnormal metabolism of ceramides may account for the pathogenesis of Parkinson's disease dementia (PDD). However, the effect of ceramides on cognitive domain impairments and neuropsychiatric symptoms of PDD remains unknown. METHODS: A total of 38 PDD, 40 PD with no cognitive impairment (PD-NC) and 40 normal controls were included. A series of cognitive tests and the Neuropsychiatric Inventory (NPI) were used to assess cognitive domains and neuropsychiatric symptoms. A non-fasting blood sample was obtained from each subject. Plasma ceramide levels were tested by HPLC-MS/MS analysis. RESULTS: C14:0 and C24:1 levels were significantly higher in PDD than in PD-NC and normal controls. Verbal memory was negatively correlated with C14:0 and C24:1. After controlling for confounding factors, C22:0, C20:0 and C18:0 were significantly associated with hallucinations, anxiety and sleep behavior disturbances, respectively. CONCLUSION: In PDD, the increase in ceramide levels was correlated with decreased memory function and associated with higher odds of multiple neuropsychiatric symptoms. PMID- 27772794 TI - MRI venous architecture of the thalamus. AB - PURPOSE: Our purpose is to describe the thalamic veins using a novel approach named venous gliography in cases with primary or secondary gliomas of the thalamus. Venous gliography is defined by authors as a method to visualize veins on MRI Brain T1-weighted post contrast scans containing gliomas which have induced regional venous congestion. METHODS: Routine clinical MR Imaging studies were reviewed to assess the presence of thalamic veins in 29 glioma cases. In addition, confocal reconstruction techniques (Anatom-e and Osirix) were used in cases that had thin sections (1.0-1.5mm) post contrast T1 weighted sequences. Multiplanar MIP and confocal volume rendered images were generated to evaluate the thalamic veins in those cases. RESULTS: Using venous gliography and confocal reconstruction techniques, two patterns in the venous architecture of the thalamus were documented. First, the branching pattern created by the tributaries of the internal cerebral vein, namely the superior thalamic vein and the anterior thalamic vein, which together formed the superior group of thalamic veins. Second, the pattern created by the un-branched vertically oriented veins, namely the inferior thalamic veins and the posterior thalamic veins, which joined the basal vein of Rosenthal and constituted the inferior group of thalamic veins. CONCLUSIONS: Venous gliography combined with the use of confocal reconstruction techniques provided a novel approach to display the thalamic veins that are usually not seen. The understanding of the venous architecture is mandated by the recent research where veins have taken on an important role in the perivenular spread of gliomas. PMID- 27772795 TI - Association of TLR8 gene rs3764880 polymorphisms with susceptibility and lipid metabolism- and inflammation response-related quantitative traits of ischemic stroke in southern Chinese Han male population. AB - Inflammatory response and lipid metabolism influence the development of ischemic stroke (IS). TLRs have an important function in inflammation and lipid metabolism. To investigate association of TLR8 rs3764880 polymorphism with susceptibility of IS and the relationship between rs3764880 with inflammation response- and lipid metabolism-related quantitative traits, we conducted a case control study in a Han Chinese population comprising 816 cases and 816 controls being matched for age and gender. The distribution of allele of TLR8 rs3764880 had statistical significance in male group (P=0.017). The G allele carrier had a higher level of IL-8 (P=0.001, PBc=0.004) than the A allele carrier in male cases. Moreover, the rs3764880 genotype was significantly associated with TC (P=0.001, PBc=0.004) and LDL level (P=0.0002, PBc=0.0008) in the allele model, and the GG carrier had a higher LDL level (P=0.009, PBc=0.036) than the AA carrier in male patients. However, no statistically significant association was found between rs3764880 and any IS-related quantitative traits in female patients. Our study also revealed that IL-1b was associated with HDL (P=0.006, PBc=0.012) in IS patients. Therefore, TLR8 gene rs3764880 polymorphism might be associated with susceptibility and involved in the inflammatory reaction and lipid metabolism of IS in southern Chinese Han. PMID- 27772796 TI - Cytotoxic dimeric xanthanolides from fruits of Xanthium chinense. AB - Nine dimeric xanthanolides, pungiolides F-N, and five known analogues, pungiolides A-E, were isolated from fruits of Xanthium chinense. Their structures were elucidated through spectroscopic and electronic circular dichroism (ECD) analyses. Pungiolide F is a xanthanolide dimer with an acyclic linkage. Five of the dimers, pungiolides H, L, A, C and E, exhibited moderate cytotoxicities with IC50 values in the range of 0.90-6.84 MUM using taxol as the positive control, which had, by comparison, IC50 values in the range of 0.00118-0.0675 MUM. These findings enrich the structural diversity of dimeric sesquiterpene lactones. PMID- 27773221 TI - 3D ultrasound estimation of the effective volume for popliteal block at the level of division. AB - : Local anaesthetic injection between the tibial and commmon peroneal nerves within connective tissue sheath results in a predictable diffusion and allows for a reduction in the volume needed to achieve a consistent sciatic popliteal block. Using 3D ultrasound volumetric acquisition, we quantified the visible volume in contact with the nerve along a 5cm segment. METHODS: We included 20 consecutive patients scheduled for bunion surgery. Ultrasound guided popliteal block was performed using a posterior, out of plane approach at the level of division of the sciatic nerve. Thirty ml of mepivacaine 1.5% and levobupivacaine 0.5% were slowly injected while assessing the injection pressure and the diffusion of the local anaesthetic. Volumetric acquisition was performed before and after the block to quantify the the volume of the sciatic nerve and the volume of the surrounding hypoechoic halo contained inside the connective tissue in a 5cm segment. RESULTS: All blocks were successful within 20min after the injection. The total estimated volume contained inside the common connective tissue sheath was 6.8+/-2.6cm3. Of this, the volume of the halo sorrounding the nerve was 4.4+/ 1.7cm3 and the volume inside the sciatic nerve was 2.4+/-1.7cm3. CONCLUSIONS: The volume of local anaesthetic in close contact with the sciatic nerve can be estimated by volumetric acquisition. Our results suggest that the effective volume of local anaesthetic needed for a successful sciatic popliteal block could be reduced to less than 7ml. PMID- 27773222 TI - Differential characteristics of bacteraemias according to age in a community hospital. AB - OBJECTIVE: To describe the characteristics of bacteraemias, according to age, in a community hospital. MATERIAL AND METHOD: A prospective study of bacteraemias was conducted in 2011. The patients were classified into 3 age groups: younger than 65 years, 65 to 79, and 80 or older. The study collected variables on the patients and episodes. RESULTS: The study analysed 233 bacteraemias in 227 patients (23.8% in those younger than 65 years; 38.3% in the 65 to 79 age group; and 37.9% in the 80 years or older group). The most common underlying disease in all the groups was diabetes mellitus. In the most elderly patients, the Charlson index was highest, there was a lower proportion of exogenous factors, and almost 25% were severely dependent (Barthel index<20). Escherichia coli was the most common germ, and the main focus was urological. The patients aged 80 years or older had predominantly healthcare-associated infections, less severe symptoms (sepsis) (66.3%) and higher mortality (29.1%) compared with the younger patients. CONCLUSIONS: The very elderly patients with bacteraemia presented fewer exogenous factors, greater comorbidity and a poorer functional situation. The most common focus was urological and the origin was healthcare related. Despite their less severe clinical presentation, these patients' mortality was greater, and their degree of dependence was a highly relevant independent risk factor. PMID- 27773224 TI - Sonochemistry in organocatalytic enamine-azide [3+2] cycloadditions: A rapid alternative for the synthesis of 1,2,3-triazoyl carboxamides. AB - We described herein the use of sonochemistry in the organocatalytic enamine-azide [3+2] cycloadditions of beta-oxo-amides with a range of substituted aryl azides. These sonochemical promoted reactions were found to be amenable to a range of beta-oxo amides or aryl azides, providing an efficient access to new N-aryl-1,2,3 triazoyl carboxamides in good to excellent yields and short times of reaction. PMID- 27773223 TI - Screening and optimization of highly effective ultrasound-assisted simultaneous adsorption of cationic dyes onto Mn-doped Fe3O4-nanoparticle-loaded activated carbon. AB - The ultrasound-assisted simultaneous adsorption of brilliant green (BG) and malachite green (MG) onto Mn-doped Fe3O4 nanoparticle-loaded activated carbon (Mn Fe3O4-NP-AC) as a novel adsorbent was investigated and analyzed using first derivative spectrophotometry. The adsorbent was characterized using FT-IR, FE SEM, EDX and XRD. Plackett-Burman design was applied to reduce the total number of experiments and to optimize the ultrasound-assisted simultaneous adsorption procedure, where pH, adsorbent mass and sonication time (among six tested variables) were identified as the most significant factors. The effects of significant variables were further evaluated by a central composite design under response surface methodology. The significance of independent variables and their interactions was investigated by means of the analysis of variance (ANOVA) within 95% confidence level together with Pareto chart. Using this statistical tool, the optimized ultrasound-assisted simultaneous removal of basic dyes was obtained at 7.0, 0.02g, 3min for pH, adsorbent mass, and ultrasonication time, respectively. The maximum values of BG and MG uptake under these experimental conditions were found to be 99.50 and 99.00%, respectively. The adsorption process was found to be followed by the Langmuir isotherm and pseudo-second order model using equilibrium and kinetic studies, respectively. According to Langmuir isotherm model, the maximum adsorption capacities of the adsorbent were obtained to be 101.215 and 87.566mgg-1 for MG and BG, respectively. The value of apparent energy of adsorption obtained from non-linear Dubinin-Radushkevich model (4.348 and 4.337kJmol-1 for MG and BG, respectively) suggested the physical adsorption of the dyes. The studies on the well regenerability of the adsorbent in addition to its high adsorption capacity make it promising for such adsorption applications. PMID- 27773225 TI - Treating soil-washing fluids polluted with oxyfluorfen by sono-electrolysis with diamond anodes. AB - This works is focused on the treatment by sono-electrolysis of the liquid effluents produced during the Surfactant-Aided Soil-Washing (SASW) of soils spiked with herbicide oxyfluorfen. Results show that this combined technology is very efficient and attains the complete mineralization of the waste, regardless of the surfactant/soil radio applied in the SASW process (which is the main parameter of the soil remediation process and leads to very different wastes). Both the surfactant and the herbicide are completely degraded, even when single electrolysis is used; and only two intermediates are detected by HPLC in very low concentrations. Conversely, the efficiency of single sonolysis approach, for the oxidation of pollutant, is very low and just small changes in the herbicides and surfactant concentrations are observed during the tests carried out. Sono electrolysis with diamond electrodes achieved higher degradation rates than those obtained by single sonolysis and/or single electrolysis with diamond anodes. A key role of sulfate is developed, when it is released after the electrochemical degradation of surfactant. The efficient catalytic effect observed which can be explained by the anodic formation of persulfate and the later, a sono-activation is attained to produce highly efficient sulfate radicals. The effect of irradiating US is more importantly observed in the pesticide than in the surfactant, in agreement with the well-known behavior of these radicals which are known to oxidize more efficiently aromatic compounds than aliphatic species. PMID- 27773226 TI - Enhanced primary sludge sonication by heat insulation to reclaim carbon source for biological phosphorous removal. AB - Ultrasound pretreatment is a potent step to disintegrate primary sludge (PS). The supernatant of sonicated PS is recycled as an alternative carbon source for biological phosphorus removal. In this study, we investigated the role of temperature on PS disintegration during sonication. We found that a temperature of 60 degrees C yielded a dissolution rate of about 2% soluble chemical oxygen demand (SCOD) as compared to 7% SCOD using sonication at the specific energy (SE) of 7359kJ/kg TS. Using the SE of 6000kJ/kg TS with heat insulation during sonication, the SCOD dissolution rate of PS was similar to the result at the SE of 7051kJ/kg TS without heat insulation. Upon treatment with sonication, the PS released low concentrations of Cu and Zn into the supernatant. The phosphorus accumulating organisms (PAOs) used the supernatant of sonicated PS as the carbon source. Supplementation with the diluted sonicated PS supernatant (SCOD~1000mg/L) in anaerobic phase resulted in the release of phosphorus (36mg/L) and the production of polyhydroxyalkanoates (PHAs) (0.36g PHA/g SS). Compared with sodium acetate, higher polyhydroxyvalerate (PHV) faction in the polyhydroxyalkanoates (PHAs) was observed in the biomass when incubated with sonicated PS as the carbon source. This work provides a simple pathway to conserve energy and to enhance efficiencies of ultrasonic pretreatment and the recovery of carbon source from the sludge for improving the phosphorus removal in the ENR system. PMID- 27773227 TI - Deposition of silver nanoparticles on polyester fiber under ultrasound irradiations. AB - The polyester fiber containing Ag nanoparticles was prepared through the chemical reduction under ultrasound irradiation. Influences of reduction reagents on the morphological properties of Ag nanoparticles@polyester fiber were studied. The sizes of metallic nanoparticles vary significantly with the types of reduction reagents used in the synthesis. A strong reduction reaction promotes a fast reaction rate and favors the formation of smaller nanoparticle. A weak reduction reagent induces a slow reaction rate and favors relatively larger particles. The products were investigated by means of scanning electron microscopy (SEM) and X ray powder diffraction (XRPD). PMID- 27773228 TI - A numerical simulation of acoustic field within liquids subject to three orthogonal ultrasounds. AB - When one beam of ultrasound propagates along a single direction in liquids, the cavitation effect is always confined to a limited volume close to the ultrasonic source. This greatly limits the application of power ultrasound in liquid processing and materials fabrication. In this study, a methodology for applying three orthogonal ultrasounds within liquids has been proposed. By solving the Helmholtz equation, the sound field distribution characteristics are investigated in 1D (one dimensional), 2D (two dimensional) and 3D (three dimensional) ultrasounds at their resonant frequencies, which show that the coherent interaction of three beams of ultrasounds is able to strikingly promote the sound pressure level and reinforce the mean acoustic energy density as compared with that in 1D case. Hence, the potential cavitation volume is enlarged remarkably. This opens new possibilities for the design and optimization of ultrasonic technology in fabricating materials. PMID- 27773229 TI - Influence of ultrasound pretreatment on wood physiochemical structure. AB - As an initial step to increase the use of renewable biomass resources, this study was aimed at investigating the effects of ultrasound pretreatment on structural changes of wood. Samples were pretreated by ultrasound with the power of 300W and frequency of 28kHz in aqueous soda solution, aqueous acetic acid, or distilled water, then pretreated and control samples were characterized via X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The results shown that ultrasound pretreatment is indeed effective in modifying the physiochemical structure of eucalyptus wood; the pretreatment decreased the quantity of alkali metals (e.g., potassium, calcium and magnesium) in the resulting material. Compared to the control group, the residual char content of samples pretreated in aqueous soda solution increased by 10.08%-20.12% and the reaction temperature decreased from 361 degrees C to 341 degrees C, however, in samples pretreated by ultrasound in acetic solution or distilled water, the residual char content decreased by 12.40%-21.45% and there were no significant differences in reactivity apart from a slightly higher maximum reaction rate. Ultrasound pretreatment increased the samples' crystallinity up to 35.5% and successfully removed cellulose, hemicellulose, and lignin from the samples; the pretreatment also increased the exposure of the sample to the treatment solutions, broke down sample pits, and generated collapses and microchannels on sample pits, and removed attachments in the samples. PMID- 27773230 TI - Performance and mechanism of low-frequency ultrasound to regenerate the biological activated carbon. AB - Biological activated carbon (BAC) filter has been widely used as an effective water treatment but regenerations of BAC are costly. Ultrasound has been successfully applied for regeneration of activated carbon but has been less frequently applied to the regenerate the BAC. In this study, bench-scale and pilot-scale experiments were conducted to evaluate the regeneration performance and mechanism of BAC with low-frequency ultrasound. Adsorption indices, microbiological parameters, pore structure and removal efficiencies were further investigated. The results showed that low-frequency ultrasound could regenerate the BAC effectively. The regeneration effects were significantly affected by the frequency, sonication intensity, sonication time, and water temperature, but not the usage time of the BAC. The optimized conditions were identified as 40kHz of frequency, 115*10-3W/cm3 of sonication intensity, 25-30 degrees C of water temperature and 5min of sonication time. The iodine value and methylene blue value increased from 480mg/g and 100mg/g to 680mg/g and 133mg/g respectively, the biomass decreased from 310nmolP/gC to 245nmolP/gC, while the biological activity increased from 0.03mg O2/hgC to 0.0355mg O2/hgC under the optimized condition. After three months of continuous operation, removal efficiencies of regenerated BAC were still high for the removal of organic contaminants, atrazine, and 2-MIB. Analysis of pore structure, BET surface area, and scanning electron microscopy indicated that ultrasound mainly acted on surface and macro-pores of BAC through the high-speed microjets and high-pressure microstreams resulted from the collapse of cavitation bubbles. PMID- 27773231 TI - Effects of high-intensity ultrasound on Maillard reaction in a model system of d xylose and l-lysine. AB - This study compared the effects of high-intensity ultrasound on Maillard reaction (MR) with those of thermally produced MR using a model system of d-xylose and l lysine. The ultrasonic MR process had higher depletion rates of reactants and higher generation rates of intermediate MR products (MRPs) and melanoidins under relatively low processing temperatures (55 and 60 degrees C). However, the rates were lower for ultrasonic MR than thermal MR when the processing temperature increased to 65, 70 and 75 degrees C. Overall, ultrasonic MR had relatively low activation energy (Ea) compared to thermal MR (e.g. 55.59 vs. 80.42kJmol-1 for d xylose depletion). Moreover, ultrasonic MR could produce at least one N containing pyrazine (3-ethyl-2,5-dimethylpyrazine), one N-containing amine (butyl amine) and one O-containing volatile compound (maltol) that were absent from thermal MR. The difference in flavour generation might be a result of the extremely high, albeit momentary, temperature and pressure condition produced by high-intensity ultrasound. PMID- 27773232 TI - Experimental investigation of conical bubble structure and acoustic flow structure in ultrasonic field. AB - The objective of this paper is to investigate the transient conical bubble structure (CBS) and acoustic flow structure in ultrasonic field. In the experiment, the high-speed video and particle image velocimetry (PIV) techniques are used to measure the acoustic cavitation patterns, as well as the flow velocity and vorticity fields. Results are presented for a high power ultrasound with a frequency of 18kHz, and the range of the input power is from 50W to 250W. The results of the experiment show the input power significantly affects the structures of CBS, with the increase of input power, the cavity region of CBS and the velocity of bubbles increase evidently. For the transient motion of bubbles on radiating surface, two different types could be classified, namely the formation, aggregation and coalescence of cavitation bubbles, and the aggregation, shrink, expansion and collapse of bubble cluster. Furthermore, the thickness of turbulent boundary layer near the sonotrode region is found to be much thicker, and the turbulent intensities are much higher for relatively higher input power. The vorticity distribution is prominently affected by the spatial position and input power. PMID- 27773233 TI - Physiochemical and cytotoxicity study of TPGS stabilized nanoemulsion designed by ultrasonication method. AB - The main aim of the present work was to prepare TPGS stabilized D-alpha Tocopherol, lemon oil, tween-80, and water nanoemulsion by low cost and highly effective sonication method. The prepared nanoemulsion showed good stability for 60days at variable temperature conditions i.e. 4, 25 and 37 degrees C. The tolerance of the prepared nanoemulsion to salt (50mM-500mM) and pH (pH 2-pH 7.4) was also studied. The morphology and droplet size of pure and quinine loaded nanoemulsion was characterized with transmission electron microscopy. The prepared formulation was transparent and the obtained average particle size ranged between 25nm and 35nm. The nanoemulsion was found to be non toxic. The cell viability study of pure nanoemulsion carried out on Hep G2 cells revealed that the cell viability was 100%. The formulation further exhibited high quinine loading and release capacity with cumulative release up to 76+/-2% and 65+/-2% at pH 7.4 and pH 5.5 respectively. The interaction between quinine and vitamins (riboflavin, thiamine and biotin) was also carried out (aqueous medium). The study revealed that riboflavin had strong interaction with quinine and vitamins vis-a-vis thiamine and biotin. PMID- 27773234 TI - Degradation of a cationic dye (Rhodamine 6G) using hydrodynamic cavitation coupled with other oxidative agents: Reaction mechanism and pathway. AB - In the present study, decolorization and mineralization of a cationic dye, Rhodamine 6G (Rh6G), has been carried out using hydrodynamic cavitation (HC). Two cavitating devices such as slit and circular venturi were used to generate cavitation in HC reactor. The process parameters such as initial dye concentration, solution pH, operating inlet pressure, and cavitation number were investigated in detail to evaluate their effects on the decolorization efficiency of Rh6G. Decolorization of Rh6G was marginally higher in the case of slit venturi as compared to circular venturi. The kinetic study showed that decolorization and mineralization of the dye fitted first-order kinetics. The loadings of H2O2 and ozone have been optimized to intensify the decolorization and mineralization efficiency of Rh6G using HC. Nearly 54% decolorization of Rh6G was obtained using a combination of HC and H2O2 at a dye to H2O2 molar ratio of 1:30. The combination of HC with ozone resulted in 100% decolorization in almost 5-10min of processing time depending upon the initial dye concentration. To quantify the extent of mineralization, total organic carbon (TOC) analysis was also performed using various processes and almost 84% TOC removal was obtained using HC coupled with 3g/h of ozone. The degradation by-products formed during the complete degradation process were qualitatively identified by liquid chromatography-mass spectrometry (LC-MS) and a detailed degradation pathway has been proposed. PMID- 27773235 TI - Different effects of sonication pretreatment on carbon nanomaterials under low hydrogen peroxide concentrations. AB - Dispersing carbon nanomaterials with the aid of sonication has become a widely used procedure for generating homogenous solutions. A systematic study was performed to evaluate the effects of a practical sample preparation procedure that involves mild sonication with/without low concentrations of hydrogen peroxide. Hydrogen peroxide is ubiquitously present in surface water and involved in advanced oxidation processes. Significant oxidation was observed for fullerene in the liquid phase, whereas an appreciable amount of hydrogen was covalently attached to the carbon cage of solid fullerene. Under the same conditions, only the removal of oxidized amorphous carbon was detected for carbon nanotubes. The presence of a low concentration of hydrogen peroxide during sonication exacerbated the effects. The changes in physicochemical properties were characterized quantitatively using X-ray photoelectron spectroscopy and elemental chemical analysis and qualitatively using matrix-assisted laser desorption ionization mass spectroscopy, 1H nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy and Raman spectroscopy. Our results highlight the effects that can occur during sample preparation step and the potential for misinterpreting the toxicity, reactivity and environmental fate of carbon nanomaterials. PMID- 27773236 TI - Ultrasound irradiation effect on morphology and size of two new potassium coordination supramolecule compounds. AB - Two new potassium coordination supramolecular compounds (2D and 1D), [K(H3L)(H2L)(H2O)]n.H2O (1) and [K(H2L')(HL')(H2O)2].H2O (2), (L=1,3,5 tricarboxylic acid, L'=2,6-pyridinedicarboxylic acid), have been synthesized under different experimental conditions. Micrometric crystals (bulk) or nano sized materials have been obtained depending on using the branch tube method or sonochemical irradiation. All materials have been characterized by field emission scanning electron microscopy (FE-SEM), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), FT-IR spectroscopy and elemental analyses. Single crystal X-ray analyses on compounds 1 and 2 show that K+ ions are 3- and 7 coordinated, respectively. Additionally, H-bonds incorporate the layers and chains in 1 and 2 into 3D and 2D (along (0,0,1) direction) frameworks. Topological analysis shows that the compound 1 and 2 are 3,6-coordinated kgd and 2,4-coordinated 2,4C4 net. The thermal stability of compounds 1 and 2 in bulk and nano-size has been studied by thermal gravimetric (TG) and differential thermal analyses (DTA) and compared each other. The role of different parameters like temperature, reaction time and ultrasound irradiation power on the growth and morphology of the nano-structures are studied. Results suggest that an increase of temperature, sonication power and reduction of reaction time led to a particle size decrease. PMID- 27773237 TI - Development and validation of ultrasound-assisted solid-liquid extraction of phenolic compounds from waste spent coffee grounds. AB - In this current work, Box-Behnken statistical experimental design (BBD) was adopted to evaluate and optimize USLE (ultrasound-assisted solid-liquid extraction) of phytochemicals from spent coffee grounds. Factors employed in this study are ultrasonic power, temperature, time and solid-liquid (SL) ratio. Individual and interactive effect of independent variables over the extraction yield was depicted through mathematical models, which are generated from the experimental data. Determined optimum process conditions are 244W of ultrasonic power, 40 degrees C of temperature, 34min of time and 1:17g/ml of SL ratio. The predicted values were in correlation with experimental values with 95% confidence level, under the determined optimal conditions. This indicates the significance of selected method for USLE of phytochemicals from SCG. PMID- 27773238 TI - Performance and mechanism of phycocyanin removal from water by low-frequency ultrasound treatment. AB - Ultrasonication pretreatment of raw water with high content of algal cells might cause an increase in dissolved organic nitrogen (DON) and proteins, which must be removed effectively before coagulation. In this study, the efficiency of sonication treatment in removing typical proteins derived from algal cells was investigated by applying ultrasonic waves at 20, 40, 60, 80, and 100kHz, and the influencing factors and removal mechanism were discussed. The results showed that low-frequency sonication could degrade phycocyanin to some extent, achieving about 95% removal rate after 150min of sonication. However, excitation emission matrix analysis indicated that ultrasonication could not entirely degrade phycocyanin into inorganic nitrogen, and many proteins and nitrogen-containing organics were found in the samples after sonication. While the total nitrogen concentration remained consistent during the entire sonication process (240min), the total inorganic nitrogen concentration increased from 0.6 to 1.3mg/L, indicating that only 33.3% of DON was oxidized into inorganic nitrogen. Nevertheless, sonication could significantly attenuate the interference of phycocyanin in coagulation and enhance coagulation. The mechanical effects and free-radical oxidation resulting from cavitation collapse could be responsible for the degradation of phycocyanin and proteins following sonication. In all, the use of ultrasonic treatment as a posttreatment following sonication to remove algal cells from raw water may not be beneficial. PMID- 27773239 TI - A comparison of ultrasound-augmented and conventional leaching of silver from sintering dust using acidic thiourea. AB - In the process of steel manufacture, up to ten millions of tons of sintering dust (SD) are produced annually in China, which contain noble metals such as Ag. Therefore, recovery of silver (Ag) from SD could be a potential economic and environmental activity. The purpose of this article is to generate information about reaction kinetics of silver leaching with thiourea from SD, comparing the conventional and ultrasonic-augment leaching. The effects of various control parameters such as the ultrasound power, particle size, leaching temperature and thiourea concentration on leaching rate of silver were studied. The results showed 89% silver recovery for conventional process against 95% for ultrasound assisted leaching. The ultrasonic wave increased the leaching rate and shorten the reaction time. The rate controlling step was analyzed using shrinking core model and the rate controlling step is identified to be the diffusion through the product layer in both conventional and ultrasonic-augment leaching processes. The activation energies were estimated to be 28.01kJ/mol and 18.19kJ/mol, and the reaction order were 0.89 and 0.71, respectively. PMID- 27773241 TI - Ionic liquid mediated extraction, assisted by ultrasound energy, of available/mobilizable metals from sediment samples. AB - A new extraction method for metals from sediment samples was developed. In this procedure, the chelating agent EDTA was combined with a minimal amount of the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (Bmim[BF4]), assisted by ultrasound energy. The available analytes -Cd, Cr, Cu, Ni, Pb and Zn- were extracted under optimal conditions for a 12.5 ratio (extractant volume/sample mass) with 0.005molL-1 EDTA solution, 0.1molL-1 NaHCO3, 5.0mmolL-1 Bmim[BF4] and 7.0min of sonication time, using an ultrasonic bath (output power of 160W). The best extractions were obtained with 100W (power dissipated in the liquid). These conditions were obtained applying the univariate method. It is important to highlight that the conventional method (extraction with 0.05molL-1 EDTA solution only) consumes 6h to extract available metals from sediment samples selectively, and with the proposed procedure the extraction time is noticeable reduced to 7.0min. Extractable metal concentrations obtained were measured by flame atomic absorption spectrometry. The results showed good agreement with those obtained by the conventional method using a Student's paired t-test. PMID- 27773240 TI - Sonophotocatalytic inactivation of E. coli using ZnO nanofluids and its mechanism. AB - The present study evaluated inactivation efficiency of a sonophotocatalytic process using ZnO nanofluids including ultrasonic parameters such as power density, frequency and time. The result showed that inactivation efficiency was increased by 20% when ultrasonic irradiation was combined with photocatalytic process in the presence of natural light. Comparison of inactivation efficiency in photocatalytic, ultrasonic and sonocatalytic processes using Escherichia coli as a model bacteria identified that inactivation efficiencies are shown in the following order: ultrasonic irradiation0.05) on CTC degradation in sludge. The estimated iron concentration in sludge (115mg/kg) was enough to degrade CTC without the addition of external iron. The only adjustment of sludge pH to 3 was enough to generate in-situ hydroxyl radicals by utilizing iron which is already present in the sludge. This observation was further supported by hydroxyl radical estimation with adjustment of water pH to 3 and with and without the addition of iron. The optimum operating UlS conditions were found to be 60% amplitude for 106min by using RSM. Compared to standalone UlS and FO at 1:1 ratio, FS showed 15% and 8% increased CTC degradation respectively. In addition, UlS of sludge increased estrogenic activity 1.5 times higher compared to FO. FS treated samples did not show any estrogenic activity. PMID- 27773255 TI - Multi-response optimization of ultrasound assisted competitive adsorption of dyes onto Cu (OH)2-nanoparticle loaded activated carbon: Central composite design. AB - This paper focuses on the development of an effective methodology to obtain the optimum removal conditions assisted by ultrasonics to maximize the simultaneous removal of dyes, eosin Y (EY), methylene blue (MB) and phenol red (PR), by Cu(OH)2-NP-AC in aqueous solution using response surface methodology (RSM). The effects of variables such as pH, initial dyes concentrations (mgL-1), and amount of sorbent (mg) and sonication time (min) on the dyes removal were studied. A central composite design (CCD) was applied to evaluate the interactive effects of adsorption variables. A good correlation (with R2>0.940) between the statistical model and experiment was found for dyes removal from aqueous wastewater using the adsorbent. The optimum removal (99.20%+/-1.48) was thus obtained at pH 6.0, ultrasound time 2.5min, adsorbent mass 20mg and initial dye concentration at 5mgL 1 for MB and EY and 12.5mgL-1 for PR. The maximum adsorption capacity (Qmax) was calculated from the Langmuir isotherm as 32.9, 26.4 and 38.5mgg-1 for the MB, EY and PR, respectively for the 0.015g of sorbent. The adsorption kinetic data of the dyes were analyzed and was found fitting well in a pseudo-second-order equation. Adsorption isotherms and separation factors showed that the adsorbent displays a high selectivity toward one dye in a three-component system with an affinity order of PR>MB>EY. On the other hand, acoustic waves emitted by the cavitation bubbles render a direct effect on the process. This is attributed to the discrete nature and high pressure amplitude of the waves, which creates excessively high convection in the medium, causing adsorption of the pollutants. The chemical nature of the pollutants influences the enhancement effect of ultrasound. PMID- 27773256 TI - An objective comparison of commercially-available cavitation meters. AB - With a number of cavitation meters on the market which claim to characterise fields in ultrasonic cleaning baths, this paper provides an objective comparison of a selection of these devices and establishes the extent to which their claims are met. The National Physical Laboratory's multi-frequency ultrasonic reference vessel provided the stable 21.06kHz field, above and below the inertial cavitation threshold, as a test bed for the sensor comparison. Measurements from these devices were evaluated in relation to the known acoustic pressure distribution in the cavitating vessel as a means of identifying the mode of operation of the sensors and to examine the particular indicator of cavitation activity which they deliver. Through the comparison with megahertz filtered acoustic signals generated by inertial cavitation, it was determined that the majority of the cavitation meters used in this study responded to acoustic pressure generated by the direct applied acoustic field and therefore tended to overestimate the occurrence of cavitation within the vessel, giving non-zero responses under conditions when there was known to be no inertial cavitation occurring with the reference vessel. This has implications for interpreting the data they provide in user applications. PMID- 27773257 TI - Particle size studies to reveal crystallization mechanisms of the metal organic framework HKUST-1 during sonochemical synthesis. AB - Systematic studies of key operating parameters for the sonochemical synthesis of the metal organic framework (MOF) HKUST-1(also called CuBTC) were performed including reaction time, reactor volume, sonication amplitude, sonication tip size, solvent composition, and reactant concentrations analyzed through SEM particle size analysis. Trends in the particle size and size distributions show reproducible control of average particle sizes between 1 and 4MUm. These results along with complementary studies in sonofragmentation and temperature control were conducted to compare these results to kinetic crystal growth models found in literature to develop a plausible hypothetical mechanism for ultrasound-assisted growth of metal-organic-frameworks composed of a competitive mechanism including constructive solid-on-solid (SOS) crystal growth and a deconstructive sonofragmentation. PMID- 27773258 TI - Effect of ultrasound and centrifugal force on carambola (Averrhoa carambola L.) slices during osmotic dehydration. AB - Osmotic dehydration (OD) of carambola slices were carried out using glucose, sucrose, fructose and glycerol as osmotic agents with 70 degrees Bx solute concentration, 50 degrees C of temperature and for time of 180min. Glycerol and sucrose were selected on the basis of their higher water loss, weight reduction and lowers solid gain. Further the optimization of OD of carambola slices (5mm thick) were carried out under different process conditions of temperature (40-60 degrees C), concentration of sucrose and glycerol (50-70 degrees Bx), time (180min) and fruit to solution ratio (1:10) against various responses viz. water loss, solid gain, texture, rehydration ratio and sensory score according to a composite design. The optimized value for temperature, concentration of sucrose and glycerol has been found to be 50 degrees C, 66 degrees Bx and 66 degrees Bx respectively. Under optimized conditions the effect of ultrasound for 10, 20, 30min and centrifugal force (2800rpm) for 15, 30, 45 and 60min on OD of carambola slices were checked. The controlled samples showed 68.14% water loss and 13.05% solid gain in carambola slices. While, the sample having 30min ultrasonic treatment showed 73.76% water loss and 9.79% solid gain; and the sample treated with centrifugal force for 60min showed 75.65% water loss and 6.76% solid gain. The results showed that with increasing in treatment time the water loss, rehydration ratio were increased and solid gain, texture were decreased. PMID- 27773259 TI - Enzymatic inactivation and antioxidant properties of blackberry juice after thermoultrasound: Optimization using response surface methodology. AB - The purpose of this research was to optimize the thermoultrasound conditions for blackberry juice using the response surface methodology and considering juice quality parameters and antioxidant capacity. With the exception of microbial growth, the response variables showed high correlation coefficients with the mathematical model (R2adj>0.91). Thermoultrasound treatment inactivated all the evaluated microorganisms, and at the optimum conditions (50+/-1 degrees C at 17+/ 1min) it increased enzyme inactivation and antioxidant activity in comparison to pasteurized juice. The results demonstrated that thermoultrasound can be an alternative to pasteurization for the production of safe and high-quality juices with the added value of higher concentration of bioactive compounds and antioxidant capacity. PMID- 27773260 TI - Synergistic effects of ultrasounds in the sonoelectrochemical oxidation of pharmaceutical carbamazepine pollutant. AB - The synergistic effects were evaluated during the oxidation of carbamazepine using a sono-electrochemical process. The sono-electrochemical oxidation was performed using two types of experimental units (having 1L and 100L of working volume, respectively) and containing one anode (Ti/PbO2) and one cathode (Ti). Different operating parameters, including power of ultrasounds, current intensity and reaction time were investigated. The degree of synergy increased when the current intensity decreased, whereas it increased with the power of ultrasounds imposed. The highest value of the synergy degree (33%) was recorded for the lowest current intensity (1.0A) and the highest power of ultrasounds (40W). Likewise, the benefits of ultrasound were observed during a long-term period of treatment of CBZ (30days of experiments without interruption). A relatively high degradation rate was recorded using the sono-electrochemical process (99.5%) (at I=1A, P=40W), compared to a percentage of CBZ degradation of 91% recorded during electrolysis alone (at I=1A, P=0W). Likewise, the scanning electron microscopy views and the measurements of the electrochemical impedance spectroscopy (EIS) revealed that there are not impurities deposited on the surface of electrode in the present of ultrasounds. PMID- 27773261 TI - Heterogeneous sono-Fenton-like process using martite nanocatalyst prepared by high energy planetary ball milling for treatment of a textile dye. AB - High energy planetary ball milling was applied to prepare sono-Fenton nanocatalyst from natural martite (NM). The NM samples were milled for 2-6h at the speed of 320rpm for production of various ball milled martite (BMM) samples. The catalytic performance of the BMMs was greater than the NM for treatment of Acid Blue 92 (AB92) in heterogeneous sono-Fenton-like process. The NM and the BMM samples were characterized by XRD, FT-IR, SEM, EDX and BET analyses. The particle size distribution of the 6h-milled martite (BMM3) was in the range of 10-90nm, which had the highest surface area compared to the other samples. Then, the impact of main operational parameters was investigated on the process. Complete removal of the dye was obtained at the desired conditions including initial pH 7, 2.5g/L BMM3 dosage, 10mg/L AB92 concentration, and 150W ultrasonic power after 30min of treatment. The treatment process followed pseudo-first order kinetic. Environmentally-friendly modification of the NM, low leached iron amount and repeated application at milder pH were the significant benefits of the BMM3. The GC-MS was successfully used to identify the generated intermediates. Eventually, an artificial neural network (ANN) was applied to predict the AB92 removal efficiency based upon the experimental data with a proper correlation coefficient (R2=0.9836). PMID- 27773262 TI - Inverse effects of flowing phase-shift nanodroplets and lipid-shelled microbubbles on subsequent cavitation during focused ultrasound exposures. AB - This paper compared the effects of flowing phase-shift nanodroplets (NDs) and lipid-shelled microbubbles (MBs) on subsequent cavitation during focused ultrasound (FUS) exposures. The cavitation activity was monitored using a passive cavitation detection method as solutions of either phase-shift NDs or lipid shelled MBs flowed at varying velocities through a 5-mm diameter wall-less vessel in a transparent tissue-mimicking phantom when exposed to FUS. The intensity of cavitation for the phase-shift NDs showed an upward trend with time and cavitation for the lipid-shelled MBs grew to a maximum at the outset of the FUS exposure followed by a trend of decreases when they were static in the vessel. Meanwhile, the increase of cavitation for the phase-shift NDs and decrease of cavitation for the lipid-shelled MBs had slowed down when they flowed through the vessel. During two discrete identical FUS exposures, while the normalized inertial cavitation dose (ICD) value for the lipid-shelled MB solution was higher than that for the saline in the first exposure (p-value <0.05), it decreased to almost the same level in the second exposure. For the phase-shift NDs, the normalized ICD was 0.71 in the first exposure and increased to 0.97 in the second exposure. At a low acoustic power, the normalized ICD values for the lipid shelled MBs tended to increase with increasing velocities from 5 to 30cm/s (r>0.95). Meanwhile, the normalized ICD value for the phase-shift NDs was 0.182 at a flow velocity of 5cm/s and increased to 0.188 at a flow velocity of 15cm/s. As the flow velocity increased to 20cm/s, the normalized ICD was 0.185 and decreased to 0.178 at a flow velocity of 30cm/s. At high acoustic power, the normalized ICD values for both the lipid-shelled MBs and the phase-shift NDs increased with increasing flow velocities from 5 to 30cm/s (r>0.95). The effects of the flowing phase-shift NDs vaporized into gas bubbles as cavitation nuclei on the subsequent cavitation were inverse to those of the flowing lipid-shelled MBs destroyed after focused ultrasound exposures. PMID- 27773263 TI - Ultrasound technology for food fermentation applications. AB - Fermentation processes involve the participation of enzymes and organic catalysts, generated by range of microorganisms to produce chemical transformations. Ultrasound can be used in such processes to either monitor the progress of fermentation or to influence its progress. High frequency ultrasound (>2MHz) has been extensively reported as a tool for the measurement of the changes in chemical composition during fermentation providing real time information on reaction progress. Low frequency ultrasound (20-50kHz) can influence the course of fermentation by improving mass transfer and cell permeability leading to improved process efficiency and production rates. It can also be used to eliminate micro-organisms which might otherwise hinder the process. This review summarises key applications of high and low frequency ultrasound in food fermentation applications. PMID- 27773264 TI - Sonocatalytic degradation of diclofenac with FeCeOx particles in water. AB - This paper studies the sonocatalytic degradation of diclofenac in water using FeCeOx-catalyzed ultrasound. The effects of pre-adsorption and gas addition were investigated. Nitrogen adsorption/desorption, SEM, XRD, Raman and XPS analyses of FeCeOx before and after sonication were characterized. The proposed mechanism was based on the microstructure changes of FeCeOx and reactive-species-scavenging performances. The results show that FeCeOx has excellent performance in catalyzing an ultrasonic system in water, and 80% of diclofenac was removed in 30min ([Diclofenac]=20mg/L, FeCeOx amount=0.5g/L, pH=6, ultrasonic density=3.0W/cm3, ultrasonic frequency=20kHz, temperature=298K). The Fe, Ce, and O elements remained highly dispersed in the structure of FeCeOx, and the solid solution structure of FeCeOx remained stable after the reaction. Ce (III) was gradually oxidized to Ce (IV) and Fe (III) was gradually reduced to Fe (II) after the reaction, which indicates that Fe and Ce ions with different valences coexisted in dynamic equilibrium. The amount of oxygen vacancies in FeCeOx significantly decreased after the reaction, which indicates that oxygen vacancy participated in the ultrasonic process. Singlet oxygen 1O2 was the primary reactive species in the degradation process, and the hydroxyl radicals OH and superoxide radical anion O2- also participated in the reaction. FeCeOx had excellent chemical stability with negligible leaching ions in the ultrasonic process. PMID- 27773266 TI - Ultrasound assisted co-precipitation synthesis and catalytic performance of mesoporous nanocrystalline NiO-Al2O3 powders. AB - Mesoporous nanocrystalline NiO-Al2O3 powders with high surface area were synthesized via ultrasound assisted co-precipitation method and the potential of the selected samples as catalyst was investigated in dry reforming reaction for preparation of synthesis gas. The prepared samples were characterized by N2 adsorption (BET), X-ray diffraction (XRD), Temperature programmed reduction and oxidation (TPR, TPO) and scanning electron microscopy (SEM) techniques. The effects of pH, power of ultrasound irradiation, aging time and calcination temperature on the textural properties of the catalysts were studied. The sample prepared under specified conditions (pH10, 70W, without aging time and calcined at 600 degrees C) exhibited the highest surface area (249.7m2g-1). This catalyst was calcined at different temperature and employed in dry reforming of methane and the catalytic results were compared with those obtained over the catalysts prepared by impregnation and co-precipitation methods. The results showed that the catalyst prepared by ultrasound assisted co-precipitation method exhibited higher activity and stability with lower degree of carbon formation compared to catalysts prepared by co-precipitation and impregnation methods. PMID- 27773265 TI - Ultrasound assisted forward osmosis concentration of fruit juice and natural colorant. AB - The present study deals with the effect of higher and lower molecular weight compounds present in the feed on concentration polarization during forward osmosis concentration and its mitigation by the application of ultrasound. The effects of ultrasound on transmembrane water flux at different forward osmosis membrane orientations and different model feed solutions consisting of sucrose and pectin have also been evaluated. The feed containing sucrose and pectin subjected towards active layer of the membrane was found to be the most suitable orientation. The application of ultrasound (30kHz) significantly reduced the concentration polarization when the feed contains sucrose concentration up to 5%. Whereas, in case of feed containing 0.5% pectin, the ultrasound was not found to be effective in dislodging the gel layer formation resulting in severe external concentration polarization on the membrane surface. In comparison to the ordinary forward osmosis process, the ultrasound-assisted forward osmosis process resulted in higher water fluxes in case of sweet lime juice as well as rose extract containing anthocyanin. The degradation of rose anthocyanin due to ultrasound was found to be 1.82%. Application of ultrasound was found to be an effective way in mitigating concentration polarization on the forward osmosis membrane resulting in increased flux. PMID- 27773267 TI - Synergistic effects of negative-charged nanoparticles assisted by ultrasound on the reversal multidrug resistance phenotype in breast cancer cells. AB - We have fabricated a negative-charged nanoparticle (Heparin-Folate-Tat-Taxol NP, H-F-Tat-T NP) with dual ligands, tumor targeting ligand folate and cell penetrating peptide Tat, to deliver taxol presenting great anticancer activity for sensitive cancer cells, while it fails to overcome multidrug resistance (MDR) in MCF-7/T cells (taxol-resistant breast cancer cells). Ultrasound (US) can increase the sensitivity of positive-charged NPs thereby making it possible to reverse MDR through inducing NPs' drug release. However, compared with the negative-charged NPs, positive-charged NPs may cause higher toxic effect. Hence, the combination of negative-charged NPs and US may be an efficient strategy for overcoming MDR. The conventional procedure to treat with NPs followed by US exposure possibly destruct multifunctional NPs resulting in its bioactivity inhibition. Herein, we have further improved the operating approach to eliminate US mechanical damage and keep the integrity of negative-charged NPs: cells are exposed to US with microbubbles (MBs) prior to the treatment of H-F-Tat-T NPs. Superior to the conventional method, US sonoporation affects the physiological property of cancer cells while preventing direct promotion of drug release from NPs. The results of the present study displayed that US in condition (1MHz, 10% duty cycle, duration of 80s, US intensity of 0.6W/cm2 and volume ratio of medium to MBs 20:1) combined with H-F-T-Tat-T NPs can achieve optimal reversal MDR effect in MCF-7/T cells. Mechanism study further disclosed that the individual effect of US was responsible for the enhancement of cell membrane permeability, inhibition of cell proliferation rate and down-regulation of MDR-related genes and proteins. Simultaneously, US sonoporation on resistant cancer cells indirectly increased the accumulation of NPs by inducing endosomal escape of negative-charged NPs. Taken together, the overcoming MDR ability for the combined strategy was achieved by the synergistic effect from individual function of NPs, physiological changes of resistant cancer cells and behavior changes of NPs caused by US. PMID- 27773268 TI - Effect of gold nanoparticle size on acoustic cavitation using chemical dosimetry method. AB - When a liquid is irradiated with high intensities of ultrasound irradiation, acoustic cavitation occurs. Acoustic cavitation generates free radicals from the breakdown of water and other molecules. Cavitation can be fatal to cells and is utilized to destroy cancer tumors. The existence of particles in liquid provides nucleation sites for cavitation bubbles and leads to decrease the ultrasonic intensity threshold needed for cavitation onset. In the present investigation, the effect of gold nanoparticles with appropriate amount and size on the acoustic cavitation activity has been shown by determining hydroxyl radicals in terephthalic acid solutions containing 15, 20, 28 and 35nm gold nanoparticles sizes by using 1MHz low level ultrasound. The effect of sonication intensity in hydroxyl radical production was considered. The recorded fluorescence signal in terephthalic acid solutions containing gold nanoparticles was considerably higher than the terephthalic acid solutions without gold nanoparticles at different intensities of ultrasound irradiation. Also, the results showed that the recorded fluorescence signal intensity in terephthalic acid solution containing finer size of gold nanoparticles was lower than the terephthalic acid solutions containing larger size of gold nanoparticles. Acoustic cavitation in the presence of gold nanoparticles can be used as a way for improving therapeutic effects on the tumors. PMID- 27773269 TI - Ultrasound irradiation based in-situ synthesis of star-like Tragacanth gum/zinc oxide nanoparticles on cotton fabric. AB - Application of natural biopolymers for green and safe synthesis of zinc oxide nanoparticles on the textiles is a novel and interesting approach. The present study offers the use of natural biopolymer, Tragacanth gum, as the reducing, stabilizing and binding agent for in-situ synthesis of zinc oxide nanoparticles on the cotton fabric. Ultrasonic irradiation leads to clean and easy synthesis of zinc oxide nanoparticles in short-time at low-temperature. FESEM/EDX, XRD, FT-IR spectroscopy, DSC, photocatalytic activities and antimicrobial assay are used to characterize Tragacanth gum/zinc oxide nanoparticles coated cotton fabric. The analysis confirmed synthesis of star-like zinc oxide nanoparticles with hexagonal wurtzite structure on the cotton fabric with the average particle size of 62nm. The finished cotton fabric showed a good photocatalytic activity on degradation of methylene blue and 100% antimicrobial properties with inhibition zone of 3.3+/ 0.1, 3.1+/-0.1 and 3.0+/-0.1mm against Staphylococcus aureus, Escherichia coli and Candida albicans. PMID- 27773270 TI - Kinetic improvement of olive leaves' bioactive compounds extraction by using power ultrasound in a wide temperature range. AB - In this study, the effect of temperature and ultrasonic application on extraction kinetics of polyphenols from dried olive leaf was investigated. Conventional (CVE) and ultrasonic-assisted extraction (UAE) were performed at 10, 20, 30, 50 and 70 degrees C using water as solvent. Extracts were characterized by measuring the total phenolic content, the antioxidant capacity and the oleuropein content (HPLC-DAD/MS-MS). Moreover, Naik's model was used to mathematically describe the extraction kinetics. The experimental results showed that phenolic extraction was faster in UAE (ultrasonic-assisted extraction) than in CVE (conventional extraction), being extraction kinetics satisfactorily described using Naik model (include VAR>98%). Besides, the total phenolic content, the antioxidant capacity and the oleuropein content were significantly (p<0.05) improved by increasing the temperature in both CVE and UAE. Oleuropein content reached 6.57+/-0.18 being extracted approximately 88% in the first minute for UAE experiments. PMID- 27773271 TI - Visualization and optimization of cavitation activity at a solid surface in high frequency ultrasound fields. AB - Despite the increasing use of high frequency ultrasound in heterogeneous reactions, knowledge about the spatial distribution of cavitation bubbles at the irradiated solid surface is still lacking. This gap hinders controllable surface sonoreactions. Here we present an optimization study of the cavitation bubble distribution at a solid sample using sonoluminescence and sonochemiluminescence imaging. The experiments were performed at three ultrasound frequencies, namely 580, 860 and 1142kHz. We found that position and orientation of the sample to the transducer, as well as its material properties influence the distribution of active cavitation bubbles at the sample surface in the reactor. The reason is a significant modification of the acoustic field due to reflections and absorption of the ultrasonic wave by the solid. This is retraced by numerical simulations employing the Finite Element Method, yielding reasonable agreement of luminescent zones and high acoustic pressure amplitudes in 2D simulations. A homogeneous coverage of the test sample surface with cavitation is finally reached at nearly vertical inclination with respect to the incident wave. PMID- 27773272 TI - Sonochemical-driven ultrafast facile synthesis of SnO2 nanoparticles: Growth mechanism structural electrical and hydrogen gas sensing properties. AB - Synthesis of SnO2 nanoparticles have been successfully accomplished moderately at lower temperature by facile, rapid, efficient and mild ultrasonic irradiation method. The as-grown SnO2 nanoparticles are investigated by various characterization techniques in terms of structural, optical, electrical and gas sensing properties. XRD investigation has shown that the SnO2 nanoparticles materials exhibit single rutile crystal phase with high crystallinity. FESEM studies showed uniform and monodisperse morphology of SnO2 nanoparticles. The chemical composition of SnO2 was systematically studied by EDX measurements. Additional confirmation of three Raman shifts (432, 630, 772cm-1) indicated the characteristic properties of the rutile phase of the as-grown SnO2 nanoparticles. The optical properties of SnO2 nanoparticles were examined by DRS, and the electronic band gap of SnO2 nanoparticles were around 3.6eV. Electrical properties of the SnO2 nanoparticles measured at various temperatures have shown the semiconducting properties. Surface area and pore size of synthesized nanoparticles were analyzed from BET. It has been revealed that SnO2 nanoparticles have surface area is 47.8574m2/g and the pore size is 10.5nm. Moreover, hydrogen gas sensor made of SnO2 nanoparticles showed good sensitivity and faster response for the hydrogen gas. This method is template-less and surfactant-free which circumvents rigorous reaction work-up for the former removal, reaction temperature and reaction time compared to hydrothermal synthesis and pertinent to many other oxide materials. PMID- 27773273 TI - Effect of ultrasonic transmission rate on microstructure and properties of the ultrasonic-assisted brazing of Cu to alumina. AB - Fluxless brazing of bare alumina with Cu was conducted with an ultrasonic assisted brazing technique by a Zn-14wt.%Al filler. The shear strength of Cu/alumina joints (84MPa) exhibited 27% larger than the alumina/Cu joints (66MPa) due to different intermetallic phases and their morphologies formed in the seam under the same parameters, which are probably attributed to the transmission rate of ultrasonic energy varying with density of the ultrasonic horn-contacted materials. Overgrowth of stalactite-like CuZn5 contributes to better thermal dissipation of the ultrasonic-assisted brazed Cu/alumina joints. PMID- 27773274 TI - Sono-photo-degradation of carbamazepine in a thin falling film reactor: Operation costs in pilot plant. AB - The photo-Fenton degradation of carbamazepine (CBZ) assisted with ultrasound radiation (US/UV/H2O2/Fe) was tested in a lab thin film reactor allowing high TOC removals (89% in 35min). The synergism between the UV process and the sonolytic one was quantified as 55.2%. To test the applicability of this reactor for industrial purposes, the sono-photo-degradation of CBZ was also tested in a thin film pilot plant reactor and compared with a 28L UV-C conventional pilot plant and with a solar Collector Parabolic Compound (CPC). At a pilot plant scale, a US/UV/H2O2/Fe process reaching 60% of mineralization would cost 2.1 and 3.8?/m3 for the conventional and thin film plant respectively. The use of ultrasound (US) produces an extra generation of hydroxyl radicals, thus increasing the mineralization rate. In the solar process, electric consumption accounts for a maximum of 33% of total costs. Thus, for a TOC removal of 80%, the cost of this treatment is about 1.36?/m3. However, the efficiency of the solar installation decreases in cloudy days and cannot be used during night, so that a limited flow rate can be treated. PMID- 27773275 TI - Investigation of mass transfer intensification under power ultrasound irradiation using 3D computational simulation: A comparative analysis. AB - This paper aims at investigating the influence of acoustic streaming induced by low-frequency (24kHz) ultrasound irradiation on mass transfer in a two-phase system. The main objective is to discuss the possible mass transfer improvements under ultrasound irradiation. Three analyses were conducted: i) experimental analysis of mass transfer under ultrasound irradiation; ii) comparative analysis between the results of the ultrasound assisted mass transfer with that obtained from mechanically stirring; and iii) computational analysis of the systems using 3D CFD simulation. In the experimental part, the interactive effects of liquid rheological properties, ultrasound power and superficial gas velocity on mass transfer were investigated in two different sonicators. The results were then compared with that of mechanical stirring. In the computational part, the results were illustrated as a function of acoustic streaming behaviour, fluid flow pattern, gas/liquid volume fraction and turbulence in the two-phase system and finally the mass transfer coefficient was specified. It was found that additional turbulence created by ultrasound played the most important role on intensifying the mass transfer phenomena compared to that in stirred vessel. Furthermore, long residence time which depends on geometrical parameters is another key for mass transfer. The results obtained in the present study would help researchers understand the role of ultrasound as an energy source and acoustic streaming as one of the most important of ultrasound waves on intensifying gas-liquid mass transfer in a two-phase system and can be a breakthrough in the design procedure as no similar studies were found in the existing literature. PMID- 27773276 TI - The issue of cavitation number value in studies of water treatment by hydrodynamic cavitation. AB - Within the last years there has been a substantial increase in reports of utilization of hydrodynamic cavitation in various applications. It has came to our attention that many times the results are poorly repeatable with the main reason being that the researchers put significant emphasis on the value of the cavitation number when describing the conditions at which their device operates. In the present paper we firstly point to the fact that the cavitation number cannot be used as a single parameter that gives the cavitation condition and that large inconsistencies in the reports exist. Then we show experiments where the influences of the geometry, the flow velocity, the medium temperature and quality on the size, dynamics and aggressiveness of cavitation were assessed. Finally we show that there are significant inconsistencies in the definition of the cavitation number itself. In conclusions we propose a number of parameters, which should accompany any report on the utilization of hydrodynamic cavitation, to make it repeatable and to enable faster progress of science and technology development. PMID- 27773277 TI - Ultrasound-assisted fabrication of a novel nickel(II)-bis-pyrazolyl borate two nuclear discrete nano-structured coordination compound. AB - Ultrasound was used to synthesize nano-structures of [Ni(bpzB)2]2(1), a new two nuclear discrete-coordination compound of divalent nickel with bis-pyrazolyl borate(bpzB). The nanostructure was characterized by scanning electron microscopy, X-ray powder diffraction, infrared, and elemental analysis. The single-crystal X-ray data show that the coordination number of Ni(II) ions is four (Ni1N4 and Ni2N4) with square planar geometry. The supramolecular features in these complexes are guided and controlled by weak directional intermolecular interactions. The discrete molecules interact with each other through labile interactions, creating a 3D supramolecular framework. PMID- 27773278 TI - Ultrasound assisted extraction of pectin from waste Artocarpus heterophyllus fruit peel. AB - Four factors three level face centered central composite response surface design was employed in this study to investigate and optimize the effect of process variables (liquid-solid (LS) ratio (10:1-20:1ml/g), pH (1-2), sonication time (15 30min) and extraction temperature (50-70 degrees C)) on the maximum extraction yield of pectin from waste Artocarpus heterophyllus (Jackfruit) peel by ultrasound assisted extraction method. Numerical optimization method was adapted in this study and the following optimal condition was obtained as follows: Liquid solid ratio of 15:1ml/g, pH of 1.6, sonication time of 24min and temperature of 60 degrees C. The optimal condition was validated through experiments and the observed value was interrelated with predicted value. PMID- 27773279 TI - The effect of high power airborne ultrasound and microwaves on convective drying effectiveness and quality of green pepper. AB - The effectiveness of hybrid drying based on convective drying with application of ultrasound and microwave enhancement is the main subject of the studies. The drying kinetics, energy consumption as well as the quality aspect of green pepper is analysed. It was shown that hybrid drying methods shorten significantly the drying time, reduce the energy consumption and affect positively the quality factors. Each of the analysed aspects depend on combination of the convective ultrasound-microwave drying programs. Besides, based on the drying model elaborated earlier by one of the authors, the effects of ultrasound on convective drying assessed by such phenomena as "heating effect", "vibration effect" and "synergistic effect" are presented. PMID- 27773280 TI - Ultrasound assisted extraction of food and natural products. Mechanisms, techniques, combinations, protocols and applications. A review. AB - This review presents a complete picture of current knowledge on ultrasound assisted extraction (UAE) in food ingredients and products, nutraceutics, cosmetic, pharmaceutical and bioenergy applications. It provides the necessary theoretical background and some details about extraction by ultrasound, the techniques and their combinations, the mechanisms (fragmentation, erosion, capillarity, detexturation, and sonoporation), applications from laboratory to industry, security, and environmental impacts. In addition, the ultrasound extraction procedures and the important parameters influencing its performance are also included, together with the advantages and the drawbacks of each UAE techniques. Ultrasound-assisted extraction is a research topic, which affects several fields of modern plant-based chemistry. All the reported applications have shown that ultrasound-assisted extraction is a green and economically viable alternative to conventional techniques for food and natural products. The main benefits are decrease of extraction and processing time, the amount of energy and solvents used, unit operations, and CO2 emissions. PMID- 27773281 TI - Rapid ultrasound-assisted magnetic microextraction of gallic acid from urine, plasma and water samples by HKUST-1-MOF-Fe3O4-GA-MIP-NPs: UV-vis detection and optimization study. AB - Magnetite (Fe3O4 nanoparticles (NPs)) HKUST-1 metal organic framework (MOF) composite as a support was used for surface imprinting of gallic acid imprinted polymer (HKUST-1-MOF-Fe3O4-GA-MIP) using vinyltrimethoxysilane (VTMOS) as the cross-linker. Subsequently, HKUST-1-MOF-Fe3O4-NPs-GA-MIP characterized by FT-IR, XRD and FE-SEM analysis and applied for fast and selective and sensitive ultrasound assisted dispersive magnetic solid phase microextraction of gallic acid (GA) by UV-Vis (UA-DMSPME-UV-Vis) detection method. Plackett-Burman design (PBD) and central composite design (CCD) according to desirability function (DF) indicate the significant variables among the extraction factors vortex (mixing) time (min), sonication time (min), temperature ( degrees C), eluent volume (L), pH and HKUST-1-MOF-Fe3O4-NPs-GA-MIP mass (mg) and their contribution on the response. Optimum conditions and values correspond to pH, HKUST-1-MOF-Fe3O4-NPs GA-MIP mass, sonication time and the eluent volume were set as follow 3.0, 1.6mg, 4.0min and 180MUL, respectively. The average recovery (ER%) of GA was 98.13% with desirability of 0.997, while the present method has best operational performance like wide linear range 8-6000ngmL-1 with a Limit of detection (LOD) of 1.377ngmL 1, limit of quantification (LOQ) 4.591ngmL-1 and precision (<3.50% RSD). The recovery of GA in urine, human plasma and water samples within the range of 92.3 100.6% that strongly support high applicability of present method for real samples analysis, which candidate this method as promise for further application. PMID- 27773282 TI - Ultrasound-synergized electrostatic field extraction of total flavonoids from Hemerocallis citrina baroni. AB - The total flavonoids from Hemerocallis citrina baroni are regarded as a green and natural health care product with many beneficial impacts on human health. In this study, ultrasound-synergized electrostatic field extraction (UEE) of the total flavonoids (TF) from H. citrina was investigated. Significant independent variables of the extraction, including the electrostatic field, ultrasonic power, ethanol concentration and extraction time, were optimized using the Box-Behnken (BB) method, and the optimal extraction conditions were obtained by response surface methodology (RSM). The extraction yield using UEE was compared with the yields obtained using only ultrasound extraction (UE) and water bath extraction (WE), using a UV-vis spectrophotometer. The best extraction yield of 1.536% using UEE was achieved under the following optimal conditions: electrostatic field of 7kV, ultrasonic power of 500W, ethanol concentration of 70% and extraction time of 20min. The optimal solid-liquid ratio (1:25g/mL) and extraction temperature (55 degrees C) were determined by single factor experiments. Compared to other extraction methods, UEE not only increases the extraction yield of TF but also exhibits an excellent antioxidant activity in assays of the scavenging capacity for DPPH, hydroxyl and superoxide anion radicals. The availability of the UEE method can be supported by the ultrasonic cavitation effect, which plays the most important role in the UEE method. The electrostatic field can be regarded as a random disturbance for sonication, which can strengthen the cavitation effect and increase the cavitation yield. Moreover, the amount of iodine release in potassium iodide solution well validated the synergetic effect between the ultrasound and electrostatic field. PMID- 27773283 TI - Persulfate-enhanced sonochemical degradation of naphthol blue black in water: Evidence of sulfate radical formation. AB - This work explores the effect of persulfate (PS) on the sonochemical degradation of organic pollutants taking naphthol blue black (NBB), an anionic diazo dye, as a substrate model. The sonolytic experiments were conducted in the absence and presence of PS under various experimental conditions including acoustic power (10 80W), frequency (20 and 585kHz) and saturating gas (argon, air and nitrogen). Experimental results showed that PS decomposition into sulfate radical (SO4-) takes place by sonolysis and increasing PS concentration up to 1g/L would result in an increase in the NBB degradation rate. It was found that the PS-enhanced effect was strongly operating parameters dependent. The positive effect of PS decreased with increasing power and the best enhancing effect was obtained for the lowest acoustic power. Correspondingly, the PS-enhanced effect was more remarkable at low frequency (20kHz) than that observed at high frequency ultrasound (585kHz). Nitrogen saturating gas gave the best enhanced effect of PS than argon and air atmospheres. Theoretical (computer simulation of bubble collapse) and experimental measurements of the yields of free radical generation under the different experimental conditions have been made for interpreting the obtained effects of PS on the sonochemical degradation of the dye pollutant. The experimental findings were attributed to the fact that radical-radical recombination reactions occur at faster rate than the radical-organic reaction when the concentration of free radicals is too high (at higher sonochemical conditions). PMID- 27773284 TI - Evaluation on the air-borne ultrasound-assisted hot air convection thin-layer drying performance of municipal sewage sludge. AB - The thin-layer drying behavior of the municipal sewage sludge in a laboratory scale hot air forced convective dryer assisted with air-borne ultrasound was investigated in between 70 and 130 degrees C hot air temperatures. The drying kinetics in the convective process alone were compared to that for ultrasound assist process at three ultrasound powers (30, 90, 150W). The average drying rates within whole drying temperature range at ultrasound powers of 30, 90 and 150W increased by about 22.6%, 27.8% and 32.2% compared with the convective drying alone (without ultrasound). As the temperature increasing from 70 degrees C to 130 degrees C, there were maximum increasing ratios for the effective moisture diffusivities of the sewage sludge in both falling rate periods at ultrasonic power of 30W in comparison with other two high powers. In between the ultrasound powers of 0 and 30W, the effect of the power on the drying rate was significant, while its effect was not obvious over 30W. Therefore, the low ultrasonic power can be just set in the drying process. The values of the apparent activation energy in the first falling rate period were down from 13.52 to 12.78kJmol-1, and from 17.21 to 15.10kJmol-1 for the second falling rate period with increasing the ultrasonic power from 30 to 150W. The values of the apparent activation energy in two falling rate periods with the ultrasound-assist were less than that for the hot air convective drying alone. PMID- 27773285 TI - Studies on an ultrasonic atomization feed direct methanol fuel cell. AB - Direct methanol fuel cell (DMFC) is promising as an energy conversion device for the replacement of conventional chemical cell in future, owing to its convenient fuel storage, high energy density and low working temperature. The development of DMFC technology is currently limited by catalyst poison and methanol crossover. To alleviate the methanol crossover, a novel fuel supply system based on ultrasonic atomization is proposed. Experimental investigations on this fuel supply system to evaluate methanol permeation rates, open circuit voltages (OCVs) and polarization curves under a series of conditions have been carried out and reported in this paper. In comparison with the traditional liquid feed DMFC system, it can be found that the methanol crossover under the ultrasonic atomization feed system was significantly reduced because the DMFC reaches a large stable OCV value. Moreover, the polarization performance does not vary significantly with the liquid feed style. Therefore, the cell fed by ultrasonic atomization can be operated with a high concentration methanol to improve the energy density of DMFC. Under the supply condition of relatively high concentration methanol such as 4M and 8M, the maximum power density fed by ultrasonic atomization is higher than liquid by 6.05% and 12.94% respectively. PMID- 27773286 TI - Synthesis of polyaniline nanoparticles and their application for the removal of Crystal Violet dye by ultrasonicated adsorption process based on Response Surface Methodology. AB - The present study focuses the synthesis of polyaniline nanoparticles (PANP) by rapid mixing polymerization method. They were recognized by FTIR and SEM techniques. Moreover they were utilized for the removal of Crystal Violet (CV) dye by ultrasonicated adsorption process. It ensures a quick alternative method compared to other conventional processes, which led to enhancement of mass transfer by ultrasound waves. The effectiveness of the process was confirmed through the effect of certain conditions like sonication time, temperature, adsorbent dosage and CV concentrations. The validity of the process was estimated by various adsorption isotherms. Kinetics and thermodynamic studies was also conducted to authenticate the process. The optimum operating parameters (OOP) were evaluated by Response Surface Methodology (RSM) based on central composite design (CCD) for the removal of CV dye. Moreover analysis of variances (ANOVA) was employed to estimate the significance of experimental variables. The predicated removal efficiency was found to be 94.29% which prove to be effectiveness of the process. PMID- 27773288 TI - Effect of ultrasonic vibration time on the Cu/Sn-Ag-Cu/Cu joint soldered by low power-high-frequency ultrasonic-assisted reflow soldering. AB - Techniques to improve solder joint reliability have been the recent research focus in the electronic packaging industry. In this study, Cu/SAC305/Cu solder joints were fabricated using a low-power high-frequency ultrasonic-assisted reflow soldering approach where non-ultrasonic-treated samples were served as control sample. The effect of ultrasonic vibration (USV) time (within 6s) on the solder joint properties was characterized systematically. Results showed that the solder matrix microstructure was refined at 1.5s of USV, but coarsen when the USV time reached 3s and above. The solder matrix hardness increased when the solder matrix was refined, but decreased when the solder matrix coarsened. The interfacial intermetallic compound (IMC) layer thickness was found to decrease with increasing USV time, except for the USV-treated sample with 1.5s. This is attributed to the insufficient USV time during the reflow stage and consequently accelerated the Cu dissolution at the joint interface during the post-ultrasonic reflow stage. All the USV-treated samples possessed higher shear strength than the control sample due to the USV-induced-degassing effect. The shear strength of the USV-treated sample with 6s was the lowest among the USV-treated samples due to the formation of plate-like Ag3Sn that may act as the crack initiation site. PMID- 27773287 TI - Molecular weight distribution, rheological property and structural changes of sodium alginate induced by ultrasound. AB - In this study, the effects of ultrasound with different ultrasonic frequencies on the properties of sodium alginate (ALG) were investigated, which were characterized by the means of the multi-angle laser light scattering photometer analysis (GPC-MALLS), rheological analysis, circular dichroism (CD) spectrometer and scanning electron microscope (SEM). It showed that the molecular weight (Mw) and molecular number (Mn) of the untreated ALG was 1.927*105g/mol and 4.852*104g/mol, respectively. The Mw of the ultrasound treated ALG was gradually increased from 3.50*104g/mol to 7.34*104g/mol while the Mn of ALG was increased and then decreased with the increase of the ultrasonic frequency. The maximum value of Mn was 9.988*104g/mol when the ALG was treated by ultrasound at 40kHz. It indicated that ultrasound could induce ALG degradation and rearrangement. The number of the large molecules and small molecules of ALG was changed by ultrasound. The value of dn/dc suggested that the ultrasound could enhance the stability of ALG. Furthermore, it was found that ALG treated by ultrasound at 50kHz tended to be closer to a Newtonian behavior, while the untreated and treated ALG solutions exhibited pseudoplastic behaviours. Moreover, CD spectra demonstrated that ultrasound could be used to improve the strength of the gel by changing the ratio of M/G, which showed that the minimum ratio of M/G of ALG treated at 135kHz was 1.34. The gel-forming capacity of ALG was correlated with the content of G-blocks. It suggested that ALG treated by ultrasound at 135kHz was stiffer in the process of forming gels. The morphology results indicated that ultrasound treatment of ALG at 135kHz increased its hydrophobic interaction and interfacial activity. This study is important to explore the effect of ultrasound on ALG in improving the physical properties of ALG as food additives, enzyme and drug carriers. PMID- 27773289 TI - Ultrasonic accelerates asparagine-glucose non-enzymatic browning reaction without acrylamide formation. AB - Ultrasonic accelerated the asparagine-glucose non-enzymatic browning reaction with significant decrease of glucose and asparagine concentrations, and marked increase of intermediate products (UV-absorbance value at 294nm, Abs294), melanoidins (UV-absorbance value at 420nm, Abs420) and in vitro antioxidant activity (DPPH free radical scavenging activity). As the ultrasonic intensity was 17.83W/cm2, the asparagine-glucose solution's Abs294, Abs420 and antioxidant activity increased from 0 to 1.26, 0.88 and 21.56%, respectively, and the glucose and asparagine concentrations of the asparagine-glucose solution reduced 58.97 and 12.57%, respectively. The high performance liquid chromatography (HPLC)-Diode Array Detector (DAD) analyses showed that no acrylamide was detected after 50-min ultrasonic reaction. This study suggested that ultrasonic at higher intensity was a potential method to accelerate the non-enzymatic browning reaction in the asparagine-glucose solution without acrylamide production. PMID- 27773290 TI - Sono-assisted TEMPO oxidation of oil palm lignocellulosic biomass for isolation of nanocrystalline cellulose. AB - Highly stable and dispersible nanocrystalline cellulose (NCC) was successfully isolated from oil palm empty fruit bunch microcrystalline cellulose (OPEFB-MCC), with yields of 93% via a sono-assisted TEMPO-oxidation and a subsequent sonication process. The sono-assisted treatment has a remarkable effect, resulting in an increase of more than 100% in the carboxylate content and a significant increase of approximately 39% in yield compared with the non-assisted process. TEM images reveal the OPEFB-NCC to have rod-like crystalline morphology with an average length and width of 122 and 6nm, respectively. FTIR and solid state 13C-NMR analyses suggest that oxidation of cellulose chain hydroxyl groups occurs at C6. XRD analysis shows that OPEFB-NCC consists primarily of a crystalline cellulose I structure. Both XRD and 13C-NMR indicate that the OPEFB NCC has a lower crystallinity than the OPEFB-MCC starting material. Thermogravimetric analysis illustrates that OPEFB-NCC is less thermally stable than OPEFB-MCC but has a char content of 46% compared with 7% for the latter, which signifies that the carboxylate functionality acts as a flame retardant. PMID- 27773291 TI - Ultrasound assisted combined molecularly imprinted polymer for selective extraction of nicotinamide in human urine and milk samples: Spectrophotometric determination and optimization study. AB - Ultrasound-assisted dispersive solid phase microextraction followed by UV-vis spectrophotometer (UA-DSPME-UV-vis) was designed for extraction and preconcentration of nicotinamide (vitamin B3) by HKUST-1 metal organic framework (MOF) based molecularly imprinted polymer (MIP). This new material was characterized by FTIR and FE-SEM techniques. The preliminary Plackett-Burman design was used for screening and subsequently the central composite design justifies significant terms and possible construction of mathematical equation which give the individual and cooperative contribution of variables like HKUST-1 MOF-NA-MIP mass, sonication time, temperature, eluent volume, pH and vortex time. Accordingly the optimum condition was set as: 2.0mg HKUST-1-MOF-NA-MIP, 200MUL eluent and 5.0min sonication time in center points other variables were determined as the best conditions to reach the maximum recovery of the analyte. The UA-DSPME-UV-vis method performances like excellent linearity (LR), limits of detection (LOD), limits of quantification of 10-5000MUgL-1 with R2 of 0.99, LOD (1.96ngmL-1), LOQ (6.53MUgL-1), respectively show successful and accurate applicability of the present method for monitoring analytes with within- and between-day precision of 0.96-3.38%. The average absolute recoveries of the nicotinamide extracted from the urine, milk and water samples were 95.85-101.27%. PMID- 27773292 TI - Characterizing the cavitation development and acoustic spectrum in various liquids. AB - A bespoke cavitometer that measures acoustic spectrum and is capable of operating in a range of temperatures (up to 750 degrees C) was used to study the cavitation behaviour in three transparent liquids and in molten aluminium. To relate these acoustic measurements to cavitation development, the dynamics of the cavitation bubble structures was observed in three Newtonian, optically transparent liquids with significantly different physical properties: water, ethanol, and glycerine. Each liquid was treated at 20kHz with a piezoelectric ultrasonic transducer coupled to a titanium sonotrode with a tip diameter of 40mm. Two different transducer power levels were deployed: 50% and 100%, with the maximum power corresponding to a peak-to-peak amplitude of 17MUm. The cavitation structures and the flow patterns were filmed with a digital camera. To investigate the effect of distance from the ultrasound source on the cavitation intensity, acoustic emissions were measured with the cavitometer at two points: below the sonotrode and near the edge of the experimental vessel. The behaviour of the three tested liquids was very different, implying that their physical parameters played a decisive role in the establishment of the cavitation regime. Non dimensional analysis revealed that water shares the closest cavitation behaviour with liquid aluminium and can therefore be used as its physical analogue in cavitation studies; this similarity was also confirmed when comparing the measured acoustic spectra of water and liquid aluminium. PMID- 27773293 TI - Sonoluminescence and dynamics of cavitation bubble populations in sulfuric acid. AB - The detailed link of liquid phase sonochemical reactions and bubble dynamics is still not sufficiently known. To further clarify this issue, we image sonoluminescence and bubble oscillations, translations, and shapes in an acoustic cavitation setup at 23kHz in sulfuric acid with dissolved sodium sulfate and xenon gas saturation. The colour of sonoluminescence varies in a way that emissions from excited non-volatile sodium atoms are prominently observed far from the acoustic horn emitter ("red region"), while such emissions are nearly absent close to the horn tip ("blue region"). High-speed images reveal the dynamics of distinct bubble populations that can partly be linked to the different emission regions. In particular, we see smaller strongly collapsing spherical bubbles within the blue region, while larger bubbles with a liquid jet during collapse dominate the red region. The jetting is induced by the fast bubble translation, which is a consequence of acoustic (Bjerknes) forces in the ultrasonic field. Numerical simulations with a spherical single bubble model reproduce quantitatively the volume oscillations and fast translation of the sodium emitting bubbles. Additionally, their intermittent stopping is explained by multistability in a hysteretic parameter range. The findings confirm the assumption that bubble deformations are responsible for pronounced sodium sonoluminescence. Notably the observed translation induced jetting appears to serve as efficient mixing mechanism of liquid into the heated gas phase of collapsing bubbles, thus potentially promoting liquid phase sonochemistry in general. PMID- 27773294 TI - In situ sonochemical reduction and direct functionalization of graphene oxide: A robust approach with thermal and biomedical applications. AB - The rapid, robust, scalable and non-hazardous sonochemical approach for in situ reduction and direct functionalization of graphene oxide has been developed for non-toxic biomedical applications. The graphene oxide (GrO) was directly functionalized with tryptamine (TA) without using any hazardous acylating and coupling reagents. The reaction was completed within 20min. An impact of ultrasound was inferred for a direct functionalization with other conventional methods. The evolved electronic states were confirmed with near edge X-ray absorption fine structure (NEXAFS). The direct covalent functionalization and formation of f-(TA) GrO was proven with FTIR, 13C solid state NMR, XPS, XRD, Raman' HRTEM, AFM and TGA. The total percentage weight loss in TGA confirms an enhanced thermal stability of f-(TA) GrO. The f-(TA) GrO was further explored for an investigation of in vitro antimicrobial activity to ensure the health and environmental safety. An outstanding antibacterial activity of f-(TA) GrO was found against gram positive Staphylococcus aureus at MIC 128mgmL-1. It confirms a suitability of f-(TA) GrO for thermally stable antibacterial coating. The f-(TA) GrO showed 39.14-48.9% antioxidant activities, evaluated with 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radical assay. The inherent cytotoxicity of f-(TA) GrO was evaluated with SRB assay to living cells, MCF-7 and Vero. The estimated cell viabilities were >80% upon addition of f-(TA) GrO over a wide concentration range of 10-80MUgmL-1. The high cytocompatibility of f-(TA) GrO confirms the low toxicity and an excellent biocompatibility. The morphological effect on Vero cell line, evidently confirmed the biocompatibility of f-(TA) GrO. Therefore, f-(TA) GrO was emerged as an advanced functional biomaterial for thermal and biomedical applications. PMID- 27773295 TI - Preparation of nanomaterials for the ultrasound-enhanced removal of Pb2+ ions and malachite green dye: Chemometric optimization and modeling. AB - Copper oxide nanoparticle-loaded activated carbon (CuO-NP-AC) was synthesized and characterized using different techniques such as FE-SEM, XRD and FT-IR. It was successfully applied for the ultrasound-assisted simultaneous removal of Pb2+ ions and malachite green (MG) dye in binary system from aqueous solution. The effect of important parameters was modeled and optimized by artificial neural network (ANN) and response surface methodology (RSM). Maximum simultaneous removal percentages (>99.0%) were found at 25mgL-1, 20mgL-1, 0.02g, 5min and 6.0 corresponding to initial Pb2+ concentration, initial MG concentration, CuO-NP-AC amount, ultrasonication time and pH, respectively. The precision of the equation obtained by RSM was confirmed by the analysis of variance and calculation of correlation coefficient relating the predicted and the experimental values of ultrasound-assisted simultaneous removal of the analytes. A good agreement between experimental and predicted values was observed. A feed-forward neural network with a topology optimized by response surface methodology was successfully applied for the prediction of ultrasound-assisted simultaneous removal of Pb2+ ions and MG dye in binary system by CuO-NPs-AC. The number of hidden neurons, MSE, R2, number of epochs and error histogram were chosen for ANN modeling. Then, Langmuir, Freundlich, Temkin and D-R isothermal models were applied for fitting the experimental data. It was found that the Langmuir model well describes the isotherm data with a maximum adsorption capacity of 98.328 and 87.719mgg-1 for Pb2+ and MG, respectively. Kinetic studies at optimum condition showed that maximum Pb2+ and MG adsorption is achieved within 5min of the start of most experiments. The combination of pseudo-second-order rate equation and intraparticle diffusion model was applicable to explain the experimental data of ultrasound-assisted simultaneous removal of Pb2+ and MG at optimum condition obtained from RSM. PMID- 27773296 TI - The choice of ultrasound assisted extraction coupled with spectrophotometric for rapid determination of gallic acid in water samples: Central composite design for optimization of process variables. AB - A sensitive procedure namely ultrasound-assisted (UA) coupled dispersive nano solid-phase microextraction spectrophotometry (DNSPME-UV-Vis) was designed for preconcentration and subsequent determination of gallic acid (GA) from water samples, while the detailed of composition and morphology and also purity and structure of this new sorbent was identified by techniques like field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD) and Energy dispersive X-ray spectroscopy (EDX) techniques. Among conventional parameters viz. pH, amount of sorbent, sonication time and volume of elution solvent based on Response Surface Methodology (RSM) and central composite design according to statistics based contour the best operational conditions was set at pH of 2.0; 1.5mg sorbent, 4.0min sonication and 150MUL ethanol. Under these pre-qualified conditions the method has linear response over wide concentration range of 15 6000ngmL-1 with a correlation coefficient of 0.9996. The good figure of merits like acceptable LOD (S/N=3) and LOQ (S/N=10) with numerical value of 2.923 and 9.744ngmL-1, respectively and relative recovery between 95.54 and 100.02% show the applicability and efficiency of this method for real samples analysis with RSDs below 6.0%. Finally the method with good performance were used for monitoring under study analyte in various real samples like tap, river and mineral waters. PMID- 27773297 TI - Zinc silicates with tunable morphology by surfactant assisted sonochemical route suitable for NUV excitable white light emitting diodes. AB - The cationic surfactants assisted ultrasound route was used to prepare Dy3+ doped Zn2SiO4 nanophosphors. The final products were characterized by powder X-ray diffraction (PXRD), ultraviolet visible spectroscopy, scanning electron microscopy, transmission electron microscopy and photoluminescence. Orthorhombic phase of Zn2SiO4:Dy3+ (JCPDS card No. 35-1485) was confirmed from PXRD. It was evident that the morphology of spherical and broom like structures were obtained with epigallocatechin gallate (EGCG) and cetyltrimethylammonium bromide (CTAB) surfactants respectively. Further the size and agglomeration of the products were varied with surfactants concentration, sonication time, pH and sonication power. The probable formation mechanisms to obtain various micro/nano superstructures were discussed. The characteristic PL peaks were observed at 484, 574 and 666nm due to the electronic transitions 4F9/2->6Hj (j=15/2, 13/2, 11/2) of Dy3+ ions upon excited at NUV pumping wavelength of 350nm [6H15/2->6P7/2 (4M15/2)]. The Judd-Ofelt intensity parameters and radiative properties were estimated by using PL emission data. The photometric studies indicated that the obtained phosphors could be promising materials in white light emitting diodes (wLED's). The present synthesis route was rapid, environmentally benign, cost-effective and useful for industrial applications such as solid state lighting and display devices. PMID- 27773298 TI - Ultrasound-assisted oxidative desulfurization process of liquid fuel by phosphotungstic acid encapsulated in a interpenetrating amine-functionalized Zn(II)-based MOF as catalyst. AB - In this work, ultrasound-assisted oxidative desulfurization (UAOD) of liquid fuels performed with a novel heterogeneous highly dispersed Keggin-type phosphotungstic acid (H3PW12O40, PTA) catalyst that encapsulated into an amino functionalized MOF (TMU-17-NH2). The prepared composite exhibits high catalytic activity and reusability in oxidative desulfurization of model fuel. Ultrasound assisted oxidative desulfurization (UAOD) is a new way to performed oxidation reaction of sulfur-contain compounds rapidly, economically, environment-friendly and safely, under mild conditions. Ultrasound waves can be apply as an efficient tool to decrease the reaction time and improves oxidative desulfurization system performance. PTA@TMU-17-NH2 could be completely performed desulfurization of the model oil by 20mg of catalyst, O/S molar ratio of 1:1 in presence of MeCN as extraction solvent. The obtained results indicated that the conversions of DBT to DBTO2 achieve 98% after 15min in ambient temperature. In this work, we prepared TMU-17-NH2 and PTA/TMU-17-NH2 composite by ultrasound irradiation for first time and employed in UAOD process. Prepared catalyst exhibit an excellent reusability without PTA leaching and loss of activity. PMID- 27773299 TI - Modeling the effect of carbon-dioxide gas on cavitation. AB - One of the controlling parameters of the physical and chemical effects produced by acoustic cavitation is the use of dissolved gas as it affects the temperature and pressure obtained at cavity collapse and, the reactions happening in a bubble. It also enhances the nucleation rates by decreasing the threshold required for cavitation by providing dissolved gas nuclei. The present study looks into the effect of carbon dioxide gas on cavitation using a diffusion limited model. The model couples the dynamics of a single bubble with 11 chemical reactions involving 8 reactive species. The effect of mass transport (diffusion of water vapor and radical species) and heat transport (by conduction) is included in the model. Simulations were carried out for different initial compositions of an Ar-CO2- bubble and the results were compared with an experimental study reported in the earlier literature. The results have indicated that intensity of collapse decreases with an increase in CO2 composition in the bubble thereby decreasing the yield of the oxidizing radicals like OH. This is due to the lower polytropic coefficient and higher specific heat of CO2 compared to that of argon. Also, the bubbles grows to a larger extent with an increase in the dissolved CO2 concentration thereby accommodating higher amounts of water vapor and ultimately decreasing the temperature obtained at collapse. Simulations were done for a bubble containing a mole fraction of 95% Ar and 5% CO2 at different values of driving frequencies (213, 355, 647 and 1000kHz) and driving pressure amplitudes (3.22, 5, 7.5 and 10bar). Higher production rate of OH radicals was predicted at a lower driving frequency, for a given driving pressure amplitude and it increased with an increase in the driving pressure amplitude. At a given driving pressure amplitude, the yield of OH radicals decreased with an increase in the CO2 concentration in the bubble for all the driving frequencies used in the simulations. PMID- 27773300 TI - Enhancements in crystallinity, thermal stability, tensile modulus and strength of sisal fibres and their PP composites induced by the synergistic effects of alkali and high intensity ultrasound (HIU) treatments. AB - In this investigation, sisal fibres were treated with the combination of alkali and high intensity ultrasound (HIU) and their effects on the morphology, thermal properties of fibres and mechanical properties of their reinforced PP composites were studied. FTIR and FE-SEM results confirmed the removal of amorphous materials such as hemicellulose, lignin and other waxy materials after the combined treatments of alkali and ultrasound. X-ray diffraction analysis revealed an increase in the crystallinity of sisal fibres with an increase in the concentration of alkali. Thermogravimetric results revealed that the thermal stability of sisal fibres obtained with the combination of both alkali and ultrasound treatment was increased by 38.5 degrees C as compared to the untreated fibres. Morphology of sisal fibre reinforced composites showed good interfacial interaction between fibres and matrix after the combined treatment. Tensile properties were increased for the combined treated sisal fibres reinforced PP composites as compared to the untreated and pure PP. Tensile modulus and strength increased by more than 50% and 10% respectively as compared to the untreated sisal fibre reinforced composite. It has been found that the combined treatment of alkali and ultrasound is effective and useful to remove the amorphous materials and hence to improve the mechanical and thermal properties. PMID- 27773301 TI - Ultrasound assisted Bradsher reaction in aqueous and non-aqueous media: First use of ultrasounds in electrophilic aromatic cyclisation leading to polyacenes. AB - The present work describes the first use of ultrasounds in the Bradsher cyclisation of activated and non-activated ortho-formyl diarylmethanes. This reaction is also the first example of electrophilic, aromatic cyclisation assisted by ultrasounds which leads to pure polycyclic, fused aromatic hydrocarbons containing 3 and 4 fused rings in excellent yields. The reaction proceeds not only in aqueous but also in non-aqueous media at milder conditions (room temperature) and in much shorter reaction times than in conventional protocols. PMID- 27773302 TI - Combination of ultrasonic and Fenton processes in the presence of magnetite nanostructures prepared by high energy planetary ball mill. AB - High energy planetary ball milling process was used to prepare magnetite nanostructures from natural magnetite. The natural and ball-milled magnetite samples were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (HR-TEM), energy-dispersive X ray spectroscopy (EDX), Brunauer-Emmett-Teller (BET) and Fourier transform infrared spectroscopy (FT-IR). The results of EDX indicated the presence of main elements including Fe and O in the structure of both unmodified and milled magnetite samples. The specific surface area of catalyst increased from 0.9116m2/g to 28.692m2/g after ball-milling process. The catalytic activity of prepared magnetite nanostructures was evaluated towards degradation of Acid Blue 185 (AB185) in ultrasonic assisted heterogeneous Fenton reaction. 6h ball-milled catalyst exhibited the higher catalytic activity in degradation of AB185. The high degradation efficiency was obtained at initial pH of 3. Increasing the concentration of H2O2 from an optimum value of 15mM led to decrease in degradation efficiency because of scavenging effect of H2O2 on hydroxyl radicals. The optimized catalyst concentration was obtained 1.5g/L. Increasing initial dye concentration from 20 to 120mg/L led to decrease in degradation efficiency from 99 to 88%. The prepared magnetite nanostructures exhibited good stability in repeated cycles. The produced intermediates of the degradation of AB185 in ultrasonic assisted heterogeneous Fenton process were monitored by GC-MS analysis. PMID- 27773304 TI - Fe-based heterogeneous catalysts for the Fischer-Tropsch reaction: Sonochemical synthesis and bench-scale experimental tests. AB - The sonochemical synthesis of nanostructured materials owes its origins to the extreme conditions created during acoustic cavitation, i.e., the formation of localized hot spots in the core of collapsing bubbles in a liquid irradiated with high intensity ultrasound (US). In particular, in the present work a sonochemical synthesis has been investigated for the production of three different iron-based samples supported on SiO2 and loaded with different metals and promoters (10 %wt of Fe; 30 %wt of Fe; 30 %wt of Fe, 2 %wt of K and 3.75 %wt of Cu) active in the Fischer-Tropsch (FT) process. Sonochemically synthesized heterogeneous catalysts were characterized by BET, XRPD, TPR, ICP, CHN, TEM, SEM and then tested in a fixed bed FT-bench-scale rig fed with a mixture of H2 and CO at a H2/CO molar ratio equal to 2, at activation temperatures of 350-400 degrees C and reaction temperatures of 250-260 degrees C. The experimental results showed that the ultrasonic samples are effective catalysts for the FT process. Notably, increasing the activation temperature increased CO conversion, while product selectivity did not diminish. All the sonochemically prepared samples presented in this work provided better catalytic results compared to the corresponding traditional FT impregnated catalysts. PMID- 27773305 TI - Photostability and visible-light-driven photoactivity enhancement of hierarchical ZnS nanoparticles: The role of embedment of stable defect sites on the catalyst surface with the assistant of ultrasonic waves. AB - Zinc sulfide is a UV-active photocatalyst and it undergoes photocorrosion under light irradiation. In this work, the defect sites on ZnS nanoparticles (NPs) surfaces were induced with the help of powerful ultrasonic waves. The defect sites caused (1) suppression of photocorrosion in a large extent under UV light irradiation and (2) enhancement of visible light photo activity. The photocorrosion inhibition was induced by raising valence band (VB) position through the formation of interstitial zinc and sulfur vacancy states in the ZnS band structure and weakening of oxidative capacity of hole. The enhancement of visible light photocatalytic activity may be related to the generation of more defect energy states in the ZnS band gap. Under visible light irradiation, the electron was excited from the ZnS VB to the interstitial sulfur and zinc vacancy states before injecting into the conduction band of ZnS. Therefore, we modified the band gap of ZnS so that it acts as a visible light active photocatalyst. ZnS NPs were prepared using two different classical and ultrasound methods. The prepared ZnS using ultrasound method, exhibited more outstanding photocatalytic activity for degrading reactive black 5 (RB5) under UV and sunlight irradiation in comparison with the classical method. Details of the degradation mechanism under UV light were investigated. This work provides new insights to understanding the photocorrosion stability and visible light activity of bare ZnS photocatalyst. PMID- 27773303 TI - Preparation of (5.0%)Er3+:Y3Al5O12/Pt-(TiO2-Ta2O5) nanocatalysts and application in sonocatalytic decomposition of ametryn in aqueous solution. AB - (5.0%)Er3+:Y3Al5O12/Pt-(TiO2-Ta2O5) powder, as a high effective sonocatalyst, was prepared using sol-gel and calcination method. Then it was characterized by X-ray diffractometer (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX). In order to evaluate the sonocatalytic activity of the prepared (5.0%)Er3+:Y3Al5O12/Pt-(TiO2 Ta2O5) powder, the sonocatalytic decomposition of ametryn was studied. In addition, some influencing factors such as different Ti/Ta molar ratios on the sonocatalytic activity of the prepared (5.0%)Er3+:Y3Al5O12/Pt-(TiO2-Ta2O5) powder, catalyst added amount with ultrasonic irradiation time and used times on the sonocatalytic decomposition efficiency were examined by using ion chromatogram determination. The experimental results showed that the best sonocatalytic decomposition ratio of ametryn were 77.50% based on the N atom calculation and 95.00% based on the S atom calculation, respectively, when the conditions of 10.00mg/L initial concentration, 1.00g/L prepared (5.0%)Er3+:Y3Al5O12/Pt-(TiO2-Ta2O5) powder (Ti/Ta=1.00:0.25 heat-treated at 550 degrees C for 3.0h) added amount, 150min ultrasonic irradiation (40kHz frequency and 300W output power), 100mL total volume and 25-28 degrees C temperature were adopted. Therefore, the (5.0%)Er3+:Y3Al5O12/Pt-(TiO2-Ta2O5) composite nanoparticles could be considered as an effective sonocatalyst for decomposition of ametryn in aqueous solution. PMID- 27773306 TI - Synthesis of chitosan capped copper oxide nanoleaves using high intensity (30kHz) ultrasound sonication and their application in antifouling coatings. AB - The synthesis of chitosan capped copper oxide nanoleaves (CCCO NLs) was carried out under three different reaction conditions viz. 1) room temperature, 2) 70 degrees C and 3) high intensity ultrasound (30kHz) sonication method and it has been found that the high intensity ultrasound (30kHz) sonication is the best method when compared to other two methods. The advantages of the present synthetic method are: i) easy one step process, ii) lesser reaction time, iii) good yield, iv) reproducible and v) calcination is not required. The resulting chitosan capped copper oxide nanoleaves were characterized by Diffuse Reflectance UV-Visible Spectroscopy (DRS), Fourier Transform Infra-Red Spectroscopy (FT-IR), X-ray Diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), Field Emission Scanning Electron Microscopy (FESEM), High Resolution Transmission Electron Microscopy (HRTEM) and Thermo gravimetric analysis (TGA). The CCCO NLs were blended with commercial paints such as polyurethane clear, polyurethane white and acrylic emulsion and applied on to three different surfaces (wood, mild steel and cement slab panels). The hydrophilicity of CCCONP coated panels was analyzed by water contact angle measurement and their antifouling behavior was investigated against three different green and marine algae viz. Arthrospira, Chlorella and Amphora. The antifouling efficiency of the CCCO NLs against the algae was found to be 78-92%. PMID- 27773307 TI - The performance of nanorods material as adsorbent for removal of azo dyes and heavy metal ions: Application of ultrasound wave, optimization and modeling. AB - The present research is focused on the synthesis and characterization of zinc (II) oxide nanorods loaded on activated carbon (ZnO-NRs-AC) to prepare an outstanding adsorbent for the simultaneous adsorption of heavy metals and dyes as hazardous pollutant using ultrasound energy. The adsorbent was identified by Scanning Electron Microscope (SEM), Transmission Electron Microscopy (TEM), Energy-dispersive X-ray spectroscopy (EDS) and X-ray diffraction (XRD) analysis. The individual effects and possible interactions between the most effective variables including initial metal ions (Cd2+ and Co2+) and azo dyes (methylene blue (MB) and crystal violet (CV)) concentration, adsorbent dosage and ultrasonic time on the responses were investigated by response surface methodology (RSM) and optimum conditions was fixed at Cd2+, Co2+, MB and CV concentrations were 25, 24, 18 and 14mgL-1, respectively, 0.025g of ZnO-NRs-AC and 5.1min sonication to achieve maximum removal percentage (>97.0%) for targets compounds. The artificial neural network (ANN) model was applied for prediction of data with Levenberg Marquardt algorithm (LMA), a linear transfer function (purelin) at output layer and a tangent sigmoid transfer function (tansig) in the hidden layer with 14 neurons. The minimum mean squared error (MSE) of 0.9646, 0.0402 and 0.0753 with high determination coefficient (R2) of 0.9996, 0.9991 and 0.9999 for train, test and validation, respectively, were able to predict and model the adsorption process. The results of examination of the time on experimental adsorption data and their subsequent fitting reveal applicability of pseudo-second-order and intraparticle diffusion model. The experimental equilibrium data was analyzed by Langmuir, Freundlich, Temkin and D-R isotherm models and explored that the data well presented by Langmuir model with maximum adsorption capacity of 97.1, 92.6, 83.9 and 81.6mgg-1 for Cd+2, Co+2 ions, MB and CV dyes, respectively. PMID- 27773308 TI - Dual color emitting Eu doped strontium orthosilicate phosphors synthesized by bio template assisted ultrasound for solid state lightning and display applications. AB - A novel Sr2SiO4:Eu (1-5mol %) superstructures (SS) were synthesized using bio sacrificial A.V. gel assisted ultrasound method. Powder X-ray diffraction patterns confirmed the presence of both alpha and beta phase formation. It was evident that the morphological growth was highly reliant on A.V. gel concentration, sonication time, pH and sonication power. The formation mechanisms for different hierarchical SS were proposed. From diffuse reflectance spectra, the energy band gap was estimated and found to be ~4.70-5.11eV. The photoluminescence emission spectra for the excitation at 392nm, shows characteristic emission peaks at 593, 613, 654 and 702nm which were attributed to 5D0->7F0, 7F1,7F2 and 7F3 transitions of Eu3+ ions respectively. Conversely, when the samples were subjected to the heat treatment at 850 degrees C for 3h under argon atmosphere, display an intense broad emission peak with two de-convoluted peaks at 490 and 550nm due to 4f65d1->4f1 (8S7/2) transitions of Eu2+ ions. The concentration quenching phenomenon was discussed which attributes to energy transfer, electron-phonon coupling and ion-ion interaction. The Judd-Ofelt intensity parameters and other radiative properties were estimated by using emission spectra. The CIE chromaticity coordinate values of Sr2SiO4:Eu2+ and Eu3+ nanophosphors were located in green and red regions respectively. The calculated CCT and CRI values specify that the present phosphor can be fairly useful for both green and red components of white LED's. Luminescence decay and quantum yield suggest the suitability of this phosphor as an efficient luminescent medium for light emitting diodes. Overall, the results elucidated a rapid, environmentally benign, cost-effective and convenient method for Sr2SiO4:Eu3+ synthesis and for the possible applications such as solid state lighting and display devices. PMID- 27773309 TI - Green ultrasound-assisted extraction of carotenoids from pomegranate wastes using vegetable oils. AB - The objective of this work was to develop a new process for pomegranate peels application in food industries based on ultrasound-assisted extraction of carotenoids using different vegetable oils as solvents. In this way, an oil enriched with antioxidants is produced. Sunflower oil and soy oil were used as alternative solvents and the effects of various parameters on extraction yield were studied. Extraction temperature, solid/oil ratio, amplitude level, and extraction time were the factors investigated with respect to extraction yield. Comparative studies between ultrasound-assisted and conventional solvent extraction were carried out in terms of processing procedure and total carotenoids content. The efficient extraction period for achieving maximum yield of pomegranate peel carotenoids was about 30min. The optimum operating conditions were found to be: extraction temperature, 51.5 degrees C; peels/solvent ratio, 0.10; amplitude level, 58.8%; solvent, sunflower oil. A second-order kinetic model was successfully developed for describing the mechanism of ultrasound extraction under different processing parameters. PMID- 27773310 TI - Ag3PO4/rectorite nanocomposites: Ultrasound-assisted preparation, characterization and enhancement of stability and visible-light photocatalytic activity. AB - To overcome the drawback of low stable brought by the transformation of Ag+ into Ag, a highly efficient and stable photocatalyst Ag3PO4/rectorite composite was successfully synthesized by ultrasound-assisted precipitation method. The as prepared samples were characterized by field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, N2 adsorption-desorption, room-temperature photoluminescence spectra, Fourier transform infrared spectrum measurements and UV-vis diffuse reflectance spectra. The absorption edges of the Ag3PO4/rectorite display a noticeable shift to the visible light region as compared to that of the Ag3PO4. Compared with bare Ag3PO4, the Ag3PO4/rectorite composite by ultrasound assisted precipitation process exhibits significantly enhanced photocatalytic activity and stable for methyl orange (MO) degradation under visible light irradiation. The improved activity of the Ag3PO4/rectorite photocatalyst could be attributed to the expanded visible light absorption, the enhanced interfacial charge transfer and the inhibited recombination of electron-hole pairs. Therefore, the facile ultrasound-assisted preparation process provides some insight into the application of Ag3PO4/rectorite nanocomposites in photocatalytic degradation of organic pollutants. PMID- 27773311 TI - An experimental study on the coalescence process of binary droplets in oil under ultrasonic standing waves. AB - The coalescence process of binary droplets in oil under ultrasonic standing waves was investigated with high-speed photography. Three motion models of binary droplets in coalescence process were illustrated: (1) slight translational oscillation; (2) sinusoidal translational oscillation; (3) migration along with acoustic streaming. To reveal the droplets coalescence mechanisms, the influence of main factors (such as acoustic intensity, droplet size, viscosity and interfacial tension, etc) on the motion and coalescence of binary droplets was studied under ultrasonic standing waves. Results indicate that the shortest coalescence time is achieved when binary droplets show sinusoidal translational oscillation. The corresponding acoustic intensity in this case is the optimum acoustic intensity. Under the optimum acoustic intensity, drop size decrease will bring about coalescence time decrease by enhancing the binary droplets oscillation. Moreover, there is an optimum interfacial tension to achieve the shortest coalescence time. PMID- 27773312 TI - Determination of carboxylic acids in non-alcoholic beer samples by an ultrasonic assisted dispersive micro-solid phase extraction based on Ni/Cu-Al layered double hydroxide nanocomposites followed by gas chromatography. AB - Magnetically separable layered double hydroxide Ni/CuAl-LDH nanocomposites were synthesized and employed as ultrasonic-assisted dispersive micro-solid phase extraction (UA-D-MUSPE) sorbent to extract several carboxylic acids (namely propionic, butyric, pentanoic, hexanoic, heptanoic, octanoic, and decanoic) from non-alcoholic beer samples. Ni/CuAl-LDH sorbent was characterized by Fourier transform-infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), and vibrating sample magnetometry (VSM). Effective variables such as amount of sorbent (mg), pH and ionic strength of sample solution, volume of eluent solvent (MUL), vortex, and ultrasonic times (min) were investigated via fractional factorial design (FFD). The significant variables were optimized by a Box-Behnken design and combined by a desirability function (DF). Under optimized conditions, the calibration graphs of analytes were linear in a concentration range of 0.05 100MUg/mL and had correlation coefficients more than 0.997. The limits of detection and quantification were in the ranges of 16-40MUg/L and 53-133MUg/L, respectively. This procedure was successfully employed in the determination of target analytes in spiked beer samples, and the relative mean recoveries ranged from 87 to 110%. PMID- 27773313 TI - Ultrasound assisted simultaneous reduction and direct functionalization of graphene oxide with thermal and cytotoxicity profile. AB - The new sonochemical approach for simultaneous reduction and direct functionalization of graphene oxide (GrO) has been developed. The GrO was functionalized with 2-Aminobenzoxazole (2-ABOZ) in twenty min with complete deletion of hazardous steps. The significance of ultrasound was exemplified with the comparative conventional methods. The newly prepared f-(2-ABOZ)GrO was extensively characterized with near edge X-ray absorption fine structure (NEXAFS) spectroscopy, 13C solid state NMR, XPS, XRD, HRTEM, SAED, AFM, Raman, UV-vis, FTIR and TGA. The thermal stability of f-(2-ABOZ)GrO was confirmed with total percentage weight loss in TGA. The biological activity of f-(2-ABOZ)GrO was explored with MCF-7 and Vero cell lines. The inherent cytotoxicity was evaluated with SRB assay at 10, 20, 40 and 80MUgmL-1. The estimated cell viabilities were >78% with f-(2-ABOZ) GrO. A high cytocompatibility of f-(2-ABOZ)GrO was ensured with in vitro evaluation on living cell lines, and low toxicity of f-(2-ABOZ)GrO was confirmed its excellent biocompatibility. The morphological effect on Vero cell line evidently supports the formation of biocompatible f-(2-ABOZ)GrO. Therefore, f-(2-ABOZ)GrO was emerged as an advanced functional material for thermally stable biocompatible coatings. PMID- 27773314 TI - Ultrasound promoted mild and facile one-pot, three component synthesis of 2H indazoles by consecutive condensation, CN and NN bond formations catalysed by copper-doped silica cuprous sulphate (CDSCS) as an efficient heterogeneous nano catalyst. AB - An ultrasonic promoted facile and convenient one-pot three-component procedure for the synthesis of 2H-indazole derivatives using copper-doped silica cuprous sulphate (CDSCS) as a heterogeneous nano-catalyst has been described. In this approach, ultrasonic mediated reaction of different substituted 2 bromobenzaldehydes, structurally diverse primary amines, and tetrabutylammonium azide (TBAA) as an azide source in the presence of CDSCS in DMSO at room temperature furnishes 2H-indazoles in good to excellent yields. Utilizing ultrasonic irradiation techniques provided the dramatic improvements in terms of higher yields and shorter reaction times compared with conventional heating method. PMID- 27773315 TI - Effects of ultrasonication and conventional mechanical homogenization processes on the structures and dielectric properties of BaTiO3 ceramics. AB - The effects of the homogenization process on the structures and dielectric properties of pure and Nb-doped BaTiO3 ceramics have been investigated using an ultrasonic homogenization and conventional mechanical methods. The reagents were homogenized using an ultrasonic processor with high-intensity ultrasonic waves and using a compact mixer-shaker. The components and crystal types of the powders were determined by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analyses. The complex permittivity (epsilon', epsilon") and AC conductivity (sigma') of the samples were analyzed in a wide frequency range of 20Hz to 2MHz at room temperature. The structures and dielectric properties of pure and Nb-doped BaTiO3 ceramics strongly depend on the homogenization process in a solid-state reaction method. Using an ultrasonic processor with high intensity ultrasonic waves based on acoustic cavitation phenomena can make a significant improvement in producing high-purity BaTiO3 ceramics without carbonate impurities with a small dielectric loss. PMID- 27773316 TI - A numerical model for the study of the difference frequency generated from nonlinear mixing of standing ultrasonic waves in bubbly liquids. AB - The aim of this paper is the study of the behavior of nonlinear standing ultrasonic waves in bubbly liquids and the generation of the difference frequency by nonlinear mixing of several signals. To this end we present a new numerical model based on the finite-volume method and the finite-difference method. This model solves the differential system formed by the wave equation and a Rayleigh Plesset equation coupling the acoustic pressure field with the bubble vibrations. We consider a resonator filled with a bubbly liquid excited by an ultrasonic pressure source. The numerical experiments presented here are performed by modifying the source amplitude and frequency, the void fraction in the liquid, as well as the length of the resonator. The results allow us to observe the physical effects due to the presence of the bubbles in the liquid: nonlinearity, dispersion, attenuation. The nonlinear frequency mixing performed in the resonator is also evidenced. The amplitude of the generated difference frequency is studied as a function of the pressure amplitude and for several primary frequencies. Our results suggest that a better response is obtained for primary frequencies situated below the bubble resonance. They show a very high difference frequency amplitude response for a cavity resonant at one wavelength of the difference frequency in the bubbly medium. This analyze could be useful for some practical applications. PMID- 27773317 TI - Efficient sonochemical green reaction of aldehyde, thiobarbituric acid and ammonium acetate using magnetically recyclable nanocatalyst in water. AB - A facile one-pot and four-component economical synthesis of pyrido[2,3-d:6,5 d]dipyrimidines using aldehyde, 2-thiobarbituric acid and ammonium acetate in the presence of magnetically heterogeneous catalyst under ultrasonic irradiation in water is described. The present synthesis shows attractive characteristics such as; the use of magnetically recoverable and reusable catalyst, convenient one-pot operation, short reaction periods, high to excellent yields and the use of water as a green reaction medium, mild reaction conditions and is considered to be relatively environmentally benign. PMID- 27773318 TI - Ultrasound assisted crystallization of mefenamic acid: Effect of operating parameters and comparison with conventional approach. AB - The current work investigates the application of low intensity ultrasonic irradiation for improving the cooling crystallization of Mefenamic Acid for the first time. The crystal shape and size has been analyzed with the help of optical microscope and image analysis software respectively. The effect of ultrasonic irradiation on crystal size, particle size distribution (PSD) and yield has been investigated, also establishing the comparison with conventional approach. It has been observed that application of ultrasound not only enhances the yield but also reduces the induction time for crystallization as compared to conventional cooling crystallization technique. In the presence of ultrasound, the maximum yield was obtained at optimum conditions of power dissipation of 30W and ultrasonic irradiation time of 10min. The yield was further improved by application of ultrasound in cycles where the formed crystals are allowed to grow in the absence of ultrasonic irradiation. It was also observed that the desired crystal morphology was obtained for the ultrasound assisted crystallization. The conventionally obtained needle shaped crystals transformed into plate shaped crystals for the ultrasound assisted crystallization. The particle size distribution was analyzed using statistical means on the basis of skewness and kurtosis values. It was observed that the skewness and excess kurtosis value for ultrasound assisted crystallization was significantly lower as compared to the conventional approach. XRD analysis also revealed better crystal properties for the processed mefenamic acid using ultrasound assisted approach. The overall process intensification benefits of mefenamic acid crystallization using the ultrasound assisted approach were reduced particle size, increase in the yield and uniform PSD coupled with desired morphology. PMID- 27773319 TI - Investigations on dynamics of interacting cavitation bubbles in strong acoustic fields. AB - Given its importance to the dynamics of cavitation bubbles, the mutual interaction between bubbles was carefully investigated in this work. The cavitation noises emitted in different sonication conditions were recorded to study the dynamical behavior of the bubbles. The frequency spectra of the noises suggest that the dispersing state of the bubbles severely influence the oscillations of bubbles, and that the nonlinear feature of the dynamics of cavitation bubbles, imposed by the mutual bubble-bubble interaction, gradually develops with the decrease of the dispersing height. Theoretical analysis shows that the size difference between the interacting bubbles should be responsible for the increase of nonlinearity of the oscillation, and that the decrease of the distance between them could effectively enhance the nonlinear feature of the oscillation of the bubble, both of which agree well with the experimental observation. PMID- 27773320 TI - Production of pyrite nanoparticles using high energy planetary ball milling for sonocatalytic degradation of sulfasalazine. AB - Sonocatalytic performance of pyrite nanoparticles was evaluated by the degradation of sulfasalazine (SSZ). Pyrite nanoparticles were produced via a high energy mechanical ball milling (MBM) in different processing time from 2h to 6h, in the constant milling speed of 320rpm. X-ray diffraction (XRD), scanning electron microscopy (SEM) coupled with energy dispersive X-ray (EDX), Fourier transform infrared spectroscopy (FT-IR) analysis and Brunauer-Emmett-Teller (BET) confirmed the production of pyrite nanoparticles during 6h of ball milling with the average size distribution of 20-80nm. The effects of various operational parameters including pH value, catalyst amount (mg/L), SSZ concentration (mg/L), ultrasonic frequency (kHz) and reaction time on the SSZ removal efficiency were examined. The obtained results showed that the maximum removal efficiency of 97.00% was obtained at pH value of 4, catalyst dosage of 0.5g/L, SSZ concentration of 10mg/L and reaction time of 30min. Experimental results demonstrated that the kinetic of the degradation process can be demonstrated using Langmuir-Hinshelwood (L-H) kinetic model. The effect of different inorganic ions such as Cl-, CO32- and SO42- was investigated on the L-H reaction rate (kr) and adsorption (Ks) constants. Results showed that the presence of the mentioned ions significantly influenced the L-H constants. The impact of ethanol as a OH radical scavenger and some enhancers including H2O2 and K2S2O8 was investigated on the SSZ removal efficiency. Accordingly, the presence of ethanol suppressed SSZ degradation due to the quenching of OH radicals and the addition of K2S2O8 and H2O2 increased the SSZ removal efficiency, due to the formation of SO4- and additional OH radicals, respectively. Under the identical conditions of operating parameters, pyrite nanoparticles maintained their catalytic activity during four consecutive runs. PMID- 27773321 TI - Novel ionic liquid supported on Fe3O4 nanoparticles and its application as a catalyst in Mannich reaction under ultrasonic irradiation. AB - A family of novel ionic liquid with l-alanine and choline chloride as environmentally benign materials have been synthesized and grafted on Fe3O4 nanoparticles using easy preparation techniques. The structure of ionic liquid supported on Fe3O4 nanoparticles (IL-Fe3O4 NPs) characterized by various analyses such as FE-SEM, EDX, XRD, NMR, FTIR and VSM. The catalytic activities of this catalyst are examined in the Mannich reaction for synthesis of beta-aminocarbonyl compounds under ultrasonic irradiation. The recyclability of catalyst is investigated, and the results have indicated that the catalyst can be recycled six times without obvious activity decreasing. PMID- 27773322 TI - Ultrasound-assisted mineralization of organic contaminants using a recyclable LaFeO3 and Fe3+/persulfate Fenton-like system. AB - A recyclable heterogeneous catalyst has been successfully developed for application in a Fenton-type advanced oxidation process without adding external H2O2. LaFeO3 was prepared from Fe(NO3)3.9H2O and La(NO3).6H2O by a simple sol-gel method and its catalytic efficiency was evaluated for mineralization of 4 chlorophenol using a Fenton-like process. The mineralization process was carried out under ultrasonication in presence of heterogeneous LaFeO3 catalyst with H2O2 that was produced during ultrasonication. The mineralization process was monitored through total organic carbon (TOC) analysis. Very importantly, utmost 5 fold synergism was evidenced by the ultrasound mediated LaFeO3-catalyzed system. Besides, more than twofold synergism was observed by combining the ultrasound assisted LaFeO3 catalytic process and potassium persulfate (KPS) assisted advanced oxidation process. It is worth to mention that complete mineralization (~96%) of 4-chlorophenol (initial concentration of 1.25*10-4M) was observed within 1h in the presence of LaFeO3 (0.5gL-1) and KPS (1.0mmol) under ultrasonication (40kHz). Even after four cycles, the activity of LaFeO3 remained intact which proved its recyclability. Extremely reusable heterogeneous LaFeO3 catalyst makes the system more interesting from both economic and environmental points of view. PMID- 27773323 TI - Solvent extraction of cadmium and zinc from sulphate solutions: Comparison of mechanical agitation and ultrasonic irradiation. AB - This research was conducted to evaluate the potential of ultrasonic irradiation during the solvent extraction of metals, and comparing its efficiency with a mechanically stirred system (MSSX). The simultaneous extraction of zinc and cadmium from sulphate solutions was investigated by di-(2-ethylhexyl) phosphoric acid (D2EHPA) as an organic extractant which was diluted (20%) in kerosene at the organic: aqueous phase ratio of 1:1 and the temperature of 25 degrees C. The influence of some critical parameters, including contact time, solution pH, ultrasonic power, and zinc/cadmium ratio were investigated on the extraction of the metals. Results show that D2EHPA selectively extract zinc rather than cadmium in both mechanically and ultrasonically mixed systems. It was also found that increase of ultrasonic power from 10 to 120W cause a small decrease in zinc extraction; while, at low and high levels of the induced power, cadmium extraction was significantly decreased. Results also show that maximum extraction amounts of zinc (88.7%) and cadmium (68.2%) by the MSSX system occurred at the pH of 3 and the contact times of 3 and 20min, respectively. Although capability of extraction in the ultrasonically assisted solvent extraction (USAX) system for both metals was higher, the selectivity was lower than that of MSSX system under different conditions especially in high zinc/cadmium ratios. It can be concluded that physical effects (i.e. mixing) inducing at low ultrasonic powers (below 60W) mainly results in increasing solvent extraction rate, while the chemical actions applied at the higher powers have a negative outcome on the extraction rate particularly for cadmium. PMID- 27773324 TI - Enhanced boron adsorption onto synthesized MgO nanosheets by ultrasonic method. AB - MgO nanosheets with high adsorption performance were fabricated by an ultrasonic method. It was revealed that, nest-like MgO was formed from the magnesium salt solution precipitation and further calcination. Then the nest-like MgO was exfoliated by ultrasonic waves to obtain MgO nanosheets with approximately a lateral of 200-600nm and a thickness of 10nm. Adjusting the ultrasonic time and power, the specific surface areas of MgO nanosheets could be tuned in a range of 79-168m2/g. The synthesized MgO nanosheets were used as adsorbents to remove boron from aqueous solution, and the maximum boron adsorption capacity of these MgO nanosheets reached 87mgg-1. The high uptake capability of the MgO nanosheets makes it potentially adsorbent for the removal of boron from wastewaters. PMID- 27773325 TI - Rapid ultrasound-induced transient-liquid-phase bonding of Al-50Si alloys with Zn interlayer in air for electrical packaging application. AB - Al-50Si alloys were joined by rapid ultrasound-induced transient-liquid-phase bonding method using Zn foil as interlayer at 390 degrees C in air, below the melt point of interlayer. The fracture of oxide films along the edge of Si particles led to contact and inter-diffusion between aluminum substrate and Zn interlayer, and liquefied Zn-Al alloys were developed. The width of Zn-Al alloys gradually decreased with increasing the ultrasonic vibration time due to liquid squeezing out and accelerated diffusion. A stage of isothermal solidification existed, and the completion time was significantly shortened. In the liquid metal, the acoustic streaming and ultrasonic cavitations were induced. As the process developed, much more Si particles, which were particulate-reinforced phases of Al-50Si, gradually migrated to the center of soldering seam. The highest average shear strength of joints reached to 94.2MPa, and the fracture mainly occurred at the base metal. PMID- 27773326 TI - Ultrasound irritation enhanced heterogeneous activation of peroxymonosulfate with Fe3O4 for degradation of azo dye. AB - Magnetic Fe3O4 nanoparticles were synthesized and used as peroxymonosulfate (PMS) activator in the presence of ultrasound (US) irritation for azo dye degradation in this study. At pH 7.0 and temperature 298K, Fe3O4 nanoparticles were able to activate PMS under ultrasound irritation to produce sulfate radicals for acid orange 7 (AO7) removal in 30min. Higher catalysts dosage, neutral pH as well as optimum values of PMS dosage and ultrasound power favored the AO7 degradation. Fe3O4 displayed excellent stability and reusability in the US/PMS system. Both of the sulfate radicals and hydroxyl radicals were produced in the reaction and sulfate radicals were the dominant according to the scavenging tests and electron paramagnetic resonance (ESR) tests. The mechanisms of ultrasound irritation enhanced PMS activation in the presence of Fe3O4 were proposed based on the results and literatures. PMID- 27773327 TI - Effects of high intensity ultrasound modification on physicochemical property and water in myofibrillar protein gel. AB - The effects of high intensity ultrasound (HIU) modification (power: 200, 400, 600, 800 and 1000W, corresponding to intensities of: 88, 117, 150, 173 and 193Wcm 2) on the physicochemical properties of myofibrillar protein (MP) and water in MP gel were studied. As the HIU power increased, the solubility, surface hydrophobicity and absolute value of the zeta potential increased, while turbidity and total sulfhydryl (SH) group content decreased. The G' and G" of MP during thermal gelation decreased as ultrasound intensity increased due to greater protein denaturation. Low field NMR data showed that bound water (T2b) had lower water mobility and was more closely associated with proteins in HIU treated MP gel, while the proportions of immobilized water (PT21) and free water (PT22) had their maximum and minimum value, respectively, at 600W. Moderate HIU (?600W) treatments had denser and uniform gel microstructure, which improved water holding capacity (WHC) of the gels, while stronger HIU (>600W) treatments had larger and irregular gel microstructures, accompanied by decreased WHC. PMID- 27773328 TI - Influences of temperature, power ultrasound and reaction time on the morphological properties of two new mercury(II) coordination supramolecular compounds. AB - Nanoparticles of two new coordination compounds, [Hg2(L)2(Br)4]n (1) and [Hg(L')(SCN)2] (2), (L=2-amino-4-methylpyridine, L'=2,6-pyridinedicarboxlic acid), have been synthesized by use of a sonochemical process and characterized by scanning electron microscopy (SEM), field emission scanning electron microscopy(FESEM), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) spectroscopy and elemental analyses. The single crystal X-ray data of compounds 1 and 2 imply that the Hg(II) ions are four and five coordinated, respectively. Topological analysis shows that 1D and 0D coordination networks of 1 and 2 can be classified as underlying nets of topological types 2C1 and 1,3M4-1, respectively. The thermal stability of compounds has been studied by thermal gravimetric (TG) and differential thermal analyses (DTA). The role of temperature, reaction time and ultrasound irradiation power on the size and morphology of "nano-structures" 1 and 2, has been investigated. Results claim that an increase of temperature, sonication power and decrease in reaction time leads to a decrease of particle size. PMID- 27773329 TI - Ultrasonic-assisted cathodic electrochemical discharge for graphene synthesis. AB - We present a novel and highly efficient method for exfoliating of graphite to produce graphene via the synergistic effects of in-situ plasma induced electrochemical exfoliation with ultrasonic energy, called ultrasonic-assisted cathodic electrochemical discharge. This method can work at moderate temperatures without the need of acidic media or expensive ionic electrolyte. The produced graphene exhibited a large lateral dimension of approximately 6MUm and a thickness of 2.5nm, corresponding to approximately seven layers of graphene. An exfoliating mechanism of graphite to produce graphene sheets is also proposed in this study. PMID- 27773330 TI - Kinetic modeling of sonocatalytic degradation of reactive orange 29 in the presence of lanthanide-doped ZnO nanoparticles. AB - The sonocatalytic degradation of reactive orange 29 (RO29) was examined from the reaction kinetics point of view. Sonochemically synthesized lanthanides (Ho3+ and Er3+)-doped ZnO nanoparticles were utilized as catalyst during the sonocatalytic process. The prepared nanoparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The aqueous RO29 solution was irradiated with a 36kHz ultrasonic bath (150W) for investigation of the degradation kinetics by varying of the initial dye concentration (10-30mg/L) and catalyst dosage (0.25-1g/L). A novel kinetic model was developed and validated for prediction of the RO29 sonocatalytic degradation efficiency using generally accepted intrinsic elementary reactions. The proposed kinetic model clearly demonstrates the dependence of the apparent first-order rate constant on the mentioned operational parameters. The predicted values of degradation efficiency and experimental results were in good agreement with appropriate correlation coefficient (R2>0.945). PMID- 27773331 TI - Ultrasonic assisted synthesis of two new coordination polymers and their applications as precursors for preparation of nano-materials. AB - Two new isostructural coordination polymers, [Zn3(Oba)4][Me2NH2)2].6DMF.3H2O (1) and [Cd3(Oba)4][Me2NH2)2].2DMF.2H2O (2), were synthesized using the nonlinear dicarboxylate ligand, 4,4'-oxybis(benzoic acid) (H2oba) and characterized by IR spectroscopy and single-crystal X-ray crystallography. Single-crystal X-ray data show that 1 and 2 are two-dimensional coordination polymers that can be extended to three-dimensional supramolecular networks by CH...O interactions. These two new coordination polymers were also sonochemically synthesized while sonication time and power of irradiation influencing size and morphology of nano-structured compounds were also studied. Moreover, calcination of these coordination polymers creates ZnO and CdO nanostructures. PMID- 27773332 TI - Pad ultrasonic batch dyeing of causticized lyocell fabric with reactive dyes. AB - Conventionally, cellulosic fabric dyed with reactive dyes requires significant amount of salt. However, the dyeing of a solvent spun regenerated cellulosic fiber is a critical process. This paper presents the dyeing results of lyocell fabrics dyed with conventional pad batch (CPB) and pad ultrasonic batch (PUB) processes. The dyeing of lyocell fabrics was carried out with two commercial dyes namely Drimarine Blue CL-BR and Ramazol Blue RGB. Dyeing parameters including concentration of sodium hydroxide, sodium carbonate and dwell time were compared for the two processes. The outcomes show that PUB dyed samples offered reasonably higher color yield and dye fixation than CPB dyed samples. A remarkable reduction of 12h in batching time, 18ml/l in NaOH and 05g/l in Na2CO3 quantity was observed for PUB processed samples producing similar results compared to CPB process, making PUB a more economical, productive and an environment friendly process. Color fastness examination witnessed identical results for both PUB and CPB methods. No significant change in surface morphology of PUB processed samples was observed through scanning electron microscope (SEM) analysis. PMID- 27773333 TI - Ossifying inverted papilloma and ossifying polyp of the sinonasal tract: comparison of CT and MRI features. AB - AIM: To investigate the key imaging points in distinguishing ossifying inverted papilloma (IP) from polyps. MATERIALS AND METHODS: The native computed tomography (CT), conventional and enhanced MRI manifestations of 20 ossifying IPs and eight polyps, which were confirmed histopathologically, were retrospectively evaluated by two doctors majoring in head and neck imaging. RESULTS: A significant difference was detected between the two entities for the involved sites (p<0.05). Although two lesions had similar CT findings, the MRI features differed significantly (p<0.05). Twenty ossifying IPs demonstrated heterogeneously isointense with moderate gadolinium enhancement, and a convoluted "cerebriform" configuration. Seven ossifying polyps revealed low T1 and high T2 signal, with marginal enhancement, and one showed isointense with moderate enhancement. The ossification appeared as oval or striped bone-like high attenuation, which consisted of peripheral hyperattenuating cortical bone and central fat-like attenuation of the medullary cavity. The corresponding MRI findings of the ossifying regions were peripherally low signal and centrally high signal on both T1- and T2-weighted images. The occurrence of two key MRI features of cystic appearance and the "cerebriform" sign were significantly different between two entities (p<0.05). CONCLUSIONS: CT can better detect intralesional ossification, but MRI is the optimal imaging technique for discriminating between two disease entities. PMID- 27773334 TI - WITHDRAWN: Practical Guidelines for the Use of Electronic Applications by Advanced Practice Nurses in the Emergency Department. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in < YMEN 42 (2016) 544 - 545 >, http://dx.doi.org/10.1016/j.jen.2016.09.010. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 27773335 TI - Nurse Staffing and Hospital Characteristics Predictive of Time to Diagnostic Evaluation for Patients in the Emergency Department. AB - : In the 2014 Emergency Department Benchmarking Alliance Summit, for the first time, participants recommended tracking nursing and advanced practice nurse hours. Performance data from the Centers for Medicare and Medicaid Services provides an opportunity to analyze factors associated with delays in emergency care. The purpose of this study was to investigate hospital characteristics associated with time to a diagnostic evaluation in 67 Massachusetts emergency departments from 2013 to 2014. METHODS: Covariates significantly correlated with time to diagnostic evaluation, and factors associated with timely care in emergency departments were included in the stepwise linear regression analysis. Differences in nurse staffing and performance measures in trauma and nontrauma emergency departments were examined with analysis of variance and t tests. RESULTS: Two predictors explained 38% of the variance in time a diagnostic evaluation (1): nurse staffing (P < .001) and (2) trauma centers (P <.001). In trauma centers, the time to a diagnostic evaluation significantly increased (P = .042) from 30.2 minutes when a nurse cared for fewer than 11.32 patients in 24 hours to 61.4 minutes when a nurse cared for 14.85 or more patients in 24 hours. DISCUSSION: Efforts to improve patient flow often focus on process interventions such as improved utilization of observation beds or transfers of patients to inpatient units. In this study, time to diagnostic evaluation significantly increased when emergency nurses care for higher numbers of patients. The findings present new evidence identifying the relationship of specific nurse to patient ratios to wait time in emergency departments. PMID- 27773336 TI - Closing the Research-Practice Gap: Increasing Evidence-Based Practice for Nasogastric Tube Insertion Using Education and an Electronic Order Set. AB - : Patients and practitioners rate the insertion of a nasogastric tube as one of the most painful and distressing procedures performed. Research supports using lidocaine and a nasal vasoconstrictor to significantly decrease patient discomfort. The recommended medications were not being used routinely in a large urban emergency department. METHODS: We identified departmental barriers using a nurse survey and physician interviews. We educated the nursing and physician staff about the comfort medications for nasogastric tube insertion recommended in the literature. In collaboration with the information technology department, we created an order set for the department's computerized physician order entry system linking the order for a nasogastric tube with the recommended comfort medications. RESULTS: Six months after the educational campaign and availability of the new electronic order set, we compared the data from pre- and post-project chart reviews and found the use of literature-recommended comfort medications had increased from 23% to 93%. IMPLICATIONS FOR PRACTICE: Nurses have a professional obligation to use the most current evidence-based practice available and to advocate for adequate pain management before, during, and after painful procedures. The use of evidence-based practice has been associated with an increase in both patient and staff satisfaction, improved clinical outcomes, and greater patient safety. An electronic order set combined with staff education resulted in a dramatic increase in the use of evidence-based practice for nasogastric tube insertion. PMID- 27773338 TI - Biomacromolecules based core/shell architecture toward biomedical applications. AB - Polyelectrolyte multilayer capsules have become a novel and promising class of hybrid materials with great potential since they can be applied in various areas, such as pharmaceutical sciences, biotechnology, and biomedicine. The concept of using such carriers for biology application is diagnosis and treatment of diseases for convenience, safety and specific targeting. Therefore, the development of biocompatible, biodegradable and specific characteristic nanostructure material is highly desirable. Much effort has been devoted to exploring innovative and effective techniques to fabricate such materials. Among the available techniques, layer-by-layer (LbL) assembly capsules have attracted considerable attention attributing to the flexibly controlled size, shape, composition, wall thickness and functions. Protein, as the large class of biomacromolecules, was incorporated into capsules for improving the biocompatibility and specific function. In this review we provide an overview of the recent progress in biomacromolecular capsules or core/shell architecture with different diameters for the variety of purposes. The size ranging from micro-, sub-micro to nano scale based on the choice of the template. Their advantages are discussed here. The applications of these biomacromolecular capsules in biotechnological fields have also been summarized, for instance blood substitute, ATP carriers, photodynamic therapy and nanomedicines. PMID- 27773339 TI - Liquid-liquid and liquid-solid phase separation in protein-polyelectrolyte systems. AB - The coacervation of systems containing colloids (e.g. proteins or micelles) and polyelectrolytes (notably ionic polysaccharides) is often accompanied by precipitation. This can introduce inhomogeneity, irreversibility and irreproducible kinetics in applications in food science and bioengineering, with negative impact on texture and stability of food products, and unpredictable delivery of active "payloads." The relationship between coacervation and precipitation is obscure in that coacervates might be intermediates in the formation of precipitates, or else the two phenomena might proceed by different but possibly simultaneous mechanisms. This review will summarize the recent literature on coacervation/precipitation in protein-polyelectrolyte systems for which reports are most abundant, particularly in the context of food science. We present current findings and opinions about the relationship between the two types of phase separation. Results vary considerably depending not only on the protein-polyelectrolyte pairs chosen, but also on conditions including macromolecular concentrations and ionic strength. Nevertheless, we offer some general approaches that could explain a variety of observations. PMID- 27773337 TI - Donor Human Milk Update: Evidence, Mechanisms, and Priorities for Research and Practice. PMID- 27773341 TI - Layering mechanism of MDP-Ca salt produced in demineralization of enamel and dentin apatite. AB - OBJECTIVE: The 10-methacryloyloxydecyl dihydrogen phosphate (MDP) (EX adhesives) based one-step self-etch adhesives have become widely utilized due to their simplified application procedures. The aim of this study was to determine the type of the molecular species of calcium salts of MDP (MDP-Ca salts) that form a layered structure and to understand the layering mechanism of MDP-Ca salts. METHODS: The EX adhesives were prepared by varying the amounts of MDP (25.6, 49.9, 80.5 and 116.1mg) added in 1g of the EX adhesive. Enamel and dentin reactant residues were obtained after the reaction of each EX adhesive to enamel or dentin particles for 30s. The chemical analyses of both reactant residues were then performed. RESULTS: The molecular species of MDP-Ca salts that form a layered structure were determined as mono-calcium salt (MCS-MD) and di-calcium salts of the MDP dimer (DCS-MD). The dentin sample showed two types of characteristic XRD peaks assigned to the layer structure, since the dentin produced DCS-MD along with MCS-MD in contrast to the enamel sample. A mono calcium salt of the MDP monomer (MCS-MM), a predominant molecular species, was not contributed to a layered-structure formation, since the intensities of characteristic XRD peaks are limited by the production of DCS-MD and MCS-MD. SIGNIFICANCE: The self-assembled layering of MCS-MD and DCS-MD is associated by a hydrophobic bond between two 10-methylene groups in MCS-MD and DCS-MD. The MCS-MD may form a more tightly-packed layered structure than DCS-MD by the hydrogen bonded interaction between hydroxy groups bonded to each phosphorous atom. PMID- 27773340 TI - Influence of the location and number of metastases in the survival of metastatic prostatic cancer patients. AB - INTRODUCTION: The prognosis of patients diagnosed with metastatic prostate cancer seems to be modulated by factors such as the number and site of metastases. Our objective is to evaluate survival outcomes according to the number and site of metastases in our series of metastatic patients over the last 15 years. MATERIALS AND METHODS: A retrospective analysis was performed on patients diagnosed between 1998 and 2014. We analyzed overall survival and progression-free survival, depending on the number and location of metastases on patients with newly diagnosed metastatic prostate cancer. Other potential prognostic factors were also evaluated: age, clinical stage, PSA at diagnosis, Gleason, PSA nadir, time till PSA nadir and first-line or second-line treatment after progression. RESULTS: We analyzed a series of 162 patients. The mean age was 72.7yr (SD: 8.5). The estimated median overall survival was 3.9 yr (95% CI 2.6-5.2). The overall survival in patients with only lymph node metastases was 7 yr (95% CI 4.1-9.7), 3.9 (95%CI 2.3-5.5) in patients with only bone metastases, 2.5 yr (95% CI 2-2.3) in lymph nodes and bone metastases, and 2.2 yr (95% CI 1.4-3) in patients with visceral metastases (P<.001). In multivariate analysis, the location of metastasesis significantly associated with overall survival and progression-free survival. The number of metastases showed no association with survival. CONCLUSIONS: The site of metastases has a clear impact on both overall survival and progression-free survival. Patients with only lymph node involvement had a better prognosis. The number of metastases showed no significant impact on survival in our series. PMID- 27773342 TI - [Health vulnerability mapping in the Community of Madrid (Spain)]. AB - The Public Health General Directorate of Madrid has developed a health vulnerability mapping methodology to assist regional social health teams in health planning, prioritisation and intervention based on a model of social determinants of health and an equity approach. This process began with the selection of areas with the worst social indicators in health vulnerability. Then, key stakeholders of the region jointly identified priority areas of intervention and developed a consensual plan of action. We present the outcomes of this experience and its connection with theoretical models of asset-based community development, health-integrated georeferencing systems and community health interventions. PMID- 27773343 TI - [Indicators of governance in mental health policies and programmes in Mexico: a perspective of key actors]. AB - OBJECTIVE: To analyse the role of Mexico's mental health system governance in the development of mental health policies and programmes, from the perspective of its own actors. METHODS: A map was developed for identifying the actors in Mexico's mental health system. A guide was designed for in-depth interviews, which were recorded and arranged in categories for their analysis. The Atlas-ti v.7 software was used for the organisation of qualitative data and Policy Maker v.4 was used to determine the position and influence of actors within the health system. RESULTS: The actors were identified according to their level of influence in mental health policies: high, medium and low. Actors with a high level of influence participate in national policies, actors with medium influence are involved in regional or local policies and the participation of actors with a low level of influence is considered marginal. CONCLUSIONS: This study facilitated understanding of governance in mental health. The level of influence of the actors directly affects the scope of governance indicators. Relevant data were obtained to improve policies in mental health care. PMID- 27773344 TI - [An automatic tool to evaluate women's health education groups]. PMID- 27773346 TI - Clinical productivity of primary care nurse practitioners in ambulatory settings. AB - BACKGROUND: Nurse practitioners are increasingly being integrated into primary care delivery to help meet the growing demand for primary care. It is therefore important to understand nurse practitioners' productivity in primary care practice. PURPOSE: We examined nurse practitioners' clinical productivity in regard to number of patients seen per week, whether they had a patient panel, and patient panel size. We further investigated practice characteristics associated with their clinical productivity. METHODS: We conducted cross-sectional analysis of the 2012 National Sample Survey of Nurse Practitioners. The sample included full-time primary care nurse practitioners in ambulatory settings. Multivariable survey regression analyses were performed to examine the relationship between practice characteristics and nurse practitioners' clinical productivity. RESULTS: Primary care nurse practitioners in ambulatory settings saw an average of 80 patients per week (95% confidence interval [CI]: 79-82), and 64% of them had their own patient panel. The average patient panel size was 567 (95% CI: 522 612). Nurse practitioners who had their own patient panel spent a similar percent of time on patient care and documentation as those who did not. However, those with a patient panel were more likely to provide a range of clinical services to most patients. Nurse practitioners' clinical productivity was associated with several modifiable practice characteristics such as practice autonomy and billing and payment policies. DISCUSSIONS: The estimated number of patients seen in a typical week by nurse practitioners is comparable to that by primary care physicians reported in the literature. However, they had a significantly smaller patient panel. Nurse practitioners' clinical productivity can be further improved. PMID- 27773345 TI - Evaluating Affordable Cranial Ultrasonography in East African Neonatal Intensive Care Units. AB - Neuroimaging is a valuable diagnostic tool for the early detection of neonatal brain injury, but equipment and radiologic staff are expensive and unavailable to most hospitals in developing countries. We evaluated an affordable, portable ultrasound machine as a quantitative and qualitative diagnostic tool and to establish whether a novice sonographer could effectively operate the equipment and obtain clinically important information. Cranial ultrasonography was performed on term healthy, pre-term and term asphyxiated neonates in Rwandan and Kenyan hospitals. To evaluate the detection of ventriculomegaly and compression injuries, we measured the size of the lateral ventricles and corpus callosum. The images were also assessed for the presence of other cerebral abnormalities. Measurements were reliable across images, and cases of clinically relevant ventriculomegaly were detected. A novice sonographer had good-to-excellent agreement with an expert. This study demonstrates that affordable equipment and cranial ultrasound protocols can be used in low-resource settings to assess the newborn brain. PMID- 27773347 TI - Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: The inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial. AB - AIMS: To provide pharmacodynamic data of crushed and chewed ticagrelor tablets, in comparison with standard integral tablets. METHODS: Ninety nine patients with stable angina were randomly assigned, in a 3:1:1 fashion, to one of the following 180mg ticagrelor loading dose (LD) formulations: A) Integral B) Crushed or C) Chewed tablets. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60min after LD. High residual platelet reactivity (HRPR) was defined as >208 P2Y12 reaction units (PRU). RESULTS: There was no significant difference in PRU values at baseline. PRU 20min after LD were 237 (182-295), 112 (53-238) and 84 (29-129) and 60min after LD, 56 (15-150), 51 (18-85) and 9 (7-34) in integral, crushed and chewed ticagrelor LD, respectively (p<0.01 for both). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60min. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20min whereas no difference was observed at 60min. At 20min, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01). CONCLUSION: With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared to standard integral tablets. We also show that administration of chewed tablets is feasible and provides faster inhibition than either crushed or integral tablets. CLINICAL TRIAL REGISTRATION: European Clinical Trial Database (EudraCT number 2014-002227-96). PMID- 27773348 TI - Endometrial prostaglandin synthases, ovarian steroids, and oxytocin receptors in mares with oxytocin-induced luteal maintenance. AB - Oxytocin (OXT) has been used to prolong the luteal phase in mares, but its mechanism of action is unknown. The aim of this study was to evaluate the effect of chronic exogenous OXT administration to mid-luteal phase mares on luteal maintenance. Also, endometrial expression of prostaglandin endoperoxide synthase 2 (PTGS2), prostaglandin F2alpha, E2 and I2 synthases (AKR1C3, PTGES, and PTGIS), oxytocin receptor (OXTR), progesterone receptor (PGR), and estrogen receptors 1 (ESR1) and 2 (ESR2) were assessed in mares experiencing luteal maintenance 2 weeks after chronic exogenous OXT administration. Control mares (n = 5; C group) received 6 mL of saline im, whereas OXT (60 units/mare) was administered im (n = 6; OXT group), every 12 hours, on days 7 to 14 postovulation. After endometrial biopsy in groups C (Day 10) and OXT (Day 24), luteolysis occurred within 3 or 6 days, respectively. Luteal maintenance took place in 4 of 6 (67%) of OXT-treated mares. Progesterone in C group was the highest on biopsy day (P < 0.05). In OXT mares, PTGS2, ESR1 (P < 0.05), PTGES, PTGIS, PGR, and ESR2 (P < 0.01) gene transcription decreased, whereas OXTR increased (P < 0.05) in comparison with the C group. In OXT-treated mares, endometrial ESR2 protein expression decreased (P < 0.05), but OXTR increased (P < 0.05) compared with control animals. In both experimental groups, PTGS2 was mainly immunolocalized in surface epithelium, whereas AKR1C3, PTGES, PTGIS, and PGR were in surface and glandular epithelia. ESR1 and ESR2 were found in glandular epithelium and OXTR in stromal cells. High immunolabeling for PTGES, PTGIS, PGR, and OXTR and low for ESR2 was detected in endometrium of OXT-group mares with extended diestrus. Prolonged luteal function associated with chronic OXT treatment may be related to different spatial expression of OXTR and PGR in the endometrium. The observed reduction of endometrial ESR2 may be responsible for the maintenance of PGR in luminal and glandular epithelium. Also, ESR2 may attenuate the transcriptional activity of ESR1 in mare endometrium. This study offers new knowledge on the endometrial expression of ovarian steroids and OXT receptors in OXT pharmacologically induced luteal maintenance in the mare. PMID- 27773349 TI - The Effect of a Youth-Centered Sexual Risk Event History Calendar (SREHC) Assessment on Sexual Risk Attitudes, Intentions, and Behavior. AB - INTRODUCTION: The purpose of this study was to examine the effect of a youth centered assessment, the Sexual Risk Event History Calendar (SREHC), compared with the Guidelines for Adolescent Preventive Services (GAPS) assessment, on sexual risk attitudes, intentions, and behaviors. METHODS: The Interaction Model of Client Health Behavior guided this participatory research-based randomized control trial. Youth participants recruited from university and community clinics in the Midwestern United States were randomized to a health care provider visit using either the SREHC or GAPS and completed surveys at baseline, postintervention, and 3, 6, and 12 months. RESULTS: Participants included 181 youth (15-25 years old) and nine providers. Findings showed that youth in the SREHC group reported stronger intentions to use condoms compared with those in the GAPS group. Age and race were also significant predictors of sexual experience. DISCUSSION: This study highlights the importance of using a youth centered, systematic approach in the assessment of sexual risk behaviors. PMID- 27773350 TI - Global end-diastolic volume index vs CVP goal-directed fluid resuscitation for COPD patients with septic shock: a randomized controlled trial. AB - PURPOSE: This study aimed to investigate the clinical effects of early goal directed therapy according to the global end-diastolic volume index (GEDI) on chronic obstructive pulmonary disease (COPD) patients with septic shock. METHODS: A total of 71 COPD patients with septic shock were randomly assigned to 2 groups. In the control group (n = 37), fluid resuscitation was performed based on the central venous pressure. In the study group (n = 34), fluid resuscitation was performed until GEDI reached 800 mL/m2. The following indices were observed for the 2 groups: 6- and 24-hour fluid volumes, norepinephrine dosage, 24-hour blood lactate clearance rate, duration of mechanical ventilation, intensive care unit (ICU) length of stay, ICU mortality, and 90-day survival rate. RESULTS: At both 6 and 24-hour measurements, the fluid volume was lower and norepinephrine dosage was higher in the control group than in the study group (P < .05). The blood lactate clearance rate was lower, the duration of mechanical ventilation was longer, and the length of stay in the ICU was longer in the control group than in the study group (P < .05). No significant difference in mortality or 90-day survival rate was found between the 2 groups. CONCLUSIONS: The GEDI goal-directed fluid resuscitation shows better clinical effects than that shown by central venous pressure for COPD patients with septic shock; however, it cannot reduce the mortality rate. PMID- 27773351 TI - Introduction of a pan-scan protocol for blunt trauma activations: what are the consequences? AB - STUDY OBJECTIVE: The aim of this study is to determine if the introduction of a pan-scan protocol during the initial assessment for blunt trauma activations would affect missed injuries, incidental findings, treatment times, radiation exposure, and cost. METHODS: A 6-month prospective study was performed on patients with blunt trauma at a level 1 trauma center. During the last 3 months of the study, a pan-scan protocol was introduced to the trauma assessment. Categorical data were analyzed by Fisher exact test and continuous data were analyzed by Mann-Whitney nonparametric test. RESULTS: There were a total of 220 patients in the pre-pan-scan period and 206 patients during the pan-scan period. There was no significant difference in injury severity or mortality between the groups. Introduction of the pan-scan protocol substantially reduced the incidence of missed injuries from 3.2% to 0.5%, the length of stay in the emergency department by 68.2 minutes (95% confidence interval [CI], -134.4 to -2.1), and the mean time to the first operating room visit by 1465 minutes (95% CI, -2519 to -411). In contrast, fixed computed tomographic scan cost increased by $48.1 (95% CI, 32-64.1) per patient; however, total radiology cost per patient decreased by $50 (95% CI, -271.1 to 171.4). In addition, the rate of incidental findings increased by 14.4% and the average radiation exposure per patient was 8.2 mSv (95% CI, 5.0-11.3) greater during the pan-scan period. CONCLUSION: Although there are advantages to whole-body computed tomography, elucidation of the appropriate blunt trauma patient population is warranted when implementing a pan-scan protocol. PMID- 27773352 TI - DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218. AB - BACKGROUD: Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction. METHODS: With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors. RESULTS: We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia. CONCLUSIONS: These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders. PMID- 27773353 TI - Suicide in Tourette's and Chronic Tic Disorders. AB - BACKGROUND: Persons with neuropsychiatric disorders are at increased risk of suicide, but there is little data concerning Tourette's and chronic tic disorders (TD/CTD). We aimed to quantify the risk of suicidal behavior in a large nationwide cohort of patients with TD/CTD, establish the contribution of psychiatric comorbidity to this risk, and identify predictors of suicide. METHODS: Using a validated algorithm, we identified 7736 TD/CTD cases in the Swedish National Patient Register during a 44-year period (1969-2013). Using a matched case-cohort design, patients were compared with general population control subjects (1:10 ratio). Risk of suicidal behavior was estimated using conditional logistic regressions. Predictors of suicidal behavior in the TD/CTD cohort were studied using Cox regression models. RESULTS: In unadjusted models, TD/CTD patients, compared with control subjects, had an increased risk of both dying by suicide (odds ratio: 4.39; 95% confidence interval [CI]: 2.89-6.67) and attempting suicide (odds ratio: 3.86; 95% CI: 3.50-4.26). After adjusting for psychiatric comorbidities, the risk was reduced but remained substantial. Persistence of tics beyond young adulthood and a previous suicide attempt were the strongest predictors of death by suicide in TD/CTD patients (hazard ratio: 11.39; 95% CI: 3.71-35.02, and hazard ratio: 5.65; 95% CI: 2.21-14.42, respectively). CONCLUSIONS: TD/CTD are associated with substantial risk of suicide. Suicidal behavior should be monitored in these patients, particularly in those with persistent tics, history of suicide attempts, and psychiatric comorbidities. Preventive and intervention strategies aimed to reduce the suicidal risk in this group are warranted. PMID- 27773354 TI - Cognitive Performance Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects. AB - BACKGROUND: The UK Biobank is a unique resource for biomedical research, with extensive phenotypic and genetic data on half a million adults from the general population. We aimed to examine the effect of neurodevelopmental copy number variants (CNVs) on the cognitive performance of participants. METHODS: We used Affymetrix Power Tools and PennCNV-Affy software to analyze Affymetrix microarrays of the first 152,728 genotyped individuals. We annotated a list of 93 CNVs and compared their frequencies with control datasets. We analyzed the performance on seven cognitive tests of carriers of 12 CNVs associated with schizophrenia (n = 1087) and of carriers of another 41 neurodevelopmental CNVs (n = 484). RESULTS: The frequencies of the 93 CNVs in the Biobank subjects were remarkably similar to those among 26,628 control subjects from other datasets. Carriers of schizophrenia-associated CNVs and of the group of 41 other neurodevelopmental CNVs had impaired performance on the cognitive tests, with nine of 14 comparisons remaining statistically significant after correction for multiple testing. They also had lower educational and occupational attainment (p values between 10-7 and 10-18). The deficits in cognitive performance were modest (Z score reductions between 0.01 and 0.51), compared with individuals with schizophrenia in the Biobank (Z score reductions between 0.35 and 0.90). CONCLUSIONS: This is the largest study on the cognitive phenotypes of CNVs to date. Adult carriers of neurodevelopmental CNVs from the general population have significant cognitive deficits. The UK Biobank will allow unprecedented opportunities for analysis of further phenotypic consequences of CNVs. PMID- 27773356 TI - Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility. AB - One of the most effective methods to tackle obesity and its related comorbidities is bariatric surgery. Polycystic ovary syndrome (PCOS) and endometrial hyperplasia (EH), which are associated with increased risk of endometrial carcinoma, have been identified as potentially new indications for bariatric surgery. PCOS is the most common endocrine disorder in women in the reproductive age and is associated with several components of the metabolic syndrome such as obesity, insulin resistance and hypertension. EH is a pre-cancerous condition which arises in the presence of chronic exposure to estrogen unopposed by progesterone such as both in PCOS and obesity. The main bariatric procedures are Roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy and laparoscopic adjustable gastric banding. These procedures are well established and when correctly selected and performed by experienced bariatric surgeons, they can achieve significant weight loss and remission of obesity related co-morbidities. Studies have shown that bariatric surgery can play an important role in the management of patients with PCOS and improve fertility. Similarly, bariatric surgery has a positive effect on endometrial hyperplasia, making surgically induced weight loss a potentially attractive option for endometrial cancer prevention and treatment. Obesity has an adverse impact on spontaneous pregnancy, assisted reproduction methods and feto-maternal outcomes. After bariatric surgery obese women with subfertility can achieve spontaneous pregnancy. However, while bariatric surgery reduces the risk of pre-eclampsia and gestational diabetes, there is an increased risk of small for gestational age and possible increased risk of stillborn or neonatal death. In this article we will review the evidence regarding the use of bariatric surgery as a treatment modality in patients with PCOS and EH. We also provide an overview of the common bariatric procedures. PMID- 27773357 TI - Relating pessimistic memory predictions to Alzheimer's disease brain structure. AB - Patients with Alzheimer's disease (AD) show impairment of episodic memory and related metacognitive processes. The present study examined subjective metacognitive judgments preceding objective memory retrieval and investigated the neural correlates of pessimistic predictions for successfully retrieved memories in AD patients. AD patients and healthy older (HO) participants provided predictive judgments on their recognition performance before retrieval of famous (semantic) and recently learned (episodic) names. Correlations between gray matter volume (GMV) in T1 images and behavioral scores were examined with multivariate (partial least square - PLS) and univariate (general linear model - GLM) analyses in AD patients. AD patients showed a significant proportion of successful name recognition preceded by pessimistic prediction in episodic memory. PLS revealed that the behavioral pattern in AD patients was related with a mainly right lateralized pattern of GMV decrease including medial temporal lobe and posterior cingulate cortex (PCC), but also right ventrolateral prefrontal cortex (VLPFC). GLM further confirmed that pessimistic prediction negatively correlated with GMV in VLPFC. Thus, impaired monitoring processes (possibly influenced by inaccurate beliefs) allowing inferences about one's own memory performance are primarily related to decrease GMV in VLPFC in AD patients. PMID- 27773358 TI - Avoiding unseen obstacles: Subcortical vision is not sufficient to maintain normal obstacle avoidance behaviour during reaching. AB - Previous research found that a patient with cortical blindness (homonymous hemianopia) was able to successfully avoid an obstacle placed in his blind field, despite reporting no conscious awareness of it [Striemer, C. L., Chapman, C. S., & Goodale, M. A., 2009, PNAS, 106(37), 15996-16001]. This finding led to the suggestion that dorsal stream areas, that are assumed to mediate obstacle avoidance behaviour, may obtain their visual input primarily from subcortical pathways. Hence, it was suggested that normal obstacle avoidance behaviour can proceed without input from the primary visual cortex. Here we tried to replicate this finding in a group of patients (N = 6) that suffered from highly circumscribed lesions in the occipital lobe (including V1) that spared the subcortical structures that have been associated with action-blindsight. We also tested if obstacle avoidance behaviour differs depending on whether obstacles are placed only in the blind field or in both the blind and intact visual field of the patients simultaneously. As expected, all patients successfully avoided obstacles placed in their intact visual field. However, none of them showed reliable avoidance behaviour - as indicated by adjustments in the hand trajectory in response to obstacle position - for obstacles placed in their blind visual field. The effects were not dependent on whether one or two obstacles were present. These findings suggest that behaviour in complex visuomotor tasks relies on visual input from occipital areas. PMID- 27773355 TI - Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder that affects one in 45 children in the United States, with a similarly striking prevalence in countries around the world. However, mechanisms underlying its etiology and manifestations remain poorly understood. Although ASD is diagnosed based on the presence and severity of impaired social communication and repetitive behavior, immune dysregulation and gastrointestinal issues are common comorbidities. The microbiome is an integral part of human physiology; recent studies show that changes in the gut microbiota can modulate gastrointestinal physiology, immune function, and even behavior. Links between particular bacteria from the indigenous gut microbiota and phenotypes relevant to ASD raise the important question of whether microbial dysbiosis plays a role in the development or presentation of ASD symptoms. Here we review reports of microbial dysbiosis in ASD. We further discuss potential effects of the microbiota on ASD-associated symptoms, drawing on signaling mechanisms for reciprocal interactions among the microbiota, immunity, gut function, and behavior. In addition, we discuss recent findings supporting a role for the microbiome as an interface between environmental and genetic risk factors that are associated with ASD. These studies highlight the integration of pathways across multiple body systems that together can impact brain and behavior and suggest that changes in the microbiome may contribute to symptoms of neurodevelopmental disease. PMID- 27773359 TI - Pesticide exposure and neurodevelopment in children aged 6-9 years from Talamanca, Costa Rica. AB - Certain pesticides may affect children's neurodevelopment. We assessed whether pesticide exposure was associated with impaired neurobehavioral outcomes in children aged 6-9 years. We conducted a cross-sectional study in 140 children living near banana plantations and plantain farms in the Talamanca County, Costa Rica and assessed their neurobehavioral performance. Exposure was determined by analyzing urinary metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol, TCPy), mancozeb (ethylenethiourea, ETU), and pyrethroids (3-phenoxybenzoic acid, 3-PBA). Repeated urine samples were obtained for 36 children. We estimated associations of pesticide concentrations with neurobehavioral outcomes using multivariable linear and logistic regression models. Median (25th-75th percentiles) TCPy, ETU, and 3-PBA concentrations were 1.4 (.7-3.1), 1.2 (.7-3.0), and .8 (.5-1.5) MUg/L, respectively. Intraclass correlation coefficients (ICC) ranged between .32 and .67. After adjustment for potential confounders, higher urinary TCPy concentrations were associated with poorer working memory in boys (n = 59) (beta per 10-fold increase in TCPy concentrations = -7.5, 95% CI: -14.4, .7); poorer visual motor coordination (beta = -1.4, 95% CI: -2.7, -.1); increased prevalence of parent-reported cognitive problems/inattention (adjusted OR per 10 fold increase in urinary concentrations = 5.8, 95% CI: 1.6, 22.9), oppositional disorders (aOR = 3.9, 95% CI: 1.0, 16.0), and ADHD (aOR = 6.8, 95% CI: 1.8, 28.6), and; decreased ability to discriminate colors (aOR = 6.6, 95% CI: 1.6, 30.3; the higher the score the worse). Higher ETU concentrations were associated with poorer verbal learning outcomes (beta = -7.0, 95% CI: -12.7, -1.3). Higher 3 PBA concentrations were associated with poorer processing speed scores, particularly in girls (beta = -8.8, 95% CI: -16.1, -1.4). Our findings indicate that children living near banana and plantain plantations are exposed to pesticides that may affect their neurodevelopment, which for certain domains may differ between boys and girls. We recommend the implementation of measures to reduce pesticide exposure in children living nearby banana plantations. PMID- 27773360 TI - STING versus HIT technique of endoscopic treatment for vesicoureteral reflux: A systematic review and meta-analysis. AB - AIM: Our study aimed to compare the efficacy of two endoscopic techniques used for the correction of vesicoureteral reflux (VUR): subureteral transurethral injection (STING) and hydrodistension implantation technique (HIT). METHODS: A systematic review was conducted using MEDLINE, Google scholar, and Cochrane databases from 1984 to 2015. Meta-analysis of the selected studies was performed to compare the extent of reflux resolution following both techniques. RESULTS: Six observational studies met the inclusion criteria for content. These comprised 632 ureters treated by STING and 895 ureters treated by HIT procedure. All included studies utilized dextranomer/hyaluronic acid (Deflux) as the bulking agent. The overall resolution of VUR was significantly higher in HIT (82.5%) compared to STING (71.4%) [pooled odds ratio (OR)=0.54; 95% confidence interval (CI) 0.42-0.69; P<0.0001; I2=8%]. A subgroup analysis showed that HIT had better outcomes than STING for both lower grade (I-III) [OR=0.43; 95% CI 0.23-0.82; P=0.01; I2=0%] and high-grade VUR (IV-V) [OR=0.43; 95% CI 0.20-0.91; P=0.03; I2=0%]. However, there was no statistical difference in the requirement of additional injections between STING and HIT groups. CONCLUSION: HIT is superior to STING technique for resolution of VUR after Deflux injection. However, more randomized trials with longer follow-up are necessary to demonstrate the benefit of HIT compared to STING procedure. LEVEL OF EVIDENCE: Retrospective comparative studies - level III. PMID- 27773361 TI - Structured white light scanning of rabbit Achilles tendon. AB - BACKGROUND: The cross-sectional area (CSA) of a material is used to calculate stress under load. The mechanical behaviour of soft tissue is of clinical interest in the management of injury; however, measuring CSA of soft tissue is challenging as samples are geometrically irregular and may deform during measurement. This study presents a simple method, using structured light scanning (SLS), to acquire a 3D model of rabbit Achilles tendon in vitro for measuring CSA of a tendon. METHOD: The Artec SpiderTM 3D scanner uses structured light and stereophotogrammetry technologies to acquire shape data and reconstruct a 3D model of an object. In this study, the 3D scanner was integrated with a custom mechanical rig, permitting 360-degree acquisition of the morphology of six New Zealand White rabbit Achilles tendons. The reconstructed 3D model was then used to measure CSA of the tendon. SLS, together with callipers and micro-CT, was used to measure CSA of objects with a regular or complex shape, such as a drill flute and human cervical vertebra, for validating the accuracy and repeatability of the technique. RESULTS: CSA of six tendons was measured with a coefficient of variation of less than 2%. The mean CSA was 9.9+/-1.0mm2, comparable with those reported by other researchers. Scanning of phantoms demonstrated similar results to MUCT. CONCLUSION: The technique developed in this study offers a simple and accurate method for effectively measuring CSA of soft tissue such as tendons. This allows for localised calculation of stress along the length, assisting in the understanding of the function, injury mechanisms and rehabilitation of tissue. PMID- 27773362 TI - A new validation technique for estimations of body segment inertia tensors: Principal axes of inertia do matter. AB - The aims of this study were to: (i) establish a new criterion method to validate inertia tensor estimates by setting the experimental angular velocity data of an airborne objects as ground truth against simulations run with the estimated tensors, and (ii) test the sensitivity of the simulations to changes in the inertia tensor components. A rigid steel cylinder was covered with reflective kinematic markers and projected through a calibrated motion capture volume. Simulations of the airborne motion were run with two models, using inertia tensor estimated with geometric formula or the compound pendulum technique. The deviation angles between experimental (ground truth) and simulated angular velocity vectors and the root mean squared deviation angle were computed for every simulation. Monte Carlo analyses were performed to assess the sensitivity of simulations to changes in magnitude of principal moments of inertia within +/ 10% and to changes in orientation of principal axes of inertia within +/-10 degrees (of the geometric-based inertia tensor). Root mean squared deviation angles ranged between 2.9 degrees and 4.3 degrees for the inertia tensor estimated geometrically, and between 11.7 degrees and 15.2 degrees for the compound pendulum values. Errors up to 10% in magnitude of principal moments of inertia yielded root mean squared deviation angles ranging between 3.2 degrees and 6.6 degrees , and between 5.5 degrees and 7.9 degrees when lumped with errors of 10 degrees in principal axes of inertia orientation. The proposed technique can effectively validate inertia tensors from novel estimation methods of body segment inertial parameter. Principal axes of inertia orientation should not be neglected when modelling human/animal mechanics. PMID- 27773363 TI - [Heart transplantation for the treatment of isolated left ventricular myocardial noncompaction. First case in Mexico]. AB - BACKGROUND: Myocardial noncompaction of the left ventricle is a congenital cardiomyopathy characterised by left ventricular hypertrabeculation and prominent intertrabecular recesses. The incidence ranges from 0.15% to 2.2%. Clinical manifestations include heart failure, arrhythmias, and stroke. Prognosis is fatal in most cases. Heart transplantation is a therapeutic option for this cardiomyopathy, and few had been made worldwide. CLINICAL CASE: The case is presented of a 20 year-old male with noncompacted myocardium of the left ventricle, who had clinical signs of heart failure. His functional class was IV on the New York Heart Association scale. He was successfully transplanted. Its survival to 15 months is optimal in class I New York Heart Association, and endomyocardial biopsies have been reported without evidence of acute rejection. CONCLUSION: It is concluded that heart transplantation modified the natural history and improved survival in patients with this congenital heart disease. PMID- 27773364 TI - [Adolescent with paraovarian cyst. Surgycal treatment]. AB - BACKGROUND: Adnexal paraovarian cysts are not frequently seen during teen development, their incidence is around 10% and usually benign. CLINICAL CASE: Adolescent female 15 years old with no pathological family and personal history relevant to her current condition. Chief complaint: Six months ago she complained with abdominal pain in meso, hypogastrium and right iliac fossa. Later, she observed an increased volume on her lower quadrant of the abdomen, mostly on her right side. During physical examination an abdominal tumor was palpated. By an abdominal-rectal manouvre, the presence of tumor was confirmed and located in front of the rectum and no implants. Imaging studies confirmed a paraovarian cyst. She underwent on surgical laparatomy and a paraovarian cyst was found. The histological diagnosis was a cystadenoma. The postoperative course was satisfactory. DISCUSSION: Epidemiological data and ultrasonographic findings are examined to confirm the diagnosis of paraovarian cyst. The laparoscopic treatment for adnexal problems is described. PMID- 27773365 TI - [Imploding antrum syndrome: three cases with different management approaches]. AB - BACKGROUND: Silent sinus or imploding antrum syndrome is a very rare condition, consisting of a usually asymptomatic spontaneous collapse of the sinus walls and floor of the orbit. It is associated with negative pressures, and when this occurs, it presents with manifestations such as enophthalmos, hypoglobus, and tilt flow orbital floor. As its incidence is very low, it is frequently missed as a diagnosis, and in fact there are currently fewer than 150 cases reported in the literature. CLINICAL CASES: Three patients have been identified in our practice over a period of two years, with different symptoms that influenced the decision of the treatment modality, which were: watch and wait, endoscopic sinus surgery, or endoscopic sinus surgery plus orbitoplasty. CONCLUSIONS: Despite being a rare entity, it stills catches the attention of the ENT, OMF surgery and Ophthalmologist. The diagnosis is mainly radiological, due to the late clinical manifestations and symptomatology. The treatment should be individualised and based on the symptoms and the individual decision of each patient, firstly by Functional Endoscopic sinus surgery, and once sinus permeability is restored, it may require augmentation surgery of the orbital floor, either with autologous bone implant, titanium or other material. It is important to be aware of this pathology, to know and to suspect it, avoiding misdiagnosis. PMID- 27773366 TI - Synthesis and antimalarial activity of N-benzylated (N arylcarbamoyl)alkylphosphonic acid derivatives. AB - A series of novel and readily accessible N-benzylated (N arylcarbamoyl)alkylphosphonate esters and related compounds have been prepared as potential antimalarial agents. Bioassays reveal that some of these compounds exhibit promising activity against Plasmodium falciparum, and exhibit no significant growth inhibition of HeLa cells. PMID- 27773367 TI - Bayesian change-point analysis reveals developmental change in a classic theory of mind task. AB - Although learning and development reflect changes situated in an individual brain, most discussions of behavioral change are based on the evidence of group averages. Our reliance on group-averaged data creates a dilemma. On the one hand, we need to use traditional inferential statistics. On the other hand, group averages are highly ambiguous when we need to understand change in the individual; the average pattern of change may characterize all, some, or none of the individuals in the group. Here we present a new method for statistically characterizing developmental change in each individual child we study. Using false-belief tasks, fifty-two children in two cohorts were repeatedly tested for varying lengths of time between 3 and 5 years of age. Using a novel Bayesian change point analysis, we determined both the presence and-just as importantly the absence of change in individual longitudinal cumulative records. Whenever the analysis supports a change conclusion, it identifies in that child's record the most likely point at which change occurred. Results show striking variability in patterns of change and stability across individual children. We then group the individuals by their various patterns of change or no change. The resulting patterns provide scarce support for sudden changes in competence and shed new light on the concepts of "passing" and "failing" in developmental studies. PMID- 27773368 TI - Which factors influence the need for inpatient rehabilitation after severe trauma? AB - INTRODUCTION: Despite the importance of rehabilitation in the treatment of patients with severe trauma or even of severely injured patients, the cooperation between acute and rehabilitation hospitals is often inadequate. The present study aims to identify factors that make it probable that a severely injured patient requires inpatient rehabilitation following the acute treatment. MATERIAL AND METHODS: A retrospective analysis of 75.357 cases from the TraumaRegister DGU(r) (TR-DGU) was performed. All cases from 2002 until 2013 with an ISS>=9, who were taken to the ICU were included. Regarding the discharge destination the subgroups "at home" and "rehabilitation hospital" were analyzed in detail. Finally, we performed a multivariate regression analysis based on the parameters previously collected. RESULTS: 24.208 patients (32.1%) were transferred to a rehabilitation clinic. In the multivariate regression analysis the most relevant independent parameters for discharge in a rehabilitation hospital were age (18-54: OR 1.65; 55-74: OR 2.86 and 75 and older: OR 5.07, all p<=0.001), AIS pelvis>=2 (OD 1.94), AIS legs (OR 2.02), AIS spine (AIS 4: OR 5.78 and AIS 5-6: OR 6.36) and the AIS head (AIS 3: OR 1.88; AIS 4: OR 3.11 and AIS 5-6: OR 7.55) (all p<=0.001). The length of stay in the ICU (3-7 days: OR 1.88; 8-28 Days: OR 5.42 and 29 and more days: OR 14.7, all p<=0.001) was also a relevant parameter. The overall ISS presented no relevant influence with an OR of 1.02 (p=0.03). DISCUSSION AND CONCLUSION: Knowing independent factors for a required inpatient rehabilitation helps the treating physicians to identify the patients at an early stage in acute hospitals. So the transfer to a rehabilitation clinic can be organized faster and more selective in future. PMID- 27773369 TI - Impact of cement-augmented condylar screws in locking plate osteosynthesis for distal femoral fractures - A biomechanical analysis. AB - INTRODUCTION: Compromised bone quality and the need for early mobilization continue to lead to implant failure in elderly patients with distal femoral fractures. The cement augmentation of screws might facilitate improving implant anchorage. The aim of this study was to analyse the impact of cement augmentation of the condylar screws on implant fixation in a human cadaveric bone model. MATERIAL AND METHODS: Ten pairs of osteoporotic femora (mean age: 90 years, range: 84-99 years) were used. A 2-cm gap osteotomy was created in the metaphyseal region to simulate an unstable AO/OTA 33-A3 fracture. All specimens were treated with a polyaxial locking plate. Specimens randomly assigned to the augmented group received an additional cement augmentation of the condylar screws using bone cement. A servohydraulic testing machine was used to perform incremental cyclic axial loading using a load-to-failure mode. RESULTS: All specimens survived at least 800N of axial compressive force. The mean compressive forces leading to failure were 1620N (95% CI: 1382-1858N) in the non-augmented group and 2420N (95% CI: 2054-2786N) in the group with cement-augmented condylar screws (p=0.005). Deformation with cutting out of the condylar screws and condylar fracture were the most common reasons for failure in both groups. Whereas axial stiffness was comparable between both osteosyntheses (p=0.508), significant differences were observed for the plastic deformation of the constructs (p=0.014). CONCLUSION: The results of the present study showed that the cement augmentation of the condylar screws might be a promising technique for the fixation of distal femoral fractures in elderly patients with osteoporotic bones. PMID- 27773370 TI - Improvement in osteoporosis detection in a fracture liaison service with integration of a geriatric hip fracture care program. AB - INTRODUCTION: Care gaps have been identified in the treatment of osteoporosis after the occurrence of a fragility hip fracture. HiROC (High Risk Osteoporosis Clinic) is a fracture liaison service implemented at our institution. In ProvenCare geriatric hip fracture care program at our institution pre-set orders for the inpatient HiROC consults were prescribed. We hypothesized that there will be a significant increase in the rate of enrollment of patients in the HiROC program after the integration of the pre-set orders. PATIENTS AND METHODS: The trauma database at a level-I trauma center was reviewed retrospectively for the charts of patients >50 years of age with fragility intertrochanteric fractures. Patients not treated under the geriatric hip fracture care program and patients treated under the geriatric hip fracture care program were identified and reviewed for the enrollment in HiROC and subsequent follow up. RESULTS: Out of 589 patients treated before the implementation of ProvenCare, 443 patients (75%) were enrolled in HiROC at the index consult. In comparison, out of 153 patients treated after the implementation of ProvenCare, 131 patients (85.6%) were enrolled in HiROC at the index consult. The difference between the two groups was statistically significant (p=0.008). CONCLUSION: Our experience shows that the occurrence of a fragility intertrochanteric fracture can be effectively utilized for the detection and initiation of treatment of osteoporosis. With the implementation of pre-set orders in the geriatric hip fracture care program significantly better enrollment can be achieved. PMID- 27773371 TI - Circular frame fixation for calcaneal fractures risks injury to the medial neurovascular structures: A cadaveric description. AB - AIM: There is a risk of iatrogenic injury to the soft tissues of the calcaneus and this study assesses the risk of injury to these structures in circular frame calcaneal fracture fixation. MATERIALS AND METHODS: After olive tip wires were inserted, an L-shaped incision on the lateral and medial aspects of 5 formalin fixed cadaveric feet was performed to expose the underlying soft tissues. The calcaneus was divided into zones corresponding to high, medium and low risk using a grading system. RESULTS: Structures at high risk included the posterior tibial artery, posterior tibial vein and posterior tibial nerve on the medial aspect. Soft tissue structures on the lateral side that were shown to be at lower risk of injury were the small saphenous vein and the sural nerve and the tendons of fibularis longus and fibularis brevis. CONCLUSION: The lateral surface of the calcaneus provides a lower risk area for external fixation. The risk of injury to significant soft tissues using a circular frame fixation approach has been shown to be greater on the medial aspect. CLINICAL RELEVANCE: This study highlights the relevant anatomical relations in circular frame fixation for calcaneal fractures to minimise damage to these structures. PMID- 27773372 TI - Cerebral oxidative metabolism failure in traumatic brain injury: "Brain shock". AB - Shock is a systemic form of acute circulatory failure leading to cellular dysoxia and death. Such a state of aerobic metabolism failure also underlies neuronal cell death in severe traumatic brain injury. It is becoming increasingly recognized that ischemic hypoxia is not the sole mechanism and that multiple alternate cooperating mechanisms may be responsible for compromising neuronal oxidative metabolism. These different mechanisms can be usefully understood via analysis of the classic subdivisions of tissue hypoxia. This approach could lead to an alternative treatment paradigm toward cerebral oxygen metabolic rate targeting instead of the traditional targets of intracranial and perfusion pressures. PMID- 27773373 TI - Is sentinel lymph node biopsy indicated in patients with a diagnosis of ductal carcinoma in situ? A systematic literature review and meta-analysis. AB - BACKGROUND: Recent discussion has suggested that some cases of ductal carcinoma in situ (DCIS) with high risk of invasive disease may require sentinel lymph node biopsy (SLNB). METHODS: Systematic literature review identified 48 studies (9,803 DCIS patients who underwent SLNB). Separate analyses for patients diagnosed preoperatively by core sampling and patients diagnosed postoperatively by specimen pathology were conducted to determine the percentage of patients with axillary nodal involvement. Patient factors were analyzed for associations with risk of nodal involvement. RESULTS: The mean percentage of positive SLNBs was higher in the preoperative group (5.95% vs 3.02%; P = .0201). Meta-regression analysis showed a direct association with tumor size (P = .0333) and grade (P = .00839) but not median age nor tumor upstage rate. CONCLUSIONS: The SLNB should be routinely considered in patients with large (>2 cm) high-grade DCIS after a careful multidisciplinary discussion. In the context of breast conserving surgery, the SLNB is not routinely indicated for low- and intermediate-grade DCIS, high-grade DCIS smaller than 2 cm, or pure DCIS diagnosed by definitive surgical excision. PMID- 27773374 TI - Barriers to genetic testing in newly diagnosed breast cancer patients: Do surgeons limit testing? AB - BACKGROUND: Genetic testing results influence treatment recommendations in newly diagnosed breast cancer patients. However, at-risk patients do not uniformly undergo genetic testing. The goal of this study was to identify barriers to genetic testing in newly diagnosed breast cancer patients. METHODS: A prospective database of newly diagnosed breast cancer patients meeting specific criteria over an 18-month period was created and retrospectively reviewed. RESULTS: A total of 532 patients were identified at risk for genetic mutation. Of these 313 (59%) patients completed a genetic counseling appointment and 292 (55%) underwent genetic testing. One hundred seven (24%) were never referred to genetic counselors and 89 (17%) were referred but did not complete an appointment. Patients referred to genetics were younger than the nonreferred patients (50.9 vs 60.6 years, P < .001). The 89 women referred to genetics who did not complete an appointment were surveyed and had varied reasons for not completing an appointment. CONCLUSIONS: The largest barrier to genetic testing was lack of physician referral; therefore, provider education must be improved. Appointments should be convenient and providers should proactively discuss the significant implications of testing results. PMID- 27773375 TI - Improved knowledge gain and retention for third-year medical students during surgical journal club using basic science review: A pilot study. AB - BACKGROUND: As they enter the clinical years, medical students face large adjustments in the acquisition of medical knowledge. We hypothesized that basic science review related to the topic of journal club papers would increase the educational benefit for third-year medical students. METHODS: Students were randomized either to participation in a review session about basic science related to the journal club paper, or to no review. After one day, and after three months, students were given a 10-question quiz encompassing the basic science and the clinical implications of the paper. RESULTS: Twenty-six of 50 students were randomized to basic science review. These students scored better on both sections of the quiz one day after journal club, but only on basic science questions after three months. CONCLUSIONS: Students who participated in basic science review had better knowledge gain and retention. Educational activities building upon foundational knowledge improves learning on clinical rotations. PMID- 27773376 TI - Is forgoing chemical venous thromboembolism prophylaxis for women undergoing breast-conserving surgery for breast cancer safe? AB - BACKGROUND: Cancer patients have a 4 to 7 fold increased risk of venous thromboembolism (VTE) vs the normal population. Chest guidelines recommend no chemical VTE prophylaxis for women with a <1.5% risk for VTE. Although the risk of VTE among women undergoing breast-conserving therapy is reported to be low overall, the rate without chemical prophylaxis has not been defined. The objective of the study was to establish the VTE risk among women undergoing breast-conserving surgery (BCS) who did not receive chemical VTE prophylaxis. METHODS: From a prospective breast cancer database, 1,000 consecutive patients who underwent BCS without chemical VTE prophylaxis and with mechanical prophylaxis (support hose and intermittent pneumatic compression devices) were analyzed for VTE occurrence within 30 days postoperatively. Institutional review board approval was obtained. RESULTS: The mean age was 65.4 +/- 11.7 years, and mean body mass index was 27.3 +/- 5.7. About 81.9% of the patients were postmenopausal. Median tumor size was 1.1 cm, and 24.7% of patients had lymph node metastases. The 30-day rate of clinically significant VTE was 0% (95% CI 0% to .37%). Hematomas requiring surgical intervention occurred among .6% of patients. CONCLUSIONS: This cohort demonstrates that breast cancer patients undergoing BCS may be safely managed without chemical VTE prophylaxis because the risk with only mechanical prophylaxis is acceptable. PMID- 27773377 TI - Outcomes in elderly fall victims: what happens after hospital discharge? AB - BACKGROUND: Falls are the leading cause of trauma-related death in the elderly, but postdischarge outcomes' data are lacking. The purpose of this study was to evaluate 12-month postdischarge mortality and causes of death. METHODS: A retrospective review was conducted of patients 65 years and older admitted for a fall and discharged alive. Data collection included demographics, injury characteristics, hospitalization details, and outcomes. A state death database and hospital records were queried to identify patients who died within 12 months of hospital discharge. RESULTS: Of 347 patients meeting inclusion criteria, 74 (21.3%) died within 12 months postdischarge. These patients were older than those who survived (83.4 vs 79.1 years, P < .001). Most injury patterns were not predictive of postdischarge death, whereas several comorbidities were more common in those who died. Death was fall-related in 13 of 74 (17.6%) who died. CONCLUSIONS: Injury characteristics do not predict postdischarge mortality. However, pre-existing comorbidities, including advanced age were predictive of postdischarge mortality. Further study is needed to determine whether a focus on medical optimization can reduce 1-year postdischarge death. PMID- 27773378 TI - The effect of a simple intraprocedural checklist on the task performance of laparoscopic novices. AB - BACKGROUND: Surgical checklists are used for error reduction. Checklists are infrequently applied during procedures and have been limited to lists of procedural steps as aid memoires. We aimed to study the effect of a self administered checklist on the laparoscopic task performance of novices during a standardized task. METHODS: Twenty novices were randomized into 2 equal groups, those receiving paper feedback (control group) and those receiving paper feedback and the checklist (checklist group). Subjects performed laparoscopic double knots, repeated over 5 separate stages. Human reliability assessment technique was used for error analysis. RESULTS: 2,341 errors were detected during the 5 stages. During the first stage, the errors were not significantly different between the 2 groups. The checklist group committed significantly fewer errors as compared with the control group during all the later 4 stages (P < .01). CONCLUSIONS: The simple intraprocedural checklist significantly improved the laparoscopic task performance and the learning curve of laparoscopic novices. PMID- 27773379 TI - Preference adjustable multi-objective NMPC: An unreachable prioritized point tracking method. AB - This paper proposes a new preference adjustable multi-objective model predictive control (PA-MOMPC) law for constrained nonlinear systems. With this control law, a reasonable prioritized optimal solution can be directly derived without constructing the Pareto front by solving a minimal optimization problem, which is a novel development of recently proposed utopia tracking approaches by additionally considering objective preferences with more flexible terminal and stability constraints. The tracking point of the proposed PA-MOMPC law is represented by a parametric vector with the parameters adjustable on the basis of objective preferences. The main result of this paper is that the solution obtained through the proposed PA-MOMPC law is demonstrated to have two important properties. One is the inherent Pareto optimality, and the other is the priority consistency between the solution and the tuning parametric vector. This combination makes the objective priorities tuning process transparent and efficient. The proposed PA-MOMPC law is supported by feasibility analyses, proof of nominal stability, and a numerical case study. PMID- 27773380 TI - Anti-windup adaptive PID control design for a class of uncertain chaotic systems with input saturation. AB - In this paper, the stabilization problem of actuators saturation in uncertain chaotic systems is investigated via an adaptive PID control method. The PID control parameters are auto-tuned adaptively via adaptive control laws. A multi level augmented error is designed to account for the extra terms appearing due to the use of PID and saturation. The proposed control technique uses both the state feedback and the output-feedback methodologies. Based on Lyapunov's stability theory, new anti-windup adaptive controllers are proposed. Demonstrative examples with MATLAB simulations are studied. The simulation results show the efficiency of the proposed adaptive PID controllers. PMID- 27773381 TI - Analysis and synthesis of networked control systems: A survey of recent advances and challenges. AB - A networked control system (NCS) is a control system which involves a communication network. In NCSs, the continuous-time measurement is usually sampled and quantized before transmission. Then, the measurement is transmitted to the remote controller via the communication channel, during which the signal may be delayed, lost or even sometimes not allowed for transmission due to the communication or energy constraints. In recent years, the modeling, analysis and synthesis of networked control systems (NCSs) have received great attention, which leads to a large number of publications. This paper attempts to present an overview of recent advances and unify them in a framework of network-induced issues such as signal sampling, data quantization, communication delay, packet dropouts, medium access constraints, channel fading and power constraint, and present respective solution approaches to each of these issues. We draw some conclusions and highlight future research directions in end. PMID- 27773382 TI - Global fast dynamic terminal sliding mode control for a quadrotor UAV. AB - A control method based on global fast dynamic terminal sliding mode control (TSMC) technique is proposed to design the flight controller for performing the finite-time position and attitude tracking control of a small quadrotor UAV. Firstly, the dynamic model of the quadrotor is divided into two subsystems, i.e., a fully actuated subsystem and an underactuated subsystem. Secondly, the dynamic flight controllers of the quadrotor are formulated based on global fast dynamic TSMC, which is able to guarantee that the position and velocity tracking errors of all system state variables converge to zero in finite-time. Moreover, the global fast dynamic TSMC is also able to eliminate the chattering phenomenon caused by the switching control action and realize the high precision performance. In addition, the stabilities of two subsystems are demonstrated by Lyapunov theory, respectively. Lastly, the simulation results are given to illustrate the effectiveness and robustness of the proposed control method in the presence of external disturbances. PMID- 27773383 TI - Atomistic modeling of nanoparticle generation in short pulse laser ablation of thin metal films in water. AB - Laser ablation in liquids is actively used for generation of clean colloidal nanoparticles with unique shapes and functionalities. The fundamental mechanisms of the laser ablation in liquids and the key processes that control the nanoparticle structure, composition, and size distribution, however, are not yet fully understood. In this paper, we report the results of first atomistic simulations of laser ablation of metal targets in liquid environment. A model combining a coarse-grained representation of the liquid environment (parameterized for water), a fully atomistic description of laser interactions with metal targets, and acoustic impedance matching boundary conditions is developed and applied for simulation of laser ablation of a thin silver film deposited on a silica substrate. The simulations, performed at two laser fluences in the regime of phase explosion, predict a rapid deceleration of the ejected ablation plume and the formation of a dense superheated molten layer at the water plume interface. The water in contact with the hot metal layer is brought to the supercritical state and transforms into an expanding low density metal-water mixing region that serves as a precursor for the formation of a cavitation bubble. Two distinct mechanisms of the nanoparticle formation are predicted in the simulations: (1) the nucleation and growth of small (mostly ?10nm) nanoparticles in the metal-water mixing region and (2) the formation of larger (tens of nm) nanoparticles through the breakup of the superheated molten metal layer triggered by the emergence of complex morphological features attributed to the Rayleigh-Taylor instability of the interface between at the superheated metal layer and the supercritical water. The first mechanism is facilitated by the rapid cooling of the growing nanoparticles in the supercritical water environment, resulting in solidification of the nanoparticles located in the upper part of the mixing region on the timescale of nanoseconds. The computational prediction of the two mechanisms of nanoparticle formation yielding nanoparticles with different characteristic sizes is consistent with experimental observations of two distinct nanoparticle populations appearing at different stages of the ablation process. PMID- 27773384 TI - Development of a dual permeability model within a hydrological catchment modeling framework: 1D application. AB - Preferential flow contributes significantly to pesticide fast transfer from surface to groundwater. Modeling this process at several scales is an important challenge for improving the representation of this process which is often neglected. In this study, we developed a dual permeability approach in a hydrological modeling framework, CMF, which is a collaborative environment for developing spatially-integrated models of water fluxes. In the development we propose here, infiltration in macropores which are connected to the surface is activated when the first matrix layer reaches saturation. A transfer function is used to represent water fluxes from macropores to matrix. This approach is tested in 1D by comparison with the dual permeability approach included in Hydrus1D, on 4 typical soil-types (sandy-loam, silty-loam, clay-loam and sandy-clay-loam). The results showed an underestimation of the flux infiltrated in the matrix surface and important infiltration in macropores with the new model, for most of soil types, comparing to Hydrus1D. Similarities are observed for fluxes transferred from macropores to matrix. Solute transport is then coupled to CMF-DP model considering a convection transport and a linear adsorption to represent pesticides behavior in macroporous soils. The approach we developed is similar to Hydrus though having the advantage to need less input parameters, especially for the exchange between the two porous media. In the future, it could be applied for predicting pesticides transfer in macroporous soils at different scales for operational applications. PMID- 27773386 TI - Vortex-homogenized matrix solid-phase dispersion for the extraction of short chain chlorinated paraffins from indoor dust samples. AB - A simple and effective method for determining short chain chlorinated paraffins (SCCPs) in indoor dust is presented. The method employed a modified vortex homogenized matrix solid-phase dispersion (VH-MSPD) prior to its detection by gas chromatography - electron-capture negative-ion mass spectrometry (GC-ECNI-MS) operating in the selected-ion-monitoring (SIM) mode. Under the best extraction conditions, 0.1-g of dust sample was dispersed with 0.1-g of silica gel by using vortex (2min) instead of using a mortar and pestle (3min). After that step, the blend was transferred to a glass column containing 3-g acidic silica gel, 2-g basic silica gel, and 2-g of deactivated silica gel, used as clean-up co sorbents. Then, target analytes were eluted with 5mL of n-hexane/dichloromethane (2:1, v/v) mixture. The extract was evaporated to dryness under a gentle stream of nitrogen. The residue was then re-dissolved in n-hexane (10MUL), and subjected to GC-ECNI-MS analysis. The limits of quantitation (LOQs) ranged from 0.06 to 0.25MUg/g for each SCCP congener. Precision was less than 7% for both intra- and inter-day analysis. Trueness was above 89%, which was calculated by mean extraction recovery. The VH-MSPD combined with GC-ECNI-MS was successfully applied to quantitatively detect SCCPs from various indoor dust samples, and the concentrations ranged from 1.2 to 31.2MUg/g. PMID- 27773387 TI - A sub-minute electrophoretic method for simultaneous determination of naphazoline and zinc. AB - This paper reports for the first time, a method for simultaneous determination of naphazoline (NPZ) and zinc (Zn) using an analytical separation technique (capillary electrophoresis with capacitively coupled contactless conductivity detection -CE-C4D). A single run is possible every 55s (sampling rate=65h-1). The separation by CE-C4D was achieved on a fused silica capillary (50cm length - 10cm effective, 50MUm i.d.) with a background electrolyte (BGE) composed by 20mmolL-1 of 2-(morpholin-4-yl)ethane-1-sulfonic acid (MES) and 20mmolL-1 of histidine (HIS) (pH 6.0). Detection limits were estimated at 20 and 30MUmolL-1 and recovery values for spiked samples were 98 and 102% for NPZ and Zn, respectively. The developed procedure was compared to HPLC (NPZ) and FAAS (Zn) and no statistically significant differences were observed (95% confidence level). PMID- 27773385 TI - Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia. AB - Glycosylation is a post-translational modification that is an essential element in cell signaling and neurodevelopmental pathway regulation. Glycan attachment can influence the tertiary structure and molecular interactions of glycosylated substrates, adding an additional layer of regulatory complexity to functional mechanisms underlying central cell biological processes. One type of enzyme mediated glycan attachment, fucosylation, can mediate glycoprotein and glycolipid cell surface expression, trafficking, secretion, and quality control to modulate a variety of inter- and intracellular signaling cascades. Building on prior reports of glycosylation abnormalities and evidence of dysregulated glycosylation enzyme expression in schizophrenia, we examined the protein expression of 5 key fucose-modifying enzymes: GDP-fucose:protein O-fucosyltransferase 1 (POFUT1), GDP fucose:protein O-fucosyltransferase 2 (POFUT2), fucosyltransferase 8 (FUT8), fucosyltransferase 11 (FUT11), and plasma alpha-l-fucosidase (FUCA2) in postmortem superior temporal gyrus of schizophrenia (N=16) and comparison (N=14) subjects. We also used the fucose binding protein, Aleuria aurantia lectin (AAL), to assess alpha-1,6-fucosylated N-glycoprotein abundance in the same subjects. In schizophrenia, we found increased expression of POFUT2, a fucosyltransferase uniquely responsible for O-fucosylation of thrombospondin-like repeat domains that is involved in a non-canonical endoplasmic reticulum quality control pathway. We also found decreased expression of FUT8 in schizophrenia. Given that FUT8 is the only alpha-1,6-fucosyltransferase expressed in mammals, the concurrent decrease in AAL binding in schizophrenia, particularly evident for N glycoproteins in the ~52-58kDa and ~60-70kDa molecular mass ranges, likely reflects a consequence of abnormal FUT8 expression in the disorder. Dysregulated FUT8 and POFUT2 expression could potentially explain a variety of molecular abnormalities in schizophrenia. PMID- 27773388 TI - Enantiomeric determination and evaluation of the racemization process of atropine in Solanaceae seeds and contaminated samples by high performance liquid chromatography-tandem mass spectrometry. AB - A new method has been developed for the enantioselective separation of (-) and (+) hyoscyamine in Solanaceaes seeds and contaminated buckwheat. Chromatographic separation was optimized, evaluating two chiral columns, Chirobiotic V and Chiralpal-AY3. Better resolution was obtained using a Chiralpak-AY3 column, utilizing as mobile phase ethanol (0.1% diethanolamine). An extraction procedure based on a modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) was applied, using water and acetonitrile containing 1% of acetic acid, and a clean up step utilizing primary secondary amine (PSA) and graphitized carbon black (GCB) as sorbents. The extract was diluted with ethanol (50/:50, v/v) prior to chromatographic analysis, and the separation was carried out avoiding the racemization during this stage. Enantiomerization process of atropine was studied in samples at different conditions such as temperature (30, 50 and 80 degrees C) and pH (3, 5, 7 and 9), observing that racemization occurs at high pH (9) and temperature (80 degrees C). Stramonium and Brugmansia seeds were analyzed and the concentration of (-)-hyoscyamine was 1500mg/kg and 320mg/kg respectively. Contaminated buckwheat was also determined and (-)-hyoscyamine was detected at 170MUg/kg. PMID- 27773390 TI - Rapid determination of hydrodynamic radii beyond the limits of Taylor dispersion. AB - Taylor dispersion analysis (TDA) is an absolute method for determining the diffusion coefficients, and hence the hydrodynamic radii, of particles by measuring the dispersion in a carrier medium flowing within a capillary. It is applicable under conditions which allow the particles to radially diffuse appreciably across the cross-section of the flow before the measurement and therefore implies long measurement times are required for large particles with small diffusion coefficients. In this paper, a method has been developed by which the diffusion coefficients of large particles can be rapidly estimated from the shapes of the concentration profiles obtained at much earlier measurement times. The method relies on the fact that the shapes of the early-time concentration profiles are dependent on the diffusion coefficient, flow rate and the capillary radius through the dimensionless residence time which, theoretically, is a measure of the amount of radial diffusion undergone by the particles. The amount of radial diffusion for nanospheres of varying sizes was estimated by quantifying the relative change in the shapes of concentration profiles obtained at two points in the flow and a correlation was obtained with the variation of the dimensionless residence time to confirm the theory. This correlation was then tested by applying it to another set of measurements of solutes and solute mixtures of different sizes including a protein. The estimated diffusion coefficients were found to be in good agreement with the expected values. This demonstrates the potential for the method to extend dispersion analysis to regimes well outside the TDA limits to enable the rapid characterization of large particles. PMID- 27773389 TI - Enantioseparation of the carboxamide-type synthetic cannabinoids N-(1-amino-3 methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide and methyl [1-(5-fluoropentyl)-1H-indazole-3-carbonyl]-valinate in illicit herbal products. AB - Synthetic cannabinoids, recently used as alternatives to Cannabis sativa, are among the most frequently abused drugs. Identified in 2014, the synthetic cannabinoids N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indazole 3-carboxamide (5F-AB-PINACA) and methyl [1-(5-fluoropentyl)-1H-indazole-3 carbonyl]-valinate (5F-AMB) are carboxamides composed of 1-(5-fluoropentyl)-1H indazole-3-carboxylic acid and valine amide/methyl ester. Because of their composition, these molecules have pairs of enantiomers derived from the chiral center of their amino acid structures. Previous studies on the identification of 5F-AB-PINACA and 5F-AMB did not consider the existence of enantiomers, and there have been no reports on the enantiopurities of synthetic cannabinoids. We synthesized both enantiomers of these compounds and then separated the enantiomers by liquid chromatography-high-resolution mass spectrometry using a column with a chiral stationary phase consisted with amylose tris (3-chloro-4 methylphenylcarbamate). Under the optimized conditions, the enantiomer resolutions were 2.2 and 2.3 for 5F-AB-PINACA and 5F-AMB, respectively. Analysis of 10 herbal samples containing 5F-AB-PINACA and one herbal sample containing 5F AMB showed that they all contained the (S)-enantiomer, but the (R)-enantiomer was only detected in two samples and at a ratio of less than 20%. PMID- 27773391 TI - Bridging the gap between gas and liquid chromatography. AB - The rapid and complete baseline separation of both volatile (C5 to C16 alkanes in gasoline or terpenes in plant extracts) and non-volatile (>C20 alkanes) organic compounds was achieved by combining (1) low-density fluid chromatography (LDFC) using carbon dioxide at elevated temperature (>90 degrees C) and low pressure (1500psi) designed to increase the retention of the most volatile compounds and (2) high-vacuum technology (<10-4Torr) in order to preserve the maximum efficiency of short analytical columns (3.0mm*150mm packed with 1.8MUm fully porous HSS-SB-C18 particles) when used in LDFC. The volatile compounds are eluted first under isobaric conditions (1500psi) in less than a minute followed by a linear gradient of the column back pressure (from 1500 to 3500psi in 5min) for the elution of the non-volatile compounds up to C40. The experimental results demonstrate that LDFC performed with short 3.0mm i.d. columns packed with sub 2MUm particles and placed under adiabatic conditions enables the analysts to deliver a single, fast, and high-resolution separation of both volatile and non volatile compounds. PMID- 27773393 TI - Are all stents equal - Need for scoring system to evaluate stents? AB - Currently drug eluting stents (DES) have reached a high degree of sophistication where there seems very little scope of improvement. Even so every year or so there is some advancement in technology and a new version is released, which is claimed to be a new generation (rather than pipeline innovation). It is really important to define what pipeline extension is and what is new innovation (generation)? This classification would not only be useful from regulatory perspective but also determining the true value of a product allowing for a correct pricing, which should ideally be able to mark-up for a real innovation. PMID- 27773392 TI - Tryptophan tags and de novo designed complementary affinity ligands for the expression and purification of recombinant proteins. AB - A common strategy for the production and purification of recombinant proteins is to fuse a tag to the protein terminal residues and employ a "tag-specific" ligand for fusion protein capture and purification. In this work, we explored the effect of two tryptophan-based tags, NWNWNW and WFWFWF, on the expression and purification of Green Fluorescence Protein (GFP) used as a model fusion protein. The titers obtained with the expression of these fusion proteins in soluble form were 0.11mgml-1 and 0.48mgml-1 for WFWFWF and NWNWNW, respectively. A combinatorial library comprising 64 ligands based on the Ugi reaction was prepared and screened for binding GFP-tagged and non-tagged proteins. Complementary ligands A2C2 and A3C1 were selected for the effective capture of NWNWNW and WFWFWF tagged proteins, respectively, in soluble forms. These affinity pairs displayed 106M-1 affinity constants and Qmax values of 19.11+/-2.60ugg-1 and 79.39ugg-1 for the systems WFWFWF AND NWNWNW, respectively. GFP fused to the WFWFWF affinity tag was also produced as inclusion bodies, and a refolding-on column strategy was explored using the ligand A4C8, selected from the combinatorial library of ligands but in presence of denaturant agents. PMID- 27773394 TI - Balloon aortic valvuloplasty. PMID- 27773395 TI - Differential residual dyslipidemia/cardiovascular risk after statin treatment between Asian-Indians and western whites. Call for action. PMID- 27773397 TI - Long-term results of percutaneous balloon valvuloplasty of congenital aortic stenosis in adolescents and young adults. AB - : Balloon aortic valvuloplasty (BAV) is a well accepted modality of treatment in congenital aortic stenosis in all age groups. Although in infants and children it is the modality of choice, in adolescents and young adults, it is of debatable efficacy. AIM: To evaluate long-term results of aortic valvuloplasty particularly in adolescent and adults (>12 years) and compare the outcome in other age groups that are <1 year and between 1 are 11 years. SETTING: Tertiary referral center. PATIENTS: 165 consecutive patients treated at the median age of 9 years (1 day to 64 years). The follow-up was up to 14 years (median 3 years). The whole cohort was divided into 3 age-based subgroups: Group A (<1 year) n=45, Group B (1 year 11 years) n=52, and Group C (>12 years) n=68. The characteristics of each subgroup were mutually compared. INTERVENTION: Percutaneous balloon valvuloplasty with mean (SD) balloon to annulus ratio of 0.93. Main outcome measures were repeat BAV, significant aortic regurgitation (AR), and aortic valve replacement/repair. RESULTS: The incidence of significant AR from the whole cohort was 9.9% (8% moderate, 1.9% severe); n=16. Group A=significant AR 9.5% (7.1% moderate, 2.4% severe), Group B=significant AR 11.3% (9.4% moderate, 1.9% severe), and Group C=significant AR 9% (7.5% moderate, 1.5% severe); p value=0.99 (Group C vs Group A) and 0.92 (Group C vs Group B). Repeat BAV rate was 13.3% (n=22 out of 165 patients). Group A - n=5 (11.9%), Group B - n=10 (18.2%), and Group C - n=7 (10.3%). p Value=0.78 (C vs A) and 0.19 (C vs B). Surgery in follow up was needed in n=4 (2.4%), none in Group A, 2 patients in Group B (3.6%), and 2 patients in group C (2.9%). Patients were followed up for a period of 14 years; Group A=up to 8 years, Group B=up to 13 years, and Group C=up to 14 years. Mean survival probability after the procedure was 8 years (Group A=6.5 years, Group B=8.1 years, and Group C=9.9 years), and p value=0.49 (A vs B), 0.23 (B vs C), and 0.4 (A vs C). CONCLUSION: There is no statistical difference in the long-term outcome in the adults and adolescents as compared to the children; thus BAV remains an obvious treatment of choice with good long-term outcome. PMID- 27773396 TI - One-year outcomes of a BioMimeTM Sirolimus-Eluting Coronary Stent System with a biodegradable polymer in all-comers coronary artery disease patients: The meriT-3 study. AB - OBJECTIVES: The aim of the merit-3 study was to determine the safety and performance of the BioMime Sirolimus-Eluting Coronary Stent System (SES) in all comer patients with coronary artery disease (CAD) in one-year clinical follow-up period. METHODS: The meriT-3 was a multi-centre, observational, post-marketing study conducted in 1161 patients with CAD who were implanted with BioMime SES at 15 sites in India. The primary endpoint was major adverse cardiac event (MACE) at one year defined as the composite of cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR). Clinical follow-up was performed at 1, 6, and 12 months. Major adverse cardiac event occurred at 30 days and subsequently at 6 months and at long-term follow-up of 1 year was analyzed. RESULTS: MACE observed at 1 and 6 months follow-up was 16 (1.38%) and 21 (1.83%) respectively. Cumulative 1 year MACE was 26 (2.35%) with 16 (1.39%) all cause death, 4 (0.35%) MI and 6 (0.52%) TLR. In addition, ST was observed in 1 (0.09%) patient. CONCLUSIONS: The present study suggests that the BioMime SES is safe and effective in a "real-world", all-comers CAD patients, indicating low rates of MACE. CTRI ACKNOWLEDGEMENT NO: REF/2016/07/011808. PMID- 27773398 TI - Effect of balloon mitral valvotomy on left ventricular function in rheumatic mitral stenosis. AB - AIM: Mitral stenosis (MS) is found to produce left ventricular (LV) dysfunction in some studies. We sought to study the left ventricular function in patients with rheumatic MS undergoing balloon mitral valvotomy (BMV). Ours is the first study to analyze effect of BMV on mitral annular plane systolic excursion (MAPSE), and to quantify prevalence of longitudinal left ventricular dysfunction in rheumatic MS. METHODS: In this prospective cohort study, we included 43 patients with severe rheumatic mitral stenosis undergoing BMV. They were compared to twenty controls whose distribution of age and gender were similar to that of patients. The parameters compared were LV ejection fraction (EF) by modified Simpson's method, mitral annular systolic velocity (MASV), MAPSE, mitral annular early diastolic velocity (E'), and myocardial performance index (MPI). These parameters were reassessed immediately following BMV and after 3 months of procedure. RESULTS: MASV, MAPSE, E', and EF were significantly lower and MPI was higher in mitral stenosis group compared to controls. Impaired longitudinal LV function was present in 77% of study group. MAPSE and EF did not show significant change after BMV while MPI, MASV, and E' improved significantly. MASV and E' showed improvement immediately after BMV, while MPI decreased only at 3 months follow-up. CONCLUSIONS: There were significantly lower mitral annular motion parameters including MAPSE in patients with rheumatic mitral stenosis. Those with atrial fibrillation had higher MPI. Immediately after BMV, there was improvement in LV long axis function with a gradual improvement in global LV function. There was no significant change of MAPSE after BMV. PMID- 27773399 TI - A novel approach in the use of radiofrequency catheter ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy. AB - OBJECTIVE: Alcohol septal ablation (ASA) is a therapeutic alternative to surgical myectomy in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, the anatomical variability of the septal branch, risk of complete heart block, and late onset ventricular arrhythmias are limitations to its therapeutic usage. There is recent interest in the use of radiofrequency catheter ablation (RFCA) as a therapeutic option in HOCM. We aimed to assess the safety and efficacy of RFCA in the treatment of symptomatic HOCM. METHODS: Seven patients with symptomatic HOCM (mean age 43.7+/-15.6 years, five males), and significant left ventricular outflow tract (LVOT) gradient despite optimal drug therapy, underwent ablation of the hypertrophied interventricular septum. These patients had unfavorable anatomy for ASA. Ablation was performed under 3D electro anatomical system guidance using an open irrigated tip catheter. The region of maximal LV septal bulge as seen on intracardiac echocardiography was targeted. Patients were followed up at 1, 6, and 12 months post-procedure. RESULTS: The mean baseline LVOT gradient by Doppler echocardiography was 81+/-14.8mm of Hg which reduced to 48.5+/-22.6 (p=0.0004), 49.8+/-19.3 (p=0.0004), and 42.8+/ 26.1mm of Hg (p=0.05) at 1, 6, and 12 months respectively. Symptoms improved at least by one NYHA class in all but one patient. One patient developed transient pulmonary edema post-RFA. There were no other complications. CONCLUSION: RFCA of the hypertrophied septum causes sustained reduction in the LVOT gradient and symptomatic improvement among patients with HOCM. Electroanatomical mapping helps to perform the procedure safely. PMID- 27773400 TI - Oral antiplatelet therapy and platelet inhibition: An experience from a tertiary care center. AB - AIMS AND OBJECTIVES: Although clopidogrel combined with aspirin is the most commonly used dual drug combination to avert thrombotic events in patients with coronary artery disease, the poor responsiveness to clopidogrel remains a concern. The objective of the current study is to assess the extent of resistance to clopidogrel, prasugrel, and ticagrelor in a real life set of patients with coronary artery disease who underwent percutaneous coronary intervention (PCI). MATERIALS AND METHODS: A total of 539 patients, who underwent PCI and were on aspirin and on any of the three drugs, namely, clopidogrel, prasugrel and ticagrelor, were followed up regularly in the outpatient department. After 24h of initiation of antiplatelet medication, response to the treatment in all the patients was assessed using thrombelastography. The average percentage platelet inhibition was assessed along with the resistance and sensitivity to the drug in each patient. Sensitivity and resistance to the specific drug was defined as >50% and <50% of mean platelet inhibition, respectively. RESULTS: About 99.15% of the patients treated with ticagrelor were sensitive to the drug and the difference between ticagrelor, clopidogrel, and prasugrel groups for sensitivity was significant with a p value of 0.00001, in favor of ticagrelor. It was also found that ticagrelor was significantly (p value of 0.001) associated with least resistance as compared with the other drugs assessed in the study. CONCLUSIONS: Use of ticagrelor as dual therapy along with aspirin in patients with coronary artery disease (CAD) and undergoing PCI was associated with a significantly higher mean percentage platelet inhibition, higher sensitivity, and lower resistance as compared with the usage of clopidogrel or prasugrel. PMID- 27773401 TI - CRUSADE bleeding score as a predictor of bleeding events in patients with acute coronary syndrome in Zagazig University Hospital. AB - AIM: To examine the value of CRUSADE bleeding score in predicting bleeding events in our local patients with acute coronary syndrome (ACS) in Zagazig University Hospitals. METHODS: Our study included 240 patients with ACS. They underwent history and clinical examination; 12-lead electrocardiography; echocardiography; troponin I, hematocrit value; estimated glomerular filtration rate (eGFR); application of CRUSADE score; and follow-up of the hospital stay and documentations of events. Patients were classified into two groups: Group I: patients with major bleeding, and Group II: patients without major bleeding. RESULTS: Patients with major bleeding were significantly older, with more diabetic and hypertensive patients, more prior vascular disease, heart failure, and less patients with unstable angina, higher heart rate and systolic blood, lower eGFR, and higher CRUSADE risk score. CRUSADE bleeding score was the strongest predictor of major bleeding. Sensitivity of CRUSADE score >=33 in prediction of major bleeding in the whole study group was 80%, specificity was 73.4%, positive predictive value was 26.9%, negative predictive value was 96.9%, overall accuracy was 74.1%. Sensitivity of CRUSADE score >=38.5 in prediction of major bleeding in the STEMI patients was 70%, specificity was 84.8%, positive predictive value was 50%, negative predictive value was 92.9%, and overall accuracy was 82.1%. CONCLUSION: CRUSADE score is a good predictor for major bleeding in Egyptian patients with ACS. It is applicable in UA/NSTEMI as well as in STEMI patients and in women as well as in men. PMID- 27773402 TI - Spectrum of congenital mitral valve abnormalities associated with solitary undifferentiated papillary muscle in adults. AB - BACKGROUND: Congenital anomaly wherein the mitral valve leaflets are directly attached to the papillary muscle(s) (PM) with or without short under-developed chords is rarely reported in adults. Patients with two PMs with an intervening fibrous bridge have also been included under this head in previous studies. METHODS: Echocardiography enables accurate evaluation of the morphology and function of valve leaflets, chordae tendineae, and PM. This report describes a series of six patients aged 56-84 years who had abnormal mitral valve with a large solitary and anomalously inserted PM seen over a period of 3 years. Only those patients who had a single pillar or bridge-like PM and either absent tendinous chords or small under-developed chords were included in the analysis. RESULTS: Among 9600 consecutive echocardiograms performed, six patients met the criteria of an abnormal mitral valve with solitary large PM. Two patients underwent mitral valve replacement with partial excision of the PM wherein echocardiographic observations were confirmed. The patients were previously followed with the diagnosis of hypertrophic cardiomyopathy (3) and rheumatic mitral valve disease (3). Multi-planar reconstruction of 3D echocardiographic images provided incremental value in assessing the detailed patho-anatomy of PMs in these cases. CONCLUSION: In adult patients, a high index of suspicion is required to detect congenital mitral stenosis/regurgitation with large solitary PM (resembling a parachute mitral valve) which may masquerade as hypertrophic cardiomyopathy or rheumatic mitral valve disease. PMID- 27773403 TI - Statin therapy/lipid lowering therapy among Indian adults with first acute coronary event: The dyslipidemia Residual and Mixed Abnormalities IN spite of Statin therapy (REMAINS) study. AB - OBJECTIVE: The primary objective was to evaluate the effect of statin therapy/lipid lowering therapy (LLT) on lipid profile, in adults presenting with first acute coronary event. METHODS AND MATERIAL: A multicentre, observational, prospective cohort study of lipid profiles pre- and post-statin therapy/LLT, among adult patients with confirmed diagnosis of first acute coronary event. The primary outcome measures were low-density lipoprotein cholesterol (LDL-C) in mg/dl, high-density lipoprotein cholesterol (HDL-C) in mg/dl and triglycerides (TG) in mg/dl at baseline and end of study (EOS, 12 weeks [mean: 13.5 weeks]). RESULTS: Totally 474 patients completed the study. Number of patients with any LDL-C abnormality (LDL-C [all; LDL was abnormal, either alone or along with other lipid parameter(s)]) decreased from 118 (24.9%) to 27 (5.7%), and for LDL-C (only; only the LDL was abnormal), from 46 (9.7%) to 13 (2.7%), both from baseline to EOS. Of 118 patients with high LDL-C (all) at baseline, 91 (77.1%) had reduction in LDL-C to <100mg/dl, of which 54 (45.8%) had LDL-C <70mg/dl at EOS. The patients with LDL-C fraction abnormalities decreased, while HDL-C abnormalities increased at EOS from baseline. No major difference was observed at baseline and EOS in levels of TG (all [TG was abnormal, either alone or along with other lipid parameter(s)]) and TG (only [only the TG was abnormal]). Six (1.3%) had seven serious adverse events. CONCLUSIONS: Though statin therapy is effective in lowering LDL-C, there still remains residual dyslipidemia, which probably should be tackled with therapeutic and non-therapeutic options. PMID- 27773404 TI - Epidemiological study of non-communicable diseases (NCD) risk factors in tribal district of Kinnaur, HP: A cross-sectional study. AB - BACKGROUND: There are no data available on the prevalence of non-communicable diseases (NCD) risk factors among the tribal population of hill state of Himachal Pradesh (HP). The epidemiological study of NCD risk factors was done in the tribal population of district Kinnaur of HP to estimate the burden of NCD risk factors and their risk determinants. METHODS: WHO STEP wise approach was used for screening of the core NCD risk indicators in 3582 randomly selected natives of Kinnaur aged 20-70 years by trained Health workers of the district health services. RESULTS: The hypertension was prevalent in 19.7% (18.4-21.1%) and diabetes in 6.9% (6.1-7.8%) of the population. Awareness of hypertension and diabetes was 39.8% and 40.8% respectively. The adherence to prescribed medications was reported in 52.1% and 56.4% of patients of aware hypertension and diabetes respectively. Overall, 23.3% and 8.5% of the patients with hypertension and diabetes had controlled BP and blood glucose respectively. Overweight and obesity were observed in 38.2% (36.6-39.9%) and 8.8% (7.9-9.8%) of the population respectively. The consumption of tobacco and alcohol was reported in 22.6% and 24.9% of the population, respectively, and 34.5% were physically inactive. Physical inactivity, BMI, high alcohol consumption, and age were independently associated with risk of hypertension, while age was the only determinant of risk of diabetes. Education and women gender had a significant influence on tobacco and alcohol consumption behavior adjusted for age. CONCLUSION: NCD risk factors are prevalent in the tribal district of Kinnaur. The awareness, treatment, control of blood pressure and blood glucose were found to be suboptimum in the study subjects. INTERPRETATION: Strengthening of primary health care services and community based interventions are urgently required to improve awareness and control of NCD risk factors in this tribal district of HP. PMID- 27773405 TI - Cardiovascular risk profile and management of atrial fibrillation in India: Real world data from RealiseAF survey. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia with high risk for many cardiovascular (CV) complications. Adherence to recommended management guidelines is important to avoid complications. In India, there is little knowledge on how AF is managed in real world. METHODS: This is a cross sectional study of patients in India enrolled in RealiseAF survey between February 2010 and March 2010 with a diagnosis of AF within the last 12 months. RESULTS: From 15 centers, 301 patients {mean age 59.9 years (14.4); 52.5% males} were recruited. AF was controlled in 50% of patients with 77 (26.7%) in sinus rhythm and 67 (23.3%) with heart rate <80beats/min. Hypertension (50.8%), valvular heart disease (40.7%), heart failure (25.9%), and diabetes (20.4%) were the most common underlying CV diseases. Increased risk for stroke (CHADS2 score>=2) was present in 36.6%. Most of the patients (85%) were symptomatic. AF was paroxysmal, persistent, and permanent in 28.7%, 22.7%, and 34.3% respectively. In 14%, AF was diagnosed as first episode. Forty-six percent of patients had rate control, 35.2% rhythm control, 0.3% both strategies, and 18.4% received no therapy for AF before the visit. At the end of the visit, adoption to rate control strategy increased to 52.3% and patients with no therapy decreased to 7%. CONCLUSION: AF in India is not adequately controlled. Concomitant CV risk factors and risk of stroke are high. The study underscores the need for improved adoption of guideline-directed management for optimal control of AF and reducing the risk of stroke. PMID- 27773407 TI - A simple method for Bachmann's bundle pacing with indigenous modification of J stylet. AB - BACKGROUND: Pacing in the Bachmann's bundle (BB) area (upper atrial septum) appears superior to right atrial appendage or free wall stimulation for the prevention of paroxysmal atrial fibrillation in patients with atrial conduction delay. However, insertion of active fixation lead in the upper atrial septal position is difficult and time consuming with conventional stylet, inhibiting application of this pacing method in routine practice. METHODS: The technique of positioning the atrial lead in BB with hand-made stylet is presented with emphasis on electrocardiographic P-wave pattern and fluoroscopic landmarks. RESULTS: The results demonstrate an acute implantation and short-term success of BB pacing of 14 patients out of 15 patients without major complications. Pacing parameters at implantation and 3 months postprocedure were noted which were within normal limits. CONCLUSION: These favorable initial results indicate that the positioning of active fixation atrial lead in BB with fluoroscopic landmarks is feasible and reproducible with a simple technique. PMID- 27773406 TI - A randomized placebo-controlled trial with amiodarone for persistent atrial fibrillation in rheumatic mitral stenosis after successful balloon mitral valvuloplasty. AB - OBJECTIVE: Atrial fibrillation is the most common sustained arrhythmia in patients with rheumatic heart disease (RHD). This study was conducted to determine the maintenance of sinus rhythm with amiodarone therapy following DC cardioversion (DCCV), early after successful balloon mitral valvuloplasty (BMV). METHODS: Patients were randomized to amiodarone group and placebo group and their baseline characteristics were recorded. DCCV was done 48h after BMV. After cardioversion, oral amiodarone was started initially 200mg three times a day for 2 weeks, then 200mg twice daily for two weeks followed by 200mg once daily for 12 months. Patients in placebo group received DCCV alone without preloading amiodarone. After DCCV, they were given placebo for 12 months. RESULTS: The 3 months follow-up period was completed by 77 patients (95%). Of them, 31 (77.5%) patients in amiodarone group and 14 (34.1%) in placebo group remained in sinus rhythm (SR). The 12 months follow-up period was completed by 73 patients (90.1%). Of them, 22 (55%) patients in amiodarone group and 7 (17.1%) in placebo group remained in SR. CONCLUSION: We conclude that amiodarone is more effective than placebo in maintenance of SR at the end of 3 months following successful cardioversion and more patients continued to remain in SR even at the end of 12 months without major serious adverse effects. PMID- 27773408 TI - Assessment of left ventricular ejection force and sympathetic skin response in normotensive and hypertensive subjects: A double-blind observational comparative case-control study. AB - BACKGROUND: Pathophysiology of essential hypertension remains obscure. Correlation among ventricular ejection force, sympathetic activity, and hypertension is less clearly narrated in hypertensive subjects. AIMS AND OBJECTIVES: To assess correlation among ventricular ejection force, sympathetic activity, and hypertension in hypertensive subjects, and to be compared with normotensive subjects. METHODS: This is a case-control study to assess left ventricular ejection force (LVEF) and sympathetic skin response, in normotensive (group 1; control), and hypertensive subjects (group 2; cases). 100 cases were selected. Subjects having stages 1 and 2 hypertension were categorized in groups 2A and 2B, respectively. LVEF was calculated by using echocardiography observing aortic acceleration time (AT) and peak systolic velocity. Comparison among groups was done by using one-way ANOVA. RESULTS: Both groups were comparable. In group 2, 60 cases had stage 1 hypertension and 40 had stage 2 hypertension. Significantly short AT and significantly high LVEF were found in hypertension (groups 2A and 2B) (p<0.0001). Sympathetic activity was high in group 2A (p<0.0001). Stroke volume (SV) was high in group 2B (p<0.0001). CONCLUSION: Stage 1 hypertension is a stage of increased sympathetic activity, leading to increased LVEF and hypertension (resetting of baroreceptors); stage 2 hypertension is a stage of normal sympathetic activity, increased LVEF, increased SV, and hypertension (possibly a stage of shift of renal equilibrium curve/renal output curve and blood pressure to a newer level). PMID- 27773410 TI - Total arterial anaortic off-pump coronary artery bypass grafting in a patient with heart failure - Case report. AB - A 69-year-old male diabetic patient of heart failure underwent successful off pump coronary artery bypass grafting (CABG) using both internal thoracic arteries and left radial artery. There was improvement of left ventricular ejection fraction within 4 days. This is the first ever case report of off-pump CABG in a heart failure patient. PMID- 27773409 TI - Role of PET-CT in the assessment of myocardial viability in patients with left ventricular dysfunction. AB - AIM: Role of PET-CT in assessment of myocardial viability in patients with LV dysfunction. METHODS: This prospective study included 120 patients with LV dysfunction who underwent 99mTechnetium-Sestamibi myocardial perfusion SPECT-CT and 18FFDG cardiac PET-CT. They also underwent serial echocardiography and coronary angiography along with myocardial perfusion and FDG PET study. RESULTS: Thirty-three patients had single vessel disease, 48 had triple vessel disease, and rest had double vessel disease. Among 786 segments, matched defects were seen in 432 (55%) and mismatched defects in 354 (45%) segments. 78 patients were surgically managed, and 42 were medically managed. The change in LVEF after surgical management was statistically significant compared to medical management. CONCLUSION: Viability assessment should be performed in patients who present after 12h of acute myocardial infarction or with LV dysfunction due to ischemic heart disease to decide upon appropriate surgical management. PMID- 27773411 TI - An experience with off pump technique for repair of anomalous left coronary artery from pulmonary artery (ALCAPA). AB - BACKGROUND: Anomalous origin of left coronary artery from pulmonary artery is a very rare disease with incidence of one every 300,000 live births. It has a high mortality of 80% in the first year of life. This observational study summarized our experience using the technique of subclavian arterial bypass without the use of cardiopulmonary bypass (CPB) for treatment of this coronary anomaly in pediatric population. The study aims to revive an earlier technique, with modifications, as an alternative to the existing coronary translocation. METHODS: From 2009 till 2015, six consecutive infants were operated by a single surgeon using subclavian artery to left coronary artery bypass done off pump, to establish a two coronary circulation. RESULTS: Five patients had an improvement in their LV ejection fractions at the time of the last follow-up. Angiography done in two cases after 2 and 6 years after surgery revealed good flow in the left coronary artery and good growth in the length of subclavian artery. There was one surgical mortality in this series. CONCLUSIONS: The technique of off pump subclavian arterial bypass for anomalous origin of the left coronary artery from the pulmonary artery is a viable alternative to the existing standard technique of coronary translocation. It essentially eliminates extracorporeal circulatory support or a left heart bypass that may be needed after coronary translocation. Also, the advantage of avoiding CPB, both in economic terms and also the adverse effects related to use of bypass in this very sick hearts, cannot be disregarded. PMID- 27773412 TI - Pulmonary Hypertension Registry of Kerala (PROKERALA) - Rationale, design and methods. AB - BACKGROUND: Pulmonary hypertension (PH) is a disease associated with a high morbidity and mortality. There is paucity of data regarding PH from the developing countries including India. Idiopathic pulmonary arterial hypertension is the most important etiological factor in the western world, but PH secondary to rheumatic heart disease, chronic obstructive pulmonary disease and untreated congenital heart disease could well be the predominant causes in developing countries like India. The main objective of the PROKERALA study - Pulmonary hypertension Registry Of Kerala is to collect data regarding the etiology, practice patterns and one-year outcomes of patients diagnosed to have PH. METHODS: The study is a hospital-based registry in the state of Kerala supported and funded by the Cardiological Society of India, Kerala Chapter. A total of 77 hospitals have agreed to participate in the registry. PH was defined as systolic pulmonary artery pressure derived by echocardiography of more than 50mmHg (by tricuspid regurgitation jet) or mean PA pressure more than 25mmHg obtained at cardiac catheterization. A detailed questionnaire is administered which includes the demographic characteristics, risk factors, family history, ECG data, 6 minute walk test distance, chest X ray findings and echocardiographic data. Details of PH specific therapy and one-year follow-up data are collected. From a preliminary survey in the region, we estimated that we will be able to collect 2000 cases over a period of one year. PMID- 27773413 TI - A case of recurrent unstable angina - Insight from optical coherence tomography imaging. AB - Intimal tear is a rare cause of ACS and is angiographically indistinguishable. OCT provides unprecendented insight to the mechanism of ACS with its near tissue level definition. This is a case of unstable angina with non-significant RCA lesion. OCT showed intimal tear/flaps with evidence of thrombi, thus clinching the diagnosis. PMID- 27773414 TI - Embolised ASD device in LV. PMID- 27773415 TI - Diuretics in primary hypertension - Reloaded. AB - Diuretics have long been cherished as drugs of choice for uncomplicated primary hypertension. Robust mortality and morbidity data is available for diuretics to back this strategy. Off-late the interest for diuretics has waned off perhaps due to availability of more effective drugs but more likely due to perceived lack of tolerance and side-effect profile of high-dose of diuretics required for mortality benefit. Low-dose diuretics particularly thiazide diuretics are safer but lack the mortality benefit shown by high-dose. However, indapamide and low dose chlorthalidone have fewer side-effects but continue to provide mortality benefit. PMID- 27773416 TI - Vascular complications post-transcatheter aortic valve procedures. AB - Transcatheter aortic valve replacement (TAVR) has rapidly emerged as the standard of care for severe symptomatic aortic stenosis in patients whose comorbidities put them at prohibitive risk for surgical aortic valve replacement (SAVR). Several trials have demonstrated superior outcomes with TAVR compared to medical management alone. TAVR has also shown favorable outcomes in patients at high risk for SAVR. TAVR can be associated with significant vascular complications, which adversely impact outcomes, and operators should be cognizant of their early recognition and appropriate management. In this article, we review the major vascular complications associated with TAVR, along with optimal prevention and management strategies. PMID- 27773417 TI - Setting up a transcatheter aortic valve implantation program: Indian perspective. AB - Transcatheter aortic valve implantation (TAVI) has revolutionized the management of elderly patients with symptomatic severe aortic stenosis in the western world. It is a valuable alternative to surgical aortic valve replacement in patients, who are inoperable or at high surgical risk due to co-morbidities. The prevalence of aortic stenosis increases sharply with age after the sixth decade and is expected to have a significant impact on the geriatric health care system of India, given the rapid increase in life expectancy in recent years. Although a decade has passed since the first TAVI implantation, it is yet to penetrate most of the developing countries in a major way. This short review focuses on fundamentals of initiating a TAVI program based on the experience of a high volume TAVI center with a successful program in Germany. PMID- 27773418 TI - Complications encountered in coronary chronic total occlusion intervention: Prevention and bailout. AB - Despite the continuing developments of improved medical devices and increasing operator expertize, coronary chronic total occlusion (CTO) remains as one of the most challenging lesion subsets in interventional cardiology. Percutaneous coronary intervention (PCI) of CTO is a complex procedure carrying the risk of complications that are responsible for significant morbidity and mortality. The complications can be classified as coronary (such as coronary occlusion, perforation, device embolization, or entrapment); cardiac non-coronary (such as periprocedural myocardial infarction); extra cardiac (such as vascular access complications, systemic embolization, contrast-induced nephropathy, and radiation induced injury). Further, certain complications (such as donor vessel dissection or thrombosis) are unique to CTO-PCI. There are also complications related to specialized techniques, such as dissection/reentry and retrograde crossing techniques. A thorough understanding of the potential complications is critical to mitigate risk during these complex procedures. PMID- 27773419 TI - Is evidence-based medicine a gold standard or can it be influenced? PMID- 27773420 TI - Violence against doctors in the Indian subcontinent: A rising bane. AB - Incidents of violence against doctors in the Indian subcontinent have increased in the last few years. Most doctors in India, China, Pakistan, Nepal and Sri Lanka are concerned about their safety at work. The problem is worse in government hospitals, which characteristically lack appropriate security protocols. In order to tackle the issue, doctors need to accept the problem, discuss the various causative factors, understand the public sentiment and collaborate with the government to find a solution. Formulation of legal provisions and standards to ensure the safety of health workers is the need of the hour. PMID- 27773421 TI - Dominant Transmission Observed in Adolescents and Families With Orthostatic Intolerance. AB - BACKGROUND: Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction. We sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features. METHODS: Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and evaluation were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives. RESULTS: Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance and 40 individuals suspected of having orthostatic intolerance) demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8%, 28/39; F:M, 2.5:1). Male-to-male transmission, although less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common. CONCLUSIONS: Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggest a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives. PMID- 27773422 TI - Clinical Characteristics and Long-Term Outcomes of Movement Disorders in Childhood Thalamic Tumors. AB - BACKGROUND: We studied the outcomes of movement disorders that were associated with childhood thalamic tumors. METHODS: We retrospectively reviewed 83 children with thalamic tumors treated at our institution from 1996 to 2013 to document the incidence and outcome of movement disorders. Magnetic resonance imaging was used to analyze the involvement of thalamic nuclei, and three instruments were used to rate the severity of the disorders. RESULTS: Nine (11%) patients had one or more of the following movement disorders: postural tremor, resting tremor, ballism, dystonia, myoclonus, and athetosis. Median age at tumor diagnosis was seven years (range, 0.25 to 11 years), and the average age at movement disorder onset was eight years (range, 1.5 to 11 years). Movement disorders developed at a median of 1.5 months (range, 0 to 4 months) after surgical resection. The severity of the disorders was either unchanged or slightly improved during follow-up. The red nuclei were the only thalamic structures that showed tumor involvement in all nine patients. CONCLUSIONS: No specific injury of the thalamic nuclei was associated with movement disorders in children with thalamic tumors, and the severity of these disorders did not change over time. PMID- 27773423 TI - Applicability of human osteoarthritic chondrocytes for in vitro efficacy testing of anti-TNFalpha drugs. AB - In vitro cell-based models are important tools for assessing efficacies of new leads in early phases of drug development. Human osteoarthritic chondrocytes (OACs), obtained from biomedical waste material, represent a valuable, relatively accessible cellular source that could be used for this purpose. By employing reverse transcription-polymerase chain reaction (qRT-PCR) we compared gene expression profiles of key anabolic, catabolic and inflammatory genes of freshly isolated vs. monolayer cultured OACs (passages P0-P2) and non-stimulated vs. tumor necrosis factor alpha (TNF-alpha) stimulated P2 OACs. After expansion of OACs in monolayer cultures, the expression of almost all analyzed genes significantly decreased. The subsequent addition of TNF-alpha to OACs at P2 significantly increased expressions of all catabolic and inflammatory genes, leaving the anabolic profile almost unchanged. TNF-alpha-treated OACs were later utilized for efficacy testing of anti-TNF-alpha drugs infliximab and etanercept and both significantly reduced the expressions of all catabolic and inflammatory genes tested. PMID- 27773424 TI - Fertility treatment and childhood type 1 diabetes mellitus: a nationwide cohort study of 565,116 live births. AB - OBJECTIVE: To investigate the association between specific types of fertility treatment and childhood type 1 diabetes mellitus. DESIGN: Nationwide birth cohort study. SETTING: Not applicable. PATIENT(S): All pregnancies resulting in a live born singleton child in Denmark from 1995 to 2003. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Childhood type 1 diabetes mellitus identified from redeemed prescriptions for insulin until 2013. RESULT(S): The study included 565,116 singleton pregnancies. A total of 14,985 children were conceived by ovulation induction or intrauterine insemination, and 8,490 children were conceived by in vitro fertilization or intracytoplasmic sperm injection. During the follow-up period, 2,011 (0.4%) children developed type 1 diabetes mellitus. The primary analyses showed no association between fertility treatment and childhood type 1 diabetes mellitus. In secondary analyses, ovulation induction or intrauterine insemination with follicle-stimulating hormone was associated with an increased risk of type 1 diabetes mellitus (hazard ratio 3.22; 95% confidence interval 1.20 to 8.64). No clear associations were seen with other types of fertility treatment or with specific treatment indications. CONCLUSION(S): No association between fertility treatment and childhood type 1 diabetes mellitus was found. Ovulation induction or intrauterine insemination with follicle-stimulating hormone may be associated with an increased risk of childhood type 1 diabetes mellitus. However, this finding may be due to chance or to confounding by indication and thus requires further investigation. PMID- 27773425 TI - Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management. AB - Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by tissue deposition of a truncated monoclonal immunoglobulin heavy chain lacking the first constant domain. Pathophysiological mechanisms are unclear and management remains to be defined. Here we retrospectively studied 15 patients with biopsy-proven HCDD of whom 14 presented with stage 3 or higher chronic kidney disease, with nephrotic syndrome in 9. Renal lesions were characterized by nodular glomerulosclerosis, with linear peritubular and glomerular deposits of gamma-heavy chain in 12 patients or alpha-heavy chain in 3 patients, without concurrent light chain staining. Only 2 patients had symptomatic myeloma. By serum protein electrophoresis/immunofixation, 13 patients had detectable monoclonal gammopathy. However, none of these techniques allowed detection of the nephrotoxic truncated heavy chain, which was achieved by immunoblot and/or bone marrow heavy chain sequencing in 14 of 15 patients. Serum free kappa to lambda light chain ratio was abnormal in 11 of 11 patients so examined. Immunofluorescence studies of bone marrow plasma cells showed coexpression of the pathogenic heavy chain with light chain matching the abnormal serum-free light chain in all 3 tested patients. Heavy chain sequencing showed first constant domain deletion in 11 of 11 patients, with high isoelectric point values of the variable domain in 10 of 11 patients. All patients received chemotherapy, including bortezomib in 10 cases. Renal parameters improved in 11 patients who achieved a hematological response, as assessed by normalization of the free light chain ratio in 8 cases. Tissue deposition in HCDD relates to physicochemical peculiarities of both variable and constant heavy chain domains. Early diagnosis and treatment with bortezomib-based combinations appear important to preserve renal prognosis. Thus, monitoring of serum-free light chain is an indirect but useful method to evaluate the hematological response. PMID- 27773426 TI - Peritoneal or hemodialysis for the frail elderly patient, the choice of 2 evils? AB - Management of older people on dialysis requires focus on the wider aspects of aging as well as dialysis. Almost all frail and older patients receiving dialysis will default to in-center hemodialysis, although the availability of assisted peritoneal dialysis enables dialysis at home. As with any disease management decision, patients approaching end-stage renal disease need all the appropriate facts about their prognosis, the natural history of their disease without dialysis, and the resulting outcomes and complications of the different dialysis modalities. Hemodialysis in the older age group can be complicated by intradialytic hypotension, prolonged time to recovery, and vascular access related problems. Peritoneal dialysis can be difficult for older patients with impaired physical or cognitive function and can become a considerable burden. Use of incremental dialysis, changes in hemodialysis frequency, and delivery and use of assistance for peritoneal dialysis can ameliorate quality of life for older patients. Understanding each individual's goals of care in the context of his or her life experience is particularly important in the elderly, when overall life expectancy is relatively short, and life experience or quality of life may be the priority. Indeed, some patients select the option of no dialysis or conservative care. With multifaceted assessments of care, physicians should be able to give individual patients the ability to select and continue to make the best decisions for their care. PMID- 27773427 TI - Progression of chronic kidney disease: too much cellular talk causes damage. AB - Tubulointerstitial fibrosis, tubular atrophy, and peritubular capillary rarefaction are major hallmarks of chronic kidney disease. The tubulointerstitium consists of multiple cell components including tubular epithelial, mesenchymal (fibroblasts and pericytes), endothelial, and inflammatory cells. Crosstalk among these cell components is a key component in the pathogenesis of this complex disease. After severe or recurrent injury, the renal tubular epithelial cells undergo changes in structure and cell cycle that are accompanied by altered expression and production of cytokines. These cytokines contribute to the initiation of the fibrotic response by favoring activation of fibroblasts, recruitment of inflammatory cells, and loss of endothelial cells. This review focuses on how augmented growth factor and cytokine production induces epithelial crosstalk with cells in the interstitium to promote progressive tubulointerstitial fibrosis after renal injury. PMID- 27773428 TI - Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. AB - Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement. PMID- 27773429 TI - Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine. AB - Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine. PMID- 27773432 TI - Biology and control of nausea and vomiting 2015: Perspectives and overview of the conference. PMID- 27773431 TI - Population Structure of UK Biobank and Ancient Eurasians Reveals Adaptation at Genes Influencing Blood Pressure. AB - Analyzing genetic differences between closely related populations can be a powerful way to detect recent adaptation. The very large sample size of the UK Biobank is ideal for using population differentiation to detect selection and enables an analysis of the UK population structure at fine resolution. In this study, analyses of 113,851 UK Biobank samples showed that population structure in the UK is dominated by five principal components (PCs) spanning six clusters: Northern Ireland, Scotland, northern England, southern England, and two Welsh clusters. Analyses of ancient Eurasians revealed that populations in the northern UK have higher levels of Steppe ancestry and that UK population structure cannot be explained as a simple mixture of Celts and Saxons. A scan for unusual population differentiation along the top PCs identified a genome-wide-significant signal of selection at the coding variant rs601338 in FUT2 (p = 9.16 * 10-9). In addition, by combining evidence of unusual differentiation within the UK with evidence from ancient Eurasians, we identified genome-wide-significant (p = 5 * 10-8) signals of recent selection at two additional loci: CYP1A2-CSK and F12. We detected strong associations between diastolic blood pressure in the UK Biobank and both the variants with selection signals at CYP1A2-CSK (p = 1.10 * 10-19) and the variants with ancient Eurasian selection signals at the ATXN2-SH2B3 locus (p = 8.00 * 10-33), implicating recent adaptation related to blood pressure. PMID- 27773430 TI - Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. AB - Lissencephaly is a malformation of cortical development typically caused by deficient neuronal migration resulting in cortical thickening and reduced gyration. Here we describe a "thin" lissencephaly (TLIS) variant characterized by megalencephaly, frontal predominant pachygyria, intellectual disability, and seizures. Trio-based whole-exome sequencing and targeted re-sequencing identified recessive mutations of CRADD in six individuals with TLIS from four unrelated families of diverse ethnic backgrounds. CRADD (also known as RAIDD) is a death domain-containing adaptor protein that oligomerizes with PIDD and caspase-2 to initiate apoptosis. TLIS variants cluster in the CRADD death domain, a platform for interaction with other death-domain-containing proteins including PIDD. Although caspase-2 is expressed in the developing mammalian brain, little is known about its role in cortical development. CRADD/caspase-2 signaling is implicated in neurotrophic factor withdrawal- and amyloid-beta-induced dendritic spine collapse and neuronal apoptosis, suggesting a role in cortical sculpting and plasticity. TLIS-associated CRADD variants do not disrupt interactions with caspase-2 or PIDD in co-immunoprecipitation assays, but still abolish CRADD's ability to activate caspase-2, resulting in reduced neuronal apoptosis in vitro. Homozygous Cradd knockout mice display megalencephaly and seizures without obvious defects in cortical lamination, supporting a role for CRADD/caspase-2 signaling in mammalian brain development. Megalencephaly and lissencephaly associated with defective programmed cell death from loss of CRADD function in humans implicate reduced apoptosis as an important pathophysiological mechanism of cortical malformation. Our data suggest that CRADD/caspase-2 signaling is critical for normal gyration of the developing human neocortex and for normal cognitive ability. PMID- 27773433 TI - "A new imaging modality to non-invasively assess multiple sclerosis pathology". AB - We describe a novel imaging method to assess central nervous system pathology called "Diffusion Basis Spectrum Imaging" (DBSI). Diffusion tensor imaging (DTI) has been widely used to estimate axonpathology and demyelination. However, in the settings of acute inflammation and chronic tissue loss asare common in multiple sclerosis, DTI signals can lead to false interpretations. DBSI is a computationallynovel method that separates isotropic from anisotropic components in imaging voxels. Isotropicdiffusion is believed to reflect inflammatory components (cells, edema), as well as intrinsic cells andextracellular space. DBSI enables the measurement of axial and radial diffusivities within the anisotropiccomponents of imaging voxels, which reflect the integrity of axon fibers and myelin, respectively. PMID- 27773434 TI - Early- and late-stage morphea subtypes with deep tissue involvement is treatable with Abatacept (Orencia). AB - OBJECTIVES: This case series explores the potential efficacy of Abatacept in patients presenting with morphea subtypes and deep tissue involvement. METHODS: Three patients with established morphea subtypes and deep tissue involvement and with no contraindication to Abatacept were included in this prospective open label study. The index patient was exceptionally severely affected with a mean Modified Rodnan Skin Score (MRSS) of 38/51. At baseline, whole-body MRI and skin biopsy were performed which confirmed classical deposition of dense fibrous tissue in the appropriate layer of the skin. MRSS was performed independently by three clinicians and VAS scores (10cm) were measured at baseline for Patient Global Disease Activity (PGDA), Patient Global Pain (PGP), Patient Day Pain (PDP), Patient Night Pain (PNP), and Physician Global Disease Activity (PhGDA). Patients 2 and 3 were similarly screened at baseline except for MRI. Patients were commenced on Abatacept as per body weight (10mg/kg) given intravenously with concomitant tapering dose of oral prednisolone. All three were re-assessed at 6 months and the index case was further re-assessed at 18 months. RESULTS: All patients tolerated the Abatacept well and showed dramatic improvement. The index patient's clinical signs and symptoms, whole-body MRI, and mean Modified Rodnan Skin Score improved dramatically from baseline by 37% at 6 months and by 74% at 18 months. There were no clinically significant adverse outcomes noted. CONCLUSION: We present three cases, one with exceptionally severe disease, which demonstrated excellent clinical response to Abatacept. Abatacept is a promising option for the treatment of severe or resistant morphea, especially in those with deep tissue involvement. PMID- 27773435 TI - A serine protease inhibitor attenuates aldosterone-induced kidney injuries via the suppression of plasmin activity. AB - Emerging evidence has suggested that aldosterone has direct deleterious effects on the kidney independently of its hemodynamic effects. However, the detailed mechanisms of these direct effects remain to be elucidated. We have previously reported that camostat mesilate (CM), a synthetic serine protease inhibitor, attenuated kidney injuries in Dahl salt-sensitive rats, remnant kidney rats, and unilateral ureteral obstruction rats, suggesting that some serine proteases would be involved in the pathogenesis of kidney injuries. The current study was conducted to investigate the roles of serine proteases and the beneficial effects of CM in aldosterone-related kidney injuries. We observed a serine protease that was activated by aldosterone/salt in rat kidney lysate, and identified it as plasmin with liquid chromatography-tandem mass spectrometry. Plasmin increased pro-fibrotic and inflammatory gene expressions in rat renal fibroblast cells. CM inhibited the protease activity of plasmin and suppressed cell injury markers induced by plasmin in the fibroblast cells. Furthermore, CM ameliorated glomerulosclerosis and interstitial fibrosis in the kidney of aldosterone/salt treated rats. Our findings indicate that plasmin has important roles in kidney injuries that are induced by aldosterone/salt, and that serine protease inhibitor could provide a new strategy for the treatment of aldosterone-associated kidney diseases in humans. PMID- 27773436 TI - Police officers' perceptions and experiences with mentally disordered suspects. AB - Despite mentally disordered suspects being over-represented within the criminal justice system, there is a dearth of published literature that examines police officers' perceptions when interviewing this vulnerable group. This is concerning given that police officers are increasingly the first point of contact with these individuals. Using a Grounded Theory approach, this study examined 35 police officers' perceptions and experiences when interviewing mentally disordered suspects. Current safeguards, such as Appropriate Adults, and their experiences of any training they received were also explored. A specially designed questionnaire was developed and distributed across six police forces in England and Wales. Nine conceptual categories emerged from the data that highlighted how police officers' level of experience impacted upon their perceptions when dealing with this cohort. As a consequence, a new model grounded within Schema Theory has emerged termed Police Experience Transitional Model. Implications include the treatment and outcome of mentally disordered suspects being heavily dependent on whom they encounter within the criminal justice system. PMID- 27773437 TI - Carbon quantum dots prepared with polyethyleneimine as both reducing agent and stabilizer for synthesis of Ag/CQDs composite for Hg2+ ions detection. AB - A stable silver nanoparticles/carbon quantum dots (Ag/CQDs) composite was prepared by using CQDs as reducing and stabilizing agent. The CQDs synthesized with polyethyleneimine (PEI) showed an extraordinary reducibility. When Hg2+ was presented in the Ag/CQDs composite solution, a color change from yellow to colorless was observed, accompanied by a shift of surface plasmon resonance (SPR) band and decrease in absorbance of the Ag/CQDs composite. On the basis of the further studies on TEM, XPS and XRD analysis, the possible mechanism is attributed to the formation of a silver-mercury amalgam. Hence, a two dimensional sensing platform for Hg2+ detection was constructed upon the Ag/CQDs composite. Based on the change of absorbance, a good linear relationship was obtained from 0.5 to 50MUM for Hg2+. And the limit of detection for Hg2+ was as low as 85nM, representing high sensitivity to Hg2+. More importantly, the proposed method also exhibits a good selectivity toward Hg2+ over other metal ions. Besides, this strategy demonstrates practicability for the detection of Hg2+ in real water samples with satisfactory results. PMID- 27773438 TI - The behavior of melamine in biological wastewater treatment system. AB - Melamine (MA) is a significant raw material for industry and home furnishing, and an intermediate for pharmacy. However it is also a hazardous material when being added to food as a protein substitute due to the high nitrogen content. In this study, the behavior of MA in activated sludge was investigated. Experiments showed that MA was removed during biological wastewater treatment process, and the removal was mainly achieved by activated sludge adsorption instead of biodegradation. Low levels of MA (0.001-0.10mg/L) in wastewater had negligible influence on the performance of activated sludge, but high levels of MA deteriorated biological nitrogen and phosphorus removal. The presence of MA (1.00 and 5.00mg/L) decreased total nitrogen removal efficiency from 94.15% to 79.47% and 68.04%, respectively. The corresponding concentration of effluent phosphorus increased from 0.11 to 1.45 and 2.06mg/L, respectively. It was also observed that MA inhibited the enzyme activities of nitrite oxidoreductase, nitrate reductase, nitrite reductase and exopolyphosphatase, which were closely relevant to nitrogen and phosphorus removal. Further investigation showed that the presence of high MA concentrations promoted the consumption and synthesis of glycogen, thereby providing the advantage for the growth of glycogen accumulating organisms. PMID- 27773439 TI - Co-treatment of waste smelting slags and gypsum wastes via reductive-sulfurizing smelting for valuable metals recovery. AB - In this work, a new innovative slag cleaning technique was presented to economically and environmentally friendly recover valuable metals from cobalt bearing copper smelter slag. CaSO4-rich gypsum waste was used as sulfurizing agent to efficiently and selectively sulfurize and recover valuable metals lost in the slag at reductive atmosphere. Thermodynamic analysis and laboratory experiments were carried out to determine the feasibility and reliability of this new process. The optimum slag cleaning conditions were determined as follow: reductive agent coke dosage of 12%, 20% CaSO4 addition of smelter slag weight, smelting at 1350 degrees C for 3h. Under the optimum conditions, 92.04% Cu and 95.62% Co were enriched and recovered in copper-cobalt matte. The contents of Cu and Co in cleaned slag dropped to levels lower than 0.2% and 0.045% respectively. Selectivity recovery ratio of Cu/Fe and Co/Fe can reach 6.00 and 6.24 respectively. Calcium-rich and iron-poor cleaned slag property was more beneficial for minimizing cobalt and copper losses in slag. The products were characterized by XRD and SEM-EDS techniques. The Cu-Co matte primarily comprised iron sulphide (FeS), geerite (Cu8S5), iron cobalt sulphide (Fe0.92Co0.08S), independent cobalt sulphide (CoS) and some metallic Cu, Co and Fe. Copper and cobalt in resultant matte attended to appear separately in different mineral phases. The cleaned slag mainly contained fayalite (Fe2SiO4), hedenbergite (CaFeSi2O6) and magnetite (Fe3O4). PMID- 27773440 TI - A simple model to predict chromate partitioning in selected soils from China. AB - Due to its mobility and toxicity, chromate [Cr(VI)] partitioning in soils, especially in the vadose zone, is an important environmental concern. The aim of this study was to develop a mechanism-based multi-surface complexation model using published parameters to predict the soil/water partitioning of Cr(VI) in 12 soils (previously depleted of organic matter) from China. The retention of Cr(VI) in soils was attributed to two reactive oxide surfaces: goethite and hydrous ferric oxide (HFO); however, modeling results showed that the best prediction was obtained with goethite alone, whereas the addition of HFO resulted in an overestimation of adsorption in some soils. Cr(VI) adsorption onto goethite could be described using our previously proposed CD-MUSIC model. In the absence of a specific value for the soil-reactive surface area of goethite, a general value of 45.8m2/g was used. The available phosphate in soils was identified as a strong competitor for Cr(VI) adsorption; thus, for soils with a low Fe/P ratio (<1) the effect of phosphate on Cr(VI) retention should not be neglected. The simple method presented herein can be applied to soils with a wide range of properties, pH values, and Cr(VI) loading concentrations. PMID- 27773441 TI - Effect of rhamnolipid solubilization on hexadecane bioavailability: enhancement or reduction? AB - In this study, liquid culture systems containing rhamnolipid-solubilized, separate-phase, and multi-state hexadecane as the carbon source were employed for examining the effect of rhamnolipid solubilization on the bioavailability of hexadecane. Experimental results showed that the uptake of rhamnolipid solubilized hexadecane by Pseudomonas aeruginosa ATCC 9027, a rhamnolipid producing strain, was enhanced compared to the uptake of mass hexadecane as a separate phase, indicating rhamnolipid solubilization increased the bioavailability of hexadecane for this bacterium. For Pseudomonas putida CICC 20575 which does not produce but degrade rhamnolipid, the uptake of either rhamnolipid-solubilized hexadecane or multi-state hexadecane was inhibited. The reduction of bioavailability was assumed to be the consequence of the blocking effect caused by the partition of rhamnolipid molecules at the hexadecane-water interface. The results show that how rhamnolipid solubilization changes the bioavailability of hexadecane depends on the bacterial compatibility to rhamnolipid. The study adds insight into the knowledge of biosurfactant associated bioavailability of hydrophobic organic compounds (HOCs), and is of importance for application of biosurfactants in bioremediation of HOCs. PMID- 27773443 TI - Reversible electrokinetic adsorption barriers for the removal of atrazine and oxyfluorfen from spiked soils. AB - This study demonstrates the application of reversible electrokinetic adsorption barrier (REKAB) technology to soils spiked with low-solubility pollutants. A permeable reactive barrier (PRB) of granular activated carbon (GAC) was placed between the anode and cathode of an electrokinetic (EK) soil remediation bench scale setup with the aim of enhancing the removal of two low-solubility herbicides (atrazine and oxyfluorfen) using a surfactant solution (sodium dodecyl sulfate) as the flushing fluid. This innovative study focused on evaluating the interaction between the EK system and the GAC-PRB, attempting to obtain insights into the primary mechanisms involved. The obtained results highlighted the successful treatment of atrazine and oxyfluorfen in contaminated soils. The results obtained from the tests after 15days of treatment were compared with those obtained using the more conventional electrokinetic soil flushing (EKSF) technology, and very important differences were observed. Although both technologies are efficient for removing the herbicides from soils, REKAB outperforms EKSF. After the 15-day treatment tests, only approximately 10% of atrazine and oxyfluorfen remained in the soil, and adsorption onto the GAC bed was an important removal mechanism (15-17% of herbicide retained). The evaporation loses in REKAB were lower than those obtained in EKSF (45-50% compared to 60-65%). PMID- 27773442 TI - Acute and chronic effects of magnetic microparticles potentially used in lake restoration on Daphnia magna and Chironomus sp. AB - Magnetic microparticles (MPs) have been recently proposed as a new and promising tool for restoring eutrophicated waters. In this study, we analyzed the acute (immobilization) and chronic effects of iron (Fe) MPs on Daphnia magna and on the benthic macroinvertebrate Chironomus sp. In the chronic toxicity tests the offspring production (male and female) in D. magna and the mortality of larvae and pupae, and adult emergence in Chironomus sp. experiments were used as the endpoints. The concentration of MPs that caused 50% of immobilized individuals (EC50) in the acute toxicity test was much higher in D. magna (0.913g MPs l-1) than in Chironomus sp. (0.445g MPs l-1). The results of chronic toxicity tests in D. magna showed that in presence of dissolved Fe (dFe), parthenogenetic reproduction was significantly affected, while no significant effect on mortality of larvae and pupae and on adult emergence was detected in Chironomus sp. test. Taking into account both that long-term exposure is not likely to occur and the regular dose of MPs potentially used in a restoration plan, we conclude that MPs is a riskless (no toxic effect on planktonic and benthic organisms) and efficient (high P adsorption capacity) tool for lake restoration. PMID- 27773444 TI - Influence of water chemistry on the environmental behaviors of commercial ZnO nanoparticles in various water and wastewater samples. AB - Zinc oxide nanoparticles (ZnO NPs) are widely used nanomaterials and their environmental impacts have received increasing attention. The fate and toxicity of ZnO NPs in the environment are determined by their stability and dissolution. In this study, the influence of water chemistry on aggregation, sedimentation, and dissolution of ZnO NPs was investigated. The stabilized ZnO NPs aggregated and precipitated when the aqueous pH closed to their zero point of charge (pHzpc). Counter-ions neutralized the surface charge of NPs and promoted their destabilization. However, a high concentration of counter-ion (SO42-, >10meq/L) made the NPs more stable because of the inverted surface potential. The stability of ZnO NPs was maintained by high concentration of Suwannee River humic acid (SRHA, 10mg/L) even the concentration of electrolytes was high. The influence of water chemistry on the stability and dissolution of ZnO NPs was further demonstrated in different wastewaters. In one wastewater sample, ZnO NPs was unexpectedly stable and with a high dissolution, which was due to the effects of pH value, organic matter concentration, as well as the concentration of counter ions. Our findings facilitate the predictions of the fate of stabilized ZnO NPs in the environment. PMID- 27773445 TI - Abdominal organ motion during inhalation and exhalation breath-holds: pancreatic motion at different lung volumes compared. AB - PURPOSE: Contrary to what is commonly assumed, organs continue to move during breath-holding. We investigated the influence of lung volume on motion magnitude during breath-holding and changes in velocity over the duration of breath holding. MATERIALS AND METHODS: Sixteen healthy subjects performed 60-second inhalation breath-holds in room-air, with lung volumes of ~100% and ~70% of the inspiratory capacity, and exhalation breath-holds, with lung volumes of ~30% and ~0% of the inspiratory capacity. During breath-holding, we obtained dynamic single-slice magnetic-resonance images with a time-resolution of 0.6s. We used 2 dimensional image correlation to obtain the diaphragmatic and pancreatic velocity and displacement during breath-holding. RESULTS: Organ velocity was largest in the inferior-superior direction and was greatest during the first 10s of breath holding, with diaphragm velocities of 0.41mm/s, 0.29mm/s, 0.16mm/s and 0.15mm/s during BH100%, BH70%, BH30% and BH0%, respectively. Organ motion magnitudes were larger during inhalation breath-holds (diaphragm moved 9.8 and 9.0mm during BH100% and BH70%, respectively) than during exhalation breath-holds (5.6 and 4.3mm during BH30% and BH0%, respectively). CONCLUSION: Using exhalation breath holds rather than inhalation breath-holds and delaying irradiation until after the first 10s of breath-holding may be advantageous for irradiation of abdominal tumors. PMID- 27773446 TI - Mitochondrial movement disorders. PMID- 27773447 TI - Acute methotrexate neurotoxicity revealed by a cerebellar syndrome. PMID- 27773448 TI - Recurrent strokes associated with uncontrollable giant cell arteritis. PMID- 27773449 TI - Health literacy in heart transplantation: Prevalence, correlates and associations with health behaviors-Findings from the international BRIGHT study. AB - BACKGROUND: Health literacy (HL) is a major determinant of health outcomes; however, there are few studies exploring the role of HL among heart transplant recipients. The objectives of this study were to: (1) explore and compare the prevalence of inadequate HL among heart transplant recipients internationally; (2) determine the correlates of HL; and (3) assess the relationship between HL and health-related behaviors. METHODS: A secondary analysis was conducted using data of the 1,365 adult patients from the BRIGHT study, an international multicenter, cross-sectional study that surveyed heart transplant recipients across 11 countries and 4 continents. Using the Subjective Health Literacy Screener, inadequate HL was operationalized as being confident in filling out medical forms none/a little/some of the time (HL score of 0 to 2). Correlates of HL were determined using backward stepwise logistic regression. The relationship between HL and the health-related behaviors were examined using hierarchical logistic regression. RESULTS: Overall, 33.1% of the heart transplant recipients had inadequate HL. Lower education level (adjusted odds ratio [AOR] 0.24, p < 0.001), unemployment (AOR 0.69, p = 0.012) and country (residing in Brazil, AOR 0.25, p < 0.001) were shown to be associated with inadequate HL. Heart transplant recipients with adequate HL had higher odds of engaging in sufficient physical activity (AOR 1.6, p = 0.016). HL was not significantly associated with the other health behaviors. CONCLUSIONS: Clinicians should recognize that almost one third of heart transplant participants have inadequate health literacy. Furthermore, they should adopt communication strategies that could mitigate the potential negative impact of inadequate HL. PMID- 27773450 TI - Effects of angiotensin-converting-enzyme inhibitor therapy on the regulation of the plasma and cardiac tissue renin-angiotensin system in heart transplant patients. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors (ACEis) are beneficial in patients with heart failure, yet their role after heart transplantation (HTx) remains ambiguous. Particularly, the effects of ACEis on plasma and cardiac metabolites of the "classical" and "alternative" renin-angiotensin system (RAS) in HTx patients are unknown. METHODS: This cross-sectional study used a novel mass spectrometry-based approach to analyze plasma and tissue RAS regulation in homogenates of heart biopsy specimens from 10 stable HTx patients without RAS blockade and in 15 patients with ACEi therapy. Angiotensin (Ang) levels in plasma and Ang formation rates in biopsy tissue homogenates were measured. RESULTS: Plasma Ang II formation is exclusively ACE dependent, whereas cardiac Ang II formation is primarily chymase dependent in HTx patients. ACEi therapy substantially increased plasma Ang-(1-7), the key effector of the alternative RAS, leaving plasma Ang II largely intact. Importantly, neprilysin and prolyl carboxypeptidase but not angiotensin converting enzyme 2 are essential for cardiac tissue Ang-(1-7) formation. CONCLUSION: ACE is the key enzyme for the generation of plasma Ang II, whereas chymase is responsible for cardiac tissue production of Ang II. Furthermore, our findings reveal that neprilysin and prolyl carboxypeptidase are the essential cardiac enzymes for the alternative RAS after HTx. These novel insights into the versatile regulation of the RAS in HTx patients might affect future therapeutic avenues, such as chymase and neprilysin inhibition, beyond classical Ang II blockade. PMID- 27773451 TI - Discriminatory performance of positive urine hemoglobin for detection of significant hemolysis in patients with continuous-flow left ventricular assist devices. AB - BACKGROUND: Serum lactate dehydrogenase (LDH) is the standard measure for detection of hemolysis and thus surveillance for device thrombosis in patients on continuous-flow left ventricular assist device (CF-LVAD) support. Significant hemolysis has been defined as LDH >=600 IU/L. However, LDH testing requires phlebotomy, precluding frequent home monitoring. Simple dipstick urinalysis (UA) for urine hemoglobin (U-Hb) overcomes this limitation. This study correlated U-Hb and LDH levels and evaluated the performance of UA for detection of significant hemolysis in patients with CF-LVADs. METHODS: U-Hb and LDH were measured concurrently 956 times in 221 patients with CF-LVADs. Statistics were computed to determine accuracy of UA in detecting LDH >=600 IU/L, with a positive result being any detected U-Hb. All analyses were performed with and without excluding for 1) conditions associated with tissue damage, which are known to increase LDH, and 2) suspected or confirmed urinary tract infections or hematuria, which are known to cause hemoglobinuria for reasons other than hemolysis. RESULTS: Mean LDH for absent/mild/severe U-Hb was 360 IU/L/467 IU/L IU/L/777 IU/L without exclusions, 354 IU/L/444 IU/L IU/L/651 IU/L after excluding non-hemolytic LDH elevations, 370 IU/L/513 IU/L IU/L/1,357 IU/L after excluding urinary tract infections and hematuria, and 367 IU/L/470 IU/L IU/L/1,217 IU/L when both exclusions applied (all p < 0.001). Absent U-Hb had a negative predictive value for LDH >=600 IU/L of >90% for all analyses. CONCLUSIONS: Serum LDH is significantly associated with U-Hb levels. Absence of U-Hb appears to efficiently exclude significant hemolysis in patients with CF-LVADs. Because it can be performed by patients at home, hemoglobinuria monitoring may enable more intense surveillance and earlier diagnosis of device thrombosis. PMID- 27773452 TI - Significant role for microRNA-21 affecting toll-like receptor pathway in primary graft dysfunction after human lung transplantation. AB - BACKGROUND: MicroRNAs (miRNAs) were recently identified as modulators of immune responses after human lung transplantation (LTx). This study was undertaken to assess the contribution of miRNAs to the pathogenesis of primary graft dysfunction (PGD) after LTx. METHODS: Of the 39 recipients, 14 (35.9%) developed Grade 3 PGD (i.e., severe PGD) within the first 72 hours of LTx. The remaining 25 recipients (64.1%) had Grade 2 or less PGD, and served as the control group. miRNAs were isolated from cells purified by bronchoalveolar lavage (BAL). Bioinformatic prediction and validation by luciferase reporter assays were performed to identify targets regulated by miR-21. Transfection of human monocytic cell line (THP-1) was conducted to determine miR-21's cellular function. RESULTS: Pilot miRNA profiling of donor BAL samples before implantation in PGD (n = 6) revealed significant upregulation in 44 miRNAs and downregulation in 80 miRNAs compared with control (n = 6). Validation using a separate cohort demonstrated significant underexpression of miR-21 in patients with severe PGD. Furthermore, underexpression of miR-21 levels was negatively correlated with clinical PGD grades (Grade 2 PGD vs Grade 0 PGD: p = 0.042; Grade 3 PGD vs Grade 0 PGD: p = 0.004). Molecular analysis demonstrated that miR-21 targeted key components in the toll-like receptor (TLR) signaling pathway, including TLR4, IRAK3 and CXCL10. Further, incubation of THP-1 cells with cell-free BAL from severe PGD resulted in transactivation of inflammatory cytokines interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). In contrast, increased expression of miR-21 resulted in marked suppression of IL-1-beta and TNF-alpha production. CONCLUSIONS: Underexpression of miR-21 may lead to the development of severe PGD by activating key components of the TLR pathway. PMID- 27773453 TI - Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis. AB - BACKGROUND: Since 2005, the Lung Allocation Score (LAS) has prioritized patient benefit and post-transplant survival, reducing waitlist to transplant time to <200 days and decreasing mortality on the waitlist. A current challenge is the wait for the waitlist-the time between the patient's transplant-eligible diagnosis and waitlist registration. METHODS: We investigated whether sociodemographic (age, sex, race, insurance, marital status, median household income) and clinical (forced expiratory volume in 1 second [FEV1] percent of predicted, body mass index, depression/anxiety, alcohol/substance misuse, absolute/relative contraindications) factors influenced referral and waitlist registration. We conducted a retrospective cohort study through chart review of hospitalized patients on the University of Chicago general medicine service from 2006 to 2014 who met transplant-eligible criteria and ICD-9 billing codes for cystic fibrosis (CF) and pulmonary fibrosis (PF). We analyzed the times from transplant eligibility to referral, work-up and waitlisting using Kaplan-Meier curves and log-rank tests. RESULTS: Overall, the referral rate for transplant eligible patients was 64%. Of those referred, approximately 36% reach the lung transplant waitlist. Referred CF patients were significantly more likely to reach the transplant waitlist than PF patients (CF 60% vs PF 22%, p < 0.05). In addition, CF patients had a shorter wait from transplant eligibility to waitlist than PF patients (329 vs 2,369 days, respectively [25th percentile], p < 0.05). Patients with PF and CF both faced delays from eligibility to referral and waitlist. CONCLUSIONS: Quality improvement efforts are needed to better identify and refer appropriate patients for lung transplant evaluation. Targeted interventions may facilitate more efficient evaluation completion and waitlist appearance. PMID- 27773454 TI - Sex differences and in-hospital outcomes in patients undergoing mechanical circulatory support implantation. AB - BACKGROUND: Mechanical circulatory support (MCS) is a widely available management strategy. No studies have described sex differences in both extracorporeal and durable MCS. We analyzed sex-related differences of in-hospital outcomes for extracorporeal and durable MCS using administrative hospital data. METHODS: In total, 134.5 million hospital records between 1994 and 2012 were screened for placement of MCS using procedure codes of the International Classification of Diseases-9, Clinical Modification. Major adverse events (MAEs) were defined as death, major bleeding, stroke, device infection or mechanical complication. Participation in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry was determined on an annual basis using quarterly reports of the INTERMACS. Associations between characteristics and outcomes were determined using multivariable logistic regression. RESULTS: Sex was reported in 3,523 of 4,337 patients undergoing MCS placement from 45 INTERMACS sites (n = 1,383) and 246 non-INTERMACS sites (n = 2,954). Twenty-two percent were female. Baseline characteristics were significantly different with women being slightly younger (33.5% vs 27.4% age <50 years, p < 0.001; mean 55.7 +/- 17.3 vs 56.1 +/- 14.6 years) with fewer comorbidities. Women had higher rates of in-hospital mortality (52.3% vs 40.8%, p < 0.001) and MAEs (64.8% vs 52.5%, p < 0.001). Women had an 89% higher likelihood of MAEs when corrected for multivariate predictors (p < 0.001). In-hospital mortality decreased over time for both men and women (10% relative risk reduction/year, p < 0.001), but mortality in women was higher than in men throughout the study period. CONCLUSION: There are significant sex differences in characteristics and outcomes of patients receiving MCS. Women had higher in-hospital mortality and were at increased risk of MAEs, which could not be explained by age or comorbid conditions. Further research on the causes of these disproportionate outcomes is needed. PMID- 27773455 TI - Maintaining airway integrity after lung transplantation-Could an ounce of prevention be worth a pound of cure? PMID- 27773457 TI - Lung transplantation in patients who have undergone prior cardiothoracic procedures. AB - BACKGROUND: Patients who have undergone prior cardiothoracic procedures offer technical challenges that may affect post-transplant outcomes and be a reason to decline listing. Data are currently limited regarding the indication for lung transplantation among recipients who have had prior cardiothoracic procedures. METHODS: Of 453 lung transplants performed at Cleveland Clinic from January 2005 to July 2010, 206 recipients (45%) had undergone prior cardiothoracic procedures: 157 lung only, 15 cardiac only, 10 cardiac + lung, 10 pleurodesis + lung, and 14 other. Chest tube placement was performed in 202 patients. Survival, post transplant length of intensive care unit and hospital stays, primary graft dysfunction, and pulmonary function outcomes were compared with outcomes of patients not having prior procedures using propensity score adjustment. RESULTS: Short-term and long-term survival was similar between the 2 groups. Survival at 30 days, 1 year, and 5 years was 94%, 83%, and 55% for the prior cardiothoracic procedure group and 96%, 84%, and 53% for the no prior cardiothoracic procedure group (log-rank p = 0.9). Intensive care unit stay was longer (6 days vs 5 days, p = 0.02) in the prior cardiothoracic procedure group; this was particularly true for pleurodesis + lung (10 days, p = 0.05), although post-transplant hospital stay was similar (16 days, 16 days, and 22 days; p = 0.13). Primary graft dysfunction was not increased in the prior cardiothoracic procedure group. Forced expiratory volume in 1 second was similar for both groups but lower for thoracotomy and lung procedures using a bilateral chest tube (p < 0.05 each). CONCLUSIONS: A prior cardiothoracic procedure is not a contraindication for lung transplantation. PMID- 27773456 TI - Clinical hemodynamic evaluation of patients implanted with a fully magnetically levitated left ventricular assist device (HeartMate 3). AB - BACKGROUND: The HeartMate 3 (HM3) is a Conformitee Europeenne (CE) mark-approved left ventricular assist device (LVAD) with a fully magnetically levitated rotor with features consisting of a wide range of operational speeds, wide flow paths and an artificial pulse. We performed a hemodynamic and echocardiographic evaluation of patients implanted with the HM3 LVAD to assess the speed range for optimal hemodynamic support. METHODS: Sixteen HM3 patients underwent pump speed ramp tests with right heart catheterization (including central venous pressure [CVP], pulmonary artery pressure, pulmonary capillary wedge pressure [PCWP] and blood pressure [BP]) and 3-dimensional echocardiography (3DE). Data were recorded at up to 13 speed settings. Speed changes were in steps of 100 revolutions per minute (rpm), starting at 4,600 rpm and ramping up to 6,200 rpm. RESULTS: Mean original speed was 5,306 +/- 148 rpm, with a majority of patients (10 of 16, 62.5%) having normal CVPs and PCWPs at their original rpm settings. Going from lowest to highest speeds, cardiac output improved at the rate of 0.08 +/- 0.08 liter/min per 100 rpm (total change 1.25 +/- 1.20 liters/min) and PCWP decreased at the rate of -0.48 +/- 0.27 mm Hg per 100 rpm (total change -6.13 +/- 3.72 mm Hg). CVP and systolic BP did not change significantly with changes in rpm. Left ventricular end-diastolic dimension (LVEDD) decreased at a rate of -0.15 +/- 0.09 cm per 100 rpm. Number of rpm was adjusted based on test results to achieve CVPs and PCWPs as close to normal limits as possible, which was feasible in 13 (81.3%) patients. For the remaining 3 patients, medical management was pursued to optimize hemodynamic support. CONCLUSION: Hemodynamic normalization of pressures was achieved in the majority of patients implanted with the HM3 pump within a narrow speed range. PMID- 27773458 TI - Contrast-enhanced Spectral Mammography: Technique, Indications, and Clinical Applications. AB - RATIONALE AND OBJECTIVES: Contrast-enhanced spectral mammography (CESM) combines the benefits of full field digital mammography with the concept of tumor angiogenesis. Technique and practical applications of CESM are discussed. MATERIALS AND METHODS: An overview of the technique is followed by a demonstration of practical applications of CESM in our practice. RESULTS: We have successfully implemented CESM into our practice as a screening, diagnostic, staging, and treatment response tool. CONCLUSION: It is important to understand the technique of CESM and how to incorporate it into practice. PMID- 27773459 TI - Creation and Validation of a Simulator for Neonatal Brain Ultrasonography: A Pilot Study. AB - RATIONALE AND OBJECTIVES: Historically, skills training in performing brain ultrasonography has been limited to hours of scanning infants for lack of adequate synthetic models or alternatives. The aim of this study was to create a simulator and determine its utility as an educational tool in teaching the skills that can be used in performing brain ultrasonography on infants. MATERIALS AND METHODS: A brain ultrasonography simulator was created using a combination of multi-modality imaging, three-dimensional printing, material and acoustic engineering, and sculpting and molding. Radiology residents participated prior to their pediatric rotation. The study included (1) an initial questionnaire and resident creation of three coronal images using the simulator; (2) brain ultrasonography lecture; (3) hands-on simulator practice; and (4) a follow-up questionnaire and re-creation of the same three coronal images on the simulator. A blinded radiologist scored the quality of the pre- and post-training images using metrics including symmetry of the images and inclusion of predetermined landmarks. Wilcoxon rank-sum test was used to compare pre- and post-training questionnaire rankings and image quality scores. RESULTS: Ten residents participated in the study. Analysis of pre- and post-training rankings showed improvements in technical knowledge and confidence, and reduction in anxiety in performing brain ultrasonography. Objective measures of image quality likewise improved. Mean reported value score for simulator training was high across participants who reported perceived improvements in scanning skills and enjoyment from simulator use, with interest in additional practice on the simulator and recommendations for its use. CONCLUSIONS: This pilot study supports the use of a simulator in teaching radiology residents the skills that can be used to perform brain ultrasonography. PMID- 27773460 TI - Don't throw the baby out with the bathwater: Appropriate or inappropriate shocks after implantable cardioverter-defibrillator. PMID- 27773461 TI - Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes: Methodological issues. PMID- 27773463 TI - The addicted brain: imaging neurological complications of recreational drug abuse. AB - Recreational drug abuse represents a serious public health problem. Neuroimaging traditionally played a secondary role in this scenario, where it was limited to detecting acute vascular events. However, thanks to advances in knowledge about disease and in morphological and functional imaging techniques, radiologists have now become very important in the diagnosis of acute and chronic neurological complications of recreational drug abuse. The main complications are neurovascular disease, infection, toxicometabolic disorders, and brain atrophy. The nonspecific symptoms and denial of abuse make the radiologist's involvement fundamental in the management of these patients. Neuroimaging makes it possible to detect early changes and to suggest an etiological diagnosis in cases with specific patterns of involvement. We aim to describe the pattern of abuse and the pathophysiological mechanisms of the drugs with the greatest neurological repercussions as well as to illustrate the depiction of the acute and chronic cerebral complications on conventional and functional imaging techniques. PMID- 27773464 TI - Quality-of-life after bile duct injury: intraoperative detection is crucial. A national case-control study. AB - BACKGROUND: Existing reports on quality-of-life (QoL) after bile duct injury (BDI) are conflicting. METHODS: Case-control study were QoL assessment was performed using SF-36 (36-item short Form health survey). Patients with BDI were compared to a matched control group (1:2) subject to cholecystectomy. RESULTS: In total 168 BDIs (0.3%) were eligible for participation and 64% returned SF-36. Median follow-up was 4.3 years. Intraoperative cholangiography was performed/attempted in 93% of BDI patients and 92% were diagnosed intraoperatively. Lesions <5 mm dominated (59%) and QoL was comparable for BDIs and controls (physical composite score PCS; p = 0.052 and mental composite score MCS; p = 0.478). Patients with an immediate intraoperative repair reported a better PCS than patients subjected to a later repair and/or referral (p = 0.002). No difference in SF-36 was detected when the BDI was repaired by the index compared to non-index surgeon (PCS p = 0.446, MCS p = 0.525). CONCLUSION: QoL after bile duct injury is comparable to uneventful cholecystectomy, as long as the injury is diagnosed intraoperatively. Immediate repair, in this cohort of mainly minor injuries, also performed by the index surgeon, resulted in similar QoL as in the control group. We suggest liberal use of cholangiography for early detection of BDI, and intraoperative repair whenever possible. PMID- 27773465 TI - Empowerment evaluation: Exemplary is its openness to dialogue, reflective practice, and process use. AB - On the occasion of the 21 st anniversary of empowerment evaluation, congratulations are in order for having established global credibility, demonstrated utility, and for its exemplary openness to dialogue, reflective practice, and process use. PMID- 27773466 TI - [Unusually infected sebaceous cyst by Dermabacter hominis]. AB - Dermabacter hominis species is constituted by Gram positive facultative anaerobic coryneform rods being part of the resident microbiota human skin, and exceptionally associated to infections in immunocompromised or severely debilitated patients. An immunocompetent young adult woman with a neck sebaceous cyst infected by D. hominis as unique etiologic agent is presented. Phenotypic identification of the causative agent was achieved through simple tests, based on the originally scheme proposed by Funke and Bernard, and feasible to be performed in a hospital Microbiology Laboratory. Phenotypic characteristics as coccoid morphology, the acrid/spermatic odor, esculin hydrolysis, the production of pyrrolidonyl-arylamidase, lysine and ornithine decarboxylase, are key tests to identify D. hominis. The matrix-asisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) confirmed the phenotypic identification. PMID- 27773467 TI - Advances in the non-invasive assessment of vascular dysfunction in metabolic syndrome and diabetes: Focus on endothelium, carotid mechanics and renal vessels. AB - AIM: The present paper is a selective review on the methodology and clinical significance of techniques to assess specifically endothelial function, carotid mechanics and renal vascular function, particularly in the light of vascular dysfunction in metabolic syndrome and type 2 diabetes. DATA SYNTHESIS: Endothelial dysfunction appears to be earlier detectable in the microcirculation of patients with altered glucose metabolism, while it attains significance in the macrocirculation at more advanced disease stages. Smooth muscle cell dysfunction is now increasingly recognized to play a role both in the development of endothelial dysfunction and abnormal arterial distensibility. Furthermore, impaired glucose metabolism affects carotid mechanics through medial calcification, structural changes in extracellular matrix due to advanced glycation and modification of the collagen/elastin material stiffness. The assessment of renal vascular function by dynamic ultrasound or magnetic resonance imaging has recently emerged as an appealing target for identifying subtle vascular alterations responsible for the development of diabetic nephropathy. CONCLUSIONS: Vascular dysfunction represents a major mechanism for the development of cardiovascular disease in patients with abnormal glucose metabolism. Hence, the currently available non-invasive techniques to assess early structural and vascular abnormalities merit recommendation in this population, although their predictive value and sensitivity to monitor treatment induced changes have not yet been established and are still under investigation. PMID- 27773462 TI - NF-kappaB signaling pathway and its potential as a target for therapy in lymphoid neoplasms. AB - The NF-kappaB pathway, a critical regulator of apoptosis, plays a key role in many normal cellular functions. Genetic alterations and other mechanisms leading to constitutive activation of the NF-kappaB pathway contribute to cancer development, progression and therapy resistance by activation of downstream anti apoptotic pathways, unfavorable microenvironment interactions, and gene dysregulation. Not surprisingly, given its importance to normal and cancer cell function, the NF-kappaB pathway has emerged as a target for therapy. In the review, we present the physiologic role of the NF-kappaB pathway and recent advances in better understanding of the pathologic roles of the NF-kappaB pathway in major types of lymphoid neoplasms. We also provide an update of clinical trials that use NF-kappaB pathway inhibitors. These trials are exploring the clinical efficiency of combining NF-kappaB pathway inhibitors with various agents that target diverse mechanisms of action with the goal being to optimize novel therapeutic opportunities for targeting oncogenic pathways to eradicate cancer cells. PMID- 27773468 TI - Homocysteine concentration in coronary artery disease: Influence of three common single nucleotide polymorphisms. AB - BACKGROUND AND AIMS: Whether single nucleotide polymorphisms (SNPs) of homocysteine metabolism enzymes influence the rate of cardiovascular (CV) events in coronary artery disease (CAD) patients remains controversial. METHODS AND RESULTS: In this analysis, 1126 subjects from the AtheroGene study with CAD and 332 control subjects without known CAD were included. The following SNPs were investigated: methylentetrahydrofolate reductase (MTHFR-C667T), methionin synthetase (MS-D919G), and cystathionin beta synthetase (CBS-I278T). The endpoint was the combination of cardiovascular death, stroke, and non-fatal myocardial infarction (N = 286). The median follow-up time was 6.4 years. Kaplan-Meier curve analysis showed an increasing event rate with rising homocysteine levels (p < 0.001) in CAD patients. Further, in Cox-Regression analysis homocysteine was a predictor of the endpoint with a hazard ratio (HR) of 6.5 (95% CI: 2.9-14.6, p < 0.001) in the adjusted model including cardiovascular risk factors. Of the three SNPs, homozygous MTHFR SNP increased homocysteine levels significantly in patients with CAD and individuals without CAD (both p < 0.001). The SNPs in MS and CBS were not related to relevant changes in homocysteine levels in CAD patients or controls. The different SNPs of MTHFR, MS, and CBS were not related to an increased event rate. CONCLUSION: Homocysteine level is a strong predictor of CV events. Subjects with and without CAD and SNPs in the enzyme MTHFR had increased homocysteine levels. This was not observed for MS and CBS SNPs. Although MTHFR SNPs alter homocysteine levels in patients and controls, these polymorphisms had no impact on prognosis in CAD patients. PMID- 27773470 TI - Exploring the interconnections between gender, health and nature. AB - OBJECTIVES: Public health has recognized that nature is good for health but there are calls for a review of its gendered aspects. This review attempts to develop and explore a broad analytical theme - the differing interconnections between gender, health and nature. The paper summarizes the interconnections that have been subject to extensive academic enquiry between gender and health, health and space, and gender and space. METHODS: A combination of key terms including place; gender; health; outdoor space; green space; natural environment; national parks; femininity; masculinity; recreation; physical activity; sustainability; ecofeminism; feminism; environmental degradation; and environmental justice were used to search the electronic databases Sociological Abstracts, Web of Science and Scopus to identify relevant articles. We took two approaches for this review to provide an overview and analysis of the range of research in the field, and to present a framework of research that is an analysis of the intersection of gender, health and nature. RESULTS: Four dimensions are distinguished: (1) evaluations of health benefits and 'toxicities' of nature; (2) dimensions and qualities of nature/space; (3) environmental justice including accessibility, availability and usability; and (4) identification of boundaries (symbolic/material) that construct differential relationships between nature, gender and health. This paper offers an understanding of how environmental and social conditions may differentially shape the health of women and men. The dimensions direct analytical attention to the diverse linkages that constitute overlapping and inseparable domains of knowledge and practice, to identify complex interconnections between gender, health and nature. CONCLUSION: This review therefore analyses assumptions about the health benefits of nature, and its risks, for gender from an in-depth, analytical perspective that can be used to inform policy. PMID- 27773471 TI - Can the design of glove dispensing boxes influence glove contamination? AB - BACKGROUND: Few studies have explored the microbial contamination of glove boxes in clinical settings. The objective of this observational study was to investigate whether a new glove packaging system in which single gloves are dispensed vertically, cuff end first, has lower levels of contamination on the gloves and on the surface around the box aperture compared with conventional glove boxes. METHODS: Seven participating sites were provided with vertical glove dispensing systems (modified boxes) and conventional boxes. Before opening glove boxes, the surface around the aperture was sampled microbiologically to establish baseline levels of superficial contamination. Once the glove boxes were opened, the first pair of gloves in each box was sampled for viable bacteria. Thereafter, testing sites were visited on a weekly basis over a period of six weeks and the same microbiological assessments were made. RESULTS: The surface near the aperture of the modified boxes became significantly less contaminated over time compared with the conventional boxes (P<0.001), with an average of 46.7% less contamination around the aperture. Overall, gloves from modified boxes showed significantly less colony-forming unit contamination than gloves from conventional boxes (P<0.001). Comparing all sites over the entire six-week period, gloves from modified boxes had 88.9% less bacterial contamination. CONCLUSION: This simple improvement to glove box design reduces contamination of unused gloves. Such modifications could decrease the risk of microbial cross transmission in settings that use gloves. However, such advantages do not substitute for strict hand hygiene compliance and appropriate use of non-sterile, single-use gloves. PMID- 27773469 TI - Lipophilic index, kidney function, and kidney function decline. AB - BACKGROUND AND AIMS: Unhealthy dietary fats are associated with faster kidney function decline. The cell membrane composition of phospholipid fatty acids (FAs) is a determinant of membrane fluidity and rheological properties. These properties, which have been linked to kidney damage, are thought to be reflected by the lipophilic index (LI). We prospectively investigated the associations of LI with kidney function and its decline. METHODS AND RESULTS: Observational study from the Prospective Investigation of Vasculature in Uppsala Seniors including 975 men and women with plasma phospholipid FAs composition and cystatin-C estimate glomerular filtration rate (eGFR). Of these, 780 attended re-examination after 5 years, and eGFR changes were assessed. Participants with a 5-year eGFR reduction >=30% were considered chronic kidney disease (CKD) progressors (n = 198). LI was calculated as the sum of the products of the FA proportions with the respective FAs melting points. Blood rheology/viscosity measurements were performed in a random subsample of 559 subjects at baseline. Increased LI showed a statistically significant but overall weak association with blood, plasma viscosity (both Spearman rho = 0.16, p < 0.01), and erythrocyte deformability (rho = -0.09, p < 0.05). In cross-sectional analyses, LI associated with lower eGFR (regression coefficient 3.00 ml/min/1.73 m2 1-standard deviation (SD) increment in LI, 95% CI: -4.31, -1.69, p < 0.001). In longitudinal analyses, LI associated with a faster eGFR decline (-2.13 [95% CI -3.58, -0.69] ml/min/1.73 m2, p < 0.01) and with 32% increased odds of CKD progression (adjusted OR 1.32 [95%, CI 1.05-1.65]). CONCLUSIONS: A high LI was associated with lower kidney function, kidney function decline, and CKD progression. PMID- 27773472 TI - Immunogenicity of live attenuated Japanese encephalitis SA 14-14-2 vaccine among Sri Lankan children with previous receipt of inactivated JE vaccine. AB - BACKGROUND: The performance of live attenuated Japanese Encephalitis SA 14-14-2 vaccine (CD-JEV) among children previously given inactivated mouse brain-derived JE vaccine (IMBV) is unknown. We evaluated the safety and immunogenicity of CD JEV administered to 2- and 5-year-old children in Sri Lanka. METHODS: In this open-label, single arm trial in the Colombo District of Sri Lanka, generally healthy children 2 and 5years of age who had previously received two and three doses of IMBV, respectively, were administered one dose of CD-JEV subcutaneously. Participants were monitored for adverse events for one year post-vaccination. Serum neutralizing antibody responses were evaluated pre and 28 and 365days post vaccination using JE plaque reduction neutralization test and characterized as the proportion of participants seroconverting. Seroconversion was defined as either reaching a titer considered seroprotective (?1:10) among participants with a baseline titer <1:10 or achieving at least a 4-fold rise in titer among participants with a baseline titer ?1:10. RESULTS: Of 305 children given CD-JEV, 294 were included in the primary analysis of immunogenicity. Prior to vaccination, 144/147 (98.0%) 2-year-olds and 146/147 (99.3%) 5-year-olds had seroprotective levels. 28days post-vaccination, 79/147 [53.7% (95% CI, 45.3 62.0)] 2-year olds and of 60/147 [40.8% (95% CI, 32.8-49.2)] 5-year olds achieved seroconversion. Among 2-year-olds, geometric mean titers (GMTs) rose from 697 to 3175 28days post-vaccination. Among 5-year-olds, GMTs rose from 926 to 2776. Most adverse reactions were mild, and no serious adverse events were related to study vaccination. CONCLUSION: Administration of CD-JEV to these children with pre existing neutralizing JE antibody titers was safe and resulted in substantial boosting of antibody levels. These results may inform other countries in Asia considering switching from IMBV to now WHO-prequalified CD-JEV vaccine to combat this disease of public health importance. PMID- 27773474 TI - Knowledge, attitudes, and practices of healthcare providers in the country of Georgia regarding influenza vaccinations for pregnant women. AB - OBJECTIVE: To document knowledge, attitudes, and practices of Georgian obstetrician-gynecologists concerning influenza infection and vaccination during pregnancy. METHODS: We conducted a cross-sectional study of obstetrician gynecologists in 8 cities in the country of Georgian, from June to July, 2015, using an anonymous, self-administered, written survey. Collected data included demographics; knowledge, attitudes, and practices related to influenza vaccination during pregnancy; perceptions of influenza infection in pregnancy; perceived barriers to influenza vaccination during pregnancy; and willingness to receive education about influenza infection and vaccination during pregnancy. RESULTS: A total of 278 obstetrician-gynecologists completed surveys. Most physicians perceived influenza to be a serious infectious disease (88%) and that pregnant women are more susceptible to it than the general population. Only 43% of physicians reported recommending influenza vaccination during pregnancy; 18% reported vaccinating any pregnant patients during the last influenza season. Most (75%) physicians reported a perception that there is insufficient evidence supporting influenza vaccination during pregnancy. Most (93%) were receptive to receiving additional education on maternal vaccination. CONCLUSIONS: Georgian physicians are hesitant to vaccinate pregnant women, but are receptive to education about maternal vaccination. Future educational outreach to Georgian physicians could reduce concerns about maternal vaccination, potentially increasing influenza vaccination among pregnant Georgian women. PMID- 27773475 TI - Vaccine impact: Benefits for human health. AB - Unlike most drugs, whose benefit is restricted to the individual who takes the drug, prophylactic vaccines have the potential for far-reaching effects that encompass health service utilisation, general health and wellbeing, cognitive development and, ultimately, economic productivity. The impact of immunisation is measured by evaluating effects directly on the vaccinated individual, indirectly on the unvaccinated community (herd protection), the epidemiology of the pathogen (such as changing circulating serotypes or prevention of epidemic cycles), and the additional benefits arising from improved health. Aside from protection of the individual, the broader success of immunisation is dependent on achieving a level of coverage sufficient to interrupt transmission of the pathogen. When evaluating the cost-effectiveness of vaccines, all of these potential benefits need to be accounted for. In many countries where immunisation programmes have been highly successful, the control of disease has meant that the benefits of immunisation have become less obvious. Once a well-known and much-feared disease appears to have disappeared, individuals, including healthcare professionals, no longer view ongoing prevention with the same sense of urgency. Reduced coverage is inevitably associated with resurgence in disease, with outbreaks potentially leading to significant morbidity and loss of life. Ensuring the continued success of immunisation programmes is the responsibility of all: individuals, healthcare professionals, government and industry. PMID- 27773473 TI - A monoclonal antibody that targets the conserved core/lipid A region of lipopolysaccharide affects motility and reduces intestinal colonization of both classical and El Tor Vibrio cholerae biotypes. AB - Vibrio cholerae is the causative agent of cholera, an acute diarrheal disease that remains endemic in many parts of the world. The mechanisms underlying immunity to cholera remain poorly defined, though it is increasingly clear that protection is associated with antibodies against lipopolysaccharide (LPS). Here we report that ZAC-3, a monoclonal antibody against the core/lipid A region of V. cholerae LPS is a potent inhibitor of V. cholerae flagellum-based motility in viscous and liquid environments. ZAC-3 arrested motility of the classical Ogawa strain O395, as well as the El Tor Inaba strain C6706. In addition, we demonstrate, in the neonatal mouse model, that ZAC-3 IgG and Fab fragments significantly reduced the ability of both V. cholerae strains O395 and C6706 to colonize the intestinal epithelium, revealing the potential of antibodies against the core/lipid A to contribute to immunity across biotypes, possibly through a mechanism involving motility arrest. PMID- 27773476 TI - Dead or alive? Predicting fetal loss in Japanese macaques (Macaca fuscata) by fecal metabolites. AB - Dehydroepiandrosterone-sulfate (DHEAS) is the main steroid product of the primate fetal adrenal during mid to late gestation and it plays a major role in providing estrogens needed for parturition. We tested the hypothesis that this hormone can indicate fetal health status and attempted to use fecal DHEAS (fDHEAS) to predict pregnancy outcome in Japanese macaques. The subjects were 16 adult females and 3 neonatal Japanese macaques living in captivity at the Primate Research Institute, Kyoto University. We classified females that gave birth to healthy infants as successful and females that gave birth to dead infants as stillbirth (late fetal loss) and miscarriage (early fetal loss). The remaining females did not become pregnant and were used as controls. We collected fecal samples from all cycling, pregnant, and post-pregnant females as well as the three neonates for analysis of fDHEAS, fecal estrogen (fE) and fecal progesterone (fP) by enzyme immunoassay. We found that fE and fP increased during gestation in both successful and stillbirth groups, but increased only during the first two months in the female that had a miscarriage. Levels of fDHEAS only increased in the second half of gestation in successful pregnancies. Neonates had extremely elevated concentrations of fDHEAS in comparison to post-parturition females, which confirms that DHEAS metabolites are a product of the fetal adrenal. Low DHEAS levels could be a marker of an unsuccessful pregnancy in primates. Monitoring fDHEAS levels can be useful in zoos and institute management and can be applied to wild and free-ranging populations. PMID- 27773477 TI - Identification and profiling of microRNAs from ovary of estrous Kazakh sheep induced by nutritional status in the anestrous season. AB - Estrous regulation in sheep has an important role in the sheep industry in improving production of meat and wool. It has been reported that an enhanced nutritional status can induce estrus resulting in an end of the anestrous season earlier than occurs in ewes with a lesser nutritional status. However, the endocrine and physiological mechanisms that induce the increased incidence of estrus remains unclear. In the present study, the differences in amounts and characteristics of miRNAs in ewes at estrus or during the anestrous season were screened by using the Illumina HiSeq sequencing technology. In total, 294 miRNAs, including 174 novel miRNA candidates, were identified in ewes with an enhanced nutritional status (OEN) through assessment of the OEN library for this group and 307 miRNAs including 186 novel miRNA candidates were identified in the ewes with a lesser nutritional status (OAN) through assessing the OAN library, among which there were nine conserved and 104 novel miRNAs in differential amounts between the two libraries. Based on poly (A) q-PCR, six miRNAs were assessed to verify the accuracy of the library database. Furthermore, the family of the known miRNAs, the target genes and related pathways were also analyzed. The results indicated that the nutritional status had important roles in estrous regulation in sheep. The PLA2G4D can directly regulate ovarian follicle development, or indirectly influence leptin secretion involved in the regulation of the reproductive endocrine and physiological systems during the anestrous season. The identification of significantly different miRNAs expanded the repertoire of sheep miRNAs that have been examined and could contribute to further studies on the molecular mechanism of regulation of initiation of estrous cycles in previously anestrous ewes as influenced by different nutritional status. PMID- 27773478 TI - Effect of three different lumbar splints on posturokinetic capacity when performing the sit-to-stand task. PMID- 27773479 TI - Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults. AB - BACKGROUND: Hyponatremia may occur after initiation of a second-generation antidepressant drug. However, the magnitude of this risk among older adults in routine care is not well characterized. STUDY DESIGN: Retrospective, population based, matched-cohort study. SETTING & PARTICIPANTS: In Ontario, Canada, 2003 to 2012, we compared older adults with a mood or anxiety disorder who were dispensed 1 of 9 second-generation antidepressant drugs with matched adults with comparable indicators of baseline health who were not dispensed an antidepressant drug (n=138,246 per group). A similar comparison was made in a subpopulation with available laboratory data (n=4,186 per group). PREDICTOR: Second-generation antidepressant prescription versus no antidepressant prescription. OUTCOMES: The primary outcome was hospitalization with hyponatremia. A secondary outcome was hospitalization with both hyponatremia and delirium. MEASUREMENTS: We assessed hospitalization with hyponatremia using a diagnosis code and, in the subpopulation, serum sodium values. We assessed hospitalization with hyponatremia and delirium using a combination of diagnosis codes. RESULTS: Second-generation antidepressant use versus nonuse was associated with higher 30-day risk for hospitalization with hyponatremia (450/138,246 [0.33%] vs 84/138,246 [0.06%]; relative risk [RR], 5.46 [95% CI, 4.32-6.91]). This association was consistent in the subpopulation with serum sodium values (73/4,186 [1.74%] vs 18/4,186 [0.43%]; RR, 4.23 [95% CI, 2.50-7.19]; absolute risk increase, 1.31% [95% CI, 0.87% 1.75%]). Second-generation antidepressant use versus nonuse was also associated with higher 30-day risk for hospitalization with both hyponatremia and delirium (28/138,246 [0.02%] vs 7/138,246 [0.005%]; RR, 4.00 [95% CI, 1.75-9.16]). LIMITATIONS: Measures of serum sodium could be ascertained in only a subpopulation. CONCLUSIONS: Use of a second-generation antidepressant in routine care by older adults is associated with an approximate 5-fold increase in 30-day risk for hospitalization with hyponatremia compared to nonuse. However, the absolute increase in 30-day incidence is low. PMID- 27773480 TI - Effects of the stimulus phase on the air-conducted ocular vestibular evoked myogenic potential in healthy subjects. AB - OBJECTIVE: The study aimed to examine the effect of the stimulus phase of air conducted sound on ocular vestibular evoked myogenic potentials (oVEMPs). METHODS: oVEMPs were recorded after air-conducted sounds (500Hz, 4ms duration), presented with initial condensation (positive), rarefaction (negative), and alternant polarities from 12 healthy subjects. RESULTS: Most responses showed a bifid n10 peak separated by ~1.9ms. The most prominent sub-peak after condensation was shorter than the most prominent sub-peak after rarefaction; however, the first sub-peak was shorter after the rarefaction stimuli. When a third sub-peak appeared, it occurred before the most prominent sub-peak after condensation and after the most prominent sub-peak after rarefaction. The latency difference between this third sub-peak and the closest sub-peak was shorter than the difference among the others sub-peaks, in both cases; the oVEMPs after alternating stimuli was an amalgam of the responses to the different stimuli. CONCLUSIONS: The findings suggest that the negative to positive change of the stimulus was the main event responsible for the stimulation, and that when a third sub-peak appeared it was related to the initiation or the end of the stimulus. SIGNIFICANCE: These findings suggested that the oVEMP response, obtained by air conducted sound, was secondary to stimulation of the same type of afferent vestibular unit, independent of the stimulus polarity. PMID- 27773481 TI - Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval. AB - Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility. PMID- 27773482 TI - Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans. AB - FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy. PMID- 27773483 TI - Securing safe and informative thoracic CT examinations-Progress of radiation dose reduction techniques. AB - The increase in the radiation exposure from CT examinations prompted the investigation on the various dose-reduction techniques. Significant dose reduction has been achieved and the level of radiation exposure of thoracic CT is expected to reach the level equivalent to several chest X-ray examinations. With more scanners with advanced dose reduction capability deployed, knowledge on the radiation dose reduction methods has become essential to clinical practice as well as academic research. This article reviews the history of dose reduction techniques, ongoing changes brought by newer technologies and areas of further investigation. PMID- 27773484 TI - Mechanisms of Aneuploidy in Human Eggs. AB - Eggs and sperm develop through a specialized cell division called meiosis. During meiosis, the number of chromosomes is reduced by two sequential divisions in preparation for fertilization. In human female meiosis, chromosomes frequently segregate incorrectly, resulting in eggs with an abnormal number of chromosomes. When fertilized, these eggs give rise to aneuploid embryos that usually fail to develop. As women become older, errors in meiosis occur more frequently, resulting in increased risks of infertility, miscarriage, and congenital syndromes, such as Down's syndrome. Here, we review recent studies that identify the mechanisms causing aneuploidy in female meiosis, with a particular emphasis on studies in humans. PMID- 27773485 TI - Sunitinib as adjuvant therapy for renal cell carcinoma. PMID- 27773486 TI - HBV and HCV co-infection increases cancer risk in HIV patients. PMID- 27773488 TI - Update on infections with human herpesviruses 6A, 6B, and 7. AB - Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7) are genetically related to cytomegalovirus. They belong to the Roseolovirus genus and to the Betaherpesvirinae subfamily. They infect T cells, monocytes-macrophages, epithelial cells, and central nervous system cells. These viruses are ubiquitous and are responsible for lifelong chronic infections, most often asymptomatic, in the vast majority of the general adult population. HHV-6B is responsible for exanthema subitum, which is a benign disease of infants. HHV-6A and HHV-6B also cause opportunistic infections in immunocompromised patients: encephalitis, hepatitis, bone marrow suppression, colitis, and pneumonitis. Their etiological role in chronic diseases such as multiple sclerosis, cardiomyopathy, and thyroiditis is still controversial. The pathogenicity of HHV-7 is less clear and seems to be much more restricted. Chromosomal integration of HHV-6A and HHV-6B is transmissible from parents to offspring and observed in about 1% of the general population. This integration raises the question of potential associated diseases and can be a confounding factor for the diagnosis of active infections by both viruses. The diagnosis of HHV-6A, HHV-6B, and HHV-7 infections is rather based on gene amplification (PCR), which allows for the detection and quantification of the viral genome, than on serology, which is mainly indicated in case of primary infection. Ganciclovir, foscarnet, and cidofovir inhibit the replication of HHV 6A, HHV-6B, and HHV-7. Severe infections may thus be treated but these therapeutic indications are still poorly defined. PMID- 27773487 TI - Apical Sarcomere-like Actomyosin Contracts Nonmuscle Drosophila Epithelial Cells. AB - Actomyosin networks generate contractile force that changes cell and tissue shape. In muscle cells, actin filaments and myosin II appear in a polarized structure called a sarcomere, in which myosin II is localized in the center. Nonmuscle cortical actomyosin networks are thought to contract when nonmuscle myosin II (myosin) is activated throughout a mixed-polarity actin network. Here, we identified a mutant version of the myosin-activating kinase, ROCK, that localizes diffusely, rather than centrally, in epithelial cell apices. Surprisingly, this mutant inhibits constriction, suggesting that centrally localized apical ROCK/myosin activity promotes contraction. We determined actin cytoskeletal polarity by developing a barbed end incorporation assay for Drosophila embryos, which revealed barbed end enrichment at junctions. Our results demonstrate that epithelial cells contract with a spatially organized apical actomyosin cortex, involving a polarized actin cytoskeleton and centrally positioned myosin, with cell-scale order that resembles a muscle sarcomere. PMID- 27773490 TI - Adapting immunisation schedules for children undergoing chemotherapy. AB - INTRODUCTION: Children undergoing chemotherapy for cancer have special vaccination needs after completion of the treatment. The aim of this study was to evaluate the adaptation of post-chemotherapy vaccination schedules. METHOD: An observational study was performed on a retrospective cohort that included all children aged from 0 to 14 years, who completed chemotherapy in a tertiary hospital between 2009 and 2015. Inclusion and exclusion criteria were applied. Immunisation was administered in accordance with the guidelines of the Vaccine Advisory Committee of the Spanish Association of Paediatrics. Primary Care immunisation and clinical records of the Preventive Medicine and Public Health Department were reviewed. RESULTS: Of the 99 children who had received chemotherapy, 51 (70.6% males) were included in the study. As regards the type of tumour, 54.9% had a solid organ tumour, and 45.1% had a haematological tumour. Post-chemotherapy immunisation was administered to 70.6%. The most common vaccines received were: diphtheria-tetanus-pertussis or diphtheria-tetanus (54.9%), meningococcus C (41.2%), and seasonal influenza (39.2%). The rate of adaptation of the immunisation schedule after chemotherapy was 9.8%. The pneumococcal conjugate vaccine against 7v or 13v was administered to 21.6% of study subjects. However, only 17.6% received polysaccharide 23v. None received vaccination against hepatitis A. No statistically significant differences were observed between adherence to immunisation schedules and type of tumour (P=.066), gender (P=.304), or age (P=.342). CONCLUSION: Post-chemotherapy immunisation of children with cancer is poor. The participation of health professionals in training programs and referral of paediatric cancer patients to Vaccine Units could improve the rate of schedule adaptation and proper immunisation of this population. PMID- 27773489 TI - Repair of rotator cuff injuries using different composites. AB - AIM: Rotator cuff repairs have shown a high level of re-ruptures. It is hypothesised that the use of rhBMP-2 in a carrier could improve the biomechanical and histological properties of the repair. MATERIAL AND METHODS: Controlled experimental study conducted on 40 rats with section and repair of the supraspinatus tendon and randomisation to one of five groups: Group 1 (control) only suture; Group 2 (double control), suture and alginate-chitin carrier; Group 3 (alginate-control), the rhBMP-2 was added to the alginate; Group 4 (chitin control) application of the rhBMP-2 to the chitin, and Group 5 (double sample): The two components of the carrier (alginate and chitin) have rhBMP-2. A biomechanical and histological analysis was performed at 4 weeks. RESULTS: A gap was observed in all cases 4 weeks after supraspinatus detachment. The re-rupture rate was 7.5%, with 20% of them in the control-alginate Group. Histologically the best results were obtained in the double sample group: 4.5 (3.3-5.0). Double sample were also able to support higher loads to failure: 62.9N (59.8 to 69.4) with lower rigidity 12.7 (9.7 to 15.9). CONCLUSIONS: The use of alginate-chitin carrier with rhBMP-2 improves the biomechanical and histological properties of the repair site in a chronic rotator cuff tear. PMID- 27773492 TI - What should be the appropriate duration of cardiopulmonary resuscitation? PMID- 27773491 TI - Papillophlebitis versus paediatric venous thrombosis. A case with 46C/T polymorphism in the F12 coagulation gene. AB - CLINICAL CASE: An 8 year-old boy with no known diseases, with sudden loss of visual acuity (VA) in the left eye (LE). EXAMINATION: VA 1 in right eye, and 0.1 in LE, discrete left relative afferent pupil defect (RAPD). Normal biomicroscopy. Funduscopy: congestive papilla, venous tortuosity, peripapillary haemorrhages with macular oedema in LE. The systemic study only revealed A C46Tpolymorphism in the F12 coagulation gene. He had a VA of 1 and normal funduscopy 8 months later. DISCUSSION: Papillophlebitis is an inflammatory and non-ischaemic central retinal vein occlusion, ophthalmoscopically similar to central retinal vein thrombosis. The systemic study is essential to rule out underlying diseases. PMID- 27773493 TI - Assessment of knowledge and skills in using an Automated External Defibrillator (AED) by university students. A quasi-experimental study. AB - AIM: To evaluate layperson (university student) ability to use an automated external defibrillator (AED). DESIGN: A repeated measures quasi-experimental study with non-probabilistic sampling and a control group was carried out. SCOPE: Teacher training degree students at the University of Santiago de Compostela (Spain). PARTICIPANTS: The sample consisted of 129 subjects (69% women and 31% men), between 19-47 years of age (mean 23.2+/-4.7 years). As inclusion criterion, the subjects were required to have no previous knowledge of AED. INTERVENTIONS: Times to apply defibrillation with an AED to a mannequin were recorded untrained (T0), after a theoretical and practice explanation lasting less than one minute (T1), and 6 months after the training process (T2). MAIN VARIABLES OF INTEREST: The primary endpoint was the time taken to deliver a defibrillation discharge. The "improvement effect" variable was defined by the absolute time difference between T1 and T0, while the "degree of forgetfulness effect" variable was defined as the absolute difference between T1 and T2. RESULTS: The mean times were T0=67.7s; T1=44.2s; T2=45.9s. The time to apply defibrillation was reduced after explanation training (T1=3 log10 CFU/mL reduction by 4 h against both strains at 106 CFU/mL, whereas maximum reductions against strain 03-149-1 at 108 CFU/mL were 1.0, 3.2, 2.2 and 3.3 log10 CFU/mL for ertapenem, doripenem, meropenem and imipenem, respectively. None of the combinations were capable of reducing 108 CFU/mL of N16870 by >=2 log10 CFU/mL. Ertapenem combinations consistently displayed the least activity, whereas doripenem, meropenem and imipenem combinations had similar activities that were poorly predicted by carbapenem MICs. As doripenem, meropenem, or imipenem displayed similar pharmacodyanmics in combination, the decision of which carbapenem to use in combination with PMB may be based on toxicodynamic profiles if drastic discordance in MICs is not present. PMID- 27773499 TI - [Mycoplasma genitalium]. PMID- 27773500 TI - [Balanitis]. PMID- 27773501 TI - [Trichomoniasis]. PMID- 27773502 TI - [STD and STI screening]. PMID- 27773503 TI - [Chlamydia trachomatis]. PMID- 27773504 TI - [Lymphogranuloma venereum]. PMID- 27773505 TI - [Epididymo-orchitis]. PMID- 27773506 TI - [External genital warts (condylomata)]. PMID- 27773508 TI - [Primary syphilis]. PMID- 27773507 TI - [Soft chancre]. PMID- 27773509 TI - [Donovanosis (granuloma inguinale)]. PMID- 27773510 TI - [Anorectal STD]. PMID- 27773511 TI - [Leucorrhoea]. PMID- 27773512 TI - [Late syphilis]. PMID- 27773513 TI - [Diagnostic and therapeutic recommendations for sexually transmissible diseases]. PMID- 27773514 TI - [Gonococcus]. PMID- 27773515 TI - [Minor STD]. PMID- 27773516 TI - Development of a nomogram for predicting the probability of postoperative delirium in patients undergoing free flap reconstruction for head and neck cancer. AB - PURPOSE: To develop nomogram for prediction of postoperative delirium (POD) in patients undergoing ablative and reconstruction surgery for head and neck cancer. METHODS: Total 341 patients were retrospectively analyzed, and clinical variables in preoperative, intraoperative and postoperative periods were compared between delirium group (n = 89) and non-delirium group (n = 252). Multivariate logistic regression, receiver operating characteristics curve, and area under the curve (AUC) were used to generate and test a nomogram, which performance was evaluated by 10-fold cross validation (CV) procedure. RESULTS: In univariate and multivariate analysis, age, history of psychiatric disorder, marital status, preoperative numeric rating scale for pain, ASA classification, and ICU stay period were identified as significant risk factors. Using these factors, nomogram for predicting the POD was developed and it showed sensitivity of 61.8%, specificity of 75.4%, PPV of 47.0%, and NPV of 84.8% (Youden's index of 0.372). In 10-fold cross validation set, corresponding values were 44.9%, 84.1%, 50.0% and 81.2% (Youden's index of 0.337). AUC was comparable between two sets (0.7407 and 0.6898). CONCLUSIONS: Proposed nomogram showed fair discriminative power for POD risk in head and neck cancer patients undergoing major surgery. PMID- 27773517 TI - Primary cardiac B cell lymphoma: Manifestation of Felty's syndrome or TNFalpha antagonist. AB - Primary cardiac B cell lymphoma is rare. To date, fewer than 90 cases have been described in the literature. We report a 67-year-old woman with a 30-year history of rheumatoid arthritis, who had received treatment with leflunomide for 10 years and infliximab for 2 years. Secondary Felty's syndrome appeared. She was admitted to the hospital for abdominal pain. Investigations disclosed a 5cm cardiac mass in the right atrium. Histopathologic examination of tissue specimens obtained at surgical myocardial biopsy demonstrated primary cardiac B cell lymphoma. The other iatrogenic lymphoproliferative disorders are reviewed. This lesion might be a manifestation of long term TNFalpha antagonists treatment. PMID- 27773519 TI - Immunomodulatory potential of particular Trichinella spiralis muscle larvae excretory-secretory components. AB - Excretory-secretory antigens of Trichinella spiralis muscle larvae can induce the semi-matured status of rat dendritic cells. This may at least partly be the consequence of transient activation of extracellular signal-regulated kinases 1/2 (ERK1/2). Here we investigated the potential of several components of excretory secretory antigens (native fraction containing 45, 49 and 53kDa proteins and recombinant Tsp53, representing one of the constituents of this fraction) to demonstrate previously observed effects of excretory-secretory antigens on dendritic cells in vitro, characterised by establishment of a particular phenotype (very low MHC II expression, moderate CD86 expression and significant ICAM-1 expression) and functional properties (low production of pro-inflammatory cytokine IL-12p70, and high production of IL-10 and TGF-beta). Dendritic cells activated by these components were able to provoke proliferation of naive T cells and their polarisation towards Th2 and anti-inflammatory responses. The investigated antigens had almost the same capacity to induce IL-4 and IL-10 production from T cells as excretory-secretory antigens, but failed to induce significant TGF-beta synthesis. It could be concluded that the investigated excretory-secretory antigens components can largely reproduce the immunomodulatory effects of the complete excretory-secretory antigens and therefore may be considered as molecules important for creation of the anti inflammatory milieu achieved by the parasite. PMID- 27773520 TI - Predictive Models for Normal Fetal Cardiac Structures. AB - BACKGROUND: Clinicians rely on age- and size-specific measures of cardiac structures to diagnose cardiac disease. No universally accepted normative data exist for fetal cardiac structures, and most fetal cardiac centers do not use the same standards. The aim of this study was to derive predictive models for Z scores for 13 commonly evaluated fetal cardiac structures using a large heterogeneous population of fetuses without structural cardiac defects. METHODS: The study used archived normal fetal echocardiograms in representative fetuses aged 12 to 39 weeks. Thirteen cardiac dimensions were remeasured by a blinded echocardiographer from digitally stored clips. Studies with inadequate imaging views were excluded. Regression models were developed to relate each dimension to estimated gestational age (EGA) by dates, biparietal diameter, femur length, and estimated fetal weight by the Hadlock formula. Dimension outcomes were transformed (e.g., using the logarithm or square root) as necessary to meet the normality assumption. Higher order terms, quadratic or cubic, were added as needed to improve model fit. Information criteria and adjusted R2 values were used to guide final model selection. RESULTS: Each Z-score equation is based on measurements derived from 296 to 414 unique fetuses. EGA yielded the best predictive model for the majority of dimensions; adjusted R2 values ranged from 0.72 to 0.893. However, each of the other highly correlated (r > 0.94) biometric parameters was an acceptable surrogate for EGA. In most cases, the best fitting model included squared and cubic terms to introduce curvilinearity. CONCLUSIONS: For each dimension, models based on EGA provided the best fit for determining normal measurements of fetal cardiac structures. Nevertheless, other biometric parameters, including femur length, biparietal diameter, and estimated fetal weight provided results that were nearly as good. Comprehensive Z-score results are available on the basis of highly predictive models derived from gestational age or other biometrics as preferable for clinical reasons. These results supplant current equations and will provide a foundation for future multicenter collaborations. PMID- 27773521 TI - Association between Cardiovascular Health Score and Carotid Intima-Media Thickness: Cross-Sectional Analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Baseline Assessment. AB - BACKGROUND: The American Heart Association aims to reduce the burden of cardiovascular disease in this decade by improving seven ideal cardiovascular health (CVH) characteristics in the population. The aim of this study was to quantify the association between the American Heart Association's CVH score and values for carotid intima-media thickness (CIMT) in the Brazilian Longitudinal Study of Adult Health baseline assessment. METHODS: The Brazilian Longitudinal Study of Adult Health is a multicenter cohort study of civil servants aged 35 to 74 years in Brazil. In this study, the investigators analyzed 9,662 individuals with no previous cardiovascular disease. The distribution of CIMT values (categorized into age-, sex-, and race-specific quartiles) was analyzed according to CVH scores using chi2 trend tests. Linear and multinomial regression models were built to evaluate the association between CIMT and CVH score. RESULTS: A significant increase was observed in the proportion of individuals within the first and second CIMT quartiles, as well as a decrease within the fourth quartile with higher CVH score strata (P for trend < .001). A 1-point increase in CVH score was associated in adjusted models with a decrease of 0.011 mm in CIMT and an odds ratio of 0.79 (95% CI, 0.77-0.81) of having CIMT in the fourth quartile. However, nearly 16% of individuals with optimal CVH scores had CIMT values in the highest quartile. CONCLUSIONS: In this study, significant associations were found between CIMT and CVH score in a large sample of middle-aged adults. However, a high CVH score did not warrant the absence of a significant subclinical atherosclerotic burden. PMID- 27773522 TI - Type III CRISPR-Cas Immunity: Major Differences Brushed Aside. AB - For a long time the mechanism of immunity provided by the Type III CRISPR-Cas systems appeared to be inconsistent: the Type III-A Csm complex of Staphylococcus epidermidis was first reported to target DNA while Type III-B Cmr complexes were shown to target RNA. This long-standing conundrum has now been resolved by finding that the Type III CRISPR-Cas systems are both RNases and target RNA activated DNA nucleases. The immunity is achieved by coupling binding and cleavage of RNA transcripts to the degradation of invading DNA. The base-pairing potential between the target RNA and the CRISPR RNA (crRNA) 5'-handle seems to play an important role in discriminating self and non-self nucleic acids; however, the detailed mechanism remains to be uncovered. PMID- 27773518 TI - The apicoplast: now you see it, now you don't. AB - Parasites such as Plasmodium and Toxoplasma possess a vestigial plastid homologous to the chloroplasts of algae and plants. The plastid (known as the apicoplast; for apicomplexan plastid) is non-photosynthetic and very much reduced, but has clear endosymbiotic ancestry including a circular genome that encodes RNAs and proteins and a suite of bacterial biosynthetic pathways. Here we review the initial discovery of the apicoplast, and recount the major new insights into apicoplast origin, biogenesis and function. We conclude by examining how the apicoplast can be removed from malaria parasites in vitro, ultimately completing its reduction by chemical supplementation. PMID- 27773523 TI - Does Sequence Conservation Provide Evidence for Biological Function? AB - Finding a signature of purifying selection in a gene is usually interpreted as evidence for the gene providing a function that is targeted by natural selection. This opinion offers a very different hypothesis: purifying selection may be due to removing harmful mutations from the population, that is, the gene and its encoded protein become harmful after a mutation occurred, possibly because the mutated protein interferes with the translation machinery, or because of toxicity of the misfolded protein. Finding a signature of purifying selection should not automatically be considered proof of the gene's selectable function. PMID- 27773524 TI - The Slow Relaxation Dynamics in the Amorphous Pharmaceutical Drugs Cimetidine, Nizatidine, and Famotidine. AB - The slow molecular mobility in the amorphous solid state of 3 active pharmaceutical drugs (cimetidine, nizatidine, and famotidine) has been studied using differential scanning calorimetry and the 2 dielectric-related techniques of dielectric relaxation spectroscopy and thermally stimulated depolarization currents. The glass-forming ability, the glass stability, and the tendency for crystallization from the equilibrium melt were investigated by differential scanning calorimetry, which also provided the characterization of the main relaxation of the 3 glass formers. The chemical instability of famotidine at the melting temperature and above it prevented the preparation of the amorphous for dielectric studies. In contrast, for cimetidine and nizatidine, the dielectric study yielded the main kinetic features of the alpha relaxation and of the secondary relaxations. According to the obtained results, nizatidine displays the higher fragility index of the 3 studied glass-forming drugs. The thermally stimulated depolarization current technique has proved useful to identify the Johari-Goldstein relaxation and to measure taubetaJG in the amorphous solid state, that is, in a frequency range which is not easily accessible by dielectric relaxation spectroscopy. PMID- 27773525 TI - Silicone Migration From Baked-on Silicone Layers. Particle Characterization in Placebo and Protein Solutions. AB - A significant number of therapeutic proteins are marketed as pre-filled syringes or other drug/device combination products and have been safely used in these formats for years. Silicone oil, which is used as lubricant, can migrate into the drug product and may interact with therapeutic proteins. In this study, particles in the size range of 0.2-5 MUm and >=1 MUm as determined by resonant mass measurement and micro-flow imaging/light obscuration, respectively, resulted from silicone sloughing off the container barrel after agitation. The degree of droplet formation correlated well with the applied baked-on silicone levels of 13 MUg and 94 MUg per cartridge. Silicone migration was comparable in placebo, 2 mg/mL and 33 mg/mL IgG1 formulations containing 0.04% (w/v) polysorbate 20. Headspace substantially increased the formation of silicone droplets during agitation. The highest particle concentrations reached, however, were still very low compared to numbers described for spray-on siliconized containers. When applying adequate baked-on silicone levels below 100 MUg, bake-on siliconization efficiently limits silicone migration into the drug product without compromising device functionality. PMID- 27773527 TI - A Moral or Medical Problem? The Relationship between Legal Penalties and Treatment Practices for Opioid Use Disorders in Pregnant Women. AB - OBJECTIVE: The relationship between use of medication-assisted treatment (MAT) in pregnant women with opioid use disorders, the standard of care, and state laws that permit child abuse charges for illicit drug use during pregnancy has not been described. METHODS: Using publicly available data on substance abuse treatment in the United States, we describe patterns in the use of MAT for pregnant women with opioid use disorders in states with prenatal child abuse laws compared with states without such laws. A binary logistic regression analysis was conducted to predict the presence or absence of MAT in the treatment plan of pregnant women using the following independent variables: state prenatal child abuse law, referral source, geographical region, and Medicaid coverage of methadone. RESULTS: In 2012, there were 8,292 treatment episodes of pregnant women with a primary opioid use disorder in the United States for which data on MAT use were available. Among states with laws that permit child abuse charges for illicit drug use in pregnancy (18 states), MAT was used in 33.15% of treatment admissions compared with 51.33% of admissions in states without a law. The following levels of the independent variables have a greater effect on the lack of use of MAT in descending order of importance: criminal justice referral, other community referral, Southern region, Medicaid coverage, drug abuse care provider referral, unknown referral, other health care provider referral, and presence of state law that permits child abuse charges. CONCLUSION: Referral source, geographic region, Medicaid funding, and prenatal child abuse laws were associated with significantly lower rates of use of MAT. PMID- 27773526 TI - An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities. AB - Fibroblast growth factor-1 (FGF-1), a potent human mitogen and insulin sensitizer, signals through both tyrosine kinase receptor-mediated autocrine/paracrine pathways as well as a nuclear intracrine pathway. Phosphorylation of FGF-1 at serine 116 (S116) has been proposed to regulate intracrine signaling. Position S116 is located within a ~17 amino acid C-terminal loop that contains a rich set of functional determinants including heparin?heparan sulfate affinity, thiol reactivity, nuclear localization, pharmacokinetics, functional half-life, nuclear ligand affinity, stability, and structural dynamics. Mutational targeting of specific functionality in this region without perturbing other functional determinants is a design challenge. S116R is a non-phosphorylatable variant present in bovine FGF-1 and other members of the human FGF family. We show that the S116R mutation in human FGF-1 is accommodated with no perturbation of biophysical or structural properties, and is therefore an attractive mutation with which to elucidate the functional role of phosphorylation. Characterization of S116R shows reduction in NIH 3T3 fibroblast mitogenic stimulation, increase in fibroblast growth factor receptor-1c activation, and prolonged duration of glucose lowering in ob/ob hyperglycemic mice. A novel FGF-1/fibroblast growth factor receptor-1c dimerization interaction combined with non-phosphorylatable intracrine signaling is hypothesized to be responsible for these observed functional effects. PMID- 27773528 TI - Antenatal Maternity Leave and Childbirth Using the First Baby Study: A Propensity Score Analysis. AB - BACKGROUND: Most employed American women work during pregnancy and continue working through the month they deliver. Yet, few studies estimate the relationship between maternity leave taken during pregnancy and maternal health. We evaluate the association of antenatal leave (ANL) uptake with obstetric outcomes, assessing the potential role of protective and adverse selection pathways on this relationship. METHODS: We sample 1,740 employed women who delivered at term from the First Baby Study, a prospective cohort of nulliparous women in Pennsylvania. We use propensity scores to estimate the relationship between ANL and negative delivery outcomes (labor induction, long labor duration, unplanned cesarean delivery, and self-reported negative birth experience). We estimated propensity scores using a range of employment, health, and sociodemographic variables. RESULTS: One-half of the sampled women worked until the day before or day of delivery. Women who stopped working at least 2 days before delivery experienced 16% more negative delivery outcomes, on average, than women who worked until delivery, driven largely by a 25% higher predicted probability of unplanned cesarean section deliveries. These robust findings hold up to a range of sensitivity analyses and demonstrate selective mechanisms operating in ANL uptake. CONCLUSION: Our findings suggest that, even after controlling for an extensive set of observable employment, health, and sociodemographic characteristics, women who take ANL continue to differ in unobserved characteristics that lead to negative delivery outcomes. Like most U.S. states, Pennsylvania does not grant paid maternity leave. In a context of limited maternity leave availability, only relatively unhealthy women take ANL. PMID- 27773529 TI - Time from Screening Mammography to Biopsy and from Biopsy to Breast Cancer Treatment among Black and White, Women Medicare Beneficiaries Not Participating in a Health Maintenance Organization. AB - PURPOSE: There is a breast cancer mortality gap adversely affecting Black women in the United States. This study assessed the relationship between number of days between abnormal mammogram, biopsy, and treatment among Medicare (Part B) beneficiaries ages 65 to 74 and 75 to 84 years, accounting for race and comorbidity. METHODS: A cohort of non-Hispanic Black and non-Hispanic White women residing in the continental United States and receiving no services from a health maintenance organization was randomly selected from the Center for Medicare and Medicaid Services denominator file. The cohort was followed from 2005 to 2008 using Center for Medicare and Medicaid Services claims data. The sample included 4,476 women (weighted n = 70,731) with a diagnosis of breast cancer. Cox proportional hazard modeling was used to identify predictors of waiting times. FINDINGS: Black women had a mean of 16.7 more days between biopsy and treatment (p < .001) and 15.7 more days from mammogram to treatment (p = .003) than White women. Median duration from abnormal mammogram to treatment exceeded National Quality Measures for Breast Centers medians regardless of race, age, or number of comorbidities (overall 43 days vs. the National Quality Measures for Breast Centers value of 28 days). CONCLUSIONS: Medical care delays may contribute, in part, to the widening breast cancer mortality gap between Black women and White women. Further study, with additional clinical and social information, is needed to broaden scientific understanding of racial determinants and assess the clinical significance of mammogram to treatment times among Medicare beneficiaries. PMID- 27773530 TI - Is It Safe to Vape? Analyzing Online Forums Discussing E-Cigarette Use during Pregnancy. AB - INTRODUCTION: Electronic cigarette (e-cigarette) use, or vaping, is increasing against a backdrop of declining smoking rates. E-cigarettes contain fewer toxicants than cigarettes, but their appearance and mode of use has the potential to satisfy the habitual aspects of smoking. To date, we know little about lay perceptions of the safety of using e-cigarettes in pregnancy. METHODS: We conducted a thematic discourse analysis of 13 online discussion forum threads that discussed e-cigarette use during pregnancy. We focused on the major discursive strategies that forum posters used to debate the safety of e-cigarette use during pregnancy. RESULTS: We identified three distinct ways in which forum posters debated the safety of using e-cigarettes during pregnancy: 1) quitting (nicotine) cold turkey is unsafe, 2) vaping is the lesser of two evils, and 3) vaping is not worth the risk. CONCLUSIONS: Discussions about the safety of e cigarettes drew on the premise that 1) immediate cessation of nicotine was potentially harmful and unsafe, 2) e-cigarettes were a harm reduction tool, or 3) vaping could be dangerous and should be avoided. Although these arguments are not necessarily specific to pregnancy (beside mentions of fetal-specific risks), this analysis points to the need to educate and support women about harm reduction options. IMPLICATIONS: Health professionals should be aware that some women may be currently using or considering using e-cigarettes in an effort to quit or reduce smoking. It is important that health professionals are equipped to educate women with accurate, up-to-date, and balanced information about the risks and benefits of e-cigarette use during pregnancy. PMID- 27773531 TI - Recommendations about Pregnancy from Women with Mobility Disability to Their Peers. AB - BACKGROUND: Although growing numbers of women with mobility disability are becoming pregnant and desiring motherhood, relatively little is known about their pregnancy experiences or what they might recommend to other women with mobility disability contemplating pregnancy. METHODS: Using a semistructured, open-ended interview protocol, we conducted 2-hour telephone interviews with 22 women who had a significant mobility disability before becoming pregnant and had delivered babies within the prior 10 years. We recruited most interviewees through online social networks. We used NVivo software to sort interview transcript texts and performed conventional content analyses to identify major themes. RESULTS: Participants' mean +/- standard deviation age was 34.8 +/- 5.3 years; most were White, well-educated, and middle income and 18 used wheeled mobility aids. Recommendations for other women with mobility disability coalesced around five themes: recognizing the possibility of giving birth, advocacy and support, being informed, approaches toward obstetrical practitioners, and managing fears about losing custody of their child. Lacking information about what to expect during their pregnancy was a significant problem. Women got information about pregnancy from diverse sources, but questions arose about accuracy and relevance of this information to individual circumstances. Women urged their peers to advocate for their preferences and needs with obstetrical practitioners. CONCLUSIONS: Women with mobility disability who had delivered babies offered constructive advice for their peers who desire pregnancy. Increasing availability of accurate and relevant information about pregnancy among women with mobility disability is critically important, as is training obstetrical practitioners to provide patient centered care to these women during pregnancy. PMID- 27773532 TI - Ecological risk assessment of a coastal zone in Southern Vietnam: Spatial distribution and content of heavy metals in water and surface sediments of the Thi Vai Estuary and Can Gio Mangrove Forest. AB - Enrichment of heavy metals was assessed in the Thi Vai Estuary and in the Can Gio Mangrove Forest (SE, Vietnam). Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn contents in water and in sediments were measured. Total organic carbon, nitrogen, phosphorus and C/N ratios were determined. Cu and Cr values were higher than threshold effect level of toxicity, while Ni exceeded probable effect level, indicating the risk of probable toxicity effects. Enrichment factors (EF), contamination factor (CF) and Geo-accumulation index (I-geo) were determined. CF reveals moderate to considerable pollution with Cr and Ni. EF suggests anthropogenic sources of Cr, Cu and Ni. I-geo indicates low contamination with Co, Cu and Zn and moderate contamination with Cr and Ni. Overall metal contents were lower than expected for this highly industrialized region, probably due to dilution, suggesting that erosion rates and hydrodynamics may also play a role in metal contents distribution. PMID- 27773533 TI - Temporal dynamics of bacterioplankton communities in response to excessive nitrate loading in oligotrophic coastal water. AB - Coastal ecosystems are receiving elevated loads of nitrogen (N) from anthropogenic sources. Understanding how excessive N loading affects bacterioplankton communities is critical to predict the biodiversity of marine ecosystems under conditions of eutrophic disturbance. In this study, oligotrophic coastal water microcosms were perturbed with nitrate in two loading modes: 1) one off loading at the beginning of the incubation period; and 2) periodic loading every two days for 16days. Turnover in the bacterioplankton community was investigated by 16S rDNA gene amplicon sequencing. The alpha diversity of the bacterioplankton community showed great temporal variability and similar responses to the different treatments. Bacterioplankton community composition was influenced remarkably by time and N loading mode. The effects of N loading on bacterioplankton community structure showed obvious temporal variation, probably because of the great temporal variation in environmental parameters. This study provides insights into the effects of N pollution in anthropogenically perturbed marine environments. PMID- 27773534 TI - An in-depth survey of the oil spill literature since 1968: Long term trends and changes since Deepwater Horizon. AB - In order to characterize the state of oil spill research and describe how the field has changed since its inception in the 1960s and since the Deepwater Horizon spill in 2010, we examined approximately 10% of oil spill literature (1255 of over 11,000 publications) published from 1968 to 2015. We find that, despite its episodic nature, oil spill research is a rapidly expanding field with a growth rate faster than that of science as a whole. There is a massive post Deepwater Horizon shift of research attention to the Gulf of Mexico, from 2% of studies in 2004-2008 to 61% in 2014-2015, thus ranking Deepwater Horizon as the most studied oil spill. There is, however, a longstanding gap in research in that only 1% of studies deal with the effects of oil spills on human health. These results provide a better understanding of the current trends and gaps within the field. PMID- 27773537 TI - Total Body Less Head Measurement Is Most Appropriate for Lean Mass Assessment in Adults. PMID- 27773538 TI - ? PMID- 27773536 TI - Dynamics of Human and Viral RNA Methylation during Zika Virus Infection. AB - Infection with the flavivirus Zika (ZIKV) causes neurological, immunological, and developmental defects through incompletely understood mechanisms. We report that ZIKV infection affects viral and human RNAs by altering the topology and function of N6-adenosine methylation (m6A), a modification affecting RNA structure and function. m6A nucleosides are abundant in ZIKV RNA, with twelve m6A peaks identified across full-length ZIKV RNA. m6A in ZIKV RNA is controlled by host methyltransferases METTL3 and METTL14 and demethylases ALKBH5 and FTO, and knockdown of methyltransferases increases, while silencing demethylases decreases, ZIKV production. YTHDF family proteins, which regulate the stability of m6A-modified RNA, bind to ZIKV RNA, and their silencing increases ZIKV replication. Profiling of the m6A methylome of host mRNAs reveals that ZIKV infection alters m6A location in mRNAs, methylation motifs, and target genes modified by methyltransferases. Our results identify a mechanism by which ZIKV interacts with and alters host cell functions. PMID- 27773535 TI - N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection. AB - The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification, as well as m6A-binding YTHDF proteins that promote the translation or degradation of m6A modified mRNA. We demonstrate that m6A modulates infection by hepatitis C virus (HCV). Depletion of m6A methyltransferases or an m6A demethylase, respectively, increases or decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m6A sites across the HCV genome and determined that inactivating m6A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m6A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m6A. Altogether, this work identifies m6A as a conserved regulatory mark across Flaviviridae genomes. PMID- 27773539 TI - Implementation of new physics models for low energy electrons in liquid water in Geant4-DNA. AB - A new alternative set of elastic and inelastic cross sections has been added to the very low energy extension of the Geant4 Monte Carlo simulation toolkit, Geant4-DNA, for the simulation of electron interactions in liquid water. These cross sections have been obtained from the CPA100 Monte Carlo track structure code, which has been a reference in the microdosimetry community for many years. They are compared to the default Geant4-DNA cross sections and show better agreement with published data. In order to verify the correct implementation of the CPA100 cross section models in Geant4-DNA, simulations of the number of interactions and ranges were performed using Geant4-DNA with this new set of models, and the results were compared with corresponding results from the original CPA100 code. Good agreement is observed between the implementations, with relative differences lower than 1% regardless of the incident electron energy. Useful quantities related to the deposited energy at the scale of the cell or the organ of interest for internal dosimetry, like dose point kernels, are also calculated using these new physics models. They are compared with results obtained using the well-known Penelope Monte Carlo code. PMID- 27773541 TI - Salt Intake, Overweight, and High Blood Pressure, With Special Reference to Sex Difference. PMID- 27773540 TI - Secondary CV Prevention in South America in a Community Setting: The PURE Study. AB - BACKGROUND: Despite the availability of evidence-based therapies, there is no information on the use of medications for the secondary prevention of cardiovascular disease in urban and rural community settings in South America. OBJECTIVES: This study sought to assess the use, and its predictors, of effective secondary prevention therapies in individuals with a history of coronary heart disease (CHD) or stroke. METHODS: In the PURE (Prospective Urban Rural Epidemiological) study, we enrolled 24,713 individuals from South America ages 35 to 70 years from 97 rural and urban communities in Argentina, Brazil, Chile, and Colombia. We assessed the use of proven therapies with standardized questionnaires. We report estimates of drug use at national, community, and individual levels and the independent predictors of their utilization through a multivariable analysis model. RESULTS: Of 24,713 individuals, 910 had a self reported CHD event (at a median of 5 years earlier) and 407 had stroke (6 years earlier). The proportions of individuals with CHD who received antiplatelet medications (30.1%), beta-blockers (34.2%), angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers (36.0%), or statins (18.0%) were low; with even lower proportions among stroke patients (antiplatelets 24.3%, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers 37.6%, statins 9.8%). A substantial proportion of patients did not receive any proven therapy (CHD 31%, stroke 54%). A minority of patients received either all 4 (4.1%) or 3 proven therapies (3.3%). Male sex, age >60 years, better education, more wealth, urban location, diabetes, and obesity were associated with higher rates of medication use. In a multivariable model, markers of wealth had the largest impact in secondary prevention. CONCLUSIONS: There are large gaps in the use of proven medications for secondary prevention of cardiovascular disease in South America. Strategies to improve the sustained use of these medications will likely reduce cardiovascular disease burden substantially. PMID- 27773542 TI - HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection. AB - Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes. Key event was the Nef-mediated routing of the TNF-converting enzyme ADAM17 into Rab4+ early endosomes and the Rab27+ secretory pathway. Analysis of lymph-node tissue by multi-epitope-ligand-cartography (MELC) confirmed a vesicular TNF secretion phenotype that co-localized with persistent Nef expression, and implicated Notch1 as an essential co-factor. Surprisingly Notch1 had no transcriptional effect but was required for the endosomal trafficking of ADAM17. We conclude that Nef expression and Nef-containing pEV mobilize TNF from endosomal compartments in acute and chronic infection. PMID- 27773543 TI - High-virulence CMY-2- and CTX-M-2-producing avian pathogenic Escherichia coli strains isolated from commercial turkeys. AB - This study reports the high-virulence phylogenetic backgrounds of CMY-2- and CTX M-2-producing avian pathogenic Escherichia coli strains isolated from turkeys sent to slaughter and condemned by airsacculitis in Brazil. Among 300 air sac samples, seven E. coli strains produced plasmid-mediated CMY-2-type AmpC, of which three carried also the blaCTX-M-2 Extended Spectrum Beta-Lactamase encoding gene. Interestingly, the transfer of the blaCMY-2 gene was positive for three E. coli strains, being associated with the presence of IncI1 plasmids. The complete sequence of the representative pJB10 plasmid revealed that the blaCMY-2 gene was within a transposon-like element in the classical genetic environment consisting of tnpA-blaCMY-2-blc-sugE structure. This plasmid with 94-kb belonged to the sequence type (ST) 12 among IncI1 plasmids, which has been associated with the worldwide spread of blaCMY-2 among Salmonella enterica and E. coli. Furthermore, to the best of our knowledge, this is the first complete sequence of a CMY-2 encoding plasmid derived from an Escherichia coli isolated from food-producing animals in Latin America. PMID- 27773544 TI - Molecular characteristics of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae causing intra-abdominal infections from 9 tertiary hospitals in China. AB - BACKGROUND: Recently, the emergence of multidrug-resistant organisms such as extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae has raised considerable concern regarding the appropriate treatment of intra-abdominal infections (IAIs). In this study, we investigated the molecular characteristics of ESBL among clinical isolates of Escherichia coli and Klebsiella pneumoniae causing IAIs and their pattern of antimicrobial resistance, which can provide useful information about the epidemiology and risk factors associated with these infections. MATERIALS AND METHODS: One hundred sixty-seven E.coli and 47 K. pneumoniae ESBL-producing strains causing IAIs were collected from 9 hospitals in China, during 2012 and 2013. The antimicrobial susceptibility profile of these strains was determined. Polymerase chain reaction and sequencing were performed to identify genes for beta-lactamase (blaTEM, blaSHV, blaOXA-1-like, and blaCTX M). The isolates were also analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS: In 167 ESBL-producing E. coli strains, 104 strains (62.3%) were positive for CTX-M, and 9 strains (5.39%) were positive for SHV. Among the 47 K. pneumoniae strains, 35 strains (74.5%) were positive for SHV-2a, 12 strains (25.5%) were positive for CTX-M. No TEM-type and OXA-1-like strain was detected among all the ESBL-producing strains. Regarding the CTX-M-positive E. coli and K. pneumoniae strains, CTX-M-15 was the most common genotype in E. coli and K. pneumoniae strains, accounting for 28.7% and 17.0%, respectively, followed by CTX M-55 accounting for 16.2% and 2.13%, respectively; the remaining genotypes included CTX-M-123 and CTX-M-82. PFGE showed that E.coli and K. pneumoniae ESBL producing strains causing IAIs were diverse and that emerging resistance may not be due to the dissemination of national clones. CONCLUSION: The present study revealed that in ESBL-producing strains causing IAIs in China, the most common genotype for E.coli was CTX-M-15 and for K. pneumoniae was SHV-2a. However, there was a wide diversity of strains causing IAIs among the ESBL-producing E. coli and K. pneumoniae. PMID- 27773545 TI - CADASIL mimicking multiple sclerosis: The importance of clinical and MRI red flags. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease, manifesting as recurrent ischaemic events, migraine with aura, behavioural disturbance and cognitive decline. We report two patients with CADASIL masquerading as multiple sclerosis (MS). A 23year old female presented with a visual scotoma and was discovered to have a corresponding retinal cotton wool spot. MRI brain revealed diffuse T2 hyperintensities suggestive of demyelination. A 56year old male presented with transient sequential paraesthesia, initially of the perineum followed by the right leg. He also reported memory and mood impairment with a history of migraine with aura. MRI of the brain showed diffuse bilateral white matter lesions with sparing of the anterior temporal poles. Both patients satisfied the modified McDonald diagnostic criteria and were initially thought to have MS. However, they did not satisfy the caveat of "no better explanation" and on subsequent testing NOTCH 3 mutations were identified in both patients [1]. These cases highlight the importance of careful clinical assessment and neuroimaging findings in identifying clinical and paraclinical 'red-flags' for a diagnosis other than MS. PMID- 27773546 TI - Evaluating the effect of hydrocephalus cause on the manner of changes in the effective parameters and clinical symptoms of the disease. AB - In the present study, the heads of 11 normal subjects and 21 patients affected by hydrocephalus due to three different causes were simulated using fluid-structure interaction (FSI). To validate the results, the calculated diagram of CSF velocity in aqueduct of Sylvius (AS) was compared with the similar velocity diagram measured using Cine PC-MRI for the same subject. After ensuring the agreement of results, other outputs such as CSF pressure were calculated non invasively using FSI. The intracranial pressure and CSF pressure in AS and behind the optic nerve sheath were in patients 5-5.3 times the value in normal subjects and the ventricular system volume in patients was 10.2-11.1 times the value in normal subjects. However, the difference between the coefficient of variation and the maximum value of pressure and volume in different types of hydrocephalus was small. Furthermore, the difference between CSF stroke volumes in various types of hydrocephalus patients was less than 4.4%. Results showed that the intensity of clinical symptoms was similar in patients with similar CSF pressure and the cause of the hydrocephalus disease didn't have any significant effect on the intensity of patients' clinical symptoms and the manner of changes in effective parameters on disease. It was also found that the relation of CSF pressure and volume was 16.7% greater in patients with non-communicating hydrocephalus than in patients with communicating hydrocephalus. These results enhance the insight into hydrocephalus bio-mechanism and can help to choose the proper treatment method for hydrocephalus patients. PMID- 27773547 TI - [Post-abortion contraception]. AB - OBJECTIVE: To establish guidelines of the French National College of Gynecologists and Obstetricians about post-abortion contraception. MATERIALS AND METHODS: A systematic review of the literature about post-abortion contraception was performed on Medline and Cochrane Database between 1978 and March 2016. The guidelines of the French and foreign scientific societies were also consulted. RESULTS AND DISCUSSION: After an abortion, if the woman wishes to use a contraception, it should be started as soon as possible because of the very early ovulation resumption. The contraception choice must be done in accordance with the woman's expectations and lifestyle. The contraindications of each contraception must be respected. The long-acting reversible contraception, intra uterine device (IUD) and implant, could be preferred (grade C) as the efficacy is not dependent on compliance. Thus, they could better prevent repeat abortion (LE3). In case of surgical abortion, IUD should be proposed and inserted immediately after the procedure (grade A), as well as the implant (grade B). In case of medical abortion, the implant can be inserted from the day of mifepristone, the IUD after an ultrasound examination confirming the success of the abortion (no continuing pregnancy or retained sac) (grade C). PMID- 27773548 TI - A financial feasibility model of gasification and anaerobic digestion waste-to energy (WTE) plants in Saudi Arabia. AB - Municipal Solid Waste (MSW) generation in Saudi Arabia is increasingly growing at a fast rate, as it hurtles towards ever increasing urban development coupled with rapid developments and expanding population. Saudi Arabia's energy demands are also rising at a faster rate. Therefore, the importance of an integrated waste management system in Saudi Arabia is increasingly rising and introducing Waste to Energy (WTE) facilities is becoming an absolute necessity. This paper analyzes the current situation of MSW management in Saudi Arabia and proposes a financial model to assess the viability of WTE investments in Saudi Arabia in order to address its waste management challenges and meet its forecasted energy demands. The research develops a financial model to investigate the financial viability of WTE plants utilizing gasification and Anaerobic Digestion (AD) conversion technologies. The financial model provides a cost estimate of establishing both gasification and anaerobic digestion WTE plants in Saudi Arabia through a set of financial indicators, i.e. net present value (NPV), internal rate of return (IRR), modified internal rate of return (MIRR), profitability index (PI), payback period, discounted payback period, Levelized Cost of Electricity (LCOE) and Levelized Cost of Waste (LCOW). Finally, the analysis of the financial model reveals the main affecting factors of the gasification plants investment decision, namely: facility generation capacity, generated electricity revenue, and the capacity factor. Similarly, the paper also identifies facility waste capacity and the capacity factor as the main affecting factors on the AD plants' investment decision. PMID- 27773549 TI - Effects of acute dietary weight loss on postprandial plasma bile acid responses in obese insulin resistant subjects. AB - BACKGROUND & AIMS: Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism. The physiochemical properties of different BA species affect their enterohepatic dynamics and their affinity for bile acid receptors. The BA pool composition is altered in patients with type 2 diabetes and obesity. In this study we used a 2-week very-low-calorie diet (VLCD) to investigate the effects of weight loss on BA pool composition and postprandial dynamics. METHODS: We performed mixed meal tests in obese, insulin resistant subjects before and after the VLCD. We measured postprandial plasma levels of glucose, insulin, BA and the BA-induced enterokine fibroblast growth factor 19 (FGF19). RESULTS: The VLCD decreased weight by 4.5 +/- 2.3 kg (p < 0.0001) within 14 days. Weight loss increased peak postprandial deoxycholate (DCA) levels (median [IQR]: 0.90 [0.90] vs. 1.25 [1.35] MUmol/L; p = 0.045*). Other BA species, glucose, insulin and FGF19 levels and prandial excursions were not significantly affected. The VLCD decreased resting and postprandial energy expenditure by 7 and 11% respectively. CONCLUSIONS: VLCD induced weight loss increased postprandial DCA peak levels and decreased resting energy expenditure in obese insulin resistant subjects. PMID- 27773551 TI - Professor Ken Fearon - 3 August 1960 to 3 September 2016. PMID- 27773550 TI - Association between rice, bread, and noodle intake and the prevalence of non alcoholic fatty liver disease in Japanese middle-aged men and women. AB - BACKGROUND & AIMS: Prevention of non-alcoholic fatty liver disease (NAFLD) through lifestyle modification is an important public health issue. Carbohydrate intake from soft drinks has received particular interest. Owing to differences in dietary habits, however, major contributors to the intake of dietary carbohydrates, such as rice, bread, and noodles, might have more influence on NAFLD prevalence in East Asian countries than consumption of soft drinks. We examined the relationship of the intake of rice, bread, and noodles, as well as overall carbohydrate intake, with NAFLD prevalence in middle-aged Japanese. METHODS: This is a cross-sectional study of 977 men and 1467 women aged 40-69 y. Dietary information was obtained using a validated self-administered diet history questionnaire. Diagnosis of NAFLD was based on the following criteria: presence of steatosis on abdominal ultrasound, alcohol intake <20 g/day in women and <30 g/day in men, and exclusion of other liver diseases. Logistic regression was performed as multivariate analysis. RESULTS: The presence of NAFLD was 34.9% (n = 341) in men and 11.7% (n = 171) in women. Carbohydrate intake was positively associated with NAFLD prevalence in women (p for trend = 0.008). There was also a positive association between rice intake and NAFLD prevalence in women; the multi adjusted odds ratio for the highest versus the lowest quartiles of rice intake was 1.87 (95% CI: 1.03, 3.41; p for trend = 0.006). These associations were not observed in men. No association was observed between bread and noodle intake and the prevalence of NAFLD in either sex. CONCLUSIONS: Consumption of carbohydrates and rice was positively associated with NAFLD prevalence in middle-aged Japanese women. PMID- 27773553 TI - Emerging role of immunotherapy in urothelial carcinoma-Future directions and novel therapies. AB - Tremendous advances in our understanding of the tumor immunology and molecular biology of urothelial carcinoma (UC) have led to the recent approval of immunotherapy as a novel option for patients with UC with advanced disease. Despite the promising data of novel immune checkpoint inhibitors, only a small subset of patients with UC achieves durable remissions. Because an optimal antitumor response requires coordination of multiple immune, tumor, and microenvironment effector cells, novel approaches targeting distinct mechanisms of action likely in combination are needed. In addition, discovery of reliable immune biomarkers, understanding of mechanisms of resistance, and novel clinical trial designs are warranted for maximum benefit of UC immunotherapy. PMID- 27773552 TI - Interferon-gamma in Salmonella pathogenesis: New tricks for an old dog. AB - Salmonella enterica is a facultative intracellular bacterium that is the leading cause of food borne illnesses in humans. The cytokine IFN-gamma has well established antibacterial properties against Salmonella and other intracellular microbes, for example its capacity to activate macrophages, promote phagocytosis, and destroy phagocytosed microbes by free radical-driven toxification of phagosomes. But IFN-gamma induces the expression of hundreds of uncharacterized genes, suggesting that this cytokine deploys additional antimicrobial strategies that await discovery. Recently, one such mechanism, mediated by a family of IFN inducible small GTPases called Guanylate Binding Proteins (GBPs) has been uncovered. GBPs were shown to facilitate the pyroptotic clearance of Salmonella from infected macrophages by rupturing the protective intracellular vacuole this microbe forms around itself. Once this protective vacuole is lost, exposed Salmonella activates pyroptosis, which destroys the infected cell. In this review, we summarize such emerging roles for IFN-gamma in restricting Salmonella pathogenesis. PMID- 27773554 TI - The magnificent two: histamine and the H3 receptor as key modulators of striatal circuitry. AB - Histaminergic dysfunction has been recently linked to tic disorders and to aberrant striatal function. There is a particular interest in the histamine 3 receptor (H3R) due to its clinical implications for treating multiple disorders and its high expression in the brain. Striatal histamine (HA) modulates through the H3R in complex ways the release of striatal neurotransmitters into this brain region. The H3R has been classically described to be coupled to Gi, although there is evidence that revealed that striatal H3R forms heteromers with the dopamine receptors 1 and 2 in the medium spiny neurons (MSNs) than changes this signaling. Moreover, new data described for the first time a complete, segregated and time dependent signaling after H3R activation in the two types of MSNs (D1R MSNs and D2R-MSNs). The aim of this review is to update the role of HA and H3R in striatal function at a molecular and signaling levels. PMID- 27773555 TI - Increased expression of markers of early atherosclerosis in patients with inflammatory bowel disease. AB - BACKGROUND & AIMS: Recent studies documented an increased cardiovascular risk in patients with inflammatory bowel disease (IBD). Our study aimed at investigating the prevalence of intima-media thickness (IMT) of the carotid arteries and the arterial stiffness indices as markers of early atherosclerosis in young IBD patients. METHODS: We recruited 68 consecutive IBD patients, and 38 matched healthy controls less than 45years old (median age 31.6+/-8.1years). Clinical and demographic features, cardiovascular risk factors, history of cardiovascular events, concomitant therapies were registered on a dedicate database. Carotid IMT was evaluated by using high resolution B-mode ultrasonography. Arterial stiffness was assessed by measurement of carotid-femoral Pulse Wave Velocity (PWV) and Augmentation Index (AIx). RESULTS: Total cholesterol (P<0.013) and LDL cholesterol (P<0.019) levels were significantly lower in IBD patients compared to controls. Carotid IMT was higher in IBD than in controls (P<0.047), but there was no statistically significant difference among Crohn's Disease (CD) and Ulcerative Colitis (UC) patients. Moreover, PWV and AIx were significantly higher in patients as compared to controls (P<0.006 and P<0.004 respectively). No medication seemed to affect vascular measurements, though stiffness parameters were significantly higher in patients treated with 5-ASA (11.9 (9.7) vs 18.2 (10.2), P<0.021), suggesting a lack of efficacy of 5-ASA in protecting IBD patients from early atherogenesis. CONCLUSIONS: Young IBD patients show an increase in subclinical markers of atherosclerosis. Future studies need to address whether these markers result in an increased risk of cardiovascular events in these patient. PMID- 27773557 TI - [The health care provider's experience with fathers of overweight and obese children: A qualitative analysis]. PMID- 27773556 TI - Sudden death in epilepsy: Insights from the last 25 years. AB - Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with refractory epilepsy, and as such has been a major research focus over the last 25 years. The earliest SUDEP research papers were published in Seizure, as have scores of SUDEP papers since. In this review we discuss the efforts to try and describe the pathophysiological basis of SUDEP, the drive to discover the clinical risk factors that increase the likelihood of SUDEP, and the motivation to increase awareness of SUDEP. These three areas are the prime factors that, when answered, will allow us to better mitigate against SUDEP and help individuals monitor their personal risk. The field has benefited from strong definitions, multinational collaboration, the use of cutting edge genetic analysis, and ensuring that bereaved families are able to take part in research when this is appropriate. Clearly there is much that we do not know and yet, has any area of epilepsy research come so far in the last 25 years? PMID- 27773558 TI - The 2015 emergency care reform in Poland: Some improvements, some unmet demands and some looming conflicts. AB - Between 2006 and 2015, the Act on the State Emergency Medical System was the key act governing the organization, financing and provision of emergency care in Poland. From the moment it entered into force, it had been heavily criticized. The critique focused, among others, on the lack of provisions allowing for emergency medical services (EMS) to be performed outside the EMS units, the lack of a separate Act regulating the profession of a medical rescuer and the lack of a separate professional organization representing medical rescuers. As early as 2008 a team of specialists was set up to work on amending the Act and these works resulted in the draft Act on the State Emergency Medical System that was submitted to public consultations on 19 August, 2014. This draft was further reworked in 2015 and was signed by the President on 25 September of the same year. The Act addressed some of the shortcomings of the EMS legislation that was previously in place. However, the new Act did not meet the key demands of medical rescuers; namely, it did not introduce a separate legal act regulating this profession nor established a professional organisation representing their interests. An analysis of the vested interests of various groups of medical professionals indicates that these interests are likely to have influenced the final legislative outcome. The Act, as well as its implementing executive regulation from April 2016, may reduce support of certain medical professional groups during the Act's implementation as well as create tensions between these groups, especially between medical rescuers and nurses. PMID- 27773559 TI - Immunophenotypic and genetic characteristics of diffuse large B-cell lymphoma in Taiwan. AB - BACKGROUND/PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma type. The immunophenotypic and genetic features of DLBCL in Taiwan have not been characterized. METHODS: In this study, we performed immunohistochemical analysis and interphase fluorescence in situ hybridization (FISH) using tissue microarray sections to investigate a cohort of unselected DLBCL cases in a single institution in Taiwan from 1990 to 2010. RESULTS: Of the 153 cases investigated, CD10, bcl-6, and MUM1 were expressed in 16.3%, 71.2%, and 71.9% cases, respectively, with 27.5% (n = 42) of cases being classified as having a germinal center B-cell (GCB) origin by the Hans algorithm. By FISH analysis, 19.6%, 4.6%, 26.1%, and 3.9% cases showed rearrangement at IGH, BCL2, BCL6, and MYC loci, respectively, including three (2.0%) cases of double-hit lymphoma. As compared with the non-GCB tumors, GCB tumors more frequently expressed CD10 (p < 0.001) and bcl-6 (p = 0.001) with less frequent expression of MUM1 (p = 0.007). Moreover, GCB tumors more frequently exhibited rearrangement at the BCL2 (p = 0.024) and MYC (p = 0.038) loci than non-GCB tumors. However, there was no survival difference between these two groups. CONCLUSION: In this first series of DLBCL evaluation from Taiwan, we found that the relative frequency of GCB tumors among DLBCL was low in most East Asian countries. There is a wide range of BCL2 rearrangement rates, higher in the West and lower in East Asia. A larger and/or national study is warranted to better understand the immunophenotypic and molecular features of DLBCL in Taiwan and their respective impact on patient survival. PMID- 27773560 TI - Surgical resection of sinonasal hemangiopericytoma involving anterior skull base: Case reports and literature review. AB - Hemangiopericytomas are soft tissue tumors composed of pericytic cells that are characterized by their "staghorn" vascular branching and their variable clinical presentation. Fifteen to 25% of all HPC occur in the head and neck, with only 5% found in the nose or paranasal sinuses. Sinonasal hemangiopericytoma (SNHPC) is considered distinct from its soft tissue counterpart - the former showing a more uniform cellular organization, has convincing pericytic differentiation and is associated with a far better prognosis. With less than 200 cases of SNHPC reported in the literature, only limited assumptions can be made about this rare tumor. The purpose of this article is to add to the growing body of literature on this disease. We report two new cases of SNHCP - both in female patients who presented with epistaxis and anosmia. Pulsatile vascular masses were visualized with nasal endoscopy - one in the left middle meatus and the second one near the cribriform plate. CT and MRI studies show enhancing masses in the left nasal cavities with thinning and erosion of the skull base. Diagnoses were confirmed by pathology which reported spindle cell neoplasm staining positively for VEGF, NSE, factor XIIIa, S-100 protein, and CD34, and negative for actin, desmin, CD31, and pankeratin, consistent with hemangiopericytoma. In one patient, embolization of the sphenopalatine and labial artery as well as pre-operative radiation therapy was performed before complete endoscopic resection was undertaken. The second patient had a tumor invading the skull base, so a craniofacial resection was performed. Both patients remained free of disease two years after surgery. Review of the literature and treatment options are discussed. PMID- 27773561 TI - NBI utility in the pre-operative and intra-operative assessment of oral cavity and oropharyngeal carcinoma. AB - PURPOSE: Despite advances in the surgical management of head and neck squamous cell carcinoma, the identification of synchronous lesions, precancerous lesions around the main tumor, or the unknown primary in the case of neck metastasis remains a problem, as these lesions may be invisible to the naked eye or with standard white light (WL) endoscopy. However, the advent of tools such as narrow band imaging (NBI) could help the clinician. The purpose of this study was to assess the impact of NBI during the pre-operative and intra-operative stages of management of oral and oropharyngeal cancers. MATERIALS AND METHODS: NBI was used pre-operatively in 47 patients with oral or oropharyngeal squamous cell carcinoma to identify the involvement of adjacent subsites, multifocality, synchronous lesions or an unknown primary. NBI was used intra-operatively in 30 patients to better define the tumor limits and guide the resection. The advantage of NBI versus WL endoscopy was analyzed by calculating the true and false positive rate pre-operatively, and the need for resection enlargements, histology of the enlargement, and the rate of clear margins at definitive histology, intra operatively. RESULTS: Pre-operatively, the diagnostic gain of NBI was 8.5%, allowing identification of three synchronous tumors and one unknown primary. Intra-operatively, NBI improved the definition of tumor limits in 67.7% of cases, with resection enlargements showing dysplasia and carcinoma in 8 and 12 patients, respectively; we obtained 74.2% negative margins at histology. CONCLUSIONS: NBI could represent an added value in the pre-operative and intra-operative assessment of oral cavity and oropharyngeal carcinoma. PMID- 27773562 TI - The need for a better indicator of when FGF-2 should be applied to treat subacute tympanic membrane perforations. PMID- 27773563 TI - Evolution of the Arden Syntax: Key Technical Issues from the Standards Development Organization Perspective. AB - BACKGROUND: The initial version of the Arden Syntax for Medical Logic Systems was created to facilitate explicit representation of medical logic in a form that could be easily composed and interpreted by clinical experts in order to facilitate clinical decision support (CDS). Because of demand from knowledge engineers and programmers to improve functionality related to complex use cases, the Arden Syntax evolved to include features typical of general programming languages but that were specialized to meet the needs of the clinical decision support environment, including integration into a clinical information system architecture. METHOD: Review of the design history and evolution of the Arden Syntax by workers who participated in this evolution from the perspective of the standards development organization (SDO). RESULTS: In order to meet user needs, a variety of features were successively incorporated in Arden Syntax. These can be grouped in several classes of change, including control flow, data structures, operators and external links. These changes included expansion of operators to manipulate lists and strings; a formalism for structured output; iteration constructs; user-defined objects and operators to manipulate them; features to support international use and output in different natural languages; additional control features; fuzzy logic formalisms; and mapping of the entire syntax to XML. The history and rationale of this evolution are summarized. CONCLUSION: In response to user demand and to reflect its growing role in clinical decision support, the Arden Syntax has evolved to include a number of powerful features. These depart somewhat from the original vision of the syntax as simple and easily understandable but from the SDO perspective increase the utility of this standard for implementation of CDS. Backwards compatibility has been maintained, allowing continued support of the earlier, simpler decision support models. PMID- 27773564 TI - Evaluation of the eyebrow position after levator resection. AB - Although we commonly observe eyebrow drooping during and after blepharoptosis surgery, it may not occur in some cases. After levator resection was performed in 47 patients (84 eyelids) with blepharoptosis, the eyebrow heights at the medial canthus, the center of the pupil, and the lateral canthus were measured using scanned photographs obtained preoperatively and 3 months postoperatively. In the 84 eyelids, after levator resection, the eyebrow position was lowered at the medial canthus in 76 patients (90%), at the center of the pupil in 75 (89%), and at the lateral canthus in 76 (90%). The mean distance of eyebrow drooping in the 84 pupils was 2.74 mm at the medial canthus, 2.91 mm at the center of the pupil, and 2.58 mm at the lateral canthus. In addition, there was a significant difference between the extra skin excision group and the no skin excision group at the medial canthus (p = 0.027), the center of the pupil (p = 0.001), and the lateral canthus (p < 0.001) (Mann-Whitney test). Unfortunately, there was a significant difference in ages between the extra skin excision group and the no skin excision group. In conclusion, eyebrow drooping was caused after levator resection in most cases. However, it is difficult to anticipate eyebrow drooping distance before surgery. PMID- 27773565 TI - The cytotoxic activity of miltefosine against Leishmania and macrophages is associated with dynamic changes in plasma membrane proteins. AB - In this study, we combined electron paramagnetic resonance (EPR) spectroscopy with an analysis of biophysical cellular parameters to study the mechanisms underlying the in vitro anti-leishmanial activity of miltefosine (MT). A thiol specific spin label attached to membrane-bound proteins of Leishmania amazonensis and peritoneal macrophages indicated that MT may bind to plasma membrane proteins in large quantities via a detergent-like action and cause structural changes associated with a marked increase in dynamics and exposure to an aqueous environment. EPR spectra of a spin-labeled stearic acid indicated strong interactions between the probe and membrane proteins and a marked increase in the membrane fluidity of MT-treated cells. The cytotoxicity of MT was found to depend on the cell concentration used in the assay. This dependence was described by an equation involving the 50% inhibitory concentrations of MT in the aqueous medium (cw50) and the cell membrane (cm50) and the membrane-aqueous medium partition coefficient of MT (K). With a cw50 of 8.7MUM, macrophages were less sensitive to MT than amastigotes and promastigotes of Leishmania, which had cw50 values of 2.4 3.1MUM. The estimated cm50 of MT for Leishmania was 1.8M, which appears sufficient to cause ruptures or formation of pores in the plasma membrane. Additionally, we demonstrated that the changes in the plasma membrane detected by EPR spectroscopy occurred at cytotoxic concentrations of MT, as assessed through in vitro assays. PMID- 27773566 TI - Behavioral and Neural Indices of Metacognitive Sensitivity in Preverbal Infants. AB - Humans adapt their behavior not only by observing the consequences of their actions but also by internally monitoring their performance. This capacity, termed metacognitive sensitivity [1, 2], has traditionally been denied to young children because they have poor capacities in verbally reporting their own mental states [3-5]. Yet, these observations might reflect children's limited capacities for explicit self-reports, rather than limitations in metacognition per se. Indeed, metacognitive sensitivity has been shown to reflect simple computational mechanisms [1, 6-8], and can be found in various non-verbal species [7-10]. Thus, it might be that this faculty is present early in development, although it would be discernible through implicit behaviors and neural indices rather than explicit self-reports. Here, by relying on such non-verbal indices, we show that 12- and 18-month-old infants internally monitor the accuracy of their own decisions. At the behavioral level, infants showed increased persistence in their initial choice after making a correct as compared to an incorrect response, evidencing an appropriate evaluation of decision confidence. Moreover, infants were able to use decision confidence adaptively to either confirm their initial choice or change their mind. At the neural level, we found that a well-established electrophysiological signature of error monitoring in adults, the error-related negativity, is similarly elicited when infants make an incorrect choice. Hence, although explicit forms of metacognition mature later during childhood, infants already estimate decision confidence, monitor their errors, and use these metacognitive evaluations to regulate subsequent behavior. PMID- 27773567 TI - Vision Drives Accurate Approach Behavior during Prey Capture in Laboratory Mice. AB - The ability to genetically identify and manipulate neural circuits in the mouse is rapidly advancing our understanding of visual processing in the mammalian brain [1, 2]. However, studies investigating the circuitry that underlies complex ethologically relevant visual behaviors in the mouse have been primarily restricted to fear responses [3-5]. Here, we show that a laboratory strain of mouse (Mus musculus, C57BL/6J) robustly pursues, captures, and consumes live insect prey and that vision is necessary for mice to perform the accurate orienting and approach behaviors leading to capture. Specifically, we differentially perturbed visual or auditory input in mice and determined that visual input is required for accurate approach, allowing maintenance of bearing to within 11 degrees of the target on average during pursuit. While mice were able to capture prey without vision, the accuracy of their approaches and capture rate dramatically declined. To better explore the contribution of vision to this behavior, we developed a simple assay that isolated visual cues and simplified analysis of the visually guided approach. Together, our results demonstrate that laboratory mice are capable of exhibiting dynamic and accurate visually guided approach behaviors and provide a means to estimate the visual features that drive behavior within an ethological context. PMID- 27773568 TI - Termination of Shoot Gravitropic Responses by Auxin Feedback on PIN3 Polarity. AB - Plants adjust their growth according to gravity. Gravitropism involves gravity perception, signal transduction, and asymmetric growth response, with organ bending as a consequence [1]. Asymmetric growth results from the asymmetric distribution of the plant-specific signaling molecule auxin [2] that is generated by lateral transport, mediated in the hypocotyl predominantly by the auxin transporter PIN-FORMED3 (PIN3) [3-5]. Gravity stimulation polarizes PIN3 to the bottom sides of endodermal cells, correlating with increased auxin accumulation in adjacent tissues at the lower side of the stimulated organ, where auxin induces cell elongation and, hence, organ bending. A curvature response allows the hypocotyl to resume straight growth at a defined angle [6], implying that at some point auxin symmetry is restored to prevent overbending. Here, we present initial insights into cellular and molecular mechanisms that lead to the termination of the tropic response. We identified an auxin feedback on PIN3 polarization as underlying mechanism that restores symmetry of the PIN3-dependent auxin flow. Thus, two mechanistically distinct PIN3 polarization events redirect auxin fluxes at different time points of the gravity response: first, gravity mediated redirection of PIN3-mediated auxin flow toward the lower hypocotyl side, where auxin gradually accumulates and promotes growth, and later PIN3 polarization to the opposite cell side, depleting this auxin maximum to end the bending. Accordingly, genetic or pharmacological interference with the late PIN3 polarization prevents termination of the response and leads to hypocotyl overbending. This observation reveals a role of auxin feedback on PIN polarity in the termination of the tropic response. PMID- 27773569 TI - Loss and Re-emergence of Legs in Snakes by Modular Evolution of Sonic hedgehog and HOXD Enhancers. AB - Limb reduction and loss are hallmarks of snake evolution. Although advanced snakes are completely limbless, basal and intermediate snakes retain pelvic girdles and small rudiments of the femur. Moreover, legs may have re-emerged in extinct snake lineages [1-5], suggesting that the mechanisms of limb development were not completely lost in snakes. Here we report that hindlimb development arrests in python embryos as a result of mutations that abolish essential transcription factor binding sites in the limb-specific enhancer of Sonic hedgehog (SHH). Consequently, SHH transcription is weak and transient in python hindlimb buds, leading to early termination of a genetic circuit that drives limb outgrowth. Our results suggest that degenerate evolution of the SHH limb enhancer played a role in reduction of hindlimbs during snake evolution. By contrast, HOXD digit enhancers are conserved in pythons, and HOXD gene expression in the hindlimb buds progresses to the distal phase, forming an autopodial (digit) domain. Python hindlimb buds then develop transitory pre-chondrogenic condensations of the tibia, fibula, and footplate, raising the possibility that re-emergence of hindlimbs during snake evolution did not require de novo re evolution of lost structures but instead could have resulted from persistence of embryonic legs. VIDEO ABSTRACT. PMID- 27773570 TI - Reversed Procrastination by Focal Disruption of Medial Frontal Cortex. AB - An enduring puzzle in the neuroscience of voluntary action is the origin of the remarkably wide dispersion of the reaction time distribution, an interval far greater than is explained by synaptic or signal transductive noise [1, 2]. That we are able to change our planned actions-a key criterion of volition [3]-so close to the time of their onset implies decision-making must reach deep into the execution of action itself [4-6]. It has been influentially suggested the reaction time distribution therefore reflects deliberate neural procrastination [7], giving alternative response tendencies sufficient time for fair competition in pursuing a decision threshold that determines which one is behaviorally manifest: a race model, where action selection and execution are closely interrelated [8-11]. Although the medial frontal cortex exhibits a sensitivity to reaction time on functional imaging that is consistent with such a mechanism [12 14], direct evidence from disruptive studies has hitherto been lacking. If movement-generating and movement-delaying neural substrates are closely co localized here, a large-scale lesion will inevitably mask any acceleration, for the movement itself could be disrupted. Circumventing this problem, here we observed focal intracranial electrical disruption of the medial frontal wall in the context of the pre-surgical evaluation of two patients with epilepsy temporarily reversing such hypothesized procrastination. Effector-specific behavioral acceleration, time-locked to the period of electrical disruption, occurred exclusively at a specific locus at the ventral border of the pre supplementary motor area. A cardinal prediction of race models of voluntary action is thereby substantiated in the human brain. PMID- 27773571 TI - NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum. AB - It is well recognized that G-protein-coupled receptors (GPCRs) can activate Ras regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here, we identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gbetagamma subunits in the striatum. We find that binding of Gbetagamma to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates its coupling to Akt-mTOR signaling pathway. By acting in the striatal medium spiny neurons of the direct pathway, NF1 regulates opioid-induced changes in Ras activity, thereby sensitizing mice to psychomotor and rewarding effects of morphine. These results delineate a novel mechanism of GPCR signaling to Ras pathways and establish a critical role of NF1 in opioid addiction. PMID- 27773572 TI - Neural Basis for Economic Saving Strategies in Human Amygdala-Prefrontal Reward Circuits. AB - Economic saving is an elaborate behavior in which the goal of a reward in the future directs planning and decision-making in the present. Here, we measured neural activity while subjects formed simple economic saving strategies to accumulate rewards and then executed their strategies through choice sequences of self-defined lengths. Before the initiation of a choice sequence, prospective activations in the amygdala predicted subjects' internal saving plans and their value up to two minutes before a saving goal was achieved. The valuation component of this planning activity persisted during execution of the saving strategy and predicted subjects' economic behavior across different tasks and testing days. Functionally coupled amygdala and prefrontal cortex activities encoded distinct planning components that signaled the transition from saving strategy formation to execution and reflected individual differences in saving behavior. Our findings identify candidate neural mechanisms for economic saving in amygdala and prefrontal cortex and suggest a novel planning function for the human amygdala in directing strategic behavior toward self-determined future rewards. PMID- 27773574 TI - A case study: Glycosaminoglycan profiles of autologous chondrocyte implantation (ACI) tissue improve as the tissue matures. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) has been used to treat cartilage defects in thousands of patients worldwide with good clinical effectiveness 10-20years after implantation. Information concerning the quality of the repair cartilage is still limited because biopsies are small and rare. Glycosaminoglycan structure influences physiological function and is likely to be important in the long term stability of the repair tissue. The aim of this study was to assess glycosaminoglycans in ACI tissue over a two year period. METHODS: Biopsies were taken from one patient (25years old) at 12months and 20months post ACI-treatment and from three normal cadavers (21, 22 and 25years old). Fluorophore-assisted carbohydrate electrophoresis (FACE) was used to quantitatively assess the individual glycosaminoglycans. RESULTS: At 12months the ACI biopsy had 40% less hyaluronan than the age-matched cadaveric biopsies but by 20months the ACI biopsy had the same amount of hyaluronan as the controls. Both the 12 and 20month ACI biopsies had less chondroitin sulphate disaccharides and shorter chondroitin sulphate chains than the age-matched cadaveric biopsies. However, chondroitin sulphate chain length doubled as the ACI repair tissue matured at 12months (3913Da+/-464) and 20months (6923Da+/-711) and there was less keratan sulphate as compared to the controls. CONCLUSIONS: Although the glycosaminoglycan composition of the repair tissue is not identical to mature articular cartilage its quality continues to improve with time. PMID- 27773575 TI - Efficacy of a newly modified technique for distal limited open stenting in octogenarians with aortic arch aneurysm. AB - OBJECTIVE: We assessed the efficacy of distal limited open stenting procedure in octogenarians with distal aortic arch aneurysm. METHODS: During the last 5 years, 24 patients underwent distal limited open stenting. Mean patient age was 81.6 +/- 2.5 years, ranging from 80 to 90 years. The hemicircumference of the anterior surface of the arch around the left common carotid artery was obliquely incised, and a J-Graft Open Stent (Japan Lifeline Co, Ltd, Tokyo, Japan) was inserted into the descending aorta. During open stenting, circulatory arrest was induced at a rectal temperature of 28 degrees C without any cerebral perfusion. As soon as the proximal side of the stent graft and aortic incision were concomitantly sutured, rapid rewarming was initiated through heated blood perfusion. RESULTS: The durations of circulatory arrest, aortic crossclamping, cardiopulmonary bypass, the overall operation, postoperative mechanical ventilation, and hospital stay were 17.0 minutes, 27.8 minutes, 106.1 minutes, 167.6 minutes, 11.0 hours, and 13.9 days, respectively. The in-hospital mortality was 0%. There were no incidences of brain damage, renal failure, or respiratory failure. At the time of this study, 21 patients were doing well and visiting the outpatient clinic, and 19 scored more than 20 points on the Mini-Mental State Examination, indicating no development of dementia. The actuarial survival at 5 years was 82.4%. CONCLUSIONS: This unique technique is safe and effective. It is a very attractive procedure that can contribute to maintaining a good long-term quality of life for octogenarians with distal aortic arch aneurysm. PMID- 27773577 TI - Surgical economics: MACRA, MIPS, and bundles-Lessons learned in the first 3 years of a coronary artery bypass grafting alternative payment model. PMID- 27773576 TI - In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: Implications for clinical myocardial regeneration. AB - OBJECTIVE: The reprogramming of cardiac fibroblasts into induced cardiomyocyte like cells improves ventricular function in myocardial infarction models. Only integrating persistent expression vectors have thus far been used to induce reprogramming, potentially limiting its clinical applicability. We therefore tested the reprogramming potential of nonintegrating, acute expression adenoviral (Ad) vectors. METHODS: Ad or lentivirus vectors encoding Gata4 (G), Mef2c (M), and Tbx5 (T) were validated in vitro. Sprague-Dawley rats then underwent coronary ligation and Ad-mediated administration of vascular endothelial growth factor to generate infarct prevascularization. Three weeks later, animals received Ad or lentivirus encoding G, M, or T (AdGMT or LentiGMT) or an equivalent dose of a null vector (n = 11, 10, and 10, respectively). Outcomes were analyzed by echocardiography, magnetic resonance imaging, and histology. RESULTS: Ad and lentivirus vectors provided equivalent G, M, and T expression in vitro. AdGMT and LentiGMT both likewise induced expression of the cardiomyocyte marker cardiac troponin T in approximately 6% of cardiac fibroblasts versus <1% cardiac troponin T expression in AdNull (adenoviral vector that does not encode a transgene) treated cells. Infarcted myocardium that had been treated with AdGMT likewise demonstrated greater density of cells expressing the cardiomyocyte marker beta myosin heavy chain 7 compared with AdNull-treated animals. Echocardiography demonstrated that AdGMT and LentiGMT both increased ejection fraction compared with AdNull (AdGMT: 21% +/- 3%, LentiGMT: 14% +/- 5%, AdNull: -0.4% +/- 2%; P < .05). CONCLUSIONS: Ad vectors are at least as effective as lentiviral vectors in inducing cardiac fibroblast transdifferentiation into induced cardiomyocyte-like cells and improving cardiac function in postinfarct rat hearts. Short-term expression Ad vectors may represent an important means to induce cardiac cellular reprogramming in humans. PMID- 27773573 TI - A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive alpha-Dicarbonyl Detoxification. AB - Reactive alpha-dicarbonyls (alpha-DCs), like methylglyoxal (MGO), accumulate with age and have been implicated in aging and various age-associated pathologies, such as diabetic complications and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Evolutionarily conserved glyoxalases are responsible for alpha-DC detoxification; however, their core biochemical regulation has remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase (glod-4/GLO1), to broadly study alpha-DC-related stress. We show that, in comparison to wild-type (N2, Bristol), glod-4 animals rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for alpha-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify alpha-DCs. Interestingly, this pathway is in stark contrast to the TRPA 1 activation and the ensuing calcium flux implicated in cold sensation in C. elegans, whereby DAF-16/FOXO gets activated via complementary kinase signaling. Finally, a phenotypic drug screen using C. elegans identified podocarpic acid as a novel activator of TRPA1 that rescues alpha-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of alpha-DC stress, which represents a viable option to address aging-related pathologies in diabetes and neurodegenerative diseases. PMID- 27773578 TI - Is subvalvular repair worthwhile in severe ischemic mitral regurgitation? Subanalysis of the Papillary Muscle Approximation trial. AB - OBJECTIVE: The symmetry of mitral valve tethering and regional left ventricle wall dysfunction are reported to play a fundamental role in the outcomes and long term durability of surgical repair in ischemic mitral regurgitation (IMR). We recently demonstrated in a randomized clinical trial (the Papillary Muscle Approximation trial) the superiority of papillary muscle approximation (PMA) in combination with standard restrictive annuloplasty (RA) in severe IMR over annuloplasty alone in terms of adverse left ventricular remodeling and mitral regurgitation (MR) recurrence. This approach, however, failed to produce a survival advantage and was still plagued by a high incidence of reoperation. We therefore performed a subanalysis of the PMA trial on the basis of preoperative parameters to elucidate the value of subvalvular surgery in certain subcategories of patients with the aim of creating a decisional algorithm on the best operative strategy. METHODS: We performed a subanalysis of PMA trial, evaluating 96 patients with severe IMR and eligible for myocardial revascularization randomized to PMA + RA (n = 48) versus RA alone (n = 48) in association with coronary artery bypass grafting. Endpoints included left ventricular remodeling, MR recurrence, overall mortality, reoperation, and a composite cardiac endpoint (cardiac death, stroke, reintervention, hospitalization for heart failure, or New York Heart Association class worsening). Stratification variables were preoperative symmetry of mitral valve tethering and regional wall motion abnormality. RESULTS: PMA improved ventricular remodeling and recurrence of MR in both preoperative symmetric and asymmetric tethering and in case of inferior wall dyskinesia but did not produce an additional benefit in anterolateral wall dysfunction. CONCLUSIONS: Preoperative symmetric and asymmetric tethering and isolated inferior wall dyskinesia are an indication for subvalvular apparatus surgery in IMR. PMID- 27773579 TI - Non-Infectious Lead Extractions: Enemy of Good? PMID- 27773580 TI - Heartmate II Inflow Path Thrombosis: Emphasis on a Comprehensive Approach to Diagnosis. PMID- 27773581 TI - Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System. AB - HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ~2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1. VIDEO ABSTRACT. PMID- 27773582 TI - Fast 3D Imaging of Spine, Dendritic, and Neuronal Assemblies in Behaving Animals. AB - Understanding neural computation requires methods such as 3D acousto-optical (AO) scanning that can simultaneously read out neural activity on both the somatic and dendritic scales. AO point scanning can increase measurement speed and signal-to noise ratio (SNR) by several orders of magnitude, but high optical resolution requires long point-to-point switching time, which limits imaging capability. Here we present a novel technology, 3D DRIFT AO scanning, which can extend each scanning point to small 3D lines, surfaces, or volume elements for flexible and fast imaging of complex structures simultaneously in multiple locations. Our method was demonstrated by fast 3D recording of over 150 dendritic spines with 3D lines, over 100 somata with squares and cubes, or multiple spiny dendritic segments with surface and volume elements, including in behaving animals. Finally, a 4-fold improvement in total excitation efficiency resulted in about 500 * 500 * 650 MUm scanning volume with genetically encoded calcium indicators (GECIs). PMID- 27773583 TI - Molecular fMRI of Serotonin Transport. AB - Reuptake of neurotransmitters from the brain interstitium shapes chemical signaling processes and is disrupted in several pathologies. Serotonin reuptake in particular is important for mood regulation and is inhibited by first-line drugs for treatment of depression. Here we introduce a molecular-level fMRI technique for micron-scale mapping of serotonin transport in live animals. Intracranial injection of an MRI-detectable serotonin sensor complexed with serotonin, together with serial imaging and compartmental analysis, permits neurotransmitter transport to be quantified as serotonin dissociates from the probe. Application of this strategy to much of the striatum and surrounding areas reveals widespread nonsaturating serotonin removal with maximal rates in the lateral septum. The serotonin reuptake inhibitor fluoxetine selectively suppresses serotonin removal in septal subregions, whereas both fluoxetine and a dopamine transporter blocker depress reuptake in striatum. These results highlight promiscuous pharmacological influences on the serotonergic system and demonstrate the utility of molecular fMRI for characterization of neurochemical dynamics. PMID- 27773584 TI - Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination. AB - Developmental axon remodeling is characterized by the selective removal of branches from axon arbors. The mechanisms that underlie such branch loss are largely unknown. Additionally, how neuronal resources are specifically assigned to the branches of remodeling arbors is not understood. Here we show that axon branch loss at the developing mouse neuromuscular junction is mediated by branch specific microtubule severing, which results in local disassembly of the microtubule cytoskeleton and loss of axonal transport in branches that will subsequently dismantle. Accordingly, pharmacological microtubule stabilization delays neuromuscular synapse elimination. This branch-specific disassembly of the cytoskeleton appears to be mediated by the microtubule-severing enzyme spastin, which is dysfunctional in some forms of upper motor neuron disease. Our results demonstrate a physiological role for a neurodegeneration-associated modulator of the cytoskeleton, reveal unexpected cell biology of branch-specific axon plasticity and underscore the mechanistic similarities of axon loss in development and disease. PMID- 27773586 TI - Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. AB - BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the alpha-galactosidase A gene (GLA) that result in absent or markedly reduce alpha-galactosidase A (alpha-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte alpha-GalA activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring. METHODS: Among our GLA mutation proven FD patients, we screened 18 heterozygotes whose leukocyte alpha GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. RESULTS: We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte alpha-GalA activities were in the normal range. CONCLUSION: LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring. PMID- 27773585 TI - Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer. PMID- 27773587 TI - Clinical relevance commentary in response to: Relative motion orthoses in the management of various hand conditions: A scoping review. PMID- 27773589 TI - The Role of Left Atrial Volume Index in Patients with a First-ever Acute Ischemic Stroke. AB - BACKGROUND: Although an enlarged left atrium has recently emerged as a marker of adverse outcomes in various diseases, its discriminatory value and prognostic role in acute ischemic stroke (AIS) are not well studied. We studied whether left atrial volume index (LAVI) predicts mortality and discriminates stroke subtypes after AIS. METHODS: We prospectively followed 310 consecutive first-ever AIS patients aged 50 years or older who were admitted to the hospital within 24 hours of the onset of stroke symptoms. The type of AIS was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. All of the patients underwent transthoracic echocardiography within the first 24 hours. LAVI was measured with the biplane area-length method and categorized as 28 mL/m2 or lower (normal), 28.1-32 mL/m2, 32.1-36 mL/m2, and >36 mL/m2. The patients were followed for 1 year or until death, whichever came first. RESULTS: The LAVI of the cardioembolic group was significantly higher than that of the noncardioembolic group (32.4 +/- 4.0 versus 29.7 +/- 3.4 mL/m2, respectively; P < .001). The optimal cutoff value, sensitivity, and specificity of LAVI to distinguish cardioembolic stroke from noncardioembolic stroke were 30 mL/m2, 81%, and 64%, respectively. Mortality in each LAVI category was 4%, 7.8%, 25.9%, and 70.9%, respectively (P = .026). Kaplan-Meier analysis showed that there was a stepwise increase in risk of mortality with each increment of LAVI category. CONCLUSIONS: The LAVI can distinguish cardioembolic stroke from noncardioembolic stroke and provides an independent information over clinical and other echocardiographic variables for predicting mortality in patients with first-ever AIS. PMID- 27773588 TI - Differences in active range of motion measurements in the upper extremity of patients with writer's cramp compared with healthy controls. AB - STUDY DESIGN: Exploratory case-control study. INTRODUCTION: Writer's cramp (WC) is a type of focal hand dystonia. The central nervous system plays a role in its pathophysiology, but abnormalities in the affected musculoskeletal components may also be relevant. PURPOSE OF THE STUDY: We compared the active range of motion (ROM) in patients with WC and healthy volunteers (HVs) and correlated the findings with disease duration and severity. METHODS: Affected limb joints were measured with goniometers. Patients were assessed at least 3 months after their last botulinum toxin (botulinum neurotoxin) injection, and strength was clinically normal. t tests were used to compare the ROMs of WC with matched HVs. The Spearman correlation coefficient assessed the relationship of active ROMs to the disease duration and handwriting subscore of the Dystonia Disability Scale. RESULTS: ROMs of D1 metacarpophalangeal (MCP) joint extension as well as D2 and D5 MCP flexion were significantly smaller in WC, and distal interphalangeal joint extension in D3 and D5 was significantly greater compared with HVs. There were negative correlations between D2 MCP flexion and disease duration and with Dystonia Disability Scale. DISCUSSION: Abnormalities in ROMs in WC were found. Severity and disease duration correlated with reduced D2 MCP flexion. This may be related to intrinsic biomechanical abnormalities, co-contraction of muscles, or a combination of subclinical weakness and atrophy from repeated botulinum neurotoxin injections. CONCLUSIONS: Hand biomechanical properties should not be ignored in the pathophysiology of WC. LEVEL OF EVIDENCE: 2c. PMID- 27773590 TI - Variant Type of Posterior Reversible Encephalopathy Syndrome with Diffuse Cerebral White Matter and Brainstem Involvement Associated with Intracranial Hemorrhage. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological syndrome characterized by reversible vasogenic edema typically at a posterior location of the cerebrum. PRES with prominent brainstem or basal ganglia involvement is defined as central-variant, which is rare. We herein report an atypical case of a 35-year-old man with a 2-year history of untreated hypertension who complained of recurrent dizziness. The patient presented with brainstem and diffuse white matter involvement associated with intracranial hemorrhage and recovered fully after therapy. Recognition of this uncommon benign syndrome as a potentially treatable disorder can be of great importance. PMID- 27773591 TI - Diagnostic and prognostic significance of systemic alkyl quinolones for P. aeruginosa in cystic fibrosis: A longitudinal study. AB - BACKGROUND: Pulmonary P. aeruginosa infection is associated with poor outcomes in cystic fibrosis (CF) and early diagnosis is challenging, particularly in those who are unable to expectorate sputum. Specific P. aeruginosa 2-alkyl-4-quinolones are detectable in the sputum, plasma and urine of adults with CF, suggesting that they have potential as biomarkers for P. aeruginosa infection. AIM: To investigate systemic 2-alkyl-4-quinolones as potential biomarkers for pulmonary P. aeruginosa infection. METHODS: A multicentre observational study of 176 adults and 68 children with CF. Cross-sectionally, comparisons were made between current P. aeruginosa infection using six 2-alkyl-4-quinolones detected in sputum, plasma and urine against hospital microbiological culture results. All participants without P. aeruginosa infection at baseline were followed up for one year to determine if 2-alkyl-4-quinolones were early biomarkers of pulmonary P. aeruginosa infection. RESULTS: Cross-sectional analysis: the most promising biomarker with the greatest diagnostic accuracy was 2-heptyl-4-hydroxyquinoline (HHQ). In adults, areas under the ROC curves (95% confidence intervals) for HHQ analyses were 0.82 (0.75-0.89) in sputum, 0.76 (0.69-0.82) in plasma and 0.82 (0.77-0.88) in urine. In children, the corresponding values for HHQ analyses were 0.88 (0.77-0.99) in plasma and 0.83 (0.68-0.97) in urine. Longitudinal analysis: Ten adults and six children had a new positive respiratory culture for P. aeruginosa in follow-up. A positive plasma HHQ test at baseline was significantly associated with a new positive culture for P. aeruginosa in both adults and children in follow-up (odds ratio (OR)=6.67;-95% CI:-1.48-30.1;-p=0.01 and OR=70; 95% CI: 5-956;-p<0.001 respectively). CONCLUSIONS: AQs measured in sputum, plasma and urine may be used to diagnose current infection with P. aeruginosa in adults and children with CF. These preliminary data show that plasma HHQ may have potential as an early biomarker of pulmonary P. aeruginosa. Further studies are necessary to evaluate if HHQ could be used in clinical practice to aid early diagnosis of P. aeruginosa infection in the future. PMID- 27773592 TI - Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor. AB - Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor. The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials. For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV1 were not correlated for individual patients. However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV1 changes was observed (p<0.0001). Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals. PMID- 27773593 TI - FOXK2 Elicits Massive Transcription Repression and Suppresses the Hypoxic Response and Breast Cancer Carcinogenesis. AB - Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1beta and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERalpha and transrepressed via reciprocal successive feedback by HIF1beta/EZH2. Significantly, the expression of FOXK2 is progressively lost during breast cancer progression, and low FOXK2 expression is strongly correlated with higher histologic grades, positive lymph nodes, and ERalpha-/PR-/HER2- status, all indicators of poor prognosis. PMID- 27773595 TI - Changes in corticospinal excitability during consolidation predict acute exercise induced off-line gains in procedural memory. AB - A single bout of cardiovascular exercise performed immediately after practicing a motor task improves the long-term retention of the skill through an optimization of memory consolidation. However, the specific brain mechanisms underlying the effects of acute cardiovascular exercise on procedural memory are poorly understood. We sought to determine if a single bout of exercise modifies corticospinal excitability (CSE) during the early stages of memory consolidation. In addition, we investigated if changes in CSE are associated with exercise induced off-line gains in procedural memory. Participants practiced a serial reaction time task followed by either a short bout of acute exercise or a similar rest period. To monitor changes in CSE we used transcranial magnetic stimulation applied to the primary motor cortex (M1) at baseline, 15, 35, 65 and 125min after exercise or rest. Participants in the exercise condition showed larger (~24%) improvements in procedural memory through consolidation although differences between groups did not reach statistical significance. Exercise promoted an increase in CSE, which remained elevated 2h after exercise. More importantly, global increases in CSE following exercise correlated with the magnitude of off line gains in skill level assessed in a retention test performed 8h after motor practice. A single bout of exercise modulates short-term neuroplasticity mechanisms subserving consolidation processes that predict off-line gains in procedural memory. PMID- 27773594 TI - 5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5 HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. PMID- 27773597 TI - The beneficial place for the treatment of ruptured abdominal aortic aneurysms. AB - OBJECTIVE: To study the beneficial place for the treatment of ruptured abdominal aortic aneurysms (RAAAs). METHOD: A retrospective chart review of consecutive RAAA patients was performed. Patients were divided into two groups: direct group and transfer group. We retrospectively reviewed patients' hospital charts and recorded various clinical factors apparent on presentation. The primary consequence was mortality during hospitalization, and some other parameters such as duration of intensive care unit (ICU). All patients were followed up at 1 month, 3 months, 6 months and one year after discharge. RESULTS: During 4-year period, 56 RAAA patients were treated (24 in direct group, and 32 in transfer group). Significant differences were shown for systolic blood pressure, pulse oxygen saturation, hemoglobin, the time interval from diagnosis to operation et al. There was no difference concerning age and comorbidity among two groups. All the patients were treated by open surgical aneurysm repair. The mortality rate was 68.8% ((6 + 16)/32) in transfer group and 33.3% (8/24) in direct group (P = 0.00067). Both the duration of ICU stay and entire hospitalization were a bit longer in the transfer group, but there was no significant difference. The mean follow-up time was 25.2 +/- 12.9 months. The cumulative survival difference was significant (P = 0.042) between the two groups. CONCLUSION: It is beneficial that we treat RAAAs in the diagnosed hospital. The reasons are: 1) to avoid the development of unstable state of aneurysm after rupturing of stable state; 2) the time interval from initial symptoms to operation will be shortened. PMID- 27773596 TI - Early antiretroviral therapy initiation: access and equity of viral load testing for HIV treatment monitoring. AB - Scaling up access to HIV viral load testing for individuals undergoing antiretroviral therapy in low-resource settings is a global health priority, as emphasised by research showing the benefits of suppressed viral load for the individual and the whole population. Historically, large-scale diagnostic test implementation has been slow and incomplete because of service delivery and other challenges. Building on lessons from the past, in this Personal View we propose a new framework to accelerate viral load scale-up and ensure equitable access to this essential test. The framework includes the following steps: (1) ensuring adequate financial investment in scaling up this test; (2) achieving pricing agreements and consolidating procurement to lower prices of the test; (3) strengthening functional tiered laboratory networks and systems to expand access to reliable, high-quality testing across countries; (4) strengthening national leadership, with prioritisation of laboratory services; and (5) demand creation and uptake of test results by clinicians, nurses, and patients, which will be vital in ensuring viral load tests are appropriately used to improve the quality of care. The use of dried blood spots to stabilise and ship samples from clinics to laboratories, and the use of point-of-care diagnostic tests, will also be important for ensuring access, especially in settings with reduced laboratory capacity. For countries that have just started to scale up viral load testing, lessons can be learnt from countries such as Botswana, Brazil, South Africa, and Thailand, which have already established viral load programmes. This framework might be useful for guiding the implementation of viral load with the aim of achieving the new global HIV 90-90-90 goals by 2020. PMID- 27773598 TI - Accuracy of conventional MRI for preoperative diagnosis of intracranial tumors: A retrospective cohort study of 762 cases. AB - BACKGROUND: Conventional magnetic resonance imaging (MRI) is considered a valuable tool for preoperative diagnosis of intracranial tumors. We assessed its accuracy in the diagnosis of intracranial tumors in usual clinical practice. MATERIALS AND METHODS: MRI reports of 762 patients who had undergone conventional brain MRI prior to surgery were retrospectively reviewed. A 4-grade scoring system was devised to establish diagnostic agreement. Each tumor type was compared with the corresponding pathological diagnoses by dichotomization. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the overall patient population as well as for each tumor type. RESULTS: 664 cases (87.1%) were tumor-positive, and 98 cases (12.9%) were tumor-negative. The most common tumor types were meningiomas, gliomas, pituitary adenomas and schwannomas. These four types together comprised 74.5% of all cases reviewed. Sensitivity and PPV for the overall population were 72.0-90.7% and 91.9-95.4%, respectively. Diagnostic accuracy differed among tumor types. Meningiomas, pituitary adenomas, schwannomas and cholesteatomas were more likely to be diagnosed correctly (sensitivities were 82.6-96.9%, 86.1-96.7%, 88.9-98.2% and 91.3-100.0%, respectively); while some other types like solitary fibrous tumors (SFTs) seemed difficult to identify. Gliomas tended to be confused with metastases, meningiomas with SFTs, and pituitary adenomas with craniopharyngiomas. CONCLUSION: The accuracy of conventional MRI for diagnosing intracranial tumors is generally satisfactory but should not be too heavily relied upon, especially for certain tumor types. In cases of discrepancy, neurosurgeons are encouraged to confer with the reporting neuroradiologists to achieve optimal preoperative diagnoses. PMID- 27773599 TI - Fast track for open hepatectomy: A systemic review and meta-analysis. AB - BACKGROUND: Liver resection (LR) is preferred treatment for malignancies or benign masses of liver. Using multiple elements, fast track (FT) program was introduced to abdominal surgery associating with fast functional recovery and shorter hospital length of stay (LoS). This meta-analysis aims to evaluate the effect of FT program for patients following liver resection. MATERIALS AND METHODS: We searched the PubMed/Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase for trials up to December 2015 to compare the FT program to the conventional group. The main outcome was assessed of complication rate (including liver specific or general complication rate), thirty-day postoperative mortality, readmission rate and the length of hospital stay. RESULTS: Four randomized control trials (RCTs) and three cohort trials (CTs) were to make a quantitative synthesis including 1027 patients. The LoS was reduced following FT groups (weighted mean difference [WMD], 2.24 days; 95% CI 3.69-0.79; P < 0.005). No significant differences were noted in overall complication (risk ratio [RR], 0.94; 95% CI, 0.79-1.12; p = 0.49), mortality (RR, 0.63; 95% CI, 0.19-2.15; p = 0.46) and readmission rate (RR, 0.99; 95% CI, 0.54-1.79; p = 0.97). However, the general complication showed a difference favoring FT group (RR, 0.68; 95% CI, 0.49-0.95; p = 0.03). CONCLUSIONS: This review, firstly using the quantitative synthesis in FT program following LR, indicates that FT program can shorten the length of hospital stay and accelerate the postoperative recovery in a safe and effective ways without increasing in mortality, morbidity and readmission rate. PMID- 27773600 TI - The physician-patient working alliance: Theory, research, and future possibilities. AB - OBJECTIVE: This article discusses the physician-patient working alliance and reviews the empirical research that has been generated on the working alliance to date. METHODS: The paper presents a brief history of the study of the physician patient relationship, and discusses constructs that have examined aspects of the relationship, such as empathy, trust, and shared decision-making. Lastly, a meta analysis was conducted based on the seven empirical studies (a total N of 1023 patients) that have examined the physician-patient working alliance. RESULTS: Results of the meta-analysis found medium to large effect sizes between the working alliance and various behavioral care indices. The working alliance is positively associated with patient adherence, satisfaction, and improved patient outcomes. CONCLUSION: Overall, the physician-patient working alliance provides researchers and medical-care providers with a unified construct that combines cognitive and affective dimensions inherent in the relationship in medical care. Furthermore, the PPWAI provides an efficient and inexpensive way to assess the physician-patient relationship in medical treatment. PRACTICE IMPLICATIONS: The present findings warrant the development of an intervention focused on working alliance training that could be offered to healthcare providers. PMID- 27773602 TI - Anterior process of the Calcaneum - Not to be missed. PMID- 27773601 TI - MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate. AB - 3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3*10mg/kg, ip) resulted in a reduction of 37-58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures. PMID- 27773603 TI - Threshold dose distribution and eliciting dose of cashew nut allergy. PMID- 27773604 TI - Engineering Escherichia coli to bind to cyanobacteria. AB - We engineered Escherichia coli cells to bind to cyanobacteria by heterologously producing and displaying lectins of the target cyanobacteria on their surface. To prove the efficacy of our approach, we tested this design on Microcystis aeruginosa with microvirin (Mvn), the lectin endogenously produced by this cyanobacterium. The coding sequence of Mvn was C-terminally fused to the ice nucleation protein NC (INPNC) gene and expressed in E. coli. Results showed that E. coli cells expressing the INPNC::Mvn fusion protein were able to bind to M. aeruginosa and the average number of E. coli cells bound to each cyanobacterial cell was enhanced 8-fold. Finally, a computational model was developed to simulate the binding reaction and help reconstruct the binding parameters. To our best knowledge, this is the first report on the binding of two organisms in liquid culture mediated by the surface display of lectins and it may serve as a novel approach to mediate microbial adhesion. PMID- 27773605 TI - Potential of water surface-floating microalgae for biodiesel production: Floating biomass and lipid productivities. AB - Microalgae have been accepted as a promising feedstock for biodiesel production owing to their capability of converting solar energy into lipids through photosynthesis. However, the high capital and operating costs, and high energy consumption, are hampering commercialization of microalgal biodiesel. In this study, the surface-floating microalga, strain AVFF007 (tentatively identified as Botryosphaerella sudetica), which naturally forms a biofilm on surfaces, was characterized for use in biodiesel production. The biofilm could be conveniently harvested from the surface of the water by adsorbing onto a polyethylene film. The lipid productivity of strain AVFF007 was 46.3 mg/L/day, allowing direct comparison to lipid productivities of other microalgal species. The moisture content of the surface-floating biomass was 86.0 +/- 1.2%, which was much lower than that of the biomass harvested using centrifugation. These results reveal the potential of this surface-floating microalgal species as a biodiesel producer, employing a novel biomass harvesting and dewatering strategy. PMID- 27773606 TI - Engineering a family 27 carbohydrate-binding module into an Aspergillus usamii beta-mannanase to perfect its enzymatic properties. AB - A family 27 carbohydrate-binding module of a Thermotoga maritima beta-mannanase (TmCBM27) was chosen from the carbohydrate-active enzyme database by computer aided design, possessing the lowest binding free energy with mannopentaose. To improve the enzymatic properties of a glycoside hydrolase family 5 beta-mannanase from Aspergillus usamii (AuMan5A), two fusion beta-mannanases, AuMan5A-F-M and AuMan5A-R-M, were designed by fusing a TmCBM27 into its C-terminus linked with a flexible peptide F (GGGGS)3 and rigid peptide R (EAAAK)3. Two fusion enzyme genes, Auman5A-F-m and Auman5A-R-m, were constructed as designed theoretically by overlapping PCR. Then, Auman5A and two fusion genes were expressed in Pichia pastoris GS115. Three recombinant beta-mannanases, reAuMan5A, reAuMan5A-F-M and reAuMan5A-R-M, were purified to homogeneity with specific activities of 230.6, 153.3 and 241.7 U/mg. The temperature optimum of reAuMan5A-R-M was 70 degrees C, identical with that of reAuMan5A, while its thermostability and melting temperature (Tm) reached 68 degrees C and 74.9 degrees C, being 8.0 degrees C and 8.4 degrees C higher than those of the latter, respectively. Additionally, the Km values of reAuMan5A-R-M, towards locust bean gum, konjac gum and guar gum, significantly decreased to 0.9, 1.9 and 2.5 mg/mL from 1.7, 3.8 and 4.2 mg/mL of reAuMan5A, while its kcat/Km (catalytic efficiency) values increased to 287.8, 163.7 and 84.4 mL/mg?s from 171.2, 97.6 and 56.0 mL/mg?s of the latter, respectively. These results verified that the fusion of a TmCBM27 into the C terminus of AuMan5A mediated by (EAAAK)3 linker contributed to its improved thermostability and catalytic efficiency. PMID- 27773607 TI - Identification of 4-mercapto-4-methylpentan-2-one as the characteristic aroma of sake made from low-glutelin rice. AB - The grassy characteristic aroma perceived in brewed sake made from low-glutelin rice (Oryza sativa L. Mizuhonoka) was examined by gas chromatography-olfactometry and gas chromatography-mass spectrometry. By comparing the odor properties and Kovats retention indices to those of standard compounds, 4-mercapto-4 methylpentan-2-one (4MMP) was found to contribute to the characteristic aroma. Sake brewing using Mizuhonoka, low-glutelin rice, and Gin-ohmi (a control) revealed that 4MMP concentrations in Mizuhonoka sake samples were higher than those in Gin-ohmi samples over the fermentation period. The concentration in final Mizuhonoka sake was twice that of Gin-ohmi. To investigate the mechanism of 4MMP formation, the putative precursors, 4-S-cycteinyl-4-methylpentan-2-one (cys 4MMP) and 4-S-glutathionyl-4-methylpentan-2-one (glut-4MMP), in sake and its materials (rice and koji) were analyzed by ultra-performance liquid chromatography tandem mass-spectrometry. Cys-4MMP was not detected in all samples, while glut-4MMP was present in sake and its materials. The glut-4MMP concentration in sake was lower than that in Gin-ohmi over nearly the entire fermentation period, suggesting that conversion of the precursors to 4MMP was more effective in the mash of low-glutelin rice Mizuhonoka than in Gin-ohmi. The release of 4MMP during alcoholic fermentation from a model medium containing its precursors was examined. While no 4MMP release was observed in the control (no addition), with the addition of its precursors, the release of 4MMP increased as fermentation progressed. It was suggested that 4MMP was generated from both cys- and glut-4MMP by sake yeast. The perception threshold of 4MMP in sake was determined as 1.2 ng/L. PMID- 27773608 TI - Breastfeeding initiation and support: A literature review of what women value and the impact of early discharge. AB - PROBLEM: Early discharge following birth has become an emerging phenomenon in many countries. It is likely early discharge has an impact on the establishment of breastfeeding. OBJECTIVE: To critically appraise the evidence on what women value in relation to breastfeeding initiation and support, and investigate the impact early discharge can have on these values. METHOD: A literature search was conducted for publications since 2005 using the following databases: Cumulative Index of Nursing and Allied Health Literature (CINAHL), Medline, Scopus and PsycINFO; 21 primary articles were selected and included in the review. FINDINGS: There is no standard definition for 'early discharge' worldwide. Due to inconsistent definitions worldwide and minimal literature using a 24h definition, research defining early discharge as up to 72h postpartum is included. Seven key factors in relation to breastfeeding initiation and support following early discharge were identified, namely trust and security, consistent advice, practical breastfeeding support, breastfeeding education, comfortable environment, positive attitudes and emotional support, and individualised care. CONCLUSION: The findings suggest individualised postnatal lengths of stay may be beneficial for the initiation of breastfeeding. Five values were not impacted by early discharge, but rather individual midwives' practice. There is consensus in the literature that early discharge promoted a comfortable environment to support breastfeeding initiation. Wide variations in the definition of early postnatal discharge made it difficult to draw influential conclusions. Therefore, further research is required. PMID- 27773609 TI - Impact of intervention on breastfeeding outcomes and determinants based on theory of planned behavior. AB - BACKGROUND: Breastfeeding knowledge, attitude, subjective norm, and perceived control are significant determinants of breastfeeding, according to the theory of planned behavior (TPB). However, evidence concerning the effectiveness of the TPB based intervention in breastfeeding promotion is sparse. Meanwhile, the changes of these determinants with time have not been examined in previous studies. AIM: To investigate the effectiveness of the TPB-based intervention program in improving exclusive breastfeeding, and the interaction of time and intervention on these determinants of breastfeeding. METHODS: 285 primiparous mothers were included, with 157 mothers in the experimental group and 128 mothers in the control group. The experimental group received the TPB-based intervention program delivered during 6 weeks postpartum, while both the experimental and control groups received the standard obstetric care. FINDINGS: Scores of breastfeeding knowledge, attitude and breastfeeding control increased with time from baseline to 6 weeks postpartum, while breastfeeding subjective norm decreased at 6 weeks both in the experimental and the control groups. Besides, scores of the four determinants were significantly higher in the experimental group than these in the control group at 3days and 6 weeks, except for breastfeeding control at 6 weeks, which resulted in the higher exclusive breastfeeding rates at 3days and 6 weeks in the experimental group than the control group. DISCUSSION AND CONCLUSIONS: The TPB-based intervention was effective in promoting exclusive breastfeeding during 6 weeks postpartum. Future interventions are recommended to adjust intervention strategies with time, and give more focus on providing continued breastfeeding support after discharge. PMID- 27773612 TI - Bowel occlusion in an infertile woman with documented deep endometriosis of the sigmoid colon: Why was it not unexpected? PMID- 27773610 TI - The Sal-like 4 - integrin alpha6beta1 network promotes cell migration for metastasis via activation of focal adhesion dynamics in basal-like breast cancer cells. AB - During metastasis, cancer cell migration is enhanced. However, the mechanisms underlying this process remain elusive. Here, we addressed this issue by functionally analyzing the transcription factor Sal-like 4 (SALL4) in basal-like breast cancer cells. Loss-of-function studies of SALL4 showed that this transcription factor is required for the spindle-shaped morphology and the enhanced migration of cancer cells. SALL4 also up-regulated integrin gene expression. The impaired cell migration observed in SALL4 knockdown cells was restored by overexpression of integrin alpha6 and beta1. In addition, we clarified that integrin alpha6 and beta1 formed a heterodimer. At the molecular level, loss of the SALL4 - integrin alpha6beta1 network lost focal adhesion dynamics, which impairs cell migration. Over-activation of Rho is known to inhibit focal adhesion dynamics. We observed that SALL4 knockdown cells exhibited over-activation of Rho. Aberrant Rho activation was suppressed by integrin alpha6beta1 expression, and pharmacological inhibition of Rho activity restored cell migration in SALL4 knockdown cells. These results indicated that the SALL4 - integrin alpha6beta1 network promotes cell migration via modulation of Rho activity. Moreover, our zebrafish metastasis assays demonstrated that this gene network enhances cell migration in vivo. Our findings identify a potential new therapeutic target for the prevention of metastasis, and provide an improved understanding of cancer cell migration. PMID- 27773611 TI - Involvement of caveolin-1 in low shear stress-induced breast cancer cell motility and adhesion: Roles of FAK/Src and ROCK/p-MLC pathways. AB - Tumor cells translocating to distant sites are subjected to hemodynamic shear forces during their passage in the blood vessels. Low shear stress (LSS) plays a critical role in the regulation of various aspects of tumor cells functions, including motility and adhesion. Beyond its structural role, caveolin-1 (Cav-1), the important component of caveolae, represents a modulator of several cancer associated functions as tumor progression and metastasis. However, the role of Cav-1 in regulating tumor cells response to shear stress remains poorly explored. Here, we characterized the role of LSS and Cav-1 in mediating cell motility and adhesion on human breast carcinoma MDA-MB-231 cells. We first showed that LSS exposure promoted cell polarity and focal adhesion (FA) dynamics, thus indicating elevated cell migration. Silencing of Cav-1 leaded to a significantly lower formation of stress fibers. However, LSS exposure was able to rescue it via the alteration of actin-associated proteins expression, including ROCK, p-MLC, cofilin and filamin A. Time-lapse migration assay indicated that Cav-1 expression fostered MDA-MB-231 cells motility and LSS triggered cells to rapidly generate new lamellipodia. Furthermore, Cav-1 and LSS significantly influenced cell adhesion. Taken together, our findings provide insights into mechanisms underlying LSS triggered events mediated by downstream Cav-1, including FAK/Src and ROCK/p-MLC pathways, involved in the reorganization of the cytoskeleton, cell motility, FA dynamics and breast cancer cell adhesion. PMID- 27773613 TI - A perilous journey through the heart: Ventricular tachycardia caused by a foreign body. PMID- 27773614 TI - Geographical variations in incidence, management and survival of hepatocellular carcinoma in a Western country. AB - BACKGROUND & AIMS: Information on the incidence, management, and prognosis of hepatocellular carcinoma (HCC) is derived from population samples, regional data, or registries. Comprehensive national evaluations within a given country are lacking. This study aimed to investigate regional variations in HCC care within France. METHODS: This observational study analysed data from French administrative databases for more than 30,000 patients with HCC diagnosed between 2009 and 2012, and followed-up until 2013. The incidence of HCC, access to surgery, and survival, at both the national level and two geographical levels (the 21 French regions and 95 French departments into which France is divided administratively), were determined. The influence on outcome of the structure of the hospital where HCC was first managed was assessed. RESULTS: At the national level, the median survival was 9.4months and only 22.8% of patients had curative treatment. There were marked variations between regions and departments in incidence, access to curative treatment (range 1.3-28.8% and 8.1-32.3% respectively), and in median survival (range 5.7-12.1 and 4.3-16.5months respectively). The administrative type and annual HCC-caseload of the hospital where patients were first admitted also had an independent influence on treatment and survival. CONCLUSION: Despite full insurance coverage for all citizens, national measures to reduce inequities in the management of cancer patients, standardised recommendations for HCC surveillance and management, the percentage of patients undergoing curative treatment and their survival may vary four-fold depending on their postcode. The hospital in which patients are first managed has a clear influence on accessibility to both good care and survival. LAY SUMMARY: Population-based studies have highlighted large and sometimes unexpected differences between countries in the survival of patients with malignancy. As these differences are considered to indicate the overall effectiveness of health systems, in addition to the incidence of the cancer or quality of registration, variations within a given country should be minimal. However, similar to between countries differences, this study shows differences within the same country in the incidence, curative treatment rate, and survival of patients with HCC. Evidence that access to care and survival varies within a country can strengthen the impetus for government and clinicians to address these disparities. PMID- 27773615 TI - Quantifying tap-to-household water quality deterioration in urban communities in Vellore, India: The impact of spatial assumptions. AB - Municipal water sources in India have been found to be highly contaminated, with further water quality deterioration occurring during household storage. Quantifying water quality deterioration requires knowledge about the exact source tap and length of water storage at the household, which is not usually known. This study presents a methodology to link source and household stored water, and explores the effects of spatial assumptions on the association between tap-to household water quality deterioration and enteric infections in two semi-urban slums of Vellore, India. To determine a possible water source for each household sample, we paired household and tap samples collected on the same day using three spatial approaches implemented in GIS: minimum Euclidean distance; minimum network distance; and inverse network-distance weighted average. Logistic and Poisson regression models were used to determine associations between water quality deterioration and household-level characteristics, and between diarrheal cases and water quality deterioration. On average, 60% of households had higher fecal coliform concentrations in household samples than at source taps. Only the weighted average approach detected a higher risk of water quality deterioration for households that do not purify water and that have animals in the home (RR=1.50 [1.03, 2.18], p=0.033); and showed that households with water quality deterioration were more likely to report diarrheal cases (OR=3.08 [1.21, 8.18], p=0.02). Studies to assess contamination between source and household are rare due to methodological challenges and high costs associated with collecting paired samples. Our study demonstrated it is possible to derive useful spatial links between samples post hoc; and that the pairing approach affects the conclusions related to associations between enteric infections and water quality deterioration. PMID- 27773616 TI - Compartmentalized Metabolic Engineering for Artemisinin Biosynthesis and Effective Malaria Treatment by Oral Delivery of Plant Cells. AB - Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills >500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (~0.8 mg/g dry weight) at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of dihydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants. PMID- 27773618 TI - Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. AB - BACKGROUND/OBJECTIVES: We have recently described copy number variants (CNVs) of the human carboxyl-ester lipase (CEL) gene, including a recombined deletion allele (CEL-HYB) that is a genetic risk factor for chronic pancreatitis. Associations with pancreatic disease have also been reported for the variable number of tandem repeat (VNTR) region located in CEL exon 11. Here, we examined if CEL CNVs and VNTR length polymorphisms affect the risk for developing pancreatic cancer. METHODS: CEL CNVs and VNTR were genotyped in a German family with non-alcoholic chronic pancreatitis and pancreatic cancer, in 265 German and 197 Norwegian patients diagnosed with pancreatic adenocarcinoma, and in 882 controls. CNV screening was performed using PCR assays followed by agarose gel electrophoresis whereas VNTR lengths were determined by DNA fragment analysis. RESULTS: The investigated family was CEL-HYB-positive. However, an association of CEL-HYB or a duplication CEL allele with pancreatic cancer was not seen in our two patient cohorts. The frequency of the 23-repeat VNTR allele was borderline significant in Norwegian cases compared to controls (1.2% vs. 0.3%; P = 0.05). For all other VNTR lengths, no statistically significant difference in frequency was observed. Moreover, no association with pancreatic cancer was detected when CEL VNTR lengths were pooled into groups of short, normal or long alleles. CONCLUSIONS: We could not demonstrate an association between CEL CNVs and pancreatic cancer. An association is also unlikely for CEL VNTR lengths, although analyses in larger materials are necessary to completely exclude an effect of rare VNTR alleles. PMID- 27773619 TI - Response to "Re. Psychiatric dimensions in mothers of children with primary nocturnal enuresis: A controlled study". PMID- 27773620 TI - Preputial reconstruction in hypospadias repair. AB - OBJECTIVE: In principle, the prepuce can be reconstructed during hypospadias repair, but the procedure has not gained wide acceptance and preputial reconstruction (PR) is surrounded by several controversies. MATERIAL AND METHODS: A review is provided of the technique for PR, how PR combines with the other steps of hypospadias repair, the risks of complications related to the urethroplasty and specific to PR, and the results of PR with particular regard to the relevance for the patient and his family. RESULTS: PR can be important for patients requiring hypospadias repair and their parents. It can be performed in almost all patients with distal hypospadias except perhaps those with the most asymmetrical prepuces or severe ventral skin deficiency. PR does not seem to increase urethroplasty complications, but combination of PR with tubularisation of the urethral plate urethroplasty seems to offer the best chance of success. Specific complications occur in around 8% of patients and include partial or complete dehiscence of the prepuce and secondary phimosis. To prevent the latter, the reconstructed prepuce should be easily retractile at the end of surgery. Technical modifications can help to achieve this goal. Cosmetically, reconstructed prepuces are not fully normal, but the abnormality could be less important for a patient and his parents that the complete absence of the prepuce. CONCLUSION: On the basis of the evidence summarised above, an algorithm for PR in patients with distal hypospadias is proposed. PR can be offered to the vast majority of distal hypospadias patients, although some modification of the technique for hypospadias repair can be required. Retractility of the reconstructed prepuce at the end of surgery seems paramount for final success. PMID- 27773621 TI - Testis sparing surgery for Leydig cell pathologies in children. AB - OBJECTIVE: The aim was to analyze testis-sparing surgical procedures in boys with Leydig cell pathologies. STUDY DESIGN: The hospital records of four boys with Leydig cell hyperplasia who underwent testis-sparing surgery for testicular masses between 2000 and 2012 were analyzed retrospectively. Tumor markers were evaluated and all boys underwent scrotal ultrasonography preoperatively. The hormonal profile was also analyzed for symptoms of precocious puberty. The testis was delivered through a high transverse inguinal incision and the tumor was excised by enucleation. After confirming the benign nature of the tumor with frozen-section examination, the testis was reinserted and fixed into the scrotum with absorbable sutures. All cases were followed-up with physical examination, scrotal ultrasonography, and measurement of beta-human chorionic gonadotropin (HCG), alpha-fetoprotein, and hormone levels. RESULTS: The mean age of the patients was 9.4 years (1.5-15 years). Testicular mass and scrotal asymmetry were detected in all cases. Ultrasonography was the main initial diagnostic modality for detecting testicular masses (Table). beta-HCG and alpha-fetoprotein levels were normal. Three cases had Leydig cell hyperplasia and one patient was diagnosed to have a Leydig cell tumor. Signs of precocious puberty were detected in the four patients. The mean follow-up period was 4.8 years (2-8 years). Neither recurrence nor testicular atrophy developed in the follow-up. Findings of precocious puberty continued in one patient with Leydig cell hyperplasia, in whom a 2-mm contralateral metachronous lesion was detected and enucleated successfully. DISCUSSION: Testis-sparing surgery with its potential long-term psychological, cosmetic, and functional advantages should be used in pediatric patients in whom a benign Leydig cell pathology is confirmed histopathologically. CONCLUSION: This intervention with good long-term results can easily be applied through a proper dissection plane in the testicle. Since testicular Leydig cell tumors in childhood have small rates of recurrence, this choice of treatment is efficient in patients with salvageable testicular tissues and normal levels of tumor markers. PMID- 27773622 TI - [Mirogabalin: The next pregabalin?] PMID- 27773623 TI - [Increasing incidence of community-acquired pneumonia caused by atypical microorganisms]. AB - INTRODUCTION: Knowing the most common microorganisms in our environment can help us to make proper empirical treatment decisions. The aim is to identify those microorganisms causing community-acquired pneumonia. PATIENTS AND METHODS: An observational, descriptive and prospective study was conducted, including patients over 14 years with a clinical and radiographic diagnosis of community acquired pneumonia during a 383 consecutive day period. A record was made of sociodemographic variables, personal history, prognostic severity scales, progress, and pathogenic agents. The aetiological diagnosis was made using blood cultures, detection of Streptococcus pneumoniae and Legionella pneumophila urinary antigens, sputum culture, influenza virus and Streptococcus pyogenes detection. Categorical variables are presented as absolute values and percentages, and continuous variables as their means and standard deviations. RESULTS: Of the 287 patients included in the study (42% women, mean age 66+/-22 years), 10.45% died and 70% required hospital admission. An aetiological diagnosis was achieved in 43 patients (14.98%), with 16 microorganisms found in 59 positive samples. The most frequently isolated pathogen was Streptococcus pneumonia (24/59, 41%), followed by gram-negative enteric bacilli, Klebsiella pneumonia, Escherichia coli, Serratia marcescens and Enterobacter cloacae isolated in 20% of the samples (12/59), influenza virus (5/59, 9%), methicillin resistant Staphylococcus aureus (3/59, 5%), Pseudomonas aeruginosa (2/59, 3%), Moraxella catarrhalis (2/59, 3%), Legionella pneumophila (2/59, 3%), and Haemophilus influenza (2/59, 3%). Polymicrobial infections accounted for 14% (8/59). CONCLUSION: A high percentage of atypical microorganisms causing community-acquired pneumonia were found. PMID- 27773624 TI - [Validation of taking arterial pulse in Primary Care for the detection of atrial fibrillation and other cardiac rhythm disorders in patients over 65 years old]. AB - INTRODUCTION: Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice and has important prognostic implications. The objective of this study was to demonstrate the validity and the reliability of taking the arterial pulse (TAP) in patients over 65 years for detecting in AF and other rhythm disorders. MATERIALS AND METHODS: A descriptive, observational, multicentre study to validate a diagnostic test within in a controlled clinical trial. SETTING: 39 Primary Care Centres in the Spanish National Health Service. A total of 318 physicians and nurses took part in the analysis of validity, and 166 of them took part in the analysis of reliability. The professionals were previously called to a meeting in which they took the arterial pulses, and were given 4 ECGs to interpret. The participants TAP of 864 patients followed by an ECG to confirm the cardiac rhythm. Sensitivity, specificity and predictive values were estimated to assess the criterial validity and the simple concordance index to check reproducibility. RESULTS: The sensitivity of pulse measurement for detecting AF detection was 99.4% (95% CI: 97.9-100.0), with a specificity of 30.7% (95% CI: 26.1-35.3), a positive predictive value of 36.6% (95% CI 32.0 41.2), and negative predictive value of 99.2% (97.3-100.0). The simple concordance between the researchers and the cardiologist for the ECG diagnosis of AF ranged between 84.9% and 91.6%. CONCLUSIONS: The TAP has a high sensitivity but a low specificity to detect AF. It is a reliable test for the opportunistic screening of arrhythmias in patients aged over 65 years. PMID- 27773625 TI - [Thoughts aloud on conflicts of interest: Beyond the authors]. PMID- 27773626 TI - [EULAR revised recommendations for the management of fibromyalgia]. PMID- 27773627 TI - [What would you do in front of a patient with a Horner syndrome?] AB - Horner's syndrome (HS) occurs when there is disruption to the oculosympathetic pathway. Its features include eyelid ptosis, miosis and anhidrosis. The aetiology of this syndrome is varied and includes tumours, trauma, vascular disease and iatrogenic. Different pharmacologic tests are used for diagnosis, such as cocaine, hydroxyamphetamine and apraclonidine; while neuroimaging helps elucidating the aetiology. We present a case of a 63-year-old female referred to our service with a 4-month history of right eyelid ptosis. During examination right miosis was noted. The patient reported a history of multinodular goiter. Pharmacologic tests and neuroimaging confirmed the diagnosis of HS secondary to thyroid disease. PMID- 27773629 TI - RNA-DNA Triplex Formation by Long Noncoding RNAs. AB - Long noncoding RNAs (lncRNAs) play a pivotal role in the regulation of biological processes through various mechanisms that are not fully understood. Proposed mechanisms include regulation based on RNA-protein interactions, as well as RNA RNA interactions and RNA-DNA interactions. Here, we focus on one possible mechanism that lncRNA might be using to impact biological function, the RNA-DNA triplex formation. We summarize currently available examples of lncRNA triplex formation and discuss the details surrounding orientation of triplex formation as one of the key properties guiding this process. We propose that symmetrical triplex-forming motifs, especially those in cis-acting lncRNAs, favor triplex formation. We also consider the effects of lncRNA structures, protein or ligand binding, and chromatin structures on the lncRNAs triplex formation. PMID- 27773630 TI - Distribution and sub-types of afferent fibre in the mouse urinary bladder. AB - AIM: Increased afferent fibre activity contributes to pathological conditions such as the overactive bladder syndrome. Nerve fibres running near the urothelium are considered to be afferent as no efferent system has yet been described. The aim of this study was to identify sub-types of afferent nerve fibres in the mouse bladder wall based on morphological criteria and analyse regional differences. MATERIALS AND METHODS: 27 bladders of six month old C57BL/6 mice were removed and tissues were processed for immunohistochemistry. Cryostat sections were cut and stained for Protein Gene Product 9.5 (PGP), calcitonin gene related polypeptide (CGRP), neurofilament (NF), vesicular acetylcholine transporter (VAChT) and neuronal nitric oxide synthase (nNOS). RESULTS: In the sub-urothelium, different types of afferent nerve fibre were found, i.e. immunoreactive (IR) to; CGRP, NF, VAChT, and/or nNOS. At the bladder base, the sub-urothelium was more densely innervated by CGRP-IR and VAChT-IR nerve fibres, then at the lateral wall. NF- and nNOS nerves were sparsely distributed in the sub-urothelium throughout the bladder. At the lateral wall the inner muscle is densely innervated by CGRP-IR nerve fibres. NF, VAChT and nNOS nerves were evenly distributed in the different muscle layers throughout the bladder. Nerve fibre terminals expressing CGRP and NF were found within the extra-mural ganglia at the bladder base. CONCLUSIONS: Different types of afferent nerve fibres were identified in the sub-urothelium of the mouse bladder. At the bladder base the sub-urothelium is more densely innervated than the lateral wall by CGRP-IR and VAChT-IR afferent nerve fibres. CGRP and NF afferent nerve fibres in the muscle layer probably relay afferent input to external ganglia located near the bladder base. The identification of different afferent nerves in the sub-urothelium suggests a functional heterogeneity of the afferent nerve fibres in the urinary bladder. PMID- 27773628 TI - A Small-Molecule Inhibitor of Iron-Sulfur Cluster Assembly Uncovers a Link between Virulence Regulation and Metabolism in Staphylococcus aureus. AB - The rising problem of antimicrobial resistance in Staphylococcus aureus necessitates the discovery of novel therapeutic targets for small-molecule intervention. A major obstacle of drug discovery is identifying the target of molecules selected from high-throughput phenotypic assays. Here, we show that the toxicity of a small molecule termed '882 is dependent on the constitutive activity of the S. aureus virulence regulator SaeRS, uncovering a link between virulence factor production and energy generation. A series of genetic, physiological, and biochemical analyses reveal that '882 inhibits iron-sulfur (Fe S) cluster assembly most likely through inhibition of the Suf complex, which synthesizes Fe-S clusters. In support of this, '882 supplementation results in decreased activity of the Fe-S cluster-dependent enzyme aconitase. Further information regarding the effects of '882 has deepened our understanding of virulence regulation and demonstrates the potential for small-molecule modulation of Fe-S cluster assembly in S. aureus and other pathogens. PMID- 27773631 TI - The pharmacy (organization) divide: A focus on the impact in pediatric pharmacy. PMID- 27773635 TI - Molecular expression of aquaporin mRNAs in the northern house mosquito, Culex pipiens. AB - Aquaporins (AQPs) are a family of membrane-bound proteins, originally described as water-channels, that broadly exist in prokaryotic and eukaryotic cells. However, some AQPs can transport small molecules (e.g. urea, glycerol) along with or preferentially to water. Previous work in the mosquitoes Aedes aegypti and Anopheles gambiae have characterized the molecular expression of one or more AQP genes and shown that they are involved in water homeostasis after blood feeding, tolerance to dehydration and heat stresses, and development of Plasmodium falciparum in the mosquito. However, the molecular expression of AQPs in the northern house mosquito Culex pipiens, the primary vector of West Nile virus, is presently unknown. Here we characterize the relative mRNA expression of six AQP genes in C. pipiens. We used quantitative RT-PCR (qPCR) to compare AQP mRNA levels 1) among different life stages and sexes, 2) between blood fed and non blood fed adult females, 3) between adult females injected with phosphate buffered saline (PBS) and non-injected females, and 4) between adult females exposed to a low vs. high relative humidity. We found that: 1) four AQP mRNAs (Drip, Bib, Eglp1, Aqp12L) were differentially expressed between larval and adult life stages, but not between sexes; 2) after a blood meal, the expression of two AQP mRNAs (Drip and Aqp12L) were down-regulated and one AQP mRNA (Eglp2) was up regulated; 3) the expression of two AQP mRNAs (Drip and Prip) were down-regulated and one AQP mRNA (Eglp1) was up regulated after injecting the hemolymph of mosquitoes with PBS; and 4) the expression of Prip and Eglp2 mRNAs were both down regulated in response to a low relative humidity. Our study is the first to characterize the molecular expression patterns of AQPs in C. pipiens, thus providing a foundation for future research elucidating the physiological and functional roles of AQPs in this important disease vector. PMID- 27773633 TI - Patient-centered imaging and the imaging team. PMID- 27773634 TI - Diagnostic accuracy of static CT perfusion for the detection of myocardial ischemia. A systematic review and meta-analysis. AB - OBJECTIVES: The aim of this study is to provide a meta-analysis of all published studies assessing the diagnostic accuracy of stress CT myocardial perfusion imaging (CTP) in patients suspected of or with known coronary artery disease. This analysis is limited to static stress CTP. METHODS: Systematic literature review and meta-analysis of studies examining the diagnostic accuracy of static CTP imaging alone or combined with coronary CT angiography (CTA) in comparison to single photon emission computed tomography (SPECT), magnetic resonance perfusion (MRP), and/or invasive coronary angiography with and without fractional flow reserve (FFR). RESULTS: The search revealed 19 eligible studies including 1188 patients. Pooled results showed that CTP had a good agreement with SPECT and MRP. On a per-patient level, sensitivity, specificity and AUC were 0.85 (95% CI: 0.70 0.93), 0.81 (95% CI: 0.59-0.93), 0.90 (95% CI: 0.87-0.92). On a per-artery level, sensitivity, specificity and AUC were 0.80 (95% CI: 0.67-0.88), 0.81 (95% CI: 0.72-0.88) and 0.87 (95% CI: 0.84-0.90). When invasive coronary angiography was used as reference standard, combined coronary CTA and CTP compared to coronary CTA alone significantly improved the specificity from 0.62 (95% CI: 0.52-0.70) to 0.84 (95% CI: 0.74-0.91) on a per-patient level (p = 0.008) and from 0.72 (95% CI: 0.63-0.79) to 0.90 (95% CI: 0.85-0.93) on a per-artery level (p = 0.0001) without significant decrease in sensitivity (p = 0.59 and p = 0.23, respectively). CONCLUSION: In selected patients, static CT myocardial perfusion has high diagnostic accuracy to detecting myocardial ischemia. Specificity increases significantly when CT myocardial perfusion is combined with coronary CTA. PMID- 27773636 TI - Searching for particular traits of sawfly (Hymenoptera: Tenthredinidae) larvae that emit hemolymph as a defence against predators. AB - Easy bleeding is a defence strategy that allows the larvae of some Tenthredinidae sawfly species to emit deterrent hemolymph when attacked by a predator. However, a drawback of this defence is that hemolymph is frequently in contact with the exterior, thus potentially subjected to multiple microbial infections at any body's integumental spot. Here we aimed to identify physiological traits that are linked to easy bleeding. First, larvae of several sawfly species were subjected to daily experimental losses of hemolymph equivalent to 10% of their body weight, and changes in body weight and survival were recorded. Easy bleeders' survival rates were better compared to non-easy bleeders. Second, testing hemolymph melanisation revealed that nearly all sawfly hemolymph samples did not melanise over a 24h period. Third, inhibition zone tests against live Escherichia coli were conducted using hemolymph collected 24-48h after a sterile wounding and an infection with Micrococcus luteus, as well as from control, untouched individuals. Sterile wounding induced similar antibacterial activities compared to those detected in the control group. However, the activity was significantly enhanced upon infection in some species, similarly to other insects. Thus, easy bleeders have a tendency to compensate for hemolymph loss resulting from predator prey interactions, whereas a non-melanising hemolymph is probably a characteristic of sawflies, and the antimicrobial activity can be high but is comparable in easy bleeders versus other insects. PMID- 27773637 TI - Human sirtuins: Structures and flexibility. AB - In recent years, sirtuins (SIRTs), members of histone deacetylases (HDACs) class III, have been found to modulate cellular processes related to the development of human aging-related pathologies (i.e. cancer, neurodegeneration, metabolic disorders). Several crystallographic structures and computational studies have shed light into their catalytic mechanism of action, identifying also the structural elements for the design of selective drug candidates. In this review, we first aim at summarizing the structural features characterizing human SIRTs. We then describe the observed mass and one-off movements related to conformational changes upon SIRT-mediated recognition events. Such information will be useful not only for rationalizing the design of new SIRT modulators, but also for improving the comprehension of SIRT-related biological roles. PMID- 27773632 TI - Repression activity of Tailless on h 1 and eve 1 pair-rule stripes. AB - We investigated the hypothesis that several transcriptional repressors are necessary to set the boundaries of anterior pair-rule stripes in Drosophila. Specifically, we tested whether Tailless (Tll) is part of a repression mechanism that correctly sets the anterior boundaries of hairy 1 (h 1) and even-skipped 1 (eve 1) stripes. Single mutant tll embryos displayed subtle deviations from the normal positions of h 1 and eve 1 stripes. Moreover, we observed stronger stripe deviations in embryos lacking both Tll and Sloppy-paired 1 (Slp 1), a common repressor for anterior pair-rule stripes. Using h 1 and eve 1 reporter constructs in the genetic assays, we provided further evidence that interference with normal mechanisms of stripe expression is mediated by Tll repression. Indeed, Tll represses both h 1 and eve 1 reporter stripes when misexpressed. Investigating the expression of other anterior gap genes in different genetic backgrounds and in the misexpression assays strengthened Tll direct repression in the regulation of h 1 and eve 1. Our results are consistent with tll being a newly-identified component of a combinatorial network of repressor genes that control pair-rule stripe formation in the anterior blastoderm of Drosophila. PMID- 27773638 TI - Diagnosis and Risk Factors of Acute Kidney Injury in Very Low Birth Weight Infants. AB - BACKGROUND: Acute kidney injury (AKI) is common in critically ill premature infants. There is a lack of consensus on the diagnostic definition of AKI in very low birth weight (VLBW) infants. The primary aim of this study was to determine the incidence and risk factors for AKI in VLBW infants using the AKI network (AKIN) and pRIFLE (pediatric Risk, Injury, Failure, Loss, End-Stage) criteria and to evaluate whether Clinical Risk Index for Babies (CRIB II) score is a predictor of AKI. The secondary objective was to determine the extent of agreement between the AKIN and pRIFLE criteria in the diagnosis of AKI in VLBW infants. METHODS: This was a retrospective chart review of 115 VLBW (< 1500 g) infants born in an academic center with a Level 3B neonatal intensive care unit. Multiple congenital anomalies, transfer to other centers, or death within the first 2 weeks were the exclusion criteria. Relevant data were collected and analyzed in the first 2 weeks postnatally. RESULTS: AKI incidence, according to AKIN and pRIFLE criteria, was 20.1% and 22.6%, respectively. As per the interrater reliability analysis, there was a fair agreement between the two criteria (kappa = 0.217). AKI was nonoliguric. The length of stay was significantly longer in the AKI group. Prenatal nonsteroidal anti-inflammatory drug exposure, lower gestational age, lower birth weight, respiratory distress syndrome, mechanical ventilation, patent ductus arteriosus, hypotension, late onset sepsis, and higher CRIB II scores were significantly associated with AKI. Our regression analysis found CRIB II scores to be an independent risk factor for AKI (odds ratio = 1.621; 95% confidence interval, 1.230-2.167; p = 0.001). CONCLUSION: The determination of AKI using the pRIFLE and AKIN criteria yielded different results. pRIFLE appears to be more sensitive in VLBW infants. A high CRIB II score was recorded for AKI. Future studies are necessary to develop a uniform definition and identify the risk factors to improve the outcomes in this population. PMID- 27773639 TI - Analysis of Outcomes for High Tibial Osteotomies Performed With Cartilage Restoration Techniques. AB - PURPOSE: To evaluate reported medium- to long-term outcomes after high tibial osteotomy (HTO) with associated cartilage restoration procedures. METHODS: A review of the MEDLINE database was performed. The inclusion criteria were English language, clinical outcome study with HTO as the primary procedure, use of a form of cartilage repair included, and the mean follow-up period of at least 2 years. Each identified study was reviewed for study design, patient demographics, type of procedures performed, clinical outcomes, progression to total knee arthroplasty, and complications. RESULTS: Eight hundred and twenty-seven patients (839 knees) were included. The most common cartilage preservation technique used in conjunction with HTO was microfracture (4 studies; 22.2%). The mean Lyscholm scores, reported in 50% of the studies, ranged from 40 to 65.7 preoperatively and improved to a range of 67 to 94.6 postoperatively. Four studies (22.2%) used a visual analog scale for evaluation of pain and all had a mean visual analog scale of less than 3 postoperatively. Among studies evaluating conversion to arthroplasty, the rate of conversion was 6.8% and the range of mean number of years from HTO to conversion was 4.9 to 13.0. The overall reported complication rate was 10.3%. CONCLUSIONS: HTO with cartilage restoration procedures provides reliable improvement in functional status in the medium- to long-term period after surgery and has potential to delay or avoid the need for knee arthroplasty surgery. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies. PMID- 27773640 TI - Comparative Influence of Sport Type on Outcome After Anterior Cruciate Ligament Reconstruction at Minimum 2-Year Follow-up. AB - PURPOSE: To investigate differences between sport types for patient-reported outcome after anterior cruciate ligament reconstruction (ACLR). METHODS: Included patients were enrolled as part of a prospective institutional ACL registry. Inclusion criteria were preoperative self-identification as a competitive athlete, maximum score on the preoperative Marx Activity Scale, and minimum 2 year follow-up. Demographic, intraoperative, and outcome data were extracted from the registry. Outcome tools administered as part of the registry included International Knee Documentation Committee (IKDC), Lysholm-Tegner Scales, Marx Activity Scale (MAS), and 12-Item Short Form Health Survey (SF-12). RESULTS: A total of 294 patients with a mean age of 25.5 years (standard deviation 12.1) met the study inclusion criteria; mean follow-up was 3.7 years. Included sports categories were soccer (n = 92; 31.3%), skiing (n = 67; 22.8%), basketball (n = 56; 19.1%), lacrosse (n = 38; 12.9%), football (n = 29; 9.9%), and Tennis (n = 12; 4.1%). At baseline, compared with other sports, lacrosse players have higher outcome scores while skiers had lower scores. At 2-year follow-up, however, across all outcome tools, football players demonstrated significantly higher outcome scores than all other athletes (IKDC, 93.2, P = .001; Lysholm, 93.2, P = .03; MAS, 13.1, P = .03; SF-12 Mental Component Summary, 57.9, P = .0002). Conversely, at 2-year follow-up, soccer players demonstrated a significantly lower Lysholm (86.7, P = .02) and a trend toward lower IKDC (85.6, P = .09) scores. CONCLUSIONS: Patient-reported outcomes after ACLR among active athletes are comparable. Football players demonstrate quantitatively higher outcome scores whereas soccer players have lower scores. However, these outcome score differences may not be clinically significant and may be subject to confounding variables. Continued attention should be paid to understanding sport-specific outcome after ACLR. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27773641 TI - Apparent diffusion coefficient measurement of ovarian stroma: A potential tool for the diagnosis of polycystic ovary syndrome. AB - PURPOSE: The purpose of this study was to assess the diagnostic value of measuring the apparent diffusion coefficient (ADC) of ovarian stroma in polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: This study was approved by the institutional review board and informed consent was obtained from each women. A total of 17 women (mean age, 22.2 years+/-5.1 [SD]; range, 16-33 years) with a diagnosis of PCOS according to the Androgen Excess and PCOS Society criteria and 18 healthy women (mean age, 22.8 years+/-5.2 [SD]; range, 16-31 years) who served as a control group were included in this prospective study. ADC values of the ovarian stroma during the early follicular phase were calculated by two observers in the two groups. Comparisons were performed using the Student t test. RESULTS: The mean ADC value in woman with PCOS (1.29+/-0.27*10-3 mm2/s; range: 0.59*10-3 - 1.88*10-3 mm2/s) was significantly lower than that in the control group (1.48+/-0.17*10-3 mm2/s; range: 1.12*10-3 - 1.86*10-3 mm2/s) (P<0.001). The ADC cutoff value for the determination of PCOS with maximum accuracy was 1.38*10-3 mm2/s (AUC: 0.720; 95% CI: 0.597, 0.843), yielding 78% sensitivity and 62.9% specificity. CONCLUSION: ADC values of ovarian stroma are lower in patients with PCOS than in control subjects. ADC measurement of ovarian stroma in women with PCOS might help improve the diagnosis of PCOS. PMID- 27773642 TI - Parafascicular nucleus circuits: Implications for the alteration of gastrointestinal functions during epileptogenesis. PMID- 27773643 TI - Restored Asymmetry of Prefrontal Cortical Oscillatory Activity after Bilateral Theta Burst Stimulation Treatment in a Patient with Major Depressive Disorder: A TMS-EEG Study. PMID- 27773644 TI - Does weight cycling promote obesity and metabolic risk factors? AB - BACKGROUND: There remains common belief in the general community that weight cycling or 'yo-yo dieting' is associated with potential adverse effects on obesity and metabolic risk factors. In 1994, a review by the National Task Force on the Prevention and Treatment of Obesity concluded that weight cycling did not impact metabolism, and that weight loss attempts should not be discouraged. This study is an updated review of the literature published since 1994, to determine if weight cycling is associated with metabolic risk factors for obesity and type 2 diabetes. METHODS: A systematic literature search was conducted in PubMed, ISI Web of Science and SCOPUS to identify primary studies that examined weight cycling in relation to obesity and metabolic risk factors. Thirty-one studies with human subjects were retained. RESULTS: Fifty-eight percent (11/19) of publications reported that a history of weight cycling was correlated with increased body fat and central adiposity. Another fifty percent (4/8) of studies reported that the presence of weight cycling increased the likelihood of future weight gain, suggesting that weight cycling is potentially problematic for individuals attempting to lose weight. The majority of studies (13/17; 76%) did not show a detrimental effect of weight cycling on risk of type 2 diabetes. CONCLUSIONS: There is some evidence showing that weight cycling has no effect on risk of type 2 diabetes and inconclusive evidence that a history or presence of weight cycling influences body composition, or predisposes to future obesity. The available evidence so far suggests that there is little detrimental effect of weight cycling on current and future obesity and metabolic risk, and therefore weight loss efforts in individuals with overweight/obesity should continue to be encouraged. PMID- 27773645 TI - DMSO modulates CNS function in a preclinical Alzheimer's disease model. AB - DMSO has a widespread use as a vehicle for water-insoluble therapeutic drug candidates but may also exert disease-relevant pharmacological effects by itself. However, its influence on the CNS has hardly been addressed. Here we examined the brain structure and function following chronic exposure to low DMSO dose at a paradigm with flawed synaptic connectivity in a preclinical transgenic mouse model for Alzheimer's disease (APPSDL mice). DMSO treatment increased spine density in a region-specific manner in the hippocampus of APPSDL mice ex vivo and in vivo. Moreover, DMSO exhibited clear influence on the behavior of this mouse line by enhancing hippocampal-dependent spatial memory accuracy, modulating hippocampal-independent olfactory habituation and displaying anxiolytic effect. Despite that most of the action of DMSO was observed in animals with elevated Abeta levels, the drug did not exert its function via decreasing the oligomeric Abeta species. However, challenging organotypic hippocampal slice cultures with NMDA receptor antagonist MK-801 recapitulated the effect of DMSO on spine density, indicating a tuning influence of DMSO on receptor signalization. Our findings demonstrate that DMSO should be considered as a true bioactive compound, which has the potential to be a beneficial adjuvant to counteract Abeta-mediated synaptotoxicity and behavioral impairment. PMID- 27773646 TI - MicroRNA and protein profiles in invasive versus non-invasive oral tongue squamous cell carcinoma cells in vitro. AB - Complex molecular pathways regulate cancer invasion. This study overviewed proteins and microRNAs (miRNAs) involved in oral tongue squamous cell carcinoma (OTSCC) invasion. The human highly aggressive OTSCC cell line HSC-3 was examined in a 3D organotypic human leiomyoma model. Non-invasive and invasive cells were laser-captured and protein expression was analyzed using mass spectrometry-based proteomics and miRNA expression by microarray. In functional studies the 3D invasion assay was replicated after silencing candidate miRNAs, miR-498 and miR 940, in invasive OTSCC cell lines (HSC-3 and SCC-15). Cell migration, proliferation and viability were also studied in the silenced cells. In HSC-3 cells, 67 proteins and 53 miRNAs showed significant fold-changes between non invasive vs. invasive cells. Pathway enrichment analyses allocated "Focal adhesion" and "ECM-receptor interaction" as most important for invasion. Significantly, in HSC-3 cells, miR-498 silencing decreased the invasion area and miR-940 silencing reduced invasion area and depth. Viability, proliferation and migration weren't significantly affected. In SCC-15 cells, down-regulation of miR 498 significantly reduced invasion and migration. This study shows HSC-3 specific miRNA and protein expression in invasion, and suggests that miR-498 and miR-940 affect invasion in vitro, the process being more influenced by mir-940 silencing in aggressive HSC-3 cells than in the less invasive SCC-15. PMID- 27773648 TI - Sling Surgery for the Treatment of Urinary Incontinence After Transurethral Resection of the Prostate: New Data on the Virtue Male Sling and an Evaluation of Literature. AB - OBJECTIVE: To provide a review of literature regarding the role of male slings in the treatment of stress urinary incontinence (SUI) following a transurethral resection of the prostate (TURP) and to evaluate the effects of the Virtue male sling in patients with post-TURP SUI. MATERIALS AND METHODS: A systematic review of literature was performed to identify all papers on the use of male slings in patients with post-TURP SUI. Second, a prospective cohort study was conducted on 8 patients who received the Virtue as surgical treatment of post-TURP SUI. Questionnaires were collected preoperatively and 1, 3, 6, and 12 months postoperatively. Success and improvement were defined as pad usage (0 pads: success, pad reduction of >=50%: improvement). Primary end point was the continence rate 1 year postoperatively. Data were analyzed using the paired 2 tailed t test. RESULTS: Sling surgery appears to be significantly less successful in the treatment of SUI post TURP when compared to other types of prostate surgery. The clinical trial on the Virtue sling observed continence in 4 of 8 patients, with another 2 patients with improved continence after 1-year follow up. No difference in success was observed between patients with mild and patients with severe SUI. CONCLUSIONS: Little is currently known about the effects of sling surgery in patients with mild to severe SUI following a TURP. Although the Virtue male sling seems to be an efficient and safe device in the treatment of this complication, longer follow-up and larger cohorts will be needed to further confirm these results. PMID- 27773647 TI - Effects of brain-derived neurotrophic factor (BDNF) on the cochlear nucleus in cats deafened as neonates. AB - Many previous studies have shown significant neurotrophic effects of intracochlear delivery of BDNF in preventing degeneration of cochlear spiral ganglion (SG) neurons after deafness in rodents and our laboratory has shown similar results in developing cats deafened prior to hearing onset. This study examined the morphology of the cochlear nucleus (CN) in a group of neonatally deafened cats from a previous study in which infusion of BDNF elicited a significant improvement in survival of the SG neurons. Five cats were deafened by systemic injections of neomycin sulfate (60 mg/kg, SQ, SID) starting one day after birth, and continuing for 16-18 days until auditory brainstem response (ABR) testing demonstrated profound bilateral hearing loss. The animals were implanted unilaterally at about 1 month of age using custom-designed electrodes with a drug-delivery cannula connected to an osmotic pump. BDNF (94 MUg/ml; 0.25 MUl/hr) was delivered for 10 weeks. The animals were euthanized and studied at 14 23 weeks of age. Consistent with the neurotrophic effects of BDNF on SG survival, the total CN volume in these animals was significantly larger on the BDNF-treated side than on the contralateral side. However, total CN volume, both ipsi- and contralateral to the implants in these deafened juvenile animals, was markedly smaller than the CN in normal adult animals, reflecting the severe effects of deafness on the central auditory system during development. Data from the individual major CN subdivisions (DCN, Dorsal Cochlear Nucleus; PVCN, Posteroventral Cochlear Nucleus; AVCN, Anteroventral Cochlear Nucleus) also were analyzed. A significant difference was observed between the BDNF-treated and control sides only in the AVCN. Measurements of the cross-sectional areas of spherical cells showed that cells were significantly larger in the AVCN ipsilateral to the implant than on the contralateral side. Further, the numerical density of spherical cells was significantly lower in the AVCN ipsilateral to the implant than on the contralateral side, consistent with the larger AVCN volume observed with BDNF treatment. Together, findings indicate significant neurotrophic effects of intracochlear BDNF infusion on the developing CN. PMID- 27773649 TI - Postoperative Urinary Retention and Urinary Tract Infections Predict Midurethral Sling Mesh Complications. AB - OBJECTIVE: To determine if postoperative urinary retention and urinary tract infections (UTIs) were predictors of future mesh complications requiring surgical intervention after midurethral sling (MUS). MATERIALS AND METHODS: Administrative data in Ontario, Canada, between 2002 and 2013 were used to identify all women who underwent a mesh-based MUS. The primary outcome was revision of the transvaginal mesh sling (including mesh removal/erosion/fistula, or urethrolysis). Two potential risk factors were analyzed: postoperative retention (within 30 days of procedure) and number of postoperative emergency room visits or hospital admissions for UTI symptoms. RESULTS: A total of 59,556 women had a MUS, of which 1598 (2.7%) required revision surgery. Of the 2025 women who presented to the emergency room or were admitted to hospital for postoperative retention, 212 (10.5%) required operative mesh revision. Of the 11,747 patients who had at least one postoperative UTI, 366 (3.1%) patients required operative mesh revision. In adjusted analysis, postoperative retention was significantly predictive of future reoperation (hazard ratio [HR] 3.46, 95% confidence interval [CI] 2.97-4.02), and this difference persisted when urethrolysis was excluded as a reason for sling revision (HR 3.08, 95% CI 2.62-3.63). Similarly, in adjusted analysis, each additional postoperative hospital visit for UTI symptoms increased the risk for surgical intervention for mesh complications (HR 1.74, 95% CI 1.61 1.87). CONCLUSION: Postoperative urinary retention and hospital presentation for UTI symptoms are associated with an increased risk of reoperation for MUS complications. These patients should be followed and investigated for mesh complications when appropriate. PMID- 27773650 TI - Is Preoperative Assessment and Treatment of Asymptomatic Bacteriuria Necessary for Reducing the Risk of Postoperative Symptomatic Urinary Tract Infections After Urologic Surgical Procedures? AB - OBJECTIVE: To evaluate whether it is always necessary to test for the presence of asymptomatic bacteriuria (AB) in patients undergoing urologic surgical procedures, and if present, whether to treat AB with antimicrobial prophylaxis. MATERIALS AND METHODS: All patients who underwent urologic surgical procedures from December 2008 to October 2013 in a tertiary referral urologic center were considered for this study. All patients received antimicrobial prophylaxis in line with European Association of Urology guidelines on urologic infections. AB was diagnosed if >=105 colony-forming units/mL were cultured. The population was subdivided into 2 groups: group A, patients with preoperative AB, and group B, patients without AB. Data on postoperative symptomatic urinary tract infections (UTIs) were compared for the 2 groups. RESULTS: A total of 2201 patients were considered eligible for this study and were analyzed; 668 (30.4%) patients were found to harbor AB (group A), and 1533 (69.6%) patients did not have AB (group B). Microbiologically verified symptomatic postoperative UTIs occurred in 198 patients (8.9%). No difference in terms of overall rate of postoperative symptomatic UTI was found between the 2 groups (group A: 70 [10.4%] and group B: 128 [8.3%]; OR: 1.28 95%CI 0.94-1.74; P = .12), as well as in terms of urosepsis (group A: 2 [0.30%] and group B: 4 [0.26%]; P = 1.0). CONCLUSION: In patients undergoing urologic surgical procedures who are receiving antimicrobial prophylaxis in accordance with European Association of Urology guidelines, the preoperative presence of AB in this study was not associated with a higher incidence of postoperative symptomatic UTI. PMID- 27773651 TI - Micro-scale variability enhances trophic transfer and potentially sustains biodiversity in plankton ecosystems. AB - We develop moment closure approximations to represent micro-scale spatial variability in the concentrations of nutrients (N), phytoplankton (P) and zooplankton (Z) in an NPZ model, which we apply to examine the impact of different levels of micro-scale variability on both ecosystem dynamics and trophic transfer. Accounting explicitly for both the mean-field and fluctuating components of each prognostic variable in the NPZ model yields different dynamics for the mean-field concentrations, as well as lower phytoplankton biomass and greater zooplankton biomass, compared to the conventional NPZ model without micro scale variability. The biomass of zooplankton consistently increases with increasing total micro-scale variability, and a minimum threshold of such variability is required for the existence of stable steady state solutions in the NPZ closure model. Compared to the conventional NPZ model, the domain of parameter space over which stable solutions exist is larger than for the NPZ closure model, and this stable domain widens with increasing total variability. The latter result suggests that natural systems with greater micro-scale variability may have the potential to sustain greater biodiversity. We find that with the NPZ closure model: (1) the stability domains increases with micro-scale variability, (2) increase of the level of total micro-scale variability enhances trophic transfer, i.e. increases the biomass of zooplankton, and (3) the coefficient of variation (CVP) of phytoplankton increases with micro-scale variability. PMID- 27773652 TI - Refractoriness in human atria: Time and voltage dependence of sodium channel availability. AB - BACKGROUND: Refractoriness of cardiac cells limits maximum frequency of electrical activity and protects the heart from tonic contractions. Short refractory periods support major arrhythmogenic substrates and augmentation of refractoriness is therefore seen as a main mechanism of antiarrhythmic drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation. This study therefore aims to characterise how sodium channel inactivation affects refractoriness in human atria. METHODS AND RESULTS: Steady-state activation and inactivation parameters of sodium channels measured in vitro in isolated human atrial cardiomyocytes were used to parameterise a mathematical human atrial cell model. Action potential data were acquired from human atrial trabeculae of patients in either sinus rhythm or chronic atrial fibrillation. The ex vivo measurements of action potential duration, effective refractory period and resting membrane potential were well-replicated in simulations using this new in silico model. Notably, the voltage threshold potential at which refractoriness was observed was not different between sinus rhythm and chronic atrial fibrillation tissues and was neither affected by changes in frequency (1 vs. 3Hz). CONCLUSIONS: Our results suggest a preferentially voltage-dependent, rather than time-dependent, effect with respect to refractoriness at physiologically relevant rates in human atria. However, as the resting membrane potential is hyperpolarized in chronic atrial fibrillation, the voltage-dependence of excitability dominates, profoundly increasing the risk for arrhythmia re initiation and maintenance in fibrillating atria. Our results thereby highlight resting membrane potential as a potential target in pharmacological management of chronic atrial fibrillation. PMID- 27773653 TI - Leveraging the immune system to treat advanced thyroid cancers. AB - Inflammation has long been associated with the thyroid and with thyroid cancers, raising seminal questions about the role of the immune system in the pathogenesis of advanced thyroid cancers. With a growing understanding of dynamic tumour immune cell interactions and the mechanisms by which tumour cells evade antitumour immunity, the field of cancer immunotherapy has been revolutionised. In this Review, we provide evidence to support the presence of an antitumour immune response in advanced thyroid cancers linked to cytotoxic T cells and NK cells. This antitumour response, however, is likely blunted by the presence of immunosuppressive pathways within the microenvironment, facilitated by tumour associated macrophages or increased expression of negative regulators of cytotoxic T-cell function. Current and future efforts to incorporate immune-based therapies into existing tumour cell or endothelial-derived therapies-eg, with kinase inhibitors targeting tumour-associated macrophages or antibodies blocking negative regulators on T cells-could provide improved and durable responses for patients with disease that is otherwise refractory to treatment. PMID- 27773654 TI - A practical guide to in vivo proton magnetic resonance spectroscopy at high magnetic fields. AB - Localized proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive tool for measuring in vivo neurochemical information in animal and human brains. With the increase of magnetic field strength, whereas localized 1H-MRS benefits from higher sensitivity and spectral dispersion, it is challenged by increased spatial inhomogeneity of the B0 and B1 fields, larger chemical shift displacement error, and shortened T2 relaxation times of metabolites. Advanced localized 1H-MRS methodologies developed for high magnetic fields have shown promising results and allow the measurement of neurochemical profiles with up to 19 brain metabolites, including less-abundant metabolites, such as glutathione, glycine, gamma aminobutyric acid and ascorbate. To provide a practical guide for conducting in vivo1H-MRS studies at high magnetic field strength, we reviewed various essential technical aspects from data acquisition (hardware requirements, B1 and B0 inhomogeneity, water suppression, localization sequences and acquisition strategies) to data processing (frequency and phase correction, spectral quality control, spectral fitting and concentration referencing). Additionally, we proposed guidelines for choosing the most appropriate data acquisition and processing approaches to maximize the achievable neurochemical information. PMID- 27773656 TI - Reducing the lag of accommodation by auditory biofeedback: A pilot study. AB - The purpose of this study was to investigate whether a reduction of the accommodative lag is possible by training the accuracy of accommodation using auditory biofeedback. Accommodation responses were measured in thirty-one young adults with myopia for dioptric target distances of 2.0, 2.5, and 3.0D using an eccentric infrared photorefractor. For the biofeedback training, subjects were randomly assigned to an experimental (n=15) or a control group (n=16). Subjects of the experimental group were provided with two tones while fixating a target, one tone was related to their accommodative response and the second to the target distance. Their task was to match these tones. The control group did not receive any auditory biofeedback. Two different training methods were applied, a continuous training of 200s, and ten consecutive sessions of 20s each. The training effects on the lag of accommodation (change Delta) were highly variable. Regarding the entire study group, the observed change in the accommodative lag was greater at closer distances, while no difference between the two training methods was revealed. Nevertheless, seven experimental subjects reduced their lag by ?0.3D (3.0D target distance: Deltalong=-0.29+/-0.20D, Deltashort=-0.24+/ 0.21D). This reduction was also seen in two control subjects. Remeasurement revealed that the average training effect cannot be preserved over a period of 5 7days. The current investigation has shown that the accuracy of accommodation can be trained in some subjects using auditory biofeedback for target distances of 2.5D or closer. PMID- 27773657 TI - Contrast dependence of saccadic blanking and landmark effects. AB - Two phenomena have been reported to affect the perceived displacement of a visual target during saccadic eye movements: the blanking effect and landmark effect. In the blanking effect, temporarily blanking the target after a saccade improves displacement judgments. In the landmark effect, illusory target displacement occurs when a continuously presented landmark is displaced during a saccade, and the target is temporarily blanked after the saccade without displacement. We show that the strengths of the blanking and landmark effects vary with stimulus contrast. In the blanking effect, target displacement detection rate increased with luminance contrast of the target. In the landmark effect, illusory target displacement decreased with luminance contrast of the target. Moreover, the landmark effect was found even for stimuli without luminance contrast (equiluminant color stimuli), while the blanking effect disappeared. These results can be attributed to a reduction in sensitivity of target displacement by a reduction of luminance contrast, which suggests that changes in luminance, or transient signals, play a critical role in visual stability across saccades. PMID- 27773655 TI - Structural determinants for transport of lactase phlorizin-hydrolase in the early secretory pathway as a multi-domain membrane glycoprotein. AB - BACKGROUND: Lactase phlorizin-hydrolase (LPH) is a membrane anchored type I glycoprotein of the intestinal epithelium that is composed of four homologous structural domains. The role of each distinct domain in the intramolecular organization and function of LPH is not completely understood. METHODS: Here, we analyzed the early events of LPH biosynthesis and trafficking by directed restructuring of the domain compositions. RESULTS: Removal of domain I (LPH?1) results in a malfolded ER-localized protein. By contrast, LPH without domain II (LPH?2) is normally transported along the secretory pathway, but does not dimerize nor is enzymatically active. Interestingly a polypeptide stretch in domain II between L735-R868 exerts an intriguing role in modulating the trafficking behavior of LPH and its biological function. In fact, association of this stretch with transport-competent LPH chimeras results in their ER-arrest or aberrant trafficking. This stretch harbors a unique N-glycosylation site that is responsible for LPH retention in the ER via association with calnexin and facilitates proper folding of domains I and III before ER exit of LPH. Notably, a similar N-glycosylation site is also found in domain IV with comparable effects on the trafficking of LPH-derived molecules. CONCLUSIONS: Our study provides novel insights into the intramolecular interactions and the sequence of events involved in the folding, dimerization and transport of LPH. GENERAL SIGNIFICANCE: Elucidation of the structural-functional relevance of the domains in pro-LPH is crucial in unravelling and understanding the molecular basis of carbohydrate malabsorption disorders that are associated with lactase deficiency or lactase malfunction. PMID- 27773658 TI - The plasma levels of CST and BCKDK in patients with sepsis. AB - OBJECTIVES: CST has been recently identified as a mediator of various beneficial effects in animal models of sepsis. At present, no data are available concerning the levels of CST in sepsis patients. In sepsis the plasma amino acid pattern is characterized by decreased branced chain amino acids (BCAAs). We investigated the levels of plasma CST or branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK) and their relationship to component traits in patients with sepsis. DESIGN AND METHODS: We studied 228 patients and divided them into two groups based on severity of infection. Blood samples were taken at study entry, and CST, BCKDK were measured. RESULTS: CST and BCKDK levels were significantly higher in patients with sepsis than in controls: the median plasma CST concentration was 103.1ng/ml (range, <83.13-189.7ng/ml) in patients with sepsis and 49.69ng/ml (range, <19.38-100.8ng/ml) in controls (p=0.0022); the median plasma BCKDK concentration was 801.7ng/ml in sepsis group and 745ng/ml in controls (p=0.0292). Additionally, there was correlation between the plasma concentrations of CST and BCKDK in sepsis patients (r2=0.6357, p<0.01). CONCLUSIONS: We conclude that the plasma levels of CST in sepsis patients were higher than in controls, and there is a relationship between CST and BCKDK in sepsis patients. Future experimental and clinical studies are needed to evaluate CST as a novel prognostic tool in sepsis patients and its potential therapeutic use in sepsis. PMID- 27773659 TI - Ascending aortic adventitial remodeling and fibrosis are ameliorated with Apelin 13 in rats after TAC via suppression of the miRNA-122 and LGR4-beta-catenin signaling. AB - Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50MUg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFbeta1, CTGF, NFAT5, LGR4, and beta-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-beta catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100nmolL-1) led to significant increases in cellular migration and levels of TGFbeta1, CTGF, NFAT5, LGR4 and beta-catenin, which were effectively reversed by pre-treatment with Apelin (100nmolL-1) and miRNA-122 inhibitor (50nmolL-1). In conclusion, Apelin counterregulated against TAC mediated ascending aortic remodeling and angiotensin II-induced promotion of cellular migration by blocking AT1 receptor and miRNA-122 levels and preventing activation of the TGFbeta1-CTGF-NFAT5 and LGR4-beta-catenin signaling, ultimately contributing to attenuation of aortic adventitial fibrosis. Our data point to Apelin as an important regulator of aortic remodeling and adventitial fibrosis and a promising target for vasoprotective therapies. PMID- 27773661 TI - Insights into the interaction of CD4 with anti-CD4 antibodies. AB - Knowledge about the mechanism by which some antibodies can block HIV-1 entry is critical to our understanding of their function and may offer new avenues for controlling the adhesion of HIV-1 to the host cells. While much progress has been made, this mechanism remains unclear. Here, atomic force microscopy, isothermal titration calorimetry (ITC), and circular dichroism spectroscopy were used to measure some biophysical characteristics of the interaction of four-domains (D1 D4) membrane protein CD4 with anti-D3 antibody OKT4 and with HIV-1 entry blocking anti-D1 antibody Leu3a. The results showed that at 37 degrees C they bind with similar binding strength, thermodynamics, and kinetics but with different assembly states. Further analyzing the interactions at different temperatures by ITC showed that binding of CD4 with Leu3a is characteristic for specific hydrophobic binding as well as for protein folding while with OKT4 comes from an extensive additional hydration upon binding and charge-related interactions within the binding site. Comparing these characteristics with those of HIV-1 gp120-CD4 interaction revealed that Leu3a binds to CD4 faster than HIV-1 followed by changing local structure of D1 to which HIV-1 binds leading to a prevention of viral entry. PMID- 27773662 TI - Regulatory T cells in malignant pleural effusions subsequent to lung carcinoma and their impact on the course of the disease. AB - Tumors exert suppressive effects on the host immune system and tumor progression can be linked to functional impairments of immune cells. Regulatory T cells (Treg) are a subpopulation of T lymphocytes and play a key role in suppressing immune responses against autoimmune diseases and cancer. The aim of the study was to investigate the prevalence of Treg in malignant and benign pleural effusions and to evaluate the relationship between Treg frequency and disease advance. Pleural effusions from 76 patients were subjected to a routine laboratory diagnosis and analyzed by conventional cytology. Biological materials were divided into three groups: malignant pleural effusions with malignant cells, effusions from patients with malignancy but without malignant cells, and non malignant pleural effusions. The frequency of Treg in malignant pleural effusions was significantly higher compared to non-malignant effusions. In general, the increase in Treg frequency was correlated with a decrease in the percentage of lymphocytes and an increase in T CD4+ and T CD4+ CD25+ cells. The highest percentage of Treg was observed among patients with the most advanced clinical stage of lung cancer in terms of size and location of a primary tumor, T4. A Kaplan-Meier survival analysis showed a statistically significant trend towards an adverse outcome for patients representing higher Treg counts. Overall, our results support the extraordinary potential of Treg control in future anticancer therapy. PMID- 27773660 TI - Psoriatic inflammation causes hepatic inflammation with concomitant dysregulation in hepatic metabolism via IL-17A/IL-17 receptor signaling in a murine model. AB - Psoriatic inflammation has been shown to be associated with cardiovascular dysfunction and systemic inflammation. Recently, psoriasis has also been linked to hepatic disorders, however underlying mechanism connecting the two are unknown. IL-17A being a central pro-inflammatory cytokine in the pathogenesis of psoriasis may be involved in hepatic inflammation through its receptor and downward signaling; however so far no study has investigated IL-17A related signaling in the liver during psoriasis in a murine model. Therefore, this study explored psoriasis-induced hepatic inflammation and concurrent metabolic changes. Mice were applied topically imiquimod (IMQ) to develop psoriatic inflammation. Additionally mice were also treated either with IL-17A or anti-IL17A antibody to explore the role of IL-17 related signaling in liver. Mice were then assessed for hepatic inflammation through assessment of inflammatory/oxidative stress markers (IL-17RC, NFkappaB, IL-6, MCP-1, IL-1beta, GM-CSF, ICAM-1, iNOS, lipid peroxides and myeloperoxidase activity) as well as hepatic injury (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) and protein/lipid metabolic biomarkers (total proteins, albumin, total bilirubin, triglycerides, HDL cholesterol, and total cholesterol). IMQ treatment led to hepatic inflammation as evidenced by increased pro-inflammatory cytokines and oxidative stress with concomitant dysregulation in hepatic protein/lipid metabolism. Treatment with IL-17A further aggravated, whereas treatment with anti IL17A antibody ameliorated IMQ-induced changes in hepatic injury/inflammation and protein/lipid metabolism. Our study shows for the first time that psoriatic inflammation leads to hepatic inflammation which results in dysregulated protein/lipid metabolism through IL-17RC/NFkappaB signaling. This could result in increased risk of cardiovascular dysfunction in patients with psoriasis. PMID- 27773663 TI - Alterations of TRIM21-mRNA expression during monocyte maturation. AB - Tripartite motif-containing protein 21 (TRIM21) play a dual role in the cytoplasm of the cells where it facilitates destruction of some antibody-coated viruses and some bacteria, and initiates synthesis of proinflammatory cytokines. Macrophages and CD16+ monocyte subset can particularly participate in a proinflammatory response caused by viral infection, however, the molecular mechanisms underlying these processes are not fully understood. The aim of this study was to determine the level of TRIM21-mRNA expression in monocyte subsets including: classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes, as well as during in vitro differentiation of the isolated monocytes towards dendritic cells or macrophages. Our results revealed that the level of TRIM21 mRNA expression was significantly lower in CD16- monocytes, when compared to CD16+ cells and the whole monocyte population, yet no significant differences were observed when CD16+ population was divided into intermediate and non classical subsets. More pronounced differences were observed in the case of monocyte-derived macrophages (MDM) and dendritic cells (DCs). TRIM21-mRNA expression level was app. 6-fold higher in DCs, and app. 16-fold higher in MDM (p<0,01), when compared to freshly isolated monocytes. Our results may suggest the new mechanism of increased proinflammatory cytokine production by CD16+ (intermediate and non-classical) monocytes and macrophages, at least in patients with acute or chronic infections, caused by enveloped viruses. We suggest that TRIM21 may be one of the factors associated with the "switching on" the proinflammatory programme in CD16+ monocytes or monocyte-derived macrophages. PMID- 27773664 TI - Strategic approach to minimally invasive mediastinal nodal staging-a brave new world? PMID- 27773666 TI - Added value of combined endobronchial and oesophageal endosonography for mediastinal nodal staging in lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Guidelines recommend endosonography with fine-needle aspiration for mediastinal nodal staging in non-small-cell lung cancer, but most do not specify whether this should be through endobronchial endoscopy (EBUS), oesophageal endoscopy (EUS), or both. We assessed the added value and diagnostic accuracy of the combined use of EBUS and EUS. METHODS: For this systematic review and random effects meta-analysis, we searched MEDLINE, Embase, BIOSIS Previews, and Web of Science, without language restrictions, for studies published between Jan 1, 2000, and Feb 25, 2016. We included studies that assessed the accuracy of the combined use of EBUS and EUS in detecting mediastinal nodal metastases (N2/N3 disease) in patients with lung cancer. For each included study, we extracted data on the age and sex of participants, inclusion criteria regarding tumour stage on imaging, details of the endoscopic testing protocol, duration of each endoscopic procedure, number of lymph nodes sampled, serious adverse events occurring during the endoscopic procedures, the reference standard, and 2 * 2 tables for EBUS, EUS, and the combined approach. We evaluated the added value (absolute increase in sensitivity and in detection rate) of the combined use of EBUS and EUS in detecting mediastinal nodal metastases over either test alone, and the diagnostic accuracy (sensitivity and negative predictive value) of the combined approach. This study is registered with PROSPERO, number CRD42015019249. FINDINGS: We identified 2567 unique manuscripts by database search, of which 13 studies (including 2395 patients) were included in the analysis. Median prevalence of N2/N3 disease was 34% (range 23-71). On average, addition of EUS to EBUS increased sensitivity by 0.12 (95% CI 0.08-0.18) and addition of EBUS to EUS increased sensitivity by 0.22 (0.16-0.29). Mean sensitivity of the combined approach was 0.86 (0.81-0.90), and the mean negative predictive value was 0.92 (0.89-0.93). The mean negative predictive value was significantly higher in studies with a prevalence of 34% or less (0.93 [95% CI 0.91-0.95]) compared with studies with a prevalence of more than 34% (0.89 [0.85-0.91]; p=0.013). We found no significant differences in mean sensitivity and negative predictive value between studies that did EBUS first or EUS first, or between studies that used an EBUS-scope or a regular echoendoscope to do EUS. INTERPRETATION: The combined use of EBUS and EUS significantly improves sensitivity in detecting mediastinal nodal metastases, reducing the need for surgical staging procedures. FUNDING: No external funding. PMID- 27773665 TI - Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV positive individuals: a nested substudy within the multicentre, international, randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial. AB - BACKGROUND: Observational data have been conflicted regarding the potential role of HIV antiretroviral therapy (ART) as a causative factor for, or protective factor against, COPD. We therefore aimed to investigate the effect of immediate versus deferred ART on decline in lung function in HIV-positive individuals. METHODS: We did a nested substudy within the randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial at 80 sites in multiple settings in 20 high-income and low-to-middle-income countries. Participants were HIV-1 infected individuals aged at least 25 years, naive to ART, with CD4 T-cell counts of more than 500 per MUL, not receiving treatment for asthma, and without recent respiratory infections (baseline COPD was not an exclusion criterion). Participants were randomly assigned to receive ART (an approved drug combination derived from US Department of Health and Human Services guidelines) either immediately, or deferred until CD4 T-cell counts decreased to 350 per MUL or AIDS developed. The randomisation was determined by participation in the parent START study, and was not specific to the substudy. Because of the nature of our study, site investigators and participants were not masked to the treatment group assignment; however, the assessors who reviewed the outcomes were masked to the treatment group. The primary outcome was the annual rate of decline in lung function, expressed as the FEV1 slope in mL/year; spirometry was done annually during follow-up for up to 5 years. We analysed data on an intention-to-treat basis, and planned separate analyses in smokers and non-smokers because of the known effects of smoking on FEV1 decline. The substudy was registered at ClinicalTrials.gov number NCT01797367. FINDINGS: Between March 11, 2010, and Aug 23, 2013, we enrolled 1026 participants to our substudy, who were then randomly assigned to either immediate (n=518) or deferred (n=508) ART. Median baseline characteristics included age 36 years (IQR 30-44), CD4 T-cell count 648 per MUL (583-767), and HIV plasma viral load 4.2 log10 copies per mL (3.5-4.7). 29% were female and 28% were current smokers. Median follow-up time was 2.0 years (IQR 1.9 3.0). We noted no differences in FEV1 slopes between the immediate and deferred ART groups either in smokers (difference of -3.3 mL/year, 95% CI -38.8 to 32.2; p=0.86) or in non-smokers (difference of -5.6 mL/year, -29.4 to 18.3; p=0.65) or in pooled analyses adjusted for smoking status at each study visit (difference of -5.2 mL/year, -25.1 to 14.6; p=0.61). INTERPRETATION: The timing of ART initiation has no major short-term effect on rate of lung function decline in HIV positive individuals who are naive to ART, with CD4 T-cell counts of more than 500 per MUL. In light of updated WHO recommendations that all HIV-positive individuals should be treated with ART, regardless of their CD4 T-cell count, our results suggest an absence of significant pulmonary harm with such an approach. FUNDING: US National Heart Lung and Blood Institute, US National Institute of Allergy and Infectious Diseases, Division of AIDS, Agence Nationale de Recherches sur le SIDA et les Hipatites Virales (France), Australian National Health and Medical Research Council, Danish National Research Foundation, European AIDS Treatment Network, German Ministry of Education and Research, UK Medical Research Council and National Institute for Health Research, and US Veterans Health Administration Office of Research and Development. PMID- 27773668 TI - Study does not support early intubation in paediatric in-hospital cardiac arrest. PMID- 27773667 TI - Pulmonary effects of timing of antiretroviral therapy initiation. PMID- 27773670 TI - Pollen Acceptance or Rejection: A Tale of Two Pathways. AB - While the molecular and cellular basis of self-incompatibility leading to self pollen rejection in the Brassicaceae has been extensively studied, relatively little attention has been paid to compatible pollen recognition and the corresponding cellular responses in the stigmatic papillae. This is now changing because research has started to uncover steps in the Brassicaceae 'basal compatible pollen response pathway' in the stigma leading to pollen hydration and germination. Furthermore, recent studies suggest that self-incompatible pollen activates both the basal compatible pathway and the self-incompatibility pathway in the stigma, with the self-incompatibility response ultimately prevailing to reject self-pollen. We review here recent discoveries in both pathways and discuss how compatible pollen is accepted by the stigma versus the rejection of self-incompatible pollen. PMID- 27773669 TI - CYTOKININ RESPONSE FACTORs Gating Environmental Signals and Hormones. AB - CYTOKININ RESPONSE FACTORs (CRFs) encode transcription factors belonging to a small family within the APETALA2/ETHYLENE RESPONSIVE FACTOR (AP2/ERF) superfamily. Recent studies have revealed the biological functions of some arabidopsis CRFs, providing insight into the role of these plant transcription factors in integrating environmental and hormonal signals for plant adaptation. PMID- 27773671 TI - MOZ and BMI1 act synergistically to maintain hematopoietic stem cells. AB - Chromatin plays a central role in maintaining hematopoietic stem cells and during their stepwise differentiation. Although a large number of histone modifications and chromatin-modifying enzymes have been identified, how these act in concert to produce specific phenotypic outcomes remains to be established. MOZ (KAT6A) is a lysine acetyltransferase and enhances transcription at target gene loci. In contrast, the Polycomb group protein BMI1 (PCGF4) is part of the transcriptionally repressive PRC1 complex. Despite their opposing effects on transcription, MOZ and BMI1 regulate biological systems in a similar manner. MOZ and BMI1 are required for the development of transplantable HSCs, for restraining cellular senescence, for the proper patterning of the anterior-posterior axis during development and for the specification and maintenance of the B-cell lineage. Thus, we set out to explore the relationship between MOZ and BMI1. We recently established that MOZ and BMI1 have opposing effects on the initiation of Hox gene expression during embryonic development and that defects in body segment identity specification observed in single Moz and Bmi1 mutants were rescued in compound mutants. We report here the relationship between MOZ and BMI1 in hematopoiesis. Using Moz+/-;Bmi1+/- compound mutant mice, we found that MOZ and BMI1, but not the BMI1-related protein MEL18 (PCGF2), play synergistic roles in maintaining adult HSCs. Although BMI1 restrains premature senescence, we established that MOZ acts to maintain the quiescent state of HSCs. Our work revealed that MOZ and BMI1 regulate HSCs in a synergistic manner by acting on distinct processes required to maintain HSCs. PMID- 27773672 TI - Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2. AB - SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A.X (encoded by H2AFX). Upon genotoxic stress in G2, high levels of H2A.X lead to persistent gammaH2A.X signaling, high levels of H2A.X phosphorylated on Tyr142, high levels of p53, and induction of apoptosis. We propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX mRNA to mediate SLBP degradation, thereby limiting H2A.X synthesis and cell death upon genotoxic stress. PMID- 27773673 TI - Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival. AB - MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N Myc. PLK1 specifically binds to the SCFFbw7 ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers. PMID- 27773675 TI - Mediator Undergoes a Compositional Change during Transcriptional Activation. AB - Mediator is a transcriptional co-activator recruited to enhancers by DNA-binding activators, and it also interacts with RNA polymerase (Pol) II as part of the preinitiation complex (PIC). We demonstrate that a single Mediator complex associates with the enhancer and core promoter in vivo, indicating that it can physically bridge these transcriptional elements. However, the Mediator kinase module associates strongly with the enhancer, but not with the core promoter, and it dissociates from the enhancer upon depletion of the TFIIH kinase. Severing the kinase module from Mediator by removing the connecting subunit Med13 does not affect Mediator association at the core promoter but increases occupancy at enhancers. Thus, Mediator undergoes a compositional change in which the kinase module, recruited via Mediator to the enhancer, dissociates from Mediator to permit association with Pol II and the PIC. As such, Mediator acts as a dynamic bridge between the enhancer and core promoter. PMID- 27773674 TI - Expanding the Circuitry of Pluripotency by Selective Isolation of Chromatin Associated Proteins. AB - Maintenance of pluripotency is regulated by a network of transcription factors coordinated by Oct4, Sox2, and Nanog (OSN), yet a systematic investigation of the composition and dynamics of the OSN protein network specifically on chromatin is still missing. Here we have developed a method combining ChIP with selective isolation of chromatin-associated proteins (SICAP) followed by mass spectrometry to identify chromatin-bound partners of a protein of interest. ChIP-SICAP in mouse embryonic stem cells (ESCs) identified over 400 proteins associating with OSN, including several whose interaction depends on the pluripotent state. Trim24, a previously unrecognized protein in the network, converges with OSN on multiple enhancers and suppresses the expression of developmental genes while activating cell cycle genes. Consistently, Trim24 significantly improved efficiency of cellular reprogramming, demonstrating its direct functionality in establishing pluripotency. Collectively, ChIP-SICAP provides a powerful tool to decode chromatin protein composition, further enhanced by its integrative capacity to perform ChIP-seq. PMID- 27773676 TI - The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation. AB - Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4E-BPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E. Here, we describe crystal structures of human and Drosophila melanogaster eIF4E-eIF4G complexes, which unexpectedly reveal that the eIF4G auxiliary sequences bind to the lateral surface of eIF4E, using a similar mode to that of 4E-BPs. Our studies provide a molecular model of the eIF4E-eIF4G complex, shed light on the competition mechanism of 4E-BPs, and enable the rational design of selective eIF4G inhibitors to dampen dysregulated translation in disease. PMID- 27773679 TI - Wheelchair control by elderly participants in a virtual environment with a brain computer interface (BCI) and tactile stimulation. AB - Tactile event-related potential (ERP) are rarely used as input signal to control brain-computer-interfaces (BCI) due to their low accuracy and speed (information transfer rate, ITR). Age-related loss of tactile sensibility might further decrease their viability for the target population of BCI. In this study we investigated whether training improves tactile ERP-BCI performance within a virtual wheelchair navigation task. Elderly subjects participated in 5 sessions and tactors were placed at legs, abdomen and back. Mean accuracy and ITR increased from 88.43%/4.5bitsmin-1 in the 1st to 92.56%/4.98bitsmin-1 in the last session. The mean P300 amplitude increased from 5.46MUV to 9.22MUV. In an optional task participants achieved an accuracy of 95,56% and a mean ITR of 20,73bitsmin-1 which is the highest ever achieved with tactile stimulation. Our sample of elderly people further contributed to the external validity of our results. PMID- 27773678 TI - Heart rate variability: Pre-deployment predictor of post-deployment PTSD symptoms. AB - Heart rate variability is a physiological measure associated with autonomic nervous system activity. This study hypothesized that lower pre-deployment HRV would be associated with higher post-deployment post-traumatic stress disorder (PTSD) symptoms. Three-hundred-forty-three Army National Guard soldiers enrolled in the Warriors Achieving Resilience (WAR) study were analyzed. The primary outcome was PTSD symptom severity using the PTSD Checklist - Military version (PCL) measured at baseline, 3- and 12-month post-deployment. Heart rate variability predictor variables included: high frequency power (HF) and standard deviation of the normal cardiac inter-beat interval (SDNN). Generalized linear mixed models revealed that the pre-deployment PCL*ln(HF) interaction term was significant (p<0.0001). Pre-deployment SDNN was not a significant predictor of post-deployment PCL. Covariates included age, pre-deployment PCL, race/ethnicity, marital status, tobacco use, childhood abuse, pre-deployment traumatic brain injury, and previous combat zone deployment. Pre-deployment heart rate variability predicts post-deployment PTSD symptoms in the context of higher pre deployment PCL scores. PMID- 27773677 TI - Tail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo. AB - Mediator is a highly conserved transcriptional coactivator organized into four modules, namely Tail, Middle, Head, and Kinase (CKM). Previous work suggests regulatory roles for Tail and CKM, but an integrated model for these activities is lacking. Here, we analyzed the genome-wide distribution of Mediator subunits in wild-type and mutant yeast cells in which RNA polymerase II promoter escape is blocked, allowing detection of transient Mediator forms. We found that although all modules are recruited to upstream activated regions (UAS), assembly of Mediator within the pre-initiation complex is accompanied by the release of CKM. Interestingly, our data show that CKM regulates Mediator-UAS interaction rather than Mediator-promoter association. In addition, although Tail is required for Mediator recruitment to UAS, Tailless Mediator nevertheless interacts with core promoters. Collectively, our data suggest that the essential function of Mediator is mediated by Head and Middle at core promoters, while Tail and CKM play regulatory roles. PMID- 27773681 TI - Topological language for RNA. AB - : In this paper we introduce a novel, context-free grammar, RNAFeatures*, capable of generating any RNA structure including pseudoknot structures (pk-structure). We represent pk-structures as orientable fatgraphs, which naturally leads to a filtration by their topological genus. Within this framework, RNA secondary structures correspond to pk-structures of genus zero. RNAFeatures* acts on formal, arc-labeled RNA secondary structures, called lambda-structures. lambda structures correspond one-to-one to pk-structures together with some additional information. This information consists of the specific rearrangement of the backbone, by which a pk-structure can be made cross-free. RNAFeatures* is an extension of the grammar for secondary structures and employs an enhancement by labelings of the symbols as well as the production rules. We discuss how to use RNAFeatures* to obtain a stochastic context-free grammar for pk-structures, using data of RNA sequences and structures. The induced grammar facilitates fast Boltzmann sampling and statistical analysis. As a first application, we present an O(nlog (n)) runtime algorithm which samples pk-structures based on ninety tRNA sequences and structures from the Nucleic Acid Database (NDB). AVAILABILITY: the source code for simulation results is available at http://staff.vbi.vt.edu/fenixh/TPstructure.zip. The code is written in C and compiled by Xcode. PMID- 27773680 TI - Vasopressin V1A receptor mediates cell proliferation through GRK2-EGFR-ERK1/2 pathway in A7r5 cells. AB - Abnormal proliferation and hypertrophy of vascular smooth muscle (VSMC), as the main structural component of the vasculature, is an important pathological mechanism of hypertension. Recently, increased levels of arginine vasopressin (AVP) and copeptin, the C-terminal fragment of provasopressin, have been shown to correlate with the development of preeclampsia. AVP targets on the Gq-coupled vasopressin V1A receptor and the Gs-coupled V2 receptor in VSMC and the kidneys to regulate vascular tone and water homeostasis. However, the role of the vasopressin receptor on VSM cell proliferation during vascular remodeling is unclear. Here, we studied the effects of AVP on the proliferation of the rat VSMC derived A7r5 cells. AVP, in a time- and concentration-dependent manner, promoted A7r5 cell proliferation as indicated by the induction of proliferating cell nuclear antigen expression, methylthiazolyldiphenyl-tetrazolium reduction and incorporation of 5'-bromodeoxyuridine into cellular DNA. These effects, coupled with the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), were blocked by a V1A receptor antagonist SR45059 but not by a V2 receptor antagonist lixivaptan. Although acute activation of V1A receptor induced ERK1/2 phosphorylation via a protein kinase C-dependent pathway, this effect was not involved in cell proliferation. Cell proliferation and ERK1/2 phosphorylation in response to prolonged stimulation with AVP were abolished by inhibition of G protein-coupled receptor kinase 2 (GRK2) and epidermal growth factor receptor (EGFR) using specific inhibitors or small hairpin RNA knock-down. These results suggest that activation of V1A, but not V2 receptor, produces a cell proliferative signal in A7r5 cells via a GRK2/EGFR/ERK1/2-dependent mechanism. PMID- 27773682 TI - Transmission dynamics of two dengue serotypes with vaccination scenarios. AB - In this work we present a mathematical model that incorporates two Dengue serotypes. The model has been constructed to study both the epidemiological trends of the disease and conditions that allow coexistence in competing strains under vaccination. We consider two viral strains and temporary cross-immunity with one vector mosquito population. Results suggest that vaccination scenarios will not only reduce disease incidence but will also modify the transmission dynamics. Indeed, vaccination and cross immunity period are seen to decrease the frequency and magnitude of outbreaks but in a differentiated manner with specific effects depending upon the interaction vaccine and strain type. PMID- 27773684 TI - Tuberculosis: An Infection-Initiated Autoimmune Disease? AB - Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and provided original proof that an infectious agent can cause human disease. However, key steps in TB pathogenesis remain poorly understood. We propose that autoimmunity is a critical and overlooked process driving pathology in TB, and present clinical and experimental observations supporting this hypothesis. PMID- 27773683 TI - Autophagy-lysosome dysfunction is involved in Abeta deposition in STZ-induced diabetic rats. AB - beta-Amyloid (Abeta) deposition has a central role in the pathogenesis of Alzheimer disease (AD). Previous studies have indicated that as a risk factor for AD, diabetes mellitus (DM) could induce Abeta deposition in the brain, but the mechanism is not fully elucidated. Autophagy-lysosome is a cellular pathway involved in protein and organelle degradation. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether autophagy lysosome is related to Abeta1-42 clearance in DM. We found that DM rats had a longer escape latency and less frequent entry into the target zone than that of the control group (p<0.05) in the Morris water maze test. Meanwhile, hippocampal neuron damage and apoptosis (p<0.05) were found in the DM rats. The Abeta1-42 expression in the hippocampus significantly increased in the DM group compared with the control group (p<0.05). The markers of autophagy, beclin-1 and LC3 II, were increased (p<0.05), whereas LC3 I was decreased (p<0.05), and the ratio of LC3 II / I was increased as the time advanced (p<0.01). LAMP1 and LAMP2, which are the markers of lysosome function, were decreased in the hippocampus of DM rats (p<0.05). The Abeta1-42 deposition was correlated with beclin-1, LC3 II, and LC3 I positively (p<0.05), but with LAMP1 and LAMP2 negatively (p<0.05). These findings indicate that DM activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in the Abeta deposition in diabetic cognitive impairment. PMID- 27773686 TI - Differential modulation of FXR activity by chlorophacinone and ivermectin analogs. AB - Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3 indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z) Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRalpha), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs. PMID- 27773685 TI - Harnessing NK Cell Memory for Cancer Immunotherapy. AB - Due to their ability to kill cancer cells and produce proinflammatory cytokines, natural killer (NK) cells have long been of clinical interest for their antitumor properties. The recent discovery of NK cell memory demonstrates that NK cell functions, and potentially antitumor responses, can be enhanced long term. Following nonspecific activation with the cytokines IL-12, IL-15, and IL-18 or in response to antigens or cytomegalovirus (CMV), human and mouse NK cells exhibit stable, enhanced functional responses with phenotypic and molecular changes. Here we review mechanisms driving the differentiation of NK cell memory-like properties, evidence for antitumor activity, and the challenges and opportunities in harnessing memory-like NK cells for cancer immunotherapy. PMID- 27773690 TI - Interactive roles of the cerebellum and striatum in sub-second and supra-second timing: Support for an initiation, continuation, adjustment, and termination (ICAT) model of temporal processing. AB - The contributions of cortico-cerebellar and cortico-striatal circuits to timing and time perception have often been a point of contention. In this review we propose that the cerebellum principally functions to reduce variability, through the detection of stimulus onsets and the sub-division of longer durations, thus contributing to both sub-second and supra-second timing. This sensitivity of the cerebellum to stimulus dynamics and subsequent integration with motor control allows it to accurately measure intervals within a range of 100-2000ms. For intervals in the supra-second range (e.g., >2000ms), we propose that cerebellar output signals from the dentate nucleus pass through thalamic connections to the striatum, where cortico-thalamic-striatal circuits supporting higher-level cognitive functions take over. Moreover, the importance of intrinsic circuit dynamics as well as behavioral, neuroimaging, and lesion studies of the cerebellum and striatum are discussed in terms of a framework positing initiation, continuation, adjustment, and termination phases of temporal processing. PMID- 27773687 TI - Scaffolding in the Spliceosome via Single alpha Helices. AB - The spliceosomal B complex-specific protein Prp38 forms a complex with the intrinsically unstructured proteins MFAP1 and Snu23. Our binding and crystal structure analyses show that MFAP1 and Snu23 contact Prp38 via ER/K motif stabilized single alpha helices, which have previously been recognized only as rigid connectors or force springs between protein domains. A variant of the Prp38 binding single alpha helix of MFAP1, in which ER/K motifs not involved in Prp38 binding were mutated, was less alpha-helical in isolation and showed a reduced Prp38 affinity, with opposing tendencies in interaction enthalpy and entropy. Our results indicate that the strengths of single alpha helix-based interactions can be tuned by the degree of helix stabilization in the unbound state. MFAP1, Snu23, and several other spliceosomal proteins contain multiple regions that likely form single alpha helices via which they might tether several binding partners and act as intermittent scaffolds that facilitate remodeling steps during assembly of an active spliceosome. PMID- 27773689 TI - Energetics and Dynamics Across the Bcl-2-Regulated Apoptotic Pathway Reveal Distinct Evolutionary Determinants of Specificity and Affinity. AB - Critical regulatory pathways are replete with instances of intra- and interfamily protein-protein interactions due to the pervasiveness of gene duplication throughout evolution. Discerning the specificity determinants within these systems has proven a challenging task. Here, we present an energetic analysis of the specificity determinants within the Bcl-2 family of proteins (key regulators of the intrinsic apoptotic pathway) via a total of ~20 MUs of simulation of 60 distinct protein-protein complexes. We demonstrate where affinity and specificity of protein-protein interactions arise across the family, and corroborate our conclusions with extensive experimental evidence. We identify energy and specificity hotspots that may offer valuable guidance in the design of targeted therapeutics for manipulating the protein-protein interactions within the apoptosis-regulating pathway. Moreover, we propose a conceptual framework that allows us to quantify the relationship between sequence, structure, and binding energetics. This approach may represent a general methodology for investigating other paralogous protein-protein interaction sites. PMID- 27773691 TI - Meaning, intention, and inference in primate vocal communication. AB - Two core questions in the study of speech evolution are whether nonhuman primate signals should be conceived as referential, and what the role of social cognition is in primate communication. Current evidence suggests that the structure of primate vocalizations is largely innate and related to the affective/motivational state of the caller, with a probabilistic and underdetermined relationship between specific events and calls. Moreover, nonhuman primates do not appear to express or comprehend communicative or informative intent, which is in line with a lack of mental state attribution to others. We argue that nonhuman primate vocalizations as well as gestures should be best conceived as goal-directed, where signallers are sensitive to the relation between their signalling and receivers' responses. Receivers in turn use signals to predict signaller behaviour. In combination with their ability to integrate information from multiple sources, this renders the system as a whole relatively powerful, despite the lack of higher-order intentionality on the side of sender or receiver. PMID- 27773688 TI - Structure of the EndoMS-DNA Complex as Mismatch Restriction Endonuclease. AB - Archaeal NucS nuclease was thought to degrade the single-stranded region of branched DNA, which contains flapped and splayed DNA. However, recent findings indicated that EndoMS, the orthologous enzyme of NucS, specifically cleaves double-stranded DNA (dsDNA) containing mismatched bases. In this study, we determined the structure of the EndoMS-DNA complex. The complex structure of the EndoMS dimer with dsDNA unexpectedly revealed that the mismatched bases were flipped out into binding sites, and the overall architecture most resembled that of restriction enzymes. The structure of the apo form was similar to the reported structure of Pyrococcus abyssi NucS, indicating that movement of the C-terminal domain from the resting state was required for activity. In addition, a model of the EndoMS-PCNA-DNA complex was preliminarily verified with electron microscopy. The structures strongly support the idea that EndoMS acts in a mismatch repair pathway. PMID- 27773692 TI - Pretreatment and prophylaxis against nerve agent poisoning: Are undesirable behavioral side effects unavoidable? AB - The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment (pyridostigmine) may cause some side effects in a small number of individuals. A comprehensive research on animals has been performed to clarify effects on behavior. The results from these studies are far from unambiguous, since pyridostigmine may produce adverse effects on behavior in animals in relatively high doses, but not in a consistent way. Other animal studies have examined the potential of drugs like physostigmine, galantamine, benactyzine, trihexyphenidyl, and procyclidine, but they all produce marked behavioral impairment at doses sufficient to contribute to protection against a convulsant dose of soman. Attempts have also been made to develop a combination of drugs capable of assuring full protection (prophylaxis) against nerve agents. However, common to all combinations is that they at anticonvulsant doses cause behavioral deficits. Therefore, the use of limited pretreatment doses may be performed without marked side effects followed by post-exposure therapy with a combination of drugs. PMID- 27773693 TI - Hippocampal volume in subjects at clinical high-risk for psychosis: A systematic review and meta-analysis. AB - Several magnetic resonance imaging studies have reported reductions in hippocampal volume in patients with psychosis. It is unclear whether structural abnormalities predate illness onset. We conducted a detailed, systematic literature search for studies reporting hippocampal volume in subjects with clinical high-risk, compared to healthy controls. The overall sample size comprised 1429 subjects. Meta-analysis revealed no difference for left, but a small, albeit significant, difference for right hippocampal volume, such that clinical high-risk patients had slightly smaller hippocampal volume than healthy controls (g=0.24, p=0.0418). Meta-regression indicated a moderating effect of manual tracing approach, due to one outlying site. The small difference on the right side did not remain significant (g=0.14, 95%CI=[-0.03-0.32], p=0.11) after removal of this outlier. This meta-analysis suggests that there is no reduction in hippocampal volume before transition to psychosis and hippocampal volume cannot be used as a biomarker in clinical high-risk individuals. PMID- 27773694 TI - Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis. AB - Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis. PMID- 27773699 TI - FEMA expert panel review of p-mentha-1,8-dien-7-al genotoxicity testing results. AB - p-Mentha-1,8-dien-7-al is a naturally occurring cyclic alpha,beta-unsaturated aldehyde that is used as a flavoring substance throughout the world. Due to the chemical structure and the potential DNA reactivity of the alpha,beta-unsaturated carbonyl moiety, a battery of genotoxicity assays was requested by the European Food Safety Authority. Previous genotoxicity studies on the substance gave mixed results, but both positive and negative results were hampered by not always being performed to any standard guideline. The new test battery data indicated some evidence of mutagenicity in vitro, but an in vivo comet/micronucleus combination assay performed in rats was concluded by the study directors to not result in any biologically relevant positive responses. However, EFSA concluded that the in vivo assay gave evidence that p-mentha-1,8-dien-7-al was of potential genotoxic concern. The Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) has reviewed the newly available data and considered its interpretation relative to standard guidelines such as that established by the Organization for Economic Cooperation and Development, and has concluded that the results in the comet/micronucleus combination assay are consistent with the interpretation by the study directors; namely, that p-mentha-1,8-dien-7-al does not appear to have any in vivo genotoxic potential. PMID- 27773696 TI - Circadian Clock Interaction with HIF1alpha Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle. AB - Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1alpha (HIF1alpha) under hypoxic conditions. Bmal1-/- myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1alpha targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1alpha in response to hypoxia. HIF1alpha bound directly to core clock gene promoters, and, when co-expressed with BMAL1, led to transactivation of PER2-LUC and HRE-LUC reporters. Further, genetic stabilization of HIF1alpha in Vhl-/- cells altered circadian transcription. Finally, induction of clock and HIF1alpha target genes in response to strenuous exercise varied according to the time of day in wild-type mice. Collectively, our results reveal bidirectional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia. PMID- 27773695 TI - Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1alpha. AB - The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1alpha-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1alpha. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild type but not of HIF1alpha-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1alpha activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag. PMID- 27773698 TI - Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J. AB - : Mouse models of acetaminophen (APAP) hepatotoxicity are considered relevant for the human pathophysiology. The C57BL/6 strain is most popular because it is the background strain of gene knock-out mice. However, conflicting results in the literature may have been caused by sub-strain mismatches, e.g. C57BL/6J and C57BL/6N. This study was initiated to determine the mechanism behind the sub strain susceptibility to APAP toxicity. C57BL/6N and C57BL/6J mice were dosed with 200 mg/kg APAP and sacrificed at different time points. C57BL/6N mice developed significantly more liver injury as measured by plasma ALT activities and histology. Although there was no difference in glutathione depletion or cytochrome P450 activity between groups, C57BL/6N had a higher glutathione disulfide-to-glutathione ratio and more APAP protein adducts. C57BL/6N showed more mitochondrial translocation of phospho-JNK and BAX, and more release of mitochondrial intermembrane proteins apoptosis-inducing factor (AIF), second mitochondria-derived activator of caspases (SMAC), which caused more DNA fragmentation. The increased mitochondrial dysfunction was confirmed in vitro as C57BL/6N hepatocytes had a more precipitous drop in JC-1 fluorescence after APAP exposure. CONCLUSION: C57BL/6N mice are more susceptible to APAP-induced hepatotoxicity, likely due to increased formation of APAP-protein adducts and a subsequent enhancement of mitochondrial dysfunction associated with aggravated nuclear DNA fragmentation. PMID- 27773697 TI - Reciprocal Regulation between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals. AB - Circadian regulation is critically important in maintaining metabolic and physiological homeostasis. However, little is known about the possible influence of the clock on physiological abnormalities occurring under pathological conditions. Here, we report the discovery that hypoxia, a condition that causes catastrophic bodily damage, is gated by the circadian clock in vivo. Hypoxia signals conversely regulate the clock by slowing the circadian cycle and dampening the amplitude of oscillations in a dose-dependent manner. ChIP-seq analyses of hypoxia-inducible factor HIF1A and the core clock component BMAL1 revealed crosstalk between hypoxia and the clock at the genome level. Further, severe consequences caused by acute hypoxia, such as those that occur with heart attacks, were correlated with defects in circadian rhythms. We propose that the clock plays functions in fine-tuning hypoxic responses under pathophysiological conditions. We argue that the clock can, and likely should, be exploited therapeutically to reduce the severity of fatal hypoxia-related diseases. PMID- 27773700 TI - Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells. AB - We established two human embryonic stem cell (hESC) lines with a GGGGCC expansion in the C9orf72 gene (C9), and compared them with haploidentical and unrelated C9 induced pluripotent stem cells (iPSCs). We found a marked difference in C9 methylation between the cells. hESCs and parental fibroblasts are entirely unmethylated while the iPSCs are hypermethylated. In addition, we show that the expansion alters promoter usage and interferes with the proper splicing of intron 1, eventually leading to the accumulation of repeat-containing mRNA following neural differentiation. These changes are attenuated in C9 iPSCs, presumably owing to hypermethylation. Altogether, this study highlights the importance of neural differentiation in the pathogenesis of disease and points to the potential role of hypermethylation as a neuroprotective mechanism against pathogenic mRNAs, envisaging a milder phenotype in C9 iPSCs. PMID- 27773702 TI - Transcriptional and Chromatin Dynamics of Muscle Regeneration after Severe Trauma. AB - Following injury, adult skeletal muscle undergoes a well-coordinated sequence of molecular and physiological events to promote repair and regeneration. However, a thorough understanding of the in vivo epigenomic and transcriptional mechanisms that control these reparative events is lacking. To address this, we monitored the in vivo dynamics of three histone modifications and coding and noncoding RNA expression throughout the regenerative process in a mouse model of traumatic muscle injury. We first illustrate how both coding and noncoding RNAs in tissues and sorted satellite cells are modified and regulated during various stages after trauma. Next, we use chromatin immunoprecipitation followed by sequencing to evaluate the chromatin state of cis-regulatory elements (promoters and enhancers) and view how these elements evolve and influence various muscle repair and regeneration transcriptional programs. These results provide a comprehensive view of the central factors that regulate muscle regeneration and underscore the multiple levels through which both transcriptional and epigenetic patterns are regulated to enact appropriate repair and regeneration. PMID- 27773703 TI - N-Glycoform-dependent interactions of megalin with its ligands. AB - BACKGROUND: Megalin is a 600-kDa single-spanning transmembrane glycoprotein and functions as an endocytic receptor, distributed not only in the kidney but also in other tissues. Structurally and functionally distinct ligands for megalin have been identified. Megalin has 30 potential N-glycosylation sites in its extracellular domain. We found that megalin interacts with its ligands in a glycoform-dependent manner. METHODS: Distribution of megalin and glycans was histochemically analyzed in mouse kidneys. Kidney absorption of Cy5-labeled ligands was examined in vivo. Megalin-ligand interactions were analyzed using ligand blotting and ELISA. RESULTS: Megalins expressed on renal proximal convoluted tubules (PCTs) and proximal straight tubules (PSTs) have different N glycans. PCT megalin stained with Lens culinaris agglutinin (LCA), which recognizes core-fucosyl N-glycans catalyzed by alpha1,6-fucosyltransferase (Fut8). In contrast, PST megalin stained with wheat germ agglutinin (WGA), which recognizes hybrid-type N-glycans. Retinol-binding protein-Cy5 (RBP-Cy5) was endocytosed by megalin on PCTs but minimally endocytosed by PSTs. BSA-Cy5 was endocytosed nearly equally by both tubules. The purified LCA-positive glycoform megalin had higher binding activity for RBP and vitamin D-binding protein than did WGA-positive glycoform megalin. Both glycoforms had nearly the same BSA- and kanamycin-binding activities. RBP-binding analysis of megalin lacking core fucose, in Fut8-/- mouse kidneys, had significantly decreased binding activity. CONCLUSIONS: N-Glycosylation of megalin can modulate its ligand-binding activity. Core fucosylation, in particular, is a modification crucial for megalin-RBP interactions. GENERAL SIGNIFICANCE: Cell type-specific glycoforms of megalin exist in the proximal tubular cells and modulate ligand absorption capacity. PMID- 27773704 TI - Membrane damage by betulinic acid provides insights into cellular aging. AB - BACKGROUND: Cell senescence is a process of central importance to the understanding of aging as well as to the development of new drugs. It is related with genomic instability, which has been shown to occur in the presence of autophagy deficiency. Yet, the mechanism that triggers genomic instability and senescence from a condition of autophagy deficiency remains unknown. By analyzing the consequences of treating human keratinocytes (HaCaT) with the pentacyclic triterpenoid Betulinic Acid (BA) we were able to propose that cell senescence can develop as a response to parallel damage in the membranes of mitochondria and lysosome. METHODS: We performed biochemical, immunocytochemical and cytometric assays after challenging HaCaT cells with BA. We also evaluated membrane leakage induced by BA in liposomes and giant unilamellar vesicles. RESULTS: By destabilizing lipid bilayers of mitochondria and lysosomes, BA triggers the misbalance in the mitochondrial-lysosomal axis leading to perceived autophagy impairment, lipofuscinogenesis, genomic instability and cell senescence. The progressive accumulation of mitochondria and lipofuscin, which comes from imperfect mitophagy triggered by BA, provides a continuous source of reactive species further damaging lysosomes and leading to cell aging. CONCLUSIONS: This work reveals that the initial trigger of cell senescence can be the physical damage in the membranes of lysosomes and mitochondria. GENERAL SIGNIFICANCE: This concept will help in the search of new drugs that act as senescence-inductors. BA is under evaluation as chemotherapeutic agent against several types of tumors and induction of cell senescence should be considered as one of its main mechanisms of action. PMID- 27773701 TI - Rare SOX2+ Airway Progenitor Cells Generate KRT5+ Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection. AB - Recent studies have implicated keratin 5 (KRT5)+ cells in repopulation of damaged lung tissue following severe H1N1 influenza virus infection. However, the origins of the cells repopulating the injured alveolar region remain controversial. We sought to determine the cellular dynamics of lung repair following influenza infection and define whether nascent KRT5+ cells repopulating alveolar epithelium were derived from pre-existing alveolar or airway progenitor cells. We found that the wound-healing response begins with proliferation of SOX2+ SCGB1A1- KRT5- progenitor cells in airways. These cells generate nascent KRT5+ cells as an early response to airway injury and yield progeny that colonize damaged alveolar parenchyma. Moreover, we show that local alveolar progenitors do not contribute to nascent KRT5+ cells after injury. Repopulation of injured airway and alveolar regions leads to proximalization of distal airways by pseudostratified epithelium and of alveoli by airway-derived epithelial cells that lack the normal characteristics of mature airway or alveolar epithelium. PMID- 27773705 TI - Genomic organization and evolution of olfactory receptors and trace amine associated receptors in channel catfish, Ictalurus punctatus. AB - BACKGROUND: Channel catfish (Ictalurus punctatus) live in turbid waters with limited visibility to chase prey within a certain distance. This can be compensated through detecting specific water-soluble substances by the olfactory receptors (ORs) and trace amine associated receptors (TAARs) expressed on the olfactory epithelium. METHODS: We identified the OR and TAAR repertoires in channel catfish, and characterized the genomic organizations of these two gene families by data mining available genomic resources. RESULTS: A total of 47 putative OR genes and 36 putative TAAR genes were identified in the channel catfish genome, including 27 functional OR genes and 28 functional TAAR genes. Phylogenetic and orthogroup analyses were conducted to illustrate the evolutionary dynamics of the vertebrate ORs and TAARs. Collinear analysis revealed the presence of two conserved orthologous blocks that contain OR genes between the catfish genome and zebrafish genome. The complete loss of a conserved motif in fish OR family H may contribute to the divergence of family H from other families. The dN/dS analysis indicated that the highest degree of selection pressure was imposed on TAAR subfamily 14 among all fish ORs and TAARs. CONCLUSIONS: The present study provides understanding of the evolutionary dynamics of the two gene families (OR and TAAR) associated with olfaction in channel catfish. GENERAL SIGNIFICANCE: This is the first systematic study of ORs and TAARs in catfish, which could provide valuable genomic resources for further investigation of olfactory mechanisms in teleost fish. PMID- 27773706 TI - Synthesis, biological characterization and evaluation of molecular mechanisms of novel copper complexes as anticancer agents. AB - BACKGROUND: To overcome the hurdles of cisplatin, majorly its toxicity and resistance, there has been extensive search for alternative anti-cancer metal based compounds. Here, three Cu(II)-complexes, Cu(Sal-Gly)(phen), Cu(Sal Gly)(pheamine), Cu(Sal-Gly)(phepoxy) are characterized for their interaction with DNA, cytotoxicity and mechanism of action. METHODS: The binding ability of the complexes to Calf-Thymus DNA was evaluated by competition fluorescence studies with thiazole-orange, UV-Vis and circular dichroism spectroscopic titrations. Cytotoxicity was evaluated by MTT analysis. The DNA damage was analyzed through cleavage of supercoiled DNA via agarose gel-electrophoresis, and 8-oxo-guanidine and gammaH2AX staining in cells. Apoptosis was detected via DNA condensation/fragmentation, mitochondrial membrane potential, Annexin V staining and caspase 3/7 activity. Formation of reactive oxygen species was determined by DCFDA- and GSSG/GSH-analysis. RESULTS: Binding constants to DNA were evaluated as 1.7*106 (Cu(Sal-Gly)(phen)), 2.5*106 (Cu(Sal-Gly)(pheamine)) and 3.2*105 (Cu(Sal Gly)(phepoxy)). All compounds induced DNA damage. Apoptosis was the main form of cell death. There was an increase in ROS, which is most likely responsible for the observed DNA-damage. Although the compounds were cytotoxic to all tested cancer cell lines, only Cu(Sal-Gly)(pheamine) displayed significantly lower toxicity towards non-cancer cells, its associated phenotypes differing from the other two Cu-complexes. Thus, Cu(Sal-Gly)(pheamine) was further assayed for molecular changes in response to drug treatment using a custom designed RT-qPCR array. Results showed that Harakiri was significantly upregulated. Presence of p53 was not required for apoptosis in response to Cu-complexes. CONCLUSIONS AND GENERAL SIGNIFICANCE: These Cu-complexes, namely Cu(Sal-Gly)(pheamine), may be considered promising anticancer agents with activity in cancer cells even with deficient p53 status. PMID- 27773707 TI - Moving targets: Promoting physical activity in public spaces via open streets in the US. AB - Popularity of Open Streets, temporarily opening streets to communities and closing streets to vehicles, in the US has recently surged. As of January 2016, 122 cities have hosted an Open Streets program. Even with this great expansion, the sustainability of Open Streets remains a challenge in many cities and overall Open Streets in the US differ from their successful counterparts in Central and South America. Between summer 2015 and winter 2016, we reviewed the websites and social media of the 122 identified programs and interviewed 32 unique Open Streets programs. Websites and social media were reviewed for program initiation, number of Open Streets days, length of routes, duration of program, and reported participation. Interview questions focused on barriers and facilitators of expanding Open Streets and specific questioning regarding local evaluation activities. All interviews were transcribed verbatim and analyzed with constant comparative methodology. Over three-quarters of US Open Streets programs have been initiated since 2010, with median frequency of one time per year, 4h per date, and 5000-9999 participants. Seventy-seven percent of program routes are under 5km in length. Success of programs was measured by enthusiasm, attendance, social media, survey metrics, and sustainability. Thirteen of 32 program organizers expressed interest in expanding their programs to 12 dates per year, but noted consistent barriers to expansion including funding, permitting, and branding. Though many cities now host Open Streets programs, their ability to effect public health remains limited with few program dates per year. Coordinated efforts, especially around funding, permitting, and branding may assist in expanding program dates. PMID- 27773708 TI - The impact of an IUD and implant intervention on dual method use among young women: Results from a cluster randomized trial. AB - Long-acting reversible contraceptives (LARCs) are highly effective at preventing pregnancy but do not protect against sexually transmitted infection (STI). Recent efforts to improve access to intrauterine devices (IUDs) and implants have raised concerns about STI prevention and reduced condom use, particularly among teenagers and young women. We evaluated whether a provider-targeted intervention to increase LARC access negatively impacted dual method use and STI incidence among an at-risk patient population. We conducted a cluster randomized trial in 40 reproductive health centers across the United States from May 2011 to May 2013. After training providers at 20 intervention sites, we recruited 1500 sexually-active women aged 18-25years who did not desire pregnancy and followed them for one year. We assessed intervention effects on dual method use, condom use and STI incidence, modeling dual method use with generalized estimating equations and STI incidence with Cox proportional hazard regression models, accounting for clustering. We found no differences between intervention and control groups in dual method use (14.3% vs. 14.4%, aOR 1.03, 95% CI 0.74-1.44) or condom use (30% vs. 31%, aOR 1.03, 95% CI 0.79-1.35) at last sex at one year. STI incidence was 16.5 per 100 person-years and did not differ between intervention and control groups (aHR 1.20, 95% CI 0.88-1.64). A provider training intervention to increase LARC access neither compromised condom use nor increased STI incidence among young women. Dual method use was very low overall, highlighting the need to bolster STI prevention efforts among adolescents and young women. PMID- 27773709 TI - Effects of aerobic, resistance, and combined exercise training on insulin resistance markers in overweight or obese children and adolescents: A systematic review and meta-analysis. AB - OBJECTIVE: To assess the associations of aerobic, resistance, and combined exercise with changes in insulin resistance, fasting glucose, and fasting insulin in children and adolescents who are overweight or obese. DATA SEARCHES: MEDLINE via Pubmed, Cochrane-CENTRAL, SPORTDiscus, and LILACS. STUDY SELECTION: Randomized clinical trials of at least six weeks of duration that evaluated the ability of exercise training to lower at least one of the following outcomes: insulin resistance-HOMA, fasting glucose, and fasting insulin in children and/or adolescents classified as obese or overweight. DATA EXTRACTION AND ANALYSIS: Two independent reviewers extracted data and assessed the quality of the included studies. Differences (exercise training group minus control group) in the outcomes evaluated were analyzed using a random effects model. RESULTS: Of 1853 articles retrieved, 17 studies were included. The meta-analysis showed that physical training in general was not associated with a reduction in fasting glucose levels compared to the control, but it was associated with reductions in fasting insulin levels (-3.37MUU/ml; CI 95%, -5.16MUU/ml to -1.57MUU/ml; I2, 54%, p=0.003) and HOMA (-0.61; CI 95%, -1.19 to -0.02; I2, 49%, p=0.040). In addition, each modality (aerobic, resistance, and combined) was compared to the control group. Aerobic exercise was associated with declines in fasting insulin levels ( 4.52MUU/ml; CI 95%, -7.40 to -1.65; I2, 65%, p=0.002) and in HOMA (-1.33; 95% confidence interval, -2.47 to -0.18; I2, 73%, p=0.005). CONCLUSIONS: Exercise training, especially aerobic training, is associated with the reduction of fasting insulin levels and HOMA in children and adolescents with obesity and overweight, and may prevent metabolic syndrome and type 2 diabetes. PMID- 27773710 TI - Using cost-effectiveness analysis to prioritize policy and programmatic approaches to physical activity promotion and obesity prevention in childhood. AB - Participation in recommended levels of physical activity promotes a healthy body weight and reduced chronic disease risk. To inform investment in prevention initiatives, we simulate the national implementation, impact on physical activity and childhood obesity and associated cost-effectiveness (versus the status quo) of six recommended strategies that can be applied throughout childhood to increase physical activity in US school, afterschool and childcare settings. In 2016, the Childhood Obesity Intervention Cost Effectiveness Study (CHOICES) systematic review process identified six interventions for study. A microsimulation model estimated intervention outcomes 2015-2025 including changes in mean MET-hours/day, intervention reach and cost per person, cost per MET-hour change, ten-year net costs to society and cases of childhood obesity prevented. First year reach of the interventions ranged from 90,000 youth attending a Healthy Afterschool Program to 31.3 million youth reached by Active School Day policies. Mean MET-hour/day/person increases ranged from 0.05 MET-hour/day/person for Active PE and Healthy Afterschool to 1.29 MET-hour/day/person for the implementation of New Afterschool Programs. Cost per MET-hour change ranged from cost saving to $3.14. Approximately 2500 to 110,000 cases of children with obesity could be prevented depending on the intervention implemented. All of the six interventions are estimated to increase physical activity levels among children and adolescents in the US population and prevent cases of childhood obesity. Results do not include other impacts of increased physical activity, including cognitive and behavioral effects. Decision-makers can use these methods to inform prioritization of physical activity promotion and obesity prevention on policy agendas. PMID- 27773712 TI - Perinatal regionalization: a geospatial view of perinatal critical care, United States, 2010-2013. AB - BACKGROUND: Perinatal services exist today as a dyad of maternal and neonatal care. When perinatal care is fragmented or unavailable, excess morbidity and mortality may occur in pregnant women and newborns. OBJECTIVE: The objective of the study was to describe spatial relationships between women of reproductive age, individual perinatal subspecialists (maternal-fetal medicine and neonatology), and obstetric and neonatal critical care facilities in the United States to identify gaps in health care access. STUDY DESIGN: We used geographic visualization and conducted surface interpolation, nearest neighbor, and proximity analyses. Source data included 2010 US Census, October 2013 National Provider Index, 2012 American Hospital Association, 2012 National Center for Health Statistics Natality File, and the 2011 American Academy of Pediatrics directory. RESULTS: In October 2013, there were 2.5 neonatologists for every maternal-fetal medicine specialist in the United States. In 2012 there were 1.4 level III or higher neonatal intensive care units for every level III obstetric unit (hereafter, obstetric critical care unit). Nationally, 87% of women of reproductive age live within 50 miles of both an obstetric critical care unit and a neonatal intensive care unit. However, 18% of obstetric critical care units had no neonatal intensive care unit, and 20% of neonatal intensive care units had no obstetric critical care unit within a 10 mile radius. Additionally, 26% of obstetric critical care units had no maternal-fetal medicine specialist practicing within 10 miles of the facility, and 4% of neonatal intensive care units had no neonatologist practicing within 10 miles. CONCLUSION: Gaps in access and discordance between the availability of level III or higher obstetric and neonatal care may affect the delivery of risk-appropriate care for high-risk maternal fetal dyads. Further study is needed to understand the importance of these gaps and discordance on maternal and neonatal outcomes. PMID- 27773713 TI - Reassessing the importance of long-acting contraception. AB - BACKGROUND: Several recent studies have highlighted the need for greater use of long-acting contraception. The most influential of these studies is the Contraceptive CHOICE Project, which was credited with substantially reducing participants' pregnancy risk by increasing their use of long-acting methods such as intrauterine devices and subdermal implants. However, because participants' rates of nonuse and condom use fell to zero at the outset of the intervention, it is possible that sizable pregnancy reductions could still have been achieved if enrollees had chosen shorter-acting, female-controlled methods such as oral contraception. OBJECTIVE: The objective of the study was to estimate the proportion of the CHOICE Project's fertility impacts that could have been achieved without any increase in long-acting method use. STUDY DESIGN: The FamilyScape 3.0 microsimulation model was used to estimate CHOICE's impact on pregnancy risk and to simulate the counterfactual effect of moving all nonusers and condom users onto shorter-acting, female-controlled methods. FamilyScape models the sexual and contraceptive behaviors of women in the United States between 2006 and 2010, which is the period when CHOICE was implemented. RESULTS: Nearly three quarters of the CHOICE intervention's effects on pregnancy risk could have been achieved if participants had chosen shorter-acting, female controlled methods over long-acting methods. CONCLUSION: Prioritizing the adoption of long-acting contraception may not be the most advisable strategy for reducing unintended pregnancy. The most impactful interventions will likely be those that increase the use of female-controlled methods, long-acting or otherwise. PMID- 27773715 TI - Reply. PMID- 27773714 TI - Nonurgent and urgent emergency department use during pregnancy: an observational study. AB - BACKGROUND: Emergency department use is common among pregnant women. Nonurgent emergency department use may represent care that would be better provided by an established obstetric provider in an ambulatory setting. OBJECTIVE: The objective of the study was to identify sociodemographic factors associated with nonurgent emergency department use in pregnancy. STUDY DESIGN: This is a cross-sectional study of women recruited during their postpartum hospitalization. Data regarding prenatal care and emergency department visits were collected from medical records; participants completed a survey with questions regarding demographics and emergency department use. Urgency of an emergency department visit was prespecified based on a priori criteria abstracted from medical record review. Women with any nonurgent emergency department use were compared with women without nonurgent emergency department use. Logistic regression was performed to identify factors associated with nonurgent emergency department use. RESULTS: Two hundred thirty-three women participated in this study; 197 (84%) received care in the emergency department during pregnancy. Eighty-three women (35.6%) had at least 1 visit to the emergency department that was nonurgent. In a regression analysis, the increased odds of nonurgent emergency department use was associated with a preferred language other than English (odds ratio, 2.02; 95% confidence interval,1.01-4.05) and lack of private insurance (odds ratio, 5.55; 95% confidence interval, 2.54-12.12). The 2 most common reasons for presentation to the emergency department were concern that there was an emergency (45%) or being referred by a health care provider (36%). CONCLUSION: Women frequently use the emergency department during pregnancy, including visits for nonurgent indications. Identifying risk factors for nonurgent emergency department use in pregnancy is important for identifying women likely to use the emergency department, including for nonurgent visits, and the development of strategies to decrease nonurgent emergency department utilization in pregnancy. PMID- 27773711 TI - Adolescents' attitudes towards e-cigarette ingredients, safety, addictive properties, social norms, and regulation. AB - E-cigarette use has dramatically increased. While studies have examined adolescents' attitudes towards smoking, few have extended this research to adolescents' attitudes towards e-cigarettes. The goal of this study was to examine adolescents' attitudes regarding e-cigarette ingredients, safety, addictive properties, social norms, accessibility, price, and regulation; and determine whether attitudes differ by past cigarette/e-cigarette use. Participants were 786 9th and 12th graders from California (63.21% females; mean age=16.10years [SD=1.6]; 26.61% White, 21.98% Asian/Pacific Islander, 29.82% Hispanic, and 21.59% other). Results indicated that 19.05% of participants believed smoke from e-cigarettes is water; 23.03% believed e-cigarettes aren't a tobacco product; 40.36% considered e-cigarettes to be for cessation, and 43.13% felt they were safer than cigarettes. Participants felt it was more acceptable to use e-cigarettes indoors and outdoors compared to cigarettes (p<0.0001), 23.13% felt raising e-cigarette taxes is a bad idea, 63.95% thought e-cigarettes were easier to get than cigarettes, 54.42% felt e-cigarettes cost too much, 64.33% felt the age for buying e-cigarettes should be raised, and 64.37% favored e cigarette regulation. Adolescents who used e-cigarettes and/or cigarettes had significantly more favorable e-cigarette attitudes than non-users. This study indicates that adolescents are aware of some of the risks of e-cigarettes, although many harbor misperceptions and hold more favorable attitudes towards e cigarettes than cigarettes. Of concern is the relationship between favorable e cigarette attitudes and use. Findings suggest the need to provide adolescents with correct information about e-cigarette ingredients, risks, and the insufficient evidence of their role in cigarette cessation. PMID- 27773716 TI - The limited utility of currently available venous thromboembolism risk assessment tools in gynecological oncology patients. PMID- 27773719 TI - Fat body remodeling and homeostasis control in Drosophila. AB - Remarkable advances have been made in recent years in our understanding of the Drosophila fat body and its functions in energy storage, immune response and nutrient sensing. The fat body interplays with other tissues to respond to the physiological needs of the body's growth and coordinates various metabolic processes at different developmental stages and under different environmental conditions. The identification of various conserved genetic functions and signaling pathways relating to the Drosophila fat body may provide clues to lipometabolic disease and other aspects of tissue remodeling in humans. Here, we discuss recent insights into how regulation of fat body remodeling contributes to hemostasis with a special focus on how signaling networks and internal physiological states shape different aspects of the lipid metabolism in Drosophila. PMID- 27773717 TI - Cardioprotective effects of monocyte locomotion inhibitory factor on myocardial ischemic injury by targeting vimentin. AB - Monocyte locomotion inhibitory factor (MLIF), a heat-stable pentapeptide produced by Entamoeba histolytica, has anti-inflammatory function and protective effect on ischemic stroke. In this study, we evaluated the effect of MLIF on myocardial ischemia. Mice were subjected to ischemia/reperfusion by occlusion of the left anterior descending artery (LAD). After sacrifice, the serum concentrations of cardiac troponin I (cTnI), creatine kinase (CK), lactate dehydrogenase (LDH) as well as the heart infarct size were measured. HE and TUNEL staining were used to observe the pathological damage and the apoptotic cells. For in vitro study, the oxygen-glucose deprivation(OGD) model was established in H9c2 cells. MTT assay and flow cytometry assay were performed to evaluate cell viability and apoptosis. The expression of JNK and caspase 3 was assessed by western blot analysis. Pull down assay was used to detect the specific binding protein of MLIF in myocardial cells. MLIF significantly reduced the infarct size, and the cTnI, CK and LDH levels, amelioratived pathological damage and reduced the apopotosis compared with the myocardial I/R model group. MLIF improved cell survival and inhibited apoptosis and necrosis by inhibiting the p-JNK and cleaved caspase3 expression. Furthermore, the binding protein of MLIF in myocardial cells was vimentin. Inhibition of vimentin expression by withaferin A or vimentin siRNA repressed the protective effects of MLIF in OGD-provoked H9c2 cells. Taken together, our results demonstrate that the cardioprotective effects of MLIF on myocardial ischemia injury are related to reductions in the inflammatory response and apoptosis by targeting vimentin. PMID- 27773720 TI - The role of spinal interleukin-1beta and astrocyte connexin 43 in the development of mirror-image pain in an inflammatory pain model. AB - Although we have recently demonstrated that carrageenan-induced inflammation upregulates the expression of spinal interleukin (IL)-1beta, which inhibits spinal astrocyte activation and results in the delayed development of Mirror Image Pain (MIP), little is known regarding the mechanisms that underlie how spinal IL-1beta inhibits the astrocyte activation. In this study, we examined the effect of spinal IL-1beta on astrocyte gap junctions (GJ) and the development of MIP. Following unilateral carrageenan (CA) injection, mechanical allodynia (MA) was evaluated at various time points. Immunohistochemistry and Western blot analysis were used to determine changes in the expression of GFAP and connexins (Cx) in the spinal cord dorsal horn. Carrageenan rats showed a delayed onset of contralateral MA, which mimicked the temporal expression pattern of spinal Cx43 (an astrocyte gap junctional protein) and GFAP. Intrathecal administration of an interleukin-1 receptor antagonist (IL-1ra) twice-a-day on post-carrageenan injection days 0 to 3 caused a significant increase in contralateral MA and spinal Cx43 and GFAP expression. In addition, co-administration of IL-1beta with IL-1ra blocked the IL-1ra-induced increase in contralateral MA and the upregulated expression of spinal Cx43 and GFAP. Finally, co-administration of carbenoxolone (CBX; a GJ decoupler) or Gap26 (a specific Cx43 mimetic blocking peptide) with IL-1ra significantly blocked the IL-1ra-induced early development of contralateral MA and the associated upregulation of spinal Cx43 and GFAP expression. These results demonstrate that spinal IL-1beta suppresses Cx43 expression and astrocyte activation during the early phase of CA-induced inflammation resulting in the delayed onset of contralateral MA. These findings imply that spinal IL-1beta can inhibit astrocyte activation and regulate the time of induction of contralateral MA through modulation of spinal Cx43 expression. PMID- 27773718 TI - Inhibition of p38 mitogen-activated protein kinases attenuates renal interstitial fibrosis in a murine unilateral ureteral occlusion model. AB - AIMS: Cellular hypoxia has been proposed as a major factor contributing to the pathogenesis of chronic renal injury. Much of our understanding of how mitogen activated protein kinases (MAPK) signaling promotes renal fibrosis has been based on cell culture studies. Therefore, we used the unilateral ureteral occlusion (UUO) model to further elucidate the role of the p38 MAPK pathway in renal interstitial fibrosis induced by hypoxia. MATERIALS AND METHODS: In the present study, 24 male mice were randomized into the following three groups (n=8 each): Sham group (DMSO solution), UUO group (UUO+DMSO solution) and UP group (UUO+p38 inhibitor). The model of UUO was conducted using an established procedure described previously. Histological changes in renal tubular interstitium were observed with hematoxylin-eosin (HE) and Masson's trichrome. The protein levels of hypoxia inducible factor-1alpha (HIF-1alpha),transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and collagen type I were analyzed by western blotting and immunohistochemistry at 2weeks. KEY FINDINGS: Increased expression of hypoxia inducible factor-1alpha (HIF-1alpha) in UUO mice confirmed the existence of hypoxia in renal interstitial. Hypoxia result in tubulointerstitial fibrosis via the molecular activation of connective tissue growth factor (CTGF). p38 inhibitor administration markedly downregulates the protein of connective tissue growth factor (CTGF) and collagen type I expression induced by hypoxia. SIGNIFICANCE: An increase in p38 MAPK activation is induced by hypoxia. The hypoxia up-regulates the protein connective tissue growth factor (CTGF) and collagen I expression in a p38-dependent manner. PMID- 27773723 TI - VX toxicity in the Gottingen minipig. AB - The present experiments determined the intramuscular LD50 of VX in male Gottingen minipigs at two stages of development. In pubertal animals (115 days old), the LD50 of VX was indeterminate, but approximated 33.3MUg/kg. However, in sexually mature animals (152 days old), the LD50 was estimated to be only 17.4MUg/kg. Signs of nerve agent toxicity in the Gottingen minipig were similar to those described for other species, with some notable exceptions (such as urticaria and ejaculation). Latencies to the onset of sustained convulsions were inversely related to the administered dose of VX in both ages of minipigs. Additionally, actigraphy was used to quantify the presence of tremor and convulsions and, in some cases, was useful for precisely estimating time of death. The main finding indicates that in minipigs, as in other species, even relatively small differences in age can substantially alter the toxicity of nerve agents. Additionally, actigraphy can serve as a non-invasive method of characterizing the tremors and convulsions that often accompany nerve agent intoxication. PMID- 27773722 TI - Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches. AB - In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/PerceptaTM and MetaDrugTM software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. PMID- 27773721 TI - Identification of KRT16 as a target of an autoantibody response in complex regional pain syndrome. AB - OBJECTIVE: Using a mouse model of complex regional pain syndrome (CRPS), our goal was to identify autoantigens in the skin of the affected limb. METHODS: A CRPS like state was induced using the tibia fracture/cast immobilization model. Three weeks after fracture, hindpaw skin was homogenized, run on 2-d gels, and probed by sera from fracture and control mice. Spots of interest were analyzed by liquid chromatography-mass spectroscopy (LC-MS) and the list of targets validated by examining their abundance and subcellular localization. In order to measure the autoantigenicity of selected protein targets, we quantified the binding of IgM in control and fracture mice sera, as well as in control and CRPS human sera, to the recombinant protein. RESULTS: We show unique binding between fracture skin extracts and fracture sera, suggesting the presence of auto-antigens. LC-MS analysis provided us a list of potential targets, some of which were upregulated after fracture (KRT16, eEF1a1, and PRPH), while others showed subcellular redistribution and increased membrane localization (ANXA2 and ENO3). No changes in protein citrullination or carbamylation were observed. In addition to increased abundance, KRT16 demonstrated autoantigenicity, since sera from both fracture mice and CRPS patients showed increased autoantibody binding to recombinant kRT16 protein. CONCLUSIONS: Pursuing autoimmune contributions to CRPS provides a novel approach to understanding the condition and may allow the development of mechanism-based therapies. The identification of autoantibodies against KRT16 as a biomarker in mice and in humans is a critical step towards these goals, and towards redefining CRPS as having an autoimmune etiology. PMID- 27773724 TI - Cooling down the bath salts: Carvedilol attenuation of methylone and mephedrone mediated hyperthermia. AB - The use of the synthetic cathinones ("bath salts"), methylone and mephedrone, has been associated with the development of life-threatening hyperthermia. To date, no direct pharmacological intervention to mitigate the hyperthermia induced by synthetic cathinones has been identified. Here, we investigated the effects of the non-selective alpha1 and beta adrenergic receptor antagonist carvedilol (5mg/kg ip) on established hyperthermia mediated by methylone and mephedrone (30mg/kg sc) in Sprague-Dawley rats. Methylone and mephedrone induced a hyperthermic response that peaked 60min post treatment. The administration of carvedilol 30min after methylone or mephedrone significantly attenuated these hyperthermic responses. Analysis of the Temperature Area Under the Curve (TAUC) demonstrated carvedilol significantly reduced the TAUC associated with methylone or mephedrone alone. The present study provides the first direct pharmacological intervention for the treatment of synthetic cathinone induced hyperthermia. PMID- 27773726 TI - The genome of serotype VI Streptococcus agalactiae serotype VI and comparative analysis. AB - Streptococcus agalactiae (GBS) causes serious infections in humans and other species. A total of 25 complete GBS genomes, including the first sequenced serotype VI genome (GBS-M002), were compared in this study. The power law model suggested that the pan-genome of GBS is open, with approximately 1300 genes in the core genome of GBS, accounting for approximately 60% of the average genome content. GBS-M002 has 73 specific genes and is one of the five strains containing >60 specific genes. Based on COG (Cluster of Orthologous Groups of proteins) functional classification, 24% of the genes related to defense mechanisms are specific among the strains. A phylogenetic tree shows that GBS-M002 is closely related to certain strains of serotypes III and V from humans and to isolates of unknown serotype from dog and bovine hosts, suggesting the universal infection potential of GBS from humans to other mammal and fish hosts. PMID- 27773727 TI - Integrated late onset Alzheimer's disease (LOAD) susceptibility genes: Cholesterol metabolism and trafficking perspectives. AB - Late onset Alzheimer's disease (LOAD) is the most common type of dementia and is characterized by decreased amyloid-beta (Abeta) clearance from the brain. Cholesterol regulates the production and clearance of Abeta. Genome-wide association study (GWAS) suggests that at least 20 genes are associated with LOAD. The genes APOE, CLU, SORL1, PICALM, and BIN1 have a relatively high LOAD susceptibility. Additional experimental and bioinformatic approaches to integrate data from genetics, epigenetics, and molecular networks may further increase our understanding of LOAD in relation to cholesterol metabolism and trafficking. PMID- 27773725 TI - Remote malignant intravascular thrombi: EUS-guided FNA diagnosis and impact on cancer staging. AB - BACKGROUND AND AIMS: Malignant vascular invasion usually results from gross direct infiltration from a primary tumor and impacts cancer staging, prognosis, and therapy. However, patients may also develop a remote malignant thrombi (RMT), defined as a malignant intravascular thrombus located remote and noncontiguous to the primary tumor. Our aim was to compare EUS, CT, and magnetic resonance imaging (MRI) findings of RMT and to explore the potential impact on cancer staging. METHODS: Patients with RMT were identified from a prospectively maintained EUS database. Retrospective chart review was performed to obtain EUS, CT/MRI, clinical, and outcome data. RESULTS: A median of 3 FNAs (range, 1-8) was obtained from RMT in 17 patients (60 +/- 14.1 years, 56% men) between April 2003 and August 2016, with the finding of malignant cytology in 12 patients (70.6%; 10 positive, 2 suspicious). CT/MRI detected the RMT in 5 patients (29.4%), 4 of whom had positive or suspicious EUS-FNA cytology. Among the 8 newly diagnosed pancreatic adenocarcinoma (PaC) patients, CT did not detect the RMT in 5 (63%), of whom 3 patients had positive or suspicious intravascular EUS-FNA cytology. For newly diagnosed PaC patients (n = 8), the EUS-FNA diagnosis of a biopsy specimen proven RMT upstaged 3 patients (37.5%) and converted 2 patients (25%) from CT resectable to unresectable disease. No adverse events were reported. The mean follow-up was 18.9 +/- 27.7 months. CONCLUSIONS: Our study demonstrates the ability and potential safety of intravascular FNA to detect radiographically occult RMT, which substantially impacts cancer staging and resectability. PMID- 27773728 TI - Clinical presentation, management, follow-up, and outcomes of isolated celiac and superior mesenteric artery dissections. AB - OBJECTIVE: Isolated visceral artery dissections are rare entities with no current consensus guidelines for treatment and follow-up. This study aims to evaluate the presentation, management, outcomes, and follow-up practices for patients with isolated visceral artery dissections and to compare those with and without symptoms. METHODS: In this retrospective analysis, we identified all patients with isolated celiac artery and/or isolated superior mesenteric artery dissections at a single institution between September 2006 and December 2014. Patients with concomitant aortic dissections were excluded. Cases were stratified by symptom status. Presentation, anatomic findings, treatment, outcomes, and follow-up imaging were then compared between symptomatic and asymptomatic patients. RESULTS: We identified 25 patients including 15 with symptoms and 10 without. There were no differences in patient comorbidities; however, symptomatic patients more frequently presented with thrombus (n = 10; 67% vs n = 1; 10%; P = .01) and inflammation (n = 8; 53% vs n = 1; 10%; P = .04), and trended toward increased stenosis (n = 12; 80% vs n = 4; 40%; P = .09) compared with asymptomatic patients. All asymptomatic patients were treated with observation alone with vessel diameter enlargement noted in 33% (n = 2) of patients on follow up imaging. Among symptomatic patients, standard treatment included a short course of anticoagulation (mean, 4.5 months) with lifelong antiplatelet therapy. Three patients underwent operative intervention for persistent or worsening symptoms, two during the index admission and one 10 months after presentation for chronic abdominal pain. Approximately 70% (n = 17) of patients in each group had follow-up imaging (computed tomography angiography: n = 14; 56%; magnetic resonance angiography: n = 4; 16%; ultrasound: n = 13; 52%). Among patients treated nonoperatively, no patients complained of symptoms at follow-up, and 50% of those with inflammation on initial imaging had resolution. Twenty-five percent (n = 4) of patients had an increase in vessel size; however, all vessels remained less than 2 cm in maximal diameter. There were no ruptures or related deaths in either group. CONCLUSIONS: Among patients with visceral artery dissection, no ruptures occurred but diameter enlargement was documented. This disease progression suggests that routine surveillance may be appropriate; however, transitioning early to ultrasound imaging should be considered to decrease radiation, contrast, and associated costs. PMID- 27773731 TI - Effects of dietary administration of Rose hip and Safflower on growth performance, haematological, biochemical parameters and innate immune response of Beluga, Huso huso (Linnaeus, 1758). AB - The aim of this study was to investigate effects of two dietary medicinal herbs, Rose hip (Rosa canina) and Safflower (Carthamus tinctorius) supplementation on growth performance, haematological, biochemical parameters and innate immune response of in juvenile beluga, Huso huso. Fish (26.3 +/- 0.4 g) were allocated into 15 tanks (20 fish per tank) and triplicate groups were fed a control diet or diets containing 1% and 2% of medicinal herbs, respectively. Feed conversion ratio (FCR), specific growth rate (SGR) and condition factor (CF) did not show significant differences (P > 0.05) in fish given herbal diets. Significant differences were observed in number of white blood cells (WBC) and haemoglobin (Hb) values among the dietary treatments. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly lower in supplemented diet groups compared with the control. Innate immune responses (lysozyme activity and ACH50) were significantly higher in 2% Safflower-fed fish compared with other groups (P < 0.05). These results indicate that medicinal herbs in diets can be considered as a beneficial dietary supplement for improving the physiological parameters and enhance the immune response of Persian sturgeon. PMID- 27773732 TI - Chicken albumin exhibits natural resistance to glycation. AB - Glycation of proteins and subsequent production of advanced glycation end products (AGEs) is a major contributor to the pathophysiology of diabetes. The objective of the present study was to compare the glycation of avian and human serum albumin to elucidate the mechanisms by which protein glycation in birds is prevented in the presence of naturally high plasma glucose concentrations. Solutions of purified chicken and human serum albumin (CSA and HSA) were prepared with four different glucose concentrations (0, 5.56, 11.1, and 22.2mM) and incubated at three temperatures (37.0, 39.8, and 41.4 degrees C) for seven days. The solutions were sampled on Days 0, 3, and 7 and analyzed by liquid chromatography-electrospray ionization-mass spectrometry for the presence of glycated albumin. Four-way repeated measures ANOVA (p=0.032) indicate that all independent variables (albumin type, glucose concentration, temperature and time) interacted to affect the degree of glycation. With increasing glucose concentration, the glycation of both HSA and CSA increased with time at all temperatures. In addition, HSA was glycated to a greater extent than CSA at the two higher glucose concentrations for all temperature conditions. Glycation was elevated with increasing temperatures for HSA but not CSA. The results suggest an inherent difference between human and chicken albumin that contributes to the observed differences in glycation. Further research is needed to characterize this inherent difference in an effort to elucidate mechanisms by which avian plasma protein is glycated to a lesser degree than that of mammals (humans). PMID- 27773729 TI - Do you see me? The role of visual fixation in chronic disorders of consciousness differential diagnosis. AB - Visual fixation (VF) of a target is a possible, although atypical, feature of the Unresponsive Wakefulness Syndrome (UWS). Whether VF may indicate residual awareness in these patients is debatable, since it may simply subtend a series of reflex processes. Objective tools should therefore be used to identify aware VF, which depends on the integrity of visuomotor networks encompassing frontal parietal-occipital areas. The aim of our study was to detect residual visuomotor network functionality potentially sustaining aware VF. To this end, we evaluated the visuomotor integration (VMI) and visual P300 patterns in a chronic Disorder of Consciousness (DOC) sample and a control group of healthy individuals (HC), using an associative stimulation protocol combining transcranial magnetic stimulation (TMS) with visual stimulation through transorbital alternating current stimulation. The Minimally Conscious State (MCS) patients showed preserved patterns of VMI and P300, whereas nearly all the UWS patients showed no significant VMI. Notably, the electrophysiological findings were correlated with the visual domain of the Coma Recovery Scale-Revised. Nonetheless, two fixating UWS individuals had a VMI similar to MCS patients. Our data suggest that some UWS patients showing VF could be aware, but unable to manifest it clearly, probably because of a severe motor output impairment, which is a condition compatible with the Functional Locked-In Syndrome. PMID- 27773733 TI - Percutaneous Coronary Intervention: A Rare Cause of Acute Traumatic Aortic Regurgitation. PMID- 27773730 TI - Molecular cloning of orange-spotted grouper (Epinephelus coioides) heat shock transcription factor 1 isoforms and characterization of their expressions in response to nodavirus. AB - Heat shock transcription factor 1 (HSF1) regulates heat shock proteins (HSPs), which assist in protein folding and inhibit protein denaturation following stress. HSF1 was firstly cloned from orange-spotted grouper and exists as two isoforms, one with (osgHSF1a) and one without (osgHSF1b) exon 11. Heat exposure increased the expression of osgHSF1b while cold exposure increased that of osgHSF1a. Both isoforms were mainly expressed in the brains, eyes, and fins. Expression of osgHSF1b was higher than osgHSF1a during development. Poly I:C and LPS could also induce osgHSF1 isoforms expression differentially. Exposure to nervous necrosis virus (NNV) increased the level of both osgHSF1 isoforms at 12 h. GF-1 cells with overexpression of osgHSF1 isoforms enhanced viral loads within 24 h, whereas both pharmacological inhibition and RNA interference of HSF1 reduced virus infection. This study shows that osgHSF1 can support the early stage of virus infection and provides a new insight into the molecular regulation of osgHSF1 between the influence of temperatures and immunity. PMID- 27773735 TI - Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer. AB - Cancer cells generate protons (H+) that are extruded to the extracellular medium mainly via the Na+/H+ exchanger 1 (NHE1), which regulates intracellular pH (pHi) and cell proliferation. In primary cultures of human ascites-derived ovarian cancer cells (haOC) we assayed whether NHE1 was required for pHi modulation and cell proliferation. Human ovary expresses NHE1, which is higher in haOC and A2780 (ovarian cancer cells) compared with HOSE cells (normal ovarian cells). Basal pHi and pHi recovery (following a NH4Cl pulse) was higher in haOC and A2780, compared with HOSE cells. Zoniporide (NHE1 inhibitor) caused intracellular acidification and pHi recovery was independent of intracellular buffer capacity, but reduced in NHE1 knockdown A2780 cells. Zoniporide reduced the maximal proliferation capacity, cell number, thymidine incorporation, and ki67 (marker of proliferation) fluorescence in haOC cells. SLC9A1 (for NHE1) amplification associated with lower overall patient survival. In conclusion, NHE1 is expressed in human ovarian cancer where it has a pro-proliferative role. Increased NHE1 expression and activity constitute an unfavourable prognostic factor in these patients. PMID- 27773734 TI - Liposomal prednisolone inhibits tumor growth in a spontaneous mouse mammary carcinoma model. AB - Cancers are abundantly infiltrated by inflammatory cells that are modulated by tumor cells to secrete mediators fostering tumor cell survival and proliferation. Therefore, agents that interfere with inflammatory signaling molecules or specific immune cell populations have been investigated as anticancer drugs. Corticosteroids are highly potent anti-inflammatory drugs, whose activity is intensified when targeted by nanocarrier systems. Liposome-targeted corticosteroids have been shown to inhibit tumor growth in different syngeneic murine tumor models as well as human xenograft mouse models, which is attributed to a switch in the tumor microenvironment from a pro-inflammatory to an anti inflammatory state. Despite the recognized value of implantation tumor models in preclinical research, the "acute" inflammation induced by inoculation of tumor cells together with the exponential tumor growth in a relatively short period of time does not resemble slow progressive human disease that develops in situ. Therefore, in this study, the antitumor effect of liposomal corticosteroids was investigated in a clinically more relevant setting of transgenic mice developing spontaneous breast carcinomas. Here we show that liposomal prednisolone phosphate inhibits the growth of spontaneous breast carcinoma. Interestingly, the liposomal prednisolone was significantly more active than free drug. At 72h after injection of the liposomal formulation, 3MUg prednisolone per gram of tumor tissue was recovered whereas no drug could be recovered after injection of the free agent. This indicates that, despite etiological and morphological differences between implanted and spontaneous tumor models, EPR-mediated accumulation of drug occurs to similar extent in this spontaneous mammary carcinoma model as in the syngeneic tumor models. Finally, we analyzed miRNA profiles in the MMTV/neu model and showed that the top 10 of miRNAs in the MMTV/neu tumor consisted of miRNAs with a known involvement in breast carcinoma proliferation and metastasis. The only exception was the appearance of miR-146b, a known inflammation-regulating miRNA species, after liposomal prednisolone treatment. PMID- 27773740 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 27773736 TI - Apoptosis and gene expression in Jurkat human T cells and lymphoid tissues of fusarenon-X-treated mice. AB - Fusarenon X, a member of the type B trichothecene mycotoxin group, has been frequently observed, along with deoxynivalenol (DON) and nivalenol (NIV) as a contaminant in cereals. Our previous study demonstrated that a 14-day FX exposure caused apoptosis in the lymphoid tissues of mice, especially at 0.5 mg/kg bodyweight. However, the relationship between low concentrations of FX and apoptotic molecular machinery remains unclear. In the present study, we investigated the genetic regulatory mechanisms in the thymus and Peyer's patches of mice after 14 days oral administration of FX at 0.5 mg/kg bodyweight. FX caused the up-regulation of Bax, Bid, Trp53, and Caspase-9 mRNA but the relative expression of Fas, TNF, and Caspase-8 remained unchanged. Furthermore, we also determined the toxicity of FX in Jurkat T-cells. FX exhibited a concentration- and time-dependent inhibition of cell viability. Thus, incubation time and FX concentration influence the percentage of apoptotic cells. These data suggested that treatment with low dosage of FX can induce apoptosis in lymphocytes through an effect on Bax, Bid, Trp53, and Caspase-9 and therefore the mitochondrial apoptotic pathway. PMID- 27773741 TI - Arterial dysgenesis and limb defects: Clinical and experimental examples. AB - Limb malformations are amongst the most common and visible birth effects. Causes have been purported to include genetic aberrations as well as teratogens, such as thalidomide. Here we review the evidence for vascular disruption in the genesis of limb malformations through abnormal arterial transitioning and from events such as amniocentesis, uterine constriction, and through teratogen exposure. We use several clinical and experimental examples and highlight the need to understand more about the role the vascular system plays in the molecular mechanisms underpinning normal limb development. PMID- 27773738 TI - The Involvement of Serum Amyloid A in Psoriatic Inflammation. PMID- 27773737 TI - Microcystin-LR causes sexual hormone disturbance in male rat by targeting gonadotropin-releasing hormone neurons. AB - Microcystin-LR (MC-LR), which generates strong reproductive toxicity, reduces serum testosterone level without directly damaging Leydig cells. The purpose of this study was to identify the target cells of MC-LR in the rat hypothalamic pituitary axis and to investigate the underlying mechanisms. We found that the gonadotropin-releasing hormone (GnRH) neurons were the direct target of MC-LR. In vivo results showed that upon exposure to rats, cells around the third ventricle of hypothalamus underwent apoptosis. Gnrh1 expression was steadily decreased. The serum levels of GnRH, luteinizing hormone, follicle-stimulating hormone and testosterone showed a similar pattern of early-stage increase and late-stage decline. After treatment with MC-LR in immortalized hypothalamic (GT1-7) neurons, increase in cellular Ca2+ and ATP resulted in downregulation of the transcriptional activators Oct-1, Otx-2, Pbx1a and Dlx2, and upregulation of the transcriptional repressor c-Jun, which may mechanistically account for the downregulation of GnRH synthesis. Ca2+ and ATP could also stimulate the release of GnRH, contributing to its unique serum release pattern. PMID- 27773739 TI - Basic Fibroblast Growth Factor Induces Angiogenic Properties of Fibrocytes to Stimulate Vascular Formation during Wound Healing. AB - The role of fibrocytes in wound angiogenesis remains unclear. We therefore demonstrated the specific changes in fibrocyte accumulation for angiogesis in basic fibroblast growth factor (bFGF)-treated wounds. bFGF-treated wounds exhibited marked formation of arterioles and inhibition of podoplanin+ lymph vessels that were lacking in vascular endothelial growth factor-A-treated wounds. Real-time PCR in bFGF-treated wounds manifested enhanced expression of CD34, CD31, and bFGF mRNA and reduced expression of podoplanin and collagen type I, III, and IV mRNA. Double immunofluorescence staining focusing on fibrocyte detection in bFGF-treated wounds showed increased formation of capillary-like structures composed of CD34+/procollagen I+ fibrocytes, with a lack of capillary like structures formed by CD45+/procollagen I+ or CD11b+/procollagen I+ fibrocytes. However, vascular endothelial growth factor-A-treated wounds lacked capillary-like structures composed of CD34+/procollagen I+ fibrocytes, with increased numbers of CD34+/fetal liver kinase-1+ endothelial progenitor cells. Furthermore, fibroblast growth factor receptor 1 siRNA injection into wounds, followed by bFGF, inhibited the formation of capillary-like structures composed of CD34+/procollagen I+ fibrocytes, together with inhibited mRNA expression of CD34 and CD31 and enhanced mRNA expression of collagen type I, indicating the requirements of bFGF/fibroblast growth factor receptor 1 system for capillary structure formation. This study highlights the angiogenic properties of CD34+/procollagen I+ fibrocytes specifically induced by bFGF, providing new insight into the active contribution of fibrocytes for vascular formation during wound healing. PMID- 27773746 TI - Rebuttal From Drs Lessne and Sing. PMID- 27773745 TI - POINT: Do the Benefits Outweigh the Risks for Most Patients Under Consideration for Inferior Vena Cava Filters? Yes. PMID- 27773747 TI - COUNTERPOINT: Do the Benefits Outweigh the Risks for Most Patients Under Consideration for Inferior Vena Cava Filters? No. PMID- 27773742 TI - Effects of isoliquiritigenin on ovarian antral follicle growth and steroidogenesis. AB - Isoliquiritigenin is a botanical estrogen used as a dietary supplement. Previous studies show that other botanical estrogens affect ovarian estradiol synthesis, but isoliquiritigenin's effects on the ovary are unknown. Thus, this study tested the hypothesis that isoliquiritigenin inhibits ovarian antral follicle growth and steroidogenesis. Antral follicles from CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or isoliquiritigenin (0.6MUM, 6 MUM, 36 MUM, and 100 MUM) for 48-96h. During culture, follicle diameters were measured daily to assess follicle growth. After culture, media were collected for hormone assays and follicles were collected for gene expression analysis of steroidogenic enzymes. Isoliquiritigenin inhibited antral follicle growth and altered estradiol, testosterone, and progesterone levels. Additionally, isoliquiritigenin altered the mRNA levels of cytochrome P450 steroid 17-alpha-hydroxylase 1, aromatase, 17beta-hydroxysteroid dehydrogenase 1, and steroidogenic acute regulatory protein. These data indicate that exposure to isoliquiritigenin inhibits growth and disrupts steroid production in antral follicles. PMID- 27773748 TI - Rebuttal From Drs Funaki and Haskal. PMID- 27773744 TI - Fhit and Wwox loss-associated genome instability: A genome caretaker one-two punch. AB - Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs. As for consequences of Wwox loss in cancer, we show in a small panel of breast cancer cells and mouse embryonic fibroblasts that Wwox expression predicts response to radiation and mitomycin C, all agents that cause DSBs. In addition, loss of Wwox significantly reduced progression free survival in a cohort of ovarian cancer patients treated with platin-based chemotherapies. Finally, stratification of a cohort of squamous lung cancers by Fhit expression reveals that Wwox expression is significantly reduced in the low Fhit-expressing group, suggesting that loss of Fhit is quickly succeeded by loss of Wwox. We propose that Fhit and Wwox loss work synergistically in cancer progression and that DNA damage caused by Fhit could be targeted early in cancer initiation for prevention, while DNA damage caused by Wwox loss could be targeted later in cancer progression, particularly in cancers that develop resistance to genotoxic therapies. PMID- 27773743 TI - Zinc plus cyclo-(His-Pro) promotes hippocampal neurogenesis in rats. AB - Zinc is a central actor in regulating stem cell proliferation and neurogenesis in the adult brain. High levels of vesicular zinc are found in the presynaptic terminals. It has been demonstrated that high levels of vesicular zinc are localized in the presynaptic terminals of the granule cells of the dentate gyrus (DG) and that neurogenesis occurs in the subgranular zone (SGZ). Furthermore, zinc chelation reduces hippocampal neurogenesis in pathological conditions such as hypoglycemia, epilepsy and traumatic brain injury. Here we test the effects of zinc plus cyclo-(His-Pro) (CHP) treatment on neurogenesis in the adult SGZ. In order to increase brain zinc, Sprague-Dawley (SD) rats, aged 5weeks, were given zinc plus CHP (ZC, 27mg/kg) orally available once per day for 2weeks. BrdU was intraperitoneally injected 2 times per day for 4 consecutive days starting 1week after initial ZC treatment. Neurogenesis was analyzed by BrdU, Ki67 and doublecortin (DCX) immunostaining. The number of progenitor cells and immature neurons were significantly increased in the DG following 2weeks of ZC treatment. Hippocampal vesicular zinc content was evaluated with TSQ staining. Vesicular TSQ fluorescent intensity was seen to increase in the mossy fiber area at 2weeks after ZC treatment. The present study demonstrates that zinc supplementation by ZC treatment increases hippocampal neurogenesis and levels of vesicular zinc. These findings provide evidence in support of the essential role of zinc in modulating hippocampal neurogenesis. PMID- 27773750 TI - Statin suppresses Hippo pathway-inactivated malignant mesothelioma cells and blocks the YAP/CD44 growth stimulatory axis. AB - Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation. Importantly, we discovered that YAP/TEAD activated CD44 transcription by binding to the CD44 promoter at TEAD-binding sites. On the other hand, CD44 regulated Merlin phosphorylation according to cell density and sequentially promoted YAP transcriptional co-activator, suggesting that CD44 plays two pivotal functional roles as an upstream suppressor of the Hippo pathway and one of downstream targets regulated by YAP/TEAD. Moreover, the YAP/CD44 axis conferred cancer stem cell (CSC)-like properties in MM cells leading to chemoresistance, which was blocked by statin. Together, our findings suggest that YAP mediates CD44 up-regulation at the transcriptional level, conferring CSC-like properties in MM cells, and statin represents a potential therapeutic option against MM by inactivating YAP. PMID- 27773754 TI - Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: Challenges and perspectives in translatability from nonclinical toxicology studies to the clinic. AB - Antibody drug conjugates (ADC) consist of potent cytotoxic drugs conjugated to antibodies via chemical linkers, which enables specific targeting of tumor cells while reducing systemic exposure to the cytotoxic drug and improving the therapeutic window. The valine citrulline monomethyl auristatin E (vcMMAE, conventional linker-drug) ADC platform has shown promising clinical activity in several cancers, but peripheral neuropathy (PN) is a frequent adverse event leading to treatment discontinuation and dose reduction. This was not predicted based on nonclinical toxicology studies in monkeys or rats treated with vcMMAE ADCs. We evaluated four hypotheses for the lack of translatability of PN with vcMMAE ADCs: 1) species differences in exposure; 2) insensitivity of animal models; 3) species differences in target biology and other vcMMAE ADC properties in peripheral nerves and 4) increased susceptibility of patient population. The result of this hypothesis-based approach identified opportunities to improve the predictivity of PN in our animal models by increasing duration of exposure and adding an expanded neurohistopathology assessment of peripheral nerves. The utility of a predictive animal model would be to provide possible mitigation strategies in the clinic with vcMMAE ADCs and help to screen the next generation microtubule inhibitor (MTI) ADCs for reduced PN. PMID- 27773755 TI - Interview with Dale Sanders. PMID- 27773751 TI - Soluble coxsackie- and adenovirus receptor (sCAR-Fc); a highly efficient compound against laboratory and clinical strains of coxsackie-B-virus. AB - Coxsackie-B-viruses (CVB) cause a wide variety of diseases, ranging from mild syndromes to life-threatening conditions such as pancreatitis, myocarditis, meningitis and encephalitis. Especially newborns and young infants develop severe diseases and long-term sequelae may occur among survivors. Due to lack of specific antiviral therapy the current treatment of CVB infection is limited to symptomatic treatment. Here we analyzed the antiviral activity of a soluble receptor fusion protein, containing the extracellular part of the coxsackievirus and adenovirus receptor (CAR) fused to the constant domain of the human IgG - sCAR-Fc - against laboratory and clinical CVB strains. We found a high overall antiviral activity of sCAR-Fc against various prototypic laboratory strains of CVB, with an inhibition of viral replication up to 3 orders of magnitude (99.9%) at a concentration of 2.5 MUg/ml. These include isolates that are not dependent on CAR for infection and isolates that are resistant against pleconaril, the currently most promising anti-CVB therapeutic. A complete inhibition was observed using higher concentration of sCAR-Fc. Further analysis of 23 clinical CVB isolates revealed overall high antiviral efficiency (up to 99.99%) of sCAR-Fc. In accordance with previous data, our results confirm the strong antiviral activity of sCAR-Fc against laboratory CVB strains and demonstrate for the first time that sCAR-Fc is also highly efficient at neutralizing clinical CVB isolates. Importantly, during the sCAR-Fc inhibition experiments, no naturally occurring resistant mutants were observed. PMID- 27773749 TI - Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression. AB - Emerging evidence suggests that metformin, an activator of AMP-activated protein kinase (AMPK), may be useful in preventing and treating pancreatic ductal adenocarcinoma (PDAC). However, whether metformin has an effect on the stromal reaction of PDAC remains unknown. In this study, we first evaluated the expression of AMPK and phosphorylated-AMPK (P-AMPK) in normal and PDAC tissues, our data indicate that reduced P-AMPK expression is a frequent event in PDAC and correlated with poor prognosis and the dense stromal reaction. We then determined the efficacy of metformin on PDAC growth in vitro and in vivo. We reveal that metformin reduces the production of fibrogenic cytokines from pancreatic cancer cells (PCs) and inhibits paracrine-mediated pancreatic stellate cells (PSCs) activation under PCsPSCs co-culture conditions. By using a xenograft PDAC mouse model, we show that metformin intervention prevents tumor growth and enhances the antitumor effect of gemcitabine via suppression of desmoplastic reaction. Taken together, these results suggest that induction of AMPK activation by metformin represents a novel therapeutic approach for treating advanced PDAC through reducing the desmoplastic reaction in PDAC. PMID- 27773753 TI - Acute and repeated doses (28 days) oral toxicity study of Vicenin-1, a flavonoid glycoside isolated from fenugreek seeds in laboratory mice. AB - Vicenin-1 (fenugreek glycoside) has been proven to possess potent anti inflammatory and anti-oxidant activity. The objective of the present investigation was to determine in-vivo acute and subacute (28-days repeated dose) oral toxicity of Vicenin-1 isolated from fenugreek seed. Vicenin-1 (93%) was isolated from a hydroalcoholic extract of fenugreek seed and characterized using HPLC, TLC, 1H NMR and 13C NMR. Acute oral toxicity (AOT) and subacute toxicity studies of Vicenin-1 were carried out according to OECD 425 (up-and-down procedure) and OCED 407 guidelines in Swiss albino mice. In AOT, Vicenin-1 showed 10% mortality when administered at a dose of 5000 mg/kg. However, when vicenin-1 was administered for at doses of 37.5, 75, or 150 mg/kg 28-days it did not show any mortality at the administered doses. Vicenin-1 (75 mg/kg) did not show observational, behavioral, biochemical or histopathological toxic effects. There were minor alterations in body weight, hematology, and histopathology of mice administered with Vicenin-1 (150 mg/kg), but these changes were within normal laboratory ranges. The highest concentration of Venicin-1 was found in liver (3.46%) followed by lung (0.65%). In conclusion, Vicenin-1 showed median lethal dose (LD50) of 4837.5 mg/kg with no-observed-adverse-effect levels (NOAEL) at 75 mg/kg and lowest adverse effect levels (LOAEL) at 150 mg/kg for both sexes of mice during AOT and sub-acute toxicity study, respectively. PMID- 27773756 TI - Comparative studies on osmosis based encapsulation of sodium diclofenac in porcine and outdated human erythrocyte ghosts. AB - The objective of our study was to develop controlled drug delivery system based on erythrocyte ghosts for amphiphilic compound sodium diclofenac considering the differences between erythrocytes derived from two readily available materials - porcine slaughterhouse and outdated transfusion human blood. Starting erythrocytes, empty erythrocyte ghosts and diclofenac loaded ghosts were compared in terms of the encapsulation efficiency, drug releasing profiles, size distribution, surface charge, conductivity, surface roughness and morphology. The encapsulation of sodium diclofenac was performed by an osmosis based process - gradual hemolysis. During this process sodium diclofenac exerted mild and delayed antihemolytic effect and increased potassium efflux in porcine but not in outdated human erythrocytes. FTIR spectra revealed lack of any membrane lipid disorder and chemical reaction with sodium diclofenac in encapsulated ghosts. Outdated human erythrocyte ghosts with detected nanoscale damages and reduced ability to shrink had encapsulation efficiency of only 8%. On the other hand, porcine erythrocyte ghosts had encapsulation efficiency of 37% and relatively slow drug release rate. More preserved structure and functional properties of porcine erythrocytes related to their superior encapsulation and release performances, define them as more appropriate for the usage in sodium diclofenac encapsulation process. PMID- 27773757 TI - Purification, enzymatic activity and inhibitor discovery for recombinant human carbonic anhydrase XIV. AB - Human carbonic anhydrase XIV (CA XIV), a transmembrane protein, highly expressed in the central nervous system, is difficult to recombinantly express and purify in large scale for the measurements of inhibitor binding and drug design. CA XIV belongs to the family of twelve catalytically active CA isoforms in the human body. Disorders in the expression of CA XIV cause serious diseases and CA XIV has been described as a possible drug target for the treatment of epilepsy, some retinopathies, and skin tumors. In this study, the effect of different promoters, E. coli strains, and the length of recombinant CA XIV protein construct were analyzed for the production CA XIV in large scale by using affinity purification. Active site titration by inhibitors and the isothermal titration calorimery revealed over 96% purity of the protein. Enzymatic activity of the purified CA XIV was determined by following the CO2 hydration using the stopped-flow technique. Several inhibitors were discovered that exhibited selectivity towards CA XIV over other CA isoforms and could be developed as drugs. PMID- 27773752 TI - A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents. AB - : Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug loaded liposomes in an injectable hydrogel permits local liposome retention, thus providing a prolonged release in target tissues. Moreover, release can be controlled through the use of a minimally invasive external hyperthermic stimulus. Temporal control of release is particularly important for complex multi step physiological processes, such as angiogenesis, in which different signals are required at different times in order to produce a robust vasculature. In the present work, we demonstrate the ability of Lipogel to provide a flexible, easily modifiable release platform. It is possible to tune the release kinetics of different drugs providing a passive release of one therapeutic agent loaded within the gel and activating the release of a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within Lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. As an in vitro proof of concept with this system, we investigated Lipogels ability to recruit stem cells and then elevate their production of vascular endothelial growth factor (VEGF) by controlling the release of a pro-angiogenic drug, desferroxamine (DFO) with an external hyperthermic stimulus. Initial cell recruitment was accomplished by the passive release of hepatocyte growth factor (HGF) from the hydrogel, inducing a migratory response in cells, followed by the delayed release of DFO from thermosensitive liposomes, resulting in a significant increase in VEGF expression. This delayed release could be controlled up to 14days. Moreover, by changing the duration of the hyperthermic pulse, a fine control over the amount of DFO released was achieved. The ability to trigger the release of therapeutic agents at a specific timepoint and control dosing level through changes in duration of hyperthermia enables sequential multi-dose profiles. STATEMENT OF SIGNIFICANCE: This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications. PMID- 27773765 TI - New acetylenic acids and derivatives from the Basidiomycete Craterellus lutescens (Cantharellaceae). AB - Five new acetylenic acid analogues, craterellynes A-E (1-5), together with three known compounds (6-8), were isolated from the fruiting bodies of Craterellus lutescens. Their structures were elucidated on the basis of spectroscopic and chemical means. The absolute configurations of 1-6 were determined by the modified Mosher method. PMID- 27773764 TI - Opened Proton Pump Inhibitor Capsules Reduce Time to Healing Compared With Intact Capsules for Marginal Ulceration Following Roux-en-Y Gastric Bypass. AB - BACKGROUND & AIMS: Marginal ulceration, or ulceration at the gastrojejunal anastomosis, is a common complication of Roux-en-Y gastric bypass (RYGB). Acidity likely contributes to the pathophysiology, and proton pump inhibitors (PPIs) frequently are prescribed for treatment. However, patients with gastric bypass only have a small gastric pouch and rapid small-bowel transit, which limits the opportunity for capsule breakdown and PPI absorption. Soluble PPIs (open capsules [OCs]) might be absorbed more easily than intact capsules (ICs). We compared time to ulcer healing, number of endoscopic procedures, and use of health care for patients with marginal ulceration who received PPIs in OC vs IC form. METHODS: We performed a retrospective study of 164 patients diagnosed with marginal ulceration who underwent RYGB at the Brigham and Women's Hospital from 2000 through 2015. Patients received high-dose PPIs and underwent repeat endoscopy every 3 months until ulcer healing was confirmed. We used time-to-event analysis with a Cox proportional hazards model to evaluate the association between mode of PPI administration and time to ulcer healing, in addition to Cox multivariate regression analysis. Total charge (procedural and maintenance) was determined by comparison of categorized charges incurred from time of ulcer diagnosis to resolution. The primary outcome was time to healing of marginal ulceration in RYGB patients receiving high-dose PPIs in OC vs IC form. RESULTS: A total of 162 patients were included (115 received OC and 49 received IC). All patients were followed up until ulcer healing was confirmed. The median time to ulcer healing was 91.0 days for the OC group vs 342.0 days for the IC group (P < .001). OC was the only independent predictor of time to ulcer healing (P < .001) when we controlled for known risk factors. The number of endoscopic procedures (P = .02) and overall health care utilization (P = .05) were lower in the OC than the IC group. CONCLUSIONS: Patients with marginal ulceration after RYGB who receive OC PPIs have shorter ulcer healing times, fewer endoscopic procedures, and use less health care resources compared with patients who receive IC PPIs. Given these results and the high prevalence of marginal ulceration in this patient population, the use of OC PPIs is a low-risk, low-cost alternative that should be considered. PMID- 27773763 TI - Development of a measure of hypodontia patients' expectations of the process and outcome of combined orthodontic and restorative treatment. AB - OBJECTIVES: To devise and assess the psychometric properties of a measure that investigates hypodontia patients' expectations of the process and outcome of combined orthodontic/restorative treatment. SETTING: Specialised secondary care facility for individuals with hypodontia. MATERIALS AND METHODS: Mixed research design with three phases: (a) Thematic analysis of data from individual interviews with 25 hypodontia patients/16 parents to generate the questionnaire items. (b) Questionnaire design, assessment of readability and face/content validity with 10 patients. (c) Survey of 32 new hypodontia patients to determine the internal consistency of the measure. RESULTS: Three main themes related to the treatment process emerged from the qualitative data: 'hypodontia clinic', 'orthodontic treatment' and 'restorative treatment'. Three main themes were also revealed relating to treatment outcome: 'changes in appearance', 'psychosocial changes' and 'functional changes'. A 28 item questionnaire was constructed using a mix of visual analogue scale (VAS) and categorical response format. The Flesch reading ease score of the measure was 78, equivalent to a reading age of 9-10 years. Face and content validity were good. The overall Cronbach's alpha was 0.80 while for the treatment process and treatment outcome subscales it was 0.71 and 0.88 respectively. CONCLUSIONS: A patient-based measure of the process and outcome of combined orthodontic/restorative treatment for hypodontia patients has been developed which has good face and construct validity and satisfactory internal consistency. CLINICAL SIGNIFICANCE: Patient expectations of treatment are important in determining not only their satisfaction with treatment outcomes but also their engagement with the clinical process. This questionnaire is a first step in operationalising the expectations of hypodontia patients through assessment tools that can then determine whether pre-treatment counselling is required and aid the consent and treatment planning process, thus improving the quality of treatment provided by approximating the expectations the patients hold to their actual experience. PMID- 27773762 TI - Sol-gel methods for synthesis of aluminosilicates for dental applications. AB - INTRODUCTION: Amorphous aluminosilicates glasses containing fluorine, phosphorus and calcium are used as a component of the glass ionomer dental cement. This cement is used as a restorative, basis or filling material, but presents lower mechanical resistance than resin-modified materials. The Sol-Gel method is a possible route for preparation of glasses with lower temperature and energy consumption, with higher homogeneity and with uniform and nanometric particles, compared to the industrial methods Glass ionomer cements with uniform, homogeneous and nanometric particles can present higher mechanical resistance than commercial ionomers. OBJECTIVES: The aim of this work was to adapt the Sol Gel methods to produce new aluminosilicate glass particles by non-hydrolytic, hydrolytic acid and hydrolytic basic routes, to improve glass ionomer cements characteristics. Three materials were synthesized with the same composition, to evaluate the properties of the glasses produced from the different methods, because multicomponent oxides are difficult to prepare with homogeneity. The objective was to develop a new route to produce new glass particles for ionomer cements with possible higher resistance. CHARACTERIZATION METHODS: The particles were characterized by thermal analysis (TG, DTA, DSC), transmission electron microscopy (TEM), X-ray diffraction (XRD), infrared spectroscopy (FTIR) and scanning electron microscopy coupled with energy dispersive spectroscopy (SEM EDS). The glasses were tested with polyacrylic acid to form the glass ionomer cement by the setting reaction. CONCLUSIONS: It was possible to produce distinct materials for dental applications and a sample presented superior characteristics (homogeneity, nanometric particles, and homogenous elemental distribution) than commercial glasses for ionomer cements. The new route for glass production can possible improve the mechanical resistance of the ionomer cements. PMID- 27773758 TI - Chlamydia related bacteria (Chlamydiales) in early pregnancy: community-based cohort study. AB - OBJECTIVES: Serological case-control studies suggest that certain chlamydia related bacteria (Chlamydiales) which cause cows to abort may do the same in humans. Chlamydiales include Waddlia chondrophila, Chlamydia abortus and Chlamydia trachomatis. Data on prevalence of Chlamydiales in pregnancy are sparse. Using stored urine samples from a carefully characterised cohort of 847 newly pregnant women recruited from 37 general practices in London, UK, we aimed to investigate the prevalence and types of Chlamydiales infections. We also explored possible associations with miscarriage or spontaneous preterm birth. METHODS: Samples were tested using W. chondrophila and pan-Chlamydiales specific real-time PCRs targeting the 16S rRNA gene. Samples positive on either PCR were subjected to DNA sequencing and C. trachomatis PCR. RESULTS: The overall prevalence of Chlamydiales was 4.3% (36/847, 95% CI 3.0% to 5.8%). The prevalence of W. chondrophila was 0.6% (n = 5), C. trachomatis 1.7% (n = 14), and other Chlamydiales species 2.0% (n = 17). Infection with C. trachomatis was more common in women aged <25, of black ethnicity or with bacterial vaginosis, but this did not apply to W. chondrophila or other Chlamydiales. Follow up was 99.9% at 16 weeks gestation and 90% at term. No infection was significantly associated with miscarriage at <=12 weeks (prevalence 10%, 81/827) or preterm birth <37 weeks (prevalence 4%, 23/628). Of 25 samples sequenced, seven (28%) were positive for Chlamydiales bacterium sequences associated with respiratory tract infections in children. CONCLUSION: In the first study to use the pan-Chlamydiales assay on female urine samples, 4% of pregnant women tested positive for Chlamydiales, including species known to be pathogenic in mothers and neonates. PMID- 27773761 TI - Expression, purification, immunogenicity and protective efficacy of a recombinant nucleoside hydrolase from Leishmania donovani, a vaccine candidate for preventing cutaneous leishmaniasis. AB - The nucleoside hydrolase gene from Leishmania donovani was cloned and expressed in Escherichia coli as a full length 36-kDa protein (LdNH36). Following lysis and extraction, the protein was purified by anion exchange and gel filtration chromatography. The purified protein had a molecular mass of approximately 36-kDa and was confirmed to be >99% pure. Using a nucleoside hydrolase assay, the protein was found to exhibit a Km of 741 +/- 246 MUM. Protein integrity was confirmed by lithium dodecyl sulfate polyacrylamide gel electrophoresis (LDS PAGE), mass spectrometry (MS), and enzymatic assay. Analysis of antibody levels from immunized mice indicated that LdNH36 alone or in a stable emulsion with the Toll-like receptor-4 ligand glucopyranosyl lipid adjuvant (GLA-SE) as immunostimulant induced high levels of antigen-specific IgG antibodies. The cellular immune response indicated a Th1 response in mice immunized with LdNH36, but only when formulated with GLA-SE. Mice immunized with the LdNH36 antigen in combination with the GLA-SE adjuvant and challenged with Leishmania mexicana showed significant reductions (>20 fold) in parasite burden, confirming the protective efficacy of this vaccine candidate. PMID- 27773766 TI - Affinity purification of bacterial outer membrane vesicles (OMVs) utilizing a His tag mutant. AB - To facilitate the rapid purification of bacterial outer membrane vesicles (OMVs), we developed two plasmid constructs that utilize a truncated, transmembrane protein to present an exterior histidine repeat sequence. We chose OmpA, a highly abundant porin protein, as the protein scaffold and utilized the lac promoter to allow for inducible control of the epitope-presenting construct. OMVs containing mutant OmpA-His6 were purified directly from Escherichia coli culture media on an immobilized metal affinity chromatography (IMAC) Ni-NTA resin. This enabling technology can be combined with other molecular tools directed at OMV packaging to facilitate the separation of modified/cargo-loaded OMV from their wt counterparts. In addition to numerous applications in the pharmaceutical and environmental remediation industries, this technology can be utilized to enhance basic research capabilities in the area of elucidating endogenous OMV function. PMID- 27773760 TI - Preferential expression of domain cassettes 4, 8 and 13 of Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria imported in France. AB - OBJECTIVES: Severe Plasmodium falciparum malaria (SM) involves cytoadhesion of parasitized red blood cells, mediated by P. falciparum erythrocyte membrane protein 1, which is encoded by var genes. Expression of var gene group A and B or encoding domain cassettes DC4, DC5, DC8 and DC13 has been implicated in SM in African children, but no data exist in the context of imported malaria. The aim of this study was to investigate var gene expression linked to clinical presentation and host factors in SM imported into France. METHODS: Expression level of var gene groups A, B, C, var1, var2csa, var3 and var genes encoding DC4, DC5, DC8 and DC13 was measured by quantitative RT-PCR and expressed in transcript units. Seventy SM and 48 uncomplicated malaria (UM) P. falciparum cases were analysed according to disease severity, epidemiological characteristics (migrants or travellers) and anti-P. falciparum antibodies. Cluster analysis was performed to identify gene expression profiles. RESULTS: Var1 and B/C expression were higher in UM than SM (0.66 (0-1.1) and 1.88 (1.3-2.4); p <0.04, respectively). Group C expression differed between migrants and travellers (0.21 (0-0.75) versus 0 (0-0); p 0.002). Group A differed in naive and pre-exposed patients (1.1 (0.7 1.5) versus 0.4 (0-1.1); p 0.01). Population clusters revealed increased expression from group A and B var genes, and DC4, DC8 and DC13 in SM. CONCLUSIONS: These results corroborate the implication of DC4, DC8 and DC13 in severe imported malaria cases as African children, and their expression depends of host factors. PMID- 27773759 TI - Extended-spectrum beta-lactamase- and pAmpC-producing Enterobacteriaceae among the general population in a livestock-dense area. AB - OBJECTIVES: In the Netherlands there is an ongoing debate regarding environmental health risks of livestock farming for neighbouring residents. This explorative study aims to determine the prevalence of carriage of extended-spectrum beta lactamase and/or plasmid-mediated AmpC-producing Enterobacteriaceae (ESBL/pAmpC E) in the general population living in a livestock-dense area, and to study associations between determinants, including exposure through contact with animals and the environment, and human carriage of ESBL/pAmpC-E. METHODS: A cross sectional study was performed among 2432 adults (aged 20-72 years) in 12 temporary research centres in the south of the Netherlands, consisting of a questionnaire and analysis of a faecal sample to assess carriage of ESBL/pAmpC-E. Risk factors were analysed using logistic regression. RESULTS: The prevalence for carriage of ESBL/pAmpC-E was 4.5% (109/2432; 95% CI 3.7-5.4) ranging from 1.4% to 10.9% among the research centres. ESBL/pAmpC resistance genes were detected in Escherichia coli and Klebsiella pneumoniae isolates obtained from these 109 persons and the most common ESBL-resistance genes were blaCTX-M-15, blaCTX-M 14/17 and blaCTX-M-1, originating from 76 participants. Travel in the previous 12 months to Africa, Asia or Latin America (OR 2.82; 95% CI 1.71-4.63), having kept cows for a hobby in the previous 5 years (OR 3.77; 95% CI 1.22-11.64), usage of proton-pump inhibitors (OR 1.84; 95% CI 1.05-3.23), and living within 1000 m of a mink farm (OR 2.26; 95% CI 1.28-3.98) were identified as risk factors. Exposure to poultry was not identified as a risk factor. CONCLUSIONS: Overall, living in close proximity to livestock animals and farms does not seem to be a risk factor for carriage of ESBL/pAmpC-E. PMID- 27773768 TI - Structural and functional specificity of Influenza virus haemagglutinin and paramyxovirus fusion protein anchoring peptides. AB - Two enveloped virus families, Orthomyxoviridae and Paramyxoviridae, comprise a large number of dangerous pathogens that enter the host cell via fusion of their envelope with a target cell membrane at acidic or neutral pH. The Class I prototypic glycoproteins responsible for this reaction are the Influenza virus haemagglutinin (HA) protein or paramyxovirus fusion (F) protein. X-ray crystallography and cryoelectron microscopy data are available for the HA and F ectodomains in pre- and post-fusion conformations, revealing similar spiky architectures, albeit with clear differences in the details. In contrast, their anchoring segments, which possess a linker region, transmembrane domain and cytoplasmic tail that is specifically modified with long fatty acids (highly conserved in HA and occasional in F), are not resolved. Recent experimental, bioinformatics and molecular modelling data showing the primary, secondary and quaternary organization of the HA and F anchoring segments are summarized in this review. Some amino acid patterns that are crucial for protein thermal stability or lipid membrane order/cholesterol binding are addressed, and new achievements in vaccine practice using HA transmembrane domain chimaeras are discussed. The oligomerization properties of the transmembrane domains are considered in the context of Group-1 and Group-2 antigenic HA subtypes and various genera/subfamilies of paramyxoviruses. A specific focus is the late steps of fusion that are reportedly facilitated by (1) beta-sheet-promoting beta-branched amino acids (valine and isoleucine) that are enriched in the transmembrane domain of paramyxovirus F or (2) a post-translational modification of C-terminal cysteines with palmitate/stearate (differential S-acylation) that is highly conserved in Influenza virus HA. PMID- 27773776 TI - Trust: The Keystone of the Patient-Physician Relationship. PMID- 27773773 TI - How the Anatomische Gesellschaft excluded unwanted members after 1945-among them Eugen Fischer and Max Clara. AB - The Anatomische Gesellschaft, an international Germany-based association of anatomists, was closed down in 1945, after the end of the "Third Reich". It was eventually re-founded in 1949, continuing its tradition from its foundation in 1886, based in large part on the membership prior to 1945. Newly available archival material reveals, however, that at least six members were explicitly prevented from re-joining the society. This includes Max Clara, who was accused of plagiarism and, at least implicitly, of basing his career on Nazi party support. It also includes Eugen Fischer, a leading anthropologist of the Nazi period, who was seen to be indirectly responsible for Nazi crimes like forced sterilisation or extermination of "anthropologically defined" groups of people. Therefore, Fischer's honorary membership, which had already been published in the membership directory, was revoked after a heated internal debate. Nevertheless, these exclusions cannot be interpreted as a self-directed "denazification" of the Anatomische Gesellschaft, as political activity in line with the Nazis was not the main criterion for these exclusions. Incidentally, the archival sources also reveal that Wolfgang Bargmann, who had been elected as the first post-war secretary of the Gesellschaft in 1949, resigned from this post after only one year in office because his management of this "Fischer affair" was felt to be too autocratic. PMID- 27773770 TI - Sonochemical synthesis of porous NiTiO3 nanorods for photocatalytic degradation of ceftiofur sodium. AB - Porous NiTiO3 nanorods were synthesized through the sonochemical route followed by calcination at various temperature conditions. Surface morphology of the samples was tuned by varying the heat treatment temperature from 100 to 600 degrees C. The synthesized NiTiO3 nanorods were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, diffused reflectance spectroscopy, photoluminescence spectroscopy and Brunauer Emmett-Teller (BET) analyses. The characterization studies revealed that the NiTiO3 nanomaterial was tuned to porous and perfectly rod shaped structure during the heat treatment at 600 degrees C. The porous NiTiO3 nanorods showed visible optical response and thus can be utilized in the photocatalytic degradation of ceftiofur sodium (CFS) under direct sunlight. The photoluminescence intensity of the porous NiTiO3 nanorods formed while heating at 600 degrees C was lower than that of the as-synthesized NiTiO3 sample owing to the photogenerated electrons delocalization along the one dimensional nanorods and this delocalization resulted in the reduction of the electron-hole recombination rate. The photocatalytic degradation of ceftiofur sodium (CFS) was carried out using NiTiO3 nanorods under the direct sunlight irradiation and their intermediate products were analysed through HPLC to deduce the possible degradation mechanism. The porous NiTiO3 nanorods exhibited an excellent photocatalytic activity towards the CFS degradation and further, the photocatalytic activity was increased by the addition of peroxomonosulfate owing to the simultaneous generation of both OH and SO4-. PMID- 27773772 TI - Pulmonary surfactant metabolism in the alveolar airspace: Biogenesis, extracellular conversions, recycling. AB - Pulmonary surfactant is a lipid-protein complex that lines and stabilizes the respiratory interface in the alveoli, allowing for gas exchange during the breathing cycle. At the same time, surfactant constitutes the first line of lung defense against pathogens. This review presents an updated view on the processes involved in biogenesis and intracellular processing of newly synthesized and recycled surfactant components, as well as on the extracellular surfactant transformations before and after the formation of the surface active film at the air-water interface. Special attention is paid to the crucial regulation of surfactant homeostasis, because its disruption is associated with several lung pathologies. PMID- 27773774 TI - Does Management of True Aneurysms of Peripancreatic Arteries Require Repair of Associated Celiac Artery Stenosis? AB - BACKGROUND: True aneurysms of the gastroduodenal (GDA) and pancreaticoduodenal (PDA) arteries have been attributed to increased collateral flow due to tandem celiac artery stenosis or occlusion. Although GDA and PDA aneurysm exclusion is recommended because of the high reported risk of rupture, it remains uncertain whether simultaneous celiac artery reconstruction is necessary to preserve end organ flow. STUDY DESIGN: We conducted a retrospective analysis of consecutive patients admitted from 1996 to 2015 with true aneurysms of the GDA or PDA. RESULTS: Twenty patients with true aneurysms of the PDA (n = 16) or GDA (n = 4) were identified. Mean age was 61.5 years (range 35 to 85 years) and 11 (55%) were women. Nine (45%) presented with rupture, 8 (40%) presented with pain, and 3 (15%) were asymptomatic. All 9 patients who presented with rupture had contained retroperitoneal hematomas, and none experienced rebleeding. Fifteen (75%) patients had an associated celiac artery >60% stenosis or occlusion, and 2 (10%) had both celiac and superior mesenteric artery stenoses. Thirteen (65%) patients underwent successful endovascular coiling, only 1 of which had a prophylactic celiac artery bypass. Three (15%) patients underwent open aneurysm exclusion and celiac bypass, and 4 (20%) others were observed. There were no aneurysm-related deaths in this series, and none of the patients who underwent coiling without celiac revascularization had hepatic ischemia or other mesenteric morbidity develop during a median follow-up of 6 months (maximum 200 months). CONCLUSIONS: Gastroduodenal artery and PDA aneurysms present most commonly with pain or bleeding, and all should be considered for repair, regardless of size. Aneurysm exclusion is safely and effectively achieved with endovascular coiling. Although associated celiac artery stenosis is found in the majority of cases, celiac revascularization might not be necessary. PMID- 27773777 TI - Bibliometrics of global Ebola Virus Disease research as seen through Science Citation Index Expanded during 1987-2015. PMID- 27773771 TI - Ultrasonic-assisted Kabachnik-Fields reaction for rapid fabrication of AIE-active fluorescent organic nanoparticles. AB - Aggregation-induced emission (AIE)-active fluorescent organic nanoparticles (FNPs) have been extensively explored for fluorescence "turn-on" bio-imaging applications with the unique advantages over conventional FNPs. Transformation of AIE-active molecules into FNPs can greatly expand their biomedical application potential. Here we reported a novel "one-pot" strategy for fabricating AIE-active FNPs through an ultrasonic-assisted, catalysts-free and solvent-free Kabachnik Fields (KF) reaction for the first time. The KF reaction can be completed within 10min to generate AIE-active PTH-CHO-PEI-DEP FNPs through mixing polyethylenimine and aldehyde group containing AIE dyes and diethyl phosphate. These PTH-CHO-PEI DEP FNPs were confirmed by proton nuclear magnetic resonance (1H NMR) spectroscopy, transmission electron microscopy (TEM) and fluorescence spectroscopy etc. The cell uptake behavior as well as cell viability of PTH-CHO PEI-DEP FNPs was examined to evaluate their potential for biomedical application. We demonstrated that the amphiphilic alpha-aminophosphonate polymers could self assemble into PTH-CHO-PEI-DEP FNPs in aqueous solution and showed excellent water dispersibility. TEM image shows the size of PTH-CHO-PEI-DEP FNPs is 100-200nm. More importantly, the PTH-CHO-PEI-DEP FNPs emit strong green fluorescence and desirable biocompatibility, making them very suitable for biomedical applications. Finally, thus smart FNPs design together with their excellent performance will open a new avenue in the development of FNPs for following biological processes such as carcinogenesis. PMID- 27773778 TI - The dialogue among Islamic countries and groups for a healthy and safe Hajj. PMID- 27773767 TI - Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma. AB - Glaucomatous visual field progression has both personal and societal costs and therefore has a serious impact on quality of life. At the present time, intraocular pressure (IOP) is considered to be the most important modifiable risk factor for glaucoma onset and progression. Reduction of IOP has been repeatedly demonstrated to be an effective intervention across the spectrum of glaucoma, regardless of subtype or disease stage. In the setting of approval of IOP lowering therapies, it is expected that effects on IOP will translate into benefits in long-term patient-reported outcomes. Nonetheless, the effect of these medications on IOP and their associated risks can be consistently and objectively measured. This helps to explain why regulatory approval of new therapies in glaucoma has historically used IOP as the outcome variable. Although all approved treatments for glaucoma involve IOP reduction, patients frequently continue to progress despite treatment. It would therefore be beneficial to develop treatments that preserve visual function through mechanisms other than lowering IOP. The United States Food and Drug Administration (FDA) has stated that they will accept a clinically meaningful definition of visual field progression using Glaucoma Change Probability criteria. Nonetheless, these criteria do not take into account the time (and hence, the speed) needed to reach significant change. In this paper we provide an analysis based on the existing literature to support the hypothesis that decreasing the rate of visual field progression by 30% in a trial lasting 12-18 months is clinically meaningful. We demonstrate that a 30% decrease in rate of visual field progression can be reliably projected to have a significant effect on health-related quality of life, as defined by validated instruments designed to measure that endpoint. PMID- 27773779 TI - A closer look at travellers' infections abroad: Finnish nationwide data with incidences, 2010 to 2012. AB - BACKGROUND: Although infections represent the most common health problem of travellers abroad, data on morbidity and incidences of various infections are scarce. METHOD: Data on infections of Finnish travellers during 2010-2012 were retrieved from the database of SOS International, an assistance organization covering 95% of Finns requiring aid abroad. The study included 30,086 cases. For incidence calculation, the data were linked to the numbers of Finns visiting these regions during the same period as recorded by the Official Statistics of Finland. RESULTS: The incidence of infections was particularly high in Africa, southern Europe plus the eastern Mediterranean, and Asia plus Oceania. The most frequent diagnoses were acute gastroenteritis (38.0%) and respiratory-tract infections (RTI) (34.5%), followed by infections of the ear (12.6%), skin or subcutaneous tissue (5.1%), urogenital tract (4.2%), eye (3.1%), and systemic febrile infections (2.2%). Vaccine-preventable diseases (VPD) accounted for 0.8% of cases, with varicella as most (49%) and influenza as second-most (27%) common. CONCLUSIONS: Incidence of infections was higher in southern than in eastern and western Europe. Gastroenteritis and RTI proved the most frequent diagnoses, whereas systemic febrile infections were uncommon. Despite pre-travel immunizations, VPDs still occurred; pre-travel consultation should cover both varicella and influenza. PMID- 27773781 TI - The Na+-D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer. AB - Orally applied SGLT2 (SLC5A2) inhibitors that enter the blood and decrease renal reabsorption of glucose have been approved as antidiabetic drugs. They decrease blood glucose levels, slightly reduce body weight and blood pressure, and decrease the risk for diabetic nephropathy. The SGLT2 inhibitor empagliflozin has been shown to reduce the risk of severe cardiac failure. This review summarizes knowledge about the functions of SGLT2 and the pathophysiology of type 2 diabetes (T2D) and diabetic follow-up diseases. In addition, proposed pathophysiological mechanisms of therapeutic effects and of side effects of SGLT2 inhibitors are described. A recently investigated strategy to employ orally applied SGLT1 (SLC5A1) inhibitors for treatment of diabetes is discussed. The SGLT1 inhibitors reduce glucose absorption and decrease blood glucose excursions after the intake of glucose-rich food. Knowledge concerning the expression of SGLT1 in different organs is compiled and potential side effects of SGLT1 inhibitors entering the blood are discussed. Because selective targeting of SGLT1 expression presents a strategy to decrease SGLT1-mediated glucose absorption, current knowledge about the regulation of SGLT1 is also discussed. This includes the possibility to decrease SGLT1 abundance in the small intestinal brush-border membrane by a peptide derived from protein RS1 (RSC1A1) that regulates membrane trafficking. Finally the possibility to employ SGLT1 and SGLT2 as targets for anticancer therapy is discussed. SGLT1 and SGLT2 are expressed in various tumors where they supply the tumor cells with glucose for euglycemic glycolysis. Tumor growth of carcinoma expressing SGLT2 can be slowed down by an SGLT2 inhibitor. PMID- 27773775 TI - Using Quality Improvement Principles to Enhance Long-Term Completion of Patient Reported Outcomes after Ventral Hernia Repair. AB - BACKGROUND: Ventral hernia repair (VHR) is a commonly performed surgical procedure. Unfortunately, long-term prospective information about quality of life and outcomes after VHR has been challenging to obtain. Decoupling follow-up from clinical visits via patient-reported outcomes (PROs) has been proposed as a means of achieving better long-term assessments after VHR. The Americas Hernia Society Quality Collaborative (AHSQC) is a national quality improvement (QI) effort in hernia repair that uses PROs to obtain long-term follow-up. However, the modality of PRO engagement to maximize participation has not been well established. A formal QI initiative was undertaken to determine if long-term PRO follow-up could be increased at a single AHSQC site by adding telephone communication to email communication for long-term postoperative VHR assessment. METHODS: Between September 2015 and July 2016, the long-term (greater than 1 year) AHSQC PRO completion rates after VHR at our institution were analyzed using plan-do-study act cycles. Two interventions were implemented: contacting patients by telephone and changing timing of telephone calls. RESULTS: Two hundred thirty-two patients were identified, of whom 99 (42.7%) met eligibility criteria. Before this initiative, the long-term PRO completion rate was 16.3% in postoperative VHR patients. The completion rate after introducing telephone calls (intervention 1) was 35.7% and after changing the timing of telephone calls (intervention 2), was 55.1%. The mean participation rate was 45.4% (+/- 9.7%). CONCLUSIONS: A telephone based approach markedly improved long-term PRO participation rates in postoperative VHR patients. Ultimately, a combination of email and telephone communication may be necessary to achieve higher levels of PRO follow-up in the VHR population. PMID- 27773780 TI - Differences in prevalence of community-associated MRSA and MSSA among U.S. and non-U.S. born populations in six New York Community Health Centers. AB - BACKGROUND: Staphylococcus aureus is the most common cause of Skin and Soft Tissue Infections (SSTIs) in the community in the United States of America. Community Health Centers (CHC) serve as primary care providers for thousands of immigrants in New York. METHODS: As part of a research collaborative, 6 New York City-area CHCs recruited patients with SSTIs. Characterization was performed in all S. aureus isolates from wounds and nasal swabs collected from patients. Statistical analysis examined the differences in wound and nasal cultures among immigrant compared to native-born patients. RESULTS: Wound and nasal specimens were recovered from 129 patients and tested for antibiotic susceptibility. 40 patients were immigrants from 15 different countries. Although not statistically significant, immigrants had lower rates of MRSA infections (n = 15) than did native-born participants, and immigrants showed significantly higher rates of MSSA wound cultures (n = 11) (OR = 3.5, 95% CI: 1.3, 9.7). CONCLUSIONS: In our study, immigrants were more likely to present with SSTIs caused by MSSA than US born patients. Immigants also reported lower frequencies of antibiotic prescription or consumption in the months prior to SSTI infection. This suggests that antibiotic resistance may vary regionally and that immigrants presenting with SSTIs may benefit from a broader range of antibiotics. PMID- 27773769 TI - The family Rhabdoviridae: mono- and bipartite negative-sense RNA viruses with diverse genome organization and common evolutionary origins. AB - The family Rhabdoviridae consists of mostly enveloped, bullet-shaped or bacilliform viruses with a negative-sense, single-stranded RNA genome that infect vertebrates, invertebrates or plants. This ecological diversity is reflected by the diversity and complexity of their genomes. Five canonical structural protein genes are conserved in all rhabdoviruses, but may be overprinted, overlapped or interspersed with several novel and diverse accessory genes. This review gives an overview of the characteristics and diversity of rhabdoviruses, their taxonomic classification, replication mechanism, properties of classical rhabdoviruses such as rabies virus and rhabdoviruses with complex genomes, rhabdoviruses infecting aquatic species, and plant rhabdoviruses with both mono- and bipartite genomes. PMID- 27773784 TI - Treatment of brain metastases in the modern genomic era. AB - Development of brain metastasis (BM) portends a dismal prognosis for patients with cancer. Melanomas and carcinomas of the lung, breast, and kidney are the most common malignancies to metastasize to the brain. Recent advances in molecular genetics have enabled the identification of actionable, clinically relevant genetic alterations within primary tumors and their corresponding metastases. Adoption of genotype-guided treatment strategies for the management of systemic malignancy has resulted in dramatic and durable responses. Unfortunately, despite these therapeutic advances, central nervous system (CNS) relapses are not uncommon. Although these relapses have historically been attributed to limited blood brain barrier penetration of anti-neoplastic agents, recent work has demonstrated genetic heterogeneity such that metastatic sites, including BM, harbor relevant genetic alterations that are not present in primary tumor biopsies. This improved insight into molecular mechanisms underlying site specific recurrences can inform strategies for targeting these oncogenic drivers. Thus, development of rational, genomically guided CNS-penetrant therapies is crucial for ongoing therapeutic success. PMID- 27773783 TI - Chitosan oligosaccharide: Biological activities and potential therapeutic applications. AB - Chitosan oligosaccharide (COS) is an oligomer of beta-(1?4)-linked d-glucosamine. COS can be prepared from the deacetylation and hydrolysis of chitin, which is commonly found in the exoskeletons of arthropods and insects and the cell walls of fungi. COS is water soluble, non-cytotoxic, readily absorbed through the intestine and mainly excreted in the urine. Of particular importance, COS and its derivatives have been demonstrated to possess several biological activities including anti-inflammation, immunostimulation, anti-tumor, anti-obesity, anti hypertension, anti-Alzheimer's disease, tissue regeneration promotion, drug and DNA delivery enhancement, anti-microbial, anti-oxidation and calcium-absorption enhancement. The mechanisms of actions of COS have been found to involve the modulation of several important pathways including the suppression of nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPK) and the activation of AMP-activated protein kinase (AMPK). This review summarizes the current knowledge of the preparation methods, pharmacokinetic profiles, biological activities, potential therapeutic applications and safety profiles of COS and its derivatives. In addition, future research directions are discussed. PMID- 27773785 TI - Mast cell and eosinophil surface receptors as targets for anti-allergic therapy. PMID- 27773786 TI - Monoclonal antibody therapy for the treatment of asthma and chronic obstructive pulmonary disease with eosinophilic inflammation. AB - Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala(r) (mepolizumab; anti-interleukin [IL]-5) and Cinquair(r) (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils. PMID- 27773788 TI - Modulating putative endothelial progenitor cells for the treatment of endothelial dysfunction and cardiovascular complications in diabetes. AB - Diabetes induces a decrease in the number and function of different pro angiogenic cell types generically designated as putative endothelial progenitor cells (EPC), which encompasses cells from myeloid origin that act in a paracrine fashion to promote angiogenesis and putative "true" EPC that contribute to endothelial replacement. This not only compromises neovasculogenesis in ischemic tissues but also impairs, at an early stage, the reendotheliziation process at sites of injury, contributing to the development of endothelial dysfunction and cardiovascular complications. Hyperglycemia, insulin resistance and dyslipidemia promote putative EPC dysregulation by affecting the SDF-1/CXCR-4 and NO pathways and the p53/SIRT1/p66Shc axis that contribute to their mobilization, migration, homing and vasculogenic properties. To optimize the clinical management of patients with hypoglycemic agents, statins and renin-angiotensin system inhibitors, which display pleiotropic effects on putative EPC, is a first step to improve their number and angiogenic potential but specific strategies are needed. Among them, mobilizing therapies based on G-CSF, erythropoietin or CXCR-4 antagonism have been developed to increase putative EPC number to treat ischemic diseases with or without prior cell isolation and transplantation. Growth factors, genetic and pharmacological strategies are also evaluated to improve ex vivo cultured EPC function before transplantation. Moreover, pharmacological agents increasing in vivo the bioavailability of NO and other endothelial factors demonstrated beneficial effects on neovascularization in diabetic ischemic models but their effects on endothelial dysfunction remain poorly evaluated. More experiments are warranted to develop orally available drugs and specific agents targeting p66Shc to reverse putative EPC dysfunction in the expected goal of preventing endothelial dysfunction and diabetic cardiovascular complications. PMID- 27773787 TI - Atrial fibrillation in heart failure with preserved ejection fraction: Insights into mechanisms and therapeutics. AB - Atrial fibrillation (AF) and heart failure (HF) often coexist, and the outcomes of patients who have both AF and HF are considerably worse than those with either condition in isolation. Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical entity and accounts for approximately one-half of current HF. At least one-third of patients with HFpEF are burdened by comorbid AF. The current understanding of the relationship between AF and HFpEF is limited, but the clinical implications are potentially important. In this review, we explore 1) the pathogenesis that drives AF and HFpEF to coexist; 2) pharmacologic therapies that may attenuate the impact of AF in HFpEF; and 3) future directions in the management of this complex syndrome. PMID- 27773789 TI - Cellular thiamine status is coupled to function of mitochondrial 2-oxoglutarate dehydrogenase. AB - Decreased thiamine and reduced activity of thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase (OGDH) cause neurodegeneration. We hypothesized on concerted cell-specific regulation of the thiamine metabolism and ThDP-dependent reactions. We identified a smaller thiamine pool, a lower expression of the mitochondrial ThDP transporter, and a higher expression of OGDH in rat astrocytes versus neuroblastoma N2A. According to the data, the astrocytic OGDH may be up regulated by an increase in intracellular ThDP, while the neuroblastomal OGDH functions at full ThDP saturation. Indeed, in rat astrocytes and brain cortex, OGDH inhibition by succinyl phosphonate (SP) enlarged the pool of thiamine compounds. Increased ThDP level in response to the OGDH inhibition presumably up regulated the enzyme to compensate for a decrease in reducing power which occurred in SP-treated astrocytes. Under the same SP treatment of N2A cells, their thiamine pool and reducing power were unchanged, although SP action was evident from accumulation of glutamate. The presented data indicate that functional interplay between OGDH, other proteins of the tricarbocylic acid cycle and proteins of thiamine metabolism is an important determinant of physiology specific networks and their homeostatic mechanisms. PMID- 27773792 TI - Establishment and characterization of porcine focal cerebral ischemic model induced by endothelin-1. AB - BACKGROUND AND PURPOSE: Due to well-developed Circle of Willis in pigs, it is technically challenging to make persistent focal ischemic stroke based on occlusion of cerebral arteries. Endothelin-1 could cause a focal lesion by forcing transient but strong vasoconstriction in the circumscribed injected area. Its use in porcine stroke model has drawn attention lately. However, all the porcine endothelin-1 induced models were euthanized soon after surgery. Whether the brain lesion is persistent, and whether they could cause neurological deficit are not known. This research aims to provide a more detailed characterization of endothelin-1 induced porcine cerebral ischemic model by evaluating the change of neurological function and the brain lesion monitored by MRI of the pigs. METHODS: Danish Domestic pigs were randomly divided into two groups: a group receiving endothelin-1 (ET-1 group, n=6) and a sham group (n=6). After the fronto-temporal craniotomy, pigs in the ET-1 group received 200MUl endothelin-1 injected within a cortical area of one cm2; pigs in the sham group received only saline injections. Neurological deficit evaluation and MRI scanning were done 24h and 72h after operation. Afterwards, hematoxylin and eosin staining was conducted to detect the morphological characteristics of the damaged brain tissue. RESULTS: The average performance score in the pigs of the ET-1 group was 9.67+/-1.03 and 9.00+/-1.26 respectively, at 24h and 72h after surgery, which was significantly higher than that of the pigs in sham group. The brain lesion percentage detected by MRI was 12.26+/-0.60%, and 10.33+/-0.51% respectively, at 24h and 72h after surgery in the ET-1 group. Microscopy showed extended pyknotic neuronal perikarya in neurons located in the ischemic area. CONCLUSIONS: The endothelin-1 induced porcine cerebral ischemic model is technically easier, and able to create cerebral ischemia severe enough to cause a functional neurological deficit as well as observable lesions on MRI. It is a suitable model for long-term cerebral ischemia research. PMID- 27773791 TI - Mir363-3p improves ischemic stroke outcomes in female but not male rats. AB - With age, stroke prevalence is higher, and stroke outcome, worse, in women. Thus there is an urgent need to identify stroke neuroprotectants for this population. Using a preclinical stroke model, our studies focused on microRNAs (miRNAs), a class of translational repressors, as neuroprotectants. Analysis of circulating miRNA in the acute phase of stroke indicated potential neuroprotective capacity for miR363. Specifically, mir363 is elevated in serum of adult female rats that typically have small infarct volumes, but is deficient in age-matched males or middle-aged males and females, groups that have greater stroke-associated impairment. To directly test the effect of mir363 on stroke outcomes, first, adult females were treated with antagomirs to mir363 post stroke and next, middle aged females were treated with mimic to mir363-3p post stroke. Antagomir treatment to adult females significantly increased infarct volume and impaired sensory motor performance. Reciprocally, mir363 mimic to middle-aged females reduced infarct volume, preserved forebrain microvessels and improved sensory motor performance. In the early acute stroke phase, mir363-3p mimic reduced the expression and functional activity of caspase-3, a critical component of the apoptotic cell cascade. In contrast, mir363-3p mimic treatment had no effect on stroke outcomes or caspase regulation in young males. Collectively, these studies show that mir363 is neuroprotective for stroke in females and implicates caspase 3 as a sex-specific miRNA-sensitive node for recovery from ischemic stroke. PMID- 27773793 TI - Homocysteine inhibits neural stem cells survival by inducing DNA interstrand cross-links via oxidative stress. AB - Elevated plasma levels of homocysteine have been implicated in neurodevelopmental and neurodegenerative disorders in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) cytotoxicity on the nervous system are not yet fully unknown, induction of DNA interstrand cross links and inhibition of neural stem cells (NSCs) survival may be involved. The objective of our study was to investigate the effects of Hcy on DNA interstrand cross-links in NSCs, and to explore its possible mechanisms. We also found that Hcy induced cell DNA damage on a dose-dependent manner and evoked reactive oxidative species (ROS) production, leading to elevated apoptosis in NSCs. Moreover, Hcy exposure activated the Fanconi anemia (FA) pathway, which was characterized by increases in monoubiquitination of Fanci and Fancd2 and enhancement of the interaction between above two proteins. On contrary, N-Acety-l Cysteine (NAC) decreased Hcy-evoked ROS production and significantly ameliorated DNA damage and improved cell survival. These data suggest that Hcy may play a role in the pathogenesis of neurological diseases via a molecular mechanism that induces DNA interstrand cross-links via oxidative stress and involves in negative regulation of NSCs survival. PMID- 27773790 TI - Partial MHC class II constructs as novel immunomodulatory therapy for stroke. AB - The worldwide prevalence of stroke continues to rise despite recent successes in treating acute ischemic stroke. With limited patient eligibility and associated risk of tPA and mechanical thrombectomy, new preventive and therapeutic modalities are needed to stave the rising wave of stroke. Inflammation plays a key role in brain damage after cerebral ischemia, and novel therapies that target pro-inflammatory cells have demonstrated promise for treatment for stroke. Partial MHC class II constructs have been shown to prevent and/or reverse clinical signs of various inflammatory diseases such as experimental autoimmune encephalomyelitis, collagen-induced arthritis and experimental autoimmune uveitis, by reducing the number and frequency of activated cells in the damaged CNS. Herein, we review the use of partial MHC class II constructs as a novel treatment for ischemic stroke. These constructs have been shown to reduce infarct volume and neurological deficit in various cerebral ischemia models in young adult and aging male and female mice. In addition, partial MHC class II constructs were shown to reverse stroke-associated splenic atrophy and promote a protective M2 macrophage/microglia phenotype in the CNS which contributes to tissue repair and recovery after stroke. By addressing remaining STAIR criteria, such as efficacy in large animal models of stroke, these constructs will be prime candidates for clinical trials of acute ischemic stroke. PMID- 27773795 TI - Polymorphisms in the 5-hydroxytryptamine receptor 3B gene are associated with heroin dependence in the Chinese Han population. AB - Previous studies suggested that the 5-hydroxytryptamine receptor 3B (HTR3B) is involved in heroin dependence by modulating dopamine (DA) release in the reward pathway and that the genetic polymorphisms in HTR3B play plausible role in modulating the risk of developing heroin addiction. To identify markers that contribute to the genetic susceptibility to heroin dependence, we examined the potential associations between heroin dependence and 7 single nucleotide polymorphisms (SNPs) of the HTR3B gene using multiplex SNaPshot technology in a Chinese Han population. Participants included 418 heroin-dependent subjects and 422 healthy controls. The results suggested that the genotype distribution of HTR3B rs1176746 and rs1185027 were significantly different between heroin dependent subjects and healthy controls (both p=0.004). The frequency of the GG of rs1176746 and AA of rs1185027 genotype in heroin-dependent subjects were significantly higher than that of healthy controls, while the GA of rs1176746 and AT of rs1185027 genotype distributions were much lower. Another SNP, rs10789970, showed a nominally significant p-value in the genotype distribution between heroin dependent subjects and controls (p=0.022). These findings indicate the important role of HTR3B polymorphisms in heroin dependence among the Chinese Han population and provide valuable information for further genetic and neurobiological investigations of heroin dependence. PMID- 27773794 TI - 7,8-Dihydroxyflavone reverses the depressive symptoms in mouse chronic mild stress. AB - 7,8-Dihydroxyflavone (7,8-DHF) is a naturally-occurring flavone which possesses good bioavailability. Due to its ability to cross the blood-brain barrier, previous studies have demonstrated that 7,8-DHF was a potent tropomyosin-related kinase B (TrkB) agonist, and produced antidepressant-like effects in mouse forced swimming test and tail suspension test. However, it has not been evaluated in chronic mild stress (CMS), a classical depression model modulating the processes of major depression in human. In the present study, we not only evaluated the depressive-like behaviors, but also measured the key proteins of TrkB signaling in mice exposed to CMS. Our results firstly found that long term but not single injection of 7,8-DHF restored the depressive-like behaviors in sucrose preference test and novelty suppressed feeding test. In addition, 7,8-DHF not only increased TrkB phosphorylation and brain-derived neurotrophic factor (BDNF) levels, but also activated the expression of TrkB downstream synaptic proteins such as PSD95 and synaptophysin. Furthermore, the TrkB antagonist K252a blocked the antidepressant-like effects of 7,8-DHF. In summary, the present results demonstrated that chronic 7,8-DHF treatment exerted significant antidepressant like effects, which were likely attributed to regulating TrkB signaling and thus promoting synaptic protein expression. PMID- 27773796 TI - MicroRNA expression profiles of multiple system atrophy from formalin-fixed paraffin-embedded samples. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression. Recently, we have shown that informative miRNA data can be derived from archived formalin-fixed paraffin-embedded (FFPE) samples from postmortem cases of amyotrophic lateral sclerosis and normal controls. miRNA analysis has now been performed on FFPE samples from affected brain regions in patients with multiple system atrophy (MSA) and the same areas in neurologically normal controls. We evaluated 50 samples from patients with MSA (n=13) and controls (n=13). Twenty six samples were selected for miRNA analysis on the basis of the criteria reported previously: (i) a formalin fixation time of less than 4 weeks, (ii) a total RNA yield per sample of more than 500ng, and (iii) sufficient quality of the RNA electrophoresis pattern. These included 11 cases of MSA and 5 controls. Thus, the success rate for analysis of RNA from FFPE samples was 52% (26 of 50). For MSA, a total of 395 and 383 miRNAs were identified in the pons and cerebellum, respectively; 5 were up-regulated and 33 were down-regulated in the pons and 5 were up-regulated and 18 were down-regulated in the cerebellum. Several miRNAs down-regulated in the pons (miR-129-2-3p and miR-129-5p) and cerebellum (miR-129-2-3p, miR-129-5p and miR-132-3p) had already been identified in frozen cerebellum from MSA patients. These findings suggest that archived FFPE postmortem samples can be a valuable source for miRNA profiling in MSA. PMID- 27773782 TI - Obesity: Current and potential pharmacotherapeutics and targets. AB - Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P(r)), orlistat (Xenical(r)), lorcaserin (Belviq(r)) and liraglutide (Saxenda(r)). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia(r)) and naltrexone/bupropion (Contrave(r)). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti obesity drug development are discussed. PMID- 27773798 TI - Larix laricina bark, a traditional medicine used by the Cree of Eeyou Istchee: Antioxidant constituents and in vitro permeability across Caco-2 cell monolayers. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Larix laricina, a native tree of North America, is a highly respected medicinal plant used for generations by Indigenous Peoples across its range, including the Cree of northern Quebec who use the bark to treat symptoms of diabetes. This study investigates the antioxidant capacity and bioavailability of active constituents identified in L. laricina bark extracts. MATERIALS AND METHODS: (1) Oxygen radical absorbance capacity (ORAC) assay was employed to test antioxidant capacity of organic extracts (80% ethanol) from bark of L. laricina as well as fractions, isolated compounds, and media samples collected during permeability assays. (2) Caco-2 cell monolayer cultures were used to determine the permeability of identified antioxidants, which were quantified in basolateral media samples using liquid chromatography - tandem mass spectrometry (HPLC-ESI-MS/MS). RESULTS: Crude ethanolic extract possessed strong antioxidant potential in vitro (7.1+/-0.3 Trolox equivalents (TE) MUM/mg). Among the 16 L. laricina fractions obtained by chromatographic separation, fraction 10 (F10) showed the highest antioxidant capacity (21.8+/-1.7um TE/mg). Among other identified antioxidants, the stilbene rhaponticin (isolated from F10) was the most potent (24.6+/-1.1um TE/mg). Caco-2 transport studies revealed that none of the identified compounds were detectable in basolateral samples after 2-h treatment with crude extract. In monolayers treated with F10 (60% rhaponticin), small quantities of rhaponticin were increasingly detected over time in basolateral samples with an apparent permeability coefficient (Papp) of 1.86*10 8cm/s (0-60min). To model potential effects on blood redox status, we evaluated the antioxidant capacity of collected basolateral samples and observed enhanced activity over time after exposure to both extract and F10 (75MUg/mL) relative to control. CONCLUSIONS: By profiling the antioxidant constituents of L. laricina bark, we identified rhaponticin as the most potent oxygen radical scavenger and observed low permeability in Caco-2 cell monolayers but an increase in basolateral antioxidant capacity. PMID- 27773797 TI - Exploring the effect and mechanism of Hibiscus sabdariffa on urinary tract infection and experimental renal inflammation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hibiscus sabdariffa Linn., also known as roselle, is used in folk medicine as an anti-inflammatory agent. Urinary tract infection (UTI) is a common problem in long-term care facilities. However, effects of roselle on UTI and renal inflammation remained to be analyzed. AIM: Here we surveyed the effect of roselle drink on the prevention of UTI in long-term care facilities and analyzed the anti-inflammatory potential of roselle on lipopolysaccharide (LPS)-induced renal inflammation in mice. MATERIALS AND METHODS: Survey questionnaires and clinical observation were applied to evaluate the use of roselle and the incidence of UTI in long-term care facilities. Mice were administrated roselle orally for 7 consecutive days and then challenged with LPS. Anti-renal inflammatory effects of roselle were analyzed by microarray and immunohistochemical staining. RESULTS: Clinical observation showed that taking roselle drink in residents with urinary catheters reduced the incidence of UTI in long-term care facilities. Renal inflammation is a key event of UTI. Roselle suppressed LPS-induced nuclear factor-kappaB (NF-kappaB) activation in cells and LPS-induced interleukin-1beta production in mice a dose-dependent manner. Immunohistochemical staining showed that roselle inhibited LPS-induced NF-kappaB activation and inflammatory cell infiltration in kidney. Gene expression profiling further showed that roselle suppressed the expression of pro inflammatory cytokine genes and enzyme genes involved in the production of prostaglandin and nitric oxide. In addition, NF-kappaB was the main transcription factor involved in the regulation of roselle-regulated gene expression in kidney. CONCLUSIONS: This is the first report applying clinical observation-guided transcriptomic study to explore the application and mechanism of roselle on UTI. Our findings suggested that roselle drink ameliorated LPS-induced renal inflammation via downregulation of cytokine network, pro-inflammatory product production, and NF-kappaB pathway. Moreover, this report suggested the potential benefit of roselle drink on UTI. PMID- 27773799 TI - Adverse effects of Croton urucurana B. exposure during rat pregnancy. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Croton urucurana presents several beneficial pharmacological properties. In Brazil, women who intend to interrupt the pregnancy indiscriminately use extracts of this plant as an abortifacient agent. AIM OF STUDY: To evaluated the effect of aqueous extract of Croton urucurana latex on the maternal-fetal repercussions in rats. METHODS: Pregnant rats were randomly distributed into four experimental groups: Control=treated with water (vehicle); Treated 200=treated with a dose 200mg/kg; Treated 400=dose 400mg/kg and; and Treated 800=dose 800mg/kg. The rats were orally treated by gavage with Croton urucurana or vehicle (water) during whole pregnancy. At term of pregnancy, all rats were killed to obtain maternal blood and tissues samples and fetal weight and anomaly analyses. RESULTS: C. urucurana treatment (Treated 400 and Treated 800) showed elevated liver enzymatic activities, reduced fetal body weight and placental efficiency. The Treated 800 group presented increased maternal total protein and cholesterol levels, and heart relative weight. All treated groups presented reduced maternal body weight and food intake, and increased pre-implantation loss rate compared to those of Control group. In addition, the treatment contributed to increased skeletal and visceral anomalies with higher doses. CONCLUSION: Croton urucurana treatment caused maternal toxicity, which contributed for impairment embryo fetal development. These results showed that the indiscriminate use of plants during pregnancy should be avoided to prevent potential risk on maternal health as well as their offspring. PMID- 27773801 TI - A review of ethnoboatany, therapeutic value, phytochemistry and pharmacology of Crinum macowanii Baker: A highly traded bulbous plant in Southern Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Crinum macowanii is a deciduous bulbous plant which grows in east, central and southern Africa. Crinum macowanii has been used as herbal medicine by the indigenous people of east and southern Africa has for several centuries. The bulb, leaves and roots of C. macowanii are reported to possess diverse medicinal properties and used to treat or manage various human and animal diseases and ailments throughout its distributional range. Crinum macowanii is used traditionally as a remedy for boils, diarrhoea, fever, inflammation, respiratory system problems, skin rashes, tuberculosis, wounds and urinary tract problems. AIM OF THE REVIEW: The present review aims to summarize comprehensively the research that has been done on the ethnomedicinal uses, botany, phytochemistry and pharmacology of C. macowanii in different locations throughout its geographical range in east, central and southern African region so as to highlight research gaps and provide a foundation for further investigations on the plant species. MATERIALS AND METHODS: A review of the literature was undertaken and an in-depth analysis of previous research on ethnobotany, therapeutic value, phytochemistry and pharmacology of C. macowanii throughout its distributional range in east, central and southern Africa. Literature sources included papers published in international journals, reports from international, regional and national organizations, conference papers, books, theses, websites and other grey literature. Electronic search engines such as Google, Google scholar, publishing sites such as Elsevier, scienceDirect, BMC, PubMed and other scientific database sites such as ChemSpider, PubChem were used as well as searching the library collections of the National Herbarium and Botanic Gardens (SRGH), Harare, Zimbabwe and the University of Fort Hare, South Africa. RESULTS: A total of 32 ethnomedicinal uses of C. macowanii are documented in literature, which can be grouped into seven major ethnomedicinal general purpose usages, namely "fever", "wounds, sores and skin rashes", "boils and inflammation", "respiratory system problems", "blood cleansing", "urinary tract problem" and "veterinary uses". The chemical composition of C. macowanii is dominated by various isoquinoline alkaloids, which have been isolated from the bulbs, flowering stalks, leaves and roots. Major biological activities demonstrated by C. macowanii include antifungal, antiviral and antiplasmodial activities, cardiovascular effects as well as effects on the central nervous system. The population of C. macowanii is declining in the wild as the bulbs are over collected for sale in medicinal (muthi) markets in southern Africa. CONCLUSION: A literature search revealed that C. macowanii has a lot of potential as a possible source of pharmaceutical products for the treatment of a wide range of human and animal diseases and ailments. Some of the alkaloids isolated from C. macowanii have demonstrated various biological activities when investigated in in vitro assays. However, some of the ethnomedicinal uses of C. macowanii still require pharmacological investigations. Therefore, further studies are required to improve our knowledge about the mechanisms of action, efficacy, toxicity and clinical relevance of the plant species as well as its bioactive compounds. PMID- 27773800 TI - In vitro and In vivo antimycobacterial, hepatoprotective and immunomodulatory activity of Euclea natalensis and its mode of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Natal gwarri or Natal ebony (Euclea natalensis A.DC.) is a deciduous tree found widespread throughout southern Africa, especially in Kwazulu-Natal and the southern cost. It has been widely used by indigenous communities such as the Zulus, Tsongas and Vendas for symptoms related to tuberculosis (TB). The decoctions made from the plant parts are administered for chest diseases to treat complications such as chest pains, bronchitis, pleurisy and asthma. TB is prevalent in immune-compromised patients and it is evident that TB-drugs cause hepatotoxicity. The objective of the present study was therefore to evaluate the antimycobacterial activity of the ethanolic extract of E. natalensis against TB and its hepatoprotective and immunomodulatory activities. MATERIALS AND METHODS: The antimycobacterial, antioxidant, hepatoprotective, immunomodulatory activity and cytotoxicity of the ethanolic extract of the shoots of E. natalensis were determined in vitro. The mechanism of action of the antituberculosis activity was determined by investigating the inhibitory effect on mycothiol disulfide reductase enzyme. Furthermore, the acute, sub-acute toxicity (50-2000mg/kg) and antimycobacterial effect (300mg/kg) of E. natalensis shoot extract were investigated in Balb/c mice. Hepatoprotective activity of the extract (50-150mg/kg) was evaluated on isoniazid and rifampicin (50mg/kg; i.p.) induced hepatic damage in a rat model. RESULTS: The minimum inhibitory concentration of the extract was found to be 125ug/ml against Mycobacterium tuberculosis. The extracts 50% inhibitory concentration (IC50) against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical was found to be 22.55ug/ml. The plant showed a hepatoprotective effect (50% at 12.5ug/ml) and the ability to increase T-helper 1 cell cytokines; Interleukin 12, Interleukin 2 and Interferon alpha by up to 12 fold and the ability to decrease the T-helper 2 cell cytokine Interleukin 10 4 fold when compared to baseline cytokine production. No cellular toxicity was observed in primary peripheral blood mononuclear cells (PBMC's) and two secondary cell lines; U937 monocytes and Chang liver cells (a derivative of the HepG2 cell line). During mechanistic studies, the extract showed a 50% inhibition of mycothiol reductase activity at 38.62ug/ml. During the acute and sub-acute studies, E. natalensis exhibited no toxic effect and the 50% lethal dose (LD50) was established to be above 2000mg/kg. The extract was able to reduce the mycobacterial load (1.5-fold reduction) in infected mice. Isoniazid and rifampicin caused significant hepatic damage in rats, and the extract was able to reduce the toxicity by 15% and 40% at 50 and 150mg/kg respectively. CONCLUSION: The present study supports the traditional usage of the plant against tuberculosis symptoms. The study showed the ability of E. natalensis shoot extract to inhibit mycobacterial growth, stimulate an appropriate immune response and have a hepatic protective effect. Due to the extract's significant results for hepatoprotective, immunomodulatory effects and antimycobacterial activity, it may prove to be effective to serve as an adjuvant for TB-patients. PMID- 27773802 TI - Effects of the traditional Chinese herb Astragalus membranaceus in patients with poststroke fatigue: A double-blind, randomized, controlled preliminary study. AB - BACKGROUND AND PURPOSE: Astragalus membranaceus (AM) is the first-choice herb for fatigue treatment in traditional Chinese medicine and the main herb used for stroke treatment in China and Taiwan. The purpose of this study was to evaluate the effect of AM on poststroke fatigue (PSF). MATERIALS AND METHODS: This study was designed as a double-blind, randomized, controlled preliminary study. Sixty four patients with PSF were assigned to treatment group (TG; 31 patients), which received oral administration of AM (2.8g three times per day) for 28 days, and a control group (CG; 33 patients), which received a placebo. The primary outcome measures were the changes in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Brief Fatigue Index (BFI) scores RESULTS: A total of 61 patients (29 patients in the TG and 32 patients in the CG) completed the trial. The difference in BFI scores between Visit 2 and Visit 1 was -17.83+/-17.70 in the TG, which was greater than that in the CG (-8.03+/-9.95; p=0.01); additionally, the difference in BFI scores between Visit 3 and Visit 1 was -16.48+/-16.41 in the TG, which was also greater than that in the CG (-9.47+/-13.39; p=0.05). In the EORTC QLQ-C30, the difference in cognitive functioning scores between Visit 2 and Visit 1 was 14.37+/-13.89 in the TG, which was greater than that in the CG (3.65+/-19.74; p=0.02); additionally, the difference in these scores between Visit 3 and Visit 1 was 14.37+/-16.50 in the TG, which again was greater than that in the CG (6.25+/-19.74; p=0.04). The difference in social functioning scores between Visit 3 and Visit 1 was 9.77+/ 15.12 in the TG, which was greater than that in the CG (-1.56+/-20.46; p=0.01). The difference in global quality of life (QOL) scores between Visit 2 and Visit 1 was 14.08+/-18.78 in the TG, which was also greater than that in the CG (1.56+/ 18.14; p=0.003); moreover, the difference in these scores between Visit 3 and Visit 1 was 10.92+/-17.55 in the TG, and this was greater than that in the CG (1.82+/-15.8; p=0.05). CONCLUSION: AM can improve BFI scores; cognitive functioning, social functioning, and global QOL scores in the EORTC QLQ-C30. Our results suggest that physicians should pay close attention to the unmet medical needs of patients with PSF. AM is helpful for treating patients with PSF; however, additional studies with a larger sample and a longer period of investigation are required. PMID- 27773803 TI - The genus Boschniakia in China: An ethnopharmacological and phytochemical review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: As a group of important medicine plants, Boschniakia rossica (Cham. et Schltdl) Fedtsch. and B. himalaica Hook.f.et Thoms, which are the only two species in the genus Boschniakia (Orobanchaceae), have long been used in traditional Chinese medicine for their multiple therapeutic uses related to enhanced renal function, erectile dysfunction, defaecate and hepatoprotective. Additionally, the two species are also used as dietary supplements in wine, cosmetics, and other healthy food. AIM OF THE REVIEW: By providing comprehensive information and data of genus Boschniakia on botany, traditional medicinal uses, phytochemistry, pharmacological research and toxicology, this review aims to summary the group of natural compounds from Boschniakia discovered so far. The other aims are to reference research findings of their biological activities and functions in medicine, physiology, and cell biology to highlight the compound candidates which can be used for further drug discovery in several pharmaceutical areas including antioxidation, anticancer, anti-inflammation, anti-senile, and immunology. MATERIALS AND METHODS: All of the available information on B. rossica and B. himalaica was collected from the electronic resources (such as PubMed, SciFinder Scholar, CNKI, TPL (www.theplantlist.org), Google Scholar, Baidu Scholar, and Web of Science). RESULTS: After a comprehensive analysis of the literatures from available online sources, the results show that both species of genus Boschniakia are valuable and popular herbal medicines with potentials to cure various ailments. The phytochemical studies revealed that the chemical compositions of this genus were mainly iridoid glycosides and phenylpropanoid glycosides. To date, 112 compounds have been isolated from the genus, while their crude extracts and purified compounds have been found to possess a wide range of biological activities including anti-senile, antitumor and anticancer, anti-inflammatory, protecting liver, boost memory, anti-oxidation, anti-lipid peroxidative, and antiviral activities. CONCLUSIONS: The existing traditional uses of the genus Boschniakia have been evaluated, and the properties of the genus are summarized based on botany, phytochemistry, pharmacological research, and toxicology. This review aims to introduce the utilization and application of the genus Boschniakia to modern drug discovery, traditional medicinal plant utilization, herbal species conservation, and the development of medicinal and health-maintaining products. PMID- 27773804 TI - Aliskiren attenuates the effects of interleukin-6 on endothelial nitric oxide synthase and caveolin-1 in human aortic endothelial cells. AB - Renin inhibitors enhance endothelial nitric oxide synthase (eNOS) bioavailability and have protective effects on endothelial function and atherosclerotic changes. This study was designed to investigate whether aliskiren attenuates the effects of interleukin-6 (IL-6) on eNOS and the eNOS-caveolin-1 interaction in human aortic endothelial cells (HAECs). In this study, we examined the effects of pretreatment with aliskiren on the changes of IL-6-induced expression and activation of eNOS and caveolin-1 in cultured HAECs. IL-6 inhibited and aliskiren increased the phosphorylation of eNOS at Ser1177; however, eNOS protein and mRNA expression were not changed. Pretreatment with aliskiren attenuated the inhibitory effects of IL-6 on eNOS phosphorylation and nitric oxide production. IL-6 increased the phosphorylation of caveolin-1 at Tyr14 without affecting the caveolin-1 protein and mRNA expression. Pretreatment with aliskiren attenuated the effects of IL-6 on caveolin-1 phosphorylation. The binding of eNOS and caveolin-1, as determined by a co-immunoprecipitation assay, was increased by IL 6 treatment and decreased by aliskiren pretreatment. Furthermore, treatment with short interfering RNA of the extracellular signal-regulated kinase gene reversed the effects of IL-6 and aliskiren on eNOS and caveolin-1. In conclusion, aliskiren attenuates the inhibitory effects of IL-6 on eNOS phosphorylation and nitric oxide production and IL-6 induced caveolin-1 phosphorylation. In addition, aliskiren reverses the effects of IL-6 on the eNOS-caveolin-1 interaction. PMID- 27773807 TI - Outcomes of Pregnancies for Women Undergoing Endoscopy While They Were Pregnant: A Nationwide Cohort Study. AB - BACKGROUND & AIMS: Endoscopy is an integral part of the investigation and management of gastrointestinal disease. We aimed to examine outcomes of pregnancies for women who underwent endoscopy during their pregnancy. METHODS: We performed a nationwide population-based cohort study, linking data from the Swedish Medical Birth Registry (for births from 1992 through 2011) with those from the Swedish Patient Registry. We identified 3052 pregnancies exposed to endoscopy (2025 upper endoscopies, 1109 lower endoscopies, and 58 endoscopic retrograde cholangiopancreatographies). Using Poisson regression, we calculated adjusted relative risks (ARRs) for adverse outcomes of pregnancy according to endoscopy status using 1,589,173 unexposed pregnancies as reference. To consider the effects of disease activity, we examined pregnancy outcomes (preterm birth, stillbirth, small for gestational age, or congenital malformations) in women who underwent endoscopy just before or after pregnancy. Secondary outcome measures included induction of labor, low birth weight (<2500 g), cesarean section, Apgar score <7 at 5 minutes, and neonatal death within 28 days. To consider intrafamilial factors, we compared pregnancies within the same mother. RESULTS: Exposure to any endoscopy during pregnancy was associated with an increased risk of preterm birth (ARR, 1.54; 95% confidence interval [CI], 1.36-1.75) or small for gestational age (ARR, 1.30; 95% CI, 1.07-1.57) but not of congenital malformation (ARR, 1.00; 95% CI, 0.83-1.20) or stillbirth (ARR, 1.45; 95% CI, 0.87-2.40). None of the 15 stillbirths to women with endoscopy occurred <2 weeks after endoscopy. ARRs were independent of trimester. Compared to women with endoscopy <1 year before or after pregnancy, endoscopy during pregnancy was associated with preterm birth (ARR, 1.16) but not with small for gestational age (ARR, 1.19), stillbirth (ARR, 1.11), or congenital malformation (ARR, 0.90). Restricting the study population to women having an endoscopy during pregnancy or before/after, and only analyzing data from women without a diagnosis of inflammatory bowel disease, celiac disease, or liver disease, endoscopy during pregnancy was not linked to preterm birth (ARR, 1.03; 95% CI, 0.84-1.27). Comparing births within the same mother, for which only 1 birth had been exposed to endoscopy, we found no association between endoscopy and gestational age or birth weight. CONCLUSIONS: In a nationwide population-based cohort study, we found endoscopy during pregnancy to be associated with increased risk of preterm birth or small for gestational age, but not of congenital malformation or stillbirth. However, these risks are small and likely due to intrafamilial factors or disease activity. PMID- 27773805 TI - Pathophysiology, Evaluation, and Management of Chronic Watery Diarrhea. AB - Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (>4 weeks in duration) are more elusive. We review the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extraepithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in the assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented. PMID- 27773808 TI - Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir. AB - BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection. PMID- 27773806 TI - Using Big Data to Discover Diagnostics and Therapeutics for Gastrointestinal and Liver Diseases. AB - Technologies such as genome sequencing, gene expression profiling, proteomic and metabolomic analyses, electronic medical records, and patient-reported health information have produced large amounts of data from various populations, cell types, and disorders (big data). However, these data must be integrated and analyzed if they are to produce models or concepts about physiological function or mechanisms of pathogenesis. Many of these data are available to the public, allowing researchers anywhere to search for markers of specific biological processes or therapeutic targets for specific diseases or patient types. We review recent advances in the fields of computational and systems biology and highlight opportunities for researchers to use big data sets in the fields of gastroenterology and hepatology to complement traditional means of diagnostic and therapeutic discovery. PMID- 27773811 TI - Prevalence and Impact of Chronic Endometritis in Patients With Intrauterine Adhesions: A Prospective Cohort Study. AB - STUDY OBJECTIVE: To evaluate the prevalence and impact of chronic endometritis (CE) in patients with intrauterine adhesions (IUAs). DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: University-affiliated hospital. PATIENTS: Eighty-two women with moderate to severe IUAs. INTERVENTIONS: Transcervical resection of adhesions (TCRA) and endometrial biopsy were performed in all patients. According to results of the endometrial biopsy, participants were classified into 2 groups: 29 patients with CE (CE group) and 53 women without CE (NCE group). Second-look hysteroscopy assessed the impact of TCRA using the American Fertility Society classification system. MEASUREMENTS AND MAIN RESULTS: Prevalence of CE, reformation of adhesions, and reduction of adhesion score were studied. Thirty-one women (37.8%) presented with visual signs of CE at hysteroscopy, confirmed by histology in 29 of 82 patients (35.4%). In hysteroscopic diagnosis of CE, sensitivity and specificity were 79.3% (23/29) and 84.9% (45/53), respectively. At second-look hysteroscopy, the recurrence of adhesions in the CE group was significantly higher than in the NCE group (44.8% vs 20.8%, respectively; p = .022). The median reduction of adhesion score was significantly greater in the NCE group (median, 8; range, 0-12) than in the CE group (median, 5; range, 0-10). CONCLUSION: CE in women with IUAs may be a contributing factor in higher adhesion recurrence, indicating chronic inflammation may play a role in IUA recurrence. (Clinical Trial Registration No.: NCT02744807.). PMID- 27773812 TI - 3beta-Hydroxy-urs-12-en-28-oic acid prolongs lifespan in C. elegans by modulating JNK-1. AB - Remarkably the c-Jun-NH2-terminal kinase (JNK) pathway is all evolutionarily conserved across species. In view of the hypothesis that increased stress resistance subdue aging, we investigated the role of ursolic acid (3beta-Hydroxy urs-12-en-28-oic acid; UA) in the pioneering aging model Caenorhabditis elegans with an increase in mean and maximum lifespan by up to 30%. Our genetic study unravelled the underlying pathway where JNK-1 is acting independently of insulin IGF-1 signalling (IIS) pathway to modulate longevity. In support of in vivo results in silico docking study of UA with C. elegans JNK-1 ATP-binding site suggested promising binding affinity exhibiting binding energy of -8.11 kcalmol 1. UA induced JNK-1 activation in wild-type animals underlie the importance of pharmacological interventions in the delineation of molecular targets for aging and associated pathologies. PMID- 27773810 TI - Incidence and Risk Factors for Pelvic Pain After Mesh Implant Surgery for the Treatment of Pelvic Floor Disorders. AB - STUDY OBJECTIVE: Our aim was to assess incidence and risk factors for pelvic pain after pelvic mesh implantation. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Single university hospital. PATIENTS: Women who have undergone surgery with pelvic mesh implant for treatment of pelvic floor disorders including prolapse and incontinence. INTERVENTIONS: Telephone interviews to assess pain, sexual function, and general health. MEASUREMENTS AND MAIN RESULTS: Pain was measured by the McGill Short-Form Pain Questionnaire for somatic pain, Neuropathic Pain Symptom Inventory for neuropathic pain, Pennebaker Inventory of Limbic Languidness for somatization, and Female Sexual Function Index (FSFI) for sexual health and dyspareunia. General health was assessed with the 12-item Short-Form Health Survey. Among 160 enrolled women, mean time since surgery was 20.8 +/- 10.5 months, mean age was 62.1 +/- 11.2 years, 93.8% were white, 86.3% were postmenopausal, and 3.1% were tobacco users. Types of mesh included midurethral sling for stress incontinence (78.8%), abdominal/robotic sacrocolpopexy (35.7%), transvaginal for prolapse (6.3%), and perirectal for fecal incontinence (1.9%), with 23.8% concomitant mesh implants for both prolapse and incontinence. Our main outcome, self-reported pelvic pain at least 1 year after surgery, was 15.6%. Women reporting pain were younger, with fibromyalgia, worse physical health, higher somatization, and lower surgery satisfaction (all p < .05). Current pelvic pain correlated with early postoperative pelvic pain (p < .001), fibromyalgia (p = .002), worse physical health (p = .003), and somatization (p = .003). Sexual function was suboptimal (mean FSFI, 16.2 +/- 12.1). Only 54.0% were sexually active, with 19.0% of those reporting dyspareunia. CONCLUSION: One in 6 women reported de novo pelvic pain after pelvic mesh implant surgery, with decreased sexual function. Risk factors included younger age, fibromyalgia, early postoperative pain, poorer physical health, and somatization. Understanding risk factors for pelvic pain after mesh implantation may improve patient selection. PMID- 27773813 TI - Cross-sensitization between xeno- and allo-antigens on subsequent allogeneic and xenogeneic pancreatic islet transplantation in a murine model. AB - The number of patients in need of organ transplantation is continuously on the rise. However, because of organ donor shortage, xenotransplantation has been highlighted as an alternative. Among the various porcine organs and tissues, porcine islets are considered to be the best-matching implantable candidates for clinical application based on recent progress in nonhuman primate pre-clinical studies. Nevertheless, before initiation of clinical trials, it should be confirmed whether the requisite xeno-antigen sensitization would have a deleterious effect on subsequent allo-transplantation or vice versa. Therefore, in the present study, the survival rate of islets grafted in naive recipients was compared with that in cross-sensitized recipients. Enzyme-linked immunosorbent spot, fluorescence-activated cell sorting, and immunohistochemistry were conducted to assess the cellular and humoral immune responses. The survival days of Balb/c mouse islets transplanted into B6 mice that had been previously sensitized with porcine cells (i.e., xeno-sensitized) showed no significant difference from that of naive B6 mice. Moreover, the survival days of porcine islets transplanted into allo-antigen (Balb/c)-sensitized B6 recipients was not significantly different from that in naive B6 mice. Furthermore, our data provide the first demonstration that the cellular xenogeneic immune response (against porcine antigen) measured by an enzyme-linked immunosorbent spot assay is not cross-reactive to the allogeneic immune responses in a murine islet transplantation model. These results suggest that clinical application of islet xenotransplantation is not likely to have a deleterious effect on subsequent allogeneic islet transplantation. PMID- 27773809 TI - Transforming Growth Factor beta Superfamily Signaling in Development of Colorectal Cancer. AB - Transforming growth factor (TGF)-beta cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-beta family member signaling. We review how TGF-beta family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies. PMID- 27773814 TI - Role of Sirtuin3 in high glucose-induced apoptosis in renal tubular epithelial cells. AB - The apoptosis of renal tubular epithelial cells contributes to the pathogenesis of diabetic nephropathy. High glucose-induced mitochondrial oxidative stress is considered to be an important mediator for renal tubular cell apoptosis. Sirtuin3(Sirt3), a kind of mitochondria-localized nicotinamide adenine dinucleotide(NAD+)-dependent protein deacetylase, has been reported to regulate the generation of ROS in mitochondria through regulating acetylation level and activity of several key mitochondrial enzymes. In this study, we investigated the role of Sirt3 on high glucose-induced apoptosis in HK-2 cells. High glucose decreased the protein and mRNA expression of Sirt3 in a time-dependent manner, along with increased cell apoptosis in HK-2 cells. Furthermore, high glucose induced oxidative stress and apoptosis were reversed by Sirt3 overexpression or antioxidant treatment. Meanwhile, we also found that overexpression of Sirt3 or antioxidant could regulate the activity of Akt/FoxO signaling pathway associated with cell apoptosis in diabetic nephropathy. In conclusion, our data suggest that Sirt3 overexpression antagonize high glucose-induced apoptosis by controlling ROS accumulation and ROS-sensitive Akt/FoxO signaling pathway in HK-2 cells. PMID- 27773815 TI - cIAPs promote the proteasomal degradation of mutant SOD1 linked to familial amyotrophic lateral sclerosis. AB - Although the ubiquitin-proteasome system is believed to play an important role in the pathogenesis of familial amyotrophic lateral sclerosis (FALS), caused by mutations in Cu/Zn-superoxide dismutase 1 (SOD1), the mechanism of how mutant SOD1 protein is regulated in cells is still poorly understood. Here we have demonstrated that cellular inhibitor of apoptosis proteins (cIAPs) are specifically associated with FALS-linked mutant SOD1 (mSOD1) and that this interaction promotes the ubiquitin-dependent proteasomal degradation of mutant SOD1. By utilizing cumate inducible SOD1 cells, we also showed that knock-down or pharmacologic depletion of cIAPs leads to H2O2 induced cytotoxicity in mSOD1 expressing cells. Altogether, our results reveal a novel role of cIAPs in FALS associated mutant SOD1 regulation. PMID- 27773816 TI - High expression of CREPT promotes tumor growth and is correlated with poor prognosis in colorectal cancer. AB - CREPT (cell cycle-related and expression elevated protein in tumor) is highly expressed in many kinds of cancer, and has been shown to be prognostic in certain cancers. However, the clinical significance of CREPT in colorectal cancer (CRC) has not been sufficiently investigated. In this study, we examined the CREPT expression in 225 clinical CRC tissues and paired adjacent normal tissues, and analyzed the correlation between CREPT expression and other clinicopathological features. We also evaluated the biological function of CREPT both in vitro and in vivo using knockdown or overexpressing CRC cells. Our results showed that CREPT expressed in 175 of 225 (77.8%) CRC patients and the CREPT expression was significantly associated with tumor differentiation (P = 0.000), Dukes' stages (P = 0.013) and metastasis (P = 0.038). Patients with high CREPT expression tended to have shorter survival time. Multivariate analysis showed that positive CREPT expression can be used as an independent predictor for CRC prognosis. CREPT knockdown cells showed inhibited cell proliferation and arrested cell cycle, while CREPT overexpressing cells showed increased proliferation and promoted cell cycle. In addition, CREPT overexpression significantly promoted tumor growth in vivo. Mechanism study showed that CREPT may regulate cell proliferation and cell cycle through the regulation on cyclin D3, CDK4 and CDK6. PMID- 27773817 TI - Lgr5 regulates the regeneration of lesioned nasal respiratory epithelium. AB - Nasal respiratory epithelium is a ciliated pseudostratified columnar epithelium. The cellular components of nasal respiratory epithelium include ciliated cells, goblet cells, and basal cells. Until now, our knowledge in the development of nasal respiratory epithelium is still limited and the cellular mechanism of regeneration is still elusive. In this study, we found that adult stem cell marker leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is expressed in the mice nasal respiratory epithelium. Both immunostaining and lineage tracing analysis indicated Lgr5 positive cells in the nasal respiratory epithelium are proliferative stem/progenitor cells. Using the Rosa-Tdtomato and Rosa26-DTR mice, we elucidated that Lgr5+ cells participate in the regeneration of lesioned nasal respiratory epithelium, and this group of cells is necessary in the process of epithelium recovery. Using the in vitro culture system, we observed the formation of spheres from Lgr5+ cells and these spheres have the capacity to generate other types of cells. Above all, this study reported a group of previously unidentified progenitor/stem cells in nasal respiratory epithelium, unveiling the potential cellular mechanism in nasal respiratory epithelium regeneration. PMID- 27773818 TI - Muscarinic acetylcholine receptors mediate eIF4B phosphorylation in SNU-407 colon cancer cells. AB - We have previously shown that muscarinic acetylcholine receptors (mAChRs) promote global protein biosynthesis in SNU-407 colon cancer cells. To gain insight into the molecular mechanisms underlying this event, we examined whether mAChRs regulate the phosphorylation of eIF4B (eukaryotic initiation factor 4B), an essential component of the translation machinery. When SNU-407 cells were treated with the cholinergic agonist carbachol, eIF4B was phosphorylated in a dose- and time-dependent manner. This carbachol effect was almost completely blocked by the muscarinic antagonist atropine, demonstrating that mAChRs specifically mediate the phosphorylation of eIF4B. Carbachol-stimulated eIF4B phosphorylation was significantly reduced by the MEK1/2 inhibitor U0126, indicating that the MEK1/2 ERK1/2 pathway plays an important role in mAChR-mediated eIF4B phosphorylation. However, treating the cells with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 or the mTORC1 (mammalian target of rapamycin complex 1) inhibitor rapamycin had little effect on carbachol-stimulated eIF4B phosphorylation, suggesting that PI3K and mTORC1 are not the key participants in this process. We also observed that the inhibition of protein kinase C (PKC) by GF109203X greatly diminished carbachol-stimulated eIF4B phosphorylation. Together, our data show that mAChRs modulate eIF4B phosphorylation via the ERK1/2 and PKC signaling pathways in SNU-407 colon cancer cells. PMID- 27773819 TI - FANCD2 protects against bone marrow injury from ferroptosis. AB - Bone marrow injury remains a serious concern in traditional cancer treatment. Ferroptosis is an iron- and oxidative-dependent form of regulated cell death that has become part of an emerging strategy for chemotherapy. However, the key regulator of ferroptosis in bone marrow injury remains unknown. Here, we show that Fanconi anemia complementation group D2 (FANCD2), a nuclear protein involved in DNA damage repair, protects against ferroptosis-mediated injury in bone marrow stromal cells (BMSCs). The classical ferroptosis inducer erastin remarkably increased the levels of monoubiquitinated FANCD2, which in turn limited DNA damage in BMSCs. FANCD2-deficient BMSCs were more sensitive to erastin-induced ferroptosis (but not autophagy) than FANCD2 wild-type cells. Knockout of FANCD2 increased ferroptosis-associated biochemical events (e.g., ferrous iron accumulation, glutathione depletion, and malondialdehyde production). Mechanically, FANCD2 regulated genes and/or expression of proteins involved in iron metabolism (e.g., FTH1, TF, TFRC, HAMP, HSPB1, SLC40A1, and STEAP3) and lipid peroxidation (e.g., GPX4). Collectively, these findings indicate that FANCD2 plays a novel role in the negative regulation of ferroptosis. FANCD2 could represent an amenable target for the development of novel anticancer therapies aiming to reduce the side effects of ferroptosis inducers. PMID- 27773821 TI - Tyrosine phosphorylation of RalGDS by c-Met receptor blocks its interaction with Ras. AB - RalGDS is a guanine nucleotide exchange factor that promotes the active GTP-bound form of Ral GTPases, RalA and RalB. GTP-bound Ras has the capacity to activate Ral GTPases at least in part by binding to the C-terminal Ras-binding domain (RBD) of RalGDS and directing the protein to Ral GTPases in the plasma membrane. In many cases, activation of Ral proteins complements other Ras effector pathways to carry out a cell function, but in others it opposes them. Moreover, in many cases activation of Ral proteins contributes to the oncogenic potential of Ras. However, in some cell types Ral proteins suppresses tumor formation, suggesting oncogenic stimuli that function through Ras may need to suppress Ral activation in order to transform cells. In this paper, we demonstrate a potential biochemical mechanism for such phenomena by showing that c-Met receptors promote the tyrosine phosphorylation of RalGDS at Y752 in its RBD, which blocks the binding of Ras to RalGDS. PMID- 27773820 TI - MiR-107 suppresses proliferation of hepatoma cells through targeting HMGA2 mRNA 3'UTR. AB - BACKGROUND AND AIM: Aberrant expression of miR-107 is involved in the development of several human cancers. However, the role of miR-107 in hepatocellular carcinoma (HCC) is not well documented. In the present study, we aim to explore the function of miR-107 in hepatocarcinogenesis. METHODS: Bioinformatics analysis was applied to predict the target genes of miR-107. Luciferase reporter gene assay was performed to verify the miR-107 binding sites in 3'-untranslated region (3'UTR) of high mobility group A2 (HMGA2) mRNA. The expression levels of mRNA and protein were examined using qRT-PCR and Western blot analysis. Functionally, MTT and EdU assays were carried out for proliferation analysis. Clinically, thirty HCC samples and their corresponding peritumor liver tissues were collected. RESULTS: Bioinformatics analysis revealed that miR-107 might target HMGA2 mRNA 3'UTR. Luciferase reporter gene assays verified that the miR-107 binding site was located in the 3'UTR of HMGA2 mRNA. Furthermore, miR-107 could down-regulate HMGA2 at the levels of mRNA and protein in a dose-dependent manner. Interestingly, miR-107 inhibited the proliferation of hepatoma cells, while anti miR-107 could promote the cell proliferation, which was blocked by the interference of HMGA2. Clinically, miR-107 was lower in HCC samples relative to peritumor liver tissues. The expression levels of miR-107 were negatively correlated with those of HMGA2 mRNA in HCC samples. CONCLUSION: MiR-107 suppresses the proliferation of hepatoma cells by targeting HMGA2 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. PMID- 27773822 TI - Histamine H3 receptor antagonist OUP-186 attenuates the proliferation of cultured human breast cancer cell lines. AB - Histamine is involved in various physiological functions, including its neurotransmitter actions in the central nervous system and its action as a causative agent of inflammation, allergic reactions, and gastric acid secretions. Histamine expression and biosynthesis have been detected in breast cancer cells. It was recently suggested that the histamine H3 receptor (H3R) plays a role in the proliferation of breast cancer cells. We recently developed the non-imidazole H3R antagonist OUP-186 which exhibited a potent and selective human H3R antagonistic activity as well as no activity against the human histamine H4 receptor (H4R). In this study, we compared the effects of OUP-186 on the proliferation of estrogen receptor negative (ER-) breast cancer cells (MDA-MB 231) and ER+ breast cancer cells (MCF7) to the effects of clobenpropit (potent imidazole-containing H3R antagonist). OUP-186 and clobenpropit suppressed the proliferation of breast cancer cells. The IC50 values at 48 h for OUP-186 and clobenpropit were approximately 10 MUM and 50 MUM, respectively. Furthermore, OUP 186 potently induced cell death by activating caspase-3/7, whereas cell death was only slightly induced by clobenpropit. In addition, OUP-186 treatment blocked the proliferation increase triggered by 100 MUM (R)-(-)-alpha-methylhistamine (H3R agonist). The use of 4-methylhistamine (H4R agonist) and JNJ10191584 (selective H4R antagonist) did not affect breast cancer proliferation. These results indicate that OUP-186 potently suppresses proliferation and induces caspase dependent apoptotic death in both ER+ and ER-breast cancer cells. PMID- 27773823 TI - Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells. AB - Short-chain fatty acids (SCFAs) are gut microbial fermentation products derived from dietary fiber sources. Although depletion of gut microflora has been linked to the development of liver disease, the direct effects of SCFAs on intracellular hepatic processes are not well understood. In this study, we demonstrated that the SCFAs, propionate and butyrate, regulated autophagic flux in hepatic cells in a cell-autonomous manner. Induction of autophagy by SCFAs required PPARgamma stimulation of Uncoupling Protein 2 (UCP2) expression that was associated with reduced intracellular ATP levels and activation of PRKAA1/AMPK (protein kinase, AMP-activated, alpha 1 catalytic subunit). In addition, elimination of gut flora by chronic antibiotic treatment diminished basal hepatic autophagy in mice suggesting that gut microbiota can regulate hepatic autophagy. These findings provide novel insights into the interplay between diet, gut microbiota, short chain fatty acids, and hepatic autophagic signaling. PMID- 27773825 TI - NADPH oxidases and vascular remodeling in cardiovascular diseases. AB - Reactive oxygen species (ROS) are key signaling molecules that regulate vascular function and structure in physiological conditions. A misbalance between the production and detoxification of ROS increases oxidative stress that is involved in the vascular remodeling associated with cardiovascular diseases such as hypertension by affecting inflammation, hypertrophy, migration, growth/apoptosis and extracellular matrix protein turnover. The major and more specific source of ROS in the cardiovascular system is the NADPH oxidase (NOX) family of enzymes composed of seven members (NOX1-5, DUOX 1/2). Vascular cells express several NOXs being NOX-1 and NOX-4 the most abundant NOXs present in vascular smooth muscle cells. This review focuses on specific aspects of NOX-1 and NOX-4 isoforms including information on regulation, function and their role in vascular remodeling. In order to obtain a more integrated view about the role of the different NOX isoforms in different types of vascular remodeling, we discuss the available literature not only on hypertension but also in atherosclerosis, restenosis and aortic dilation. PMID- 27773824 TI - Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems. AB - Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals-prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval; neuropathic pain did not return. The opioid receptor antagonist naloxone blocked the antinociceptive effects of both prophylactic and therapeutic desipramine treatments throughout the entire timecourse of desipramine-induced antinociception. By contrast, cannabinoid CB1 and CB2 receptor antagonists partially attenuated the antinociceptive actions of desipramine in a manner that was restricted to the development phase of paclitaxel-induced neuropathic pain only. Paclitaxel decreased cell viability in TMD231 tumor cells in an MTT assay in vitro. Notably, desipramine (1nM-1MUM) alone did not alter tumor cell viability and did not prevent the cytotoxic effects of paclitaxel under identical conditions. The highest concentration of desipramine (10MUM) reduced tumor cell viability alone and enhanced the cytotoxic effects of paclitaxel. Our study identifies a previously unrecognized preemptive analgesic strategy that prevents development of paclitaxel-induced neuropathic pain, and also dissects receptor mechanisms underlying desipramine-induced antinociceptive effects. This information may be applied to improve current therapeutic strategies with the goal of preventing and managing neuropathic pain induced by chemotherapeutic treatment. PMID- 27773826 TI - Risk of encountering ticks and tick-borne pathogens in a rapidly growing metropolitan area in the U.S. Great Plains. AB - The prevalence of tick-borne diseases has increased dramatically in many urban areas of the U.S., yet little is known about the ecology of ticks and tick-borne pathogens in relation to characteristics of North American urban and suburban landscapes. This study aimed to begin identification of the risk of encountering ticks and tick-borne pathogens within a rapidly expanding metropolitan area in the U.S. Great Plains region. Ten sites across Oklahoma City, Oklahoma were selected for tick sampling based on presence of tick habitat and level of urbanization intensity. Sampling was conducted using CO2 traps and flagging in June, July and October 2015. A total of 552 ticks were collected from eight of the ten sampled greenspaces. The majority of ticks collected in summer were Amblyomma americanum (N=534 (97.8%)), followed by Dermacentor variabilis (N=10 (1.8%)) and Amblyomma maculatum (N=2 (0.3%)). Ixodes scapularis adult females (N=4) and nymphal A. americanum (N=2) were also collected in October 2015. Tick species diversity was highest in sites with >15% of the surrounding landscape composed of undeveloped land. Rickettsia sp. (including R. amblyommii and 'Candidatus R. andeanae'), Ehrlichia chaffeensis and/or E. ewingii were detected in tick pools from all eight sites where ticks were found. Our data suggest that the risk of encountering ticks and tick-borne pathogens exists throughout the Oklahoma City metropolitan area and that tick populations are likely influenced by urbanization intensity. Continued research is needed to clarify the full range of abiotic and biotic features of urban landscapes that influence the risk of encountering ticks and transmitting tick-borne diseases. PMID- 27773827 TI - Variance decomposition for single-subject task-based fMRI activity estimates across many sessions. AB - Here we report an exploratory within-subject variance decomposition analysis conducted on a task-based fMRI dataset with an unusually large number of repeated measures (i.e., 500 trials in each of three different subjects) distributed across 100 functional scans and 9 to 10 different sessions. Within-subject variance was segregated into four primary components: variance across-sessions, variance across-runs within a session, variance across-blocks within a run, and residual measurement/modeling error. Our results reveal inhomogeneous and distinct spatial distributions of these variance components across significantly active voxels in grey matter. Measurement error is dominant across the whole brain. Detailed evaluation of the remaining three components shows that across session variance is the second largest contributor to total variance in occipital cortex, while across-runs variance is the second dominant source for the rest of the brain. Network-specific analysis revealed that across-block variance contributes more to total variance in higher-order cognitive networks than in somatosensory cortex. Moreover, in some higher-order cognitive networks across block variance can exceed across-session variance. These results help us better understand the temporal (i.e., across blocks, runs and sessions) and spatial distributions (i.e., across different networks) of within-subject natural variability in estimates of task responses in fMRI. They also suggest that different brain regions will show different natural levels of test-retest reliability even in the absence of residual artifacts and sufficiently high contrast-to-noise measurements. Further confirmation with a larger sample of subjects and other tasks is necessary to ensure generality of these results. PMID- 27773828 TI - Pooled individual patient data from five countries were used to derive a clinical prediction rule for coronary artery disease in primary care. AB - OBJECTIVE: To construct a clinical prediction rule for coronary artery disease (CAD) presenting with chest pain in primary care. STUDY DESIGN AND SETTING: Meta Analysis using 3,099 patients from five studies. To identify candidate predictors, we used random forest trees, multiple imputation of missing values, and logistic regression within individual studies. To generate a prediction rule on the pooled data, we applied a regression model that took account of the differing standard data sets collected by the five studies. RESULTS: The most parsimonious rule included six equally weighted predictors: age >=55 (males) or >=65 (females) (+1); attending physician suspected a serious diagnosis (+1); history of CAD (+1); pain brought on by exertion (+1); pain feels like "pressure" (+1); pain reproducible by palpation (-1). CAD was considered absent if the prediction score is <2. The area under the ROC curve was 0.84. We applied this rule to a study setting with a CAD prevalence of 13.2% using a prediction score cutoff of <2 (i.e., -1, 0, or +1). When the score was <2, the probability of CAD was 2.1% (95% CI: 1.1-3.9%); when the score was >= 2, it was 43.0% (95% CI: 35.8 50.4%). CONCLUSIONS: Clinical prediction rules are a key strategy for individualizing care. Large data sets based on electronic health records from diverse sites create opportunities for improving their internal and external validity. Our patient-level meta-analysis from five primary care sites should improve external validity. Our strategy for addressing site-to-site systematic variation in missing data should improve internal validity. Using principles derived from decision theory, we also discuss the problem of setting the cutoff prediction score for taking action. PMID- 27773829 TI - Redescription and phylogenetic position of Myxobolus aeglefini and Myxobolus platessae n. comb. (Myxosporea), parasites in the cartilage of some North Atlantic marine fishes, with notes on the phylogeny and classification of the Platysporina. AB - Myxobolus 'aeglefini' Auerbach, 1906 was originally described from cranial cartilage of North sea haddock (Melanogrammus aeglefinus), but has subsequently been recorded from cartilaginous tissues of a range of other gadoid hosts, from pleuronectids and from lumpsucker (Cyclopterus lumpus) in the North Atlantic and from a zoarcid fish in the Japan Sea (Pacific). We obtained partial small-subunit rDNA sequences of Myxobolus 'aeglefini' from gadoids and pleuronectids from Norway and Iceland. The sequences from gadoids and pleuronectids represented two different genotypes, showing 98.2% identity. Morphometric studies on the spores from selected gadids and pleuronectids revealed slight but statistically significant differences in spore dimensions associated with the genotypes, the spores from pleuronectids were thicker and with larger polar capsules. We identify the morpho- and genotype from gadoids with Myxobolus 'aeglefini' sensu Auerbach, and the one from pleuronectids with Sphaerospora platessae Woodcock, 1904 as Myxobolus platessae n. comb. The latter species was originally described from Irish Sea plaice (Pleuronectes platessa). Myxobolus albi Picon et al., 2009 described from the common goby Pomatoschistus microps in Scotland is a synonym of M. 'aeglefini'. The Pacific Myxobolus 'aeglefini' represents a separate species, showing only 97.4-97.6% identity to the Atlantic species. In phylogenetic analyses based on SSU rDNA sequences, these and some related marine chondrotropic Myxobolus spp. form a distinct well supported group. This clusters with freshwater and marine myxobolids and Triangula and Cardimyxobolus species, in a basal clade in the phylogeny of the Platysporina. Members of family Myxobilatidae, Ortholinea spp. (currently Ortholineidae) and sequences of some other urinary system infecting myxosporeans form a well supported clade among members of the suborder Platysporina. Based on phylogenetic analyses, we propose the following changes to the classification of Myxosporea: i) Ortholineidae is dismantled and Ortholinea spp. transferred to Myxobilatidae, and ii) Myxobilatidae is transferred from suborder Variisporina to Platysporina. PMID- 27773830 TI - A computational assessment of the hemodynamic effects of crossed and non-crossed bifurcated stent-graft devices for the treatment of abdominal aortic aneurysms. AB - There are several issues attributed with abdominal aortic aneurysm endovascular repair. The positioning of bifurcated stent-grafts (SG) may affect SG hemodynamics. The hemodynamics and geometrical parameters of crossing or non crossing graft limbs have not being totally accessed. Eight patient-specific SG devices and four pre-operative cases were computationally simulated, assessing the hemodynamic and geometrical effects for crossed (n= 4) and non-crossed (n= 4) configurations. SGs eliminated the occurrence of significant recirculations within the sac prior treatment. Dean's number predicted secondary flow locations with the greatest recirculations occurring at the outlets especially during the deceleration phase. Peak drag force varied from 3.9 to 8.7N, with greatest contribution occurring along the axial and anterior/posterior directions. Average resultant drag force was 20% smaller for the crossed configurations. Maximum drag force orientation varied from 1.4 degrees to 51 degrees . Drag force angle varied from 1 degrees to 5 degrees during one cardiac cycle. 44% to 62% of the resultant force acted along the proximal centerline where SG migration is most likely to occur. The clinician's decision for SG positioning may be a critical parameter, and should be considered prior to surgery. All crossed SG devices had an increased spiral flow effect along the distal legs with reductions in drag forces. PMID- 27773832 TI - Nomenclature for factors of the HLA system, update July 2016. PMID- 27773831 TI - Kidney transplantation of highly sensitized recipients under the new kidney allocation system: A reflection from five different transplant centers across the United States. AB - Deceased donor kidney allocation was reorganized in the United States to address several problems, including the highly sensitized patients disadvantaged with large, diverse repertoires of antibodies. Here, five transplant surgeons review their center's experience with the new allocation changes: highlighting areas of accomplishment, opportunities for improvement and, in some cases, stark differences in practice. Across these five centers the highly sensitized patients (CPRA ?98%) range from 5.5 to 9.2% of the 12,364 candidates on their collective waitlist. All centers reported greater rates of kidney transplantations in highly sensitized patients (12.4-27%). Three of the programs (Emory, UCSF, UW) relied upon the virtual crossmatch prior to organ acceptance in a majority of cases (70 86%)-the mere presence of antibody on HLA antibody screen was sufficient to exclude the donor in most cases at Emory and UCSF. Penn and UAB relied upon the physical flow crossmatch in almost all cases prior to proceeding with transplantation. Current or historical donor-specific antibody was occasionally crossed in certain cases at UW and UAB necessitating IVIG/plasmapheresis and/or B cell depletion perioperatively. Some authors raised concerns for cost efficiency given the increased need for organ/specimen transportation, and extensive use of hospital resources and ancillary services. In general, we found that the new allocation system has successfully achieved one of its primary goals-increased kidney transplantation in the disadvantaged, highly sensitized patients; the long term outcomes in all patients and the cost ramifications of these changes will require continued reassessment and clarification. PMID- 27773833 TI - Nomenclature for factors of the HLA system, update September 2016. PMID- 27773834 TI - Nomenclature for factors of the HLA system, update August 2016. PMID- 27773835 TI - Levodopa-induced morphologic changes of prefrontal pyramidal tract-type neurons in a rat model of Parkinson's disease. AB - Long-term administration of levodopa for Parkinson's disease is associated with various motor and non-motor complications. We examined the dendritic spine morphology of pyramidal tract-type neurons in the prefrontal cortex in a rat model of Parkinson's disease chronically treated with levodopa. Dendritic spines showed decreased density and increased average volume after dopamine denervation and levodopa treatment. These morphologic alterations suggest that the prefrontal neurons may maladaptively respond to excitatory input, which might be one of the mechanisms underlying various levodopa-induced complications in patients with Parkinson's disease. PMID- 27773836 TI - In vivo evaluation of supersaturation/precipitation/re-dissolution behavior of cinnarizine, a lipophilic weak base, in the gastrointestinal tract: the key process of oral absorption. AB - The aim of this study is to evaluate how supersaturation, precipitation, and re dissolution processes influence the intestinal absorption of cinnarizine (CNZ), a lipophilic weak base, by monitoring its plasma and luminal concentration-time profile, after oral administration as a HCl solution containing fluorescein isothiocyanate dextran (FD-4), a non-absorbable marker. In the in vitro pH shift experiment, the supersaturation stability was significantly lower when the higher concentration solution of CNZ (pH1.5) was added to the simulated intestinal fluid. However, although the in vivo bioavailability after oral administration of high and low dose as HCl solutions was greatly improved compared to those as neutral suspensions, the difference in the supersaturation stability was not reflected in the improvement of the in vivo bioavailability. Analysis of CNZ and FD-4 concentrations in each segment of the gastrointestinal tract revealed that most of the CNZ precipitated in the duodenum after gastric emptying, and supersaturation was observed only in the duodenum. Thereafter, the precipitate was rapidly re-dissolved and absorbed in the upper and middle small intestine. The rapid re-dissolution may be caused by smaller particles of the precipitate. In this case, it is considered that the key process for the absorption of CNZ was re-dissolution, not supersaturation. Therefore, different supersaturation stabilities in different doses observed in in vitro precipitation experiment was not reflected to in vivo absorption. These findings may be useful to design efficient supersaturable formulations and to validate and improve current prediction methods. PMID- 27773838 TI - Chitosan stabilized Ag-Au nanoalloy for colorimetric sensing and 5-Fluorouracil delivery. AB - Fluorescent CS/Ag-Au (chitosan/silver-gold) nanocomposite containing different weight percentage of Ag and Au was synthesized using the chemical reduction method. 5-Fluorouracil (5-FU) encapsulated nanocomposite was also synthesized and its cytotoxicity towards breast cancer cell lines (MCF-7) studied. The XRD pattern of the nanocomposite shows peaks of chitosan, silver and gold. The peaks corresponding to gold and silver indicate the face centered cubic structure of silver and gold nanoparticles. The polymer matrix nanocomposite structure with chitosan as the matrix and silver-gold as the filler phase is evident from the high resolution transmission electron microscopy (HRTEM) images and an increase in particle size from~5nm to about 12nm is noticeable on encapsulation of 5 Fluorouracil (5-FU). The presence of fluorine in the case of 5-FU encapsulated nanocomposite and the presence of reflections corresponding to 5-FU in the SAED pattern confirms the encapsulation of 5-FU into the nanocomposite, which is also confirmed by elemental mapping. The presence of a single surface plasmon resonance (SPR) peak in the case of the nanocomposite in a position in between the SPR bands of pure silver and gold nanoparticles confirms the formation of Ag Au alloy and the elemental mapping results obtained for the nanocomposite also supports the UV-vis results. The photoluminescence (PL) spectrum clearly shows an emission peak in the near infrared region (700-900nm), which makes the nanocomposite suitable for use in cellular imaging. The application of the nanocomposite as a colorimetric sensor was also studied and it was found to be useful for the specific detection of mercury (Hg) without much interference and the detection limit was found to be 5.0*10-8M. PMID- 27773837 TI - New E-beam-initiated hyaluronan acrylate cryogels support growth and matrix deposition by dermal fibroblasts. AB - Cryogels made of components of natural extracellular matrix components are potent biomaterials for bioengineering and regenerative medicine. Human dermal fibroblasts are key cells for tissue replacement during wound healing. Thus, any biomaterial for wound healing applications should enable growth, differentiation and matrix synthesis by these cells. Cryogels are highly porous scaffolds consisting of a network of interconnected pores. Here, we used a novel group of cryogels generated from acrylated hyaluronan where the polymerization was initiated by accelerated electrons (E-beam). This novel procedure omits any toxic polymerization initiators and results in sterile, highly elastic scaffolds with adjustable pore size, excellent swelling and low flow resistance properties. We show that these cryogels are effective 3D-substrates for long-term cultures of human dermal fibroblasts in vitro. The cells proliferate for at least 28days throughout the cryogels and deposit their own matrix in the pores. Moreover, key modulators of dermal fibroblasts during wound healing like TGFbeta and PDGF efficiently stimulated the expression of wound healing-relevant genes. In conclusion, electron beam initiated cryogels of acrylated hyaluronan represent a functional and cell compatible biomaterial that could be adapted for special wound healing applications by further functionalization. PMID- 27773839 TI - Biophysical characterization of soluble Pseudomonas syringae ice nucleation protein InaZ fragments. AB - Ice nucleation protein (INP) with its functional domain consisting of multiple 48 residue repeat units effectively induces super-cooled water into ice. Circular dichroism and infrared deconvolution analyses on a soluble 240-residue fragment of Pseudomonas syringae InaZ (InaZ240) containing five 48-residue repeat units indicated that it is mostly composed of beta-sheet and random coil. Analytical ultracentrifugation suggested that InaZ240 behaves as a monomer of an elongated ellipsoid. However, InaZ240 showed only minimum ice binding compared to anti freeze proteins. Other P. syringae InaZ proteins with more 48-residue repeat units were made, in which the largest soluble fragment obtainable was an InaZ with twelve 48-residue repeat units. Size-exclusion chromatography analyses further suggested that the overall shape of the expressed InaZ fragments is pH dependent, which becomes compact as the numbers of 48-residue repeat unit increase. PMID- 27773840 TI - Smart nanoparticles based on pullulan-g-poly(N-isopropylacrylamide) for controlled delivery of indomethacin. AB - Double hydrophilic thermo-responsive pullulan-g-poly(N-isopropylacrylamide) (P-g pNIPAM) copolymers with two different molecular weight of thermosensitive grafts were synthesized and used for preparation of indomethacin-loaded nanoparticles by dialysis and nanoprecipitation method. The polymers form aggregates in aqueous solution at a concentration of 10g/L, above their critical aggregation concentration (3.36g/L) and below the lower critical solution temperature (LCST). After indomethacin loading, nanoparticles with compact and uniform structure were formed below the LCST. The effects of copolymer composition, concentration, and the feed polymer/drug ratio on the particle size, drug loading content (DLC) and entrapment efficiency (EE) were investigated. DLC increased with drug feeding, reaching a maximum value of 40% at the ratios of 1/1. Smaller particles (145nm) with narrower size distribution were obtained from polymer with a higher molecular weight of pNIPAM grafts. FT-IR and 1H NMR spectra proved that the main driven force for the aggregation was the hydrogen bonding between indomethacin and the pNIPAM side chains of copolymer. The indomethacin release rate from nanoparticles was influenced by temperature, because of the dissociation of the hydrogen bonds at high temperatures, the degree of drug loading, and the pH of the release media. PMID- 27773841 TI - Purification, partial characterization and bioactivity of sulfated polysaccharides from Grateloupia livida. AB - Purification, preliminary characterization and bioactivity of polysaccharides from Grateloupia livida (GL) were investigated. Three water-soluble sulfated polysaccharide fractions (GLP-1, GLP-2 and GLP-3) were isolated and purified from the edible and medicinal red seaweed, Grateloupia livida (Harv.) Yamada by DEAE Sepharose CL-6B and Sephadex G-100 column chromatography, and chemical characterization was performed by HPGPC, GC-MS, FT-IR and SEM. In addition, anticoagulant activities were determined by activated partial thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT) using normal human plasma in vitro. The antioxidant activities against DPPH and ABTS+ radicals were evaluated and compared. The molecular weights of GLP-1, GLP-2 and GLP-3 were 39.5, 60.4 and 3.36kDa, respectively. Monosaccharide analysis revealed that three polysaccharide fractions were homopolysaccharides and comprised of galactose only. Anticoagulant assays indicated that crude GLP, and purified GLP-1 and GLP-2 effectively prolonged APTT and TT, but not PT. All polysaccharide fractions exhibited significant in vitro antioxidant activities in a dose-dependent manner. GLP-2 showed consistently better anticoagulant and antioxidant activities compared with GLP, GLP-1 and GLP-3. These results demonstrate that sulfated polysaccharides isolated from Grateloupia livida can serve as readily available alternative natural sources of anticoagulant and antioxidant agents. PMID- 27773842 TI - PC-FACS. AB - PC-FACS(FastArticleCriticalSummaries for Clinicians inPalliativeCare) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at pc facs@aahpm.org. PMID- 27773843 TI - Using Tiletamine-Zolazepam-Xylazine Anesthesia Compared to CO2-inhalation for Terminal Clinical Chemistry, Hematology, and Coagulation Analysis in Mice. AB - INTRODUCTION: It is important that the method of anesthesia of mice does not considerably alter the animal's physiological and metabolic status before terminal blood sampling taken in order to analyze clinical pathology parameters. METHODS: Hematology, hemostasis, and clinical chemistry parameters were compared in male and female BALB/c mice exposed to either tiletamine-zolazepam-xylazine (TZX) anesthesia or euthanasia in carbon dioxide (CO2) chamber to reveal an alternative method of anesthesia vs. the recommended CO2 inhalation. Blood samples were taken from the inferior vena cava. RESULTS: Clinical blood parameters in mice exposed to CO2 inhalation or TZX anesthesia proved to be substantially different. The TZX group had lower activated partial thromboplastin time (APTT) and fibrinogen (statistically in males and tending in females) and lower platelets (PLT), red blood cells (RBC), hemoglobin (HGB), and white blood cells (WBC) in both sexes. TZX anesthesia resulted in lower blood serum concentrations of total protein, albumin and globulins, creatinine in males (higher in females); cholesterol, triglycerides, alanine aminotransferase (ALT) and alkaline phosphatase (AP) in both sexes, and bilirubin in males. The calcium level decreased in TZX-anesthetized males and females while the phosphates decreased only in females. The volume of serum obtained from females of TZX group was approximately two times higher than in the CO2-anesthetized group, with the degree of hemolysis tending to decrease. DISCUSSION: The studied method of mouse anesthesia, followed by terminal blood sampling and analysis of clinical pathology parameters, suggests that TZX is a good alternative to CO2 inhalation in toxicological and other nonclinical studies. The differences in hemostasis, hematology, and clinical chemistry parameters between these groups are supposedly associated with alterations in physiological and metabolic status of mice under conditions of increasing hypoxia, respiratory standstill, and circulatory arrest after CO2 inhalation. PMID- 27773844 TI - A murine model of type 2 diabetes mellitus developed using a combination of high fat diet and multiple low doses of streptozotocin treatment mimics the metabolic characteristics of type 2 diabetes mellitus in humans. AB - INTRODUCTION: A murine model of type 2 diabetes mellitus was used to compare the antidiabetic effects of the dipeptidyl peptidase-4 (DPP4) inhibitor vildagliptin and biguanide, metformin. METHODS: Swiss albino mice (n=20 males; n=25 females) were given high fat diet (HFD) ad libitum for 3weeks followed by low dose (40mgkg 1 body weight, bw daily) of streptozotocin (STZ) intraperitoneally five times from the 22nd day of treatment onwards, with HFD continued up to 26th day. Controls (n=15 males; n=15 females) were fed normal balanced diet without administration of STZ. Successful induction of diabetes mellitus was confirmed by testing for fasting blood glucose, intraperitoneal glucose tolerance and intraperitoneal insulin sensitivity. Diabetic mice were administered vildagliptin (10mgkg-1 bw daily) and metformin (50mgkg-1 bw daily) orally for 4weeks. Control, diabetic, vildagliptin and metformin-treated diabetic mice were evaluated for alterations in lipid profile using blood serum and histopathology and oxidative stress using tissues including liver, kidney and heart. RESULTS: Diabetic mice showed significant alterations in lipid profile, tissue histopathology, impaired glucose tolerance, lower insulin sensitivity and elevated lipid peroxidation and protein carbonylation, with depressed catalase activity, when compared to age and gender-matched controls. Metformin and vildagliptin ameliorated the abovementioned diabetic conditions, with vildagliptin found to be more effective. DISCUSSION: A murine model developed by the combination of HFD and multiple low dose of STZ mimics the metabolic characteristics of type 2 diabetes mellitus in humans, and may be useful for antidiabetic drug screening. PMID- 27773845 TI - Harmonised high throughput microsomal stability assay. AB - INTRODUCTION: Prediction of human pharmacokinetics from in vitro assays and pre clinical data is an integral part of drug discovery. In vitro stability metabolic studies can provide an estimate of in vivo hepatic intrinsic clearance through inclusion of biological scaling factors. Many labs have personalised stability protocols including marker compounds and have adopted QC criteria and assay limits to ensure data integrity. Contract research organisations (CRO's) provide integrated drug discovery support to academic and pharmaceutical/biotechnology institutions to progress their in-house projects. The majority of these clients have established in-house protocols with associated criteria to ensure data consistency between in-house and external labs. METHODS: In this study, numerous assay variables were condensed into one harmonised assay format and a range of compounds with diverse physicochemical properties were evaluated. The protocols were diverse with respect to the following attributes: buffer, microsomal concentration and species strain. RESULTS: Comparison of human lots in vitro CLint between the traditional and consolidated assay formats showed a good correlation with no significant difference. A clear relationship was demonstrated between strains. Interpretation of in vitro intrinsic clearance between the strains for each species was consistent. Using strict classes of in vitro hepatic intrinsic clearance values (<50, 50-100, >150MUL/min/mg protein) comparisons across different conditions such as, assay variables, human lots, mouse and rat strains showed >80% agreement. DISCUSSION: A high throughput assay was developed that enables the simultaneous measurement of CLint using mouse, rat and human hepatic microsomes (consolidated assay). By condensing all possible variables into one assay format, consistent data were obtained during head to head tests. PMID- 27773846 TI - Emergency Department Imaging Modality Effect on Surgical Management of Nephrolithiasis: A Multicenter, Randomized Clinical Trial. AB - PURPOSE: In the emergency department ultrasonography is emerging as an alternative to computerized tomography for diagnosing patients with nephrolithiasis. In this multicenter randomized clinical trial we examined rates of urological referral and intervention to elucidate whether the initial diagnostic imaging modality affected the management of nephrolithiasis. MATERIALS AND METHODS: Patients 18 to 76 years old who presented to the emergency department with renal colic across 15 diverse treatment centers were randomized to receive abdominal ultrasonography by an emergency department physician or a radiologist, or abdominal computerized tomography. We analyzed the 90-day followup for patients diagnosed with nephrolithiasis to assess subsequent urological evaluation, procedure type and time to intervention. RESULTS: Of 1,666 patients diagnosed with nephrolithiasis in the emergency department 241 (14.5%) had a consultation with urology at initial presentation, 503 (30%) saw a urologist in followup and 192 (12%) underwent at least 1 urological procedure. Median time to outpatient procedure and type of procedure performed did not vary significantly among imaging groups. Most patients (78%) had computerized tomography performed before elective intervention. Patients with ultrasonography performed by an emergency department physician were 2.6 times more likely to undergo computerized tomography before intervention than those who had ultrasonography performed by a radiologist. CONCLUSIONS: Patients undergoing a urological intervention who had ultrasonography as initial imaging do not experience a significant delay to intervention or different procedure types, but the majority ultimately undergoes computerized tomography before surgery. Formal ultrasonography by a radiologist may encourage less computerized tomography preoperatively. PMID- 27773847 TI - Recent views of heavy metals as possible risk factors and potential preventive and therapeutic agents in prostate cancer. AB - Prostate cancer is the most common cancer in men in many industrialized countries. A role for androgens in prostate tumor progression is well recognized, while estrogens may cooperate with androgens in prostate carcinogenesis. The incidence of prostate cancer is highly variable in the different countries, suggesting an important role of environmental factors. Heavy metals are common environmental contaminants and some of them are confirmed or suspected human carcinogens. Some metals are endowed with estrogenic and/or androgenic activities and may play a role as cancer risk factors through this mechanism. Moreover, prostate cancer may present alterations in the intracellular balance of trace metals, such as zinc and copper, which are involved in several regulatory proteins. Herein, we review the possible role of environmental heavy metals and of metal-dyshomeostasis in prostate cancer development and promotion as well as the potential use of some metals in the prevention and therapy of prostate cancer. PMID- 27773848 TI - Appetite and weight gain suppression effects of alcohol depend on the route and pattern of administration in Long Evans rats. AB - Ethanol can be a food source but its effects on energy balance and contribution to obesity remain inconclusive. In this study, we hypothesized that the effects of ethanol on energy intake and body weight would depend on the administration dose, pattern and the blood ethanol concentration (BEC) time-course. Experiment 1 examined changes in food intake, diet preference, and body weight after saline or ethanol (1 and 3g/kg) injection (IP). Experiment 2 compared the effects in rats that received either 3g/kg/day ethanol administered all at once (EtOH_S) or 2 1.5g/kg injections spaced by 3h (EtOH_D). Experiment 3 examined the effects of 7.5h/day, Mon through Fri for 8weeks, voluntary ethanol drinking (5% and 10% ethanol) on food intake and body weight. Results of Experiments 1 and 2 indicate that acute ethanol administrations dose-dependently reduced energy intake, high fat diet preference and weight gain. Acute 3g/kg ethanol injection in the EtOH_S group decreased energy intake, weight gain and visceral fat to a greater extent than in the EtOH_D group. Results of Experiment 3 show that male and female rats voluntarily drank 1.65-2.31g/kg ethanol within 3.5h with reduced chow intake but unchanged total energy intake and weight gain. Furthermore, 3g/kg ethanol injection resulted in BEC that remained at intoxicating levels e.g. >120mg/dL for several hours post-administration and was higher in the EtOH_S than in the EtOH_D group. In contrast, BEC in voluntarily drinking was ~67mg/dL and decreased to below 10mg/dL 5h after termination of ethanol access. Taken together, these data suggest that 3g/kg ethanol injection robustly suppresses appetite and weight gain due to the higher BECs attained. Furthermore, BEC attained and maintained is a determining factor for how ethanol administration affects appetite and long-term energy balance. PMID- 27773849 TI - Intranasal administration of a polyvalent bacterial lysate induces self restricted inflammation in the lungs and a Th1/Th17 memory signature. AB - Respiratory tract infections are among the most frequent infections in humans causing millions of deaths especially in children and the elderly. Antibiotics and vaccines are the main available tools of control, but resistant strains are continuously arising and available vaccines only account for few of many pathogens involved. Non-specific immunotherapies are an emerging alternative to induce protective immunity at the airways. Mucosally administered polyvalent bacterial lysates (PBLs) have been widely used for decades for prevention of respiratory diseases, but the bases of their proposed therapeutic effectiveness are still controversial. Here, we show that PBL engages a pro-inflammatory gene expression program in macrophages and epithelial cells, induces an acute lung inflammatory response and elicits full protection against pneumococcal pneumonia. Chronic lung inflammation may have pathological consequences, so the capacity to regain local homeostasis after treatment is central. We found that local inflammation is fully resolved and 30 days after treatment lungs become undistinguishable from naive mice. Nevertheless, this process leaves an immunological imprinting with a Th1/Th17 memory phenotype that may be a marker of the protective immunity elicited. Increasing our understanding of the mechanism of action of PBLs may improve the efficiency of these immunotherapies and expand their range of action. PMID- 27773850 TI - Dental screening of medical patients for oral infections and inflammation: consideration of risk and benefit. AB - The primary purpose of preoperative dental screening of medical patients is to detect acute or chronic oral conditions that may require management prior to planned medical interventions. The aim of this communication is to discuss the background of preoperative dental screening and the link between dental pathologies and systemic diseases. PMID- 27773851 TI - Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms. AB - BACKGROUND: Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. OBJECTIVE: We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis. METHODS: We randomly assigned 93 adults with grass pollen-induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment. RESULTS: There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, -172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, -11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense-specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03). CONCLUSION: Intradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms. PMID- 27773853 TI - Advancing pharmaceutical quality: An overview of science and research in the U.S. FDA's Office of Pharmaceutical Quality. AB - Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support drug quality review, inspection, surveillance, standards, and policy development. Science and research is the foundation of risk-based quality assessment of new drugs, generic drugs, over-the-counter drugs, and biotechnology products including biosimilars. This is an overview of the science and research activities in OPQ that support the mission of ensuring that safe, effective, and high-quality drugs are available to the American public. PMID- 27773854 TI - Fabrication of antimicrobial silver-doped carbon structures by combinatorial pulsed laser deposition. AB - We report on the selection by combinatorial pulsed laser deposition of Silver doped Carbon structures with reliable physical-chemical characteristics and high efficiency against microbial biofilms. The investigation of the films was performed by scanning electron microscopy, high resolution atomic force microscopy, energy dispersive X-Ray Spectroscopy, X-ray diffraction, Raman spectroscopy, bonding strength "pull-out" tests, and surface energy measurements. In vitro biological assays were carried out using a large spectrum of bacterial and fungal strains, i.e., Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Enterococcus faecalis and Candida albicans. The biocompatibility of the films obtained was evaluated on MG63 mammalian cell cultures. The optimal combination with reasonable physical-chemical properties, efficient protection against microbial colonization and beneficial effects on human cells was found for Silver-doped Carbon films containing 2 to 7 at.% silver. These mixtures can be used to fabricate safe and efficient coatings of metallic implants, with the goal to decrease the risk of implant associated biofilm infections which are difficult to treat and often responsible for implant failure. PMID- 27773856 TI - Management of Foramen Magnum Meningioma During Pregnancy: Literature Review and Case Report. AB - BACKGROUND: Foramen magnum meningiomas are very rare and challenging lesions. Their presentation in women during pregnancy tremendously complicates the course of gestation. Conservative management is always the first option, but in cases of a deteriorating clinical picture, there are currently no clear guidelines on best management. CASE DESCRIPTION: A woman presents in the 30th week of pregnancy with pain and progressive numbness in right posterior aspect of neck and right arm. Foramen magnum meningioma was diagnosed and successful surgical resection was performed with intraoperative fetal hearth monitoring and three fourths prone position of the patient. CONCLUSIONS: We believe a three fourths prone position of a pregnant patient is safe and adequate for the far-lateral exposure of craniocervical lesions. Rapid growing of tumor can be precipitated by steroids management during pregnancy. PMID- 27773855 TI - Buccal delivery of low molecular weight heparin by cationic polymethacrylate nanoparticles. AB - Buccal delivery seems to be a very promising administration route for macromolecular drugs. Here, we explored the potential of cationic polymethacrylate nanoparticles (NPs) as a carrier system for the buccal delivery of low molecular weight heparin (LMWH). LMWH-loaded NPs were prepared by emulsification solvent diffusion method and the NPs were analyzed for their physiochemical properties, rheological evaluations and ex vivo transport studies across buccal mucosa. The prepared LMWH-loaded NPs showed a mean diameter between 400 and 500nm with unimodal size distribution with negative surface charge. Viscosity measurements revealed a positive rheological synergism between the prepared NPs and mucin when mixed under physiological conditions. After 4h, about 6.3+/-0.9% of LMWH was released in case of using Eudragit(r) RS (ERS); while Eudragit(r) RL (ERL) NPs released only 3.0+/-0.3 % of its LMWH content and this incomplete release was slightly ameliorated in the presence of mucin reaching to 7.2+/-0.3 % and 4.8+/-0.3 % for ERS and ERL, respectively. The ex-vivo permeability of heparin through the buccal mucosa was significantly increased after using polymetharylate NPs while no heparin permeation was detected from free heparin solution. Confocal laser scanning microscopy (CLSM) imaging indicated the mucoadhesive properties of the polymetharylate NPs where the drug free NPs were detected in the superficial layers of buccal mucosa. LMWH-loaded NPs had less mucoadhesive properties showing significant deeper penetration of the mucosa. The results indicated that mucoadhesive cationic polymethacrylate NPs offer a possible approach for the buccal delivery of heparin. PMID- 27773857 TI - Epidemiology of Traumatic Brain Injuries at a Major Government Hospital in Cambodia. AB - BACKGROUND: Traumatic brain injury (TBI) is a critical public health problem worldwide with a significant socioeconomic burden. Although improved safety regulations in high-income countries have resulted in a decline in traffic related TBI, the incidence of TBI in low-income countries is on the rise. We illustrate the trends and factors involved in TBI in a large Cambodian governmental hospital in Phnom Penh. In addition, suggestions for improvement of the country's road traffic safety are discussed. METHODS: This is a cross sectional study of all patients who presented with traumatic brain injury to Department of Neurosurgery at Preah Kossamak Hospital in Phnom Penh, Cambodia between November 2013 and March 2016. RESULTS: TBIs in Cambodia are on the rise; 34% occur during rush hour, 5-9 pm, and 40% during the weekend. The vast majority (74%) occur as the result of road traffic accidents, of which 81% are motorcycle related. Helmet wear remains low at 13%, and recent alcohol use was reported as 38%. The most common diagnosis is skull fracture. The subdural to epidural hematoma ratio was 1:1.05. Lastly, in both subdural and epidural hematomas the frontal lobe was most commonly involved, with 60% of epidural hematomas associated with a lucid interval. CONCLUSIONS: Our study suggests prevention and management of TBIs can have a measurable public health impact in Cambodia. Initiative examples include helmet safety awareness campaigns, stricter penalties, improvement of prehospital care, and more efficient triage. A high proportion of unhelmeted motorcycle accidents correlates with an increase in epidural hematomas. PMID- 27773858 TI - Percutaneous Endoscopic Lumbar Diskectomy and Minimally Invasive Transforaminal Lumbar Interbody Fusion for Recurrent Lumbar Disk Herniation. AB - OBJECTIVE: To compare the clinical outcomes of patients with recurrent lumbar disk disease undergoing percutaneous endoscopic lumbar diskectomy or minimally invasive transforaminal lumbar interbody fusion at a single clinic. METHODS: From January 2008 to January 2014, 401 consecutive patients with first recurrence of lumbar disk herniation were treated with percutaneous endoscopic lumbar diskectomy (PELD) or minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). These data collected prospectively for analysis were clinical and radiographic results after revision surgery and complications. RESULTS: During the follow-up period, postoperative data between both groups showed no significant differences in the mean total postoperative visual analog scale score for leg pain, Japanese Orthopaedic Association score, and Oswestry Disability Index score. The recovery rate was 92.3% in the PELD and 97.4% in the MIS-TLIF group. Regarding satisfactory rate, the PELD group (91.3%) was lower than the MIS TLIF group (95.2%). Six cases of dural tear were observed in the MIS-TLIF group. The second recurrence occurred in 12 patients in the PELD group. In the PELD group, 1 patient suffered from permanent neurologic deficit. One case of postoperative intervertebral infection was captured in the MIS-TLIF group. CONCLUSIONS: Both PELD and MIS-TLIF showed favorable clinical outcomes for recurrent disk herniation. Compared with MIS-TLIF, PELD has the following several advantages: 1) performed under local anesthesia; 2) performed with very few approach-related complications, such as dural tear; and 3) rare possibility of fusion disease, such as adjacent segment. However, PELD is also faced with several problems, such as 1) the relative higher rate of postoperative long-term chronic low back pain, and (2) the possibility of recurrence, despite the opportunity being low. PMID- 27773852 TI - U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. AB - BACKGROUND: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. OBJECTIVES: We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. METHODS: Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. RESULTS: Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. CONCLUSION: Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways. PMID- 27773859 TI - Long-Term Follow-Up of Primary Medical Versus Surgical Treatment of Prolactinomas in Men: Effects on Hyperprolactinemia, Hypogonadism, and Bone Health. AB - OBJECTIVE: In men with prolactinomas, impaired bone density is the principle consequence of hyperprolactinemia-induced hypogonadism. Although dopamine agonists (DAs) are the first-line approach in prolactinomas, surgery can be considered in selected cases. In this study, we aimed to investigate the long term control of hyperprolactinemia, hypogonadism, and bone health comparing primary medical and surgical therapy in men who had not had prior DA treatment. METHODS: This is a retrospective case-note study of 44 consecutive men with prolactinomas and no prior DAs managed in a single tertiary referral center. Clinical, biochemical, and radiologic response to the first-line approach were analyzed in the 2 cohorts. RESULTS: Mean age at diagnosis was 47 years (range, 22 78 years). The prevalence of hypogonadism was 86%, and 27% of patients had pathologic bone density at baseline. The primary therapeutic strategy was surgery for 34% and DAs for 66% of patients. Median long-term follow-up was 63 months (range, 17-238 months). Long-term control of hyperprolactinemia required DAs in 53% of patients with primary surgical therapy, versus 90% of patients with primary medical therapy (P = 0.02). Hypogonadism was controlled in 73% of patients. The prevalence of patients with pathologic bone density was 37% at last follow-up, with no differences between the 2 therapeutic cohorts (P = 0.48). CONCLUSIONS: Despite control of hyperprolactinemia and hypogonadism in most patients independent of the primary treatment modality, the prevalence of impaired bone health status remains high, and osteodensitometry should be recommended. PMID- 27773860 TI - Topical use of topical fibrin sealant can reduce the need for transfusion, total blood loss and the volume of drainage in total knee and hip arthroplasty: A systematic review and meta-analysis of 1489 patients. AB - OBJECTIVE: To evaluate the efficacy and safety of fibrin sealant for the reduction of postoperative blood loss and transfusion requirements in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Electronic databases including PubMed, Embase, CENTRAL (Cochrane Controlled Trials Register), Web of Science and Google Scholar were searched from database inception to February 2016. All randomized controlled trials evaluating the efficacy and safety of topical administration of fibrin glue during primary THA or TKA were included in our meta-analysis. Transfusion requirements, total blood loss, length of hospital stay and the occurrence of infection were calculated using Stata 12.0 software. RESULTS: A total of nineteen clinical trials with 1489 patients (405 hips and 1084 knees) were finally included for meta-analysis. The results indicated that the topical administration of fibrin sealant can decrease the need for transfusion (RR = 0.33, 95%CI 0.28-0.40, P < 0.001), total blood loss (MD = -138.25, 95% CI -203.49 to -75.00), blood loss in drainage (MD -321.44, 95% CI -351.96 to -290.92, P < 0.001) and hospital stay length (MD -0.98, 95% CI -1.35 to -0.62, P < 0.001) without increasing the occurrence of infection (RR = 0.87, 95% CI 0.33 to 2.27, P = 0.775). CONCLUSION: The topical use of fibrin sealant can effectively reduce the need for transfusion, total blood loss and the volume of drainage without increasing the rate of infection. PMID- 27773862 TI - Possible mechanical causes of scaffold thrombosis: insights from case reports with intracoronary imaging. AB - The advent of intracoronary stents has greatly increased the safety and applicability of percutaneous coronary interventions. One of the drawbacks of drug-eluting stents (DES) is the increased risk of late and very late stent thrombosis (ST). It was anticipated that the risks of ST after DES implantation would be solved with the advent of fully biodegradable scaffolds, which offer the possibility of transient scaffolding of the vessel to prevent acute vessel closure and recoil while also transiently eluting an antiproliferative drug to counteract constrictive remodelling and excessive neointimal hyperplasia. In spite of the enthusiasm for the concept of bioresorbable scaffolds, current clinical data on the Absorb bioresorbable vascular scaffold (BVS) have generated concerns about scaffold thrombosis (ScT) in both the early and late phases. However, the causes of ScT in both the early and late phases have yet to be fully elucidated. This article seeks to provide insights into the possible mechanical causes of ScT in the early and late phases with data stemming from intracoronary imaging (intravascular ultrasound and optical coherence tomography) of the currently published ScT cases following the implantation of BVS and reviews the practical recommendations for implantation of the BVS made by a group of experts. PMID- 27773861 TI - Mesial temporal lobe epilepsy - An overview of surgical techniques. AB - Mesial temporal lobe epilepsy is one of the commonest indications for epilepsy surgery. Presurgical evaluation for drug resistant epilepsy and identification of appropriate candidates for surgery is essential for optimal seizure freedom. The anatomy of mesial temporal lobe is complex and needs to be understood in the context of the advanced imaging, ictal and interictal Video_EEG monitoring, neuropsychology and psychiatric considerations. The completeness of disconnection of epileptogenic neural networks is paramount and is correlated with the extent of resection of the mesial temporal structures. In the Indian subcontinent, a standard but extended anterior temporal lobectomy is a viable option in view of the diverse socioeconomic, cultural and pathological considerations. The maximum utilization of epilepsy surgery services in this region is also a challenge. There is a need for regional comprehensive epilepsy care teams in a tertiary care academic hospital to form centers of excellence catering to a large population. PMID- 27773863 TI - Surgical rescue after transcatheter interventional procedures in congenital heart disease patients: an existing problem. AB - AIMS: Nowadays, transcatheter approaches are the treatment of choice for several congenital heart defects. However, adverse events may occur during interventional procedures. Even if the complication rate has been reduced remarkably because of learning curve and technological improvements, catastrophic events are still possible. The aim of this study was to review cardiac catheter complications that required surgical treatment during or after a percutaneous procedure. METHODS AND RESULTS: We evaluated retrospectively a thirteen-year experience at our centre. We examined all transcatheter procedures involving device release or implantation needing surgical rescue. We performed 3,205 interventional catheterisation procedures with device release or implantation: ASD device closure (n=2,205), PDA device occlusion (n=355), VSD device closure (n=218), aortic coarctation or recoarctation stenting (n=199), pulmonary artery stenting (n=154) and pulmonary valve implantation (n=74). Complications that required surgical treatment occurred in 1.2% of cases. Early surgery was performed in 22 cases, while in 18 patients a surgical treatment related to late complications was performed in a mean follow-up of 17 months. There were no deaths in either group. CONCLUSIONS: A spectrum of CHD can be treated today by transcatheter interventional procedures with good results and a low, but not negligible, risk of complications that require a surgical operation. The risk of developing late complications makes a long-term follow-up mandatory in such patients. PMID- 27773864 TI - Comparison of clinical outcomes after multivessel versus single-vessel stenting with the zotarolimus-eluting stent in the RESOLUTE Global Clinical Trial Program. AB - AIMS: Our aim was to investigate whether long-term (three-year) clinical outcomes after multivessel treatment with the Resolute zotarolimus-eluting stent (R-ZES) were similar to single-vessel treatment. METHODS AND RESULTS: The RESOLUTE Global Clinical Trial Program enrolled 7,618 patients, of whom 1,562 underwent multivessel and 6,053 single-vessel treatment with the R-ZES. Patients in the multivessel group were more likely to have complex lesions (58% vs. 44%, p<0.001). Clinical outcomes were compared using a Cox regression model adjusted by propensity score to account for differences in baseline characteristics. Compared with single-vessel treatment, multivessel treatment was associated with more complex anatomy and longer mean total stent length (57.8+/-28.6 vs. 26.7+/ 15.2 mm, p<0.001). At three years, the cumulative incidence of target lesion failure was similar in patients with multivessel and single-vessel treatment (11.0% vs. 9.1%, adjusted p=0.986), as was the incidence of cardiac death or target vessel myocardial infarction (6.7% vs. 5.7%, adjusted p=0.793), the incidence of clinically driven target lesion revascularisation (5.1% vs. 4.4%, adjusted p=0.904), and the incidence of Academic Research Consortium definite or probable stent thrombosis (1.2% vs. 0.9%, adjusted p=0.544). CONCLUSIONS: Multivessel treatment with R-ZES provided good long-term clinical outcomes that were comparable to those achieved with single-vessel stenting, supporting the efficacy and safety of R-ZES in patients in this setting. PMID- 27773865 TI - Air pollution in early life and adult mortality from chronic rheumatic heart disease. AB - Background: Chronic rheumatic heart disease (RHD) remains a globally important cause of heart disease. The reasons for the continuing high prevalence of this disease are obscure, but it may have its origins in the poor social and economic conditions with which the disease has been consistently and strongly linked. Mortality studies from the UK have suggested the importance of adverse environmental factors in early life; these studies demonstrated specific geographical associations between high rates of chest infection during infancy and subsequent RHD. They raised the possibility that early air pollution, which is known to be strongly linked with chest infection during infancy, may predispose to RHD. Methods: We related estimates of air pollution and social conditions developed by Daly in 1951-52 for 78 urban areas in England and Wales to their subsequent RHD mortality rates at ages 35-74 in men and women during 1993-2012. Results: There were strong relationships between domestic air pollution and RHD [relative risk per standard deviation (SD) increase in pollution 1.168, 95% confidence interval (CI): 1.128 to 1.210, P < 0.001). Inclusion of published data on social class, education, crowding and population density in multiple regression analyses showed that the air pollution association was independent of these; only overcrowding was separately linked with RHD. Conclusions: We present the first evidence of an association between air pollution in early life and RHD. Although there are several limitations to this study, the strength and consistency of the results, together with their biological plausibility, suggest a causal link. This deserves attention because it may have important consequences for the control of RHD in resource-poor countries where widespread use of biomass fuels and domestic pollution remain a problem. PMID- 27773867 TI - EACTS clinical statement: guidance for the provision of adult cardiac surgery. PMID- 27773866 TI - Rickettsia parkeri and "Candidatus Rickettsia andeanae" in Questing Amblyomma maculatum (Acari: Ixodidae) From Mississippi. AB - Amblyomma maculatum Koch (Acari: Ixodidae), the primary vector for Rickettsia parkeri, may also be infected with a rickettsia of unknown pathogenicity, "Candidatus Rickettsia andeanae." Infection rates with these rickettsiae vary geographically, and coinfected ticks have been reported. In this study, infection rates of R. parkeri and "Ca. R. andeanae" were evaluated, and rickettsial DNA levels quantified, in 335 questing adult A. maculatum collected in 2013 (n = 95), 2014 (n = 139), and 2015 (n = 101) from Oktibbeha County, MS. Overall infection rates of R. parkeri and "Ca. R. andeanae" were 28.7% and 9.3%, respectively, with three additional A. maculatum (0.9%) coinfected. While R. parkeri-infected ticks were detected all three years (34.7% in 2013; 13.7% in 2014; 43.6% in 2015), "Ca. R. andeanae" was not detected in 2013, and was detected at rates of 10.8% in 2014, and 15.8% in 2015. Interestingly, rickettsial DNA levels in singly-infected ticks were significantly lower in "Ca. R. andeanae"-infected ticks compared to R. parkeri-infected ticks (P < 0.0001). Thus, both infection rates and rickettsial DNA levels were higher for R. parkeri than "Ca. R. andeanae." Infection rates of R. parkeri were also higher, and "Ca. R. andeanae" lower, here compared to A. maculatum reported previously in Kansas and Oklahoma. As we continue to monitor infection rates and levels, we anticipate that understanding temporal changes will improve our awareness of human risk for spotted fever rickettsioses. Further, these data may lead to additional studies to evaluate potential interactions among sympatric Rickettsia species in A. maculatum at the population level. PMID- 27773868 TI - Outcomes of segmentectomy and wedge resection for pulmonary metastases from colorectal cancer. AB - Objectives: Although wedge resection is the most common surgical procedure for pulmonary metastases from colorectal cancer, there are few reports about segmentectomy for colorectal metastasectomy. Methods: This was a subset analysis of a Japanese nationwide retrospective study of resected pulmonary metastases from colorectal cancer. The study included 553 patients who underwent segmentectomies ( n = 98) or wedge resections ( n = 455) without preoperative chemotherapy between January 2004 and December 2008. Recurrence patterns, recurrence-free survival and overall survival were analysed for each procedure. Results: As for the patients' background factors, only the median size of resected metastases was different between patients with segmentectomies (median 18 mm, range 5-50 mm) and wedge resections (14 mm, 5-51 mm) ( P < 0.001). Prolonged air leak developed more frequently in those undergoing segmentectomy compared with wedge resection (5.1% vs 1.8%) ( P = 0.048). The resection-margin recurrence rate was higher in patients who underwent wedge resection compared with segmentectomy (7.3% vs 2.0%; P = 0.035). The 5-year recurrence-free survival was 48.8% in patients with segmentectomy and 36.0% in patients with wedge resections. The 5-year overall survival was 80.1% in patients with segmentectomy and 68.5% in patients with wedge resection. Multivariable analysis revealed that the surgical procedure, segmentectomy, was a significant favourable factor for recurrence (hazard ratio: 0.63, 95% confidence interval: 0.44-0.87, P = 0.005), but not for overall survival (hazard ratio: 0.65, 95% confidence interval: 0.38-1.05, P = 0.080). Conclusions: Segmentectomy demonstrated a good efficacy with less resection-margin recurrence in patients with resectable pulmonary-limited metastasis from colorectal cancer. PMID- 27773869 TI - Valve-in-valve outcome: design impact of a pre-existing bioprosthesis on the hydrodynamics of an Edwards Sapien XT valve. AB - Objectives: Bioprosthetic aortic heart valves are increasingly implanted in younger patients. Therefore, a strategy for potential valve failure should be developed before implanting the 'first valve'. The goal of this in vitro study was to provide insight into the effects of the design of a bioprosthesis on a valve-in-valve implanted Sapien XT valve. Methods: The hydrodynamic performance of a 23-mm Sapien XT valve implanted in Vascutek Aspire, Edwards Perimount, Medtronic Mosaic and St. Jude Medical Trifecta heart valves was investigated in a left heart simulator. In addition to the hydrodynamic results, the leaflet dynamics were analysed in high-speed video recordings of the tests. Results: All valve-in-valve combinations in this study fulfilled the minimum acceptance criteria defined by relevant approval standards (e.g. ISO 5840) but displayed significant differences in their performances. Small inner diameters of the bioprostheses were associated with increased mean pressure gradients, decreased effective orifice areas and geometric opening areas as well as with pin-wheeling and uneven leaflet motion. In addition, implantation in bioprostheses with internally mounted leaflets was associated with lower paravalvular leakage. Conclusions: The results of this study suggest that a surgical bioprosthesis with a large inner diameter and internally mounted leaflets improves the heamodynamics and potentially the durability of a valve-in-valve combination. These results should give the attending physicians critical information to consider when deciding on a bioprosthesis for younger patients. PMID- 27773872 TI - Inconsistent Results With Different Secondary Reflex Assays for Resolving HER2 Status. AB - Objectives: Guidelines suggest that secondary reflex testing may be useful for resolving HER2 status in breast cancers with equivocal results by both immunohistochemistry (IHC) and in situ hybridization (ISH). We compared two reflex ISH assays and a polymerase chain reaction (PCR) assay for this application. Methods: Twenty-nine breast cancers with equivocal IHC and ISH results were retested two ways: (1) ISH using differentially labeled probes targeting ERBB2 ( HER2 , 17q12) and either RAI1 (17p11.2) or ORC4 (2q22.3-2q23.1) in two separate assays and (2) real-time quantitative PCR amplification of ERBB2 and a control locus ( EIF5B , 2q11.2). Results: Results of the HER2 / RAI1 and HER2 / ORC4 ISH assays were concordant for 21 (72%) cases, and results of all three secondary reflex assays were concordant for only 18 (62%) cases. Result discrepancies between the two ISH readers were observed for cases close to the cutoff threshold. Conclusions: Use of different control loci for ISH is associated with discordant results, and PCR is more likely to classify cases as nonamplified, possibly due to contamination with nontumor cells. While resolution of HER2 -equivocal results is desirable from a clinical perspective, different secondary reflex assays yield different results, and the correlation of these results with clinical outcomes is unknown. PMID- 27773873 TI - Performance Characteristics of the Reverse Syphilis Screening Algorithm in a Population With a Moderately High Prevalence of Syphilis. AB - Objectives: With the recent introduction of automated treponemal tests, a new reverse syphilis algorithm has been proposed and now used by many clinical laboratories. We analyzed the impact of instituting the reverse screening syphilis algorithm in a laboratory that serves a geographic area with a moderately high prevalence of syphilis infection. Methods: Serum samples sent for syphilis testing were tested using a treponemal enzyme immunoassay (EIA) as the screening assay. EIA reactive samples were tested by rapid plasma reagin (RPR) and titered to end point if reactive. RPR nonreactive samples were analyzed by the Treponema pallidum particle agglutination test (TP-PA). Pertinent medical records were reviewed for false-reactive screens and samples with evidence of past syphilis infection. Results: Among 10,060 patients tested, 502 (5%) were reactive on the initial EIA screen. The RPR was reactive in 150 (1.5%). TP-PA testing determined that 103 (1.0%) were falsely reactive on initial EIA screen. The reverse screening algorithm, however, identified 242 (2.4%) with evidence of latent, secondary, or past syphilis, 21 of whom had no or unknown prior treatment with antibiotics. Conclusions: Despite a 1.0% false-reactive rate, the reverse syphilis algorithm detected 21 patients with possible latent syphilis that may have gone undetected by traditional syphilis screening. PMID- 27773874 TI - Is there a difference in physical activity levels in patients before and up to one year after unilateral total hip replacement? A systematic review and meta analysis. AB - OBJECTIVE: To determine the difference in physical activity levels before and up to one year after unilateral primary total hip replacement. DATA SOURCES: A search was performed on 13 July 2016. Studies were eligible for inclusion if they presented preoperative and up to one year postoperative measures of physical activity for patients who had undergone unilateral primary total hip replacement. REVIEW METHODS: Any article that used a measure of physical activity pre and up to one year post-unilateral primary total hip replacement. Data was synthesised using a meta-analysis with 95% confidence intervals (CI), if appropriate. The Critical Appraisal Skills Programme cohort study checklist was used to assess the quality of evidence. RESULTS: From 6024 citations, 17 studies were selected: Nine studies were analysed in a meta-analysis and eight studies were analysed qualitatively. The quality of the evidence was 'low' to 'moderate'. There was no statistically significant difference in physical activity pre- to post-total hip replacement when assessed using: movement-related activity (mean difference (MD): -0.08; 95% CI: 1.60, 1.44; I2 = 0%; n = 77), percentage of 24-hours spent walking (MD: -0.21; 95% CI: -1.36, 0.93; I2 = 12%; n = 65), 6-minute walk test (MD: 60.85; 95% CI: -122.41, 0.72; I2 = 84%; n = 113) or the cardiopulmonary exercise test (MD: -0.24; 95% CI: -1.36, 0.87; I2 = 0%; n = 76). CONCLUSION: There is no statistically significant difference in physical activity levels before and up to one year after unilateral primary total hip replacement. However, the low to moderate methodological quality of the included articles should be taken into consideration when drawing conclusions. PMID- 27773875 TI - Density and Egg Parasitism of Stink Bugs (Hemiptera: Pentatomidae) in Elderberry and Dispersal Into Crops. AB - Chinavia hilaris (Say), Euschistus servus (Say), Euschistus tristigmus (Say), and Thyanta custator custator (F.) (Hemiptera: Pentatomidae) are serious pests of crops in the southeastern United States but little is known concerning their dispersal from noncrop hosts in woodlands into crops. This 2-yr study was conducted to investigate whether elderberry [Sambucus nigra subsp. canadensis (L.) R. Bolli] in woodlands serves as a source of stink bugs dispersing into adjacent crops and to examine parasitism of C. hilaris and E. servus eggs on this plant. Elderberry was a reproductive host for each of the four stink bug species; females oviposited on plants with subsequent nymphs feeding on elderberry and developing into adults. Anastatus mirabilis (Walsh & Riley) (Hymenoptera: Eupelmidae), Anastatus reduvii (Howard), and Trissolcus edessae Fouts (Hymenoptera: Scelionidae) were prevalent egg parasitoids of C. hilaris but A. reduvii was the prevalent parasitoid of E. servus Newly developed stink bug adults were first detected on elderberry around mid-July. Then in late July and early August, as elderberry fruit senesced and cotton bolls became available, stink bugs began dispersing from elderberry into cotton based on recapture of stink bugs on cotton that had previously been marked on elderberry. In addition, in 2015, density of C. hilaris, E. servus, and E. tristigmus was higher in cotton with elderberry than in cotton without it. Over the study, economic threshold was reached for four of seven cotton fields. Elimination of elderberry in woodlands adjacent to cotton may be a viable management tactic for control of stink bugs in cotton. PMID- 27773876 TI - The Importance of Publishing Negative Results. PMID- 27773877 TI - Erratum to: SGLT1 does compensate for SGLT2 inhibition. PMID- 27773879 TI - Ultrasound Acceleration of rt-PA Thrombolysis Depends on Acoustic Intensity. AB - Recombinant tissue-type plasminogen activator (rt-PA) is effective and widely used in the treatment of acute ischemic stroke (AIS). However, symptomatic intracranial hemorrhage (ICH), an adverse reaction of rt-PA, is known to occur depending on underlying diseases and rt-PA doses, and to occur more frequently with a greater delay from stroke onset until initiation of rt-PA. Therefore, limitations on the use of rt-PA, such as having to be started within 4.5 h of stroke onset, mean that rt-PA is only indicated in some stroke patients. However, the number of patients in whom rt-PA is indicated could increase if symptomatic ICH induced by rt-PA could be reduced. Therefore, we believe that, if the incidence of adverse reactions such as ICH could be reduced by using lower rt-PA doses together with ultrasound (US), the number of patients eligible for rt-PA treatment would increase. In other words, we hypothesized that, if thrombolysis can be accelerated by US, then recanalization rates similar to currently used doses of rt-PA can be achieved at reduced rt-PA doses. Therefore, to investigate to what extent US enhances the thrombolytic efficacy of rt-PA, the relationship between acceleration of rt-PA thrombolysis and US acoustic intensity was quantitatively evaluated in an in vitro bovine thrombus model. It was found that, within a range of US output that is noninvasive in humans, the combined use of US can increase thrombolytic activity up to 2.5 times more than with rt-PA alone. These findings suggest that US can greatly reduce the required doses of rt-PA. PMID- 27773878 TI - A genomic view of food-related and probiotic Enterococcus strains. AB - The study of enterococcal genomes has grown considerably in recent years. While special attention is paid to comparative genomic analysis among clinical relevant isolates, in this study we performed an exhaustive comparative analysis of enterococcal genomes of food origin and/or with potential to be used as probiotics. Beyond common genetic features, we especially aimed to identify those that are specific to enterococcal strains isolated from a certain food-related source as well as features present in a species-specific manner. Thus, the genome sequences of 25 Enterococcus strains, from 7 different species, were examined and compared. Their phylogenetic relationship was reconstructed based on orthologous proteins and whole genomes. Likewise, markers associated with a successful colonization (bacteriocin genes and genomic islands) and genome plasticity (phages and clustered regularly interspaced short palindromic repeats) were investigated for lifestyle specific genetic features. At the same time, a search for antibiotic resistance genes was carried out, since they are of big concern in the food industry. Finally, it was possible to locate 1617 FIGfam families as a core proteome universally present among the genera and to determine that most of the accessory genes code for hypothetical proteins, providing reasonable hints to support their functional characterization. PMID- 27773880 TI - High-calcium exposure to frog heart: a simple model representing hypercalcemia induced ECG abnormalities. AB - By simply adding a high concentration of calcium solution to the surface of the bullfrog heart, we reproduced electrocardiogram (ECG) abnormalities representing those observed in hypercalcemia, such as Osborn waves and shortening of the QT interval. The rise in extracellular calcium concentration may have activated the outward potassium currents during phase 3 of the action potential, and thus decreased its duration. In addition to the known decrease in the duration of phase 2, such changes in phase 3 were also likely to contribute to the shortening of the QT interval. The dual recordings of the action potential in cardiomyocytes and the ECG waves enabled us to demonstrate the mechanisms of ECG abnormalities induced by hypercalcemia. PMID- 27773881 TI - Pathogenic characterization of Erysipelothrix rhusiopathiae Met-203 type SpaA strains from chronic and subacute swine erysipelas in Japan. AB - To characterize the Erysipelothrix rhusiopathiae Met-203 type surface protective antigen (Spa) A strains causing swine erysipelas in Japan, the nucleotide sequence of the hypervariable region of the spaA gene was determined in 80 E. rhusiopathiae (serotype 1a) isolates collected from pigs with chronic and subacute swine erysipelas in 14 prefectures in 2008-2014. In this study, 14 (17.5%) isolates were Met-203 type SpaA strains. We confirmed the pathogenicity of a Met-203 type SpaA strain in specific-pathogen-free pigs. In this experiment, the two challenged pigs displayed arthritis, urticaria and other clinical signs, but recovered within 10 days. Our results reveal the existence of the E. rhusiopathiae Met-203 type strains that have been causing chronic erysipelas in Japan. PMID- 27773882 TI - Multifocal suppurative granuloma caused by Actinobacillus lignieresii in the peritoneum of a beef steer. AB - An imported crossbred Angus beef steer aged eight to twelve months died suddenly on the eighth day of a quarantine period in Japan. Gross examination showed the peritoneum and mesentery consisted of numerous nodules of various sizes. Histological examination revealed chronic suppurative granulomatous peritonitis with eosinophilic rosettes surrounding colonies of Gram-negative bacilli. The bacteria isolated from the nodules were confirmed to be Actinobacillus lignieresii based on the results of 16S rRNA gene sequencing and immunohistochemistry. Antibiotic sensitivity testing showed that the isolate was resistant to penicillin. Thus, a diagnosis of atypical actinobacillosis caused by A. lignieresii was made. PMID- 27773883 TI - Experimental infections using the foot-and-mouth disease virus O/JPN/2010 in animals administered a vaccine preserved for emergency use in Japan. AB - The effectiveness of a vaccine preserved for emergency use in Japan was analyzed under experimental conditions using cows and pigs in order to retrospectively evaluate the effectiveness of the emergency vaccination performed in the 2010 epidemic in Japan. Cows and pigs were administered a vaccine preserved for emergency use in Japan at 3 or 30 days before virus infection (dbv) and were subsequently infected with the foot-and-mouth disease virus (FMDV) O/JPN/2010, which was isolated in the 2010 epidemic in Japan. All animals vaccinated at 30 dbv and one of three pigs vaccinated at 3 dbv showed no vesicular lesions during the experimental period. The virus titers and viral RNA loads obtained from clinical samples were lower in the vaccinated cows than in the non-vaccinated cows. The viral excretion periods were shorter in the vaccinated cows than in the non-vaccinated cows. In contrast, in the vaccinated pigs, the virus titers and viral RNA loads obtained from the samples, except for those obtained from sera, were not decreased significantly, and the viral excretion periods were not sufficiently shortened. These results suggest that the vaccine can protect against clinical signs of infection by the FMDV O/JPN/2010 in animals; however, it should be noted that in vaccinated and infected animals, especially pigs, clinical samples, such as saliva and nasal swabs, may contain excreted viruses, even if no clinical signs were exhibited. PMID- 27773884 TI - Efficient mutagenesis by CRISPR/Cas system during meiotic maturation of porcine oocytes. AB - Genome editing using the CRISPR/Cas system can induce mutations with high efficiency, and allows easier production of genome-modified animals than that offered by the conventional method where embryonic stem cells are used. However, studies using CRISPR/Cas systems have been mostly limited to proliferating somatic cells and pronuclear-stage fertilized eggs. In contrast, the efficiency of a CRISPR/Cas system in immature and maturing oocytes progressing through meiosis has not yet been assessed. In the present study, we evaluated the genome modification efficiency of the CRISPR/Cas system during meiotic maturation of porcine oocytes. Additionally, the localization of the Cas9 protein in immature oocytes was analyzed in relation to nuclear transport and mutation induction. The results showed that CRISPR/Cas induced mutation with high efficiency even in maturing oocytes with condensed chromosomes, whereas mutations were not induced in GV-stage oocytes. The localization analysis of enhanced green fluorescent protein (EGFP)-tagged Cas9 (Cas9-EGFP) revealed that the nuclei contained lesser Cas9 than the cytoplasm in immature oocytes. Treatment with leptomycin B, a nuclear export inhibitor, increased the amount of nuclear Cas9 and enabled mutation induction in GV oocytes. Our results suggest that CRISPR/Cas systems can be applied to oocytes during meiotic maturation and be implemented in novel applications targeting female genomes. PMID- 27773885 TI - Involvement of DNA methylation in regulating rat Prop1 gene expression during pituitary organogenesis. AB - PROP1 is a pituitary specific transcription factor that plays a crucial role in pituitary organogenesis. The Prop1 shows varied expression patterns that promptly emerge and then fade during the early embryonic period. However, the regulatory mechanisms governing Prop1 expression remain unclear. Here, we investigated whether Prop1 was under epigenetic regulation by DNA methylation. Bisulfite sequencing was performed on DNA obtained from the pituitary glands and livers of rats on embryonic days (E) 13.5 and E14.5, and postnatal days (P) 4 and P30. The methylation of CpG sites in seven regions from 3-kb upstream of the Prop1 transcription start site through to its second intron were examined. Certain differences in CpG-methylation levels were observed in Region-1 (-2772 b to -2355 b), Region-4 (-198 b to +286 b), Region-5 (+671 b to +990 b), and Region-6 (+1113 b to +1273 b) based on comparisons between pituitary and liver DNA on E13.5. DNA methylation in pituitary glands on E14.5, P4, and P30 was generally similar to that observed in in the pituitary gland on E13.5, whereas the anterior and intermediate lobes of the pituitary gland on P4 and P30 showed only small differences. These results indicate that Prop1 is under regulation by CpG methylation during the early period of pituitary primordium development around E13.5. PMID- 27773887 TI - Influence on sleep and burden on visiting nurses engaged in on-call service during the night. AB - OBJECTIVE: The objective of this study is to elucidate the influence on sleep and burden on visiting nurses engaged in on-call service during the night. METHODS: A questionnaire survey was conducted among 614 visiting nurses, with the contents being as follows: outline of each subject, on-call night service schedule, mental and physical burden of such on-call service, and the state of sleep. The state of sleep on days when the subject was in charge of the on-call service and on days when the subject was not in charge was compared. In addition, to analyze the burden factors of on-call service and their influence on the state of sleep, a logistic regression analysis was performed, setting the target variables as "mental burden," "physical burden," and "imperfect sleep". RESULTS: In total, 187 respondents were targeted for analysis (response rate: 30.5%). A total of 81.3% of the subjects felt mental burden when in charge of the on-call service and 69.4% felt physical burden. The sleep time was shorter and the occurrence of interrupted sleep was more frequent on days when the subject was in charge of the on-call service compared with the days when the subject was not in charge. Furthermore, the following worsened: depth of sleep, comfort of sleep, refreshed feeling, satisfaction of sleep, and difficulty in falling asleep. The logistic regression analysis revealed that mental and physical burden on nurses who received more than three calls in a month were significantly higher in comparison with those who did not [adjusted odds ratio and 95% confidence interval: 2.51 (1.05-6.00) and 2.44 (1.20-5.00), respectively]. CONCLUSIONS: We found that more nurses who received more than three calls in a month felt mental and physical burden. The state of sleep was worse on the days when the subjects were in charge of the on-call service than on the days when they were not in charge. It is necessary to properly establish clear policies for extra pay, sufficient breaks, and days off. PMID- 27773886 TI - CDKN2B Methylation and Aortic Arch Calcification in Patients with Ischemic Stroke. AB - AIM: CDKN2A/2B near chromosome 9p21 has been proposed as a potential genetic etiology for both atherosclerosis and arterial calcification. DNA methylation, which can change the expression of CDKN2A/2B, may be an underlying mechanism for this association. This study aimed to evaluate whether CDKN2A/2B methylation is related to aortic arch calcification (AAC) in patients with ischemic stroke. METHODS: DNA methylation levels of CDKN2A/2B was measured using venous blood samples in 322 patients with ischemic stroke. A total of 36 CpG sites around promoter regions of CDKN2A/2B were examined. AAC was quantified with Agatston score based on results of computed tomography angiography. RESULTS: There were 248 (77.0%) patients with and 74 (23.0%) patients without evident AAC. Compared with patients without AAC, patients with AAC had higher methylation levels of CDKN2B (5.72 vs 4.94, P<0.001). Using a generalized linear model, positive correlation between methylation levels and log-transformed calcification scores was detected at CDKN2B (beta=0.275+/-0.116, P= 0.018). CONCLUSION: Patients with higher levels of DNA methylation of CDKN2B may bear increased risk for AAC. Further studies to reveal the underlying mechanisms of this association are warranted for establishing a cause-effect relationship. PMID- 27773889 TI - Nucleic Acid Drugs and DNA-based Delivery Systems. AB - Nucleic acids are biologically active materials, and chemically modified nucleic acids are now being used in nucleic acid drugs. DNA, one of the two types of nucleic acids, can also be used as a material to construct DNA-based delivery systems, such as DNA hydrogel, for therapeutic compounds. Use of chemically modified nucleic acids would greatly increase the therapeutic potency of such DNA based delivery systems. However, attention should be paid to the differences in the physicochemical properties of natural and chemically modified nucleic acids. Another, more important concern for chemically modified nucleic acids is the high cost of their synthesis. Reducing the cost of synthesizing oligonucleotides, and especially ones with chemically modified nucleic acids, is crucial to the expanded use of both nucleic acid drugs and DNA-based delivery systems. PMID- 27773888 TI - gamma-Aminobutyric acid suppresses enhancement of hamster sperm hyperactivation by 5-hydroxytryptamine. AB - Sperm hyperactivation is regulated by hormones present in the oviduct. In hamsters, 5-hydroxytryptamine (5HT) enhances hyperactivation associated with the 5HT2 receptor and 5HT4 receptor, while 17beta-estradiol (E2) and gamma aminobutyric acid (GABA) suppress the association of the estrogen receptor and GABAA receptor, respectively. In the present study, we examined the regulatory interactions among 5HT, GABA, and E2 in the regulation of hamster sperm hyperactivation. When sperm were exposed to E2 prior to 5HT exposure, E2 did not affect 5HT-enhanced hyperactivation. In contrast, GABA partially suppressed 5HT enhanced hyperactivation when sperm were exposed to GABA prior to 5HT. GABA suppressed 5HT-enhanced hyperactivation associated with the 5HT2 receptor although it did not suppress 5HT-enhanced hyperactivation associated with the 5HT4 receptor. These results demonstrate that hamster sperm hyperactivation is regulated by an interaction between the 5HT2 receptor-mediated action of 5HT and GABA. PMID- 27773890 TI - Effect of Overweight and Obesity (Defined by Asian-Specific Cutoff Criteria) on Left Ventricular Diastolic Function and Structure in a General Korean Population. AB - BACKGROUND: Although obesity is a well-known risk factor for cardiovascular disease, the cutoff of body mass index (BMI) for elevated cardiovascular risk is still controversial in Asian. Thus, this study was conducted to investigate the functional and structural changes of the left ventricle (LV) according to the degree of obesity in a general Korean population.Methods and Results:A total of 31,334 apparently healthy Korean adults who underwent echocardiography were enrolled. The study population was stratified into 5 groups according to the degree of obesity classified by the Asian-Pacific obesity guideline. The odd ratios (ORs) with 95% confidence interval (CI) of impaired LV diastolic function, LV remodeling, and hypertrophy were compared among the 5 groups using multivariable logistic regression analysis. When the normal group was set as the reference, the adjusted ORs (95% CI) for impaired LV diastolic function showed a proportional relationship with BMI [OR; 0.86 (95% CI 0.59-1.22) in underweight, 1.81 (95% CI 1.63-2.00) in overweight, 2.75 (95% CI 2.49-3.03) in obese, and 4.34 (95% CI 3.65-5.16) in severe obese]. Adjusted ORs for LV remodeling and hypertrophy significantly increased proportional to BMI. CONCLUSIONS: Even with strict classification of obesity by the Asian-Pacific guideline, BMI of more than overweight (>=23 kg/m2) was significantly associated with impaired LV diastolic function, remodeling, and hypertrophy. (Circ J 2016; 80: 2489-2495). PMID- 27773892 TI - The significance of low levels of LINC RP1130-1 expression in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common neoplasms. Little progress has been made in the diagnosis and treatment of HCC and its prognosis remains poor. Studies have increasingly found that long non-coding RNA (lncRNA) is involved in the regulation of the occurrence and development of HCC. To investigate the diagnostic and prognostic value of lncRNA in HCC, the current study examined 25 lncRNAs with differing levels of expression (according to the fold change) in microarray databases. Expression of LINC RP1130-1 was found to be markedly down regulated in 51 HCC tissues compared to matching adjacent non-tumor liver tissues. The pattern of expression and clinical significance of LINC RP1130-1 were examined in HCC. The area under the receiver operating characteristic (ROC) curve was 0.74 for LINC RP1130-1. The expression of LINC RP1130-1 was associated with clinical stage, the number of tumors, portal vein tumor thrombus (PVTT), and microvascular invasion (MVI). More importantly, patients with a low level of LINC RP1130-1 expression had a shorter recurrence-free survival (RFS) (n = 51, p < 0.05) than those with a high level of LINC RP1130-1 expression. Taken together, these findings indicate that a low level of LINC RP1130-1 expression in patients with HCC may be a powerful tumor biomarker, with potential clinical use in diagnosing and predicting the prognosis for patients with HCC. PMID- 27773891 TI - Ferulic acid prevents liver injury induced by Diosbulbin B and its mechanism. AB - The rhizome of Dioscorea bulbifera Linn, traditionally used to treat thyroid disease and cancer in China, is reported to induce serious liver injury during clinical practice. Diosbulbin B (DB), a diterpene lactone, has been found to be the main toxic compound in D. bulbifera. The present study aims to investigate the protection of ferulic acid (FA) against DB-induced acute liver injury and its engaged mechanism. Mice were orally administered FA (20, 40, 80 mg/kg) once daily for 6 consecutive days; and then orally given DB (250 mg/kg) on the last day. Daily FA (40, 80 mg/kg) decreased DB (250 mg/kg)-induced increase in serum levels of alanine/aspartate aminotransferase (ALT/AST) and alkaline phosphatase (ALP). Histological evaluation showed that FA (80 mg/kg) ameliorated DB-induced hepatocellular degeneration and lymphocyte infiltration. Results of terminal dUTP nick-end labeling (TUNEL) staining assay showed that FA (80 mg/kg) decreased the DB-increased number of apoptotic hepatocytes. FA (40, 80 mg/kg) reduced DB increased liver malondialdehyde (MDA) amount. FA (40, 80 mg/kg) decreased DB increased serum levels of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), and liver myeloperoxidase (MPO) activity. FA (80 mg/kg) reversed the DB-induced decrease in expression of inhibitor of kappa B (IkappaB) and the increase in nuclear translocation of the p65 subunit of nuclear factor kappa B (NFkappaBp65). Taken together, our results demonstrate that FA prevents DB-induced acute liver injury via inhibiting intrahepatic inflammation and liver apoptosis. PMID- 27773893 TI - Polyphosphate-induced matrix metalloproteinase-13 is required for osteoblast-like cell differentiation in human adipose tissue derived mesenchymal stem cells. AB - Inorganic polyphosphate [Poly(P)] induces differentiation of osteoblastic cells. In this study, matrix metalloproteinase (MMP)-13 small interfering RNA (siRNA) was transfected into human adipose tissue-derived mesenchymal stem cells (hAT MSC) to investigate whether MMP-13 activity induced by Poly(P) is associated with osteogenic differentiation. Real-time quantitative polymerase chain reaction, Western blotting, and an MMP-13 activity assay were used in this study. Poly(P) enhanced expression of mature osteoblast markers, such as osteocalcin (BGLAP) and osteopontin (SPP1), osterix (OSX), and bone sialoprotein (BSP), and increased alkaline phosphatase (ALP) activity and calcification capacity in hAT-MSCs. These cells also developed an osteogenic phenotype with increased expression of Poly(P) induced expression of MMP-13 mRNA and protein, and increased MMP-13 activity. MMP 13 siRNA potently suppressed the expression of osteogenic biomarkers BGLAP, SPP1, OSX, BSP, and ALP, and blocked osteogenic calcification. Taken together, Poly(P) induced MMP-13 regulates differentiation of osteogenic cells from hAT-MSCs. PMID- 27773895 TI - Microtensile bond strength between a UDMA fiber post and different resin cements: Effect of pre-surface treatment. AB - During a fiber post cementation, bonding failure often occurs at the junction between the fiber-post and resin-cement. Because this failure requires better characterization, we evaluated if different post surface treatment can affect the bond strength of urethane dimethacrylate (UDMA) fiber-posts with resin-cements. Three groups were created: G1: no treatment/silane; G2: ethyl alcohol (96 degrees GL)/silane; G3: 24% H2O2/silane and further divided into four subgroups: I Unicem/3MESPE; II-BisCem/Bisco; III-Panavia SA/Kuraray and IV-DuoLink/Bisco. Blocks of cured resin cements and posts placed in the center were serially cut into bar-shaped specimens and loaded into a micro tensile testing machine. ANOVA indicated no significant differences among post surface treatments (p>0.05), however, significant within the resin cements (p<0.05) and the interaction of both (p<0.05). The G3/IV showed the highest bond strength values. SEM showed that surface treatments on UDMA fiber posts presented no benefits in terms of surface roughness, thus, should not be performed. PMID- 27773896 TI - A comparative study of the susceptibility of cut and uncut enamel to erosive demineralization. AB - This study aimed to evaluate the susceptibility of cut and uncut enamel surfaces to an erosive challenge and to examine the resultant characteristics/morphological changes. Ten extracted human incisors were used for preparation of enamel samples, and samples were immersed in citric acid. After 3 (total 3 min) and 6 cycles (total 6 min) of erosive challenges, surface loss (SL) and morphological changes were measured using scanning microscopy and FIB-TEM. Ca release (CA) and surface hardness (SH) were measured using a calcium-sensitive electrode and hardness tester respectively. Mean values of all measurements were statistically analyzed by using a t-test. Uncut enamel samples had significantly lower SL and greater SH than cut enamel (p<0.01). Cut enamel samples after 3 cycles showed higher CA compared with those from uncut enamel samples (p<0.05). Cut enamel was shown to be more susceptible to acidic dissolution and deeper acid penetration than uncut enamel after erosive demineralization. PMID- 27773897 TI - Moving toward the reduction of publication/reporting biases in clinical trials using a new international standard. AB - Evidence-based medicine (EBM) is fundamental to ensuring high-quality medical care. It requires systematic reviews and meta-analyses to synthesize diverse information available from individual clinical studies. However, the literature reviewed may represent an incomplete and selective set of research findings, which could lead to publication/reporting biases and distort the true picture of research as a whole. Prospective registry of all clinical trials in the world is mandatory to reduce the biases, which have been disclosed on the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) since 2007. The Japan Primary Registries Network (JPRN) is included in the ICTRP. ClinicalTrials.gov, the U.S. clinical trial registry, reports the standardized data of registered trials and offers access to submitted outcomes online. However, the JPRN does not systematically include the outcomes. On April 14, 2015, the WHO published a new statement online on the public disclosure of clinical trial results, which requires researchers to define the timeframes of reporting main findings and key outcomes, to call for results-reporting older, but still unpublished trials, and to outline steps to improve linkages between clinical trial registry entries and their published results. The WHO's new position will facilitate global efforts to reduce publication/reporting biases in clinical trials. Japan will have to actively participate in these efforts as well. PMID- 27773894 TI - Calcium silicate-based cements and functional impacts of various constituents. AB - Calcium silicate-based cements have superior sealing ability, bioactivity, and marginal adaptation, which make them suitable for different dental treatment applications. However, they exhibit some drawbacks such as long setting time and poor handling characteristics. To overcome these limitations calcium silicates are engineered with various constituents to improve specific characteristics of the base material, and are the focus of this review. An electronic search of the PubMed, MEDLINE, and EMBASE via OVID databases using appropriate terms and keywords related to the use, application, and properties of calcium silicate based cements was conducted. Two independent reviewers obtained and analyzed the full texts of the selected articles. Although the effects of various constituents and additives to the base Portland cement-like materials have been investigated, there is no one particular ingredient that stands out as being most important. Applying nanotechnology and new synthesis methods for powders most positively affected the cement properties. PMID- 27773898 TI - Use of focus group interviews with public health nurses to identify the efforts of and challenges faced by branches of the Japan Health Insurance Association to achieve good performance of the Specific Health Guidance initiatives. AB - Objectives Aiming at improvement of the Japan Health Insurance Association's Specific Health Guidance initiatives and human resource development, we conducted a qualitative study to clarify the features necessary for and the challenges hindering the achievement of good performance of the initiatives.Methods From November 2014 to January 2015, we conducted 10 focus group interviews, each 90 minutes long, with 64 public health nurses from 10 Japan Health Insurance Association branches. In addition, self-administered questionnaires were administered to obtain the participants' basic characteristics. After we excluded one group for failing to meet our performance targets, we divided the remaining nine focus groups according to two patterns: Maintenance and Progress. The four focus groups fitting the Maintenance pattern had a well-established track record, and the five focus groups fitting the Progress pattern had a track record of good growth. Using open coding of the interview transcripts, we extracted efforts or needs in two domains, individual and branch, Then, we placed codes in eight main categories: [quality], [general practice], [dietary guidance practice], [success factor], [branch system], [training and skill development], [approach to the member office], and [past efforts]. We further extracted important subcategories based on their rates of appearance within branches.Results Data from 56 female public health nurses working at nine branches were included in the analysis. With respect to the individual domain, subcategories such as "building rapport," "creating the physical environment," and "taking the initiative in evaluating one's own lifestyle" in the segment of the [general practice] category were common to both patterns. In addition, "increasing opportunities for training" and "enhancement of training program content" were found for both patterns in relation to the segment of the [training and skill development] category. However, most participants chose "yes" in response to whether there was ample training opportunity.Conclusion This study showed some common efforts and practices among public health nurses in both patterns, which indicates good performance of the Specific Health Guidance initiatives. However, there is a need to further enhance the training program to strengthen the entire organization. Future studies should focus on understanding the characteristics of and factors involved in low-performing branches. PMID- 27773899 TI - Analysis of community support for patients who have been tried in accordance with the Medical Treatment and Supervision Act (MTSA). PMID- 27773900 TI - Exploring factors related to adoption and continuation of a family peer-education program on mental disorders in psychiatric hospitals: A case study. PMID- 27773901 TI - A case of bacterial meningitis caused by methicillin-resistant Staphylococcus lugdunensis after surgery. AB - An 51-year-old man had undergone surgery for Rathke's cleft cyst by transsphenoidal approach on October 2015. After the surgery, cerebrospinal fluid (CSF) rhinorrhea arose. Surgical treatment of CSF rhinorrhea was performed by the same approach. Ten days after reoperation, he suffered from severe headache, high fever, and nuchal rigidity. CSF findings indicated bacterial meningitis. CSF culture showed methicillin-resistant Staphylococcus lugdunensis. He received vancomycin intravenously for 19 days and recovered from the bacterial meningitis with no serious complication. PMID- 27773902 TI - Posterior reversible encephalopathy syndrome in Parkinson disease probably caused by prominent supine hypertension and blood pressure fluctuation. AB - We present the case of a 77-year-old man with a 10-year history of Parkinson disease (PD), who developed posterior reversible encephalopathy syndrome (PRES). We diagnosed the case as PRES based on clinical features and MRI findings. He experienced orthostatic hypotension and supine hypertension, including nocturnal hypertension. PRES may result from marked supine/nocturnal hypertension and fluctuation in blood pressure. In addition, exacerbated factors could be representative of neuroleptic malignant syndrome. The hypertensive effect of istradefylline should also not be excluded. We believe this is the first case report of a patient with PD developing PRES without vasopressor use. PMID- 27773903 TI - Efficacy of potassium bromide in the treatment of drug-resistant epilepsy: a case of new-onset refractory status epilepticus. AB - A 40-year-old man presented with a series of generalized tonic-clonic seizures after febrile illness. He developed status epilepticus and required mechanical ventilation with anesthetics. Steroid pulse, intravenous immunoglobulin, and immunoadsorption therapy were administrated, and the status epilepticus improved; however, drug-resistant seizures remained. Despite the use of several antiepileptic drugs, seizures frequently occurred. Additional administration of potassium bromide resulted in significant suppression of seizures. Potassium bromide is regarded as an effective medication for pediatric refractory epilepsy after encephalitis. The present case is considered to be new-onset refractory status epilepticus (NORSE) syndrome based on clinical features, and potassium bromide could be effective in treating adult refractory epilepsy, such as NORSE syndrome. PMID- 27773904 TI - Frontal cortical dysfunction in Parkinson's disease (PD): Comparison of memory based smooth-pursuit and anti-saccade tasks, and neuropsychological and motor symptom evaluations. AB - We reported recently that during a memory-based smooth-pursuit task, most Parkinson's disease (PD) patients exhibited normal cue-information memory but impaired smooth-pursuit preparation and execution. A minority of PD patients had abnormal cue-information memory or difficulty in understanding the task. To further examine differences between these two groups, we assigned an anti-saccade task and compared correct rates with various neuropsychological and motor symptom evaluations. The anti-saccade task requires voluntary saccades in the opposite direction to a visual stimulus, and patients with frontal cortical impairments are known to exhibit reflexive saccades (errors). We classified PD patients into 2 groups: one with normal cue-information memory during memory-based smooth pursuit (n = 14), and the other with abnormal cue-information memory or with difficulty in understanding the memory task (n = 6). The two groups had significantly different anti-saccade correct rates and frontal assessment battery (FAB) scores (P < 0.01). Anti-saccade correct rates of individual patients (n = 20) correlated significantly with FAB scores (P < 0.01) but not with age, Hoehn Yahr stage, unified PD rating scale (UPDRS) part III or mini-mental state examination (MMSE) scores. Among FAB subtests, significant correlation was obtained only with motor programming scores. These results suggest that performance of memory-based smooth-pursuit and/or anti-saccades depend on frontal cortical function or dysfunction. PMID- 27773906 TI - Lateral geniculate body presenting only hemorrhage homonymous hemianopia-A case report. AB - We report a case of a 55-year-old man who developed acute-onset narrowing of his visual field. He showed right homonymous hemianopsia without any other neurological symptoms and signs. Brain CT and MRI showed localized hemorrhage (about 1.6 ml) in the left lateral geniculate body (LGB). A cerebral angiography showed no vascular anomalies of cerebral vessels, and the left anterior choroidal artery and left lateral posterior choroidal artery could be visualized well. He had hypertension, polycythemia and dyslipidemia and was a habitual smoker and an alcoholic. In the literature, various kinds of visual field defects including hemianopsia, upper quadrant hemianopsia, lower quadrant hemianopsia, and horizontal sectoranopia have been reported in eight cases of LGB hemorrhage. Localized LGB hemorrhage was found in only one case out of 2,763 cerebral hemorrhage patients enrolled in our stroke registry for 11 years from 2005 to 2016. Localized hemorrhage of LGB very rarely occurred. PMID- 27773905 TI - A case of relapsing encephalitis positive for gamma aminobutyric acid (GABA)A receptor antibody associated with Type B3 thymoma. AB - A 87-year-old female presented with subacute progression of cognitive decline. Fluid-attenuated inversion recovery images of brain MRI showed multifocal high intensity lesions. Thoracic CT image revealed the presence of thymoma, and serum autoantibody screening showed positivity for anti-gamma aminobutyric acid (GABA)A receptor antibody. Histopathological analysis confirmed type B3 thymoma after thymectomy. The patient received both plasmapheresis and intravenous methylprednisolone therapy, and showed remarkable amelioration of clinical symptoms and MRI abnormal high intensity. However, after 2 month from the clinical recovery, the patient showed recurrence of brain lesions and intravenous methylprednisolone monotherapy was performed. Continuation of oral steroid therapy was required to maintain the quienscent state of inflammation within the central nervous system. Anti-GABAA receptor antibody is a recently discovered novel autoantibody associated with autoimmue encephalitis. Due to the limited number of literature reported, clinical course and therapeutic response of GABAA receptor antibody encephalitis remains elusive. Here we reported a rare case of GABAA receptor antibody encephalitis with type B3 thymoma. Clinical, radiological and therapeutic courses described in our report highlight the importance of immunotherapy for treatment of the disease. PMID- 27773907 TI - Subacute cerebellar ataxia with amphiphysin antibody developing in a patient with follicular thyroid adenoma: a case report. AB - The patient was a 61-year-old woman with thyroid enlargement since her 20s. She began to fall down repeatedly towards the end of June 2015. She was admitted to our hospital in the middle of August because of difficulty in walking. Upon admission, she presented with neck tremor and was unable to maintain a sitting position due to ataxia of the trunk and limbs. We studied serum anti-neuronal antibodies and obtained a positive result for anti-amphiphysin antibody (AMPH Ab). Cerebrospinal fluid analysis revealed elevated protein levels and IgG index. Other than the thyroid mass, a tumor was not detected. The resected thyroid specimen showed follicular adenoma. After performing immunotherapies, the cerebrospinal fluid protein levels and IgG index decreased, and her ataxia did not progress. When subacute cerebellar ataxia is suspected, studying AMPH-Ab should be considered. PMID- 27773908 TI - Herpes simplex virus type 2-associated recurrent aseptic meningitis (Mollaret's meningitis) with a recurrence after 11-year interval: a case report. AB - A 55-year-old woman was diagnosed with aseptic meningitis at the age of 43 and 44. She developed sudden fever and headache, and she showed nuchal rigidity. Cerebrospinal fluid examination revealed pleocytosis (cell count 208/mm3) and was positive for herpes simplex virus type 2 (HSV-2) DNA by PCR. Acyclovir was started on the first day of admission, and she was complete recovery. Preserved cerebrospinal fluid specimen from aseptic meningitis at the age of 44 was also positive for HSV-2 DNA by PCR. She was diagnosed with HSV-2 associated recurrent aseptic meningitis (Mollaret's meningitis) with a recurrence after 11-year interval. She repeatedly relapsed genital herpes after 44 years old and she was treated with valacyclovir whenever genital herpes relapses. But she showed no genital herpes at the onset of meningitis. Because HSV-2 is one of the most significant causes of recurrent meningitis, we would like to stress that HSV-2 infection and antiviral therapy should always be kept in mind for a recurrent meningitis case. PMID- 27773910 TI - Team-Based Learning, a Learning Strategy for Clinical Reasoning, in Students with Problem-Based Learning Tutorial Experiences. PMID- 27773909 TI - Blunted Autonomic Responses and Low-Grade Inflammation in Mongolian Adults Born at Low Birth Weight. AB - Low birth weight (LBW) has been considered as a risk factor for adult hypertension that is associated with deterioration of autonomic functions and low grade inflammation. To explore the above effects of LBW, we measured blood pressure (BP) and heart rate variability during postural change from a supine position to a sitting position in 21 healthy Mongolian adults aged 23-34 years: 4 with LBW (birth weight < 2,500 g), 13 with normal birth weight (NBW, 2,500 g <= birth weight < 4,000 g), and 4 with high birth weight (HBW, >= 4,000 g). Mongolian population is known to have higher prevalence of hypertension. The ratio of low frequency (LF, 0.04-0.15 Hz) to high frequency components (HF, 0.15 0.40 Hz) was used as an index of sympathetic nerve activity, and HF was used as an index of parasympathetic nerve activity. In contrast to the NBW group, the LBW and HBW groups showed no significant increase in heart rate, systolic BP and LF/HF following postural change. We also measured blood cell counts and other blood parameters related to inflammation. After adjusting for age, BMI, sex and family history of hypertension, LBW was retained as an independent predictor only for higher counts of leukocytes (beta = -0.51, p < 0.05), basophils (beta = 0.62, p < 0.01), eosinophils (beta = -0.83, p < 0.001), and platelets (beta = 0.61, p < 0.05). We propose that LBW leads to blunted autonomic responses and low grade inflammation in seemingly healthy Mongolian adults. PMID- 27773911 TI - Predictors of Depression in Patients Diagnosed with Myocardial Infarction after Undergoing Percutaneous Coronary Intervention: A literature review. AB - AIM: This study identified the factors associated with depression in patients diagnosed with myocardial infarction (MI) who underwent percutaneous coronary intervention (PCI). METHODS: We searched the literature using PubMed and CINAHL from their inception in 1946 to December 2014. The search terms were "myocardial infarction," "depression," and "percutaneous coronary intervention." Studies which investigated factors associated with depression in patients diagnosed with MI who underwent typical medical procedures were searched. RESULTS: Eleven studies met our inclusion criteria. None of these limited their samples to patients with MI who underwent PCI. Twenty-one factors were identified as possible risk factors for depression in patients who were diagnosed with MI and underwent PCI: gender; negative illness beliefs; neuroticism; autonomy; baseline depression scores; previous diagnosis of depression, anxiety, or stress; smoking; marital status; Type D personality; procedure; length of hospital stay; fat intake; functional disability; time engaged in physical activity; social support; and a history of angina, MI, coronary artery bypass graft surgery, PCI, diabetes mellitus, and stroke. CONCLUSIONS: This review suggests that these 21 factors should be considered in future studies as possible independent variables or covariates of depression among MI patients who have undergone PCI. PMID- 27773912 TI - Study on Evaluation of Alanine Aminotransferase (ALT) as Surrogate Marker in Hepatitis Virus Test. AB - Nucleic acid amplification test (NAT), which was introduced by the Japanese Red Cross Society in October 1999, began to be performed for screening of blood transfusion formulations in Japan in August 2014. In this study, the precision of immunological screenings of hepatitis B (HBsAg, HBcAb, and HBsAb), hepatitis C (HCVAb), and human immunodeficiency (HIVAb) virus antigens in donated blood were evaluated. In addition, the sensitivity of the alanine aminotransferase (ALT) test for detection of the hepatitis B and C viruses was re-evaluated. Immunological screenings showed high precision of detecting the viral antigens. In contrast, the ALT test showed much lower precision of detecting the presence of the hepatitis B and C viruses. Results of the NAT and immunological screenings revealed that ALT levels in donors were more strongly correlated with their levels of gammaglutamyltranspeptidase (gammaGTP) and body mass index (BMI), than with the results of NAT and immunological screening. Our study indicates that elevated level(s) of ALT, were more likely to be associated with lifestyles factors such as high intake of alcohol or obesity than with infection. Therefore, ALT may be excluded as surrogate markers of HBV, HCV, and HIV in donated blood. PMID- 27773913 TI - Identification of frequency, severity and risk factors of complications after open gastrectomy: Retrospective analysis of prospectively collected database using the Clavien-Dindo classification. AB - Introduction The purpose of this study was to identify the frequency, severity, and risk factors of complications after open gastrectomy using the Clavien- Dindo classification because institution-specific criteria were mostly used in the previous articles. Materials and Methods All complication data were obtained from our prospectively collected database of open gastrectomy from January 1999 to December 2012 (n=539). Complications were classified into either major surgical complications such as pancreatic fistula, abdominal abscess, and anastomotic leakage, or others. Frequency and severity were graded retrospectively according to the Clavien- Dindo classification for subsequent analysis of risk factors. Results There were 222 events occurred in 156 patients (28.9%). Complications of grade IIIa or greater were 8.3% for major surgical complications and 10.6% for all complications. The mortality rate was 1.1%. Blood loss was the only independent risk factor for major surgical complications of grade IIIa or greater (odds ratio 1.923, 95% Confidence Interval 0.320-0.786, p=0.003). Total gastrectomy was the only independent risk factor for all complications of grade IIIa or greater (Odds ratio 2.075, 95% Confidence Interval 0.260-0.896, p=0.021). Disscussion The present study provided the objective overview regarding complications after open gastrectomy. Blood loss and total gastrectomy were revealed as the significant risk factors for complications. PMID- 27773914 TI - Diet-Dependent Modular Dynamic Interactions of the Equine Cecal Microbiota. AB - Knowledge on dynamic interactions in microbiota is pivotal for understanding the role of bacteria in the gut. We herein present comprehensive dynamic models of the horse cecal microbiota, which include short-chained fatty acids, carbohydrate metabolic networks, and taxonomy. Dynamic models were derived from time-series data in a crossover experiment in which four cecum-cannulated horses were fed a starch-rich diet of hay supplemented with barley (starch intake 2 g kg-1 body weight per day) and a fiber-rich diet of only hay. Cecal contents were sampled via the cannula each h for 24 h for both diets. We observed marked differences in the microbial dynamic interaction patterns for Fibrobacter succinogenes, Lachnospiraceae, Streptococcus, Treponema, Anaerostipes, and Anaerovibrio between the two diet groups. Fluctuations and microbiota interactions were the most pronounced for the starch rich diet, with Streptococcus spp. and Anaerovibrio spp. showing the largest fluctuations. Shotgun metagenome sequencing revealed that diet differences may be explained by modular switches in metabolic cross feeding between microbial consortia in which fermentation is linked to sugar alcohols and amino sugars for the starch-rich diet and monosaccharides for the fiber-rich diet. In conclusion, diet may not only affect the composition of the cecal microbiota, but also dynamic interactions and metabolic cross-feeding. PMID- 27773915 TI - Occurrence of penta-amines, hexa-amines and N-methylated polyamines in unicellular eukaryotic organisms belonging to the phyla Heterokontophyta and Labyrinthulomycota of the subdomain Stramenopiles. PMID- 27773917 TI - High-cell-density cultivation of Nitrosomonas europaea in a membrane bioreactor for performing protein purification and characterization studies. PMID- 27773916 TI - Acetyltransferase activity in Pseudomonas sp. capable of acetylating the C-4 hydroxyl group of nivalenol-type trichothecenes. PMID- 27773918 TI - Ion-specific Effect on Oil-in-water Emulsion Gels Containing a Stimuli-responsive Fibrous Assembly of Amidoamine-derivative Hydrogelator. AB - Amidoamine derivative C18AA forms a highly viscous oil-in-water (O/W) emulsion, called an "emulsion gel." Previously, it was showed that the viscosity sensitively changes with the C18AA concentration, temperature, pH changes, and salt addition. In this work, C18AA concentration in the continuous aqueous phase ([C18AA]w) was investigated at different compositions, and it was found that a threshold concentration value of 16.5 wt% was required to obtain a highly viscous emulsion gel below 45 degrees C. C18AA formed micellar networks in the aqueous phase, and stimuli or additives increase the value of [C18AA]w, so that the C18AA micellar network could grow in the continuous aqueous phase. PMID- 27773919 TI - High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report. AB - BACKGROUND In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. CASE REPORT We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7-15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment. CONCLUSIONS This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment. PMID- 27773921 TI - Genetic variation: Diving deep into the genome. PMID- 27773920 TI - Evaluation of Early Atherosclerosis Markers in Patients with Inflammatory Bowel Disease. AB - BACKGROUND The aim of this study was to investigate relationships between early atherosclerosis and inflammatory bowel disease (IBD) using laboratory, functional, and morphological markers of atherosclerosis. MATERIAL AND METHODS In the present prospective single-center study, 96 patients with IBD (58 patients with ulcerative colitis and 36 patients with Crohn's disease) and 65 healthy control subjects were included. The demographic data of each patient and control subject were recorded. The patients with IBD and healthy controls were compared in terms of the carotid intima-media thickness (CIMT), the values of flow mediated dilatation (FMD) and nitroglycerine-mediated dilatation (NMD), and the levels of von Willebrand factor antigen (VWF-Ag), D-dimer, and lipoprotein (a). RESULTS There were no significant differences between the IBD patients and controls in terms of age, sex, BMI, systolic and diastolic BPs, serum levels of total cholesterol, low-density lipoprotein, or triglycerides. IBD patients had significantly higher levels of VWF-Ag (156.6+/-58.9 vs. 104.2+/-43.3, P<0.001) and D-dimer (337.2+/-710.8 vs. 175.9+/-110.9, P<0.001) as compared to the controls. No significant differences were determined between the 2 groups in terms of FMD and NMD values. Although statistically not significant, the CIMT values were higher in the IBD patients than in the controls (0.517+/-0.141 mm vs. 0.467+/-0.099 mm, P=0.073). In the correlation analysis, the CIMT was found to be correlated negatively with FMD and positively with high sensitive C-reactive protein, VWF-Ag, and D-dimer. CONCLUSIONS These findings suggest that VWF-Ag and D-dimer can be beneficial early atherosclerosis markers in IBD patients. PMID- 27773923 TI - Technique: See and seq the regulome. PMID- 27773924 TI - Bacterial toxins: A true competitor. PMID- 27773925 TI - Complete mutational spectrum of the autophagy interactome: a novel class of tumor suppressor genes in myeloid neoplasms. PMID- 27773926 TI - Do hematopoietic stem cells get old? PMID- 27773922 TI - The state of play in higher eukaryote gene annotation. AB - A genome sequence is worthless if it cannot be deciphered; therefore, efforts to describe - or 'annotate' - genes began as soon as DNA sequences became available. Whereas early work focused on individual protein-coding genes, the modern genomic ocean is a complex maelstrom of alternative splicing, non-coding transcription and pseudogenes. Scientists - from clinicians to evolutionary biologists - need to navigate these waters, and this has led to the design of high-throughput, computationally driven annotation projects. The catalogues that are being produced are key resources for genome exploration, especially as they become integrated with expression, epigenomic and variation data sets. Their creation, however, remains challenging. PMID- 27773927 TI - MZH29 is a novel potent inhibitor that overcomes drug resistance FLT3 mutations in acute myeloid leukemia. AB - More than one-third of patients with acute myeloid leukemia (AML) harbor aberrant mutations in Fms-like tyrosine kinase 3 (FLT3). Among them, the internal tandem duplication (ITD) mutation predicts poor prognosis. MZH29 is a novel FLT3 inhibitor synthesized in our laboratory that showed that cellular and kinase assays sustained inhibitory effects on wild-type and mutant FLT3, including the FLT3-ITD, FLT3-D835H/Y/V and FLT3-K663Q mutants. More importantly, MZH29 retained its potent inhibitory effect against the FLT3-ITD/F691L mutation, a drug resistance mutation against the well-known FLT3 inhibitor, AC220. MZH29 is a type II FLT3 inhibitor that tolerated the F691L mutation in molecular docking studies. Oral administration of 10 mg/kg MZH29 caused complete tumor regression and extended survival in a mouse model of AML with less toxicity. Subsequent proteomics study revealed less proteome perturbation in the MZH29-treated group than in the AC220-treated group. MZH29 demonstrates potential and potent novel FLT3 inhibitory effects for the treatment of AML. PMID- 27773928 TI - E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. PMID- 27773930 TI - Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial. PMID- 27773929 TI - A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. AB - RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ?4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ?65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ?4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 * 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC transfusion-independence response rates in persons with MPN-associated RBC transfusion dependence. PMID- 27773932 TI - NPM-ALK expression levels identify two distinct subtypes of paediatric anaplastic large cell lymphoma. PMID- 27773934 TI - Fibromyalgia: Optic nerve damaged in patients with fibromyalgia. PMID- 27773931 TI - The LIN28B/let-7 axis is a novel therapeutic pathway in multiple myeloma. AB - MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well. PMID- 27773933 TI - Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. AB - Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53 independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells. PMID- 27773935 TI - Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation. AB - Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from the traditional Chinese medicine rhizoma alismatis, which exhibits a number of pharmacological activities, including anti-hepatitis virus, anti-cancer and antibacterial effects. In this study we examined whether AB23A protected against non-alcoholic steatohepatitis (NASH) in mice, and the mechanisms underlying the protective effects. NASH was induced in mice fed a methionine and choline deficient (MCD) diet for 4 weeks. The mice were simultaneously treated with AB23A (15, 30, and 60 mg.kg-1.d-1, ig) for 4 weeks. On the last day, blood samples and livers were collected. Serum liver functional enzymes, inflammatoru markers were assessed. The livers were histologically examined using H&E, Oil Red O, Masson's trichrome and Sirius Red staining. Mouse primary hepatocytes were used for in vitro experiments. The mechanisms underlying AB23A protection were analyzed using siRNA, qRT-PCR, and Western blot assays. AB23A treatment significantly and dose dependently decreased the elevated levels of serum ALT and AST in MCD diet-fed mice. Furthermore, AB23A treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration and hepatic fibrosis in the mice. AB23A-induced decreases in serum and hepatic lipids were related to decreased hepatic lipogenesis through decreasing hepatic levels of SREBP-1c, FAS, ACC1 and SCD1 and increased lipid metabolism via inducing PPARalpha, CPT1alpha, ACADS and LPL. The reduction in inflammatory cell infiltration corresponded to deceased serum levels of mKC and MCP-1 and decreased hepatic gene expression of MCP-1 and VCAM-1. The reduction in hepatic fibrosis was correlated with decreased hepatic gene expression of fibrosis markers. The protective effects of AB23A were FXR dependent, because treatment with the FXR agonist CDCA mimicked AB23A-induced hepato-protection in the mice, whereas co-administration of FXR antagonist guggulsterone abrogated AB23A-induced hepato-protection. In mouse primary hepatocytes, FXR gene silencing abrogated AB23A-induced changes in gene expression of Apo C-II, CPT1alpha, ACADS and LPL. AB23A produces protective effects against NASH in mice via FXR activation. PMID- 27773937 TI - Effect of phentermine on weight reduction in a pediatric weight management clinic. AB - Phentermine is the most widely prescribed obesity medication in adults, yet studies of its use in the pediatric population are limited. We conducted a retrospective chart review of adolescents with obesity treated in a pediatric weight management clinic to examine the weight loss effectiveness of phentermine added to standard of care (SOC) lifestyle modification therapy versus SOC alone. All patients receiving phentermine plus SOC (n=25) were matched with a comparison group receiving only SOC (n=274). Differences at 1, 3 and 6 months were evaluated using generalized estimated equations adjusting for age, sex and baseline body mass index (BMI) and robust variance standard error estimates for confidence intervals and P-values. Phentermine use was associated with a greater percent change in BMI at 1 month (-1.6%; 95% confidence interval (CI): -2.6, -0.6%; P=0.001), 3 months (-2.9%; 95% CI: -4.5, -1.4%; P<0.001) and 6 months (-4.1%; 95% CI: -7.1, -1.0%; P=0.009) compared with SOC alone, with no differences in systolic or diastolic blood pressure between groups. Heart rate was higher at all time-points in the phentermine plus SOC compared with SOC-only group. These data suggest that short-term use of phentermine added to SOC may enhance weight loss in adolescents with obesity in the clinical setting. PMID- 27773936 TI - A novel matrine derivate inhibits differentiated human hepatoma cells and hepatic cancer stem-like cells by suppressing PI3K/AKT signaling pathways. AB - Matrine is an alkaloid extracted from a Chinese herb Sophora flavescens Ait, which has shown chemopreventive potential against various cancers. In this study, we evaluated the anticancer efficacy of a novel derivative of matrine, (6aS, 10S, 11aR, 11bR, 11cS)-10- methylamino-dodecahydro- 3a,7a-diazabenzo (de) (MASM), against human hepatocellular carcinoma (HCC) cells and their corresponding sphere cells in vitro and in vivo. Human HCC cell lines (Hep3B and Huh7) were treated with MASM. Cell proliferation was assessed using CCK8 and colony assays; cell apoptosis and cell cycle distributions were examined with flow cytometry. The expression of cell markers and signaling molecules was detected using Western blot and qRT-PCR analyses. A sphere culture technique was used to enrich cancer stem cells (CSC) in Hep3B and Huh7 cells. The in vivo antitumor efficacy of MASM was evaluated in Huh7 cell xenograft model in BALB/c nude mice, which were administered MASM (10 mg.kg-1.d-1, ig) for 3 weeks. After the treatment was completed, tumor were excised and weighed. A portion of tumor tissue was enzymatically dissociated to obtain a single cell suspension for the spheroid formation assays. MASM (2, 10, 20 MUmol/L) dose-dependently inhibited the proliferation of HCC cells, and induced apoptosis, which correlated with a reduction in Bcl-2 expression and an increase in PARP cleavage. MASM also induced cell cycle arrest in G0/G1 phase, which was accompanied by increased p27 and decreased Cyclin D1 expression. Interestingly, MASM (2, 10, and 20 MUmol/L) drastically reduced the EpCAM+/CD133+ cell numbers, suppressed the sphere formation, inhibited the expression of stem cell marker genes and promoted the expression of mature hepatocyte markers in the Hep3B and Huh7 spheroids. Additionally, MASM dose-dependently suppressed the PI3K/AKT/mTOR and AKT/GSK3beta/beta-catenin signaling pathways in Hep3B and Huh7 cells. In Huh7 xenograft bearing nude mice, MASM administration significantly inhibited Huh7 xenograft tumor growth and markedly reduced the number of surviving cancer stem like cells in the tumors. MASM administration also reduced the expression of stem cell markers while increasing the expression of mature hepatocyte markers in the tumor tissues. The novel derivative of matrine, MASM, markedly suppresses HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the treatment of hepatocellular carcinoma. PMID- 27773940 TI - Phylogenetic classifications are informative, stable, and pragmatic: the case for monophyletic taxa. PMID- 27773938 TI - High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-alpha on appetite-regulating NPY neurons. AB - BACKGROUND: Consumption of dietary fat is one of the key factors leading to obesity. High-fat diet (HFD)-induced obesity is characterized by induction of inflammation in the hypothalamus; however, the temporal regulation of proinflammatory markers and their impact on hypothalamic appetite-regulating neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons remains undefined. METHODS: Mice were injected with an acute lipid infusion for 24 h or fed a HFD over 8-20 weeks. Characterized mouse NPY/AgRP hypothalamic cell lines were used for in vitro experimentation. Immunohistochemistry in brain slices or quantitative real-time PCR in cell lines, was performed to determine changes in the expression of key inflammatory markers and neuropeptides. RESULTS: Hypothalamic inflammation, indicated by tumor necrosis factor (TNF)-alpha expression and astrocytosis in the arcuate nucleus, was evident following acute lipid infusion. HFD for 8 weeks suppressed TNF-alpha, while significantly increasing heat-shock protein 70 and ciliary neurotrophic factor, both neuroprotective components. HFD for 20 weeks induced TNF-alpha expression in NPY/AgRP neurons, suggesting a detrimental temporal regulatory mechanism. Using NPY/AgRP hypothalamic cell lines, we found that palmitate provoked a mixed inflammatory response on a panel of inflammatory and endoplasmic reticulum (ER) stress genes, whereas TNF-alpha significantly upregulated IkappaBalpha, nuclear factor (NF)-kappaB and interleukin-6 mRNA levels. Palmitate and TNF-alpha exposure predominantly induced NPY mRNA levels. Utilizing an I kappa B kinase beta (IKKbeta) inhibitor, we demonstrated that these effects potentially occur via the inflammatory IKKbeta/NF-kappaB pathway. CONCLUSIONS: These findings indicate that acute lipid and chronic HFD feeding in vivo, as well as acute palmitate and TNF-alpha exposure in vitro, induce markers of inflammation or ER stress in the hypothalamic appetite-stimulating NPY/AgRP neurons over time, which may contribute to a dramatic alteration in NPY/AgRP content or expression. Acute and chronic HFD feeding in vivo temporally regulates arcuate TNF-alpha expression with reactive astrocytosis, which suggests a time-dependent neurotrophic or neurotoxic role of lipids. PMID- 27773939 TI - An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort. AB - BACKGROUND/OBJECTIVES: The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study. SUBJECTS/METHODS: The Sister Study is a cohort of 50 884 US women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with BMI, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450 K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing. RESULTS: Four CpG sites reached genome-wide significance (false discovery rate (FDR) q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and five were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 and CRHR2 have been linked to obesity and obesity-related chronic diseases. CONCLUSIONS: Our findings support the hypothesis that obesity related epigenetic differences are detectable in blood and may be related to risk of chronic disease. PMID- 27773941 TI - Discriminatory abilities of facultative slave-making ants and their slaves. AB - Intra-colony odor variability can disturb ants' ability to discriminate against intruders. The evolutionary relevance of this phenomenon can be revealed by studies on colonies of slave-making ants in which the parasite, and not the host, is subject to selection pressures associated with living in a mixed colony. We examined how the European facultative slave-making species Formica sanguinea and its F. fusca slaves perform in discriminating ants from alien colonies. Results of behavioral assays showed that slave-maker ants respond with hostility to conspecific individuals from alien colonies but are relatively tolerant to alien slaves. Furthermore, the behavior of slaves indicated a limited ability to discriminate ants from alien parasitic colonies. The subdivision of colony fragments into mixed and species-separated groups demonstrated that contact with the parasite is necessary for F. fusca slaves to be re-accepted by former nestmates after a period of separation from the stock colony. The results presented in this paper are consistent with the following hypotheses: (1) F. sanguinea ants, as opposed to their slaves, are adapted to discriminate alien individuals in the conditions of odor variability found in a mixed-species colony, (2) the recognition of slaves by F. sanguinea ants involves a dedicated adaptive mechanism that prevents aggression toward them, (3) the odor of slaves is strongly influenced by the parasite with beneficial effect on the colony integrity. PMID- 27773942 TI - Environmental DNA (eDNA) detects the invasive rusty crayfish Orconectes rusticus at low abundances. AB - Early detection is invaluable for the cost-effective control and eradication of invasive species, yet many traditional sampling techniques are ineffective at the low population abundances found at the onset of the invasion process. Environmental DNA (eDNA) is a promising and sensitive tool for early detection of some invasive species, but its efficacy has not yet been evaluated for many taxonomic groups and habitat types.We evaluated the ability of eDNA to detect the invasive rusty crayfish Orconectes rusticus and to reflect patterns of its relative abundance, in upper Midwest, USA, inland lakes. We paired conventional baited trapping as a measure of crayfish relative abundance with water samples for eDNA, which were analysed in the laboratory with a qPCR assay. We modelled detection probability for O. rusticus eDNA using relative abundance and site characteristics as covariates and also tested the relationship between eDNA copy number and O. rusticus relative abundance.We detected O. rusticus eDNA in all lakes where this species was collected by trapping, down to low relative abundances, as well as in two lakes where trap catch was zero. Detection probability of O. rusticus eDNA was well predicted by relative abundance of this species and lake water clarity. However, there was poor correspondence between eDNA copy number and O. rusticus relative abundance estimated by trap catches. Synthesis and applications. Our study demonstrates a field and laboratory protocol for eDNA monitoring of crayfish invasions, with results of statistical models that provide guidance of sampling effort and detection probabilities for researchers in other regions and systems. We propose eDNA be included as a tool in surveillance for invasive or imperilled crayfishes and other benthic arthropods. PMID- 27773943 TI - Do Young Mothers and Fathers Differ in the Likelihood of Returning Home? AB - Building on research examining "boomerang" adult children, I examine multigenerational living among young parents. Returning home likely differs between young mothers and fathers given variation in socioeconomic characteristics, health and risk-taking, their own children's coresidence, and union stability. Using the National Longitudinal Survey of Youth 1997 (NLSY97), I find that more than 40% of young parents (N = 2,721) live with their own parents at first birth or subsequently. Mothers are generally less likely to move home than fathers but only when not controlling for child coresidence and union stability. Individuals who live with all their children are less likely to return home, and controlling for child coresidence reverses gender differences, though this association disappears in the full model. Young parents who are stably single and those who experience dissolution are highly likely to return home compared to the stably partnered, with the association significantly stronger for fathers than mothers. PMID- 27773944 TI - On the Linear Stability of Crystals in the Schrodinger-Poisson Model. AB - We consider the Schrodinger-Poisson-Newton equations for crystals with one ion per cell. We linearize this dynamics at the periodic minimizers of energy per cell and introduce a novel class of the ion charge densities that ensures the stability of the linearized dynamics. Our main result is the energy positivity for the Bloch generators of the linearized dynamics under a Wiener-type condition on the ion charge density. We also adopt an additional 'Jellium' condition which cancels the negative contribution caused by the electrostatic instability and provides the 'Jellium' periodic minimizers and the optimality of the lattice: the energy per cell of the periodic minimizer attains the global minimum among all possible lattices. We show that the energy positivity can fail if the Jellium condition is violated, while the Wiener condition holds. The proof of the energy positivity relies on a novel factorization of the corresponding Hamilton functional. The Bloch generators are nonselfadjoint (and even nonsymmetric) Hamilton operators. We diagonalize these generators using our theory of spectral resolution of the Hamilton operators with positive definite energy (Komech and Kopylova in, J Stat Phys 154(1-2):503-521, 2014, J Spectral Theory 5(2):331-361, 2015). The stability of the linearized crystal dynamics is established using this spectral resolution. PMID- 27773945 TI - Cross-Language Activation Begins During Speech Planning and Extends Into Second Language Speech. AB - Three groups of native English speakers named words aloud in Spanish, their second language (L2). Intermediate proficiency learners in a classroom setting (Experiment 1) and in a domestic immersion program (Experiment 2) were compared to a group of highly proficient English-Spanish speakers. All three groups named cognate words more quickly and accurately than matched noncognates, indicating that all speakers experienced cross-language activation during speech planning. However, only the classroom learners exhibited effects of cross-language activation in their articulation: Cognate words were named with shorter overall durations, but longer (more English-like) voice onset times. Inhibition of the first language during L2 speech planning appears to impact the stages of speech production at which cross-language activation patterns can be observed. PMID- 27773946 TI - The Hospital Community Benefit Program: Implications for Food and Nutrition Professionals. AB - This article briefly explains the food and nutrition implications of the new standards, tax penalties and reporting requirements for non-profit hospitals and healthcare systems to maintain a tax-exempt or charitable status under section 501(c)(3) of the Federal Internal Revenue Code set forth in The Patient Protection and Affordable Care Act (P.L. 111-148, Sec. 9007). The newly created 501(r) of the Internal Revenue Code requires, beginning with the first tax year on or after March 23, 2012, that such hospitals demonstrate community benefit by conducting a community health needs assessment (CHNA) at least once every three years and annually file information by means of a Schedule H (Form 990) regarding progress towards addressing identified needs. As hospitals conduct their CHNA and work further and collaboratively with community stakeholders on developing and monitoring their proposed action plans, the breadth and depth of food and nutrition activities occurring as a result of the Affordable Care Act Hospital Community Benefit Program will likely increase. The CHNA requirement, along with other emerging initiatives focused on improving the food environments and nutrition-related activities of hospitals and healthcare systems offer fruitful opportunities for food and nutrition professionals to partner on innovative ways to leverage hospital infrastructure and capacity to influence those residing, working or visiting the hospital campus, as well as the surrounding community. PMID- 27773947 TI - Work-Family Context and the Longevity Disadvantage of US Women. AB - Female life expectancy is currently shorter in the United States than in most high-income countries. This study examines work-family context as a potential explanation. While work-family context changed similarly across high-income countries during the past half century, the United States has not implemented institutional supports, such as universally available childcare and family leave, to help Americans contend with these changes. We compare the United States to Finland-a country with similar trends in work-family life but generous institutional supports-and test two hypotheses to explain US women's longevity disadvantage: (1) US women may be less likely than Finnish women to combine employment with childrearing; and (2) US women's longevity may benefit less than Finnish women's longevity from combining employment with childrearing. We used data from women aged 30-60 years during 1988-2006 in the US National Health Interview Survey Linked Mortality File and harmonized it with data from Finnish national registers. We found stronger support for hypothesis 1, especially among low-educated women. Contrary to hypothesis 2, combining employment and childrearing was not less beneficial for US women's longevity. In a simulation exercise, more than 75 percent of US women's longevity disadvantage was eliminated by raising their employment levels to Finnish levels and reducing mortality rates of non-married/non-employed US women to Finnish rates. PMID- 27773948 TI - Gendered Social Capital in a Johannesburg Township. AB - Social capital research rarely takes a gendered approach. This article explores how black women and men from a marginalized community in Johannesburg, South Africa, rely on family, friends, and community members to survive and strategize for the future by utilizing social capital. The results from 30 semi-structured interviews and ego network mapping illustrate that gender moderates the type of social capital used and benefits associated with bonding and bridging social capital in important ways. This research builds upon knowledge of gendered advantages and disadvantages in social networks and informs researchers how women and men survive in pervasive poverty. I posit that identifying potential sources of support is an important consideration within social capital or any network research because the prospect of receiving assistance in the future undoubtedly alters the development of these individuals' livelihood strategies. PMID- 27773949 TI - Synthesis of (2R,8' S,3' E)-delta-tocodienol, a tocoflexol family member designed to have a superior pharmacokinetic profile compared to delta-tocotrienol. AB - A group of side chain partially saturated tocotrienol analogues, namely tocoflexols, have been previously designed in an effort to improve the pharmacokinetic properties of tocotrienols. (2R,8'S,3'E,11'E)-delta-Tocodienol (1) was predicted to be a high value tocoflexol for further pharmacological evaluation. We now report here an efficient 8-step synthetic route to compound 1 utilizing naturally-occurring delta-tocotrienol as a starting material (24% total yield). The key step in the synthesis is oxidative olefin cleavage of delta tocotrienol to afford the chroman core of 1 with retention of chirality at the C 2 stereocenter. PMID- 27773950 TI - Sleep Disturbances in Posttraumatic Stress Disorder: Updated Review and Implications for Treatment. AB - Sleep disturbances are common in adults with PTSD and range from insomnia and nightmares to periodic leg movements and disruptive nocturnal behaviors. Together these findings suggest profound disturbances in rapid eye movement (REM) and non REM (NREM) sleep, although there is a lack of consensus regarding a distinct profile of objective sleep disturbances associated with PTSD. Prospective, longitudinal studies have established that sleep disturbances represent a risk factor for the development and course of PTSD, suggesting that sleep is an important neurobiological mechanism in the etiology and maintenance of this disorder. This research highlights the importance of early identification and treatment of sleep disturbances in at-risk and trauma exposed populations. A number of psychological and pharmacological treatments are effective at treating sleep disturbances in PTSD. Additional research is needed to further develop clinical guidelines informing when and how to integrate sleep-specific treatment with PTSD focused clinical care. PMID- 27773951 TI - Enhanced detection of terrestrial gamma-ray flashes by AGILE. AB - At the end of March 2015 the onboard software configuration of the Astrorivelatore Gamma a Immagini Leggero (AGILE) satellite was modified in order to disable the veto signal of the anticoincidence shield for the minicalorimeter instrument. The motivation for such a change was the understanding that the dead time induced by the anticoincidence prevented the detection of a large fraction of Terrestrial Gamma-Ray Flashes (TGFs). The configuration change was highly successful resulting in an increase of one order of magnitude in TGF detection rate. As expected, the largest fraction of the new events has short duration (<100 MUs), and part of them has simultaneous association with lightning sferics detected by the World Wide Lightning Location Network. The new configuration provides the largest TGF detection rate surface density (TGFs/km2/yr) to date, opening prospects for improved correlation studies with lightning and atmospheric parameters on short spatial and temporal scales along the equatorial region. PMID- 27773952 TI - Spatially resolved SO2 flux emissions from Mt Etna. AB - We report on a systematic record of SO2 flux emissions from individual vents of Etna volcano (Sicily), which we obtained using a permanent UV camera network. Observations were carried out in summer 2014, a period encompassing two eruptive episodes of the New South East Crater (NSEC) and a fissure-fed eruption in the upper Valle del Bove. We demonstrate that our vent-resolved SO2 flux time series allow capturing shifts in activity from one vent to another and contribute to our understanding of Etna's shallow plumbing system structure. We find that the fissure eruption contributed ~50,000 t of SO2 or ~30% of the SO2 emitted by the volcano during the 5 July to 10 August eruptive interval. Activity from this eruptive vent gradually vanished on 10 August, marking a switch of degassing toward the NSEC. Onset of degassing at the NSEC was a precursory to explosive paroxysmal activity on 11-15 August. PMID- 27773953 TI - Small global effect on terrestrial net primary production due to increased fossil fuel aerosol emissions from East Asia since the turn of the century. AB - The global terrestrial carbon sink has increased since the start of this century at a time of growing carbon emissions from fossil fuel burning. Here we test the hypothesis that increases in atmospheric aerosols from fossil fuel burning enhanced the diffuse light fraction and the efficiency of plant carbon uptake. Using a combination of models, we estimate that at global scale changes in light regimes from fossil fuel aerosol emissions had only a small negative effect on the increase in terrestrial net primary production over the period 1998-2010. Hereby, the substantial increases in fossil fuel aerosol emissions and plant carbon uptake over East Asia were effectively canceled by opposing trends across Europe and North America. This suggests that if the recent increase in the land carbon sink would be causally linked to fossil fuel emissions, it is unlikely via the effect of aerosols but due to other factors such as nitrogen deposition or nitrogen-carbon interactions. PMID- 27773954 TI - Abrupt Bolling warming and ice saddle collapse contributions to the Meltwater Pulse 1a rapid sea level rise. AB - Elucidating the source(s) of Meltwater Pulse 1a, the largest rapid sea level rise caused by ice melt (14-18 m in less than 340 years, 14,600 years ago), is important for understanding mechanisms of rapid ice melt and the links with abrupt climate change. Here we quantify how much and by what mechanisms the North American ice sheet could have contributed to Meltwater Pulse 1a, by driving an ice sheet model with two transient climate simulations of the last 21,000 years. Ice sheet perturbed physics ensembles were run to account for model uncertainties, constraining ice extent and volume with reconstructions of 21,000 years ago to present. We determine that the North American ice sheet produced 3-4 m global mean sea level rise in 340 years due to the abrupt Bolling warming, but this response is amplified to 5-6 m when it triggers the ice sheet saddle collapse. PMID- 27773955 TI - The role of prominence in determining the scope of boundary-related lengthening in Greek. AB - This study aims at examining and accounting for the scope of the temporal effect of phrase boundaries. Previous research has indicated that there is an interaction between boundary-related lengthening and prominence such that the former extends towards the nearby prominent syllable. However, it is unclear whether this interaction is due to lexical stress and/or phrasal prominence (marked by pitch accent) and how far towards the prominent syllable the effect extends. Here, we use an electromagnetic articulography (EMA) study of Greek to examine the scope of boundary-related lengthening as a function of lexical stress and pitch accent separately. Boundaries are elicited by the means of a variety of syntactic constructions.. The results show an effect of lexical stress. Phrase final lengthening affects the articulatory gestures of the phrase-final syllable that are immediately adjacent to the boundary in words with final stress, but is initiated earlier within phrase-final words with non-final stress. Similarly, the articulatory configurations during inter-phrasal pauses reach their point of achievement later in words with final stress than in words with non-final stress. These effects of stress hold regardless of whether the phrase-final word is accented or de-accented. Phrase-initial lengthening, on the other hand, is consistently detected on the phrase-initial constriction, independently of where the stress is within the preceding, phrase-final, word. These results indicate that the lexical aspect of prominence plays a role in determining the scope of boundary-related lengthening in Greek. Based on these results, a gestural account of prosodic boundaries in Greek is proposed in which lexical and phrasal prosody interact in a systematic and coordinated fashion. The cross-linguistic dimensions of this account and its implications for prosodic structure are discussed. PMID- 27773956 TI - A multiple imputation approach to the analysis of clustered interval-censored failure time data with the additive hazards model. AB - Clustered interval-censored failure time data can occur when the failure time of interest is collected from several clusters and known only within certain time intervals. Regression analysis of clustered interval-censored failure time data is discussed assuming that the data arise from the semiparametric additive hazards model. A multiple imputation approach is proposed for inference. A major advantage of the approach is its simplicity because it avoids estimating the correlation within clusters by implementing a resampling-based method. The presented approach can be easily implemented by using the existing software packages for right-censored failure time data. Extensive simulation studies are conducted, indicating that the proposed imputation approach performs well for practical situations. The proposed approach also performs well compared to the existing methods and can be more conveniently applied to various types of data representation. The proposed methodology is further demonstrated by applying it to a lymphatic filariasis study. PMID- 27773957 TI - Addiction Vulnerability and Binge Eating in Women: Exploring Reward Sensitivity, Affect Regulation, Impulsivity & Weight/Shape Concerns. AB - Almost 40% of individuals with eating disorders have a comorbid addiction. The current study examined weight/shape concerns as a potential moderator of the relation between the hypothesized latent factor "addiction vulnerability" (i.e., impairments in reward sensitivity, affect regulation and impulsivity) and binge eating. Undergraduate women (n=272) with either high or low weight/shape concerns completed self-report measures examining reward sensitivity, emotion regulation, impulsivity and disordered (binge) eating. Results showed that (1) reward sensitivity, affect regulation and impulsivity all loaded onto a latent "addiction vulnerability" factor for both women with high and with low weight/shape concerns, (2) women with higher weight/shape concerns reported more impairment in these areas, and (3) weight/shape concerns moderated the relation between addiction vulnerability and binge eating. These findings suggest that underlying processes identified in addiction are present in individuals who binge eat, though weight/shape concerns may be a unique characteristic of disordered eating. PMID- 27773958 TI - Measurement of oxygen transfer from air into organic solvents. AB - BACKGROUND: The use of non-aqueous organic media is becoming increasingly important in many biotechnological applications in order to achieve process intensification. Such media can be used, for example, to directly extract poorly water-soluble toxic products from fermentations. Likewise many biological reactions require the supply of oxygen, most normally from air. However, reliable online measurements of oxygen concentration in organic solvents (and hence oxygen transfer rates from air to the solvent) has to date proven impossible due to limitations in the current analytical methods. RESULTS: For the first time, online oxygen measurements in non-aqueous media using a novel optical sensor are demonstrated. The sensor was used to measure oxygen concentration in various organic solvents including toluene, THF, isooctane, DMF, heptane and hexane (which have all been shown suitable for several biological applications). Subsequently, the oxygen transfer rates from air into these organic solvents were measured. CONCLUSION: The measurement of oxygen transfer rates from air into organic solvents using the dynamic method was established using the solvent resistant optical sensor. The feasibility of online oxygen measurements in organic solvents has also been demonstrated, paving the way for new opportunities in process control. (c) 2015 The Authors. Journal of Chemical Technology & Biotechnology published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 27773959 TI - An adaptive grid for graph-based segmentation in retinal OCT. AB - Graph-based methods for retinal layer segmentation have proven to be popular due to their efficiency and accuracy. These methods build a graph with nodes at each voxel location and use edges connecting nodes to encode the hard constraints of each layer's thickness and smoothness. In this work, we explore deforming the regular voxel grid to allow adjacent vertices in the graph to more closely follow the natural curvature of the retina. This deformed grid is constructed by fixing node locations based on a regression model of each layer's thickness relative to the overall retina thickness, thus we generate a subject specific grid. Graph vertices are not at voxel locations, which allows for control over the resolution that the graph represents. By incorporating soft constraints between adjacent nodes, segmentation on this grid will favor smoothly varying surfaces consistent with the shape of the retina. Our final segmentation method then follows our previous work. Boundary probabilities are estimated using a random forest classifier followed by an optimal graph search algorithm on the new adaptive grid to produce a final segmentation. Our method is shown to produce a more consistent segmentation with an overall accuracy of 3.38 MUm across all boundaries. PMID- 27773960 TI - Effects of Spatial Resolution on Image Registration. AB - This paper presents a theoretical analysis of the effect of spatial resolution on image registration. Based on the assumption of additive Gaussian noise on the images, the mean and variance of the distribution of the sum of squared differences (SSD) were estimated. Using these estimates, we evaluate a distance between the SSD distributions of aligned images and non-aligned images. The experimental results show that by matching the resolutions of the moving and fixed images one can get a better image registration result. The results agree with our theoretical analysis of SSD, but also suggest that it may be valid for mutual information as well. PMID- 27773961 TI - KIF2A Overexpression and Its Association with Clinicopathologic Characteristics and Poor Prognoses in Patients with Gastric Cancer. AB - Kinesin family protein 2A (KIF2A), an M-type nonmotile microtubule depolymerase, has attracted attention for its role in carcinogenesis and poor prognoses in various human cancers. In this study, we aimed to evaluate the expression of KIF2A and its robustness and potential to predict clinical outcomes in gastric cancer (GC) patients. The messenger RNA (mRNA) expression of KIF2A was determined in 24 pairs of cancerous and adjacent nontumor tissues by real-time polymerase chain reaction. Immunohistochemistry of KIF2A was performed on a tissue microarray composed of 461 GC and 65 matched adjacent nontumor tissues removed during surgeries and 18 chronic gastritis, 15 intestinal metaplasia, and 37 low grade and 62 high-grade intraepithelial neoplasias acquired through gastric endoscopic biopsies. Univariate and multivariate Cox regression models were used to perform survival analyses. The high KIF2A expression was significantly correlated to histological type, TNM stage, and lymph node metastasis. A negative correlation was found between KIF2A expression and the 5-year survival rate of GC patients. In addition, multivariate analysis indicated that KIF2A is an independent prognostic factor in GC. This study demonstrated the high KIF2A expression might serve as an independent marker for poor prognoses in GC patients. PMID- 27773963 TI - U.S. Civil Air Show Crashes, 1993 to 2013: Burden, Fatal Risk Factors, and Evaluation of a Risk Index for Aviation Crashes. AB - This study provides new public health data about U.S. civil air shows. Risk factors for fatalities in civil air show crashes were analyzed. The value of the FIA score in predicting fatal outcomes was evaluated. With the use of the FAA's General Aviation and Air Taxi Survey and the National Transportation Safety Board's data, the incidence of civil air show crashes from 1993 to 2013 was calculated. Fatality risk factors for crashes were analyzed by means of regression methods. The FIA index was validated to predict fatal outcomes by using the factors of fire, instrument conditions, and away-from-airport location, and was evaluated through receiver operating characteristic (ROC) curves. The civil air show crash rate was 31 crashes per 1,000 civil air events. Of the 174 civil air show crashes that occurred during the study period, 91 (52%) involved at least one fatality; on average, 1.1 people died per fatal crash. Fatalities were associated with four major risk factors: fire [adjusted odds ratio (AOR) = 7.1, 95% confidence interval (CI) = 2.4 to 20.6, P < .001], pilot error (AOR = 5.2, 95% CI = 1.8 to 14.5, P = .002), aerobatic flight (AOR = 3.6, 95% CI = 1.6 to 8.2, P = .002), and off-airport location (AOR = 3.4, 95% CI = 1.5 to 7.5, P = .003). The area under the FIA score's ROC curve was 0.71 (95% CI = 0.64 to 0.78). Civil air show crashes were marked by a high risk of fatal outcomes to pilots in aerobatic performances but rare mass casualties. The FIA score was not a valid measurement of fatal risk in civil air show crashes. PMID- 27773962 TI - Is GERD a Factor in Osteonecrosis of the Jaw? Evidence of Pathology Linked to G6PD Deficiency and Sulfomucins. AB - Osteonecrosis of the jaw (ONJ), a rare side effect of bisphosphonate therapy, is a debilitating disorder with a poorly understood etiology. FDA's Adverse Event Reporting System (FAERS) provides the opportunity to investigate this disease. Our goals were to analyze FAERS data to discover possible relationships between ONJ and specific conditions and drugs and then to consult the scientific literature to deduce biological explanations. Our methodology revealed a very strong association between gastroesophageal reflux and bisphosphonate-induced ONJ, suggesting acidosis as a key factor. Overgrowth of acidophilic species, particularly Streptococcus mutans, in the oral microbiome in the context of insufficient acid buffering due to impaired salivary glands maintains the low pH that sustains damage to the mucosa. Significant associations between ONJ and adrenal insufficiency, vitamin C deficiency, and Sjogren's syndrome were found. Glucose 6 phosphate dehydrogenase (G6PD) deficiency can explain much of the pathology. An inability to maintain vitamin C and other antioxidants in the reduced form leads to vascular oxidative damage and impaired adrenal function. Thus, pathogen-induced acidosis, hypoxia, and insufficient antioxidant defenses together induce ONJ. G6PD deficiency and adrenal insufficiency are underlying factors. Impaired supply of adrenal-derived sulfated sterols such as DHEA sulfate may drive the disease process. PMID- 27773964 TI - Technology-assisted Interventions for Parents of Young Children: Emerging Practices, Current Research, and Future Directions. AB - Technology can potentially expand the reach and cut the costs of providing effective, evidence-based interventions. This paper reviews existing publications that describe the application and evaluation of technology-assisted interventions for parents of young children. A broad review of the early childhood literature revealed 48 studies describing technology-assisted parent education and interventions. Across these studies, multiple forms of technology were used, including web-based platforms, discussion forums, mobile devices, and video conferencing. Results are described moving from feasibility and acceptability of technology-based delivery systems to more rigorous evaluations examining their impact on parent and child outcomes. Potential exists for technology to deliver interventions to parents. Limitations are discussed including differential acceptability and elevated attrition associated with internet-only intervention delivery. PMID- 27773965 TI - Developmental Foundations of Children's Fraction Magnitude Knowledge. AB - The conceptual insight that fractions represent magnitudes is a critical yet daunting step in children's mathematical development, and the knowledge of fraction magnitudes influences children's later mathematics learning including algebra. In this study, longitudinal data were analyzed to identify the mathematical knowledge and domain-general competencies that predicted 8th and 9th graders' (n=122) knowledge of fraction magnitudes and its cross-grade gains. Performance on the fraction magnitude measures predicted 9th grade algebra achievement. Understanding and fluently identifying the numerator-denominator relation in 7th grade emerged as the key predictor of later fraction magnitudes knowledge in both 8th and 9th grades. Competence at using fraction procedures, knowledge of whole number magnitudes, and the central executive contributed to 9th but not 8th graders' fraction magnitude knowledge, and knowledge of whole number magnitude contributed to cross-grade gains. The key results suggest fluent processing of numerator-denominator relations presages students' understanding of fractions as magnitudes and that the integration of whole number and fraction magnitudes occurs gradually. PMID- 27773966 TI - The place and role of (moral) anger in organizational behavior studies. AB - The aim of this article is to conceptually delineate moral anger from other related constructs. Drawing upon social functional accounts of anger, we contend that distilling the finer nuances of morally motivated anger and its expression can increase the precision with which we examine prosocial forms of anger (e.g., redressing injustice), in general, and moral anger, in particular. Without this differentiation, we assert that (i) moral anger remains theoretically elusive, (ii) that this thwarts our ability to methodologically capture the unique variance moral anger can explain in important work outcomes, and that (iii) this can promote ill-informed organizational policies and practice. We offer a four factor definition of moral anger and demonstrate the utility of this characterization as a distinct construct with application for workplace phenomena such as, but not limited to, whistle-blowing. Next, we outline a future research agenda, including how to operationalize the construct and address issues of construct, discriminant, and convergent validity. Finally, we argue for greater appreciation of anger's prosocial functions and concomitant understanding that many anger displays can be justified and lack harmful intent. If allowed and addressed with interest and concern, these emotional displays can lead to improved organizational practice. PMID- 27773968 TI - The relationship between national culture and safety culture: Implications for international safety culture assessments. AB - : In this article, we examine the relationship between safety culture and national culture, and the implications of this relationship for international safety culture assessments. Focussing on Hofstede's uncertainty avoidance (UA) index, a survey study of 13,616 Air Traffic Management employees in 21 European countries found a negative association between safety culture and national norm data for UA. This is theorized to reflect the influence of national tendencies for UA upon attitudes and practices for managing safety (e.g., anxiety on risk; reliance on protocols; concerns over reporting incidents; openness to different perspectives). The relationship between UA and safety culture is likely to have implications for international safety culture assessments. Specifically, benchmarking exercises will consistently indicate safety management within organizations in high UA countries to be poorer than low UA countries due to the influence of national culture upon safety practices, which may limit opportunities for identifying and sharing best practice. We propose the use of safety culture against international group norms (SIGN) scores to statistically adjust for the influence of UA upon safety culture data, and to support the identification of safety practices effective and particular to low or high UA cultures. PRACTITIONER POINTS: National cultural tendencies for uncertainty avoidance (UA) are negatively associated with safety culture.This indicates that employee safety-related attitudes and practices may be influenced by national culture, and thus factors outside the direct control of organizational management.International safety culture assessments should attempt to determine the influence of national culture upon safety culture in order that benchmarking exercises compare aspects of safety management and not national culture.Safety culture against international group norms (SIGN) scores provide a potential way to do this, and can facilitate the identification of best practice within countries operating in a low or high UA cultural cluster. PMID- 27773969 TI - Beyond Cumulative Risk: A Dimensional Approach to Childhood Adversity. AB - Children who have experienced environmental adversity-such as abuse, neglect, or poverty-are more likely to develop physical and mental health problems, perform poorly at school, and have difficulties in social relationships than children who have not encountered adversity. What is less clear is how and why adverse early experiences exert such a profound influence on children's development. Identifying developmental processes that are disrupted by adverse early environments is the key to developing better intervention strategies for children who have experienced adversity. Yet, much existing research relies on a cumulative risk approach that is unlikely to reveal these mechanisms. This approach tallies the number of distinct adversities experienced to create a risk score. This risk score fails to distinguish between distinct types of environmental experience, implicitly assuming that very different experiences influence development through the same underlying mechanisms. We advance an alternative model. This novel approach conceptualizes adversity along distinct dimensions, emphasizes the central role of learning mechanisms, and distinguishes between different forms of adversity that might influence learning in distinct ways. A key advantage of this approach is that learning mechanisms provide clear targets for interventions aimed at preventing negative developmental outcomes in children who have experienced adversity. PMID- 27773970 TI - A quasi-Monte-Carlo comparison of parametric and semiparametric regression methods for heavy-tailed and non-normal data: an application to healthcare costs. AB - We conduct a quasi-Monte-Carlo comparison of the recent developments in parametric and semiparametric regression methods for healthcare costs, both against each other and against standard practice. The population of English National Health Service hospital in-patient episodes for the financial year 2007 2008 (summed for each patient) is randomly divided into two equally sized subpopulations to form an estimation set and a validation set. Evaluating out-of sample using the validation set, a conditional density approximation estimator shows considerable promise in forecasting conditional means, performing best for accuracy of forecasting and among the best four for bias and goodness of fit. The best performing model for bias is linear regression with square-root-transformed dependent variables, whereas a generalized linear model with square-root link function and Poisson distribution performs best in terms of goodness of fit. Commonly used models utilizing a log-link are shown to perform badly relative to other models considered in our comparison. PMID- 27773967 TI - Ultrasonic Transducer-Guided Electrochemical Impedance Spectroscopy to Assess Lipid-Laden Plaques. AB - Plaque rupture causes acute coronary syndromes and stroke. Intraplaque oxidized low density lipoprotein (oxLDL) is metabolically unstable and prone to induce rupture. We designed an intravascular ultrasound (IVUS)-guided electrochemical impedance spectroscopy (EIS) sensor to enhance the detection reproducibility of oxLDL-laden plaques. The flexible 2-point micro-electrode array for EIS was affixed to an inflatable balloon anchored onto a co-axial double layer catheter (outer diameter = 2 mm). The mechanically scanning-driven IVUS transducer (45 MHz) was deployed through the inner catheter (diameter = 1.3 mm) to the acoustic impedance matched-imaging window. Water filled the inner catheter to match acoustic impedance and air was pumped between the inner and outer catheters to inflate the balloon. The integrated EIS and IVUS sensor was deployed into the ex vivo aortas dissected from the fat-fed New Zealand White (NZW) rabbits (n=3 for fat-fed, n= 5 normal diet). IVUS imaging was able to guide the 2-point electrode to align with the plaque for EIS measurement upon balloon inflation. IVUS-guided EIS signal demonstrated reduced variability and increased reproducibility (p < 0.0001 for magnitude, p < 0.05 for phase at < 15 kHz) as compared to EIS sensor alone (p < 0.07 for impedance, p < 0.4 for phase at < 15 kHz). Thus, we enhanced topographic and EIS detection of oxLDL-laden plaques via a catheter-based integrated sensor design to enhance clinical assessment for unstable plaque. PMID- 27773971 TI - Integrated modelling of age and sex patterns of European migration. AB - Age and sex patterns of migration are essential for understanding drivers of population change and heterogeneity of migrant groups. We develop a hierarchical Bayesian model to estimate such patterns for international migration in the European Union and European Free Trade Association from 2002 to 2008, which was a period of time when the number of members expanded from 19 to 31 countries. Our model corrects for the inadequacies and inconsistencies in the available data and estimates the missing patterns. The posterior distributions of the age and sex profiles are then combined with a matrix of origin-destination flows, resulting in a synthetic database with measures of uncertainty for migration flows and other model parameters. PMID- 27773972 TI - The stability of ethnic identity in England and Wales 2001-2011. AB - The instability of ethnicity measured in the national census is found to have doubled from the period 1991-2001 to the period 2001-2011, using the Longitudinal Study that links a sample of individuals' census records across time. From internal evidence and comparison with results from the Census Quality Survey and the Labour Force Survey, estimates are made of instability due to changing question wording, imputation of missing answers, proxy reporting, recording errors and changes in the allocation of write-in answers. Of the remaining instability, durable changes of ethnicity by individuals are thought to be considerably less common than changes due to a person's sense of identity not closely fitting the categories offered in the census question. The instability creates a net change in size of some ethnic groups that is usually small compared with the change in population between censuses from births, deaths and migration. Consequences for analysis of census aggregate and microdata are explored. PMID- 27773973 TI - Associations of Neighborhood Safety and Neighborhood Support with Overweight and Obesity in US Children and Adolescents. AB - OBJECTIVES: To examine the association of neighborhood safety and support with overweight and obesity and whether these associations vary with age, sex, and race/ethnicity among children and adolescents. DESIGN: Cross-sectional. SETTING: United States. MAIN OUTCOME MEASURES: Childhood overweight and obesity. METHODS: We used data from the 2011-12 National Survey of Children's Health, a representative sample of US children and adolescents, for the analyses (N=40,730). Using the age-sex adjusted growth chart, parent self-reported weight and height data were used to classify participants as overweight (those with body mass index [BMI] percentile [%] at or above the 85th%) and obese (those with BMI% at or above the 95th%). We used log-binomial regression to quantify the association of neighborhood safety and support with overweight and obesity among children and adolescents before and after adjusting for selected characteristics including physical activity and amount of time spent in sedentary activities. RESULTS: Children and adolescents living in non-supportive neighborhoods had a 21% (95%CI: 1.10-1.33) higher probability of being obese than their peers living in supportive neighborhoods after controlling for age, sex, race/ethnicity, parent's education, poverty, asthma, physical activity and sedentary activities. Similarly, the probabilities of obesity associated with neighborhood safety and support were 1.30 (95%CI:1.08-156) and 1.18 (95%CI:1.01-1.38), respectively. However, these probabilities vary with race/ethnicity with higher probability being observed among non-Hispanic Whites and Hispanics for overweight and non Hispanic Whites for obesity. CONCLUSIONS: Living in unsafe and non-supportive neighborhoods may be associated with overweight and obesity among US children and adolescents. Longitudinal studies, accounting for race/ethnicity, are needed to examine the importance of social context where children and adolescents live. PMID- 27773974 TI - PPARG-LYPLAL1 Multi-Allelic Combination Associated with Obesity and Overweight in Mexican Adolescent Females. AB - OBJECTIVE: We studied multi-loci variants to identify the contribution of six candidate genes (ADIPOQ, CDH13, LYPLAL1, MC4R, PPARG and PGC1A) in the development of obesity and overweight. DESIGN: We genotyped 404 chromosomes with eleven SNPs in Mexican female adolescents, who were subdivided into two groups (obesity-overweight and normal-weight) using the World Health Organization parameters. Genomic (800 chromosomes) and ancestral (208 chromosomes) controls were included to reduce the population bias. Anthropometric measurements, biochemical parameters, and caloric intake were obtained only in the groups of Mexican female adolescents. RESULTS: A positive genotype-phenotype association was found that involves the multi-allelic combination of three risk alleles (one in PPARG and two in LYPLAL1) with obesity and overweight (OR=3.1, P=.010). This combination also exhibited a significant association with waist circumference (P=.030) and triglycerides levels (P=.030). These associations were supported by a logistic regression analysis adjusted for several confounding variables. CONCLUSIONS: Our data suggest the joint participation of PPARG-LYPLAL1 genes in metabolic disorders development. Hence, these genes could act as potential biomarkers in obesity and overweight. Our findings underscore the complexity of metabolic disorders and provide evidence about the importance of multi-loci analysis to study complex diseases. PMID- 27773975 TI - The Association of Body Fat and Leisure Time Physical Activity Called into Question for Asian Indians. AB - OBJECTIVE: Thrifty genotypes may predispose to type 2 diabetes and body fat (%BF) excess through a differentiated relationship between physical activity and body fat. We explored this hypothesis in Asian Indians, a population thought to be thrifty. METHODS: Three hundred and nine Guadeloupian adolescents responded to the modifiable activity questionnaire. Their body fat was assessed by bioimpedancemetry. We first studied the relationship between %BF and leisure time physical activity (LTPA). We then explored the associations of ethnicity with this relationship in a subgroup of 93 Asian Indians matched with 93 controls for age, sex, and LTPA class. The alpha risk retained was .05. RESULTS: The analyses showed that Asian Indians had higher %BF even when matched with controls for age, sex and LTPA quartile, and the relationship between LTPA and %BF observed in controls was not evidenced in Asian Indians. CONCLUSIONS: The higher %BF in Asian Indians remained significant even when they were matched with controls for age, sex and LTPA quartile, and their LTPA was not associated - or was at least less robustly associated - with %BF. These findings are consistent with the hypothesis of thriftiness in Asian Indians, with the weaker relationship of high LTPA and low %BF a possible path to thriftiness. PMID- 27773976 TI - Association between Race, Household Income and Grip Strength in Middle- and Older Aged Adults. AB - BACKGROUND: Poor grip strength is an indicator of frailty and a precursor to functional limitations. Although poor grip strength is more prevalent in older disabled African American women, little is known about the association between race and poverty-related disparities and grip strength in middle-aged men and women. METHODS: We examined the cross-sectional relationship between race, socioeconomic status as assessed by household income, and hand grip strength in men and women in the Healthy Aging in Neighborhoods of Diversity across the Life Span study. General linear models examined grip strength (maximum of two trials on both sides) by race and household income adjusted for age, weight, height, hand pain, education, insurance status, family income, and two or more chronic conditions. RESULTS: Of 2,091 adults, 422(45.4%) were male, 509(54.8%) were African American, and 320 (34.5%) were living in households with incomes below 125% of the federal poverty level (low SES). In adjusted models, African American women had greater grip strength than White women independent of SES (low income household: 29.3 vs 26.9 kg and high income household: 30.5 vs. 28.3kg; P<.05 for both); whereas in men, only African Americans in the high income household group had better grip strength than Whites (46.3 vs. 43.2; P<.05). CONCLUSIONS: The relationship between grip strength, race and SES as assessed by household income varied in this cohort. Efforts to develop grip strength norms and cut points that indicate frailty and sarcopenia may need to be race- and income-specific. PMID- 27773977 TI - Dimensions of Racial Identity and Perceived Discrimination in Health Care. AB - OBJECTIVE: Perceived discrimination is an important risk factor for minority health. Drawing from the scholarship on multidimensionality of race, this study examines the relationships between perceived discrimination in health care and two dimensions of racial identity: self-identified race/ethnicity and perceived attributed race/ethnicity (respondents' perceptions of how they are racially classified by others). METHODS: We used Behavioral Risk Factor Surveillance System data collected in 2004-2013 and we specifically examined the data on perceived racial discrimination in health care during the past 12 months, perceived attributed race/ethnicity, and self-identified race/ethnicity. RESULTS: In models adjusting for sociodemographic and other factors, both dimensions of racial/ethnic identity contributed independently to perceived discrimination in health care. After controlling for self-identified race/ethnicity, respondents who reported being classified as Black, Asian, Hispanic, and Native American had higher likelihood of perceived discrimination than respondents who reported being classified as White. Similarly, after taking perceived attributed race/ethnicity into account, self-identified Blacks, Native Americans, and multiracial respondents were more likely to report perceived discrimination than counterparts who self-identified as White. The model using only perceived attributed race/ethnicity to predict perceived discrimination showed a superior fit with the data than the model using only self-identified race/ethnicity. CONCLUSION: Perceived attributed race/ethnicity captures an aspect of racial/ethnic identity that is correlated, but not interchangeable, with self-identified race/ethnicity and contributes uniquely to perceived discrimination in health care. Applying the concept of multidimensionality of race/ethnicity to health disparities research may reveal understudied mechanisms linking race/ethnicity to health risks. PMID- 27773978 TI - Insulin Resistance and Inflammation in Black Women with and without Breast Cancer: Cause for Concern. AB - OBJECTIVE: After chemotherapy for breast cancer, Black women gain more weight and have an increased mortality rate compared with White women. Our study objective was to compare biomarkers associated with obesity in Black women with and without a history of breast cancer. DESIGN: Case-control. SETTING: Academic/federal institution. PARTICIPANTS: Black women with a history of breast cancer (cases) and age-matched controls. MAIN OUTCOME MEASURES: Insulin resistance (HOMA-IR); inflammation (TNF-alpha, IL-1b, IL-6, IL-8, CRP); lipids (cholesterol, triglycerides). METHODS: We compared insulin resistance, inflammation, and lipids in overweight and obese Black women with a history of breast cancer (n=19), age similar controls (n=25), and older controls (n=32). Groups did not differ on mean body mass index (BMI), which was 35.4 kg/m2, 36.0 kg/m2, and 33.0 kg/m2, respectively. RESULTS: Cases had 1.6 and 1.38 times higher HOMA-IR values compared with age similar and older controls, respectively (P<=.001 for both). TNF-alpha and IL-1b were significantly higher in cases compared with both control groups (P<.001 for both). IL-6 was also higher in cases compared with age-similar controls (P=.007), and IL-8 was lower in cases compared with older controls (P<.05). Lipids did not differ between cases and either control group. CONCLUSIONS: Black women with breast cancer were significantly more insulin resistant with increased inflammation compared not only with age similar controls but with women who were, on average, a decade older. These biomarkers of insulin resistance and inflammation may be associated with increased risk of breast cancer recurrence and require ongoing evaluation, especially given the relatively abnormal findings compared with the controls in this underserved group. PMID- 27773979 TI - Self-Reported Sleep in Older African Americans and White Americans. AB - OBJECTIVE: Assess the relationship of self-reported sleep quality and possible sleep disorders with disability in a racially diverse sample of community dwelling older adults. METHODS: Participants included 943 non-demented older African Americans (n=452) and Whites (n=491) from two cohort studies, the Minority Aging Research Study (MARS) and the Rush Memory and Aging Project (MAP). Participants completed a 32-item questionnaire assessing sleep quality and the possible presence of three sleep disorders (sleep apnea, restless leg syndrome [RLS] and REM behavior disorder [RBD]). Disability was assessed with scales that quantified the ability to perform instrumental activities of daily living (IADL), basic activities of daily living (ADL), and physical mobility activities. RESULTS: More than half of the participants reported impaired sleep quality (51%), or the possible presence of at least one sleep disorder (57%; sleep apnea 44%, RLS 25% and RBD 7%). Sleep quality was rated poorer in African Americans, those with advancing age and fewer years of education (all P<.05). Only sleep apnea risk was associated with age (P<.02). In logistic regression models adjusted for age, sex, years of education, and race, both sleep quality and disorders were associated with disability (sleep quality with mobility disability (P<.001), sleep apnea risk with mobility disability and IADL disability (all P<.001) and RLS symptoms with mobility disability (P<.01). CONCLUSIONS: Results indicate that self-assessed impaired sleep is common in old age and is associated with disability. PMID- 27773980 TI - Explaining Racial/Ethnic Dietary Patterns in Relation to Type 2 Diabetes: An Analysis of NHANES 2007-2012. AB - OBJECTIVE: The purpose of this article is to examine sociodemographic and health behavior factors associated with dietary intake as measured by the healthy eating index (HEI-2010) for persons with and without diabetes (T2D). DESIGN: A secondary data analysis of three NHANES data cycles spanning 2007-2012. Multiple linear regression assessed racial/ethnic differences in HEI-2010 scores in those without T2D, with T2D, and with undiagnosed T2D. PARTICIPANTS: The sample included non pregnant adults aged >=20 years who had two days of reliable dietary recall data. OUTCOME MEASURES: Total scores for the HEI-2010. RESULTS: For those without T2D, there was a significant association between race/ethnicity and HEI score, with non-Hispanic Blacks achieving significantly lower scores than their non-Hispanic White counterparts. Differences in HEI-2010 score were also associated with age, sex, smoking status and time spent in the United States. Racial/ethnic differences in dietary patterns were present, but not significant in those with undiagnosed or diagnosed T2D. CONCLUSIONS: Racial/ethnic disparities in dietary patterns are present in individuals without T2D, but differences are not statistically significant in those with undiagnosed or diagnosed T2D. Non Hispanic Blacks without T2D received significantly lower HEI-2010 scores than non Hispanic Whites. Further research is necessary to determine whether or not similarities in dietary intake across racial/ethnic groups with T2D will be reflected in diabetes-related health outcomes in this population. PMID- 27773981 TI - Identifying Spanish Language Competent Physicians: The Diabetes Study of Northern California (DISTANCE). AB - OBJECTIVES: Language barriers negatively impact health care access and quality for US immigrants. Latinos are the second largest immigrant group and the largest, fastest growing minority. Health care systems need simple, low cost and accurate tools that they can use to identify physicians with Spanish language competence. We sought to address this need by validating a simple and low-cost tool already in use in a major health plan. DESIGN SETTING PARTICIPANTS: A web based survey conducted in 2012 among physicians caring for patients in a large, integrated health care delivery system. Of the 2,198 survey respondents, 111 were used in additional analysis involving patient report of those physicians' fluency. MAIN OUTCOME MEASURES: We compared health care physicians' responses to a single item, Spanish language self-assessment tool (measuring "medical proficiency") with patient-reported physician language competence, and two validated physician self-assessment tools (measuring "fluency" and "confidence"). RESULTS: Concordance between medical proficiency was moderate with patient reports (weighted Kappa .45), substantial with fluency (weighted Kappa .76), and moderate-to-substantial with confidence (weighted Kappas .53 to .66). CONCLUSIONS: The single-question self-reported medical proficiency tool is a low cost tool useful for quickly identifying Spanish competent physicians and is potentially suitable for use in clinical settings. A reasonable approach for health systems is to designate only those physicians who self-assess their Spanish medical proficiency as "high" as competent to provide care without an interpreter. PMID- 27773982 TI - Review: Hemodynamic Characteristics and Outcomes of Sickle Cell Disease Associated Pulmonary Hypertension. AB - Pulmonary hypertension (PH) is a leading cause of morbidity and early mortality in adults with sickle cell disease (SCD). However, the prevalence, hemodynamic profile and prognosis of SCD-PH remain controversial and need frequent updates. Pulmonary hypertension determined by right heart catheterization (RHC) occurs in 6% to 10% of adults with SCD. Hemodynamically, SCD-PH may be pre-capillary or post-capillary in nature. The exact etiology is unknown and often multifactorial; hence a thorough diagnostic evaluation following established PH guidelines is essential to determine disease prevalence, etiology and outcomes. Data on the efficacy and safety of pulmonary arterial hypertension (PAH) therapy are limited in SCD; clinical trials in these patients are urgently needed. This review provides an overview of RHC-determined hemodynamic characteristics, current management modality and outcomes; we also highlight recent advances and unmet research needs in SCD-PH. PMID- 27773984 TI - Adaptive designs for comparative effectiveness research trials. AB - CONTEXT: Medical and health policy decision makers require improved design and analysis methods for comparative effectiveness research (CER) trials. In CER trials, there may be limited information to guide initial design choices. In general settings, adaptive designs (ADs) have effectively overcome limits on initial information. However, CER trials have fundamental differences from standard clinical trials including population heterogeneity and a vaguer concept of a "minimum clinically meaningful difference". OBJECTIVE: To explore the use of a particular form of ADs for comparing treatments within the CER trial context. METHODS: We review the current state of clinical CER, identify areas of CER as particularly strong candidates for application of novel ADs, and illustrate potential usefulness of the designs and methods for two group comparisons. RESULTS: ADs can stabilize power. The designs ensure adequate power for true effects are at least at clinically significant preplanned effect size, or when variability is larger than expected. The designs allow for sample size savings when the true effect is larger or when variability is smaller than planned. CONCLUSION: ADs in CER have great potential to allow trials to successfully and efficiently make important comparisons. PMID- 27773985 TI - Integrating Motivational Interviewing and Self Determination Theory with Cognitive Behavioral Therapy to Prevent Suicide. AB - Cognitive Behavioral Therapy (CBT) has been found to be effective in preventing suicide-related behavior. However, it is often difficult to engage patients who are at-risk in treatment. Motivational Interviewing (MI) has been shown to increase treatment engagement and improve treatment outcomes when it is used to complement other treatments. As a general theory of human motivation that is consistent with MI, Self-Determination Theory (SDT) provides a framework for understanding how MI may be added to CBT to increase treatment engagement and effectiveness. In this paper, we use SDT to explain how MI may complement CBT to reduce suicide-related behavior, provide a case example of using MI with a suicidal patient before CBT-based treatment, and explore future directions for research. PMID- 27773983 TI - Protection from Cardiovascular Disease Due to Increased High-Density Lipoprotein Cholesterol in African Black Populations: Myth or Reality? AB - The burden of cardiovascular disease (CVD) in sub-Saharan Africa has increased over the last decade. Despite this, African Black populations present with relatively low incidences of coronary heart disease and ischemic heart disease, which may be attributed to their lower total cholesterol, triglycerides and low density lipoprotein cholesterol concentrations, compared with White populations. Commensurate with these lower lipid levels, it was believed that high-density lipoprotein cholesterol (HDL-C) concentrations would be higher in Black populations compared with their White counterparts. This is based on data from previous studies of African and African American populations; however, recent studies conducted in Africa found similar or lower HDL-C concentrations in Black compared with White individuals. Current research, therefore, suggests that HDL-C may not be a good indicator of cardiovascular risk and future research should focus on HDL quality (vs quantity), by measuring HDL functionality and subclass. PMID- 27773986 TI - Implementing the EQUiPPED Medication Management Program at 5 VA Emergency Departments. AB - The Enhancing Quality of Prescribing Practices for Older Veterans Discharged From the Emergency Department (EQUiPPED) program aimed to reduce potentially inappropriate medication prescribing to older adults at 5 VAMCs. PMID- 27773988 TI - A Novel Graph-based Algorithm to Infer Recurrent Copy Number Variations in Cancer. AB - Many cancers have been linked to copy number variations (CNVs) in the genomic DNA. Although there are existing methods to analyze CNVs from individual samples, cancer-causing genes are more frequently discovered in regions where CNVs are common among tumor samples, also known as recurrent CNVs. Integrating multiple samples and locating recurrent CNV regions remain a challenge, both computationally and conceptually. We propose a new graph-based algorithm for identifying recurrent CNVs using the maximal clique detection technique. The algorithm has an optimal solution, which means all maximal cliques can be identified, and guarantees that the identified CNV regions are the most frequent and that the minimal regions have been delineated among tumor samples. The algorithm has successfully been applied to analyze a large cohort of breast cancer samples and identified some breast cancer-associated genes and pathways. PMID- 27773990 TI - Propionibacterium acnes Susceptibility and Correlation with Hemolytic Phenotype. AB - BACKGROUND: Many studies have noted an increase in the number of recognized cases of invasive infections due to Propionibacterium acnes, especially after shoulder replacement surgery. The increase in the number of recognized cases of P. acnes, a nonspore-forming, anaerobic, Gram-positive organism, appears due to both an increase in the number of shoulder operations being performed and more specimens being sent for anaerobic cultures. Nevertheless, the optimal surgical and antibiotic management of P. acnes remains controversial. METHODS: We tested the susceptibility of 106 P. acnes strains from sterile body sites collected at the Erie County Medical Center between 2012 and 2015, using Etest gradient antibiotic strips. RESULTS: P. acnes is very susceptible to the penicillins and the first generation cephalosporins. We noted an association between hemolytic phenotype on Brucella Blood Agar and clindamycin resistance. CONCLUSIONS: Antimicrobial susceptibility testing of P. acnes should no longer just be confined to the research laboratory but expanded and incorporated into routine microbiological evaluation of P. acnes. This would improve patient care as well as help clarify the relationship between hemolysis and clindamycin resistance. PMID- 27773989 TI - Residual Isocyanates in Medical Devices and Products: A Qualitative and Quantitative Assessment. AB - We conducted a pilot qualitative and quantitative assessment of residual isocyanates and their potential initial exposures in neonates, as little is known about their contact effect. After a neonatal intensive care unit (NICU) stockroom inventory, polyurethane (PU) and PU foam (PUF) devices and products were qualitatively evaluated for residual isocyanates using Surface SWYPETM. Those containing isocyanates were quantitatively tested for methylene diphenyl diisocyanate (MDI) species, using UPLC-UV-MS/MS method. Ten of 37 products and devices tested, indicated both free and bound residual surface isocyanates; PU/PUF pieces contained aromatic isocyanates; one product contained aliphatic isocyanates. Overall, quantified mean MDI concentrations were low (4,4'-MDI = 0.52 to 140.1 pg/mg) and (2,4'-MDI = 0.01 to 4.48 pg/mg). The 4,4'-MDI species had the highest measured concentration (280 pg/mg). Commonly used medical devices/products contain low, but measurable concentrations of residual isocyanates. Quantifying other isocyanate species and neonatal skin exposure to isocyanates from these devices and products requires further investigation. PMID- 27773987 TI - How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data. AB - BACKGROUND AND OBJECTIVE: To clarify mechanisms of genetic regulation of human aging and longevity traits, a number of genome-wide association studies (GWAS) of these traits have been performed. However, the results of these analyses did not meet expectations of the researchers. Most detected genetic associations have not reached a genome-wide level of statistical significance, and suffered from the lack of replication in the studies of independent populations. The reasons for slow progress in this research area include low efficiency of statistical methods used in data analyses, genetic heterogeneity of aging and longevity related traits, possibility of pleiotropic (e.g., age dependent) effects of genetic variants on such traits, underestimation of the effects of (i) mortality selection in genetically heterogeneous cohorts, (ii) external factors and differences in genetic backgrounds of individuals in the populations under study, the weakness of conceptual biological framework that does not fully account for above mentioned factors. One more limitation of conducted studies is that they did not fully realize the potential of longitudinal data that allow for evaluating how genetic influences on life span are mediated by physiological variables and other biomarkers during the life course. The objective of this paper is to address these issues. DATA AND METHODS: We performed GWAS of human life span using different subsets of data from the original Framingham Heart Study cohort corresponding to different quality control (QC) procedures and used one subset of selected genetic variants for further analyses. We used simulation study to show that approach to combining data improves the quality of GWAS. We used FHS longitudinal data to compare average age trajectories of physiological variables in carriers and non-carriers of selected genetic variants. We used stochastic process model of human mortality and aging to investigate genetic influence on hidden biomarkers of aging and on dynamic interaction between aging and longevity. We investigated properties of genes related to selected variants and their roles in signaling and metabolic pathways. RESULTS: We showed that the use of different QC procedures results in different sets of genetic variants associated with life span. We selected 24 genetic variants negatively associated with life span. We showed that the joint analyses of genetic data at the time of bio-specimen collection and follow up data substantially improved significance of associations of selected 24 SNPs with life span. We also showed that aging related changes in physiological variables and in hidden biomarkers of aging differ for the groups of carriers and non-carriers of selected variants. CONCLUSIONS: . The results of these analyses demonstrated benefits of using biodemographic models and methods in genetic association studies of these traits. Our findings showed that the absence of a large number of genetic variants with deleterious effects may make substantial contribution to exceptional longevity. These effects are dynamically mediated by a number of physiological variables and hidden biomarkers of aging. The results of these research demonstrated benefits of using integrative statistical models of mortality risks in genetic studies of human aging and longevity. PMID- 27773991 TI - Trojan Horse Antibiotics-A Novel Way to Circumvent Gram-Negative Bacterial Resistance? AB - Antibiotic resistance has been emerged as a major global health problem. In particular, gram-negative species pose a significant clinical challenge as bacteria develop or acquire more resistance mechanisms. Often, these bacteria possess multiple resistance mechanisms, thus nullifying most of the major classes of drugs. Novel approaches to this issue are urgently required. However, the challenges of developing new agents are immense. Introducing novel agents is fraught with hurdles, thus adapting known antibiotic classes by altering their chemical structure could be a way forward. A chemical addition to existing antibiotics known as a siderophore could be a solution to the gram-negative resistance issue. Siderophore molecules rely on the bacterial innate need for iron ions and thus can utilize a Trojan Horse approach to gain access to the bacterial cell. The current approaches to using this potential method are reviewed. PMID- 27773993 TI - Toxico-Neurological Effects of Piroxicam in Monogastric Animals. AB - Piroxicam is a benzothiazine compound with anti-inflammatory, antipyretic, and analgesic properties. Because of the very high efficacy of piroxicam and its increasing use in the treatment of carcinomas in dogs and cats, there is a need for acute toxicity study of piroxicam in monogastric animals and its potential for causing secondary poisoning in puppies. Piroxicam manufactured by Shanxi Federal Pharmaceutical Co, Ltd. was used for this study. Revised up-and-down procedure was used for the estimation of median lethal dose in mouse (259.4 +/- 51.9 mg/kg), rat (259.4 +/- 69.6 mg/kg), rabbit (707.5 +/- 130.8 mg/kg), cat (437.5 +/- 128.1 mg/kg), guinea pig (218.7 +/- 64.1 mg/kg), monkey (733.3 +/- 83.3 mg/kg), broiler (285.3 +/- 62.5 mg/kg), hen (638.3 +/- 115.4 mg/kg), turkey (707.5 +/- 130.8 mg/kg), pigeon (375 +/- 55.9 mg/kg), and duck (311.3 +/- 46.6 mg/kg). The acute toxicity signs of piroxicam at doses 207.5 mg/kg and above observed in the animals are torticollis, opisthotonos, somnolence, lethargy, diarrhea, gastroenteritis, generalized internal bleeding, anemia, congestion of the lung and liver, flaccid paralysis, cheesy lung, urinary incontinence, engorged urinary bladder, convulsive jerking of the limbs, lying in ventral recumbency, gasping for air, roaring, and death. Three out of six puppies died after being fed the carcasses of poisoned turkey, duck, and hen administered piroxicam at doses of 1000, 415, and 1000 mg/kg, respectively. White flaky cheesy materials observed in turkeys were also observed in the gastrointestinal content of the puppies. Paleness of carcasses, watery crop content, dryness of pericardium, gastroenteritis, intestinal perforation, and whitish pericardium were observed in broilers. There were effusions in thoracic and abdominal cavities as seen in all other carcasses poisoned primarily by piroxicam. Administration of atropine (0.02 mg/kg) led to survival of the remaining puppies. In conclusion, piroxicam is very to moderately toxic in monogastric animals. PMID- 27773995 TI - Amiodarone-Induced Pulmonary Toxicity - A Frequently Missed Complication. AB - INTRODUCTION: Amiodarone is often used in the suppression of tachyarrhythmias. One of the more serious adverse effects includes amiodarone pulmonary toxicity (APT). Several pulmonary diseases can manifest including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules or masses, and pleural effusion. Incidence of APT varies from 5-15% and is correlated to dosage, age of the patient, and preexisting lung disease. DESCRIPTION: A 56-year-old male with a past medical history of coronary artery disease and chronic obstructive pulmonary disease was admitted for a coronary artery bypass graft. Post-operatively, the patient was admitted to the ICU for ventilator management and continued to receive his home dose of amiodarone 400 mg orally twice daily, which he had been taking for the past 3 months. The patient was found to be hypoxemic with a PaO2 52 mmHg and bilateral infiltrates on chest x-ray. Patient also complained of new onset dyspnea. Physical exam found bilateral rhonchi with bibasilar crackles and subcutaneous emphysema along the left anterior chest wall. Daily chest x-rays showed worsening of bilateral interstitial infiltrates and pleural effusions. A chest high-resolution computed tomography on post-operative day 3 showed extensive and severe bilateral ground glass opacities. APT was suspected and amiodarone was discontinued. A course of oral prednisone without antibiotics was initiated, and after one week of treatment the chest film cleared, the PaO2 value normalized and dyspnea resolved. DISCUSSION: APT occurs via cytotoxic T cells and indirectly by immunological reaction. Typically the lungs manifest a diffuse interstitial pneumonitis with varying degrees of fibrosis. Infiltrates with a 'ground-glass' appearance appreciated on HRCT are more definitive than chest x ray. Pulmonary nodules can be seen, frequently in the upper lobes. These are postulated to be accumulations of amiodarone in areas of previous inflammation. Those undergoing major cardiothoracic surgery are known to be predisposed to APT. Some elements require consideration: a baseline pulmonary function test (PFT) did not exist prior. APT would manifest a restrictive pattern of PFTs. In APT diffusing capacity (DLCO) is generally >20 percent from baseline. A DLCO was not done in this patient. Therefore, not every type of interstitial lung disease could be ruled out. Key features support a clinical diagnosis: (1) new dyspnea, (2) exclusion of lung infection, (3) exclusion of heart failure, (4) new radiographic features, (5) improvement with withdrawal of amiodarone. Our case illustrates consideration of APT in patients who have extensive use of amiodarone and new onset dyspnea. PMID- 27773992 TI - The Kynurenine Pathway Is a Double-Edged Sword in Immune-Privileged Sites and in Cancer: Implications for Immunotherapy. AB - The term "immune privilege" was originally coined to describe the suppression of inflammatory responses within organs protected by anatomic barriers, ie, the eyes, brain, placenta, and testes. However, cellular and metabolic processes, which orchestrate immune responses, also control inflammation within these sites. Our current understanding of tolerogenic mechanisms has extended the definition of immune privilege to include hair follicles, the colon, and cancer. By catabolizing tryptophan, cells expressing the enzyme indoleamine-2,3-dioxygenase produce kynurenine metabolites, which orchestrate local and systemic responses to control inflammation, thus maintaining immune privilege. This review highlights the double-edged role played by the kynurenine pathway (KP), which establishes and maintains immune-privileged sites while contributing to cancer immune escape. The identification of the underlying molecular drivers of the KP in immune privileged sites and in cancer is essential for the development of novel therapies to treat autoimmunity and cancer and to improve transplantation outcomes. PMID- 27773994 TI - A Review of the External Validity of Clinical Trials with Beta-Blockers in Heart Failure. AB - BACKGROUND: Beta-blockers (BBs) are the mainstay prognostic medication for all stages of chronic heart failure (CHF). There are many classes of BBs, each of which has varying levels of evidence to support its efficacy in CHF. However, most CHF patients have one or more comorbid conditions such as diabetes, renal impairment, and/or atrial fibrillation. Patient enrollment to randomized controlled trials (RCTs) often excludes those with certain comorbidities, particularly if the symptoms are severe. Consequently, the extent to which evidence drawn from RCTs is generalizable to CHF patients has not been well described. Clinical guidelines also underrepresent this point by providing generic advice for all patients. The aim of this review is to examine the evidence to support the use of BBs in CHF patients with common comorbid conditions. METHODS: We searched MEDLINE, PubMed, and the reference lists of reviews for RCTs, post hoc analyses, systematic reviews, and meta-analyses that report on use of BBs in CHF along with patient demographics and comorbidities. RESULTS: In total, 38 studies from 28 RCTs were identified, which provided data on six BBs against placebo or head to head with another BB agent in ischemic and nonischemic cardiomyopathies. Several studies explored BBs in older patients. Female patients and non-Caucasian race were underrepresented in trials. End points were cardiovascular hospitalization and mortality. Comorbid diabetes, renal impairment, or atrial fibrillation was detailed; however, no reference to disease spectrum or management goals as a focus could be seen in any of the studies. In this sense, enrollment may have limited more severe grades of these comorbidities. CONCLUSIONS: RCTs provide authoritative information for a spectrum of CHF presentations that support guidelines. RCTs may provide inadequate information for more heterogeneous CHF patient cohorts. Greater Phase IV research may be needed to fill this gap and inform guidelines for a more global patient population. PMID- 27773997 TI - Electronic Cigarette: Role in the Primary Prevention of Oral Cavity Cancer. AB - BACKGROUND: Cigarette smoke has been identified as the main cause of oral cavity carcinoma. Recently, the electronic cigarette, a battery-operated device, was developed to help smokers stop their tobacco addiction. This study aimed to evaluate the safety of electronic cigarettes and to establish the possible role of such device in the primary prevention of oral cavity cancer. SUBJECTS AND METHODS: This study included 65 subjects who were divided into three groups (smokers, e-cigarette smokers, and nonsmokers). All subjects were submitted to cytologic examination by scraping of oral mucosa. The slides were microscopically evaluated through a micronucleus assay test. RESULTS: The prevalence of micronuclei was significantly decreased in the e-cigarette smoker group. There were no statistically significant differences in micronuclei distribution according to the type of cigarette, gender, and age. CONCLUSIONS: The use of electronic cigarettes seems to be safe for oral cells and should be suggested as an aid to smoking cessation. PMID- 27773996 TI - Albuterol Improves Alveolar-Capillary Membrane Conductance in Healthy Humans. AB - BACKGROUND: Beta-2 adrenergic receptors (beta2ARs) are located throughout the body including airway and alveolar cells. The beta2ARs regulate lung fluid clearance through a variety of mechanisms including ion transport on alveolar cells and relaxation of the pulmonary lymphatics. We examined the effect of an inhaled beta2-agonist (albuterol) on alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (VC) in healthy humans. METHODS: We assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) at baseline, 30 minutes, and 60 minutes following nebulized albuterol (2.5 mg, diluted in 3 mL normal saline) in 45 healthy subjects. Seventeen subjects repeated these measures following nebulized normal saline (age = 27 +/- 9 years, height = 165 +/- 21 cm, weight = 68 +/- 12 kg, BMI = 26 +/- 9 kg/m2). Cardiac output (Q), heart rate, systemic vascular resistance (SVR), blood pressure, oxygen saturation, forced expiratory volume at one-second (FEV1), and forced expiratory flow at 50% of forced vital capacity (FEF50) were assessed at baseline, 30 minutes, and 60 minutes following the administration of albuterol or saline. RESULTS: Albuterol resulted in a decrease in SVR, and an increase in Q, FEV1, and FEF50 compared to saline controls. Albuterol also resulted in a decrease in VC at 60 minutes post albuterol. Both albuterol and normal saline resulted in no change in DLCO or DM when assessed alone, but a significant increase was observed in DM when accounting for changes in VC. CONCLUSION: These data suggest that nebulized albuterol improves pulmonary function in healthy humans, while nebulization of both albuterol and saline results in an increase in DM/VC. PMID- 27774003 TI - Stop the escalators: using the built environment to increase usual daily activity. AB - BACKGROUND: Obesity is an epidemic in the United States. Two-thirds of the population is overweight and does not get enough exercise. Eastern cities are full of escalators that transport obese Americans to and from the subway. Walking stairs is a moderate activity requiring 3-6 metabolic equivalent tasks (METS) and burning 3.5-7 kcal/min. We determined the caloric expenditure and potential weight change of the population of one eastern city if all the subway riders walked the stairs rather than ride the escalators. METHODS: There are 5,000,000 daily journeys made on the New York City Subway. Subway entrances include a stairway or escalator of approximately 25 steps. Each step up requires 0.11-0.15 kcals; each step down requires 0.05 kcals. To lose one pound requires burning 3500 kcals. We assumed each rider made a round trip so about 2.5 million individual people ride the subway each day. RESULTS: By walking stairs rather than riding escalators, the riders of the New York Subway would lose more than 2.6 million pounds per year. DISCUSSION: The average subway rider would lose about one pound per year. While this may sound insignificant, in one decade the average subway rider would lose 10 pounds, effectively reversing the trend in the United States of gaining 10 pounds per decade. This conservative estimate of the number of stairs ascended daily means that subway riders might lose even more weight. We believe that this novel approach might lead to other public and private efforts to increase physical activity such as elevators that only stop on even numbered floors, making stairwells more attractive and well lit, and stopping moving sidewalks. The built environment may support small, incremental changes in usual daily physical activity that can have significant impact on populations and individuals. PMID- 27773999 TI - Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer. AB - Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development. PMID- 27774002 TI - Benefits of an older persons' assessment and liaison team in acute admissions areas of a general hospital. AB - OBJECTIVE: To analyze and describe the operational benefits that followed the introduction of a multiprofessional older person assessment and liaison service (OPAL) into the acute admissions areas of a general hospital. OPAL delivered comprehensive geriatric assessment and a range of early medical, nursing, therapy, and social interventions to all eligible elderly and frail patients. METHODS: A mix of numeric data, case note narrative, historic comparison, and staff opinion was used to reach a reliable view of the impact that OPAL had on a number of key indicators pertaining to the timing of assessments, treatments, and discharge planning. RESULTS: We found that the new service reduced the time required to achieve several critical interventions including medical, nursing, and therapy reviews. We were also able to show that OPAL activity played a critical role in reducing the length of hospital stay of frail older people and made available the equivalent of 9-16 beds per day (8%-14% of acute admission area beds). CONCLUSION: OPAL was shown to be effective as a medium for timely review and intervention of frail elderly patients in an acute medical setting, and as a mechanism for reducing length of stay. PMID- 27774004 TI - Use of image transformation to track the natural history of diseases. AB - The inability to precisely measure the area of a lesion can impair the study of its natural history and response to therapy. This is especially true in case of gastrointestinal lesions, where a standard imaging technique is endoscopy and an unaided visual interpretation of the size of the lesion is difficult. This study presents a novel technique that provides precise measurement of 2-dimensional lesions in cylinder-like organs. PMID- 27774005 TI - Cancer risk in patients with chronic obstructive pulmonary disease. AB - PURPOSE: The goal of this study was to compare the risk of developing cancer between patients with or without chronic obstructive pulmonary disease (COPD), and to assess the role of gender as well as the use of respiratory medication on the risk of developing lung cancer in COPD patients. PATIENTS AND METHODS: We used the UK-based General Practice Research Database to conduct a follow-up study with a nested case-control analysis. We identified all patients with a first-time COPD diagnosis aged 40-79 years between 1995 and 2005 and a matched COPD-free comparison group. We then identified all patients who received an incident cancer diagnosis during follow-up. RESULTS: Among 35,772 COPD patients and 35,772 COPD free patients, we identified 4506 patients with an incident cancer diagnosis, of whom 2585 (57.4%) had a previous COPD diagnosis, yielding a crude incidence rate ratio of 1.64 (95% CI 1.55-1.74). The increased risk was mainly driven by a high lung cancer risk among COPD patients, while other cancers not associated with smoking were not statistically significantly associated with an altered COPD risk. In the nested case-control analysis, the odds ratio (OR) for lung cancer associated with COPD was higher for women (OR 5.26, 95% CI 3.64-7.61) than for men (OR 2.10, 95% CI 1.70-2.60). In the nested case-control analysis, none of the respiratory drugs were associated with a substantially altered risk of developing lung cancer among COPD patients. CONCLUSION: Our findings provide further evidence that COPD is associated with an elevated lung cancer risk, and that women with COPD may be more susceptible to developing lung cancer than men. Overall, respiratory medication did not have an influence on cancer risk. PMID- 27774000 TI - Interferon Gamma: Influence on Neural Stem Cell Function in Neurodegenerative and Neuroinflammatory Disease. AB - Interferon-gamma (IFNgamma), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNgamma mediates non cytolytic viral control in infected neurons. However, IFNgamma also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNgamma, neural stem/progenitor cells (NSPCs), the only pluripotent cells in the developing and adult brain, are often altered during CNS insults. Recent studies highlight the complex effects of IFNgamma on NSPC activity in neurodegenerative diseases. However, the mechanisms that mediate these effects, and the eventual outcomes for the host, are still being explored. Here, we review the effects of IFNgamma on NSPC activity during different pathological insults. An improved understanding of the role of IFNgamma would provide insight into the impact of immune responses on the progression and resolution of neurodegenerative diseases. PMID- 27774006 TI - Biological correlates of migraine and cluster headaches: an overview of their potential use in diagnosis and treatment. AB - Current diagnostic criteria for headaches are based on the International Classification for Headache Disorders, second edition, which is largely built on data obtained from clinical examinations and patients' medical histories. Despite decades of vigorous basic and clinical research, we still lack reliable clinical laboratory diagnostic markers for headaches, which clearly obstructs the physician's ability to optimize and follow the patient's response to treatment protocols as well as holds back the discovery and implementation of new therapeutic modalities. In this paper, we review and discuss current efforts to identify and characterize biochemical and immunological changes in biological fluids and tissue that may be specifically associated with the etiology and/or pathophysiology of migraine and cluster headaches; we also discuss some of the recent genetic findings and ion channel modulation studies that may help to distinguish among various headache populations. PMID- 27774007 TI - Causal diagrams, information bias, and thought bias. AB - Information bias might be present in any study, including randomized trials, because the values of variables of interest are unknown, and researchers have to rely on substitute variables, the values of which provide information on the unknown true values. We used causal directed acyclic graphs to extend previous work on information bias. First, we show that measurement is a complex causal process that has two components, ie, imprinting and synthesizing. Second, we explain how the unknown values of a variable may be imputed from other variables, and present examples of valid and invalid substitutions for a variable of interest. Finally, and most importantly, we describe a previously unrecognized bias, which may be viewed as antithetical to information bias. This bias arises whenever a variable does not exist in the physical world, yet researchers obtain "information" on its nonexistent values and estimate nonexistent causal parameters. According to our thesis, the scientific literature contains many articles that are affected by such bias. PMID- 27774008 TI - Future of translational research: Why go pragmatic? AB - Translational research has succeeded in expanding our medical knowledge and bringing many discoveries to the clinic. However, the prevailing research enterprise is plagued with many challenges that may limit the ability to realize the full potential benefits of these advances. The main challenge of current research approaches is the inability to reach all potential candidates who may benefit from the findings in a timely and systematic way. There are many factors contributing to this limitation, including the differences between the study population and the research setting from larger, more heterogeneous populations in variable health care settings. Understanding the current research limitations may help in developing more practical research interventions that are relevant to real-life patients in real-life settings. The adoption of pragmatic research culture will include designing new and innovative approaches for research projects, maximizing the benefits of the existing research methodologies, and enhancing the research infrastructure. The gap between the discovery and the intended patients should be bridged by pragmatic research approaches that bring a timely and appropriate benefit to those who need it the most. This paper presents the limitations of the current research enterprise and the suggested solutions to adopt more pragmatic approaches. PMID- 27773998 TI - Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth? AB - In this review, we analyze the effects of growth hormone on a number of tissues and organs and its putative role in the longitudinal growth of an organism. We conclude that the hormone plays a very important role in maintaining the homogeneity of tissues and organs during the normal development of the human body or after an injury. Its effects on growth do not seem to take place during the fetal period or during the early infancy and are mediated by insulin-like growth factor I (IGF-I) during childhood and puberty. In turn, IGF-I transcription is dependent on an adequate GH secretion, and in many tissues, it occurs independent of GH. We propose that GH may be a prohormone, rather than a hormone, since in many tissues and organs, it is proteolytically cleaved in a tissue-specific manner giving origin to shorter GH forms whose activity is still unknown. PMID- 27774009 TI - Introducing candesartan 32 mg plus hydrochlorothiazide 25 mg in previously untreated patients with severe essential hypertension. AB - PURPOSE: To investigate the efficacy of candesartan 32 mg and hydrochlorothiazide (HCTZ) 25 mg combination in patients with severe essential hypertension. PATIENTS AND METHODS: In this prospective, open-label, single-group study, 106 previously untreated patients with a baseline systolic blood pressure (SBP) of 150-200 mmHg, and a diastolic blood pressure (DBP) of 110 to 120 mmHg, started with candesartan 16 mg during the first week. HCTZ 12.5 mg was added at week 2 and from fourth week onwards candesartan 32 mg plus HCTZ 25 mg was given over 6 weeks. The primary efficacy endpoint was mean reduction in SBP and DBP after 9 weeks. Response was defined as a decrease in SBP to <140 mmHg and/or by >=20 mmHg and in DBP to <90 mmHg and/or by >=10 mmHg. A second response criterion defined blood pressure reduction below 140/90 mmHg. RESULTS: Blood pressure was lowered from 180.0 +/- 11.7/114.7 +/- 3.1 mmHg by SBP 44.4 +/- 16.8 and DBP 32.0 +/- 11.3 mmHg (P < 0.0001). Response was 92.4% and 64.8% achieved <140/90 mmHg. Each titration step produced a statistically significant and clinically relevant decrease in SBP and DBP, but a level below 140/90 mmHg was achieved by >50% of the patients only after the third titration step. Adverse reactions were reported by 3.8% of the patients. The disorders were in line with the known safety profile of the study drugs. CONCLUSION: A stepped treatment approach with candesartan/HCTZ combinations is effective and safe to achieve a swift blood pressure reduction in newly diagnosed, severe hypertension. The target of <140/90 mmHg was reached by >50% of the patients only after taking the full dose of candesartan 32 mg and HCTZ 25 mg. PMID- 27774010 TI - Significant pain relief with loading dose zoledronic acid in bone metastases is only seen in patients with elevated initial serum C telopeptide (CTX). AB - In symptomatic bone metastases with significant pain, refractory to standard analgesics and radiotherapy, loading dose zoledronic acid (ZA) represents a simple and nontoxic treatment to obtain significant pain relief in a very short time. Its analgesic effect is limited to patients with massive osteoclast activation with high initial serum C-telopeptide (CTX). The pain reduction is proportionally correlated with the reduction of CTX. PMID- 27774011 TI - The evaluation of music therapy process in the intersubjective perspective: the music therapy rating scale. A pilot study. AB - This study presents a tool (Music Therapy Rating Scale [MTRS]) to evaluate the progression of the relationship between the patient and the therapist during music therapy sessions. The rating scale was developed from an intersubjective framework and from an improvisational music therapy technique. It mainly consists of two behavioral classes: non-verbal communication (NVC) and sonorous-musical communication (SMC). Five levels for each class are given (from 0 to 4). Every 15 seconds, two sets of two music therapists coded the behaviors in seven sessions with different patients. The patients were seven children (four males; three females) aged 3-10 years (mean age = 6.28), diagnosed with Pervasive Developmental Disorder. The reliability indices were computed and there was a substantial agreement in the assessments of the video raters (non-verbal relationship: rho = 0.70; sonorous-musical relationship: rho = 0.77). A digital output of the program to use the MTRS is presented and clinical implications are discussed. PMID- 27774001 TI - The Significance of the Enteric Microbiome on the Development of Childhood Disease: A Review of Prebiotic and Probiotic Therapies in Disorders of Childhood. AB - Recent studies have highlighted the fact that the enteric microbiome, the trillions of microbes that inhabit the human digestive tract, has a significant effect on health and disease. Methods for manipulating the enteric microbiome, particularly through probiotics and microbial ecosystem transplantation, have undergone some study in clinical trials. We review some of the evidence for microbiome alteration in relation to childhood disease and discuss the clinical trials that have examined the manipulation of the microbiome in an effort to prevent or treat childhood disease with a primary focus on probiotics, prebiotics, and/or synbiotics (ie, probiotics + prebiotics). Studies show that alterations in the microbiome may be a consequence of events occurring during infancy and/or childhood such as prematurity, C-sections, and nosocomial infections. In addition, certain childhood diseases have been associated with microbiome alterations, namely necrotizing enterocolitis, infantile colic, asthma, atopic disease, gastrointestinal disease, diabetes, malnutrition, mood/anxiety disorders, and autism spectrum disorders. Treatment studies suggest that probiotics are potentially protective against the development of some of these diseases. Timing and duration of treatment, the optimal probiotic strain(s), and factors that may alter the composition and function of the microbiome are still in need of further research. Other treatments such as prebiotics, fecal microbial transplantation, and antibiotics have limited evidence. Future translational work, in vitro models, long-term and follow-up studies, and guidelines for the composition and viability of probiotic and microbial therapies need to be developed. Overall, there is promising evidence that manipulating the microbiome with probiotics early in life can help prevent or reduce the severity of some childhood diseases, but further research is needed to elucidate biological mechanisms and determine optimal treatments. PMID- 27774012 TI - Physicians' attitudes towards combination therapy with inhaled corticosteroids and long-acting beta2-agonists: an observational study in UK specialist care. AB - PURPOSE: Recent real-world studies have demonstrated that asthma control remains suboptimal in many patients. The aim of this study was to evaluate physicians' perceptions of the effectiveness of combination therapy with an inhaled corticosteroid (ICS) and a long-acting beta2-agonist (LABA) in routine clinical practice. METHODS: In November 2009, UK respiratory specialists were invited by medeConnect Healthcare Insight to complete a survey on the effectiveness of different single- or dual-inhaler combinations of an ICS and a LABA in the context of asthma management. Respondents were permitted to specify combinations of available ICSs and LABAs, based on their knowledge and experience of the individual components. Questions elicited both unprompted free-text responses and prompted responses selected from a list of options. RESULTS: A total of 98 physicians completed the survey, of whom 82 (84%) gave permission to publish their data. The majority of respondents (63%) were consultants and 57% reported a caseload of more than 40 patients with asthma or chronic obstructive pulmonary disease per month. Fluticasone and formoterol were considered to be the most effective combination for the treatment of asthma (37% unprompted, 41% prompted), followed by budesonide and formoterol (22% unprompted, 24% prompted). The most common reasons for choosing specific combinations were: rapid onset of action (60%), high potency of the ICS (39%), efficacy (15%), experience of prescribing (13%), clinical evidence (12%), and long-lasting effect (10%). Key properties of the preferred fluticasone and formoterol combination were rapid onset of action and high potency of the ICS (79% for both). CONCLUSION: The results of this survey suggest that the ICS and LABA combination considered most effective by UK physicians in the management of asthma is fluticasone and formoterol, which is not currently available as a single-inhaler combination. The development of new single-inhaler combinations of ICSs and LABAs may improve real-world asthma management. PMID- 27774013 TI - Discontinuation of low-dose acetylsalicylic acid therapy in UK primary care: incidence and predictors in patients with cardiovascular disease. AB - BACKGROUND: Discontinuation of low-dose acetylsalicylic acid (ASA) leads to an increased risk of cardiovascular and cerebrovascular events in patients taking low-dose ASA for secondary cardiovascular prevention. However, little is known about the rate of discontinuation in everyday clinical practice. OBJECTIVES: To assess the rate of low-dose ASA discontinuation in primary care, and identify factors that predict discontinuation. METHODS: The Health Improvement Network, a large UK primary care database, was used to identify patients aged 50-84 years who received at least two consecutive prescriptions for low-dose ASA for secondary cardiovascular or cerebrovascular prevention in 2000-2007 (n = 35,639). Discontinuation was defined as a period of at least 90 days after completion of the last prescribed course of ASA during which no repeat prescription was issued. RESULTS: During the study, 11,729 patients (32.9%) discontinued ASA therapy (mean follow-up 2.5 years). The discontinuation rate was lower in patients with ASA indicated for myocardial infarction than for other indications. The diagnosis of gastrointestinal disorders during the study (overall odds ratio: 1.74; 95% confidence interval: 1.61-1.88) was associated with increased rates of ASA discontinuation, whereas co-prescription of a proton pump inhibitor from the start of ASA therapy was associated with a decreased rate of discontinuation (odds ratio: 0.80; 95% confidence interval: 0.75-0.86). Co-prescription of several other cardioprotective medications was also associated with a reduced risk of discontinuation, as were increasing age, prior hospitalization and overall number of co-medications. CONCLUSION: Continuous co-prescription of a PPI with low-dose ASA may improve adherence and outcomes, particularly in patients at both cardiovascular and gastrointestinal risk. PMID- 27774015 TI - Schizophrenia Outpatient Health Outcomes study: twelve-month findings. AB - BACKGROUND: The purpose of this study was to assess the 12-month outcomes associated with naturalistic antipsychotic treatment of patients participating in the Schizophrenia Outpatient Health Outcomes (SOHO) study. METHODS: SOHO is a 3 year, prospective, observational study of the health outcomes associated with antipsychotic treatment in 10 European countries. The study included over 10,000 outpatients who were initiating or changing their antipsychotic medication. Medication use pattern, change in symptom severity, social functioning, and health-related quality of life were assessed, as well as rates of response, remission, treatment discontinuation, adverse events, and hospitalization. RESULTS: Clinical Global Impression-Severity for Schizophrenia (CGI-SCH) and quality of life scores improved in all treatment cohorts. There were greater improvements in the CGI-SCH overall symptom score and in the CGI-SCH positive, negative, cognitive, and depressive symptom scores in the olanzapine and clozapine cohorts compared with other treatment cohorts. Changes were associated with an improvement in quality of life. Patients treated with olanzapine, quetiapine, and clozapine had better tolerability per extrapyramidal symptoms and sexual-related dysfunction measures compared with patients receiving risperidone, amisulpride, or typicals. Patients treated with olanzapine had greater weight gain than patients in all other treatment cohorts. CONCLUSION: Patients initiated on olanzapine and clozapine tend to have better outcomes at 12 months than patients initiated on other antipsychotics in routine outpatient clinical practice. Results should be interpreted conservatively due to the nonrandomized study design. PMID- 27774014 TI - Pragmatic research and outcomes in asthma and COPD. AB - Asthma and chronic obstructive pulmonary disease (COPD) are common diseases which cause patients and society considerable difficulties. These are costly diseases which cause substantial morbidity and death. Health care policy makers have made improving outcomes in asthma and COPD a priority. Application of guideline recommended approaches to asthma and COPD care in the real-life setting has been emphasized but outcomes have not improved. Failure to improve outcomes may not be because of inconsistent applications of guideline recommendations, but rather because there are difficulties implementing the Expert Panel Report III (EPR 3) method for categorizing asthma severity and the Global Initiative for Obstructive Lung Disease (GOLD) method for diagnosing COPD. As these serve as the foundation for treatment recommendations for these diseases, alternative approaches should be considered for categorizing asthma severity and identifying COPD patients. Claims-based algorithms provide an intriguing option for identifying persistent asthma patients and symptomatic COPD patients in administrative databases. These methods could be used as the basis for pragmatic research, both retrospective and prospective, on assessing outcomes of guideline recommended treatment approaches in asthma and COPD. Important questions urgently need to be answered about how guideline recommended approaches regarding use of long-acting inhaled beta agonist/inhaled corticosteroid (LABA/ICS) in asthma and long-acting inhaled anti muscarinic agent (LAMA) and LABA/ICS in COPD affect outcomes in real-life situations. PMID- 27774016 TI - One-year outcomes in schizophrenia after switching from typical antipsychotics to olanzapine in Japan: an observational study. AB - BACKGROUND: The purpose of this study was to assess the 1-year clinical, functional, and safety-related outcomes following a switch to olanzapine of at least one typical antipsychotic drug in the previous regimen in the treatment of patients of schizophrenia in Japan. METHODS: Using data from a large 1-year prospective, multicenter, naturalistic study of olanzapine for the treatment of schizophrenia in Japan, patients who were switched from any oral typical antipsychotic to olanzapine were identified. Mixed models for repeated measures, controlling for baseline demographics, were utilized to assess outcomes for clinical and functional measures. RESULTS: Of the 262 patients who switched from typical antipsychotics to olanzapine, 41% were outpatients and 59% were inpatients. Most of these patients were switched due to poor medication efficacy (71.0%) or medication intolerability (25.6%). Most patients (71.4%) completed the 1-year study. Clinically and statistically significant (P < 0.01) improvements were observed in patient illness severity and health-related quality of life, including improvements in global symptom severity and in positive, negative, depressive, and cognitive symptoms. Over half of the patients (58.3%) demonstrated a treatment response to olanzapine and 47.4% achieved symptom remission. Mean weight gain from baseline to endpoint was 2.31 +/- 4.72 kg, with 30.4% of patients experiencing clinically significant weight gain (at least 7% of baseline weight). CONCLUSION: During this 1-year naturalistic treatment of schizophrenia patients in Japan, switching from typical antipsychotics to olanzapine resulted in significant improvements in patients' clinical and functional outcomes. Approximately one-third of patients had clinically significant weight gain. These findings highlight the favorable benefit to risk profile of switching to olanzapine following failure on typical antipsychotics. PMID- 27774017 TI - The challenge of recruiting in primary care for a trial of telemonitoring in asthma: an observational study. AB - AIM: Achieving target recruitment in randomized controlled trials (RCTs) is challenging. This paper compares our experience of recruiting for an RCT with the predictions made in our proposal. METHODS: Participating UK primary care practices searched their computer databases to identify patients (12 years and over) with asthma who may be poorly controlled. Postal invitations were sent to all patients identified. Respondees were prescreened by phone, to assess their asthma control and establish their mobile phone suitability. Potentially eligible patients were booked for a trial recruitment visit. RESULTS: We recruited 288 patients (2.4% of those invited) across 32 practices, with a total list size of 311,926 patients. This compares to our predicted recruitment of 312 patients from a population of 72,000 patients in six to eight practices. In addition to the recognized problem of poor response rates, the major challenges were insufficiently discriminating computer searches and incompatibilities between mobile phone handsets, networks and the asthma application. CONCLUSION: Our data have implications for clinicians, managers, and researchers in primary care. Researchers in this area may wish to consider our data when designing their recruitment strategies. Improved coding of asthma morbidity data in clinical practice would ease identification of poorly controlled patients, both for clinical interventions and recruitment to trials. If telehealth is to become mainstream, there needs to be standardization of applications, operating platforms, and network capabilities. PMID- 27774018 TI - Partial response to proton pump inhibitor therapy for GERD: observational study of patient characteristics, burden of disease, and costs in the USA. AB - BACKGROUND: Disease burden and associated costs are not well understood among patients with gastroesophageal reflux disease (GERD) who have persistent symptoms despite optimized proton pump inhibitor (PPI) therapy. The aim of this study was to investigate disease burden and costs of GERD in partial responders to PPI therapy. METHODS: The Partial Response to PPI treatment: the Cost to Society and the Burden to the Patient in the US (REMAIN US) study was a 12-month, multicenter, noninterventional, observational study of 552 partial PPI responders in the USA. Participating sites were comprised of family practice (n = 30), internal medicine (n = 8), and specialist (gastroenterologist) centers (n = 15). GERD symptoms, health-related quality of life (HRQL), and impact on productivity were evaluated from patient-reported outcome instruments. Resource utilization data were also collected. RESULTS: Patients had a high symptom burden, impaired HRQL, and reduced productivity while at work and in daily activities, despite optimized PPI therapy. Mean annual GERD-related costs were US$9944 per patient, comprising total direct costs and mean productivity loss costs of US$4068 and US$5876 per patient, respectively. CONCLUSION: Patients with GERD and a partial response to PPI therapy have considerable direct and indirect costs, along with substantial impairments in HRQL and productivity. PMID- 27774019 TI - Exacerbations in the pre- and post-COPD diagnosis periods. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is usually recognized in its later stages, delaying therapeutic opportunities. Screening questionnaires have modest sensitivities and specificities. Adding questions about prior respiratory events might improve screening characteristics. METHODS: Using administrative data from all health care facilities in Olmsted County, Minnesota USA, we identified all adults with an initial diagnosis of COPD from 2005 through 2007. For each individual we identified all coded lower and upper respiratory events in the 2 years before and the 2 years after the COPD diagnosis and categorized them as probable or possible COPD exacerbations. RESULTS: 356 women and 346 men (N = 702) with a mean age of 67.5 years and 66.6 years respectively had a first diagnosis of COPD during the study period. Respiratory events in the 2 years prior to a COPD diagnosis were common with a range of 0 to 16 events per individual and a mean (SD) of 2.04 (2.14), 1.38 (1.86) all of which were probable COPD exacerbations. Prediagnostic respiratory events were predictive of similar events in the post diagnostic period (odds ratio = 1.6, 95% confidence interval [CI] 1.3 to 1.8). CONCLUSION: Inquiring about the number and type of upper or lower respiratory events in the 2 past years may be a useful addition to the "screening" criteria to improve COPD identification, especially those at risk of frequent exacerbations. PMID- 27774021 TI - Autoinjectors for administration of interferon beta-1b in multiple sclerosis: patient preferences and the ExtaviProTM 30G and Betacomfort(r) devices. AB - BACKGROUND: The ExtaviProTM 30G autoinjector has been developed for self administration of interferon beta-1b (Extavia(r)), which is used as a first-line, parenteral, disease-modifying therapy in multiple sclerosis (MS). The aim of this survey was to investigate patients' perceptions of the importance of different general attributes of autoinjectors, and patient preferences when comparing the ExtaviProTM 30G and Betacomfort(r) autoinjectors. METHOD: The survey was conducted in France, Germany, Italy, and the USA in patients with relapsing remitting MS who had been using an autoinjector for at least 1 year. Participants examined the ExtaviProTM 30G and Betacomfort(r) devices, viewed fact sheets, and watched a video of these autoinjectors in use, then scored nine prespecified attributes of autoinjectors in terms of importance on a scale of 1-7 (1 = not at all important; 7 = extremely important). They then indicated which device they preferred, both overall and by individual attribute. RESULTS: Among the 201 participants who completed the survey, being reliable to use was considered the most important general attribute of autoinjectors, followed by attributes associated with convenience (ease of operation, one-handed injection, ease of reach of injection sites, ergonomic shape). For each of the nine attributes, a significantly higher proportion of participants (74%-94% by attribute; P < 0.05 for each) preferred ExtaviProTM 30G to the Betacomfort(r) autoinjector, and 173 (86%) participants indicated that they preferred ExtaviProTM 30G overall (P < 0.05). CONCLUSION: The results of this survey suggest that patients with MS rate reliability and convenience as the most important general attributes of autoinjectors, and are more likely to prefer ExtaviProTM 30G to the Betacomfort(r) autoinjector for routine self-administration of interferon beta 1b. PMID- 27774020 TI - Protocol for the asthma tools study: a pragmatic practice-based research network trial. AB - BACKGROUND: Asthma is common among children, adolescents, and adults. However, management of asthma often fails to follow evidence-based guidelines. Control assessments have been developed, validated against expert opinion, and disseminated. However, in primary care, assessment of control is only one step in asthma management. To facilitate integration of the evidence-based guidelines into practice, tools should also guide the next steps in care. The Asthma APGAR tools do just that, incorporating a control assessment as well as assessment of the most common reasons for inadequate and poor control. The Asthma APGAR tool is also linked to a care algorithm based on the 2007 National Heart, Lung, and Blood Institute asthma guidelines. The objective of this study is to assess the impact of implementation of the Asthma APGAR on patient asthma outcomes in primary care practices. METHODS: A total of 1400 patients aged 5-60 years with physician diagnosed asthma are enrolled in 20 practice-based research network (PBRN) practices randomized to intervention or usual care. The primary outcomes are changes in patient self-reported asthma control, asthma-related quality of life, and rates of exacerbations documented in medical records over the 18-24 months of enrollment. Process measures related to implementation of the Asthma APGAR system into daily care will also be assessed using review of medical records. Qualitative assessments will be used to explore barriers to and facilitators for integrating the Asthma APGAR tools into daily practice in primary care. DISCUSSION: Data from this pivotal pragmatic study are intended to demonstrate the importance of linking assessment of asthma and management tools to improve asthma-related patient outcomes. The study is an effectiveness trial done in real world PBRN practices using patient-oriented outcome measures, making it generalizable to the largest possible group of asthma care providers and primary care clinics. PMID- 27774022 TI - Incidence of diabetic peripheral neuropathic pain in primary care - a retrospective cohort study using the United Kingdom General Practice Research Database. AB - PURPOSE: To determine the incidence of diabetic peripheral neuropathic pain (DPNP) in the United Kingdom (UK) primary care population using the General Practice Research Database (GPRD). PATIENTS AND METHODS: This retrospective cohort study identified incident cases of DPNP in the UK GPRD between July 1, 2002 and June 30, 2011, using diagnostic codes. Trends in the incidence rate were examined by dividing the study period into 3-year periods: (1) July 1, 2002-June 30, 2005; (2) July 1, 2005-June 30, 2008; and (3) July 1, 2008-June 30, 2011. Patient characteristics (age, sex, comorbidities) and initial pharmacological treatment were described; the proportion of patients with incident DPNP, who had previously been screened for neuropathic symptoms, was determined. RESULTS: Among almost 7.5 million persons contributing 38,118,838 person-years of observations in the GPRD, 6,779 new cases of DPNP were identified (45.5%, women), giving an incidence rate of 17.8 per 100,000 person-years (95% confidence interval [CI] 17.4-18.2). The incidence of DPNP increased with age, but it was stable over the three consecutive 3-year periods: 17.9, 17.2, and 18.4 cases per 100,000 person years. Of the 6,779 patients with incident DPNP, 15.5% had prior neuropathic screening during the study period. The majority of patients with incident DPNP (84.5%) had a treatment for pain initiated within 28 days of first diagnosis. The most common first-line treatments prescribed were tricyclic antidepressants (27.2%), anticonvulsants (17.0%), and nonsteroidal anti-inflammatory drugs (14.9%), with 26.6% of patients receiving combination therapy as their initial treatment. CONCLUSION: The incidence of DPNP in UK primary care has remained steady over the past 10 years. Our results suggest that DPNP is underdiagnosed, and initial treatment prescribed does not follow clinical guidelines. PMID- 27774023 TI - An 8-week multimodal treatment program improves symptoms of knee osteoarthritis: a real-world multicenter experience. AB - PURPOSE: To report outcomes from a 5-year real-world clinical experience with a multimodal treatment program in patients with symptomatic knee osteoarthritis (OA). METHODS: Patients with symptomatic, radiographically confirmed knee OA resistant to traditional conservative treatments underwent a supervised 8-week multimodal treatment program consisting of low-impact aerobic exercise, muscle flexibility exercises, joint mobilization, physical therapy modalities, muscle strengthening and functional training, patient education, and a series of 3 or 5 weekly hyaluronic acid injections. Patients were evaluated at admission, 4 weeks, and 8 weeks. Patient-reported outcomes included knee pain severity using an 11 point (0-10) numerical scale and the Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS: A total of 3,569 patients completed an 8-week treatment course between January 2008 and April 2013 at 66 dedicated treatment centers in the United States. Knee pain severity assessed on a numeric scale decreased 59% on average, from 5.4+/-2.9 to 2.2+/-2.2 (P<0.001). Western Ontario and McMaster Universities Osteoarthritis Index subscores decreased by 44% to 51% (all P<0.001) during the 8-week program. The percentage of patients achieving the threshold for Western Ontario and McMaster Universities Osteoarthritis Index minimally perceptible clinical improvement was 79% for the Pain subscale, 75% for Function, and 76% for Stiffness. Favorable patient outcomes were reported in all subgroups, regardless of age, sex, body mass index, disease severity, or number of treatment cycles. DISCUSSION: A real-world 8-week multimodal treatment program results in clinically meaningful improvements in knee OA symptoms, with excellent generalizability across a broad range of patient characteristics. PMID- 27774024 TI - Cancer pain therapy with a fixed combination of prolonged-release oxycodone/naloxone: results from a non-interventional study. AB - BACKGROUND: Strong opioids, including oxycodone, are the most effective analgesics used to combat moderate to severe cancer pain, but opioid-induced bowel dysfunction is a relevant problem associated with the therapy. Clinical studies have demonstrated equivalent analgesic efficacy and improved bowel function in treatment with a fixed combination of prolonged-release (PR) oxycodone and PR naloxone compared to oxycodone alone in patients with nonmalignant pain. Here, we report of a prospective, non-interventional study evaluating the effectiveness and safety of PR oxycodone/PR naloxone in a subgroup of patients with severe cancer pain. PATIENTS AND METHODS: Within the non interventional multicenter study, 1,178 cancer patients with severe chronic pain received PR oxycodone/PR naloxone, dosed according to pain intensity, for 4 weeks. Recorded variables included pain intensity, patient-reported bowel function (Bowel Function Index), and pain-related functional impairment as a measure of quality of life (QoL). RESULTS: During treatment with PR oxycodone/PR naloxone, clinically relevant improvements in pain intensity were observed in opioid-naive patients and in patients pretreated with weak or strong opioids, as reflected by reductions in pain scores of 51%, 53%, and 33%, respectively. Improvement in analgesia was paralleled by a significant reduction of opioid induced bowel dysfunction in opioid-pretreated patients. The reductions in the mean Bowel Function Index of -20.5 and -36.5 in patients pretreated with weak and strong opioids, respectively, represent clinically relevant improvements in bowel function. Pain-related functional impairment decreased consistently across all seven domains, which is equivalent to a substantial improvement in QoL. CONCLUSION: This subgroup analysis of cancer patients within a large non interventional study demonstrates that treatment with PR oxycodone/PR naloxone provides effective analgesia with minimization of bowel dysfunction and improved QoL. These data extend our knowledge of the effectiveness and tolerability of PR oxycodone/PR naloxone to the population of patients with cancer under real-life conditions. PMID- 27774025 TI - Cognitive stimulation therapy: training, maintenance and implementation in clinical trials. AB - There are around 35 million people worldwide with dementia, more than half of whom have Alzheimer's disease (AD). Presently there are only four licensed pharmacological treatments available for treating the neuropsychological symptoms of AD. These include cholinesterase inhibitors, licensed for the treatment of people with mild to moderate AD, and an N-methyl-D-aspartate antagonist (memantine) licensed for the treatment of people with moderate to severe AD. These treatment options have modest symptomatic benefits for at least 6 months and possibly for 2 years or longer. Increasing evidence from randomized controlled trials has shown the potential value of cognitive training and cognitive rehabilitation in people with AD. There is a good evidence base to support the use of cognitive stimulation as a nonpharmacological treatment approach for people with AD, of which the most promising is cognitive stimulation therapy (CST). CST has shown benefits for cognition and well-being in people with dementia across a number of randomized controlled trials. There are important key issues related to the use of CST for people with AD, such as long-term benefits, implementation of individualized CST, adjunctive benefits with pharmacological treatments, and optimizing overall implementation of CST. Some of these key issues are already being addressed by ongoing clinical trials. Nevertheless, the strength of the current evidence from randomized controlled trials gives strong support to clinical implementation of CST in practice. Ongoing clinical trials will help to refine and optimize the use of CST in clinical practice. PMID- 27774026 TI - Diagnosis, treatment, and burden of illness among adults with attention deficit/hyperactivity disorder in Europe. AB - PURPOSE: To quantitatively address the burden of attention-deficit/hyperactivity disorder (ADHD) in Europe (Germany, the UK, Sweden, Denmark, and the Netherlands), to describe adult experience leading to diagnosis and treatment of ADHD, and to compare those findings with results from the US. SURVEY RESPONDENTS AND METHODS: Data were collected from an international web-based survey of adults from Europe and the US. Sociodemographics, comorbidities, work productivity/activity impairments, and health care utilization of adults reporting an ADHD diagnosis (n=431) and a similar number of adults without ADHD (n=449) were compared. Respondents' experiences with the diagnosis and treatment of ADHD and the perceived effects of the condition on psychosocial functioning were assessed. In addition, multivariate regression analyses were performed to compare the burden of ADHD between the two regions. RESULTS: Adults with ADHD in both regions were generally less likely to be married, employed, or rate their health as good/very good/excellent and were more likely to smoke, have experienced alcoholism, have other mental health conditions, have work productivity/activity impairments, and use health care resources. Although the specialties of health care professionals consulted prior to diagnosis were similar between the two regions, there was a notable difference in the length of time it took to receive a first ADHD diagnosis. Only 55% of European respondents received a diagnosis within 6 months of their first physician consultation regarding their ADHD symptoms, compared to 90% in the US. The results of regression analyses confirmed a greater impact of ADHD on psychosocial functioning, work productivity impairments, and the total number of provider visits in Europe. CONCLUSION: The results revealed a significant impact of ADHD on adults over a range of outcomes, including social, family, and work relationships, health-related work productivity impairment, and health care resource use, with a generally greater burden of illness among European study participants than those from the US. PMID- 27774027 TI - Effects on hypertensive patients' satisfaction with information about their medication after nurses' consultation training. AB - BACKGROUND: There is a well-known problem in hypertension care with patients' adherence to treatment. Patients who score high in answering the instrument Satisfaction with Information about Medicine Scale are reported to have greater adherence to their medication. AIM: To explore how hypertensive patients' satisfaction with information about their medicines was affected by nurses' education in Motivational Interviewing. MATERIAL AND METHODS: The Stages of Change model and Motivational Interviewing was the theoretical base for consultation training for nurses. Nineteen nurses attended 3 days of video recorded consultation training with simulated patients. They were updated in hypertensive medication and were trained in motivating patients to improve their self-management as well as adherence to lifestyle changes and medication. The satisfaction with information instrument identifies patients' satisfaction with information about the action and usage of medication as well as potential problems with it. The instrument was used to assess how well the needs of individual patients for medicine information were met at baseline and 2 years after the training. The 19 trained nurses in the intervention group worked with 137 patients, and a control group of 16 nurses, who gave normal care, worked with 51 patients. RESULTS: There was a difference between the intervention and control group in total score (P=0.028) 2 years after the intervention. Patients in the intervention group perceived higher satisfaction with the action and usage of their medication (P=0.001) and a lower degree of potential problems with their medication (P=0.001). Patients in the control group also perceived a lower degree of potential problems with their medication (P=0.028). CONCLUSION: We suggest that consultation training for nurses with the aim of motivating patients to be more self-directed in their self-care improves satisfaction with information about medication. PMID- 27774028 TI - Challenges in designing, conducting, and reporting oral health behavioral intervention studies in primary school age children: methodological issues. AB - Often within oral health, clinical outcome measures dominate trial design rather than behavioral outcome measures, and often there is a reliance on proxy self reporting of children's behavior with no corroboration through triangulation of measures. The complexity of the interventions involved in oral health intervention is often overlooked in trial design, and more flexible pragmatic designs that take account of the research context may be more appropriate. Some of the limitations in oral health behavioral intervention studies (trials) in primary school age children were reported in a recently published Cochrane review. This paper aims to critically discuss the findings of a recent Cochrane review in terms of the methodological implications that arise for future design, development, measurement, and reporting of oral health trials in primary school age children. Key components of the UK Medical Research Council's framework for the design and evaluation of complex interventions are discussed in relation to using taxonomies of behavior change. This paper is not designed to be a definitive guide but aims to bring learning from other areas of public health and health promotion into dental public health. Ultimately, the aim is to aid the design of more successful interventions that produce long-term behavioral changes in children in relation to toothbrushing and nighttime sugar snacking. PMID- 27774029 TI - Autoinjector preference in multiple sclerosis and the role of nurses in treatment decisions: results from an international survey in Europe and the USA. AB - PURPOSE: This international survey recorded the opinions of multiple sclerosis (MS) nurses about their role in treatment decision making and about the importance of different attributes of autoinjectors used to deliver first-line parenteral therapy. METHODS: The survey involved 52 MS nurses in different practice settings in France, Germany, Italy, the UK, and the USA. Nurses described their role in patient education and in treatment decision making. They also rated the importance of nine prespecified attributes of autoinjectors and stated their preference, both overall and by attribute, for one of two autoinjectors used to deliver interferon beta-1b (ExtaviPro(r) 30G and Betacomfort(r)). Nurses' preferences were compared with those previously collected from patients using an identical questionnaire. RESULTS: There were pronounced differences between practice settings and between countries in the opinions of MS nurses about their influence on treatment decision making. Nurses considered themselves instrumental in helping patients decide between treatment options offered by neurologists. Of the nine autoinjector attributes, nurses rated "reliable to use" as most important, followed by attributes associated with convenience ("easy to operate," "ergonomic shape," "reach" [of injection sites], and "one-handed injection"). Nurses' and patients' rankings of attributes were closely aligned. For the nine attributes, 74%-98% of nurses preferred ExtaviPro(r) 30G to Betacomfort(r), 94% preferring ExtaviPro(r) 30G overall. Nurses showed a greater preference than patients for ExtaviPro(r) 30G with respect to "easy to operate" (92% vs 78%), "intuitive to use" (98% vs 78%), and "attractive design" (98% vs 83%; P<0.05, all), but preference rates were otherwise similar across the two groups. The most common reasons in both groups for preferring ExtaviPro(r) 30G to Betacomfort(r) were "easy to use" and "ergonomic shape." CONCLUSION: MS nurses play a key role in patient guidance and education. Their preferences for ExtaviPro(r) 30G likely reflect their understanding of the challenges patients face when self-administering treatment. PMID- 27774030 TI - Understanding the treatment of attention deficit hyperactivity disorder in newly diagnosed adult patients in general practice: a UK database study. AB - BACKGROUND: Adult attention deficit hyperactivity disorder (ADHD) has been largely ignored in psychiatric and general practice guidance until recently. Adult ADHD has a high social and medical burden, but health care is not well described in the UK. The main study objective was to evaluate a primary care adult ADHD population in terms of prescribing and health care contact rates. METHODS: This was a retrospective observational study using data from the Clinical Practice Research Database from January 1, 2002 to July 31, 2011. Adult patients with an incident ADHD diagnosis or ADHD medication were identified as having been free of ADHD medication or diagnoses in the previous 2 years. Patients were followed for 12-24 months after diagnosis. RESULTS: Of the 663 patients with ADHD in the cohort, 54.1% were prescribed ADHD medication during the observation period. During the first 6 months, 34.2% of patients initiated methylphenidates and 14.0% atomoxetine. In total, 36.3% patients were referred to secondary care psychiatry during observation, with the remaining population (63.7%) never having a referral. Most of the referrals were before diagnosis in primary care. At the end of the observation period, 16.2% of patients were on antipsychotics, 17.3% hypnotics, and 34.8% antidepressants or anxiolytics; however, some patients appeared to be prescribed antipsychotic or antidepressant medications even if they did not have an observable diagnosis in their records. Health care contact rates (general practitioner or hospital) increased by 39.2% post-diagnosis (incidence rate ratio: 1.39; 95% confidence interval: 1.32, 1.47), which may be related to the need for medication monitoring and titration. CONCLUSION: This study has shown in primary care that there is relatively low use of ADHD medication, low referrals into secondary care, high rates of usage of psychiatric non-ADHD medications for different indications, and an increasing burden in terms of health care contacts in adult ADHD patients post-diagnosis. PMID- 27774031 TI - Remission, response, and relapse rates in patients with acute schizophrenia treated with olanzapine monotherapy or other atypical antipsychotic monotherapy: 12-month prospective observational study. AB - PURPOSE: To compare the rates of antipsychotic response, remission, and relapse in patients with schizophrenia treated with olanzapine or other antipsychotics in usual clinical care in Japan. PATIENTS AND METHODS: This analysis of a 12-month, prospective, noninterventional study examined outcomes for 1,089 inpatients and outpatients with schizophrenia who initiated antipsychotic monotherapy. All treatment decisions, including medication choice, were left to the discretion of the treating physician. The rates of treatment response, relapse, and 6-month sustained remission were compared between olanzapine monotherapy (OLZ) and other anti-psychotic monotherapy (OAN), and between OLZ and other atypical antipsychotic monotherapy (OAT). Visit-wise comparisons of treatment response and remission were examined using repeated-measures logistic regressions. Propensity scores were used to control for potential baseline differences between groups. RESULTS: Response rates were higher for OLZ patients and relapse rates were consistently lower for OLZ patients, however the differences were not statistically significant. Rates of 6-month sustained remission were significantly higher for OLZ than OAN patients (P=0.032) and for OLZ than OAT patients (P=0.041). An exploratory analysis of OLZ and OAN comparison found outpatients treated with OLZ or OAN had similar sustained remission rates (OLZ: 22.2%, OAN: 22.8%), while inpatients treated with OLZ had significantly higher sustained remission rates than inpatients treated with OAN (OLZ: 17.1%, OAN: 6.6%, odds ratio [95% confidence interval] =3.54 [2.00-6.25]). CONCLUSION: In usual care in Japan, treating the acute symptoms of schizophrenia with olanzapine was not found to be significantly different for response and relapse rates; however, treatment with olanzapine was found to have significantly greater sustained remission rates than treatment with other antipsychotics. In the inpatient setting, where patients tend to be more severe and difficult to manage, olanzapine treatment may lead to higher sustained remission rates than other antipsychotics. PMID- 27774032 TI - Efficacy and effectiveness trials have different goals, use different tools, and generate different messages. AB - The discussion about the optimal design of clinical trials reflects the perspectives of theory-based scientists and practice-based clinicians. Scientists compare the theory with published results. They observe a continuum from explanatory to pragmatic trials. Clinicians compare the problem they want to solve by completing a clinical trial with the results they can read in the literature. They observe a mixture of what they want and what they get. None of them can solve the problem without the support of the other. Here, we summarize the results of discussions with scientists and clinicians. All participants were interested to understand and analyze the arguments of the other side. As a result of this process, we conclude that scientists tell what they see, a continuum from clear explanatory to clear pragmatic trials. Clinicians tell what they want to see, a clear explanatory trial to describe the expected effects under ideal study conditions and a clear pragmatic trial to describe the observed effects under real-world conditions. Following this discussion, the solution was not too difficult. When we accept what we see, we will not get what we want. If we discuss a necessary change of management, we will end up with the conclusion that two types of studies are necessary to demonstrate efficacy and effectiveness. Efficacy can be demonstrated in an explanatory, ie, a randomized controlled trial (RCT) completed under ideal study conditions. Effectiveness can be demonstrated in an observational, ie, a pragmatic controlled trial (PCT) completed under real world conditions. It is impossible to design a trial which can detect efficacy and effectiveness simultaneously. The RCTs describe what we may expect in health care, while the PCTs describe what we really observe. PMID- 27774033 TI - Preliminary Evidence of Reduced Urge to Cough and Cough Response in Four Individuals following Remote Traumatic Brain Injury with Tracheostomy. AB - Cough and swallow protect the lungs and are frequently impaired following traumatic brain injury (TBI). This project examined cough response to inhaled capsaicin solution challenge in a cohort of four young adults with a history of TBI within the preceding five years. All participants had a history of tracheostomy with subsequent decannulation and dysphagia after their injuries (resolved for all but one participant). Urge to cough (UTC) and cough response were measured and compared to an existing database of normative cough response data obtained from 32 healthy controls (HCs). Participants displayed decreased UTC and cough responses compared to HCs. It is unknown if these preliminary results manifest as a consequence of disrupted sensory (afferent) projections, an inability to perceive or discriminate cough stimuli, disrupted motor (efferent) response, peripheral weakness, or any combination of these factors. Future work should attempt to clarify if the observed phenomena are borne out in a larger sample of individuals with TBI, determine the relative contributions of central versus peripheral nervous system structures to cough sensory perceptual changes following TBI (should they exist), and formulate recommendations for systematic screening and assessment of cough sensory perception in order to facilitate rehabilitative efforts. This project is identified with the National Clinical Trials NCT02240329. PMID- 27774035 TI - More reliable inference for the dissimilarity index of segregation. AB - The most widely used measure of segregation is the so-called dissimilarity index. It is now well understood that this measure also reflects randomness in the allocation of individuals to units (i.e. it measures deviations from evenness, not deviations from randomness). This leads to potentially large values of the segregation index when unit sizes and/or minority proportions are small, even if there is no underlying systematic segregation. Our response to this is to produce adjustments to the index, based on an underlying statistical model. We specify the assignment problem in a very general way, with differences in conditional assignment probabilities underlying the resulting segregation. From this, we derive a likelihood ratio test for the presence of any systematic segregation, and bias adjustments to the dissimilarity index. We further develop the asymptotic distribution theory for testing hypotheses concerning the magnitude of the segregation index and show that the use of bootstrap methods can improve the size and power properties of test procedures considerably. We illustrate these methods by comparing dissimilarity indices across school districts in England to measure social segregation. PMID- 27774034 TI - Longitudinal Predictors of Homelessness: Findings from the National Longitudinal Survey of Youth-97. AB - Homeless youth represent a vulnerable and understudied population. Little research has prospectively identified factors that may place youth at risk for experiencing homelessness. The current study utilizes data from the National Longitudinal Survey of Youth-97 (NLSY-97) to examine predictors of experiencing homelessness as a young adult (before age 25). The NLSY-97 includes a nationally representative sample of 8,984 youth. Data were first collected from these youth when they were between the ages of 12 to 18 years. The current study examined whether individual and family risk factors reported during adolescence predict homelessness by the age of 25. The findings showed that multiple runaway episodes, non-traditional family structure, lower educational attainment, and parental work limitations due to health increased the risk of homelessness. A permissive parenting style and being Hispanic protected against homelessness. This study offers unique insight into risk and protective factors for youth homelessness, and has important clinical implications. PMID- 27774036 TI - Effect of sonication on particle dispersion, administered dose and metal release of non-functionalized, non-inert metal nanoparticles. AB - ABSTRACT: In this study, we elucidate the effect of different sonication techniques to efficiently prepare particle dispersions from selected non functionalized NPs (Cu, Al, Mn, ZnO), and corresponding consequences on the particle dose, surface charge and release of metals. Probe sonication was shown to be the preferred method for dispersing non-inert, non-functionalized metal NPs (Cu, Mn, Al). However, rapid sedimentation during sonication resulted in differences between the real and the administered doses in the order of 30-80 % when sonicating in 1 and 2.56 g/L NP stock solutions. After sonication, extensive agglomeration of the metal NPs resulted in rapid sedimentation of all particles. DLVO calculations supported these findings, showing the strong van der Waals forces of the metal NPs to result in significant NP agglomeration. Metal release from the metal NPs was slightly increased by increased sonication. The addition of a stabilizing agent (bovine serum albumin) had an accelerating effect on the release of metals in sonicated solutions. For Cu and Mn NPs, the extent of particle dissolution increased from <1.6 to ~5 % after sonication for 15 min. A prolonged sonication time (3-15 min) had negligible effects on the zeta potential of the studied NPs. In all, it is shown that it is of utmost importance to carefully investigate how sonication influences the physico-chemical properties of dispersed metal NPs. This should be considered in nanotoxicology investigations of metal NPs. GRAPHICAL ABSTRACT: PMID- 27774037 TI - Uptake of silver nanoparticles by monocytic THP-1 cells depends on particle size and presence of serum proteins. AB - Human health risks by silver nanoparticle (AgNP) exposure are likely to increase due to the increasing number of NP-containing products and demonstrated adverse effects in various cell lines. Unfortunately, results from (toxicity) studies are often based on exposure dose and are often measured only at a fixed time point. NP uptake kinetics and the time-dependent internal cellular concentration are often not considered. Macrophages are the first line of defense against invading foreign agents including NPs. How macrophages deal with the particles is essential for potential toxicity of the NPs. However, there is a considerable lack of uptake studies of particles in the nanometer range and macrophage-like cells. Therefore, uptake rates were determined over 24 h for three different AgNPs sizes (20, 50 and 75 nm) in medium with and without fetal calf serum. Non toxic concentrations of 10 ng Ag/mL for monocytic THP-1 cells, representing realistic exposure concentration for short-term exposures, were chosen. The uptake of Ag was higher in medium without fetal calf serum and showed increasing uptake for decreasing NP sizes, both on NP mass and on number basis. Internal cellular concentrations reached roughly 32/10 %, 25/18 % and 21/15 % of the nominal concentration in the absence of fetal calf serum/with fetal calf serum for 20-, 50- and 75-nm NPs, respectively. Our research shows that uptake kinetics in macrophages differ for various NP sizes. To increase the understanding of the mechanism of NP toxicity in cells, the process of uptake (timing) should be considered. PMID- 27774038 TI - Synthesis of a Crushed Fullerene C60H24 through Sixfold Palladium-Catalyzed Arylation. AB - The synthesis of a new C3v -symmetric crushed fullerene C60H24 (5) has been accomplished in three steps from truxene through sixfold palladium-catalyzed intramolecular arylation of a syn-trialkylated truxene precursor. Laser irradiation of 5 induces cyclodehydrogenation processes that result in the formation of C60, as detected by LDI-MS. PMID- 27774039 TI - TRANSLATION AND ADAPTATION OF COMPUTER ASSISTED SMOKING PREVENTION PROGRAM IN ROMANIA (ASPIRA). AB - ASPIRA smoking prevention online program consists in studying five modules that include tests, videos and interactive games. It was tested on a group of schoolchildren and students from Tirgu Mures by completing a questionnaire with reference to the opinions of the young people and the functionality of the software. The vast majority of those questioned reported a good or very good impression about the ASPIRA program and believed that the information presented was suitable. High school pupils and boys were more critical. PMID- 27774040 TI - Structural and electronic characterisation of pi-extended tetrathiafulvalene derivatives as active components in field-effect transistors. AB - The electronic and structural properties of two tetrathiafulvalene derivatives bearing aromatic benzene rings are reported. Thin film transistors of these materials show p-type characteristics with comparable mobility values. It is found that the rigidification of the molecule is beneficial for reducing the reorganisation energy but also has an unfavorable impact on the electronic structure dimensionality. PMID- 27774042 TI - GLUMIP 2.0: SAS/IML Software for Planning Internal Pilots. AB - Internal pilot designs involve conducting interim power analysis (without interim data analysis) to modify the final sample size. Recently developed techniques have been described to avoid the type I error rate inflation inherent to unadjusted hypothesis tests, while still providing the advantages of an internal pilot design. We present GLUMIP 2.0, the latest version of our free SAS/IML software for planning internal pilot studies in the general linear univariate model (GLUM) framework. The new analytic forms incorporated into the updated software solve many problems inherent to current internal pilot techniques for linear models with Gaussian errors. Hence, the GLUMIP 2.0 software makes it easy to perform exact power analysis for internal pilots under the GLUM framework with independent Gaussian errors and fixed predictors. PMID- 27774041 TI - Birth of Archaeal Cells: Molecular Phylogenetic Analyses of G1P Dehydrogenase, G3P Dehydrogenases, and Glycerol Kinase Suggest Derived Features of Archaeal Membranes Having G1P Polar Lipids. AB - Bacteria and Eukarya have cell membranes with sn-glycerol-3-phosphate (G3P), whereas archaeal membranes contain sn-glycerol-1-phosphate (G1P). Determining the time at which cells with either G3P-lipid membranes or G1P-lipid membranes appeared is important for understanding the early evolution of terrestrial life. To clarify this issue, we reconstructed molecular phylogenetic trees of G1PDH (G1P dehydrogenase; EgsA/AraM) which is responsible for G1P synthesis and G3PDHs (G3P dehydrogenase; GpsA and GlpA/GlpD) and glycerol kinase (GlpK) which is responsible for G3P synthesis. Together with the distribution of these protein encoding genes among archaeal and bacterial groups, our phylogenetic analyses suggested that GlpA/GlpD in the Commonote (the last universal common ancestor of all extant life with a cellular form, Commonote commonote) acquired EgsA (G1PDH) from the archaeal common ancestor (Commonote archaea) and acquired GpsA and GlpK from a bacterial common ancestor (Commonote bacteria). In our scenario based on this study, the Commonote probably possessed a G3P-lipid membrane synthesized enzymatically, after which the archaeal lineage acquired G1PDH followed by the replacement of a G3P-lipid membrane with a G1P-lipid membrane. PMID- 27774043 TI - Polyanionic Biopolymers for the Delivery of Pt(II) Cationic Antiproliferative Complexes. AB - Phenanthriplatin, that is, (SP-4-3)-diamminechlorido(phenanthridine)platinum(II) nitrate, an effective antitumor cationic Pt(II) complex, was loaded on negatively charged dextran sulfate (DS) as a model vector for drug delivery via electrostatic interactions. The free complex and the corresponding conjugate with DS were tested on two standard human tumor cell lines, namely, ovarian A2780 and colon HCT 116, and on several malignant pleural mesothelioma cell lines (namely, epithelioid BR95, mixed/biphasic MG06, sarcomatoid MM98, and sarcomatoid cisplatin-resistant MM98R). The in vitro results suggest that the conjugate releases the active metabolite phenanthriplatin with a biphasic fashion. In these experimental conditions, the conjugate is slightly less active than free phenanthriplatin; but both exhibited antiproliferative potency higher than the reference metallodrug cisplatin and were able to overcome the acquired cisplatin chemoresistance in MM98R cells. PMID- 27774044 TI - Structural and Antioxidant Properties of Compounds Obtained from Fe2+ Chelation by Juglone and Two of Its Derivatives: DFT, QTAIM, and NBO Studies. AB - The chelating ability of juglone and two of its derivatives towards Fe2+ion and the antioxidant activity (AOA) of the resulting chelates and complexes (in the presence of H2O and CH3OH as ligands) in gas phase is reported via bond dissociation enthalpy, ionization potential, proton dissociation enthalpy, proton affinity, and electron transfer enthalpy. The DFT/B3LYP level of theory associated with the 6-31+G(d,p) and 6-31G(d) Pople-style basis sets on the atoms of the ligands and the central Fe(II), respectively, was used. Negative chelation free energies obtained revealed that juglone derivatives possessing the O-H substituent (L2) have the greatest ability to chelate Fe2+ ion. Apart from 1B, thermodynamic descriptors of the AOA showed that the direct hydrogen atom transfer is the preferred mechanism of the studied molecules. NBO analysis showed that the Fe-ligand bonds are all formed through metal to ligand charge transfer. QTAIM studies revealed that among all the Fe-ligand bonds, the O1-Fe bond of 1A is purely covalent. The aforementioned results show that the ligands can be used to fight against Fe(II) toxicity, thus preserving human health, and fight against the deterioration of industrial products. In addition, most of the complexes studied have shown a better AOA than their corresponding ligands. PMID- 27774045 TI - Automated small-scale protein purification and analysis for accelerated development of protein therapeutics. AB - Small-scale protein purification presents opportunities for accelerated process development of biotherapeutic molecules. Miniaturization of purification conditions reduces time and allows for parallel processing of samples, thus offering increased statistical significance and greater breadth of variables. The ability of the miniaturized platform to be predictive of larger scale purification schemes is of critical importance. The PerkinElmer JANUS BioTx Pro and Pro-Plus workstations were developed as intuitive, flexible, and automated devices capable of performing parallel small-scale analytical protein purification. Preprogrammed methods automate a variety of commercially available ion exchange and affinity chromatography solutions, including miniaturized chromatography columns, resin-packed pipette tips, and resin-filled microtiter vacuum filtration plates. Here, we present a comparison of microscale chromatography versus standard fast protein LC (FPLC) methods for process optimization. In this study, we evaluated the capabilities of the JANUS BioTx Pro Plus robotic platform for miniaturized chromatographic purification of proteins with the GE ?KTA Express system. We were able to demonstrate predictive analysis similar to that of larger scale purification platforms, while offering advantages in speed and number of samples processed. This approach is predictive of scale-up conditions, resulting in shorter biotherapeutic development cycles and less consumed material than traditional FPLC methods, thus reducing time-to-market from discovery to manufacturing. PMID- 27774046 TI - Optimizing the Face Paradigm of BCI System by Modified Mismatch Negative Paradigm. AB - Many recent studies have focused on improving the performance of event-related potential (ERP) based brain computer interfaces (BCIs). The use of a face pattern has been shown to obtain high classification accuracies and information transfer rates (ITRs) by evoking discriminative ERPs (N200 and N400) in addition to P300 potentials. Recently, it has been proved that the performance of traditional P300 based BCIs could be improved through a modification of the mismatch pattern. In this paper, a mismatch inverted face pattern (MIF-pattern) was presented to improve the performance of the inverted face pattern (IF-pattern), one of the state of the art patterns used in visual-based BCI systems. Ten subjects attended in this experiment. The result showed that the mismatch inverted face pattern could evoke significantly larger vertex positive potentials (p < 0.05) and N400s (p < 0.05) compared to the inverted face pattern. The classification accuracy (mean accuracy is 99.58%) and ITRs (mean bit rate is 27.88 bit/min) of the mismatch inverted face pattern was significantly higher than that of the inverted face pattern (p < 0.05). PMID- 27774048 TI - Design and Evaluation of Fusion Approach for Combining Brain and Gaze Inputs for Target Selection. AB - Gaze-based interfaces and Brain-Computer Interfaces (BCIs) allow for hands-free human-computer interaction. In this paper, we investigate the combination of gaze and BCIs. We propose a novel selection technique for 2D target acquisition based on input fusion. This new approach combines the probabilistic models for each input, in order to better estimate the intent of the user. We evaluated its performance against the existing gaze and brain-computer interaction techniques. Twelve participants took part in our study, in which they had to search and select 2D targets with each of the evaluated techniques. Our fusion-based hybrid interaction technique was found to be more reliable than the previous gaze and BCI hybrid interaction techniques for 10 participants over 12, while being 29% faster on average. However, similarly to what has been observed in hybrid gaze and-speech interaction, gaze-only interaction technique still provides the best performance. Our results should encourage the use of input fusion, as opposed to sequential interaction, in order to design better hybrid interfaces. PMID- 27774047 TI - Linking Resting-State Networks in the Prefrontal Cortex to Executive Function: A Functional Near Infrared Spectroscopy Study. AB - Executive function (EF) plays vital roles in our everyday adaptation to the ever changing environment. However, limited existing studies have linked EF to the resting-state brain activity. The functional connectivity in the resting state between the sub-regions of the brain can reveal the intrinsic neural mechanisms involved in cognitive processing of EF without disturbance from external stimuli. The present study investigated the relations between the behavioral executive function (EF) scores and the resting-state functional network topological properties in the Prefrontal Cortex (PFC). We constructed complex brain functional networks in the PFC from 90 healthy young adults using functional near infrared spectroscopy (fNIRS). We calculated the correlations between the typical network topological properties (regional topological properties and global topological properties) and the scores of both the Total EF and components of EF measured by computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB). We found that the Total EF scores were positively correlated with regional properties in the right dorsal superior frontal gyrus (SFG), whereas the opposite pattern was found in the right triangular inferior frontal gyrus (IFG). Different EF components were related to different regional properties in various PFC areas, such as planning in the right middle frontal gyrus (MFG), working memory mainly in the right MFG and triangular IFG, short-term memory in the left dorsal SFG, and task switch in the right MFG. In contrast, there were no significant findings for global topological properties. Our findings suggested that the PFC plays an important role in individuals' behavioral performance in the executive function tasks. Further, the resting-state functional network can reveal the intrinsic neural mechanisms involved in behavioral EF abilities. PMID- 27774049 TI - Histological Basis of Laminar MRI Patterns in High Resolution Images of Fixed Human Auditory Cortex. AB - Functional magnetic resonance imaging (fMRI) studies of the auditory region of the temporal lobe would benefit from the availability of image contrast that allowed direct identification of the primary auditory cortex, as this region cannot be accurately located using gyral landmarks alone. Previous work has suggested that the primary area can be identified in magnetic resonance (MR) images because of its relatively high myelin content. However, MR images are also affected by the iron content of the tissue and in this study we sought to confirm that different MR image contrasts did correlate with the myelin content in the gray matter and were not primarily affected by iron content as is the case in the primary visual and somatosensory areas. By imaging blocks of fixed post-mortem cortex in a 7 T scanner and then sectioning them for histological staining we sought to assess the relative contribution of myelin and iron to the gray matter contrast in the auditory region. Evaluating the image contrast in [Formula: see text]-weighted images and quantitative [Formula: see text] maps showed a reasonably high correlation between the myelin density of the gray matter and the intensity of the MR images. The correlation with T1-weighted phase sensitive inversion recovery (PSIR) images was better than with the previous two image types, and there were clearly differentiated borders between adjacent cortical areas in these images. A significant amount of iron was present in the auditory region, but did not seem to contribute to the laminar pattern of the cortical gray matter in MR images. Similar levels of iron were present in the gray and white matter and although iron was present in fibers within the gray matter, these fibers were fairly uniformly distributed across the cortex. Thus, we conclude that T1- and [Formula: see text]-weighted imaging sequences do demonstrate the relatively high myelin levels that are characteristic of the deep layers in primary auditory cortex and allow it and some of the surrounding areas to be reliably distinguished. PMID- 27774050 TI - Regulation of mRNA Translation by MID1: A Common Mechanism of Expanded CAG Repeat RNAs. AB - Expansion of CAG repeats, which code for the disease-causing polyglutamine protein, is a common feature in polyglutamine diseases. RNA-mediated mechanisms that contribute to neuropathology in polyglutamine diseases are important. RNA toxicity describes a phenomenon by which the mutant CAG repeat RNA recruits RNA binding proteins, thereby leading to aberrant function. For example the MID1 protein binds to mutant huntingtin (HTT) RNA, which is linked to Huntington's disease (HD), at its CAG repeat region and induces protein synthesis of mutant protein. But is this mechanism specific to HD or is it a common mechanism in CAG repeat expansion disorders? To answer this question, we have analyzed the interaction between MID1 and three other CAG repeat mRNAs, Ataxin2 (ATXN2), Ataxin3 (ATXN3), and Ataxin7 (ATXN7), that all differ in the sequence flanking the CAG repeat. We show that ATXN2, ATXN3, and ATXN7 bind to MID1 in a CAG repeat length-dependent manner. Furthermore, we show that functionally, in line with what we have previously observed for HTT, the binding of MID1 to ATXN2, ATXN3, and ATXN7 mRNA induces protein synthesis in a repeat length-dependent manner. Our data suggest that regulation of protein translation by the MID1 complex is a common mechanism for CAG repeat containing mRNAs. PMID- 27774051 TI - C9orf72's Interaction with Rab GTPases-Modulation of Membrane Traffic and Autophagy. AB - Hexanucleotide repeat expansion in an intron of Chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). While functional haploinsufficiency of C9orf72 resulting from the mutation may play a role in ALS/FTD, the actual cellular role of the protein has been unclear. Recent findings have now shown that C9orf72 physically and functionally interacts with multiple members of the Rab small GTPases family, consequently exerting important influences on cellular membrane traffic and the process of autophagy. Loss of C9orf72 impairs endocytosis in neuronal cell lines, and attenuated autophagosome formation. Interestingly, C9orf72 could influence autophagy both as part of a Guanine nucleotide exchange factor (GEF) complex, or as a Rab effector that facilitates transport of the Unc-51-like Autophagy Activating Kinase 1 (Ulk1) autophagy initiation complex. The cellular function of C9orf72 is discussed in the light of these recent findings. PMID- 27774053 TI - Calretinin-Periglomerular Interneurons in Mice Olfactory Bulb: Cells of Few Words. AB - Within the olfactory bulb (OB), periglomerular (PG) cells consist of various types of interneurons, generally classified by their chemical properties such as neurotransmitter and calcium binding proteins. Calretinin (CR) characterizes morphologically and functionally the more numerous and one of the less known subpopulation of PG cells in the OB. Using of transgenic mice expressing eGFP under the CR promoter, we have tried to obtain the first functional characterization of these cells. Electrophysiological recordings were made in these cells using the patch-clamp technique in thin slices. Using ion substitution methods and specific blockers, we dissected the main voltage dependent conductances present, obtaining a complete kinetic description for each of them. The more peculiar property of these cells from the electrophysiological point of view is the presence only of a single K-current, A-type - there is no trace of delayed rectifier or of Ca-dependent K-current. Other currents identified, isolated and fully characterized are a fast sodium current, a small L type calcium current, and an inward rectifier, h-type cationic current. As a consequence of the peculiar complement of voltage-dependent conductances present in these cells, and in particular the absence of delayed-rectifier potassium currents, under the functional point of view these cells present two interesting properties. First, in response to prolonged depolarisations, after the inactivation of the A-current these cells behave as a purely ohmic elements, showing no outward rectification. Second, the CR cells studied can respond only with a single action potential to excitatory inputs; since they send inhibitory synapses to projection neurones, they seem to be designed to inhibit responses of the main neurones to isolated, random excitatory signals, rapidly losing their vetoing effect in response to more structured, repetitive excitatory signals. We propose that a possible role for these rather untalkative interneurons in the intense exchange of messages within the OB might be that of improving the signal to-noise ratio in the first stages of the olfactory information processing. PMID- 27774052 TI - Altered Expression of Genes Encoding Neurotransmitter Receptors in GnRH Neurons of Proestrous Mice. AB - Gonadotropin-releasing hormone (GnRH) neurons play a key role in the central regulation of reproduction. In proestrous female mice, estradiol triggers the pre ovulatory GnRH surge, however, its impact on the expression of neurotransmitter receptor genes in GnRH neurons has not been explored yet. We hypothesized that proestrus is accompanied by substantial changes in the expression profile of genes coding for neurotransmitter receptors in GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact, proestrous, and metestrous female GnRH-GFP transgenic mice, respectively. About 1500 individual GnRH neurons were sampled from both groups and their transcriptome was analyzed using microarray hybridization and real-time PCR. In this study, changes in mRNA expression of genes involved in neurotransmitter signaling were investigated. Differential gene expression was most apparent in GABA-ergic (Gabbr1, Gabra3, Gabrb3, Gabrb2, Gabrg2), glutamatergic (Gria1, Gria2, Grin1, Grin3a, Grm1, Slc17a6), cholinergic (Chrnb2, Chrm4) and dopaminergic (Drd3, Drd4), adrenergic (Adra1b, Adra2a, Adra2c), adenosinergic (Adora2a, Adora2b), glycinergic (Glra), purinergic (P2rx7), and serotonergic (Htr1b) receptors. In concert with these events, expression of genes in the signaling pathways downstream to the receptors, i.e., G-proteins (Gnai1, Gnai2, Gnas), adenylate-cyclases (Adcy3, Adcy5), protein kinase A (Prkaca, Prkacb) protein kinase C (Prkca) and certain transporters (Slc1a4, Slc17a6, Slc6a17) were also changed. The marked differences found in the expression of genes involved in neurotransmitter signaling of GnRH neurons at pro- and metestrous stages of the ovarian cycle indicate the differential contribution of these neurotransmitter systems to the induction of the pre-ovulatory GnRH surge, the known prerequisite of the subsequent hormonal cascade inducing ovulation. PMID- 27774054 TI - TMSEEG: A MATLAB-Based Graphical User Interface for Processing Electrophysiological Signals during Transcranial Magnetic Stimulation. AB - Concurrent recording of electroencephalography (EEG) during transcranial magnetic stimulation (TMS) is an emerging and powerful tool for studying brain health and function. Despite a growing interest in adaptation of TMS-EEG across neuroscience disciplines, its widespread utility is limited by signal processing challenges. These challenges arise due to the nature of TMS and the sensitivity of EEG to artifacts that often mask TMS-evoked potentials (TEP)s. With an increase in the complexity of data processing methods and a growing interest in multi-site data integration, analysis of TMS-EEG data requires the development of a standardized method to recover TEPs from various sources of artifacts. This article introduces TMSEEG, an open-source MATLAB application comprised of multiple algorithms organized to facilitate a step-by-step procedure for TMS-EEG signal processing. Using a modular design and interactive graphical user interface (GUI), this toolbox aims to streamline TMS-EEG signal processing for both novice and experienced users. Specifically, TMSEEG provides: (i) targeted removal of TMS induced and general EEG artifacts; (ii) a step-by-step modular workflow with flexibility to modify existing algorithms and add customized algorithms; (iii) a comprehensive display and quantification of artifacts; (iv) quality control check points with visual feedback of TEPs throughout the data processing workflow; and (v) capability to label and store a database of artifacts. In addition to these features, the software architecture of TMSEEG ensures minimal user effort in initial setup and configuration of parameters for each processing step. This is partly accomplished through a close integration with EEGLAB, a widely used open source toolbox for EEG signal processing. In this article, we introduce TMSEEG, validate its features and demonstrate its application in extracting TEPs across several single- and multi-pulse TMS protocols. As the first open-source GUI-based pipeline for TMS-EEG signal processing, this toolbox intends to promote the widespread utility and standardization of an emerging technology in brain research. PMID- 27774055 TI - Stimulation of Baroresponsive Parts of the Nucleus of the Solitary Tract Produces Nitric Oxide-mediated Choroidal Vasodilation in Rat Eye. AB - Preganglionic parasympathetic neurons of the ventromedial part of the superior salivatory nucleus (SSN) mediate vasodilation of orbital and choroidal blood vessels, via their projection to the nitrergic pterygopalatine ganglion (PPG) neurons that innervate these vessels. We recently showed that the baroresponsive part of the nucleus of the solitary tract (NTS) innervates choroidal control parasympathetic preganglionic neurons of SSN in rats. As this projection provides a means by which blood pressure (BP) signals may modulate choroidal blood flow (ChBF), we investigated if activation of baroresponsive NTS evokes ChBF increases in rat eye, using Laser Doppler Flowmetry (LDF) to measure ChBF transclerally. We found that electrical activation of ipsilateral baroresponsive NTS and its efferent fiber pathway to choroidal SSN increased mean ChBF by about 40-80% above baseline, depending on current level. The ChBF responses obtained with stimulation of baroresponsive NTS were driven by increases in both choroidal blood volume (ChBVol; i.e., vasodilation) and choroidal blood velocity (ChBVel; possibly due to orbital vessel dilation). Stimulation of baroresponsive NTS, by contrast, yielded no significant mean increases in systemic arterial blood pressure (ABP). We further found that the increases in ChBF with NTS stimulation were significantly reduced by administration of the neuronal nitric oxide (NO) synthase inhibitor Nomega-propyl-l-arginine (NPA), thus implicating nitrergic PPG terminals in the NTS-elicited ChBF increases. Our results show that the NTS neurons projecting to choroidal SSN do mediate increase in ChBF, and thus suggest a role of baroresponsive NTS in the BP-dependent regulation of ChBF. PMID- 27774056 TI - Microglomerular Synaptic Complexes in the Sky-Compass Network of the Honeybee Connect Parallel Pathways from the Anterior Optic Tubercle to the Central Complex. AB - While the ability of honeybees to navigate relying on sky-compass information has been investigated in a large number of behavioral studies, the underlying neuronal system has so far received less attention. The sky-compass pathway has recently been described from its input region, the dorsal rim area (DRA) of the compound eye, to the anterior optic tubercle (AOTU). The aim of this study is to reveal the connection from the AOTU to the central complex (CX). For this purpose, we investigated the anatomy of large microglomerular synaptic complexes in the medial and lateral bulbs (MBUs/LBUs) of the lateral complex (LX). The synaptic complexes are formed by tubercle-lateral accessory lobe neuron 1 (TuLAL1) neurons of the AOTU and GABAergic tangential neurons of the central body's (CB) lower division (TL neurons). Both TuLAL1 and TL neurons strongly resemble neurons forming these complexes in other insect species. We further investigated the ultrastructure of these synaptic complexes using transmission electron microscopy. We found that single large presynaptic terminals of TuLAL1 neurons enclose many small profiles (SPs) of TL neurons. The synaptic connections between these neurons are established by two types of synapses: divergent dyads and divergent tetrads. Our data support the assumption that these complexes are a highly conserved feature in the insect brain and play an important role in reliable signal transmission within the sky-compass pathway. PMID- 27774057 TI - Bayesian Alternation during Tactile Augmentation. AB - A large number of studies suggest that the integration of multisensory signals by humans is well-described by Bayesian principles. However, there are very few reports about cue combination between a native and an augmented sense. In particular, we asked the question whether adult participants are able to integrate an augmented sensory cue with existing native sensory information. Hence for the purpose of this study, we build a tactile augmentation device. Consequently, we compared different hypotheses of how untrained adult participants combine information from a native and an augmented sense. In a two interval forced choice (2 IFC) task, while subjects were blindfolded and seated on a rotating platform, our sensory augmentation device translated information on whole body yaw rotation to tactile stimulation. Three conditions were realized: tactile stimulation only (augmented condition), rotation only (native condition), and both augmented and native information (bimodal condition). Participants had to choose one out of two consecutive rotations with higher angular rotation. For the analysis, we fitted the participants' responses with a probit model and calculated the just notable difference (JND). Then, we compared several models for predicting bimodal from unimodal responses. An objective Bayesian alternation model yielded a better prediction (chired2 = 1.67) than the Bayesian integration model (chired2 = 4.34). Slightly higher accuracy showed a non-Bayesian winner takes all (WTA) model (chired2 = 1.64), which either used only native or only augmented values per subject for prediction. However, the performance of the Bayesian alternation model could be substantially improved (chired2 = 1.09) utilizing subjective weights obtained by a questionnaire. As a result, the subjective Bayesian alternation model predicted bimodal performance most accurately among all tested models. These results suggest that information from augmented and existing sensory modalities in untrained humans is combined via a subjective Bayesian alternation process. Therefore, we conclude that behavior in our bimodal condition is explained better by top down-subjective weighting than by bottom-up weighting based upon objective cue reliability. PMID- 27774058 TI - "It Don't Mean a Thing if It Ain't Got that Swing"- an Alternative Concept for Understanding the Evolution of Dance and Music in Human Beings. AB - The functions of dance and music in human evolution are a mystery. Current research on the evolution of music has mainly focused on its melodic attribute which would have evolved alongside (proto-)language. Instead, we propose an alternative conceptual framework which focuses on the co-evolution of rhythm and dance (R&D) as intertwined aspects of a multimodal phenomenon characterized by the unity of action and perception. Reviewing the current literature from this viewpoint we propose the hypothesis that R&D have co-evolved long before other musical attributes and (proto-)language. Our view is supported by increasing experimental evidence particularly in infants and children: beat is perceived and anticipated already by newborns and rhythm perception depends on body movement. Infants and toddlers spontaneously move to a rhythm irrespective of their cultural background. The impulse to dance may have been prepared by the susceptibility of infants to be soothed by rocking. Conceivable evolutionary functions of R&D include sexual attraction and transmission of mating signals. Social functions include bonding, synchronization of many individuals, appeasement of hostile individuals, and pre- and extra-verbal communication enabling embodied individual and collective memorizing. In many cultures R&D are used for entering trance, a base for shamanism and early religions. Individual benefits of R&D include improvement of body coordination, as well as painkilling, anti-depressive, and anti-boredom effects. Rhythm most likely paved the way for human speech as supported by studies confirming the overlaps between cognitive and neural resources recruited for language and rhythm. In addition, dance encompasses visual and gestural communication. In future studies attention should be paid to which attribute of music is focused on and that the close mutual relation between R&D is taken into account. The possible evolutionary functions of dance deserve more attention. PMID- 27774059 TI - Music Upper Limb Therapy-Integrated: An Enriched Collaborative Approach for Stroke Rehabilitation. AB - : Stroke is a leading cause of disability worldwide. It leads to a sudden and overwhelming disruption in one's physical body, and alters the stroke survivors' sense of self. Long-term recovery requires that bodily perception, social participation and sense of self are restored; this is challenging to achieve, particularly with a single intervention. However, rhythmic synchronization of movement to external stimuli facilitates sensorimotor coupling for movement recovery, enhances emotional engagement and has positive effects on interpersonal relationships. In this proof-of-concept study, we designed a group music-making intervention, Music Upper Limb Therapy-Integrated (MULT-I), to address the physical, psychological and social domains of rehabilitation simultaneously, and investigated its effects on long-term post-stroke upper limb recovery. The study used a mixed-method pre-post design with 1-year follow up. Thirteen subjects completed the 45-min intervention twice a week for 6 weeks. The primary outcome was reduced upper limb motor impairment on the Fugl-Meyer Scale (FMS). Secondary outcomes included sensory impairment (two-point discrimination test), activity limitation (Modified Rankin Scale, MRS), well-being (WHO well-being index), and participation (Stroke Impact Scale, SIS). Repeated measures analysis of variance (ANOVA) was used to test for differences between pre- and post-intervention, and 1-year follow up scores. Significant improvement was found in upper limb motor impairment, sensory impairment, activity limitation and well-being immediately post-intervention that persisted at 1 year. Activities of daily living and social participation improved only from post-intervention to 1-year follow up. The improvement in upper limb motor impairment was more pronounced in a subset of lower functioning individuals as determined by their pre-intervention wrist range of motion. Qualitatively, subjects reported new feelings of ownership of their impaired limb, more spontaneous movement, and enhanced emotional engagement. The results suggest that the MULT-I intervention may help stroke survivors re-create their sense of self by integrating sensorimotor, emotional and interoceptive information and facilitate long-term recovery across multiple domains of disability, even in the chronic stage post-stroke. Randomized controlled trials are warranted to confirm the efficacy of this approach. CLINICAL TRIAL REGISTRATION: National Institutes of Health, clinicaltrials.gov, NCT01586221. PMID- 27774061 TI - Retraction: Prediction of Mortality Based on Facial Characteristics. AB - [This retracts the article on p. 173 in vol. 10, PMID: 27242466.]. PMID- 27774062 TI - ViSimpl: Multi-View Visual Analysis of Brain Simulation Data. AB - After decades of independent morphological and functional brain research, a key point in neuroscience nowadays is to understand the combined relationships between the structure of the brain and its components and their dynamics on multiple scales, ranging from circuits of neurons at micro or mesoscale to brain regions at macroscale. With such a goal in mind, there is a vast amount of research focusing on modeling and simulating activity within neuronal structures, and these simulations generate large and complex datasets which have to be analyzed in order to gain the desired insight. In such context, this paper presents ViSimpl, which integrates a set of visualization and interaction tools that provide a semantic view of brain data with the aim of improving its analysis procedures. ViSimpl provides 3D particle-based rendering that allows visualizing simulation data with their associated spatial and temporal information, enhancing the knowledge extraction process. It also provides abstract representations of the time-varying magnitudes supporting different data aggregation and disaggregation operations and giving also focus and context clues. In addition, ViSimpl tools provide synchronized playback control of the simulation being analyzed. Finally, ViSimpl allows performing selection and filtering operations relying on an application called NeuroScheme. All these views are loosely coupled and can be used independently, but they can also work together as linked views, both in centralized and distributed computing environments, enhancing the data exploration and analysis procedures. PMID- 27774060 TI - Pre-stimulus Alpha Oscillations and Inter-subject Variability of Motor Evoked Potentials in Single- and Paired-Pulse TMS Paradigms. AB - Inter- and intra-subject variability of the motor evoked potentials (MEPs) to TMS is a well-known phenomenon. Although a possible link between this variability and ongoing brain oscillations was demonstrated, the results of the studies are not consistent with each other. Exploring this topic further is important since the modulation of MEPs provides unique possibility to relate oscillatory cortical phenomena to the state of the motor cortex probed with TMS. Given that alpha oscillations were shown to reflect cortical excitability, we hypothesized that their power and variability might explain the modulation of subject-specific MEPs to single- and paired-pulse TMS (spTMS, ppTMS, respectively). Neuronal activity was recorded with multichannel electroencephalogram. We used spTMS and two ppTMS conditions: intracortical facilitation (ICF) and short-interval intracortical inhibition (SICI). Spearman correlations were calculated within and across subjects between MEPs and the pre-stimulus power of alpha oscillations in low (8 10 Hz) and high (10-12 Hz) frequency bands. Coefficient of quartile variation was used to measure variability. Across-subject analysis revealed no difference in the pre-stimulus alpha power among the TMS conditions. However, the variability of high-alpha power in spTMS condition was larger than in the SICI condition. In ICF condition pre-stimulus high-alpha power variability correlated positively with MEP amplitude variability. No correlation has been observed between the pre stimulus alpha power and MEP responses in any of the conditions. Our results show that the variability of the alpha oscillations can be more predictive of TMS effects than the commonly used power of oscillations and we provide further support for the dissociation of high and low-alpha bands in predicting responses produced by the stimulation of the motor cortex. PMID- 27774063 TI - A Novel Asp121Asn Mutation of Myelin Protein Zero Is Associated with Late-Onset Axonal Charcot-Marie-Tooth Disease, Hearing Loss and Pupil Abnormalities. AB - Myelin protein zero (MPZ) is a major component of compact myelin in peripheral nerves. Mutations in MPZ have been associated with different Charcot-Marie-Tooth disease (CMT) phenotypes (CMT1B, CMT2I/J, CMTDI), Dejerine-Sottas syndrome, and congenital hypomyelination neuropathy. Here, we report phenotypic variability in a four-generation Chinese family with the MPZ mutation Asp121Asn. Genetic testing was performed on nine family members and 200 controls. Clinical, electrophysiological and skeletal muscle MRI assessments were available for review in six family members. A novel heterozygous missense mutation, Asp121Asn, was observed in five affected members of the family. Unaffected relatives and 200 normal controls were without the mutation. Four of the affected members of the family displayed late-onset, predominantly axonal sensory and motor neuropathy, pupil abnormalities, and progressive sensorineural hearing loss. One young affected member presented with Argyll-Robertson pupils and diminished deep tendon reflexes in the lower limbs. The MPZ mutation Asp121Asn may be associated with late-onset axonal neuropathy, early onset hearing loss and pupil abnormalities. Our report expands the number and phenotypic spectrum of MPZ mutations. PMID- 27774064 TI - SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer. AB - Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI), which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI's function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies. PMID- 27774065 TI - Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents. AB - Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated by the endocannabinoid system (ECS), which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death. However, many studies investigated these effects using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical animal models and to examine the current standing of cannabinoids that are being tested in human cancer patients. PMID- 27774066 TI - Rhizoma Coptidis: A Potential Cardiovascular Protective Agent. AB - Cardiovascular diseases (CVDs) are among the leading causes of morbidity and mortality in both the developed and developing world. Rhizoma coptidis (RC), known as Huang Lian in China, is the dried rhizome of medicinal plants from the family Ranunculaceae, such as Coptis chinensis Franch, C. deltoidea C.Y. Cheng et Hsiao, and C. teeta Wall which has been used by Chinese medicinal physicians for more than 2000 years. In China, RC is a common component in traditional medicines used to treat CVD associated problems including obesity, diabetes mellitus, hyperlipidemia, hyperglycemia and disorders of lipid metabolism. In recent years, numerous scientific studies have sought to investigate the biological properties of RC to provide scientific evidence for its traditional medical uses. RC has been found to exert significant beneficial effects on major risk factors for CVDs including anti-atherosclerotic effect, lipid-lowering effect, anti-obesity effect and anti-hepatic steatosis effect. It also has myocardioprotective effect as it provides protection from myocardial ischemia-reperfusion injury. These properties have been attributed to the presence of bioactive compounds contained in RC such as berberine, coptisine, palmatine, epiberberine, jatrorrhizine, and magnoflorine; all of which have been demonstrated to have cardioprotective effects on the various parameters contributing to the occurrence of CVD through a variety of pathways. The evidence available in the published literature indicates that RC is a herb with tremendous potential to reduce the risks of CVDs, and this review aims to summarize the cardioprotective properties of RC with reference to the published literature which overall indicates that RC is a herb with remarkable potential to reduce the risks and damage caused by CVDs. PMID- 27774067 TI - Species Comparison of Pre-systemic Bioactivation of Vicagrel, a New Acetate Derivative of Clopidogrel. AB - Previously we have found vicagrel, a new acetate derivative of clopidogrel, underwent hydrolysis to 2-oxo-clopidogrel and subsequent conversions to its pharmacological active metabolite (AM) and inactive carboxylic acid metabolite (CAM). This study demonstrated the interspecies differences of the vicagrel bioactivation by comparing the critical vicagrel metabolites formation in rats, dogs and human. The pharmacokinetic studies with rats and dogs were conducted after intragastric administration of vicagrel, followed by in vitro metabolism investigation in venous system, intestinal/hepatic microsomes from rats, dogs and human. An obvious disparity was observed in system exposure to AM (99.0 vs. 635.1 MUg?h/L, p < 0.05) and CAM (10119 vs. 2634 MUg?h/L, p < 0.05) in rats and dogs. It was shown that the cleavage of vicagrel was almost completed in intestine with great different clearance (53.28 vs. 3.643 L?h-1?kg-1, p < 0.05) in rats and dogs. With no further hydrolysis to CAM, the greatest clearance of AM (3.26 mL?h 1?kg-1) was found in dog intestine. In rat plasma, 2-oxo-clopidogrel was much more extensively hydrolyzed to CAM than in dog and human. Albeit similar hydrolysis clearance and AM production was observed among hepatic microsomes of the three species, the production velocity of CAM ranked highest in dogs (7.55 pmol/min/mg protein). Therefore, the unconformity of AM and CAM exposure cross species mainly came from the metabolism of 2-oxo-clopidogrel associated largely with tissue specificity and interspecies differences of esterases. In human, the pharmacokinetics of vicagrel might be more optimistic due to less inactivation hydrolysis before reaching liver. PMID- 27774068 TI - The Apical Localization of Na+, K+-ATPase in Cultured Human Retinal Pigment Epithelial Cells Depends on Expression of the beta2 Subunit. AB - Na+, K+-ATPase, or the Na+ pump, is a key component in the maintenance of the epithelial phenotype. In most epithelia, the pump is located in the basolateral domain. Studies from our laboratory have shown that the beta1 subunit of Na+, K+ ATPase plays an important role in this mechanism because homotypic beta1-beta1 interactions between neighboring cells stabilize the pump in the lateral membrane. However, in the retinal pigment epithelium (RPE), the Na+ pump is located in the apical domain. The mechanism of polarization in this epithelium is unclear. We hypothesized that the apical polarization of the pump in RPE cells depends on the expression of its beta2 subunit. ARPE-19 cells cultured for up to 8 weeks on inserts did not polarize, and Na+, K+-ATPase was expressed in the basolateral membrane. In the presence of insulin, transferrin and selenic acid (ITS), ARPE-19 cells cultured for 4 weeks acquired an RPE phenotype, and the Na+ pump was visible in the apical domain. Under these conditions, Western blot analysis was employed to detect the beta2 isoform and immunofluorescence analysis revealed an apparent apical distribution of the beta2 subunit. qPCR results showed a time-dependent increase in the level of beta2 isoform mRNA, suggesting regulation at the transcriptional level. Moreover, silencing the expression of the beta2 isoform in ARPE-19 cells resulted in a decrease in the apical localization of the pump, as assessed by the mislocalization of the alpha2 subunit in that domain. Our results demonstrate that the apical polarization of Na+, K+-ATPase in RPE cells depends on the expression of the beta2 subunit. PMID- 27774070 TI - Modeling the Behavior of Red Blood Cells within the Caudal Vein Plexus of Zebrafish. AB - Due to the important biological role of red blood cells (RBCs) in vertebrates, the analysis of reshaping and dynamics of RBCs motion is a critical issue in physiology and biomechanics. In this paper the behavior of RBCs within the immature capillary plexus during embryonic development of zebrafish has been analyzed. Relying on the fact that zebrafish embryos are small and optically transparent, it is possible to image the blood flow. In this way the anatomy of blood vessels is monitored along with the circulation throughout their development. Numerical simulations were performed using a specific numerical model that combines fluid flow simulation, modeling of the interaction of individual RBCs immersed in blood plasma with the surrounding fluid and modeling the deformation of individual cells. The results of numerical simulations are in accordance with the in vivo observed region of interest within the caudal vein plexus of the zebrafish embryo. Good agreement of results demonstrates the capabilities of the developed numerical model to predict and analyze the motion and deformation of RBCs in complex geometries. The proposed model (methodology) will help to elucidate different rheological and hematological related pathologies and finally to design better treatment strategies. PMID- 27774069 TI - The Effects of Disease Models of Nuclear Actin Polymerization on the Nucleus. AB - Actin plays a crucial role in regulating multiple processes within the nucleus, including transcription and chromatin organization. However, the polymerization state of nuclear actin remains controversial, and there is no evidence for persistent actin filaments in a normal interphase nucleus. Further, several disease pathologies are characterized by polymerization of nuclear actin into stable filaments or rods. These include filaments that stain with phalloidin, resulting from point mutations in skeletal alpha-actin, detected in the human skeletal disease intranuclear rod myopathy, and cofilin/actin rods that form in response to cellular stressors like heatshock. To further elucidate the effects of these pathological actin structures, we examined the nucleus in both cell culture models as well as isolated human tissues. We find these actin structures alter the distribution of both RNA polymerase II and chromatin. Our data suggest that nuclear actin filaments result in disruption of nuclear organization, which may contribute to the disease pathology. PMID- 27774072 TI - Processing Load Imposed by Line Breaks in English Temporal Wh-Questions. AB - Prosody plays an important role in online sentence processing both explicitly and implicitly. It has been shown that prosodically packaging together parts of a sentence that are interpreted together facilitates processing of the sentence. This applies not only to explicit prosody but also implicit prosody. The present work hypothesizes that a line break in a written text induces an implicit prosodic break, which, in turn, should result in a processing bias for interpreting English wh-questions. Two experiments-one self-paced reading study and one questionnaire study-are reported. Both supported the "line break" hypothesis mentioned above. The results of the self-paced reading experiment showed that unambiguous wh-questions were read faster when the location of line breaks (or frame breaks) matched the scope of a wh-phrase (main or embedded clause) than when they did not. The questionnaire tested sentences with an ambiguous wh-phrase, one that could attach either to the main or the embedded clause. These sentences were interpreted as attaching to the main clause more often than to the embedded clause when a line break appeared after the main verb, but not when it appeared after the embedded verb. PMID- 27774071 TI - Characterization of a Mouse Model of Emphysema Induced by Multiple Instillations of Low-Dose Elastase. AB - Many experimental models have been proposed to study the pathophysiological features of emphysema, as well as to search for new therapeutic approaches for acute or chronically injured lung parenchyma. We aimed to characterize an emphysema model induced by multiple instillations of elastase by tracking changes in inflammation, remodeling, and cardiac function after each instillation. Forty eight C57BL/6 mice were randomly assigned across two groups. Emphysema (ELA) animals received 1, 2, 3, or 4 intratracheal instillations of pancreatic porcine elastase (PPE, 0.2 IU) with a 1-week interval between them. Controls (C) received saline following the same protocol. Before and after implementation of the protocol, animals underwent echocardiographic analysis. After the first instillation of PPE, the percentage of mononuclear cells in the lung parenchyma increased compared to C (p = 0.0001). The second instillation resulted in hyperinflated alveoli, increased mean linear intercept, and reduced elastic fiber content in lung parenchyma compared to C (p = 0.0197). Following the third instillation, neutrophils and collagen fiber content in alveolar septa and airways increased, whereas static lung elastance was reduced compared to C (p = 0.0094). After the fourth instillation, the percentage of M1 macrophages in lungs; levels of interleukin-1beta (IL-1beta), keratinocyte-derived chemokine, hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF); and collagen fiber content in the pulmonary vessel wall were increased compared to C (p = 0.0096). At this time point, pulmonary arterial hypertension was apparent, with increased diastolic right ventricular wall thickness. In conclusion, the initial phase of emphysema was characterized by lung inflammation with predominance of mononuclear cells, whereas at the late stage, impairment of pulmonary and cardiovascular functions was observed. This model enables analysis of therapies at different time points during controlled progression of emphysema. Accordingly, early interventions could focus on the inflammatory process, while late interventions should focus on restoring cardiorespiratory function. PMID- 27774073 TI - Effects of Music Therapy on Drug Therapy of Adult Psychiatric Outpatients: A Pilot Randomized Controlled Study. AB - Objective: Framed in the patients' engagement perspective, the current study aims to determine the effects of group music therapy in addition to drug care in comparison with drug care in addition to other non-expressive group activities in the treatment of psychiatric outpatients. Method: Participants (n = 27) with ICD 10 diagnoses of F20 (schizophrenia), F25 (schizoaffective disorders), F31 (bipolar affective disorder), F32 (depressive episode), and F60 (specific personality disorders) were randomized to receive group music therapy plus standard care (48 weekly sessions of 2 h) or standard care only. The clinical measures included dosages of neuroleptics, benzodiazepines, mood stabilizers, and antidepressants. Results: The participants who received group music therapy demonstrated greater improvement in drug dosage with respect to neuroleptics than those who did not receive group music therapy. Antidepressants had an increment for both groups that was significant only for the control group. Benzodiazepines and mood stabilizers did not show any significant change in either group. Conclusion: Group music therapy combined with standard drug care was effective for controlling neuroleptic drug dosages in adult psychiatric outpatients who received group music therapy. We discussed the likely applications of group music therapy in psychiatry and the possible contribution of music therapy in improving the psychopathological condition of adult outpatients. In addition, the implications for the patient-centered perspective were also discussed. PMID- 27774074 TI - Technology as Teammate: Examining the Role of External Cognition in Support of Team Cognitive Processes. AB - In this paper we advance team theory by describing how cognition occurs across the distribution of members and the artifacts and technology that support their efforts. We draw from complementary theorizing coming out of cognitive engineering and cognitive science that views forms of cognition as external and extended and integrate this with theorizing on macrocognition in teams. Two frameworks are described that provide the groundwork for advancing theory and aid in the development of more precise measures for understanding team cognition via focus on artifacts and the technologies supporting their development and use. This includes distinctions between teamwork and taskwork and the notion of general and specific competencies from the organizational sciences along with the concepts of offloading and scaffolding from the cognitive sciences. This paper contributes to the team cognition literature along multiple lines. First, it aids theory development by synthesizing a broad set of perspectives on the varied forms of cognition emerging in complex collaborative contexts. Second, it supports research by providing diagnostic guidelines to study how artifacts are related to team cognition. Finally, it supports information systems designers by more precisely describing how to conceptualize team-supporting technology and artifacts. As such, it provides a means to more richly understand process and performance as it occurs within sociotechnical systems. Our overarching objective is to show how team cognition can both be more clearly conceptualized and more precisely measured by integrating theory from cognitive engineering and the cognitive and organizational sciences. PMID- 27774075 TI - False-Belief Understanding and Language Ability Mediate the Relationship between Emotion Comprehension and Prosocial Orientation in Preschoolers. AB - Emotion comprehension (EC) is known to be a key correlate and predictor of prosociality from early childhood. In the present study, we examined this relationship within the broad theoretical construct of social understanding which includes a number of socio-emotional skills, as well as cognitive and linguistic abilities. Theory of mind, especially false-belief understanding, has been found to be positively correlated with both EC and prosocial orientation. Similarly, language ability is known to play a key role in children's socio-emotional development. The combined contribution of false-belief understanding and language to explaining the relationship between EC and prosociality has yet to be investigated. Thus, in the current study, we conducted an in-depth exploration of how preschoolers' false-belief understanding and language ability each contribute to modeling the relationship between children's comprehension of emotion and their disposition to act prosocially toward others, after controlling for age and gender. Participants were 101 4- to 6-year-old children (54% boys), who were administered measures of language ability, false-belief understanding, EC and prosocial orientation. Multiple mediation analysis of the data suggested that false-belief understanding and language ability jointly and fully mediated the effect of preschoolers' EC on their prosocial orientation. Analysis of covariates revealed that gender exerted no statistically significant effect, while age had a trivial positive effect. Theoretical and practical implications of the findings are discussed. PMID- 27774076 TI - Academic Failure and Child-to-Parent Violence: Family Protective Factors. AB - A reduction in academic achievement over the course of adolescence has been observed. School failure is characterized by difficulties to teaching school goals. A variety of other behavioral problems are often associated with school failure. Child-to-parent violence has been associated with different school problems. The main objective of current study was to examine the contribution of family variables (parental education level, family cohesion, and positive family discipline) on academic failure and child-to-parent violence of adolescents from a community sample. Moreover, a goal was to explore if academic failure was a valid predictor of child-to-parent violence. To this end, it has been developed a comprehensive statistical model through Structural Equation Modeling (SEM). Participants were 584 children from eight secondary schools in the Basque Country (Spain) and aged between 12 and 18. Among other scales Conflict Tactics Scale and Family Environment Scale were administrated for measuring child-to-parent violence and family cohesion environment, respectively. The structural model revealed that parental education level is a relevant protective factor against academic failure. Positive family discipline (inductive discipline, supervision, and penalty) show a significant association with child-to-parent violence and academic failure. Disciplinary practices could be more efficient to prevent child to-parent violence or school failure if children perceive a positive environment in their home. However, these findings could be explained by inverse causality, because some parents respond to child-to-parent violence or academic failure with disciplinary strategies. School failure had indirect effects on child-to-parent violence through family cohesion. For all that, education policies should focus on parental education courses for disadvantaged families in order to generate appropriate learning environments at home and to foster improvement of parent child relationships. PMID- 27774077 TI - Clustering Vector Autoregressive Models: Capturing Qualitative Differences in Within-Person Dynamics. AB - In psychology, studying multivariate dynamical processes within a person is gaining ground. An increasingly often used method is vector autoregressive (VAR) modeling, in which each variable is regressed on all variables (including itself) at the previous time points. This approach reveals the temporal dynamics of a system of related variables across time. A follow-up question is how to analyze data of multiple persons in order to grasp similarities and individual differences in within-person dynamics. We focus on the case where these differences are qualitative in nature, implying that subgroups of persons can be identified. We present a method that clusters persons according to their VAR regression weights, and simultaneously fits a shared VAR model to all persons within a cluster. The performance of the algorithm is evaluated in a simulation study. Moreover, the method is illustrated by applying it to multivariate time series data on depression-related symptoms of young women. PMID- 27774078 TI - The Relationship between Sleep Complaints, Depression, and Executive Functions on Older Adults. AB - Aim: In this manuscript, we report data on the association between executive functions screened by Frontal Assessment Battery, Five Digit Test and Digit Span with self-reported depressive symptoms and sleep complaints in non-demented older adults. Methods: A total sample of 95 non-demented older adults performed Geriatric Depression Scale short version, Frontal Assessment Battery, Five Digit Test, Digit Span, and clinical interview. We split participants in groups stratified by age according to: young-old (60-69 years of age), old-old (70-79 years), and oldest-old (>80 years) and compared these three groups on the sociodemographic characteristics and executive functions performance. We carried out Poisson regression with robust error variance to verify sleep complaints and depression effects on executive functions performance. Gender, age, years of formal education, use of antidepressants and of benzodiazepines were considered as confounding variables, taking into account executive functions as dependent and sleep complaints and depression as independent variables. Results: Controlling the effect of age, gender, years of formal education, use of benzodiazepines and of antidepressants there was a significant influence of depression in motor programming, inhibitory control, and working memory. Individuals without depression show motor programming scores 68.4% higher, inhibitory control scores 3 times greater and working memory scores also 3 times greater than individuals without depression. There was a significant influence of sleep complaints in phonemic fluency, motor programming, inhibitory control, and working memory. Individuals without sleep complaints show phonemic fluency scores 2 times greater than, motor programming scores 85.9% higher, inhibitory control scores 3 times greater and working memory scores also 3 times greater than individuals without sleep complaints. Conclusions: Sleep complaints are associated with phonemic fluency, motor programming, inhibitory control, and working memory impairment. Depression symptoms presence are associated with motor programming and working memory performances. Depression and sleep complaints interaction would determine worse phonemic fluency, inhibitory control and working memory cognitive performance than these two conditions alone. PMID- 27774079 TI - Music Ensemble as a Resilient System. Managing the Unexpected through Group Interaction. AB - The present contribution provides readers from diverse fields of psychology with a new and comprehensive model for the understanding of the characteristics of music ensembles. The model is based on a novel heuristic approach whose key construct is resilience, intended here as the ability of a system to adapt to external perturbations and anticipate future events. The paper clarifies the specificity of music ensemble as an original social and creative activity, and how some mechanisms, at an individual (cognitive) and group (coordination) level, are enacted in a particular way that endows these groups with exceptional capacity for resilience. There is now a wealth of evidence isolating the psychological mechanisms involved in these processes. However, there is much less focus on conditions in which the group has to face unexpected and potentially performance-disruptive events. The resilience approach offers a more thorough explanation of the regulatory strategies that musicians may resort to in order to maintain their performance at an optimal level. Music ensembles of different size are presented as case studies of how such systems (and their individual members) resist error and maintain joint performance. Three hypothetical scenarios are further proposed that epitomize resilient or non-resilient musical teams. The present contribution further proposes hypotheses and formulates predictions on which combinations of individual and group factors foster team resilience. This model further accommodates the most recent findings in neuroscience and experimental psychology. Besides highlighting the potential of music ensemble for psychological research, it offers hints about how resilience could be trained. PMID- 27774080 TI - Temporal Characteristics of Radiologists' and Novices' Lesion Detection in Viewing Medical Images Presented Rapidly and Sequentially. AB - Although viewing multiple stacks of medical images presented on a display is a relatively new but useful medical task, little is known about this task. Particularly, it is unclear how radiologists search for lesions in this type of image reading. When viewing cluttered and dynamic displays, continuous motion itself does not capture attention. Thus, it is effective for the target detection that observers' attention is captured by the onset signal of a suddenly appearing target among the continuously moving distractors (i.e., a passive viewing strategy). This can be applied to stack viewing tasks, because lesions often show up as transient signals in medical images which are sequentially presented simulating a dynamic and smoothly transforming image progression of organs. However, it is unclear whether observers can detect a target when the target appears at the beginning of a sequential presentation where the global apparent motion onset signal (i.e., signal of the initiation of the apparent motion by sequential presentation) occurs. We investigated the ability of radiologists to detect lesions during such tasks by comparing the performances of radiologists and novices. Results show that overall performance of radiologists is better than novices. Furthermore, the temporal locations of lesions in CT image sequences, i.e., when a lesion appears in an image sequence, does not affect the performance of radiologists, whereas it does affect the performance of novices. Results indicate that novices have greater difficulty in detecting a lesion appearing early than late in the image sequence. We suggest that radiologists have other mechanisms to detect lesions in medical images with little attention which novices do not have. This ability is critically important when viewing rapid sequential presentations of multiple CT images, such as stack viewing tasks. PMID- 27774081 TI - Nation, Face, and Identity: An Initial Investigation of National Face in East Asia. AB - This research investigates a key concept in East Asia, face, and represents the first attempt to empirically examine the concept of face at the national level. Controlling for the level of national identification, Study 1 employed the scenario experiment method among samples of native Chinese and Taiwanese populations and revealed that national face exhibits patterns reverse of personal face. Using the experimental method, Study 2 replicated the findings of Study 1 and provided support for the different mechanisms underneath national face and personal face. Study 3 replicated the findings of Study 2 and additionally showed that national face exerts a significant inhibitory effect on face process. Findings are discussed in terms of possible implications for intergroup and international relations. Expanding on extant scholarship on face and across three studies with different experimental paradigms, this research turns our attention from face at the personal level to face at the national level by introducing the construct of national face and examining its manifestations in East Asia. The results advance our understanding of the psychological mechanism driving face concern in East Asia. They make a strong and unique case for the psychological existence of national face as an empirically distinct construct and an important psychological resource for East Asians. PMID- 27774082 TI - Selection History Modulates Working Memory Capacity. AB - Recent studies have shown that past selection history affects the allocation of attention on target selection. However, it is unclear whether context-driven selection history can modulate the efficacy of attention allocation on working memory (WM) representations. This study tests the influences of selection history on WM capacity. A display of one item (low load) or three/four items (high load) was shown for the participants to hold in WM in a delayed response task. Participants then judged whether a probe item was in the memory display or not. Selection history was defined as the number of items attended across trials in the task context within a block, manipulated by the stimulus set-size in the contexts with fewer possible stimuli (4-item or 5-item context) or more possible stimuli (8-item or 9-item context) from which the memorized content was selected. The capacity measure (i.e., the K measure) was estimated to reflect the number of items that can be held in WM. Across four behavioral experiments, the results revealed that the capacity was significantly reduced in the context with more possible stimuli relative to the context with fewer possible stimuli. Moreover, the reduction in capacity was significant for high WM load and not observed when the focus was on only a single item. Together, these findings indicate that context-driven selection history and focused attention influence WM capacity. PMID- 27774083 TI - Comparison of Classical Kinematics, Entropy, and Fractal Properties As Measures of Complexity of the Motor System in Swimming. AB - The aim of this study was to compare the non-linear properties of the four competitive swim strokes. Sixty-eight swimmers performed a set of maximal 4 * 25 m using the four competitive swim strokes. The hip's speed-data as a function of time was collected with a speedo-meter. The speed fluctuation (dv), approximate entropy (ApEn) and the fractal dimension by Higuchi's method (D) were computed. Swimming data exhibited non-linear properties that were different among the four strokes (14.048 <= dv <= 39.722; 0.682 <= ApEn <= 1.025; 1.823 <= D <= 1.919). The ApEn showed the lowest value for front-crawl, followed by breaststroke, butterfly, and backstroke (P < 0.001). Fractal dimension and dv had the lowest values for front-crawl and backstroke, followed by butterfly and breaststroke (P < 0.001). It can be concluded that swimming data exhibits non-linear properties, which are different among the four competitive swimming strokes. PMID- 27774084 TI - Effects of Educational Music Therapy on State Hope for Recovery in Acute Care Mental Health Inpatients: A Cluster-Randomized Effectiveness Study. AB - Background: There has been an increasing emphasis on recovery as the expectation for people with mental health disorders. Purpose: The purpose of this effectiveness study is to determine if group-based educational music therapy can immediately impact state hope for recovery in acute care mental health patients. Research questions included: will acute care mental health inpatients who participate in a single music therapy session have higher agency and pathway aspects of state hope for recovery than patients in a control condition? Will there be differences in state hope for recovery as a result of hope-oriented songwriting or lyric analysis interventions? Method: Participants (N = 169) were cluster randomized to one of three single-session conditions: lyric analysis, songwriting, or wait-list control. Results: There was no significant between group difference. However, both music therapy conditions tended to have slightly higher mean pathway, agency, and total state hope scores than the control condition even within the temporal parameters of a single music therapy session. There was no between-group difference in the songwriting and lyric analysis interventions. Conclusion: Although not significant, results support that educational music therapy may impact state hope for recovery within the temporal parameters of a single session. The specific type of educational music therapy intervention did not affect results. Implications for practice, limitations, and suggestions for future research are provided. PMID- 27774086 TI - Editorial: Alternative Therapeutics against MDR Bacteria - "Fighting the Epidemic of Antibiotic Resistance". PMID- 27774085 TI - Metabolic Complementation in Bacterial Communities: Necessary Conditions and Optimality. AB - Bacterial communities may display metabolic complementation, in which different members of the association partially contribute to the same biosynthetic pathway. In this way, the end product of the pathway is synthesized by the community as a whole. However, the emergence and the benefits of such complementation are poorly understood. Herein, we present a simple model to analyze the metabolic interactions among bacteria, including the host in the case of endosymbiotic bacteria. The model considers two cell populations, with both cell types encoding for the same linear biosynthetic pathway. We have found that, for metabolic complementation to emerge as an optimal strategy, both product inhibition and large permeabilities are needed. In the light of these results, we then consider the patterns found in the case of tryptophan biosynthesis in the endosymbiont consortium hosted by the aphid Cinara cedri. Using in-silico computed physicochemical properties of metabolites of this and other biosynthetic pathways, we verified that the splitting point of the pathway corresponds to the most permeable intermediate. PMID- 27774087 TI - Identification of Genes Involved in Indole-3-Acetic Acid Biosynthesis by Gluconacetobacter diazotrophicus PAL5 Strain Using Transposon Mutagenesis. AB - Gluconacetobacter diazotrophicus is a beneficial nitrogen-fixing endophyte found in association with sugarcane plants and other important crops. Beneficial effects of G. diazotrophicus on sugarcane growth and productivity have been attributed to biological nitrogen fixation process and production of phytohormones especially indole-3-acetic acid (IAA); however, information about the biosynthesis and function of IAA in G. diazotrophicus is still scarce. Therefore, the aim of this work was to identify genes and pathways involved in IAA biosynthesis in this bacterium. In our study, the screening of two independent Tn5 mutant libraries of PAL5T strain using the Salkowski colorimetric assay revealed two mutants (Gdiaa34 and Gdiaa01), which exhibited 95% less indolic compounds than the parental strain when grown in LGIP medium supplemented with L-tryptophan. HPLC chromatograms of the wild-type strain revealed the presence of IAA and of the biosynthetic intermediates indole-3-pyruvic acid (IPyA) and indole-3-lactate (ILA). In contrast, the HPLC profiles of both mutants showed no IAA but only a large peak of non-metabolized tryptophan and low levels of IPyA and ILA were detected. Molecular characterization revealed that Gdiaa01 and Gdiaa34 mutants had unique Tn5 insertions at different sites within the GDI2456 open read frame, which is predicted to encode a L-amino acid oxidase (LAAO). GDI2456 (lao gene) forms a cluster with GDI2455 and GDI2454 ORFs, which are predicted to encode a cytochrome C and an RidA protein, respectively. RT-qPCR showed that transcript levels of lao. cccA, and ridA genes were reduced in the Gdiaa01 as compared to PAL5T. In addition, rice plants inoculated with Gdiaa01 showed significantly smaller root development (length, surface area, number of forks and tips) than those plants inoculated with PAL5T. In conclusion, our study demonstrated that G. diazotrophicus PAL5T produces IAA via the IPyA pathway in cultures supplemented with tryptophan and provides evidence for the involvement of an L-amino acid oxidase gene cluster in the biosynthesis of IAA. Furthermore, we showed that the mutant strains with reduction in IAA biosynthesis ability, in consequence of the lower transcription levels of genes of the lao cluster, had remarkable effects on development of rice roots. PMID- 27774088 TI - Fermented Alorena Table Olives as a Source of Potential Probiotic Lactobacillus pentosus Strains. AB - A collection of 31 Lactobacillus pentosus strains isolated from naturally fermented Alorena green table olives were screened in depth in the present study for their probiotic potential. Several strains could be considered promising probiotic candidates since they showed good growth capacity and survival under simulated gastro-intestinal conditions (acidic pH of 1.5, up to 4% of bile salts and 5 mM of nitrate), good ability to auto-aggregate which may facilitate their adhesion to host cells as multiple aggregates and the subsequent displacement of pathogens. Moreover, co-aggregation of lactobacilli with pathogenic bacteria was shown with Listeria innocua, Staphylococcus aureus, Escherichia coli, and Salmonella Enteritidis as good defense strategy against gut and food pathogens. Furthermore, they exhibited adherence to intestinal and vaginal cell lines, such property could be reinforced by their capacity of biofilm formation which is also important in food matrices such as the olive surface. Their antagonistic activity against pathogenic bacteria by means of acids and plantaricins, and also their different functional properties may determine their efficacy not only in the gastro-intestinal tract but also in food matrices. Besides their ability to ferment several prebiotics, the new evidence in the present study was their capacity to ferment lactose which reinforces their use in different food matrices including dairy as a dietary adjunct to improve lactose digestibility. Lactobacillus pentosus CF2-10N was selected to have the best probiotic profile being of great interest in further studies. In conclusion, spontaneous fermented Alorena table olives are considered a natural source of potential probiotic L. pentosus to be included as adjunct functional cultures in different fermented foods. PMID- 27774089 TI - The Madeira Archipelago As a Significant Source of Marine-Derived Actinomycete Diversity with Anticancer and Antimicrobial Potential. AB - Marine-derived actinomycetes have demonstrated an ability to produce novel compounds with medically relevant biological activity. Studying the diversity and biogeographical patterns of marine actinomycetes offers an opportunity to identify genera that are under environmental pressures, which may drive adaptations that yield specific biosynthetic capabilities. The present study describes research efforts to explore regions of the Atlantic Ocean, specifically around the Madeira Archipelago, where knowledge of the indigenous actinomycete diversity is scarce. A total of 400 actinomycetes were isolated, sequenced, and screened for antimicrobial and anticancer activities. The three most abundant genera identified were Streptomyces, Actinomadura, and Micromonospora. Phylogenetic analyses of the marine OTUs isolated indicated that the Madeira Archipelago is a new source of actinomycetes adapted to life in the ocean. Phylogenetic differences between offshore (>100 m from shore) and nearshore (< 100 m from shore) populations illustrates the importance of sampling offshore in order to isolate new and diverse bacterial strains. Novel phylotypes from chemically rich marine actinomycete groups like MAR4 and the genus Salinispora were isolated. Anticancer and antimicrobial assays identified Streptomyces, Micromonospora, and Salinispora as the most biologically active genera. This study illustrates the importance of bioprospecting efforts at unexplored regions of the ocean to recover bacterial strains with the potential to produce novel and interesting chemistry. PMID- 27774090 TI - Dose Assessment of Cefquinome by Pharmacokinetic/Pharmacodynamic Modeling in Mouse Model of Staphylococcus aureus Mastitis. AB - This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 MUg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log10CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC) was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC0-24/MIC exceeding 16571.55 h?mL/g, considerable activity of about 1.5 log10CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection. PMID- 27774091 TI - MicroRNA-7 Deficiency Ameliorates the Pathologies of Acute Lung Injury through Elevating KLF4. AB - Recent evidence showed that microRNA-7 (miR-7) played an important role in the pathologies of lung-related diseases. However, the potential role of miR-7 in acute lung injury (ALI) still remains poorly understood. Here, we assessed the effect of miR-7 deficiency on the pathology of ALI. We, first, found that the expression of miR-7 was upregulated in lung tissue in murine LPS-induced ALI model. Notably, we generated miR-7 knock down mice by using miRNA-Sponge technique and found that miR-7 deficiency could ameliorate the pathologies of lung as evidenced by accelerated body weight recovery, reduced level of bronchoalveolar lavage (BAL) proinflammatory cytokines and decreased number of BAL cells in ALI mice. Moreover, the proportion and number of various immune cells in BAL, including innate immune cell F4/80+ macrophages, gammadeltaT cells, NK1.1+ T cells, and CD11c+DCs, as well as adaptive immune cell CD4+ T cells and CD8+ T cells, also significantly changed, respectively. Mechanistic evidence showed that KLF4, a target molecule of miR-7, was upregulated in lung tissues in ALI model, accompanied by altered transduction of NF-kappaB, AKT, and ERK pathway. These data provided a previously unknown role of miR-7 in pathology of ALI, which could ultimately aid the understanding of development of ALI and the development of new therapeutic strategies against clinical inflammatory lung diseases. PMID- 27774093 TI - Supplementation with Lactobacillus plantarum WCFS1 Prevents Decline of Mucus Barrier in Colon of Accelerated Aging Ercc1-/Delta7 Mice. AB - Although it is clear that probiotics improve intestinal barrier function, little is known about the effects of probiotics on the aging intestine. We investigated effects of 10-week bacterial supplementation of Lactobacillus plantarum WCFS1, Lactobacillus casei BL23, or Bifidobacterium breve DSM20213 on gut barrier and immunity in 16-week-old accelerated aging Ercc1-/Delta7 mice, which have a median lifespan of ~20 weeks, and their wild-type littermates. The colonic barrier in Ercc1-/Delta7 mice was characterized by a thin (< 10 MUm) mucus layer. L. plantarum prevented this decline in mucus integrity in Ercc1-/Delta7 mice, whereas B. breve exacerbated it. Bacterial supplementations affected the expression of immune-related genes, including Toll-like receptor 4. Regulatory T cell frequencies were increased in the mesenteric lymph nodes of L. plantarum- and L. casei-treated Ercc1-/Delta7 mice. L. plantarum- and L. casei-treated Ercc1 /Delta7 mice showed increased specific antibody production in a T cell-dependent immune response in vivo. By contrast, the effects of bacterial supplementation on wild-type control mice were negligible. Thus, supplementation with L. plantarum - but not with L. casei and B. breve - prevented the decline in the mucus barrier in Ercc1-/Delta7 mice. Our data indicate that age is an important factor influencing beneficial or detrimental effects of candidate probiotics. These findings also highlight the need for caution in translating beneficial effects of probiotics observed in young animals or humans to the elderly. PMID- 27774096 TI - Illumina Sequencing of Common (Short) Ragweed (Ambrosia artemisiifolia L.) Reproductive Organs and Leaves. PMID- 27774092 TI - Close Encounters of Lymphoid Cells and Bacteria. AB - During infections, the first reaction of the host against microbial pathogens is carried out by innate immune cells, which recognize conserved structures on pathogens, called pathogen-associated molecular patterns. Afterward, some of these innate cells can phagocytose and destroy the pathogens, secreting cytokines that would modulate the immune response to the challenge. This rapid response is normally followed by the adaptive immunity, more specific and essential for a complete pathogen clearance in many cases. Some innate immune cells, usually named antigen-presenting cells, such as macrophages or dendritic cells, are able to process internalized invaders and present their antigens to lymphocytes, triggering the adaptive immune response. Nevertheless, the traditional boundary of separated roles between innate and adaptive immunity has been blurred by several studies, showing that very specialized populations of lymphocytes (cells of the adaptive immunity) behave similarly to cells of the innate immunity. These "innate-like" lymphocytes include gammadelta T cells, invariant NKT cells, B-1 cells, mucosal-associated invariant T cells, marginal zone B cells, and innate response activator cells, and together with the newly described innate lymphoid cells are able to rapidly respond to bacterial infections. Strikingly, our recent data suggest that conventional CD4+ T cells, the paradigm of cells of the adaptive immunity, also present innate-like behavior, capturing bacteria in a process called transinfection. Transinfected CD4+ T cells digest internalized bacteria like professional phagocytes and secrete large amounts of proinflammatory cytokines, protecting for further bacterial challenges. In the present review, we will focus on the data showing such innate-like behavior of lymphocytes following bacteria encounter. PMID- 27774095 TI - Transcriptome Sequencing Identified Genes and Gene Ontologies Associated with Early Freezing Tolerance in Maize. AB - Originating in a tropical climate, maize has faced great challenges as cultivation has expanded to the majority of the world's temperate zones. In these zones, frost and cold temperatures are major factors that prevent maize from reaching its full yield potential. Among 30 elite maize inbred lines adapted to northern China, we identified two lines of extreme, but opposite, freezing tolerance levels-highly tolerant and highly sensitive. During the seedling stage of these two lines, we used RNA-seq to measure changes in maize whole genome transcriptome before and after freezing treatment. In total, 19,794 genes were expressed, of which 4550 exhibited differential expression due to either treatment (before or after freezing) or line type (tolerant or sensitive). Of the 4550 differently expressed genes, 948 exhibited differential expression due to treatment within line or lines under freezing condition. Analysis of gene ontology found that these 948 genes were significantly enriched for binding functions (DNA binding, ATP binding, and metal ion binding), protein kinase activity, and peptidase activity. Based on their enrichment, literature support, and significant levels of differential expression, 30 of these 948 genes were selected for quantitative real-time PCR (qRT-PCR) validation. The validation confirmed our RNA-Seq-based findings, with squared correlation coefficients of 80% and 50% in the tolerance and sensitive lines, respectively. This study provided valuable resources for further studies to enhance understanding of the molecular mechanisms underlying maize early freezing response and enable targeted breeding strategies for developing varieties with superior frost resistance to achieve yield potential. PMID- 27774094 TI - Human NK Cell Subsets Redistribution in Pathological Conditions: A Role for CCR7 Receptor. AB - Innate and adaptive immunity has evolved complex molecular mechanisms regulating immune cell migration to facilitate the dynamic cellular interactions required for its function involving the chemokines and their receptors. One important chemokine receptor in the immune system is represented by CCR7. Together with its ligands CCL19 and CCL21, this chemokine receptor controls different arrays of migratory events, both in innate and adaptive immunity, including homing of CD56bright NK cells, T cells, and DCs to lymphoid compartments, where T cell priming occurs. Only recently, a key role for CCR7 in promoting CD56dim NK cell migration toward lymphoid tissues has been described. Remarkably, this event can influence the shaping and polarization of adaptive T cell responses. In this review, we describe recent progress in understanding the mechanisms and the site where CD56dim KIR+ NK cells can acquire the capability to migrate toward lymph nodes. The emerging significance of this event in clinical transplantation is also discussed. PMID- 27774098 TI - Social Media Meets Big Urban Data: A Case Study of Urban Waterlogging Analysis. AB - With the design and development of smart cities, opportunities as well as challenges arise at the moment. For this purpose, lots of data need to be obtained. Nevertheless, circumstances vary in different cities due to the variant infrastructures and populations, which leads to the data sparsity. In this paper, we propose a transfer learning method for urban waterlogging disaster analysis, which provides the basis for traffic management agencies to generate proactive traffic operation strategies in order to alleviate congestion. Existing work on urban waterlogging mostly relies on past and current conditions, as well as sensors and cameras, while there may not be a sufficient number of sensors to cover the relevant areas of a city. To this end, it would be helpful if we could transfer waterlogging. We examine whether it is possible to use the copious amounts of information from social media and satellite data to improve urban waterlogging analysis. Moreover, we analyze the correlation between severity, road networks, terrain, and precipitation. Moreover, we use a multiview discriminant transfer learning method to transfer knowledge to small cities. Experimental results involving cities in China and India show that our proposed framework is effective. PMID- 27774097 TI - PPARgamma in Bacterial Infections: A Friend or Foe? AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARgamma activation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARgamma agonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARgamma and its activation during bacterial infections, with focus on the potential of PPARgamma agonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARgamma agonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system. PMID- 27774099 TI - Improving Eye Motion Sequence Recognition Using Electrooculography Based on Context-Dependent HMM. AB - Eye motion-based human-machine interfaces are used to provide a means of communication for those who can move nothing but their eyes because of injury or disease. To detect eye motions, electrooculography (EOG) is used. For efficient communication, the input speed is critical. However, it is difficult for conventional EOG recognition methods to accurately recognize fast, sequentially input eye motions because adjacent eye motions influence each other. In this paper, we propose a context-dependent hidden Markov model- (HMM-) based EOG modeling approach that uses separate models for identical eye motions with different contexts. Because the influence of adjacent eye motions is explicitly modeled, higher recognition accuracy is achieved. Additionally, we propose a method of user adaptation based on a user-independent EOG model to investigate the trade-off between recognition accuracy and the amount of user-dependent data required for HMM training. Experimental results show that when the proposed context-dependent HMMs are used, the character error rate (CER) is significantly reduced compared with the conventional baseline under user-dependent conditions, from 36.0 to 1.3%. Although the CER increases again to 17.3% when the context dependent but user-independent HMMs are used, it can be reduced to 7.3% by applying the proposed user adaptation method. PMID- 27774100 TI - Recurrence of Dysplastic Nevi Is Strongly Associated with Extension of the Lesions to the Lateral Margins and into the Deep Margins through the Hair Follicles in the Original Shave Removal Specimens. AB - Melanocytic nevi, including dysplastic or atypical nevi (DN), can recur or persist following shave removal procedures, and recurrence may resemble melanoma, both clinically and histologically (pseudomelanoma). Recurrence may originate from proliferation of the remaining neoplastic melanocytes following incomplete removal. The present study determines the rate and etiology of this event. A cross-sectional analysis of 110 excision specimens showing histological recurrence was performed, and these specimens were compared to the slides of the original shave specimens showing mildly atypical DN. In the second portion of the study, a retrospective review of 167 cases with biopsy-proven mildly atypical DN which were followed up for at least two years was conducted to determine the rate of recurrence/persistence. When followed up for two years, DN, with positive shave margins, defined by extension or very close extension (<=0.2 mm) of the lesions to the lateral margins and into the deep margins through the hair follicles in the shave removal specimens, have a higher probability of recurrence than DN with negative (or clear) margins (odds ratio (OR) = 158; 95% confidence interval (CI) = 36.62-683; P < 0.001). The overall rate of histologically confirmed recurrence/persistence was approximately 10%. PMID- 27774101 TI - Evaluation of the Diagnostic Ability of Optical Enhancement System in Early Gastric Cancer Demarcation. AB - This study aimed to evaluate the utility of optical enhancement (OE) in early gastric cancer demarcation. Twenty lesions of early gastric cancer were examined by PENTAX endoscopy system with OE-1 and OE-2 functions. The areas of tumor demarcation identified by 12 evaluators (6 novice and 6 experienced) were compared to the corresponding correct areas determined by postoperative histopathology findings. The misdiagnosed scores that were the sums of false positive and false-negative areas were compared. Color of one hundred pixels from the inside of the cancerous area and the outside of the cancerous area was expressed as three-dimensional RGB component vectors. The mean vectors and covariance matrixes were calculated and the Mahalanobis distance, indicative of color differences between two areas, was tested. Comparisons of the misdiagnosed score revealed that OE-1 was preferred over WL-1 for gastric cancer demarcation for all 12 evaluators (p = 0.008) and in novice evaluators (p = 0.026). OE-2 was not significantly different from WL-2 in all cases. OE-1 images gave significantly larger Mahalanobis distances, indicative of color differences, than WL-1 images (p = 0.002). It was demonstrated that the OE Mode 1 has a significant advantage over the white light mode in demarcation of early gastric cancer. PMID- 27774102 TI - A Coupled Phase-Temperature Model for Dynamics of Transient Neuronal Signal in Mammals Cold Receptor. AB - We propose a theoretical model consisting of coupled differential equation of membrane potential phase and temperature for describing the neuronal signal in mammals cold receptor. Based on the results from previous work by Roper et al., we modified a nonstochastic phase model for cold receptor neuronal signaling dynamics in mammals. We introduce a new set of temperature adjusted functional parameters which allow saturation characteristic at high and low steady temperatures. The modified model also accommodates the transient neuronal signaling process from high to low temperature by introducing a nonlinear differential equation for the "effective temperature" changes which is coupled to the phase differential equation. This simple model can be considered as a candidate for describing qualitatively the physical mechanism of the corresponding transient process. PMID- 27774103 TI - Does Tumor Size Influence the Diagnostic Accuracy of Ultrasound-Guided Fine Needle Aspiration Cytology for Thyroid Nodules? AB - Background. Fine-needle aspiration cytology (FNAC) is diagnostic standard for thyroid nodules. However, the influence of size on FNAC accuracy remains unclear especially in too small or too large thyroid nodules. The objective of this retrospective cohort study was to investigate the effect of nodule size on FNAC accuracy. Methods. All consecutive patients who underwent thyroidectomy for nodules in 2010 were enrolled. FNAC results (according to the Bethesda system) were compared to pathological diagnosis. The nodules were categorized into groups A-E on the basis of maximal diameter on ultrasound (<=0.5, >0.5-1, >1-2, >2-4, and >4 cm, resp.). Results. There were 502 cases with 690 nodules. Overall FNAC sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95.4%, 98.2%, 99.4%, 86.4%, and 96.0%, respectively. False negative rates (FNRs) of groups A-E were 3.2%, 5.1%, 1.3%, 13.3%, and 50%, respectively. Accuracy rates of groups A-E were 96.8%, 94.8%, 99%, 94.7%, and 87.5%, respectively. Conclusion. Although accuracy rates of FNAC in thyroid nodules smaller than 0.5 cm are comparable to the other group, thyroid nodules larger than 4 cm with benign cytology carry a higher risk of malignancy, which suggest that those should be considered for intensive follow-up or repeated biopsy. PMID- 27774105 TI - Perceptions of Altered Smile Esthetics: A Comparative Evaluation in Orthodontists, Dentists, and Laypersons. AB - Objective. The current investigation was proposed to determine the impression of trained dental professionals and laypeople towards the modified smile esthetics. Materials and Methods. Twenty-six images were randomized in a survey and graded according to attractiveness by the orthodontists, general dentists, and laypeople. Photographs of gingival display, midline diastema, central incisor crown length, and lateral incisor crown width were manipulated with five minor changes in each. For smile arc and buccal corridor, two major changes were incorporated besides the ideal photograph. One-way ANOVA and Post Hoc analysis of the responses were measured for each group. Results. Most evaluators opined that the ideal smile in each category was the most acceptable. Orthodontists were more perceptive and exacting in accepting variations in the smile arc and buccal corridors. Dental professionals and laypeople indicated that either complete absence or a 0.5 mm of alterations in a gingival display, midline diastema, and crown length makes a smile beautiful and pleasant. Changes in crown width were not perceivable by all the three groups. Conclusion. Eastern Arabic laymen are more conscious about alterations in gingival display, midline diastema, and crown length in their smile. Hence, the orthodontist should pay attention to these factors during any orthodontic treatment. PMID- 27774104 TI - Arterial Stiffness in Nonhypertensive Type 2 Diabetes Patients in Ghana. AB - Background. Increased arterial stiffness is an independent cardiovascular risk factor in diabetes patients and general population. However, the contribution of diabetes to arterial stiffness is often masked by coexistent obesity and hypertension. In this study, we assessed arterial stiffness in nonhypertensive, nonobese type 2 diabetes (T2DM) patients in Ghana. Methods. In case-control design, 166 nonhypertensive, nonobese participants, comprising 96 T2DM patients and 70 nondiabetes controls, were recruited. Peripheral and central blood pressure (BP) indices were measured, and arterial stiffness was assessed as aortic pulse wave velocity (PWVao), augmentation index (AIx), cardioankle vascular index (CAVI), and heart-ankle pulse wave velocity (haPWV). Results. With similar peripheral and central BP indices, T2DM patients had higher PWVao (8.3 +/ 1 versus 7.8 +/- 1.3, p = 0.044) and CAVI (7.9 +/- 1.2 versus 6.9 +/- 0.7, p = 0.021) than nondiabetic control. AIx and haPWV were similar between T2DM and nondiabetic controls. Multiple regression models showed that, in the entire study participants, the major determinants of PWVao were diabetes status, age, gender, systolic BP, and previous smoking status (beta = 0.22, 0.36, 0.48, 0.21, and 0.25, resp.; all p < 0.05); the determinants of CAVI were diabetes status, age, BMI, heart rate, HbA1c, total cholesterol, HDL cholesterol, and previous smoking status (beta = 0.21, 0.38, 0.2, 0.18, 0.24. 0.2, -0.19, and 0.2, resp.; all p < 0.05). Conclusion. Our findings suggest that nonhypertensive, nonobese T2DM patients have increased arterial stiffness without appreciable increase in peripheral and central pressure indices. PMID- 27774106 TI - Highly Efficient In Vitro Reparative Behaviour of Dental Pulp Stem Cells Cultured with Standardised Platelet Lysate Supplementation. AB - Dental pulp is an accessible source of multipotent mesenchymal stromal cells (MSCs). The perspective role of dental pulp stem cells (DPSCs) in regenerative medicine demands an in vitro expansion and in vivo delivery which must deal with the safety issues about animal serum, usually required in cell culture practice. Human platelet lysate (PL) contains autologous growth factors and has been considered as valuable alternative to fetal bovine serum (FBS) in cell cultures. The optimum concentration to be added of such supplement is highly dependent on its preparation whose variability limits comparability of results. By in vitro experiments, we aimed to evaluate a standardised formulation of pooled PL. A low selected concentration of PL (1%) was able to support the growth and maintain the viability of the DPSCs. The use of PL in cell cultures did not impair cell surface signature typically expressed by MSCs and even upregulated the transcription of Sox2. Interestingly, DPSCs cultured in presence of PL exhibited a higher healing rate after injury and are less susceptible to toxicity mediated by exogenous H2O2 than those cultured with FBS. Moreover, PL addition was shown as a suitable option for protocols promoting osteogenic and chondrogenic differentiation of DPSCs. Taken together, our results indicated that PL is a valid substitute of FBS to culture and differentiate DPSCs for clinical-grade use. PMID- 27774109 TI - Multilevel processes and cultural adaptation: Examples from past and present small-scale societies. AB - Cultural adaptation has become central in the context of accelerated global change with authors increasingly acknowledging the importance of understanding multilevel processes that operate as adaptation takes place. We explore the importance of multilevel processes in explaining cultural adaptation by describing how processes leading to cultural (mis)adaptation are linked through a complex nested hierarchy, where the lower levels combine into new units with new organizations, functions, and emergent properties or collective behaviours. After a brief review of the concept of "cultural adaptation" from the perspective of cultural evolutionary theory and resilience theory, the core of the paper is constructed around the exploration of multilevel processes occurring at the temporal, spatial, social and political scales. We do so by examining small-scale societies' case studies. In each section, we discuss the importance of the selected scale for understanding cultural adaptation and then present an example that illustrates how multilevel processes in the selected scale help explain observed patterns in the cultural adaptive process. We end the paper discussing the potential of modelling and computer simulation for studying multilevel processes in cultural adaptation. PMID- 27774110 TI - Chinese Herbal Medicine for Postpartum Depression: A Systematic Review of Randomized Controlled Trials. AB - Background. Postpartum depression (PPD) does great harm to women following childbirth. The aim of this study was to conduct a systematic review of the literature to assess the efficacy and safety of CHM for the treatment of PPD. Methods. Published or ongoing registered trials were searched for from the inception of the various databases to December 31, 2015. Data extraction and methodology assessment were conducted independently by two researchers. RevMan 5.3 software was used to analyze the data. Results. Forty-seven registered clinical trials (RCTs) were identified and reviewed. The results showed CHM alone or in combination with routine treatments could reduce HAMD score, EPDS score, incidence of adverse events, TESS, and SERS. CHM combined with routine treatment was more effective in increasing serum estradiol levels and reducing progesterone levels than routine treatment alone. Meanwhile, pooled data revealed that MRLQS combined with routine treatments or MRLQS plus MSHS combined with routine treatments were more effective than other therapeutic methods in TCM. MRLQS plus MSHS alone was found to be an effective alternative when compared to routine treatments. Conclusions. This review suggested that CHM was safe and effective in the treatment of PPD. However, this could not be proven conclusively. To ensure evidence-based clinical practice, more rigorously designed trials are warranted. PMID- 27774108 TI - A Controlled Release Codelivery System of MSCs Encapsulated in Dextran/Gelatin Hydrogel with TGF-beta3-Loaded Nanoparticles for Nucleus Pulposus Regeneration. AB - Mesenchymal stem cell- (MSC-) based therapy is regarded as a potential tissue engineering strategy to achieve nucleus pulposus (NP) regeneration for the treatment of intervertebral disc degeneration (IDD). However, it is still a challenge to induce MSC differentiation in NP-like cells when MSCs are implanted into the NP. The purpose of this study was to construct poly(D,L-lactide-co glycolide) (PLGA) nanoparticles as carriers for TGF-beta3 controlled release and establish a codelivery system of a dextran/gelatin hydrogel with the nanoparticles for long-term processing of discogenesis differentiation. TGF-beta3 loaded PLGA nanoparticles were prepared by the double-emulsion solvent evaporation method and seeded uniformly into the hydrogel. Morphological observations, an assessment of the release kinetics of TGF-beta3, a cytotoxic assay, a cell proliferation test, a biochemical content assay, qRT-PCR, and immunohistological analyses of the codelivery system were conducted in the study. The results showed that the TGF-beta3-loaded nanoparticles could release TGF beta3 gradually. The codelivery system exhibited favorable cytocompatibility, and the TGF-beta3 that was released could induce MSCs to NP-like cells while promoting ECM-related biosynthesis. These results suggest this codelivery system may be employed as a promising carrier for discogenesis of MSCs in situ. PMID- 27774111 TI - Compatibility and Conjugacy on Partial Arrays. AB - Research in combinatorics on words goes back a century. Berstel and Boasson introduced the partial words in the context of gene comparison. Alignment of two genes can be viewed as a construction of two partial words that are said to be compatible. In this paper, we examine to which extent the fundamental properties of partial words such as compatbility and conjugacy remain true for partial arrays. This paper studies a relaxation of the compatibility relation called k compability. It also studies k-conjugacy of partial arrays. PMID- 27774107 TI - Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs Mediated Angiogenesis. AB - Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues. PMID- 27774112 TI - Theory and practice of uncommon molecular electronic configurations. AB - The electronic configuration of the molecule is the foundation of its structure and reactivity. The spin state is one of the key characteristics arising from the ordering of electrons within the molecule's set of orbitals. Organic molecules that have open-shell ground states and interesting physicochemical properties, particularly those influencing their spin alignment, are of immense interest within the up-and-coming field of molecular electronics. In this advanced review, we scrutinize various qualitative rules of orbital occupation and spin alignment, viz., the aufbau principle, Hund's multiplicity rule, and dynamic spin polarization concept, through the prism of quantum mechanics. While such rules hold in selected simple cases, in general the spin state of a system depends on a combination of electronic factors that include Coulomb and Pauli repulsion, nuclear attraction, kinetic energy, orbital relaxation, and static correlation. A number of fascinating chemical systems with spin states that fluctuate between triplet and open-shell singlet, and are responsive to irradiation, pH, and other external stimuli, are highlighted. In addition, we outline a range of organic molecules with intriguing non-aufbau orbital configurations. In such quasi-closed shell systems, the singly occupied molecular orbital (SOMO) is energetically lower than one or more doubly occupied orbitals. As a result, the SOMO is not affected by electron attachment to or removal from the molecule, and the products of such redox processes are polyradicals. These peculiar species possess attractive conductive and magnetic properties, and a number of them that have already been developed into molecular electronics applications are highlighted in this review. WIREs Comput Mol Sci 2015, 5:440-459. doi: 10.1002/wcms.1233 For further resources related to this article, please visit the WIREs website. PMID- 27774113 TI - GPU-accelerated Chemical Similarity Assessment for Large Scale Databases. AB - The assessment of chemical similarity between molecules is a basic operation in chemoinformatics, a computational area concerning with the manipulation of chemical structural information. Comparing molecules is the basis for a wide range of applications such as searching in chemical databases, training prediction models for virtual screening or aggregating clusters of similar compounds. However, currently available multimillion databases represent a challenge for conventional chemoinformatics algorithms raising the necessity for faster similarity methods. In this paper, we extensively analyze the advantages of using many-core architectures for calculating some commonly-used chemical similarity coefficients such as Tanimoto, Dice or Cosine. Our aim is to provide a wide-breath proof-of-concept regarding the usefulness of GPU architectures to chemoinformatics, a class of computing problems still uncovered. In our work, we present a general GPU algorithm for all-to-all chemical comparisons considering both binary fingerprints and floating point descriptors as molecule representation. Subsequently, we adopt optimization techniques to minimize global memory accesses and to further improve efficiency. We test the proposed algorithm on different experimental setups, a laptop with a low-end GPU and a desktop with a more performant GPU. In the former case, we obtain a 4-to-6-fold speed-up over a single-core implementation for fingerprints and a 4-to-7-fold speed-up for descriptors. In the latter case, we respectively obtain a 195-to-206-fold speed up and a 100-to-328-fold speed-up. PMID- 27774114 TI - The disintegrin-metalloproteinases ADAM10 and ADAM17 are upregulated in cutaneous squamous cell carcinomas. PMID- 27774115 TI - Upregulation of Heme Oxygenase-1 in Response to Wild Thyme Treatment Protects against Hypertension and Oxidative Stress. AB - High blood pressure is the most powerful contributor to the cardiovascular morbidity and mortality, and inverse correlation between consumption of polyphenol-rich foods or beverages and incidence of cardiovascular diseases gains more importance. Reactive oxygen species plays an important role in the development of hypertension. We found that wild thyme (a spice plant, rich in polyphenolic compounds) induced a significant decrease of blood pressure and vascular resistance in hypertensive rats. The inverse correlation between vascular resistance and plasma heme oxygenase-1 suggests that endogenous vasodilator carbon monoxide generated by heme oxidation could account for this normalization of blood pressure. Next product of heme oxidation, bilirubin (a chain-breaking antioxidant that acts as a lipid peroxyl radical scavenger), becomes significantly increased after wild thyme treatment and induces the reduction of plasma lipid peroxidation in hypertensive, but not in normotensive rats. The obtained results promote wild thyme as useful supplement for cardiovascular interventions. PMID- 27774116 TI - Protective Effects of Hydrogen against Low-Dose Long-Term Radiation-Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice. AB - Molecular hydrogen (H2) has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects of H2 on the alterations induced by low-dose long-term radiation (LDLTR). All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM) observation, forced swim test (FST), the open field test (OFT), the chromosome aberration (CA), the peripheral blood cells parameters analysis, the sperm abnormality (SA), the lymphocyte transformation test (LTT), and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing that H2 could diminish the detriment induced by LDLTR and suggesting the protective efficacy of H2 in multiple systems in mice against LDLTR. PMID- 27774118 TI - Nuclear Factor (Erythroid-Derived)-Related Factor 2-Associated Retinal Pigment Epithelial Cell Protection under Blue Light-Induced Oxidative Stress. AB - Purpose. It is a matter of increasing concern that exposure to light-emitting diodes (LED), particularly blue light (BL), damages retinal cells. This study aimed to investigate the retinal pigment epithelium (RPE) damage caused by BL and to elucidate the role of nuclear factor (erythroid-derived)-related factor 2 (Nrf2) in the pathogenesis of BL-induced RPE damage. Methods. ARPE-19, a human RPE cell line, and mouse primary RPE cells from wild-type and Nrf2 knockout (Nrf2 /-) mice were cultured under blue LED exposure (intermediate wavelength, 450 nm). Cell death rate and reactive oxygen species (ROS) generation were measured. TUNEL staining was performed to detect apoptosis. Real-time polymerase chain reaction was performed on NRF2 mRNA, and western blotting was performed to detect Nrf2 proteins in the nucleus or cytoplasm of RPE cells. Results. BL exposure increased cell death rate and ROS generation in ARPE-19 cells in a time-dependent manner; cell death was caused by apoptosis. Moreover, BL exposure induced NRF2 mRNA upregulation and Nrf2 nuclear translocation in RPE. Cell death rate was significantly higher in RPE cells from Nrf2-/- mice than from wild-type mice. Conclusions. The Nrf2 pathway plays an important role in protecting RPE cells against BL-induced oxidative stress. PMID- 27774117 TI - Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity. AB - Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals) to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage. PMID- 27774121 TI - Therapeutic Potential of Smurf-1 Inhibitors for the Treatment of Pulmonary Arterial Hypertension (PAH). PMID- 27774120 TI - Oxidative Stress Markers and Their Dynamic Changes in Patients after Acute Ischemic Stroke. AB - We have focused on determining the range of oxidative stress biomarkers and their dynamic changes in patients at different time points after the acute ischemic stroke (AIS). 82 patients with AIS were involved in our study and were tested: within 24 h from the onset of the attack (group A); at 7-day follow-up (group B); and at 3-month follow-up (group C). 81 gender and age matched volunteers were used as controls. Stroke patients in group A had significantly higher concentrations of plasma lipid peroxides and urine 8-isoprostanes when compared with controls. Protein carbonyls were not significantly different in any experimental group compared to controls. Antioxidant capacity of plasma was increased only in experimental group C. Activities of superoxide dismutase and catalase were elevated in all three experimental AIS groups compared to controls. Paraoxonase activity was reduced in groups A and B and unchanged in group C when compared to controls. Glutathione peroxide activity was elevated only in group A. Our results suggest that free radical damage is the highest within 24 h after the attack. During the next 3 months oxidative damage to lipids caused by free radicals is reduced due to activated antioxidant system. PMID- 27774122 TI - Protease-Activated Receptor 1 (PAR-1) Antagonists as Potential Treatment for Acute Coronary Syndrome. PMID- 27774123 TI - Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease. AB - Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7 (AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease. PMID- 27774119 TI - Role of Oxidative Stress in the Neurocognitive Dysfunction of Obstructive Sleep Apnea Syndrome. AB - Obstructive sleep apnea syndrome (OSAS) is characterized by chronic nocturnal intermittent hypoxia and sleep fragmentations. Neurocognitive dysfunction, a significant and extraordinary complication of OSAS, influences patients' career, family, and social life and reduces quality of life to some extent. Previous researches revealed that repetitive hypoxia and reoxygenation caused mitochondria and endoplasmic reticulum dysfunction, overactivated NADPH oxidase, xanthine oxidase, and uncoupling nitric oxide synthase, induced an imbalance between prooxidants and antioxidants, and then got rise to a series of oxidative stress (OS) responses, such as protein oxidation, lipid peroxidation, and DNA oxidation along with inflammatory reaction. OS in brain could trigger neuron injury especially in the hippocampus and cerebral cortex regions. Those two regions are fairly susceptible to hypoxia and oxidative stress production which could consequently result in cognitive dysfunction. Apart from continuous positive airway pressure (CPAP), antioxidant may be a promising therapeutic method to improve partially reversible neurocognitive function. Understanding the role that OS played in the cognitive deficits is crucial for future research and therapeutic strategy development. In this paper, recent important literature concerning the relationship between oxidative stress and cognitive impairment in OSAS will be summarized and the results can provide a rewarding overview for future breakthrough in this field. PMID- 27774124 TI - Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds. AB - The novel quinuclidine anti-1,2,3-triazole derivatives T1-T6 were designed based on the structure of QND8. The binding studies revealed that the stereochemistry at the C3 position of the quinuclidine scaffold plays an important role in the nAChR subtype selectivity. Whereas the (R)-enantiomers are selective to alpha7 over alpha4beta2 (by factors of 44-225) and to a smaller degree over alpha3beta4 (3-33), their (S)-counterparts prefer alpha3beta4 over alpha4beta2 (62-237) as well as over alpha7 (5-294). The (R)-derivatives were highly selective to alpha7 over alpha3beta4 subtypes compared to (RS)- and (R)-QND8. The (S)-enantiomers are 5-10 times more selective to alpha4beta2 than their (R) forms. The overall strongest affinity is observed for the (S)-enantiomer binding to alpha3beta4 (Ki, 2.25-19.5 nM) followed by their (R)-counterpart binding to alpha7 (Ki, 22.5-117 nM), with a significantly weaker (S)-enantiomer binding to alpha4beta2 (Ki, 414 1980 nM) still above the very weak respective (R)-analogue affinity (Ki, 5059 10436 nM). PMID- 27774125 TI - Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice. AB - A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 MUM lactate IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 MUM) that also possessed good exposure when dosed orally to mice. PMID- 27774126 TI - Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective alphavbeta1 Integrin Inhibitors. AB - One small molecule inhibitor of alphavbeta1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in alphavbeta1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against alphavbeta1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of alphavbeta1 integrin inhibitors as antifibrotics. PMID- 27774127 TI - Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6 ones as Selective PI3K-delta/gamma Inhibitors. AB - Dual inhibition of PI3K-delta and PI3K-gamma is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-delta/gamma selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-delta/gamma inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next generation PI3K-delta/gamma targeting therapeutics. PMID- 27774128 TI - Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead. AB - Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the alpha1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy. PMID- 27774129 TI - Concise SAR Exploration Based on the "Head-to-Tail" Approach: Discovery of PI4KIIIalpha Inhibitors Bearing Diverse Scaffolds. AB - In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIalpha is one of four mammalian phosphatidylinositol 4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIalpha inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs. PMID- 27774130 TI - Enhancing Therapeutic Efficacy of Cisplatin by Blocking DNA Damage Repair. AB - Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, we combined a PP2A inhibitor LB (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2 carbonyl) piperazine-1-carboxylic acid tert-butyl ester) and the DNA damage chemotherapeutic drug cisplatin through a simple physical superposition. The two drugs administrated at a ratio of 1:1 exhibited an optional synergistic antitumor efficacy in vitro and in vivo. LB was demonstrated to specifically activate the protein kinase B (Akt) and mitogen-activated protein kinases (MAPK) signaling pathways by PP2A inhibition to overcome cell cycle arrest caused by cisplatin induced DNA damage. PMID- 27774131 TI - Development of a Potent and Selective HDAC8 Inhibitor. AB - A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8. PMID- 27774132 TI - Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor. AB - The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1 (4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4 yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials. PMID- 27774133 TI - NO Photoreleaser-Deoxyadenosine and -Bile Acid Derivative Bioconjugates as Novel Potential Photochemotherapeutics. AB - This contribution reports the synthesis of some novel bioconjugates with anticancer activity and able to release nitric oxide (NO) under visible light excitation. The 4-nitro-2-(trifluoromethyl)aniline derivative, a suitable NO photodonor, was conjugated with 2'-deoxyadenosine and urso- and cheno-deoxycholic acid derivatives, through a thioalkylic chain or the 4-alkyl-1,2,3-triazole moiety. Photochemical experiments demonstrated the effective release of NO from 2'-deoxyadenosine and ursodeoxycholic acid conjugates under the exclusive control of visible light inputs. Studies for the in vitro antiproliferative activity against leukemic K562 and colon carcinoma HCT116 cell lines are reported for all the compounds as well as a case study of photocytotoxicity against HCT116. PMID- 27774134 TI - Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1. AB - Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1 R132H inhibitors having improved pharmacological properties. PMID- 27774135 TI - Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors. AB - Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from in vitro protein kinase inhibition experiments indicated that compounds 3a-f and 11b are potent JAKs inhibitors. For example, the IC50 values of compound 3f against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound 3f showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound 11b showed selective cytotoxicity at submicromolar levels against HEL (IC50: 0.35 MUM) and K562 (IC50: 0.37 MUM) cell lines. It is worth noting that both 3f and 11b showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib. PMID- 27774136 TI - Combined Interactions with I1-, I2-Imidazoline Binding Sites and alpha2 Adrenoceptors To Manage Opioid Addiction. AB - Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including alpha2-adrenoceptors (alpha2-ARs) and I1- and I2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including alpha2-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I1-/I2-IBS or I1-/I2-IBS/alpha2-ARs. The compounds showing the highest affinities for I1-/I2-IBS or I1-/I2-IBS/alpha2-ARs have been selected for their in vivo evaluation on opiate withdrawal syndrome. Interestingly, 9, displaying I1-/I2-IBS/alpha2-ARs interaction profile, appears more effective in reducing expression and acquisition of morphine dependence and, therefore, might be considered a promising tool in managing opioid addiction. PMID- 27774137 TI - Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor. AB - Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAFV600E mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAFV600E/K mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2. This novel compound could be isolated and biologically characterized in vitro. Both enzymatic and cellular assays proved that 2 is still a potent BRAFV600E inhibitor. The intracellular formation of 2 from dabrafenib upon ultraviolet irradiation is shown. The herein presented findings should be taken in account when handling dabrafenib both in preclinical research and in clinical applications. PMID- 27774138 TI - Discovery of Fluorescence Polarization Probe for the ELISA-Based Antagonist Screening of alpha1-Adrenergic Receptors. AB - High-throughput screening (HTS) of ligand library to find new active molecules for G protein-coupled receptors is still a major interest, as well as an actual challenge. Fluorescence polarization (FP) assay portrays an essential role in HTS; however, in many cases, it was restricted by the absence of FP probes, the narrow measurement window, and low signal-to-noise (S/N) ratio. Herein, based on the modification of our previous probe 1 (QFL), we discovered an FP probe 3 (QGGFL) for alpha1-adrenergic receptors (alpha1-ARs), which has satisfactory fluorescence intensity, specific binding ability to receptors, and suitable fluorescence properties that were compatible with the filters in the FP system. Meanwhile, an "ELISA-like" strategy was designed for FP-based HTS assay in which proteins were adhered into a solid phase to improve the measurement window and S/N ratio. With fluorescent antagonist QGGFL and the ELISA strategy, we succeeded in establishing the first competitive binding FP assay for alpha1-AR antagonists as the alternative of the radioligand binding assay. PMID- 27774139 TI - Self-assembled Multifunctional DNA Nanoflowers for the Circumvention of Multidrug Resistance in Targeted Anticancer Drug Delivery. AB - Cancer chemotherapy has been impeded by side effects and multidrug resistance (MDR) partially caused by drug efflux from cancer cells, which call for targeted drug delivery systems additionally able to circumvent MDR. Here we report multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR cancer cells and circumvent MDR in both leukemia and breast cancer cell models. NFs are self-assembled via liquid crystallization of DNA generated by Rolling Circle Replication, during which NFs are incorporated with aptamers for specific cancer cell recognition, fluorophores for bioimaging, and Doxorubicin (Dox)-binding DNA for drug delivery. NF sizes are tunable (down to ~200 nm in diameter), and the densely packed drug-binding motifs and porous intrastructures endow NFs with high drug loading capacity (71.4%, wt/wt). The Dox loaded NFs (NF-Dox) are stable at physiological pH, yet drug release is facilitated in acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. Consequently, NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising to circumvent MDR in targeted cancer therapy. PMID- 27774140 TI - Open PHACTS computational protocols for in silico target validation of cellular phenotypic screens: knowing the knowns. AB - Phenotypic screening is in a renaissance phase and is expected by many academic and industry leaders to accelerate the discovery of new drugs for new biology. Given that phenotypic screening is per definition target agnostic, the emphasis of in silico and in vitro follow-up work is on the exploration of possible molecular mechanisms and efficacy targets underlying the biological processes interrogated by the phenotypic screening experiments. Herein, we present six exemplar computational protocols for the interpretation of cellular phenotypic screens based on the integration of compound, target, pathway, and disease data established by the IMI Open PHACTS project. The protocols annotate phenotypic hit lists and allow follow-up experiments and mechanistic conclusions. The annotations included are from ChEMBL, ChEBI, GO, WikiPathways and DisGeNET. Also provided are protocols which select from the IUPHAR/BPS Guide to PHARMACOLOGY interaction file selective compounds to probe potential targets and a correlation robot which systematically aims to identify an overlap of active compounds in both the phenotypic as well as any kinase assay. The protocols are applied to a phenotypic pre-lamin A/C splicing assay selected from the ChEMBL database to illustrate the process. The computational protocols make use of the Open PHACTS API and data and are built within the Pipeline Pilot and KNIME workflow tools. PMID- 27774141 TI - Toward Hemocompatible Self-assembling Antimicrobial Nanofibers: Understanding the Synergistic Effect of Supramolecular Structure and PEGylation on Hemocompatibility. AB - A significant challenge associated with systemic delivery of cationic antimicrobial peptides and polymers lies in their limited hemocompatibility toward vast numbers of circulating red blood cells (RBCs). Supramolecular assembly of cationic peptides and polymers can be an effective strategy to develop an array of antimicrobial nanomaterials with tunable material structures, stability and thus optimized bioactivity to overcome some of the existing challenges associated with conventional antimicrobials. In this work, we will demonstrate the supramolecular design of self-assembling antimicrobial nanofibers (SAANs) which have tunable supramolecular nanostructures, stability, internal molecular packing and surface chemistry through self-assembly of de novo designed cationic peptides and peptide-PEG conjuguates. The interaction of the SAANs with human RBCs was evaluated in a stringent biological assay (beyond a traditional hemolysis assay) where both hemolytic and eryptotic activity were examined to establish a fundamental understanding on the correlation between material structure and hemocompatibility. It was found that although the SAANs showed moderate hemolytic activities, their abilities to induce eryptosis vary significantly and are much more sensitive to the internal molecular packing, supramolecular nanostructure and stability of the nanofiber. Improved hemocompatibility requires PEGylation on stable supramolecular nanofibers composed of highly organized beta-sheet structure while PEG conjugation on weakly packed nanofibers composed of partially denatured beta-sheets did not show improvement. The current study reveals the fundamental mechanism involved in the selective hemocompatibility improvement of the SAANs upon PEG conjugation. The structure-activity relationship developed in this study will provide important guidance for the future design of a broader family of peptide and polymer-based assemblies with optimized antimicrobial activity and hemocompatibility. PMID- 27774142 TI - ICG-conjugated Magnetic Graphene Oxide for Dual Photothermal and Photodynamic Therapy. AB - Aptamer-functionalized magnetic graphene oxide conjugates loaded with indocyanine green (ICG) dye, or Apt@ICG@mGO, have been successfully developed for dual targeted photothermal and photodynamic therapy. In general, a drug or its carrier or their dosage can be imprtant important issues in terms of toxicity. However, in this system, each component used is quite safe, biocompatibe and clean. For instance, ICG, a Food and Drug Administration (FDA) approved near-infrared (NIR) dye, serves as both a photothermal and photodynamic agent. It is immobilized on the surface of mGO via a physical interaction called "pi-pi stacking". The mGO, as a most biocomptible member of the carbo family, is selected for use as a platform for aptamer and ICG dye conjugation, as well as as a photothermal agent. The light in the near-infrared region (NIR) was chosen as a harmless light source for activating the agents for photothermal therapy (PTT) and photodynamic therapy (PDT). The magnetic properties of mGO are also used for separation of Apt@ICG@mGO conjugates from the reaction medium. Aptamer sgc8 acts as a targeting ligand to selectively and specifically bind to a protein on the membrane of cancer cell line CCRF-CEM. After the aptamer- functionalized ICG@mGO conjugates are incubated with target CEM cells at 37 degrees C for 2 hours, they are bound to cells or they may be internalized into the cell via endocytosis. More significantly, we demonstrated that the Apt@ICG@mGO conjugates produce heat for photothermal therapy (PTT) and singlet oxygen for photodynamic therapy (PDT) upon NIR laser irradiation at 808 nm. Thus, remarkably efficient cancer cell destructions with ~41% and ~60% and ~82% cell killing using 10, 50 and 100 ppm Apt@ICG@mGO, respectively are achieved in 5 min light exposure. PMID- 27774143 TI - A Facile Approach to Upconversion Crystalline CaF2:Yb3+,Tm3+@mSiO2 Nanospheres for Tumor Therapy. AB - A new facile approach, namely chemical-assisted sol-gel growth (CASGG), was successfully developed to induce the formation of fine CaF2:Yb3+, Tm3+ nanocrytals within the pore channels of mesoporous silica (mSiO2) nanoparticles. A series of upconversion photoluminescent crystalline CaF2:Yb3+,Tm3+@mSiO2 nanospheres with controlled diameters from ~65 nm to ~290 nm were fabricated. All nanospheres presented sound cyto-compatibility and unique ratiometric spectral monitoring functionalities for drug release kinetics. The nanospheres with smallest dimension (UCNP-2.5, ~65nm) induced the most sustained DOX release kinetics. More importantly, the in-vitro study demonstrated that the DOX loaded UCNP-2.5 nanopheres presented the strongest anti-cancer efficacy to MCF-7 human breast cancer cells due to its stronger penetration ability to cell nuclei due to the size effect. PMID- 27774144 TI - Self-Strengthening Hybrid Dental Adhesive via Visible-light Irradiation Triple Polymerization. AB - A self-strengthening methacrylate-based dental adhesive system was developed by introducing an epoxy cyclohexyl trimethoxysilane (TS) which contains both epoxy and methoxysilyl functional groups. The experimental formulation, HEMA/BisGMA/TS (22.5/27.5/50, wt%), was polymerized by visible-light. Real-time Fourier transform infrared spectroscopy (FTIR) was used to investigate in situ the free radical polymerization of methacrylate, ring-opening cationic polymerization of epoxy, and photoacid-induced sol-gel reactions. Among the three simultaneous reactions, the reaction rate of the free radical polymerization was the highest and the hydrolysis/condensation rate was the lowest. With 40s-irradiation, the degrees of conversion of the double bond and epoxy groups at 600 s were 73.2+/ 1.2%, 87.9+/-2.4%, respectively. Hydrolysis of the methoxysilyl group was initially <5%, and increased gradually to about 50% after 48 h dark storage. Photoacids generated through the visible-light-induced reaction were effective in catalyzing both epoxy ring-opening polymerization and methoxysilyl sol-gel reaction. The mechanical properties of copolymers made with TS concentrations from 5 to 35 wt% were obtained using dynamic mechanical analysis (DMA). In wet conditions, the storage moduli at 70 degrees C and glass transition temperature were significantly higher than that of the control (p<0.05); these properties increased with TS concentration and storage time. The post reaction of hydrolysis/condensation of alkoxysilane could provide persistent strengthening whether in a neutral or acidic environment and these characteristics could lead to enhanced mechanical properties in the oral environment. The cumulative amount of leached species decreased significantly in the TS-containing copolymers. These results provide valuable information for the development of dental adhesives with reduced leaching of methacrylate monomers and enhanced mechanical properties under the wet, oral environment. PMID- 27774145 TI - Nafion-stabilised bimetallic Pt-Cr nanoparticles as electrocatalysts for proton exchange membrane fuel cells (PEMFCs). AB - The current study investigated the unique combination of alloying (Pt with Cr) and Nafion stabilisation to reap the benefits of catalyst systems with enhanced catalytic activity and improved durability in PEMFCs. Pt-Cr alloy nanoparticles stabilised with Nafion were chosen in the current study owing to their higher stability in acidic and oxidising media at high temperatures compared to other Pt transition metal alloys (e.g. Pt-Ni, Pt-Co). Two different precursor : reducing agent (1 : 10 and 1 : 20) ratios were used in order to prepare two different alloys, denoted as Pt-Cr 10 and Pt-Cr 20. The Pt-Cr 20 alloy system (with composition Pt80Cr20) demonstrated higher electrocatalytic activity for the oxygen reduction reaction compared to commercial Pt/C (TKK) catalysts. Accelerated stress tests and single cell tests revealed that Nafion stabilised alloy catalyst systems displayed significantly enhanced durability (only ~20% loss of ECSA) compared with Pt/C (50% loss of ECSA) due to improved catalyst ionomer interaction. Furthermore, the Pt-Cr 20 alloy system demonstrated a current density comparable to that of Pt/C making them promising potential electrocatalysts for proton exchange membrane fuel cells. PMID- 27774146 TI - Photovoltaically Self-Charging Cells with WO3.H2O/CNTs/PVDF Composite. AB - Two-electrode photovoltaically self-charging cells (PSCs) possess compact structures for both energy conversion and storage with shared electrolyte and electrodes. It remains challenging to develop PSCs that are efficient in both energy conversion and storage. In this work, WO3.H2O nanoplates were synthesized by a modified acid-directed hydrothermal process and used to prepare a WO3.H2O/CNTs/PVDF composite film for energy storage in PSCs. The method with the assistance of polyethylenimine was essential to form smaller sized WO3.H2O nanoplates, thus larger surface area and higher columbic efficiency in cyclic voltammetry tests. Such an electrode composite made it more facile to assemble PSCs, which displayed an energy conversion efficiency of 2.12% with simultaneous energy storage of 1.38 C cm-2. Higher Li+ concentration in the electrolyte will be helpful to maintain the photocurrent at a larger value during irradiation. A higher performance of PSCs can be potentially obtained by optimizing the contact of electron collector and pseudocapacitive electrode materials. PMID- 27774147 TI - Photoelectrochemical water splitting strongly enhanced in fast-grown ZnO nanotree and nanocluster structures. AB - We demonstrate selective growth of ZnO branched nanostructures: from nanorod clusters (with branches parallel to parent rods) to nanotrees (with branches perpendicular to parent rods). The growth of these structures was realized using a three-step approach: electrodeposition of nanorods (NRs), followed by the sputtering of ZnO seed layers, followed by the growth of branched arms using hydrothermal growth. The density, size and direction of the branches were tailored by tuning the deposition parameters. To our knowledge, this is the first report of control of branch direction. The photoelectrochemical (PEC) performance of the ZnO nanostructures follows the order: nanotrees (NTs) > nanorod clusters (NCs) > parent NRs. The NT structure with the best PEC performance also possesses the shortest fabrication period which had never been reported before. The photocurrent of the NT and NC photoelectrodes is 0.67 and 0.56 mA cm-2 at 1 V vs. Ag/AgCl, respectively, an enhancement of 139% and 100% when compared to the ZnO NR structures. The key reason for the improved performance is shown to be the very large surface-to-volume ratios in the branched nanostructures, which gives rise to enhanced light absorption, improved charge transfer across the nanostructure/electrolyte interfaces to the electrolyte and efficient charge transport within the material. PMID- 27774149 TI - An assessment of silver copper sulfides for photovoltaic applications: theoretical and experimental insights. AB - As the worldwide demand for energy increases, low-cost solar cells are being looked to as a solution for the future. To attain this, non-toxic earth-abundant materials are crucial, however cell efficiencies for current materials are limited in many cases. In this article, we examine the two silver copper sulfides AgCuS and Ag3CuS2 as possible solar absorbers using hybrid density functional theory, diffuse reflectance spectroscopy, XPS and Hall effect measurements. We show that both compounds demonstrate promising electronic structures and band gaps for high theoretical efficiency solar cells, based on Shockley-Queisser limits. Detailed analysis of their optical properties, however, indicates that only AgCuS should be of interest for PV applications, with a high theoretical efficiency. From this, we also calculate the band alignment of AgCuS against various buffer layers to aid in future device construction. PMID- 27774148 TI - Optical analysis of CH3NH3Sn x Pb1-x I3 absorbers: a roadmap for perovskite-on perovskite tandem solar cells. AB - Organic-inorganic perovskite structures in which lead is substituted by tin are exceptional candidates for broadband light absorption. Herein we present a thorough analysis of the optical properties of CH3NH3Sn x Pb1-x I3 films, providing the field with definitive insights about the possibilities of these materials for perovskite solar cells of superior efficiency. We report a user's guide based on the first set of optical constants obtained for a series of tin/lead perovskite films, which was only possible to measure due to the preparation of optical quality thin layers. According to the Shockley-Queisser theory, CH3NH3Sn x Pb1-x I3 compounds promise a substantial enhancement of both short circuit photocurrent and power conversion efficiency in single junction solar cells. Moreover, we propose a novel tandem architecture design in which both top and bottom cells are made of perovskite absorbers. Our calculations indicate that such perovskite-on-perovskite tandem devices could reach efficiencies over 35%. Our analysis serves to establish the first roadmap for this type of cells based on actual optical characterization data. We foresee that this study will encourage the research on novel near-infrared perovskite materials for photovoltaic applications, which may have implications in the rapidly emerging field of tandem devices. PMID- 27774150 TI - A single-source precursor approach to solution processed indium arsenide thin films. AB - This paper reports the synthesis of the novel single-source precursor, [{(MeInAs t Bu)3}2(Me2InAs( t Bu)H)2] and the subsequent first report of aerosol-assisted chemical vapour deposition of InAs thin films. Owing to the use of the single source precursor, highly crystalline and stoichiometric films were grown at a relatively low deposition temperature of 450 degrees C. Core level XPS depth profiling studies showed some partial oxidation of the film surface, however this was self-limiting and disappeared on etch profiles. Valence band XPS analysis matched well with the simulated density of state spectrum. Hall effect measurements performed on the films showed that the films were n-type with promising resistivity (3.6 * 10-3 Omega cm) and carrier mobility (410 cm2 V-1 s 1) values despite growth on amorphous glass substrates. PMID- 27774151 TI - The impact of charge transfer and structural disorder on the thermoelectric properties of cobalt intercalated TiS2. AB - A family of phases, Co x TiS2 (0 <= x <= 0.75) has been prepared and characterised by powder X-ray and neutron diffraction, electrical and thermal transport property measurements, thermal analysis and SQUID magnetometry. With increasing cobalt content, the structure evolves from a disordered arrangement of cobalt ions in octahedral sites located in the van der Waals' gap (x <= 0.2), through three different ordered vacancy phases, to a second disordered phase at x >= 0.67. Powder neutron diffraction reveals that both octahedral and tetrahedral inter-layer sites are occupied in Co0.67TiS2. Charge transfer from the cobalt guest to the TiS2 host affords a systematic tuning of the electrical and thermal transport properties. At low levels of cobalt intercalation (x < 0.1), the charge transfer increases the electrical conductivity sufficiently to offset the concomitant reduction in |S|. This, together with a reduction in the overall thermal conductivity leads to thermoelectric figures of merit that are 25% higher than that of TiS2, ZT reaching 0.30 at 573 K for Co x TiS2 with 0.04 <= x <= 0.08. Whilst the electrical conductivity is further increased at higher cobalt contents, the reduction in |S| is more marked due to the higher charge carrier concentration. Furthermore both the charge carrier and lattice contributions to the thermal conductivity are increased in the electrically conductive ordered vacancy phases, with the result that the thermoelectric performance is significantly degraded. These results illustrate the competition between the effects of charge transfer from guest to host and the disorder generated when cobalt cations are incorporated in the inter-layer space. PMID- 27774152 TI - First case of isolation of Nocardia wallacei reported in Mexico. AB - Nocardia species are aerobic, Gram-positive bacteria with branched filaments reported as opportunistic microorganisms associated with infectious diseases of the skin. We report the isolation of N. wallacei in Mexico from a 43-year-old man, an HIV-positive construction worker who sought care for difficulty breathing and abundant sputum. PMID- 27774153 TI - Editorial. PMID- 27774154 TI - Towards an ethics safe harbor for global biomedical research. AB - Although increasingly global, data-driven genomics and other 'omics'-focused research hold great promise for health discoveries, current research ethics review systems around the world challenge potential improvements in human health from such research. To overcome this challenge, we propose a 'Safe Harbor Framework for International Ethics Equivalency' that facilitates the harmonization of ethics review of specific types of data-driven international research projects while respecting globally transposable research ethics norms and principles. The Safe Harbor would consist in part of an agency supporting an International Federation for Ethics Review (IFER), formed by a voluntary compact among countries, granting agencies, philanthropies, institutions, and healthcare, patient advocacy, and research organizations. IFER would be both a central ethics review body, and also a forum for review and follow-up of policies concerning ethics norms for international research projects. It would be built on five principle elements: (1) registration, (2) compliance review, (3) recognition, (4) monitoring and enforcement, and (5) public participation. The Safe Harbor would create many benefits for researchers, countries, and the general public, and may eventually have application beyond (gen)omics to other areas of biomedical research that increasingly engage in secondary use of data and present only negligible risks. PMID- 27774155 TI - Public preferences and the challenge to genetic research policy. AB - Modern genetic research requires scientists to collect, store, and study DNA samples and health information from thousands of people. Longstanding policy allows researchers to use samples and information without a person's informed consent as long as the person's identity is protected. Under existing policy, researchers must neither disclose study results to interested research participants nor compensate people who contribute to genetic research. Research and ethics experts developed these policy approaches without input from the people whose contributions are essential to the genetic research enterprise. A growing body of evidence shows that many research participants and would-be participants disagree with the current policy approaches. For ethical and practical reasons, participants should have a greater role in determining how genetic research is conducted. PMID- 27774157 TI - Editorial. PMID- 27774156 TI - A review of the key issues associated with the commercialization of biobanks. PMID- 27774159 TI - Gene patents at the Supreme Court: Association for Molecular Pathology v. Myriad Genetics. PMID- 27774158 TI - Egg freezing and egg banking: empowerment and alienation in assisted reproduction. AB - With the development of rapid freezing of human oocytes, many programs have reported IVF success rates comparable to those achieved with fresh eggs and thawed frozen embryos. Egg freezing is now gaining professional and regulatory acceptance as a safe and effective technique for women who wish to avoid discarding excess embryos, who face fertility-threatening medical treatments, or who want to preserve their eggs for use when they are better situated to have a family. This article focuses on the uses of and justification for egg freezing, the path to professional acceptance, the variability in success rates, and the controversy over freezing eggs for social rather than medical reasons. It also addresses the emergence of egg banking as a separate sector in the infertility industry, the regulatory issues that it poses, and its effect on egg donation. Key here is the legal control of stored eggs by banking women and their options when they wish to dispose of those eggs. The analysis is framed around empowerment and alienation. Egg freezing is generally empowering for women, but the donation or sale of unused eggs to infertile women, egg bankers, and researchers also raises issues of alienation. PMID- 27774160 TI - State-level legislation on follow-on biologic substitution. PMID- 27774162 TI - Cook v. FDA and the importation and release of lethal injection drugs. PMID- 27774161 TI - FDA regulation of clinical decision support software. PMID- 27774164 TI - Letter. PMID- 27774163 TI - Considering advances in neuroscience through the lenses of law and human rights. AB - Advances in neuroscience should be subject to a robust public dialogue that includes attention to the legal and human rights issues raised by both research and its applications. PMID- 27774165 TI - Environmental neuroethics: changing the environment-changing the brain Recommendations submitted to the Presidential Commission for the Study of Bioethical Issues. PMID- 27774167 TI - Ethical considerations of neuroscience research and the application of neuroscience research findings for the Presidential Commission for the Study of Bioethical Issues. PMID- 27774168 TI - Editorial. PMID- 27774166 TI - Law and neuroscience: recommendations submitted to the President's Bioethics Commission. PMID- 27774169 TI - Innovation in the public sphere: reimagining law and economics to solve the National Institutes of Health publishing controversy. AB - The National Institutes of Health (NIH) are responsible for the largest proportion of biological science funding in the United States. To protect the public interest in access to publicly funded scientific research, the NIH amended terms and conditions in funding agreements after 2009, requiring funded Principal Investigators to deposit published copies of research in PubMed, an Open Access repository. Principal Investigators have partially complied with this depository requirement, and the NIH have signaled an intent to enforce grant agreement terms and conditions by stopping funding deposits and engaging in legal action. The global economic value of accessible knowledge offers a unique opportunity for courts to evaluate the impact of enforcing 'openness' contract terms and conditions within domestic and international economies for public and economic benefit. Through judicial enforcement of Open Access terms and conditions, the United States can increase economic efficiency for university libraries, academic participants, and public consumers, while accelerating global innovation, improving financial returns on science funding investments, and advancing more efficient scientific publishing models. PMID- 27774170 TI - Outstanding questions concerning the regulation of cognitive enhancement devices. AB - The authors (Maslen et al., 2014) propose to regulate cognitive enhancement devices (CEDs) as medical devices. Extending medical device regulations to CEDs raises some important questions that need to be adequately addressed before it makes sense to pursue this path. A first problem concerns the definition of 'cognitive enhancement' and 'CEDs'. Where does treatment end and enhancement begin? Secondly, since most CEDs such as neurofeedback and transcranial direct current stimulation are currently performed by non-medical health care providers, how will this regulation impact the current practice, and which requirements need to be put in place to regulate their use? Thirdly, distributive justice issues present an obvious ethical limitation. Fourthly, if CEDs are indeed prescribed off-label similar to the off-label prescription of psychopharmacological enhancers by MDs, this will pose problems regarding a lack of sufficient knowledge and expertise due to the highly specialized nature of CEDs. And finally, are we faced with unnecessary worries and unrealistic hopes when it comes to CEDs? In sum, we propose to regulate them regarding product safety and restrict them to competent adult use including professional oversight where indicated. PMID- 27774171 TI - Buttressing regulation of cognitive enhancement devices with principles of harm reduction. AB - Maslen and colleagues offer an excellent model for regulating cognitive enhancement devices (CEDs), and we largely endorse their approach of extending medical device policy to include CEDs. Maslen et al. argue that since the risks and benefits of CEDs can be identified, consumers are best placed to evaluate the impact of these effects on their own wellbeing: 'experts are to assess what the risks are, the consumer how much they matter'. In principle, we agree: consumers should be allowed to decide what risks are worth taking, but the situation is somewhat more complicated, for the evidence that consumers are in a strong position to evaluate the many risks associated with CED use is lacking. Indeed, a glance at online forums on CEDs suggests that undue risks are already being taken. Importantly, given the ease with which devices can be built using easily obtainable parts, overly tough regulation will not effectively curtail use, but rather push it underground. For these reasons, we suggest that any regulatory framework be buttressed by principles of harm reduction, providing real-world users with expert-backed recommendations for safe use. We argue for the development of tools that facilitate this dialogue, while recognizing the challenges in so doing. PMID- 27774172 TI - Regulation of cognitive enhancement devices: commentary. AB - Maslen et al. (2013) have provided us with a comprehensive overview of the current legislation regulating non-clinical cognitive enhancement devices (CEDs) in the European Union and have proposed a specific model whereby CEDs would be regulated in the same way as medical devices. An alternative model would be to require manufacturers to quantify risks only. Irrespective of the purported 'benefits' of a product, this would allow the consumer freedom of choice to use the product at their will and allow the periodic review of worthwhile indications and unexpected adverse events. Although this departs from the standard Cochrane type assessment, it takes into account the facts that (i) the evaluation of clinically used cognitive enhancement techniques may not be as rigorous as one might expect, (ii) variations and case-by-case use might be widespread, and (iii) independent variables of significance and useful endpoints may not be obvious ab initio. We consider cerebrospinal fluid diversion techniques which are widely used clinically to enhance cognition in patients with normal pressure hydrocephalus despite any large-scale clinical studies demonstrating substantial benefit, and the real risks of paralysis and death from these invasive procedures. The risks of CEDs which have been available for some time need to be kept in perspective: are the risks really more than using conventional cognitive enhancement techniques such as imbibing too caffeinated drinks? Furthermore, the loss of Europe as a market for CEDs which do not comply with the proposed regulatory model implies a potential gain in the market for other parts of the world. This could impact on the ability of companies in Europe being able to compete in an evolving market demand for CEDs. Legislation to regulate CEDs should be guided by the principle of 'do no harm' and allow for innovation and competition. PMID- 27774173 TI - Medical regulation of cognitive enhancement devices: some concerns. AB - The authors present a cogent and detailed case for altering the Medical Devices Directive to allow regulation of cognitive enhancement devices (CEDs). Protection against significant risk of harm, especially for the vulnerable, and promotion of benefit through informed use of CEDs are all good features of the proposal. However, the pre-market approval process has limitations, which we explore. We raise the possibility of 'risk compensation' in response to the introduction of safety measures, which could alter its effectiveness. The proposal alludes to use of 'formally trained practitioners,' which provide a further tier of regulation for CEDs within the proposal. We consider some positive and negative implications of this aspect of the proposal that might warrant further consideration. PMID- 27774174 TI - The brain, cognitive enhancement devices, and European regulation. PMID- 27774175 TI - What's in a name: the Vermont Genetically Engineered Food Labeling Act. AB - On May 8, 2014, Vermont passed the Vermont Genetically Engineered Food Labeling Act (Act) requiring labels on certain genetically engineered foods. Once the bill takes effect July 1, 2016, all Vermont-retailed foods with more than 0.9% of their total weight in genetically modified ingredients must be labeled with language stating, "may be partially produced with genetic engineering." As genetically engineered food are considered scientifically equivalent to their traditional counterparts and are not subject to federal labeling by the FDA, the Act presents several legal questions. Several of the legal questions have been raised in a recent lawsuit filed by the Grocery Manufactures Association that claims the Act violates the First Amendment, Supremacy Clause, and Commerce Clause. This paper will discuss why the Second Circuit could strike down the Act as unconstitutional as to each claim. PMID- 27774176 TI - Newborn screening in the genomics era. AB - Newborn screening (NBS) exists in every state for the purpose of testing newborns for genetic medical conditions that can be severe, may be treatable, and are often not clinically evident at birth. While almost all of the diseases screened for in newborns have underlying genetic causes, NBS in its current form is performed not by testing for genetic mutations, but by testing for biochemical markers that indicate a disorder. The potential use of whole-genome newborn screening (WG-NBS) as an alternative to the current biochemical testing utilized for NBS would dramatically expand the quantity and types of information parents could learn from screening and is likely to have many implications, both positive and negative. As whole-genome sequencing (WGS) becomes more economical, it probably will be used for the purposes of NBS. However, such an expansion of NBS would contradict many of the principles that have historically guided public health screening programs and, if implemented without sufficient preparation, could result in insufficient infrastructure to accommodate the health care and data management needs that would arise. This article will first look at the past and present of NBS, then the rise of whole genome sequencing, before considering the challenges of WG-NBS, and will end with some thoughts on the path forward. PMID- 27774177 TI - Incidental findings and future testing methodologies: potential application of the ACMG 2013 recommendations. AB - Reactions to the first clinical recommendations for the return of incidental findings (IFs) from genomic sequencing published by the American College of Medical Genetics and Genomics (ACMG) were polarized and resolute. Exploring the three main points of controversy: mandatory testing, testing children for adult conditions, and selection of conditions to be reported on, illuminates concerns for and conservation of bioethical principles-specifically, autonomy and non directiveness. With the historical context of genetic testing in mind, this article studies the potential application of the ACMG recommendations to embryonic testing in the form of preimplantation genetic diagnosis. Theoretical extension of the current recommendations assists in the identification of bioethical dilemmas and possible societal impacts. The recommendations make a statement on the importance of diagnosis and intervention for specific genetic conditions, setting a precedent for disease classification and patient autonomy. In the extreme, the clinical application of such recommendations prenatally may result in discarded embryos, and less societal tolerance of specific conditions. Skilled professionals, such as genetic counselors, researchers, and lawmakers must work together to maintain patient autonomy, providing care in the best interest of each patient. PMID- 27774178 TI - Editorial. PMID- 27774179 TI - Surrogacy litigation in China and beyond. AB - Chinese law neither generally prohibits nor expressly permits surrogacy. As there has been a massive underground surrogacy market in the country, surrogacy lawsuits have occurred from time to time. Chinese courts are called to decide a number of disputed issues regarding validity of surrogacy contract, parenthood of the surrogate child, and sole care and control of the surrogate child. This article examines the judicial solutions to these disputes through a case study, and analyses whether Chinese courts have adopted appropriate approaches in applying the existing law to surrogacy lawsuits. The article further discusses the inadequacies of Chinese law in solving surrogacy disputes and regulating surrogacy, and recommends a set of suggestions for improvement so that Chinese law may better adapt to the social demand of surrogacy. PMID- 27774180 TI - The growth and gaps of genetic data sharing policies in the United States. AB - The 1996 Bermuda Principles launched a new era in data sharing, reflecting a growing belief that the rapid public dissemination of research data was crucial to scientific progress in genetics. A historical review of data sharing policies in the field of genetics and genomics reflects changing scientific norms and evolving views of genomic data, particularly related to human subjects' protections and privacy concerns. The 2013 NIH Draft Genomic Data Sharing (GDS) Policy incorporates the most significant protections and guidelines to date. The GDS Policy, however, will face difficult challenges ahead as geneticists seek to balance the very real concerns of research participants and the scientific norms that propel research forward. This article provides a novel evaluation of genetic and GDS policies' treatment of human subjects' protections. The article examines not only the policies, but also some of the most pertinent scientific, legal, and regulatory developments that occurred alongside data sharing policies. This historical perspective highlights the challenges that future data sharing policies, including the recently disseminated NIH GDS Draft Policy, will encounter. PMID- 27774181 TI - Consent in escrow. AB - Disasters such as flash flooding, mass shootings, and train and airplane accidents involving large numbers of victims produce significant opportunity for research in the biosciences. This opportunity exists in the extreme tails of life events, however, during which decisions about life and death, valuing and foregoing, speed and patience, trust and distrust, are tested simultaneously and abundantly. The press and urgency of these scenarios may also challenge the ability of researchers to comprehensively deliver information about the purposes of a study, risks, benefits, and alternatives. Under these circumstances, we argue that acquiring consent for the immediate use of data that are not time sensitive represents a gap in the protection of human study participants. In response, we offer a two-tiered model of consent that allows for data collected in real-time to be held in escrow until the acute post-disaster window has closed. Such a model not only respects the fundamental tenet of consent in research, but also enables such research to take place in an ethically defensible manner. PMID- 27774182 TI - Yesterday's war; tomorrow's technology: peer commentary on 'Ethical, legal, social and policy issues in the use of genomic technologies by the US military'. AB - A recent article by Maxwell J. Mehlman and Tracy Yeheng Li, in the Journal of Law and the Biosciences, sought to examine the ethical, legal, social, and policy issues associated with the use of genetic screening and germ-line therapies ('genomic technologies') by the US Military. In this commentary, we will elaborate several related matters: the relationship between genetic and non genetic screening methods, the history of selection processes and force strength, and the consequences and ethics of, as Mehlman and Li suggest, engineering enhanced soldiers. We contend, first, that the strengths of genomic testing as a method of determining enrollment in the armed forces has limited appeal, given the state of current selection methods in the US armed forces. Second, that the vagaries of genetic selection, much like other forms of selection that do not bear causally or reliably on soldier performance (such as race, gender, and sexuality), pose a systematic threat to force strength by limiting the (valuable) diversity of combat units. Third, that the idea of enhancing warfighters through germ-line interventions poses serious ethical issues in terms of the control and ownership of 'enhancements' when members separate from service. PMID- 27774183 TI - Military genomic testing: proportionality, expected benefits, and the connection between genotypes and phenotypes. AB - Mehlman and Li offer a framework for approaching the bioethical issues raised by the military use of genomics that is compellingly grounded in both the contemporary civilian and military ethics of medical research, arguing that military commanders must be bound by the two principles of paternalism and proportionality. I agree fully. But I argue here that this is a much higher bar than we may fully realize. Just as the principle of proportionality relies upon a thorough assessment of harms caused and military advantage gained, the use of genomic research, on Mehlman and Li's view, will require an accurate understanding of the connection between genotypes and phenotypes - accurate enough to ameliorate the risk undertaken by our armed forces in being subject to such research. Recent conceptual work in evolutionary theory and the philosophy of biology, however, renders it doubtful that such knowledge is forthcoming. The complexity of the relationship between genotypic factors and realized traits (the so-called 'G->P map') makes the estimation of potential military advantage, as well as potential harm to our troops, incredibly challenging. Such fundamental conceptual challenges call into question our ability to ever satisfactorily satisfy the demands of a sufficiently rigorous ethical standard. PMID- 27774184 TI - 'Good soldiers are made, not born'?: the dangers of medicalizing ability in the military use of genetics. AB - Advances in genetic and genomic science are of particular interest to the United States military. Responding to Maxwell J. Mehlman's and Tracy Yeheng Li's article Ethical, Legal, Social, and Policy Issues in the Use of Genomic Technology by the U.S. Military, this Commentary explores the social consequences of medicalizing what it means to be a good soldier. It begins by reviewing the well-documented consequences of medicalization in the contexts of the eugenics movement and modern genetic and genomic science. It then applies that analysis to the military use of genetics and genomics, focusing on the ways in which genetic or genomic accounts of military ability could entrench existing gender and racial disparities. PMID- 27774185 TI - Science wars-How much risk should soldiers be exposed to in military experimentation? AB - With the threat of biological war becoming a more and more distinct possibility, there is a growing need for vaccines and cures for diseases. As warfare moves from the battlefield to the laboratory, the military must adapt its tactics in order to preserve national security. At the moment, soldiers consent to the risk associated with combat, but with the changing nature of war, the need may arise for soldiers to put themselves at risk not only through combat, but also through scientific experimentation, in order to produce vaccines or cures and ultimately maintain national security. By allowing soldiers to trade risk on the battlefield with risk in the laboratory, deeper research can be made into diseases and biological agents, and this would therefore lessen the threat of biological war or terrorism. PMID- 27774186 TI - Commentary. PMID- 27774187 TI - Egg freezing, stratified reproduction and the logic of not. AB - This commentary examines social and political implications of social egg freezing in a market that is stratified, globalized, and part of a larger bioeconomy. John Robertson's article and public discourse prompted by Facebook and Apple's 'corporate egg freezing' benefits provide touchstones for interrogating social and industry practices that embrace making reproductive capacity marketable. Supply of the cells and bodies necessary for assisted reproductive technology use depends on market thinking and structural inequality. What the industry produces are carefully calibrated social-political distances between participants in egg freezing and banking, as well as 'third party reproduction.' PMID- 27774188 TI - The most plausible pro-coercion view: requiring informed agreement while penalizing non-participation in research. AB - In '(Why) should we require consent to research?' Alan Wertheimer probes whether it is legitimate for the government to 'coerce' people into participating in biomedical research, including interventional biomedical research. In debating the rules that ought to govern participation in interventional biomedical research, we should distinguish two separate moral claims. First, interventional research should proceed only when the subject has given her informed agreement. Second, it is legitimate for the state to set a requirement that people participate in interventional biomedical research, and to penalize or punish those who refuse to participate. The most plausible 'pro-coercion' view accepts both of these claims. Though I stop short of endorsing this view, it captures important 'pro-coercion' and 'anti-coercion' intuitions. PMID- 27774189 TI - Informed consent to participation in interventional studies: second-order in a different sense. PMID- 27774190 TI - Executive action to combat the rise of drug-resistant bacteria: is agricultural antibiotic use sufficiently addressed? AB - On September 18, 2014, President Barack Obama issued an Executive Order titled Combating Antibiotic-Resistant Bacteria. The order demands a 'strategic, coordinated, and sustained effort' to detect, prevent, and control antibiotic resistance. According to the Centers for Disease Control and Prevention (CDC), antibiotic-resistant infections are a rising health concern that result in at least two million illnesses and 23,000 deaths each year in the United States. The Executive Order and accompanying documents have been criticized for taking a weak stance against the use of antibiotics in agriculture; however, they include goals to promote antibiotic stewardship on farms, better surveillance of antibiotic use, and the development of alternatives to antibiotics. The criticisms are also unwarranted based on the current state of scientific evidence; nevertheless, there remain compelling reasons to limit the use of antibiotics in agriculture, and if fully implemented, the executive action is set to achieve this goal. This paper will explore why the criticisms are unwarranted, present the conflicting evidence on whether antibiotic use in farm animals poses a significant health threat to humans, offer other reasons to limit the use of antibiotics in livestock, and suggest ways that the government can maximize the efficacy of the proposed actions. PMID- 27774191 TI - The case for pain neuroimaging in the courtroom: lessons from deception detection. AB - From an observer's perspective, pain is a fairly nebulous concept-it is not externally visible, its cause is not obvious, and perceptions of its intensity are mainly subjective. If difficulties in understanding the source and degree of pain are troublesome in contexts requiring social empathy, they are especially problematic in the legal setting. Tort law applies to both acute and chronic pain cases, but the lack of objective measures demands high thresholds of proof. However, recent developments in pain neuroimaging may clarify some of these inherent uncertainties, as studies purport detection of pain on an individual level. In analyzing the scientific and legal barriers of utilizing pain neuroimaging in court, it is prudent to discuss neuroimaging for deception, a topic that has garnered significant controversy due to premature attempts at introduction in the courtroom. Through comparing and contrasting the two applications of neuroimaging to the legal setting, this paper argues that the nature of tort law, the distinct features of pain, and the reduced vulnerability to countermeasures distinguish pain neuroimaging in a promising way. This paper further contends that the mistakes and lessons involving deception detection are essential to consider for pain neuroimaging to have a meaningful future in court. PMID- 27774192 TI - New science, old convictions - Texas Senate Bill 344: identifying further necessary reform in forensic science. AB - In June 2013, Texas Senate Bill 344 (SB 344) was signed into law after strong Innocence Project support. SB 344 has since transformed the Texan judicial landscape. Known as the 'Junk Science Writ', SB 344 enables the court to grant habeas corpus relief based on scientific evidence that '(1) was not available to be offered by a convicted person at the convicted person's trial; or (2) contradicts scientific evidence relied on by the state at trial'. Inmates, such as the 'San Antonio Four', whose convictions were based upon what is now considered 'faulty' medical and forensic testimony, have been released under SB 344. Yet, science, as a field dependent on innovation, is inherently prone to debunking the scientific and forensic methods the law has relied upon to convict individuals. This commentary identifies policy behind SB 344, how SB 344 may influence the perception of science in the courtroom, and how 'junk science' is defined and/or limited. Furthermore, this commentary concludes that to achieve justice in the legal system through habeas relief based on 'junk science', it is necessary to revitalize and standardize forensic science. PMID- 27774193 TI - The FDA and genetic testing: improper tools for a difficult problem. AB - The US Food and Drug Administration (FDA) has recently issued draft guidance on how it intends to regulate laboratory-developed tests, including genetic tests. This article argues that genetic tests differ from traditional targets of FDA regulation in both product as well as industry landscape, and that the FDA's traditional tools are ill-suited for regulating this space. While existing regulatory gaps do create risks in genetic testing, the regulatory burden of the FDA's proposal introduces new risks for both test providers and patients that may offset the benefits. Incremental expansion of current oversight outside of the FDA can mitigate many of the risks necessitating increased oversight while avoiding the creation of new ones that could undermine this industry. PMID- 27774194 TI - EDITORIAL. PMID- 27774195 TI - Back to first principles: a new model for the regulation of drug promotion. AB - The US Food and Drug Administration's ('FDA' or the 'Agency') current regulatory framework for drug promotion, by significantly restricting the ability of drug manufacturers to communicate important, accurate, up-to-date scientific information about their products that is truthful and non-misleading, runs afoul of the First Amendment and actually runs counter to the Agency's public health mission. Our article proposes a New Model that represents an initial proposal for a modern, sustainable regulatory framework that comprehensively addresses drug promotion while protecting the public health, protecting manufacturers' First Amendment rights, establishing clear and understandable rules, and maintaining the integrity of the FDA approval process. The New Model would create three categories of manufacturer communications-(1) Scientific Exchange and Other Exempt Communications, (2) Non-Core Communications, and (3) Core Communications that would be regulated consistent with the First Amendment and according to the strength of the government's interest in regulating the specific communications included within each category. The New Model should address the FDA's concerns related to off-label speech while protecting drug manufacturers' freedom to engage in truthful and non-misleading communications about their products. PMID- 27774196 TI - Orphan drug incentives in the pharmacogenomic context: policy responses in the US and Canada. AB - Advances in pharmacogenomic research and increasing industry interest in personalized medicine have important implications for the way that orphan drug policies are interpreted and applied. Concerns have been raised about the potential impact of pharmacogenomics and new genomic technologies on our understanding of how disease categories are delineated, and subsequently, how the concept of rare disease should be defined for the purposes of orphan drug policies. This article considers whether orphan drug legislation can be drafted in a way that will maximize benefits and minimize concerns relating to the impact of pharmacogenomics on orphan drug research and development. After reviewing the issues that may arise at the intersection of orphan drug policies and pharmacogenomics, this article will discuss the potential impact of pharmacogenomics at two critical points: orphan designation and approval of the drug product. At each of these points, the relevant aspects of current US orphan drug legislation are examined, focusing on the extent to which recent amendments may address concerns that have been raised previously. This analysis will then provide the foundation for a critical review and recommendations regarding the proposed new Canadian orphan drug framework. PMID- 27774197 TI - Early adopters of the magical thinking cap: a study on do-it-yourself (DIY) transcranial direct current stimulation (tDCS) user community. AB - Among currently available technologies, transcranial direct current stimulation (tDCS) is one of the most promising neuroenhancements because it is relatively effective, safe, and affordable. Recently, lay people have begun to build-or purchase-the tDCS device to use it at home for treatment or as a cognitive enhancer. The tDCS device is currently not covered by the existing regulatory framework, but there are still significant potential risks of misusing this device, and its long-term effects on the brain have not been fully explored. Thus, researchers have argued the need for regulations or official guidelines for the personal use of tDCS. However, until now, no systematic research on the do-it yourself (DIY) tDCS user community has been done. The present study explores the basic demographic characteristics of DIY tDCS users as well as why and how they are using this device through a questionnaire survey, in-depth interviews, and a content analysis of web postings on the use of tDCS. This preliminary but valuable picture of the DIY tDCS user community will shed light on future studies and policy analysis to craft sound regulations and official guidelines for the use of tDCS. PMID- 27774198 TI - A hypothetical neurological association between dehumanization and human rights abuses. AB - Dehumanization is anecdotally and historically associated with reduced empathy for the pain of dehumanized individuals and groups and with psychological and legal denial of their human rights and extreme violence against them. We hypothesize that 'empathy' for the pain and suffering of dehumanized social groups is automatically reduced because, as the research we review suggests, an individual's neural mechanisms of pain empathy best respond to (or produce empathy for) the pain of people whom the individual automatically or implicitly associates with her or his own species. This theory has implications for the philosophical conception of 'human' and of 'legal personhood' in human rights jurisprudence. It further has implications for First Amendment free speech jurisprudence, including the doctrine of 'corporate personhood' and consideration of the potential harm caused by dehumanizing hate speech. We suggest that the new, social neuroscience of empathy provides evidence that both the vagaries of the legal definition or legal fiction of 'personhood' and hate speech that explicitly and implicitly dehumanizes may (in their respective capacities to artificially humanize or dehumanize) manipulate the neural mechanisms of pain empathy in ways that could pose more of a true threat to human rights and rights based democracy than previously appreciated. PMID- 27774199 TI - Ensuring the safe and effective FDA regulation of fecal microbiota transplantation. AB - Scientists, policymakers, and medical professionals alike have become increasingly worried about the rise of antibiotic resistance, and the growing number of infections due to bacteria like Clostridium difficile, which cause a significant number of deaths and are imposing increasing costs on our health care system. However, in the last few years, fecal microbiota transplantation (FMT), the transplantation of stool from a healthy donor into the bowel of a patient, has emerged as a startlingly effective means to treat recurrent C. difficile infections. At present, the FDA is proposing to regulate FMT as a biologic drug. However, this proposed classification is both underregulatory and overregulatory. The FDA's primary goal is to ensure that patients have access to safe, effective treatments-and as such they should regulate some aspects of FMT more stringently than they propose to, and others less so. This essay will examine the nature of the regulatory challenges the FDA will face in deciding to regulate FMT as a biologic drug, and will then evaluate available policy alternatives for the FDA to pursue, ultimately concluding that the FDA ought to consider adopting a hybrid regulatory model as it has done in the case of cord blood. PMID- 27774200 TI - Commentary: Is there a problem Consent in Escrow can solve? PMID- 27774201 TI - Are ethics promulgations self-defeating? AB - Alan Wertheimer argues that promulgating some ethical standards of international clinical research may be self-defeating: the intended purpose of these standards is to promote the interests of subjects and communities in LMICs, while the outcome of promulgation could be to undermine these very same interests. If enforced, such standards would increase the costs of performing beneficial research in LMICs, potentially diverting opportunities to participate in this research away from those who have no other access to the care participation allows. I argue that these standards are really intended as deontological constraints protecting subjects from being exploited by research sponsors. First, I show that Wertheimer begs the question against this deontological interpretation of ethics promulgations, rejecting it on non-deontological grounds. I go on to show that non-exploitation is an important goal on its own, sometimes independent from-and sometimes even outweighing-the goal of promoting the interests of subjects and communities in LMICs. I conclude by suggesting that those who criticize the promulgation of non-exploitation on the grounds that exploitative practices help those badly off might do best to reconsider the background assumption that sponsors in wealthier countries have no pre-existing obligation to promote the interests of the world's poor. PMID- 27774202 TI - Addressing diversion effects. AB - Alan Wertheimer argues that those who promulgate principles of research ethics have a responsibility to take into account the diversion effects of those principles. In this commentary, I argue that Wertheimer's proposal that diversion effects should be considered when promulgating principles of research ethics makes sense, but it often may be best to deal with these effects once a principle has been accepted and implemented, rather than focusing on them at the outset. PMID- 27774203 TI - Two kinds of rule regulating human subjects research. AB - Alan Wertheimer argues that before we promulgate some rule regarding the conduct of research on human subjects we ethically ought to consider the consequences of the rule being followed. This ethical requirement has an exception, though, Wertheimer maintains: it doesn't apply to rules that are not motivated by considerations of outcome. I agree that there is an exception to be made to Wertheimer's proposed ethical requirement, but not Wertheimer's exception. The important distinction is not that between rules motivated by considerations of outcome and rules motivated otherwise, but between rules designed to enforce ethics and rules not so designed. Before we promulgate the latter kind of rule, we are ethically required to consider the consequences of doing so. This is not so for the former kind of rule. My exception, unlike Wertheimer's, yields the conclusion that we should promulgate, regardless of the consequences of doing so, a rule requiring that the potential benefit to the subject of participation in a study outweigh the risks. This rule is motivated by considerations of outcome, so it would land on the wrong side of Wertheimer's divide. But it's also designed to enforce ethics, so it lands on the correct side of my divide. PMID- 27774204 TI - Diversion effects, incentive effects, and the goals of research ethics promulgations. AB - It was with great sadness that the philosophical and ethical communities noted the recent passing of Alan Wertheimer. It is not possible to engage in serious work regarding international research ethics (nor much of political philosophy more broadly) without encountering and wrestling with his careful contributions. He was welcoming of discussion and generous with his intellectual energies. Ongoing work in these areas will be so much the poorer for his absence. PMID- 27774205 TI - Response to peer commentaries. PMID- 27774206 TI - Concussions and youth football: using a public health law framework to head off a potential public health crisis. AB - Concussion from sport is increasingly recognized as a public health priority. In response, all states and the District of Columbia have enacted youth concussion legislation. This paper first examines key developments in concussion-related policy and legislation and then uses the findings from recent scientific studies to highlight the need to incorporate evolving scientific evidence into concussion legislation in order to better protect youth and adolescent athletes. Next, the paper discusses the framework of empirical health law research and why it should be applied in the case of concussion legislation. Finally, this paper argues that empirical health law research should be considered in any decision about whether legislation can help improve the health and safety of young players, a particularly vulnerable population whose unique needs have not yet been adequately addressed. PMID- 27774207 TI - Forward, Gillick: Are competent children autonomous medical decision makers? New developments in Australia. AB - Another chapter has opened in the tortured history of the status of Gillick competence. Never before has Gillick been extended to permit a mature child to make autonomous medical decisions over and above the curial 'parens patriae' power. In 2013, two judicial decisions promulgated from different Australian courts are in conflict over this most fundamental of questions. This Article situates the law of the 'parens patriae' power in Australia and, drawing on overseas conceptualizations of analogous doctrine, explores the bases for and potential consequences of this conflict. PMID- 27774209 TI - EDITORIAL. PMID- 27774208 TI - Genetic citizenship: DNA testing and the Israeli Law of Return. AB - The Israeli State recently announced that it may begin to use genetic tests to determine whether potential immigrants are Jewish or not. This development would demand a rethinking of Israeli law on the issue of the definition of Jewishness. In this article, we discuss the historical and legal context of secular and religious definitions of Jewishness and rights to immigration in the State of Israel. We give a brief overview of different ways in which genes have been regarded as Jewish, and we discuss the relationship between this new use of genetics and the society with which it is co-produced. In conclusion, we raise several questions about future potential impacts of Jewish genetics on Israeli law and society. PMID- 27774210 TI - Neuroscience and behavioral genetics in US criminal law: an empirical analysis. AB - The goal of this study was to examine the growing use of neurological and behavioral genetic evidence by criminal defendants in US criminal law. Judicial opinions issued between 2005-12 that discussed the use of neuroscience or behavioral genetics by criminal defendants were identified, coded and analysed. Criminal defendants are increasingly introducing such evidence to challenge defendants' competency, the effectiveness of defense counsel at trial, and to mitigate punishment. PMID- 27774211 TI - The use of neuroscientific evidence in the courtroom by those accused of criminal offenses in England and Wales. AB - This examination of the extent of the use of neuroscientific evidence in England and Wales identifies 204 reported cases in which such evidence has been used by those accused of criminal offenses during the eight-year period from 2005-12. Based on the number of reported cases found, the use of such evidence appears well established with those accused of criminal offenses utilizing such evidence in approximately 1 per cent of cases in the Court of Appeal (Criminal Division). Neuroscientific evidence is used to quash convictions, to lead to convictions for lesser offenses and to lead to reduced sentences. In addition, cases are identified where neuroscientific evidence is used to avoid extradition, to challenge bail conditions and to resist prosecution appeals against unduly lenient sentences. The range of uses identified is wide: including challenging prosecution evidence as to the cause of death or injury, challenging the credibility of witnesses and arguing that those convicted were unfit to plead, lacked mens rea or were entitled to mental condition defenses. The acceptance of such evidence reflects the willingness of the courts in England and Wales to hear novel scientific argument, where it is valid and directly relevant to the issue(s) to be decided. Indeed, in some of the cases the courts expressed an expectation that structural brain scan evidence should have been presented to support the argument being made. PMID- 27774212 TI - The use of neuroscientific evidence in Canadian criminal proceedings. AB - This article addresses the question of how neuroscientific evidence is currently used in the Canadian criminal justice system, with a view to identifying the main contexts in which this evidence is raised, as well as to discern the impact of this evidence on judgements of responsibility, dangerousness, and treatability. The most general Canadian legal database was searched for cases in the five-year period between 2008 and 2012 in which neuroscientific evidence related to the responsibility and recidivism risk of criminal offenders was considered. Canadian courts consider neuroscientific evidence of many types, particularly evidence of prenatal alcohol exposure, traumatic brain injury, and neuropsychological testing. The majority of the cases are sentencing decisions, which is useful given that it offers an opportunity to observe how judges wrestle with the tension that evidence of diminished capacity due to brain damage tends to reduce moral blameworthiness, while it also tends to increase perceptions of risk and dangerousness. This so-called double-edged sword of the biological explanation of criminal behavior was reflected in this study, and raises questions about whether and when the pursuit of such evidence is advisable from the defense perspective. PMID- 27774213 TI - Neuroscientific and behavioral genetic information in criminal cases in the Netherlands. AB - In this contribution an empirical approach is used to gain more insight into the relationship between neuroscience and criminal law. The focus is on case law in the Netherlands. Neuroscientific information and techniques have found their way into the courts of the Netherlands. Furthermore, following an Italian case in which a mentally ill offender received a penalty reduction in part because of a 'genetic vulnerability for impulsive aggression', the expectation was expressed that such 'genetic defenses' would appear in the Netherlands too. To assess how neuroscientific and behavioral genetic information are used in criminal justice practice in the Netherlands, we systematically collect Dutch criminal cases in which neuroscientific or behavioral genetic information is introduced. Data and case law examples are presented and discussed. Although cases are diverse, several themes appear, such as prefrontal brain damage in relation to criminal responsibility and recidivism risk, and divergent views of the implications of neurobiological knowledge about addiction for judging criminal responsibility. Whereas in the international 'neurolaw literature' the emphasis is often on imaging techniques, the Dutch findings also illustrate the role of neuropsychological methods in criminal cases. Finally, there appears to be a clear need of practice oriented instruments and guidelines. PMID- 27774214 TI - Dolly and Alice. AB - The opinion of the United States Court of Appeals for the Federal Circuit, In re Roslin Institute, rejecting patent claims to mammals cloned from somatic cells, was rendered about a month before the United States Supreme Court's decision in Alice Corp. v. CLS Bank International. The Alice opinion explicitly sets out the standard for determining whether an invention falls within statutory patentable subject matter. Thus one is thus left to wonder what the Roslin opinion might have looked like had it been decided only a few weeks later, after the Alice decision was published, with the benefit of the Supreme Court's further direction on patentable subject matter. In this essay I explore whether in hindsight the Alice standard might have dictated a different outcome in Roslin, suggesting how the two-part test articulated by the Supreme Court in Alice might apply to a 'products of nature' analysis for cloned mammals. Drawing on that analysis, I then use the Roslin case as a vehicle to highlight certain issues with the Supreme Court's current subject matter jurisprudence as applied to biotechnology. By juxtaposing Dolly with Alice, it becomes clear that the Supreme Court has revivified a number of dormant biotechnology patent problems in the guise of subject matter analysis. PMID- 27774215 TI - Marginally scientific? Genetic testing of children and adolescents for lifestyle and health promotion. PMID- 27774216 TI - Just compensation: a no-fault proposal for research-related injuries. AB - Biomedical research, no matter how well designed and ethically conducted, carries uncertainties and exposes participants to risk of injury. Research injuries can range from the relatively minor to those that result in hospitalization, permanent disability, or even death. Participants might also suffer a range of economic harms related to their injuries. Unlike the vast majority of developed countries, which have implemented no-fault compensation systems, the United States continues to rely on the tort system to compensate injured research participants-an approach that is no longer morally defensible. Despite decades of US advisory panels advocating for no-fault compensation, little progress has been made. Accordingly, this article proposes a novel and necessary no-fault compensation system, grounded in the ethical notion of compensatory justice. This first-of-its-kind concrete proposal aims to treat like cases alike, offer fair compensation, and disburse compensation with maximum efficiency and minimum administrative cost. It also harmonizes national and international approaches-an increasingly important goal as research becomes more globalized, multi-site trials grow in number, and institutions and sponsors in the United States move to single-IRB review. PMID- 27774217 TI - A pragmatic analysis of the regulation of consumer transcranial direct current stimulation (TDCS) devices in the United States. AB - Several recent articles have called for the regulation of consumer transcranial direct current stimulation (tDCS) devices, which provide low levels of electrical current to the brain. However, most of the discussion to-date has focused on ethical or normative considerations; there has been a notable absence of scholarship regarding the actual legal framework in the United States. This article aims to fill that gap by providing a pragmatic analysis of the consumer tDCS market and relevant laws and regulations. In the five main sections of this manuscript, I take into account (a) the history of the do-it-yourself tDCS movement and the subsequent emergence of direct-to-consumer devices; (b) the statutory language of the Federal Food, Drug and Cosmetic Act and how the definition of a medical device-which focuses on the intended use of the device rather than its mechanism of action-is of paramount importance for discussions of consumer tDCS device regulation; (c) how both the Food and Drug Administration (FDA) and courts have understood the FDA's jurisdiction over medical devices in cases where the meaning of 'intended use' has been challenged; (d) an analysis of consumer tDCS regulatory enforcement action to-date; and (e) the multiple US authorities, other than the FDA, that can regulate consumer brain stimulation devices. Taken together, this paper demonstrates that rather than a 'regulatory gap,' there are multiple, distinct pathways by which consumer tDCS can be regulated in the United States. PMID- 27774218 TI - It depends whose data are being shared: considerations for genomic data sharing policies. AB - There is an urgent need for consistent data sharing policies that promote the advancement of science while respecting the values and interests of those providing their genetic data for research. Responding to the article of Jalayne J. Arias, Genevieve Pham-Kanter, and Eric G. Campbell, 'The Growth and Gaps of Genetic Data Sharing Policies in the United States', this commentary further explores the challenges of human subjects' protection in existing data sharing policies. We will elaborate on the need for data sharing policies to accommodate variation in individual and group preferences around data sharing and privacy concerns by comparing our previously published data on patients' and parents' consent to data sharing and attitudes about privacy to data from focus groups with HIV-positive, underserved individuals who were asked about their willingness to participate in genetic research and share their data broadly. These studies support the observation of Arias, Pham-Kanter, and Campbell that researchers, and funding agencies will need to balance the privacy interests of groups as well as individuals in future genomic data sharing policies. PMID- 27774219 TI - Off-label drug promotion and the ephemeral line between marketing and education. AB - Fueled by massive settlements and concerns about pharmaceutical company influence over medical practice, the fight over off-label promotion has become a rancorous one with little middle ground. For some, off-label restrictions are both bad law and bad medicine, violating the First Amendment while denying physicians access to crucial information. For others, the battle pits the very soul of the FDA against the excesses of a profit-driven marketplace. Far from ameliorating concerns over manufacturer influence, the New Model proposed by Bennett et al. would exacerbate them. The Model would limit FDA authority to core communications proposing immediate commercial transactions, giving manufacturers unfettered discretion over scientific exchanges and nearly free rein over truthful quasi commercial communications. Most problematically, the New Model relies on the longstanding assumption that truly educational and scientific activities can be distinguished from simple product promotion - a dichotomy that exists not only in federal law and professional association codes, but also underlies the jurisdiction of the federal agencies overseeing the pharmaceutical sector. Experience invites skepticism that these activities can be cleanly separated, suggesting that the New Model may simply perpetuate abusive behaviors without offering concomitant benefits to physicians or patients. PMID- 27774220 TI - Regulating drug promotion to promote the public health: a response to Bennett et al. PMID- 27774221 TI - Universities and Patent Demands. AB - Research universities have made enormous contributions to the field of medicine and the treatment of human disease. Alone or in collaboration with pharmaceutical companies, academic researchers have added to the store of knowledge that has led to numerous life science breakthroughs. A new chapter may be opening for academic researchers, however, that could lead to a darker tale. 'The mouse that trolled: the long and tortuous history of a gene mutation patent that became an expensive impediment to Alzheimer's research, by Bubela et al., chronicles one such tale.' The authors do an excellent job of bringing to life the twisting saga that engulfed numerous academic and non-profit Alzheimer's researchers over many years. The authors note that the story is an outlier, but sadly, that may not be the case. There are increasing signs that academic researchers and their institutions are being caught up in the rush for gold that is accompanying the proliferation of the non-practicing entity business model. As I have noted before, academic institutions have a dual role, as keepers of the academic flame and guardians of the public monies entrusted to them through state and federal research funding. The specter of taxpayer money being used, not to advance research and for the betterment of society, but as part of schemes to extract money from productive companies may not sit well with voters, and ultimately, with legislators. In that case, researchers and institutions themselves may have much to lose. PMID- 27774222 TI - The mouse that trolled. PMID- 27774223 TI - The patent law Duchy of Grand Fenwick: a comment on The mouse that trolled: the long and tortuous history of a gene mutation patent that became an expensive impediment to Alzheimer's research. AB - This comment on The mouse that trolled by Tania Bubela, Saurabh Vishnubhakat, and Robert Cook-Deegan discusses the authors' description of how patents relating to the gene coding for a protein involved in Alzheimer's disease were obtained and used to sue scientific researchers, of how conflicts can arise among groups of researchers, and of how important research can be delayed or foregone by the exercise of patent rights. The authors sought to counter with evidence the optimistic views that patents on such research tools are not used to sue researchers and thus do not impede sequential innovation. The authors proposed legal reforms to avoid such impediments, particularly adoption of a broader experimental use limit to the patent infringement right. This comment agrees with the authors' analysis, but suggests that their descriptions have more substantial implications that extend beyond their example and that their recommendation for limited expansion of the experimental use doctrine does not go far enough. PMID- 27774224 TI - A problem not yet manifest: gaps in insurance coverage of medical interventions after genetic testing. PMID- 27774225 TI - The problems of liminal states, line drawing, and false dichotomies. AB - This commentary focuses on the tenuous line between health and disease and the conflicting characterizations of genetic predisposition that sometimes place it on one side of that line, and sometimes on the other. For example, GINA uses the line between health and disease to distinguish between, respectively, the healthy (including, those with genetic predispositions), who are shielded from discrimination, and those with 'manifested illness,' who are not. At the same time, some have argued that the Americans with Disabilities Act protects individuals with genetic predispositions, relying on a label akin to disability, as opposed to health, to characterize this group. Similarly, courts have described genetic predisposition as a disease of sorts to justify insurance payment for medical intervention. Attempts to fit genetic predisposition neatly into the binary world of health or illness can be problematic because this dichotomy doesn't capture the complex continuum between those states. Some individuals reside in yet another 'liminal' state when they develop mild symptoms or biomarkers, placing them somewhere between genetic predisposition and actual disease manifestation. As a result, they may be unprotected under existing frameworks. Liminal states are therefore problematic not only with respect to insurance reimbursement, but in other areas as well. PMID- 27774226 TI - FDA's pathway for regulation of FMT: not so fraught. PMID- 27774227 TI - Trust, vulnerable populations, and genetic data sharing. AB - Recent policies and proposed regulations, including the Notice of Proposed Rulemaking for the Common Rule and the 2014 NIH Genetic Data Sharing Policy, seek to improve research subject protections. Protections for subjects whose genetic data is shared are critical to reduce risks such as loss of confidentiality, stigma, and discrimination. In the article 'It depends whose data are being shared: considerations for genomic data sharing policies', Robinson et al. provide a response to our article, 'The Growth and Gaps of Genetic Data Sharing Policies'. Robinson et al. highlight the importance of individual and group preferences. In this article, we extend the conversation on models for improving protections which will mitigate consequences for individuals and groups that are vulnerable to stigma and discrimination. PMID- 27774228 TI - The regulation of cognitive enhancement devices: refining Maslen et al.'s model. AB - Our (2014) model for the regulation of cognitive enhancement devices (CEDs) received a great deal of interest from those involved in European device regulation and from academic commentators. Further, since the publication of our recommendations, the number of manufacturers of brain stimulation devices for non medical purposes has increased, underscoring the need for a regulatory response. In this paper, we clarify aspects of our original proposal and address additional regulatory issues beyond our original focus on the sale of devices. We begin with theoretical points pertaining to the definition of a CED and the distinction between treatment and enhancement. We then respond to practical challenges raised by the prospect of implementing our regulatory framework. Next, we address some wider societal considerations relating to users and other stakeholders. Finally, we revisit the broader regulatory context within which the various discussions are situated. PMID- 27774230 TI - EDITORIAL. PMID- 27774229 TI - Consent in escrow: opting to opt in. AB - In this paper, we reply to Taylor's (2015) peer commentary on consent-in-escrow. Specifically, we clarify the utility of this novel approach, the way in which it minimizes risks to participants, and how it differs from existing opt-out methods. We further explore its potential use in fields beyond disaster research. PMID- 27774231 TI - Paper trails, trailing behind: improving informed consent to IVF through multimedia applications. AB - Though intended to educate patients on the risks, benefits, side effects and alternatives within medical treatment, informed consent documents may have unanticipated consequences for patients. Patients may regard these forms as little more than a ritual to access treatment. Or patients may perceive that these forms exist to protect doctors rather than to contribute to a meaningful, patient-protective educational interaction. To rehabilitate the informed consent project, this essay considers the baggage that informed consent documents have acquired through practical use, explores patients' and providers' lived experience of informed consent, and considers whether a multimedia consent application would be a viable solution to the various difficulties that currently erode perceptions of and confidence in the informed consent process. PMID- 27774232 TI - Gamete donor anonymity and limits on numbers of offspring: the views of three stakeholders. AB - This paper discusses the attitudes of three groups of stakeholders in the world of assisted reproduction gamete donors, parents who use donated gamete, and offspring conceived with donated gametes with respect to the two issues of donor anonymity and limits on the number of offspring a single donor can produce. The data are drawn from on-line surveys which were made available between May 12, 2104 and August 15, 2014 to gamete donors, donor-conceived offspring, and parents who used donated gametes to conceive. A total of 325 donors (176 egg donors; 149 sperm donors) responded to the survey as did 2134 parents and 419 offspring. The data show that offspring are more opposed to donor anonymity than are parents and donors. Among offspring opposition to anonymity grows as they age. On the other hand, parents are most in favor of limits on numbers of offspring produced by a single donor. Parents worry about health and accidental contact between people conceived from the same donor. PMID- 27774233 TI - Other women's wombs: uterus transplants and gestational surrogacy. AB - The birth of a child after uterus transplant from a living donor in Sweden in October, 2013 has spurred reproductive and transplant physicians in Europe and North America to investigate whether uterus transplants, from living or cadaveric donors, will be a safe and effective therapy for women with uterine insufficiency. While progress with uterus transplant depends on medical factors, there are also important ethical and legal concerns. Uterus transplant is essential for women without access to surrogacy. It may also be sought by infertile women who dislike surrogacy. This article examines medical, ethical, legal, and policy issues that arise with womb transplant, including the role of surrogacy policies that make them necessary. The conclusion is that there is a clear ethical path for either surrogacy or uterus transplant to be used by women with uterine insufficiency. PMID- 27774234 TI - In vitro gametogenesis: just another way to have a baby? AB - Advances in science have made possible the derivation of reproductively viable gametes in vitro from mice. The research on human cells suggests that in vitro gametogenesis ("IVG") with reproductive potential may one day be possible with humans. This technology would allow same-sex couples to have children who are biologically related to both of them; allow single individuals to procreate without the genetic contribution of another individual; and facilitate "multiplex" parenting, where groups of more than two individuals procreate together, producing children who are the genetic progeny of them all. IVG could also make prenatal selection a much more refined and comprehensive process than it is today, allowing for the selection of embryos on the basis of multiple factors. Evaluating IVG under a relational autonomy framework, this article argues that the potential benefits or harms of IVG depend on the social, scientific, and legal context in which it is situated and how it is used. It concludes that IVG is preferable to some forms of assisted reproductive technologies in certain instances and substantially more problematic in others. Finally, it suggests that its capacity to "perfect" prenatal selection in many ways exacerbates the problematic aspects of increasingly expansive prenatal selection. PMID- 27774235 TI - What does recent neuroscience tell us about criminal responsibility? AB - A defendant is criminally responsible for his action only if he is shown to have engaged in a guilty act-actus reus (eg for larceny, voluntarily taking someone else's property without permission)-while possessing a guilty mind-mens rea (eg knowing that he had taken someone else's property without permission, intending not to return it)-and lacking affirmative defenses (eg the insanity defense or self-defense). We therefore first review neuroscientific studies that bear on the nature of voluntary action, and so could, potentially, tell us something of importance about the actus reus of crimes. Then we look at studies of intention, perception of risk, and other mental states that matter to the mens rea of crimes. And, last, we discuss studies of self-control, which might be relevant to some formulations of the insanity defense. As we show, to date, very little is known about the brain that is of significance for understanding criminal responsibility. But there is no reason to think that neuroscience cannot provide evidence that will challenge our understanding of criminal responsibility. PMID- 27774236 TI - Orphan drug incentives in the pharmacogenomic context: policy responses in the USA and Canada. PMID- 27774238 TI - Hate speech, volition, and neurology. PMID- 27774237 TI - Neuroscience cannot answer these questions: a response to G. and R. Murrow's essay hypothesizing a link between dehumanization, human rights abuses and public policy. AB - The Murrows' paper, 'A hypothetical link between dehumanization and human rights abuses', in which they propose that neuroscience may answer some difficult public policy questions, including questions about the First Amendment, is an unfortunate foray into law and public policy unjustified by the current state of neuroscience. Neuroscientific insights may one day have important implications for the law, and for some of the folk psychological assumptions embedded in the law, but they will never change the words of the written Constitution, or answer difficult policy questions in the interstices of those words. Suggesting that neuroscience can today inform these questions does a disservice to science, law and the complexity of the human condition. PMID- 27774239 TI - Dehumanization: its operations and its origins. AB - Murrow and Murrow offer a novel account of dehumanization, by synthesizing data which suggest that where subject S has a dehumanized view of group G, S's neural mechanisms of empathy show a dampened response to the suffering of members of G, and S's judgments about the humanity of members of G are largely non-conscious. Here I examine Murrow and Murrow's suggestions about how identity-based hate speech bears responsibility for dehumanization in the first place. I identify a distinction between (i) accounts of the nature of the harm effected by identity prejudice, and (ii) accounts of how hate speech contributes to the harms of identity prejudice. I then explain why Murrow and Murrow's proposal is more aptly construed as an account of type (i), and explain why accounts of this type, even if they're plausible and evidentially well-supported, have limited implications in relation to justifications for anti-hate speech law. PMID- 27774241 TI - Affirming the need for a new model for the regulation of drug promotion: a rebuttal to Krause and Zettler. PMID- 27774240 TI - The mouse that trolled (again). PMID- 27774242 TI - A valid question: Could hate speech condition bias in the brain? PMID- 27774243 TI - Response to peer commentaries: prevention for those who can pay. PMID- 27774244 TI - Recently proposed changes to legal and ethical guidelines governing human subjects research. PMID- 27774245 TI - Patenting nature or protecting culture? Ethnopharmacology and indigenous intellectual property rights. AB - Ethnopharmacologists are scientists and anthropologists that study indigenous medicines and healing practices, and who often develop new therapies and medicines for wider use. Ethnopharmacologists do fieldwork with indigenous peoples in traditional societies, where they encounter a wide range of cultural values and varying ideas about the nature of property relations. This poses difficulties for protecting indigenous intellectual property and for making just trade agreements. This Note reviews the legal issues relevant to the protection of indigenous resources in ethnopharmacology trade agreements, and suggests that recent developments in anthropology and the social study of science could be instructive in furthering the legal discourse and in providing policy directions. Specifically, the Note introduces the concepts of 'ontological pluralism' and 'epistemic subsidiarity', which could help lawmakers write sui generis trade agreements to better protect indigenous knowledge and resources. PMID- 27774246 TI - Inherited proclivity: When should neurogenetics mitigate moral culpability for purposes of sentencing? AB - Certain genes and neurobiology ('neurogenetics') may predispose some people to violent behavior. Increasingly, defendants introduce neurogenetic evidence as a mitigating factor during criminal sentencing. Identifying the cause of a criminal act, biological or otherwise, does not necessarily preclude moral or legal liability. However, valid scientific evidence of an inherited proclivity sometimes should be considered when evaluating whether a defendant is less morally culpable for a crime and perhaps less deserving of punishment. This Note proposes a two-pronged test to understand whether and when neurogenetic evidence should be considered to potentially mitigate an individual's culpability for criminal behavior. The first prong normatively assesses whether a defendant meets a threshold of having meaningfully managed his risk of harming others based on what he knew, or should have known, about his own proclivities to violence. The second prong considers the admissibility of the evidence based on whether the specific neurogenetic proclivity claimed by the defendant is relevant and adequately supported by science so as to be reliable. This proposed two-pronged test, beginning with an ethical threshold and followed by a scientific hurdle, can help judges and juries establish when to accept arguments for neurogenetic mitigation at sentencing, and when to reject them. PMID- 27774247 TI - Off-patent drugs at brand-name prices: a puzzle for policymakers. AB - In August 2015, Turing Pharmaceuticals acquired the marketing rights to Daraprim (pyrimethamine), a drug used to treat parasitic infections like malaria and toxoplasmosis. Soon after, Turing caused an uproar when it announced that it would raise the price per tablet of Daraprim from [Formula: see text], a 5500% price hike for a drug that has been on the market for over 60 years and off patent since the 1970s. Old, off-patent drugs are becoming increasingly expensive; Daraprim is the archetypal example. Turing had the power to set a high price for Daraprim because the drug's limited patient population, the absence of competing manufacturers, and a lack of therapeutic alternatives all created an effective monopoly. Similar forces have driven up the prices of other off-patent drugs that treat diseases as diverse as heart failure and multi-drug-resistant tuberculosis. Thus, policymakers will have to consider how the high cost of off patent drugs impacts public health as well as public spending. In this Note I outline the extent of the high-cost off-patent drug problem, drawing special attention to the problem's negative effects on both health outcomes and government budgets. After discussing some of the problem's underlying causes, I present several solutions to the problem that policymakers could consider, with a focus on proposals like reference pricing and expanded compounding that have received relatively little media attention. PMID- 27774249 TI - Editorial. PMID- 27774248 TI - Sugars and adiposity: the long-term effects of consuming added and naturally occurring sugars in foods and in beverages. AB - OBJECTIVE: The aim of this study was to determine if the association with adiposity varies by the type (added vs. naturally occurring) and form (liquid vs. solid) of dietary sugars consumed. METHODS: Data from the 10-year National Heart, Lung, and Blood Institute (NHLBI) Growth and Health Study (n = 2,021 girls aged 9 10 years at baseline; n = 5,156 paired observations) were used. Using mixed linear models, 1-year changes in sugar intake, body mass index z-score (BMIz) and waist circumference (WC) were assessed. RESULTS: The results showed mean daily added sugar (AS) intake: 10.3 tsp (41 g) liquid; 11.6 tsp (46 g) solid and naturally occurring sugar intake: 2.6 tsp (10 g) liquid; 2.2 tsp (9 g) solid. Before total energy adjustment, each additional teaspoon of liquid AS was associated with a 0.222-mm increase in WC (p = 0.0003) and a 0.002 increase in BMIz (p = 0.003). Each teaspoon of solid AS was associated with a 0.126-mm increase in WC (p = 0.03) and a 0.001 increase in BMIz (p = 0.03). Adjusting for total energy, this association was maintained only between liquid AS and WC among all and between solid AS and WC among those overweight/obese only. There was no significant association with naturally occurring sugar. CONCLUSIONS: These findings demonstrate to suggest a positive association between AS intake (liquid and solid) and BMI that is mediated by total energy intake and an association with WC that is independent of it. PMID- 27774250 TI - Obesity and the extent of liver damage among adult New Zealanders: findings from a national survey. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD), defined as excessive fat accumulation in hepatocytes when no other pathologic causes are present, is an increasingly common obesity-related disorder. We sought to describe the prevalence of elevated liver enzymes, a marker of liver damage, among New Zealand adults, and high-risk subgroups including those with an elevated body mass index and those with pre-diabetes or diabetes, to gain a better understanding of the burden of liver disease. METHODS: A total of 4,721 New Zealanders aged 15+ years participated in a nationally representative nutrition survey. Liver enzymes, alanine transaminase (ALT) and gamma glutamyl transpeptidase (GGT) were measured in serum. Results were available for 3,035 participants, of whom 10.8% were Maori and 4.5% Pacific. RESULTS: Overall, the prevalence of elevated ALT and elevated GGT was 13.1% (95% confidence interval [CI]: 11.2 - 15.0) and 13.7% (95% CI: 12.0 - 15.4), respectively. Odds ratios for an elevated ALT or GGT markedly increased with increasing body mass index. Men with obesity had the highest elevated ALT prevalence (28.5%; 95% CI: 21.7-35.4), and women with diabetes had the highest elevated GGT prevalence (36.5%; 95% CI: 26.0-47.0). Adding alcohol consumption categories to each of the adjusted models did not meaningfully change any results, although for women, heavy alcohol consumption was associated with an elevated GGT (overall p = 0.03). CONCLUSIONS: Obesity-related liver disease is likely to increasingly burden the New Zealand health sector and contribute to health disparities unless effective obesity treatment and prevention measures are given high priority. (c) 2015 The Authors. Obesity Science & Practice published by John Wiley & Sons Ltd, World Obesity and The Obesity Society. PMID- 27774251 TI - Low-income African-American adults share weight status, food-related psychosocial factors and behaviours with their children. AB - OBJECTIVE: This study aims to examine the extent to which low-income African American children's weight status, psychosocial characteristics and food-related behaviours are associated with that of their adult caregivers. METHODS: Cross sectional data from baseline evaluation of B'More Healthy Communities for Kids obesity prevention trial were used. Outcomes of interest were children's overweight and/or obesity status, food-related self-efficacy, knowledge, intentions and healthier/less healthy food acquisition scores. The primary exposures were adult caregiver's overweight and/or obesity status, their psychosocial factors and food acquisition scores. Multiple logistic regression analyses were used to assess associations. RESULTS: Children had higher odds of overweight or obesity if they had an overweight/obese caregiver (odds ratio [OR] 4.04, 95% confidence interval [95%CI] 1.59-10.28) or an obese caregiver (OR 2.50, 95%CI 1.39-4.51). Having a caregiver in the highest quartile of self-efficacy, food intentions and healthy food acquisition patterns was associated with higher odds of their child also having a higher score on these factors (self-efficacy: OR 3.77 [95%CI 1.76-8.04]; food intentions: OR 1.13 [95%CI 1.01-1.27]; and healthy food acquisition: OR 2.19 [95%CI 1.05-4.54]). CONCLUSIONS: Child and adult caregiver weight status and psychosocial characteristics were positively associated in this low-income, urban population. These findings may help inform obesity treatment or prevention programmes and interventions aimed at parents and families. PMID- 27774252 TI - Proxy measures of vitamin D status - season and latitude - correlate with adverse outcomes after bariatric surgery in the Nationwide Inpatient Sample, 2001-2010: a retrospective cohort study. AB - OBJECTIVE: To investigate the association between adverse surgical outcomes following bariatric surgery and proxy measures of vitamin D (VitD) status (season and latitude) in the Nationwide Inpatient Sample (NIS). BACKGROUND: Obesity is an independent risk factor for VitD deficiency (25(OH)D < 20 ng ml-1). VitD deficiency compounds the chronic inflammation of obesity, increasing the risk of adverse outcomes following bariatric surgery. Epidemiology has long used season and latitude as proxies for group VitD, as VitD status is largely determined by sun exposure, which is greatest during summer and at the Equator. METHODS: We assessed proxy measures of group VitD status. We compared surgeries in VitD Summer (July to September), Winter (January to March), and Fall/Spring (October to December and April to June) and in the North (>=37 degrees N) vs. the South (<37 degrees N). RESULTS: We identified 932,091 bariatric surgeries; 81.2% were women and 74.4% were white. Sex was unequally distributed by season (p = 0.005). Median age was 43.0 years (all groups). Most surgeries occurred in the North (64.8%). Adverse outcome rates ranged from 0.01% (wound infections) to 39.4% [prolonged length of stay {LOS}]. Season was inversely associated with wound infection (p = 0.018) and dehiscence (p = 0.001). Extended LOS was inversely correlated with season (p < 0.001). These relationships held after adjustment. Prolonged LOS (p < 0.001) and any complication (p = 0.108) were more common in the North. CONCLUSIONS: We have demonstrated a graded relationship between seasonality and adverse outcomes following bariatric surgery. The association was strongest for dehiscence and prolonged LOS. These relationships held when using latitude. A prospective study measuring pre-operative 25(OH)D concentration would strengthen the case for causality in adverse surgical outcomes. PMID- 27774253 TI - Effects of meal composition on postprandial incretin, glucose and insulin responses after surgical and medical weight loss. AB - BACKGROUND: Meal tolerance tests are frequently used to study dynamic incretin and insulin responses in the postprandial state; however, the optimal meal that is best tolerated and suited for hormonal response following surgical and medical weight loss has yet to be determined. OBJECTIVE: To evaluate the tolerability and effectiveness of different test meals in inducing detectable changes in markers of glucose metabolism in individuals who have undergone a weight loss intervention. METHODS: Six individuals who underwent surgical or medical weight loss (two Roux-en-Y gastric bypass, two sleeve gastrectomy and two medical weight loss) each completed three meal tolerance tests using liquid-mixed, solid-mixed and high-fat test meals. The tolerability of each test meal, as determined by the total amount consumed and palatability, as well as fasting and meal-stimulated glucagon-like peptide, glucose-dependent insulinotropic polypeptide, insulin and glucose were measured. RESULTS: Among the six individuals, the liquid-mixed meal was better and more uniformly tolerated with a median meal completion rate of 99%. Among the four bariatric surgical patients, liquid-mixed meal stimulated on average a higher glucagon-like peptide (percent difference: 83.7, 89), insulin secretion (percent difference: 155.1, 158.7) and glucose-dependent insulinotropic polypeptide (percent difference: 113.5, 34.3) compared with solid-mixed and high fat meals. CONCLUSIONS: The liquid-mixed meal was better tolerated with higher incretin and insulin response compared with the high-fat and solid-mixed meals and is best suited for the evaluation of stimulated glucose homeostasis. PMID- 27774254 TI - Development and validation of a brief version of the Stigmatizing Situations Inventory. AB - OBJECTIVE: The Stigmatizing Situations Inventory (SSI) is one of the most commonly used measures of weight stigma experiences but may be impractical for some researchers because of its length (50 items). The present report describes the development and validation of a brief version of the SSI that could be used as a more efficient tool for assessing experiences with weight stigma. METHODS: In stage 1, data from three existing studies (total n = 257) were used to create two 10-item versions of the SSI. One version was primarily based on items that showed the highest item-total correlations, and the second version maintained the content coverage of the original measure by including one item (the one with the highest item-total correlation) from each of 10 subscales of the SSI. Stage 1 also provided a test of the convergent validity of these brief measures. In stage 2, four new samples (total n = 832) provided an independent test of the reliability and validity of the brief measures. RESULTS: The brief SSIs showed good reliability across all samples. Furthermore, the magnitude of the correlations between the brief versions of the SSI and other associated constructs was comparable with the magnitude of the correlations between those constructs and the full SSI. CONCLUSIONS: The brief versions of the SSI are reliable and valid measures of stigmatizing experiences that provide a more efficient means of capturing stigma experiences without sacrificing the reliability and validity of the original measure. PMID- 27774255 TI - Fast food, soft drink and candy intake is unrelated to body mass index for 95% of American adults. AB - OBJECTIVE: Excessive intake of fast food, soft drinks and candy are considered major factors leading to overweight and obesity. This article examines whether the epidemiological relationship between frequency of intake of these foods and body mass index (BMI) is driven by the extreme tails (+/-2 standard deviations). If so, a clinical recommendation to reduce frequency intake may have little relevance to 95% of the population. METHODS: Using 2007-2008 Centers for Disease Control's National Health and Nutrition Examination Survey, the consumption incidence of targeted foods on two non-continuous days was examined across discrete ranges of BMI. Data were analysed in 2011. RESULTS: After excluding the clinically underweight and morbidly obese, consumption incidence of fast food, soft drinks or candy was not positively correlated with measures of BMI. This was true for sweet snacks (r = 0.005, p = <0.001) and salty snacks (r = 0.001, p = 0.040). No significant variation was found between BMI subcategories in weekly consumption frequency of fast food meals. CONCLUSIONS: For 95% of this study's sample, the association between the intake frequency of fast food, soft drinks and candy and BMI was negative. This result suggests that a strategy that focuses solely on these problem foods may be ineffective in reducing weight. Reducing the total calories of food eaten at home and the frequency of snacking may be more successful dieting advice for the majority of individuals. PMID- 27774256 TI - Delayed reward discounting and grit in men and women with and without obesity. AB - OBJECTIVE: The objective of this study was to examine how sensitivity to short term reward and long-term goal perseverance are related to body mass index (BMI; kg m2) in a large sample of men and women with and without obesity. METHODS: A total of 450 participants (56.2% male; 73.1% non-Hispanic White) with mean +/- standard deviation age of 30.7 +/- 10.4 years and BMI of 29.3 +/- 8.2 completed online versions of the Delayed Reward Discounting task to measure sensitivity to short-term reward and the Grit Scale to measure long-term goal perseverance. RESULTS: In regression analysis, higher sensitivity to short-term reward (i.e. a preference for receiving smaller rewards after a shorter delay; b = 0.49, p = 0.016) and lower long-term goal perseverance (b = -1.26, p = 0.042) were independently associated with higher BMIs. Individuals with a favourable score on one measure were not 'protected' from the risk associated with an unfavourable score on the other measure. CONCLUSIONS: An overvaluation of short-term reward (e.g. the taste of palatable food and the comfort of engaging in sedentary activities) and undervaluation of long-term health goals (e.g. achieving a healthy weight and avoiding obesity-related comorbidities) may contribute to excess weight. Additional research incorporating prospective experimental designs is needed to determine whether decision-making strategies can be targeted to improve weight management. PMID- 27774257 TI - The appropriate dose of angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers in patients with dilated cardiomyopathy. The higher, the better? AB - Heart failure is a major public issue, and dilated cardiomyopathy (DCM) is one of the common etiologies of heart failure. DCM is generally progressive, and some patients with DCM need heart transplant despite optimal medical and mechanical therapy. Current guidelines recommend inhibitors of renin-angiotensin-aldosterone system, namely angiotensin-converting-enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and mineralocorticoid receptor antagonist as well as beta blockers for the medical treatment of heart failure with reduced ejection fraction, including DCM. Furthermore, because they have beneficial effects on the outcome of heart failure in a dose-related fashion, they should be titrated to the target dose. In clinical practice, the underuse and under-dose of these agents matter; however, the efficacy and safety of supramaximal dose of ACE inhibitor or ARB have never been investigated in the patients with DCM. In this issue of ESC Heart Failure, it is demonstrated that benazepril or valsartan at supramaximal dose improved left ventricular function and reduced cardiovascular events compared with each drug at low dose, respectively. In this editorial, the current evidence concerning the use of ACE inhibitor or ARB in patients with HF and future prospective will be discussed. PMID- 27774258 TI - Single baseline serum creatinine measurements predict mortality in critically ill patients hospitalized for acute heart failure. AB - BACKGROUND: Acute heart failure (AHF) is a leading cause of death in critically ill patients and is often accompanied by significant renal dysfunction. Few data exist on the predictive value of measures of renal dysfunction in large cohorts of patients hospitalized for AHF. METHODS: Six hundred and eighteen patients hospitalized for AHF (300 male, aged 73.3 +/- 10.3 years, 73% New York Heart Association Class 4, mean hospital length of stay 12.9 +/- 7.7 days, 97% non ischaemic AHF) were included in a retrospective single-centre data analysis. Echocardiographic data, serum creatinine/urea levels, estimated glomerular filtration rate (eGFR), and clinical/laboratory markers were recorded. Mean follow-up time was 2.9 +/- 2.1 years. All-cause mortality was recorded, and univariate/multivariate analyses were performed. RESULTS: Normal renal function defined as eGFR > 90 mL/min/1.73 m2 was noted in only 3% of AHF patients at baseline. A significant correlation of left ventricular ejection fraction with serum creatinine levels and eGFR (all P < 0.002) was noted. All-cause mortality rates were 12% (90 days) and 40% (at 2 years), respectively. In a multivariate model, increased age, higher New York Heart Association class at admission, higher total cholesterol levels, and lower eGFR independently predicted death. Patients with baseline eGFR < 30 mL/min/1.73 m2 had an exceptionally high risk of death (odds ratio 2.80, 95% confidence interval 1.52-5.15, P = 0.001). CONCLUSIONS: In a large cohort of patients with mostly non-ischaemic AHF, enhanced serum creatinine levels and reduced eGFR independently predict death. It appears that patients with eGFR < 30 mL/min/1.73 m2 have poorest survival rates. Our data add to mounting data indicating that impaired renal function is an important risk factor for non-survival in patients hospitalized for AHF. PMID- 27774259 TI - Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study. AB - AIMS: Peripartum cardiomyopathy (PPCM) is a major cause of acute heart failure in the peripartum period and considered potentially life threatening. While many aspects of its clinical profiles have been frequently reported, functional analysis, in particular of the right ventricle, and tissue characterization by cardiovascular magnetic resonance (CMR) imaging have been only sporadically described. The aim of the present study was to analyse pathological alterations and their prognostic relevance found in CMR imaging of patients newly diagnosed with PPCM. METHODS AND RESULTS: In this multicenter study 34 patients with confirmed PPCM underwent CMR imaging at the time of diagnosis and at 5 +/- 1 months follow-up. Cine imaging of PPCM patients showed moderate to severe reduction of systolic left ventricular (LV) function (mean LVEF: 29.7 +/- 12.8%). In 35% of the patients right ventricular (RV) systolic function was also reduced with a mean RVEF of 42.9 +/- 13.9%. Dilatation of the LV was observed in 91% (mean LV-EDV/BSA 128.5 +/- 32.1 mL/m2), and dilatation of the RV was present in 24% (mean RV-EDV/BSA 87.4 +/- 18.5 mL/m2) of the patients. Focal non-ischemic late gadolinium enhancement (LGE) was visible in 71%, and regional wall motion abnormalities were evident in 88% of the patients. LGE and wall motion abnormalities were predominantly located in the anteroseptal and basal to midventricular segments. RV dysfunction at baseline was associated with reduced probability of full cardiac recovery at 5 +/- 1 months follow-up. CONCLUSIONS: Besides LV systolic dysfunction, RV dysfunction and dilatation are observed in about one third of PPCM patients at the time of diagnosis. RV dysfunction is associated with unfavourable outcome. A distinct pattern of LV wall motion abnormalities and myocardial scar is evident in most PPCM patients. The present study may help to establish a set of CMR criteria suitable for diagnosis in patients with suspected PPCM and may add further knowledge to the pathology of the disease. PMID- 27774260 TI - Improvement of left ventricular filling and pulmonary artery pressure following unilateral renal artery total occlusion stenting in a patient with recurrent congestive heart failure complicated by renovascular hypertension and renal failure. AB - Recurrent congestive heart failure related to renal artery disease is an important clinical entity that is typically observed in bilateral renal artery stenosis or solitary functioning kidney. However, the relationship between heart failure and unilateral renal artery disease, especially that with total occlusion, remains unclear. We report a successful management by unilateral renal artery total occlusion stenting with an evidence of improvement of left ventricular filling and pulmonary artery pressure in case of a patient suffering from medical therapy resistant recurrent congestive heart failure with preserved ejection fraction. PMID- 27774261 TI - Expecting the unexpected: right atrial mass in a transplant patient. AB - We present a 71-year-old male, who had had a heart transplantation 24 years prior, who came to our clinic with a low-grade fever and a new II/VI holosystolic murmur. Echocardiography showed a large mass in the right atrium with attachment near the junction of the right atrium and superior vena cava. The patient was taken to the operating room for resection of the mass. Microscopic evaluation was consistent with thrombus. Differential diagnosis of cardiac masses after cardiac transplant includes tumour, thrombus, and vegetation. Final diagnosis can be challenging; multimodality imaging and biopsy or resection often are required for final diagnosis. PMID- 27774262 TI - Biomarkers in heart failure: the importance of inconvenient details. AB - The proliferation of cardiac-related biomarkers and advocacy for their use has often come without adequate discussion of limitations in the interpretation of values and their best use in heart failure (HF) patients to provide a balanced assessment of how cardiac biomarkers are advocated for use in HF and areas where we would argue there are no gaps in knowledge. We include suggestions to address these issues. We have focused on peer-reviewed publications over the period 2000 to present. Most studies have used samples at one or at most two points in time to define risk. Although biomarkers might add to the magnitude of risk, it is unclear how often they lead to changes in treatment. We suggest that defining the use of serial biomarker testing over time would be more helpful. To do this, it is necessary to take into account the biomarker's analytical and biological variability in addition to its ability to define and monitor therapy. These factors are often overlooked leading to conclusions that may be statistically significant but not clinically or analytically robust. An appreciation of the value and limitations of biomarker use is important to all clinicians who manage HF patients. If the proper studies are done so that biomarkers are used optimally, they will likely be helpful in defining when and how to intervene. If we continue as we have, we will continue to have ambiguity about the use of these valuable probes in the assessment and management of HF. PMID- 27774263 TI - Child ego state is associated with high prevalence of repeated hospitalizations in patients with heart failure. AB - AIMS: Inadequate self-care management is a leading cause of re-hospitalization in patients with heart failure (HF). Psychological factors such as some ego functions interfere with self-care behaviour modification, leading to poor outcomes in patients with several chronic diseases. However, characteristics of ego states in patients with repeated hospitalization for HF remain undefined. METHODS AND RESULTS: The present study enrolled 40 HF outpatients with previous history of HF hospitalization and receiving self-care management. Patients' psychological characteristics were assessed by Patient Health Questionnaire (PHQ 9) for screening depressive symptoms, and the Tokyo University Egogram (TEG) New Version II for analysing human behaviour based on five functional ego states; critical parent, nurturing parent, adult, free child, and adapted child (AC). Twelve patients (30.0%) had previous history of repeated (two or more) HF hospitalization. Most of them (75%) had a history of at least one or more re hospitalizations related to inadequate self-care. Patients with repeated HF hospitalization had significantly lower AC score, which represents uncooperative and uncompromising behaviours, compared with those without repeated HF hospitalization (P < 0.05). There were no significant differences in other parameters, including PHQ-9, between the two groups. CONCLUSIONS: Low AC ego state was associated with high prevalence of repeated hospitalization in patients with HF. Assessing ego functions may be helpful to tailor educational approaches in these patients. PMID- 27774264 TI - Initial 3-year outcomes with left ventricular assist devices in a country with a nascent heart transplantation program. AB - AIMS: The need for the left ventricular assist devices (LVAD) in patients with end-stage heart failure is well established, but prior to 2011, this was not available to patients in Kazakhstan. We describe the development of the sole LVAD programme in the context of a nascent heart transplantation programme and clinical outcomes for the first three years. METHODS AND RESULTS: From November 2011 to November 2014, 146 patients underwent implantation of 152 VADs (approximately 50 devices implanted per year). We retrospectively analyzed data from 135 LVAD patients who received HeartMate II (n = 95) or HeartWare (n = 40) devices. In 75 patients LVAD was used as a bridge-to-transplantation and in 60 patients as destination therapy, but only 3 of 135 LVAD patients received heart transplant. Forty-three patients of the LVAD cohort had died by the end of the follow-up period. The mean time on LVAD was 466 +/- 330 days (range 5-1200 days). Kaplan-Meier survival estimates for patients who continued on LVAD support were 93% after 1 month, 86% after 6 months and 77% after 12 months. The most common complications within the first 30 days after implant included right ventricular failure (n = 20, 1.85 events/patient-year), renal failure (n = 19, 1.76 events/patient-year) and bleeding (n = 33, 3.0 events/patient-year). Beyond 30 days adverse events included driveline infections (n = 46, 0.56 events/patient year) and stroke (n = 33, 0.21 events/patient-year). CONCLUSIONS: LVADs are an important therapeutic alternative to heart transplantation in the context of a developing heart transplant programme with outcomes that are comparable to those reported by other centres. PMID- 27774265 TI - Ventricular conduction abnormalities as predictors of long-term survival in acute de novo and decompensated chronic heart failure. AB - AIMS: Data on the prognostic role of left and right bundle branch blocks (LBBB and RBBB), and nonspecific intraventricular conduction delay (IVCD; QRS >= 110 ms, no BBB) in acute heart failure (AHF) are controversial. Our aim was to investigate electrocardiographic predictors of long-term survival in patients with de novo AHF and acutely decompensated chronic heart failure (ADCHF). METHODS AND RESULTS: We analysed the admission electrocardiogram of 982 patients from a multicenter European cohort of AHF with 3.9 years' mean follow-up. Half (51.5%, n = 506) of the patients had de novo AHF. LBBB, and IVCD were more common in ADCHF than in de novo AHF: 17.2% vs. 8.7% (P < 0.001) and 20.6% vs. 13.2% (P = 0.001), respectively, and RBBB was almost equally common (6.9% and 8.1%; P = 0.5), respectively. Mortality during the follow-up was higher in patients with RBBB (85.4%) and IVCD (73.7%) compared with patients with normal ventricular conduction (57.0%); P < 0.001 for both. The impact of RBBB on prognosis was prominent in de novo AHF (adjusted HR 1.93, 1.03-3.60; P = 0.04), and IVCD independently predicted death in ADCHF (adjusted HR 1.79, 1.28-2.52; P = 0.001). Both findings were pronounced in patients with reduced ejection fraction. LBBB showed no association with increased mortality in either of the subgroups. The main results were confirmed in a validation cohort of 1511 AHF patients with 5.9 years' mean follow-up. CONCLUSIONS: Conduction abnormalities predict long-term survival differently in de novo AHF and ADCHF. RBBB predicts mortality in de novo AHF, and IVCD in ADCHF. LBBB has no additive predictive value in AHF requiring hospitalization. PMID- 27774266 TI - ECG as a first step in the detection of left ventricular systolic dysfunction in the elderly. AB - AIMS: Due to the demographic development there is an increasing number of senior citizens with left ventricular systolic dysfunction (LVSD), defined as ejection fraction (EF) < 40%. Unfortunately there are under-diagnosis and under-treatment in the elderly of this serious condition. Echocardiography is the gold standard to diagnose LVSD, but access is limited. Simple screening methods may ensure reduction of undetected cases, and this study investigates if electrocardiogram (ECG) can be used to screen for LVSD in the geriatric population. METHODS AND RESULTS: A total of 260 persons aged 75 to 92 years had an echocardiography, a 12 leads ECG, and NT-proBNP; 61 had EF < 40%, and of these 60 had an abnormal ECG. EF < 40% was significantly related to atrial fibrillation (A), pacing (P), LBBB (L), Q-waves (Q), and QRS duration >= 120 ms (D). EF < 40%, atrial fibrillation, pacing, and LBBB were related to NT-proBNP > 35 pmol/L. When APL was absent, NT proBNP had discriminatory value regarding LVSD in the presence of Q-waves or QRS duration > 120 ms. Algorithms to screen for LVSD had sensitivity >90% and specificity >80% and claimed at least one of five (A/P/L/Q/D), one of 4 (A/P/L/Q), or one of three (A/Q/D) ECG changes. The optimal algorithm to reduce the need for diagnostic echocardiographies included four (A/P/L/Q) ECG changes and measurement of NT-proBNP when Q-waves were the only ECG change present. CONCLUSIONS: Ninety percent of LVSD may be detected, and when there is atrial fibrillation, pacing or LBBB, or QRS >= 120 ms/Q-waves and NT-proBNP>35 pmol/L, a diagnostic echocardiography should be considered. PMID- 27774267 TI - The clinical significance of plasma neopterin in heart failure with preserved left ventricular ejection fraction. AB - AIMS: Although inflammation plays an important role in the pathogenesis of heart failure (HF), the precise pathophysiological role of inflammation in HF with preserved left ventricular ejection fraction (HFpEF) still remains unclear. Hence, we examined the clinical significance of plasma neopterin, an inflammatory biomarker, in HFpEF patients. METHODS AND RESULTS: In the present study, we recruited consecutive HFpEF patients hospitalized in Kumamoto University Hospital, and further measured plasma neopterin by high-performance liquid chromatography and serum derivatives of reactive oxidative metabolites (DROM), a new biomarker of reactive oxygen species. Compared with risk factors (number of patients, age, sex, and equal incidence of diabetes mellitus, hypertension, and dyslipidemia) -matched non-HF patients (n = 68), plasma neopterin levels, but not serum high-sensitivity C-reactive protein levels, were significantly increased in patients with HFpEF (n = 68) (P < 0.001 and P = 0.15, respectively), accompanied by an elevation in serum DROM levels (P < 0.001). Plasma neopterin levels in New York Heart Association (NYHA) class III/IV HFpEF patients were significantly higher than in NYHA class II patients (P < 0.004). Furthermore, plasma ln neopterin levels had significant and positive correlation with ln-DROM values (r = 0.57) and parameters of cardiac diastolic dysfunction [the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (r = 0.34), left atrial volume index (r = 0.17), and B-type natriuretic peptide (r = 0.38)]. Kaplan-Meier analysis showed that the high-neopterin group (>51.5 nM: median value of neopterin in HFpEF patients) had a higher probability of cardiovascular events than the low-neopterin group (log-rank test, P = 0.003). CONCLUSIONS: Plasma neopterin levels significantly increased in HFpEF and correlated with the severity of HF. Furthermore, high neopterin were significantly correlated with future cardiovascular events, indicating that measurement of plasma neopterin might provide clinical benefits for risk stratification of HFpEF patients. (c) 2015 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. PMID- 27774268 TI - Permanent catheter drainage system for palliation of diuretic-resistant cardiac ascites. AB - We report the case of a 69-year-old man with dilated cardiomyopathy treated with a permanent catheter drainage system for diuretic resistant cardiac ascites. At 1 year follow-up, the patient had no heart failure related hospitalisations, displayed improved quality of life measures and had incurred no complications related to the catheter. Permanent tunnelled catheters are widely used to treat malignant ascites but may also be considered for palliation of cardiac ascites. PMID- 27774269 TI - Rationale and design of a pilot randomized controlled trial to assess the role of intravenous ferric carboxymaltose in Asian patients with heart failure (PRACTICE ASIA-HF). AB - AIMS: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) worldwide regardless of haemoglobin levels. Results from therapeutic trials of intermittently dosed intravenous (i.v.) iron are promising in the ambulatory Caucasian population with HF with reduced left ventricular ejection fraction, although evidence is scarce in Asia. The Pilot Randomized Controlled Trial to Assess the Role of Intravenous Ferric Carboxymaltose in Asian Patients with Heart Failure aims to assess the effect of single-dose i.v. ferric carboxymaltose (FCM) in a multi-ethnic Asian population with HF and ID. METHODS AND RESULTS: This is an open-label, randomized, placebo-controlled trial recruiting stabilized inpatients with decompensated HF (regardless of left ventricular ejection fraction), ID [defined as serum ferritin <300 ng/mL if transferrin saturation <20%] and haemoglobin <=14 g/dL. Patients from two tertiary institutions were randomized in a 1:1 ratio to receive a single dose of either i.v. FCM (Ferinject(r)) 1000 mg or i.v. normal saline. The primary endpoint is the change in 6-min walk distance at Weeks 4 and 12, and secondary endpoints are changes at Weeks 4 and 12 in (i) quality of life as measured by the Kansas City Cardiomyopathy Questionnaire and Visual Analogue Scale scores and (ii) New York Heart Association functional class. CONCLUSIONS: Preliminary efficacy data on i.v. FCM therapy in Asian HF are expected from this pilot study to support larger scale multicentre therapeutic i.v. FCM trials within Asia. PMID- 27774272 TI - Microcurrent stimulation promotes reverse remodelling in cardiomyocytes. AB - AIMS: It has been shown that electrical stimulation can improve tissue repair in patients. Imbalances in the extracellular matrix composition induce manifestation of heart failure. Here we investigated the application of microcurrent (MC) to modulate the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in cardiomyocytes in vitro and in vivo to reverse remodelling in the heart in spontaneous hypertensive rats (SHR). METHODS: Cardiomyocytes from young SHR (7 months) and old SHR (14 months) were stimulated in vitro and in vivo with MC. MMP and TIMP expression were analysed by qPCR and immunofluorescence to evaluate the modulation of MC treatment. RESULTS: Modulation of cardiomyocytes with MC enhances proliferation with no morphological changes in vitro. By electrical stimulation dual effects, increase and decrease, on MMP-2, MMP-9, TIMP-3, and TIMP-4 mRNA as well as protein expression were observed, depending on the age of the cardiomyocytes. In our in vivo study, MC down-regulated MMP-2, MMP-9, and TIMP-4 and increased TIMP-3 in young SHR. In old SHR MMP-2, MMP-9, and TIMP-4 were up-regulated, whereas TIMP-3 was unaffected. CONCLUSIONS: Our data indicate that treatment of MC can modulate the expression of MMPs and TIMPs in vitro and in vivo in SHR. Based on these results new treatments for heart failure could be developed. PMID- 27774270 TI - Associations of dipeptidyl peptidase-4 inhibitors with mortality in hospitalized heart failure patients with diabetes mellitus. AB - BACKGROUND: Heart failure (HF) and diabetes mellitus (DM) often co-exist. Treatment of DM in HF patients is challenging because some therapies for DM are contraindicated in HF. Although previous experimental studies have reported that dipeptidyl peptidase-4 (DPP-4) inhibitors improve cardiovascular function, whether DPP-4 inhibition improves mortality of HF patients with DM remains unclear. Therefore, we examined the impact of DPP-4 inhibition on mortality in hospitalized HF patients using propensity score analyses. METHODS AND RESULTS: We performed observational study analysed by propensity score method with 962 hospitalized HF patients. Of these patients, 293 (30.5%) had DM, and 122 of these DM patients were treated with DPP-4 inhibitors. Propensity scores for treatment with DPP-4 inhibitors were estimated for each patient by logistic regression with clinically relevant baseline variables. The propensity-matched 1:1 cohorts were assessed based on propensity scores (DPP-4 inhibitors, n = 83, and non-DPP-4 inhibitors, n = 83). Kaplan-Meier analysis in the propensity score-matched cohort demonstrated that cardiac and all-cause mortality was significantly lower in the DPP-4 inhibitor group than in the non-DPP-4 inhibitor group (cardiac mortality: 4.8% vs. 18.1%, P = 0.015; all-cause mortality: 14.5% vs. 41.0%, P = 0.003, by a log-rank test). In the multivariable Cox proportional hazard analyses, after adjusting for other potential confounding factors, the use of DPP-4 inhibitors was an independent predictor of all-cause mortality (pre-matched cohort: hazard ratio 0.467, P = 0.010; post-matched cohort: hazard ratio 0.370, P = 0.003) in HF patients with DM. CONCLUSIONS: Our data suggest that DPP-4 inhibitors may improve cardiac and all-cause mortality in hospitalized HF patients with DM. PMID- 27774273 TI - Reversible transition from a hypertrophic to a dilated cardiomyopathy. AB - We report the case of a 17-year-old female patient with known hypertrophic cardiomyopathy and a Wolff-Parkinson-White syndrome. She came to our department for further evaluation of a new diagnosed dilated cardiomyopathy characterized by an enlargement of the left ventricle and a fall in ejection fraction. Clinically, she complained about atypical chest pain, arrhythmic episodes with presyncopal events, and dyspnea (NYHA III) during the last 6 months. Non-invasive and invasive examinations including magnetic resonance imaging, electrophysiological examinations, and angiography did not lead to a conclusive diagnosis. Therefore, endomyocardial biopsies (EMBs) were taken to investigate whether a specific myocardial disease caused the impairment of the left ventricular function. EMB analysis resulted in the diagnosis of a virus-negative, active myocarditis. Based on this diagnosis, an immunosuppressive treatment with prednisolone and azathioprine was started, which led to an improvement of cardiac function and symptoms within 3 months after initiating therapy. In conclusion, we show that external stress triggered by myocarditis can induce a reversible transition from a hypertrophic cardiomyopathy to a dilated cardiomyopathy phenotype. This case strongly underlines the need for a thorough and invasive examination of heart failure of unknown causes, including EMB investigations as recommend by the actual ESC position statement. PMID- 27774271 TI - Circulating biomarker responses to medical management vs. mechanical circulatory support in severe inotrope-dependent acute heart failure. AB - BACKGROUND: Severe inotrope-dependent acute heart failure (AHF) is associated with poor clinical outcomes. There are currently no well-defined blood biomarkers of response to treatment that can guide management or identify recovery in this patient population. In the present study, we characterized the levels of novel and emerging circulating biomarkers of heart failure in patients with AHF over the first 30 days of medical management or mechanical circulatory support (MCS). We hypothesized a shared a plasma proteomic treatment response would be identifiable in both patient groups, representing reversal of the AHF phenotype. METHODS AND RESULTS: Time course plasma samples of the first 30 days of therapy, obtained from patients managed medically (n = 8) or with implantable MCS (n = 5), underwent semi-targeted and candidate biomarker analyses, using multiple reaction monitoring (MRM) mass spectrometry, antibody arrays, and enzyme-linked immunosorbent assays. Differentially expressed proteins were identified using robust limma for MRM and antibody array data. Patients managed medically or with implantable MCS had a shared proteomic signature of six plasma proteins: circulating cardiotrophin 1, cardiac troponin T, clusterin, and dickopff 1 increased, while levels of C-reactive protein and growth differentiation factor 15 decreased in both groups over the 30 day time course. CONCLUSIONS: We have characterized the temporal proteomic signature of clinical recovery in AHF patients managed medically or with MCS, over the first 30 days of treatment. Changes in biomarker expression over the time course of treatment may provide a basis for understanding the biological basis of AHF, potentially identifying novel markers and pathophysiologic mechanisms of recovery. PMID- 27774274 TI - The challenge of conducting gambling research. AB - SUMMARY: Responding to the survey of 5580 college students in South India in the study of George et al, the author discusses the universality of addictive gambling and its stereotyped nature. This study, together with work in North America and elsewhere, argues for more research that targets prevalence, risk factors, course, and treatment. The author points out the challenge of conducting research when funding is hard to obtain. DECLARATION OF INTERESTS: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 27774275 TI - Editorial: A home for virology, ecology, epidemiology, and evolutionary biology. PMID- 27774276 TI - The genomes of many yam species contain transcriptionally active endogenous geminiviral sequences that may be functionally expressed. AB - Endogenous viral sequences are essentially 'fossil records' that can sometimes reveal the genomic features of long extinct virus species. Although numerous known instances exist of single-stranded DNA (ssDNA) genomes becoming stably integrated within the genomes of bacteria and animals, there remain very few examples of such integration events in plants. The best studied of these events are those which yielded the geminivirus-related DNA elements found within the nuclear genomes of various Nicotiana species. Although other ssDNA virus-like sequences are included within the draft genomes of various plant species, it is not entirely certain that these are not contaminants. The Nicotiana geminivirus related DNA elements therefore remain the only definitively proven instances of endogenous plant ssDNA virus sequences. Here, we characterize two new classes of endogenous plant virus sequence that are also apparently derived from ancient geminiviruses in the genus Begomovirus. These two endogenous geminivirus-like elements (EGV1 and EGV2) are present in the Dioscorea spp. of the Enantiophyllum clade. We used fluorescence in situ hybridization to confirm that the EGV1 sequences are integrated in the D. alata genome and showed that one or two ancestral EGV sequences likely became integrated more than 1.4 million years ago during or before the diversification of the Asian and African Enantiophyllum Dioscorea spp. Unexpectedly, we found evidence of natural selection actively favouring the maintenance of EGV-expressed replication-associated protein (Rep) amino acid sequences, which clearly indicates that functional EGV Rep proteins were probably expressed for prolonged periods following endogenization. Further, the detection in D. alata of EGV gene transcripts, small 21-24 nt RNAs that are apparently derived from these transcripts, and expressed Rep proteins, provides evidence that some EGV genes are possibly still functionally expressed in at least some of the Enantiophyllum clade species. PMID- 27774277 TI - RDP4: Detection and analysis of recombination patterns in virus genomes. AB - RDP4 is the latest version of recombination detection program (RDP), a Windows computer program that implements an extensive array of methods for detecting and visualising recombination in, and stripping evidence of recombination from, virus genome sequence alignments. RDP4 is capable of analysing twice as many sequences (up to 2,500) that are up to three times longer (up to 10 Mb) than those that could be analysed by older versions of the program. RDP4 is therefore also applicable to the analysis of bacterial full-genome sequence datasets. Other novelties in RDP4 include (1) the capacity to differentiate between recombination and genome segment reassortment, (2) the estimation of recombination breakpoint confidence intervals, (3) a variety of 'recombination aware' phylogenetic tree construction and comparison tools, (4) new matrix-based visualisation tools for examining both individual recombination events and the overall phylogenetic impacts of multiple recombination events and (5) new tests to detect the influences of gene arrangements, encoded protein structure, nucleic acid secondary structure, nucleotide composition, and nucleotide diversity on recombination breakpoint patterns. The key feature of RDP4 that differentiates it from other recombination detection tools is its flexibility. It can be run either in fully automated mode from the command line interface or with a graphically rich user interface that enables detailed exploration of both individual recombination events and overall recombination patterns. PMID- 27774278 TI - The effect of ecosystem biodiversity on virus genetic diversity depends on virus species: A study of chiltepin-infecting begomoviruses in Mexico. AB - Current declines in biodiversity put at risk ecosystem services that are fundamental for human welfare. Increasing evidence indicates that one such service is the ability to reduce virus emergence. It has been proposed that the reduction of virus emergence occurs at two levels: through a reduction of virus prevalence/transmission and, as a result of these epidemiological changes, through a limitation of virus genetic diversity. Although the former mechanism has been studied in a few host-virus interactions, very little is known about the association between ecosystem biodiversity and virus genetic diversity. To address this subject, we estimated genetic diversity, synonymous and non synonymous nucleotide substitution rates, selection pressures, and frequency of recombinants and re-assortants in populations of Pepper golden mosaic virus (PepGMV) and Pepper huasteco yellow vein virus (PHYVV) that infect chiltepin plants in Mexico. We then analyzed how these parameters varied according to the level of habitat anthropization, which is the major cause of biodiversity loss. Our results indicated that genetic diversity of PepGMV (but not of PHYVV) populations increased with the loss of biodiversity at higher levels of habitat anthropization. This was mostly the consequence of higher rates of synonymous nucleotide substitutions, rather than of adaptive selection. The frequency of recombinants and re-assortants was higher in PepGMV populations infecting wild chiltepin than in those infecting cultivated ones, suggesting that genetic exchange is not the main mechanism for generating genetic diversity in PepGMV populations. These findings provide evidence that biodiversity may modulate the genetic diversity of plant viruses, but it may differentially affect even two closely related viruses. Our analyses may contribute to understanding the factors involved in virus emergence. PMID- 27774279 TI - Determinants of taxonomic composition of plant viruses at the Nature Conservancy's Tallgrass Prairie Preserve, Oklahoma. AB - The role of biotic and abiotic factors in shaping the diversity and composition of communities of plant viruses remain understudied, particularly in natural settings. In this study, we test the effects of host identity, location, and sampling year on the taxonomic composition of plant viruses in six native plant species [Ambrosia psilostachya (Asteraceae), Vernonia baldwinii (Asteraceae), Asclepias viridis (Asclepiadaceae), Ruellia humilis (Acanthaceae), Panicum virgatum (Poaceae) and Sorghastrum nutans (Poaceae)] from the Nature Conservancy's Tallgrass Prairie Preserve in northeastern Oklahoma. We sampled over 400 specimens of the target host plants from twenty sites (plots) in the Tallgrass Prairie Preserve over 4 years and tested them for the presence of plant viruses applying virus-like particle and double-stranded RNA enrichment methods. Many of the viral sequences identified could not be readily assigned to species, either due to their novelty or the shortness of the sequence. We thus grouped our putative viruses into operational viral taxonomic units for further analysis. Partial canonical correspondence analysis revealed that the taxonomic composition of plant viruses in the target species had a significant relationship with host species (P value: 0.001) but no clear relation with sampling site or year. Variation partitioning further showed that host identity explained about 2-5 per cent of the variation in plant virus composition. We could not interpret the significant relationship between virus composition and host plants with respect to host taxonomy or ecology. Only six operational viral taxonomic units had over 5 per cent incidence over a 4-year period, while the remainder exhibited sporadic infection of the target hosts. This study is the first of its kind to document the dynamics of the entire range of viruses in multiple plant species in a natural setting. PMID- 27774280 TI - Experimental evolution of an RNA virus in cells with innate immunity defects. AB - Experimental evolution studies have shown that RNA viruses respond rapidly to directional selection and thus can adapt efficiently to changes in host cell tropism, antiviral drugs, or other imposed selective pressures. However, the evolution of RNA viruses under relaxed selection has been less extensively explored. Here, we evolved vesicular stomatitis virus in mouse embryonic fibroblasts knocked-out for PKR, a protein with a central role in antiviral innate immunity. Vesicular stomatitis virus adapted to PKR-negative mouse embryonic fibroblasts in a gene-specific manner, since the evolved viruses exhibited little or no fitness improvement in PKR-positive cells. Full-length sequencing revealed the presence of multiple parallel nucleotide substitutions arising in independent evolution lines. However, site-directed mutagenesis showed that the effects of these substitutions were not PKR dependent. In contrast, we found evidence for sign epistasis, such that a given substitution which was positively selected was strongly deleterious when tested as a single mutation. Our results suggest that virus evolution in cells with specific innate immunity defects may drive viral specialization. However, this process is not deterministic at the molecular level, probably because the fixation of mutations which are tolerated under a relaxed selection regime is governed mainly by random genetic drift. PMID- 27774281 TI - The global distribution of Banana bunchy top virus reveals little evidence for frequent recent, human-mediated long distance dispersal events. AB - Banana bunchy top virus (BBTV; family Nanoviridae, genus Babuvirus) is a multi component single-stranded DNA virus, which infects banana plants in many regions of the world, often resulting in large-scale crop losses. We analyzed 171 banana leaf samples from fourteen countries and recovered, cloned, and sequenced 855 complete BBTV components including ninety-four full genomes. Importantly, full genomes were determined from eight countries, where previously no full genomes were available (Samoa, Burundi, Republic of Congo, Democratic Republic of Congo, Egypt, Indonesia, the Philippines, and the USA [HI]). Accounting for recombination and genome component reassortment, we examined the geographic structuring of global BBTV populations to reveal that BBTV likely originated in Southeast Asia, that the current global hotspots of BBTV diversity are Southeast Asia/Far East and India, and that BBTV populations circulating elsewhere in the world have all potentially originated from infrequent introductions. Most importantly, we find that rather than the current global BBTV distribution being due to increases in human-mediated movements of bananas over the past few decades, it is more consistent with a pattern of infrequent introductions of the virus to different parts of the world over the past 1,000 years. PMID- 27774282 TI - Effect of mismatch repair on the mutation rate of bacteriophage phiX174. AB - Viral mutation rates vary widely in nature, yet the mechanistic and evolutionary determinants of this variability remain unclear. Small DNA viruses mutate orders of magnitude faster than their hosts despite using host-encoded polymerases for replication, which suggests these viruses may avoid post-replicative repair. Supporting this, the genome of bacteriophage phiX174 is completely devoid of GATC sequence motifs, which are required for methyl-directed mismatch repair in Escherichia coli. Here, we show that restoration of the randomly expected number of GATC sites leads to an eightfold reduction in the rate of spontaneous mutation of the phage, without severely impairing its replicative capacity over the short term. However, the efficacy of mismatch repair in the presence of GATC sites is limited by inefficient methylation of the viral DNA. Therefore, both GATC avoidance and DNA under-methylation elevate the mutation rate of the phage relative to that of the host. We also found that the effects of GATC sites on the phage mutation rate vary extensively depending on their specific location within the phage genome. Finally, the mutation rate reduction afforded by GATC sites is fully reverted under stress conditions, which up-regulate repair pathways and expression of error-prone host polymerases such as heat and treatment with the base analog 5-fluorouracil, suggesting that access to repair renders the phage sensitive to stress-induced mutagenesis. PMID- 27774283 TI - Elucidating the phylodynamics of endemic rabies virus in eastern Africa using whole-genome sequencing. AB - Many of the pathogens perceived to pose the greatest risk to humans are viral zoonoses, responsible for a range of emerging and endemic infectious diseases. Phylogeography is a useful tool to understand the processes that give rise to spatial patterns and drive dynamics in virus populations. Increasingly, whole genome information is being used to uncover these patterns, but the limits of phylogenetic resolution that can be achieved with this are unclear. Here, whole genome variation was used to uncover fine-scale population structure in endemic canine rabies virus circulating in Tanzania. This is the first whole-genome population study of rabies virus and the first comprehensive phylogenetic analysis of rabies virus in East Africa, providing important insights into rabies transmission in an endemic system. In addition, sub-continental scale patterns of population structure were identified using partial gene data and used to determine population structure at larger spatial scales in Africa. While rabies virus has a defined spatial structure at large scales, increasingly frequent levels of admixture were observed at regional and local levels. Discrete phylogeographic analysis revealed long-distance dispersal within Tanzania, which could be attributed to human-mediated movement, and we found evidence of multiple persistent, co-circulating lineages at a very local scale in a single district, despite on-going mass dog vaccination campaigns. This may reflect the wider endemic circulation of these lineages over several decades alongside increased admixture due to human-mediated introductions. These data indicate that successful rabies control in Tanzania could be established at a national level, since most dispersal appears to be restricted within the confines of country borders but some coordination with neighbouring countries may be required to limit transboundary movements. Evidence of complex patterns of rabies circulation within Tanzania necessitates the use of whole-genome sequencing to delineate finer scale population structure that can that can guide interventions, such as the spatial scale and design of dog vaccination campaigns and dog movement controls to achieve and maintain freedom from disease. PMID- 27774284 TI - CodonShuffle: a tool for generating and analyzing synonymously mutated sequences. AB - Because synonymous mutations do not change the amino acid sequence of a protein, they are generally considered to be selectively neutral. Empiric data suggest, however, that a significant fraction of viral mutational fitness effects may be attributable to synonymous mutation. Bias in synonymous codon usage in viruses may result from selection for translational efficiency, mutational bias, base pairing requirements in RNA structures, or even selection against specific dinucleotides by innate immune effectors. Experimental analyses of codon usage and genome evolution have been facilitated by advances in synthetic biology, which now make it feasible to generate viral genomes that contain large numbers of synonymous mutations. The generally pleiotropic effects of synonymous mutation on viral fitness have, at times, made it difficult to define the mechanistic basis for the observed attenuation of these heavily mutated viruses. We have addressed this problem by developing a bioinformatic tool for the generation and analysis of viral sequences with large-scale synonymous mutation. A variety of permutation strategies are applied to shuffle codons within an open reading frame. After measuring the dinucleotide frequency, codon usage, codon pair bias, and free energy of RNA folding for each permuted genome, we used z-score normalization and a least squares regression model to quantify their overall distance from the starting sequence. Using this approach, the user can easily identify a large number of synonymously mutated sequences with varying similarity to a wild-type genome across a range of nucleic-acid-based determinants of viral fitness. We believe that this tool will be useful in designing genomes for subsequent experimental studies of the fitness impacts of synonymous mutation. PMID- 27774285 TI - Connecting within-host dynamics to the rate of viral molecular evolution. AB - Viruses evolve rapidly, providing a unique system for understanding the processes that influence rates of molecular evolution. Neutral theory posits that the evolutionary rate increases linearly with the mutation rate. The occurrence of deleterious mutations causes this relationship to break down at high mutation rates. Previous studies have identified this as an important phenomenon, particularly for RNA viruses which can mutate at rates near the extinction threshold. We propose that in addition to mutation dynamics, viral within-host dynamics can also affect the between-host evolutionary rate. We present an analytical model that predicts the neutral evolution rate for viruses as a function of both within-host parameters and deleterious mutations. To examine the effect of more detailed aspects of the virus life cycle, we also present a computational model that simulates acute virus evolution using target cell limited dynamics. Using influenza A virus as a case study, we find that our simulation model can predict empirical rates of evolution better than a model lacking within-host details. The analytical model does not perform as well as the simulation model but shows how the within-host basic reproductive number influences evolutionary rates. These findings lend support to the idea that the mutation rate alone is not sufficient to predict the evolutionary rate in viruses, instead calling for improved models that account for viral within-host dynamics. PMID- 27774286 TI - The evolution, diversity, and host associations of rhabdoviruses. AB - Metagenomic studies are leading to the discovery of a hidden diversity of RNA viruses. These new viruses are poorly characterized and new approaches are needed predict the host species these viruses pose a risk to. The rhabdoviruses are a diverse family of RNA viruses that includes important pathogens of humans, animals, and plants. We have discovered thirty-two new rhabdoviruses through a combination of our own RNA sequencing of insects and searching public sequence databases. Combining these with previously known sequences we reconstructed the phylogeny of 195 rhabdovirus sequences, and produced the most in depth analysis of the family to date. In most cases we know nothing about the biology of the viruses beyond the host they were identified from, but our dataset provides a powerful phylogenetic approach to predict which are vector-borne viruses and which are specific to vertebrates or arthropods. By reconstructing ancestral and present host states we found that switches between major groups of hosts have occurred rarely during rhabdovirus evolution. This allowed us to propose seventy six new likely vector-borne vertebrate viruses among viruses identified from vertebrates or biting insects. Based on currently available data, our analysis suggests it is likely there was a single origin of the known plant viruses and arthropod-borne vertebrate viruses, while vertebrate- and arthropod-specific viruses arose at least twice. There are also few transitions between aquatic and terrestrial ecosystems. Viruses also cluster together at a finer scale, with closely related viruses tending to be found in closely related hosts. Our data therefore suggest that throughout their evolution, rhabdoviruses have occasionally jumped between distantly related host species before spreading through related hosts in the same environment. This approach offers a way to predict the most probable biology and key traits of newly discovered viruses. PMID- 27774287 TI - Host ecology determines the dispersal patterns of a plant virus. AB - Since its isolation in 1966 in Kenya, rice yellow mottle virus (RYMV) has been reported throughout Africa resulting in one of the economically most important tropical plant emerging diseases. A thorough understanding of RYMV evolution and dispersal is critical to manage viral spread in tropical areas that heavily rely on agriculture for subsistence. Phylogenetic analyses have suggested a relatively recent expansion, perhaps driven by the intensification of agricultural practices, but this has not yet been examined in a coherent statistical framework. To gain insight into the historical spread of RYMV within Africa rice cultivations, we analyse a dataset of 300 coat protein gene sequences, sampled from East to West Africa over a 46-year period, using Bayesian evolutionary inference. Spatiotemporal reconstructions date the origin of RMYV back to 1852 (1791-1903) and confirm Tanzania as the most likely geographic origin. Following a single long-distance transmission event from East to West Africa, separate viral populations have been maintained for about a century. To identify the factors that shaped the RYMV distribution, we apply a generalised linear model (GLM) extension of discrete phylogenetic diffusion and provide strong support for distances measured on a rice connectivity landscape as the major determinant of RYMV spread. Phylogeographic estimates in continuous space further complement this by demonstrating more pronounced expansion dynamics in West Africa that are consistent with agricultural intensification and extensification. Taken together, our principled phylogeographic inference approach shows for the first time that host ecology dynamics have shaped the historical spread of a plant virus. PMID- 27774289 TI - Tobamoviruses have probably co-diverged with their eudicotyledonous hosts for at least 110 million years. AB - A phylogeny has been calculated by maximum likelihood comparisons of the concatenated consensus protein sequences of 29 tobamoviruses shown to be non recombinant. This phylogeny has statistically significant support throughout, including its basal branches. The viruses form eight lineages that are congruent with the taxonomy of the hosts from which each was first isolated and, with the exception of three of the twenty-nine species, all fall into three clusters that have either asterid or rosid or caryophyllid hosts (i.e. the major subdivisions of eudicotyledonous plants). A modified Mantel permutation test showed that the patristic distances of virus and host phylogenies are significantly correlated, especially when the three anomalously placed viruses are removed. When the internal branches of the virus phylogeny were collapsed the congruence decreased. The simplest explanation of this congruence of the virus and host phylogenies is that most tobamovirus lineages have co-diverged with their primary plant hosts for more than 110 million years, and only the brassica-infecting lineage originated from a major host switch from asterids to rosids. Their co-divergence seems to have been 'fuzzy' rather than 'strict', permitting viruses to switch hosts within major host clades. Our conclusions support those of a coalesence analysis of tobamovirus sequences, that used proxy node dating, but not a similar analysis of nucleotide sequences from dated samples, which concluded that the tobamoviruses originated only 100 thousand years ago. PMID- 27774288 TI - A diverse group of small circular ssDNA viral genomes in human and non-human primate stools. AB - Viral metagenomics sequencing of fecal samples from outbreaks of acute gastroenteritis from the US revealed the presence of small circular ssDNA viral genomes encoding a replication initiator protein (Rep). Viral genomes were ~2.5 kb in length, with bi-directionally oriented Rep and capsid (Cap) encoding genes and a stem loop structure downstream of Rep. Several genomes showed evidence of recombination. By digital screening of an in-house virome database (1.04 billion reads) using BLAST, we identified closely related sequences from cases of unexplained diarrhea in France. Deep sequencing and PCR detected such genomes in 7 of 25 US (28 percent) and 14 of 21 French outbreaks (67 percent). One of eighty five sporadic diarrhea cases in the Gambia was positive by PCR. Twenty-two complete genomes were characterized showing that viruses from patients in the same outbreaks were closely related suggesting common origins. Similar genomes were also characterized from the stools of captive chimpanzees, a gorilla, a black howler monkey, and a lemur that were more diverse than the human stool associated genomes. The name smacovirus is proposed for this monophyletic viral clade. Possible tropism include mammalian enteric cells or ingested food components such as infected plants. No evidence of viral amplification was found in immunodeficient mice orally inoculated with smacovirus-positive stool supernatants. A role for smacoviruses in diarrhea, if any, remains to be demonstrated. PMID- 27774290 TI - Co-infection with two strains of Brome mosaic bromovirus reveals common RNA recombination sites in different hosts. AB - We have previously reported intra-segmental crossovers in Brome mosaic virus (BMV) RNAs. In this work, we studied the homologous recombination of BMV RNA in three different hosts: barley (Hordeum vulgare), Chenopodium quinoa, and Nicotiana benthamiana that were co-infected with two strains of BMV: Russian (R) and Fescue (F). Our work aimed at (1) establishing the frequency of recombination, (2) mapping the recombination hot spots, and (3) addressing host effects. The F and R nucleotide sequences differ from each other at many translationally silent nucleotide substitutions. We exploited this natural variability to track the crossover sites. Sequencing of a large number of cDNA clones revealed multiple homologous crossovers in each BMV RNA segment, in both the whole plants and protoplasts. Some recombination hot spots mapped at similar locations in different hosts, suggesting a role for viral factors, but other sites depended on the host. Our results demonstrate the chimeric ('mosaic') nature of the BMV RNA genome. PMID- 27774291 TI - Increasing virulence, but not infectivity, associated with serially emergent virus strains of a fish rhabdovirus. AB - Surveillance and genetic typing of field isolates of a fish rhabdovirus, infectious hematopoietic necrosis virus (IHNV), has identified four dominant viral genotypes that were involved in serial viral emergence and displacement events in steelhead trout (Oncorhynchus mykiss) in western North America. To investigate drivers of these landscape-scale events, IHNV isolates designated 007, 111, 110, and 139, representing the four relevant genotypes, were compared for virulence and infectivity in controlled laboratory challenge studies in five relevant steelhead trout populations. Viral virulence was assessed as mortality using lethal dose estimates (LD50), survival kinetics, and proportional hazards analysis. A pattern of increasing virulence for isolates 007, 111, and 110 was consistent in all five host populations tested, and correlated with serial emergence and displacements in the virus-endemic lower Columbia River source region during 1980-2013. The fourth isolate, 139, did not have higher virulence than the previous isolate 110. However, the mG139M genotype displayed a conditional displacement phenotype in that it displaced type mG110M in coastal Washington, but not in the lower Columbia River region, indicating that factors other than evolution of higher viral virulence were involved in some displacement events. Viral infectivity, measured as infectious dose (ID50), did not correlate consistently with virulence or with viral emergence, and showed a narrow range of variation relative to the variation observed in virulence. Comparison among the five steelhead trout populations confirmed variation in resistance to IHNV, but correlations with previous history of virus exposure or with sites of viral emergence varied between IHNV source and sink regions. Overall, this study indicated increasing viral virulence over time as a potential driver for emergence and displacement events in the endemic Lower Columbia River source region where these IHNV genotypes originated, but not in adjacent sink regions. PMID- 27774292 TI - Evolution in spatially mixed host environments increases divergence for evolved fitness and intrapopulation genetic diversity in RNA viruses. AB - Virus populations may be challenged to evolve in spatially heterogeneous environments, such as mixtures of host cells that pose differing selection pressures. Spatial heterogeneity may select for evolved polymorphisms, where multiple virus subpopulations coexist by specializing on a narrow subset of the available hosts. Alternatively, spatial heterogeneity may select for evolved generalism, where a single genotype dominates the virus population by occupying a relatively broader host niche. In addition, the extent of spatial heterogeneity should influence the degree of divergence among virus populations encountering identical environmental challenges. Spatial heterogeneity creates environmental complexity that should increase the probability of differing adaptive phenotypic solutions, thus producing greater divergence among replicate virus populations, relative to counterparts evolving in strictly homogeneous host environments. Here, we tested these ideas using experimental evolution of RNA virus populations grown in laboratory tissue culture. We allowed vesicular stomatitis virus (VSV) lineages to evolve in replicated environments containing BHK-21 (baby hamster kidney) cells, HeLa (human epithelial) cells, or spatially heterogeneous host cell mixtures. Results showed that generalist phenotypes dominated in evolved virus populations across all treatments. Also, we observed greater variance in host-use performance (fitness) among VSV lineages evolved under spatial heterogeneity, relative to lineages evolved in homogeneous environments. Despite measurable differences in fitness, consensus Sanger sequencing revealed no fixed genetic differences separating the evolved lineages from their common ancestor. In contrast, deep sequencing of evolved VSV populations confirmed that the degree of divergence among replicate lineages was correlated with a larger number of minority variants. This correlation between divergence and the number of minority variants was significant only when we considered variants with a frequency of at least 10 per cent in the population. The number of lower-frequency minority variants per population did not significantly correlate with divergence. PMID- 27774293 TI - MERS-CoV recombination: implications about the reservoir and potential for adaptation. AB - Recombination is a process that unlinks neighboring loci allowing for independent evolutionary trajectories within genomes of many organisms. If not properly accounted for, recombination can compromise many evolutionary analyses. In addition, when dealing with organisms that are not obligately sexually reproducing, recombination gives insight into the rate at which distinct genetic lineages come into contact. Since June 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has caused 1,106 laboratory-confirmed infections, with 421 MERS-CoV-associated deaths as of 16 April 2015. Although bats are considered as the likely ultimate source of zoonotic betacoronaviruses, dromedary camels have been consistently implicated as the source of current human infections in the Middle East. In this article, we use phylogenetic methods and simulations to show that MERS-CoV genome has likely undergone numerous recombinations recently. Recombination in MERS-CoV implies frequent co-infection with distinct lineages of MERS-CoV, probably in camels given the current understanding of MERS-CoV epidemiology. PMID- 27774295 TI - Evolution and phylogeographic dissemination of endemic porcine picornaviruses in Vietnam. AB - Members of the Picornaviridae are important and often zoonotic viruses responsible for a variety of human and animal diseases. However, the evolution and spatial dissemination of different picornaviruses circulating in domestic animals are not well studied. We examined the rate of evolution and time of origin of porcine enterovirus G (EV-G) and porcine kobuvirus species C lineages (PKV-C) circulating in pig farms in Vietnam and from other countries. We further explored the spatiotemporal spread of EV-G and PKV-C in Southwest Vietnam using phylogeographic models. Multiple types of EV-G are co-circulating in Vietnam. The two dominant EV-G types among isolates from Vietnam (G1 and G6) showed strong phylogenetic clustering. Three clades of PKV-C (PKV-C1-3) represent more recent introductions into Vietnam; PKV-C2 is closely related to PKV-C from Southwest China, indicating possible cross-border dissemination. In addition, high virus lineage migration rates were estimated within four districts in Dong Thap province in Vietnam for both EV-G types (G1, G6) and all PKV-C (C1-3) clades. We found that Chau Thanh district is a primary source of both EV-G and PKV-C clades, consistent with extensive pig trading in and out of the district. Understanding the evolution and spatial dissemination of endemic picornaviruses in pigs may inform future strategies for the surveillance and control of picornaviruses. PMID- 27774294 TI - Determination of antigenicity-altering patches on the major surface protein of human influenza A/H3N2 viruses. AB - Human influenza viruses are rapidly evolving RNA viruses that cause short-term respiratory infections with substantial morbidity and mortality in annual epidemics. Uncovering the general principles of viral coevolution with human hosts is important for pathogen surveillance and vaccine design. Protein regions are an appropriate model for the interactions between two macromolecules, but the currently used epitope definition for the major antigen of influenza viruses, namely hemagglutinin, is very broad. Here, we combined genetic, evolutionary, antigenic, and structural information to determine the most relevant regions of the hemagglutinin of human influenza A/H3N2 viruses for interaction with human immunoglobulins. We estimated the antigenic weights of amino acid changes at individual sites from hemagglutination inhibition data using antigenic tree inference followed by spatial clustering of antigenicity-altering protein sites on the protein structure. This approach determined six relevant areas (patches) for antigenic variation that had a key role in the past antigenic evolution of the viruses. Previous transitions between successive predominating antigenic types of H3N2 viruses always included amino acid changes in either the first or second antigenic patch. Interestingly, there was only partial overlap between the antigenic patches and the patches under strong positive selection. Therefore, besides alterations of antigenicity, other interactions with the host may shape the evolution of human influenza A/H3N2 viruses. PMID- 27774296 TI - The effects of sampling strategy on the quality of reconstruction of viral population dynamics using Bayesian skyline family coalescent methods: A simulation study. AB - The ongoing large-scale increase in the total amount of genetic data for viruses and other pathogens has led to a situation in which it is often not possible to include every available sequence in a phylogenetic analysis and expect the procedure to complete in reasonable computational time. This raises questions about how a set of sequences should be selected for analysis, particularly if the data are used to infer more than just the phylogenetic tree itself. The design of sampling strategies for molecular epidemiology has been a neglected field of research. This article describes a large-scale simulation exercise that was undertaken to select an appropriate strategy when using the GMRF skygrid, one of the Bayesian skyline family of coalescent methods, in order to reconstruct past population dynamics. The simulated scenarios were intended to represent sampling for the population of an endemic virus across multiple geographical locations. Large phylogenies were simulated under a coalescent or structured coalescent model and sequences simulated from these trees; the resulting datasets were then downsampled for analyses according to a variety of schemes. Variation in results between different replicates of the same scheme was not insignificant, and as a result, we recommend that where possible analyses are repeated with different datasets in order to establish that elements of a reconstruction are not simply the result of the particular set of samples selected. We show that an individual stochastic choice of sequences can introduce spurious behaviour in the median line of the skygrid plot and that even marginal likelihood estimation can suggest complicated dynamics that were not in fact present. We recommend that the median line should not be used to infer historical events on its own. Sampling sequences with uniform probability with respect to both time and spatial location (deme) never performed worse than sampling with probability proportional to the effective population size at that time and in that location and frequently was superior. As a result, we recommend this approach in the design of future studies. We also confirm that the inclusion of many recent sequences from a single geographical location in an analysis tends to result in a spurious bottleneck effect in the reconstruction and caution against interpreting this as genuine. PMID- 27774297 TI - Driving forces behind the evolution of the Aleutian mink disease parvovirus in the context of intensive farming. AB - Aleutian mink disease virus (AMDV) causes plasmacytosis, an immune complex associated syndrome that affects wild and farmed mink. The virus can also infect other small mammals (e.g., ferrets, skunks, ermines, and raccoons), but the disease in these hosts has been studied less. In 2007, a mink plasmacytosis outbreak began on the Island of Newfoundland, and the virus has been endemic in farms since then. In this study, we evaluated the molecular epidemiology of AMDV in farmed and wild animals of Newfoundland since before the beginning of the outbreak and investigated the epidemic in a global context by studying AMDV worldwide, thereby examining its diffusion and phylogeography. Furthermore, AMDV evolution was examined in the context of intensive farming, where host population dynamics strongly influence viral evolution. Partial NS1 sequences and several complete genomes were obtained from Newfoundland viruses and analyzed along with numerous sequences from other locations worldwide that were either obtained as part of this study or from public databases. We observed very high viral diversity within Newfoundland and within single farms, where high rates of co infection, recombinant viruses and polymorphisms were observed within single infected individuals. Worldwide, we documented a partial geographic distribution of strains, where viruses from different countries co-exist within clades but form country-specific subclades. Finally, we observed the occurrence of recombination and the predominance of negative selection pressure on AMDV proteins. A surprisingly low number of immunoepitopic sites were under diversifying pressure, possibly because AMDV gains no benefit by escaping the immune response as viral entry into target cells is mediated through interactions with antibodies, which therefore contribute to cell infection. In conclusion, the high prevalence of AMDV in farms facilitates the establishment of co-infections that can favor the occurrence of recombination and enhance viral diversity. Viruses are then exchanged between different farms and countries and can be introduced into the wild, with the rapidly evolving viruses producing many parallel lineages. PMID- 27774298 TI - A Novel Astrovirus-Like RNA Virus Detected in Human Stool. AB - Several novel clades of astroviruses have recently been identified in human faecal samples. Here, we describe a novel astrovirus-like RNA virus detected in human stools, which we have tentatively named bastrovirus. The genome of this novel virus consists of 6,300 nucleotides organized in three open reading frames. Several sequence divergent strains were detected sharing 67-93 per cent nucleotide identity. Bastrovirus encodes a putative structural protein that is homologous to the capsid protein found in members of the Astroviridae family (45% amino acid identity). The virus also encodes a putative non-structural protein that is genetically distant from astroviruses but shares some homology to the non structural protein encoded by members of the Hepeviridae family (28% amino acid identity). This novel bastrovirus is present in 8.7 per cent (35/400) of faecal samples collected from 300 HIV-1-positive and 100 HIV-1-negative individuals suggesting common occurrence of the virus. However, whether the source of the virus is infected human cells or other, for example, dietary, remains to be determined. PMID- 27774299 TI - Genetic variation in fitness within a clonal population of a plant RNA virus. AB - A long-standing observation in evolutionary virology is that RNA virus populations are highly polymorphic, composed by a mixture of genotypes whose abundances in the population depend on complex interaction between fitness differences, mutational coupling and genetic drift. It was shown long ago, though in cell cultures, that most of these genotypes had lower fitness than the population they belong, an observation that explained why single-virion passages turned on Muller's ratchet while very large population passages resulted in fitness increases in novel environments. Here we report the results of an experiment specifically designed to evaluate in vivo the fitness differences among the subclonal components of a clonal population of the plant RNA virus tobacco etch potyvirus (TEV). Over 100 individual biological subclones from a TEV clonal population well adapted to the natural tobacco host were obtained by infectivity assays on a local lesion host. The replicative fitness of these subclones was then evaluated during infection of tobacco relative to the fitness of large random samples taken from the starting clonal population. Fitness was evaluated at increasing number of days post-inoculation. We found that at early days, the average fitness of subclones was significantly lower than the fitness of the clonal population, thus confirming previous observations that most subclones contained deleterious mutations. However, as the number of days of viral replication increases, population size expands exponentially, more beneficial and compensatory mutations are produced, and selection becomes more effective in optimizing fitness, the differences between subclones and the population disappeared. PMID- 27774300 TI - Exploring the temporal structure of heterochronous sequences using TempEst (formerly Path-O-Gen). AB - Gene sequences sampled at different points in time can be used to infer molecular phylogenies on a natural timescale of months or years, provided that the sequences in question undergo measurable amounts of evolutionary change between sampling times. Data sets with this property are termed heterochronous and have become increasingly common in several fields of biology, most notably the molecular epidemiology of rapidly evolving viruses. Here we introduce the cross platform software tool, TempEst (formerly known as Path-O-Gen), for the visualization and analysis of temporally sampled sequence data. Given a molecular phylogeny and the dates of sampling for each sequence, TempEst uses an interactive regression approach to explore the association between genetic divergence through time and sampling dates. TempEst can be used to (1) assess whether there is sufficient temporal signal in the data to proceed with phylogenetic molecular clock analysis, and (2) identify sequences whose genetic divergence and sampling date are incongruent. Examination of the latter can help identify data quality problems, including errors in data annotation, sample contamination, sequence recombination, or alignment error. We recommend that all users of the molecular clock models implemented in BEAST first check their data using TempEst prior to analysis. PMID- 27774301 TI - Sendai virus intra-host population dynamics and host immunocompetence influence viral virulence during in vivo passage. AB - In vivo serial passage of non-pathogenic viruses has been shown to lead to increased viral virulence, and although the precise mechanism(s) are not clear, it is known that both host and viral factors are associated with increased pathogenicity. Under- or overnutrition leads to a decreased or dysregulated immune response and can increase viral mutant spectrum diversity and virulence. The objective of this study was to identify the role of viral mutant spectra dynamics and host immunocompetence in the development of pathogenicity during in vivo passage. Because the nutritional status of the host has been shown to affect the development of viral virulence, the diet of animal model reflected two extremes of diets which exist in the global population, malnutrition and obesity. Sendai virus was serially passaged in groups of mice with differing nutritional status followed by transmission of the passaged virus to a second host species, guinea pigs. Viral population dynamics were characterized using deep sequence analysis and computational modeling. Histopathology, viral titer and cytokine assays were used to characterize viral virulence. Viral virulence increased with passage and the virulent phenotype persisted upon passage to a second host species. Additionally, nutritional status of mice during passage influenced the phenotype. Sequencing revealed the presence of several non-synonymous changes in the consensus sequence associated with passage, a majority of which occurred in the hemagglutinin-neuraminidase and polymerase genes, as well as the presence of persistent high frequency variants in the viral population. In particular, an N1124D change in the consensus sequences of the polymerase gene was detected by passage 10 in a majority of the animals. In vivo comparison of an 1124D plaque isolate to a clone with 1124N genotype indicated that 1124D was associated with increased virulence. PMID- 27774302 TI - Inference of Japanese encephalitis virus ecological and evolutionary dynamics from passive and active virus surveillance. AB - A comprehensive monitoring strategy is vital for tracking the spread of mosquito borne Japanese encephalitis virus (JEV), the leading cause of viral encephalitis in Asia. Virus detection consists of passive surveillance of primarily humans and swine, and/or active surveillance in mosquitoes, which may be a valuable proxy in providing insights into ecological processes underlying the spread and persistence of JEV. However, it has not been well characterized whether passive surveillance alone can capture the circulating genetic diversity to make reasonable inferences. Here, we develop phylogenetic models to infer JEV host changes, spatial diffusion patterns, and evolutionary dynamics from data collected through active and passive surveillance. We evaluate the feasibility of using JEV sequence data collected from mosquitoes to estimate the migration histories of genotypes GI and GIII. We show that divergence times estimated from this dataset were comparable to estimates from all available data. Increasing the amount of data collected from active surveillance improved time of most recent common ancestor estimates and reduced uncertainty. Phylogenetic estimates using all available data and only mosquito data from active surveillance produced similar results, showing that GI epidemics were widespread and diffused significantly faster between regions than GIII. In contrast, GIII outbreaks were highly structured and unlinked suggesting localized, unsampled infectious sources. Our results show that active surveillance of mosquitoes can sufficiently capture circulating genetic diversity of JEV to confidently estimate spatial and evolutionary patterns. While surveillance of other hosts could contribute to more detailed disease tracking and evaluation, comprehensive JEV surveillance programs should include systematic surveillance in mosquitoes to infer the most complete patterns for epidemiology, and risk assessment. PMID- 27774303 TI - HIV-1 transmission between MSM and heterosexuals, and increasing proportions of circulating recombinant forms in the Nordic Countries. AB - Increased knowledge about HIV-1 transmission dynamics in different transmission groups and geographical regions is fundamental for assessing and designing prevention efforts against HIV-1 spread. Since the first reported cases of HIV infection during the early 1980s, the HIV-1 epidemic in the Nordic countries has been dominated by HIV-1 subtype B and MSM transmission. HIV-1 pol sequences and clinical data of 51 per cent of all newly diagnosed HIV-1 infections in Sweden, Denmark, and Finland in the period 2000-2012 (N = 3,802) were analysed together with a large reference sequence dataset (N = 4,537) by trend analysis and phylogenetics. Analysis of the eight dominating subtypes and CRFs in the Nordic countries (A, B, C, D, G, CRF01_AE, CRF02_AG, and CRF06_cpx) showed that the subtype B proportion decreased while the CRF proportion increased over the study period. A majority (57 per cent) of the Nordic sequences formed transmission clusters, with evidence of mixing both geographically and between transmission groups. Detailed analyses showed multiple occasions of transmissions from MSM to heterosexuals and that active transmission clusters more often involved single than multiple Nordic countries. The strongest geographical link was between Denmark and Sweden. Finally, Denmark had a larger proportion of heterosexual domestic spread of HIV-1 subtype B (75 per cent) compared with Sweden (49 per cent) and Finland (57 per cent). We describe different HIV-1 transmission patterns between countries and transmission groups in a large geographical region. Our results may have implications for public health interventions in targeting HIV-1 transmission networks and identifying where to introduce such interventions. PMID- 27774304 TI - Genetic diversity of STLV-2 and interspecies transmission of STLV-3 in wild living bonobos. AB - There are currently four known primate T-cell lymphotropic virus groups (PTLV1 4), each of which comprises closely related simian (STLV) and human (HTLV) viruses. For PTLV-1 and PTLV-3, simian and human viruses are interspersed, suggesting multiple cross-species transmission events; however, for PTLV-2 this is not so clear because HTLV-2 and STLV-2 strains from captive bonobos (Pan paniscus) form two distinct clades. To determine to what extent bonobos are naturally infected with STLV, we screened fecal samples (n = 633) from wild living bonobos (n = 312) at six different sites in the Democratic Republic of Congo (DRC) for the presence of STLV nucleic acids. STLV infection was detected in 8 of 312 bonobos at four of six field sites, suggesting an overall prevalence of 2.6% (ranging from 0 to 8%). Six samples contained STLV-2, while the two others contained STLV-3, as determined by phylogenetic analysis of partial tax and Long Terminal Repeats (LTR) sequences. The new STLV-2 sequences were highly diverse, but grouped with previously identified STLV-2 strains as a sister clade to HTLV-2. In contrast, the new STLV-3 sequences did not cluster together, but were more closely related to STLVs from sympatric monkey species. These results show for the first time that fecal samples can be used to detect STLV infection in apes. These results also show that wild-living bonobos are endemically infected with STLV-2, but have acquired STLV-3 on at least two occasions most likely by cross-species transmission from monkey species on which they prey. Future studies of bonobos and other non-human primate species in Central Africa are needed to identify the simian precursor of HTLV-2 in humans. PMID- 27774306 TI - Identifying predictors of time-inhomogeneous viral evolutionary processes. AB - Various factors determine the rate at which mutations are generated and fixed in viral genomes. Viral evolutionary rates may vary over the course of a single persistent infection and can reflect changes in replication rates and selective dynamics. Dedicated statistical inference approaches are required to understand how the complex interplay of these processes shapes the genetic diversity and divergence in viral populations. Although evolutionary models accommodating a high degree of complexity can now be formalized, adequately informing these models by potentially sparse data, and assessing the association of the resulting estimates with external predictors, remains a major challenge. In this article, we present a novel Bayesian evolutionary inference method, which integrates multiple potential predictors and tests their association with variation in the absolute rates of synonymous and non-synonymous substitutions along the evolutionary history. We consider clinical and virological measures as predictors, but also changes in population size trajectories that are simultaneously inferred using coalescent modelling. We demonstrate the potential of our method in an application to within-host HIV-1 sequence data sampled throughout the infection of multiple patients. While analyses of individual patient populations lack statistical power, we detect significant evidence for an abrupt drop in non-synonymous rates in late stage infection and a more gradual increase in synonymous rates over the course of infection in a joint analysis across all patients. The former is predicted by the immune relaxation hypothesis while the latter may be in line with increasing replicative fitness during the asymptomatic stage. PMID- 27774305 TI - Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy. AB - To design effective eradication strategies, it may be necessary to target HIV reservoirs in anatomic compartments other than blood. This study examined HIV RNA rebound following interruption of antiretroviral therapy (ART) in blood and cerebrospinal fluid (CSF) to determine whether the central nervous system (CNS) might serve as an independent source of resurgent viral replication. Paired blood and CSF samples were collected longitudinally from 14 chronically HIV-infected individuals undergoing ART interruption. HIV env (C2-V3), gag (p24) and pol (reverse transcriptase) were sequenced from cell-free HIV RNA and cell-associated HIV DNA in blood and CSF using the Roche 454 FLX Titanium platform. Comprehensive sequence and phylogenetic analyses were performed to search for evidence of unique or differentially represented viral subpopulations emerging in CSF supernatant as compared with blood plasma. Using a conservative definition of compartmentalization based on four distinct statistical tests, nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound. The degree and duration of viral compartmentalization varied considerably between subjects and between time-points within a subject. In 10 cases, we identified viral populations within the CSF supernatant at the first sampled time-point after ART interruption, which were phylogenetically distinct from those present in the paired blood plasma and mostly persisted over time (when longitudinal time-points were available). Our data suggest that an independent source of HIV RNA contributes to viral rebound within the CSF after treatment interruption. The most likely source of compartmentalized HIV RNA is a CNS reservoir that would need to be targeted to achieve complete HIV eradication. PMID- 27774307 TI - Mapping the genomic diversity of HCV subtypes 1a and 1b: Implications of structural and immunological constraints for vaccine and drug development. AB - Despite significant progress in hepatitis C (HCV) treatment, global viral eradication remains a challenge. An in-depth map of its genome diversity within the context of structural and immunological constraints could contribute to the design of pan-genotypic antivirals and preventive vaccines. For such analyses, extensive information is only available for the highly prevalent HCV genotypes (GT) 1a and 1b. Using 647 GT1a and 408 GT1b full-genome sequences obtained from the Los Alamos database, we found that respectively 3 per cent and 82 per cent of all codon positions are under positive and negative selective pressure, suggesting variation mainly accumulates due to random genetic drift. An association between conservation and both structured RNA and secondary protein structures confirmed the important role of structural elements at nucleotide and at amino acid level. Remarkably, CD8+ T-cell epitopes in HCV GT1a were significantly more conserved, while at the same time containing more sites under positive selection. Similarly, CD4+ T-cell epitopes were significantly more conserved in both HCV subtypes, but under less positive selective pressure in GT1b and more negative selective pressure in GT1a. In contrast, B-cell epitopes in both subtypes were less conserved and under less stringent negative selection. These findings argue against immune selective pressure as the main force of between-host diversifying evolution. Despite its high variability, HCV is under strict evolutionary constraints, most probably to keep its genes and proteins functional during the replication cycle. These are encouraging findings for vaccine and drug design, which could consider these newly established genetic diversity profiles. PMID- 27774308 TI - Towards a rational design of solid drug nanoparticles with optimised pharmacological properties. AB - Solid drug nanoparticles (SDNs) are a nanotechnology with favourable characteristics to enhance drug delivery and improve the treatment of several diseases, showing benefit for improved oral bioavailability and injectable long acting medicines. The physicochemical properties and composition of nanoformulations can influence the absorption, distribution, and elimination of nanoparticles; consequently, the development of nanoparticles for drug delivery should consider the potential role of nanoparticle characteristics in the definition of pharmacokinetics. The aim of this study was to investigate the pharmacological behaviour of efavirenz SDNs and the identification of optimal nanoparticle properties and composition. Seventy-seven efavirenz SDNs were included in the analysis. Cellular accumulation was evaluated in HepG2 (hepatic) and Caco-2 (intestinal), CEM (lymphocyte), THP1 (monocyte), and A-THP1 (macrophage) cell lines. Apparent intestinal permeability (Papp) was measured using a monolayer of Caco-2 cells. The Papp values were used to evaluate the potential benefit on pharmacokinetics using a physiologically based pharmacokinetic model. The generated SDNs had an enhanced intestinal permeability and accumulation in different cell lines compared to the traditional formulation of efavirenz. Nanoparticle size and excipient choice influenced efavirenz apparent permeability and cellular accumulation, and this appeared to be cell line dependent. These findings represent a valuable platform for the design of SDNs, giving an empirical background for the selection of optimal nanoparticle characteristics and composition. Understanding how nanoparticle components and physicochemical properties influence pharmacological patterns will enable the rational design of SDNs with desirable pharmacokinetics. PMID- 27774309 TI - Microparticulate/Nanoparticulate Powders of a Novel Nrf2 Activator and an Aerosol Performance Enhancer for Pulmonary Delivery Targeting the Lung Nrf2/Keap-1 Pathway. AB - This systematic and comprehensive study reports for the first time on the successful rational design of advanced inhalable therapeutic dry powders containing dimethyl fumarate, a first-in-class Nrf2 activator drug to treat pulmonary inflammation, using particle engineering design technology for targeted delivery to the lungs as advanced spray dried (SD) one-component DPIs. In addition, two-component co-spray dried (co-SD) DMF:D-Man DPIs with high drug loading were successfully designed for targeted lung delivery as advanced DPIs using organic solution advanced spray drying in closed mode. Regional targeted deposition using design of experiments (DoE) for in vitro predictive lung modeling based on aerodynamic properties was tailored based on composition and spray drying parameters. These findings indicate the significant potential of using D-Man in spray drying to improve particle formation and aerosol performance of small molecule with a relatively low melting point. These respirable microparticles/nanoparticles in the solid-state exhibited excellent aerosol dispersion performance with an FDA-approved human DPI device. Using in vitro predictive lung deposition modeling, the aerosol deposition patterns of these particles show the capability to reach lower airways to treat inflammation in this region in pulmonary diseases such as acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), and pulmonary endothelial disease. PMID- 27774310 TI - Translating Stem Cell Biology Into Drug Discovery. AB - Pluripotent stem cell research has made extraordinary progress over the last decade. The robustness of nuclear reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has created entirely novel opportunities for drug discovery and personalized regenerative medicine. Patient- and disease-specific iPSCs can be expanded indefinitely and differentiated into relevant cell types of different organ systems. As the utilization of iPSCs is becoming a key enabling technology across various scientific disciplines, there are still important challenges that need to be addressed. Here we review the current state and reflect on the issues that the stem cell and translational communities are facing in bringing iPSCs closer to clinical application. PMID- 27774311 TI - Anal Squamous Cell Carcinoma in African Americans with and without HIV: A Comparative Study. AB - BACKGROUND: The incidence of anal carcinoma has increased over the last few decades especially in African Americans (AA) despite the use of highly active anti-retroviral therapy (HAART). Here, we retrospectively review oncologic outcomes of AA patients with anal squamous cell carcinoma (SCC) with and without HIV to further examine the cause of this trend. MATERIALS AND METHODS: All adult AA patients diagnosed with anal SCC from 2000 to 2007 who met inclusion were examined. All patients were staged according to the American Joint Committee on Carcinoma (AJCC) sixth edition staging classification. Patients were divided into two cohorts: HIV (-) and HIV (+). Demographics, comorbidities, and oncologic outcomes were analyzed. RESULTS: Twenty-two AA patients with anal SCC were analyzed. Fifteen (68.%) were HIV (+) and seven (32%) were negative. Seventy-four percent of HIV (+) patients were on HAART therapy at the time of diagnosis. The HIV (+) cohort was significantly younger, mostly male, and had more comorbidities compared to the negative cohort. There was no difference in tumor, nodal or metastasis (TNM) stage for both cohorts. HIV (+) patients were more likely to receive non-operative therapy. The 5-year survival rate for HIV negative and positive patients was 57% and 58%, respectively. AJCC stage was the only factor predictive of survival after performing Cox hazard proportional regression analysis, HR: 1.96 (95% CI, 0.987 to 3.881). CONCLUSIONS: In the HAART era, HIV (+) AA patients are at high risk of developing anal SCC. However, the prognosis of HIV (+) AA with anal SSC is similar to that of their HIV (-) counterparts. Carcinoma stage is the only factor predictive of survival. PMID- 27774312 TI - Repeatability and Reproducibility of Quantitative Corneal Shape Analysis after Orthokeratology Treatment Using Image-Pro Plus Software. AB - Purpose. To evaluate the repeatability and reproducibility of quantitative analysis of the morphological corneal changes after orthokeratology treatment using "Image-Pro Plus 6.0" software (IPP). Methods. Three sets of measurements were obtained: two sets by examiner 1 with 5 days apart and one set by examiner 2 on the same day. Parameters of the eccentric distance, eccentric angle, area, and roundness of the corneal treatment zone were measured using IPP. The intraclass correlation coefficient (ICC) and repetitive coefficient (COR) were used to calculate the repeatability and reproducibility of these three sets of measurements. Results. ICC analysis suggested "excellent" reliability of more than 0.885 for all variables, and COR values were less than 10% for all variables within the same examiner. ICC analysis suggested "excellent" reliability for all variables of more than 0.90, and COR values were less than 10% for all variables between different examiners. All extreme values of the eccentric distance and area of the treatment zone pointed to the same material number in three sets of measurements. Conclusions. IPP could be used to acquire the exact data of the characteristic morphological corneal changes after orthokeratology treatment with good repeatability and reproducibility. This trial is registered with trial registration number: ChiCTR-IPR-14005505. PMID- 27774313 TI - An Analysis of Anthropometric Indicators and Modifiable Lifestyle Parameters Associated with Hypertensive Nephropathy. AB - The surge in prevalence of chronic noncommunicable diseases like hypertension and chronic kidney disease has been linked with modifiable lifestyle practices and increased body fat. This study sought to compare the association between different modifiable lifestyle practices, adiposity indices, renal function parameters, and hypertension as well as the predictive implications for levels of these parameters in target cardiac organ damage among an urban Ghanaian hypertensive population. Using a hospital-based case-control study design, 241 Ghanaian indigenes from the Kumasi metropolis were recruited for this study. The case group was made up of 180 hypertensives and 61 normotensives served as controls. In addition to sociodemographic data, standard haemodynamic, anthropometric, renal function, and cardiac organ damage assessments were done. The prevalence of chronic kidney disease (CKD) ranged from 13.3% to 16.6% depending on the equation used in estimating the glomerular filtration rate (eGFR). Percentage cluster distribution by chronic kidney disease was observed to be significantly tilted toward the upper quartiles (3rd and 4th) of the haemodynamic parameters measured. Chronic kidney disease was significantly higher among self-reported smokers and alcoholic hypertensives. In this urban population, adiposity was associated with hypertension and renal insufficiency. Chronic kidney disease was associated with hypertension and cardiac abnormalities. PMID- 27774314 TI - Breastfeeding Practices among Native Hawaiians and Pacific Islanders. AB - Background. Breastfeeding is associated with a decreased risk of obesity in the early and adult years. Native Hawaiians and Pacific Islanders (NHPI) experience high rates of obesity which is often obfuscated with aggregated data. Using disaggregated data, we examined breastfeeding practices among NHPI. Methods. Seven databases and reference lists were searched. Two independent researchers extracted relevant studies based on predetermined criteria. Nine studies met our inclusion criteria and a meta-analysis was conducted using random-effects, inverse-various weighted models. Results. Few studies disaggregated NHPI populations when examining breastfeeding practices. Most studies were cross sectional and our search yielded no randomized or quasirandomized control trials. The results of the meta-analysis indicated that 46.5% NHPI women initiated breastfeeding with 40.8% breastfeeding exclusively. These pooled analyses show that NHPI breastfeeding practices are below the recommended national and international goals and guidelines. Conclusion. Breastfeeding practices among NHPI are heterogeneous and critical disparities exist among certain NHPI subgroups and additional research needs to be conducted to determine the reasons for the disparity. Future studies should work to disaggregate data for NHPI and the various subpopulations. Multicomponent, multilevel strategies are needed to support breastfeeding practices among NHPI. PMID- 27774315 TI - Cardiovascular Endurance, Body Mass Index, Physical Activity, Screen Time, and Carotenoid Intake of Children: NHANES National Youth Fitness Survey. AB - Background. Approximately 17% of children aged 6-11 years were classified as obese in the United States. Obesity adversely affects physical functioning and leads to reduced quality of life. Heart function for overweight and obese children has not been reported. Methods. Data for this study were from NHANES National Youth Fitness Survey (NNYFS) conducted in conjunction with the National Health and Nutrition Examination Survey (NHANES) in 2012. This study used data from children aged 6-12 (N = 732) that had the cardiorespiratory endurance measure, body mass index for age and sex, and dietary data (N = 682). Cardiovascular endurance was estimated by heart rate reserve. Results. Compared to the highest percentile of heart rate reserve, those in the first percentile had 3.52 (2.36, 5.24) odds and those in the second percentile had 3.61 (1.84, 7.06) odds of being in the overweight/obese as compared to the under/normal weight category. Considering the highest percentile, boys had a heart rate reserve of 35%, whereas girls had a heart rate reserve of 13% (less than half that of boys). Conclusion. Having an overweight or obese classification for children in this study demonstrated a compromise in cardiovascular endurance. Parental awareness should be raised as to the detrimental consequence of overweight and heart health. PMID- 27774317 TI - Malnutrition: The Importance of Identification, Documentation, and Coding in the Acute Care Setting. AB - Malnutrition is a significant issue in the hospital setting. This cross sectional, observational study determined the prevalence of malnutrition amongst 189 adult inpatients in a teaching hospital using the Patient-Generated Subjective Global Assessment tool and compared data to control groups for coding of malnutrition to determine the estimated unclaimed financial reimbursement associated with this comorbidity. Fifty-three percent of inpatients were classified as malnourished. Significant associations were found between malnutrition and increasing age, decreasing body mass index, and increased length of stay. Ninety-eight percent of malnourished patients were coded as malnourished in medical records. The results of the medical history audit of patients in control groups showed that between 0.9 and 5.4% of patients were coded as malnourished which is remarkably lower than the 52% of patients who were coded as malnourished from the point prevalence study data. This is most likely to be primarily due to lack of identification. The estimated unclaimed annual financial reimbursement due to undiagnosed or undocumented malnutrition based on the point prevalence study was AU$8,536,200. The study found that half the patients were malnourished, with older adults being particularly vulnerable. It is imperative that malnutrition is diagnosed and accurately documented and coded, so appropriate coding, funding reimbursement, and treatment can occur. PMID- 27774316 TI - Effect of Treatment with Salsalate, Menhaden Oil, Combination of Salsalate and Menhaden Oil, or Resolvin D1 of C57Bl/6J Type 1 Diabetic Mouse on Neuropathic Endpoints. AB - Aims. In this study a streptozotocin induced type 1 diabetes mouse model was used to assess the effectiveness of salsalate, menhaden oil, the combination of salsalate and menhaden oil, or resolvin D1 on neuropathic endpoints. Materials and Methods. Changes in body weight, blood glucose, serum markers for triglycerides, free fatty acids, cholesterol, and resolvin D1, motor and sensory nerve conduction velocities and thermal sensitivity were assessed, as well as performing in vivo confocal microscopy of subepithelial corneal nerves and immunohistochemistry of nerves in the cornea and foot pad. Results. Diabetic animals failed to gain weight and had elevated blood glucose levels. Diabetic mice had slowed nerve conduction velocity, reduced innervation of the foot pad and cornea subepithelial and epithelial layers, and reduced thermal sensitivity. Monotherapy treatment with salsalate, menhaden oil, and resolvin D1 reduced the pathological signs of diabetic neuropathy. The combination of salsalate and menhaden oil also reduced signs of pathology and generated elevated plasma levels of resolvin D1 compared to other groups. Conclusions. Additional studies are needed to determine whether the combination of salsalate and menhaden oil may be more efficacious than monotherapy alone for the treatment of diabetic peripheral neuropathy. PMID- 27774318 TI - Radium-223 Therapy for Patients with Metastatic Castrate-Resistant Prostate Cancer: An Update on Literature with Case Presentation. AB - Background and Purpose. Radium-223 dichloride (Xofigo(r), Bayer HealthCare Pharmaceuticals Inc.) is the first alpha-particle emitter therapeutic agent approved by the FDA, with benefits in overall survival and delay in symptomatic skeletal event for patients with metastatic castrate-resistant prostate cancer (CRPC). Recent post hoc analyses of the phase III ALSYMPCA trial support the previously established safety profile as well as therapeutic effect and clinical outcome of Radium-223. Currently, Radium-223 is approved as a single agent therapy for metastatic CRPC. Clinical trials are currently investigating Radium 223 in additional clinical settings such as earlier asymptomatic disease and in combination with other agents including hormonal therapeutic agents and immunotherapeutic as well as chemotherapeutic agents. Trials are also ongoing in patients with other primary cancers such as breast cancer, thyroid cancer, and renal cancer metastatic to bone. In this article, the physics and radiobiology, as well as a literature update on the use of Radium-223, are provided along with case presentations, aiming at a better appreciation of research data as well as the assimilation of research data into clinical practice. PMID- 27774319 TI - Does Sensory Function Decline Independently or Concomitantly with Age? Data from the Baltimore Longitudinal Study of Aging. AB - Objectives. To investigate whether sensory function declines independently or in parallel with age within a single individual. Methods. Cross-sectional analysis of Baltimore Longitudinal Study of Aging (BLSA) participants who underwent vision (visual acuity threshold), proprioception (ankle joint proprioceptive threshold), vestibular function (cervical vestibular-evoked myogenic potential), hearing (pure-tone average audiometric threshold), and Health ABC physical performance battery testing. Results. A total of 276 participants (mean age 70 years, range 26-93) underwent all four sensory tests. The function of all four systems declined with age. After age adjustment, there were no significant associations between sensory systems. Among 70-79-year-olds, dual or triple sensory impairment was associated with poorer physical performance. Discussion. Our findings suggest that beyond the common mechanism of aging, other distinct (nonshared) etiologic mechanisms may contribute to decline in each sensory system. Multiple sensory impairments influence physical performance among individuals in middle old-age (age 70-79). PMID- 27774320 TI - Awareness, Knowledge, and Acceptance of Haematopoietic Stem Cell Transplantation for Sickle Cell Anaemia in Nigeria. AB - Background. Sickle cell anaemia (SCA) is an inherited condition whose clinical manifestations arise from the tendency of haemoglobin to polymerize and deform red blood cells into characteristic sickle shape. Allogeneic bone marrow transplantation offers a cure. The aim of this study was to determine the level of awareness, knowledge, and acceptance of this beneficial procedure in Nigeria. Materials and Methods. This multicentre cross-sectional study was conducted in 7 tertiary hospitals in Nigeria in 2015. Approval was obtained from each institution's research and ethics committee. A pretested structured questionnaire was administered to respondents aged 18 years and above and to the parents or guardians of those below 18 years of age. Results. There were 265 respondents comprising 120 males and 145 females. One hundred and seventy-one (64.5%) respondents were aware of BMT for the treatment of SCA. About 67.8% (116 of 171) of those who were aware believed SCA can be cured with BMT (p = 0.001) and 49.7% (85 of 171) of the respondents accepted BMT (p = 0.001). Conclusion. Awareness of BMT in Nigeria is low when compared with reports from developed countries. The knowledge is poor and acceptance is low. With adequate information, improved education, and psychological support, more Nigerians will embrace BMT. PMID- 27774323 TI - Syndrome of Reduced Sensitivity to Thyroid Hormones: Two Case Reports and a Literature Review. AB - Resistance to thyroid hormone (RTH) is an extremely rare dominantly inherited condition of impaired tissue responsiveness to thyroid hormone (TH). Most patients with RTH have mutations in the gene that encodes the beta isoform of the receptor of thyroid hormone (THR-beta gene). Mutant receptors are unable to activate or repress target genes. The majority of them are asymptomatic or rarely have hypo- or hyperthyroidism. RTH is suspected by the finding of persistent elevation of serum levels of free T3 (FT3) and free T4 (FT4) and nonsuppressed TSH. We present two cases of RTH diagnosed after total thyroidectomy. The first patient was initially diagnosed with primary hyperthyroidism due to toxic multinodular goiter. The second patient had undergone thyroidectomy for multinodular goiter 16 years before diagnosis of RTH. After thyroidectomy, although on relatively high doses of levothyroxine, both of them presented with the laboratory findings of RTH. Genetic analysis revealed RTH. PMID- 27774322 TI - Traumatic Brain Injury and Substance Related Disorder: A 10-Year Nationwide Cohort Study in Taiwan. AB - Whether traumatic brain injury (TBI) is causally related to substance related disorder (SRD) is still debatable, especially in persons with no history of mental disorders at the time of injury. This study analyzed data in the Taiwan National Health Insurance Research Database for 19,109 patients aged >=18 years who had been diagnosed with TBI during 2000-2010. An additional 19,109 randomly selected age and gender matched patients without TBI (1 : 1 ratio) were enrolled in the control group. The relationship between TBI and SRD was estimated with Cox proportional hazard regression models. During the follow-up period, SRD developed in 340 patients in the TBI group and in 118 patients in the control group. After controlling for covariates, the overall incidence of SRD was 3.62-fold higher in the TBI group compared to the control group. Additionally, patients in the severe TBI subgroup were 9.01 times more likely to have SRD compared to controls. Notably, patients in the TBI group were prone to alcohol related disorders. The data in this study indicate that TBI is significantly associated with the subsequent risk of SRD. Physicians treating patients with TBI should be alert to this association to prevent the occurrence of adverse events. PMID- 27774324 TI - CD7 Positive Diffuse Large B-Cell Lymphoma Arising in a Background of Follicular Lymphoma: A Case Report and Review of the Literature. AB - Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large B-lymphocytes with a diffuse growth pattern. The neoplastic cells express B-cell markers such as CD20 and PAX-5 and there may be coexpression of BCL-2, BCL-6, CD10, and MUM-1. With the exception of CD5, other T-cell markers are not commonly expressed in this neoplasm. Here, we describe the first reported case of a DLBCL with abnormal expression CD7 arising in a background of follicular lymphoma in an 81-year-old male who presented with a nontender left axillary mass. Additionally, no other T cell antigens were expressed in this B-cell lymphoma. Expression of CD7 in DLBCL is exceptionally rare and its prognostic significance is unknown. Here, we describe this rare case with review of literature of known DLBCLs with expression of T-cell antigens. PMID- 27774321 TI - Electroacupuncture Treatment Alleviates Central Poststroke Pain by Inhibiting Brain Neuronal Apoptosis and Aberrant Astrocyte Activation. AB - Electroacupuncture (EA) is reported to effectively relieve the central poststroke pain (CPSP). However, the underlying mechanism remains unclear. The present study investigated the detailed mechanisms of action of EA treatment at different frequencies for CPSP. A CPSP model was established with a single collagenase injection to the left ventral posterolateral nucleus of the thalamus. The EA treated groups then received EA treatment at frequency of 2, 2/15, or 15 Hz for 30 min daily for five days. The pain-related behavioral responses, neuronal apoptosis, glial activation, and the expression of pain signal transmission related factors (beta-catenin, COX-2, and NK-1R) were assessed using behavioral tests, Nissl staining, TUNEL staining, and immunohistochemical staining, respectively. The low-frequency EA treatment significantly (1) reduced brain tissue damage and hematoma sizes and (2) inhibited neuronal apoptosis, thereby exerting abirritative effects. Meanwhile, the high-frequency EA treatment induced a greater inhibition of the aberrant astrocyte activation, accompanied by the downregulation of the expressions of COX-2, beta-catenin, and subsequently NK-1R, thereby alleviating inflammation and producing strong analgesic effects. Together, these findings suggest that CPSP is closely related to pathological changes of the neocortex and hippocampus. EA treatments at different frequencies may exert abirritative effects by inhibiting brain neuronal apoptosis and aberrant astrocyte activation in the brain. PMID- 27774325 TI - Acute Hemolysis with Renal Failure due to Clostridium Bacteremia in a Patient with AML. AB - We present a case of acute hemolytic anemia, renal failure, and Clostridium perfringens bacteremia in a patient with acute myelogenous leukemia. The high fatality of C. perfringens bacteremia requires that clinicians recognize and rapidly treat patients at risk for this infection. Although other hemolytic processes are in the differential diagnosis of these events, the presence of high fever, chills, and rapidly positive blood cultures may help narrow the diagnosis. Most cases of C. perfringens bacteremia have a concomitant coinfection, which makes broad spectrum empiric therapy essential. There is a high mortality rate of C. perfringens infections associated with leukemia. PMID- 27774326 TI - Accurate Diagnosis of Severe Hypospadias Using 2D and 3D Ultrasounds. AB - The hypospadias is the most common urogenital anomaly of male neonates but the prenatal diagnosis of this is often missed before birth. We present the prenatal diagnosis of a severe penoscrotal hypospadias using 2D and 3D ultrasounds. 3D sonography allowed us the best evaluation of the genitals and their anatomical relations. This ample detailed study allowed us to show the findings to the parents and the pediatric surgeon and to configure the best information about the prognosis and surgical treatment. PMID- 27774327 TI - Poor Outcomes in Hepatic Amyloidosis: A Report of 2 Cases. AB - Hepatic amyloidosis is a rare disease entity that results from insoluble amyloid protein deposition in the liver. The disease often presents with vague, nonspecific clinical features. Currently, there is little literature describing treatment outcomes for biopsy-proven hepatic amyloidosis and current treatment guidelines recommend that patients enroll in a clinical trial due to insufficient evidence to suggest an optimal treatment regimen. Here, we present two cases of hepatic amyloidosis at an academic medical center and describe their presentation, treatment, and outcomes. These cases highlight the poor outcomes and difficult management of hepatic amyloidosis. Further understanding and investigation of this rare disease are warranted. PMID- 27774328 TI - A Case of Bilateral Permanent Subluxation of the Lateral Meniscus. AB - We report a case of bilateral, permanent subluxation of the lateral meniscus. To our knowledge, the present case is the first reported description of bilateral irreducible anterior dislocation of the posterior segment of the lateral meniscus. This disorder is characterized by a flipped meniscus sign of the lateral meniscus on sagittal magnetic resonance images of the knee joint, with no history of trauma or locking symptoms. A detailed examination of serial magnetic resonance images of the lateral meniscus can help differentiate this condition from malformation of the lateral meniscus, that is, a double-layered meniscus. We recommend two-stage treatment for this disorder. First, the knee joint is kept in straight position for 3 weeks after the lateral meniscus is reduced to the normal position. Second, if subluxation of the lateral meniscus recurs, meniscocapsular suture is then performed. Although subluxation of the lateral meniscus without locking symptoms is rare, it is important to be familiar with this condition to diagnose and treat it correctly. PMID- 27774329 TI - Two Extension Block Kirschner Wires' Technique for Bony Mallet Thumb. AB - Mallet fingers with an avulsion fracture of the distal phalanx or rupture of the terminal tendon of the extensor mechanism is known as a common injury, while mallet thumb is very rare. In this paper, the case of a 19-year-old woman with a sprained left thumb sustained while playing basketball is presented. Plain radiographs and computed tomography revealed an avulsion fracture involving more than half of the articular surface at the base of the distal phalanx. Closed reduction and percutaneous fixation were performed using the two extension block Kirschner wires' technique under digital block anesthesia. At 4 months postoperatively, the patient had achieved excellent results according to Crawford's evaluation criteria and had no difficulties in working or playing basketball. Various conservative and operative treatment strategies have been reported for management of mallet thumb. We chose the two extension block Kirschner wires' technique to minimize invasion of the extensor mechanism and nail bed and to stabilize the large fracture fragment. PMID- 27774330 TI - Knee-Extension Training with a Single-Joint Hybrid Assistive Limb during the Early Postoperative Period after Total Knee Arthroplasty in a Patient with Osteoarthritis. AB - The knee range of motion is an important outcome of total knee arthroplasty (TKA). According to previous studies, the knee range of motion temporarily decreases for approximately 1 month after TKA due to postoperative pain and quadriceps dysfunction following surgical invasion into the knee extensor mechanism. We describe our experience with a knee-extension training program based on a single-joint hybrid assistive limb (HAL-SJ, Cyberdyne Inc., Tsukuba, Japan) during the acute recovery phase after TKA. HAL-SJ is a wearable robot suit that facilitates the voluntary control of knee joint motion. A 76-year-old man underwent HAL-SJ-based knee-extension training, which enabled him to perform knee function training during the acute phase after TKA without causing increased pain. Thus, he regained the ability to fully extend his knee postoperatively. HAL SJ-based knee-extension training can be used as a novel post-TKA rehabilitation modality. PMID- 27774331 TI - Metastatic Papillary Thyroid Carcinoma with Multifocal Synchronous Transformation to Anaplastic Thyroid Carcinoma. AB - Papillary thyroid carcinoma is a common malignancy to affect the thyroid and is typified by a nonaggressive nature and low rates of mortality. In contrast, anaplastic thyroid carcinoma is the most aggressive thyroid malignancy with a mortality rate of nearly 90% and survival typically of only six months after the diagnosis is made. The transformation of papillary thyroid carcinoma to anaplastic thyroid carcinoma is well documented in the literature but is uncommon and in most instances is reported as a case report or small series only. Transformation of papillary thyroid carcinoma to anaplastic thyroid carcinoma usually takes place in the thyroid itself or in the adjacent lymph nodes. Only on rare occasions does a transformation occur in a papillary thyroid carcinoma metastasis outside of these locations. In the present case report and subsequent discussion we highlight an unusual case of PTC with transformation to anaplastic thyroid carcinoma, which is shown to involve numerous locations to include near total lung parenchyma obliteration. We also discuss the differential diagnostic challenges when faced with a thyroid malignancy that is negative for thyroglobulin. PMID- 27774332 TI - A Case of Infective Endocarditis and Pulmonary Septic Emboli Caused by Lactococcus lactis. AB - Infective endocarditis is a rare condition in children with normal hearts. We present here a case of previously healthy eleven-year-old girl with infective endocarditis and pulmonary septic emboli caused by a very rare bacterial etiology (Lactococcus lactis). Identification of this pathogen was only made by polymerase chain reaction. PMID- 27774333 TI - Comparing Cognitive Profiles of Licensed Drivers with Mild Alzheimer's Disease and Mild Dementia with Lewy Bodies. AB - Purpose. Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB) constitute two of the most common forms of dementia in North America. Driving is a primary means of mobility among older adults and the risk of dementia increases with advanced age. The purpose of this paper is to describe the cognitive profile of licensed drivers with mild AD and mild DLB. Method. Licensed drivers with mild AD, mild DLB, and healthy controls completed neuropsychological tests measuring general cognition, attention, visuospatial/perception, language, and cognitive fluctuations. Results. The results showed differences between healthy controls and demented participants on almost all neuropsychological measures. Participants with early DLB were found to perform significantly worse on some measures of attention and visuospatial functioning in comparison with early AD. Discussion. Future research should examine the relationship between neuropsychological measures and driving outcomes among individuals with mild AD and mild DLB. PMID- 27774335 TI - N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells. AB - Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson's disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration. PMID- 27774334 TI - Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update. AB - Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson's disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome. PMID- 27774336 TI - A Simple and Quick Method for the Determination of Pesticides in Environmental Water by HF-LPME-GC/MS. AB - This paper describes a simple and quick method for sampling and also for carrying out the preconcentration of pesticides in environmental water matrices using two phased hollow fiber liquid phase microextraction (HF-LPME). Factors such as extraction mode, time, solvents, agitation, and salt addition were investigated in order to validate the LPME method. The following conditions were selected: 6 cm of polypropylene hollow fiber, ethyl octanoate as an acceptor phase, and extraction during 30 min under stirring at 200 rpm. The optimized method showed good linearity in the range of 0.14 to 200.00 MUg L-1; the determination coefficient (R2) was in the range of 0.9807-0.9990. The LOD ranged from 0.04 MUg L-1 to 0.44 MUg L-1, and LOQ ranged from 0.14 MUg L-1 to 1.69 MUg L-1. The recovery ranged from 85.17% to 114.73%. The method was applied to the analyses of pesticides in three environmental water samples (a spring and few streams) collected in a rural area from the state of Minas Gerais, Brazil. PMID- 27774337 TI - A New Proof of Concept in Bacterial Reduction: Antimicrobial Action of Violet Blue Light (405 nm) in Ex Vivo Stored Plasma. AB - Bacterial contamination of injectable stored biological fluids such as blood plasma and platelet concentrates preserved in plasma at room temperature is a major health risk. Current pathogen reduction technologies (PRT) rely on the use of chemicals and/or ultraviolet light, which affects product quality and can be associated with adverse events in recipients. 405 nm violet-blue light is antibacterial without the use of photosensitizers and can be applied at levels safe for human exposure, making it of potential interest for decontamination of biological fluids such as plasma. As a pilot study to test whether 405 nm light is capable of inactivating bacteria in biological fluids, rabbit plasma and human plasma were seeded with bacteria and treated with a 405 nm light emitting diode (LED) exposure system (patent pending). Inactivation was achieved in all tested samples, ranging from low volumes to prebagged plasma. 99.9% reduction of low density bacterial populations (<=103 CFU mL-1), selected to represent typical "natural" contamination levels, was achieved using doses of 144 Jcm-2. The penetrability of 405 nm light, permitting decontamination of prebagged plasma, and the nonrequirement for photosensitizing agents provide a new proof of concept in bacterial reduction in biological fluids, especially injectable fluids relevant to transfusion medicine. PMID- 27774338 TI - Quantification of Cell-Free DNA in Red Blood Cell Units in Different Whole Blood Processing Methods. AB - Background. Whole blood donations in Canada are processed by either the red cell filtration (RCF) or whole blood filtration (WBF) methods, where leukoreduction is potentially delayed in WBF. Fresh WBF red blood cells (RBCs) have been associated with increased in-hospital mortality after transfusion. Cell-free DNA (cfDNA) is released by neutrophils prior to leukoreduction, degraded during RBC storage, and is associated with adverse patient outcomes. We explored cfDNA levels in RBCs prepared by RCF and WBF and different storage durations. Methods. Equal numbers of fresh (stored <=14 days) and older RBCs were sampled. cfDNA was quantified by spectrophotometry and PicoGreen. Separate regression models determined the association with processing method and storage duration and their interaction on cfDNA. Results. cfDNA in 120 RBC units (73 RCF, 47 WBF) were measured. Using PicoGreen, WBF units overall had higher cfDNA than RCF units (p = 0.0010); fresh WBF units had higher cfDNA than fresh RCF units (p = 0.0093). Using spectrophotometry, fresh RBC units overall had higher cfDNA than older units (p = 0.0031); fresh WBF RBCs had higher cfDNA than older RCF RBCs (p = 0.024). Conclusion. Higher cfDNA in fresh WBF was observed compared to older RCF blood. Further study is required for association with patient outcomes. PMID- 27774339 TI - Choice of a suitable diabetes risk assessment tool in Nepal - can we learn from Canada? PMID- 27774340 TI - The need to establish local Diabetes Mellitus registries. PMID- 27774342 TI - Rising burden of Diabetes-Public Health Challenges and way out. PMID- 27774341 TI - Incretin - based therapy in diabetes mellitus: present scenario and expanding horizons. PMID- 27774343 TI - Occupational injuries: Global and local perspectives. PMID- 27774344 TI - Scrub Typhus in Nepal. PMID- 27774345 TI - Age specific incidence of five major cancers in Nepal, 2012. AB - BACKGROUND: Population based cancer registry is inevitable to measure the indicators of cancer. This retrospective study was conducted to perform the age specific incidence and age standardized rate of cancer by sex, age and sites in Nepal, 2012. MATERIALS AND METHODS: The data collected by hospital based National cancer registry programme of Nepal were used to calculate the age specific incidence of five major cancers by sex and sites. The age standardized rate of ten major cancers, both in males and females of 2012 was also performed. RESULTS: The 70-74 years age group had the highest incidence rate (188.08) for men while for women the age group of 65-69 years had the highest incidence (140.61) per 100,000. For male, lung cancer had the highest incidence rate (4.45) whereas bladder had the lowest rate (0.98). Similarly for female, Cervix Uteri cancer had the highest incidence rate (5.35) whereas stomach had the lowest (1.06). CONCLUSION: This study presented that cancer was increased with age both in males and females. The leading cancer in males was bronchus and lung while in females it was cervix uteri. . PMID- 27774346 TI - Self-medication practice among preclinical university students in a medical school from the city of Pokhara, Nepal. AB - BACKGROUND: In developing countries like Nepal medicines can be acquired from the chemist's without of a prescription which sometime may have many drawbacks due to intake of excessive drugs without a proper diagnosis. The primary objective of the study was to find out the pattern of self-medication practice among the preclinical medical students at Manipal College of Medical Sciences. MATERIALS AND METHODS: This was a cross sectional study carried out using structured questionnaire at Manipal College of Medical Sciences, Pokhara, Nepal between November 2012- July 2014. RESULTS: The overall response rate of this study was 95.31%. 81.35% of the students were practicing self-medication in this institution. Most common group of drugs that were consumed were antipyretics 31%, antibiotics 26.2%, analgesics 18.89%, antihistaminics 10.1% respectively. Paracetamol was the most common drug used for self-medication 31%, followed by Azithromycin 17.6% and combination of Paracetamol and Ibuprofen 15.6%, Cetirizine 8.6%, Amoxicillin 6.5%, Omeprazole 6.3%, Albendazole 3.3%, Mefenemic acid 2.8%, Cefpodoxime2% respectively. CONCLUSION: Medical student should be educated through awareness programme regarding pros and cons of self-medication practice and they should be motivated regarding the rationale use of antibiotics. . PMID- 27774347 TI - Harrowing Blindness and Ocular Morbidity in a Himalayan Village. PMID- 27774348 TI - Burden of Fungal Infections in Nepal. PMID- 27774351 TI - Impact of a 10 minute Seated Yoga Practice in the Management of Diabetes. AB - OBJECTIVE: We sought to prospectively evaluate the impact of a 10 minute seated yoga program added to standard comprehensive diabetes care on glucose control and cardiovascular health in the severely ill, medically complex diabetic population. METHOD: A total of 10 patients with type 2 diabetes, ages 49-77, with duration of diabetes >10 years and haemoglobin A1C >9% (75 mmol/mol) were included in the study. Patients randomized to a yoga intervention were taught a 10 minute seated yoga practice, were given an explanatory DVD and a fold-out pocket guide to encourage adherence at home, and were instructed to incorporate the practice as often as they could. The patients in the control arm were provided information and hand outs on the available yoga classes on campus. RESULTS: At 3 month clinical follow up, the mean decrease in fasting capillary blood glucose (CBG) was 45% among yoga participants (-5.2 +/- 4.1 mmol/L). Heart rate (HR) dropped by 18% and Diastolic blood pressure (BP) dropped by 29% in the intervention arm, ( 12.4 +/- 6.69 and -26 +/- 12.05 mmHg, respectively). There were no statistically significant changes in the haemoglobin A1C, systolic blood pressure, weight, or body mass index in either group. CONCLUSION: Our small pilot study reinforces the current medical evidence supporting the use of yoga, combined with standard care, to improve health outcomes in diabetes. PMID- 27774349 TI - A Two-Metal-Ion-Mediated Conformational Switching Pathway for HDV Ribozyme Activation. AB - RNA enzymes serve as a potentially powerful platform from which to design catalysts and engineer new biotechnology. A fundamental understanding of these systems provides insight to guide design. The hepatitis delta virus ribozyme (HDVr) is a small, self-cleaving RNA motif widely distributed in nature, that has served as a paradigm for understanding basic principles of RNA catalysis. Nevertheless, questions remain regarding the precise roles of divalent metal ions and key nucleotides in catalysis. In an effort to establish a reaction mechanism model consistent with available experimental data, we utilize molecular dynamics simulations to explore different conformations and metal ion binding modes along the HDVr reaction path. Building upon recent crystallographic data, our results provide a dynamic model of the HDVr reaction mechanism involving a conformational switch between multiple non-canonical G25:U20 base pair conformations in the active site. These local nucleobase dynamics play an important role in catalysis by modulating the metal binding environments of two Mg2+ ions that support catalysis at different steps of the reaction pathway. The first ion plays a structural role by inducing a base pair flip necessary to obtain the catalytic fold in which C75 moves towards to the scissile phosphate in the active site. Ejection of this ion then permits a second ion to bind elsewhere in the active site and facilitate nucleophile activation. The simulations collectively describe a mechanistic scenario that is consistent with currently available experimental data from crystallography, phosphorothioate substitutions, and chemical probing studies. Avenues for further experimental verification are suggested. PMID- 27774352 TI - Feasibility of a Community-Based Sickle Cell Trait Testing and Counseling Program. AB - BACKGROUND: Sickle cell trait (SCT) screening is required at birth in the United States; however, adults rarely know their SCT status prior to having children. PURPOSE: Assess feasibility of a community-based SCT education and testing intervention. METHODS: Participants were recruited from eight community sites to complete an educational program and offered a hemoglobin analysis. A genetic counselor met individually with participants to discuss lab results. RESULTS: Between July 14, 2010 and May 31, 2012, 637 participants completed the educational program. Five hundred seventy (89.5%) provided a blood sample, and 61 (10.9%) had SCT or other hemoglobinopathies. The genetic counselor met with 321 (56.3%) participants. CONCLUSIONS: Community-based SCT testing shows initial feasibility and may increase the number of individuals who know their trait status. PMID- 27774350 TI - The Art of HIV Elimination: Past and Present Science. AB - INTRODUCTION: Remarkable strides have been made in controlling the HIV epidemic, although not enough to achieve epidemic control. More recently, interest in biomedical HIV control approaches has increased, but substantial challenges with the HIV cascade of care hinder successful implementation. We summarise all available HIV prevention methods and make recommendations on how to address current challenges. DISCUSSION: In the early days of the epidemic, behavioural approaches to control the HIV dominated, and the few available evidence-based interventions demonstrated to reduce HIV transmission were applied independently from one another. More recently, it has become clear that combination prevention strategies targeted to high transmission geographies and people at most risk of infections are required to achieve epidemic control. Biomedical strategies such as male medical circumcision and antiretroviral therapy for treatment in HIV positive individuals and as pre-exposure prophylaxis in HIV-negative individuals provide immense promise for the future of HIV control. In resource-rich settings, the threat of HIV treatment optimism resulting in increased sexual risk taking has been observed and there are concerns that as ART roll-out matures in resource poor settings and the benefits of ART become clearly visible, behavioural disinhibition may also become a challenge in those settings. Unfortunately, an efficacious vaccine, a strategy which could potentially halt the HIV epidemic, remains elusive. CONCLUSION: Combination HIV prevention offers a logical approach to HIV control, although what and how the available options should be combined is contextual. Therefore, knowledge of the local or national drivers of HIV infection is paramount. Problems with the HIV care continuum remain of concern, hindering progress towards the UNAIDS target of 90-90-90 by 2020. Research is needed on combination interventions that address all the steps of the cascade as the steps are not independent of each other. Until these issues are addressed, HIV elimination may remain an unattainable goal. PMID- 27774353 TI - Stratification, Hypothesis Testing, and Clinical Trial Simulation in Pediatric Drug Development. AB - BACKGROUND: Pediatric drug development is plagued by small sample sizes, unvalidated clinical endpoints, and limited studies. OBJECTIVES: The objective of this study was to determine whether age stratification within the pediatric population could be used to (1) assess response to a pharmacologic intervention and to (2) design future trials based upon published stratified disease data using clinical trial simulation (CTS). METHODS: Data available from the literature for Kawasaki disease (KD) was used in the model. Age-stratified CTS for a theoretical new drug was conducted. RESULTS: Population-specific differences due to age might affect trial success if not taken into account. CTS predicted inflammatory indices, and inclusion cutoff significantly altered the trial outcome. Finally, altered pharmacokinetics/pharmacodynamics in varying age groups of KD patients may alter drug exposure and response. CONCLUSIONS: If assumptions regarding a pediatric disease process, such as KD, do not include age stratification with inclusion or response, then the wrong decision could result with regard to age-appropriateness or approval of a drug. PMID- 27774354 TI - Smoke Inhalation in a Rural Emergency Setting: A Simulation Session. AB - Smoke inhalation-associated lung injuries (SI-ALI) present multiple challenges to the rural emergency department, and they require timely and appropriate management to prevent significant mortality and morbidity. In this report, we outline an adaptable simulation of an SI-ALI patient that is designed for use in a rural emergency department. The aim of this simulation is to better equip clinicians and emergency department staff who may encounter SI-ALI in rural settings. The case is suitable for resident doctors and emergency department staff. PMID- 27774355 TI - Herpes Simplex Encephalitis of the Parietal Lobe: A Rare Presentation. AB - A 69-year-old female with a history of breast cancer and hypertension presented with a rare case of herpes simplex encephalitis (HSE) isolated to her left parietal lobe. The patient's first biopsy was negative for herpes simplex virus (HSV) I/II antigens, but less than two weeks later, the patient tested positive on repeat biopsy. This initial failure to detect the virus and the similarities between HSE and symptoms of intracranial hemorrhage (ICH) suggests repeat testing for HSV in the presence of ICH. Due to the frequency of patients with extra temporal HSE, a diagnosis of HSE should be more readily considered, particularly when a patient may not be improving and a concrete diagnosis has not been solidified. PMID- 27774357 TI - Predictors of Prolonged Hospitalization in Patients with Fever. AB - OBJECTIVE: The study was conducted to analyze the predictors of prolonged hospitalization in patients with fever. PATIENTS AND METHODS: This was a prospective cohort study conducted from July - December 2015 at Ayub Teaching Hospital, Pakistan. Convenience sampling was used to enroll the patients who visited the hospital during the study duration. A sample size of 115 patients was calculated. It included patients who presented with a new onset fever which started in the last month, and the cause of fever was undiagnosed at the time of admission. Critical patients were excluded. Data for more than 30 variables was collected on a pro forma. Univariate regression methods were used to analyze the data in the Statistical Package for Social Sciences (SPSS), version 23. RESULTS: A total of 115 patients were analyzed. Males constituted 66/115 (57.4%). The mean age for patients was 43.6 years (standard deviation (SD) = 20.2). On admission, low platelet counts (p = 0.001), high erythrocyte sedimentation rate (ESR) counts (p = 0.007), a high total leukocyte count (TLC) (p = 0.029), and involvement of nervous (p = 0.021), cardiovascular (p = 0.04), respiratory (p = 0.043), gastroenterological (p = 0.042), hematological (p = 0.028), or urogenital system (p = 0.016) were associated with a longer stay in the hospital. CONCLUSION: Patients with an undiagnosed and new onset fever will have a longer hospital stay if, on admission, they have low platelet counts, a higher ESR, a high TLC, or involvement of nervous, cardiovascular, respiratory, gastrointestinal, hematological, or urogenital systems. An early identification of risk factors can lead to better treatment and may also lead to a decreased hospital stay. PMID- 27774356 TI - Ewing Sarcoma of the Pelvis with an Atypical Radiographic Appearance: A Mimicker of Non-malignant Etiologies. AB - Ewing sarcoma (ES) is a primary malignant bone tumor which most commonly arises in children and young adults. The common clinical presentation with ES includes nighttime pain or pain related to activity, though patients may also present with a combination of localized swelling, a palpable mass, pathologic fracture, and constitutional symptoms. Clinical diagnosis may be delayed when a patient presents with clinical or imaging findings that overlap with non-malignant etiologies, such as fibrous dysplasia (FD) or osteomyelitis. Furthermore, multimodality imaging, including computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine may prove inconclusive in particular cases. Suspicion for malignancy should not be overlooked. A biopsy must be considered, unless the diagnosis is evident, such as a clinical response to antibiotics in the setting of osteomyelitis. PMID- 27774358 TI - Resuscitation of the Newborn: Simulating for Confidence. AB - INTRODUCTION: Non-pediatric trainees working in pediatrics in the UK are expected to attend newborn deliveries and provide initial newborn life support if needed. In Swindon, new junior doctors receive a 90-minute teaching session at the start of their pediatrics rotation, but the content has not previously been standardized, and it may be several weeks before a doctor attends a newborn delivery. Thus, the confidence and competence in newborn resuscitation of doctors attending deliveries can vastly vary. METHODS: A standardized teaching package was developed as part of the pediatrics induction program. This includes an interactive lecture on the physiology of the newborn, skills stations, and mini simulations to consolidate skills. This is accompanied by a program of regular neonatal mini-simulations as part of the departmental morning teaching program. These sessions allow junior doctors to practice their skills in a safe, simulated environment and reinforce the newborn life support pathway. RESULTS: Qualitative and quantitative feedback was sought following delivery of the induction training session. Junior doctors were asked to rate their confidence before and after the induction session using Likert scales from 1 (least confident) to 5 (most confident). Median confidence in attending term deliveries increased from 2 (range 1 - 4) to 4 (2 - 5), P=0.008. There was evidence that confidence was maintained at one month following induction. CONCLUSIONS: A simulation program has been successful at improving confidence among junior doctors in attending newborn deliveries. This has the potential to improve patient care and trainees' experiences of their pediatrics placement. PMID- 27774359 TI - Technical Report of Successful Deployment of Tandem Visual Tracking During Live Laparoscopic Cholecystectomy Between Novice and Expert Surgeon. AB - With the recent advances in eye tracking technology, it is now possible to track surgeons' eye movements while engaged in a surgical task or when surgical residents practice their surgical skills. Several studies have compared eye movements of surgical experts and novices and developed techniques to assess surgical skill on the basis of eye movement utilizing simulators and live surgery. None have evaluated simultaneous visual tracking between an expert and a novice during live surgery. Here, we describe a successful simultaneous deployment of visual tracking of an expert and a novice during live laparoscopic cholecystectomy. One expert surgeon and one chief surgical resident at an accredited surgical program in Lubbock, TX, USA performed a live laparoscopic cholecystectomy while simultaneously wearing the visual tracking devices. Their visual attitudes and movements were monitored via video recordings. The recordings were then analyzed for correlation between the expert and the novice. The visual attitudes and movements correlated approximately 85% between an expert surgeon and a chief surgical resident. The surgery was carried out uneventfully, and the data was abstracted with ease. We conclude that simultaneous deployment of visual tracking during live laparoscopic surgery is a possibility. More studies and subjects are needed to verify the success of our results and obtain data analysis. PMID- 27774360 TI - An Analysis of Scalp Thickness and Other Novel Risk Factors for Deep Brain Stimulator Infections. AB - INTRODUCTION: Deep brain stimulator (DBS) infections are a persistent problem for patients undergoing this procedure. They may require further surgery, treatment with antibiotics, or even removal of the device. To date, no consensus exists on the best practices to avoid DBS infections or what factors predispose patients to an eventual infection. The goal of this study was to examine several patient factors for association with DBS infection. METHODS: A single-center, single-surgeon quality improvement database was queried. All patients who experienced an infection were identified. The primary variable analyzed was scalp thickness. Other pre-specified, secondary variables included routine intraoperative cultures, operative time, diagnosis, and age. RESULTS: None of the independent variables examined were significantly associated with DBS infections. Only two of the 46 infections qualified as surgical site infections as defined by the Centers for Disease Control. CONCLUSION: DBS infections are independent of all of the predictor variables analyzed. Surgical site infections, according to traditional definitions, are not the optimal definition for evaluating DBS infections/erosions. New studies must examine new variables that are not routinely gathered in this population. Also, because of the rare event rates and difficulty in randomizing patients to exposures, a large, multicenter registry may be the optimal study design to solve this clinical problem. PMID- 27774361 TI - Application of the Harms Technique to Treat Undiagnosed Intractable C1-C2 Unilateral Neck Pain: A Case Report. AB - A 79-year-old female presented with incapacitating chronic neck pain. The patient's pain which was greatest on the left side persisted for 18 months and was described as stabbing in nature (10/10 intensity). In addition to her neck pain, the patient described having frequent headaches. After six weeks of physical therapy and undergoing a rhizotomy procedure, she showed no prolonged improvement. An epidural steroid injection provided only temporary pain relief and was followed by a successful posterior fusion using the Harms technique with iliac crest autogenous bone grafting and placement of polyaxial screws in the C1 lateral masses and C2 pedicles. At the one-year follow-up the patient reported no pain or complaints. In general, C1-C2 arthrodesis is a surgical challenge due to the proximity of neurovascular structures (vertebral arteries and spinal cord) and wide range of the joint motion. The Harms technique is one of many techniques developed to reduce anatomical risk and improve results related to biomechanical stability and fusion rates. PMID- 27774362 TI - A Rare Location of a Neuroendocrine Tumor. AB - Neuroendocrine tumors (NETs) arising in the duodenum are rare neoplasms that are often classified as indolent and have a low potential to metastasize. Although rare, multiple reports cite an increasing incidence of duodenal NETs. Symptoms are usually nonspecific and the diagnosis is made via endoscopy. Endoscopic resection is the mainstay of therapy. The prognosis is usually favorable. We describe a case of a duodenal NET that presented with vague symptoms in order to increase the awareness of this rare but increasing in frequency entity. PMID- 27774363 TI - Extracranial Facial Nerve Schwannoma Treated by Hypo-fractionated CyberKnife Radiosurgery. AB - Facial nerve schwannoma is a rare intracranial tumor. Treatment for this benign tumor has been controversial. Here, we report a case of extracranial facial nerve schwannoma treated successfully by hypo-fractionated CyberKnife (Accuray, Sunnyvale, CA) radiosurgery and discuss the efficacy of this treatment. A 34-year old female noticed a swelling in her right mastoid process. The lesion enlarged over a seven-month period, and she experienced facial spasm on the right side. She was diagnosed with a facial schwannoma via a magnetic resonance imaging (MRI) scan of the head and neck and was told to wait until the facial nerve palsy subsides. She was referred to our hospital for radiation therapy. We planned a fractionated CyberKnife radiosurgery for three consecutive days. After CyberKnife radiosurgery, the mass in the right parotid gradually decreased in size, and the facial nerve palsy disappeared. At her eight-month follow-up, her facial spasm had completely disappeared. There has been no recurrence and the facial nerve function has been normal. We successfully demonstrated the efficacy of CyberKnife radiosurgery as an alternative treatment that also preserves neurofunction for facial nerve schwannomas. PMID- 27774364 TI - Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5 Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism. AB - 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50 year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5'TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor. PMID- 27774365 TI - Quantitative Analysis of Metabolic Abnormality Associated with Brain Developmental Venous Anomalies. AB - BACKGROUND AND PURPOSE: Abnormal hypometabolism is common in the brain parenchyma surrounding developmental venous anomalies (DVAs), although the degree of DVA associated hypometabolism (DVAAh) has not been quantitatively analyzed. In this study, we demonstrate a simple method for the measurement of DVAAh and test the hypothesis that DVAs are associated with a quantifiable decrement in metabolic activity. MATERIALS AND METHODS: Measurements of DVAAh using ratios of standardized uptake values (SUVs) and comparison to a normal database were performed on a cohort of 25 patients (12 male, 13 female), 14 to 76 years old, with a total of 28 DVAs (20 with DVAAh, seven with isometabolic activity, and one with hypermetabolic activity). RESULTS: Qualitative classification of none, mild, moderate, and severe DVAAh corresponded to quantitative measurements of DVAAh of 1 +/- 3%, 12 +/- 7%, 18 +/- 6%, and 37 +/- 6%, respectively. A statistically significant linear correlation between DVAAh and age was observed (P = 0.003), with a 3% reduction in metabolic activity per decade. A statistically significant linear correlation between DVAAh and DVA size was observed (P = 0.01), with a 4% reduction in metabolic activity per each 1 cm in the longest dimension. The SUVDVA-based measures of DVAAh correlated (P = 0.001) with measures derived from comparison with a standardized database. CONCLUSION: We present a simple method for the quantitative measurement of DVAAh using ratios of SUVs, and find that this quantitative analysis is consistent with a qualitative classification. We find that 54% (15 of 28) of DVAs are associated with a greater than 10% decrease in metabolic activity. PMID- 27774367 TI - Short-term favorable weather conditions are an important control of interannual variability in carbon and water fluxes. AB - Ecosystem models often perform poorly in reproducing interannual variability in carbon and water fluxes, resulting in considerable uncertainty when estimating the land-carbon sink. While many aggregated variables (growing season length, seasonal precipitation, or temperature) have been suggested as predictors for interannual variability in carbon fluxes, their explanatory power is limited and uncertainties remain as to their relative contributions. Recent results show that the annual count of hours where evapotranspiration (ET) is larger than its 95th percentile is strongly correlated with the annual variability of ET and gross primary production (GPP) in an ecosystem model. This suggests that the occurrence of favorable conditions has a strong influence on the annual carbon budget. Here we analyzed data from eight forest sites of the AmeriFlux network with at least 7 years of continuous measurements. We show that for ET and the carbon fluxes GPP, ecosystem respiration (RE), and net ecosystem production, counting the "most active hours/days" (i.e., hours/days when the flux exceeds a high percentile) correlates well with the respective annual sums, with correlation coefficients generally larger than 0.8. Phenological transitions have much weaker explanatory power. By exploiting the relationship between most active hours and interannual variability, we classify hours as most active or less active and largely explain interannual variability in ecosystem fluxes, particularly for GPP and RE. Our results suggest that a better understanding and modeling of the occurrence of large values in high-frequency ecosystem fluxes will result in a better understanding of interannual variability of these fluxes. PMID- 27774366 TI - Differential Response of Human Embryonic Stem and Somatic Cells to Non-Cytotoxic Hydrogen Peroxide Exposure: An Attempt to Model In Vitro the Effects of Oxidative Stress on the Early Embryo. AB - Human Embryonic Stem Cells (hESCs) potentially offer a unique in vitro model to study how an adverse environment during the early developmental stages post fertilization can affect the physiology of the undifferentiated embryonic stem cells existing in the early embryo and predispose to long term effects on the offspring, according to the Developmental Origins of Health and Disease (DOHaD) concept. A number of unfavourable conditions can affect the development of the early embryo inducing oxidative stress both in vivo, for instance in gestational diabetes and in vitro, when embryos are derived from Assisted Reproductive Technologies (ART). Therefore, the aim of this study was the development of a novel in vitro model to analyse the effects of oxidative stress and the antioxidant response against Reactive Oxygen Species (ROS) in embryonic stem cells in comparison with somatic cells, fibroblasts and endothelial cells. To this purpose we designed an in vitro protocol based on hydrogen peroxide (H2O2) treatment of 72 h, in order to better resemble the period of embryonic development from the early cleavages to the blastocyst stage. We demonstrate that H2O2 treatment induces the modification of crucial oxidative stress biomarkers like ROS and lipid peroxidation levels, and mobilizes several antioxidant enzymes through NFkbeta translocation. Moreover we show differences between somatic and embryonic cells in their antioxidant response towards H2O2 induced damage. Therefore this study presents a promising in vitro model to investigate the effects of oxidative stress conditions on early human embryonic cells. PMID- 27774368 TI - Radio emissions from double RHESSI TGFs. AB - A detailed analysis of Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) terrestrial gamma ray flashes (TGFs) is performed in association with World Wide Lightning Location Network (WWLLN) sources and very low frequency (VLF) sferics recorded at Duke University. RHESSI clock offset is evaluated and found to experience changes on the 5 August 2005 and 21 October 2013, based on the analysis of TGF-WWLLN matches. The clock offsets were found for all three periods of observations with standard deviations less than 100 MUs. This result opens the possibility for the precise comparative analyses of RHESSI TGFs with the other types of data (WWLLN, radio measurements, etc.) In case of multiple peak TGFs, WWLLN detections are observed to be simultaneous with the last TGF peak for all 16 cases of multipeak RHESSI TGFs simultaneous with WWLLN sources. VLF magnetic field sferics were recorded for two of these 16 events at Duke University. These radio measurements also attribute VLF sferics to the second peak of the double TGFs, exhibiting no detectable radio emission during the first TGF peak. Possible scenarios explaining these observations are proposed. Double (multipeak) TGFs could help to distinguish between the VLF radio emission radiated by the recoil currents in the +IC leader channel and the VLF emission from the TGF producing electrons. PMID- 27774369 TI - Perchlorate formation on Mars through surface radiolysis-initiated atmospheric chemistry: A potential mechanism. AB - Recent observations of the Martian surface by the Phoenix lander and the Sample Analysis at Mars indicate the presence of perchlorate (ClO4-). The abundance and isotopic composition of these perchlorates suggest that the mechanisms responsible for their formation in the Martian environment may be unique in our solar system. With this in mind, we propose a potential mechanism for the production of Martian perchlorate: the radiolysis of the Martian surface by galactic cosmic rays, followed by the sublimation of chlorine oxides into the atmosphere and their subsequent synthesis to form perchloric acid (HClO4) in the atmosphere, and the surface deposition and subsequent mineralization of HClO4 in the regolith to form surface perchlorates. To evaluate the viability of this mechanism, we employ a one-dimensional chemical model, examining chlorine chemistry in the context of Martian atmospheric chemistry. Considering the chlorine oxide, OClO, we find that an OClO flux as low as 3.2 * 107 molecules cm 2 s-1 sublimated into the atmosphere from the surface could produce sufficient HClO4 to explain the perchlorate concentration on Mars, assuming an accumulation depth of 30 cm and integrated over the Amazonian period. Radiolysis provides an efficient pathway for the oxidation of chlorine, bypassing the efficient Cl/HCl recycling mechanism that characterizes HClO4 formation mechanisms proposed for the Earth but not Mars. PMID- 27774370 TI - Natural and unnatural oil slicks in the Gulf of Mexico. AB - When wind speeds are 2-10 m s-1, reflective contrasts in the ocean surface make oil slicks visible to synthetic aperture radar (SAR) under all sky conditions. Neural network analysis of satellite SAR images quantified the magnitude and distribution of surface oil in the Gulf of Mexico from persistent, natural seeps and from the Deepwater Horizon (DWH) discharge. This analysis identified 914 natural oil seep zones across the entire Gulf of Mexico in pre-2010 data. Their ~0.1 um slicks covered an aggregated average of 775 km2. Assuming an average volume of 77.5 m3 over an 8-24 h lifespan per oil slick, the floating oil indicates a surface flux of 2.5-9.4 * 104 m3 yr-1. Oil from natural slicks was regionally concentrated: 68%, 25%, 7%, and <1% of the total was observed in the NW, SW, NE, and SE Gulf, respectively. This reflects differences in basin history and hydrocarbon generation. SAR images from 2010 showed that the 87 day DWH discharge produced a surface-oil footprint fundamentally different from background seepage, with an average ocean area of 11,200 km2 (SD 5028) and a volume of 22,600 m3 (SD 5411). Peak magnitudes of oil were detected during equivalent, ~14 day intervals around 23 May and 18 June, when wind speeds remained <5 m s-1. Over this interval, aggregated volume of floating oil decreased by 21%; area covered increased by 49% (p < 0.1), potentially altering its ecological impact. The most likely causes were increased applications of dispersant and surface burning operations. PMID- 27774372 TI - The 27 day solar rotational effect on mesospheric nighttime OH and O3 observations induced by geomagnetic activity. AB - Observations performed by the Earth Observing System Microwave Limb Sounder instrument on board the Aura satellite from 2004 to 2009 (2004 to 2014) were used to investigate the 27 day solar rotational cycle in mesospheric OH (O3) and the physical connection to geomagnetic activity. Data analysis was focused on nighttime measurements at geomagnetic latitudes connected to the outer radiation belts (55 degrees N/S-75 degrees N/S). The applied superposed epoch analysis reveals a distinct 27 day solar rotational signal in OH and O3 during winter in both hemispheres at altitudes >70 km. The OH response is positive and in-phase with the respective geomagnetic activity signal, lasting for 1-2 days. In contrast, the O3 feedback is negative, delayed by 1 day, and is present up to 4 days afterward. Largest OH (O3) peaks are found at ~75 km, exceeding the 95% significance level and the measurement noise of <2% (<0.5%), while reaching variations of +14% (-7%) with respect to their corresponding background. OH at 75 km is observed to respond to particle precipitation only after a certain threshold of geomagnetic activity is exceeded, depending on the respective OH background. The relation between OH and O3 at 75 km in both hemispheres is found to be nonlinear. In particular, OH has a strong impact on O3 for relatively weak geomagnetic disturbances and accompanying small absolute OH variations (<0.04 ppb). In contrast, catalytic O3 depletion is seen to slow down for stronger geomagnetic variations and OH anomalies (0.04-0.13 ppb), revealing small variations around -0.11 ppm. PMID- 27774371 TI - Turmoil at Turrialba Volcano (Costa Rica): Degassing and eruptive processes inferred from high-frequency gas monitoring. AB - Eruptive activity at Turrialba Volcano (Costa Rica) has escalated significantly since 2014, causing airport and school closures in the capital city of San Jose. Whether or not new magma is involved in the current unrest seems probable but remains a matter of debate as ash deposits are dominated by hydrothermal material. Here we use high-frequency gas monitoring to track the behavior of the volcano between 2014 and 2015 and to decipher magmatic versus hydrothermal contributions to the eruptions. Pulses of deeply derived CO2-rich gas (CO2/Stotal > 4.5) precede explosive activity, providing a clear precursor to eruptive periods that occurs up to 2 weeks before eruptions, which are accompanied by shallowly derived sulfur-rich magmatic gas emissions. Degassing modeling suggests that the deep magmatic reservoir is ~8-10 km deep, whereas the shallow magmatic gas source is at ~3-5 km. Two cycles of degassing and eruption are observed, each attributed to pulses of magma ascending through the deep reservoir to shallow crustal levels. The magmatic degassing signals were overprinted by a fluid contribution from the shallow hydrothermal system, modifying the gas compositions, contributing volatiles to the emissions, and reflecting complex processes of scrubbing, displacement, and volatilization. H2S/SO2 varies over 2 orders of magnitude through the monitoring period and demonstrates that the first eruptive episode involved hydrothermal gases, whereas the second did not. Massive degassing (>3000 T/d SO2 and H2S/SO2 > 1) followed, suggesting boiling off of the hydrothermal system. The gas emissions show a remarkable shift to purely magmatic composition (H2S/SO2 < 0.05) during the second eruptive period, reflecting the depletion of the hydrothermal system or the establishment of high-temperature conduits bypassing remnant hydrothermal reservoirs, and the transition from phreatic to phreatomagmatic eruptive activity. PMID- 27774373 TI - Miniature atomic scalar magnetometer for space based on the rubidium isotope 87Rb. AB - A miniature atomic scalar magnetometer based on the rubidium isotope 87Rb was developed for operation in space. The instrument design implements both Mx and Mz mode operation and leverages a novel microelectromechanical system (MEMS) fabricated vapor cell and a custom silicon-on-sapphire (SOS) complementary metal oxide-semiconductor (CMOS) integrated circuit. The vapor cell has a volume of only 1 mm3 so that it can be efficiently heated to its operating temperature by a specially designed, low-magnetic-field-generating resistive heater implemented in multiple metal layers of the transparent sapphire substrate of the SOS-CMOS chips. The SOS-CMOS chip also hosts the Helmholtz coil and associated circuitry to stimulate the magnetically sensitive atomic resonance and temperature sensors. The prototype instrument has a total mass of fewer than 500 g and uses less than 1 W of power, while maintaining a sensitivity of 15 pT/?Hz at 1 Hz, comparable to present state-of-the-art absolute magnetometers. PMID- 27774374 TI - Magnetic Nanodrug Delivery Through the Mucus Layer of Air-Liquid Interface Cultured Primary Normal Human Tracheobronchial Epithelial Cells. AB - Superparamagnetic iron oxide (Fe3O4) and highly anisotropic barium hexaferrite (BaFe12O19) nanoparticles were coated with an anti-inflammatory drug and magnetically transported through mucus produced by primary human airway epithelial cells. Using wet planetary ball milling, dl-2-amino-3 phosphonopropionic acid-coated BaFe12O19 nano-particles (BaNPs) of 1-100 nm in diameter were prepared in water. BaNPs and conventional 20-30-nm Fe3O4 nanoparticles (FeNPs) were then encased in a polymer (PLGA) loaded with dexamethasone (Dex) and tagged for imaging. PLGA-Dex-coated BaNPs and FeNPs were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and superconducting quantum interference device (SQUID) magnetometry. Both PLGA-Dex-coated BaNPs and FeNPs were transferred to the surface of a ~100-MUm thick mucus layer of air-liquid interface cultured primary normal human tracheobronchial epithelial (NHTE) cells. Within 30 min, the nanoparticles were pulled successfully through the mucus layer by a permanent neodymium magnet. The penetration time of the nanomedicine was monitored using confocal microscopy and tailored by varying the thickness of the PLGA-Dex coating around the particles. PMID- 27774376 TI - Sungas Instead of Syngas: Efficient Coproduction of CO and H2 with a Single Beam of Sunlight. AB - The electrolytic coproduction of CO and H2 is achieved from air, water, and a single beam of sunlight rather than from fossil fuels. H2 and CO cosynthesis is driven by a single concentrator photovoltaic to simultaneously drive molten hydroxide and molten carbonate electrolyses. The carbon neutral process captures carbon without the need for the preconcentration of atmospheric carbon dioxide. PMID- 27774375 TI - Underwater Superoleophobic Surfaces Prepared from Polymer Zwitterion/Dopamine Composite Coatings. AB - Hydration is central to mitigating surface fouling by oil and microorganisms. Immobilization of hydrophilic polymers on surfaces promotes retention of water and a reduction of direct interactions with potential foulants. While conventional surface modification techniques are surface-specific, mussel inspired adhesives based on dopamine effectively coat many types of surfaces and thus hold potential as a universal solution to surface modification. Here, we describe a facile, one-step surface modification strategy that affords hydrophilic, and underwater superoleophobic, coatings by the simultaneous deposition of polydopamine (PDA) with poly(methacryloyloxyethyl phosphorylcholine) (polyMPC). The resultant composite coating features enhanced hydrophilicity (i.e., water contact angle of ~10 degrees in air) and antifouling performance relative to PDA coatings. PolyMPC affords control over coating thickness and surface roughness, and results in a nearly 10 fold reduction in Escherichia coli adhesion relative to unmodified glass. The substrate-independent nature of PDA coatings further promotes facile surface modification without tedious surface pretreatment, and offers a robust template for codepositing polyMPC to enhance biocompatibility, hydrophilicity and fouling resistance. PMID- 27774377 TI - Shifting the Sun: Solar Spectral Conversion and Extrinsic Sensitization in Natural and Artificial Photosynthesis. AB - Solar energy harvesting is largely limited by the spectral sensitivity of the employed energy conversion system, where usually large parts of the solar spectrum do not contribute to the harvesting scheme, and where, of the contributing fraction, the full potential of each photon is not efficiently used in the generation of electrical or chemical energy. Extrinsic sensitization through photoluminescent spectral conversion has been proposed as a route to at least partially overcome this problem. Here, we discuss this approach in the emerging context of photochemical energy harvesting and storage through natural or artificial photosynthesis. Clearly contrary to application in photovoltaic energy conversion, implementation of solar spectral conversion for extrinsic sensitization of a photosynthetic machinery is very straightforward, and-when compared to intrinsic sensitization-less-strict limitations with regard to quantum coherence are seen. We now argue the ways in which extrinsic sensitization through photoluminescent spectral converters will-and will not-play its role in the area of ultra-efficient photosynthesis, and also illustrate how such extrinsic sensitization requires dedicated selection of specific conversion schemes and design strategies on system scale. PMID- 27774378 TI - Mesoporous Li3VO4/C Submicron-Ellipsoids Supported on Reduced Graphene Oxide as Practical Anode for High-Power Lithium-Ion Batteries. AB - Despite the enormous efforts devoted to high-performance lithium-ion batteries (LIBs), the present state-of-the-art LIBs cannot meet the ever-increasing demands. With high theoretical capacity, fast ionic conductivity, and suitable charge/discharge plateaus, Li3VO4 shows great potential as the anode material for LIBs. However, it suffers from poor electronic conductivity. In this work, we present a novel composite material with mesoporous Li3VO4/C submicron-ellipsoids supported on rGO (LVO/C/rGO). The synthesized LVO/C/rGO exhibits a high reversible capacity (410 mAh g-1 at 0.25 C), excellent rate capability (230 mAh g 1 at 125 C), and outstanding long-cycle performance (82.5% capacity retention for 5000 cycles at 10 C). The impressive electrochemical performance reveals the great potential of the mesoporous LVO/C/rGO as a practical anode for high-power LIBs. PMID- 27774379 TI - Simulation Evidence of Hexagonal-to-Tetragonal ZnSe Structure Transition: A Monolayer Material with a Wide-Range Tunable Direct Bandgap. AB - 2D material with tunable direct bandgap in the intermediate region (i.e., ~2-3 eV) is key to the achievement of high efficiency in visible-light optical devices. Herein, a simulation evidence of structure transition of monolayer ZnSe from the experimental pseudohexagonal structure to the tetragonal structure (t ZnSe) under lateral pressure is shown, suggesting a possible fabrication route to achieve the t-ZnSe monolayer. The as-produced t-ZnSe monolayer exhibits highly tunable bandgap under the biaxial strains, allowing strain engineering of t ZnSe's bandgap over a wide range of 2-3 eV. Importantly, even under the biaxial strain up to 7%, the t-ZnSe monolayer still keeps its direct-gap property in the desirable range of 2.40-3.17 eV (corresponding to wavelength of green light to ultraviolet). The wide-range tunability of direct bandgap appears to be a unique property of the t-ZnSe monolayer, suggesting its potential application as a light emitting 2D material in red-green-blue light emission diodes or as complementary light-absorption material in the blue-yellow region for multijunction solar cells. The straddling of the band edge of the t-ZnSe monolayer over the redox potential of water splitting reaction also points to its plausible application for visible-light-driven water splitting. PMID- 27774380 TI - Propagating Surface Plasmon Polaritons: Towards Applications for Remote Excitation Surface Catalytic Reactions. AB - Plasmonics is a well-established field, exploiting the interaction of light and metals at the nanoscale; with the help of surface plasmon polaritons, remote excitation can also be observed by using silver or gold plasmonic waveguides. Recently, plasmonic catalysis was established as a new exciting platform for heterogeneous catalytic reactions. Recent reports present remote-excitation surface catalytic reactions as a route to enhance the rate of chemical reactions, and offer a pathway to control surface catalytic reactions. In this review, we focus on recent advanced reports on silver plasmonic waveguide for remote excitation surface catalytic reactions. First, the synthesis methods and characterization techniques of sivelr nanowire plasmonic waveguides are summarized, and the properties and physical mechanisms of plasmonic waveguides are presented in detail. Then, the applications of plasmonic waveguides including remote excitation fluorescence and SERS are introduced, and we focus on the field of remote-excitation surface catalytic reactions. Finally, forecasts are made for possible future applications for the remote-excitation surface catalysis by plasmonic waveguides in living cells. PMID- 27774382 TI - Efficient Charging of Li-Ion Batteries with Pulsed Output Current of Triboelectric Nanogenerators. AB - The triboelectric nanogenerator (TENG) is a promising mechanical energy harvesting technology, but its pulsed output and the instability of input energy sources make associated energy-storage devices necessary for real applications. In this work, feasible and efficient charging of Li-ion batteries by a rotating TENG with pulsed output current is demonstrated. In-depth discussions are made on how to maximize the power-storage efficiency by achieving an impedance match between the TENG and a battery with appropriate design of transformers. With a transformer coil ratio of 36.7, ~72.4% of the power generated by the TENG at 250 rpm can be stored in an LiFePO4-Li4Ti5O12 battery. Moreover, a 1 h charging of an LiCoO2-C battery by the TENG at 600 rpm delivers a discharge capacity of 130 mAh, capable of powering many smart electronics. Considering the readily scale-up capability of the TENG, promising applications in personal electronics can be anticipated in the near future. PMID- 27774381 TI - Metal-Organic Frameworks as Promising Photosensitizers for Photoelectrochemical Water Splitting. AB - Ti-based metal-organic frameworks (MOFs) are demonstrated as promising photosensitizers for photoelectrochemical (PEC) water splitting. Photocurrents of TiO2 nano wire photoelectrodes can be improved under visible light through sensitization with aminated Ti-based MOFs. As a host, other sensitizers or catalysts such as Au nanoparticles can be incorporated into the MOF layer thus further improving the PEC water splitting efficiency. PMID- 27774383 TI - Extremely Stable Current Emission of P-Doped SiC Flexible Field Emitters. AB - Novel P-doped SiC flexible field emitters are developed on carbon fabric substrates, having both low Eto of 1.03-0.73 VMUm-1 up to high temperatures of 673 K, and extremely high current emission stability when subjected to different bending states, bending circle times as well as high temperatures (current emission fluctuations are typically in the range +/-2.1%-3.4%). PMID- 27774384 TI - Janus Separator of Polypropylene-Supported Cellular Graphene Framework for Sulfur Cathodes with High Utilization in Lithium-Sulfur Batteries. AB - Owing to the conversion chemistry of the sulfur cathode, the lithium-sulfur (Li S) batteries exhibit high theoretical energy density. However, the intrinsic mobile redox centers during the sulfur/Li2S-to-lithium polysulfides solid-to liquid phase transition induce low sulfur utilization and poor cycling life. Herein, the Janus separator of mesoporous cellular graphene framework (CGF)/polypropylene membrane to promote the utilization of sulfur cathode is introduced. The porous polypropylene membrane serves as an insulating substrate in contact with lithium anode while CGFs that possess high electrical conductivity of 100 S cm-1, a large mesopore volume of 3.1 cm3 g-1, and a huge surface area of 2120 m2 g-1 are adhered on cathode side to reactivate the shuttling-back polysulfides and to preserve the ion channels. Therefore, the Li-S cell with the "two-face" CGF Janus separator exhibit a high initial capacity of 1109 mAh g-1 and superior capacity preserved upon 800 mAh g-1 after 250 cycles at 0.2 C, which is 40% higher on sulfur utilization efficiency than the corresponding results with routine polypropylene separators. There are significant improvements on capacity as well as electrochemical kinetics. A very high areal capacity of 5.5 mAh cm-2 combined with high sulfur content of 80% and areal loading amount of 5.3 mg cm-2 is achieved for such advanced configuration. The negative impact of shuttle mechanism on lowering the utilization of sulfur and overall energy density of a Li-S battery is well eliminated by applying CGF separators. Consequently, employing carbonaceous materials as Janus face of separators enlightens new opportunities for improving the utilization of active materials and energy density of devices that involve complex phase evolution and conversion electrochemistry. PMID- 27774385 TI - Self-Regulative Nanogelator Solid Electrolyte: A New Option to Improve the Safety of Lithium Battery. AB - The lack of suitable nonflammable electrolytes has delayed battery application in electric vehicles. A new approach to improve the safety performance for lithium battery is proposed here. This technology is based on a nanogelator-based solid electrolyte made of porous oxides and an ionic liquid. The electrolyte is fabricated using an in situ method and the porous oxides serve as a nonflammable "nanogelator" that spontaneously immobilizes the ionic liquid. The electrolyte exhibits a high liquid-like apparent ionic conductivity of 2.93 * 10-3 S cm-1 at room temperature. The results show that the nanogelator, which possess self regulating ability, is able to immobilize imidazolium-, pyrrolidinium-, or piperidinium-based ionic liquids, simply by adjusting the ion transport channels. Our prototype batteries made of Ti-nanogeltor solid electrolyte outperform conventional lithium batteries made using ionic liquid and commercial organic liquid electrolytes. PMID- 27774386 TI - Redox-Reversible Iron Orthovanadate Cathode for Solid Oxide Steam Electrolyzer. AB - A redox-reversible iron orthovanadate cathode is demonstrated for a solid oxide electrolyser with up to 100% current efficiency for steam electrolysis. The iron catalyst is grown on spinel-type electronic conductor FeV2O4 by in situ tailoring the reversible phase change of FeVO4 to Fe+FeV2O4 in a reducing atmosphere. Promising electrode performances have been obtained for a solid oxide steam electrolyser based on this composite cathode. PMID- 27774387 TI - Co-doping Strategy for Developing Perovskite Oxides as Highly Efficient Electrocatalysts for Oxygen Evolution Reaction. AB - A synergistic co-doping strategy is proposed to identify a series of BaCo0.9-x Fe x Sn0.1O3-delta perovskites with tunable electrocatalytic activity for the oxygen evolution reaction (OER). Simply through tailoring the relative concentrations of less OER-active tin and iron dopants, a cubic perovskite structure (BaCo0.7Fe0.2Sn0.1O3-delta) is stabilized, showing intrinsic OER activity >1 order of magnitude larger than IrO2 and a Tafel slope of 69 mV dec-1. PMID- 27774388 TI - A Nanosystem Capable of Releasing a Photosensitizer Bioprecursor under Two-Photon Irradiation for Photodynamic Therapy. AB - The applications of photodynamic therapy (PDT) are usually limited by photosensitizers' side effects and singlet oxygen's short half-life. Herein, a mitochondria-targeted nanosystem is demonstrated to enhance the PDT efficacy by releasing a bio-precursor of photosensitizer under two-photon irradiation. A phototriggerable coumarin derivative is first synthesized by linking 5 aminolevulinic acid (5-ALA, the bio-precursor) to coumarin; and the nanosystem (CD-ALA-TPP) is then fabricated by covalently incorporating this coumarin derivative and a mitochondria-targeting compound triphenylphosphonium (TPP) onto carbon dots (CDs). Upon cellular internalization, the nanosystem preferentially accumulates in mitochondria; and under one- or two-photon irradiation, it releases 5-ALA molecules that are then metabolized into protoporphyrin IX in mitochondria through a series of biosynthesis processes. The subsequent red light irradiation induces this endogenously synthesized photosensitizer to generate singlet oxygen, thereby causing oxidant damage to mitochondria and then the apoptosis of the cells. Analysis via 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyltetrazolium bromide (MTT) assays indicate that the novel PDT system exhibits enhanced cytotoxicity toward cancer cells. This study may offer a new strategy for designing PDT systems with high efficacy and low side effects. PMID- 27774389 TI - Novel Piezoelectric Paper-Based Flexible Nanogenerators Composed of BaTiO3 Nanoparticles and Bacterial Cellulose. AB - A piezoelectric paper based on BaTiO3 (BTO) nanoparticles and bacterial cellulose (BC) with excellent output properties for application of nanogenerators (NGs) is reported. A facile and scalable vacuum filtration method is used to fabricate the piezoelectric paper. The BTO/BC piezoelectric paper based NG shows outstanding output performance with open-circuit voltage of 14 V and short-circuit current density of 190 nA cm-2. The maximum power density generated by this unique BTO/BC structure is more than ten times higher than BTO/polydimethylsiloxane structure. In bending conditions, the NG device can generate output voltage of 1.5 V, which is capable of driving a liquid crystal display screen. The improved performance can be ascribed to homogeneous distribution of piezoelectric BTO nanoparticles in the BC matrix as well as the enhanced stress on piezoelectric nanoparticles implemented by the unique percolated networks of BC nanofibers. The flexible BTO/BC piezoelectric paper based NG is lightweight, eco-friendly, and cost effective, which holds great promises for achieving wearable or implantable energy harvesters and self-powered electronics. PMID- 27774390 TI - Exceptionally Stable CH3NH3PbI3 Films in Moderate Humid Environmental Condition. AB - An unprecedentedly stable CH3NH3PbI3 film synthesized by a modified chemical vapor transport method is demonstrated. The results show that the crystal structure, light absorption, and device efficiency do not degrade after storing for 100 d in air with 40% relative humidity, while the conventional solution processed perovskites are usually stable for less than 20 d in similar conditions. PMID- 27774391 TI - Metal-Organic-Framework-Derived Dual Metal- and Nitrogen-Doped Carbon as Efficient and Robust Oxygen Reduction Reaction Catalysts for Microbial Fuel Cells. AB - A new class of dual metal and N doped carbon catalysts with well-defined porous structure derived from metal-organic frameworks (MOFs) has been developed as a high-performance electrocatalyst for oxygen reduction reaction (ORR). Furthermore, the microbial fuel cell (MFC) device based on the as-prepared Ni/Co and N codoped carbon as air cathode catalyst achieves a maximum power density of 4335.6 mW m-2 and excellent durability. PMID- 27774392 TI - An Organic Mixed Ion-Electron Conductor for Power Electronics. AB - A mixed ionic-electronic conductor based on nanofibrillated cellulose composited with poly(3,4-ethylene-dioxythio-phene):-poly(styrene-sulfonate) along with high boiling point solvents is demonstrated in bulky electrochemical devices. The high electronic and ionic conductivities of the resulting nanopaper are exploited in devices which exhibit record values for the charge storage capacitance (1F) in supercapacitors and transconductance (1S) in electrochemical transistors. PMID- 27774393 TI - A Review of Solid Electrolyte Interphases on Lithium Metal Anode. AB - Lithium metal batteries (LMBs) are among the most promising candidates of high energy-density devices for advanced energy storage. However, the growth of dendrites greatly hinders the practical applications of LMBs in portable electronics and electric vehicles. Constructing stable and efficient solid electrolyte interphase (SEI) is among the most effective strategies to inhibit the dendrite growth and thus to achieve a superior cycling performance. In this review, the mechanisms of SEI formation and models of SEI structure are briefly summarized. The analysis methods to probe the surface chemistry, surface morphology, electrochemical property, dynamic characteristics of SEI layer are emphasized. The critical factors affecting the SEI formation, such as electrolyte component, temperature, current density, are comprehensively debated. The efficient methods to modify SEI layer with the introduction of new electrolyte system and additives, ex-situ-formed protective layer, as well as electrode design, are summarized. Although these works afford new insights into SEI research, robust and precise routes for SEI modification with well-designed structure, as well as understanding of the connection between structure and electrochemical performance, is still inadequate. A multidisciplinary approach is highly required to enable the formation of robust SEI for highly efficient energy storage systems. PMID- 27774394 TI - A Targeted "Capture" and "Removal" Scavenger toward Multiple Pollutants for Water Remediation based on Molecular Recognition. AB - For the water remediation techniques based on adsorption, the long-standing contradictories between selectivity and multiple adsorbability, as well as between affinity and recyclability, have put it on weak defense amid more and more severe environment crisis. Here, a pollutant-targeting hydrogel scavenger is reported for water remediation with both high selectivity and multiple adsorbability for several pollutants, and with strong affinity and good recyclability through rationally integrating the advantages of multiple functional materials. In the scavenger, aptamers fold into binding pockets to accommodate the molecular structure of pollutants to afford perfect selectivity, and Janus nanoparticles with antibacterial function as well as anisotropic surfaces to immobilize multiple aptamers allow for simultaneously handling different kinds of pollutants. The scavenger exhibits high efficiencies in removing pollutants from water and it can be easily recycled for many times without significant loss of loading capacities. Moreover, the residual concentrations of each contaminant are well below the drinking water standards. Thermodynamic behavior of the adsorption process is investigated and the rate controlling process is determined. Furthermore, a point of use device is constructed and it displays high efficiency in removing pollutants from environmental water. The scavenger exhibits great promise to be applied in the next generation of water purification systems. PMID- 27774395 TI - Fast-Rate Capable Electrode Material with Higher Energy Density than LiFePO4: 4.2V LiVPO4F Synthesized by Scalable Single-Step Solid-State Reaction. AB - Use of compounds that contain fluorine (F) as electrode materials in lithium ion batteries has been considered, but synthesizing single-phase samples of these compounds is a difficult task. Here, it is demonstrated that a simple scalable single-step solid-state process with additional fluorine source can obtain highly pure LiVPO4F. The resulting material with submicron particles achieves very high rate capability ~100 mAh g-1 at 60 C-rate (1-min discharge) and even at 200 C rate (18 s discharge). It retains superior capacity, ~120 mAh g-1 at 10 C charge/10 C discharge rate (6-min) for 500 cycles with >95% retention efficiency. Furthermore, LiVPO4F shows low polarization even at high rates leading to higher operating potential >3.45 V (~3.6 V at 60 C-rate), so it achieves high energy density. It is demonstrated for the first time that highly pure LiVPO4F can achieve high power capability comparable to LiFePO4 and much higher energy density (~521 Wh g-1 at 20 C-rate) than LiFePO4 even without nanostructured particles. LiVPO4F can be a real substitute of LiFePO4. PMID- 27774396 TI - Calix-Like Metal-Organic Complex for High-Sensitivity X-Ray-Induced Photochromism. AB - Metal-organic complexes (MOCs) as promising candidates for directly visual X-ray detection at room temperature are rare and discovered unexpectedly, even though every crystalline material needs X-ray diffraction studies. Here, we report a rational strategy of mimicking host-guest system for developing high-sensitive X ray-induced photochromic materials. Two resulting calix-like metal-organic complexes (cMOC-1 and cMOC-2) were prepared by encapsulating the electron capturing "guest" into the cavity of calix-like electron-donating "host." One of them (cMOC-1) achieves instantaneous X-ray-induced photochromism and easy recovery by synergizing the aprotic matrix of MOC and similar host-guest interaction. Their strikingly different response to X-ray irradiation resulting from the structural difference demonstrates the feasibility and acceptability of our design strategy. This strategy may open new perspectives for developing high performance photo-responsive functional materials. PMID- 27774397 TI - RhCu 3D Nanoframe as a Highly Active Electrocatalyst for Oxygen Evolution Reaction under Alkaline Condition. AB - One pot synthesis of RhCu alloy truncated octahedral nanoframes, Cu@Rh core-shell nanoparticles, and a bundle of five RhCu nanowires is demonstrated. The RhCu alloy 3D nanoframe, in particular, exhibits excellent catalytic activity toward the oxygen evolution reaction under alkaline conditions. PMID- 27774398 TI - Significant Stability Enhancement in High-Efficiency Polymer:Fullerene Bulk Heterojunction Solar Cells by Blocking Ultraviolet Photons from Solar Light. AB - Achievement of extremely high stability for inverted-type polymer:fullerene solar cells is reported, which have bulk heterojunction (BHJ) layers consisting of poly[4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-alt-3 fluorothieno[3,4-b]thiophene-2-carboxylate] (PTB7-Th) and [6,6]-phenyl-C71 butyric acid methyl ester (PC71BM), by employing UV-cut filter (UCF) that is mounted on the front of glass substrates. The UCF can block most of UV photons below 403 nm at the expense of ~20% reduction in the total intensity of solar light. Results show that the PTB7-Th:PC71BM solar cell with UCF exhibits extremely slow decay in power conversion efficiency (PCE) but a rapidly decayed PCE is measured for the device without UCF. The poor device stability without UCF is ascribed to the oxidative degradation of constituent materials in the BHJ layers, which give rise to the formation of PC71BM aggregates, as measured with high resolution and scanning transmission electron microscopy and X-ray photoelectron spectroscopy. The device stability cannot be improved by simply inserting poly(ethylene imine) (PEI) interfacial layer without UCF, whereas the lifetime of the PEI-inserted PTB7-Th:PC71BM solar cells is significantly enhanced when UCF is attached. PMID- 27774399 TI - Graphene-Nanowall-Decorated Carbon Felt with Excellent Electrochemical Activity Toward VO2+/VO2+ Couple for All Vanadium Redox Flow Battery. AB - 3D graphene-nanowall-decorated carbon felts (CF) are synthesized via an in situ microwave plasma enhanced chemical vapor deposition method and used as positive electrode for vanadium redox flow battery (VRFB). The carbon fibers in CF are successfully wrapped by vertically grown graphene nanowalls, which not only increase the electrode specific area, but also expose a high density of sharp graphene edges with good catalytic activities to the vanadium ions. As a result, the VRFB with this novel electrode shows three times higher reaction rate toward VO2+/VO2+ redox couple and 11% increased energy efficiency over VRFB with an unmodified CF electrode. Moreover, this designed architecture shows excellent stability in the battery operation. After 100 charging-discharging cycles, the electrode not only shows no observable morphology change, it can also be reused in another battery and practical with the same performance. It is believed that this novel structure including the synthesis procedure will provide a new developing direction for the VRFB electrode. PMID- 27774400 TI - Hole-Accepting-Ligand-Modified CdSe QDs for Dramatic Enhancement of Photocatalytic and Photoelectrochemical Hydrogen Evolution by Solar Energy. AB - Solar H2 evolution of CdSe QDs can be significantly enhanced simply by introducing a suitable hole-accepting-ligand for achieving efficient hole extraction and transfer at the nanoscale interfaces, which opens an effective pathway for dissociation of excitons to generate long-lived charge separation, thus improving the solar-to-fuel conversion efficiency. PMID- 27774401 TI - A Bifunctional Organic Redox Catalyst for Rechargeable Lithium-Oxygen Batteries with Enhanced Performances. AB - An organic bifunctional catalyst poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl methacrylate) (PTMA) has been prepared and coated on carbon surface during electrode preparation. The PTMA has been applied as an efficient bifunctional catalyst for lithium-oxygen batteries with lower overpotentials, enhanced rate performances, and prolonged cycle life. PMID- 27774402 TI - High Performance Perovskite Solar Cells. AB - Perovskite solar cells fabricated from organometal halide light harvesters have captured significant attention due to their tremendously low device costs as well as unprecedented rapid progress on power conversion efficiency (PCE). A certified PCE of 20.1% was achieved in late 2014 following the first study of long-term stable all-solid-state perovskite solar cell with a PCE of 9.7% in 2012, showing their promising potential towards future cost-effective and high performance solar cells. Here, notable achievements of primary device configuration involving perovskite layer, hole-transporting materials (HTMs) and electron-transporting materials (ETMs) are reviewed. Numerous strategies for enhancing photovoltaic parameters of perovskite solar cells, including morphology and crystallization control of perovskite layer, HTMs design and ETMs modifications are discussed in detail. In addition, perovskite solar cells outside of HTMs and ETMs are mentioned as well, providing guidelines for further simplification of device processing and hence cost reduction. PMID- 27774403 TI - Solar Trees: First Large-Scale Demonstration of Fully Solution Coated, Semitransparent, Flexible Organic Photovoltaic Modules. AB - The technology behind a large area array of flexible solar cells with a unique design and semitransparent blue appearance is presented. These modules are implemented in a solar tree installation at the German pavilion in the EXPO2015 in Milan/IT. The modules show power conversion efficiencies of 4.5% and are produced exclusively using standard printing techniques for large-scale production. PMID- 27774405 TI - Ultrafast-Charging Supercapacitors Based on Corn-Like Titanium Nitride Nanostructures. AB - Ultrahigh rates realized by ALD-made TiN. The symmetric full-cell supercapacitors deliver a typical capacitance of 20.7 F cm-3 at a scan rate of 1 V s-1, and retain 4.3 F cm-3 at high rate of 100 V s-1. The devices can be charged and discharged for 20 000 cycles with negligible capacitance loss and with an ultralow self-discharge current (~1 MUA). PMID- 27774404 TI - Flexible Photodetectors Based on 1D Inorganic Nanostructures. AB - Flexible photodetectors with excellent flexibility, high mechanical stability and good detectivity, have attracted great research interest in recent years. 1D inorganic nanostructures provide a number of opportunities and capabilities for use in flexible photodetectors as they have unique geometry, good transparency, outstanding mechanical flexibility, and excellent electronic/optoelectronic properties. This article offers a comprehensive review of several types of flexible photodetectors based on 1D nanostructures from the past ten years, including flexible ultraviolet, visible, and infrared photodetectors. High performance organic-inorganic hybrid photodetectors, as well as devices with 1D nanowire (NW) arrays, are also reviewed. Finally, new concepts of flexible photodetectors including piezophototronic, stretchable and self-powered photodetectors are examined to showcase the future research in this exciting field. PMID- 27774406 TI - Stabilized Wide Bandgap MAPbBr x I3-x Perovskite by Enhanced Grain Size and Improved Crystallinity. AB - The light instability of CH3NH3PbI x Br3-x is one of the biggest challenges for its application in tandem solar cells. Here we show that an improved crystallinity and grain size of CH3NH3PbI x Br3-x films could stabilize these materials under one sun illumination, improving both the efficiency and stability of the wide-bandgap perovskite solar cells. PMID- 27774407 TI - A Critical Review of Methodologies to Detect Reactive Oxygen and Nitrogen Species Stimulated by NADPH Oxidase Enzymes: Implications in Pesticide Toxicity. AB - In this review, potential fluorescent probe applications for detecting reactive oxygen and nitrogen species (ROS/RNS) generated from NADPH oxidases (e.g., Nox2) and nitric oxide synthase enzymes are discussed in the context of pesticide toxicology. Identification of the specific marker products derived from the interaction between ROS/RNS and the fluorescent probes (e.g., hydroethidine and coumarin boronate) is critical. Due to the complex nature of reactions between the probes and ROS/RNS, we suggest avoiding the use of fluorescence microscopy for detecting oxidizing/nitrating species. We also critically examined the viability of using radiolabeling or positron emission tomography (PET) for ROS/RNS detection. Although these techniques differ in sensitivity and detection modalities, the chemical mechanism governing the reaction between these probes and ROS/RNS should remain the same. To unequivocally detect superoxide with these probes (i.e., radiolabeled and PET-labeled hydroethidine analogs), the products should be isolated and characterized by LC-MS/MS or HPLC using an appropriate standard. PMID- 27774408 TI - Bioinformatic Analysis of DNA Methylation in Neural Progenitor Cell Models of Alcohol Abuse. AB - Several recent publications sought to investigate the effects of ethanol treatment on models of central nervous system development, specifically through changes in DNA methylation. Regulation of DNA methylation causes a long-lasting, epigenetic change in the capacity of the genome to respond to developmental or metabolic stimuli. Changes in technologies for quantifying DNA methylation have increased the ability to identify and interpret potential effects of ethanol. Here, we review these recent studies in order to evaluate the detection technologies and bioinformatic analyses. Our evaluation finds that whole- or targeted-genome sequencing combined with bisulfite conversion of unmethylated G to U residues is now the standard for assessing genome-wide effects, and specific differentially methylated regions can be validated by one of several widely available techniques. The acceptance of these technologies should help understand how ethanol leads to life-long developmental or behavioral deficits, and, perhaps, suggest therapies to reverse these effects. PMID- 27774409 TI - Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen. AB - BACKGROUND: Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol. OBJECTIVE: The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen. METHOD: AmB existed primarily in a monomeric state in poly(ethylene glycol)-block-poly(N-hexyl stearate L-aspartamide) (PEG-b-PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone(r), was highly self-aggregated based on absorption spectroscopy. RESULTS: After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (Vd) and total systemic clearance (CL) relative to Fungizone(r). After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone(r) were similar to day 1. The treatment of Fungizone(r) also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H&E) staining of excised kidneys. CONCLUSION: In summary, mAmB has less renal toxicity than AmB as Fungizone(r) in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB in vivo. PMID- 27774410 TI - Analyzing clinical outcomes in laparoscopic right vs. left colectomy in colon cancer patients using the NSQIP database. AB - INTRODUCTION: Optimization of surgical outcomes after colectomy continues to be actively studied, but most studies group right-sided and left-sided colectomies together. The aim of our study was to determine whether the complication rate differs between right-sided and left-sided colectomies for cancer. METHODS: We identified patients who underwent laparoscopic colectomy for colon cancer between 2005 and 2010 in the American College of Surgeons National Surgical Quality Improvement Program database and stratified cases by right and left side. The two groups were matched using propensity score matching for demographics, previous abdominal surgery, pre-operative chemotherapy and radiotherapy, and preoperative laboratory data. Outcome measures were: 30-day mortality and morbidity. RESULTS: We identified 2512 patients who underwent elective laparoscopic colectomy for right-sided or left-sided colon cancer. The two groups were similar in demographics, and pre-operative characteristics. There was no difference in overall morbidity (15% vs. 17.7%; p value < 0.08) or 30-day mortality (1.5% vs. 1.5%; p value < 0.9) between the two groups. Sub-analysis revealed higher surgical site infection rates (9% vs. 6%; p value < 0.04), higher incidence of ureteral injury (0.6% vs. 0.4%; p value < 0.04), higher conversion rate to open colectomy (51% vs. 30%; p value < 0.01) and a longer hospital length of stay (10.5 +/- 4 vs. 7.1 +/- 1.3 days; p value < 0.02) in patients undergoing laparoscopic left colectomy. CONCLUSION: Our study highlights the difference in complications between right-sided and left-sided colectomies for cancer. Further research on outcomes after colectomy should incorporate right vs. left side colon resection as a potential pre-operative risk factor. PMID- 27774411 TI - Effectiveness of fast mapping to promote learning in schizophrenia. AB - Fast mapping (FM), a process that promotes the expeditious incidental learning of information, is thought to support rapid vocabulary acquisition in young children through extra-medial temporal lobe (MTL) regions. A recent study suggested that patients with MTL damage resulting in profound amnesia were able to learn novel word-image associations using an FM paradigm. The present study investigated whether FM would be an effective strategy to promote learning for individuals with schizophrenia, a severe mental illness associated with compromised MTL functionality. Twenty-five patients with schizophrenia and 27 healthy control subjects completed trials of incidental FM encoding (experimental condition) and explicit encoding (EE, control condition) over the course of three visits spaced one week (+/- 2 days) apart. All participants were evaluated for recognition 10 minutes after each encoding condition was presented, and again one week (+/- 2 days) later. Results indicate that both groups performed better on the EE recognition trials when compared to FM (p's < 0.05). For the FM recognition trials, both groups performed similarly. However, participants with schizophrenia performed significantly worse on the EE recognition trials than healthy control participants (p's < 0.05). While participants with schizophrenia did not perform significantly worse when assessed for FM recognition, these results do not provide enough evidence to suggest that FM facilitates learning to a greater extent in schizophrenia when compared to EE. Whether FM may benefit a subgroup of patients with schizophrenia remains a focus of further investigation. PMID- 27774412 TI - 100 Hz neutron radiography at the BOA beamline using a parabolic focussing guide. AB - The recent developments in scientific complementary metal oxide semiconductor (sCMOS) detector technology allow for imaging of relevant processes with very high temporal resolution with practically negligible readout time. However, it is neutron intensity that limits the high temporal resolution neutron imaging. In order to partially overcome the neutron intensity problem for the high temporal resolution imaging, a parabolic neutron focussing guide was utilized in the test arrangement and placed upstream the detector in such a manner that the focal point of the guide was positioned slightly behind the scintillator screen. In such a test arrangement, the neutron flux can be increased locally by about one order of magnitude, albeit with the reduced spatial resolution due to the increased divergence of the neutron beam. In a pilot test application, an in-situ titration system allowing for a remote delivery of well-defined volumes of liquids onto the sample stage was utilized. The process of droplets of water (H2O) falling into the container filled with heavy water (D2O) and the subsequent process of the interaction and mixing of the two liquids were imaged with temporal resolution of 0.01 s. *Combination of neutron focussing device and use of sCMOS detector allows for very high temporal resolution neutron imaging to be achieved (albeit with reduced spatial resolution and field of view).*In-situ neutron imaging titration device for liquid interaction experiments.*Interaction of otherwise indiscernible liquids (H2O and D2O) visualized using neutron radiography with 0.01 s temporal resolution. PMID- 27774413 TI - Use of complementary and alternative medicines among Malaysian cancer patients: A descriptive study. AB - The use of Complementary and Alternative Medicine (CAM; bu chong yu ti dai yi xue) has been rapidly increasing among cancer patients. However, this pervasiveness is still largely unexplored among Malaysian cancer patients. The current study aimed to evaluate the patterns of CAM use among cancer patients from a local hospital in Malaysia. In addition, the study focused on the information-seeking behavior and CAM use disclosure to doctors. Of 393 patients, 184 (46.1%) had used CAM for their cancers. CAM usage was significantly associated with gender (p = 0.021), level of education (p = 0.001), employment status (p = 0.02), and monthly income (p < 0.001). Among frequently used CAM were nutritional supplements (n = 77, 41.8%), natural products (n = 74, 40.2%), and multivitamin (n = 62, 33.6%). Friends and family members were the most common source of CAM information (n = 139, 75.5%). Seventy-nine (43%) reported to disclose their CAM use to the health care providers. The most common (n = 63, 34.2%) reason of nondisclosure was "it is not important to discuss it with oncologist." This study confirmed that CAM use is common among Malaysian cancer patients, thus highlighting a greater need for patient education regarding CAM therapies and their potential interactions with conventional therapies. Although some types of CAM therapies may help patients to cope with emotional distress and improve quality of life, CAM, with no proven efficacy, may pose dangers to patients' health due to interactions with conventional therapies. Doctors and other health care providers including nurses and pharmacists should engage cancer patients in an open nonjudgmental dialog to ascertain CAM use disclosure to their health care providers. PMID- 27774414 TI - Antioxidant effects of Spirulina supplement against lead acetate-induced hepatic injury in rats. AB - Lead is a toxic metal that induces a wide range of behavioral, biochemical and physiological effects in humans. Oxidative damage has been proposed as a possible mechanism involved in lead toxicity. The current study was carried out to evaluate the antioxidant activities of Spirulina supplement against lead acetate induced hepatic injury in rats. Five groups of rats were used in this study, Control, Lead acetate (100 mg/kg), Lead acetate (100 mg/kg) + 0.5 g/kg Spirulina, Lead acetate (100 mg/kg) + 1 g/kg Spirulina and Lead acetate + 25 mg/100 g Vitamin C (reference drug). All experimental groups received the oral treatment by stomach tube once daily for 4 weeks. Lead intoxication resulted in a significant increase in serum alanine transaminae (ALT), aspartate transaminae (AST) activities, liver homogenate tumor necrosis factor-alpha (TNF-alpha), caspase-3, malondialdehyde (MDA), nitric oxide (NO) levels and a significant decline of total serum protein, liver homogenate reduced glutathione (GSH) level and superoxide dismutase (SOD) activity. Both doses of Spirulina supplement as well as Vitamin C succeeded to improve the biochemical parameters of serum and liver and prevented the lead acetate-induced significant changes on plasma and antioxidant status of the liver. Both doses of Spirulina supplement had the same anti-apoptotic activity and high dose exhibited more antioxidant activity than that of low dose. In conclusion, the results of the present work revealed that Spirulina supplement had protective, antioxidant and anti-apoptotic effects on lead acetate-induced hepatic damage. PMID- 27774415 TI - Cinnamon extract lowers glucose, insulin and cholesterol in people with elevated serum glucose. AB - Cinnamon ( rou gui) has in vitro insulin potentiating activity, and proanthocyanidins from cinnamon prevent in vitro formation of advanced glycation end products. Some human studies were equivocal, but several have shown beneficial effects of cinnamon supplementation on circulating glucose, lipids, and/or insulin. This placebo-controlled double-blind trial tested the effects of a dried water extract of cinnamon (Cinnamomum cassia) on circulating glucose, lipids, insulin, and insulin resistance. Men and women from Beijing and Dalian, China, were invited to participate if they had fasting serum glucose >6.1 mmol/L or 2-h glucose >7.8 mmol/L. Participants, (173 were enrolled and 137 completed the study) were randomly assigned to receive either a spray-dried, water extract of cinnamon (CinSulin(r)), 250 mg/capsule, or a placebo, twice a day for two months. Mean +/- SEM age of participants was 61.3 +/- 0.8 years, BMI was 25.3 +/- 0.3 and M/F ratio was 65/72. After 2 mo, fasting glucose decreased (p < 0.001) in the cinnamon extract-supplemented group (8.85 +/- 0.36 to 8.19 +/- 0.29 mmol/L) compared with the placebo group (8.57 +/- 0.32 to 8.44 +/- 0.34 mmol/L, p = 0.45). Glucose 2 h after a 75 g carbohydrate load, fasting insulin, and HOMA-IR also decreased with cinnamon extract compared with placebo. Total and LDL cholesterol decreased with cinnamon extract and HDL-cholesterol decreased in both the cinnamon-extract and placebo groups. In conclusion, supplementation with 500 mg of water-extract of cinnamon for two months reduced fasting insulin, glucose, total cholesterol, and LDL cholesterol and enhanced insulin sensitivity of subjects with elevated blood glucose. PMID- 27774416 TI - A randomized ethnomedicinal survey of snakebite treatment in southwestern parts of Bangladesh. AB - Snakebite is the single most important toxin-related injury, causing substantial mortality in many parts of the Africa, Asia and the Americas. Incidence of snakebite is usually recorded in young people engaged in active physical work in rural areas. The various plant parts used to treat snakebite included whole plant, leaves, barks, roots and seeds. Most bites in Bangladesh are recorded between May and October with highest number in June. Lower and upper limbs are most common sites of snakebite, but it may happen in other sites as well. Snake venom ( she du) has been the cause of innumerable deaths worldwide. However, antiserum does not provide enough protection against venom induced hemorrhage, necrosis, nephrotoxicity and hypersensitivity reactions. Informed consent was obtained from the practitioners prior to interviews. After the survey, it is concluded that the medicinal plants used by tribal medicinal practitioners in Bangladesh for treatment against snakebite are Acyranthes aspera L. ( tu niu xi), Amaranthus Viridis L. ( ye xiang cai), Asparagus racemosus Willd ( zong xu tian dong) and Emblica officinalis Gaertn ( you gan), while the non-tribal communities used 35 plant species among them, most of the plants reported as new species used against snakebite in the belonging family. The plants present a considerable potential for discovery of novel compounds with fewer side effects for treatment of antisnake venom and can, at least in Bangladesh, become a source of affordable and more easily available drugs. PMID- 27774417 TI - Green tea catechin inhibits the activity and neutrophil release of Matrix Metalloproteinase-9. AB - Green tea (Camellia sinensis; lu cha) extracts have been shown to possess anti oxidant and anti-inflammatory effects in various cell types. Green tea extract (GTX) has been shown to significantly inhibit the activity of collagenase-3 (matrix metalloproteinase-13 (MMP-13)) in vitro. MMPs, such as MMP-9, are known to be involved in many inflammatory diseases including periodontal disease. GTX and a major catechin, epigallocatechin-gallate (EGCG), were examined for their ability to inhibit purified MMP-9 activity and its release from stimulated neutrophils. Methanol extract of Green tea and commercially purchased EGCG (>95 % purity) were tested in vitro for their ability to inhibit MMP-9 activity and/or its release from neutrophils using a beta-casein cleavage assay and gelatin zymography, respectively. Statistical analysis was performed by Student's t-test. GTX and EGCG at 0.1% (w/v) completely inhibited the activity of MMP-9. In addition, GTX and EGCG (0.1 %) significantly inhibited (p < 0.001) the release of MMP-9 from formyl-Met-Leu-Phe (FMLP)-stimulated human neutrophils by 62.01% +/- 6.717 and 79.63% +/- 1.308, respectively. The inhibitory effects of GTX and EGCG occurred in unstimulated neutrophils (52.42% +/- 3.443 and 62.33% +/- 5.809, respectively). When the inhibitory effect of EGCG was further characterized, it significantly inhibited the release of MMP-9 from the FMLP-stimulated human neutrophils in a dose-dependent manner. The effects of GTX and EGCG on MMPs could be extrapolated to clinical/in vivo studies for the development of oral care products to prevent or treat chronic inflammatory diseases including periodontal diseases. PMID- 27774418 TI - Nephroprotective effect of ethanolic extract of Azima tetracantha root in glycerol induced acute renal failure in Wistar albino rats. AB - The gravity of the impact of renal failure on human health is well known and as there is no specific pharmacotherapy for renal failure, the current study was undertaken to evaluate the effect of root extract of Azima tetracantha, an ancient medicinal plant used in Siddha and Ayurvedhic systems of medicine. The experiment was done in glycerol-induced acute renal failure in Wistar albino rats. Thirty rats were divided into five groups. Group 1 was given normal saline (10 ml/kg) per oral, group 2 with single dose of hypertonic glycerol (8 ml/kg) by intramuscular injection into the hind limbs, group 3 with glycerol and ethanolic extract of A. tetracantha root (ATR) 250 mg/kg, group 4, glycerol and ATR 500 mg/kg and group 5, 500 mg/kg ATR. Extract was given orally 60 min prior to glycerol injection. 24 h urine output, serum creatinine, blood urea nitrogen, total proteins and albumin were measured for all the groups. Kidneys were examined for histopathological changes. The antioxidant activity of the extract was tested in vitro and in vivo. Rats treated with ATR showed significant improvement in biochemical parameters and histopathological changes compared to glycerol treated group. The protective effect was highly significant at 500 mg/kg. Both in vitro and in vivo assays showed significant antioxidant activity. The in vitro activity was comparable to vitamin-C. The ethanolic extract of ATR has nephroprotective effect in glycerol-induced acute renal failure and the mechanism of action could be the antioxidant effect. PMID- 27774419 TI - Evaluation of anti-inflammatory activity of selected medicinal plants used in Indian traditional medication system in vitro as well as in vivo. AB - The present study was carried out to evaluate in vivo and in vitro anti inflammatory potential of selected medicinal plants used in Indian traditional medication. The sequentially extracted plant samples as, Cissus quadrangularis, Plumbago zeylanica, Terminalia bellarica and Terminalia chebula in water, ethanol and hexane were evaluated in-vitro for COX-1 and 2 inhibitory and antioxidant activities. The in vivo anti-inflammatory activity of selected samples showing promising COX-2 inhibition was assessed using carrageenan and Phorbol Myristate Acetate (PMA) induced mice edema animal model. The results obtained reveals that most of the plants were found to inhibit COX-2 activity as compared to COX-1. It was observed that the extracts of T. bellarica (73.34 %) and T. chebula (74.81 %) showed significant COX-2 selective inhibition as compared to other samples. The ethanol extract of the selected plants demonstrated effective DPPH, OH and superoxide radical scavenging activity. In vivo anti-inflammatory study shows that, T. bellarica and T. chebulla had a significant impact on inhibition of edema formation. The cytotoxicity evaluation study of ethanolic fraction of selected medicinal plants indicates that the selected samples have no effect on cell viability. HPTLC fingerprint of flavonoids of the selected samples was also prepared as a measure of quality control. The results obtained may be useful in strengthening the standardization of the selected botanicals. Moreover the selected plants can be considered as a resource for searching novel anti inflammatory agents possessing COX-2 inhibition. PMID- 27774420 TI - Centella asiatica extract protects against amyloid beta1-40-induced neurotoxicity in neuronal cells by activating the antioxidative defence system. AB - Centella asiatica ( lei gong gen) is a traditional medicinal herb with high antioxidant activity, which decreases amyloid-beta (Abeta) deposition in the brain. At the same time, aggregated Abeta-induced oxidative stress is the trigger in the pathogenesis of Alzheimer's disease (AD). Here, we investigated the ability of C. asiatica ethanol extract (CAE) to protect PC12 and IMR32 cells from Abeta1-40-induced production of reactive oxygen species (ROS) and concomitant neurotoxicity. Aggregated Abeta1-40 treatment resulted in reduced cell viability, which can be reversed by cotreatment with 25, 50, and 100 MUg/mL CAE. Moreover, CAE eliminated the Abeta1-40-mediated increase in ROS production. Thus, CAE mediated protection against aggregated Abeta1-40-induced neurotoxicity is attributable to modulation of the antioxidative defense system in cells, including the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and levels of glutathione and glutathione disulfide by CAE. This emphasizes the potential therapeutic and preventive value of CAE in the treatment of AD. PMID- 27774422 TI - Complementary and alternative medicine in Indian Parkinson's disease patients. AB - Use of complementary and alternative medicine (CAM; bu chong yu ti dai yi xue) in Parkinson disease (PD) ranged 40-70%. The objective of this study was to determine the frequency, types and factors associated with the use of CAM in Indian PD patients. PD patients, fulfilling UKPD-Society brain-bank diagnostic criteria, attending Movement-disorders clinic of a tertiary-care teaching hospital in India from 1st May to 15th December 2012 were enrolled. Information on socio-demographic, clinical data and treatment along with factors (source of information, benefits, harms, reason for use and cost) associated with CAM use were recorded. Out of 233 consecutive PD patients, 106 (46%) used CAM. Mean +/- SD age of CAM users was 56 +/- 11.2 years. Among CAM users, 72% were males, with mean age-onset 49 +/- 11.16 years (P = 0.042) and 73% receiving levodopa therapy (p = 0.006). Longer duration PD, higher education (graduates and above), urban residence, and fairly good perceived health were other factors seen among CAM users. Reasons for using CAM were 'feel good factor' (73%), 9% took CAM due to side effects from allopathic-medicines. Commonly used CAM were Ayurvedic, homeopathic medicines, and acupuncture ( zhen jiu) [74/106 (70%)]. Median CAM cost in Indian Rupees (INR) was 1000/month (USD16, range: 0-400USD/month in year 2012). Almost half of PD patients use CAM. Three-quarters of Indian CAM using PD patients believe that CAM is harmless, using it at a substantial cost. CAM-users are educated, young, urban dwellers, longer duration PD and receiving levodopa. Commonly used CAM was Ayurvedic, Homeopathic medicines and acupuncture. PMID- 27774421 TI - Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats. AB - Previously explored combination therapies mostly involved the use of bioactive molecules. It is believed that herbal compounds containing multiple plant products have synergistic hepatoprotective effects and could enhance the desired actions. To investigate the combination of ethanolic fruits extract of Solanum xanthocarpum (SX) and Juniperus communis (JC) against Paracetamol (PCM) and Azithromycin (AZM) induced liver toxicity in rats. Liver toxicity was induced by combine oral administration of PCM (250 mg/kg) and AZM (200 mg/kg) for 7 days in Wistar rats. Fruit extract of SX (200 and 400 mg/kg) and JC (200 and 400 mg/kg) were administered daily for 14 days. The hepatoprotective activity was assessed using liver functional test, oxidative parameters and histopathological examination. The results demonstrated that combine administration of AZM and PCM significantly produced liver toxicity by increasing the serum level of hepatic enzymes and oxidative parameters in liver of rats. Histopathological examination also indicated that AZM and PCM produced liver damage in rats. Chronic treatment of SX and JC extract significantly and dose-dependently attenuated the liver toxicity by normalizing the biochemical factors and no gross histopathological changes were observed in liver of rats. Furthermore, combine administration of lower dose of SX and JC significantly potentiated their hepatoprotective effect which was significant as compared to their effect per se. The results clearly indicated that SX and JC extract has hepatoprotective potential against AZM and PCM induced liver toxicity due to their synergistic anti-oxidant properties. PMID- 27774424 TI - Anti-arthritic activity of a classical Ayurvedic formulation Vatari Guggulu in rats. AB - In India, Vatari Guggulu has been traditionally used in the Ayurvedic system of medicine to treat rheumatoid arthritis (RA). The current study was undertaken to evaluate anti-arthritic activity of alcoholic extract of Vatari Guggulu in rats. Arthritis was induced by administration of formaldehyde (2%v/v) or Complete Freund's Adjuvant (CFA) into the sub-plantar surface of left hind paw of the animals. The extract was administered to the rats by oral gavages in different doses. Joint swelling was measured in formaldehyde induced arthritis. Various physical, biochemical and histopathological parameters were determined in CFA induced arthritis. Vatari Guggulu extract (VGE) produced significant (P < 0.05) inhibition of joint swelling in both formaldehyde and CFA induced arthritis. The treatment also brought to normalcy the increased white blood cell (WBC) count, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), cholesterol, triglycerides and LDL with an enhancement of haemoglobin (Hb) levels and red blood cell (RBC) count. These effects were found to be dose dependent. These effects were comparable with standard drug indomethacin. Histo-pathological studies of the ankles of VGE treated animals exhibited significant improvements. VGE did not show any toxic symptoms even at a dose of 2000 mg/kg in acute toxicity studies on rats. Thus, Vatari Guggulu, a classical Ayurvedic formulation of the Indian System of Medicine, exhibited significant anti-arthritic activity in formaldehyde and CFA induced arthritis in rats. This study corroborates the claims of Ayurveda on Vatari Guggulu. PMID- 27774423 TI - Evaluation of in vivo antitumor activity of cleistanthin B in Swiss albino mice. AB - To evaluate the in vivo antitumor activity of cleistanthin B in Ehrlich's ascites carcinoma (EAC) and Dalton's ascites lymphoma (DAL) cell lines induced malignant ascites mouse models and DAL cell line induced solid tumor mouse model. All animals were injected with 2 * 106 EAC/DAL cells i.p./s.c. to induce malignant ascites and solid tumor and treated with 5-fluorouracil (5-FU) 20 mg/kg or cleistanthin B for 10 days. Cleistanthin B was given at three doses viz. 25, 50 and 100 mg/kg. The percentage increase in life span and the overall survival in malignant ascites animals and the tumor volume in solid tumor animals were measured. The haematological parameters were assessed in all animals before and 2 weeks after the treatment. Cleistanthin B 50 mg/kg and 5-FU significantly prolonged the life span (>25%) of malignant ascites tumor bearing animals. The overall survival was significantly improved by both. Only cleistanthin B 50 mg/kg significantly reduced the elevated WBC counts in EAC tumor bearing animals. Both 5-FU and cleistanthin B 50 mg/kg reversed the malignancy induced increase in neutrophils and platelet counts and decrease in lymphocyte counts but not to the normal range. Only 5-FU significantly reduced the solid tumor volume. None of the three doses of cleistanthin B was effective against the solid tumor. Cleistanthin B has antitumor activity against EAC and DAL tumor mice but it is not as effective as 5-FU. At 50 mg/kg dose cleistanthin B exerts significant antitumor activity compared to 25 and 100 mg/kg dose. Its effect on WBC count is higher and advantageous when compared to 5-FU. But cleistanthin B in the doses used is not effective against solid tumor. PMID- 27774425 TI - A case series of the effects of a novel composition of a traditional natural preparation for the treatment of psoriasis. AB - The objective of this study was to assess the effectiveness of a specific composition of a traditional herbal preparation (DurrDerma) in adult patients with moderate to severe skin psoriasis. The preparation is a newly developed topical combination containing plant-based extracts traditionally used in skin disease as black cumin, olive oil, tea tree oil, cocoa butter completed by vitamin A and vitamin B12. We documented the effectiveness of the preparation in a first case series. A total of 12 patients (8 males and 4 females, 21-86 y) with manifest and treatment-resistant psoriasis were included and treated for 12 weeks. All patients were assigned to twice-daily treatment with the DurrDerma preparation. Treatment success as determined by the Psoriasis Area and Severity Index (PASI) score, the body surface area, and the dermatology life index was achieved (PASI reduction of >75%) in 10 of the 12 treated patients (83%). The remaining two patients showed a PASI reduction of <=50%. In 5 of the patients PASI reduction was achieved <12 weeks (between week 3-11). The beneficial effect in responder patients might be explained by a synergistic anti-oxidative and anti inflammatory activity of all components present in DurrDerma. We conclude that the new preparation using a traditional approach seems to be a promising complementary treatment for psoriasis. PMID- 27774426 TI - Antibacterial and antibiotic potentiating activity of Vangueria madagascariensis leaves and ripe fruit pericarp against human pathogenic clinical bacterial isolates. AB - This study aimed to assess the antibacterial and antibiotic potentiating property of Vangueria madagascariensis (VM) (fruit and leaf extracts) against 10 clinical isolates. A microdilution broth susceptibility assay for bacteria was used for the determination of the minimum inhibitory concentration (MIC) and associated with antibiotics to evaluate any synergistic effect. VM extracts were found to potentiate the activity of 3 conventional antibiotics. Chloramphenicol and Ciprofloxacin showed no activity against Acinetobacter spp. but when mixed with VM (in a ratio of 50% VM extracts: 30% antibiotic), showed potentiating effect. The methanolic fruit extract at lower concentration of Chloramphenicol (30%) gave better synergistic effect (MIC = 3.75 MUg/mL) as compared to 50% (MIC = 12.5 MUg/mL). With Gentamicin, no activity was detected with leaf decoction but other extracts (methanolic leaf/fruit extract and fruit decoction) showed enhancement (MIC- 0.47, 7.5 and 15 MUg/mL respectively). Interestingly, Chloramphenicol showed no activity against MRSA, but when mixed with VM, produced low MICs (<0.39 0.78 MUg/mL with 50% antibiotic and from <0.47 to 0.94 MUg/mL with 30% antibiotic). Combining Gentamicin with VM extracts showed an enhancement in the potentiating activity against MRSA. In conclusion, the observed antimicrobial property of VM tend to suggest a promising alternative and complementary strategy to manage bacterial infections and hence can open new avenues for further research using traditional medicinal food plant. PMID- 27774427 TI - Influence of traditional Chinese medicine syndrome groups on quality of life in women with metabolic syndrome. AB - Traditional Chinese medicine (TCM; zhong yi) syndrome groups are based on the symptoms of human diseases and guide the use of Chinese herbs. The aim of this study was to examine the effects of TCM syndrome groups on biochemical characteristics and quality of life (QOL) in women with metabolic syndrome (MS). Among the 1080 registered female patients screened at our outpatient clinic, a total of 322 women aged between 18 and 65 years and meeting the requirements of MS were enrolled. All the patients were asked to fill out a questionnaire on metabolic TCM syndrome groups and a questionnaire on the QOL, the Medical Outcomes Study (MOS) Short Form-12 (SF-12). Data of biochemical characteristics were collected at the same time. The present study showed MS women in TCM syndrome groups had significantly lower physical and mental component scores in SF-12 compared with those not in TCM syndrome groups. We also found MS patients in TCM syndrome groups, except Kidney Deficiency syndrome, showed higher body mass indexes, waist circumference, and hip circumference. However, there was almost no difference in most biochemical characteristics between TCM syndrome groups. The MS patients diagnosed as belonging to TCM syndrome groups had poor QOL. PMID- 27774428 TI - Acupuncture combined with Chinese herbs for the treatment in hemivertebral French bulldogs with emergent paraparesis. AB - This study follows the treatment of six French bulldogs with paraparesis caused by congenital hemivertebra which were structurally mild but clinically severe. A standardized acupuncture ( zhen jiu) treatment using Hua-Tuo-Jiaji (HTJJ) as local points and other distant points combined with Chinese herbs improved the clinical signs. Few, if any, published papers mention Traditional Chinese Veterinary Medicine (TCVM) for treatment of hemivertebral paraparesis in French bulldogs. Based on the rapid treatment outcome, we encourage practitioners to integrate this form of conservative management into emergency treatment. PMID- 27774430 TI - Enhancement of the Th1-phenotype immune system by the intake of Oyster mushroom (Tamogitake) extract in a double-blind, placebo-controlled study. AB - Pleurotus cornucopiae (Oyster mushroom, Tamogitake) has long been eaten as a functional food for enhancement of the immune system, but its effectiveness has not been well confirmed in humans. To this end, we set up a double-blind placebo controlled human clinical trial to investigate the potential of Oyster mushrooms with respect to the up-regulation of the immune system. The subjects ingested Oyster mushroom extract for 8 weeks. We measured the serum cytokine levels involved in regulation of the immune system, including interferon (IFN)-gamma, interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, and tumor-necrosis factor (TNF) alpha. We found that intake of Oyster mushroom extract elevated IFN-gamma (P = 0.013) and IL-12, whereas serum levels of IL-10 and IL-13 and other cytokines were minimally changed. We also measured natural killer (NK) cell activity, the levels of which tended to increase, but not significantly. Taken together, these facts suggest that Oyster mushrooms have the potential to enhance the immune system, through Th1 phenotype potentiation as the macrophage-IL-12 - IFN-gamma pathway. This results in activation of the cell-mediated immune system as exemplified by up-regulation of NK cell activity. Oyster mushroom extract may be beneficial for the prevention of various diseases, including infectious diseases and cancer, due to its stimulation of the immune system. PMID- 27774429 TI - Preventive potentials of piperlongumine and a Piper longum extract against stress responses and pain. AB - AIM: To compare stress resistance increasing and analgesic activities of piperlongumine and a methanolic Piper longum fruit extract (PLE). METHODS: Efficacies of a single and repeated daily oral doses (1-256 mg/kg/day) of PLE, piperlongumine, and 50 mg/kg/day doxycycline against foot shock stress triggered alteration in body weights and core temperatures, and of their 11 daily doses on antidepressants like activity in tail suspension test and on pentobarbital induced sedation in male mice were compared. In another experiment, analgesic activities of single and repeated daily 5 mg/kg oral doses of piperlongumine and PLE in mice hot plate test and in acetic acid induced writing tests were compared with those of aspirin and doxycycline. RESULTS: After their single oral doses no effects of piperlongumine or PLE or doxycycline were observed in the footshock stress induced hyperthermia test or in hot plate test. However, significant effects of piperlongumine and PLE in both the tests were observed after their 5 or more daily doses. Both of them also dose dependently suppressed daily handling and repetitive testing triggered alterations in body weights and core temperatures. Their doxycycline like antidepressant activity in tail suspension test and aspirin like analgesic effects in acetic acid writhing test were observed after their 11 daily 5 mg/kg oral dose. CONCLUSION: Piperlongumine is another bioactive secondary metabolite of P. longum and other plants of piper species with stress response suppressing, analgesic, and anti-inflammatory activities. Its bactericidal activities can also contribute to its therapeutically interesting bio-activity profile. PMID- 27774431 TI - Diuretic and antiurolithiatic activities of an ethanolic extract of Acorus calamus L. rhizome in experimental animal models. AB - Acorus calamus is a plant commonly used as a traditional herbal medicine and possesses the wide range of pharmacological applications. The present study investigated the diuretic and antiurolithiatic activities of an ethanolic extract of Acorus calamus L. (Family: Araceae) rhizome (EEAC). For diuretic activity, three doses of EEAC (250, 500 and 750 mg/kg) were studied, and measurement of the urinary volume and electrolytes (Na+ and K+) concentration were taken as evaluation parameters. On the other hand, ethylene glycol induced urolithiasis (0.75% v/v in drinking water for 28 days) was used to study the antiurolithiatic effect of EEAC at the oral dose of 750 mg/kg in male Wistar albino rats. CYSTONE (750 mg/kg, p.o.) was used as a standard reference drug in the present study. After completion of the 28-days respective treatments, the level of various urolithiatic promoters in the biological samples (urine, serum and kidney homogenate) and renal function were used as criteria for assessing the antiurolithiatic effect of EEAC. Results indicate that, the EEAC (750 mg/kg, p.o.) produced significant increase in urine volume (p < 0.001) and urinary excretion of Na+ and K+ electrolytes (p < 0.05) in a pattern comparable to that of furosemide. In ethylene glycol induced urolithiatic model, EEAC significantly (p < 0.05) decreased excretion and deposition of various urolithiatic promoters as compared to urolithiatic control in a pattern comparable to that of CYSTONE. The EEAC supplementation also prevents the impairment of renal functions. The antiurolithiatic mechanism is mediated possibly through diuretic and nephroprotective actions of the active compounds of rhizomes. PMID- 27774432 TI - Inhibitory effect of curcumin on angiogenesis in a streptozotocin-induced diabetic rat model: An aortic ring assay. AB - BACKGROUND: Curcumin (diferuloylmethane) has been associated with the inhibition of angiogenesis, as well as the prevention of cancers and inflammatory processes. The aim of this study was to assess the efficacy of curcumin in suppressing angiogenesis in the cultured endothelial cells of rat aortic rings. METHODS: Eight-week-old male Wistar rats were randomized into five groups each with a different treatment and cell culturing paradigm: controls cultured in the absence of VEGF (vascular endothelial growth factor) (C), controls cultured in the presence of VEGF (C-V), controls treated with curcumin and then cultured in media lacking VEGF (C-TC), diabetics cultured in media supplemented with VEGF (D-V) and diabetics treated with curcumin and then cultured in media supplemented with VEGF (D-V-TC). Each group consisted of 8 animals. Diabetes was induced in by streptozotocin (STZ; 60 mg/kg body weight, IV). After 8 weeks, animals were sacrificed and their aortas were excised. Ring-shaped explants were embedded in a 96-well culture plate. Angiogenesis response was measured by counting the number of primary microtubules in each well. RESULTS: Optic microscopy revealed that the D-V group had the highest number of microvessels, while angiogenesis was not observed in the C or C-TC groups. The number of primary microtubules was significantly lower in the D-V-TC group compared to the D-V group (P < 0.05). The D-V-TC group had a significantly higher number of microvessels compared to the C TC group (P < 0.05). CONCLUSION: Curcumin attenuates angiogenesis response in stertozotocin-induced diabetic rats. PMID- 27774433 TI - Non-sedentary Lifestyle Can Reduce Hip Fracture Risk among Older Caucasians Adults: The Adventist Health Study-2. AB - AIMS: The beneficial effect of physical activity on reducing hip fracture risk has been supported in many previous studies. The present cohort study explores the relationship between total daily physical activity expressed as MET-hour/day and hip fracture risk among men over 50 years of age and postmenopausal women (n=22,836). METHODOLOGY: Associations between self-reported hip fracture incidence and total daily physical activity and selected lifestyle factors were assessed using Cox proportional hazard regression. RESULTS: In gender-specific multivariable models, total activity above average (>= 51 MET-hours per day for men, >= 48 MET-hours per day for women) compared to those with sedentary lifestyle (< 40 MET-hours per day) reduced the risk of hip fracture by 60% among men (HR=0.40, 95%CI: 0.23-0.70) (Ptrend=0.002) and 48% among women (HR=0.52, 95%CI: 0.32-0.84) (Ptrend=0.01). CONCLUSION: Our findings suggest that a moderate level of physical activity and avoiding a sedentary lifestyle can reduce the risk of hip fracture among the elderly. PMID- 27774434 TI - Fatal Liver and Bone Marrow Toxicity by Combination Treatment of Dichloroacetate and Artesunate in a Glioblastoma Multiforme Patient: Case Report and Review of the Literature. AB - A 52-year-old male patient was treated with standard radiochemotherapy with temozolomide for glioblastoma multiforme (GBM). After worsening of his clinical condition, further tumor-specific treatment was unlikely to be successful, and the patient seeked help from an alternative practitioner, who administered a combination of dichloroacetate (DCA) and artesunate (ART). A few days later, the patient showed clinical and laboratory signs of liver damage and bone marrow toxicity (leukopenia, thrombocytopenia). Despite successful restoration of laboratory parameters upon symptomatic treatment, the patient died 10 days after the infusion. DCA bears a well-documented hepatotoxic risk, while ART can be considered as safe concerning hepatotoxicity. Bone marrow toxicity can appear upon ART application as reduced reticulocyte counts and disturbed erythropoiesis. It can be assumed that the simultaneous use of both drugs caused liver injury and bone marrow toxicity. The compassionate use of DCA/ART combination therapy outside of clinical trials cannot be recommended for GBM treatment. PMID- 27774435 TI - Combining Radiation Therapy with Immune Checkpoint Blockade for Central Nervous System Malignancies. AB - Malignancies of the central nervous system (CNS), particularly glioblastoma and brain metastases from a variety of disease sites, are difficult to treat despite advances in multimodality approaches consisting of surgery, chemotherapy, and radiation therapy (RT). Recent successes of immunotherapeutic strategies including immune checkpoint blockade (ICB) via anti-PD-1 and anti-CTLA-4 antibodies against aggressive cancers, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, have presented an exciting opportunity to translate these strategies for CNS malignancies. Moreover, via both localized cytotoxicity and systemic proinflammatory effects, the role of RT in enhancing antitumor immune response and, therefore, promoting tumor control is being re examined, with several preclinical and clinical studies demonstrating potential synergistic effect of RT with ICB in the treatment of primary and metastatic CNS tumors. In this review, we highlight the preclinical evidence supporting the immunomodulatory effect of RT and discuss the rationales for its combination with ICB to promote antitumor immune response. We then outline the current clinical experience of combining RT with ICB in the treatment of multiple primary and metastatic brain tumors. Finally, we review advances in characterizing and modifying tumor radioimmunotherapy responses using biomarkers and microRNA (miRNA) that may potentially be used to guide clinical decision-making in the near future. PMID- 27774436 TI - Evolution and Diversity of the Antimicrobial Resistance Associated Mobilome in Streptococcus suis: A Probable Mobile Genetic Elements Reservoir for Other Streptococci. AB - Streptococcus suis is a previously neglected, newly emerging multidrug-resistant zoonotic pathogen. Mobile genetic elements (MGEs) play a key role in intra- and interspecies horizontal transfer of antimicrobial resistance (AMR) determinants. Although, previous studies showed the presence of several MGEs, a comprehensive analysis of AMR-associated mobilome as well as their interaction and evolution has not been performed. In this study, we presented the AMR-associated mobilome and their insertion hotspots in S. suis. Integrative conjugative elements (ICEs), prophages and tandem MGEs were located at different insertion sites, while 86% of the AMR-associated MGEs were inserted at rplL and rum loci. Comprehensive analysis of insertions at rplL and rum loci among four pathogenic Streptococcus species (Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, and S. suis) revealed the existence of different groups of MGEs, including Tn5252, ICESp1108, and TnGBS2 groups ICEs, Phim46.1 group prophage, ICE_ICE and ICE_prophage tandem MGEs. Comparative ICE genomics of ICESa2603 family revealed that module exchange and acquisition/deletion were the main mechanisms in MGEs' expansion and evolution. Furthermore, the observation of tandem MGEs reflected a novel mechanism for MGE diversity. Moreover, an in vitro competition assay showed no visible fitness cost was observed between different MGE-carrying isolates and a conjugation assay revealed the transferability of ICESa2603 family of ICEs. Our statistics further indicated that the prevalence and diversity of MGEs in S. suis is much greater than in other three species which prompted our hypothesis that S. suis is probably a MGEs reservoir for other streptococci. In conclusion, our results showed that acquisition of MGEs confers S. suis not only its capability as a multidrug resistance pathogen, but also represents a paradigm to study the modular evolution and matryoshkas of MGEs. PMID- 27774437 TI - Pathogenic Lifestyles of E. coli Pathotypes in a Standardized Epithelial Cell Model Influence Inflammatory Signaling Pathways and Cytokines Secretion. AB - Inflammatory response is key for the host defense against diarrheagenic Escherichia coli and contributes to the pathogenesis of the disease but there is not a comparative study among different diarrheagenic pathotypes. We analyzed the inflammatory response induced by five diarrheagenic pathotypes in a HT-29 cell infection model. The model was unified to reproduce the pathogenesis of each pathotype. To compare the inflammatory responses we evaluated: (i) nuclear NF kappaB and ERK1/2 translocation by confocal microscopy; (ii) kinetics of activation by each pathway detecting p65 and ERK1/2 phosphorylation by Western blotting; (iii) pathways modulation through bacterial infections with or without co-stimulation with TNF-alpha or EGF; (iv) cytokine profile induced by each pathotype with and without inhibitors of each pathway. EHEC but mainly EPEC inhibited translocation and activation of p65 and ERK1/2 pathways, as well as cytokines secretion; inhibition of p65 and ERK1/2 phosphorylation prevailed in the presence of TNF-alpha and EGF, respectively. Intracellular strains, EIEC/Shigella flexneri, caused a strong translocation, activation, and cytokines secretion but they could not inhibit TNF-alpha and EGF stimulation. ETEC and mainly EAEC caused a moderate translocation, but a differential activation, and high cytokines secretion; interestingly TNF-alpha and EGF stimulation did no modify p65 and ERK1/2 activation. The use of inhibitors of NF-kappaB and/or ERK1/2 showed that NF-kappaB is crucial for cytokine induction by the different pathotypes; only partially depended on ERK1/2 activation. Thus, in spite of their differences, the pathotypes can also be divided in three groups according to their inflammatory response as those (i) that inject effectors to cause A/E lesion, which are able to inhibit NF-kappaB and ERK1/2 pathways, and cytokine secretion; (ii) with fimbrial adherence and toxin secretion with a moderate inhibition of both pathways but high cytokines secretion through autocrine cytokine regulation; and (iii) the intracellular bacteria that induce the highest pathways activation and cytokines secretion by using different activation mechanisms. This study provides a comprehensive analysis of how the different pathogenesis schemes of E. coli pathotypes manipulate inflammatory signaling pathways, which leads to a specific proinflammatory cytokine secretion in a cell model infection that reproduce the hallmarks of infection of each pathotype. PMID- 27774440 TI - Frontal augmentation as an adjunct to orthognathic or facial contouring surgery. AB - BACKGROUND: The dimensions and shape of the forehead determine the esthetics of the upper third of the face. Korean young people consider a broad and smooth, rounded forehead more attractive. As a result, frontal augmentation becomes more popular in patients with dentofacial deformities. Various surgical procedures and materials have been used in frontal augmentation surgery, with associated advantages and disadvantages. Silicone is a good candidate for frontal augmentation. The author presents two cases of esthetic frontal augmentation with a prefabricated silicone implant in female patients with dentofacial deformities. CASE PRESENTATION: In case 1, a 24-year-old female patient underwent frontal augmentation surgery with simultaneous maxillomandibular and zygomatic osteotomies to correct facial asymmetry. A silicone implant was fabricated preoperatively using a positive template stone mold of her forehead. In case 2, a 23-year-old female patient underwent total facial contouring surgery including frontal augmentation for improved facial esthetics. A computed tomography (CT) guided rapid prototype (RP) model was used to make the silicone implants. The operative procedure was safe and simple, and the silicone implants were reliable for a larger degree of frontal augmentation. Six months later, both patients had recovered from the surgery and were satisfied with their frontal shape and projection. CONCLUSIONS: Frontal augmentation with silicone implants can be an effective adjuvant strategy to improve facial esthetics in patients with a flat and narrow forehead who undergo orthognathic reconstruction or total facial contouring surgery. PMID- 27774439 TI - The DUF582 Proteins of Chlamydia trachomatis Bind to Components of the ESCRT Machinery, Which Is Dispensable for Bacterial Growth In vitro. AB - Chlamydiae are Gram negative bacteria that develop exclusively inside eukaryotic host cells, within a membrane-bounded compartment. Members of the family Chlamydiaceae, such as Chlamydia trachomatis, are pathogenic species infecting vertebrates. They have a very reduced genome and exploit the capacities of their host for their own development, mainly through the secretion of proteins tailored to interfere with eukaryotic processes, called effector proteins. All Chlamydiaceae possess genes coding for four to five effectors that share a domain of unknown function (DUF582). Here we show that four of these effectors, which represent the conserved set in all Chlamydiaceae, accumulate in the infectious form of C. trachomatis, and are therefore likely involved in an early step of the developmental cycle. The fifth member of the family, CT621, is specific to C. trachomatis, and is secreted during the growth phase. Using a two-hybrid screen in yeast we identified an interaction between the host protein Hrs and the DUF582, which we confirmed by co-immunoprecipitations in co-transfected mammalian cells. Furthermore, we provide biochemical evidence that a second domain of one of the DUF582 proteins, CT619, binds the host protein Tsg101. Hrs and Tsg101 are both implicated in a well conserved machinery of the eukaryotic cell called the ESCRT machinery, which is involved in several cellular processes requiring membrane constriction. Using RNA interference targeting proteins implicated at different stages of ESCRT-driven processes, or inhibition by expression of a dominant negative mutant of VPS4, we demonstrated that this machinery was dispensable for bacterial entry, multiplication and differentiation into infectious progeny, and for uptake of glycogen into the parasitophorous vacuole. In light of these observations we discuss how the DUF582 proteins might target the ESCRT machinery during infection. PMID- 27774441 TI - Changes of lip morphology following mandibular setback surgery using 3D cone-beam computed tomography images. AB - BACKGROUND: The aims of this study are to evaluate the lip morphology and change of lip commissure after mandibular setback surgery (MSS) for class III patients and analyze association between the amount of mandibular setback and change of lip morphology. METHODS: The samples consisted of 14 class III patients treated with MSS using bilateral sagittal split ramus osteotomy. Lateral cephalogram and cone-beam CT were taken before and about 6 months after MSS. Changes in landmarks and variables were measured with 3D software program OndemandTM. Paired and independent t tests were performed for statistical analysis. RESULTS: Landmarks in the mouth corner (cheilion, Ch) moved backward and downward (p < .005, p < .01). However, cheilion width was not statistically significantly changed. Landmark in labrale superius (Ls) was not altered significantly. Upper lip prominence angle (ChRt-Ls-ChLt degrees ) became acute. Landmarks in stomion (Stm), labrale inferius (Li) moved backward (p < .005, p < .001). Lower lip prominence angle (ChRt-Li-ChLt degrees ) became obtuse (p < .001). Height of the upper and lower lips was not altered significantly. Length of the upper lip vermilion was increased (p =< 0.01), and length of the lower lip vermilion was decreased (p < .05). Lip area on frontal view was not statistically significantly changed, but the upper lip area on lateral view was increased and change of the lower lip area decreased (p > .05, p < .005). On lateral view, upper lip prominent point (UP) moved downward and stomion moved backward and upward and the angle of Ls-UP-Stm ( degrees ) was decreased. Lower lip prominent point (LP) moved backward and downward, and the angle of Stm-LP-Li ( degrees ) was increased. Li moved backward. Finally, landmarks in the lower incisor tip (L1) moved backward and upward, but stomion moved downward. After surgery, lower incisor tip (L1) was positioned more superiorly than stomion (p < .05). There were significant associations between horizontal soft tissue and corresponding hard tissue. The posterior movement of L1 was related to statistically significantly about backward and downward movement of cheilion. CONCLUSIONS: The lip morphology of patients with dento-skeletal class III malocclusion shows a significant improvement after orthognathic surgery. Three-dimensional lip morphology changes in class III patients after MSS exhibited that cheilion moved backward and downward, upper lip projection angle became acute, lower lip projection angle became obtuse, change of upper lip area on lateral view was increased, change of lower lip area decreased, and morphology of lower lip was protruding. L1 was concerned with the lip tissue change in statistically significant way. PMID- 27774442 TI - The sequential management of recurrent temporomandibular joint ankylosis in a growing child: a case report. AB - BACKGROUND: Temporomandibular joint (TMJ) ankylosis in children often leads to facial deformity, functional deficit, and negative influence of the psychosocial development, which worsens with growth. The treatment of TMJ ankylosis in the pediatric patient is much more challenging than in adults because of a high incidence of recurrence and unfavorable growth of the mandible. CASE REPORT: This is a case report describing sequential management of the left TMJ ankylosis resulted from trauma in early childhood. The multiple surgeries including a costochondral graft and gap arthroplasty using interpositional silicone block were performed, but re-ankylosis of the TMJ occurred after surgery. Alloplastic TMJ prosthesis was conducted to prevent another ankylosis, and signs or symptoms of re-ankylosis were not found. Additional reconstruction surgery was performed to compensate mandibular growth after confirming growth completion. During the first 3 years of long-term follow-up, satisfactory functional and esthetic results were observed. CONCLUSIONS: This is to review the sequential management for the recurrent TMJ ankylosis in a growing child. Even though proper healing was expected after reconstruction of the left TMJ with costal cartilage graft, additional surgical interventions, including interpositional arthroplasty, were performed due to re-ankylosis of the affected site. In this case, alloplastic prosthesis could be an option to prevent TMJ re-ankylosis for growing pediatric patients with TMJ ankylosis in the beginning. PMID- 27774438 TI - Experimental Models of Foamy Macrophages and Approaches for Dissecting the Mechanisms of Lipid Accumulation and Consumption during Dormancy and Reactivation of Tuberculosis. AB - Despite a slight decline since 2014, tuberculosis (TB) remains the major deadly infectious disease worldwide with about 1.5 million deaths each year and with about one-third of the population being latently infected with Mycobacterium tuberculosis, the etiologic agent of TB. During primo-infection, the recruitment of immune cells leads to the formation of highly organized granulomas. Among the different cells, one outstanding subpopulation is the foamy macrophage (FM), characterized by the abundance of triacylglycerol-rich lipid bodies (LB). M. tuberculosis can reside in FM, where it acquires, from host LB, the neutral lipids which are subsequently processed and stored by the bacilli in the form of intracytosolic lipid inclusions (ILI). Although host LB can be viewed as a reservoir of nutrients for the pathogen during latency, the molecular mechanisms whereby intraphagosomal mycobacteria interact with LB and assimilate the LB derived lipids are only beginning to be understood. Past studies have emphasized that these physiological processes are critical to the M. tuberculosis infectious life cycle, for propagation of the infection, establishment of the dormancy state and reactivation of the disease. In recent years, several animal and cellular models have been developed with the aim of dissecting these complex processes and of determining the nature and contribution of their key players. Herein, we review some of the in vitro and in vivo models which allowed to gain significant insight into lipid accumulation and consumption in M. tuberculosis, two important events that are directly linked to pathogenicity, granuloma formation/maintenance and survival of the tubercle bacillus under non-replicative conditions. We also discuss the advantages and limitations of each model, hoping that this will serve as a guide for future investigations dedicated to persistence and innovative therapeutic approaches against TB. PMID- 27774443 TI - The Utility of Fecal Calprotectin in the Real-World Clinical Care of Patients with Inflammatory Bowel Disease. AB - Objectives. To determine the relationship between fecal calprotectin (FCAL) and imaging studies and other biochemical inflammatory markers and the impact of FCAL measurements on decision-making in IBD patient management in usual clinical practice. Methods. 240 persons with IBD were enrolled. The correlation between FCAL values and other markers for disease activity such as serum albumin (alb), hemoglobin (Hg), and C-reactive protein (CRP) and diagnostic imaging or colonoscopy was examined. FCAL >= 250 mcg/g of stool was considered a positive result indicating active IBD. Results. 183 stool samples (76.3%) were returned. The return rate in the pediatric and adult cohorts was 91% (n = 82) and 67.3% (n = 101), respectively (P < 0.0001). Positive FCAL was associated with colonoscopy findings of active IBD (P < 0.05), low albumin (P < 0.05), anemia (P < 0.01), and elevated CRP (P < 0.01). There was no significant difference for FCAL results by outcomes on small bowel evaluation among the 21 persons with small bowel CD. Most persons (87.5%) with normal FCAL and no change in therapy remained in remission during subsequent 3 months. Conclusions. FCAL is a useful marker of disease activity and a valuable tool in managing persons with IBD in clinical practice. Clinicians have to be cautious in interpreting FCAL results in small bowel CD. PMID- 27774444 TI - Changes in Urine Microalbumin-to-Creatinine Ratio in Children with Sickle Cell Disease over Time. AB - BACKGROUND: Approximately 20% of children with sickle cell disease (SCD) have microalbuminuria (MA). Very little is known about the progression of MA in children and young adults with SCD. METHODS: In this study, we analyzed 5-year EMR data of 373 children [with >=2 microalbumin-to-creatinine (MA/Cr) ratio measurements] followed at the Medical University of South Carolina to determine the rate, direction, magnitude, and predictors of MA/Cr change over time. RESULTS: Age range was 1-22 years; mean 10.2 +/- 5.2 years, 49.5% were males. Median follow-up duration was 3.12 +/- 1.16 years. At baseline, 328 children had normal (<20 mg/L) MA level. Forty-five (12.1%) of children had MA (>=20 mg/L), of which 91% were >=8 years and 21 (47%) continued to have MA at the end of the study period. On the other hand, during the study period, 24 new patients developed MA and 24 normalized their MA to levels <20 mg/L. In multivariate logistic regression model, age and bilirubin levels were predictive of MA/Cr increase in patients who received at least one blood transfusion during the study period. Baseline MA level was not predictive of the change in MA/Cr. CONCLUSION: In children and young adults, microalbuminuria is considered a marker of early renal injury. Over time, MA/Cr levels may increase or decrease. Further studies are needed to confirm our findings, assess the reliability of MA as marker of long-term renal injury, and identify high risk patients with SCD likely to have worsening of MA over time. PMID- 27774445 TI - ECLS in Pediatric Cardiac Patients. AB - Extracorporeal life support (ECLS) is an important device in the management of children with severe refractory cardiac and or pulmonary failure. Actually, two forms of ECLS are available for neonates and children: extracorporeal membrane oxygenation (ECMO) and use of a ventricular assist device (VAD). Both these techniques have their own advantages and disadvantages. The intra-aortic balloon pump is another ECLS device that has been successfully used in larger children, adolescents, and adults, but has found limited applicability in smaller children. In this review, we will present the "state of art" of ECMO in neonate and children with heart failure. ECMO is commonly used in a variety of settings to provide support to critically ill patients with cardiac disease. However, a strict selection of patients and timing of intervention should be performed to avoid the increase in mortality and morbidity of these patients. Therefore, every attempt should be done to start ECLS "urgently" rather than "emergently," before the presence of dysfunction of end organs or circulatory collapse. Even though exciting progress is being made in the development of VADs for long-term mechanical support in children, ECMO remains the mainstay of mechanical circulatory support in children with complex anatomy, particularly those needing rapid resuscitation and those with a functionally univentricular circulation. With the increase in familiarity with ECMO, new indications have been added, such as extracorporeal cardiopulmonary resuscitation (ECPR). The literature supporting ECPR is increasing in children. Reasonable survival rates have been achieved after initiation of support during active compressions of the chest following in hospital cardiac arrest. Contraindications to ECLS have reduced in the last 5 years and many centers support patients with functionally univentricular circulations. Improved results have been recently achieved in this complex subset of patients. PMID- 27774446 TI - Revealing Facts and Avoiding Biases: A Review of Several Common Problems in Statistical Analyses of Epidemiological Data. AB - This paper reviews several common challenges encountered in statistical analyses of epidemiological data for epidemiologists. We focus on the application of linear regression, multivariate logistic regression, and log-linear modeling to epidemiological data. Specific topics include: (a) deletion of outliers, (b) heteroscedasticity in linear regression, (c) limitations of principal component analysis in dimension reduction, (d) hazard ratio vs. odds ratio in a rate comparison analysis, (e) log-linear models with multiple response data, and (f) ordinal logistic vs. multinomial logistic models. As a general rule, a thorough examination of a model's assumptions against both current data and prior research should precede its use in estimating effects. PMID- 27774448 TI - Psoriasis-Specific RNA Isoforms Identified by RNA-Seq Analysis of 173,446 Transcripts. AB - BACKGROUND: Several studies have been published that investigated potential links between transcriptome changes and psoriasis using microarrays and RNA-seq technologies, but no previous study has analyzed expression profile of alternatively spliced transcripts in psoriasis. OBJECTIVES: Identification of potential alternatively spliced RNA isoforms with disease-specific expression profile. METHODS: Using our published RNA sequencing data from lesional psoriatic (LP), non-lesional psoriatic (NLP), and normal control skin (C), we analyzed the differential expression of RNA splicing variants. LP sample was compared with NLP, as was LP with C and NLP with C. RESULTS: Transcript-based annotation analyzed 173,446 transcripts (RNA isoforms), and around 9,000 transcripts were identified as differentially expressed between study groups. Several previously undescribed RNA variants were found. For instance, transcript ETV3_3 (ENST00000326786) was significantly downregulated in LP and NLP skin. ETV3 is a transcriptional repressor that contributes to the downstream anti-inflammatory effects of IL-10. We also identified diseases-specific transcripts (S100A7A, IL36RN_4, and IL36G_3) of genes already recognized to be involved in inflammation and immune response. CONCLUSION: Psoriasis is characterized by significant differences in the expression of RNA alternative isoforms. Description of these new isoforms improves our knowledge about this complex disease. PMID- 27774449 TI - Unsustainability of Obesity: Metabolic Food Waste. AB - The obesity burden, with 1.5 billion overweight (OW) and 500 million obese (OB) worldwide, significantly increased the risk of degenerative diseases. Excessive consumption of foods that are energy dense lead to obesity, which represents a titanic cost for not only the world's health systems but also a substantial ecological cost to the environment. The waste of resources and the unnecessary green house gas emissions (GHGs) emission, due to "obesigen" consumption of foods, have been ignored so far in practical assessments of ecological impacts. Our position is that food eaten above physiological needs, manifesting as obesity, should be considered waste. In this study, we developed a new indicator, metabolic food waste [MFW(kg of food)], corresponding to the amount of food leading to excess body fat and its impact on environment expressed as carbon [Formula: see text], water [MFW(*10 L)], and land footprint [Formula: see text]. Results shows that the average amount of MFW(kg of food) was of 63.1 and 127.2 kg/capita in a observational study on 60 OW and OB subjects. Animal products contributed mostly to MFW(kg of food) in both OW (24.3 kg) and OB (46.5 kg), followed by cereals, legumes and starchy roots (19.4 kg OW; 38.9 kg OB), sugar and sweets (9.0 kg OW; 16.4 kg OB), and alcoholic beverages (7.5 kg OW; 20.1 kg OB). When dietary intake corresponding to MFW was transformed in ecological indexes, animal products displayed the highest values for carbon emissions, water consumption, and land use in both OW and OB followed by cereals, legumes, and starchy roots. The estimated MFW(kg of food) of the Italian population resulted to be 2.081 million kilograms of food for OB and OW. Reducing obesity will make a contribution toward achieving sustainable and functional diets, preserving and re allocating natural resources for fighting hunger and malnutrition, and reducing GHGs emissions. Although further evidences in epidemiological studies are needed, MFW represents an innovative and reliable tool to unravel the diet-environment health trilemma. PMID- 27774447 TI - In vitro Engineering of Novel Bioactivity in the Natural Enzymes. AB - Enzymes catalyze various biochemical functions with high efficiency and specificity. In vitro design of the enzyme leads to novel bioactivity in this natural biomolecule that give answers of some vital questions like crucial residues in binding with substrate, molecular evolution, cofactor specificity etc. Enzyme engineering technology involves directed evolution, rational designing, semi-rational designing, and structure-based designing using chemical modifications. Similarly, combined computational and in vitro evolution approaches together help in artificial designing of novel bioactivity in the natural enzyme. DNA shuffling, error prone PCR and staggered extension process are used to artificially redesign active site of enzyme, which can alter its efficiency and specificity. Modifications of the enzyme can lead to the discovery of new path of molecular evolution, designing of efficient enzymes, locating active sites and crucial residues, shift in substrate, and cofactor specificity. The methods and thermodynamics of in vitro designing of the enzyme are also discussed. Similarly, engineered thermophilic and psychrophilic enzymes attain substrate specificity and activity of mesophilic enzymes that may also be beneficial for industry and therapeutics. PMID- 27774451 TI - The Hyponatremia Epidemic: A Frontier Too Far? AB - Hyponatremia is the most common electrolyte abnormality and is often neglected, especially in elderly and seemingly terminal patients. Hyponatremia can be asymptomatic or can cause symptoms ranging from nausea and lethargy to convulsions and coma. This condition has become increasingly common over time with a similar time course to the increase in adoption of low salt diets. The popularization of low salt may not be justified in people with normal kidney function in whom the compatible statistically based evidence that salt causes hypertension has been challenged by experimental evidence to the contrary. PMID- 27774450 TI - Effects of a Mutation in the HSPE1 Gene Encoding the Mitochondrial Co-chaperonin HSP10 and Its Potential Association with a Neurological and Developmental Disorder. AB - We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature. To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although, we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient. PMID- 27774453 TI - Dual-Modality Imaging of the Human Finger Joint Systems by Using Combined Multispectral Photoacoustic Computed Tomography and Ultrasound Computed Tomography. AB - We developed a homemade dual-modality imaging system that combines multispectral photoacoustic computed tomography and ultrasound computed tomography for reconstructing the structural and functional information of human finger joint systems. The fused multispectral photoacoustic-ultrasound computed tomography (MPAUCT) system was examined by the phantom and in vivo experimental tests. The imaging results indicate that the hard tissues such as the bones and the soft tissues including the blood vessels, the tendon, the skins, and the subcutaneous tissues in the finger joints systems can be effectively recovered by using our multimodality MPAUCT system. The developed MPAUCT system is able to provide us with more comprehensive information of the human finger joints, which shows its potential for characterization and diagnosis of bone or joint diseases. PMID- 27774452 TI - RNA Sequencing of Formalin-Fixed, Paraffin-Embedded Specimens for Gene Expression Quantification and Data Mining. AB - Background. Proper rRNA depletion is crucial for the successful utilization of FFPE specimens when studying gene expression. We performed a study to evaluate two major rRNA depletion methods: Ribo-Zero and RNase H. RNAs extracted from 4 samples were treated with the two rRNA depletion methods in duplicate and sequenced (N = 16). We evaluated their reducibility, ability to detect RNA, and ability to molecularly subtype these triple negative breast cancer specimens. Results. Both rRNA depletion methods produced consistent data between the technical replicates. We found that the RNase H method produced higher quality RNAseq data as compared to the Ribo-Zero method. In addition, we evaluated the RNAseq data generated from the FFPE tissue samples for noncoding RNA, including lncRNA, enhancer/super enhancer RNA, and single nucleotide variation (SNV). We found that the RNase H is more suitable for detecting high-quality, noncoding RNAs as compared to the Ribo-Zero and provided more consistent molecular subtype identification between replicates. Unfortunately, neither method produced reliable SNV data. Conclusions. In conclusion, for FFPE specimens, the RNase H rRNA depletion method performed better than the Ribo-Zero. Neither method generates data sufficient for SNV detection. PMID- 27774454 TI - Computer Based Melanocytic and Nevus Image Enhancement and Segmentation. AB - Digital dermoscopy aids dermatologists in monitoring potentially cancerous skin lesions. Melanoma is the 5th common form of skin cancer that is rare but the most dangerous. Melanoma is curable if it is detected at an early stage. Automated segmentation of cancerous lesion from normal skin is the most critical yet tricky part in computerized lesion detection and classification. The effectiveness and accuracy of lesion classification are critically dependent on the quality of lesion segmentation. In this paper, we have proposed a novel approach that can automatically preprocess the image and then segment the lesion. The system filters unwanted artifacts including hairs, gel, bubbles, and specular reflection. A novel approach is presented using the concept of wavelets for detection and inpainting the hairs present in the cancer images. The contrast of lesion with the skin is enhanced using adaptive sigmoidal function that takes care of the localized intensity distribution within a given lesion's images. We then present a segmentation approach to precisely segment the lesion from the background. The proposed approach is tested on the European database of dermoscopic images. Results are compared with the competitors to demonstrate the superiority of the suggested approach. PMID- 27774455 TI - DTI Image Registration under Probabilistic Fiber Bundles Tractography Learning. AB - Diffusion Tensor Imaging (DTI) image registration is an essential step for diffusion tensor image analysis. Most of the fiber bundle based registration algorithms use deterministic fiber tracking technique to get the white matter fiber bundles, which will be affected by the noise and volume. In order to overcome the above problem, we proposed a Diffusion Tensor Imaging image registration method under probabilistic fiber bundles tractography learning. Probabilistic tractography technique can more reasonably trace to the structure of the nerve fibers. The residual error estimation step in active sample selection learning is improved by modifying the residual error model using finite sample set. The calculated deformation field is then registered on the DTI images. The results of our proposed registration method are compared with 6 state of-the-art DTI image registration methods under visualization and 3 quantitative evaluation standards. The experimental results show that our proposed method has a good comprehensive performance. PMID- 27774456 TI - Potential of Polycyclic Aromatic Hydrocarbon-Degrading Bacterial Isolates to Contribute to Soil Fertility. AB - Restoration of polycyclic aromatic hydrocarbon- (PAH-) polluted sites is presently a major challenge in agroforestry. Consequently, microorganisms with PAH-degradation ability and soil fertility improvement attributes are sought after in order to achieve sustainable remediation of polluted sites. This study isolated PAH-degrading bacteria from enriched cultures of spent automobile engine oil polluted soil. Isolates' partial 16S rRNA genes were sequenced and taxonomically classified. Isolates were further screened for their soil fertility attributes such as phosphate solubilization, atmospheric nitrogen fixation, and indoleacetic acid (IAA) production. A total of 44 isolates were obtained and belong to the genera Acinetobacter, Arthrobacter, Bacillus, Flavobacterium, Microbacterium, Ochrobactrum, Pseudomonas, Pseudoxanthomonas, Rhodococcus, and Stenotrophomonas. Data analysed by principal component analysis showed the Bacillus and Ochrobactrum isolates displayed outstanding IAA production. Generalized linear modelling statistical approaches were applied to evaluate the contribution of the four most represented genera (Pseudomonas, Acinetobacter, Arthrobacter, and Rhodococcus) to soil fertility. The Pseudomonas isolates were the most promising in all three soil fertility enhancement traits evaluated and all isolates showed potential for one or more of the attributes evaluated. These findings demonstrate a clear potential of the isolates to participate in restorative bioremediation of polluted soil, which will enhance sustainable agricultural production and environmental protection. PMID- 27774457 TI - Relationship between Frontal Gap and Postoperative Stability in the Treatment of Mandibular Prognathism. AB - Objectives. To investigate the correlation between frontal gaps and skeletal stability after intraoral vertical ramus osteotomy (IVRO) for correction of mandibular prognathism. Materials and Methods. Thirty-three patients with frontal gaps after IVRO-based mandibular prognathism correction were included. Three lateral and frontal cephalometric radiographs were obtained: preoperatively (T1), immediately postoperatively (T2), and 2 years postoperatively (T3). Two linear measurements (menton [Me] and frontal gap) were compared from T1 to T3 (T21: immediate surgical changes; T32: postoperative stability; T31: 2-year surgical change). Data were analyzed using Pearson's correlation coefficient and multiple linear regression. Results. The T21 mean surgical horizontal change in the Me position was 12.4 +/- 4.23 mm. Vertically, the mean downward Me movement was 0.6 +/- 1.73 mm. The mean frontal gaps were 4.7 +/- 2.68 mm and 4 +/- 2.48 mm in the right and left gonial regions, respectively. Postoperative stability (T32) significantly correlated with the amount of setback. Frontal gaps did not have a significant effect on postoperative stability. However, multiple regression model (R2 = 0.341, P = 0.017) showed value predictability, especially in the amount of setback. Conclusion. Frontal gaps occur after IVRO but have no significant effect on long-term postoperative skeletal stability. The primary risk factor for postoperative relapse remains the amount of mandibular setback. PMID- 27774458 TI - Short-Term High-Intensity Interval Training on Body Composition and Blood Glucose in Overweight and Obese Young Women. AB - This study was to determine the effects of five-week high-intensity interval training (HIIT) on cardiorespiratory fitness, body composition, blood glucose, and relevant systemic hormones when compared to moderate-intensity continuous training (MICT) in overweight and obese young women. Methods. Eighteen subjects completed 20 sessions of HIIT or MICT for five weeks. HIIT involved 60 * 8 s cycling at ~90% of peak oxygen consumption ([Formula: see text]) interspersed with 12 s recovery, whereas MICT involved 40-minute continuous cycling at 65% of [Formula: see text]. [Formula: see text], body composition, blood glucose, and fasting serum hormones, including leptin, growth hormone, testosterone, cortisol, and fibroblast growth factor 21, were measured before and after training. Results. Both exercise groups achieved significant improvements in [Formula: see text] (+7.9% in HIIT versus +11.7% in MICT) and peak power output (+13.8% in HIIT versus +21.9% in MICT) despite no training effects on body composition or the relevant systemic hormones. Blood glucose tended to be decreased after the intervention (p = 0.062). The rating of perceived exertion in MICT was higher than that in HIIT (p = 0.042). Conclusion. Compared with MICT, short-term HIIT is more time-efficient and is perceived as being easier for improving cardiorespiratory fitness and fasting blood glucose for overweight and obese young women. PMID- 27774461 TI - Editorial: an introduction and welcome to Hypoxia. PMID- 27774459 TI - Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice. AB - Aim. Models combining diabetes and atherosclerosis are important in evaluating the cardiovascular (CV) effects and safety of antidiabetes drugs in the development of treatments targeting CV complications. Our aim was to evaluate if crossing the heterozygous glucokinase knockout mouse (GK+/-) and hyperlipidemic mouse deficient in apolipoprotein E (ApoE-/-) will generate a disease model exhibiting a diabetic and macrovascular phenotype. Methods. The effects of defective glucokinase on the glucose metabolism and on the progression and regression of atherosclerosis on high-fat diets were studied in both genders of GK+/-ApoE-/- and ApoE-/- mice. Coronary vascular function of the female GK+/-ApoE /- and ApoE-/- mice was also investigated. Results. GK+/-ApoE-/- mice show a stable hyperglycemia which was increased on Western diet. In oral glucose tolerance test, GK+/-ApoE-/- mice showed significant glucose intolerance and impaired glucose-stimulated insulin secretion. Plasma lipids were comparable with ApoE-/- mice; nevertheless the GK+/-ApoE-/- mice showed slightly increased atherosclerosis development. Conclusions. The GK+/-ApoE-/- mice showed a stable and reproducible hyperglycemia, accelerated atherosclerotic lesion progression, and no lesion regression after lipid lowering. This novel model provides a promising tool for drug discovery, enabling the evaluation of compound effects against both diabetic and cardiovascular endpoints simultaneously in one animal model. PMID- 27774460 TI - Activated Circulating T Follicular Helper Cells Are Associated with Disease Severity in Patients with Psoriasis. AB - Circulating T follicular helper (cTfh) cells are known to be involved in numerous immune-mediated diseases, but their pathological role in psoriasis is less fully investigated. Herein, we aimed to identify whether cTfh cells contributed to the pathogenesis of psoriasis. The frequency and function of cTfh cells were compared between patients with psoriasis vulgaris and healthy controls, and the infiltration of Tfh cells was detected between lesional and nonlesional skin tissues of psoriasis patients. Moreover, the dynamic change of cTfh cells before and after acitretin treatment was evaluated. Our results showed both increased frequency and activation (indicated by higher expression of ICOS, PD-1, HLA-DR, and Ki-67 and increased production of IL-21, IL-17, and IFN-gamma) of cTfh cells in psoriasis patients. Compared with nonlesional skin tissues of psoriasis patients, the number of infiltrated Tfh cells was significantly increased in psoriasis lesions. In addition, positive correlations between the percentage of cTfh, functional markers on cTfh cells in peripheral blood and disease severity were noted. Furthermore, the frequency of cTfh cells and the levels of cytokines secreted by cTfh cells were all significantly decreased after 1-month treatment. PMID- 27774463 TI - Hypoxia and the modulation of the actin cytoskeleton - emerging interrelations. AB - Recent progress in understanding the influence of hypoxia on cell function has revealed new information about the interrelationship between the actin cytoskeleton and hypoxia; nevertheless, details remain cloudy. The dynamic regulation of the actin cytoskeleton during hypoxia is complex, varies in different cells and tissues, and also depends on the mode of hypoxia. Several molecular players and pathways are emerging that contribute to the modulation of the actin cytoskeleton and that affect the large repertoire of actin-binding proteins in hypoxia. This review describes and discusses the accumulated knowledge about actin cytoskeleton dynamics in hypoxia, placing special emphasis on the Rho family of small guanosine triphosphatases (Rho GTPases). Given that RhoA, Rac and Cdc42 are very well characterized, the review is focused on these family members of Rho GTPases. Notably, in several cell types and tissues, hypoxia, presumably via Rho GTPase signaling, induces actin rearrangement and actin stress fiber assembly, which is a prevalent modulation of the actin cytoskeleton in hypoxia. PMID- 27774462 TI - One more stem cell niche: how the sensitivity of chronic myeloid leukemia cells to imatinib mesylate is modulated within a "hypoxic" environment. AB - This is a review (by no means comprehensive) of how the stem cell niche evolved from an abstract concept to a complex system, implemented with a number of experimental data at the cellular and molecular levels, including metabolic cues, on which we focused in particular. The concept was introduced in 1978 to model bone marrow sites suited to host hematopoietic stem cells (HSCs) and favor their self-renewal, while restraining clonal expansion and commitment to differentiation. Studies of the effects of low oxygen tension on HSC maintenance in vitro led us to hypothesize niches were located within bone marrow areas where oxygen tension is lower than elsewhere. We named these areas hypoxic stem cell niches, although a low oxygen tension is to be considered physiological for the environment where HSCs are maintained. HSCs were later shown to have the option of cycling in low oxygen, which steers this cycling to the maintenance of stem cell potential. Cell subsets capable of withstanding incubation in very low oxygen were also detected within leukemia cell populations, including chronic myeloid leukemia (CML). The oncogenetic Bcr/Abl protein is completely suppressed in these subsets, whereas Bcr/Abl messenger ribonucleic acid is not, indicating that CML cells resistant to low oxygen are independent of Bcr/Abl for persistence in culture but remain genetically leukemic. Accordingly, leukemia stem cells of CML selected in low oxygen are refractory to the Bcr/Abl inhibitor imatinib mesylate. Bcr/Abl protein suppression turned out to be actually determined when glucose shortage complicated the effects of low oxygen, indicating that ischemia like conditions are the driving force of leukemia stem cell refractoriness to imatinib mesylate. These studies pointed to "ischemic" stem cell niches as a novel scenario for the maintenance of minimal residual disease of CML. A possible functional relationship of the "ischemic" with the "hypoxic" stem cell niche is discussed. PMID- 27774464 TI - Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer. AB - Hypoxia and the hypoxia-inducible factor (HIF) signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2), which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2alpha dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2alpha, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2alpha silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2alpha tumor levels with prolonged overall survival of patients with breast cancer. PMID- 27774465 TI - Direct phosphorylation events involved in HIF-alpha regulation: the role of GSK 3beta. AB - Hypoxia-inducible factors (HIFs), consisting of alpha- and beta-subunits, are critical regulators of the transcriptional response to hypoxia under both physiological and pathological conditions. To a large extent, the protein stability and the recruitment of coactivators to the C-terminal transactivation domain of the HIF alpha-subunits determine overall HIF activity. The regulation of HIF alpha-subunit protein stability and coactivator recruitment is mainly achieved by oxygen-dependent posttranslational hydroxylation of conserved proline and asparagine residues, respectively. Under hypoxia, the hydroxylation events are inhibited and HIF alpha-subunits stabilize, translocate to the nucleus, dimerize with the beta-subunits, and trigger a transcriptional response. However, under normal oxygen conditions, HIF alpha-subunits can be activated by various growth and coagulation factors, hormones, cytokines, or stress factors implicating the involvement of different kinase pathways in their regulation, thereby making HIF-alpha-regulating kinases attractive therapeutic targets. From the kinases known to regulate HIF alpha-subunits, only a few phosphorylate HIF alpha directly. Here, we review the direct phosphorylation of HIF-alpha with an emphasis on the role of glycogen synthase kinase-3beta and the consequences for HIF-1alpha function. PMID- 27774466 TI - HIF-mediated innate immune responses: cell signaling and therapeutic implications. AB - Leukocytes recruited to infected, damaged, or inflamed tissues during an immune response must adapt to oxygen levels much lower than those in the circulation. Hypoxia inducible factors (HIFs) are key mediators of cellular responses to hypoxia and, as in other cell types, HIFs are critical for the upregulation of glycolysis, which enables innate immune cells to produce adenosine triphosphate anaerobically. An increasing body of evidence demonstrates that hypoxia also regulates many other innate immunological functions, including cell migration, apoptosis, phagocytosis of pathogens, antigen presentation and production of cytokines, chemokines, and angiogenic and antimicrobial factors. Many of these functions are mediated by HIFs, which are not only stabilized posttranslationally by hypoxia, but also transcriptionally upregulated by inflammatory signals. Here, we review the role of HIFs in the responses of innate immune cells to hypoxia, both in vitro and in vivo, with a particular focus on myeloid cells, on which the majority of studies have so far been carried out. PMID- 27774467 TI - Complex role of HIF in cancer: the known, the unknown, and the unexpected. AB - Tumor hypoxia has long been recognized as a driving force of malignant progression and therapeutic resistance. The discovery of hypoxia-inducible transcription factors (HIFs) has greatly advanced our understanding of how cancer cells cope with hypoxic stress by maintaining bioenergetics through the stimulation of glycolysis. Until recently, however, it remained perplexing why proliferative cancer cells opt for aerobic glycolysis, an energy-inefficient process of glucose metabolism. Furthermore, the role of HIF in cancer has also become complex. In this review, we highlight recent groundbreaking findings in cancer metabolism, put forward plausible explanations to the complex role of HIF, and underscore remaining issues in cancer biology. PMID- 27774470 TI - The role of HIFs in ischemia-reperfusion injury. AB - The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury. PMID- 27774468 TI - The role of PHD2 mutations in the pathogenesis of erythrocytosis. AB - The transcription of the erythropoietin (EPO) gene is tightly regulated by the hypoxia response pathway to maintain oxygen homeostasis. Elevations in serum EPO level may be reflected in an augmentation in the red cell mass, thereby causing erythrocytosis. Studies on erythrocytosis have provided insights into the function of the oxygen-sensing pathway and the critical proteins involved in the regulation of EPO transcription. The alpha subunits of the hypoxia-inducible transcription factor are hydroxylated by three prolyl hydroxylase domain (PHD) enzymes, which belong to the iron and 2-oxoglutarate-dependent oxygenase superfamily. Sequence analysis of the genes encoding the PHDs in patients with erythrocytosis has revealed heterozygous germline mutations only occurring in Egl nine homolog 1 (EGLN1, also known as PHD2), the gene that encodes PHD2. To date, 24 different EGLN1 mutations comprising missense, frameshift, and nonsense mutations have been described. The phenotypes associated with the patients carrying these mutations are fairly homogeneous and typically limited to erythrocytosis with normal to elevated EPO. However, exceptions exist; for example, there is one case with development of concurrent paraganglioma (PHD2 H374R). Analysis of the erythrocytosis-associated PHD2 missense mutations has shown heterogeneous results. Structural studies reveal that mutations can affect different domains of PHD2. Some are close to the hypoxia-inducible transcription factor alpha/2-oxoglutarate or the iron binding sites for PHD2. In silico studies demonstrate that the mutations do not always affect fully conserved residues. In vitro and in cellulo studies showed varying effects of the mutations, ranging from mild effects to severe loss of function. The exact mechanism of a potential tumor-suppressor role for PHD2 still needs to be elucidated. A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels) and demonstrates that haploinsufficiency and partial deregulation of PHD2 is sufficient to cause erythrocytosis. PMID- 27774471 TI - Modulation of hydrogen sulfide by vascular hypoxia. AB - Hydrogen sulfide (H2S) has emerged as a key regulator of cardiovascular function. This gasotransmitter is produced in the vasculature and is involved in numerous processes that promote vascular homeostasis, including vasodilation and endothelial cell proliferation. Although H2S plays a role under physiological conditions, it has become clear in recent years that hypoxia modulates the production and action of H2S. Furthermore, there is growing evidence that H2S is cytoprotective in the face of hypoxic insults. This review focuses on the synthesis and signaling of H2S in hypoxic conditions in the vasculature, and highlights recent studies providing evidence that H2S is a potential therapy for preventing tissue damage in hypoxic conditions. PMID- 27774469 TI - The impact of hypoxia in pancreatic cancer invasion and metastasis. AB - Intratumoral hypoxia is a common feature of solid tumors. Recent advances in cancer biology indicate that hypoxia is not only a consequence of unrestrained tumor growth, but also plays an active role in promoting tumor progression, malignancy, and resistance to therapy. Hypoxia signaling is mediated by the hypoxia-inducible factors (HIFs), which are not only stabilized under hypoxia, but also by activated oncogenes or inactivated tumor suppressors under normoxia. Hypoxia is a prominent feature of the tumor microenvironment of pancreatic tumors, also characterized by the presence of a fibrotic reaction that promotes, and is also modulated by, hypoxia. As the mechanisms by which hypoxia signaling impacts invasion and metastasis in pancreatic cancer are being elucidated, hypoxia is emerging as a key determinant of pancreatic cancer malignancy as well as an important target for therapy. Herein we present an overview of recent advances in the understanding of the impact that hypoxia has in pancreatic cancer invasion and metastasis. PMID- 27774473 TI - Arginine-vasopressin marker copeptin is a sensitive plasma surrogate of hypoxic exposure. AB - BACKGROUND: A reduced oxygen supply puts patients at risk of tissue hypoxia, organ damage, and even death. In response, several changes are activated that allow for at least partial adaptation, thereby increasing the chances of survival. We aimed to investigate whether the arginine vasopressin marker, copeptin, can be used as a marker of the degree of acclimatization/adaptation in rats exposed to hypoxia. METHODS: Sprague-Dawley rats were exposed to 10% oxygen for up to 48 hours. Arterial and right ventricular pressures were measured, and blood gas analysis was performed at set time points. Pulmonary changes were investigated by bronchoalveolar lavage, wet and dry weight measurements, and lung histology. Using a newly developed specific rat copeptin luminescence immunoassay, the regulation of vasopressin in response to hypoxia was studied, as was atrial natriuretic peptide (ANP) by detecting mid-regional proANP. RESULTS: With a decreasing oxygen supply, the rats rapidly became cyanotic and inactive. Despite continued exposure to 10% oxygen, all animals recuperated within 16 hours and ultimately survived. Their systemic blood pressure fell with acute (5 minutes) hypoxia but was partially recovered over time. In contrast, right ventricular pressures increased with acute (5 minutes) hypoxia and normalized after 16 hours. No signs of pulmonary inflammation or edema were found despite prolonged hypoxia. Whereas copeptin levels increased significantly after acute (5 minutes) hypoxia and then returned to near baseline after 16 hours, mid-regional proANP levels were even further increased after 16 hours of exposure to hypoxia. CONCLUSION: Plasma copeptin is a sensitive marker of acute (5 minutes) exposure to severe hypoxia, and subsequent regulation can indicate recovery. Copeptin levels can therefore reflect clinical and physiological changes in response to hypoxia and indicate recovery from ongoing hypoxic exposure. PMID- 27774474 TI - Effects of copper sulfate-oxidized or myeloperoxidase-modified LDL on lipid loading and programmed cell death in macrophages under hypoxia. AB - Atheromatous plaques contain heavily lipid-loaded macrophages that die, hence generating the necrotic core of these plaques. Since plaque instability and rupture is often correlated with a large necrotic core, it is important to understand the mechanisms underlying foam cell death. Furthermore, macrophages within the plaque are associated with hypoxic areas but little is known about the effect of low oxygen partial pressure on macrophage death. The aim of this work was to unravel macrophage death mechanisms induced by oxidized low-density lipoproteins (LDL) both under normoxia and hypoxia. Differentiated macrophages were incubated in the presence of native, copper sulfate-oxidized, or myeloperoxidase-modified LDL. The unfolded protein response, apoptosis, and autophagy were then investigated. The unfolded protein response and autophagy were triggered by myeloperoxidase-modified LDL and, to a larger extent, by copper sulfate-oxidized LDL. Electron microscopy observations showed that oxidized LDL induced excessive autophagy and apoptosis under normoxia, which were less marked under hypoxia. Myeloperoxidase-modified LDL were more toxic and induced a higher level of apoptosis. Hypoxia markedly decreased apoptosis and cell death, as marked by caspase activation. In conclusion, the cell death pathways induced by copper sulfate-oxidized and myeloperoxidase-modified LDL are different and are differentially modulated by hypoxia. PMID- 27774472 TI - Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism. AB - The hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its alpha subunit in an oxygen-dependent manner. Trans-4-prolyl hydroxylation of HIFalpha under normal oxygen (O2) availability enables its association with the von Hippel-Lindau (VHL) tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFalpha via the ubiquitin proteasome pathway. Due to the obligatory requirement of molecular O2 as a co substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIFalpha, which dimerizes with HIFbeta and, together with transcriptional co-activators CBP/p300, activates the transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, HIF plays important roles in multiple cellular processes and its overexpression has been detected in various cancers. The HIF1alpha isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O2-dependent, metabolism of glucose. The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O2, such as by metabolic status, oxidative stress, and abnormal levels of endogenous metabolites (oncometabolites) that have been observed in some types of cancers. In this review, we aim to summarize current understandings of the function and regulation of PHDs in cancer with an emphasis on their roles in metabolism. PMID- 27774475 TI - Regulation of obesity and insulin resistance by hypoxia-inducible factors. AB - In obesity, dysregulated metabolism and aberrant expansion of adipose tissue lead to the development of tissue hypoxia that plays an important role in contributing to obesity-associated metabolic disorders. Recent studies utilizing adipocyte specific hypoxia-inducible factor-alpha (HIF-alpha) gain- or loss-of-function animal models highlight the pivotal involvement of hypoxic responses in the pathogenesis of obesity-associated inflammation and insulin resistance. HIF 1alpha, a master transcription factor of oxygen homeostasis, induces inflammation and insulin resistance in obesity, whereas its isoform, HIF-2alpha, exerts opposing functions in these obesity-associated metabolic phenotypes. In this review, recent evidence elucidating functional implications of adipocyte HIFs in obesity and, more importantly, how these regulate obesity-associated inflammation, fibrosis, and insulin resistance will be discussed. Further, we propose that modulation of HIF-1 could be a potential novel therapeutic strategy for antidiabetic treatment. PMID- 27774476 TI - Macrophage-mediated response to hypoxia in disease. AB - Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment. PMID- 27774479 TI - Resistance of subventricular neural stem cells to chronic hypoxemia despite structural disorganization of the germinal center and impairment of neuronal and oligodendrocyte survival. AB - Chronic hypoxemia, as evidenced in de-acclimatized high-altitude residents or in patients with chronic obstructive respiratory disorders, is a common medical condition that can produce serious neurological alterations. However, the pathogenesis of this phenomenon is unknown. We have found that adult rodents exposed for several days/weeks to hypoxia, with an arterial oxygen tension similar to that of chronically hypoxemic patients, manifest a partially irreversible structural disarrangement of the subventricular neurogenic niche (subventricular zone) characterized by displacement of neurons and myelinated axons, flattening of the ependymal cell layer, and thinning of capillary walls. Despite these abnormalities, the number of neuronal and oligodendrocyte progenitors, neuroblasts, and neurosphere-forming cells as well as the proliferative activity in subventricular zone was unchanged. These results suggest that neural stem cells and their undifferentiated progeny are resistant to hypoxia. However, in vivo and in vitro experiments indicate that severe chronic hypoxia decreases the survival of newly generated neurons and oligodendrocytes, with damage of myelin sheaths. These findings help explain the effects of hypoxia on adult neurogenesis and provide new perspectives on brain responsiveness to persistent hypoxemia. PMID- 27774477 TI - Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives. AB - By the early 1900s, the close matching of oxygen supply with demand was recognized to be a fundamental requirement for physiological function, and multiple adaptive responses to environment hypoxia had been described. Nevertheless, the widespread operation of mechanisms that directly sense and respond to levels of oxygen in animal cells was not appreciated for most of the twentieth century with investigators generally stressing the regulatory importance of metabolic products. Work over the last 25 years has overturned that paradigm. It has revealed the existence of a set of "oxygen-sensing" 2 oxoglutarate dependent dioxygenases that catalyze the hydroxylation of specific amino acid residues and thereby control the stability and activity of hypoxia inducible factor. The hypoxia-inducible factor hydroxylase pathway regulates a massive transcriptional cascade that is operative in essentially all animal cells. It transduces a wide range of responses to hypoxia, extending well beyond the classical boundaries of hypoxia physiology. Here we review the discovery and elucidation of these pathways, and consider the opportunities and challenges that have been brought into focus by the findings, including new implications for the integrated physiology of hypoxia and therapeutic approaches to ischemic/hypoxic disease. PMID- 27774480 TI - Frequently asked questions in hypoxia research. AB - "What is the O2 concentration in a normoxic cell culture incubator?" This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level. PMID- 27774481 TI - Induction of long noncoding RNA MALAT1 in hypoxic mice. AB - Long thought to be "junk DNA", in recent years it has become clear that a substantial fraction of intergenic genomic DNA is actually transcribed, forming long noncoding RNA (lncRNA). Like mRNA, lncRNA can also be spliced, capped, and polyadenylated, affecting a multitude of biological processes. While the molecular mechanisms underlying the function of lncRNAs have just begun to be elucidated, the conditional regulation of lncRNAs remains largely unexplored. In genome-wide studies our group and others recently found hypoxic transcriptional induction of a subset of lncRNAs, whereof nuclear-enriched abundant/autosomal transcript 1 (NEAT1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appear to be the lncRNAs most ubiquitously and most strongly induced by hypoxia in cultured cells. Hypoxia-inducible factor (HIF)-2 rather than HIF-1 seems to be the preferred transcriptional activator of these lncRNAs. For the first time, we also found strong induction primarily of MALAT1 in organs of mice exposed to inspiratory hypoxia. Most abundant hypoxic levels of MALAT1 lncRNA were found in kidney and testis. In situ hybridization revealed that the hypoxic induction in the kidney was confined to proximal rather than distal tubular epithelial cells. Direct oxygen-dependent regulation of MALAT1 lncRNA was confirmed using isolated primary kidney epithelial cells. In summary, high expression levels and acute, profound hypoxic induction of MALAT1 suggest a hitherto unrecognized role of this lncRNA in renal proximal tubular function. PMID- 27774482 TI - Measuring oxygen levels in Caco-2 cultures. AB - PURPOSE: Measuring oxygen levels in three different systems of Caco-2 cell culture. METHODS: Caco-2 cells were cultured in three different systems, using conventional polystyrene 24-well plates, special 24-well gas permeable plates, or on membrane inserts in conventional plates. Optical sensor spots were used to measure dissolved O2 levels in these cultured cells over the course of 6 days under normoxia (143 mmHg) and for 6 hours under hypoxia (7 mmHg). Western blot analysis was used to determine the protein levels of hypoxia-inducible factor 1alpha (HIF-1alpha) in the different cultures. RESULTS: All culture systems displayed lower O2 levels over time than expected when cultured under normoxia conditions. On average, O2 levels reached as low as 25 mmHg in 24-well plates but remained at 97 and 117 mmHg in gas permeable plates and membrane inserts, respectively. Under hypoxia, 1 mL cell cultures equilibrated to 7 mmHg O2 within the first 60 minutes and dropped to 0.39 and 0.61 mmHg O2 in 24-well and gas permeable plates, respectively, after the 6-hour incubation period. Cultures in membrane inserts did not equilibrate to 7 mmHg by the end of the 6-hour incubation period, where the lowest O2 measurements reached 23.12 mmHg. Western blots of HIF-1alpha protein level in the whole cell lysates of the different Caco 2 cultures revealed distinct stabilization of HIF-1alpha after hypoxic incubation for 1, 2, and 4 hours in 24-well plates as well as gas permeable plates. For membrane inserts, notable HIF-1alpha was seen after 4 hours of hypoxic incubation. CONCLUSION: Cellular oxygen depletion was achieved in different hypoxic Caco-2 culture systems. However, different oxygen levels comparing different culture systems indicate that O2 level should be carefully considered in oxygen-dependent experiments. PMID- 27774478 TI - Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges. AB - Oxygen is essential for metazoans to generate energy. Upon oxygen deprivation adaptive and protective pathways are induced, mediated by hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain-containing enzymes (PHDs). Both play a pivotal role in various conditions associated with prolonged ischemia and inflammation, and are promising targets for therapeutic intervention. This review focuses on aspects of therapeutic PHD modulation in surgically relevant disease conditions such as hepatic and intestinal disorders, wound healing, innate immune responses, and tumorigenesis, and discusses the therapeutic potential and challenges of PHD inhibition in surgical patients. PMID- 27774483 TI - Hypoxia: from basic mechanisms to therapeutics - a meeting report on the Keystone and HypoxiaNet Symposium. AB - In May 2015, the hypoxia research community came together at the largest meeting in this field to date, to present and discuss their most recent and mainly unpublished findings. This meeting report aims to summarize the data presented at this conference, which were broadly separated into the areas of the cellular hypoxic response, the relevance of the hypoxic response in health and disease, and the development of new therapeutics targeting the hypoxic response. PMID- 27774484 TI - Hypoxic regulation of osteoclast differentiation and bone resorption activity. AB - Bone integrity is maintained throughout life via the homeostatic actions of bone cells, namely, osteoclasts, which resorb bone, and osteoblasts, which produce bone. Disruption of this balance in favor of osteoclast activation results in pathological bone loss, which occurs in conditions including osteoporosis, rheumatoid arthritis, primary bone cancer, and cancer metastasis to bone. Hypoxia also plays a major role in these conditions, where it is associated with disease progression and poor prognosis. In recent years, considerable interest has arisen in the mechanisms whereby hypoxia and the hypoxia-inducible transcription factors, HIF-1alpha and HIF-2alpha, affect bone remodeling and bone pathologies. This review summarizes the current evidence for hypoxia-mediated regulation of osteoclast differentiation and bone resorption activity. Role(s) of HIF and HIF target genes in the formation of multinucleated osteoclasts from cells of the monocyte-macrophage lineage and in the activation of bone resorption by mature osteoclasts will be discussed. Specific attention will be paid to hypoxic metabolism and generation of ATP by osteoclasts. Hypoxia-driven increases in both glycolytic flux and mitochondrial metabolic activity, along with consequent generation of mitochondrial reactive oxygen species, have been found to be essential for osteoclast formation and resorption activity. Finally, evidence for the use of HIF inhibitors as potential therapeutic agents targeting bone resorption in osteolytic disease will be discussed. PMID- 27774487 TI - A Visualization of Evolving Clinical Sentiment Using Vector Representations of Clinical Notes. AB - Our objective in this paper was to visualize the evolution of clinical language and sentiment with respect to several common population-level categories including: time in the hospital, age, mortality, gender and race. Our analysis utilized seven years of unstructured free text notes from the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) database. The text data was partitioned by category and used to generate several high dimensional vector space representations. We generated visualizations of the vector spaces using Distributed Stochastic Neighbor Embedding (tSNE) and Principal Component Analysis (PCA). We also investigated representative words from clusters in the vector space. Lastly, we inferred the general sentiment of the clinical notes toward each parameter by gauging the average distance between positive and negative keywords and all other terms in the space. We found intriguing differences in the sentiment of clinical notes over time, outcome, and demographic features. We noted a decrease in the homogeneity and complexity of clusters over time for patients with poor outcomes. We also found greater positive sentiment for females, unmarried patients, and patients of African ethnicity. PMID- 27774488 TI - Designing Reliable Cohorts of Cardiac Patients across MIMIC and eICU. AB - The design of the patient cohort is an essential and fundamental part of any clinical patient study. Knowledge of the Electronic Health Records, underlying Database Management System, and the relevant clinical workflows are central to an effective cohort design. However, with technical, semantic, and organizational interoperability limitations, the database queries associated with a patient cohort may need to be reconfigured in every participating site. i2b2 and SHRINE advance the notion of patient cohorts as first class objects to be shared, aggregated, and recruited for research purposes across clinical sites. This paper reports on initial efforts to assess the integration of Medical Information Mart for Intensive Care (MIMIC) and Philips eICU, two large-scale anonymized intensive care unit (ICU) databases, using standard terminologies, i.e. LOINC, ICD9-CM and SNOMED-CT. Focus of this work is lab and microbiology observations and key demographics for patients with a primary cardiovascular ICD9-CM diagnosis. Results and discussion reflecting on reference core terminology standards, offer insights on efforts to combine detailed intensive care data from multiple ICUs worldwide. PMID- 27774486 TI - New perspectives on the molecular basis of the interaction between oxygen homeostasis and iron metabolism. AB - Oxygen and iron are two elements closely related from a (bio)chemical point of view. Moreover, they share the characteristic of being indispensable for life, while also being potentially toxic. Therefore, their level is strictly monitored, and sophisticated pathways have evolved to face variations in either element. In addition, the expression of proteins involved in iron and oxygen metabolism is mainly controlled by a complex interplay of proteins that sense both iron levels and oxygen availability (ie, prolyl hydroxylases, hypoxia inducible factors, and iron regulatory proteins), and in turn activate feedback mechanisms to re establish homeostasis. In this review, we describe how cells and organisms utilize these intricate networks to regulate responses to changes in oxygen and iron levels. We also explore the role of these pathways in some pathophysiological settings. PMID- 27774489 TI - Hemodynamic Monitoring Using Switching Autoregressive Dynamics of Multivariate Vital Sign Time Series. AB - In a critical care setting, shock and resuscitation endpoints are often defined based on arterial blood pressure values. Patient-specific fluctuations and interactions between heart rate (HR) and blood pressure (BP), however, may provide additional prognostic value to stratify individual patients' risks for adverse outcomes at different blood pressure targets. In this work, we use the switching autoregressive (SVAR) dynamics inferred from the multivariate vital sign time series to stratify mortality risks of intensive care units (ICUs) patients receiving vasopressor treatment. We model vital sign observations as generated from latent states from an autoregressive Hidden Markov Model (AR-HMM) process, and use the proportion of time patients stayed in different latent states to predict outcome. We evaluate the performance of our approach using minute-by-minute HR and mean arterial BP (MAP) of an ICU patient cohort while on vasopressor treatment. Our results indicate that the bivariate HR/MAP dynamics (AUC 0.74 [0.64, 0.84]) contain additional prognostic information beyond the MAP values (AUC 0.53 [0.42, 0.63]) in mortality prediction. Further, HR/MAP dynamics achieved better performance among a subgroup of patients in a low MAP range (median MAP < 65 mmHg) while on pressors. A realtime implementation of our approach may provide clinicians a tool to quantify the effectiveness of interventions and to inform treatment decisions. PMID- 27774485 TI - The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. AB - Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFKB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment. PMID- 27774490 TI - Implications of Visual Attention Phenomena for Models of Preferential Choice. AB - We use computational modeling to examine the ability of evidence accumulation models to produce the reaction time (RT) distributions and attentional biases found in behavioral and eye-tracking research. We focus on simulating RTs and attention in binary choice with particular emphasis on whether different models can predict the late onset bias (LOB), commonly found in eye movements during choice (sometimes called the gaze cascade). The first finding is that this bias is predicted by models even when attention is entirely random and independent of the choice process. This shows that the LOB is not evidence of a feedback loop between evidence accumulation and attention. Second, we examine models with a relative evidence decision rule and an absolute evidence rule. In the relative models a decision is made once the difference in evidence accumulated for 2 items reaches a threshold. In the absolute models, a decision is made once 1 item accumulates a certain amount of evidence, independently of how much is accumulated for a competitor. Our core result is simple-the existence of the late onset gaze bias to the option ultimately chosen, together with a positively skewed RT distribution means that the stopping rule must be relative not absolute. A large scale grid search of parameter space shows that absolute threshold models struggle to predict these phenomena even when incorporating evidence decay and assumptions of either mutual inhibition or feedforward inhibition. PMID- 27774491 TI - New polymorphism of the influenza virus resistance Mx1 gene in Iberian domestic pigs. AB - Mx1 (Myxovirus (Influenza virus) resistance 1, interferon-inducible protein p78) gene has been implicated in the resistance to a wide range of RNA viruses including influenza A in several species such as Sus scrofa. In the present study a 28-bp deletion in exon 14 of the Mx1 gene has been identified in Iberian domestic pigs but not in other domestic breeds neither in wild boars. The mutation produces a frameshift giving a protein with 6 amino acid substitutions and the extension of the C-terminal region with additional 20 amino acids with respect to the wild type MX1 protein. The new allelic polymorphism affects the antiviral domain of the MX1 protein and therefore might impact its anti-influenza virus activity. It has been demonstrated that polymorphisms in the Mx1 murine locus, affect the survival rate of mice upon experimental infection with influenza virus. It might be possible to improve the innate resistance of pigs to influenza virus infection by determining the porcine Mx1 alleles with more potent antiviral activity and genetically selecting animals bearing such alleles. PMID- 27774492 TI - College Status, Perceived Drinking Norms, and Alcohol Use among Sexual Minority Women. AB - Lesbian, gay, and bisexual young adults are at elevated risk for drinking compared to heterosexual young adults, and this discrepancy is particularly striking for sexual minority women (SMW). Perceived social norms are strong predictors of young adult alcohol use, especially among college students. The college environment is often one where increases in alcohol use are seen, but the impact of college status on SMW's drinking has been understudied. The present study explored patterns of alcohol use and consequences among SMW and the extent to which social norms relate to use and consequences. Participants were recruited via social networking sites for a larger national study on SMW's health behaviors. Present analyses focused on 875 SMW between 18 and 25 who were categorized as either a 2-year college student (n = 196), 4-year college student (n = 418), or non-student (n = 261). Several differences emerged between college and non-college SMW, with non-college women reporting higher alcohol use and social norms compared to 4-year college women. In terms of alcohol-related consequences, students in both 2-year and 4-year colleges reported a higher likelihood of any consequences. There was some evidence that perceived norms partially explained differences in typical drinking among the college status groups. The present findings suggest that college may play a protective role against heavy drinking for this population of young women, however, the results are not straightforward and additional research is warranted. PMID- 27774494 TI - Optimized SIFTFlow for registration of whole-mount histology to reference optical images. AB - The registration of two-dimensional histology images to reference images from other modalities is an important preprocessing step in the reconstruction of three-dimensional histology volumes. This is a challenging problem because of the differences in the appearances of histology images and other modalities, and the presence of large nonrigid deformations which occur during slide preparation. This paper shows the feasibility of using densely sampled scale-invariant feature transform (SIFT) features and a SIFTFlow deformable registration algorithm for coregistering whole-mount histology images with blockface optical images. We present a method for jointly optimizing the regularization parameters used by the SIFTFlow objective function and use it to determine the most appropriate values for the registration of breast lumpectomy specimens. We demonstrate that tuning the regularization parameters results in significant improvements in accuracy and we also show that SIFTFlow outperforms a previously described edge-based registration method. The accuracy of the histology images to blockface images registration using the optimized SIFTFlow method was assessed using an independent test set of images from five different lumpectomy specimens and the mean registration error was [Formula: see text]. PMID- 27774493 TI - Two-photon microscopy measurement of cerebral metabolic rate of oxygen using periarteriolar oxygen concentration gradients. AB - The cerebral metabolic rate of oxygen ([Formula: see text]) is an essential parameter for evaluating brain function and pathophysiology. However, the currently available approaches for quantifying [Formula: see text] rely on complex multimodal imaging and mathematical modeling. Here, we introduce a method that allows estimation of [Formula: see text] based on a single measurement modality-two-photon imaging of the partial pressure of oxygen ([Formula: see text]) in cortical tissue. We employed two-photon phosphorescence lifetime microscopy (2PLM) and the oxygen-sensitive nanoprobe PtP-C343 to map the tissue [Formula: see text] distribution around cortical penetrating arterioles. [Formula: see text] is subsequently estimated by fitting the changes of tissue [Formula: see text] around arterioles with the Krogh cylinder model of oxygen diffusion. We measured the baseline [Formula: see text] in anesthetized rats and modulated tissue [Formula: see text] levels by manipulating the depth of anesthesia. This method provides [Formula: see text] measurements localized within [Formula: see text] and it may provide oxygen consumption measurements in individual cortical layers or within confined cortical regions, such as in ischemic penumbra and the foci of functional activation. PMID- 27774495 TI - Impact of Cervical Dystonia on Work Productivity: An Analysis From a Patient Registry. AB - BACKGROUND: Cervical dystonia is thought to result in high disease burden, but limited information exists on its impact on employment and work productivity. We utilized data from the Cervical Dystonia Patient Registry for the Observation of OnabotulinumtoxinA Efficacy (ClinicalTrials.gov identifier: NCT00836017) to assess the impact of cervical dystonia on employment and work productivity and examine the effect of onabotulinumtoxinA treatments on work productivity. METHODS: Subjects completed a questionnaire on employment status and work productivity at baseline and final visit. Baseline data were examined by severity of cervical dystonia, predominant subtype, presence of pain, prior exposure to botulinum toxin, and/or utility of a sensory trick. Work productivity results at baseline and final visit were compared in subjects who were toxin-naive at baseline and received three onabotulinumtoxinA treatments. RESULTS: Of 1,038 subjects, 42.8% were employed full- or part-time, 6.1% unemployed, 32.7% retired, and 11.8% disabled. Of those currently employed, cervical dystonia affected work status of 26.0%, caused 29.8% to miss work in the past month (mean, 5.1 +/- 6.4 days), and 57.8% reported decreased productivity. Half of those unemployed were employed when symptoms began, and 38.5% attributed lost employment to cervical dystonia. Pain, increasing severity, and anterocollis/retrocollis had the largest effects on work status/productivity. Preliminary analyses showed that absenteeism and presenteeism were significantly decreased following onabotulinumtoxinA treatments in the subpopulation that was toxin-naive at baseline. CONCLUSIONS: This analysis confirms the substantial negative impact of cervical dystonia on employment, with cervical dystonia-associated pain being a particularly important driver. OnabotulinumtoxinA treatment appears to improve work productivity. PMID- 27774496 TI - Parkinson's Impulse-Control Scale for the Severity Rating of Impulse-Control Behaviors in Parkinson's Disease: A Semistructured Clinical Assessment Tool. AB - BACKGROUND: Impulse-control behaviors (ICBs) are increasingly recognized in Parkinson's disease (PD) as drug-related effects of dopaminergic mediation that occur in 15% to 35% of patients with PD. The authors describe the design and evaluation of a new, clinician-rated severity scale for the assessment of syndromal and subsyndromal forms of impulse-control disorders (ICDs), simple (punding) and complex (hobbyism) repetitive behaviors, and compulsive overuse of medication (dopamine dysregulation syndrome). METHODS: The Parkinson's Impulse Control Scale (PICS), the first PD-specific, semistructured interview to cover the full range of PD-related ICBs, is described along with initial evidence on its clinimetric properties including interrater reliability, discriminant validity and sensitivity to change. A convenience sample of PD patients with ICBs and those without were administered a semistructured interview (n = 92). RESULTS: The scale distinguished between those with and without clinically detected ICBs and between patients with syndromal ICD and subsyndromal ICB (receiver operating characteristic areas under the curve, 92%-95%). Cutoff values were suggested, and substantial agreement was reported on weighted kappa (Kappa) values for clinician clinician rating of severity (Kappa = 0.92). Significant improvements were detected on the scale after a randomized controlled trial of cognitive-behavioral therapy and medication adjustment (t[22] = 5.47; P < 0.001). CONCLUSIONS: The PICS appears to be a reliable measure of the full range of PD ICBs with good levels of interrater reliability. It may provide a useful measure to assess the severity of ICBs and monitor change in clinical and research settings; although, given the specialized centers used for recruitment of this sample, further psychometric evaluation is required. PMID- 27774497 TI - Mercury concentration in muscle, bellyfat and liver from Oreochromis niloticus and Lates niloticus consumed in Lake Albert fishing communities in Uganda. AB - Without surveillance studies on mercury (Hg) levels in predominant fish species and parts eaten in a fishing community, the FAO/WHO guidelines might be surpassed, hence health risk. A monitoring study in a developing country with 29 Oreochromis niloticus (Nile tilapia) and 34 Lates niloticus (Nile perch) from landing sites provided muscle, bellyfat and liver samples for Mercury detection using Inductive Couple Plasma-optical emission spectroscopy. The study shows that fish eaten in the fishing community are small with fewer risks from mercury. Tilapia accumulated more mercury in muscle and liver than Nile perch. Fish consumed has mercury levels higher than FAO/WHO guidelines, and the bellyfat of Nile perch bioaccumulated more mercury than Tilapia. Based on the above, it is clear that some fish species should not be eaten by the vulnerable groups due to levels of Hg found in the muscle and bellyfat. This research will serve as a base for future studies, sensitization campaigns and policy design on mercury uptake through fish in fishing communities of developing countries. PMID- 27774498 TI - Large-scale Phenotypic Profiling of Gene Deletion Mutants in Candida glabrata. AB - Here, we describe a method enabling the phenotypic profiling of genome-scale deletion collections of fungal mutants to detect phenotypes for various stress conditions. These stress conditions include among many others antifungal drug susceptibility, temperature-induced and osmotic as well as heavy metal or oxidative stress. The protocol was extensively used to phenotype a collection of gene deletion mutants in the human fungal pathogen Candida glabrata (C. glabrata) (Schwarzmuller et al., 2014). PMID- 27774499 TI - Genetic Transformation of Candida glabrata by Electroporation. AB - Here, we report a method for the transformation by electroporation of the human fungal pathogen Candida glabrata (C. glabrata). The protocol can be used for transformations in single well or in 96-well microtiter plates. It has been extensively used to generate a genome-scale gene deletion library using the C. glabrata background recipient strain ATCC2001 (Schwarzmuller et al., 2014). PMID- 27774500 TI - Surgical Technique and Clinically Relevant Resection Cavity Dynamics Following Implantation of Cesium-131 (Cs-131) Brachytherapy in Patients With Brain Metastases. AB - BACKGROUND: Cesium-131 (Cs-131) brachytherapy is used to reduce local recurrence of resected brain metastases. In order to ensure dose homogeneity and reduce risk of radiation necrosis, inter-seed distance and cavity volume must remain stable during delivery. OBJECTIVE: To investigate the efficacy of the "seeds-on-a string" technique with intracavitary fibrin glue in achieving cavity volume stability. METHODS: We placed intra-operative Cs-131 brachytherapy in 30 cavities post-resection of brain metastases. Seeds-on-a-string were placed like barrel staves within the cavity with fibrin glue. Serial MRI imaging occurred post operatively. Pre-operative tumor volumes were compared with post-operative cavity volumes to evaluate volume stability. Thirty patients who underwent post resective stereotactic radiosurgery (SRS) were used as a control group for volumetric comparison. RESULTS: Cs-131 and SRS patients exhibited consistent cavity shrinkage over the median 110-day follow-up (p<.001), with total median shrinkage of 56.5% (Cs-131) and 84.8% (SRS). During the first month when ~88% of Cs-131 dosage is delivered, however, there was non-significant volume decrease in the Cs-131 group (median 22.0%; p=.063), while SRS patients showed significantly more shrinkage (46.7%; p=.042). No events of radiation necrosis occurred in either group. CONCLUSION: Cs-131 patients exhibited significantly less cavity shrinkage than SRS patients during the first critical month with 88% Cs-131 dose delivery. This significant difference in shrinkage suggests that the intracavitary seeds-on-a-string technique facilitates increased cavity stability, promoting more homogenous dose delivery. PMID- 27774501 TI - In which neighborhoods are older adult populations expanding?: Sociodemographic and built environment characteristics across neighborhood trajectory classes of older adult populations in four U.S. cities over 30 Years. AB - OBJECTIVES: We sought to examine characteristics of neighborhoods with changing older adult populations. METHODS: We used 30 years (1980-2011) of data from four U.S. cities (n=392 neighborhoods; Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA) and finite mixture modeling to identify trajectory classes: neighborhoods with "stable", declining, or increasing older adult populations (>=65 years). We then compared mean baseline and change in their characteristics. RESULTS: Neighborhoods with increasing (vs. "stable") percentage of older adult populations had lower initial poverty and greater increases in education and income, with lower increases in road connectivity, population density, and housing prices/debt over time. The same was true for neighborhoods with declining older adult populations, with the exception of having higher increases in housing prices/debt. We observed few significant differences in neighborhood amenities or parks across classes. CONCLUSIONS: Our results emphasize the need to consider built and social environments when planning communities for older adults. PMID- 27774503 TI - Is biological aging accelerated in drug addiction? AB - Drug-addiction may trigger early onset of age-related disease, due to drug induced multi-system toxicity and perilous lifestyle, which remains mostly undetected and untreated. We present the literature on pathophysiological processes that may hasten aging and its relevance to addiction, including: oxidative stress and cellular aging, inflammation in periphery and brain, decline in brain volume and function, and early onset of cardiac, cerebrovascular, kidney, and liver disease. Timely detection of accelerated aging in addiction is crucial for the prevention of premature morbidity and mortality. PMID- 27774502 TI - Dextran functionalization enhances nanoparticle-mediated siRNA delivery and silencing. AB - Understanding the endocytosis and intracellular trafficking of short interfering RNA (siRNA) delivery vehicle complexes remains a critical bottleneck in designing siRNA delivery vehicles for highly active RNA interference (RNAi)-based therapeutics. In this study, we show that dextran functionalization of silica nanoparticles enhanced uptake and intracellular delivery of siRNAs in cultured cells. Using pharmacological inhibitors for endocytotic pathways, we determined that our complexes are endocytosed via a previously unreported mechanism for siRNA delivery in which dextran initiates scavenger receptor-mediated endocytosis through a clathrin/caveolin-independent process. Our findings suggest that siRNA delivery efficiency could be enhanced by incorporating dextran into existing delivery platforms to activate scavenger receptor activity across a variety of target cell types. PMID- 27774504 TI - Data analyses of honokiol-induced autophagy of human glioma cells in vitro and in vivo. AB - This article contains raw and processed data related to a research, "Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway" (C.J. Lin, T.L. Chen, Y.Y. Tseng, G.J. Wu, M.H. Hsieh, Y.W. Lin, R.M. Chen, 2016) [1]. Data were obtained by immunoblotting analyses of light chain 3 (LC3)-II, beclin-1, Akt, and mTOR in human glioma U87 MG cells and mouse glioma tissues treated with honokiol, an active constituent extracted from the bark of Magnolia officinalis, "Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration" (P.S. Yeh, W. Wang, Y.A. Chang, C.J. Lin, J.J. Wang, R.M. Chen, 2016) [2]. The processed data show the effects of honokiol on induction of autophagy in human glioma U87 MG cells by analyzing levels of LC3-II, p62, and bectin-1, "Honokiol-induced apoptosis and autophagy in glioblastoma multiforme cells" (K.H. Chang, M.D Yan, C.J. Yao, P.C. Lin, G.M. Lai, 2013) [3]. In addition, chloroquine, a lysosomal inhibitor, was administered to the cells to further confirm honokiol-induced cell autophagy. Sequentially, mice with gliomas were created and treated with honokiol. Amounts of phosphorylated and non phosphorylated Akt and mTOR in glioma tissues were analyzed to determine the possible mechanisms of honokiol-induced autophagy. PMID- 27774505 TI - An Evaluation of the Significance of Work-Related Influence Factors on Fitness and the Development of Medical and Orthopaedic Conditions in Military Executives. AB - Occupational health promotion is an effective tool to improve the state of health of employees. As part of occupational health promotion in the German Bundeswehr, top-ranking military executives are offered a medical examination and training programme. Health-related data is collected as a basis for training and lifestyle counselling. This data was subjected to a retrospective evaluation in order to identify occupational risk factors and their correlation with cardiovascular resilience, trunk strength, and the development of orthopaedic and internal disorders. A total of 122 military executives (all male, age 54.6 +/- 4.2 years) answered a questionnaire aimed at evaluating private and occupational stress factors. The medical history was followed by a medical and orthopaedic examination involving a lactate performance test (treadmill or bicycle ergometry) and an isometric trunk strength measurement. The data obtained was then statistically evaluated. For military executives, work-related travelling and commuting involve a high risk of medical and orthopaedic conditions. Regular exercise leads to improved fitness levels. In order to prevent medical problems, military executives working long hours should regularly take part in fitness and weight training under professional instructions. PMID- 27774506 TI - Environmental Aspects of Domestic Cat Care and Management: Implications for Cat Welfare. AB - Domestic cats (Felis silvestris catus) are the most commonly kept companion animals in the US with large populations of owned (86 million), free-roaming (70 million), research (13,000), and shelter (2-3 million) cats. Vast numbers of cats are maintained in homes and other facilities each year and are reliant on humans for all of their care. Understanding cat behavior and providing the highest quality environments possible, including positive human-cat interactions, based on research could help improve the outcomes of biomedical research, shelter adoptions, and veterinary care, as well as overall cat welfare. Often, however, cats' needs are inadequately met in homes and some aspects may also not be well met in research colonies and shelters, despite the fact that similar problems are likely to be encountered in all of these environments. This paper provides a brief overview of common welfare challenges associated with indoor housing of domestic cats. Essential considerations for cage confinement are reviewed, along with implications of poor cat coping, such as weakening of the human-animal bond and relinquishment to shelters. The important role that environmental management plays in cat behavior and welfare outcomes is explored along with the need for additional research in key areas. PMID- 27774508 TI - Prevalence of Osteoporosis and Its Risk Factors in Men with COPD in Qazvin. AB - Introduction. Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Proper diagnosis of osteoporosis as a systemic adverse effect of COPD is of significant importance. The present study aimed at evaluating the prevalence of osteoporosis and its risk factors in men suffering from COPD in Qazvin (2014). Methods. This descriptive-analytical study was conducted on 90 patients with COPD using random sampling. Anthropometric data and results from physical examination were collected. Pulmonary function test and bone mineral densitometry were done for all participants as well. Results. The prevalence of osteopenia and osteoporosis in COPD patients was 31.5 and 52.8 percent, respectively. Bone mineral density (BMD) at the femoral neck was associated significantly with body mass index (BMI), increased severity of COPD, and use of oral corticosteroid (P < 0.05). Conclusion. The results showed that patients' BMI and severity of COPD are two valuable risk factors for osteoporosis screening in COPD patients. PMID- 27774509 TI - Primary Hyperparathyroidism and Pancreatitis: A Rare Association with Multiple Facets. AB - Primary hyperparathyroidism (PHPT) is rarely associated with the occurrence of acute or chronic pancreatitis. Hypercalcemia plays a major role in the pathogenesis. We report five cases of pancreatitis revealing PHPT. Patients and Methods. This is a retrospective study of 4 years, including all patients admitted to intensive care unit or gastroenterology department, for an acute or chronic pancreatitis revealing primary hyperparathyroidism. Results. We included 5 patients, all female, with mean age 54 years [40-76 years]. The PHPT was in all cases revealed by acute pancreatitis (AP). This one was oedematous in four cases and severe in one case. It occurred twice in calcified chronic pancreatitis (CCP). There was hypercalcemia in all cases. The PHPT was associated with a high rate of parathyroid hormone in 4 cases. The secreting lesion was an adenoma in 5 cases. Two patients had in addition bilateral renal calcifications. The outcome was favorable in 4 patients among whom 3 have had parathyroid surgery. A death was noted by superinfection of necrosis in the case of severe AP. Conclusion. The occurrence of pancreatitis during hyperparathyroidism is rare. Normal or elevated calcemia during acute or chronic pancreatitis should always get attention. PMID- 27774507 TI - Reactive Oxygen Species: A Key Hallmark of Cardiovascular Disease. AB - Cardiovascular diseases (CVDs) have been the prime cause of mortality worldwide for decades. However, the underlying mechanism of their pathogenesis is not fully clear yet. It has been already established that reactive oxygen species (ROS) play a vital role in the progression of CVDs. ROS are chemically unstable reactive free radicals containing oxygen, normally produced by xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, lipoxygenases, or mitochondria or due to the uncoupling of nitric oxide synthase in vascular cells. When the equilibrium between production of free radicals and antioxidant capacity of human physiology gets altered due to several pathophysiological conditions, oxidative stress is induced, which in turn leads to tissue injury. This review focuses on pathways behind the production of ROS, its involvement in various intracellular signaling cascades leading to several cardiovascular disorders (endothelial dysfunction, ischemia-reperfusion, and atherosclerosis), methods for its detection, and therapeutic strategies for treatment of CVDs targeting the sources of ROS. The information generated by this review aims to provide updated insights into the understanding of the mechanisms behind cardiovascular complications mediated by ROS. PMID- 27774510 TI - Robotic QM/MM-driven maturation of antibody combining sites. AB - In vitro selection of antibodies from large repertoires of immunoglobulin (Ig) combining sites using combinatorial libraries is a powerful tool, with great potential for generating in vivo scavengers for toxins. However, addition of a maturation function is necessary to enable these selected antibodies to more closely mimic the full mammalian immune response. We approached this goal using quantum mechanics/molecular mechanics (QM/MM) calculations to achieve maturation in silico. We preselected A17, an Ig template, from a naive library for its ability to disarm a toxic pesticide related to organophosphorus nerve agents. Virtual screening of 167,538 robotically generated mutants identified an optimum single point mutation, which experimentally boosted wild-type Ig scavenger performance by 170-fold. We validated the QM/MM predictions via kinetic analysis and crystal structures of mutant apo-A17 and covalently modified Ig, thereby identifying the displacement of one water molecule by an arginine as delivering this catalysis. PMID- 27774511 TI - "Uphill" cation transport: A bioinspired photo-driven ion pump. AB - Biological ion pumps with active ionic transport properties lay the foundation for many life processes. However, few analogs have been produced because extra energy is needed to couple to this "uphill" process. We demonstrate a bioinspired artificial photo-driven ion pump based on a single polyethylene terephthalate conical nanochannel. The pumping process behaving as an inversion of zero-volt current can be realized by applying ultraviolet irradiation from the large opening. The light energy can accelerate the dissociation of the benzoic acid derivative dimers existing on the inner surface of nanochannel, which consequently produces more mobile carboxyl groups. Enhanced electrostatic interaction between the ions traversing the nanochannel and the charged groups on the inner wall is the key reason for the uphill cation transport behavior. This system creates an ideal experimental and theoretical platform for further development and design of various stimuli-driven and specific ion-selective bioinspired ion pumps, which anticipates wide potential applications in biosensing, energy conversion, and desalination. PMID- 27774512 TI - Social transfer of pain in mice. AB - A complex relationship exists between the psychosocial environment and the perception and experience of pain, and the mechanisms of the social communication of pain have yet to be elucidated. The present study examined the social communication of pain and demonstrates that "bystander" mice housed and tested in the same room as mice subjected to inflammatory pain or withdrawal from morphine or alcohol develop corresponding hyperalgesia. Olfactory cues mediate the transfer of hyperalgesia to the bystander mice, which can be measured using mechanical, thermal, and chemical tests. Hyperalgesia in bystanders does not co occur with anxiety or changes in corticosterone and cannot be explained by visually dependent emotional contagion or stress-induced hyperalgesia. These experiments reveal the multifaceted relationship between the social environment and pain behavior and support the use of mice as a model system for investigating these factors. In addition, these experiments highlight the need for proper consideration of how experimental animals are housed and tested. PMID- 27774513 TI - Brain stimulation reveals crucial role of overcoming self-centeredness in self control. AB - Neurobiological models of self-control predominantly focus on the role of prefrontal brain mechanisms involved in emotion regulation and impulse control. We provide evidence for an entirely different neural mechanism that promotes self control by overcoming bias for the present self, a mechanism previously thought to be mainly important for interpersonal decision-making. In two separate studies, we show that disruptive transcranial magnetic stimulation (TMS) of the temporo-parietal junction-a brain region involved in overcoming one's self centered perspective-increases the discounting of delayed and prosocial rewards. This effect of TMS on temporal and social discounting is accompanied by deficits in perspective-taking and does not reflect altered spatial reorienting and number recognition. Our findings substantiate a fundamental commonality between the domains of self-control and social decision-making and highlight a novel aspect of the neurocognitive processes involved in self-control. PMID- 27774514 TI - Missing link between the Hayward and Rodgers Creek faults. AB - The next major earthquake to strike the ~7 million residents of the San Francisco Bay Area will most likely result from rupture of the Hayward or Rodgers Creek faults. Until now, the relationship between these two faults beneath San Pablo Bay has been a mystery. Detailed subsurface imaging provides definitive evidence of active faulting along the Hayward fault as it traverses San Pablo Bay and bends ~10 degrees to the right toward the Rodgers Creek fault. Integrated geophysical interpretation and kinematic modeling show that the Hayward and Rodgers Creek faults are directly connected at the surface-a geometric relationship that has significant implications for earthquake dynamics and seismic hazard. A direct link enables simultaneous rupture of the Hayward and Rodgers Creek faults, a scenario that could result in a major earthquake (M = 7.4) that would cause extensive damage and loss of life with global economic impact. PMID- 27774515 TI - A Novel Model of Transient Occlusion of the Middle Cerebral Artery in Awake Mice. AB - BACKGROUND: Stroke is one of the leading causes of death and disability worldwide. As a consequence, several excellent rodent models have been developed to gain insight into the pathophysiology of stroke and testing the efficacy of neuroprotective interventions. However, one potential problem is that albeit roughly 80% of strokes occur in awake patients, all existing murine stroke models employ anesthesia. Moreover, epidemiological studies have shown that stroke injury is more severe in the minority of patients that suffer stroke while asleep. To better mimic the clinical situation, it is therefore preferable to analyze the pathobiology of experimental stroke in awake animals. NEW METHOD: This model of transient middle cerebral artery occlusion (MCAO) in awake mice is based on insertion of an intraluminal suture via the external carotid artery during isoflurane anesthesia. Isoflurane is discontinued during the 60 min MCAO while cerebral blood flow is continuously monitored using laser doppler in the awake unrestrained mouse. RESULTS: Sixty minutes of awake MCAO model reliably induced infarction in striatum and cortex (relative infarct volume is 24.34% of contralateral hemisphere volume; absolute infarct volume is 47.94 mm3). COMPARISON WITH EXISTING METHODS: The animals in this method are awake during the one hour occlusion period, which may provide a more translational research approach than existing methods that apply anesthesia during the occlusion. CONCLUSIONS: Since the state of brain activity likely affects stroke injury and most anesthetics have neuroprotective effects, this model more accurately mimics the condition during which the majority of human ischemic stroke occurs. PMID- 27774516 TI - A Comparison of the Effects of Continuous versus Discontinuous Movement Patterns on Parkinsonian Rigidity and Reflex Responses to Passive Stretch and Shortening. AB - OBJECTIVE: Quantify the effect of a continuous compared to discontinuous movement trajectory on parkinsonian rigidity and reflex responses to passive stretch and shortening. METHODS: Eighteen participants with Parkinson's disease (PD) performed passive wrist flexion and extension movements through a 90 degrees range of motion at 50 degrees /sec using continuous (CONT) and discontinuous (DISC) movement trajectories. Participants were tested in both the OFF-MED and ON MED states. Rigidity was quantified by rigidity work score and slopes of the moment-angle plots during both flexion and extension. Reflex response was quantified by mean EMG amplitudes of forearm musculature. RESULTS: No differences were observed between CONT and DISC for rigidity (p = 0.18) or moment-angle plot slopes (Flexion: p = 0.97; Extension: p = 0.89). However, medication was associated with reductions in rigidity (p = 0.02) and increases in moment-angle plot slopes (Flexion: p = 0.03; Extension: p = 0.02). The CONT compared to DISC trajectory was associated with greater EMG amplitudes in the shortened muscles (p = 0.04) and smaller EMG ratios (p < 0.05) during flexion, and greater EMG amplitudes in the lengthened muscles (p = 0.02) during extension. Dopaminergic medication reduced EMG amplitudes in stretched muscles during extension (p < 0.05). CONCLUSIONS: The nature of the movement trajectory (continuous vs. discontinuous) used during clinical assessment does not alter the presentation of rigidity in PD. Rigidity is reduced with the administration of dopaminergic medication, independent of movement trajectory. SIGNIFICANCE: These data suggest that the presentation of rigidity used in the determination of diagnosis, treatment and prognosis in PD will not be affected by the continuous nature of the movement trajectory used during clinical assessment. PMID- 27774517 TI - Augmented Reality Imaging System: 3D Viewing of a Breast Cancer. AB - OBJECTIVE: To display images of breast cancer from a dedicated breast CT using Depth 3-Dimensional (D3D) augmented reality. METHODS: A case of breast cancer imaged using contrast-enhanced breast CT (Computed Tomography) was viewed with the augmented reality imaging, which uses a head display unit (HDU) and joystick control interface. RESULTS: The augmented reality system demonstrated 3D viewing of the breast mass with head position tracking, stereoscopic depth perception, focal point convergence and the use of a 3D cursor and joy-stick enabled fly through with visualization of the spiculations extending from the breast cancer. CONCLUSION: The augmented reality system provided 3D visualization of the breast cancer with depth perception and visualization of the mass's spiculations. The augmented reality system should be further researched to determine the utility in clinical practice. PMID- 27774518 TI - Magnetic Resonance Imaging-Based Radiomic Profiles Predict Patient Prognosis in Newly Diagnosed Glioblastoma Before Therapy. AB - Magnetic resonance imaging (MRI) is used to diagnose and monitor brain tumors. Extracting additional information from medical imaging and relating it to a clinical variable of interest is broadly defined as radiomics. Here, multiparametric MRI radiomic profiles (RPs) of de novo glioblastoma (GBM) brain tumors is related with patient prognosis. Clinical imaging from 81 patients with GBM before surgery was analyzed. Four MRI contrasts were aligned, masked by margins defined by gadolinium contrast enhancement and T2/fluid attenuated inversion recovery hyperintensity, and contoured based on image intensity. These segmentations were combined for visualization and quantification by assigning a 4 digit numerical code to each voxel to indicate the segmented RP. Each RP volume was then compared with overall survival. A combined classifier was then generated on the basis of significant RPs and optimized volume thresholds. Five RPs were predictive of overall survival before therapy. Combining the RP classifiers into a single prognostic score predicted patient survival better than each alone (P < .005). Voxels coded with 1 RP associated with poor prognosis were pathologically confirmed to contain hypercellular tumor. This study applies radiomic profiling to de novo patients with GBM to determine imaging signatures associated with poor prognosis at tumor diagnosis. This tool may be useful for planning surgical resection or radiation treatment margins. PMID- 27774519 TI - Radiotherapy: Changing the Game in Immunotherapy. AB - Immune checkpoint inhibitors are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a pre-requisite for response. Within such infiltrated tumors, referred as "hot", immune checkpoint inhibitors rescue anti-tumor T cells activity. In contrast, "cold" tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to immune checkpoint inhibitors by recruiting anti-tumor T cells. Despite the growing number of clinical studies testing radiation's ability to enhance immunotherapy, clinical evidence that it converts cold tumors into responsive ones remains elusive. Here we review evidence that radiotherapy is not only an occasional enhancer of immunotherapy's effects but a "game changer", and propose a blueprint to test this. PMID- 27774521 TI - Fluoroquinolone-Resistant Escherichia coli Infections After Transrectal Biopsy of the Prostate in the Veterans Affairs Healthcare System. AB - BACKGROUND: Recent reports suggest that infections due to fluoroquinolone resistant Escherichia coli (E. coli) are an increasingly common complication of transrectal biopsy of the prostate (TBP) in the United States. A better understanding of the magnitude and scope of these infections is needed to guide prevention efforts. Our objective is to determine whether the incidence of infections due to fluoroquinolone-resistant E. coli after TBP has increased nationwide in the Veterans Affairs Health Care System and to identify risk factors for infection. METHODS: We performed a retrospective, observational cohort study and a nested case-control study within the US Deparment of Veterans Affairs Healthcare System. The primary outcomes were the incidence of urinary tract infection (UTI) and bacteremia with E. coli and with fluoroquinolone- resistant E. coli strains within 30 days after TBP. Secondary endpoints focused on the correlation between fluoroquinolone-resistance in all urinary E. coli isolates and post-TBP infection and risk factors for infection due to fluoroquinolone-resistant E. coli infection. RESULTS: 245 618 patients undergoing 302 168 TBP procedures from 2000 through 2013 were included in the cohort study, and 59 469 patients undergoing TBP from 2011 through 2013 were included in the nested case-control study. Between 2000 and 2013, there was a 5-fold increase in the incidence of E. coli UTI (0.18%-0.93%) and a 4-fold increase in the incidence of E. coli bacteremia (0.04%-0.18%) after TBP that was attributable to an increase in the incidence of fluoroquinolone- resistant E. coli UTI (0.03%-0.75%) and bacteremia (0.01%-0.14%). The increasing incidence of fluoroquinolone resistant E. coli infections after TBP occurred in parallel with increasing rates of fluoroquinolone-resistance in all urinary E. coli isolates. By multivariable logistic regression analysis, independent risk factors for fluoroquinolone resistant E. coli UTI after TBP included diabetes mellitus, fluoroquinolone exposure, prior hospitalization, and prior cultures with fluoroquinolone resistant gram-negative bacilli. CONCLUSION: In the Veterans Affairs Healthcare System, the incidence of E. coli infection after TBP has increased significantly since 2000 due to a dramatic rise in infections with fluoroquinolone- resistant E. coli. PMID- 27774522 TI - The Effect of Treatment with Resiniferatoxin and Capsaicin on Dynamic Weight Bearing Measures and Evoked Pain Responses in a Chronic Inflammatory Arthritis Murine Model. AB - OBJECTIVE: Capsaicin (CAP) and Resiniferatoxin (RTX) are vanilloid receptor agonists that can normalize Evoked Pain Scores (EPS) and Automated Dynamic Weight Bearing (ADWB) measures in murine acute inflammatory arthritis when given by intra-articular (IA) injection. To determine whether these vanilloid receptor agonists have benefit in Complete Freund's Adjuvant (CFA) induced chronic inflammatory arthritis pain, we measured changes in ADWB and EPS in arthritic mice with and without treatment with IA CAP and RTX. METHODS AND MATERIALS: Chronic inflammatory arthritis was produced by IA injection of 30 ul of Complete Freund's Adjuvant (CFA) into the left knee of C57BL6 male mice 3 weeks prior to pain behavior testing. Mice were injected with either low or high dose IA RTX (10ul of 0.001 or 0.003%), or IA CAP (10 uL of 0.01%) 7 days prior to pain behavior testing. RESULTS: Chronic Inflammatory arthritis pain produced increased EPS and reduced ADWB measures for weight bearing in the affected limb of arthritic mice compared to naive mice. ADWB measurements for time in CFA when compared with Naive were not significantly different, but suggested off-loading the arthritic limb to the normal limb. Treatment with IA CAP or RTX 7 days prior to pain behavior testing produced significant improvement in EPS but no improvement in ADWB measures. Neither IA CAP nor IA RTX had any impact on EPS or ADWB measurements in non-arthritic mice when given 7 days prior to pain behavioral testing. CONCLUSION: Using ADWB and EPS, we quantified pain in a murine chronic inflammatory arthritis model. IA CFA caused a significant increase in EPS and decreased ADWB measures in the affected limb. Treatment with IA RTX and CAP produced significant improvement in EPS in mice with mono-articular inflammatory arthritis. IA vanilloid treatment produced no improvement in ADWB measurements for weight and for time. PMID- 27774520 TI - Inducible nitric oxide synthase (NOS-2) in subarachnoid hemorrhage: Regulatory mechanisms and therapeutic implications. AB - Aneurysmal subarachnoid hemorrhage (SAH) typically carries a poor prognosis. Growing evidence indicates that overabundant production of nitric oxide (NO) may be responsible for a large part of the secondary injury that follows SAH. Although SAH modulates the activity of all three isoforms of nitric oxide synthase (NOS), the inducible isoform, NOS-2, accounts for a majority of NO mediated secondary injuries after SAH. Here, we review the indispensable physiological roles of NO that must be preserved, even while attempting to downmodulate the pathophysiologic effects of NO that are induced by SAH. We examine the effects of SAH on the function of the various NOS isoforms, with a particular focus on the pathological effects of NOS-2 and on the mechanisms responsible for its transcriptional upregulation. Finally, we review interventions to block NOS-2 upregulation or to counteract its effects, with an emphasis on the potential therapeutic strategies to improve outcomes in patients afflicted with SAH. There is still much to be learned regarding the apparently maladaptive response of NOS-2 and its harmful product NO in SAH. However, the available evidence points to crucial effects that, on balance, are adverse, making the NOS-2/NO/peroxynitrite axis an attractive therapeutic target in SAH. PMID- 27774523 TI - Interferon-Gamma Receptor Signaling Plays an Important Role in Restraining Murine Ovarian Tumor Progression. AB - Immune cell-derived cytotoxic pathways have been implicated in antitumor immune responses. The goal of this study is to characterize how these cytotoxic pathways influence ovarian cancer development. We have utilized the TgMISIIR-TAg transgenic mouse model which expresses the transforming SV40 TAg in the ovary, leading to spontaneous development of ovarian tumors that closely mimic human epithelial ovarian cancer. To test how perforin (Prf1), granzyme B (GzmB) and interferon-gamma (IFNg) impact tumor occurrence and progression, we bred the TgMISIIR-TAg transgene into Prf1-/-, GzmB-/-, and IFNgR1-/- mice. The transgenic females developed peritoneal tumors at 9-15 weeks and succumbed at 184 +/- 37 days of age with 100% penetrance (n=41). Knockout of these cytotoxic genes does not affect tumor occurrence. However, loss of function in the IFNg signaling pathway significantly expedited tumor progression with all of the IFNg R1-/- TgMISIIR-TAg females succumbing to tumor outgrowth at 167 +/- 27 days of age (p=0.0074, n=24). In contrast, loss of function of Prf1 or GzmB did not significantly impact tumor progression and host survival. Since tumor cells in the IFNg R1-/- TgMISIIR-TAg mice are IFNg R1 deficient, we used the implantable MOSEC (mouse ovarian surface epithelial cell) tumor line to validate that IFNg R signaling in host immune cells but not in tumor cells impacts tumor progression. Indeed, when the IFNg -responsive MOSEC cells were inoculated, IFNg R1-/- mice exhibited significantly higher tumor burden compared to WT mice. Furthermore, a MOSEC-splenocyte co-culture system confirmed that IFNg R1-/- immune cells were less effective than WT immune cells in controlling MOSEC tumor growth in vitro. Together, these results indicate that the IFNg R signaling pathway plays an important role in restraining murine ovarian tumor progression. PMID- 27774524 TI - Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4+ T Cells. AB - Granzyme B (GzmB) is a key cytotoxic molecule utilized by T cells to kill pathogen-infected cells or transformed tumor cells. Previous studies using allogeneic hematopoietic cell transplantation (allo-HCT) murine models showed that GzmB is required for CD8+ T cells to cause graft-versus-host disease (GVHD). However, our recent study demonstrated that GzmB-mediated damage of CD8+ T cells diminished their graft-versus-tumor (GVT) activity. In this study, we examined the role of GzmB in GVT effect mediated by conventional CD4+CD25- T cells (CD4+ Tcon). GzmB-/-CD4+ Tcon cells exhibited decreased GVT activity compared to wild type (WT) CD4+ Tcon cells, suggesting that GzmB is required for the optimal GVT activity of CD4+ Tcon cells. On the other hand, GzmB-/- CD4+CD25+ regulatory T cells were as suppressive as WT regulatory T cells in suppressing GVT activity, which is consistent with our previous report showing that GzmB is not required for regulatory T cell-mediated suppression of GVHD. These results demonstrate that GzmB causes opposite impacts on GVT effect mediated by CD4+CD25- versus CD8+ T cells. Interestingly, GzmB-/- total T cells exhibited GVT activity equivalent to that of WT total T cells, suggesting that the opposite impacts of GzmB on the GVT effect of CD4+CD25- versus CD8+ T cells may neutralize each other, which can only be observed when an individual T cell subset is examined. Importantly, these differential roles suggest that targeting GzmB in selective T cell subsets may have the potential to enhance the beneficial GVT effect. PMID- 27774526 TI - The Inflammatory Cytokine IL-21 is Expressed by Splenic Neutrophils in Response to Transplantation of Allogeneic Cells. AB - We have previously reported that GR-1 neutrophil/monocytes rose dramatically in the spleen, peaked by day 7 and declined through day 14. This period corresponded to the peak of acute Graft-Versus-Host Disease (aGVHD) in BALB/c mice transplanted with allogeneic donor cells. We now asked: what cytokines did these splenic neutrophil/monocytes express on day 7 and 14 post transplant? BALB/c mice were transplanted with allogeneic B6 or syngeneic BALB/c donor cells. Long term survival was recorded through day 31. Other groups were sacrificed on days 3, 5, 7, 14, 21 and 31 days post transplant to record the total number of cells in the spleens and their phenotypes. Neutrophils were isolated from the spleens of mice transplanted with B6 and BALB/c cells on days 7 and 14. Daily body weight demonstrated a transient drop in the syngeneic transplants on day 2 but a much greater drop with its nadir at day 7 and never fully recovering through 31 days. CD8/CD4 T lymphocytes peaked in the spleen on day 5 and were followed on day 7 by GR-I cells in all of the allogeneic transplants. In syngeneic transplants this early rise in lymphocytes did not occur and GR-1 cells peaked on day 14. Highly purified neutrophils were isolated in two separate experiments from the spleens on days 7 and 14 post transplant. In both experiments day 7 allogeneic neutrophils expressed significantly elevated levels of Interleukin-21 (IL-21) mRNA whereas the day 7 and 14 syngeneic cells expressed lower but significant levels of TNFalpha. Intracellular IL-21 was demonstrated in the allogeneic neutrophils on day 7 before and after in vitro stimulation. In conclusion Purified neutrophils isolated from the spleen on day 7, the early peak of allogeneic transplantation a GVHD, express high levels of IL-21 message and intracellular IL-21. PMID- 27774527 TI - R/X exchange reactions in cis-[M(R)2{P(X)(NMeCH2)2}2] (M = Pd, Pt), via a phosphenium intermediate. AB - R/X exchange reactions in cis-[M(R)2{P(X)(NMeCH2)2}2] (M = Pd, Pt; R = aryl, alkyl; X = Cl, Br) were achieved for the first time to give cis [M(X)2{P(R)(NMeCH2)2}2]. DFT calculations suggested that the exchange reaction proceeds via a phosphenium intermediate. PMID- 27774528 TI - Energetics of native defects in anatase TiO2: a hybrid density functional study. AB - The energetics and electronic structures of native defects in anatase TiO2 are comprehensively studied using hybrid density functional calculations. We demonstrate that oxygen vacancies (VO) and titanium interstitials (Tii) act as shallow donors, and can form at substantial concentrations, giving rise to free electrons with carrier densities from 1011 to 1019 cm-3 under oxygen-rich and oxygen-poor conditions, respectively. The titanium vacancies (VTi), identified as deep acceptors and induced hole carriers, are incapable of fully compensating for the free electrons originating from the donor-type defects at any oxygen chemical potential. Even under extreme oxygen-rich conditions, the Fermi level, which is determined from the charge neutrality condition among charge defects, electron and hole carriers, is located 2.34 eV above the valence band maximum, indicating that p-type conductivity can never be realized under any growth conditions without external doping. This is consistent with common observations of intrinsic n-type conductivity of TiO2. At a typical annealing temperature and under a typical oxygen partial pressure, the carrier concentration is found to be approximately 5 * 1013 cm-3. PMID- 27774529 TI - Theoretical study of the H/D isotope effect on phase transition of hydrogen bonded organic conductor kappa-H3(Cat-EDT-TTF)2. AB - kappa-H3(Cat-EDT-TTF)2 (H-TTF) is a hydrogen-bonded pi-electron system which was found to reveal C2/c symmetry at 50-293 K, while its isotopologue, kappa-D3(Cat EDT-TTF)2 (D-TTF), showed the phase transition at 185 K from C2/c to P1[combining macron]. To elucidate the origin of such a difference, we calculated the potential energy curves (PECs) for the hydrogen transfer along the H-bonds in these conductors. We found that both the pi-stacking and the hydrogen nuclear quantum effect drastically affected the hydrogen transfer energy. By taking account of both effects, we obtained a symmetric single-well effective PEC for H TTF, which indicated that the hydrogen was always located at the center of the H bond. By contrast, the effective PEC of D-TTF was a low-barrier double-well, indicating that the position of the H-bonded deuterium would change according to the temperature. We concluded that the pi-stacking and the nuclear quantum effect were the key factors for the appearance of phase transition only in D-TTF. PMID- 27774525 TI - Dynamic Metabolism in Immune Response. AB - Cell, the basic unit of life depends for its survival on nutrients and thereby energy to perform its physiological function. Cells of lymphoid and myeloid origin are key in evoking an immune response against "self" or "non-self" antigens. The thymus derived lymphoid cells called T cells are a heterogenous group with distinct phenotypic and molecular signatures that have been shown to respond against an infection (bacterial, viral, protozoan) or cancer. Recent studies have unearthed the key differences in energy metabolism between the various T cell subsets, natural killer cells, dendritic cells, macrophages and myeloid derived suppressor cells. While a number of groups are dwelling into the nuances of the metabolism and its role in immune response at various strata, this review focuses on dynamic state of metabolism that is operational within various cellular compartments that interact to mount an effective immune response to alleviate disease state. PMID- 27774530 TI - Microscopic investigations of site and functional selectivity of triazole for CO2 capture and catalytic applications. AB - Ab initio and DFT studies on CO2 interacting with different tautomers and isomers of triazole (TZ) are carried out to understand the adsorption mechanism and their mutual preferential sites. We used post Hartree-Fock methods (MP2, CCSD(T), and CCSD(T)-F12) and various DFTs (PBE, PBE0, M05-2X, and M11) with and without considering the dispersion correction for comparison. We determined hence the equilibrium structures, vibrational frequencies and binding energies of TZ-CO2 clusters and mapped their potential energy surfaces along the intermonomer coordinates. We find that the most stable TZ-CO2 clusters, some of them are already known, are not relevant for CO2 capture in porous materials. In addition, we show that the bonding between TZ and CO2 is due to various kinds of noncovalent interactions such as pi-stacking, acid-base pair electron donor electron acceptor (EDA) interactions along with N-HO and C-HO H-bonds with CO2. Our analysis reveals the existence of site selectivity effects when CO2 binds to TZ. These effects are related to the magnitude of the interaction potentials, in the order EDA (+N-HO) > EDA (+C-HO) > Cdelta+N[double bond, length as m-dash]N > pi-stacking > sigma type N-HO > C-HO H-bonds. This is the first report on the importance of competition between EDA, pi-stacking and sigma-bonds for CO2 capture and catalytic applications. Findings from this work may be used to give insights into the site specific CO2 capture ability of porous materials such as metal organic frameworks (MOFs), zeolitic imidazolate frameworks (ZIFs) or functionalized polymers. Finally, we show that IR spectroscopy of CO2 within the pores is neither a specific nor an efficient marker in probe-molecule experiments. PMID- 27774531 TI - Depth profiles of hydrogen bound water molecule types and their relation to lipid and protein interaction in the human stratum corneum in vivo. AB - Confocal Raman microscopy has been used to measure depth-dependent profiles of human SC in vivo in the high wavenumber (HWN) region. In order to keep the linearity of HWN region boundaries and to not remove an informative signal from Raman spectra, a new baseline subtraction procedure has been introduced. After baseline subtraction, the HWN spectrum was deconvoluted using 10 Gaussian functions with individual chemical meanings. The results show that the hydrogen bound water molecule types contributed differently to the water diffusion process in the SC. The most concentrated double donor-double acceptor (DDAA) and single donor-single acceptor (DA) water molecule types in the SC represent more than 90% of the SC's water and mostly contribute to the water flux in the skin. Single donor-double acceptor (DAA) and weakly-bound water molecule types represent less than 10% of the SC's water content. The most tightly hydrogen bound water molecule type, DAA, reaches its maximum concentration near the skin surface and does not take part in the water diffusion process via the SC. The results show that the hydrogen bonding state of water (DA/DDAA water molecule type ratio) reaches its maximum at the depth of approx. 30% of the SC thickness, which correlates well with the maximum lateral packing order of intercellular lipids (ICL) and the natural moisturizing factor (NMF), and does not coincide with the folding/unfolding state of keratin. The NMF's contribution to the bonding of water in the SC is supposed to dominate over that of ICL. PMID- 27774532 TI - Accurate quantification of apoptosis progression and toxicity using a dielectrophoretic approach. AB - A loss of ability of cells to undergo apoptosis (programmed cell death, whereby the cell ceases to function and destroys itself) is commonly associated with cancer, and many anti-cancer interventions aim to restart the process. Consequently, the accurate quantification of apoptosis is essential in understanding the function and performance of new anti-cancer drugs. Dielectrophoresis has previously been demonstrated to detect apoptosis more rapidly than other methods, and is low-cost, label-free and rapid, but has previously been unable to accurately quantify cells through the apoptotic process because cells in late apoptosis disintegrate, making cell tracking impossible. In this paper we use a novel method based on light absorbance and multi-population tracking to quantify the progress of apoptosis, benchmarking against conventional assays including MTT, trypan blue and Annexin-V. Analyses are performed on suspension and adherent cells, and using two apoptosis-inducing agents. IC50 measurements compared favourably to MTT and were superior to trypan blue, whilst also detecting apoptotic progression faster than Annexin-V. PMID- 27774533 TI - Probing conformational and functional substates of calmodulin by high pressure FTIR spectroscopy: influence of Ca2+ binding and the hypervariable region of K Ras4B. AB - The ubiquitous Ca2+-sensing protein calmodulin (CaM) interacts with more than 300 diverse target proteins that are involved in numerous signaling pathways in eukaryotic cells. This unique promiscuous target binding behavior and the underlying functional versatility of CaM is a result of its structural flexibility. CaM spans multiple conformational substates in solution providing adaptable binding surfaces for different target proteins. The conformational space of this protein needs to be explored to shed more light on the mechanism of target recognition and protein function. Here, we used pressure modulation in combination with FTIR spectroscopy to populate and probe otherwise transient low lying excited conformational substates of CaM close in energy to its ground state, which are supposed to be functionally relevant in recognition and ligand binding events. The pressure-induced conformational changes of CaM were studied in its Ca2+-free and Ca2+-bound state and in the presence of the hypervariable region (HVR) of the signaling peptide K-Ras4B as a binding partner. We demonstrate that the conformational dynamics of CaM is vastly affected by binding of both Ca2+ ions and the lipidated signaling peptide K-Ras4B. Moreover, we could uncover conformational substates of CaM by pressure perturbation that are partially unfolded and more solvated and conceivably facilitate target recognition by exposing the required binding surfaces. PMID- 27774534 TI - Correction: Proton conduction through oxygen functionalized few-layer graphene. AB - Correction for 'Proton conduction through oxygen functionalized few-layer graphene' by Chanderpratap Singh et al., Chem. Commun., 2016, 52, 12661-12664. PMID- 27774535 TI - A decacobalt(ii) cluster with triple-sandwich structure obtained by partial reductive hydrolysis of a pentacobalt(ii/iii) Weakley-type polyoxometalate. AB - Partial reductive hydrolysis of a penta-CoII/III cluster [Co(H2O)2(CoIIIW9O34)(PW9O34)]12- (1) leads to the formation of [Co2{Co3(H2O)(Co(OH)2W7O26)(PW9O34)}2]22- (2). This polyoxometalate is made up of two capping [PW9O34]9- units and two bridging [W7O26]10- units that assemble to encapsulate a novel deca-CoII cluster core comprising octahedral and tetrahedral CoII ions. PMID- 27774536 TI - Interaction of osmium(ii) redox probes with DNA: insights from theory. AB - In the course of developing ultrasensitive and quantitative electrochemical point of-care analytical tools for genetic detection of infectious diseases, osmium(ii) metallointercalators were revealed to be suitable and efficient redox probes to monitor the in vitro DNA amplification [Defever etal, Anal. Chem., 2011, 83, 1815 1821]. In this work, we thus propose a complete computational protocol in order to evaluate the affinity between Os(ii) complexes with double-stranded DNA. This protocol is based on molecular dynamics, with the parametrization of the GAFF force field for the Os(ii) complexes presenting an octahedral environment with polypyridine ligands, and QM/QM' calculations to evaluate the binding energy. For three Os(ii) probes and different binding sites, molecular dynamics simulations and interaction energies calculated at the QM/QM' level are successively discussed and compared to experimental data in order to identify the most stable binding sites. The computational protocol we propose should then be used to design more efficient Os(ii) metallointercalators. PMID- 27774537 TI - Hydroamination of carbodiimides, isocyanates, and isothiocyanates by a bis(phosphinoselenoic amide) supported titanium(iv) complex. AB - The hydroamination of heterocumulenes such as carbodiimides, isocyanates, and isothiocyanates by a bis(phosphinoselenoic amide) supported titanium(iv) complex as a precatalyst is reported here. The titanium(iv) complex [{Ph2P(Se)NCH2CH2NPPh2(Se)}Ti(NMe2)2] (1) was synthesised by the reaction of tetrakis-(dimethylamido)titanium(iv) [Ti(NMe2)4] with [{Ph2P(Se)NHCH2CH2NHPPh2(Se)}] in toluene at ambient temperature. Titanium complex 1 proved to be a competent pre-catalyst for the addition of an amine N-H bond to carbodiimides, isocyanates, and isothiocyanates. The reaction scope was expanded to reactions of aliphatic and aromatic amines with phenylisocyanates and phenylisothiocyanates in toluene solvents proceeding rapidly at room temperature with 5 mol% catalyst loadings to yield the corresponding urea and thio-urea derivatives up to 99%. However, ambient temperature was needed for hydroamination of 1,3-dicyclohexylcarbodiimide. The amine addition reactions with isocyanates showed first order kinetics with respect to catalyst 1 as well as substrates. The most plausible mechanism for the hydroamination reaction was established by isolating 1,1-dimethylphenyl urea as a side product. PMID- 27774538 TI - Enhanced mechanical properties of photo-clickable thiol-ene PEG hydrogels through repeated photopolymerization of in-swollen macromer. AB - Current hydrogels used for tissue engineering are limited to a single range of mechanical properties within the replicated tissue construct. We show that repeated in-swelling by a single hydrogel pre-cursor solution into an existing polymerized hydrogel followed by photo-exposure increases hydrogel mechanical properties. The process is demonstrated with a photo-clickable thiol-ene hydrogel using a biocompatible precursor solution of poly(ethylene glycol) dithiol and 8 arm poly(ethylene glycol) functionalized with norbornene. The polymer fraction in the precursor solution was varied by 5, 10, and 20 percent by weight and an off stoichiometric ratio of thiol : ene was used, leaving free enes available for subsequent reaction. Multiple swelling and exposure cycles for the same precursor solution were performed. The compressive modulus increased by a factor between three and ten (formulation dependent), while volume swelling ratio decreased by a factor of two, consistent with increased crosslink density. The modified hydrogels also demonstrate increased toughness by fracturing at compressive forces five times greater than the initial hydrogel. We attribute the increased toughness to subsequent increases in crosslink density created by the repeated photopolymerization of in-swollen macromer. This technique demonstrates the ability to significantly modify hydrogel network properties by exploiting swelling and polymerization processes that can be applied to traditional three dimensional printing systems to spatially control local mechanical properties. PMID- 27774539 TI - One-dimensional Gaussian-core fluid: ordering and crossover from normal diffusion to single-file dynamics. AB - The peculiarity of a bounded pair potential in combination with strong confinement brings some quite interesting new phenomenology in the structure and dynamics of one-dimensional colloidal systems. Such behaviour is atypical in comparison with colloidal systems interacting with potentials that diverge at the origin. In this contribution, by means of molecular dynamics simulations, a confined one-dimensional model of particles interacting via a Gaussian-core pair potential is studied. We explore the effects of confinement, density and temperature on the structural and dynamical correlation functions. Our findings indicate that the static and dynamic liquid-state anomalies already reported in open systems are also present in this 1D model system. Using the radial distribution function and the static structure factor to characterise the spatial ordering, it is observed that the system remains fluid at all densities. However, when the reduced temperature is above 0.03, it displays typical features of a liquid regime, i.e., there exist short-range spatial correlations among particles. In contrast, at lower temperatures and densities, where the particle particle interaction dominates, the system behaves structurally and dynamically similar to a hard-core repulsive system. In such a region, interestingly, there is a crossover from a liquid to a solid-like regime. At any given temperature, the system undergoes a sort of reentrant structural behaviour as the density increases. At either high densities or temperatures, particle correlations vanish, thus, the system exhibits structural and dynamical properties similar to those of an ideal gas. To examine a possible correlation between the structural anomalies and the diffusive behaviour, the mean-square displacement and the self intermediate scattering function are also computed. From these observables, we establish the thermodynamic phase-space points where the dynamical behaviour is non-monotonic. In conjunction with the observed anomalous diffusion, we have found a dynamical crossover from single-file diffusion, which is characteristic of one-dimensional systems with a well-defined hard-core, to the ordinary Fickian diffusion present in open systems. PMID- 27774540 TI - Rational design of MnO2@MnO2 hierarchical nanomaterials and their catalytic activities. AB - Hierarchically structured materials have special properties and possess potential in applications in the catalytic and electrochemical fields. Herein, two kinds of hierarchical core-shell nanostructures, lavender-like alpha-MnO2@alpha-MnO2 and balsam pear-like alpha-MnO2@gamma-MnO2, were prepared by a facile room temperature method using alpha-MnO2 nanowires as a backbone under acidic and alkaline conditions, respectively. When being used as a catalyst for dimethyl ether combustion, alpha-MnO2@gamma-MnO2 exhibited a better performance than alpha MnO2@alpha-MnO2 (T10 = 171 vs. 196 degrees C; T90 = 220 vs. 258 degrees C, SV = 30, 000 mL g-1 h-1). It is concluded that the larger surface area, higher reducibility/oxygen mobility, richer surface oxygen species, and the relatively smaller apparent activation energy are responsible for the superior performance of alpha-MnO2@gamma-MnO2. PMID- 27774541 TI - Unraveling the synthesis of homoleptic [Ag(N,N-diaryl-NHC)2]Y (Y = BF4, PF6) complexes by ball-milling. AB - A user-friendly and general mechanochemical method was developed to access rarely described NHC (N-heterocyclic carbene) silver(i) complexes featuring N,N diarylimidazol(idin)ene ligands and non-coordinating tetrafluoroborate or hexafluorophosphate counter anions. Comparison with syntheses in solution clearly demonstrated the superiority of the ball-milling conditions. PMID- 27774542 TI - Flow-induced nonequilibrium self-assembly in suspensions of stiff, apolar, active filaments. AB - Active bodies in viscous fluids interact hydrodynamically through self-generated flows. A stiff, apolar, active filament generates symmetric fluid flow around it and thus cannot self-propel. Here we study the mobility and aggregation induced by hydrodynamic flow in a suspension of stiff, apolar, active filaments. We consider two types of active filaments, with those producing extensile or contractile flows along their long axis. Lateral hydrodynamic attractions in extensile filaments lead, independent of the volume fraction, to anisotropic aggregates which translate and rotate ballistically. Lateral hydrodynamic repulsions in contractile filaments lead to microstructured states, where the degree of clustering increases with the volume fraction and the filament motion is always diffusive. Our results demonstrate that the interplay between active hydrodynamic flows and anisotropic excluded volume interactions provides a generic nonequilibrium mechanism for hierarchical self-assembly of active soft matter. PMID- 27774543 TI - Cooperative supramolecular helical assembly of a pyridinium-tailored methyl glycyrrhetate. AB - Taking a natural triterpenoid as the building block, we have regulated a pyridinium-functionalized methyl glycyrrhetate (C4-MGP) into P-type helices in water primarily driven by hydrophobic forces. By analysing their temperature dependent CD and UV-Vis spectra, these hierarchical chiral assemblies were found to be formed in a cooperative supramolecular polymerization manner. PMID- 27774544 TI - Palladacycle catalysis: an innovation to the Suzuki-Miyaura cross-coupling reaction. AB - Herein we report a Suzuki-Miyaura type cross-coupling between an aryl halide and a functionalized boronic acid palladacycle in the absence of an external catalyst. This reaction is an unprecedented case of catalysis in palladium metallacycle chemistry. PMID- 27774545 TI - Kagome-type isostructural 3D-transition metal fluorosulfates with spin 3/2 and 1: synthesis, structure and characterization. AB - Two isostructural transition metal fluorosulfates based on Co and Ni metal ions with the molecular composition of [H3O][M(SO4)F] (where M = Co(II) for 1 and Ni(II) for 2) were synthesized under solvothermal conditions and structurally characterized by single crystal X-ray analysis. The materials were further characterized by complementary techniques like TGA, FTIR and PXRD. The 3D-crystal lattice consists of a kagome-type entity where sulfate groups replaced one of the metal nodes when compared with true kagome structures. Magnetic studies of the complexes were also performed which showed that the interactions at the metal center are antiferromagnetic in nature. The proton conductivity increases with the increase in humidity and was found to be 7.9 * 10-6 S cm-1 for 2 at RH = 98%. PMID- 27774546 TI - Phenyl substitution of cationic bis-cyclometalated iridium(iii) complexes for iTMC-LEECs. AB - A series of seven cationic bis-cyclometalated iridium(iii) complexes of the form [(C^N)2(N^N)Ir][PF6] has been designed in order to examine the effect of bulky, hydrophobic phenyl substituents on the structure-property relationship of these ionic transition metal complexes (iTMCs) in light-emitting electrochemical cells (LEECs). Capping phenyl substituents on the cyclometalating and ancillary ligands allows for individual tuning of the HOMO and LUMO energy levels, respectively, yielding an emission range from yellow to red. The complexes in this series exhibit increased quantum yields, up to 70% higher than the unoptimized, archetypal [(2-phenylpyridine)2(2,2'-bipyridine)Ir][PF6]. Among these, one complex, C3, was recently reported to produce devices with superior luminance and efficiency. Simultaneous measure of the series of complexes enabled the clear discernment of trends in device performance connected to fundamental structure property relationships that elucidate the origin of enhanced luminance. In general, phenyl substitution of the 2-phenylpyridine ligands of the parent complex produced higher luminance and faster device response than phenyl substitution of the 2,2'-bipyridine ligand. Overall, complex design and device engineering produce competitive LEECs from simple, single-layer architectures. The synthesis, crystallographic, photophysical, and electrochemical properties of the iTMCs, along with the electroluminescence properties of the LEEC devices are reported herein. PMID- 27774547 TI - Understanding and tuning the properties of redox-accumulating manganese helicates. AB - The pentanuclear Mn complex [Mn5(MU3-O)(bpp)6]n+ can access six consecutive total oxidation levels from Mn(ii)5 to Mn(iii)5. The electronic structure and redox behavior of this cluster are studied computationally and the results are compared with experimental data. The tunability of the redox potential span and of the absolute potential position is explored through systematic modifications of the 3,5-bis(pyridin-2-yl)-pyrazole (Hbpp) ligand. By substitutions with electron donating and electron-withdrawing groups, the position of the redox events can be shifted by ca. 1 eV, however no ligand modification is predicted to alter the total redox span. By changing the pyridyl groups to benzimidazole groups, yielding the 3,5-bis(benzimidazol-2-yl)pyrazole (H3bbp) ligand, it is predicted that higher oxidation states can be stabilized, from Mn(iii)4Mn(iv) up to Mn(iv)5. In this system, the redox span for the same number of redox equivalents accumulated is slightly smaller than that in the original system. The manganese system is compared with its pentanuclear iron analogue that was recently reported to be catalytically active in oxygen evolution (Okamura et al., Nature, 2016, 530, 465). The electronic and structural requirements for utilization of the stored oxidizing equivalents in water oxidation are discussed. PMID- 27774548 TI - A biotin-conjugated glutathione-responsive FRET-based fluorescent probe with a ferrocenyl BODIPY as the dark quencher. AB - An efficient ferrocenyl BODIPY based dark quencher has been developed and employed to construct a FRET-based fluorescent probe that contains a biotin moiety as a potential directing ligand for cancer cells and a glutathione cleavable disulfide linker connecting the quencher and a distyryl BODIPY fluorophore. This molecular probe is deactivated in the native form through FRET followed by intramolecular charge transfer due to the ferrocenyl unit. However, upon interaction with glutathione in phosphate buffered saline and inside cancer cells, the fluorescence emission is significantly increased due to detachment of the fluorophore from the quencher. As shown by flow cytometry, this probe also exhibits preferential uptake by the biotin-receptor-expressing A549 human lung adenocarcinoma epithelial cells over the Chinese hamster ovary CHO-K1 cells used as the negative control. On the basis that both biotin receptor and GSH level are often overexpressed or elevated in cancer cells, this dual functional fluorescent probe serves as a promising agent for cancer imaging. PMID- 27774549 TI - The quest towards epitaxial BaMgF4 thin films: exploring MOCVD as a chemical scalable approach for the deposition of complex metal fluoride films. AB - Conventional and Pulsed Liquid Injection MOCVD processes (C-MOCVD and PLI-MOCVD) have been explored as synthetic routes for the growth of BaMgF4 on Si (100) and single crystalline SrTiO3 (100) substrates. For the two applied approaches, the volatile, thermally stable beta-diketonate complexes Ba(hfa)2tetraglyme and Mg(hfa)2(diglyme)2(H2O)2 have been used as single precursors (C-MOCVD) or as a solution multimetal source (PLI-MOCVD). Structural characterization through X-ray diffraction (XRD) measurements and transmission electron microscopy (TEM) analyses confirmed the formation of epitaxial BaMgF4 films on SrTiO3 substrates. Energy dispersive X-ray (EDX) analyses have been used to confirm composition and purity of deposited films. The impact of process parameters on film properties has been addressed, highlighting the strong influence of precursor ratio, deposition temperature and oxygen partial pressure on composition, microstructure and morphology of the films. Both methods appear well suited for the growth of the BaMgF4 phase, but while PLI-MOCVD yields a more straightforward control of the precursor composition that reflects on film stoichiometry, C-MOCVD provides easier control of the degree of texturing as a function of temperature. PMID- 27774550 TI - A critical assessment of the mechanisms governing the formation of aqueous biphasic systems composed of protic ionic liquids and polyethylene glycol. AB - An extensive study on the formation of aqueous biphasic systems (ABS) using aqueous solutions of protic ionic liquids (PILs) and polyethylene glycol (PEG) was performed in order to understand the mechanisms underlying the phase separation. Aqueous solutions of PEG polymers with different molecular weights (600, 1000, 2000, and 3400 g mol-1) and several N-alkyl-, dialkyl-, and trialkyl ammonium salts of acetate, propanoate, butanoate, hexanoate and octanoate were prepared and their ability to form ABS at several temperatures assessed. The ternary liquid-liquid phase diagrams were determined at several temperatures, as well as binary PIL (or salt)-PEG-1000 and salt-water solubility data to better clarify the mechanisms responsible for the phase separation. All data gathered indicate that the formation of PEG-PIL-based ABS is mainly governed by the PIL PEG mutual interactions, where PILs with a higher solubility in the polymer exhibit a lower aptitude to form ABS displaying thus a smaller biphasic region, for which a direct correlation was identified. The effects of the molecular weight and temperature of the polymer were also addressed. The increase of the PEG hydrophobicity or molecular weight favours the phase separation, whereas the effect of temperature was found to be more complex and dependent on the nature of the PIL, with an increase or decrease of the biphasic regime with an increase in temperature. PMID- 27774551 TI - Heteroleptic ruthenium(ii) chromophores based on tunable polytopic 4' (benzamidinato)-2,2':6',2''-terpyridines. AB - A modulable and simple approach towards heteroleptic ruthenium(ii) complexes of amidine-based polypyridine ligands is presented. New complexes 1 and 2 ([(terpyridine)Ru(terpyridine-C6H4-C(NR)(NHR))]2+ with R = propyl and R = phenyl derivatives, respectively) were characterized by NMR spectroscopy in solution and by X-ray diffraction, which confirmed the obtention of the (E) stereoisomer alone. Depending on the bulkiness of the R-substituents introduced on the amidine moiety, rotational isomerism around the C-N bond could be observed at r.t. Spectroscopic and electrochemical studies showed that the nature of the R substituents introduced on the amidine moiety can significantly influence the redox and ground-state acido-basic properties of the complexes, while maintaining their electronic features. This particular tunability of polytopic 4'-(amidinato) terpyridines offers an interesting perspective for photoactive units in larger multi-functional arrays. PMID- 27774552 TI - Cyclisation of biscarbenoids - a novel mode of cyclobutadiene stabilisation. AB - The reaction of the vicinal biscarbenoid Pip-C[triple bond, length as m-dash]C Pip with dimethyltin dichloride yields a unique tetraamino-substituted cyclobutadienyl system featuring a dative C-Sn interaction. DFT investigation of the reaction mechanism revealed that coordination of the stannyl fragment to the nucleophilic carbon leads to a metal-stabilised zwitterion, allowing for [2+2] cycloaddition under thermal conditions. The compound features a homoaromatic pi system comprising the three sp2-hybridised carbon atoms of the four-membered ring as a consequence of charge separation. PMID- 27774553 TI - Tunable slow dynamics in a new class of soft colloids. AB - By means of extensive simulations, we investigate concentrated solutions of globular single-chain nanoparticles (SCNPs), an emergent class of synthetic soft nano-objects. By increasing the concentration, the SCNPs show flattening, and even reentrant behaviour, in the density dependence of their structural and dynamic correlations, as well as a soft caging regime and weak dynamic heterogeneity. The latter is confirmed by validation of the Stokes-Einstein relation up to concentrations far beyond the overlap density. Therefore SCNPs arise as a new class of soft colloids, exhibiting slow dynamics and actualizing in a real system the structural and dynamic anomalies proposed by models of ultrasoft particles. Quantitative differences in the dynamic behaviour depend on the SCNP deformability, which can be tuned through the degree of internal cross linking. PMID- 27774554 TI - Nitrosodisulfide [S2NO]- (perthionitrite) is a true intermediate during the "cross-talk" of nitrosyl and sulfide. AB - Nitrosodisulfide S2NO- is a controversial intermediate in the reactions of S nitrosothiols with HS- that produce NO and HNO. QM-MM molecular dynamics simulations combined with TD-DFT analysis contribute to a clear identification of S2NO- in water, acetone and acetonitrile, accounting for the UV-Vis signatures and broadening the mechanistic picture of N/S signaling in biochemistry. PMID- 27774555 TI - Electrochemical detection and quantification of gingerol species in ginger (Zingiber officinale) using multiwalled carbon nanotube modified electrodes. AB - We demonstrate the potential of electrochemical detection for the analysis of the 'strength' of ginger in ginger sample. This facile and fast detection method is aimed at the quality control in food industry. Specifically, we report adsorptive stripping voltammetry (AdsSV) as a technique for detection of gingerol compounds, the pungent components of ginger rhizome. Among the gingerols, 6-gingerol is the most abundant and is chosen as a model to characterise the behaviour of a wider range of related compounds. Multiwalled carbon nanotube modified basal plane pyrolytic graphite electrodes (MWCNT-BPPG electrode) are employed to enhance the sensitivity of the measurement. A linearity range from 1 MUM to 50 MUM with limit of detection of 0.21 MUM and limit of quantification of 0.71 MUM is obtained. Further, the simple and rapid extraction procedure by simply vortexing the ginger sample with ethanol is developed for extraction of gingerol related species. PMID- 27774556 TI - Swelling, structure, and phase stability of compressible microgels. AB - Microgels are soft colloidal particles that, when dispersed in a solvent, swell and deswell in response to changes in environmental conditions, such as temperature, concentration, and pH. Using Monte Carlo simulation, we model bulk suspensions of microgels that interact via Hertzian elastic interparticle forces and can expand or contract via trial moves that allow particles to change size in accordance with the Flory-Rehner free energy of cross-linked polymer gels. We monitor the influence of particle compressibility, size fluctuations, and concentration on bulk structural and thermal properties by computing particle swelling ratios, radial distribution functions, static structure factors, osmotic pressures, and freezing densities. For microgels in the nanoscale size range, particle compressibility and associated size fluctuations suppress crystallization, shifting the freezing transition to a higher density than for the hard-sphere fluid. As densities increase beyond close packing, microgels progressively deswell, while their intrinsic size distribution grows increasingly polydisperse. PMID- 27774557 TI - Targeted delivery of doxorubicin to tumour tissues by a novel legumain sensitive polygonal nanogel. AB - Targeted delivery of cytotoxic drugs to tumour tissue has great importance for successful chemotherapy. Legumain is an asparaginyl endopeptidase that is highly up-regulated in a number of solid tumours. The aim of this work was to prepare a novel hyaluronic acid (HA) based legumain sensitive nanogel for the delivery of doxorubicin with a high targeting efficiency both in vitro and in vivo. The legumain sensitive property is achieved by the conjugation of doxorubicin with HA via a legumain substrate peptide bridge. This HA derivative is further crosslinked in a water/oil solvent system to form a polygonal nanogel. Doxorubicin released in the tumour tissue is sustained thanks to the combined action of legumain and hyaluronidase, which are both overexpressed in tumour tissues. Hyaluronic acid could act as a targeting agent to CD44 (HA receptor), which further improved the in vivo target effect and enhanced in vitro cellular uptake. The developed nanogel exhibited a high therapeutic index that improved tumour inhibition effects and reduced system toxicity in a lung cancer mice model. These results highlighted the advantages of using this multi-functional material for a successful delivery of doxorubicin against cancer. PMID- 27774559 TI - 1,1'-Diacetyloctamethylferrocene: an overlooked and overdue synthon leading to the facile synthesis of an octamethylferrocenophane. AB - This paper describes the facile preparation of 1,1'-diacetyloctamethylferrocene (2) by acylation of octamethylferrocene (1) with acetyl chloride. Chloroformylation with POCl3/DMF of 2 affords a variety of products, including 1,1'-bis-(1-chlorovinyl)octamethylferrocene (3b) in high yield. Compound 3b cyclises in aqueous sodium hydroxide/DMF to an octamethyl[1,4]-ferrocenophane bearing a 1-dimethylaminobuta-1,3-diene-handle (4). PMID- 27774558 TI - Intramolecular torque, an indicator of the internal rotation direction of rotor molecules and similar systems. AB - Rotation-inducing torque is ubiquitous in many molecular systems. We present a straightforward theoretical method based on forces acting on atoms and obtained from atomistic quantum mechanics calculations to quickly and qualitatively determine whether a molecule or sub-unit thereof has a tendency to rotate and, if so, around which axis and in which sense: clockwise or counterclockwise. The method also indicates which atoms, if any, are predominant in causing the rotation. Our computational approach can in general efficiently provide insights into the internal rotational degrees of freedom of all molecules and help to theoretically screen or modify them in advance of experiments or to efficiently guide a detailed analysis of their rotational behavior with more extensive computations. As an example, we demonstrate the effectiveness of the approach using a specific light-driven molecular rotary motor which was successfully synthesized and analyzed in prior experiments and simulations. PMID- 27774560 TI - Investigating the all-solid-state batteries based on lithium garnets and a high potential cathode - LiMn1.5Ni0.5O4. AB - All-solid-state Li-ion batteries based on lithium garnets give new prospects for safer battery operations avoiding liquids, and could enable the integration of high energy density electrode materials. Herein, we critically investigate the structural and chemical stability of the high voltage cathode material, LiMn1.5Ni0.5O4, based on the solid lithium garnet electrolyte LLZO (c Li6.4Ga0.2La3Zr2O12) for all-solid Li-ion batteries. We manufacture battery cells based on nano-grained synthesized LLZO and composite cathodes (LiMn1.5Ni0.5O4/LLZO/C) fabricated via direct slurry casting of the cathode material and additives on sintered LLZO pellets against metallic Li anodes. The galvanostatic tests of such all-solid-state batteries up to 4.9 V at 95 degrees C reveal the incompatibility of the solid electrolyte and the cathode material under given conditions. Post-mortem analyses of the all-solid-state batteries demonstrate the formation of new inactive phases at the LLZO/LiMn1.5Ni0.5O4 interfacial region through an irreversible reaction starting at ~3.8 V during charging. The discovered limited chemical stability under the investigated conditions raises the question if LLZO could be a promising solid-electrolyte for future all-solid-state Li-ion batteries especially at higher operation potentials and demanding operation conditions. PMID- 27774561 TI - The breast cancer stem cell potency of copper(ii) complexes bearing nonsteroidal anti-inflammatory drugs and their encapsulation using polymeric nanoparticles. AB - We report the cancer stem cell (CSC) potency of a novel series of copper(ii) phenanthroline complexes bearing nonsteriodial anti-inflammatory drugs: naproxen, tolfenamic acid, and indomethacin (2a-3c). Two of the complexes, 2a and 3c, kill breast CSC-enriched HMLER-shEcad cells (grown in both monolayer and three dimensional cell cultures) to a significantly better extent than salinomycin, a well-established CSC toxin. The most potent complex in the series, 3c induces its cytotoxic effect by generating intracellular reactive oxygen species (ROS) and inhibiting cyclooxgenase-2 (COX-2) activity. Encapsulation of 3c using biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactic-co-glycolic) acid (PEG-PLGA) copolymers at the appropriate feed (5%, 3c NP5) enhances breast CSC uptake and reduces overall toxicity. The nanoparticle formulation, 3c NP5 selectively kills breast CSCs over bulk breast cancer cells, and evokes a similar cellular response to the payload, 3c. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver CSC-potent metal complexes into CSCs. PMID- 27774562 TI - Diruthenium(ii)-NNN pincer complex catalysts for transfer hydrogenation of ketones. AB - Dinuclear ruthenium(ii)-NNN pincer complexes bearing a pi linker-supported bis(pyrazolyl-imidazolyl-pyridine) ligand were synthesized and structurally characterized, and they exhibited excellent catalytic activity for the transfer hydrogenation of ketones in refluxing isopropanol, reaching TOF values up to 1.3 * 106 h-1. Compared with the corresponding mononuclear Ru(ii)-NNN pincer complexes, the bimetallic complexes could be applied at concentrations as low as 0.03 mol% Ru and demonstrated remarkably enhanced catalytic activity in the transfer hydrogenation reactions of ketones. The high catalytic activity of the diruthenium(ii) complexes is attributed to the excellent stability and possible cooperativity of the two coordinated Ru(ii) metal centers through the pi linker. The present synthetic methodology has established an applicable strategy to construct highly active bimetallic NNN pincer complex catalysts. PMID- 27774563 TI - A pentacoordinated norbornenyl-acyl-rhodium(iii) complex as a likely intermediate in the catalytic hydroacylation of norbornadiene. AB - [RhCl(NCO)(nbyl)(PR3)] (nbyl = sigma-norbornenyl; NCO = quinoline-8-acyl; R = p-F C6H4) (1) has been synthesized by the reaction of [Rh(nbd)Cl]2 (nbd = norbornadiene) with 2 equivalents of NCHO (quinoline-8-carbaldehyde) and 2 equivalents of PR3. Compound 1 has been fully characterized in solution and also in the solid state by X-ray diffraction. Compound 1 shows low stability in solution and undergoes slow ring closure isomerization to [RhCl(NCO)(ntyl)(PR3)] (ntyl = sigma-nortricyclyl) (2) after 12 hours. Reaction of 1 with an extra equivalent of aldehyde (NCHO) and PR3 led to the formation of [RhCl(H)(NCO)(PR3)2] (3) and an equivalent of ketone, which is a hydroacylation product. The catalytic activity of 3 in the hydroacylation of nbd with NCHO is reported as well as the catalytic activity of compound 1. Compounds 1 and 3 are proposed as intermediate species in the catalytic hydroacylation of norbornadiene with NCHO. PMID- 27774564 TI - A comparative study of nine berberine salts in the solid state: optimization of the photoluminescence and self-association properties through the choice of the anion. AB - The arrangement of an ionic fluorophore in the crystalline state was regulated by the presence of various counter-ions and the effect on spectroscopic and self association properties was studied. To do so, nine salts of berberine (i.e. a fluorescent natural alkaloid) were investigated. Most of them contained organic anions and were prepared using an ion-exchange process. Berberine chloride and hemisulfate were also used for the sake of comparison. The diffuse reflectance and photoluminescence spectra were recorded on powder compounds. All salts were emissive in the solid state and the emission efficiency was increased seven-fold with the nature of the anion. The optical properties were tentatively discussed on the basis of the crystal-packing mode. The possibility of implementing a bottom-up approach to generate microparticles was investigated using the reprecipitation method. Salts that contain the most hydrophobic anions gave a large number of homogeneous, elongated microparticles. This study showed that most of the berberine salts could be used as fluorescent materials, but proper choice of the anion allows using the self-association properties to best advantage. PMID- 27774566 TI - Effects of a controlled freeze-thaw event on dissolved and colloidal soil organic matter. AB - This study investigated the effects of the freezing and thawing that accompany the warming process on the composition of the soil organic matter in the dissolved and colloidal fractions. Temperate soil samples were incubated in a refrigerator at 2 degrees C for 4 weeks and compared with those frozen at -20 degrees C in the second week followed by thawing at 2 degrees C to study a freeze-thaw effect with minimal effect from the thawing temperature. The freeze thaw group was compared with those incubated at 25 degrees C in the last week to investigate a warming effect after thawing. Thawing at 2 degrees C after freezing at -20 degrees C increased the dissolved organic carbon (DOC), but decreased colloidal Ca. The subsequent warming condition greatly increased both DOC and colloidal Ca. The colloidal organic carbon (COC) and dissolved Ca showed rather subtle changes in response to the freeze-thaw and warming treatments compared to the changes in DOC and colloidal Ca. The fluorescence excitation emission matrix (EEM) and Fourier transformation-infrared spectrometry (FT-IR) results showed that the freeze-thaw and warming treatments gave the opposite effects on the compositions of dissolved humic-like substances, polysaccharides or silicates, and aliphatic alcohols. A principal component analysis (PCA) with the DOC, fluorescence EEM, and FT-IR spectra produced two principal components that successfully distinguished the effects of the freeze-thaw and warming treatments. Due to the contrasting effects of the freeze-thaw and warming treatments, the overall effects of freeze-thaw events in nature on the dissolved and colloidal soil organic matter could vary depending on the thawing temperature. PMID- 27774565 TI - The time to and determinants of first fractures in boys with Duchenne muscular dystrophy. AB - : Boys with vertebral fractures (VF) identified through routine spine radiographs had milder, less symptomatic, and fewer VF compared to those diagnosed with VF following consultation for back pain. Spontaneous (i.e., medication-unassisted) reshaping of fractured vertebral bodies was absent. Long bone fractures were present even before Duchenne muscular dystrophy (DMD) diagnosis in some boys. INTRODUCTION: The objective of the study was to determine the time to and characteristics of first fractures in Duchenne muscular dystrophy. METHODS: This study was a retrospective longitudinal study of 30 boys with DMD <18 years. Boys were classified into four groups according to their first fracture: those with VF identified on routine lateral spine radiographs, those with VF diagnosed following consultation for back pain, those with long bone fractures, and those without fractures. RESULTS: Compared to boys diagnosed with VF as their initial fracture following consultation for back pain, those with VF surveillance radiographs had shorter durations of glucocorticoid (GC) therapy at the time of VF diagnosis (median 1.6 versus 5.3 years, p < 0.01), higher areal (mean +/- standard deviation -1.4 +/- 0.7 versus -3.1 +/- 0.8, p = 0.01), and volumetric ( 0.3 +/- 0.5 versus -2.6 +/- 0.8, p < 0.01) lumbar spine bone mineral density Z scores, as well as fewer VF (median 1.4 versus 5.2 per person, p < 0.01) and a lower median spinal deformity index (median 1.5 versus 9.5, p < 0.01). Vertebral body reshaping following VF was not observed. Ten boys sustained a long bone fracture as their first fracture at a mean age of 8.9 +/- 4.0 years; four of these boys later sustained a total of 27 incident VF. CONCLUSIONS: Routine lateral spine radiographs led to detection of VF in their earlier stages, vertebral body reshaping following VF was absent, and VF were frequent after the first long bone fracture. These results support the inclusion of a lateral spine radiograph starting at the time of GC initiation as part of routine bone health monitoring in DMD. PMID- 27774568 TI - "In the NICU" and "Another Hospital Poem". PMID- 27774570 TI - Celiac disease in Kerala. PMID- 27774571 TI - Should patients presenting with peptic ulcer bleed be screened to rule out cirrhosis of the liver? PMID- 27774567 TI - Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline. AB - RATIONALE: Members of the c-Jun N-terminal kinase (JNK) family of mitogen activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. OBJECTIVE: In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. METHODS: Attentional function in mice haploinsufficient for Map2k7 (Map2k7 +/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT). RESULTS: Once stable performance had been achieved, Map2k7 +/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected. CONCLUSIONS: Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline. PMID- 27774569 TI - An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female anorectal dysfunction. AB - INTRODUCTION AND HYPOTHESIS: The terminology for anorectal dysfunction in women has long been in need of a specific clinically-based Consensus Report. METHODS: This Report combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted on Committee by experts in their fields to form a Joint IUGA/ICS Working Group on Female Anorectal Terminology. Appropriate core clinical categories and sub classifications were developed to give an alphanumeric coding to each definition. An extensive process of twenty rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for anorectal dysfunction, encompassing over 130 separate definitions, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Female-specific anorectal investigations and imaging (ultrasound, radiology and MRI) has been included whilst appropriate figures have been included to supplement and help clarify the text. Interval review (5-10 years) is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSIONS: A consensus-based Terminology Report for female anorectal dysfunction terminology has been produced aimed at being a significant aid to clinical practice and a stimulus for research. PMID- 27774572 TI - Amiodarone-Induced Retinal Neuronal Cell Apoptosis Attenuated by IGF-1 via Counter Regulation of the PI3k/Akt/FoxO3a Pathway. AB - Amiodarone (AM) is the most effective antiarrhythmic agent currently available. However, clinical application of AM is limited by its serious toxic adverse effects including optic neuropathy. The purpose of this study was to explore the effects of AM and to assess if insulin-like growth factor-1 (IGF-1) could protect retinal neuronal cells from AM-induced apoptosis, and to determine the molecular mechanisms underlying the effects. Accordingly, the phosphorylation/activation of Akt and FoxO3a were analyzed by Western blot while the possible pathways involved in the protection of IGF-1 were investigated by application of various pathway inhibitors. The full electroretinogram (FERG) was used to evaluate in vivo effect of AM and IGF-1 on rat retinal physiological functions. Our results showed that AM concentration dependently caused an apoptosis of RGC-5 cells, while IGF-1 protected RGC-5 cells against this effect by AM. The protective effect of IGF-1 was reversed by PI3K inhibitors LY294002 and wortmannin as well as the Akt inhibitor VIII. AM decreased p-Akt and p-FoxO3a while increased the nuclear localization of FoxO3a in the RGC-5 cells. IGF-1 reversed the effect of AM on the p-Akt and p-FoxO3a and the nuclear translocation of FoxO3a. Similar results were obtained in primary cultured retinal ganglia cells. Furthermore, FERG in vivo recording in rats showed that AM decreased a-wave and b-wave of FERG while IGF-1 reversed the effects of AM. These data show that AM induced apoptosis of retinal neuronal cells via inhibiting the PI3K/Akt/FoxO3a pathway while IGF-1 protected RGC-5 cells against AM-induced cell apoptosis by stimulating this pathway. PMID- 27774575 TI - Modeling impacts of climate change on the potential distribution of the carcinogenic liver fluke, Opisthorchis viverrini, in Thailand. AB - Global climate change is now regarded as imposing a significant threat of enhancing transmission of parasitic diseases. Maximum entropy species distribution modeling (MaxEnt) was used to explore how projected climate change could affect the potential distribution of the carcinogenic liver fluke, Opisthorchis viverrini, in Thailand. A range of climate variables was used: the Hadley Global Environment Model 2-Earth System (HadGEM2-ES) climate change model and also the IPCC scenarios A2a for 2050 and 2070. Occurrence data from surveys conducted in 2009 and 2014 were obtained from the Department of Disease Control, Ministry of Public Health, Thailand. The MaxEnt model performed better than random for O. viverrini with training AUC values greater than 0.8 under current and future climatic conditions. The current distribution of O. viverrini is significantly affected by precipitation and minimum temperature. According to current conditions, parts of Thailand climatically suitable for O. viverrini are mostly in the northeast and north, but the parasite is largely absent from southern Thailand. Under future climate change scenarios, the distribution of O. viverrini in 2050 should be significantly affected by precipitation, maximum temperature, and mean temperature of the wettest quarter, whereas in 2070, significant factors are likely to be precipitation during the coldest quarter, maximum, and minimum temperatures. Maps of predicted future distribution revealed a drastic decrease in presence of O. viverrini in the northeast region. The information gained from this study should be a useful reference for implementing long-term prevention and control strategies for O. viverrini in Thailand. PMID- 27774574 TI - Constrained Spherical Deconvolution Tractography Reveals Cerebello-Mammillary Connections in Humans. AB - According to the classical view, the cerebellum has long been confined to motor control physiology; however, it has now become evident that it exerts several non somatic features other than the coordination of movement and is engaged also in the regulation of cognition and emotion. In a previous diffusion-weighted imaging constrained spherical deconvolution (CSD) tractography study, we demonstrated the existence of a direct cerebellum-hippocampal pathway, thus reinforcing the hypothesis of the cerebellar role in non-motor domains. However, our understanding of limbic-cerebellar interconnectivity in humans is rather sparse, primarily due to the intrinsic limitation in the acquisition of in vivo tracing. Here, we provided tractographic evidences of connectivity patterns between the cerebellum and mammillary bodies by using whole-brain CSD tractography in 13 healthy subjects. We found both ipsilateral and contralateral connections between the mammillary bodies, cerebellar cortex, and dentate nucleus, in line with previous studies performed in rodents and primates. These pathways could improve our understanding of cerebellar role in several autonomic functions, visuospatial orientation, and memory and may shed new light on neurodegenerative diseases in which clinically relevant impairments in navigational skills or memory may become manifest at early stages. PMID- 27774573 TI - The Role of MicroRNAs in Cerebellar Development and Autism Spectrum Disorder During Embryogenesis. AB - MicroRNAs (miRNAs) are a class of small non-coding RNA molecules with wide ranging and subtle effects on protein production. Their activity during the development of the cerebellum provides a valuable exemplar of how non-coding molecules may assist the development and function of the central nervous system and drive neurodevelopmental disorders. Three distinct aspects of miRNA contribution to early cerebellar development will here be reviewed. Aspects are the establishment of the cerebellar anlage, the generation and maturation of at least two principal cell types of the developing cerebellar microcircuit, and the etiology and early progression of autism spectrum disorder. It will be argued here that the autism spectrum is an adept model to explore miRNA impact on the cognitive and affective processes that descend from the developing cerebellum. PMID- 27774577 TI - Retrospective case-control study of correlation between MTHFR gene and OSCC risk in North India. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) occurrence appears to be the number one among all cancers in India. Folate is a methyl donor during DNA methylation, as it provides substrate for methylenetetrahydrofolate reductase (MTHFR) to convert 5,10-MTHF to 5-MTHF and subsequently metabolizes it to methionine. The purpose of this study was to identify MTHFR C677T gene polymorphism in patients with OSCC. MATERIALS AND METHODS: A total of 350 OSCC cases and 350 healthy controls participated in this study. MTHFR C677T single nucleotide polymorphism was evaluated by PCR-RFLP. RESULTS: In the present study, MTHFR gene 677CC, CT, and TT genotype frequencies of the total OSCC cases were 74.8; 19.4 and 5.71; and 88.5, 9.42, and 2.0 % in controls. The average frequency of the MTHFR 677T allele was 15.4 % in OSCC cases compared to 6.71 % in the controls. The CT genotype occurrence prevailed more in patients than controls in contrast to TT genotype, although both the genotypes were statistically significant for OSCC. Moreover, we found that T allele was significant in cases of smoking and tobacco chewing. CONCLUSIONS: In this study, we found that the homozygous mutant T allele appeared to have significantly higher risk of OSCC especially in late stages and therefore supporting in OSCC susceptibility and its progression. PMID- 27774576 TI - Neurocysticercosis: a review on status in India, management, and current therapeutic interventions. AB - Tapeworms (cestodes) are segmented flatworms responsible for causing diseases that may prove fatal and difficult to treat in the absence of proper treatment and efficient drugs. Neurocysticercosis (NCC) is a common parasitic infection of the central nervous system and a major contributor to epilepsy caused by the metacestode (larva) of the human tapeworm Taenia solium, characterized by a range of pathological symptoms including epileptic seizures, headaches, and hydrocephalus. Cysticercosis is considered as a "biological imprint" of the socioeconomic development of a community in general and a country in particular. It is the single most common cause of epilepsy in the resource-poor endemic regions of the world, including most of South and Central America, India, Southeast Asia, China, and sub-Saharan Africa. A vast degree of variation in the neuropathology and clinical symptoms of NCC often makes it difficult to diagnose and manage. To add to it, emerging drug resistance to known anti-parasitic agents, together with the inability of these agents to prevent re-infection and relapse, further complicates the disease scenario. The aim of the current review was to provide the latest update on NCC with special emphasis on the Indian scenario, along with current and novel methods of diagnosis as well as scope of development for novel detection techniques, novel targets for drug development, and therapeutic interventions, as well as future challenges. PMID- 27774579 TI - Extravillous trophoblasts invade more than uterine arteries: evidence for the invasion of uterine veins. AB - During the first trimester of pregnancy, extravillous trophoblasts (EVTs) invade into the decidual interstitium to the first third of the myometrium, thereby anchoring the placenta to the uterus. They also follow the endovascular and endoglandular route of invasion; plug, line and remodel spiral arteries, thus being responsible for the establishment of hemotrophic nutrition with the beginning of the second trimester and invade and open uterine glands toward the intervillous space for a histiotrophic nutrition during the first trimester. The aim of this study was to provide proof that uterine veins are invaded by EVTs similar to uterine arteries and glands in first trimester of pregnancy. Therefore, serial sections from in situ first trimester placenta were immuno single- and immuno-double-stained to distinguish in a first step between arteries and veins and secondly between invaded and non-invaded vessels. Subsequently, invasion of EVTs into uterine vessels was quantified. Our data show that uterine veins are significantly more invaded by EVTs than uterine arteries (29.2 +/- 15.7 %) during early pregnancy. Counted vessel cross sections revealed significantly higher EVT invasion into veins (59.5 +/- 7.9 %) compared to arteries (29.2 +/- 15.7 %). In the lumen of veins, single EVTs were repeatedly found, beside detached glandular epithelial cells or syncytial fragments. This study allows the expansion of our hitherto postulated concept of EVT invasion during first trimester of pregnancy. We suggest that invasion of EVTs into uterine veins is responsible the draining of waste and blood plasma from the intervillous space during the first trimester of pregnancy. PMID- 27774578 TI - Propensity score-matched analysis of robotic versus endoscopic bilateral axillo breast approach (BABA) thyroidectomy in papillary thyroid carcinoma. AB - PURPOSE: The da Vinci surgical robot system was developed to overcome the weaknesses of endoscopic surgery. However, whether robotic surgery is superior to endoscopic surgery remains uncertain. Therefore, the purpose of this study was to compare the surgical and oncologic outcomes between endoscopic and robotic thyroidectomy using bilateral axillo-breast approach (BABA). METHODS: Between January 2008 and June 2015, papillary thyroid carcinoma patients who underwent thyroidectomy with central neck dissection using endoscopic (n = 480) or robotic (n = 705) BABA were primarily reviewed. We performed 1:1 propensity score matching and 289 matched pairs were yielded. RESULTS: Operation time was significantly longer in the robotic thyroidectomy than in the endoscopic thyroidectomy (184.9 vs. 128.9 min, P < 0.001). A significantly higher number of central lymph nodes (CLNs) were resected in the robotic thyroidectomy than in the endoscopic thyroidectomy (5.3 vs. 4.4, P = 0.003). However, the incidence of other outcomes including hospital stay, postoperative duration, thyroglobulin level, radioactive iodine ablation, hemorrhage, chyle leakage, wound infection, recurrent laryngeal nerve injury, and loco-regional recurrence did not significantly differ between the endoscopic thyroidectomy and the robotic thyroidectomy. CONCLUSIONS: Endoscopic thyroidectomy is comparable with robotic thyroidectomy in view of surgical complications and LRR. Because robotic thyroidectomy resected a larger number of CLNs than did endoscopic thyroidectomy, further long-term follow-up studies will be required to clarify the possible prognostic benefits of robotic thyroidectomy. PMID- 27774580 TI - TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension. AB - The phenotypic modulation of contractile vascular smooth muscle cell (VSMC) is widely accepted as the pivotal process in the arterial remodeling induced by hypertension. This study aimed to investigate the potential role of transient receptor potential vanilloid type 1 (TRPV1) on regulating VSMC plasticity and intracranial arteriole remodeling in hypertension. Spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats and TRPV1-/- mice on a C57BL/6J background were used. By microscopic observation of the histopathological sections of vessels from hypertensive SHR and age-matched normotensive WKY control rats, we found that hypertension induced arterial remodeling. Decreased alpha-smooth muscle actin (alpha-SMA) and SM22alpha while increased osteopontin (OPN) were observed in aorta and VSMCs derived from SHR compared with those in WKY, and VSMCs derived from SHR upregulated inflammatory factors. TRPV1 activation by capsaicin significantly increased expression of alpha-SMA and SM22alpha, reduced expression of OPN, retarded proliferative and migratory capacities and inhibited inflammatory status in VSMCs from SHR, which was counteracted by TRPV1 antagonist 5'-iodoresiniferatoxin (iRTX) combined with capsaicin. TRPV1 activation by capsaicin ameliorated intracranial arteriole remodeling in SHR and deoxycorticosterone acetate (DOCA)-salt hypertensive mice. However, the attenuation of arteriole remodeling by capsaicin was not observed in TRPV1-/- mice. Furthermore, TRPV1 activation significantly decreased the activity of PI3K and phosphorylation level of Akt in SHR-derived VSMCs. Taken together, we provide evidence that TRPV1 activation by capsaicin attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation during hypertension, which may be at least partly attributed to the suppression PI3K/Akt signaling pathway. These findings highlight the prospect of TRPV1 in prevention and treatment of hypertension. PMID- 27774582 TI - Blastic plasmacytoid dendritic cell neoplasm with t(11;19)(q23;p13.3);KMT2A(MLL) rearranged: a diagnostic challenge. PMID- 27774581 TI - A preliminary study of new single polymorphisms in the T helper type 17 pathway for psoriasis in the Korean population. AB - Psoriasis is a polygenic and multi-factorial disease showing ethnic differences in terms of its severity and frequency. Therapies targeting interleukin (IL)-17A, IL-17 receptor (IL-17R) and Janus kinases (JAKs) are in clinical development for the treatment of psoriasis, and their success suggests the essential role of these molecules in psoriasis. To investigate the genetic susceptibility in T helper type 17 (Th17) cell signal transduction pathways for promoting psoriasis, we performed candidate gene and linkage disequilibrium analysis. In 208 patients and 266 normal controls, we analysed 31 single nucleotide polymorphisms in 12 genes (CAMP, IL17A, IL17F, IL17RA, IL22, JAK1, JAK2, JAK3, STAT3, TLR7, TLR9 and TYK2; abbreviations: CAMP, human cathelicidin antimicrobial peptide; STAT-3, signal transducer and activator of transcription 3; TLR, Toll-like receptor; TYK2, tyrosine kinase 2). Patients with psoriasis showed a strong association for IL17F rs763780 [odds ratio (OR) = 3.27, P = 0.04], which results in a histidine to-arginine substitution, and JAK2 rs2274471 (OR = 2.66, P = 0.02). In addition, JAK2 rs7849191 showed a protective pattern, met the significance threshold (OR = 0.77, P = 0.05) and showed a tendency for an inverse association with the frequency of early-onset psoriasis under age 40 years (P = 0.07). In haplotype analysis, JAK1 rs310241A/rs2780889T showed a protective effect (OR = 0.73, P = 0.03) in psoriasis. In conclusion, we report two new psoriasis-susceptibility loci, in IL17F and JAK2, as well as a newly identified late-onset associated protective JAK2 locus and a protective JAK1 haplotype in the Korean population. PMID- 27774583 TI - Cortisol stress responses and children's behavioral functioning at school. AB - The present study investigated whether cortisol stress responses of 6-year-olds were associated with their behavioral functioning at school. Additionally, the moderating role of stress in the family environment was examined. To this end, 149 healthy children (Mage = 6.09 years; 70 girls) participated in an age appropriate innovative social evaluative stress test. Saliva cortisol samples were collected six times during the stress test to calculate two indices of the cortisol stress response: cortisol stress reactivity and total stress cortisol. Teachers assessed children's internalizing, externalizing, and prosocial behaviors. Stress in the family environment was operationalized as maternally reported parenting stress. Results indicated a significant increase in cortisol concentrations in response to the stressor. No significant associations were found between cortisol stress responses and behavioral functioning at school and there was no evidence for moderation by maternal parenting stress. Potential theoretical and methodological explanations for these results are discussed. PMID- 27774584 TI - Montefiore-Einstein Center for the Aging Brain: Preliminary Data. AB - Given the multifaceted nature of dementia care management, an interdisciplinary comprehensive clinical approach is necessary. We describe our one-year experience with outpatient based dementia care at the Montefiore-Einstein Center for the Aging Brain (CAB) involving an multispecialty team of geriatricians, neurologists, and neuropsychologists, supported by geriatric psychiatrists, physiatrists, and social services. The goals of the CAB is to maximize dementia outcomes, including regular monitoring of patient's health and cognition, education and support to patients, their families and caregivers; initiation of pharmacological and non-pharmacological treatments as appropriate, and the facilitation of access to clinical trials. The CAB follows a consultative model where patients referred to the center receive a comprehensive three step evaluation and management plan from Geriatric, Neuropsychology and Neurology specialists that is shared with patient, caregivers and primary care physicians. Of the 366 patients seen for cognitive complaints in our first year, 71% were women with a mean age of 74 years. Self-identified ethnicity of patients included Caucasian (26%), African-American (25%), Hispanic (18%) and multiracial (5%). Common final diagnoses assigned at the CAB included mild cognitive impairment syndromes (31%), Alzheimer's disease (20%), mixed dementia (11%), vascular dementia (9%), Frontotemporal dementia (4%) and dementia with Lewy bodies (4%). Our one-year progress report indicates that an interdisciplinary clinical dementia care model is feasible in the outpatient setting as well as highly accepted by patients, caregivers and referring physicians. PMID- 27774585 TI - The importance of people compliance (social desirability bias) in the assessment of epilepsy prevalence in rural areas of developing countries. Results of the Atahualpa Project. AB - Epilepsy is a major health issue in rural areas of developing countries. However, heterogeneity of epilepsy prevalence in different studies precludes assessment of the magnitude of the problem. Using similar protocols, two population-based surveys were conducted 12 years apart (2003 and 2015) in a rural Ecuadorian village (Atahualpa). The only difference was a higher people compliance with interviewers during the second survey. Epilepsy prevalence in the 2003 survey was 13.5 per 1,000 (18/1,332) in villagers aged >=20 years. This rate increased to 26.8 per 1,000 (41/1,530) in the 2015 survey. Thirty-three persons with epilepsy detected during the second survey lived in the village in 2003; six of them had seizures starting after 2003. Of the remaining 27 cases, 13 (48%) denied their problem during the first survey. Further interview revealed that denial was related to lack of confidence with unacquainted field personnel. Social Desirability Scale-17 scores were lower in those who admitted having epilepsy than in those who denied their condition (p = 0.048). Lack of confidence with interviewers and a social desirability bias account for a sizable proportion of epilepsy denial in the study population, and may explain heterogeneity of epilepsy prevalence reported in studies conducted in poor rural settings. PMID- 27774586 TI - Focus on the upper limb in Duchenne muscular dystrophy. PMID- 27774587 TI - Unique CT Perfusion Imaging in a Case of HaNDL: New Insight into HaNDL Pathophysiology and Vasomotor Principles of Cortical Spreading Depression. AB - BACKGROUND: The etiology of HaNDL is not known. Recent neuroimaging studies have suggested that there may be altered cerebrovascular blood flow during acute episodes. However, what exactly these vascular changes represent and how they may relate to the overall pathogenesis of HaNDL is uncertain. CASE: A 42-year-old, right-handed male, presented with acute aphasia and right arm weakness. Urgent CT/CT-angiogram were normal except for an incidental hypoplastic right anterior cerebral artery (ACA) A1 segment. However, CT perfusion revealed global left hemisphere hypoperfusion in the range of oligemia. Also, the right ACA territory, supplied by the dominant left A1, shared the same pattern of hypoperfusion. Further investigations and clinical course were consistent with HaNDL. DISCUSSION/CONCLUSIONS: The pattern of global left hemispheric hypoperfusion seen in this case of HaNDL supports a hypothesis of secondary oligemia induced by a hemispheric wave of cortical spreading depression (CSD). However, the extension of hypoperfusion to the right ACA territory represents a phenomenon not previously reported in this field. We speculate that the direct spread of CSD induced vasomotor changes across the anomalous vasculature could account for this finding. This case provides a valuable contribution toward understanding HaNDL pathophysiology and in doing so may also yield broader implications regarding neurophysiological principles of CSD. PMID- 27774589 TI - Hormonal Contraceptives and Migraine With Aura-Is There Still a Risk? AB - Unnecessary confusion still surrounds the use of combined hormonal contraceptives (CHCs) in the setting of migraine with aura (MwA). Clearing this confusion is a key issue for headache specialists, since most women with migraine have menstrual related migraine (MRM), and some CHCs can prevent this particularly severe migraine. Their use, however, is still restricted by current guidelines due to concerns of increased stroke risk - concerns that originated over half a century ago in the era of high dose contraceptives. Yet studies consistently show that stroke risk is not increased with today's very low dose CHCs containing 20-25 ug ethinyl estradiol (EE), and continuous ultra low-dose formulations (10-15 ug EE) may even reduce aura frequency, thereby potentially decreasing stroke risk. This article clarifies the stroke risk of CHCs and examines their impact on migraine. It also examines how stroke risk is altered by the estrogen content of the CHC, by contributing factors such as smoking, age and hypertension, and by aura frequency. And finally, it puts these risks into a meaningful context with a risk/benefit assessment. PMID- 27774588 TI - The geographic distribution of the otolaryngology workforce in the United States. AB - OBJECTIVES: To describe the deployment of otolaryngologists and evaluate factors associated with the geographic distribution of otolaryngologists in the United States. STUDY DESIGN: Cross-sectional study. METHODS: The otolaryngology physician supply was defined as the number of otolaryngologists per 100,000 in the hospital referral region (HRR). The otolaryngology physician supply was derived from the American Medical Association Masterfile or from the Medicare Enrollment and Provider Utilization Files. Multiple linear regression tested the association of population, physician, and hospital factors on the supply of Medicare-enrolled otolaryngologists/HRR. RESULTS: Two methods of measuring the otolaryngology workforce were moderately correlated across hospital referral regions (Pearson coefficient 0.513, P = .0001); regardless, the supply of otolaryngology providers varies greatly over different geographic regions. Otolaryngologists concentrate in regions with many other physicians, particularly specialist physicians. The otolaryngology supply also increases with regional population income and education levels. Using AMA-derived data, there was no association between the supply of otolaryngologists and staffed acute-care hospital beds and the presence of an otolaryngology residency-training program. In contrast, the supply of otolaryngology providers enrolled in Medicare independently increases for each HRR by 0.8 per 100,000 for each unit increase in supply of hospital beds (P < .0001) and by 0.49 per 100,000 in regions with an otolaryngology residency-training program (P = .006), accounting for all other factors. CONCLUSION: Irrespective of methodology, the supply of otolaryngologists varies widely across geographic regions in the United States. For Medicare beneficiaries, regional hospital factors-including the presence of an otolaryngology residency program-may improve access to otolaryngology services. LEVEL OF EVIDENCE: NA Laryngoscope, 127:95-101, 2017. PMID- 27774590 TI - Development of hemiacetal esterified levofloxacin to prevent chelation with metal containing drugs. AB - OBJECTIVES: To avoid the chelate formation between levofloxacin (LVFX) and aluminium hydroxide in gastrointestinal tract, an ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) was synthesised as a prodrug. METHODS: The effects of aluminium hydroxide on the bioavailability of LVFX following oral administration of LVFX-EHE were investigated in rats. Furthermore, the effects of aluminium hydroxide on small intestinal absorption of LVFX and LVFX-EHE when subjected to a hydrolysis experiment using in situ everted gut sac were investigated, and the minimal inhibitory concentrations (MICs) of LVFX and LVFX-EHE for various intestinal bacteria were measured. KEY FINDINGS: When LVFX EHE was co-administered with and without aluminium hydroxide, the AUC0-4 h values of LVFX hydrolysed from LVFX-EHE were similar to that of LVFX alone. In everted gut sac experiments, LVFX-EHE was efficiently absorbed even in the presence of aluminium ions after 1 h of incubation, whereas the absorption of LVFX decreased significantly in the presence of aluminium ions. MIC values of LVFX-EHE were far higher than LVFX. CONCLUSIONS: This study suggests the benefit of ethoxycarbonyl 1-ethyl hemiacetal esterification of the carboxyl group of new quinolone as a prodrug which is able to avoid chelate formation. PMID- 27774591 TI - Effects of age-based movement on the estimation of growth assuming random-at-age or random-at-length data. AB - Simulation methods were used to generate paired data from a simulated population that included the age-based process of movement and the length-based process of gear selection. The age-based process caused bias in the estimates of growth parameters assuming random at length, even when relatively few age classes were affected. Methods that assumed random at age were biased by the subsequent inclusion of the length-based process of gear selection. Additional knowledge of the age structure of the sampled area is needed to ensure an unbiased estimate of the growth parameters when using the length-conditional approach in the presence of age-based movement. Estimates of the variability in the length-at-age relationship were better estimated with the length-conditional than the traditional method even when the assumptions of random at length were violated. Inclusion of paired observations of length and associated age inside the population dynamics model may be the most appropriate way of estimating growth. PMID- 27774592 TI - Rifampicin attenuates experimental autoimmune encephalomyelitis by inhibiting pathogenic Th17 cells responses. AB - Rifampicin, a broad-spectrum antibiotic, has neuroprotective, immunosuppressive, and anti-inflammatory properties. However, the effect of rifampicin on autoimmune disorders of the nervous system is not clear. In this study, we investigated whether rifampicin was beneficial to myelin oligodendrocyte glycoprotein peptide (MOG33-35 )-induced female C57BL/6 experimental autoimmune encephalomyelitis (EAE) mice, the well-established animal model of multiple sclerosis. Rifampicin treatment (daily from the first day after EAE immunization) remarkably attenuated clinical signs and loss of body weight, which are associated with suppression of inflammatory infiltration and demyelination in spinal cords of EAE mice. Furthermore, rifampicin dramatically reduced the disruption of blood-brain barrier integrity, down-regulated serum concentration of IL-6 and IL-17A, inhibited pathological Th17 cell differentiation, and modulated the expression of p-STAT3 and p-p65. These results suggest that rifampicin is effective for attenuating the clinical severity of EAE mice, which may be related to its inhibitive ability in differentiation of Th17 cell and secretion of its key effector molecule IL-17A via regulation of excessive activation of the key signaling molecules of JAK/STAT pathway. Our findings may be helpful for developing therapeutic and preventive strategies for multiple sclerosis. PMID- 27774593 TI - Properties of the DASS-21 in an Australian Community Adolescent Population. AB - BACKGROUND: Although developed for adults, the Depression Anxiety Stress Scales Short Version (DASS-21) has been used in many research studies with adolescent samples. Evidence as to the applicability of the DASS subscale scores to represent the distinct states of depression, anxiety, and stress as experienced by adolescents is mixed, and the age at which it may be possible to differentiate these 3 states using the DASS-21 has not yet been determined. OBJECTIVE: This study evaluated evidence for a multifactor structure in the DASS-21 in adolescents and the specificity of the 3 subscales for adolescents in general and at different ages. METHOD: Data were from a large cross-sectional survey of 2,873 school students in Grades 6-12 (aged 12-18 years) in Australia. We conducted confirmatory bifactor analyses testing a general mental health distress factor and 3 domain-specific factors for anxiety, depression, and stress for the whole sample and across gender by age groups. The internal consistency reliability of the DASS total and subscale scores was determined using omega coefficients. RESULTS: Analyses identified that most of the variation in the items was explained by the dominance of a single, general factor and the subscales lacked specificity across all age groups. CONCLUSION: The DASS-21 can be reliably used to measure general distress in adolescents, but the subscales fail to discriminate between the 3 states. Our results indicate that this lack of discrimination does not reduce with increasing age. These findings caution against the use of adult theoretical models and measures within adolescent populations. PMID- 27774595 TI - Comparison of potential fecundity models for walleye pollock Gadus chalcogrammus in the Pacific waters off Hokkaido, Japan. AB - Potential fecundity models of walleye or Alaska pollock Gadus chalcogrammus in the Pacific waters off Hokkaido, Japan, were developed. They were compared using a generalized linear model with using either standard body length (LS ) or total body mass (MT ) as a main covariate along with Fulton's condition factor (K) and mean diameter of oocytes (DO ) as additional potential covariates to account for maternal conditions and maturity stage. The results of model selection showed that MT was a better single predictor of potential fecundity (FP ) than LS . The biological importance of K on FP was obscure, because it was statistically significant when used in the predictor with LS (i.e. length-based model), but not significant when used with MT (i.e. mass-based model). Meanwhile, DO was statistically significant in both length and mass-based models, suggesting the importance of downregulation on the number of oocytes with advancing maturation. Among all candidate models, the model with MT and DO in the predictor had the lowest Akaike's information criterion value, suggesting its better predictive power. These newly developed models will improve future comparisons of the potential fecundity within and among stocks by excluding potential biases other than body size. PMID- 27774594 TI - Cellular source and proinflammatory roles of high-mobility group box 1 in surgically injured rat vocal folds. AB - OBJECTIVES/HYPOTHESIS: High-mobility group box 1 (HMGB1) is a chromatin-binding protein located in the cell nucleus. Following injury, immunocompetent cells secrete HMGB1 to the extracellular milieu under the stimulation of proinflammatory cytokines. Extracellular HMGB1 acts a danger signal that instigates the innate immunity and tissue repair. We previously reported HMGB1 in the vocal fold extracellular compartment between day 3 and day 7 following surgical injury. In this study, we further investigated the cell source of HMGB1 and the relationship of proinflammatory cytokine expression and HMGB1 translocation in wounded vocal folds. STUDY DESIGN: Prospective animal study. METHODS: Bilateral vocal fold injury was performed on 122 Sprague-Dawley rats. An additional 18 rats served as uninjured controls. Animals were sacrificed at multiple time points up to 4 weeks after surgery. Immunohistochemical costaining was performed to identify the cell source of HMGB1. Cell markers ED1, fibroblast specific protein 1 (FSP1), and alpha smooth muscle actin (alpha-SMA) were used to identify macrophages, fibroblasts, and myofibroblasts, respectively. Enzyme linked immunosorbent assays were performed to measure cytokine levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in vocal fold tissue. RESULTS: Costaining of HMGB1 was strong with ED1 and FSP1 but was minimal with alpha-SMA in injured vocal folds. Compared to uninjured controls, IL 1beta and TNF-alpha expression increased significantly the first 2 days after injury. CONCLUSIONS: Macrophages and fibroblasts were a major cell source of vocal fold HMGB1. Translocation of HMGB1 may be an active response to the early accumulation of IL-1beta and TNF-alpha in the wounded vocal folds. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E193-E200, 2017. PMID- 27774596 TI - A novel field method to distinguish between cryptic carcharhinid sharks, Australian blacktip shark Carcharhinus tilstoni and common blacktip shark C. limbatus, despite the presence of hybrids. AB - Multivariate and machine-learning methods were used to develop field identification techniques for two species of cryptic blacktip shark. From 112 specimens, precaudal vertebrae (PCV) counts and molecular analysis identified 95 Australian blacktip sharks Carcharhinus tilstoni and 17 common blacktip sharks Carcharhinus limbatus. Molecular analysis also revealed 27 of the 112 were C. tilstoni * C. limbatus hybrids, of which 23 had C. tilstoni PCV counts and four had C. limbatus PCV counts. In the absence of further information about hybrid phenotypes, hybrids were assigned as either C. limbatus or C. tilstoni based on PCV counts. Discriminant analysis achieved 80% successful identification, but machine-learning models were better, achieving 100% successful identification, using six key measurements (fork length, caudal-fin peduncle height, interdorsal space, second dorsal-fin height, pelvic-fin length and pelvic-fin midpoint to first dorsal-fin insertion). Furthermore, pelvic-fin markings could be used for identification: C. limbatus has a distinct black mark >3% of the total pelvic-fin area, while C. tilstoni has markings with diffuse edges, or has smaller or no markings. Machine learning and pelvic-fin marking identification methods were field tested achieving 87 and 90% successful identification, respectively. With further refinement, the techniques developed here will form an important part of a multi-faceted approach to identification of C. tilstoni and C. limbatus and have a clear management and conservation application to these commercially important sharks. The methods developed here are broadly applicable and can be used to resolve species identities in many fisheries where cryptic species exist. PMID- 27774597 TI - A new species of the leopard pleco genus Pseudacanthicus (Siluriformes: Loricariidae) from the Rio Xingu, Brazil. AB - The genus Pseudacanthicus comprises six valid species distributed in the Amazon basin and Caribbean coastal drainages from Guyana to French Guiana: P. serratus, P. fordii, P. histrix, P. spinosus, P. leopardus and P. pitanga. A new species of Pseudacanthicus is described from the Rio Xingu Basin, distinguished from its congeners by the following combination of characters: presence of anastomose dark blotches forming continuous zigzag bands alongside longitudinal keels; presence of dark blotches on ventral surface of body and head; all fins with orange to red colour on unbranched rays and sometimes subsequent branched rays. Brief comments on ornamental fisheries and conservation of the new species are also provided. PMID- 27774598 TI - In Sync and in Control: A Meta-Analysis of Parent-Child Positive Behavioral Synchrony and Youth Self-Regulation. AB - A growing body of research has highlighted the connection between parent-child positive behavioral synchrony and youth self-regulation; however, this association has yet to be the focus of a meta-analytic review. Therefore, the present meta-analysis aimed to estimate the magnitude of the relation between parent-child positive behavioral synchrony and youth self-regulation and to identify moderator variables that can explain the variability in the degree of this association across the extant literature. A thorough literature search of two major databases, in addition to scanning the reference sections of relevant articles, yielded a total of 10 peer-reviewed articles (24 effect sizes, 658 children) that were eligible for inclusion in the current meta-analysis. Results from the overall mean effect size calculation using a random-effects model indicated that parent-child positive behavioral synchrony was significantly, positively correlated with youth self-regulation and the effect size was medium. Children's ages at the time of synchrony and self-regulation measurements, as well as parent gender, served as significant moderator variables. Findings from the present meta-analysis can help to refine existing theoretical models on the role of the parent-child relationship in youth adjustment. Prevention and intervention efforts may benefit from an increased emphasis on building parent child positive behavioral synchrony to promote youth self-regulation and thus children's overall well-being. PMID- 27774599 TI - Density-dependent effects of non-native brown trout Salmo trutta on the species area relationship in stream fish assemblages. AB - The spatial scale and density-dependent effects of non-native brown trout Salmo trutta on species richness of fish assemblages were examined at 48 study sites in Mamachi Stream, a tributary of Chitose River, Hokkaido, Japan. The density of age >=1 year S. trutta was high in the upstream side of the main stem of Mamachi Stream. Fish species richness increased with increasing area of study sites (habitat size), but the increasing magnitude of the species richness with area decreased with increasing age of >=1 year S. trutta density. The relationships between age >=1 year S. trutta, however, and presence-absence of each species seemed to be different among species. Species richness was also determined by location and physical environmental variables, i.e. it was high on the downstream side and in structurally complex environments. PMID- 27774600 TI - Characteristics of tinnitus in adolescents and association with psychoemotional factors. AB - OBJECTIVES/HYPOTHESIS: The characteristics and underlying mechanisms of tinnitus remain more elusive in the pediatric population than in adults. We investigated the prevalence of tinnitus, its characteristics, and associated factors, with a focus on psychoemotional problems in adolescents. STUDY DESIGN: Cross-sectional study METHODS: In total, 962 adolescents were surveyed for tinnitus and possibly related otologic and socioeconomic factors. The participants completed a visual analog scale (VAS) pertaining to various aspects of tinnitus, as well as the Tinnitus Handicap Inventory, Children's Depression Inventory (CDI), State Anxiety Inventory for Children, Trait Anxiety Inventory for Children (TAIC), Internet Addiction Test, Conners' Abbreviated Parent Rating Scale, and a learning disability score. Characteristics of tinnitus were analyzed, and psychoemotional and other factors were compared between tinnitus and nontinnitus groups. RESULTS: Approximately one-third of subjects reported experiencing tinnitus. A family history of tinnitus, subjective hearing loss, dizziness, and CDI and TAIC abnormalities were significantly associated with tinnitus. In the tinnitus-always group, tinnitus showed significant relationships with subjective hearing loss, bilateral tinnitus, and VAS, CDI, and TAIC scores. CONCLUSIONS: The results suggest that about one-third of adolescents experience tinnitus, which may be related to psychoemotional factors. In particular, anxiety and depression may be important factors to consider in managing tinnitus in adolescents. Further study of tinnitus in adolescents, including efforts toward diagnosis and management, is needed to determine whether there is a causal relationship with anxiety and depression, and the extent to which adverse outcomes may be associated with these psychoemotional factors. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:2113-2119, 2017. PMID- 27774601 TI - High-sensitivity FEES with NBI-illumination. PMID- 27774602 TI - Site fidelity and homing behaviour of intertidal sculpins revisited. AB - To assess the repeatability of an ecological study, this study both partially replicates and extends a previous study on the site fidelity and homing ability of two abundant and ecologically important species of rocky intertidal sculpin fishes, Oligocottus maculosus and Oligocottus snyderi. A traditional mark and recapture approach was utilized and found that both of these species display high site fidelity to a home range of tidepools and homing ability to these pools, confirming the findings of previous work. Unlike the previous study, however, there was no effect of body size on homing ability and a modelling approach that incorporates encounter probability provided evidence for a sex effect on homing ability. In addition, this study extends the maximum homing ability of O. snyderi to 179 m and O. maculosus to 218 m, which were the maximum displacement distances for each species in this study, suggesting they may be capable of even greater homing distances. This work, however, finds that homing success was negatively related to displacement distance. These findings suggest adult sculpin populations are likely to be highly sub-structured geographically, possibly contributing to the exceptionally high species richness of the group. PMID- 27774603 TI - Identification of a novel B allele with missense mutation (c.98G > C) in the ABO gene. PMID- 27774605 TI - Is esophagoscopy necessary during panendoscopy? PMID- 27774606 TI - Mechanism involved in interleukin-21-induced phagocytosis in human monocytes and macrophages. AB - The interleukin (IL)-21/IL-21 receptor (R) is a promising system to be exploited for the development of therapeutic strategies. Although the biological activities of IL-21 and its cell signalling events have been largely studied in immunocytes, its interaction with human monocytes and macrophages have been neglected. Previously, we reported that IL-21 enhances Fc gamma receptor (FcRgamma)-mediated phagocytosis in human monocytes and in human monocyte-derived macrophages (HMDM) and identified Syk as a novel molecular target of IL-21. Here, we elucidate further how IL-21 promotes phagocytosis in these cells. Unlike its ability to enhance phagocytosis of opsonized sheep red blood cells (SRBCs), IL-21 did not promote phagocytosis of Escherichia coli and zymosan by monocytes and did not alter the cell surface expression of CD16, CD32 and CD64. In HMDM, IL-21 was found to enhance phagocytosis of zymosan. In addition, we found that IL-21 activates p38, protein kinase B (Akt), signal transducer and activator of transcription (STAT)-1 and STAT-3 in monocytes and HMDM. Using a pharmacological approach, we demonstrate that IL-21 enhances phagocytosis by activating some mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) Akt and Janus kinase (JAK)-STAT pathways. These results obtained in human monocytes and macrophages have to be considered for a better exploitation of the IL-21/IL-21R system for therapeutic purposes. PMID- 27774607 TI - Erythrocytosis in hepatocellular carcinoma portends poor prognosis by respiratory dysfunction secondary to mitochondrial DNA mutations. AB - : Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma. Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. We demonstrate an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas. In the subset of hepatocellular carcinoma patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting in impairment of respiratory metabolism, which sequentially led to depletion of alpha-ketoglutarate, stabilization of hypoxia inducible factor alpha, and expression of target genes such as EPO. Cell lines and patient-derived xenograft models were used to demonstrate that EPO promoted cancer stem cell self renewal and expansion in an autocrine/paracrine manner through enhanced Janus kinase/signal transducer and activator of transcription signaling both in vitro and in vivo. Furthermore, to explore the therapeutic targeting of EPO-induced tumor changes, we found that blocking EPO signaling with soluble EPO receptor extracellular domain Fc fusion protein could inhibit tumor growth both in vitro and in vivo. CONCLUSION: These findings suggest clinical and therapeutic implications for erythrocytosis in hepatocellular carcinoma. There is an underlying link between mitochondrial function and hypoxia inducible factor alpha signaling, revealing a mechanism of erythrocytosis in a subset of hepatocellular carcinoma patients who may benefit from treatment involving EPO signaling interference. (Hepatology 2017;65:134-151). PMID- 27774604 TI - Distribution, physiology and pharmacology of relaxin-3/RXFP3 systems in brain. AB - : Relaxin-3 is a member of a superfamily of structurally-related peptides that includes relaxin and insulin-like peptide hormones. Soon after the discovery of the relaxin-3 gene, relaxin-3 was identified as an abundant neuropeptide in brain with a distinctive topographical distribution within a small number of GABAergic neuron populations that is well conserved across species. Relaxin-3 is thought to exert its biological actions through a single class-A GPCR - relaxin-family peptide receptor 3 (RXFP3). Class-A comprises GPCRs for relaxin-3 and insulin like peptide-5 and other peptides such as orexin and the monoamine transmitters. The RXFP3 receptor is selectively activated by relaxin-3, whereas insulin-like peptide-5 is the cognate ligand for the related RXFP4 receptor. Anatomical and pharmacological evidence obtained over the last decade supports a function of relaxin-3/RXFP3 systems in modulating responses to stress, anxiety-related and motivated behaviours, circadian rhythms, and learning and memory. Electrophysiological studies have identified the ability of RXFP3 agonists to directly hyperpolarise thalamic neurons in vitro, but there are no reports of direct cell signalling effects in vivo. This article provides an overview of earlier studies and highlights more recent research that implicates relaxin 3/RXFP3 neural network signalling in the integration of arousal, motivation, emotion and related cognition, and that has begun to identify the associated neural substrates and mechanisms. Future research directions to better elucidate the connectivity and function of different relaxin-3 neuron populations and their RXFP3-positive target neurons in major experimental species and humans are also identified. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 27774608 TI - Hemovigilance in Massachusetts and the adoption of statewide hospital blood bank reporting using the National Healthcare Safety Network. AB - A collaboration that grew over time between local hemovigilance stakeholders and the Massachusetts Department of Public Health (MDPH) resulted in the change from a paper-based method of reporting adverse reactions and monthly transfusion activity for regulatory compliance purposes to statewide adoption of electronic reporting via the National Healthcare Safety Network (NHSN). The NHSN is a web based surveillance system that offers the capacity to capture transfusion-related adverse events, incidents, and monthly transfusion statistics from participating facilities. Massachusetts' hospital blood banks share the data they enter into NHSN with the MDPH to satisfy reporting requirements. Users of the NHSN Hemovigilance Module adhere to specified data entry guidelines, resulting in data that are comparable and standardized. Keys to successful statewide adoption of this reporting method include the fostering of strong partnerships with local hemovigilance champions and experts, engagement of regulatory and epidemiology divisions at the state health department, the leveraging of existing relationships with hospital NHSN administrators, and the existence of a regulatory deadline for implementation. Although limitations exist, successful implementation of statewide use of the NHSN Hemovigilance Module for hospital blood bank reporting is possible. The result is standardized, actionable data at both the hospital and state level that can facilitate interfacility comparisons, benchmarking, and opportunities for practice improvement. PMID- 27774609 TI - A randomized trial to evaluate the use of text messaging, letter, and telephone call reminders to improve return of blood donors with reactive serologic tests. AB - BACKGROUND: Low return rates for notification and counseling among donors with reactive serologic screening tests have been reported worldwide. A randomized trial to test the effectiveness of text message, letter, or telephone call reminders to improve return among nonresponding first-time blood donors with reactive serologic tests was conducted. STUDY DESIGN AND METHODS: Donors with serologically reactive screening test results who had a cell phone and resided in the metropolitan telephone area code of Sao Paulo in the period from August 2013 through July 2014 were eligible. A consecutive sample of first-time donors with reactive screening tests who had not responded to a standard letter requesting the donor return to the blood center were randomly assigned to receive a text, a new letter, or a telephone call requesting return for notification and counseling. Return rates were measured over the subsequent 30 days. RESULTS: The return rate after a phone call reminder was better than that for a text message (39.8% vs. 28.4%; odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.64) but not better than that for a letter (39.8% vs. 34.4%; OR, 1.26; 95% CI, 0.80 1.99). Older age was a predictor of higher rate of return with each year increase in age associated with a 2% increase in the odds of return (OR, 1.02; 95% CI, 1.01-1.04). CONCLUSION: In nonresponding serologic reactive donors, telephone call led to a higher return rate than text message. The results of this study suggest that use of text messages, while attractive for its simplicity, will not lead to increased donor notification success after serologically reactive marker results from blood donation in Brazil. PMID- 27774610 TI - Functional antibodies to Haemophilus influenzae type B, Neisseria meningitidis, and Streptococcus pneumoniae contained in intravenous immunoglobulin products. AB - BACKGROUND: Intravenous immunoglobulin G (IVIG) replacement therapy is used to prevent invasive infections in patients with primary antibody deficiency (PAD). However, few studies have functionally evaluated specific antibodies against encapsulated bacteria that cause invasive infection in patients with PAD. In this study, functional antibodies against Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (pneumococci), and Neisseria meningitidis (meningococci) in IVIG therapy were evaluated. STUDY DESIGN AND METHODS: Sixteen lots of IVIG products prepared by two Korean manufacturers (Products A and B) were evaluated. The functional antibodies were measured by serum bactericidal assay for Hib and four meningococcal serogroups and by multiplexed opsonophagocytic assay for 26 pneumococcal serotypes. The estimated trough levels of antibodies against Hib, pneumococcus, and meningococcus were calculated to determine whether the usual IVIG dose is appropriate for protecting patients with PAD. RESULTS: The functional antibody levels for Hib were similar in all of the IVIG products. In contrast, serum bacterial indices of meningococcal serogroups A and Y showed significant differences between products A and B. Opsonic indices to pneumococci varied depending on the serotype in each IVIG product. The estimated trough levels of antibodies against Hib, pneumococcus, and meningococcus exceeded the protective levels in most of the IVIG products except for the antibodies against two pneumococcal serotypes. CONCLUSION: Most of the tested commercial IVIG products had sufficient functional antibodies against Hib, pneumococcus, and meningococcus to protect patients with PAD receiving IVIG treatment. Regular and continuous evaluation of IVIG products is necessary to maintain an optimal therapeutic effect. PMID- 27774612 TI - The contributions of mental state understanding and executive functioning to preschool-aged children's lie-telling. AB - In this study, preschool-aged children's lie-telling behaviour was examined in relation to mental state understanding and executive functioning. Sixty-seven children aged between 25 and 43 months (Mage in months = 34.80, SD = 4.39) participated in a temptation resistance paradigm (TRP). Children completed emerging ToM tasks measuring the following mental states: (1) diverse beliefs, (2) diverse desires, and (3) knowledge access. Children also completed measures of inhibitory control and working memory. In total, 63 of the 67 children peeked at the toy during the TRP, and a total of 26 of those children denied their transgression to the research assistant. Inhibitory control and understanding of knowledge access predicted lie-telling behaviour. Results are discussed in relation to a developmental model of children's lie-telling behaviour. Statement of contribution What is already known on this subject? The relationship between lie-telling, executive functioning, and ToM has been established in older children (aged 4 and above). Inhibitory control plays a role in young children's lie-telling (aged 2-4). Children above 3 years of age have some understanding of mental states. What does this study add? Very young children (2-3-year-olds) also possess an understanding of mental states. Mental state understanding is related to 2-3-year-old children's lie-telling behaviours and may be more predictive than inhibitory control. While the results were not significant, this study is the first to look at the unique role of working memory in very young children's lie telling. PMID- 27774613 TI - Modelling goal adjustment in social relationships: Two experimental studies with children and adults. AB - In two experiments, we investigated observational learning in social relationships as one possible pathway to the development of goal adjustment processes. In the first experiment, 56 children (M = 9.29 years) observed their parent as a model; in the second, 50 adults (M = 32.27 years) observed their romantic partner. Subjects were randomly assigned to three groups: goal engagement (GE), goal disengagement (GD), or control group (CO) and were asked to solve (unsolvable) puzzles. Before trying to solve the puzzles by themselves, subjects observed the instructed model, who was told to continue with the same puzzle (GE) or to switch to the next puzzle (GD). Results show that children in the GE group switched significantly less than in the GD or CO group. There was no difference between the GD group and CO group. Adults in the GE group switched significantly less than in the GD or CO group, whereas subjects in the GD group switched significantly more often than the CO group. Statement of contribution What is already known on this subject? Previous research focused mainly on the functions of goal adjustment processes. It rarely considered processes and conditions that contribute to the development of goal engagement and goal disengagement. There are only two cross-sectional studies that directly investigate this topic. Previous research that claims observational learning as a pathway of learning emotion regulation or adjustment processes has (only) relied on correlational methods and, thus, do not allow any causal interpretations. Previous research, albeit claiming a life span focus, mostly investigated goal adjustment processes in one specific age group (mainly adults). There is no study that investigates the same processes in different age groups. What does this study add? In our two studies, we focus on the conditions of goal adjustment processes and sought to demonstrate one potential pathway of learning or changing the application of goal adjustment processes, namely observational learning. We employed an experimental design to study observational learning, instead of using a correlational design. The present studies are the first to apply an experimental design to investigate observational learning of adjustment processes. In our studies, we implemented the same design and studied the same process in different age groups. Thus, they expand knowledge beyond a particular age group and under a life span perspective. PMID- 27774611 TI - CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. AB - : Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to nonfunctional intrahepatic CD8+ T-cell responses. In light of dampened CD8+ T-cell responses, liver disease often manifests systemically as immunoglobulin (Ig)-related syndromes due to aberrant B-cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4+ T-cell help. Elevated CD4+ forkhead box P3-positive (Foxp3+) T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8+ T-cell responses, aberrant B-cell activities were maintained due to expression of CD40 ligand on a subset of CD4+ Foxp3+ T cells. In vivo blockade of CD40 ligand attenuated B-cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4+ Foxp3+, CD40 ligand positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. CONCLUSION: Liver disease elicits alterations in the intrahepatic CD4+ T-cell compartment that suppress T-cell immunity while concomitantly promoting aberrant IgG mediated manifestations. (Hepatology 2017;65:661-677). PMID- 27774614 TI - Blood component transfusion and wastage rates in the setting of massive transfusion in three regional trauma centers. AB - BACKGROUND: The purpose of massive transfusion protocols (MTPs) is to provide large quantities of blood products rapidly to exsanguinating patients. The expected rates of blood product transfusion and wastage in this setting have not been defined. This study was undertaken to assess the transfusion and wastage rates for bleeding patients requiring emergency issue of blood components at three American Level I trauma centers. STUDY DESIGN AND METHODS: Three hospitals participated, all of which are Level I trauma centers that have MTPs in place where uncrossmatched red blood cells (RBCs) can be ordered with or without platelets (PLTs), plasma, and cryoprecipitate. Data on the transfusion, return to blood bank, and wastage rates were recorded on all products issued within 3 hours after MTP activation. RESULTS: The majority of products were issued to the emergency department and/or operating room at all three institutions (84%-95%). The percentage of RBCs, plasma, and PLTs transfused during MTPs were 39% to 65%, 43% to 66%, and 75% to 100%, respectively. Wastage rates were comparable for RBCs (0%-9%), plasma (0%-7%), and PLTs (0%-7%). Cryoprecipitate had the highest wastage rates at all three sites (7%-33%). CONCLUSION: A large portion of blood products issued during MTPs are not transfused. Some are wasted due to stringent storage requirements and/or limited shelf lives. The optimum ratio of transfused to returned products in these patients is likely to be determined more by clinical need than by transfusion service policy. PMID- 27774616 TI - Ab initio potential energy surface and vibration-rotation energy levels of beryllium monohydroxide. AB - The accurate potential energy surface of beryllium monohydroxide, BeOH, in its ground electronic state X 2A' has been determined from ab initio calculations using the coupled-cluster approach in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. The higher-order electron correlation, scalar relativistic, and adiabatic effects were taken into account. The BeOH molecule was confirmed to be bent at equilibrium, with the BeOH angle of 141.2 degrees and the barrier to linearity of 129 cm-1 . The vibration-rotation energy levels of the BeOH and BeOD isotopologues were predicted using a variational approach and compared with recent experimental data. The results can be useful in a further analysis of high-resolution vibration-rotation spectra of these interesting species. (c) 2016 Wiley Periodicals, Inc. PMID- 27774617 TI - Rural Young Adults' Lay Theories of Intimate Partner Violence: A Qualitative Examination. AB - This study qualitatively examined rural emerging adults' ways of thinking (i.e., lay theories) about the causes of intimate partner violence (IPV) and ideas on how to prevent IPV most effectively. Participants were 74 individuals (majority Caucasian, heterosexual, low income) between the ages of 18 and 24 who resided in one of 16 rural communities. Participants' perceptions of the causes of IPV included (a) individual-level pathology, stress, and lack of education; (b) intergenerational transmission of violence and early-life factors; (c) relationship stressors and challenges; and (d) community factors. Furthermore, participants felt that IPV could most effectively be prevented through (a) education and awareness; (b) victim-focused efforts (e.g., teaching self-esteem); and (c) job creation. Overall, participants identified a number of established risk factors for IPV perpetration across the social ecological model, although a number were never or rarely mentioned (e.g., peer group norms, positive bystander action, and collective efficacy). Future research should examine if and how perceptions of the causes of IPV impact IPV prevention engagement and impact. Further, prevention initiatives that take into account understandings of lay theories about IPV may be more impactful in reducing IPV than prevention initiatives that do not. PMID- 27774618 TI - Does the Badal optometer stimulate accommodation accurately? AB - PURPOSE: To study whether the accommodation response to Badal optometer is equivalent to the response for real space targets. METHODS: Accommodative responses were measured for 28 young eyes with the WAM-5500 autorefractometer in eight configurations for 0.17 D, 2.0 D and 5.0 D accommodation stimuli. Parameters that might contribute to differences in response were systematically isolated: stimulation method (real space vs Badal targets), field of view, instrument's cover proximity, the looming effect, and the peripheral interposition of objects in depth. RESULTS: Mean accommodative response differences between a natural view configuration and a configuration with a Badal Optometer were 0.50 +/- 0.43 D and 0.58 +/- 0.53 D for 2.0 D and 5.0 D stimulation, respectively (p < 0.001), with accommodation lags for the latter condition. Of the isolated parameters that might contribute to these differences, varying the interposition of objects in depth affected accommodation response more markedly. CONCLUSIONS: It is likely that Badal optometers affect accommodation through a combination of some or all of the studied parameters. We conclude that accommodation response to closed-view Badal optometers is not equivalent to real space target response. PMID- 27774619 TI - Evaluation of bonding, electron affinity, and optical properties of M@C28 (M = Zr, Hf, Th, and U): Role of d- and f-orbitals in endohedral fullerenes from relativistic DFT calculations. AB - The experimentally characterized endohedral metallic fullerenes involving the small C28 cage, has shown to be able to encapsulate zirconium, hafnium, and uranium atoms, among other elements. Here, we explore the formation and nature of concentric bonds from purely d- to f-block elements, given by Zr, Hf, and uranium, along a borderline metal between such blocks, thorium. We explore the interplay of d- and f-orbitals in the chemistry of the early actinides, where the features of a d- or f-block metal can be mixed. Our results indicate that the bonding of Th@C28 involves contributions from both d- and f-type bonds, as characteristic of this early actinide element. Even uranium in U@C28 , also exhibits a contribution from d-type bonds in addition to its relevant f-block character. Electron affinity and optical properties were evaluated to gain more insights into the variation of these molecular properties in this small endohedral fullerene, along Zr, Hf, Th, and U. The current results, allows to unravel the role of (n - 1)d and (n - 2)f orbitals in confined elements ranging from d- to f-blocks, which can be useful to gain a deeper understanding of the bonding situation in other endohedral species. (c) 2016 Wiley Periodicals, Inc. PMID- 27774615 TI - Incidence and prognostic impact of bleeding and transfusion after coronary surgery in low-risk patients. AB - BACKGROUND: Excessive bleeding and blood transfusion are associated with adverse outcome after cardiac surgery, but their mechanistic effects are difficult to disentangle in patients with increased operative risk. This study aimed to evaluate the incidence and prognostic impact of bleeding and transfusion of blood products in low-risk patients undergoing coronary artery bypass grafting (CABG). STUDY DESIGN AND METHODS: Sixteen tertiary European centers of cardiac surgery contributed to the prospective European registry of CABG (E-CABG). The severity of bleeding was defined by the E-CABG bleeding severity classification and universal definition of perioperative bleeding (UDPB) classification. RESULTS: Of 1213 patients with EuroSCORE II of less than 2% (mean, 1.1 +/- 0.4%), 18.5% suffered from mild bleeding (E-CABG bleeding Grade 1) and 3.4% experienced severe bleeding (E-CABG bleeding Grade 2-3). Similarly, 19.7% had UDPB Class 2 and 5.9% had UDPB Classes 3 and 4. Mild and severe bleeding defined by the E-CABG and UDPB classifications were associated with an increased risk of several adverse events as adjusted by multiple covariates. The risk of death, stroke, and acute kidney injury was particularly increased in patients with severe bleeding. CONCLUSION: Severe bleeding is rather uncommon in low-risk patients undergoing CABG, but it is associated with an increased risk of major adverse events. Prevention of excessive perioperative bleeding and patient blood management may improve the outcome of cardiac surgery also in low-risk patients. PMID- 27774620 TI - A single-center prospective study on the safety of plasma exchange procedures using a double-viral-inactivated and prion-reduced solvent/detergent fresh-frozen plasma as the replacement fluid in the treatment of thrombotic microangiopathy. AB - BACKGROUND: Patients presenting with acute episodes of thrombotic microangiopathies (TMAs) require urgent access to plasma exchange (PEX). OctaplasLG, a solvent/detergent fresh-frozen plasma product that has undergone viral inactivation and prion reduction step, has been used in our institution since 2013, replacing Octaplas. STUDY DESIGN AND METHODS: We prospectively reviewed 981 PEX procedures where OctaplasLG was the replacement fluid in 90 patients admitted acutely with a TMA presentation within our institution from January 1, 2013, to December 31, 2015. We recorded citrate toxicities, plasma reactions, viral transfer, complications related to central venous catheter, and venous thrombotic events (VTEs). RESULTS: Citrate toxicities were 5.4%, plasma reactions were 2%, and all were classified as Grade 1 or 2. VTE had an incidence of 12.2%, although 50% of the episodes occurred in early remission when patients were not receiving PEX. No line insertions complications were recorded. Line associated infections were 2.2%. Hepatitis B and C serology and human immunodeficiency virus (HIV) were checked on admission. There were four patients who may have had passive transient transfer of hepatitis B antibodies from pooled plasma. No hepatitis C or HIV viral transfer was documented after treatment and no seroconversion was detected after treatment. CONCLUSION: Our data have demonstrated that the incidence of complications during PEX is low and using OctaplasLG is comparable to the low incidence of reactions. No cases of anaphylaxis, transfusion-related acute lung injury, or fatal plasma reactions were seen. There was no evidence of viral transmission or seroconversion after treatment. PMID- 27774622 TI - What is your diagnosis? Squash preparation from the lung of a hedgehog. PMID- 27774621 TI - Evaluation of a new microbeads assay for granulocyte antibody detection. AB - BACKGROUND: To reduce the risk of transfusion-associated acute lung injury (TRALI), a high number of plasma donors were tested for human leukocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies. For HNA antibody detection, the gold standard is a combination of the granulocyte immunofluorescence test (GIFT) and the granulocyte agglutination test (GAT). However, these tests are not suitable for a high-throughput of samples. STUDY DESIGN AND METHODS: To evaluate the new generation of the LABScreen MULTI assay (One Lambda, Inc.), which has special new beads for all the known HNA specificities, including HNA-3a, 97 sera samples containing well-defined HNA antibodies were used. For background testing, we used 91 samples from plasma donors previously identified by GAT, GIFT, and the monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA) assay. RESULTS: Compared with previous tests, the new LABScreen MULTI assay was highly specific for the HNA-1a, HNA-1b, HNA-2, and HNA-3a antibody specificities required to prevent TRALI. Ninety-eight percent of the HNA-1a, HNA-1b, and HNA-2 antibodies could be detected as true positive; and 90% of the HNA-3a antibodies were recognized correctly as positive. False-positive reactions were identified in 5.5% of samples that previously tested negative. CONCLUSION: The detection of HNA-3a antibody specificities could be integrated into the new LABScreen MULTI assay; however, we detected only 90%. In addition, we detected further HNA antibodies, such as HNA-1c, HNA-1d, and some HNA-3b and HNA-4a antibodies. The new generation of LABScreen MULTI is a great step toward feasible high-throughput testing for HNA antibodies. Nevertheless, GIFT and GAT remain the gold-standard methods for the differentiation of rare and currently unknown HNA specificities. PMID- 27774623 TI - Reversal of functional loss in a rat model of chronic intraocular pressure elevation. AB - PURPOSE: This pilot study considered whether intraocular pressure (IOP) lowering could reverse ganglion cell dysfunction in a rat model of chronic ocular hypertension. METHODS: A circumlimbal suture was applied in one eye to induce ocular hypertension (n = 7) in Long-Evans rats. The contralateral eye served as an untreated control. After 8 weeks of IOP elevation the suture was removed to lower IOP for the remaining 7 weeks. Electroretinogram (ERG) and optical coherence tomography (OCT) were measured at baseline, 2, 4, 8, 12 and 15 weeks. Retinae were collected for histology at week 15. RESULTS: In sutured eyes, IOP was elevated by 7-11 mmHg above control eyes (12 +/- 0.2 mmHg [standard error of the mean]). Eight weeks of chronic IOP elevation resulted in a reduction of the ganglion cell mediated positive Scotopic Threshold Response (pSTR, -25 +/- 7% of baseline), as well as smaller photoreceptor (-7 +/- 4%) and bipolar cell mediated responses (-6 +/- 5%). After suture removal, IOP recovered to normal. By 15 weeks the a-wave (0 +/- 6%), b-wave (-2 +/- 6%) and pSTR had recovered back to baseline (from -25 +/- 7% to -4 +/- 6%). The retinal nerve fiber layer was thinned by -9 +/- 3% at week 8 and showed no further decline at week 15 (-10 +/- 2%). Cell numbers in the ganglion cell layer were similar between suture removal and control eyes at week 15 (3543 +/- 478 vs 4057 +/- 476 cells mm-2 ). CONCLUSIONS: The circumlimbal suture model might be a useful platform to study the reversibility of neuronal dysfunction from chronic IOP challenge. PMID- 27774625 TI - Optimal allosteric stabilization sites using contact stabilization analysis. AB - Proteins can be destabilized by a number of environmental factors such as temperature, pH, and mutation. The ability to subsequently restore function under these conditions by adding small molecule stabilizers, or by introducing disulfide bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location to best confer stability to the active site and restore function. Here, we present a general framework for predicting which allosteric binding sites correlate with stability in the active site. Using the Karanicolas-Brooks Go-like model, we examine the dynamics of the enzyme beta-glucuronidase using an Umbrella Sampling method to thoroughly sample the conformational landscape. Each intramolecular contact is assigned a score termed a "stabilization factor" that measures its correlation with structural changes in the active site. We have carried out this analysis for three different scaling strengths for the intramolecular contacts, and we examine how the calculated stabilization factors depend on the ensemble of destabilized conformations. We further examine a locally destabilized mutant of beta glucuronidase that has been characterized experimentally, and show that this brings about local changes in the stabilization factors. We find that the proximity to the active site is not sufficient to determine which contacts can confer active site stability. (c) 2016 Wiley Periodicals, Inc. PMID- 27774624 TI - The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-kappaB and MAPK activation. AB - BACKGROUND AND PURPOSE: There is increasing evidence indicating that bromodomain and extra-terminal domain (BET) proteins play a critical role in the regulation of immune and inflammatory responses; however, their contribution to vascular inflammation has not yet been elucidated. In this study, we investigated the effect of inhibiting BET bromodomain on vascular inflammation and the underlying mechanisms. EXPERIMENTAL APPROACH: HUVECs were isolated from fresh umbilical cords. JQ1, a specific BET bromodomain inhibitor, and Brd shRNA were used to evaluate the regulation of the BET proteins in vascular inflammation. Leukocyte adhesion to HUVECs was measure by an adhesion assay. Western blot or immunohistochemical analysis was used to detect the protein expression. Real-time PCR was used to evaluate mRNA expression. Leukocyte accumulation in vivo was determined by an acute lung inflammation model. KEY RESULTS: BET bromodomain inhibition suppressed the expression of adhesion molecules induced by TNF-alpha- or LPS, including ICAM-1, VCAM-1 and E-selectin, and inhibited leukocyte adhesion to activated HUVEC monolayers. Treatment with JQ1 also attenuated the LPS-induced accumulation of leukocytes and expression of endothelial adhesion molecules in the acute lung inflammation model in vivo. Furthermore, BET bromodomain inhibition reduced the activity of p38 and JNK MAPKs and NF-kappaB in TNF-alpha stimulated HUVECs. TNF-alpha-induced NF-kappaB activation was also blocked by inhibitors of p38 (SB203580) or JNK (SP600125). CONCLUSIONS AND IMPLICATIONS: BET bromodomain is important for regulating endothelial inflammation. Strategies targeting endothelial BET bromodomain may provide a new therapeutic approach for controlling inflammatory-related diseases. PMID- 27774626 TI - Revisiting the gastric pull-up for pharyngoesophageal reconstruction: A systematic review and meta-analysis of mortality and morbidity. AB - Gastric pull-up (GPU) is among the oldest techniques for reconstructing the pharyngoesophageal junction following cancer resection. This review examines morbidity and mortality rates following GPU pharyngoesophageal junction reconstruction from 1959 until present: 77 studies, 2,705 patients. The odds of mortality, anastomotic complications, and other complications decreased by 37.2% (95%CI = 28.0-45.3%; P < 0.0001), 8.0% (95%CI = -2.1 to 17.1%; P = 0.12), 21.0% (95%CI 3.5-35.2%; P = 0.021) per decade respectively. J. Surg. Oncol. 2016;114:907-914. (c) 2016 Wiley Periodicals, Inc. PMID- 27774627 TI - A case-cohort approach for multi-state models in hospital epidemiology. AB - Analysing the determinants and consequences of hospital-acquired infections involves the evaluation of large cohorts. Infected patients in the cohort are often rare for specific pathogens, because most of the patients admitted to the hospital are discharged or die without such an infection. Death and discharge are competing events to acquiring an infection, because these individuals are no longer at risk of getting a hospital-acquired infection. Therefore, the data is best analysed with an extended survival model - the extended illness-death model. A common problem in cohort studies is the costly collection of covariate values. In order to provide efficient use of data from infected as well as uninfected patients, we propose a tailored case-cohort approach for the extended illness death model. The basic idea of the case-cohort design is to only use a random sample of the full cohort, referred to as subcohort, and all cases, namely the infected patients. Thus, covariate values are only obtained for a small part of the full cohort. The method is based on existing and established methods and is used to perform regression analysis in adapted Cox proportional hazards models. We propose estimation of all cause-specific cumulative hazards and transition probabilities in an extended illness-death model based on case-cohort sampling. As an example, we apply the methodology to infection with a specific pathogen using a large cohort from Spanish hospital data. The obtained results of the case cohort design are compared with the results in the full cohort to investigate the performance of the proposed method. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27774628 TI - T cell receptor repertoires after adoptive transfer of expanded allogeneic regulatory T cells. AB - Regulatory T cell (Treg ) therapy has been exploited in autoimmune disease, solid organ transplantation and in efforts to prevent or treat graft-versus-host disease (GVHD). However, our knowledge on the in-vivo persistence of transfused Treg is limited. Whether Treg transfusion leads to notable changes in the overall Treg repertoire or whether longevity of Treg in the periphery is restricted to certain clones is unknown. Here we use T cell receptor alpha chain sequencing (TCR-alpha-NGS) to monitor changes in the repertoire of Treg upon polyclonal expansion and after subsequent adoptive transfer. We applied TCR-alpha-NGS to samples from two patients with chronic GVHD who received comparable doses of stem cell donor derived expanded Treg . We found that in-vitro polyclonal expansion led to notable repertoire changes in vitro and that Treg cell therapy altered the peripheral Treg repertoire considerably towards that of the infused cell product, to different degrees, in each patient. Clonal changes in the peripheral blood were transient and correlated well with the clinical parameters. We suggest that T cell clonotype analyses using TCR sequencing should be considered as a means to monitor longevity and fate of adoptively transferred T cells. PMID- 27774629 TI - Longitudinal Effects of Latino Parent Cultural Stress, Depressive Symptoms, and Family Functioning on Youth Emotional Well-Being and Health Risk Behaviors. AB - U.S. Latino parents can face cultural stressors in the form of acculturative stress, perceived discrimination, and a negative context of reception. It stands to reason that these cultural stressors may negatively impact Latino youth's emotional well-being and health risk behaviors by increasing parents' depressive symptoms and compromising the overall functioning of the family. To test this possibility, we analyzed data from a six-wave longitudinal study with 302 recently immigrated (<5 years in the United States) Latino parents (74% mothers, Mage = 41.09 years) and their adolescent children (47% female, Mage = 14.51 years). Results of a cross-lagged analysis indicated that parent cultural stress predicted greater parent depressive symptoms (and not vice versa). Both parent cultural stress and depressive symptoms, in turn, predicted lower parent-reported family functioning, which mediated the links from parent cultural stress and depressive symptoms to youth alcohol and cigarette use. Parent cultural stress also predicted lower youth-reported family functioning, which mediated the link from parent cultural stress to youth self-esteem. Finally, mediation analyses indicated that parent cultural stress predicted youth alcohol use by a way of parent depressive symptoms and parent-reported family functioning. Our findings point to parent depressive symptoms and family functioning as key mediators in the links from parent cultural stress to youth emotional well-being and health risk behaviors. We discuss implications for research and preventive interventions. PMID- 27774630 TI - Redox-dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice. AB - : Sterile liver inflammation, such as liver ischemia-reperfusion, hemorrhagic shock after trauma, and drug-induced liver injury, is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here, we identify a mechanism for redox-mediated regulation of absent in melanoma 2 (AIM2) inflammasome activation in hepatocytes after redox stress in mice, which occurs through interaction with cytosolic high mobility group box 1 (HMGB1). We show that in liver during hemorrhagic shock in mice and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase-1 in response to cytosolic DNA. Activation of caspase-1 through AIM2 leads to subsequent hepatoprotective responses such as autophagy. HMGB1 binds to AIM2 at a non-DNA-binding site on the hematopoietic interferon inducible nuclear antigen domain of AIM2 to facilitate inflammasome and caspase-1 activation in hepatocytes. Furthermore, binding of HMGB1 to AIM2 is stronger with fully reduced all-thiol HMGB1 than with partially oxidized disulfide-HMGB1, and binding strength corresponds to caspase-1 activation. These data suggest that HMGB1 redox status regulates AIM2 inflammasome activation. CONCLUSION: These findings suggest a novel and important mechanism for regulation of AIM2 inflammasome activation in hepatocytes during redox stress and may suggest broader implications for how this and other inflammasomes are activated and how their activation is regulated during cell stress, as well as the mechanisms of inflammasome regulation in nonimmune cell types. (Hepatology 2017;65:253-268). PMID- 27774631 TI - Resting-state functional MRI as a tool for evaluating brain hemodynamic responsiveness to external stimuli in rats. AB - PURPOSE: Anesthesia is a major confounding factor in functional MRI (fMRI) experiments attributed to its effects on brain function. Recent evidence suggests that parameters obtained with resting-state fMRI (rs-fMRI) are coupled with anesthetic depth. Therefore, we investigated whether parameters obtained with rs fMRI, such as functional connectivity (FC), are also directly related to blood oxygen-level-dependent (BOLD) responses. METHODS: A simple rs-fMRI protocol was implemented in a pharmacological fMRI study to evaluate the coupling between hemodynamic responses and FC under five anesthetics (alpha-chloralose, isoflurane, medetomidine, thiobutabarbital, and urethane). Temporal change in the FC was evaluated at 1-hour interval. Supplementary forepaw stimulation experiments were also conducted. RESULTS: Under thiobutabarbital anesthesia, FC was clearly coupled with nicotine-induced BOLD responses. Good correlation values were also obtained under isoflurane and medetomidine anesthesia. The observations in the thiobutabarbital group were supported by forepaw stimulation experiments. Additionally, the rs-fMRI protocol revealed significant temporal changes in the FC in the alpha-chloralose, thiobutabarbital, and urethane groups. CONCLUSION: Our results suggest that FC can be used to estimate brain hemodynamic responsiveness to stimuli and evaluate the level and temporal changes of anesthesia. Therefore, analysis of the fMRI baseline signal may be highly valuable tool for controlling the outcome of preclinical fMRI experiments. Magn Reson Med 78:1136-1146, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27774632 TI - What is your diagnosis? Peritoneal effusion in a 10-year-old horse. PMID- 27774634 TI - Simultaneous onset of sporotrichosis in mother and daughter. PMID- 27774633 TI - Revised guideline for the diagnosis and treatment of acquired idiopathic generalized anhidrosis in Japan. AB - Acquired idiopathic generalized anhidrosis (AIGA) is characterized by an acquired impairment in total body sweating despite exposure to heat or exercise. Severe cases may result in heatstroke. Most cases of AIGA have been reported in Asia, especially in Japan. However, there is limited information on the epidemiology of this condition, and no diagnostic criteria or appropriate treatment options have been established. This guideline was developed to fill this gap. It contains information on the etiology, diagnosis, evaluation of disease severity and evidence-based recommendations for the treatment of AIGA. Appropriate treatment according to disease severity may relieve the clinical manifestations and emotional distress experienced by patients with AIGA. PMID- 27774635 TI - Comments on cutaneous surgical specimen shrinkage. PMID- 27774636 TI - Vitiligo and tumoral melanosis: signs of metastasis in a patient with melanoma. PMID- 27774637 TI - Presence of the Merkel cell polyomavirus in Merkel cell carcinoma combined with squamous cell carcinoma in a patient with chronic arsenism. AB - We present a case of Merkel cell carcinoma (MCC) coincident with squamous cell carcinoma (SCC) on the breast of a woman with chronic arsenism. This case demonstrates the distinct association of chronic arsenism with two different primary cutaneous carcinomas. Merkel cell polyomavirus (MCPyV) was identified in the lesional skin of the MCC but not in that of the SCC, suggesting there are different interactions of MCPyV in the pathogenesis of SCC and MCC related to arsenic. Physicians need to be vigilant in the occurrence of both SCC and MCC in patients with chronic arsenism. To our knowledge, this is the first study to show the presence of MCPyV in the MCC but not the SCC portion of an arsenic-induced tumour. PMID- 27774639 TI - A comparison of likelihood ratio tests and Rao's score test for three separable covariance matrix structures. AB - The problem of testing the separability of a covariance matrix against an unstructured variance-covariance matrix is studied in the context of multivariate repeated measures data using Rao's score test (RST). The RST statistic is developed with the first component of the separable structure as a first-order autoregressive (AR(1)) correlation matrix or an unstructured (UN) covariance matrix under the assumption of multivariate normality. It is shown that the distribution of the RST statistic under the null hypothesis of any separability does not depend on the true values of the mean or the unstructured components of the separable structure. A significant advantage of the RST is that it can be performed for small samples, even smaller than the dimension of the data, where the likelihood ratio test (LRT) cannot be used, and it outperforms the standard LRT in a number of contexts. Monte Carlo simulations are then used to study the comparative behavior of the null distribution of the RST statistic, as well as that of the LRT statistic, in terms of sample size considerations, and for the estimation of the empirical percentiles. Our findings are compared with existing results where the first component of the separable structure is a compound symmetry (CS) correlation matrix. It is also shown by simulations that the empirical null distribution of the RST statistic converges faster than the empirical null distribution of the LRT statistic to the limiting chi2 distribution. The tests are implemented on a real dataset from medical studies. PMID- 27774640 TI - gammadelta T-cell in cutaneous and subcutaneous lymphoid infiltrates: malignant or not? PMID- 27774638 TI - Psychosocial problems of children whose parents visit the emergency department due to intimate partner violence, substance abuse or a suicide attempt. AB - BACKGROUND: High levels of maltreatment are found in children who are identified because their parents visit the emergency department due to partner violence, substance abuse or suicide attempt. However, it is unknown if these children experience psychosocial problems. This study aims to assess their levels of post traumatic stress, anxiety, depression, behavioural problems and health-related quality of life. METHODS: A cross-sectional study was conducted in six hospitals. All consecutive families of which a parent visited the emergency department due to partner violence, substance abuse or suicide attempt between 1 July 2012 and 1 March 2014 with children aged 1.5-17 years were approached for participation. Parents and children aged 8 years and older filled out questionnaires measuring post-traumatic stress [13-item version of Children's Revised Impact of Event Scale (CRIES-13)], anxiety, depression (Revised Child Anxiety and Depression Scale), behavioural problems [Child Behavior Checklist (CBCL) and Youth Self Report (YSR)] and health-related quality of life (PedsQL). Scores of participants were compared with reference data obtained in children in similar age ranges from representative Dutch community samples (CRIES-13, Revised Child Anxiety and Depression Scale, PedsQL and CBCL) and to a normed cutoff score (CRIES-13). RESULTS: Of 195 eligible families, 89 (46%) participated in the study. Participating children did not score different from community children, both on child-reported and parent-reported instruments. Standardized mean differences of total sum scores were 0 (CRIES-13 and CBCL 1.5-5), 0.1 (YSR), 0.2 (CBCL 6-18) and -0.3 (PedsQL) and not statistically different from community children. Thirty five percent of the participating children scored above the cutoff score on the CRIES-13, indicating post-traumatic stress disorder, but this difference was not statistically significant from community children (mean difference 8%; 95% CI -4 22%). CONCLUSIONS: We found no differences in psychosocial problems between children whose parents visited the emergency department due to partner violence, substance abuse or suicide attempt and children from community samples. Because 35% of the children scored in the range of post-traumatic stress disorder, we advise healthcare providers to pay attention to post-traumatic stress symptoms. PMID- 27774642 TI - Basal cell carcinoma, arising within a granular cell-type fibrous papule. PMID- 27774641 TI - High-resolution gradient-recalled echo imaging at 9.4T using 16-channel parallel transmit simultaneous multislice spokes excitations with slice-by-slice flip angle homogenization. AB - PURPOSE: In order to fully benefit from the improved signal-to-noise and contrast to-noise ratios at 9.4T, the challenges of B1+ inhomogeneity and the long acquisition time of high-resolution 2D gradient-recalled echo (GRE) imaging were addressed. THEORY AND METHODS: Flip angle homogenized excitations were achieved by parallel transmission (pTx) of 3-spoke pulses, designed by magnitude least squares optimization in a slice-by-slice fashion; the acquisition time reduction was achieved by simultaneous multislice (SMS) pulses. The slice-specific spokes complex radiofrequency scaling factors were applied to sinc waveforms on a per channel basis and combined with the other pulses in an SMS slice group to form the final SMS-pTX pulse. Optimal spokes locations were derived from simulations. RESULTS: Flip angle maps from presaturation TurboFLASH showed improvement of flip angle homogenization with 3-spoke pulses over CP-mode excitation (normalized root mean-square error [NRMSE] 0.357) as well as comparable excitation homogeneity across the single-band (NRMSE 0.119), SMS-2 (NRMSE 0.137), and SMS-3 (NRMSE 0.132) 3-spoke pulses. The application of the 3-spoke SMS-3 pulses in a 48-slice GRE protocol, which has an in-plane resolution of 0.28 * 0.28 mm, resulted in a 50% reduction of scan duration (total acquisition time 6:52 min including reference scans). CONCLUSION: Time-efficient flip angle homogenized high resolution GRE imaging at 9.4T was accomplished by using slice-specific SMS-pTx spokes excitations. Magn Reson Med 78:1050-1058, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. PMID- 27774644 TI - MRI with phaseless encoding. AB - PURPOSE: Fourier encoded MRI signal is complex and, therefore, sensitive to uncontrolled phase variations caused, e.g., by object motion. An alternative encoding is proposed which leads to phaseless (positive real) signals and allows the phase fluctuations to be removed by simple magnitude calculation before the Fourier transform. THEORY AND METHODS: Phaseless encoding uses harmonic modulation of the longitudinal magnetization with different frequencies and phases before excitation. It can be combined with Fourier encoding of complementary dimensions to produce, e.g., a 3D version of echo planar imaging insensitive to intershot phase variations. It can also be mixed with Fourier encoding of the same dimension allowing a high-resolution image to be obtained from magnitude-reconstructed low-resolution components. The latter is a generalization of the super-resolution MRI with microscopic tagging proposed recently. Improved reconstruction for this technique was adopted from its optical analogue, harmonic excitation light microscopy (HELM). RESULTS: Artifact free images were obtained despite phase fluctuations caused by random receiver reference and object motion during diffusion weighting. Proposed reconstruction of mixed-encoded data reaches higher resolution than the original super resolution method. CONCLUSION: Spatial information can be encoded in the magnitude of the MR signal rendering the experiment insensitive to phase fluctuations. Magn Reson Med 78:1029-1037, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27774643 TI - Prothrombin and factor X are elevated in multiple sclerosis patients. AB - Animal models have implicated an integral role for coagulation factors in neuroinflammatory diseases such as multiple sclerosis (MS) beyond their role in hemostasis. However, their relevance in humans requires further elucidation. This study aimed to determine whether levels of coagulation factors differ between patients with neuroimmunological disorders and respective controls. Individuals suffering from relapsing-remitting and secondary progressive MS had significantly higher prothrombin and factor X levels than healthy donors, whereas levels were unchanged in primary progressive MS and neuromyelitis optica patients. Our study demonstrates that coagulation factors may be key mediators in neuroinflammation and may therefore provide future targets for therapeutic strategies. Ann Neurol 2016;80:946-951. PMID- 27774645 TI - Rapid 3D in vivo 1H human lung respiratory imaging at 1.5 T using ultra-fast balanced steady-state free precession. AB - PURPOSE: To introduce a reproducible, nonenhanced 1H MRI method for rapid in vivo functional assessment of the whole lung at 1.5 Tesla (T). METHODS: At different respiratory volumes, the pulmonary signal of ultra-fast steady-state free precession (ufSSFP) follows an adapted sponge model, characterized by a respiratory index alpha. From the model, alpha reflects local ventilation-related information, is virtually independent from the lung density and thus from the inspiratory phase and breathing amplitude. Respiratory alpha-mapping is evaluated for healthy volunteers and patients with obstructive lung disease from a set of five consecutive 3D ultra-fast steady-state free precession (ufSSFP) scans performed in breath-hold and at different inspiratory volumes. For the patients, alpha-maps were compared with CT, dynamic contrast-enhanced MRI (DCE-MRI), and Fourier decomposition (FD). RESULTS: In healthy volunteers, respiratory alpha maps showed good reproducibility and were homogeneous on iso-gravitational planes, but showed a gravity-dependent respiratory gradient. In patients with obstructive pulmonary disease, the functional impairment observed in respiratory alpha-maps was associated with emphysematous regions present on CT images, perfusion defects observable on DCE-MRI, and impairments visualized on FD ventilation and perfusion maps. CONCLUSION: Respiratory alpha-mapping derived from multivolumetric ufSSFP provides insights into functional lung impairment and may serve as a reproducible and normative measure for clinical studies. Magn Reson Med 78:1059-1069, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27774646 TI - Association of Gestational Age and Severe Neonatal Morbidity with Mortality in Early Childhood. AB - BACKGROUND: Although infant and child mortality rates have decreased substantially worldwide over the past two decades, efforts continue in many nations to further these declines. The identification of pertinent perinatal factors that are associated with early childhood mortality would help with these efforts. We investigated the association of two crucial perinatal factors, gestational age and severe neonatal morbidity at birth, with mortality during infancy (29-364 days) and early childhood (1-5 years). METHODS: The study population included all singleton livebirths, >=32 weeks' gestation in New South Wales, Australia in 2001-11. Birth data were linked to hospitalisation morbidity data and deaths data (linked birth cohort n = 871 916), and multivariable Cox regression models were used to assess mortality. RESULTS: The median follow-up time per child was 4.95 years (range 0.00-5.92 years; 3 614 738 total person years), with 984 deaths observed. Gestational age was associated with increased mortality, and specifically from deaths attributable to infections, respiratory conditions, and injuries during infancy, but not during early childhood. Severe neonatal morbidity strongly mediated the effects of gestational age during infancy, but not during early childhood, and was associated with increased mortality from circulatory, nervous, and respiratory system causes. CONCLUSIONS: The direct effects of gestational age on mortality extended up to 1 year of age, whereas severe neonatal morbidity remained associated with heightened mortality into early childhood. Efforts to maximise the health and well-being of vulnerable infants, with emphasis on preventing infections and injuries, may help further reduce early childhood mortality. PMID- 27774648 TI - Phytoconstituents as pharmacotherapeutics in rheumatoid arthritis: challenges and scope of nano/submicromedicine in its effective delivery. AB - OBJECTIVES: The present review explores the therapeutic application of herbals in rheumatoid arthritis (RA) therapy, and how nano/submicromedicine can be fit in the scope of its therapeutic delivery in RA has been addressed. KEY FINDINGS: Incorporation of bioactive such as polyphenols, thymoquinone, resveratrol, hesperidin, curcumin, celastrol and gambogic acid in a dose-dependent manner showed quite high efficacy for the treatment of RA. It can be attributed to their targeting ability against various inflammatory mediators including nitric oxide (NO), cytokines, chemokines, adhesion molecules, NF-kbeta, lipoxygenase (LOXs) and arachidonic acid (AA). Despite the presence of significant merits, the use of these bioactives has several demerits such as poor bioavailability as a function of low aqueous solubility and higher first-pass metabolism upon oral administration. The impact of nano/submicromedicine in the delivery of these bioactives against RA has gained wider attention owing to bioavailability enhancement, higher stability and better efficacy. CONCLUSION: Phytoconstituents possess immense potential in RA pharmacotherapy, but the obstacles for their effective delivery can be overcome using nano/submicrocarrier-based drug delivery technologies, which maximize the efficacy of these herbal antirheumatic drugs without any systemic adverse effects. PMID- 27774647 TI - Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. AB - : Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator activated receptor-gamma coactivator 1alpha, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-gamma coactivator 1alpha overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice. CONCLUSIONS: Decreased proliferator activated receptor-gamma coactivator 1alpha expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201). PMID- 27774649 TI - Development of a novel dengue virus serotype-specific multiplex real-time reverse transcription-polymerase chain reaction assay for blood screening. AB - BACKGROUND: Dengue fever is caused by four related RNA viruses of the genus Flavivirus, dengue virus (DENV)-1, -2, -3, and -4, which are transmitted to humans by mosquitoes. Although DENV is not endemic in Japan, an autochthonous dengue outbreak occurred in 2014. Several transfusion-transmitted cases have also been reported after the use of blood and plasma products in DENV-endemic countries. The aim of this study was to develop a novel multiplex reverse transcription-polymerase chain reaction (RT-PCR) assay for DENV blood screening. STUDY DESIGN AND METHODS: Large-scale oligonucleotide screening was performed to obtain DENV-specific primers and probes using a variety of DENV clinical isolates. A multiplex RT-PCR assay was then developed using the identified oligonucleotides and the ability of this assay to detect DENV RNA was evaluated. RESULTS: A number of oligonucleotides suitable for DENV RNA detection were identified and a novel DENV serotype-specific multiplex RT-PCR assay was successfully established. Comparative analysis revealed that the multiplex assay could detect levels of viral contamination as low as 100 viral copies/mL. CONCLUSION: This established serotype-specific multiplex RT-PCR assay provides a simple, sensitive, and quantitative detection method for DENV, which could be applied in the screening of blood samples to prevent transfusion-transmitted DENV infection. PMID- 27774650 TI - Chronic restraint stress increases angiotensin II potency in the rat carotid: role of cyclooxygenases and reactive oxygen species. AB - OBJECTIVES: To investigate the mechanisms underlying the effects of chronic restraint stress on the vascular contractile response induced by angiotensin (Ang) II in rat carotid. METHODS: Concentration-response curves for AngII were obtained in endothelium-intact or endothelium-denuded carotid rings, in the absence or presence of SC-560 (COX-1 inhibitor), SC-236 (COX-2 inhibitor), wortmannin (PI3 K-Akt inhibitor), ML171 (NOX-1 inhibitor), VAS2870 (NOX-4 inhibitor), tiron (O2- scavenger) or PEG-catalase (H2 O2 scavenger). 6 ketoPGF1alpha , TXB2 , O2- or H2 O2 levels and superoxide dismutase and catalase activity or expression were also measured in rat carotid. KEY FINDINGS: Stress increased AngII potency in rat carotid. Muscular COX-1 or COX-2-derived metabolites negatively modulated AngII-induced contraction in control rat carotid. Endothelial COX-1 or COX-2-derived metabolites positively modulated AngII-induced contraction in stressed rat carotid. PI3 K-Akt, NOX-1, NOX-4, O2- and H2 O2 positively modulated AngII-induced contraction in stressed rat carotid. Stress increased 6-ketoPGF1alpha or H2 O2 generation and reduced catalase activity in rat carotid. Protein expression of COX-1, NOX-4 or p-Akt was increased in stressed rat carotid. CONCLUSIONS: Stress increases AngII potency in rat carotid by a mechanism that involves the increased generation of PGI2 and H2 O2 and the activation of Akt pathway. Such mechanism could play a pathophysiological role in cardiovascular diseases correlated with stress. PMID- 27774651 TI - Toxicokinetics and toxicodynamics of chlorpyrifos is altered in embryos of Japanese medaka exposed to oil sands process-affected water: evidence for inhibition of P-glycoprotein. AB - Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface mining oil sands industry in Alberta, Canada. Studies were performed in vitro by use of Caco-2 cells, and in vivo with larvae of Japanese medaka (Oryzias latipes) to determine if organic compounds from the aqueous phase of OSPW inhibit ATP binding cassette protein ABCB1 (permeability-glycoprotein, P gp). Neutral and basic fractions of OSPW inhibited activity of P-gp in Caco-2 cells by 1.9- and 2.0-fold, respectively, while the acidic fraction had the least effect. The organophosphate pesticides chlorpyrifos (a substrate of P-gp) and malathion (not a substrate of P-gp), were used as model chemicals to investigate inhibition of P-gp in larvae. Co-exposure to chlorpyrifos and an extract of OSPW containing basic and neutral compounds reduced survival of larvae to 26.5% compared to survival of larvae exposed only to chlorpyrifos, which was 93.7%. However, co-exposure to malathion and the extract of OSPW did not cause acute lethality compared to exposure only to malathion. Accumulation and bioconcentration of chlorpyrifos, but not malathion, was greater in larvae co exposed with the extract of OSPW. The terminal elimination half-life of chlorpyrifos in larvae exposed to chlorpyrifos in freshwater was 5 days compared with 11.3 days in larvae exposed to chlorpyrifos in OSPW. Results suggest that in non-acute exposures, basic and neutral organic compounds in the water-soluble fraction of OSPW inhibit activity of P-gp, which suggests that OSPW has the potential to cause adverse effects by chemosensitization. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27774652 TI - METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6 -methyladenosine-dependent primary MicroRNA processing. AB - : N6 -Methyladenosine (m6 A) modification has been implicated in many biological processes. However, its role in cancer has not been well studied. Here, we demonstrate that m6 A modifications are decreased in hepatocellular carcinoma, especially in metastatic hepatocellular carcinoma, and that methyltransferase like 14 (METTL14) is the main factor involved in aberrant m6 A modification. Moreover, METTL14 down-regulation acts as an adverse prognosis factor for recurrence-free survival of hepatocellular carcinoma and is significantly associated with tumor metastasis in vitro and in vivo. We confirm that METTL14 interacts with the microprocessor protein DGCR8 and positively modulates the primary microRNA 126 process in an m6 A-dependent manner. Further experiments show that microRNA 126 inhibits the repressing effect of METTL14 in tumor metastasis. CONCLUSION: These studies reveal an important role of METTL14 in tumor metastasis and provide a fresh view on m6 A modification in tumor progression. (Hepatology 2017;65:529-543). PMID- 27774653 TI - In vivo demonstration of whole-brain multislice multispoke parallel transmit radiofrequency pulse design in the small and large flip angle regimes at 7 Tesla. AB - PURPOSE: A multispoke specific absorption rate (SAR) -aware pulse design approach for homogeneous multiple-slice small and large flip angle (FA) excitations with parallel transmission is proposed. The approach aims at optimizing in a slice specific manner the spokes locations and radiofrequency pulses. METHODS: The problem is posed as a set of slice-specific magnitude-least-squares problems, linked together by hardware and SAR constraints, and solved jointly using an active-set algorithm. Average Hamiltonian theory is exploited in the large FA case to greatly reduce the computational burden. The approach is validated numerically by means of simulations and experimentally on two volunteers at 7 Tesla through application of a high-resolution T2*-weighted brain imaging protocol. RESULTS: The optimization of up to 1300 variables under 745 explicit constraints could be performed in less than 1 and 4 min for the small and large FA cases, respectively. The joint design proves valuable for SAR demanding protocols. Compared with the conventional circularly polarized mode, the designed pulses increased the signal by more than 40% in 70% of the voxels. CONCLUSION: The B1+ inhomogeneity problem was mitigated efficiently in a multislice near whole-brain coverage protocol in the small and large FA regimes using a rapid slice-specific pulse design algorithm where the pulses were optimized jointly. Magn Reson Med 78:1009-1019, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27774654 TI - Endoplasmic reticulum stress in the regulation of liver diseases: Involvement of Regulated IRE1alpha and beta-dependent decay and miRNA. AB - Compromised protein folding capacity in the endoplasmic reticulum (ER) leads to a protein traffic jam that produces a toxic environment called ER stress. However, the ER smartly handles such a critical situation by activating a cascade of proteins responsible for sensing and responding to the noxious stimuli of accumulated proteins. The ER protein load is higher in secretory cells, such as liver hepatocytes, which are thus prone to stress-mediated toxicity and various diseases, including alcohol-induced liver injury, fatty liver disease, and viral hepatitis. Therefore, we discuss the molecular cues that connect ER stress to hepatic diseases. Moreover, we review the literature on ER stress-regulated miRNA in the pathogenesis of liver diseases to give a comprehensive overview of mechanistic insights connecting ER stress and miRNA in the context of liver diseases. We also discuss currently discovered regulated IRE1 dependent decay in regulation of hepatic diseases. PMID- 27774657 TI - Transplantation of amniotic membrane-derived multipotent cells ameliorates and delays the progression of chronic kidney disease in cats. AB - Chronic kidney disease (CKD) is a common clinical condition in domestic cats, characterized by tubulointerstitial, vascular and glomerular inflammation and severe fibrosis. Studies in rodent model of induced CKD have shown a decrease and stabilization of the clinical condition. In this study was evaluated the safety and effect of intrarenal and intravenous infusion of allogeneic mesenchymal stem cells (AMSCs) derived from feline amniotic membrane in cats with naturally occurring CKD. Cat AMSCs were harvested after mechanical and enzymatic digestion of amnion. A healthy cat received intrarenal injection of AMSCs guided by ultrasound in both kidneys (5 * 105 cells/kidney). Nine cats with CDK received repeated intravenous infusions of AMSCs (2 * 106 cells * 2 treatments). The clinical parameters of healthy cat did not change, but sedation and general anaesthesia was required. The number of interventions stressed the animal, and he developed transient haematuria after AMSC injection. Cats with CDK registered a significant improvement of renal function (decrease in serum creatinine and urine protein concentrations and increase in urine specific gravity). The kidney architecture and morphology did not change following the treatment. The feline AMSCs have a renoprotective effect and improve renal function in cats with naturally occurring CKD, stabilizing the clinical condition and disease progression. Thus, intravenous injection of AMSCs may be an important tool to provide welfare in cats with chronic kidney disease. PMID- 27774655 TI - Phenolic compounds alone or in combination may be involved in propolis effects on human monocytes. AB - OBJECTIVES: Propolis is a natural product with a complex chemical composition. Its isolated compounds exert biological activities; however, its synergistic effects are unknown. The involvement of phenolic acids (caffeic - Caf, dihydrocinnamic - Cin and p-coumaric - Cou) alone or in combination was investigated in the action of propolis in human monocytes. METHODS: Cell viability was analysed by MTT assay; TNF-alpha, IL-6 and IL-10 production by enzyme-linked immunosorbent assay (ELISA); cell markers expression by flow cytometry; colony-forming units were counted to assess the microbicidal activity; and H2 O2 production was analysed by colorimetric assay. KEY FINDINGS: Treatments did not affect monocytes viability. Propolis and combinations containing Caf enhanced TNF-alpha production by resting cells. Propolis, Cin, Cou and Caf + Cin stimulated IL-6 production. All treatments upregulated IL-10. In LPS-stimulated cells, treatments downregulated IL-6 and maintained TNF-alpha and IL-10 production. A lower TLR-2 expression was seen than propolis. Caf + Cin enhanced TLR-4 expression. Propolis, Caf and Caf + Cin stimulated H2 O2 production, whereas propolis, Cin, Cou, and Caf + Cin + Cou induced a higher fungicidal activity. Cin and Cin + Cou increased the bactericidal activity of human monocytes. CONCLUSION: Propolis activated human monocytes, and acids were involved differently in propolis activity. PMID- 27774656 TI - Improving the robustness of pseudo-continuous arterial spin labeling to off resonance and pulsatile flow velocity. AB - PURPOSE: To improve pseudo-continuous arterial spin labeling (PCASL) robustness to off-resonance and pulsatile blood flow velocity. METHODS: Bloch equations were solved to evaluate the effect of labeling parameters in a pulsatile flow model for a range of off-resonance. Experimental confirmation was achieved in volunteers using linear phase increase between labeling pulses to approximate off resonance errors. We first assessed the location of the labeling plane in four volunteers. Next, we explored a range of parameters-including balanced and unbalanced gradients-in five more volunteers at an optimal labeling plane location. RESULTS: Simulations demonstrated that 1) high velocities are vulnerable to off-resonance, 2) unbalanced PCASL outperforms balanced PCASL, 3) increased B1 and low average gradient improve the labeling efficiency for high velocity flow, and 4) a low ratio of selective to average gradient improves off resonance robustness. A good agreement between theory and experiment was observed. CONCLUSION: The robustness of PCASL can be increased by selecting an unbalanced scheme with a low average gradient (0.5 mT/m), a low ratio (7*) of selective to average gradients, and the highest feasible B1 (1.8 MUT). Placing the labeling plane above the carotid bifurcation and below the V3 segment, usually between the second and third vertebrae, yielded robust results. Magn Reson Med 78:1342-1351, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27774658 TI - The localization of kisspeptin and kisspeptin receptor in the canine ovary during different stages of the reproductive cycle. AB - Kisspeptin is a neuropeptide involved in the hypothalamic regulation of reproduction in many species. Recent studies have revealed kisspeptin within the ovaries of rats, Siberian hamsters and humans, indicating a local role in reproduction. However, the role of kisspeptin in the ovary is poorly understood in the bitch. This study investigated the presence and location of kisspeptin protein (KISS1) and kisspeptin receptors (KISS1R) in the canine ovary during different stages of the reproductive cycle (pre-pubertal, anoestrus and cycling) by means of immunohistochemical staining. Ovaries from 24 bitches presented at local veterinary clinics for routine ovariohysterectomy were collected and grouped based on reproductive stage (pre-pubertal, anoestrus and cycling (proestrus, oestrus and dioestrus)). The presence or absence of immunoreactive KISS1 and KISS1R was recorded without any quantification of the levels of expression within cells. Immunoreactive KISS1 was found in the oocytes during all stages of the oestrous cycle, in the granulosa cells during all stages except anoestrus and in the corpus luteum (CL) during dioestrus. KISS1 was absent in the ovaries of pre-pubescent bitches. Immunoreactive KISS1R were consistently found in the oocytes, primordial follicles, the granulosa cells and CL in cycling bitches. The finding of KISS1R in the granulosa cells is suggestive that kisspeptin and progesterone may be linked as this pattern of staining is seen in animals that show preovulatory luteinisation of follicles during oestrus, KISS1R were also observed in the ovaries of pre-pubescent and anoestrous bitches, suggesting a possible role of kisspeptin in oocyte proliferation, development and maturation of granulosa cells, and progesterone production. This study provides a starting point for the establishment of a canine model for kisspeptin regulation within the ovary. PMID- 27774659 TI - The role of drug efflux pumps in Malassezia pachydermatis and Malassezia furfur defence against azoles. AB - This study aims to evaluate the effect of efflux pump modulators (EPMs) on the minimal inhibitory concentration (MIC) of fluconazole (FLZ) and voriconazole (VOR) in Malassezia furfur and Malassezia pachydermatis. The in vitro efficacy of azoles, in combination with EPMs (ie haloperidol-HAL, promethazine-PTZ and cyclosporine A-CYS), against 21 M. furfur from bloodstream infection patients and 14 M. pachydermatis from the skin of dogs with dermatitis, was assessed using a broth microdilution chequerboard analysis. Data were analysed using the model fractional inhibitory concentration index (FICI) method. The MIC of FLZ and VOR of Malassezia spp. decreased in the presence of sub-inhibitory concentrations of HAL and/or PTZ. The synergic effect was observed only in strains with FLZ MIC>=128 MUg/mL for M. furfur, FLZ MIC>=64 MUg/mL for M. pachydermatis and VOR MIC>=4 MUg/mL in both Malassezia spp. These results suggest that the drug efflux pumps are involved as defence mechanisms to azole drugs in Malassezia yeast. The synergism might be related to an increased expression of efflux pump genes, eventually resulting in azole resistance phenomena. Finally, the above FLZ and VOR MIC values might be considered the cut-off to discriminate susceptible and resistant strains. PMID- 27774660 TI - The influence of benign prostatic hyperplasia on sperm morphological features and sperm DNA integrity in dogs. AB - Benign prostatic hyperplasia (BPH) has a high incidence in older intact dogs. Due to the increased prostatic oxidative stress and hormonal imbalance of BPH, sperm damage can arise, such as sperm morphological alterations and DNA fragmentation. This study aimed to compare the reproductive potential of healthy dogs and those affected by benign prostatic hyperplasia. Ten dogs were assigned to two experimental groups: dogs without BPH (control; n = 5) and dogs diagnosed with BPH (n = 5), based on clinical signs and ultrasonographic findings. Three semen collections were performed from each dog within one month and analysed using computer-assisted sperm analysis (CASA) and functional tests. Control group showed higher percentage of sperm DNA integrity (95 +/- 1.8%) compared to the BPH group (79.2 +/- 6.4%). On the other hand, the percentage of minor sperm defects, amplitude of lateral sperm head displacement of the spermatozoa and medium sperm mitochondrial activity were higher in the BPH group. In conclusion, BPH decreases sperm DNA integrity, increases mitochondrial activity, as well as modifies sperm movement pattern. Therefore, a careful sperm analysis of aged dogs with BPH is required before a reproductive programme can be established for such patients. PMID- 27774661 TI - The relation between dyadic coping and relationship satisfaction in couples dealing with haematological cancer. AB - Couples' ability to cope with cancer is significantly associated with how satisfied they are with their relationship. However, little evidence specific to haemato-oncological patients exists. The objective of this study was to examine how dyadic coping (DC) affects relationship satisfaction among couples facing haematological cancer. Furthermore, we tested complex interactions between distress, disease-related and socio-demographic factors. In a multicentre study, 327 patients (haemato-oncological cancer; mean age: 57 years, 63% male) and their partners responded to surveys examining their relationship satisfaction, DC and distress. The Actor-Partner-Interdependence-Model (APIM) and moderator analyses were used to assess interactions between these concepts. In the APIM, positive DC was significantly related to greater levels of relationship satisfaction, and negative DC was related to lower levels of relationship satisfaction (all p < .001). The partners' distress was significantly related to lower levels of relationship satisfaction of the partners (p < .05). Furthermore, distress, age and relationship duration had significant moderating effects on the association between DC and relationship satisfaction (p < .05). Our results enable describing patient and partner as an interactional unit in which positive DC supports a satisfying relationship. They imply that strengthening positive DC in a couple facing haematological cancer can contribute to them having a well-functioning and sustaining relationship. PMID- 27774663 TI - Liver and serum expression of matrix metalloproteinases in asymptomatic pediatric liver transplant recipients. AB - We related hepatic gene and serum expression of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) to liver histology in pediatric LT recipients. Liver biopsies and serum samples were obtained from 52 patients 10.6 years post LT and age-matched controls for analyses of MMPs and TIMPs. Patients with fibrosis had significantly higher hepatic gene expression of MMP-2, MMP-9, MMP 14, TIMP-1, and TIMP-2 than patients without. Expression of these genes correlated with graft Metavir fibrosis stage (r = 0.494-0.684, P <= 0.006 for all). Gene expression of MMP-1, MMP-3, MMP-8, TIMP-3, and TIMP-4 was undetectable in both patients and controls. Portal inflammation and cytokeratin 7 correlated positively with gene expression of TIMP-1. Gene expression of MMP-2, MMP-9, and TIMP-2 correlated negatively with the time of low-dose cortisone usage (r = 0.448 to -0.422, P < 0.05 for all). Serum concentrations of MMP-8 and TIMP-1 were significantly increased and MMP-9 decreased among patients compared with controls, but no correlations to graft histology or gene expression were observed. Hepatic gene expression of certain MMPs and TIMPs is increased in stable pediatric LT recipients displaying graft fibrosis, but this did not reflect to their serum concentrations. Increased hepatic gene expression of TIMP 1 correlated with graft fibrosis stage, inflammation, and chronic cholestasis. PMID- 27774662 TI - Kisspeptin-10 and the G protein-coupled receptor 54 are differentially expressed in the canine pregnant uterus and trophoblast cells. AB - Uterine tissue was collected from bitches after ovariohysterectomy at different times after ovulation. Samples were assigned to four groups: metestrous non pregnant, day 10-12, n = 4; pre-implantation, day 10-12, n = 9; post implantation, day 18-25, n = 13; mid-gestation, day 30-40, n = 7. RT-qPCR detection was performed for kiss1 and the G protein-coupled receptor 54 (GPR54, specific receptor for kisspeptin). In addition, immunohistochemistry was performed for detection of kisspeptin-10 (KP-10), GPR54, as well as pan cytokeratin and vimentin. The latter two were included to differentiate the different placental cell types. The percentage of positive stained cells was evaluated, and an immunoreactivity score (IRS) was obtained by multiplying the labelling intensity score (0-3) with the percentage of immunolabelled cells (range: 0-300). In non-pregnant and pre-implantation tissues, gene expression was highly variable for kiss1 and GPR54. Expression of GPR54 was higher before embryo adhesion than during post-implantation and mid-gestation (p < .05), whereas there was no difference found between groups for kiss1. Except during the pre implantation period, KP-10 expression was higher in the non-pregnant uterus compared to all gestational periods investigated, indicating a pregnancy-related downregulation. In the pre-implantation period, KP-10 was present in larger vessels only, whereas the presence of GPR54 in vessels was found in all samples, with most labelling in the post-implantation period. KP-10 was present in superficial uterine glands, GPR54 in superficial and deep uterine glands of the post-implantation uterus. In myocytes, the highest staining for KP-10 was seen in the non-pregnant uterus, whereas the highest staining for GPR54 was seen in post implantation and mid-gestation. Syncytiotrophoblast cells stained for both KP-10 and GPR54 in post-implantation and mid-gestation, with maximum intensity for GPR54 in the latter. We conclude that KP-10 and GPR54 are expressed in the canine uterus and trophoblast cells. However, during pregnancy, expression of both proteins seems to be differentially regulated. PMID- 27774665 TI - Potential inhibition of development of rapidly progressive interstitial lung disease by prompt and sufficient immunosuppressive treatment in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis. PMID- 27774664 TI - Assessing psychological and supportive care needs in glioma patients - feasibility study on the use of the Supportive Care Needs Survey Short Form (SCNS SF34-G) and the Supportive Care Needs Survey Screening Tool (SCNS-ST9) in clinical practice. AB - Neuro-oncological patients experience high symptom and psychosocial burden. The aim was to test feasibility and practicability of the Supportive Care Needs Survey Short Form (SCNS-SF34-G) and the SCNS-Screening Tool (SCNS-ST9) to assess supportive care needs of neuro-oncological patients in clinical routine. A total of 173 patients, most with a primary diagnosis of high-grade glioma (81%), were assessed first using SCNS-SF34-G in comparison to two well-established patient reported outcome measures, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQC30 + QLQ-BN20) and Distress Thermometer (DT). In a follow-up assessment, SCNS-ST9 was used in a subgroup (n = 90). Questionnaires were completed either with personal guidance offered (group A) or by patients alone (group B). Feasibility was compared between instruments and groups for possible associations with patient and treatment-related factors. Missing values occurred in similar frequencies in all instruments. Errors in completion occurred in SCNS-SF34-G in 20% and in SCNS-ST9 in 16%; difficulties in completion were observed more often in SCNS-SF34-G and SCNS-ST9 (39%) compared to DT and EORTC (13%, p < .001). Distress was found to be associated with difficulties in completion of SCNS (OR 1.4, [95% CI 1.1-1.9], p = .013). SCNS SF34 and SCNS-ST9 are suitable tools for glioma patients as long as personal guidance is offered. PMID- 27774666 TI - Factors associated with frequency of discussion of or referral for counselling about fertility issues in female cancer patients. AB - Current practices in counselling of female cancer patients with respect to fertility issues need considerable improvement, particularly given the general underuse of fertility preservation options and the negative impact that infertility can have on quality of life. We investigated the relationship between physicians' and physician-related factors and the frequency of physicians discussing fertility issues and referring to a reproductive specialist. We invited 1,832 physicians in the Netherlands who had treated at least five reproductive-age female cancer patients within the past year to complete a questionnaire. Of the 748 respondents, 406 met our inclusion criteria, and 280 participated. Analysis revealed that 79% of the participants usually or always discuss fertility issues. Specialty, confidence in knowledge regarding fertility issues and a lack of reproductive specialists in their region contributed independently to the variance in the frequency of discussing fertility issues. Moreover, 54% either regularly or always refer. Specialty and frequency of discussion contributed independently to the variance in referral. In conclusion, although high, frequency of discussion of fertility issues is not optimal, and referral seems limited. Patients would benefit from more knowledge among physicians regarding fertility issues and referral options, both in terms of informed choice, and more importantly, quality of life. PMID- 27774667 TI - Morbidity and Health Care Costs After Early Term Birth. AB - BACKGROUND: Early term birth is associated with increased need for hospital care during the early postnatal period. The objective of this study was to assess the morbidity and health care-related costs during the first 3 years of life in children born early term. METHODS: Data come from a population-based birth cohort study in the municipalities of Helsinki, Espoo, and Vantaa, Finland using data from the national medical birth register and outpatient, inpatient, and primary care registers. All surviving infants born in 2006-08 (n = 29 970) were included. The main outcome measures were morbidities, based on ICD-10 codes recorded during inpatient and outpatient hospital visits, and health care costs, based on all care received, including well child visits (specialised care, primary care, private care, and medications). RESULTS: 7.0% of children born full term had at least one of the studied morbidities by 3 years of age. This percentage was significantly higher in children born early term: 8.6% (adjusted odds ratio 1.2, 95% confidence interval (CI) 1.1, 1.4). The increased morbidity of children born early term was attributed to obstructive airway diseases and ophthalmological and motor problems. Health care-related costs during the first 3 years of life were 4813? (95% CI 4385, 5241) per child in the early term group, higher than for full term children 4047? (95% CI 3884, 4210). CONCLUSIONS: Infants born early term have increased morbidity and higher health care-related costs during early childhood than full term infants. Early term birth seems to be associated with a health disadvantage. PMID- 27774668 TI - Bio- and chemical syntheses of mangiferin and congeners. AB - Mangiferin (2C-beta-d-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone) is a xanthone C-glycoside occurring in many plant species. Composed of a glucose unit C1->2 linked to a 1,3,6,7-tetrahydroxyxanthone aglycone, mangiferin exhibits a wide range of biological activities, which recently renewed its interest as a potential pharmacophore. Mangiferin is mainly isolated after extraction procedures from natural sources alongside with its isoforms isomangiferin, homomangiferin, and neomangiferin. However, enzymatic and chemical approaches have been developed to access these phytochemicals, which address the challenging construction of the C-glycosidic linkage. In addition, both approaches have been exploited to modify the aglycone and the sugar moiety in order to afford analogues with specific and improved pharmacological activities. Herein, we provide a comprehensive review on the biosynthesis and chemical synthesis of mangiferin and its congeners. (c) 2016 BioFactors, 42(5):445-458, 2016. PMID- 27774669 TI - Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. AB - : Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein-binding protein-associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells. CONCLUSION: These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2017;65:515-528). PMID- 27774670 TI - Examining dental expenditure and dental insurance accounting for probability of incurring expenses. AB - OBJECTIVES: There are few studies of dental service expenditure in Australia. Although dental insurance status is strongly associated with a higher probability of dental visiting, some studies indicate that there is little variation in expenditure by insurance status among those who attend for care. Our objective was to assess the overall impact of insurance on expenditures by modelling the association between insurance and expenditure accounting for variation in the probability of incurring expenses, that is dental visiting. METHODS: A sample of 3000 adults (aged 30-61 years) was randomly selected from the Australian electoral roll. Dental service expenditures were collected prospectively over 2 years by client-held log books. Questionnaires collecting participant characteristics were administered at baseline, 12 months and 24 months. Unadjusted and adjusted ratios of expenditure were estimated using marginalized two-part log-skew-normal models. Such models accommodate highly skewed data and estimate effects of covariates on the overall marginal mean while accounting for the probability of incurring expenses. RESULTS: Baseline response was 39%; of these, 40% (n = 438) were retained over the 2-year period. Only participants providing complete data were included in the analysis (n = 378). Of these, 68.5% were insured, and 70.9% accessed dental services of which nearly all (97.7%) incurred individual dental expenses. The mean dental service expenditure for the total sample (those who did and did not attend) for dental care was AUS$788. Model-adjusted ratios of mean expenditures were higher for the insured (1.61; 95% CI 1.18, 2.20), females (1.38; 95% CI 1.06, 1.81), major city residents (1.43; 95% CI 1.10, 1.84) and those who brushed their teeth twice or more a day (1.50; 95% CI 1.15, 1.96) than their respective counterparts. CONCLUSION: Accounting for the probability of incurring dental expenses, and other explanatory factors, insured working-aged adults had (on average) approximately 60% higher individual dental service expenditures than uninsured adults. The analytical approach adopted in this study is useful for estimating effects on dental expenditure when a variable is associated with both the probability of visiting for care, and with the types of services received. PMID- 27774673 TI - Seminars in Dialysis: The 100 Most Highly Cited Papers. PMID- 27774674 TI - Estimating Weekly Urine Flow Rate And Residual Kidney Urea Clearance: A Method To Deal With Interdialytic Variability. AB - Both urine volume and residual kidney clearances are known to increase over the course of an interdialytic interval. However, no strategy has been proposed for adjusting data from an interdialytic urine collection to a weekly value for urine flow rate or residual kidney urea clearance. Data from a reanalysis of published results allows a proposal for such an adjustment, which assigns a relative value to each dialysis day of the week based on its distance from a preceding hemodialysis treatment. The strategy also identifies which urine collection periods and interdialytic intervals give results that should be most representative of weekly average values. PMID- 27774675 TI - Case of lichen planus induced by sitagliptin phosphate hydrate. PMID- 27774671 TI - Centriole positioning in epithelial cells and its intimate relationship with planar cell polarity. AB - Planar cell polarity (PCP)-signaling and associated tissue polarization are evolutionarily conserved. A well documented feature of PCP-signaling in vertebrates is its link to centriole/cilia positioning, although the relationship of PCP and ciliogenesis is still debated. A recent report in Drosophila established that Frizzled (Fz)-PCP core signaling has an instructive input to polarized centriole positioning in non-ciliated Drosophila wing epithelia as a PCP read-out. Here, we review the impact of this observation in the context of recent descriptions of the relationship(s) of core Fz-PCP signaling and cilia/centriole positioning in epithelial and non-epithelial cells. All existing data are consistent with a model where Fz-PCP signaling functions upstream of centriole/cilia positioning, independent of ciliogenesis. The combined data sets indicate that the Fz-Dsh PCP complex is instructive for centriole/ciliary positioning via an actin-based mechanism. Thereby, centriole/cilia/centrosome positioning can be considered an evolutionarily conserved readout and common downstream effect of PCP-signaling from flies to mammals. PMID- 27774676 TI - Case of autosomal recessive woolly hair/hypotrichosis with atopic dermatitis. PMID- 27774677 TI - The impact of proton pump inhibitor therapy on patients with liver disease. AB - BACKGROUND: Proton pump inhibitor (PPI) therapy has been reported to be an independent mortality risk factor in patients with cirrhosis. AIM: To identify the prevalence of PPI prescription, the appropriateness of this therapy and to investigate the relationship between PPI therapy and overall survival in patients with liver disease. METHODS: This retrospective cohort study used patient data for 2012 to 2014 collected from the Scottish Liver Transplant Unit and the Hepatology Ward at the New Royal Infirmary of Edinburgh. RESULTS: A total of 64% of the 198 patients discharged from the Hepatology ward were prescribed a PPI. Of the 206 patients assessed and listed for orthotopic liver transplant (OLT), 55% were prescribed a PPI. These percentages are significant, particularly as the majority had no recorded appropriate indication for this therapy. For patients listed for OLT, a logistic regression model revealed significant associations between PPI treatment and male sex, higher model of end-stage liver disease (MELD) scores and patient encephalopathy. A multivariate Cox regression model showed that MELD and UK model for end-stage liver disease scores were independent predictors of patient mortality, while alcoholic liver disease aetiology was a protective factor. There was no statistically significant difference in survival between patients who were prescribed a PPI at assessment and those who were not. CONCLUSION: Associations between PPI use, encephalopathy and higher MELD scores imply caution should be exercised in prescribing gastric acid suppressants to patients with cirrhosis, particularly in the absence of clear indications. PMID- 27774678 TI - Post-diagnostic dietary changes in prostate cancer: associations with patients' wellbeing and the perceptions of GPs. AB - This article aims to investigate associations between perceived control and health-related quality of life (HRQOL) with dietary changes after prostate cancer diagnosis and to explore General Practitioners' (GPs) perceptions on the role of diet in prostate cancer post-diagnosis. Ninety-five prostate cancer patients completed measures of dietary change, one for after diagnosis and another for after therapy. They also scored their HRQOL and perceived control. There were discrepancies in dietary changes reported between a general question (28.4% no dietary changes) and a specific (42.1%-51.5% range of no change for various food items). Most patients initiated healthy changes. Patients who changed their diet after diagnosis had lower cognitive functioning and external locus of control (doctors). Patients who changed their diet after therapy had lower cognitive and emotional functioning, quality of life and external locus of control (doctors). Then, fourty-four GPs responded to an online survey. Their open-ended responses were analysed using Content Analysis. They reported interest in the role of diet in cancer but also lack of relevant knowledge. They were skeptical on providing information. Clinical interventions should consider patients' cognitive ability, their relationship with their health professional and their wellbeing. Also, GPs' confidence to provide dietary advice needs to be addressed. PMID- 27774679 TI - Validity of prescribing indicators for assessing quality of antibiotic use in Australian general practice. AB - OBJECTIVES: The aim of this study was to assess the validity of a set of European quality indicators for assessing antimicrobial prescribing in Australian General Practice. METHODS: A modified UCLA/RAND appropriateness method was used to assess the validity of 30 antimicrobial prescribing indicators. An expert panel of 12 general practitioners scored the validity of each indicator for measuring quality in Australian general practice. Four quality domains were considered: monitoring antibiotic resistance, benefit to individual patients, value for money and value to policymakers. Panel members were also asked to comment on the relevance to the Australian context and proposed benchmarks for each indicator. KEY FINDINGS: All panel members were in agreement regarding the validity of each indicator in each of the specified domains with exception of the indicator assessing the use of systemic antibiotics for pneumonia. The majority of the indicators and their associated benchmarks were considered valid for assessing quality in Australian General Practice, however, there were differences regarding the quality domain that each indicator was considered valid for. Monitoring quality considering individual patient benefit was the most problematic domain with respect to validity. CONCLUSIONS: This study demonstrates the validity of 30 European indicators for assessing quality of antimicrobial prescribing in general practice in a non-European setting and provides guidance regarding acceptable benchmarks for the indicators. With international concerns regarding misuse of antibiotics and global interest in prescribing quality, valid evidence-based antimicrobial prescribing indicators and associated benchmarks are an essential tool for assessing prescribing quality. PMID- 27774680 TI - Threat and fear of pain induces attentional bias to pain words: An eye-tracking study. AB - BACKGROUND: This study aimed to investigate the effects of fear of pain (FOP) and threat on attentional biases, using eye-tracking methods. METHOD: One hundred and seven undergraduate students were randomized to receive threatening or reassuring information about the cold pressor task; and divided into high and low FOP groups. Participants completed the dot-probe task, while their eye movements were tracked. RESULTS: Results showed that those who received threatening information were less likely to have their first fixation on pain words, particularly affective pain words. Furthermore, under conditions of high threat, the high FOP group who did fixate on affective pain words, fixated more quickly than for sensory pain words, whereas the opposite was the case under low threat. In regression analyses, initial vigilance towards affective pain words was a significant predictor of reporting pain more quickly on the cold pressor. CONCLUSIONS: Taken together, these results suggest that initial vigilance of affective pain stimuli predicts actual hypervigilance to an acute experimental pain task. However, under conditions of high threat, participants show evidence of avoidance of affective pain words, even though when they do fixate on these stimuli, the high FOP group does so more quickly. These results confirm that attentional processes, characterized by vigilance avoidance, appear important. SIGNIFICANCE: Interventions that change attention towards pain to reduce vigilance and subsequent avoidance may be indicated to improve pain outcomes. PMID- 27774681 TI - Frequent whole blood donors: understanding this population and predictors of lapse. AB - BACKGROUND: Frequent blood donors are an important resource as they contribute many donations over their lifetime. The aim of this research was to develop a demographic profile of Australian frequent whole blood donors and to determine predictors of lapse within this group. STUDY DESIGN AND METHODS: Routinely collected data were used to profile individuals who had donated whole blood frequently (three or more times) between December 2010 and November 2011. Two segments were identified: 1) existing donors who had donated before December 2010 and 2) new donors who had not donated before December 2010. Donation records were followed to the end of December 2013 to examine retention. RESULTS: A total of 90,867 donated frequently between December 2010 and November 2011. The group was composed of slightly more men (51.4%), was typically of middle socioeconomic status, and many were employed in skilled trades such as a builder or a plumber (21.3%). Existing donors (n = 81,762) were significantly older, more likely to be male, and more likely to have a D- blood type compared to the smaller group of new donors (n = 9105). For both segments, being older and male and having a D- blood type increased the likelihood of return in the follow-up period. Deferrals and adverse events had negative impacts on retention for both groups. CONCLUSIONS: This study highlights specific factors that blood collection agencies may focus on to support continued donation among frequent donors. PMID- 27774682 TI - Evaluation of a Prison Occupational Therapy Informal Education Program: A Pilot Study. AB - This pilot study explored the strengths and weaknesses of an informal education program and identified elements of the program valued by participants. Participants were men living in a minimum security prison who had been incarcerated for ten or more years. The outside researcher was joined by three former program participants as co-researchers. Together, they interviewed 27 residents who completed the informal education program. Interviews were transcribed and de-identified. Researchers used the summative content analysis approach to analyze the data. Initial content analysis yielded five concepts: doing (engaging in purposeful activities); information (program handouts and discussions that included data and descriptions of all of the topics discussed); re-entry fears (socialization; making amends with victims and/or reuniting with family and friends); technology (includes, but not limited to, using smartphones, internet and other technology in all areas of occupation); and self-worth as a person. Further interpretation per the summative content analysis method yielded three themes: doing (engaged in purposeful activities), validation of self-worth (confirmation of being a valued human being in spite of having committed a serious crime) and concerns about the future (being able to successfully engage in virtually all occupations). Whilst informal education programs may help people who are incarcerated gain information, gain a sense of self-worth and allay some reentry fears, understanding the long-term affect such programs may have such as preparing them for successful re-entry to society or reducing recidivism rates, will require long-term follow-up. Regardless of the occupational therapy intervention, the practice of occupational therapy in the criminal justice system needs to be client-centred. Because of the small number of participants and limited access to participants, one should not generalize the findings of this study to other situations or populations. Further research to examine the effectiveness of an occupational therapy education program is warranted. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27774684 TI - PCL-PLLA Semi-IPN Shape Memory Polymers (SMPs): Degradation and Mechanical Properties. AB - Thermoresponsive shape memory polymers (SMPs) based on poly(epsilon-caprolactone) (PCL) whose shape may be actuated by a transition temperature (T trans ) have shown utility for a variety of biomedical applications. Important to their utility is the ability to modulate mechanical and degradation properties. Thus, in this work, SMPs are formed as semi-interpenetrating networks (semi-IPNs) comprised of a cross-linked PCL diacrylate (PCL-DA) network and thermoplastic poly(l-lactic acid) (PLLA). The semi-IPN uniquely allows for requisite crystallization of both PCL and PLLA. The influence of PLLA (PCL:PLLA wt% ratio) and PCL-DA molecular weight (n) on film properties are investigated. PCL-PLLA semi-IPNs are able to achieve enhanced mechanical properties and accelerated rates of degradation. PMID- 27774683 TI - Stress as a mnemonic filter: Interactions between medial temporal lobe encoding processes and post-encoding stress. AB - Acute stress has been shown to modulate memory for recently learned information, an effect attributed to the influence of stress hormones on medial temporal lobe (MTL) consolidation processes. However, little is known about which memories will be affected when stress follows encoding. One possibility is that stress interacts with encoding processes to selectively protect memories that had elicited responses in the hippocampus and amygdala, two MTL structures important for memory formation. There is limited evidence for interactions between encoding processes and consolidation effects in humans, but recent studies of consolidation in rodents have emphasized the importance of encoding "tags" for determining the impact of consolidation manipulations on memory. Here, we used functional magnetic resonance imaging in humans to test the hypothesis that the effects of post-encoding stress depend on MTL processes observed during encoding. We found that changes in stress hormone levels were associated with an increase in the contingency of memory outcomes on hippocampal and amygdala encoding responses. That is, for participants showing high cortisol reactivity, memories became more dependent on MTL activity observed during encoding, thereby shifting the distribution of recollected events toward those that had elicited relatively high activation. Surprisingly, this effect was generally larger for neutral, compared to emotionally negative, memories. The results suggest that stress does not uniformly enhance memory, but instead selectively preserves memories tagged during encoding, effectively acting as mnemonic filter. (c) 2016 Wiley Periodicals, Inc. PMID- 27774685 TI - Do neglected Australian arboviruses pose a global epidemic threat? PMID- 27774686 TI - Implantation: Cell biology of embryo penetration route revisited. PMID- 27774688 TI - Social determinants of health and local government: understanding and uptake of ideas in two Australian states. AB - OBJECTIVE: To examine the awareness and perceptions of local government staff about the social determinants of health (SDoH) and health inequity and use of these ideas to shape policy and practice. METHODS: 96 staff at 17 councils in South Australia or New South Wales responded to questions in a pilot online survey concerning: sources of knowledge about, familiarity with the evidence on, attitudes towards, and uses of ideas about the social determinants of health. Eight of 68 SA councils and 16 of 152 NSW councils were randomly selected stratified by state and metropolitan status. Differences between states and metropolitan/non-metropolitan status were explored. RESULTS: The majority of respondents (88.4%) reported some familiarity with ideas about the broad determinants of health and 90% agreed that the impact of policy action on health determinants should be considered in all major government policy and planning initiatives. Research articles, government/professional reports, and professional contacts were rated as important sources of knowledge about the social determinants of health. CONCLUSION: Resources need to be dedicated to systematic research on practical implementation of interventions on social determinants of health inequities and towards providing staff with more practical information about interventions and tools to evaluate those interventions. IMPLICATIONS: The findings suggest there is support for action addressing the social determinants of health in local government. The findings extend similar research regarding SDoH and government in NZ and Canada to Australian local government. PMID- 27774689 TI - Perfluoroalkylation of Alkenes by Frustrated Lewis Pairs. AB - The activation of perfluoroalkyl iodides by the frustrated Lewis pair tris(pentafluorophenyl)borane and tri-tert-butylphosphine is described. By abstraction of both a fluorine and an iodine atom, an iodophosphonium fluoroborate salt is formed. In the presence of alkenes the corresponding iodoperfluoroalkylation products are generated regioselectively. First mechanistic investigations support a radical mechanism. PMID- 27774687 TI - Human CaaX protease ZMPSTE24 expressed in yeast: Structure and inhibition by HIV protease inhibitors. AB - The function and localization of proteins and peptides containing C-terminal "CaaX" (Cys-aliphatic-aliphatic-anything) sequence motifs are modulated by post translational attachment of isoprenyl groups to the cysteine sulfhydryl, followed by proteolytic cleavage of the aaX amino acids. The zinc metalloprotease ZMPSTE24 is one of two enzymes known to catalyze this cleavage. The only identified target of mammalian ZMPSTE24 is prelamin A, the precursor to the nuclear scaffold protein lamin A. ZMPSTE24 also cleaves prelamin A at a second site 15 residues upstream from the CaaX site. Mutations in ZMPSTE24 result in premature-aging diseases and inhibition of ZMPSTE24 activity has been reported to be an off target effect of HIV protease inhibitors. We report here the expression (in yeast), purification, and crystallization of human ZMPSTE24 allowing determination of the structure to 2.0 A resolution. Compared to previous lower resolution structures, the enhanced resolution provides: (1) a detailed view of the active site of ZMPSTE24, including water coordinating the catalytic zinc; (2) enhanced visualization of fenestrations providing access from the exterior to the interior cavity of the protein; (3) a view of the C-terminus extending away from the main body of the protein; (4) localization of ordered lipid and detergent molecules at internal and external surfaces and also projecting through fenestrations; (5) identification of water molecules associated with the surface of the internal cavity. We also used a fluorogenic assay of the activity of purified ZMPSTE24 to demonstrate that HIV protease inhibitors directly inhibit the human enzyme in a manner indicative of a competitive mechanism. PMID- 27774690 TI - A nurse-led intervention improved blood-borne virus testing and vaccination in Victorian prisons. AB - OBJECTIVES: Testing is the first step in treatment and care for blood-borne viruses (BBVs) and sexually transmitted infections (STIs). As new treatments for viral hepatitis emerge, it is important to document effective models for BBV/STI testing. A nurse-led intervention was implemented across three prisons in Victoria to improve BBV/STI testing. We evaluated the impact of the intervention on BBV/STI testing rates and hepatitis B (HBV) vaccination for reception prisoners. METHODS: BBV/STI testing and HBV vaccination data were collected from the medical files of 100 consecutive reception prisoners at three prisons (n=300) prior to and after the intervention was implemented. RESULTS: BBV testing increased significantly from 21% of prisoners to 62% post-intervention. Testing for some STIs increased significantly, but remained low: 5% to 17% for chlamydia and 1% to 5% for gonorrhoea. HBV vaccination increased significantly from 2% to 19%. CONCLUSIONS: The nurse-led intervention resulted in substantially increased testing and vaccination, demonstrating the benefits of a concerted effort to improve BBV and STI management in correctional settings. IMPLICATIONS: The availability of new treatments for hepatitis C has precipitated expansion of treatment in prisons. Improving the testing rate of prisoners, the first step in the treatment cascade, will maximise the benefits. PMID- 27774691 TI - A case study of enhanced clinical care enabled by Aboriginal health research: the Hearing, EAr health and Language Services (HEALS) project. AB - OBJECTIVE: To describe and evaluate Hearing EAr health and Language Services (HEALS), a New South Wales (NSW) health initiative implemented in 2013 and 2014 as a model for enhanced clinical services arising from Aboriginal health research. METHODS: A case-study involving a mixed-methods evaluation of the origins and outcomes of HEALS, a collaboration among five NSW Aboriginal Community Controlled Health Services (ACCHS), the Sydney Children's Hospitals Network, NSW Health, the Aboriginal Health and Medical Research Council, and local service providers. Service delivery data was collected fortnightly; semi structured interviews were conducted with healthcare providers and caregivers of children who participated in HEALS. RESULTS: To circumvent health service barriers, HEALS used relationships established through the Study of Environment on Aboriginal Resilience and Child Health (SEARCH) to form a specialist healthcare network. HEALS employed dedicated staff and provided a Memorandum of Understanding (detailing mutual goals and responsibilities) for each ACCHS. Despite very tight timeframes, HEALS provided services for 653 Aboriginal children, including 5,822 speech-language pathology sessions and 219 Ear, Nose and Throat procedures. Four themes reflecting the perceived impact of HEALS were identified: valued clinical outcomes, raising community awareness, developing relationships/networks and augmented service delivery. CONCLUSIONS: HEALS delivered rapid and effective specialist healthcare services through an existing research collaboration with five ACCHS, cooperation from local health service providers, and effective community engagement. Implications for Public Health: HEALS serves as a framework for targeted, enhanced healthcare that benefits Aboriginal communities by encapsulating the 'no research without service' philosophy. PMID- 27774692 TI - Isolation and partial characterization of 3 nontoxic d-galactose-specific isolectins from seeds of Momordica balsamina. AB - Three isolectins denoted hereforth MBaL-30, MBaL-60, and MBaL-80 were isolated from seeds extract of Momordica balsamina by 30%, 60%, and 80% ammonium sulfate saturations, respectively. The native molecular weights of these lectins, as judged by gel filtration, were 108, 56, and 160 kDa, respectively. On SDS-PAGE, under reduced condition, 27 kDa band was obtained for all isolectins. The lectins hemagglutinating activities were variably inhibited by d-galactose (minimum inhibitory concentrations = 12.5mM, 50mM, and 0.391mM, respectively). MBaL-30 and -60 could agglutinate all human blood types with slight preference for the A and O blood groups, whereas MBaL-80 did not agglutinate B and AB blood types. The 3 isolectins were purified from crude seeds extract, collectively, in a single step on the affinity matrix Lactamyl-Seralose 4B; this purified lectin fraction, which contains all isolectins, is termed MBaL. The N-terminal of MBaL till the 25th amino acid was NLSLSELDFSADTYKSFIKNLRKQL, which shares 88% sequence identity with Momordica charantia lectin type-2 ribosomal inactivating protein from Momordica charantia and 50% with momordin II from Momordica balsamina. MBaL retained 100% activity at up to 50 degrees C for 30 minutes. MBaL-30 and MBaL-60 exhibited maximum activities in the pH range between 4 and 8, while MBaL-80 was showing maximum activity in the pH range between 3 and 5. Treatment of MBaL-30 and MBaL 60 with EDTA completely abolished their hemagglutinating activities. Addition of Zn and Fe ions to the ethylenediaminetetraacetic acid-treated MBaL-30 and MBaL-60 lectins did not only regained the loss of activity but also resulted in 200% to 300% increase in activity, respectively. MBaL-30 and -60 agglutinated gram positive Listeria monocytogenes and Staphylococcus aureus, whereas MBaL-30 could merely agglutinate Escherichia coli. None of these lectins could arrest bacterial growth. Addition of MBaL to cancer cell lines (Gastric cancer cell line (AGS) and Gastric cencer cell line (MKN45), Glioblastoma (ECV-304), and Human urinary bladder cancer cell line (U87-MG)) at varying concentrations did not cause statistically significant changes on cell growth and viability. PMID- 27774693 TI - Limited incremental effect of inflammatory bowel disease on risk of comorbidities in patients with psoriasis. PMID- 27774694 TI - Impact of adalimumab treatment on cardiovascular risk biomarkers in psoriasis: Results of a pilot study. AB - Psoriasis is a chronic systemic immune-mediated inflammatory dermatosis associated with several comorbidities. Psoriasis patients are at increased risk of developing cardiovascular diseases (CVD), namely, coronary heart disease, stroke or peripheral vascular disease, and psoriasis seems to be an independent cardiovascular risk factor. Antipsoriatic systemic therapy, especially anti-tumor necrosis factor (TNF)-alpha, seems to exert a beneficial effect on these comorbidities. The purpose of this study was: (i) to measure the level of cardiovascular serum markers in psoriasis patients in comparison with healthy volunteers; and (ii) to compare the serum level of the same markers in patients before and 3 months after adalimumab therapy. We investigated six biomarkers connected to CVD: C-reactive protein (measured high sensitively, hsCRP), oxidized low-density lipoproteins (oxLDL), oxLDL/beta-glycoprotein I complex (oxLDL/beta2GPI), vascular endothelial adhesion molecule 1 (VCAM-1), E-selectin and interleukin (IL)-22. These biomarkers were measured in 21 patients with moderate/severe psoriasis before and after treatment with adalimumab and in healthy volunteers. hsCRP (P < 0.05), oxLDL-beta2GPI complex (P < 0.05), E selectin (P < 0.001) and IL-22 (P < 0.001) were significantly increased in comparison with healthy controls, whereas oxLDL and VCAM-1 were also higher in psoriasis patients but the difference did not reach statistical significance. A decrease of E-selectin (P < 0.001) and IL-22 (P < 0.001) was observed after 3 months of adalimumab therapy. Inhibition of TNF-alpha seems to not only improve psoriasis but also decreases serum cardiovascular biomarkers. E-selectin and IL 22 could serve for monitoring of the efficacy of antipsoriatic systemic therapy on cardiovascular risk. PMID- 27774695 TI - Similarities and differences in the default mode network across rest, retrieval, and future imagining. AB - The default mode network (DMN) has been identified reliably during rest, as well as during the performance of tasks such as episodic retrieval and future imagining. It remains unclear why this network is engaged across these seemingly distinct conditions, though many hypotheses have been proposed to account for these effects. Prior to generating hypotheses explaining common DMN involvement, the degree of commonality in the DMN across these conditions, within individuals, must be statistically determined to test whether or not the DMN is truly a unitary network, equally engaged across rest, retrieval and future imagining. To provide such a test, we used comparable paradigms (self-directed, uninterrupted thought of equal duration) across the three conditions (rest, retrieval, and future imagining) in a within-participant design. We found lower than expected pattern similarity in DMN functional connectivity across the three conditions. Similarity in connectivity accounted for only 40-50% of the total variance. Partial Least Squares (PLS) analyses revealed the medial temporal regions of the DMN were preferentially coupled with one another during episodic retrieval and future imagining, whereas the non-medial temporal regions of the DMN (e.g., medial prefrontal cortex, lateral temporal cortex, and temporal pole) were preferentially coupled during rest. These results suggest that DMN connectivity may be more flexible than previously considered. Our findings are in line with emerging evidence that the DMN is not a static network engaged commonly across distinct cognitive processes, but is instead a dynamic system, topographically changing in relation to ongoing cognitive demands. Hum Brain Mapp 38:1155-1171, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27774696 TI - Utility of Computed Tomography versus Abdominal Ultrasound Examination to Identify Iliosacral Lymphadenomegaly in Dogs with Apocrine Gland Adenocarcinoma of the Anal Sac. AB - BACKGROUND: Apocrine gland adenocarcinoma of the anal sac (AGAAS) is associated with high rates of iliosacral lymph node metastasis, which may influence treatment and prognosis. Magnetic resonance imaging (MRI) recently has been shown to be more sensitive than abdominal ultrasound examination (AUS) in affected patients. OBJECTIVE: To compare the rate of detection of iliosacral lymphadenomegaly between AUS and computed tomography (CT) in dogs with AGAAS. ANIMALS: Cohort A: A total of 30 presumed normal dogs. Cohort B: A total of 20 dogs with AGAAS that underwent AUS and CT. METHODS: Using cohort A, mean normalized lymph node : aorta (LN : AO) ratios were established for medial iliac, internal iliac, and sacral lymph nodes. The CT images in cohort B then were reviewed retrospectively and considered enlarged if their LN : AO ratio measured 2 standard deviations above the mean normalized ratio for that particular node in cohort A. Classification and visibility of lymph nodes identified on AUS were compared to corresponding measurements obtained on CT. RESULTS: Computed tomography identified lymphadenomegaly in 13 of 20 AGAAS dogs. Of these 13 dogs, AUS correctly identified and detected all enlarged nodes in only 30.8%, and either misidentified or failed to detect additional enlarged nodes in the remaining dogs. Despite limitations in identifying enlargement in all affected lymph nodes, AUS identified at least 1 enlarged node in 100% of affected dogs. CONCLUSION AND CLINICAL IMPORTANCE: Abdominal ultrasound examination is an effective screening test for lymphadenomegaly in dogs with AGAAS, but CT should be considered in any patient in which an additional metastatic site would impact therapeutic planning. PMID- 27774697 TI - Livedoid vasculopathy and popliteal artery occlusion in a patient with protein S deficiency. AB - Livedoid vasculopathy (LV) is a chronic disease with recurrent reticularis and ulcers, mainly affecting the feet and lower legs. The pathogenesis of LV has not been yet thoroughly understood, but thrombosis is thought to play a major role because fibrin deposition within both the wall and lumen of affected vessels is pathologically detected. A 68-year-old woman first presented to our hospital in 2004 with a 6-year history of a reticular rash and ulceration on the lower legs. Screening tests for vasculitis and collagen disease were mostly normal, leading to diagnosis of LV. After failed treatment with steroid and aspirin, she was started on warfarin, to which she had a favorable response. However, she had to be admitted to the hospital because complication of swelling and infection in her left lower leg in 2004 + 10. Contrast-enhanced computed tomography showed thrombosis in the left popliteal artery. Screening tests for thrombotic tendency revealed that protein S activity was low (27%) although total protein S antigen was within normal range (73%). Analysis of protein S-alpha gene revealed 155 Lys>Glu mutation in exon VI, which was reported in 1994 and named as protein S Tokushima. Thus, we conclude that protein S deficiency could contribute to LV. PMID- 27774700 TI - Acquired anhidrosis in a case of autoimmune autonomic ganglionopathy. PMID- 27774699 TI - Characterization of teratogenic potential and gene expression in canine and feline amniotic membrane-derived stem cells. AB - The biosafety of innovative procedures that utilize stem cells in regenerative medicine has been addressed in several studies. Previous work has showed no tumour formation following the use of feline and human amniotic membrane-derived stem cells (AMSCs). In contrast, tumour formation was observed when canine AMSCs were utilized. These findings suggested that feline and human, but not canine, AMSCs are suitable for cell transplantation trials. This study aimed to further evaluate the feasibility of utilizing canine AMSCs for transplantation purposes as well as for felines. We tested teratoma formation following cell injection into BALB/c nude mice and then assessed expression of haematopoietic, mesenchymal, tumorigenic, pluripotency and cellular regulation markers using flow cytometry and qPCR. The use of canine AMSCs did not result in macroscopic tumour formation as determined 60 days after transplantation. The immunophenotypic characterization by flow cytometry revealed expression of mesenchymal markers (CD73 and CD90) and expression of the pluripotent marker OCT4 and SOX2. Quantitative PCR analysis revealed that there were no differences in the patterns of gene expression (CD34, CD73, OCT4, CD30 and P53) between canine and feline AMSCs, with the exception of the expression of SOX2 and CD90. PMID- 27774701 TI - Integrating personalised genomics into risk stratification models of population screening for colorectal cancer. PMID- 27774698 TI - The macro domain as fusion tag for carrier-driven crystallization. AB - Obtaining well-ordered crystals remains a significant challenge in protein X-ray crystallography. Carrier-driven crystallization can facilitate crystal formation and structure solution of difficult target proteins. We obtained crystals of the small and highly flexible SPX domain from the yeast vacuolar transporter chaperone 4 (Vtc4) when fused to a C-terminal, non-cleavable macro tag derived from human histone macroH2A1.1. Initial crystals diffracted to 3.3 A resolution. Reductive protein methylation of the fusion protein yielded a new crystal form diffracting to 2.1 A. The structures were solved by molecular replacement, using isolated macro domain structures as search models. Our findings suggest that macro domain tags can be employed in recombinant protein expression in E. coli, and in carrier-driven crystallization. PMID- 27774702 TI - Risk factors, incidence, consequences and prevention strategies for falls and fall-injury within older indigenous populations: a systematic review. AB - OBJECTIVE: To examine the risk factors, incidence, consequences and existing prevention strategies for falls and fall-related injury in older indigenous people. METHODS: Relevant literature was identified through searching 14 electronic databases, a range of institutional websites, online search engines and government databases, using search terms pertaining to indigenous status, injury and ageing. RESULTS: Thirteen studies from Australia, the United States, Central America and Canada were identified. Few studies reported on fall rates but two reported that around 30% of indigenous people aged 45 years and above experienced at least one fall during the past year. The most common hospitalised fall injuries among older indigenous people were hip fracture and head injury. Risk factors significantly associated with falls within indigenous populations included poor mobility, a history of stroke, epilepsy, head injury, poor hearing and urinary incontinence. No formally evaluated, indigenous-specific fall prevention interventions were identified. CONCLUSION: Falls are a significant and growing health issue for older indigenous people worldwide that can lead to severe health consequences and even death. No fully-evaluated, indigenous specific fall prevention programs were identified. Implications for Public Health: Research into fall patterns and fall-related injury among indigenous people is necessary for the development of appropriate fall prevention interventions. PMID- 27774703 TI - Association of beta-blocker treatment with mortality following myocardial infarction in patients with chronic obstructive pulmonary disease and heart failure or left ventricular dysfunction: a propensity matched-cohort analysis from the High-Risk Myocardial Infarction Database Initiative. AB - AIMS: To determine the influence of baseline beta-blocker use on long-term prognosis of myocardial infarction (MI) survivors complicated with heart failure (HF) or with left ventricular dysfunction and with history of chronic obstructive pulmonary disease (COPD). METHODS AND RESULTS: Among the 28 771 patients from the High-Risk MI Database Initiative we identified 1573 patients with a baseline history of COPD. We evaluated the association between beta-blocker use at baseline (822 with beta-blocker and 751 without) on the rates of all-cause and cardiovascular mortality. On univariable Cox analysis, beta-blocker use was found to be associated with lower rates of both all-cause [hazard ratio (HR) = 0.61, 95% confidence interval (CI) 0.51-0.75, P < 0.0001] and cardiovascular mortality (HR = 0.63, 95% CI 0.51-0.78, P < 0.0001). After extensive adjustment for confounding, including 24 baseline covariates, COPD patients still benefited from beta-blocker usage (HR = 0.73, 95% CI 0.60-0.90, P = 0.002 for all-cause mortality; HR = 0.77, 95% CI 0.61-0.97, P = 0.025 for cardiovascular mortality). Adjusting for propensity scores (PS) constructed from the 24 aforementioned baseline characteristics provided similar results. In a cohort of 561 pairs of patients taking or not taking beta-blocker matched on PS using a 1:1 nearest neighbour matching method, patients treated with beta-blocker experienced fewer all-cause deaths (HR = 0.71, 95% CI 0.56-0.89, P = 0.003) and cardiovascular deaths (HR = 0.76, 95% CI 0.59-0.97, P = 0.032). CONCLUSIONS: In the specific setting of a well-treated cohort of high-risk MI survivors, beta-blockers were associated with better outcomes in patients with COPD. PMID- 27774704 TI - The association between exposure to interpersonal violence and suicide among women: a systematic review. AB - OBJECTIVE: To review the association between exposure to interpersonal violence and suicide among women. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P), this review examined articles identified by using the key terms 'interpersonal violence', 'suicide' and 'death'. Of 5,536 articles identified, 38 met the a priori inclusion criteria. These required that studies examined interpersonal violence, included women and completed suicide was a measured outcome. RESULTS: Thirty eight studies were identified. These examined suicides among women exposed to interpersonal violence as a victim (n=27) or perpetrator (n=14). A history of interpersonal violence was identified in 3.5-62.5% of female suicides, with many articles finding victims of abuse have an increased risk of death from suicide. Females perpetrating violence may also be at increased the risk of death from suicide. However, several papers have questioned these associations. Further, the contribution of mental illness to this association is unclear. CONCLUSIONS: Although the association between suicide and interpersonal violence requires further investigation, being a victim or perpetrator of violence appears to be associated with risk of suicide. Future research should focus on the impact that the type of violence, victim-perpetrator relationship and proximity of violence has on the risk of death from suicide. Implications for Public Health: There may be significant opportunity for targeted suicide prevention strategies among women who have been victims or perpetrators of interpersonal violence. PMID- 27774705 TI - Adolescent inhalant abuse leads to other drug use and impaired growth; implications for diagnosis. AB - OBJECTIVE: Abuse of inhalants containing the volatile solvent toluene is a significant public health issue, especially for adolescent and Indigenous communities. Adolescent inhalant abuse can lead to chronic health issues and may initiate a trajectory towards further drug use. Identification of at-risk individuals is difficult and diagnostic tools are limited primarily to measurement of serum toluene. Our objective was to identify the effects of adolescent inhalant abuse on subsequent drug use and growth parameters, and to test the predictive power of growth parameters as a diagnostic measure for inhalant abuse. METHODS: We retrospectively analysed drug use and growth data from 118 Indigenous males; 86 chronically sniffed petrol as adolescents. RESULTS: Petrol sniffing was the earliest drug used (mean 13 years) and increased the likelihood and earlier use of other drugs. Petrol sniffing significantly impaired height and weight and was associated with meeting 'failure to thrive' criteria; growth diagnostically out-performed serum toluene. CONCLUSIONS: Adolescent inhalant abuse increases the risk for subsequent and earlier drug use. It also impairs growth such that individuals meet 'failure to thrive' criteria, representing an improved diagnostic model for inhalant abuse. Implications for Public Health: Improved diagnosis of adolescent inhalant abuse may lead to earlier detection and enhanced health outcomes. PMID- 27774706 TI - Most recent risky drinking session with Australian teenagers. AB - OBJECTIVE: Despite declines in Australian alcohol consumption, youth alcohol related harms remain prevalent. These alcohol-related consequences appear to be driven by a subset of risky drinkers who engage in 'high intensity' drinking episodes and are underrepresented in national health surveys. This project aims to investigate high risk drinking practices and alcohol-related harms amongst young people not otherwise recorded in existing data. METHODS: A community sample of the heaviest drinking 20-25% 16-19 year olds were surveyed across three Australian states (n=958; 80% metropolitan). We examined the context of their last risky drinking session through online and face-to-face surveys. RESULTS: Males consumed a mean of 17 and females 14 standard drinks, and 86% experienced at least one alcohol-related consequence during this session. More than a quarter of the face-to-face sample had Alcohol Use Disorders Identification Test (AUDIT) scores indicative of alcohol dependence. Indications of dependence were 2.3 times more likely among those who felt uncomfortable about seeking alcohol treatment, and less likely if harm reduction strategies were frequently used while drinking. CONCLUSIONS: It is clear this underrepresented population experiences substantial acute and potentially chronic consequences. IMPLICATIONS: Within the context of increasing alcohol-related harms among young Australians, the understanding of this group's drinking habits should be prioritised. PMID- 27774707 TI - Bocavirus infection following paediatric liver transplantation. AB - HBoV is an emergent virus, which is frequently detected as a co-infective agent. However, it can cause disease on its own. It is associated with respiratory and diarrhoeal illness in children and adults, whether immunocompetent or immunocompromised. We report HBoV infection in a child post-liver transplantation, who presented with persistent fever and mild tachypnea, 3 weeks after a successful transplant. She recovered spontaneously with no graft dysfunction. PMID- 27774708 TI - Falls from ladders in Australia: comparing occupational and non-occupational injuries across age groups. AB - OBJECTIVE: To examine national ladder-related fall injury patterns and trends, and compare the changes over time in occupational and non-occupational falls across age groups. METHODS: Analysis of national hospital morbidity data to examine trends over time and differences between groups. RESULTS: There were 41,092 hospitalised falls from ladders in Australia over the ten year period from July 2002 to June 2012, rising from 3,374 hospitalisations in 2002/03 to 4,945 hospitalisations in 2011/12. The age standardised rate of ladder-related fall hospitalisations rose significantly for males, and a higher increase was evident in people aged over 60 years. Occupational falls accounted for 20% of hospitalisations, and the hospitalisation rate for both occupational and non occupational falls increased significantly over the ten year period. CONCLUSIONS: With almost 5,000 hospital admissions per year in recent years and a significant rise in the rate of hospitalisations over the past decade, this paper highlights the importance of focusing injury prevention efforts to reduce the growing number of ladder-related falls. IMPLICATIONS: This study demonstrates the significant burden that ladder-related falls are continuing to have on the community, both in the occupational and domestic setting. PMID- 27774709 TI - The effect of Korean-group cognitive behavioural therapy among patients with panic disorder in clinic settings. AB - : WHAT IS KNOWN ON THE SUBJECT?: Panic disorder patients display various panic related physical symptoms and catastrophic misinterpretation of bodily sensations, which lower their quality of life by interfering with daily activities. Cognitive behavioural therapy (CBT) is a useful strategy for panic disorder patients to manage symptoms associated with inaccurate cognitive interpretation of situations resulting from the patient's cognitive vulnerability. In South Korea, however, despite the increasing prevalence of panic disorder, CBT is not a common element of nursing care plans for panic disorder patients. Moreover, few Korean researchers have attempted to assess the effects of CBT on such patients. WHAT THIS PAPER ADD TO EXISTING KNOWLEDGE?: In a strategy combining CBT and routine treatments, patients with panic disorder can experience greater positive effects in the acute treatment phase than those they experience when receiving only routine treatment. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Mental health professionals, especially psychiatric nurses in local clinics who operate most special mental health programmes for panic disorder patients, should apply a panic disorder management programme that integrates CBT and routine treatments. The integrated approach is more effective for reducing the number of panic attacks and cognitive misinterpretation in patients than providing routine treatment alone. For patients with panic disorder, the objective of CBT is to understand the relationship between psychological panic disorder sensations, emotions, thoughts and behaviours. Therefore, nurses can help patients address and improve biological, social and psychological aspects of physical health problems as well as help them improve their coping skills in general. ABSTRACT: Introduction In panic disorder, sensitivity to bodily sensations increases due to the patient's cognitive vulnerability. Cognitive behavioural therapy (CBT) can help to decrease sensitivity to bodily sensations by correcting these cognitive distortions by controlling negative thoughts and panic attacks. Aims This study verified whether group CBT is more effective than treatment as usual (TAU) in South Korean patients with panic disorder. Methods The study participants consisted of 76 panic disorder patients. Patients in the therapy condition attended sessions once a week for a total of 12 sessions in addition to drug treatment. Results In the therapy condition, there were significant decreases in panic-related bodily sensations and ranking and belief scores for catastrophic misinterpretation of external events. Discussion Group CBT, in comparison to TAU, decreases panic and agoraphobia symptom severity in South Korean patients with panic disorder. Our study provides evidence for the effectiveness of a panic disorder management programme that integrates group CBT and traditional pharmacotherapeutic treatment for patients with panic disorder. Implications for Practice The cognitive behavioural approach is needed to reduce panic and agoraphobia symptoms for hospitalized patients with panic disorder more than activity therapies, medications and supportive counselling by doctors and nurses. PMID- 27774710 TI - Closing the Aboriginal child injury gap: targets for injury prevention. AB - OBJECTIVE: To describe the leading mechanisms of hospitalised unintentional injury in Australian Aboriginal children and identify the injury mechanisms with the largest inequalities between Aboriginal and non-Aboriginal children. METHODS: We used linked hospital and mortality data to construct a whole of population birth cohort including 1,124,717 children (1,088,645 non-Aboriginal and 35,749 Aboriginal) born in the state of New South Wales (NSW), Australia, between 1 July 2000 and 31 December 2012. Injury hospitalisation rates were calculated per person years at risk for injury mechanisms coded according to the ICD10-AM classification. RESULTS: The leading injury mechanisms in both groups of children were falls from playground equipment. For 66 of the 69 injury mechanisms studied, Aboriginal children had a higher rate of hospitalisation compared with non Aboriginal children. The largest relative inequalities were observed for injuries due to exposure to fire and flame, and the largest absolute inequalities for injuries due to falls from playground equipment. CONCLUSION: Aboriginal children in NSW experience a significant higher burden of unintentional injury compared with their non-Aboriginal counterparts. Implications for Public Health: We suggest the implementation of targeted injury prevention measures aimed at injury mechanism and age groups identified in this study. PMID- 27774711 TI - Versatile Catalytic Hydrogenation Using A Simple Tin(IV) Lewis Acid. AB - Despite the rapid development of frustrated Lewis pair (FLP) chemistry over the last ten years, its application in catalytic hydrogenations remains dependent on a narrow family of structurally similar early main-group Lewis acids (LAs), inevitably placing limitations on reactivity, sensitivity and substrate scope. Herein we describe the FLP-mediated H2 activation and catalytic hydrogenation activity of the alternative LA iPr3 SnOTf, which acts as a surrogate for the trialkylstannylium ion iPr3 Sn+ , and is rapidly and easily prepared from simple, inexpensive starting materials. This highly thermally robust LA is found to be competent in the hydrogenation of a number of different unsaturated functional groups (which is unique to date for main-group FLP LAs not based on boron), and also displays a remarkable tolerance to moisture. PMID- 27774712 TI - The histological quantification of alpha-smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients. AB - Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, "baseline" and "follow-up" biopsies taken at 1- to 2 year intervals from 18 stable pediatric LT recipients, transplanted between 2006 and 2012 were selected. Morphometric quantification of "ASMA-positive area percentage" was performed on the baseline biopsy. Histological and fibrosis assessment using Metavir and LAFSc was performed on all biopsies. The difference of fibrosis severity between the "baseline" and "follow-up" was termed "prospective change in fibrosis." Significant association was seen between extent of ASMA positivity on baseline biopsy and "prospective change in fibrosis" using Metavir (P=.02), cumulative LAFSc (P=.02), and portal LAFSc (P=.01) values. ASMA positive area percentage >1.05 predicted increased fibrosis on next biopsy with 90.0% specificity. Additionally, an association was observed between extent of ASMA positivity and concomitant ductular reaction (P=.06), but not with histological inflammation in the portal tract or lobular area. Hence, ASMA quantification can predict the future course of fibrosis. PMID- 27774714 TI - Synthesis of Mesoporous Lithium Titanate Thin Films and Monoliths as an Anode Material for High-Rate Lithium-Ion Batteries. AB - Mesoporous Li4 Ti5 O12 (LTO) thin film is an important anode material for lithium ion batteries (LIBs). Mesoporous films could be prepared by self-assembly processes. A molten-salt-assisted self-assembly (MASA) process is used to prepare mesoporous thin films of LTOs. Clear solutions of CTAB, P123, LiNO3 , HNO3 , and Ti(OC4 H9 )4 in ethanol form gel-like meso-ordered films upon either spin or spray coating. In the assembly process, the CTAB/P123 molar ratio of 14 is required to accommodate enough salt species in the mesophase, in which the LiI /P123 ratio can be varied between molar ratios of 28 and 72. Calcination of the meso-ordered films produces transparent mesoporous spinel LTO films that are abbreviated as Cxx-yyy-zzz or CAxx-yyy-zzz (C=calcined, CA=calcined-annealed, xx=LiI /P123 molar ratio, and yyy=calcination and zzz=annealing temperatures in Celsius) herein. All samples were characterized by using XRD, TEM, N2 -sorption, and Raman techniques and it was found that, at all compositions, the LTO spinel phase formed with or without an anatase phase as an impurity. Electrochemical characterization of the films shows excellent performance at different current rates. The CA40-350-450 sample performs best among all samples tested, yielding an average discharge capacity of (176+/-1) mA h g-1 at C/2 and (139+/-4) mA h g-1 at 50 C and keeping 92 % of its initial discharge capacity upon 50 cycles at C/2. PMID- 27774713 TI - On the brain structure heterogeneity of autism: Parsing out acquisition site effects with significance-weighted principal component analysis. AB - Neuroimaging studies have reported structural and physiological differences that could help understand the causes and development of Autism Spectrum Disorder (ASD). Many of them rely on multisite designs, with the recruitment of larger samples increasing statistical power. However, recent large-scale studies have put some findings into question, considering the results to be strongly dependent on the database used, and demonstrating the substantial heterogeneity within this clinically defined category. One major source of variance may be the acquisition of the data in multiple centres. In this work we analysed the differences found in the multisite, multi-modal neuroimaging database from the UK Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) in terms of both diagnosis and acquisition sites. Since the dissimilarities between sites were higher than between diagnostic groups, we developed a technique called Significance Weighted Principal Component Analysis (SWPCA) to reduce the undesired intensity variance due to acquisition site and to increase the statistical power in detecting group differences. After eliminating site-related variance, statistically significant group differences were found, including Broca's area and the temporo-parietal junction. However, discriminative power was not sufficient to classify diagnostic groups, yielding accuracies results close to random. Our work supports recent claims that ASD is a highly heterogeneous condition that is difficult to globally characterize by neuroimaging, and therefore different (and more homogenous) subgroups should be defined to obtain a deeper understanding of ASD. Hum Brain Mapp 38:1208-1223, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27774715 TI - Real-Time NMR Studies of Oxyamine Ligations of Reducing Carbohydrates under Equilibrium Conditions. AB - Ligation reactions at the anomeric center of carbohydrates have gained increasing importance in the field of glycobiology. Oxyamines are frequently used in labeling, immobilization, and bioconjugation of reducing carbohydrates. Herein, we present a systematic investigation of these ligation reactions under aqueous conditions. A series of four unprotected monosaccharides (glucose, N acetylglucosamine, mannose, and 2-deoxyglucose) and one disaccharide (N,N' diacetylchitobiose) was reacted with three primary and one secondary oxyamine. We monitored the concentrations of the starting materials and products by 1 H NMR spectroscopy and determined reaction times and equilibrium yields. Our experiments show that the outcome of the ligation reaction is not only dependent on the sugar and oxyamine used but also strongly on the reaction conditions. In the case of glucose, lowering the pH from 6 to 3 led to steadily increasing reaction rates, whereas the yields were decreasing at the same time. Variation of the temperature did not only influence the product ratio in equilibrium but can also have a strong impact on the equilibrium yield. In the case of reactions of a primary oxyamine, increased temperatures led to a higher proportion of acyclic products. Reaction of the secondary oxyamine with glucose unexpectedly led to lower yields at higher temperatures. PMID- 27774716 TI - The perceived value of clinical pharmacy service provision by pharmacists and physicians: an initial assessment of family medicine and internal medicine providers. AB - BACKGROUND: Few publications have addressed the perceptions of pharmacists and physicians regarding the value of clinical pharmacist services. A survey-based study was conducted to determine whether Internal Medicine (IM) and Family Medicine (FM) pharmacists and physicians differed in their attitudes regarding the benefits of collaboration in an acute care setting. OBJECTIVES: The primary objective was to evaluate perceived differences regarding self-assessment of value between IM and FM pharmacists. The secondary objective was to evaluate perceived differences of clinical pharmacist benefit between IM and FM physicians. METHODS: An eight-item questionnaire assessed the attitudes and beliefs of pharmacists and physicians regarding the value of clinical pharmacy services. Surveys were emailed and participants marked their responses using a 7 point Likert scale for each item. Demographic data and overall comments were collected from each participant. KEY FINDINGS: Overall, 167 surveys were completed. When comparing cumulative physician and pharmacist responses, none of the eight questions showed significant differences. Statistically significant differences were noted when comparing IM and FM clinical pharmacists on five of the eight survey items; for each of these items, FM pharmacists had more favourable perceptions than their IM counterparts. No statistically significant differences were noted when comparing responses of IM and FM physicians. CONCLUSIONS: This study found that FM pharmacists perceived a greater benefit regarding participation in inpatient acute care rounds when compared to their IM pharmacist counterparts. Future studies are necessary to determine if other medical specialties' perceptions of clinical pharmacy provision differ from our findings and to evaluate the rationale behind specific attitudes and behaviours. PMID- 27774717 TI - Evaluation and comparison of tools for diagnosing problematic prescription opioid use among chronic pain patients. AB - Prescription opioid medications are commonly used for the treatment of chronic pain. Assessments of problematic opioid use among pain patients are inconsistent across studies, partially due to differences between various measures. Therefore, the most appropriate measure to use is often unclear. In this study we assessed problematic opioid use in a sample of 551 individuals receiving treatment for chronic pain, using three questionnaires: the Alcohol Use Disorder and Associated Disabilities Interview Schedule - Fourth Edition (AUDADIS-IV), the Current Opioid Misuse Measure (COMM) questionnaire and Portenoy's criteria (PC). These questionnaires yielded discordant positive rates of problematic use: 52.6%, 28.7%, and 17.1%, respectively, which did not change substantially when excluding AUDADIS-IV criteria of physical symptoms of tolerance and withdrawal. Although these three questionnaires share some statistically correlated content-based congruent questions, positive response rates to them were significantly different based on construction features, including questionnaires' referred time-frame, wording of questions and response alternatives. The findings of the present study illustrate strengths and limitations of the AUDADIS-IV, COMM and PC in diagnosing problematic opioid use in a population of adults suffering from chronic pain, and highlight the importance of recognizing and addressing specific questionnaire and question-related differences when identifying problematic opioid use in this population. PMID- 27774718 TI - A review of the public health management of shigellosis in Australia in the era of culture-independent diagnostic testing. AB - OBJECTIVE: To review the national case definition for shigellosis following the introduction of culture independent diagnostic testing by clinical laboratories and provide evidence to reform jurisdictional public health practices for the management shigellosis., . METHODS: A review of all Australian jurisdictional public health guidelines for shigellosis was conducted. Victorian 2014 shigellosis data were analysed: demographics and risk factors for cases identified by conventional culture or culture-independent diagnostic methods were described. RESULTS: There was considerable variation in reporting of cases to the National Notifiable Disease Surveillance System (NNDSS) by the eight Australian jurisdictions, with an array of classifications based on diagnostic testing methodologies. Analysis of Victorian 2014 shigellosis data found that culture positive cases were more likely to have reported men who have sex with men (MSM) as a risk factor than PCR positive only cases (p<0.0001) and less likely to have reported overseas travel during their incubation period (p<0.0001). Over a 10 year period (2005 to 2014), only two of 86 cases who were employed in high-risk occupations had ongoing positive faecal cultures after appropriate treatment. CONCLUSIONS: The national surveillance case definition for shigellosis should be reviewed to facilitate standardised reporting across Australia. All jurisdictions must consider the public health significance of PCR positive only results in their surveillance risk assessments to inform management of shigellosis cases. PMID- 27774719 TI - Age of onset of obesity and risk of type 2 diabetes. AB - OBJECTIVE: To compare a simple measure - age of onset of obesity - to an obese years construct (a product of duration and magnitude of obesity) as risk factors for type 2 diabetes. METHOD: Participants from the Framingham Heart Study who were not obese and did not have diabetes at baseline were included (n=4,320). The Akaike Information Criterion (AIC) was computed to compare four Cox proportional hazards models with incident diabetes as the outcome and: (i) obese-years; (ii) age of onset of obesity; (iii) body mass index (BMI); and (iv) age of onset of obesity plus magnitude of BMI combined, as exposures. RESULTS: AIC indicated that the model with obese-years provided a more effective explanation of incidence of type 2 diabetes compared to the remaining three models. Models including age of onset of obesity plus BMI were not appreciably different from the model with BMI alone, except in those aged >=60. CONCLUSIONS: While obese-years was the optimal obesity construct to explain risk of type 2 diabetes, age of onset may be a useful, practical addition to current BMI in the elderly. IMPLICATIONS: Where computation of obese-years is not possible or impractical, age of onset of obesity combined with BMI may provide a useful alternative. PMID- 27774720 TI - Immunolocalization of proteins in the spermatogenesis process of canine. AB - Spermatogenesis is a process in which differentiated cells are produced and the adult stem cell population-known as spermatogonial stem cells (SSCs)-is continuously replenished. However, the molecular mechanisms underlying these processes are not fully understood in the canine species. We addressed this in this study by analysing the expression of specific markers in spermatogonia of seminiferous tubules of canine testes. SSCs at different stages of reproductive development (prepubertal and adult) were examined by immunohistochemistry and flow cytometry. Glial cell-derived neurotrophic factor family receptor alpha-1 (GFRA1), deleted in azoospermia-like (DAZL) and promyelocytic leukaemia zinc finger (PLZF) were expressed in SSCs, while stimulated by retinoic acid gene 8 (STRA8) was detected only in undifferentiated spermatogonia in prepubertal testis and differentiated spermatogonia and spermatocytes in adult canine. Octamer binding transcription factor 4 (OCT4) showed an expression pattern, and the levels did not differ between the groups examined. However, C-kit expression varied as a function of reproductive developmental stage. Our results demonstrate that these proteins play critical roles in the self-renewal and differentiation of SSCs and can serve as markers to identify canine spermatogonia at specific stages of development. PMID- 27774721 TI - Altered brain network integrity after childhood maltreatment: A structural connectomic DTI-study. AB - Childhood maltreatment is associated with alterations in neural architecture that potentially put these children at increased risk for psychopathology. Alterations in white matter (WM) tracts have been reported, however no study to date has investigated WM connectivity in brain networks in maltreated children to quantify global and local abnormalities through graph theoretical analyses of DTI data. We aimed for a multilevel investigation examining the DTI-based structural connectome and its associations with basal cortisol levels of 25 children with documented maltreatment experiences before age 3, and 24 matched controls (age: 10.6 +/- 1.75 years). On the global and lobar level, maltreated children showed significant reductions in global connectivity strength, local connectivity and increased path length, suggesting deviations from the small-world network architecture previously associated with psychopathology. Reductions in global connectivity were associated with placement instability, attenuated cortisol secretion and higher levels of internalizing and externalizing behaviours. Regional measures revealed lower connectivity strength especially in regions within the ventromedial prefrontal cortex (vMPFC) in maltreated children. These findings show that childhood maltreatment is associated with systemic global neurodevelopmental alterations in WM networks next to regional alterations in areas involved in the regulation of affect. These alterations in WM organization could underlie global functional deficits and multi-symptom patterns frequently observed in children with maltreatment experiences. Hum Brain Mapp 38:855-868, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27774722 TI - Heart transplant outcomes in recipients of Centers for Disease Control (CDC) high risk donors. AB - BACKGROUND: A lack of donor hearts remains a major limitation of heart transplantation. Hearts from Centers for Disease Control (CDC) high-risk donors can be utilized with specific recipient consent. However, outcomes of heart transplantation with CDC high-risk donors are not well known. We sought to define outcomes, including posttransplant hepatitis and human immunodeficiency virus (HIV) status, in recipients of CDC high-risk donor hearts at our institution. METHODS: All heart transplant recipients from August 2010 to December 2014 (n = 74) were reviewed. Comparison of 1) CDC high-risk donor (HRD) versus 2) standard risk donor (SRD) groups were performed using chi-squared tests for nominal data and Wilcoxon two-sample tests for continuous variables. Survival was estimated with Kaplan-Meier curves. RESULTS: Of 74 heart transplant recipients reviewed, 66 (89%) received a SRD heart and eight (11%) received a CDC HRD heart. We found no significant differences in recipient age, sex, waiting list 1A status, pretransplant left ventricular assist device (LVAD) support, cytomegalovirus (CMV) status, and graft ischemia times (p = NS) between the HRD and SRD groups. All of the eight HRD were seronegative at the time of transplant. Postoperatively, there was no significant difference in rejection rates at six and 12 months posttransplant. Importantly, no HRD recipients acquired hepatitis or HIV. Survival in HRD versus SRD recipients was not significantly different by Kaplan-Meier analysis (log rank p = 0.644) at five years posttransplant. CONCLUSION: Heart transplants that were seronegative at the time of transplant had similar posttransplant graft function, rejection rates, and five-year posttransplant survival versus recipients of SRD hearts. At our institution, no cases of hepatitis or HIV occurred in HRD recipients in early follow-up. PMID- 27774723 TI - Organic-Base-Driven Intercalation and Delamination for the Production of Functionalized Titanium Carbide Nanosheets with Superior Photothermal Therapeutic Performance. AB - The delamination of titanium carbide sheets, an intriguing class of two dimensional materials, has been critically dependent on the extraction of interlayer Al in acidic media, such as concentrated hydrofluoric acid (HF) or a mixture of hydrochloric acid (HCl) and a fluoride salt. Herein, we report an organic-base-driven intercalation and delamination of titanium carbide that takes advantage of the amphoteric nature of interlayer Al. The resulting aluminum oxoanion-functionalized titanium carbide sheets manifested unusually strong optical absorption in the near-infrared (NIR) region with a mass extinction coefficient as high as 29.1 L g-1 cm-1 at 808 nm. Thus, the performance of this material is comparable or even superior to that of state-of-the-art photoabsorption materials, including gold-based nanostructures, carbon-based materials, and transition-metal dichalcogenides. Preliminary studies show that the titanium carbide sheets serve as efficient photothermal agents against tumor cells. PMID- 27774724 TI - Modulated Luminescence of a Stable Open-Shell Triarylmethyl Radical: Effects of Chemical Modification on Its Electronic Structure and Physical Properties. AB - The open-shell luminescent (3,5-dichloro-4-pyridyl)bis(2,4,6 trichlorophenyl)methyl (PyBTM) radical contains a nitrogen atom that behaves as a stimulus-responsive site. Chemical modification at this nitrogen atom, such as coordination of B(C6 F5 )3 or methylation, shifts the emission maximum to the low energy region and increases the reduction potential. The emission colour may be regulated by the reversible Lewis acid-base reaction between B(C6 F5 )3 and PyBTM. Comparison of the optical and electrochemical properties of the radicals with the electronic structures calculated by density functional theory has indicated that the chemical modification decreased the energy level of the beta singly occupied molecular orbital, a key orbital in determining the optical and electrochemical properties of such systems. PMID- 27774725 TI - Nanoscale Biodegradable Organic-Inorganic Hybrids for Efficient Cell Penetration and Drug Delivery. AB - We report a comprehensive study on novel, highly efficient, and biodegradable hybrid molecular transporters. To this end, we designed a series of cell penetrating, cube-octameric silsesquioxanes (COSS), and investigated cellular uptake by confocal microscopy and flow cytometry. A COSS with dense spatial arrangement of guanidinium groups displayed fast uptake kinetics and cell permeation at nanomolar concentrations in living HeLa cells. Efficient uptake was also observed in bacteria, yeasts, and archaea. The COSS-based carrier was significantly more potent than cell-penetrating peptides (CPPs) and displayed low toxicity. It efficiently delivered a covalently attached cytotoxic drug, doxorubicin, to living tumor cells. As the uptake of fluorescently labeled carrier remained in the presence of serum, the system could be considered particularly attractive for the in vivo delivery of therapeutics. PMID- 27774726 TI - During warfarin induction, the Fiix-prothrombin time reflects the anticoagulation level better than the standard prothrombin time. AB - : Essentials Fiix-prothrombin time (PT) monitoring of warfarin measuring factor (F) II and X, is effective. Plasma obtained during warfarin induction and stable phase in Fiix-trial was assayed. Fiix-PT stabilized anticoagulation earlier than monitoring with traditional PT-INR. FVII had little effect on thrombin generation that was mainly determined by FII and FX. SUMMARY: Background The prothrombin time (PT) is equally prolonged by reduction of each of the vitamin K-dependent (VKD) factors (F) II, VII and X. The Fiix-PT is only affected by FII and FX, the main contributors to thrombin generation (TG). Objective To test the hypothesis that variability in warfarin anticoagulation is reduced early during monitoring with the normalized PT-ratio calculated from Fiix-PT (Fiix-International Normalized Ratio [INR]) compared with traditional PT-INR monitoring. Also, that because of its insensitivity to FVII, Fiix-PT more accurately reflects TG when Fiix-INR and PT-INR are discrepant. Methods Samples from Fiix-trial participants monitored with either Fiix-PT or PT were used. VKD coagulation factors and TG were measured in samples from 40 patients during stable anticoagulation and in serial samples obtained from 26 patients during warfarin induction. TG was assessed in relation to selective reduction in single VKD factors. Results During Fiix-warfarin induction full anticoagulation measured as FII or FX activity was achieved at a similar rate to that with PT-warfarin but subsequently stabilized better. Fiix-INR but not PT-INR mirrored total TG during initiation. During induction, FII (R2 = 0.66) and FX (R2 = 0.52) correlated better with TG and with a steeper slope than did FIX (R2 = 0.37) and in particular FVII (R2 = 0.21). In vitro, FII and FX were the main determinants of TG at concentrations observed during VKA anticoagulation, whereas FVII and FIX had little influence. Conclusions Fiix-PT monitoring reduces anticoagulation variability, suggesting that monitoring FVII has a limited role during VKA management. TG is better reflected by Fiix-PT. PMID- 27774727 TI - Simultaneous Chain-Growth and Step-Growth Polymerization of Methoxystyrenes by Rare-Earth Catalysts. AB - The simultaneous chain-growth and step-growth polymerization of a monomer is of great interest and importance because it can produce unique macromolecules which are difficult to prepare by other means. However, such a transformation is usually difficult to achieve in one polymerization system because chain-growth polymerization and step-growth polymerization proceed by different reaction mechanisms. Reported here is the simultaneous chain-growth and step-growth polymerization of para- and meta-methoxystyrenes catalyzed by half-sandwich rare earth alkyl complexes, and the step-growth polymerization proceeds by the C-H polyaddition of anisyl units to vinyl groups. This unprecedented transformation affords a new family of macromolecules containing unique alternating anisole ethylene sequences. In contrast to para- and meta-methoxystyrenes, ortho methoxystyrene exclusively undergo syndiospecific, living chain-growth polymerization by continuous C=C bond insertion to give perfect syndiotactic poly(ortho-methoxystyrene) with high molecular weight and narrow polydispersity (rrrr >99 %, Mn up to 280 kg mol-1 , Mw /Mn <1.10). PMID- 27774728 TI - Mycoestrogen determination in cow milk: Magnetic solid-phase extraction followed by liquid chromatography and tandem mass spectrometry analysis. AB - Recently, magnetic solid-phase extraction has gained interest because it presents various operational advantages over classical solid-phase extraction. Furthermore, magnetic nanoparticles are easy to prepare, and various materials can be used in their synthesis. In the literature, there are only few studies on the determination of mycoestrogens in milk, although their carryover in milk has occurred. In this work, we wanted to develop the first (to the best of our knowledge) magnetic solid-phase extraction protocol for six mycoestrogens from milk, followed by liquid chromatography and tandem mass spectrometry analysis. Magnetic graphitized carbon black was chosen as the adsorbent, as this carbonaceous material, which is very different from the most diffuse graphene and carbon nanotubes, had already shown selectivity towards estrogenic compounds in milk. The graphitized carbon black was decorated with Fe3 O4 , which was confirmed by the characterization analyses. A milk deproteinization step was avoided, using only a suitable dilution in phosphate buffer as sample pretreatment. The overall process efficiency ranged between 52 and 102%, whereas the matrix effect considered as signal suppression was below 33% for all the analytes even at the lowest spiking level. The obtained method limits of quantification were below those of other published methods that employ classical solid-phase extraction protocols. PMID- 27774729 TI - Efficient methods for isolating five phytochemicals from Gentiana macrophylla using high-performance countercurrent chromatography. AB - Efficient high-performance countercurrent chromatography methods were developed to isolate five typical compounds from the extracts of Gentiana macrophylla. n Butanol-soluble extract of G. macrophylla contained three hydrophilic iridoids, loganic acid (1), swertiamarin (2) and gentiopicroside (3), and a chromene derivative, macrophylloside D (4) which were successfully isolated by flow rate gradient (1.5 mL/min in 0-60 min, 5.0 mL/min in 60-120 min), and consecutive flow rate gradient HPCCC using n-butanol/0.1% aqueous trifluoroacetic acid (1:1, v/v, normal phase mode) system. The yields of 1-4 were 22, 16, 122, and 6 mg, respectively, with purities over 97% in a flow rate gradient high-performance countercurrent chromatography, and consecutive flow rate gradient high performance countercurrent chromatography gave 1, 2, 3 (54, 41, 348 mg, respectively, purities over 97%) and 4 (13 mg, purity at 95%) from 750 mg of sample. The main compound in methylene chloride soluble extract, 2 methoxyanofinic acid, was successfully separated by n-hexane/ethyl acetate/methanol/water (4:6:4:6, v/v/v/v, flow-rate: 4 mL/min, reversed phase mode) condition. The structures of five isolates were elucidated by 1 H, 13 C NMR and ESI-Q-TOF-MS spectroscopic data which were compared with previously reported values. PMID- 27774730 TI - Hyperprolactinemia in end-stage renal disease and effects of frequent hemodialysis. AB - INTRODUCTION: End-stage renal disease is associated with elevations in circulating prolactin concentrations, but the association of prolactin concentrations with intermediate health outcomes and the effects of hemodialysis frequency on changes in serum prolactin have not been examined. METHODS: The FHN Daily and Nocturnal Dialysis Trials compared the effects of conventional thrice weekly hemodialysis with in-center daily hemodialysis (6 days/week) and nocturnal home hemodialysis (6 nights/week) over 12 months and obtained measures of health related quality of life, self-reported physical function, mental health and cognition. Serum prolactin concentrations were measured at baseline and 12-month follow-up in 70% of the FHN Trial cohort to examine the associations among serum prolactin concentrations and physical, mental and cognitive function and the effects of hemodialysis frequency on serum prolactin. FINDINGS: Among 177 Daily Trial and 60 Nocturnal Trial participants with baseline serum prolactin measurements, the median serum prolactin concentration was 65 ng/mL (25th-75th percentile 48-195 ng/mL) and 81% had serum prolactin concentrations >30 ng/mL. While serum prolactin was associated with sex (higher in women), we observed no association between baseline serum prolactin and age, dialysis vintage, and baseline measures of physical, mental and cognitive function. Furthermore, there was no significant effect of hemodialysis frequency on serum prolactin in either of the two trials. DISCUSSION: Serum prolactin concentrations were elevated in the large majority of patients with ESRD, but were not associated with several measures of health status. Circulating prolactin levels also do not appear to decrease in response to more frequent hemodialysis over a one-year period. PMID- 27774731 TI - Impact of phosphoproteomics in the translation of kinase-targeted therapies. AB - Signaling pathways driven by protein and lipid kinases are altered in most human diseases. Therefore, pharmacological inhibitors of cell signaling are one of the most intensively pursued therapeutic approaches for the treatment of diseases such as cancer, neurodegeneration, and metabolic syndromes. Phosphoproteomics is a technique that measures the products of kinase activities and, with the appropriate bioinformatics techniques, the methodology can also provide measures of kinase pathway activation and network circuitry. Hence, due to recent technological advantages, LC-MS-based quantitative phosphoproteomics provides relevant information for the design and implementation of kinase inhibitor based therapies. Here, we review how phosphoproteome profiling is being used in translational research as a means to identify drug targets and biomarkers for personalizing therapies based on kinase inhibitors. PMID- 27774732 TI - Hydrogen Sulfide Donors Activated by Reactive Oxygen Species. AB - Hydrogen sulfide (H2 S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H2 S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)-triggered H2 S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H2 S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H2 S until triggered by ROS, such as hydrogen peroxide (H2 O2 ), superoxide (O2- ), and peroxynitrite (ONOO- ). We demonstrate ROS-triggered H2 S donation in live cells and also demonstrate that PeroxyTCM-1 provides protection against H2 O2 -induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H2 S-related therapies. PMID- 27774734 TI - Fronto-temporal connectivity predicts cognitive empathy deficits and experiential negative symptoms in schizophrenia. AB - Impaired cognitive empathy is a core social cognitive deficit in schizophrenia associated with negative symptoms and social functioning. Cognitive empathy and negative symptoms have also been linked to medial prefrontal and temporal brain networks. While shared behavioral and neural underpinnings are suspected for cognitive empathy and negative symptoms, research is needed to test these hypotheses. In two studies, we evaluated whether resting-state functional connectivity between data-driven networks, or components (referred to as, inter component connectivity), predicted cognitive empathy and experiential and expressive negative symptoms in schizophrenia subjects. Study 1: We examined associations between cognitive empathy and medial prefrontal and temporal inter component connectivity at rest using a group-matched schizophrenia and control sample. We then assessed whether inter-component connectivity metrics associated with cognitive empathy were also related to negative symptoms. Study 2: We sought to replicate the connectivity-symptom associations observed in Study 1 using an independent schizophrenia sample. Study 1 results revealed that while the groups did not differ in average inter-component connectivity, a medial-fronto-temporal metric and an orbito-fronto-temporal metric were related to cognitive empathy. Moreover, the medial-fronto-temporal metric was associated with experiential negative symptoms in both schizophrenia samples. These findings support recent models that link social cognition and negative symptoms in schizophrenia. Hum Brain Mapp 38:1111-1124, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27774733 TI - Maternal and infant affect at 4 months predicts performance and verbal IQ at 4 and 7 years in a diverse population. AB - Using existing longitudinal data from 570 infants in the Maternal Lifestyle Study, we explored the predictive value of maternal and infant affect and maternal vocalizations during 2 minutes of face-to-face interactions at 4 months on IQ scores at 4.5 and 7 years. After controlling for demographic factors, maternal depression, and prenatal drug exposure, maternal positive affect and maternal positive vocalizations emerged as predictors of both verbal and performance IQ at 4.5 and 7 years. Although infant positive affect during the interaction with the mother was not predictive of these outcome measures, infant positive affect towards an examiner predicted verbal but not performance IQ at 4.5 years. These results suggest that maternal positive affect may index emotional engagement in interaction that facilitates both verbal and nonverbal cognitive development, while infant social positive affect is specifically related to the acquisition of verbal reasoning abilities. These findings are significant because they are based on a discrete snapshot of observable behavior in infancy (just 2 minutes of interaction), because they extend the range of maternal behaviors and characteristics known to support positive developmental outcomes, and because they are derived from high-risk infants where prevention efforts may be beneficial. Potential mechanisms for these associations are discussed, as are the clinical implications for identifying dyads most in need of targeted interventions. PMID- 27774735 TI - Consumer knowledge about over-the-counter NSAIDs: they don't know what they don't know. AB - OBJECTIVE: To investigate consumers' knowledge about commonly purchased over-the counter (OTC) products containing ibuprofen. METHODS: Customers buying two popular OTC ibuprofen-containing products (NurofenTM or Nurofen PlusTM ) were asked to complete a short survey assessing their knowledge about the products. RESULTS: The survey was completed by 262 respondents, most of whom were older than 50 years of age; female; well-educated; with adequate functional health literacy. The majority correctly identified ibuprofen as an active ingredient and knew the correct intervals between doses. However, almost a third couldn't correctly identify the maximum daily dose and were unaware of some contraindications. Furthermore, fewer than half recognised potential side effects. Those who hadn't completed high school were significantly less likely to seek medical advice (when required) and significantly less likely to know when it was safe to take these products. CONCLUSIONS: The gaps in consumer knowledge, especially about the maximum daily dose, contraindications and potential side effects may be placing consumers at risk of experiencing ibuprofen-related adverse events. Implications for public health: Improving consumer knowledge to address these gaps in their understanding about the safe use of popular OTC ibuprofen-containing products is an important public health concern. PMID- 27774736 TI - Design of Potent Mannose 6-Phosphate Analogues for the Functionalization of Lysosomal Enzymes To Improve the Treatment of Pompe Disease. AB - Improving therapeutics delivery in enzyme replacement therapy (ERT) for lysosomal storage disorders is a challenge. Herein, we present the synthesis of novel analogues of mannose 6-phosphate (M6P), known as AMFAs and functionalized at the anomeric position for enzyme grafting. AMFAs are non-phosphate serum-resistant derivatives that efficiently bind the cation-independent mannose 6-phosphate receptor (CI-M6PR), which is the main pathway to address enzymes to lysosomes. One of the AMFAs was used to improve the treatment of the lysosomal myopathy Pompe disease, in which acid alpha-glucosidase (GAA) is defective. AMFA grafting on a M6P-free recombinant GAA led to a higher uptake of the GAA in adult Pompe fibroblasts in culture as compared to Myozyme, the M6P recombinant GAA. Moreover, the treatment of Pompe adult mice with the AMFA-grafted recombinant enzyme led to a remarkable improvement, even at low doses, in muscle functionality and regeneration, whereas Myozyme had limited efficacy. PMID- 27774737 TI - Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. AB - The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2. This exercise identified eight compounds that increased the thermal stability of PMM2. Of these, four compounds functioned as potential PCs that significantly increased the stability of several destabilizing and oligomerization mutants and also increased PMM activity in a disease model of cells overexpressing PMM2 mutations. Structural analysis revealed one of these compounds to provide an excellent starting point for chemical optimization since it passed tests based on a number of pharmacochemical quality filters. The present results provide the first proof-of-concept of a possible treatment for PMM2-CDG and describe a promising chemical structure as a starting point for the development of new therapeutic agents for this severe orphan disease. PMID- 27774739 TI - Physician agreement regarding the expansion of pharmacist professional activities in the management of patients with asthma. AB - BACKGROUND: Asthma control remains suboptimal in Canada. Expansion of pharmacist's professional activities offers the opportunity to improve the interdisciplinary management of patients with asthma. OBJECTIVE: The aim of this study was to determine the level of agreement of physicians regarding the expansion of pharmacists' professional activities in the management of asthma patients. METHODS: We conducted a survey of randomly selected Quebec physicians in family medicine, paediatrics and emergency medicine. A 102-item questionnaire, including 10 questions regarding pharmacist's expanded professional activities, was sent using the Tailored Design Method. Questions were answered on a 6-point Likert-like scale (0 - strong disagreement to 5 - strong agreement). RESULTS: With a 56% response rate, 421 (250 family medicine, 115 paediatric and 56 emergency medicine) physicians participated; the median years of practice (25%, 75%) was 13 (5-21) years and 69% of respondents were women. Physicians were in favour of the expansion of pharmacist's professional activities with strong endorsement rates (rating of >=4 on a maximum of 5) exceeding 60% for all but three activities: suggesting a written action plan to the physician (55%), adjusting the dose of prescribed asthma medication to achieve a therapeutic target (52%) and offering spirometry testing in pharmacies (45%). Emergency physicians, physicians with fewer years of practice, and those with a favourable perception of an interprofessional approach were associated with higher endorsement of these activities. CONCLUSION: Physicians are favourable to the expansion of pharmacist activities in the management of patients with asthma. More complex activities were less frequently endorsed. The characteristics of strong intenders have been identified. PMID- 27774741 TI - RETROSPECTIVE STUDY EVALUATING ASSOCIATIONS BETWEEN MIDLINE BRAIN SHIFT ON MAGNETIC RESONANCE IMAGING AND SURVIVAL IN DOGS DIAGNOSED WITH MENINGOENCEPHALITIS OF UNKNOWN ETIOLOGY. AB - Difficulty has been encountered when trying to identify ante mortem prognostic indicators for dogs with meningoencephalitis of unknown etiology (MUE). Identifying MRI imaging parameters associated with prognosis may impact treatment decision-making for clinician and owner. Our hypotheses for this retrospective cohort study are that dogs diagnosed with MUE that had midline shift on brain MRI would have a poorer survival compared to dogs without midline shift; and that younger age, lower weight, and low cerebrospinal fluid (CSF) cell count would be correlated with improved survival. Medical records were reviewed from two institutions. Inclusion criteria included: clinical signs referable to intracranial disease, brain MRI at presentation, abnormal CSF analysis, and negative infectious disease testing. Magnetic resonance imaging scans were evaluated for midline shift using the T2-weighted transverse image at the interthalamic adhesion and at the site of maximal deviation. Fifty-two dogs met the inclusion criteria. Median midline deviation was 0.12 cm. Median survival for dogs with no shift was 906 days and with shift was 84 days. Survival was not significantly different between groups (P = 0.11). This remained true when correcting for age (P = 0.22) and CSF TNCC (total nucleated cell count) (P = 0.12). Age at the time of diagnosis (P = 0.02) and CSF TNCC (P = 0.03) were significantly associated with survival. Cerebrospinal fluid protein value (P = 0.84) and weight (P = 0.82) were not significantly associated with survival. In this study of 52 dogs with MUE, MRI evidence of midline brain shift between 0.04 and 0.3 cm at the level of the interthalamic adhesion was not associated with shorter survival. PMID- 27774740 TI - Development and utilization of a new chemically-induced soybean library with a high mutation density . AB - Mutagenized populations have provided important materials for introducing variation and identifying gene function in plants. In this study, an ethyl methanesulfonate (EMS)-induced soybean (Glycine max) population, consisting of 21,600 independent M2 lines, was developed. Over 1,000 M4 (5) families, with diverse abnormal phenotypes for seed composition, seed shape, plant morphology and maturity that are stably expressed across different environments and generations were identified. Phenotypic analysis of the population led to the identification of a yellow pigmentation mutant, gyl, that displayed significantly decreased chlorophyll (Chl) content and abnormal chloroplast development. Sequence analysis showed that gyl is allelic to MinnGold, where a different single nucleotide polymorphism variation in the Mg-chelatase subunit gene (ChlI1a) results in golden yellow leaves. A cleaved amplified polymorphic sequence marker was developed and may be applied to marker-assisted selection for the golden yellow phenotype in soybean breeding. We show that the newly developed soybean EMS mutant population has potential for functional genomics research and genetic improvement in soybean. PMID- 27774742 TI - Enantioselective comprehensive two-dimensional gas chromatography of lavender essential oil. AB - The enantiomeric composition of several chiral markers in lavender essential oil was studied by flow modulated comprehensive two-dimensional gas chromatography operated in the reverse flow mode and hyphenated to flame ionization and quadrupole mass spectrometric detection. Two capillary column series were used in this study, 2,3-di-O-ethyl-6-O-tert-butyldimethylsilyl-beta-cyclodextrin or 2,3,6 tri-O-methyl-beta-cyclodextrin, as the chiral column in the first dimension and alpha polyethylene glycol column in the second dimension. Combining the chromatographic data obtained on these column series, the enantiomeric and excess ratios for alpha-pinene, beta-pinene, camphor, lavandulol, borneol, and terpinen 4-ol were determined. This maybe a possible route to assess the authenticity of lavender essential oil. PMID- 27774743 TI - Executive functioning in Spanish- and English-speaking Head Start preschoolers. AB - A growing percentage of low-income children in the United States come from Spanish-speaking homes and are dual language learners (DLLs). Recent research shows that bilingual children, compared to monolinguals, have enhanced executive functioning (EF), a set of foundational cognitive skills that predict higher social-emotional competence and academic achievement in preschool and beyond. Although this association has been found among children of different backgrounds, no study to date has assessed whether bilingual Latino preschoolers from low income backgrounds have higher EF than their monolingual peers and their emerging bilingual peers, respectively. The current study assessed 303 predominantly Latino Head Start preschoolers (83.5% Latino and 13.5% African American) to examine this relationship. Using a language screener, three groups were formed (148 Spanish-English bilinguals, 83 English monolinguals, and 72 Spanish-dominant emerging bilinguals) and subsequently compared on a latent factor of EF. As predicted, results indicated that the bilingual group outperformed the monolingual English group on EF. Implications for the findings of the lack of EF differences between the Spanish-dominant emerging bilinguals and the other two groups are also discussed. This study advances our understanding of the intersection between language and cognitive development for young low-income Latino DLLs growing up in the United States and highlights bilingualism as a potential advantage in this population. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=J2Eq_MwLRfQ. PMID- 27774744 TI - SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. AB - The SATB2-associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2-associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations. (c) 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID- 27774745 TI - REPEATABILITY AND RELIABILITY OF GLOMERULAR FILTRATION RATE DETERMINATION VIA GAMMA CAMERA UPTAKE OF TC-99M-DTPA IN CATS WITH CHRONIC KIDNEY DISEASE. AB - Measurement of glomerular filtration rate (GFR) via gamma camera uptake of 99mTc diethylenetriaminepentaacetic acid is a standard method for quantifying renal function. Aims of this retrospective, observer agreement study were to determine intra- and interobserver variation in GFR values for cats with chronic kidney disease and to determine whether renal insufficiency classification changed between observers. Guideline cut-points were established for the difference in repeated GFRs to differentiate changes caused by therapeutic effect vs. inherent variation. Included cats had a diagnosis of chronic kidney disease and had undergone GFR examinations between the years of 2010 and 2013. Twenty-nine GFR studies were sampled. Each study was read twice, 6 months apart, by two veterinary radiologists and one radiology resident. Modified Bland-Altman plots were used to investigate differences between readings 1 and 2 by observer and between pairs of observers by reading. Reliability of clinical classification was assessed through comparisons between readings and observers. Measurements were not systematically different between readings for the experienced observers but were higher in reading 1 than reading 2 for the inexperienced observer. Measurements were not systematically different between the experienced observers in reading 1 or between any two observers in reading 2. Reliability for GFR measurements was high among experienced observers; variations in GFR measurements rarely led to differences in clinical classification. Results suggested that, for experienced observers, changes in GFR values following treatment in cats with chronic kidney disease between -0.4 and 0.4 mL/min/kg may be due to inherent variability rather than treatment effect. PMID- 27774746 TI - Prevalence of human papillomavirus, Epstein-Barr virus, and cytomegalovirus in fine needle aspirates from lung carcinoma: A case-control study with review of literature. AB - BACKGROUND: Oncogenic viruses have recently been allied with lung carcinoma, however, the causal association has not been established till date. The study was conducted to determine the prevalence of high-risk Human papillomavirus (HPV; subtypes 16, 18, 31, 33 and 45), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in lung carcinoma using polymerase chain reaction (PCR) on fine needle aspirates. METHODS: Fine needle aspirates of patients with lung carcinoma were included as cases. The control samples included normal lung tissue, collected at the time of medico legal autopsies. DNA was extracted from samples of both cases and controls and analysed by PCR for the presence of HPV, EBV and CMV. RESULTS: A total of 5/73 (6.8%) cases demonstrated the presence of HPV. Of these, 3 were positive for HPV-16 and one each for HPV-18 and HPV-45. A significant association of HPV with squamous cell carcinoma (SCC) (P = 0.01) was observed. Two cases were positive for EBV; however, the difference was not statistically significant for EBV (P = 0.5) as well as CMV. None of the controls were positive for HPV, EBV or CMV. CONCLUSION: We conclude that fine needle aspirates can serve as reliable sample for PCR based detection of viruses. A significantly higher prevalence of HPV in lung cancer and a significant association with SCC was observed, thereby, indicating a positive link between HPV and etiopathogenesis of lung carcinoma. Diagn. Cytopathol. 2016;44:987-993. (c) 2016 Wiley Periodicals, Inc. PMID- 27774747 TI - Improved quantification of collagen anisotropy with polarization-resolved second harmonic generation microscopy. AB - Imaging tissue samples by polarization-resolved second harmonic generation microscopy provides both qualitative and quantitative insights into collagen organization in a label-free manner. Polarization-resolved second harmonic generation microscopy goes beyond simple intensity-based imaging by adding the laser beam polarization component and applying different quantitative metrics such as the anisotropy factor. It thus provides valuable information on collagen arrangement not available with intensity measurements alone. Current established approaches are limited to calculating the anisotropy factor for only a particular laser beam polarization and no general guidelines on how to select the best laser beam polarization have yet been defined. Here, we introduce a novel methodology for selecting the optimal laser beam polarization for characterizing tissues using the anisotropy in the purpose of identifying cancer signatures. We show that the anisotropy factor exhibits a similar laser beam polarization dependence to the second harmonic intensity and we combine it with the collagen orientation index computed by Fast Fourier Transform analysis of the recorded images to establish a framework for choosing the laser beam polarization that is optimal for an accurate interpretation of polarization-resolved second harmonic generation microscopy images and anisotropy maps, and hence a better differentiation between healthy and dysplastic areas. SHG image of skin tissue (a) and a selected area of interest for which we compute the SHG intensity (b) and anisotropy factor (c) dependence on the laser beam polarization and also the FFT spectrum (d) to evaluate the collagen orientation index. PMID- 27774748 TI - Pretreatment 14-3-3 epsilon level is predictive for advanced extranodal NK/T cell lymphoma therapeutic response to asparaginase-based chemotherapy. AB - PURPOSE: The aim of the present study was to identify the potential relevant biomarkers to predict the therapeutic response of advanced extranodal natural killer/T cell lymphoma(ENKTL) treated with asparaginase-based treatment. EXPERIMENTAL DESIGN: Proteomic technology is used to identify differentially expressed proteins between chemotherapy-resistant and chemotherapy-sensitive patients. Then enzyme-linked immunosorbent assay is used to validate the predictive value of selective biomarkers. RESULTS: A total of 61 upregulated and 22 downregulated proteins are identified in chemotherapy-resistant patients compared with chemotherapy-sensitive patients. Furthermore, they validated that pretreatment high level 14-3-3 epsilon(epsilon)(>=61.95 ng/mL, 84.0 and 95.2% for sensitivity and specificity, respectively) is associated with poor 2-year overall survival (OS) (5.3 vs 68.8%, p<0.0001) and PFS (4.5 vs 76.9%, p<0.0001). In multivariate survival analysis, pretreatment high level 14-3-3 epsilon significantly is correlated with both inferior OS (p = 0.033) and PFS (p = 0.005). CONCLUSION AND CLINICAL RELEVANCE: These findings indicate that pretreatment high level 14-3-3 epsilon is an independent predictor of chemotherapy-resistance and poor prognosis for patients with advanced ENKTL in the era of asparaginase. PMID- 27774749 TI - IL-12B and IL-10 gene polymorphisms in the development of Hashimoto's thyroiditis. AB - Functional genetic polymorphisms that altered gene expression of cytokines are candidate genetic factors that could modulate the development and progression of Hashimoto's thyroiditis (HT). IL-12B gene encoded the IL-12p40 subunit, which is included in the pro-inflammatory heterodimeric cytokines IL-12p70 and IL-23. IL 10 is an important Treg cytokine suppressing inflammatory cytokine production and autoimmunity. This study was designed to compare -1082A/GIL-10 and +1188A/C3'UTRIL-12B genotype distribution in 130 patients with HT to a group of 157 healthy controls in attempts to determine an association with HT development. Genotyping for the 3'UTRA/C IL-12B polymorphism was performed using RFLP-PCR and genotyping for -1082A/G IL-10 by ARMS-PCR assay. Patients with HT were divided into euthyroid and hypothyroid stages. There were no significant differences in the genotype and allele frequencies of the IL-12B polymorphism between patients with HT and controls. We observed higher euthyroid HT risk for individuals with CC genotype, unlike to develop hypothyroidism with OR = 1.68. Regarding the polymorphism rs1800896, it was shown the significantly higher frequency of homozygous genotype GG in cases vs controls (OR = 2.19; P = 0.024). Moreover, the combination of genotype AA of 3'UTRIL-12B with GG of -1082IL-10 was associated with a threefold increasing risk (OR = 3.188; P = 0.022) of developing HT compared to individuals with the presence of 3'UTR allele C (AC+CC) simultaneously with AA genotype of -1082IL-10. Our data raise the possibility that the combined effect of polymorphisms from proinflammatory and anti inflammatory cytokines may be more decisive to HT development. PMID- 27774750 TI - Pulmonary hypertension in childhood interstitial lung disease: A systematic review of the literature. AB - Childhood interstitial lung disease (chILD) comprises a wide heterogeneous group of rare parenchymal lung disorders associated with substantial morbidity and mortality. Pulmonary hypertension is a common comorbidity in adults with interstitial lung disease (ILD) and associated with poor survival. We aimed to systematically review the literature regarding the occurrence of pulmonary hypertension (PH) in chILD, its effect on prognosis and healthcare use, and its treatment in clinical practice. Searches of PubMed and EMBASE databases (up to February 2016), and American Thoracic Society conference abstracts (2009-2015) were conducted using relevant keywords. References from selected articles and review papers were scanned to identify further relevant articles. A total of 20 articles were included; estimates of PH in chILD ranged from 1% to 64% with estimates among specific chILD entities ranging from 0% to 43%. Comparisons between studies were limited by differences in the study populations, including the size, age range, and heterogeneous composition of the ILD case series in terms of the nature and severity of the clinical entities, and also the methods used to diagnose PH. Three studies found that among patients with chILD, those with PH had a significantly higher risk (up to sevenfold) of death compared with those without PH. Information on the treatment of pulmonary hypertension in chILD or the effect of PH on healthcare use was not available. Data on the use and effectiveness of treatments for pulmonary hypertension in chILD are required to address this area of unmet need. Pediatr Pulmonol. 2017;52:689-698. (c) 2016 Wiley Periodicals, Inc. PMID- 27774751 TI - Functional and structural cortical reorganization in complex regional pain syndrome and implications for treatment. PMID- 27774752 TI - Sergio Henrique Ferreira (1934-2016). PMID- 27774753 TI - Preoperative pain and sensory function in groin hernia. PMID- 27774755 TI - Fine-needle aspiration biopsy of prostate synovial sarcoma: A case report and review of the literature. AB - We describe a case of synovial sarcoma originating from prostate gland. The diagnosis was confirmed by fluorescent in situ hybridization analysis (FISH) for SYT rearrangement on the cell block. Synovial sarcoma is a high grade soft tissue malignancy with exceedingly rare involvement of genitourinary tract. However this entity should be considered in the differential diagnosis when dealing with aspiration biopsies of particularly deep seated lesions with spindle cell or small round blue cell cytomorphology. Diagn. Cytopathol. 2017;45:168-172. (c) 2016 Wiley Periodicals, Inc. PMID- 27774754 TI - Impact of elosulfase alfa in patients with morquio A syndrome who have limited ambulation: An open-label, phase 2 study. AB - Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open-label, phase 2, multi-national study in Morquio A patients aged >=5 years unable to walk >=30 meters in the 6-min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25-foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug-related adverse events, the other was not drug-related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received >=80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. (c) 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID- 27774756 TI - In Situ Generated Janus Fabrics for the Rapid and Efficient Separation of Oil from Oil-in-Water Emulsions. AB - A cotton fabric was coated with a polymer that contains both poly(dimethyl siloxane) (PDMS) and poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA). When the repeat unit number of PDMS is about three-fold that of PDMAEMA and the fabric is exposed to air, the fabric is superhydrophobic because PDMS in the coating covers the PDMAEMA chains. Upon contact with an oil-in-water emulsion, the water soluble PDMAEMA rises to the top and the side in contact with the emulsion becomes hydrophilic. The emerged PDMAEMA chains then cause the emulsion droplets to coagulate, and the aggregated oil fills the pores on the superhydrophobic side of the fabric. The oil-impregnated side remains hydrophobic even upon prolonged contact with water. Thus, a Janus fabric is elegantly generated in situ and sustained. This easy-to-prepare Janus fabric rapidly and efficiently separates oil from emulsions and may find practical applications. PMID- 27774757 TI - The influences and outcomes of phonological awareness: a study of MA, PA and auditory processing in pre-readers with a family risk of dyslexia. AB - The direct influence of phonological awareness (PA) on reading outcomes has been widely demonstrated, yet PA may also exert indirect influence on reading outcomes through other cognitive variables such as morphological awareness (MA). However, PA's own development is dependent and influenced by many extraneous variables such as auditory processing, which could ultimately impact reading outcomes. In a group of pre-reading children with a family risk of dyslexia and low-risk controls, this study sets out to answer questions surrounding PA's relationship at various grain sizes (syllable, onset/rime and phoneme) with measures of auditory processing (frequency modulation (FM) and an amplitude rise-time task (RT)) and MA, independent of reading experience. Group analysis revealed significant differences between high- and low-risk children on measures of MA, and PA at all grain sizes, while a trend for lower RT thresholds of high-risk children was found compared with controls. Correlational analysis demonstrated that MA is related to the composite PA score and syllable awareness. Group differences on MA and PA were re-examined including PA and MA, respectively, as control variables. Results exposed PA as a relevant component of MA, independent of reading experience. PMID- 27774758 TI - A prospective evaluation of a standardized strategy for the use of a polymeric everolimus-eluting bioresorbable scaffold in ST-segment elevation myocardial infarction: Rationale and design of the BVS STEMI STRATEGY-IT study. AB - OBJECTIVES: To assess the feasibility and the clinical results following a prespecified bioresorbable vascular scaffold (Absorb BVS) implantation strategy in ST-elevation myocardial infarction (STEMI) patients. BACKGROUNDS: Concerns raised about the BVS safety in STEMI setting because a not negligible thrombosis rate was reported within 30 days and 12 months after implantation. Technical procedural issues related to the structural BVS features were advocated as probable causes for the thrombotic events. METHODS: This is an investigators owned and -directed, prospective, nonrandomized, single-arm multicenter registry intended to obtain data from 500 consecutive STEMI patients undergoing primary PCI with BVS (1.1 or GT1) following a prespecified implantation protocol. The study is recorded in ClinicalTrials.gov with the identifier: NCT02601781. RESULTS: The primary endpoint is a device-oriented composite end-point (DOCE) of cardiac death, any myocardial infarction clearly attributable to the intervention culprit vessel and ischemic-driven target lesion revascularization within 30 days after the index procedure. The DOCE will be assessed even at 6-month, 1-, 3-, and 5-year follow-up. CONCLUSIONS: This will be the first study investigating the feasibility and the early- and long-term clinical impact of a prespecified BVS implantation protocol in thrombotic lesions causing STEMI. Here, we describe the rationale and the design of the study. (c) 2016 Wiley Periodicals, Inc. PMID- 27774760 TI - Why public health should embrace the autonomous car. PMID- 27774759 TI - Psychopathology in 7-year-old children: Differences in maternal and paternal ratings and the genetic epidemiology. AB - The assessment of children's psychopathology is often based on parental report. Earlier studies have suggested that rater bias can affect the estimates of genetic, shared environmental and unique environmental influences on differences between children. The availability of a large dataset of maternal as well as paternal ratings of psychopathology in 7-year old children enabled (i) the analysis of informant effects on these assessments, and (ii) to obtain more reliable estimates of the genetic and non-genetic effects. DSM-oriented measures of affective, anxiety, somatic, attention-deficit/hyperactivity, oppositional defiant, conduct, and obsessive-compulsive problems were rated for 12,310 twin pairs from the Netherlands Twin Register by mothers (N = 12,085) and fathers (N = 8,516). The effects of genetic and non-genetic effects were estimated on the common and rater-specific variance. For all scales, mean scores on maternal ratings exceeded paternal ratings. Parents largely agreed on the ranking of their child's problems (r 0.60-0.75). The heritability was estimated over 55% for maternal and paternal ratings for all scales, except for conduct problems (44 46%). Unbiased shared environmental influences, i.e., on the common variance, were significant for affective (13%), oppositional (13%), and conduct problems (37%). In clinical settings, different cutoffs for (sub)clinical scores could be applied to paternal and maternal ratings of their child's psychopathology. Only for conduct problems, shared environmental and genetic influences explain an equal amount in differences between children. For the other scales, genetic factors explain the majority of the variance, especially for the common part that is free of rater bias. (c) 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID- 27774762 TI - Hearing characterization in oculoauriculovertebral spectrum: A prospective study with 10 patients. AB - Oculoauriculovertebral spectrum (OAVS), also known as Goldenhar syndrome, is considered a condition associated to failing of embryogenesis involving the first and second branchial arches, leading to structural abnormalities arising from it. The aim of this study is to verify the hearing features presented by patients with OAVS and provide additional information that may contribute to improvement of speech therapy. The sample consisted of 10 individuals diagnosed with OAVS and cared for by the Clinical Genetics Service. All patients underwent objective assessment of auditory function through tonal and vocal audiometry. This evaluation was completed using TOAE and BERA. The patient's age ranged from 1 year and 9 months to 27 years and 4 months. At physical examination it was found that 10 had microtia, 7 preauricular tags, 6 low-set ears, 6 ear canal atresia, and 2 preauricular pits. Among the patients, five presented with abnormal hearing. Three patients had conductive hearing loss ranging from mild to moderate, and two patients had sensorineural hearing loss from mild to profound. Three patients had hearing loss in both ears. Speech-language disorders are common in children with OAVS. Thus, the referral to the audiologist and speech pathologist is indicated as soon as possible. Early recognition and detailed understanding of aspects related to the etiology, clinical features, and outcome of patients with OAVS are essential for their proper management. (c) 2016 Wiley Periodicals, Inc. PMID- 27774761 TI - Human leucocyte antigen class I and II imputation in a multiracial population. AB - Human leucocyte antigen (HLA) genes play a central role in response to pathogens and in autoimmunity. Research to understand the effects of HLA genes on health has been limited because HLA genotyping protocols are labour intensive and expensive. Recently, algorithms to impute HLA genotype data using genome-wide association study (GWAS) data have been published. However, imputation accuracy for most of these algorithms was based primarily on training data sets of European ancestry individuals. We considered performance of two HLA-dedicated imputation algorithms - SNP2HLA and HIBAG - in a multiracial population of n = 1587 women with HLA genotyping data by gold standard methods. We first compared accuracy - defined as the percentage of correctly predicted alleles - of HLA-B and HLA-C imputation using SNP2HLA and HIBAG using a breakdown of the data set into an 80% training group and a 20% testing group. Estimates of accuracy for HIBAG were either the same or better than those for SNP2HLA. We then conducted a more thorough test of HIBAG imputation accuracy using five independent 10-fold cross-validation procedures with delineation of ancestry groups using ancestry informative markers. Overall accuracy for HIBAG was 89%. Accuracy by HLA gene was 93% for HLA-A, 84% for HLA-B, 94% for HLA-C, 83% for HLA-DQA1, 91% for HLA-DQB1 and 88% for HLA-DRB1. Accuracy was highest in the African ancestry group (the largest group) and lowest in the Hispanic group (the smallest group). Despite suboptimal imputation accuracy for some HLA gene/ancestry group combinations, the HIBAG algorithm has the advantage of providing posterior estimates of accuracy which enable the investigator to analyse subsets of the population with high predicted (e.g. >95%) imputation accuracy. PMID- 27774763 TI - On Materials for Cardiac Tissue Engineering. AB - In this essay the authors argue that chamber pressure dominates the biomechanics of the contraction cycle of the heart, while tissue stiffness dominates the relaxation cycle. This appears to be an under-recognized challenge in cardiac tissue engineering. Optimal approaches will involve constructing chambers or modulating the stiffness of the scaffold/substrate in synchrony with the beating cycle. PMID- 27774764 TI - Amygdala-orbitofrontal connectivity predicts alcohol use two years later: a longitudinal neuroimaging study on alcohol use in adolescence. AB - This study tested the relation between cortical-subcortical functional connectivity and alcohol consumption in adolescents using an accelerated longitudinal design, as well as normative developmental patterns for these measures. Participants between ages 8 and 27 completed resting-state neuroimaging scans at two time points separated by two years (N = 274 at T1, N = 231 at T2). In addition, participants between ages 12 and 27 reported on recent and lifetime alcohol use (N = 193 at T1, N = 244 at T2). Resting-state connectivity analyses focused on amygdala-orbitofrontal connectivity given prior research linking reduced coupling between these regions to alcohol use. Mixed model analyses revealed that age had a cubic relationship with alcohol use, with little to no use in childhood, steep increases in adolescence and leveling off in adulthood. No age effects were found for amygdala-OFC connectivity. Prediction analyses showed that left amygdala-orbitofrontal connectivity at the first time point predicted recent and lifetime alcohol use two years later. There was no evidence for the reversed relation, suggesting that brain connectivity measures precede explorative risk-taking behavior in adolescence, possibly because decreased subcortical-frontal connectivity biases towards more explorative or risky behavior. PMID- 27774766 TI - Abdominal paraganglioma in a young woman with 1p36 deletion syndrome. AB - 1p36 deletion syndrome is the most common terminal deletion syndrome, and the genomic regions that contribute to specific 1p36 deletion syndrome-related phenotypes were recently identified. Deletions in the 1p36 region have been documented in various tumor tissues, which indicates correlation between loss of heterozygosity of 1p36 and tumor development, and the existence of tumor suppressors in this region. Therefore, it was suspected that patients with 1p36 deletion syndrome have a higher risk of tumor development; however, only a few child cases of neuroblastoma with 1p36 deletion syndrome have been reported. We report the first case of 1p36 deletion syndrome with paraganglioma (PGL) and include genetic investigation. The 24-year-old woman with 1p36 deletion syndrome had severe intellectual disability, dilated cardiomyopathy, and distinct dysmorphic features, and presented with persistent vomiting accompanied by hypertension (178/115 mmHg). Abdominal CT revealed a 40 * 50 mm retroperitoneal mass and substantial elevations of plasma and urine norepinephrine (15.4 nmol/L and 1022 umol/mol creatinine, respectively); abnormal uptake of 123 I-MIBG in the tumor led to PGL diagnosis. The patient was not able to have surgery because of substantial surgical risks; however, a combination of alpha- and beta-blockade was effective for blood pressure control. Array CGH revealed a deletion over 4.5 Mb, from the 1p telomere but excluding the SDHB region. Comprehensive mutational analysis of PGL-associated genes (RET, VHL, TMEM127, MAX, and SDHA/B/C/D) was negative. These results indicate that the germline 1p36 deletion might be "1st hit" of tumor development, and PGL might be a novel complication of 1p36 deletion syndrome. (c) 2016 Wiley Periodicals, Inc. PMID- 27774767 TI - Bicoronal and metopic craniosynostosis in association with a de novo unbalanced t(2;7) chromosomal translocation. AB - We report the case of a developmentally appropriate infant male with a de novo unbalanced chromosome translocation involving bands 2q32.1 and 7p21.3. The child was noted to have metopic and bicoronal craniosynostosis with closely spaced eyes, turricephaly, and flattening of the forehead. (c) 2016 Wiley Periodicals, Inc. PMID- 27774768 TI - Melanoma niche formation: it is all about melanosomes making CAFs. PMID- 27774765 TI - Progress in the clinical detection of heterogeneity in breast cancer. AB - Breast cancer is currently the most common form of cancer and the second-leading cause of death from cancer in women. Though considerable progress has been made in the treatment of breast cancer, the heterogeneity of tumors (both inter- and intratumor) remains a considerable diagnostic and prognostic challenge. From clinical observation to genetic mutations, the history of understanding the heterogeneity of breast cancer is lengthy and detailed. Effectively detecting heterogeneity in breast cancer is important during treatment. Various methods of depicting this heterogeneity are now available and include genetic, pathologic, and imaging analysis. These methods allow characterization of the heterogeneity of breast cancer on a genetic level, providing greater insight during the process of establishing an effective therapeutic plan. This study reviews how the understanding of tumor heterogeneity in breast cancer evolved, and further summarizes recent advances in the detection and monitoring of this heterogeneity in patients with breast cancer. PMID- 27774769 TI - Developmental DNA methyltransferase expression in the fire ant Solenopsis invicta. AB - DNA methylation is accomplished in animals by 2 classes of enzymes known as DNA methyltransferases, DNMT3 and DNMT1, which perform de novo methylation and maintenance methylation, respectively. Several studies of hymenopteran eusocial insects suggest that DNA methylation is capable of influencing developmental plasticity. However, fundamental questions remain about the patterning of DNA methylation during the course of insect development. In this study, we performed quantitative real-time PCR (qPCR) on transcripts from the single-copy orthologs of DNMT1 and DNMT3 in the red imported fire ant, Solenopsis invicta. In particular, we assessed the expression of S. invicta Dnmt1 and Dnmt3 mRNA during 7 stages of worker development, among behaviorally distinct adults, and among male and female gonads. Dnmt3 was most highly expressed during embryonic development, whereas Dnmt1 was similarly expressed throughout the course of development. Moreover, Dnmt1 and Dnmt3 were highly expressed in testes and ovaries. Neither Dnmt was significantly differentially expressed among heads of behaviorally distinct adult castes. Our results support the hypothesis that extensive patterning of DNA methylation occurs during gametogenesis and embryogenesis in the insect order Hymenoptera. PMID- 27774771 TI - Copper-Organic Framework Fabricated with CuS Nanoparticles: Synthesis, Electrical Conductivity, and Electrocatalytic Activities for Oxygen Reduction Reaction. AB - To apply electrically nonconductive metal-organic frameworks (MOFs) in an electrocatalytic oxygen reduction reaction (ORR), we have developed a new method for fabricating various amounts of CuS nanoparticles (nano-CuS) in/on a 3D Cu MOF, [Cu3 (BTC)2 ?(H2 O)3 ] (BTC=1,3,5-benzenetricarboxylate). As the amount of nano-CuS increases in the composite, the electrical conductivity increases exponentially by up to circa 109 -fold, while porosity decreases, compared with that of the pristine Cu-MOF. The composites, nano-CuS(x wt %)@Cu-BTC, exhibit significantly higher electrocatalytic ORR activities than Cu-BTC or nano-CuS in an alkaline solution. The onset potential, electron transfer number, and kinetic current density increase when the electrical conductivity of the material increases but decrease when the material has a poor porosity, which shows that the two factors should be finely tuned by the amount of nano-CuS for ORR application. Of these materials, CuS(28 wt %)@Cu-BTC exhibits the best activity, showing the onset potential of 0.91 V vs. RHE, quasi-four-electron transfer pathway, and a kinetic current density of 11.3 mA cm-2 at 0.55 V vs. RHE. PMID- 27774770 TI - Protection of Nrf2 against arsenite-induced oxidative damage is regulated by the cyclic guanosine monophosphate-protein kinase G signaling pathway. AB - Arsenite has been shown to induce a variety of oxidative damage in mammalian cells. However, the mechanisms underlying cellular responses to its adverse effects remain unknown. We previously showed that the level of Nrf2, a nuclear transcription factor significantly increased in arsenite-treated human bronchial epithelial (HBE) cells suggesting that Nrf2 is involved in responding to arsenite induced oxidative damage. To explore how Nrf2 can impact arsenite-induced oxidative damage, in this study, we examined Nrf2 activation and its regulation upon cellular arsenite exposure as well as its effects on arsenite-induced oxidative damage in HBE cells. We found that Nrf2 mRNA and protein levels were significantly increased by arsenite in a dose- and time-dependent manner. Furthermore, we showed that over-expression of Nrf2 significantly reduced the level of arsenite-induced oxidative damage in HBE cells including DNA damage, chromosomal breakage, lipid peroxidation and depletion of antioxidants. This indicates a protective role of Nrf2 against arsenite toxicity. This was further supported by the fact that activation of Nrf2 by its agonists, tertiary butylhydroquinone (t-BHQ) and sulforaphane (SFN) resulted in the same protective effects against arsenite toxicity. Moreover, we demonstrated that arsenite induced activation of Nrf2 was mediated by the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway. This is the first evidence showing that Nrf2 protects against arsenite-induced oxidative damage through the cGMP-PKG pathway. Our study suggests that activation of Nrf2 through the cGMP-PKG signaling pathway in HBE cells may be developed as a new strategy for prevention of arsenite toxicity. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2004 2020, 2017. PMID- 27774773 TI - Experimental and computational examination of anastellin (FnIII1c)-polymer interactions. AB - Using a combination of experimental and computational approaches, the interaction between anastellin, a recombinant fragment of fibronectin, and representative biomaterial surfaces has been examined. Anastellin and superfibronectin have been seen to exhibit antiangiogenic properties and other properties that may make it suitable for consideration for incorporation into biomaterials. The molecular interaction was directly quantified by atomic force microscope (AFM)-based force spectroscopy, complemented by adsorption measurements using quartz crystal microbalance (QCM). Using AFM, it was found that the anastellin molecule facilitates a stronger adhesion on polyurethane films (72.0 pN nm-1 ) than on poly (methyl methacrylate) films (68.6 pN nm-1 ). However, this is not consistent with the QCM adsorption measurements, which show no significant difference. Molecular dynamics simulations of the behavior of anastellin on polyurethane in aqueous solution were performed to rationalize the experimental data, and show that anastellin is capable of rapid adsorption to PU while its secondary structure is stable upon adsorption in water. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 737-745, 2017. PMID- 27774772 TI - Touch imprint cytology with massively parallel sequencing (TIC-seq): a simple and rapid method to snapshot genetic alterations in tumors. AB - Identifying genetic alterations in tumors is critical for molecular targeting of therapy. In the clinical setting, formalin-fixed paraffin-embedded (FFPE) tissue is usually employed for genetic analysis. However, DNA extracted from FFPE tissue is often not suitable for analysis because of its low levels and poor quality. Additionally, FFPE sample preparation is time-consuming. To provide early treatment for cancer patients, a more rapid and robust method is required for precision medicine. We present a simple method for genetic analysis, called touch imprint cytology combined with massively paralleled sequencing (touch imprint cytology [TIC]-seq), to detect somatic mutations in tumors. We prepared FFPE tissues and TIC specimens from tumors in nine lung cancer patients and one patient with breast cancer. We found that the quality and quantity of TIC DNA was higher than that of FFPE DNA, which requires microdissection to enrich DNA from target tissues. Targeted sequencing using a next-generation sequencer obtained sufficient sequence data using TIC DNA. Most (92%) somatic mutations in lung primary tumors were found to be consistent between TIC and FFPE DNA. We also applied TIC DNA to primary and metastatic tumor tissues to analyze tumor heterogeneity in a breast cancer patient, and showed that common and distinct mutations among primary and metastatic sites could be classified into two distinct histological subtypes. TIC-seq is an alternative and feasible method to analyze genomic alterations in tumors by simply touching the cut surface of specimens to slides. PMID- 27774775 TI - Galactosylated Lipidoid Nanoparticles for Delivery of Small Interfering RNA to Inhibit Hepatitis C Viral Replication In Vivo. AB - Small interfering RNA (siRNA) delivery can provide an effective therapy for treating viral diseases by silencing genes involved in viral replication. In this study, a liver-targeting formulation of lipidoid nanoparticle for delivery of siRNA that targets protein kinase C-related kinase 2 (PRK2) to inhibit hepatitis C virus (HCV) replication is reported. The most effective, minimally cytotoxic lipidoid for siRNA delivery to hepatic cells is identified from a small library of alkyl epoxide-polyamine conjugates. In vitro transfection of PRK2 siRNA (siPRK2) using this lipidoid induces significant silencing of PRK2 (~80%), suppressing HCV replication in human hepatic cells transfected with the HCV subgenomic replicon. Systemic administration of siPRK2 using the lipidoid nanoparticles results in significant reduction of host PRK2 in the mouse liver (~60%). This treatment significantly suppresses HCV replication in an HCV xenograft mouse model. siRNA delivery to the liver is further improved via galactosylation of the lipidoid. Compared with the unmodified lipidoid formulation, galactosylated lipidoids induce greater silencing of host PRK2 in mouse livers (~80%) and more rapid suppression of HCV replication in an HCV xenograft mouse. This study suggests that galactosylated lipidoid nanoparticles could provide a treatment for hepatitis C by mediating delivery of anti-viral RNA interference therapeutics to the liver. PMID- 27774776 TI - Biased dispersal of Metrioptera bicolor, a wing dimorphic bush-cricket. AB - In the highly fragmented landscape of central Europe, dispersal is of particular importance as it determines the long-term survival of animal populations. Dispersal not only secures the recolonization of patches where populations went extinct, it may also rescue small populations and thus prevent local extinction events. As dispersal involves different individual fitness costs, the decision to disperse should not be random but context-dependent and often will be biased toward a certain group of individuals (e.g., sex- and wing morph-biased dispersal). Although biased dispersal has far-reaching consequences for animal populations, immediate studies of sex- and wing morph-biased dispersal in orthopterans are very rare. Here, we used a combined approach of morphological and genetic analyses to investigate biased dispersal of Metrioptera bicolor, a wing dimorphic bush-cricket. Our results clearly show wing morph-biased dispersal for both sexes of M. bicolor. In addition, we found sex-biased dispersal for macropterous individuals, but not for micropters. Both, morphological and genetic data, favor macropterous males as dispersal unit of this bush-cricket species. To get an idea of the flight ability of M. bicolor, we compared our morphological data with that of Locusta migratoria and Schistocerca gregaria, which are very good flyers. Based on our morphological data, we suggest a good flight ability for macropters of M. bicolor, although flying individuals of this species are seldom observed. PMID- 27774774 TI - Positioning of second-line treatment for advanced gastric and gastroesophageal junction adenocarcinoma. AB - Tumors of the upper gastrointestinal tract are increasing in incidence; yet, approaches to the treatment of advanced gastric and/or gastroesophageal junction cancer vary widely, with no internationally agreed first-line regimens. Recent clinical trials have shown that second-line treatment is now possible for selected patients with advanced disease, and current data suggest that the combination of ramucirumab plus paclitaxel may become a standard of care in the second-line setting for metastatic gastric cancer. Several prognostic factors have been identified for overall survival in the second-line setting; this emphasizes the need for careful sequencing of all treatments to ensure that individual patients receive optimum care. This article reviews published data on the treatment of advanced gastric cancer, with a particular emphasis on second line chemotherapy, and suggests treatment sequences based on current understanding. PMID- 27774778 TI - The grey literature is far from drab. PMID- 27774777 TI - MiR-17-5p promotes cancer cell proliferation and tumorigenesis in nasopharyngeal carcinoma by targeting p21. AB - MicroRNAs (miRNAs) may act as either tumor suppressors or oncogenes in various types of cancers. Previous studies have indicated that miR-17-5p is involved in the initiation and development of human tumors. However, its mechanism and function in nasopharyngeal carcinoma (NPC) remain largely unclear. In this study, we evaluated the expression profiles of miR-17-5p and p21 in NPC cell lines and tissues by quantitative real-time PCR (qRT-PCR). For the analysis, we have established a stable overexpression or depletion of miR-17-5p NPC cell lines for analyzing the effects of cell proliferation by MTT, colony formation, and cell cycle assay. A nude mice xenograft model was used to verify the tumor growth in vivo. MiR-17-5p was overexpressed, whereas the expression of p21 was downregulated in NPC cell lines and tissues. The miR-17-5p expression level was inversely correlated with the p21 mRNA level in NPC samples. Furthermore, analysis of 2-DeltaDeltaCt value in 81 NPC patients suggested that the elevated expression level of miR-17-5p or the downregulated expression level of p21 was significantly correlated with tumor size (T classification) and tumor stage, and Kaplan-Meier survival analysis revealed a correlation between miR-17-5p or p21 expression level and overall survival times in 81 NPC patients. MiR-17-5p promoted cell growth in vivo and in vitro by directly targeting p21. Our results indicate that miR-17-5p can promote the occurrence of NPC and it may serve as a potential novel diagnostic maker or therapeutic target for NPC in the future. PMID- 27774779 TI - Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). AB - AIMS: The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG). METHODS: The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and CV outcomes. RESULTS: Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time. A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall CV incidence rate was 1522 per 100 000 person years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events. CONCLUSIONS: Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry. PMID- 27774780 TI - Understanding patient and physician perceptions of benign prostatic hyperplasia in Asia Pacific, Latin America and the Commonwealth of Independent States: the Prostate Research on Behaviour and Education (PROBE) II survey. AB - AIM: To assess attitudes and beliefs towards benign prostatic hyperplasia (BPH)/ lower urinary tract symptoms (LUTS) and its treatment among patients and physicians in Latin America, Asia Pacific and the Commonwealth of Independent States (CIS). METHODS: Cross-sectional, quantitative study conducted between December 2014 and September 2015. Separate questionnaires were administered to BPH/LUTS patients receiving drug treatment for their condition and to practising physicians who treat patients with BPH/LUTS. RESULTS: In total, 1094 patients and 202 physicians completed a questionnaire. Most patients (61%) felt very/fairly well informed about BPH/LUTS, and 60% of physicians perceived patients to be very/somewhat informed. Overall, 70% of physicians felt that it would be valuable to raise awareness of BPH/LUTS and encourage men to consult a physician. The first symptoms most commonly noticed by patients were need to urinate more frequently, slower/weaker stream and nocturia. At first consultation, 71% of patients recalled providing a urine sample, 57% having a blood test for prostate specific antigen and 56% a digital rectal examination being performed. Over two thirds of patients (69%) were satisfied with their current medication; highest satisfaction rates (among both patients and physicians) were reported for alpha blockers and 5ARIs, either as monotherapies or used in combination. Patients were prepared to wait longer for symptom relief in order to have a reduced risk of surgery. Most physicians (90%) thought that at least some patients believe BPH/LUTS to be a progressive condition. Most physicians thought that patients were very/fairly concerned about BPH surgery (92%) and acute urinary retention (72%); 52% of physicians thought treatment adherence was "extremely" important. CONCLUSIONS: This study provides valuable insights into the attitudes and beliefs of patients and physicians in Asia Pacific, Latin America and CIS about BPH/LUTS and its management. It also highlights areas of discordance between patient/physician perceptions and beliefs about BPH/LUTS, and potential areas of focus to improve the experience of affected patients. PMID- 27774781 TI - Fetal programming of neuropsychiatric disorders. AB - Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207-223, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27774782 TI - Reference-independent wide field fluorescence lifetime measurements using Frequency-Domain (FD) technique based on phase and amplitude crossing point. AB - Fluorescence lifetime imaging microscopy (FLIM) is an essential tool in many scientific fields such as biology and medicine thanks to the known advantages of the fluorescence lifetime (FLT) over the classical fluorescence intensity (FI). However, the frequency domain (FD) FLIM technique suffers from its strong dependence on the reference and its compliance to the sample. In this paper, we suggest a new way to calculate the FLT by using the crossing point (CRPO) between the modulation and phase FLTs measured over several light emitting diode (LED) DC currents values instead of either method alone. This new technique was validated by measuring homogeneous substances with known FLT, where the CRPO appears to be the optimal measuring point. Furthermore, the CRPO method was applied in heterogeneous samples. It was found that the CRPO in known mixed solutions is the weighted average of the used solutions. While measuring B16 and lymphocyte cells, the CRPO of the DAPI compound in single FLT regions was measured at 3.5 +/- 0.06 ns and at 2.83 +/- 0.07 ns, respectively, both of which match previous reports and multi-frequency analyses. This paper suggests the CRPO as a new method to extract the FLT in problematic cases such as high MCP gains and heterogeneous environments. In traditional FD FLIM measurements, the variation in phase angle and modulation are measured. By measuring over varying DC currents, another variation is detected in the FLT determined through the phase and modulation methods, with the CRPO indicating the true FLT. PMID- 27774783 TI - Access to the Phosphorylindenopyrazole Scaffold via a Metal-Free Domino Reaction of Diazoalkylphosphonates with 3-Bromophthalides. AB - A novel strategy is reported here for the synthesis of an indenopyrazole scaffold bearing a phosphonate group. The entire sequence includes nucleophilic addition elimination, Seyferth-Gilbert homologation, transphosphorylation, and a 1,3 dipolar cycloaddition reaction of diazoalkylphosphonates in a perfect "domino" manner. PMID- 27774784 TI - Monitoring In Vivo Changes in Tonic Extracellular Dopamine Level by Charge Balancing Multiple Waveform Fast-Scan Cyclic Voltammetry. AB - Dopamine (DA) modulates central neuronal activity through both phasic (second to second) and tonic (minutes to hours) terminal release. Conventional fast-scan cyclic voltammetry (FSCV), in combination with carbon fiber microelectrodes, has been used to measure phasic DA release in vivo by adopting a background subtraction procedure to remove background capacitive currents. However, measuring tonic changes in DA concentrations using conventional FSCV has been difficult because background capacitive currents are inherently unstable over long recording periods. To measure tonic changes in DA concentrations over several hours, we applied a novel charge-balancing multiple waveform FSCV (CBM FSCV), combined with a dual background subtraction technique, to minimize temporal variations in background capacitive currents. Using this method, in vitro, charge variations from a reference time point were nearly zero for 48 h, whereas with conventional background subtraction, charge variations progressively increased. CBM-FSCV also demonstrated a high selectivity against 3,4 dihydroxyphenylacetic acid and ascorbic acid, two major chemical interferents in the brain, yielding a sensitivity of 85.40 +/- 14.30 nA/MUM and limit of detection of 5.8 +/- 0.9 nM for DA while maintaining selectivity. Recorded in vivo by CBM-FSCV, pharmacological inhibition of DA reuptake (nomifensine) resulted in a 235 +/- 60 nM increase in tonic extracellular DA concentrations, while inhibition of DA synthesis (alpha-methyl-dl-tyrosine) resulted in a 72.5 +/ 4.8 nM decrease in DA concentrations over a 2 h period. This study showed that CBM-FSCV may serve as a unique voltammetric technique to monitor relatively slow changes in tonic extracellular DA concentrations in vivo over a prolonged time period. PMID- 27774785 TI - Fluorescence Detection of a Broad Class of Explosives with One Zinc(II) Coordination Nanofiber. AB - In this work, we report the development of one fluorescent carbazole-based oligomer 1-zinc(II) coordination nanofiber which enabled the detection of five classes of explosives, i.e., nitroaromatics (dinitrotoluene, DNT, and trinitrotoluene, TNT), aliphatic nitro-organics (2,3-dimethyl-2,3-dinitrobutane, DMNB), nitramines (cyclotrimethylenetrinitramine, RDX), nitro-esters (pentaerythritol tetranitrate, PETN), and black powder (sulfur). We demonstrate that the coordination of zinc ion with a carbazole-based oligomer 1 allows the formation of the Lewis acid-base complex between explosives and the nanofiber that enhances the electron-accepting ability of the nitro-based explosives and the binding interactions between the sensing nanofibers and explosives. Furthermore, the resulting nanofiber-based sensor exhibited highly sensitive fluorescence quenching when exposed to trace sulfur, thereby enabling the sensitive detection of black powder. Herein, we present a new fluorescent sensor for five classes of explosives, which represents an important advance toward a richer identification of threats. PMID- 27774786 TI - Polyhedral Oligomeric Silsesquioxane Enhances the Brightness of Perovskite Nanocrystal-Based Green Light-Emitting Devices. AB - The beneficial role of the insulating material polyhedral oligomeric silsesquioxane (POSS) as a solution additive or an additional hole-blocking layer to enhance the performance of electroluminescent green light-emitting devices (LEDs) based on CsPbBr3 perovskite nanocrystals is demonstrated. POSS improves the surface coverage and the morphological features of the films deposited either from supernatant or suspension of perovskite nanocrystals. The external quantum efficiency and the luminance efficiency of LEDs with an additional POSS layer reach 0.35% and 1.20 cd/A, respectively, constituting a more than 17-fold enhancement to the reference devices without POSS; the LED peak luminance reaches 2983 cd/m2, and the device stability is improved. The POSS acts as a hole blocking layer between the perovskite nanocrystals and TPBi, keeping both electrons and holes located within the active layer for an efficient recombination. PMID- 27774787 TI - Template-Free Synthesis of Hollow/Porous Organosilica-Fe3O4 Hybrid Nanocapsules toward Magnetic Resonance Imaging-Guided High-Intensity Focused Ultrasound Therapy. AB - Entirely differing from the common templating-based multistep strategy for fabricating multifunctional hollow mesoporous silica nanoparticles (HMSN), a facile and template-free synthetic strategy has been established to construct a unique hollow/mesoporous organosilica nanocapsule (OSNC) concurrently encapsulating both isopentyl acetate (PeA) liquid and superparamagnetic iron oxides inside (denoted as PeA@OSNC). This novel material exhibits ultrasmall and uniform particle size (~82 nm), high surface area (~534 m2.g-1), and excellent colloidal stability in aqueous solution. The oil-phase PeA with relatively low boiling point (142 degrees C) and high volatility not only plays a crucial role in formation of a large hollow cavity from the viewpoint of structural design but also enables the PeA@OSNC to act as an efficient enhancement agent in high intensity focused ultrasound (HIFU) therapy. Moreover, the unique satellite-like distribution of Fe3O4 nanoparticles (NP) on the organosilica shell offered excellent magnetic resonance imaging (MRI) contrast capability of PeA@OSNC in vitro and in vivo. More importantly, such a novel theranostic agent has favorable biosafety, which is very promising for future clinical application in MRI-guided HIFU therapy. PMID- 27774788 TI - Site- and Regioselective Monoalkenylation of Pyrroles with Alkynes via Cp*CoIII Catalysis. AB - A site-, regio-, syn-, and monoselective alkenylation of dimethylcarbamoyl protected pyrroles proceeded using a catalytic amount of [Cp*Co(CH3CN)3](SbF6)2 and KOAc. A variety of internal alkynes with several functional groups and a terminal alkyne afforded hydropyrrolation products in a selective manner in good to excellent yield. The site-selectivity (C2/C5 selectivity) observed for C3 substituted pyrroles is noteworthy because Cp*RhIII-catalyzed conditions afforded only a moderate yield and low selectivity. The conditions described here provide general and straightforward access to unsymmetrically mono- and disubstituted pyrrole derivatives. PMID- 27774789 TI - Tailoring Molecular Permeability of Nanochannel-Micelle Membranes for Electrochemical Analysis of Antioxidants in Fruit Juices without Sample Treatment. AB - Antioxidants are widely found or used in food, pharmaceutical, and cosmetics industries; thus, rapid and sensitive detection of antioxidants is of great interest. The present work reports a simple and fast electrochemical method for direct analysis of antioxidants in fruit juices by modulating the permeability of mesochannels on the electrode surface. This goal was achieved by growing vertical silica mesochannel array (SMA) with a channel diameter of 2-3 nm on the indium tin oxide (ITO) electrode surface using the cylindrical micelles (CMs) as the template. As-prepared electrodes, designed as CM@SMA/ITO, are only permeable to lipophilic antioxidants, e.g., retinol, with the hydrophobic hydrocarbon cores of CMs. After excluding CMs from silica mesochannels, the ITO electrode modified with bare SMA, namely SMA/ITO, possesses a high density of silanol groups on the channel wall and thus is only permeable to hydrophilic antioxidants, such as ascorbic acid (AA). Two types of sensors allowed the selective analyses of retinol and AA in buffer solutions and demonstrated a wide linear range for retinol (1-60 MUM) and AA (10-2000 MUM), respectively, and a low detection limit (0.65 MUM for retinol and 0.52 MUM for AA). Moreover, the SMA/ITO electrode can selectively determine the concentration of AA in orange juice. The CM@SMA/ITO electrode can measure the sum activity of lipophilic antioxidants, such as retinol, alpha-tocopherol, and others possibly coexisting, in carrot juice. In addition, the ultrasmall mesochannels and CMs could effectively exclude the access of large substances, rendering an excellent antifouling and anti interference ability for direct analysis of antioxidants in fruit juices without sample pretreatment. PMID- 27774791 TI - Site-Selective Silylation of Aliphatic C-H Bonds Mediated by [1,5]-Hydrogen Transfer: Synthesis of alpha-Sila Benzamides. AB - The first example of site-selective silylation of C(sp3)-H bonds mediated by a [1,5]-hydrogen transfer is reported. This reaction occurs selectively at the alpha-position of benzamides with a combination of tert-butylmagnesium chloride and a catalytic amount of 4,4'-di-tert-butylbipyridine (dtbpy) ligand and provides a facile route for the creation of biologically interesting alpha-sila benzamides. Late-stage functionalization of the incorporated silyl moieties facilitates the synthesis of N-formyl, cis-enamine, beta-hydroxyl, amino, and pyrrole-containing derivatives. PMID- 27774790 TI - Prediction of Protein Lysine Acylation by Integrating Primary Sequence Information with Multiple Functional Features. AB - Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic methods have been widely used to identify lysine acylation proteins. However, these experimental approaches often fail to detect proteins that are in low abundance or absent in specific biological samples. To circumvent these problems, we developed a computational method to predict lysine acylation, including acetylation, malonylation, succinylation, and glutarylation. The prediction algorithm integrated flanking primary sequence determinants and evolutionary conservation of acylated lysine as well as multiple protein functional annotation features including gene ontology, conserved domains, and protein-protein interactions. The inclusion of functional annotation features increases predictive power oversimple sequence considerations for four of the acylation species evaluated. For example, the Matthews correlation coefficient (MCC) for the prediction of malonylation increased from 0.26 to 0.73. The performance of prediction was validated against an independent data set for malonylation. Likewise, when tested with independent data sets, the algorithm displayed improved sensitivity and specificity over existing methods. Experimental validation by Western blot experiments and LC-MS/MS detection further attested to the performance of prediction. We then applied our algorithm on to the mouse proteome and reported the global-scale prediction of lysine acetylation, malonylation, succinylation, and glutarylation, which should serve as a valuable resource for future functional studies. PMID- 27774792 TI - Fast Nanoscale Surface Charge Mapping with Pulsed-Potential Scanning Ion Conductance Microscopy. AB - A vast range of interfacial systems exhibit charge heterogeneities on the nanoscale. These differences in local surface charge density are challenging to visualize, but recent work has shown the scanning ion conductance microscope (SICM) to be a very promising tool to spatially resolve and map surface charge and topography via a hopping potential sweep technique with a single nanopipette probe, with harmonic modulation of a bias applied between quasi-reference counter electrodes in the nanopipette and bulk solution, coupled with lock-in detection. Although powerful, this is a relatively slow process, with limitations on resolution and the size of the images that can be collected. Herein, we demonstrate a new scanning routine for mapping surface charge and topography with SICM, which increases the data acquisition rate by an order of magnitude and with the potential for further gains. Furthermore, the method is simplified, eliminating the need for bias modulation lock-in detection, by utilizing a potential-pulse, chronoamperometric approach, with self-referencing calibration of the response at each pixel in the image. We demonstrate the application of this new method to both a model substrate and living PC-12 cells under physiological (high ionic strength) conditions, where charge mapping is most challenging (small Debye length). This work contributes significantly to the emergence of SICM as a multifunctional technique for simultaneously probing interfacial structure and function with nanometer resolution. PMID- 27774793 TI - Liposomal drug delivery systems for targeted cancer therapy: is active targeting the best choice? AB - Liposomes are biodegradable and biocompatible self-forming spherical lipid bilayer vesicles. They can encapsulate and deliver one or more hydrophobic and hydrophilic therapeutic agents with poor therapeutic indices to tumor sites. Properties such as lipid bilayer fluidity, charge, size and surface hydration can be modified to extend liposome circulation time in the bloodstream and enhance efficacy. The focus of this review is on ligand-conjugated liposomes and their potential application in tumor-targeted delivery. Ligand-conjugated liposomes are designed to target receptors which are overexpressed on tumor cells to decrease drugs side effects by enhancing their selective delivery to tumor site. Despite the extensive research in this area, no small molecule ligand-conjugated liposome has been approved up to date for cancer therapy. PMID- 27774794 TI - Intravaginal practices are associated with greater odds of high-risk HPV infection in Haitian women. AB - OBJECTIVE: Haitian women have the highest incidence of cervical cancer within the Western hemisphere. Intravaginal hygiene practices have been linked with human papilloma virus (HPV) infection and cervical dysplasia. These practices, known as 'twalet deba' in Haitian Creole, are common among Haitian women and are performed with various natural and synthetic agents. As part of a community-based participatory research initiative aimed at reducing cervical cancer disparities in rural Haiti, we explored the use of intravaginal agents and their associations with high-risk HPV infection. DESIGN: Community Health Workers recruited 416 women for cervical self-sampling from two neighborhoods within Thomonde, Haiti. Participants were interviewed regarding intravaginal hygiene practices and completed a cervical self-sampling procedure. Cervical samples were analyzed for the presence of high-risk HPV infection. Associations between each intravaginal agent and high-risk HPV infection were examined via univariate logistic regression analyses, as well as via multivariate analyses controlling for sociodemographic factors and concurrent agent use. RESULTS: Nearly all women (97.1%) performed twalet deba, using a variety of herbal and commercially produced intravaginal agents. Approximately 11% of the participants tested positive for high-risk HPV. Pigeon pea and lime juice were the only agents found to be associated with high-risk HPV in the univariate analyses, with women who used these agents being approximately twice as likely to have high-risk HPV as those who did not. Only pigeon pea remained significantly associated with high risk HPV after controlling for sociodemographic factors and concurrent agent use. CONCLUSION: Two agents, pigeon pea and lime juice, may contribute to risk for HPV infection in this population. Results suggest that in addition to cervical cancer screening interventions, future preventive initiatives should focus on minimizing risk by advocating for the use of less-toxic twalet deba alternatives. PMID- 27774795 TI - Recent progress of cyclin-dependent kinase inhibitors as potential anticancer agents. AB - Deregulation of the cell cycle is a common feature in human cancer. The inhibition of cyclin-dependent kinases (CDKs), which play a crucial role in control of the cell cycle, has always been one of the most promising areas in cancer chemotherapy. This review first summarizes the biology of CDKs and then focuses on the recent advances in both broad-range and selective CDK inhibitors during the last 5 years. The design rationale, structural optimization and structure-activity relationships analysis of these small molecules have been discussed in detail and the key interactions with the amino-acid residues of the most important compounds are highlighted. Future perspectives for CDKs inhibitors will be defined in the development of highly selective CDK inhibitors, an accurate knowledge of gene control mechanism and further predictive biomarker research. PMID- 27774797 TI - Managing global health security: the World Health Organization and Disease outbreak control. PMID- 27774796 TI - Lignans from the shed trunk barks of the critically endangered plant Abies beshanzuensis and their anti-neuroinflammatory activities. AB - During a further and comprehensive phytochemical investigation on the shed trunk barks of the critically endangered plant Abies beshanzuensis, one new (1) and ten known (2-11) lignans with diverse structures were isolated. On the basis of spectroscopic methods, the new structure was established to be (7S,8R,8'R)-4' methoxyl-alpha-conidendrin (1). Among the isolated lignans, (-)-matairesinol (5) and (-)-arctigenin (6) showed significant anti-neuroinflammatory activities by inhibiting the overproduction of nitric oxide in lipopolysaccharide-stimulated murine BV-2 microglial cells, with IC50 values of 11.5 and 19.0 MUM, respectively. PMID- 27774799 TI - Corrigendum. PMID- 27774798 TI - Opening the door to the development of novel Abl kinase inhibitors. AB - The discovery of the importance of kinase activity and its relationship to the emergence and proliferation of cancer cells, due to changes in normal physiology, opened a remarkable pathway for the treatment of chronic myelogenous leukemia through intense search of drug candidates. Six Abl kinase inhibitors have received the US FDA approval as chronic myelogenous leukemia treatment, and continuous efforts in obtaining new, more effective and selective molecules are being carried out. Herein we discuss the mechanisms of Abl inhibition, structural features and ligand/protein interactions that are important for the design of new Abl kinase inhibitors. This review provides a broad overview of binding mode predictions, through molecular docking, which can be an approach to discover novel Abl kinase inhibitors. PMID- 27774800 TI - Neighborhood contributions to psychological distress among Latino New York City adults. AB - OBJECTIVE: Neighborhood-level factors such as ethnic densities and social cohesion have been negatively associated with psychological distress among Latino Americans. Yet, existing evidence is based on either specific neighborhood factors or particular Latino subgroups. The objective of the study was to assess difference in psychological distress between each of four Latino subgroups (Puerto Ricans, Dominicans, Mexicans, other Latinos) and non-Latino white adults in New York City, and quantify total neighborhood-level influence on these differences. DESIGN: We used the combined Community Health Survey data from 2009, 2010, and 2012 surveys. We estimated the odds ratios (ORs) for self-reported non specific psychological distress (Kessler-6 questions scale >= 13) by race/ethnicity using logistic regression models. We further adjusted these estimates for both observed and unobserved neighborhood-level confounding using the conditional pseudolikelihood method for complex survey data. RESULTS: Puerto Ricans were more likely to be psychologically distressed (OR = 1.58, 95% CI = 1.18, 2.12) compared with non-Latino whites, whereas the opposite was seen in other Latino subgroups. Accounting for full neighborhood-level confounding increased the disparity for Puerto Ricans (OR = 1.79, 95% CI = 1.26-2.54). For the other subgroups, lower odds of psychological distress were no longer observed or attenuated after accounting for neighborhood-level confounding. Overall neighborhood-level factors were associated with lower psychological distress at greater extent among all Latinos subgroups versus non-Latino whites in New York City. CONCLUSION: Despite substantial variations of psychological distress across Latino subgroups, the study shows evidence that neighborhood-level factors might play a protective role in all Latino subgroups. PMID- 27774801 TI - The effect of adult children living in the United States on the likelihood of cognitive impairment for older parents living in Mexico. AB - OBJECTIVE: The increased risk for poor physical and mental health outcomes for older parents in Mexico who have an adult child living in the United States may contribute to an increased risk for cognitive impairment in this population. The objective of this study was to examine if older adults in Mexico who have one or more adult children living in the United States are more or less likely to develop cognitive impairment over an 11-year period compared to older adults who do not have any adult children living in the United States. DESIGN: Data for this study came from Wave I (2001) and Wave III (2012) of the Mexican Health and Aging Study. The final sample included 2609 participants aged 60 and over who were not cognitively impaired in 2001 and had one or more adult children (age >=15). Participants were matched using a propensity score that was estimated with a multivariable logistic regression model that included sociodemographic characteristics and migration history of the older parents. RESULTS: Having one or more adult children living in the United States is associated with lower socioeconomic status and higher number of depressive symptoms, but greater social engagement for older parents living in Mexico. No significant differences in the odds for developing cognitive impairment according to having one or more adult children living in the United States were detected. CONCLUSION: In summary, having one or more adult children living in the United States was associated with characteristics that may increase and decrease the risk for cognitive impairment. This may contribute to the non-significant relationship between migration status of adult children and likelihood for cognitive impairment for older parents living in Mexico. PMID- 27774802 TI - [Relationship between corneal surface temperature and air flow conditions during refractive laser eye surgery using three different excimer lasers]. AB - INTRODUCTION: Thermal conditions during photorefractive keratectomy might be an important issue related to the corneal wound healing and long-term outcomes. AIM: Authors tried to find out the importance of temperature conditions during the treatment. METHOD: One eye of 90 patients has been included into the study. Photorefractive keratoctomy was applied with Carl Zeiss MEL 70, MEL 80 and Wavelight Allegretto excimer lasers. EBRO TLC 730 infrared thermometer was used for the measurement of surface temperature of the cornea before epithelial removal, as well as before and after the treatment. Average age of the patients was 25.5 +/- 3 yr. Average myopic correction was -3.2 +/- 0.8 Dpt. RESULTS: Statistically significant difference was found in temperature change between MEL 80 and the other two types of excimer laser devices. CONCLUSIONS: Different air flow conditions of the smoke removal system might have an influence on changes of the corneal temperature during treatment, but the refractive results were not influenced by this issue. Orv. Hetil., 2016, 157(43), 1717-1721. PMID- 27774804 TI - [Echocardiographic evaluation of the right atrium - from M-mode to 3D speckle tracking imaging]. AB - Echocardiographic assessment of the right atrium is a great challenge in present practice and only limited opportunities are available. Technical improvements in the last decades enable volumetric and functional analysis of the complex right atrial cardiac cyclic movements. The aim of the present review is to demonstrate the most recent three-dimensional and/or speckle tracking echocardiographic techniques over routine methodologies in the evaluation of the right atrium. Orv. Hetil., 2016, 157(43), 1698-1707. PMID- 27774803 TI - [Dental and oral surgical treatment of medication-induced bleeding patients: Audit of the national guideline in Hungary]. AB - INTRODUCTION: In 2015 a new Hungarian guideline was published regarding dental treatment and management of anticoagulated patients in agreement of the Hungarian Association of Oral and Maxillofacial Surgeons and the Dental Implantology Association of Hungarian Dentists. AIM: The aim of the authors was to evaluate the efficiency and safety of local hemostatic measures recommended by the guideline in anticoagulated patients. METHOD: In these patients, postoperative bleeding episodes were examined after dental and oral surgical treatments, retrospectively. RESULTS: Overall 263 bleeding risk cases were treated; 138 patients with vitamin K antagonists, 97 patients with antiplatelet therapy and 6 patients with novel oral anticoagulants. Six patients (2.3%) had minor postoperative bleeding after the "one hour control", while one patient needed a night duty support (0.5%). In contrast, 86 patients who were treated in rural practices neglecting the guideline attended the night duty with postoperative bleeding (3 patients treated with vitamin K antagonists, 24 patients taking low molecular weight heparin, 30 patients receiving antiplatelet therapy and one patient on novel oral anticoagulant therapy. CONCLUSIONS: The Hungarian guideline can be applied safely, without increasing the risk of postoperative bleeding, however, rural dental practices are frequently unprepared for these treatments. Orv. hetil., 2016, 157(43), 1722-1728. PMID- 27774805 TI - [Fructose and fructose intolerance]. AB - Although fructose was discovered in 1794, it was realised in recent decades only that its malabsorption can lead to intestinal symptoms while its excessive consumption induces metabolic disturbances. Fructose is a monosaccharide found naturally in most fruits and vegetables. Dietary intake of fructose has gradually increased in the past decades, especially because of the consumption of high fructose corn syrup. With its 16.4 kg/year consumption, Hungary ranks secondly after the United States. Fructose is absorbed in the small intestine by facilitated transport mediated by glucose transporter proteins-2 and -5, and arrives in the liver cells. Here it is transformed enzymatically into fructose-1 phosphate and then, fructose-1,5-diphosphate, which splits further into glyceraldehyde and dihydroxyacetone-phosphate, entering the process of glycolysis, triglyceride and uric acid production. The prevalence of fructose intolerance varies strongly, depending on the method used. The leading symptoms of fructose intolerance are similar, but less severe than those of lactose intolerance. Multiple secondary symptoms can also occur. A symptom-based diagnosis of fructose intolerance is possible, but the gold standard is the H2 breath test, though this is less accurate than in lactose testing. Measuring fructosaemia is costly, cumbersome and not widely used. Fructose intolerance increases intestinal motility and sensitivity, promotes biofilm formation and contributes to the development of gastrooesophageal reflux. Long-term use of fructose fosters the development of dental caries and non-alcoholic steatohepatitis. Its role in carcinogenesis is presently investigated. The cornerstone of dietary management for fructose intolerance is the individual reduction of fructose intake and the FODMAP diet, led by a trained dietetician. The newly introduced xylose-isomerase is efficient in reducing the symptoms of fructose intolerance. Orv. Hetil., 2016, 157(43), 1708-1716. PMID- 27774806 TI - [Retired physicians in Hungary - nationwide, representative study]. AB - INTRODUCTION: The aging population and the aging physician society is an important challenge of the New Millenium. Despite this, very few publications are dealing with the older generations' physical and mental well-being, quality of life and working conditions. AIM: The aim of this study was to describe the retired physicians populations' (n = 2112) demographic data, work status, income and health status. METHOD: Data of this representative, cross-sectional epidemiological study was obtained from online and paper-based questionnaires completed by 2112 retired physicians. RESULTS: The retired physicians' average age is 72 years, nearly two-thirds of the respondents retired after 35-45 years of service. Currently, nearly 60% are working, almost a quarter of them more than 40 hours per week. 35% of the respondents' income is below HUF 150,000. On this issue, significant differences emerge between female doctors and their male colleagues. CONCLUSIONS: The employment data of the results is consistent with the international trend, but the gender perspectives has unique significance in the international literature. Orv. Hetil., 2016, 157(43), 1729-1736. PMID- 27774808 TI - The color of child survival in Colombia, 1955-2005. AB - OBJECTIVE(S): Colombia has the third largest black population in the Americas after Brazil and the USA. In 2005 mortality rate under 5 in Colombia was 21.5 per 1000, with a reduction of 82% between 2005 and 1955. That rate is not in line with rates for Cuba (6.8), Chile (9.1) or Costa Rica (10.4). Here we aim to provide evidence that a further reduction of child mortality relates to the unspoken racial gap in a pioneering country in family planning and praised in the 2000 WHO report as having the world's fairest health care reform in terms of coverage and financial access. DESIGN: The lack of nationally representative data to estimate black/white differences in child mortality is overcome by using the ratio of children born and alive as the measure of mortality and the 2005 census data from IPUMS-I, which provides racial categories based on self-identification. The working sample contains 617,985 mothers between 15 and 49 years of age, of whom 7.7% have experienced the death of at least one child. Using individual weights, a logistic regression is regressed on race, individual and community socio-economic status (SES), and demographic variables. Second, a model by cohort is regressed to capture the evolution of the racial gap over time. Third, interactions are run to examine the racial gap across SES groups. RESULTS: The chances of losing a child are over 25% higher among black mothers relative to white mothers after controlling for individual and community SES characteristics. The racial gap remains stagnant and high for the period 1955-2005. The racial gap also is robust to changes in education and income levels. CONCLUSION: Failing to account for race slows down the improvement of child survival in Colombia relative to other countries of the region. PMID- 27774807 TI - Does one size fit all? The role of body mass index and waist circumference in systemic inflammation in midlife by race and gender. AB - OBJECTIVE: This study investigates the associations of body mass index (BMI) and waist circumference (WC) with markers of systemic inflammation in midlife by race and gender. DESIGN: Data were obtained from the Survey of Midlife in the United States, a cross-sectional, observational study of Americans 35 years old or older (White men: N = 410; White women: N = 490; Black men: N = 58; Black women: N = 117). Inflammation was measured by concentrations of fibrinogen and C-reactive protein (CRP) in fasting plasma and concentrations of E-selectin and interleukin 6 (IL-6) in fasting serum. Anthropometric data were used to obtain BMI and WC. Socio-demographic and health-related factors were assessed with a survey. Multivariate models by race and gender were estimated to test the roles of BMI and WC for each inflammation marker. RESULTS: Compared to White men, Black women have higher BMI and higher levels of all four inflammation markers; White women have lower BMI, lower WC, and lower E-selectin and fibrinogen but higher CRP; and Black men have higher fibrinogen. After adjusting for socio-demographic and health-related covariates as well as perceived discrimination, WC is associated with all four markers of inflammation among White men and women; with three markers (fibrinogen, CRP, and IL-6) of inflammation among Black women; and with CRP (and marginally with fibrinogen and E-selectin) among Black men. BMI is associated with higher CRP and fibrinogen among Black men (marginally so for White men) but not for women of either race. CONCLUSIONS: WC shows more consistent associations with inflammation markers than BMI, although the relationships vary by inflammation marker and population group. Our findings suggest that WC is a risk factor for systemic inflammation among White and Black men and women, and BMI is an additional risk factor for Black men. PMID- 27774809 TI - The moderation effect of personality on healthcare utilization in Chinese people living with HIV. AB - There is evidence that Type D personality can predict impaired quality of life and health status in various chronic conditions. The evidence is conflicting as to whether Type D is associated with increased healthcare services, and no study has reported on the healthcare utilization of people living with HIV (PLWH) who have a Type D personality. This study investigated the impact of Type D personality on healthcare utilization in a sample of Chinese PLWH and examined physical and emotional symptoms as possible mechanisms of healthcare utilization. This was a cross-sectional study of 199 PLWH in rural China. Participants completed a survey on physical symptoms, emotional symptoms, healthcare utilization, and Type D personality. Those PLWH with a Type D personality reported more physical and emotional symptoms and healthcare utilization than patients without this personality. Among PLWH who had a Type D personality, physical symptoms had a direct effect on healthcare utilization, and emotional symptoms did not significantly mediate this association. However, among PLWH without a Type D personality, emotional symptoms significantly mediated the effects of physical symptoms on healthcare utilization. PLWH with a Type D personality reported more healthcare utilization, which was attributed to their high physical symptoms rather than their emotional symptoms. These findings suggest that PLWH with a Type D personality might be bothered by intensified emotional symptoms, which might be too severe to be associated with physical symptoms and healthcare utilization. New prospective studies should focus on the pattern of healthcare utilization among patients with a Type D personality and their intensified physical and emotional symptoms. PMID- 27774810 TI - Labor market integration, immigration experience, and psychological distress in a multi-ethnic sample of immigrants residing in Portugal. AB - OBJECTIVES: This study aims at examining how factors relating to immigrants' experience in the host country affect psychological distress (PD). Specifically, we analyzed the association among socio-economic status (SES), integration in the labor market, specific immigration experience characteristics, and PD in a multi ethnic sample of immigrant individuals residing in Lisbon, Portugal. DESIGN: Using a sample (n = 1375) consisting of all main immigrant groups residing in Portugal's metropolitan area of Lisbon, we estimated multivariable linear regression models of PD regressed on selected sets of socio-economic independent variables. A psychological distress scale was constructed based on five items (feeling physically tired, feeling psychologically tired, feeling happy, feeling full of energy, and feeling lonely). RESULTS: Variables associated with a decrease in PD are being a male (demographic), being satisfied with their income level (SES), living with the core family and having higher number of children (social isolation), planning to remain for longer periods of time in Portugal (migration project), and whether respondents considered themselves to be in good health condition (subjective health status). Study variables negatively associated with immigrants' PD were job insecurity (labor market), and the perception that health professionals were not willing to understand immigrants during a clinical interaction. CONCLUSION: The study findings emphasized the importance of labor market integration and access to good quality jobs for immigrants' psychological well-being, as well as the existence of family ties in the host country, intention to reside long term in the host country, and high subjective (physical) health. Our research suggests the need to foster cross national studies of immigrant populations in order to understand the social mechanisms that transverse all migrant groups and contribute to lower psychological well-being. PMID- 27774811 TI - The financial outcome of traumatic brain injury: a single centre study. AB - OBJECTIVES: Severe traumatic brain injury (TBI) is a potentially devastating insult to the brain with high rates of fatality and neurological deficits. TBI can result in substantial costs to the centre providing care. We sought to present the experience of a Major Trauma Centre (MTC) and ascertain the financial implications of this healthcare provision, in particular detailed costs, reimbursement and the surplus or deficit accrued by the centre. DESIGN: All cranial non-elective neurosurgical admissions with a TBI over 4.5 months (26 October 2014 to 15 March 2015) were analysed retrospectively, excluding cases of chronic subdural haematoma, at an MTC in England. Demographic data were collected alongside detailed cost and income data. RESULTS: Ninety four patients were identified. The majority of patients presented with more than one diagnosis of cranial trauma. Average length of stay was 18.8 +/- 21.6 days. Total deficits as a result of treating this cohort amounted to L558,034. There was a significant association between (i) more complex presentations and (ii) a longer length of stay and the deficit accrued by the centre. The major drivers of the financial outcome were costs associated with wards, medical staffing and overheads. CONCLUSION: There was a substantial deficit accrued as a result of the management of patients with TBI at an MTC. The more complex the presentation, extensive the intervention, and lengthy the stay, the greater the deficit accrued by the centre. The current tariff payment system is not effectively reflecting the severity of injury or intensity of management of patients with TBI. PMID- 27774812 TI - Characteristics of self-identified sexual addicts in a behavioral addiction outpatient clinic. AB - Background and aims Research on sexual addiction flourished during the last decade, promoted by the development of an increased number of online sexual activities. Despite the accumulation of studies, however, evidence collected in clinical samples of treatment-seeking people remains scarce. The aim of this study was to describe the characteristics (socio-demographics, sexual habits, and comorbidities) of self-identified "sexual addicts." Methods The sample was composed of 72 patients who consulted an outpatient treatment center regarding their sexual behaviors. Data were collected through a combination of structured interviewing and self-report measures. Results Most patients were males (94.4%) aged 20-76 years (mean 40.3 +/- 10.9). Endorsement of sexual addiction diagnosis varied from 56.9% to 95.8% depending on the criteria used. The sexual behaviors reported to have the highest degree of functional impairment were having multiple sexual partners (56%), having unprotected sexual intercourse (51.9%), and using cybersex (43.6%). Ninety percent of patients endorsed a comorbid psychiatric diagnosis, and 60.6% presented at least one paraphilia. Conclusions Results showed highly different profiles in terms of sexual preferences and behaviors, as well as comorbidities involved. These findings highlight the need to develop tailored psychotherapeutic interventions by taking into account the complexity and heterogeneity of the disorder. PMID- 27774814 TI - Recent progress in repositioning Alzheimer's disease drugs based on a multitarget strategy. AB - Alzheimer's disease (AD) is a serious progressive neurological disorder, characterized by impaired cognition and profound irreversible memory loss. The multifactorial nature of AD and the absence of a cure so far have stimulated medicinal chemists worldwide to follow multitarget drug-design strategies based on repositioning approved drugs. This review describes a summary of recently published works focused on tailoring new derivatives of US FDA-approved acetylcholinesterase inhibitors, in addition to huperzine (a drug approved in China), either by hybridization with other pharmacophore elements (to hit more AD targets), or by combination of two FDA-approved drugs. Besides the capacity for improving the cholinergic activity, these polyfunctional derivatives are also able to tackle other important neuroprotective properties, such as anti-beta amyloid aggregation, scavenging of radical oxygen species, modulation of redox active metals or inhibition of monoamine oxidase, thereby resulting in potentially novel and more effective therapeutics for the treatment of AD. PMID- 27774813 TI - Cognitive distortions and ADHD in pathological gambling: A national longitudinal case-control cohort study. AB - Introduction The primary outcome of our study was to assess the links between the level of cognitive distortions and the severity of gambling disorder. We also aimed at assessing the links between patient gambling trajectories and attention deficit and hyperactivity disorder (ADHD). Materials and methods The study population (n = 628) was comprised of problem and non-problem gamblers of both sexes between 18 and 65 years of age, who reported gambling on at least one occasion during the previous year. Data encompassed socio-demographic characteristics, gambling habits, the South Oaks Gambling Screen, the Gambling Attitudes and Beliefs Survey - 23, the Wender Utah Rating Scale - Child, and the Adult ADHD Self-report Scale. Results The cognitive distortions with the greatest correlation to the severity of gambling disorder were the "Chasing" and "Emotions." These two dimensions were able to distinguish between problem gamblers seeking treatment or not. While age of onset of gambling and length of gambling practice were not associated with the level of distorted cognitions, a period of abstinence of at least 1 month was associated with a lower level of distorted cognitions. The presence of ADHD resulted in a higher level of distorted cognitions. Conclusion Cognitive work is essential to the prevention, and the treatment, of pathological gambling, especially with respect to emotional biases and chasing behavior. The instauration of an abstinence period of at least 1 month under medical supervision could be a promising therapeutic lead for reducing gambling-related erroneous thoughts and for improving care strategies of pathological gamblers. PMID- 27774815 TI - Immunomic approaches for antigen discovery of human parasites. AB - INTRODUCTION: Genetics combined with proteomics allows for a better understanding of parasite-host interactions and host immune responses. Immunomics elucidates that antigens are targets of induced or naturally acquired immunity (NAI), a promising solution to the challenge of eradicating human infections. High throughput protein microarrays enhance rapid antigen discovery for the development of serodiagnostic tests/vaccines. Areas covered: This review systematically analyzes the emergence of protein microarrays as a powerful technology for parasite antigen discovery and subsequently summarizes some of the attributes and disadvantages of these approaches. Major insights on novel/validated serological biomarkers or vaccine candidates against malaria and Neglected Tropical Diseases (NTDs) are highlighted. We conclude with a brief description of the processes involved in immunomic protein microarrays. Expert commentary: Interesting discoveries have been made using protein microarrays. However, there is a need to evaluate targets that elicit strong immunogenicity and correlates of protective efficacy to aid prioritization and guide further clinical development. The goal of parasitic disease elimination will be best achieved through an integrated strategy that will incorporate and implement the different control components. PMID- 27774816 TI - Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases. AB - The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.1.3.48) are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors. The most promising molecules proved to inhibit CDC25 isoforms at single digit micromolar concentration, becoming valuable tools in chemical biology investigations and profitable leads for further optimization. [Formula: see text]. PMID- 27774817 TI - Designing, synthesis and bioactivities of 4-[3-(4-hydroxyphenyl)-5-aryl-4,5 dihydro-pyrazol-1-yl]benzenesulfonamides. AB - In this study, 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1 yl]benzenesulfonamide (1-9) types compounds were synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity experiments pointed out that compound 4, (4-[5-(4-chlorophenyl)-3-(4 hydroxyphenyl)-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide), exerting the highest tumor selectivity (TS) and potency selectivity expression (PSE) values, can be considered as a lead compound of this study in terms of development of novel anticancer agents. All synthesized sulfonamides showed a good inhibition profile on hCA IX and XII in the range of 53.5-923 nM and 6.2-95 nM, respectively. These compounds were 2.5-13.4 times more selective for the inhibition of hCA XII versus hCA IX, except compound 2 which had similar inhibitory action towards both isoenzymes. PMID- 27774818 TI - Synthesis, carbonic anhydrase I and II inhibition studies of the 1,3,5 trisubstituted-pyrazolines. AB - 4-(3-(4-Substituted-phenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamides (9-16) were successfully synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, and HRMS spectra. Carbonic anhydrase I and II inhibitory effects of the compounds were investigated. Ki values of the compounds were in the range of 316.7 +/- 9.6-533.1 +/- 187.8 nM towards hCA I and 412.5 +/- 115.4-624.6 +/- 168.2 nM towards hCA II isoenzymes. While Ki values of the reference compound Acetazolamide were 278.8 +/- 44.3 nM and 293.4 +/- 46.4 nM towards hCA I and hCA II izoenzymes, respectively. Compound 14 with bromine and compound 13 with fluorine substituents can be considered as the leader compounds of the series because of the lowest Ki values in series to make further detailed carbonic anhydrase inhibiton studies. PMID- 27774819 TI - Multicomponent pattern and biological activities of seven Asphodeline taxa: potential sources of natural-functional ingredients for bioactive formulations. AB - The current study was carried out to evaluate multicomponent pattern, biological and enzymatic activities of seven Asphodeline taxa root extracts as useful ingredients, due to the fact that these plants are commonly used as traditional food supplements in Turkish regions. The extracts were characterized for free anthraquinones and phenolics to obtain a specific chemical fingerprint useful for quality control. These analyzes were coupled to biological and enzymatic activities in order to obtain comprehensive information of the natural product. Free anthraquinones and phenolics were determined using validated HPLC-PDA methods. Antioxidant properties were determined by different procedures including free radical scavenging, reducing power, phosphomolybdenum and metal chelating assays. Ames assay was performed to evaluate mutagenic/antimutagenic properties. Enzyme inhibitory activities were tested against cholinesterase, tyrosinase, alpha-amylase and alpha-glucosidase. From the herein reported results, Asphodeline could be valuable for the production of bioactive products or food supplements for cosmetic and pharmaceutical industries. PMID- 27774821 TI - Schiff bases in medicinal chemistry: a patent review (2010-2015). AB - INTRODUCTION: Schiff bases are synthetically accessible and structurally diverse compounds, typically obtained by facile condensation between an aldehyde, or a ketone with primary amines. Schiff bases contain an azomethine (-C = N-) linkage that stitches together two or more biologically active aromatic/heterocyclic scaffolds to form various molecular hybrids with interesting biological properties. Schiff bases are versatile metal complexing agents and have been known to coordinate all metals to form stable metal complexes with vast therapeutic applications. Areas covered: This review aims to provide a comprehensive overview of the various patented therapeutic applications of Schiff bases and their metal complexes from 2010 to 2015. Expert opinion: Schiff bases are a popular class of compounds with interesting biological properties. Schiff bases are also versatile metal complexing ligands and have been used to coordinate almost all d-block metals as well as lanthanides. Therapeutically, Schiff bases and their metal complexes have been reported to exhibit a wide range of biological activities such as antibacterial including antimycobacterial, antifungal, antiviral, antimalarial, antiinflammatory, antioxidant, pesticidal, cytotoxic, enzyme inhibitory, and anticancer including DNA damage. PMID- 27774822 TI - Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2. AB - INTRODUCTION: Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts. The authors have ordered recent patents according to the primary applicant's name, with part 2 covering J through Z. Expert opinion: Inhibition of JAK-family kinases is an area of growing interest, catalysed by the maturity of data on marketed inhibitors ruxolitinib and tofacitinib in late stage clinical trials. Many applicants are pursuing traditional fast-follower strategies around these inhibitors, with a range of chemical strategies adopted. The challenge will be to show sufficient differentiation to the originator compounds, since dose limiting toxicities with such agents appear to be on target and mechanism-related and also considering that such agents may be available as generic compounds by the time follower agents reach market. PMID- 27774820 TI - Myelofibrosis: an update on drug therapy in 2016. AB - INTRODUCTION: Primary myelofibrosis (PMF) is the least common but the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms. Survival is much shorter in PMF than in polycythemia vera (PV) or essential thrombocythemia (ET). Post-PV/ET myelofibrosis (MF) is clinically indistinguishable from PMF and approached similarly. Areas covered: Current pharmacologic therapy of MF revolves around the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, which dramatically improves constitutional symptoms and splenomegaly in the majority of patients, and improves overall survival (OS). However, allogeneic stem cell transplantation remains the only potential cure. Other JAK inhibitors continue to be developed for MF, and momelotinib and pacritinib are in phase III clinical trials. Anemia is common in MF, and initially worsened by ruxolitinib. Momelotinib and pacritinib may prove advantageous in this regard. Current strategies for managing anemia of MF include danazol, immunomodulatory drugs and erythroid stimulating agents, either alone or in combination with ruxolitinib. Expert opinion: A number of other agents, representing diverse drug classes, are in various stages of development for MF. These include newer JAK inhibitors, other signaling inhibitors, epigenetic modifiers, anti-fibrotic agents, telomerase inhibitors, and activin receptor ligand traps (for anemia). Hopefully, these novel therapies will further extend the clinical benefits of ruxolitinib. PMID- 27774823 TI - Endoscopic third ventriculostomy: A historical review. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) has become one of the most common neuroendoscopic procedures. METHODS: In this article, we will review the major milestones in the history of ETV development from its early use by Walter Dandy to the techniques currently employed with advanced technology. CONCLUSIONS: ETV has become an important technique in the armamentarium of the neurosurgeon. From a meager beginning with few applications, our knowledge of long-term outcomes has evolved. ETV has a rich history and more recently, has had a renewed interest in its use. Our current understanding of its indications is growing and is based on a century of development through trial and error. PMID- 27774824 TI - Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1. AB - INTRODUCTION: Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera. Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013-2015 inclusive, and covers 95 patents from 42 applicants, split over two parts. The authors have ordered recent patents according to the primary applicant's name, with part 1 covering A through to I. Expert opinion: Inhibition of JAK-family kinases is an area of growing interest, catalysed by the maturity of data on marketed inhibitors ruxolitinib and tofacitinib in late stage clinical trials. Many applicants are pursuing traditional fast-follower strategies around these inhibitors, with a range of chemical strategies adopted. The challenge will be to show sufficient differentiation to the originator compounds, since dose limiting toxicities with such agents appear to be on target and mechanism-related and also considering that such agents may be available as generic compounds by the time follower agents reach market. PMID- 27774825 TI - Optimum treatment of vasopressor-dependent distributive shock. AB - INTRODUCTION: Distributive shock is associated with decreased systemic vascular resistance and altered oxygen extraction. Septic shock is the most frequent form of distributive shock. In shock states, duration of hypotension is associated with poor outcomes. The speed at which treatment to restore adequate perfusion pressure is initiated is, therefore, important to improve survival. Areas covered: This review presents an overview of the literature related to the management of vasopressor-dependent distributive shock, and in particular the relationship between arterial pressure and organ perfusion and function. Studies that have tried to determine an optimal blood pressure level are discussed demonstrating that it is difficult to define and will vary according to individual patient factors, including age and a history of chronic hypertension. An initial target mean arterial pressure (MAP) of 65-70 mmHg is probably sufficient in most patients. The influence of increasing MAP on the microcirculation is also covered. Expert commentary: Microcirculatory monitoring may be the best way to individualize management of these patients, but remains experimental at present. In the meantime, repeated blood lactate levels and venous oxygen saturations, combined with hemodynamic variables and the clinical picture, can provide an indication of the response to treatment and adequacy of tissue perfusion. PMID- 27774827 TI - Stereoselective hepatic disposition of ibuprofen in the perfused liver of rat with adjuvant-induced arthritis. AB - 1. The effects of adjuvant-induced arthritis (AA) on the stereoselective hepatic disposition and chiral inversion of "profens" have scarcely been investigated. Ibuprofen (IB) undergoes unidirectional chiral inversion from R-IB to S-IB and is metabolized to IB-glucuronide (IB-Glu). 2. We used an in situ perfused rat liver system to clarify the effects of inflammation on the metabolic activities and chiral inversion of IB without protein binding. 3. After dosing of R-IB, AA had minimal effect on the elimination of R-IB from the perfusate. Larger amounts of S IB-Glu than R-IB-Glu were observed in the bile at the dose of 2.4 and 4.8 MUmol. However, after dosing of S-IB, the elimination of S-IB from the perfusate in AA rats was delayed, indicating a significant decrease in the hepatic clearance in AA rats. The cumulative biliary excretion of S-IB-Glu in AA rats was promoted after dosing with S-IB. There was little difference between the chiral inversion ratios of the control and AA rats. 4. The present study demonstrated that AA results in the delayed elimination of S-IB, the active form, without changes to the chiral inversion ratio. Thus, further attention to the altered stereoselective pharmacokinetics of IB during inflammation is required. PMID- 27774826 TI - Mesenchymal stem cells: a future experimental exploration for recession of diabetic nephropathy. AB - BACKGROUND: The progresses made in stem cell therapy offer an innovative approach and exhibit great potential for the repair of damaged organs and tissues. This study was conducted with a view to find the mechanisms responsible for the effectiveness of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the suppression of diabetes and experimentally-induced diabetic nephropathy. METHODS: To realize this objective, diabetic and diabetic nephropathy subject groups that underwent MSC treatment were studied through numerous biochemistry and molecular genetics analyses. RESULTS: The findings show that, relative to the control groups, the rats in the diabetic and diabetic nephropathy groups treated with stem cells infused with BM-MSCs showed a significant reversal in the levels of their insulin, glucose, heme-oxygenase-1 (HO-1) serum, and advanced glycation end product (AGEP). Moreover, BM-MSC therapy was also found to have a definite positive effect on the kidney functions. In addition, it also corresponded with a significant decrease in the availability of certain growth factors, namely the fibroblast growth factor (FGF), the platelet-derived growth factor (PDGF), and the transforming growth factor-beta (TGF-beta). BM-MSC treatment also improved the levels of expression of monocyte chemoatractant-1 (MCP-1) and interleukin-8 (IL-8) genes within kidney tissues. Lastly, the treatment recovered the organizational structure of the kidney and pancreas, a result demonstrated by a histopathological analysis. These results greatly coincide with those obtained through the biochemistry and molecular genetics analyses. CONCLUSION: Treatment using BM-MSCs is determined to be definitely effective in cases of diabetes and diabetic nephropathy. PMID- 27774828 TI - Integrating mental health in primary healthcare in low-income countries: changing the future for people with mental disorders. AB - BACKGROUND: Untreated mental disorders are a huge challenge for healthcare systems worldwide. Treatment possibilities are particularly scarce in low-income countries (LICs). WHO estimates that up to 85% of all people with a mental disorder in LICs do not have access to evidence-based treatment. AIMS: This paper seeks to explore the rationale behind the WHO recommendations for improving mental health services in LICs. At the core of these recommendations is an integration of mental health services into existing primary healthcare. This article presents available research supporting this approach. Furthermore, it highlights challenges needing special attention and opportunities demanding additional research to guide a comprehensive restructuring of a healthcare system. METHODS: A literature review of WHO documents and searches on PubMed for relevant supporting literature. RESULTS: Research from LICs that investigate mental health interventions is scarce. The evidence that does exist favours integration into primary healthcare. There is evidence that collaborative- and stepped-care interventions can provide viable treatment options for patients. CONCLUSION: Integration of mental health services into primary healthcare seems like a viable solution to ensure that treatment becomes more available, even though the evidence is limited. Locally conducted research is needed to guide the development of sustainable evidence-based mental health treatment, involving relevant healthcare providers, with optimal task-sharing and possibilities for referral of complex cases. Furthermore, to achieve this, comprehensive political will and investments are necessary pre-requisites. PMID- 27774829 TI - Association between satisfaction and participation in everyday occupations after stroke. AB - BACKGROUND: Within occupational therapy, it is assumed that individuals are satisfied when participating in everyday occupations that they want to do. However, there is little empirical evidence to show this. AIMS: The aim of this study is to explore and describe the relation between satisfaction and participation in everyday occupations in a Swedish cohort, 5 years post stroke. METHODS: Sixty-nine persons responded to the Occupational Gaps Questionnaire (OGQ). The questionnaire measures subjective restrictions in participation, i.e. the discrepancy between doing and wanting to do 30 different occupations in everyday life, and satisfaction per activity. Results were analysed with McNemar/chi-square. RESULTS: Seventy percent of the persons perceived participation restrictions. Individuals that did not perceive restrictions in their participation had a significantly higher level of satisfaction (p = .002) compared to those that had restrictions. Participants that performed activities that they wanted to do report between 79 and 100% satisfaction per activity. CONCLUSION: In this cohort, there was a significant association between satisfaction and participating in everyday occupations one wants to do, showing that satisfaction is an important aspect of participation and substantiates a basic assumption within occupational therapy. The complexity of measuring satisfaction and participation in everyday occupations is discussed. PMID- 27774830 TI - In response to: The lack of public health teaching for medical students reinforces false stereotypes. PMID- 27774831 TI - Risk factors of severe peritoneal sclerosis in chronic peritoneal dialysis patients. AB - Peritoneal dialysis (PD) offers the healthiest way for starting renal replacement therapy (RRT) in End Stage Renal Disease patients, however exposes long-term PD patients to a dangerous complication named encapsulating peritoneal sclerosis (EPS). In this study, we searched for possible risk factors of EPS. Data were collected from two PD centers covering period 1995-2012 and comprised 464 patients. Control group defined as PD patients stayed on PD >42 month (n = 122), and case group was 12 confirmed EPS patients. Associations were analyzed using linear regression analysis. Prevalence and incidence of EPS were 2.59% and 8.9% with an incidence of 0.7% patient-years, respectively. The age at start of PD in EPS patients (32.75 +/- 10.8 year) was significantly lower compared with control group (49.61 +/- 16.18 year, p = .0001). The mean duration of PD in EPS and control group were 2494.4 +/- 940.9 and 1890.2 +/- 598.8 days (p = .002). Control group had 145 episodes of peritonitis during total duration of 7686 patient months (peritonitis rate of 1/53). This was 1/26 with a total 38 episodes of peritonitis during the total duration of 997 patient months (p = .01) for EPS group. In regression analysis, PD duration, age at PD start and duration of Ultrafiltration failure (UFF) were associated with EPS. Longer time being on PD, younger age, and higher UFF duration were the risk factors for EPS development. PMID- 27774832 TI - Gender differences in first onset Schizophrenia spectrum psychoses. AB - BACKGROUND: Mental health profiles differ between boys and girls from puberty onwards. It is not known whether differences also extend to symptom presentation in schizophrenia spectrum disorders. It may be that girls and boys are not treated entirely equally by the professionals. AIMS: To study gender differences in symptom profiles, family adversities, pathway to care, and characteristics of inpatient treatment at the first episode of diagnosed schizophrenia spectrum disorder (F20-29) among adolescents aged 13-17. METHODS: A retrospective chart review of all (n = 106) consecutive adolescents diagnosed for the first time with schizophrenia spectrum disorder (F20-29) in a specified catchment area. Girls and boys were compared with regard to sociodemographics, pathways to care, living arrangements, symptom profiles, and treatment received. RESULTS: During the study period more adolescent girls (n = 70, 66%) than boys (n = 36, 34%) were diagnosed with schizophrenia spectrum (F20-29) psychoses, most commonly F29. Girls were moreover younger (mean age = 15.46) than boys (mean age = 16.62) at admission. Girls more often displayed mood symptoms and boys aggressive behaviours, alcohol abuse problems, and isolation. Family adversities recorded as current stressors were more numerous among girls. Girls were more likely to be referred to specialized after-care than boys. CONCLUSIONS: The gender differences observed in symptoms presentation are reminiscent of differences encountered in the general adolescent population. Prior to transition to psychosis, girls and boys are equally in contact with psychiatric services due to other (possibly prodromal) symptoms/disorders. Family adversities may be more stressful for girls vulnerable to psychosis than to boys. PMID- 27774833 TI - Outcome after pin fixation of supracondylar humerus fractures in children: postoperative radiographic examinations are unnecessary. AB - Background and purpose - The quality of pin fixation of displaced supracondylar humerus fractures in children has not been assessed, and the clinical value of radiographic examinations after pin fixation is unclear. We evaluated pin configuration, quality of osteosynthesis, and outcome in 264 supracondylar fractures. The clinical significance of postoperative radiographs was analyzed. Patients and methods - 252 Gartland-III and 12 flexion-type supracondylar humerus fractures were pin-fixed in the periods 2002-2006 and 2012-2014. During 2012 2014, staff were intructed that postoperative radiographs should not be taken. Quality of reduction was assessed by measuring Baumann and lateral capitellohumeral angles (LCHA) and also by recording the crossing point of the anterior humeral line (AHL) with bony capitellum. Rotatory alignment was registered as normal or abnormal. Pin configuration and quality of osteosynthesis were evaluated. The clinical significance of postoperative radiographs was analyzed. Results - Postoperatively, Baumann angle was normal in 66% of the fractures, AHL crossed the capitellum in 84%, and no malrotation was evident in 85% of the fractures. Crossed pins were used in 89% of the cases. 2 or more pins fixed both fracture fragments in 66%. Radiographic examinations were inadequate for assessment of LCHA in 13%, of Bauman angle in 8%, of AHL in 2%, of rotation in 1%, and of pin fixation in 2% of the cases. Postoperative radiographs did not give useful information except in 1 patient who had corrective osteotomy. All 94 patients with follow-up (97%) who were treated during 2012-2014 were satisfied with the outcome. Interpretation - Despite pin fixation being deemed unsatisfactory in one-third of the cases, significant malunion was rare. Postoperative radiography did not alter management or outcome. PMID- 27774835 TI - The contributions to the human dorsal column tracts from the spinal cord laminae. AB - The dorsal column tracts (fasciculus gracilis and fasciculus cuneatus) are concerned with discriminative qualities of sensation. There are controversial descriptions related to the relations of dorsal column tracts with the dorsal horn laminae in text-books. The present study aims to define the laminae of the dorsal horn of the spinal cord that contribute fibers to the dorsal column tracts in the cervical, thoracic and lumbar spinal level. Series paraffin spinal cords sections of six formalin-embalmed adult human cadavers were evaluated. The present study shows that dorsal column tracts receive fiber contributions from laminae III and V and from Clarke's dorsal nucleus at varying spinal levels. At upper cervical levels (C1-C4) fiber contributions were from lamina V and few from lamina III, and at lower cervical levels (C5-C8) there were, in addition to these laminae, also contributions from the Clarke's dorsal nucleus. At upper thoracic levels (T1-T4) fiber contributions were from lamina V and few from Clarke's dorsal nucleus. At lower thoracic (T5-T12) and lumbar levels (L1-L5), in contrast, fiber contributions were only from Clarke's dorsal nucleus. The detailed knowledge of organization of the dorsal column tracts of the spinal cord may pave the way for future treatments of the spinal cord injuries. PMID- 27774834 TI - The role of race/ethnicity in cerclage efficacy. AB - OBJECTIVE: To measure the impact of race/ethnicity on cerclage efficacy, as measured by the prevalence of spontaneous preterm birth (PTB), in a cohort of patients with history-indicated, ultrasound-indicated and physical-exam indicated cerclages. METHODS: We conducted a retrospective cohort study of patients undergoing history-indicated, ultrasound-indicated and physical-exam indicated cerclage placement from January 2003 to July 2013 at a tertiary care hospital. Patients' race/ethnicity was self-declared. Our primary outcome was spontaneous preterm birth (SPTB) < 37 weeks. Subgroup analyses were performed for each of the three indications for cerclage. RESULTS: One hundred and eighty-one subjects met inclusion criteria. Forty-seven percent self-identified as non-Hispanic black (NHB), 12% as Hispanic and 41% as non-Hispanic white (NHW). There was no significant difference in the prevalence of SPTB < 37 weeks between the three race/ethnicity groups (33% versus 19% versus 40%, respectively, p = 0.22), nor for SPTB less than 34 or 28 weeks. Finally, there was no difference in SPTB prevalence by race after controlling for smoking, history of CKC/LEEP, and 17 OHPC with logistic regression. CONCLUSION: Race/ethnicity does not appear to be associated with cerclage efficacy, as measured by the risk of SPTB, in a cohort of patients with history-indicated, ultrasound-indicated and physical-exam indicated cerclages. PMID- 27774836 TI - A neural network model for visual selection and shifting. AB - In this paper, a two-layer network is built to simulate the mechanism of visual selection and shifting based on the mapping dynamic model for instantaneous frequency. Unlike the differential equation model using limit cycle to simulate neuron oscillation, we build an instantaneous frequency mapping dynamic model to describe the change of the neuron frequency to avoid the difficulty of generating limit cycle. The activity of the neuron is rebuilt based on the instantaneous frequency and in this work, we use the first layer of neurons to implement image segmentation and the second layer of neurons to act as visual selector. The frequency of the second neuron (central neuron) is always changing, while central neuron resonates with the neurons corresponding to an object, the object is selected, then with the central neuron frequency changing, the selected object loses attention, the process goes on. PMID- 27774837 TI - Parameter pattern discovery in nonlinear dynamic model for EEGs analysis. AB - We propose a nonlinear dynamic model for an invasive electroencephalogram analysis that learns the optimal parameters of the neural population model via the Levenberg-Marquardt algorithm. We introduce the crucial windows where the estimated parameters present patterns before seizure onset. The optimal parameters minimizes the error between the observed signal and the generated signal by the model. The proposed approach effectively discriminates between healthy signals and epileptic seizure signals. We evaluate the proposed method using an electroencephalogram dataset with normal and epileptic seizure sequences. The empirical results show that the patterns of parameters as a seizure approach and the method is efficient in analyzing nonlinear epilepsy electroencephalogram data. The accuracy of estimating the optimal parameters is improved by using the nonlinear dynamic model. PMID- 27774839 TI - Differences in Brain Glucose Metabolism During Preparation for 131I Ablation in Thyroid Cancer Patients: Thyroid Hormone Withdrawal Versus Recombinant Human Thyrotropin. AB - BACKGROUND: In preparation for 131I ablation, temporary withdrawal of thyroid hormone is commonly used in patients with thyroid cancer after total thyroidectomy. The current study aimed to investigate brain glucose metabolism and its relationships with mood or cognitive function in these patients using 18F fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET). METHOD: A total of 40 consecutive adult patients with thyroid carcinoma who had undergone total thyroidectomy were recruited for this cross-sectional study. At the time of assessment, 20 patients were hypothyroid after two weeks of thyroid hormone withdrawal, while 20 received thyroid hormone replacement therapy and were euthyroid. All participants underwent brain 18F-FDG-PET scans and completed mood questionnaires and cognitive tests. Multivariate spatial covariance analysis and univariate voxel-wise analysis were applied for the image data. RESULTS: The hypothyroid patients were more anxious and depressed than the euthyroid participants. The multivariate covariance analysis showed increases in glucose metabolism primarily in the bilateral insula and surrounding areas and concomitant decreases in the parieto-occipital regions in the hypothyroid group. The level of thyrotropin was positively associated with the individual expression of the covariance pattern. The decreased 18F-FDG uptake in the right cuneus cluster from the univariate analysis was correlated with the increased thyrotropin level and greater depressive symptoms in the hypothyroid group. CONCLUSIONS: These results suggest that temporary hypothyroidism, even for a short period, may induce impairment in glucose metabolism and related affective symptoms. PMID- 27774840 TI - Cost effectiveness of adding clostridial collagenase ointment to selective debridement in individuals with stage IV pressure ulcers. AB - OBJECTIVE: The purpose of this study was to determine the cost effectiveness (from a payer's perspective) of adding clostridial collagenase ointment (CCO) to selective debridement compared with selective debridement alone (non-CCO) in the treatment of stage IV pressure ulcers among patients identified from the US Wound Registry. METHODS: A 3-state Markov model was developed to determine costs and outcomes between the CCO and non-CCO groups over a 2-year time horizon. Outcome data were derived from a retrospective clinical study and included the proportion of pressure ulcers that were closed (epithelialized) over 2 years and the time to wound closure. Transition probabilities for the Markov states were estimated from the clinical study. In the Markov model, the clinical outcome is presented as ulcer-free weeks, which represents the time the wound is in the epithelialized state. Costs for each 4-week cycle were based on frequencies of clinic visits, debridement, and CCO application rates from the clinical study. The final model outputs were cumulative costs (in US dollars), clinical outcome (ulcer-free weeks), and incremental cost-effectiveness ratio (ICER) at 2 years. RESULTS: Compared with the non-CCO group, the CCO group incurred lower costs ($11,151 vs $17,596) and greater benefits (33.9 vs 16.8 ulcer-free weeks), resulting in an economically dominant ICER of -$375 per ulcer. Thus, for each additional ulcer free week that can be gained, there is a concurrent cost savings of $375 if CCO treatment is selected. Over a 2-year period, an additional 17.2 ulcer-free weeks can be gained with concurrent cost savings of $6,445 for each patient. CONCLUSIONS: In this Markov model based on real-world data from the US Wound Registry, the addition of CCO to selective debridement in the treatment of pressure ulcers was economically dominant over selective debridement alone, resulting in greater benefit to the patient at lower cost. PMID- 27774841 TI - Patient demographics and psychological functioning as predictors of unilateral termination of psychodynamic therapy. AB - : Approximately one in five patients drops out of treatment before its completion. Little is known about consistent predictors of dropout, and most studies focus on patients' demographic characteristics. A mass of information is collected daily at intake in clinical practice. Based on psychodynamic theoretical conceptualizations and accumulative clinical experience, this information may help predict dropout, and thereby expand the empirically based predictors of dropout. OBJECTIVE: The present study aims at bridging between scientific research and clinical practice by investigating potential predictors of unilateral termination collected at intake, before therapy, in addition to predictors already identified in the literature. METHOD: The study was based on data from 413 patients from a university consulting center. Each patient completed a pre-intake questionnaire collecting demographic information, and underwent an interview conducted by a professional intaker. RESULTS: Results indicate that the consistent predictors described in the literature, education, and age, were related to unilateral termination rates. Additionally, lower intrapsychic functionality, as evaluated by the intakers, was also found to contribute uniquely to higher unilateral termination rates. CONCLUSION: This finding attests to the unique value of professional evaluations of patients' intrapsychic functionality, frequently conducted in clinical practice, to detect patients at risk of unilateral termination of treatment. PMID- 27774838 TI - Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. AB - BACKGROUND: Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid may have prothrombotic and proconvulsant effects. METHODS: In a trial with a 2-by-2 factorial design, we randomly assigned patients who were scheduled to undergo coronary-artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS: Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fisher's exact test). CONCLUSIONS: Among patients undergoing coronary-artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639 .). PMID- 27774842 TI - Epidemiology, management and survival outcomes of primary cutaneous melanoma: a ten-year overview. AB - BACKGROUND: Malignant melanoma (MM) is the most aggressive type of skin cancer, accounting for 90% of all the skin cancer mortality. The objective of this study was providing an overview of current patient- and tumour characteristics, treatment strategies, complications and survival in patients with MM over the past ten years. Hereby, an up-to-date view of every day clinical practice is obtained. METHODS: Files of patients treated for primary cutaneous melanoma (n = 686) in the VieCuri Medical Centre in the Netherlands between January 2002 and December 2013 were retrospectively reviewed. Relevant patient features, tumour characteristics, and (surgical) outcomes were evaluated. RESULTS: The majority of all the patients presented thin tumours (59.1% stage 1A/in situ melanoma). Men showed more ulceration (17.7% vs. 8.4%, p < .01) and a significantly higher Breslow thickness than women (1.2 mm vs. 0.9 mm, p < .01). 14.6% (40/273) underwent sentinel lymph node biopsy (SLNB); 10/40 (25%) showed nodal metastasis, 50 patients (7.3%) developed distant metastases (M: 10.6%, F: 5%, p < .01). One-, 5- and 10- year disease specific survival rates were 96%, 86% and 84%, respectively. Median survival for stage 4 MM was 3 months. Extensive surgery was uncommon (n = 3). CONCLUSIONS: Patients generally presented with thin melanomas. Lymph node disease and distant metastases remained infrequently observed during following years, and general 1- and 5-year overall disease-specific survival rates exceeded 85%. Small numbers of rescue surgery and palliative medical treatment warrant further centralisation and investigation. PMID- 27774843 TI - Employment outcome and predictors of competitive employment at 2-year follow-up of a vocational rehabilitation programme for individuals with schizophrenia in a high-income welfare society. AB - BACKGROUND: Employment is an important part of recovery for individuals with schizophrenia. The employment rate for this group is as low as 10% in Norway, and major system related barriers to employment are evident. AIMS: This study reports the competitive employment outcome at 2-year follow-up of a vocational rehabilitation study augmented with cognitive remediation (CR) or elements from cognitive behaviour therapy (CBT) for individuals with schizophrenia spectrum disorders. It also investigates if global functioning, self-esteem, and depression at baseline predicts employment outcome, and if change in these variables during the intervention period is associated with employment outcome. METHOD: One hundred and forty-eight participants with schizophrenia spectrum disorders in six Norwegian counties received 10 months vocational rehabilitation augmented with either CBT (n = 84) or CR (n = 64). Both competitive and sheltered workplaces were used. Participants were assessed at baseline, at the end of the intervention period, and at 2-year follow-up. RESULTS: At 2-year follow-up, 21.2% had obtained competitive employment. A further 25.3% had work placements in competitive workplaces. Significant improvements were found in global functioning, self-esteem, and depression during the intervention period, but no significant differences between the two intervention groups. High baseline global functioning and self-esteem, as well as positive change in these variables during the intervention period, were significantly associated with higher competitive employment outcome at 2-year follow-up. CONCLUSION: The results add to existing evidence that competitive employment is attainable for individuals with schizophrenia. High global functioning and self-esteem were strongly associated with competitive employment outcome. PMID- 27774845 TI - [Formula: see text]A longitudinal analysis of the attention networks in 6- to 11 year-old children. AB - Attention is critical for everyday functioning. Posner and Petersen's model of attention describes three neural networks involved in attention control-the alerting network for arousal, the orienting network for selecting sensory input and reorienting attention, and the executive network for the regulatory control of attention. No longitudinal research has examined relative change in these networks in children. A modified version of the attention network task (ANT) was used to examine changes in the three attention networks, three times over 12 months, in 114 6-, 8- and 10-year-olds. Findings showed that the alerting network continued to develop over this period, the orienting network had stabilized by 6 years, and the conflict network had largely stabilized by 7 years. The reorienting of attention was also assessed using invalid cues, which showed a similar developmental trajectory to the orienting attention network and had stabilized by 6 years. The results confirm that age 6 to 7 years is a critical period in the development of attention, in particular executive attention. The largest improvement over the evaluation period was between 6 and 7 years; however, subtle changes were found in attention beyond 8 years of age. PMID- 27774844 TI - The Estimated Verbal GCS Subscore in Intubated Traumatic Brain Injury Patients: Is it Really Better? AB - The Glasgow Coma Scale (GCS) has limited utility in intubated patients due to the inability to assign verbal subscores. The verbal subscore can be derived from the eye and motor subscores using a mathematical model, but the advantage of this method and its use in outcome prognostication in traumatic brain injury (TBI) patients remains unknown. We compared the validated "Core+CT"-IMPACT-model performance in 251 intubated TBI patients prospectively enrolled in the longitudinal OPTIMISM study between November 2009 and May 2015 when substituting the original motor GCS (mGCS) with the total estimated GCS (teGCS; with estimated verbal subscore). We hypothesized that model performance would improve with teGCS. Glasgow Outcome Scale (GOS) scores were assessed at 3 and 12 months by trained interviewers. In the complete case analysis, there was no statistically or clinically significant difference in the discrimination (C-statistic) at either time-point using the mGCS versus the teGCS (3 months: 0.893 vs. 0.871;12 months: 0.926 vs. 0.92). At 3 months, IMPACT-model calibration was excellent with mGCS and teGCS (Hosmer-Lemeshow "goodness-of-fit" chi square p value 0.9293 and 0.9934, respectively); it was adequate at 12 months with teGCS (0.5893) but low with mGCS (0.0158), possibly related to diminished power at 12 months. At both time-points, motor GCS contributed more to the variability of outcome (Nagelkerke DeltaR2) than teGCS (3 months: 5.8% vs. 0.4%; 12 months: 5% vs. 2.6%). The sensitivity analysis with imputed missing outcomes yielded similar results, with improved calibration for both GCS variants. In our cohort of intubated TBI patients, there was no statistically or clinically meaningful improvement in the IMPACT-model performance by substituting the original mGCS with teGCS. PMID- 27774846 TI - MLL-rearranged mixed phenotype acute leukemia masquerading as B-cell ALL. PMID- 27774850 TI - Anton T. Boisen's "Psychiatric Examination: Content of Thought" (c. 1925-31): An Attempt to Grasp the Meaning of Mental Disorder. PMID- 27774847 TI - Differential response to hypomethylating agents based on sex: a report on behalf of the MDS Clinical Research Consortium (MDS CRC). AB - First-line therapy for higher-risk myelodysplastic syndromes (MDS) includes decitabine (DAC) or azacitidine (AZA). Variables have not identified differential response rates between these. We assessed the influence of patient sex on outcomes including overall survival (OS) in 642 patients with higher-risk MDS treated with AZA or DAC. DAC-treated patients (35% of females, 31% of males) had marginally better OS than AZA-treated patients (p = .043), (median OS of 18.7 months versus 16.4 months), but the difference varied strongly by sex. Female patients treated with DAC had a longer median OS (21.1 months, 95% CI: 16.0-28.0) than female patients treated with AZA (13.2 months, 95% CI: 11.0-15.9; p = .0014), while for males there was no significant difference between HMAs (median OS 18.3 months with DAC versus 17.9 months for AZA, p = .59). The biological reason for this variability is unclear, but may be a consequence of differences in cytidine deaminase activity between men and women. PMID- 27774853 TI - Detection of pseudocowpox virus in water buffalo (Bubalus bubalis) with vesicular disease in the state of Sao Paulo, Brazil, in 2016. AB - BACKGROUND: Parapoxviruses are zoonotic viruses that infect cattle, goats and sheep; there have also been reports of infections in camels, domestic cats and seals. OBJECTIVE: The objective of this report was to describe a case of vesicular disease caused by pseudocowpox virus (PCPV) in water buffalo (Bubalus bubalis) in Brazil. ANIMALS: Sixty buffalo less than 6 months old exhibited ulcers and widespread peeling of the tongue epithelium. There were no cases of vesicular disease in pigs or horses on the same property. METHODS: Samples were analysed by PCR and sequencing. Phylogenetic analysis in MEGA 7.01 was reconstructed using major envelope protein (B2L) by the Tamura three-parameter nucleotide substitution model and the maximum likelihood and neighbor joining models, both with 1000 bootstrap replicates. The genetic distance between the groups was analysed in MEGA using the maximum composite likelihood model. The rate variation among sites was modeled using gamma distribution. RESULTS: The presence of PCPV in the buffalo herd could be demonstrated in epithelium and serum. The minimum genetic distance between the isolated PCPV strain (262-2016) and orf virus and bovine papular stomatitis virus was 6.7% and 18.4%, respectively. The maximum genetic distance calculated was 4.6% when compared with a PCPV detected in a camel. Conclusions/Clinical Importance: The peculiar position of the isolated strain in the phylogenetic trees does not necessarily indicate a different kind of PCPV that infects buffalo. More samples from cattle and buffalo in Brazil must be sequenced and compared to verify if PCPV from buffalo are genetically different from samples derived from cattle. PMID- 27774854 TI - Detection of Leishmania (L.) infantum in stray dogs by molecular techniques with sensitive species-specific primers. AB - BACKGROUND: Canine visceral leishmaniasis (CVL) is a worldwide parasitic zoonosis caused by Leishmania (Leishmania) infantum around the world. Canids are the definitive hosts and sand flies the intermediate hosts. OBJECTIVE: To test the hypothesis that a new species-specific primers (Lch14:Lch15, targeting a multiple alignment for L. infantum kDNA minicircle) is an efficient diagnostic tool for L. infantum. METHODS: The presence of L. infantum DNA was assessed in blood samples of 69 stray dogs using the conventional PCR (cPCR) and quantitative PCR (qPCR). Additional 50 lymph nodes and 50 bone marrow samples (positive and negative samples for parasitological tests) from dogs from endemic and nonendemic areas for CVL were also used. RESULTS: L. infantum strains, and all positive lymph node and bone marrow samples for parasitological test gave positive results for cPCR and qPCR, presenting analytical sensitivity of ~100 parasite mL-1. For the blood samples, 40/69 (58%; CI 95%; 46%-69%) resulted positive for L. infantum in both tests. All positive samples were confirmed by sequencing. CONCLUSION: This study showed the importance of the specific detection of L. infantum based on species specific primers by molecular techniques, highlighting the application as a confirmation method in epidemiological studies and to adopt the best control measures. PMID- 27774855 TI - Preparation and properties of biomedical segmented polyurethanes based on poly(ether ester) and uniform-size diurethane diisocyanates. AB - This study describes the preparation and properties of a novel aliphatic cost effective segmented polyurethanes (SPUs) based on poly(ether ester) (poly (epsilon-caprolactone-co-l-lactide)-poly(ethylene glycol)-poly-(epsilon caprolactone-co-l-lactide), PECLA) and uniform-size diurethane diisocyanates (HDI BDO-HDI). PECLA was synthesized via bulk ring-opening polymerization with poly(ethylene glycol) (PEG) as an initiator and epsilon-caprolactone, l-lactide as monomers. By chain extension of PECLA diol with HDI-BDO-HDI, three SPUs with different hydrophilic segments content and hard segments content were obtained. The chemical structures of the chain extender, PECLA and SPUs were confirmed by 1H NMR, 13C NMR, FT-IR, HR-TOF-MS and GPC. The influences of PEG content and uniform-size hard segments on in vitro degradability and mechanical properties of SPU films were researched. Similar thermostability observed in TGA curves of SPU films indicated that the hard segments and PEG content had little influence on the thermostability. The formation of microsphase-separated morphologies, which were demonstrated by the results of DSC and XRD, and physical-linking (H-bonds) network structures led to better mechanical properties of SPU films (ultimate stress: 23.1-17.9 MPa; elongation at break: 840-1130%). The results of water absorption and water contact angle showed that the bulk and surface hydrophilicity were closely related with the hydrophilic PEG content in SPU backbone. And the water absorption being less than 10 wt% indicated that the SPU films had low swelling property. In vitro hydrolytic degradation studies showed that the time of the SPU films becoming fragments was 34-19 days and the degradation rate increased with the increasing content of hydrophilic segments in SPUs, indicating that the degradation rate of SPU films could be controlled by adjusting PEG content. Cytotoxicity test of film extracts were conducted using L929 cells, and the relative growth rate exceeded 90% after incubation for 24, 48 and 72 h, showing excellent cytocompatibility. The acceptable mechanical properties, controllable biodegradability and excellent cytocompatibility of the polyurethanes can make them good candidates for further biomedical applications. PMID- 27774856 TI - ST-depression in right precordial leads with inferior STEMI and occluded right coronary artery: intertwined anatomy and ischemic areas. AB - Right coronary artery (RCA) occlusion in inferior acute myocardial infarction is usually heralded by ST-elevation both in inferior and in right precordial leads. We report the case of a 68-year-old male, who presented marked ST-elevation in inferior leads, mirrored by ST-depression in anterior-septal and lateral leads. Right precordial lead electrocardiogram unexpectedly showed ST-depression V1R-V5R leads. Coronary angiography showed mid-left anterior descending (LAD) coronary near-complete occlusion with distal wrapping LAD. Left circumflex artery was not occluded, while RCA was occluded mid tract. The patient was treated with coronary angioplasty on RCA and LAD. Absence of ST-elevation in right precordial leads may be presumably explained by the presence of a large ischemic area distal to mid LAD near-occlusive stenosis and of a long-wrapping LAD. Complex coronary anatomy and intertwined ischemic areas may underlie apparently discording electrocardiograms. PMID- 27774857 TI - In-vitro activity of ceftriaxone combined with newer agents against MRSA. AB - In this study, in vitro synergism in combinations of agents as ceftriaxone/dalbavancin, ceftriaxone/linezolid and ceftriaxone/daptomycin against MRSA strains were investigated. Thirty clinical MRSA strains were tested. The minimum inhibitory concentrations of all antibiotics were determined using reference broth microdilution method. In-vitro activities of antibiotics combined against the strains were tested using two-dimensional checkerboard microdilution method. Results were interpreted as follows: synergy = FICI <=0.5; 'no interaction' effect = FICI ?0.5-<=4; antagonism = FICI ?4. The MIC50, MIC90 and MICrange of ceftriaxone, daptomycin, dalbavancin and linezolid were found as 128, 1024 and 16-2048 mg/L; 1, 1 and 0.5-1 mg/L; 0.12, 0.12 and 0.03-0.12 mg/L; and 1, 2 and 1-2 mg/L, respectively. Our results showed that the frequency of synergistic effects (FICI: <=0.5) of three combinations were all at the same rate of 77% (23/30). No in vitro antagonism (FICI >4) was observed. PMID- 27774858 TI - Josiah Royce - A Personal Impression. PMID- 27774859 TI - The Social Self. PMID- 27774860 TI - Appendix to the Harry Stack Sullivan Colloquium: The Development of Interactional Concepts of the Self. PMID- 27774861 TI - Session Opening. PMID- 27774862 TI - Editorial Notes. PMID- 27774863 TI - Welcoming Remarks. PMID- 27774864 TI - George Herbert Mead and Harry Stack Sullivan: An Unfinished Synthesis. PMID- 27774865 TI - Harry Stack Sullivan and Object Relations. PMID- 27774866 TI - The Significance of Ego Interpretive States in Insight-Directed Psychotherapy. PMID- 27774868 TI - Sullivan's Clinical Contribution During the Sheppard Pratt Era-19,23-1930. PMID- 27774870 TI - A two-step integrated approach to detect differentially expressed genes in RNA Seq data. AB - One of the primary objectives of ribonucleic acid (RNA) sequencing or RNA-Seq experiment is to identify differentially expressed (DE) genes in two or more treatment conditions. It is a common practice to assume that all read counts from RNA-Seq data follow overdispersed (OD) Poisson or negative binomial (NB) distribution, which is sometimes misleading because within each condition, some genes may have unvarying transcription levels with no overdispersion. In such a case, it is more appropriate and logical to consider two sets of genes: OD and non-overdispersed (NOD). We propose a new two-step integrated approach to distinguish DE genes in RNA-Seq data using standard Poisson and NB models for NOD and OD genes, respectively. This is an integrated approach because this method can be merged with any other NB-based methods for detecting DE genes. We design a simulation study and analyze two real RNA-Seq data to evaluate the proposed strategy. We compare the performance of this new method combined with the three [Formula: see text]-software packages namely edgeR, DESeq2, and DSS with their default settings. For both the simulated and real data sets, integrated approaches perform better or at least equally well compared to the regular methods embedded in these [Formula: see text]-packages. PMID- 27774871 TI - phraSED-ML: A paraphrased, human-readable adaptation of SED-ML. AB - MOTIVATION: Model simulation exchange has been standardized with the Simulation Experiment Description Markup Language (SED-ML), but specialized software is needed to generate simulations in this format. Text-based languages allow researchers to create and modify experimental protocols quickly and easily, and export them to a common machine-readable format. RESULTS: phraSED-ML language allows modelers to use simple text commands to encode various elements of SED-ML (models, tasks, simulations, and results) in a format easy to read and modify. The library can translate this script to SED-ML for use in other softwares. AVAILABILITY: phraSED-ML language specification, libphrasedml library, and source code are available under BSD license from http://phrasedml.sourceforge.net/ . PMID- 27774872 TI - Analysis of multiple related phenotypes in genome-wide association studies. AB - Most genome-wide association studies (GWAS) have been conducted by focusing on one phenotype of interest for identifying genetic variants associated with common complex phenotypes. However, despite many successful results from GWAS, only a small number of genetic variants tend to be identified and replicated given a very stringent genome-wide significance criterion, and explain only a small fraction of phenotype heritability. In order to improve power by using more information from data, we propose an alternative multivariate approach, which considers multiple related phenotypes simultaneously. We demonstrate through computer simulation that the multivariate approach can improve power for detecting disease-predisposing genetic variants and pleiotropic variants that have simultaneous effects on multiple related phenotypes. We apply the multivariate approach to a GWA dataset of 8,842 Korean individuals genotyped for 327,872 SNPs, and detect novel genetic variants associated with metabolic syndrome related phenotypes. Considering several related phenotype simultaneously, the multivariate approach provides not only more powerful results than the conventional univariate approach but also clue to identify pleiotropic genes that are important to the pathogenesis of many related complex phenotypes. PMID- 27774873 TI - Conditional estimation of local pooled dispersion parameter in small-sample RNA Seq data improves differential expression test. AB - High throughput sequencing technology in transcriptomics studies contribute to the understanding of gene regulation mechanism and its cellular function, but also increases a need for accurate statistical methods to assess quantitative differences between experiments. Many methods have been developed to account for the specifics of count data: non-normality, a dependence of the variance on the mean, and small sample size. Among them, the small number of samples in typical experiments is still a challenge. Here we present a method for differential analysis of count data, using conditional estimation of local pooled dispersion parameters. A comprehensive evaluation of our proposed method in the aspect of differential gene expression analysis using both simulated and real data sets shows that the proposed method is more powerful than other existing methods while controlling the false discovery rates. By introducing conditional estimation of local pooled dispersion parameters, we successfully overcome the limitation of small power and enable a powerful quantitative analysis focused on differential expression test with the small number of samples. PMID- 27774874 TI - Recent Developments of Phototherapy Based on Graphene Family Nanomaterials. AB - Graphene-based nanomaterials have drawn abundant interest in various fields such as biomedicine in recent years. Thanks to the ultra-high surface area of single layered graphene, higher molecular loading is obtained. In addition, easy modifications were acquired because of its ample oxygen-content functional groups. Owing to its excellent physical- chemical properties, graphene-based nanomaterials have been widely explored as novel nanovectors for disease theranostics. In this article, we gave a comprehensive review of graphenebased nanomaterials, including introduction about different members of graphene family nanomaterials (GFNs), various modifications, toxicity and biomedical applications of graphene- based derivatives. More attentions were given to phototherapy in this paper. The mechanisms of photothermal and photodynamic therapy were also offered. Finally, the prospects and challenges of the graphene-based nanomaterials were discussed in this review. PMID- 27774875 TI - Brain SPECT with Perfusion Radiopharmaceuticals and Dopaminergic System Radiocompounds in Dementia Disorders. AB - As well known, the increase in life expectancy and the better physical condition of people in western countries will lead in the next 20 years to a dramatic development of neurodegenerative diseases, especially of dementia that could be considered one of the most important problems in clinical, social and economic fields for the future. Therefore, the differential diagnosis of the various types of dementia is a critical step for patients, clinicians and researchers since an accurate "in vivo" diagnosis can lead to a better patients management. Neuroimaging techniques and in particular the most diffuse and affordable single photon emission computed tomography (SPECT) have provided useful information about dementia disorders and these methods, on the basis of the recent advances, will have an increasingly important role in research and clinical practice. The purpose of this article is to analyze the different SPECT techniques now available which proved clinically useful in correctly formulating the differential diagnosis of dementia. PMID- 27774876 TI - A Pathological Brain Detection System based on Extreme Learning Machine Optimized by Bat Algorithm. AB - AIM: It is beneficial to classify brain images as healthy or pathological automatically, because 3D brain images can generate so much information which is time consuming and tedious for manual analysis. Among various 3D brain imaging techniques, magnetic resonance (MR) imaging is the most suitable for brain, and it is now widely applied in hospitals, because it is helpful in the four ways of diagnosis, prognosis, pre-surgical, and postsurgical procedures. There are automatic detection methods; however they suffer from low accuracy. METHOD: Therefore, we proposed a novel approach which employed 2D discrete wavelet transform (DWT), and calculated the entropies of the subbands as features. Then, a bat algorithm optimized extreme learning machine (BA-ELM) was trained to identify pathological brains from healthy controls. A 10x10-fold cross validation was performed to evaluate the out-of-sample performance. RESULT: The method achieved a sensitivity of 99.04%, a specificity of 93.89%, and an overall accuracy of 98.33% over 132 MR brain images. CONCLUSION: The experimental results suggest that the proposed approach is accurate and robust in pathological brain detection. PMID- 27774877 TI - Genitourinary Complications of Diabetes Mellitus: An Overview of Pathogenesis, Evaluation, and Management. AB - BACKGROUND: Diabetes mellitus is a vastly prevalent metabolic disorder with escalating global health concerns. Particularly when mismanaged, chronic micro- and macrovascular complications may highly impair physiological systems while immunodeficiency disposes us to infection. OBJECTIVE: We investigate infections, localized complications, and neoplasms of the genitourinary system secondary to the chronic complications of diabetes mellitus in males and females. METHOD: A comprehensive MEDLINE(r) search was guided using key words relevant to diabetes mellitus and the genitourinary system. RESULTS: Pathogen-friendly environments may implicate the sequelae of urinary tract and genital mycotic infections, potentially generating necrosis, abscess, and other inflammatory complications, which may present concomitantly with neurogenic and/or vasculogenic dysfunction to further exacerbate an existing genitourinary condition. Manifestations of the adrenal, renal, and genital organs and tissues are discussed as they relate to vascular, immunodeficient, and other hyperglycemic complications of the diabetic state. Among those, chronic kidney disease and cystopathy are the most prevailing and detrimental. Though studies have connected diabetes to either an increased risk of developing or poor prognosis of bladder, renal, prostate, endometrial, and cervical cancers, the explicit biological relationships are as of yet inconclusive. CONCLUSION: Despite the availability of precise treatments to ameliorate most presently reviewed conditions, particularly urinary tract and genital mycotic infection-related sequelae, reversing permanent vascular damage remains a great challenge. Leading a healthier lifestyle and managing diabetes mellitus with a patient-centric approach from the outset are the most putative methods for preventing critical long-term genitourinary manifestations of diabetes mellitus. PMID- 27774878 TI - Docking and QSAR Studies of Aryl-valproic Acid Derivatives to Identify Antiproliferative Agents Targeting the HDAC8. AB - BACKGROUND: Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. METHOD: In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds. Docking results identified pi-pi, hydrogen bonds as the most important noncovalent interactions between HDAC8 (PDB: 3F07) and the ligands tested, whereas Belm4 was the best QSAR descriptor and classified as a 2D BCUT descriptor. RESULT: Based on theoretical studies, compound DAVP042 was synthesized and evaluated in vitro for its antiproliferative activities on several cancer cell lines (A549-lung, MCF-7-breast, HCT116-colon and U937- lymphoid tissue) in comparison to VPA, as well as for its inhibitory activity on HDAC8 using in vitro models. DAVP042 demonstrated to have antiproliferative activity on all cancer cell lines employed, not only suggesting that this compound should be further studied, but also demonstrating that the methodology herein employed is appropriated to identify new therapeutic candidates. PMID- 27774880 TI - Editorial: The faces of mania: the legacy of Athanasios Koukopoulos PMID- 27774879 TI - Strong Anti-tumorous Potential of Nardostachys jatamansi Rhizome Extract on Glioblastoma and In Silico Analysis of its Molecular Drug Targets. AB - BACKGROUND: Glioblastoma has been reckoned as the prime cause of death due to brain tumours, being the most invasive and lethal. Available treatment options, i.e. surgery, radiotherapy, chemotherapy and targeted therapies are not effective in improving prognosis, so an alternate therapy is insistent. Plant based drugs are efficient due to their synergistic action, multi-targeted approach and least side effects. METHODS: The anti-tumorous potential of Nardostachys jatamansi rhizome extract (NJRE) on U87 MG cell line was evaluated through various in vitro and in silico bio-analytical tools. RESULTS: NJRE had a strong anti-proliferative effect on U87 MG cells, Its IC50 was 33.73+/-3.5, 30.59+/-3.4 and 28.39+/-2.9 MUg/mL, respectively after 24, 48 and 72 h. NJRE at 30 MUg/mL induced DNA fragmentation, indicating apoptosis, early apoptosis began in the cells at 20 MUg/mL, whereas higher doses exhibited late apoptosis as revealed by dual fluorescence staining. NJRE at 60 and 80 MUg /mL caused a G0/G1 arrest and at 20 and 40 MUg/mL showed excessive nucleation and mitotic catastrophe in the cells. Immuno-blotting validated the apoptotic mode of cell death through intrinsic pathway. NJRE was harmless to normal cells. In silico docking of NJRE marker compounds: oroselol, jatamansinol, nardostachysin, jatamansinone and nardosinone have revealed their synergistic and multi-targeted interactions with Vestigial endothelial growth factor receptor 2 (VEGFR2), Cyclin dependent kinase 2 (CDK2), B-cell lymphoma 2 (BCL2) and Epidermal growth factor receptor (EGFR). CONCLUSION: A strong dose specific and time dependent anti-tumorous potential of NJRE on U87 MG cells was seen. The extract can be used for the development of safe and multi targeted therapy to manage glioblastoma, which has not been reported earlier. PMID- 27774882 TI - Sol-gel Derived Warfarin - Silica Composites for Controlled Drug Release. AB - BACKGROUND: Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of the efficient ways for the improvement of pharmacological and consumer properties of drugs is the development of optimal drug delivery systems. OBJECTIVE: The aim of this work is to synthesize novel warfarin - silica composites and to study in vitro the drug release kinetics to obtain the composites with controlled release. METHODS: The composites of warfarin with unmodified (UMS) and mercaptopropyl modified silica (MPMS) were synthesized by sol-gel method. The composite formation was confirmed by FTIR spectra. The concentrations of warfarin released to media with pH 1.6, 6.8 and 7.4 were measured using UV spectroscopy. The drug release profiles from the solid composites were described by a series of kinetic models which includes zero order kinetics, first order kinetics, the modified Korsmeyer Peppas model and Hixson-Crowell model. RESULTS: The synthesized sol-gel composites have different kinetic behavior in the studied media. In contrast to the warfarin composite with unmodified silica, the drug release from the composite with mercaptopropyl modified silica follows zero order kinetics for 24 h irrespective to the release medium pH due to mixed mechanism (duffusion + degradation and/or disintegration of silica matrix). CONCLUSION: The obtained results showed that warfarin - silica sol-gel composites have a potential application for the development of novel oral formulation of the drug with controlled delivery. PMID- 27774883 TI - Novel Aspects in the Pathogenesis of Nonalcoholic Steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease, characterized by inflammation, hepatocyte injury and fibrogenesis. Overall mortality, and liver-related mortality, are both increased in NASH patients. Considering that nonalcoholic fatty liver disease is the most prevalent hepatic abnormality in the Western world, understanding the mechanisms leading to NASH and its progression to cirrhosis is critical for a better management of these patients. Moreover, a more detailed knowledge of this condition may be helpful to identify those subjects which are more susceptible to develop progressive liver disease. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, and the gastrointestinal tract. In this review we highlight some of the most recent findings reported on the pathogenesis of NASH and its fibrogenic progression to cirrhosis, in an effort to identify possible targets for treatment or biomarkers of disease progression. PMID- 27774884 TI - Peculiarities of the Clinical Course of Oxidative Protein and Lipid Modification in Children with Acute Rheumatic Fever. AB - BACKGROUND: Measuring indicators of oxidative protein and lipid metabolism is a diagnostic criterion of oxidative metabolism disruption at the early stages of chronic somatic pathology formation. Purpose was to assess the status of protein and lipid oxidative metabolism as a pathogenic link of acute rheumatic fever by measuring markers of early lesion. METHODS: Research included measurement of lipid peroxidation products and efficiency of antioxidant protection. RESULTS: It revealed unidirectional changes that confirm significant cellular membrane lesion. Determined changes correlated with the activity level of the pathological process while comparing the indicators of ill children in remission and during exacerbation. It was found that despite the active traditional treatment in hospitals for in-patients, a number of studied indicators did not return to normal in remission. This shows the persistence of membrane destruction processes in the body, which supports the pathological process and requires an investigation of the lesion severity at the level of cell metabolism. CONCLUSION: Determination of disruption in the oxidative metabolism system of lipids and proteins, and the presence of mitochondrial insufficiency signs are universal pathogenic mechanism that reflects the multifactorial nature of the lesion with acute rheumatic fever. PMID- 27774885 TI - Therapy of Chronic Hepatitis C in the Era of Nanotechnology: Drug Delivery Systems and Liver Targeting. AB - Since the British scientist Michael Houghton along with George Kuo, Qui-Lim Choo (Chiron Corporation Emeryville), and Daniel W. Bradley (Centers for Disease Control and Prevention) codiscovered the causative agent of hepatitis C in 1989, so much progress has been made for the screening of blood donors and management of this chronic liver disease. In this regard, direct-acting antiviral agents (DAAs) have emerged as the potential "cure" of this slowly progressing and devastating disease. However, improvements are still clearly required since the anti-hepatitis C drugs currently available in the market are so extremely expensive (i.e. $94,500 for a 12-week course of treatment), that many patients will have a denied access to such drugs by their insurers.

In the last few years, nanotechnology has emerged as a new platform for drug development, contributing significantly to the improvement of the administration and delivery of many drugs. Additionally, nanotechnologies can provide unique solutions even in poorer societies.

This manuscript reviews the current knowledges on the available anti-hepatitis C drugs and the new drug candidates being investigated as well, and introduces the recent advances in nanocarrier-based delivery systems. Finally, the challenges in the development of drug delivery systems for the targeting of antiviral drugs to the liver are also discussed. PMID- 27774886 TI - Clinico-Hematological Features and Management Outcome in Neonatal Malaria: A Nine Years Analysis from North India. AB - BACKGROUND: Malaria is an important cause of death and illness in children worldwide. Most cases of neonatal malaria are misdiagnosed because of lack of specific symptoms and general lack of awareness. Nothing much is known in literature about the hematological changes during malaria infection and outcome of disease in neonates. Neonatal malaria is an underdiagnosed entity. So this hospital based observational study aims to assess diagnostic features of neonatal malaria. METHODS: From August 2004 to August 2013, information of all slide positive for malaria cases aged 0 to 28 days admitted to our pediatric hospital was collected and analysed. RESULTS: 28 slide positive cases of neonatal malaria were studied, four out of them were congenital malaria. Fever (93%) was the most common symptom followed by pallor (72%) and diarrhoea (50%). We also found respiratory distress in four (14%) cases. Apart from anemia and atypical lymphocytosis, We also found thrombocytopenia and low hematocrit, MCV and RBC count. Two cases with bleeding manifestations expired during course of treatment. DISCUSSION: Malaria in the first few months of life can simulate transplacentally or postnatally acquired infection such as TORCH, syphilis, neonatal hepatitis and septicemia all having an important symptom complex of fever jaundice, hepatosplenomegaly and anemia. Although in our cases clinical presentation has been similar to septicemia but culture of blood, CSF and urine were sterile. The dilemma of distinguishing neonatal malaria alone versus neonatal sepsis or both existing does not seem to be easily resolved by the use of clinical features alone. The laboratory diagnosis of parasitemia in neonates require special attention in Giemsa staining as well as the technical skill involved in malaria microscopy because parasite densities are low. So high degree of suspicion is needed to diagnose malaria in newborns presenting with fever and anemia. PMID- 27774887 TI - Lipoprotein Subfractions, Uric Acid and Cardiovascular Risk in End-Stage Renal Disease (ESRD) Patients. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem and an independent risk factor for cardiovascular disease (CVD). OBJECTIVE: We assessed cardiovascular risk in end-stage renal disease (ESRD) patients and evaluated the relationship between serum uric acid (SUA) and lipoprotein subfractions. METHODS: The study group consisted of 66 patients on dialysis and a control group of 25 healthy volunteers. Concentration of high-density lipoproteins (HDL) and low-density lipoproteins (LDL) subfractions were analysed using a LipoprintTM. Lipid profiles and SUA were measured. RESULTS: There were significant differences in the distribution of HDL1-HDL5 subfractions levels, which were significantly higher in patients with impaired renal function than in the control group (p<=0.013 for all comparisons). HDL7-HDL10 subfractions were significantly more prevalent in healthy volunteers compared with CKD patients (p<=0.001 for all comparisons). The analysis of LDL subfractions revealed significant differences only in IDL-B (p<0.05), IDL-A (p<0.05) and LDL2 (p<0.001) between patients with CKD stage 5 and controls. CONCLUSION: Our study demonstrated that higher SUA level might be associated with lower prevalence of CVD among haemodialysis patients. An elevated SUA concentration in haemodialysis population may be a marker of better nutritional status and also represent the antioxidant properties SUA. PMID- 27774889 TI - Antibacterial Effect of Gallic Acid against Aeromonas hydrophila and Aeromonas sobria Through Damaging Membrane Integrity. AB - In the study, we investigated the antibacterial activity and mechanism of gallic acid against Aeromonas hydrophila and Aeromonas sobria. Gallic acid showed strong antimicrobial activity against the two bacteria. Furthermore, the antibacterial mechanism of gallic acid (0, 3, 6, 12 mM) was performed by membrane integrity assay and scanning electron microscopy (SEM) assay. The results showed that gallic acid notably increased the released material absorption value at 260, 280 nm and electric conductivity in a dose-dependent manner. Moreover, the SEM assay showed that gallic acid induced severe shrink of bacterial intima and irregular morphology in a dose-dependent manner. The SDS-PAGE profiles further confirmed that gallic acid could damage bacterial cells. These results indicated gallic acid exhibited antibacterial effect by destroying membrane integrity of A. hydrophila and A. sobria. Hence, gallic acid has great potential as a new natural food preservative in food fresh-keeping and storage. PMID- 27774888 TI - Genipin Inhibits the Induction of Inducible Nitric Oxide Synthase Through the Inhibition of NF-kappaB Activation in Rat Hepatocytes. AB - BACKGROUND/AIMS: Genipin is a component of Japanese traditional herbal medicine (Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory cytokines including tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta stimulate liver cells, followed by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by iNOS have been implicated as one of the factors in liver injury. Thus it is essential to inhibit iNOS induction for the prevention of liver injury. In this study, we examined IL-1beta-stimulated hepatocytes as a simple "in vitro liver injury model" to investigate liver protective effects of genipin. METHODS: Primary cultured rat hepatocytes were treated with IL-1beta in the presence or absence of genipin. The induction of NO production and iNOS, and its signaling pathway were analyzed. RESULTS: In IL-1beta-stimulated hepatocytes, genipin inhibited the production of NO dose- and timedependently, and reduced the levels of iNOS protein and its mRNA expression. Genipin also reduced mRNA expressions of TNF-alpha and IL-6. Genipin inhibited two essential signaling pathways for iNOS induction, IkappaB degradation/NF-kappaB activation and type I IL-1 receptor upregulation. Transfection experiments revealed that genipin decreased the expression of iNOS mRNA through both inhibitions of the promoter activation and mRNA stabilization. Delayed administration of genipin after IL-1beta addition also inhibited iNOS induction. CONCLUSION: Genipin influenced the induction of inflammatory mediators, iNOS and TNF-alpha, in part through the inhibition of NF kappaB activation in hepatocytes. Genipin may have therapeutic potential for organ injuries including liver. PMID- 27774890 TI - A New Era for Cancer Target Therapies: Applying Systems Biology and Computer Aided Drug Design to Cancer Therapies. AB - In recent years, many systems biology approaches have been used with various cancers. The materials described here can be used to build bases to discover novel cancer therapy targets in connection with computer-aided drug design (CADD). A deeper understanding of the mechanisms of cancer will provide more choices and correct strategies in the development of multiple target drug therapies, which is quite different from the traditional cancer single target therapy. Targeted therapy is one of the most powerful strategies against cancer and can also be applied to other diseases. Due to the large amount of progress in computer hardware and the theories of computational chemistry and physics, CADD has been the main strategy for developing novel drugs for cancer therapy. In contrast to traditional single target therapies, in this review we will emphasize the future direction of the field, i.e., multiple target therapies. Structure based and ligand-based drug designs are the two main topics of CADD. The former needs both 3D protein structures and ligand structures, while the latter only needs ligand structures. Ordinarily it is estimated to take more than 14 years and 800 million dollars to develop a new drug. Many new CADD software programs and techniques have been developed in recent decades. We conclude with an example where we combined and applied systems biology and CADD to the core networks of four cancers and successfully developed a novel cocktail for drug therapy that treats multiple targets. PMID- 27774891 TI - Evaluation of Antioxidant Activity of Phytol Using Non- and Pre-Clinical Models. AB - BACKGROUND: Phytol (3,7,11,15-tetramethylhexadec-2-en-1-ol; PHY), the alcoholic diterpenoid is particularly interesting due to its diverse activities found in literature. This study evaluated in vitro and in vivo antioxidant capacity of PHY. METHODS: We conducted DPPH* (2,2-diphenyl-1-picrylhydrazyl) and ABTS*+ (2,2'-azino-bis(3- ethylbenzthiazoline-6-sulphonic acid)) radical scavenging tests as in vitro, while Saccharomyces cerevisiae test as in vivo. For in vitro tests, trolox and for in vivo test hydrogen peroxide (H2O2) were taken as standard and stressor, respectively. Additionally, we measured the superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), lipid peroxidation (LP) and nitrite (NO2 -) contents in mouse hippocampus taking 0.05% Tween 80 dissolved in 0.9% saline (0.25 ml) and ascorbic acid (250 mg/kg; AA) as vehicle and standard, respectively. PHY was administered at doses 25, 50 and 75 mg/kg. In the latter case, all the treatments were administered via intraperitoneal (i.p.) route. RESULTS: PHY at 7.2 MUg/ml exhibited 59.89 +/- 0.73% and 62.79 +/- 1.99% scavenging capacity of DPPH* and ABTS*+, respectively. In S. cerevisiae strains, PHY showed prominent protective effects. Moreover, in Swiss mouse hippocampus; PHY reduced the LP and NO2 - contents, while increased in GSH, SOD and CAT activities. CONCLUSION: PHY exerted antioxidant potential in our current non- and preclinical test systems and can be a good candidate for the development of treatments of oxidative stress mediated diseases. PMID- 27774892 TI - Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial. AB - OBJECTIVES: Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naive adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF), at Weeks 48 and 144, with high rates of virologic success for both regimens (85.2% and 87.4%, respectively, at Week 48; and 72.1% and 74.1% at Week 144), and with comparable safety and tolerability. Here, we describe virologic response and treatment discontinuation by a wider range of subgroups than previously presented. METHODS: Subgroup analyses by baseline CD4 count (<=200, 201-350, >350 cells/mm3), baseline HIV-1 RNA level (<=100,000, >100,000 copies/mL), race, sex, and age (<40, >=40 years) evaluated ATV+COBI versus ATV+RTV univariate odds ratios (ORs) for virologic success (viral load <50 copies/mL, intention-to-treat US Food and Drug Administration Snapshot algorithm) and discontinuation due to adverse events (AEs) at Weeks 48 and 144. Of 692 patients randomized, 344 received ATV+COBI and 348 ATV+RTV. RESULTS: ATV+COBI versus ATV+RTV ORs for virologic success did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.90; 95% confidence interval [CI]: 0.64, 1.26) or within subgroups, except in females, for whom ATV+COBI was favored at Week 144 (OR 2.36; 95% CI: 1.02, 5.47). However, there were more discontinuations due to withdrawal of consent and pregnancies in females receiving ATV+RTV versus ATV+COBI. ORs for discontinuation due to AEs did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.98; 95% CI: 0.61, 1.58) or within subgroups. CONCLUSION: These findings indicate that both ATV+COBI and ATV+RTV, each with FTC/TDF, are effective and well-tolerated treatment options across a wide demographic range of HIV-infected patients. PMID- 27774893 TI - OPMSP: A Computational Method Integrating Protein Interaction and Sequence Information for the Identification of Novel Putative Oncogenes. AB - Oncogenes are genes that have the potential to cause cancer. Oncogene research can provide insight into the occurrence and development of cancer, thereby helping to prevent cancer and to design effective treatments. This study proposes a network method called the oncogene prediction method based on shortest path algorithm (OPMSP) for the identification of novel oncogenes in a large protein network built using protein-protein interaction data. Novel putative genes were extracted from the shortest paths connecting any two known oncogenes. Then, they were filtered by a randomization test, and the linkages among them and known oncogenes were measured by protein interaction and sequence data. Thirty-seven new putative oncogenes were identified by this method. The enrichment analysis of the 37 putative oncogenes indicated that they are highly associated with several biological processes related to the initiation, progression and metastasis of tumors. Six of these genes-ESR1, CDK9, SEPT2, HOXA10, LMX1B, and NR2C2-are extensively discussed. Several lines of evidence indicate that they may be novel oncogenes. PMID- 27774894 TI - Acid-Induced Unfolding of Champedak Galactose-Binding Lectin. AB - Acid denaturation of champedak galactose-binding (CGB) lectin was studied in the pH range, 7.0-1.0 using intrinsic fluorescence and ANS fluorescence measurements. The lectin remained stable up to pH 5.0 and showed local disordering in the vicinity of the protein fluorophores within the pH range, 5.0-3.5. Decrease in the pH from pH 3.5 to pH 2.5 led to structural transition, marked by the decrease in the intrinsic fluorescence and increase in the ANS fluorescence signals. This can be ascribed to the dissociation of the tetrameric lectin into monomeric forms. Further decrease in the pH up to pH 1.5 produced another transition, which specified the unfolding of monomers as reflected from the decrease in both intrinsic fluorescence and ANS fluorescence signals. Characterization of the conformational states obtained at pH 7.0, pH 2.5 and pH 1.5 based on intrinsic and ANS fluorescence spectra, gel chromatographic behavior and thermal denaturation confirmed the existence of folded monomeric forms at pH 2.5 and unfolded states at pH 1.5. However, the aciddenatured state of CGB lectin at pH 1.5 retained significant residual structure, as evident from the greater loss of both secondary and tertiary structures in the presence of 6 M guanidine hydrochloride at low pH values. Anion-induced refolding below pH 1.5 was also seen using ANS fluorescence measurements. PMID- 27774895 TI - Redox Regulation of Fertility in Aging Male and the Role of Antioxidants: A Savior or Stressor. AB - Oxidative stress (OS), an imbalance between reactive oxygen species (ROS) and antioxidant scavengers, is considered an important underlying mechanism associated with ageing, age-related chronic diseases and reproductive decline in males. However, OS is an important regulator of numerous molecular pathways essential for homeostasis within cells, tissues and systems. A fine balance between factors promoting OS and those that scavenge ROS is critically important. In the male reproductive tract and ejaculate, ROS are critical molecular players in essential reproductive processes, including spermatogenesis, epididymal transport, spermatozoa maturation and post-ejaculation processes such as motility, capacitation and the acrosome reaction. Increasing evidence suggests there is an overlap between age-related OS and male reproductive tract dysfunction correlating with reduced fertility potential due to semen quality decline, endocrine changes and sexual dysfunction. With increasing life expectancy in many regions of the world, together with an increasing paternal age and associated risk of for infertility, pregnancy complications and reduced health potential in the offspring, it is becoming increasingly important to fully understand the mechanism linked with these associations. This review considers the role of ROS and OS in fertility regulation, the ageing process, the role for OS in age-related reproductive decline, the approach to assessment in male infertility and the current use of antioxidants as a therapeutic option. Although evidence suggests exogenous antioxidant supplementation is useful in male infertility, caution to excessive or unnecessary use of these approaches is required to avoid the paradox of antioxidants inhibiting essential and beneficial ROS activities in male reproductive biology. PMID- 27774896 TI - Propagation on Molecular Interaction Networks: Prediction of Effective Drug Combinations and Biomarkers in Cancer Treatment. AB - BACKGROUND: Biomedical sciences use a variety of data sources on drug molecules, genes, proteins, diseases and scientific publications etc. This system can be best pictured as a giant data-network linked together by physical, functional, logical and similarity relationships. A new hypothesis or discovery can be considered as a new link that can be deduced from the existing connections. For instance, interactions of two pharmacons - if not already known - represent a testable novel hypothesis. Such implicit effects are especially important in complex diseases such as cancer. METHODS: The method we applied was to test whether novel drug combinations or novel biomarkers can be predicted from a network of existing oncological databases. We start from the hypothesis that novel, implicit links can be discovered between the network neighborhoods of data items. RESULTS: We showed that the overlap of network neighborhoods is strongly correlated with the pairwise interaction strength of two pharmacons used in cancer therapy, and it is also well correlated with clinical data. In a second case study we employed this strategy to the discovery of novel biomarkers based on text analysis. In 2012 we prioritized 10 potential biomarkers for ovarian cancers, 2 of which were in fact described as such in the subsequent years. CONCLUSION: The strategy seems to hold promises for prioritizing new drug combinations or new biomarkers for experimental testing. Its use is naturally limited by the sparsity and the quality of experimental data, however both of these aspects are expected to improve given the development of current databases. PMID- 27774897 TI - The Role of Biologically Active Ingredients from Chinese Herbal Medicines in the Regulation of Autophagy in Treating Cardiovascular Diseases and Other Chronic Diseases. AB - Autophagy, a highly conserved starvation response mechanism with both defensive and protective effects in eukaryotic cells, is a lysosome-mediated degradation process for non-essential or damaged cellular constituents. It plays an important role in the cell survival, differentiation and development to maintain homeostasis. Autophagy is involved in cardiovascular diseases, cerebrovascular diseases, and neurodegenerative diseases, as well as tumours. Thus, modulating autophagy may provide potential therapeutic strategies. Recently, many active components of Chinese herbal medicines (CHM) have been found to modulate autophagy in myocardial cells, cerebral vascular cells, endothelial cells and tumour cells. This paper reviews the advances in studies on the active components of CHM that modulating autophagy in treating cardiovascular diseases and other chronic diseases over the past five years. PMID- 27774898 TI - Medicinal Plants with Multiple Effects on Cardiovascular Diseases: A Systematic Review. AB - INTRODUCTION: Hyperlipidemia, obesity, hypertension, and diabetes are the most important risk factors for cardiovascular diseases. The aim of this systematic review article is to introduce the medicinal plants that exert significant clinical effects on hypertension, hyperlipidemia, obesity, and diabetes. METHODS: In this review article, the international research databases including MEDLINE, Google scholar, EBSCO, Academic Search, Web of Science, SciVerse, Scopus (SCOPUS), EBSCO, Academic Search, Cochrane, Central Register of Controlled Trials (CENTRAL) and a Chinese database (China Network Knowledge Infrastructure [CNKI]) were searched using the key words hyperlipidemia, hypertension, diabetes, herbal, obesity, and phytomedicine, matched by MESH, from their respective inceptions up to March, 2016. The plants that were effective on one, two, three, or all of four diseases were determined. The doses, side effects, the most important pharmaceutically effective compounds, the used organs, and important points regarding usage were separately recorded. Also known clinically significant interactions were presented. RESULTS: 1023 articles were found to be about medicinal plants and hypertension, 1912 articles about medicinal plants and hyperlipidemia, 810 articles about medicinal plants and obesity, 1174 articles about medicinal plants and diabetes. Of 144 plants included in the analysis, 83 were found to be effective on hyperlipidemia, 100 on hypertension, 66 on obesity, and 72 on diabetes. 43 plants were found to be effective on two diseases, 14 on three diseases, and 34 on all four diseases. Three plants (Tomato, Cranberry and Pomegranate), in food and therapeutic doses, were found to be used to treat cardiovascular diseases especially in pre-eclampsia and hyperlipidemia in pregnancy. CONCLUSION: Regarding the findings of this study, we can argue that the medicinal plants, other than monotherapy, can be used as poly-therapy, to treat cardiovascular diseases. PMID- 27774899 TI - Spices: Therapeutic Potential in Cardiovascular Health. AB - BACKGROUND: Dietary factors play a key role in the development as well as prevention of certain human diseases, including cardiovascular diseases. Currently there has been an increase in global interest to identify medicinal plants that are pharmacologically effective and have low or no side effects for use in preventive medicine. Culinary herbs and spices are an important part of human nutrition in all the cultures of the world. There is a growing amount of literature concerning the potential benefits of these herbs and spices from a health perspective especially in conferring protection against cardiovascular diseases. OBJECTIVE: The objective of this review is to provide information on the recent scientific findings on some common spices that have a distinct place in folk medicine in several of the Asian countries as well as on their traditional uses for the role they can play in the management of heart diseases and which may be useful in defining cost effective and inexpensive interventions for the prevention and control of CVDs. METHOD: Systematic literature searches were carried out and the available information on various medicinal plants traditionally used for cardiovascular disorders was collected via electronic search (using Pubmed, SciFinder, Scirus, GoogleScholar, JCCC@INSTIRC and Web of Science) and a library search for articles published in peerreviewed journals. No restrictions regarding the language of publication were imposed. RESULTS: This article highlights the recent scientific findings on four common spices viz. Greater cardamom (Amomum subulatum Roxb.), Coriander (Coriandrum sativum L.), Turmeric (Curcuma longa L.) and Ginger (Zingiber officinale Roscoe), for the role they can play in the management of heart diseases. Although they have been used by many cultures since ancient times and have been known to exhibit several medicinal properties, current research shows that they can also be effectively used for the prevention and control of CVDs. CONCLUSION: Although scientific evidences supporting the benefits of spices in maintaining a healthy heart are available, more complete information is needed about the actual exposures to these dietary components that are required to bring about a response. The innumerable actions of spices that have been shown in in vitro experiments need to be demonstrated in more systematic, well-designed animal model studies. More rigorous clinical trials at the normally consumed levels are needed to determine long-term benefits as well as to assess adverse effects if any at higher concentrations, especially if consumed over longer periods. Once these extensive studies are carried out, it will be easy to define the appropriate intervention strategies utilizing these commonly used spices for achieving the maximum benefits on cardiovascular health without producing any ill-effects. PMID- 27774900 TI - Phytochemicals Against Advanced Glycation End Products (AGEs) and the Receptor System. AB - Reducing sugars can react non-enzymatically with amino groups of proteins and lipids to form irreversibly cross-linked macroprotein derivatives called as advanced glycation end products (AGEs). Cross-linking modification of extracellular matrix proteins by AGEs deteriorate their tertiary structural integrity and function, contributing to aging-related organ damage and diabetes associated complications, such as cardiovascular disease (CVD). Moreover, engagement of receptor for AGEs, RAGE with the ligands evoke oxidative stress generation and inflammatory, thrombotic and fibrotic reactions in various kinds of tissues, further exacerbating the deleterious effects of AGEs on multiple organ systems. So the AGE-RAGE axis is a novel therapeutic target for numerous devastating disorders. Several observational studies have shown the association of dietary consumption of fruits and vegetables with the reduced risk of CVD in a general population. Although beneficial effects of fruits and vegetables against CVD could mainly be ascribed to its anti-oxidative properties, blockade of the AGERAGE axis by phytochemicals may also contribute to cardiovascular event protection. Therefore, in this review, we focus on 4 phytochemicals (quercetin, sulforaphane, iridoids, and curcumin) and summarize their effects on AGE formation as well as RAGE-mediated signaling pathway in various cell types and organs, including endothelial cells, vessels, and heart. PMID- 27774901 TI - Perspectives on Strategies Using Swellable Polymers in Solid Dispersions for Controlled Drug Release. AB - Poorly water-soluble drugs, which commonly face the issue of poor absorption and low bioavailability, have been under ongoing research of many formulation scientists for the past few decades. Solid dispersion is one of the most effective strategies in concerns for improving bioavailability of poorly water soluble drugs. Either application of solid dispersions in dissolution enhancement of poorly water-soluble drugs or the use of swellable polymers in controlled drug release has been reported in pharmaceutical designs widely. However, a review of strategies of using swellable polymers in solid dispersion to take a full advantage of these polymers as a current perspective in facilitating drug bioavailability enhancement is still missing. In this review, we aim to provide a summary of techniques used to formulate a swellable polymer in solid dispersion especially a description of a suitable fabrication method in design of a controlled release solid dispersion. PMID- 27774902 TI - Ginseng in Dermatology: A Review. AB - Ginseng has gained fame as one of the most popular herbs originating from Eastern countries. Among different species which are known as ginseng, Panax ginseng C. A. Mey. (Korean or Asian ginseng) is the most frequently used one. Ginsenosides have been proposed to account for most of the biological activities of ginseng. The widely appreciated health-promoting effect of ginseng pertains to the beneficial effects of this plant against immune, cardiovascular and sexual diseases and cancer. In addition, there are some new aspects of the pharmacological activity of this plant which justify its use in dermatologic diseases. In dermatology, ginseng has been investigated mechanistically for its therapeutic effects in photoaging, wound and injury, skin cancer, dermatitis, hair loss, alopecia and cold hypersensitivity. Here, we reviewed experimental and clinical studies exploring the therapeutic efficacy of ginseng and ginsenosides in the field of dermatology. PMID- 27774903 TI - Sulfur Mustard-Induced Ocular Injuries: Update on Mechanisms and Management. AB - Sulfur mustard (SM; mustard gas) is a classic chemical warfare agent that has been used in several wars and is still a potential threat especially in the Middle-East region. Victims experience acute symptoms in airexposed organs including skin, respiratory tract and the eyes. Survivors of the acute stage might develop chronic or delayed-onset complications in the exposed organs. The exact mechanism(s) of SM-induced tissue damage is still unknown, however DNA alkylation and oxidative damage are the most relevant mechanisms. Eye is the most sensitive organ to the SM vapor and ocular symptoms usually precede other manifestations. Ocular findings including blepharitis, dry eye disease, corneal vascularization, persistent epithelial defects, limbal ischemia, limbal stem cell deficiency, corneal thinning, corneal opacity and corneal innervation abnormalities have been reported several years after SM exposure. In this review, mechanisms of acute and chronic/delayed ocular manifestations of SM and their current management and potential future therapies have been discussed. We have also included recent advances in amniotic membrane transplantation, cultivated stem cell transplantation and anti-angiogenic therapies which might be considered as therapeutic options in SM-induced ocular damage in the future. PMID- 27774904 TI - Medicinal Plants for the Treatment of Asthma: A Traditional Persian Medicine Perspective. AB - OBJECTIVE: To search major Traditional Persian Medicine (TPM) textbooks for medicinal plants used to treat asthma. The conformity of the TPM findings on the anti-asthmatic efficacy of plants with the findings of pharmacological studies was also explored. METHODS: Major TPM textbooks were hand searched to find medicinal plants used for the treatment of asthma. Scientific names of TPM suggested plants were determined using botanical databases and were used for a multidatabase electronic search in PubMed, Scopus, ScienceDirect and Google Scholar databases. Then, the antiasthmatic effectiveness of TPM-recommended plants was verified in view of the findings from modern pharmacological investigations. RESULTS: According to the main TPM texts, Adianthum capillus veneris, Boswellia oleogumresin, Crocus sativus, Glycyrrhiza glabra, Hyssopus officinalis and Ruta graveolens were the most efficacious medicinal plants for the treatment of asthma. This finding was confirmed by pharmacological studies which showed counterbalancing effects of the above-mentioned plants on inflammation, oxidative stress, allergic response, tracheal smooth muscle cell constriction and airway remodeling. CONCLUSION: The strong ethnobotanical background of plants used in TPM could be a valuable tool to find new anti asthmatic medications. In this review, TPM-suggested anti-asthmatic plants were found to possess several mechanisms relevant to the treatment of respiratory diseases according to the information retrieved from modern pharmacological studies. This high degree of conformity suggested further proof-of-concept trials to ascertain the role of these plants in the routine management of asthmatic patients. PMID- 27774905 TI - Estradiol Uptake in a Combined Magnetic Ion Exchange - Ultrafiltration (MIEX-UF) Process During Water Treatment. AB - BACKGROUND: Estrogens and their synthetic analogues are widely used as pharmaceuticals. Upon oral administration these drugs are eventually excreted via urine. The persistence of these pharmaceuticals and inefficient removal by water treatment lead to accumulation in surface water and effluents with negative effects for aquatic life and human health. METHODS: In this study, the uptake of estradiol by a combined magnetic ion exchange resin - ultrafiltration process (MIEX-UF) was investigated. This is a relatively common process used in drinking water treatment for the removal of natural organic matter. However, uptake of micropollutants, such as steroidal pharmaceuticals, may occur as a side effect of water treatment due to the high affinity for polymeric materials. To elucidate the mechanism governing estradiol partitioning between water, resin and membrane, the influence of different parameters, such as pH, humic acid concentration and membrane molecular-weight-cut-off (MWCO) was studied. RESULTS: Humic acid concentration and pH affected estradiol uptake most. At pH 11 the most significant increase of estradiol uptake was observed for MIEX-UF process (30 ng/g corresponding to 80%) compared with individual UF (17 ng/g corresponding to 12%). The presence of humic acid slightly reduced estradiol uptake at pH 11 (about 55%) due to competition for the ion exchange binding sites. CONCLUSION: Results demonstrated that the uptake of estradiol, which is amongst the most potent EDCs detected in surface water, in the MIEX-UF process can reach significant quantities (30 ng/g of resin) leading to uncontrolled accumulation of this micropollutant during drinking water treatment. This study gives a novel contribution in the understanding the mechanism of the unanticipated accumulation of pharmaceuticals, such as estradiol, in the drinking water treatment process. PMID- 27774906 TI - Concentration and Fractionation of Polyphenols by Membrane Operations. AB - BACKGROUND: This review aims to present the relevant background information and current research status in concentration of polyphenols using membrane technologies. The potential implementation of membrane separation to bioactive compounds like soluble phenolics from aqueous and organic solvent solutions is gaining increasing interest in the recent years. This review does not pretend to cover the abundant published literature on the subject, but to be representative for the observed tendencies in membrane processes applications for concentration of polyphenols derived from natural products. The first part of the article includes general information regarding the polyphenols and the traditional methods for their separation (such as: thin layer chromatography; paper chromatography; gas chromatography; high performance liquid chromatography; capillary electrophoresis), while the second part presents a review of different membrane processes applied for concentration of polyphenols. Three main sources for such implementations are discussed: (1) aqueous or organic solvent extracts from plant material, (2) fruits, and (3) recovery of polyphenols from industrial waste liquids. A diversity of membrane processes are considered in a large scope of implementations ranging from lab-scale studies to pilot and semiindustrial scale operations. CONCLUSION: Membrane technology is an excellent candidate to make a paradigm shift in biological active compounds fractionation/separation processes. Presented results clearly demonstrate that membrane processes are of great advantages over traditionally used methods; however, characterization of separated polyphenols has to be improved. Most of citied authors concentrated their investigation only on the total amount of polyphenols determination. Exhaustive studies including: antioxidant activities, retention index, total soluble solids, or volume reduction factor, have been only carried out by a few authors. PMID- 27774907 TI - Percutaneous Treatment of Aortic Valve Disease: Contemporary Overview and Future Trends. AB - Efforts to develop and refine percutaneous approaches to cardiac valve repair and replacement have advanced rapidly over the past several years, having exceeded even the most optimistic expectations. New innovations have been predominantly directed toward the most frequent form of valvular heart disease (VHD) in the industrialized world; aortic stenosis (AS). Approximately 250,000 transcatheter aortic valve implantation (TAVI) procedures have been done so far addressing this significant medical need. Because of the predominance of degenerative etiologies, the prevalence of VHD increases markedly in population above the age of 65 years, in particular with regard to severe AS. As the populations of the industrialized countries continue to be older, the need for less invasive and safer methods of treating severe AS will continue to grow. In this review we provide comprehensive and up-to-date overview of TAVI in current clinical practice. We have also addressed dilemmas and unanswered questions related to TAVI procedures in different groups of patients and highlighted opportunities and trends related to future TAVI implementation. PMID- 27774909 TI - Molecularly Engineered Polymer-Based Systems in Drug Delivery and Regenerative Medicine. AB - BACKGROUND: Polymer-based systems are attractive in drug delivery and regenerative medicine due to the possibility of tailoring their properties and functions to a specific application. METHODS: The present review provides several examples of molecularly engineered polymer systems, including stimuli responsive polymers and supramolecular polymers. RESULTS: The advent of controlled polymerization techniques has enabled the preparation of polymers with controlled molecular weight and well-defined architecture. By using these techniques coupled to orthogonal chemical modification reactions, polymers can be molecularly engineered to incorporate functional groups able to respond to small changes in the local environment or to a specific biological signal. This review highlights the properties and applications of stimuli-responsive systems and polymer therapeutics, such as polymer-drug conjugates, polymer-protein conjugates, polymersomes, and hyperbranched systems. The applications of polymeric membranes in regenerative medicine are also discussed. CONCLUSION: The examples presented in this review suggest that the combination of membranes with polymers that are molecularly engineered to respond to specific biological functions could be relevant in the field of regenerative medicine. PMID- 27774908 TI - Epigenetically Active Drugs Inhibiting DNA Methylation and Histone Deacetylation. AB - Epigenetic mechanisms, which are involved in the regulation of gene expression, are tightly controlled. Loss of a proper epigenetic control can lead to global epigenetic alterations frequently observed in various diseases including cancer. Aberrant epigenetic changes induced in malignant cells lead to emergence of neoplastic properties, which inhibit cell differentiation and strict cell cycle control but greatly enhance stemness-related features. However, abnormal epigenetic patterns can be reversed by action of epigenetically active agents. Epigenetic machinery comprises a variety DNA/histone modifiers and chromatin remodelers. Chemical substances able to influence on the activity of epigenetic factors such as inhibitors of DNA methyltransferases or histone deacetylase inhibitors can be used as therapeutic agents for improving aberrant epigenetic signatures in cancer cells. Preclinical studies showed efficiency of such epigenetic drugs for the treatment of variety of cancers. So far, several epigenetically active compounds were approved for therapy of hematological malignancies. However, many challenges should be resolved for efficient use of epidrugs in the treatment of non-hematological solid tumors and advanced cancers associated with chemoresistance and higher risk of relapse. PMID- 27774910 TI - 18F-Fluoroestradiol Positron Emission Tomography in Breast Cancer Patients: Systematic Review of the Literature & Meta-Analysis. AB - PURPOSE: The aim of the study was to determine the correlation between 16alpha 18F-fluoro- 17beta-estradiol (18F-FES) uptake and the expression and functionality of estrogen receptors (ERs), as well as to evaluate the ability of 18F-FES PET to predict the response to hormonal therapy (HT) in patients with locally advanced or metastatic breast cancer (BC). METHODS: Literature searches in the major literature databases were carried out in order to select English language articles dealing with 18F-FES PET and BC. Studies that included patients with BC undergoing 18F-FES PET alone or in combination with other imaging modalities and included the absolute numbers of true-positive, true-negative, false-positive and false-negative test results were selected. RESULTS: We found 23 journal articles, published between 1988 and December 2014, that critically evaluated the role of 18F-FES PET in BC patients. Two separate meta-analyses were carried out: 1- to assess the correlation between 18F-FES uptake and ER expression and 2- to determine the predictive value of 18F-FES in response to HT. For the first, we considered nine selected studies with a total of 238 patients. A pooled sensitivity of 82% (95% CI: 74-88%) and a pooled specificity of 95% (95% CI: 86-99%) for the evaluation of ER functional status by 18F-FES PET were found. Seven studies, with a total of 226 patients, were considered eligible for the analysis of prediction for response. The pooled sensitivities and specificities were 63.9% (95% CI: 46.2-79.2%) vs. 66.7% (95% CI: 52.1-79.2%), and 28.6% (95% CI: 17.3-42.2%) vs. 62.1% (95% CI: 48.4-74.5%), for a SUV cutoff of 1.5 and 2.0, respectively. CONCLUSION: A good correlation between 18F-FES uptake and ER expression by immunohistochemistry emerges, while the role of 18F-FES in predicting the response to endocrine therapy in advanced BC remains undetermined. PMID- 27774911 TI - Self-emulsifying Pellets Prepared by Extrusion/Spheronization: In vitro/In vivo Evaluation. AB - AIMS: The purpose of the current study was to investigate the feasibility of producing solid self-emulsifying pellets using the extrusion/spheronization technique with an aim to increase the bioavailability of selected drug and also to encounter the problems associated with liquid lipid formulations. Selfemulsifying formulations are experiencing a very active development as reflected by the numerous publications and patents being granted on these systems. The patents on self-emulsifying formulation (US20036630150) and (US20006054136) helped in selecting the drug and excipients. MATERIAL AND METHODS: These pellets were prepared using liquid SNEDDS (24.59 % LBF M 2125 CS + Maisine35-1; 1:1 ratio) (oil), 50.27 % Labrasol (surfactant) and 25.13% Lauroglycol 90 (cosurfactant), adsorbent (silicon dioxide), pellet forming excipient (microcrystalline cellulose), binder (pregelatinized starch), disintegrant (croscarmelose sodium) and lubricant (corn starch). RESULTS: The resulting self-emulsified pellets loaded with about 32% liquid SNEDDS exhibited uniform pellet size and round shape, droplet size distribution following self emulsification was nearly same to the liquid SNEDDS (26.5 nm and 24.8 nm, respectively). The in vitro release was significantly higher than the plain drug (p<0.01). AUC0-36h of sertraline from the pellets showed about 5-fold greater than the plain drug and no significant difference compared with the liquid SNEDDS (p>0.05). CONCLUSION: In conclusion, spherical pellets with low friability and self-emulsifying properties can be produced by the standard extrusion/spheronization technique. The pellets are capable of transferring lipophilic compounds into the aqueous phase and have a high potential to increase the oral absorption of lipophilic drugs. PMID- 27774912 TI - Development of Self Emulsifying Formulations of Poorly Soluble Naproxen for Enhanced Drug Delivery. AB - BACKGROUND: The objective of this investigation was to develop a self emulsifying drug delivery system (SEDDS) of naproxen, a poorly water soluble drug, which could improve its solubility and oral bioavailability. METHODS: The recent patents on SEDDS of abiraterone acetate (WO2014/009434 A1) and tamoxifen (WO2013/0080083) helped in selecting the naproxen and excipients. Phase diagrams were constructed and the formulations were taken from the micro emulsion region. Formulations were subjected to thermodynamic stability, dispersibility and precipitation tests for optimization. Physico chemical characterization was carried out by FTIR and DSC studies. The selected SEDDS consisted of IPM+labrafac lipophile WL 1349, tween 80, PEG 400 and naproxen. The optimized formulation has globule size- 187.6 nm, zeta potential- -9.81 mv, viscosity- 1.772 cps and infinite dilution ability. RESULTS: In vitro drug release was 98.21% and was found to be significantly different from the marketed product and plain drug. After oral administration in rats the SEDDS of naproxen showed anti inflammatory activity (69.82%) which was much improved as compared to the marketed formulation. The Cmax, AUC0t of naproxen was boosted with SEDDS to 133.63 g/ml and 698.29 hr. g/ml respectively. The optimized formulation was found to be stable for 6 months during stability studies conducted according to the ICH Q1A (R2) guidelines. CONCLUSION: Thus this developed self emulsifying drug delivery system may be a useful tool to enhance the solubility of oral poorly water soluble drug naproxen. PMID- 27774913 TI - Association between sucrose intake and acute coronary event risk and effect modification by lifestyle factors: Malmo Diet and Cancer Cohort Study. AB - Previous studies have suggested that a high intake of sugar-sweetened beverages is positively associated with the risk of a coronary event. However, a few studies have examined the association between sucrose (the most common extrinsic sugar in Sweden) and incident coronary events. The objective of the present study was to examine the associations between sucrose intake and coronary event risk and to determine whether these associations are specific to certain subgroups of the population (i.e. according to physical activity, obesity status, educational level, alcohol consumption, smoking habits, intake of fat and intake of fruits and vegetables). We performed a prospective analysis on 26 190 individuals (62 % women) free from diabetes and without a history of CVD from the Swedish population-based Malmo Diet and Cancer cohort. Over an average of 17 years of follow-up (457 131 person-years), 2493 incident cases of coronary events were identified. Sucrose intake was obtained from an interview-based diet history method, including 7-d records of prepared meals and cold beverages and a 168-item diet questionnaire covering other foods. Participants who consumed >15 % of their energy intake (E%) from sucrose showed a 37 (95 % CI 13, 66) % increased risk of a coronary event compared with the lowest sucrose consumers (<5 E%) after adjusting for potential confounders. The association was not modified by the selected lifestyle factors. The results indicated that sucrose consumption higher than 15 E% (5 % of this population) is associated with an increased risk of a coronary event. PMID- 27774914 TI - Interplay of hippocampal volume and hypothalamus-pituitary-adrenal axis function as markers of stress vulnerability in men at ultra-high risk for psychosis. AB - BACKGROUND: Altered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results. METHOD: Study participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol. RESULTS: Cortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (rho = 0.42, p = 0.036 and rho = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size). CONCLUSIONS: Our findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women. PMID- 27774915 TI - Summation of blood glucose and TAG to characterise the 'metabolic load index'. AB - Research points to postprandial glucose and TAG measures as preferable assessments of cardiovascular risk as compared with fasting values. Although elevated postprandial glycaemic and lipaemic responses are thought to substantially increase chronic disease risk, postprandial glycaemia and lipaemia have historically only been considered separately. However, carbohydrates and fats can generally 'compete' for clearance from the stomach, small intestine, bloodstream and within the peripheral cell. Further, there are previous data demonstrating that the addition of carbohydrate to a high-fat meal blunts the postprandial lipaemic response, and the addition of fat to a high-carbohydrate meal blunts the postprandial glycaemic response. Thus, postprandial glycaemia and lipaemia are interrelated. The purpose of this brief review is 2-fold: first, to review the current evidence implicating postprandial glycaemia and lipaemia in chronic disease risk, and, second, to examine the possible utility of a single postprandial glycaemic and lipaemic summative value, which will be referred to as the metabolic load index. The potential benefits of the metabolic load index extend to the clinician, patient and researcher. PMID- 27774916 TI - Substitution of meat and fish with vegetables or potatoes and risk of myocardial infarction. AB - Red meat has been suggested to be adversely associated with risk of myocardial infarction (MI), whereas vegetable consumption has been found to be protective. The aim of this study was to investigate substitutions of red meat, poultry and fish with vegetables or potatoes for MI prevention. We followed up 29 142 women and 26 029 men in the Danish Diet, Cancer and Health study aged 50-64 years with no known history of MI at baseline. Diet was assessed by a validated 192-item FFQ at baseline. Adjusted Cox proportional hazard models were used to calculate hazard ratios (HR) and 95 % CI for MI associated with specified food substitutions of 150 g/week. During a median follow-up of 13.6 years, we identified 656 female and 1694 male cases. Among women, the HR for MI when replacing red meat with vegetables was 0.94 (95 % CI 0.90, 0.98). Replacing fatty fish with vegetables was associated with a higher risk of MI (HR 1.23; 95 % CI 1.05, 1.45), whereas an inverse, statistically non-significant association was found for lean fish (HR 0.93; 95 % CI 0.83, 1.05). Substituting poultry with vegetables was not associated with risk of MI (HR 1.00; 95 % CI 0.90, 1.11). Findings for substitution with potatoes were similar to findings for vegetables. Among men, a similar pattern was observed, but the associations were weak and mostly statistically non-significant. This study suggests that replacing red meat with vegetables or potatoes is associated with a lower risk of MI, whereas replacing fatty fish with vegetables or potatoes is associated with a higher risk of MI. PMID- 27774917 TI - No difference in acute effects of supplemental v. dietary calcium on blood pressure and microvascular function in obese women challenged with a high-fat meal: a cross-over randomised study. AB - Recent studies suggest that supplemental Ca (SC) increases the risk of cardiovascular events, whereas dietary Ca (DC) decreases the risk of cardiovascular events. Although frequently consumed with meals, it remains unclear whether Ca can mitigate or aggravate the deleterious effects of a high fat meal on cardiovascular risk factors. This study aimed to evaluate the effects of SC or DC on blood pressure (BP) and microvascular function (MVF) in the postprandial period in obese women challenged with a high-fat meal. In this cross over controlled trial, sixteen obese women aged 20-50 years were randomly assigned to receive three test meals (2908 kJ (695 kcal); 48 % fat): high DC (HDCM; 547 mg DC), high SC (HSCM; 500 mg SC-calcium carbonate) and low Ca (LCM; 42 mg DC). BP was continuously evaluated from 15 min before to 120 min after meals by digital photoplethysmography. Before and 120 min after meals, participants underwent evaluation of serum Ca and microvascular flow after postocclusive reactive hyperaemia (PORH) by laser speckle contrast imaging. Ionised serum Ca rose significantly only after HSCM. Systolic BP increased after the three meals, whereas diastolic BP increased after LCM and HDCM. Hyperaemia peak, hyperaemia amplitude and AUC evaluated after PORH decreased with LCM. After HDCM, there was a reduction in hyperaemia peak and hyperaemia amplitude, whereas HSCM decreased only hyperaemia peak. However, comparative analyses of the effects of three test meals on serum Ca, BP and MVF revealed no significant meal*time interaction. This study suggests that in obese women SC and DC do not interfere with the effects of a high-fat meal on BP and MVF. PMID- 27774918 TI - Older Adults' Online Dating Profiles and Successful Aging. AB - This study examined how relevant Rowe and Kahn's three criteria of successful aging were to older adults' self-portrayals in online dating profiles: low probability of disease and disability, high functioning, and active life engagement. In this cross-sectional study, 320 online dating profiles of older adults were randomly selected and coded based on the criteria. Logistic regression analyses determined whether age, gender, and race/ethnicity predicted self-presentation. Few profiles were indicative of successful aging due to the low prevalence of the first two criteria; the third criterion, however, was identified in many profiles. Native Americans were significantly less likely than other ethnic groups to highlight the first two criteria. Younger age predicted presenting the first criterion. Women's presentation of the third criterion remained significantly high with age. The findings suggest that the criteria may be unimportant to older adults when seeking partners, or they may reflect the exclusivity of this construct. PMID- 27774919 TI - W. Horsley Gantt, Nick, and the Pavlovian Science at Phipps Clinic. AB - William Horsley Gantt is well known as one to the principal proponents of Pavlovian methodology in the U.S. After a long stay at Ivan Petrovich Pavlov's laboratory in Leningrad from 1925 to 1929, Gantt was invited by Adolf Meyer to join the Henry Phipps Psychiatric Clinic, where he founded and directed the Pavlovian Laboratory from 1930 to 1964. Soon after his arrival at Phipps Clinic in 1931, Gantt began a Pavlovian research program that included the investigation of nervous disturbances in dogs and clinical researches with psychiatric patients. In these studies, Gantt combined a physiological method (the conditional reflexes approach), with a psychiatric problem (nervous disorders) in the context of Meyer's psychobiology that established the person or individual as unit of analysis. This fact, concentrating upon a single individual, made Gantt studies with dogs recognizable and interesting to physicians, psychologists, and psychiatrists who also worked on individuals. In this paper, we use archival materials -including correspondence, notebooks, and unpublished autobiographical material- to present a case study, that of William Horsley Gantt and his dog Nick. We will explore the reasons why Gantt' studies on nervous disturbances with this dog captured the interest of psychiatrists and clinical psychologists. PMID- 27774920 TI - Panel of Oxidative Stress and Inflammatory Biomarkers in ALS: A Pilot Study. AB - BACKGROUND: Pathophysiological mechanisms that contribute to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) include oxidative stress and inflammation. We conducted a preliminary study to explore these mechanisms, to discuss their link in ALS, and to determine the feasibility of incorporating this combined analysis into current biomarkers research. METHODS: We enrolled 10 ALS patients and 10 controls. We measured the activities of glutathione peroxidase, glutathione reductase, superoxyde dismutase (SOD), and the levels of serum total antioxidant status (TAS), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and glutathione status (e.g. glutathione disulfide, GSSG/reduced glutathione, GSH). We analysed the concentrations of homocysteine, several cytokines, vitamins and metals by standard methods used in routine practice. RESULTS: There was a significant decrease in TAS levels (p=0.027) and increase in 8-OHdG (p=0.014) and MDA (p=0.011) levels in ALS patients. We also observed a significantly higher GSSG/GSH ratio (p=0.022), and IL-6 (p=0.0079) and IL-8 (p=0.009) concentrations in ALS patients. Correlations were found between biological and clinical markers (homosysteine vs. clinical status at diagnosis, p=0.02) and between some biological markers such as IL-6 vs. GSSG/GSH (p=0.045) or SOD activity (p=0.017). CONCLUSION: We confirmed the systemic alteration of both the redox and the inflammation status in ALS patients, and we observed a link with some clinical parameters. These promising results encourage us to pursue this study with collection of combined oxidative stress and inflammatory markers. PMID- 27774922 TI - Clinical and histopathological prognostic factors in locoregional advanced laryngeal cancer. AB - OBJECTIVE: To evaluate the clinical and histopathological factors affecting the prognosis of patients with squamous cell locoregional advanced laryngeal cancer. METHODS: A retrospective chart review was conducted of 121 patients with locoregional advanced laryngeal cancer, primarily treated with surgery from 2007 to 2011. Disease-free survival and overall survival rates were analysed as oncological outcomes. Prognostic variables, namely gender, pharyngeal invasion, pathological assessment of tumour and nodal stage, adjuvant therapy, margin status, nodal extracapsular extension, tumour differentiation, lymphovascular and perineural invasion, and predominant growth pattern, were also analysed. RESULTS: One-year and three-year disease-free survival rates were 81.3 per cent and 63.5 per cent, respectively. One-year and three-year overall survival rates were 88.3 per cent and 61.4 per cent, respectively. Multivariate analysis showed that nodal extracapsular extension (p < 0.05) and an infiltrative growth pattern (p < 0.05) were associated with disease progression. Nodal extracapsular extension (p < 0.05) was associated with higher mortality. CONCLUSION: Nodal extracapsular extension and an infiltrative growth pattern were the main prognostic factors in locoregional advanced laryngeal cancer. The presence of pharyngeal invasion, pathologically confirmed node-positive stage 2-3 disease, close or microscopic positive margins, and lymphovascular and perineural invasion have a negative impact on prognosis. PMID- 27774921 TI - Therapeutic effect of Castellani's paint in patients with an itchy ear canal. AB - OBJECTIVE: To examine the effects of Castellani's paint on symptomatic relief and skin flora in patients with an itchy external ear canal. METHODS: Subjective pruritus scores, and erythema and desquamation scores, were noted in 61 patients with an itchy external ear canal. External ear canal skin swabs were taken for bacterial and fungal cultures. Patients were then randomly divided into three groups: either Castellani's paint (group one) or steroid ear drops (group two) were instilled, or non-impacted cerumen was removed (group three). Patients were re-assessed at one month after the initial visit. RESULTS: After treatment, subjective pruritus scores were significantly lower in all groups, erythema scores were significantly decreased in group one, and desquamation scores were significantly reduced in groups one and two, when compared with pre-treatment scores. Reproduction density of bacteria including normal flora was decreased in group one. However, the types of bacteria that constitute the normal flora of the external ear canal were unchanged. CONCLUSION: Castellani's paint can be administered safely, effectively and easily, without affecting the type of external ear canal skin bacteria, in patients with an itchy external ear canal. PMID- 27774923 TI - Development and validation of a low-cost microsurgery Ear Trainer for low resource settings. AB - OBJECTIVE: Chronic suppurative otitis media is a neglected condition affecting up to 330 million people worldwide, with the burden of the disease in impoverished countries. The need for non-governmental organisations to hardwire training into their programmes has been highlighted. An ear surgery simulator appropriate for training in resource-poor settings was developed, and its effectiveness in facilitating the acquisition of headlight and microsurgical skills necessary to safely perform procedures via the ear canal was investigated. METHODS: Face validity was assessed via questionnaires. Six tasks were developed: a headlight foreign body removal task, and microscope tasks of foreign body removal, ventilation tube insertion, tympanomeatal flap raising, myringoplasty and middle ear manipulation. Participants with varying ENT experience were video-recorded performing each task and scored by a blinded expert observer to assess construct validity. RESULTS: Face validity results confirmed that our Ear Trainer was a realistic representation of the ear. Construct validity results showed a statistically significant trend, with experts performing the best and those with limited experience performing better than novices. CONCLUSION: This study validates our Ear Trainer as a useful training tool for assessing headlight and microsurgical skills required to perform otological procedures. PMID- 27774924 TI - Tracheal T-tube: a novel endoscopic insertion technique. AB - BACKGROUND: Laryngotracheal stenosis is a complex condition of airway compromise involving either the larynx or trachea, or both. OBJECTIVES: This paper describes a new method of endoscopically inserting a silicone tracheal T-tube as treatment for laryngotracheal stenosis. The advantages of this method over previously described methods are discussed. PMID- 27774925 TI - Improving paranasal sinus computed tomography reporting prior to functional endoscopic sinus surgery - an ENT-UK panel perspective. AB - BACKGROUND: Functional endoscopic sinus surgery is recognised to have a significant complication profile (e.g. blindness, cerebrospinal fluid leak and intracranial sepsis). Pre-operative computed tomography imaging is considered mandatory for surgical planning to reduce intra-operative risk. A radiological report is the 'gold standard' in image interpretation; however, because of a lack of otolaryngological or radiological guidance, its contents may be variable. By surveying practising otolaryngologists, this study aimed to provide some guidance which may be used by radiologists to produce more surgically relevant radiological reports. METHOD: A prospective questionnaire was distributed to the ENT-UK panel. RESULTS: A total of 117 consultant members of the panel completed the survey. Twenty-nine per cent indicated that they were uncomfortable interpreting all areas of the computed tomography scan. Greatest importance was given to areas including the ethmoid roof (dehiscence, asymmetry and angle), lamina papyracea (dehiscence) and sphenoid sinus (carotid canal dehiscence and optic nerve relationships). CONCLUSION: Functional endoscopic sinus surgery is commonly performed by non-subspecialist rhinologists. The information obtained from this study can be used by radiologists to improve report relevance, particularly for the generalist ENT surgeon. This contributes to improving patient safety and helps avoid medicolegal litigation when complications arise. PMID- 27774926 TI - Post-tonsillectomy dietary advice: systematic review. AB - OBJECTIVE: To determine if there is evidence that post-tonsillectomy dietary advice affects post-operative morbidity. METHOD: A systematic review was conducted of Embase, Medline, the Cumulative Index to Nursing and Allied Health Literature and PsycInfo, to November 2014. RESULTS: Seventeen articles were included; their heterogeneous nature prevented meta-analysis. Of these, all three small, randomised studies showed no statistical difference in morbidity between restricted and non-restricted diets. CONCLUSION: Most post-tonsillectomy dietary advice is based on historical anecdotes and not rigorous scientific testing. The existing small-scale, randomised studies show no statistical difference in morbidity between non-restricted and restricted diets. PMID- 27774927 TI - Analysis of the incidence and factors predictive of inadvertent parathyroidectomy during thyroid surgery. PMID- 27774928 TI - Magenta red, Castellani's paint and an array of autumn colours. PMID- 27774929 TI - Neuropsychological Functioning in Preterm-Born Twins and Singletons at Preschool Age. AB - OBJECTIVES: A limited body of research is available on the relationships between multiplicity of birth and neuropsychological functioning in preterm children who were conceived in the age of assisted reproductive technology and served by the modern neonatal intensive care unit. Our chief objective was to evaluate whether, after adjustment for sociodemographic factors and perinatal complications, twin birth accounted for a unique portion of developmental outcome variance in children born at-risk in the surfactant era. METHODS: We compared the neuropsychological functioning of 77 twins and 144 singletons born preterm (<34 gestational weeks) and served by William Beaumont Hospital, Royal Oak, MI. Children were evaluated at preschool age, using standardized tests of memory, language, perceptual, and motor abilities. RESULTS: Multiple regression analyses, adjusting for sociodemographic and perinatal variables, revealed no differences on memory or motor indices between preterm twins and their singleton counterparts. In contrast, performance of language and visual processing tasks was significantly lower in twins despite reduced perinatal risk in comparison to singletons. Effect sizes ranged from .33 to .38 standard deviations for global language and visual processing ability indices, respectively. No significant group by sex interactions were observed, and comparison of first-, or second-born twins with singletons yielded medium effect sizes (Cohen's d=.56 and .40, respectively). CONCLUSIONS: The modest twin disadvantage on language and visual processing tasks at preschool-age could not be readily attributable to socioeconomic or perinatal variables. The possibility of biological or social twinning-related phenomena as mechanisms underlying the observed performance gaps are discussed. (JINS, 2016, 22, 865-877). PMID- 27774930 TI - Effects of dietary grape proanthocyanidins on the growth performance, jejunum morphology and plasma biochemical indices of broiler chicks. AB - Grape proanthocyanidins (GPCs) are a family of naturally derived polyphenols that have aroused interest in the poultry industry due to their versatile role in animal health. This study was conducted to investigate the potential benefits and appropriate dosages of GPCs on growth performance, jejunum morphology, plasma antioxidant capacity and the biochemical indices of broiler chicks. A total of 280 newly hatched male Cobb 500 broiler chicks were randomly allocated into four treatments of seven replicates each, and were fed a wheat-soybean meal-type diet with or without (control group), 7.5, 15 or 30 mg/kg of GPCs. Results show that dietary GPCs decrease the feed conversion ratio and average daily gain from day 21 to day 42, increase breast muscle yield by day 42 and improve jejunum morphology between day 21 and day 42. Chicks fed 7.5 and 15 mg/kg of GPCs show increased breast muscle yield and exhibit improved jejunum morphologies than birds in the control group. Dietary GPCs fed at a level of 15 mg/kg markedly increased total superoxide dismutase (T-SOD) activity between day 21 and day 42, whereas a supplement of GPCs at 7.5 mg/kg significantly increased T-SOD activity and decreased lipid peroxidation malondialdehyde content by day 42. A supplement of 30 mg/kg of GPCs has no effect on antioxidant status but adversely affects the blood biochemical indices, as evidenced by increased creatinine content, increased alkaline phosphatase by day 21 and increased alanine aminotransferase by day 42 in plasma. GPC levels caused quadratic effect on growth, jejunum morphology and plasma antioxidant capacity. The predicted optimal GPC levels for best plasma antioxidant capacity at 42 days was 13 to 15 mg/kg, for best feed efficiency during grower phase was 16 mg/kg, for best jejunum morphology at 42 days was 17 mg/kg. In conclusion, GPCs (fed at a level of 13 to 17 mg/kg) have the potential to be a promising feed additive for broiler chicks. PMID- 27774931 TI - [C1q and tumor necrosis factor related protein 4 (CTRP4) suppresses caspase-1/IL 1beta inflammatory pathway in trophoblasts of rat models with preeclampsia]. AB - Objective To explore the effect of C1q/tumor necrosis factor related protein 4 (CTRP4) on the placental trophoblasts of preeclampsia model rats. Methods Placental trophoblastic tissues were respectively collected from normal pregnant rats and model rats with preeclampsia, and then mRNA and protein expression levels of CTRP4, interleukin 1beta (IL-1beta), and caspase-1 were detected with quantitative real-time PCR (qRT-PCR) and Western blotting. Primary placental trophoblasts were isolated from normal pregnant rats and model rats; at different time points, flow cytometry was used to detect the number of PI+caspase-1+ pyroptotic cells; and qRT-PCR and Western blotting were used to detect expression levels of IL-1beta and caspase-1. Finally, recombinant CTRP4 protein (at the doses of 0.5, 5, 15, 25 or 50 ng/mL) or neutralizing CTRP4 antibody (at the doses of 10 or 20 ng/mL) were added into the medium of trophoblasts from model rats; after incubation for 72 h, the number of pyroptotic cells and the expression levels of IL-1beta and caspase-1 were detected. ResultsCaspase-1/IL-1beta inflammatory pathway was activated and CTRP4 expression was downregulated in placenta trophoblastic tissue from rats with preeclampsia. CTRP4 recombinant protein treatment significantly inhibited pyroptosis and the caspase-1/IL-1beta pathway in trophoblasts derived from rats with preeclampsia, while CTRP4 neutralizing antibody treatment had an opposite effect on pyroptosis and inflammation. Conclusion CTRP4 can significantly inhibit the activation of caspase-1/IL-1beta inflammatory pathway, and suppress the pyroptosis of trophoblasts derived from rats with preeclampsia. PMID- 27774932 TI - [Construction of Rev-erbbeta gene knockout HEK293 cell line with CRISPR/Cas9 system]. AB - Objective To prepare Rev-erbbeta knockout HEK293 cells using clustered regularly interspaced short palindromic repeats/Cas 9 nuclease (CRISPR/Cas9) gene editing technology. Methods The knock-in or knockout of Rev-erbbeta gene could be realized by single-guide RNA (sgRNA)-mediated Cas9 cutting of target DNA, and followed by DNA homologous recombination or non-homologous end joining-mediated DNA repair. Firstly, four sgRNAs were designed for Rev-erbbeta gene. The sgRNA1 and sgRNA2 with the higher activity were respectively used to construct pCMV hCas9-U6-Rev-erbbeta sgRNA1 and pCMV-hCas9-U6-Rev-erbbeta sgRNA2. Then, pCMV hCas9-U6-Rev-erbbeta sgRNA1, pCMV-hCas9-U6-Rev-erbbeta sgRNA2 and pAd5-E1/hRev erbbeta donor plasmid vectors were co-transfected into HEK293 cells. Through drug screening, cloning and sequencing, the Rev-erbbeta gene-knockout HEK293 (Rev erbbeta-/-) cell lines were obtained with one chain integrated with exogenous gene fragment and the other chain for deletion mutants. Finally, the HEK293 (Rev erbbeta-/-) cell lines (C3-6) was detected with real-time quantitative PCR and Western blotting. Results Expression of Rev-erbbeta mRNA and protein was undetectable in HEK293 Rev-erbbeta-/- cell line. Conclusion Using CRISPR/Cas9 technology, the HEK293 Rev-erbbeta-/- cell line has been successfully constructed, which would provide an effective tool for the study on the function of Rev-erbbeta. PMID- 27774933 TI - [Acquirement of autologous murine cytotoxic T lymphocytes via cryopreservation of lymphocytes]. AB - Objective To evaluate the effects of cryopreservation on the proliferation and killing activity of lymphocytes, and explore a novel protocol of preparing autologous mouse cytotoxic T lymphocytes (CTLs). Methods Mononuclear cells derived from spleen (5.0*106/mL) were cryopreserved in CELLBANKER2 for 6 days and recovered in water bath at 39DegreesCelsius. The fresh lymphocytes and post cryopreservation lymphocytes were induced by CD3 mAb (100 ng/mL) and recombinant mouse interleukin 2 (rmIL-2, 100 ng/mL) to obtain cytokine-induced killer cells (CIKs). Dendritic cells (DCs) were co-cultured with fresh allogenic lymphocytes and post-cryopreservation autologous lymphocytes to obtain CTLs. The viable cells were counted by trypan blue staining; the percentages of CD3+T cells and regulatory T cells (Tregs) were determined by flow cytometry; the levels of supernatant IFN-gamma were detected through ELISA and the cytotoxicity was evaluated by lactate dehydrogenase (LDH) assay. Results The rate of viable lymphocytes declined to 78% after cryopreservation, and there were no significant differences in the percentages of CD3+T cells and Tregs between pre cryopreservation and post-cryopreservation. There were no significant differences in the proliferation of Tregs, the level of IFN-gamma and the cytotoxicity between the fresh CIKs and cryopreservation CIKs, and the similar results were get between the autologous CTLs and allogenic CTLs. Conclusion The autologous CTLs acquired via cryopreservation of lymphocytes is equivalent to the allogenic CTLs with the similar proliferation and killing activity in vitro. PMID- 27774934 TI - [C1q/tumor necrosis factor related protein 6 (CTRP6) is involved in gentamicin induced acute kidney injury in rats]. AB - Objective To explore the role of the anti-inflammatory cytokine C1q/tumor necrosis factor related protein 6 (CTRP6) in gentamicin-induced acute kidney injury in rats. Methods SD rats were divided into 5 groups including control group, model group and the other 3 experimental groups. The rats in model group and experimental groups were subcutaneously injected with gentamicin at the dose of 400 mg/(kg.d) for consecutive 2 days to induce acute renal injury. Two days before gentamicin injection, the rats in the 3 experimental groups were given pAd CTRP6 at the doses of 0.5, 5 and 50 mg/kg, respectively. The serum levels of blood urea nitrogen (BUN) and creatinine (Cr) were respectively assayed with picric acid colorimetry and ultraviolet spectrophotometry; ELISA was used to detect serum CTRP6 content and the production of interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in the kidney homogenate; Western blotting was performed to detect the expressions of CTRP6, caspase-1 and pyrin domain containing 3 (NLRP3) proteins in the renal tissues of rats. Results Compared with control group, serum BUN and Cr contents increased in the model rats; the secretion of inflammatory factors IL-1beta and TNF-alpha, as well as the expressions of caspase-1 and NLRP3 were also enhanced in the model group. Compared with the model group, serum BUN and Cr contents decreased in the experimental groups; the secretion of IL-1beta and TNF-alpha, as well as the expressions of caspase-1 and NLRP3 were also attenuated in the experimental groups. Moreover, with the increase of the injection dosage of pAd-CTRP6, the suppressive effect was gradually strengthened. Conclusion CTRP6 can attenuate gentamicin-induced acute renal injury in rats in a dose-dependent manner. PMID- 27774935 TI - [Multi-organ lesions of C57BL/6J mouse models with immune-mediated Sjogren's syndrome]. AB - Objective To observe multi-organ damages at different stages in immune-mediated mouse models of Sjogren's syndrome. Methods Eighty C57BL/6J mice were divided randomly into 2 groups, a blank control group and a model group. Sjogren's syndrome was induced in the 40 mice in the latter group by immune injury. Every 10 mice were killed at 4, 6, 8 and 10 weeks. The submandibular gland, thymus, lung, spleen and kidney were isolated under sterile condition. HE staining was used to observe the pathological changes of the organs under a light microscope. Results Compared with the blank control group, the organs of the model group appeared obvious pathological changes since the 6th weeks, which were characterized by submandibular gland damage and infiltrating lymphocytes, as well as the damages of the lung, kidney, spleen and other organs. The most severe damage was observed at the 8th and 10th week. Conclusion C57BL/6J mouse models of Sjogren's syndrome show the characteristics of multi-system damage, especially obvious at the 8th weeks. PMID- 27774936 TI - [Toll-like receptor 4 activation inhibits melanogenesis in melanocytes]. AB - Objective To explore the effect of Toll-like receptor 4 (TLR4) activation on melanogenesis in melanocytes. Methods The primary melanocytes were isolated, cultured and then stimulated by TLR4 agonist lipopolysaccharide (LPS). Firstly, the melanin content changes were detected in melanocytes, and then quantitative real-time PCR and Western blotting were employed to determine the expression levels of pre-melanosomal protein (Pmel17), tyrosinase (TYR) and microphthalmia associated transcription factor (MITF). Finally, the melanosomes were observed by electron microscopy. Results After stimulated by LPS, melanin formation in melanocytes was significantly reduced. The expressions of Pmel17 and TYR were markedly suppressed, which depended on the regulation of transcription factor MITF. The electron microscopy showed that melanosome synthesis was inhibited. Conclusion TLR4 activation reduces melanin synthesis in melanocytes, which indicates that the bacterial products may affect melanin synthesis through innate immunity. PMID- 27774937 TI - [Tetramethylpyrazine attenuates experimental autoimmune myasthenia gravis in rats via regulating related cytokines and antibodies]. AB - Objective To investigate the effects of tetramethylpyrazine (TMP) on experimental autoimmune myasthenia gravis (EAMG) in rats and explore the possible immune regulation mechanism. Methods Lewis rats were randomly divided into 4 groups: control group, EAMG group, TMP low-dose group (TMP-L, 10 mg/kg) and TMP high-dose group (TMP-H, 20 mg/kg). Except the control group, the other 3 groups were subjected to EAMG modeling. The body mass was determined and the symptoms of muscular weakness in rats were scored by Lennon EAMG criteria. The expressions of acetylcholine receptor (AChR), IgG and C3 in neuromuscular junctions were examined by immunofluorescence. The levels of R97-116 antibody (IgG1, IgG2a, IgG2b), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma) and interleukin 10 (IL-10) were detected by ELISA. Results TMP decreased the scores in the evaluation of the symptoms of muscle weakness in EAMG rats. Moreover, TMP administration significantly inhibited AChR expression and increased IgG and C3 expression in neuromuscular junctions of EAMG rats. In addition, after TMP treament, the levels of IgG1, IgG2a and TNF-alpha were remarkably reduced, while IL-10 level was elevated. However, there was no significant change in serum levels of IgG2b and IFN-gamma. Conclusion TMP can exert inhibitory effects on Th1, Th2 and B cells and modulate the levels of IgG1, IgG2a, TNF-alpha and IL-10. All these effects contribute to relieve the symptoms of muscle weakness in EAMG rats. PMID- 27774939 TI - [Knockdown of SOST in MDA-MB-231 breast cancer cells increase MG-63 osteoblast like cell function in co-culture system]. AB - Objective To construct a recombinant adenovirus expressing siRNA targeting human sclerostin (SOST) gene, and test the function of MG-63 cells while co-cultured with MDA-MB-231 cells infected by Ad-siSOST. MethodsAccording to the RNA sequence of SOST gene, two pairs of primers which contained 3 siRNA sequences were designed, and a pB2B plasmid was taken as template to amplify 2 DNA sequences. Both of the 2 DNA sequences were ligated to pAdTrace-OK by Gibson DNA Assembly way. After homologous recombination between recombinant shuttle plasmid and adenovirus vector plasmid, the adenovirus was packaged in HEK-293 cells. PCR and ELISA were used to test the expression of SOST in MDA-MB-231 cells which were infected with Ad-siSOST. In the co-culture system of MG-63 cells and MDA-MB-231 cells infected Ad-siSOST, osteoprotegerin (OPG), osteocalcin (OCN), integrin binding sialoprotein (IBSP) and receptor activator of nuclear factor-kappaB ligand (RANKL) were tested by quantitative real-time PCR. Results Recombinant shuttle plasmid which contained 3 interfering fragments was constructed successfully, and Ad-siSOST was obtained after homologous recombination and packaging. SOST expression in MDA-MB-231 cells was downregulated significantly after infeceted with Ad-siSOST. The mRNA levels of OPG, OCN, IBSP in MG-63 cells increased significantly, while the level of RANKL mRNA decreased significantly, and all 4 gene expressions were reversed after the infection of Ad-siSOST. Conclusion Knockdown of SOST in MG-63 cells increases osteogenesis and ratio of OPG/RANKL in vitro. PMID- 27774940 TI - [Wnt/beta-catenin pathway involved in the regulation of rat mesangial cell proliferation by adipose-derived mesenchymal stem cells]. AB - Objective To investigate the effect of adipose-derived mesenchymal stem cells (ADSCs) on glomerular mesangial cell proliferation via Wnt/beta-catenin pathway. Methods The rat glomerular mesangial cells (HBZY-1) were incubated in conditioned ADSC medium. Cell cycle was analyzed with flow cytometry; the proliferation rate of HBZY-1 and the expression levels of relative genes and proteins of Wnt signaling pathway were measured using RNA interference, quantitative real-time PCR and Western blotting, respectively. Results HBZY-1 proliferation was significantly inhibited under the action of conditioned ADSC medium, whereas dickkopf WNT signaling pathway inhibitor 1 (DKK1) mRNA level was up-regulated. Fibronectin and TGF-beta1 mRNA expression as well as beta-catenin and Bcl-2 protein levels of HBZY-1 were significantly down-regulated. DKK1 gene expression level in ADSCs was significantly higher than that of HBZY-1. After RNA interference, DKK1 expression level in ADSCs was markedly inhibited, yet the beta catenin protein level was notably elevated. The beta-catenin and Bcl-2 protein levels of HBZY-1 were also significantly raised in HBZY-1 after cultured with conditioned medium containing ADSCs treated with RNA interference. Conclusion Wnt/beta-catenin may be a potential signaling pathway involved in the regulative effect of ADSCs on glomerular mesangial cell proliferation. PMID- 27774938 TI - [miR-338-5p modulates B cell biological functions by targeting NF-kappaB1]. AB - Objective To explore the effects of miR-338-5p on the nuclear factor kappaB1 (NF kappaB1) expression and the IgG-producing ability of B cells. Methods Dual luciferase reporter assay was used to test the target gene of miR-338-5p. The purified CD20+ B cells were transfected with miR-338-5p agomiR, miR-338-5p antagomiR, NF-kappaB1 siRNA (siNF-kappaB1) and their corresponding negative control reagents, and then cultured with anti-IgM antibody and/or recombinant human B cell activating factor (rhBAFF). Real-time RCR and Western boltting were applied to determine the mRNA and protein levels of NF-kappaB1. IgG level in the supernatant was detected by ELISA. Results Compared with the control group, the hRluc/hLuc relative luciferase activity was significantly elevated in miR-338-5p mimic and NF-kappaB1-3'-UTR reporter co-transfected group. In the co-culture system with anti-IgM antibody and rhBAFF, the NF-kappaB1 mRNA, p105, p50 and IgG levels in B cells transfected with miR-338-5p agomiR were significantly increased, while the NF-kappaB1 mRNA and IgG levels in B cells transfected with miR-338-5p antagomiR were significantly decreased. The effect of siNF-kappaB1 on B cells was opposite to that of miR-338-5p agomiR. Correlation analysis suggested that NF-kappaB1 mRNA level was significantly positively correlated with IgG concentration. Conclusion miR-338-5p regulates the biological functions of B cells by positively regulating NF-kappaB1 expression and indirectly regulating BAFF signal. PMID- 27774942 TI - [Resolvin D1 inhibits the injury of PC12 cells induced by activated microglia]. AB - Objective To investigate the effect of resolvin D1 (RvD1) on the injury of PC12 cells induced by activated BV-2 microglia and the related mechanisms. Methods BV 2 cells were divided into control group, lipopolysaccharide (LPS)-treated group, RvD1-treated group and RvD1 combined with LPS (RvD1-LPS)-treated group. After BV 2 cells were incubated with the corresponding substances for 12 and 24 hours, the levels of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF alpha) in the supernatants were determined by ELISA. The culture supernatants of BV-2 cells were collected at 24 hours and added into PC12 cells for another 24 hour culture. Thereafter, the survival rate of PC12 cells was tested by MTT assay. The expression of NF-kappaB p65 protein in BV-2 cells was deteced by Western blotting. Results Compared with the control group, the survival rate of PC12 cells in the LPS group significantly decreased; the levels of IL-1beta, IL-6 and TNF-alpha in the supernatant of BV-2 cells and the nuclear translocation of NF-kappaB p65 significantly increased in the LPS group. Compared with the LPS group, the survival rate of PC12 cells in RvD1-LPS group was significantly elevated; the levels of IL-1, IL-6, TNF-alpha and the nuclear translocation of NF kappaB p65 were significantly reduced in RvD1-LPS group. Conclusion RvD1 can inhibit the injury of PC12 cells induced by activated BV-2 microglia through inhibiting the nuclear translocation of NF-kappaB p65 and inflammatory factor levels in BV-2 cells. PMID- 27774941 TI - [Over-expression of Raf kinase inhibitor protein (RKIP) inhibits the proliferation of LX-2 human hepatic stellate cells]. AB - Objective To investigate the effect of Raf kinase inhibitor protein (RKIP) over expression on the proliferation of LX-2 human hepatic stellate cells. Methods Recombinant plasmid pcDNA3.1-RKIP was transfected into LX-2 cells. G418 was used to screen and culture stably infected cells. MTT assay and colony formation assay were used to examine the effect of RKIP over-expression on cell proliferation and colony formation, respectively. Western blotting was performed to assess the expressions of RKIP, alpha-smooth muscle actin (alpha-SMA), type 1 collagen (Col1) and matrix metalloproteinase 1(MMP-1) and MMP-2 as well as extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK/MAPK) signaling pathway-related proteins. Results Compared with the control cells, RKIP over expression significantly inhibited LX-2 cell proliferation and colony formation, and reduced the protein expressions of Col1, alpha-SMA, MMP-1 and MMP-2. Moreover, RKIP over-expression remarkably inhibited the phosphorylation of ERK/MAPK. Conclusion Over-expressed RKIP inhibits LX-2 cell proliferation and the mechanism is related to the inhibition of ERK/MAPK signaling pathway. PMID- 27774943 TI - [Overexpression of inhibitor of beta-catenin and T cell factor (ICAT) promotes proliferation and migration of cervical cancer Caski cells]. AB - Objective To investigate the effect of overexpressed inhibitor of beta-catenin and T cell factor (ICAT) on the proliferation and migration of human cervical cancer Caski cells. Methods Caski cells were transfected with ICAT recombinant adenovirus (AdICAT). The levels of ICAT mRNA and protein were detected by quantitative real-time PCR (qRT-PCR) and Western blotting, respectively. Effect of ICAT overexpression on proliferation, cell cycle and migration in Caski cells was respectively evaluated by MTT assay, flow cytometry and TranswellTM migration assays. Results The expression of ICAT remarkably increased in Caski cells after AdICAT infection. Overexpression of ICAT promoted Caski cells' proliferation, arrested the cell cycle in the S phase and enhanced cell migration. Conclusion Overexpression of ICAT can promote the proliferation and migration of Caski cervical cancer cells. PMID- 27774944 TI - [Overexpression of aplysia Ras homolog I (ARHI) increases apoptosis in colon cancer SW480 cells]. AB - Objective To observe the effect of aplysia Ras homolog I (ARHI) gene on human colon cancer cell (SW480) apoptosis. Methods The pcDNA3.1-FLAG-ARHI plasmid was adopted to transfect the SW480 cell line, and G418 screening to obtain stably ARHI-transfected SW480 cells. Reverse transcription PCR and Western blotting were used to detect mRNA and protein expression of ARHI, respectively. The flow cytometry was applied to detect the effect of ARHI overexpression on colon cancer cell apoptosis. The levels of protein kinase B (Akt), phosphorylated Akt (p-Akt), p53 and Bcl-2 were determined by Western blotting. Results SW480 cells stably overexpressing ARHI were successfully established. Cell apoptosis rate in the cells significantly increased. The protein levels of Bcl-2 and p-Akt substantially decreased, whereas the protein expression level of P53 increased; Akt had no obvious changes. Conclusion The overexpression of ARHI promotes colon cancer SW480 cell apoptosis by inhibiting the level of Akt. PMID- 27774946 TI - [Construction and application of eukaryotic expression vector of fragile X mental retardation 1 (FMR1) gene]. AB - Objective To construct a eukaryotic expression vector of human fragile X mental retardation 1 (FMR1) gene and establish stably transfected HeLa cells. Methods The full-length FMR1 cDNA fragment was amplified by PCR and inserted into eukaryotic expression vector pEGFP-N2 using restriction enzyme. The recombinant plasmid pEGFP-N2-FMR1, after identified by restriction digestion and DNA sequencing, was transfected into HeLa cells by lipofectamine 2000. The stably transfected cell line was obtained by screening with G418. The expression and subcellular distribution of FMR protein was identified by Western blotting and immunofluorescence staining combined with laser-scanning confocal microscopy. Results Restriction digestion and DNA sequencing revealed that the eukaryotic expression plasmid of pEGFP-N2-FMR1 was successfully constructed. Besides, Western blotting and immunofluorescence staining showed that GFP-FMR protein was expressed in HeLa cells, which mainly was localized in the cytoplasm. Conclusion The recombinant eukaryotic expression vector of pEGFP-N2-FMR1 has been constructed successfully and stably expressed FMR protein in HeLa cells. PMID- 27774945 TI - [Baicalein promotes the apoptosis of HeLa cells by inhibiting ERK1/2 expression]. AB - Objective To investigate the effects of baicalein and U0126 treatment on the apoptosis of human cervical carcinoma HeLa cells and the potential mechanism. Methods HeLa cells were subjected to (1, 2, 5, 10, 20, 50, 100, 200, 300) MUmol/L baicalein or (1, 2, 5, 10, 20, 30) MUmol/L U0126 treatment for 24 hours. The optimal concentrations of baicalein and U0126 for HeLa inhibition was determined by a cell counting Kit-8 assay. HeLa cells were then treated with these inhibitory concentrations for 24 hours separately or in combination. The cell cycle and the degree of apoptosis were analyzed by flow cytometry. The cell apoptosis index was evaluated by the TUNEL assay. The expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), Bax, and Bcl-2 at the mRNA and protein levels were examined by real-time PCR and Western blotting, respectively. Results Optimal inhibitory concentrations of baicalein and U0126 for HeLa cells were 200 MUmol/L and 10 MUmol/L, respectively. Compared with the control group, baicalein treatment increased the growth rate of cells in the G0/G1 phase but decreased the S phase. Combination treatment of 200 MUmol/L baicalein and 10 MUmol/L U0126 for 24 hours further reduced the S phase growth rate. Treatment with 10 MUmol/L U0126 or 200 MUmol/L baicalein for 24 hours induced cell apoptosis, and the combination treatment induced more apoptosis. Treatment by baicalein alone or in combination with U0126 for 24 hours significantly decreased ERK1/2 and Bcl-2 mRNA expressions, and upregulated Bax mRNA expression. It also downregulated ERK1/2 phosphorylation and Bcl-2 protein expression, while increasing Bax protein expression. Conclusion Both baicalein and U012 appear to inhibit proliferation, induce apoptosis, and increase the growth rate in the G0/G1 phase but reduce the S phase of HeLa cells. This effect is enhanced when they are used synergistically. PMID- 27774947 TI - [Human papillomavirus 16 E5 protein inhibits keratinocyte growth factor-triggered autophagy]. AB - Objective To investigate the effect of E5 protein of human papillomavirus type 16 (HPV16 E5) on keratinocyte growth factor-triggered autophagy. Methods Firstly, pCI-neo-E5 recombinant plasmid was constructed. After that, the recombinant plasmid harboring pCI-neo-E5 was transfected into HaCaT cells using LipofectamineTM2000 reagent, and the mRNA transcriptional level of 16 E5 was evaluated by quantitative real-time PCR (qRT-PCR). Then, the expression of LC3BIIwas detected by Western blotting and the localization of LC3B was observed by immunofluorescence in pCI-neo-E5-HA-transfected HaCaT cells triggered with keratinocyte growth factor. Finally, the mRNA transcriptional levels of several autophagy-associated proteins including beclin1, ATG5, ATG7 and LC3B were assayed by qRT-PCR. Results pCI-neo-E5 recombinant plasmid was constructed successfully. After transfection of pCI-neo-E5, a significant increase of HPV16 E5 mRNA was found in HaCaT cells. HPV16 E5 oncoprotein obviously reduced the expression level of LC3BII and the amount of LC3B puncta in HaCaT cells stimulated with keratinocyte growth factor, and inhibited the mRNA transcription of several autophagy-associated proteins. Conclusion HPV16 E5 can suppress keratinocyte growth factor-triggered autophagy in human keratinocytes through down-regulating autophagy-associated protein expression. PMID- 27774948 TI - [Alterations and clinical signifecance of exosome-containing innate immunity related lncRNAs in patients of hemorrhagic fever with renal syndrome]. AB - Objective To observe the alterations of innate immunity related long non-coding RNAs (lncRNAs) in exosomes extracted from the plasma of hemorrhagic fever with renal syndrome (HFRS) patients, and analyze their relationship with the disease stage and severity. Methods Exosomes were extracted from the plasma samples of HFRS patients, healthy controls and recovered HFRS patients. Transmission electronic microscopy and Western blotting were performed to confirm the efficiency of the extraction. lncRNA profiles in the different groups were determined by high-throughput sequencing. The contents of several innate immunity related lncRNAs were detected by quantitative real-time PCR, and their relationship with the disease stage and severity was analyzed. Results Exosomes from the plasma were accurately extracted. Innate immunity related lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), negative regulator of interferon response (NRIR), negative regulator of antiviral response (NRAV) were found in exosomes. NEAT1 content was significantly reduced in the exosomes from HFRS patients compared with healthy controls and it was significantly restored in recovered HFRS patients. The exosome NEAT1 content was correlated with the epidemic of HFRS but had no relationship with the stage and severity of the disease. Conclusion Several innate immunity related lncRNAs exist in the exosome from HFRS patients, among which NEAT1 content significantly decreases in HFRS patients compared with healthy controls and recovered HFRS patients. The reduced NEAT1 level is correlated with the epidemic of HFRS. PMID- 27774950 TI - [Knock-down of BCL11A expression in breast cancer cells promotes MDA-MB-231 cell apoptosis]. AB - Objective To detect the expression and pathological significance of B-cell CLL/lymphoma 11A (BCL11A) in breast cancer and investigate the effect of its silencing on the apoptosis of human MDA-MB-231 breast cancer cells. MethodsImmunohistochemistry was used to detect the expression of BCL11A in 62 cases of human breast cancer tissues and 8 cases of normal tissues. We synthesized siRNA targeting BCL11A, and then siRNA was transfected into MDA-MB 231 cells. Forty-eight hours later, the suppression effect of siRNA on BCL11A was determined by quantitative real-time PCR and Western blotting. The apoptosis of MDA-MB-231 cells was detected by flow cytometry. Results The BCL11A protein was mainly expressed in cytoplasm. The expression level of BCL11A in breast cancer tissues was higher than that in paracancerous tissues. The expression had correlations with tumor grade, tumor stage, while it had no correlations with the patients' age and tumor size. BCL11A-siRNA significantly suppressed the expression of BCL11A mRNA and protein as compared with the control group. MDA-MB 231 cells transfected with BCL11A-siRNA had higher apoptosis rate compared with the control group. Conclusion The BCL11A protein is highly expressed in breast cancer and knock-down of BCL11A promotes the apoptosis of MDA-MB-231 cells. PMID- 27774949 TI - [Analysis of the numbers and subsets of MTB-HAg specific TNF-alpha+ gammadelta T cells in peripheral blood of patients with active pulmonary tuberculosis]. AB - Objective To investigate the differences of proportions of tumor necrosis factor alpha (TNF-alpha)-producing cells in peripheral blood gammadelta T cells stimulated with Mycobacterium tuberculosis heat resistant antigen (MTB-HAg) among patients with pulmonary tuberculosis (PTB), latent tuberculosis infection (LTBI) and healthy subjects (HC). Methods The peripheral blood specimens were collected from 15 normal adults, which were divided into HC group (n=9) and LTBI group (n=6), by enzyme-linked immunospot (ELISPOT) kit for diagnosis of Mycobacterium tuberculosis infection, and 12 patients with active PTB. The peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation and simulated with MTB-HAg for 20 hours. Then the cells were collected, and the proportions of TNF-alpha-producing cells in TCRalphabeta+ T cells, TCRgammadelta+ T cells, CD4+alphabeta T cells, CD8+alphabeta T cells, and TCR-Vdelta2+ T cells were measured with flow cytometry. Results The proportion of TNF-alpha-producing cells in gammadelta T cells in patients with PTB was obviously lower than that in LTBI group and HC group; the proportion of TNF-alpha-producing cells in Vdelta2 T cells in PTB patients was apparently lower than that in LTBI and HC; the proportion of Vdelta2 T cells in TNF-alpha+gammadelta T cells in the peripheral blood of PTB patients was remarkably lower than that in LTBI and HC groups. The proportions of TNF-alpha-producing cells in peripheral alphabeta T cells, CD4+ and CD8+alphabeta T cells were dramatically lower than those in gammadelta T cells of the three according groups. Moreover, there were no statistical differences in regard with the proportions of TNF-alpha-producing cells in alphabeta T cells, and CD4+ and CD8+alphabeta T cells among the three groups. Conclusion The TNF-alpha production capacity of MTB-HAg specific gammadelta T cells and Vdelta2 T cell subsets in patients with tuberculosis is obviously lower than that of LTBI and HC. PMID- 27774951 TI - [Low-intensity pulsed ultrasound promotes extracellular matrix synthesis of human osteoarthritis chondrocytes]. AB - Objective To investigate the effect of low-intensity pulsed ultrasound (LIPUS) on the extracellular matrix synthesis of human osteoarthritis (OA) chondrocytes and explore the underlying mechanism. Methods Human osteoarthritis chondrocytes were collected from abandoned articular cartilage. Then the cells were cultured and identified by toluidine blue staining and immunocytochemical staining of type 2 collagen. The passage 2 cells were randomly divided into 3 groups: control OA group, 30 mW/cm2 LIPUS-treated OA group, 30 mW/cm2 LIPUS combined with 5 MUmol/L LY294002-treated OA group. LIPUS treatment was performed for 20 minutes per day, totally 7 days. The mRNA levels of Col2, aggrecan and matrix metalloprotease 13 (MMP-13) were determined by quantitative real-time PCR. The protein levels of Col2, aggrecan, Akt, p-Akt and MMP-13 were evaluated by Western blotting. Results Compared with the control OA group, the expressions of Col2 and aggrecan at both mRNA and protein levels significantly increased, and MMP-13 significantly reduced in the LIPUS-treated OA group. The p-Akt protein level was significantly elevated after LIPUS stimulation, but there was no significant difference in the Akt protein levels between the two groups. Moreover, LY294002, an inhibitor of PI3K/Akt, significantly suppressed the biological effect activated by LIPUS. Conclusion LIPUS enhances the synthesis and inhibits the degradation of the extracellular matrix in human osteoarthritis chondrocytes. PMID- 27774952 TI - [Preparation and biological activity of anti-human c-mesenchymal epithelial transition factor (c-Met) monovalent antibody]. AB - Objective To construct lentiviral vectors for the expression of monovalent antibody against human c-mesenchymal epithelial transition factor (c-Met) using anti-c-Met chimeric antibody ch3E1D7 plasmid, and test the affinity and neutralizing ability of the purified monovalent antibody in transfected HEK293T cells. Methods The anti-c-Met monovalent antibody was designed, namely mono3E1D7. Three different lentiviral expression vectors of the monovalent antibody were then constructed using genetic engineering technology. The three expression vectors were co-transfected in HEK293T cells to express the monovalent antibody, which was later purified by protein A-sepharose 4B affinity chromatography. The antibody structural integrity was identified by SDS-PAGE. Ability of the monovalent antibody to bind and neutralize hepatocyte growth factor (HGF) was tested by ELISA. Results Heavy, light and Knob chains of the mono3E1D7, with molecular masses of about 55, 25 and 30 kD, respectively, were observed on reduced 10% SDS-PAGE. ELISA showed that the expressed protein could bind to c-Met specifically and neutralize c-Met/HGF binding. Conclusion Monovalent antibody targeting c-Met has been successfully constructed, expressed and identified, which could help to study the important role of monovalent antibody targeting to c-Met in following experiments. PMID- 27774953 TI - [Preparation and identification of rabbit anti-AKR1B10 polyclonal antibody]. AB - Objective To prepare rabbit anti-aldo-keto reductase family 1 member B10 (AKR1B10) polyclonal antibody and identify its specificity. Methods AKR1B10 cDNA was amplified by reverse transcription PCR (RT-PCR) and inserted into prokaryotic expression vector pET-15b to form recombinant plasmid pET-15b-AKR1B10. The recombinant plasmid pET-15b-AKR1B10 was transformed into E.coli DH5alpha. Isopropylthio-beta-D-galactoside (IPTG) was used to induce the expression of the recombinant protein His-tagged AKR1B10 in E.coli DH5alpha. The expression products from different clones of E.coli DH5alpha were identified by SDS-PAGE. The positive bacteria were picked out and amplified. His-Tag-AKR1B10 protein was purified from the expression product of the positive clones by His-tagged purification column. The purified recombinant protein His-Tag-AKR1B10 was used to immunize New Zealand white rabbits. Antisera were acquired after two months. Anti AKR1B10 polyclonal antibodies were purified by antigen purification column with AKR1B10 recombinant protein. Lastly, the purified polyclonal antibodies were identified by SDS-PAGE, ELISA, Western blotting. Results The recombinant plasmid pET-15b-AKR1B10 was constructed successfully, and the recombinant protein His-Tag AKR1B10 with high purity was acquired. The purified polyclonal antibodies were able to specifically recognize AKR1B10 protein. Conclusion The rabbit anti AKR1B10 polyclonal antibodies is prepared successfully with high specificity. PMID- 27774954 TI - Regularity effect in prospective memory during aging. AB - BACKGROUND: Regularity effect can affect performance in prospective memory (PM), but little is known on the cognitive processes linked to this effect. Moreover, its impacts with regard to aging remain unknown. To our knowledge, this study is the first to examine regularity effect in PM in a lifespan perspective, with a sample of young, intermediate, and older adults. OBJECTIVE AND DESIGN: Our study examined the regularity effect in PM in three groups of participants: 28 young adults (18-30), 16 intermediate adults (40-55), and 25 older adults (65-80). The task, adapted from the Virtual Week, was designed to manipulate the regularity of the various activities of daily life that were to be recalled (regular repeated activities vs. irregular non-repeated activities). We examine the role of several cognitive functions including certain dimensions of executive functions (planning, inhibition, shifting, and binding), short-term memory, and retrospective episodic memory to identify those involved in PM, according to regularity and age. RESULTS: A mixed-design ANOVA showed a main effect of task regularity and an interaction between age and regularity: an age-related difference in PM performances was found for irregular activities (older < young), but not for regular activities. All participants recalled more regular activities than irregular ones with no age effect. It appeared that recalling of regular activities only involved planning for both intermediate and older adults, while recalling of irregular ones were linked to planning, inhibition, short-term memory, binding, and retrospective episodic memory. CONCLUSION: Taken together, our data suggest that planning capacities seem to play a major role in remembering to perform intended actions with advancing age. Furthermore, the age PM-paradox may be attenuated when the experimental design is adapted by implementing a familiar context through the use of activities of daily living. The clinical implications of regularity effect are discussed. PMID- 27774957 TI - Erratum. PMID- 27774955 TI - Incidence of syphilis seroconversion among HIV-infected persons in Asia: results from the TREAT Asia HIV Observational Database. AB - INTRODUCTION: Outbreaks of syphilis have been described among HIV-infected men who have sex with men (MSM) in Western communities, whereas reports in Asian countries are limited. We aimed to characterize the incidence and temporal trends of syphilis among HIV-infected MSM compared with HIV-infected non-MSM in Asian countries. METHODS: Patients enrolled in the TREAT Asia HIV Observational Database cohort and with a negative non-treponemal test since enrolment were analyzed. Incidence of syphilis seroconversion, defined as a positive non treponemal test after previously testing negative, was evaluated among patients at sites performing non-treponemal tests at least annually. Factors associated with syphilis seroconversion were investigated at sites doing non-treponemal testing in all new patients and subsequently testing routinely or when patients were suspected of having syphilis. RESULTS: We included 1010 patients from five sites that performed non-treponemal tests in all new patients; those included had negative non-treponemal test results during enrolment and subsequent follow-ups. Among them, 657 patients were from three sites conducting regular non-treponemal testing. The incidence of syphilis seroconversion was 5.38/100 person-years (PY). Incidence was higher in MSM than non-MSM (7.64/100 PY vs. 2.44/100 PY, p<0.001). Among MSM, the incidence rate ratio (IRR) for every additional year from 2009 was 1.19 (p=0.051). MSM status (IRR 3.48, 95% confidence interval (CI) 1.88-6.47), past syphilis diagnosis (IRR 5.15, 95% CI 3.69-7.17) and younger age (IRR 0.84 for every additional 10 years, 95% CI 0.706-0.997) were significantly associated with syphilis seroconversion. CONCLUSIONS: We observed a higher incidence of syphilis seroconversion among HIV-infected MSM and a trend to increasing annual incidence. Regular screening for syphilis and targeted interventions to limit transmission are needed in this population. PMID- 27774956 TI - Current decline in the number and size of Galba truncatula and Omphiscola glabra populations, intermediate hosts of Fasciola hepatica, on the acidic soils of Central France. AB - Field investigations on the habitats colonized by Galba truncatula or Omphiscola glabra were carried out on 162 farms of the Limousin region, Central France, to determine whether there is currently a decline in the number and size of snail populations. Seven types of snail habitats were considered here. Compared to the numbers of snail populations recorded from 1976 to 1992, the values noted from 2013 to 2016 were significantly lower, with a decline rate of 34% for G. truncatula and 23% for O. glabra. Variations in this decline rate with the type of snail habitat were also noted. The greatest decreases in the numbers of snail populations were noted for spring heads located in meadows and for road ditches, while the lowest were noted for open drainage furrows present in meadows. The distribution of these habitats according to their area did not show any significant change over time. In contrast, overwintering snails were significantly less numerous in 2013-2016 in five types of habitats for G. truncatula and in three types only for O. glabra. Several causes underlie this population decline. Among them, the current development of mechanical cleaning in open drainage systems and road ditches, that of subsurface drainage in meadows, and regular gyro-crushing of vegetation around temporary spring heads were the most important. PMID- 27774960 TI - Obesity, leptin, and thrombosis: Focus on clopidogrel resistance. PMID- 27774961 TI - Fragmented QRS and serum propeptide of type I procollagen in hypertensive patients: Putting another brick in the wall. PMID- 27774962 TI - Effect of obesity and serum leptin level on clopidogrel resistance. AB - OBJECTIVE: Clopidogrel inhibits platelet aggregation by blockade of platelet adenosine diphosphate (ADP) P2Y12 receptor. Leptin is the obesity gene product, and its serum level increases with obesity. Platelets have leptin receptors on their surfaces. Hyperleptinemia may induce ADP-mediated platelet aggregation. It has been proposed that clopidogrel effect could be diminished with high serum leptin levels. The aim of the present trial was to further investigate the relationship between serum leptin level and clopidogrel resistance. METHODS: A total of 100 subjects who underwent percutaneous coronary intervention were enrolled. Two groups were organized according to presence of clopidogrel resistance, and serum leptin levels were compared. Threshold for clopidogrel resistance and hyperleptinemia were accepted as >=P2Y12 reaction unit (PRU) 240 and >=15 ng/mL leptin, respectively. Body mass index (BMI) of 30 kg/m2 or greater was considered obese. RESULTS: A total of 37% of patients were considered clopidogrel-resistant. Comparison of groups revealed significantly higher clopidogrel resistance (p=0.017) and PRU levels (p=0.001) in hyperleptinemic patients. No significant difference in serum leptin levels (p=0.116) was found. Increased clopidogrel resistance was observed in patients with BMI >30 kg/m2 (p=0.015). CONCLUSION: Clopidogrel resistance is more common in obese and hyperleptinemic patients. Dosage should be individualized in these populations. PMID- 27774963 TI - Fragmented QRS complexes are a marker of myocardial fibrosis in hypertensive heart disease. AB - OBJECTIVE: Carboxy-terminal propeptide of type 1 procollagen (PICP) is a marker of extracellular collagen synthesis. Fragmented QRS (fQRS) on a 12-lead electrocardiogram (ECG) has been demonstrated as a marker of myocardial fibrosis. The present objective was to investigate the association between serum PICP concentration and presence of fQRS on ECG in hypertensive patients. METHODS: Consecutive patients with previously or newly diagnosed hypertension were included. fQRS was defined as the presence of additional R-wave (R'), or notching of R- or S-waves, or the presence of fragmentation in 2 contiguous ECG leads. Serum PICP levels were measured by ELISA method. RESULTS: The study group consisted of 90 hypertensive patients (74% females, with a mean age of 54.7+/-8.5 years). Of these patients, 47 (52.2%) had fQRS on ECG. Age (p=0.121) and gender distribution (p=0.625) were similar in patients with or without fQRS. Receiver operating characteristic curve analysis yielded a strong predictive ability of PICP levels for the presence of fQRS (area under the curve: 0.850; 95% CI: 0.772 0.929; p<0.0001). In multivariate logistic regression analysis, PICP levels were strongly and independently associated with the presence of fQRS (OR: 1.938; 95% CI: 1.398-2.688). CONCLUSION: Serum PICP level is a strong and independent predictor of fQRS. Discriminative performance of serum PICP levels for the presence of fQRS is high. The present results are the first to demonstrate that fQRS may indicate myocardial fibrosis in patients with hypertension. PMID- 27774964 TI - Single-center experience with percutaneous mitral valve repair using the MitraClip in a high-risk series in Turkey. AB - OBJECTIVE: Mitral valve regurgitation (MR) is the second most common heart valve disease in Europe. Without intervention, prognosis of severe symptomatic MR is poor. Percutaneous edge-to-edge mitral valve repair with MitraClip is a promising mitral regurgitation treatment technique in select, high-surgical-risk patients. The present objective was to describe the experience of a single center with MitraClip use in a high-risk series in Turkey. METHODS: Between May 2013 and September 2014, 28 high-surgical-risk patients with MR of at least grade 3+ and mean EuroSCORE of 26% underwent MitraClip implantation at our institution. In hospital and follow-up safety and efficacy results are presented. RESULTS: Mean patient age was 58 years, and 75% were male. Grade 3 or 4 MR was present in all patients, and was primarily the result of restrictive functional mitral regurgitation (in 89% of cases). Mean left ventricular ejection fraction (LVEF) was 27% and New York Heart Association (NYHA) classification was III or IV in 89% of the population. Acute procedural success was 89%, with 47% of patients receiving a single clip, 39% receiving 2 clips, and 14% receiving 3 clips. One periprocedural death occurred, and 2 deaths occurred during follow-up (mean: 13.9 months). After 1 year, more than 75% of patients had MR severity of <=2+ and NYHA classification of I or II, but no significant change in left ventricular volume or systolic function. Significant improvement in 6-minute walk test and quality of life was also observed. CONCLUSION: Initial experience with the MitraClip system showed promising results in patients considered high-surgical-risk, particularly in those with end-stage heart failure. PMID- 27774965 TI - Coronary artery disease detected by coronary computed tomography angiography is associated with red cell distribution width. AB - OBJECTIVE: Increased red blood cell distribution width (RDW) is associated with severity of coronary artery disease (CAD). The aim of the present study was to retrospectively evaluate the relationship between CAD detected by coronary computed tomography angiography (CCTA) and RDW. METHODS: Records of 291 patients who underwent 16-slice CCTA due to the presence of angina-like chest pain were retrospectively evaluated. Exclusion criteria were applied. Clinical characteristics, risk factors for CAD, and RDW values on CCTA were noted. RESULTS: RDW levels in patients with CAD were significantly higher than in those with normal coronary arteries (NCAs) (15.50+/-1.57 compared to 14.80+/-1.41, p=0.001). Diabetes mellitus, hypertension, and history of smoking were significantly more common in the CAD group (p=0.018, p=0.007, and p=0.013, respectively). On multivariate logistic regression analysis, RDW (p=0.009 [odds ratio (OR): 1.352; 95% confidence interval (CI): 1.081-1.683]), age (p<0.001 [OR: 1.063; 95% CI 1.031-1.090]), and history of smoking (p=0.003 [OR: 2.672; 95% CI: 1.360-5.232]) were shown to be independent predictors for CAD detected by CCTA. CONCLUSION: The present results suggest that higher RDW levels are independently associated with presence of CAD detected by CCTA in patients without known CAD. Further studies are warranted to clarify the exact role of RDW in risk stratification. PMID- 27774966 TI - Evaluation of arterial stiffness and subclinical atherosclerosis in patients with Behcet's disease without cardiovascular involvement. AB - OBJECTIVE: This study was conducted to evaluate arterial structure and function with assessment of pulse wave velocity (PWV) and carotid intima-media thickness (CIMT) in patients with Behcet's disease (BD). METHODS: Thirty patients (13 female, 17 male) with BD and 30 age, sex-matched healthy controls (12 female, 18 male) with no known cardiovascular disease were enrolled in this study. Carotid femoral PWV and CIMT were measured. RESULTS: PWV was higher in BD patients compared with control group (6.35+/-1.05 vs. 5.75+/-0.83, respectively; p=0.017). There was no significant difference in maximum CIMT (0.751+/-0.077 mm vs. 0.735+/ 0.079 mm, respectively; p=0.435), or mean CIMT (0.643+/-0.070 mm vs. 0.629+/ 0.069, respectively; p=0.452). Maximum CIMT, mean CIMT, and PWV were positively correlated with duration of disease (r=0.410, p=0.025; r=0.404, p=0.027; and r=0.362, p=0.049, respectively). CONCLUSION: Findings suggest that endothelial function is impaired in cases of BD before visible structural changes to arterial wall. PWV is more useful measurement than CIMT in determination of vascular damage in BD, especially in early stage of disease duration. PMID- 27774967 TI - Trans-subclavian aortic valve replacement with various bioprosthetic valves: Single-center experience. AB - OBJECTIVE: Transcatheter aortic valve replacement (TAVR) has been accepted as an alternative to surgery in high risk or inoperable patients with severe aortic stenosis (AS). Although transfemoral approach is the most often preferred means of access, in patients with severe ilio-femoral arteriopathy, other vascular access sites may be required. The aim of the present study was to report our experience with trans-subclavian approach for TAVR using different valve systems. METHODS: Among 273 patients undergoing TAVR between June 2011 and May 2016, 10 patients (mean age: 68.3+/-7.6 years; 6 males) with high surgical risk were excluded from transfemoral TAVR because of ilio-femoral arteriopathy. Under general anesthesia, 9 of these patients underwent TAVR via left subclavian artery (SCA) and 1 patient via right SCA. Surgical cut-down and closure techniques were utilized in all patients. Eight balloon-expandable Edwards Sapien XT valves (size: one 23 mm, six 26 mm, and one 29 mm) were used, 1 patient received 26 mm balloon-expandable Sapien 3 valve, and 1 patient had 27 mm self-expandable Lotus valve implanted. RESULTS: Procedural success rate was 90%. Mean aortic gradient decreased to 10.6 mmHg from 47.4 mmHg. Emergent surgery was required in 1 patient due to complication of ventricular valve embolization. Thrombus formation at right SCA was detected in 1 patient and resolved with medical therapy. In hospital mortality was not observed in any patients. CONCLUSION: Trans-subclavian approach for TAVR is safe and feasible. Proper patient and valve selection concurrent with utilization of multimodal imaging techniques are crucial for successful and uncomplicated procedure. PMID- 27774968 TI - [Ultrasound-assisted, catheter-directed thrombolysis of acute pulmonary embolism via the subclavian vein: alternative access path]. AB - Routinely, the femoral vein is used for access in ultrasound-assisted, catheter directed thrombolysis (USAT). Presently described is a case of bilateral femoral venous occlusion caused by chronic thrombosis, successfully treated with USAT, using subclavian vein for access. PMID- 27774969 TI - Treatment of severe hemolysis following Nit-Occlud Le VSD coil implantation with Amplatzer Duct Occluder II. AB - Hemolysis after percutaneous device closure of ventricular septal defect (VSD) is a rare complication that can be conservatively managed in the majority of cases. However, surgery or transcatheter occlusion may be necessary. Presently described is the successful treatment of hemolysis that developed after implantation of the Nit-Occlud Le VSD coil, using the Amplatzer Duct Occluder II (ADO II) in a patient with aneurysmatic perimembranous VSD. Systolic murmur and symptoms immediately disappeared after the procedure. PMID- 27774970 TI - Massive pulmonary embolism and a cardiac mass: Thrombus or metastasis? AB - Cardiac mass can be described as an abnormal structure within or directly contiguous to the heart. Tumors and thrombi are the most common types of cardiac masses. Intracardiac thrombi have been encountered in various clinical settings and can result in severe morbidity and mortality due to embolic events. Cardiac neoplasms are extremely rare, and are usually metastatic tumors. The major primary malignancies associated with cardiac metastases include cancers of the lung, breast, stomach, and liver, and lymphoma, leukemia, and melanoma. Osteosarcoma (OS) is the most common type of bone malignancy, and is almost always highly malignant. A previous study demonstrated that OS very rarely metastasizes to the heart. Presently reported is an unusual case of OS with intracaval, right atrial, and right ventricular extension that was misdiagnosed as venous thrombus. PMID- 27774971 TI - Acute myocardial infarction in a patient with sickle cell trait. AB - Presently described is the rare complication of sickle cell trait (HbAS) with acute inferior myocardial infarction in a young adult patient. Angiogram revealed microemboli in the distal thin segment of the circumflex (Cx) artery. Anticoagulant and anti-aggregant therapies were initiated to restore Cx artery flow. HbAS was detected as an underlying pathology. ST segments returned to the isoelectric line and the patient became asymptomatic. PMID- 27774972 TI - Balloon angioplasty of severe aortic coarctation in a newborn, using axillary artery access: The first experience in Turkey. AB - Axillary artery access for demanding interventions in newborns is rarely described, in spite of the many clear advantages. This access route in newborns with critical congenital heart disease is a real alternative to the more commonly used femoral or carotid artery routes. In brief, axillary access is an attractive alternative approach in newborns with complex heart diseases. It is advisable to stop an elective procedure if axillary access is not successful. Presently described is the use of axillary artery access for balloon angioplasty in a newborn with critical aortic coarctation. To the best of our knowledge, it was the first instance in Turkey. PMID- 27774973 TI - Rare combination and transcatheter treatment during single session in an infant: Patent ductus arteriosus and major aortopulmonary collateral artery concordance. AB - Major aortopulmonary collateral arteries are abnormal vascular structures that may be seen in cyanotic diseases that progress with reduced pulmonary flow. They occur rather rarely in the absence of cyanotic congenital heart disease. Presently described is the case of an infant who underwent patent ductus arteriosus (PDA) and major aortopulmonary collateral artery occlusion in a single session, without presence of cyanotic congenital heart disease. To the best of our knowledge, this is the first case of congenital aortopulmonary collateral artery to be reported in a symptomatic infant with PDA. PMID- 27774974 TI - [The doctor in a vise between health and the law: What to do?] AB - The relationship between patients and physicians has maintained its importance throughout human history because of special features of the medical profession. This relationship engendered true loyalty of patients to their physicians as well as serious legal conflicts. Medical malpractice has gained importance among physicians and ignited discussion because of new articles added to the Turkish Penal Code in 2005. In a very short time, the penalties mandated had a chilling, negative effect on doctors, resulting in loss of affection for the profession, hesitation to intervene, and burnout syndrome. Cardiologists work in an environment where the line between life and death is very thin. The aim of the present study was to raise awareness and avoid possible grievances by informing them of their responsibilities under the law. PMID- 27774975 TI - Case images: 'Ping-pong' ball thrombus in the left atrium. PMID- 27774976 TI - Case images: Cardiac infiltration of leukemia with persistent ST segment elevation. PMID- 27774977 TI - Case images: Rare source of cardioembolism: transient ischemic attack in a patient with Lambl's excrescence. PMID- 27774978 TI - Case images: Left apical hemothorax: A rare complication of device implantation. PMID- 27774979 TI - Knockdown of High Mobility Group-Box 3 (HMGB3) Expression Inhibits Proliferation, Reduces Migration, and Affects Chemosensitivity in Gastric Cancer Cells. AB - BACKGROUND High mobility group-box 3 (HMGB3) has been shown to affect tumor initiation and progression. This research aimed to investigate the role of HMGB3 in gastric cancer (GC) cell proliferation, migration, invasion, chemoresistance, and its potential molecular mechanisms. MATERIAL AND METHODS GC MGC803 and BGC823 cells were transfected with siRNA targeting the HMGB3 gene. The expressions of HMGB3 protein in MGC803 and BGC823 cells after transfection were detected by Western blot assays. We detected cell proliferation and cell cycle by MTT and flow cytometry assay. Cell migration and invasion were determined by wound scratch and transwell assay. MGC803 and BGC823 cells were treated with various concentrations of oxaliplatin, cisplatin, and paclitaxel. After 24 hours of drug exposure, we performed MTT assays to investigate chemoresistance in both groups. Western blot assays were used to detect related proteins expression. RESULTS Silencing of HMGB3 inhibited cell proliferation and induced G0/G1 phase arrest of GC cells partly via modulating p53 and p21 pathways, and downregulating Bcl-2/Bax ratio. RNA interference of HMGB3 inhibited cell invasion and migration by downregulating MMP2 and MMP9. Silencing of HMGB3 enhanced sensitive to cisplatin and paclitaxel, and reduced sensitive to oxaliplatin. CONCLUSIONS These findings suggest the importance of HMGB3 in the regulation of growth, migration, and apoptosis of GC, improve our understanding of the mechanisms of GC pathogenesis, and may promote the development of novel targeted therapies. PMID- 27774980 TI - Diversity-oriented synthetic strategy for developing a chemical modulator of protein-protein interaction. AB - Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase-RagD protein-protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure based DOS strategy can be a powerful research tool for the construction of drug like compounds to address challenging biological targets. PMID- 27774981 TI - Single-molecule imaging reveals modulation of cell wall synthesis dynamics in live bacterial cells. AB - The peptidoglycan cell wall is an integral organelle critical for bacterial cell shape and stability. Proper cell wall construction requires the interaction of synthesis enzymes and the cytoskeleton, but it is unclear how the activities of individual proteins are coordinated to preserve the morphology and integrity of the cell wall during growth. To elucidate this coordination, we used single molecule imaging to follow the behaviours of the two major peptidoglycan synthases in live, elongating Escherichia coli cells and after perturbation. We observed heterogeneous localization dynamics of penicillin-binding protein (PBP) 1A, the synthase predominantly associated with cell wall elongation, with individual PBP1A molecules distributed between mobile and immobile populations. Perturbations to PBP1A activity, either directly through antibiotics or indirectly through PBP1A's interaction with its lipoprotein activator or other synthases, shifted the fraction of mobile molecules. Our results suggest that multiple levels of regulation control the activity of enzymes to coordinate peptidoglycan synthesis. PMID- 27774983 TI - Retro-dimension-cue benefit in visual working memory. AB - In visual working memory (VWM) tasks, participants' performance can be improved by a retro-object-cue. However, previous studies have not investigated whether participants' performance can also be improved by a retro-dimension-cue. Three experiments investigated this issue. We used a recall task with a retro-dimension cue in all experiments. In Experiment 1, we found benefits from retro-dimension cues compared to neutral cues. This retro-dimension-cue benefit is reflected in an increased probability of reporting the target, but not in the probability of reporting the non-target, as well as increased precision with which this item is remembered. Experiment 2 replicated the retro-dimension-cue benefit and showed that the length of the blank interval after the cue disappeared did not influence recall performance. Experiment 3 replicated the results of Experiment 2 with a lower memory load. Our studies provide evidence that there is a robust retro dimension-cue benefit in VWM. Participants can use internal attention to flexibly allocate cognitive resources to a particular dimension of memory representations. The results also support the feature-based storing hypothesis. PMID- 27774984 TI - Energy Transfer Sensitization of Luminescent Gold Nanoclusters: More than Just the Classical Forster Mechanism. AB - Luminescent gold nanocrystals (AuNCs) are a recently-developed material with potential optic, electronic and biological applications. They also demonstrate energy transfer (ET) acceptor/sensitization properties which have been ascribed to Forster resonance energy transfer (FRET) and, to a lesser extent, nanosurface energy transfer (NSET). Here, we investigate AuNC acceptor interactions with three structurally/functionally-distinct donor classes including organic dyes, metal chelates and semiconductor quantum dots (QDs). Donor quenching was observed for every donor-acceptor pair although AuNC sensitization was only observed from metal-chelates and QDs. FRET theory dramatically underestimated the observed energy transfer while NSET-based damping models provided better fits but could not reproduce the experimental data. We consider additional factors including AuNC magnetic dipoles, density of excited-states, dephasing time, and enhanced intersystem crossing that can also influence ET. Cumulatively, data suggests that AuNC sensitization is not by classical FRET or NSET and we provide a simplified distance-independent ET model to fit such experimental data. PMID- 27774982 TI - Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer. AB - Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease associated effects of SNPs in ccRCC. PMID- 27774985 TI - Thousands of microbial genomes shed light on interconnected biogeochemical processes in an aquifer system. AB - The subterranean world hosts up to one-fifth of all biomass, including microbial communities that drive transformations central to Earth's biogeochemical cycles. However, little is known about how complex microbial communities in such environments are structured, and how inter-organism interactions shape ecosystem function. Here we apply terabase-scale cultivation-independent metagenomics to aquifer sediments and groundwater, and reconstruct 2,540 draft-quality, near complete and complete strain-resolved genomes that represent the majority of known bacterial phyla as well as 47 newly discovered phylum-level lineages. Metabolic analyses spanning this vast phylogenetic diversity and representing up to 36% of organisms detected in the system are used to document the distribution of pathways in coexisting organisms. Consistent with prior findings indicating metabolic handoffs in simple consortia, we find that few organisms within the community can conduct multiple sequential redox transformations. As environmental conditions change, different assemblages of organisms are selected for, altering linkages among the major biogeochemical cycles. PMID- 27774986 TI - Targeted inhibition of the COP9 signalosome for treatment of cancer. AB - The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy. PMID- 27774988 TI - A cohesive granular material with tunable elasticity. AB - By mixing glass beads with a curable polymer we create a well-defined cohesive granular medium, held together by solidified, and hence elastic, capillary bridges. This material has a geometry similar to a wet packing of beads, but with an additional control over the elasticity of the bonds holding the particles together. We show that its mechanical response can be varied over several orders of magnitude by adjusting the size and stiffness of the bridges, and the size of the particles. We also investigate its mechanism of failure under unconfined uniaxial compression in combination with in situ x-ray microtomography. We show that a broad linear-elastic regime ends at a limiting strain of about 8%, whatever the stiffness of the agglomerate, which corresponds to the beginning of shear failure. The possibility to finely tune the stiffness, size and shape of this simple material makes it an ideal model system for investigations on, for example, fracturing of porous rocks, seismology, or root growth in cohesive porous media. PMID- 27774987 TI - Implication of vaccination against dengue for Zika outbreak. AB - Zika virus co-circulates with dengue in tropical and sub-tropical regions. Cases of co-infection by dengue and Zika have been reported, the implication of this co infection for an integrated intervention program for controlling both dengue and Zika must be addressed urgently. Here, we formulate a mathematical model to describe the transmission dynamics of co-infection of dengue and Zika with particular focus on the effects of Zika outbreak by vaccination against dengue among human hosts. Our analysis determines specific conditions under which vaccination against dengue can significantly increase the Zika outbreak peak, and speed up the Zika outbreak peak timing. Our results call for further study about the co-infection to direct an integrated control to balance the benefits for dengue control and the damages of Zika outbreak. PMID- 27774989 TI - Use of next generation sequence to investigate potential novel macrolide resistance mechanisms in a population of Moraxella catarrhalis isolates. AB - Although previous studies have confirmed that 23S rRNA gene mutation could be responsible for most of macrolide resistance in M. catarrhalis, a recent study suggested otherwise. Next generation sequence based comparative genomics has revolutionized the mining of potential novel drug resistant mechanisms. In this study, two pairs of resistant and susceptible M. catarrhalis isolates with different multilocus sequence types, were investigated for potential differential genes or informative single nucleotide polymorphisms (SNPs). The identified genes and SNPs were evaluated in 188 clinical isolates. From initially 12 selected differential genes and 12 informative SNPs, 10 differential genes (mboIA, mcbC, mcbI, mboIB, MCR_1794, MCR_1795, lgt2B/C, dpnI, mcbB, and mcbA) and 6 SNPs (C619T of rumA, T140C of rplF, G643A of MCR_0020, T270G of MCR_1465, C1348A of copB, and G238A of rrmA) were identified as possibly linked to macrolide resistance in M. catarrhalis. Most of the identified differential genes and SNPs are related to methylation of ribosomal RNA (rRNA) or DNA, especially MCR_0020 and rrmA. Further studies are needed to determine the function and/or evolution process, of the identified genes or SNPs, to establish whether some novel or combined mechanisms are truly involved in M. catarrhalis macrolide resistance mechanism. PMID- 27774991 TI - Two identified looming detectors in the locust: ubiquitous lateral connections among their inputs contribute to selective responses to looming objects. AB - In locusts, two lobula giant movement detector neurons (LGMDs) act as looming object detectors. Their reproducible responses to looming and their ethological significance makes them models for single neuron computation. But there is no comprehensive picture of the neurons that connect directly to each LGMD. We used high-through-put serial block-face scanning-electron-microscopy to reconstruct the network of input-synapses onto the LGMDs over spatial scales ranging from single synapses and small circuits, up to dendritic branches and total excitatory input. Reconstructions reveal that many trans-medullary-afferents (TmAs) connect the eye with each LGMD, one TmA per facet per LGMD. But when a TmA synapses with an LGMD it also connects laterally with another TmA. These inter-TmA synapses are always reciprocal. Total excitatory input to the LGMD 1 and 2 comes from 131,000 and 186,000 synapses reaching densities of 3.1 and 2.6 synapses per MUm2 respectively. We explored the computational consequences of reciprocal synapses between each TmA and 6 others from neighbouring columns. Since any lateral interactions between LGMD inputs have always been inhibitory we may assume these reciprocal lateral connections are most likely inhibitory. Such reciprocal inhibitory synapses increased the LGMD's selectivity for looming over passing objects, particularly at the beginning of object approach. PMID- 27774990 TI - Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis. AB - Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms. Pomalidomide, an immune-modifying drug, is reported to improve anaemia and thrombocytopenia in some patients with MPN-associated myelofibrosis. We designed a phase 2 study of pomalidomide in patients with MPN-associated myelofibrosis and anaemia and/or thrombocytopenia and/or neutropenia. Subjects received pomalidomide 2.0 mg/day in cohort 1 (n=38) or 0.5 mg/day in cohort 2 (n=58). Prednisolone was added if there was no response after 3 months in cohort 1 and based on up-front randomization in cohort 2 if there was no response at 3 or 6 months. Response rates were 39% (95% confidence interval (CI), 26-55%) in cohort 1 and 24% (95% CI, 15-37%) in cohort 2. In a multivariable logistic regression model pomalidomide at 2.0 mg/day (odds ratio (OR), 2.62; 95% CI, 1.00-6.87; P=0.05) and mutated TET2 (OR, 5.07; 95% CI, 1.16-22.17; P=0.03) were significantly associated with responses. Median duration of responses was 13.0 months (range 0.9-52.7). There was no significant difference in response rates or duration in subjects receiving or not receiving prednisolone. Clinical trial MPNSG 01-09 is registered at ClinicalTrials.gov (NCT00949364) and clinicaltrialsregister.eu (EudraCT Number: 2009-010738-23). PMID- 27774992 TI - Emodin ameliorates bleomycin-induced pulmonary fibrosis in rats by suppressing epithelial-mesenchymal transition and fibroblast activation. AB - Aberrant activation of TGF-beta1 is frequently encountered and promotes epithelial-mesenchymal transition (EMT) and fibroblast activation in pulmonary fibrosis. The present study investigated whether emodin mediates its effect via suppressing TGF-beta1-induced EMT and fibroblast activation in bleomycin (BLM) induced pulmonary fibrosis in rats. Here, we found that emodin induced apoptosis and inhibited cellular proliferation, migration and differentiation in TGF-beta1 stimulated human embryonic lung fibroblasts (HELFs). Emodin suppressed TGF-beta1 induced EMT in a dose- and time-dependent manner in alveolar epithelial A549 cells. Emodin also inhibited TGF-beta1-induced Smad2, Smad3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediated the emodin induced effects on TGF-beta1-induced EMT. Additionally, we provided in vivo evidence suggesting that emodin apparently alleviated BLM-induced pulmonary fibrosis and improved pulmonary function by inhibiting TGF-beta1 signaling and subsequently repressing EMT, fibroblast activation and extracellular matrix (ECM) deposition. Taken together, our data suggest that emodin mediates its effects mainly via inhibition of EMT and fibroblast activation and thus has a potential for the treatment of pulmonary fibrosis. PMID- 27774993 TI - Knowledge-guided fuzzy logic modeling to infer cellular signaling networks from proteomic data. AB - Modeling of signaling pathways is crucial for understanding and predicting cellular responses to drug treatments. However, canonical signaling pathways curated from literature are seldom context-specific and thus can hardly predict cell type-specific response to external perturbations; purely data-driven methods also have drawbacks such as limited biological interpretability. Therefore, hybrid methods that can integrate prior knowledge and real data for network inference are highly desirable. In this paper, we propose a knowledge-guided fuzzy logic network model to infer signaling pathways by exploiting both prior knowledge and time-series data. In particular, the dynamic time warping algorithm is employed to measure the goodness of fit between experimental and predicted data, so that our method can model temporally-ordered experimental observations. We evaluated the proposed method on a synthetic dataset and two real phosphoproteomic datasets. The experimental results demonstrate that our model can uncover drug-induced alterations in signaling pathways in cancer cells. Compared with existing hybrid models, our method can model feedback loops so that the dynamical mechanisms of signaling networks can be uncovered from time-series data. By calibrating generic models of signaling pathways against real data, our method supports precise predictions of context-specific anticancer drug effects, which is an important step towards precision medicine. PMID- 27774994 TI - Implementations of two-photon four-qubit Toffoli and Fredkin gates assisted by nitrogen-vacancy centers. AB - It is desirable to implement an efficient quantum information process demanding fewer quantum resources. We designed two compact quantum circuits for determinately implementing four-qubit Toffoli and Fredkin gates on single-photon systems in both the polarization and spatial degrees of freedom (DoFs) via diamond nitrogen-vacancy (NV) centers in resonators. The gates are heralded by the electron spins associated with the diamond NV centers. In contrast to the ones with one DoF, our implementations reduce the quantum resource and are robust against the decoherence. Evaluations of fidelities and efficiencies of our gates show that our schemes may be implemented with current technology. PMID- 27774995 TI - Velocimetry of superconducting vortices based on stroboscopic resonances. AB - An experimental determination of the mean vortex velocity in superconductors mostly relies on the measurement of flux-flow resistance with magnetic field, temperature, or driving current. In the present work we introduce a method combining conventional transport measurements and a frequency-tuned flashing pinning potential to obtain reliable estimates of the vortex velocity. The proposed device is characterized using the time-dependent Ginzburg-Landau formalism, where the velocimetry method exploits the resonances in mean vortex dissipation when temporal commensuration occurs between the vortex crossings and the flashing potential. We discuss the sensitivity of the proposed technique on applied current, temperature and heat diffusion, as well as the vortex core deformations during fast motion. PMID- 27774997 TI - A programmable metasurface with dynamic polarization, scattering and focusing control. AB - Diverse electromagnetic (EM) responses of a programmable metasurface with a relatively large scale have been investigated, where multiple functionalities are obtained on the same surface. The unit cell in the metasurface is integrated with one PIN diode, and thus a binary coded phase is realized for a single polarization. Exploiting this anisotropic characteristic, reconfigurable polarization conversion is presented first. Then the dynamic scattering performance for two kinds of sources, i.e. a plane wave and a point source, is carefully elaborated. To tailor the scattering properties, genetic algorithm, normally based on binary coding, is coupled with the scattering pattern analysis to optimize the coding matrix. Besides, inverse fast Fourier transform (IFFT) technique is also introduced to expedite the optimization process of a large metasurface. Since the coding control of each unit cell allows a local and direct modulation of EM wave, various EM phenomena including anomalous reflection, diffusion, beam steering and beam forming are successfully demonstrated by both simulations and experiments. It is worthwhile to point out that a real-time switch among these functionalities is also achieved by using a field-programmable gate array (FPGA). All the results suggest that the proposed programmable metasurface has great potentials for future applications. PMID- 27774996 TI - RNA sequencing analysis of human podocytes reveals glucocorticoid regulated gene networks targeting non-immune pathways. AB - Glucocorticoids are steroids that reduce inflammation and are used as immunosuppressive drugs for many diseases. They are also the mainstay for the treatment of minimal change nephropathy (MCN), which is characterised by an absence of inflammation. Their mechanisms of action remain elusive. Evidence suggests that immunomodulatory drugs can directly act on glomerular epithelial cells or 'podocytes', the cell type which is the main target of injury in MCN. To understand the nature of glucocorticoid effects on non-immune cell functions, we generated RNA sequencing data from human podocyte cell lines and identified the genes that are significantly regulated in dexamethasone-treated podocytes compared to vehicle-treated cells. The upregulated genes are of functional relevance to cytoskeleton-related processes, whereas the downregulated genes mostly encode pro-inflammatory cytokines and growth factors. We observed a tendency for dexamethasone-upregulated genes to be downregulated in MCN patients. Integrative analysis revealed gene networks composed of critical signaling pathways that are likely targeted by dexamethasone in podocytes. PMID- 27774998 TI - Asymptotic theory of time-varying social networks with heterogeneous activity and tie allocation. AB - The dynamic of social networks is driven by the interplay between diverse mechanisms that still challenge our theoretical and modelling efforts. Amongst them, two are known to play a central role in shaping the networks evolution, namely the heterogeneous propensity of individuals to i) be socially active and ii) establish a new social relationships with their alters. Here, we empirically characterise these two mechanisms in seven real networks describing temporal human interactions in three different settings: scientific collaborations, Twitter mentions, and mobile phone calls. We find that the individuals' social activity and their strategy in choosing ties where to allocate their social interactions can be quantitatively described and encoded in a simple stochastic network modelling framework. The Master Equation of the model can be solved in the asymptotic limit. The analytical solutions provide an explicit description of both the system dynamic and the dynamical scaling laws characterising crucial aspects about the evolution of the networks. The analytical predictions match with accuracy the empirical observations, thus validating the theoretical approach. Our results provide a rigorous dynamical system framework that can be extended to include other processes shaping social dynamics and to generate data driven predictions for the asymptotic behaviour of social networks. PMID- 27775000 TI - Different responses of rhizosphere and non-rhizosphere soil microbial communities to consecutive Piper nigrum L. monoculture. AB - Soil microorganisms have important influences on plant growth and health. In this study, four black pepper fields consecutively monocultured for 12, 18, 28 and 38 years were selected for investigating the effect of planting age on rhizosphere and non-rhizosphere soil microbial communities and soil physicochemical properties. The results revealed that the relative abundance of the dominant bacterial phyla in rhizosphere soil increased considerably with long-term consecutive monoculture but decreased in non-rhizosphere soil with a significant decline in Firmicutes. For fungi, an increasing trend over time was observed in both rhizosphere and non-rhizosphere soils, with the abundance of the pathogenic fungi Fusarium increasing significantly accompanied by a decrease in the bacteria Pseudomonas and Bacillus that is beneficial for black pepper. Consecutive monoculture, especially for 38 years, considerably decreased soil microbial diversity. Additionally, the rhizosphere soil pH and organic matter and available K contents decreased with increasing planting duration, though available N and P increased. All soil nutrient contents and microbial diversity indices were higher in rhizosphere soil compared to non-rhizosphere soil. The results suggest that long-term consecutive monoculture leads to variations in soil microbial community composition and physicochemical properties in both rhizosphere and non rhizosphere soils, thus inhibiting the black pepper growth. PMID- 27774999 TI - Nucleotide diversity analysis highlights functionally important genomic regions. AB - We analyzed functionality and relative distribution of genetic variants across the complete Oryza sativa genome, using the 40 million single nucleotide polymorphisms (SNPs) dataset from the 3,000 Rice Genomes Project (http://snp seek.irri.org), the largest and highest density SNP collection for any higher plant. We have shown that the DNA-binding transcription factors (TFs) are the most conserved group of genes, whereas kinases and membrane-localized transporters are the most variable ones. TFs may be conserved because they belong to some of the most connected regulatory hubs that modulate transcription of vast downstream gene networks, whereas signaling kinases and transporters need to adapt rapidly to changing environmental conditions. In general, the observed profound patterns of nucleotide variability reveal functionally important genomic regions. As expected, nucleotide diversity is much higher in intergenic regions than within gene bodies (regions spanning gene models), and protein-coding sequences are more conserved than untranslated gene regions. We have observed a sharp decline in nucleotide diversity that begins at about 250 nucleotides upstream of the transcription start and reaches minimal diversity exactly at the transcription start. We found the transcription termination sites to have remarkably symmetrical patterns of SNP density, implying presence of functional sites near transcription termination. Also, nucleotide diversity was significantly lower near 3' UTRs, the area rich with regulatory regions. PMID- 27775001 TI - Transstadial Transmission and Long-term Association of Crimean-Congo Hemorrhagic Fever Virus in Ticks Shapes Genome Plasticity. AB - The trade-off hypothesis, the current paradigm of arbovirus evolution, proposes that cycling between vertebrate and invertebrate hosts presents significant constraints on genetic change of arboviruses. Studying these constraints in mosquito-borne viruses has led to a new understanding of epizootics. The trade off hypothesis is assumed to be applicable to tick-borne viruses too, although studies are lacking. Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the family Bunyaviridae, is a major cause of severe human disease worldwide and shows an extraordinary amount of genetic diversity compared to other arboviruses, which has been linked to increased virulence and emergence in new environments. Using a transmission model for CCHFV, utilizing the main vector tick species and mice plus next generation sequencing, we detected a substantial number of consensus-level mutations in CCHFV recovered from ticks after only a single transstadial transmission, whereas none were detected in CCHFV obtained from the mammalian host. Furthermore, greater viral intra-host diversity was detected in the tick compared to the vertebrate host. Long-term association of CCHFV with its tick host for 1 year demonstrated mutations in the viral genome become fixed over time. These findings suggest that the trade-off hypothesis may not be accurate for all arboviruses. PMID- 27775003 TI - Rayleigh scattering in few-mode optical fibers. AB - The extremely low loss of silica fibers has enabled the telecommunication revolution, but single-mode fiber-optic communication systems have been driven to their capacity limits. As a means to overcome this capacity crunch, space division multiplexing (SDM) using few-mode fibers (FMF) has been proposed and demonstrated. In single-mode optical fibers, Rayleigh scattering serves as the dominant mechanism for optical loss. However, to date, the role of Rayleigh scattering in FMFs remains elusive. Here we establish and experimentally validate a general model for Rayleigh scattering in FMFs. Rayleigh backscattering not only sets the intrinsic loss limit for FMFs but also provides the theoretical foundation for few-mode optical time-domain reflectometry, which can be used to probe perturbation-induced mode-coupling dynamics in FMFs. We also show that forward inter-modal Rayleigh scattering ultimately sets a fundamental limit on inter-modal-crosstalk for FMFs. Therefore, this work not only has implications specifically for SDM systems but also broadly for few-mode fiber optics and its applications in amplifiers, lasers, and sensors in which inter-modal crosstalk imposes a fundamental performance limitation. PMID- 27775002 TI - Auxotrophy-based High Throughput Screening assay for the identification of Bacillus subtilis stringent response inhibitors. AB - The stringent response is a central adaptation mechanism that allows bacteria to adjust their growth and metabolism according to environmental conditions. The functionality of the stringent response is crucial for bacterial virulence, survival during host invasion as well as antibiotic resistance and tolerance. Therefore, specific inhibitors of the stringent response hold great promise as molecular tools for disarming and pacifying bacterial pathogens. By taking advantage of the valine amino acid auxotrophy of the Bacillus subtilis stringent response-deficient strain, we have set up a High Throughput Screening assay for the identification of stringent response inhibitors. By screening 17,500 compounds, we have identified a novel class of antibacterials based on the 4-(6 (phenoxy)alkyl)-3,5-dimethyl-1H-pyrazole core. Detailed characterization of the hit compounds as well as two previously identified promising stringent response inhibitors - a ppGpp-mimic nucleotide Relacin and cationic peptide 1018 - showed that neither of the compounds is sufficiently specific, thus motivating future application of our screening assay to larger and more diverse molecular libraries. PMID- 27775004 TI - M-DNA/Transition Metal Dichalcogenide Hybrid Structure-based Bio-FET sensor with Ultra-high Sensitivity. AB - Here, we report a high performance biosensor based on (i) a Cu2+-DNA/MoS2 hybrid structure and (ii) a field effect transistor, which we refer to as a bio-FET, presenting a high sensitivity of 1.7 * 103 A/A. This high sensitivity was achieved by using a DNA nanostructure with copper ions (Cu2+) that induced a positive polarity in the DNA (receptor). This strategy improved the detecting ability for doxorubicin-like molecules (target) that have a negative polarity. Very short distance between the biomolecules and the sensor surface was obtained without using a dielectric layer, contributing to the high sensitivity. We first investigated the effect of doxorubicin on DNA/MoS2 and Cu2+-DNA/MoS2 nanostructures using Raman spectroscopy and Kelvin force probe microscopy. Then, we analyzed the sensing mechanism and performance in DNA/MoS2- and Cu2+-DNA/MoS2 based bio-FETs by electrical measurements (ID-VG at various VD) for various concentrations of doxorubicin. Finally, successful operation of the Cu2+-DNA/MoS2 bio-FET was demonstrated for six cycles (each cycle consisted of four steps: 2 preparation steps, a sensing step, and an erasing step) with different doxorubicin concentrations. The bio-FET showed excellent reusability, which has not been achieved previously in 2D biosensors. PMID- 27775005 TI - Direct observation of photocarrier electron dynamics in C60 films on graphite by time-resolved two-photon photoemission. AB - Time-resolved two-photon photoemission (TR-2PPE) spectroscopy is employed to probe the electronic states of a C60 fullerene film formed on highly oriented pyrolytic graphite (HOPG), acting as a model two-dimensional (2D) material for multi-layered graphene. Owing to the in-plane sp2-hybridized nature of the HOPG, the TR-2PPE spectra reveal the energetics and dynamics of photocarriers in the C60 film: after hot excitons are nascently formed in C60 via intramolecular excitation by a pump photon, they dissociate into photocarriers of free electrons and the corresponding holes, and the electrons are subsequently detected by a probe photon as photoelectrons. The decay rate of photocarriers from the C60 film into the HOPG is evaluated to be 1.31 * 1012 s-1, suggesting a weak van der Waals interaction at the interface, where the photocarriers tentatively occupy the lowest unoccupied molecular orbital (LUMO) of C60. The photocarrier electron dynamics following the hot exciton dissociation in the organic thin films has not been realized for any metallic substrates exhibiting strong interactions with the overlayer. Furthermore, the thickness dependence of the electron lifetime in the LUMO reveals that the electron hopping rate in C60 layers is 3.3 +/- 1.2 * 1013 s 1. PMID- 27775007 TI - Coupling of carbon and silicon geochemical cycles in rivers and lakes. AB - Carbon (C) and silicon (Si) biogeochemical cycles are important factors in the regulation of atmospheric CO2 concentrations and hence climate change. Theoretically, these elements are linked by chemical weathering and organism stoichiometry, but this coupling has not been investigated in freshwaters. Here we compiled data from global rivers and lakes in the United States of America and the United Kingdom, in order to characterize the stoichiometry between the biogeochemical cycles of C and Si. In rivers this coupling is confirmed by a significant relationship between HCO3-/Na+ and DSi/Na+, and DSi:HCO3- ratio can reflect the mineral source of chemical weathering. In lakes, however, these characteristic ratios of chemical weathering are altered by algal activity. The lacustrine Si:C atomic ratio is negative feedback regulation by phytoplankton, which may result in this ratio in algal assemblages similar to that in water column. And this regulation suggests lacustrine photosynthetic C fixation in this equilibrium state is quantitative and depends on the DSi concentration. These findings provide new insights into the role of freshwaters in global C and Si biogeochemical cycles. PMID- 27775006 TI - Synthetic oligonucleotide antigens modified with locked nucleic acids detect disease specific antibodies. AB - New techniques to detect and quantify antibodies to nucleic acids would provide a significant advance over current methods, which often lack specificity. We investigate the potential of novel antigens containing locked nucleic acids (LNAs) as targets for antibodies. Particularly, employing molecular dynamics we predict optimal nucleotide composition for targeting DNA-binding antibodies. As a proof of concept, we address a problem of detecting anti-DNA antibodies that are characteristic of systemic lupus erythematosus, a chronic autoimmune disease with multiple manifestations. We test the best oligonucleotide binders in surface plasmon resonance studies to analyze binding and kinetic aspects of interactions between antigens and target DNA. These DNA and LNA/DNA sequences showed improved binding in enzyme-linked immunosorbent assay using human samples of pediatric lupus patients. Our results suggest that the novel method is a promising tool to create antigens for research and point-of-care monitoring of anti-DNA antibodies. PMID- 27775009 TI - Deep-submicron Graphene Field-Effect Transistors with State-of-Art fmax. AB - In order to conquer the short-channel effects that limit conventional ultra-scale semiconductor devices, two-dimensional materials, as an option of ultimate thin channels, receive wide attention. Graphene, in particular, bears great expectations because of its supreme carrier mobility and saturation velocity. However, its main disadvantage, the lack of bandgap, has not been satisfactorily solved. As a result, maximum oscillation frequency (fmax) which indicates transistors' power amplification ability has been disappointing. Here, we present submicron field-effect transistors with specially designed low-resistance gate and excellent source/drain contact, and therefore significantly improved fmax. The fabrication was assisted by the advanced 8-inch CMOS back-end-of-line technology. A 200-nm-gate-length GFET achieves fT/fmax = 35.4/50 GHz. All GFET samples with gate lengths ranging from 200 nm to 400 nm possess fmax 31-41% higher than fT, closely resembling Si n-channel MOSFETs at comparable technology nodes. These results re-strengthen the promise of graphene field-effect transistors in next generation semiconductor electronics. PMID- 27775010 TI - Optimal Universal Uncertainty Relations. AB - We study universal uncertainty relations and present a method called joint probability distribution diagram to improve the majorization bounds constructed independently in [Phys. Rev. Lett. 111, 230401 (2013)] and [J. Phys. A. 46, 272002 (2013)]. The results give rise to state independent uncertainty relations satisfied by any nonnegative Schur-concave functions. On the other hand, a remarkable recent result of entropic uncertainty relation is the direct-sum majorization relation. In this paper, we illustrate our bounds by showing how they provide a complement to that in [Phys. Rev. A. 89, 052115 (2014)]. PMID- 27775008 TI - Coordinated regulation of endocannabinoid-mediated retrograde synaptic suppression in the cerebellum by neuronal and astrocytic monoacylglycerol lipase. AB - The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates retrograde synaptic depression including depolarization-induced suppression of excitation (DSE) and inhibition (DSI). 2-AG is degraded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes. Using knockout mice in which MAGL is deleted globally or selectively in neurons or astrocytes, we investigated the relative contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells (PCs) in cerebellar slices. We report that neuronal MAGL plays a predominant role in terminating DSE at climbing fiber (CF) to PC synapses, while both neuronal and astrocytic MAGL significantly contributes to the termination of DSE at parallel fiber (PF) to PC synapses and DSI at putative Stellate cell to PC synapses. Thus, DSE and DSI at different synapses is not uniformly affected by global and cell type-specific knockout of MAGL. Additionally, MAGL global knockout, but not cell type-specific knockout, caused tonic activation and partial desensitization of the CB1 receptor at PF-PC synapses. This tonic CB1 activation is mediated by 2-AG since it was blocked by the diacylglycerol lipase inhibitor DO34. Together, these results suggest that both neuronal and astrocytic MAGL contribute to 2-AG clearance and prevent CB1 receptor over-stimulation in the cerebellum. PMID- 27775011 TI - The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency. AB - Although activation of the ErbB family of receptor tyrosine kinases (ErbB1-4) is driven by oligomerization mediated by intermolecular interactions between the extracellular, the kinase and the transmembrane domains, the transmembrane domain has been largely neglected in this regard. The largest contributor to the intramembrane electric field, the dipole potential, alters the conformation of transmembrane peptides, but its effect on ErbB proteins is unknown. Here, we show by Forster resonance energy transfer (FRET) and number and brightness (N&B) experiments that the epidermal growth factor (EGF)-induced increase in the homoassociation of ErbB1 and ErbB2 and their heteroassociation are augmented by increasing the dipole potential. These effects were even more pronounced for ErbB2 harboring an activating Val -> Glu mutation in the transmembrane domain (NeuT). The signaling capacity of ErbB1 and ErbB2 was also correlated with the dipole potential. Since the dipole potential decreased the affinity of EGF to ErbB1, the augmented growth factor-induced effects at an elevated dipole potential were actually induced at lower receptor occupancy. We conclude that the dipole potential plays a permissive role in the clustering of ErbB receptors and that the effects of lipid rafts on ligand binding and receptor signaling can be partially attributed to the dipole potential. PMID- 27775012 TI - Comparison of incubation period distribution of human infections with MERS-CoV in South Korea and Saudi Arabia. AB - The incubation period is an important epidemiologic distribution, it is often incorporated in case definitions, used to determine appropriate quarantine periods, and is an input to mathematical modeling studies. Middle East Respiratory Syndrome coronavirus (MERS) is an emerging infectious disease in the Arabian Peninsula. There was a large outbreak of MERS in South Korea in 2015. We examined the incubation period distribution of MERS coronavirus infection for cases in South Korea and in Saudi Arabia. Using parametric and nonparametric methods, we estimated a mean incubation period of 6.9 days (95% credibility interval: 6.3-7.5) for cases in South Korea and 5.0 days (95% credibility interval: 4.0-6.6) among cases in Saudi Arabia. In a log-linear regression model, the mean incubation period was 1.42 times longer (95% credibility interval: 1.18 1.71) among cases in South Korea compared to Saudi Arabia. The variation that we identified in the incubation period distribution between locations could be associated with differences in ascertainment or reporting of exposure dates and illness onset dates, differences in the source or mode of infection, or environmental differences. PMID- 27775013 TI - Altered mitochondrial DNA copy number contributes to human cancer risk: evidence from an updated meta-analysis. AB - Accumulating epidemiological evidence indicates that the quantitative changes in human mitochondrial DNA (mtDNA) copy number could affect the genetic susceptibility of malignancies in a tumor-specific manner, but the results are still elusive. To provide a more precise estimation on the association between mtDNA copy number and risk of diverse malignancies, a meta-analysis was conducted by calculating the pooled odds ratios (OR) and the 95% confidence intervals (95% CI). A total of 36 case-control studies involving 11,847 cases and 15,438 controls were finally included in the meta-analysis. Overall analysis of all studies suggested no significant association between mtDNA content and cancer risk (OR = 1.044, 95% CI = 0.866-1.260, P = 0.651). Subgroup analyses by cancer types showed an obvious positive association between mtDNA content and lymphoma and breast cancer (OR = 1.645, 95% CI = 1.117-2.421, P = 0.012; OR = 1.721, 95% CI = 1.130-2.622, P = 0.011, respectively), and a negative association for hepatic carcinoma. Stratified analyses by other confounding factors also found increased cancer risk in people with drinking addiction. Further analysis using studies of quartiles found that populations with the highest mtDNA content may be under more obvious risk of melanoma and that Western populations were more susceptible than Asians. PMID- 27775014 TI - New generation ICG-based contrast agents for ultrasound-switchable fluorescence imaging. AB - Recently, we developed a new technology, ultrasound-switchable fluorescence (USF), for high-resolution imaging in centimeter-deep tissues via fluorescence contrast. The success of USF imaging highly relies on excellent contrast agents. ICG-encapsulated poly(N-isopropylacrylamide) nanoparticles (ICG-NPs) are one of the families of the most successful near-infrared (NIR) USF contrast agents. However, the first-generation ICG-NPs have a short shelf life (<1 month). This work significantly increases the shelf life of the new-generation ICG-NPs (>6 months). In addition, we have conjugated hydroxyl or carboxyl function groups on the ICG-NPs for future molecular targeting. Finally, we have demonstrated the effect of temperature-switching threshold (Tth) and the background temperature (TBG) on the quality of USF images. We estimated that the Tth of the ICG-NPs should be controlled at ~38-40 degrees C (slightly above the body temperature of 37 degrees C) for future in vivo USF imaging. Addressing these challenges further reduces the application barriers of USF imaging. PMID- 27775016 TI - Predictable Components of ENSO Evolution in Real-time Multi-Model Predictions. AB - The most predictable components of the El Nino-Southern Oscillation (ENSO) evolution in real-time multi-model predictions are identified by applying an empirical orthogonal function analysis of the model data that maximizes the signal-to-noise ratio (MSN EOF). The normalized Nino3.4 index is analyzed for nine 3-month overlapping seasons. In this sense, the first most predictable component (MSN EOF1) is the decaying phase of ENSO during the Northern Hemisphere spring, followed by persistence through autumn and winter. The second most predictable component of ENSO evolution, with lower prediction skill and smaller explained variance than MSN EOF1, corresponds to the growth during spring and then persistence in summer and autumn. This result suggests that decay phase of ENSO is more predictable than the growth phase. Also, the most predictable components and the forecast skills in dynamical and statistical models are similar overall, with some differences arising during spring season initial conditions. Finally, the reconstructed predictions, with only the first two MSN components, show higher skill than the model raw predictions. Therefore this method can be used as a diagnostic for model comparison and development, and it can provide a new perspective for the most predictable components of ENSO. PMID- 27775015 TI - HandKAchip - Hands-free killing assay on a chip. AB - Small animals such as the roundworm C. elegans are excellent models for studying bacterial infection and host response, as well as for genetic and chemical screens. A key methodology is the killing assay, in which the number of surviving animals is tracked as a function of the time post infection. This is a labor intensive procedure, prone to human error and subjective choices, and often involves undesired perturbation to the animals and their environment. In addition, the survival of animals is just one aspect of a multi-dimensional complex biological process. Here we report a microfluidic-based approach for performing killing assays in worms, compatible with standard assays performed on solid media. In addition to providing accurate and reproducible survival curves at a considerably reduced labor, this approach allows acquisition of a multitude of quantitative data with minimal undesired perturbations. These measurements are obtained automatically at a worm-by-worm resolution using a custom image processing workflow. The proposed approach is simple, scalable, and extendable, and is significantly more economical than standard manual protocols. PMID- 27775017 TI - Multifunctional SPIO/DOX-loaded A54 Homing Peptide Functionalized Dextran-g-PLGA Micelles for Tumor Therapy and MR Imaging. AB - Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 MUg. mL-1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection. PMID- 27775018 TI - Loss of variation of state detected in soybean metabolic and human myelomonocytic leukaemia cell transcriptional networks under external stimuli. AB - Soybean (Glycine max) is sensitive to flooding stress, and flood damage at the seedling stage is a barrier to growth. We constructed two mathematical models of the soybean metabolic network, a control model and a flooded model, from metabolic profiles in soybean plants. We simulated the metabolic profiles with perturbations before and after the flooding stimulus using the two models. We measured the variation of state that the system could maintain from a state-space description of the simulated profiles. The results showed a loss of variation of state during the flooding response in the soybean plants. Loss of variation of state was also observed in a human myelomonocytic leukaemia cell transcriptional network in response to a phorbol-ester stimulus. Thus, we detected a loss of variation of state under external stimuli in two biological systems, regardless of the regulation and stimulus types. Our results suggest that a loss of robustness may occur concurrently with the loss of variation of state in biological systems. We describe the possible applications of the quantity of variation of state in plant genetic engineering and cell biology. Finally, we present a hypothetical "external stimulus-induced information loss" model of biological systems. PMID- 27775019 TI - The bacterial toxin CNF1 as a tool to induce retinal degeneration reminiscent of retinitis pigmentosa. AB - Retinitis pigmentosa (RP) comprises a group of inherited pathologies characterized by progressive photoreceptor degeneration. In rodent models of RP, expression of defective genes and retinal degeneration usually manifest during the first weeks of postnatal life, making it difficult to distinguish consequences of primary genetic defects from abnormalities in retinal development. Moreover, mouse eyes are small and not always adequate to test pharmacological and surgical treatments. An inducible paradigm of retinal degeneration potentially extensible to large animals is therefore desirable. Starting from the serendipitous observation that intraocular injections of a Rho GTPase activator, the bacterial toxin Cytotoxic Necrotizing Factor 1 (CNF1), lead to retinal degeneration, we implemented an inducible model recapitulating most of the key features of Retinitis Pigmentosa. The model also unmasks an intrinsic vulnerability of photoreceptors to the mechanism of CNF1 action, indicating still unexplored molecular pathways potentially leading to the death of these cells in inherited forms of retinal degeneration. PMID- 27775021 TI - Disentangling the drivers of taxonomic and phylogenetic beta diversities in disturbed and undisturbed subtropical forests. AB - Understanding the relative importance of dispersal limitation and environmental filtering processes in structuring the beta diversities of subtropical forests in human disturbed landscapes is still limited. Here we used taxonomic (TBD) and phylogenetic (PBD), including terminal PBD (PBDt) and basal PBD (PBDb), beta diversity indices to quantify the taxonomic and phylogenetic turnovers at different depths of evolutionary history in disturbed and undisturbed subtropical forests. Multiple linear regression model and distance-based redundancy analysis were used to disentangle the relative importance of environmental and spatial variables. Environmental variables were significantly correlated with TBD and PBDt metrics. Temperature and precipitation were major environmental drivers of beta diversity patterns, which explained 7-27% of the variance in TBD and PBDt, whereas the spatial variables independently explained less than 1% of the variation for all forests. The relative importance of environmental and spatial variables differed between disturbed and undisturbed forests (e.g., when Bray Curtis was used as a beta diversity metric, environmental variable had a significant effect on beta diversity for disturbed forests but had no effect on undisturbed forests). We conclude that environmental filtering plays a more important role than geographical limitation and disturbance history in driving taxonomic and terminal phylogenetic beta diversity. PMID- 27775020 TI - gamma-Glutamyltranspeptidase is an endogenous activator of Toll-like receptor 4 mediated osteoclastogenesis. AB - Chronic inflammation-associated bone destruction, which is observed in rheumatoid arthritis (RA) and periodontitis, is mediated by excessive osteoclastogenesis. We showed previously that gamma-glutamyltranspeptidase (GGT), an enzyme involved in glutathione metabolism, acts as an endogenous activator of such pathological osteoclastogenesis, independent of its enzymatic activity. GGT accumulation is clinically observed in the joints of RA patients, and, in animals, the administration of recombinant GGT to the gingival sulcus as an in vivo periodontitis model induces an increase in the number of osteoclasts. However, the underlying mechanisms of this process remain unclear. Here, we report that Toll-like receptor 4 (TLR4) recognizes GGT to activate inflammation-associated osteoclastogenesis. Unlike lipopolysaccharide, GGT is sensitive to proteinase K treatment and insensitive to polymyxin B treatment. TLR4 deficiency abrogates GGT induced osteoclastogenesis and activation of NF-kappaB and MAPK signaling in precursor cells. Additionally, GGT does not induce osteoclastogenesis in cells lacking the signaling adaptor MyD88. The administration of GGT to the gingival sulcus induces increased osteoclastogenesis in wild-type mice, but does not induce it in TLR4-deficient mice. Our findings elucidate a novel mechanism of inflammation-associated osteoclastogenesis, which involves TLR4 recognition of GGT and subsequent activation of MyD88-dependent signaling. PMID- 27775023 TI - Colloidal Organometal Halide Perovskite (MAPbBrxI3-x, 0<=x<=3) Quantum Dots: Controllable Synthesis and Tunable Photoluminescence. AB - Organic-inorganic perovskite materials, typically methylammonium lead trihalide (MAPbX3: MA = methylammonium; X = Br, I), are recently attract enormous attention for their distinguished photo-electronic properties. The control of morphology, composition and dispersability of MAPbX3 perovskite nanocrystals is crucial for the property tailoring and still a major challenge. Here we report the synthesis of colloidal MAPbBrxI3-x(0 <= x <= 3) nanocrystals at room temperature by using alkyl carboxylate as capping ligands. These nanocrystals exhibit continuously tunable UV-vis absorption and photoluminescence (PL) across the visible spectrum, which is attributed to the quantum confinement effect with certain stoichiometry. Their unique exciton recombination dynamics was investigated and discussed. PMID- 27775022 TI - Proteomic and phosphoproteomic analysis of renal cortex in a salt-load rat model of advanced kidney damage. AB - Salt plays an essential role in the progression of chronic kidney disease and hypertension. However, the mechanisms underlying pathogenesis of salt-induced kidney damage remain largely unknown. Here, Sprague-Dawley rats, that underwent 5/6 nephrectomy (5/6Nx, a model of advanced kidney damage) or sham operation, were treated for 2 weeks with a normal or high-salt diet. We employed aTiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for proteomic and phosphoproteomic profiling of the renal cortex. We found 318 proteins differentially expressed in 5/6Nx group relative to sham group, and 310 proteins significantly changed in response to salt load in 5/6Nx animals. Totally, 1810 unique phosphopeptides corresponding to 550 phosphoproteins were identified. We identified 113 upregulated and 84 downregulated phosphopeptides in 5/6Nx animals relative to sham animals. Salt load induced 78 upregulated and 91 downregulated phosphopeptides in 5/6Nx rats. The differentially expressed phospholproteins are important transporters, structural molecules, and receptors. Protein-protein interaction analysis revealed that the differentially phosphorylated proteins in 5/6Nx group, Polr2a, Srrm1, Gsta2 and Pxn were the most linked. Salt-induced differential phosphoproteins, Myh6, Lmna and Des were the most linked. Altered phosphorylation levels of lamin A and phospholamban were validated. This study will provide new insight into pathogenetic mechanisms of chronic kidney disease and salt sensitivity. PMID- 27775024 TI - Neurobiochemical changes in the vicinity of a nanostructured neural implant. AB - Neural interface technologies including recording and stimulation electrodes are currently in the early phase of clinical trials aiming to help patients with spinal cord injuries, degenerative disorders, strokes interrupting descending motor pathways, or limb amputations. Their lifetime is of key importance; however, it is limited by the foreign body response of the tissue causing the loss of neurons and a reactive astrogliosis around the implant surface. Improving the biocompatibility of implant surfaces, especially promoting neuronal attachment and regeneration is therefore essential. In our work, bioactive properties of implanted black polySi nanostructured surfaces (520-800 nm long nanopillars with a diameter of 150-200 nm) were investigated and compared to microstructured Si surfaces in eight-week-long in vivo experiments. Glial encapsulation and local neuronal cell loss were characterised using GFAP and NeuN immunostaining respectively, followed by systematic image analysis. Regarding the severity of gliosis, no significant difference was observed in the vicinity of the different implant surfaces, however, the number of surviving neurons close to the nanostructured surface was higher than that of the microstructured ones. Our results imply that the functionality of implanted microelectrodes covered by Si nanopillars may lead to improved long-term recordings. PMID- 27775026 TI - Size effect, critical resolved shear stress, stacking fault energy, and solid solution strengthening in the CrMnFeCoNi high-entropy alloy. AB - High-entropy alloys (HEAs) comprise a novel class of scientifically and technologically interesting materials. Among these, equatomic CrMnFeCoNi with the face-centered cubic (FCC) structure is noteworthy because its ductility and strength increase with decreasing temperature while maintaining outstanding fracture toughness at cryogenic temperatures. Here we report for the first time by single-crystal micropillar compression that its bulk room temperature critical resolved shear stress (CRSS) is ~33-43 MPa, ~10 times higher than that of pure nickel. CRSS depends on pillar size with an inverse power-law scaling exponent of -0.63 independent of orientation. Planar 1/2 < 110 > {111} dislocations dissociate into Shockley partials whose separations range from ~3.5-4.5 nm near the screw orientation to ~5-8 nm near the edge, yielding a stacking fault energy of 30 +/- 5 mJ/m2. Dislocations are smoothly curved without any preferred line orientation indicating no significant anisotropy in mobilities of edge and screw segments. The shear-modulus-normalized CRSS of the HEA is not exceptionally high compared to those of certain concentrated binary FCC solid solutions. Its rough magnitude calculated using the Fleischer/Labusch models corresponds to that of a hypothetical binary with the elastic constants of our HEA, solute concentrations of 20-50 at.%, and atomic size misfit of ~4%. PMID- 27775025 TI - Basal Tumor Cell Isolation and Patient-Derived Xenograft Engraftment Identify High-Risk Clinical Bladder Cancers. AB - Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients. PMID- 27775028 TI - Environmental hydro-refugia demonstrated by vegetation vigour in the Okavango Delta, Botswana. AB - Climate shifts at decadal scales can have environmental consequences, and therefore, identifying areas that act as environmental refugia is valuable in understanding future climate variability. Here we illustrate how, given appropriate geohydrology, a rift basin and its catchment can buffer vegetation response to climate signals on decadal time-scales, therefore exerting strong local environmental control. We use time-series data derived from Normalised Difference Vegetation Index (NDVI) residuals that record vegetation vigour, extracted from a decadal span of MODIS images, to demonstrate hydrogeological buffering. While this has been described previously it has never been demonstrated via remote sensing and results in relative stability in vegetation vigour inside the delta, compared to that outside. As such the Delta acts as a regional hydro-refugium. This provides insight, not only to the potential impact of future climate in the region, but also demonstrates why similar basins are attractive to fauna, including our ancestors, in regions like eastern Africa. Although vertebrate evolution operates on time scales longer than decades, the sensitivity of rift wetlands to climate change has been stressed by some authors, and this work demonstrates another example of the unique properties that such basins can afford, given the right hydrological conditions. PMID- 27775027 TI - Phase Transition of the Bacterium upon Invasion of a Host Cell as a Mechanism of Adaptation: a Mycoplasma gallisepticum Model. AB - What strategies do bacteria employ for adaptation to their hosts and are these strategies different for varied hosts? To date, many studies on the interaction of the bacterium and its host have been published. However, global changes in the bacterial cell in the process of invasion and persistence, remain poorly understood. In this study, we demonstrated phase transition of the avian pathogen Mycoplasma gallisepticum upon invasion of the various types of eukaryotic cells (human, chicken, and mouse) which was stable during several passages after isolation of intracellular clones and recultivation in a culture medium. It was shown that this phase transition is manifested in changes at the proteomic, genomic and metabolomic levels. Eukaryotic cells induced similar proteome reorganization of M. gallisepticum during infection, despite different origins of the host cell lines. Proteomic changes affected a broad range of processes including metabolism, translation and oxidative stress response. We determined that the activation of glycerol utilization, overproduction of hydrogen peroxide and the upregulation of the SpxA regulatory protein occurred during intracellular infection. We propose SpxA as an important regulator for the adaptation of M. gallisepticum to an intracellular environment. PMID- 27775029 TI - Protein Kinase D1 regulates focal adhesion dynamics and cell adhesion through Phosphatidylinositol-4-phosphate 5-kinase type-l gamma. AB - Focal adhesions (FAs) are highly dynamic structures that are assembled and disassembled on a continuous basis. The balance between the two processes mediates various aspects of cell behavior, ranging from cell adhesion and spreading to directed cell migration. The turnover of FAs is regulated at multiple levels and involves a variety of signaling molecules and adaptor proteins. In the present study, we show that in response to integrin engagement, a subcellular pool of Protein Kinase D1 (PKD1) localizes to the FAs. PKD1 affects FAs by decreasing turnover and promoting maturation, resulting in enhanced cell adhesion. The effects of PKD1 are mediated through direct phosphorylation of FA localized phosphatidylinositol-4-phosphate 5-kinase type-l gamma (PIP5Klgamma) at serine residue 448. This phosphorylation occurs in response to Fibronectin-RhoA signaling and leads to a decrease in PIP5Klgammas' lipid kinase activity and binding affinity for Talin. Our data reveal a novel function for PKD1 as a regulator of FA dynamics and by identifying PIP5Klgamma as a novel PKD1 substrate provide mechanistic insight into this process. PMID- 27775030 TI - alphabeta T cell receptor germline CDR regions moderate contact with MHC ligands and regulate peptide cross-reactivity. AB - alphabeta T cells respond to peptide epitopes presented by major histocompatibility complex (MHC) molecules. The role of T cell receptor (TCR) germline complementarity determining regions (CDR1 and 2) in MHC restriction is not well understood. Here, we examine T cell development, MHC restriction and antigen recognition where germline CDR loop structure has been modified by multiple glycine/alanine substitutions. Surprisingly, loss of germline structure increases TCR engagement with MHC ligands leading to excessive loss of immature thymocytes. MHC restriction is, however, strictly maintained. The peripheral T cell repertoire is affected similarly, exhibiting elevated cross-reactivity to foreign peptides. Our findings are consistent with germline TCR structure optimising T cell cross-reactivity and immunity by moderating engagement with MHC ligands. This strategy may operate alongside co-receptor imposed MHC restriction, freeing germline TCR structure to adopt this novel role in the TCR-MHC interface. PMID- 27775031 TI - Evolutionary plasticity of restorer-of-fertility-like proteins in rice. AB - Hybrid seed production in rice relies on cytoplasmic male sterility (CMS) induced by specific mitochondrial proteins, whose deleterious effects are suppressed by nuclear Restorer of Fertility (RF) genes. The majority of RF proteins belong to a specific clade of the RNA-binding pentatricopeptide repeat protein family. We have characterised 'restorer-of-fertility-like' (RFL) sequences from 13 Oryza genomes and the Brachypodium distachyon genome. The majority of the RFL sequences are found in genomic clusters located at two or three chromosomal loci with only a minor proportion being present as isolated genes. The RFL genomic cluster located on Oryza chromosome 10, the location of almost all known active rice RF genes, shows extreme variation in structure and gene content between species. We show evidence for homologous recombination events as an efficient mechanism for generating the huge repertoire of RNA sequence recognition motifs within RFL proteins and a major driver of RFL sequence evolution. The RFL sequences identified here will improve our understanding of the molecular basis of CMS and fertility restoration in plants and will accelerate the development of new breeding strategies. PMID- 27775033 TI - New Insecticidal Agents from Halogenation/Acylation of the Furyl-Ring of Fraxinellone. AB - Introduction of the halogen atom or the acyl group at the C-ring of fraxinellone was investigated. Some unexpected halogenation products were obtained with the different chlorination/bromination reagents, and their possible reaction mechanisms were also proposed. Seven key steric structures of 2a', 2b, 2b', 2c', 3a, 3b, and one isomer (5'alpha-Cl) of 2a were further confirmed by single crystal X-ray diffraction. Especially compounds 2a, 2a', 3a and 3c exhibited more potent insecticidal activity than toosendanin. Some structure-activity relationships of tested compounds were also described. PMID- 27775032 TI - Early nucleation events in the polymerization of actin, probed by time-resolved small-angle x-ray scattering. AB - Nucleators generating new F-actin filaments play important roles in cell activities. Detailed information concerning the events involved in nucleation of actin alone in vitro is fundamental to understanding these processes, but such information has been hard to come by. We addressed the early process of salt induced polymerization of actin using the time-resolved synchrotron small-angle X ray scattering (SAXS). Actin molecules in low salt solution maintain a monomeric state by an electrostatic repulsive force between molecules. On mixing with salts, the repulsive force was rapidly screened, causing an immediate formation of many of non-polymerizable dimers. SAXS kinetic analysis revealed that tetramerization gives the highest energetic barrier to further polymerization, and the major nucleation is the formation of helical tetramers. Filaments start to grow rapidly with the formation of pentamers. These findings suggest an acceleration mechanism of actin assembly by a variety of nucleators in cells. PMID- 27775034 TI - Thermal referral: evidence for a thermoceptive uniformity illusion without touch. AB - When warm thermal stimulators are placed on the ring and index fingers of one hand, and a neutral-temperature stimulator on the middle finger, all three fingers feel warm. This illusion is known as thermal referral (TR). On one interpretation, the heterogenous thermal signals are overridden by homogenous tactile signals. This cross-modal thermo-tactile interaction could reflect a process of object recognition, based on the prior that many objects are thermally homogenous. Interestingly, the illusion was reported to disappear when the middle digit was lifted off the thermal stimulator, suggesting that tactile stimulation is necessary. However, no study has investigated whether purely thermal stimulation might induce TR, without any tactile object to which temperature can be attributed. We used radiant thermal stimulation to deliver purely thermal stimuli, which either were or were not accompanied by simultaneous touch. We found identical TR effects in both the original thermo-tactile condition, and in a purely thermoceptive condition where no tactile object was present. Control experiments ruled out explanations based on poor spatial discrimination of warm signals. Our purely thermoceptive results suggest that TR could reflect low-level organization of the thermoceptive pathway, rather than a cognitive intermodal modulation based on tactile object perception. PMID- 27775036 TI - Evolution from the plasmon to exciton state in ligand-protected atomically precise gold nanoparticles. AB - The evolution from the metallic (or plasmonic) to molecular state in metal nanoparticles constitutes a central question in nanoscience research because of its importance in revealing the origin of metallic bonding and offering fundamental insights into the birth of surface plasmon resonance. Previous research has not been able to probe the transition due to the unavailability of atomically precise nanoparticles in the 1-3 nm size regime. Herein, we investigate the transition by performing ultrafast spectroscopic studies on atomically precise thiolate-protected Au25, Au38, Au144, Au333, Au~520 and Au~940 nanoparticles. Our results clearly map out three distinct states: metallic (size larger than Au333, that is, larger than 2.3 nm), transition regime (between Au333 and Au144, that is, 2.3-1.7 nm) and non-metallic or excitonic state (smaller than Au144, that is, smaller than 1.7 nm). The transition also impacts the catalytic properties as demonstrated in both carbon monoxide oxidation and electrocatalytic oxidation of alcohol. PMID- 27775037 TI - In-depth analysis of chloride treatments for thin-film CdTe solar cells. AB - CdTe thin-film solar cells are now the main industrially established alternative to silicon-based photovoltaics. These cells remain reliant on the so-called chloride activation step in order to achieve high conversion efficiencies. Here, by comparison of effective and ineffective chloride treatments, we show the main role of the chloride process to be the modification of grain boundaries through chlorine accumulation, which leads an increase in the carrier lifetime. It is also demonstrated that while improvements in fill factor and short circuit current may be achieved through use of the ineffective chlorides, or indeed simple air annealing, voltage improvement is linked directly to chlorine incorporation at the grain boundaries. This suggests that focus on improved or more controlled grain boundary treatments may provide a route to achieving higher cell voltages and thus efficiencies. PMID- 27775035 TI - Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport. AB - The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) facilitates fast axonal transport in neurons. However, given that GAPDH does not produce ATP, it is unclear whether glycolysis per se is sufficient to propel vesicles. Although many proteins regulating transport have been identified, the molecular composition of transported vesicles in neurons has yet to be fully elucidated. Here we selectively enrich motile vesicles and perform quantitative proteomic analysis. In addition to the expected molecular motors and vesicular proteins, we find an enrichment of all the glycolytic enzymes. Using biochemical approaches and super-resolution microscopy, we observe that most glycolytic enzymes are selectively associated with vesicles and facilitate transport of vesicles in neurons. Finally, we provide evidence that mouse brain vesicles produce ATP from ADP and glucose, and display movement in a reconstituted in vitro transport assay of native vesicles. We conclude that transport of vesicles along microtubules can be autonomous. PMID- 27775038 TI - Gentamicin removal in submerged fermentation using the novel fungal strain Aspergillus terreus FZC3. AB - Social concern and awareness of the potential risk posed by environmental residues of antibiotics such as gentamicin in the development of antibiotic resistance genes have increased. The present study used laboratory-scale experiments to develop methods for gentamicin removal from the environment. A fungus, strain FZC3, which could remove gentamicin in submerged fermentation, was isolated from solid waste and sewage water from a gentamicin production factory. The fungus was identified as Aspergillus terreus by sequencing the PCR-amplified ITS fragments of its rRNA-coding genes and by its morphology. The gentamicin removal efficiency exceeded 95% by day 7 under optimized culture conditions. The results showed that both biosorption and biodegradation were involved. We speculated that Aspergillus terreus FZC3 absorbed gentamicin and subsequently degraded it. We also found that Aspergillus terreus FZC3 survived and maintained a high bioremediation efficiency over a wide pH range, indicating its potential for future use in the large-scale bioremediation of gentamicin. PMID- 27775039 TI - Microchip-based ultrafast serodiagnostic assay for tuberculosis. AB - Access to point-of-care (POC), rapid, inexpensive, sensitive, and instrument-free tests for the diagnosis of tuberculosis (TB) remains a major challenge. Here, we report a simple and low-cost microchip-based TB ELISA (MTBE) platform for the detection of anti-mycobacterial IgG in plasma samples in less than 15 minutes. The MTBE employs a flow-less, magnet-actuated, bead-based ELISA for simultaneous detection of IgG responses against multiple mycobacterial antigens. Anti trehalose 6,6'-dimycolate (TDM) IgG responses were the strongest predictor for differentiating active tuberculosis (ATB) from healthy controls (HC) and latent tuberculosis infections (LTBI). The TDM-based MTBE demonstrated superior sensitivity compared to sputum microscopy (72% vs. 56%) with 80% and 63% positivity among smear-positive and smear-negative confirmed ATB samples, respectively. Receiver operating characteristic analysis indicated good accuracy for differentiating ATB from HC (AUC = 0.77). Thus, TDM-based MTBE can be potentially used as a screening device for rapid diagnosis of active TB at the POC. PMID- 27775040 TI - REAC technology modifies pathological neuroinflammation and motor behaviour in an Alzheimer's disease mouse model. AB - The search for new therapeutic approaches to Alzheimer disease (AD) is a major goal in medicine and society, also due to the impressive economic and social costs of this disease. In this scenario, biotechnologies play an important role. Here, it is demonstrated that the Radio Electric Asymmetric Conveyer (REAC), an innovative technology platform for neuro- and bio-modulation, used according to the neuro-regenerative protocol (RGN-N), significantly increases astroglial reaction around the amyloid plaques in an AD mouse model, as evaluated by GFAP immunoreactivity, and reduces microglia-associated neuroinflammation markers, as evaluated by Iba1-immunoreactivity and mRNA expression level of inflammatory cytokines TREM. IL1beta, iNOS and MRC1 were not affected neither by the genotype or by REAC RGN-N treatment. Also observed was an increase in locomotion in treated animals. The study was performed in 24-month-old male Tg2576 mice and age matching wild-type animals, tested for Y-maze, contextual fear conditioning and locomotion immediately after the end of a specific REAC treatment administered for 15 hours/day for 15 days. These results demonstrated that REAC RGN-N treatment modifies pathological neuroinflammation, and mitigates part of the complex motor behaviour alterations observed in very old Tg2576 mice. PMID- 27775041 TI - Stretching human mesenchymal stromal cells on stiffness-customized collagen type I generates a smooth muscle marker profile without growth factor addition. AB - Using matrix elasticity and cyclic stretch have been investigated for inducing mesenchymal stromal cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage but not in combination. We hypothesized that combining lineage specific stiffness with cyclic stretch would result in a significantly increased expression of SMC markers, compared to non-stretched controls. First, we generated dense collagen type I sheets by mechanically compressing collagen hydrogels. Atomic force microscopy revealed a nanoscale stiffness range known to support myogenic differentiation. Further characterization revealed viscoelasticity and stable biomechanical properties under cyclic stretch with >99% viable adherent human MSC. MSCs on collagen sheets demonstrated a significantly increased mRNA but not protein expression of SMC markers, compared to on culture flasks. However, cyclic stretch of MSCs on collagen sheets significantly increased both mRNA and protein expression of alpha-smooth muscle actin, transgelin, and calponin versus plastic and non-stretched sheets. Thus, lineage-specific stiffness and cyclic stretch can be applied together for inducing MSC differentiation towards SMCs without the addition of recombinant growth factors or other soluble factors. This represents a novel stimulation method for modulating the phenotype of MSCs towards SMCs that could easily be incorporated into currently available methodologies to obtain a more targeted control of MSC phenotype. PMID- 27775042 TI - Male food defence as a by-product of intersexual cooperation in a non-human primate. AB - Males in a number of group-living species fight in intergroup conflicts to defend access to food resources, a seemingly paradoxical behaviour, given that this resource does not usually limit male fitness directly. We investigated the mechanism(s) driving apparent male food defence in wild vervet monkeys (Chlorocebus aethiops pygerythrus) by testing the effect that female resource access, and female audience size and activity had on the response of focal males during simulated intergroup encounters. Males do not appear to defend food to increase the reproductive success of female group members because their response was not influenced by the presence of provisioning boxes that only females could access. Female audience size was also unimportant, suggesting males do not participate in intergroup encounters to advertise their quality to potential mates. However, focal males almost always followed/supported female group members who initiated an approach towards simulated intruders, supporting that male participation largely functions to gain status as a cooperative group member, and that apparent male food defence in this species arises as a by-product of intersexual cooperation. Our study highlights that considering audience composition and activity can reveal the presence of social incentives and illuminate the evolutionary mechanism(s) promoting joint action in intergroup aggression. PMID- 27775043 TI - HDL Cholesterol Level Is Associated with Contrast Induced Acute Kidney Injury in Chronic Kidney Disease Patients Undergoing PCI. AB - Chronic kidney disease (CKD) is a significant risk factor for contrast induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI). This study included 1592 CKD patients extracted from a prospective multicenter, all comer-based registry of patients undergoing PCI. In multivariate logistic analysis for CI-AKI development, a significant linear trend was observed between the quartiles of HDL-C (quartile 1 vs. 2: odds ratio [OR], 0.716; 95% confidence interval [CI], 0.421-1.219; quartile 1 vs. 3: OR, 0.534; 95% CI, 0.301-0.947; quartile 1 vs. 4: OR, 0.173; 95% CI, 0.079-0.377; P for trend < 0.001). HDL-C quartiles were also negatively correlated with the incidence of CI-AKI; 19.0%, 12.1%, 8.7%, and 3.7% for quartile 1(Q1) (<34 mg/dL), Q2 (34-40 mg/dL), Q3 (40-48 mg/dL), and Q4 (>48 mg/dL) respectively (P < 0.001 overall and for the trend). Multivariate Cox regression analysis for the long term mortality, the highest HDL C quartile was associated with decreased mortality compared with the lowest HDL-C quartile (hazard ratio [HR] 0.516, 95% CI, 0.320-0.832, P = 0.007). Our study suggests more intensive strategies should be considered for preventing CI-AKI in CKD patients with low serum HDL-C level who is planned for PCI. PMID- 27775044 TI - Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Regulates Chondrocyte Differentiation and Secondary Ossification in Mice. AB - Endochondral ossification plays an important role in the formation of the primary ossification centers (POCs) and secondary ossification centers (SOCs) of mammalian long bones. However, the molecular mechanisms that regulate POC and SOC formation are different. We recently demonstrated that Prolyl Hydroxylase Domain containing Protein 2 (Phd2) is a key mediator of vitamin C effects on bone. We investigated the role of Phd2 on endochondral ossification of the epiphyses by conditionally deleting the Phd2 gene in osteoblasts and chondrocytes. We found that the deletion of Phd2 in osteoblasts did not cause changes in bone parameters in the proximal tibial epiphyses in 5 week old mice. In contrast, deletion of Phd2 in chondrocytes resulted in increased bone mass and bone formation rate (normalized to tissue volume) in long bone epiphyses, indicating that Phd2 expressed in chondrocytes, but not osteoblasts, negatively regulates secondary ossification of epiphyses. Phd2 deletion in chondrocytes elevated mRNA expression of hypoxia-inducible factor (HIF) signaling molecules including Hif-1alpha, Hif 2alpha, Vegfa, Vegfb, and Epo, as well as markers for chondrocyte hypertrophy and mineralization such as Col10, osterix, alkaline phosphatase, and bone sialoprotein. These data suggest that Phd2 expressed in chondrocytes inhibits endochondral ossification at the epiphysis by suppressing HIF signaling pathways. PMID- 27775045 TI - Supernova: A Versatile Vector System for Single-Cell Labeling and Gene Function Studies in vivo. AB - Here we describe "Supernova" series of vector systems that enable single-cell labeling and labeled cell-specific gene manipulation, when introduced by in utero electroporation (IUE) or adeno-associated virus (AAV)-mediated gene delivery. In Supernova, sparse labeling relies on low TRE leakage. In a small population of cells with over-threshold leakage, initial tTA-independent weak expression is enhanced by tTA/TRE-positive feedback along with a site-specific recombination system (e.g., Cre/loxP, Flpe/FRT). Sparse and bright labeling by Supernova with little background enables the visualization of the morphological details of individual neurons in densely packed brain areas such as the cortex and hippocampus, both during development and in adulthood. Sparseness levels are adjustable. Labeled cell-specific gene knockout was accomplished by introducing Cre/loxP-based Supernova vectors into floxed mice. Furthermore, by combining with RNAi, TALEN, and CRISPR/Cas9 technologies, IUE-based Supernova achieved labeled cell-specific gene knockdown and editing/knockout without requiring genetically altered mice. Thus, Supernova system is highly extensible and widely applicable for single-cell analyses in complex organs, such as the mammalian brain. PMID- 27775047 TI - Repetitive Electroacupuncture Attenuates Cold-Induced Hypertension through Enkephalin in the Rostral Ventral Lateral Medulla. AB - Acupuncture lowers blood pressure (BP) in hypertension, but mechanisms underlying its action are unclear. To simulate clinical studies, we performed electroacupuncture (EA) in unanesthetized rats with cold-induced hypertension (CIH) induced by six weeks of cold exposure (6 degrees C). EA (0.1 - 0.4 mA, 2 Hz) was applied at ST36-37 acupoints overlying the deep peroneal nerve for 30 min twice weekly for five weeks while sham-EA was conducted with the same procedures as EA except for no electrical stimulation. Elevated BP was reduced after six sessions of EA treatment and remained low 72 hrs after EA in 18 CIH rats, but not in sham-EA (n = 12) and untreated (n = 6) CIH ones. The mRNA level of preproenkephalin in the rostral ventrolateral medulla (rVLM) 72 hr after EA was increased (n = 9), compared to the sham-EA (n = 6), untreated CIH rats (n = 6) and normotensive control animals (n = 6). Microinjection of ICI 174,864, a delta opioid receptor antagonist, into the rVLM of EA-treated CIH rats partially reversed EA's effect on elevated BP (n = 4). Stimulation of rVLM of CIH rats treated with sham-EA using a delta-opioid agonist, DADLE, decreased BP (n = 6). These data suggest that increased enkephalin in the rVLM induced by repetitive EA contributes to BP lowering action of EA. PMID- 27775046 TI - Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan. AB - Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 preemptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1-5 years old), 67 older children (6-17 years old) and 101 adults (>=18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers <=80, 90% young children, 73% older children and 72% adults seroconverted (>=4 fold titer rise) after the 1st OCV dose; with no additional seroconversion after the 2nd dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed. PMID- 27775048 TI - Multifunctional Cu2-xTe Nanocubes Mediated Combination Therapy for Multi-Drug Resistant MDA MB 453. AB - Hypermethylated cancer populations are hard to treat due to their enhanced chemo resistance, characterized by aberrant methylated DNA subunits. Herein, we report on invoking response from such a cancer lineage to chemotherapy utilizing multifunctional copper telluride (Cu2-XTe) nanocubes (NCs) as photothermal and photodynamic agents, leading to significant anticancer activity. The NCs additionally possessed photoacoustic and X-ray contrast imaging abilities that could serve in image-guided therapeutic studies. PMID- 27775049 TI - A high-throughput microfluidic approach for 1000-fold leukocyte reduction of platelet-rich plasma. AB - Leukocyte reduction of donated blood products substantially reduces the risk of a number of transfusion-related complications. Current 'leukoreduction' filters operate by trapping leukocytes within specialized filtration material, while allowing desired blood components to pass through. However, the continuous release of inflammatory cytokines from the retained leukocytes, as well as the potential for platelet activation and clogging, are significant drawbacks of conventional 'dead end' filtration. To address these limitations, here we demonstrate our newly-developed 'controlled incremental filtration' (CIF) approach to perform high-throughput microfluidic removal of leukocytes from platelet-rich plasma (PRP) in a continuous flow regime. Leukocytes are separated from platelets within the PRP by progressively syphoning clarified PRP away from the concentrated leukocyte flowstream. Filtrate PRP collected from an optimally designed CIF device typically showed a ~1000-fold (i.e. 99.9%) reduction in leukocyte concentration, while recovering >80% of the original platelets, at volumetric throughputs of ~1 mL/min. These results suggest that the CIF approach will enable users in many fields to now apply the advantages of microfluidic devices to particle separation, even for applications requiring macroscale flowrates. PMID- 27775050 TI - Nutrient stoichiometry in winter wheat: Element concentration pattern reflects developmental stage and weather. AB - At least 16 nutrient elements are required by plants for growth and survival, but the factors affecting element concentration and their temporal evolution are poorly understood. The objective was to investigate i) element concentration pattern in winter wheat as affected by crop developmental stage and weather, and ii) whether, in the short term, element stoichiometry reflects the type of preceding crop. We assessed the temporal trajectories of element concentration pattern (N, P, K, Ca, Mg, S, Mn, Fe, Cu, Na, Zn) across the life cycle (from seed to seed) of winter wheat field-grown in cool-temperate Sweden during two years with contrasting weather and when cultivated in monoculture or after different non-wheat preceding crops. We found strong influence of developmental stage on concentration pattern, with the greatest deviation from grain concentrations found in plants at the start of stem elongation in spring. Inter-annual differences in weather affected stoichiometry, but no evidence was found for a short-term preceding-crop effect on element stoichiometry. Winter wheat element stoichiometry is similar in actively growing plant tissues and seeds. Nitrogen exerts a strong influence on the concentration pattern for all elements. Three groups of elements with concentrations changing in concert were identified. PMID- 27775052 TI - Conditions Optimizing and Application of Laccase-mediator System (LMS) for the Laccase-catalyzed Pesticide Degradation. AB - A high capacity of laccase from Trametes versicolor capable of degrading pesticides has been revealed. The conditions for degrading of five selected pesticides including chlorpyrifos, chlorothalonil, pyrimethanil, atrazine and isoproturon with the purified laccases from Trametes versicolor were optimized. The results showed that the optimum conditions for the highest activity were pH at 5.0 and temperature at 25 degrees C. The best mediators were violuric acid for pyrimethanil and isoproturon, vanillin for chlorpyrifos, and acetosyringone and HBT for chlorothalonil and atrazine, respectively. The laccase was found to be stable at a pH range from 5.0 to 7.0 and temperature from 25 to 30 degrees C. It was observed that each pesticide required a different laccase mediator concentration typically between 4.0-6.0 mmol/L. In the experiment, the degradation rates of pyrimethanil and isoproturon were significantly faster than those of chlorpyrifos, chlorothalonil and atrazine. For example, it was observed that pyrimethanil and isoproturon degraded up to nearly 100% after 24 hours while the other three pesticides just reached up 90% of degradation after 8 days of incubation. PMID- 27775051 TI - Fucoidan inhibits CCL22 production through NF-kappaB pathway in M2 macrophages: a potential therapeutic strategy for cancer. AB - In tumor microenvironment, macrophages as a polarized M2 population promote tumor progression via releasing multiple cytokines and chemokines. A brown seaweed fucose-rich polysaccharide, fucoidan has antitumor activity and immune modulation through affecting tumor cells and lymphocytes. Here, we focused on the effect of fucoidan on macrophages especially M2 subtype. Our results demonstrated that fucoidan down-regulated partial cytokines and chemokines, especially a M2-type chemokine CCL22. Furthermore, fucoidan inhibited tumor cells migration and CD4+ T lymphocytes, especially Treg cells, recruitment induced by M2 macrophages conditioned medium through suppression of CCL22. Mechanismly, fucoidan inhibited CCL22 via suppressing p65-NF-kappaB phosphorylation and nuclear translocation. In addition, p38-MAPK and PI3K-AKT also affected the expression of CCL22 through differential modulation of NF-kappaB transcriptional activity. Taken together, we reveal an interesting result that fucoidan can inhibit tumor cell migration and lymphocytes recruitment by suppressing CCL22 in M2 macrophages via NF-kappaB dependent transcription, which may be a novel and promising mechanism for tumor immunotherapy. PMID- 27775053 TI - Multifunctional substrate of Al alloy based on general hierarchical micro/nanostructures: superamphiphobicity and enhanced corrosion resistance. AB - Aluminum alloys are vulnerable to penetrating and peeling failures in seawater and preparing a barrier coating to isolate the substrate from corrosive medium is an effective anticorrosion method. Inspired by the lotus leaves effect, a wetting alloy surface with enhanced anticorrosion behavior has been prepared via etch, deposition, and low-surface-energy modification. Results indicate that excellent superamphiphobicity has been achieved after the modification of the constructed hierarchical labyrinth-like microstructures and dendritic nanostructures. The as prepared surface is also found with good chemical stability and mechanical durability. Furthermore, superior anticorrosion behaviors of the resultant samples in seawater are investigated by electrochemical measurements. Due to trapped air in micro/nanostructures, the newly presented solid-air-liquid contacting interface can help to resist the seawater penetration by greatly reducing the interface interaction between corrosive ions and the superamphiphobic surface. Finally, an optimized two-layer perceptron artificial neural network is set up to model and predict the cause-and-effect relationship between preparation conditions and the anticorrosion parameters. This work provides a great potential to extend the applications of aluminum alloys especially in marine engineering fields. PMID- 27775054 TI - Thromboxane A2 receptor antagonist SQ29548 reduces ischemic stroke-induced microglia/macrophages activation and enrichment, and ameliorates brain injury. AB - Thromboxane A2 receptor (TXA2R) activation is thought to be involved in thrombosis/hemostasis and inflammation responses. We have previously shown that TXA2R antagonist SQ29548 attenuates BV2 microglia activation by suppression of ERK pathway, but its effect is not tested in vivo. The present study aims to explore the role of TXA2R on microglia/macrophages activation after ischemia/reperfusion brain injury in mice. Adult male ICR mice underwent 90-min transient middle cerebral artery occlusion (tMCAO). Immediately and 24 h after reperfusion, SQ29548 was administered twice to the ipsilateral ventricle (10 MUl, 2.6 MUmol/ml, per dose). Cerebral infarction volume, inflammatory cytokines release and microglia/macrophages activation were measured using the cresyl violet method, quantitative polymerase chain reaction (qPCR), and immunofluorescence double staining, respectively. Expression of TXA2R was significantly increased in the ipsilateral brain tissue after ischemia/reperfusion, which was also found to co-localize with activated microglia/macrophages in the infarct area. Administration of SQ29548 inhibited microglia/macrophages activation and enrichment, including both M1 and M2 phenotypes, and attenuated ischemia-induced IL-1beta, IL-6, and TNF-alpha up regulation and iNOS release. TXA2R antagonist SQ29548 inhibited ischemia-induced inflammatory response and furthermore reduced microglia/macrophages activation and ischemic/reperfusion brain injury. PMID- 27775055 TI - Adverse Cardiovascular Outcomes associated with Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention with Everolimus Eluting Stents: A Meta Analysis. AB - This study aimed to compare the mid-term adverse cardiovascular outcomes associated with Coronary Artery Bypass Surgery (CABG) and Percutaneous Coronary Intervention (PCI) with Everolimus Eluting Stents (EES). Electronic databases were searched for studies comparing the mid-term (>1 year) adverse cardiovascular outcomes between CABG and PCI with EES. Odd Ratios (OR) with 95% Confidence Intervals (CIs) were calculated and the pooled analyses were performed with RevMan 5.3 software. A total number of 5207 patients were involved in this analysis. No significant difference was observed in mortality between CABG and EES with OR: 0.90, 95% CI: 0.73-1.10; P = 0.30. Moreover, CABG was associated with a high stroke rate, with OR: 0.73, 95% CI: 0.45-1.17; P = 0.19, without any statistical significant. CABG was associated with significantly lower Major Adverse Cardiac Events and Myocardial Infarction with OR: 1.46, 95% CI: 1.05 2.04; P = 0.03 and OR: 1.46, 95% CI: 1.01-2.12; P = 0.05 respectively whereas PCI was associated with a significantly higher repeated revascularization with OR: 2.21; 95% CI: 1.76-2.77; P = 0.00001. In conclusion, significant differences were noted in several subgroups analyzing the mid-term cardiovascular outcomes between CABG and EES. PMID- 27775056 TI - Jointed magnetic skyrmion lattices at a small-angle grain boundary directly visualized by advanced electron microscopy. AB - The interactions between magnetic skyrmions and structural defects, such as edges, dislocations, and grain boundaries (GBs), which are all considered as topological defects, will be important issues when magnetic skyrmions are utilized for future memory device applications. To investigate such interactions, simultaneous visualization of magnetic skyrmions and structural defects at high spatial resolution, which is not feasible by conventional techniques, is essential. Here, taking advantages of aberration-corrected differential phase contrast scanning transmission electron microscopy, we investigate the interaction of magnetic skyrmions with a small-angle GB in a thin film of FeGe1 xSix. We found that the magnetic skyrmions and the small-angle GB can coexist each other, but a domain boundary (DB) was formed in the skyrmion lattice along the small-angle GB. At the core of the DB, unexpectedly deformed magnetic skrymions, which appear to be created by joining two portions of magnetic skyrmions in the adjacent lattices, were formed to effectively compensate misorientations between the two adjacent magnetic skyrmion lattices. These observations strongly suggest the flexible nature of individual magnetic skyrmions, and also the significance of defect engineering for future device applications. PMID- 27775057 TI - Pre-amyloid oligomers budding:a metastatic mechanism of proteotoxicity. AB - The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology. PMID- 27775058 TI - Extracellular vesicles from Paracoccidioides brasiliensis induced M1 polarization in vitro. AB - Extracellular vesicles (EVs) released by eukaryotes, archaea, and bacteria contain proteins, lipids, polysaccharides, and other molecules. The cargo analysis of EVs shows that they contain virulence factors suggesting a role in the pathogenesis of infection. The proteome, lipidome, RNA content, and carbohydrate composition of EVs from Paracoccidioides brasiliensis and Paracoccidioides lutzii were characterized. However, the effects of P. brasiliensis EVs on the host immune system have not yet been investigated. Herein, we verified that EVs from P. brasiliensis induce the production of proinflammatory mediators by murine macrophages in a dose-dependent manner. Addition of EV to macrophages also promoted transcription of the M1-polarization marker iNOs and diminish that of the M2 markers Arginase-1, Ym-1, and FIZZ-1. Furthermore, the augmented expression of M2-polarization markers, stimulated by IL-4 plus IL-10, was reverted toward an M1 phenotype in response to secondary stimulation with EVs from P. brasiliensis. The ability of EVs from P. brasiliensis to promote M1 polarization macrophages favoring an enhanced fungicidal activity, demonstrated by the decreased CFU recovery of internalized yeasts, with comparable phagocytic efficacy. Our results suggest that EVs from P. brasiliensis can modulate the innate immune response and affect the relationship between P. brasiliensis and host immune cells. PMID- 27775059 TI - The human laryngeal microbiome: effects of cigarette smoke and reflux. AB - Prolonged diffuse laryngeal inflammation from smoking and/or reflux is commonly diagnosed as chronic laryngitis and treated empirically with expensive drugs that have not proven effective. Shifts in microbiota have been associated with many inflammatory diseases, though little is known about how resident microbes may contribute to chronic laryngitis. We sought to characterize the core microbiota of disease-free human laryngeal tissue and to investigate shifts in microbial community membership associated with exposure to cigarette smoke and reflux. Using 454 pyrosequencing of the 16S rRNA gene, we compared bacterial communities of laryngeal tissue biopsies collected from 97 non-treatment-seeking volunteers based on reflux and smoking status. The core community was characterized by a highly abundant OTU within the family Comamonadaceae found in all laryngeal tissues. Smokers demonstrated less microbial diversity than nonsmokers, with differences in relative abundances of OTUs classified as Streptococcus, unclassified Comamonadaceae, Cloacibacterium, and Helicobacter. Reflux status did not affect microbial diversity nor community structure nor composition. Comparison of healthy laryngeal microbial communities to benign vocal fold disease samples revealed greater abundance of Streptococcus in benign vocal fold disease suggesting that mucosal dominance by Streptococcus may be a factor in disease etiology. PMID- 27775062 TI - On-chip generation of heralded photon-number states. AB - Beyond the use of genuine monolithic integrated optical platforms, we report here a hybrid strategy enabling on-chip generation of configurable heralded two-photon states. More specifically, we combine two different fabrication techniques, i.e., non-linear waveguides on lithium niobate for efficient photon-pair generation and femtosecond-laser-direct-written waveguides on glass for photon manipulation. Through real-time device manipulation capabilities, a variety of path-coded heralded two-photon states can be produced, ranging from product to entangled states. Those states are engineered with high levels of purity, assessed by fidelities of 99.5 +/- 8% and 95.0 +/- 8%, respectively, obtained via quantum interferometric measurements. Our strategy therefore stands as a milestone for further exploiting entanglement-based protocols, relying on engineered quantum states, and enabled by scalable and compatible photonic circuits. PMID- 27775060 TI - Adipose tissue hyperplasia with enhanced adipocyte-derived stem cell activity in Tc1(C8orf4)-deleted mice. AB - Adipose tissue hyperplasia with increased number of adipocytes is implicated in a protective rather than deleterious effect on obesity-associated metabolic disorder. It is poorly understood how the adipose tissue cellularity is regulated. Tc1 is a gene of vertebrates that regulates diverse downstream genes. Young Tc1-deleted mice fed on standard chow diet show expanded adipose tissue with smaller adipocytes in size compared to wild type controls, representing adipose tissue hyperplasia. Tc1-/- mice show enhanced glucose tolerance and reduced serum lipids. Adipocyte-derived stem cells (ADSCs) from Tc1-/- mice show enhanced proliferative and adipogenic capacity compared to wild type controls, suggesting that the adipose hyperplasia is regulated at the stem cell level. PPARgamma and CEBPalpha are up-regulated robustly in Tc1-/- ADSCs upon induction for adipogenesis. Wisp2 and Dlk1, inhibitors of adipogenesis, are down-regulated in Tc1-/- ADSCs compared to controls. Tc1-transfected NIH3T3 cells show higher beta-catenin reporter signals than vector transfected controls, suggesting a role of canonical Wnt signaling in the Tc1-dependent adipose regulation. Our data support that Tc1 is a novel regulator for adipose stem cells. Adipose tissue hyperplasia may be implicated in the metabolic regulation of Tc1-/- mice. PMID- 27775061 TI - Foundations of cumulative culture in apes: improved foraging efficiency through relinquishing and combining witnessed behaviours in chimpanzees (Pan troglodytes). AB - A vital prerequisite for cumulative culture, a phenomenon often asserted to be unique to humans, is the ability to modify behaviour and flexibly switch to more productive or efficient alternatives. Here, we first established an inefficient solution to a foraging task in five captive chimpanzee groups (N = 19). Three groups subsequently witnessed a conspecific using an alternative, more efficient, solution. When participants could successfully forage with their established behaviours, most individuals did not switch to this more efficient technique; however, when their foraging method became substantially less efficient, nine chimpanzees with socially-acquired information (four of whom witnessed additional human demonstrations) relinquished their old behaviour in favour of the more efficient one. Only a single chimpanzee in control groups, who had not witnessed a knowledgeable model, discovered this. Individuals who switched were later able to combine components of their two learned techniques to produce a more efficient solution than their extensively used, original foraging method. These results suggest that, although chimpanzees show a considerable degree of conservatism, they also have an ability to combine independent behaviours to produce efficient compound action sequences; one of the foundational abilities (or candidate mechanisms) for human cumulative culture. PMID- 27775064 TI - Geometric phase coded metasurface: from polarization dependent directive electromagnetic wave scattering to diffusion-like scattering. AB - Ultrathin metasurface compromising various sub-wavelength meta-particles offers promising advantages in controlling electromagnetic wave by spatially manipulating the wavefront characteristics across the interface. The recently proposed digital coding metasurface could even simplify the design and optimization procedures due to the digitalization of the meta-particle geometry. However, current attempts to implement the digital metasurface still utilize several structural meta-particles to obtain certain electromagnetic responses, and requiring time-consuming optimization especially in multi-bits coding designs. In this regard, we present herein utilizing geometric phase based single structured meta-particle with various orientations to achieve either 1-bit or multi-bits digital metasurface. Particular electromagnetic wave scattering patterns dependent on the incident polarizations can be tailored by the encoded metasurfaces with regular sequences. On the contrast, polarization insensitive diffusion-like scattering can also been successfully achieved by digital metasurface encoded with randomly distributed coding sequences leading to substantial suppression of backward scattering in a broadband microwave frequency. The proposed digital metasurfaces provide simple designs and reveal new opportunities for controlling electromagnetic wave scattering with or without polarization dependence. PMID- 27775063 TI - The effect of physiological levels of South African puff adder (Bitis arietans) snake venom on blood cells: an in vitro model. AB - A significant burden of illness is caused globally by snakebites particularly by the puff adder, Bitis arietans. Presently there is no reliable and rapid method to confirm envenomation on blood chemistry; although coagulation parameters like prothrombin time, partial thromboplastin time, international normalized ratio and also serum electrolytes are tested. Here, we found that direct in vitro exposure of physiological relevant whole venom levels to human healthy blood (N = 32), caused significant physiological changes to platelet activity using a hematology analyzer, and measuring occlusion time, as well as lyses time, with the global thrombosis test (GTT). Disintegrated platelets were confirmed by scanning electron microscopy (SEM). We also confirmed the pathologic effects on erythrocytes (RBCs) (visible as eryptotic RBCs), by looking at both light microscopy and SEM. Thromboelastography showed that no clot formation in whole blood could be induced after addition of whole venom. We propose further clinical studies to investigate the use of light microscopy smears and hematology analyzer results immediately after envenomation, as a possible first-stage of clinical confirmation of envenomation. PMID- 27775065 TI - Insertion of a knockout-first cassette in Ampd1 gene leads to neonatal death by disruption of neighboring genes expression. AB - AMPD1 is an adenosine monophosphate deaminase that catalyzes the deamination of AMP to IMP. To understand the physiological function of AMPD1, we obtained a strain of Ampd1 mutant mice from KOMP repository, which was generated by a knockout-first strategy. An elevated AMP level and almost complete lack of IMP was detected in the skeletal muscle of E18.5 Ampd1tm1a/tm1a mice. However, Ampd1tm1a/tm1a mice died in 2 days postnatally, which was contradicting to previous reports. After removal of the knockout-first cassette and critical exon, mice homozygous for the Ampd1tm1c/tm1c and Ampd1tm1d/tm1d alleles survived to adulthood. RNA-seq analysis indicated that the expression of two neighboring genes, Man1a2 and Nras, were disrupted in the Ampd1tm1a/tm1a mice, but normal in the Ampd1tm1c/tm1c and Ampd1tm1d/tm1d mice. The neonatal lethality phenotype in the Ampd1tm1a/tm1a mice was consistent with the Man1a2-deficient mice. Our results indicated the knockout-first cassette may cause off-target effect by influence the expression of neighboring genes. This study, together with other reports, strongly suggests that removal of targeting cassette by site-specific recombinases is very important for the accurate phenotypic interpretation on mice generated by target mutations. PMID- 27775066 TI - Laser recrystallization and inscription of compositional microstructures in crystalline SiGe-core fibres. AB - Glass fibres with silicon cores have emerged as a versatile platform for all optical processing, sensing and microscale optoelectronic devices. Using SiGe in the core extends the accessible wavelength range and potential optical functionality because the bandgap and optical properties can be tuned by changing the composition. However, silicon and germanium segregate unevenly during non equilibrium solidification, presenting new fabrication challenges, and requiring detailed studies of the alloy crystallization dynamics in the fibre geometry. We report the fabrication of SiGe-core optical fibres, and the use of CO2 laser irradiation to heat the glass cladding and recrystallize the core, improving optical transmission. We observe the ramifications of the classic models of solidification at the microscale, and demonstrate suppression of constitutional undercooling at high solidification velocities. Tailoring the recrystallization conditions allows formation of long single crystals with uniform composition, as well as fabrication of compositional microstructures, such as gratings, within the fibre core. PMID- 27775068 TI - Immunology: Skin inflammation predisposes to cancer. PMID- 27775067 TI - Tumour metabolism: Targeting proline metabolism? PMID- 27775069 TI - Immunotherapy: Checkpoint barriers. PMID- 27775070 TI - Tumour metabolism: Location matters. PMID- 27775071 TI - Extracellular region of epidermal growth factor receptor: a potential target for anti-EGFR drug discovery. AB - The epidermal growth factor receptor (EGFR) is a transmembrane receptor with tyrosine kinase activity involved in regulation of cellular multiplication, survival, differentiation and metastasis. Our knowledge about function and complex management of these receptors has driving the development of specific and targeted treatment modalities for human cancers in the last 20 years. EGFR is the first receptor target against which monoclonal antibodies (mAb) have been evolved for cancer treatment. Here we review the biology of ErbB receptors, including their architecture, signaling, regulation and therapeutic strategies and the mechanisms of resistances offered by the receptors against small-molecule tyrosine kinases and resistance overcome implications of mAbs. The efficacy of EGFR-specific mAb in cancer depends on site specific extracellular region of EGFR, which has crucial role in process of dimerization and activation. This review highlights evolution of various resistance mechanisms due to consequences of current small-molecule anti-EGFR therapies. PMID- 27775072 TI - Metformin alters DNA methylation genome-wide via the H19/SAHH axis. AB - The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH. H19 knockdown activates SAHH, enabling DNA methyltransferase 3B to methylate a subset of genes. This metformin-induced H19 repression and alteration of gene methylation are recapitulated in endometrial cancer tissue samples obtained from patients treated with antidiabetic doses of metformin. Our findings unveil a novel mechanism of action for the drug metformin with implications for the molecular basis of epigenetic dysregulation in cancer. This novel mechanism of action also may be occurring in normal cells. PMID- 27775073 TI - p53 deficiency induces cancer stem cell pool expansion in a mouse model of triple negative breast tumors. AB - Triple-negative breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Triple-negative tumors often display activated Wnt/beta-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/beta-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5DeltaNbetacat mice displaying a constitutive activation of Wnt/beta-catenin signaling in basal cells. K5DeltaNbetacat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5DeltaNbetacat mice led to an early expansion of mammary stem/progenitor cells and accelerated the formation of triple-negative tumors. In particular, p53 deficient tumors expressed high levels of integrins and extracellular matrix components and were enriched in cancer stem cells. They also overexpressed the tyrosine kinase receptor Met, a feature characteristic of human triple-negative breast tumors. The inhibition of Met kinase activity impaired tumorsphere formation, demonstrating the requirement of Met signaling for cancer stem cell growth in this model. Human basal-like breast cancers with predicted mutated p53 status had higher levels of MET expression than tumors with wild-type p53. These results connect p53 loss and beta-catenin activation to stem cell regulation and tumorigenesis in triple-negative cancer and highlight the role of Met signaling in maintaining cancer stem cell properties, revealing new cues for targeted therapies. PMID- 27775074 TI - In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma. AB - Activating mutations in KRAS and EGFR, the two most frequent oncogenes in human lung adenocarcinoma, are mutually exclusive, a phenotype attributed to functional redundancy implying lack of positive selection. Employing a mouse model expressing EGFRL858R in advanced KrasG12V-driven tumors we show that their mutual exclusivity can be explained by detrimental effects of their co-expression in lung adenocarcinoma. In vivo, expression of EGFRL858R in KrasG12V-driven tumors triggers replicative stress and apoptosis, while the surviving cells enter a transient cytostatic state incompatible with tumor development that is fully reversible upon discontinued EGFRL858R expression. Eventually, sustained expression of both mutants induces attenuation of oncogenic signaling to levels compatible with proliferation and tumor growth resulting in high sensitivity to Mek inhibition. Our results indicate that the mutual exclusivity of KRAS and EGFR mutations occurs as a combination of cellular toxicity and signal adjustment resulting in lack of selective advantage for cells expressing both oncogenes. PMID- 27775075 TI - Myoferlin regulates cellular lipid metabolism and promotes metastases in triple negative breast cancer. AB - Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients. PMID- 27775076 TI - Multiplatform-based molecular subtypes of non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) demonstrates remarkable molecular diversity. With the completion of The Cancer Genome Atlas (TCGA), there is opportunity for systematic analyses of the entire TCGA NSCLC cohort, including comparisons and contrasts between different disease subsets. On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy, and RNA and protein expression), 1023 NSCLC cases-519 from TCGA adenocarcinoma (AD) project and 504 from TCGA squamous cell carcinoma (SQCC) project-were classified using a 'cluster-of-clusters' analytic approach. Patterns from TCGA NSCLC subsets were examined in independent external databases, including the PROSPECT (Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax) NSCLC data set. Nine genomic subtypes of NSCLC were identified, three within SQCC and six within AD. SQCC subtypes were associated with transcriptional targets of SOX2 or p63. One predominately AD subtype (with a large proportion of SQCC) shared molecular features with neuroendocrine tumors. Two AD subtypes manifested a CpG island methylator phenotype. Three AD subtypes showed high p38 and mTOR pathway activation. AD subtypes associated with low differentiation showed relatively worse prognosis. SQCC subtypes and two of the AD subtypes expressed cancer testis antigen genes, whereas three AD subtypes expressed several immune checkpoint genes including PDL1 and PDL2, corresponding with patterns of greater immune cell infiltration. Subtype associations for several immune-related markers-including PD1, PDL1, CD3 and CD8-were confirmed in the PROSPECT cohort using immunohistochemistry. NSCLC molecular subtypes have therapeutic implications and lend support to a personalized approach to NSCLC management based on molecular characterization. PMID- 27775077 TI - The cancer/testis antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling. AB - The biological function of MAGEC2, a cancer/testis antigen highly expressed in various cancers, remains largely unknown. Here we demonstrate that expression of MAGEC2 induces rounded morphology and amoeboid-like movement of tumor cells in vitro and promotes tumor metastasis in vivo. The pro-metastasis effect of MAGEC2 was mediated by signal transducer and activator of transcription 3 (STAT3) activation. Mechanistically, MAGEC2 interacts with STAT3 and inhibits the polyubiquitination and proteasomal degradation of STAT3 in the nucleus of tumor cells, resulting in accumulation of phosphorylated STAT3 and enhanced transcriptional activity. Notably, expression levels of MAGEC2 and phosphorylated STAT3 are positively correlated and both are associated with incidence of metastasis in human hepatocellular carcinoma. This study not only reveals a previously unappreciated role of MAGEC2 in promoting tumor metastasis, but also identifies a new molecular mechanism by which MAGEC2 sustains hyperactivation of STAT3 in the nucleus of tumor cells. Thus, MAGEC2 may represent a new antitumor metastasis target for treatment of cancer. PMID- 27775078 TI - Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease. AB - Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays revealed that CYLD represses MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-kappaB and Wnt/beta-catenin signaling and loss of CYLD sensitizes MM cells to NF-kappaB-stimuli and Wnt ligands. Interestingly, in primary MMs, low CYLD expression strongly correlated with a proliferative and Wnt signaling-gene expression signature, but not with an NFkappaB target gene signature. Altogether, our findings identify CYLD as a negative regulator of NF kappaB and Wnt/beta-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation. Thus, targeting the Wnt pathway could be a promising therapeutic strategy in MM with loss of CYLD activity. PMID- 27775079 TI - CD133+ brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence. AB - Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells (MBSCs), a subset of MB patients remains untreatable despite standard therapy. CD133 is used to identify MBSCs although its functional role in tumorigenesis has yet to be determined. In this work, we showed enrichment of CD133 in Group 3 MB is associated with increased rate of metastasis and poor clinical outcome. The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133+ MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB. We screened compound libraries for STAT3 inhibitors and treatment with the selected STAT3 inhibitors resulted in tumor size reduction in vivo. We propose that inhibition of STAT3 signaling in MBSCs may represent a potential therapeutic strategy to treat patients with recurrent MB. PMID- 27775081 TI - High endemism at cave entrances: a case study of spiders of the genus Uthina. AB - Endemism, which is typically high on islands and in caves, has rarely been studied in the cave entrance ecotone. We investigated the endemism of the spider genus Uthina at cave entrances. Totally 212 spiders were sampled from 46 localities, from Seychelles across Southeast Asia to Fiji. They mostly occur at cave entrances but occasionally appear at various epigean environments. Phylogenetic analysis of DNA sequence data from COI and 28S genes suggested that Uthina was grouped into 13 well-supported clades. We used three methods, the Bayesian Poisson Tree Processes (bPTP) model, the Bayesian Phylogenetics and Phylogeography (BPP) method, and the general mixed Yule coalescent (GMYC) model, to investigate species boundaries. Both bPTP and BPP identified the 13 clades as 13 separate species, while GMYC identified 19 species. Furthermore, our results revealed high endemism at cave entrances. Of the 13 provisional species, twelve (one known and eleven new) are endemic to one or a cluster of caves, and all of them occurred only at cave entrances except for one population of one species. The only widely distributed species, U. luzonica, mostly occurred in epigean environments while three populations were found at cave entrances. Additionally, eleven new species of the genus are described. PMID- 27775082 TI - Functionalized magnetic nanowires for chemical and magneto-mechanical induction of cancer cell death. AB - Exploiting and combining different properties of nanomaterials is considered a potential route for next generation cancer therapies. Magnetic nanowires (NWs) have shown good biocompatibility and a high level of cellular internalization. We induced cancer cell death by combining the chemotherapeutic effect of doxorubicin (DOX)-functionalized iron NWs with the mechanical disturbance under a low frequency alternating magnetic field. (3-aminopropyl)triethoxysilane (APTES) and bovine serum albumin (BSA) were separately used for coating NWs allowing further functionalization with DOX. Internalization was assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal analysis, BSA formulations demonstrated higher internalization and less agglomeration. The functionalized NWs generated a comparable cytotoxic effect in breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by free DOX and non-functionalized NWs formulations. A synergistic cytotoxic effect is obtained when a magnetic field (1 mT, 10 Hz) is applied to cells treated with DOX-functionalized BSA or APTES-coated NWs, (~70% at the highest concentration). In summary, a bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of iron NWs with the effect of DOX producing better results than the individual effects. PMID- 27775080 TI - Substitution rate and natural selection in parvovirus B19. AB - The aim of this study was to estimate substitution rate and imprints of natural selection on parvovirus B19 genotype 1. Studied datasets included 137 near complete coding B19 genomes (positions 665 to 4851) for phylogenetic and substitution rate analysis and 146 and 214 partial genomes for selection analyses in open reading frames ORF1 and ORF2, respectively, collected 1973-2012 and including 9 newly sequenced isolates from Serbia. Phylogenetic clustering assigned majority of studied isolates to G1A. Nucleotide substitution rate for total coding DNA was 1.03 (0.6-1.27) x 10-4 substitutions/site/year, with higher values for analyzed genome partitions. In spite of the highest evolutionary rate, VP2 codons were found to be under purifying selection with rare episodic positive selection, whereas codons under diversifying selection were found in the unique part of VP1, known to contain B19 immune epitopes important in persistent infection. Analyses of overlapping gene regions identified nucleotide positions under opposite selective pressure in different ORFs, suggesting complex evolutionary mechanisms of nucleotide changes in B19 viral genomes. PMID- 27775084 TI - Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity. AB - Clinical development of Chk1 inhibitors is currently focussed on evaluating activity as monotherapy and as potentiators of chemotherapy. To aid translation of pre-clinical studies, we sought to understand the effects of the tumour growth environment on Chk1 signalling and sensitivity to small molecule Chk1 inhibition. Spheroid culture altered Chk1 signalling to a more xenograft like state but decreased sensitivity to Chk1 inhibition. Growth in low serum did not alter DDR signalling but increased the sensitivity of A2058 and U2OS tumour cells to Chk1 inhibition. An analysis of the expression levels of replication associated proteins identified a correlation between Cdc6 and pChk1 (S296) as well as total Chk1 in xenograft derived samples and between Cdc6 and total Chk1 in anchorage dependent growth derived protein samples. No apparent correlation between Chk1 or Cdc6 expression and sensitivity to Chk1 inhibition in vitro was observed. A database analysis revealed upregulation of CDC6 mRNA expression in tumour compared to normal tissue and a correlation between CDC6 and CHEK1 mRNA expression in human cancers. We suggest that Cdc6 overexpression in human tumours requires a concomitant increase in Chk1 to counterbalance the deleterious effects of origin hyperactivation-induced DNA damage. PMID- 27775085 TI - Effect of location of opening incision on astigmatic correction after small incision lenticule extraction. AB - We compared the visual and refractive outcomes between 2 different incisional sites in small incision lenticule extraction (SMILE) for low myopic astigmatism. This was a contralateral eye study. Consecutive cases that underwent bilateral SMILE surgery were included. Procedures for both eyes were identical apart from the location of opening incision. The incision was set on the temporal side for the right eye (Group 1), while a superior incision was set for the left eye (Group 2). Twenty-nine patients with a mean age of 35.0 +/- 9.6 years were included. Preoperative visual and refractive parameters were comparable between the 2 groups (p > 0.250). At 3 months, the logMAR uncorrected distance visual acuity was 0.074 +/- 0.090 in Group 1 and 0.084 +/- 0.130 in Group 2 (p = 0.861). No difference was found in the postoperative manifest spherical equivalent (p = 0.501) and manifest cylinder (p = 0.178) between the 2 groups. The efficacy index was 0.85 +/- 0.16 in Group 1 and 0.85 +/- 0.20 in Group 2 (p = 0.828). Astigmatic correction was not significantly affected by the location of opening incisions using vector analysis. Our study did not find significant differences in visual and refractive outcomes with temporal or superior opening incision during SMILE surgery. PMID- 27775083 TI - Bacterial mimetics of endocrine secretory granules as immobilized in vivo depots for functional protein drugs. AB - In the human endocrine system many protein hormones including urotensin, glucagon, obestatin, bombesin and secretin, among others, are supplied from amyloidal secretory granules. These granules form part of the so called functional amyloids, which within the whole aggregome appear to be more abundant than formerly believed. Bacterial inclusion bodies (IBs) are non-toxic, nanostructured functional amyloids whose biological fabrication can be tailored to render materials with defined biophysical properties. Since under physiological conditions they steadily release their building block protein in a soluble and functional form, IBs are considered as mimetics of endocrine secretory granules. We have explored here if the in vivo implantation of functional IBs in a given tissue would represent a stable local source of functional protein. Upon intratumoral injection of bacterial IBs formed by a potent protein ligand of CXCR4 we have observed high stability and prevalence of the material in absence of toxicity, accompanied by apoptosis of CXCR4+ cells and tumor ablation. Then, the local immobilization of bacterial amyloids formed by therapeutic proteins in tumors or other tissues might represent a promising strategy for a sustained local delivery of protein drugs by mimicking the functional amyloidal architecture of the mammals' endocrine system. PMID- 27775087 TI - Magnesium diboride coated bulk niobium: a new approach to higher acceleration gradient. AB - Bulk niobium Superconducting Radio-Frequency cavities are a leading accelerator technology. Their performance is limited by the cavity loss and maximum acceleration gradient, which are negatively affected by vortex penetration into the superconductor when the peak magnetic field at the cavity wall surface exceeds the vortex penetration field (Hvp). It has been proposed that coating the inner wall of an SRF cavity with superconducting thin films increases Hvp. In this work, we utilized Nb ellipsoid to simulate an inverse SRF cavity and investigate the effect of coating it with magnesium diboride layer on the vortex penetration field. A significant enhancement of Hvp was observed. At 2.8 K, Hvp increased from 2100 Oe for an uncoated Nb ellipsoid to 2700 Oe for a Nb ellipsoid coated with ~200 nm thick MgB2 thin film. This finding creates a new route towards achieving higher acceleration gradient in SRF cavity accelerator beyond the theoretical limit of bulk Nb. PMID- 27775086 TI - Synergistic effect of sunlight induced photothermal conversion and H2O2 release based on hybridized tungsten oxide gel for cancer inhibition. AB - A highly efficient photochromic hydrogel was successfully fabricated via casting precursor, which is based on amorphous tungsten oxide and poly (ethylene oxide) block-poly (propylene oxide)-block-poly (ethylene oxide). Under simulated solar illumination, the hydrogel has a rapid and controlled temperature increasing ratio as its coloration degree. Localized electrons in the amorphous tungsten oxide play a vital role in absorption over a broad range of wavelengths from 400 nm to 1100 nm, encompassing the entire visible light and infrared regions in the solar spectrum. More importantly, the material exhibits sustainable released H2O2 induced by localized electrons, which has a synergistic effect with the rapid surface temperature increase. The amount of H2O2 released by each film can be tuned by the light irradiation, and the film coloration can indicate the degree of oxidative stress. The ability of the H2O2-releasing gels in vitro study was investigated to induce apoptosis in melanoma tumor cells and NIH 3T3 fibroblasts. The in vivo experimental results indicate that these gels have a greater healing effect than the control in the early stages of tumor formation. PMID- 27775088 TI - Low-temperature-dependent property in an avalanche photodiode based on GaN/AlN periodically-stacked structure. AB - In ultra-high sensitive APDs, a vibrate of temperature might bring a fatal decline of the multiplication performance. Conventional method to realize a temperature-stable APD focuses on the optimization of device structure, which has limited effects. While in this paper, a solution by reducing the carrier scattering rate based on an GaN/AlN periodically-stacked structure (PSS) APD is brought out to improve temperature stability essentially. Transport property is systematically investigated. Compared with conventional GaN homojunction (HJ) APDs, electron suffers much less phonon scatterings before it achieves ionization threshold energy and more electrons occupy high energy states in PSS APD. The temperature dependence of ionization coefficient and energy distribution is greatly reduced. As a result, temperature stability on gain is significantly improved when the ionization happens with high efficiency. The change of gain for GaN (10 nm)/AlN (10 nm) PSS APD from 300 K to 310 K is about 20% lower than that for HJ APD. Additionally, thicker period length is found favorable to ionization coefficient ratio but a bit harmful to temperature stability, while increasing the proportion of AlN at each period in a specific range is found favorable to both ionization coefficient ratio and temperature stability. PMID- 27775090 TI - Electrochemical Li Topotactic Reaction in Layered SnP3 for Superior Li-Ion Batteries. AB - The development of new anode materials having high electrochemical performances and interesting reaction mechanisms is highly required to satisfy the need for long-lasting mobile electronic devices and electric vehicles. Here, we report a layer crystalline structured SnP3 and its unique electrochemical behaviors with Li. The SnP3 was simply synthesized through modification of Sn crystallography by combination with P and its potential as an anode material for LIBs was investigated. During Li insertion reaction, the SnP3 anode showed an interesting two-step electrochemical reaction mechanism comprised of a topotactic transition (0.7-2.0 V) and a conversion (0.0-2.0 V) reaction. When the SnP3-based composite electrode was tested within the topotactic reaction region (0.7-2.0 V) between SnP3 and LixSnP3 (x <= 4), it showed excellent electrochemical properties, such as a high volumetric capacity (1st discharge/charge capacity was 840/663 mA h cm 3) with a high initial coulombic efficiency, stable cycle behavior (636 mA h cm-3 over 100 cycles), and fast rate capability (550 mA h cm-3 at 3C). This layered SnP3 anode will be applicable to a new anode material for rechargeable LIBs. PMID- 27775089 TI - Cell resistance to the Cytolethal Distending Toxin involves an association of DNA repair mechanisms. AB - The Cytolethal Distending Toxin (CDT), produced by many bacteria, has been associated with various diseases including cancer. CDT induces DNA double-strand breaks (DSBs), leading to cell death or mutagenesis if misrepaired. At low doses of CDT, other DNA lesions precede replication-dependent DSB formation, implying that non-DSB repair mechanisms may contribute to CDT cell resistance. To address this question, we developed a proliferation assay using human cell lines specifically depleted in each of the main DNA repair pathways. Here, we validate the involvement of the two major DSB repair mechanisms, Homologous Recombination and Non Homologous End Joining, in the management of CDT-induced lesions. We show that impairment of single-strand break repair (SSBR), but not nucleotide excision repair, sensitizes cells to CDT, and we explore the interplay of SSBR with the DSB repair mechanisms. Finally, we document the role of the replicative stress response and demonstrate the involvement of the Fanconi Anemia repair pathway in response to CDT. In conclusion, our work indicates that cellular survival to CDT induced DNA damage involves different repair pathways, in particular SSBR. This reinforces a model where CDT-related genotoxicity primarily involves SSBs rather than DSBs, underlining the importance of cell proliferation during CDT intoxication and pathogenicity. PMID- 27775091 TI - One-step solvothermal deposition of ZnO nanorod arrays on a wood surface for robust superamphiphobic performance and superior ultraviolet resistance. AB - In the present paper, uniformly large-scale wurtzite-structured ZnO nanorod arrays (ZNAs) were deposited onto a wood surface through a one-step solvothermal method. The as-prepared samples were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetry (TG), and differential thermal analysis (DTA). ZNAs with a diameter of approximately 85 nm and a length of approximately 1.5 MUm were chemically bonded onto the wood surface through hydrogen bonds. The superamphiphobic performance and ultraviolet resistance were measured and evaluated by water or oil contact angles (WCA or OCA) and roll-off angles, sand abrasion tests and an artificially accelerated ageing test. The results show that the ZNA-treated wood demonstrates a robust superamphiphobic performance under mechanical impact, corrosive liquids, intermittent and transpositional temperatures, and water spray. Additionally, the as-prepared wood sample shows superior ultraviolet resistance. PMID- 27775092 TI - Enhanced methane steam reforming activity and electrochemical performance of Ni0.9Fe0.1-supported solid oxide fuel cells with infiltrated Ni-TiO2 particles. AB - Ni0.9Fe0.1 alloy-supported solid oxide fuel cells with NiTiO3 (NTO) infiltrated into the cell support from 0 to 4 wt.% are prepared and investigated for CH4 steam reforming activity and electrochemical performance. The infiltrated NiTiO3 is reduced to TiO2-supported Ni particles in H2 at 650 degrees C. The reforming activity of the Ni0.9Fe0.1-support is increased by the presence of the TiO2 supported Ni particles; 3 wt.% is the optimal value of the added NTO, corresponding to the highest reforming activity, resistance to carbon deposition and electrochemical performance of the cell. Fueled wet CH4 at 100 mL min-1, the cell with 3 wt.% of NTO demonstrates a peak power density of 1.20 W cm-2 and a high limiting current density of 2.83 A cm-2 at 650 degrees C. It performs steadily for 96 h at 0.4 A cm-2 without the presence of deposited carbon in the Ni0.9Fe0.1-support and functional anode. Five polarization processes are identified by deconvoluting and data-fitting the electrochemical impedance spectra of the cells under the testing conditions; and the addition of TiO2 supported Ni particles into the Ni0.9Fe0.1-support reduces the polarization resistance of the processes ascribed to CH4 steam reforming and gas diffusion in the Ni0.9Fe0.1-support and functional anode. PMID- 27775093 TI - 'Artilysation' of endolysin lambdaSa2lys strongly improves its enzymatic and antibacterial activity against streptococci. AB - Endolysins constitute a promising class of antibacterials against Gram-positive bacteria. Recently, endolysins have been engineered with selected peptides to obtain a new generation of lytic proteins, Artilysins, with specific activity against Gram-negative bacteria. Here, we demonstrate that artilysation can also be used to enhance the antibacterial activity of endolysins against Gram-positive bacteria and to reduce the dependence on external conditions. Art-240, a chimeric protein of the anti-streptococcal endolysin lambdaSa2lys and the polycationic peptide PCNP, shows a similar species specificity as the parental endolysin, but the bactericidal activity against streptococci increases and is less affected by elevated NaCl concentrations and pH variations. Time-kill experiments and time lapse microscopy demonstrate that the killing rate of Art-240 is approximately two-fold higher compared to wildtype endolysin lambdaSa2lys, with a reduction in viable bacteria of 3 log units after 10 min. In addition, lower doses of Art-240 are required to achieve the same bactericidal effect. PMID- 27775094 TI - Pharmacokinetic comparison between quercetin and quercetin 3-O-beta-glucuronide in rats by UHPLC-MS/MS. AB - Quercetin is a natural flavonoid widely distributed in human diet and functional foods. Quercetin 3-O-beta-glucuronide (Q3G) is present in wine and some medicinal plants. Quercetin and Q3G may be metabolized from each other in vivo. While quercetin has been the subject of many studies, the pharmacokinetic profiles of quercetin and Q3G (in animals) have not yet been compared. Herein, we prepared a column-based method for rapid isolation of Q3G from Nelumbo nucifera. Then, we developed an UHPLC-MS/MS method to compare the pharmacokinetics of quercetin and Q3G. Our results showed that the plasma concentration-time curves of quercetin and Q3G show two maxima (Tmax1 ~ 0.75 h, Tmax2 ~ 5 h). After oral administration of 100 mg/kg quercetin or 100 mg/kg Q3G in rats, predominantly Q3G was detected in plasma with AUC at 39529.2 +/- 6108.2 mg.h.L-1 or 24625.1 +/- 1563.8 mg.h.L-1, 18-fold higher than quercetin with AUC at 1583.9 +/- 583.3 mg.h.L-1 or 1394.6 +/- 868.1 mg.h.L-1, respectively. After intravenous injection of 10 mg/kg in rats, Q3G showed extensive tissue uptake in kidney (409.2 +/- 118.4 ng/g), liver (166.1 +/- 52.9 ng/g), heart (97.7 +/- 22.6 ng/g), and brain (5.8 +/- 1.2 ng/g). In conclusion, we have shown that Q3G is a major active component in plasma and tissue for oral administration of quercetin or Q3G. PMID- 27775095 TI - Estimating individual optimal sleep duration and potential sleep debt. AB - In this study, we hypothesized that dynamics of sleep time obtained over consecutive days of extended sleep in a laboratory reflect an individual's optimal sleep duration (OSD) and that the difference between OSD and habitual sleep duration (HSD) at home represents potential sleep debt (PSD). We found that OSD varies among individuals and PSD showed stronger correlation with subjective/objective sleepiness than actual sleep time, interacting with individual's vulnerability of sleep loss. Furthermore, only 1 h of PSD takes four days to recover to their optimal level. Recovery from PSD was also associated with the improvement in glycometabolism, thyrotropic activity and hypothalamic pituitary-adrenocortical axis. Additionally, the increase (rebound) in total sleep time from HSD at the first extended sleep would be a simple indicator of PSD. These findings confirmed self-evaluating the degree of sleep debt at home as a useful clinical marker. To establish appropriate sleep habits, it is necessary to evaluate OSD, vulnerability to sleep loss, and sleep homeostasis characteristics on an individual basis. PMID- 27775096 TI - Genetic analysis of innate immunity in Behcet's disease identifies an association with IL-37 and IL-18RAP. AB - Interleukin-1 (IL-1) and the IL-1 receptor (IL-1R) family play an important role in the pathogenesis of inflammatory diseases. This study aimed to investigate the association between single nucleotide polymorphisms (SNP) of IL-1 and IL-1R family genes with Vogt-Koyanagi-Harada (VKH) and Behcet's disease (BD) in Han Chinese. The case-control study was divided into two stages and included 419 VKH cases, 1063 BD cases and 1872 healthy controls. The MassARRAY platform (Sequenom), iPLEX Gold Assay and TaqMan SNP assays were used to score genotypes of 24 SNPs. The expression of IL-37 and IL-18Rap was measured by ELISA and real time PCR in genotyped healthy individuals. A significantly lower frequency of the AG genotype, and a higher frequency of the GG genotype and G allele of IL 37/rs3811047 were observed in BD as compared to controls. AA genotype and A allele frequency of IL-18RAP/rs2058660 was significantly decreased in BD as compared to controls. Functional studies performed in healthy controls showed that rs3811047 AG genotype carriers had a higher IL-37 gene expression in peripheral blood mononuclear cells (PBMCs) than GG carriers. GG carriers showed a higher cytokine expression as compared to AG carriers. No association was detected between the tested SNPs and VKH. PMID- 27775097 TI - Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice. AB - Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates the in vitro and in vivo effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC/CD4+ T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1beta, TGF beta1, IL-23p19 and IL-6). Exposure to CII induced the elevation of mRNAs encoding retinoic acid receptor-related orphan receptor alpha and gammat, which were abolished by pretreatment with P2X7R antagonists. Furthermore, blocking P2X7R signaling abolished the CII-mediated increase in IL-17A. Blockade of P2X7R remarkably inhibited hind paw swelling and ameliorated pathological changes in ankle joint of the collagen-induced arthritis mice. Thus, we demonstrated a novel function for P2X7R signaling in regulating CII-induced differentiation of Th17 cells. P2X7R signaling facilitates the development of the sophisticated network of DC-derived cytokines that favors a Th17 phenotype. PMID- 27775099 TI - Opting out against defection leads to stable coexistence with cooperation. AB - Cooperation coexisting with defection is a common phenomenon in nature and human society. Previous studies for promoting cooperation based on kin selection, direct and indirect reciprocity, graph selection and group selection have provided conditions that cooperators outcompete defectors. However, a simple mechanism of the long-term stable coexistence of cooperation and defection is still lacking. To reveal the effect of direct reciprocity on the coexistence of cooperation and defection, we conducted a simple experiment based on the Prisoner's Dilemma (PD) game, where the basic idea behind our experiment is that all players in a PD game should prefer a cooperator as an opponent. Our experimental and theoretical results show clearly that the strategies allowing opting out against defection are able to maintain this stable coexistence. PMID- 27775098 TI - Clinical Charateristics and Outcome of Pyogenic Liver Abscess with Different Size: 15-Year Experience from a Single Center. AB - The standard therapeutic protocols of pyogenic liver abscess (PLA) have not been well established yet. We investigated the clinical characteristics, disease progression, choices of treatments and outcomes of PLA with different size. 410 cases of patients with PLA were enrolled retrospectively from 2000 to 2014, and were grouped as small abscess (<=5 cm, n = 125), large abscess (5 cm to 10 cm, n = 218) and giant abscess (>10 cm, n = 36). The most common bacteria were Klebsiella pneumonia (22%) and Escherichia coli (11%) by pus culture, and Escherichia coli (36.7%), gram-positive coccus,(36.7%) and Klebsiella pneumonia (33.3%) by blood culture. 115 patients (28.0%) received antibiotics treatment alone, 161 patients (39.3%) received percutaneous drainage (PD) and 134 patients (32.7%) underwent surgical incision and drainage (SD). The size of abscess was correlated with leukocytes increase, albumin decrease, and time duration for body temperature normalization (all p < 0.05). Antibiotics treatment alone, PD and SD was mainly used in patients with small abscess (42.4%), large abscess (44.0%) and giant abscess (47.2%), respectively. For patients with giant abscess, SD group (n = 17) had higher morbidity than PD group (n = 14) (76.4% vs. 35.7%, p = 0.022). PD might achieve the same curative rate as SD in giant abscess, but with less trauma, lower morbidity and shorter hospital stay. PMID- 27775100 TI - Saharan dust inputs and high UVR levels jointly alter the metabolic balance of marine oligotrophic ecosystems. AB - The metabolic balance of the most extensive bioma on the Earth is a controversial topic of the global-change research. High ultraviolet radiation (UVR) levels by the shoaling of upper mixed layers and increasing atmospheric dust deposition from arid regions may unpredictably alter the metabolic state of marine oligotrophic ecosystems. We performed an observational study across the south western (SW) Mediterranean Sea to assess the planktonic metabolic balance and a microcosm experiment in two contrasting areas, heterotrophic nearshore and autotrophic open sea, to test whether a combined UVR * dust impact could alter their metabolic balance at mid-term scales. We show that the metabolic state of oligotrophic areas geographically varies and that the joint impact of UVR and dust inputs prompted a strong change towards autotrophic metabolism. We propose that this metabolic response could be accentuated with the global change as remote-sensing evidence shows increasing intensities, frequencies and number of dust events together with variations in the surface UVR fluxes on SW Mediterranean Sea. Overall, these findings suggest that the enhancement of the net carbon budget under a combined UVR and dust inputs impact could contribute to boost the biological pump, reinforcing the role of the oligotrophic marine ecosystems as CO2 sinks. PMID- 27775104 TI - In situ X-ray photoelectron and Auger electron spectroscopic characterization of reaction mechanisms during Li-ion cycling. AB - The complex nature of Li-ion battery reactions along with their sensitivity to environmental exposure necessitates in situ characterization, particularly for surface sensitive methods. In this work, we demonstrate in situ X-ray photoelectron spectroscopy and in situ Auger electron spectroscopy applied to characterize the evolution of bonding and chemistry during cycling of nanoparticle electrodes. We apply the method to study the conversion reaction associated with Li insertion and extraction from CuO nanoparticle electrodes. This approach circumvents the need for ion sputtering and mechanical erosion, previously required to remove solid electrolyte interphase during ex situ measurements. This allows the elucidation of the changes in Cu oxidation state, during initial Li insertion, without the introduction of artifacts that have caused prior disagreement in the published literature. PMID- 27775103 TI - Formation of continuous and highly permeable ZIF-8 membranes on porous alumina and zinc oxide hollow fibers. AB - Herein, we report the in situ synthesis of ZIF-8 membranes on the external surface of asymmetric ZnO-Al2O3 composite hollow fibers. The prepared ZIF-8 hollow fiber membrane exhibits exceeding performance for hydrogen separation and high reproducibility for an easy scale-up. PMID- 27775102 TI - Imaging plasma membrane phase behaviour in live cells using a thiophene-based molecular rotor. AB - Molecular rotors have emerged as versatile probes of microscopic viscosity in lipid bilayers, although it has proved difficult to find probes that stain both phases equally in phase-separated bilayers. Here, we investigate the use of a membrane-targeting viscosity-sensitive fluorophore based on a thiophene moiety with equal affinity for ordered and disordered lipid domains to probe ordering and viscosity within artificial lipid bilayers and live cell plasma membranes. PMID- 27775105 TI - A macromolecular cyclometalated gold(iii) amphiphile displays long-lived emissive excited state in water: self-assembly and in vitro photo-toxicity. AB - We report an amphiphilic macromolecule containing a cyclometalated gold(iii) complex that self-assembles into nano-sized micelles and also displays a long lived emissive triplet excited state with a lifetime of 84 MUs in degassed water. This amphiphilic AuIII complex exhibits good biocompatibility and activity towards in vitro photo-toxicity, as well as enhanced permeability and retention effects in vivo. PMID- 27775106 TI - Radiosynthesis of SPECT tracers via a copper mediated 123I iodination of (hetero)aryl boron reagents. AB - A general method for the copper mediated nucleophilic 123I-iodination of (hetero)aryl boronic esters and acids has been developed. The broad substrate scope of this radiosynthetic approach allows access to [123I]DPA-713, [123I]IMPY, [123I]MIBG and [123I]IPEB that are four commonly used SPECT radiotracers. Our results infer that aryl boronic reagents can now be employed as common precursors for both fluorine-18 and iodine-123 radiolabelling. PMID- 27775107 TI - Continuous catalytic upgrading of ethanol to n-butanol over Cu-CeO2/AC catalysts. AB - Cu-CeO2/AC catalysts exhibited extraordinary catalytic performance in the upgradation of ethanol to n-butanol. To the best of our knowledge, this is the first report that the highest n-butanol yields of 21.6% and nearly 20% could be achieved over heterogeneous catalysts under mild reaction conditions in batch and fixed-bed reactors, respectively. The high catalytic activity, selectivity and stability of these catalysts could be ascribed to the synergy of Cu, CeO2 and the activated carbon support. PMID- 27775108 TI - Synthesis and coordination ability of a partially silicon based crown ether. AB - The first hybrid crown ether with two adjacent disilane fragments was synthesized through reaction of O(Si2Me4Cl)2 (3) with O(C2H4OH)2. By means of DFT calculations, the complexation ability of 1,2,4,5-tetrasila[12]crown-4 (7) towards Li+ was determined to be considerably higher compared to [12]crown-4. PMID- 27775109 TI - Visual detection of single-nucleotide polymorphisms and DNA methyltransferase based on cation-exchange of CuS nanoparticles and click chemistry of functionalized gold nanoparticles. AB - A novel biosensor was developed based on the cation-exchange of CuS nanoparticles (NPs) and Cu(i)-based click chemistry of functionalized gold nanoparticles (AuNPs). As a proof-of-principle, novel applications of this method as a versatile biosensor for single-nucleotide polymorphisms (SNPs) and DNA methyltransferase (MTase) were presented. PMID- 27775110 TI - Charge transfer process at the Ag/MPH/TiO2 interface by SERS: alignment of the Fermi level. AB - A nanoscale metal-molecule-semiconductor assembly (Ag/4-mercaptophenol/TiO2) has been fabricated over Au nanoparticle (NP) films as a model to study the interfacial charge transfer (CT) effects involved in Ag/MPH/TiO2. Due to the interaction between Au NPs and Ag NPs, some distinct differences occur in the SERS spectra. We also measured the SERS of Ag/MPH (4-mercaptophenol), Ag/MPH/TiO2, and Au/Ag/MPH/TiO2 assemblies at excitation wavelengths of 477, 514, 532, 633, and 785 nm. We found that the changes in the CT process, caused by the introduction of TiO2 and Au, can be reflected in SERS. Then in combination with other detection methods, we proposed a possible CT process involved in the Ag/MPH, Ag/MPH/TiO2, and Au/Ag/MPH/TiO2 assemblies. A Pt/Ag/MPH/TiO2 assembly was also constructed to verify our proposed CT mechanism. This work not only provides more details about CT between metal-molecule-semiconductor interfaces but also aids in constructing nanoscale models to study interfacial problems with the SERS technique. PMID- 27775111 TI - Dynamic nuclear polarisation by thermal mixing: quantum theory and macroscopic simulations. AB - A theory of dynamic nuclear polarisation (DNP) by thermal mixing is suggested based on purely quantum considerations. A minimal 6-level microscopic model is developed to test the theory and link it to the well-known thermodynamic model. Optimal conditions for the nuclear polarization enhancement and effects of inhomogeneous broadening of the electron resonance are discussed. Macroscopic simulations of nuclear polarization spectra displaying good agreement with experiments, involving BDPA and trityl free radicals, are presented. PMID- 27775112 TI - Electrons, excitons and hydrogen bonding: electron-promoted desorption from molecular ice surfaces. AB - Desorption of benzene (C6H6) from thick methanol (CH3OH) and diethyl ether (CH3CH2OCH2CH3) ices during irradiation with 250 eV electrons is reported and compared with our previous work on C6H6 desorption from water (H2O) ice systems. C6H6 electron-promoted desorption (EPD) is seen to be sensitive to the chemical nature of the substrate reflecting both the importance of the excitations localised around the O-atom versus those involving the C-atom; and the role of hydrogen bonding interactions in transporting non-dissociative electronic excitation to the substrate/C6H6 interfaces during the electron irradiation. PMID- 27775113 TI - A comparative study of Ni-Mn layered double hydroxide/carbon composites with different morphologies for supercapacitors. AB - A variety of carbon materials varying from 0D to 2D, i.e. 0D nanoparticles, 1D carbon nanotubes (CNTs) and 2D reduced graphene oxide (rGO) are selected to in situ combine with Ni-Mn layered double hydroxide (LDH) to prepare electrode materials for supercapacitors. Through a simple solution method, hierarchical Ni Mn LDH/carbon composites can be easily fabricated. A comparative study is carried out on the sandwich-like LDH/rGO, flower-like LDH/carbon black, turbostratic structured LDH/CNTs and ternary LDH/CNTs/rGO for their structure, morphology, porous properties and electrochemical performances. The results show that the ternary Ni-Mn LDH/CNTs/rGO composite yields the highest specific capacitance of 1268 F g-1 in 2 M KOH electrolyte and a long lifespan, exhibiting great potential for supercapacitor applications. Meanwhile, investigation on the influence of the cation species of MOH (M = Li+, Na+ or K+) and the alkali concentration of the KOH electrolyte illustrates that increasing the concentration of the KOH electrolyte can benefit the capacitive performance of the electrode and that NaOH shows great advantages as an electrolyte for the Ni-Mn LDH/CNTs/rGO electrode due to its high capacitance and small resistance. PMID- 27775114 TI - Extracting nano-gold from HAuCl4 solution manipulated with electrons. AB - It has been fundamentally important and technologically challenging to elucidate the migration behavior of solute atoms in solvents, which can help to understand the growth of nanoparticles. Recently, ascribed to the booming development of start-of-the-art liquid environmental transmission electron microscopes (LETEMs), it has become possible to disclose, in situ, the phase segregation mechanism of elementary units in a solvent at the nanoscale. In addition, bombardment with an electron beam can induce a locally positive potential, with the application of low-conductive Si3N4 and water in LETEMs. Such merits can enable modification of the dynamic distribution and reductive behavior of the solute ions in water solutions. Herein we report the migration and segregation behaviors of Au atoms in a solvent during real time, by exploiting a charging effect in a dilute HAuCl4 water solution under electron irradiation. As a consequence, the growth kinetics of Au nanoparticles can be successfully controlled with an accelerated kinetics model. Through dynamically capturing the segregation behavior of the hydrated atoms, a resultant size-controlling mechanism is clarified with three cycles of nanoparticle growth behavior. A new insight is consequently gained into microscopically manipulating the hydrothermal synthesis of nanomaterials. PMID- 27775115 TI - Predicted low thermal conductivities in antimony films and the role of chemical functionalization. AB - Chemical functionalization is an effective means of tuning the electronic and crystal structure of a two-dimensional material, but very little is known regarding the correlation between thermal transport and chemical functionalization. Based on the first-principles calculation and an iterative solution of the Boltzmann transport equation, we find that antimonene is a potential excellent thermal material with relatively low thermal conductivity k, and furthermore, chemical functionalization can make this value of k decrease greatly. More interestingly, the origin of the reduction in k is not the anharmonic interaction but the harmonic interaction from the depressed phonon spectrum mechanism, and for some chemical functional atom in halogen, flat modes appearing in the low frequency range play also a key factor in the reduction of k by significantly increasing the three-phonon scattering channels. Our work provides a new view to adjust thermal transport which can benefit thermal material design, and analyzes the reduction mechanism in k from the chemical functionalization of antimonene. PMID- 27775116 TI - Protocol for the purification of protected carbohydrates: toward coupling automated synthesis to alternate-pump recycling high-performance liquid chromatography. AB - Given recent advances in automated oligosaccharide synthesis, analytical techniques that can be coupled to a synthetic framework are needed to not just identify but also purify to homogeneity protected carbohydrate compounds at levels of >=99.5% purity. Herein, an alternate-pump recycling high-performance liquid chromatography (R-HPLC) method has been developed to allow purification of protected carbohydrates at levels of >=99.5% purity. PMID- 27775117 TI - On the origin of the great rigidity of self-assembled diphenylalanine nanotubes. AB - The elastic properties of the nanotubes of self-assembled aromatic dipeptide diphenylalanine are investigated by means of Raman spectroscopy and a mass-in mass 1D model. Analysis of nanotubes' lattice vibrations reveals the essential contribution of the water in the nanochannel core of the tubes to the Young's modulus and high water mobility along the channel. Direct measurements of the Young's modulus performed by nanoindentation confirm the obtained results. PMID- 27775118 TI - The spectral heterogeneity and size distribution of the carbon dots derived from time-resolved fluorescence studies. AB - We performed comprehensive studies on the photoluminescence properties of the carbon dots prepared from citric acid (C-dotsCA) and citric acid + ethylenediamine (C-dotsCA+EDA). The cryogenic experiment confirmed that the excitation dependent fluorescence and the spectral relaxation dynamics of the C dots are associated with the presence of multiple emissive states/species in the C-dots instead of solvation dynamics. Moreover, we also compared the size of the C-dots estimated from the TEM/AFM images and fluorescence anisotropy methods. The experimental results indicate that the fluorescence anisotropy method not only avoids the formation of aggregates during the sample preparation processes, but also selectively detects the size of emissive C-dots in the solution. Therefore, the fluorescence anisotropy method is ideal for studying the size dependent optical properties of the C-dots. PMID- 27775119 TI - Novel metal-free organic dyes possessing fused heterocyclic structural motifs for efficient molecular photovoltaics. AB - Reported herein are six novel metal free organic dyes such as PCA1-PCA3 and PCTA1 PCTA3 featuring fused heterocyclic structural motifs such as phenothiazine and alkylcarbazole. Photophysical/electrochemical properties and nanocrystalline TiO2 based dye-sensitized solar cell performance of the same have been investigated. Electronic distribution within the molecules has been determined through a computational approach. The overall power conversion efficiencies of the devices with the utilization of dyes PCA1-PCA3 and PCTA1-PCTA3 as sensitizers ranges between 4.67 and 8.08%. The novel dyes possessing cyanoacrylic acid as electron acceptor, PCA1-PCA3, exhibit higher power conversion efficiency, short-circuit current, open-circuit voltage, and electron lifetime those with thioxothiazolidinylacetic acid, PCTA1-PCTA3, as the same. Of the devices fabricated by employing the new metal-free organic sensitizers, that with the dye PCA2 exerted a power conversion efficiency (PCE, eta) of 8.08% with a short circuit current density (JSC) of 16.45 mA cm-2, an open circuit voltage (VOC) of 735 mV and a fill factor (ff) of 0.68; this PCE is the highest amongst the devices fabricated. PMID- 27775120 TI - High temperature electrical energy storage: advances, challenges, and frontiers. AB - With the ongoing global effort to reduce greenhouse gas emission and dependence on oil, electrical energy storage (EES) devices such as Li-ion batteries and supercapacitors have become ubiquitous. Today, EES devices are entering the broader energy use arena and playing key roles in energy storage, transfer, and delivery within, for example, electric vehicles, large-scale grid storage, and sensors located in harsh environmental conditions, where performance at temperatures greater than 25 degrees C are required. The safety and high temperature durability are as critical or more so than other essential characteristics (e.g., capacity, energy and power density) for safe power output and long lifespan. Consequently, significant efforts are underway to design, fabricate, and evaluate EES devices along with characterization of device performance limitations such as thermal runaway and aging. Energy storage under extreme conditions is limited by the material properties of electrolytes, electrodes, and their synergetic interactions, and thus significant opportunities exist for chemical advancements and technological improvements. In this review, we present a comprehensive analysis of different applications associated with high temperature use (40-200 degrees C), recent advances in the development of reformulated or novel materials (including ionic liquids, solid polymer electrolytes, ceramics, and Si, LiFePO4, and LiMn2O4 electrodes) with high thermal stability, and their demonstrative use in EES devices. Finally, we present a critical overview of the limitations of current high temperature systems and evaluate the future outlook of high temperature batteries with well controlled safety, high energy/power density, and operation over a wide temperature range. PMID- 27775122 TI - Chemoselective reduction of carboxamides. AB - The reduction of amides gives access to a wide variety of important compounds such as amines, imines, enamines, nitriles, aldehydes and alcohols. The chemoselective transformation into these functional groups is challenging due to the intrinsic stability of the amide bond; nevertheless, the ability to reduce highly stable carboxamides selectively in the presence of sensitive functional groups is of high synthetic value for academic and industrial chemists. Hydride based reagents such as LiAlH4 or diboranes are today the most commonly used compounds for amide reductions, and apart from the substantial amount of waste generated using these methods, they lack tolerance to most other functional groups. This tutorial review provides an overview of the recent progress made in the development of chemoselective protocols for amide reduction and gives an insight to their advantages and drawbacks. PMID- 27775123 TI - Narrow-band red emitting phosphor BaTiF6:Mn4+: preparation, characterization and application for warm white LED devices. AB - As a new class of non-rare-earth red phosphors for high-efficiency warm white light-emitting diodes (white LEDs), Mn4+ ion activated fluoride compounds have been extensively investigated recently and hold the potential to supersede commercial rare earth doped nitride phosphors. Herein, a series of Mn4+ ions doped BaTiF6 phosphors have been prepared via the hydrothermal route using citric acid as a surfactant. After a systematic investigation, we illustrate the effects of reaction time, nominal concentration of HF solution, and reaction temperature on the luminescence performance of the phosphor. The BaTiF6:Mn4+ phosphor generates narrow red emission, which is highly perceived by the human eyes and leads to excellent chromatic saturation of red emission spectra. Simultaneously, concentration and thermal quenching are investigated systematically, and the quenching mechanisms are elucidated in detail. Employing BaTiF6:Mn4+ as a red phosphor, we fabricate a high-performance white LED with low correlated color temperature of 3974 K, high color rendering index of 90.6 and luminous efficacy of 132.54 lm W-1. Based on the improvement in correlated color temperature and color rendering index, the BaTiF6:Mn4+ red phosphor supplements the deficiency of LEDs fabricated by combining blue chips and only YAG:Ce3+, which suggests that it is a promising commercial red phosphor in warm white LEDs. PMID- 27775124 TI - K3[Mo2(SNO5)4Cl]3[Mo2(SNO5)4]: the first example of a heterometallic extended metal atom node (HEMAN). AB - We present the synthesis, structure, and electrochemistry of K3[Mo2(SNO5)4Cl]3[Mo2(SNO5)4] (1, HSNO5 = monothiosuccinimide), the first example of a heterometallic extended metal atom node (HEMAN). The HEMAN consists of two perpendicular, intersecting lines of metal atoms formed by three [Mo2(SNO5)4Cl]- units and one [Mo2(SNO5)4] unit tethered together by K+ ions. PMID- 27775126 TI - Temperature dependent charge transport across tunnel junctions of single molecules and self-assembled monolayers: a comparative study. AB - In this work we present a comparative study of the temperature behavior of charge current in both single-molecule transistors and self-assembled monolayer-based tunnel junctions with symmetrical molecules of alkanethiolates functionalized with a ferrocene (Fc) unit. The Fc unit is separated from the electrodes with two equal alkyl chains of enough length to ensure weak coupling of the Fc unit with the electrodes. These junctions do not rectify charge current and display exponential dependence with temperature with moderate slopes, which can be directly associated to the thermal broadening of the electronic occupation Fermi distribution in the electrodes. The capability to electrically gate the molecular frontier orbital of the Fc (here the highest occupied molecular orbital, HOMO) in the single-molecule transistor, not possible in the two-terminal SAM-based junctions, allows for a detailed comparative between the two classes of junctions. Our findings demonstrate that, although most transport characteristics are equivalent, collective effects arising from interactions between molecules in the self-assembled monolayer greatly affect the energetics of SAM-based junctions, resulting in a bias-independent tunnel current, contrary to the case of the single-molecule junction and as expected from the thermal broadening of the electronic occupation around the Fermi energy in the electrodes. PMID- 27775125 TI - Bioactive and functional properties of sour cherry juice (Prunus cerasus). AB - Sour cherry juice (Prunus cerasus) is consumed as a nutritional supplement claiming health effects. The aim of the study was to evaluate the different properties of sour cherry juice in terms of antioxidant activity and inhibition of target enzymes in the central nervous system and diabetes. The content of polyphenols and anthocyanins was quantified. Different experiments were carried out to determine the radical scavenging properties of the juice. The activity of sour cherry juice was also tested in physiological relevant enzymes of the central nervous system (acetylcholinesterase, monoamine oxidase A, tyrosinase) and others involved in type 2 diabetes (alpha-glucosidase, dipeptidyl peptidase 4). Sour cherry juice showed significant antioxidant effects but the activity of the lyophilized juice was not superior to compounds such as ascorbic, gallic or chlorogenic acid. Furthermore, sour cherry juice and one of its main polyphenols known as chlorogenic acid were also able to inhibit monoamine oxidase A and tyrosinase as well as enzymes involved in diabetes. This is the first time that sour cherry juice is reported to inhibit monoamine oxidase A, alpha-glucosidase and dipeptidyl peptidase-4 in a dose dependent manner, which may be of interest for human health and the prevention of certain diseases. PMID- 27775127 TI - Composite foods: from structure to sensory perception. AB - An understanding of the effect of structural features of foods in terms of specific sensory attributes is necessary to design foods with specific functionalities, such as reduced fat or increased protein content, and increased feeling of satiety or liking. Although the bulk rheological properties of both liquid and solid foods can be related to textural attributes such as thickness and firmness, they do not always correlate to more complex sensory attributes, such as creamy and smooth. These attributes are often a result of different contributions, including lubrication aspects and interactions between food and components present in the oral cavity. In this review, the different contributions for a variety of composite foods, such as dispersions, emulsions and emulsion-filled gels, are discussed. The rheological properties are discussed in relation to specific structural characteristics of the foods, which are then linked to lubrication aspects and sensory perception. PMID- 27775128 TI - Regioselective oxidation and metalation of meso-unsubstituted azuliporphyrins. AB - Azuliporphyrins are intriguing porphyrin analogues that incorporate an azulene ring in place of a pyrrolic unit. This system undergoes regioselective oxidation reactions and favors the formation of stable organometallic derivatives. Reaction of meso-unsubstituted azuliporphyrins with Co2(CO)8 or CoCl2.6H2O gave 21 oxyazuliporphyrins, while Cu(OAc)2 produced the corresponding copper(ii) complexes. Treatment of an oxyazuliporphyrin with Ni(OAc)2 or Pd(OAc)2 afforded analogous nickel(ii) and palladium(ii) derivatives. Silver(i) acetate in pyridine reacted with azuliporphyrins to give moderate yields of silver(iii) benzocarbaporphyrins, and the prevalence of structures with a formyl moiety at the sterically crowded 21-position suggested that the ring contraction reactions were triggered in part by intramolecular attack from an axial peroxide ligand. Related thiaazuliporphyrins reacted with palladium(ii) acetate to give palladium(ii) benzothiacarbaporphyrins but this chemistry did not give rise to structures with 21-formyl groups, suggesting that the ring contraction reactions occurred by a different mechanistic pathway. These results demonstrate the existence of a rich tapestry of oxidation and metalation reactions for azuliporphyrin systems. PMID- 27775129 TI - Oral administration of green algae, Euglena gracilis, inhibits hyperglycemia in OLETF rats, a model of spontaneous type 2 diabetes. AB - In the present study, the effects of Euglena and paramylon on hyperglycemia were examined in Otsuka Long-Evans Tokushima fatty (OLETF; type 2 diabetes mellitus model) rats. OLETF rats were fed an AIN-93 M diet containing cellulose, Euglena, or paramylon for 10 weeks. Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic controls. An oral glucose-tolerance test (OGTT) was performed at 0 and 10 weeks. OLETF control rats were obese because of bulimia and showed abdominal fat accumulation and hyperglycemia. Euglena supplementation improved hyperglycemia and decreased food intake, body weight gain, and abdominal fat. However, there were no changes in the paramylon-supplemented group compared to the OLETF control group. Triglyceride concentrations in the serum and liver were lower in Euglena-supplemented rats than in OLETF control rats. There was a correlation between hepatic triglyceride concentration and the area under the curve (AUC) of OGTT at 10 weeks. This suggests that the improvement in glycemic control in the Euglena-supplemented group may depend on substances other than paramylon present in Euglena. PMID- 27775130 TI - Acid-catalysed intramolecular addition of beta-ketoesters to 1,3-dienes. AB - 1,3-Dienyl beta-keto esters are cyclised into bicyclolactones using the Bi(OTf)3/TfOH catalytic system. This reaction represents a rare case of simultaneous C-C and C-O bond formation at positions 1 and 3 of a 1,3-diene. Application to the synthesis of ramulosin is presented. PMID- 27775132 TI - High-sensitivity imaging with lateral resonance mode atomic force microscopy. AB - In the operation of a dynamic mode atomic force microscope, a micro-fabricated rectangular cantilever is typically oscillated at or near its mechanical resonance frequency. Lateral bending resonances of cantilevers are rarely used because the resonances are not expected to be detected by the beam-deflection method. In this work, we found that micro-cantilevers with a large tip produced an out-of-plane displacement in lateral resonance (LR), which could be detected with the beam-deflection method. Finite-element analysis indicated that the presence of a large tip is the major source of the out-of-plane coupling for the LR. We also imaged a heterogeneous sample by operating a cantilever in LR, torsional resonance, and tapping modes. LR mode yielded a small deformation and noise level in the height maps as well as a high contrast and small noise level in the phase maps. LR mode also had a resonance frequency that was orders of magnitude higher than that of tapping mode. Operation with LR mode may have the benefits of high-speed scanning, high-sensitivity imaging, and mapping of in plane mechanical properties of the sample surface. In general, LR mode may become a powerful new atomic force microscopy technique for characterizing sample materials. PMID- 27775133 TI - Characteristic single glucosinolates from Moringa oleifera: Induction of detoxifying enzymes and lack of genotoxic activity in various model systems. AB - Leaves of Moringa oleifera are used by tribes as biological cancer medicine. Scientific investigations with M. oleifera conducted so far have almost exclusively used total plant extracts. Studies on the activity of single compounds are missing. Therefore, the biological effects of the two main aromatic multi-glycosylated glucosinolates of M. oleifera were investigated in the present study. The cytotoxic effects of M. oleifera glucosinolates were identified for HepG2 cells (NRU assay), for V79-MZ cells (HPRT assay, SCE assay), and for two Salmonella typhimurium strains (Ames test). Genotoxic effects of these glucosinolates were not observed (Ames test, HPRT assay, and SCE assay). Reporter gene assays revealed a significant increase in the ARE-dependent promoter activity of NQO1 and GPx2 indicating an activation of the Nrf2 pathway by M. oleifera glucosinolates. Since both enzymes can also be induced via activation of the AhR, plasmids containing promoters of both enzymes mutated in the respective binding sites (pGL3enh-hNQO1-ARE, pGL3enh-hNQO1-XRE, pGL3bas-hGPX2-mutARE, pGL3bas-hGPX2-mutXRE) were transfected. Analyses revealed that the majority of the stimulating effects was mediated by the ARE motif, whereas the XRE motif played only a minor role. The stimulating effects of M. oleifera glucosinolates could be demonstrated both at the transcriptional (reporter gene assay, real time PCR) and translational levels (enzyme activity) making them interesting compounds for further investigation. PMID- 27775135 TI - Single-molecule electrochemistry in nanochannels: probing the time of first passage. AB - The diffusive mass transport of individual redox molecules was probed experimentally in microfabricated nanogap electrodes. The residence times for molecules inside a well-defined detection volume were extracted and the resulting distribution was compared with quantitative analytical predictions from random walk theory for the time of first passage. The results suggest that a small number of strongly adsorbing sites strongly influence mass transport at trace analyte levels. PMID- 27775136 TI - Dendrimer solutions: a Monte Carlo study. AB - We study the conformational properties of dendrimers with flexible spacers in solutions over a wide range of concentrations from dilute solutions to melts. By combining large scale computer simulations using the bond fluctuation model with scaling arguments we identify the semi-dilute regime of dendrimers which is controlled by the concentration behavior of the linear spacers. Associated with this observation we find that the decrease in the size of flexible dendrimers is accompanied by increasing interpenetration between the molecules with increasing concentration of the solution. In the melt state we show that the size of individual dendrimers follows the scaling prediction for isolated dendrimers at the theta-point rather than that of collapsed dendrimers. The pair correlation functions between the centers of dendrimers indicate that for short spacers dendrimer solutions retain the morphological characteristics of simple liquids. For long spacers the functions reveal high penetration of neighboring dendrimers in the melt state. Our studies show that flexible dendrimers in solution can be understood with arguments similar to those of linear polymers. The role of generation is to influence the particular form of the crossover-function. PMID- 27775138 TI - Spinning micropipette liquid emulsion generator for single cell whole genome amplification. AB - Many on-chip approaches that use flow-focusing to pinch the continuous aqueous phase into droplets have become the most popular methods that provide monodisperse emulsion droplets. However, not every lab can easily adapt a microfluidic workflow into their familiar protocols. We develop an off-chip approach, spinning micro-pipette liquid emulsion (SiMPLE) generator, to produce highly stable monodisperse water-in-oil emulsions using a moving micropipette to disperse the aqueous phase in an oil-filled microcentrifuge tube. This method provides a simple way to produce picoliter-size droplets in situ with no dead volume during emulsification. With SiMPLE, single-cell emulsion whole genome amplification was performed to demonstrate that this novel method can seamlessly be integrated with experimental operations and supplies that most researchers are familiar with. The SiMPLE generator has effectively lowered the technical difficulties in applications relying on emulsion droplets. PMID- 27775140 TI - Highly enantioselective synthesis of spirocyclopropyloxindoles via a Rh(ii) catalyzed asymmetric cyclopropanation reaction. AB - A chiral dirhodium(ii) carboxylate complex catalyzed enantioselective cyclopropanation reaction of N-Boc diazooxindoles with olefins, including aryl, alkyl, cyclic, and disubstituted olefins, under mild conditions is described. This reaction provides complementary access to the corresponding chiral spirocyclopropyloxindole products in good to high yields with good to excellent enantioselectivities. PMID- 27775139 TI - Separation of nanoparticles by a nano-orifice based DC-dielectrophoresis method in a pressure-driven flow. AB - A novel DC-dielectrophoresis (DEP) method employing a pressure-driven flow for the continuous separation of micro/nano-particles is presented in this paper. To generate the DEP force, a small voltage difference is applied to produce a non uniformity of the electric field across a microchannel via a larger orifice of several hundred microns on one side of the channel wall and a smaller orifice of several hundred nanometers on the opposite channel wall. The particles experience a DEP force when they move with the flow through the vicinity of the small orifice, where the strongest electrical field gradient exists. Experiments were conducted to demonstrate the separation of 1 MUm and 3 MUm polystyrene particles by size by adjusting the applied electrical potentials. In order to separate smaller nanoparticles, the electrical conductivity of the suspending solution is adjusted so that the polystyrene nanoparticles of a given size experience positive DEP while the polystyrene nanoparticles of another size experience negative DEP. Using this method, the separation of 51 nm and 140 nm nanoparticles and the separation of 140 nm and 500 nm nanoparticles were demonstrated. In comparison with the microfluidic DC-DEP methods reported in the literature which utilize hurdles or obstacles to induce the non-uniformity of an electric field, a pair of asymmetrical orifices on the channel side walls is used in this method to generate a strong electrical field gradient and has advantages such as capability of separating nanoparticles, and locally applied lower electrical voltages to minimize the Joule heating effect. PMID- 27775141 TI - Impurity effects on solid-solid transitions in atomic clusters. AB - We use the harmonic superposition approach to examine how a single atom substitution affects low-temperature anomalies in the vibrational heat capacity (CV) of model nanoclusters. Each anomaly is linked to competing solidlike "phases", where crossover of the corresponding free energies defines a solid solid transition temperature (Ts). For selected Lennard-Jones clusters we show that Ts and the corresponding CV peak can be tuned over a wide range by varying the relative atomic size and binding strength of the impurity, but excessive atom size mismatch can destroy a transition and may produce another. In some tunable cases we find up to two additional CV peaks emerging below Ts, signalling one- or two-step delocalisation of the impurity within the ground-state geometry. Results for Ni74X and Au54X clusters (X = Au, Ag, Al, Cu, Ni, Pd, Pt, Pb), modelled by the many-body Gupta potential, further corroborate the possibility of tuning, engineering, and suppressing finite-system analogues of a solid-solid transition in nanoalloys. PMID- 27775143 TI - Nickel hydroxide nanosheet membranes with fast water and organics transport for molecular separation. AB - Two-dimensional nanosheets of late show great promise as novel materials for size selective separation membranes of high efficiency. Herein, we demonstrate a novel laminated nanofiltration membrane for fast water purification and organic solvent nanofiltration using the 1 nm-thick and 50 nm-wide nickel hydroxide nanosheets that are facilely prepared by a green chemistry method. The resulting membranes exhibit uniform and flectional two-dimensional laminated structure. With about 1 nm high laminated channels, they allow super-fast transport of water and organic solvents. The water and organic fluxes are three orders of magnitude higher than commercially available polymeric nanofiltration membranes. In addition, the membranes have high retention for organic dyes in aqueous and organic solutions. Typically, the 3.18 MUm-thick membrane with the molecular weight cut-off of 328 g mol-1 has an outstanding pure water flux of 99 L m-2 h-1 bar-1 and up to 97% rejection for direct yellow dye molecules. The newly developed nickel hydroxide nanosheets and the subsequent membranes have great potential application in water purification, organic solvent filtration and electronic devices. PMID- 27775144 TI - Correction: Stereoselective synthesis of (-)-desethyleburnamonine, (-) vindeburnol and (-)-3-epitacamonine: observation of a substrate dependent diastereoselectivity reversal of an aldol reaction. AB - Correction for 'Stereoselective synthesis of (-)-desethyleburnamonine, (-) vindeburnol and (-)-3-epitacamonine: observation of a substrate dependent diastereoselectivity reversal of an aldol reaction' by Pravat Mondal et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c6ob01438k. PMID- 27775146 TI - Wild Fragaria vesca L. fruits: a rich source of bioactive phytochemicals. AB - Wild Fragaria vesca L. fruits were studied regarding nutritional and phytochemical compounds, and also antioxidant, antibacterial and biofilm formation inhibition activities. The fruits are good sources of carbohydrates (e.g., sucrose), soluble dietary fiber and polyunsaturated fatty acids, mainly linoleic and linolenic acids, as well as other components such as citric and succinic acids, and vitamins B9 and E (mainly gamma-tocopherol). Significant amounts of soluble sugars, citric acid and some amounts of ascorbic acid, vitamins B9 and E (only alpha-tocopherol) were found also in the infusions. The hydromethanolic extracts revealed higher amounts of phenolic compounds, mainly ellagic acid derivatives and dihydroflavonol taxifolin-3-O-arabinofuranoside. Consistently, these extracts also showed higher antioxidant and antibacterial activities than the infusions, and were able to inhibit the formation of bacterial biofilms. Despite the lower content of bioactive compounds in the infusions compared to the fruits, both forms could be potentially applied in functional foods and/or nutraceuticals/pharmaceutical formulations. PMID- 27775145 TI - Loading of an anti-cancer drug into mesoporous silica nano-channels and its subsequent release to DNA. AB - Mesoporous silica nano-channel (MCM-41) based molecular switching of a biologically important anticancer drug, namely, ellipticine (EPT) has been utilized to probe its efficient loading onto MCM-41, and its subsequent release to intra-cellular biomolecules, like DNA. By exploiting various spectroscopic techniques (like, steady state fluorescence, time-resolved fluorescence and circular dichroism), it has been shown that EPT can be easily translocated from MCM-41 to DNA without using any external stimulant. Blue emission of EPT in a polar aprotic solvent, i.e., dichloromethane (DCM), completely switches to green upon loading inside MCM-41 due to the conversion from a neutral to a protonated form of the drug inside nano-pores. Powder X-ray diffraction (PXRD), N2 gas adsorption and confocal fluorescence microscopy results confirm the adsorption of EPT inside the nano-pores of MCM-41. Here, the lysozyme (Lyz) protein has been utilized as a pore blocker of MCM-41 in order to prevent premature drug release. Interestingly, EPT is released to DNA even from the EPT-MCM-Lyz composite system, and results in intensification of green fluorescence. Electron microscopy results reveal the formation of a distinctive garland kind of morphology involving MCM-41 and DNA probably through non-covalent interactions, and this is believed to be responsible for the DNA assisted release of drug molecules from silica nano pores. Confocal laser scanning microscopy (CLSM) imaging revealed that EPT-MCM is successfully internalized into the HeLa cervical cancer cells and localized into the nucleus. Cell viability assay results infer that EPT-MCM and EPT-MCM-Lyz showed much improved efficacy in HeLa cancer cells compared to free ellipticine. PMID- 27775147 TI - Systematic XAS study on the reduction and uptake of Tc by magnetite and mackinawite. AB - The mechanisms for the reduction and uptake of Tc by magnetite (Fe3O4) and mackinawite (FeS) are investigated using X-ray absorption spectroscopy (XANES and EXAFS), in combination with thermodynamic calculations of the Tc/Fe systems and accurate characterization of the solution properties (pHm, pe, [Tc]). Batch sorption experiments were performed under strictly anoxic conditions using freshly prepared magnetite and mackinawite in 0.1 M NaCl solutions with varying initial Tc(vii) concentrations (2 * 10-5 and 2 * 10-4 M) and Tc loadings (400-900 ppm). XANES confirms the complete reduction of Tc(vii) to Tc(iv) in all investigated systems, as predicted from experimental (pHm + pe) measurements and thermodynamic calculations. Two Tc endmember species are identified by EXAFS in the magnetite system, Tc substituting for Fe in the magnetite structure and Tc-Tc dimers sorbed to the magnetite {111} faces through a triple bond. The sorption endmember is favoured at higher [Tc], whereas incorporation prevails at low [Tc] and less alkaline pH conditions. The key role of pH in the uptake mechanism is interpreted in terms of magnetite solubility, with higher [Fe] and greater recrystallization rates occurring at lower pH values. A TcSx-like phase is predominant in all investigated mackinawite systems, although the contribution of up to 20% of TcO2.xH2O(s) (likely as surface precipitate) is observed for the highest investigated loadings (900 ppm). These results provide key inputs for an accurate mechanistic interpretation of the Tc uptake by magnetite and mackinawite, so far controversially discussed in the literature, and represent a highly relevant contribution to the investigation of Tc retention processes in the context of nuclear waste disposal. PMID- 27775148 TI - Neurobehaviour at term-equivalent age and neurodevelopmental outcomes at 2 years in infants born moderate-to-late preterm. AB - AIM: To examine the association between newborn neurobehavioural assessments and neurodevelopmental outcomes at 2 years in infants born moderate-to-late preterm (MLPT). METHOD: Two-hundred and one infants born MLPT (born 32-36+6 wks' gestation) were assessed with the Hammersmith Neonatal Neurological Examination (HNNE) and NICU Network Neurobehavioral Scale (NNNS), with suboptimal performance defined as scores lower than the 10th centile. Development was assessed at 2 years corrected age with the Bayley Scales of Infant and Toddler Development 3rd Edition, with delay defined as scores less than 1 standard deviation (SD) below the mean. The relationships between neurobehaviour at term and Bayley-III cognitive, language, and motor scales at 2 years were examined using linear regression. RESULTS: Increased odds for cognitive delay were associated with suboptimal HNNE total scores (odds ratio [OR] 2.66; 95% confidence interval [CI] 1.14-6.23, p=0.020) and suboptimal NNNS excitability (OR 3.01; 95% CI 1.33-6.82, p=0.008) and lethargy (OR 4.05; 95% CI 1.75-9.31, p=0.001) scores. Suboptimal lethargy scores on the NNNS were associated with increased odds of language (OR 5.64; 95% CI 1.33-23.85, p=0.019) and motor delay (OR: 6.86; 95% CI 1.64-28.71, p=0.08). INTERPRETATION: Suboptimal performance on specific aspects of newborn neurobehavioural assessments is associated with neurodevelopmental delay at 2 years in children born MLPT. PMID- 27775149 TI - Amitriptyline Dose and Treatment Outcomes in Specialty Headache Practice: A Retrospective Cohort Study. AB - OBJECTIVE: To characterize treatment patterns and real world outcomes in headache patients treated with amitriptyline in an academic headache center. DESIGN AND METHODS: A retrospective chart review identified 178 patients in our center who were given a new prescription for amitriptyline in treatment of headache, and who were seen in follow-up within one year. Charts were reviewed to identify dosing patterns (initial and maximum dose) and persistence, patient-reported headache benefit, and reported side effects. Variables assessed in relation to medication use were comorbid psychiatric disease, headache characteristics, and prior use of a preventive medication. RESULTS: We followed patients for an average of 6.5 months. Initial and maximum prescribed amitriptyline doses were characterized as: "very low" (<=10 mg daily), "low" (11-25 mg daily), and "traditional" (>=25 mg daily). The initial dose of amitriptyline ranged from 2.5 to 50 mg daily, though most patients were started on a dose of 10 mg daily (112/178, 63%). Approximately 3/4 of the patients were found to have improvement (134/178) and 85% (129/151) were still taking amitriptyline at the last follow-up appointment. Maximum dosing ranged from 2.5 to 100 mg daily with most patients taking 10-25 mg (86/146, 58%). The most commonly reported adverse effect was daytime fatigue (17/151, 11%). There did not appear to be any effect from gender, ethnicity, race, diagnosis of sleep apnea, chronicity of migraine, presence of aura on our outcome measures. CONCLUSION: Our study supports the common clinical practice of using low doses of amitriptyline to treat chronic headache disorders and suggests that it was effective and well tolerated at doses lower than those used in many clinical trials. Use of low dosage amitriptyline may also improve medication persistence, an important clinical consideration in the management of this common and chronic condition. A subgroup of patients may experience a dramatic benefit from amitriptyline and this could warrant further investigation. PMID- 27775150 TI - Integrated process design for biocatalytic synthesis by a Leloir Glycosyltransferase: UDP-glucose production with sucrose synthase. AB - Nucleotide sugar-dependent ("Leloir") glycosyltransferases (GTs), represent a new paradigm for the application of biocatalytic glycosylations to the production of fine chemicals. However, it remains to be shown that GT processes meet the high efficiency targets of industrial biotransformations. We demonstrate in this study of uridine-5'-diphosphate glucose (UDP-glc) production by sucrose synthase (from Acidithiobacillus caldus) that a holistic process design, involving coordinated development of biocatalyst production, biotransformation, and downstream processing (DSP) was vital for target achievement at ~100 g scale synthesis. Constitutive expression in Escherichia coli shifted the recombinant protein production mainly to the stationary phase and enhanced the specific enzyme activity to a level (~480 U/gcell dry weight ) suitable for whole-cell biotransformation. The UDP-glc production had excellent performance metrics of ~100 gproduct /L, 86% yield (based on UDP), and a total turnover number of 103 gUDP-glc /gcell dry weight at a space-time yield of 10 g/L/h. Using efficient chromatography-free DSP, the UDP-glc was isolated in a single batch with >=90% purity and in 73% isolated yield. Overall, the process would allow production of ~0.7 kg of isolated product/L E. coli bioreactor culture, thus demonstrating how integrated process design promotes the practical use of a GT conversion. Biotechnol. Bioeng. 2017;114: 924-928. (c) 2016 Wiley Periodicals, Inc. PMID- 27775151 TI - Collagen and collagen-chondroitin sulfate scaffolds with uniaxially aligned pores for the biomimetic, three dimensional culture of trabecular meshwork cells. AB - Glaucoma is a disease in which damage to the optic nerve leads to progressive, irreversible vision loss. The intraocular pressure (IOP) is the only modifiable risk factor for glaucoma and its lowering is considered a useful strategy for preventing or slowing down the progression of glaucomatous neuropathy. Elevated intraocular pressure associated with glaucoma is due to increased aqueous humor outflow resistance, primarily through the trabecular meshwork (TM) of the eye. Current in vitro models of the trabecular meshwork are oversimplified and do not capture the organized and complex three-dimensional nature of this tissue that consists primarily of collagen and glycoasaminoglycans. In this work, collagen and collagen-chondroitin sulfate (CS) scaffolds were fabricated via unidirectional freezing and lyophilization to induce the formation of aligned pores. Scaffolds were characterized by scanning electron microscopy, dynamic mechanical analysis, and a chondroitin sulfate quantification assay. Scaffold characterization confirmed the formation of aligned pores, and also that the CS was leaching out of the scaffolds over time. Primary porcine trabecular meshwork (TM) cells were seeded onto the surface of scaffolds and their gene expression, proliferation, viability, migration into the scaffolds, and morphology were examined. The TM cells were viable and proliferated 2 weeks after seeding. The cells migrated down into the internal scaffold structure and their morphology reflected the topography and alignment of the scaffold structure. This work is a promising step toward the development of a three dimensional in vitro model of the TM that can be used for testing of glaucoma pharmacological agents in future experimentation and to better our understanding of the trabecular meshwork and its complex physiology. Biotechnol. Bioeng. 2017;114: 915-923. (c) 2016 Wiley Periodicals, Inc. PMID- 27775152 TI - On the role of dominance and nurturance in the confluence model: A person centered approach to the prediction of sexual aggression. AB - Malamuth's (1998) confluence model holds that the combination of hostile masculinity, impersonal sexuality, and the constellation of high dominance and low nurturance plays a crucial role in explaining men's sexual aggression against women. Most studies on the confluence model concentrate on hostile masculinity and impersonal sexuality rather than dominance and nurturance. Using a person centered approach, we investigated whether sexual aggressive men could be better identified in a sample of 692 men when not only hostile masculinity and impersonal sexuality but also dominance and nurturance were used as indicators in a latent profile analysis. Regardless of whether dominance and nurturance were considered or not, latent profile analyses revealed a high-risk group, which showed higher sexual aggression than other groups. In both cases, the sensitivity (i.e., the proportion of sexually aggressive men correctly assigned to the high risk group) was low (33% and 31%, respectively) but increased substantially for the identification of severe sexual aggression. The positive prediction value, however, increased from 68% to 78% when dominance and nurturance were considered as predictor variables in addition to hostile masculinity and impersonal sexuality, indicating that more men assigned to the high-risk group were indeed sexually aggressive. These results demonstrate the power of the confluence model for identifying sexually aggressive men from a person-centered perspective. They also point to the necessity of expanding this perspective by considering further (e.g., situational) risk factors, which have previously been identified as predicting sexually aggressive behavior in men. Aggr. Behav. 43:251-262, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775153 TI - Ethylene and nitric oxide interact to regulate the magnesium deficiency-induced root hair development in Arabidopsis. AB - Nitric oxide (NO) and ethylene respond to biotic and abiotic stresses through either similar or independent processes. This study examines the mechanism underlying the effects of NO and ethylene on promoting root hair development in Arabidopsis under magnesium (Mg) deficiency. The interaction between NO and ethylene in the regulation of Mg deficiency-induced root hair development was investigated using NO- and ethylene-related mutants and pharmacological methods. Mg deficiency triggered a burst of NO and ethylene, accompanied by a stimulated development of root hairs. Interestingly, ethylene facilitated NO generation by activation of both nitrate reductase and nitric oxide synthase-like (NOS-L) in the roots of Mg-deficient plants. In turn, NO enhanced ethylene synthesis through stimulating the activities of 1-aminocyclopropane-1-carboxylate (ACC) oxidase and ACC synthase (ACS). These two processes constituted an NO-ethylene feedback loop. Blocking either of these two processes inhibited the stimulation of root hair development under Mg deficiency. In conclusion, we suggest that Mg deficiency increases the production of NO and ethylene in roots, each influencing the accumulation and role of the other, and thus these two signals interactively regulate Mg deficiency-induced root hair morphogenesis. PMID- 27775154 TI - Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression. AB - BACKGROUND: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). METHODS: A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. RESULTS: The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. CONCLUSIONS: These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775155 TI - Recent Developments of Hydrazide/Hydrazone Derivatives and Their Analogs as Anticonvulsant Agents in Animal Models. AB - Preclinical Research Epilepsy is a chronic devastating neurological disorder characterized by synchronous interictal discharges. Treatment with antiepileptic drugs (AEDs) can alleviate spontaneous seizure activity without preventing the progression and development of epileptogenesis. Current design and development of new AEDs and strategies for the prevention of epilepsy is focused mainly on attenuating uncontrolled seizures, severe side effects and toxicity in chronic drug therapy. It has thus become necessary to discover new chemical pharmacophores with a broad spectrum of activity and less neurotoxicity. Hydrazide/hydrazone derivatives that possess a -CO-NHN=CH- group constitute an important class of compounds for drug development. This review highlights the specific characteristics of various hydrazide/hydrazone derivatives and structurally related semicarbazones, semicarbazides and Schiff base compounds and their anticonvulsant activities. It is focused on the influence of differently substituted pharmacophores developed through SAR studies and testing their activity against different pharmcological targets. Drug Dev Res 77 : 379-392, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27775156 TI - Assessing reading comprehension with narrative and expository texts: Dimensionality and relationship with fluency, vocabulary and memory. AB - Reading comprehension assessment should rely on valid instruments that enable adequate conclusions to be taken regarding students' reading comprehension performance. In this article, two studies were conducted to collect validity evidence for the vertically scaled forms of two Tests of Reading Comprehension for Portuguese elementary school students in the second to fourth grades, one with narrative texts (TRC-n) and another with expository ones (TRC-e). Two samples of 950 and 990 students participated in Study 1, the study of the dimensionality of the TRC-n and TRC-e forms, respectively. Confirmatory factor analyses provided evidence of an acceptable fit for the one-factor solution for all test forms. Study 2 included 218 students to collect criterion-related validity. The scores obtained in each of the test forms were significantly correlated with the ones obtained in other reading comprehension measures and with the results obtained in oral reading fluency, vocabulary and working memory tests. Evidence suggests that the test forms are valid measures of reading comprehension. PMID- 27775157 TI - Genome-wide copy number variation in the bovine genome detected using low coverage sequence of popular beef breeds. AB - Copy number variations (CNVs) are large insertions, deletions or duplications in the genome that vary between members of a species and are known to affect a wide variety of phenotypic traits. In this study, we identified CNVs in a population of bulls using low coverage next-generation sequence data. First, in order to determine a suitable strategy for CNV detection in our data, we compared the performance of three distinct CNV detection algorithms on benchmark CNV datasets and concluded that using the multiple sample read depth approach was the best method for identifying CNVs in our sequences. Using this technique, we identified a total of 1341 copy number variable regions (CNVRs) from genome sequences of 154 purebred sires used in Cycle VII of the USMARC Germplasm Evaluation Project. These bulls represented the seven most popular beef breeds in the United States: Hereford, Charolais, Angus, Red Angus, Simmental, Gelbvieh and Limousin. The CNVRs covered 6.7% of the bovine genome and spanned 2465 protein-coding genes and many known quantitative trait loci (QTL). Genes harbored in the CNVRs were further analyzed to determine their function as well as to find any breed specific differences that may shed light on breed differences in adaptation, health and production. PMID- 27775158 TI - Factors Influencing the Use of Intermittent Bladder Catheterization by Individuals With Spina Bifida in Brazil and Germany. AB - PURPOSE: Intermittent catheterization (IC) often is essential for individuals with spina bifida/myelomeningocele (SBM) and neurogenic bladder. This study aimed to identify and analyze the factors that influence the use of IC. DESIGN AND METHODS: Descriptive study with convenience sampling. Data were collected using printed (Brazil) and online (Germany) questionnaires, and analyzed using multivariate logistical regression and analysis of variance. The study included 100 Brazilian and 100 German patients, aged 0-55 years, with SBM who utilized IC. FINDINGS: Intermittent catheterization was used by 188 of the 200 patients. Three variables were important for predicting who did or did not use IC: no discontinuation of IC, absence of technical difficulty, and daily frequency of IC. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggest that difficulties with IC use experienced by spina bifida patients and their family members that predicted full discontinuation tended to be personal variables, rather than demographic or medical characteristics. PMID- 27775101 TI - Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response. AB - Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 * 10-7 to p = 1.76 * 10-5, by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available. PMID- 27775160 TI - Violent behavior among military reservists. AB - Large numbers of British and American Reservists have been deployed to operations in Iraq and Afghanistan. Little is known about the impact of deployment and combat exposure on violent behavior in Reservists. The purpose of this study was to determine the prevalence of self-reported violent behavior among a representative sample of United Kingdom Reservists, the risk factors associated with violence and the impact of deployment and combat exposure on violence. This study used data from a large cohort study of randomly selected UK military personnel and included Reservists who were in service at the time of sampling (n = 1710). Data were collected by questionnaires that asked about socio-demographic and military characteristics, pre-enlistment antisocial behavior, deployment experiences, post-deployment mental health, and self-reported interpersonal violent behavior. The prevalence of violence among Reservists was 3.5%. Deployment was found to be a risk factor for violent behavior even after adjustment for confounders. The association with violence was similar for those deployed in either a combat role or non-combat role. Violence was also strongly associated with mental health risk factors (PTSD, common mental disorders, and alcohol misuse). This study demonstrated higher levels of self-reported post deployment violence in UK Reservists who had served in either Iraq or Afghanistan. Deployment, irrespective of the role was associated with higher levels of violent behavior among Reservists. The results also emphasize the risk of violent behavior associated with post-deployment mental health problems. Aggr. Behav. 43:273-280, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775159 TI - A dual purpose universal influenza vaccine candidate confers protective immunity against anthrax. AB - Preventive influenza vaccines must be reformulated annually because of antigen shift and drift of circulating influenza viral strains. However, seasonal vaccines do not always match the circulating strains, and there is the ever present threat that avian influenza viruses may adapt to humans. Hence, a universal influenza vaccine is needed to provide protective immunity against a broad range of influenza viruses. We designed an influenza antigen consisting of three tandem M2e repeats plus HA2, in combination with a detoxified anthrax oedema toxin delivery system (EFn plus PA) to enhance immune responses. The EFn 3*M2e-HA2 plus PA vaccine formulation elicited robust, antigen-specific, IgG responses; and was protective against heterologous influenza viral challenge when intranasally delivered to mice three times. Moreover, use of the detoxified anthrax toxin system as an adjuvant had the additional benefit of generating protective immunity against anthrax. Hence, this novel vaccine strategy could potentially address two major emerging public health and biodefence threats. PMID- 27775162 TI - First record of Stegomyia albopicta (= Aedes albopictus) in Morocco: a major threat to public health in North Africa? AB - The Asian tiger mosquito Stegomyia albopicta (= Aedes albopictus) (Diptera: Culicidae), native to Asian forests, is a nuisance mosquito and is responsible for the transmission of arboviruses of public health importance, such as dengue, chikungunya and Zika viruses. It has colonized parts of all continents, except Antarctica, over the past 30-40 years. However, to date, the only records of S. albopicta in North Africa refer to occasional collections in 2010 and 2014 in Algeria. In early September 2015, S. albopicta larvae and adults were collected in a district of Rabat, Morocco. Morphological identification was confirmed by molecular analysis. This is the first record of this invasive mosquito in Morocco. A national surveillance programme will be implemented in 2016 to establish its geographical distribution in Morocco and to instigate control measures to prevent the establishment of new populations and the transmission of arboviruses. PMID- 27775163 TI - Functional Roles of Eph A-Ephrin A1 System in Endometrial Luminal Epithelial Cells During Early Pregnancy. AB - Eph and ephrin regulate diverse biological events such as proliferation, adhesion, migration, and angiogenesis through cell-to-cell interactions. However, little is known of their functional role and mechanisms of action in uterine endometrial cells. In the present study, we demonstrated the effects of the Eph and ephrin on interactions between blastocysts and endometrial luminal epithelial (pLE) cells in the pig that is regarded as an excellent biomedical animal model for research on the peri-implantation period of pregnancy. Results of this study indicated that among eight members of the Eph A family, expression of Eph A1, A2, A4, and A7 was strongly detected in endometrial epithelial cells during early pregnancy. Of these, for identification of signal transduction pathways induced by ephrin A1, a major ligand for Eph A, cell proliferation assays, and immunofluorescence and cell cycle regulation were analyzed following treatment of pLE cells with ephrin A1. Ephrin A1 stimulated proliferation of pLE cells as evidenced by abundant PCNA expression and an increase in the G2/M phase. Western blot analysis showed that ephrin A1 activated PI3K and MAPK signaling proteins in a time-dependent manner. Moreover, phosphorylation of AKT, ERK1/2, P38, and JNK proteins were suppressed by their inhibitors wortmannin, U0126, SB203580, and SP600125, respectively. Also, phosphor-AKT was reduced by ERK1/2 and P38 inhibitors. Ephrin A1-induced proliferation and migration of pLE cells was also blocked by those inhibitors. Collectively, these results suggest that ephrin A1 enhances interactions between porcine blastocysts and endometrial luminal epithelial cells by activating PI3K and MAPK signal transduction pathways. J. Cell. Physiol. 232: 1527-1538, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775161 TI - Prospective Analysis of Behavioral Economic Predictors of Stable Moderation Drinking Among Problem Drinkers Attempting Natural Recovery. AB - BACKGROUND: As interventions have expanded beyond clinical treatment to include brief interventions for persons with less severe alcohol problems, predicting who can achieve stable moderation drinking has gained importance. Recent behavioral economic (BE) research on natural recovery has shown that active problem drinkers who allocate their monetary expenditures on alcohol and saving for the future over longer time horizons tend to have better subsequent recovery outcomes, including maintenance of stable moderation drinking. This study compared the predictive utility of this money-based "Alcohol-Savings Discretionary Expenditure" (ASDE) index with multiple BE analogue measures of behavioral impulsivity and self-control, which have seldom been investigated together, to predict outcomes of natural recovery attempts. METHODS: Community-dwelling problem drinkers, enrolled shortly after stopping abusive drinking without treatment, were followed prospectively for up to a year (N = 175 [75.4% male], M age = 50.65 years). They completed baseline assessments of preresolution drinking practices and problems, analogue behavioral choice tasks (Delay Discounting, Melioration-Maximization, and Alcohol Purchase Tasks), and a Timeline Followback interview including expenditures on alcohol compared to voluntary savings (ASDE index) during the preresolution year. RESULTS: Multinomial logistic regression models showed that, among the BE measures, only the ASDE index predicted stable moderation drinking compared to stable abstinence or unstable resolutions involving relapse. As hypothesized, stable moderation was associated with more balanced preresolution allocations to drinking and savings (odds ratio = 1.77, 95% confidence interval = 1.02 to 3.08, p < 0.05), suggesting it is associated with longer-term behavior regulation processes than abstinence. CONCLUSIONS: The ASDE's unique predictive utility may rest on its comprehensive representation of contextual elements to support this patterning of behavioral allocation. Stable low-risk drinking, but not abstinence, requires such regulatory processes. PMID- 27775164 TI - Implementation of the Agitated Behavior Scale in the Electronic Health Record. AB - PURPOSE: The purpose of the study was to implement an Agitated Behavior Scale through an electronic health record and to evaluate the usability of the scale in a brain injury unit at a rehabilitation hospital. DESIGN: A quality improvement project was conducted in the brain injury unit at a large rehabilitation hospital with registered nurses as participants using convenience sampling. METHODS: The project consisted of three phases and included education, implementation of the scale in the electronic health record, and administration of the survey questionnaire, which utilized the system usability scale. FINDINGS: The Agitated Behavior Scale was found to be usable, and there was 92.2% compliance with the use of the electronic Electronic Agitated Behavior Scale. CONCLUSION: The Agitated Behavior Scale was effectively implemented in the electronic health record and was found to be usable in the assessment of agitation. CLINICAL RELEVANCE: Utilization of the scale through the electronic health record on a daily basis will allow for an early identification of agitation in patients with traumatic brain injury and enable prompt interventions to manage agitation. PMID- 27775166 TI - The Effectiveness of Discharge Training for Patients After Cardiac Surgery. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of written and verbal discharge training given to patients who underwent cardiac surgery. DESIGN AND METHODS: It was conducted on 180 patients between November 2011 and June 2012. The patients were divided into two groups. The first 90 patients were given verbal discharge training, whereas the others were provided with both written and verbal trainings. Using pretest and posttest questionnaires, knowledge levels of the patients were evaluated before training and 1 month after discharge. Patients given verbal discharge training had a success rate of 10.2% pretest, 48.1% posttest, whereas the success rate of patients who received both written and verbal discharge training was 6.35% pretest, 90.7% posttest. FINDINGS: The findings show both written and verbal discharge training increased the knowledge levels. CONCLUSION AND CLINICAL RELEVANCE: The findings imply written-verbal discharge training may help patients to solve the problems after discharge, which may reduce the number of patients presenting at hospital and in turn, related healthcare costs. PMID- 27775165 TI - Predicting Prostate Cancer Recurrence After Radical Prostatectomy. AB - BACKGROUND: Prostate cancer prognosis is variable, and management decisions involve balancing patients' risks of recurrence and recurrence-free death. Moreover, the roles of body mass index (BMI) and race in risk of recurrence are controversial [1,2]. To address these issues, we developed and cross-validated RAPS (Risks After Prostate Surgery), a personal prediction model for biochemical recurrence (BCR) within 10 years of radical prostatectomy (RP) that includes BMI and race as possible predictors, and recurrence-free death as a competing risk. METHODS: RAPS uses a patient's risk factors at surgery to assign him a recurrence probability based on statistical learning methods applied to a cohort of 1,276 patients undergoing RP at the University of Pennsylvania. We compared the performance of RAPS to that of an existing model with respect to calibration (by comparing observed and predicted outcomes), and discrimination (using the area under the receiver operating characteristic curve (AUC)). RESULTS: RAPS' cross validated BCR predictions provided better calibration than those of an existing model that underestimated patients' risks. Discrimination was similar for the two models, with BCR AUCs of 0.793, 95% confidence interval (0.766-0.820) for RAPS, and 0.780 (0.745-0.815) for the existing model. RAPS' most important BCR predictors were tumor grade, preoperative prostate-specific antigen (PSA) level and BMI; race was less important [3]. RAPS' predictions can be obtained online at https://predict.shinyapps.io/raps. CONCLUSION: RAPS' cross-validated BCR predictions were better calibrated than those of an existing model, and BMI information contributed substantially to these predictions. RAPS predictions for recurrence-free death were limited by lack of co-morbidity data; however the model provides a simple framework for extension to include such data. Its use and extension should facilitate decision strategies for post-RP prostate cancer management. Prostate 77:291-298, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775167 TI - Genetic diversity and phylogeographic structure of Bactrian camels shown by mitochondrial sequence variations. AB - The Bactrian camel includes various domestic (Camelus bactrianus) and wild (Camelus ferus) breeds that are important for transportation and for their nutritional value. However, there is a lack of extensive information on their genetic diversity and phylogeographic structure. Here, we studied these parameters by examining an 809-bp mtDNA fragment from 113 individuals, representing 11 domestic breeds, one wild breed and two hybrid individuals. We found 15 different haplotypes, and the phylogenetic analysis suggests that domestic and wild Bactrian camels have two distinct lineages. The analysis of molecular variance placed most of the genetic variance (90.14%, P < 0.01) between wild and domestic camel lineages, suggesting that domestic and wild Bactrian camel do not have the same maternal origin. The analysis of domestic Bactrian camels from different geographical locations found there was no significant genetic divergence in China, Russia and Mongolia. This suggests a strong gene flow due to wide movement of domestic Bactrian camels. PMID- 27775168 TI - Extracellular Matrix and Colorectal Cancer: How Surrounding Microenvironment Affects Cancer Cell Behavior? AB - Colorectal cancer (CRC) whit more than a million of new cases per year is one of the most common registered cancers worldwide with few treatment options especially for advanced and metastatic patients.The tumor microenvironment is composed by extracellular matrix (ECM), cells, and interstitial fluids. Among all these constituents, in the last years an increased interest around the ECM and its potential role in cancer tumorigenesis is arisen. During cancer progression the ECM structure and composition became disorganized, allowing cellular transformation and metastasis. Up to now, the focus has mainly been on the characterization of CRC microenvironment analyzing separately structural ECM components or cell secretome modifications. A more extensive view that interconnects these aspects should be addressed. In this review, biochemical (secretome) and biomechanical (structure and architecture) changes of tumor microenvironment will be discussed, giving suggestions on how these changes can affect cancer cell behavior. J. Cell. Physiol. 232: 967-975, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775169 TI - An Interactive System for Fine Motor Rehabilitation. AB - PURPOSE: One of the most important aspects in neuromotor rehabilitation is the need of feedback for patients. The rehabilitation system's efficiency relies on the therapist's judgment, who tells the patient whether he/she is performing the exercises correctly. This process may be quite subjective, because it depends on the therapist's personal opinion. On the other hand, recent studies have shown that vibrotactile biofeedback can improve the effectiveness of interaction as it is a very helpful tool in the physiological process of neuromotor rehabilitation. DESIGN: We designed an interactive system focused on rehabilitation of the upper limbs using active markers and image processing, which consists of drawing activities in both augment and virtual reality. METHODS: System gives to the user a correction through multimodal stimuli feedback (vibrotactile, visual and sound stimulus) and force measurement to let the patients know if they are not achieving the tasks' goals. FINDINGS: The developed system could be used by nursing assistants to better help patients. The purpose of this system was assisting patients with injuries to shoulders, elbows or wrists, providing an audio-vibrotactile feedback as a factor of correction in the movements of the patient. To examine our system, 11 participants were asked to participate in an experiment where they performed activities focussed to strengthen their fine motor movements. CONCLUSIONS AND CLINICAL RELEVANCE: Our results show that patients' fine motor skills improved 10% on average by comparing their error rates throughout the sessions. PMID- 27775170 TI - Engineering three dimensional micro nerve tissue using postnatal stem cells from human dental apical papilla. AB - The in vitro generation of cell-based three dimensional (3D) nerve tissue is an attractive subject to improve graft survival and integration into host tissue for neural tissue regeneration or to model biological events in stem cell differentiation. Although 3D organotypic culture strategies are well established for 3D nerve tissue formation of pluripotent stem cells to study underlying biology in nerve development, cell-based nerve tissues have not been developed using human postnatal stem cells with therapeutic potential. Here, we established a culture strategy for the generation of in vitro cell-based 3D nerve tissue from postnatal stem cells from apical papilla (SCAPs) of teeth, which originate from neural crest-derived ectomesenchyme cells. A stem cell population capable of differentiating into neural cell lineages was generated during the ex vivo expansion of SCAPs in the presence of EGF and bFGF, and SCAPs differentiated into neural cells, showing neural cell lineage-related molecular and gene expression profiles, morphological changes and electrophysical property under neural inductive culture conditions. Moreover, we showed the first evidence that 3D cell based nerve-like tissue with axons and myelin structures could be generated from SCAPs via 3D organotypic culture using an integrated bioprocess composed of polyethylene glycol (PEG) microwell-mediated cell spheroid formation and subsequent dynamic culture in a high aspect ratio vessel (HARV) bioreactor. In conclusion, the culture strategy in our study provides a novel approach to develop in vitro engineered nerve tissue using SCAPs and a foundation to study biological events in the neural differentiation of postnatal stem cells. Biotechnol. Bioeng. 2017;114: 903-914. (c) 2016 Wiley Periodicals, Inc. PMID- 27775171 TI - Discovery of porcine miRNA-196a/b may influence porcine adipogenesis in longissimus dorsi muscle by miRNA sequencing. AB - Intramuscular fat (IMF) is one of the fat traits that has economic importance in the pork industry. Longissimus dorsi muscle contains IMF and is suitable for studying adipogenesis. To discover further potential regulatory miRNAs that may influence adipogenesis, we analyzed miRNA in the longissimus dorsi muscle of Yorkshire (YY, lean-type) and Chinese Wannanhua (WH, fatty) pigs using miRNA sequencing (miRNA-seq). From this dataset, we identified 598 unique miRNAs comprising 325 pre-miRNAs and 273 novel pre-miRNAs through comparison with known miRNAs in miRBase version 21. We found 42 miRNAs including nine up- and 33 down regulated between the YY and WH pigs. Moreover, we found two miRNAs, miR-196a/b (miR-196a, miR-196b-5p), that had the highest level of expression in WH pigs, and miR-196a/b may influence porcine adipogenesis in longissimus dorsi muscle through an adipocytokine signaling pathway. PMID- 27775172 TI - Differential adaptation drives ecological speciation in campions (Silene): evidence from a multi-site transplant experiment. AB - In order to investigate the role of differential adaptation for the evolution of reproductive barriers, we conducted a multi-site transplant experiment with the dioecious sister species Silene dioica and S. latifolia and their hybrids. Crosses within species as well as reciprocal first-generation (F1 ) and second generation (F2 ) interspecific hybrids were transplanted into six sites, three within each species' habitat. Survival and flowering were recorded over 4 yr. At all transplant sites, the local species outperformed the foreign species, reciprocal F1 hybrids performed intermediately and F2 hybrids underperformed in comparison to F1 hybrids (hybrid breakdown). Females generally had slightly higher cumulative fitness than males in both within- and between-species crosses and we thus found little evidence for Haldane's rule acting on field performance. The strength of selection against F1 and F2 hybrids as well as hybrid breakdown increased with increasing strength of habitat adaptation (i.e. the relative fitness difference between the local and the foreign species) across sites. Our results suggest that differential habitat adaptation led to ecologically dependent post-zygotic reproductive barriers and drives divergence and speciation in this Silene system. PMID- 27775173 TI - Testosterone Levels Correlate With Grade Group 5 Prostate Cancer: Another Step Toward Personalized Medicine. AB - BACKGROUND: Controversial results have shown a significant association with either low or high total testosterone (tT) levels and high risk prostate cancer (PCa). We tested the relationship between circulating tT and grade group 5 (G5) PCa at radical prostatectomy (RP) in patients with preoperative low- to intermediate-risk disease. METHODS: Serum sex hormones were assessed the day before RP in a cohort of 846 patients with low- to intermediate-risk PCa. Patients were segregated using the new 5-tiered Gleason grade groups. Restricted cubic spline functions and logistic regression analyses tested the association between sex hormones and G5 PCa. Differences in potential predictive accuracy (PA) were assessed for tT and prostate-specific antigen (PSA) levels. RESULTS: Overall, 27 men (3.2%) had G5 PCa at RP, and this group had higher PSA values than patients with G1-G4 PCa (P = 0.02). The groups did not differ in terms of preoperative mean hormonal values. Both low and high circulating tT values depicted a nonlinear U-shaped correlation with G5 PCa at RP. The lowest and highest (10th and 90th percentiles) tT values and biopsy PCa grade emerged as multivariable independent predictors of G5 PCa at RP (all P < 0.05). PA for G5 PCa did not differ between tT (area under the curve [AUC] 0.631) and PSA (AUC 0.636). CONCLUSIONS: Circulating tT was a significant predictor of G5 PCa at RP in patients with preoperative low- to intermediate-risk disease. Preoperative tT and PSA values showed similar PA for the most aggressive disease, confirming a potential role for circulating androgens in preoperative risk assessment of PCa patients. Prostate 77:234-241, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775174 TI - Clinically Relevant Concentrations of Ketamine Inhibit Osteoclast Formation In Vitro in Mouse Bone Marrow Cultures. AB - Ketamine has been used safely in clinics for decades for analgesia and anesthesia. It is increasingly popular in clinical practice due to its new uses and importance for emergency procedures. It is known that ketamine is sequestered in the bone marrow and the major receptors for ketamine, noncompetitive N-methyl d-aspartate receptors (NMDARs), are expressed in osteoclasts (OCs) and osteoblasts. However, the impact of ketamine on OCs or osteoblasts is unknown. In this study, we investigated the effects of ketamine on osteoclastogenesis and regulation of NMDARs expression in vitro. Bone marrows (BMs) or bone marrow macrophages (BMMs) were cultured in the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) with or without ketamine for up to 6 days. OC formation peaked at day 5. On day 5 of culture, ketamine inhibited OC formation from both BM and BMM cultures at clinically relevant concentrations (3-200 uM). Ketamine inhibited RANKL-induced expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin dependent 1 (NFATc1) in BMM cultures. Inhibition of ketamine on RANKL-induced osteoclastogenesis is associated with down-regulation of NMDARs. In addition, ketamine significantly inhibited the M-CSF induced migration of BMMs, inhibited cell fusion and significantly increased mature OC apoptosis. We conclude that clinically relevant concentrations of ketamine inhibit OC formation in both BM and BMM cultures in vitro through inhibiting migration and fusion process and enhancing mature OC apoptosis. It is likely that ketamine regulates osteoclastogenesis, at least in part, via its effects on NMDAR expression. J. Cell. Biochem. 118: 914-923, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775176 TI - The Impact of Stroke Nurse Navigation on Patient Compliance Post Discharge. AB - PURPOSE: The purpose of this study was to describe the impact a Stroke Nurse Navigation Program has on concurrent chart reviews and patient compliance post discharge. DESIGN: Phase I: Concurrent chart review of The Joint Commission Primary Stroke Center core measures for ischemic stroke patients. Phase II: Longitudinal study of 100 ischemic stroke patients discharged to home. METHODS: Telephone surveys were conducted at prescribed intervals posthospital discharge (Phase II). Surveys focused on medication compliance, follow-up medical appointment compliance, and neurovascular Emergency Department (ED) visits/readmissions. FINDINGS: Phase I trends included increased stroke performance measures compliance. Phase II favorable trends included increased medication compliance (>98%), increased follow-up appointments (100%), decreased rate of neurovascular ED visits/rehospitalizations (3%), and improvement in Activities of Daily Living and quality of life measures through 12 months post discharge. CONCLUSIONS: Stroke Nurse Navigation increased conformity of stroke performance measures and stroke patient discharge compliance through 12 months post discharge. PMID- 27775175 TI - Genetic risk mechanisms of posttraumatic stress disorder in the human brain. AB - Posttraumatic stress disorder (PTSD) follows exposure to a traumatic event in susceptible individuals. Recently, genome-wide association studies have identified a number of genetic sequence variants that are associated with the risk of developing PTSD. To follow up on identifying the molecular mechanisms of these risk variants, we performed genotype to RNA sequencing-derived quantitative expression (whole gene, exon, and exon junction levels) analysis in the dorsolateral prefrontal cortex (DLPFC) of normal postmortem human brains. We further investigated genotype-gene expression associations within the amygdala in a smaller independent RNA sequencing (Genotype-Tissue Expression [GTEx]) dataset. Our DLPFC analyses identified significant expression quantitative trait loci (eQTL) associations for a "candidate" PTSD risk SNP rs363276 and the expression of two genes: SLC18A2 and PDZD8, where the PTSD risk/minor allele T was associated with significantly lower levels of gene expression for both genes, in the DLPFC. These eQTL associations were independently confirmed in the amygdala from the GTEx database. Rs363276 "T" carriers also showed significantly increased activity in the amygdala during an emotional face-matching task in healthy volunteers. Taken together, our preliminary findings in normal human brains represent a tractable approach to identify mechanisms by which genetic variants potentially increase an individual's risk for developing PTSD. (c) 2016 Wiley Periodicals, Inc. PMID- 27775178 TI - The influence of vitamin C on the urine dipstick tests in the clinical specimens: a multicenter study. AB - BACKGROUND: Vitamin C may interfere with the results of urine dipstick tests. We investigated the incidence of urinary vitamin C and its interference with urine dipstick reagents using a vitamin C dipstick. METHODS: The incidence of urinary vitamin C was determined in patients and healthy individuals undergoing routine medical check-ups. Interference tests were performed using samples with various amounts of added vitamin C. For clinical samples, we identified false-negative dipstick glucose, hemoglobin, and leukocyte esterase results based on the urine sediment and serum glucose results. RESULTS: Vitamin C was found in the urine of 18.1% of the subjects overall, and 23.1% of those undergoing medical check-ups. Dipstick results for glucose, leukocyte esterase, and hemoglobin differed between samples without vitamin C and with added vitamin C. When vitamin C was detected in clinical urine samples, 42.3%, 10.6%, and 8.2% of the glucose, hemoglobin, and leukocyte esterase dipstick tests were rated as false negative, respectively. CONCLUSIONS: Vitamin C was frequently found in clinical urine samples, and its concentration was higher in individuals undergoing medical check-ups. Urinary vitamin C can interfere with the urine dipstick results. This study gives useful information for predicting false-negative rates of urine dipstick tests caused by vitamin C. PMID- 27775177 TI - Recent Advances and Structural Features of Enoyl-ACP Reductase Inhibitors of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB). Hence, there is a need for new drugs that can combat MDR-TB. The rationale for the development of new drugs to combat MDR-TB strains is the design of InhA inhibitors that can bypass bioactivation by KatG. In the present review, special attention was paid to discuss the chemical nature and recent developments of direct InhA inhibitors. The InhA inhibitors reported here have significant inhibitory effects against Mtb InhA. The diphenyl ether derivatives have shown slow onset, a tight-binding mechanism, and high affinity at the InhA active site. However, some of the diphenyl ethers have significant in vitro efficacy, which fails to transform into in vivo efficacy. Among the InhA inhibitors, 4-hydroxy-2 pyridones have emerged as a new chemical class with significant InhA inhibitory activity and better pharmacokinetic parameters when compared to diphenyl ethers. PMID- 27775179 TI - Combined effects of road salt and an insecticide on wetland communities. AB - As the numbers of chemical contaminants in freshwater ecosystems increase, it is important to understand whether contaminants interact in ecologically important ways. The present study investigated the independent and interactive effects of 2 contaminants that frequently co-occur in freshwater environments among higher latitudes, including a commonly applied insecticide (carbaryl) and road salt (NaCl). The hypothesis was that the addition of either contaminant would result in a decline in zooplankton, an algal bloom, and the subsequent decline of both periphyton and periphyton consumers. Another hypothesis was that combining the contaminants would result in synergistic effects on community responses. Outdoor mesocosms were used with communities that included phytoplankton, periphyton, zooplankton, amphipods, clams, snails, and tadpoles. Communities were exposed to 4 environmentally relevant concentrations of salt (27 mg Cl- L-1 , 77 mg Cl- L-1 , 277 mg Cl- L-1 , and 727 mg Cl- L-1 ) fully crossed with 4 carbaryl treatments (ethanol, 0 ug L-1 , 5 ug L-1 , and 50 ug L-1 ) over 57 d. Contaminants induced declines in rotifer and cladoceran zooplankton, but only carbaryl induced an algal bloom. Consumers exhibited both positive and negative responses to contaminants, which were likely the result of both indirect community interactions and direct toxicity. In contrast to the hypothesis, no synergistic effects were found, although copepod densities declined when high concentrations of both chemicals were combined. The results suggest that low concentrations of salt and carbaryl are likely to have mostly independent effects on aquatic communities. Environ Toxicol Chem 2017;36:771-779. (c) 2016 SETAC. PMID- 27775180 TI - Robust water fat separated dual-echo MRI by phase-sensitive reconstruction. AB - PURPOSE: The purpose of this work was to develop and evaluate a robust water-fat separation method for T1-weighted symmetric two-point Dixon data. THEORY AND METHODS: A method for water-fat separation by phase unwrapping of the opposite phase images by phase-sensitive reconstruction (PSR) is introduced. PSR consists of three steps; (1), identification of clusters of tissue voxels; (2), unwrapping of the phase in each cluster by solving Poisson's equation; and (3), finding the correct sign of each unwrapped opposite-phase cluster, so that the water-fat images are assigned the correct identities. Robustness was evaluated by counting the number of water-fat swap artifacts in a total of 733 image volumes. The method was also compared to commercial software. RESULTS: In the water-fat separated image volumes, the PSR method failed to unwrap the phase of one cluster and misclassified 10. One swap was observed in areas affected by motion and was constricted to the affected area. Twenty swaps were observed surrounding susceptibility artifacts, none of which spread outside the artifact affected regions. The PSR method had fewer swaps when compared to commercial software. CONCLUSION: The PSR method can robustly produce water-fat separated whole-body images based on symmetric two-echo spoiled gradient echo images, under both ideal conditions and in the presence of common artifacts. Magn Reson Med 78:1208-1216, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27775181 TI - Comparison of telomere length and insulin-like growth factor-binding protein 7 promoter methylation between breast cancer tissues and adjacent normal tissues in Turkish women. AB - BACKGROUND: Both insulin-like growth factor-binding protein 7 (IGFBP7) and telomere length (TL) are associated with proliferation and senescence of human breast cancer. This study assessed the clinical significance of both TL and IGFBP7 methylation status in breast cancer tissues compared with adjacent normal tissues. We also investigated whether IGFBP7 methylation status could be affecting TL. METHODS: Telomere length was measured by quantitative PCR to compare tumors with their adjacent normal tissues. The IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. RESULTS: Telomeres were shorter in tumor tissues compared to controls (P<.0001). The mean TL was higher in breast cancer with invasive ductal carcinoma (IDC; n=72; P=.014) compared with other histological type (n=29), and TL in IDC with HER2 negative (n=53; P=.017) was higher than TL in IDC with HER2 positive (n=19). However, telomeres were shortened in advanced stages and growing tumors. IGFBP7 methylation was observed in 90% of tumor tissues and 59% of controls (P=.0002). Its frequency was significantly higher in IDC compared with invasive mixed carcinoma (IMC; P=.002) and it was not correlated either with protein expression or the other clinicopathological parameters. CONCLUSION: These results suggest that IGFBP7 promoter methylation and shorter TL in tumor compared with adjacent tissues may be predictive biomarkers for breast cancer. Telomere maintenance may be indicative of IDC and IDC with HER2 (-) of breast cancer. Further studies with larger number of cases are necessary to verify this association. PMID- 27775182 TI - Glycated albumin is associated with body mass index in euglycemic adults but is not predictive of postprandial blood glucose response. AB - BACKGROUND: The level of glycated albumin in circulation is an indicator of blood glucose control over the preceding 2 weeks. It is not known if the level of glycated albumin in circulation relates to an individual's postprandial blood glucose response. METHODS: Eighty-four euglycemic young adults (21.1 [3.9] years, BMI 23.9 [4.0] kg/m2 ) primarily of European descent underwent a fasted meal test of 50 g carbohydrate from white bread. Capillary blood was then sampled at regular intervals over 2 hours. Correlations were sought between glycated albumin, fasted and 2-hour post-load blood glucose measurements, incremental area under the blood glucose curve, glycemic range, body mass index (BMI), and C reactive protein (CRP). RESULTS: When adjusted for age and sex, glycated albumin was inversely correlated with BMI (r=-.25, P=.027). No significant correlations existed for glycated albumin and postprandial markers of blood glucose control. BMI and CRP values correlate in this population (r=.30, P=.009). CONCLUSIONS: Glycated albumin in circulation is not related to postprandial blood glucose response in young euglycemic adults. Glycated albumin is lower in euglycemic adults with higher BMI values. Contrary to research with older adults or those with impaired glucose control, glycated albumin did not correlate to CRP. PMID- 27775183 TI - Asymptomatic and symptomatic individuals with the same radiographic evidence of knee osteoarthritis walk with different knee moments and muscle activity. AB - There is an established discordance between the structural joint damage and clinical symptoms of knee osteoarthritis; however, there has been little investigation into the differences in joint level biomechanics and muscle activation patterns during gait between symptomatic and asymptomatic individuals with the same radiographic evidence of osteoarthritis. The objective of this study was to examine three-dimensional knee joint biomechanics and muscle activation differences during gait between asymptomatic and symptomatic individuals with radiographic knee osteoarthritis. A total of 54 asymptomatic and 59 symptomatic individuals with a Kellgren-Lawrence osteoarthritis radiographic grade of 2 underwent a comprehensive gait analysis to examine differences in the magnitude and patterns of the knee flexion angle, three-dimensional net resultant moments, and electromyography of the quadriceps, hamstrings, and gastrocnemii during over ground walking between the two groups. The symptomatic group walked with significantly higher overall magnitudes and less mid-stance unloading of the net resultant knee adduction moment, lower peak flexion moments, and higher lateral hamstrings and quadriceps activity during stance than the Asymptomatic group (p < 0.05, sex-adjusted analysis), with a trend (p = 0.07) toward greater transverse plane range of moment over stance. The differences found suggest a "stiffer" frontal and sagittal plane pattern with symptomatic individuals, but with more muscle activity and a trend toward more torsional loading in the transverse plane, which may have implications for shear loading of the joint. This is the first evidence of differences in three-dimensional knee joint biomechanics and muscle activation between asymptomatic and symptomatic individuals with the same radiographic grade. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1661-1670, 2017. PMID- 27775184 TI - Is the CABIC Clean Intermittent Catheterization Patient Education Effective? AB - PURPOSE: This study examined the effectiveness of the consensus model (Clinical Advisory Board for Intermittent Catheterization [CABIC] method) for teaching clean intermittent self-catheterization (ISC). The primary hypothesis was that the CABIC method of teaching ISC would result in higher ISC knowledge and performance scores. DESIGN: Prospective, non randomized, pre-post study of an educational intervention of ISC education with nursing students. METHODS: Nursing students completed a self-report pre-/posttest, education of the CABIC method, and video recording of the CABIC method using same-gendered manikins. The Le Danseur Instrument (LDI) was used to grade the video-recorded demonstration. FINDINGS: Fifty participants completed three phases of the study. Paired t test showed statistically significant improvement in ISC knowledge. A mean score of 92 93 demonstrated a high level of participant education retention. CONCLUSIONS: The CABIC method of teaching clean ISC is associated with improvement in generalized clean ISC knowledge and performance scores. CLINICAL RELEVANCE: The CABIC method can be integrated into clinical practice as an evidence-based approach to teaching ISC. PMID- 27775186 TI - A Cationic Phosphapyramidane. AB - Pyramidanes C[C4 R4 ] constitute a novel class of highly strained and reactive polyhedral clusters that attracted a great deal of attention of both theoreticians and experimentalists. Although well-studied from the theoretical viewpoint, pyramidanes were synthetically inaccessible, and only very recently their very first isolable representatives have been described. In this Communication, we report on the synthesis and structural studies of the cationic pyramidane with the Group 15 element at the apex, namely, phosphapyramidane, an isoelectronic analogue of the neutral pyramidanes of the Group 14 elements. PMID- 27775187 TI - 3-tert-Butyl-Substituted Cyclohexa-1,4-dienes as Isobutane Equivalents in the B(C6 F5 )3 -Catalyzed Transfer Hydro-tert-Butylation of Alkenes. AB - Cyclohexa-1,4-dienes with a tert-butyl group at C3 are shown to function as isobutane equivalents when activated by the strong boron Lewis acid tris(pentafluorophenyl)borane. The hitherto unprecedented transfer hydro-tert butylation from one unsaturated hydrocarbon to another is achieved with 1,1 diarylalkenes as substrates, thereby presenting itself as a new way of incorporating tertiary alkyl groups into carbon frameworks. Transient carbocation intermediates give rise to competing reaction pathways that could not be fully suppressed. PMID- 27775185 TI - Discovery of McrA, a master regulator of Aspergillus secondary metabolism. AB - Fungal secondary metabolites (SMs) are extremely important in medicine and agriculture, but regulation of their biosynthesis is incompletely understood. We have developed a genetic screen in Aspergillus nidulans for negative regulators of fungal SM gene clusters and we have used this screen to isolate mutations that upregulate transcription of the non-ribosomal peptide synthetase gene required for nidulanin A biosynthesis. Several of these mutations are allelic and we have identified the mutant gene by genome sequencing. The gene, which we designate mcrA, is conserved but uncharacterized, and it encodes a putative transcription factor. Metabolite profiles of mcrA deletant, mcrA overexpressing, and parental strains reveal that mcrA regulates at least ten SM gene clusters. Deletion of mcrA stimulates SM production even in strains carrying a deletion of the SM regulator laeA, and deletion of mcrA homologs in Aspergillus terreus and Penicillum canescens alters the secondary metabolite profile of these organisms. Deleting mcrA in a genetic dereplication strain has allowed us to discover two novel compounds as well as an antibiotic not known to be produced by A. nidulans. Deletion of mcrA upregulates transcription of hundreds of genes including many that are involved in secondary metabolism, while downregulating a smaller number of genes. PMID- 27775188 TI - Asymmetric Morita-Baylis-Hillman Reaction: Catalyst Development and Mechanistic Insights Based on Mass Spectrometric Back-Reaction Screening. AB - An efficient protocol for the evaluation of catalysts for the asymmetric Morita Baylis-Hillman (MBH) reaction was developed. By mass spectrometric back-reaction screening of quasi-enantiomeric MBH products, an efficient bifunctional phosphine catalyst was identified that outperforms literature-known catalysts in the MBH reaction of methyl acrylate with aldehydes. The close match between the selectivities measured for the forward and back reaction and kinetic measurements provided strong evidence that the aldol step and not the subsequent proton transfer is rate- and enantioselectivity-determining. PMID- 27775189 TI - Laparoscopic repair with hysteroscopy of cesarean scar diverticulum. AB - AIM: The aim of this study was to investigate the clinical data of laparoscopic repair with hysteroscopy of cesarean scar diverticulum (CSD). METHODS: We retrospectively evaluated 49 patients with CSD in our hospital who had undergone laparoscopic repair with hysteroscopy from January 2014 to June 2015. All patients had a history of cesarean section deliveries and prolonged postmenstrual spotting (duration 16.1 +/- 3.4 days). The diagnosis of CSD was established by using 2-D transvaginal ultrasound. RESULTS: All patients underwent the surgical repair successfully, without evident complications. The mean operation time was 90.4 +/- 9.1 min, the mean volume of blood loss was 31.2 +/- 14.3 mL, and the mean length of hospital stay was 4.1 +/- 0.3 days. All patients were followed for 6 months after the operation; the mean duration of menstruation was 7.5 +/- 2.5 days shorter on average than the pre-surgical menstrual days, and the difference was statistically significant (P = 0.001). According to the clinical symptoms assessment, 89.8% (44/49) of the surgeries were effective, while according to the anatomic assessment, 95.9% (47/49) were effective. CONCLUSION: Laparoscopic repair with hysteroscopy of CSD was confirmed to be a safe, effective, and minimally invasive treatment, and should be widely used to treat patients with CSD. PMID- 27775190 TI - Parasite genetic distance and local adaptation in co-evolving bacteria bacteriophage populations. AB - Antagonistic co-evolution between hosts and parasites can lead to local adaptation (LA) such that parasite fitness is greatest in sympatric hosts (or vice versa). The magnitude of LA typically increases with geographical distance, which is assumed to be because genetic (and hence phenotypic) distance increases with geographical distance. Here, we explicitly test the relationships between parasite genetic and phenotypic distance and LA using isolates of co-evolved viral parasites (lytic bacteriophage phi2) and the host bacterium Pseudomonas fluorescens SBW25. We find positive relationships between parasite genotype and infectivity phenotype, but the strength of the relationship was greater when infectivity was defined by the identity of hosts that could be infected rather than the actual number of hosts infected (host range), and when measurements were compared within rather than among populations. Crucially, we find a monotonic relationship between LA and genetic distance across phage isolates from different populations, although in contrast to many geographical studies, parasite LA decreased with genetic distance. These results can be explained by the fact that bacteria can rapidly adapt to phage infectivity mutations, but that evolved resistance has a degree of specificity to the local phage population. Our results show that antagonistic co-evolution alone can result in predictable links between genetic distance and host-parasite local adaptation. PMID- 27775191 TI - Catalytic Enantioselective Aza-Reformatsky Reaction with Cyclic Imines. AB - A catalytic highly enantioselective aza-Reformatsky reaction with cyclic aldimines and ketimines for the synthesis of chiral beta-amino esters with good yields and excellent enantioselectivities is reported. A readily available diaryl prolinol is used as a chiral ligand, ZnMe2 as a zinc source and ethyl iodoacetate as reagent in the presence of air atmosphere. The reaction with cyclic ketimines generates a quaternary stereocenter with excellent levels of enantioselectivity. Furthermore, five-membered N-sulfonyl ketimines were used as electrophiles with good enantiomeric excesses, under the optimized reaction conditions. Moreover, several chemical transformations were performed with the chiral beta-amino esters. PMID- 27775192 TI - Dual-Sensitized Luminescent Europium(IotaIotaIota) and Terbium(IotaIotaIota) Complexes as Bioimaging and Light-Responsive Therapeutic Agents. AB - Dual-photosensitized stable EuIotaIotaIota and TbIotaIotaIota complexes, namely [Eu(dpq)(tfnb)3 ] (1) and [Tb(dpq)(tfnb)3 ] (2), in which dpq=dipyrido[3,2 d:2',3'-f]quinoxaline and Htfnb=4,4,4-trifluoro-1-(2-napthyl)-1,3-butanedione, were designed as bioimaging and light-responsive therapeutic agents. Their X-ray structures, photophysical properties, biological interactions, photoinduced DNA damage, photocytotoxicity, and cellular uptake properties were studied. Discrete mononuclear complexes adopt an eight-coordinated {LnN2 O6 } distorted square antiprism geometry with bidentate N,N-donor dpq and O,O-donor tfnb ligands. The designed probes have the advantage of dual-sensitizing antennae (dpq, Htfnb) to modulate their desirable optical properties for cellular imaging and light responsive intracellular damage. The remarkable photostability, absence of inner sphere water (q<1), and longer excited-state lifetimes of the complexes make them suitable as cellular-imaging probes. The dpq 3 T state is well located energetically to allow efficient energy transfer (ET) to the emissive 5 D0 and 5 D4 states of EuIotaIotaIota and TbIotaIotaIota . This leads to higher quantum yields (phi=0.15-0.20) in aqueous media and makes these compounds suitable cellular-imaging probes. The complexes display significant binding ability toward DNA and bovine serum albumin (K~105 m-1 ). They effectively cleave supercoiled DNA to its nicked circular form at lambda=365 nm through photoredox pathways. The cellular internalization studies showed cytosolic and nuclear localization. The remarkable photocytotoxicity of these probes offers a strategy towards developing photoresponsive LnIotaIotaIota probes as cellular-imaging and phototherapeutic agents. PMID- 27775193 TI - Draft genome assembly and annotation of Glycyrrhiza uralensis, a medicinal legume. AB - Chinese liquorice/licorice (Glycyrrhiza uralensis) is a leguminous plant species whose roots and rhizomes have been widely used as a herbal medicine and natural sweetener. Whole-genome sequencing is essential for gene discovery studies and molecular breeding in liquorice. Here, we report a draft assembly of the approximately 379-Mb whole-genome sequence of strain 308-19 of G. uralensis; this assembly contains 34 445 predicted protein-coding genes. Comparative analyses suggested well-conserved genomic components and collinearity of gene loci (synteny) between the genome of liquorice and those of other legumes such as Medicago and chickpea. We observed that three genes involved in isoflavonoid biosynthesis, namely, 2-hydroxyisoflavanone synthase (CYP93C), 2,7,4' trihydroxyisoflavanone 4'-O-methyltransferase/isoflavone 4'-O-methyltransferase (HI4OMT) and isoflavone-7-O-methyltransferase (7-IOMT) formed a cluster on the scaffold of the liquorice genome and showed conserved microsynteny with Medicago and chickpea. Based on the liquorice genome annotation, we predicted genes in the P450 and UDP-dependent glycosyltransferase (UGT) superfamilies, some of which are involved in triterpenoid saponin biosynthesis, and characterised their gene expression with the reference genome sequence. The genome sequencing and its annotations provide an essential resource for liquorice improvement through molecular breeding and the discovery of useful genes for engineering bioactive components through synthetic biology approaches. PMID- 27775194 TI - Stepwise Assembly of MII7 Clusters Revealed by Mass Spectrometry, EXAFS, and Crystallography. AB - The square-planar monomer NiL2 (Ni1 ), L=2-ethoxy-6-(N-methyl iminomethyl)phenolate, reacts with M(H2 O)6 (ClO4 )2 , M=Ni or Co, to form heptanuclear disks [Cox Ni7-x (OH)6 (L)6 ](ClO4 )2 ?2 CH3 CN (Cox Ni7-x , x=0-7) and the co-crystal [Cox Ni7-x (OH)6 L6 ][NiL2 ](ClO4 )2 ?2 CH3 CN (Cox Ni7-x -Ni1 ) under ambient conditions. It has proved possible to explore the bottom-up assembly process of Cox Ni7-x and Cox Ni7-x -Ni1 in real time. The final products have been characterized by thermogravimetric analysis, IR, elemental analysis, ICP-MS, and single-crystal X-ray diffraction. Time-dependent mass spectrometry (MS) revealed the following reaction steps: Ni1 ->[M2 L3 ]+ ->[M4 (OH)2 L4 ]2+ >[M7 (OH)6 L6 ]2+ . In contrast, the reaction of Ni1 with Zn2+ only reaches halfway, and crystallographic evidence indicates a butterfly structure for [Zn2 Ni2 (OH)2 Cl2 ] (Zn2 Ni2 ), an intermediate that is difficult to isolate in the above Ni-Co series. A summation method has been used to analyze the MS of bimetallic clusters with very similar atomic masses, as is the case for Co and Ni. The results provide ample information on the distribution of Co and Ni within each cluster and their statistical distribution within selected crystals. PMID- 27775195 TI - 17-alpha-hydroxyprogesterone caproate versus vaginal progesterone suppository for the prevention of preterm birth in women with a sonographically short cervix: A randomized controlled trial. AB - AIM: The aim of this study was to compare 17-alpha-hydroxyprogesterone caproate (17OHP-C) with vaginal progesterone suppository for the prevention of preterm birth in women with a sonographically short cervix and to evaluate the changes of the cervical length (CL) over time. METHODS: In this prospective randomized controlled trial, eligible patients were asymptomatic pregnant women with a sonographically short cervix. The participants in group 1 (n = 147) received vaginal progesterone suppositories at a dose of 400 mg daily and the women in group 2 (n = 150) received an i.m. dose of 250 mg 17OHP-C once a week. Transvaginal sonography was repeated every 3 weeks until 36 gestational weeks or the occurrence of preterm labor. RESULTS: A total of 304 singleton pregnant women between 16 and 24 gestational weeks with CL < 25 mm were enrolled in our study. The rates of preterm birth were 10.4% in the progesterone group and 14% in the 17OHP-C group: a difference that was not statistically significant (P = 0.416). Moreover, 264 participants underwent ultrasound examination five times and CL changes were studied for 15 weeks. The results showed that the CL changes over 15 weeks were statistically significant (P < 0.001), but the method of intervention (progesterone/17OHP-C) had no significant effect on CL change (P = 0.64). CONCLUSION: Our findings showed that vaginal progesterone and 17OHP-C had the same effect on the risk of preterm labor in asymptomatic women with a sonographically short cervix. We detected no significant difference between the effect of 17OHP-C and vaginal progesterone on CL changes over time. PMID- 27775196 TI - 3D Lattice Structure Control of Ordered Macroporous Material by Self-Assembly of Liquid Droplets. AB - Microfluidic devices, which can continuously fabricate single emulsion with monodispersed droplets having a pore diameter of more than 100 MUm in large numbers, can be applied to manufacture ordered macroporous films. 3D ordered macroporous films with a diameter of more than 100 MUm can be fabricated using ordered arrays of the monodispersed droplets as templates of the macropores, which are self-assembled in the space between two parallel flat glass plates. As the gap between the glass plates increases, the number of the layer increases. Furthermore, in the case with two or more layers, the lattice structure of the macroporous films also changes due to the confinement effects. PMID- 27775197 TI - Survival by genotype: patterns at Mc1r are not black and white at the White Sands ecotone. AB - Measuring links among genotype, phenotype and survival in the wild has long been a focus of studies of adaptation. We conducted a 4-year capture-recapture study to measure survival by genotype and phenotype in the Southwestern Fence Lizard (Sceloporus cowlesi) at the White Sands ecotone (transition area between white sands and dark soil habitats). We report several unanticipated findings. First, in contrast with previous work showing that cryptic blanched coloration in S. cowlesi from the heart of the dunes is associated with mutations in the melanocortin-1 receptor gene (Mc1r), ecotonal S. cowlesi showed minimal association between colour phenotype and Mc1r genotype. Second, the frequency of the derived Mc1r allele in ecotonal S. cowlesi appeared to decrease over time. Third, our capture-recapture data revealed a lower survival rate for S. cowlesi individuals with the derived Mc1r allele. Thus, our results suggest that selection at the ecotone may have favoured the wild-type allele in recent years. Even in a system where a genotype-phenotype association appeared to be black and white, our study suggests that additional factors - including phenotypic plasticity, epistasis, pleiotropy and gene flow - may play important roles at the White Sands ecotone. Our study highlights the importance of linking molecular, genomic and organismal approaches for understanding adaptation in the wild. Furthermore, our findings indicate that dynamics of natural selection can be particularly complex in transitional habitats like ecotones and emphasize the need for future research that examines the patterns of ongoing selection in other ecological 'grey' zones. PMID- 27775198 TI - Resource: Mapping the Triticum aestivum proteome. AB - Yield and quality improvement of bread wheat (Triticum aestivum) is a focus in efforts to meet new demands from population growth and changing human diets. As the complexity of the wheat genome is unravelled, determining how it is used to build the protein machinery of wheat plants is a key next step in explaining detailed aspects of wheat growth and development. The specific functions of wheat organs during vegetative development and the role of metabolism, protein degradation and remobilisation in driving grain production are the foundations of crop performance and have recently become accessible through studies of the wheat proteome. We present a large scale, publicly accessible proteome mapping of wheat consisting of 24 organ and developmental samples. Tissue specific sub-proteomes and ubiquitously expressed markers of the wheat proteome are identified, alongside hierarchical assessment of protein functional classes, their presence in different tissues and correlations between the abundance of functional classes of proteins. Gene-specific identifications and protein family relationships are accounted for in the organisation of the data and 202 new protein-coding transcripts identified by proteogenomic mapping. The interactive database will serve as a vehicle to build, refine and deposit confirmed targeted proteomic assays for wheat proteins and protein families to assess function (www.wheatproteome.org). PMID- 27775199 TI - Aqueous Dispersions of Graphene from Electrochemically Exfoliated Graphite. AB - A facile and environmentally friendly synthetic strategy for the production of stable and easily processable dispersions of graphene in water is presented. This strategy represents an alternative to classical chemical exfoliation methods (for example the Hummers method) that are more complex, harmful, and dangerous. The process is based on the electrochemical exfoliation of graphite and includes three simple steps: 1) the anodic exfoliation of graphite in (NH4 )2 SO4 , 2) sonication to separate the oxidized graphene sheets, and 3) reduction of oxidized graphene to graphene. The procedure makes it possible to convert around 30 wt % of the initial graphite into graphene with short processing times and high yields. The graphene sheets are well dispersed in water, have a carbon/oxygen atomic ratio of 11.7, a lateral size of about 0.5-1 MUm, and contain only a few graphene layers, most of which are bilayer sheets. The processability of this type of aqueous dispersion has been demonstrated in the fabrication of macroscopic graphene structures, such as graphene aerogels and graphene films, which have been successfully employed as absorbents or as electrodes in supercapacitors, respectively. PMID- 27775200 TI - Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl-Alkenyl (sp2 vs. sp2 ) Substituted Secondary Alcohols. AB - The non-enzymatic acylative kinetic resolution of challenging aryl-alkenyl (sp2 vs. sp2 ) substituted secondary alcohols is described, with effective enantiodiscrimination achieved using the isothiourea organocatalyst HyperBTM (1 mol %) and isobutyric anhydride. The kinetic resolution of a wide range of aryl alkenyl substituted alcohols has been evaluated, with either electron-rich or naphthyl aryl substituents in combination with an unsubstituted vinyl substituent providing the highest selectivity (S=2-1980). The use of this protocol for the gram-scale (2.5 g) kinetic resolution of a model aryl-vinyl (sp2 vs. sp2 ) substituted secondary alcohol is demonstrated, giving access to >1 g of each of the product enantiomers both in 99:1 e.r. PMID- 27775201 TI - A Soft Grip: Magnesium Complexes with a Phosphine-Modified Phosphonium Diylidic Lewis Base. AB - Simple strategies to obtain magnesium complexes with the soft chelating diylidic ligand [Ph2 PCHPPh2 (fluorenylidene)]- (dppmflu- ) were developed to evaluate the influence of the hard acid (cation) and soft base (anion) mismatch on the stability and reactivity of the formed derivatives. Deprotonation of the precursor Ph2 PCH2 PPh2 (flu) (dppmfluH) by an alkylmagnesium derivative or magnesium amide provided access to [{Mg(dppmflu)(MU-nBu)}2 ], [Mg(dppmflu){N(SiMe3 )2 }], and [{Mg(dppmflu)(MU-Me)}2 ], which were used as starting materials for further investigations. The reaction of [{Mg(dppmflu)(MU nBu)}2 ] with PhSiH3 in the presence of THF allowed isolation of the magnesium hydride complex [{Mg(dppmflu)(MU-H)(thf)}2 ] without a stabilizing nitrogen donor ligand. Prolonged heating enforced ligand redistribution and [{Mg(dppmflu)(MU H)(thf)}2 ] was converted to [Mg(dppmflu)2 ] and MgH2 . The homoleptic derivative [Mg(dppmflu)2 ], in which the magnesium center is in a very soft ligand environment, can open a THF molecule by frustrated Lewis pair reactivity to give [{Mg(dppmflu)(MU-OC4 H8 dppmflu)}2 ]. PMID- 27775202 TI - Highly Swellable, Dual-Responsive Hydrogels Based on PNIPAM and Redox Active Poly(ferrocenylsilane) Poly(ionic liquid)s: Synthesis, Structure, and Properties. AB - Highly swellable, dual-responsive hydrogels, consisting of thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) and redox-responsive poly(ferrocenylsilane) (PFS) based poly(ionic liquid)s (PILs) are formed by photo-polymerization. PFS chains bearing cross-linkable vinylimidazolium (VIm) side groups are copolymerized with NIPAM in aqueous solutions under ultraviolet light (lambda = 365 nm) in the presence of a photoinitiator. The PFS-PILs serve as a macro-cross linker and also provide redox responsiveness. The swelling ratio, morphology, and lower critical solution temperature (LCST) of the hydrogels are studied as a function of the PNIPAM/PFS ratio. The value of the LCST is dependent on the choice of the counterion of the PIL and the PNIPAM/PFS ratio. The hydrogel is employed as a reducing environment for the in situ fabrication of gold nanoparticles (AuNPs), forming AuNP-hydrogel composites. The localized surface plasmon resonance peak of the as-synthesized Au nanoparticles inside the hydrogel could be tuned by altering the temperature. PMID- 27775203 TI - Topological Polymer Chemistry Enters Surface Science: Linear versus Cyclic Polymer Brushes. AB - The cyclic polymer topology strongly alters the interfacial, physico-chemical properties of polymer brushes, when compared to the linear counterparts. In this study, we especially concentrated on poly-2-ethyl-2-oxazoline (PEOXA) cyclic and linear grafts assembled on titanium oxide surfaces by the "grafting-to" technique. The smaller hydrodynamic radius of ring PEOXAs favors the formation of denser brushes with respect to linear analogs. Denser and more compact cyclic brushes generate a steric barrier that surpasses the typical entropic shield by a linear brush. This phenomenon, translates into an improved resistance towards biological contamination from different protein mixtures. Moreover, the enhancement of steric stabilization coupled to the intrinsic absence of chain ends by cyclic brushes, produce surfaces displaying a super-lubricating character when they are sheared against each other. All these topological effects pave the way for the application of cyclic brushes for surface functionalization, enabling the modulation of physico-chemical properties that could be just marginally tuned by applying linear grafts. PMID- 27775204 TI - Inherent Conformational Preferences of Ac-Gln-Gln-NHBn: Sidechain Hydrogen Bonding Supports a beta-Turn in the Gas Phase. AB - Gas-phase single-conformation spectroscopy is used to study Ac-Gln-Gln-NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide-rich peptide offers many possibilities for backbone-backbone, sidechain-backbone, and sidechain-sidechain interactions. The major conformer observed experimentally features a type-I beta turn with a canonical 10-membered ring C=O-H-N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven-membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen-bonding potential is satisfied in a manner that is consistent with and stabilizes the beta-turn secondary structure. This turn-forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins. PMID- 27775205 TI - Evidence of hepatitis E virus transmission by renal graft. AB - Hepatitis E virus (HEV) can cause chronic infection among immunocompromised patients, especially solid organ transplant recipients, and can evolve to cirrhosis. Several modes of transmission are known. Here we describe the first two cases, to our knowledge, of HEV infection transmitted by a kidney graft from the same infected donor that led to chronic hepatitis. Consequently, systematic screening of donors by HEV serology and HEV RNA detection by polymerase chain reaction, particularly in endemic regions, should be considered. PMID- 27775206 TI - An improved method for calculating toxicity-based pollutant loads: Part 2. Application to contaminants discharged to the Great Barrier Reef, Queensland, Australia. AB - Pollutant loads are widely used to set pollution reduction targets and assess regulatory compliance for the protection of receiving waterbodies. However, when a pollutant load consists of a mixture of chemicals, reducing the overall load (mass) will not necessarily reduce the toxicity by a similar amount. This can be overcome by setting targets based on toxicity-based loads (toxic loads, TLs), where the load is modified according to the relative toxicity (expressed as toxic equivalency factors [TEFs]) of each toxicant. Here, we present the second article of a 2-part series in which a case study is used to demonstrate the application of the toxic load method proposed in Part 1. The toxic load method converts a pollutant load, comprised of multiple chemicals, to a toxic load, using a modified TEF approach. The modified approach uses a cumulative distribution of relative potency (ReP) estimates of multiple species to determine a TEF. It further improves upon previously published methods by including two tests to select the optimal percentile of the ReP distribution to determine the TEF. The first test is a test for environmental relevance that compares results against an independent mixture method, identifying the percentile that produces the most environmentally relevant TEFs and TLs. The second is a test for robustness which ensures the results are independent of the ReP of the selected reference chemical. Here, the TL method is applied to mixtures of pesticides that are discharged from agricultural land to the Great Barrier Reef (GBR) to test its utility. In this case study, the most environmentally relevant and robust TLs were generated using the 75th percentile of the ReP cumulative distribution. The results demonstrate that it is essential to develop pollution reduction targets based on toxic loads and making progress to meeting them will lead to a commensurate reduction in toxic effects caused by toxicants in waters of the GBR. Integr Environ Assess Manag 2017;13:754-764. (c) 2016 SETAC. PMID- 27775207 TI - The Origin of the Efficient, Thermal Chemisorption of Methane by the Heteronuclear Metal-Oxide Cluster [Al2 TaO5 ]. AB - The thermal gas-phase reactions of the closed-shell metal-oxide cluster [Al2 TaO5 ]+ with methane have been explored by using FT-ICR mass spectrometry complemented by high-level quantum chemical calculations. Mechanistic aspects have been addressed to reveal the origins of the efficient addition process which results in activating the C-H bond of methane. The [Al2 TaO5 ]+ /CH4 couple has been compared with several other systems reported previously, and the electronic origins of their rather distinct performances are discussed. PMID- 27775208 TI - Formation of Triple-Shelled Molybdenum-Polydopamine Hollow Spheres and Their Conversion into MoO2 /Carbon Composite Hollow Spheres for Lithium-Ion Batteries. AB - Unique triple-shelled Mo-polydopamine (Mo-PDA) hollow spheres are synthesized through a facile solvothermal process. A sequential self-templating mechanism for the multi-shell formation is proposed, and the number of shells can be adjusted by tuning the size of the Mo-glycerate templates. These triple-shelled Mo-PDA hollow spheres can be converted to triple-shelled MoO2 /carbon composite hollow spheres by thermal treatment. Owing to the unique multi-shells and hollow interior, the as-prepared MoO2 /carbon composite hollow spheres exhibit appealing performance as an anode material for lithium-ion batteries, delivering a high capacity of ca. 580 mAh g-1 at 0.5 A g-1 with good rate capability and long cycle life. PMID- 27775209 TI - Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection. AB - BACKGROUND: Hepatocellular carcinoma recurrence following liver resection remains a great concern. The study aims to examine the chemopreventive effect of metformin in patients undergoing liver resection for hepatocellular carcinoma from a population-based study. METHODS: All patients registered as having hepatocellular carcinoma between January 1995 and December 2011 in a nationwide database were retrospectively analysed. Outcomes related to liver resection and the presence of diabetes mellitus were assessed. Prognosis in terms of the use of metformin was further explored, in which only patients in the long-term follow-up starting at 2 years were included for analysis. RESULTS: Patients with diabetes mellitus had a significantly poorer outcome than patients without diabetes mellitus. Among diabetes mellitus patients, metformin users had significantly better survival curves in both recurrence-free survival (P<.0001) and overall survival (P<.0001) after liver resection. The hazard ratio of metformin use in hepatocellular carcinoma patients with diabetes mellitus was 0.65 (P<.05, 95% CI=0.60-0.72) for hepatocellular carcinoma recurrence and 0.79 (P<.05, 95% CI=0.72-0.88) for overall survival after liver resection. The risk reduction in hepatocellular carcinoma recurrence after liver resection was significantly associated with a dose/duration dependent of accumulated metformin usage. CONCLUSION: Diabetes mellitus has an adverse effect on patients with hepatocellular carcinoma regardless of treatment modality. The use of metformin significantly reduces the risk of hepatocellular carcinoma recurrence and improves the overall outcome of patients after liver resection if patients survives the initial 2 years. Nonetheless, a prospective controlled study is recommended for validating the metformin use on preventing postoperative hepatocellular carcinoma recurrence. PMID- 27775210 TI - G-Protein-Coupled Receptors: Sustained Signaling via Intracellular Megaplexes and Pathway-Specific Drugs. AB - Together forever? Functional selection was applied to finally achieve separation of the analgesic properties of opiods from serious side effects such as potentially lethal respiratory depression. A Gi-biased MU-opioid-receptor agonist (PZM21) was identified that stabilizes previously unexplored receptor conformations. This compound relieves pain in mice without causing hypoventilation or addiction. PMID- 27775211 TI - Azaborabutadienes: Synthesis by Metal-Free Carboboration of Nitriles and Utility as Building Blocks for B,N-Heterocycles. AB - Metal-free regioselective carboboration of arylnitriles with L2 PhB: (1: L=oxazol 2-ylidene) catalyzed by Et3 B afforded the unprecedented acyclic 2-aza-4 borabutadienes 2, thus demonstrating a new strategy to construct a B,C,N-mixed pi system involving B=C and C=N bonds. Thermal isomerization of 2 gave C-borylimines (3), and diverse reactivity of 2 a towards several substrates, such as H+ , F+ , O2 , S, Se, and isonitriles, allowed construction of boron-containing heterocycles with various ring sizes, thus illustrating the utility of 2 as a synthetic building block. PMID- 27775212 TI - A comparison of two methods to measure choroidal thickness by enhanced depth imaging optical coherence tomography. PMID- 27775213 TI - Cesium Platinide Hydride 4Cs2 Pt?CsH: An Intermetallic Double Salt Featuring Metal Anions. AB - With Cs9 Pt4 H a new representative of ionic compounds featuring metal anions can be added to this rare-membered family. Cs9 Pt4 H exhibits a complex crystal structure containing Cs+ cations, Pt2- and H- anions. Being a red, transparent compound its band gap is in the visible range of the electromagnetic spectrum and the ionic type of bonding is confirmed by quantum chemical calculations. This cesium platinide hydride can formally be considered as a double salt of the "alloy" cesium-platinum, or better cesium platinide, Cs2 Pt, and the salt cesium hydride CsH according to Cs9 Pt4 H=4 Cs2 Pt?CsH. PMID- 27775215 TI - Corrigendum. PMID- 27775214 TI - Metabolic switching of astringent and beneficial triterpenoid saponins in soybean is achieved by a loss-of-function mutation in cytochrome P450 72A69. AB - Triterpenoid saponins are major components of secondary metabolites in soybean seeds and are divided into two groups: group A saponins, and 2,3-dihydro-2,5 dihydroxy-6-methyl-4H-pyran-4-one (DDMP) saponins. The aglycone moiety of group A saponins consists of soyasapogenol A (SA), which is an oxidized beta-amyrin product, and the aglycone moiety of the DDMP saponins consists of soyasapogenol B (SB). Group A saponins produce a bitter and astringent aftertaste in soy products, whereas DDMP saponins have known health benefits for humans. We completed map-based cloning and characterization of the gene Sg-5, which is responsible for SA biosynthesis. The naturally occurring sg-5 mutant lacks group A saponins and has a loss-of-function mutation (L164*) in Glyma15g39090, which encodes the cytochrome P450 enzyme, CYP72A69. An enzyme assay indicated the hydroxylase activity of recombinant CYP72A69 against SB, which also suggested the production of SA. Additionally, induced Glyma15g39090 mutants (R44* or S348P) lacked group A saponins similar to the sg-5 mutant, indicating that Glyma15g39090 corresponds to Sg-5. Endogenous levels of DDMP saponins were higher in the sg-5 mutant than in the wild-type lines due to the loss of the enzyme activity that converts SB to SA. Interestingly, the genomes of palaeopolyploid soybean and the closely related common bean carry multiple Sg-5 paralogs in a genomic region syntenic to the soybean Sg-5 region. However, SA did not accumulate in common bean samples, suggesting that Sg-5 activity evolved after gene duplication event(s). Our results demonstrate that metabolic switching of undesirable saponins with beneficial saponins can be achieved in soybean by disabling Sg-5. PMID- 27775216 TI - Near-Infrared Fluorescent Probe with New Recognition Moiety for Specific Detection of Tyrosinase Activity: Design, Synthesis, and Application in Living Cells and Zebrafish. AB - Fluorescence imaging of tyrosinase (a cancer biomarker) in living organisms is of great importance for biological studies. However, selective detection of tyrosinase remains a great challenge because current fluorescent probes that contain the 4-hydroxyphenyl moiety show similar fluorescence responses to both tyrosinase and some reactive oxygen species (ROS), thereby suffering from ROS interference. Herein, a new tyrosinase-recognition 3-hydroxybenzyloxy moiety, which exhibits distinct fluorescence responses for tyrosinase and ROS, is proposed. Using the recognition moiety, we develop a near-infrared fluorescence probe for tyrosinase activity, which effectively eliminates the interference from ROS. The high specificity of the probe was demonstrated by imaging and detecting endogenous tyrosinase activity in live cells and zebrafish and further validated by an enzyme-linked immunosorbent assay. The probe is expected to be useful for the accurate detection of tyrosinase in complex biosystems. PMID- 27775217 TI - The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level. AB - PURPOSE: Despite being the third most common ABCA4 variant observed in patients with Stargardt disease, the functional effect of the intronic ABCA4 variant c.5461-10T>C is unknown. The purpose of this study was to investigate the molecular effect of this variant. METHODS: Fibroblast samples from patients carrying the ABCA4 variant c.5461-10T>C were analysed by isolating total RNA, followed by real-time polymerase chain reaction (RT-PCR) using specific primers spanning the variant. For detection of ABCA4 protein, fibroblast samples were lysed and analysed by SDS-PAGE followed by immunoblotting using a monoclonal ABCA4 antibody. RESULTS: The ABCA4 variant c.5461-10T>C causes a splicing defect resulting in the reduction of full-length mRNA in fibroblasts from patients and the presence of alternatively spliced mRNAs where exon 39-40 is skipped. A reduced level of full-length ABCA4 protein is observed compared to controls not carrying the variant. CONCLUSIONS: This study describes the functional effect and the molecular mechanism of the pathogenic ABCA4 variant c.5461-10T>C. The variant is functionally important as it leads to splicing defects and a reduced level of ABCA4 protein. PMID- 27775218 TI - Reflections in the mirror - Idiopathic intracranial hypertension and non-specific orbital inflammation in identical twins. PMID- 27775220 TI - ITS all right mama: investigating the formation of chimeric sequences in the ITS2 region by DNA metabarcoding analyses of fungal mock communities of different complexities. AB - The formation of chimeric sequences can create significant methodological bias in PCR-based DNA metabarcoding analyses. During mixed-template amplification of barcoding regions, chimera formation is frequent and well documented. However, profiling of fungal communities typically uses the more variable rDNA region ITS. Due to a larger research community, tools for chimera detection have been developed mainly for the 16S/18S markers. However, these tools are widely applied to the ITS region without verification of their performance. We examined the rate of chimera formation during amplification and 454 sequencing of the ITS2 region from fungal mock communities of different complexities. We evaluated the chimera detecting ability of two common chimera-checking algorithms: perseus and uchime. Large proportions of the chimeras reported were false positives. No false negatives were found in the data set. Verified chimeras accounted for only 0.2% of the total ITS2 reads, which is considerably less than what is typically reported in 16S and 18S metabarcoding analyses. Verified chimeric 'parent sequences' had significantly higher per cent identity to one another than to random members of the mock communities. Community complexity increased the rate of chimera formation. GC content was higher around the verified chimeric break points, potentially facilitating chimera formation through base pair mismatching in the neighbouring regions of high similarity in the chimeric region. We conclude that the hypervariable nature of the ITS region seems to buffer the rate of chimera formation in comparison with other, less variable barcoding regions, due to shorter regions of high sequence similarity. PMID- 27775221 TI - Light Chain Podocytopathy Mimicking Recurrent Focal Segmental Glomerulosclerosis. AB - Kidney injury related to paraproteinemia is common and typically occurs after the fourth decade of life in association with an underlying plasma cell dyscrasia or other lymphoproliferative disease. Kidney transplantation in paraprotein-related kidney disease can be successful in conjunction with treatment of the underlying hematopoietic process; however, when hematologic response to therapy is not achieved, recurrent kidney injury is frequently seen. We describe a young male patient who presented at the age of 23 years with end-stage kidney disease thought to be secondary to focal segmental glomerulosclerosis; this patient ultimately received two kidney allografts. He experienced recurrent proteinuria in both kidneys, with a biopsy from his second allograft showing kappa-restricted crystalline light chain podocytopathy, which was identified in both his native and first allograft kidneys upon retrospective review. Recurrent light chain podocytopathy has not been previously reported but poses a diagnostic challenge as it can mimic focal segmental glomerulosclerosis, particularly in young patients in whom paraprotein-related kidney injury is usually not suspected. PMID- 27775219 TI - Towards comprehensive and quantitative proteomics for diagnosis and therapy of human disease. AB - Given superior analytical features, MS proteomics is well suited for the basic investigation and clinical diagnosis of human disease. Modern MS enables detailed functional characterization of the pathogenic biochemical processes, as achieved by accurate and comprehensive quantification of proteins and their regulatory chemical modifications. Here, we describe how high-accuracy MS in combination with high-resolution chromatographic separations can be leveraged to meet these analytical requirements in a mechanism-focused manner. We review the quantification methods capable of producing accurate measurements of protein abundance and posttranslational modification stoichiometries. We then discuss how experimental design and chromatographic resolution can be leveraged to achieve comprehensive functional characterization of biochemical processes in complex biological proteomes. Finally, we describe current approaches for quantitative analysis of a common functional protein modification: reversible phosphorylation. In all, current instrumentation and methods of high-resolution chromatography and MS proteomics are poised for immediate translation into improved diagnostic strategies for pediatric and adult diseases. PMID- 27775222 TI - Monitoring macular pigment changes in macular holes using fluorescence lifetime imaging ophthalmoscopy. AB - PURPOSE: To investigate the impact of macular pigment (MP) on fundus autofluorescence (FAF) lifetimes in vivo by characterizing full-thickness idiopathic macular holes (MH) and macular pseudo-holes (MPH). METHODS: A total of 37 patients with MH and 52 with MPH were included. Using the fluorescence lifetime imaging ophthalmoscope (FLIO), based on a Heidelberg Engineering Spectralis system, a 30 degrees retinal field was investigated. FAF decays were detected in a short (498-560 nm; ch1) and long (560-720 nm; ch2) wavelength channel. taum , the mean fluorescence lifetime, was calculated from a three exponential approximation of the FAF decays. Macular coherence tomography scans were recorded, and macular pigment's optical density (MPOD) was measured (one wavelength reflectometry). Two MH subgroups were analysed according to the presence or absence of an operculum above the MH. A total of 17 healthy fellow eyes were included. A longitudinal FAF decay examination was conducted in nine patients, which were followed up after surgery and showed a closed MH. RESULTS: In MH without opercula, significant taum differences (p < 0.001) were found between the hole area (MHa) and surrounding areas (MHb) (ch1: MHa 238 +/- 64 ps, MHb 181 +/- 78 ps; ch2: MHa 275 +/- 49 ps, MHb 223 +/- 48 ps), as well as between MHa and healthy eyes or closed MH. Shorter taum , adjacent to the hole, can be assigned to areas with equivalently higher MPOD. Opercula containing MP also show short taum . In MPH, the intactness of the Hele fibre layer is associated with shortest taum . CONCLUSIONS: Shortest taum originates from MP-containing retinal layers, especially from the Henle fibre layer. Fluorescence lifetime imaging ophthalmoscope (FLIO) provides information on the MP distribution, the pathogenesis and topology of MH. Macular pigment (MP) fluorescence may provide a biomarker for monitoring pathological changes in retinal diseases. PMID- 27775223 TI - Imaging retinal inflammatory biomarkers after intravitreal steroid and anti-VEGF treatment in diabetic macular oedema. AB - PURPOSE: To evaluate changes of specific retinal imaging biomarkers [intraretinal hyper-reflective retinal spots: HRS ; subfoveal neuroretinal detachment: SND; and increased foveal autofluorescence: IFAF after intravitreal steroid or anti vascular endothelial growth factor treatment in diabetic macular oedema (DME)] as possible indicators of retinal inflammatory condition. METHODS: Retrospective analysis of images and clinical charts of 49 eyes (49 patients) with DME treated with intravitreal dexamethasone (dexamethasone, 23 eyes) or intravitreal ranibizumab (ranibizumab, 26 eyes). All patients had fundus colour photograph, spectral domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF), best-corrected visual acuity (BCVA) and microperimetry recorded before and 1 month after the end of treatment. Central macular thickness (CMT), number of HRS and presence of SND were evaluated by SD OCT. Fundus autofluorescence images were evaluated for area of (IFAF). Retinal sensitivity within 4 degrees and 12 degrees from fovea was quantified by microperimetry. Changes in morphologic and functional parameters were assessed, and correlation was performed by Pearson's correlation. RESULTS: Best-corrected visual acuity and CMT improved in all patients, (p < 0.05, for both groups). Mean number of HRS decreased after both treatments (p < 0.0001). Subfoveal neuroretinal detachment resolved in 85.7% dexamethasone-treated eyes (p = 0.014) and in 50% ranibizumab-treated eyes (p = 0.025). Mean IFAF area decreased in both groups, (p < 0.0001, for both). A significantly higher decrease in CMT was observed in dexamethasone- versus ranibizumab-treated eyes, (p = 0.032). In dexamethasone group, higher number of HRS at baseline and larger IFAF were correlated with higher increase in retinal sensitivity; eyes with SND at baseline had major decrease in CMT versus those without SND, (p = 0.003). CONCLUSION: Higher number of HRS, larger area of IFAF and presence of SND may indicate a prevalent inflammatory condition in DME with specific response to targeted treatment. PMID- 27775224 TI - Urine cytology of nonurothelial malignancies-a 10-year experience in a large multihospital healthcare system. AB - BACKGROUND: Urine cytology is the most frequently utilized test to detect urothelial cancer. Secondary bladder neoplasms need to be recognized as this impacts patient management. We report our experience on nonurothelial malignancies (NUM) detected in urine cytology over a 10-year period. METHODS: A 10-year retrospective search for patients with biopsy-proven NUM to the urothelial tract yielded 25 urine samples from 14 patients. Two cytopathologists blinded to the original cytology diagnosis reviewed the cytology and histology slides. The incidence, cytomorphologic features, diagnostic accuracy, factors influencing the diagnostic accuracy, and clinical impact of the cytology result were studied. RESULTS: The incidence of NUM was <1%. The male:female ratio was 1.3. An abnormality was detected in 60% of the cases; however, in only 4% of the cases, a primary site was identified accurately. Of the false negatives, 96% was deemed as sampling errors and 4% was interpretational. Patient management was not impacted in any of the false-negative cases due to concurrent or past tissue diagnosis. CONCLUSION: Colon cancer was the most frequent secondary tumor. Sampling error attributed to the false-negative results. Necrosis and dirty background was often associated with metastatic lesions from colon. Obtaining history of a primary tumor elsewhere was a key factor in diagnosis of a metastatic lesion. Hematopoietic malignancies remain to be a diagnostic challenge. Cytospin preparations were superior for evaluating nuclear detail and background material as opposed to monolayer (Thinprep) technology. Diagnostic accuracy was improved by obtaining immunohistochemistry. Diagn. Cytopathol. 2016. (c) 2016 Wiley Periodicals, Inc. Diagn. Cytopathol. 2017;45:22-28. (c) 2016 Wiley Periodicals, Inc. PMID- 27775225 TI - Characterization of Phenotypic and Transcriptional Differences in Human Pluripotent Stem Cells under 2D and 3D Culture Conditions. AB - Human pluripotent stem cells hold great promise for applications in drug discovery and regenerative medicine. Microfluidic technology is a promising approach for creating artificial microenvironments; however, although a proper 3D microenvironment is required to achieve robust control of cellular phenotypes, most current microfluidic devices provide only 2D cell culture and do not allow tuning of physical and chemical environmental cues simultaneously. Here, the authors report a 3D cellular microenvironment plate (3D-CEP), which consists of a microfluidic device filled with thermoresponsive poly(N-isopropylacrylamide)-beta poly(ethylene glycol) hydrogel (HG), which enables systematic tuning of both chemical and physical environmental cues as well as in situ cell monitoring. The authors show that H9 human embryonic stem cells (hESCs) and 253G1 human induced pluripotent stem cells in the HG/3D-CEP system maintain their pluripotent marker expression under HG/3D-CEP self-renewing conditions. Additionally, global gene expression analyses are used to elucidate small variations among different test environments. Interestingly, the authors find that treatment of H9 hESCs under HG/3D-CEP self-renewing conditions results in initiation of entry into the neural differentiation process by induction of PAX3 and OTX1 expression. The authors believe that this HG/3D-CEP system will serve as a versatile platform for developing targeted functional cell lines and facilitate advances in drug screening and regenerative medicine. PMID- 27775227 TI - Retinal oxygen saturation before and after glaucoma surgery. AB - PURPOSE: This study compared retinal vessel oxygen saturation before and after glaucoma surgery. METHODS: Retinal oxygen saturation in glaucoma patients was measured using a non-invasive spectrophotometric retinal oximeter. Adequate image quality was found in 49 of the 108 consecutive glaucoma patients recruited, with 30 undergoing trabeculectomy, 11 EX-PRESS and eight trabeculotomy. Retinal oxygen saturation measurements in the retinal arterioles and venules were performed at 1 day prior to and at approximately 10 days after surgery. Statistical analysis was performed using a Student's t-test. RESULTS: After glaucoma surgery, intraocular pressure (IOP) decreased from 19.8 +/- 7.7 mmHg to 9.0 +/- 5.7 mmHg (p < 0.001). Although oxygen saturation in retinal arterioles remained unchanged before and after surgery (104.7 +/- 10.6% before and 105.4 +/- 9.3% after surgery, p = 0.58), the oxygen saturation in the venules increased from 54.9 +/- 7.4% to 57.4 +/- 5.7% (p = 0.01). CONCLUSION: Intraocular pressure (IOP) decreases caused by glaucoma surgery had an effect on the retinal venous oxygen saturation. PMID- 27775226 TI - Porphyrin-Sensitized Evolution of Hydrogen using Dawson and Keplerate Polyoxometalate Photocatalysts. AB - Hydrogen evolution using photocatalytic systems based on artificial photosynthesis is a major approach toward solar energy conversion and storage. In the polyoxometalate-based photocatalytic systems proposed in the past, middle/near UV light irradiation and noble-metal catalysts were mainly used. Although recently polyoxometalates were sensitized in visible light, photosensitizers or catalysts based on noble metals, and/or poor activity of polyoxometalates were generally obtained. Here we show the highly efficient [turnover number (TON)=215] hydrogen evolution induced by the zinc(II) mesotetrakis(N-methyl-pyridinium-4-yl)porphyrin (ZnTMPyP4+ ) sensitization of a series of polyoxometalate catalysts (two Dawson type, P2 Mo18 O626- and P2 W18 O626- anions, and one Keplerate {Mo132 } cluster) in a visible-light-driven, noble-metal-free, and fully water-soluble system. We attributed the high efficiency for hydrogen evolution to the multi-electron reduction of polyoxometalates and found that: (a) both Dawson polyoxometalates exhibit higher hydrogen evolution efficiency upon ZnTMPyP4+ sensitization in relation to the direct photoreduction of those compounds; (b) the P2 Mo18 O626- anion is more efficient (TON=65 vs. 38, respectively) for hydrogen evolution than the P2 W18 O626- anion; and (c) the high nuclearity Keplerate {Mo132 } cluster exhibits the highest efficiency (TON=215) for hydrogen evolution compared with the polyoxometalates studied. PMID- 27775228 TI - Dynamic changes of the intraocular pressure and the pressure of cerebrospinal fluid in nonglaucomatous neurological patients. AB - PURPOSE: To describe the dynamic changes of the intraocular pressure (IOP) and intracranial pressure (ICP) with normal or pathological values (intracranial hypertension) in nonglaucomatous neurological patients during lumbar punction (LP). METHODS: Case-control study, prospective measurement of tonometry in both groups referred for LP. Intraocular pressure, ICP and translaminar pressure difference (TPD) were compared pre- and post-LP. RESULTS: Thirty-six patients (72 eyes) with mean age of 38.5 (16-64) years and BMI of 26.81 kg/m2 were analysed. The initial mean ICP was 12.81 (+/- 6.6) mmHg. The mean TPD before and after the LP was 1.48 mmHg and 0.65 mmHg, respectively. The mean IOP of both eyes decreased to 0.8 mmHg post-LP in patients with pathological ICP (p = 0.0193) and normal ICP (p = 0.006). CONCLUSIONS: We found a statistically significant decrease of the IOP post-LP compared to the pre-LP in both groups, being higher in patients with pathological ICP. There were no significant differences of the IOP in patients with normal versus pathological ICP pre-LP/post-LP; neither was found a correlation between ICP and IOP. PMID- 27775229 TI - A Bimetallic Aluminium(Salphen) Complex for the Synthesis of Cyclic Carbonates from Epoxides and Carbon Dioxide. AB - A bimetallic aluminium(salphen) complex is reported as a sustainable, efficient and inexpensive catalyst for the synthesis of cyclic carbonates from epoxides and carbon dioxide. In the presence of this complex and tetrabutylammonium bromide, terminal and internal epoxides reacted at 50 degrees C and 10 bar carbon dioxide pressure to afford their corresponding cyclic carbonates in yields of 50-94 % and 30-71 % for terminal and internal cyclic carbonates, respectively. Mechanistic studies using deuterated epoxides and an analogous monometallic aluminium(salphen) chloride complex support a mechanism for catalysis by the bimetallic complex, which involves intramolecular cooperative catalysis between the two aluminium centres. PMID- 27775230 TI - Clinical and genetic heterogeneity in Slovenian patients with BEST disease. AB - PURPOSE: To determine the spectrum of BEST1 mutations and to study the phenotype in Slovenian families with Best vitelliform macular dystrophy (BVMD) to identify genotype-phenotype correlations. METHODS: Twenty patients from five families underwent the ophthalmological examination including electrooculogram (EOG; N = 17), fundus autofluorescence imaging (N = 16) and optical coherence tomography (N = 14). Mutational screening was performed by direct DNA sequencing of the BEST1 gene. RESULTS: Mutation c.43G>C (p.Gly15Arg) was detected in three patients from family M presenting with different clinical stages of Best disease. Mutation c.313G>C (p.Arg105Gly) was found in families K, ST, S, B and was associated with incomplete clinical penetrance and variable retinal changes, including extramacular and multifocal lesions. In three patients from family K, an atypical form of BVMD was observed; there were additional peripheral lesions outside of the vascular arcades in addition to the typical macular lesions. Multiple alterations between the vitelliruptive and pseudohypopyon stages over a period of 11 years were seen in one patient. CONCLUSION: Two previously unreported disease associated variants in the BEST1 gene (p.Gly15Arg and p.Arg105Gly) were found in Slovenian patients with Best disease. Our data expand the mutation spectrum of the BEST1 gene and further support the broad phenotypic variability observed clinically and with optical coherence tomography (OCT) and AF imaging. PMID- 27775231 TI - Genomic full-length sequence of two HLA-A alleles, A*24:08 and A*24:10, identified by cloning and sequencing. AB - Genomic full-length sequences of HLA-A*24:08 and A*24:10, were identified by cloning and sequencing. PMID- 27775232 TI - Sentinel lymph node biopsy for ocular adnexal melanoma. AB - BACKGROUND: We sought to update our prior report of findings on sentinel lymph node biopsy (SLNB) and predictors of a positive SLN in patients with conjunctival or eyelid melanoma. METHODS: We reviewed the records of all patients with ocular adnexal melanoma who underwent SLNB at one institution during 2000-2015. We determined rates of positive and false-negative findings on SLNB, primary tumour features correlated with positive findings and rate of nodal recurrence (false negative event) after negative findings. RESULTS: The study included 51 patients, 31 with conjunctival and 20 with eyelid melanoma. These patients include 30 patients who underwent SLNB during 2000-2008, described in our previous report, and 21 additional patients who underwent SLNB during 2008-2015. There were 30 women and 21 men with median age at SLNB of 62 years (range, 24-83). The nodal basins most commonly sampled were intraparotid (27 patients) and level II (14 patients). Ten patients had positive SLNB findings. Compared to tumours with negative findings, tumours with positive findings had greater median thickness (3.5 mm versus 2.2 mm, p = 0.04), greater median number of mitotic figures (6 versus 2, p = 0.03) and greater incidence of ulceration (80% versus 26%, p = 0.003). Perineural and vascular invasion were not significantly associated with positive findings. There were three false-negative events. Three patients (6%) had temporary marginal mandibular weakness which resolved spontaneously. CONCLUSION: SLNB in patients with ocular adnexal melanoma is safe and identifies nodal micrometastasis in approximately 20% of cases. Histologic features associated with a positive SLN included greater tumour thickness, greater number of mitotic figures and ulceration. PMID- 27775233 TI - An enlarged cell wall proteome of Arabidopsis thaliana rosettes. AB - Plant cells are surrounded by cell walls playing many roles during development and in response to environmental constraints. Cell walls are mainly composed of polysaccharides (cellulose, hemicelluloses and pectins), but they also contain proteins which are critical players in cell wall remodeling processes. Today, the cell wall proteome of Arabidopsis thaliana, a major dicot model plant, comprises more than 700 proteins predicted to be secreted (cell wall proteins-CWPs) identified in different organs or in cell suspension cultures. However, the cell wall proteome of rosettes is poorly represented with only 148 CWPs identified after extraction by vacuum infiltration. This new study allows enlarging its coverage. A destructive method starting with the purification of cell walls has been performed and two experiments have been compared. They differ by the presence/absence of protein separation by a short 1D-electrophoresis run prior to tryptic digestion and different gradient programs for peptide separation before mass spectrometry analysis. Altogether, the rosette cell wall proteome has been significantly enlarged to 361 CWPs, among which 213 newly identified in rosettes and 57 newly described. The identified CWPs fall in four major functional classes: 26.1% proteins acting on polysaccharides, 11.1% oxido-reductases, 14.7% proteases and 11.7% proteins possibly related to lipid metabolism. PMID- 27775234 TI - Sterile corneal infiltrates after corneal collagen cross-linking: evaluation of risk factors. AB - PURPOSE: To evaluate possible risk factors leading to sterile corneal infiltrates following corneal collagen cross-linking (CXL). METHODS: A total of 588 eyes of 459 patients treated with Epi-off (n = 461) or Epi-on (n = 127) CXL were retrospectively evaluated. Risk factors, including preoperative blepharitis and vernal conjunctivitis, the postoperative use of topical non-steroidal anti inflammatory drugs (NSAIDs), as well as Kmax and pachymetry measurements, were assessed. In vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) analyses were performed in patients with sterile infiltrates. RESULTS: Sterile infiltrates developed in 19 cases (3.2%). No patients in the Epi-on group developed sterile infiltrates. The evaluation of acceleration of the CXL procedure as a risk factor revealed no specific difference in the incidence of infiltrates among four different Epi-off groups (3 mW/cm2 -30 min, 9 mW/cm2 -10 min, 18 mW/cm2 -5 min, 30 mW/cm2 -4 min procedures; p > 0.05, all). Blepharitis, vernal conjunctivitis, Kmax and pachymetry were not identified as risk factors (p > 0.05). Postoperative use of NSAIDs was a significant contributor (p = 0.007), and it increased the chance of sterile infiltrates 4.09 times (95% CI, 1.463-11.428). In vivo confocal microscopy (IVCM) showed non-specific inflammation with dendritic cells at the epithelium and at Bowman's layer. In AS-OCT, a hyper-reflective band at the level of the anterior stroma to a depth of 100-140 MUm was observed. CONCLUSION: The evaluation of the risk factors such as blepharitis, the use of NSAIDs, vernal conjunctivitis, the duration of CXL procedure and amount of light intensity showed that epithelial damage is possibly the common pathway in the pathogenesis, as no sterile infiltrates in Epi-on CXL occurred, and the postoperative use of NSAIDs increased the risk of developing sterile infiltrates about four times. PMID- 27775235 TI - Towards better characterization and quantification of emulsification of silicone oil in vitro. AB - PURPOSE: Emulsification is related to complications arising from silicone oil (SO) tamponade. Currently, there is no widely accepted method for testing the propensity of SO to emulsify that are physiologically realistic and quantitative. METHODS: We compared different ways of inducing emulsification namely vortex mixing, sonication and homogenization. Silicone oil (SO) emulsification was quantitatively assessed using the Coulter counter and laser light scattering. The in vitro results are compared with the droplet size distribution profile of vitreous clinical washout. Conventional SO was compared with two novel SO blends with high-molecular-weight (HMW) additives (SOHMW2000 and SOHMW5000 ). RESULTS: Of the three methods for inducing emulsification, homogenization generated the most consistent emulsion samples with the smallest variance. The results from the Coulter counter measurement correlated strongly with the laser light scattering measurement within the range of 1 to 30 um. The droplet size distribution profiles from human eyes were similar to that of emulsions generated in vitro by homogenization. The human size distribution profile was within the range of values obtained by the in vitro experiment. Compared to the conventional SO, the emulsion droplet counts for the new SO blends were significantly lower (SOHMW2000 and SOHMW5000 were 79% (+/-17%) and 49% (+/-18%) of the SO2000 and SO5000 , respectively; p = 0.03 and p = 0.002). CONCLUSION: Emulsion generated in vitro by homogenization has similar droplet size profile as human eyes filled with SO. Using this method to induce emulsion, SO blends with HMW additives demonstrated less propensity to emulsification with lower droplet counts compared to conventional SO with similar shear viscosity. PMID- 27775236 TI - Half-Life Extension of Biopharmaceuticals using Chemical Methods: Alternatives to PEGylation. AB - Peptides and proteins constitute a vast pool of excellent drug candidates. Evolution has equipped these molecules with superior drug-like properties such as high specificity and potency. However, native peptides and proteins suffer from an inadequate pharmacokinetic profile, and their outstanding pharmacological potential can only be realized if this issue is addressed during drug development. To overcome this challenge, a variety of half-life extension techniques relying on covalent chemical modification have been developed. These methods include PEGylation, fusion to unstructured polypeptide-based PEG mimetics, conjugation of large polysaccharides, native-like glycosylation, lipidation, fusion to albumin or the Fc domain of IgG, and derivatization with bio-orthogonal moieties that direct self-assembly. This review provides an overview of available conjugation chemistries, biophysical properties, and safety data associated with these concepts. Moreover, the effects of these modifications on peptide and protein pharmacokinetics are demonstrated through key examples. PMID- 27775237 TI - Validation, test-retest reliability and norm scores for the Dutch Catquest-9SF. AB - PURPOSE: The Catquest-9SF questionnaire is a unidimensional, reliable, valid and short patient-reported outcome measure for quantifying benefits in visual functioning from cataract surgery. Our aim was to develop a formal Dutch translation, calculate norm scores, assess its validity and test-retest reliability and provide an easy way for use in clinical practice. METHODS: Translation of the questionnaire was performed according to guidelines of the International Society for Pharmacoeconomics and Outcomes Research. Catquest-9SF was obtained in 657 patients pre- and postcataract surgery. We applied Rasch and classical analyses to determine the questionnaire performance with characteristics such as unidimensionality, reliability, separation and differential item functioning. Test-retest reliability was assessed in another group of 145 patients. A cut-off value to discriminate between people with and without cataract, norm scores and a reliable change index (RCI) were calculated using data from a sample of 916 'healthy' persons from the normal population. RESULTS: The Dutch Catquest-9SF was unidimensional, and both person and item reliability were high; 0.87 and 0.99, respectively. Cronbach's alpha was 0.94, test-retest reliability was 0.85 and the intraclass correlation coefficient was 0.93. Catquest-9SF showed to be responsive to the effect of cataract surgery (effect size = 1.27; p < 0.001). The cut-off value was -1.90, and RCI was 2.27. A quick-access table with norm scores and percentiles was established to facilitate clinical interpretation. CONCLUSION: This investigation provides validity and reliability of the Dutch Catquest-9SF as well as norm scores and a new tool to facilitate the clinical interpretation of patient scores. This makes Catquest-9SF suitable for routine use in clinical practice. PMID- 27775238 TI - Thickness of macular inner retinal layers and peripapillary retinal nerve fibre layer in neuromyelitis optica spectrum optic neuritis and isolated optic neuritis with one episode. AB - PURPOSE: The aim of this study was to evaluate the differences between macular inner retinal layers and peripapillary retinal nerve fibre layer (pRNFL) thickness in Chinese patients with neuromyelitis spectrum optic neuritis (NMOSD ON) and isolated optic neuritis (ION) with only one episode. METHODS: This cross sectional study included 35 patients (35 eyes) with NMOSD-ON (NMO-IgG seropositive) and 46 patients (46 eyes) with ION after one episode. Spectral domain optical coherence tomography (SD-OCT) was used to quantify pRNFL, macular RNFL (mRNFL), ganglion cell and inner plexiform layers (GCIPL) and inner nuclear layer (INL) thickness using an automated algorithm. Differences in OCT parameters between NMOSD-ON and ION were compared after adjusting for age, sex and disease duration. RESULTS: The pRNFL and mRNFL in some locations (average pRNFL, nasal pRNFL, nasal inferior (NI) pRNFL, nasal/temporal (N/T) ratio pRNFL, average mRNFL, inner temporal mRNFL, outer nasal mRNFL and outer temporal mRNFL) in NMOSD ON differed significantly from those in ION (all p < 0.05). These parameters had moderate diagnostic accuracy, with area under curves (AUCs) ranging from 0.684 to 0.762 for pRNFL and from 0.660 to 0.700 for mRNF. The thickness of GC-IPL and INL in all sectors was similar in NMOSD-ON and ION (p > 0.05). This study and our meta-analysis of four previous studies obtained consistent results, with pooled mean difference (MD) -10.4 MUm (95% CI: -12.4 to -8.4, p < 0.001) for pRNFL, -1.5 MUm (95% CI: -3.5 to 0.6, p = 0.158) for mRNFL and 0.2 MUm (95% CI: -0.4 to 0.9, p = 0.490) for GC-IPL, respectively. CONCLUSIONS: Neuromyelitis spectrum optic neuritis (NMOSD-ON) patients had more pRNFL and mRNFL loss compared to ION patients after one episode. Spectral domain optical coherence tomography (SD-OCT) may help to distinguish NMOSD-ON from ION with only moderate diagnostic accuracy. PMID- 27775239 TI - Block Copolymer Capsules with Structure-Dependent Release Behavior. AB - Although high-boiling non-solvent induced macrophase separation in emulsion droplets has been widely applied for the fabrication of polymeric capsules, precise control of their structures remains a great challenge. Herein, block copolymer capsules with tunable shell structures were fabricated by employing a non-solvent as a liquid template in emulsion droplets. The properties of the non solvents dictate the phase separation sequence in the droplets and the capsule formation mechanism. Two different pathways for capsule formation were observed, and could be applied to predict the shell structure. The structured capsules could be transformed into mesoporous capsules, which demonstrated an intriguing structure-dependent release behavior. Capsules with spherical shell structures displayed the best permeability, while those with lamellar shell structures showed the slowest release, but with a stepwise profile. After loading with an anticancer drug, different capsules induced different apoptosis ratios in cancer cell studies. PMID- 27775240 TI - Semiconductor-Based, Solar-Driven Photochemical Cells for Fuel Generation from Carbon Dioxide in Aqueous Solutions. AB - There has been active interest to identify new methods to reduce CO2 into usable fuel sources. In this work, we demonstrate two types of photo-electrochemical cells (PECs) that photoreduce CO2 directly to formate in aqueous solutions both in the presence and absence of external bias or additional electron sources. The photocathodes were either a CuFeO2 /CuO electrode or a bilayer of CdTe on NiO, whereas the photoanode was a bilayer of NiOx on CdS. The PECs were characterized by using both electrochemistry and spectroscopy, and the products formed from CO2 reduction were characterized and quantified by using 1 H NMR spectroscopy and ESI MS. In addition, an organohydride catalyst was tested in conjunction with the PECs, which not only showed a significant gain of 85 times in CO2 reduction (27 MUm formate without the catalyst, 2.3 mm formate with it) compared to the NiO/CdTe photocathode system but could also generate methanol under an external bias (10 MUm). PMID- 27775241 TI - Cytological features of inflammatory pseudotumor-like follicular dendritic cell sarcoma of spleen: A case report. AB - Here, we present the first cytological report of a primary splenic inflammatory pseudotumor-like follicular dendritic cell sarcoma. The 57 year-old male was incidentally found with a 2.2 cm well-demarcated splenic nodule. A sonography guided fine needle aspiration of the lesion was performed. The cytologic smears revealed loosely cohesive fragments of oval to spindle cells in a background of prominent lymphoplasmacytic infiltration. The cells showed sparse chromatin, distinct nucleoli, syncytial cell borders, and occasional cytoplasmic processes. On the liquid-based preparation, several histiocyte-like cells with emperipolesis phenomenon were noted. Scant large atypical cells with prominent, cherry-red nucleoli were found on the cell block sections. The initial cytologic interpretation was "atypical cells cannot exclude classical Hodgkin lymphoma." The subsequent partial splenectomy showed an inflammatory pseudotumor-like follicular dendritic cell sarcoma. The tumor cells were positive for CD21, CD35, smooth muscle actin, and EBER in situ hybridization. The cytologic differential diagnoses are briefly discussed. The knowledge of this rare entity, awareness of its cytomorphology, and proper ancillary tests would be helpful for correct cytologic diagnosis. Diagn. Cytopathol. 2017;45:230-234. (c) 2016 Wiley Periodicals, Inc. PMID- 27775242 TI - Corneal confocal microscopy alterations in Sjogren's syndrome dry eye. AB - PURPOSE: To evaluate light backscattering (LB) in corneal layers in patients with primary Sjogren's syndrome dry eye (SSDE) utilizing in vivo corneal confocal microscopy (IVCM) and to determine the eventual association with the lacrimal functional test values. METHODS: A complete ophthalmic evaluation, Schirmer test with and without stimulation, break-up time (BUT) and IVCM were performed on 55 patients affected by SSDE and in an age- and sex-matched cohort of healthy participants (HP). Light backscattering, measures as light reflectivity unit (LRU), detected by IVCM at Bowman's membrane (BM) at 50 MUm, at 100 MUm and at 200 MUm deeper than BM was compared in the two groups. The correlations between LB values and lacrimal function results were evaluated. RESULTS: In patients affected by SSDE, LB was significantly higher (p < 0.001) in each corneal layer examined (+14 +/- 6.33 LRU at BM), compared with HP. A good reverse correlation between the light reflectivity measures at BM with Schirmer test with (r = -0.91) and without (r = -0.90) stimulation and BUT (r = -0.88) was found. Correlations were lower in the deeper corneal layers. CONCLUSION: Even if our results should be confirmed in further studies with a larger population, these findings show that IVCM is a device able to detect alterations in corneal layers in SSDE patients related to the lacrimal function. Light backscattering (LB) could be very useful for clinical diagnosis and management of SSDE. PMID- 27775244 TI - EDITOR'S NOTE - About This Supplement. PMID- 27775245 TI - PREFACE. PMID- 27775243 TI - Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases. AB - Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF) are key virulence factors with adenylate cyclase (AC) activity that substantially contribute to the pathogenesis of whooping cough and anthrax, respectively. There is an urgent need to develop potent and selective inhibitors of bacterial ACs with prospects for the development of potential antibacterial therapeutics and to study their molecular interactions with the target enzymes. Novel fluorescent 5-chloroanthraniloyl-substituted acyclic nucleoside phosphonates (Cl-ANT-ANPs) were designed and synthesized in the form of their diphosphates (Cl-ANT-ANPpp) as competitive ACT and EF inhibitors with sub micromolar potency (IC50 values: 11-622 nm). Fluorescence experiments indicated that Cl-ANT-ANPpp analogues bind to the ACT active site, and docking studies suggested that the Cl-ANT group interacts with Phe306 and Leu60. Interestingly, the increase in direct fluorescence with Cl-ANT-ANPpp having an ester linker was strictly calmodulin (CaM)-dependent, whereas Cl-ANT-ANPpp analogues with an amide linker, upon binding to ACT, increased the fluorescence even in the absence of CaM. Such a dependence of binding on structural modification could be exploited in the future design of potent inhibitors of bacterial ACs. Furthermore, one Cl ANT-ANP in the form of a bisamidate prodrug was able to inhibit B. pertussis ACT activity in macrophage cells with IC50 =12 MUm. PMID- 27775246 TI - Quantifying Burden of Disease to Measure Population Health in Korea. AB - Quantitative assessments of the health status of a population are essential to make decisions and set priorities in the field of public health. Changing epidemiologic patterns increase the demand for comprehensive estimates of population health across the full health spectrum, including non-communicable diseases and injuries. Burden of disease (BoD) analysis has helped meet this need. With the success of the Global Burden of Disease (GBD) Study, the BoD technique has become predominantly associated with the GBD approach and its methodology using disability-adjusted life year (DALY) has been rapidly disseminated and generally accepted over the last several years. The first Korean BoD study using the DALY metric was presented in 2002. Various BoD studies have since been conducted, but the DALY concept has remained primarily academic and has not yet been actively utilized in the health policy arena. Here, we review the DALY metric and population-based Korean BoD studies using national health data, with the intent of increasing the understanding of their value and their potential role in strengthening future assessments of the Korean population's health status. PMID- 27775247 TI - Burden of Disease Study and Priority Setting in Korea: an Ethical Perspective. AB - When thinking about priority setting in access to healthcare resources, decision making requires that cost-effectiveness is balanced against medical ethics. The burden of disease has emerged as an important approach to the assessment of health needs for political decision-making. However, the disability adjusted life years approach hides conceptual and methodological issues regarding the claims and value of disabled people. In this article, we discuss ethical issues that are raised as a consequence of the introduction of evidence-based health policy, such as economic evidence, in establishing resource allocation priorities. In terms of ethical values in health priority setting in Korea, there is no reliable rationale for the judgment used in decision-making as well as for setting separate and distinct priorities for different government bodies. An important question, therefore, is which ethical values guiding the practice of decision making should be reconciled with the economic evidence found in Korean healthcare. The health technology assessment core model from the European network for Health Technology Assessment (EUnetHTA) project is a good example of incorporating ethical values into decision-making. We suggest that a fair distribution of scarce healthcare resources in South Korea can be achieved by considering the ethical aspects of healthcare. PMID- 27775248 TI - Health Performance and Challenges in Korea: a Review of the Global Burden of Disease Study 2013. AB - The global burden of disease study (GBD) provides valuable information for evaluating population health in terms of disease burden. This study collected and reviewed GBD data in Korea for the year 1990 and 2013. The burdens of cancer, cardiovascular disease, communicable disease, and injuries have decreased remarkably, thereby greatly diminishing the overall disease burden on Korea. Meanwhile, the burdens due to non-fatal chronic diseases such as neuropsychiatric and musculoskeletal disease became major burden contributors. Responding to this circumstance presents a complex challenge to the Korean health system and Korean health policy. PMID- 27775249 TI - Application of a Modified Garbage Code Algorithm to Estimate Cause-Specific Mortality and Years of Life Lost in Korea. AB - Years of life lost (YLLs) are estimated based on mortality and cause of death (CoD); therefore, it is necessary to accurately calculate CoD to estimate the burden of disease. The garbage code algorithm was developed by the Global Burden of Disease (GBD) Study to redistribute inaccurate CoD and enhance the validity of CoD estimation. This study aimed to estimate cause-specific mortality rates and YLLs in Korea by applying a modified garbage code algorithm. CoD data for 2010 2012 were used to calculate the number of deaths. The garbage code algorithm was then applied to calculate target cause (i.e., valid CoD) and adjusted CoD using the garbage code redistribution. The results showed that garbage code deaths accounted for approximately 25% of all CoD during 2010-2012. In 2012, lung cancer contributed the most to cause-specific death according to the Statistics Korea. However, when CoD was adjusted using the garbage code redistribution, ischemic heart disease was the most common CoD. Furthermore, before garbage code redistribution, self-harm contributed the most YLLs followed by lung cancer and liver cancer; however, after application of the garbage code redistribution, though self-harm was the most common leading cause of YLL, it is followed by ischemic heart disease and lung cancer. Our results showed that garbage code deaths accounted for a substantial amount of mortality and YLLs. The results may enhance our knowledge of burden of disease and help prioritize intervention settings by changing the relative importance of burden of disease. PMID- 27775250 TI - Disability Weights Measurement for 228 Causes of Disease in the Korean Burden of Disease Study 2012. AB - Disability weight for each disease plays a key role in combining years lived with disability and years of life lost in disability adjusted life year. For the Korean Burden of Disease 2012 study, we have conducted a re-estimation of disability weights for causes of disease by adapting the methodology of a recent Global Burden of Disease study. Our study was conducted through a self administered web-based survey using a paired comparison (PC) as the main valuation method. A total of 496 physicians and medical college students who were attending in third or fourth grade of a regular course conducted the survey. We applied a probit regression on the PC data and computed the predicted probabilities of each cause of disease from the coefficient estimates of the probit regression. We used 'being dead (1)' and 'full health (0)' as anchor points to rescale the predicted probability of each cause of disease on a scale of 0 to 1. By this method, disability weights for a total of 228 causes of disease were estimated. There was a fairly high correlation between the disability weights of overlapping causes of disease from this study and a previous South Korean study despite the differences in valuation methods and time periods. In conclusion, we have shown that disability weights can be estimated based on a PC by including 'full health' and 'being dead' as anchor points without resorting to a person trade-off. Through developments in the methodology of disability weights estimation from this study, disability weights can be easily estimated and continuously revised. PMID- 27775251 TI - Health-Adjusted Life Expectancy (HALE) in Korea: 2005-2011. AB - Health-Adjusted Life Expectancy (HALE) is a summary measurement that estimates the average number of years that a person at a given age can expect to live an equivalent of full health. HALE has not been previously reported at national or regional levels in Korea. This study aimed to measure HALE from 2005 to 2011 in Korea at both the national and regional levels as part of the Korean National Burden Study of 2012. To measure life expectancy (LE) and HALE, we used the life table method and an approach proposed by Sullivan. We used three main data sets to estimate HALE: probability of death, prevalence of disease, and disability weights. Overall, LE and HALE have increased from 2005 to 2011. For example, in 2011, LE and HALE at birth in males were 77.6 and 65.8 years, respectively, and 84.4 and 68.9 in females. It might be assumed that the overall health status of Korean population has been increasing. However, we confirmed that a gap between LE and HALE still exists. Additionally, we found out that there was a significant difference between LE and HALE among various sub-regions. This study is the first to measure HALE using our own database, including disability weight that reflected Korean preferences. Finally, the Korean government and society should make an effort to reduce the gap between LE and HALE and to reduce regional differences. PMID- 27775252 TI - Disability-adjusted Life Years for 313 Diseases and Injuries: the 2012 Korean Burden of Disease Study. AB - This study is part of a 5-year research project on the national burden of diseases, injuries, and risk factors in Korea. Using disability-adjusted life years (DALYs), a metric introduced by the 1990 Global Burden of Disease (GBD) project, we performed a comprehensive and detailed assessment of the magnitude and distribution of both fatal and non-fatal health problems in the Korean population. The concept and general approach were consistent with the original GBD study, with some methodological modifications to make the study more suitable for Korea. We computed DALYs for 313 causes in both sexes and nine age groups using the entire population's medical records and newly generated Korean disability weights. In 2012, the dominant disease burden was non-communicable diseases, which accounted for 85.21% of total DALYs, while injuries accounted for 7.77% and communicable, maternal, neonatal, and nutritional disorders for 7.02%. Of the total DALYs, 88.67% were from years lived with disability and 11.32% were from years of life lost due to premature mortality. Diabetes mellitus was the leading cause of DALYs, followed by low back pain, chronic obstructive pulmonary disease, ischemic heart disease, ischemic stroke, cirrhosis of the liver, falls, osteoarthritis, motorized vehicle with three or more wheels, and self-harm. The results reported here identify key health challenges and opportunities for future health interventions and policy changes, and provide information that will help assess the major public health issues in Korea, a nation faced with one of the world's most rapidly ageing populations. PMID- 27775253 TI - The Non-Communicable Disease Burden in Korea: Findings from the 2012 Korean Burden of Disease Study. AB - In recognition of Korea's rising burden of non-communicable diseases (NCDs), we investigated the nation's NCD status and extracted detailed information from the 2012 Korean Burden of Disease study. Consistent with that study, we used disability-adjusted life year (DALY) as a metric. Using national data sources and disability weights specific to the Korean population, we analyzed 116 disaggregated NCDs from the study's four-level disease and injury hierarchy for both sexes and nine age groups. Per 100,000 population, 21,019 DALYs were lost to 116 NCDs. Of those, 13.97% were due to premature death (death prior to the standard life expectancy for a subject's age) and 86.03% to non-fatal health outcomes. Based on traditional statistics, the main causes of health loss were mortality of neoplasms; cardiovascular and circulatory diseases; diabetes, urogenital, blood, and endocrine diseases; and chronic respiratory diseases. When combined with analyses of premature death and non-fatal outcomes, however, a substantially different view emerged: the main causes of health loss were diabetes mellitus, low back pain, chronic obstructive pulmonary disease, ischemic heart disease, ischemic stroke, cirrhosis of the liver, osteoarthritis, asthma, gastritis and duodenitis, and periodontal disease (in that order), collectively causing 49.20% of DALYs. Thus, burden of disease data using DALYs rather than traditional statistics brings a new perspective to characterization of the population's health that provides practical information useful for developing and targeting national NCD control programs to better meet national needs. PMID- 27775254 TI - The Burden of Cancer in Korea during 2012: Findings from a Prevalence-Based Approach. AB - Cancer causes a significant deterioration in health and premature death and is a national socioeconomic burden. This study aimed to measure the burden of cancer using the disability-adjusted life year (DALY) metric based on the newly adopted methodology from the Global Burden of Disease Study in 2010. This study was conducted based on data from the Korean National Cancer Registry. The DALYs were calculated using a prevalence-based method instead of the incidence-based method used by previous studies. The total burden of cancer in 2012 was 3,470.79 DALYs per 100,000 persons. Lung cancer was the most prevalent cancer burden, followed by liver, stomach, colorectal, and breast cancer. The DALYs for lung, liver, stomach, colon and rectum, and pancreatic cancer were high in men, whereas the DALYs for breast, lung, stomach, colorectal, and liver cancer were high in women. Health loss from leukemia and cancer of the brain and nervous system was prevalent for those younger than age 20; from stomach, breast, and liver for those aged 30-50; and from lung, colon and rectum, and pancreas for a large proportion of individuals over the age of 60. The most important differences were that the DALYs were calculated by prevalence and that other components of the DALYs were measured by a population-based perspective. Thus, prevalence-based DALYs could provide more suitable data for decision making in the healthcare field. PMID- 27775255 TI - Disability-Adjusted Life Years for Communicable Disease in the Korean Burden of Disease Study 2012. AB - Globally, the incidence of communicable diseases has decreased compared to non communicable diseases. However, chronic communicable diseases such as HIV/AIDS and tuberculosis persist worldwide. Furthermore, emerging new infections such as H1N1 influenza pose a new threat to public health. However, most studies have focused on non-communicable diseases because of their increasing incidence, with fewer studies investigating communicable diseases. Therefore, we estimated the burden of communicable diseases in Korea using national representative 2012 data. To estimate the disability-adjusted life years (DALY), we used cause of death data from the Statistics Korea to estimate the years of life lost (YLL), applied the Korean garbage code algorithm, and used national claims data from the National Health Insurance Service (NHIS) to estimate years lived with disability (YLD). In 2012, the total DALYs of communicable disease were 445 per 100,000, with 129 YLLs per 100,000 and 316 YLDs per 100,000. The total DALYs in men were 468 per 100,000, greater than the 422 per 100,000 DALYs seen in women. The DALYs of lower respiratory infections were the highest value among communicable diseases at 143/100,000 DALYs followed by tuberculosis and upper respiratory infections. The 40-49 years old age group had the largest number of total DALYs. In contrast, the over 80 years old age group had the largest number of total DALYs per 100,000 followed by the 70-79 and 0-9 years old age groups. These results enable the prioritization of interventions related to communicable diseases and can be used for evidence-based public health policies. PMID- 27775256 TI - Disability-Adjusted Life Years for Maternal, Neonatal, and Nutritional Disorders in Korea. AB - Maternal and child health is an important issue throughout the world. Given their impact on maternal and child health, nutritional issues need to be carefully addressed. Accordingly, the effect of maternal, child, and nutritional disorders on disability-adjusted life years (DALYs) should be calculated. The present study used DALYs to estimate the burden of disease of maternal, neonatal, and nutritional disorders in the Korean population in 2012. For this purpose, we used claim data of the Korean National Health Insurance Service, DisMod II, and death data of the Statistics Korea and adhered to incidence-based DALY estimation methodology. The total DALYs per 100,000 population were 376 in maternal disorders, 64 in neonatal disorders, and 58 in nutritional deficiencies. The leading causes of DALYs were abortion in maternal disorders, preterm birth complications in neonatal disorders, and iron-deficiency anemia in nutritional deficiencies. Our findings shed light on the considerable burden of maternal, neonatal, and nutritional conditions, emphasizing the need for health care policies that can reduce morbidity and mortality. PMID- 27775257 TI - Disability-adjusted Life Years (DALYs) for Mental and Substance Use Disorders in the Korean Burden of Disease Study 2012. AB - The purpose of this study was to estimate the national burden of mental substance disorders on medical care utilization in Korea using National Health Insurance System (NHIS) data and updated disability weight, in terms of disability-adjusted life years (DALYs). For each of the 24 disorders, the incident years lived with disability (YLDs) was calculated, using NHIS data to estimate prevalence and incidence rates. The DisMod-II software program was used to model duration and remission. The years of life lost (YLLs) due to premature death were calculated from causes of death statistics. DALYs were computed as the sum of YLDs and YLLs, and time discounting and age weighting were applied. The year examined was 2012, and the subjects were divided into 9 groups according to age. In 2012, the Korean burden of mental and substance use disorders was 945,391 DALYs. More than 98% of DALYs were from YLDs, and the burden in females was greater than that in males, though the burden in males aged less than 19 years old was greater than that in females. Unipolar depressive disorders, schizophrenia, and anxiety disorders were found to be major diseases that accounted for more than 70% of the burden, and most DALYs occurred in their 30-59. Mental and substance use disorders accounted for 6.2% of the total burden of disease and were found to be the 7th greatest burden of disease. Therefore, mental and substance use disorders need to be embraced by mainstream health care with resources commensurate with the burden. PMID- 27775258 TI - Disability-Adjusted Life Years (DALYs) for Injuries Using Death Certificates and Hospital Discharge Survey by the Korean Burden of Disease Study 2012. AB - A system for assessing the burdens imposed by disease and injury was developed to meet healthcare, priority setting, and policy planning needs. The first such system, the Global Burden of Disease (GBD), was implemented in 1990. However, problems associated with limited data and assumed disability weightings remain to be resolved. The purpose of the present study was to estimate national burdens of injuries in Korea using more reliable data and disability weightings. The incidences of injuries were estimated using the Korean National Hospital Discharge Survey and the mortality data from the Korean National Statistical Office in 2010. Additionally, durations of injuries and age at injury onset were used to calculate disability-adjusted life years (DALY) using disability weightings derived from the Korean Burden of Disease (KBD) study. Korea had 1,581,072 DALYs resulting from injuries (3,170 per 100,000), which was 22.9% higher than found by the GBD 2010 study. Males had almost twice as heavy an injury burden as females. Road injury, fall, and self-harm ranked 1st, 2nd, and 3rd in terms of burden of injury in 2010. Total injury burden peaked in the forties, while burden per person declined gradually from early adulthood. We hope that this study contributes to the reliable evaluation of injury burden and a better understanding of injury-related health status using nation-specific, dependable data. PMID- 27775260 TI - The 5th Shanghai Gynecologic Oncology Group (SGOG)-Korean Gynecologic Oncology Group (KGOG) joint meeting and 2016 Asia-Pacific Ovarian cancer Laparotomy and Laparoscopic Operation (APOLLO) symposium in Shanghai. PMID- 27775262 TI - [Certification, recertification and regular checks]. PMID- 27775261 TI - The epidemiologic status of gynecologic cancer in Thailand. AB - Between the years of 2010-2012, it was estimated there were a total of 112,392 new cases of cancers in Thailand, thus, the total age-standardized rate (ASR) per 100,000 is 137.6. In regards to the most prevalent types of cancer in female, breast cancer has the highest ASR, followed by cervical cancer (ASR=14.4); liver and bile duct cancer; colon and rectum cancer; trachea, bronchus and lung cancer; ovarian cancer (ASR=6.0); thyroid cancer; non-Hodgkin lymphoma and uterine cancer (ASR=4.3). The trend of cervical cancer in Thailand is decreasing, one key factor in making this possible was the employment of dual tract strategy (Pap smear and visual inspection with acetic acid [VIA]) by the government in 2005. In the future, the government is also considering integrating human papillomavirus (HPV) vaccination into the national immunization program, which may assist in the prevention of cervical cancer. By studying the statistical data of gynecologic cancer, it will be possible to formulate measures for the prevention, control and treatment of gynecologic cancer. Eventually, it will potentially improve the quality of life (QoL) of patients as well as decrease the mortality rate caused by gynecologic cancer. PMID- 27775259 TI - Major clinical research advances in gynecologic cancer in 2015. AB - In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed. There was no sign of abating in great interest in immunotherapy as well as targeted therapies in various gynecologic cancers. The fifth Ovarian Cancer Consensus Conference which was held in November 7-9 in Tokyo was briefly introduced. For cervical cancer, update of human papillomavirus vaccines regarding two-dose regimen, 9-valent vaccine, and therapeutic vaccine was reviewed. For corpus cancer, the safety concern of power morcellation in presumed fibroids was explored again with regard to age and prevalence of corpus malignancy. Hormone therapy and endometrial cancer risk, trabectedin as an option for leiomyosarcoma, endometrial cancer and Lynch syndrome, and the radiation therapy guidelines were also discussed. In addition, adjuvant therapy in vulvar cancer and the updated of targeted therapy in gynecologic cancer were addressed. For breast cancer, palbociclib in hormone receptor-positive advanced disease, oncotype DX Recurrence Score in low-risk patients, regional nodal irradiation to internal mammary, supraclavicular, and axillary lymph nodes, and cavity shave margins were summarized as the last topics covered in this review. PMID- 27775263 TI - [Training in laparoscopy and appendicitis]. AB - BACKGROUND: In order to improve laparoscopic skills, appendectomy is the most common procedure because of its high frequency and low difficulty. In spite of that, during the learning curve (each surgeon's first 35 interventions) the incidence of complications may increase, so improvement in training means a bigger risk for some patients. METHODS: We retrospectively reviewed major complications (intra-abdominal abscess, intestinal occlusion, hemorrhage) of 1,710 appendectomies performed at our service between 1997 and 2013. We divided them in three groups: open appendectomy (OA, n= 1,258), laparoscopic appendectomy during the learning curve (LDC, n= 154) and laparoscopic appendectomy after the learning curve (LAC, n= 298). In addition, we distinguish between simple appendicitis (n= 1,233) and peritonitis (n= 477). RESULTS: In the OA group we detected110/1,258 major complications (8.7%), 28/154 major complications (18.2%) in the LDC group and 19/298 (6.4%) in the LAC group (p<0.05 LDC vs OA and LAC). In the simple appendicitis group, we found 13/889 major complications (1.5%) in OA, 3/115 (2.6%) in LDC group and 2/229 (0.9%) in LAC group (p= ns LDC vs OA and LAC). In the peritonitis group, 97/369 (26.3%) major complications were found in OA group, 25/39 (64%) in LDC group and 17/69 (24.6%) in LAC group (p<0.05 LDC vs OA and LAC). CONCLUSIONS: Educational purpose laparoscopic appendectomy must be used in simple appendicitis cases. PMID- 27775264 TI - [Uroflowmetric review of pediatric distal urethroplasty]. AB - INTRODUCTION: Urethral stricture is the most common complication in hypospadias surgery. The monitoring of operated patients allows rapid detection of this complication and the uroflowmetry is the main diagnostic method. OBJECTIVES: To study of functional results in patients who underwent distal urethroplasty, using uroflowmetry. PATIENTS AND METHODS: A retrospective chart review was conducted of 81 patients who underwent distal hypospadias repair (7 coronal, 51 subcoronal and 23 distal penile shaft) and a postoperatory uroflowmetric study. The patients were divided into two groups, in each type of hypospadias, according to the presence or absence of stenotic complications (0 coronal, 10 subcoronal and 5 distal penile shaft). The functional effects in both groups were studied. RESULTS: All patients with stenotic complications showed maximum flow rates and mean flow rates below 15 and 20 percentiles respectively and a plateauing layout of the urinary flow curve. The treatment of these conditions resulted in the normalization of the maximum flow values (in 100% of the subcoronal and 100% of the distal penile shaft hypospadias), as well as in the mean flow values (in 88% of the subcoronal and 75% of the distal penile shaft hypospadias). The curve also adapted a bell-shaped in 100% of the H. coronal and 50% of the H. distal penile shaft. The uroflowmetry presented a spontaneous improvement in all patients without stenotic complications but with low flows in their first uroflowmetric. CONCLUSIONS: Uroflowmetry is an objective method for the evaluation of hypospadias surgery, being easy to perform, noninvasive and reliable. Obstructed uroflow patterns point to the presence of a stenotic complication. PMID- 27775265 TI - [Isolated intestinal perforation in neonates: treatment with ostomy or primary anastomosis?] AB - INTRODUCTION: Necrotizing enterocolitis and isolated intestinal perforation (IIP) are two different entities that have been often analysed together in the literature. We present our series of IIP cases who received surgical treatment by laparotomy. MATERIAL AND METHODS: A retrospective cohort study was conducted with neonates diagnosed of IPP and operated on between 2002 and 2013. We divided the sample into two groups: group O (laparotomy and ostomy) and Group S (laparotomy and primary repair of the perforation). We compared the following variables: mortality, development of complications and number of days of total parenteral nutrition (TPN). Categorical variables were compared with the chi2 test. Time of TPN was analysed with Kaplan Meier curves and comparison between groups with the log-rank test. RESULTS: Thirty-four patients underwent surgery. Fourteen patients were included in group O and 20 in group S. Four (28,6%) cases died in group O and six (30.0%) in group S: no statistically significant differences were found in mortality (chi2= 0.08; p= 0.9). Four (28,6%) patients in group O presented complications compared with 7 (35%) in group S: there were no statistically significant differences (chi2= 0.1; p= 0.7). The median number of days of TPN was 38 in group O and 34 in group S: no significant differences were found (chi2= 1.4; p = 0.2). CONCLUSIONS: No significant differences were found in terms of mortality, surgical complications and TPN between patients with IIP treated with primary anastomosis and patients treated with an ostomy. PMID- 27775266 TI - [Clinical assessment of fecal incontinence in patients with anorectal malformation surgery]. AB - BACKGROUND/PURPOSE: To review our management of anorectal malformations (ARM) and to compare two quantitative scales for clinical assessment of fecal incontinence. MATERIAL AND METHODS: We reviewed all patients with ARM surgery who are currently 3 to 15 years old. Several variables were collected and fecal incontinence was evaluated using two scales: the Holschneider scale and one used previously in our Service, both were filled out through clinical interview. RESULTS: 48 patients were studied, 29 males and 19 females. According to the Pena's classification, 81% had good prognosis indicators (group A) and 19% had bad prognosis indicators (group B). Posterior sagittal anorectoplasty (PSARP) was performed in 32 patients, PSARP and abdominal approach in 3, abdomino-perineal pullthrough in 2, and a "Cut-back" anoplasty in 14 patients. There were not statistical significative differences in average age of continence between both groups. We found no significative differences on the average score of fecal incontinence between both groups using our scale (17.57/20 in group A vs 14/20 in group B; p= 0.05) but it was significantly lower in group B using the Holschneider scale (12.39/14 in group A vs 10.43/14; p= 0.04). Constipation was detected in 16 patients, half of whom had overflow pseudoincontinence. CONCLUSIONS: Our scale penalizes constipation, for this reason the average score of group A was lower and we didn't find differences with respect to group B, contrary to what it happened using Holschneider's scale, so we believe our scale could be more precise to evaluate fecal incontinence of these patients. PMID- 27775267 TI - [Neonatal surgical site infection: multicentric survey on prophylactic measures]. AB - OBJECTIVES: Surgical site infection (SSI) has a considerable impact on neonatal morbidity. There are known risk factors such type of surgery (clean/contaminated), prematurity, surgical length, hypoalbuminemia, previous infection, prolonged mechanical ventilation, and so on. Many perioperative factors have not been studied, opposite to adults. We have developed a survey on intraoperative attitudes and measures, as surgical wound management in Neonates among pediatric surgeons, to seek for a wider consense. METHODS: Multi-response survey with 22 items, based on the Surgical Infection Society NIH 2008 clinical guideline. Each item poses a question on perioperative attitudes, surgical aspects and wound management. Each question is subdivided in two categories, depending on urgency and type of surgery (clean/contaminated). RESULTS: 159 surveys were sent. Among those, we received back 51 (32%). 69% of the interviewed surgeons use clorhexidin to prepare surgical field, 25% use Iodine solutions. 69% never use diathermy to incise skin. There was no agreement on the use of sterile plastic adhesive drapes, intra-cavity lavage, changing surgical gloves/material, or wound irrigation during closure. 82% never use cyanocrilate dressing. Intracuticular skin suture and simple stitches were used indistinctly. Wound management and dressings were not uniform and depended on each pediatric unit. CONCLUSIONS: The survey reflects the lack of consensus regarding prophylactic measures and wound management among pediatric surgeons who care after surgical neonates. PMID- 27775268 TI - [Ultrasound markers in the follow up of pyeloplasty]. AB - INTRODUCTION: There are few studies on the long term follow up of pyeloplasty. Is there a residual pelvis dilatation in all successful procedures? How is the long term evolution of the ecographic parameters and measures postoperatively (PO)? PATIENTS AND METHODS: We reviewed all successful Anderson-Hynes pyeloplasties performed on obstructed renal pelvis with an anterio-posterior diameter >15 mm during 2001-2010. Ultrasound controls were made at 3 and 6 months postoperatively and then yearly afterwards. We aimed to describe time course of hydronephrotic changes following unilateral pyeloplasties, using three parameters: pelvic anterior-posterior diameter (APD), pelvis/cortex ratio (P/C R) and the percentage of improvement in APD (PI-APD). RESULTS: 41 patientswereincluded. Age at intervention ranged from 2 months to 10.3 years (mean 13 months, 83% were operated in the first year of life). Median of follow up was 4 years (range 1-12 years). Mean APD preoperatively was 25 mm (range 16-54). At the third month PO, PI-APD was 28%. At the sixth month control, it was 51%, and remained stable during the next consecutive yearly controls, without statistically significant variations (50%, 57%, 60%, 51%, 39%, 46%, 38%, 42%). P/C R diminished significantly already in the third month control (4.6 vs. 1.8, p=0.03). We observed complete disappearance of hidronephrosis in 8 patients (19.5%). DISCUSSION: Although early postoperative ultrasound changes occur, the ultrasound parameters remain often stable during long term follow up. We documented the complete normalization of renal pelvis (no hydronephrosis) in one of every five patients. PMID- 27775269 TI - [Neonatal intussusception]. AB - Intussusception in infants and young children is a relatively common entity with a well defined clinical picture and a favorable outcome in most cases.The neonatal intussusceptions is extremely rare and does not have a well-defined clinical picture since its clinical manifestations vary according to the gestational time it occurs, the response of the injured intestine and the gestational age of the child concerned. Two new cases of neonatal intussusceptions are presented and a review of the world literature is performed. Given the stage of intussusceptions (pre- or postnatal) occurs and gestational age of the affected infant (preterm or term), there are three entities with clinical characteristics, topography and evolution rather different: prenatal or intrauterine intussusception, postnatal intussusception in the preterm and postnatal intussusception in the term infant. PMID- 27775270 TI - [Rupture of a superior mesenteric artery aneurysm in pediatric age: case report and literature review]. AB - INTRODUCTION: Splanchnic artery aneurysms are rare in children. High mortality from rupture justifies its treatment, with various therapeutic options among which stand out surgery and recently, endovascular treatment. CASE REPORT: A 11 year old girl presented with abdominal pain and sudden drop in hematocrit. The urgent abdominal CT angiography showed a saccular aneurysm of the superior mesenteric artery (SMA) at 4 cm from the ostium with dissection and active bleeding. A selective angiography was performed which confirmed the dissection. A self-expanding stent was placed in the main trunk of the SMA and a transcatheter coil and onyx embolization of the aneurysm was performed. The control angiogram showed no evidence of residual perfusion of the false lumen and demonstrated proper vascularization of the distal jejunum-ileal branches. Dual antiplatelet therapy with aspirin and dipyridamole was begun. After 24 months of follow-up the patient is asymptomatic. COMMENTS: Endovascular treatment of a SMA aneurysm is effective in the pediatric patient, even in emergency situations. PMID- 27775271 TI - [Genital-urinary rhabdomyosarcoma in childhood: our experience]. AB - INTRODUCTION: Rhabdomyosarcoma (RSM) becomes the most common tumour of the soft tissues during the paediatric age. It represents among 2-3% of child tumours. The genital-urinary location is the second most common location, only after head and neck. The treatment is usually medical, being the surgery a mere contribution, except for the cases in which the situation is not under control, when very aggressive surgery is necessary. The aim of this study is to analyse the cases of genial-urinary RMS that have been treated in our centre and the role that surgery has in their treatment. MATERIAL AND METHODS: Retrospective study of 20 patient (7 girls and 13 boys) with a median age of 24 months (range from 1 month to 12 years) with RMS in the aurochs-genial tract who have been treated in our hospital from 1990 to 2012. The variables described are demographic, location of the primary tumour, state at diagnosis, received treatment, both medical and surgical, with greater emphasis on the kind of surgery applied and monitoring in terms of survival. RESULTS: The location of the primary tumour was: bladder (6), paratesticular (5), vagina (3) retroperitoneal space (3), lesser pelvis (2) and prostate (1). All of them received medical treatment with chemotherapy and radiotherapy following International Society of Pediatric Oncology protocol after diagnostic biopsy. Surgery, which was always used as help, was: reappraisal of biopsy (1), orchiectomy (5), tumoral resection (8) and radical surgery (cystoprostatectomy or pelvic exenteration) in 6 patients. There were 3 deaths, 2 because of the evolution of the disease and 1 because of postoperative sepsis. The survival rate is 80% with a median follow - up of 14 years. CONCLUSIONS: The RMS is the most common tumour of soft tissues in childhood and the genital urinary location is the second most common after the parameningeal one. The treatment is multidisciplinary and the surgery has a contributing role when there is no answer to the medical treatment or when there is a residual tumour even if some patients do not respond to medical treatment and they need a radical surgery for recovery. PMID- 27775272 TI - [Salivaly gland tumors in childhood: importance of an early diagnosis and treatment]. AB - OBJECTIVE: Review of our series of salivaly gland tumors at pediatric age, given its low frequency and their higher rate of malignancy compared with the adult population. MATERIAL AND METHODS: Retrospective study of the medical records of all pediatric patients with salivaly gland tumors treated in our center between 1998 and 2013. RESULTS: We identified 12 patients. The most common site of tumor location was the parotid gland in 11 patients followed by the sublingual gland in 1 patient. Three patients had previous cancer and radiotherapy history. The diagnosis (histological or radiological) were: 4 hemangiomas, 2 pleomorphic adenomas, 4 mucoepidermoid carcinomas, one acinar cell carcinoma and 1 primitive neuroectodermal tumor (PNET). No patient had metastasis at diagnosis. Preoperative fine needle aspiration (FNA) was performed in 6 patients with solid masses, being diagnostic in all cases. Eight patients underwent surgery. In two cases of total parotidectomy initial neuroapraxia appeared but none had permanent facial paralysis. There were no cases of Frey syndrome. The aesthetic results were good. There was only one tumor recurrence and all patients, except one who died of leukemia relapse, survive today. CONCLUSIONS: Salivaly gland tumors are uncommon in pediatric age but their high rate of malignancy makes it necessary to establish a rapid diagnosis. In our experience, FNA showed a high sensitivity. For malignant tumors, definitive treatment is surgical excision, preserving the facial nerve whenever possible. For vascular tumors, surgery is reserved for cases refractory to medical treatment. PMID- 27775273 TI - [Augmented-pressure colostogram in the radiological assessment of anorectal malformations]. AB - OBJECTIVES: To present our experience in detecting the existence of a possible associated fistula between the pouch colon and the urogenital tract in patients with anorectal malformations by carrying out an augmented-pressure colostogram, and its subsequent correlation between radiological and surgical findings. MATERIAL AND METHODS: A 17-year retrospective revision of 43 patients with anorectal malformations was performed. 34 of them were referred to the Radiology Department in order to carry out an augmented-pressure distal colostogram prior to surgery. RESULTS: A fistula was demonstrated in 26 of the 34 patients who had an augmented-pressure distal colostogram done. In the remaining 8 patients, this technique failed to demonstrate a fistula. The radiological findings were confirmed during the surgery in each case. CONCLUSIONS: The augmented-pressure distal colostogram is a simple and accurate study to delineate the altered anatomy of anorectal malformations, to define the distance between pouch colon and perineum, and to identify the localization of any associated fistulous communication. It is the most dependable test for a surgeon in order to choose the type of surgical approach, which depends on the presence or absence of an associated fistula. PMID- 27775274 TI - [Laparoscopic splenectomy in hematologic diseases in children. Analysis of 11 year experience]. AB - OBJECTIVES: A common indication for splenectomy in children is hematologic diseases. Indications, clinical course and complications of laparoscopic splenectomy are shown; factors associated with open conversion are analyzed. MATERIAL AND METHODS: Retrospective, longitudinal, descriptive series of laparoscopic splenectomy during 11 years and its long-term follow-up. RESULTS: We studied 88 laparoscopic splenectomies. Average age was 9 years and weight 30 kg. The indication was hemolytic anemia in 77% and thrombocytopenic purpura in 18%. Eleven percent was operated with severe thrombocytopenia and two patients urgently; cholecystectomy was done in 13%. The median surgical time was 180 minutes and bleeding 100 ml. Conversion rate was 5.7% mainly because of persistent bleeding, being risk bleeding greater than 300 ml and the need for red cell concentrate transfusion. The median length of stay was 3 days, longer in those affected by purpura. Three patients developed pneumonia and one, intra abdominal abscess. Follow-up was 3.6 years average with two late complications. Treatment response was cure in 72%, improvement in 11.3% and failure in 6.8%. DISCUSSION: It is feasible to operate patients under 5 years of age and patients with anemia or thrombocytopenia at the time of surgery without major problems. The conversion rate is low and risk factors for conversion are bleeding more than 300 ml and needing to transfuse erythrocyte concentrate. PMID- 27775275 TI - [Laparoscopic extravesical ureteral reimplantation following Lich-Gregoire technique. Medium-term prospective study]. AB - OBJECTIVES: To evaluate our results of Laparoscopic extravesical ureteral reimplantation according to Lich-Gregoire technique in the of vesicoureteral reflux treatment. MATERIAL AND METHODS: Between August 2007 and January 2013, 108 renal units in 80 patients were treated. There were 23 patients with double renal system; in 5 cases were associated with obstruction, and 3 with completely impaired function of the upper pole and ipsilateral ureterocele presence. RESULTS: Laparoscopic extravesical ureteral reimplantation was performed in all cases. The mean age was 52 months; The mean operative time was 70 minutes in unilateral and 144 minutes in bilateral. Three laparoscopic heminephroureterectomies were performed at the same time, with incision of ureterocele. The average hospital stay was 27 hours. Complete resolution was 96.5%. Mean follow-up was 27 months. CONCLUSION: Laparoscopic extravesical ureteral reimplantation following Lich-Gregoire technique is effective against the unilateral, bilateral and associated with double renal system vesicoureteral reflux. It's possible to perform others procedures in a securely and concomitantly way (eg., heminephroureterectomy). A shorter hospital stay, more comfort and quicker recovery are achieved, with similar succes rates to open surgery. PMID- 27775276 TI - [Enterocolitis associated with Hirschsprung's Disease. Experience in a pediatric teaching hospital]. AB - Hirschsprung's associated enterocolitis (HAEC) is the most serious and potentially fatal complication of the disease, with a significant morbidity and mortality. The effect of HAEC varies remarkably among the publications since the lack of consensus and the absence of established diagnostic criteria. Patients diagnosed with Hirschsprung's disease (HD) were selected and treated between January 2009 and December 2012 in Fundacion HOMI, finding 41 cases of HD, 6 of them with total aganglionosis. 76% of the patients had HAEC, 18 of them during the neonatal period and 6 of them after the final pull-through; 23% presented recurrent enterocolitis episodes. HAEC was the first clinical manifestation in 25 (61%) of the patients with HD. From HD patients limited to the rectum and sigmoid 67% had enterocolitis unlike TCA (total colonic agangliniosis) cases in which all presented HAEC episodes. In our setting, HAEC remains to be an unknown complication; this revision demonstrates its high incidence and mortality. PMID- 27775277 TI - [Enterocolitis episodes in patients who have previously undergone Hirschsprung disease surgery]. AB - OBJECTIVES: To highlight the risk factors for the occurrence of this complication in order to achieve an early diagnosis. METHODS: Retrospective descriptive study in which the medical records of patients diagnosed with enterocolitis and who have previously undergone surgery for Hirschsprung's disease in a tertiary hospital from 1994 to 2013, inclusive (N=29), were reviewed. Epidemiological, surgical and clinical data from two groups of patients: Group A (6 patients with ECPD) and Group B (23 patients without ECPD) were compared. Enterocolitis episode data in the Group A were studied too. RESULTS: The incidence of an episode of ECPD was 20.6% and the incidence of two episodes of ECPD was 33.3%. The onset occurred at 12.17 months (SD 13.04) after pull-through procedure. The incidence was higher in patients operated at a younger age [10 months in Group A [6-16] versus 14 months in the group B (1-153)] and in those patients with the longest segment resected [23.20 cm in group A (DS 10,52) versus 19.20 cm in group B (DS 6.92)]. No patient with a discharge colostomy before pull-through surgery showed this complication. It must be highlighted the highest incidence in patients undergone by Swenson's technique (25%) compared to other surgical techniques (Georgeson (15.80%), Soave (0%)). CONCLUSION: Just the length of the resected segment and the patient's age at the time of the pull-through procedure appear to influence the outcome. It is considered advisable to be extremely vigilant in children operated at an early age and subjected to extensive intestinal resection for an early diagnosis and establishment of a treatment to avoid high morbidity. PMID- 27775278 TI - [Exceptional causes of hematuria in childhood and infancy]. AB - INTRODUCTION: Hematuria is not uncommon in pediatric patients, even though it remains a diagnostic challenge in many cases. In this study we aim to draw attention to health professionals to have in mind rare diseases as a cause of hematuria. CASE REPORTS: We report 3 representative clinical cases of hematuria from very different origins: traumatic, congenital and infectious, illustrating the broad spectrum of causes of hematuria. COMMENTS: There are exceptional causes of hematuria which should be considered in clinical practice. The study of hematuria should always include a complete personal and familiar medical history, a careful physical examination and urine cultures. It is important to try to propose an algorithm study, avoiding unnecessary and invasive diagnostic tests that can be associated with complications. PMID- 27775279 TI - [Compressive anterior thoracoplasty (modified Abramson's repair) for pectus carinatum repair]. AB - OBJECTIVES: For anterior protruding chest wall deformities treatment, mainly pectus carinatum, pediatric surgeons have been managing either orthotic methods or open surgical repairs. Anterior compressive thoracoplasty (Abramson's technique) has widened the therapeutic options. We describe herein a modification of this technique in the first reported Europen series. PATIENTS AND METHODS: From 2010 to 2012, a total of five patients (four male and one female) underwent a modified Abramson's technique to correct pectus carinatum or combined protrusion of the chest at our center. We report the operative technique used for these reconstructions. RESULTS: In all five cases, the operation was completed uneventfully and with excellent results either for the surgical team or the patients. Mean operative time was 190 minutes and hospitalization lasted for three to six days, at the time of analgesic drugs withdrawal. CONCLUSIONS: We consider the anterior compresive thorocoplasty (modified Abramson's technique) a safe and feasible method to correct protruding chest deformities, particularly in those patients with stiff chest or lack of compliance, in order to avoid the agressive open procedures. PMID- 27775280 TI - [Left cardiac sympathetic denervation in congenital ventricular arrythmias: initial experience]. AB - BACKGROUND: Left cardiac sympathetic denervation (LCSD) has been proposed as a second-line therapy for potentially lethal ventricular arrythmia with no response to the gold standard treatment with beta-blockers. It has been used mainly in channelopathies such as long QT syndrome (LQTS) and polymorphic cathecolaminergic ventricular tachycardia (PCVT). AIM: Analizing our preliminary experience in the treatment of congenital ventricular arrythmia with thoracoscopic LCSD. MATERIAL AND METHODS: We have reviewed the first 5 LCSD performed in the last two years (2011-2013) to 5 female patients with a mean age of 8 years (1 month-15 years). The underlying disease was the LQTS in three and the PCVT in two. RESULTS: Selective contralateral bronchial intubation was used in two cases and double lumen tube in three. We performed in all cases T1 sympathicolysis, denervation of T2 ganglion and sympathicolysis of T3 and T5 levels. No intraoperatory nor postoperatory complications were observed. In four cases ventricular tachycardia disappeared after the procedure and in one case, although they did not completely disappeared, they could be better controled on medical therapy. Ventricular extrasystoles reappeared 17 months after the procedure in one PCTV case, but disappeared completely after T1-T5 left sympathectomy completion. With a mean follow-up time of 20 months, all patients are sympthom-free and continue on betablocker oral therapy. CONCLUSIONS: Thoracoscopic DCSI is a safe and effective therapy for prevention of severe congenital ventricular arrythmias. PMID- 27775281 TI - [Efficacy of the retroperitoneal-assisted laparoscopic pyeloplasty versus the mini posterior lumbotomy approach]. AB - OBJECTIVE: To evaluate the results of the retroperitoneal-assisted laparoscopic pyeloplasty (RALP) versus the mini posterior lumbotomy pyeloplasty (MPLP). MATERIAL AND METHODS: A retrospective study of 77 patients diagnosed with ureteropelvic junction obstruction between 2007 and 2013 was made, analyzing the surgical technique, complications and results. The anteroposterior pelvic diameter of the kidney, the thickness of the renal parenchyma, the renal function and the morphology of the renogram curve were also evaluated and compared. RESULTS: We performed 50 RALP and 21 MPLP. Median age of intervention: 10.85 moths (ICR 86.8) in RALP and 23.30 moths (ICR 54.7) in MPLP. No significant differences were found in surgical time (p>0.05). Double J was left in 90% of the RALP and 52.4% of the MPLP. Median length of incision was 1.5 cm of the RALP and 3.0cm in MPLP(p<0.05). The Median hospital stay was 2.0 days and 3.0 respectively (p<0.05). We found surgical complications (restenosis and urinoma) in 9 patients of the RALP group and 1 in the mini lumbotomy group (p>0,05). The follow-up was performed using ultrasound in an average of 68,04 months of age (range 7.5-186.5) and diuretic renogram in an average of 50,25 months of age (range 6,6-173,8). The above parameters showed improvements in both groups of patients without significant differences. CONCLUSIONS: In our experience, the RALP is a technique with a greater rate of complications than the expected. Moreover, the MPLP, is a technique we consider safe and with adequate aesthetic and functional results. PMID- 27775282 TI - [Ileostomy closure after necrotizing enterocolitis. When is the best moment?] AB - INTRODUCTION: In more than 50% of the necrotizing enterocolitis that underwent surgery will require an ileostomy. The optimal time to reestablish intestinal transit still is a controversial subject. Many times ileostomies cause medical issues that require early intestinal reconstruction. Our objective is to compare the early closure against late close, being the shift point 35 days according to other published research. MATERIAL AND METHODS: Retrospective study off all patients that in the last 10 years have had an episode of necrotizing enterocolitis which required an intestinal derivation like ileostomy. RESULTS: We studied 39 patients, 22 had an early closure (EC) and 17 in had a late closure (LC). There were statistically significant differences in age and weight between both groups, being younger in the EC group (p<0,05). All the morbidity factors were greater in the EC group (days of parenteral nutrition, days of central venous catheter, inotropic use, surgical wound infection and intestinal occlusions). The days of mechanical ventilation were greater in the EC group (2,33 vs p=0,017). The rate of reoperation was higher in the EC group (31%) against the LE group (17%). CONCLUSIONS: It is necessary to perform prospective studies with larger number of patients to be able to recommend a late closure ileostomy. In our experience the early closure has more morbidity and a higher rate of surgical reoperations. PMID- 27775283 TI - [Pediatric Extracorporeal Shock Wave Lithotripsy]. AB - INTRODUCTION: Extracorporeal Shock Wave lithotripsy (ESWL) is the cornerstone of pediatric urolitiasis management. We evaluated its efficacy and complications in a series of children. MATERIAL AND METHODS: Children who were managed with ESWL between 2003 and 2012 were retrospectively reviewed. We studied etiology, clinical presentation, stonefree ratio and relevant complications. SPSS 17.0 software was used. RESULTS: 90 children aged 0 to 10 years (median 2.9 years) were included in the study; that accounted for 122 stones and 162 ESWL sessions. Mean follow up was 20 months. Mean stone diameter was 12.2 mm. (range 4-25). Most prevalent clinical sign was urinary infection (55.6%, 50 patients). 75.4% of the lithiasis were found in renal pelvis or calices. A mean of 1.42 ESWL sessions per stone was performed. Stonefree status was reached in 80.3% (98) of the lithiasis. This rate was higher in patients below 5 years of age (86.1% vs., 69.8%, p=0.03), and worse in staghorn calculi (66% vs. 87.2%) and cystine ones (30% vs. 84.8%, p<0.001). We observed 17 complications (10.4% among 162 sessions), 6 UTIs, 6 episodes of fever and 6 episodes of UTI associated with steinstrasse. Almost all complications were associated with bigger size, staghorn calculi and struvite. DISCUSSION: Best results are found in younger patients and small calculi. ESWL is a safe and efficient procedure in pediatric patients. PMID- 27775284 TI - [Congenital portosistemic shunt. Importance of early treatment]. AB - AIM: Congenital portosistemic shunt (CPSS) is an uncommon condition that can cause serious complications such as encephalopathy and liver tumors at risk of malignant degeneration. Occlusion of the shunt by surgery or interventional radiology can prevent and even improve such complications. In some cases, liver transplantation is the only curative option. We describe our experience with this condition. PATIENTS AND METHODS: Between 1992 and 2013, eight children (four male and four female) were diagnosed with CPSS (four extrahepatic and four intrahepatic) in our center, of which seven were diagnosed after 2007. The mean age at diagnosis was 5.5 years (1 month-15 years). Five patients had associated comorbidities. RESULTS: Five patients had developed hyperammonemia and intellectual impairment, one of those manifested with an onset of coma. Four patients have developed at diagnosis liver tumors, including focal nodular hyperplasia/regenerative nodules (n=3) and adenomas (n=3). One patient with multiple tumors required a hepatectomy owing to compressive symptoms. Two patients, developed malignant degeneration, a child under five years treated with liver transplantation and another in adulthood treated with hepatectomy. In one patient, diagnosed in the neonatal period, the shunt occlusion occurred spontaneously. Direct portography with the occlusion test was performed in five patients, the shunt was occluded with interventional radiology in three cases, surgery in one and liver transplantation in the remaining. CONCLUSIONS: The treatment of the SPSC must be early to prevent and even to reverse its complications, avoiding liver transplantation. Currently, interventional radiology is essential in the strategy to follow and treatment of these patients. PMID- 27775285 TI - [Testicular and paratesticular tumors in prepubertal children]. AB - OBJECTIVES: To describe our experience in testicular and paratesticular tumors during the prepubertal stage, focusing especially on its character of benignity/malignancy and surgical treatment used. MATERIAL AND METHODS: Retrospective review of all testicular tumors in children under 12 years diagnosed and treated in our clinical setting from 1998-2015. Data on their presentation, study and management were collected. RESULTS: 17 children with prepubertal testicular tumors were identified. The clinical presentation as palpable testicular mass occurred in 12 cases (70.5%). Levels of tumor markers (alpha-fetoprotein and betahCG) were only increased alpha-fetoprotein in two cases. In the histopathological study, 64.7% of the tumors were benign (five mature teratomas, four Leydig cells tumors, one immature teratoma and one sexual cords-stromal tumor). Malignant tumors were three rhabdomyosarcoma (17.6%), two yolk-sac tumors (11.8%) and one Burkitt lymphoma (5.9%). The mean age of benign was 5.9 years old and malignant 2.9 years old (p=0.68). From neoplastic lesions nine were non-germline (53%) and eight germline (47%). In the management testis sparing surgery was performed in six benign tumors, and orchiectomy in five benign tumors and in all malignant tumors except lymphoma which received chemotherapy. CONCLUSIONS: Benign primary testicular and paratesticular tumors are more frequent in prepubertals and testis-sparing surgery is indicated by inguinal approach. PMID- 27775286 TI - [Cricopharyngeal achalasia: diagnosis and therapeutic alternatives]. AB - INTRODUCTION: The cricopharyngeal achalasia is an esophageal motor disorder that entails a lack of relaxation of the upper esophageal sphincter. It is rare in children and its etiology is related to multiple factors. The symptoms are nonspecific and may be masked by other diseases. CLINICAL CASE: Report two infants with dysphagia and choking episodes. Upper gastrointestinal series confirmed cricopharyngeal achalasia. The first patient was treated with endoscopic dilatation, and did not require further therapies. In the second patient, despite numerous dilatations and myotomy, the symptoms persisted so he received botulinum toxin injections. COMMENTS: Diagnosis of achalasia is obtained by upper gastrointestinal series and thanks to a high index of clinical suspicion. The use of endoscopic dilatation is the first option because it is not an invasive technique, but it usually requires several sessions. The second-line therapy is surgery, a more aggressive technique. In addition, the injection of botulinum toxin represents a safe and effective alternative, although it is a less widespread method in pediatrics. PMID- 27775287 TI - [Distal pancreatectomy as surgical option in Pancreas divisum associated with Rubinstein-Taybi syndrome]. AB - INTRODUCTION: The Rubinstein-Taybi syndrome and pancreas divisum are uncommon diseases in children. The Rubinstein-Taybi syndrome diagnosis is only clinical, and mental retardation and dysmorphic features mainly characterize it. The PD relates to idiopathic pancreatitis in 7.5% of patients suffering from this disorder. It has not been found any cases reported where these diseases are associated and the management of patients with pancreatitis associated with PD is still a challenge. CLINICAL CASE: A patient diagnosed with Rubinstein-Taybi syndrome has recurrent abdominal pain of six months and elevated pancreatic enzymes, he underwent a magnetic resonance imaging where pancreas divisum is suspected. Endoscopic drainage was foiled so he underwent intraoperative retrograde pancreatography where aberrant pancreas is confirmed and a distal pancreactectomy and yeyunopancreatic anastomosis is the chosen option. COMMENTS: The pancreatectomy with pancreato-jejunal anastomosis is an excellent therapeutic option surgical is proposed for a patient with difficulty endoscopic approach and chronic pancreatitis. PMID- 27775288 TI - [Video-assisted sigmoidectomy as an option for Sigmoid volvulus management in the pediatric population]. AB - INTRODUCTION: The aim of the present study was to evaluate clinical presentation and management of sigmoid volvulus in children. Sigmoid volvulus is one of the three leading causes of acute obstruction of the colon and is between 50 and 90% of all large bowel volvulus. In the pediatric population only 3 to 5% of bowel obstructions are caused by volvulus and there are less than 100 cases reported in the literature. The presence of a redundant sigmoid with a narrow mesentery (dolicosigmoide) is a prerequisite for the volvulus formation. The etiology in the pediatric population is considered secondary to the presence of a broad meso with a narrow base associated with abnormal fixation colon. Other factors include history of anorectal malformation, Prune Belly syndrome, intestinal malrotation and Hirschsprung disease. Initial management followed by endoscopic minimally invasive sigmoidectomy has proven safe and effective. MATERIALS AND METHODS: This paper presents the experience of 4 patients between 9 and 14 managed in our department in 2013, with a diagnosis of volvulus of the sigmoid, which were initially taken to a first surgical endoscopic decompression of volvulus and a second half were carried sigmoid which took place in a video-assisted. In this series, no intraoperative complications were documented and monitoring more than six months only one patient has required new interventions, in a special case because the patient has associated myopathy; inflammatory leiomioscitis, which predisposes to episodes of intestinal obstruction. CONCLUSION: We believe that endoscopic detorsion followed by an early video-assisted sigmoid is the ideal technique for the management of these patients. PMID- 27775289 TI - [Anterior urethral valves and anterior urethral diverticulum, are they same entity?] AB - OBJECTIVE: We present our experience in the diagnosis and management of anterior urethral valves (AUV) and anterior urethral diverticula (AUD) as well as review of the bibliography. MATERIALS AND METHODS: We retrospectively evaluated all the cases of the AUV and AUD treated in our hospital during the last 10 years. The clinical exploration, renal function study and renal and bladder ultrasound were evaluated in all the children. The diagnosis was completed with voiding cystography (VCUG) and cystoscopy as well as nuclear study in the relevant patients. RESULTS: Four patients have been treated in our center. AUV was suspected in those children with narrowing of the anterior urethra and thickened bladder with trabeculations at the VCUG. These findings were noticed in 50% of the patients, which also had a neonatal presentation. The diagnosis was confirmed by cystoscopy that allowed the endoscopic resection at the same procedure. The boys with AUD were managed by excision of the diverticulum with urethroplasty. On the follow up, one patient who had AUV, presented renal involvement in the nuclear scans with normal renal function. CONCLUSION: In our experience, the AUV and AUD behave as two different entities in terms of clinical presentation and treatment. The AUV have been effectively treated with endoscopic surgery and the AUD have pointed out open surgery, as described in the literature. PMID- 27775291 TI - [Pablo Lozano and Ponce de Leon (1859-1924) and the dispensary of Child Surgery Institute Rubio]. PMID- 27775290 TI - [Gastric volvulus as a cause of acute abdomen in a pre-school child]. AB - INTRODUCTION: Gastric volvulus is rare in the pediatric population. CLINICAL CASE: We report here a case of a patient of 5 years of age. COMMENTS: For its rarity, it requires a high degree of suspicion by the clinician, making it generally diagnosed very late which increases mortality. PMID- 27775292 TI - [Laryngotracheal traumatic injuries (LTI) in children: when to operate?] AB - INTRODUCTION: Paediatric LTI is associated with significant morbid-mortality. Although historically first line treatment was surgical, conservative management is making headway. The purpose of this study was to analyze the management and surgical indications of LTI treated at our institution. MATERIAL AND METHODS: Retrospective study of patients with LTI treated between 2007 and 2014. RESULTS: Six out of seven patients, with a median age of 4 years (2-15), had blunt traumas and one had an open trauma. Respiratory distress, pain and subcutaneous emphysema were presented in 71.4% of the patients. Five children were intubated (3 pre hospital care and 2 after reaching the hospital), all of them underwent fibrobronchoscopy, determining the location, the extention, and assessing the possibility of extubation. Esophagoscopy was made in 2 cases. The remaining 2 cases were bounded to observation as they did not have respiratory symptoms or progressive emphysema, precluding bronchoscopy. Conservative management was followed in 71.4% of the patients, with a 100% success rate. Conservative management criteria were no progression of emphysema or respiratory distress, regardless the degree and location of the lesions. Two patients needed surgery: one tracheoesophageal fistula caused by a button battery, and the other was a tracheal open section associated with vascular injury. Both of them recovered uneventfully. CONCLUSIONS: If the respiratory symptoms or the emphysema do not progress, patients with LTI can be managed conservatively, regardless of size or location of the injury. Associated esophageal lesions and open injuries require surgical management. An early diagnosis is mandatory in order to minimize morbidity and mortality. PMID- 27775293 TI - [Thoracoscopic resection of lung metastases guided by hook wire]. AB - OBJECTIVE: To describe our experience in the use of the guided hook wire placement to undergo thoracoscopic resection of pulmonary metastases in children. MATERIAL AND METHODS: We conducted a retrospective review, between January 2008 and December 2014 of the patients that were diagnosed with pulmonary metastases by image and who underwent a thoracoscopic metastasectomy. Patients in whom a CT- guided hook was done before the surgery were included. RESULTS: Eleven procedures were done in ten patients with a median age of 10 years (range 2-16 years). The cancer diagnoses were: 4 osteosarcoma, 1 nephroblastoma, 1 suprarrenal carcinoma, 1 liver sarcoma, 1 pseudopappilary tumor of pancreas 2 hepatoblastomas. All patients had subpleural metastases (size 2-11 mm) and only one hook was used in each procedure. 8 patients had metastases at the time of diagnosis, and the other 2 were diagnosed during the follow-up of the primary cancer. The median follow-up was 27 months (range 2-28 months). In this period, two patients had relapse of the primary tumor, with exitus. At present, the other children are free disease. The CT-guided hook wire fixation was successful and without major complications in all patients. The lesion indentified by image was resected. The result was 4 malignant lesions, and 7 benigns. CONCLUSION: The use of the CT- guided needle and hook wire placement for the resection of the metastases lesions is a safe and effective technique. We consider it the technique to choice in case of solitary and subpleural lesions. PMID- 27775294 TI - [Fast track protocol for children undergoing appendicectomy]. AB - BACKGROUND: Multiple approaches to the treatment of simple and complicated (gangrenous or perforated) appendicitis in children have been promoted. Our goal is to develop a new protocol for these patients that allows shorter hospital stays without increasing complications rates. METHODS: Prospective collected data of patients undergoing appendicitis treated according to the new protocol for a period of 7 months were reviewed. This protocol consists on antibiotic prophylaxis in all cases continued with triple antibiotic regimen in complicated appendicitis. Antibiotics were stopped when specific clinical and laboratory criteria were met. Outcomes are compared to a historical group of patients treated under standard protocol (antibiotic prophylaxis followed by 48 hours of dual antibiotic therapy in simple appendicitis or 5 day-course of triple antibiotic therapy in complicated as postooperative antibiotic regimen). RESULTS: A total of 196 patients (96 current group and 100 historical group) were reviewed. In simple appendicitis average length of postoperative hospitalization was significantly lower in the current group (no statistical difference). 52.9% of complicated appendicitis in the current group were discharged home before 5th day without increasing the complication rate. When a wound infection or intraabdominal abscess occurs thrombocytosis (52%) and prolonged vomiting are the most frequent symptoms. CONCLUSION: No further postoperative treatment is needed in simple appendicitis. In complicated appendictis a short course of antibiotics according to clinical and laboratory criteria allows early discharge without major morbidity. Prolonged postoperative vomiting and thrombocytosis suggest infectious complications. PMID- 27775295 TI - [Conservative or early surgical management of appendiceal mass. Does it affect the appearance of complications?] AB - OBJECTIVES: Currently the management of appendicular mass remains controversial. Many authors advocate conservative management followed by delayed appendectomy, whereas others favour inmediate appendectomy. The aim of our study is to compare both treatments. METHODS: A descriptive and observational study over 46 patients treated for appendiceal mass at our center in the last ten years was performed. Patients were categorized as group 1, early surgical intervention (54.3%) and group 2, conservative management and interval appendectomy (45.7%), with a mean interval of 5.3 +/- 1.5 months. RESULTS: Mean age was 9.2 +/- 3.8 years in group 1 and 3.7 +/- 3 years in group 2 (p<0.001). Median delay between the first symptoms and diagnosis was 4 +/- 2.2 days in group 1 and 7.9 +/- 4.2 days in group 2 (p<0.001). Antibiotics were administered before diagnosis in 24% of patients in group 1 and 42.9% in group 2 (p = 0.297). Ultrasound was performed in all patients, while 19.6% of patients requiered TAC for definitive diagnosis. Median hospital stay was 7.9 +/- 2.9 days in group 1 and 8.3 +/- 2.2 days in group 2 (p = 0.441). Complicactions were found in 64% of patients (group 1) and 23% of patients (group 2) (p = 0.015). Three patients from group 2 requiered readmission because of recurrent abdominal pain, but just one requiered early surgery. CONCLUSION: Conservative management of appendicular mass has a lower complication rate compared to the initial surgical management. PMID- 27775296 TI - [Preaxial polydactyly of the hand: 15 years of experience]. AB - INTRODUCTION: Preaxial polydactyly is one of the most common congenital malformations of the hand. The treatment is surgical and should be done early, between 6 and 12 months old. The purpose of this paper is to review our experience in terms of casuistry, treatment and functional and aesthetic results of duplicity of thumb, since 2000 until today. MATERIAL AND METHODS: A retrospective study of patients with diagnosis of preaxial polydactyly from 2000 to january 2016 was performed. RESULTS: Thirty patients with duplicity of thumb and thirty one bifid thumbs were diagnosed. No difference was found in terms of gender. The right hand was the most affected. Wassel type IV was the most common, followed by type II. Age at time of surgery had a median and mode of 12 months. All were treated surgically, using the model of preservation of the dominant thumb in 97% of the cases. According to Tada system, our postoperative results were good in 26 cases (83.8%). Our most frequent complication was slight radial clinodactyly, which was found in 5 cases. CONCLUSIONS: Preaxial polydactyly of the hand is one of the most common congenital malformations. It is usually unilateral and without gender predominance. Surgical treatment provides good results. The most common technique for reconstruction is the model of preservation of the dominant thumb. Clinodactyly is the most common complication after surgery, however its presence is more aesthetic than a functional problem. PMID- 27775297 TI - [Outcome of posterior anorectal myectomy for the treatment of idiopathic chronic constipation]. AB - OBJECIVES: The aim of this study is to assess the outcome of surgery (Lynn's myectomy) in patients with chronic persistent constipation and failure of medical treatment. MATERIAL AND METHODS: Descriptive study of patients with severe chronic constipation treated by posterior anorectal myectomy (Lynn's technique). We report data from the last 15 years, with a minimum postoperative follow-up of one year. Patients included in the study suffered from a long-term constipation refractory to medical management. Data regarding contrast enema, anorectal manometry and rectal biopsy were recorded. The procedure's outcome is classified following clinical criteria: Asymptomatic: >3 bowel movements per week, with no soiling/incontinence and with no medical treatment; Improvement: >3 bowel movements per week, with no soiling/incontinence but using laxatives occasionally. RESULTS: Nineteen myectomies were performed (median age of 8.47 years). Median time of constipation before surgery was 7.89 years. Rectal biopsy findings: 10 with ganglion cells, 4 without ganglion cells and other abnormalities in 5. Anorectal manometry was performed in 6 patients, 4 presented rectoanal inhibitory reflex. Four patients were diagnosed of Hirschsprung's disease (1 was asymptomatic after myectomy, 2 needed further surgery and 1 was lost in follow-up). Of the remaining 15 patients, 8 were asymptomatic (53.3%), 4 experienced improvement (26.6%) and 1 without clinical changes is on pelvic floor physiotherapy. Two were lost in follow-up. There were no other postoperative complications after long term follow-up. CONCLUSIONS: Lynn's myectomy is an effective and safe procedure in patients suffering from persistent chronic constipation despite of medical treatment. It is also the definitive treatment for patients with ultrashort-segment Hirschsprung's disease. PMID- 27775298 TI - [Hypertrophy of labia minora. A growing problem in adolescence]. AB - OBJECIVE: Hypertrophy of labia minora in adolescence is a little known disease. However, the growing demand for the solution of this problem pushes us to include it in our clinical practice. We evaluated the aesthetic and functional results of labiaplasty using straight amputation of the protuberant tissue of the labial edges. METHODS: Patients treated by hypertrophy of labia minora were reviewed. We evaluated the results of aesthetic, functional and surgical complications. A survey on the degree of satisfaction was also conducted. RESULTS: We collected 16 patients with 28 labioplasty, indicated by discomfort with the clothing and exercise. They were performed at a median age of 13.43 years (range 11.25-14.31). Bilateral 11 (64.7%), left 4 (23.5%) and rights 2 (11.8%). The median hospital stay was 1 day (range 1-3). There was evidence of immediate complications (partial dehiscence of the scar) in 1 (3.57%) patient and late complications in 2 (7.14%) patients (granuloma in the scar and recurrence), in a median follow up time of 1.58 years (range 0.19-7.76). The survey was answered by 13 patients. All of them said that preoperative discomfort was resolved. Postoperative discomfort (pain or straps) were nothing or very few in 61.54% and the median time of inconvenience was 5 days (range 1-30). They felt an improvement in self-esteem 69.23% and the 30.77% remaining never presented a problem about that. Median overall satisfaction was 8 (range 7-10) over 10, and the 100% of patients would repeat surgery. CONCLUSION: The labiaplasty by straight amputation in adolescence is an effective technique with few complications, and with a high degree of satisfaction for patients. PMID- 27775299 TI - [Spontaneous pneumothorax in children: factors associated with their recurrence]. AB - INTRODUCTION: Recurrence of spontaneous pneumothorax (SP) is more frequent in pediatric patients. The purpose of our study was to identify factors associated with this recurrence. MATERIAL AND METHODS: Retrospective review of the chart of patients with SP treated at our institution between 2004 and 2014. Statistic methods (chi2 and logistic regression) were used analyzing age, gender, side and size of pneumothorax and therapeutic approach as possible predictive factors of SP recurrence. RESULTS: A total of 81 SP cases in 43 patients (29 men, 14 women) were reviewed: 50 primary (PSP) and 31 secondary (SSP). Median age at presentation was 15,1 years (0.5-18.59). Follow up was 3.52 years (0.21-18.59). Twenty-three cases (28.4%) underwent surgery (22 thoracoscopies, 1 thoracotomy), consisting of bleb resection with abrasive and chemical pleurodesis. Ipsilateral recurrence after surgery was 21.7% (22.2% in PSP, 20% in SSP, p = 0.096) and 41.4% after non-surgical treatment. Age was a risk factor for recurrence (p= 0.049; OR = 1.16), especially between 10 and 15 years (44.6% in front of 19%, p = 0.013). Male gender and size >20% were associated with higher recurrence risk in SSP that received non-surgical treatment (p<0.05). CONCLUSIONS: Recurrences of SP in children are frequent even after surgical treatment. Age (preadolescence and early adolescence), male gender and initial size of pneumothorax may be factors associated with higher recurrence risk. PMID- 27775300 TI - [Neonatal intestinal obstruction due to cecal duplication]. AB - INTRODUCTION: Cecal duplications are rare, representing 0.4% of all gastrointestinal duplications, with few cases reported in the literature. CLINICAL CASE: A 48 hours-old newborn presented with bilious vomiting and abdominal distension; the ultrasound revealed a cystic mass in the right abdomen; ileocolic resection was performed with end to end anastomosis. Microscopy confirmed cecal duplication cyst. COMMENTS: In patients with intestinal obstruction, contrast enema allows differential diagnosis with other colonic pathologies in the newborn; when the cecal duplication cyst is connected to the lumen of the colon, enema reveals a filling defect, and cecal duplication can be suspected. Although cystic lesions are asymptomatic, they should be excised when detected to prevent complications. PMID- 27775301 TI - [Is there appendiceal stump appendicitis?] AB - INTRODUCTION: Stump appendicitis is the remaining appendicular tissue inflammation after a variable length of time. It is a very infrequent pathology with a paucity in pediatric publications, and given the fact that a delay in its diagnosis could lead to an increased morbidity, this is the reason of its clinical relevance. CLINICAL CASE: A 10 years old girl who had laparoscopic excision of a flemonous-gangrenous appendicitis and who 45 days after surgery showed new clinical symptoms compatible with a diagnosis of acute appendicitis. Abdominal ultrasound and CAT scans were suggestive of stump appendicitis. On a second laparoscopic operation, the rest of the stump was removed with full recovery and without complications. COMMENTS: What is interesting about this case is to describe this rarely seen pathology, specially in paediatrics, as well as the treatment and the prevention of such complication highlighting the importance of the correct identification of the appendicular base o caecum-appendicular union in the initial surgery. PMID- 27775302 TI - [Minimally Invasive Surgery in Pediatric Oncology. Tertiary center experience]. AB - AIMS: To describe our experience using Minimally Invasive Surgery (MIS) techniques in tertiary center with specific oncological pediatric surgery unit. METHODS: Retrospective review of patients undergoing MIS techniques in pediatric oncology surgery unit between January 2011 and December 2014. MIS procedures were considered made by both techniques such as laparoscopy and thoracoscopy with both diagnostic and therapeutic intent. RESULTS: 4 procedures were diagnostic and the rest were therapeutic: During the study, 56 procedures were performed by MIS. By type of technique, 13 were thoracoscopic (7 metastasectomies, 6 thoracic masses) and 43 laparoscopic (3 hepatic masses, 3 pancreatic masses 7 abdominal masses, 2 ovarian masses, 2 typhlitis 1 splenic mass and 25 oophorectomy for ovarian cryopreservation). In 5 cases (2 thoracic masses 1 pancreatic mass abdominal masses) conversion to open surgery to complete the procedure (2 for caution in the absence of vascular control bleeding 1 and 2 for lack of space) was necessary. In all cases safety principles of oncological surgery were respected. CONCLUSIONS: Providing an adecuate selection of patiens, MIS techniques are safe, reproducible and fulfill the objectives of quality of cancer surgery. PMID- 27775303 TI - [Implementation of a Plan of Patient Safety in Service of Pediatric Surgery. First results]. AB - OBJECTIVES: In 2014 our department starts to apply the PatientSafety Strategic in Pediatric Surgery. Our aim is to describe the results obtained. METHODS: For the measurement of adverse events (AE) we used a modification of the Global Trigger Tool of the Institute for Healthcare Improvement. Population analysed: patients undergoing surgery with hospitalization. On a monthly basis, audits of the medical records of 12 patients discharged in the prior week of the assessment were performed. The evaluation team was composed by experienced pediatric surgeon, two staff nurses, and a doctor and nurse from the Quality Department. RESULTS: 95 clinical records and a total of 406 days of hospital stay were reviewed. 31 patients (32.6%) experienced one or more AE. Total AE: 43. The AE/1000 patients/day ratio: 105.9. The most common AE were: vomiting, itching and pain. 28 EA were considerd mild and 3 moderate in severity, according to the classification of the National Coordinating Council for Medication Error Reporting and Prevention. No EA were considered serious or critical. CONCLUSIONS: The analysis of prevalence through regular assessments of medical records is an easy method to obtain information about the frequency of occurrence, exact understanding of the AE types and the implementation of corrective measures. The main limitation of this method is that it can miss some of the serious EA and miss the records and analysis of sentinel events that may occur in the period between assessments. PMID- 27775304 TI - [Administration of water-soluble contrast for the treatment of adhesive intestinal occlusion]. AB - OBJECTIVE: The water-soluble contrast has shown its effectiveness for the resolution of adhesive small bowel obstruction (SBO) in adults. The objective of this study is to compare the value of water-soluble contrast in children with SBO versus control group. METHODS: We conducted a case-control trial. Patients with a history of abdominal surgery and SBO diagnosed between 2008 and 2013 were included as controls. Conservative treatment or surgery depending on clinical evolution was performed in control group. The patients with SBO diagnosed from December 2012 were treated with water-soluble contrast. The main variable was the number of patients requiring surgery and the hospital stay and complications were the secondary variable. RESULTS: Twenty controls and 8 cases were admitted with SBO. Surgery was required in 50% of control group patients and 25% in the contrast group (p>0.05). The hospital stay length was 6 days in control group versus 4 days in study group (p>0.05). No complications were attributed to the use of water-soluble contrast and 20% of complications happened in control group. CONCLUSIONS: The need for surgery was lower in study group but not statically significant due to the small size of the sample. We concluded that water-soluble contrast is safe and effective in the management of SBO in children. We propose a multicentre study. PMID- 27775305 TI - [Treatment of the postoperative bowel obstructions in children: laparoscopic vs. open adhesiolysis]. AB - OBJECTIVE: To compare the results of laparoscopic versus open adhesiolysis in children affected by postoperative bowel obstruction. METHODS: Retrospective study reviewing charts of all patients who were operated on due to postoperative adhesions in our Department. Demographic data, clinical characteristics and postoperative data were collected. RESULTS: During the last 8 years, 37 patients were operated on for postoperative intestinal obstructions. 40.5% were operated by laparoscopy and 59.5% by laparotomy. Mean ages were 6.31 and 4.32 years in laparoscopic and open groups, respectively. There were no differences in days of evolution of the occlusion, neither in their medical history. Patients in laparoscopic group had better outcomes in the need of central lines (15% vs 61.90% p= 0.012), use of parenteral nutrition (38.46% vs 83.33% p= 0.005), beginning of the enteral nutrition (4.04 vs 8.17 days p= 0.004) and hospital stay (7.77 vs 13.05 days p= 0.027). CONCLUSIONS: Open and laparoscopic adhesiolysis are effective to treat adhesive cases. Laparoscopic adhesiolysis has some advantages over open surgery: less need of central lines and parenteral nutrition, earlier start of enteral nutrition, less rate of complications and shorter hospital stay. PMID- 27775306 TI - [Endocrine disrupting chemicals exposure and other parental factors in hypospadias and cryptorchidism etiology]. AB - AIM OF THE STUDY: To investigate the association between endocrine disrupting chemicals (EDC) exposure and other paternal factors in the etiology of hipospadias and cryptorchidism. METHODS: A case-control study. Cases were infants between 0 and 6 years of age diagnosed with hypospadias or cryptorchidism in our pediatric urology and general pediatric surgery services during a period of 6 months, and controls were infants with the same range of age attending the same services without any urological problem. Several variables were collected by face to-face interviews with both parents. After data abstraction, we compared the characteristics of both groups using parametric statistical tests. MAIN RESULTS: A total of 180 patients were studied, 90 cases (45 hypospadias/45 cryptorchidism) and 90 controls with a mean age of 2,37 +/- 1.50 years [range 0,5-6]. Median of mother's age was significantly greater in case group (34,40 +/- 5,64 versus 31,74 +/- 5,05; p= 0,001). Significant differences were observed between cases and controls in regard to maternal occupational exposure to EDC (mainly phthalates), adjusted Odds ratio (OR) was 3.67 [95% confidence interval (CI): 1.28-10.51; p= 0,018] and regarding the paternal occupational exposure to EDC (mainly pesticides and herbicides), adjusted OR was 6.65 [95% CI: 2.60-17.02; p= 0,001]. Increased risk was also observed in smoking fathers and fathers who drink alcohol, adjusted Odds ratio were 2.36 [95% CI: 1.11. CONCLUSIONS: This study represents a little contribution to the possible etiologic factors of hypospadias and cryptorchidism, further studies with higher statistical power would be needed to prove it. PMID- 27775307 TI - [Balanitis xerotica obliterans, underdiagnosed pathology of clinical relevance]. AB - OBJECTIVES: Balanitis xerotica obliterans (BXO) is a chronic inflamatory disease, a genital form of Lichen Sclerosus in males. MATERIAL AND METHODS: This retrospective and descriptive analysis was carried out by rewiew of the medical records of boys who underwent circumcision from April 2013 to April 2014. The study group consisted of boys that were circumcised due it persistant phimosis at 4 years of age, urinary symptoms or painful erection. The histopathological examination was performed only in patients with clinical suspicion of BXO. RESULTS: 339 patients were circumcised. The mean age of surgery was 6.5 years (Median 5, Mode 4). BXO was confirmed in eleven boys (3.9%) out of 16 biopsies (5.7%), with a mean age of 8.2 years (6-12). Of all the biopsies that were analysed for clinical BXO, 9 had scarring phimosis (2 meatal stenosis), 2 had balanitis and 1 had acute urinary retention, 2 presented descamative foreskin or glands, and 1 had recurrent phimosis. The histopathological examination revealed lichen sclerosus in 10 patients. Meatotomy was performed in 3 boys, one of them in during the follow-up period. 10 patients with BXO were treated with topical corticosteroid cream after circumcision. CONCLUSIONS: Our incidence is low in compared to literature (10-40%) as we did not refer the foreskin routinely to histopathological analysis. The clinical suspicion underestimates the incidence of BXO up to 49%. The circumcision is curative in most cases with BXO. The BXO may produce meatoestenosis and urethral abnormalities, and it is associated with a high incidence of penile carcinoma of the penis. PMID- 27775308 TI - [Appendicular actinomycosis as a cause of ileocecal mass in children: Case report]. AB - INTRODUCTION: Appendicular actinomycosis is a rare disease produced by cecal appendix invasion by Actinomyces gender bacteria after a predisposing cause that disrupts mucosal barrier, such as acute appendicitis. The highest frequency appears in adults; however, there are cases in paediatric age described in literature. The aim of this article is to introduce a case of appendicular actinomycosis in a child with atypical presentation and to review the literature. CLINICAL CASE: 10-year-old boy transferred to our hospital due to intraoperative finding at a different centre of a right flank tumor, without identification of cecal appendix. After completing the study with image tests, the patient was re intervened with the diagnosis of complicated acute appendicitis. Intraoperatively, an organized plastron lacking of acute inflammatory signs was found. Post-surgical evolution was positive with conventional antibiotic treatment. Histological study of the specimen revealed an appendicular actinomycosis, so antibiotic treatment was widened in an outpatient basis and predisposing diseases were ruled out. COMMENTS: Appendicular actinomycosis is an infrequent cause of appendicitis that can simulate an intra-abdominal tumor in children and adults. It is necessary to rule out predisposing diseases and to administer an adequate antibiotic treatment. PMID- 27775309 TI - [Neonatal use of propranolol for segmental facial hemangiomas]. AB - INTRODUCTION: Segmental cervico facial hemangiomas are defined as those longer than 5 cm, affecting a specific facial area. These lesions can be eventually associated with the PHACE syndrome. Our aim is to propose neonatal treatment with propranolol, showing its efficacy/safety, given the scarce evidence on its neonatal use. CLINICAL OBSERVATION: After written informed consent, four patients with segmental facial hemangioma were treated with propranolol in the neonatal period. Adverse effects were registered during initial admission. Three of the four patients had PHACE syndrome. Propranolol was effective in 100% of patients, showing hemangioma's involution without any adverse effect. COMMENTS: In our series, propranolol was effective and showed no side effects in the neonatal period. If propranolol benefits are greater than its risks, administration of the lowest effective dose is recommended, under hospital surveillance, starting shortly after diagnosis, in order to achieve improved efficacy. PMID- 27775310 TI - [Periorbital lymphatic malformations: Report of two cases]. AB - INTRODUCTION: Periorbital lymphatic malformations are a rare entity in which diagnosis and treatment could be a challenge for surgeons. Management may be conservative, or they can be treated by sclerotherapy, surgery or combination of both. CLINICAL OBSERVATION: We present two cases of periorbital lymphatic malformations treated by sclerotherapy (OK-432 or bleomycin) and surgery in which we achieve good results with minimum morbidity. COMMENTS: Surgery combined with sclerotherapy is a good option of treatment for periorbital lymphatic malformations because surgery can be more conservative and therefore, sequelae are lower. PMID- 27775311 TI - [Infantile hypertrofic pyloric stenosis or gastric adenomyoma? Differential diagnosis of gastric outlet obstruction in children]. AB - PURPOSE: Gastrointestinal adenomyoma is a rare benign tumor most frequently located in the stomach. The differential diagnosis is wide because of its large clinical spectrum and unspecific radiological findings. Surgical excision is both diagnostic and therapeutic. CASE REPORT: A 49-days old girl presented with nonbilious vomiting of 48 hours of evolution. Infantile hypertrofic pyloric stenosis was suspected. Ultrasound showed a nonobstructive nodular lesion in the anterior pyloric wall. MRI suggested a myofibroblastic tumor. We proceeded to laparotomy and complete resection of the pyloric tumor. Histologic diagnosis was gastric adenomyoma. CONCLUSIONS: Pyloric adenomyoma causes obstructive symptoms similar to other common entities such as hypertrophic pyloric stenosis or cystic duplication. We have to consider this condition in children with digestive symptoms and radiological images of intussusceptions or duplication. Surgical excision is recommended to reach a definitive diagnosis and to avoid a possible malignant degeneration. PMID- 27775312 TI - [Pediatric surgery addiction]. PMID- 27775313 TI - A New 2H-2H'/1T Cophase in Polycrystalline MoS2 and MoSe2 Thin Films. AB - We report on 2H-2H'/1T phase conversion of MoS2 and MoSe2 polycrystalline films grown by thermally assisted conversion. The structural conversion of the transition metal dichalcogenides was successfully carried out by organolithium treatment on chip. As a result we obtained a new 2H-2H'/1T cophase system of the TMDs thin films which was verified by Raman spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The conversion was successfully carried out on selected areas yielding a lateral heterostructure between the pristine 2H phase and the 2H'/1T cophase regions. Scanning electron microscopy and atomic force microscopy revealed changes in the surface morphology and work function of the cophase system in comparison to the pristine films, with a surprisingly sharp lateral interface region. PMID- 27775314 TI - Spectroscopic Characterization of Azo Dyes Aggregation Induced by DABCO-Based Ionene Polymers and Dye Removal Efficiency as a Function of Ionene Structure. AB - The aggregation mode of three azo dyes, methyl orange (MO), ponceau SS (PSS), and direct blue 1 (DB1) induced by three 1,4-diazabicyclo[2.2.2]octane (DABCO)-based ionene polymers having different topologies (i.e., 1,2-ionene, 1,3-ionene, and 1,4-ionene) was investigated in this work. Metachromatic behavior of the dyes in the presence of ionenes, and the stability of the ionene/dye complex were discussed as a function of ionene structure. It was demonstrated that the association of the dye molecules with the ionenes and the metachromasy were strongly influenced by both the dye structure and the ionene topology. Thus, MO, having one -SO3Na group per molecule, was almost stoichiometrically bound to all ionenes regardless of their topology, showing also a metachromatic effect. In sharp contrast, the interaction of PSS and DB1 molecules with ionenes was strongly dependent on the polymer topology. It was found that PSS having two SO3Na groups per molecule was preferentially bound onto both 1,2-ionene and 1,3 ionene, but DB1, having four -SO3Na groups per molecule and a more complex structure, was efficiently bound only onto 1,2-ionene. The dye removal efficiency with each ionene was evaluated in batch mode taking into account the affinity of ionenes for azo dyes. The experimental isotherms of the dye sorption were fitted with four isotherm models, i.e., Langmuir, Freundlich, Sips, and Dubinin Radushkevich. It was found that the best fitting of the experimental data was given by the Langmuir, Sips, and Dubinin-Radushkevich isotherm models. The maximum equilibrium sorption capacity, qm, evaluated by the Langmuir model, at 35 degrees C, was as follows: 985.71 mg MO/g 1,3-ionene, 483.71 mg PSS/g 1,3 ionene, 1010.49 mg PSS/g 1,2-ionene, and 976.7 mg DB1/g 1,2-ionene. Kinetic study of the dye removal indicated chemisorption as the main mechanism of sorption. PMID- 27775315 TI - Volumetric Physics of Polypeptide Coil-Helix Transitions. AB - Volumetric properties of proteins bear directly on their biological functions in hyperbaric environments and are useful in general as a biophysical probe. To gain insight into conformation-dependent protein volume, we developed an implicit solvent atomic chain model that transparently embodies two physical origins of volume: (1) a fundamental geometric term capturing the van der Waals volume of the protein and the particulate, finite-size nature of the water molecules, modeled together by the volume encased by the protein's molecular surface, and (2) a physicochemical term for other solvation effects, accounted for by empirical proportionality relationships between experimental partial molar volumes and solvent-accessible surface areas of model compounds. We tested this construct by Langevin dynamics simulations of a 16-residue polyalanine. The simulated trajectories indicate an average volume decrease of 1.73 +/- 0.1 A3/residue for coil-helix transition, ~80% of which is caused by a decrease in geometric void/cavity volume, and a robust positive activation volume for helical hydrogen bond formation originating from the transient void created by an approaching donor-acceptor pair and nearby atoms. These findings are consistent with prior experiments with alanine-rich peptides and offer an atomistic analysis of the observed overall volume changes. The results suggest, in general, that hydrostatic pressure likely stabilizes helical conformations of short peptides but slows the process of helix formation. In contrast, hydrostatic pressure is more likely to destabilize natural globular proteins because of the void volume entrapped in their folded structures. The conceptual framework of our model thus affords a coherent physical rationalization for experiments. PMID- 27775316 TI - Making Silicone Rubber Highly Resistant to Bacterial Attachment Using Thiol-ene Grafting. AB - Biomedical devices are indispensable in modern medicine yet offer surfaces that promote bacterial attachment and biofilm formation, resulting in acute and chronic healthcare-associated infections. We have developed a simple method to graft acrylates to silicone rubber, polydimethylsiloxane (PDMS), a commonly used device material that is often colonized by bacteria. We demonstrate a novel method whereby nontoxic bacteria attachment-resistant polymers can be readily grafted from and grafted to the surface using thiol-ene chemistry, substantially reducing bacterial colonization. With use of this approach, bacterial biofilm coverage can be reduced by 99% compared with standard PDMS in an in vitro assay. This grafting approach offers significant advantages over commonly used physisorbed coatings, especially in areas of high shear or mechanical stress. Furthermore, the approach is versatile such that the grafted material properties can be tailored for the desired final application. PMID- 27775317 TI - Gold-Nanorods-Based Gene Carriers with the Capability of Photoacoustic Imaging and Photothermal Therapy. AB - Multifunctional nanoparticles with high gene transfection activity, low cytotoxicity, photoacoustic imaging ability, and photothermal therapeutic properties were prepared by conjugating low-molecular-weight polyethylenimine onto the surfaces of gold nanorods through the formation of stable S-Au bonded conjugates. Results revealed that the gene transfection efficiency of the prepared polyethylenimine-modified gold nanorods (GNRs-PEI1.8k) was higher and their cytotoxicity was less than those of the commercial reagent PEI25k. GNRs PEI1.8k could also be potentially used as a photoacoustic and photothermal reagent to evaluate the pharmacokinetics, biodistribution, and antitumor effects of gene/drug nanoparticles. Therefore, GNRs-PEI1.8k can be considered a promising candidate for the clinical diagnosis and treatment of tumors. PMID- 27775318 TI - "Rocking-Chair"-Type Metal Hybrid Supercapacitors. AB - Hybrid supercapacitors that follow a "rocking-chair"-type mechanism were developed by coupling divalent metal and activated carbon electrodes in nonaqueous electrolytes. Conventional supercapacitors require a large amount of electrolyte to provide a sufficient quantity of ions to the electrodes, due to their Daniell-type mechanism that depletes the ions from the electrolyte while charging. The alternative "rocking-chair"-type mechanism effectively enhances the energy density of supercapacitors by minimizing the necessary amount of electrolyte, because the ion is replenished from the metal anode while it is adsorbed to the cathode. Newly developed nonaqueous electrolytes for Mg and Zn electrochemistry, based on bis(trifluoromethylsulfonyl)imide (TFSI) salts, made the metal hybrid supercapacitors possible by enabling reversible deposition on the metal anodes and reversible adsorption on an activated carbon cathode. Factoring in gains through the cell design, the energy density of the metal hybrid supercapacitors is projected to be a factor of 7 higher than conventional devices thanks to both the "rocking-chair"-type mechanism that minimizes total electrolyte volume and the use of metal anodes, which have substantial merits in capacity and voltage. Self-discharge was also substantially alleviated compared to conventional supercapacitors. This concept offers a route to build supercapacitors that meet dual criteria of power and energy densities with a simple cell design. PMID- 27775319 TI - Dibenzopyran-Based Wide Band Gap Conjugated Copolymers: Structural Design and Application for Polymer Solar Cells. AB - With the efficient synthesis of the crucial dibenzopyran building block, a series of PDBPTBT polymers containing different alkyl side chains and/or fluorine substitution were designed and synthesized via the microwave-assisted Suzuki polycondensation. Quantum chemistry calculations based on density functional theory indicated that different substitutions have significant impacts on the planarity and rigidity of the polymer backbones. Interestingly, the alkyloxy chains of PDBPTBT-4 tend to stay in the same plane with the benzothiadiazole unit, but the others appear to be out of plane. With the S...O and F...H/F...S supramolecular interactions, the conformations of the four polymers will be locked in different ways as predicted by the quantum chemistry calculation. Such structural variation resulted in varied solid stacking and photophysical properties as well as the final photovoltaic performances. Conventional devices based on these four polymers were fabricated, and PDBPTBT-5 displayed the best PCE of 5.32%. After optimization of the additive types, ratios, and the interlayers at the cathode, a high PCE of 7.06% (Voc = 0.96 V, Jsc = 11.09 mA/cm2, and FF = 0.67) is obtained for PDBPTBT-5 with 2.0% DIO as the additive and PFN-OX as the electron-transporting layer. These results indicated DBP-based conjugated polymers are promising wide band gap polymer donors for high efficiency polymer solar cells. PMID- 27775320 TI - Anisotropic Self-Assembly of Organic-Inorganic Hybrid Microtoroids. AB - Toroidal structures based on self-assembly of predesigned building blocks are well-established in the literature, but spontaneous self-organization to prepare such structures has not been reported to date. Here, organic-inorganic hybrid microtoroids synthesized by simultaneous coordination-driven assembly of amphiphilic molecules and hydrophilic polymers are reported. Mixing amphiphilic molecules with iron(III) chloride and hydrophilic polymers in water leads, within minutes, to the formation of starlike nanostructures. A spontaneous self organization of these nanostructures is then triggered to form stable hybrid microtoroids. Interestingly, the toroids exhibit anisotropic hierarchical growth, giving rise to a layered toroidal framework. These microstructures are mechanically robust and can act as templates to host metallic nanoparticles such as gold and silver. Understanding the nature of spontaneous assembly driven by coordination multiple non-covalent interactions can help explain the well-ordered complexity of many biological organisms in addition to expanding the available tools to mimic such structures at a molecular level. PMID- 27775321 TI - Exploring Coupled Plasmonic Nanostructures in the Near Field by Photoemission Electron Microscopy. AB - The extraordinary optical properties of coupled plasmonic nanostructures make these materials potentially useful in many applications; thus, they have received enormous attention in basic and applied research. Coupled plasmon modes have been characterized predominantly using far-field spectroscopy. In near-field spectroscopy, the spectral response of local field enhancement in coupled plasmonic nanostructures remains largely unexplored, especially experimentally. Here, we investigate the coupled gold dolmen nanostructures in the near field using photoemission electron microscopy, with wavelength-tunable femtosecond laser pulses as an excitation source. The spatial evolution of near-field mapping of an individual dolmen structure with the excitation wavelength was successfully obtained. In the near field, we spatially resolved an anti-bonding mode and a bonding mode as the result of plasmon hybridization. Additionally, the quadrupole plasmon mode that could be involved in the formation of a Fano resonance was also revealed by spatially resolved near-field spectra, but it only contributed little to the total near-field enhancement. On the basis of these findings, we obtained a better understanding of the near-field properties of coupled plasmonic nanostructures, where the plasmon hybridization and the plasmonic Fano resonance were mixed. PMID- 27775322 TI - Inactivation of Antibiotic Resistant Bacteria and Resistance Genes by Ozone: From Laboratory Experiments to Full-Scale Wastewater Treatment. AB - Ozone, a strong oxidant and disinfectant, seems ideal to cope with future challenges of water treatment, such as micropollutants, multiresistant bacteria (MRB) and even intracellular antibiotic resistance genes (ARG), but information on the latter is scarce. In ozonation experiments we simultaneously determined kinetics and dose-dependent inactivation of Escherichia coli and its plasmid encoded sulfonamide resistance gene sul1 in different water matrixes. Effects in E. coli were compared to an autochthonous wastewater community. Furthermore, resistance elimination by ozonation and post-treatment were studied in full-scale at a wastewater treatment plant (WWTP). Bacterial inactivation (cultivability, membrane damage) and degradation of sul1 were investigated using plate counts, flow cytometry and quantitative real-time PCR. In experiments with E. coli and the more ozone tolerant wastewater community disruption of intracellular genes was observed at specific ozone doses feasible for full-scale application, but flocs seemed to interfere with this effect. At the WWTP, regrowth during postozonation treatment partly compensated inactivation of MRB, and intracellular sul1 seemed unaffected by ozonation. Our findings indicate that ozone doses relevant for micropollutant abatement from wastewater do not eliminate intracellular ARG. PMID- 27775323 TI - Fluorescent Detection of Phosphate Ion via a Tetranuclear Zinc Complex Supported by a Tetrakisquinoline Ligand and MU4-PO4 Core. AB - The tetrakisquinoline ligand HT(6-MeO8Q)HPN (N,N,N',N'-tetrakis(6-methoxy-8 quinolylmethyl)-2-hydroxy-1,3-propanediamine) exhibited Zn2+-induced fluorescence enhancement with high specificity and sensitivity (IZn/I0 = 57 and ICd/IZn = 6% in the presence of 2 equiv of Zn2+; LOD (limit of detection) = 15 nM). This ligand also exhibited fluorescence enhancement specific to inorganic phosphate (PO43-) in DMF-HEPES buffer (50 mM HEPES, 100 mM KCl, pH = 7.5) (1:1) in the presence of 2 equiv of Zn2+. The structure of the unprecedented tetranuclear zinc complex with a MU4-PO4 bridge was elucidated by X-ray crystallography as the key species responsible for fluorescence enhancement. PMID- 27775324 TI - Diffuse Phase Transitions and Giant Electrostrictive Coefficients in Lead-Free Fe3+-Doped 0.5Ba(Zr0.2Ti0.8)O3-0.5(Ba0.7Ca0.3)TiO3 Ferroelectric Ceramics. AB - The electrostrictive effect has some advantages over the piezoelectric effect, including temperature stability and hysteresis-free character. In the present work, we report the diffuse phase transitions and electrostrictive properties in lead-free Fe3+-doped 0.5Ba(Zr0.2Ti0.8)O3-0.5(Ba0.7Ca0.3)TiO3 (BZT-0.5BCT) ferroelectric ceramics. The doping concentration was set from 0.25 to 2 mol %. It is found that by introducing Fe3+ ion into BZT-0.5BCT, the temperature corresponding to permittivity maximum Tm was shifted toward lower temperature monotonically by 37 degrees C per mol % Fe3+ ion. Simultaneously, the phase transitions gradually changed from classical ferroelectric-to-paraelectric phase transitions into diffuse phase transitions with a weak relaxor characteristic. Purely electrostrictive responses with giant electrostrictive coefficient Q33 between 0.04 and 0.05 m4/C2 are observed from 25 to 100 degrees C for the compositions doped with 1-2 mol % Fe3+ ion. The Q33 of Fe3+-doped BZT-0.5BCT ceramics is almost twice the Q33 of other ferroelectric ceramics. These observations suggest that the present system can be considered as a potential lead-free material for the applications in electrostrictive area and that BT based ferroelectric ceramics would have giant electrostrictive coefficient over other ferroelectric systems. PMID- 27775325 TI - A TPX2 Proteomimetic Has Enhanced Affinity for Aurora-A Due to Hydrocarbon Stapling of a Helix. AB - Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly and is a promising target for anticancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker. To characterize the contributions of these three structural elements, we prepared a series of TPX2 proteomimetics and investigated their binding affinity for Aurora A using isothermal titration calorimetry. A novel stapled TPX2 peptide was developed that has improved binding affinity for Aurora-A and mimics the function of TPX2 in activating Aurora-A's autophosphorylation. We conclude that the helical region of TPX2 folds upon binding Aurora-A, and that stabilization of this helix does not compromise Aurora-A activation. This study demonstrates that the preparation of these proteomimetics using modern synthesis methods is feasible and their biochemical evaluation demonstrates the power of proteomimetics as tool compounds for investigating PPIs involving intrinsically disordered regions of proteins. PMID- 27775326 TI - Ni-Mo Nanocatalysts on N-Doped Graphite Nanotubes for Highly Efficient Electrochemical Hydrogen Evolution in Acid. AB - Developing noble-metal-free catalysts for electrochemical hydrogen evolution reactions (HER) with superior stability in acid is of critical importance for large-scale, low-cost hydrogen production from water electrolysis. Herein, we report a highly efficient and stable noble-metal-free HER catalyst, which is composed of Ni and Mo2C nanocrystals supported on N-doped graphite nanotubes. This catalyst shows very low overpotential (65 mV in 0.5 M H2SO4 at a current density of 10 mA cm-2 with a Tafel plot of 67 mV/dec) and good stability for HER in acidic electrolyte, which is a promising noble-metal-free HER catalyst. PMID- 27775327 TI - lambda5-Phosphorus-Containing alpha-Diazo Compounds: A Valuable Tool for Accessing Phosphorus-Functionalized Molecules. AB - The compounds characterized by the presence of a lambda5-phosphorus functionality at the alpha-position with respect to the diazo moiety, here referred to as lambda5-phosphorus-containing alpha-diazo compounds (PCDCs), represent a vast class of extremely versatile reagents in organic chemistry and are particularly useful in the preparation of phosphonate- and phosphinoxide-functionalized molecules. Indeed, thanks to the high reactivity of the diazo moiety, PCDCs can be induced to undergo a wide variety of chemical transformations. Among them are carbon-hydrogen, as well as heteroatom-hydrogen insertion reactions, cyclopropanation, ylide formation, Wolff rearrangement, and cycloaddition reactions. PCDCs can be easily prepared from readily accessible precursors by a variety of different methods, such as diazotization, Bamford-Stevens-type elimination, and diazo transfer reactions. This evidence along with their relative stability and manageability make them appealing tools in organic synthesis. This Review aims to demonstrate the ongoing utility of PCDCs in the modern preparation of different classes of phosphorus-containing compounds, phosphonates, in particular. Furthermore, to address the lack of precedent collective papers, this Review also summarizes the methods for PCDCs preparation. PMID- 27775328 TI - Organophosphate Ester Flame Retardants and Plasticizers in the Global Oceanic Atmosphere. AB - Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers and have been detected ubiquitously in the remote atmosphere. Fourteen OPEs were analyzed in 115 aerosol phase samples collected from the tropical and subtropical Atlantic, Pacific, and Indian Oceans during the MALASPINA circumnavigation campaign. OPEs were detected in all samples with concentrations ranging from 360 to 4400 pg m-3 for the sum of compounds. No clear concentration trends were found between the Northern and Southern hemispheres. The pattern was generally dominated by tris(1-chloro-2-propyl) phosphate (TCPP), although tri-n-butyl phosphate (TnBP) had a predominant role in samples close to continents and in those influenced by air masses originating in continents. The dry deposition fluxes of aerosol phase ?14OPE ranged from 4 to 140 ng m-2 d-1. An estimation of the OPE gas phase concentration and gross absorption fluxes by using three different sets of physical chemical properties suggested that the atmosphere-ocean diffusive exchange of OPEs could be 2-3 orders of magnitude larger than dry deposition. The associated organic phosphorus inputs coming from diffusive OPE fluxes were estimated to potentially trigger up to 1.0% of the reported primary production in the most oligotrophic oceanic regions. However, the uncertainty associated with these calculations is high and mostly driven by the uncertainty of the physical chemical properties of OPEs. Further constraints of the physical chemical properties and fluxes of OPEs are urgently needed, in order to estimate their environmental fate and relevance as a diffusive source of new organic phosphorus to the ocean. PMID- 27775329 TI - Smart Polymeric Hydrogels for Cartilage Tissue Engineering: A Review on the Chemistry and Biological Functions. AB - Stimuli responsive hydrogels (SRHs) are attractive bioscaffolds for tissue engineering. The structural similarity of SRHs to the extracellular matrix (ECM) of many tissues offers great advantages for a minimally invasive tissue repair. Among various potential applications of SRHs, cartilage regeneration has attracted significant attention. The repair of cartilage damage is challenging in orthopedics owing to its low repair capacity. Recent advances include development of injectable hydrogels to minimize invasive surgery with nanostructured features and rapid stimuli-responsive characteristics. Nanostructured SRHs with more structural similarity to natural ECM up-regulate cell-material interactions for faster tissue repair and more controlled stimuli-response to environmental changes. This review highlights most recent advances in the development of nanostructured or smart hydrogels for cartilage tissue engineering. Different types of stimuli-responsive hydrogels are introduced and their fabrication processes through physicochemical procedures are reported. The applications and characteristics of natural and synthetic polymers used in SRHs are also reviewed with an outline on clinical considerations and challenges. PMID- 27775330 TI - Simultaneous Nitrogen Doping and Pore Generation in Thermo-Insulating Graphene Films via Colloidal Templating. AB - We report a simple method for preparing highly efficient thermoelectric materials through the fabrication of nitrogen-doped reduced graphene oxide (GO) with a porous structure. The samples were produced by thermal annealing of GO/nitrogen rich polystyrene (N-PS) particle composite films using a colloidal templating method. N-PS particles served as a nitrogen dopant source for the nitrogen-doped thermally reduced graphene oxide (TrGO) as well as sacrificial particles for the porous structure. The S values of the porous TrGO films were negative, indicating that the samples were transformed into n-type materials. Their porous structures simultaneously resulted in materials with high sigma values and low in-plane kappa values by providing numerous air cavities for phonon scattering and destruction of the anisotropic structure, maintaining an interconnected structure for an electron transport path. Thus, the porous TrGO films exhibited enhanced power factors and low kappa values. The highest ZT value of 1.39 * 10-4 was attained for a porous TrGO film annealed at 1100 degrees C, which was 1200 times higher than that of a nonporous TrGO film. This study emphasizes that an isotropic orientation of two-dimensional materials has a significant effect on the suppression of in-plane kappa, leading to their enhanced thermoelectric performance. PMID- 27775331 TI - Temporal Trends and Geographical Differences of Perfluoroalkyl Acids in Baltic Sea Herring and White-Tailed Sea Eagle Eggs in Sweden. AB - Temporal and spatial trends of perfluoroalkyl acids (PFAAs) were investigated in Baltic Sea herring liver (Clupea harengus) from three sites, and white-tailed sea eagle (WTSE) eggs (Haliaeetus albicilla) from two freshwater and two marine areas in Sweden. Trends of most quantifiable PFAAs increased over the monitored period (1980-2014 in herring, 1960s/1980s-2010 in WTSE). No significant decreasing trends were observed for the most recent ten years for any substances, except perfluorooctane sulfonamide (FOSA). Concentrations of perfluorooctanesulfonic acids (PFOS) in herring showed a distinct decreasing spatial trend moving from the more southern site toward the more northern site, indicating main input of PFOS into the southern Baltic Sea. For WTSE, PFOS concentration was higher in the marine compared to the freshwater environment, explained by the cumulative historic contamination of the Baltic Sea. Similarly, concentrations in WTSE were lower in the northern part of the Baltic Sea compared to further south. Concentrations of PFUnDA, representing long-chain perfluoroalkyl carboxylic acids (PFCAs), showed a more homogeneous spatial distribution compared to PFOS for both herring and WTSE, indicating that atmospheric inputs (via precursors) of the long chain PFCAs are important contributors in the study areas. PMID- 27775332 TI - How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction. AB - Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells. Both are required for an immune response. In addition, drugs may induce an immune response through inflammasome activation. We have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exceptions, these hypotheses are unlikely to be able to completely explain IDRs. However, some types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects us from IDRs appears to be immune tolerance. Consistent with this hypothesis, we used checkpoint inhibition to develop the first animal model of idiosyncratic drug induced liver injury that has the same characteristics as the idiosyncratic injury in humans. This was accomplished by treating Pd-1-/- mice with anti-CTLA-4 antibodies and amodiaquine. The combination of the Pd-1-/- mouse and anti-CTLA-4 also unmasks the ability of other drugs such as isoniazid to cause delayed type liver injury. This model should allow rigorous testing of mechanistic hypotheses that was impossible in the past. PMID- 27775333 TI - Encapsulation of Two Potassium Cations in Preyssler-Type Phosphotungstates: Preparation, Structural Characterization, Thermal Stability, Activity as an Acid Catalyst, and HAADF-STEM Images. AB - Dipotassium cation (K+)-encapsulated Preyssler-type phosphotungstate, [P5W30O110K2]13-, was prepared by heating monobismuth (Bi3+)-encapsulated Preyssler-type phosphotungstate, [P5W30O110Bi(H2O)]12-, in acetate buffer in the presence of an excess amount of potassium cations. Characterization of the isolated potassium salt, K13[P5W30O110K2] (1a), and its acid form, H13[P5W30O110K2] (1b), by single crystal X-ray structure analysis, 31P and 183W nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR) spectroscopy, cyclic voltammetry (CV), high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS), and elemental analysis revealed that two potassium cations are encapsulated in the Preyssler-type phosphotungstate molecule with formal D5h symmetry, which is the first example of a Preyssler-type compound with two encapsulated cations. Incorporation of two potassium cations enhances the thermal stability of the potassium salt, and the acid form shows catalytic activity for hydration of ethyl acetate. Packing of the Preyssler-type molecules was observed by high-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). PMID- 27775334 TI - pH-Induced Surface Modification of Atomically Precise Silver Nanoclusters: An Approach for Tunable Optical and Electronic Properties. AB - Noble metal nanoclusters (NCs) play a pivotal role in bridging the gap between molecules and quantum dots. Fundamental understanding of the evolution of the structural, optical, and electronic properties of these materials in various environments is of paramount importance for many applications. Using state-of-the art spectroscopy, we provide the first decisive experimental evidence that the structural, electronic, and optical properties of Ag44(MNBA)30 NCs can now be tailored by controlling the chemical environment. Infrared and photoelectron spectroscopies clearly indicate that there is a dimerization between two adjacent ligands capping the NCs that takes place upon lowering the pH from 13 to 7. PMID- 27775335 TI - Capillary Bridging as a Tool for Assembling Discrete Clusters of Patchy Particles. AB - Janus and patchy particles are emerging as models for studying complex directed assembly patterns and as precursors of new structured materials and composites. Here we show how lipid-induced capillary bridging could serve as a new and nonconventional method of assembling patchy particles into ordered structures. Iron oxide surface patches on latex microspheres were selectively wetted with liquid lipid, driving the particle assembly into two- and three-dimensional clusters via interparticle capillary bridge formation. The liquid phase of the bridges allows local reorganization of the particles within the clusters and assists in forming true equilibrium configurations. The temperature-driven fluid to-gel and gel-to-fluid phase transitions of the fatty acids within the bridge act as a thermal switch for cluster assembly and disassembly. By complementing the experiments with Monte Carlo simulations, we show that the equilibrium cluster morphology is determined by the patch characteristics, namely, their size, number, and shape. This study demonstrates the ability of capillary bridging as a versatile tool to assemble thermoresponsive clusters and aggregates. This method of binding particles is simple, robust, and generic and can be extended further to assemble particles with nonspherical shapes and complex surface chemistries enabling the formation of sophisticated colloidal molecules. PMID- 27775336 TI - Induction of Circularly Polarized Luminescence from Europium by Amino Acid Based Ionic Liquids. AB - Materials that emit circularly polarized light have application in several important industries. Because they show large optical activity and emit sharp visible light transitions, europium complexes are often exploited in applications that require circularly polarized luminescence (CPL). Chiral and coordinating ionic liquids based on prolinate, valinate, and aspartate anions are used to induce CPL from a simple achiral europium triflate salt. The sign of the induced CPL is dependent on the handedness (l vs d) of the amino acid anion. Comparison of the CPL spectra in ionic liquid with proline and valine vs aspartate shows that the number of carboxylate groups in the amino acid anion influences the europium coordination environment. DFT calculations predict a chiral eight coordinate Eu(Pro)4- structure in the prolinate ionic liquid and a chiral seven- or eight-coordinate Eu(Asp)33- structure in the aspartate ionic liquid. PMID- 27775337 TI - Quartz Crystal Microbalance Analysis of Diels-Alder Reactions of Alkene Gases to Functional Ionic Liquids on Chips. AB - We demonstrated here a successful development of the use of functional ionic liquids FIL 1 and FIL 3 for chemoselective detection of alkene gases measured by quartz crystal microbalance. This detection of gaseous alkenes was achieved by the Diels-Alder [4 + 2] cycloadditions with FIL 1 and FIL 3 thin-coated on quartz chips. Our functional ionic liquids could be prepared by straightforward synthetic chemistry in short steps and are superior in alkene gas detection. The QCM platform developed in this work is chemoselective with fast gas diffusion into ionic liquids, readily applicable to low molecular weight alkene gases and insensitive to moisture. To the best of our knowledge, this is the first report based upon the Diels-Alder reactions demonstrating sensitive alkene gas detection in ionic liquids on a QCM. This work is a proof-of-concept inspection of the promising use of a QCM-based sensor method for reaction-directed detection of gas samples, which is part of an ongoing program aimed at studying diseases. PMID- 27775338 TI - Ligand Optimization by Improving Shape Complementarity at a Hepatitis C Virus RNA Target. AB - Crystal structure analysis revealed key interactions of a 2-amino-benzimidazole viral translation inhibitor that captures an elongated conformation of an RNA switch target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV). Here, we have designed and synthesized quinazoline derivatives with improved shape complementarity at the ligand binding site of the viral RNA target. A spiro-cyclopropyl modification aimed at filling a pocket in the back of the RNA binding site led to a 5-fold increase of ligand affinity while a slightly more voluminous dimethyl substitution at the same position did not improve binding. We demonstrate that precise shape complementarity based solely on hydrophobic interactions contributes significantly to ligand binding even at a hydrophilic RNA target site such as the HCV IRES conformational switch. PMID- 27775339 TI - From Chromonic Self-Assembly to Hollow Carbon Nanofibers: Efficient Materials in Supercapacitor and Vapor-Sensing Applications. AB - Carbon nanofibers (CNFs) with high surface area (820 m2/g) have been successfully prepared by a nanocasting approach using silica nanofibers obtained from chromonic liquid crystals as a template. CNFs with randomly oriented graphitic layers show outstanding electrochemical supercapacitance performance, exhibiting a specific capacitance of 327 F/g at a scan rate of 5 mV/s with a long life cycling capability. Approximately 95% capacitance retention is observed after 1000 charge-discharge cycles. Furthermore, about 80% of capacitance is retained at higher scan rates (up to 500 mV/s) and current densities (from 1 to 10 A/g). The high capacitance of CNFs comes from their porous structure, high pore volume, and electrolyte-accessible high surface area. CNFs with ordered graphitic layers were also obtained upon heat treatment at high temperatures (>1500 degrees C). Although it is expected that these graphitic CNFs have increased electrical conductivity, in the present case, they exhibited lower capacitance values due to a loss in surface area during thermal treatment. High-surface-area CNFs can be used in sensing applications; in particular, they showed selective differential adsorption of volatile organic compounds such as pyridine and toluene. This behavior is attributed to the free diffusion of these volatile aromatic molecules into the pores of CNFs accompanied by interactions with sp2 carbon structures and other chemical groups on the surface of the fibers. PMID- 27775340 TI - Chemical Etching of Bovine Serum Albumin-Protected Au25 Nanoclusters for Label Free and Separation-Free Ratiometric Fluorescent Detection of Tris(2 carboxyethyl)phosphine. AB - This study describes a novel ratiometric fluorescent sensor based on chemical etching of gold nanocluster (GNCs) for label-free, separation-free determination of tris(2-carboxyethyl)phosphine (TCEP). TCEP was discovered to exhibit unusual chemical behavior toward fluorescent gold nanoclusters: it quenched the red fluorescent emission of the bovine serum album (BSA)-protected GNCs (GNCs@BSA) and simultaneously restored the blue fluorescent emission of the dityrosine (diTyr) residues of the BSA ligand. The TCEP-induced quenching of the fluorescent GNCs@BSA was investigated with the UV-vis adsorption spectrum, the matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), inductively coupled plasma-mass spectrometry (ICP-MS) and X-ray photoelectron spectroscopy (XPS), revealing the chemical etching of the gold(0) core of the GNCs@BSA by TCEP. Furthermore, the ratio of the blue fluorescence intensity of the diTyr to the red fluorescence intensity of the GNCs@BSA was found to be dependent on TCEP concentration and showed a linear relationship in the TCEP concentration range of 500 nM to 50, 000 nM (R2 = 0.9943) with a limit of detection (LOD) of 130 nM, achieving the higher sensitivity over previous reports. This ratiometric sensor also showed superior selectivity for TCEP over certain common interferences including glutathione, 20 kinds of natural amino acids, and the oxidized form of TCEP. With the developed ratiometric method, the deproteinized human serum samples spiked with TCEP were analyzed with satisfactory results. In addition, it is worth noting that compared with conventional ratiometric fluorescent sensors, the ratiometric sensor developed in this study does not require external fluorophores, avoiding the additional derivation procedures. PMID- 27775341 TI - Directional Electron Transfer in Crystals of [CrCo] Dinuclear Complexes Achieved by Chirality-Assisted Preparative Method. AB - The polarization switching mechanism is used in various devices such as pyroelectric sensors and memory devices. The change in polarization mostly occurs by ion displacement. The development of materials whose polarization switches via electron transfer in order to enhance operation speed is a challenge. We devised a synthetic and crystal engineering strategy that enables the selective synthesis of a [CrCo] heterometallic dinuclear complex with a polar crystal structure, wherein polarization changes stem from intramolecular charge transfer between Co and the ligand. Polarization can be modulated both by visible-light irradiation and temperature change. The introduction of chiral ligands was paramount to the successful polarization switching in the valence tautomeric compound. Mixing Cr and Co complexes with enantiopure chiral ligands resulted in the selective formation of only pseudosymmetric [CrCo] heterometallic complexes. Furthermore, the left-handed chiral ligands preferentially interacted with their right-handed counterparts, enabling molecules to form a polar crystal structure. PMID- 27775342 TI - Polybrominated Diphenyl Ethers (PBDEs) in Surface Soils across Five Asian Countries: Levels, Spatial Distribution, and Source Contribution. AB - A total of 23 polybrominated diphenyl ether (PBDE) congeners were measured in soil samples collected in areas with no known point source [urban/rural/background (U/R/B) sites] and in areas with known point source [brominated flame retardant (BFR)-related industrial sites (F sites) and e-waste recycling sites (E sites)] across five Asian countries. The highest PBDE concentrations were found in BFR-related industrial and e-waste recycling sites. The concentrations of PBDEs in U/R/B sites decreased in the following order: urban > rural > background sites. Total PBDE concentrations were dominated by BDE 209, while BDE-17, -85, -138, -191, -204, and -205 were the least abundant compounds. In both urban sites and rural sites, the mean concentrations of total PBDEs (?23BDEs) in soils decreased in the following order: Japan > China > South Korea > India > Vietnam. The concentrations of PBDEs in soils were comparable with those reported in other studies. Among the three commercial PBDE mixtures, relatively large contributions of commercial penta-BDE were observed in Vietnam, whereas deca-BDE was the dominant form in mixtures contributing from 55.8 +/- 2.5 to 100.0 +/- 1.2% of the total PBDEs in soils collected from other four countries. Regression analysis suggested that local population density (PD) is a good indicator of PBDEs in soils of each country. Significant and positive correlation between soil organic content and PBDE level was observed in Chinese soil for most nondeca-BDE homologues with their usage stopped 10 years ago, indicating its important role in controlling the revolatilization of PBDEs from soil and changing the spatial trend of PBDE in soil from the primary distribution pattern to the secondary distribution pattern, especially when primary emission is ceased. PMID- 27775343 TI - Advances and Promises of Layered Halide Hybrid Perovskite Semiconductors. AB - Layered halide hybrid organic-inorganic perovskites (HOP) have been the subject of intense investigation before the rise of three-dimensional (3D) HOP and their impressive performance in solar cells. Recently, layered HOP have also been proposed as attractive alternatives for photostable solar cells and revisited for light-emitting devices. In this review, we combine classical solid-state physics concepts with simulation tools based on density functional theory to overview the main features of the optoelectronic properties of layered HOP. A detailed comparison between layered and 3D HOP is performed to highlight differences and similarities. In the same way as the cubic phase was established for 3D HOP, here we introduce the tetragonal phase with D4h symmetry as the reference phase for 2D monolayered HOP. It allows for detailed analysis of the spin-orbit coupling effects and structural transitions with corresponding electronic band folding. We further investigate the effects of octahedral tilting on the band gap, loss of inversion symmetry and possible Rashba effect, quantum confinement, and dielectric confinement related to the organic barrier, up to excitonic properties. Altogether, this paper aims to provide an interpretive and predictive framework for 3D and 2D layered HOP optoelectronic properties. PMID- 27775345 TI - Non-Perturbative Calculation of Two-Dimensional Spectra Using the Stochastic Hierarchy of Pure States. AB - Two-dimensional electronic spectroscopy has become an important experimental technique to obtain information on, for example, electronic coherences in large molecular complexes or vibronic couplings. For the correct interpretation of two dimensional spectra, however, detailed theoretical calculations are required. Reliable theoretical calculations are impeded by large system sizes and large numbers of vibrational degrees of freedom that need to be explicitly taken into account. Here, we demonstrate that a numerical approach based on a stochastic hierarchy of pure states (HOPS) does allow the calculation of two-dimensional spectra, notwithstanding the stochasticity of the method. The number of coupled equations as well as the hierarchy depth shows a superior scaling with system size as compared to the previously developed hierarchical equations of motion (HEOM). Large systems thus become accessible for numerical calculation of two dimensional spectra. PMID- 27775344 TI - Single-Stranded Nucleic Acids Bind to the Tetramer Interface of SAMHD1 and Prevent Formation of the Catalytic Homotetramer. AB - Sterile alpha motif and HD domain protein 1 (SAMHD1) is a unique enzyme that plays important roles in nucleic acid metabolism, viral restriction, and the pathogenesis of autoimmune diseases and cancer. Although much attention has been focused on its dNTP triphosphohydrolase activity in viral restriction and disease, SAMHD1 also binds to single-stranded RNA and DNA. Here we utilize a UV cross-linking method using 5-bromodeoxyuridine-substituted oligonucleotides coupled with high-resolution mass spectrometry to identify the binding site for single-stranded nucleic acids (ssNAs) on SAMHD1. Mapping cross-linked amino acids on the surface of existing crystal structures demonstrated that the ssNA binding site lies largely along the dimer-dimer interface, sterically blocking the formation of the homotetramer required for dNTPase activity. Surprisingly, the disordered C-terminus of SAMHD1 (residues 583-626) was also implicated in ssNA binding. An interaction between this region and ssNA was confirmed in binding studies using the purified SAMHD1 583-626 peptide. Despite a recent report that SAMHD1 possesses polyribonucleotide phosphorylase activity, we did not detect any such activity in the presence of inorganic phosphate, indicating that nucleic acid binding is unrelated to this proposed activity. These data suggest an antagonistic regulatory mechanism in which the mutually exclusive oligomeric state requirements for ssNA binding and dNTP hydrolase activity modulate these two functions of SAMHD1 within the cell. PMID- 27775346 TI - Photoactivated Production of Secondary Organic Species from Isoprene in Aqueous Systems. AB - Photoactivated reactions of organic species in atmospheric aerosol particles are a potentially significant source of secondary organic aerosol material (SOA). Despite recent progress, the dominant chemical mechanisms and rates of these reactions remain largely unknown. In this work, we characterize the photophysical properties and photochemical reaction mechanisms of imidazole-2-carboxaldehyde (IC) in aqueous solution, alone and in the presence of isoprene. IC has been shown previously in laboratory studies to participate in photoactivated chemistry in aerosols, and it is a known in-particle reaction product of glyoxal. Our experiments confirmed that the triplet excited state of IC is an efficient triplet photosensitizer, leading to photosensitization of isoprene in aqueous solution and promoting its photochemical processing in aqueous solution. Phosphorescence and transient absorption studies showed that the energy level of the triplet excited state of IC (3IC*) was approximately 289 kJ/mol, and the lifetime of 3IC* in water under ambient temperature is 7.9 MUs, consistent with IC acting as an efficient triplet photosensitizer. Laser flash photolysis experiments displayed fast quenching of 3IC* by isoprene, with a rate constant of (2.7 +/- 0.3) * 109 M-1 s-1, which is close to the diffusion-limited rate in water. Mass spectrometry analysis showed that the products formed include IC isoprene adducts, and chemical mechanisms are discussed. Additionally, oxygen quenches 3IC* with a rate constant of (3.1 +/- 0.1) * 109 M-1 s-1. PMID- 27775347 TI - Molecular Dynamics and Free Energy Simulations of Phenylacetate and CO2 Release from AMDase and Its G74C/C188S Mutant: A Possible Rationale for the Reduced Activity of the Latter. AB - Arylmalonate decarboxylase (AMDase) catalyzes the decarboxylation of alpha-aryl alpha-methyl malonates to produce optically pure alpha-arylpropionates of industrial and medicinal importance. Herein, atomistic molecular dynamics simulations have been carried out to delineate the mechanism of the release of product molecules phenylacetate (PAC) and carbon dioxide (CO2), from the wild type (WT) and its G74C/C188S mutant enzymes. Both of the product molecules follow a crystallographically characterized solvent-accessible channel to come out of the protein interior. A higher free energy barrier for the release of PAC from G74C/C188S compared to that in the WT is consistent with the experimentally observed compromised efficiency of the mutant. The release of CO2 precedes that of PAC; free energy barriers for CO2 and PAC release in the WT enzyme are calculated to be ~1-2 and ~23 kcal/mol, respectively. Postdecarboxylation, CO2 moves toward a hydrophobic pocket formed by Pro 14, Leu 38, Leu 40, Leu 77, and the side chain of Tyr 48 which serves as its temporary "reservoir". CO2 releases following a channel mainly decorated by apolar residues, unlike in the case of oxalate decarboxylase where polar residues mediate its transport. PMID- 27775348 TI - Synthesis of d-Galactosamine and d-Allosamine Derivatives via a Microwave Assisted Preparation of 1,6-Anhydroglucosamine. AB - We report a microwave-assisted intramolecular anomeric protection (iMAP) of glucosamine, which facilitates concise transformation of 1,6-anhydroglucosamine into 1,6-anhydrogalactosamine and 1,6-anhydroallosamine. The iMAP simultaneously obviates both the O1 and O6 protection, and the differentiation between O3 and O4 can be well-controlled by the N2 functionality because of the hydrogen bonding between N2 and O4. Epimerization of O4 afforded the galactosamine derivative and that of O3 yielded allosamine. PMID- 27775349 TI - Coarse-Grained Simulations of Membrane Insertion and Folding of Small Helical Proteins Using the CABS Model. AB - The CABS coarse-grained model is a well-established tool for modeling globular proteins (predicting their structure, dynamics, and interactions). Here we introduce an extension of the CABS representation and force field (CABS-membrane) to the modeling of the effect of the biological membrane environment on the structure of membrane proteins. We validate the CABS-membrane model in folding simulations of 10 short helical membrane proteins not using any knowledge about their structure. The simulations start from random protein conformations placed outside the membrane environment and allow for full flexibility of the modeled proteins during their spontaneous insertion into the membrane. In the resulting trajectories, we have found models close to the experimental membrane structures. We also attempted to select the correctly folded models using simple filtering followed by structural clustering combined with reconstruction to the all-atom representation and all-atom scoring. The CABS-membrane model is a promising approach for further development toward modeling of large protein-membrane systems. PMID- 27775350 TI - Chemical Synthesis of a Complex-Type N-Glycan Containing a Core Fucose. AB - A chemical synthesis of a core fucose containing N-glycan was achieved. Asparagine was introduced at an early stage of the synthesis, and the sugar chain was convergently elongated. As for the fragment synthesis, we reinvestigated alpha-sialylation, beta-mannosylation, and N-glycosylation to reveal that precise temperature control was essential for these glycosylations. Intermolecular hydrogen bonds involving acetamide groups were found to reduce the reactivity in glycosylations: the protection of NHAc as NAc2 dramatically improved the reactivity. The dodecasaccharide-asparagine framework was constructed via the (4 + 4) glycosylation and the (4 + 8) glycosylation using the tetrasaccharide donor and the tetrasaccharide-asparagine acceptor. An ether-type solvent enhanced the yields of these key glycosylations between large substrates. After the whole deprotection of the dodecasaccharide, the target N-glycan was obtained. PMID- 27775351 TI - pH-Dependent Ordered Fibrinogen Adsorption on Polyethylene Single Crystals. AB - Nanostructured surfaces have the potential to influence the assembly as well as the orientation of adsorbed proteins and may, thus, strongly influence the biomaterials' performance. For the class of polymeric (bio)materials a reproducible and well-characterized nanostructure is the ordered chain folded surface of a polyethylene single crystal (PE-SC). We tested the hypothesis that the trinodal-rod-shaped protein human plasma fibrinogen (HPF) adsorbs on the (001) surface of PE-SCs along specific crystallographic directions. The PE-SC samples were prepared by isothermal crystallization in dilute solution and characterized by atomic force microscopy (AFM) before as well as after HPF adsorption at different concentrations and pH values. At a physiological pH of 7.4, connected HPF molecules, or e.g., fibrils, fibril networks, or sponge-like structures, were observed on PE-SC surfaces that featured no preferential orientation. The observation of these nonoriented multiprotein assemblies was explained by predominant protein-protein interactions and limited surface diffusion. However, at an increased pH of 9.2, single HPF molecules, e.g., spherical-shaped and trinodal-rod-shaped HPF molecules as well as agglomerates, were observed on the PE-SC surface. The presence of single HPF molecules at increased pH was explained by decreased protein-protein interactions. These single trinodal-rod-shaped HPF molecules oriented preferentially along crystallographic [100] and [010] directions on the PE-SC surface which was explained by an increased amount of intermolecular bonds along these crystallographic directions with increased surface atom density. The study established that HPF molecules can align on chemically homogeneous surface topographies one order of magnitude smaller than the dimension of the protein. This advances the understanding of how to control the assembly and orientation of proteins on nanostructured polymer surfaces. Controlled protein adsorption is a crucial key to improve the surface functionality of future implants and biosensors. PMID- 27775352 TI - Mechanistic Insights into Oxidative Oligomerization of p-Phenylenediamine and Resorcinol. AB - An efficient synthesis of a green dye from oxidative coupling of p phenylenediamine (PPD) and resorcinol (in a 2:1 ratio) has been developed. Reactivity studies of this dye molecule with a variety of reagents (PPD, resorcinol, the oxidized form of the green dye itself, and a dinuclear indo dye) demonstrate that it cannot be the key reactive intermediate in reported oxidative oligomerization of PPD and resorcinol. However, the trinuclear species does form large aggregates. At least one viable pathway of oligomerization has been demonstrated with the dinuclear indo dye. PMID- 27775353 TI - Atmospheric Chemistry of 1-Methoxy 2-Propyl Acetate: UV Absorption Cross Sections, Rate Coefficients, and Products of Its Reactions with OH Radicals and Cl Atoms. AB - The rate coefficients for the reactions of OH and Cl with 1-methoxy 2-propyl acetate (MPA) in the gas phase were measured using absolute and relative methods. The kinetic study on the OH reaction was conducted in the temperature (263-373) K and pressure (1-760) Torr ranges using the pulsed laser photolysis-laser-induced fluorescence technique, a low pressure fast flow tube reactor-quadrupole mass spectrometer, and an atmospheric simulation chamber/GC-FID. The derived Arrhenius expression is kMPA+OH(T) = (2.01 +/- 0.02) * 10-12 exp[(588 +/- 123/T)] cm3 molecule-1 s-1. The absolute and relative rate coefficients for the reaction of Cl with MPA were measured at room temperature in the flow reactor and the atmospheric simulation chamber, which led to k(Cl+MPA) = (1.98 +/- 0.31) * 10-10 cm3 molecule-1 s-1. GC-FID, GC-MS, and FT-IR techniques were used to investigate the reaction mechanism in the presence of NO. The products formed from the reaction of MPA with OH and their yields were methyl formate (80 +/- 7.3%), acetic acid (50 +/- 4.8%), and acetic anhydride (22 +/- 2.4%), while for Cl reaction, the obtained yields were 60 +/- 5.4, 41 +/- 3.8, and 11 +/- 1.2%, respectively, for the same products. The UV absorption cross section spectrum of MPA was determined in the wavelength range 210-370 nm. The study has shown no photolysis of MPA under atmospheric conditions. The obtained results are used to derive the atmospheric implication. PMID- 27775354 TI - In Vivo and In Vitro Optimization of Screening Antimalarial Hits toward Lead Molecules for Preclinical Development. AB - In order to overcome one of the greatest challenges in malaria treatment, drug resistance, new drug candidates are urgently needed, which should preferably act via novel mechanisms. Successful optimization of a phenotypic screening hit based on a quinoline-4-carboxamide derivative resulted in the highly promising lead structure 4, which according to the Medicines for Malaria Venture (MMV) met the efficacy and drug metabolism and pharmacokinetics (DMPK) requirements for a malaria drug target candidate and consequently was selected for preclinical development. PMID- 27775355 TI - Correction to Ethylene Induced a High Accumulation of Dietary Isoflavones and Expression of Isoflavonoid Biosynthetic Genes in Soybean (Glycine max) Leaves. PMID- 27775356 TI - Optical Activity and Optical Anisotropy in Photomechanical Crystals of Chiral Salicylidenephenylethylamines. AB - Introducing chirality into photomechanical crystals is beneficial for the diversification of mechanical motion. Measurement of the chiroptical and optical anisotropic properties of chiral crystals is indispensable for evaluating photomechanical crystals. The platelike crystals of S- and R-enantiomers of photochromic N-3,5-di-tert-butylsalicylidene-1-phenylethylamine in enol form (enol-(S)-1 and enol-(R)-1) caused bending motion with twisting upon ultraviolet (UV) light irradiation, due to shrinkage along the length and width directions of the irradiated surface, based on the optimized crystal structure of the photoisomerized trans-keto-(S)-1. By employing the generalized high-accuracy universal polarimeter (G-HAUP), optical anisotropic (linear birefringence, LB; linear dichroism, LD) as well as chiroptical (circular birefringence, CB; circular dichroism, CD) spectra of both the enantiomeric crystals on the (001) face were simultaneously measured before and under continuous UV irradiation. The LD peak was observed at 330 nm in the negative sign, derived from the pi-pi* transition of the intramolecularly hydrogen-bonded salicylidenimino moiety. The CD spectra of the S and R crystals revealed the negative and positive Cotton effect at 330 nm, respectively, and new peaks appeared at 460 nm under UV light irradiation due to photoisomerization to the S and R trans-keto isomers at around 10% conversion. The CB and CD spectra evaluated by the HAUP measurement were opposite to those measured in the hexane solution, as well as those simulated by quantum chemical calculation. The dissymmetry parameter, g, of the enol-(S)-1 crystal along the c axis (0.013) was approximately 10 times larger than the g values in the solution (0.0010) and by calculation (0.0016). PMID- 27775357 TI - Calculated Mechanism of Cyanobacterial Aldehyde-Deformylating Oxygenase: Asymmetric Aldehyde Activation by a Symmetric Diiron Cofactor. AB - Cyanobacterial aldehyde-deformylating oxygenase (cADO) is a nonheme diiron enzyme that catalyzes the conversion of aldehyde to alk(a/e)ne, an important transformation in biofuel research. In this work, we report a highly desired computational study for probing the mechanism of cADO. By combining our QM/MM results with the available 57Fe Mossbauer spectroscopic data, the gained detailed structural information suggests construction of asymmetry from the symmetric diiron cofactor in an aldehyde substrate and O2 activation. His160, one of the two iron-coordinate histidine residues in cADO, plays a pivotal role in this asymmetric aldehyde activation process by unprecedented reversible dissociation from the diiron cofactor, a behavior unknown in any other nonheme dinuclear or mononuclear enzymes. The revealed intrinsically asymmetric interactions of the substrate/O2 with the symmetric cofactor in cADO are inspirational for exploring diiron subsite resolution in other nonheme diiron enzymes. PMID- 27775358 TI - Reusable Green Aerogels from Cross-Linked Hairy Nanocrystalline Cellulose and Modified Chitosan for Dye Removal. AB - A novel biopolymer-based aerogel was developed by freeze-drying a hydrogel, synthesized from cross-linking bifunctional hairy nanocrystalline cellulose and carboxymethylated chitosan through a Schiff base reaction. The nanocelluloses, bearing aldehyde and carboxylic acid groups, facilitated the cross-linking with chitosan through imine bond formation while providing negatively charged functional groups, and chitosan was modified to accommodate carboxylic acid. The potential of this bioaerogel in environmental remediation was examined in a model system comprising methylene blue, a cationic dye. Electrostatic complexation between acidic groups on the anionic aerogel with the dye resulted in time dependent dye adsorption, with long-time equilibrium dye concentration fitting well to the Langmuir isotherm, yielding a maximum adsorption capacity of ~785 mg g-1 and equilibrium constant K ~ 0.0089 at room temperature. Dynamics of adsorption was modeled by numerically solving the unsteady-state diffusion adsorption mass balance in a 1D spherical coordinate, which attested to a diffusion-controlled process with a Langmuir adsorption time constant tauads ~ 7.6 s. To the best of our knowledge, this bioaerogel exhibits the highest removal capacity as yet for any reusable adsorbents prepared from biopolymers. Successful adsorption-regeneration cycles proved an excellent reusability, and the adsorption capacity remained constant over a wide pH range (e.g., pH > 7). This work may pave the way toward ultralight green functional materials. PMID- 27775359 TI - Aggregation Control of Robust Water-Soluble Zinc(II) Phthalocyanine-Based Photosensitizers. AB - A water-soluble zinc phthalocyanine (ZnPc) complex with four negatively charged electron-withdrawing sulfonic acid substituents at the nonperipheral positions (alpha-ZnTSPc) is found to have a high singlet oxygen (1O2) quantum yield and exhibits high photostability. The formation of aggregates is hindered and the highest occupied molecular orbital is significantly stabilized, making alpha ZnTSPc potentially suitable for its use as a photosensitizer for photodynamic therapy and photoimmunotherapy. Atomic force microscopy (AFM) reveals that mixtures of the negatively charged alpha-ZnTSPc complex with a similar positively charged ZnPc were found to result in the self-assembly of one-dimensional accordion-like fibers. Supramolecular fibers can be formed in aqueous solutions through intermolecular electrostatic and donor-acceptor interactions between the two water-soluble ZnPcs. PMID- 27775361 TI - Single-Molecule Dynamics in the Presence of Strong Intermolecular Interactions. AB - In contrast to conventional spectroscopic studies of adsorbates at high coverage that provide only spatially averaged information, we have characterized the laterally confined shuttling dynamics of a single molecule under the influence of intermolecular interactions by vibrational spectroscopy using a scanning tunneling microscope. The bridge sites on Pt(111) are only occupied by a CO molecule that is surrounded by four other CO molecules at on-top sites. The bridge-site CO undergoes laterally confined shuttling toward an adjacent on-top site to transiently occupy a metastable site, which is slightly displaced from the center of an on-top site through repulsive interaction with adjacent on-top CO molecules. Analysis of action spectra for the shuttling events reveals the C-O stretch frequency of the metastable CO. We also constructed a modified potential energy surface incorporating the intermolecular interaction, which reveals the underlying mechanism and provides a new way to experimentally determine detailed information on the energetics of the metastable state. PMID- 27775360 TI - Determination of Equilibrium Constant and Relative Brightness in Fluorescence Correlation Spectroscopy by Considering Third-Order Correlations. AB - Fluorescence correlation spectroscopy (FCS) is a powerful tool to investigate molecular diffusion and relaxations, which may be utilized to study many problems such as molecular size and aggregation, chemical reaction, molecular transportation and motion, and various kinds of physical and chemical relaxations. This article focuses on a problem related to using the relaxation term to study a reaction. If two species with different fluorescence photon emission efficiencies are connected by a reaction, the kinetic and equilibrium properties will be manifested in the relaxation term of the FCS curve. However, the conventional FCS alone cannot simultaneously determine the equilibrium constant (K) and the relative fluorescence brightness (Q), both of which are indispensable in the extraction of thermodynamic and kinetic information from the experimental data. To circumvent the problem, an assumption of Q = 0 is often made for the weak fluorescent species, which may lead to numerous errors when the actual situation is not the case. We propose to combine the third-order FCS with the conventional second-order FCS to determine K and Q without invoking other resources. The strategy and formalism are verified by computer simulations and demonstrated in a classical example of the hairpin DNA-folding process. PMID- 27775362 TI - Effect of Mutation on an Aggregation-Prone Segment of p53: From Monomer to Dimer to Multimer. AB - Protein aggregation and amyloid formation are implicated in many diseases as well as in other biological phenomena. Recent studies have suggested that amyloid formation of tumor suppressor p53 can lead to loss of its physiological function, resulting in accelerated cancer progression. Design of cancer therapeutics, therefore, requires understanding of the mechanism of p53 aggregation. Here, we have employed atomistic simulations to characterize the aggregation process of the aggregation-prone (as suggested by experimental studies) p53 fragment (LTIITLE, 252-258) and to assess the efficiency of its I254R mutant as an aggregation suppressor. We show that the wild-type sequence attains stable beta sheet rich structure in the parallely arranged dimeric form, which dissociates in a sequential manner under mechanical force. The wild-type sequence further displays high aggregation propensity self-assembling into structures with parallel peptide arrangement. The I254R mutation destabilizes the dimer, changes the mechanical dissociation of the dimer to cooperative unfolding, reduces the aggregation propensity of the sequence, and alters the relative orientation of the peptides in the aggregate. Addition of the wild-type sequence, however, partially restores the aggregation propensity of the I254R mutant. PMID- 27775363 TI - Gold Triangular Nanoprisms and Nanodecahedra: Synthesis and Interaction Studies with Luminol toward Biosensor Applications. AB - Gold triangular nanoprisms and nanodecahedra (pentagonal bipyramids) were synthesized in the absence and presence of nanoseeds by a simple solvothermal synthesis through the reduction of Auric Chloride (HAuCl4) with poly(vinylpyrrolidone) (PVP) in N,N-dimethylformamide (DMF), respectively. These gold nanoparticles exhibit two plasmon resonance bands. The interaction of these gold nanoparticles with luminol was investigated using UV-vis and fluorescence spectroscopy since hefty number of environmental and biological sensors are based on the combination of luminol and gold nanoparticles. The gold nanoparticles quenches the fluorescence of luminol through a static quenching mechanism, i.e., ground state complex formation, which was confirmed by both absorption spectroscopy as well as time-resolved fluorescence spectroscopy. The Stern-Volmer quenching constant and the effective quenching constant determine that gold nanodecahedra has more interaction with luminol than that of triangular gold nanoprisms. The distance between the gold nanoparticles and luminol, calculated using FRET theory, is less than 8 nm, which indicates efficient energy transfer during interaction. These results are expected to be useful for the development of novel sensors. PMID- 27775364 TI - Metal-Free One-Pot Synthesis of N,N'-Diarylamidines and N-Arylbenzimidazoles from Arenediazonium Salts, Nitriles, and Free Anilines. AB - A highly efficient and facile metal-free, one-pot reaction has been developed to afford diversely substituted N-arylbenzimidazoles through chemoselective in situ generation of N,N'-diarylamidines from arenediazonium salts, nitriles, and free anilines. The advantages of this protocol consist of the operationally easy and simple one-pot procedure under metal-free and mild conditions, the direct use of inexpensive and commercially available chemicals, and thus, a cost-effective and greener process. PMID- 27775365 TI - Correction to "Metal-Free Remote C-H Bond Amidation of 8-amidoquinolines on the C5 Position under Mild Conditions". PMID- 27775366 TI - Regiocontrolled Coupling of Aromatic and Vinylic Amides with alpha-Allenols To Form gamma-Lactams via Rhodium(III)-Catalyzed C-H Activation. AB - A mild, regiocontrolled coupling of aromatic and vinylic amides with alpha allenols to form gamma-lactams via rhodium(III)-catalyzed C-H activation has been demonstrated. This [4 + 1] annulation reaction provides an efficient method for the synthesis of isoindolinones and 1,5-dihydro-pyrrol-2-ones bearing a tetrasubstituted carbon atom alpha to the nitrogen atom with good functional group tolerance. The hydroxyl group in the allene substrate is essential in controlling the chemo- and regioselectivity of the reaction probably by coordination interaction with the rhodium catalyst. PMID- 27775367 TI - One-Pot Reactions for Modular Synthesis of Polysubstituted and Fused Pyridines. AB - A 2-fluoro-1,3-dicarbonyl-initiated one-pot Michael addition/[5 + 1] annulation/dehydrofluorinative aromatization reaction sequence is introduced for regioselective synthesis of di-, tri-, tetra-, and pentasubstituted pyridines as well as fused pyridines. This simple and modular synthesis is performed using readily available starting materials and under transition-metal catalyst-free conditions. PMID- 27775368 TI - Large-Area Dry Transfer of Single-Crystalline Epitaxial Bismuth Thin Films. AB - We report the first direct dry transfer of a single-crystalline thin film grown by molecular beam epitaxy. A double cantilever beam fracture technique was used to transfer epitaxial bismuth thin films grown on silicon (111) to silicon strips coated with epoxy. The transferred bismuth films retained electrical, optical, and structural properties comparable to the as-grown epitaxial films. Additionally, we isolated the bismuth thin films on freestanding flexible cured epoxy post-transfer. The adhesion energy at the bismuth/silicon interface was measured to be ~1 J/m2, comparable to that of exfoliated and wet transferred graphene. This low adhesion energy and ease of transfer is unexpected for an epitaxially grown film and may enable the study of bismuth's unique electronic and spintronic properties on arbitrary substrates. Moreover, this method suggests a route to integrate other group-V epitaxial films (i.e., phosphorus) with arbitrary substrates, as well as potentially to isolate bismuthene, the atomic thin-film limit of bismuth. PMID- 27775369 TI - Mathematical methods in systems biology. AB - The editors of this Special Issue of Mathematical Biosciences and Engineering were the organizers for the Third International Workshop "Mathematical Methods in System Biology" that took place on June 15-18, 2015 at the University College Dublin in Ireland. As stated in the workshop goals, we managed to attract a good mix of mathematicians and statisticians working on biological and medical applications with biologists and clinicians interested in presenting their challenging problems and looking to find mathematical and statistical tools for their solutions. PMID- 27775370 TI - Classification of Alzheimer's disease using unsupervised diffusion component analysis. AB - The goal of this study is automated discrimination between early stage Alzheimer's disease (AD) magnetic resonance imaging (MRI) and healthy MRI data. Unsupervised Diffusion Component Analysis, a novel approach based on the diffusion mapping framework, reduces data dimensionality and provides pattern recognition that can be used to distinguish AD brains from healthy brains. The new algorithm constructs coordinates as an extension of diffusion maps and generates efficient geometric representations of the complex structure of the MRI data. The key difference between our method and others used to classify and detect AD early in its course is our nonlinear and local network approach, which overcomes calibration differences among different scanners and centers collecting MRI data and solves the problem of individual variation in brain size and shape. In addition, our algorithm is completely automatic and unsupervised, which could potentially be a useful and practical tool for doctors to help identify AD patients. PMID- 27775371 TI - Adjoint sensitivity analysis of a tumor growth model and its application to spatiotemporal radiotherapy optimization. AB - We investigate a spatial model of growth of a tumor and its sensitivity to radiotherapy. It is assumed that the radiation dose may vary in time and space, like in intensity modulated radiotherapy (IMRT). The change of the final state of the tumor depends on local differences in the radiation dose and varies with the time and the place of these local changes. This leads to the concept of a tumor's spatiotemporal sensitivity to radiation, which is a function of time and space. We show how adjoint sensitivity analysis may be applied to calculate the spatiotemporal sensitivity of the finite difference scheme resulting from the partial differential equation describing the tumor growth. We demonstrate results of this approach to the tumor proliferation, invasion and response to radiotherapy (PIRT) model and we compare the accuracy and the computational effort of the method to the simple forward finite difference sensitivity analysis. Furthermore, we use the spatiotemporal sensitivity during the gradient based optimization of the spatiotemporal radiation protocol and present results for different parameters of the model. PMID- 27775372 TI - Mathematical model of the atrioventricular nodal double response tachycardia and double-fire pathology. AB - A proposed model consisting of two coupled models (Hodgkin-Huxley and Yanagihara Noma-Irisawa model) is considered as a description of the heart's action potential. System of ordinary differential equations is used to recreate pathological behaviour in the conducting heart's system such as double fire and the most common tachycardia: atrioventricular nodal reentrant tachycardia (AVNRT). Part of the population has an abnormal accessory pathways: fast and slow (Fujiki, 2008). These pathways in the atrioventricular node (AV node) are anatomical and functional contributions of supraventricular tachycardia. However, the appearance of two pathways in the AV node may be a contribution of arrhythmia, which is caused by coexistent conduction by two pathways (called double fire). The difference in the conduction time between these pathways is the most important factor. This is the reason to introduce three types of couplings and delay to our system in order to reproduce various types of the AVNRT. In our research, introducing the feedback loops and couplings entails the creation of waves which can correspond to the re-entry waves occurring in the AVNRT. Our main aim is to study solutions of the given equations and take into consideration the influence of feedback and delays which occur in these pathological modes. We also present stability analysis for both components, that is Hodgkin-Huxley and Yanagihara-Noma-Irisawa models, as well as for the final double-fire model. PMID- 27775373 TI - Modelling random antibody adsorption and immunoassay activity. AB - One of the primary considerations in immunoassay design is optimizing the concentration of capture antibody in order to achieve maximal antigen binding and, subsequently, improved sensitivity and limit of detection. Many immunoassay technologies involve immobilization of the antibody to solid surfaces. Antibodies are large molecules in which the position and accessibility of the antigen binding site depend on their orientation and packing density. In this paper we propose a simple mathematical model, based on the theory known as random sequential adsorption (RSA), in order to calculate how the concentration of correctly oriented antibodies (active site exposed for subsequent reactions) evolves during the deposition process. It has been suggested by experimental studies that high concentrations will decrease assay performance, due to molecule denaturation and obstruction of active binding sites. However, crowding of antibodies can also have the opposite effect by favouring upright orientations. A specific aim of our model is to predict which of these competing effects prevails under different experimental conditions and study the existence of an optimal coverage, which yields the maximum expected concentration of active particles (and hence the highest signal). PMID- 27775374 TI - A model of thermotherapy treatment for bladder cancer. AB - In this work, we investigate chemo- thermotherapy, a recently clinically-approved post-surgery treatment of non muscle invasive urothelial bladder carcinoma. We developed a mathematical model and numerically simulated the physical processes related to this treatment. The model is based on the conductive Maxwell's equations used to simulate the therapy administration and Convection-Diffusion equation for incompressible fluid to study heat propagation through the bladder tissue. The model parameters correspond to the data provided by the thermotherapy device manufacturer. We base our computational domain on a CT image of a human bladder. Our numerical simulations can be applied to further research on the effects of chemo- thermotherapy on bladder and surrounding tissues and for treatment personalization in order to maximize the effect of the therapy while avoiding burning of the bladder. PMID- 27775376 TI - Sensitivity of signaling pathway dynamics to plasmid transfection and its consequences. AB - This paper deals with development of signaling pathways models and using plasmid based experiments to support parameter estimation. We show that if cells transfected with plasmids are used in experiments, the models should include additional components that describe explicitly effects induced by plasmids. Otherwise, when the model is used to analyze responses of wild type, i.e. non transfected cells, it may not capture their dynamics properly or even lead to false conclusions. In order to illustrate this, an original mathematical model of miRNA-mediated control of gene expression in the NFkappaB pathway is presented. The paper shows what artifacts might appear due to experimental procedures and how to develop the models in order to avoid pursuing these artifacts instead of real kinetics. PMID- 27775375 TI - Limiting the development of anti-cancer drug resistance in a spatial model of micrometastases. AB - While chemoresistance in primary tumors is well-studied, much less is known about the influence of systemic chemotherapy on the development of drug resistance at metastatic sites. In this work, we use a hybrid spatial model of tumor response to a DNA damaging drug to study how the development of chemoresistance in micrometastases depends on the drug dosing schedule. We separately consider cell populations that harbor pre-existing resistance to the drug, and those that acquire resistance during the course of treatment. For each of these independent scenarios, we consider one hypothetical cell line that is responsive to metronomic chemotherapy, and another that with high probability cannot be eradicated by a metronomic protocol. Motivated by experimental work on ovarian cancer xenografts, we consider all possible combinations of a one week treatment protocol, repeated for three weeks, and constrained by the total weekly drug dose. Simulations reveal a small number of fractionated-dose protocols that are at least as effective as metronomic therapy in eradicating micrometastases with acquired resistance (weak or strong), while also being at least as effective on those that harbor weakly pre-existing resistant cells. Given the responsiveness of very different theoretical cell lines to these few fractionated-dose protocols, these may represent more effective ways to schedule chemotherapy with the goal of limiting metastatic tumor progression. PMID- 27775377 TI - Optimal control of a mathematical model for cancer chemotherapy under tumor heterogeneity. AB - We consider cancer chemotherapy as an optimal control problem with the aim to minimize a combination of the tumor volume and side effects over an a priori specified therapy horizon when the tumor consists of a heterogeneous agglomeration of many subpopulations. The mathematical model, which accounts for different growth and apoptosis rates in the presence of cell densities, is a finite-dimensional approximation of a model originally formulated by Lorz et al. [18,19] and Greene et al. [10,11] with a continuum of possible traits. In spite of an arbitrarily high dimension, for this problem singular controls (which correspond to time-varying administration schedules at less than maximum doses) can be computed explicitly in feedback form. Interestingly, these controls have the property to keep the entire tumor population constant. Numerical computations and simulations that explore the optimality of bang-bang and singular controls are given. These point to the optimality of protocols that combine a full dose therapy segment with a period of lower dose drug administration. PMID- 27775378 TI - A posterior probability approach for gene regulatory network inference in genetic perturbation data. AB - Inferring gene regulatory networks is an important problem in systems biology. However, these networks can be hard to infer from experimental data because of the inherent variability in biological data as well as the large number of genes involved. We propose a fast, simple method for inferring regulatory relationships between genes from knockdown experiments in the NIH LINCS dataset by calculating posterior probabilities, incorporating prior information. We show that the method is able to find previously identified edges from TRANSFAC and JASPAR and discuss the merits and limitations of this approach. PMID- 27775379 TI - Competition for a single resource and coexistence of several species in the chemostat. AB - We study a model of the chemostat with several species in competition for a single resource. We take into account the intra-specific interactions between individuals of the same population of micro-organisms and we assume that the growth rates are increasing and the dilution rates are distinct. Using the concept of steady-state characteristics, we present a geometric characterization of the existence and stability of all equilibria. Moreover, we provide necessary and sufficient conditions on the control parameters of the system to have a positive equilibrium. Using a Lyapunov function, we give a global asymptotic stability result for the competition model of several species. The operating diagram describes the asymptotic behavior of this model with respect to control parameters and illustrates the effect of the intra-specific competition on the coexistence region of the species. PMID- 27775380 TI - An adaptive feedback methodology for determining information content in stable population studies. AB - We develop statistical and mathematical based methodologies for determining (as the experiment progresses) the amount of information required to complete the estimation of stable population parameters with pre-specified levels of confidence. We do this in the context of life table models and data for growth/death for three species of Daphniids as investigated by J. Stark and J. Banks [17]. The ideas developed here also have wide application in the health and social sciences where experimental data are often expensive as well as difficult to obtain. PMID- 27775381 TI - Optimal harvesting policy for the Beverton--Holt model. AB - In this paper, we establish the exploitation of a single population modeled by the Beverton--Holt difference equation with periodic coefficients. We begin our investigation with the harvesting of a single autonomous population with logistic growth and show that the harvested logistic equation with periodic coefficients has a unique positive periodic solution which globally attracts all its solutions. Further, we approach the investigation of the optimal harvesting policy that maximizes the annual sustainable yield in a novel and powerful way; it serves as a foundation for the analysis of the exploitation of the discrete population model. In the second part of the paper, we formulate the harvested Beverton--Holt model and derive the unique periodic solution, which globally attracts all its solutions. We continue our investigation by optimizing the sustainable yield with respect to the harvest effort. The results differ from the optimal harvesting policy for the continuous logistic model, which suggests a separate strategy for populations modeled by the Beverton--Holt difference equation. PMID- 27775382 TI - A toxin-mediated size-structured population model: Finite difference approximation and well-posedness. AB - The question of the effects of environmental toxins on ecological communities is of great interest from both environmental and conservational points of view. Mathematical models have been applied increasingly to predict the effects of toxins on a variety of ecological processes. Motivated by the fact that individuals with different sizes may have different sensitivities to toxins, we develop a toxin-mediated size-structured model which is given by a system of first order fully nonlinear partial differential equations (PDEs). It is very possible that this work represents the first derivation of a PDE model in the area of ecotoxicology. To solve the model, an explicit finite difference approximation to this PDE system is developed. Existence-uniqueness of the weak solution to the model is established and convergence of the finite difference approximation to this unique solution is proved. Numerical examples are provided by numerically solving the PDE model using the finite difference scheme. PMID- 27775383 TI - Global stability of a network-based SIS epidemic model with a general nonlinear incidence rate. AB - In this paper, we develop and analyze an SIS epidemic model with a general nonlinear incidence rate, as well as degree-dependent birth and natural death, on heterogeneous networks. We analytically derive the epidemic threshold R0 which completely governs the disease dynamics: when R0 < 1, the disease-free equilibrium is globally asymptotically stable, i.e., the disease will die out; when R0 > 1, the disease is permanent. It is interesting that the threshold value R0 bears no relation to the functional form of the nonlinear incidence rate and degree-dependent birth. Furthermore, by applying an iteration scheme and the theory of cooperative system respectively, we obtain sufficient conditions under which the endemic equilibrium is globally asymptotically stable. Our results improve and generalize some known results. To illustrate the theoretical results, the corresponding numerical simulations are also given. PMID- 27775384 TI - A two-strain TB model with multiple latent stages. AB - A two-strain tuberculosis (TB) transmission model incorporating antibiotic generated TB resistant strains and long and variable waiting periods within the latently infected class is introduced. The mathematical analysis is carried out when the waiting periods are modeled via parametrically friendly gamma distributions, a reasonable alternative to the use of exponential distributed waiting periods or to integral equations involving ''arbitrary'' distributions. The model supports a globally-asymptotically stable disease-free equilibrium when the reproduction number is less than one and an endemic equilibriums, shown to be locally asymptotically stable, or l.a.s., whenever the basic reproduction number is greater than one. Conditions for the existence and maintenance of TB resistant strains are discussed. The possibility of exogenous re-infection is added and shown to be capable of supporting multiple equilibria; a situation that increases the challenges faced by public health experts. We show that exogenous re infection may help established resilient communities of actively-TB infected individuals that cannot be eliminated using approaches based exclusively on the ability to bring the control reproductive number just below 1. PMID- 27775385 TI - Competition between a nonallelopathic phytoplankton and an allelopathic phytoplankton species under predation. AB - We propose a model of two-species competition in the chemostat for a single growth-limiting, nonreproducing resource that extends that of Roy [38]. The response functions are specified to be Michaelis-Menten, and there is no predation in Roy's work. Our model generalizes Roy's model to general uptake functions. The competition is exploitative so that species compete by decreasing the common pool of resources. The model also allows allelopathic effects of one toxin-producing species, both on itself (autotoxicity) and on its nontoxic competitor (phytotoxicity). We show that a stable coexistence equilibrium exists as long as (a) there are allelopathic effects and (b) the input nutrient concentration is above a critical value. The model is reconsidered under instantaneous nutrient recycling. We further extend this work to include a zooplankton species as a fourth interacting component to study the impact of predation on the ecosystem. The zooplankton species is allowed to feed only on the two phytoplankton species which are its perfectly substitutable resources. Each of the models is analyzed for boundedness, equilibria, stability, and uniform persistence (or permanence). Each model structure fits very well with some harmful algal bloom observations where the phytoplankton assemblage can be envisioned in two compartments, toxin producing and non-toxic. The Prymnesium parvum literature, where the suppressing effects of allelochemicals are quite pronounced, is a classic example. This work advances knowledge in an area of research becoming ever more important, which is understanding the functioning of allelopathy in food webs. PMID- 27775386 TI - Global dynamics of a vaccination model for infectious diseases with asymptomatic carriers. AB - In this paper, an epidemic model is investigated for infectious diseases that can be transmitted through both the infectious individuals and the asymptomatic carriers (i.e., infected individuals who are contagious but do not show any disease symptoms). We propose a dose-structured vaccination model with multiple transmission pathways. Based on the range of the explicitly computed basic reproduction number, we prove the global stability of the disease-free when this threshold number is less or equal to the unity. Moreover, whenever it is greater than one, the existence of the unique endemic equilibrium is shown and its global stability is established for the case where the changes of displaying the disease symptoms are independent of the vulnerable classes. Further, the model is shown to exhibit a transcritical bifurcation with the unit basic reproduction number being the bifurcation parameter. The impacts of the asymptomatic carriers and the effectiveness of vaccination on the disease transmission are discussed through through the local and the global sensitivity analyses of the basic reproduction number. Finally, a case study of hepatitis B virus disease (HBV) is considered, with the numerical simulations presented to support the analytical results. They further suggest that, in high HBV prevalence countries, the combination of effective vaccination (i.e. >= 3 doses of HepB vaccine), the diagnosis of asymptomatic carriers and the treatment of symptomatic carriers may have a much greater positive impact on the disease control. PMID- 27775387 TI - Modeling eating behaviors: The role of environment and positive food association learning via a Ratatouille effect. AB - Eating behaviors among a large population of children are studied as a dynamic process driven by nonlinear interactions in the sociocultural school environment. The impact of food association learning on diet dynamics, inspired by a pilot study conducted among Arizona children in Pre-Kindergarten to 8th grades, is used to build simple population-level learning models. Qualitatively, mathematical studies are used to highlight the possible ramifications of instruction, learning in nutrition, and health at the community level. Model results suggest that nutrition education programs at the population-level have minimal impact on improving eating behaviors, findings that agree with prior field studies. Hence, the incorporation of food association learning may be a better strategy for creating resilient communities of healthy and non-healthy eaters. A Ratatouille effect can be observed when food association learners become food preference learners, a potential sustainable behavioral change, which in turn, may impact the overall distribution of healthy eaters. In short, this work evaluates the effectiveness of population-level intervention strategies and the importance of institutionalizing nutrition programs that factor in economical, social, cultural, and environmental elements that mesh well with the norms and values in the community. PMID- 27775388 TI - Bifurcation analysis of a diffusive plant-wrack model with tide effect on the wrack. AB - This paper deals with the spatial, temporal and spatiotemporal dynamics of a spatial plant-wrack model. The parameter regions for the stability and instability of the unique positive constant steady state solution are derived, and the existence of time-periodic orbits and non-constant steady state solutions are proved by bifurcation method. The nonexistence of positive nonconstant steady state solutions are studied by energy method and Implicit Function Theorem. Numerical simulations are presented to verify and illustrate the theoretical results. PMID- 27775389 TI - Immune response in virus model structured by cell infection-age. AB - This paper concerns modeling the coupled within-host population dynamics of virus and CTL (Cytotoxic T Lymphocyte) immune response. There is substantial evidence that the CTL immune response plays a crucial role in controlling HIV in infected patients. Recent experimental studies have demonstrated that certain CTL variants can recognize HIV infected cells early in the infected cell lifecycle before viral production, while other CTLs only detect viral proteins (epitopes) presented on the surface of infected cells after viral production. The kinetics of epitope presentation and immune recognition can impact the efficacy of the immune response. We extend previous virus models to include cell infection-age structure in the infected cell compartment and immune response killing/activation rates of a PDE-ODE system. We characterize solutions to our system utilizing semigroup theory, determine equilibria and reproduction numbers, and prove stability and persistence results. Numerical simulations show that ' early immune recognition' precipitates both enhanced viral control and sustained oscillations via a Hopf bifurcation. In addition to inducing oscillatory dynamics, considering immune process rates to be functions of cell infection-age can also lead to coexistence of multiple distinct immune effector populations. PMID- 27775391 TI - Dynamics of a diffusive age-structured HBV model with saturating incidence. AB - In this paper, we propose and investigate an age-structured hepatitis B virus (HBV) model with saturating incidence and spatial diffusion where the viral contamination process is described by the age-since-infection. We first analyze the well-posedness of the initial-boundary values problem of the model in the bounded domain Omega ? Rn and obtain an explicit formula for the basic reproductive number R0 of the model. Then we investigate the global behavior of the model in terms of R0: if R0 <= 1, then the uninfected steady state is globally asymptotically stable, whereas if R0 > 1, then the infected steady state is globally asymptotically stable. In addition, when R0> 1, by constructing a suitable Lyapunov-like functional decreasing along the travelling waves to show their convergence towards two steady states as t tends to infinity, we prove the existence of traveling wave solutions. Numerical simulations are provided to illustrate the theoretical results. PMID- 27775390 TI - Using drinking data and pharmacokinetic modeling to calibrate transport model and blind deconvolution based data analysis software for transdermal alcohol biosensors. AB - Alcohol researchers/clinicians have two ways to collect subject /patient field data, standard-drink self-report and the breath analyzer, neither of which is passive or accurate because active subject participation is required. Transdermal alcohol sensors have been developed to measure transdermal alcohol concentration (TAC), but they are used primarily as abstinence monitors because converting TAC into more meaningful blood/breath alcohol concentration (BAC/BrAC) is difficult. In this paper, BAC/BrAC is estimated from TAC by first calibrating forward distributed parameter-based convolution models for ethanol transport from the blood through the skin using patient-collected drinking data for a single drinking episode and a nonlinear pharmacokinetic metabolic absorption/elimination model to estimate BAC. TAC and estimated BAC are then used to fit the forward convolution filter. Nonlinear least squares with adjoint-based gradient computation are used to fit both models. Calibration results are compared with those obtained using BAC/BrAC from alcohol challenges and from standard, linear, metabolic absorption, and zero order kinetics-based elimination models, by considering peak BAC, time of peak, and area under the BAC curve. Our models (with population parameters) could be included in a smart phone app that makes it convenient for the subject/patient to enter drinking data for a single episode in the field. PMID- 27775392 TI - Modeling the spread of bed bug infestation and optimal resource allocation for disinfestation. AB - A patch-structured multigroup-like $SIS$ epidemiological model is proposed to study the spread of the common bed bug infestation. It is shown that the model exhibits global threshold dynamics with the basic reproduction number as the threshold parameter. Costs associated with the disinfestation process are incorporated into setting up the optimization problems. Procedures are proposed and simulated for finding optimal resource allocation strategies to achieve the infestation free state. Our analysis and simulations provide useful insights on how to efficiently distribute the available exterminators among the infested patches for optimal disinfestation management. PMID- 27775393 TI - Type-dependent stochastic Ising model describing the dynamics of a non-symmetric feedback module. AB - We study an alternative approach to model the dynamical behaviors of biological feedback loop, that is, a type-dependent spin system, this class of stochastic models was introduced by Fernandez et. al [13], and are useful since take account to inherent variability of gene expression. We analyze a non-symmetric feedback module being an extension for the repressilator, the first synthetic biological oscillator, invented by Elowitz and Leibler [7]. We consider a mean-field dynamics for a type-dependent Ising model, and then study the empirical magnetization vector representing concentration of molecules. We apply a convergence result from stochastic jump processes to deterministic trajectories and present a bifurcation analysis for the associated dynamical system. We show that non-symmetric module under study can exhibit very rich behaviours, including the empirical oscillations described by repressilator. PMID- 27775394 TI - Epidemic characteristics of two classic models and the dependence on the initial conditions. AB - The epidemic characteristics, including the epidemic final size, peak, and turning point, of two classical SIR models with disease-induced death are investigated when a small initial value of the infective population is released. The models have mass-action (i.e. bilinear), or density dependent (i.e. standard) incidence, respectively. For the two models, the conditions that determining whether the related epidemic characteristics of an epidemic outbreak appear are explicitly determine by rigorous mathematical analysis. The dependence of the epidemic final size on the initial values of the infective class is demonstrated. The peak, turning point (if it exists) and the corresponding time are found. The obtained results suggest that their basic reproduction numbers are one factor determining the epidemic characteristics, but not the only one. The characteristics of the two models depend on the initial values and proportions of various compartments as well. At last, the similarities and differences of the epidemic characteristics between the two models are discussed. PMID- 27775395 TI - Modeling the role of healthcare access inequalities in epidemic outcomes. AB - Urban areas, with large and dense populations, offer conditions that favor the emergence and spread of certain infectious diseases. One common feature of urban populations is the existence of large socioeconomic inequalities which are often mirrored by disparities in access to healthcare. Recent empirical evidence suggests that higher levels of socioeconomic inequalities are associated with worsened public health outcomes, including higher rates of sexually transmitted diseases (STD's) and lower life expectancy. However, the reasons for these associations are still speculative. Here we formulate a mathematical model to study the effect of healthcare disparities on the spread of an infectious disease that does not confer lasting immunity, such as is true of certain STD's. Using a simple epidemic model of a population divided into two groups that differ in their recovery rates due to different levels of access to healthcare, we find that both the basic reproductive number (R0) of the disease and its endemic prevalence are increasing functions of the disparity between the two groups, in agreement with empirical evidence. Unexpectedly, this can be true even when the fraction of the population with better access to healthcare is increased if this is offset by reduced access within the disadvantaged group. Extending our model to more than two groups with different levels of access to healthcare, we find that increasing the variance of recovery rates among groups, while keeping the mean recovery rate constant, also increases R0 and disease prevalence. In addition, we show that these conclusions are sensitive to how we quantify the inequalities in our model, underscoring the importance of basing analyses on appropriate measures of inequalities. These insights shed light on the possible impact that increasing levels of inequalities in healthcare access can have on epidemic outcomes, while offering plausible explanations for the observed empirical patterns. PMID- 27775396 TI - Development of a computational model of glucose toxicity in the progression of diabetes mellitus. AB - Diabetes mellitus is a disease characterized by a range of metabolic complications involving an individual's blood glucose levels, and its main regulator, insulin. These complications can vary largely from person to person depending on their current biophysical state. Biomedical research day-by-day makes strides to impact the lives of patients of a variety of diseases, including diabetes. One large stride that is being made is the generation of techniques to assist physicians to ''personalize medicine''. From available physiological data, biological understanding of the system, and dimensional analysis, a differential equation-based mathematical model was built in a sequential matter, to be able to elucidate clearly how each parameter correlates to the patient's current physiological state. We developed a simple mathematical model that accurately simulates the dynamics between glucose, insulin, and pancreatic $?beta$-cells throughout disease progression with constraints to maintain biological relevance. The current framework is clearly capable of tracking the patient's current progress through the disease, dependent on factors such as latent insulin resistance or an attrite $?beta$-cell population. Further interests would be to develop tools that allow the direct and feasible testing of how effective a given plan of treatment would be at returning the patient to a desirable biophysical state. PMID- 27775397 TI - Dynamical properties and tumor clearance conditions for a nine-dimensional model of bladder cancer immunotherapy. AB - Understanding the global interaction dynamics between tumor and the immune system plays a key role in the advancement of cancer therapy. Bunimovich-Mendrazitsky et al. (2015) developed a mathematical model for the study of the immune system response to combined therapy for bladder cancer with Bacillus Calmette-Guerin (BCG) and interleukin-2 (IL-2) . We utilized a mathematical approach for bladder cancer treatment model for derivation of ultimate upper and lower bounds and proving dissipativity property in the sense of Levinson. Furthermore, tumor clearance conditions for BCG treatment of bladder cancer are presented. Our method is based on localization of compact invariant sets and may be exploited for a prediction of the cells populations dynamics involved into the model. PMID- 27775398 TI - A two-sex matrix population model to represent harem structure. AB - Population dynamic models often include males in the calculation of population change, but even in those cases males have rarely been introduced to represent polygyny (harem social structure), where it is particularly important to include males in the reproductive performance of the population. In this article we develop an adaptable matrix population modeling framework for species that have a harem-like social structure under an assumption that the transitions from newborn to juvenile and juvenile to adult both take one time step. We are able to calculate not only the growth rates and stable stage distributions, but also the mathematical expressions for harem size for this model. We then provide applications of this model to two mammal species with slightly different harem behavior. PMID- 27775399 TI - Heterogeneous population dynamics and scaling laws near epidemic outbreaks. AB - In this paper, we focus on the influence of heterogeneity and stochasticity of the population on the dynamical structure of a basic susceptible-infected susceptible (SIS) model. First we prove that, upon a suitable mathematical reformulation of the basic reproduction number, the homogeneous system and the heterogeneous system exhibit a completely analogous global behaviour. Then we consider noise terms to incorporate the fluctuation effects and the random import of the disease into the population and analyse the influence of heterogeneity on warning signs for critical transitions (or tipping points). This theory shows that one may be able to anticipate whether a bifurcation point is close before it happens. We use numerical simulations of a stochastic fast-slow heterogeneous population SIS model and show various aspects of heterogeneity have crucial influences on the scaling laws that are used as early-warning signs for the homogeneous system. Thus, although the basic structural qualitative dynamical properties are the same for both systems, the quantitative features for epidemic prediction are expected to change and care has to be taken to interpret potential warning signs for disease outbreaks correctly. PMID- 27775401 TI - Provider perceptions of an integrated primary care quality improvement strategy: The PPAQ toolkit. AB - The Primary Care Behavioral Health (PCBH) model of integrated primary care is challenging to implement with high fidelity. The Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ) was designed to assess provider adherence to essential model components and has recently been adapted into a quality improvement toolkit. The aim of this pilot project was to gather preliminary feedback on providers' perceptions of the acceptability and utility of the PPAQ toolkit for making beneficial practice changes. Twelve mental health providers working in Department of Veterans Affairs integrated primary care clinics participated in semistructured interviews to gather quantitative and qualitative data. Descriptive statistics and qualitative content analysis were used to analyze data. Providers identified several positive features of the PPAQ toolkit organization and structure that resulted in high ratings of acceptability, while also identifying several toolkit components in need of modification to improve usability. Toolkit content was considered highly representative of the (PCBH) model and therefore could be used as a diagnostic self-assessment of model adherence. The toolkit was considered to be high in applicability to providers regardless of their degree of prior professional preparation or current clinical setting. Additionally, providers identified several system-level contextual factors that could impact the usefulness of the toolkit. These findings suggest that frontline mental health providers working in (PCBH) settings may be receptive to using an adherence-focused toolkit for ongoing quality improvement. (PsycINFO Database Record PMID- 27775402 TI - Youth psychotherapy outcomes in usual care and predictors of outcome group membership. AB - Improving mental health services for youth in usual care (UC) is one of the most critical issues in mental health services research. Identification of change groups in UC (e.g., recovery, improvement, no response, deterioration) can help researchers gain a richer understanding of UC and facilitate efforts to tailor UC to individuals who may not be responding well to treatment. This study used the reliable change index (RCI; Jacobson & Truax, 1991) to examine change groups within youth UC on two parent report outcome measures-symptom severity and functioning-using a large, naturalistic sample of youth (N = 672) treated in UC served at four clinics operating under a large county-wide public mental health authority. Results indicated that the majority of youth exhibited no reliable change. Furthermore, findings revealed low concordance between how youth were classified on both outcome measures. Multinomial logistic regression was used to predict group membership from an expanded set of youth demographic and clinical variables. Findings indicated that baseline problem severity and lower baseline functioning generally predicted higher likelihood of being classified into a more positive change group. Older age predicted increased likelihood of being in a more positive change group, while diagnosis of an internalizing disorder or serious mental illness (SMI) both predicted greater likelihood of falling into a more negative change group. Overall, these results suggest the importance of a more nuanced understanding of change in UC, as well as work aimed at identifying targets for improvement for youth who are not responding well. (PsycINFO Database Record PMID- 27775400 TI - Dynamic functional connectivity in bipolar disorder is associated with executive function and processing speed: A preliminary study. AB - OBJECTIVE: Disturbances in functional connectivity have been suggested to contribute to cognitive and emotion processing deficits observed in bipolar disorder (BD). Functional connectivity between medial prefrontal cortex (mPFC) and other brain regions may be particularly abnormal. The goal of the present study was to characterize the temporal dynamics of the default mode network (DMN) connectivity in BD and examine its association with cognition. METHOD: In a preliminary study, euthymic BD (n = 15) and healthy comparison (HC, n = 19) participants underwent resting-state functional MRI, using high-resolution sequences adapted from the Human Connectome Project, and completed neuropsychological measures of processing speed and executive function. A seed based approach was used to measure DMN correlations in each participant, with regions of interest in the mPFC, posterior cingulate cortex (PCC), and lateral parietal cortex. Subsequently, to characterize temporal dynamics, correlational analyses between the mPFC and other DMN nodes were repeated using a sliding window correlational analysis with subsets of the time series. RESULTS: When averaged across the entire scan, there were no group differences in overall connectivity strength between the mPFC and other regions of the DMN. However, dynamic connectivity between the mPFC and PCC was altered in BD, such that connectivity was less variable (i.e., more rigid) over time. Decreased connectivity variability was associated with slower processing speed and reduced cognitive set-shifting in BD patients. CONCLUSIONS: Variability in resting-state functional connectivity may be an index of internetwork flexibility that is reduced in BD and a correlate of ongoing cognitive impairment during periods of euthymia. (PsycINFO Database Record PMID- 27775403 TI - Can unstructured clinical risk judgment have incremental validity in the prediction of recidivism in a non-Western juvenile context? AB - Research has consistently shown that actuarial measures are superior to unstructured clinical judgments in predicting recidivism of offenders. However, in a non-Western context, clinical judgment may capture contextually relevant risk-related factors. The purpose of the current research is to investigate the incremental value of clinical risk judgment in a sample of Japanese youths. With a sample of 299 released youths, the relative accuracy of the actuarial predictor (Youth Level of Service/Case Management Inventory [YLS/CMI]) and unstructured clinical judgment (recommendation of placement by psychologists) was examined. Results show that an unstructured clinical judgment failed to add incremental variance to the actuarial measure in the prediction of future offenses. The current study results are similar to other studies from North America. Possible reasons why unstructured risk judgment did not add incrementally to the actuarial assessment of risk are discussed. (PsycINFO Database Record PMID- 27775404 TI - Conceptual match as a determinant of reference reuse in dialogue. AB - As speakers interact, they add references to their common ground, which they can then reuse to facilitate listener comprehension. However, all references are not equally likely to be reused. The purpose of this study was to shed light on how the speakers' conceptualizations of the referents under discussion affect reuse (along with a generation effect in memory documented in previous studies on dialogic reuse). Two experiments were conducted in which participants interactively added references to their common ground. From each participant's point of view, these references either did or did not match their own conceptualization of the referents discussed, and were either self- or partner generated. Although self-generated references were more readily accessible in memory than partner-generated ones (Experiment 1), reference reuse was mainly guided by conceptualization (Experiment 2). These results are in line with the idea that several different cues (conceptual match, memory accessibility) constrain reference reuse in dialogue. (PsycINFO Database Record PMID- 27775405 TI - Bored in the USA: Experience sampling and boredom in everyday life. AB - We report new evidence on the emotional, demographic, and situational correlates of boredom from a rich experience sample capturing 1.1 million emotional and time use reports from 3,867 U.S. adults. Subjects report boredom in 2.8% of the 30-min sampling periods, and 63% of participants report experiencing boredom at least once across the 10-day sampling period. We find that boredom is more likely to co occur with negative, rather than positive, emotions, and is particularly predictive of loneliness, anger, sadness, and worry. Boredom is more prevalent among men, youths, the unmarried, and those of lower income. We find that differences in how such demographic groups spend their time account for up to one third of the observed differences in overall boredom. The importance of situations in predicting boredom is additionally underscored by the high prevalence of boredom in specific situations involving monotonous or difficult tasks (e.g., working, studying) or contexts where one's autonomy might be constrained (e.g., time with coworkers, afternoons, at school). Overall, our findings are consistent with cognitive accounts that cast boredom as emerging from situations in which engagement is difficult, and are less consistent with accounts that exclusively associate boredom with low arousal or with situations lacking in meaning. (PsycINFO Database Record PMID- 27775407 TI - Positivity bias in judging ingroup members' emotional expressions. AB - We investigated how group membership impacts valence judgments of ingroup and outgroup members' emotional expressions. In Experiment 1, participants, randomized into 2 novel, competitive groups, rated the valence of in- and outgroup members' facial expressions (e.g., fearful, happy, neutral) using a circumplex affect grid. Across all emotions, participants judged ingroup members' expressions as more positive than outgroup members' expressions. In Experiment 2, participants categorized fearful and happy expressions as being either positive or negative using a mouse-tracking paradigm. Participants exhibited the most direct trajectories toward the "positive" label for ingroup happy expressions and an initial attraction toward positive for ingroup expressions of fear, with outgroup emotion trajectories falling in between. Experiment 3 replicated Experiment 2 and demonstrated that the effect could not be accounted for by targets' gaze direction. Overall, people judged ingroup faces as more positive, regardless of emotion, both in deliberate and implicit judgments. (PsycINFO Database Record PMID- 27775406 TI - Homesickness and adjustment across the first year of college: A longitudinal study. AB - Homesickness can put individuals at risk for a host of adjustment difficulties. The millions of students that leave home for college each year may be particularly susceptible to experiencing homesickness. There is little work, however, examining individual variation in homesickness over time and how these changes predict different outcomes in college. The present study examines weekly levels of homesickness during the first term of college and tests the associations between homesickness and various aspects of adjustment. Results showed that, on average, homesickness decreased slightly across the first semester of college, but there were individual differences in homesickness trajectories. Freshmen who reported higher levels of homesickness showed worse overall adjustment to college, even when controlling for negative emotional experience and prior adjustment. Homesickness was associated with poorer social outcomes, but these social difficulties were limited to interactions with others in the college environment. Academic outcomes were not adversely impacted by homesickness. Findings suggest that homesickness is a common experience for freshmen, and, despite its relatively transient nature, homesickness has important implications for college adjustment. (PsycINFO Database Record PMID- 27775408 TI - Symptoms, circumstances, and service systems: Pathways to psychiatric crisis service use among uninsured young adults. AB - Young adults have low rates of outpatient service utilization and higher rates of emergency service use compared to older adults. This study explored pathways to crisis service use for uninsured young adults who accessed emergency psychiatric treatment. Participants were 55 young adults (ages 18-25) who were on an inpatient short-term stabilization unit and had qualifying diagnoses for outpatient services (bipolar, major depression, or schizophrenia). Semistructured qualitative interviews were conducted to understand decision-making and the events that led to service use. A team of coders used an open coding approach to develop a codebook and participated in iterative discussions of coded text to generate results presented. Themes across 3 dimensions were identified. Participants formed the intention to seek treatment through the interaction of escalating symptoms, triggering events, and motivating factors. Intention was translated to actualized service use through individual and systemic facilitators. Natural supports and service systems influenced the entire process. Findings highlight the importance of understanding motivating factors to better engage young people in treatment and including their support systems in efforts to increase awareness of problems and treatments. Systemic barriers identified suggest the need for enhanced coordination of care across systems such as drug and alcohol treatment, homeless services, and criminal justice and for ready access to outpatient services to reduce crisis psychiatric service use. (PsycINFO Database Record PMID- 27775409 TI - Adult women survivors of intrafamilial child sexual abuse and their current relationship with the abuser. AB - This article examines the adult perceptions of women survivors of intrafamilial child sexual abuse and their current relationship with the family member who abused them in their childhood. Twenty Jewish Israeli women were interviewed in depth between 2008 and 2009. Interviews were tape-recorded and transcribed verbatim. Data analysis produced 2 interrelated continua with regard to the presence of the perpetrator in the women's life: a continuum of his actual daily presence in the woman's living space, ranging from complete absence to a continuous presence, and a continuum of his experiential presence, ranging from a high level of intrusiveness to encapsulation and total dissociation. The 2 continua are discussed and implications for practice are suggested. (PsycINFO Database Record PMID- 27775410 TI - From awareness to action: Examining predictors of lesbian, gay, bisexual, and transgender (LGBT) activism for heterosexual people. AB - In recent history, heterosexual allies have played an integral role in promoting change for lesbian, gay, bisexual, and transgender (LGBT) populations in the United States; however, questions have been raised as to what drives heterosexual allies to promote change via activism. To delineate factors important in engagement in activism, 207 self-identified heterosexual allies completed an online survey measuring components associated with LGBT activism using Bandura's (1986) model of triadic reciprocal determinism: personal factors (ally identity, social justice self-efficacy and outcome expectations, empathetic perspective taking, and gender) and environmental factors (social justice related supports and barriers, positive marginality, and education level) to predict behaviors (LGBT activism). A hierarchical multiple regression analysis revealed a model accounting for 62% of the variance in LGBT activism, with dimensions of ally identification, social justice self-efficacy, outcome expectations, and education level emerging as significant predictors of engagement in activism behaviors. Empathetic perspective taking and social justice related barriers predicted lack of engagement in LGBT activism, however. Supporting the notion that personal and environmental factors simultaneously impact engagement in LGBT activism. (PsycINFO Database Record PMID- 27775411 TI - Information processing capacity in psychopathy: Effects of anomalous attention. AB - Hamilton and colleagues (2015) recently proposed that an integrative deficit in psychopathy restricts simultaneous processing, thereby leaving fewer resources available for information encoding, narrowing the scope of attention, and undermining associative processing. The current study evaluated this parallel processing deficit proposal using the Simultaneous-Sequential paradigm. This investigation marks the first a priori test of the Hamilton et al.'s theoretical framework. We predicted that psychopathy would be associated with inferior performance (as indexed by lower accuracy and longer response time) on trials requiring simultaneous processing of visual information relative to trials necessitating sequential processing. Results were consistent with these predictions, supporting the proposal that psychopathy is characterized by a reduced capacity to process multicomponent perceptual information concurrently. We discuss the potential implications of impaired simultaneous processing for the conceptualization of the psychopathic deficit. (PsycINFO Database Record PMID- 27775412 TI - Personality pathology and relationship satisfaction in dating and married couples. AB - Personality disorders (PDs) are inherently associated with deficits in relating to other people. Previous research has shown consistent negative associations between categorical PD symptoms and relationship satisfaction. The present studies extend on these findings by examining the role of maladaptive traits in a number of ways. Self- and partner-reported maladaptive traits of both partners are included. Moreover, the present studies add a couple-centered approach by investigating the effects of actual similarity, perceptual similarity, and perceptual accuracy of the maladaptive trait profile on relationship satisfaction. PDs are conceptualized using 2 dimensional maladaptive trait models, that is, the Dimensional Assessment of Personality Pathology-Basic Questionnaire in Study 1 and the Personality Inventory for DSM-5 in Study 2. A total of 167 heterosexual couples participated in Study 1 and 52 heterosexual couples in Study 2. The actor-partner interdependence model was used to examine the associations between traits and relationship satisfaction, whereas the coefficient of profile agreement was used for the couple-centered analyses. Overall, results showed that the presence of maladaptive traits within romantic relationships has a detrimental effect on relationship satisfaction. Self-ratings on maladaptive traits, how we perceive our partners, and how we are perceived by our partners on maladaptive traits make significant contributions to our relationship (dis)satisfaction. Among the maladaptive traits, negative affect and detachment were most consistently negatively associated with relationship satisfaction. The couple-centered perspective showed less explanatory value but nontrivial associations between perceptual similarity and relationship satisfaction were found in Study 2. (PsycINFO Database Record PMID- 27775413 TI - Therapist-client agreement in assessments of clients' functioning. AB - OBJECTIVE: We aimed to assess the extent to which therapists' reports of client functioning track their clients' changing experience of their own functioning from session to session (temporal congruence) as well as the extent to which they over- or underestimate their clients' functioning (level or directional bias) and to examine whether these indices predict treatment outcomes. METHOD: The participants included 384 clients who were treated by 77 therapists. Both clients and therapists rated the clients' functioning each session. The clients also completed pre- and posttreatment outcome measures. RESULTS: Using multilevel modeling, we found that therapists' reports regarding their clients' functioning tended to be temporally congruent from session to session with their clients' reported functioning. In addition, on average, therapists did not show a level bias (i.e., did not over- or underestimate their clients' functioning). Finally, temporal congruence (but not level bias) predicted better treatment outcomes. CONCLUSION: These findings highlight the importance of tracking clients' fluctuating symptoms over time. Thus, we discuss their implication for the policy and practice of providing session-by-session feedback to therapists. (PsycINFO Database Record PMID- 27775414 TI - For better or worse: An individual patient data meta-analysis of deterioration among participants receiving Internet-based cognitive behavior therapy. AB - OBJECTIVE: Psychological treatments can relieve mental distress and improve well being, and the dissemination of evidence-based methods can help patients gain access to the right type of aid. Meanwhile, Internet-based cognitive-behavioral therapy (ICBT) has shown promising results for many psychiatric disorders. However, research on the potential for negative effects of psychological treatments has been lacking. METHOD: An individual patient data meta-analysis of 29 clinical trials of ICBT (N = 2,866) was performed using the Reliable Change Index for each primary outcome measures to distinguish deterioration rates among patients in treatment and control conditions. Statistical analyses of predictors were conducted using generalized linear mixed models. Missing data was handled by multiple imputation. RESULTS: Deterioration rates were 122 (5.8%) in treatment and 130 (17.4%) in control conditions. Relative to receiving treatment, patients in a control condition had higher odds of deteriorating, odds ratios (ORs) = 3.10, 95% confidence interval (CI) [2.21, 4.34]. Clinical severity at pretreatment was related to lower odds, OR = 0.62, 95% CI [0.50, 0.77], and OR = 0.51, 95% CI [0.51, 0.80], for treatment and control conditions. In terms of sociodemographic variables, being in a relationship, OR = 0.58, 95% CI [0.35, 0.95], having at least a university degree, OR = 0.54, 95% CI [0.33, 0.88], and being older, OR = 0.78, 95% CI, [0.62, 0.98], were also associated with lower odds of deterioration, but only for patients assigned to a treatment condition. CONCLUSION: Deterioration among patients receiving ICBT or being in a control condition can occur and should be monitored by researchers to reverse and prevent a negative treatment trend. (PsycINFO Database Record PMID- 27775415 TI - Education and job-based interventions for unmarried couples living with low incomes: Benefit or burden? AB - OBJECTIVE: Government initiatives undertaken to improve the earning potential of disadvantaged unmarried parents assume that job training and additional schooling will strengthen these families, yet alternative models predict that these same interventions could overwhelm couples' limited resources, undermining family stability. METHOD: We use 3 waves of dyadic data and propensity score analysis to test these competing perspectives by examining the effects of job-related and school-related interventions on 3-year marriage rates. The sample consists of unmarried new parents averaging $20,475 in household income, 52% of whom are African American and 20% of whom are Hispanic/Latino. RESULTS: Marriage rates decreased, from 17% to 10%, for couples in which men participated in school related interventions. Mediation analyses indicate that school-related interventions reduce the amount of time men spend with their child and the amount of money they contribute to their household, reducing marriage rates in turn. Marriage rates were unaffected by women's participation in school-related interventions, and by men's and women's participation in job-related interventions. CONCLUSION: Implementing economic interventions that increase income while minimizing demands on the limited resources of economically distressed couples may prove necessary for strengthening society's most vulnerable families. (PsycINFO Database Record PMID- 27775416 TI - The SENSE study: Post intervention effects of a randomized controlled trial of a cognitive-behavioral and mindfulness-based group sleep improvement intervention among at-risk adolescents. AB - OBJECTIVE: Sleep problems are a major risk factor for the emergence of mental health problems in adolescence. The aim of this study was to investigate the post intervention effects of a cognitive-behavioral/mindfulness-based group sleep intervention on sleep and mental health among at-risk adolescents. METHOD: A randomized controlled trial (RCT) was conducted across High schools in Melbourne, Australia. One hundred forty-four adolescents (aged 12-17 years) with high levels of anxiety and sleeping difficulties, but without past or current depressive disorder, were randomized into either a sleep improvement intervention or an active control 'study skills' intervention. Both programs consisted of 7 90-min long group sessions delivered over 7 weeks. One hundred twenty-three participants began the interventions (female = 60%; mean age = 14.48, SD = 0.95), with 60 in the sleep condition and 63 in the control condition. All participants were required to complete a battery of mood and sleep questionnaires, 7 days of wrist actigraphy (an objective measure of sleep), and sleep diary entry at pre- and post intervention. RESULTS: The sleep intervention condition was associated with significantly greater improvements in subjective sleep (global sleep quality [with a medium effect size], sleep onset latency, daytime sleepiness [with small effect sizes]), objective sleep (sleep onset latency [with a medium effect size]), and anxiety (with a small effect size) compared with the control intervention condition. CONCLUSION: The SENSE study provides evidence that a multicomponent group sleep intervention that includes cognitive-behavioral and mindfulness-based therapies can reduce sleep initiation problems and related daytime dysfunction, along with concomitant anxiety symptoms, among at-risk adolescents. (PsycINFO Database Record PMID- 27775418 TI - Cardiovascular effects of gasotransmitter donors. AB - Gasotransmitters represent a subfamily of the endogenous gaseous signaling molecules that include nitric oxide (NO), carbon monoxide (CO), and hydrogen sulphide (H(2)S). These particular gases share many common features in their production and function, but they fulfill their physiological tasks in unique ways that differ from those of classical signaling molecules found in tissues and organs. These gasotransmitters may antagonize or potentiate each other's cellular effects at the level of their production, their downstream molecular targets and their direct interactions. All three gasotransmitters induce vasodilatation, inhibit apoptosis directly or by increasing the expression of anti-apoptotic genes, and activate antioxidants while inhibiting inflammatory actions. NO and CO may concomitantly participate in vasorelaxation, anti-inflammation and angiogenesis. NO and H(2)S collaborate in the regulation of vascular tone. Finally, H(2)S may upregulate the heme oxygenase/carbon monoxide (HO/CO) pathway during hypoxic conditions. All three gasotransmitters are produced by specific enzymes in different cell types that include cardiomyocytes, endothelial cells and smooth muscle cells. As translational research on gasotransmitters has exploded over the past years, drugs that alter the production/levels of the gasotransmitters themselves or modulate their signaling pathways are now being developed. This review is focused on the cardiovascular effects of NO, CO, and H(2)S. Moreover, their donors as drug targeting the cardiovascular system are briefly described. PMID- 27775417 TI - The role of hydrogen sulphide in blood pressure regulation. AB - Cardiovascular studies have confirmed that hydrogen sulphide (H(2)S) is involved in various signaling pathways in both physiological and pathological conditions, including hypertension. In contrast to nitric oxide (NO), which has a clear vasorelaxant action, H(2)S has both vasorelaxing and vasoconstricting effects on the cardiovascular system. H(2)S is an important antihypertensive agent, and the reduced production of H(2)S and the alterations in its functions are involved in the initiation of spontaneous hypertension. Moreover, cross-talk between H(2)S and NO has been reported. NO-H(2)S interactions include reactions between the molecules themselves, and each has been shown to regulate the endogenous production of the other. In addition, NO and H(2)S can interact to form a nitrosothiol/s complex, which has original properties and represents a novel nitroso-sulphide signaling pathway. Furthermore, recent results have shown that the interaction between H(2)S and NO could be involved in the endothelium regulated compensatory mechanisms that are observed in juvenile spontaneously hypertensive rats. The present review is devoted to role of H(2)S in vascular tone regulation. We primarily focus on the mechanisms of H(2)S-NO interactions and on the role of H(2)S in blood pressure regulation in normotensive and spontaneously hypertensive rats. PMID- 27775419 TI - Blood pressure regulation in stress: focus on nitric oxide-dependent mechanisms. AB - Stress is considered a risk factor associated with the development of various civilization diseases including cardiovascular diseases, malignant tumors and mental disorders. Research investigating mechanisms involved in stress-induced hypertension have attracted much attention of physicians and researchers, however, there are still ambiguous results concerning a causal relationship between stress and long-term elevation of blood pressure (BP). Several studies have observed that mechanisms involved in the development of stress-induced hypertension include increased activity of sympathetic nervous system (SNS), glucocorticoid (GC) overload and altered endothelial function including decreased nitric oxide (NO) bioavailability. Nitric oxide is well known neurotransmitter, neuromodulator and vasodilator involved in regulation of neuroendocrine mechanisms and cardiovascular responses to stressors. Thus NO plays a crucial role in the regulation of the stress systems and thereby in the BP regulation in stress. Elevated NO synthesis, especially in the initial phase of stress, may be considered a stress-limiting mechanism, facilitating the recovery from stress to the resting levels via attenuation of both GC release and SNS activity as well as by increased NO-dependent vasorelaxation. On the other hand, reduced levels of NO were observed in the later phases of stress and in subjects with genetic predisposition to hypertension, irrespectively, in which reduced NO bioavailability may account for disruption of NO-mediated BP regulatory mechanisms and accentuated SNS and GC effects. This review summarizes current knowledge on the role of stress in development of hypertension with a special focus on the interactions among NO and other biological systems affecting blood pressure and vascular function. PMID- 27775420 TI - The role of PPARgamma in cardiovascular diseases. AB - The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear superfamily of ligand-activated transcription factors. PPARgamma acts as a nutrient sensor that regulates several homeostatic functions. Its disruption can lead to vascular pathologies, disorders of fatty acid/lipid metabolism and insulin resistance. PPARgamma can modulate several signaling pathways connected with blood pressure regulation. Firstly, it affects the insulin signaling pathway and endothelial dysfunction by modulation of expression and/or phosphorylation of signaling molecules through the PI3K/Akt/eNOS or MAPK/ET-1 pathways. Secondly, it can modulate gene expression of the renin- angiotensin system - cascade proteins, which potentially slow down the progression of atherosclerosis and hypertension. Thirdly, it can modulate oxidative stress response either directly through PPAR or indirectly through Nrf2 activation. In this context, activation and functioning of PPARgamma is very important in the regulation of several disorders such as diabetes mellitus, hypertension and/or metabolic syndrome. PMID- 27775421 TI - Saccadic eye movements as a marker of mental disorders. AB - It is accepted that the formulation of the motor program in the brain is not only the perceptual and motor function but also the cognitive one. Therefore it is not surprising that the execution of saccadic eye movements can by substantially affected be the on-going mental activity of a given person. Not only the distribution of attention, but also the focusing the attention may influence the main gain of saccades, their accuracy. Patients suffering from mental disorders have strongly engaged their attention focused at their mental processes. The nature of their problems may be linked to perceptual and/or analytical processing. Such so-called mental set may significantly affect their oculomotor activity in the course of their saccadic eye movement examinations. This short comment points out not only to the influence of the contextually guided and generated saccadic eye movements upon their accuracy but also to the distribution and focusing the attention. The effect of the functional brain asymmetry upon the visually generated saccades and the possible effect of biologically active substances upon the voluntary generated saccades are briefly mentioned. All these influences should be taken into account when planning the saccadic eye movement task. It may be concluded that the repetition of the same oculomotor task in a given person has to be introduced. This may help to follow the effect of complex therapy namely. PMID- 27775422 TI - Effect of melatonin on blood pressure and nitric oxide generation in rats with metabolic syndrome. AB - Melatonin, a multitasking indolamine, seems to be involved in a variety of physiological and metabolic processes via both receptor-mediated and receptor independent mechanisms. The aim of our study was to find out whether melatonin can affect blood pressure (BP), nitric oxide synthase (NOS) activity, eNOS and nNOS protein expressions in rats with metabolic syndrome (SHR/cp). Rats were divided into four groups: 6-week-old male WKY andSHR/cp and age-matched WKY and SHR/cp treated with melatonin (10 mg/kg/day) for 3 weeks. BP was measured by tail cuff plethysmography. NOS activity, eNOS and nNOS protein expressions were determined in the heart, aorta, brain cortex and cerebellum. MT(1) receptors were analyzed in the brain cortex and cerebellum. In SHR/cp rats, BP was decreased after melatonin treatment. In the same group, melatonin did not affect NOS activity and eNOS protein expression in the heart and aorta, while it increased both parameters in the brain cortex and cerebellum. Interestingly, melatonin elevated MT1 protein expression in the cerebellum. Neuronal NOS protein expression was not changed within the groups. In conclusion, increased NOS activity/eNOS upregulation in particular brain regions may contribute partially to BP decrease in SHR/cp rats after melatonin treatment. Participation of MT(1) receptors in this melatonin action may be supposed. PMID- 27775423 TI - Lack of reactive oxygen species deteriorates blood pressure regulation in acute stress. AB - This study investigated the contribution of reactive oxygen species (ROS) to blood pressure regulation in conscious adult male Wistar rats exposed to acute stress. Role of ROS was investigated in rats with temporally impaired principal blood pressure regulation systems using ganglionic blocker pentolinium (P, 5 mg/kg), angiotensin converting enzyme inhibitor captopril (C, 10 mg/kg), nitric oxide synthase inhibitor L-NAME (L, 30 mg/kg) and superoxide dismutase mimeticum tempol (T, 25 mg/kg). Mean arterial pressure (MAP) was measured by the carotid artery catheter and inhibitors were administered intravenously. MAP was disturbed by a 3-s air jet, which increased MAP by 35.2+/-3.0 % vs. basal MAP after the first exposure. Air jet increased MAP in captopril- and tempol-treated rats similarly as observed in saline-treated rats. In pentolinium-treated rats stress significantly decreased MAP vs. pre-stress value. In L-NAME-treated rats stress failed to affect MAP significantly. Treatment of rats with P+L+C resulted in stress-induced MAP decrease by 17.3+/-1.3 % vs. pre-stress value and settling time (20.1+/-4.2 s). In P+L+C+T-treated rats stress led to maximal MAP decrease by 26.4+/-2.2 % (p<0.005 vs. P+L+C) and prolongation of settling time to 32.6+/ 3.3 s (p<0.05 vs. P+L+C). Area under the MAP curve was significantly smaller in P+L+C-treated rats compared to P+L+C+T-treated ones (167+/-43 vs. 433+/-69 a.u., p<0.008). In conclusion, in rats with temporally impaired blood pressure regulation, the lack of ROS resulted in greater stress-induced MAP alterations and prolongation of time required to reach new post-stress steady state. PMID- 27775424 TI - Interaction of perivascular adipose tissue and sympathetic nerves in arteries from normotensive and hypertensive rats. AB - The inhibitory action of perivascular adipose tissue (PVAT) in modulation of arterial contraction has been recently recognized and contrasted with the prohypertensive effect of obesity in humans. In this study we demonstrated that PVAT might have opposing effect on sympatho-adrenergic contractions in different rat conduit arteries. In superior mesenteric artery isolated from normotensive Wistar-Kyoto rats (WKY), PVAT exhibited inhibitory influence on the contractions to exogenous noradrenaline as well as to endogenous noradrenaline released from arterial sympathetic nerves during transmural electrical stimulation or after application of tyramine. In contrast, the abdominal aorta with intact PVAT responded with larger contractions to transmural electrical stimulation and tyramine when compared to the aorta after removing PVAT; the responses to noradrenaline were similar in both. This indicates that PVAT may contain additional sources of endogenous noradrenaline which could be responsible for the main difference in the modulatory effect of PVAT on adrenergic contractions between abdominal aortas and superior mesenteric arteries. In spontaneously hypertensive rats (SHR), the anticontractile effect of PVAT in mesenteric arteries was reduced, and the removal of PVAT completely eliminated the difference in the dose-response curves to exogenous noradrenaline between SHR and WKY. These results suggest that in mesenteric artery isolated from SHR, the impaired anticontractile influence of PVAT might significantly contribute to its increased sensitivity to adrenergic stimuli. PMID- 27775425 TI - Effect of deuterium-depleted water on selected cardiometabolic parameters in fructose-treated rats. AB - Deuterium-depleted water (DDW) has a lower concentration of deuterium than occurs naturally (less than 145 ppm). While effects of DDW on cancer started to be intensively studied, the effects on cardiovascular system are completely unknown. Thus, we aimed to analyze the effects of DDW (55+/-5 ppm) administration to 12 week-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) treated with 15 % fructose for 6 weeks. Blood pressure (BP) and selected biochemical parameters were measured together with determination of nitric oxide synthase (NOS) activity and iNOS and eNOS protein expressions in the left ventricle (LV) and aorta. Neither DDW nor fructose had any significant effect on BP in both strains. DDW treatment decreased total cholesterol and triglyceride levels in WKY, but it was not able to prevent increase in the same parameters elevated due to fructose treatment in SHR. Both fructose and DDW increased insulin level in WKY. Fructose did not affect NOS activity either in WKY or SHR. DDW increased NOS activity in LV of both WKY and SHR, while it decreased NOS activity and iNOS expression in the aorta of SHR with or without fructose treatment. In conclusion, DDW treatment significantly modified biochemical parameters in WKY together with NOS activity elevation in the heart. On the other hand, it did not affect biochemical parameters in SHR, but decreased NOS activity elevated due to iNOS upregulation in the aorta. PMID- 27775426 TI - Postural stability and responses to vibrations in patients after anterior cruciate ligament surgical reconstruction. AB - The aim of the study was to evaluate the effect of surgical reconstruction of anterior cruciate ligament (ACL) on postural stability and responses to lower limb (LL) muscles vibrations. Centre of pressure (CoP) was measured in 17 subjects during stance on firm/foam surface with eyes open/closed and during unilateral vibrations of LL muscles (m. triceps surae - TS, m. quadriceps femoris - Q, m. quadriceps femoris and hamstrings simultaneously - QH). The measurements were performed: 1) preoperatively, 2) six weeks and 3) three months after the reconstruction. Decreased postural stability was documented six weeks after the reconstruction compared to preoperative measurement. Three months after the reconstruction significant improvement was observed during stance on foam surface with eyes closed. Preoperatively, altered reactions of LL with ACL lesion compared to intact LL were manifested by slower response in first 3 s of TS vibration and by increased CoP shift in last 5 s of QH vibration. After the reconstruction, we observed slower CoP reaction and decreased CoP shift during TS vibration of LL with ACL lesion compared to preoperative level. Posturography during quiet stance and during TS vibration reliably detect postural changes due to ACL reconstruction and can be potentially useful in clinical practice. PMID- 27775427 TI - Plasma levels and diagnostic utility of VEGF, MMP-2 and TIMP-2 in the diagnostics of breast cancer patients. AB - OBJECTIVE: We investigated plasma levels and diagnostic utility of vascular endothelial growth factor VEGF, matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinase-2 (TIMP-2) in comparison to cancer antigen 15-3 (CA 15-3). METHODS: Plasma levels of tested parameters were determined using enzyme-linked immunosorbent assay (ELISA) while CA 15-3 with chemiluminescent microparticle immunoassay (CMIA). RESULTS: The plasma levels of VEGF, TIMP-2 showed significantly higher than CA 15-3 values of the diagnostic sensitivity, the predictive values of positive and negative test results (PPV, NPV) and the area under the receiver-operating characteristics (ROC) curve (AUC) in early stages of breast cancer (BC). The combined use of the tested parameters with CA 15-3 resulted in the increase in sensitivity, NPV and AUC, especially in the combination with VEGF (83%; 72%; 0.888) and TIMP-2 (83%; 72%; 0.894). The highest values were obtained for combination of all three parameters (93%; 85%; 0.923). CONCLUSIONS: These findings suggest the usefulness of the tested parameters in the diagnosis of BC, especially VEGF and TIMP-2 with CA 15-3 in early stages of BC, which could be a new diagnostic panel. PMID- 27775428 TI - Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents. AB - Evidence indicates an overrepresentation of youth with co-occurring autism spectrum disorders (ASD) and gender dysphoria (GD). The clinical assessment and treatment of adolescents with this co-occurrence is often complex, related to the developmental aspects of ASD. There are no guidelines for clinical care when ASD and GD co-occur; however, there are clinicians and researchers experienced in this co-occurrence. This study develops initial clinical consensus guidelines for the assessment and care of adolescents with co-occurring ASD and GD, from the best clinical practices of current experts in the field. Expert participants were identified through a comprehensive international search process and invited to participate in a two-stage Delphi procedure to form clinical consensus statements. The Delphi Method is a well-studied research methodology for obtaining consensus among experts to define appropriate clinical care. Of 30 potential experts identified, 22 met criteria as expert in co-occurring ASD and GD youth and participated. Textual data divided into the following data nodes: guidelines for assessment; guidelines for treatment; six primary clinical/psychosocial challenges: social functioning, medical treatments and medical safety, risk of victimization/safety, school, and transition to adulthood issues (i.e., employment and romantic relationships). With a cutoff of 75% consensus for inclusion, identified experts produced a set of initial guidelines for clinical care. Primary themes include the importance of assessment for GD in ASD, and vice versa, as well as an extended diagnostic period, often with overlap/blurring of treatment and assessment. PMID- 27775429 TI - Evidence-Based Assessment of ADHD in Youth Using a Receiver Operating Characteristic Approach. AB - Guidelines exist for the assessment of attention deficit/hyperactivity disorder (ADHD), but they are often unclear as to how a clinician should consider multiple informants, methods, and co-occurring symptoms to reach an overall diagnostic probability for an individual patient. The current study used receiver operating characteristic analyses and evidence-based medicine methods to evaluate the Achenbach System of Empirically Based Assessment measures and the Conners' Continuous Performance Test for ADHD diagnosis in youth. Children (n = 379) and their parent(s) presented at an outpatient clinic for a psychoeducational assessment. Analyses examined the diagnostic efficiency and utility of study measures for predicting a best-estimate ADHD diagnosis. The Child Behavior Checklist Attention Problems construct, Teacher Report Form Attention Problems construct, and Hit Reaction Time Standard Error showed adequate diagnostic efficiency and unique contributions to the prediction of ADHD, Combined Type diagnosis. None of these measures showed good diagnostic efficiency or utility for the prediction of ADHD, Predominantly Inattentive Type. Child anxiety did not moderate the relations between predictors and ADHD diagnosis. Both the Child Behavior Checklist and Teacher Report Form Attention Problems constructs can discriminate youth with ADHD, Combined Type from other clinic-referred youth. Although Hit Reaction Time Standard Error also showed diagnostic utility, the decision to include a computerized measure should consider time and expense and be utilized in cases where diagnostic probability is unclear. Finally, anxiety may be associated with elevated attention problems, but it does not appear that anxiety affects diagnostic cutoffs for ADHD. PMID- 27775430 TI - The two sides of goal intentions: Intention self-concordance and intention strength as predictors of physical activity. AB - OBJECTIVE: The present research introduces an extended conceptualisation of self concordance, which is considered an attribute not only of goals, but also of goal intentions. Based on a corresponding operationalisation, we investigate the interplay of both intention strength and intention self-concordance in the prediction of physical activity. DESIGN: Data were taken from a longitudinal study of 134 obese people who were asked to fill out a questionnaire three times every six months. MAIN MEASURES: Physical activity and intention self-concordance were measured by validated scales. Intentions strength was assessed by an item typically employed in the extant literature. RESULTS: Logistic regression analyses and path analyses showed both intention strength and self-concordance to be significant predictors of changes in physical activity over time. Additional analyses found self-efficacy to be a significant predictor of intention strength and self-concordance; for outcome expectations this was not the case. CONCLUSIONS: Findings support the idea that intention strength and self concordance are two critical facets of a goal intention that need to be considered in the prediction of physical activity participation. Whereas intention strength refers to the degree of determination with which a goal intention is adopted, self-concordance rather captures the quality of this intention. PMID- 27775431 TI - Prognostic significance of insulin-like growth factor-I serum levels in acute decompensation of cirrhosis. AB - CONTEXT: IGF-I serum levels are suppressed in cirrhosis, but its prognostic significance is unknown. OBJECTIVES: To investigate the prognostic value of IGF-I in patients admitted for acute decompensation of cirrhosis. MATERIALS AND METHODS: Cohort study that included 103 patients. IGF-I was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Ninety-day mortality was 26.2% and it was independently associated with MELD, age and IGF-I. The Kaplan-Meier survival probability at 90 days was 94.3% in patients with IGF-I >=13 ng/mL and 63.2% for patients with IGF-I <13 ng/mL (p = .001). DISCUSSION AND CONCLUSION: IGF-I levels are independently associated with mortality in acute decompensation of cirrhosis. PMID- 27775432 TI - Positive changes among patients with advanced colorectal cancer and their family caregivers: a qualitative analysis. AB - OBJECTIVE: This study assessed positive changes in patients with advanced colorectal cancer and their family caregivers following diagnosis. We compared self-reported positive changes within patient-caregiver dyads as well as self reports and patient reports of positive changes in caregivers. DESIGN: Individual, semi-structured qualitative interviews were conducted with 23 patients with advanced colorectal cancer and 23 caregivers. A theoretical thematic analysis of interview transcripts was framed by posttraumatic growth theory. RESULTS: Patients and caregivers described five positive changes: closer relationships with others, greater appreciation of life, clarifying life priorities, increased faith, and more empathy for others. Additionally, only caregivers reported better health habits following the cancer diagnosis, and a minority of patients and caregivers reported no positive changes. In about half of cases, patients reported at least one positive change that was identical to that of their caregiver. However, in most cases, patient and caregiver reports of the caregiver's positive change were discrepant. CONCLUSION: Findings suggest that positive changes are a shared experience for many patient-caregiver dyads and obtaining both patient and caregiver reports of caregiver positive changes provides a more comprehensive understanding of their experience. Interventions may capitalise on positive changes to promote meaningful living in the context of advanced cancer. PMID- 27775433 TI - Nickel exposure and plasma levels of biomarkers for assessing oxidative stress in nickel electroplating workers. AB - CONTEXT: The mechanism of nickel-induced pathogenesis remains elusive. OBJECTIVE: To examine effects of nickel exposure on plasma oxidative and anti-oxidative biomarkers. MATERIALS AND METHODS: Biomarker data were collected from 154 workers with various levels of nickel exposure and from 73 controls. Correlations between nickel exposure and oxidative and anti-oxidative biomarkers were determined using linear regression models. RESULTS: Workers with a exposure to high nickel levels had significantly lower levels of anti-oxidants (glutathione and catalase) than those with a lower exposure to nickel; however, only glutathione showed an independent association after multivariable adjustment. DISCUSSION AND CONCLUSION: Exposure to high levels of nickel may reduce serum anti-oxidative capacity. PMID- 27775434 TI - Resistin may be an independent predictor of subclinical atherosclerosis formale smokers. AB - To investigate whether resistin is associated with early atherosclerosis in male smokers. The present study consecutively enrolled 50 male smokers. Their serum resistin contents were detected with enzyme linked immunosorbent assay (ELISA), and subclinical atherosclerosis indices, including carotid inner middle thickness (IMT) and arterial elasticity indices (C1 and C2), were measured. The association between serum resistin levels and IMT, C1 and C2 were respectively evaluated with the Pearson's correlation coefficient method. The results showed that the serum resistin level had a positive association with IMT (r = 0.307, p = .030), but were both inversely associated with C1 (r = -0.440, p = .001) and C2 (r = -0.381, p = .006). These associations remained significant even after adjustment for cardiovascular confounders. In conclusion, serum resistin concentration was independently associated with early atherosclerosis in male smokers. PMID- 27775435 TI - Copeptin, resistant hypertension and renal sympathetic denervation. AB - BACKGROUND: Renal denervation is used as a treatment option for patients with resistant hypertension. But only a subgroup of patients benefits from renal sympathetic denervation (RDN). Biomarkers might be helpful to identify patients who respond to RDN. Copeptin as a surrogate for vasopressin levels is increased in hypertension and other cardiovascular diseases. This study aims to evaluate the effect of RDN on Copeptin and its prognostic value for response to RDN. METHOD AND RESULTS: A total of 40 patients have been included in the study. The responder rate was 47.5% on 24 h ambulatory blood pressure measurements. The mean systolic 24 h blood pressure dropped from 152 +/- 10 mmHg to 147 +/- 17 mmHg (p = .044) in the six month follow up. The mean baseline level of Copeptin was 7.4 pmol/l (interquartile range 3.7-11.6) for responders and 8.4 pmol/l (interquartile range 5.7-11-8) for non-responders (p = .53). The Copeptin levels did not change over time after renal denervation. CONCLUSION: Baseline measurements of Copeptin in patients undergoing RDN for resistant hypertension have no predictive value for response to RDN. Despite lowering the blood pressure RDN has no influence on Copeptin levels in this short time follow up period. PMID- 27775436 TI - Ecotoxicity interspecies QAAR models from Daphnia toxicity of pharmaceuticals and personal care products. AB - Pharmaceutical and Personal Care Products (PPCPs) became a class of contaminants of emerging concern because are ubiquitously detected in surface water and soil, where they can affect wildlife. Ecotoxicological data are only available for a few PPCPs, thus modelling approaches are essential tools to maximize the information contained in the existing data. In silico methods may be helpful in filling data gaps for the toxicity of PPCPs towards various ecological indicator organisms. The good correlation between toxicity toward Daphnia magna and those on two fish species (Pimephales promelas and Oncorhynchus mykiss), improved by the addition of one theoretical molecular descriptor, allowed us to develop predictive models to investigate the relationship between toxicities in different species. The aim of this work is to propose quantitative activity-activity relationship (QAAR) models, developed in QSARINS and validated for their external predictivity. Such models can be used to predict the toxicity of PPCPs to a particular species using available experimental toxicity data from a different species, thus reducing the tests on organisms of higher trophic level. Similarly, good QAAR models, implemented by molecular descriptors to improve the quality, are proposed here for fish interspecies. We also comment on the relevance of autocorrelation descriptors in improving all studied interspecies correlations. PMID- 27775437 TI - Polymorphisms and expression of IL-32: impact on genetic susceptibility and clinical outcome of lung cancer. AB - CONTEXT: Polymorphisms of IL-32 related closely to tumoregenesis. MATERIALS AND METHODS: Two IL-32 polymorphisms (rs12934561 and rs28372698) and mRNA expression were conducted by SNP genotype assay and real-time PCR in 423 lung cancer patients and 437 controls. RESULTS: T allele of rs28372698 associated significantly with poor prognosis in moderate and well-differentiated lung cancer patients. TT genotype of rs12934561 related closely to poor survival status in squamous carcinoma. IL-32 mRNA expression decreased in lung cancer. DISCUSSION AND CONCLUSION: Our study indicates the importance of IL-32 polymorphism and mRNA expression in susceptibility and influence of survival status in lung cancer. PMID- 27775438 TI - Lectin adhesion proteins (P-, L- and E-selectins) as biomarkers in colorectal cancer. AB - CONTEXT: Selectins probably participate in the interactions between platelets and other inflammatory cells in cancer invasion and metastasis formation. We assessed a potential relationship of P-, L- and E-selectin in colorectal cancer (CRC) patients in relation to tumour advancement according to TNM classification, and tumour location. MATERIALS AND METHODS: The study group was composed of 53 CRC patients and 25 healthy subjects. Plasma levels of soluble P-, L- and E-selectins were measured using the immunoenzymatic method with Quantikine kits (R&D Systems, Minneapolis, MN). RESULTS: The mean levels of all selectins were significantly higher in CRC patients compared to healthy controls. The highest level of sP selectin was observed in patients with metastases to the liver (stage IV), and was significantly higher than in patients without metastases (stage I/II) and with lymph node metastases (stage III), p = .02. The highest levels of sL- and sE selectin were observed in patients with lymph node metastasis. We also found sP selectin to be the best predictor of CRC. CONCLUSION: Our finding show possible involvement of tested selectins in CRC advancement and forming metastasis. Among sL- and E- selectins, P-selectin plays an important role in the progression of CRC and could be an attractive biomarker with clinical significance. PMID- 27775439 TI - Panel of SEREX-defined antigens for breast cancer autoantibodies profile detection. AB - CONTENT: Identification of panel of SEREX-defined antigens for breast cancer autoantibodies profile detection. OBJECTIVE: To create panel of antigens that can differentiate breast cancer patients and healthy individuals. METHODS: SEREX (serological analysis of cDNA expression libraries) method, ELISA (enzyme-linked immunosorbent assay), qPCR (quantitative polymerase chain reaction). RESULTS: In large-scale screening of 16 SEREX-antigens by sera of breast cancer patients and healthy donors, a combination of six antigens (RAD50, PARD3, SPP1, SAP30BP, NY-BR 62 and NY-CO-58) was identified, which can differentiate breast cancer patients and healthy donors with 70% sensitivity and 91% specificity. Elevated mRNA expression of SPP1 gene was revealed in breast tumors (2-7-fold) that correlated with SPP1 antigen immunoreactivity in autologous patients' sera. CONCLUSIONS: The new panel of six SEREX-antigens was proposed, which enables creation of serological assay for breast cancer diagnostics and/or prognosis. PMID- 27775440 TI - Assessment of genotoxicity in female agricultural workers exposed to pesticides. AB - OBJECTIVE: This study was designed to determine the genotoxic effect of exposure to a mixture of pesticides in 106 female agricultural workers employed in cotton fields from India. METHODS: Comet, micronucleus and chromosomal aberrations tests were carried out in peripheral blood lymphocytes. Micronucleus test was also performed in buccal epithelial cells. Levels of antioxidant enzymes, RBC acetylcholinesterase and hematological parameters were analyzed in the blood samples of the study subjects. RESULTS: The results indicated significant DNA damage, increased frequency of micronuclei and chromosomal aberrations in the exposed subjects (p < 0.05). The levels of antioxidant enzymes were significantly lowered and the rate of lipid peroxidation was elevated in the exposed subjects. CONCLUSION: The outcome of the study revealed an increased risk of genotoxicity and health implications in female agricultural workers. PMID- 27775441 TI - CA9 as a biomarker in preoperative biopsy of small solid renal masses for diagnosis of clear cell renal cell carcinoma. AB - PURPOSE: The purpose of our study was to test the utility of CA9 expression in preoperative biopsy samples to identify the ccRCC. MATERIALS AND METHODS: A total of 55 patients with a small solid renal mass (<=4 cm) entered into this study. The immunohistochemical staining (51 samples) and RT-PCR (33 samples) were performed to detect CA9 expression. RESULTS: For immunohistochemistry detection, CA9 was positive in 31/34 of biopsy samples of ccRCCs. CA9 was also positive in five suspected diagnosis of ccRCC. For RT-PCR detection, CA9 was positive in 25/25 biopsy samples of ccRCCs. The diagnostic accuracy of CA9 expression for ccRCC was 100%. RT-PCR was performed in four biopsies where immunohistochemistry could not be performed because of limited tissue materials or necrosis. Two ccRCCs with a negative staining by immunohistochemistry were CA9 positive by RT PCR. CONCLUSIONS: CA9 may be potentially useful biomarker in help making a diagnosis of ccRCC in the biopsy of renal mass. RT-PCR might be a preferred method to immunohistochemistry for the detection of CA9 in renal biopsy samples. PMID- 27775442 TI - Release kinetics of high-sensitivity cardiac troponins I and T and troponin T upstream open reading frame peptide (TnTuORF) in clinically induced acute myocardial infarction. AB - CONTEXT: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes. OBJECTIVE: The study examined the early release kinetics of TnTuORF. MATERIALS AND METHODS: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n = 31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH). RESULTS: Fifteen minutes after TASH, the levels of both troponins increased significantly (cTnT median: 18 ng/L versus 27 ng/L; cTnI median: 15 ng/L versus 25 ng/L). TnTuORF showed no variation. DISCUSSION: We observed a significantly greater increase in cTnI compared with cTnT. CONCLUSION: Our results demonstrate that troponin assays allow early detection of myocardial injury, whereas TnTuORF levels remain unchanged in this setting. PMID- 27775444 TI - Response to Ghembaza and Lounici's Letter: "Retinal Vasculitis in Patients with Systemic Lupus Erythematosus". PMID- 27775443 TI - Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers. AB - CONTEXT: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable. OBJECTIVE: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach. METHOD: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs. RESULTS: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation. CONCLUSION: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis. PMID- 27775445 TI - Evaluating photographic scales of facial pores and diagnostic agreement of tests using latent class models. AB - BACKGROUND: Ordinal severity scales illustrated by photographs have been widely developed to help dermatologists in evaluating skin problems or improvements. Numerous scales have been published, and none of them were used for assessing facial pores. METHODS: A five-point photographic scale of facial pores was formulated, and photographs of pores on nasal ala from 128 female volunteers were acquired. Five dermatologists with similar experiences rated the 128 photographs independently using the reference photographs. Latent Class Models (LCM) were used to analyze the data. Firstly, we hypothesized that the conditional probabilities of the five dermatologists were identical to build the first LCM and without the restriction to formulate the second LCM. Conditional probability and posterior probability were also calculated. RESULTS: The five-point scales were ambiguous as the raters actually had difficulties in distinguishing between some adjacent categories. Adjacent categories were pooled for reanalyzing, and the model fitted well. CONCLUSIONS: The newly developed photographic scale of Chinese facial pores should be redefined to improve their quality and reproducibility in future studies. Standardized scales for the measurement of aging and response to cosmetic therapy were essential for assessing diagnostic experiment. The LCM can effectively deal with diagnostic test of agreement and reproducibility. PMID- 27775446 TI - Quantification of 1-hydroxypyrene, 1- and 2-hydroxynaphthalene, 3 hydroxybenzo[a]pyrene and 6-hydroxynitropyrene by HPLC-MS/MS in human urine as exposure biomarkers for environmental and occupational surveys. AB - CONTEXT: Several urinary PAHs metabolites can be detected by HPLC-MS/MS for individual exposure assessment. OBJECTIVE: Quantitation of urinary metabolites of four PAHs, selected on the basis of their significance, with reduced costs and high sensitivity. MATERIALS AND METHODS: HPLC-MS/MS was used and pure standards and isotope-labeled internal analogs of the analytes. Two hundred samples were tested after enzymatic hydrolysis. RESULTS: Accuracy was higher than 90% and variability lower than 19%; LODs permit to measure 1-hydroxypyrene, 1 and 2 hydroxynaphthalene in all subjects, 6-hydroxynitropyrene in the 65% and 3 hydroxybenzo[a]pyrene in the 70%. DISCUSSION AND CONCLUSION: The method is suitable both for occupational and for environmental studies. This is the first paper reporting urinary levels of 6-hydroxynitropyrene in European subjects, nonoccupationally exposed to nitro-PAHs. PMID- 27775447 TI - A pediatric fatality due to accidental hydromorphone ingestion. AB - BACKGROUND: Death due to prescription opioid exposure has increased dramatically in North America. Currently, there is a lack of literature detailing potentially lethal doses as well as postmortem tissue analysis concentrations from prescription opioid fatalities in children. We report a pediatric hydromorphone fatality with postmortem peripheral blood, central blood, liver, and gastric concentrations. CASE REPORT: A 3-year-old male was found unresponsive on a couch. Emergency services were contacted and responders found him pulseless, apneic, and asystolic. Resuscitative measures were unsuccessful and he was pronounced dead at a local hospital soon after arrival. Postmortem investigations revealed that two hydromorphone tablets (2 mg each) were missing. There was no demonstrable natural disease or traumatic injury to which to attribute his death upon autopsy; while postmortem concentrations of hydromorphone were confirmed and quantitated in peripheral blood at 0.03 mg/L, central blood 0.06 mg/L, and liver 0.10 mg/kg. CONCLUSION: Given the paucity of reported pediatric opioid-related fatalities, we describe a hydromorphonep-related death in a child, which includes postmortem hydromorphone concentrations. PMID- 27775448 TI - Immune Regulatory Function of Tregs. PMID- 27775449 TI - Letter from the Editor 2016. PMID- 27775450 TI - Adalimumab Treatment in Patients with Vogt-Koyanagi-Harada Disease. AB - PURPOSE: To evaluate the clinical outcome and safety of adalimumab in patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: VKH patients treated with adalimumab seen at the University of Buenos Aires were reviewed. Main outcome measures were visual acuity, anterior segment inflammation, optic nerve inflammation (ONI), steroid sparing effect, number of immunosuppressives, and relapses. RESULTS: In total, 14 VKH patients, mean age 23.07 +/- 8 years; median of adalimumab treatment 10 months, were analyzed. At start of adalimumab treatment (baseline), median of corticosteroid dose was 20 mg and at 6 months, 4 mg. At baseline, 11 patients were on immunosuppressive treatment and at 6 months only four continued with immunosuppressive therapy. In the 28 eyes, the median of active inflammation was 2 at baseline and 0 after 6 months on adalimumab. CONCLUSIONS: Treatment with adalimumab is an effective and safe option, reducing the need for oral corticosteroid and conventional immunosuppressive therapy. PMID- 27775451 TI - Closure of skin incision by dual wavelength (980 and 1064 nm) laser application. AB - Thermal effect of dual wavelength (980 and 1064 nm) laser application in skin incision closure was assessed on 18 male and female Wister rats. 1-cm-long incisions were made on the shaved dorsal region of 220-250 g animals. The incisions were closed by laser irradiation at 1 W and exposure time, 5 seconds in continuous-wave mode (CW) and 1 W and exposure time, 10 seconds in pulsed mode to deliver total energies of 5 J and 10 J per spot onto the incisions, respectively. Animals from each group were sacrificed at 0th, 4th, and 7th days and the skin samples of the weld area were excised for histological analysis using Hematoxylin and Eosin (H & E) stain. Mean thermally altered area (TAA) of CW-mode laser treated groups was found to increase significantly (p < 0.05) compared with pulsed mode laser treated group at 0th and 4th days post-irradiation while no significant difference (p > 0.05) was statistically found at 7th day post irradiation. Moreover, tighter closure was observed with CW group at 7th day post irradiation. We thus conclude that 1 W, 5 J for 5 seconds CW mode laser application of 980 and 1064 nm combined beam form in skin incision closure was found to have absolute wound healing capability with minimal thermal alteration. PMID- 27775452 TI - Isatin: a privileged scaffold for the design of carbonic anhydrase inhibitors. AB - The isatin scaffold is the constitutive fragment of several natural and synthetic bioactive molecules. Albeit several benzene sulphonamide-based carbonic anhydrase inhibitors (CAIs) have been reported, only recently isatin benzene sulphonamides have been studied and proposed as CAIs. In this study we have designed, synthesised, and evaluated the biological activity of a series of differently substituted isatin-based benzene sulphonamides which have been designed for the inhibition of carbonic anhydrase isoforms. The activity of all the synthesised compounds was evaluated towards human carbonic anhydrase I, II, IX, and XII isozymes. Our results indicate that the nature and position of substituents on the isatin ring can modulate both activity and isozyme selectivity. PMID- 27775453 TI - The association between insulin-like growth factor 1 (IGF-1), IGF-binding proteins (IGFBPs), and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis. AB - OBJECTIVES: To assess the association between plasma levels of the insulin-like growth factor (IGF) system including IGF-1, IGF-binding proteins (IGFBPs) including IGFBP-1, total (t-)IGFBP-3 and functional (f-)IGFBP-3, and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis (RA). METHOD: Plasma concentrations of IGF-1, IGFBP-1, t-IGFBP-3, f-IGFBP-3, and PICP were measured by immunoassay. RESULTS: No significant difference was observed in plasma IGF-1 levels between pre- and postmenopausal subjects. Plasma levels of IGFBP-1 were elevated in RA. PICP and f-IGFBP-3 were greatly affected by menopausal status. Of the three IGFBPs tested, only f-IGFBP-3 plasma levels in RA women correlated negatively with age and disease duration. A positive correlation was demonstrated between PICP and erythrocyte sedimentation rate (ESR) in RA. Moreover, there was no correlation between PICP and IGF-1 and any of the IGFBPs in RA women. CONCLUSIONS: Considerable disruption of the IGF system in RA was found to be related to disease activity and duration. Changes in the IGF-IGFBP axis and PICP levels were different in pre- and postmenopausal women with RA. Elevated plasma PICP concentrations may indicate an increased rate of bone formation in postmenopausal RA women. Additionally, the observed changes in the IGF/IGFBP system did not affect bone formation during RA. PMID- 27775454 TI - Baseline Trachoma Surveys in Kaskazini A and Micheweni Districts of Zanzibar: Results of Two Population-Based Prevalence Surveys Conducted with the Global Trachoma Mapping Project. AB - PURPOSE: Based on health care records and trachoma rapid assessments, trachoma was suspected to be endemic in Kaskazini A and Micheweni districts of Zanzibar. This study aimed to investigate the prevalence of trachomatous inflammation follicular (TF), and trachomatous trichiasis (TT) in each of those districts. METHODS: The survey was undertaken in Kaskazini A and Micheweni districts on Unguja and Pemba Islands, respectively. A multi-stage cluster random sampling design was applied, whereby 25 census enumeration areas (clusters) and 30 households per cluster were included. Consenting eligible participants (children aged 1-9 years and people aged 15 years and older) were examined for trachoma using the World Health Organization simplified grading system. RESULTS: A total of 1673 households were surveyed and 6407 participants (98.0% of those enumerated) were examined for trachoma. Examinees included a total of 2825 children aged 1-9 years and 3582 people aged 15 years and older. TF prevalence in 1-9-year-olds was 2.7% (95% confidence interval, CI, 2.7-4.1%) in Kazkazini A and 11.4% (95% CI 6.6-16.5%) in Micheweni. Among people aged 15 years and older, TT prevalence was 0.01% (95% CI 0.00-0.04%) in Kazkazini A and 0.21% (95% CI 0.08 0.39%) in Micheweni. CONCLUSION: Trachoma is a public health problem in Micheweni district, where implementation of all four components of the SAFE strategy (surgery, antibiotics, facial cleanliness, and environmental improvement), including mass drug administration with azithromycin, is required. These findings will facilitate planning for trachoma elimination. PMID- 27775456 TI - A Case of Necrobiotic Xanthogranuloma Presenting as Bilateral Posterior Scleritis. PMID- 27775457 TI - Serum Vitamin D Levels in Children with Vernal Keratoconjunctivitis. AB - PURPOSE: To evaluate serum 25-hydroxyvitamin D [25(OH)D3] levels of vernal keratoconjunctivitis (VKC) children. METHODS: A total of 62 non-atopic healthy children (64.5% male, mean age 10.79 +/- 3.3 years) and 29 VKC children (75.9%, mean age 12.17 +/- 2.7 years) were included in the study. Serum 25(OH)D3 levels measured by HPLC were compared between the two groups and a p value of <0.05 was considered as statistically significant. RESULTS: The mean serum 25(OH)D3 level of VKC group was significantly lower than in the control group (11.02 +/- 5.16 ng/mL and 15.99 +/- 7.36 ng/mL, respectively) (p = 0.002). Severe vitamin D deficiency (<10 ng/mL) was detected in 48.3% of VKC children and 22.6% of the controls (p = 0.017). Time spent outdoors during daylight was higher in the control group (229.5 +/- 101.2 min) compared with the VKC group (160.7 +/- 65.9 min) (p = 0.008), and showed a significant correlation with serum 25(OH)D3 levels (Spearman rho = 0.812) (p<0.001). CONCLUSIONS: Children with VKC should be evaluated for vitamin D deficiency, which might occur secondary to sun avoidance. PMID- 27775455 TI - Progress of Trachoma Mapping in Mainland Tanzania: Results of Baseline Surveys from 2012 to 2014. AB - PURPOSE: Following surveys in 2004-2006 in 50 high-risk districts of mainland Tanzania, trachoma was still suspected to be widespread elsewhere. We report on baseline surveys undertaken from 2012 to 2014. METHODS: A total of 31 districts were surveyed. In 2012 and 2013, 12 at-risk districts were selected based on proximity to known trachoma endemic districts, while in 2014, trachoma rapid assessments were undertaken, and 19 of 55 districts prioritized for baseline surveys. A multi-stage cluster random sampling methodology was applied whereby 20 villages (clusters) and 36 households per cluster were surveyed. Eligible participants, children aged 1-9 years and people aged 15 years and older, were examined for trachoma using the World Health Organization simplified grading system. RESULTS: A total of 23,171 households were surveyed and 104,959 participants (92.3% of those enumerated) examined for trachoma signs. A total of 44,511 children aged 1-9 years and 65,255 people aged 15 years and older were examined for trachomatous inflammation-follicular (TF) and trichiasis, respectively. Prevalence of TF varied by district, ranging from 0.0% (95% confidence interval, CI 0.0-0.1%) in Mbinga to 11.8% (95% CI 6.8-16.5%) in Chunya. Trichiasis prevalence was lowest in Urambo (0.03%, 95% CI 0.00-0.24%) and highest in Kibaha (1.08%, 95% CI 0.74-1.43%). CONCLUSION: Only three districts qualified for mass drug administration with azithromycin. Trichiasis is still a public health problem in many districts, thus community-based trichiasis surgery should be considered to prevent blindness due to trachoma. These findings will facilitate achievement of trachoma elimination objectives. PMID- 27775458 TI - Efficacy of Anti-TNF-alpha Therapy for the Treatment of Non-infectious Uveitis: A Retrospective Study of 21 Patients. AB - PURPOSE: To assess the efficacy of anti-TNF alpha (TNF-alpha) therapy in patients with non-infectious uveitis. METHODS: This was a monocentric observational study of 21 patients with non-infectious uveitis treated with anti-TNF-alpha. The primary endpoint was the control of ocular inflammation. The secondary endpoints included the study of macular thickness and visual acuity, changes in other treatments, and adverse effects. RESULTS: The etiologies of uveitis were Behcet disease (33.3%), birdshot (14.3%), sarcoidosis (9.5%), and idiopathic uveitis (42.9%). Ocular inflammation was controlled at 3 months for 80.9% of patients, at 6 months for 94.7%, at 12 months for 83.3%, and at >12 months for 86.7%. Central macular thickness improved from 452 um at baseline to 307.5 um at 12 months (p = 0.002). Visual acuity also improved from 0.51(logMAR) before treatment to 0.24 at 12 months. The mean daily dose of prednisone decreased from 19.7 mg before treatment to 5.2 mg at 12 months (p < 0.001). A total of 9.5% of patients experienced serious side-effects. CONCLUSIONS: Our study confirms the efficacy of anti-TNF for the control of short-term and long-term ocular inflammation, with high rates of complete clinical remission. PMID- 27775459 TI - Intravitreal Administration of Ranibizumab and Bevacizumab for Choroidal Neovascularization Secondary to Ocular Toxocariasis: A Case Report. AB - PURPOSE: To report a case of a choroidal neovascularization (CNV) secondary to ocular toxocariasis treated with intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. METHODS: A 66-year-old woman presented with decreased vision (20/40) and metamorphopsia in the right eye. Fundus examination revealed inferotemporal retinal whitish lesion and subretinal hemorrhage in the right eye. RESULTS: She was diagnosed with ocular toxocariasis based on the clinical features and positive serological anti-toxocara antibody test result. Ophthalmic examination revealed classic CNV formation adjacent to a retinal granuloma. She was treated with intravitreal ranibizumab and bevacizumab injections combined with oral albendazole. Her vision decreased to 20/100 following CNV recurrence. However, after additional bevacizumab treatment, the CNV became inactive and her vision recovered to 20/40. CONCLUSIONS: CNV can be combined with retinal granuloma due to ocular toxocariasis. Repeated intravitreal injections of anti-VEGF agents can be efficacious for regressing toxocariasis associated CNV and improving vision. PMID- 27775460 TI - Survivorship and relative risk of revision in computer-navigated versus conventional total knee replacement at 8-year follow-up. AB - Background and purpose - The long-term effects of computer-assisted surgery in total knee replacement (CAS) compared to conventionally operated knee replacement (CON) are still not clear. We compared survivorship and relative risk of revision in CAS and CON based on data from the Norwegian Arthroplasty Register. Patients and methods - We assessed primary total knee replacements without patellar resurfacing reported to the Norwegian Arthroplasty Register from 2005 through 2014. The 5 most used implants and the 3 most common navigation systems were included. The groups (CAS, n = 3,665; CON, n = 20,019) were compared using a Cox regression analysis adjusted for age, sex, ASA category, prosthesis brand, fixation method, previous surgery, and diagnosis with the risk of revision for any reason as endpoint. Secondary outcomes were reasons for revision and effects of prosthesis brand, fixation method, age (+/- 65 years), and hospital volume. Results - Prosthesis survival and risk of revision were similar for CAS and CON. CAS had significantly fewer revisions due to malalignment. Otherwise, no statistically significant difference was found between the groups in analyses of secondary outcomes. Mean operating time was 13 minutes longer in CAS. Interpretation - At 8 years of follow-up, CAS and CON had similar rates of overall revision, but CAS had fewer revisions due to malalignment. According to our findings, the benefits of CAS at medium-term follow-up are limited. Further research may identify subgroups that benefit from CAS, and it should also emphasize patient-reported outcomes. PMID- 27775462 TI - Reduced ability to detect surface-related biofilm bacteria after antibiotic exposure under in vitro conditions. AB - Background and purpose - Antibiotic treatment of patients before specimen collection reduces the ability to detect organisms by culture. We investigated the suppressive effect of antibiotics on the growth of non-adherent, planktonic, and surface-related biofilm bacteria in vitro by using sonication and microcalorimetry methods. Patients and methods - Biofilms of Staphylococcus aureus, S. epidermidis, Escherichia coli, and Propionibacterium acnes were formed on porous glass beads and exposed for 24 h to antibiotic concentrations from 1 to 1,024 times the minimal inhibitory concentration (MIC) of vancomycin, daptomycin, rifampin, flucloxacillin, or ciprofloxacin. The beads were then sonicated to dislodge biofilm, followed by culture and measurement of growth-related heat flow by microcalorimetry of the resulting sonication fluid. Results - Vancomycin did not inhibit the heat flow of staphylococci and P. acnes at concentrations <=1,024 MUg/mL, whereas flucloxacillin at >128 MUg/mL inhibited S. aureus. Daptomycin inhibited heat flow of S. aureus, S. epidermidis, and P. acnes at lower concentrations (32-128 times MIC, p < 0.001). Rifampin showed inconsistent results in staphylococci due to random emergence of resistance, which was observed at concentrations <=1,024 times MIC (i.e. 8 MUg/mL). Ciprofloxacin inhibited heat flow of E. coli at >=4 times MIC (i.e. >= 0.06 MUg/mL). Interpretation - Whereas time-dependent antibiotics (i.e. vancomycin and flucloxacillin) showed only weak growth suppression, concentration-dependent drugs (i.e. daptomycin and ciprofloxacin) had a strong suppressive effect on bacterial growth and reduced the ability to detect planktonic and biofilm bacteria. Exposure to rifampin rapidly caused emergence of resistance. Our findings indicate that preoperative administration of antibiotics may have heterogeneous effects on the ability to detect biofilm bacteria. PMID- 27775461 TI - Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethasone with or without additional cyclosporin on MRI-assessed synovitis, osteitis, tenosynovitis, bone erosion, and joint space narrowing in early rheumatoid arthritis: results from a 2-year randomized double-blind placebo controlled trial (CIMESTRA). AB - OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect. METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods. RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, 3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups. CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated. PMID- 27775464 TI - Walking and the Perception of Neighborhood Attributes Among U.S. Adults-2012. AB - BACKGROUND: The association between walking and environmental attributes depends on walking purpose. This study, based on a large survey of U.S. adults, examined the association between perceived neighborhood safety and built environment attributes, and walking for transportation and leisure. METHODS: Data were obtained on transportation and leisure-time walking, perceived neighborhood safety and built environment attributes, and demographic characteristics from the summer wave of the 2012 ConsumerStyles survey of 3951 U.S. adults. Associations were examined by demographic characteristics. RESULTS: Seventy-five percent of respondents reported walking for either transportation (54%) or leisure (56%) in the past week, 59% reported no safety concern, and 36% reported absence of any built environment attribute of walkability nearby. Respondents with more education, and those who lived in metropolitan areas were more likely to report built environment attributes supportive of walking. All built environment attributes examined, as well as safety concern due to speeding vehicles, were associated with walking after adjustment for demographic characteristics. CONCLUSION: Walking, particularly for transportation, is associated with many built environment attributes among U.S. adults. These attributes may be important to consider when designing and modifying the built environment of communities, especially those which are less walkable. PMID- 27775463 TI - Prevalence of Trachoma in Katsina State, Nigeria: Results of 34 District-Level Surveys. AB - PURPOSE: To determine the local government area (LGA)-level prevalence of trachoma in all 34 LGAs of Katsina State. METHODS: A population-based prevalence survey was conducted in each LGA of Katsina State, using the Global Trachoma Mapping Project methodology. We used a 3-stage cluster random sampling strategy to select 25 households from each of 25 clusters. We examined all residents of selected households aged 1 year and older for the clinical signs of trachomatous inflammation-follicular (TF), trachomatous inflammation-intense and trichiasis, using the World Health Organization (WHO) simplified grading scheme. RESULTS: We examined 129,281 persons. Six LGAs had a TF prevalence >=10%, and another six LGAs had a TF prevalence between 5% and 9.9%; all 12 require mass drug administration with azithromycin plus other interventions. The prevalence of trichiasis was >=1.0% in 13 LGAs, and there is a need to perform trichiasis surgery in over 26,000 persons to reach targets set by the WHO for elimination of trichiasis. CONCLUSION: The prevalence of TF is generally low in Katsina state, but urgent steps must be taken to implement the full SAFE strategy (surgery, antibiotics, facial cleanliness, environmental improvement) in at least 12 LGAs while also stepping up efforts to provide community-based trichiasis surgery throughout the whole state, in order to make trachoma elimination by 2020 a reality. PMID- 27775465 TI - A Multicomponent Schoolyard Intervention Targeting Children's Recess Physical Activity and Sedentary Behavior: Effects After One Year. AB - Background Aim of the study was to test the 12-month effects of a multicomponent physical activity (PA) intervention at schoolyards on recess PA levels of 6th and 7th grade children in primary schools, combining Global Positioning System (GPS) and accelerometry data. Methods A quasi-experimental study design was used with 20 paired intervention and control schools. GPS confirmatory analyses were applied to validate attendance at schoolyards during recess. Data from 376 children from 7 pairs of schools were included in the final analyses. Pooled intervention effectiveness was tested by multilevel linear regression analyses, whereas effectiveness of intervention components was tested by multivariate linear regression analyses. Results Children exposed to the multicomponent intervention increased their time spent in light PA (+5.9%) during recess. No pooled effects on Moderate-to-Vigorous PA were found. In depth-analyses on intervention components showed that physical schoolyard interventions particularly predicted a decrease in time spent in sedentary behavior during recess at follow-up. Intervention intensity and school's commitment to the project strengthened this effect. Conclusions The multicomponent schoolyard PA intervention was effective in making children spend a larger proportion of recess time in light PA, which was most likely the result of a shift from sedentary behavior to light PA. PMID- 27775466 TI - The Effect of New Shower Facilities on Physical Activity Behaviors of Employees: A Quasi-experiment. AB - BACKGROUND: This quasi-experimental study assessed the effects of new workplace showers on physical activity behaviors in a sample of downtown employees in Austin, TX. METHODS: The study design was quasi-experimental with 2 comparison groups. Data were collected via internet-based surveys before and 4 months after shower installation at 1 worksite. Differences across study groups in the ranks of change in past-week minutes of physical activity from baseline to follow-up were assessed. Adjusted odds ratios and 95% confidence intervals for reporting an increase of >=10 min past-week physical activity and workday physical activity among those with new showers and existing showers relative to those with no showers were also assessed. RESULTS: No significant differences in changes in physical activity from baseline to follow-up across study groups were found. One quarter of participants with new workplace showers and 46.9% of those with existing workplace showers at baseline reported ever using the showers. CONCLUSIONS: This prospective study did not find significant changes in employee physical activity 4 months after installation of worksite showers. Worksite shower users were highly active at baseline, suggesting a possible early adopter effect, with potential for diffusion. Future studies may benefit from longer exposure times and larger samples. PMID- 27775467 TI - Effects of Distant Green Space on Physical Activity in Sydney, Australia. AB - BACKGROUND: The aim was to investigate the association between distant green space and physical activity modified by local green space. METHODS: Information about physical activity, demographic and socioeconomic background at the individual level was extracted from the New South Wales Population Health Survey. The proportion of a postcode that was parkland was used as a proxy measure for access to parklands and was calculated for each individual. RESULTS: There was a significant relationship between distant green space and engaging in moderate-to vigorous physical activity (MVPA) at least once a week. No significant relationship was found between adequate physical activity and distant green space. No significant relationships were found between adequate physical activity, engaging in MVPA, and local green space. However, if respondents lived in greater local green space (>=25%), there was a significant relationship between engaging in MVPA at least once a week and distance green space of >=20%. CONCLUSION: This study highlights the important effect of distant green space on physical activity. Our findings also suggest that moderate size of local green space together with moderate size of distant green space are important levers for participation of physical activity. PMID- 27775468 TI - Vicinity of Schools, But Not of Residences, Seems to Regulate Physical and Sports Activities of 13-Year-Old Teenagers in a South European Setting. AB - BACKGROUND: Proximity to urban green spaces (UGS) and open sports spaces (OSS) benefits health, promotes physical activity (PA) and sports practice (SP). OBJECTIVE: Analyze the association between PA or SP according to distances between UGS or OSS and teenagers' residences or schools. METHODS: We evaluated 1333 (53.9% girls) teenagers (13 years old) living and studying in Porto, Portugal (EPITeen cohort). PA was classified as light or moderate/vigorous. Distances were the shortest routes from residences or schools to UGS/OSS, and classified in <=250 m; >250 m to <=500 m; >500 m to <=750 m; >750 m. Chi-square test and chi-square for trends were used to compare proportions; associations were measured using logistic regression, through odds ratio and 95% confidence intervals, adjusting to BMI and parental education. RESULTS: Regarding vicinity' of schools, the prevalence of moderate/vigorous PA among boys, decreases as distances to OSS increases. For girls, the prevalence of sports decreases as distances to UGS increase. For boys, we found an association between moderate/vigorous PA and proximity to OSS in the vicinity of schools: considering <=250 m as reference, the odds of moderate/vigorous PA is 0.20 (0.06-0.63) for >250 m to <=500 m; 0.21 (0.07-0.61) for >500 m to <=750 m and 0.19 (0.06-0.58) for >750 m. CONCLUSION: Vicinities of schools seem to influence teenagers to be more physically active and increase sports participation. PMID- 27775469 TI - Association of Different Physical Activity Domains on All-Cause Mortality in Adults Participating in Primary Care in the Brazilian National Health System: 4 Year Follow-up. AB - BACKGROUND: Evidence has shown that physical activity (PA) is associated with low mortality risk. However, data about reduced mortality due to PA are scarce in developing countries and the dose-response relationship between PA from different domains and all-cause mortality remains unclear. Thus, the aim of this study is to investigate the association of PA from different domains on all-cause mortality among Brazilian adults. METHODS: 679 males and females composed the study sample. Participants were divided into quartile groups according to PA from different domains (occupational, sports, and leisure-time). Medical records were used to identify the cause of the death. Cox regression analysis was performed to determine the independent associations of PA from different domains and all-cause mortality. RESULTS: During the follow-up period, 59 participants died. The most prevalent cause of death was circulatory system diseases (n = 20; 33.9% [21.8% 45.9%]). Higher scores of occupational (HR= 0.45 [95% CI: 0.20-0.97]), sports (HR= 0.44 [95% CI: 0.20-0.95]) and overall PA (HR= 0.40 [95% CI: 0.17-0.90]) were associated with lower mortality, even after adjustment for confounders. CONCLUSIONS: The findings in this study showed the importance of being active in different domains to reduce mortality risk. PMID- 27775470 TI - The Association Between Sedentary Behavior and Cognitive Function Among Older Adults May Be Attenuated With Adequate Physical Activity. AB - OBJECTIVE: Examine the independent association of sedentary behavior and cognitive function in older adults, as well as whether physical activity attenuates this potential association. METHODS: Data from the 1999-2002 National Health and Nutrition Examination Survey were used (N = 2472 adults 60 to 85 yrs). Sedentary behavior was subjectively assessed and the Digit Symbol Substitution Test (DSST) was employed to assess cognitive function. RESULTS: Among an unadjusted and an adjusted model not accounting for physical activity, only 5+ hrs/day (vs. < 1 hr) of sedentary time was independently associated with lower DSST scores (beta = -3.1; 95% CI: -5.8 to -0.4; P= .02). However, a fully adjusted model (adding in moderate-to-vigorous physical activity as a covariate) did not yield a statistically significant association between 5+ hrs/day of sedentary time and DSST scores (beta = -2.5; 95% CI: -5.1 to 0.2; P = .07). CONCLUSION: Accumulated daily sedentary behavior of 5+ hrs is associated with lower cognitive function in an older adult population when physical activity is not taken into account. However, physical activity may account for 19% of the total association between sedentary behavior and cognitive function, thus attenuating the sedentary-cognitive function association. Efforts should be made to promote physical activity in the aging population. PMID- 27775471 TI - Evaluation of a Shelter-Based Diet and Physical Activity Intervention for Homeless Adults. AB - BACKGROUND: The current study evaluated the feasibility and effectiveness of a diet and physical activity intervention for homeless adults. METHODS: Shelter residents (N = 32) were randomly assigned to a 4-week diet and physical activity intervention (n = 17) or an assessment-only control group (n = 15). Intervention participants received tailored educational newsletters, pedometers with step goals, and twice daily fruit/vegetable snacks. Key measures included 24-hour dietary recall interviews and accelerometer-measured moderate-to-vigorous intensity physical activity (MVPA). RESULTS: At baseline, 68.8% of participants were overweight or obese, 93.8% reported food insecurity, and 43.8% reported activity levels below physical activity guidelines. Baseline dietary recall interviews indicated low fruit/vegetable consumption, and elevated intake of added sugar, saturated fat, and sodium relative to current dietary recommendations. During the 4-week study period, intervention participants engaged in significantly greater accelerometer-measured daily MVPA (P < .001) than controls (median = 60 daily minutes p vs. 41 daily minutes). Between groups differences in fruit/vegetable consumption at the end of treatment did not reach statistical significance. Most participants reported that the intervention was helpful for increasing fruit/vegetable intake and physical activity. CONCLUSIONS: Findings highlight the potential to improve dietary quality and increase physical activity among sheltered homeless adults. PMID- 27775472 TI - Exploring Attitudes, Perceived Norms, and Personal Agency: Insights Into Theory Based Messages to Encourage Park-Based Physical Activity in Low-Income Urban Neighborhoods. AB - BACKGROUND: Public parks hold promise for promoting population-level PA, but studies show a significant portion of park use is sedentary. Past research has documented the effectiveness of message-based strategies for influencing diverse behaviors in park settings and for increasing PA in nonpark contexts. Therefore, to inform message-based interventions (eg, point-ofdecision prompts) to increase park-based PA, the purpose of this study was to elicit insights about key attitudes, perceived norms, and personal agency that affect park use and park based PA in low-income urban neighborhoods. METHODS: This study used 6 focus groups with youth and adults (n = 41) from low-income urban areas in Kansas City, MO, to examine perceptions of key attitudinal outcomes and motivations, perceived norms, key referents, and personal agency facilitators and constraints that affect park use and park-based PA. RESULTS: Participant attitudes reflected the importance of parks for mental and physical health, with social interaction and solitude cited as key motivations. Of 10 themes regarding perceived norms, influential others reflected participants' ethnic makeup but little consensus emerged among groups. Social and safety themes were cited as both facilitators and constraints, along with park offerings and setting. CONCLUSIONS: Information about attitudes, perceived norms, and personal agency can increase understanding of theoretically derived factors that influence park-based PA and help park and health professionals create communication strategies to promote PA. PMID- 27775473 TI - Physical Activity in Older Adults in Relation to Place of Residence and Coexistent Chronic Diseases. AB - BACKGROUND: The goal of this study was to assess the physical activity (PA) and its determinants of older people living in the 3 different environments. METHODS: Three equal (n = 693 each) groups of individuals aged >=65 years living in urban, rural and institutional environments took part in this study. PA was measured by the Seven Day Recall PA Questionnaire (energy expenditure-PA-EE) and the Stanford Usual Activity Questionnaire (health-related behaviors-PA-HRB). RESULTS: PA-EE was highest in the rural environment and lowest in nursing homes. PA-HRB were most common in urban area. Older age, lower education level, several concomitant diseases and the number of systematically used medications were consistently related to lower PA-EE and PA-HRB. Smoking habit, presence of hypertension, musculoskeletal and gastrointestinal disorders had different association to PA-EE and PA-HRB in the 3 environments. CONCLUSIONS: Subpopulations of older people differ from the general population with regard to their level of PA and its association with sociodemographic data and concomitant diseases. Concomitant serious diseases significantly decrease the level of PA of older subjects. The relationship between PA and nondebilitating disorders may vary depending on the living environment or PA assessment methodology. PMID- 27775475 TI - Defining and Measuring Active Play Among Young Children: A Systematic Review. AB - BACKGROUND: Many young children are not meeting the Canadian physical activity guidelines. In an effort to change this, the term active play has been used to promote increased physical activity levels. Among young children, physical activity is typically achieved in the form of active play behavior. The current study aimed to review and synthesize the literature to identify key concepts used to define and describe active play among young children. A secondary objective was to explore the various methods adopted for measuring active play. METHODS: A systematic review was conducted by searching seven online databases for English language, original research or reports, and were eligible for inclusion if they defined or measured active play among young children (ie, 2 to 6 years). RESULTS: Nine studies provided a definition or description of active play, six measured active play, and 13 included both outcomes. While variability in active play definitions did exist, common themes included: increased energy exerted, rough and tumble, gross motor movement, unstructured, freely chosen, and fun. Alternatively, many researchers described active play as physical activity (n = 13) and the majority of studies used a questionnaire (n = 16) to assess active play among young children. CONCLUSION: Much variability in the types of active play, methods of assessing active play, and locations where active play can transpire were noted in this review. As such, an accepted and consistent definition is necessary, which we provide herein. PMID- 27775474 TI - Characterization of the Antibody Response after Cervical Spinal Cord Injury. AB - The immune system plays a critical and complex role in the pathobiology of spinal cord injury (SCI), exerting both beneficial and detrimental effects. Increasing evidence suggests that there are injury level-dependent differences in the immune response to SCI. Patients with traumatic SCI have elevated levels of circulating autoantibodies against components of the central nervous system, but the role of these antibodies in SCI outcomes remains unknown. In rodent models of mid thoracic SCI, antibody-mediated autoimmunity appears to be detrimental to recovery. However, whether autoantibodies against the spinal cord are generated following cervical SCI (cSCI), the most common level of injury in humans, remains undetermined. To address this knowledge gap, we investigated the antibody responses following cSCI in a rat model of injury. We found increased immunoglobulin G (IgG) and IgM antibodies in the spinal cord in the subacute phase of injury (2 weeks), but not in more chronic phases (10 and 20 weeks). At 2 weeks post-cSCI, antibodies were detected at the injury epicenter and co localized with the astroglial scar and neurons of the ventral horn. These increased levels of antibodies corresponded with enhanced activation of immune responses in the spleen. Higher counts of antibody-secreting cells were observed in the spleen of injured rats. Further, increased levels of secreted IgG antibodies and enhanced proliferation of T-cells in splenocyte cultures from injured rats were found. These findings suggest the potential development of autoantibody responses following cSCI in the rat. The impact of the post traumatic antibody responses on functional outcomes of cSCI is a critical topic that requires further investigation. PMID- 27775476 TI - Alteration of Selected Neurotrophic Factors and their Receptor Expression in Mouse Brain Response to Whole-Brain Irradiation. AB - Ionizing radiation can significantly affect brain function in children and young adults, particularly in the hippocampus where neurogenic niches are located. Injury to normal tissue is a major concern when whole-brain irradiation (WBI) is used to treat central nervous system (CNS) tumors, and the pathogenesis of this injury remains poorly understood. We assessed the expression of selected neurotrophins (NTs) and NT receptors (NTRs) in brains of young mice after a single 10 Gy gamma-ray exposure using morphological and molecular analyses [qRT PCR, Western blot, immunohistochemistry (IHC)] to evaluate WBI-induced injury in its acute phase. Activity of the NT-NTR axes was examined by analysis of ERK and Akt phosphorylation. Using Nissl staining of hippocampus slices to visualize morphological changes, and TUNEL assay and active caspase-3 detection to assess apoptotic cell death, we found evidence of apoptosis and degenerative changes in hippocampal tissue after WBI. Shortly after WBI, we also observed significant overexpression of several NTs (BDNF, NT-3, NGF and GDNF) and NTRs (TrkA, TrkB, TrkC, GFRalpha-1, and p75NTR) compared to control animals. The upregulated NT and NTR proteins, in part, originated from two analyzed neurogenic areas: the subgranular zone of the hippocampal dentate gyrus and the subventricular zone, as confirmed by IHC. Finally, components of intracellular signaling pathways, including Akt and MAPK, were activated in acute phase after WBI. Given the role of NTs in diverse biological mechanisms, including maintenance and growth of neurons in the adult brain, our findings of altered expression of neurotrophins and their receptors in brain tissue shortly after irradiation suggest that these molecules play a vital role in the pathophysiology of the acute phase of WBI induced injury. PMID- 27775479 TI - Park Use and Physical Activity Among Mostly Low-to-Middle Income, Minority Parents and Their Children. AB - BACKGROUND: Limited research has examined park use and physical activity among economically and ethnically diverse families. This study fills that gap. METHODS: Parents (n = 326) completed a questionnaire about their park use (yes/no, parks visited, reasons for nonuse) and physical activity (Godin Leisure Time questionnaire). Geographical Information Systems was used to calculate the distance from respondents' home address to their nearest park. The number of activity features (eg, playgrounds) in parks was determined objectively using the Community Park Audit Tool. RESULTS: Half of respondents were sufficiently active; 87.6% reported park use in the prior 6 months. Among sufficiently active respondents, 92.4% reported park use (P = .011). We found no difference in park proximity between respondents who did and did not report distance as a park use barrier. An objective assessment confirmed fewer activity features in parks near the homes of respondents reporting few activity features as a barrier to park use. The most often visited parks were significantly larger than the less-often visited parks. CONCLUSION: Parks might best support physical activity for families when activity features are carefully planned and equitably distributed across parks. Efforts to promote families' awareness of park locations might be warranted to reduce perceived proximity barriers. PMID- 27775480 TI - How Self-Objectification Impacts Physical Activity Among Adolescent Girls in Costa Rica. AB - BACKGROUND: In Latin America, more than 80% of adolescent girls are physically inactive. Inactivity may be reinforced by female stereotypes and objectification in the Latin American sociocultural context. METHODS: We examined the influence of objectification on the adoption of an active lifestyle among 192 adolescents (14 and 17 years old) from urban and rural areas in Costa Rica. Analyses of 48 focus-groups sessions were grounded in Objectification Theory. RESULTS: Vigorous exercises were gender-typed as masculine while girls had to maintain an aesthetic appearance at all times. Adolescents described how girls were anxious around the prospect of being shamed and sexually objectified during exercises. This contributed to a decrease in girls' desire to engage in physical activities. Among males, there is also a budding tolerance of female participation in vigorous sports, as long as girls maintained a feminine stereotype outside their participation. CONCLUSION: Self-objectification influenced Costa Rican adolescent girls' decisions to participate in physical activities. Interventions may include: procuring safe environments for physical activity where girls are protected from fear of ridicule and objectification; sensitizing boys about girl objectification and fostering the adoption of a modern positive masculine and female identities to encourage girls' participation in sports. PMID- 27775477 TI - RNA modification in Cajal bodies. AB - Aside from nucleoli, Cajal bodies (CBs) are the best-characterized organelles of mammalian cell nuclei. Like nucleoli, CBs concentrate ribonucleoproteins (RNPs), in particular, spliceosomal small nuclear RNPs (snRNPs) and small nucleolar RNPs (snoRNPs). In one of the best-defined functions of CBs, most of the snoRNPs are involved in site-specific modification of snRNAs. The two major modifications are pseudouridylation and 2'-O-methylation that are guided by the box H/ACA and C/D snoRNPs, respectively. This review details the modifications, their function, the mechanism of modification, and the machineries involved. We dissect the different classes of noncoding RNAs that meet in CBs, guides and substrates. Open questions and conundrums, often raised and appearing due to experimental limitations, are pointed out and discussed. The emphasis of the review is on mammalian CBs and their function in modification of noncoding RNAs. PMID- 27775478 TI - Subconcussive Head Impact Exposure and White Matter Tract Changes over a Single Season of Youth Football. AB - Purpose To examine the effects of subconcussive impacts resulting from a single season of youth (age range, 8-13 years) football on changes in specific white matter (WM) tracts as detected with diffusion-tensor imaging in the absence of clinically diagnosed concussions. Materials and Methods Head impact data were recorded by using the Head Impact Telemetry system and quantified as the combined probability risk-weighted cumulative exposure (RWECP). Twenty-five male participants were evaluated for seasonal fractional anisotropy (FA) changes in specific WM tracts: the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus, and superior longitudinal fasciculus (SLF). Fiber tracts were segmented into a central core and two fiber terminals. The relationship between seasonal FA change in the whole fiber, central core, and the fiber terminals with RWECP was also investigated. Linear regression analysis was conducted to determine the association between RWECP and change in fiber tract FA during the season. Results There were statistically significant linear relationships between RWEcp and decreased FA in the whole (R2 = 0.433; P = .003), core (R2 = 0.3649; P = .007), and terminals (R2 = 0.5666; P < .001) of left IFOF. A trend toward statistical significance (P = .08) in right SLF was observed. A statistically significant correlation between decrease in FA of the right SLF terminal and RWECP was also observed (R2 = 0.2893; P = .028). Conclusion This study found a statistically significant relationship between head impact exposure and change of FA fractional anisotropy value of whole, core, and terminals of left IFOF and right SLF's terminals where WM and gray matter intersect, in the absence of a clinically diagnosed concussion. (c) RSNA, 2016. PMID- 27775482 TI - Rapid proportion comparison with spatial arrays of frequently used meaningful visual symbols. AB - It has been shown that when two arrays of Arabic numerals were briefly presented, observers could accurately indicate which array contained the larger number of a target numeral. This study investigated whether this rapid proportion comparison can be extended to other meaningful symbols that share some of notable properties of Arabic numerals. We tested mainly several Japanese Kanji letters, each of which represents a meaning and can work as a word. Using physically identical stimulus sets that could be interpreted as different types of letters, Experiment 1 first confirmed the rapid proportion comparison with Arabic numerals for Japanese participants. Experiment 2 showed that the rapid proportion comparison can be extended to Kanji numerals. Experiment 3 successfully demonstrated that rapid proportion judgments can be found with non-quantitative Kanji letters that are used frequently. Experiment 4 further demonstrated the rapid proportion comparison with frequently used meaningful non-letter symbols (gender icons). The rapid processing cannot be attributed to fluent processing of familiar items, because it was not found with familiar phonograms (Japanese Kana letters). These findings suggest that the rapid proportion comparison can be commonly found with frequently used meaningful symbols, even though their meaning is not relevant to the task. PMID- 27775481 TI - Isolation and RFLP Genotyping of Toxoplasma gondii in Free-Range Chickens (Gallus domesticus) in Grenada, West Indies, Revealed Widespread and Dominance of Clonal Type III Parasites. AB - The objectives of the present cross-sectional study were to isolate and genotype Toxoplasma gondii in free-range chickens from Grenada, West Indies. Using the modified agglutination test, antibodies to T. gondii were found in 39 (26.9%) of 145 free-range chickens with titers of 25 in 7 chickens, 50 in 6 chickens, 100 in 2 chickens, and 200 or higher in 24 chickens. The hearts of the 39 seropositive chickens were bioassayed in mice; viable T. gondii was isolated from 20 and further propagated in cell culture. Genotyping of T. gondii DNA extracted from cell-cultured tachyzoites using the 10 PCR-restriction fragment length polymorphism (RFLP) markers SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico revealed 4 genotypes, including ToxoDB PCR-RFLP no. 2 (Type III), no. 7, no. 13, and no. 259 (new). These results indicated that T. gondii population genetics in free-range chickens seems to be moderately diverse with ToxoDB no. 2 (Type III) as the most frequent (15/20 = 75%) compared to other genotypes in Grenada. PMID- 27775483 TI - Context learning for threat detection. AB - It is hypothesised that threatening stimuli are detected better due to their salience or physical properties. However, these stimuli are typically embedded in a rich context, motivating the question whether threat detection is facilitated via learning of contexts in which threat stimuli appear. To address this question, we presented threatening face targets in new or old spatial configurations consisting of schematic faces and found that detection of threatening targets was faster in old configurations. This indicates that individuals are able to learn regularities within visual contexts and use this contextual information to guide detection of threatening targets. Next, we presented threatening and non-threatening face targets embedded in new or old spatial configurations. Detection of threatening targets was facilitated in old configurations, and this effect was reversed for non-threatening targets. Present findings show that detection of threatening targets is driven not only by stimulus properties as theorised traditionally but also by learning of contexts in which threatening stimuli appear. Further, results show that context learning for threatening targets obstructs context learning for non-threatening targets. Overall, in addition to typically emphasised bottom-up factors, our findings highlight the importance of top-down factors such as context and learning in detection of salient, threatening stimuli. PMID- 27775484 TI - Levels and Patterns of Objectively Measured Physical Activity and Sedentary Time in 4-Year-Old Swedish Children. AB - BACKGROUND: Levels of physical activity (PA) affect health already at 4 years of age. The aims of this study were to describe levels and patterns of PA and sedentary time (ST) in a sample of 4-year-old Swedish children and to assess the number of children achieving PA guidelines throughout the week. METHODS: Data from 540 4-year-old children enrolled in the population-based PRIMROSE trial was used. PA was measured for a period of 1 week by the Actigraph GT3X+ accelerometer. Average PA, time spent in light PA, moderate-to-vigorous PA (MVPA) and ST were assessed. RESULTS: On average children spent 6.7% of the day in MVPA and 45% of the day being sedentary and 33% (n = 178) of the children met the PA guidelines of 60 minutes of MVPA per day. Boys spent 56.8 (SD 21.8) minutes/day in MVPA, while girls spent 43.0 (SD 18.1) minutes/day in MVPA (P < .001). CONCLUSIONS: Four-year-old children spent almost half of the day being sedentary and only one-third meet the recommended PA guidelines. This finding is alarming as higher levels of PA, already at 4 years of age, seem to reduce the risk of childhood obesity and provides long-term health benefits. PMID- 27775485 TI - Computerized tabletop games as a form of a video game training for old-old. AB - This research aimed at investigating the utility of a computerized version of a cognitively stimulating activity as a video game intervention for elderly. The study focused on the effect of a 6-week extensive practice intervention on aspects of cognitive functioning (vigilance, working memory (WM), inhibition, reasoning) of old-old participants (N = 29), randomly assigned to trained or active control group. The difference between groups was in the content of the extended video game practice - cognitively complex card game for trained and computerized version of a simple dice-game of chance for control participants. A pretest, posttest and a 4-month follow-up measurement was conducted. Results revealed improvements in both groups, except for improved reasoning found only in trained participants. These results suggest that: (1) improvements are dependent on the complexity of the program, (2) cognitively stimulating activity are a valid training procedure for old-old, (3) novelty of computer use is an important factor in determining training efficacy. PMID- 27775486 TI - Role of grapevine vegetative expression on Aspergillus spp. incidence and OTA accumulation in wines produced in a temperate humid climate. AB - Aspergillus spp. and Penicillium spp. are the main producers of ochratoxin A (OTA), a mycotoxin responsible for fatal human diseases. Some authorities have established a maximum of 2 MUg/L of OTA in wine. Although the incidence and occurrence of OTA in grapes and wine is highly related to climate conditions, as has been extensively documented, there is no conclusive information on the effects of cultivation systems on the presence of OTA. This study focuses on determining the effect of the trellis system, planting density and cordon height on plant microclimate and thus on Aspergillus spp. contamination and OTA production in Tannat wines in Southern Uruguay. Two experiments were conducted during the 2010-2011 growing season: (1) a strip split plot design with five replicates and two cordon heights (CH) (0.5 m and 1.0 m above the soil) were compared in two planting densities (PD) (0.8 and 1.5 m between plants); (2) a randomised complete block design, vertical shoot positioning (VSP) versus Lyra trellis systems were evaluated. The results suggest that, even the macro- and micro-climate growing conditions play an important part in Aspergillus developing on grapes. Agronomical practices also have an undoubted impact on the risk and control of OTA accumulation in wine. PMID- 27775488 TI - Fluctuations in negative emotions predict binge eating both in women and men: An experience sampling study. AB - This study investigated the associations between emotional fluctuations and emotion regulation difficulties in predicting binge eating and overeating episodes using the experience sampling method among 97 women and 61 men. Among women, fluctuations in negative emotion, emotion regulation difficulties, restrained eating, and the interaction of negative emotion fluctuations and emotion regulation difficulties predicted binge eating. Among men, trait impulsivity and fluctuations in negative emotion predicted binge eating. However, overeating did not associate with aforementioned aspects. Results suggest that fluctuations in negative emotions should be studied in the context of emotion regulation difficulties. PMID- 27775487 TI - Raising awareness of research evidence among health professionals delivering dementia care: Are knowledge translation workshops useful? AB - Providing information about the latest research via educational sessions to health professionals caring for people with dementia may be insufficient to drive change. This project explored self-reported impacts on practice change of adding information about knowledge translation (KT) to a national dementia education program. Six national workshop days were held. Each provided the option of participating in a Principles of KT and innovation implementation seminar in addition to a clinical topic update (sexualities and dementia, or managing behavioral and psychological symptoms of dementia). Six months postworkshop, 321 participants were invited to complete a research utilization survey. Seventy-five responded. KT seminar participants were more likely to report instrumental outcomes (e.g. changed policies, procedures) than those who did not participate in the KT seminar. Including KT information in educational sessions for health professionals may increase the likelihood of practice change in the field of dementia care and warrants further research. PMID- 27775490 TI - Neuroticism and clinical course of weight restoration in a meal-based, rapid weight gain, inpatient-partial hospitalization program for eating disorders. AB - We evaluated the impact of personality on weight restoration in 211 underweight (BMI <= 19 kg/m2) females admitted to an inpatient-partial hospitalization program for eating disorders. Symptomatology and personality were assessed by questionnaires, and clinical and demographic variables were assessed by chart review. Neuroticism, a personality trait associated with reactivity to stress, was correlated with higher symptomatology, chronicity, length of stay, and income source. Contrary to our hypothesis, neuroticism was positively associated with weight restoration. Length of stay mediated this relationship such that longer length of stay in patients with high neuroticism explained their higher likelihood of weight restoration prior to program discharge. Higher neuroticism is therefore associated with better weight restoration outcomes but may also indicate greater difficulty transitioning out of intensive treatment. PMID- 27775489 TI - Head injury screening and intimate partner violence: A brief report. AB - OBJECTIVE: Although the importance of traumatic brain injury has gained public attention in recent years, relatively little attention has been paid to head injuries among women who have experienced intimate partner violence (IPV). The present study screened for lifetime exposure to mild traumatic brain injuries (mTBIs) among a sample of women who had experienced recent IPV (median days since target incident = 26). METHOD: Participants included ethnically diverse women whose IPV experiences were reported to law enforcement. Women (n = 225) were asked about injuries to the head sustained during the target IPV incident as well as over the lifetime, and related symptoms. RESULTS: The vast majority of women (80%) reported a lifetime head injury. More than half (56%) screened positive for mTBI, defined as at least one instance in which they experienced a change in consciousness or a period of being dazed and confused as a result of a head injury. A minority of women (13%) reported injuries to the head during the target IPV incident. Most women who had experienced a lifetime head injury reported frequent and current cognitive difficulties. CONCLUSION: These findings highlight the importance of assessing head injuries and related symptoms among women who have experienced IPV, pointing to important implications for policy and practice. PMID- 27775491 TI - A multifactorial study on duration of temporary disabilities in Spain. AB - The extreme variability of temporary disability duration has a deep effect in public health. We tried to understand what factors duration of disability depends on. Through cohort study with data of temporary disabilities collected by Ibermutuamur from 2008 to 2012, we used statistical multivariate methods. The most reliable and convenient algorithm to predict duration was a categorical classification tree that distinguished between brief and long disabilities, taking into account both medical-biological and socioeconomic factors. The influence of socioeconomic factors in the disability process made numeric predictive models not accurate enough. Some of these socioeconomic factors were isolated and their influences were quantified. In particular, the one we named factor unemployment could explain a huge increase in duration for certain common diagnoses such as anxiety, low back pain, headache, and depression. PMID- 27775492 TI - Validity and reliability of the Turkish version of the DSM-5 Dissociative Symptoms Severity Scale-Child Form. AB - The goal of this study was to assess the validity and reliability of the Turkish version of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) Dissociative Symptoms Severity Scale-Child Form. The scale was prepared by translating and then back-translating the DSM-5 Dissociative Symptoms Severity Scale. The study groups included one group of 30 patients diagnosed with posttraumatic stress disorder who were treated in a child and adolescent psychiatry unit and another group of 83 healthy volunteers from middle and high schools in the community. For assessment, the Adolescent Dissociative Experiences Scale (ADES) was used in addition to the DSM-5 Dissociative Symptoms Severity Scale. Regarding the reliability of the DSM-5 Dissociative Symptoms Severity Scale, Cronbach's alpha was .824 and item-total score correlation coefficients were between .464 and .648. The test-retest correlation coefficient was calculated to be r = .784. In terms of construct validity, one factor accounted for 45.2% of the variance. Furthermore, in terms of concurrent validity, the scale showed a high correlation with the ADES. In conclusion, the Turkish version of the DSM-5 Dissociative Symptoms Severity Scale-Child Form is a valid and reliable tool for both clinical practice and research. PMID- 27775493 TI - Letter to the Editor: Author's Response. PMID- 27775494 TI - Letter to the Editor: Re: Comparative Analysis of Calcium-Binding Myeloid-Related Protein-8/14 in Saliva and Serum of Patients With Periodontitis and Healthy Individuals. PMID- 27775495 TI - Letter to the Editor: Authors' Response. PMID- 27775497 TI - List of referees - 2016. PMID- 27775496 TI - Letter to the Editor: Re: Comparison of Clinical and Radiographic Periodontal Status Between Habitual Water-Pipe Smokers and Cigarette Smokers. PMID- 27775498 TI - Virulence and Molecular Characterization of Experimental Isolates of the Stripe Rust Pathogen (Puccinia striiformis) Indicate Somatic Recombination. AB - Puccinia striiformis causes stripe rust on wheat, barley, and grasses. Natural population studies have indicated that somatic recombination plays a possible role in P. striiformis variation. To determine whether somatic recombination can occur, susceptible wheat or barley plants were inoculated with mixed urediniospores of paired isolates of P. striiformis. Progeny isolates were selected by passing through a series of inoculations of wheat or barley genotypes. Potential recombinant isolates were compared with the parental isolates on the set of 18 wheat or 12 barley genotypes that are used to differentiate races of P. striiformis f. sp. tritici (the wheat stripe rust pathogen) and P. striiformis f. sp. hordei (the barley stripe rust pathogen), respectively, for virulence changes. They were also tested with 51 simple sequence repeat and 90 single-nucleotide polymorphism markers for genotype changes. From 68 possible recombinant isolates obtained from nine combinations of isolates based on virulence tests, 66 were proven to be recombinant isolates by molecular markers. Various types of recombinants were determined, including lost virulence from both virulent parental isolates, gained virulence from both avirulent isolates, combined virulences from both parents, and inherited virulence from one parent and avirulence from another. Marker data indicate that most of the recombinants were produced through chromosome reassortment and crossover after the hybridization of two parental isolates. The results demonstrate that somatic recombination is a mechanism by which new variants can be generated in P. striiformis. PMID- 27775499 TI - Evaluation of Resistance to Phytophthora sojae in Soybean Mini Core Collections Using an Improved Assay System. AB - Stem and root rot disease caused by Phytophthora sojae is devastating to soybean crops worldwide. Developing host resistance to P. sojae, considered the most effective and stable means to control this disease, is partly hampered by limited germplasm resources. In this study, we first modified conventional methods for a P. sojae resistance assay to a simpler and more cost-effective version, in which the P. sojae inoculum was mixed into the soil and the resistance was evaluated by survival rate (%) of soybean seedlings. This rating had significant correlations (P < 0.01) with the reduction in root fresh weight and the visual root rot severity. Applying this method to evaluate P. sojae resistance in soybean mini core collections comprising either 79 accessions originating from Japan (JMC) or 80 accessions collected around the world (WMC) revealed a wide variation in resistance among the individual varieties. In total, 38 accessions from the JMC and 41 from the WMC exhibited resistance or moderate resistance to P. sojae isolate N1 (with virulence to Rps1b, 3c, 4, 5, and 6), with >=50% survival. Of these, 26 from the JMC and 29 from the WMC showed at least moderate resistance to P. sojae isolate HR1 (vir Rps1a-c, 1k, 2, 3a-c, 4-6, and 8). Additionally, 24 WCS accessions, in contrast to only 6 from the JMC, exhibited 100% survival after being challenged with both the N1 and HR1 isolates, suggesting a biogeographical difference between the two collections. We further verified two JMC varieties, Daizu and Amagi zairai 90D, for their resistance to an additional four P. sojae isolates (60 to 100% survival), which may provide new and valuable genetic sources for P. sojae resistance breeding in soybean. PMID- 27775500 TI - Molecular Mapping of Stem Rust Resistance Loci Effective Against the Ug99 Race Group of the Stem Rust Pathogen and Validation of a Single Nucleotide Polymorphism Marker Linked to Stem Rust Resistance Gene Sr28. AB - Wheat landrace PI 177906 has seedling resistance to stem rust caused by Puccinia graminis f. sp. tritici races TTKSK, TTKST, and BCCBC and field resistance to the Ug99 race group. Parents, 140 recombinant inbred lines, and 138 double haploid (DH) lines were evaluated for seedling resistance to races TTKSK and BCCBC. Parents and the DH population were evaluated for field resistance to Ug99 in Kenya. The 90K wheat single nucleotide polymorphism (SNP) genotyping platform was used to genotype the parents and populations. Goodness-of-fit tests indicated that two dominant genes in PI 177906 conditioned seedling resistance to TTKSK. Two major loci for seedling resistance were consistently mapped to the chromosome arms 2BL and 6DS. The BCCBC resistance was mapped to the same location on 2BL as the TTKSK resistance. Using field data from the three seasons, two major QTL were consistently detected at the same regions on 2BL and 6DS. Based on the mapping result, race specificity, and the infection type observed in PI 177906, the TTKSK resistance on 2BL is likely due to Sr28. One SNP marker (KASP_IWB1208) was found to be predictive for the presence of the TTKSK resistance locus on 2BL and Sr28. PMID- 27775501 TI - Fine-Scale Genetic Structure and Reproductive Biology of the Blueberry Pathogen Monilinia vaccinii-corymbosi. AB - The fungus Monilinia vaccinii-corymbosi, a pathogen of Vaccinium spp., requires asexual and sexual spore production to complete its life cycle. A recent study found population structuring of M. vaccinii-corymbosi over a broad spatial scale in the United States. In this study, we examined fine-scale genetic structuring, temporal dynamics, and reproductive biology within a 125-by-132-m blueberry plot from 2010 to 2012. In total, 395 isolates of M. vaccinii-corymbosi were sampled from infected shoots and fruit to examine their multilocus haplotype (MLH) using microsatellite markers. The MLH of 190 single-ascospore isolates from 21 apothecia was also determined. Little to no genetic differentiation and unrestricted gene flow were detected among four sampled time points and between infected tissue types. Discriminant analysis of principal components suggested genetic structuring within the field, with at least K = 3 genetically distinct clusters maintained over four sampled time points. Single-ascospore progeny from eight apothecia had identical MLH and at least two distinct MLH were detected from 13 apothecia. Tests for linkage disequilibrium suggested that genetically diverse ascospore progeny were the product of recombination. This study supports the idea that the fine-scale dynamics of M. vaccinii-corymbosi may be complex, with genetic structuring, inbreeding, and outcrossing detected in the study area. PMID- 27775502 TI - A study on detection of glucose concentration using changes in color coordinates. AB - Glucose concentration is closely related to the metabolic activity of cells and it is the most important substance as the energy source of a living body which plays an important role in the human body. This paper proposes an optical method that can measure the concentration of glucose. The change in glucose concentration was observed by using CIE diagram, and wavelength and purity values were detected. Also, even small changes in glucose concentration can be evaluated through mathematical modeling. This system is simple, economical, and capable of quantifying optical signals with numerical values for glucose sensing. This method can be applicable to the clinical field that examines diabetes mellitus or metabolic syndrome. PMID- 27775504 TI - Red Cells - Aging Gracefully in the Blood Bank. PMID- 27775503 TI - Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion. AB - BACKGROUND: Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients. METHODS: In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type. RESULTS: From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer). CONCLUSIONS: Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744 .). PMID- 27775506 TI - Reflections. PMID- 27775505 TI - Insights Into French Emergency Planning, Response, and Resilience Procedures From a Hospital Managerial Perspective Following the Paris Terrorist Attacks of Friday, November 13, 2015. AB - On Friday, November 13, 2015, Paris was subjected to a multiple terrorist attack that caused widespread carnage. Although French emergency planning, response, and resilience procedures (Plan Blanc) anticipated crisis management of a major incident, these had to be adapted to the local context of Pitie-Salpetriere University Teaching Hospital. Health care workers had undergone Plan Blanc training and exercises and it was fortunate that such a drill had occurred on the morning of the attack. The procedures were observed to work well because this type of eventuality had been fully anticipated, and staff performance exceeded expectations owing to prior in-depth training and preparations. Staff performance was also facilitated by overwhelming staff solidarity and professionalism, ensuring the smooth running of crisis management and improving victim survival rates. Although lessons learned are ongoing, an initial debriefing of managers found organizational improvements to be made. These included improvements to the activation of Plan Blanc and how staff were alerted, bed management, emergency morgue facilities, and public relations. In conclusion, our preparations for an eventual terrorist attack on this unprecedented scale ensured a successful medical response. Even though anticipating the unthinkable is difficult, contingency plans are being made to face other possible terrorist threats including chemical or biological agents. (Disaster Med Public Health Preparedness. 2016;page 1 of 6). PMID- 27775507 TI - Evidence-Based Management Of Potassium Disorders In The Emergency Department. AB - Hypokalemia and hyperkalemia are the most common electrolyte disorders managed in the emergency department. The diagnosis of these potentially life-threatening disorders is challenging due to the often vague symptomatology a patient may express, and treatment options may be based upon very little data due to the time it may take for laboratory values to return. This review examines the most current evidence with regard to the pathophysiology, diagnosis, and management of potassium disorders. In this review, classic paradigms, such as the use of sodium polystyrene and the routine measurement of serum magnesium, are tested, and an algorithm for the treatment of potassium disorders is discussed. PMID- 27775508 TI - Correction: Cell type-specific long-range connections of basal forebrain circuit. PMID- 27775509 TI - Automatic Identification of Pathology-Distorted Retinal Layer Boundaries Using SD OCT Imaging. AB - OBJECTIVE: We propose an effective automatic method for identification of four retinal layer boundaries from the spectral domain optical coherence tomography images in the presence and absence of pathologies and morphological changes due to disease. METHODS: The approach first finds an approximate location of three reference layers and then uses these to bound the search space for the actual layers, which is achieved by modeling the problem as a graph and applying Dijkstra's shortest path algorithm. The edge weight between nodes is determined using pixel distance, slope similarity to a reference, and nonassociativity of the layers, which is designed to overcome the distorting effects that pathology can play in the boundary determination. RESULTS: The accuracy of our method was evaluated on three different datasets. It outperforms the current five state-of the-art methods. On average, the mean and standard deviation of the root-mean square error in the form of mean +/- standard deviation in pixels for our method is 1.57 +/- 0.69, which is lower than compared to the existing top five methods of 16.17 +/- 22.64, 6.66 +/- 9.11, 5.70 +/- 10.54, 3.69 +/- 2.04, and 2.29 +/- 1.54. CONCLUSION: Our method is highly accurate, robust, reliable, and consistent. This identification can enable to quantify the biomarkers of the retina in large-scale study for assessing, monitoring disease progression, as well as early detection of retinal diseases. SIGNIFICANCE: Identification of these boundaries can help to determine the loss of neuroretinal cells or layers and the presence of retinal pathology, which can be used as features for the automatic determination of the stages of retinal diseases. PMID- 27775513 TI - Smoothing Splines on Unit Ball Domains with Application to Corneal Topography. AB - Optical coherence tomography (OCT) is a non-invasive imaging technique used to study and understand internal structures of biological tissues such as the anterior chamber of the human eye. An interesting problem is the reconstruction of the shape of the biological tissue from OCT images, that is not only a good fit of the data but also respects the smoothness properties observed in the images. A similar problem arises in Magnetic Resonance Imaging (MRI). We cast the problem as a penalized weighted least squares regression with a penalty on the magnitude of the second derivative (Laplacian) of the surface. We present a novel algorithm to construct the Kimeldorf-Wahba solution for unit ball domains. Our method unifies the ad-hoc approaches currently in the literature. Application of the theory to data from an anterior segment optical coherence tomographer is presented. A detailed comparison of the reconstructed surface using different approaches is presented. PMID- 27775510 TI - Glucose Monitoring in Individuals With Diabetes Using a Long-Term Implanted Sensor/Telemetry System and Model. AB - OBJECTIVE: The use of a fully implanted first-generation prototype sensor/telemetry system is described for long-term monitoring of subcutaneous tissue glucose in a small cohort of people with diabetes. METHODS: Sensors are based on a membrane containing immobilized glucose oxidase and catalase coupled to oxygen electrodes and a telemetry system, integrated as an implant. The devices remained implanted for up to 180 days, with signals transmitted every 2 min to external receivers. RESULTS: The data include signal recordings from glucose clamps and spontaneous glucose excursions, matched, respectively, to reference blood glucose and finger-stick values. The sensor signals indicate dynamic tissue glucose, for which there is no independent standard, and a model describing the relationship between blood glucose and the signal is, therefore, included. The values of all model parameters have been estimated, including the permeability of adjacent tissues to glucose, and equated to conventional mass transfer parameters. As a group, the sensor calibration varied randomly at an average rate of -2.6%/week. Statistical correlation indicated strong association between the sensor signals and reference glucose values. CONCLUSION: Continuous long-term glucose monitoring in individuals with diabetes is feasible with this system. SIGNIFICANCE: All therapies for diabetes are based on glucose control, and therefore, require glucose monitoring. This fully implanted long-term sensor/telemetry system may facilitate a new era of management of the disease. PMID- 27775515 TI - Adaptive Greedy Dictionary Selection for Web Media Summarization. AB - Initializing an effective dictionary is an indispensable step for sparse representation. In this paper, we focus on the dictionary selection problem with the objective to select a compact subset of basis from original training data instead of learning a new dictionary matrix as dictionary learning models do. We first design a new dictionary selection model via l2,0 norm. For model optimization, we propose two methods: one is the standard forward-backward greedy algorithm, which is not suitable for large-scale problems; the other is based on the gradient cues at each forward iteration and speeds up the process dramatically. In comparison with the state-of-the-art dictionary selection models, our model is not only more effective and efficient, but also can control the sparsity. To evaluate the performance of our new model, we select two practical web media summarization problems: 1) we build a new data set consisting of around 500 users, 3000 albums, and 1 million images, and achieve effective assisted albuming based on our model and 2) by formulating the video summarization problem as a dictionary selection issue, we employ our model to extract keyframes from a video sequence in a more flexible way. Generally, our model outperforms the state-of-the-art methods in both these two tasks. PMID- 27775516 TI - Person Re-Identification via Distance Metric Learning With Latent Variables. AB - In this paper, we propose an effective person re-identification method with latent variables, which represents a pedestrian as the mixture of a holistic model and a number of flexible models. Three types of latent variables are introduced to model uncertain factors in the re-identification problem, including vertical misalignments, horizontal misalignments and leg posture variations. The distance between two pedestrians can be determined by minimizing a given distance function with respect to latent variables, and then be used to conduct the re identification task. In addition, we develop a latent metric learning method for learning the effective metric matrix, which can be solved via an iterative manner: once latent information is specified, the metric matrix can be obtained based on some typical metric learning methods; with the computed metric matrix, the latent variables can be determined by searching the state space exhaustively. Finally, extensive experiments are conducted on seven databases to evaluate the proposed method. The experimental results demonstrate that our method achieves better performance than other competing algorithms. PMID- 27775517 TI - Sequential Discrete Hashing for Scalable Cross-Modality Similarity Retrieval. AB - With the dramatic development of the Internet, how to exploit large-scale retrieval techniques for multimodal web data has become one of the most popular but challenging problems in computer vision and multimedia. Recently, hashing methods are used for fast nearest neighbor search in large-scale data spaces, by embedding high-dimensional feature descriptors into a similarity preserving Hamming space with a low dimension. Inspired by this, in this paper, we introduce a novel supervised cross-modality hashing framework, which can generate unified binary codes for instances represented in different modalities. Particularly, in the learning phase, each bit of a code can be sequentially learned with a discrete optimization scheme that jointly minimizes its empirical loss based on a boosting strategy. In a bitwise manner, hash functions are then learned for each modality, mapping the corresponding representations into unified hash codes. We regard this approach as cross-modality sequential discrete hashing (CSDH), which can effectively reduce the quantization errors arisen in the oversimplified rounding-off step and thus lead to high-quality binary codes. In the test phase, a simple fusion scheme is utilized to generate a unified hash code for final retrieval by merging the predicted hashing results of an unseen instance from different modalities. The proposed CSDH has been systematically evaluated on three standard data sets: Wiki, MIRFlickr, and NUS-WIDE, and the results show that our method significantly outperforms the state-of-the-art multimodality hashing techniques. PMID- 27775519 TI - Single Image Super-Resolution via Adaptive High-Dimensional Non-Local Total Variation and Adaptive Geometric Feature. AB - Single image super-resolution (SR) is very important in many computer vision systems. However, as a highly ill-posed problem, its performance mainly relies on the prior knowledge. Among these priors, the non-local total variation (NLTV) prior is very popular and has been thoroughly studied in recent years. Nevertheless, technical challenges remain. Because NLTV only exploits a fixed non shifted target patch in the patch search process, a lack of similar patches is inevitable in some cases. Thus, the non-local similarity cannot be fully characterized, and the effectiveness of NLTV cannot be ensured. Based on the motivation that more accurate non-local similar patches can be found by using shifted target patches, a novel multishifted similar-patch search (MSPS) strategy is proposed. With this strategy, NLTV is extended as a newly proposed super-high dimensional NLTV (SHNLTV) prior to fully exploit the underlying non-local similarity. However, as SHNLTV is very high-dimensional, applying it directly to SR is very difficult. To solve this problem, a novel statistics-based dimension reduction strategy is proposed and then applied to SHNLTV. Thus, SHNLTV becomes a more computationally effective prior that we call adaptive high-dimensional non local total variation (AHNLTV). In AHNLTV, a novel joint weight strategy that fully exploits the potential of the MSPS-based non-local similarity is proposed. To further boost the performance of AHNLTV, the adaptive geometric duality (AGD) prior is also incorporated. Finally, an efficient split Bregman iteration-based algorithm is developed to solve the AHNLTV-AGD-driven minimization problem. Extensive experiments validate the proposed method achieves better results than many state-of-the-art SR methods in terms of both objective and subjective qualities. PMID- 27775518 TI - Depth-Guided Disocclusion Inpainting of Synthesized RGB-D Images. AB - We propose to tackle the problem of RGB-D image disocclusion inpainting when synthesizing new views of a scene by changing its viewpoint. Indeed, such a process creates holes both in depth and color images. First, we propose a novel algorithm to perform depth-map disocclusion inpainting. Our intuitive approach works particularly well for recovering the lost structures of the objects and to inpaint the depth-map in a geometrically plausible manner. Then, we propose a depth-guided patch-based inpainting method to fill-in the color image. Depth information coming from the reconstructed depth-map is added to each key step of the classical patch-based algorithm from Criminisi et al. in an intuitive manner. Relevant comparisons to the state-of-the-art inpainting methods for the disocclusion inpainting of both depth and color images are provided and illustrate the effectiveness of our proposed algorithms. PMID- 27775521 TI - Augmented Reality Marker Hiding with Texture Deformation. AB - Augmented reality (AR) marker hiding is a technique to visually remove AR markers in a real-time video stream. A conventional approach transforms a background image with a homography matrix calculated on the basis of a camera pose and overlays the transformed image on an AR marker region in a real-time frame, assuming that the AR marker is on a planar surface. However, this approach may cause discontinuities in textures around the boundary between the marker and its surrounding area when the planar surface assumption is not satisfied. This paper proposes a method for AR marker hiding without discontinuities around texture boundaries even under nonplanar background geometry without measuring it. For doing this, our method estimates the dense motion in the marker's background by analyzing the motion of sparse feature points around it, together with a smooth motion assumption, and deforms the background image according to it. Our experiments demonstrate the effectiveness of the proposed method in various environments with different background geometries and textures. PMID- 27775522 TI - An Exploratory Study of Word-Scale Graphics in Data-Rich Text Documents. AB - We contribute an investigation of the design and function of word-scale graphics and visualizations embedded in text documents. Word-scale graphics include both data-driven representations such as word-scale visualizations and sparklines, and non-data-driven visual marks. Their design, function, and use has so far received little research attention. We present the results of an open ended exploratory study with nine graphic designers. The study resulted in a rich collection of different types of graphics, data provenance, and relationships between text, graphics, and data. Based on this corpus, we present a systematic overview of word-scale graphic designs, and examine how designers used them. We also discuss the designers' goals in creating their graphics, and characterize how they used word-scale graphics to visualize data, add emphasis, and create alternative narratives. Building on these examples, we discuss implications for the design of authoring tools for word-scale graphics and visualizations, and explore how new authoring environments could make it easier for designers to integrate them into documents. PMID- 27775523 TI - Example-Based Subspace Stress Analysis for Interactive Shape Design. AB - Stress analysis is a crucial tool for designing structurally sound shapes. However, the expensive computational cost has hampered its use in interactive shape editing tasks. We augment the existing example-based shape editing tools, and propose a fast subspace stress analysis method to enable stress-aware shape editing. In particular, we construct a reduced stress basis from a small set of shape exemplars and possible external forces. This stress basis is automatically adapted to the current user edited shape on the fly, and thereby offers reliable stress estimation. We then introduce a new finite element discretization scheme to use the reduced basis for fast stress analysis. Our method runs up to two orders of magnitude faster than the full-space finite element analysis, with average L2 estimation errors less than 2 percent and maximum L2 errors less than 6 percent. Furthermore, we build an interactive stress-aware shape editing tool to demonstrate its performance in practice. PMID- 27775524 TI - Homography Propagation and Optimization for Wide-Baseline Street Image Interpolation. AB - Wide-baseline street image interpolation is useful but very challenging. Existing approaches either rely on heavyweight 3D reconstruction or computationally intensive deep networks. We present a lightweight and efficient method which uses simple homography computing and refining operators to estimate piecewise smooth homographies between input views. To achieve the goal, we show how to combine homography fitting and homography propagation together based on reliable and unreliable superpixel discrimination. Such a combination, other than using homography fitting only, dramatically increases the accuracy and robustness of the estimated homographies. Then, we integrate the concepts of homography and mesh warping, and propose a novel homography-constrained warping formulation which enforces smoothness between neighboring homographies by utilizing the first order continuity of the warped mesh. This further eliminates small artifacts of overlapping, stretching, etc. The proposed method is lightweight and flexible, allows wide-baseline interpolation. It improves the state of the art and demonstrates that homography computation suffices for interpolation. Experiments on city and rural datasets validate the efficiency and effectiveness of our method. PMID- 27775525 TI - Bayesian Nonnegative CP Decomposition-Based Feature Extraction Algorithm for Drowsiness Detection. AB - Daytime short nap involves physiological processes, such as alertness, drowsiness and sleep. The study of the relationship between drowsiness and nap based on physiological signals is a great way to have a better understanding of the periodical rhymes of physiological states. A model of Bayesian nonnegative CP decomposition (BNCPD) was proposed to extract common multiway features from the group-level electroencephalogram (EEG) signals. As an extension of the nonnegative CP decomposition, the BNCPD model involves prior distributions of factor matrices, while the underlying CP rank could be determined automatically based on a Bayesian nonparametric approach. In terms of computational speed, variational inference was applied to approximate the posterior distributions of unknowns. Extensive simulations on the synthetic data illustrated the capability of our model to recover the true CP rank. As a real-world application, the performance of drowsiness detection during daytime short nap by using the BNCPD based features was compared with that of other traditional feature extraction methods. Experimental results indicated that the BNCPD model outperformed other methods for feature extraction in terms of two evaluation metrics, as well as different parameter settings. Our approach is likely to be a useful tool for automatic CP rank determination and offering a plausible multiway physiological information of individual states. PMID- 27775526 TI - EEG-Based Prediction of Epileptic Seizures Using Phase Synchronization Elicited from Noise-Assisted Multivariate Empirical Mode Decomposition. AB - In this study, we examined the phase locking value (PLV) for seizure prediction, particularly, in the gamma frequency band. We prepared simulation data and 65 clinical cases of seizure. In addition, various filtering algorithms including bandpass filtering, empirical mode decomposition, multivariate empirical mode decomposition and noise-assisted multivariate empirical mode decomposition (NA MEMD) were used to decompose spectral components from the data. Moreover, in the case of clinical data, the PLVs were used to classify between interictal and preictal stages using a support vector machine. The highest PLV was achieved with NA-MEMD with 0-dB white noise algorithm (0.9988), which exhibited statistically significant differences compared to other filtering algorithms. Moreover, the classification rate was the highest for the NA-MEMD with 0-dB algorithm (83.17%). In terms of frequency components, examining the gamma band resulted in the highest classification rates for all algorithms, compared to other frequency bands such as theta, alpha, and beta bands. We found that PLVs calculated with the NA-MEMD algorithm could be used as a potential biological marker for seizure prediction. Moreover, the gamma frequency band was useful for discriminating between interictal and preictal stages. PMID- 27775527 TI - Identification of a Time-Varying, Box-Jenkins Model of Intrinsic Joint Compliance. AB - The mechanical properties of a joint are determined by the combination of intrinsic and reflex mechanisms. However, in some situations the reflex contributions are small so that intrinsic mechanisms play the dominant role in the control of posture and movement. The intrinsic mechanisms, characterized by the joint compliance, can be described well by a second order, linear model for small perturbations around an operating point defined by mean position and torque. However, the compliance parameters depend strongly on the operating point. Thus, for functional activities, such as walking, where position and torque undergo large, rapid changes, the joint compliance will also present large, fast changes and so will appear to be Time-Varying (TV). Therefore, a TV system identification algorithm must be used to characterize these changes. This paper introduces a novel TV system identification algorithm that achieves this. The method extends an instrumental-variable based algorithm for the identification of linear, TV, parametric, Box-Jenkins models to use periodic data. Simulation studies demonstrate that the new algorithm accurately tracks the changes in intrinsic joint compliance expected during walking. Moreover, the method performs well with the complex noise encountered in practice. Consequently the new method should be a valuable tool for the study of joint mechanics during functional activities. PMID- 27775528 TI - Characterization of Drug Effect on Leukemia Cells Through Single Cell Assay With Optical Tweezers and Dielectrophoresis. AB - One of the greatest challenges in acute myeloid leukemia (AML) treatment is preventing relapse. Leukemia cells can hide in bone marrow niche or vascular niche. Hence, many chemical drugs cannot kill these cells. To characterize migration and adhesion properties of leukemia cells in specific niches, CXCR4/SDF 1alpha signal pathway has been widely used for investigation. AMD3100 is treated as one of the most common chemical drugs that can inhibit this signal. In the current study, we particularly investigate the effect of AMD3100 on the adhesion property of leukemia cells on stromal cells by using engineering tools, namely, optical tweezers (OT) and dielectrophoresis (DEP), to probe single cell property. AMD3100 not only inhibits the CXCR4/SDF- 1alpha signal pathway but also reduces gene expression of CXCR4 and VLA-4 on leukemia cells. The drug also softens leukemia cells. This work provides a new way to investigate cell behavior under drug treatment. The use of combined engineering tools will benefit drug discovery and assessment for leukemia treatment. PMID- 27775529 TI - A Biochemical Oscillator Using Excitatory Molecules for Nanonetworks. AB - For nanonetworks to be able to achieve large-scale functionality, such as to respond collectively to a trigger, synchrony between nanomachines is essential. However, to facilitate synchronization, some sort of physical clocking mechanism is required, such as the oscillators driven by auto-inhibitory molecules or by auto-inducing molecules. In this study, taking inspiration from the widely studied biological oscillatory phenomena called Calcium (Ca2+) oscillations, we undertake a different approach to design an oscillator. Our model employs three different types of excitatory molecules that work in tandem to generate oscillatory phenomenon in the concentration levels of the molecule of interest. The main objective of the study is to model a high frequency biochemical oscillator, along with the investigations to identify and determine the parameters that affect the period of the oscillations. The investigations entail and highlight the design of the reserve unit, a reservoir of the molecule of interest, as a key factor in realizing a high frequency stable biochemical oscillator. PMID- 27775530 TI - Modeling Current-Voltage Charateristics of Proteorhodopsin and Bacteriorhodopsin: Towards an Optoelectronics Based on Proteins. AB - Current-voltage characteristics of metal-protein-metal structures made of proteorhodopsin and bacteriorhodopsin are modeled by using a percolation-like approach. Starting from the tertiary structure pertaining to the single protein, an analogous resistance network is created. Charge transfer inside the network is described as a sequential tunneling mechanism and the current is calculated for each value of the given voltage. The theory is validated with available experiments, in dark and light. The role of the tertiary structure of the single protein and of the mechanisms responsible for the photo-activity is discussed. PMID- 27775531 TI - Dielectrophoretic Relay Assisted Molecular Communication for In-Sequence Molecule Delivery. AB - With current research focus to interconnect the molecular communication environment with external environment, it is imperative to design external devices working on molecular communication schemes to be interfaced with in-vivo molecular network. Recently, efforts have been made to integrate molecular communication with Lab-on-chip (LOC); one of the techniques used in LOC for manipulation and transportation of molecules is Dielctrophoresis (DEP). We propose the use of DEP in molecular communication to maintain in-sequence delivery of molecules. DEP planar electrodes are modeled as relays used in telecommunications. We describe the theoretical system model and analyze the effect of introducing DEP relays in diffusive channel in terms of probability of in-sequence delivery of molecules. Information rate of DEP-based channel is analytically obtained for in-sequence delivery. The numerical results obtained show that the information rate for in-sequence delivery of molecules through diffusive channel increases by 26% if DEP relays are used in the channel. Though the system is sensitive to noise variance, incorporation of DEP relay results in a substantial improvement in the capacity of the channel. PMID- 27775534 TI - A Global Network Alignment Method Using Discrete Particle Swarm Optimization. AB - Molecular interactions data increase exponentially with the advance of biotechnology. This makes it possible and necessary to comparatively analyze the different data at a network level. Global network alignment is an important network comparison approach to identify conserved subnetworks and get insight into evolutionary relationship across species. Network alignment which is analogous to subgraph isomorphism is known to be an NP-hard problem. In this paper, we introduce a novel heuristic Particle-Swarm-Optimization based Network Aligner (PSONA), which optimizes a weighted global alignment model considering both protein sequence similarity and interaction conservations. The particle statuses and status updating rules are redefined in a discrete form by using permutation. A seed-and-extend strategy is employed to guide the searching for the superior alignment. The proposed initialization method "seeds" matches with high sequence similarity into the alignment, which guarantees the functional coherence of the mapping nodes. A greedy local search method is designed as the "extension" procedure to iteratively optimize the edge conservations. PSONA is compared with several state-of-art methods on ten network pairs combined by five species. The experimental results demonstrate that the proposed aligner can map the proteins with high functional coherence and can be used as a booster to effectively refine the well-studied aligners. PMID- 27775532 TI - Influence of Iron-Doped Apatite Nanoparticles on Viral Infection Examined in Bacterial Versus Algal Systems. AB - The Centers for Disease Control and Prevention have estimated that each year, two million people in the United States become infected with antibiotic-resistant bacteria, of which, approximately 23000 die as a direct result of these infections. Phage therapy, or the treatment of bacterial infection by specific, antagonistic viruses, provides one alternative to traditional antibiotics. Bacteriophages, or phages, are bacteria-specific viruses that possess biological traits that allow for not only the removal of bacterial infection, but also the evasion of bacterial resistance, which renders antibiotics ineffective. Previous research has shown the addition of iron-doped apatite nanoparticles (IDANPs) to bacteria prior to phage exposure results in increased bacterial plaques in vitro. Coupled with the biocompatible nature of apatite, these results provide promise for future use of IDANPs as adjuvants to phage therapy along with anti-bacterial applications yet to be explored. Although IDANP enhancement of phage infection has been replicated many times in gram-positive and gram-negative prokaryotic hosts as well as with the utilization of both RNA and DNA viruses, the specific mechanisms involved remain elusive. To further understand increased phage infections in a prokaryotic system, and to evaluate the safety of IDANPs as a treatment used in a eukaryotic system, we have replicated plaque assay experiments in an algal system using Chlorella variabilis NC64A and its virus, Paramecium bursaria chlorella virus 1 (PBCV-1). Statistical modeling was used to evaluate alteration in numbers of plaques observed after viral introduction in IDANP-exposed versus non-IDANP-exposed bacterial and algal cell cultures. While IDANPs synthesized between 25 degrees C-45 degrees C and doped with 30% iron have been shown to influence dramatic increases in phage-induced bacterial death, experiments replicated in an algal system indicated viral infections do not increase when C. variabilis cells are pre-exposed to IDANPs. It is essential to potential use of IDANPs as an antibacterial adjuvant that IDANPs do not increase viral infection of eukaryotic host cells during treatment. PMID- 27775535 TI - GSEH: A Novel Approach to Select Prostate Cancer-Associated Genes Using Gene Expression Heterogeneity. AB - When a gene shows varying levels of expression among normal people but similar levels in disease patients or shows similar levels of expression among normal people but different levels in disease patients, we can assume that the gene is associated with the disease. By utilizing this gene expression heterogeneity, we can obtain additional information that abets discovery of disease-associated genes. In this study, we used collaborative filtering to calculate the degree of gene expression heterogeneity between classes and then scored the genes on the basis of the degree of gene expression heterogeneity to find "differentially predicted" genes. Through the proposed method, we discovered more prostate cancer associated genes than 10 comparable methods. The genes prioritized by the proposed method are potentially significant to biological processes of a disease and can provide insight into them. PMID- 27775537 TI - Can a Soft Robotic Probe Use Stiffness Control Like a Human Finger to Improve Efficacy of Haptic Perception? AB - When humans are asked to palpate a soft tissue to locate a hard nodule, they regulate the stiffness, speed, and force of the finger during examination. If we understand the relationship between these behavioral variables and haptic information gain (transfer entropy) during manual probing, we can improve the efficacy of soft robotic probes for soft tissue palpation, such as in tumor localization in minimally invasive surgery. Here, we recorded the muscle co contraction activity of the finger using EMG sensors to address the question as to whether joint stiffness control during manual palpation plays an important role in the haptic information gain. To address this question, we used a soft robotic probe with a controllable stiffness joint and a force sensor mounted at the base to represent the function of the tendon in a biological finger. Then, we trained a Markov chain using muscle co-contraction patterns of human subjects, and used it to control the stiffness of the soft robotic probe in the same soft tissue palpation task. The soft robotic experiments showed that haptic information gain about the depth of the hard nodule can be maximized by varying the internal stiffness of the soft probe. PMID- 27775539 TI - Event-Based Robust Control for Uncertain Nonlinear Systems Using Adaptive Dynamic Programming. AB - In this paper, the robust control problem for a class of continuous-time nonlinear system with unmatched uncertainties is investigated using an event based control method. First, the robust control problem is transformed into a corresponding optimal control problem with an augmented control and an appropriate cost function. Under the event-based mechanism, we prove that the solution of the optimal control problem can asymptotically stabilize the uncertain system with an adaptive triggering condition. That is, the designed event-based controller is robust to the original uncertain system. Note that the event-based controller is updated only when the triggering condition is satisfied, which can save the communication resources between the plant and the controller. Then, a single network adaptive dynamic programming structure with experience replay technique is constructed to approach the optimal control policies. The stability of the closed-loop system with the event-based control policy and the augmented control policy is analyzed using the Lyapunov approach. Furthermore, we prove that the minimal intersample time is bounded by a nonzero positive constant, which excludes Zeno behavior during the learning process. Finally, two simulation examples are provided to demonstrate the effectiveness of the proposed control scheme. PMID- 27775538 TI - A System for Electrotactile Feedback Using Electronic Skin and Flexible Matrix Electrodes: Experimental Evaluation. AB - Myoelectric prostheses are successfully controlled using muscle electrical activity, thereby restoring lost motor functions. However, the somatosensory feedback from the prosthesis to the user is still missing. The sensory substitution methods described in the literature comprise mostly simple position and force sensors combined with discrete stimulation units. The present study describes a novel system for sophisticated electrotactile feedback integrating advanced distributed sensing (electronic skin) and stimulation (matrix electrodes). The system was tested in eight healthy subjects who were asked to recognize the shape, trajectory, and direction of a set of dynamic movement patterns (single lines, geometrical objects, letters) presented on the electronic skin. The experiments demonstrated that the system successfully translated the mechanical interaction into the moving electrotactile profiles, which the subjects could recognize with a good performance (shape recognition: 86+/-8% lines, 73+/-13% geometries, 72+/-12% letters). In particular, the subjects could identify the movement direction with a high confidence. These results are in accordance with previous studies investigating the recognition of moving stimuli in human subjects. This is an important development towards closed-loop prostheses providing comprehensive and sophisticated tactile feedback to the user, facilitating the control and the embodiment of the artificial device into the user body scheme. PMID- 27775542 TI - An Efficient Representation-Based Method for Boundary Point and Outlier Detection. AB - Detecting boundary points (including outliers) is often more interesting than detecting normal observations, since they represent valid, interesting, and potentially valuable patterns. Since data representation can uncover the intrinsic data structure, we present an efficient representation-based method for detecting such points, which are generally located around the margin of densely distributed data, such as a cluster. For each point, the negative components in its representation generally correspond to the boundary points among its affine combination of points. In the presented method, the reverse unreachability of a point is proposed to evaluate to what degree this observation is a boundary point. The reverse unreachability can be calculated by counting the number of zero and negative components in the representation. The reverse unreachability explicitly takes into account the global data structure and reveals the disconnectivity between a data point and other points. This paper reveals that the reverse unreachability of points with lower density has a higher score. Note that the score of reverse unreachability of an outlier is greater than that of a boundary point. The top- ranked points can thus be identified as outliers. The greater the value of the reverse unreachability, the more likely the point is a boundary point. Compared with related methods, our method better reflects the characteristics of the data, and simultaneously detects outliers and boundary points regardless of their distribution and the dimensionality of the space. Experimental results obtained for a number of synthetic and real-world data sets demonstrate the effectiveness and efficiency of our method. PMID- 27775543 TI - On Global Dissipativity of Nonautonomous Neural Networks With Multiple Proportional Delays. AB - This brief addresses the problem of global dissipativity analysis of nonautonomous neural networks with multiple proportional delays. By using a novel constructive approach based on some comparison techniques for differential inequalities, new explicit delay-independent conditions are derived using M matrix theory to ensure the existence of generalized exponential attracting sets and the global dissipativity of the system. The method presented in this brief is also utilized to derive a generalized exponential estimate for a class of Halanay type inequalities with proportional delays. Finally, three numerical examples are given to illustrate the effectiveness and improvement of the obtained results. PMID- 27775545 TI - Fractional Brownian Motion and Rao Geodesic Distance for Bone X-Ray Image Characterization. AB - Osteoporosis diagnosis has attracted particular attention in recent decades. Textured images from the microarchitecture of osteoporotic and healthy subjects show a high degree of similarity, increasing the difficulty of classifying such textures. Thus, the evaluation of osteoporosis from the bone X-ray images presents a major challenge for pattern recognition and medical applications. The purpose of this paper is to use the fractional Brownian motion (fBm) model and the probability density function of its increments to compute a similarity measure with the Rao geodesic distance to classify trabecular bone X-ray images. When evaluated on synthetic fBm images (test vectors) with the well-known Hurst parameter H, the proposed method met our expectations in which a good classification of the synthetic images was achieved. A clinical study was conducted on textured bone X-ray images from two different female populations of osteoporotic patients (fracture cases) and control subjects. Using the proposed method, an area under curve rate of 97% was achieved. PMID- 27775546 TI - Extreme Kernel Sparse Learning for Tactile Object Recognition. AB - Tactile sensors play very important role for robot perception in the dynamic or unknown environment. However, the tactile object recognition exhibits great challenges in practical scenarios. In this paper, we address this problem by developing an extreme kernel sparse learning methodology. This method combines the advantages of extreme learning machine and kernel sparse learning by simultaneously addressing the dictionary learning and the classifier design problems. Furthermore, to tackle the intrinsic difficulties which are introduced by the representer theorem, we develop a reduced kernel dictionary learning method by introducing row-sparsity constraint. A globally convergent algorithm is developed to solve the optimization problem and the theoretical proof is provided. Finally, we perform extensive experimental validations on some public available tactile sequence datasets and show the advantages of the proposed method. PMID- 27775548 TI - IL-33 regulates the IgA-microbiota axis to restrain IL-1alpha-dependent colitis and tumorigenesis. AB - Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC. Mechanistically, we observed that IL-33 promoted IgA production from B cells, which is important for maintaining microbial homeostasis in the intestine. Il33-deficient mice developed a dysbiotic microbiota that was characterized by increased levels of mucolytic and colitogenic bacteria. In response to chemically induced colitis, this microbial landscape promoted the release of IL-1alpha, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1alpha ablation markedly ameliorated colitis susceptibility in Il33-deficient animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis and restrain IL 1alpha-dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1alpha, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC. PMID- 27775547 TI - Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment. AB - The rising success of cancer immunotherapy has produced immense interest in defining the clinical contexts that may benefit from this therapeutic approach. To this end, there is a need to ascertain how the therapeutic modulation of intrinsic cancer cell programs influences the anticancer immune response. For example, the role of autophagy as a tumor cell survival and metabolic fitness pathway is being therapeutically targeted in ongoing clinical trials that combine cancer therapies with antimalarial drugs for the treatment of a broad spectrum of cancers, many of which will likely benefit from immunotherapy. However, our current understanding of the interplay between autophagy and the immune response remains incomplete. Here, we have evaluated how autophagy inhibition impacts the antitumor immune response in immune-competent mouse models of melanoma and mammary cancer. We observed equivalent levels of T cell infiltration and function within autophagy-competent and -deficient tumors, even upon treatment with the anthracycline chemotherapeutic doxorubicin. Similarly, we found equivalent T cell responses upon systemic treatment of tumor-bearing mice with antimalarial drugs. Our findings demonstrate that antitumor adaptive immunity is not adversely impaired by autophagy inhibition in these models, allowing for the future possibility of combining autophagy inhibitors with immunotherapy in certain clinical contexts. PMID- 27775549 TI - Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. AB - Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid-low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche. CYP26 mediated inactivation of RA within the BM microenvironment prevented plasma cell differentiation and promoted a B cell-like, BTZ-resistant phenotype in human MM cells that were cocultured on BM stroma. Moreover, paracrine Hedgehog secretion by MM cells upregulated stromal CYP26 and further reinforced a protective microenvironment. These results suggest that crosstalk between Hedgehog and retinoid signaling modulates BTZ sensitivity in the BM niche. Targeting these pathological interactions holds promise for eliminating minimal residual disease in MM. PMID- 27775550 TI - MicroRNA-29b mediates altered innate immune development in acute leukemia. AB - Natural killer (NK) cells can have potent antileukemic activity following haplo mismatched, T cell-depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients. This absence was not due to elimination by cell death or selective reduction in proliferation, but rather to the result of a block in NK cell differentiation. Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation. Further, the microRNA miR-29b, a regulator of T-bet and EOMES, was elevated in leukemic NK cells. Finally, deletion of miR-29b in NK cells reversed the depletion of this NK cell subset in leukemic mice. These results indicate that leukemic evasion of NK cell surveillance occurs through miR-mediated dysregulation of lymphocyte development, representing an additional mechanism of immune escape in cancer. PMID- 27775553 TI - A Perioperative Clinical Pathway Can Dramatically Reduce Failure-to-rescue Rates After Cytoreductive Surgery for Peritoneal Carcinomatosis: A Retrospective Study of 666 Consecutive Cytoreductions. AB - OBJECTIVE: To determine whether a perioperative, standardized clinical pathway could impact the failure-to-rescue rate after cytoreductive surgery (CRS) for peritoneal carcinomatosis (PC) in a tertiary center. SUMMARY OF BACKGROUND DATA: Morbidity and mortality remain significant after CRS for PC. Clinical pathways have been associated with better outcomes after surgery. The failure-to-rescue rate is a useful metric for evaluating quality in surgery. MATERIALS AND METHODS: This study included 666 patients that received CRS for PC between 2009 and 2014. Starting in 2012, a standardized perioperative clinical pathway was introduced, which focused on patient selection, nutrition, renal protection, pain management, prevention, and early detection of complications. Complications were evaluated with the National Cancer Institute's Common Terminology Criteria for Adverse Events. We used multivariate analyses to evaluate clinicopathological and perioperative factors for associations with major complications and failure-to rescue. Complication rates were compared before and after the clinical pathway implementation. RESULTS: Major complications occurred in 341 patients (51%), leading to 15 deaths. The complication rate was similar before and after clinical pathway introduction (54.75% vs 48.9%, respectively; P = 0.138). Only prolonged surgery (longer than 240 mins) was independently associated with major complications. The failure-to-rescue rate was 4.4% for the entire period, but it significantly decreased after introducing the clinical pathway (9.02% vs 1.02%; P < 0.001). On multivariate analysis, only renal complications were associated with the failure-to-rescue. CONCLUSION: Morbidity after CRS remains significant, but standardized management facilitated a reduction in the failure-to-rescue rate and improved the quality of care. Specific effort should be dedicated to preventing postoperative renal failure. PMID- 27775554 TI - Looking Backward, Looking Forward: The Long, Torturous Struggle with Mosquitoes. AB - The American anti-mosquito movement grew out of the discovery of the role of mosquitoes in transferring pathogens and public concern about pest and nuisance mosquitoes in the late 1800s. In the 20th century, organized mosquito control in the United States passed through three eras: mechanical, chemical, and integrated mosquito control. Mosquito control in the 21st century faces the challenge of emerging pathogens, invasive mosquito species, and balancing concerns about the environment with effective control strategies. PMID- 27775552 TI - Transcription factor ETV1 is essential for rapid conduction in the heart. AB - Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart. PMID- 27775551 TI - Antibiotic effects on gut microbiota and metabolism are host dependent. AB - Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential. PMID- 27775555 TI - Microwave-Based Microfluidic Sensor for Non-Destructive and Quantitative Glucose Monitoring in Aqueous Solution. AB - This paper presents a reliable microwave and microfluidic miniature sensor dedicated to the measurement of glucose concentration in aqueous solution. The device; which is integrated with microtechnologies; is made of a bandstop filter implemented in a thin film microstrip technology combined with a fluidic microchannel. Glucose aqueous solutions have been characterized for concentration ranging from 80 g/L down to 0.3 g/L and are identified with the normalized insertion loss at optimal frequency. The sensitivity of the sensor has consequently been estimated at 7.6 * 10-3 dB/(g/L); together with the experimental uncertainty; the resolution of the sensor comes to 0.4 g/L. These results demonstrate the potentialities of such a sensor for the quantitative analysis of glucose in aqueous solution. PMID- 27775556 TI - Predicting Gilthead Sea Bream (Sparus aurata) Freshness by a Novel Combined Technique of 3D Imaging and SW-NIR Spectral Analysis. AB - A technique that combines the spatial resolution of a 3D structured-light (SL) imaging system with the spectral analysis of a hyperspectral short-wave near infrared system was developed for freshness predictions of gilthead sea bream on the first storage days (Days 0-6). This novel approach allows the hyperspectral analysis of very specific fish areas, which provides more information for freshness estimations. The SL system obtains a 3D reconstruction of fish, and an automatic method locates gilthead's pupils and irises. Once these regions are positioned, the hyperspectral camera acquires spectral information and a multivariate statistical study is done. The best region is the pupil with an R2 of 0.92 and an RMSE of 0.651 for predictions. We conclude that the combination of 3D technology with the hyperspectral analysis offers plenty of potential and is a very promising technique to non destructively predict gilthead freshness. PMID- 27775557 TI - Chemical Analysis of Extracts from Newfoundland Berries and Potential Neuroprotective Effects. AB - Various species of berries have been reported to contain several polyphenolic compounds, such as anthocyanins and flavonols, which are known to possess high antioxidant activity and may be beneficial for human health. To our knowledge, a thorough chemical analysis of polyphenolics in species of these plants native to Newfoundland, Canada has not been conducted. The primary objective of this study was to determine the polyphenolic compounds present in commercial extracts from Newfoundland berries, which included blueberries (V. angustifolium), lingonberries (V. vitis-idaea) and black currant (Ribes lacustre). Anthocyanin and flavonol glycosides in powdered extracts from Ribes lacustre and the Vaccinium species were identified using the high performance liquid chromatographic (HPLC) separation method with mass spectrometric (MS) detection. The identified compounds were extracted from dried berries by various solvents via ultrasonication followed by centrifugation. A reverse-phase analytical column was employed to identify the retention time of each chemical component before submission for LC-MS analysis. A total of 21 phenolic compounds were tentatively identified in the three species. Further, we tested the effects of the lingonberry extract for its ability to protect neurons and glia from trauma utilizing an in vitro model of cell injury. Surprisingly, these extracts provided complete protection from cell death in this model. These findings indicate the presence of a wide variety of anthocyanins and flavonols in berries that grow natively in Newfoundland. These powdered extracts maintain these compounds intact despite being processed from berry fruit, indicating their potential use as dietary supplements. In addition, these recent findings and previous data from our lab demonstrate the ability of compounds in berries to protect the nervous system from traumatic insults. PMID- 27775559 TI - Synthesis, Spatial Structure and Analgesic Activity of Sodium 3 Benzylaminocarbonyl-1-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazin-4-olate Solvates. AB - In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2lambda6,1 benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2lambda6,1-benzothiazine-3 carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam. PMID- 27775558 TI - Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis. AB - Glutamine synthetase (GS) is a cytosolic enzyme that produces glutamine, the most abundant free amino acid in the human body. Glutamine is a major substrate for various metabolic pathways, and is thus an important factor for the functioning of many organs; therefore, deficiency of glutamine due to a defect in GS is incompatible with normal life. Mutations in the human GLUL gene (encoding for GS) can cause an ultra-rare recessive inborn error of metabolism-congenital glutamine synthetase deficiency. This disease was reported until now in only three unrelated patients, all of whom suffered from neonatal onset severe epileptic encephalopathy. The hallmark of GS deficiency in these patients was decreased levels of glutamine in body fluids, associated with chronic hyperammonemia. This review aims at recapitulating the clinical history of the three known patients with congenital GS deficiency and summarizes the findings from studies done along with the work-up of these patients. It is the aim of this paper to convince the reader that (i) this disorder is possibly underdiagnosed, since decreased concentrations of metabolites do not receive the attention they deserve; and (ii) early detection of GS deficiency may help to improve the outcome of patients who could be treated early with metabolites that are lacking in this condition. PMID- 27775560 TI - FoodPro: A Web-Based Tool for Evaluating Covariance and Correlation NMR Spectra Associated with Food Processes. AB - Foods from agriculture and fishery products are processed using various technologies. Molecular mixture analysis during food processing has the potential to help us understand the molecular mechanisms involved, thus enabling better cooking of the analyzed foods. To date, there has been no web-based tool focusing on accumulating Nuclear Magnetic Resonance (NMR) spectra from various types of food processing. Therefore, we have developed a novel web-based tool, FoodPro, that includes a food NMR spectrum database and computes covariance and correlation spectra to tasting and hardness. As a result, FoodPro has accumulated 236 aqueous (extracted in D2O) and 131 hydrophobic (extracted in CDCl3) experimental bench-top 60-MHz NMR spectra, 1753 tastings scored by volunteers, and 139 hardness measurements recorded by a penetrometer, all placed into a core database. The database content was roughly classified into fish and vegetable groups from the viewpoint of different spectrum patterns. FoodPro can query a user food NMR spectrum, search similar NMR spectra with a specified similarity threshold, and then compute estimated tasting and hardness, covariance, and correlation spectra to tasting and hardness. Querying fish spectra exemplified specific covariance spectra to tasting and hardness, giving positive covariance for tasting at 1.31 ppm for lactate and 3.47 ppm for glucose and a positive covariance for hardness at 3.26 ppm for trimethylamine N-oxide. PMID- 27775561 TI - Three New Cytotoxic Polyhydroxysteroidal Glycosides from Starfish Craspidaster hesperus. AB - Three new polyhydroxysteroidal glycosides, hesperuside A (1), B (2), and C (3), as well as a known novaeguinoside A (4), were isolated from the ethanol extract of starfish Craspidaster hesperus collected from the South China Sea. Their structures were elucidated by extensive spectroscopic methods and chemical evidence. The compounds 1-3 present unprecedented carbohydrate chain 3-O-methyl beta-d-galactopyranose, which differ from each other in the side chains. These compounds exhibited cytotoxicity against human tumor cells BEL-7402, MOLT-4, and A-549 in vitro. PMID- 27775562 TI - Protective Role of Dietary Berries in Cancer. AB - Dietary patterns, including regular consumption of particular foods such as berries as well as bioactive compounds, may confer specific molecular and cellular protection in addition to the overall epidemiologically observed benefits of plant food consumption (lower rates of obesity and chronic disease risk), further enhancing health. Mounting evidence reports a variety of health benefits of berry fruits that are usually attributed to their non-nutritive bioactive compounds, mainly phenolic substances such as flavonoids or anthocyanins. Although it is still unclear which particular constituents are responsible for the extended health benefits, it appears that whole berry consumption generally confers some anti-oxidant and anti-inflammatory protection to humans and animals. With regards to cancer, studies have reported beneficial effects of berries or their constituents including attenuation of inflammation, inhibition of angiogenesis, protection from DNA damage, as well as effects on apoptosis or proliferation rates of malignant cells. Berries extend effects on the proliferation rates of both premalignant and malignant cells. Their effect on premalignant cells is important for their ability to cause premalignant lesions to regress both in animals and in humans. The present review focuses primarily on in vivo and human dietary studies of various berry fruits and discusses whether regular dietary intake of berries can prevent cancer initiation and delay progression in humans or ameliorate patients' cancer status. PMID- 27775563 TI - Where in the Cell Are You? Probing HIV-1 Host Interactions through Advanced Imaging Techniques. AB - Viruses must continuously evolve to hijack the host cell machinery in order to successfully replicate and orchestrate key interactions that support their persistence. The type-1 human immunodeficiency virus (HIV-1) is a prime example of viral persistence within the host, having plagued the human population for decades. In recent years, advances in cellular imaging and molecular biology have aided the elucidation of key steps mediating the HIV-1 lifecycle and viral pathogenesis. Super-resolution imaging techniques such as stimulated emission depletion (STED) and photoactivation and localization microscopy (PALM) have been instrumental in studying viral assembly and release through both cell-cell transmission and cell-free viral transmission. Moreover, powerful methods such as Forster resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC) have shed light on the protein-protein interactions HIV-1 engages within the host to hijack the cellular machinery. Specific advancements in live cell imaging in combination with the use of multicolor viral particles have become indispensable to unravelling the dynamic nature of these virus-host interactions. In the current review, we outline novel imaging methods that have been used to study the HIV-1 lifecycle and highlight advancements in the cell culture models developed to enhance our understanding of the HIV-1 lifecycle. PMID- 27775566 TI - Flux and Passage Enhancement in Hemodialysis by Incorporating Compound Additive into PVDF Polymer Matrix. AB - In this study, Polyvinylidene fluoride (PVDF) hollow fiber hemodialysis membranes were prepared by non-solvent induced phase separation (NIPS) with compound addtive. The compound additive was made with polyvinyl pyrrolidone (PVP) and Poly ethylene glycol (PEG). The results showed that the modified PVDF membrane had better separation performance than virgin PVDF membrane. The UF flux of modified PVDF membrane can reach 684 L.h-1.m-2 and lysozyme (LZM) passage is 72.6% while virgin PVDF membrane is 313 L.h-1.m-2 and 53.2%. At the same time, the biocompatibility of PVDF membranes was also improved. Compared with commercial polysulfone hemodialysis membrane (Fresenius F60S membrane), the modified PVDF membrane had better mechanical and separation performance. The stress and tensile elongation of modified PVDF membrane was 0.94 MPa and 352% while Fresenius F60S membrane was 0.79 MPa and 59%. The LZM passage reached 72.6% while Fresenius F60S membrane was 54.4%. It was proven that the modified PVDF membrane showed better hydrophilicity, antithrombogenicity, less BSA adsorption, and lower hemolytic ratio and adhesion of platelets. Water contact angle and BSA adsorption of the modified PVDF membrane are 38 degrees and 45 mg/m2 while Fresenius F60S membrane are 64 degrees and 235 mg/m2. Prothrombin time (PT) and activated partial thromboplastin time (APTT) of the modified PVDF membrane are 56.5 s and 25.8 s while Fresenius F60S membrane is 35.7 s and 16.6 s. However, further biocompatibility evaluation is needed to obtain a more comprehensive conclusion. PMID- 27775564 TI - Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites. AB - Approximately 200 human papillomaviruses (HPVs) infect human epithelial cells, of which the alpha and beta types have been the most extensively studied. Alpha HPV types mainly infect mucosal epithelia and a small group of these causes over 600,000 cancers per year worldwide at various anatomical sites, especially anogenital and head-and-neck cancers. Of these the most important is cervical cancer, which is the leading cause of cancer-related death in women in many parts of the world. Beta HPV types infect cutaneous epithelia and may contribute towards the initiation of non-melanoma skin cancers. HPVs encode two oncoproteins, E6 and E7, which are directly responsible for the development of HPV-induced carcinogenesis. They do this cooperatively by targeting diverse cellular pathways involved in the regulation of cell cycle control, of apoptosis and of cell polarity control networks. In this review, the biological consequences of papillomavirus targeting of various cellular substrates at diverse anatomical sites in the development of HPV-induced malignancies are highlighted. PMID- 27775565 TI - Is Hypovitaminosis D Associated with Stress Perception in the Elderly? A Nationwide Representative Study in Korea. AB - Hypovitaminosis D and stress are common problems among the elderly. The aim of this cross-sectional nationally representative study was to evaluate the association between hypovitaminosis D and stress perception using large-scale nationally representative data from the Korea National Health and Nutrition Examination Survey (2012-2013). In our study, a total of 1393 elders (>=65 years old) were included to evaluate the association between hypovitaminosis D and stress perception. Serum 25-hydroxyvitamin D levels were determined using radioimmunoassay, and perceived stress status was assessed by a self-reporting questionnaire. The association between hypovitaminosis D and stress perception according to sex was examined using logistic regression analysis. After multivariate adjustment for sociodemographic and lifestyle factors and comorbidities, hypovitaminosis D was significantly associated with perceived stress (odds ratio, 2.73; 95% confidence interval, 1.10-6.77; p = 0.029) among women; however, this association was not significant among men. Hypovitaminosis D was a risk factor for higher stress perception in older Korean women. Even though the role of vitamin D in stress perception is still unclear, we suggest screening for hypovitaminosis D among the elderly. PMID- 27775567 TI - A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors. AB - Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities. PMID- 27775570 TI - Robust Depth Image Acquisition Using Modulated Pattern Projection and Probabilistic Graphical Models. AB - Depth image acquisition with structured light approaches in outdoor environments is a challenging problem due to external factors, such as ambient sunlight, which commonly affect the acquisition procedure. This paper presents a novel structured light sensor designed specifically for operation in outdoor environments. The sensor exploits a modulated sequence of structured light projected onto the target scene to counteract environmental factors and estimate a spatial distortion map in a robust manner. The correspondence between the projected pattern and the estimated distortion map is then established using a probabilistic framework based on graphical models. Finally, the depth image of the target scene is reconstructed using a number of reference frames recorded during the calibration process. We evaluate the proposed sensor on experimental data in indoor and outdoor environments and present comparative experiments with other existing methods, as well as commercial sensors. PMID- 27775571 TI - Routing Topologies of Wireless Sensor Networks for Health Monitoring of a Cultural Heritage Site. AB - This paper provides a performance evaluation of tree and mesh routing topologies of wireless sensor networks (WSNs) in a cultural heritage site. The historical site selected was San Juan Bautista church in Talamanca de Jarama (Madrid, Spain). We report the preliminary analysis required to study the effects of heating in this historical location using WSNs to monitor the temperature and humidity conditions during periods of weeks. To test which routing topology was better for this kind of application, the WSNs were first deployed on the upper floor of the CAEND institute in Arganda del Rey simulating the church deployment, but in the former scenario there was no direct line of sight between the WSN elements. Two parameters were selected to evaluate the performance of the routing topologies of WSNs: the percentage of received messages and the lifetime of the wireless sensor network. To analyze in more detail which topology gave the best performance, other communication parameters were also measured. The tree topology used was the collection tree protocol and the mesh topology was the XMESH provided by MEMSIC (Andover, MA, USA). For the scenarios presented in this paper, it can be concluded that the tree topology lost fewer messages than the mesh topology. PMID- 27775568 TI - Viral Metagenomics on Blood-Feeding Arthropods as a Tool for Human Disease Surveillance. AB - Surveillance and monitoring of viral pathogens circulating in humans and wildlife, together with the identification of emerging infectious diseases (EIDs), are critical for the prediction of future disease outbreaks and epidemics at an early stage. It is advisable to sample a broad range of vertebrates and invertebrates at different temporospatial levels on a regular basis to detect possible candidate viruses at their natural source. However, virus surveillance systems can be expensive, costly in terms of finances and resources and inadequate for sampling sufficient numbers of different host species over space and time. Recent publications have presented the concept of a new virus surveillance system, coining the terms "flying biological syringes", "xenosurveillance" and "vector-enabled metagenomics". According to these novel and promising surveillance approaches, viral metagenomics on engorged mosquitoes might reflect the viral diversity of numerous mammals, birds and humans, combined in the mosquitoes' blood meal during feeding on the host. In this review article, we summarize the literature on vector-enabled metagenomics (VEM) techniques and its application in disease surveillance in humans. Furthermore, we highlight the combination of VEM and "invertebrate-derived DNA" (iDNA) analysis to identify the host DNA within the mosquito midgut. PMID- 27775569 TI - RNA Interference in Moths: Mechanisms, Applications, and Progress. AB - The vast majority of lepidopterans, about 90%, are moths. Some moths, particularly their caterpillars, are major agricultural and forestry pests in many parts of the world. However, some other members of moths, such as the silkworm Bombyx mori, are famous for their economic value. Fire et al. in 1998 initially found that exogenous double-stranded RNA (dsRNA) can silence the homolog endogenous mRNA in organisms, which is called RNA interference (RNAi). Soon after, the RNAi technique proved to be very promising not only in gene function determination but also in pest control. However, later studies demonstrate that performing RNAi in moths is not as straightforward as shown in other insect taxa. Nevertheless, since 2007, especially after 2010, an increasing number of reports have been published that describe successful RNAi experiments in different moth species either on gene function analysis or on pest management exploration. So far, more than 100 peer-reviewed papers have reported successful RNAi experiments in moths, covering 10 families and 25 species. By using classic and novel dsRNA delivery methods, these studies effectively silence the expression of various target genes and determine their function in larval development, reproduction, immunology, resistance against chemicals, and other biological processes. In addition, a number of laboratory and field trials have demonstrated that RNAi is also a potential strategy for moth pest management. In this review, therefore, we summarize and discuss the mechanisms and applications of the RNAi technique in moths by focusing on recent progresses. PMID- 27775573 TI - Preliminary Study on Continuous Recognition of Elbow Flexion/Extension Using sEMG Signals for Bilateral Rehabilitation. AB - Surface electromyography (sEMG) signals are closely related to the activation of human muscles and the motion of the human body, which can be used to estimate the dynamics of human limbs in the rehabilitation field. They also have the potential to be used in the application of bilateral rehabilitation, where hemiplegic patients can train their affected limbs following the motion of unaffected limbs via some rehabilitation devices. Traditional methods to process the sEMG focused on motion pattern recognition, namely, discrete patterns, which are not satisfactory for use in bilateral rehabilitation. In order to overcome this problem, in this paper, we built a relationship between sEMG signals and human motion in elbow flexion and extension on the sagittal plane. During the conducted experiments, four participants were required to perform elbow flexion and extension on the sagittal plane smoothly with only an inertia sensor in their hands, where forearm dynamics were not considered. In these circumstances, sEMG signals were weak compared to those with heavy loads or high acceleration. The contrastive experimental results show that continuous motion can also be obtained within an acceptable precision range. PMID- 27775572 TI - Responsive Boronic Acid-Decorated (Co)polymers: From Glucose Sensors to Autonomous Drug Delivery. AB - Boronic acid-containing (co)polymers have fascinated researchers for decades, garnering attention for their unique responsiveness toward 1,2- and 1,3-diols, including saccharides and nucleotides. The applications of materials that exert this property are manifold including sensing, but also self-regulated drug delivery systems through responsive membranes or micelles. In this review, some of the main applications of boronic acid containing (co)polymers are discussed focusing on the role of the boronic acid group in the response mechanism. We hope that this summary, which highlights the importance and potential of boronic acid decorated polymeric materials, will inspire further research within this interesting field of responsive polymers and polymeric materials. PMID- 27775575 TI - Extract from Maize (Zea mays L.): Antibacterial Activity of DIMBOA and Its Derivatives against Ralstonia solanacearum. AB - Many cereals accumulate hydroxamic acids involved in defense of plant against various fungi, bacteria, and insects. 2,4-dihydroxy-7-methoxy-1,4-benzoxazine-3 one, commonly known as DIMBOA, is one of the principal cyclic hydroxamic acids in aqueous extracts of maize. The aim of this study was to evaluate the antibacterial activity of the isolated DIMBOA and its derivatives 2 benzoxazolinone (BOA), 6-chloro-2-benzoxazolinone (CDHB), and 2 mercaptobenzothiazole (MBT) against Ralstonia solanacearum. MBT showed the strongest antibacterial activity, followed by CDHB and DIMBOA, with minimum inhibitory concentrations (MICs) of 50, 100 and 200 mg/L, respectively, better than the BOA with 300 mg/L. These compounds also significantly affect bacterial growth, reduce biofilm formation, and inhibit swarming motility within 24 h. This paper is the first to report the anti-R. solanacearum activity of DIMBOA from Z. mays. The bioassay and pot experiment results suggested that DIMBOA and its derivatives exhibit potential as a new matrix structure of designing target bactericide or elicitor for controlling tobacco bacterial wilt. Further studies must evaluate the efficacy of DIMBOA and its derivatives in controlling bacterial wilt under natural field conditions where low inoculum concentrations exist. PMID- 27775574 TI - Proteome and Peptidome of Vipera berus berus Venom. AB - Snake venom is a rich source of peptides and proteins with a wide range of actions. Many of the venom components are currently being tested for their usefulness in the treatment of many diseases ranging from neurological and cardiovascular to cancer. It is also important to constantly search for new proteins and peptides with properties not yet described. The venom of Vipera berus berus has hemolytic, proteolytic and cytotoxic properties, but its exact composition and the factors responsible for these properties are not known. Therefore, an attempt was made to identify proteins and peptides derived from this species venom by using high resolution two-dimensional electrophoresis and MALDI ToF/ToF mass spectrometry. A total of 11 protein classes have been identified mainly proteases but also l-amino acid oxidases, C-type lectin like proteins, cysteine-rich venom proteins and phospholipases A2 and 4 peptides of molecular weight less than 1500 Da. Most of the identified proteins are responsible for the highly hemotoxic properties of the venom. Presence of venom phospholipases A2 and l-amino acid oxidases cause moderate neuro-, myo- and cytotoxicity. All successfully identified peptides belong to the bradykinin potentiating peptides family. The mass spectrometry data are available via ProteomeXchange with identifier PXD004958. PMID- 27775576 TI - Application of Super-Amphiphilic Silica-Nanogel Composites for Fast Removal of Water Pollutants. AB - This work first reports the preparation of super-amphiphilic silica-nanogel composites to reduce the contact angle of water to increase the diffusion of pollutant into adsorbents. In this respect, the silica nanoparticles were encapsulated into nanogels based on ionic and nonionic polyacrylamides by dispersion polymerization technique. The morphologies and the dispersion stability of nanogel composites were investigated to clarify the ability of silica-nanogel composites to adsorb at different interfaces. The feasibility of silica polyacrylamide nanogel composites to act as a high-performance adsorbent for removal of methylene blue (MB) dye and heavy metals (Co2+ and Ni2+) from aqueous solution was investigated. The surface tension, contact angle, average pore size, and zeta potential of the silica-nanogel composites have been evaluated. The MB dye and heavy metal adsorption capacity achieved Qmax = 438-387 mg/g which is considerably high. The adsorption capacity results are explained from the changes in the morphology of the silica surfaces as recorded from scanning electron microscopy (SEM). PMID- 27775577 TI - The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. AB - Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp. PMID- 27775578 TI - 20(S)-Protopanaxadiol Phospholipid Complex: Process Optimization, Characterization, In Vitro Dissolution and Molecular Docking Studies. AB - 20(S)-Protopanaxadiol (PPD), a bioactive compound extracted from ginseng, possesses cardioprotective, neuroprotective, anti-inflammatory, antiestrogenic, anticancer and anxiolytic effects. However, the clinical application of PPD is limited by its weak aqueous solubility. In this study, we optimized an efficient method of preparing its phospholipid complex (PPD-PLC) using a central composite design and response surface analysis. The prepared PPD-PLC was characterized by differential scanning calorimetric, powder X-ray diffraction, Fourier-transformed infrared spectroscopy and nuclear magnetic resonance analyses associated with molecular docking calculation. The equilibrium solubility of PPD-PLC in water and n-octanol increased 6.53- and 1.53-times, respectively. Afterwards, using PPD-PLC as the intermediate, the PPD-PLC-loaded dry suspension (PPD-PLC-SU) was prepared with our previous method. In vitro evaluations were conducted on PPD-PLC and PPD PLC-SU, including dissolution behaviors and stability properties under different conditions. Results of in vitro dissolution behavior revealed the improved dissolution extents and rates of PPD-PLC and PPD-PLC-SU (p < 0.05). Results of the formulation stability investigation also exposed the better stability of PPD PLC-SU compared with free PPD. Therefore, phospholipid complex technology is a useful formulation strategy for BCS II drugs, as it could effectively improve their hydrophilicity and lipophilicity. PMID- 27775580 TI - Mode Conversion Behavior of Guided Wave in a Pipe Inspection System Based on a Long Waveguide. AB - To make clear the mode conversion behavior of S0-mode lamb wave and SH0-plate wave converting to the longitudinal mode guided wave and torsional mode guided wave in a pipe, respectively, the experiments were performed based on a previous built pipe inspection system. The pipe was wound with an L-shaped plate or a T shaped plate as the waveguide, and the S0-wave and SH0-wave were excited separately in the waveguide. To carry out the objective, a meander-line coil electromagnetic acoustic transducer (EMAT) for S0-wave and a periodic permanent magnet (PPM) EMAT for SH0-wave were developed and optimized. Then, several comparison experiments were conducted to compare the efficiency of mode conversion. Experimental results showed that the T(0,1) mode, L(0,1) mode, and L(0,2) mode guided waves can be successfully detected when converted from the S0 wave or SH0-wave with different shaped waveguides. It can also be inferred that the S0-wave has a better ability to convert to the T(0,1) mode, while the SH0 wave is easier to convert to the L(0,1) mode and L(0,2) mode, and the L-shaped waveguide has a better efficiency than T-shaped waveguide. PMID- 27775579 TI - Systematic Analysis of the 4-Coumarate:Coenzyme A Ligase (4CL) Related Genes and Expression Profiling during Fruit Development in the Chinese Pear. AB - In plants, 4-coumarate:coenzyme A ligases (4CLs), comprising some of the adenylate-forming enzymes, are key enzymes involved in regulating lignin metabolism and the biosynthesis of flavonoids and other secondary metabolites. Although several 4CL-related proteins were shown to play roles in secondary metabolism, no comprehensive study on 4CL-related genes in the pear and other Rosaceae species has been reported. In this study, we identified 4CL-related genes in the apple, peach, yangmei, and pear genomes using DNATOOLS software and inferred their evolutionary relationships using phylogenetic analysis, collinearity analysis, conserved motif analysis, and structure analysis. A total of 149 4CL-related genes in four Rosaceous species (pear, apple, peach, and yangmei) were identified, with 30 members in the pear. We explored the functions of several 4CL and acyl-coenzyme A synthetase (ACS) genes during the development of pear fruit by quantitative real-time PCR (qRT-PCR). We found that duplication events had occurred in the 30 4CL-related genes in the pear. These duplicated 4CL related genes are distributed unevenly across all pear chromosomes except chromosomes 4, 8, 11, and 12. The results of this study provide a basis for further investigation of both the functions and evolutionary history of 4CL related genes. PMID- 27775581 TI - Chemically Roughened Solid Silver: A Simple, Robust and Broadband SERS Substrate. AB - Surface-enhanced Raman spectroscopy (SERS) substrates manufactured using complex nano-patterning techniques have become the norm. However, their cost of manufacture makes them unaffordable to incorporate into most biosensors. The technique shown in this paper is low-cost, reliable and highly sensitive. Chemical etching of solid Ag metal was used to produce simple, yet robust SERS substrates with broadband characteristics. Etching with ammonium hydroxide (NH4OH) and nitric acid (HNO3) helped obtain roughened Ag SERS substrates. Scanning electron microscopy (SEM) and interferometry were used to visualize and quantify surface roughness. Flattened Ag wires had inherent, but non-uniform roughness having peaks and valleys in the microscale. NH4OH treatment removed dirt and smoothened the surface, while HNO3 treatment produced a flake-like morphology with visibly more surface roughness features on Ag metal. SERS efficacy was tested using 4-methylbenzenethiol (MBT). The best SERS enhancement for 1 mM MBT was observed for Ag metal etched for 30 s in NH4OH followed by 10 s in HNO3. Further, MBT could be quantified with detection limits of 1 pM and 100 uM, respectively, using 514 nm and 1064 nm Raman spectrometers. Thus, a rapid and less energy intensive method for producing solid Ag SERS substrate and its efficacy in analyte sensing was demonstrated. PMID- 27775582 TI - Two Mechanisms: The Role of Social Capital and Industrial Pollution Exposure in Explaining Racial Disparities in Self-Rated Health. AB - This study provides an empirical test of two mechanisms (social capital and exposure to air pollution) that are theorized to mediate the effect of neighborhood on health and contribute to racial disparities in health outcomes. To this end, we utilize the Social Capital Benchmark Study, a national survey of individuals nested within communities in the United States, to estimate how multiple dimensions of social capital and exposure to air pollution, explain racial disparities in self-rated health. Our main findings show that when controlling for individual-confounders, and nesting within communities, our indicator of cognitive bridging, generalized trust, decreases the gap in self rated health between African Americans and Whites by 84%, and the gap between Hispanics and Whites by 54%. Our other indicator of cognitive social capital, cognitive linking as represented by engagement in politics, decreases the gap in health between Hispanics and Whites by 32%, but has little impact on African Americans. We also assessed whether the gap in health was explained by respondents' estimated exposure to toxicity-weighted air pollutants from large industrial facilities over the previous year. Our results show that accounting for exposure to these toxins has no effect on the racial gap in self-rated health in these data. This paper contributes to the neighborhood effects literature by examining the impact that estimated annual industrial air pollution, and multiple measures of social capital, have on explaining the racial gap in health in a sample of individuals nested within communities across the United States. PMID- 27775583 TI - The Association of Ideal Cardiovascular Health and Atherogenic Index of Plasma in Rural Population: A Cross-Sectional Study from Northeast China. AB - In 2010, the American Heart Association has proposed a new concept "ideal cardiovascular health" (CVH) based on seven CVH metrics: smoking, body mass index, physical activity, diet score, total cholesterol, blood pressure, and fasting plasma glucose. We aimed to determine the association of CVH with atherogenic index of plasma (AIP), a strong marker for atherosclerosis (AS). This cross-sectional study was conducted in the rural areas of northeast China and 11,113 middle-aged subjects were enrolled. Seven CVH metrics were classified into ideal, intermediate, and poor groups. AIP was calculated as log (TG/HDL) (triglycerides/high-density lipoprotein cholesterol). AIP > 0.21 was classified into the high AIP group and served as dependent variable. All seven CVH metrics were correlated with AIP. A gradient relationship between the number of poor CVH metrics and the prevalence of high AIP existed. Log binomial regression analysis showed that compared to those with five to seven ideal CVH metrics, individuals with four, three, two, one, and no ideal CVH metrics had 1.67, 2.66, 4.00, 5.30 and 6.50 times higher prevalence for high AIP. The subjects with poor CVH status had 2.73 times higher prevalence for high AIP. We found an inversely gradient relationship between the number of ideal CVH metrics and lower prevalence of high AIP. PMID- 27775584 TI - Accessibility to Specialized Public Oral Health Services from the Perspective of Brazilian Users. AB - The Specialized Dental Clinics (SDCs) represent the first government initiative in Latin America aimed at providing specialized oral health services. This study sought to evaluate the organizational accessibility to specialized oral health care services in Brazil and to understand the factors that may be associated with accessibility from the user's perspective. This epidemiological, cross-sectional and quantitative study was conducted by means of interviews with individuals who sought specialized public oral health services in the city of Joao Pessoa, Paraiba, Brazil, and consisted of a sample of 590 individuals. Users expressed a favorable view of the classification and resolutive nature of specialized services offered by Brazilian public health. The binary logistic regression analysis revealed weak points highlighting the difficulty involved in obtaining such treatments leading to unfavorable evaluations. In the resolutive nature item, difficulty in accessing the location, queues and lack of materials and equipment were highlighted as statistically significant unfavorable aspects. While many of the users considered the service to be resolutive, weaknesses were mentioned that need to be detected to promote improvements and to prevent other health models adopted worldwide from reproducing the same flaws. PMID- 27775587 TI - Guilt, Shame and Compassionate Imagery in War: Traumatized German Soldiers with PTSD, a Pilot Study. AB - BACKGROUND: The consideration of specific trauma-associated emotions poses a challenge for the differential treatment planning in trauma therapy. Soldiers experiencing deployment-related posttraumatic stress disorder often struggle with emotions of guilt and shame as a central component of their PTSD. OBJECTIVE: The purpose of this study was to examine the extent to which soldiers' PTSD symptoms and their trauma-related guilt and shame may be affected as a function of their ability to develop compassionate imagery between their CURRENT SELF (today) and their TRAUMATIZED SELF (back then). METHOD: The sample comprised 24 male German soldiers diagnosed with PTSD who were examined on the Posttraumatic Diagnostic Scale (PDS) and two additional measures: the Emotional Distress Inventory (EIBE) and the Quality of Interaction between the CURRENT SELF and the TRAUMATIZED SELF (QUI-HD: Qualitat der Interaktion zwischen HEUTIGEN ICH und DAMALIGEN ICH) at pre and post-treatment and again at follow-up. The treatment used was imagery rescripting and reprocessing therapy (IRRT). RESULTS: Eighteen of the 24 soldiers showed significant improvement in their PTSD symptoms at post-treatment and at follow-up (on their reliable change index). A significant change in trauma associated guilt and shame emerged when compassionate imagery was developed towards one's TRAUMATIZED SELF. The degree and intensity of the guilt and shame felt at the beginning of treatment and the degree of compassionate imagery developed toward the TRAUMATIZED SELF were predictors for change on the PDS scores. CONCLUSIONS: For soldiers suffering from specific war-related trauma involving PTSD, the use of self-nurturing, compassionate imagery that fosters reconciling with the traumatized part of the self can effectively diminish trauma related symptoms, especially when guilt and shame are central emotions. PMID- 27775588 TI - NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer. AB - BACKGROUND: There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 expression and its clinicopathological significance in early-stage cervical cancer. METHODS: NR2F6 expression in cervical cancer cell lines and cervical cancer tissues was determined by Western blotting, real-time PCR, and immunochemistry (IHC). NR2F6 expression in 189 human early-stage cervical cancer tissue samples was evaluated using IHC. The relevance between NR2F6 expression and early-stage cervical cancer prognosis and clinicopathological features was determined. RESULTS: There was marked NR2F6 mRNA and protein overexpression in the cervical cancer cells and clinical tissues compared with an immortalized squamous cell line and adjacent noncancerous cervical tissues, respectively. In the 189 cervical cancer samples, NR2F6 expression was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.006), squamous cell carcinoma antigen (p = 0.006), vital status (p < 0.001), tumor recurrence (p = 0.001), chemotherapy (p = 0.039), and lymph node metastasis (p < 0.001). Overall and disease-free survival was shorter in patients with early-stage cervical cancer and higher NR2F6 levels than in patients with lower levels of NR2F6. Univariate and multivariate analysis determined that NR2F6 was an independent prognostic factor of survival in early stage cervical cancer. CONCLUSIONS: Taken together, our findings suggest that high NR2F6 expression predicts pelvic lymph node metastasis, tumor recurrence and poor prognosis in early-stage cervical cancer. NR2F6 might be a novel prognostic biomarker and potential therapeutic target of cervical cancer. PMID- 27775586 TI - Hepatitis B Virus Protein X Induces Degradation of Talin-1. AB - In the infected human hepatocyte, expression of the hepatitis B virus (HBV) accessory protein X (HBx) is essential to maintain viral replication in vivo. HBx critically interacts with the host damaged DNA binding protein 1 (DDB1) and the associated ubiquitin ligase machinery, suggesting that HBx functions by inducing the degradation of host proteins. To identify such host proteins, we systematically analyzed the HBx interactome. One HBx interacting protein, talin-1 (TLN1), was proteasomally degraded upon HBx expression. Further analysis showed that TLN1 levels indeed modulate HBV transcriptional activity in an HBx-dependent manner. This indicates that HBx-mediated TLN1 degradation is essential and sufficient to stimulate HBV replication. Our data show that TLN1 can act as a viral restriction factor that suppresses HBV replication, and suggest that the HBx relieves this restriction by inducing TLN1 degradation. PMID- 27775585 TI - Beneficial Effects of UV-Radiation: Vitamin D and beyond. AB - Aside from its well-known effects on bone and mineral metabolism, vitamin D may also play an important role in extra-skeletal processes like immunologic diseases, cancer, or cardiovascular diseases. Even though meta-analyses showed that vitamin D supplementation reduces fractures, falls, and overall mortality, its potential benefits did not find universal acclaim. Several health care authorities published Recommended Dietary Allowances (RDAs) for vitamin D, most of them ranging from 600 to 800 international units (IU) per day, corresponding to a serum level of 25-hydroxyvitamin D of at least 20 ng/mL (50 nmol/L). However, studies conducted in the general population revealed a much lower overall intake of vitamin D than the proposed RDAs. Thus, strategies to increase the vitamin D intake in the general population, e.g., food fortification or vitamin D supplementation, are needed to match the existing evidence and recommendations. Therefore, several currently ongoing projects aim to investigate the effect of vitamin D supplementation in the general population and try to establish food-based solutions to improve vitamin D status. PMID- 27775589 TI - Different Culture Metabolites of the Red Sea Fungus Fusarium equiseti Optimize the Inhibition of Hepatitis C Virus NS3/4A Protease (HCV PR). AB - The endophytic fungus Fusarium equiseti was isolated from the brown alga Padina pavonica, collected from the Red Sea. The fungus was identified by its morphology and 18S rDNA. Cultivation of this fungal strain in biomalt-peptone medium led to isolation of 12 known metabolites of diketopeprazines and anthraquinones. The organic extract and isolated compounds were screened for their inhibition of hepatitis C virus NS3/4A protease (HCV PR). As a result, the fungal metabolites showed inhibition of HCV protease (IC50 from 19 to 77 MUM), and the fungus was subjected to culture on Czapek's (Cz) media, with a yield of nine metabolites with potent HCV protease inhibition ranging from IC50 10 to 37 MUM. The Cz culture extract exhibited high-level inhibition of HCV protease (IC50 27.6 MUg/mL) compared to the biomalt culture extract (IC50 56 MUg/mL), and the most potent HCV PR isolated compound (Griseoxanthone C, IC50 19.8 MUM) from the bio malt culture extract showed less of an inhibitory effect compared to isolated omega-hydroxyemodin (IC50 10.7 MUM) from the optimized Cz culture extract. Both HCV PR active inhibitors omega-hydroxyemodin and griseoxanthone C were considered as the lowest selective safe constituents against Trypsin inhibitory effect with IC50 48.5 and 51.3 MUM, respectively. PMID- 27775590 TI - High Prevalence of Hyperhomocysteinemia and Its Association with Target Organ Damage in Chinese Patients with Chronic Kidney Disease. AB - Hyperhomocysteinemia (HHcy) is recognized as a risk factor for cardiovascular disease. However, the prevalence of HHcy and its role in association with target organ damage in patients with chronickidney disease (CKD) are not well understood. This cross-sectional study included 1042 CKD patients who were admitted to our hospital. Patients were divided into two groups: hyperhomocysteinemia and normohomocysteinemia. Multivariable linear regression analyses were used to evaluate the association between plasma homocysteine and renal/cardiovascular parameters. The prevalence of HHcy in patients with CKD was 52.78%, and the prevalence in CKD stage 1, stage 2, stage 3, stage 4 and stage 5 patients was 10.73%, 29.22%, 58.71%, 75.23% and 83.75%, respectively. Patients with HHcy had higher incidences of renal damage, left ventricular hypertrophy, left ventricular diastolic dysfunction and abnormal carotid intima-media thickness compared with patients with normohomocysteinemia (p < 0.05), while multivariable linear regression analyses showed plasma homocysteine was only associated with the estimated glomerular filtration rate (eGFR). eGFR, uric acid, albumin, gender, hemoglobin and calcium*phosphate were associated with levels of plasma homocysteine in these CKD patients. The prevalence of HHcy in Chinese patients with CKD was high, and serum homocysteine levels were associated with impaired renal function in these patients. PMID- 27775591 TI - Capsaicin Supplementation Reduces Physical Fatigue and Improves Exercise Performance in Mice. AB - Chili pepper is used as a food, seasoning and has been revered for its medicinal and health claims. It is very popular and is the most common spice worldwide. Capsaicin (CAP) is a major pungent and bioactive phytochemical in chili peppers. CAP has been shown to improve mitochondrial biogenesis and adenosine triphosphate (ATP) production. However, there is limited evidence around the effects of CAP on physical fatigue and exercise performance. The purpose of this study was to evaluate the potential beneficial effects of CAP on anti-fatigue and ergogenic functions following physiological challenge. Female Institute of Cancer Research (ICR) mice from four groups (n = 8 per group) were orally administered CAP for 4 weeks at 0, 205, 410, and 1025 mg/kg/day, which were respectively designated the vehicle, CAP-1X, CAP-2X, and CAP-5X groups. The anti-fatigue activity and exercise performance was evaluated using forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, BUN (blood urea nitrogen) and creatine kinase (CK) after a 15-min swimming exercise. The grip strength and exhaustive swimming time of the CAP-5X group were significantly higher than other groups. CAP supplementation dose-dependently reduced serum lactate, ammonia, BUN and CK levels, and increased glucose concentration after the 15-min swimming test. In addition, CAP also increased hepatic glycogen content, an important energy source for exercise. The possible mechanism was relevant to energy homeostasis and the physiological modulations by CAP supplementation. Therefore, our results suggest that CAP supplementation may have a wide spectrum of bioactivities for promoting health, performance improvement and fatigue amelioration. PMID- 27775592 TI - Prokaryotic Expression, Purification and Immunogenicity in Rabbits of the Small Antigen of Hepatitis Delta Virus. AB - Hepatitis delta virus (HDV) is a viroid-like blood-borne human pathogen that accompanies hepatitis B virus infection in 5% patients. HDV has been studied for four decades; however, the knowledge on its life-cycle and pathogenesis is still sparse. The studies are hampered by the absence of the commercially-available HDV specific antibodies. Here, we describe a set of reproducible methods for the expression in E. coli of His-tagged small antigen of HDV (S-HDAg), its purification, and production of polyclonal anti-S-HDAg antibodies in rabbits. S HDAg was cloned into a commercial vector guiding expression of the recombinant proteins with the C-terminal His-tag. We optimized S-HDAg protein purification procedure circumventing a low affinity of the His-tagged S-HDAg to the Ni nitrilotriacetyl agarose (Ni-NTA-agarose) resin. Optimization allowed us to obtain S-HDAg with >90% purity. S-HDAg was used to immunize Shinchilla grey rabbits which received 80 MUg of S-HDAg in two subcutaneous primes in the complete, followed by four 40 MUg boosts in incomplete Freunds adjuvant. Rabbits were bled two weeks post each boost. Antibody titers determined by indirect ELISA exceeded 107. Anti-S-HDAg antibodies detected the antigen on Western blots in the amounts of up-to 100 pg. They were also successfully used to characterize the expression of S-HDAg in the eukaryotic cells by immunofluorescent staining/confocal microscopy. PMID- 27775593 TI - Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression. AB - Tumor-derived exosomes (TEX) are emerging as critical components of an intercellular information network between the tumor and the host. The tumor escapes from the host immune system by using a variety of mechanisms designed to impair or eliminate anti-tumor immunity. TEX carrying a cargo of immunoinhibitory molecules and factors represent one such mechanism. TEX, which are present in all body fluids of cancer patients, deliver negative molecular or genetic signals to immune cells re-programming their functions. Although TEX can also stimulate immune activity, in the microenvironments dominated by the tumor, TEX tend to mediate immune suppression thus promoting tumor progression. The TEX content, in part resembling that of the parent cell, may serve as a source of cancer biomarkers. TEX also interfere with immune therapies. A better understanding of TEX and their contribution to cancer progression and cancer patients' response to immune therapies represents a challenging new field of investigation. PMID- 27775594 TI - Extracellular Metabolites from Industrial Microalgae and Their Biotechnological Potential. AB - Industrial microalgae, as a big family of promising producers of renewable biomass feedstock, have been commercially exploited for functional food, living feed and feed additives, high-value chemicals in nutraceuticals, cosmeceuticals, and chemical reagents. Recently, microalgae have also been considered as a group that might play an important role in biofuel development and environmental protection. Almost all current products of industrial microalgae are derived from their biomass; however, large amounts of spent cell-free media are available from mass cultivation that is mostly unexploited. In this contribution we discuss that these media, which may contain a remarkable diversity of bioactive substances are worthy to be recovered for further use. Obviously, the extracellular metabolites from industrial microalgae have long been neglected in the development of production methods for valuable metabolites. With the advances in the last ten years, more and more structures and properties from extracellular metabolites have been identified, and the potential utilization over wide fields is attracting attention. Some of these extracellular metabolites can be potentially used as drugs, antioxidants, growth regulators or metal chelators. The purpose of this review is to provide an overview of the known extracellular metabolites from industrial microalgae which might be of commercial interest. The attention mainly focuses on the reports of extracellular bioactive metabolites and their potential application in biotechnology. PMID- 27775596 TI - Arrhythmia Classification Based on Multi-Domain Feature Extraction for an ECG Recognition System. AB - Automatic recognition of arrhythmias is particularly important in the diagnosis of heart diseases. This study presents an electrocardiogram (ECG) recognition system based on multi-domain feature extraction to classify ECG beats. An improved wavelet threshold method for ECG signal pre-processing is applied to remove noise interference. A novel multi-domain feature extraction method is proposed; this method employs kernel-independent component analysis in nonlinear feature extraction and uses discrete wavelet transform to extract frequency domain features. The proposed system utilises a support vector machine classifier optimized with a genetic algorithm to recognize different types of heartbeats. An ECG acquisition experimental platform, in which ECG beats are collected as ECG data for classification, is constructed to demonstrate the effectiveness of the system in ECG beat classification. The presented system, when applied to the MIT BIH arrhythmia database, achieves a high classification accuracy of 98.8%. Experimental results based on the ECG acquisition experimental platform show that the system obtains a satisfactory classification accuracy of 97.3% and is able to classify ECG beats efficiently for the automatic identification of cardiac arrhythmias. PMID- 27775597 TI - Susceptibility of Bemisia tabaci MEAM1 (Hemiptera: Aleyrodidae) to Imidacloprid, Thiamethoxam, Dinotefuran and Flupyradifurone in South Florida. AB - Populations of Bemisa tabaci MEAM1 were established from nineteen locations in south Florida, primarily from commercial tomato fields, and were tested using a cotton leaf petiole systemic uptake method for susceptibility to the nicotinic acetylcholine agonist insecticides imidacloprid, thiamethoxam, dinotefuran and flupyradifurone. Eleven populations produced LC50s for one or more chemicals that were not significantly different from the susceptible laboratory colony based on overlapping fiducial limits, indicating some degree of susceptibility. LC50s more than a 100-fold the laboratory colony were measured in at least one population for each material tested, indicating tolerance. LC50s (ppm) from field populations ranged from 0.901-24.952 for imidacloprid, 0.965-24.430 for thiamethoxam, 0.043-3.350 for dinotefuran and 0.011-1.471 for flupyradifurone. Based on overlapping fiducial limits, there were no significant differences in relative mean potency estimates for flupyradifurone and dinotefuran in relation to imidacloprid and thiamethoxam. PMID- 27775595 TI - The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health. AB - Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects. PMID- 27775598 TI - Nutrient Intake Is Insufficient among Senegalese Urban School Children and Adolescents: Results from Two 24 h Recalls in State Primary Schools in Dakar. AB - Due to rapid urbanization and high food prices and in the absence of nutrition programs, school children from urban areas in West Africa often have insufficient and inadequate diet leading to nutrient deficiencies that affect their health and schooling performance. Acute malnutrition and micronutrient deficiencies are prevalent in children from primary state schools of Dakar (Senegal). The objectives of the present study were to assess the overall diet of these children, to report insufficient/excessive energy and nutrient intakes and to investigate association between insufficient nutrient intake and micronutrient deficiencies. Children attending urban state primary schools in the Dakar area were selected through a two-stage random cluster sampling (30 schools * 20 children). Dietary intake data were obtained from two 24 h recalls and blood samples were collected from 545 children (aged 5-17 years, 45% < 10 years, 53% girls) and adjusted for intra-individual variability to estimate nutrient usual intakes. Energy intake was insufficient and unbalanced with insufficient contribution of protein and excessive contribution of fat to global energy intake in one third of the children. Proportions of children with insufficient intake were: 100% for calcium, 100% for folic acid, 79% for vitamin A, 69% for zinc, 53% for vitamin C and 46% for iron. Insufficient iron and protein intake were risk factors for iron deficiency (odds ratio, OR 1.5, 2.2). Insufficient zinc intake and energy intake from protein were risk factors for zinc deficiency (OR 1.8, 3.0, 1.7, 2.9). Insufficient iron and vitamin C intake, and insufficient energy intake from protein were risk factors for marginal vitamin A status (OR 1.8, 1.8, 3.3). To address nutritional deficiencies associated with a diet deficient in energy, protein and micronutrients, nutrition education or school feeding programs are needed in urban primary schools of Senegal. PMID- 27775599 TI - Corticospinal Excitability in Children with Congenital Hemiparesis. AB - Transcranial magnetic stimulation (TMS) can be used as an assessment or intervention to evaluate or influence brain activity in children with hemiparetic cerebral palsy (CP) commonly caused by perinatal stroke. This communication report analyzed data from two clinical trials using TMS to assess corticospinal excitability in children and young adults with hemiparetic CP. The results of this communication revealed a higher probability of finding a motor evoked potential (MEP) on the non-lesioned hemisphere compared to the lesioned hemisphere (p = 0.005). The resting motor threshold (RMT) was lower on the non lesioned hemisphere than the lesioned hemisphere (p = 0.013). There was a significantly negative correlation between age and RMT (rs = -0.65, p = 0.003). This communication provides information regarding MEP responses, motor thresholds (MTs) and the association with age during TMS assessment in children with hemiparetic CP. Such findings contribute to the development of future pediatric studies in neuroplasticity and neuromodulation to influence motor function and recovery after perinatal stroke. PMID- 27775600 TI - Modulation of the Anti-Tumor Efficacy of Photodynamic Therapy by Nitric Oxide. AB - Nitric oxide (NO) produced by nitric oxide synthase (NOS) enzymes is a free radical molecule involved in a wide variety of normophysiologic and pathophysiologic processes. Included in the latter category are cancer promotion, progression, and resistance to therapeutic intervention. Animal tumor photodynamic therapy (PDT) studies several years ago revealed that endogenous NO can reduce PDT efficacy and that NOS inhibitors can alleviate this. Until relatively recently, little else was known about this anti-PDT effect of NO, including: (a) the underlying mechanisms; (b) type(s) of NOS involved; and (c) whether active NO was generated in vascular cells, tumor cells, or both. In addressing these questions for various cancer cell lines exposed to PDT-like conditions, the author's group has made several novel findings, including: (i) exogenous NO can scavenge lipid-derived free radicals arising from photostress, thereby protecting cells from membrane-damaging chain peroxidation; (ii) cancer cells can upregulate inducible NOS (iNOS) after a PDT-like challenge and the resulting NO can signal for resistance to photokilling; (iii) photostress surviving cells with elevated iNOS/NO proliferate and migrate/invade more aggressively; and (iv) NO produced by photostress-targeted cells can induce greater aggressiveness in non-targeted bystander cells. In this article, the author briefly discusses these various means by which NO can interfere with PDT and how this may be mitigated by use of NOS inhibitors as PDT adjuvants. PMID- 27775601 TI - Defining Conditions for Optimal Inhibition of Food Intake in Rats by a Grape-Seed Derived Proanthocyanidin Extract. AB - Food intake depends on homeostatic and non-homeostatic factors. In order to use grape seed proanthocyanidins (GSPE) as food intake limiting agents, it is important to define the key characteristics of their bioactivity within this complex function. We treated rats with acute and chronic treatments of GSPE at different doses to identify the importance of eating patterns and GSPE dose and the mechanistic aspects of GSPE. GSPE-induced food intake inhibition must be reproduced under non-stressful conditions and with a stable and synchronized feeding pattern. A minimum dose of around 350 mg GSPE/kg body weight (BW) is needed. GSPE components act by activating the Glucagon-like peptide-1 (GLP-1) receptor because their effect is blocked by Exendin 9-39. GSPE in turn acts on the hypothalamic center of food intake control probably because of increased GLP 1 production in the intestine. To conclude, GSPE inhibits food intake through GLP 1 signaling, but it needs to be dosed under optimal conditions to exert this effect. PMID- 27775602 TI - Age-Related Effect of Viral-Induced Wheezing in Severe Prematurity. AB - Premature children are prone to severe viral respiratory infections in early life, but the age at which susceptibility peaks and disappears for each pathogen is unclear. Methods: A retrospective analysis was performed of the age distribution and clinical features of acute viral respiratory infections in full term and premature children, aged zero to seven years. Results: The study comprised of a total of 630 hospitalizations (n = 580 children). Sixty-seven percent of these hospitalizations occurred in children born full-term (>37 weeks), 12% in preterm (32-37 weeks) and 21% in severely premature children (<32 weeks). The most common viruses identified were rhinovirus (RV; 60%) and respiratory syncytial virus (RSV; 17%). Age-distribution analysis of each virus identified that severely premature children had a higher relative frequency of RV and RSV in their first three years, relative to preterm or full-term children. Additionally, the probability of RV- or RSV-induced wheezing was higher overall in severely premature children less than three years old. Conclusions: Our results indicate that the vulnerability to viral infections in children born severely premature is more specific for RV and RSV and persists during the first three years of age. Further studies are needed to elucidate the age-dependent molecular mechanisms that underlie why premature infants develop RV- and RSV induced wheezing in early life. PMID- 27775604 TI - Quality Nutrition Care: Measuring Hospital Staff's Knowledge, Attitudes, and Practices. AB - Understanding the knowledge, attitudes, and practices (KAP) of hospital staff is needed to improve care activities that support the detection/prevention/treatment of malnutrition, yet quality measures are lacking. The purpose was to develop (study 1) and assess the administration and discriminative potential (study 2) of using such a KAP measure in acute care. In study 1, a 27-question KAP questionnaire was developed, face validated (n = 5), and tested for reliability (n = 35). Kappa and Intraclass Correlation (ICC) were determined. In study 2, the questionnaire was sent to staff at five diverse hospitals (n = 189). Administration challenges were noted and analyses completed to determine differences across sites, professions, and years of practice. Study 1 results demonstrate that the knowledge/attitude (KA) and the practice (P) subscales are reliable (KA: ICC = 0.69 95% CI 0.45-0.84, F = 5.54, p < 0.0001; P: ICC = 0.84 95% CI 0.68-0.92, F = 11.12, p < 0.0001). Completion rate of individual questions in study 2 was high and suggestions to improve administration were identified. The KAP mean score was 93.6/128 (range 51-124) with higher scores indicating more knowledge, better attitudes and positive practices. Profession and years of practice were associated with KAP scores. The KAP questionnaire is a valid and reliable measure that can be used in needs assessments to inform improvements to nutrition care in hospital. PMID- 27775603 TI - Zinc Finger and X-Linked Factor (ZFX) Binds to Human SET Transcript 2 Promoter and Transactivates SET Expression. AB - SET (SE Translocation) protein carries out multiple functions including those for protein phosphatase 2A (PP2A) inhibition, histone modification, DNA repair, and gene regulation. SET overexpression has been detected in brain neurons of patients suffering Alzheimer's disease, follicle theca cells of Polycystic Ovary Syndrome (PCOS) patients, and ovarian cancer cells, indicating that SET may play a pathological role for these disorders. SET transcript 2, produced by a specific promoter, represents a major transcript variant in different cell types. In this study, we characterized the transcriptional activation of human SET transcript 2 promoter in HeLa cells. Promoter deletion experiments and co-transfection assays indicated that ZFX, the Zinc finger and X-linked transcription factor, was able to transactivate the SET promoter. A proximal promoter region containing four ZFX binding sites was found to be critical for the ZFX-mediated transactivation. Mutagenesis study indicated that the ZFX-binding site located the closest to the transcription start site accounted for most of the ZFX-mediated transactivity. Manipulation of ZFX levels by overexpression or siRNA knockdown confirmed the significance and specificity of the ZFX-mediated SET promoter activation. Chromatin immunoprecipitation results verified the binding of ZFX to its cognate sites in the SET promoter. These findings have led to identification of ZFX as an upstream factor regulating SET gene expression. More studies are required to define the in vivo significance of this mechanism, and specifically, its implication for several benign and malignant diseases related to SET dysregulation. PMID- 27775607 TI - Antioxidant Activity of Oat Proteins Derived Peptides in Stressed Hepatic HepG2 Cells. AB - The purpose of this study was to determine, for the first time, antioxidant activities of seven peptides (P1-P7) derived from hydrolysis of oat proteins in a cellular model. In the oxygen radical absorbance capacity (ORAC) assay, it was found that P2 had the highest radical scavenging activity (0.67 +/- 0.02 uM Trolox equivalent (TE)/uM peptide) followed by P5, P3, P6, P4, P1, and P7 whose activities were between 0.14-0.61 uM TE/uM). In the hepatic HepG2 cells, none of the peptides was cytotoxic at 20-300 uM. In addition to having the highest ORAC value, P2 was also the most protective (29% increase in cell viability) against 2,2'-azobis(2-methylpropionamidine) dihydrochloride -induced oxidative stress. P1, P6, and P7 protected at a lesser extent, with an 8%-21% increase viability of cells. The protection of cells was attributed to several factors including reduced production of intracellular reactive oxygen species, increased cellular glutathione, and increased activities of three main endogenous antioxidant enzymes. PMID- 27775605 TI - Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits. AB - Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered. PMID- 27775606 TI - Phytocystatins: Defense Proteins against Phytophagous Insects and Acari. AB - This review deals with phytocystatins, focussing on their potential role as defence proteins against phytophagous arthropods. Information about the evolutionary, molecular and biochemical features and inhibitory properties of phytocystatins are presented. Cystatin ability to inhibit heterologous cysteine protease activities is commented on as well as some approaches of tailoring cystatin specificity to enhance their defence function towards pests. A general landscape on the digestive proteases of phytophagous insects and acari and the remarkable plasticity of their digestive physiology after feeding on cystatins are highlighted. Biotechnological approaches to produce recombinant cystatins to be added to artificial diets or to be sprayed as insecticide-acaricide compounds and the of use cystatins as transgenes are discussed. Multiple examples and applications are included to end with some conclusions and future perspectives. PMID- 27775608 TI - Discovery of Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors: 2 Aminoindan beta-Lactam Derivatives. AB - beta-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. beta-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that beta-lactams are inhibitors of hCA I, II and AChE. The Ki values of beta-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0.25-1.13 nM against AChE. Our findings indicate that beta-lactams (2a-k) inhibit both carbonic anhydrases (CA) isoenzymes and AChE at low nanomolar concentrations. PMID- 27775610 TI - Prediction, Detection, and Validation of Isotope Clusters in Mass Spectrometry Data. AB - Mass spectrometry is a key analytical platform for metabolomics. The precise quantification and identification of small molecules is a prerequisite for elucidating the metabolism and the detection, validation, and evaluation of isotope clusters in LC-MS data is important for this task. Here, we present an approach for the improved detection of isotope clusters using chemical prior knowledge and the validation of detected isotope clusters depending on the substance mass using database statistics. We find remarkable improvements regarding the number of detected isotope clusters and are able to predict the correct molecular formula in the top three ranks in 92 % of the cases. We make our methodology freely available as part of the Bioconductor packages xcms version 1.50.0 and CAMERA version 1.30.0. PMID- 27775609 TI - Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis. AB - The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann-Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP. PMID- 27775612 TI - Cutthroat Trout Virus-Towards a Virus Model to Support Hepatitis E Research. AB - Cutthroat trout virus (CTV) is a non-pathogenic fish virus belonging to the Hepeviridae family, and it is distantly related to hepatitis E virus (HEV). Here, we report the development of an efficient cell culture system where CTV can consistently replicate to titers never observed before with a hepevirus. By using the rainbow trout gill (RTGill-W1) cell line, CTV reaches 1010 geq/mL intracellularly and 108 geq/mL extracellularly within 5-6 days in culture. We additionally established a qPCR system to investigate CTV infectivity, and developed a specific antibody directed against the viral capsid protein encoded by ORF2. With these methods, we were able to follow the progressive accumulation of viral RNA and the capsid protein, and their intracellular distribution during virus replication. Virus progeny purified through iodixanol density gradients indicated-that similar to HEV-CTV produced in cell culture is also lipid associated. The lack of an efficient cell culture system has greatly impeded studies with HEV, a major human pathogen that causes hepatitis worldwide. Although several cell culture systems have recently been established, the replication efficiency of HEV is not robust enough to allow studies on different aspects of the virus replication cycle. Therefore, a surrogate virus that can replicate easily and efficiently in cultured cells would be helpful to boost research studies with hepeviruses. Due to its similarities, but also its key differences to HEV, CTV represents a promising tool to elucidate aspects of the replication cycle of Hepeviridae in general, and HEV in particular. PMID- 27775611 TI - Critical Analysis of the Melanogenic Pathway in Insects and Higher Animals. AB - Animals synthesize melanin pigments for the coloration of their skin and use it for their protection from harmful solar radiation. Insects use melanins even more ingeniously than mammals and employ them for exoskeletal pigmentation, cuticular hardening, wound healing and innate immune responses. In this review, we discuss the biochemistry of melanogenesis process occurring in higher animals and insects. A special attention is given to number of aspects that are not previously brought to light: (1) the molecular mechanism of dopachrome conversion that leads to the production of two different dihydroxyindoles; (2) the role of catecholamine derivatives other than dopa in melanin production in animals; (3) the critical parts played by various biosynthetic enzymes associated with insect melanogenesis; and (4) the presence of a number of important gaps in both melanogenic and sclerotinogenic pathways. Additionally, importance of the melanogenic process in insect physiology especially in the sclerotization of their exoskeleton, wound healing reactions and innate immune responses is highlighted. The comparative biochemistry of melanization with sclerotization is also discussed. PMID- 27775614 TI - Curcumin Shows Antiviral Properties against Norovirus. AB - Phytochemicals provide environmentally friendly and relatively inexpensive natural products, which could potentially benefit public health by controlling human norovirus (HuNoV) infection. In this study, 18 different phytochemicals were evaluated for antiviral effects against norovirus using murine norovirus (MNV) as a model for norovirus biology. Among these phytochemicals, curcumin (CCM) was the most potent anti-noroviral phytochemical, followed by resveratrol (RVT). In a cell culture infection model, exposure to CCM or RVT for 3 days reduced infectivity of norovirus by 91% and 80%, respectively. To confirm the antiviral capability of CCM, we further evaluated its antiviral efficacy at various doses (0.25, 0.5, 0.75, 1, and 2 mg/mL) and durations (short-term: 10, 30, 60, and 120 min; long-term: 1, 3, 7, and 14 days). The anti-noroviral effect of CCM was verified to occur in a dose-dependent manner. Additionally, we evaluated the inhibitory effect of each phytochemical on the replication of HuNoV using a HuNoV replicon-bearing cell line (HG23). Neither CCM nor RVT had a strong inhibitory effect on HuNoV replication, which suggests that their antiviral mechanism may involve viral entry or other life cycle stages rather than the replication of viral RNA. Our results demonstrated that CCM may be a promising candidate for development as an anti-noroviral agent to prevent outbreaks of foodborne illness. PMID- 27775613 TI - Brachycorynella asparagi (Mordv.) Induced-Oxidative Stress and Antioxidative Defenses of Asparagus officinalis L. AB - The aim of this study was to investigate whether and to what extent oxidative stress is induced in leaves of one- and two-month-old plants of Asparagus officinalis L. cv. Argenteuil infested by Brachycorynella asparagi (Mordvilko) at a varied population size. The pest B. asparagi has been described as the most damaging species feeding on asparagus. Analyses using electron paramagnetic resonance (EPR) demonstrated generally higher concentrations of semiquinone radicals with g-values of 2.0045 +/- 0.0005 and 2.0026 +/- 0.0005 in Asparagus officinalis (A. officinalis) leaves after Brachycorynella asparagi (B. asparagi) infestation than in the control. Observations of leaves under a confocal microscope showed a post-infestation enhanced generation of the superoxide anion radical (O2*-) and hydrogen peroxide (H2O2) in comparison to the control. Strong fluctuations in Mn2+ ion levels detected by EPR spectroscopy versus time were detected in leaves infested by aphids, which may indicate the involvement of these ions in the control of O2*- production. An enhanced superoxide dismutase activity is an important element in leaf defense against oxidative stress. Visible symptoms were found in aphid-infested A. officinalis. Damage to leaves of one- and two-month-old A. officinalis plants by the aphid B. asparagi was dependent on the intensity, duration of infestation and plant age. PMID- 27775615 TI - MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1) Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs) Transplanted into Infarcted Heart. AB - Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS) production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1) has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs) might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs) based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs) and on rat myocardial infarction (MI) models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post transplantation, leading to an increase in the efficacy of MSC-based cell therapy. PMID- 27775617 TI - Blue Light Emitting Polyphenylene Dendrimers with Bipolar Charge Transport Moieties. AB - Two light-emitting polyphenylene dendrimers with both hole and electron transporting moieties were synthesized and characterized. Both molecules exhibited pure blue emission solely from the pyrene core and efficient surface-to core energy transfers when characterized in a nonpolar environment. In particular, the carbazole- and oxadiazole-functionalized dendrimer (D1) manifested a pure blue emission from the pyrene core without showing intramolecular charge transfer (ICT) in environments with increasing polarity. On the other hand, the triphenylamine- and oxadiazole-functionalized one (D2) displayed notable ICT with dual emission from both the core and an ICT state in highly polar solvents. D1, in a three-layer organic light emitting diode (OLED) by solution processing gave a pure blue emission with Commission Internationale de l'Eclairage 1931 CIE xy = (0.16, 0.12), a peak current efficiency of 0.21 cd/A and a peak luminance of 2700 cd/m2. This represents the first reported pure blue dendrimer emitter with bipolar charge transport and surface-to-core energy transfer in OLEDs. PMID- 27775616 TI - Natural Occurring Silks and Their Analogues as Materials for Nerve Conduits. AB - Spider silk and its synthetic derivatives have a light weight in combination with good strength and elasticity. Their high cytocompatibility and low immunogenicity make them well suited for biomaterial products such as nerve conduits. Silk proteins slowly degrade enzymatically in vivo, thus allowing for an initial therapeutic effect such as in nerve scaffolding to facilitate endogenous repair processes, and then are removed. Silks are biopolymers naturally produced by many species of arthropods including spiders, caterpillars and mites. The silk fibers are secreted by the labial gland of the larvae of some orders of Holometabola (insects with pupa) or the spinnerets of spiders. The majority of studies using silks for biomedical applications use materials from silkworms or spiders, mostly of the genus Nephila clavipes. Silk is one of the most promising biomaterials with effects not only in nerve regeneration, but in a number of regenerative applications. The development of silks for human biomedical applications is of high scientific and clinical interest. Biomaterials in use for biomedical applications have to meet a number of requirements such as biocompatibility and elicitation of no more than a minor inflammatory response, biodegradability in a reasonable time and specific structural properties. Here we present the current status in the field of silk-based conduit development for nerve repair and discuss current advances with regard to potential clinical transfer of an implantable nerve conduit for enhancement of nerve regeneration. PMID- 27775618 TI - Effects of Saponins on Lipid Metabolism: A Review of Potential Health Benefits in the Treatment of Obesity. AB - Obesity is one of the greatest public health problems. This complex condition has reached epidemic proportions in many parts of the world, and it constitutes a risk factor for several chronic disorders, such as hypertension, cardiovascular diseases and type 2 diabetes. In the last few decades, several studies dealt with the potential effects of natural products as new safe and effective tools for body weight control. Saponins are naturally-occurring surface-active glycosides, mainly produced by plants, whose structure consists of a sugar moiety linked to a hydrophobic aglycone (a steroid or a triterpene). Many pharmacological properties have been reported for these compounds, such as anti-inflammatory, immunostimulant, hypocholesterolemic, hypoglycemic, antifungal and cytotoxic activities. The aim of this review is to provide an overview of recent studies about the anti-obesity therapeutic potential of saponins isolated from medicinal plants. Results on the in vitro and in vivo activity of this class of phytochemicals are here presented and discussed. The most interesting findings about their possible mechanism of action and their potential health benefits in the treatment of obesity are reported, as well. PMID- 27775619 TI - Analogs of Natural 3-Deoxyanthocyanins: O-Glucosides of the 4',7 Dihydroxyflavylium Ion and the Deep Influence of Glycosidation on Color. AB - 3-Deoxyanthocyanidins and their O-beta-d-glucosides are natural pigments abundant in black sorghum. O-glycosidation can perturb the acid-base properties of the chromophore and lower its electron density with a large impact on the distribution of colored and colorless forms in aqueous solution. In this work, the influence of O-glycosidation on color is systematically studied from a series of 3-deoxyanthocyanin analogs. The pH- and light-dependent reversible reactions of 7-beta-d-glucopyranosyloxy-4'-hydroxyflavylium (P3) and 4'-beta-d glucopyranosyloxy-7-hydroxyflavylium (P5) were completely characterized in mildly acidic solution and compared with the parent aglycone 4',7-dihydroxyflavylium ion and the O-methylethers of P3 and P5. Except P5, the chalcone forms of the pigments exhibit a high cis-trans isomerization barrier that allows a pseudo equilibrium involving all species except the trans-chalcone. At equilibrium, only the flavylium cation and trans-chalcone are observed. With all pigments, the colored flavylium ion can be generated by irradiation of the trans-chalcone (photochromism). Glycosidation of C7-OH accelerates hydration and strongly slows down cis-trans isomerization with the pH dependence of the apparent isomerization rate constant shifting from a bell-shaped curve to a sigmoid. The color of P5 is much more stable than that of its regioisomer P3 in near-neutral conditions. PMID- 27775620 TI - Iterative Diffusion-Based Distributed Cubature Gaussian Mixture Filter for Multisensor Estimation. AB - In this paper, a distributed cubature Gaussian mixture filter (DCGMF) based on an iterative diffusion strategy (DCGMF-ID) is proposed for multisensor estimation and information fusion. The uncertainties are represented as Gaussian mixtures at each sensor node. A high-degree cubature Kalman filter provides accurate estimation of each Gaussian mixture component. An iterative diffusion scheme is utilized to fuse the mean and covariance of each Gaussian component obtained from each sensor node. The DCGMF-ID extends the conventional diffusion-based fusion strategy by using multiple iterative information exchanges among neighboring sensor nodes. The convergence property of the iterative diffusion is analyzed. In addition, it is shown that the convergence of the iterative diffusion can be interpreted from the information-theoretic perspective as minimization of the Kullback-Leibler divergence. The performance of the DCGMF-ID is compared with the DCGMF based on the average consensus (DCGMF-AC) and the DCGMF based on the iterative covariance intersection (DCGMF-ICI) via a maneuvering target-tracking problem using multiple sensors. The simulation results show that the DCGMF-ID has better performance than the DCGMF based on noniterative diffusion, which validates the benefit of iterative information exchanges. In addition, the DCGMF ID outperforms the DCGMF-ICI and DCGMF-AC when the number of iterations is limited. PMID- 27775621 TI - A Self-Synthesis Approach to Perceptual Learning for Multisensory Fusion in Robotics. AB - Biological and technical systems operate in a rich multimodal environment. Due to the diversity of incoming sensory streams a system perceives and the variety of motor capabilities a system exhibits there is no single representation and no singular unambiguous interpretation of such a complex scene. In this work we propose a novel sensory processing architecture, inspired by the distributed macro-architecture of the mammalian cortex. The underlying computation is performed by a network of computational maps, each representing a different sensory quantity. All the different sensory streams enter the system through multiple parallel channels. The system autonomously associates and combines them into a coherent representation, given incoming observations. These processes are adaptive and involve learning. The proposed framework introduces mechanisms for self-creation and learning of the functional relations between the computational maps, encoding sensorimotor streams, directly from the data. Its intrinsic scalability, parallelisation, and automatic adaptation to unforeseen sensory perturbations make our approach a promising candidate for robust multisensory fusion in robotic systems. We demonstrate this by applying our model to a 3D motion estimation on a quadrotor. PMID- 27775622 TI - A 3D CFD Simulation and Analysis of Flow-Induced Forces on Polymer Piezoelectric Sensors in a Chinese Liquors Identification E-Nose. AB - Chinese liquors can be classified according to their flavor types. Accurate identification of Chinese liquor flavors is not always possible through professional sommeliers' subjective assessment. A novel polymer piezoelectric sensor electric nose (e-nose) can be applied to distinguish Chinese liquors because of its excellent ability in imitating human senses by using sensor arrays and pattern recognition systems. The sensor, based on the quartz crystal microbalance (QCM) principle is comprised of a quartz piezoelectric crystal plate sandwiched between two specific gas-sensitive polymer coatings. Chinese liquors are identified by obtaining the resonance frequency value changes of each sensor using the e-nose. However, the QCM principle failed to completely account for a particular phenomenon: we found that the resonance frequency values fluctuated in the stable state. For better understanding the phenomenon, a 3D Computational Fluid Dynamics (CFD) simulation using the finite volume method is employed to study the influence of the flow-induced forces to the resonance frequency fluctuation of each sensor in the sensor box. A dedicated procedure was developed for modeling the flow of volatile gas from Chinese liquors in a realistic scenario to give reasonably good results with fair accuracy. The flow-induced forces on the sensors are displayed from the perspective of their spatial temporal and probability density distributions. To evaluate the influence of the fluctuation of the flow-induced forces on each sensor and ensure the serviceability of the e-nose, the standard deviation of resonance frequency value (SDF) and the standard deviation of resultant forces (SDFy) in y-direction (Fy) are compared. Results show that the fluctuations of Fy are bound up with the resonance frequency values fluctuations. To ensure that the sensor's resonance frequency values are steady and only fluctuate slightly, in order to improve the identification accuracy of Chinese liquors using the e-nose, the sensors in the sensor box should be in the proper place, i.e., where the fluctuations of the flow-induced forces is relatively small. This plays a significant reference role in determining the optimum design of the e-nose for accurately identifying Chinese liquors. PMID- 27775623 TI - A Readout IC Using Two-Step Fastest Signal Identification for Compact Data Acquisition of PET Systems. AB - A readout integrated circuit (ROIC) using two-step fastest signal identification (FSI) is proposed to reduce the number of input channels of a data acquisition (DAQ) block with a high-channel reduction ratio. The two-step FSI enables the proposed ROIC to filter out useless input signals that arise from scattering and electrical noise without using complex and bulky circuits. In addition, an asynchronous fastest signal identifier and a self-trimmed comparator are proposed to identify the fastest signal without using a high-frequency clock and to reduce misidentification, respectively. The channel reduction ratio of the proposed ROIC is 16:1 and can be extended to 16 * N:1 using N ROICs. To verify the performance of the two-step FSI, the proposed ROIC was implemented into a gamma photon detector module using a Geiger-mode avalanche photodiode with a lutetium-yttrium oxyorthosilicate array. The measured minimum detectable time is 1 ns. The difference of the measured energy and timing resolution between with and without the two-step FSI are 0.8% and 0.2 ns, respectively, which are negligibly small. These measurement results show that the proposed ROIC using the two-step FSI reduces the number of input channels of the DAQ block without sacrificing the performance of the positron emission tomography (PET) systems. PMID- 27775624 TI - Decoupling Control of Micromachined Spinning-Rotor Gyroscope with Electrostatic Suspension. AB - A micromachined gyroscope in which a high-speed spinning rotor is suspended electrostatically in a vacuum cavity usually functions as a dual-axis angular rate sensor. An inherent coupling error between the two sensing axes exists owing to the angular motion of the spinning rotor being controlled by a torque rebalance loop. In this paper, a decoupling compensation method is proposed and investigated experimentally based on an electrostatically suspended micromachined gyroscope. In order to eliminate the negative spring effect inherent in the gyroscope dynamics, a stiffness compensation scheme was utilized in design of the decoupled rebalance loop to ensure loop stability and increase suspension stiffness. The experimental results show an overall stiffness increase of 30.3% after compensation. A decoupling method comprised of inner- and outer-loop decoupling compensators is proposed to minimize the cross-axis coupling error. The inner-loop decoupling compensator aims to attenuate the angular position coupling. The experimental frequency response shows a position coupling attenuation by 14.36 dB at 1 Hz. Moreover, the cross-axis coupling between the two angular rate output signals can be attenuated theoretically from -56.2 dB down to -102 dB by further appending the outer-loop decoupling compensator. The proposed dual-loop decoupling compensation algorithm could be applied to other dual-axis spinning-rotor gyroscopes with various suspension solutions. PMID- 27775625 TI - A Novel Model-Based Driving Behavior Recognition System Using Motion Sensors. AB - In this article, a novel driving behavior recognition system based on a specific physical model and motion sensory data is developed to promote traffic safety. Based on the theory of rigid body kinematics, we build a specific physical model to reveal the data change rule during the vehicle moving process. In this work, we adopt a nine-axis motion sensor including a three-axis accelerometer, a three axis gyroscope and a three-axis magnetometer, and apply a Kalman filter for noise elimination and an adaptive time window for data extraction. Based on the feature extraction guided by the built physical model, various classifiers are accomplished to recognize different driving behaviors. Leveraging the system, normal driving behaviors (such as accelerating, braking, lane changing and turning with caution) and aggressive driving behaviors (such as accelerating, braking, lane changing and turning with a sudden) can be classified with a high accuracy of 93.25%. Compared with traditional driving behavior recognition methods using machine learning only, the proposed system possesses a solid theoretical basis, performs better and has good prospects. PMID- 27775626 TI - Developing Benthic Class Specific, Chlorophyll-a Retrieving Algorithms for Optically-Shallow Water Using SeaWiFS. AB - This study evaluated the ability to improve Sea-Viewing Wide Field-of-View Sensor (SeaWiFS) chl-a retrieval from optically shallow coastal waters by applying algorithms specific to the pixels' benthic class. The form of the Ocean Color (OC) algorithm was assumed for this study. The operational atmospheric correction producing Level 2 SeaWiFS data was retained since the focus of this study was on establishing the benefit from the alternative specification of the bio-optical algorithm. Benthic class was determined through satellite image-based classification methods. Accuracy of the chl-a algorithms evaluated was determined through comparison with coincident in situ measurements of chl-a. The regionally tuned models that were allowed to vary by benthic class produced more accurate estimates of chl-a than the single, unified regionally-tuned model. Mean absolute percent difference was approximately 70% for the regionally-tuned, benthic class specific algorithms. Evaluation of the residuals indicated the potential for further improvement to chl-a estimation through finer characterization of benthic environments. Atmospheric correction procedures specialized to coastal environments were recognized as areas for future improvement as these procedures would improve both classification and algorithm tuning. PMID- 27775627 TI - Development and Application of a Wireless Sensor for Space Charge Density Measurement in an Ultra-High-Voltage, Direct-Current Environment. AB - A space charge density wireless measurement system based on the idea of distributed measurement is proposed for collecting and monitoring the space charge density in an ultra-high-voltage direct-current (UHVDC) environment. The proposed system architecture is composed of a number of wireless nodes connected with space charge density sensors and a base station. The space charge density sensor based on atmospheric ion counter method is elaborated and developed, and the ARM microprocessor and Zigbee radio frequency module are applied. The wireless network communication quality and the relationship between energy consumption and transmission distance in the complicated electromagnetic environment is tested. Based on the experimental results, the proposed measurement system demonstrates that it can adapt to the complex electromagnetic environment under the UHVDC transmission lines and can accurately measure the space charge density. PMID- 27775628 TI - Chocolate Classification by an Electronic Nose with Pressure Controlled Generated Stimulation. AB - In this work, we will analyze the response of a Metal Oxide Gas Sensor (MOGS) array to a flow controlled stimulus generated in a pressure controlled canister produced by a homemade olfactometer to build an E-nose. The built E-nose is capable of chocolate identification between the 26 analyzed chocolate bar samples and four features recognition (chocolate type, extra ingredient, sweetener and expiration date status). The data analysis tools used were Principal Components Analysis (PCA) and Artificial Neural Networks (ANNs). The chocolate identification E-nose average classification rate was of 81.3% with 0.99 accuracy (Acc), 0.86 precision (Prc), 0.84 sensitivity (Sen) and 0.99 specificity (Spe) for test. The chocolate feature recognition E-nose gives a classification rate of 85.36% with 0.96 Acc, 0.86 Prc, 0.85 Sen and 0.96 Spe. In addition, a preliminary sample aging analysis was made. The results prove the pressure controlled generated stimulus is reliable for this type of studies. PMID- 27775629 TI - High-Pressure Design of Advanced BN-Based Materials. AB - The aim of the present review is to highlight the state of the art in high pressure design of new advanced materials based on boron nitride. Recent experimental achievements on the governing phase transformation, nanostructuring and chemical synthesis in the systems containing boron nitride at high pressures and high temperatures are presented. All these developments allowed discovering new materials, e.g., ultrahard nanocrystalline cubic boron nitride (nano-cBN) with hardness comparable to diamond, and superhard boron subnitride B13N2. Thermodynamic and kinetic aspects of high-pressure synthesis are described based on the data obtained by in situ and ex situ methods. Mechanical and thermal properties (hardness, thermoelastic equations of state, etc.) are discussed. New synthetic perspectives, combining both soft chemistry and extreme pressure temperature conditions are considered. PMID- 27775630 TI - Multi-Level, Multi-Component Approaches to Community Based Interventions for Healthy Living-A Three Case Comparison. AB - There is increasing interest in integrated and coordinated programs that intervene in multiple community settings/institutions at the same time and involve policy and system changes. The purpose of the paper is to analyse three comparable cases of Multi Level, Multi Component intervention programs (ML-MC) from across the world in order to give recommendations for research, policy and practice in this field. Through the comparison of three cases: Health and Local Community (SoL-program), Children's Healthy Living (CHL) and B'More Healthy Communities for Kids (BHCK), this paper examines the potential of ML-MC community based public health nutrition interventions to create sustainable change. The paper proposes methodology, guidelines and directions for future research through analysis and examination strengths and weaknesses in the programs. Similarities are that they engage and commit local stakeholders in a structured approach to integrate intervention components in order to create dose and intensity. In that way, they all make provisions for post intervention impact sustainability. All programs target the child and family members' knowledge, attitudes, behavior, the policy level, and the environmental level. The study illustrates the diversity in communities as well as diversity in terms of which and how sites and settings such as schools, kindergartens, community groups and grocery stores became involved in the programs. Programs are also different in terms of involvement of media stakeholders. The comparison of the three cases suggests that there is a need to build collaboration and partnerships from the beginning, plan for sufficient intensity/dose, emphasize/create consistency across levels and components of the intervention, build synchronization across levels, and plan for sustainability. PMID- 27775631 TI - Seasonal Dynamics of Metabolites in Needles of Taxus wallichiana var. mairei. AB - Seasonal variations of the phytochemicals contents in needles of T. wallichiana var. mairei due to the effects of growth meteorological parameters were investigated in this study. The needles of T. wallichiana var. mairei were collected from different months and the contents of taxoids (paclitaxel, 10 deacetylbaccatin III (10-DAB), baccatin III, cephalomannine, 10-deacetyltaxol (10 DAT)), flavones (ginkgetin, amentoflavone, quercetin) and polysaccharides were quantified by ultra performance liquid chromatography (UPLC) and the resonance light scattering (RIL) method. The content of taxoids gave the highest level of 1.77 +/- 0.38 mg.g-1 in January, and the lowest value of 0.61 +/- 0.08 mg.g-1 in September. Unlike taxoids, the content of flavonoids was the highest in August. The content of polysaccharides reached peak value of 28.52 +/- 0.57 mg.g-1 in September, which was two times higher than the lowest content of 9.39 +/- 0.17 mg.g-1 in January. The contents of paclitaxel, 10-DAB, 10-DAT and polysaccharides significantly depended on meteorological parameters. The mean of minimum temperature (R = -0.61) and length of daylight (R = -0.60) were significantly correlated to 10-DAB content, while 10-DAT level showed significant correlation with length of daylight (R = -0.70) and relative humidity (R = 0.70). In addition, temperature had significantly negative effect on the content of paclitaxel and a significantly positive effect on that of polysaccharides. This study enriched the knowledge on the accumulation pattern of metabolites and could help us to determine the collecting time of T. wallichiana var. mairei for medicinal use. PMID- 27775632 TI - Identification of Novel Human Breast Carcinoma (MDA-MB-231) Cell Growth Modulators from a Carbohydrate-Based Diversity Oriented Synthesis Library. AB - The application of a cell-based growth inhibition on a library of skeletally different glycomimetics allowed for the selection of a hexahydro-2H-furo[3,2 b][1,4]oxazine compound as candidate inhibitors of MDA-MB-231 cell growth. Subsequent synthesis of analogue compounds and preliminary biological studies validated the selection of a valuable hit compound with a novel polyhydroxylated structure for the modulation of the breast carcinoma cell cycle mechanism. PMID- 27775633 TI - Improved Production and Antitumor Properties of Triterpene Acids from Submerged Culture of Ganoderma lingzhi. AB - Triterpene acids (TAs) are the major bioactive constituents in the medicinal fungus Ganoderma lingzhi. However, fermentative production of TAs has not been optimized for commercial use, and whether the TAs isolated from G. lingzhi submerged culture mycelia possess antitumor activity needs to be further proven. In this study, enhanced TA yield and productivity were attained with G. lingzhi using response surface methodology. The interactions of three variables were studied using a Box-Benhnken design, namely initial pH, dissolved oxygen (DO) and fermentation temperature. The optimum conditions were an initial pH of 5.9, 20.0% DO and 28.6 degrees C. These conditions resulted in a TA yield of 308.1 mg/L in a 5-L stirred bioreactor. Furthermore, the optimized conditions were then successfully scaled up to a production scale of 200 L, and maximum TA production and productivity of 295.3 mg/L and 49.2 mg/L/day were achieved, which represented 80.9% and 111.5% increases, respectively, compared with the non-optimized conditions. Additionally, the triterpene acid extract (TAE) from G. lingzhi mycelia was found to be cytotoxic to the SMMC-7721 and SW620 cell lines in vitro, and the TAE exhibited dose-dependent antitumor activity against the solid tumor sarcoma 180 in vivo. Chemical analysis revealed that the key active triterpene compounds, ganoderic acid T and ganoderic acid Me, predominated in the extract. PMID- 27775635 TI - Polymorphisms of HLA-DM on Treatment Response to Interferon/Ribavirin in Patients with Chronic Hepatitis C Virus Type 1 Infection. AB - BACKGROUND: HLA-DM gene, which is related to antigen processing and presentation and located in the non-classical class-II region of human leukocyte antigen (HLA) region, may play a crucial role in chronic hepatitis C virus (HCV) infection treatment outcomes. The study was conducted to evaluate the role of the variant of several single nucleotide polymorphisms (SNPs) in HLA-DM gene in HCV treatment outcomes. METHODS: We genotyped four SNPs from the candidate genes (HLA-DMA and DMB) in 336 patients who were treated with pegylated interferon-alpha and ribavirin (PEG IFN-alpha/RBV). Multivariate analysis of factors predicting sustained virological response (SVR) was conducted. RESULTS: HLA-DMA rs1063478 and DMB rs23544 were independent factors of HCV treatment outcomes in Chinese Han population. Individuals who carried favorable genotypes of rs1063478TT and rs23544GG were more likely to achieve SVR {Dominant model: odds ratio (OR) = 2.05, 95% confidence interval (CI) = 1.24-3.41; OR = 2.04, 95% CI =1.23-3.35, respectively}. Rs23544, rs1063478, baseline glucose, baseline platelet and T4 level were independent predictors of SVR. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.740. CONCLUSIONS: The genetic variation of rs1063478 and rs23544 are associated with the treatment outcomes in the Chinese Han population. PMID- 27775634 TI - Structurally Related Monoterpenes p-Cymene, Carvacrol and Thymol Isolated from Essential Oil from Leaves of Lippia sidoides Cham. (Verbenaceae) Protect Mice against Elastase-Induced Emphysema. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and inflammation. Natural products, such as monoterpenes, displayed anti-inflammatory and anti-oxidant activities and can be used as a source of new compounds to COPD treatment. Our aim was to evaluate, in an elastase-induced pulmonary emphysema in mice, the effects of and underlying mechanisms of three related natural monoterpenes (p-cymene, carvacrol and thymol) isolated from essential oil from leaves Lippia sidoides Cham. (Verbenaceae). METHODS: Mices received porcine pancreatic elastase (PPE) and were treated with p cymene, carvacrol, thymol or vehicle 30 min later and again on 7th, 14th and 28th days. Lung inflammatory profile and histological sections were evaluated. RESULTS: In the elastase-instilled animals, the tested monoterpenes reduced alveolar enlargement, macrophages and the levels of IL-1beta, IL-6, IL-8 and IL 17 in bronchoalveolar lavage fluid (BALF), and collagen fibers, MMP-9 and p-65-NF kappaB-positive cells in lung parenchyma (p < 0.05). All treatments attenuated levels of 8-iso-PGF2alpha but only thymol was able to reduced exhaled nitric oxide (p < 0.05). CONCLUSION: Monoterpenes p-cymene, carvacrol and thymol reduced lung emphysema and inflammation in mice. No significant differences among the three monoterpenes treatments were found, suggesting that the presence of hydroxyl group in the molecular structure of thymol and carvacrol do not play a central role in the anti-inflammatory effects. PMID- 27775636 TI - Morbid Obesity in Disasters: Bringing the "Conspicuously Invisible" into Focus. AB - It is a frightening reality for some people to be caught up in the midst of a disaster, alone and vulnerable due to their relative size, shape or weight. A literature search failed to find any empirical reports of data specific to body mass index (BMI) in disaster situations. A handful of largely anecdotal reports described situations in which people categorised as morbidly obese were negatively impacted in disasters because of their size and/or weight. While a small number of toolkits and training resources were found, there remains a paucity of research in relation to obesity and emergency planning or disaster risk reduction. This is somewhat surprising, considering the concern about increasing levels of obesity globally. Research is urgently needed to prioritise and address the specific considerations of people with morbid obesity and how communities plan, prepare, respond, and recover from disasters and public health emergencies. PMID- 27775637 TI - Zika Virus Infection and Microcephaly: Evidence for a Causal Link. AB - Zika virus (ZIKV) is a flavivirus related to the Dengue, yellow fever and West Nile viruses. Since the explosive outbreaks of ZIKV in Latin America in 2015, a sudden increase in the number of microcephaly cases has been observed in infants of women who were pregnant when they contracted the virus. The severity of this condition raises grave concerns, and extensive studies on the possible link between ZIKV infection and microcephaly have been conducted. There is substantial evidence suggesting that there is a causal link between ZIKV and microcephaly, however, future studies are warranted to solidify this association. To summarize the most recent evidence on this issue and provide perspectives for future studies, we reviewed the literature to identify existing evidence of the causal link between ZIKV infection and microcephaly within research related to the epidemics, laboratory diagnosis, and possible mechanisms. PMID- 27775638 TI - Exploring the Limits of Cell Adhesion under Shear Stress within Physiological Conditions and beyond on a Chip. AB - Cell adhesion processes are of ubiquitous importance for biomedical applications such as optimization of implant materials. Here, not only physiological conditions such as temperature or pH, but also topographical structures play crucial roles, as inflammatory reactions after surgery can diminish osseointegration. In this study, we systematically investigate cell adhesion under static, dynamic and physiologically relevant conditions employing a lab-on a-chip system. We screen adhesion of the bone osteosarcoma cell line SaOs-2 on a titanium implant material for pH and temperature values in the physiological range and beyond, to explore the limits of cell adhesion, e.g., for feverish and acidic conditions. A detailed study of different surface roughness Rq gives insight into the correlation between the cells' abilities to adhere and withstand shear flow and the topography of the substrates, finding a local optimum at Rq = 22 nm. We use shear stress induced by acoustic streaming to determine a measure for the ability of cell adhesion under an external force for various conditions. We find an optimum of cell adhesion for T = 37 degrees C and pH = 7.4 with decreasing cell adhesion outside the physiological range, especially for high T and low pH. We find constant detachment rates in the physiological regime, but this behavior tends to collapse at the limits of 41 degrees C and pH 4. PMID- 27775640 TI - A Multifunctional Sensor in Ternary Solution Using Canonical Correlations for Variable Links Assessment. AB - Accurately measuring the oil content and salt content of crude oil is very important for both estimating oil reserves and predicting the lifetime of an oil well. There are some problems with the current methods such as high cost, low precision, and difficulties in operation. To solve these problems, we present a multifunctional sensor, which applies, respectively, conductivity method and ultrasound method to measure the contents of oil, water, and salt. Based on cross sensitivity theory, these two transducers are ideally integrated for simplifying the structure. A concentration test of ternary solutions is carried out to testify its effectiveness, and then Canonical Correlation Analysis is applied to evaluate the data. From the perspective of statistics, the sensor inputs, for instance, oil concentration, salt concentration, and temperature, are closely related to its outputs including output voltage and time of flight of ultrasound wave, which further identify the correctness of the sensing theory and the feasibility of the integrated design. Combined with reconstruction algorithms, the sensor can realize the content measurement of the solution precisely. The potential development of the proposed sensor and method in the aspect of online test for crude oil is of important reference and practical value. PMID- 27775639 TI - Low-Protein Diets in Diabetic Chronic Kidney Disease (CKD) Patients: Are They Feasible and Worth the Effort? AB - Low-protein diets (LPDs) are often considered as contraindicated in diabetic patients, and are seldom studied. The aim of this observational study was to provide new data on this issue. It involved 149 diabetic and 300 non-diabetic patients who followed a LPD, with a personalized approach aimed at moderate protein restriction (0.6 g/day). Survival analysis was performed according to Kaplan-Meier, and multivariate analysis with Cox model. Diabetic versus non diabetic patients were of similar age (median 70 years) and creatinine levels at the start of the diet (2.78 mg/dL vs. 2.80 mg/dL). There was higher prevalence of nephrotic proteinuria in diabetic patients (27.52% vs. 13.67%, p = 0.002) as well as comorbidity (median Charlson index 8 vs. 6 p = 0.002). Patient survival was lower in diabetic patients, but differences levelled off considering only cases with Charlson index > 7, the only relevant covariate in Cox analysis. Dialysis free survival was superimposable in the setting of good compliance (Mitch formula: 0.47 g/kg/day in both groups): about 50% of the cases remained dialysis free 2 years after the first finding of e-GFR (estimated glomerular filtration rate) < 15 mL/min, and 1 year after reaching e-GFR < 10 mL/min. In patients with type 2 diabetes, higher proteinuria was associated with mortality and initiation of dialysis. In conclusion, moderately restricted LPDs allow similar results in diabetic and non non-diabetic patients with similar comorbidity. PMID- 27775641 TI - Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma. AB - Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAFV600E mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAFV600E mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAFV600E mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy. PMID- 27775643 TI - Advances in Radiotherapy Management of Esophageal Cancer. AB - Radiation therapy (RT) as part of multidisciplinary oncologic care has been marked by profound advancements over the past decades. As part of multimodality therapy for esophageal cancer (EC), a prime goal of RT is to minimize not only treatment toxicities, but also postoperative complications and hospitalizations. Herein, discussion commences with the historical approaches to treating EC, including seminal trials supporting multimodality therapy. Subsequently, the impact of RT techniques, including three-dimensional conformal RT, intensity modulated RT, and proton beam therapy, is examined through available data. We further discuss existing data and the potential for further development in the future, with an appraisal of the future outlook of technological advancements of RT for EC. PMID- 27775642 TI - Hand-to-Hand Model for Bioelectrical Impedance Analysis to Estimate Fat Free Mass in a Healthy Population. AB - This study aimed to establish a hand-to-hand (HH) model for bioelectrical impedance analysis (BIA) fat free mass (FFM) estimation by comparing with a standing position hand-to-foot (HF) BIA model and dual energy X-ray absorptiometry (DXA); we also verified the reliability of the newly developed model. A total of 704 healthy Chinese individuals (403 men and 301 women) participated. FFM (FFMDXA) reference variables were measured using DXA and segmental BIA. Further, regression analysis, Bland-Altman plots, and cross validation (2/3 participants as the modeling group, 1/3 as the validation group; three turns were repeated for validation grouping) were conducted to compare tests of agreement with FFMDXA reference variables. In male participants, the hand-to-hand BIA model estimation equation was calculated as follows: FFMmHH = 0.537 h2/ZHH - 0.126 year + 0.217 weight + 18.235 (r2 = 0.919, standard estimate of error (SEE) = 2.164 kg, n = 269). The mean validated correlation coefficients and limits of agreement (LOAs) of the Bland-Altman analysis of the calculated values for FFMmHH and FFMDXA were 0.958 and -4.369-4.343 kg, respectively, for hand-to-foot BIA model measurements for men; the FFM (FFMmHF) and FFMDXA were 0.958 and -4.356-4.375 kg, respectively. The hand-to-hand BIA model estimating equation for female participants was FFMFHH = 0.615 h2/ZHH - 0.144 year + 0.132 weight + 16.507 (r2 = 0.870, SEE = 1.884 kg, n = 201); the three mean validated correlation coefficient and LOA for the hand-to-foot BIA model measurements for female participants (FFMFHH and FFMDXA) were 0.929 and -3.880-3.886 kg, respectively. The FFMHF and FFMDXA were 0.942 and -3.511-3.489 kg, respectively. The results of both hand-to-hand and hand-to-foot BIA models demonstrated similar reliability, and the hand-to-hand BIA models are practical for assessing FFM. PMID- 27775644 TI - Computational Modeling and Analysis of Microarray Data: New Horizons. AB - High-throughput microarray technologies have long been a source of data for a wide range of biomedical investigations. Over the decades, variants have been developed and sophistication of measurements has improved, with generated data providing both valuable insight and considerable analytical challenge. The cost effectiveness of microarrays, as well as their fundamental applicability, made them a first choice for much early genomic research and efforts to improve accessibility, quality and interpretation have continued unabated. In recent years, however, the emergence of new generations of sequencing methods and, importantly, reduction of costs, has seen a preferred shift in much genomic research to the use of sequence data, both less 'noisy' and, arguably, with species information more directly targeted and easily interpreted. Nevertheless, new microarray data are still being generated and, together with their considerable legacy, can offer a complementary perspective on biological systems and disease pathogenesis. The challenge now is to exploit novel methods for enhancing and combining these data with those generated by alternative high throughput techniques, such as sequencing, to provide added value. Augmentation and integration of microarray data and the new horizons this opens up, provide the theme for the papers in this Special Issue. PMID- 27775645 TI - Fabrication of Gelatin-Based Electrospun Composite Fibers for Anti-Bacterial Properties and Protein Adsorption. AB - A major goal of biomimetics is the development of chemical compositions and structures that simulate the extracellular matrix. In this study, gelatin-based electrospun composite fibrous membranes were prepared by electrospinning to generate bone scaffold materials. The gelatin-based multicomponent composite fibers were fabricated using co-electrospinning, and the composite fibers of chitosan (CS), gelatin (Gel), hydroxyapatite (HA), and graphene oxide (GO) were successfully fabricated for multi-function characteristics of biomimetic scaffolds. The effect of component concentration on composite fiber morphology, antibacterial properties, and protein adsorption were investigated. Composite fibers exhibited effective antibacterial activity against Staphylococcus aureus and Escherichia coli. The study observed that the composite fibers have higher adsorption capacities of bovine serum albumin (BSA) at pH 5.32-6.00 than at pH 3.90-4.50 or 7.35. The protein adsorption on the surface of the composite fiber increased as the initial BSA concentration increased. The surface of the composite reached adsorption equilibrium at 20 min. These results have specific applications for the development of bone scaffold materials, and broad implications in the field of tissue engineering. PMID- 27775647 TI - Flavonoids, Inflammation and Immune System. AB - Flavonoids, including around 6000 phenolic compounds, are products of the secondary metabolism of plants which can be a part of one's diet via the consumption of many edible plants.[...]. PMID- 27775646 TI - Associated Clinical Disorders Diagnosed by Medical Specialists in 188 FMR1 Premutation Carriers Found in the Last 25 Years in the Spanish Basque Country: A Retrospective Study. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are definitely related to the fragile X mental retardation 1 (FMR1) premutation (PM). Additional medical problems have also been associated with the PM, such as fibromyalgia, endocrine, and psychiatric disorders. To improve our understanding in the field, we reviewed all PM carriers and their reasons for any medical referrals from 104 fragile X families molecularly diagnosed in our laboratory and living in the Spanish Basque Country. After signing the written informed consent, we studied their electronic medical records in order to identify the disorders associated with the PM and their frequencies. We obtained clinical data in 188 PM carriers (147 women and 41 men). In women, the frequency of FXPOI (22.61%) was similar to that previously reported in PM carriers. In men, the frequency of definite FXTAS (28.57%) was lower than reported elsewhere. Furthermore, thyroid pathology was associated with the PM, the frequency of hypothyroidism being much higher in the studied region than in the general population (8.84% vs. 0.93%). Finally, we found no association with fibromyalgia or psychiatric problems. These findings represent another population contribution in this field and may be useful for the clinical management of PM carriers. PMID- 27775648 TI - Language Problems and ADHD Symptoms: How Specific Are the Links? AB - Symptoms of inattention and hyperactivity frequently co-occur with language difficulties in both clinical and community samples. We explore the specificity and strength of these associations in a heterogeneous sample of 254 children aged 5 to 15 years identified by education and health professionals as having problems with attention, learning and/or memory. Parents/carers rated pragmatic and structural communication skills and behaviour, and children completed standardised assessments of reading, spelling, vocabulary, and phonological awareness. A single dimension of behavioural difficulties including both hyperactivity and inattention captured behaviour problems. This was strongly and negatively associated with pragmatic communication skills. There was less evidence for a relationship between behaviour and language structure: behaviour ratings were more weakly associated with the use of structural language in communication, and there were no links with direct measures of literacy. These behaviour problems and pragmatic communication difficulties co-occur in this sample, but impairments in the more formal use of language that impact on literacy and structural communication skills are tied less strongly to behavioural difficulties. One interpretation is that impairments in executive function give rise to both behavioural and social communication problems, and additional or alternative deficits in other cognitive abilities impact on the development of structural language skills. PMID- 27775652 TI - A Low-Cost Optical Remote Sensing Application for Glacier Deformation Monitoring in an Alpine Environment. AB - In this work, we present the results of a low-cost optical monitoring station designed for monitoring the kinematics of glaciers in an Alpine environment. We developed a complete hardware/software data acquisition and processing chain that automatically acquires, stores and co-registers images. The system was installed in September 2013 to monitor the evolution of the Planpincieux glacier, within the open-air laboratory of the Grandes Jorasses, Mont Blanc massif (NW Italy), and collected data with an hourly frequency. The acquisition equipment consists of a high-resolution DSLR camera operating in the visible band. The data are processed with a Pixel Offset algorithm based on normalized cross-correlation, to estimate the deformation of the observed glacier. We propose a method for the pixel-to-metric conversion and present the results of the projection on the mean slope of the glacier. The method performances are compared with measurements obtained by GB-SAR, and exhibit good agreement. The system provides good support for the analysis of the glacier evolution and allows the creation of daily displacement maps. PMID- 27775649 TI - Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway. AB - Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of liver tissue. PMID- 27775651 TI - Degree of Suppression of Mouse Myoblast Cell Line C2C12 Differentiation Varies According to Chondroitin Sulfate Subtype. AB - Chondroitin sulfate (CS), a type of glycosaminoglycan (GAG), is a factor involved in the suppression of myogenic differentiation. CS comprises two repeating sugars and has different subtypes depending on the position and number of bonded sulfate groups. However, the effect of each subtype on myogenic differentiation remains unclear. In this study, we spiked cultures of C2C12 myoblasts, cells which are capable of undergoing skeletal muscle differentiation, with one of five types of CS (CS-A, -B, -C, -D, or -E) and induced differentiation over a fixed time. After immunostaining of the formed myotubes with an anti-MHC antibody, we counted the number of nuclei in the myotubes and then calculated the fusion index (FI) as a measure of myotube differentiation. The FI values of all the CS-treated groups were lower than the FI value of the control group, especially the group treated with CS-E, which displayed notable suppression of myotube formation. To confirm that the sugar chain in CS-E is important in the suppression of differentiation, chondroitinase ABC (ChABC), which catabolizes CS, was added to the media. The addition of ChABC led to the degradation of CS-E, and neutralized the suppression of myotube formation by CS-E. Collectively, it can be concluded that the degree of suppression of differentiation depends on the subtype of CS and that CS-E strongly suppresses myogenic differentiation. We conclude that the CS sugar chain has inhibitory action against myoblast cell fusion. PMID- 27775653 TI - Achievement of High-Response Organic Field-Effect Transistor NO2 Sensor by Using the Synergistic Effect of ZnO/PMMA Hybrid Dielectric and CuPc/Pentacene Heterojunction. AB - High-response organic field-effect transistor (OFET)-based NO2 sensors were fabricated using the synergistic effect the synergistic effect of zinc oxide/poly(methyl methacrylate) (ZnO/PMMA) hybrid dielectric and CuPc/Pentacene heterojunction. Compared with the OFET sensors without synergistic effect, the fabricated OFET sensors showed a remarkable shift of saturation current, field effect mobility and threshold voltage when exposed to various concentrations of NO2 analyte. Moreover, after being stored in atmosphere for 30 days, the variation of saturation current increased more than 10 folds at 0.5 ppm NO2. By analyzing the electrical characteristics, and the morphologies of organic semiconductor films of the OFET-based sensors, the performance enhancement was ascribed to the synergistic effect of the dielectric and organic semiconductor. The ZnO nanoparticles on PMMA dielectric surface decreased the grain size of pentacene formed on hybrid dielectric, facilitating the diffusion of CuPc molecules into the grain boundary of pentacene and the approach towards the conducting channel of OFET. Hence, NO2 molecules could interact with CuPc and ZnO nanoparticles at the interface of dielectric and organic semiconductor. Our results provided a promising strategy for the design of high performance OFET based NO2 sensors in future electronic nose and environment monitoring. PMID- 27775650 TI - The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy. AB - The TAM receptor protein tyrosine kinases-Tyro3, Axl, and Mer-are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy. PMID- 27775654 TI - Germinated Pigmented Rice (Oryza Sativa L. cv. Superhongmi) Improves Glucose and Bone Metabolisms in Ovariectomized Rats. AB - The effect of germinated Superhongmi, a reddish brown pigmented rice cultivar, on the glucose profile and bone turnover in the postmenopausal-like model of ovariectomized rats was determined. The ovariectomized Sprague-Dawley rats were randomly divided into three dietary groups (n = 10): normal control diet (NC) and normal diet supplemented with non-germinated Superhongmi (SH) or germinated Superhongmi (GSH) rice powder. After eight weeks, the SH and GSH groups showed significantly lower body weight, glucose and insulin concentrations, levels of bone resorption markers and higher glycogen and 17-beta-estradiol contents than the NC group. The glucose metabolism improved through modulation of adipokine production and glucose-regulating enzyme activities. The GSH rats exhibited a greater hypoglycemic effect and lower bone resorption than SH rats. These results demonstrate that germinated Superhongmi rice may potentially be useful in the prevention and management of postmenopausal hyperglycemia and bone turnover imbalance. PMID- 27775655 TI - Effects of Proton Pump Inhibitor Administration and Intake of a Combination of Yogurt and Galactooligosaccharides on Bone and Mineral Metabolism in Rats. AB - The aim of this study was to investigate the effects of proton pump inhibitor (PPI), the most potent acid-suppressing drug, administration and intake of a combination of yogurt and galactooligosaccharides (YG) on bone and mineral metabolism in adult rats. Twelve-week-old male Wistar rats were divided into three groups: a control group fed the control diet with vehicle administration, a PPI group fed the control diet with PPI administration and a YG + PPI group fed the YG diet with PPI administration. All of the groups received their respective experimental diets and daily subcutaneous injection of the vehicle or PPI for 12 weeks. The PPI group showed significantly lower bone mineral density (BMD) of the femur and the lumbar vertebrae and serum fibroblast growth factor 23 (FGF23) and significantly higher phosphorus absorption and serum 1,25-dihydroxyvitamin D (1,25(OH)2D) than the control group, although PPI did not affect calcium absorption. The PPI + YG group showed significantly higher BMD and serum FGF23 and significantly lower phosphorus absorption and serum 1,25(OH)2D than the PPI group. Furthermore, the PPI + YG group showed higher calcium absorption than the control group. These results suggest that although PPI administration did not affect calcium absorption, it adversely affected BMD and influenced phosphorus metabolism in adult rats. Furthermore, the YG diet beneficially affected BMD and attenuated the effects of PPI administration on phosphorus metabolism. PMID- 27775657 TI - A Fiber Bragg Grating-Based Monitoring System for Roof Safety Control in Underground Coal Mining. AB - Monitoring of roof activity is a primary measure adopted in the prevention of roof collapse accidents and functions to optimize and support the design of roadways in underground coalmines. However, traditional monitoring measures, such as using mechanical extensometers or electronic gauges, either require arduous underground labor or cannot function properly in the harsh underground environment. Therefore, in this paper, in order to break through this technological barrier, a novel monitoring system for roof safety control in underground coal mining, using fiber Bragg grating (FBG) material as a perceived element and transmission medium, has been developed. Compared with traditional monitoring equipment, the developed, novel monitoring system has the advantages of providing accurate, reliable, and continuous online monitoring of roof activities in underground coal mining. This is expected to further enable the prevention of catastrophic roof collapse accidents. The system has been successfully implemented at a deep hazardous roadway in Zhuji Coal Mine, China. Monitoring results from the study site have demonstrated the advantages of FBG based sensors over traditional monitoring approaches. The dynamic impacts of progressive face advance on roof displacement and stress have been accurately captured by the novel roadway roof activity and safety monitoring system, which provided essential references for roadway support and design of the mine. PMID- 27775656 TI - RP-HPLC/MS/MS Analysis of the Phenolic Compounds, Antioxidant and Antimicrobial Activities of Salvia L. Species. AB - The identification and quantification of the phenolic contents of methanolic extracts of three Salvia L. species namely S. brachyantha (Bordz.) Pobed, S. aethiopis L., and S. microstegia Boiss. and Bal. were evaluated using reverse phase high performance liquid chromatography, UV adsorption, and mass spectrometry (RP-HPLC/MS). In order to determine the antioxidant capacity of these species, cupric ions (Cu2+) reducing assay (CUPRAC) and ferric ions (Fe3+) reducing assay (FRAP) were performed to screen the reducing capacity and 1,1 diphenyl-2-picrylhydrazyl (DPPH) assay was employed for evaluation of the radical scavenging activity for both solvents. In further investigation, the antimicrobial activities of Salvia species were tested using the disc diffusion method against three Gram-positive and four Gram-negative microbial species, as well as three fungi species. The results showed that there is a total of 18 detectable phenols, the most abundant of which was kaempferol in S. microstegia and rosmarinic acids in S. brachyantha and S aethiopis. The other major phenols were found to be apigenin, luteolin, p-coumaric acid, and chlorogenic acid. All species tested showed moderate and lower antioxidant activity than standard antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and ascorbic acid. The ethanolic extracts of Salvia species revealed a wide range of antimicrobial activity. S. brachyantha and S. microstegia showed the highest antimicrobial activities against B. subtilis, whereas S. aethiopis was more effective on Y. lipolytica. None of the extracts showed anti-fungal activity against S. cerevisiae. Thus these species could be valuable due to their bioactive compounds. PMID- 27775658 TI - First Results of a Detection Sensor for the Monitoring of Laying Hens Reared in a Commercial Organic Egg Production Farm Based on the Use of Infrared Technology. AB - The development of a monitoring system to identify the presence of laying hens, in a closed room of a free-range commercial organic egg production farm, was the aim of this study. This monitoring system was based on the infrared (IR) technology and had, as final target, a possible reduction of atmospheric ammonia levels and bacterial load. Tests were carried out for three weeks and involved 7 ISA (Institut de Selection Animale) brown laying hens. The first 5 days was used to set up the detection sensor, while the other 15 days were used to evaluate the accuracy of the resulting monitoring system, in terms of sensitivity and specificity. The setup procedure included the evaluation of different color background (CB) thresholds, used to discriminate the information contents of the thermographic images. At the end of this procedure, a CB threshold equal to an increase of 3 degrees C from the floor temperature was chosen, and a cutoff level of 196 colored pixels was identified as the threshold to use to classify a positive case. The results of field tests showed that the developed monitoring system reached a fine detection accuracy (sensitivity = 97.9% and specificity = 94.9%) and the IR technology proved to be a possible solution for the development of a detection sensor necessary to reach the scope of this study. PMID- 27775659 TI - Underwater Sensor Network Redeployment Algorithm Based on Wolf Search. AB - This study addresses the optimization of node redeployment coverage in underwater wireless sensor networks. Given that nodes could easily become invalid under a poor environment and the large scale of underwater wireless sensor networks, an underwater sensor network redeployment algorithm was developed based on wolf search. This study is to apply the wolf search algorithm combined with crowded degree control in the deployment of underwater wireless sensor networks. The proposed algorithm uses nodes to ensure coverage of the events, and it avoids the prematurity of the nodes. The algorithm has good coverage effects. In addition, considering that obstacles exist in the underwater environment, nodes are prevented from being invalid by imitating the mechanism of avoiding predators. Thus, the energy consumption of the network is reduced. Comparative analysis shows that the algorithm is simple and effective in wireless sensor network deployment. Compared with the optimized artificial fish swarm algorithm, the proposed algorithm exhibits advantages in network coverage, energy conservation, and obstacle avoidance. PMID- 27775660 TI - A Novel Gradient Vector Flow Snake Model Based on Convex Function for Infrared Image Segmentation. AB - Infrared image segmentation is a challenging topic because infrared images are characterized by high noise, low contrast, and weak edges. Active contour models, especially gradient vector flow, have several advantages in terms of infrared image segmentation. However, the GVF (Gradient Vector Flow) model also has some drawbacks including a dilemma between noise smoothing and weak edge protection, which decrease the effect of infrared image segmentation significantly. In order to solve this problem, we propose a novel generalized gradient vector flow snakes model combining GGVF (Generic Gradient Vector Flow) and NBGVF (Normally Biased Gradient Vector Flow) models. We also adopt a new type of coefficients setting in the form of convex function to improve the ability of protecting weak edges while smoothing noises. Experimental results and comparisons against other methods indicate that our proposed snakes model owns better ability in terms of infrared image segmentation than other snakes models. PMID- 27775661 TI - Printable Electrochemical Biosensors: A Focus on Screen-Printed Electrodes and Their Application. AB - In this review we present electrochemical biosensor developments, focusing on screen-printed electrodes (SPEs) and their applications. In particular, we discuss how SPEs enable simple integration, and the portability needed for on field applications. First, we briefly discuss the general concept of biosensors and quickly move on to electrochemical biosensors. Drawing from research undertaken in this area, we cover the development of electrochemical DNA biosensors in great detail. Through specific examples, we describe the fabrication and surface modification of printed electrodes for sensitive and selective detection of targeted DNA sequences, as well as integration with reverse transcription-polymerase chain reaction (RT-PCR). For a more rounded approach, we also touch on electrochemical immunosensors and enzyme-based biosensors. Last, we present some electrochemical devices specifically developed for use with SPEs, including USB-powered compact mini potentiostat. The coupling demonstrates the practical use of printable electrode technologies for application at point-of-use. Although tremendous advances have indeed been made in this area, a few challenges remain. One of the main challenges is application of these technologies for on-field analysis, which involves complicated sample matrices. PMID- 27775662 TI - Capsaicin Suppresses Cell Proliferation, Induces Cell Cycle Arrest and ROS Production in Bladder Cancer Cells through FOXO3a-Mediated Pathways. AB - Capsaicin (CAP), a highly selective agonist for transient receptor potential vanilloid type 1 (TRPV1), has been widely reported to exhibit anti-oxidant, anti inflammation and anticancer activities. Currently, several therapeutic approaches for bladder cancer (BCa) are available, but accompanied by unfavorable outcomes. Previous studies reported a potential clinical effect of CAP to prevent BCa tumorigenesis. However, its underlying molecular mechanism still remains unknown. Our transcriptome analysis suggested a close link among calcium signaling pathway, cell cycle regulation, ROS metabolism and FOXO signaling pathway in BCa. In this study, several experiments were performed to investigate the effects of CAP on BCa cells (5637 and T24) and NOD/SCID mice. Our results showed that CAP could suppress BCa tumorigenesis by inhibiting its proliferation both in vitro and in vivo. Moreover, CAP induced cell cycle arrest at G0/G1 phase and ROS production. Importantly, our studies revealed a strong increase of FOXO3a after treatment with CAP. Furthermore, we observed no significant alteration of apoptosis by CAP, whereas Catalase and SOD2 were considerably upregulated, which could clear ROS and protect against cell death. Thus, our results suggested that CAP could inhibit viability and tumorigenesis of BCa possibly via FOXO3a-mediated pathways. PMID- 27775663 TI - Differential Amino Acid, Carbohydrate and Lipid Metabolism Perpetuations Involved in a Subtype of Rheumatoid Arthritis with Chinese Medicine Cold Pattern. AB - Pattern classification is a key approach in Traditional Chinese Medicine (TCM), and it is used to classify the patients for intervention selection accordingly. TCM cold and heat patterns, two main patterns of rheumatoid arthritis (RA) had been explored with systems biology approaches. Different regulations of apoptosis were found to be involved in cold and heat classification in our previous works. For this study, the metabolic profiling of plasma was explored in RA patients with typical TCM cold or heat patterns by integrating liquid chromatography/mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS) platforms in conjunction with the Ingenuity Pathway Analysis (IPA) software. Three main processes of metabolism, including amino acid, carbohydrate and lipid were focused on for function analysis. The results showed that 29 and 19 differential metabolites were found in cold and heat patterns respectively, compared with healthy controls. The perturbation of amino acid metabolism (increased essential amino acids), carbohydrate metabolism (galactose metabolism) and lipid metabolism, were found to be involved in both cold and heat pattern RA. In particular, more metabolic perturbations in protein and collagen breakdown, decreased glycolytic activity and aerobic oxidation, and increased energy utilization associated with RA cold pattern patients. These findings may be useful for obtaining a better understanding of RA pathogenesis and for achieving a better efficacy in RA clinical practice. PMID- 27775665 TI - The Inhibition Effect of Cell DNA Oxidative Damage and LDL Oxidation by Bovine Colostrums. AB - In the present study, we investigated the effect of bovine colostrums on inhibition of DNA oxidative damage and low density lipoprotein (LDL) oxidation in vitro. Results showed that whey and skimmed milk exhibited not only higher inhibitory activities of oxidative damage of deoxyribose but also an inhibitory effect on the breakdown of supercoiled DNA into open circular DNA and linear DNA. The quantities of 8-OH-2'-dG formed under whey, caseins and skimmed milk treatment were 0.24, 0.24 and 1.24 MUg/mL, respectively. The quantity of malondialdehyde formed through LDL oxidation induced by copprous ion was significantly decreased as colostrums protein solutions were added, in which whey and caseins led to a more significant decrease than skimmed milk. The formation of conjugated dienes could be inhibited by treatment with colostrums protein solutions. Whey exhibited the longest lag time of conjugated dienes formation among the colostrums proteins. The lag time of the whey was 2.33 times that of the control. From the results of foregoing, the bovine colostrums protein has potential value in the inhibition of DNA oxidation damage and LDL oxidation. PMID- 27775664 TI - A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival. AB - MicroRNAs are small non-coding RNAs with a length of 18-25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations-tumor, associated stroma, and host tissue-can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n = 25) and lung metastases (n = 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5 fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR 21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR 192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies. PMID- 27775666 TI - Stage-Wise Identification and Analysis of miRNA from Root-Knot Nematode Meloidogyne incognita. AB - In this study, we investigated global changes in miRNAs of Meloidogyne incognita throughout its life cycle. Small RNA sequencing resulted in approximately 62, 38, 38, 35, and 39 Mb reads in the egg, J2, J3, J4, and female stages, respectively. Overall, we identified 2724 known and 383 novel miRNAs (read count > 10) from all stages, of which 169 known and 13 novel miRNA were common to all the five stages. Among the stage-specific miRNAs, miR-286 was highly expressed in eggs, miR-2401 in J2, miR-8 and miR-187 in J3, miR-6736 in J4, and miR-17 in the female stages. These miRNAs are reported to be involved in embryo and neural development, muscular function, and control of apoptosis. Cluster analysis indicated the presence of 91 miRNA clusters, of which 36 clusters were novel and identified in this study. Comparison of miRNA families with other nematodes showed 17 families to be commonly absent in animal parasitic nematodes and M. incognita. Validation of 43 predicted common and stage-specific miRNA by quantitative PCR (qPCR) indicated their expression in the nematode. Stage-wise exploration of M. incognita miRNAs has not been carried out before and this work presents information on common and stage-specific miRNAs of the root-knot nematode. PMID- 27775667 TI - Potential Anticancer Effects of Polyphenols from Chestnut Shell Extracts: Modulation of Cell Growth, and Cytokinomic and Metabolomic Profiles. AB - In this study, a hydroalcoholic chestnut shell extract was characterized and tested on six different human cell lines. Gallic, ellagic, and syringic acids were the most abundant non-condensed compounds in the chestnut extract, as determined by high performance liquid chromatography (HPLC). Tannins were mainly represented by condensed monomeric units of epigallocatechin and catechin/epicatechin. After 48 h of treatment, only the human hepatoblastoma HepG2 cells reached an inhibition corresponding to IC50 with an increase of apoptosis and mitochondrial depolarization. The cytokinome evaluation before and after treatment revealed that the vascular endothelial growth factor (VEGF) and the tumor necrosis factor (TNF)-alpha decreased after the treatment, suggesting a potential anti-angiogenic and anti-inflammatory effect of this extract. Moreover, the metabolome evaluation by 1H-NMR evidenced that the polyphenols extracted from chestnut shell (PECS) treatment affected the levels of some amino acids and other metabolites. Overall, these data highlight the effects of biomolecules on cell proliferation, apoptosis, cell cycle and mitochondrial depolarization, and on cytokinomics and metabolomics profiles. PMID- 27775668 TI - Role of Intracellular Lipid Logistics in the Preferential Usage of Very Long Chain-Ceramides in Glucosylceramide. AB - Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20-26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It is known that the proportion of VLC species in GSLs is higher than that in SM. To address the mechanism of the VLC-preference of GSLs, we used genome editing to establish three HeLa cell mutants that expressed different amounts of CERS2 and compared the acyl chain lengths of SM and GSLs by metabolic labeling experiments. VLC sphingolipid expression was increased along with that of CERS2, and the proportion of VLC species in glucosylceramide (GlcCer) was higher than that in SM for all expression levels of CERS2. This higher proportion was still maintained even when the proportion of C16-Cer to the total ceramides was increased by disrupting the ceramide transport protein (CERT)-dependent C16-Cer delivery pathway for SM synthesis. On the other hand, merging the Golgi apparatus and the endoplasmic reticulum (ER) by Brefeldin A decreased the proportion of VLC species in GlcCer probably due to higher accessibility of UDP-glucose ceramide glucosyltransferase (UGCG) to C16-rich ceramides. These results suggest the existence of a yet-to-be-identified mechanism rendering VLC-Cer more accessible than C16-Cer to UGCG, which is independent of CERT. PMID- 27775670 TI - Fine-Scale Population Estimation by 3D Reconstruction of Urban Residential Buildings. AB - Fine-scale population estimation is essential in emergency response and epidemiological applications as well as urban planning and management. However, representing populations in heterogeneous urban regions with a finer resolution is a challenge. This study aims to obtain fine-scale population distribution based on 3D reconstruction of urban residential buildings with morphological operations using optical high-resolution (HR) images from the Chinese No. 3 Resources Satellite (ZY-3). Specifically, the research area was first divided into three categories when dasymetric mapping was taken into consideration. The results demonstrate that the morphological building index (MBI) yielded better results than built-up presence index (PanTex) in building detection, and the morphological shadow index (MSI) outperformed color invariant indices (CIIT) in shadow extraction and height retrieval. Building extraction and height retrieval were then combined to reconstruct 3D models and to estimate population. Final results show that this approach is effective in fine-scale population estimation, with a mean relative error of 16.46% and an overall Relative Total Absolute Error (RATE) of 0.158. This study gives significant insights into fine-scale population estimation in complicated urban landscapes, when detailed 3D information of buildings is unavailable. PMID- 27775671 TI - Moving Object Detection Using Scanning Camera on a High-Precision Intelligent Holder. AB - During the process of moving object detection in an intelligent visual surveillance system, a scenario with complex background is sure to appear. The traditional methods, such as "frame difference" and "optical flow", may not able to deal with the problem very well. In such scenarios, we use a modified algorithm to do the background modeling work. In this paper, we use edge detection to get an edge difference image just to enhance the ability of resistance illumination variation. Then we use a "multi-block temporal-analyzing LBP (Local Binary Pattern)" algorithm to do the segmentation. In the end, a connected component is used to locate the object. We also produce a hardware platform, the core of which consists of the DSP (Digital Signal Processor) and FPGA (Field Programmable Gate Array) platforms and the high-precision intelligent holder. PMID- 27775669 TI - Towards Stratified Medicine in Plasma Cell Myeloma. AB - Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient's age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies. Clinical staging, recurring acquired cytogenetic aberrations, and serum biomarkers such as beta-2 microglobulin, and free light chains are in widespread use but often fail to predict the disease progression or inform treatment decision making. Recent scientific advances have provided considerable insight into the biology of myeloma. For example, gene expression profiling is already making a contribution to enhanced understanding of the biology of the disease whilst Next Generation Sequencing has revealed great genomic complexity and heterogeneity. Pathways involved in the oncogenesis, proliferation of the tumour and its resistance to apoptosis are being unravelled. Furthermore, knowledge of the tumour cell surface and its interactions with bystander cells and the bone marrow stroma enhance this understanding and provide novel targets for cell and antibody-based therapies. This review will discuss the development in understanding of the biology of the tumour cell and its environment in the bone marrow, the implementation of new therapeutic options contributing to significantly improved outcomes, and the progression towards more personalised medicine in this disorder. PMID- 27775673 TI - Design and Implementation of Foot-Mounted Inertial Sensor Based Wearable Electronic Device for Game Play Application. AB - Wearable electronic devices have experienced increasing development with the advances in the semiconductor industry and have received more attention during the last decades. This paper presents the development and implementation of a novel inertial sensor-based foot-mounted wearable electronic device for a brand new application: game playing. The main objective of the introduced system is to monitor and identify the human foot stepping direction in real time, and coordinate these motions to control the player operation in games. This proposed system extends the utilized field of currently available wearable devices and introduces a convenient and portable medium to perform exercise in a more compelling way in the near future. This paper provides an overview of the previously-developed system platforms, introduces the main idea behind this novel application, and describes the implemented human foot moving direction identification algorithm. Practical experiment results demonstrate that the proposed system is capable of recognizing five foot motions, jump, step left, step right, step forward, and step backward, and has achieved an over 97% accuracy performance for different users. The functionality of the system for real-time application has also been verified through the practical experiments. PMID- 27775672 TI - Screening the Toxicity of Selected Personal Care Products Using Embryo Bioassays: 4-MBC, Propylparaben and Triclocarban. AB - Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or ug/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent need to gather ecotoxicological data on PCPs as a proxy to improve risk assessment. Here, the toxicity of three different PCPs (4-Methylbenzylidene Camphor (4-MBC), propylparaben and triclocarban) was tested using embryo bioassays with Danio rerio (zebrafish) and Paracentrotus lividus (sea urchin). The No Observed Effect Concentration (NOEC) for triclocarban was 0.256 ug/L for sea urchin and 100 ug/L for zebrafish, whereas NOEC for 4-MBC was 0.32 ug/L for sea urchin and 50 ug/L for zebrafish. Both PCPs impacted embryo development at environmentally relevant concentrations. In comparison with triclocarban and 4-MBC, propylparaben was less toxic for both sea urchin (NOEC = 160 ug/L) and zebrafish (NOEC = 1000 ug/L). Overall, this study further demonstrates the sensitivity of embryo bioassays as a high-throughput approach for testing the toxicity of emerging pollutants. PMID- 27775674 TI - A Fast and Robust UHPLC-MRM-MS Method to Characterize and Quantify Grape Skin Tannins after Chemical Depolymerization. AB - A rapid, sensitive, and selective analysis method using ultra high performance liquid chromatography coupled with triple-quadrupole mass spectrometry (UHPLC-QqQ MS) has been developed for the characterization and quantification of grape skin flavan-3-ols after acid-catalysed depolymerization in the presence of phloroglucinol (phloroglucinolysis). The compound detection being based on specific MS transitions in Multiple Reaction Monitoring (MRM) mode, this fast gradient robust method allows analysis of constitutive units of grape skin proanthocyanidins, including some present in trace amounts, in a single injection, with a throughput of 6 samples per hour. This method was applied to a set of 214 grape skin samples from 107 different red and white grape cultivars grown under two conditions in the vineyard, irrigated or non-irrigated. The results of triplicate analyses confirmed the robustness of the method, which was thus proven to be suitable for high-throughput and large-scale metabolomics studies. Moreover, these preliminary results suggest that analysis of tannin composition is relevant to investigate the genetic bases of grape response to drought. PMID- 27775676 TI - Identification, Characterization and Expression of Methuselah-Like Genes in Dastarcus helophoroides (Coleoptera: Bothrideridae). AB - Dastarcus helophoroides, which has a relatively longer lifespan compared to other insects, is one of the most effective natural enemies of many large-body long horned beetles. Methuselah (Mth) is associated with the lifespan, stress resistance, and reproduction in Drosophila melanogaster, but Mth is not present in non-drosophiline insects. A number of methuselah-like genes (mth-likes, mthls) have been identified in non-drosophiline insects, but it is still unknown whether they are present in Dastarcus helophoroides. We identified three novel mth-like genes in D. helophoroides: mth-like1, mth-like2, and mth-like5, and carried out bioinformatic analysis based on the full-length nucleic acid sequences and deduced amino acid sequences. Real-time quantitative polymerase chain reaction (RT-qPCR) showed variations in expression patterns of mth-like genes in different tissues (highly expressed in reproductive systems) and at different developmental stages, indicating that mth-likes were likely be involved in reproduction and development. The altered mRNA expression in aging adults and under oxidation, high temperature, and starvation stress, indicated that mth-like genes were likely to be involved in aging and the resistance of oxidation, high temperature, and starvation. These results characterize, for the first time, the basic properties of three mth-like genes from D. helophoroides that probably play important roles in development, aging, reproduction, and stress resistance. PMID- 27775675 TI - Why Are Omics Technologies Important to Understanding the Role of Nutrition in Inflammatory Bowel Diseases? AB - For many years, there has been confusion about the role that nutrition plays in inflammatory bowel diseases (IBD). It is apparent that good dietary advice for one individual may prove inappropriate for another. As with many diseases, genome wide association studies across large collaborative groups have been important in revealing the role of genetics in IBD, with more than 200 genes associated with susceptibility to the disease. These associations provide clues to explain the differences in nutrient requirements among individuals. In addition to genes directly involved in the control of inflammation, a number of the associated genes play roles in modulating the gut microbiota. Cell line models enable the generation of hypotheses as to how various bioactive dietary components might be especially beneficial for certain genetic groups. Animal models are necessary to mimic aspects of the complex aetiology of IBD, and provide an important link between tissue culture studies and human trials. Once we are sufficiently confident of our hypotheses, we can then take modified diets to an IBD population that is stratified according to genotype. Studies in IBD patients fed a Mediterranean-style diet have been important in validating our hypotheses and as a proof-of-principle for the application of these sensitive omics technologies to aiding in the control of IBD symptoms. PMID- 27775677 TI - Concentrations of Polychlorinated Biphenyls and Organochlorine Pesticides in Umbilical Cord Blood Serum of Newborns in Kingston, Jamaica. AB - To date much of the biomonitoring related to exposure to polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides is from middle to high income countries, including the U.S., Canada and Europe, but such data are lacking for the majority of low to middle income countries. Using data from 64 pregnant mothers who were enrolled in 2011, we aimed to assess the concentrations of the aforementioned toxins in umbilical cord blood serum of 67 Jamaican newborns. For 97 of the 100 PCB congeners and 16 of the 17 OC pesticides, all (100%) concentrations were below their respective limits of detection (LOD). Mean (standard deviation (SD)) lipid-adjusted concentrations in cord blood serum for congeners PCB-153, PCB-180, PCB-206 and total PCB were 14.25 (3.21), 7.16 (1.71), 7.30 (1.74) and 28.15 (6.03) ng/g-lipid, respectively. The means (SD) for the 4,4'-dichlorodiphenyldichloroethylene (DDE)-hexane fraction and total-DDE were 61.61 (70.78) and 61.60 (70.76) ng/g-lipid, respectively. Compared to the U.S. and Canada, the concentrations of these toxins were lower in cord-blood serum of Jamaican newborns. We discuss that these differences could be partly due to differences in dietary patterns in these countries. Despite limitations in our dataset, our results provide information on the investigated toxins in cord blood serum that could serve as a reference for Jamaican newborns. PMID- 27775678 TI - Socioeconomic Inequalities and Multi-Disability among the Population Aged 15-64 Years from 1987 to 2006 in China. AB - Socioeconomic inequalities associated with multiple disabilities have not been explored in China. This is the first study to explore changes in multiple disabilities among persons aged 15-64 years in China. Data were derived from the 1987 and 2006 China National Sample Surveys on Disability, which are nationally representative population-based surveys. Both surveys used multistage, stratified, cluster random sampling with probability proportional to size to derive nationally representative samples. We used standard weighting procedures to construct sample weights considering the multistage stratified cluster sampling survey scheme. The impact of socioeconomic inequalities on multiple disabilities was examined by using logistic regression. Higher prevalence rates among rural residents than urban residents were observed. Male was more vulnerable than female in the present study. Minority ethnicity did increase the risk of multiple disabilities, but this association inversed in the logistic regression model. The widening discrepancy between urban and rural areas indicates that the most important priorities of disability prevention in China are to reinforce health promotion and to improve health services in rural communities. PMID- 27775679 TI - Integrated Application of Multivariate Statistical Methods to Source Apportionment of Watercourses in the Liao River Basin, Northeast China. AB - Source apportionment of river water pollution is critical in water resource management and aquatic conservation. Comprehensive application of various GIS based multivariate statistical methods was performed to analyze datasets (2009 2011) on water quality in the Liao River system (China). Cluster analysis (CA) classified the 12 months of the year into three groups (May-October, February April and November-January) and the 66 sampling sites into three groups (groups A, B and C) based on similarities in water quality characteristics. Discriminant analysis (DA) determined that temperature, dissolved oxygen (DO), pH, chemical oxygen demand (CODMn), 5-day biochemical oxygen demand (BOD5), NH4+-N, total phosphorus (TP) and volatile phenols were significant variables affecting temporal variations, with 81.2% correct assignments. Principal component analysis (PCA) and positive matrix factorization (PMF) identified eight potential pollution factors for each part of the data structure, explaining more than 61% of the total variance. Oxygen-consuming organics from cropland and woodland runoff were the main latent pollution factor for group A. For group B, the main pollutants were oxygen-consuming organics, oil, nutrients and fecal matter. For group C, the evaluated pollutants primarily included oxygen-consuming organics, oil and toxic organics. PMID- 27775680 TI - Occurrence of Perfluorooctanoic Acid and Perfluorooctane Sulfonate in Milk and Yogurt and Their Risk Assessment. AB - Although perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been identified in milk and dairy products in many regions, knowledge on their occurrence in Xinjiang (China) is rare. This study was conducted to measure the levels of PFOA and PFOS in milk and yogurt from Xinjiang and to investigate the average daily intake (ADI) of these two compounds. PFOA and PFOS levels were analyzed using ultrasonic extraction with methanol and solid-phase extraction followed by liquid chromatography-mass spectrometry. Retail milk and yogurt samples present higher detection rates (39.6% and 48.1%) and mean concentrations (24.5 and 31.8 ng/L) of PFOS than those of PFOA (33.0% and 37.0%; 16.2 and 22.6 ng/L, respectively). For raw milk samples, only PFOS was detected. The differences in the levels of the two compounds between samples from the north and south regions were observed, and northern regions showed higher pollution levels than southern regions. On the basis of the retail milk measurements and consumption data, the ADIs of PFOA and PFOS for Xinjiang adults were calculated to be 0.0211 and 0.0318 ng/kg/day, respectively. Furthermore, the estimated intakes of PFOA and PFOS varied among different groupings (age, area, gender, and race) and increased with increasing age. Relevant hazard ratios were found to be far less than 1.0, and this finding suggested that no imminent health damages were produced by PFOA and PFOS intake via milk and yogurt consumption in the Xinjiang population. PMID- 27775681 TI - Depth and Well Type Related to Groundwater Microbiological Contamination. AB - Use of groundwater from private wells in households has increased considerably, owing to a better cost/benefit ratio than that of water provided by local utilities for a fee. However, this water is usually untreated, which makes it a vehicle for diseases. Thus, monitoring this water is necessary to ensure its integrity and quality. We aimed to evaluate the physical, chemical, and microbiological parameters of untreated groundwater drawn from different types of wells, and the antimicrobial susceptibility profile of the bacteria isolated from this water. Wellwater samples were collected in two Brazilian cities. Although physical and chemical parameters of the water were suitable for drinking, Escherichia coli was detected in 33% of the samples. E. coli contaminated 65% of dug wells and 10.25% of drilled wells. Many bacteria isolated were resistant to multiple antibacterial agents, including beta-lactams. Microbial contamination of this water was related to the well depth, and was more common in dug wells, making this water unfit for human consumption. Consumption of such contaminated and untreated water is a public health concern. Thus, individuals who regularly use such water must be alerted so they may either take preventive measures or connect to the water distribution system operated by local utilities. PMID- 27775682 TI - Association Between Rs3807989 Polymorphism in Caveolin-1 (CAV1) Gene and Atrial Fibrillation: A Meta-Analysis. AB - BACKGROUND Atrial fibrillation (AF) is the most common sustained arrhythmia affected by multiple cardiovascular risk factors. It is reported that caveolin-1 gene (CAV1) rs3807989 polymorphism might be associated with AF risk. The goal of this meta-analysis was to confirm the association between CAV1 rs3807989 polymorphism and susceptibility to AF. MATERIAL AND METHODS We carried out a comprehensive literature search through the electronic databases PubMed, MEDLIN, and Web of Science. We performed a meta-analysis of all selected studies based on CAV1 rs3807989 polymorphism genotypes, including 3758 cases and 6126 controls. RESULTS After meta-analysis with fixed- or random-effects models, we found significant associations in all 5 comparisons: allelic model (G/A; OR=1.228, 95%CI: 1.061-1.420; P=0.006), homozygote model (GG/AA; OR=1.439, 95%CI: 1.094 1.894; P=0.009), heterozygote model (GG/GA; OR=1.257, 95%CI: 1.064-1.486; P=0.007), dominant model (GG/AA+GA; OR=1.287, 95%CI: 1.076-1.540; P=0.006), and recessive model (AA/GA+GG; OR=0.738, 95%CI: 0.629-0.867; P<0.001). Sensitivity analysis results revealed the overall results were robust. CONCLUSIONS The results revealed a significant association between CAV1 gene rs3807989 polymorphism and susceptibility to AF, suggesting that the presence of allelic G might be one of the genetic factors conferring susceptibility to AF. To confirm this association, further well-designed studies are necessary. PMID- 27775683 TI - [Hospital Emergencies Associated with the Consumption of Hypnotics and Sedatives, 2009-2013,Castilla y Leon, Spain]. AB - OBJECTIVE: Household Survey on Alcohol and Other Drugs shows the progressive increase in the consumption of hypnotics, alone or in combination with other substances. The aim of the research was to obtain information about the consumption of hypnotics and sedatives in population of Castilla y Leon treated in emergency medical services of four monitored hospitals between 2009-2013, describing clinical and epidemiological characteristics of the emergencies and what drugs were consumed, to provide information for future interventions. METHODS: A descriptive cross-sectional study was done by analyzing 3,089 emergencies related to consumption of hypnotics and sedatives, obtained from Emergency Indicator related to the use of psychoactive substances of the National Observatory on Drugs. There were used chi2 test for comparing proportions and t Student test for means. RESULTS: The total number of emergencies was 3,089, ranging in years of study. In 1,814 cases they were consumed only hypnosedatives; 64.7% women and average age of 41 years. The most frequent diagnosis was overdose/attempted suicide with benzodiazepines (29.3%), being lorazepam the most consumed. In 23.3% of cases it was consumed more than one hypnosedative and 9% was associated with psychiatric disorders. CONCLUSIONS: The number of emergencies related to the consumption of at least one hypnosedative in the monitored hospitals in the period studied presented high levels especially in middle-aged women with no psychiatric disorder to justify their use. Benzodiazepines were the most consumed hypnotics, cause of overdose/attempted suicide episodes. PMID- 27775684 TI - Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids. AB - Daptomycin is a bactericidal antibiotic of last resort for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA)1,2. Although resistance is rare, treatment failure can occur in more than 20% of cases3,4 and so there is a pressing need to identify and mitigate factors that contribute to poor therapeutic outcomes. Here, we show that loss of the Agr quorum-sensing system, which frequently occurs in clinical isolates, enhances S. aureus survival during daptomycin treatment. Wild-type S. aureus was killed rapidly by daptomycin, but Agr-defective mutants survived antibiotic exposure by releasing membrane phospholipids, which bound and inactivated the antibiotic. Although wild type bacteria also released phospholipid in response to daptomycin, Agr-triggered secretion of small cytolytic toxins, known as phenol soluble modulins, prevented antibiotic inactivation. Phospholipid shedding by S. aureus occurred via an active process and was inhibited by the beta-lactam antibiotic oxacillin, which slowed inactivation of daptomycin and enhanced bacterial killing. In conclusion, S. aureus possesses a transient defence mechanism that protects against daptomycin, which can be compromised by Agr-triggered toxin production or an existing therapeutic antibiotic. PMID- 27775685 TI - LadS is a calcium-responsive kinase that induces acute-to-chronic virulence switch in Pseudomonas aeruginosa. AB - Virulence of pathogenic bacteria is a tightly controlled process to facilitate invasion and survival in host tissues. Although pathways controlling virulence have been defined in detail, signals modulating these processes are poorly understood. The opportunistic pathogen Pseudomonas aeruginosa causes acute and chronic infections in humans. Disease progression is typically associated with a loss of acute virulence and the emergence of biofilms and chronic behaviour. The acute-to-chronic switch is governed by the global Gac/Rsm pathway. Using a newly developed acute-chronic dual reporter system we show that calcium stimulates the Gac/Rsm pathway via the Gac-associated hybrid histidine kinase LadS. We show that calcium binds to the periplasmic DISMED2 sensor domain of LadS to activate its kinase activity. Activation of the Gac/Rsm pathway by calcium leads to a switch to the chronic program and confers drug tolerance by reducing P. aeruginosa growth rate. Clinical isolates from cystic fibrosis airways retain their calcium response during chronic infections. Our data imply that calcium sensing evolved as an adaptation to the opportunistic lifestyle of P. aeruginosa and that calcium serves as a host signal to balance acute-to-chronic behaviour during infections. Establishing calcium signalling in host-pathogen interaction adds to growing evidence indicating key roles for calcium in bacterial signalling. PMID- 27775686 TI - Commentary on "What is the identity of fibroblast pneumocyte factor (FPF)?" PMID- 27775687 TI - Macropinocytosis of type XVII collagen induced by bullous pemphigoid IgG is regulated via protein kinase C. AB - Macropinocytosis is an endocytic pathway that is involved in the nonselective fluid uptake of extracellular fluid. Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies to type XVII collagen (COL17), which is a component of hemidesmosome. When keratinocytes are treated with BP-IgG, COL17 internalizes into cells by way of the macropinocytosis. We investigated the mechanism of COL17 macropinocytosis using DJM-1 cells, a cutaneous squamous cell carcinoma cell line. First, non hemidesmosomal COL17 was preferentially depleted by stimulation with the BP-IgG in the DJM-1 cells. To investigate the signaling involved in COL17 macropinocytosis, the inhibition of small GTPase family members Rac1 and Cdc42 was found to strongly repress COL17 internalization; in addition, the Rho inhibitor also partially blocked that internalization, suggesting these small GTPases are involved in signaling to mediate COL17-macropinocytosis. Western blotting using Phostag-SDS-PAGE demonstrated high levels of COL17 phosphorylation in DJM-1 cells under steady-state condition. Treatment with BP-IgG increased the intracellular calcium level within a minute, and induced the overabundant phosphorylation of COL17. The overabundant phosphorylation of COL17 was suppressed by a protein kinase C (PKC) inhibitor. In addition, PKC inhibitor repressed COL17 endocytosis using cell culture and organ culture systems. Finally, the depletion of COL17 was not observed in the HEK293 cells transfected COL17 without intracellular domain. These results suggest that COL17 internalization induced by BP-IgG may be mediated by a PKC pathway. In summary, BP-IgG initially binds to COL17 distributed on the plasma membrane, and COL17 may be internalized by means of a macropinocytic pathway related to the phosphorylation of the intracellular domain by PKC. PMID- 27775688 TI - Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer. AB - NF-kappaB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-kappaB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-kappaB activity was accomplished through the specific NF-kappaB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBalpha repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-kappaB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF kappaB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-kappaB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF kappaB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion. PMID- 27775689 TI - Earthworm extract attenuates silica-induced pulmonary fibrosis through Nrf2 dependent mechanisms. AB - Silicosis is an occupational pulmonary fibrosis caused by inhalation of silica (SiO2) and there are no ideal drugs to treat this disease. Earthworm extract (EE), a natural nutrient, has been reported to have anti-inflammatory, antioxidant, and anti-apoptosis effects. The purpose of the current study was to test the protective effects of EE against SiO2-induced pulmonary fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. We found that treatment with EE significantly reduced lung inflammation and fibrosis and improved lung structure and function in SiO2-instilled mice. Further mechanistic investigations revealed that EE administration markedly inhibited SiO2-induced oxidative stress, mitochondrial apoptotic pathway, and epithelial mesenchymal transition in HBE and A549 cells. Furthermore, we demonstrate that Nrf2 activation partly mediates the interventional effects of EE against SiO2 induced pulmonary fibrosis. Our study has identified EE to be a potential anti oxidative, anti-inflammatory, and anti-fibrotic drug for silicosis. PMID- 27775692 TI - Quantitative assessment of pancreatic cancer precursor lesions in IHC-stained tissue with a tissue image analysis platform. AB - Tissue image analysis (tIA) is emerging as a powerful tool for quantifying biomarker expression and distribution in complex diseases and tissues. Pancreatic ductal adenocarcinoma (PDAC) develops in a highly complex and heterogeneous tissue environment and, generally, has a very poor prognosis. Early detection of PDAC is confounded by limited knowledge of the pre-neoplastic disease stages and limited methods to quantitatively assess disease heterogeneity. We sought to develop a tIA approach to assess the most common PDAC precursor lesions, pancreatic intraepithelial neoplasia (PanIN), in tissues from KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-Cre (KPC) mice, a validated model of PDAC development. tIA profiling of training regions of PanIN and tumor microenvironment (TME) cells was utilized to guide identification of PanIN/TME tissue compartment stratification criteria. A custom CellMap algorithm implementing these criteria was applied to whole-slide images of KPC mice pancreata sections to quantify p53 and Ki-67 biomarker staining in each tissue compartment as a proof-of-concept for the algorithm platform. The algorithm robustly identified a higher percentage of p53 positive cells in PanIN lesions relative to the TME, whereas no difference was observed for Ki-67. Ki-67 expression was also quantified in a human pancreatic tissue sample available to demonstrate the translatability of the CellMap algorithm to human samples. Together, our data demonstrated the utility of CellMap to enable objective and quantitative assessments, across entire tissue sections, of PDAC precursor lesions in preclinical and clinical models of this disease to support efforts leading to novel insights into disease progression, diagnostic markers, and potential therapeutic targets. PMID- 27775691 TI - Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells. AB - Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy. PMID- 27775694 TI - Inhibition of FLT3 in AML: a focus on sorafenib. AB - FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma. Sorafenib monotherapy or in combination with conventional chemotherapy, has been evaluated in various settings in AML, including front-line, relapsed or refractory disease including post-allograft failures and, more recently, as post-transplant maintenance therapy. Encouraging data have emerged with several other agents like lestaurtinib, midostaurin, crenolanib, gilteritinib and quizartinib. Although transient responses to FLT3 inhibitors are often observed in case of disease relapse, the most promising approach is the use of FLT3 inhibitors either in combination with induction chemotherapy or as consolidation/maintenance therapy after allogeneic hematopoietic cell transplantation. In this review, we summarize the clinical data on sorafenib and other FLT3 inhibitors in AML. PMID- 27775690 TI - Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice. AB - Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to have a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild type (WT) and miR-21-/- mice underwent Sham or bile duct ligation (BDL) for 1 week, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and small mothers against decapentaplegic 7 (Smad-7) expression. In vitro, immortalized murine biliary cell lines (IMCLs) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL induced biliary proliferation and intrahepatic biliary mass. In addition, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers transforming growth factor-beta1 and alpha-smooth muscle actin. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared with control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury, miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis. PMID- 27775693 TI - Minimal detectable disease confirmed by flow cytometry and poor outcome after autologous stem cell transplantation in peripheral T-Cell lymphomas. PMID- 27775695 TI - Peripheral blood stem cell mobilization in multiple myeloma comparison of two consecutive regimens in a limited resources country. AB - This study compared retrospectively the effectiveness, toxicity and hematopoietic recovery after autologous peripheral blood stem cell transplantation (ASCT) of two consecutive peripheral blood stem cell mobilization regimens in newly diagnosed MM patients. Patients in group 1 (n=178) were treated with 4 g/m2 of cyclophosphamide (CY) plus G-CSF (5 MUg/kg/day). Patients in group 2 (n=117) with 750 mg/m2 of VP16 plus G-CSF (10 MUg/kg/day). Optimal mobilization, defined by a target number of 8 * 106 CD34+ cells/kg collected, was achieved in 62.4% and 89.7% of patients in groups 1 and 2, respectively (P<10-4). The median number of aphaeresis sessions was reduced from two in group 1 to one in group 2 (P<10-4). Grade4 neutropenia, febrile neutropenia and IV antibiotic use were significantly more frequent in group 1 than in group 2 (P<10-4). Red blood cell transfusion requirements were significantly greater in group 1 (P=0.007). The switch to VP16 G-CSF10 resulted in a significant reduction of the number of hospitalization days (P<10-4). Neutrophil and platelet recovery after ASCT occurred on days 11 and 12, respectively, in the two groups with no significant differences. VP16+G-CSF10 allowed liberation of resources in the clinical and aphaeresis departments and demonstrated a better effectiveness-safety profile than CY+G-CSF5. PMID- 27775696 TI - Successful haploidentical stem cell transplantation for three adults with primary hemophagocytic lymphohistiocytosis. PMID- 27775697 TI - Is complement blockade an acceptable therapeutic strategy for hematopoietic cell transplant-associated thrombotic microangiopathy? AB - Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development. Complement blockade using eculizumab has shown some promising rates of hematologic responses, however, survival may still be poor. Early discontinuation of calcineurin inhibitor where feasible, use of eculizumab, aggressive infection prophylaxis, close monitoring and early treatment of potential complications including GvHD and organ failure may improve outcomes. A number of complement inhibitors are in the development and may change treatment paradigm. Future studies are important to better understand TA-TMA as a disease process and may aim to confirm the role of complement activation in TA-TMA, enhance diagnostic strategy, determine therapeutic approaches and strategies to reduce the risk of other complications particularly infection and GvHD. PMID- 27775698 TI - Nitrogen fixation in a chemoautotrophic lucinid symbiosis. AB - The shallow water bivalve Codakia orbicularis lives in symbiotic association with a sulfur-oxidizing bacterium in its gills. The endosymbiont fixes CO2 and thus generates organic carbon compounds, which support the host's growth. To investigate the uncultured symbiont's metabolism and symbiont-host interactions in detail we conducted a proteogenomic analysis of purified bacteria. Unexpectedly, our results reveal a hitherto completely unrecognized feature of the C. orbicularis symbiont's physiology: the symbiont's genome encodes all proteins necessary for biological nitrogen fixation (diazotrophy). Expression of the respective genes under standard ambient conditions was confirmed by proteomics. Nitrogenase activity in the symbiont was also verified by enzyme activity assays. Phylogenetic analysis of the bacterial nitrogenase reductase NifH revealed the symbiont's close relationship to free-living nitrogen-fixing Proteobacteria from the seagrass sediment. The C. orbicularis symbiont, here tentatively named 'Candidatus Thiodiazotropha endolucinida', may thus not only sustain the bivalve's carbon demands. C. orbicularis may also benefit from a steady supply of fixed nitrogen from its symbiont-a scenario that is unprecedented in comparable chemoautotrophic symbioses. PMID- 27775699 TI - SUSD2 expression in high-grade serous ovarian cancer correlates with increased patient survival and defective mesothelial clearance. AB - The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs). A high-density, clinically annotated HGSOC tissue microarray was stained with an anti-SUSD2 antibody. Patients with tumors that had a low percentage of SUSD2 staining cells had a shorter median survival (31.7 months) compared with patients who had tumors with extensive SUSD2 staining (49.1 months; P-value=0.0083). To investigate the role of SUSD2 in HGSOCs, stable OVCAR3, OVSAHO and KURAMOCHI cell lines were established with knockdown (KD) or non-targeting (NT) of SUSD2. Boyden chamber and wound-healing assays demonstrated that OVCAR3, OVSAHO and KURAMOCHI SUSD2-KD cells migrated at significantly higher rates compared with their SUSD2 NT counterpart cell lines. Quantitative reverse transcription-PCR and western immunoblot analysis indicated an inverse relationship between SUSD2 and well-characterized mesenchymal proteins, including Twist-1, Zeb-1, N-cadherin, STEAP1, AHNAK, Snail-1, COL5A2 and Snail-3 in OVCAR3, OVSAHO and KURAMOCHI cell line models. In addition, OVCAR3 and KURAMOCHI SUSD2-KD spheroids displayed increased mesothelial clearance ability compared with cells that express endogenous levels of SUSD2. These data suggest that SUSD2 has a role in the inhibition of mesothelial clearance, which is required for metastasis. Altogether, our findings indicate that SUSD2 impedes migration, epithelial-to mesenchymal transitional and mesothelial clearance of HGSOC cells, consistent with prolonged survival of patients with SUSD2-expressing tumors. PMID- 27775700 TI - Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells. AB - Acquired resistance to conventional and targeted therapies is becoming a major hindrance in cancer management. It is increasingly clear that cancer cells are able to evolve and rewire canonical signalling pathways to their advantage, thus evading cell death and promoting cell invasion. The Axl receptor tyrosine kinase (RTK) has been shown to modulate acquired resistance to EGFR-targeted therapies in both breast and lung cancers. Glioblastoma multiforme (GBM) is a highly infiltrative and invasive form of brain tumour with little response to therapy. Both Axl and EGFR have been identified as major players in gliomagenesis and invasiveness. However, the mechanisms underlying a potential signalling crosstalk between EGFR and Axl RTKs are unknown. The purpose of this study was to investigate this novel and unconventional interaction among RTKs of different families in human GBM cells. With the use of western blotting, in vitro kinase activity, co-immunoprecipitation and bimolecular fluorescence complementation assays, we show that EGF stimulates activation of Axl kinase and that there is a hetero-interaction between the two RTKs. Through small interfering RNA knockdown and quantitative PCR screening, we identified distinct gene expression patterns in GBM cells that were specifically regulated by signalling from EGFR-EGFR, Axl Axl and EGFR-Axl RTK parings. These included genes that promote invasion, which were activated only via the EGFR-Axl axis (MMP9), while EGFR-EGFR distinctly regulated the cell cycle and Axl-Axl regulated invasion. Our findings provide critical insights into the role of EGFR-Axl hetero-dimerisation in cancer cells and reveal regulation of cell invasion via Axl as a novel function of EGFR signalling. PMID- 27775701 TI - GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth. AB - Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis. PMID- 27775702 TI - Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes. AB - Most migrating cells extrude their front by the force of actin polymerization. Polymerization requires an initial nucleation step, which is mediated by factors establishing either parallel filaments in the case of filopodia or branched filaments that form the branched lamellipodial network. Branches are considered essential for regular cell motility and are initiated by the Arp2/3 complex, which in turn is activated by nucleation-promoting factors of the WASP and WAVE families. Here we employed rapid amoeboid crawling leukocytes and found that deletion of the WAVE complex eliminated actin branching and thus lamellipodia formation. The cells were left with parallel filaments at the leading edge, which translated, depending on the differentiation status of the cell, into a unipolar pointed cell shape or cells with multiple filopodia. Remarkably, unipolar cells migrated with increased speed and enormous directional persistence, while they were unable to turn towards chemotactic gradients. Cells with multiple filopodia retained chemotactic activity but their migration was progressively impaired with increasing geometrical complexity of the extracellular environment. These findings establish that diversified leading edge protrusions serve as explorative structures while they slow down actual locomotion. PMID- 27775703 TI - DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. AB - Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53 expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 also induces CHIP-mediated mutp53 degradation, while its overexpression antagonizes statin-induced mutp53 degradation. Our study reveals that DNAJA1 controls the fate of misfolded mutp53, provides insights into potential strategies to deplete mutp53 through the mevalonate pathway-DNAJA1 axis, and highlights the significance of p53 status in impacting statins' efficacy on cancer therapy. PMID- 27775704 TI - PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. AB - Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death. PMID- 27775705 TI - PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. AB - Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression. PMID- 27775707 TI - Chemosynthetic symbionts of marine invertebrate animals are capable of nitrogen fixation. AB - Chemosynthetic symbioses are partnerships between invertebrate animals and chemosynthetic bacteria. The latter are the primary producers, providing most of the organic carbon needed for the animal host's nutrition. We sequenced genomes of the chemosynthetic symbionts from the lucinid bivalve Loripes lucinalis and the stilbonematid nematode Laxus oneistus. The symbionts of both host species encoded nitrogen fixation genes. This is remarkable as no marine chemosynthetic symbiont was previously known to be capable of nitrogen fixation. We detected nitrogenase expression by the symbionts of lucinid clams at the transcriptomic and proteomic level. Mean stable nitrogen isotope values of Loripes lucinalis were within the range expected for fixed atmospheric nitrogen, further suggesting active nitrogen fixation by the symbionts. The ability to fix nitrogen may be widespread among chemosynthetic symbioses in oligotrophic habitats, where nitrogen availability often limits primary productivity. PMID- 27775706 TI - Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. AB - Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD 1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable. PMID- 27775708 TI - Instrumented cardiac microphysiological devices via multimaterial three dimensional printing. AB - Biomedical research has relied on animal studies and conventional cell cultures for decades. Recently, microphysiological systems (MPS), also known as organs-on chips, that recapitulate the structure and function of native tissues in vitro, have emerged as a promising alternative. However, current MPS typically lack integrated sensors and their fabrication requires multi-step lithographic processes. Here, we introduce a facile route for fabricating a new class of instrumented cardiac microphysiological devices via multimaterial three dimensional (3D) printing. Specifically, we designed six functional inks, based on piezo-resistive, high-conductance, and biocompatible soft materials that enable integration of soft strain gauge sensors within micro-architectures that guide the self-assembly of physio-mimetic laminar cardiac tissues. We validated that these embedded sensors provide non-invasive, electronic readouts of tissue contractile stresses inside cell incubator environments. We further applied these devices to study drug responses, as well as the contractile development of human stem cell-derived laminar cardiac tissues over four weeks. PMID- 27775710 TI - Ribosome-stalk biogenesis is coupled with recruitment of nuclear-export factor to the nascent 60S subunit. AB - Nuclear export of preribosomal subunits is a key step during eukaryotic ribosome formation. To efficiently pass through the FG-repeat meshwork of the nuclear pore complex, the large pre-60S subunit requires several export factors. Here we describe the mechanism of recruitment of the Saccharomyces cerevisiae RNA-export receptor Mex67-Mtr2 to the pre-60S subunit at the proper time. Mex67-Mtr2 binds at the premature ribosomal-stalk region, which later during translation serves as a binding platform for translational GTPases on the mature ribosome. The assembly factor Mrt4, a structural homolog of cytoplasmic-stalk protein P0, masks this site, thus preventing untimely recruitment of Mex67-Mtr2 to nuclear pre-60S particles. Subsequently, Yvh1 triggers Mrt4 release in the nucleus, thereby creating a narrow time window for Mex67-Mtr2 association at this site and facilitating nuclear export of the large subunit. Thus, a spatiotemporal mark on the ribosomal stalk controls the recruitment of an RNA-export receptor to the nascent 60S subunit. PMID- 27775709 TI - RNA-binding protein CPEB1 remodels host and viral RNA landscapes. AB - Host and virus interactions occurring at the post-transcriptional level are critical for infection but remain poorly understood. Here, we performed comprehensive transcriptome-wide analyses revealing that human cytomegalovirus (HCMV) infection results in widespread alternative splicing (AS), shortening of 3' untranslated regions (3' UTRs) and lengthening of poly(A)-tails in host gene transcripts. We found that the host RNA-binding protein CPEB1 was highly induced after infection, and ectopic expression of CPEB1 in noninfected cells recapitulated infection-related post-transcriptional changes. CPEB1 was also required for poly(A)-tail lengthening of viral RNAs important for productive infection. Strikingly, depletion of CPEB1 reversed infection-related cytopathology and post-transcriptional changes, and decreased productive HCMV titers. Host RNA processing was also altered in herpes simplex virus-2 (HSV-2) infected cells, thereby indicating that this phenomenon might be a common occurrence during herpesvirus infections. We anticipate that our work may serve as a starting point for therapeutic targeting of host RNA-binding proteins in herpesvirus infections. PMID- 27775711 TI - Staggered ATP binding mechanism of eukaryotic chaperonin TRiC (CCT) revealed through high-resolution cryo-EM. AB - The eukaryotic chaperonin TRiC (or CCT) assists in the folding of 10% of cytosolic proteins. Here we present two cryo-EM structures of Saccharomyces cerevisiae TRiC in a newly identified nucleotide partially preloaded (NPP) state and in the ATP-bound state, at 4.7-A and 4.6-A resolution, respectively. Through inner-subunit eGFP tagging, we identified the subunit locations in open-state TRiC and found that the CCT2 subunit pair forms an unexpected Z shape. ATP binding induces a dramatic conformational change on the CCT2 side, thereby suggesting that CCT2 plays an essential role in TRiC allosteric cooperativity. Our structural and biochemical data reveal a staggered ATP binding mechanism of TRiC with preloaded nucleotide on the CCT6 side of NPP-TRiC and demonstrate that TRiC has evolved into a complex that is structurally divided into two sides. This work offers insight into how the TRiC nucleotide cycle coordinates with its mechanical cycle in preparing folding intermediates for further productive folding. PMID- 27775712 TI - Superconducting nanowire single-photon detectors with non-periodic dielectric multilayers. AB - We present superconducting nanowire single-photon detectors (SSPDs) on non periodic dielectric multilayers, which enable us to design a variety of wavelength dependences of optical absorptance by optimizing the dielectric multilayer. By adopting a robust simulation to optimize the dielectric multilayer, we designed three types of SSPDs with target wavelengths of 500 nm, 800 nm, and telecom range respectively. We fabricated SSPDs based on the optimized designs for 500 and 800 nm, and evaluated the system detection efficiency at various wavelengths. The results obtained confirm that the designed SSPDs with non-periodic dielectric multilayers worked well. This versatile device structure can be effective for multidisciplinary applications in fields such as the life sciences and remote sensing that require high efficiency over a precise spectral range and strong signal rejection at other wavelengths. PMID- 27775713 TI - Small-molecule factor D inhibitors targeting the alternative complement pathway. AB - Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases. PMID- 27775714 TI - Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. AB - Recognition of histone covalent modifications by 'reader' modules constitutes a major mechanism for epigenetic regulation. A recent upsurge of newly discovered histone lysine acylations, such as crotonylation (Kcr), butyrylation (Kbu), and propionylation (Kpr), greatly expands the coding potential of histone lysine modifications. Here we demonstrate that the histone acetylation-binding double PHD finger (DPF) domains of human MOZ (also known as KAT6A) and DPF2 (also known as BAF45d) accommodate a wide range of histone lysine acylations with the strongest preference for Kcr. Crystal structures of the DPF domain of MOZ in complex with H3K14cr, H3K14bu, and H3K14pr peptides reveal that these non-acetyl acylations are anchored in a hydrophobic 'dead-end' pocket with selectivity for crotonylation arising from intimate encapsulation and an amide-sensing hydrogen bonding network. Immunofluorescence and chromatin immunoprecipitation (ChIP) quantitative PCR (qPCR) showed that MOZ and H3K14cr colocalize in a DPF-dependent manner. Our studies call attention to a new regulatory mechanism centered on histone crotonylation readout by DPF family members. PMID- 27775715 TI - Design and characterization of bivalent BET inhibitors. AB - Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors. All reported antagonists of the BET protein BRD4 bind in a monovalent fashion. Here we describe, to our knowledge for the first time, a bivalent BET bromodomain inhibitor-MT1-which has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is more than 100-fold more potent, in cellular assays, than the corresponding monovalent antagonist, JQ1. MT1 significantly (P < 0.05) delayed leukemia progression in mice, as compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and a rationale for further development of multidomain inhibitors of epigenetic reader proteins. PMID- 27775716 TI - Potent and selective bivalent inhibitors of BET bromodomains. AB - Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins. PMID- 27775717 TI - Mechanism of super-assembly of respiratory complexes III and IV. AB - Respiratory chain complexes can super-assemble into quaternary structures called supercomplexes that optimize cellular metabolism. The interaction between complexes III (CIII) and IV (CIV) is modulated by supercomplex assembly factor 1 (SCAF1, also known as COX7A2L). The discovery of SCAF1 represented strong genetic evidence that supercomplexes exist in vivo. SCAF1 is present as a long isoform (113 amino acids) or a short isoform (111 amino acids) in different mouse strains. Only the long isoform can induce the super-assembly of CIII and CIV, but it is not clear whether SCAF1 is required for the formation of the respirasome (a supercomplex of CI, CIII2 and CIV). Here we show, by combining deep proteomics and immunodetection analysis, that SCAF1 is always required for the interaction between CIII and CIV and that the respirasome is absent from most tissues of animals containing the short isoform of SCAF1, with the exception of heart and skeletal muscle. We used directed mutagenesis to characterize SCAF1 regions that interact with CIII and CIV and discovered that this interaction requires the correct orientation of a histidine residue at position 73 that is altered in the short isoform of SCAF1, explaining its inability to interact with CIV. Furthermore, we find that the CIV subunit COX7A2 is replaced by SCAF1 in supercomplexes containing CIII and CIV and by COX7A1 in CIV dimers, and that dimers seem to be more stable when they include COX6A2 rather than the COX6A1 isoform. PMID- 27775718 TI - Correcting mitochondrial fusion by manipulating mitofusin conformations. AB - Mitochondria are dynamic organelles that exchange contents and undergo remodelling during cyclic fusion and fission. Genetic mutations in MFN2 (the gene encoding mitofusin 2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A). It has not yet been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is not completely understood. Here we show that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions. On the basis of this model, we engineered a cell-permeant minipeptide to destabilize the fusion constrained conformation of mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons that harbour CMT2A-associated genetic defects. The relationship between the conformational plasticity of mitofusin 2 and mitochondrial dynamism reveals a central mechanism that regulates mitochondrial fusion, the manipulation of which can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics. PMID- 27775719 TI - Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. AB - Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5 trisphosphate receptors that release Ca2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca2+ inhibits neuronally evoked capillary dilation, that astrocyte [Ca2+]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca2+ generates arachidonic acid via phospholipase D2 and diacylglycerol lipase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca2+-dependent NO generation by interneurons. These results reveal that different signaling cascades regulate cerebral blood flow at the capillary and arteriole levels. PMID- 27775720 TI - A neuronal PI(3,4,5)P3-dependent program of oligodendrocyte precursor recruitment and myelination. AB - The molecular trigger of CNS myelination is unknown. By targeting Pten in cerebellar granule cells and activating the AKT1-mTOR pathway, we increased the caliber of normally unmyelinated axons and the expression of numerous genes encoding regulatory proteins. This led to the expansion of genetically wild-type oligodendrocyte progenitor cells, oligodendrocyte differentiation and de novo myelination of parallel fibers. Thus, a neuronal program dependent on the phosphoinositide PI(3,4,5)P3 is sufficient to trigger all steps of myelination. PMID- 27775721 TI - The brain adapts to dishonesty. AB - Dishonesty is an integral part of our social world, influencing domains ranging from finance and politics to personal relationships. Anecdotally, digressions from a moral code are often described as a series of small breaches that grow over time. Here we provide empirical evidence for a gradual escalation of self serving dishonesty and reveal a neural mechanism supporting it. Behaviorally, we show that the extent to which participants engage in self-serving dishonesty increases with repetition. Using functional MRI, we show that signal reduction in the amygdala is sensitive to the history of dishonest behavior, consistent with adaptation. Critically, the extent of reduced amygdala sensitivity to dishonesty on a present decision relative to the previous one predicts the magnitude of escalation of self-serving dishonesty on the next decision. The findings uncover a biological mechanism that supports a 'slippery slope': what begins as small acts of dishonesty can escalate into larger transgressions. PMID- 27775722 TI - Gravity orientation tuning in macaque anterior thalamus. AB - Gravity may provide a ubiquitous allocentric reference to the brain's spatial orientation circuits. Here we describe neurons in the macaque anterior thalamus tuned to pitch and roll orientation relative to gravity, independently of visual landmarks. We show that individual cells exhibit two-dimensional tuning curves, with peak firing rates at a preferred vertical orientation. These results identify a thalamic pathway for gravity cues to influence perception, action and spatial cognition. PMID- 27775723 TI - Erratum: Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes. PMID- 27775724 TI - Nanostructured glycan architecture is important in the inhibition of influenza A virus infection. AB - Rapid change and zoonotic transmission to humans have enhanced the virulence of the influenza A virus (IAV). Neutralizing antibodies fail to provide lasting protection from seasonal epidemics. Furthermore, the effectiveness of anti influenza neuraminidase inhibitors has declined because of drug resistance. Drugs that can block viral attachment and cell entry independent of antigenic evolution or drug resistance might address these problems. We show that multivalent 6' sialyllactose-polyamidoamine (6SL-PAMAM) conjugates, when designed to have well defined ligand valencies and spacings, can effectively inhibit IAV infection. Generation 4 (G4) 6SL-PAMAM conjugates with a spacing of around 3 nm between 6SL ligands (S3-G4) showed the strongest binding to a hemagglutinin trimer (dissociation constant of 1.6 * 10-7 M) and afforded the best inhibition of H1N1 infection. S3-G4 conjugates were resistant to hydrolysis by H1N1 neuraminidase. These conjugates protected 75% of mice from a lethal challenge with H1N1 and prevented weight loss in infected animals. The structure-based design of multivalent nanomaterials, involving modulation of nanoscale backbone structures and number and spacing between ligands, resulted in optimal inhibition of IAV infection. This approach may be broadly applicable for designing effective and enduring therapeutic protection against human or avian influenza viruses. PMID- 27775725 TI - Evolutionary multi-objective optimization of colour pixels based on dielectric nanoantennas. AB - The rational design of photonic nanostructures consists of anticipating their optical response from systematic variations of simple models. This strategy, however, has limited success when multiple objectives are simultaneously targeted, because it requires demanding computational schemes. To this end, evolutionary algorithms can drive the morphology of a nano-object towards an optimum through several cycles of selection, mutation and cross-over, mimicking the process of natural selection. Here, we present a numerical technique that can allow the design of photonic nanostructures with optical properties optimized along several arbitrary objectives. In particular, we combine evolutionary multi objective algorithms with frequency-domain electrodynamical simulations to optimize the design of colour pixels based on silicon nanostructures that resonate at two user-defined, polarization-dependent wavelengths. The scattering spectra of optimized pixels fabricated by electron-beam lithography show excellent agreement with the targeted objectives. The method is self-adaptive to arbitrary constraints and therefore particularly apt for the design of complex structures within predefined technological limits. PMID- 27775726 TI - Shape changing thin films powered by DNA hybridization. AB - Active materials that respond to physical and chemical stimuli can be used to build dynamic micromachines that lie at the interface between biological systems and engineered devices. In principle, the specific hybridization of DNA can be used to form a library of independent, chemically driven actuators for use in such microrobotic applications and could lead to device capabilities that are not possible with polymer- or metal-layer-based approaches. Here, we report shape changing films that are powered by DNA strand exchange reactions with two different domains that can respond to distinct chemical signals. The films are formed from DNA-grafted gold nanoparticles using a layer-by-layer deposition process. Films consisting of an active and a passive layer show rapid, reversible curling in response to stimulus DNA strands added to solution. Films consisting of two independently addressable active layers display a complex suite of repeatable transformations, involving eight mechanochemical states and incorporating self-righting behaviour. PMID- 27775728 TI - Photonic multilayer structure of Begonia chloroplasts enhances photosynthetic efficiency. AB - Enhanced light harvesting is an area of interest for optimizing both natural photosynthesis and artificial solar energy capture1,2. Iridescence has been shown to exist widely and in diverse forms in plants and other photosynthetic organisms and symbioses3,4, but there has yet to be any direct link demonstrated between iridescence and photosynthesis. Here we show that epidermal chloroplasts, also known as iridoplasts, in shade-dwelling species of Begonia5, notable for their brilliant blue iridescence, have a photonic crystal structure formed from a periodic arrangement of the light-absorbing thylakoid tissue itself. This structure enhances photosynthesis in two ways: by increasing light capture at the predominantly green wavelengths available in shade conditions, and by directly enhancing quantum yield by 5-10% under low-light conditions. These findings together imply that the iridoplast is a highly modified chloroplast structure adapted to make best use of the extremely low-light conditions in the tropical forest understorey in which it is found5,6. A phylogenetically diverse range of shade-dwelling plant species has been found to produce similarly structured chloroplasts7-9, suggesting that the ability to produce chloroplasts whose membranes are organized as a multilayer with photonic properties may be widespread. In fact, given the well-established diversity and plasticity of chloroplasts10,11, our results imply that photonic effects may be important even in plants that do not show any obvious signs of iridescence to the naked eye but where a highly ordered chloroplast structure may present a clear blue reflectance at the microscale. Chloroplasts are generally thought of as purely photochemical; we suggest that one should also think of them as a photonic structure with a complex interplay between control of light propagation, light capture and photochemistry. PMID- 27775729 TI - Mitochondrial diseases. PMID- 27775727 TI - Acoustic terahertz graphene plasmons revealed by photocurrent nanoscopy. AB - Terahertz (THz) fields are widely used for sensing, communication and quality control. In future applications, they could be efficiently confined, enhanced and manipulated well below the classical diffraction limit through the excitation of graphene plasmons (GPs). These possibilities emerge from the strongly reduced GP wavelength, lambdap, compared with the photon wavelength, lambda0, which can be controlled by modulating the carrier density of graphene via electrical gating. Recently, GPs in a graphene/insulator/metal configuration have been predicted to exhibit a linear dispersion (thus called acoustic plasmons) and a further reduced wavelength, implying an improved field confinement, analogous to plasmons in two dimensional electron gases (2DEGs) near conductive substrates. Although infrared GPs have been visualized by scattering-type scanning near-field optical microscopy (s-SNOM), the real-space imaging of strongly confined THz plasmons in graphene and 2DEGs has been elusive so far-only GPs with nearly free-space wavelengths have been observed. Here we demonstrate real-space imaging of acoustic THz plasmons in a graphene photodetector with split-gate architecture. To that end, we introduce nanoscale-resolved THz photocurrent near-field microscopy, where near-field excited GPs are detected thermoelectrically rather than optically. This on-chip detection simplifies GP imaging as sophisticated s SNOM detection schemes can be avoided. The photocurrent images reveal strongly reduced GP wavelengths (lambdap ~ lambda0/66), a linear dispersion resulting from the coupling of GPs with the metal gate below the graphene, and that plasmon damping at positive carrier densities is dominated by Coulomb impurity scattering. PMID- 27775730 TI - Mitochondrial diseases. AB - Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with mitochondrial diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including mitochondrial donation, will offer a better reproductive choice for these women in the future. The treatment of patients with mitochondrial diseases remains a challenge, but guidelines are available to manage the complications of disease. Moreover, an increasing number of therapeutic options are being considered, and with the development of large cohorts of patients and biomarkers, several clinical trials are in progress. PMID- 27775731 TI - Commentary: How Bayes factors change scientific practice. PMID- 27775732 TI - Erratum: Medial Femoral Condyle Free Flap for Nasal Reconstruction: New Technique for Full-Thickness Nasal Defects: Erratum. AB - [This corrects the article DOI: 10.1097/GOX.0000000000000858.]. PMID- 27775733 TI - Timing of renal replacement therapy in critically ill patients with acute kidney injury. PMID- 27775734 TI - Letter to the Editor: Menstrual problems in women with intellectual disability. AB - The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. When letters are published, they are usually accompanied in the same issue by any responses or comments. The Committee screens out discourteous, inaccurate or libellous statements. The letters are sub-edited before publication. Authors are required to declare any conflicts of interest. The Committee's decision on publication is final. PMID- 27775735 TI - Transparency is good, independence from pharmaceutical industry is better! PMID- 27775736 TI - Novel fluorescent lapachone-based BODIPY: synthesis, computational and electrochemical aspects, and subcellular localisation of a potent antitumour hybrid quinone. AB - For the first time, a fluorescent lapachone-based BODIPY was synthesised and characterised by NMR and mass spectrometry. Computational and electrochemical aspects, as well as cytotoxic activity and subcellular localisation, were studied. Confocal microscopy experiments indicated that the probe was a specific mitochondria-staining agent. These in-detail analyses were useful in understanding the cytotoxic effects and mechanism of action of this novel hybrid compound. This molecule constitutes a promising prototype owing to its potential biological activities and the new strategies aimed at mechanistic investigations in cells and in vivo, and opens up an interesting avenue of research. PMID- 27775737 TI - Hydrogen-bonded networks of [Fe(bpp)2]2+ spin crossover complexes and dicarboxylate anions: structural and photomagnetic properties. AB - The paper reports the syntheses, crystal structures, thermal and (photo)magnetic properties of spin crossover salts of formula [Fe(bpp)2](C6H8O4).4H2O (1.4H2O), [Fe(bpp)2](C8H4O4).2CH3OH.H2O (2.2MeOH.H2O) and [Fe(bpp)2](C8H4O4).5H2O (2.5H2O) (bpp = 2,6-bis(pyrazol-3yl)pyridine; C6H8O4 = adipate dianion; C8H4O4 = terephthalate dianion). The salts exhibit an intricate network of hydrogen bonds between low-spin iron(ii) complexes and carboxylate dianions, with solvent molecules sitting in the voids. Desolvation is accompanied by a low-spin (LS) to high-spin (HS) transformation in the materials. The dehydrated phase 2 undergoes a two-step transition with a second step showing thermal hysteresis (T1/2? = 139 K and T1/2? = 118 K). 2 displays a quantitative LS to HS photomagnetic conversion, with a T(LIESST) value of 63 K. PMID- 27775738 TI - Interactions between 2,4-bis-pteridine-1,5-benzodiazepine and group 12 dihalides: synthesis, spectral and XRD structural studies and theoretical calculations. AB - 2,4-Bis(1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione-6-yl)-2,3-dihydro-2-methyl-1H 1,5-benzodiazepine (DLMBZD) has been prepared and its molecular and crystal structures have been determined from spectral and XRD data. The benzodiazepine ligand was reacted with zinc(ii), cadmium(ii) and mercury(ii) chloride, bromide and iodide to give complexes with general formula [M(DLMBZD)X2]. The complexes have been synthesized and characterized by IR, NMR and elemental analysis. The structure of seven complexes has been obtained by single crystal X-ray diffraction. In all the cases, the metal is (2 + 2 + 1)-five-coordinated by two halide ligands, two nitrogen atoms from pyrazine and diazepine rings and a carbonyl oxygen from a pteridine ring. The coordinated-metal environment is a square-based pyramid, with increasing trigonality from Hg(ii) to Zn(ii) complexes. To coordinate the metals, the ligand folds itself, establishing four intramolecular sigma-pi interactions with the pyrimidine and pyrazine rings. A topological analysis of the electron density using the Quantum Theory of Atoms in Molecules and the complexes stability has been performed. PMID- 27775739 TI - Correction: Electrocoalescence of paired droplets encapsulated in double-emulsion drops. AB - Correction for 'Electrocoalescence of paired droplets encapsulated in double emulsion drops' by Yankan Jia et al., Lab Chip, 2016, DOI: . PMID- 27775740 TI - The effect of C-OH functionality on the surface chemistry of biomass-derived molecules: ethanol chemistry on Rh(100). AB - The adsorption and decomposition of ethanol on Rh(100) was studied as a model reaction to understand the role of C-OH functionalities in the surface chemistry of biomass-derived molecules. A combination of experimental surface science and computational techniques was used: (i) temperature programmed reaction spectroscopy (TPRS), reflection absorption infrared spectroscopy (RAIRS), work function measurements (Kelvin Probe - KP), and density functional theory (DFT). Ethanol produces ethoxy (CH3CH2O) species via O-H bond breaking upon adsorption at 100 K. Ethoxy decomposition proceeds differently depending on the surface coverage. At low coverage, the decomposition of ethoxy species occurs viabeta-C-H cleavage, which leads to an oxometallacycle (OMC) intermediate. Decomposition of the OMC scissions (at 180-320 K) ultimately produces CO, H2 and surface carbon. At high coverage, along with the pathway observed in the low coverage case, a second pathway occurs around 140-200 K, which produces an acetaldehyde intermediate viaalpha-C-H cleavage. Further decomposition of acetaldehyde produces CH4, CO, H2 and surface carbon. However, even at high coverage this is a minor pathway, and methane selectivity is 10% at saturation coverage. The results suggests that biomass-derived oxygenates, which contain an alkyl group, react on the Rh(100) surface to produce synthesis gas (CO and H2), surface carbon and small hydrocarbons due to the high dehydrogenation and C-C bond scission activity of Rh(100). PMID- 27775741 TI - Spin-state diversity in a series of Co(ii) PNP pincer bromide complexes. AB - We describe the structural and electronic impacts of modifying the bridging atom in a family of Co(ii) pincer complexes with the formula Co(t-Bu)2PEPyEP(t-Bu)2Br2 (Py = pyridine, E = CH2, NH, and O for compounds 1-3, respectively). Structural characterization by single crystal X-ray diffraction indicates that compounds 1 and 3 are 5-coordinate complexes with both bromides bound to the Co(ii) ion, while compound 2 is square planar with one bromide in the outer coordination sphere. The reduction potentials of 1-3, characterized by cyclic voltammetry, are consistent with the increasing electron-withdrawing character of the pincer ligand as the linker (E) between the pyridine and phosphine arms becomes more electronegative. Magnetic property studies of compounds 1 and 2 confirm high- and low-spin behavior, respectively, through a broad temperature range. However, complex 3 features an unusual combination of high spin S = 3/2 Co(ii) and temperature dependent spin-crossover between S = 3/2 and S = 1/2 states. The different magnetic behaviors observed among the three CoBr2 pincer complexes reflects the importance of small ligand perturbations on overall coordination geometry and resulting spin state properties. PMID- 27775742 TI - Interstitial flow differentially increases patient-derived glioblastoma stem cell invasion via CXCR4, CXCL12, and CD44-mediated mechanisms. AB - Glioblastoma (GBM) prognosis remains dismal due in part to the invasiveness of GBM cells. Interstitial fluid flow (IFF) has been shown to increase invasion of glioma cells in vitro through the CXCR4 receptor interacting with autologous, pericellular gradients of CXCL12 (autologous chemotaxis) or through the CD44 receptor interactions with the extracellular matrix (hyaluronan-mediated mechanotransduction). These mechanisms have not been examined together and thus we hypothesized that both mechanisms contribute to invasion in populations of cancer cells. Therefore, we examined IFF-stimulated CXCR4-, CXCL12-, and CD44 dependent invasion in patient-derived glioblastoma stem cells (GSCs). Using our 3D in vitro assay and correlative in vivo studies we demonstrated GSC lines show increased invasion with flow. This flow-stimulated invasion was reduced by blockade of CXCR4, CXCL12, and/or CD44, revealing that GSC invasion may be mediated simultaneously by both mechanisms. Characterization of CXCR4+, CXCL12+, and CD44+ populations in four GSC lines revealed different percentages of protein positive subpopulations for each line. We developed an agent-based model to identify the contributions of each subpopulation to flow-stimulated invasion and validated the model through comparisons with experimental blocking studies. Clinically relevant radiation therapy increased flow-stimulated invasion in one GSC line. Our agent-based model predicted that IFF-stimulated invasion is driven primarily by CXCR4+CXCL12+ populations, and, indeed our irradiated cells had an increase in this subpopulation. Together, these data indicate that different mechanisms govern the flow response across GSCs, but that within a single patient, there are subpopulations of GSCs that respond to flow via either CD44- or CXCR4-CXCL12 mechanisms. PMID- 27775743 TI - Hierarchical patterning of hydrogels by replica molding of impregnated breath figures leads to superoleophobicity. AB - The surface chemistry and topography govern the spreading of liquids on a solid. When an oil drop makes a contact angle, theta > 90 degrees on a solid surface, the solid is termed as oleophobic. Adding roughness to an inherently oleophobic surface enhances its oil dewetting and can lead to superoleophobicity when theta > 150 degrees . In this study, we introduce the concept of a two-tier hierarchical roughness on the surface of soft materials such as hydrogels by forming the patterned inverse replica of breath figure polymer films impregnated with nanoparticles. The directed deposition of nanoparticles in the breath figure pores is accomplished by an aerosol assisted technique that exclusively leads to deposition within the pores and filling of the pores. The inverse replica of such impregnated films exhibits a close packed hexagonally structured second tier of surface roughness which directly leads to a superoleophobic surface. Since these structures have well defined geometries, it is possible to estimate the contact angle by assuming a partial wetting of the oil drop in a 'fakir' state on the rough surface. The estimation is in good agreement with the experimental contact angle value. While the work demonstrates a facile method to impart superoleophobicity to a hydrogel surface, it also demonstrates new methods to imbue breath figure pores with functional materials that can be easily transferred to the pores of the inverse replica. PMID- 27775744 TI - Ultra-high thermally conductive and rapid heat responsive poly(benzobisoxazole) nanocomposites with self-aligned graphene. AB - Self-alignment of thermally reduced graphene sheets (TRG) that enable highly efficient heat transfer paths in their poly(p-phenylene benzobisoxazole) (PBO) based nanocomposite films along the in-plane direction was achieved for the first time without any assistance of an external magnetic or an electric field. In the in-plane direction, the nanocomposite films possess an ultra-high thermal diffusivity (900-1000 mm2 s-1) and a thermal conductivity (50 W m-1 K-1) with a TRG concentration <5.0 vol%, setting a new record for polymer composites with such a low graphene filler loading. The arranged TRG was also found to display a high efficiency for PBO reinforcement. A 64% increase in the Young's modulus was achieved by the addition of only 0.35 vol% of TRG, corresponding to a reinforcement value as high as 747 +/- 38 GPa, due to effective load transfer between the PBO matrix and TRG sheets via strong interfacial interactions. Moreover, the highly ordered graphene in PBO could provide good candidates for effective heat shielding barriers, and thus the prepared PBO composites exhibit a thermal stability remarkably higher than that of neat PBO resin. PMID- 27775745 TI - A highly versatile platform based on geometrically well-defined 3D DNA nanostructures for selective recognition and positioning of multiplex targets. AB - We develop a versatile recognition system based on 3D triangular-shaped DNA nanotubes by integrating three different aptamer sequences along the three edges. This would allow multiple binding activities to be combined into a single system. The versatility of this nanotube platform can also provide a framework for spatial orientation and positioning of different aptamer-binding ligands in a 'pea-pod' architecture. PMID- 27775746 TI - Handheld optical-resolution photoacoustic microscopy. AB - Optical-resolution photoacoustic microscopy (OR-PAM) offers label-free 0.9) were also observed for TnI1 concentrations assessed within this time frame. The optimal cutoff value for TnI concentration was 1.78 ng/ml. CONCLUSIONS: TnI concentrations assessed within 18-24 hours after elective off-pump coronary artery bypass grafting can effectively predict early patient prognosis. PMID- 27775785 TI - Diagnostic value of joint detection of homocysteine and RDW CV on acute myocardial infarction. Retracted. AB - OBJECTIVE: We discussed the diagnostic value of joint detection of homocysteine (HCY) and red blood cell volume distribution width variable coefficient on acute myocardial infarction (AMI). PATIENTS AND METHODS: We collected 300 coronary heart disease cases, among which there were 121 cases of stenocardia, 65 cases of ischemic heart failure, and 114 cases of AMI at the Department of Cardiology of our hospital during the period from January 2012 to June 2013. At the same time, we took 100 normal physical examinees as the control group, used the full automatic cell-analyzer and the immunization to measure HCY and red blood cell distribution width (RDW) CV respectively and analyze their value in diagnosing AMI. RESULTS: The differences among the four groups of HCY and RDW CV were statistically significant (p < 0.05). The HCY and RDW CV level in the AMI group were significantly higher than those of the other three groups (p < 0.05); the differences between the positive diagnosis rate of HCY, the RDW CV and their joint diagnosis in the AMI group were statistically significant (p < 0.05) while the differences between the positive diagnosis rate of HCY, the RDW CV and their joint diagnosis in the control group were not statistically significant (p > 0.05). The detection sensitivity and specificity of HCY alone were respectively 68.42% and 86.00% with those of the RDW CV alone being 64.91% and 84.00%. The joint detection sensitivity and specificity were 83.33% and 93.00%, statistically different (p < 0.05). The concordance rate, the positive predictive value and the negative predictive value were 87.85%, 93.14% and 83.04%, respectively. CONCLUSIONS: The HCY and RDW CV joint diagnosis of AMI had relatively high sensitivity, specificity, concordance rate, positive predictive value and negative predictive value. PMID- 27775786 TI - The correlation between blood calcium level, hematoma volume, stroke severity and prognosis in patients with acute cerebral hemorrhage. AB - OBJECTIVE: The objective of the present study was to determine the correlation between blood calcium level, hematoma volume and stroke severity in the prognosis of acute cerebral hemorrhage patients. PATIENTS AND METHODS: We selected 125 patients with acute cerebral hemorrhage admitted within 24 hours of symptom onset. Blood calcium levels were assessed by standard biochemical methods. Hematoma volume was measured by quantitative computed tomography. NIHSS (National Institutes of Health Stroke Scale) scores at one month, and the differences in survival rate and survival period at follow-up visits were assessed. RESULTS: Hematoma volume and NIHSS scores of the hypocalcemic group were higher than those of the hypercalcemic group. Those of the normocalcemic group were the lowest, and the differences were statistically significant (p < 0.05). The survival rate and survival period of the normocalcemic group were higher than those of the other two groups and the differences were statistically significant (p < 0.05). The logistics regression analysis showed that the APACHE II score, blood calcium level upon admission and hematoma volume were independent risk factors for survival (p < 0.05). CONCLUSIONS: If blood calcium level is too low or too high, hematoma volume and stroke severity of acute cerebral hemorrhage patients may increase and is related to long-term survival. PMID- 27775787 TI - PTX3 expression in the plasma of elderly ACI patients and its relationship with severity and prognosis of the disease. AB - OBJECTIVE: This study aims to investigate the expression of pentraxin3 (PTX3) in elderly patients with acute cerebral infarction (ACI) and to analyze the relationship of PTX3 with the severity and prognosis of ACI. PATIENTS AND METHODS: Between June 2014 and August 2015, 96 elderly patients with first-onset of ACI admitted to our institution were enrolled in the present study. Also, 70 healthy elderly subjects were included as controls in this study. Levels of PTX3, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, homocysteine (Hcy), fibrinogen (FIB), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined in all patients both pre-therapeutically and 30 days post therapeutically. Moreover, the severity of ACI was evaluated using the National Institute of Health stroke scale (NIHSS), and the prognosis was evaluated using the Modified Rankin Scale (mRS). The differences in the levels of above parameters were compared between groups, and the relationship between PTX3 and above biochemical parameters as well as the scores were investigated. RESULTS: PTX3 levels in the plasma of ACI patients were significantly higher than those of healthy controls (p < 0.05). Compared to low score group, mRS and levels of all parameters except Hcy and HDL-C were significantly increased in the patients of the high score group. In addition, plasma levels of HDL-C in the patients of the high score group were significantly lower than those in the low score group (p < 0.05). Biochemical parameters, NIHSS scores and mRS scores were significantly higher in the patients of the high concentration group than the low concentration group (p < 0.05), while no significant differences were observed in the plasma HDL-C levels between these two groups (p > 0.05). NIHSS scores and levels of all the biochemical parameters except HDL-C were significantly lower in the patients of the good prognosis group than in the patients of the poor prognosis group. HDL C levels were significantly higher in the good prognosis group than in the poor prognosis group (p < 0.05). PTX3 levels were positively correlated with levels of CRP, TNF-alpha, Hcy, TC, TG and LDL-C as well as NIHSS score and mRS score, respectively, (r = 0.814, 0.682, 0.704, 0.726, 0.699, 0.734, 0.746, 0.753, p = 0.008, 0.043, 0.034, 0.027, 0.036, 0.024, 0.021, 0.019). However, no significant correlations were observed between FIB levels and HDL-C levels (r = 0.326, 0.626, p = 0.392, 0.071). CONCLUSIONS: Plasma levels of PTX3 are significantly elevated in elderly ACI patients, and the levels increase along with the exacerbation of the disease and deterioration in the prognosis. Also, PTX3 levels are positively correlated with levels of inflammatory markers as well as lipids. Therefore, PTX3 can be used as a biomarker for predicting and evaluating clinical conditions of ACI in elderly patients. PMID- 27775788 TI - Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies. AB - The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. Angiotensin II regulates the proliferation, differentiation, and engraftment of hematopoietic stem cells. Activation of Mas receptor or ACE2 promotes proliferation of CD34+ cells. BM contains a progenitor that expresses renin throughout development. Angiotensin II attenuates the migration and proliferation of CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in hematopoietic organs are precursor B cells. The renin cell requires RBP-J to differentiate. Mutant renin-expressing hematopoietic precursors can cause leukemia. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B-cell gene programme. Mutant cells undergo a neoplastic transformation, and mice develop a highly penetrant B-cell leukemia with multi-organ infiltration and early death. Many biological conditions during the development and function of blood cells are mediated by RAS, such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis. The aim of this paper is to review recent developments regarding the actions of local BM RAS in the genesis of leukemia and other malignancies molecules. PMID- 27775789 TI - Roles of PECAM-1 in cell function and disease progression. AB - Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) belongs to immunoglobulin superfamily, which is key factor for adhesion and accumulation of platelets. It is proved that PECAM-1 is closely correlative with cell migration, proliferation, apoptosis, signal transduction and cellular immunity. Meanwhile, PECAM-1 involves in multiple clinical diseases, such as atherosclerosis, thrombosis and leukemia. This paper reviewed the structure and function of PECAM 1, and its roles in cell function and disease generation and progression. PMID- 27775790 TI - Effect of single nucleotide polymorphisms on CDK4 and Zn supplementation in children with growth hormone deficiency. AB - OBJECTIVE: Precision medicine is a personalized disease prevention and treatment program combining modern genetic technology, molecular imaging techniques, and biological information with patients' living environment and clinical data, for accurate classification and diagnosis of diseases. CASE REPORT: Our study presents the case of a 7-year-old female patient with clinical manifestations of growth hormone (GH) deficiency. After treatment with recombinant human GH for 2 years, the patient showed a reduced growth rate. Then single nucleotide polymorphisms according to GHD was analyzed, and the 6009 site within cyclin dependent kinase 4 gene showed a weak response to IGF-1 which was a downstream signal molecules of GH. CONCLUSIONS: Based on these results, both Zn and GH were supplied to the patients, and the growth rate increased significantly. Precision medicine needs more studies on patients to make accurate treatment. PMID- 27775791 TI - Association between irisin and major chronic diseases: a review. AB - OBJECTIVE: Irisin is a muscle-secreted protein released into the circulation by cleavage of fibronectin type III domain containing protein 5(FNDC5). Since its discovery in 2012, it has been the subject of many researches due to its physiological role. It is believed that understanding irisin's function may be the key to comprehend many diseases and their development. The aim of this study is to perform a systematic review in order to establish whether there is an association of irisin's levels with obesity, diabetes mellitus, non-alcoholic steatohepatitis, chronic kidney disease and cancer in terms of prognosis. MATERIALS AND METHODS: The articles that support these findings were selected from Medline using the keyword "irisin" and filtered with "humans only". The selected articles were in English and with abstract. RESULTS: Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects. Besides, it was observed that macrovascular disease, a complication of diabetes, was developed when there were lower levels of irisin. In addition, although not statistically significant, high levels of irisin were associated with portal inflammation and severity of histological lesions. Its concentrations decreased with increasing chronic kidney disease stage, and they were not only independently and positively predicted by renal function and insulin resistance but also associated with sarcopenia and carotid atherosclerosis in patients undergoing peritoneal dialysis. Regarding cancer, irisin reduced the proliferation, viability and migration of malignant breast cells. Finally, it is also related to bone health once its concentration is associated with previous osteoporotic fractures. CONCLUSIONS: In every condition studied, irisin's concentrations were related to the development of the disease. PMID- 27775792 TI - miR-143 is involved in endothelial cell dysfunction through suppression of glycolysis and correlated with atherosclerotic plaques formation. AB - OBJECTIVE: Atherosclerosis is recognized as a chronic inflammatory disease leading to hardening of the vessel wall and narrowing of arteries. Endothelial cells (ECs) exhibit highly active glycolysis, the dysfunction of which leads to accumulation of lipids in the arterial wall and formation of atherosclerotic plaque. MATERIALS AND METHODS: qRT-PCR was performed to compare the deregulated miR-143 between atherosclerotic plaque and normal vessel tissues. The direct target of miR-143 was verified by Western blot and luciferase assay. The metabolic enzymes in atherosclerotic plaque and normal vessel tissues were measured. HUVECs were transfected with miR-143 precursor or control microRNAs, and glucose uptake, lactate production, intracellular ATP, and oxygen consumption were measured. RESULTS: In this study, we report a correlation between up regulated miR-143, EC dysfunction, and atherosclerotic plaque formation. The glycolysis rate was significantly elevated in ECs, which show relatively low levels of miR-143. Importantly, miR-143 was upregulated in clinical atherosclerotic plaque samples compared with healthy arteries, suggesting that miR-143 might play important roles in the atherosclerotic plaque formation. Moreover, mRNA levels of key enzymes of glycolysis, such as HK2, LDHA, and PKM2 are significantly down-regulated in the atherosclerotic plaque samples. Overexpression of miR-143 in HUVECs suppresses glycolysis through direct targeting of HK2, leading to EC dysfunction. Restoration of HK2 expression rescues glycolysis in miR-143-overexpressing HUVECs. CONCLUSIONS: This study provides further insight into the metabolic mechanisms involved in atherosclerotic plaque formation due to microRNAs. PMID- 27775793 TI - microRNA-125b contributes to high glucose-induced reactive oxygen species generation and apoptosis in HK-2 renal tubular epithelial cells by targeting angiotensin-converting enzyme 2. AB - OBJECTIVE: Hyperglycemia induces apoptosis of renal tubular epithelial cells and contributes to tubular injury in diabetic nephropathy. Angiotensin-converting enzyme 2 (ACE2) is known to protect against diabetic kidney injury. However, the mechanism for the dysregulation of ACE2 expression in diabetic nephropathy is unclear. MATERIALS AND METHODS: Bioinformatic analysis and luciferase reporter assay were done to identify ACE2-targeting microRNAs. Gain- and loss-of-function experiments were performed to determine the biological roles of the ACE2 targeting microRNAs in high glucose-induced damage to renal tubular epithelial cells. RESULTS: We identified microRNA-125b (miR-125b) as a negative regulator of ACE2. After high glucose treatment, HK-2 renal tubular epithelial cells showed an upregulation of miR-125b and reduction of ACE2 expression. Knockdown of miR-125b with anti-miR-125b inhibitors significantly prevented high glucose-induced downregulation of ACE2 in HK-2 cells. Moreover, depletion of miR-125b significantly blocked reactive oxygen species (ROS) formation and apoptosis in high glucose-exposed HK-2 cells. In contrast, ectopic expression of miR-125b accelerated ROS production and apoptotic response in HK-2 cells, which was coupled with induction of Bax and reduction of Bcl-2. Rescue experiments demonstrated that overexpression of ACE2 reversed the effects of miR-125b on ROS generation, apoptosis, and deregulation of Bcl-2 and Bax in HK-2 cells. CONCLUSIONS: Taken together, miR-125b mediates high glucose-induced ROS production and apoptosis in HK-2 renal tubular epithelial cells, largely through targeting ACE2. Accordingly, miR-125b represents a potential therapeutic target for the prevention of diabetic nephropathy. PMID- 27775794 TI - Fibroblast growth factor 23 serum level in type 2 diabetic italian subjects with peripheral arterial disease and critical limb ischemia. AB - OBJECTIVE: Fibroblast growth factor 23 (FGF23) was demonstrated to be involved in the occurrence and development of cardiovascular disease (CVD). The aim of this study was to investigate the potential role of FGF23 on presence and severity of peripheral arterial disease (PAD) in type 2 diabetic patients. PATIENTS AND METHODS: In this study, we analyzed FGF23 serum levels in 413 type 2 diabetic patients with PAD and in 598 diabetic controls without lower limbs atherosclerosis. RESULTS: We found that FGF23 median serum levels were significantly higher in patients than in diabetic controls (69.3 (58.8-75.1) pg/mL in PAD and 42.98 (37.1-49.8) pg/mL in subjects without PAD (p < 0.001) and were significantly and independently associated with critical limb ischemia (CLI) [OR, 7.69 (2.64-16.31); p = 0.001]. CONCLUSIONS: We have found, for the first time, that FGF23 could be associated with presence and severity of PAD in Italian patients with type 2 diabetes. PMID- 27775795 TI - Helicobacter pylori CagA antibodies and thyroid function in latent autoimmune diabetes in adults. AB - OBJECTIVE: H. pylori infection is reportedly associated with autoimmune diseases such as chronic thyroiditis and autoimmune diabetes. The aim of this study is to determine the association between H. pylori infection and its virulent strain CagA with antibodies against thyroperoxidase (TPO Ab) and thyrotropin (TSH) in a cohort of latent autoimmune diabetes in adult (LADA) patients. PATIENTS AND METHODS: We included 234 LADA patients (53.8% women). Antibodies against H. pylori whole antigens and CagA, TPO Ab and TSH were assessed in all patients. RESULTS: Prevalence of IgG against H. pylori and GagA was 52.1% and 20.9% respectively. Antibodies against H. pylori were not associated with TPO Ab and TSH (rho = 0.067, p = 0.620 and rho = 0.156, p = 0.099, respectively). Antibodies against CagA showed a positive association with TSH and TPO Ab (respectively rho = 0.309, p = 0.036 and rho = 0.419, p = 0.037). Subjects with hypothyroidism (TSH >= 3.5 MUU/ml) had an increased frequency of Ab anti CagA (p = 0.059). CONCLUSIONS: The infection by H. pylori strains expressing CagA is associated with increased TPO Ab and TSH levels in LADA patients, suggesting a possible mechanism involved in thyroid autoimmunity and dysfunction of the gland. Further research is needed to test this hypothesis. PMID- 27775796 TI - Th17 cells associated cytokines and cancer. AB - Cancer is one of the most common malignant tumors, which is a serious threat to human life. However, the etiology of cancer is not entirely clear. Under the action of tumorigenic factors, tissue cells lose normal regulation, resulting in abnormal proliferation and differentiation, so as to form a tumor. Cytokines promote the development of chronic inflammation, which may affect the development of cancer, and Th17 cells are a kind of immune cells which are closely related to the tumor. Therefore, this article focused on the role of Th17 cells and its related cytokines in tumor, which is very important for understanding the mechanism of tumor development. This will provide a direction for immunotherapy and gene-targeted therapy of cancer. PMID- 27775797 TI - Multimodal approach of advanced gastric cancer: based therapeutic algorithm. AB - Gastric cancer (GC) is the third leading cause of cancer death in both sexes worldwide, with the highest estimated mortality rates in Eastern Asia and the lowest in Northern America. However, the availability of modern treatment has improved the survival and the prognosis is often poor due to biological characteristics of the disease. In oncology, we are living in the "Era" of target treatment and, to know biological aspects, prognostic factors and predictive response informations to therapy in GC is mandatory to apply the best strategy of treatment.The purpose of this review, according to the recently published English literature, is to summarize existing data on prognostic aspects and predictive factors to response to therapy in GC and to analyze also others therapeutic approaches (surgery and radiotherapy) in locally, locally advanced and advanced GC. Moreover, the multidisciplinary approach (chemotherapy, surgery and radiotherapy) can improve the prognosis of GC. The purpose of this review, according to the recently published English literature, is to summarize existing data on prognostic aspects and predictive factors to response to therapy in GC and to analyze also others therapeutic approaches (surgery and radiotherapy) in locally, locally advanced and advanced GC. Moreover, the multidisciplinary approach (chemotherapy, surgery and radiotherapy) can improve the prognosis of GC. PMID- 27775798 TI - The role of ZNRF2 in the growth of non-small cell lung cancer. AB - OBJECTIVE: ZNRF2 belongs to ubiquitin ligases of the RING superfamily, and has been recently shown to be regulated by Akt to interact with a Mechanistic target of rapamycin (mTor). Nevertheless, a role of ZNRF2 in tumorigenesis, especially in non-small cell lung cancer (NSCLC), is unknown. Here, we assessed ZNRF2 expression in NSCLC. PATIENTS AND METHODS: We examined ZNRF2 levels by Western blot using NSCLC specimens, compared to the paired non-tumor controls. We also examined the effects of ZNRF2 on cell growth and cell survival in the presence of fluorouracil. RESULTS: We detected significant higher levels of ZNRF2 and mTor in NSCLC tissues, compared to the paired non-tumor controls. Moreover, ZNRF2 and mTor levels strongly correlated in NSCLC tissues. High ZNRF2 levels were correlated with poor prognosis of the NSCLC patients. In vitro, overexpression of ZNRF2 increased NSCLC cell growth and suppressed apoptotic cell death in the presence of Fluorouracil, while depletion of ZNRF2 decreased NSCLC cell growth and increased apoptotic cell death in the presence of fluorouracil. ZNRF2 appeared to augment mTor and its downstream targets CyclinD1 and CDK in NSCLC cells. CONCLUSIONS: ZNRF2 may be a promising target for treating NSCLC. PMID- 27775799 TI - Regulation of Twist in the metastasis of non-small cell lung cancer by miR-92b. AB - OBJECTIVE: It is well documented that some microRNAs (miRNAs) regulates tumorigenesis and cancer metastases of non-small cell lung cancer (NSCLC). Nevertheless, a role of miR-92b in control of the metastasis of NSCLC has not been acknowledged. MATERIALS AND METHODS: Here, we reported that miR-92b levels were significantly decreased and Twist levels were significantly increased in NSCLC specimens, compared to paired adjacent non-tumor lung tissue. Moreover, the levels of miR-92b and Twist inversely correlated. RESULTS: Bioinformatics analyses and luciferase-reporter assay showed that miR-92b targeted the 3'-UTR of Twist mRNA to inhibit its translation. Overexpression of miR-92b inhibited Twist mediated cell invasiveness, while depletion of miR-92b increased Twist-mediated cell invasiveness in either a transwell cell migration assay or a scratch wound healing assay. CONCLUSIONS: Together, our data suggest that re-expression of miR 92b may inhibit Twist-mediated NSCLC metastasis. PMID- 27775800 TI - Knockdown of long noncoding RNA AB073614 inhibits glioma cell proliferation and migration via affecting epithelial-mesenchymal transition. AB - OBJECTIVE: This study was aimed to explore the role of long noncoding RNA (lncRNA) AB073614 and its potential mechanisms in the glioma development. MATERIALS AND METHODS: Expression levels of lncRNA AB073614 in glioma tissues and glioma cell lines were evaluated by quantitative real-time PCR (qRT-PCR). MTT assays were conducted to explore the impact of AB073614 down-regulation on the proliferation of human glioma cells. The effects of AB073614 knockdown on cell proliferation and migration were evaluated by in vitro assays. EMT-related molecular markers expression level was detected by qRT-PCR assay and Western blot analysis. RESULTS: We confirmed that AB073614 was significantly upregulated in glioma tissues and cell lines (p < 0.01). In vitro studies demonstrated that knockdown of AB073614 inhibits U251 cell proliferation and migration. Moreover, knockdown of AB073614 could inhibit epithelial-mesenchymal transition (EMT) phenotype in glioma cells. CONCLUSIONS: AB073614 functions as a tumor promoter in glioma. This finding may provide a therapeutic approach for future treatment of glioma. PMID- 27775801 TI - Expression of long non-coding RNA CRNDE in glioma and its correlation with tumor progression and patient survival. AB - OBJECTIVE: Long non-coding RNAs (lncRNAs) CRNDE has been identified as a tumor oncogene in glioma. However, its clinical significance and prognostic value in glioma have not been investigated until now. The aim of this study was to explore CRNDE expression levels and evaluated its clinical significance in glioma patients. PATIENTS AND METHODS: Expression levels of lncRNA CRNDE in 164 glioma specimens were determined by quantitative real-time PCR (qRT-PCR). The chi-square test was used to explore CRNDE expression with respect to clinicopathological parameters. The overall survival was analyzed by log-rank test, and survival curves were plotted according to Kaplan-Meier. Univariate and multivariate analyses were performed to analyze the prognostic significance of CRNDE expression. RESULTS: Compared with nonneoplastic brain tissues, the expression level of CRNDE was significantly increased in glioma tissues (p < 0.01). CRNDE upregulation was correlated with larger tumor size (p = 0.011), higher WHO grade (p = 0.001), and recurrence (p = 0.008). Also, survival analysis proved that up regulated CRNDE expression was associated with poor overall survival of glioma patients (p < 0.001). The multivariate Cox regression analysis indicated that CRNDE expression was an independent prognostic factor for overall survival. CONCLUSIONS: These results indicated that lncRNA CRNDE was associated with tumor progression and could be an independent prognostic factor for glioma patients. PMID- 27775802 TI - Expression of lncRNA HULC in cervical cancer and its correlation with tumor progression and patient survival. AB - OBJECTIVE: To investigate Long non-coding RNA HULC (HULC) expression in cervical cancer and to evaluate its clinical significance. PATIENTS AND METHODS: HULC expression in 244 pairs of human cervical cancer and adjacent normal tissues was detected by real-time quantitative RT-PCR assay. The correlation between HULC and clinicopathological factors was also evaluated. The clinical and prognostic significance of HULC expression was analyzed statistically by Kaplan-Meier estimate and Cox regression model. RESULTS: HULC expression was high in cervical cancer (p < 0.01). Also, the high HULC expression was significantly associated with the FIGO stage, lymph node metastasis and depth of cervical invasion (p < 0.05). Kaplan-Meier analysis showed that cervical cancer pa!tients with high expression of HULC possessed poorer outcome than those with low expression of HULC (p < 0.001). Based on the univariate and multivariate analysis, the elevated expression of the HULC protein was a significant predictor of poor prognosis for cervical cancer patients (p = 0.001). CONCLUSIONS: Our data firstly showed that the expression of HULC was upregulated in cervical cancer, and associated with overall survival, indicating that HULC may serve as a predictive biomarker for the prognosis of cervical cancer. PMID- 27775803 TI - Long noncoding RNA PVT1 as a novel serum biomarker for detection of cervical cancer. AB - OBJECTIVE: To investigate long noncoding RNA PVT1 expression in the serum of cervical cancer patients, and to evaluate serum PVT1 level as a diagnostic biomarker for cervical cancer. PATIENTS AND METHODS: Eighty-eight cervical cancer patients, 64 cervical intraepithelial neoplasia patients, 25 breast cancer patients, 25 ovarian cancer patients, and 111 healthy control subjects were enrolled into this study. PVT1 serum level in these participants and PVT1 expression in 20 pairs of cervical cancer tissues and adjacent paired normal tissues was measured by quantitative reverse transcription-polymerase chain reaction. The diagnostic values of serum PVT1 were evaluated by receiver operating characteristic curves analysis. RESULTS: Serum PVT1 level is significantly increased in cervical cancer patients and correlated with tumor size, clinical stage, and lymph node metastasis of cervical cancer. Serum PVT1 could accurately discriminate cervical cancer patients from cervical intraepithelial neoplasia patients and healthy control subjects, and also discriminate early stage cervical cancer patients from healthy control subjects. But serum PVT1 level is not changed in breast cancer and ovarian cancer patients. Furthermore, serum PVT1 level is positively correlated with tissue PVT1 expression, and could indicate cervical cancer dynamics. CONCLUSIONS: Long noncoding RNA PVT1 may be a novel noninvasive biomarker for early diagnosis of cervical cancer. PMID- 27775804 TI - The impact of the multifocality and subtypes of papillary thyroid carcinoma on central compartment lymph node metastasis. AB - OBJECTIVE: Papillary thyroid carcinoma (PTC) may often appear as multifocal disease. Few studies demonstrated a higher rate of central compartment lymph node metastasis (CCLNM) in multifocal PTC patients. Therefore, the effect of different histological subtypes of multifocal PTC on CCLNM is another subject for further examination. The aim of the present study is to evaluate the rate of central lymph node positivity in multifocal PTC as compared to unifocal disease, and to identify the role of different histologic subtypes of PTC on central neck lymph node positivity. PATIENTS AND METHODS: Patients with PTC who underwent total thyroidectomy (TT) + central cervical lymph node dissection (CCLND) at authors' institution between January 2012 and June 2016 were included (n=274). Independent Samples t-test, Mann-Whitney U test and Chi-square tests were used to determine univariate associations, and multivariate analysis was conducted by logistic regression. RESULTS: The rate of CCLND positivity in multifocal PTC is higher than unifocal tumors and the difference is significant (p < 0.05). The univariate analysis demonstrated significant relation with male sex, lymphovascular invasion and size of dominant nodule > 10 mm regarding of CCLND positivity in multifocal PTC patients. The comparison between solitary and mixed histologic subtype of multifocal PTC is also significant (p < 0.05). CONCLUSIONS: Multifocality is an important risk factor for CCLNM. Male sex, dominant tumor size >10 mm and mixed histological subtype in multifocal PTC may play an important role in CCLND positivity. PMID- 27775805 TI - Craniofacial morphology and airflow in children with primary snoring. AB - OBJECTIVE: Sleep-disordered breathing (SDB) is among the most common diseases and includes a group of pathological conditions that form a severity continuum from primary snoring (PS) to obstructive sleep apnea (OSA). SDB presents a multifactorial etiology and in children, it is often linked to adenotonsillar hypertrophy, which may lead to an alteration of the breathing pattern. Therefore, several studies hinted at the existence of a correlation between SDB and the alteration of craniofacial growth. However, these studies concentrated on the most severe forms of SDB and little evidence still exists for the mildest form of SDB, namely PS. This preliminary study investigates the association between nasal airflow, measured through rhinomanometry, and cephalometric parameters in a sample of young children with PS. PATIENTS AND METHODS: A sample of 30 children with habitual snoring aged between 5 and 8 years was selected by a SDB validated questionnaire at the Pediatric Allergology and Immunology Center of "Sapienza" University of Rome, Italy. To assess the degree of nasal obstruction, all children underwent anterior active rhinomanometry while nocturnal pulse oximetry and polysomnography were used to characterize the SDB. Cephalometric analysis was used to evaluate relevant orthodontic parameters associated to the sagittal and vertical craniofacial development and to the position of the hyoid bone. RESULTS: We found a statistically significant association between the Frankfurt mandibular angle (FMA), which measures the total facial vertical divergence, and the severity of the airflow's obstruction (p = 0.014). CONCLUSIONS: The present study supports the association between the level of nasal obstruction in children with PS and the alteration of cephalometric parameters associated with the vertical craniofacial growth, thus placing the evaluation of craniofacial parameters in the growth period in a privileged position to determine an early diagnosis of a possible insurgence of sleep disorders. PMID- 27775806 TI - The efficacy of open nephron-sparing surgery in the treatment of complex renal cell carcinoma. AB - OBJECTIVE: To analyze the efficacy of open nephron-sparing surgery (NSS) in the treatment of complex renal cell carcinoma. PATIENTS AND METHODS: A total of 118 patients with complex renal cell carcinoma (T1N0M0, clear cell carcinoma) were included in this study, and assigned into open radical nephrectomy (RN) group (35 patients), open NSS group (45 patients) and laparoscopic NSS group (38 patients). After 3 years of follow-up, the clinical efficacy was analyzed. RESULTS: Both the mean surgery time and ischemia blocking time in the open NSS group were comparable to those in the RN group, and significantly shorter than the laparoscopic NSS group, p < 0.05. The rate of positive margin in the open NSS group was significantly lower than the laparoscopic NSS group. The occurrence of total complications in the open NSS group was comparable to that in the laparoscopic NSS group and significantly lower than the RN group. The successful rate of surgery in the open NSS group was significantly higher than the laparoscopic NSS group, p < 0.05. The 75% survival was 30.0 months in the RN group, > 35.0 months in the open NSS group and 34.0 months in the laparoscopic NSS group, the difference was significant (p < 0.001). The mortality was similar in the open NSS group and the laparoscopic NSS group, and significantly smaller than the RN group, p < 0.05. CONCLUSIONS: Open NSS was more safe and effective in the treatment of complex renal cell carcinoma than RN and laparoscopic NSS. PMID- 27775807 TI - Letter to the Editors - Exploring platelet indices as disease biomarkers: prospective use and methodological challenges. PMID- 27775808 TI - Letter to the Editor - DTC chemotherapy regimen is associated with higher incidence of premature ovarian failure in women of reproductive age with breast cancer. PMID- 27775809 TI - Editorial - PHACTR4/STAT3 axis as a possible target therapy for hepatocellular carcinoma treatment. PMID- 27775810 TI - Applied analysis of humanized nursing combined with wet healing therapy to prevent bedsore. AB - OBJECTIVE: To analyze and evaluate the effects of humanized nursing combined with wet healing therapy to treat the stage II and III bedsores in hospitalized patients. PATIENTS AND METHODS: From March 2013 to July 2014 we enrolled fifty patients with stage II and III bedsores. They were randomly divided into control group and experimental group, with 25 cases in each group. For the control group, we adopted a traditional method of treatment for pressure ulcer treatment, while the experimental group was treated with humanized nursing in combination with wet healing therapy. After 28 days, the treatment results in both groups were evaluated. RESULTS: The improvement rate for patients in the experimental group was significantly higher than that of the control group. In the experimental group, the improvement rates for patients suffering from stage II and III pressure ulcers were significantly higher than those of the control group. The Branden score and the area of pressure ulcer were significantly decreased in the experimental group. The frequency of dressing change, the dressing time and the average cost of hospitalization in the experimental group were significantly lower. CONCLUSIONS: The effect of wet healing therapy combined with humanized nursing in preventing and treating the bedsore is promising, and it is worthy of clinical promotion. PMID- 27775811 TI - Alternating logistic regressions with improved finite sample properties. AB - Alternating logistic regressions is an estimating equations procedure used to model marginal means of correlated binary outcomes while simultaneously specifying a within-cluster association model for log odds ratios of outcome pairs. A recent generalization of alternating logistic regressions, known as orthogonalized residuals, is extended to incorporate finite sample adjustments in the estimation of the log odds ratio model parameters for when there is a moderately small number of clusters. Bias adjustments are made both in the sandwich variance estimators and in the estimating equations for the association parameters. The proposed methods are demonstrated in a repeated cross-sectional cluster trial to reduce underage drinking in the United States, and in an analysis of dental caries incidence in a cluster randomized trial of 30 aboriginal communities in the Northern Territory of Australia. A simulation study demonstrates improved performance with respect to bias and coverage of their estimators relative to those based on the uncorrected orthogonalized residuals procedure. PMID- 27775812 TI - Corticosteroids for Guillain-Barre syndrome. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is an acute paralysing disease caused by inflammation of the peripheral nerves, which corticosteroids would be expected to benefit. OBJECTIVES: To examine the ability of corticosteroids to hasten recovery and reduce the long-term morbidity from GBS. SEARCH METHODS: On 12 January 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We also searched trials registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs of any form of corticosteroid or adrenocorticotrophic hormone versus placebo or supportive care alone in GBS. Our primary outcome was change in disability grade on a seven-point scale after four weeks. Secondary outcomes included time from randomisation until recovery of unaided walking, time from randomisation until discontinuation of ventilation (for those ventilated), death, death or disability (inability to walk without aid) after 12 months, relapse, and adverse events. DATA COLLECTION AND ANALYSIS: The review authors used standard methods expected by Cochrane. MAIN RESULTS: The review authors discovered no new trials in the new searches in June 2009, November 2011, or January 2016. Six trials with 587 participants provided data for the primary outcome. According to moderate quality evidence, the disability grade change after four weeks in the corticosteroid groups was not significantly different from that in the control groups, mean difference (MD) 0.36 less improvement (95% confidence intervals (CI) 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with 120 participants in total, there was very low quality evidence of less improvement after four weeks with corticosteroids than without corticosteroids, MD 0.82 disability grades less improvement (95% CI 0.17 to 1.47 grades less). In two trials with a combined total of 467 participants, there was moderate quality evidence of no significant difference of a disability grade more improvement after four weeks with intravenous corticosteroids (MD 0.17, 95% CI -0.06 to 0.39). According to moderate quality evidence, there was also no significant difference between the corticosteroid treated and control groups for improvement by one or more grades after four weeks (risk ratio (RR) 1.08, 95% CI 0.93 to 1.24) or for death or disability after one year (RR 1.51, 95% CI 0.91 to 2.5). We found high quality evidence that the occurrence of diabetes was more common (RR 2.21, 95% CI 1.19 to 4.12) and hypertension less common (RR 0.15, 95% CI 0.05 to 0.41) in the corticosteroid-treated participants. AUTHORS' CONCLUSIONS: According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to very low quality evidence, oral corticosteroids delay recovery. Diabetes requiring insulin was more common and hypertension less common with corticosteroids based on high quality evidence. PMID- 27775813 TI - T-Cell Phenotypes Predictive of Frailty and Mortality in Elderly Nursing Home Residents. AB - OBJECTIVES: To determine whether immune phenotypes associated with immunosenescence are predictive of frailty and mortality within 1-year in elderly nursing home residents. DESIGN: Cross sectional study of frailty; prospective cohort study of mortality. SETTING: Thirty-two nursing homes in four Canadian cities between September 2009 and October 2011. PARTICIPANTS: Nursing home residents aged 65 and older (N = 1,072, median age 86, 72% female). MEASUREMENTS: After enrollment, peripheral blood mononuclear cells were obtained and analyzed using flow cytometry for CD4+ and CD8+ T-cell subsets (naive, memory (central, effector, terminally differentiated, senescent), and regulatory T-cells) and cytomegalovirus (CMV)-reactive CD4+ and CD8+ T-cells. Multilevel linear regression analysis was performed to determine the relationship between immune phenotypes and frailty; frailty was measured at the time of enrollment using the Frailty Index. A Cox proportional hazards model was used to determine the relationship between immune phenotypes and time to death (within 1 year). RESULTS: Mean Frailty Index was 0.44 +/- 0.13. Multilevel regression analysis showed that higher percentages of naive CD4+ T-cells (P = .001) and effector memory CD8+ T-cells (P = .02) were associated with a lower mean Frailty Index, whereas a higher percentage of CD8+ central memory T-cells was associated with a higher mean Frailty Index score (P = .02). One hundred fifty one (14%) members of the cohort died within 1 year. Multivariable analysis showed a significant negative multiplicative interaction between age and percentage of CMV-reactive CD4+ T-cells (hazard ratio = 0.87, 95% confidence interval = 0.79-0.96). No other significant factors were identified. CONCLUSION: Immune phenotypes found to be predictive of frailty and mortality in this study can help further understanding of immunosenescence and may provide a rationale for future intervention studies designed to modulate immunity. PMID- 27775815 TI - Reader reaction on estimation of treatment effects in all-comers randomized clinical trials with a predictive marker. AB - For a fallback randomized clinical trial design with a marker, Choai and Matsui (2015, Biometrics 71, 25-32) estimate the bias of the estimator of the treatment effect in the marker-positive subgroup conditional on the treatment effect not being statistically significant in the overall population. This is used to construct and examine conditionally bias-corrected estimators of the treatment effect for the marker-positive subgroup. We argue that it may not be appropriate to correct for conditional bias in this setting. Instead, we consider the unconditional bias of estimators of the treatment effect for marker-positive patients. PMID- 27775814 TI - A subgroup cluster-based Bayesian adaptive design for precision medicine. AB - In precision medicine, a patient is treated with targeted therapies that are predicted to be effective based on the patient's baseline characteristics such as biomarker profiles. Oftentimes, patient subgroups are unknown and must be learned through inference using observed data. We present SCUBA, a Subgroup ClUster-based Bayesian Adaptive design aiming to fulfill two simultaneous goals in a clinical trial, 1) to treatments enrich the allocation of each subgroup of patients to their precision and desirable treatments and 2) to report multiple subgroup treatment pairs (STPs). Using random partitions and semiparametric Bayesian models, SCUBA provides coherent and probabilistic assessment of potential patient subgroups and their associated targeted therapies. Each STP can then be used for future confirmatory studies for regulatory approval. Through extensive simulation studies, we present an application of SCUBA to an innovative clinical trial in gastroesphogeal cancer. PMID- 27775816 TI - Mature peritoneal macrophages take an avascular route into the injured liver and promote tissue repair. PMID- 27775818 TI - Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double-blind, placebo-controlled trial. AB - : Decompensated cirrhosis is characterized by disturbed systemic and splanchnic hemodynamics. Bacterial translocation from the gut is considered the key driver in this process. Intestinal decontamination with rifaximin may improve hemodynamics. This double-blind, randomized, controlled trial (clinicaltrials.gov, NCT01769040) investigates the effects of rifaximin on hemodynamics, renal function, and vasoactive hormones. We randomized 54 stable outpatients with cirrhosis and ascites to rifaximin 550 mg twice a day (n = 36) or placebo twice a day (n = 18). Forty-five patients were male, mean age 56 years (+/-8.4), average Child score 8.3 (+/-1.3), and Model for End-Stage Liver Disease score 11.7 (+/-3.9). Measurements of hepatic venous pressure gradient, cardiac output, and systemic vascular resistance were made at baseline and after 4 weeks. The glomerular filtration rate and plasma renin, noradrenaline, lipopolysaccharide binding protein, troponin T, and brain natriuretic peptide levels were measured. Rifaximin had no effect on hepatic venous pressure gradient, mean 16.8 +/- 3.8 mm Hg at baseline versus 16.6 +/- 5.3 mm Hg at follow up, compared to the placebo, mean 16.4 +/- 4 mm Hg at baseline versus 16.3 +/- 4.4 mm Hg at follow-up, P = 0.94. No effect was found on cardiac output, mean 6.9 +/- 1.7 L/min at baseline versus 6.9 +/- 2.3 L/min at follow-up, compared to placebo, mean 6.6 +/- 1.9 L/min at baseline compared to 6.5 +/-2.1 L/min at follow-up, P = 0.66. No effects on the glomerular filtration rate, P = 0.14, or vasoactive hormones were found. Subgroup analyses on patients with increased lipopolysaccharide binding protein and systemic vascular resistance below the mean (1,011 dynes * s/cm5 ) revealed no effect of rifaximin. CONCLUSION: Four weeks of treatment with rifaximin did not reduce the hepatic venous pressure gradient or improve systemic hemodynamics in patients with cirrhosis and ascites; rifaximin did not affect glomerular filtration rate or levels of vasoactive hormones. (Hepatology 2017;65:592-603). PMID- 27775819 TI - Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups. AB - : Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large-scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity. CONCLUSION: Analysis of immunohistochemical assays using antibodies targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis; our results pave the way for clinical collaborative studies to validate candidate biomarkers and test their potential to improve outcome for HB patients. (Hepatology 2017;65:104-121). PMID- 27775817 TI - Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury. AB - Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721). PMID- 27775820 TI - Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis. AB - : Albumin is a potent scavenger of reactive oxygen species (ROS). However, modifications in albumin structure may reduce its antioxidant properties and modulate its immune-regulatory functions. We examined alterations in circulating albumin in severe alcoholic hepatitis (SAH) patients and their contribution to neutrophil activation, intracellular stress, and alteration in associated molecular pathways. Albumin modifications and plasma oxidative stress were assessed in SAH patients (n = 90), alcoholic cirrhosis patients (n = 60), and healthy controls (n = 30) using liquid chromatography/mass spectrometry and spectrophotometry. Activation and intracellular ROS were measured in healthy neutrophils after treatment with purified albumin from the study groups. Gene expression of SAH neutrophils was analyzed and compared to gene expression from healthy neutrophils after stimulation with purified albumin from SAH patient plasma. SAH-albumin showed the highest albumin oxidative state (P < 0.05) and prominent alteration as human nonmercaptalbumin 2 (P < 0.05). Plasma oxidative stress (advanced oxidative protein product) was higher in SAH versus alcoholic cirrhosis patients and healthy controls (P < 0.05). Neutrophil gelatinase associated lipocalin, myeloperoxidase, and intracellular ROS levels were highest in SAH-albumin-treated neutrophils (P < 0.05). Genes associated with neutrophil activation, ROS production, intracellular antioxidation, and leukocyte migration plus genes for proinflammatory cytokines and various toll-like receptors were overexpressed in SAH neutrophils compared to healthy neutrophils (P < 0.05). Expression of the above-mentioned genes in SAH-albumin-stimulated healthy neutrophils was comparable with SAH patient neutrophils, except for genes associated with apoptosis, endoplasmic reticulum stress, and autophagy (P < 0.05). CONCLUSIONS: In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro-oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (Hepatology 2017;65:631-646). PMID- 27775821 TI - An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. AB - : Although surveillance ultrasound and alpha fetoprotein (AFP) tests have minimal direct harm, downstream harms from follow-up tests must be weighed against surveillance benefits when determining the value of hepatocellular carcinoma (HCC) screening programs. Our study's aims were to characterize prevalence and correlates of surveillance benefits and harms in cirrhosis patients undergoing HCC surveillance. We conducted a retrospective cohort study among patients with cirrhosis followed at a safety-net health system between July 2010 and July 2013. We recorded surveillance-related benefits, defined as early tumor detection and curative treatment, and surveillance-related physical harms, defined as computed tomography or magnetic resonance imaging scans, biopsies, or other procedures performed for false-positive or indeterminate surveillance results. Sociodemographic and clinical correlates of surveillance harms were evaluated using multivariable logistic regression. We identified 680 patients with cirrhosis, of whom 78 (11.5%) developed HCC during the 3-year study period. Of the 48 (61.5%) HCCs identified by surveillance, 43.8% were detected by ultrasound, 31.2% by AFP, and 25.0% by both surveillance tests. Surveillance detected patients had a higher proportion of early HCC (70.2% vs. 40.0%; P = 0.009), with no difference in tumor stage between ultrasound- and AFP-detected tumors (P = 0.53). Surveillance-related physical harms were observed in 187 (27.5%) patients, with a higher proportion of ultrasound-related harm than AFP related harm (22.8% vs. 11.4%; P < 0.001). Surveillance-related harms were associated with elevated ALT (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.26-2.76), thrombocytopenia (OR, 2.06; 95% CI, 1.26-3.38), and hepatology subspecialty care (OR, 1.63; 95% CI, 1.09-2.42). CONCLUSION: Over one fourth of patients with cirrhosis experience physical harm for false-positive or indeterminate surveillance tests-more often related to ultrasound than AFP. Interventions are needed to reduce surveillance-related harm to increase the value of HCC screening programs in clinical practice. (Hepatology 2017;65:1196 1205). PMID- 27775822 TI - Polymorphisms in the IL-1 gene cluster influence systemic inflammation in patients at risk for acute-on-chronic liver failure. AB - : Acute-on-chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short-term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single-nucleotide polymorphisms (SNPs) in inflammation-related genes (interleukin [IL]-1 beta [IL-1beta], rs1143623; IL-1 receptor antagonist [IL-1ra], rs4251961; IL-10, rs1800871; suppressor of cytokine signaling-3, rs4969170; nucleotide-binding oligomerization domain-containing protein 2, rs3135500; and chemerin chemokine-like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL-1 gene cluster (IL-1beta and IL 1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL 1beta (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05) and IL-1ra (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL-1beta, IL-1alpha, IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C reactive protein at enrollment as well as after 7-14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate. CONCLUSION: These data identify two common functional polymorphisms in the IL-1 gene cluster, which are associated with the inflammatory process related to development of ACLF. (Hepatology 2017;65:202-216). PMID- 27775823 TI - Improving outcomes for patients with medication-resistant anxiety: effects of collaborative care with cognitive behavioral therapy. AB - BACKGROUND: Many patients with anxiety disorders remain symptomatic after receiving evidence-based treatment, yet research on treatment-resistant anxiety is limited. We evaluated effects of cognitive behavioral therapy (CBT) on outcomes of patients with medication-resistant anxiety disorders using data from the Coordinated Anxiety Learning and Management (CALM) trial. METHODS: Primary care patients who met study entry criteria (including DSM-IV diagnosis of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or social anxiety disorder) despite ongoing pharmacotherapy of appropriate type, dose, and duration were classified as medication resistant (n = 227). Logistic regression was used to estimate effects of CALM's CBT program (CALM-CBT; chosen by 104 of 117 medication-resistant patients randomized to CALM) versus usual care (UC; n = 110) on response [>= 50% reduction of 12-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptom score] and remission (BSI-12 < 6) at 6, 12, and 18 months. Within-group analyses examined outcomes by treatment choice (CBT vs. CBT plus medication management) and CBT dose. RESULTS: Approximately 58% of medication-resistant CALM-CBT patients responded and 46% remitted during the study. Relative to UC, CALM-CBT was associated with greater response at 6 months (AOR = 3.78, 95% CI 2.02-7.07) and 12 months (AOR = 2.49, 95% CI 1.36-4.58) and remission at 6, 12, and 18 months (AORs = 2.44 to 3.18). Patients in CBT plus medication management fared no better than those in CBT only. Some evidence suggested higher CBT dose produced better outcomes. CONCLUSIONS: CBT can improve outcomes for patients whose anxiety symptoms are resistant to standard pharmacotherapy. PMID- 27775824 TI - Successful management of Mycobacterium haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient. AB - Nontuberculous mycobacterial infections can often occur in individuals with adequate immune function. Such infections typically have cutaneous involvement and are caused by rapidly growing mycobacterium. Other nontuberculous mycobacteria species, like Mycobacterium haemophilum, almost always present as opportunistic infections occurring in severely immunocompromised hosts. Here, we present a complicated and protracted course of diagnosing M. haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient. PMID- 27775826 TI - Health service utilisation of rural-to-urban migrants in Guangzhou, China: does employment status matter? AB - OBJECTIVE: To describe the self-reported health status and service utilisation of employed, retired and unemployed migrants in Guangzhou, a megacity in southern China. METHODS: A cross-sectional study adapted from the National Health Service Survey was conducted between September and December in 2014. Based on the distribution of occupation of migrants, multistage sampling was used to recruit individuals. Logistic regression was applied to explore the factors influencing their service utilisation. RESULTS: Of 2906 respondents, 76.6% were employed, 9.2% retired and 14.2% unemployed. Only 8.1% reported having an illness in the previous 2 weeks, and 6.5% reported having been hospitalised in the previous year. Employed migrants had the lowest recent physician consultation rate (3.4%) and the lowest annual hospitalisation rate (4.5%) (P < 0.05); unemployed migrants had the highest rates (6.8% and 14.5% respectively, P < 0.05). Retired migrants were more likely to return to their hometown for health care (8.6%) than employed (1.5%) and unemployed migrants (3.4%) (P < 0.05). After adjusting for age and gender, employment status remained significant in explaining the recent two-week treatment-seeking behaviour of migrants (P < 0.05). CONCLUSION: Disparity of service utilisation continues to be a problem for migrants due to the poor health awareness, lack of time and inconvenience of medical insurance reimbursement. Employed migrants make the least use of health services. PMID- 27775827 TI - Efficacy of a disinfectant containing silver dihydrogen citrate against GI.6 and GII.4 human norovirus. AB - AIMS: Human norovirus is a major public health burden and is resistant to numerous sanitizers and disinfectants. In this study, we tested the efficacy of an antimicrobial product containing a blend of silver ions and citric acid (silver dihydrogen citrate; SDC) against GI.6 and GII.4 HuNoV. METHODS AND RESULTS: Pure(r) hard surface disinfectant (Pure Bioscience, El Cajon, CA) was evaluated using ASTM International virucidal suspension and stainless steel carrier assays. The effect of SDC (or citrate alone) exposure on viral integrity was evaluated using RT-qPCR, transmission electron microscopy, sodium dodecyl sulphate-polyacrylamide gel electrophoresis/Western blot analysis and a receptor binding assay. Suspension assays showed a 4.0 log10 reduction in RNA copy number within 5 min, while carrier assays showed a 2.0-3.0 log10 reduction in 30 min. Incorporating a simulated soil load into the sample matrix significantly reduced product efficacy. Treated particles displayed deformation and aggregation, a 50% reduction in viral capsid protein band intensity, and an 80% reduction in histo blood group antigen receptor-binding ability. CONCLUSIONS: Our results suggest that SDC acts exclusively on the viral capsid, and shows efficacy against HuNoV when used on precleaned surfaces. SIGNIFICANCE AND IMPACT OF THE STUDY: This study sheds light on the mechanisms and efficacy of a novel antimicrobial against HuNoV. Our results suggest: (i) silver ions exclusively target the viral capsid, and not the RNA genome; (ii) citrate is not crucial for HuNoV capsid deformation. PMID- 27775825 TI - Impact of type of calcineurin inhibitor on post-transplant tuberculosis: Single center study from India. AB - INTRODUCTION: Tuberculosis (TB) is an important cause of morbidity and mortality in renal transplant recipients. Immunosuppressive drugs are one of the most important risk factor for post-transplant tuberculosis (PTTB). A paucity of data exists about the impact of the type of calcineurin inhibitor on PTTB. METHODS: In this retrospective study, all adult patients on calcineurin inhibitor-based immunosuppression were included. Patients receiving TB chemoprophylaxis were excluded. Diabetes, duration of dialysis, hepatitis B and C, past treated TB, induction therapy, type of antimetabolite, acute rejection, new onset of diabetes after renal transplantation (RT) (NODAT) and cytomegalovirus (CMV) were analyzed in tacrolimus (Tac) and cyclosporine (CsA) groups. Primary outcome was incidence of TB and secondary outcomes were timeline of development of TB after RT and pattern of TB in the two groups. RESULTS: Of the 1664 patients included, 582 patients received CsA-based immunosuppression while 1082 received Tac-based immunosuppression. Duration of dialysis, positive tuberculin skin test, use of induction, mycophenolate mofetil use, CMV infection, and NODAT were significantly more, and hepatitis B infection, past treated TB, and acute rejection episodes were significantly less in the Tac group. At the end of follow-up, incidence of TB in the Tac group was significantly less than in the CsA group (6.1% vs 19.9%, P<.001). Mean time for development of TB after RT was similar in both the groups and nodal and disseminated TB were more common in the Tac group. CONCLUSION: In conclusion, our study shows that use of Tac as compared to CsA significantly decreases incidence of PTTB. Time of infection since transplant was similar in both the groups. However, nodal and disseminated TB were more common in the Tac group. PMID- 27775829 TI - Approved and Experimental Small-Molecule Oncology Kinase Inhibitor Drugs: A Mid 2016 Overview. AB - Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult-even for those working in the field-easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation. The purpose of this review is thus to provide an overview of the biomedical rationales for the kinases being targeted on the one hand, and the design principles, as well as chemical, pharmacological, pharmaceutical, and toxicological kinase inhibitor properties, on the other hand. Two issues that are especially important in kinase inhibitor research, target selectivity and drug resistance, as well as the underlying structural concepts, are discussed in general terms and in the context of relevant kinases and their inhibitors. PMID- 27775828 TI - Cross-national epidemiology of panic disorder and panic attacks in the world mental health surveys. AB - CONTEXT: The scarcity of cross-national reports and the changes in Diagnostic and Statistical Manual version 5 (DSM-5) regarding panic disorder (PD) and panic attacks (PAs) call for new epidemiological data on PD and PAs and its subtypes in the general population. OBJECTIVE: To present representative data about the cross national epidemiology of PD and PAs in accordance with DSM-5 definitions. DESIGN AND SETTING: Nationally representative cross-sectional surveys using the World Health Organization Composite International Diagnostic Interview version 3.0. PARTICIPANTS: Respondents (n = 142,949) from 25 high, middle, and lower-middle income countries across the world aged 18 years or older. MAIN OUTCOME MEASURES: PD and presence of single and recurrent PAs. RESULTS: Lifetime prevalence of PAs was 13.2% (SE 0.1%). Among persons that ever had a PA, the majority had recurrent PAs (66.5%; SE 0.5%), while only 12.8% fulfilled DSM-5 criteria for PD. Recurrent PAs were associated with a subsequent onset of a variety of mental disorders (OR 2.0; 95% CI 1.8-2.2) and their course (OR 1.3; 95% CI 1.2-2.4) whereas single PAs were not (OR 1.1; 95% CI 0.9-1.3 and OR 0.7; 95% CI 0.6-0.8). Cross-national lifetime prevalence estimates were 1.7% (SE 0.0%) for PD with a median age of onset of 32 (IQR 20-47). Some 80.4% of persons with lifetime PD had a lifetime comorbid mental disorder. CONCLUSIONS: We extended previous epidemiological data to a cross-national context. The presence of recurrent PAs in particular is associated with subsequent onset and course of mental disorders beyond agoraphobia and PD, and might serve as a generic risk marker for psychopathology. PMID- 27775830 TI - Effect of remote ischemic preconditioning on electrophysiological and biomolecular parameters in nonvalvular paroxysmal atrial fibrillation (RIPPAF study): Rationale and study design of a randomized, controlled clinical trial. AB - Remote ischemic preconditioning (RIPC) has been studied in models of different cardiovascular entities. Recently, a beneficial effect of RIPC on incidence of atrial fibrillation (AF) in postsurgical patients has been suggested. However, the potential impact of RIPC on electrophysiological- and thrombogenesis-related parameters in the setting of paroxysmal nonvalvular AF has not been investigated. The aim of the study is to answer the following questions: (1) Does RIPC have impact on inducibility of AF in patients with known paroxysmal AF? If yes, what are the direct electrophysiological mechanisms of this phenomenon, and could RIPC be implemented to reduce AF burden? (2) Does RIPC have the potential to minimize thrombogenic effects of simulated episodes of AF? If so, what are inhibited components of thrombogenesis and can this be used to reduce thromboembolic risk related to paroxysmal AF? The presented study is a 2-arm, randomized, placebo controlled, double-blinded, single-center trial in a cohort of 146 patients with paroxysmal AF referred for AF ablation in sinus rhythm. The study will collect electrophysiological data such as variability of P-wave morphology, atrial refractory period, conduction times, and inducibility/sustainability of AF. Furthermore, AF-induced prothrombotic processes will be analyzed by quantification of platelet aggregates, analysis of platelet function, and measurement of thrombogenesis-related plasma markers. Moreover, the study will provide a unique bio-database for further analysis of molecular and genetic mechanisms responsible for observed results. PMID- 27775831 TI - A Coupled Groundwater-Surface Water Modeling Framework for Simulating Transition Zone Processes. AB - There is an identified need for fully representing groundwater-surface water transition zone (i.e., the sediment zone that connects groundwater and surface water) processes in modeling fate and transport of contaminants to assist with management of contaminated sediments. Most existing groundwater and surface water fate and transport models are not dynamically linked and do not consider transition zone processes such as bioturbation and deposition and erosion of sediments. An interface module is developed herein to holistically simulate the fate and transport by coupling two commonly used models, Environmental Fluid Dynamics Code (EFDC) and SEAWAT, to simulate surface water and groundwater hydrodynamics, while providing an enhanced representation of the processes in the transition zone. Transition zone and surface water contaminant processes were represented through an enhanced version of the EFDC model, AQFATE. AQFATE also includes SEDZLJ, a state-of-the-science surface water sediment transport model. The modeling framework was tested on a published test problem and applied to evaluate field-scale two- and three-dimensional contaminant transport. The model accurately simulated concentrations of salinity from a published test case. For the field-scale applications, the model showed excellent mass balance closure for the transition zone and provided accurate simulations of all transition zone processes represented in the modeling framework. The model predictions for the two-dimensional field case were consistent with site-specific observations of contaminant migration. This modeling framework represents advancement in the simulation of transition zone processes and can help inform risk assessment at sites where contaminant sources from upland areas have the potential to impact sediments and surface water. PMID- 27775832 TI - Use of illuminance as a guide to effective light delivery during daylight photodynamic therapy in the U.K. AB - BACKGROUND: Daylight PDT (dPDT) is an effective and nearly painless treatment for field-change actinic keratosis. Measuring the protoporphyrin-IX (PpIX)-weighted exposure dose can give an indication of when conditions are most viable for effective dPDT. It would be advantageous for practitioners if more detailed information of exposure dose and appropriate treatment conditions were available. Where sophisticated measurement equipment is unavailable, simpler and more cost effective methods of dose measurement are desirable. OBJECTIVES: To devise a model whereby illuminance data can be converted into PpIX-weighted exposure dose, and to use this model to estimate appropriate times for dPDT across the U.K. and Ireland. METHODS: Spectral irradiance data were analysed to obtain a conversion model for illuminance to PpIX-weighted dose. This model was applied to historic illuminance data from nine sites to obtain PpIX-weighted dose across the U.K. and Ireland. Temperature data and an analysis of conservatory-based dPDT were also considered. RESULTS: Distribution of the expected PpIX-weighted dose across the nine locations is presented. Temperature data showed that it could be too cold for dPDT, even when there is sufficient light exposure. Conservatory-based dPDT could extend the times in the year for possible treatment. CONCLUSIONS: This proposed conversion model provides a means of using an illuminance reading to calculate the PpIX-weighted exposure dose. Dosimetry of dPDT may be carried out simply and at low cost using the presented method; however, the results presented may be used as a guide for those considering dPDT, without the need to conduct measurements themselves. PMID- 27775833 TI - Targeting Deubiquitinating Enzymes in Glioblastoma Multiforme: Expectations and Challenges. AB - Glioblastoma (GBM) is regarded as the most common primary intracranial neoplasm. Despite standard treatment with tumor resection and radiochemotherapy, the outcome remains gloomy. It is evident that a combination of oncogenic gain of function and tumor-suppressive loss of function has been attributed to glioma initiation and progression. The ubiquitin-proteasome system is a well orchestrated system that controls the fate of most proteins by striking a dynamic balance between ubiquitination and deubiquitination of substrates, having a profound influence on the modulation of oncoproteins, tumor suppressors, and cellular signaling pathways. In recent years, deubiquitinating enzymes (DUBs) have emerged as potential anti-cancer targets due to their targeting several key proteins involved in the regulation of tumorigenesis, apoptosis, senescence, and autophagy. This review attempts to summarize recent studies of GBM-associated DUBs, their roles in various cellular processes, and discuss the relation between DUBs deregulation and gliomagenesis, especially how DUBs regulate glioma stem cells pluripotency, microenvironment, and resistance of radiation and chemotherapy through core stem-cell transcriptional factors. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of DUBs, and attempted to find a potential GBM treatment by DUBs intervention. PMID- 27775834 TI - Seasonality of Coliform Bacteria Detection Rates in New Jersey Domestic Wells. AB - It is important that indicators of fecal pollution are reliable. Coliform bacteria are a commonly used indicator of fecal pollution. As other investigators have reported elsewhere, we observed a seasonal pattern of coliform bacteria detections in domestic wells in New Jersey. Examination of a statewide database of 10 years of water quality data from 93,447 samples, from 78,207 wells, generated during real estate transactions, revealed that coliform bacteria were detected in a higher proportion of wells during warm weather months. Further examination of the seasonal pattern of other data, including well water pH, precipitation, ground and surface water temperatures, surface water coliform bacteria concentrations, and vegetation, resulted in the hypothesis that these bacteria may be derived from nonfecal (or environmentally adapted) as well as fecal sources. We provide evidence that the coliform seasonality may be the result of seasonal changes in groundwater extraction volumes (and to a lesser extent precipitation), and temperature-driven changes in the concentration of surface or near-surface coliform sources. Nonfecal coliform sources may not indicate the presence of fecal wastes and hence the potential presence of pathogens, or do so in an inconsistent fashion. Additional research is needed to identify the sources of the coliforms detected in groundwater. PMID- 27775835 TI - Clinical efficacy of EDTA ultrasonic activation in the reduction of endotoxins and cultivable bacteria. AB - AIM: This clinical study was conducted to investigate the influence of 17% ethylenediaminetetraacetic acid (EDTA) ultrasonic activation after chemomechanical preparation (CMP) on eliminating/reducing oral bacterial lipopolysaccharides (known as endotoxins) and cultivable bacteria in teeth with pulp necrosis and apical periodontitis. METHODOLOGY: Samples were taken from 24 root canals at several clinical periods: S1 - before CMP; S2 - after CMP; S3 - after EDTA: G1 - with ultrasonic activation (n = 12) and G2 - without ultrasonic activation (n = 12). Root canals were instrumented using Mtwo rotary files. Culture techniques were used to determine the number of colony-forming units (CFU). Limulus amebocyte lysate (LAL) was used to measure endotoxin levels. Friedman's and Wilcoxon signed-rank tests were used to compare the amount of bacteria and endotoxin levels in each period (P < 0.05). RESULTS: Endotoxins and cultivable bacteria were recovered in 100% of the initial samples (S1). CMP was effective in reducing endotoxins and bacterial load (all with P < 0.05). Higher values of endotoxin reduction were achieved with EDTA ultrasonic activation [G1, 0.02 EU mL-1 (range 0.01-0.75)] compared with the no activation group [G2, 1.13 EU mL-1 (range 0.01-8.34)] (P < 0.05). Regarding bacterial reduction, no statistically significant difference was found in S3, regardless of the group (G1, G2, P > 0.05). CONCLUSIONS: Chemomechanical preparation was effective in reducing bacteria and endotoxins, but could not completely eliminate them. The ultrasonic activation of EDTA was effective in further reducing endotoxin levels in the root canals of teeth with pulp necrosis and apical periodontitis. PMID- 27775836 TI - Allergy in severe asthma. AB - It is well recognized that atopic sensitization is an important risk factor for asthma, both in adults and in children. However, the role of allergy in severe asthma is still under debate. The term 'Severe Asthma' encompasses a highly heterogeneous group of patients who require treatment on steps 4-5 of GINA guidelines to prevent their asthma from becoming 'uncontrolled', or whose disease remains 'uncontrolled' despite this therapy. Epidemiological studies on emergency room visits and hospital admissions for asthma suggest the important role of allergy in asthma exacerbations. In addition, allergic asthma in childhood is often associated with severe asthma in adulthood. A strong association exists between asthma exacerbations and respiratory viral infections, and interaction between viruses and allergy further increases the risk of asthma exacerbations. Furthermore, fungal allergy has been shown to play an important role in severe asthma. Other contributing factors include smoking, pollution and work-related exposures. The 'Allergy and Asthma Severity' EAACI Task Force examined the current evidence and produced this position document on the role of allergy in severe asthma. PMID- 27775838 TI - The needs and experiences of patients with skin cancer: a qualitative systematic review with metasynthesis. AB - Skin cancer incidence is increasing worldwide. This is an update of a previous review published in 2010 that identified only two studies and found that the needs and experiences of individuals with skin cancer were under-researched. Our objective was to undertake a qualitative systematic review of the needs and experiences of people with a diagnosis of skin cancer. To update the previous review, the following databases were searched from 2010 to 30 November 2015: CINAHL PsycINFO, Medline and Embase. The methodological quality of the studies was assessed using the Joanna Briggs Institute Qualitative Assessment Review Instrument. The qualitative research findings were synthesized using a pragmatic meta-aggregative approach. A total of 14 studies (16 papers) were included. Only three studies included patients with keratinocyte carcinoma. Overall, 15 categories were identified and these resulted in four overarching synthesized findings (SFs) from diagnosis (SF1), throughout treatment (SF2) and follow-up (SF3), and then a fourth SF (SF4) that addressed patients' satisfaction with their care and their relationship with healthcare professionals. Despite the fact that patients with keratinocyte carcinoma and melanoma can have a very different prognosis, they also share similar needs and concerns especially around the time of diagnosis and follow-up/surveillance for new lesions. Healthcare professionals working with patients with skin cancer need to understand their psychosocial concerns and their information needs in order to design services appropriately. Future studies need to consider patients with keratinocyte carcinoma in addition to patients with melanoma. PMID- 27775837 TI - Chemotherapy decisions and patient experience with the recurrence score assay for early-stage breast cancer. AB - BACKGROUND: The 21-gene recurrence score (RS) assay stratifies early-stage, estrogen receptor-positive breast cancer by recurrence risk. Few studies have examined the ways in which physicians use the RS to recommend adjuvant systemic chemotherapy or patients' experiences with testing and decision making. METHODS: This study surveyed 3880 women treated for breast cancer in 2013-2014; they were identified from the Los Angeles County and Georgia Surveillance, Epidemiology, and End Results registries (response rate, 71%). Women reported chemotherapy recommendations, the receipt of chemotherapy, testing experiences, and decision satisfaction. Registries linked the tumor data, RS, and surveys. Regression models examined factors associated with chemotherapy recommendations and receipt by the RS and subgroups. RESULTS: There were 1527 patients with stage I/II, estrogen receptor/progesterone receptor-positive, human epidermal growth factor 2 negative disease: 778 received an RS (62.6% of patients with node-negative, favorable disease, 24.3% of patients with node-negative, unfavorable disease, and 13.0% of patients with node-positive disease; P < .001). Overall, 47.2% of the patients received a recommendation against chemotherapy, and 40.5% received a recommendation for it. RS results correlated with recommendations: nearly all patients with high scores (31-100) received a chemotherapy recommendation (86.9% 96.5% across clinical subgroups), whereas the majority of the patients with low risk results (0-18) received a recommendation against it (65.9%-78.2% across subgroups). Most patients with high RSs received chemotherapy (87.0%, 91.1%, and 100% across subgroups), whereas few patients with low scores received it (2.9%, 9.5%, and 26.6% across subgroups). There were no substantial racial/ethnic differences in testing or treatment. Women were largely satisfied with the RS and chemotherapy decisions. CONCLUSIONS: Oncologists use the RS to personalize treatment, even for those with node-positive disease. High satisfaction and an absence of disparities in testing and treatment suggest that precision-medicine advances have improved systemic breast cancer treatment. Cancer 2017;43-51. (c) 2016 American Cancer Society. PMID- 27775839 TI - Time and Magnitude of Peak Concentration of Reactive Groundwater Contaminants Discharged to a River. AB - An analytical solution for calculating the contaminant discharge rate in an aquifer following an instantaneous release of reactive contaminant mass to groundwater is used to derive relationships for the time and magnitude of peak concentration in a river receiving the transported material. Relationships are developed for the time of peak concentration relative to the time of travel for the contaminant, and the magnitude of peak concentration relative to the concentration calculated at the time of travel. Both quantities are found to be a function of two dimensionless parameters characterizing advective-dispersive reactive transport-the Peclet number and the Damkohler number. It is shown that the time to peak concentration may occur before the time of travel, considering advection and retardation only, depending on the magnitudes of the Peclet and Damkohler numbers. Similarly, the magnitude of peak concentration may exceed the concentration calculated assuming that the time of peak concentration coincides with time of travel for the contaminant. For large Damkohler numbers, equating the time of peak concentration with the time of travel for the contaminant can significantly underestimate peak concentrations. PMID- 27775840 TI - Microscopic studies of the effect of laser irradiation parameters of photopolymer plate on the quality of flexographic printing plate produced by the digital method. AB - The process of making of flexographic printing plate by the digital method proceeds in the following stages: back exposure, laser irradiation, main exposure, washing, post exposure, and finishing of the photopolymer plate. Laser irradiation is one of the basic technological stages, in which a negative of the reproduced image is created on the black layer of photopolymer plate. The article presents the results of studies of the effect laser irradiation parameters on the quality of flexographic printing plate produced by digital method. Stereoscopic optical microscope was used to determine the effect of laser power and rotation speed of the drum of digital imager in the laser irradiation of photopolymer plate on tonal value and precision of reproducing of halftone dots in various parts of multitonal halftone image reproduced on the printing plate. The results of the studies will enable to complement our knowledge on the effect of individual parameters of laser irradiation process on the quality of digital flexographic printing plates. Microsc. Res. Tech. 79:1007-1016, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27775841 TI - Evaluation of an fMRI USPIO-based assay in healthy human volunteers. AB - PURPOSE: To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle. MATERIALS AND METHODS: This was an open-label, two-period, fixed sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron). Multiple outcome measures were analyzed including absolute percent signal change (|PSC|, primary endpoint), its contrast-to-noise ratio (CNR) and corresponding z-score, percent CBV change (DeltaCBV) and respective CNR, concentration of Fe, and baseline CBV. RESULTS: The |PSC| in the visual cortex increased with ferumoxytol dose and was up to 3 * higher than BOLD fMRI. Test-retest reliability was comparable for BOLD and CBV fMRI. Intraclass correlation coefficients (ICCs) for |PSC| were 0.3 (one-sided 95% lower confidence limit = 0.00), 0.81 (0.47), 0.48 (0.00), and 0.3 (0.00) for BOLD and the 250-, 350-, and 510-mg doses of ferumoxytol, respectively. For DeltaCBV, ICCs were 0.77 (0.37), 0.48 (0.00), and 0.49 (0.00) for 250 mg, 350 mg, and 510 mg, respectively. CONCLUSION: This work demonstrates that CBV fMRI techniques and endpoints are dose dependent, robust and have good test-retest repeatability. It also confirms previous findings that USPIO enhances sensitivity of fMRI stimulus-response endpoints. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;46:124-133. PMID- 27775842 TI - A Karnofsky performance status-based score predicts death after hospital discharge in patients with cirrhosis. AB - : Identification of patients with cirrhosis at risk for death within 3 months of discharge from the hospital is essential to individualize postdischarge plans. The objective of the study was to identify an easy-to-use prognostic model based on the Karnofsky Performance Status (KPS). The North American Consortium for the Study of End-Stage Liver Disease consists of 16 tertiary-care hepatology centers that prospectively enroll nonelectively admitted cirrhosis patients. Patients enrolled had KPS assessed 1 week postdischarge. KPS was categorized into low (score 10-40), intermediate (50-70), and high (80-100). Of 954 middle-aged patients (57 +/- 10 years, 63% men) with a median Model for End-Stage Liver Disease (MELD) score of 17 (interquartile range 13-21), the mortality rates for the low, intermediate, and high performance status groups were 23% (36/159), 11% (55/489), and 5% (15/306), respectively. Low, intermediate, and high performance status was seen in 17%, 51%, and 32% of the cohort, respectively. Low performance status was associated with older age, dialysis, hepatic encephalopathy, longer length of stay, and higher white blood cell count or MELD score at discharge. A model was derived using the three independent predictors of 3-month mortality: KPS, age, and MELD score. This score had better discrimination (area under the receiver operating characteristic curve = 0.74) than a model using MELD (area under the receiver operating characteristic curve = 0.62) or MELD and age (area under the receiver operating characteristic curve = 0.67) to predict 3-month mortality. CONCLUSIONS: Cirrhosis patients at risk for 3-month postdischarge mortality can be identified using a novel KPS-based score; this score may be adopted in practice to guide postdischarge early interventions, including the integrated provision of active and palliative management strategies. (Hepatology 2017;65:217-224). PMID- 27775843 TI - Three-dimensional ultrashort echo-time imaging using a FLORET trajectory. AB - PURPOSE: Three-dimensional ultrashort echo-time (UTE) imaging commonly makes use of an isotropic 3D radial projection acquisition. The FLORET sequence is proposed and evaluated as a more efficient alternative. METHODS: The properties of the FLORET trajectory are contrasted with those of a 3D radial projection trajectory. The theoretical advantages of FLORET, including greater sampling and SNR efficiency, are evaluated based upon experimental data. The effect of T2* decay on FLORET is analyzed in comparison to the 3D radial, Cones, and Density Adapted Radial trajectories. FLORET UTE image quality is compared with 3D radial UTE image quality. RESULTS: FLORET is shown to have several advantages over 3D radial acquisitions with respect to image quality, scan time, signal-to-noise, and off resonance blurring for UTE data. The signal and resolution losses from T2* decay for a FLORET acquisition are shown to be comparable to those of Density Adapted Radial and Density Compensated Cones trajectories. CONCLUSION: The FLORET sequence is recommended as an alternative to 3D radial projection sequences for musculoskeletal UTE imaging as well as other UTE applications that accommodate modest to long per shot sampling times. FLORET is not recommended for imaging extremely short T2 species such as dentin. Magn Reson Med 78:1038-1049, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27775844 TI - Signal localization: a new approach in signal discovery. AB - A new approach for statistical association signal identification is developed in this paper. We consider a strategy for nonprecise signal identification by extending the well-known signal detection and signal identification methods applicable to the multiple testing problem. Collection of statistical instruments under the presented approach is much broader than under the traditional signal identification methods, allowing more efficient signal discovery. Further assessments of maximal value and average statistics in signal discovery are improved. While our method does not attempt to detect individual predictors, it instead detects sets of predictors that are jointly associated with the outcome. Therefore, an important application would be in genome wide association study (GWAS), where it can be used to detect genes which influence the phenotype but do not contain any individually significant single nucleotide polymorphism (SNP). We compare power of the signal identification method based on extremes of single p values with the signal localization method based on average statistics for logarithms of p-values. A simulation analysis informs the application of signal localization using the average statistics for wide signals discovery in Gaussian white noise process. We apply average statistics and the localization method to GWAS to discover better gene influences of regulating loci in a Chinese cohort developed for risk of nasopharyngeal carcinoma (NPC). PMID- 27775845 TI - Heterologous expression of lipases YLIP4, YLIP5, YLIP7, YLIP13, and YLIP15 from Yarrowia lipolytica MSR80 in Escherichia coli: Substrate specificity, kinetic comparison, and enantioselectivity. AB - Five lipase genes, ylip4, ylip5, ylip7, ylip13, and ylip15, from Yarrowia lipolytica MSR80 were cloned and expressed in the pEZZ18-HB101 system. The lipases shared maximum sequence identity with Candida galli lipase, whereas they shared structural similarity with YLIP2 of Y. lipolytica CLIB122. The enzymes, purified using IgG sepharose, had specific activities in the range of 7-25 U mg-1 . Biochemical characteristics of all the lipases varied with respect to thermostability, substrate specificity, and enantioselectivity. All the enzymes were most active at neutral or slightly alkaline pH and were stable in the pH range 3.0-8.0, except YLIP4, which showed 50% stability at pH 10.0. Temperature optima of all the lipases varied from 30 to 50 oC. YLIP15 and YLIP13 were most thermostable with a t1/2 of 138 and 112 Min, respectively, at 60 degrees C. The lipases exhibited varied substrate specificity on p-nitrophenyl esters ranging from short-chain specificity (YLIP15), mid-chain specificity (YLIP4, YLIP5, YLIP7), and long-chain specificity (YLIP13). Catalytic efficiency on p nitrophenylcaprate was highest for YLIP13 (67 * 103 mM-1 min-1 ) and lowest for YLIP15 (6.7 * 103 mM-1 min-1 ). YLIP13 was S-enantioselective, and YLIP15 was R enantioselective with enantiomeric excess of 53 and 36%, respectively. Of all five lipases, YLIP13 and YLIP15 could be considered as industrially important enzymes as they were thermostable and enantioselective. PMID- 27775846 TI - A rare case of a pineoblastoma with a rhabdomyoblastic component. AB - Pineal anlage tumor (PAT) is a rare subtype of pineoblastoma (PB), which shows a poor prognosis. We report a case of a 5-year-old boy with PB with a rhabdomyoblastic component. He presented at a local clinic with vomiting and was transferred to our hospital following discovery of a pineal mass. An endoscopic biopsy was performed and was diagnosed as a PB with a rhabdomyoblastic component. Histopathology of PAT is characterized by both neuroectodermal and ectomesenchymal differentiation, and only a few confirmed cases have been reported. Although the histopathological features of the reported case resembled that of PAT, the ectomesenchymal component in the presented case was only a rhabdomyoblastic one. Therefore, we have diagnosed this case as PB with a rhabdomyoblastic component. As PAT is a rare pineal tumor, clinical, histopathological and genetic evaluation of additional cases is needed to define the characteristics of PAT as one of the pineal gland tumors. PMID- 27775847 TI - Extrapolating cetacean densities to quantitatively assess human impacts on populations in the high seas. AB - As human activities expand beyond national jurisdictions to the high seas, there is an increasing need to consider anthropogenic impacts to species inhabiting these waters. The current scarcity of scientific observations of cetaceans in the high seas impedes the assessment of population-level impacts of these activities. We developed plausible density estimates to facilitate a quantitative assessment of anthropogenic impacts on cetacean populations in these waters. Our study region extended from a well-surveyed region within the U.S. Exclusive Economic Zone into a large region of the western North Atlantic sparsely surveyed for cetaceans. We modeled densities of 15 cetacean taxa with available line transect survey data and habitat covariates and extrapolated predictions to sparsely surveyed regions. We formulated models to reduce the extent of extrapolation beyond covariate ranges, and constrained them to model simple and generalizable relationships. To evaluate confidence in the predictions, we mapped where predictions were made outside sampled covariate ranges, examined alternate models, and compared predicted densities with maps of sightings from sources that could not be integrated into our models. Confidence levels in model results depended on the taxon and geographic area and highlighted the need for additional surveying in environmentally distinct areas. With application of necessary caution, our density estimates can inform management needs in the high seas, such as the quantification of potential cetacean interactions with military training exercises, shipping, fisheries, and deep-sea mining and be used to delineate areas of special biological significance in international waters. Our approach is generally applicable to other marine taxa and geographic regions for which management will be implemented but data are sparse. PMID- 27775849 TI - Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation. AB - We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2 O2 ) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeII catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including . CF3 , . C4 F9 , . CH2 CN, and . CH2 CO2 Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3 I and C4 F9 I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines. PMID- 27775848 TI - Metabolic profiling of fatty liver in young and middle-aged adults: Cross sectional and prospective analyses of the Young Finns Study. AB - : Nonalcoholic fatty liver is associated with obesity-related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis-related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty-eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population-based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34-49 years (19% prevalence). Cross-sectional associations as well as 4-year and 10-year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age-adjusted and sex-adjusted cross sectional analyses). The strongest direct associations were observed for extremely large very-low-density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48-6.78), other very-low density lipoprotein measures, and branched-chain amino acids (e.g., leucine OR = 2.94, 2.51-3.44). Strong inverse associations were observed for high-density lipoprotein measures, e.g., high-density lipoprotein size (OR = 0.36, 0.30-0.42) and several fatty acids including omega-6 (OR = 0.37, 0.32-0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis. CONCLUSION: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491-500). PMID- 27775850 TI - Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBCL not otherwise specified (NOS). AB - AIMS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLsn ) in a series of 240 cases of DLBCL not otherwise specified [DLBCLall (NOS) ], including DLBCLsn training set (n = 11) and validation set (n = 18), and DLBCLnon-sn (n = 211). METHODS AND RESULTS: In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)+ . The genomic profile showed gains(+) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-) of 6q26q27 (55%) and 9p21.3 (64%); and copy number neutral loss of heterozygosity (LOH) (acquired uniparental disomy, UPD) at 6p25.3p21.31 (36%). This profile is comparable to DLBCLNOS (GSE11318, n = 203.) and closer to non-GCB/activated B-cell-like subtype (ABC). Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCLsn (P < 0.001). Array results were verified successfully by fluorescence in situ hybridization (FISH) on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), 9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82-91% agreement. Minimal common regions included biologically relevant genes of MNDA (+1q23.1), RGS1 and RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 (BLIMP1) and PARK2 ( 6q21q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1) and BCL2 (+18q21.33). Correlation between DNA copy number and protein immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-like tumour associated macrophages (TAMs) and CD8+ T lymphocytes that associated with higher genomic instability. The DLBCLsn validation set confirmed the clinicopathological characteristics, all FISH loci and immunohistochemistry (IHC) for RGS1. RGS1, one of the most frequently altered genes, was analysed by IHC in DLBCLall and high RGS1 expression associated with non-GCB, EBER+ and unfavourable overall survival (hazard ratio = 1.794; P = 0.016). CONCLUSIONS: DLBCLsn has a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCLall (NOS) . PMID- 27775851 TI - Differences in patterns of survival in metastatic adenoid cystic carcinoma of the head and neck. AB - BACKGROUND: We examined the assumption in conventional teaching about metastatic adenoid cystic carcinoma (ACC) being an indolent type of disease. METHODS: A single center analysis of 105 cases of ACC was performed. Radiographs were reviewed and tumor response to chemotherapy was measured. Distant disease-free survival (DDFS) and time to death since distant metastases diagnosis were analyzed. RESULTS: Forty-two percent of the patients were diagnosed with distant metastases. DDFS showed significant negative associations with advanced T classification, N+ classification, solid type tumor, and positive surgical margins. Distant metastases (91%) developed in the first 5 years after presentation. Median distant metastatic survival was 13.8 months. The most frequent organ sited was the lung. Solid type ACC showed a preponderance for multiorgan metastases (17/28; 61%). Distant metastases seemed not to occur in case of clear surgical margins. Solid type ACC had a significant poorer survival after development of distant metastases. CONCLUSION: Metastatic ACC is not always an indolent disease. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 456-463, 2017. PMID- 27775853 TI - Amphiphilic Metallopolymers for Photoswitchable Supramolecular Hydrogels. AB - A series of amphiphilic metallopolymers is described that features zinc(II) bis terpyridine coordination nodes as well as a backbone with hydrophobic azoaryl moieties and hydrophilic phenylene-ethynylene units decorated with PEG brushes. Using such metallopolymers at very low concentration, stable, photo-responsive and self-healing hydrogels are obtained. UV irradiation of the gel allows modulation of the degree of hydrophobic pi-pi interactions between photoisomerizable azoaryl units and a polarity switch that overall induces a fast gel-to-sol transition. Finally, the material phase can be readily and fully restored to the thermodynamically stable state either thermally or photochemically by using visible light. The presented strategy can be further generalized towards modular supramolecular metallopolymers for injectable gels in drug delivery and bio-engineering applications. PMID- 27775852 TI - Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome. AB - Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1-/- knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3beta (GSK3beta), which is abnormally active in Fmr1-/- mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3beta and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3beta, in both wild-type and Fmr1-/- mouse hippocampus. Acute cotinine treatment improved cognitive functions of Fmr1-/- mice in coordinate and categorical spatial processing, novel object recognition, and temporal ordering. However, cotinine failed to restore impaired cognition in GSK3beta knockin mice, in which a serine9 to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3beta, causing GSK3beta to be hyperactive. These results indicate that acute cotinine treatment effectively repairs impairments of these four cognitive tasks in Fmr1-/ mice, and suggest that this cognition-enhancing effect of cotinine is linked to its induction of inhibitory serine-phosphorylation of GSK3. Taken together, these results show that nicotinic receptor agonists can act as cognitive enhancers in a mouse model of Fragile X syndrome and highlight the potential role of inhibiting GSK3beta in mediating the beneficial effects of cotinine on memory. PMID- 27775854 TI - The association between race/ethnicity and the effectiveness of direct antiviral agents for hepatitis C virus infection. AB - : Black race and Hispanic ethnicity were associated with lower rates of sustained virologic response (SVR) to interferon-based treatments for chronic hepatitis C virus infection, whereas Asian race was associated with higher SVR rates compared to white patients. We aimed to describe the association between race/ethnicity and effectiveness of new direct-acting antiviral regimens in the Veterans Affairs health care system nationally. We identified 21,095 hepatitis C virus-infected patients (11,029 [52%] white, 6,171 [29%] black, 1,187 [6%] Hispanic, 348 [2%] Asian/Pacific Islander/American Indian/Alaska Native, and 2,360 [11%] declined/missing race or ethnicity) who initiated antiviral treatment with regimens containing sofosbuvir, simeprevir + sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ombitasvir/ritonavir/dasabuvir during the 18-month period from January 1, 2014, to June 30, 2015. Overall SVR rates were 89.8% (95% confidence interval [CI] 89.2-90.4) in white, 89.8% (95% CI 89.0-90.6) in black, 86.0% (95% CI 83.7-88.0) in Hispanic, and 90.7% (95% CI 87.0-93.5) in Asian/Pacific Islander/American Indian/Alaska Native patients. However, after adjustment for baseline characteristics, black (adjusted odds ratio = 0.77, P < 0.001) and Hispanic (adjusted odds ratio = 0.76, P = 0.007) patients were less likely to achieve SVR than white patients, a difference that was not explained by early treatment discontinuations. Among genotype 1-infected patients treated with ledipasvir/sofosbuvir monotherapy, black patients had significantly lower SVR than white patients when treated for 8 weeks but not when treated for 12 weeks. CONCLUSION: Direct-acting antivirals produce high SVR rates in white, black, Hispanic, and Asian/Pacific Islander/American Indian/Alaska Native patients; but after adjusting for baseline characteristics, black race and Hispanic ethnicity remain independent predictors of treatment failure. Short 8-week ledipasvir/sofosbuvir monotherapy regimens should perhaps be avoided in black patients with genotype 1 hepatitis C virus. (Hepatology 2017;65:426-438). PMID- 27775855 TI - A novel approach for osteocalcin detection by competitive ELISA using porous silicon as a substrate. AB - In this study, porous silicon (PSi) was utilized instead of prevalent polystyrene platforms, and its capability in biomolecule screening was examined. Here, two types of porous structure, macroporous silicon (Macro-PSi) and mesoporous silicon (Meso-PSi), were produced on silicon wafers by electrochemical etching using different electrolytes. Moreover, both kinds of fresh and oxidized PSi samples were investigated. Next, osteocalcin as a biomarker of the bone formation process was used as a model biomarker, and the colorimetric detection was performed by competitive enzyme-linked immunosorbent assay (ELISA). Both Macro-PSi and Meso PSi substrates in the oxidized state, specifically the Meso-porous structure, were reported to have higher surface area to volume ratio, more capacitance of surface-antigen interaction, and more ability to capture antigen in comparison with the prevalent platforms. Moreover, the optical density signal of osteocalcin detected by the ELISA technique was notably higher than the common platforms. Based on the findings of this study, PSi can potentially be used in the ELISA to achieve better results and consequently more sensitivity. A further asset of incorporating such a nanometer structure in the ELISA technique is that the system response to analyte concentration could be maintained by consuming lower monoclonal antibody (or antigen) and consequently reduces the cost of the experiment. PMID- 27775856 TI - Identification and characterization of microRNAs in the screwworm flies Cochliomyia hominivorax and Cochliomyia macellaria (Diptera: Calliphoridae). AB - MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression through post-transcriptional regulation. Here, we report the identification and characterization of miRNAs in two closely related screwworm flies with different feeding habits: Cochliomyia hominivorax and Cochliomyia macellaria. The New World screwworm, C. hominivorax, is an obligatory parasite of warm-blooded vertebrates, whereas the secondary screwworm, C. macellaria, is a free-living organism that feeds on decaying organic matter. Here, the small RNA transcriptomes of adults and third-instar larvae of both species were sequenced. A total of 110 evolutionarily conserved miRNAs were identified, and 10 putative precursor miRNAs (pre-miRNAs) were predicted. The relative expression of six selected miRNAs was further investigated, including miRNAs that are related to reproduction and neural processes in other insects. Mature miRNAs were also characterized across an evolutionary time scale, suggesting that the majority of them have been conserved since the emergence of the Arthropoda [540 million years ago (Ma)], Hexapoda (488 Ma) and Brachycera (195 Ma) lineages. This study is the first report of miRNAs for screwworm flies. We also performed a comparative analysis with the hereby predicted miRNAs from the sheep blowfly, Lucilia cuprina. The results presented may advance our understanding of parasitic habits within Calliphoridae and assist further functional studies in blowflies. PMID- 27775857 TI - DNA typing for personal identification of urine after long-term preservation for testing in doping control. AB - When the tampering of a urine sample is suspected in doping control, personal identification of the sample needs to be determined by short tandem repeat (STR) analysis using DNA. We established a method for extracting DNA from urine samples stored at -20 degrees C without using any additives or procedures, which is consistent with how samples are required to be managed for doping control. The method, using the Puregene(r) Blood Core kit followed by NucleoSpin(r) gDNA Clean up or NucleoSpin(r) gDNA Clean-up XS kit, does not need any special instrument and can provide a purified extract with high-quality DNA from up to 40 mL of urine suitable for STR analysis using an AmpFlSTR(r) Identifiler(r) PCR amplification kit. Storing urine at -20 degrees C is detrimental to the stability of DNA. The DNA concentration of preserved urine could not be predicted by specific gravity or creatinine level at the time of urine collection. The DNA concentration of a purified extract (10 MUL) was required to be >0.06 ng/MUL to ensure a successful STR analysis. Thus, the required extraction volumes of urine preserved for 3-7 years at -20 degrees C were estimated to be 30 mL and 20 mL to succeed in at least 86% of men and 91% of women, respectively. Considering the long half-life of DNA during long-term preservation, our extraction method is applicable to urine samples stored even for 10 years, which is currently the storage duration allowed (increased from 8 years) before re-examination in doping control. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27775860 TI - Crystalline, Highly Oriented MOF Thin Film: the Fabrication and Application. AB - The thin film of metal-organic frameworks (MOFs) is a rapidly developing research area which has tremendous potential applications in many fields. One of the major challenges in this area is to fabricate MOF thin film with good crystallinity, high orientation and well-controlled thickness. In order to address this challenge, different appealing approaches have been studied intensively. Among various oriented MOF films, many efforts have also been devoted to developing novel properties and broad applications, such as in gas separator, thermoelectric, storage medium and photovoltaics. As a result, there has been a large demand for fundamental studies that can provide guidance and experimental data for further applications. In this account, we intend to present an overview of current synthetic methods for fabricating oriented crystalline MOF thin film and bring some updated applications. We give our perspective on the background, preparation and applications that led to the developments in this area and discuss the opportunities and challenges of using crystalline, highly oriented MOF thin film. PMID- 27775858 TI - A phosphate starvation-driven bidirectional promoter as a potential tool for crop improvement and in vitro plant biotechnology. AB - Phosphate (Pi)-deficient soils are a major limitant factor for crop production in many regions of the world. Despite that plants have innovated several developmental and biochemical strategies to deal with this stress, there are still massive extensions of land which combine several abiotic stresses, including phosphate starvation, that limit their use for plant growth and food production. In several plant species, a genetic programme underlies the biochemical and developmental responses of the organism to cope with low phosphate (Pi) availability. Both protein- and miRNA-coding genes involved in the adaptative response are transcriptionally activated upon Pi starvation. Several of the responsive genes have been identified as transcriptional targets of PHR1, a transcription factor that binds a conserved cis-element called PHR1-binding site (P1BS). Our group has previously described and characterized a minimal genetic arrangement that includes two P1BS elements, as a phosphate-responsive enhancer (EZ2). Here, we report the engineering and successful use of a phosphate dependent bidirectional promoter, which has been designed and constructed based on the palindromic sequences of the two P1BS elements present in EZ2. This bidirectional promoter has a potential use in both plant in vitro approaches and in the generation of improved crops adapted to Pi starvation and other abiotic stresses. PMID- 27775859 TI - Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein. AB - The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream of the RhoA small GTP-binding protein. As a result, they have key roles in regulating cell morphology and proliferation, and have been implicated in numerous pathological conditions and diseases including hypertension and cancer. Here we describe the generation of a gene-targeted mouse line that enables CRE-inducible expression of a conditionally active fusion between the ROCK2 kinase domain and the hormone-binding domain of a mutated estrogen receptor (ROCK2:ER). This two-stage system of regulation allows for tissue-selective expression of the ROCK2:ER fusion protein, which then requires administration of estrogen analogues such as tamoxifen or 4 hydroxytamoxifen to elicit kinase activity. This conditional gain-of-function system was validated in multiple tissues by crossing with mice expressing CRE recombinase under the transcriptional control of cytokeratin14 (K14), murine mammary tumor virus (MMTV) or cytochrome P450 Cyp1A1 (Ah) promoters, driving appropriate expression in the epidermis, mammary or intestinal epithelia respectively. Given the interest in ROCK signaling in normal physiology and disease, this mouse line will facilitate research into the consequences of ROCK activation that could be used to complement conditional knockout models. Birth Defects Research (Part A) 106:636-646, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27775861 TI - 1,2,3,-Triazole-Based Catalysts: From Metal- to Supramolecular Organic Catalysis. AB - 1,2,3-Triazoles are unique heterocycles with intriguing physical properties that allow not only the coordination to metals, but also the establishment of supramolecular interactions based on their polarized C-H bonds. In this account, an extensive work of our group on the design and application of 1,2,3-triazole catalysts is covered. Initially, a family of BINOL triazoles (Click-BINOLs) was synthesized and employed in model test reactions in asymmetric metal catalysis such as the Ti-catalyzed addition of alkylzinc reagents to aldehydes. The evolution from the Click-BINOLs to a novel class of triazole-based anion-binding organocatalysts is further discussed. Consequently, these catalysts were successfully applied in alkylation reactions, as well as asymmetric dearomatizations of diverse N-heteroarenes. PMID- 27775862 TI - Embracing the mantra of modellers and synthesizing omics, experiments and models. PMID- 27775863 TI - Ruthenium-Catalyzed Metathesis Cascade Reactions in Natural Products Synthesis. AB - In this account, we provide a brief summary of recent developments in ruthenium catalyzed metathesis cascade reactions towards the total synthesis of natural products. We also highlight recent progress from our own laboratory regarding the synthesis of securinega alkaloids and humulanolides, which has resulted in the development of novel ruthenium-catalyzed metathesis cascade reactions. Inspired and guided by the pioneering and elegant research conducted in this area, we developed a regio-controlled relay dienyne metathesis cascade reaction and a cyclobutene-promoted RCM/ROM/RCM cascade reaction for the synthesis of securinega alkaloids and humulanolides, respectively. PMID- 27775864 TI - Cardiogenic Shock Predicts Long-term Mortality in Hospital Survivors of STEMI Treated With Primary Percutaneous Coronary Intervention. AB - BACKGROUND: ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS) has a poor prognosis. Recently published data suggested, however, that CS does not affect long-term mortality in hospital survivors of STEMI. We investigated whether this could be confirmed in a larger cohort. HYPOTHESIS: STEMI complicated by CS leads to worse long-term survival. METHODS: A prospective cohort study was performed in 7412 consecutive patients with STEMI treated by primary percutaneous coronary intervention (angioplasty). The predictive value of CS on long-term mortality was assessed in hospital survivors. Multivariate analysis, adjusting for differences in baseline variables, was performed to assess the independent prognostic value of CS. RESULTS: Cardiogenic shock was observed in 387 patients (5.2%). The total in-hospital mortality was 254 (3.4%), and mortality was significantly higher in patients with CS (20.0% vs 2.6%; P < 0.001). The 1-year mortality in hospital survivors was 10.3% in patients with CS and 3.9% in patients without CS (P < 0.001). After multivariate analysis, CS was still a significant predictor of long-term mortality in hospital survivors (hazard ratio: 2.6, 95% confidence interval: 1.64-4.01). CONCLUSIONS: Cardiogenic shock remains a strong predictor of long-term mortality in hospital survivors of STEMI treated by primary percutaneous coronary intervention. PMID- 27775865 TI - Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12 Month Data. AB - In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs. PMID- 27775866 TI - Characterising genes associated with flowering time in carrot (Daucus carota L.) using transcriptome analysis. AB - Carrot is generally regarded as a biennial plant with an obligatory vernalization requirement. Early spring cultivation makes plants vulnerable to premature bolting, which results in a loss of commercial value. However, our knowledge of flowering time genes and flowering mechanisms in carrot remain limited. Bolting behavior of D. carota ssp. carota 'Songzi', a wild species sensitive to flower induction by vernalization and photoperiod, and orange cultivar 'Amsterdam forcing', and their offspring were investigated in different growing conditions. We performed RNA-seq to identify the flowering time genes, and digital gene expression (DGE) analysis to examine their expression levels. The circadian patterns of related genes were identified by qPCR. The results showed bolting behavior of carrot was influenced by low temperature, illumination intensity and photoperiod. A total of 45 flowering time-related unigenes were identified, which were classified into five categories including photoperiod, vernalization, autonomous and gibberellin pathway, and floral integrators. Homologs of LATE ELONGATED HYPOCOTYL (LHY) and CONSTANS-LIKE 2 (COL2) were more highly expressed under short day condition than under long day condition. Homologs of COL2, CONSTANS-LIKE 5 (COL5), SUPPRESSION OF OVEREXPRESSION OF CONSTANS 1 (SOC1), FLOWERING LOCUS C (FLC) and GIBBERELLIC ACID INSENSITIVE (GAI) were differentially expressed between 'Songzi' and 'Amsterdam forcing'. The homolog of COL2 (Dct43207) was repressed by light, but that of COL5 (Dct20940) was induced. A preliminary model of genetic network controlling flowering time was constructed by associating the results of DGE analysis with correlation coefficients between genes. This study provides useful information for further investigating the genetic mechanism of flowering in carrot. PMID- 27775867 TI - Alpha-gal is a possible target of IgE-mediated reactivity to antivenom. AB - BACKGROUND: Antivenoms are mammalian immunoglobulins with the ability to neutralize snake venom components and to mitigate the progression of toxic effects. Immediate hypersensitivity to antivenoms often occurs during the first administration of these heterologous antibodies. A comparable clinical situation occurred after introduction of cetuximab, a chimeric mouse-human antibody, for cancer treatment. The carbohydrate epitope galactose-alpha-1,3-galactose, located on the Fab region of cetuximab, was identified as the target responsible for IgE reactivity. OBJECTIVE: To investigate whether serum IgE antibodies directed to the alpha-gal epitope are associated with hypersensitivity to equine antivenoms. METHODS: Antivenoms were screened for alpha-gal epitopes via immunoblot and in comparison with cetuximab and pork kidney by IgE reactivity assays. Basophil activation tests were used to investigate reactivity to antivenoms in samples from 20 patients with specific IgE antibodies to alpha-gal and 10 controls. Additional IgE detection, IgE inhibition, ImmunoCAP inhibition, and skin prick tests were performed using samples from selected patients. RESULTS: Both antivenoms and cetuximab induced positive skin prick test results in patients with sIgE to alpha-gal. Alpha-gal epitopes were detected by immunoblotting on antivenoms. Measurements of IgE reactivity and ImmunoCAP inhibition indicated that the antivenoms contained lower alpha-gal contents than cetuximab. Deglycosylation assays and IgE inhibition tests confirmed that IgE-mediated reactivity to antivenom is associated with alpha-gal. Antivenoms, pork kidney, and cetuximab activated basophils from patients with IgE to alpha-gal. CONCLUSION: Alpha-gal is a potential target of IgE-mediated reactivity to equine antivenom and a possible cause of the high incidence of hypersensitivity reactions during the first application of equine antivenom. PMID- 27775868 TI - Migrating SSU rRNA gene surveys to the metagenomics era. PMID- 27775870 TI - Arterial Blood Supply of Liver Segment IV and Its Possible Surgical Consequences. AB - The risk of ischemia of segment IV after split liver resection is high. This anatomical study was done to identify the arterial blood supply and the intrahepatic distribution of liver segment IV. The anatomy of segment IV was studied in 29 livers from adult cadavers. To identify the arterial blood supply of segment IV, water and ink were injected into the various branches of the hepatic artery and the outflow through segment IV and discoloration of the liver parenchyma were observed. In 23 of the 29 livers (79.3%), the arterial perfusion of segment IV was separated by a line drawn from the left side of the inferior vena cava at the top of and lateral to the falciform ligament to the medial point of the gallbladder bed. The area lateral to this line was supplied mainly by the right hepatic artery, and the area medial to it was supplied mainly by the left hepatic artery. In addition to the classification system of Couinaud, we describe here a new division of liver segment IV based on arterial blood supply. These anatomical findings may be useful in defining the resection line for split liver to prevent necrosis of segment IV. PMID- 27775869 TI - Degradation of lignin beta-aryl ether units in Arabidopsis thaliana expressing LigD, LigF and LigG from Sphingomonas paucimobilis SYK-6. AB - Lignin is a major polymer in the secondary plant cell wall and composed of hydrophobic interlinked hydroxyphenylpropanoid units. The presence of lignin hampers conversion of plant biomass into biofuels; plants with modified lignin are therefore being investigated for increased digestibility. The bacterium Sphingomonas paucimobilis produces lignin-degrading enzymes including LigD, LigF and LigG involved in cleaving the most abundant lignin interunit linkage, the beta-aryl ether bond. In this study, we expressed the LigD, LigF and LigG (LigDFG) genes in Arabidopsis thaliana to introduce postlignification modifications into the lignin structure. The three enzymes were targeted to the secretory pathway. Phenolic metabolite profiling and 2D HSQC NMR of the transgenic lines showed an increase in oxidized guaiacyl and syringyl units without concomitant increase in oxidized beta-aryl ether units, showing lignin bond cleavage. Saccharification yield increased significantly in transgenic lines expressing LigDFG, showing the applicability of our approach. Additional new information on substrate specificity of the LigDFG enzymes is also provided. PMID- 27775871 TI - Overexpression of the 16-kDa alpha-amylase/trypsin inhibitor RAG2 improves grain yield and quality of rice. AB - Increasing grain yield and improving grain quality are two important goals for rice breeding. A better understanding of the factors that contribute to the overall grain quantity and nutritional quality of rice will lay the foundation for developing new breeding strategies. RAG2 is a member of 14-to-16-kDa alpha amylase/trypsin inhibitors in rice, which belong to the albumin of seed storage proteins. We found that RAG2 was specifically expressed in ripening seed and its transcription peak was between 14 and 21 days after flowering. Grain size and 1000-grain weight were obviously increased in RAG2-overexpressed lines compared with wild type, and grain size was reduced in RAG2-suppressed lines. In addition, the major storage substances of the seeds differed significantly in RAG2 overexpressed and RAG2-suppressed lines compared to wild type. The protein content and amount of total lipids were increased and decreased, respectively, in the seeds of RAG2-overexpressed and RAG2-suppressed lines. Overexpression of RAG2 significantly increased grain size and improved grain quality and yield simultaneously. These results imply that RAG2 might play an important role in regulating grain weight and seed quality of rice. The functional characterization of rice RAG2 facilitates a further understanding of the mechanisms involved in grain size and seed quality and may be helpful in improving grain yield and quantity in cereal crops. PMID- 27775872 TI - ATP/pH Dual Responsive Nanoparticle with d-[des-Arg10 ]Kallidin Mediated Efficient In Vivo Targeting Drug Delivery. AB - Inflammation has been reported as one significant hallmark of breast cancer in relation to tumor development, metastasis, and invasion. The bradykinin receptor 1 (B1R) is highly expressed on inflammatory breast tumor cells thus providing a promising targeting site for tumor recognition and sufficient receptor mediated endocytosis. In this study, the authors evaluate the targeting efficiency of l form and d-form [des-Arg10 ]kallidin both in vitro and in vivo. To further improve the drug delivery efficiency, the authors establish a dandelion like nanoparticle by combining the polymeric drug conjugates and aptamer complex together. The doxorubicin conjugated polymer is complexed with adenosine-5' triphosphate (ATP) sensitive hybridized aptamer in self-assembly process by intercalating into the double strand scaffolds. The acid labile conjugating bond and ATP sensitive aptamer endow the nanoparticle with dual responsiveness to intracellular milieu, thus triggering a quick drug release in tumor cells. Remarkable therapeutic effects and tuned in vivo pharmacokinetics profiles are shown by the aptamer complexed drug conjugates nanoparticle with B1R active targeting modification. Therefore the strategies of B1R targeting and ATP/pH dual responsiveness nanoparticle help achieve enhanced drug accumulation within tumor cells and efficient chemotherapy for breast cancer. PMID- 27775873 TI - Generation and characterization of mice bearing null alleles of nradd/Nrh2. AB - The Neurotrophin receptor associated death domain gene (Nradd/Nrh2/Plaidd) is a type I transmembrane protein with a unique and short N-terminal extracellular domain and a transmembrane and intracellular domain that bears high similarity to the p75 neurotrophin receptor (p75NTR/Ngfr). Initial studies suggested that NRADD regulates neurotrophin signaling but very little is known about its physiological roles. We have generated and characterized NRADD conditional and germ-line null mouse lines. These mice are viable and fertile and dont show evident abnormalities. However, NRADD deletion results in an increase in the proportion of dorsal root ganglion neurons expressing p75NTR. The NRADD conditional and complete knockout mouse lines generated are new and useful tools to study the physiological roles of NRADD. Birth Defects Research (Part A) 106:605-612, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27775874 TI - Cooperative Trifunctional Organocatalysts for Proficient Proton Transfer Reactions. AB - Cooperativity is essential to proficient catalysis, and designing biomimetic, cooperative catalysis is a major avenue to finding new and efficient chemical reactions with practical applications. One challenge in designed cooperative catalysis is to access high catalytic proficiency (large enhancement in both rate and enantioselectivity) as seen in biocatalysis. Here described is an approach of developing and investigating trifunctional organocatalysts with three distinct catalytic functionalities, in order to understand how cooperativity could be organized for enantioselective activation that confers the observed proficiency in a tandem Michael-aldol-proton transfer elimination model reaction. This in future may assist in finding not just cooperative but also regulated catalysis to expand the level of catalytic complexity and efficiency in biomimetic systems. PMID- 27775875 TI - Accessories make the microbe. PMID- 27775876 TI - A Route to Permanent Valley Polarization in Monolayer MoS2. AB - Realization of permanent valley polarization in Cr-doped monolayer MoS2 is found to be unfeasible because of extended moment formation. Introduction of an additional hole is suggested as a viable solution. V-doped monolayer MoS2 is demonstrated to sustain permanent valley polarization and therefore can serve as a prototype material for valleytronics. PMID- 27775877 TI - Genome resources for climate-resilient cowpea, an essential crop for food security. AB - Cowpea (Vigna unguiculata L. Walp.) is a legume crop that is resilient to hot and drought-prone climates, and a primary source of protein in sub-Saharan Africa and other parts of the developing world. However, genome resources for cowpea have lagged behind most other major crops. Here we describe foundational genome resources and their application to the analysis of germplasm currently in use in West African breeding programs. Resources developed from the African cultivar IT97K-499-35 include a whole-genome shotgun (WGS) assembly, a bacterial artificial chromosome (BAC) physical map, and assembled sequences from 4355 BACs. These resources and WGS sequences of an additional 36 diverse cowpea accessions supported the development of a genotyping assay for 51 128 SNPs, which was then applied to five bi-parental RIL populations to produce a consensus genetic map containing 37 372 SNPs. This genetic map enabled the anchoring of 100 Mb of WGS and 420 Mb of BAC sequences, an exploration of genetic diversity along each linkage group, and clarification of macrosynteny between cowpea and common bean. The SNP assay enabled a diversity analysis of materials from West African breeding programs. Two major subpopulations exist within those materials, one of which has significant parentage from South and East Africa and more diversity. There are genomic regions of high differentiation between subpopulations, one of which coincides with a cluster of nodulin genes. The new resources and knowledge help to define goals and accelerate the breeding of improved varieties to address food security issues related to limited-input small-holder farming and climate stress. PMID- 27775878 TI - Identification and Expression Analysis of Tryptophan Hydroxylase in the Brain and Ventral Nerve Cord of Ragworm Neanthes japonica (Polychaeta, Annelida). AB - Tryptophan hydroxylase (TPH) was stained in the central nervous system of the Neanthes japonica (Polychaeta, Annelida), using sheep anti-tryptophan hydroxylase antibody by the Streptavidin-Peroxidase immunohistochemical method and Colophony Paraffin embedded section technique. The immunohistochemistry results revealed that the TPH is distributed in the brain and ventral nerve cord, which is consistent with that of serotonin (5-hydroxytryptamine, 5-HT) that labeled by anti-serotonin antibody. Using the rapid amplification of cDNA ends (RACE) technique, TPH cDNA cloned from Neanthes japonica's central nervous system was 1778bp, which encodes predicted protein of 463 amino acid residues. The co localization of TPH and 5-HT indicated that the specific TPH was responsible for the central serotonin synthesis in the central nervous system of annelida, TPH and 5-HT not only could be as the novel mutual corroboration marker to detect serotonergic neurons, but also provides the evidences for the evolution of aromatic amino acid hydroxylase genes. Anat Rec, 300:415-424, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27775879 TI - MicroRNA-203 inhibits tumour growth and metastasis through PDPN. AB - OBJECTIVE: MicroRNAs play an important role in regulating hypopharyngeal cancer development. miR-203 has been previously shown to possess antitumour capabilities in many cancers, but not in hypopharyngeal cancer. DESIGN: Using human normal and hypopharyngeal cancer specimens, we explored the expression levels of miR-203 in the two groups and further correlated them with different stages of cancer and lymph node metastasis. SETTING AND PARTICIPANTS: Applying human pharynx FaDu cancer cells and lentiviral transduction technique, we investigated the effects of miR-203 on cancer cell viability, migration and invasion. Moreover, we studied the novel relationship between miR-203 and podoplanin (PDPN) in hypopharyngeal cancer. RESULTS: The downregulated levels of miR-203 in human hypopharyngeal cancer tissues were associated with advanced cancer stages and lymph node metastasis. High levels of miR-203 inhibited cell viability, migration and invasion of hypopharyngeal cancer cells. Further studies suggested miR-203 directly targeted and inhibited PDPN expression. PDPN silencing suppresses hypopharyngeal cancer cell abilities. In addition, PDPN overexpression was able to reverse miR-203 inhibitory effects on cell viability, migration and invasion. CONCLUSION: PDPN acts as an oncogene to promote hypopharyngeal cancer cell viability, migration and invasion. miR-203 directly targets PDPN to suppress its expression, thus exerting inhibitory effects on cancer metastasis. PMID- 27775881 TI - Ni-C-N Nanosheets as Catalyst for Hydrogen Evolution Reaction. AB - We report a facile nitrogenation/exfoliation process to prepare hybrid Ni-C-N nanosheets. These nanosheets are <2 nm thin, chemically stable, and metallically conductive. They serve as a robust catalyst for the hydrogen evolution reaction in 0.5 M H2SO4, or 1.0 M KOH or 1.0 M PBS (pH = 7). For example, they catalyze the hydrogen evolution reaction in 0.5 M H2SO4 at an onset potential of 34.7 mV, an overpotential of 60.9 mV (at j = 10 mA cm-2) and with remarkable long-term stability (~10% current drop after 70 h testing period). They are promising as a non-Pt catalyst for practical hydrogen evolution reaction. PMID- 27775880 TI - Oculocutaneous albinism type 1: link between mutations, tyrosinase conformational stability, and enzymatic activity. AB - Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism. PMID- 27775883 TI - A Hybrid Monte Carlo Scheme for Multibackbone Protein Design. AB - Multistate protein design explores side chain mutations, with the backbone allowed to sample a small, predetermined library of conformations. To achieve Boltzmann sampling of sequences and conformations, we use a hybrid Monte Carlo (MC) scheme: a trial hop between backbone models is followed by a short MC segment where side chain rotamers adjust to the new backbone, before applying a Metropolis-like acceptance test. The theoretical form and a practical approximation for the acceptance test are derived. We then compute backbone conformational free energies for two SH2 and SH3 proteins using different routes and protocols, and verify that for simple test problems, the free energy behaves like a state function, a hallmark of Boltzmann sampling. PMID- 27775882 TI - Application of Noncanonical Amino Acids for Protein Labeling in a Genomically Recoded Escherichia coli. AB - Small synthetic fluorophores are in many ways superior to fluorescent proteins as labels for imaging. A major challenge is to use them for a protein-specific labeling in living cells. Here, we report on our use of noncanonical amino acids that are genetically encoded via the pyrrolysyl-tRNA/pyrrolysyl-RNA synthetase pair at artificially introduced TAG codons in a recoded E. coli strain. The strain is lacking endogenous TAG codons and the TAG-specific release factor RF1. The amino acids contain bioorthogonal groups that can be clicked to externally supplied dyes, thus enabling protein-specific labeling in live cells. We find that the noncanonical amino acid incorporation into the target protein is robust for diverse amino acids and that the usefulness of the recoded E. coli strain mainly derives from the absence of release factor RF1. However, the membrane permeable dyes display high nonspecific binding in intracellular environment and the electroporation of hydrophilic nonmembrane permeable dyes severely impairs growth of the recoded strain. In contrast, proteins exposed on the outer membrane of E. coli can be labeled with hydrophilic dyes with a high specificity as demonstrated by labeling of the osmoporin OmpC. Here, labeling can be made sufficiently specific to enable single molecule studies as exemplified by OmpC single particle tracking. PMID- 27775884 TI - Hyaluronate-Epidermal Growth Factor Conjugate for Skin Wound Healing and Regeneration. AB - Epidermal growth factor (EGF) has been recognized as an excellent wound healing agent due to its therapeutic function stimulating skin cell growth, proliferation and differentiation. However, the transdermal delivery of EGF poses a significant challenge due to its short half-life and lack of efficient formulation. Here, to improve the transdermal delivery efficiency, EGF was conjugated to hyaluronate (HA), which was formulated into a patch-type film for skin wound healing. HA-EGF conjugate was synthesized by coupling reaction between aldehyde-modified HA and N terminal amine group of EGF to minimize the loss of biological activities. The HA EGF conjugates exhibited similar biological activities with native EGF as confirmed by ELISA and proliferation tests using murine and human fibroblasts. For the efficient topical delivery, HA-EGF conjugates were incorporated into a matrix film of high molecular weight HA. Two-photon microscopy clearly visualized more efficient transdermal delivery of HA-EGF conjugates to both normal skin and peripheral tissues around the wound area rather than that of EGF. Optical imaging and ELISA after in vivo transdermal delivery showed that the conjugation of EGF to HA retarded its degradation and extended its residence time in the wound area. Furthermore, in vivo transdermal delivery of HA-EGF conjugate in the patch-type HA film resulted in significantly improved regeneration of skin tissues even into hypodermis. PMID- 27775885 TI - Noncovalent Bonding Controls Selectivity in Heterogeneous Catalysis: Coupling Reactions on Gold. AB - Enhancing the selectivity of catalytic processes has potential for substantially increasing the sustainability of chemical production. Herein, we establish relationships between reaction selectivity and molecular structure for a homologous series of key intermediates for oxidative coupling of alcohols on gold using a combination of experiment and theory. We establish a scale of binding for molecules with different alkyl structures and chain lengths and thereby demonstrate the critical nature of noncovalent van der Waals interactions in determining the selectivity by modulating the stability of key reaction intermediates bound to the surface. The binding hierarchy is the same for Au(111) and Au(110), which demonstrates a relative lack of sensitivity to the surface structure. The hierarchy of binding established in this work provides guiding principles for predicting how molecular structure affects the competition for binding sites more broadly. Besides the nature of the primary surface-molecule bonding, three additional factors that affect the stabilities of the reactive intermediates are clearly established: (1) the number of C atoms in the alkyl chain, (2) the presence of C-C bond unsaturation, and (3) the degree of branching of the alkyl group of the adsorbed molecules. We suggest that this is a fundamental principle that is generally applicable to a broad range of reactions on metal catalysts. PMID- 27775886 TI - Visualizing the Role of Molecular Orbitals in Charge Transport through Individual Diarylethene Isomers. AB - Diarylethene molecules are prototype molecular switches with their two isomeric forms exhibiting strikingly different conductance, while maintaining similar length. We employed low-temperature scanning tunneling microscopy (STM) to resolve the energy and the spatial extend of the molecular orbitals of the open and closed isomers when lying on a Au(111) surface. We find an intriguing difference in the extension of the respective HOMOs and a peculiar energy splitting of the formerly degenerate LUMO of the open isomer. We then lift the two isomers with the tip of the STM and measure the current through the individual molecules. By a simple analytical model of the transport, we show that the previously determined orbital characteristics are essential ingredients for the complete understanding of the transport properties. We also succeeded in switching the suspended molecules by the current, while switching the ones which are in direct contact to the surface occurs nonlocally with the help of the electric field of the tip. PMID- 27775887 TI - In Situ TEM Analysis of Organic-Inorganic Metal-Halide Perovskite Solar Cells under Electrical Bias. AB - Changes in the nanostructure of methylammonium lead iodide (MAPbI3) perovskite solar cells are assessed as a function of current-voltage stimulus by biasing thin samples in situ in a transmission electron microscope. Various degradation pathways are identified both in situ and ex situ, predominantly at the positively biased MAPbI3 interface. Iodide migrates into the positively biased charge transport layer and also volatilizes along with organic species, which triggers the nucleation of PbI2 nanoparticles and voids and hence decreases the cell performance. PMID- 27775888 TI - Effect of Sodium Sulfate, Ammonium Chloride, Ammonium Nitrate, and Salt Mixtures on Aqueous Phase Partitioning of Organic Compounds. AB - Dissolved inorganic salts influence the partitioning of organic compounds into the aqueous phase. This influence is especially significant in atmospheric aerosol, which usually contains large amounts of ions, including sodium, ammonium, chloride, sulfate, and nitrate. However, empirical data on this salt effect are very sparse. Here, the partitioning of numerous organic compounds into solutions of Na2SO4, NH4Cl, and NH4NO3 was measured and compared with existing data for NaCl and (NH4)2SO4. Salt mixtures were also tested to establish whether the salt effect is additive. In general, the salt effect showed a decreasing trend of Na2SO4 > (NH)2SO4 > NaCl > NH4Cl > NH4NO3 for the studied organic compounds, implying the following relative strength of the salt effect of individual anions: SO42- > Cl- > NO3- and of cations: Na+ > NH4+. The salt effect of different salts is moderately correlated. Predictive models for the salt effect were developed based on the experimental data. The experimental data indicate that the salt effect of mixtures may not be entirely additive. However, the deviation from additivity, if it exists, is small. Data of very high quality are required to establish whether the effect of constituent ions or salts is additive or not. PMID- 27775889 TI - Quantum Tunneling Rates of Gas-Phase Reactions from On-the-Fly Instanton Calculations. AB - The instanton method obtains approximate tunneling rates from the minimum-action path (known as the instanton) linking reactants to the products at a given temperature. An efficient way to find the instanton is to search for saddle points on the ring-polymer potential surface, which is obtained by expressing the quantum Boltzmann operator as a discrete path-integral. Here we report a practical implementation of this ring-polymer form of instanton theory into the Molpro electronic-structure package, which allows the rates to be computed on-the fly, without the need for a fitted analytic potential-energy surface. As a test case, we compute tunneling rates for the benchmark H + CH4 reaction, showing how the efficiency of the instanton method allows the user systematically to converge the tunneling rate with respect to the level of electronic-structure theory. PMID- 27775891 TI - Mechanisms of Bond Cleavage during Manganese Oxide and UV Degradation of Glyphosate: Results from Phosphate Oxygen Isotopes and Molecular Simulations. AB - Degradation of glyphosate in the presence of manganese oxide and UV light was analyzed using phosphate oxygen isotope ratios and density function theory (DFT). The preference of C-P or C-N bond cleavage was found to vary with changing glyphosate/manganese oxide ratios, indicating the potential role of sorption induced conformational changes on the composition of intermediate degradation products. Isotope data confirmed that one oxygen atom derived solely from water was incorporated into the released phosphate during glyphosate degradation, and this might suggest similar nucleophilic substitution at P centers and C-P bond cleavage both in manganese oxide- and UV light-mediated degradation. The DFT results reveal that the C-P bond could be cleaved by water, OH- or *OH, with the energy barrier opposing bond dissociation being lowest in the presence of the radical species, and that C-N bond cleavage is favored by the formation of both nitrogen- and carbon-centered radicals. Overall, these results highlight the factors controlling the dominance of C-P or C-N bond cleavage that determines the composition of intermediate/final products and ultimately the degradation pathway. PMID- 27775890 TI - Injectable Polypeptide Hydrogels with Tunable Microenvironment for 3D Spreading and Chondrogenic Differentiation of Bone-Marrow-Derived Mesenchymal Stem Cells. AB - Bone-marrow-derived mesenchymal stem cells (BMSCs) possess vast potential for tissue engineering and regenerative medicine. In this study, an injectable hydrogel comprising poly(l-glutamic acid)-graft-tyramine (PLG-g-TA) with tunable microenvironment was developed via enzyme-catalyzed cross-linking and used as an artificial extracellular matrix (ECM) to explore the behaviors of BMSCs during three-dimensional (3D) culture. It was found that the mechanical property, porous structure as well as degradation process of the hydrogels could be tuned by changing the copolymer concentration. The PLG-g-TA hydrogels showed good cytocompatibility in vitro. After being subcutaneously injected into the back of rats, the hydrogels degraded gradually within 8 weeks and exhibited good biocompatibility in vivo. BMSCs were then encapsulated in the polypeptide-based hydrogels with different copolymer concentration to investigate the influence of 3D matrix microenvironment on stem cell behaviors. It is intriguing to note that the BMSCs within the 2% hydrogel showed a well-spread morphology after 24 h and a higher proliferation rate during 7 days of culture, in contrast to a rounded morphology and lower proliferation rate of BMSCs in the 4% hydrogel. Furthermore, the hydrogels with different microenvironment also regulated the matrix biosynthesis and the gene expression of BMSCs. After incubation in the 2% hydrogel for 4 weeks, the BMSCs produced more type II collagen and expressed higher amounts of chondrogenic markers, compared to the cells in the 4% hydrogel. Therefore, the PLG-g-TA hydrogels with tunable microenvironment may serve as an efficient 3D platform for guiding the lineage specification of BMSCs. PMID- 27775892 TI - Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction. AB - Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2' pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3' (3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI 0252). PMID- 27775893 TI - 5L-Scale Magnesio-Milling Reduction of Nanostructured SiO2 for High Capacity Silicon Anodes in Lithium-Ion Batteries. AB - Nanostructured silicon (Si) is useful in many applications and has typically been synthesized by bottom-up colloid-based solution processes or top-down gas phase reactions at high temperatures. These methods, however, suffer from toxic precursors, low yields, and impractical processing conditions (i.e., high pressure). The magnesiothermic reduction of silicon oxide (SiO2) has also been introduced as an alternative method. Here, we demonstrate the reduction of SiO2 by a simple milling process using a lab-scale planetary-ball mill and industry scale attrition-mill. Moreover, an ignition point where the reduction begins was consistently observed for the milling processes, which could be used to accurately monitor and control the reaction. The complete conversion of rice husk SiO2 to high purity Si was demonstrated, taking advantage of the rice husk's uniform nanoporosity and global availability, using a 5L-scale attrition-mill. The resulting porous Si showed excellent performance as a Li-ion battery anode, retaining 82.8% of the initial capacity of 1466 mAh g-1 after 200 cycles. PMID- 27775894 TI - A Book-Type Dried Plasma Spot Card for Automated Flow-Through Elution Coupled with Online SPE-LC-MS/MS Bioanalysis of Opioids and Stimulants in blood. AB - Despite many benefits including simple point-of-care sample collection, reduced costs, and simplified shipping and storage, dried blood spot (DBS) techniques have faced adoption resistance due to factors such as the hematocrit (Hct) effects and the established preference for bioanalysis of plasma rather than whole blood. One way to potentially circumvent these challenges is to adopt the concept of dried plasma spot (DPS) techniques. One approach to accomplishing this is through an on-card red blood cell (RBC) filtration to generate plasma from whole blood without the need for centrifugation. In this report, a book-type DPS card has been developed and validated by employing fully automated flow-through elution coupled with online SPE-LC-ESI-MS/MS for the quantitative determination of four representative opioids (morphine, codeine, oxycodone, hydrocodone) and five stimulants (amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), phentermine, and mephedrone) in one method using their corresponding deuterium-labeled analogues as internal standards. Method validation results showed good linearity (R2 >= 0.9963) ranging from 5 to 1000 ng/mL. Intraday and interday precision and accuracy were within the acceptable limits at four quality control (QC) levels. Extraction recovery was >=87.9% at both the lower limit of quantitation (LLOQ) and the upper limit of quantitation (ULOQ) along with acceptable selectivity and sensitivity. DPS on-card short-term stability was compound-dependent and storage-dependent. The additional benefits of the validated book-type DPS card include a wider applicability range of Hct (30% to 60%), automated online analysis compatibility, and a higher plasma volume yield. PMID- 27775895 TI - Hierarchical Assembly of Bioactive Amphiphilic Molecule Pairs into Supramolecular Nanofibril Self-Supportive Scaffolds for Stem Cell Differentiation. AB - Molecular design of biomaterials with unique features recapitulating nature's niche to influence biological activities has been a prolific area of investigation in chemistry and material science. The extracellular matrix (ECM) provides a wealth of bioactive molecules in supporting cell proliferation, migration, and differentiation. The well-patterned fibril and intertwining architecture of the ECM profoundly influences cell behavior and development. Inspired by those features from the ECM, we attempted to integrate essential biological factors from the ECM to design bioactive molecules to construct artificial self-supportive ECM mimics to advance stem cell culture. The synthesized biomimic molecules are able to hierarchically self-assemble into nanofibril hydrogels in physiological buffer driven by cooperative effects of electrostatic interaction, van der Waals forces, and intermolecular hydrogen bonds. In addition, the hydrogel is designed to be degradable during cell culture, generating extra space to facilitate cell migration, expansion, and differentiation. We exploited the bioactive hydrogel as a growth-factor-free scaffold to support and accelerate neural stem cell adhesion, proliferation, and differentiation into functional neurons. Our study is a successful attempt to entirely use bioactive molecules for bottom-up self-assembly of new biomaterials mimicking the ECM to directly impact cell behaviors. Our strategy provides a new avenue in biomaterial design to advance tissue engineering and cell delivery. PMID- 27775896 TI - Detection of Traumatic Bone Marrow Lesions after Knee Trauma: Comparison of ADC Maps Derived from Diffusion-weighted Imaging with Standard Fat-saturated Proton Density-weighted Turbo Spin-Echo Sequences. AB - Purpose To compare single-shot echo-planar diffusion-weighted imaging-derived apparent diffusion coefficient (ADC) maps with fat-saturated (FS) proton density (PD)-weighted turbo spin-echo (TSE) imaging in the detection of bone marrow lesions (BMLs) after knee trauma. Materials and Methods Institutional review board approval was obtained from Leipzig University. Written informed consent was waived. Three radiologists retrospectively re-examined 97 consecutive patients with reported knee trauma who underwent 1.5-T magnetic resonance (MR) imaging within 90 days of knee trauma. The following sequences were used: (a) sagittal T1 weighted TSE and FS PD-weighted TSE and (b) sagittal T1-weighted TSE and single shot echo-planar diffusion-weighted imaging-derived ADC mapping. BMLs on the lateral and medial femoral condyle, lateral and medial aspect of the tibial plateau, and patella were documented. Volumetry was performed on BMLs with a thickness of at least 15 mm (major BMLs). ADC values were measured in intact bone marrow and major BMLs. A McNemar test and t tests were used as appropriate to test for significant differences between BML number and volume at an alpha level of .05. Results Significantly more patients showed at least one BML on ADC maps (98%, 95 of 97 patients) than on FS PD-weighted TSE images (86%, 84 of 97 patients) (P < .001). Of the affected regions detected on FS PD-weighted TSE images, 97% (170 of 175 regions) were identified consistently on ADC maps. Only 58% of the affected regions detected on ADC maps (170 of 293 regions) were identified on FS PD-weighted TSE images (P < .001). Median volume of concordant major BML was approximately two times larger on ADC maps (81 cm3) than on FS PD weighted TSE images (39 cm3) (P < .001). The ADC values of intact bone marrow and BMLs did not overlap. Conclusion ADC maps are more sensitive than corresponding FS PD-weighted TSE images for detection of BML after knee trauma and allow detection of significantly more and larger BMLs. ADC map evaluation improves diagnostic performance in regions with insufficient spectral fat saturation, such as the patella. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27775897 TI - Diagnostic Accuracy of a Fluid-attenuated Inversion-Recovery Sequence with Fat Suppression for Assessment of Peripatellar Synovitis: Preliminary Results and Comparison with Contrast-enhanced MR Imaging. AB - Purpose To determine the agreement of fat-suppressed (FS) fluid-attenuated inversion-recovery (FLAIR) magnetic resonance (MR) imaging and contrast material enhanced (CE) T1-weighted MR imaging for the assessment of peripatellar synovitis. Materials and Methods The institutional review board approved this retrospective study and waived the requirement for patient informed consent. Thirty-three patients with knee pain underwent 3-T MR imaging. The protocol consisted of routine clinical sequences followed by the FLAIR FS sequence (inversion time, 2200 msec) and CE T1-weighted imaging. Visibility of the synovium, synovial thickness, and severity of synovitis in five peripatellar regions were assessed with both sequences. Hoffa synovitis on unenhanced MR images was also analyzed. Then, correlations and agreements between FLAIR FS and CE T1-weighted imaging were evaluated. Diagnostic performance statistics of FLAIR FS and Hoffa synovitis were calculated by using CE T1-weighted imaging as the reference standard. Results Peripatellar synovitis on FLAIR FS images was found in 14 patients by reader 1 and in 17 patients by reader 2. Strong correlations were found between FLAIR FS and CE T1-weighted imaging in the assessment of peripatellar synovitis by both readers (correlation coefficient, 0.675-0.973). With CE T1-weighted imaging as the reference standard, FLAIR FS showed relatively good diagnostic performance for the detection of synovitis of any severity (accuracy of 92.1%-93.9% at the site level and 90.9% at the patient level), while Hoffa synovitis on unenhanced MR images showed moderate sensitivity (78.9%-87.5%) and low specificity (47.1%-64.3%) for the detection of peripatellar synovitis. There was good agreement between the two readers for the synovial visibility (weighted kappa = 0.81-0.88) and synovitis assessments (intraclass correlation coefficient = 0.95, weighted kappa = 0.72-0.79) on FLAIR FS and CE T1-weighted images. Conclusion Our preliminary study shows that FLAIR FS imaging can potentially enable evaluation of inflamed synovium with high sensitivity and specificity, without the injection of a contrast agent. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27775898 TI - Managing Acute Complications Of Sickle Cell Disease In Pediatric Patients. AB - Sickle cell disease is a chronic hematologic disease with a variety of acute, and often recurring, complications. Vaso-occlusive crisis, a unique but common presentation in sickle cell disease, can be challenging to manage. Acute chest syndrome is the leading cause of death in patients with sickle cell disease, occurring in more than half of patients who are hospitalized with a vaso occlusive crisis. Uncommon diagnoses in children, such as stroke, priapism, and transient red cell aplasia, occur more frequently in patients with sickle cell disease and necessitate a degree of familiarity with the disease process and its management. Patients with sickle cell trait generally have a benign course, but are also subject to serious complications. This issue provides a current review of evidence-based management of the most common acute complications of sickle cell disease seen in pediatric patients in the emergency department. PMID- 27775899 TI - Directed Functional Brain Connectivity Based on EEG Source Imaging: Methodology and Application to Temporal Lobe Epilepsy. AB - OBJECTIVE: The importance of functional brain connectivity to study physiological and pathological brain activity has been widely recognized. Here, we aimed to 1) review a methodological pipeline to investigate directed functional connectivity between brain regions using source signals derived from high-density EEG; 2) elaborate on some methodological challenges; and 3) apply this pipeline to temporal lobe epilepsy (TLE) patients and healthy controls to investigate directed functional connectivity differences in the theta and beta frequency bands during EEG epochs without visible pathological activity. METHODS: The methodological pipeline includes: EEG acquisition and preprocessing, electrical source imaging (ESI) using individual head models and distributed inverse solutions, parcellation of the gray matter in regions of interest, fixation of the dipole orientation for each region, computation of the spectral power in the source space, and directed functional connectivity estimation using Granger causal modeling. We specifically analyzed how the signal-to-noise ratio (SNR) changes using different approaches for the dipole orientation fixation. We applied this pipeline to 20 left TLE patients, 20 right TLE patients, and 20 healthy controls. RESULTS: Projecting each dipole to the predominant dipole orientation leads to a threefold SNR increase as compared to the norm of the dipoles. By comparing connectivity in TLE versus controls, we found significant frequency-specific outflow differences in physiologically plausible regions. CONCLUSION: The results suggest that directed functional connectivity derived from ESI can help better understand frequency-specific resting-state network alterations underlying focal epilepsy. SIGNIFICANCE: EEG-based directed functional connectivity could contribute to the search of new biomarkers of this disorder. PMID- 27775902 TI - Methods of Generating Submicrometer Phase-Shift Perfluorocarbon Droplets for Applications in Medical Ultrasonography. AB - Continued advances in the field of ultrasound and ultrasound contrast agents have created new approaches to imaging and medical intervention. Phase-shift perfluorocarbon droplets, which can be vaporized by ultrasound energy to transition from the liquid to the vapor state, are one of the most highly researched alternatives to clinical ultrasound contrast agents (i.e., microbubbles). In this paper, part of a special issue on methods in biomedical ultrasonics, we survey current techniques to prepare ultrasound-activated nanoscale phase-shift perfluorocarbon droplets, including sonication, extrusion, homogenization, microfluidics, and microbubble condensation. We provide example protocols and discuss advantages and limitations of each approach. Finally, we discuss best practice in characterization of this class of contrast agents with respect to size distribution and ultrasound activation. PMID- 27775903 TI - Contrast Enhanced Superharmonic Imaging for Acoustic Angiography Using Reduced Form-Factor Lateral Mode Transmitters for Intravascular and Intracavity Applications. AB - Techniques to image the microvasculature may play an important role in imaging tumor-related angiogenesis and vasa vasorum associated with vulnerable atherosclerotic plaques. However, the microvasculature associated with these pathologies is difficult to detect using traditional B-mode ultrasound or even harmonic imaging due to small vessel size and poor differentiation from surrounding tissue. Acoustic angiography, a microvascular imaging technique that utilizes superharmonic imaging (detection of higher order harmonics of microbubble response), can yield a much higher contrast-to-tissue ratio than second harmonic imaging methods. In this paper, two dual-frequency transducers using lateral mode transmitters were developed for superharmonic detection and acoustic angiography imaging in intracavity applications. A single element dual frequency intravascular ultrasound transducer was developed for concept validation, which achieved larger signal amplitude, better contrast-to-noise ratio (CNR), and pulselength compared to the previous work. A dual-frequency [Pb(Mg1/3Nb2/3)O3]-x[PbTiO3] array transducer was then developed for superharmonic imaging with dynamic focusing. The axial and lateral sizes of the microbubbles in a 200- [Formula: see text] tube were measured to be 269 and [Formula: see text], respectively. The maximum CNR was calculated to be 22 dB. These results show that superharmonic imaging with a low frequency lateral mode transmitter is a feasible alternative to thickness mode transmitters when the final transducer size requirements dictate design choices. PMID- 27775905 TI - The Effect of Programmable Tactile Displays on Spatial Learning Skills in Children and Adolescents of Different Visual Disability. AB - Vision loss has severe impacts on physical, social and emotional well-being. The education of blind children poses issues as many scholar disciplines (e.g., geometry, mathematics) are normally taught by heavily relying on vision. Touch based assistive technologies are potential tools to provide graphical contents to blind users, improving learning possibilities and social inclusion. Raised-lines drawings are still the golden standard, but stimuli cannot be reconfigured or adapted and the blind person constantly requires assistance. Although much research concerns technological development, little work concerned the assessment of programmable tactile graphics, in educative and rehabilitative contexts. Here we designed, on programmable tactile displays, tests aimed at assessing spatial memory skills and shapes recognition abilities. Tests involved a group of blind and a group of low vision children and adolescents in a four-week longitudinal schedule. After establishing subject-specific difficulty levels, we observed a significant enhancement of performance across sessions and for both groups. Learning effects were comparable to raised paper control tests: however, our setup required minimal external assistance. Overall, our results demonstrate that programmable maps are an effective way to display graphical contents in educative/rehabilitative contexts. They can be at least as effective as traditional paper tests yet providing superior flexibility and versatility. PMID- 27775904 TI - Design of HIFU Transducers for Generating Specified Nonlinear Ultrasound Fields. AB - Various clinical applications of high-intensity focused ultrasound have different requirements for the pressure levels and degree of nonlinear waveform distortion at the focus. The goal of this paper is to determine transducer design parameters that produce either a specified shock amplitude in the focal waveform or specified peak pressures while still maintaining quasi-linear conditions at the focus. Multiparametric nonlinear modeling based on the Khokhlov-Zabolotskaya Kuznetsov (KZK) equation with an equivalent source boundary condition was employed. Peak pressures, shock amplitudes at the focus, and corresponding source outputs were determined for different transducer geometries and levels of nonlinear distortion. The results are presented in terms of the parameters of an equivalent single-element spherically shaped transducer. The accuracy of the method and its applicability to cases of strongly focused transducers were validated by comparing the KZK modeling data with measurements and nonlinear full diffraction simulations for a single-element source and arrays with 7 and 256 elements. The results provide look-up data for evaluating nonlinear distortions at the focus of existing therapeutic systems as well as for guiding the design of new transducers that generate specified nonlinear fields. PMID- 27775906 TI - The Effect of Two Receivers on Broadcast Molecular Communication Systems. AB - Molecular communication is a paradigm that utilizes molecules to exchange information between nano-machines. When considering such systems where multiple receivers are present, prior work has assumed for simplicity that they do not interfere with each other. This paper aims to address this issue and shows to what extent an interfering receiver, [Formula: see text], will have an impact on the target receiver, [Formula: see text], with respect to Bit Error Rate (BER) and capacity. Furthermore, approximations of the Binomial distribution are applied to reduce the complexity of calculations. Results show the sensitivity in communication performance due to the relative location of the interfering receiver. Critically, placing [Formula: see text] between the transmitter [Formula: see text] and [Formula: see text] causes a significant increase in BER or decrease in capacity. PMID- 27775909 TI - Optimization-Based Wearable Tactile Rendering. AB - Novel wearable tactile interfaces offer the possibility to simulate tactile interactions with virtual environments directly on our skin. But, unlike kinesthetic interfaces, for which haptic rendering is a well explored problem, they pose new questions about the formulation of the rendering problem. In this work, we propose a formulation of tactile rendering as an optimization problem, which is general for a large family of tactile interfaces. Based on an accurate simulation of contact between a finger model and the virtual environment, we pose tactile rendering as the optimization of the device configuration, such that the contact surface between the device and the actual finger matches as close as possible the contact surface in the virtual environment. We describe the optimization formulation in general terms, and we also demonstrate its implementation on a thimble-like wearable device. We validate the tactile rendering formulation by analyzing its force error, and we show that it outperforms other approaches. PMID- 27775910 TI - A Bi-Criteria Active Learning Algorithm for Dynamic Data Streams. AB - Active learning (AL) is a promising way to efficiently build up training sets with minimal supervision. A learner deliberately queries specific instances to tune the classifier's model using as few labels as possible. The challenge for streaming is that the data distribution may evolve over time, and therefore the model must adapt. Another challenge is the sampling bias where the sampled training set does not reflect the underlying data distribution. In the presence of concept drift, sampling bias is more likely to occur as the training set needs to represent the whole evolving data. To tackle these challenges, we propose a novel bi-criteria AL (BAL) approach that relies on two selection criteria, namely, label uncertainty criterion and density-based criterion. While the first criterion selects instances that are the most uncertain in terms of class membership, the latter dynamically curbs the sampling bias by weighting the samples to reflect on the true underlying distribution. To design and implement these two criteria for learning from streams, BAL adopts a Bayesian online learning approach and combines online classification and online clustering through the use of online logistic regression and online growing Gaussian mixture models, respectively. Empirical results obtained on standard synthetic and real world benchmarks show the high performance of the proposed BAL method compared with the state-of-the-art AL methods. PMID- 27775911 TI - Development of Quantum Local Potential Function Networks Based on Quantum Assimilation and Subspace Division. AB - The centers and radii of radial basis functions (RBFs) greatly affect the approximation capability of RBF networks (RBFNs). Traditional statistics-based approaches are widely used, but they may lack adaptivity to different data structures. Quantum clustering (QC), derived from quantum mechanics and the Schrodinger equation, demonstrates excellent capability in finding the structure and conformity toward data distribution. In this paper, a novel neural networks model called quantum local potential function networks (QLPFNs) is proposed. The QLPFN inherits the outstanding properties of QC by constructing the waves and the potential functions, and the level of data concentration can be discovered to obtain the inherent structures of the given data set. The local potential functions form the basic components of the QLPFN structure, which are automatically generated from the subsets of training data following specific subspace division procedures. Therefore, the QLPFN model in fact incorporates the level of data concentration as a computation technique, which is different from the classical RBFN model that exhibits radial symmetry toward specific centers. Some application examples are given in this paper to show the effectiveness of the QLPFN model. PMID- 27775914 TI - Toward Simultaneous Visual Comfort and Depth Sensation Optimization for Stereoscopic 3-D Experience. AB - Visual comfort and depth sensation are two important incongruent counterparts in determining the overall stereoscopic 3-D experience. In this paper, we proposed a novel simultaneous visual comfort and depth sensation optimization approach for stereoscopic images. The main motivation of the proposed optimization approach is to enhance the overall stereoscopic 3-D experience. Toward this end, we propose a two-stage solution to address the optimization problem. In the first layer independent disparity adjustment process, we iteratively adjust the disparity range of each depth layer to satisfy with visual comfort and depth sensation constraints simultaneously. In the following layer-dependent disparity process, disparity adjustment is implemented based on a defined total energy function built with intra-layer data, inter-layer data and just noticeable depth difference terms. Experimental results on perceptually uncomfortable and comfortable stereoscopic images demonstrate that in comparison with the existing methods, the proposed method can achieve a reasonable performance balance between visual comfort and depth sensation, leading to promising overall stereoscopic 3-D experience. PMID- 27775916 TI - Ultra-tiny ZnMn2O4 nanoparticles encapsulated in sandwich-like carbon nanosheets for high-performance supercapacitors. AB - Known as an excellent energy storage material, ZnMn2O4 has a wide range of applications in supercapacitors. In this report, a special sandwich-like structure of ZnMn2O4/C has been first designed and synthesized via a simple hydrothermal method and subsequent calcinations. The designed special sandwich like structure can benefit ion exchange and remit the probable volume changes during a mass of electrochemical reactions. Furthermore, the porous carbon nanosheets, derived from low-cost glucose, can effectively increase ion flux. Therefore, the novel sandwich-like ZnMn2O4 nanoparticles encapsulated in carbon nanosheets can undoubtedly demonstrate an exceptional electrochemical performance for SCs. In this work, the composite material with porous sandwich-like structure exhibits excellent cyclic stability for 5000 cycles (~5% loss) and high specific capacitance of 1786 F g-1. PMID- 27775917 TI - A carbon nanotube based x-ray detector. AB - X-ray detectors based on metal-oxide semiconductor field effect transistors couple instantaneous measurement with high accuracy. However, they only have a limited measurement lifetime because they undergo permanent degradation due to x ray beam exposure. A field effect transistor based on carbon nanotubes (CNTs), however, overcomes this drawback of permanent degradation, because it can be reset into its starting state after being exposed to the x-ray beam. In this work the CNTs were deposited using a dielectrophoresis method on SiO2 coated p-type (boron-doped) Si substrates. For the prepared devices a best gate voltage shift of 244 V Gy-1 and a source-drain current sensitivity of 382 nA Gy-1 were achieved. These values are larger than those reached by the currently used MOSFET based devices. PMID- 27775918 TI - Designs and processes toward high-aspect-ratio nanostructures at the deep nanoscale: unconventional nanolithography and its applications. AB - The patterning of high-resolution-featured deep-nanoscale structures with a high aspect ratio (AR) has received increasing attention in recent years as a promising technique for a wide range of applications, including electrical, optical, mechanical and biological systems. Despite extensive efforts to develop viable nanostructure fabrication processes, a superior technique enabling defect free, high-resolution control over a large area is still required. In this review, we focus on recent important advances in the designs and processes of high-resolution nanostructures possessing a high AR, including hierarchical and 3D patterns. The unique applications of these materials are also discussed. PMID- 27775919 TI - Anisotropy and memory during cage breaking events close to a wall. AB - The slow dynamics in a glassy hard-sphere system is dominated by cage breaking events, i.e. rearrangements where a particle escapes from the cage formed by its neighboring particles. We study such events for an overdamped colloidal system by the means of Brownian dynamics simulations. While it is difficult to relate cage breaking events to structural mean field results in bulk, we show that the microscopic dynamics of particles close to a wall can be related to the anisotropic two-particle density. In particular, we study cage-breaking trajectories, mean forces on a tracked particle, and the impact of the history of trajectories. Based on our simulation results, we further construct two different one-particle random-walk models-one without and one with memory incorporated-and find the local anisotropy and the history-dependence of particles as crucial ingredients to describe the escape from a cage. Finally, our detailed study of a rearrangement event close to a wall not only reveals the memory effect of cages, but leads to a deeper insight into the fundamental mechanisms of glassy dynamics. PMID- 27775920 TI - Flexible nanopillars to regulate cell adhesion and movement. AB - Flexible polymer nanopillar substrates were used to systematically demonstrate cell alignment and migration guided by the directional formation of focal adhesions. The polymer nanopillar substrates were constructed to various height specifications to provide an extensive variation of flexibility; a rectangular arrangement created spatial confinement between adjacent nanopillars, providing less spacing in the horizontal and vertical directions. Three polymer nanopillar substrates with the diameter of 400 nm and the heights of 400, 800, and 1200 nm were fabricated. Super-resolution localization imaging and protein pair-distance analysis of vinculin proteins revealed that Chinese hamster ovary (CHO) cells formed mature focal adhesions on 1200 nm high nanopillar substrates by bending adjacent nanopillars to link dot-like adhesions. The spacing confinement of the adjacent nanopillars enhanced the orthogonal directionality of the formation tendency of the mature focal adhesions. The directional formation of the mature focal adhesions also facilitated the organization of actin filaments in the horizontal and vertical directions. Moreover, 78% of the CHO cells were aligned in these two directions, in conformity with the flexibility and nanotopographical cues of the nanopillars. Biased cell migration was observed on the 1200 nm high nanopillar substrates. PMID- 27775921 TI - Noncollinear magnetic order induced by Dzyaloshinskii-Moriya interaction in oxygen-assisted Pt nanojunctions. AB - Motivated by recent measurement of the magnetism and conductance of the oxygen assisted Pt nanojunctions, we performed first principle calculations of the magnetic order and electronic transport by explicitly including fully relativistic effects. Our results show that the spin alignment is a cycloidal spiral feature attributed to the Dzyaloshinskii-Moriya interaction, which indicates that the observed magnetism in experiments is of noncollinear nature. The oxygen concentration is the responsible for the switching of the rotational sense of the spiral magnetic order found in oxygen-assisted Pt nanojunctions. Furthermore, the magnetic moments and magnetoresistances vary with oxygen concentration in the chain, which can be used to tune the magnetism and magnetotransport. The oxygen-assisted Pt nanojunctions offer a possibility for spintronic applications in magnetic memory and quantum devices. PMID- 27775922 TI - Tunneling mechanism and contact mechanics of colloidal nanoparticle assemblies. AB - Nanoparticle assemblies with thiol-terminated alkyl chains are studied by conducting atomic force microscopy (c-AFM) regarding their use as strain gauges for touch-sensitive panels. Current-force spectroscopy is used as a characterization tool complementary to the macroscopic setup since it allows a bias to be applied to a limited number of junctions, overcoming the Coulomb blockade energy and focusing on the contact electromechanics and the transport mechanism across the ligand. First, transition voltage spectroscopy is applied with varying force to target the underlying tunneling mechanism by observing whether the transition between the ohmic and exponential current-voltage behavior is force-dependent. Secondly, current-force spectroscopy in the ohmic range below the transition voltage is performed. The current-force behavior of the AFM probe in contact with a nanoparticle multilayer is associated with the spread of force and current within the nanoparticle lattice and at the level of adjacent particles by detailed contact mechanics treatment. The result is twofold: concerning the architecture of sensors, this work is a sample case of contact electromechanics at scales ranging from the device scale down to the individual ligand molecule. Regarding transport across the molecule, the vacuum tunneling mechanism is favored over the conduction by coherent molecular states, which is a decision-making aid for the choice of ligand in applications. PMID- 27775923 TI - Influence of synthesis parameters on hyaluronic acid hydrogels intended as nerve conduits. AB - Hydrogels have widely been proposed lately as strategies for neural tissue regeneration, but there are still some issues to be solved before their efficient use in tissue engineering of trauma, stroke or the idiopathic degeneration of the nervous system. In a previous work of the authors a novel Schwann-cell structure with the shape of a hollow cylinder was obtained using a three-dimensional conduit based in crosslinked hyaluronic acid as template. This original engineered tissue of tightly joined Schwann cells obtained in a conduit lumen having 400 MUm in diameter is a consequence of specific cell-material interactions. In the present work we analyze the influence of the hydrogel concentration and of the drying process on the physicochemical and biological performance of the resulting tubular scaffolds, and prove that the cylinder-like cell sheath obtains also in scaffolds of a larger inner diameter. The diffusion of glucose and of the protein BSA through the scaffolds is studied and characterized, as well as the enzymatic degradation kinetics of the lyophilized conduits. This can be modulated from a couple of weeks to several months by varying the concentration of hyaluronic acid in the starting solution. These findings allow to improve the performance of hyaluronan intended for neural conduits, and open the way to scaffolds with tunable degradation rate adapted to the site and severity of the injury. PMID- 27775924 TI - Poly(L-lactic acid) scaffold with oriented micro-valley surface and superior properties fabricated by solid-state drawing for blood-contact biomaterials. AB - Most biomaterials composed of biodegradable polymers will contact either accidentally or consistently with blood and this commonly requires both good mechanical strength and blood compatibility. Despite this demand, current processing methods still make it difficult and complex to simultaneously improve the two properties. To overcome present limitations, the aim of this work is to develop a solid-state drawing which is a novel method for blood-contact biomaterials that can simultaneously improve the two essential factors of mechanical strength and blood compatibility, as well as induce a micro-patterned surface. Solid-state drawn (SSD) poly(L-lactic acid) (PLLA) film significantly maximally increased tensile strength and elastic modulus about ninefold and sixfold, respectively, compared to undrawn film. Furthermore, it was determined that SSD-PLLA film had highly developed molecular orientation, higher crystallinity and surface hydrophobicity. Additionally, the SSD method could greatly reduce roughness of the surface and induce the formation of aligned valleys, forming microstructures on the film surface. The topographical cue delayed hydrolytic degradation and prevented damage on the surface by NaOH of alkali compounds are compared with undrawn film. In energy-dispersive x-ray spectroscopy analysis, the surface of SSD film treated by NaOH was not detected on any ions whereas undrawn film held foreign ions on surface defects. The hemolysis rate of SSD film was considerably decreased with an increase of draw ratio up to 0.2% maximally and SSD film has shown greatly lower platelet adhesion compared to undrawn film in blood-compatibility analysis. Interestingly, one directional alignment of micro-valley structure on SSD film could promote initial adhesion of human umbilical vein endothelial cells (HUVEC) compared with undrawn film and guide the direction of HUVEC. In conclusion, the newly designed SSD method has shown potential for developing blood-contact biomaterials simply due to great mechanical properties, blood compatibility and an aligned micro patterned surface. PMID- 27775926 TI - Polyethylene glycol-coated blue-emitting silicon dots with improved properties for uses in aqueous and biological environments. AB - Grafting of polyethylene glycol (PEG) to ultrasmall photoluminescent silicon dots (SiDs) is expected to improve and expand the applications of these particles to aqueous environments and biological systems. Herein we report a novel one-pot synthesis of robust, highly water compatible PEG-coated SiDs (denoted as PEG SiDs) of (3.3 +/- 0.5) nm size. The nanoparticles' synthesis is based on the liquid phase oxidation of magnesium silicide using PEG as reaction media and leading to high PEG density grafting. PEG-SiDs enhanced photophysical, photosensitising, and solution properties in aqueous environments are described and compared to those of 2 nm size PEG-coated SiDs with low PEG density grafting (denoted as PEG-NHSiDs) obtained from a multistep synthesis strategy. PEG-SiDs form highly dispersed suspensions in water showing stable photoluminescence and quantum yields of Phi = 0.13 +/- 0.04 at 370 nm excitation in air-saturated suspensions. These particles exhibited the capacity of photosensitising the formation of singlet molecular oxygen, not observed for PEG-NHSiDs. PEG robust shielding of the silicon core luminescent properties is further demonstrated in bio-imaging experiments stressing the strong interaction between PEG-SiDs and Staphylococcus aureus smears by observing the photoluminescence of particles. PEG SiDs were found to be nontoxic to S. aureus cells at concentrations of 100 mg ml 1, though a bacteriostatic effect on S. aureus biofilms was observed upon UV-A irradiation under conditions where light alone has no effect. PMID- 27775925 TI - A facility to search for hidden particles at the CERN SPS: the SHiP physics case. AB - This paper describes the physics case for a new fixed target facility at CERN SPS. The SHiP (search for hidden particles) experiment is intended to hunt for new physics in the largely unexplored domain of very weakly interacting particles with masses below the Fermi scale, inaccessible to the LHC experiments, and to study tau neutrino physics. The same proton beam setup can be used later to look for decays of tau-leptons with lepton flavour number non-conservation, [Formula: see text] and to search for weakly-interacting sub-GeV dark matter candidates. We discuss the evidence for physics beyond the standard model and describe interactions between new particles and four different portals-scalars, vectors, fermions or axion-like particles. We discuss motivations for different models, manifesting themselves via these interactions, and how they can be probed with the SHiP experiment and present several case studies. The prospects to search for relatively light SUSY and composite particles at SHiP are also discussed. We demonstrate that the SHiP experiment has a unique potential to discover new physics and can directly probe a number of solutions of beyond the standard model puzzles, such as neutrino masses, baryon asymmetry of the Universe, dark matter, and inflation. PMID- 27775927 TI - Pulsed laser deposition of two-dimensional ZnO nanocrystals on Au(111): growth, surface structure and electronic properties. AB - Two-dimensional (2D) ZnO structures have been deposited on the Au(111) surface by means of the pulsed laser deposition technique. In situ scanning tunneling microscopy and scanning tunneling spectroscopy measurements have been performed to characterize morphological, structural and electronic properties of 2D ZnO at the nanoscale. Starting from a sub-monolayer coverage, we investigated the growth of ZnO, identifying different atomic layers (up to the fifth). At low coverage, we observed single- and bi-layer nanocrystals, characterized by a surface moire pattern that is associated to a graphene-like ZnO structure. By increasing the coverage, we revealed a morphological change starting from the fourth layer, which was attributed to a transition toward a bulk-like structure. Investigation of the electronic properties revealed the semiconducting character of 2D ZnO. We observed a dependence of the density of states (DOS) and, in particular, of the conduction band (CB) on the ZnO thickness, with a decreasing of the CB onset energy for increasing thickness. The CB DOS of 2D ZnO shows a step-like behaviour which may be interpreted as due to a 2D quantum confinement effect in ZnO atomic layers. PMID- 27775928 TI - Two alternatives for magnetic resonance electrical impedance tomography: injected or induced current. AB - In this paper, the abilities of injected current magnetic resonance electrical impedance tomography (MREIT) and induced current magnetic resonance electrical impedance tomography (ICMREIT) systems to differentiate a conductivity perturbation from an otherwise uniform conductivity distribution are compared. The sensitivity of MREIT measurements changes as a function of distance to the electrodes used for current injection. The sensitivity of ICMREIT measurements is related to the radial location, being a minimum for concentrically located small conductivity perturbations. The very low sensitivity of ICMREIT to conductivity perturbations at central locations seems to be the major drawback of the method compared with MREIT. When the diameter of a concentric and/or an eccentric circular conductivity inhomogeneity inside an otherwise homogeneous circular conductor is close to half of the diameter of the conductor region, the distinguishability of the perturbation by MREIT increases. MREIT is more sensitive to perturbations with lower conductivity with respect to background conductivity (resistive perturbations) than to conductive perturbations. In the case of ICMREIT, concentric inhomogeneities are equally distinguishable for conductive and resistive conductivity perturbations. Eccentric resistive inhomogeneities are more distinguishable then conductive inhomogeneities. Distinguishability increases with the size and number of conductivity perturbations. PMID- 27775929 TI - Liquid exfoliated pristine WS2 nanosheets for ultrasensitive and highly stable chemiresistive humidity sensors. AB - WS2 nanosheets have been synthesized by ultrasonication in a binary mixture of acetone and 2-propanol, with a volume ratio of 80:20. Hansen solubility parameters were taken into consideration as part of the process. These nanosheets have been characterized by electron microscopy, atomic force microscopy, and x ray diffraction, along with spectroscopy such as ultraviolet-visible spectroscopy, Raman spectroscopy, and x-ray photoelectron spectroscopy. The nanosheets were further used as a sensing material to fabricate a humidity sensor on interdigitated aluminum electrodes, realized over Si/SiO2 substrate using a conventional photolithography technique. The response for our sensor varied from 11.9 for 40% RH to as high as 37.5 for 80% RH. Response and recovery time were found to be 13 +/- 2 s and 17 +/- 2 s respectively. The suspended nanosheets were also treated with UV light in a nitrogen environment. The response for UV treated nanosheets shows better linearity, however its response decreases in the presence of humidity. This is due to a decrease in oxygen content of the UV treated sample. Furthermore, the effect of sonication time has been investigated, and it was found that samples with 10 h sonication are better than others due to their high surface-to-volume ratio. The repeatability and stability of the sensor have been investigated and found to be excellent. The hysteresis in the sensors was also explored. The mechanism of humidity sensing has been discussed in detail. PMID- 27775930 TI - Fetal motion estimation from noninvasive cardiac signal recordings. AB - Fetal motility is a widely accepted indicator of the well-being of a fetus. In previous research, it has be shown that fetal motion (FM) is coherent with fetal heart rate accelerations and an indicator for active/rest cycles of the fetus. The most common approach for FM and fetal heart rate (FHR) assessment is by Doppler ultrasound (DUS). While DUS is the most common approach for studying the mechanical activities of the heart, noninvasive fetal electrocardiogram (ECG) and magnetocardiogram (MCG) recording and processing techniques have been considered as a possible competitor (or complement) for the DUS. In this study, a fully automatic and robust framework is proposed for the extraction, ranking and alignment of fetal QRS-complexes from noninvasive fetal ECG/MCG. Using notions from subspace tracking, two measures, namely the actogram and rotatogram, are defined for fetal motion tracking. The method is applied to four fetal ECG/MCG databases, including twin MCG recordings. By defining a novel measure of causality, it is shown that there is significant coherency and causal relationship between the actogram/rotatogram and FHR accelerations/decelerations. Using this measure, it is shown that in many cases, the actogram and rotatogram precede the FHR variations, which supports the idea of motion-induced FHR accelerations/decelerations for these cases and raises attention for the non motion-induced FHR variations, which can be associated to the fetal central nervous system developments. The results of this study can lead to novel perspectives of the fetal sympathetic and parasympathetic brain systems and future requirements of fetal cardiac monitoring. PMID- 27775931 TI - Sublaminar Decompression: A New Technique for Spinal Canal Decompression in the Treatment of Stenosis in Degenerative Spinal Conditions. AB - STUDY DESIGN: Technical report and case illustration. OBJECTIVE: To review the rationale and steps for a sublaminar decompression in the setting of adult deformity surgery and in degenerative spondylosis. SUMMARY OF BACKGROUND DATA: Several variations of lumbar laminotomy and posterior decompressions have been reported, although these are primarily in the setting of isolated lumbar stenosis, and often focus on treatment of central stenosis. MATERIALS AND METHODS: Our operative technique is illustrated and 1 patient with a 1-year follow-up is presented to further describe this surgical approach. RESULTS AND SURGICAL TECHNIQUES: The patient underwent a lumbar decompression and fusion procedure. A sublaminar decompression with bilateral foraminotomies was performed at L4-L5, combined with instrumented posterior fusion. CONCLUSIONS: The presented sublaminar decompression technique allows for adequate decompression of the central canal, lateral recess, and neural foramina while providing maximum bone surface area for posterolateral as well as posterior fusion. PMID- 27775932 TI - The role of imaging in the assessment of severe asthma. AB - PURPOSE OF REVIEW: The present review aims to summarize the most recent evidence related to imaging and severe asthma, both with regard to advances in imaging research and to their current and potential clinical implications. RECENT FINDINGS: Recent work in imaging in severe asthma has principally been using computed tomography (CT) and MRI, as well as the integration of the two. Some of the most notable findings include the use of CT imaging biomarkers to create unique clusters of asthmatics, and the use of co-registration to link CT images of airways with regional variation in ventilation in MRI. In addition, temporal studies have shown that some the ventilation defects found using MRI in asthmatics are intermittent and others are persistent, but both are associated with lower lung function. SUMMARY: The role of imaging in severe asthma currently is primarily in the exclusion of comorbid or other conditions, or in the assessment for complications in the setting of acute decompensation. A rapidly expanding body of literature using CT and MRI suggests that these tools may soon be of utility in the chronic management of the disease. PMID- 27775933 TI - Clitoral Metastasis From Advanced Cervical Carcinoma on 18F-FDG-PET/CT. AB - Metastatic tumors of the clitoris from cervical carcinoma are extremely rare. Here, we described a 54-year-old woman with clitoral metastasis from cervical carcinoma demonstrated on F-FDG PET/CT images. PMID- 27775934 TI - Ganglion Cyst on 131I Whole-Body Scintigraphy. AB - Interpretation of iodine I whole-body scintigraphy can be challenging, as there are many nonpathologic findings that may present with increased radiotracer uptake. Radiotracer uptake has been reported in the literature involving the salivary glands, thymus, renal cysts, skin contamination, and other benign etiologies. We present the case of an incidental right wrist ganglion cyst demonstrating persistent increased uptake on I whole-body scintigraphy. PMID- 27775935 TI - PET-CT as an Alternative to Fiducial Markers Guidance in Liver Metastasis Treatment. AB - The liver is the organ most commonly affected by colorectal cancer metastasis. Currently, liver resection is the treatment of choice, but in cases where it is not possible, intensity-modulated radiation therapy is an alternative. We report the case of a 57-year-old woman whose colorectal carcinoma metastasized to the liver. She was referred for implantation of fiducial markers for intensity modulated radiation therapy planning. PET-CT stands out as an additional tool for distinguishing metabolically active tumor tissue from other tissues, ensuring effective introduction of percutaneous fiducial markers, especially in cases where use of conventional imaging techniques is limited. PMID- 27775936 TI - First Experience With SPECT/CT Using a 99mTc-Labeled Inhibitor for Prostate Specific Membrane Antigen in Patients With Biochemical Recurrence of Prostate Cancer. AB - AIM: Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancers (PCs). Here, we report our first experience using the Tc-labeled PSMA inhibitor MIP-1404 (Progenics Pharmaceuticals, Inc, Tarrytown, NY) in 60 patients with biochemically recurrent PC. METHODS: Whole-body planar scintigraphy and SPECT/CT of the lower abdominal pelvic region of 60 patients with biochemical relapse of PC were analyzed retrospectively. In these subjects, an average dose of 733.1 +/- 49.5 MBq (19.8 +/- 1.3 mCi) Tc-labeled MIP-1404 was injected 4 to 5 hours prior to imaging. In addition to visual evaluation, SUVmax were determined in the tumor lesions using a previously developed protocol for quantitative SPECT/CT. RESULTS: In 42 of 60 patients, Tc-MIP-1404-positive lesions could be detected (70%; 95% confidence interval [CI], 0.58-0.82). Twenty patients had Tc MIP-1404-positive lymph nodes suggestive of metastasis, 14 patients had pathological uptake in the prostate region indicative of local recurrence, and for another 19 patients, there was tracer accumulation in the skeleton (n = 18) or lungs (n = 1). Detection rate was 91.4% (95% CI, 0.82-1) at prostate-specific antigen levels greater than 2 ng/mL and 40.0% (95% CI, 0.21-0.59) at lower prostate-specific antigen values (P < 0.01). Of the 60 patients, in total, 82 positive lesions were analyzed quantitatively. Average SUVmax of the lesions was 16.3 +/- 21.6 with a range of 1.7 to 142.9. CONCLUSION: Tc-labeled PSMA inhibitor MIP-1404 is a promising SPECT tracer for detection of locally recurrent or metastatic prostate cancer. PMID- 27775937 TI - Bilateral Huge Incidentalomas of Isolated Adrenal Metastases From Unknown Primary Melanoma Revealed by 18F-FDG PET/CT. AB - FDG PET/CT has high sensitivity and specificity for the detection of distant metastases from cutaneous melanoma. Imaging is recommended for patients with clinical suspicion of metastasis and should be considered for those with confirmed sentinel lymph node metastasis. Metastatic melanoma bears a poor prognosis. Only a complete resection improves survival, which explains the need to detect potentially unresectable disease, and most metastatic patients are ineligible for a curative surgical procedure. Here, FDG PET/CT demonstrated isolated bilateral adrenal metastases from melanoma of unknown primary. The patient underwent curative surgery, with no sign of recurrence at 48 months after surgery. PMID- 27775938 TI - 18F-Fluorocholine PET/CT of Incidental Male Breast Cancer. AB - Breast cancer is approximately 100 times less common among men. Estrogen-related receptor alpha was detected in human prostate cancer tissue, and androgen receptors are expressed in both normal and malignant breast tissue. Thus, prostate cancer hormonal therapy may increase breast cancer risk. A 67-year-old man with prostate cancer history presented with rising prostate-specific antigen level. F-Fluorocholine PET/CT showed intense uptake in his right breast and moderate uptake in right axillary lymph node. Complementary F-FDG PET/CT demonstrated more intense tracer uptakes in both the right breast and axillary lymph node. Breast histological findings were invasive ductal cancer, with axillary lymph node invasion. PMID- 27775940 TI - Prognostic Value of FDG Uptake of Portal Vein Tumor Thrombosis in Patients With Locally Advanced Hepatocellular Carcinoma. AB - PURPOSE: This study aimed to evaluate the prognostic value of F-FDG uptake of portal vein tumor thrombosis (PVTT) for predicting progression-free survival (PFS) and overall survival (OS) in patients with locally advanced hepatocellular carcinoma (HCC). METHODS: The study retrospectively included 166 HCC patients with PVTT and no extrahepatic metastases who underwent staging FDG PET/CT. Tumor to-liver uptake ratio (TLR) and PVTT-to-liver uptake ratio (PLR) were measured for each patient, and the prognostic values of clinical factors, TLR, and PLR were assessed. Furthermore, patients were classified into 2 subgroups according to TLR, and the prognostic value of PLR was evaluated in each subgroup. RESULTS: Median PFS and OS were 6.2 and 10.1 months, respectively. On multivariate analysis, tumor size (P = 0.006) and PLR (P = 0.03) were independent prognostic factors for PFS, whereas Child-Pugh class (P = 0.02) and PLR (P = 0.02) were independent prognostic factors for OS. Tumor-to-liver uptake ratio was a significant prognostic factor for PFS and OS on univariate analysis but failed to show significance on multivariate analysis. In both patient subgroups with low and high TLR, PLR remained a significant prognostic factor for predicting OS (P = 0.04 for all). CONCLUSIONS: FDG uptake of PVTT, but not FDG uptake of HCC, is an independent prognostic factor for PFS and OS in HCC patients with PVTT and no extrahepatic metastasis. Given the prognostic significance, it is strongly encouraged to use FDG uptake of PVTT in further risk stratification for HCC patients with PVTT. PMID- 27775939 TI - Prospective Pilot Study to Evaluate the Incremental Value of PET Information in Patients With Bladder Cancer Undergoing 18F-FDG Simultaneous PET/MRI. AB - PURPOSE: The aim of this study was to conduct a prospective pilot study comparing the diagnostic performance of MRI alone and F-FDG simultaneous PET/MRI using a diuresis protocol in bladder cancer patients. METHODS: Twenty-two bladder cancer patients underwent F-FDG PET/MRI, using intravenous furosemide and oral hydration for bladder clearance. A radiologist scored probability of tumor in 3 locations (urinary bladder, pelvic lymph nodes, nonnodal pelvis) using 1- to 3-point scale (1 = negative, 2 = equivocal, 3 = definite tumor). A nuclear medicine physician reviewed fused PET/MRI images, after which scores were reassigned based on combined findings. Follow-up pathologic and imaging data served as reference. Performances of MRI alone and PET/MRI were compared. RESULTS: Of these patients, 82%, 38%, and 18% were positive for bladder, pelvic nodal, and nonnodal pelvic tumor, respectively. At a score of 3, PET/MRI exhibited greater accuracy for detection of bladder tumor (86% vs 77%), metastatic pelvic lymph nodes (95% vs 76%), and nonnodal pelvic malignancy (100% vs 91%). In the bladder, PET changed the level of suspicion in 36% of patients (50% increased suspicion, 50% decreased suspicion), with 75% of these changes deemed correct based on reference standard. For pelvic lymph nodes, PET changed suspicion in 52% (36% increase, 64% decrease), with 95% of changes deemed correct. For nonnodal pelvis, PET changed suspicion in 9% (100% increase), with 100% deemed correct. CONCLUSIONS: Additional PET information helped to appropriately determine level of suspicion in multiple anatomic sites for otherwise equivocal findings on MRI alone. Although requiring larger studies, findings suggest a possible role for simultaneous PET/MRI to assist bladder cancer management. PMID- 27775941 TI - PET/CT and MRI Imaging of a Eumycetoma of the Right Thigh. AB - Eumycetoma is a chronic tropical fungal disease that infiltrates subcutaneous tissues, mainly in the feet and legs. Standard antifungal drugs are ineffective, and mutilating surgery is common. Morphological imaging is useful for assessing the local extent of the disease before surgery. FDG PET/CT may be of potential interest for the general extent, but PET descriptions remain scarce and mostly relate to the feet. Here, the authors present FDG PET/CT and MRI study of a very rare case of an extensive, biopsy-proven eumycetoma of the right thigh that was performed to guide potential surgery. PMID- 27775942 TI - PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer. AB - AIM: Castrate-resistant prostate cancer (CRPC) often shows histological evidence of neuroendocrine differentiation (NED). To evaluate the extent of NED in patients with CRPC, we used PET/CT with Ga-[DOTA-Tyr]-octreotate (Ga-DOTA-TATE), a somatostatin analog that binds somatostatin receptor 2 with high affinity. This radiotracer is used in imaging of neuroendocrine tumors. METHODS: Twelve patients (mean age, 65 [SD, 12] years) with CRPC were studied. Their mean prostate specific antigen level at scanning was 85.6 (SD, 144.6) ng/mL. PET/CT images were obtained after the injection of 120 to 200 MBq of Ga-DOTA-TATE. RESULTS: All participants had at least 1 blastic metastasis demonstrating uptake of Ga-DOTA TATE (mean SUVmax of 5.3 [SD, 2.3]). In 6 patients, moderately high to high uptakes (SUVmax, >5) were seen. Patients with multiple bone metastases had a significantly higher SUVmax compared with patients with few metastases (mean of 5.8 vs 3.8, P = 0.05). In 4 patients, lytic bone lesions or lymph node metastases also showed uptake of the tracer (mean SUVmax of 7.2 [SD, 3.2]). Uptake of the radiotracer was also observed in bones showing normal architecture in CT, suggesting that NED cells appear early during metastases development. CONCLUSIONS: Uptake of Ga-DOTA-TATE is a common finding in metastases of CRPC patients, suggesting that NED is frequent in these patients. In half of the patients, widespread uptake of Ga-DOTA-TATE was observed. This suggests that the possibility of treating selected CRCP patients with anti-neuroendocrine tumor therapies should be explored and that Ga-DOTA-TATE scanning could have a role in predicting the efficacy of these treatments. PMID- 27775943 TI - Physiological Uptake in the Pancreatic Head on Somatostatin Receptor Scintigraphy Using [111In-DTPA]Octreotide: Incidence and Mechanism. AB - PURPOSE: Physiological uptake in the uncinate process or pancreatic head has been described with Ga-labeled PET tracers for somatostatin receptor imaging. In-DTPA octreotide is the only registered radiopharmaceutical for the imaging of neuroendocrine tumors. We studied the uptake in this region of the pancreatic head on somatostatin receptor scintigraphy (SRS) using In-DTPA-octreotide in a large group of patients. Furthermore, known physiological and clinical characteristics are discussed in an attempt to elucidate this phenomenon. METHODS: Four hundred seven patients underwent SRS using In-DTPA-octreotide in our department in 2014. After excluding patients with a known malignancy in or close to the pancreas, as well as all scans without SPECT/CT of the upper abdomen, we reviewed 178 scans in total. The uptake was graded on a 4-point scale that correlates the uptake in the pancreatic head to physiological uptake in the liver. RESULTS: Uptake in the region of the pancreatic head, including the uncinate process, was seen in 46 (26%) of 178 patients on SPECT/CT and in 12 patients (7%) on planar imaging. On SPECT/CT, uptake was lower than the liver in 26 patients (15%), equal to the liver in 17 patients (10%), and higher than the liver in 3 patients (2%). In patients with diabetes mellitus (DM), the incidence of uptake in the pancreatic head was 50% on SPECT/CT. CONCLUSIONS: Physiological uptake in the pancreatic head is seen on SPECT/CT with In-DTPA-octreotide in 26% of patients, and the incidence is doubled in patients with DM. Previous case reports showed uptake in the pancreatic head due to histologically proven pancreatic polypeptide (PP) cell hyperplasia. Also, patients with DM have elevated serum PP concentrations, which is likely due to PP cell hyperplasia. Because 90% of PP cells are present in the pancreatic head, PP cell hyperplasia is the most likely explanation for visualization of the pancreatic head on SRS in a substantial number of patients. PMID- 27775944 TI - Isolated Metachronous Splenic Metastasis From Colon Cancer Found by 18F-FDG PET/CT. AB - Isolated splenic metastases from solid malignancies are very rare. We report the case of a 58-year-old woman with isolated metachronous splenic metastasis from colon cancer detected 18 months after colectomy. F-FDG PET/CT allowed its recognition and guided the therapeutic approach toward surgery. PMID- 27775945 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Granulomatous Inflammation Mimicking High-Grade Malignancy on FDG-PET/CT. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare form of preinvasive lung lesion associated with indolent carcinoid tumor formation. This disease is characterized by multiple small pulmonary nodules with low SUVmax on F-FDG PET. Biopsy and immunohistochemical staining for neuroendocrine markers confirm diagnosis. There is no consensus for treatment, which typically involves surgical excision or management of symptoms with steroid based therapies. We report an unusual case of DIPNECH colocalizing with necrotizing granulomatous inflammation mimicking high-grade aggressive malignancy on FDG-PET and a typical case of DIPNECH for comparison with low FDG avidity. PMID- 27775946 TI - Comparison of Dopamine Transporter SPECT and 123I-MIBG Myocardial Scintigraphy to Assess Clinical Severity in Patients With Parkinson Disease. AB - PURPOSE: The aim of our study was to evaluate the use of dopamine transporter (DAT) SPECT and I-MIBG myocardial scintigraphy to determine the clinical severity of Parkinson disease (PD), with a focus on motor impairments affecting activities of daily living (ADLs). METHODS: Data for 65 consecutive PD patients who underwent both DAT and MIBG imaging were reviewed. Associations between imaging variables and Hoehn and Yahr (H&Y) staging or self-supportive care ratings were investigated. Univariate and multivariate regression analyses were performed to determine the factors associated with ADLs. RESULTS: After applying the exclusion criteria, 45 patients were analyzed (age, 73.1 +/- 9.3 years; 23 males; H&Y stage 1: n = 12, stage 2: n = 14, stage 3: n = 10, stage 4: n = 5, and stage 5: n = 4; self-supportive care rating-dependent ADLs: n = 29). Dopamine transporter variables were significantly associated with the clinical severity of PD as assessed by H&Y staging, whereas MIBG variables were not. Dopamine transporter variables gradually decreased throughout progressive stages, whereas the MIBG variables changed only in the advanced stages. In a multivariate analysis including clinical and imaging variables, both lower DAT and MIBG uptakes were significantly associated with dependent ADL status (P = 0.028 and 0.034, respectively). CONCLUSIONS: In patients with PD, DAT SPECT and MIBG myocardial scintigraphy were associated with ADL status; DAT SPECT was a stronger indicator of severity than MIBG myocardial scintigraphy in the early and middle stages. PMID- 27775947 TI - Enhanced MRI and 18F-FDG PET/CT Findings of Preoperative Primary Renal Collecting Duct Carcinoma. AB - Primary renal collecting duct carcinoma is an extremely rare neoplasm. We present a case of preoperative collecting duct carcinoma with enhanced MRI and F-FDG PET/CT findings. The MRI and PET imaging showed a round mass in the left kidney, as well as multiple retroperitoneal lesions with slight enhancement and intense FDG uptake, respectively. A left radical nephrectomy was performed. Primary renal collecting duct carcinoma and retroperitoneal lymph node metastases were confirmed histopathologically. PMID- 27775948 TI - Erythema Nodosum-Like Panniculitis as a False-Positive 18F-FDG PET/CT in Advanced Melanoma Treated With Dabrafenib and Trametinib. AB - We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases. Painless cutaneous lesions were observed on physical examination, and biopsy revealed erythema nodosum-like panniculitis. PMID- 27775949 TI - Prognostic Value of Metabolic Tumor Volume and Total Lesion Glycolysis on Preoperative 18F-FDG PET/CT in Patients With Very Early and Early Hepatocellular Carcinoma. AB - PURPOSE: The aim of this article was to evaluate the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on preoperative F FDG PET/CT for predicting intrahepatic recurrence-free survival (IHRFS), extrahepatic metastasis-free survival (EHMFS), and overall survival (OS) in patients with very early/early hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively enrolled 132 patients with very early/early HCC who underwent F-FDG PET/CT followed by surgery. The maximum tumor SUV-to-mean normal liver SUV ratio, MTV, and TLG were measured for each patient. Prognostic significances of PET/CT parameters and clinicopathologic factors for IHRFS, EHMFS, and OS were evaluated. Cumulative IHRFS, EHMFS, and OS were calculated using the Kaplan-Meier method. RESULTS: Thirty-three (25%) and 21 (15.9%) of 132 patients experienced intrahepatic and extrahepatic recurrence, respectively, during a median follow-up period of 38.1 months. In multivariate analysis, none of the factors were significant for IHRFS. Metabolic tumor volume and TLG were only significant factors for EHMFS and OS (P < 0.05). The 5-year EHMFS rates were 94.8% in patients with low MTV and TLG, and 62.1% and 63.2% in patients with high MTV and TLG, respectively (P < 0.001). The 5-year OS rates were 92.6% and 92.4% in patients with low MTV and TLG, and 63.3% and 64.3% in patients with high MTV and TLG, respectively (P < 0.001). CONCLUSIONS: Metabolic tumor volume and TLG on preoperative PET/CT were independent prognostic factors for EHMFS and OS but not IHRFS in patients with very early/early HCC. Therefore, patients with high MTV or TLG should be closely observed for extrahepatic metastasis using systemic evaluations. PMID- 27775951 TI - Aligning Public Perception With Clinical Realities. PMID- 27775950 TI - Translational Cancer Nursing Research: What Will Your Contribution Be? PMID- 27775952 TI - A 13-year time trend analysis of 3724 small bowel video capsule endoscopies and a forecast model during the financial crisis in Greece. AB - INTRODUCTION: Since its introduction, small bowel video capsule endoscopy (VCE) use has evolved considerably. AIM: Evaluation of the temporal changes of small bowel VCE utilization in three tertiary centers in Greece in Era 1 (2002-2009) and Era 2 (2010-2014) and the development a forecast model for future VCE use during 2015-2017. MATERIALS AND METHODS: Data from all small bowel VCE examinations were retrieved and analyzed in terms of the annual number of the performed examinations, their indications and the significance of their findings. RESULTS: Overall, we evaluated 3724 VCE examinations. The number of studies peaked in 2009 (n=595) and then decreased to reach 225 in 2014. Overall, more (53.8 vs. 51.4%) patients with iron-deficiency anemia and obscure gastrointestinal bleeding (IDA/OGIB) and fewer (10.7 vs. 14%) patients with chronic diarrhea were evaluated in Era 2 compared with Era 1 (P=0.046). In Era 2, there were more nondiagnostic examinations (39.5 vs. 29.3%, P<0.001), whereas the rate of cases with relevant findings decreased from 47.8 to 40.9%. According to the time trend analysis, we developed a forecast model with two scenarios: the pessimistic and the optimistic. Validation of the model with 2015 data showed that reality was close to the pessimistic scenario: the number of exams further decreased to 190, studies carried out for IDA/OGIB increased to 67%, and there were more negative than positive exams (40.7 vs. 39.2%). CONCLUSION: The number of VCE studies carried out after the emergence of the financial crisis decreased significantly and VCE indications were optimized. Our forecast model predicts lower numbers of VCE studies, with IDA/OGIB being the dominant indication. However, the predicted increase of negative exams requires further evaluation. PMID- 27775953 TI - Daylight Savings Time Transitions and the Incidence Rate of Unipolar Depressive Episodes. AB - BACKGROUND: Daylight savings time transitions affect approximately 1.6 billion people worldwide. Prior studies have documented associations between daylight savings time transitions and adverse health outcomes, but it remains unknown whether they also cause an increase in the incidence rate of depressive episodes. This seems likely because daylight savings time transitions affect circadian rhythms, which are implicated in the etiology of depressive disorder. Therefore, we investigated the effects of daylight savings time transitions on the incidence rate of unipolar depressive episodes. METHODS: Using time series intervention analysis of nationwide data from the Danish Psychiatric Central Research Register from 1995 to 2012, we compared the observed trend in the incidence rate of hospital contacts for unipolar depressive episodes after the transitions to and from summer time to the predicted trend in the incidence rate. RESULTS: The analyses were based on 185,419 hospital contacts for unipolar depression and showed that the transition from summer time to standard time were associated with an 11% increase (95% CI = 7%, 15%) in the incidence rate of unipolar depressive episodes that dissipated over approximately 10 weeks. The transition from standard time to summer time was not associated with a parallel change in the incidence rate of unipolar depressive episodes. CONCLUSION: This study shows that the transition from summer time to standard time was associated with an increase in the incidence rate of unipolar depressive episodes. Distress associated with the sudden advancement of sunset, marking the coming of a long period of short days, may explain this finding. See video abstract at, http://links.lww.com/EDE/B179. PMID- 27775954 TI - The Trend-in-trend Research Design for Causal Inference. AB - Cohort studies can be biased by unmeasured confounding. We propose a hybrid ecologic-epidemiologic design called the trend-in-trend design, which requires a strong time trend in exposure, but is unbiased unless there are unmeasured factors affecting outcome for which there are time trends in prevalence that are correlated with time trends in exposure across strata with different exposure trends. Thus, the conditions under which the trend-in-trend study is biased are a subset of those under which a cohort study is biased. The trend-in-trend design first divides the study population into strata based on the cumulative probability of exposure given covariates, which effectively stratifies on time trend in exposure, provided there is a trend. Next, a covariates-free maximum likelihood model estimates the odds ratio (OR) using data on exposure prevalence and outcome frequency within cumulative probability of exposure strata, across multiple periods. In simulations, the trend-in-trend design produced ORs with negligible bias in the presence of unmeasured confounding. In empiric applications, trend-in-trend reproduced the known positive association between rofecoxib and myocardial infarction (observed OR: 1.2, 95% confidence interval: 1.1, 1.4), and known null associations between rofecoxib and severe hypoglycemia (OR = 1.1 [0.92, 1.3]) and nonvertebral fracture (OR = 0.84 [0.64, 1.1]). The trend-in-trend method may be useful in settings where there is a strong time trend in exposure, such as a newly approved drug or other medical intervention. See video abstract at, http://links.lww.com/EDE/B178. PMID- 27775955 TI - Depression, Anxiety, and Stress Among People With Chronic Hepatitis C Virus Infection and a History of Injecting Drug Use in New South Wales, Australia. AB - OBJECTIVE: The aims of this study were to assess symptoms of depression, anxiety, and stress and associated sociodemographic factors among people living with chronic hepatitis C virus (HCV) infection with a history of injecting drug use and to assess the association between symptoms of depression, anxiety, or stress and HCV treatment intent, specialist assessment, or treatment uptake. METHODS: The Enhancing Treatment for Hepatitis C in Opioid Substitution Settings was an observational cohort study evaluating the provision of HCV assessment and treatment among people with chronic HCV and a history of injecting drug use, recruited from 9 community health centers and opioid substitution therapy (OST) clinics (New South Wales, Australia). Symptoms were assessed using the Depression Anxiety Stress Scales (DASS-21). Analyses were performed using logistic regression. RESULTS: Among 415 participants (mean age 41 years, 71% male), 47%, 52%, and 36% demonstrated moderate to extremely severe symptoms of depression, anxiety, and stress, respectively. In adjusted analyses, depression symptoms were associated with recent injecting drug use [adjusted odds ratio (aOR) 1.63, 95% confidence interval (CI) 1.07-2.49), whereas stress symptoms were associated with unemployment (aOR 2.99, 95% CI 1.09-8.15) and not living with a spouse or other relatives/friends (aOR 1.55, 95% CI 1.01-2.39). Symptoms of depression, anxiety, or stress or having a history of treated mental illness were not independently associated with HCV treatment intent, specialist assessment, or treatment uptake. CONCLUSIONS: Findings suggest a need for improved interventions and care regarding mental health among people living with chronic HCV with a history of injecting drug use, but suggest that symptoms of depression, anxiety, and stress should not be immediate contraindications to HCV assessment and treatment. PMID- 27775956 TI - The role of initial and longitudinal change in blood pressure on progression of arterial stiffness among multiethnic middle-aged men. AB - OBJECTIVE: A few studies have examined the longitudinal association of blood pressure (BP) with arterial stiffness progression, and the results were inconsistent. The objective of this study was to investigate the roles of initial BP and its longitudinal change on the progression of arterial stiffness measured using brachial-ankle pulse wave velocity (baPWV). METHOD: Study participants (n = 656) were from population-based samples of healthy men aged 40-49 years at baseline (213 White Americans, 47 African-Americans, 152 Japanese Americans and 244 Japanese in Japan). BP measures, baPWV and other factors were examined at baseline and 4-7 years later. General linear regression was applied for statistical analyses. RESULT: Annual change in SBP (standardized coefficient: 0.33, P < 0.001), but not its baseline level (standardized coefficient: 0.03, P = 0.495), had a positive significant association with the progression of baPWV after adjusting for a wide range of standard cardiovascular risk factors. Similarly, annual changes in DBP (standardized coefficient: 0.35, P < 0.001), pulse pressure (standardized coefficient: 0.15, P = 0.001) and mean arterial pressure (standardized coefficient: 0.37, P < 0.001) were positively associated with the progression of baPWV. None of the baseline measures were related to the progression of baPWV. CONCLUSION: Our findings imply that, regardless of initial BP, effective monitoring and controlling of BP is important to slow down arterial wall stiffening and hence reduce cardiovascular risk. PMID- 27775958 TI - Predicting Efficacy of Plastic Stents for Posttransplantation Biliary Strictures. AB - BACKGROUND: Biliary strictures (BS) are a common complication of liver transplantation. The standard treatment is sequential insertion of increasing numbers of plastic stents by endoscopic retrograde cholangiopancreatography (ERCP). Despite high success rates, some strictures fail to resolve and require surgery as definitive treatment. GOALS: To identify predictors of response or failure of standard endoscopic treatment, allowing earlier referral to alternative modalities when needed and avoiding unnecessary procedures. STUDY: Database of Gastroenterology Department at Tel Aviv Medical Center was retrospectively reviewed, and data regarding patients who underwent liver transplantation and developed BS were analyzed. RESULTS: Thirty-one patients met the study criteria. Twenty-four (77.4%) resolved with plastic stenting and 7 ultimately required surgery. There were no significant differences between stent responders and nonresponders regarding demographics, transplant and postoperative hospitalization data, time from transplantation to presentation with stricture, total number of ERCP sessions, or maximal number of stents.A trend toward difference was noted in the time elapsed between the first and the second ERCP, whereby ERCP nonresponders required a second procedure sooner than responders. Patients presenting to their second procedure as scheduled ultimately had a 95% endoscopic success rate, whereas those presenting urgently with acute cholangitis had a 55% failure rate (P=0.02). CONCLUSIONS: Urgent repeat ERCP is a harbinger of ultimate failure of plastic stent treatment for BS after liver transplant. This finding may assist earlier triage of these patients toward alternative treatment such as metal stents or surgery, thus sparing needless procedures and complications. PMID- 27775957 TI - Adherence to a Semiannual Surveillance Program for Hepatocellular Carcinoma in Patients With Liver Cirrhosis. AB - BACKGROUND: Patient adherence to screening for hepatocellular carcinoma (HCC) is not well known. Our aims were to analyze the adherence to a surveillance program in a prospective cohort of cirrhotic patients and to examine its association with HCC stage at diagnosis. MATERIALS AND METHODS: A total of 770 patients with cirrhosis were examined semiannually by ultrasound and alpha-fetoprotein at a tertiary center. We collected data on 17 variables at baseline. Suboptimal adherence was defined as failure to complete 2 consecutive screening rounds. RESULTS: Over a median follow-up period of 42.0 months (interquartile range: 60.0), 125 patients (16.2%) had suboptimal adherence. Active or previous intravenous drug use [hazard ratio (HR), 5.33; 95% confidence interval (CI), 3.07 9.23], active alcohol consumption (HR, 3.03; 95% CI, 2.03-4.51), absence of liver decompensation before the inclusion in the program (HR, 1.65; 95% CI, 1.07-2.55) and aspartate transaminase/alanine transaminase ratio >=1.6 (HR, 1.82; 95% CI, 1.23-2.70) were independent predictors of suboptimal adherence. Compared with those with optimal adherence, patients with suboptimal adherence had a more advanced HCC stage at diagnosis (P=0.015), they were less frequently treated with curative intention (P=0.078) and survived less (median: 14.2 mo; IQR: 36.0 vs. 22.7 mo; IQR: 47.4; P=0.160), although these differences were not significant. CONCLUSIONS: The adherence to the process of HCC surveillance can be considered as adequate among cirrhotic patients. Active alcohol consumption and a history of intravenous drug use are the strongest predictors of suboptimal adherence. These patients have a more advanced HCC stage at diagnosis and tend to be less frequently treated with curative intention. PMID- 27775959 TI - Chronic Abdominal Wall Pain. PMID- 27775960 TI - Quality of Sleep and Coexistent Psychopathology Have Significant Impact on Fatigue Burden in Patients With Inflammatory Bowel Disease. AB - BACKGROUND: Fatigue is common in inflammatory bowel disease (IBD) patients and is associated with factors such as psychopathology, sleep quality, and disease activity. GOAL: To investigate the combined role of all the above factors in the burden of fatigue among IBD patients. STUDY: We conducted an observational study of adult patients enrolled in an IBD clinical research registry at a tertiary care clinic. Fatigue burden was defined by Item 1 of the Short-form IBD Questionnaire (SIBDQ), which is scored on a 7-point Likert scale. Crohn's disease (CD) and ulcerative colitis (UC) disease activity were measured with the Harvey Bradshaw Index or the UC Activity Index, respectively. Labs were obtained to assess anemia, vitamin deficiencies, and inflammatory markers. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Use of psychotropic medications and narcotics was used as proxy measure of psychopathology and pain. RESULTS: Among 685 IBD patients enrolled in the registry, 631 (238 UC, 393 CD) had a complete SIBDQ. High fatigue burden was found in 57.5% of patients (64.4% CD, 46.2% UC). Fatigue burden was significantly associated with sleep disturbance (PSQI), SIBDQ, and disease activity. CD patients had more fatigue burden than UC patients. Multivariate regression showed that poor quality of life, sleep disturbance, and being on a psychotropic medication are significantly associated with fatigue burden for both UC and CD. CONCLUSION: Because fatigue is common in IBD patients, these findings suggest that attention to quality of sleep and psychopathology is as important as medical disease management. PMID- 27775961 TI - Gastroparesis: Quality of Life and Health Care Utilization. AB - BACKGROUND AND AIMS: Gastroparesis (GP) patients suffer from recurrent symptoms of nausea, vomiting, early satiety, and abdominal pain. The impact of GP on quality of life (QoL), health care utilization and daily activities is not well understood. MATERIALS AND METHODS: Part 1: 398 adult patients (>=18 y) with documented GP (symptoms >6 mo) were surveyed to assess QoL and pain using the Short Form 36 and McGill pain questionnaires. Part 2: 491 adult GP patients were surveyed to evaluate employment status, work and daily activities, medication use, physician visits, diagnostic testing, emergency room visits, and hospitalizations related to their GP symptoms. Both protocols received Institutional Review Board approval. RESULTS: Part 1: 250 fully evaluable surveys were returned (63%). The mean age was 46.8 years (range, 18 to 84 y); 78% were women. Mean Short Form 36 scores for mental health (56.9) and social functioning (68.1) were analogous to scores for patients with serious chronic medical disorders and depression. Pain scores were lower in patients with idiopathic GP compared with diabetic GP. Part 2: 228 evaluable surveys were analyzed (58.3% response rate). The mean age was 49.6 (19 to 86 y); 77.2% were women. GP symptoms reduced daily activities in 67.5% and lowered annual income in 28.5%. In total, 11% were disabled due to GP symptoms. CONCLUSIONS: GP reduces patients' QoL and places a significant financial burden on the health care system. Treatment strategies for GP patients should be broad based and incorporate pain management, psychological evaluation and management, and strategies to improve overall well being with a return to work and daily activities. PMID- 27775962 TI - Optical Diagnosis of Sessile Serrated Polyps: Bottleneck for the Optical Diagnosis Paradigm? AB - BACKGROUND: Optical diagnosis of diminutive (1 to 5 mm) polyps could result in a more cost-effective colonoscopy practice. Previous optical diagnosis studies did not incorporate the differentiation of sessile serrated polyps (SSPs). This study aimed to evaluate the impact of optical diagnosis of diminutive SSPs on the overall performance of endoscopic polyp differentiation in daily colonoscopy practice. METHODS: Endoscopy data were prospectively collected between 2011 and 2014 in a colonoscopy center. Each endoscopist reported a real-time optical diagnosis (SSP, adenoma or hyperplastic polyp) for all lesions in a structured colonoscopy reporting system, using narrow band imaging at their discretion. Study outcomes were accuracy of optical diagnosis, surveillance interval agreement and negative predictive value for diminutive rectosigmoid neoplastic histology based on the optical diagnosis of diminutive polyps compared to histopathology. RESULTS: Of 2853 removed diminutive polyps, 202 (7.1%) were histologically proven SSPs. Optical diagnosis of diminutive SSPs was accurate in 24.4%. Diminutive SSPs determined 6.9% of postpolypectomy surveillance assignments. Inaccurate optical diagnosis of diminutive SSPs led to lower surveillance interval agreement (78.1% vs. 53.3%, P<0.01) and pooled negative predictive value per polyp (84.3% vs. 50.0%; P<0.01) in patients with diminutive SSPs when compared to patients without diminutive SSPs. Accurate endoscopic identification of diminutive SSPs improved from 0% in 2011 to 47% in 2014 (P=0.02). CONCLUSIONS: Endoscopic characterization of diminutive SSPs is difficult, impairing overall performance of optical diagnosis in patients with diminutive SSPs. Future optical diagnosis studies should use validated trainings and classification algorithms that include differentiation of SSPs. PMID- 27775963 TI - Can Endoscopic Bleeding Control Improve the Prognosis of Advanced Gastric Cancer Patients?: A Retrospective Case-Control Study. AB - BACKGROUND: Gastric bleeding is not rare and difficult to treat in gastric cancer patients. We investigated whether this affects survival and if successful bleeding control improves the prognosis. PATIENTS/MATERIAL AND METHODS: We retrospectively reviewed medical records for 64 subjects who underwent endoscopic therapy for gastric cancer bleeding at Asan Medical Center from January 2012 to December 2014 (bleeding group). Each subject was matched 1:2 by age, sex, and American Joint Committee on Cancer staging with 128 randomly selected patients treated for stomach cancer during the same period (control group). Median survival, bleeding treatment methods, successful bleeding control, and rebleeding rate were investigated. RESULTS: The median age was 58.5 years, the male to female ratio 4.3:1. The initial hemostasis rate was 73.4%. Most patients were treated with a single method (37 patients, 57.8%); the coagrasper (32/95 cases, 33.7%) was the most frequently used treatment. Among the 47 patients in which successful bleeding control was achieved, 17 (36.2%) experienced rebleeding after 3 days. The median survival was longer in the control than in the bleeding group (18.5 vs. 6.5 mo), and in the successful bleeding control than in the failed bleeding control group (8.5 vs. 1.8 mo). However, the successful bleeding control group had lower survival than the control group (18.5 vs. 8.5 mo). Multivariate analysis showed that the risk of bleeding was lower in Borrmann type II, IV cancer, but was higher in the patients using antiplatelet or anticoagulant. CONCLUSIONS: Successful bleeding control is essential for improving survival in bleeding gastric cancer patients. PMID- 27775964 TI - Patch Testing to Essential Oils. PMID- 27775965 TI - Erythema Multiforme-Like Allergic Contact Dermatitis to Turmeric Essential Oil. PMID- 27775966 TI - Essential Oils, Part V: Peppermint Oil, Lavender Oil, and Lemongrass Oil. AB - Some aspects of peppermint oil, lavender oil, and lemongrass oil are discussed including their botanical origin, uses of the plants and the oils, chemical composition, contact allergy to and allergic contact dermatitis from these essential oils, and causative allergenic ingredients. PMID- 27775967 TI - North American Contact Dermatitis Group Patch Test Results 2013-2014. AB - BACKGROUND: Patch testing is the most important diagnostic tool for the assessment of allergic contact dermatitis. OBJECTIVE: This study documents the North American Contact Dermatitis Group (NACDG) patch testing results from January 1, 2013, to December 31, 2014. METHODS: At 13 centers in North America, patients were tested in a standardized manner with a screening series of 70 allergens. Data were manually verified and entered into a central database. Descriptive frequencies were calculated, and trends were analyzed using chi test. RESULTS: A total of 4871 patients were tested. There were 3255 patients (66.8%) who had at least 1 positive reaction and 2412 patients (49.5%) who were ultimately determined to have a primary diagnosis of allergic contact dermatitis. A total of 434 patients (8.9%) had occupationally related skin disease. There were 9726 positive allergic reactions. Compared with the previous reporting periods (2011-2012 and 2001-2012, including at least three 2-year cycles), positive reaction rates for the top 25 screening allergens statistically increased for 2 allergens: methylchloroisothiazolinone/methylisothiazolinone (6.4%; risk ratios, 1.26 [1.07-1.50] and 2.08 [1.84-2.37]) and hydroxyethyl methacrylate (2.6%; risk ratios, 1.34 [1.02-1.76] and 1.23 [1.00-1.51]). Methylisothiazolinone, which was added to the screening series for this 2013-2014 cycle, had the third highest positive reaction rate of allergens tested (10.9%). Four other newly added allergen preparations-formaldehyde 2% (7%), diphenylguanidine (3.8%), propylene glycol 100% (2.8%), and benzophenone-4 (2.1%) all had reaction rates greater than 2%. Twenty-one percent of tested patients had at least 1 relevant allergic reaction to an allergen not on the NACDG series; 14.6% of these were occupationally related. The T.R.U.E. TEST (SmartPractice Denmark, Hillerod, Denmark) would have hypothetically missed one quarter to one third of reactions detected by the NACDG screening series. CONCLUSIONS: These results confirm that the epidemic of sensitivity to methylisothiazolinone previously documented in Europe is also occurring in North America. Patch testing with allergens beyond a standard screening tray is necessary for the complete evaluation of occupational and nonoccupational allergic contact dermatitis. PMID- 27775969 TI - Allergic Contact Dermatitis Caused by Argan Oil. PMID- 27775968 TI - Toothpaste-Induced Oral Mucosal Desquamation. PMID- 27775970 TI - Hypersensitivity Reactions to Metallic Implants Containing Vanadium. PMID- 27775971 TI - Occupational Contact Dermatitis in Mechanics and Repairers Referred for Patch Testing: Retrospective Analysis From the North American Contact Dermatitis Group 1998-2014. AB - BACKGROUND: Contact dermatoses are common in mechanic and repair occupations. OBJECTIVES: This study aimed to (1) estimate the prevalence of occupationally related contact dermatitis among mechanics/repairers patch tested from 1998 to 2014 by the North American Contact Dermatitis Group, (2) characterize responsible allergens and irritants, and their sources, and (3) compare results among 3 occupational subgroups (mechanics, electrical/electronic, and other). METHODS: A cross-sectional analysis of patients patch tested by the North American Contact Dermatitis Group between 1998 and 2014. RESULTS: Of 38,784 patients patch tested, 691 (1.8%) were mechanics/repairers. Male sex (93.5%) and hand involvement (59.5%) were common overall. Occupationally related skin disease was more prevalent among vehicle and mobile equipment mechanics/repairers (52.7%) and other mechanics/repairers (41.4%) than electrical/electronic equipment mechanics/repairers (21.3%). Overall, carba mix, thiuram mix, and methylchloroisothiazolone/methylisothiazolone were the most common occupation related clinically relevant allergens. Gloves, automotive vehicles, solvents, oils, lubricants, and fuels were the most common sources of responsible allergens. CONCLUSIONS: Common occupationally related allergens included rubber accelerators and the preservative methylchloroisothiazolone/methylisothiazolone. PMID- 27775972 TI - Tolerance to a Hair Dye Product Containing 2-Methoxymethyl-P-Phenylenediamine in an Ethnically Diverse Population of P-Phenylenediamine-Allergic Individuals. AB - BACKGROUND: Allergic contact dermatitis after exposure to p-phenylenediamine (PPD)-containing hair dye products is a common and important clinical problem. Because there is a high rate of cross-elicitation of allergic contact dermatitis to other important hair dye products (such as p-toluene diamine and other aminophenol hair dyes) in PPD-allergic patients, safer alternative dyes with excellent hair coloring options are needed. OBJECTIVE: This study aimed to study tolerance to Me-PPD in a PPD-allergic cohort. METHODS: Twenty ethnically diverse volunteers with a history of contact dermatitis to hair dyes or other PPD containing chemicals and positive patch test results to 1% PPD in petrolatum were recruited to study their immediate and delayed skin reactivity to PPD, vehicle control, and 2-methoxy-methyl-PPD (Me-PPD) using the allergy alert test (simulating hair dyeing conditions) on volar forearm skin. This test is a short contact open patch test. CONCLUSIONS: The Me-PPD may offer a safer alternative for PPD-allergic patients with an absent or reduced elicitation response in the allergy alert test simulating hair dye use conditions. The absent or reduced response to Me-PPD diagnosed using the allergy alert test has been shown to help reduce the possibility of moderate to severe cross-elicitation reactions among consumers during hair dyeing. PMID- 27775973 TI - Alkyl Glucosides. AB - Alkyl glucosides are surfactants synthesized through the condensation of long chain fatty alcohols and glucose, extracted from vegetal, renewable sources. Although available for more than 4 decades, they have been rediscovered in recent years because of their eco-friendly character. They are used in various leave-on and rinse-off cosmetics and are considered of low irritancy and allergenicity. However, since the early 2000s, cases of allergic contact dermatitis to this family of molecules have been repeatedly reported. Decyl glucoside was found to be a "hidden" allergen in the sunscreen ingredient Tinosorb M and is likely responsible for most allergic contact dermatitis reported to this compound. Members of the North American Contact Dermatitis Group have seen a steady increase of the rate of sensitization to decyl glucoside. Cross-reactions with other glucosides are common but not automatic; thus, patch testing multiple compounds is recommended. PMID- 27775974 TI - Metal Hypersensitivity and Orthopedic Implants: Survey of Orthopedic Surgeons. AB - BACKGROUND: There is no clear consensus among orthopedic surgeons concerning metal hypersensitivity screening and orthopedic implants. OBJECTIVE: This study investigated practices and opinions about metal hypersensitivity and orthopedic implants via a survey administered to practicing orthopedists. METHODS: A questionnaire was sent to members of the Pennsylvania Orthopaedic Society electronically. Respondents were asked about preoperative and postoperative screening habits concerning metal hypersensitivity and implants. RESULTS: Forty four physicians completed the survey. Only 11% of respondents reported that they always or often screen patients for metal hypersensitivity. Fifty percent of respondents stated that they only rarely refer patients for patch testing (and the remainder never do). If, however, patients were found to have a positive patch test, most providers were very likely to use a different implant. Other respondents were skeptical of the relationship between metal hypersensitivity and implant failure. Dermatitis, pain, and loosening were common reasons for postoperative testing. Seventy percent of respondents said that patch testing rarely or never changed their decision making. CONCLUSIONS: This study is reflective of the lack of consensus between orthopedists regarding patch testing. It demonstrates the diversity of opinions among orthopedists, the need for additional dialogue between orthopedic and dermatology specialties, and the need for larger studies investigating outcomes and metal hypersensitivity. PMID- 27775975 TI - The Scourge of the Spurge Family-An Imitator of Rhus Dermatitis. AB - The Euphorbiaceae family (commonly known as "spurge") is a large, diverse, and widely distributed family of plants that encompass around 300 genera and more than 8000 species. Their attractiveness and hearty nature have made them popular for both indoor ornamentation and outdoor landscaping. Despite their ubiquity, the potential to cause irritant contact dermatitis (ICD) is often overlooked in favor of more notorious causes of phytodermatitis, namely, Toxicodendron species and nettles. We examined case reports spanning 40 years and discovered that spurge-induced ICD tends to befall children and middle-aged adults who unwittingly encounter the plant through play or horticulture, respectively. Clinical presentation is pleomorphic. Erythema, edema, burning, vesicles, and pruritus of acute onset and rapid resolution are frequently observed. We present a classic case of ICD in a 12-year-old girl after exposure to Euphorbia myrsinites and review the literature on phytodermatitis caused by members of the Euphorbiaceae family. PMID- 27775976 TI - Allergic Contact Dermatitis to Ophthalmic Medications: Relevant Allergens and Alternative Testing Methods. AB - Allergic contact dermatitis is an important cause of periorbital dermatitis. Topical ophthalmic agents are relevant sensitizers. Contact dermatitis to ophthalmic medications can be challenging to diagnose and manage given the numerous possible offending agents, including both active and inactive ingredients. Furthermore, a substantial body of literature reports false-negative patch test results to ophthalmic agents. Subsequently, numerous alternative testing methods have been described. This review outlines the periorbital manifestations, causative agents, and alternative testing methods of allergic contact dermatitis to ophthalmic medications. PMID- 27775978 TI - Disease Severity and Quality of Life Measurements in Contact Dermatitis: A Systematic Review 2005-2015. AB - BACKGROUND: Contact dermatitis (CD) has been assessed by numerous disease severity indices resulting in heterogeneity across published research. OBJECTIVE: This study aims to evaluate published CD severity scales and identify a criterion standard for assessment. METHODS: Scopus and Ovid MEDLINE were searched for human randomized controlled trials (RCTs) on CD severity measures published during a 10 year period. Eligible studies were English-language RCTs reporting disease severity outcome measures for CD in humans. Studies were excluded if they were duplicates, not available in English, not related to CD, not RCTs, not conducted on human subjects, or did not report relevant outcome measures. RESULTS: A total of 22 disease outcome measures were used in 81 included RCTs. Instrument-based measures were used in 40 (49.4%) studies, and visual assessments were used in 66 (81.5%) RCTs. Only 5 (6.2%) studies reported quality of life (QoL) outcomes. Two (2.5%) studies used a clinical severity scale, which combined both QoL and visual assessments. LIMITATIONS: This study was limited by the exclusion of non-RCTs and gray literature. CONCLUSIONS: Wide variation in CD outcome measures exists including instrument-based measures, visual assessments, and QoL outcomes. A standardized outcome measure must be generated to reduce heterogeneity. PMID- 27775977 TI - Epidemiology and Co-Reactivity of Novel Surfactant Allergens: A Double-Blind Randomized Controlled Study. AB - BACKGROUND: Surfactants are cleansing agents used in products such as shampoos and soaps. OBJECTIVES: The aims of this study were to identify positivity rates to 3 novel amide-containing surfactants (sodium lauroyl sarcosinate, isostearamidopropyl morpholine lactate, and disodium lauroamphodiacetate) and evaluate co-reactivity with other surfactants in patients with known surfactant sensitivity. METHODS: Previously patch-tested, surfactant-positive patients were identified via chart review and invited to participate. Participants were patch tested to screening surfactants (cocamidopropyl betaine, amidoamine, dimethylaminopropylamine, cocamide diethanolamine [DEA], oleamidopropyl dimethylamine, and decyl glucoside), as well as 3 novel surfactants: sodium lauroyl sarcosinate 0.5% and 1.0% aq, isostearamidopropyl morpholine lactate 0.5% and 1.0% aq, disodium lauroamphodiacetate 1.0 and 2.0% aq, and a hypoallergenic liquid cleanser (tested semiopen). Participants and clinicians were blinded. The order of tested allergens was randomized. RESULTS: Forty-seven participants completed the study. Excluding doubtful reactions, positive reactions were most common to oleamidopropyl dimethylamine (34%) and dimethylaminopropylamine (34%), followed by isostearamidopropyl morpholine lactate (23%). Reactivity was not associated with history of childhood eczema. Co-reactivity was high among oleamidopropyl dimethylamine, dimethylaminopropylamine, cocamidopropyl betaine, amidoamine, and isostearamidopropyl morpholine lactate. None of the participants who reacted to cocamide DEA reacted to an additional surfactant. CONCLUSIONS: Isostearamidopropyl morpholine lactate may be an important emerging allergen with sensitivity rates comparable with those of oleamidopropyl dimethylamine and dimethylaminopropylamine. Co-reactivity among surfactants was frequent except for cocamide DEA. PMID- 27775980 TI - From the Editor. PMID- 27775979 TI - Alkyl Glucosides in Contact Dermatitis. AB - Ecologically sound because they are synthesized from natural and renewable sources, the mild surfactants alkyl glucosides are being rediscovered by the cosmetic industry. They are currently found in rinse-off products such as shampoos, liquid cleansers, and shower gels, but also in leave-on products that include moisturizers, deodorants, and sunscreens. During the past 15 years, numerous cases of allergic contact dermatitis have been published, mostly to lauryl and decyl glucosides, and these compounds are considered emergent allergens. Interestingly, the sunscreen Tinosorb M contains decyl glucoside as a hidden allergen, and most cases of allergic contact dermatitis reported to this sunscreen ingredient are probably due to sensitization to decyl glucoside. This article will review the chemistry of alkyl glucosides, their sources of exposure, as well as their cutaneous adverse effects reported in the literature and encountered in various patch testing centers. PMID- 27775981 TI - Case in Health Care Management. PMID- 27775982 TI - Evaluating Pre Burn Center Intubation Practices: An Update. AB - A significant proportion of patients appeared to arrive at our American Burn Association-verified burn center intubated without clear benefit. The current study aims to evaluate regional prehospital intubation practices and their outcomes. All consecutive admissions from November 2012 to June 2014 were reviewed for data points associated with intubation. Demographics and outcomes for patients who were intubated before arrival or within 24 hours of admission were compared using chi, Fisher's exact test, and the Kruskal-Wallis test as appropriate. During this period, 958 patients were admitted. Of these, 120 were intubated before arrival, and 91 survived their injuries. Of these 91 survivors, 45 were extubated within 2 days, suggesting unnecessary intubation rate in 37.5%. Intubation-related complications were roughly three times as common among those intubated before arrival (12.5% vs 4.4%). Patients intubated before arrival to our burn center had a shorter median duration of intubation (1.0 vs 4.0 days), median hospital LOS (5.0 vs 22.0 days), and median intensive care unit length of stay (3.0 vs 10.0 days). Furthermore, we found a significant difference in the pattern of ventilator support duration between those arriving intubated, with a median of 2.0 days, and those intubated at our burn center, with a median of 5.5 days. Patients intubated by pre burn center providers have shorter intubation durations and shorter hospitalizations, suggesting inappropriate use of resources. Impending loss of airway appears unlikely among patients with adequate gas exchange at the time of examination. The current criteria for prehospital intubation should be revised to more accurately identify those who truly benefit from advanced airway maneuvers. PMID- 27775984 TI - Hydrofiber Dressing Saturated With Mafenide Acetate Extends the Duration of Antimicrobial Activity. AB - Mafenide acetate is used in some burn wounds for its ability to penetrate eschar but requires frequent uncomfortable dressing changes for its application. The authors hypothesize that hydrofiber dressings will hold mafenide acetate solution for an extended period of time and maintain antimicrobial activity longer than traditional gauze, thus possibly obviating the need for frequent dressing changes. Four experimental arms included: 1) hydrofiber, stored on a dry well plate as control, 2) gauze saturated with 2.5% mafenide acetate, stored on nonsterile porcine skin, 3) hydrofiber saturated with mafenide acetate, stored on dry well plate, and 4) hydrofiber saturated with mafenide acetate, stored on nonsterile porcine skin. At 0, 24, 48, and 72 hours, a 1-cm disk was cut from the dressing sheet of each study arm, placed on agar plates seeded with Staphylococcus aureus and Pseudomonas aeruginosa, and incubated for 24 hours, and the zone of inhibition was measured. A zone of 2 mm or greater was indicative of susceptibility. Each arm of the experiment was performed four times to demonstrate reproducibility. Plain hydrofiber (control) demonstrated no zone of inhibition at any time point, thereby possessing no antimicrobial activity alone. Gauze saturated with mafenide acetate did not reliably demonstrate antimicrobial activity beyond 0 hours. Hydrofiber saturated with mafenide acetate, whether stored on a dry well plate or nonsterile porcine skin, consistently possessed sustained antimicrobial activity as demonstrated by zones of inhibition greater than 2 mm to both S. aureus and P. aeruginosa. Mafenide acetate-soaked hydrofiber dressings stay moist and maintain antimicrobial activity against S. aureus and P. aeruginosa for at least 72 hours without repeated soaks. PMID- 27775986 TI - Treatment of Keloids With Excision and Adjuvant Radiation: A Single Center Experience and Review of the Literature. AB - BACKGROUND: Management of keloids has remained a conundrum, because an optimum treatment regimen has yet to be elucidated. Currently, treatment varies widely between more conservative measures, such as steroid injections, topical medications, and silicone sheeting, to more aggressive options, such as surgery and postoperative radiation. The latter combination has been touted to have superior results, with the lowest rates of pathologic scar recurrence. METHODS: We performed a retrospective review to critically evaluate the effectiveness of surgical excision and radiation treatment in patients with keloids. Surgical resection of surgeon-selected keloids, combined with state-of-the-art postoperative cutaneous radiation therapy, was used at a major tertiary referral center. For patients with poor follow-up, phone calls were made to determine recurrence. In addition, we present a review of the current literature to provide a comprehensive synopsis of current keloid treatment. RESULTS: A total of 69 patients' records were reviewed. There were a total of 84 keloids upon pathology review. The overall recurrence rate for all keloids was 27%, and in those followed greater than 1 year, recurrence for keloids was 74%. About half the patients with more than 1 year of follow-up experienced recurrence more than 1 year after treatment. CONCLUSIONS: At this time, the evidence supporting surgery and radiation for the treatment of keloids remains equivocal, and randomized controlled studies are needed to determine the efficacy of this treatment protocol. Most importantly, our data reinforce the need for long-term follow-up in this patient population. PMID- 27775983 TI - Improved Survival of Patients With Extensive Burns: Trends in Patient Characteristics and Mortality Among Burn Patients in a Tertiary Care Burn Facility, 2004-2013. AB - Classic determinants of burn mortality are age, burn size, and the presence of inhalation injury. Our objective was to describe temporal trends in patient and burn characteristics, inpatient mortality, and the relationship between these characteristics and inpatient mortality over time. All patients aged 18 years or older and admitted with burn injury, including inhalation injury only, between 2004 and 2013 were included. Adjusted Cox proportional hazards regression models were used to estimate the relationship between admit year and inpatient mortality. A total of 5540 patients were admitted between 2004 and 2013. Significant differences in sex, race/ethnicity, burn mechanisms, TBSA, inhalation injury, and inpatient mortality were observed across calendar years. Patients admitted between 2011 and 2013 were more likely to be women, non-Hispanic Caucasian, with smaller burn size, and less likely to have an inhalation injury, in comparison with patients admitted from 2004 to 2010. After controlling for patient demographics, burn mechanisms, and differential lengths of stay, no calendar year trends in inpatient mortality were detected. However, a significant decrease in inpatient mortality was observed among patients with extensive burns (>=75% TBSA) in more recent calendar years. This large, tertiary care referral burn center has maintained low inpatient mortality rates among burn patients over the past 10 years. While observed decreases in mortality during this time are largely due to changes in patient and burn characteristics, survival among patients with extensive burns has improved. PMID- 27775988 TI - Lamivudine-Associated Pancreatitis: Strongest Evidence to Date. PMID- 27775989 TI - Evidence for Implementation Strategies to Provide Palliative Care in the Neonatal Intensive Care Unit. AB - BACKGROUND: Palliative care is a holistic framework that is designed to improve quality of life by identifying and treating distressing symptoms of life threatening or complex conditions. Neonatal palliative care (NPC) has potential benefits for parents, staff, and patients, yet evidence suggests that implementation and utilization of organized NPC services are low. PURPOSE: The purpose of this study is to answer the clinical question: In neonatal intensive care, what evidence can be used to guide implementation of palliative care protocols? SEARCH STRATEGY: A literature search was conducted using CINAHL (Cumulative Index of Nursing and Allied Health Literature), PubMed, and the Cochrane Library databases. Publications with a focus on neonates, neonatal intensive care unit, and implementation or evaluation of a palliative care protocol, team, or educational intervention were retained. RESULTS: The search yielded 17 articles that fit with the following themes: NPC protocols or teams (n = 8), healthcare team needs (n = 3), and barriers to implementation (n = 6). Approaches to NPC implementation were varied, and outcome data were inconsistently reported. Healthcare team members cited a need for education and consistent, ethical delivery of NPC. Common barriers were identified as lack of NPC education, poor communication, and lack of adequate resources such as staff and space. IMPLICATIONS FOR PRACTICE AND RESEARCH: Successful team approaches included standardized order sets to initiate NPC, NPC education for staff, and references to NPC guidelines or protocols. Barriers such as lack of interdisciplinary cooperation, lack of appropriate physical space, and lack of education should be addressed during program development. Further research priorities for NPC include seeking parent perceptions, shifting focus from mostly end-of-life to an integrated model, and collecting outcome data with rigor and consistency. PMID- 27775990 TI - Quality Metrics: Executive Summary of Position Statement 3068: From the National Association of Neonatal Nurses. PMID- 27775991 TI - Irradiated VEGF164-modified tumor cell vaccine protected mice from the parental tumor challenge. AB - Vascular endothelial growth factor (VEGF) is an important regulating molecule of angiogenesis in tumor formation and progression. Cancer cells always secrete VEGF to stimulate angiogenesis that facilitate growth and invasion of the tumor. In this study, we established a VEGF164 overexpressing LL/2 lung cancer cell model and found that the postirradiated VEGF164-modified tumor cells protected the host against the challenge with LL/2 wild-type tumor cells. Histochemical assay showed that there were large areas of tumor necrosis with macrophage infiltration in the mice vaccinated with the VEGF164-modified tumor vaccine. T-cells isolated from the vaccinated mice showed cytotoxicity against the parental tumor cells in a dose-dependent manner. Meanwhile, sera from the mice vaccinated with LL/2-VEGF164 showed higher titers of antibodies against parental tumor cells compared with the nonvaccinated groups. Our results indicated that VEGF164-modified tumor vaccine could modulate host antitumor immune response and hold therapeutic potential for cancer. PMID- 27775992 TI - Efficacy and safety of recombinant human adenovirus p53 combined with chemoradiotherapy in the treatment of recurrent nasopharyngeal carcinoma. AB - This study aims to explore the efficacy and safety of recombinant human adenovirus p53 (rAd-p53) combined with chemoradiotherapy (CRT) in the treatment of recurrent nasopharyngeal carcinoma (NPC). A total of 162 recurrent NPC patients were selected and divided randomly into the rAd-p53+CRT, CRT, and rAd p53 groups. An electrochemical luminescence immune analyzer was used to detect serum levels of tumor markers (carcinoembryonic antigen, cancer antigen 199, and cancer antigen 153). Efficacy evaluation was in accordance with Response Evaluation Criteria in Solid Tumor. Toxicity evaluation was performed according to the WHO grading standard. A 3-year follow-up was performed. A Kaplan-Meier curve was drawn to calculate progression-free survival and the 3-year survival rate. The complete response rate and effective rate (complete response+partial response) of recurrent NPC patients in the rAd-p53+CRT group were higher than those in the CRT and rAd-p53groups. After treatment, compared with the CRT and rAd-p53 groups, the rAd-p53+CRT group had lower serum levels of carcinoembryonic antigen, cancer antigen 199, and cancer antigen 153. The incidences of leukopenia and oral mucositis in the rAd-p53+CRT group were lower than those in the CRT group, but no differences were found between the rAd-p53+CRT and rAd-p53 groups. The progression-free survival and 3-year survival rate of recurrent NPC patients in the rAd-p53+CRT group were higher than the than those in the CRT and rAd-p53 groups. Our study supports that rAd-p53 combined with CRT may provide better efficacy and lower toxicity than rAd-p53 or CRT alone for the treatment of recurrent NPC patients. PMID- 27775993 TI - Qualitative and quantitative comparison of gated blood pool single photon emission computed tomography using low-energy high-resolution and SMARTZOOM collimation. AB - OBJECTIVE: The aim of this study was to assess the feasibility of IQ-SPECT gated blood pool (MUGA) under conditions of decreased scan time (ST). PATIENTS AND METHODS: Ten patients underwent routine 26-min, two-view planar, followed by LEHR and IQ-SPECT MUGA, on a Siemens dual-head Symbia scanner. Six 'back and forth' 4 min SPECT scans were summed into 4-, 8-, 12-, 16-, 20-, and 24-min equivalent scans, and reconstructed iteratively (IQ-SPECT and LEHR) and with FBP (LEHR). Uniformity, contrast, and wall motion were scored on a five-point scale. Linear regressions of left ventricular (LV) ejection fraction (EF) were performed between FBP, Flash 3D, and IQ-SPECT versus planar and Flash 3D and IQ-SPECT versus FBP. Agreement tables between Flash 3D and IQ-SPECT versus FBP LV EF were generated using a normal versus cardiotoxicity threshold of 50%. RESULTS: IQ SPECT had the best scores for all STs, and 4, 8, and 16 min IQ-SPECT were judged to be similar to 24-min LEHR FBP, Flash 3D, and planar, respectively. The average LV EF correlation coefficients were 0.69, 0.71, and 0.63 between IQ-SPECT, Flash 3D, and FBP versus planar, respectively; 0.70 between IQ-SPECT and FBP; and 0.88 between Flash 3D and FBP, and all were statistically significant (P<0.05), except for 16-min FBP LEHR versus planar. Agreement tables showed diagnostic equivalence of IQ-SPECT, Flash 3D, and FBP. CONCLUSION: These preliminary results suggest that IQ-SPECT is equivalent to LEHR Flash 3D and FBP for MUGA SPECT, and better at reduced ST. A larger patient population study is necessary for a more definitive assessment. PMID- 27775994 TI - The role of 68Ga-DOTA-TATE PET/CT scanning in the evaluation of patients with multiple myeloma: preliminary results. AB - OBJECTIVE: In this observational pilot study, we aimed to evaluate the role of gallium-68-labelled DOTA-TATE (Ga-TATE) PET/computed tomography (CT) scanning in patients with multiple myeloma (MM), considering previous promising results obtained from conventional somatostatin receptor scintigraphy with In pentetreotide. MATERIALS AND METHODS: Twenty-one patients with a diagnosis of MM were prospectively included in this study: eight patients were referred for initial staging and 13 patients for restaging purpose. Both fluorine-18 fluorodeoxyglucose (F-FDG) and TATE PET/CT scanning were performed in all patients. RESULTS: All patients had one or more PET-positive lesion on either F FDG or TATE scans. Six patients had an additional diffusely increased bone marrow activity on F-FDG scans, five of whom also had a concordant bone marrow appearance on TATE scans. Each PET set (either F-FDG or TATE) was positive in 19 patients. There was a discordant result in four (19%) patients between F-FDG and TATE scans. F-FDG scans showed 112 lesions (86 TATE-positive; 26 TATE-negative) in 19 patients, whereas TATE scans showed 108 lesions (86 F-FDG-positive; 22 F FDG-negative) in 19 patients. No significant difference was found between the two modalities in terms of lesion numbers detected (P=0.67). However, the presence of diffuse bone marrow uptake of TATE seems to be a predicting factor for the overall survival (P=0.033, hazard ratio: 15.2 and 95% confidence interval: 1.2 185.5). CONCLUSION: TATE PET/CT seems to be an alternative imaging modality and may play a complementary role in MM management, at least by providing a different pathobiological insight into the disease. PMID- 27775995 TI - Effectiveness of an Electronic Alert for Hypotension and Low Bispectral Index on 90-day Postoperative Mortality: A Prospective, Randomized Trial. AB - BACKGROUND: We tested the hypothesis that an electronic alert for a "double low" of mean arterial pressure less than 75 mmHg and a bispectral index less than 45 reduces the primary outcome of 90-day mortality. METHODS: Adults having noncardiac surgery were randomized to receive either intraoperative alerts for double-low events or no alerts. Anesthesiologists were not blinded and not required to alter care based upon the alerts. The primary outcome was all-cause 90-day mortality. RESULTS: Patients (20,239) were randomized over 33 months, and 19,092 were analyzed. After adjusting for age, comorbidities, and perioperative factors, patients with more than 60 min of cumulative double-low time were twice as likely to die (hazard ratio, 1.99; 95% CI, 1.2 to 3.2; P = 0.005). The median number of double-low minutes (quartiles) was only slightly lower in the alert arm: 10 (2 to 30) versus 12 (2 to 34) min. Ninety-day mortality was 135 (1.4%) in the alert arm and 123 (1.3%) in the control arm. The difference in percent mortality was 0.18% (99% CI, -0.25 to 0.61). CONCLUSIONS: Ninety-day mortality was not significantly lower in patients cared for by anesthesiologists who received automated alerts to double-low states. Prolonged cumulative double-low conditions were strongly associated with mortality. PMID- 27775996 TI - Preoperative Administration of Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers: Do We Have Enough "VISION" to Stop It? PMID- 27775997 TI - Withholding versus Continuing Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers before Noncardiac Surgery: An Analysis of the Vascular events In noncardiac Surgery patIents cOhort evaluatioN Prospective Cohort. AB - BACKGROUND: The effect on cardiovascular outcomes of withholding angiotensin converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown. METHODS: In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes. RESULTS: Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery. CONCLUSIONS: Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24 h before surgery. PMID- 27775998 TI - Impact of Methylprednisolone on Postoperative Quality of Recovery and Delirium in the Steroids in Cardiac Surgery Trial: A Randomized, Double-blind, Placebo controlled Substudy. AB - BACKGROUND: Inflammation after cardiopulmonary bypass may contribute to postoperative delirium and cognitive dysfunction. The authors evaluated the effect of high-dose methylprednisolone to suppress inflammation on the incidence of delirium and postoperative quality of recovery after cardiac surgery. METHODS: Five hundred fifty-five adults from three hospitals enrolled in the randomized, double-blind Steroids in Cardiac Surgery trial were randomly allocated to placebo or 250 mg methylprednisolone at induction and 250 mg methylprednisolone before cardiopulmonary bypass. Each completed the Postoperative Quality of Recovery Scale before surgery and on days 1, 2, and 3 and 1 and 6 months after surgery and the Confusion Assessment Method scale for delirium on days 1, 2, and 3. Recovery was defined as returning to preoperative values or improvement at each time point. RESULTS: Four hundred eighty-two participants for recovery and 498 participants for delirium were available for analysis. The quality of recovery improved over time but without differences between groups in the primary endpoint of overall recovery (odds ratio range over individual time points for methylprednisolone, 0.39 to 1.45; 95% CI, 0.08-2.04 to 0.40-5.27; P = 0.943) or individual recovery domains (all P > 0.05). The incidence of delirium was 10% (control) versus 8% (methylprednisolone; P = 0.357), with no differences in delirium subdomains (all P > 0.05). In participants with normal (51%) and low baseline cognition (49%), there were no significant differences favoring methylprednisolone in any domain (all P > 0.05). Recovery was worse in patients with postoperative delirium in the cognitive (P = 0.004) and physiologic (P < 0.001) domains. CONCLUSIONS: High-dose intraoperative methylprednisolone neither reduces delirium nor improves the quality of recovery in high-risk cardiac surgical patients. PMID- 27776001 TI - Central Factors Contribute to Knee Extensor Strength Loss after 2000-m Rowing in Elite Male and Female Rowers. AB - PURPOSE: Despite growing interest in task-dependent alterations of central and peripheral fatigue after endurance exercise, little is known about the effect of rowing on quadriceps muscle fatigue. This study aimed to investigate central and peripheral mechanisms of fatigue after a 2000-m rowing time trial. METHODS: Eight competitive rowers (four males and four females, 20 +/- 4 yr) performed a 2000-m time trial on an indoor rower and a control condition (sitting). The neuromuscular function of the knee extensors was analyzed before and 3 min after each experimental condition. Maximal voluntary torque, voluntary activation, and normalized root-mean-square of the EMG signal were measured during isometric and concentric contractions. Furthermore, knee extensor twitch torque and maximal M wave amplitudes in response to electrical nerve stimulation were assessed. RESULTS: After the 2000-m rowing, there were significant reductions in isometric and concentric maximal voluntary torque of the knee extensors (-20% +/- 9% and 18% +/- 7%, respectively, P < 0.01). Both the voluntary activation of the knee extensors during isometric and concentric contractions decreased by 18% +/- 15% (P < 0.05, respectively). The normalized muscle activity of rectus femoris was significantly reduced after rowing (P = 0.007), whereas vastus medialis and vastus lateralis muscle activities did not significantly differ from baseline values. No significant change was observed for knee extensor twitch torque in response to paired electrical stimuli after rowing. CONCLUSION: The 2000-m rowing time trial resulted in significant knee extensor strength loss. Quadriceps muscle fatigue after high-intensity rowing exercise was explained primarily by central factors that lead to large reductions in voluntary drive. PMID- 27776000 TI - Construct Validity of the Neighborhood Environment Walkability Scale for Africa. AB - PURPOSE: The development of valid measures of built environments relevant for physical activity is an important step toward controlling the global epidemic of physical inactivity-related noncommunicable diseases and deaths. This study assessed the construct validity of a self-report neighborhood environment walkability scale adapted for Africa (NEWS-Africa), by examining relationships with self-reported walking for transportation and recreation using pooled data from six sub-Saharan African countries. METHODS: NEWS was systematically adapted to assess urban, periurban, and rural environments in sub-Saharan Africa. Adults (n = 469, 18-85 yr, 49.7% women) from Cameroon, Ghana, Mozambique, Nigeria, South Africa, and Uganda were purposively recruited from neighborhoods varying in walkability and socioeconomic status, with some from villages. Participants completed the 76-item (13 subscales) NEWS-Africa by structured interview and reported weekly minutes of walking for transport and recreation using items from the International Physical Activity Questionnaire. RESULTS: The overall "walkability" index had a positive relationship with both walking for transportation (eta = 0.020, P = 0.005) and recreation (eta = 0.013, P = 0.028) in the pooled analyses. The mixed-use access and stranger danger scales were positively related with transport walking (eta = 0.020, P = 0.006 and eta = 0.021, P = 0.040, respectively). Proximity of recreational facilities (eta = 0.016, P = 0.015), road/path connectivity (eta = 0.025, P = 0.002), path infrastructure (eta = 0.021, P = 0.005), and overall places for walking and cycling (eta = 0.012, P = 0.029) scales were positively related to recreational walking. Country-specific results were mostly nonsignificant except for South Africa and Uganda. CONCLUSIONS: Of 14 NEWS-Africa scales, 7 were significantly related to walking behavior in pooled analyses, providing partial support for the construct validity of NEWS-Africa. However, effect sizes appeared to be lower than those from other continents. Further study with larger and more diverse samples is needed to determine whether the instrument performs well in each country. PMID- 27776002 TI - Muscular and Aerobic Fitness, Working Memory, and Academic Achievement in Children. AB - PURPOSE: This study investigated the relationship between aerobic and muscular fitness with working memory and academic achievement in preadolescent children. METHODS: Seventy-nine 9- to 11-yr-old children completed an aerobic fitness assessment using a graded exercise test; a muscular fitness assessment consisting of upper body, lower body, and core exercises; a serial n-back task to assess working memory; and an academic achievement test of mathematics and reading. RESULTS: Hierarchical regression analyses indicated that after controlling for demographic variables (age, sex, grade, IQ, socioeconomic status), aerobic fitness was associated with greater response accuracy and d' in the 2-back condition and increased mathematic performance in algebraic functions. Muscular fitness was associated with increased response accuracy and d', and longer reaction time in the 2-back condition. Further, the associations of muscular fitness with response accuracy and d' in the 2-back condition were independent of aerobic fitness. CONCLUSION: The current findings suggest the differential relationships between the aerobic and the muscular aspects of physical fitness with working memory and academic achievement. With the majority of research focusing on childhood health benefits of aerobic fitness, this study suggests the importance of muscular fitness to cognitive health during preadolescence. PMID- 27776003 TI - Aerobic Exercise Training Modalities and Prediabetes Risk Reduction. AB - PURPOSE: Prediabetes is linked to several modifiable risk factors, in particular, physical activity participation. The optimal prescription for physical activity remains uncertain. This pilot study aimed to investigate the effectiveness of continuous moderate intensity (CON) versus high-intensity interval training (HIIT) in persons with prediabetes. Outcome measures included glycated hemoglobin (A1C), body composition, musculoskeletal and aerobic fitness. METHODS: Participants (n = 35) were recruited and screened using a questionnaire plus capillary blood point-of-care A1C analysis. After baseline screening/exclusions, 21 participants were randomly assigned to either HIIT or CON training three times per week for 12 wk. All participants also undertook resistance training two times per week. A1C, an oral glucose tolerance test, select measures of physical and physiological fitness were assessed at baseline and follow-up. RESULTS: There were no significant differences in improvements in select metabolic indicators to training between CON and HIT groups. Pooled participant data showed a mean reduction in A1C of 0.5% (95% confidence interval [CI] = 0.3%-0.7%), whereas beta cell function (%beta) improved by 28.9% (95% CI = 16.5%-39.2%) and insulin sensitivity (%S) decreased by 34.8 (95% CI = 57.8%-11.8), as assessed by the Homeostatic Model Assessment. Significant reductions in waist circumference of 4.5 cm (P < 0.001) and a 20% (P < 0.001) improvement in aerobic fitness were also observed in both training groups. CONCLUSION: The completion of a 12-wk exercise program involving both resistance training and either HIIT or CON training results in improved glycemic control, visceral adiposity, and aerobic fitness in persons with prediabetes. PMID- 27776004 TI - The Effect of Shoulder Pad Design on Head Impact Severity during Checking. AB - INTRODUCTION: Shoulder-to-head contact is the most common cause of concussions in ice hockey, accounting for 42% of cases in the National Hockey League. The goal of this project was to determine how shoulder pad stiffness, modified by adding foam padding over the shoulder cap of existing shoulder pads, affected head impact severity when participants delivered checks to an instrumented dummy. METHODS: Fifteen participants administered "the hardest shoulder checks they were comfortable delivering" to the head of a dummy equipped with triaxial accelerometers and gyros mounted in its helmet. Trials were conducted with participants wearing two common types of shoulder pads, with and without a 2-cm thick layer of polyurethane foam over the shoulder pad cap. RESULTS: When participants delivered checks with foam-modified pads versus unmodified pads, there was a decrease of 25.0% in the average peak linear head acceleration (28.73g vs 38.31g, mean difference = 9.58g, 95% confidence interval = 6.35-12.81, P < 0.0001) and a decrease of 12.4% in the average value of peak rotational head velocity (838.0 degrees .s vs 956.7 degrees .s, mean difference = 118.65 degrees .s, 95% confidence interval = 55.37-181.94, P = 0.001). The protective benefit of the foam layer did not depend on the type of shoulder pad or the checking scenario. CONCLUSION: The integration of foam padding on top of the plastic caps of shoulder pads reduced impact severity to the head and warrants further examination as a method for contributing to the prevention of brain injuries in ice hockey. PMID- 27776005 TI - The Use of a Simple Dynamic External Fixator for the Treatment of Volar Fracture Subluxation of Proximal Interphalangeal Joints of the Fingers. AB - Volar fracture dislocation is very uncommon, with few series reported in the literature. Patients with such injuries were treated by modified dynamic external fixators. The mean follow-up was 18 months (range, 6 to 92 mo). The mean range of interphalangeal (proximal interphalangeal) joints and distal interphalangeal joints were 90 and 74 degrees, respectively. The total active range of motion (TAM) was excellent (256 degrees). The mean quick disabilities of the arm, shoulder and hand score was 1.2. The advantages of our external fixators are that they are simple, cheap, adjustable, and allow immediate range of motion. PMID- 27776006 TI - Arthroscopic-assisted Acromioclavicular and Coracoclavicular Ligaments Reconstruction for Chronic Acromioclavicular Dislocations: Surgical Technique. AB - Chronic acromioclavicular (AC) instability is a rare posttraumatic shoulder condition that can lead to undesirable symptoms like persistent pain, muscle fatigue, loss of strength, or even scapular dyskinesis. It is well known that in these cases the superior functional results depend on the restoration of the anatomy and stability of the AC joint in both vertical and horizontal planes. Considering the ligaments degeneration and atrophy in chronic AC joint dislocations, we present an arthroscopic-assisted reconstruction of both the coracoclavicular and AC ligaments using autograft augmentation. In details the coracoclavicular ligaments component is reconstructed using the Tightrope suspension device augmented with a palmaris longus autograft and by the nonanatomic coracoacromial ligament transfer (modified Weaver-Dunn). The AC part is restored by suturing the remainder palmaris longus autograft on the acromion and on the deltotrapezial fascia. Using the construct provided by this technique all the possible ruptured ligaments are reconstructed, optimizing the vertical and horizontal stability of the area, and promising excellent long-term radiologic and functional results. PMID- 27776007 TI - A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms. AB - Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET. Features with the highest discriminatory value included diameter of the lesion, dermal architecture, and certain cytomorphologic features. Specifically, cases with a large diameter (>=9 mm) and wedge-shaped, plexiform dermal architecture of nests of large, spindle-shaped cells were most likely to have an ALK fusion. NTRK1-fused cases were most likely of the fusions to have Kamino bodies and were typically arranged in smaller nests with smaller predominantly spindle-shaped cells, occasionally forming rosettes. BRAF fusion cases were the only fusion subtype to have a predominance of epithelioid cells, were less organized in nests, and commonly had a sheet-like growth pattern or dysplastic Spitz architecture. BRAF fusion cases were most likely to have high-grade nuclear atypia, to be diagnosed as spitzoid melanoma, to have a positive result by melanoma fluorescence in situ hybridization assay, and to develop copy number gains in the kinase domain of the fusion protein. On the basis of experience from this cohort, BRAF-fused cases appear most likely to progress to melanoma. PMID- 27776009 TI - Mantle Cell Lymphoma With MYC Rearrangement: A Report of 17 Patients. AB - MYC rearrangement in mantle cell lymphoma (MCL) is rare, and its clinicopathologic significance is not well defined. We report 17 cases of MCL with 8q24/MYC rearrangement, detected at the time of initial diagnosis of MCL in 10 patients and subsequently during the clinical course in 7 patients. There were 12 men and 5 women with a median age of 61 years (range, 49 to 81 y). Fourteen patients had lymphadenopathy (Ann Arbor stage III/IV), and 3 patients presented with a leukemic pattern without lymphadenopathy. Thirteen of 14 patients with available karyotyping data had a complex karyotype. In 8 cases the partner chromosome locus was an IG locus: t(8;14) (n=7) and t(8;22) (n=1). When MYC rearrangement was detected, most patients had a high-risk MCL international prognostic index, and the lymphoma cells had histologically aggressive features. Immunophenotypic analysis showed that the lymphoma cells were positive for cyclin D1 (n=16/16), Myc (9/11), and P53 (n=9/9). The Ki-67 proliferation rate was high (>=60%) in 10/11 cases. All patients received chemotherapy. The median follow-up time was 23 months. Clinical follow-up was available for 14 patients and treatment response in 13 patients. Eleven of 13 patients had refractory or relapsed disease, and 11 patients died. In conclusion, MCL with MYC rearrangement is characterized by advanced-stage disease, aggressive morphologic features, a high proliferation rate, p53 expression, a complex karyotype, and a poor prognosis. We believe these neoplasms fit within the overall concept of double hit lymphoma, and the designation double-hit MCL may be helpful. We also believe that MYC rearrangement in MCL conveys important prognostic information that should be incorporated into the pathology report. PMID- 27776008 TI - Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome: A Multicenter Study. AB - The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation. PMID- 27776010 TI - Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas. AB - Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions. PMID- 27776011 TI - Uterine Serous Carcinomas Frequently Metastasize to the Fallopian Tube and Can Mimic Serous Tubal Intraepithelial Carcinoma. AB - We investigated the frequency, histopathologic, and immunohistochemical characteristics of tubal involvement in uterine serous carcinoma (USC) and aimed to clarify the relationship between "serous tubal intraepithelial carcinoma (STIC)" and USC in these cases. Cases of USC with complete tubal examination were prospectively collected and reviewed for the presence of tubal involvement. Immunohistochemical analysis for p53 and WT1 was performed on the endometrial and tubal tumor in cases with tubal involvement. Of 161 USC cases (pure USC or a component of a mixed carcinoma or a carcinosarcoma), 32 (20%) showed tubal involvement (unilateral: n=19; bilateral: n=13). The uterine tumors in cases with tubal involvement showed a trend toward increased likelihood of deep myometrial and lymphovascular invasion (LVI) compared with those without tubal involvement. The tubal fimbriae were involved in 15/32 cases. Tubal involvement was mucosal in 30/32 cases, mural in 14/32, serosal in 5/32, invasive in 22/32, and there was LVI in the tube in 13/32. STIC-like features were seen in 17/32 cases (7 as the only pattern of involvement, 9 with associated invasive carcinoma, and 5 with LVI). Immunostaining showed complete concordance of p53 and WT1 between the endometrial and tubal tumors in 26/32 cases, the majority being WT1 negative or only focally positive (19/26), and all exhibiting mutation-type p53 staining. On the basis of the histologic and immunohistochemical features, the tubal tumor was considered to represent metastatic USC in 26/32 cases, most likely metastatic USC in 2/32 cases, an independent tubal primary tumor in 3/32 cases, and to be of uncertain origin in the 1 remaining case. STIC-like lesions were considered to represent metastatic USC in 12/17 cases, most likely metastatic USC in 2/17 cases, an independent tubal primary in 2/17 cases, and of uncertain origin in the 1 remaining case. Tubal involvement, including STIC-like lesions, is seen in one fifth of USC when the tubes are examined in their entirety. The tubal involvement is metastatic in the vast majority of cases. Immunohistochemical studies assist, in most cases, in confirming the metastatic nature of the tubal disease. Consideration should be given to completely examining the fallopian tubes in apparent stage I or II USCs, as this will result in upstaging in a significant minority of cases. PMID- 27776012 TI - Peripheral neuropathic changes in pachyonychia congenita. AB - We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and control subjects. Plantar biopsies from 10 genetically confirmed patients with PC (with a mutation in KRT6A) were performed at the ball of the foot (affected skin) and the arch (unaffected) and were compared to biopsies from corresponding locations in 10 control subjects. Tissue was processed to visualize intraepidermal nerve fibers (IENF) (PGP9.5), subsets of IENF (CGRP, substance P, tyrosine hydroxylase), myelinated nerve fiber (neurofilament H, NFH), blood vessels (CD31), Meissner corpuscles, and Merkel cells (MCs). Structures were quantified using stereology or validated quantification methods. We observed that PC-affected plantar skin had significantly lower sweat gland innervation (sweat gland nerve fiber density) and reduced numbers of Meissner corpuscles compared to PC-unaffected or anatomically matched control skin. In contrast, Merkel cell densities and blood vessel counts were higher in PC-affected skin compared to either control or PC-unaffected skin. There were no differences in myelinated nerve fiber densities, SP, or CGRP between the groups. Pressure pain thresholds in PC-affected skin were lower compared to PC-unaffected and anatomically matched control skin. Additionally, MC densities in callused plantar skin from healthy runners with callus and one subject with a nonpainful palmoplantar keratoderma (AQP5 mutation) were similar to PC-unaffected and control skin consistent with callus alone not being sufficient to increase MC number. These findings suggest that alterations in PC extend beyond keratinocytes and may provide strategies to study neuropathic pain in PC. PMID- 27776016 TI - Wanted: Living Organ Donor. PMID- 27776015 TI - From Pipe Dream to Donor-Specific PC Elimination: Novel Ways to Target Alloantibodies. PMID- 27776017 TI - Levi Jay Hammond and the First Human Organ Transplantations in 1911. PMID- 27776019 TI - Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients. AB - Immune checkpoint inhibitors have changed the landscape of the treatment of multiple solid malignancies, and have been used increasingly in the recent years. Although usually well tolerated, given the relative inexperience of using immune checkpoint inhibitors, we are still learning of new side effects from the treatment. We report on two cases of ocular myasthenia gravis that occurred after treatment with pembrolizumab, an antiprogrammed-death (anti-PD1) monoclonal antibody for advanced melanoma in responding patients. One case is in an 81-year old man and the second case in an 86-year-old woman, both with BRAF-negative metastatic melanoma receiving pembrolizumab. These two cases of ocular only associated myasthenic syndrome appeared 7 and 11 weeks after the initiation of pembrolizumab. We conclude that the condition is most likely associated with pembrolizumab as symptoms started after treatment with pembrolizumab, neither patient had other evidence of neurological cause for presentation, and symptoms also improved rapidly with administration of steroids. Both patients showed good oncological response to anti-PD1 treatment and one patient successfully continued to receive ongoing treatment with no further complications. PMID- 27776020 TI - Correspondence. PMID- 27776018 TI - Inhibitor of vasculogenic mimicry restores sensitivity of resistant melanoma cells to DNA-damaging agents. AB - The increasing incidence of melanoma makes this cancer an important public health problem. Therapeutic resistance is still a major obstacle to the therapy of patients with metastatic melanomas. The aim of this study was to develop the melanoma cell line resistant to DNA-alkylating agents and to elucidate the mechanisms involved in acquired drug resistance. We established a unique melanoma subline Mel MeR resistant to DNA-alkylating drug aranoza by continuous stepwise selection of the Mel Me/WT cell line with increasing concentrations of this drug. Mel MeR cells were also cross-resistant to streptozotocin or cisplatin. Here, we show that aranoza-resistant melanoma cells modulate the ABC transporter activity, upregulate the expression of PRAME, adopt a vascular-related phenotype and engage in vasculogenic mimicry. LCS1269, a vasculogenic mimicry low-molecular-weight inhibitor, reverses the sensitivity of resistant melanoma cells to DNA-damaging agents. In this study, we provide experimental evidence that LCS1269 might be considered as a new potential anticancer agent capable of overcoming multidrug resistance for DNA-damaging agents in melanoma. PMID- 27776021 TI - Reply. PMID- 27776022 TI - Correspondence. PMID- 27776023 TI - Reply. PMID- 27776024 TI - From the Editor. PMID- 27776025 TI - From the Editors. PMID- 27776026 TI - Zika Virus and Its Impact on Pregnancy. PMID- 27776027 TI - New Approaches to Care of the Infant With Hypoglycemia. PMID- 27776028 TI - Decision to Incision and the Legal Standard of Care. PMID- 27776029 TI - Internet Resources. PMID- 27776030 TI - Sleep Quality and Health-Related Quality of Life in Pregnancy. PMID- 27776031 TI - Morbidly Adherent Placenta: Interprofessional Management Strategies for the Intrapartum Period. AB - "Morbidly adherent placenta" is a term that describes the continuum of placenta accreta, increta, and percreta. The incidence of this type of abnormal placentation has increased significantly over recent decades. The reason is probably multifactorial but, partly, because of factors such as the increasing number of cesarean births. Women at greatest risk are those who have myometrial damage caused by a previous cesarean birth, with either anterior or posterior placenta previa overlying the uterine scar. This condition poses significant risks of morbidity and/or mortality to the pregnant woman and her fetus. A multidisciplinary approach to care throughout pregnancy is essential. This article describes the classification of morbidly adherent placenta, risk factors, methods of diagnosis, potential maternal and fetal complications, and intrapartum clinical management strategies to optimize outcomes. PMID- 27776032 TI - Transition From Hospital to Home in Parents of Preterm Infants: A Literature Review. AB - Transition from hospital to home is a complex and multidimensional phenomenon for parents of prematurely born infants (<37 weeks of gestation). The absence of a clear conceptualization of this particular transition coupled with the challenges parents have when they return home and higher costs of healthcare service usage postdischarge dictates the need for a better understanding of this phenomenon. A literature review was undertaken using Whittemore and Knafl's theoretical framework for integrative review as a guide. A systematic search of the electronic databases (PsycINFO, PubMed, Medline, Cumulative Index of Nursing and Allied Health Literature, EMBASE, Cochrane Database for Systematic Reviews, and EBSCO) was performed. Fifty selected reports of research conducted on parents of preterm infants during 1980-2014 are included in this article. Five themes emerged from the review-disruption of parental role development, distorted development of parent-infant relationships, psychological consequences of a preterm birth and infant hospitalization, learning caregiving and parenting, and need for social and professional supports-which appear to reflect parental challenges during transition from hospital to home after discharge. Several inconsistencies in results of the studies dictate the need for further research in this vulnerable population; the better conceptualization and measurement of transitional challenges are warranted. PMID- 27776033 TI - Transition From Hospital to Home in Parents of Preterm Infants: A Literature Review. PMID- 27776035 TI - Use of Social Media by Fathers of Premature Infants. AB - Although parents of premature infants experience many challenges when transitioning home from the neonatal intensive care unit, healthcare providers and social support systems tend to focus on mothers and infants rather than fathers. Unfortunately, very little is known about paternal concerns and needs as compared with maternal ones. The lack of understanding about paternal needs may lead to inadequate designs of neonatal intensive care unit family support programs with less involved fathers, all of which contribute to increased burdens on mothers and poor health outcomes for their infants. Although information technology (IT) might have the potential to increase support for the fathers of preterm infants, only a few studies have examined systematically how IT applications can be beneficial. This study aims to advance the understanding of needs and concerns of fathers with preterm infants and how fathers use the IT applications (eg, social networking Web sites) to support themselves. We observed qualitatively various social networking Web sites (ie, 29 Web sites) where fathers share their experiences about preterm infants. We discovered that fathers used various social media to discuss their concerns and, in turn, obtained informational, companionship, and emotional supports. On the basis of our analysis, we provide insights into a father-centered technology intervention design. PMID- 27776034 TI - Paternal and Maternal Testosterone in Parents of NICU Infants Transitioning Home. AB - Lower testosterone during the transition to new parenthood is considered beneficial to help parents better engage with their infants. No data currently exist studying salivary testosterone of parents with infants in neonatal intensive care units (NICUs) during the transition to home. We examine testosterone levels for parents of very low-birth-weight infants, including links between salivary testosterone and infant factors (such as breast-feeding), psychosocial stress, and changes over time.Testosterone salivary samples were assayed after self-collection by 86 parents (43 fathers and 43 mothers) with NICU infants at wakeup and bedtime prior to discharge and at 3 additional times at home. Self-reported survey measures, including psychosocial reports, were also collected at these times.Using multilevel modeling approaches, we report significant associations between paternal testosterone by time and psychosocial adjustment and between both paternal and maternal testosterone and infant feeding mode (P < .05). Results were significant after accounting for covariates. Our study is the first to examine the time course of diurnal testosterone for parents of premature infants over the transition home; as such, we suggest further research into better understanding parental physiology in this vulnerable parent population. PMID- 27776036 TI - Just-in-Time Video Laryngoscopy Versus Direct Laryngoscopy for Neonatal Intubation. AB - As neonatal endotracheal intubation (ETI) is a low-frequency, high-consequence event, it is essential that providers have access to resources to aid in ETI. We sought to determine the impact of video laryngoscopy (VL) with just-in-time training on intubation outcomes over direct laryngoscopy (DL) when performed by neonatal nurses. We conducted a prospective, randomized, crossover study with neonatal nurses employed at a level 2 neonatal intensive care unit (NICU). Nurses performed both DL and VL on a neonatal mannequin using a CMAC (Karl Storz Corp, Tuttlingen, Germany) either with the assistance of the screen (VL) or without (DL). Before performing the intubation, providers were given a just-in-time, brief education presentation and allowed to practice with the device. Each ETI attempt was reviewed to obtain the percentage of glottic opening (POGO) score, time to intubation (TTI, time from insertion of the blade into the mouth until the first breath was delivered), and time from blade insertion until the best POGO score. We enrolled 19 participants, with a median (interquartile range) of 20 (9-26) years of experience and having a median of 2 (1-3) intubations within the past year. None had used VL in the NICU previously. Median TTI did not differ between DL and VL: 19.9 (15.3-41.5) vs 20.3 (17.9-24.4) (P = 1). POGO scores and the number of attempts also did not differ between DL and VL. In our simulated setting, just-in-time VL training provided similar intubation outcomes compared with DL in ETI performed by neonatal nurses. Just-in-time VL education may be an alternative to traditional DL for neonatal intubations. PMID- 27776037 TI - Effectiveness of Delayed Cord Clamping in Reducing Postdelivery Complications in Preterm Infants: A Systematic Review. AB - This systematic review evaluates the effectiveness of delayed cord clamping in preterm infants on reducing postdelivery complications of anemia, hemodynamic instability, and the development of intraventricular hemorrhages. Interventions included varying durations of delayed cord clamping with and without cord milking as compared with immediate cord clamping, shorter delays in cord clamping, and delayed cord clamping without cord milking. A comprehensive search of randomized controlled trials, observational, cohort, and before-after studies was conducted between 1946 and 2015 in the electronic databases of Ovid MEDLINE, Embase, and Google Scholar. Studies were critically appraised using the Critical Appraisal Skills Program guidelines. Twenty-seven studies were included in the review from 1997 to 2015 from varying countries. Outcome measures included hematocrit/hemoglobin levels, measured or calculated blood volumes levels, number and volume of blood transfusions, presence of hypotension and need for treatment, and development of intraventricular hemorrhage. Delayed cord clamping can lead to improved outcomes measures in preterm infants. This review supports the current recommendation to perform delayed cord clamping during preterm deliveries. PMID- 27776038 TI - On Change. PMID- 27776041 TI - The myth of muscle uptake of Tc-99m bisphosphonate in bone scan because of rhabdomyolysis. PMID- 27776039 TI - Has the phasing out of stavudine in accordance with changes in WHO guidelines led to a decrease in single-drug substitutions in first-line antiretroviral therapy for HIV in sub-Saharan Africa? AB - OBJECTIVE: We assessed the relationship between phasing out stavudine in first line antiretroviral therapy (ART) in accordance with WHO 2010 policy and single drug substitutions (SDS) (substituting the nucleoside reverse transcriptase inhibitor in first-line ART) in sub-Saharan Africa. DESIGN: Prospective cohort analysis (International epidemiological Databases to Evaluate AIDS-Multiregional) including ART-naive, HIV-infected patients aged at least 16 years, initiating ART between January 2005 and December 2012. Before April 2010 (July 2007 in Zambia) national guidelines called for patients to initiate stavudine-based or zidovudine based regimen, whereas thereafter tenofovir or zidovudine replaced stavudine in first-line ART. METHODS: We evaluated the frequency of stavudine use and SDS by calendar year 2004-2014. Competing risk regression was used to assess the association between nucleoside reverse transcriptase inhibitor use and SDS in the first 24 months on ART. RESULTS: In all, 33 441 (8.9%; 95% confience interval 8.7 8.9%) SDS occurred among 377 656 patients in the first 24 months on ART, close to 40% of which were amongst patients on stavudine. The decrease in SDS corresponded with the phasing out of stavudine. Competing risks regression models showed that patients on tenofovir were 20-95% less likely to require a SDS than patients on stavudine, whereas patients on zidovudine had a 75-85% decrease in the hazards of SDS when compared to stavudine. CONCLUSION: The decline in SDS in the first 24 months on treatment appears to be associated with phasing out stavudine for zidovudine or tenofovir in first-line ART in our study. Further efforts to decrease the cost of tenofovir and zidovudine for use in this setting is warranted to substitute all patients still receiving stavudine. PMID- 27776042 TI - News and Views-December 2016. PMID- 27776043 TI - Risk Factors for Malignancy of Branch-Duct Intraductal Papillary Mucinous Neoplasms: A Critical Evaluation of the Fukuoka Guidelines With a Systematic Review and Meta-analysis. AB - OBJECTIVES: This study aimed to evaluate the accuracy of the risk factors proposed by Fukuoka guidelines in detecting malignancy of branch-duct intraductal papillary mucinous neoplasms. METHOD: Diagnostic meta-analysis of cohort studies. A systematic literature search was conducted using MEDLINE, the Cochrane Library, Scopus, and the ISI-Web of Science databases to identify all studies published up to 2014. RESULTS: Twenty-five studies (2025 patients) were suitable for the meta analysis. The "high risk stigmata" showed the highest pooled diagnostic odds ratio (jaundice, 6.3; positive citology, 5.5; mural nodules, 4.8) together with 2 "worrisome features" (thickened/enhancing walls, 4.2; duct dilatation, 4.0) and 1 "other parameters" (carbohydrate antigen 19-9 serum levels, 4.6). CONCLUSIONS: An "ideal risk factor" capable of recognizing all malignant branch-duct intraductal papillary mucinous neoplasms was not identified and some "dismal areas" remain. However, "high risk stigmata" were strongly related to malignancy, mainly enhancing mural nodules. Among the "worrisome features," duct dilatation and thickened/enhancing walls were underestimated, and their diagnostic performance was similar to those of "high risk stigmata." The carbohydrate antigen 19-9 serum level should be added to the Fukuoka algorithm because this value could help in carrying out correct management. PMID- 27776044 TI - Homeobox-Only Protein Expression Is a Critical Prognostic Indicator of Pancreatic Neuroendocrine Tumor and Is Regulated by Promoter DNA Hypermethylation. AB - OBJECTIVES: We have identified homeobox-only protein (HOPX) as a tumor suppressor gene in various human cancer, and its expression was reduced by promoter DNA hypermethylation. Homeobox-only protein is strongly expressed on pancreatic islet cells; however, clinical relevance of HOPX expression has remained elusive in pancreatic neuroendocrine tumor (pNET). METHODS: We investigated 36 patients with pNET who undertook surgical resection between 1988 and 2012 for HOPX expression and DNA methylation to reveal its clinical significance. RESULTS: (1) Homeobox only protein is strongly expressed on pancreatic islet cells by immunohistochemistry (IHC). Homeobox-only protein expression was recognized on pNET tumor cells for 1+ in 15, for 2+ in 16, and for 3+ in 5. (2) Homeobox-only protein IHC expression was significantly associated with prognosis (P = 0.03), and survival rate was 37.5%, 70.3%, and 100% in HOPX 1+, 2+, and 3+, respectively. (3) Promoter DNA methylation was quantitatively assessed, and HOPX hypermethylation is found in 6.3%, 11.8%, and 66.7% of G1/G2/G3 pNET, respectively (P = 0.02). (4) Multivariate Cox proportional hazards model identified HOPX IHC expression and HOPX promoter DNA hypermethylation as independent prognostic factors in pNET. CONCLUSIONS: Homeobox-only protein expression is a critical prognostic indicator of pNET, and its regulation may be made through promoter DNA methylation. PMID- 27776045 TI - MicroRNA-148a Suppresses the Proliferation and Migration of Pancreatic Cancer Cells by Down-regulating ErbB3. AB - OBJECTIVES: ErbB3 (HER3) has been associated with pancreatic cancer progression, but little is known about its regulatory mechanisms. We investigated whether microRNAs (miRNAs) regulate levels of ErbB3 in pancreatic cancer cells. METHODS: We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Furthermore, the biological consequences of the targeting of ERBB3 by miR 148a were examined by cell proliferation and migration assays in vitro. RESULTS: We identified an inverse correlation between miR-148a and ErbB3 protein levels in pancreatic cancer tissue samples and cell lines. We identified that miR-148a directly recognizes the 3'-UTR of the ErbB3 transcript and regulates ErbB3 expression. We demonstrated that the repression of ERBB3 by miR-148a suppressed the proliferation and migration of pancreatic cancer cells. In PANC-1 pancreatic cancer cells, the repression of ErbB3 by miR-148a inhibited the phosphorylation of ERK1/2 and AKT, which eventually repressed the proliferation and migration of these cells. CONCLUSIONS: Taken together, the present study provides the first evidence that miR-148a plays a significant role in the suppression of pancreatic tumorigenesis via the inhibition of ErbB3 translation. PMID- 27776046 TI - Can Serum Pancreatic Amylase and Lipase Levels Be Used as Diagnostic Markers to Distinguish Between Patients With Mucinous Cystic Lesions of the Pancreas, Chronic Pancreatitis, and Pancreatic Ductal Adenocarcinoma? AB - OBJECTIVE: This study aimed to assess the presence of pancreatic hyperenzymemia in patients with pancreatic cystic lesions as compared to other chronic diseases of the pancreas. METHODS: Ninety-one patients were studied: 32 had mucinous cystic lesions, 35 had chronic pancreatitis (CP), and 24 had pancreatic ductal adenocarcinoma (PDAC). Surgery was carried out in 10 of the 32 patients with mucinous cystic lesion (7 of them had severe dysplasia), in 5 patients with CP, and in 9 patients with PDAC. RESULTS: Abnormally high serum pancreatic isoamylase activity was present in 11 (34.4%) patients with mucinous cystic lesions, in 14 (40.0%) patients with CP, and none in patients with PDAC (P = 0.002); whereas serum lipase activity was abnormally high in 8 (25.0%) patients with mucinous cystic lesion, in 17 (48.6%) patients with CP, and in 3 (12.5%) patients with PDAC (P = 0.009). In 7 patients with mucinous cystic lesions and histologically confirmed severe dysplasia, abnormally high levels of both serum pancreatic amylase and lipase were present in 3 (42.9%) patients. CONCLUSIONS: High serum concentrations of pancreatic amylase and lipase were found in no more than half of the patients with mucinous cystic lesions. High levels of pancreatic enzymes were not associated with a greater risk of malignancy. PMID- 27776047 TI - The Chronic Pancreatitis International Classification of Diseases, Ninth Revision, Clinical Modification Code 577.1 Is Inaccurate Compared With Criterion Standard Clinical Diagnostic Scoring Systems. AB - OBJECTIVES: Epidemiological studies utilizing administrative databases use the International Classification of Diseases, Ninth Revision, Clinical Modification code (577.1) to identify patients with chronic pancreatitis (CP). We hypothesized that coding of CP in these databases is inaccurate. METHODS: We retrospectively reviewed the records of 1343 consecutive patients having an International Classification of Diseases, Ninth Revision, Clinical Modification code 577.1 between October 1, 2005, and November 1, 2008. We labeled patients as definite CP or non-CP, defined as fulfilling any of the 3 diagnostic criteria for definite CP: Mayo, Ammann's, and the Japanese Pancreas Society criteria. RESULTS: Six hundred fifty-eight subjects (49%) had definite CP. Definite CP among Mayo, Ammann's, and Japanese Pancreas Society criteria was similar (49.0, 42.1, and 43.8, respectively); 84.3% of the definite CP fulfilled all 3 criteria, 6.7% fulfilled 2, and 9.0% filled 1 criterion. Etiologies of definite CP were definite/suspected nonalcohol (57.8%) or alcohol (33.5%) and not reported (8.7%). In non-CP (n = 685), 93.7% had available imaging (5.7% had endoscopic ultrasonography >=5 or Cambridge II-III scores), and 63.5% had symptoms suggestive of CP but did not fulfill other features for definite CP. The CP versus non-CP groups had similar mean ages but significantly more men and patients ever smoking and ever drinking alcohol. CONCLUSIONS: Fifty-one percent of subjects coded as CP do not fulfill the diagnostic criteria for definite CP. Relying solely on the International Classification of Diseases, Clinical Modification code for CP in administrative databases may lead to erroneous epidemiological conclusions. PMID- 27776048 TI - Role of Microvesicles From Bone Marrow Mesenchymal Stem Cells in Acute Pancreatitis. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) have shown an obvious protective effect on acute pancreatitis (AP). The purpose of the present study was to analyze the effect of bone marrow MSC-derived microvesicles (bmMSC-MVs) on AP and explore the underlying mechanisms. METHODS: Bone marrow MSCs and bmMSC-MVs were isolated from Sprague-Dawley rats. Cerulein-induced mild AP (MAP) and sodium taurocholate induced severe AP (SAP) were used as AP models in vivo and in vitro. Pancreatic injury was evaluated by measuring serum levels of amylase, lipase, chemokines, and interleukins, and by pancreatic histology, reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of bmMSC MVs on the survival rates of pancreatic acinar cells in vitro were also assessed. RESULTS: Bone marrow MSC-MVs attenuated acute pancreatic injury in MAP and SAP by regulating IL-1alpha, IL-6, and TNF-alpha, and dramatically attenuated the nuclear translocation of NF-kappaB p65 in MAP and SAP. Bone marrow MSC-MVs improved the survival rates of pancreatic acinar cells in MAP and SAP models in vitro. CONCLUSIONS: Bone marrow MSC-MVs played a protective role in AP by reducing the levels of proinflammatory cytokines and regulating the nuclear translocation of NF-kappaB p65. Bone marrow MSC-MVs could be developed as a strategy for the clinical treatment of SAP. PMID- 27776050 TI - Tibial Rotation Osteotomies in a Matched Cohort of Myelodysplasia and Cerebral Palsy Children. AB - BACKGROUND: The purpose of this study is to examine the frequency of complications in children with myelodysplasia (MD) undergoing tibial rotational osteotomies with a matched cohort of children with cerebral palsy (CP). It was postulated that because of the unique health issues facing children with MD more complications would be observed. METHODS: A retrospective chart review was performed to identify children with MD who underwent primary tibial rotational osteotomy between 1997 and 2012 and had a minimum 2-year follow-up. The 15 children thus identified were matched for age, body mass index, and functional ability with 15 children with CP. Outcome measures were complications that occurred within a year of osteotomy or hardware removal. Major complications were defined as nonunions or malunions, hardware failures, deep infections, fractures, and stage III or IV decubiti. Recurrence of rotational deformity requiring revision osteotomy at any time was also defined as a major complication. Minor wound problems healing within 6 weeks with only local care were considered minor complications. RESULTS: Fifteen children with MD, who underwent 21 tibial derotational osteotomies, were available for review with a mean 7-year follow-up. The 15 children with CP underwent 22 tibial derotational osteotomies with a mean of 6 years of follow-up. In each cohort there were 3 children classified as GMFCS I, 3 children as GMFCS II, 4 children as GMFCS III, and 5 as GMFCS IV. Three (20%) of the children with MD experienced major complications (1 infected nonunion and 2 children who experienced bilateral malunions requiring revisions). One child with a major complication was classified as GMFCS II and the other 2 as GMFCS IV. None of the children with CP experienced a major complication. CONCLUSIONS: The majority of children in both groups experienced good results, but children with MD have more frequent major complications. More frequent complications were seen in children with less functional ability. LEVEL OF EVIDENCE: Level III-prognostic study, case-control study. PMID- 27776051 TI - Age-dependent Reliability of Semmes-Weinstein and 2-Point Discrimination Tests in Children. AB - BACKGROUND: Objective sensory testing is a critical component of the physical examination in children as they may be unable to communicate whether or not numbness is present. The purpose of this study was to determine at what age objective sensory tests could reliably be performed. METHODS: Normal, uninjured participants aged 2 to 17 years were enrolled in the study. Monofilament and static/moving 2-point discrimination tests were performed bilaterally assessing the median, ulnar, and radial nerves. Performance scores were recorded using the monofilament size and 2-point discrimination distance. Statistical analysis was performed utilizing univariable linear regression, 1-way ANOVA, and Welch t test. RESULTS: A total of 396 hands were tested utilizing the Semmes-Weinstein monofilament and static/moving 2-point discrimination tests. For the monofilament test, 27% of 3-year-olds, 83% of 4-year-olds, and all participants 5 years of age and older were capable of performing the monofilament test. The average monofilament scores were 2.874, 2.868, and 3.043 for the ulnar, median, and radial nerves, respectively, with no correlation with advancing age present. The ulnar and median nerve distributions were more sensitive than the radial nerve distribution (P<0.001).For 2-point discrimination tests, 33% of 4-year-olds, 61% of 5-year-olds, 88% of 6-year-olds, 95% of 7- and 8-year-olds, and all participants 9 years and older were capable of performing the static/moving 2 point discrimination tests. The average static 2-point discrimination scores were 3.348, 2.806, and 9.637 mm for the ulnar, median, and radial nerves, respectively. The average moving 2-point discrimination scores were 2.977, 2.483, and 8.506 mm for the ulnar, median, and radial nerves, respectively. There was no correlation between advancing age and performance scores. Children are the most sensitive in the median, then ulnar, and then radial nerve distribution (P<0.001). Better discrimination is present between 2 moving points than static points (P<0.001). CONCLUSIONS: Objective threshold testing utilizing a monofilament can reliably be performed in the vast majority of children aged 4 years and above, whereas density testing utilizing 2-point discrimination can reliably be performed in the vast majority of children aged 6 years and above. LEVEL OF EVIDENCE: Level II. PMID- 27776052 TI - Fracture Classification Does Not Predict Functional Outcomes in Supracondylar Humerus Fractures: A Prospective Study. AB - BACKGROUND: Few studies have prospectively assessed functional outcomes after the surgical management of supracondylar humerus fractures (SCHFXs) and the relationship between fracture pattern and ultimate patient outcome has never been prospectively evaluated. The purpose of this study was to prospectively evaluate fracture classification and functional outcome in children with extension SCHFXs using validated outcome measures. METHODS: An Institutional Review Board-approved prospective enrollment of consecutive patients with operative SCHFX was performed over a 3-year period. Fractures were classified by the treating surgeon using the modified Gartland classification. Functional outcome was assessed at final follow up using the Pediatric Outcomes Data Collection Instruments (PODCI) and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) outcome measure. Patients with flexion-type fractures, multidirectionally unstable fractures and those with <10 weeks follow-up were excluded from analysis. Statistical analysis was used to determine the relationship between fracture classification/pattern and functional outcome. RESULTS: Seven hundred fifty-two patients were enrolled during the study period. One hundred thirty-two patients with extension-type injuries (average age 6.7 y) completed functional outcome measures at an average follow-up of 12.4 weeks. Forty-five (34%) were type II fractures and 87 (66%) were type III fractures. Forty-five (34%) of the fractures were posteromedially displaced, 43 (33%) were posterolaterally displaced, and 44 (33%) were posteriorly displaced without coronal plane deformity. The average PODCI global functioning scale score and QuickDASH scores for the entire cohort were 93.6 and 11.4, respectively, indicating excellent function. No differences in outcome scores were noted between patients with type II and III fractures. No difference in outcome was identified based upon direction of fracture displacement. CONCLUSIONS: This is the first study to prospectively analyze fracture classification and functional outcome using validated outcome measures following the operative treatment of pediatric extension-type SCHFX. Children generally have excellent functional outcomes following the operative treatment of SCHFX. Garland classification and direction of displacement do not influence functional outcomes. LEVEL OF EVIDENCE: Level II-therapeutic. PMID- 27776053 TI - The Effect of the Pucker Sign on Outcomes of Type III Extension Supracondylar Fractures in Children. AB - BACKGROUND: The pucker sign, also called skin tenting, indicates significant displacement of the supracondylar fracture and can be a cause for alarm. The purpose of this study is to compare a cohort of patients with type III supracondylar fractures presenting with a pucker sign to a group without a pucker sign by evaluating neurovascular injury at presentation, need for open reduction, persistent neurovascular injury, range of motion, and carrying angle at final follow-up. METHODS: A retrospective review was performed for Gartland type III extension type supracondylar fractures. Those with a pucker sign were identified and evaluated. Type III supracondylar fractures with a pucker sign were compared with a similar cohort without a pucker sign. RESULTS: In total, 12 patients with a pucker sign at an average age of 5.2 years were evaluated. A total of 11 patients (92%) had diminished or absent pulses, and 2 (17%) had weakness in the median nerve distribution. Nine (75%) patients in this group were transferred to the university hospital. Average time to surgery was 8.9 hours with an average operating time of 25.1 minutes. Open reduction was not needed in any case. At an average follow-up of 4.7 months no patients had persistent neurovascular compromise. Two patients lacked <5 degrees of extension and 1 lacked 10 degrees of extension. One patient lacked 10 degrees of flexion. No patients had a change in carrying angle difference compared with the contralateral side. No statistical differences were observed between the 2 groups. CONCLUSIONS: Pucker sign, in the context of a supracondylar fracture of the humerus, is a soft tissue defect with potential entrapment of median nerve and brachial artery. At a maximum time of 16 hours from injury to surgery we report excellent outcomes and no long-term complications. Using the techniques of gradual traction, and milking the soft tissue, the pucker sign can be eliminated. Closed reduction and percutaneous pinning were performed in all the cases. LEVEL OF EVIDENCE: Level III retrospective comparative study. PMID- 27776054 TI - Opioid Use Disorder in Pregnancy: Health Policy and Practice in the Midst of an Epidemic. PMID- 27776055 TI - In Reply. PMID- 27776056 TI - Opioid Use Disorder in Pregnancy: Health Policy and Practice in the Midst of an Epidemic. PMID- 27776057 TI - In Reply. PMID- 27776058 TI - Perinatal and Hemodynamic Evaluation of Sildenafil Citrate for Preeclampsia Treatment: A Randomized Controlled Trial. PMID- 27776059 TI - In Reply. PMID- 27776060 TI - Duration of Oxytocin and Rupture of the Membranes Before Diagnosing a Failed Induction of Labor. PMID- 27776061 TI - In Reply. PMID- 27776066 TI - Practice Bulletin No. 173 Summary: Fetal Macrosomia. AB - Suspected fetal macrosomia is encountered commonly in obstetric practice. As birth weight increases, the likelihood of labor abnormalities, shoulder dystocia, birth trauma, and permanent injury to the neonate increases. The purpose of this document is to quantify those risks, address the accuracy and limitations of methods for estimating fetal weight, and suggest clinical management for a pregnancy with suspected fetal macrosomia. PMID- 27776067 TI - Practice Bulletin No. 174 Summary: Evaluation and Management of Adnexal Masses. AB - Adnexal masses (ie, masses of the ovary, fallopian tube, or surrounding tissues) commonly are encountered by obstetrician-gynecologists and often present diagnostic and management dilemmas. Most adnexal masses are detected incidentally on physical examination or at the time of pelvic imaging. Less commonly, a mass may present with symptoms of acute or intermittent pain. Management decisions often are influenced by the age and family history of the patient. Although most adnexal masses are benign, the main goal of the diagnostic evaluation is to exclude malignancy. The purpose of this document is to provide guidelines for the evaluation and management of adnexal masses in adolescents, pregnant women, and nonpregnant women and to outline criteria for the identification of adnexal masses that are likely to be malignant and may warrant referral to or consultation with a gynecologic oncologist. PMID- 27776068 TI - Committee Opinion No. 678 Summary: Comprehensive Sexuality Education. AB - Current sexuality education programs vary widely in the accuracy of content, emphasis, and effectiveness. Data have shown that not all programs are equally effective for all ages, races and ethnicities, socioeconomic groups, and geographic areas. Studies have demonstrated that comprehensive sexuality education programs reduce the rates of sexual activity, sexual risk behaviors (eg, number of partners and unprotected intercourse), sexually transmitted infections, and adolescent pregnancy. One key component of an effective program is encouraging community-centered efforts. In addition to counseling and service provision to individual adolescent patients, obstetrician-gynecologists can serve parents and communities by supporting and assisting sexuality education. Because of their knowledge, experience, and awareness of a community's unique challenges, obstetrician-gynecologists can be an important resource for sexuality education programs. PMID- 27776069 TI - Committee Opinion No. 679 Summary: Immersion in Water During Labor and Delivery. AB - Immersion in water during labor or delivery has been popularized over the past several decades. The prevalence of this practice in the United States is uncertain because it has not been studied in births outside of the home and birth centers, and the data are not recorded on birth certificates. Among randomized controlled trials included in a 2009 Cochrane systematic review that addressed immersion in the first stage of labor, results were inconsistent with regard to maternal benefits. Neither the Cochrane systematic review nor any individual trials included in that review reported any benefit to the newborn from maternal immersion during labor or delivery. Immersion in water during the first stage of labor may be associated with shorter labor and decreased use of spinal and epidural analgesia and may be offered to healthy women with uncomplicated pregnancies between 37 0/7 weeks and 41 6/7 weeks of gestation. There are insufficient data on which to draw conclusions regarding the relative benefits and risks of immersion in water during the second stage of labor and delivery. Therefore, until such data are available, it is the recommendation of the American College of Obstetricians and Gynecologists that birth occur on land, not in water. A woman who requests to give birth while submerged in water should be informed that the maternal and perinatal benefits and risks of this choice have not been studied sufficiently to either support or discourage her request. Facilities that plan to offer immersion during labor and delivery need to establish rigorous protocols for candidate selection; maintenance and cleaning of tubs and pools; infection control procedures, including standard precautions and personal protective equipment for health care personnel; monitoring of women and fetuses at appropriate intervals while immersed; and moving women from tubs if urgent maternal or fetal concerns or complications develop. PMID- 27776070 TI - Committee Opinion No. 680 Summary: The Use and Development of Checklists in Obstetrics and Gynecology. AB - Checklists are used in medical and nonmedical settings as cognitive aids to ensure that users complete all the items associated with a particular task. They are ideal for tasks with many steps, for tasks performed under stressful circumstances, or for reminding people to perform tasks that they are not routinely accustomed to doing. In medicine, they are ideal for promoting standardized processes of care in situations in which variation in practice may increase patient risk and the chance of medical errors. Checklists also can be used to enhance teamwork and communication. It is a good idea to include frontline individuals who are involved in completing the procedure in the selection and development of the checklist. To be optimally effective, those who create checklists need to carefully plan for their design, implementation, evaluation, and revision. Checklists are valuable cognitive aids to help health care teams provide complete and timely care to patients, but checklists should be only one tool in the armamentarium to ensure that practitioners do the right thing for the right patient at the right time. PMID- 27776071 TI - Practice Bulletin No. 173: Fetal Macrosomia. AB - Suspected fetal macrosomia is encountered commonly in obstetric practice. As birth weight increases, the likelihood of labor abnormalities, shoulder dystocia, birth trauma, and permanent injury to the neonate increases. The purpose of this document is to quantify those risks, address the accuracy and limitations of methods for estimating fetal weight, and suggest clinical management for a pregnancy with suspected fetal macrosomia. PMID- 27776072 TI - Practice Bulletin No. 174: Evaluation and Management of Adnexal Masses. AB - Adnexal masses (ie, masses of the ovary, fallopian tube, or surrounding tissues) commonly are encountered by obstetrician-gynecologists and often present diagnostic and management dilemmas. Most adnexal masses are detected incidentally on physical examination or at the time of pelvic imaging. Less commonly, a mass may present with symptoms of acute or intermittent pain. Management decisions often are influenced by the age and family history of the patient. Although most adnexal masses are benign, the main goal of the diagnostic evaluation is to exclude malignancy. The purpose of this document is to provide guidelines for the evaluation and management of adnexal masses in adolescents, pregnant women, and nonpregnant women and to outline criteria for the identification of adnexal masses that are likely to be malignant and may warrant referral to or consultation with a gynecologic oncologist. PMID- 27776073 TI - Committee Opinion No. 678: Comprehensive Sexuality Education. AB - Current sexuality education programs vary widely in the accuracy of content, emphasis, and effectiveness. Data have shown that not all programs are equally effective for all ages, races and ethnicities, socioeconomic groups, and geographic areas. Studies have demonstrated that comprehensive sexuality education programs reduce the rates of sexual activity, sexual risk behaviors (eg, number of partners and unprotected intercourse), sexually transmitted infections, and adolescent pregnancy. One key component of an effective program is encouraging community-centered efforts. In addition to counseling and service provision to individual adolescent patients, obstetrician-gynecologists can serve parents and communities by supporting and assisting sexuality education. Because of their knowledge, experience, and awareness of a community's unique challenges, obstetrician-gynecologists can be an important resource for sexuality education programs. PMID- 27776074 TI - Committee Opinion No. 679: Immersion in Water During Labor and Delivery. AB - Immersion in water during labor or delivery has been popularized over the past several decades. The prevalence of this practice in the United States is uncertain because it has not been studied in births outside of the home and birth centers, and the data are not recorded on birth certificates. Among randomized controlled trials included in a 2009 Cochrane systematic review that addressed immersion in the first stage of labor, results were inconsistent with regard to maternal benefits. Neither the Cochrane systematic review nor any individual trials included in that review reported any benefit to the newborn from maternal immersion during labor or delivery. Immersion in water during the first stage of labor may be associated with shorter labor and decreased use of spinal and epidural analgesia and may be offered to healthy women with uncomplicated pregnancies between 37 0/7 weeks and 41 6/7 weeks of gestation. There are insufficient data on which to draw conclusions regarding the relative benefits and risks of immersion in water during the second stage of labor and delivery. Therefore, until such data are available, it is the recommendation of the American College of Obstetricians and Gynecologists that birth occur on land, not in water. A woman who requests to give birth while submerged in water should be informed that the maternal and perinatal benefits and risks of this choice have not been studied sufficiently to either support or discourage her request. Facilities that plan to offer immersion during labor and delivery need to establish rigorous protocols for candidate selection; maintenance and cleaning of tubs and pools; infection control procedures, including standard precautions and personal protective equipment for health care personnel; monitoring of women and fetuses at appropriate intervals while immersed; and moving women from tubs if urgent maternal or fetal concerns or complications develop. PMID- 27776075 TI - Committee Opinion No. 680: The Use and Development of Checklists in Obstetrics and Gynecology. AB - Checklists are used in medical and nonmedical settings as cognitive aids to ensure that users complete all the items associated with a particular task. They are ideal for tasks with many steps, for tasks performed under stressful circumstances, or for reminding people to perform tasks that they are not routinely accustomed to doing. In medicine, they are ideal for promoting standardized processes of care in situations in which variation in practice may increase patient risk and the chance of medical errors. Checklists also can be used to enhance teamwork and communication. It is a good idea to include frontline individuals who are involved in completing the procedure in the selection and development of the checklist. To be optimally effective, those who create checklists need to carefully plan for their design, implementation, evaluation, and revision. Checklists are valuable cognitive aids to help health care teams provide complete and timely care to patients, but checklists should be only one tool in the armamentarium to ensure that practitioners do the right thing for the right patient at the right time. PMID- 27776076 TI - Extracellular elevation of adrenomedullin, a gene associated with schizophrenia, suppresses heat shock protein 1A/1B mRNA. AB - Several recent gene expression studies on schizophrenia, including one using monozygotic twins discordant for the disease, have reported the upregulation of adrenomedullin (ADM), which was initially identified as a vasodilator hormone. It has been hypothesized that upregulation of ADM may be a susceptibility factor for schizophrenia, although the exact role of ADM in the central nervous system remains unclear. In this study, we used a microarray analysis to investigate the changes in global gene expression induced by the administration of exogenous ADM in SK-N-SH cells, which allowed us to evaluate the effects of elevated ADM on the central nervous system. A quantitative reverse-transcription PCR study showed that the levels of HSPA1A/1B mRNA, another gene that has been associated with schizophrenia, were significantly suppressed after exogenous ADM treatment. These results indicate that elevated ADM may be involved in the etiology of schizophrenia through the regulation of heat shock protein signaling. PMID- 27776077 TI - The neural correlates of evaluating the outcome of prosocial-helping decisions. AB - This study used the event-related potential technique to explore the neural correlates of outcome evaluation about helping others during a decision task. The results showed that the amplitude of feedback-related negativity elicited by 'failed outcome' (indicating a failure in helping others) was larger than that elicited by 'successful outcome' (indicating a success in helping others). Failed outcome also elicited a larger and longer P300 than successful outcome. The feedback-related negativity and P300 reflect the automatic process in an early stage and the control process in a late stage of outcome evaluation, respectively. Accordingly, these event-related potential results have shown the time course of outcome evaluation about helping others, and suggest that brain response to outcome information of helping others is generally similar to those in economic decision tasks. PMID- 27776078 TI - Masked hypertension in obesity: potential predictors and arterial damage. AB - BACKGROUND: Masked hypertension (MHT), defined as normal office blood pressure (BP) but high ambulatory BP, has been associated with increased cardiovascular risk. Although MHT has been associated with obesity, there is limited knowledge on the prevalence and covariates of MHT in obese cohorts. METHODS: Office and ambulatory BP recordings and other cardiovascular risk factors were assessed in 323 obese participants included in the fat-associated cardiovascular dysfunction study (mean age 48.9+/-9.0 years, 55% women, mean BMI 32.3+/-4.4 kg/m). Office BP 130-139/85-89 mmHg was considered high-normal. Subclinical arterial damage was identified as carotid-femoral pulse wave velocity more than 10 m/s by applanation tonometry or carotid plaque by ultrasound (maximal intima-media thickness >=1.5 mm). RESULTS: MHT was present in 17.1% of the population. Patients with MHT had a higher prevalence of metabolic syndrome, high-normal office BP, and were more often male compared with the normotensive (NT) individuals (all P<0.05), but were younger and had lower prevalence of diabetes and subclinical arterial damage than the sustained hypertensive group (all P<0.05). In multinomial logistic regression analysis, MHT was associated with the presence of metabolic syndrome and high normal office BP compared with NT individuals, and lower pulse wave velocity and fewer carotid plaques than sustained hypertension (all P<0.05). CONCLUSION: In obese patients, MHT was associated with the presence of metabolic syndrome and high-normal office BP compared with NT individuals, but less subclinical arterial damage than sustained hypertensive patients. PMID- 27776079 TI - Use of Low Level of Continuous Heat as an Adjunct to Physical Therapy Improves Knee Pain Recovery and the Compliance for Home Exercise in Patients With Chronic Knee Pain: A Randomized Controlled Trial. AB - Petrofsky, JS, Laymon, MS, Alshammari, FS, and Lee, H. Use of low level of continuous heat as an adjunct to physical therapy improves knee pain recovery and the compliance for home exercise in patients with chronic knee pain: a randomized controlled trial. J Strength Cond Res 30(11): 3107-3115, 2016-This study examined if the use of low level continuous heat (LLCH) wraps at home between physical therapy sessions at a clinic resulted in better therapy outcomes in patients with chronic knee pain. Fifty individuals with chronic nonspecific knee pain was randomly allocated to 2 groups: the LLCH group and the placebo group. All subjects underwent 1 hour of conventional physical therapy twice per week for 2 weeks at the outpatient clinic and they were asked to accomplish 1 hour of therapeutic exercise at home each day between sessions. The LLCH group applied LLCH knee wraps for 6 hours at home before home exercise while placebo group took a placebo ibuprofen. (This was done since placebo heat is impossible to use since subjects would notice that the wraps were cold) Before, during, and after intervention, pain intensity, active range of motion of the knee (AROM), knee strength, and home exercise compliance were measured. The LLCH group showed pain attenuation after 2 weeks of therapy sessions (p <= 0.05). AROM and strength of the knee significantly improved over time compared to the placebo group. Home exercise compliance was significantly higher in the LLCH group than placebo group (p <= 0.05). These results indicated that the use of LLCH as an adjunct to conventional physical therapy for chronic knee pain significantly improved pain attenuation and recovery of strength and movement in patients with chronic knee pain. PMID- 27776080 TI - Relationship Between Individualized Training Impulse and Aerobic Fitness Measures in Hurling Players Across a Training Period. AB - Malone, S and Collins, K. Relationship between individualized training impulse and aerobic fitness measures in Hurling players across a training period. J Strength Cond Res 30(11): 3140-3145, 2016-The current study examined the association between individual internal training load (individualized training impulse, iTRIMP) and aerobic fitness variables in male hurling players. Twenty hurling players (age, 25.5 +/- 3.2 years; height, 178.9 +/- 3.2 cm; body mass, 78.5 +/- 4.5 kg) performed treadmill testing for V[Combining Dot Above]O2max, running economy (RE), and the speed at blood lactate concentrations of 2 mmol.L (S2) and 4 mmol.L (S4) on separate occasions before and after an 8-week training period. The Yo-Yo intermittent recovery (Yo-YoIR1, Yo-YoIR2) test performance were also assessed before and after the training period. Individualized training impulse was calculated using the blood lactate and heart rate profile of each individual player and was further assessed for each training session across the intervention period (n = 990). The results showed that iTRIMP had large to very large association with the percentage improvements in V[Combining Dot Above]O2max (r = 0.77; p = 0.002; 95% confidence interval [CI], 0.38-0.93, very large), RE (r = 0.78; p = 0.002; 95% CI, 0.40-0.93; very large), S2 (r = 0.64; p = 0.004; 95% CI, from 0.25 to 0.85; large), S4 (r = 0.78; p = 0.003; 95% CI, 0.45-0.85; very large), Yo-YoIR1 (r = 0.69; p = 0.003; 95% CI, 0.45-0.92; large), and Yo-YoIR2 (r = 0.60; p = 0.005; 95% CI, 0.45-0.92; large) performance. The study shows that iTRIMP is a means of quantifying training load in team sports and can be used to prescribe training for the maintenance or improvement of aerobic fitness during the competitive season with strong relationships seen between weekly iTRIMP measures and improvements in aerobic fitness measures. PMID- 27776083 TI - Real-Time Non-Intrusive Assessment of Viewing Distance during Computer Use. AB - PURPOSE: To develop and test the sensitivity of an ultrasound-based sensor to assess the viewing distance of visual display terminals operators in real-time conditions. METHODS: A modified ultrasound sensor was attached to a computer display to assess viewing distance in real time. Sensor functionality was tested on a sample of 20 healthy participants while they conducted four 10-minute randomly presented typical computer tasks (a match-three puzzle game, a video documentary, a task requiring participants to complete a series of sentences, and a predefined internet search). RESULTS: The ultrasound sensor offered good measurement repeatability. Game, text completion, and web search tasks were conducted at shorter viewing distances (54.4 cm [95% CI 51.3-57.5 cm], 54.5 cm [95% CI 51.1-58.0 cm], and 54.5 cm [95% CI 51.4-57.7 cm], respectively) than the video task (62.3 cm [95% CI 58.9-65.7 cm]). Statistically significant differences were found between the video task and the other three tasks (all p < 0.05). Range of viewing distances (from 22 to 27 cm) was similar for all tasks (F = 0.996; p = 0.413). CONCLUSIONS: Real-time assessment of the viewing distance of computer users with a non-intrusive ultrasonic device disclosed a task-dependent pattern. PMID- 27776082 TI - Effect of Decentration on the Optical Quality of Two Intraocular Lenses. AB - PURPOSE: To analyze the effect of decentration on the optical quality of two diffractive-refractive intraocular lenses, a bifocal and a trifocal, when displaced laterally (horizontal direction) from the center. METHODS: The AT LISA 809M IOL (+3.75 D add) with two main foci and the AT LISA tri 839MP intraocular lens with three main foci (Carl Zeiss Meditec AG, Jena, Germany) were analyzed. The optical quality of the intraocular lenses was measured with the PMTF (power and modulation transfer function [MTF] measurement for refractive and diffractive intraocular lenses) optical bench (Lambda-X, Nivelles, Belgium). The optical quality of the lenses was evaluated by the MTF at different object vergences, the average modulation in the range of frequencies from 0 to 100 cycles/mm, and the through-focus MTF curves. All measures were recorded when the intraocular lenses were centered and decentered for 3.0- and 4.5-mm apertures. The Strehl ratio and the percentage of energy allocated at each focus at the centered position were also obtained. RESULTS: Our results showed a lower optical quality with increasing decentration. The MTFs for the diffractive-refractive intraocular lenses decreased when the intraocular lenses were decentered. Also, the relative percentages of light energy allocated at each object vergence, for both intraocular lenses, agreed well with theoretical specifications and were consistent with the overall design of each lens. CONCLUSIONS: The optical quality of these diffractive-refractive multifocal intraocular lenses was slightly reduced when the induced decentration was less than 0.4 mm. For a decentration of 0.4 mm, the maximum difference in average modulation values was about 18% compared to the centered position. PMID- 27776081 TI - Acute Low-Dose Caffeine Supplementation Increases Electromyographic Fatigue Threshold in Healthy Men. AB - Morse, JJ, Pallaska, G, Pierce, PR, Fields, TM, Galen, SS, and Malek, MH. Acute low-dose caffeine supplementation increases electromyographic fatigue threshold in healthy men. J Strength Cond Res 30(11): 3236-3241, 2016-The purpose of this study is to determine whether consumption of a single low-dose caffeine drink will delay the onset of the electromyographic fatigue threshold (EMGFT) in the superficial quadriceps femoris muscles. We hypothesize that the EMGFT values for the caffeine condition will be significantly higher than the EMGFT values for the placebo condition. On separate occasions, 10 physically active men performed incremental single-leg knee-extensor ergometry 1 hour after caffeine (200 mg) or placebo consumption. The EMGFT was determined for each participant for both conditions. The results indicated a significant increase for maximal power output (16%; p = 0.004) and EMGFT (45%; p = 0.004) in the caffeine condition compared with placebo. These findings suggest that acute low-dose caffeine supplementation delays neuromuscular fatigue in the quadriceps femoris muscles. PMID- 27776084 TI - The Visual Impact of Lens-Induced Astigmatism is Linked to Habitual Axis. AB - PURPOSE: Many studies have assessed the visual impact of astigmatism by inducing it using loose trial lenses at set axes. There are conflicting opinions and some confusion about the results, but the reduction in vision is typically least with lens-induced with-the-rule astigmatism. In this study, we determined whether a participant's habitual astigmatism influences the impact of lens-induced astigmatism on distance visual acuity (VA). METHODS: Participants included 35 adults (age range 19-79, average 41.3 +/- 15.4 years), who were either astigmats (>=0.75DC; N = 21) or non-astigmatic controls (N = 14). Distance VA was measured using an automated FrACT (Freiburg VA) system with the participant's habitual correction, and then with the addition of a +1.00DC lens at either 90 or 180 degrees (control) or at and perpendicular to the axis of habitual astigmatism (astigmats). RESULTS: The reduction in VA with induced astigmatism was significantly affected by whether the participant was a with-the-rule astigmat, against-the-rule astigmat, or non-astigmat (p = 0.006). Lens-induced astigmatism axis ~ 180 (160-20 degrees ) reduced the VA less than axis ~ 90 (70-120 degrees ) in the control group (reduction in mean VA of 0.32 SD +/- 0.10 with 95% confidence intervals of [0.27,0.37] compared to 0.42 +/- 0.09 [0.37,0.47] logMAR) and with-the-rule astigmats (reduction in VA of 0.31 SD +/- 0.06 [0.27,0.35] compared to 0.45 SD +/- 0.12 [0.38,0.52] logMAR). The against-the-rule astigmats had a very similar reduction in VA with the ~+1.00DC axis 180 condition compared to the ~+1.00DC axis 90 condition (reduction in VA of 0.26 SD +/- 0.09 [0.21,0.31] compared to 0.25 SD +/- 0.14 [0.17,0.33] logMAR). CONCLUSIONS: The impact of lens-induced astigmatism was dependent on the refractive status of the participants. When investigating the impact of lens-induced astigmatism, it is important to consider the participants' habitual axis of astigmatism. PMID- 27776085 TI - Patterns of Postoperative Delirium in Children. AB - OBJECTIVE: Intensive care delirium is a substantial problem in adults. Intensive care delirium is increasingly recognized in pediatrics in parallel with the development of specific scoring systems for children. However, little is known about the fluctuating course of intensive care delirium in children after surgery and possible implications on diagnostic and therapeutic strategies. DESIGN: Patients that needed treatment in the PICU following elective surgery were screened for intensive care delirium with the Cornell Assessment of Pediatric Delirium. When the patients were awake (Richmond Agitation and Sedation Score > 3), two trained investigators conducted the Cornell Assessment of Pediatric Delirium twice daily for five consecutive days. PATIENTS: Ninety-three patients aged 0 to 17 years. INTERVENTIONS: Eight hundred forty-five assessments completed. MEASUREMENTS AND MAIN RESULTS: Of the 845 scores, 230 were consistent with delirium (27.2%). Sixty-one patients (65.5%) were diagnosed with intensive care delirium. Half of these patients (n = 30; 32.2%) had a short-lasting delirium that resolved within 24 hours, and half (n = 31; 33.3%) had delirium of longer duration. Delirium could be clearly distinguished from sedation by analysis of individual test items of the Cornell Assessment of Pediatric Delirium. Time spent delirious had a measurable effect on outcome variables, including hospital length of stay. CONCLUSION: Most postoperative PICU patients develop intensive care delirium. Some have a short-lasting course, which underlines the need for early screening. Our findings support the view of delirium as a continuum of acute neurocognitive disorder. Further research is needed to investigate prophylactic and treatment approaches for intensive care delirium. PMID- 27776087 TI - Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on the Management of Patients With Positional Plagiocephaly: The Role of Repositioning. AB - BACKGROUND: Plagiocephaly, involving positional deformity of the calvarium in infants, is one of the most common reasons for pediatric neurosurgical consultation. OBJECTIVE: To answer the question: "what is the evidence for the effectiveness of repositioning for positional plagiocephaly?" Treatment recommendations are provided based on the available evidence. METHODS: The National Library of Medicine MEDLINE database and the Cochrane Library were queried using MeSH headings and key words relevant to repositioning as a means to treat plagiocephaly and brachycephaly. Abstracts were reviewed to identify which studies met the inclusion criteria. An evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III). Based on the quality of the literature, a recommendation was rendered (Level I, II, or III). RESULTS: There were 3 randomized trials (Class I), 1 prospective cohort study (Class II), and 6 retrospective cohort studies (Class III). Repositioning education was found to be equal to a repositioning device and inferior to a physical therapy program. Five of the 7 cohort studies comparing repositioning with a helmet reported helmets to be better and take less time. CONCLUSION: Within the limits of this systematic review, repositioning education is effective in affording some degree of correction in virtually all infants with positional plagiocephaly or brachycephaly. Most studies suggest that a molding helmet corrects asymmetry more rapidly and to a greater degree than repositioning education. In a Class I study, repositioning education was as effective as repositioning education in conjunction with a repositioning wrap/device. Another Class I study demonstrated that a bedding pillow was superior to physical therapy for some infants. However, in keeping with the American Academy of Pediatrics' warning against the use of soft positioning pillows in the sleeping environment, the Task Force recommends physical therapy over any positioning device. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines management-patients-positional-plagiocephaly/Chapter_3. PMID- 27776086 TI - Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for the Diagnosis of Patients With Positional Plagiocephaly: The Role of Imaging. AB - BACKGROUND: No evidence-based guidelines exist for the imaging of patients with positional plagiocephaly. OBJECTIVE: The objective of this systematic review and evidence-based guideline is to answer the question, Is imaging necessary for infants with positional plagiocephaly to make a diagnosis? METHODS: The National Library of Medicine Medline database and the Cochrane Library were queried with the use of MeSH headings and key words relevant to imaging as a means to diagnose plagiocephaly. Abstracts were reviewed, and an evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III). Based on the quality of the literature, a recommendation was rendered (Level I, II, or III). RESULTS: A total of 42 full-text articles were selected for review. Of these, 10 were eliminated; thus, 32 full-text were manuscripts selected. There was no Class I evidence, but 2 Class II and 30 Class III studies were included. Three dimensional cranial topographical imaging, ultrasound, skull x-rays, computed tomography, and magnetic resonance imaging were investigated. CONCLUSION: Clinical examination is most often sufficient to diagnose plagiocephaly (quality, Class III; strength, Level III). Within the limits of this systematic review, the evidence suggests that imaging is rarely necessary and should be reserved for cases in which the clinical examination is equivocal. Many of the imaging studies were not designed to address the diagnostic utility of the imaging modality, and authors were actually assessing the utility of the imaging in longitudinal follow up, not initial diagnosis. For this reason, some of the studies reviewed were downgraded in Level of Evidence. When needed, 3-dimensional cranial topographical photo, skull x-rays, or ultrasound imaging is almost always sufficient for definitive diagnosis. Computed tomography scanning should not be used to diagnose plagiocephaly, but it may be necessary to rule out craniosynostosis. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines management-patients-positional-plagiocephaly/Chapter_2. PMID- 27776088 TI - Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for the Management of Patients With Positional Plagiocephaly: The Role of Physical Therapy. AB - BACKGROUND: Evidence-based guidelines are not currently available for the treatment of positional plagiocephaly and, in particular, for the use of physical therapy for treatment. OBJECTIVE: To answer the question: "does physical therapy provide effective treatment for positional plagiocephaly?" Treatment recommendations are created based on the available evidence. METHODS: The PubMed and the Cochrane Library were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and recommendations were made based on the quality of the literature (Levels I-III). RESULTS: Three studies met criteria for inclusion. Two randomized, controlled trials (Class I and Class II) and 1 prospective study assessing plagiocephaly as a secondary outcome measure (Class III) were included. CONCLUSION: Within the limits of this systematic review, physical therapy is significantly more effective than repositioning education as a treatment for positional plagiocephaly. There is no significant difference between physical therapy and a positioning pillow as a treatment for positional plagiocephaly. However, given the American Academy of Pediatrics' recommendation against soft pillows in cribs to ensure a safe sleeping environment for infants, physical therapy must be recommended over the use of a positioning pillow. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional plagiocephaly/Chapter_4. PMID- 27776089 TI - Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on the Role of Cranial Molding Orthosis (Helmet) Therapy for Patients With Positional Plagiocephaly. AB - BACKGROUND: No evidence-based guidelines exist on the role of cranial-molding orthosis (helmet) therapy for patients with positional plagiocephaly. OBJECTIVE: To address the clinical question: "Does helmet therapy provide effective treatment for positional plagiocephaly?" and to make treatment recommendations based on the available evidence. METHODS: The US National Library of Medicine Medline database and the Cochrane Library were queried by using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and, based on the quality of the literature, recommendations were made (Levels I-III). RESULTS: Fifteen articles met criteria for inclusion into the evidence tables. There was 1 prospective randomized controlled trial (Class II), 5 prospective comparative studies (Class II), and 9 retrospective comparative studies (Class II). CONCLUSION: There is a fairly substantive body of nonrandomized evidence that demonstrates more significant and faster improvement of cranial shape in infants with positional plagiocephaly treated with a helmet in comparison with conservative therapy, especially if the deformity is severe, provided that helmet therapy is applied during the appropriate period of infancy. Specific criteria regarding the measurement and quantification of deformity and the most appropriate time window in infancy for treatment of positional plagiocephaly with a helmet remains elusive. In general, infants with a more severe presenting deformity and infants who are helmeted early in infancy tend to have more significant correction (and even normalization) of head shape. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines management-patients-positional-plagiocephaly/Chapter_5. PMID- 27776090 TI - Treatment of coronary artery disease in cancer survivors: an emerging challenge. PMID- 27776091 TI - Reply. PMID- 27776093 TI - Diagnostic Interview for Genetic Studies: validity and reliability of the Croatian version. AB - OBJECTIVE: To test the validity and reliability of the Diagnostic Interview for Genetic Studies (DIGS) in patients with mental illness in Croatia. MATERIALS AND METHODS: Following translation, back-translation, and pilot testing, the Croatian version of DIGS (CRO-DIGS) was administered to a total of 150 inpatients and outpatients diagnosed at the Clinical Hospital in Split with bipolar and major depressive disorder (n=56), schizophrenia and schizoaffective disorder (n=62), and alcohol dependence or use disorders (n=32). Initial testing was performed independently by one interviewer and one observer blinded to the diagnosis, and a retest was performed after 8 weeks by a third examiner. RESULTS: The validity of CRO-DIGS was high (kappa=0.916), with an excellent inter-rater (kappa=0.824) reliability, especially for bipolar disorder (kappa=0.956). Following an 8 week test-retest interval, the reliability for all diagnoses was found to be excellent (kappa=0.843). CONCLUSION: Our study has shown excellent validity and reliability of the Croatian version of DIGS, making it a promising instrument to assess mental illness of patients. The development of a valid and reliable diagnostic tool such as the CRO-DIGS will considerably advance the scientific communities' ability to carry out genetic studies of psychiatric illness in the region. PMID- 27776092 TI - Perceived Nonbeneficial Treatment of Patients, Burnout, and Intention to Leave the Job Among ICU Nurses and Junior and Senior Physicians. AB - OBJECTIVES: Perceiving nonbeneficial treatment is stressful for ICU staff and may be associated with burnout. We aimed to investigate predictors and consequences of perceived nonbeneficial treatment and to compare nurses and junior and senior physicians. DESIGN: Cross-sectional, multicenter paper-pencil survey on personal and work-related characteristics, perceived nonbeneficial treatment, burnout, and intention to leave the job. SETTING: Convenience sample of 23 German ICUs. SUBJECTS: ICU nurses and physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 847 questionnaires were returned (51% response); 778 had complete data for final multivariate analyses. Nonbeneficial treatment was in median perceived "sometimes." Adjusted for covariates, it was perceived more often by nurses and junior physicians (both p <= 0.001 in comparison to senior physicians), while emotional exhaustion was highest in junior physicians (p <= 0.015 in comparison to senior physicians and nurses), who also had a higher intention to leave than nurses (p = 0.024). Nonbeneficial treatment was predicted by high workload and low quality collaboration with other departments (both p <= 0.001). Poor nurse-physician collaboration predicted perception of nonbeneficial treatment among junior physicians and nurses (both p <= 0.001) but not among senior physicians (p = 0.753). Nonbeneficial treatment was independently associated with the core burnout dimension emotional exhaustion (p <= 0.001), which significantly mediated the effect between nonbeneficial treatment and intention to leave (indirect effect: 0.11 [95% CI, 0.06-0.18]). CONCLUSIONS: Perceiving nonbeneficial treatment is related to burnout and may increase intention to leave. Efforts to reduce perception of nonbeneficial treatment should improve the work environment and should be tailored to the different experiences of nurses and junior and senior physicians. PMID- 27776094 TI - Influence of Medical Insurance Under the Affordable Care Act on Access to Pain Management of the Trauma Patient. AB - BACKGROUND AND OBJECTIVES: The Affordable Care Act intended to "extend affordable coverage" and "ensure access" for vulnerable patient populations. This investigation examined whether the type of insurance (Medicaid, Medicare, Blue Cross, cash pay) carried by trauma patients influences access to pain management specialty care. METHODS: Investigators phoned 443 board-certified pain specialists, securing office visits with 235 pain physicians from 8 different states. Appointments for pain management were for a patient who sustained an ankle fracture requiring surgery and experiencing difficulty weaning off opioids. Offices were phoned 4 times assessing responses to the 4 different payment methodologies. RESULTS: Fifty-three percent of pain specialists contacted (235 of 443) were willing to see new patients to manage pain medication. Within the 53% of positive responses, 7.2% of physicians scheduled appointments for Medicaid patients, compared with 26.8% for cash-paying patients, 39.6% for those with Medicare, and 41.3% with Blue Cross (P < 0.0001). There were no differences in appointment access between states that had expanded Medicaid eligibility for low income adults versus states that had not expanded Medicaid eligibility. Neither Medicaid nor Medicare reimbursement levels for new patient visits correlated with ability to schedule an appointment or influenced wait times. CONCLUSIONS: Access to pain specialists for management of pain medication in the postoperative trauma patient proved challenging. Despite the Affordable Care Act, Medicaid patients still experienced curtailed access to pain specialists and confronted the highest incidence of barriers to receiving appointments. PMID- 27776095 TI - Ultrasound-Guided Cervical Medial Branch Radiofrequency Neurotomy: Can Multitined Deployment Cannulae Be the Solution? AB - BACKGROUND AND OBJECTIVES: Novel multitined cannulae constitute an attractive option for ultrasound-guided radiofrequency neurotomy of cervical medial branches. The deployment tines increase the cannula's active area, thus altering its lesion size. Despite their theoretical benefits, multitined cannulae have not been assessed. In this bench study, we sought to investigate the lesions produced by a standard 18-gauge and 2 commercially available multitined deployment cannulae. We created ex vivo models to evaluate lesion morphology at a periosteal interface using approach angles likely to be encountered during an ultrasound guided technique. METHODS: Two ex vivo models were assembled using chicken breast tissue and bovine tibia. Monopolar lesions were carried out with 3 commercially available cannulae (18-gauge curved [S], 17-gauge with laterally deploying tines [N], and 18-gauge with distally deploying tines [T]). All cannulae were positioned at 0, 25, 45, and 90 degrees to the periosteal plane. For each angulation and cannula, 2 series of measurements were recorded to document lesion morphology in the axial and sagittal planes. Data collected included the lesion's surface area, shape, and dimensions relative to the needle tip. RESULTS: A total of 240 lesions were analyzed. The performances of S and N cannulae were significantly affected by approach angle, with lesion size decreasing as the angle increased. In contrast, T cannulae displayed similar lesion surface areas at 0 and 90 degrees. The multitined N and T cannulae produced the largest lesions at 0/25 and 90 degrees, respectively. Lesion height varied inversely according to approach angle for S and N cannulae, whereas T cannulae displayed stable characteristics. CONCLUSIONS: Unlike their S and N counterparts, T cannulae demonstrated stable lesion characteristics at varying approach angles. PMID- 27776096 TI - Education in Ultrasound-Guided Regional Anesthesia: Lots of Learning Left To Do. PMID- 27776097 TI - Everybody Knows That the Dice Are Loaded: How Can We Block the Nerves That Innervate the Knee Joint Without Blocking the Nerves That Innervate That Joint? PMID- 27776098 TI - Single-Dose Adductor Canal Block With Local Infiltrative Analgesia Compared With Local Infiltrate Analgesia After Total Knee Arthroplasty: A Randomized, Double Blind, Placebo-Controlled Trial. AB - BACKGROUND AND OBJECTIVES: A single-dose adductor canal block can provide postoperative analgesia for patients undergoing total knee arthroplasty (TKA). The purpose of this study was to assess postoperative opioid consumption after ultrasound-guided single-injection bupivacaine compared with saline adductor canal block for patients undergoing TKA. METHODS: After institutional review board approval, written informed consent was obtained from patients (>18 years old) undergoing elective TKA. Subjects were randomized into 2 groups as follows: adductor canal blockade with 10 mL of bupivacaine 0.25% with epinephrine 1:300,000 or 10 mL of normal saline. All patients received a periarticular infiltration mixture intraoperatively with scheduled and patient requested oral and IV analgesics postoperatively for breakthrough pain. Personnel blinded to group allocation recorded pain scores and opioid consumption every 6 hours. Pain burden, area under the numeric rating score for pain, was calculated for 36 hours. The primary outcome was postoperative IV/IM morphine (mg morEq) consumption at 36 hours after surgery. RESULTS: Forty (28 women/12 men) subjects were studied. Postoperative opioid consumption was reduced in the bupivacaine 48 (39 to 61) mg morEq compared with saline 60 (49 to 85) mg morEq, difference -12 ( 33 to -2) mg morEq (P = 0.03). Pain burden at rest was decreased in the bupivacaine 71 (37 to 120) score . hours compared with saline 131 (92 to 161) score . hours, difference -60 (-93 to -14) score . hours (P = 0.009). CONCLUSIONS: Adductor canal blockade with bupivacaine 0.25% with epinephrine 1:300,000 effectively reduces pain and opioid requirement in the postoperative period after TKA. Adductor canal blockade is an effective pain management adjunct for patients undergoing TKA. PMID- 27776099 TI - Use Your EYES. PMID- 27776100 TI - Reply to Dr Carassiti et al. PMID- 27776101 TI - The Risk-Benefit Ratio: Why Perform a Cervical Epidural Steroid Injection? PMID- 27776102 TI - Reply to Dr Engel: The Risk-Benefit Ratio: Cervical Interlaminar Epidural Injections Are Beneficial. PMID- 27776104 TI - Reply to Dr Del Buono et al. PMID- 27776103 TI - Parasternal, Pecto-intercostal, Pecs, and Transverse Thoracic Muscle Plane Blocks: A Rose by Any Other Name Would Smell as Sweet. PMID- 27776105 TI - Smart Phone Angle Calculation Improves Success of Neuraxial Ultrasound. PMID- 27776106 TI - Enhanced Recovery Programs Increase Thoracic Epidural Opportunities for Trainees. PMID- 27776109 TI - Sall1 is a transcriptional regulator defining microglia identity and function. AB - Microglia are the resident macrophages of the central nervous system (CNS). Gene expression profiling has identified Sall1, which encodes a transcriptional regulator, as a microglial signature gene. We found that Sall1 was expressed by microglia but not by other members of the mononuclear phagocyte system or by other CNS-resident cells. Using Sall1 for microglia-specific gene targeting, we found that the cytokine receptor CSF1R was involved in the maintenance of adult microglia and that the receptor for the cytokine TGF-beta suppressed activation of microglia. We then used the microglia-specific expression of Sall1 to inducibly inactivate the murine Sall1 locus in vivo, which resulted in the conversion of microglia from resting tissue macrophages into inflammatory phagocytes, leading to altered neurogenesis and disturbed tissue homeostasis. Collectively, our results show that transcriptional regulation by Sall1 maintains microglial identity and physiological properties in the CNS and allows microglia specific manipulation in vivo. PMID- 27776107 TI - RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. AB - RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1 deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes. PMID- 27776108 TI - Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. AB - Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin alphaE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint. A distinct set of transcription factors was active in CD103+ TRM cells, including Notch. Genetic and pharmacological experiments with mice revealed that Notch activity was required for the maintenance of CD103+ TRM cells. We have thus identified specialized programs underlying the residence, persistence, vigilance and tight control of human lung TRM cells. PMID- 27776111 TI - Complex transcriptional modulation with orthogonal and inducible dCas9 regulators. AB - The ability to dynamically manipulate the transcriptome is important for studying how gene networks direct cellular functions and how network perturbations cause disease. Nuclease-dead CRISPR-dCas9 transcriptional regulators, while offering an approach for controlling individual gene expression, remain incapable of dynamically coordinating complex transcriptional events. Here, we describe a flexible dCas9-based platform for chemical-inducible complex gene regulation. From a screen of chemical- and light-inducible dimerization systems, we identified two potent chemical inducers that mediate efficient gene activation and repression in mammalian cells. We combined these inducers with orthogonal dCas9 regulators to independently control expression of different genes within the same cell. Using this platform, we further devised AND, OR, NAND, and NOR dCas9 logic operators and a diametric regulator that activates gene expression with one inducer and represses with another. This work provides a robust CRISPR dCas9-based platform for enacting complex transcription programs that is suitable for large-scale transcriptome engineering. PMID- 27776112 TI - Bright photoactivatable fluorophores for single-molecule imaging. AB - Small-molecule fluorophores are important tools for advanced imaging experiments. We previously reported a general method to improve small, cell-permeable fluorophores which resulted in the azetidine-containing 'Janelia Fluor' (JF) dyes. Here, we refine and extend the utility of these dyes by synthesizing photoactivatable derivatives that are compatible with live-cell labeling strategies. Once activated, these derived compounds retain the superior brightness and photostability of the JF dyes, enabling improved single-particle tracking and facile localization microscopy experiments. PMID- 27776110 TI - E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1. AB - TBK1 is essential for interferon-beta (IFN-beta) production and innate antiviral immunity. Here we identified the T cell anergy-related E3 ubiquitin ligase RNF128 as a positive regulator of TBK1 activation. RNF128 directly interacted with TBK1 through its protease-associated (PA) domain and catalyzed the K63-linked polyubiquitination of TBK1, which led to TBK1 activation, IRF3 activation and IFN beta production. Deficiency of RNF128 expression attenuated IRF3 activation, IFN beta production and innate antiviral immune responses to RNA and DNA viruses, in vitro and in vivo. Our study identified RNF128 as an E3 ligase for K63-linked ubiquitination and activation of TBK1 and delineated a previously unrecognized function for RNF128. PMID- 27776113 TI - Comparison of high-throughput sequencing data compression tools. AB - High-throughput sequencing (HTS) data are commonly stored as raw sequencing reads in FASTQ format or as reads mapped to a reference, in SAM format, both with large memory footprints. Worldwide growth of HTS data has prompted the development of compression methods that aim to significantly reduce HTS data size. Here we report on a benchmarking study of available compression methods on a comprehensive set of HTS data using an automated framework. PMID- 27776114 TI - Wheat Fhb1 encodes a chimeric lectin with agglutinin domains and a pore-forming toxin-like domain conferring resistance to Fusarium head blight. AB - Fusarium head blight (FHB), caused by Fusarium graminearum, is a devastating disease of wheat and barley that leads to reduced yield and mycotoxin contamination of grain, making it unfit for human consumption. FHB is a global problem, with outbreaks in the United States, Canada, Europe, Asia and South America. In the United States alone, total direct and secondary economic losses from 1993 to 2001 owing to FHB were estimated at $7.67 billion. Fhb1 is the most consistently reported quantitative trait locus (QTL) for FHB resistance breeding. Here we report the map-based cloning of Fhb1 from a Chinese wheat cultivar Sumai 3. By mutation analysis, gene silencing and transgenic overexpression, we show that a pore-forming toxin-like (PFT) gene at Fhb1 confers FHB resistance. PFT is predicted to encode a chimeric lectin with two agglutinin domains and an ETX/MTX2 toxin domain. Our discovery identifies a new type of durable plant resistance gene conferring quantitative disease resistance to plants against Fusarium species. PMID- 27776116 TI - General rules for functional microRNA targeting. AB - The functional rules for microRNA (miRNA) targeting remain controversial despite their biological importance because only a small fraction of distinct interactions, called site types, have been examined among an astronomical number of site types that can occur between miRNAs and their target mRNAs. To systematically discover functional site types and to evaluate the contradicting rules reported previously, we used large-scale transcriptome data and statistically examined whether each of approximately 2 billion site types is enriched in differentially downregulated mRNAs responding to overexpressed miRNAs. Accordingly, we identified seven non-canonical functional site types, most of which are novel, in addition to four canonical site types, while also removing numerous false positives reported by previous studies. Extensive experimental validation and significantly elevated 3' UTR sequence conservation indicate that these non-canonical site types may have biologically relevant roles. Our expanded catalog of functional site types suggests that the gene regulatory network controlled by miRNAs may be far more complex than currently understood. PMID- 27776117 TI - M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. AB - Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the classifiers are trusted as definitive in a clinical setting. We developed M-CAP, a clinical pathogenicity classifier that outperforms existing methods at all thresholds and correctly dismisses 60% of rare, missense variants of uncertain significance in a typical genome at 95% sensitivity. PMID- 27776118 TI - Genome-wide significance testing of variation from single case exomes. AB - Standard techniques from genetic epidemiology are ill-suited to formally assess the significance of variants identified from a single case. We developed a statistical inference framework for identifying unusual functional variation from a single exome or genome, what we refer to as the 'n-of-one' problem. Using this approach we assessed our ability to identify the causal genotypes in over 5 million simulated cases of Mendelian disease, identifying 39% of disease genotypes as the most damaging unit in a typical exome background. We applied our approach to 129 n-of-one families from the Undiagnosed Diseases Program, nominating 60% of 30 disease genes determined to be diagnostic by a standard clinical workup. Our method can currently produce well-calibrated P values when applied to single genomes, can facilitate integration of multiple data types for n-of-one analyses, and, with further work, could become a widely used epidemiological method like linkage analysis or genome-wide association analysis. PMID- 27776115 TI - Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. AB - Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function. PMID- 27776119 TI - Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction. AB - Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy. PMID- 27776120 TI - RNA Aptamer That Specifically Binds to Mycolactone and Serves as a Diagnostic Tool for Diagnosis of Buruli Ulcer. AB - BACKGROUND: Buruli ulcer (BU) is a subcutaneous skin disease listed among the neglected tropical diseases by the World Health Organization (WHO). Early case detection and management is very important to reduce morbidity and the accompanied characteristic disfiguring nature of BU. Since diagnosis based on clinical evidence can lead to misdiagnosis, microbiological confirmation is essential to reduce abuse of drugs; since the anti-mycobacterial drugs are also used for TB treatment. The current WHO gold standard PCR method is expensive, requires infrastructure and expertise are usually not available at the peripheral centers where BU cases are managed. Thus one of the main research agendas is to develop methods that can be applied at the point of care. In this study we selected aptamers, which are emerging novel class of detection molecules, for detecting mycolactone, the first to be conducted in a BUD endemic country. METHODS: Aptamers that bind to mycolactone were isolated by the SELEX process. To measure their affinity and specificity to mycolactone, the selected aptamers were screened by means of isothermal titration calorimetry (ITC) and an enzyme-linked oligonucleotide assay (ELONA). Selected aptamers were assessed by ELONA using swab samples from forty-one suspected BU patients with IS2404 PCR and culture as standard methods. ROC analysis was used to evaluate their accuracy and cutoff points. RESULTS: Five out of the nine selected aptamers bound significantly (p< 0.05) to mycolactone, of these, three were able to distinguish between mycolactone producing mycobacteria, M. marinum (CC240299, Israel) and other bacteria whilst two others also bounded significantly to Mycobacterium smegmatis. Their dissociation constants were in the micro-molar range. At 95% confidence interval, the ROC curve analysis among the aptamers at OD450 ranged from 0.5-0.7. Using this cut-off for the ELONA assay, the aptamers had 100% specificity and sensitivity between 0.0% and 50.0%. The most promising aptamer, Apt-3683 showed a discernible cleavage difference relative to the non-specific autocatalysis over a 3-minute time course. CONCLUSION: This preliminary proof-of-concept indicates that diagnosis of BUD with RNA aptamers is feasible and can be used as point of care upon incorporation into a diagnostic platform. PMID- 27776121 TI - Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival. AB - We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3' splice sites in S34F expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3' splice sites. Finally, we show that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo. In contrast, wild type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele. Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele. PMID- 27776122 TI - Relative Contributions of Specific Activity Histories and Spontaneous Processes to Size Remodeling of Glutamatergic Synapses. AB - The idea that synaptic properties are defined by specific pre- and postsynaptic activity histories is one of the oldest and most influential tenets of contemporary neuroscience. Recent studies also indicate, however, that synaptic properties often change spontaneously, even in the absence of specific activity patterns or any activity whatsoever. What, then, are the relative contributions of activity history-dependent and activity history-independent processes to changes synapses undergo? To compare the relative contributions of these processes, we imaged, in spontaneously active networks of cortical neurons, glutamatergic synapses formed between the same axons and neurons or dendrites under the assumption that their similar activity histories should result in similar size changes over timescales of days. The size covariance of such commonly innervated (CI) synapses was then compared to that of synapses formed by different axons (non-CI synapses) that differed in their activity histories. We found that the size covariance of CI synapses was greater than that of non-CI synapses; yet overall size covariance of CI synapses was rather modest. Moreover, momentary and time-averaged sizes of CI synapses correlated rather poorly, in perfect agreement with published electron microscopy-based measurements of mouse cortex synapses. A conservative estimate suggested that ~40% of the observed size remodeling was attributable to specific activity histories, whereas ~10% and ~50% were attributable to cell-wide and spontaneous, synapse-autonomous processes, respectively. These findings demonstrate that histories of naturally occurring activity patterns can direct glutamatergic synapse remodeling but also suggest that the contributions of spontaneous, possibly stochastic, processes are at least as great. PMID- 27776123 TI - Chronic Arsenic Exposure and Risk of Post Kala-azar Dermal Leishmaniasis Development in India: A Retrospective Cohort Study. AB - BACKGROUND: Visceral leishmaniasis (VL), with the squeal of Post-kala-azar dermal leishmaniasis (PKDL), is a global threat for health. Studies have shown sodium stibogluconate (SSG) resistance in VL patients with chronic arsenic exposure. Here, we assessed the association between arsenic exposure and risk of developing PKDL in treated VL patients. METHODS: In this retrospective study, PKDL patients (n = 139), earlier treated with SSG or any other drug during VL, were selected from the study cohort. Trained physicians, unaware of arsenic exposure, interviewed them and collected relevant data in a questionnaire format. All probable water sources were identified around the patient's house and water was collected for evaluation of arsenic concentration. A GIS-based village-level digital database of PKDL cases and arsenic concentration in groundwater was developed and individual point location of PKDL cases were overlaid on an integrated GIS map. We used multivariate logistic regression analysis to assess odds ratios (ORs) for association between arsenic exposure and PKDL development. RESULTS: Out of the 429 water samples tested, 403 had arsenic content of over 10 MUg/L, with highest level of 432 MUg/L among the seven study villages. Multivariate adjusted ORs for risk of PKDL development in comparison of arsenic concentrations of 10.1-200 MUg/L and 200.1-432.0 MUg/L were 1.85 (1.13-3.03) and 2.31 (1.39-3.8) respectively. Interestingly, similar results were found for daily dose of arsenic and total arsenic concentration in urine sample of the individual. The multivariate-adjusted OR for comparison of high baseline arsenic exposure to low baseline arsenic exposure of the individuals in the study cohort was 1.66 (95% CI 1.02-2.7; p = 0.04). CONCLUSION: Our findings indicate the need to consider environmental factors, like long time arsenic exposure, as an additional influence on treated VL patients towards risk of PKDL development in Bihar. PMID- 27776124 TI - Towards Development of Small Molecule Lipid II Inhibitors as Novel Antibiotics. AB - Recently we described a novel di-benzene-pyrylium-indolene (BAS00127538) inhibitor of Lipid II. BAS00127538 (1-Methyl-2,4-diphenyl-6-((1E,3E)-3-(1,3,3 trimethylindolin-2-ylidene)prop-1-en-1-yl)pyryl-1-ium) tetrafluoroborate is the first small molecule Lipid II inhibitor and is structurally distinct from natural agents that bind Lipid II, such as vancomycin. Here, we describe the synthesis and biological evaluation of 50 new analogs of BAS00127538 designed to explore the structure-activity relationships of the scaffold. The results of this study indicate an activity map of the scaffold, identifying regions that are critical to cytotoxicity, Lipid II binding and range of anti-bacterial action. One compound, 6jc48-1, showed significantly enhanced drug-like properties compared to BAS00127538. 6jc48-1 has reduced cytotoxicity, while retaining specific Lipid II binding and activity against Enterococcus spp. in vitro and in vivo. Further, this compound showed a markedly improved pharmacokinetic profile with a half-life of over 13 hours upon intravenous and oral administration and was stable in plasma. These results suggest that scaffolds like that of 6jc48-1 can be developed into small molecule antibiotic drugs that target Lipid II. PMID- 27776125 TI - Immunotherapeutic Potential of Eugenol Emulsion in Experimental Visceral Leishmaniasis. AB - BACKGROUND: The therapy of visceral leishmaniasis (VL) is limited by resistance, toxicity and decreased bioavailability of the existing drugs coupled with dramatic increase in HIV-co-infection, non-availability of vaccines and down regulation of cell-mediated immunity (CMI). Thus, we envisaged combating the problem with plant-derived antileishmanial drug that could concomitantly mitigate the immune suppression of the infected hosts. Several plant-derived compounds have been found to exert leishmanicidal activity via immunomodulation. In this direction, we investigated the antileishmanial activity of eugenol emulsion (EE), complemented with its immunomodulatory and therapeutic efficacy in murine model of VL. METHODOLOGY/PRINCIPAL FINDINGS: Oil-in-water emulsion of eugenol (EE) was prepared and size measured by dynamic light scattering (DLS). EE exhibited significant leishmanicidal activity with 50% inhibitory concentration of 8.43+/ 0.96 MUg ml-1 and 5.05+/-1.72 MUg ml?1, respectively against the promastigotes and intracellular amastigotes of Leishmania donovani. For in vivo effectiveness, EE was administered intraperitoneally (25, 50 and 75 mg/kg b.w./day for 10 days) to 8 week-infected BALB/c mice. The cytotoxicity of EE was assessed in RAW 264.7 macrophages as well as in naive mice. EE induced a significant drop in hepatic and splenic parasite burdens as well as diminution in spleen and liver weights 10 days post-treatment, with augmentation of 24h-delayed type hypersensitivity (DTH) response and high IgG2a:IgG1, mirroring induction of CMI. Enhanced IFN-gamma and IL-2 levels, with fall in disease-associated Th2 cytokines (IL-4 and IL-10) detected by flow cytometric bead-based array, substantiated the Th1 immune signature. Lymphoproliferation and nitric oxide release were significantly elevated upon antigen revoke in vitro. The immune-stimulatory activity of EE was further corroborated by expansion of IFN-gamma producing CD4+ and CD8+ splenic T lymphocytes and up-regulation of CD80 and CD86 on peritoneal macrophages. EE treated groups exhibited induction of CD8+ central memory T cells as evidenced from CD62L and CD44 expression. No biochemical alterations in hepatic and renal enzymes were observed. CONCLUSIONS: Our results demonstrate antileishmanial activity of EE, potentiated by Th1 immunostimulation without adverse side effects. The Th1 immune polarizing effect may help to alleviate the depressed CMI and hence complement the leishmanicidal activity. PMID- 27776126 TI - The Skp1 Homologs SKR-1/2 Are Required for the Caenorhabditis elegans SKN-1 Antioxidant/Detoxification Response Independently of p38 MAPK. AB - SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN 1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-1/Nrf activation provides insights into how cells coordinate responses to stress. Nrf2 in mammals is regulated in part by the redox sensor repressor protein named Keap1. In C. elegans, the p38 MAPK cascade in the intestine activates SKN-1 during oxidative stress by promoting its nuclear accumulation. Interestingly, we find variation in the kinetics of p38 MAPK activation and tissues with SKN-1 nuclear accumulation among different pro oxidants that all trigger strong induction of SKN-1 target genes. Using genome wide RNAi screening, we identify new genes that are required for activation of the core SKN-1 target gene gst-4 during exposure to the natural pro-oxidant juglone. Among 10 putative activators identified in this screen was skr-1/2, highly conserved homologs of yeast and mammalian Skp1, which function to assemble protein complexes. Silencing of skr-1/2 inhibits induction of SKN-1 dependent detoxification genes and reduces resistance to pro-oxidants without decreasing p38 MAPK activation. Global transcriptomics revealed strong correlation between genes that are regulated by SKR-1/2 and SKN-1 indicating a high degree of specificity. We also show that SKR-1/2 functions upstream of the WD40 repeat protein WDR-23, which binds to and inhibits SKN-1. Together, these results identify a novel p38 MAPK independent signaling mechanism that activates SKN-1 via SKR-1/2 and involves WDR-23. PMID- 27776127 TI - Integrated Healthcare Delivery: A Qualitative Research Approach to Identifying and Harmonizing Perspectives of Integrated Neglected Tropical Disease Programs. AB - BACKGROUND: While some evidence supports the beneficial effects of integrating neglected tropical disease (NTD) programs to optimize coverage and reduce costs, there is minimal information regarding when or how to effectively operationalize program integration. The lack of systematic analyses of integration experiences and of integration processes may act as an impediment to achieving more effective NTD programming. We aimed to learn about the experiences of NTD stakeholders and their perceptions of integration. METHODOLOGY: We evaluated differences in the definitions, roles, perceived effectiveness, and implementation experiences of integrated NTD programs among a variety of NTD stakeholder groups, including multilateral organizations, funding partners, implementation partners, national Ministry of Health (MOH) teams, district MOH teams, volunteer rural health workers, and community members participating in NTD campaigns. Semi-structured key informant interviews were conducted. Coding of themes involved a mix of applying in-vivo open coding and a priori thematic coding from a start list. FINDINGS: In total, 41 interviews were conducted. Salient themes varied by stakeholder, however dominant themes on integration included: significant variations in definitions, differential effectiveness of specific integrated NTD activities, community member perceptions of NTD programs, the influence of funders, perceived facilitators, perceived barriers, and the effects of integration on health system strength. In general, stakeholder groups provided unique perspectives, rather than contrarian points of view, on the same topics. The stakeholders identified more advantages to integration than disadvantages, however there are a number of both unique facilitators and challenges to integration from the perspective of each stakeholder group. CONCLUSIONS: Qualitative data suggest several structural, process, and technical opportunities that could be addressed to promote more effective and efficient integrated NTD elimination programs. We highlight a set of ten recommendations that may address stakeholder concerns and perceptions regarding these key opportunities. For example, public health stakeholders should embrace a broader perspective of community-based health needs, including and beyond NTDs, and available platforms for addressing those needs. PMID- 27776128 TI - Degradation Kinetics and Mechanism of Lithospermic Acid under Low Oxygen Condition Using Quantitative 1H NMR with HPLC-MS. AB - A novel quantitative 1H NMR (Q-NMR) combined with HPLC-MS method has been proposed for investigating the degradation process of traditional Chinese medicine (TCM) components. Through this method, in-situ monitoring of dynamics degradation process of lithospermic acid (LA), one of the popular polyphenolic acids in TCM, was realized under low oxygen condition. Additionally, this methodology was proved to be simple, rapid and specific. Degradation kinetic runs have been carried out to systematically investigate the effects of two key environmental factors, initial pH values and temperatures. Eight main degradation products of LA were detected, seven of which were tentatively structural elucidated with the help of both NMR and LC-MS in this work and salvianolic acid A (Sal A) was the primary degradation product of LA. A possible degradation pathway of LA was proposed, subsequently. The results showed that the degradation of LA followed pseudo-first-order kinetics. The apparent degradation kinetic constants increased as the initial pH value of the phosphate buffer increased. Under the given conditions, the rate constants of overall degradation as a function of temperature obeyed the Arrhenius equation. Our results proved that the Q-NMR combined with HPLC-MS method can be one of the most promising techniques for investigating degradation process of active components in TCM. PMID- 27776129 TI - Analysis of the Physiological Activities of Scd6 through Its Interaction with Hmt1. AB - Scd6, a yeast homologue of human RAP55, is a component of messenger ribonucleoproteins (mRNPs) that repress translation by binding to translation initiation factors, and also is a decapping activator along with the binding partners Edc3 and Dhh1. Herein, we report that Scd6 is a substrate of the intrinsic protein arginine methyltransferase, Hmt1, in budding yeast Saccharomyces cerevisiae. Mass spectrometric analysis revealed that several arginine residues within the Scd6 RGG motif, which is important for mRNA binding, were methylated in Hmt1 dependent manner. Under stress conditions such as glucose starvation, Scd6 localized to cytoplasmic processing bodies (P-bodies) wherein translationally repressed mRNPs and untranslated mRNAs accumulate. Localization of Scd6 to P-bodies was impaired in hmt1 deletion mutant and in the presence of methylation-deficient substitution of Scd6. In addition, deletion of scd6 and dhh1 led to severe synthetic growth defect at high temperature. Methylation deficient mutation of Scd6 suppressed the phenotypic defects of scd6 dhh1 double mutant, whereas methylation-mimic mutation did not, suggesting that the arginine methylation might negatively regulate Scd6 function relating to Dhh1. Therefore, the present data suggest that Hmt1-based arginine methylation is required for Scd6 localization and function. PMID- 27776131 TI - Measuring Life Satisfaction in Parkinson's Disease and Healthy Controls Using the Satisfaction With Life Scale. AB - The 5-item Satisfaction With Life Scale (SWLS) was designed to measure general life satisfaction (LS). Here we examined the psychometric properties of the SWLS in a cohort of persons with Parkinson's disease (PwPD) and age and gender matched individuals without PD. The SWLS was administered to PwPD and controls from the Norwegian ParkWest study at 5 and 7 years after the time of diagnosis. Data were analysed according to classical test theory (CTT) and Rasch measurement theory. CTT scaling assumptions for computation of a SWLS total score were met (corrected item-total correlations >0.58). The SWLS was reasonably well targeted to the sample and had good reliability (ordinal alpha, 0.92). The scale exhibited good fit to the Rasch model and successfully separated between 5 statistically distinct strata of people (levels of SWLS). The seven response categories did not work as intended and the scale may benefit from reduction to five response categories. There was no clinically significant differential item functioning. Separate analyses in PwPD and controls yielded very similar results to those from the pooled analysis. This study supports the SWLS as a valid instrument for measuring LS in PD and controls. However, Rasch analyses provided new insights into the performance and validity of the SWLS and identified areas for future revisions in order to further improve the scale. PMID- 27776130 TI - Central Pain Processing in Early-Stage Parkinson's Disease: A Laser Pain fMRI Study. AB - BACKGROUND & OBJECTIVE: Pain is a common non-motor symptom in Parkinson's disease. As dopaminergic dysfunction is suggested to affect intrinsic nociceptive processing, this study was designed to characterize laser-induced pain processing in early-stage Parkinson's disease patients in the dopaminergic OFF state, using a multimodal experimental approach at behavioral, autonomic, imaging levels. METHODS: 13 right-handed early-stage Parkinson's disease patients without cognitive or sensory impairment were investigated OFF medication, along with 13 age-matched healthy control subjects. Measurements included warmth perception thresholds, heat pain thresholds, and central pain processing with event-related functional magnetic resonance imaging (erfMRI) during laser-induced pain stimulation at lower (E = 440 mJ) and higher (E = 640 mJ) target energies. Additionally, electrodermal activity was characterized during delivery of 60 randomized pain stimuli ranging from 440 mJ to 640 mJ, along with evaluation of subjective pain ratings on a visual analogue scale. RESULTS: No significant differences in warmth perception thresholds, heat pain thresholds, electrodermal activity and subjective pain ratings were found between Parkinson's disease patients and controls, and erfMRI revealed a generally comparable activation pattern induced by laser-pain stimuli in brain areas belonging to the central pain matrix. However, relatively reduced deactivation was found in Parkinson's disease patients in posterior regions of the default mode network, notably the precuneus and the posterior cingulate cortex. CONCLUSION: Our data during pain processing extend previous findings suggesting default mode network dysfunction in Parkinson's disease. On the other hand, they argue against a genuine pain specific processing abnormality in early-stage Parkinson's disease. Future studies are now required using similar multimodal experimental designs to examine pain processing in more advanced stages of Parkinson's disease. PMID- 27776132 TI - Tyrosine Binding Protein Sites Regulate the Intracellular Trafficking and Processing of Amyloid Precursor Protein through a Novel Lysosome-Directed Pathway. AB - The amyloid hypothesis posits that the production of beta-amyloid (Abeta) aggregates leads to neurodegeneration and cognitive decline associated with AD. Abeta is produced by sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretase. While nascent APP is well known to transit to the endosomal/ lysosomal system via the cell surface, we have recently shown that APP can also traffic to lysosomes intracellularly via its interaction with AP-3. Because AP-3 interacts with cargo protein via interaction with tyrosine motifs, we mutated the three tyrosines motif in the cytoplasmic tail of APP. Here, we show that the YTSI motif interacts with AP-3, and phosphorylation of the serine in this motif disrupts the interaction and decreases APP trafficking to lysosomes. Furthermore, we show that phosphorylation at this motif can decrease the production of neurotoxic Abeta 42. This demonstrates that reducing APP trafficking to lysosomes may be a strategy to reduce Abeta 42 in Alzheimer's disease. PMID- 27776133 TI - Psychological Distress following Injury in a Large Cohort of Thai Adults. AB - INTRODUCTION: Injury and psychological distress are public health priorities because of their high occurrence in the population. This study examines the longitudinal effects of injury characteristics on psychological distress. METHODS: Study participants were enrolled distance learning Thai adults (N = 42,785 at 2013 follow-up) residing nationwide. We analysed 2009 and 2013 data. Injury questions included injury prevalence, causes and levels of severity. Distress was measured using the standard Kessler-6. To assess the risk for post injury distress, we used multinomial logistic regression investigating psychological distress in 2013 as an outcome including injury categories in both 2009 and 2013 as predictors, adjusted for sociodemographic factors. RESULTS: Overall injury was predictive of psychological distress. Both types of injury (traffic and non- traffic) associated with increasing psychological distress. Those that had experienced both types of injuries in the previous year had higher odds of developing psychological distress compared to those who experienced just one type. In 2013, adjusted psychological distress odds ratios were 1.46 [95% Confidence Interval 1.14-1.87] for traffic injury only; 1.26 [1.13-1.40] for non traffic injury only; and 2.71 [2.19-3.35] for both traffic and non-traffic injuries. Increasing frequency of injury and increasing injury severity were also linked to elevated psychological distress among our Thai cohort members. CONCLUSIONS: Our results revealed a significantly high risk of psychological distress following injury. With increasing occurrence of injury, especially traffic injuries in low and middle income countries such as Thailand, future policies should not only focus on physical care but also address psychological distress as an important consequence of injury. PMID- 27776134 TI - Gender Incongruence of Adolescence and Adulthood: Acceptability and Clinical Utility of the World Health Organization's Proposed ICD-11 Criteria. AB - The World Health Organization (WHO) is currently updating the tenth version of their diagnostic tool, the International Classification of Diseases (ICD, WHO, 1992). Changes have been proposed for the diagnosis of Transsexualism (ICD-10) with regard to terminology, placement and content. The aim of this study was to gather the opinions of transgender individuals (and their relatives/partners) and clinicians in the Netherlands, Flanders (Belgium) and the United Kingdom regarding the proposed changes and the clinical applicability and utility of the ICD-11 criteria of 'Gender Incongruence of Adolescence and Adulthood' (GIAA). A total of 628 participants were included in the study: 284 from the Netherlands (45.2%), 8 from Flanders (Belgium) (1.3%), and 336 (53.5%) from the UK. Most participants were transgender people (or their partners/relatives) (n = 522), 89 participants were healthcare providers (HCPs) and 17 were both healthcare providers and (partners/relatives of) transgender people. Participants completed an online survey developed for this study. Most participants were in favor of the proposed diagnostic term of 'Gender Incongruence' and thought that this was an improvement on the ICD-10 diagnostic term of 'Transsexualism'. Placement in a separate chapter dealing with Sexual- and Gender-related Health or as a Z-code was preferred by many and only a small number of participants stated that this diagnosis should be excluded from the ICD-11. In the UK, most transgender participants thought there should be a diagnosis related to being trans. However, if it were to be removed from the chapter on "psychiatric disorders", many transgender respondents indicated that they would prefer it to be removed from the ICD in its entirety. There were no large differences between the responses of the transgender participants (or their partners and relatives) and HCPs. HCPs were generally positive about the GIAA diagnosis; most thought the diagnosis was clearly defined and easy to use in their practice or work. The duration of gender incongruence (several months) was seen by many as too short and required a clearer definition. If the new diagnostic term of GIAA is retained, it should not be stigmatizing to individuals. Moving this diagnosis away from the mental and behavioral chapter was generally supported. Access to healthcare was one area where retaining a diagnosis seemed to be of benefit. PMID- 27776135 TI - Top-Down Network Effective Connectivity in Abstinent Substance Dependent Individuals. AB - OBJECTIVE: We hypothesized that compared to healthy controls, long-term abstinent substance dependent individuals (SDI) will differ in their effective connectivity between large-scale brain networks and demonstrate increased directional information from executive control to interoception-, reward-, and habit-related networks. In addition, using graph theory to compare network efficiencies we predicted decreased small-worldness in SDI compared to controls. METHODS: 50 SDI and 50 controls of similar sex and age completed psychological surveys and resting state fMRI. fMRI results were analyzed using group independent component analysis; 14 networks-of-interest (NOI) were selected using template matching to a canonical set of resting state networks. The number, direction, and strength of connections between NOI were analyzed with Granger Causality. Within-group thresholds were p<0.005 using a bootstrap permutation. Between group thresholds were p<0.05, FDR-corrected for multiple comparisons. NOI were correlated with behavioral measures, and group-level graph theory measures were compared. RESULTS: Compared to controls, SDI showed significantly greater Granger causal connectivity from right executive control network (RECN) to dorsal default mode network (dDMN) and from dDMN to basal ganglia network (BGN). RECN was negatively correlated with impulsivity, behavioral approach, and negative affect; dDMN was positively correlated with impulsivity. Among the 14 NOI, SDI showed greater bidirectional connectivity; controls showed more unidirectional connectivity. SDI demonstrated greater global efficiency and lower local efficiency. CONCLUSIONS: Increased effective connectivity in long-term abstinent drug users may reflect improved cognitive control over habit and reward processes. Higher global and lower local efficiency across all networks in SDI compared to controls may reflect connectivity changes associated with drug dependence or remission and requires future, longitudinal studies to confirm. PMID- 27776136 TI - Zeta Inhibitory Peptide as a Novel Therapy to Control Chronic Visceral Hypersensitivity in a Rat Model. AB - BACKGROUND: The pathogenesis of multiple chronic visceral pain syndromes, such as irritable bowel syndrome (IBS), is not well known, and as a result current therapies are ineffective. The objective of this study was to investigate the effect of spinal protein kinase M zeta (PKMzeta) on visceral pain sensitivity in rats with IBS to better understand the pathogenesis and investigate the effect of zeta inhibitory peptide (ZIP) as a therapy for chronic visceral pain. METHODS: Visceral hypersensitivity rats were produced by neonatal maternal separation (NMS). Visceral pain sensitivity was assessed by electromyographic (EMG) responses of abdominal muscles to colorectal distention (CRD). Spinal PKMzeta and phosphorylated PKMzeta (p-PKMzeta) were detected by western blot. Varying doses of ZIP were intrathecally administered to investigate the role of spinal PKMzeta in chronic visceral hypersensitivity. The open field test was used to determine if ZIP therapy causes spontaneous motor activity side effects. RESULTS: Graded CRD pressure significantly increased EMG responses in NMS rats compared to control rats (p < 0.05). p-PKMzeta expression increased in the thoracolumbar and lumbosacral spinal cord in the IBS-like rats with notable concomitant chronic visceral pain compared to control rats (p < 0.05). EMG data revealed that intrathecal ZIP injection (1, 5, and 10 MUg) dose-dependently attenuated visceral pain hypersensitivity in IBS-like rats. CONCLUSIONS: Phosphorylated PKMzeta may be involved in the spinal central sensitization of chronic visceral hypersensitivity in IBS, and administration of ZIP could effectively treat chronic visceral pain with good outcomes in rat models. PMID- 27776137 TI - Dabigatran for the Treatment and Secondary Prevention of Venous Thromboembolism; A Cost-Effectiveness Analysis for the Netherlands. AB - BACKGROUND: Dabigatran was proven to have similar effect on the prevention of recurrence of venous thromboembolism (VTE) and a lower risk of bleeding compared to vitamin K antagonists (VKA). The aim of this study is to assess the cost effectiveness (CE) of dabigatran for the treatment and secondary prevention in patients with VTE compared to VKAs in the Dutch setting. METHODS: Previously published Markov model was modified and updated to assess the CE of dabigatran and VKAs for the treatment and secondary prevention in patients with VTE from a societal perspective in the base-case analysis. The model was populated with efficacy and safety data from major dabigatran trials (i.e. RE-COVER, RECOVER II, RE-MEDY and RE-SONATE), Dutch specific costs, and utilities derived from dabigatran trials or other published literature. Univariate, probabilistic sensitivity and a number of scenario analyses evaluating various decision analytic settings (e.g. the perspective of analysis, use of anticoagulants only for treatment or only for secondary prevention, or comparison to no treatment) were tested on the incremental cost-effectiveness ratio (ICER). RESULTS: In the base-case scenario, patients on dabigatran gained an additional 0.034 quality adjusted life year (QALY) while saving ?1,598. Results of univariate sensitivity analysis were quite robust. The probability that dabigatran is cost-effective at a willingness-to-pay threshold of ?20,000/QALY was 98.1%. From the perspective of healthcare provider, extended anticoagulation with dabigatran compared to VKAs was estimated at ?2,158 per QALY gained. The ICER for anticoagulation versus no treatment in patients with equipoise risk of recurrent VTE was estimated at ?33,379 per QALY gained. Other scenarios showed dabigatran was cost-saving. CONCLUSION: From a societal perspective, dabigatran is likely to be a cost effective or even cost-saving strategy for treatment and secondary prevention of VTE compared to VKAs in the Netherlands. PMID- 27776138 TI - Classification of Benign and Malignant Thyroid Nodules Using a Combined Clinical Information and Gene Expression Signatures. AB - BACKGROUND: A key challenge in thyroid carcinoma is preoperatively diagnosing malignant thyroid nodules. A novel diagnostic test that measures the expression of a 3-gene signature (DPP4, SCG5 and CA12) has demonstrated promise in thyroid carcinoma assessment. However, more reliable prediction methods combining clinical features with genomic signatures with high accuracy, good stability and low cost are needed. METHODOLOGY/PRINCIPAL FINDINGS: 25 clinical information were recorded in 771 patients. Feature selection and validation were conducted using random forest. Thyroid samples and clinical data were obtained from 142 patients at two different hospitals, and expression of the 3-gene signature was measured using quantitative PCR. The predictive abilities of three models (based on the selected clinical variables, the gene expression profile, and integrated gene expression and clinical information) were compared. Seven clinical characteristics were selected based on a training set (539 patients) and tested in three test sets, yielding predictive accuracies of 82.3% (n = 232), 81.4% (n = 70), and 81.9% (n = 72). The predictive sensitivity, specificity, and accuracy were 72.3%, 80.5% and 76.8% for the model based on the gene expression signature, 66.2%, 81.8% and 74.6% for the model based on the clinical data, and 83.1%, 84.4% and 83.8% for the combined model in a 10-fold cross-validation (n = 142). CONCLUSIONS: These findings reveal that the integrated model, which combines clinical data with the 3-gene signature, is superior to models based on gene expression or clinical data alone. The integrated model appears to be a reliable tool for the preoperative diagnosis of thyroid tumors. PMID- 27776139 TI - Identification of Blood Let-7e-5p as a Biomarker for Ischemic Stroke. AB - Circulating microRNAs (miRNAs) are emerging as novel disease biomarkers. Using a miRNA microarray, we previously showed that the whole blood level of let-7e-5p was significantly higher in ischemic stroke patients than in control subjects. However, the association between let-7e-5p expression and the occurrence of ischemic stroke remains unknown. In this study, we validated the expression levels of let-7e-5p in two case-control populations using miRNA TaqMan assays and further investigated the potential targets of let-7e-5p. The results suggest that the blood level of let-7e-5p was significantly higher in patients with ischemic stroke than in controls (p<0.05). Higher levels of let-7e-5p were associated with increased occurrence of ischemic stroke (adjusted OR, 1.89; 95% CI, 1.61~2.21, p<0.001) in the combined population. The addition of let-7e-5p to traditional risk factors led to an improvement in the area under the curve, which increased from 0.74 (95% CI, 0.70~0.78) to 0.82 (95% CI, 0.78~0.85), with a net reclassification improvement of 16.76% (p<0.0001) and an integrated discrimination improvement of 0.10 (p<0.0001) for patients with ischemic stroke. Bioinformatics prediction and cell experiments suggested that the expression levels of four genes enriched in the MAPK signaling pathway were down-regulated by let-7e-5p transfection. Specifically, the expression levels of the genes CASP3 and NLK were significantly lower in ischemic stroke patients than in controls and were negatively correlated with let-7e-5p expression. In summary, our study suggests the potential use of blood let-7e-5p as a biomarker for ischemic stroke and indicates its involvement in the related pathomechanism. PMID- 27776140 TI - Comparison of Adsorption/Desorption of Volatile Organic Compounds (VOCs) on Electrospun Nanofibers with Tenax TA for Potential Application in Sampling. AB - The objective of this study was to compare the adsorption/desorption of target compounds on homemade electrospun nanofibers, polystyrene (PS) nanofibers, acrylic resin (AR) nanofibers and PS-AR composite nanofibers with Tenax TA. Ten volatile organic compounds (VOCs) were analyzed by preconcentration onto different sorbents followed by desorption (thermal and solvent orderly) and analysis by capillary gas chromatography. In comparison to Tenax TA, the electrospun nanofibers displayed a significant advantage in desorption efficiency and adsorption selectivity. Stability studies were conducted as a comparative experiment between PS-AR nanofibers and Tenax TA using toluene as the model compound. No stability problems were observed upon storage of toluene on both PS AR nanofibers and Tenax TA over 60 hours period when maintained in an ultra freezer (-80 degrees C). The nanofibers provided slightly better stability for the adsorbed analytes than Tenax TA under other storage conditions. In addition, the nanofibers also provided slightly better precision than Tenax TA. The quantitative adsorption of PS-AR nanofibers exhibited a good linearity, as evidenced by the 0.988-0.999 range of regression coefficients (R). These results suggest that for VOCs sampling the electrospun nanofibers can be a potential ideal adsorbent. PMID- 27776141 TI - A Systematic Review of Outcome Measures Use, Analytical Approaches, Reporting Methods, and Publication Volume by Year in Low Back Pain Trials Published between 1980 and 2012: Respice, adspice, et prospice. AB - BACKGROUND: Increasing patient-reported outcome measures in the 1980s and 1990s led to the development of recommendations at the turn of the millennium for standardising outcome measures in non-specific low back pain (LBP) trials. Whether these recommendations impacted use is unclear. Previous work has examined citation counts, but actual use and change over time, has not been explored. Since 2011, there has been some consensus on the optimal methods for reporting back pain trial outcomes. We explored reporting practice, outcome measure use, and publications over time. METHODS: We performed a systematic review of LBP trials, searching the European Guidelines for the management of LBP, extending the search to 2012. We abstracted data on publications by year, outcome measure use, analytical approach, and approaches taken to reporting trials outcomes. Data were analysed using descriptive statistics and regression analyses. RESULTS: We included 401 trials. The number of published trials per year has increased by a factor of 4.5 from 5.4 (1980-1999) to 24.4 (2000-2012). The most commonly used outcome measures have been the Visual Analogue Scale for pain intensity, which has slowly increased in use since 1980/81 from 20% to 60% of trials by 2012, and the Roland-Morris Disability Questionnaire, which rose to 55% in 2002/2003, and then fell back to 28% by 2012. Most trialists (85%) report between-group mean differences. Few (8%) report individual improvements, and some (4%) report only within-group analyses. Student's t test, ANOVA, and ANCOVA regression, or mixed models, were the most common approaches to analysis. CONCLUSIONS: Recommendations for standardising outcomes may have had a limited or inconsistent effect on practice. Since the research community is again considering outcome measures and modifying recommendations, groups offering recommendations should be cognisant that better ways of generating trialist buy-in may be required in order for their recommendations to have impact. PMID- 27776142 TI - Menstrual and Reproductive Factors and Risk of Gastric and Colorectal Cancer in Spain. AB - BACKGROUND: Sex hormones play a role in gastric cancer and colorectal cancer etiology, however, epidemiological evidence is inconsistent. This study examines the influence of menstrual and reproductive factors over the risk of both tumors. METHODS: In this case-control study 128 women with gastric cancer and 1293 controls, as well as 562 female and colorectal cancer cases and 1605 controls were recruited in 9 and 11 Spanish provinces, respectively. Population controls were frequency matched to cases by age and province. Demographic and reproductive data were directly surveyed by trained staff. The association with gastric, colon and rectal cancer was assessed using logistic and multinomial mixed regression models. RESULTS: Our results show an inverse association of age at first birth with gastric cancer risk (five-year trend: OR = 0.69; p-value = 0.006). Ever users of hormonal contraception presented a decreased risk of gastric (OR = 0.42; 95%CI = 0.26-0.69), colon (OR = 0.64; 95%CI = 0.48-0.86) and rectal cancer (OR = 0.61; 95%CI = 0.43-0.88). Postmenopausal women who used hormone replacement therapy showed a decreased risk of colon and rectal tumors. A significant interaction of educational level with parity and months of first child lactation was also observed. CONCLUSION: These findings suggest a protective role of exogenous hormones in gastric and colorectal cancer risk. The role of endogenous hormones remains unclear. PMID- 27776144 TI - Increased Abundance of Proteins Involved in Resistance to Oxidative and Nitrosative Stress at the Last Stages of Growth and Development of Leishmania amazonensis Promastigotes Revealed by Proteome Analysis. AB - Leishmania amazonensis is one of the major etiological agents of the neglected, stigmatizing disease termed american cutaneous leishmaniasis (ACL). ACL is a zoonosis and rodents are the main reservoirs. Most cases of ACL are reported in Brazil, Bolivia, Colombia and Peru. The biological cycle of the parasite is digenetic because sand fly vectors transmit the motile promastigote stage to the mammalian host dermis during blood meal intakes. The amastigote stage survives within phagocytes of the mammalian host. The purpose of this study is detection and identification of changes in protein abundance by 2DE/MALDI-TOF/TOF at the main growth phases of L. amazonensis promastigotes in axenic culture and the differentiation process that takes place simultaneously. The average number of proteins detected per gel is 202 and the non-redundant cumulative number is 339. Of those, 63 are differentially abundant throughout growth and simultaneous differentiation of L. amazonensis promastigotes. The main finding is that certain proteins involved in resistance to nitrosative and oxidative stress are more abundant at the last stages of growth and differentiation of cultured L. amazonensis promastigotes. These proteins are the arginase, a light variant of the tryparedoxin peroxidase, the iron superoxide dismutase, the regulatory subunit of the protein kinase A and a light HSP70 variant. These data taken together with the decrease of the stress-inducible protein 1 levels are additional evidence supporting the previously described pre-adaptative hypothesis, which consists of preparation in advance towards the amastigote stage. PMID- 27776145 TI - Is the Thatcher Illusion Modulated by Face Familiarity? Evidence from an Eye Tracking Study. AB - Thompson (1980) first detected and described the Thatcher Illusion, where participants instantly perceive an upright face with inverted eyes and mouth as grotesque, but fail to do so when the same face is inverted. One prominent but controversial explanation is that the processing of configural information is disrupted in inverted faces. Studies investigating the Thatcher Illusion either used famous faces or non-famous faces. Highly familiar faces were often thought to be processed in a pronounced configural mode, so they seem ideal candidates to be tested in one Thatcher study against unfamiliar faces-but this has never been addressed so far. In our study, participants evaluated 16 famous and 16 non famous faces for their grotesqueness. We tested whether familiarity (famous/non famous faces) modulates reaction times, correctness of grotesqueness assessments (accuracy), and eye movement patterns for the factors orientation (upright/inverted) and Thatcherisation (Thatcherised/non-Thatcherised). On a behavioural level, familiarity effects were only observable via face inversion (higher accuracy and sensitivity for famous compared to non-famous faces) but not via Thatcherisation. Regarding eye movements, however, Thatcherisation influenced the scanning of famous and non-famous faces, for instance, in scanning the mouth region of the presented faces (higher number, duration and dwell time of fixations for famous compared to non-famous faces if Thatcherised). Altogether, famous faces seem to be processed in a more elaborate, more expertise-based way than non-famous faces, whereas non-famous, inverted faces seem to cause difficulties in accurate and sensitive processing. Results are further discussed in the face of existing studies of familiar vs. unfamiliar face processing. PMID- 27776143 TI - Defining Priorities for Future Research: Results of the UK Kidney Transplant Priority Setting Partnership. AB - BACKGROUND: It has been suggested that the research priorities of those funding and performing research in transplantation may differ from those of end service users such as patients, carers and healthcare professionals involved in day-to day care. The Kidney Transplant Priority Setting Partnership (PSP) was established with the aim of involving all stakeholders in prioritising future research in the field. METHODS: The PSP methodology is as outlined by the James Lind Alliance. An initial survey collected unanswered research questions from patients, carers and clinicians. Duplicate and out-of-scope topics were excluded and the existing literature searched to identify topics answered by current evidence. An interim prioritisation survey asked patients and professionals to score the importance of the remaining questions to create a ranked long-list. These were considered at a final consensus workshop using a modified nominal group technique to agree a final top ten. RESULTS: The initial survey identified 497 questions from 183 respondents, covering all aspects of transplantation from assessment through to long-term follow-up. These were grouped into 90 unanswered "indicative" questions. The interim prioritisation survey received 256 responses (34.8% patients/carers, 10.9% donors and 54.3% professionals), resulting in a ranked list of 25 questions that were considered during the final workshop. Participants agreed a top ten priorities for future research that included optimisation of immunosuppression (improved monitoring, choice of regimen, personalisation), prevention of sensitisation and transplanting the sensitised patient, management of antibody-mediated rejection, long-term risks to live donors, methods of organ preservation, induction of tolerance and bioengineering of organs. There was evidence that patient and carer involvement had a significant impact on shaping the final priorities. CONCLUSIONS: The final list of priorities relates to all stages of the transplant process, including access to transplantation, living donation, organ preservation, post-transplant care and management of the failing transplant. This list of priorities will provide an invaluable resource for researchers and funders to direct future activity. PMID- 27776146 TI - A Root-Colonizing Pseudomonad Lessens Stress Responses in Wheat Imposed by CuO Nanoparticles. AB - Nanoparticle (NPs) containing essential metals are being considered in formulations of fertilizers to boost plant nutrition in soils with low metal bioavailability. This paper addresses whether colonization of wheat roots by the bacterium, Pseudomonas chlororaphis O6 (PcO6), protected roots from the reduced elongation caused by CuO NPs. There was a trend for slightly elongated roots when seedlings with roots colonized by PcO6 were grown with CuO NPs; the density of bacterial cells on the root surface was not altered by the NPs. Accumulations of reactive oxygen species in the plant root cells caused by CuO NPs were little affected by root colonization. However, bacterial colonization did reduce the extent of expression of an array of genes associated with plant responses to stress induced by root exposure to CuO NPs. PcO6 colonization also reduced the levels of two important chelators of Cu ions, citric and malic acids, in the rhizosphere solution; presumably because these acids were used as nutrients for bacterial growth. There was a trend for lower levels of soluble Cu in the rhizosphere solution and reduced Cu loads in the true leaves with PcO6 colonization. These studies indicate that root colonization by bacterial cells modulates plant responses to contact with CuO NPs. PMID- 27776147 TI - Astrocytic beta2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice. AB - In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the beta2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific beta2-adrenergic receptor knock-out mice were generated by crossing homozygous beta2-adrenergic receptor floxed mice (Adrb2flox) and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2). Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment) test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle) administration did not reveal any differences in physical health or motor functions between the knock out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP) was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that beta2 adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function. PMID- 27776148 TI - The Responsiveness of Patients' Quality of Life to Dental Caries Treatment-A Prospective Study. AB - The objective of this study was to determine the responsiveness of oral health related quality of life (OHRQoL) (oral health impact profile [OHIP] and oral impact on daily performance [OIDP]) and health-related quality of life (HRQoL) (World Health Organization quality of life scale, brief [WHOQOL-BREF]) in dental caries restoration treatment. The study also aimed to assess the influence of treatment on the responsiveness of patients' quality of life (QoL). A total of 126 patients (aged 16-40 years) received dental caries restoration treatment with a 2-week follow-up and pre- and posttreatment interviews by questionnaire. Patients were assessed for their perceptions of OHRQoL and HRQoL by using the OHIP, OIDP, and WHOQOL-BREF measures. The responsiveness of all outcome measurements was assessed by effect size (ES). Stepwise multiple regression analysis was used to examine the association with the responsiveness of all outcome measurements. Significant differences were found between OIDP (ES = 0.39), OHIP (ES = 0.54), and WHOQOL-BREF (ES = 0.13) with regard to pretreatment and posttreatment (p-values: <0.0001, <0.0001, and 0.0120, respectively). Sex and dental caries status at baseline were significantly associated with responsiveness by all measurements. This study suggests that dental caries treatment moderately improves OHRQoL, but is less related to HRQoL. Furthermore, the number of dental caries and restoration are important factors affecting the improvement of patients' perceived OHRQoL. PMID- 27776150 TI - Environmental DNA (eDNA) Detection Probability Is Influenced by Seasonal Activity of Organisms. AB - Environmental DNA (eDNA) holds great promise for conservation applications like the monitoring of invasive or imperiled species, yet this emerging technique requires ongoing testing in order to determine the contexts over which it is effective. For example, little research to date has evaluated how seasonality of organism behavior or activity may influence detection probability of eDNA. We applied eDNA to survey for two highly imperiled species endemic to the upper Black Warrior River basin in Alabama, US: the Black Warrior Waterdog (Necturus alabamensis) and the Flattened Musk Turtle (Sternotherus depressus). Importantly, these species have contrasting patterns of seasonal activity, with N. alabamensis more active in the cool season (October-April) and S. depressus more active in the warm season (May-September). We surveyed sites historically occupied by these species across cool and warm seasons over two years with replicated eDNA water samples, which were analyzed in the laboratory using species-specific quantitative PCR (qPCR) assays. We then used occupancy estimation with detection probability modeling to evaluate both the effects of landscape attributes on organism presence and season of sampling on detection probability of eDNA. Importantly, we found that season strongly affected eDNA detection probability for both species, with N. alabamensis having higher eDNA detection probabilities during the cool season and S. depressus have higher eDNA detection probabilities during the warm season. These results illustrate the influence of organismal behavior or activity on eDNA detection in the environment and identify an important role for basic natural history in designing eDNA monitoring programs. PMID- 27776149 TI - Acute Effects of Caffeine on Heart Rate Variability, Blood Pressure and Tidal Volume in Paraplegic and Tetraplegic Compared to Able-Bodied Individuals: A Randomized, Blinded Trial. AB - : Caffeine increases sympathetic nerve activity in healthy individuals. Such modulation of nervous system activity can be tracked by assessing the heart rate variability. This study aimed to investigate the influence of caffeine on time- and frequency-domain heart rate variability parameters, blood pressure and tidal volume in paraplegic and tetraplegic compared to able-bodied participants. Heart rate variability was measured in supine and sitting position pre and post ingestion of either placebo or 6 mg caffeine in 12 able-bodied, 9 paraplegic and 7 tetraplegic participants in a placebo-controlled, randomized and double-blind study design. Metronomic breathing was applied (0.25 Hz) and tidal volume was recorded during heart rate variability assessment. Blood pressure, plasma caffeine and epinephrine concentrations were analyzed pre and post ingestion. Most parameters of heart rate variability did not significantly change post caffeine ingestion compared to placebo. Tidal volume significantly increased post caffeine ingestion in able-bodied (p = 0.021) and paraplegic (p = 0.036) but not in tetraplegic participants (p = 0.34). Systolic and diastolic blood pressure increased significantly post caffeine in able-bodied (systolic: p = 0.003; diastolic: p = 0.021) and tetraplegic (systolic: p = 0.043; diastolic: p = 0.042) but not in paraplegic participants (systolic: p = 0.09; diastolic: p = 0.33). Plasma caffeine concentrations were significantly increased post caffeine ingestion in all three groups of participants (p<0.05). Plasma epinephrine concentrations increased significantly in able-bodied (p = 0.002) and paraplegic (p = 0.032) but not in tetraplegic participants (p = 0.63). The influence of caffeine on the autonomic nervous system seems to depend on the level of lesion and the extent of the impairment. Therefore, tetraplegic participants may be less influenced by caffeine ingestion. TRIAL REGISTRATION: ClinicalTrials.gov NCT02083328. PMID- 27776151 TI - An Assessment of the Spatial and Temporal Variability of Biological Responses to Municipal Wastewater Effluent in Rainbow Darter (Etheostoma caeruleum) Collected along an Urban Gradient. AB - Municipal wastewater effluent (MWWE) and its constituents, such as chemicals of emerging concern, pose a potential threat to the sustainability of fish populations by disrupting key endocrine functions in aquatic organisms. While studies have demonstrated changes in biological markers of exposure of aquatic organisms to groups of chemicals of emerging concern, the variability of these markers over time has not been sufficiently described in wild fish species. The aim of this study was to assess the spatial and temporal variability of biological markers in response to MWWE exposure and to test the consistency of these responses between seasons and among years. Rainbow darter (Etheostoma caeruleum) were collected in spring and fall seasons over a 5-year period in the Grand River, Ontario, Canada. In addition to surface water chemistry (nutrients and selected pharmaceuticals), measures were taken across levels of biological organization in rainbow darter. The measurements of hormone production, gonad development, and intersex severity were temporally consistent and suggested impaired reproduction in male fish collected downstream of MWWE outfalls. In contrast, ovarian development and hormone production in females appeared to be influenced more by urbanization than MWWE. Measures of gene expression and somatic indices were highly variable between sites and years, respectively, and were inconclusive in terms of the impacts of MWWE overall. Robust biomonitoring programs must consider these factors in both the design and interpretation of results, especially when spatial and temporal sampling of biological endpoints is limited. Assessing the effects of contaminants and other stressors on fish in watersheds would be greatly enhanced by an approach that considers natural variability in the endpoints being measured. PMID- 27776152 TI - Serum and Urinary Progranulin in Diabetic Kidney Disease. AB - Progranulin has been recognized as an adipokine related to obesity, insulin resistance and type 2 diabetes mellitus (T2DM). There are scarce data regarding progranulin and kidney disease, but there are some data linking diabetic kidney disease (DKD) and increased progranulin levels. We aimed to better describe the relationship between serum and urinary progranulin levels and DKD in T2DM. This is a case-control study including four groups of subjects: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2; 2) Albuminuric DKD cases: T2DM patients with urinary albumin excretion (UAE) >=30 mg/g creatinine and eGFR >=60 mL/min/1.73m2; 3) Diabetic controls: T2DM patients with UAE <30 mg/g creatinine and eGFR >=60 mL/min/1.73m2; and 4) Non-diabetic controls: individuals without T2DM. Progranulin was determined by enzyme-linked immunosorbent assay. One hundred and fourteen patients were included (23 advanced DKD cases, 25 albuminuric DKD cases, 40 diabetic controls and 26 non-diabetic controls). Serum progranulin was increased in advanced DKD compared to other groups [70.84 (59.04-83.16) vs. albuminuric cases 57.16 (42.24-67.38), diabetic controls 57.28 (42.08-70.47) and non-diabetic controls 44.54 (41.44-53.32) ng/mL; p<0.001]. Urinary progranulin was decreased in advanced DKD cases compared to albuminuric cases [10.62 (6.30-16.08) vs. 20.94 (12.35-30.22); diabetic controls 14.06 (9.88-20.82) and non-diabetic controls 13.51 (7.94-24.36) ng/mL; p = 0.017]. There was a positive correlation between serum progranulin and body mass index (r = 0.27; p = 0.004), waist circumference (r = 0.25; p = 0.007); body fat percentage (r = 0.20; p = 0.042), high-sensitive C reactive protein (r = 0.35; p<0.001) and interleukin-6 (r = 0.37; p<0.001) and a negative correlation with eGFR (r = -0.22; p = 0.023). Urinary progranulin was positively associated with albuminuria (r = 0.25; p = 0.010). In conclusion, progranulin is affected by a decrease in eGFR, being at a higher concentration in serum and lower in urine of DKD patients with T2DM and eGFR <60 mL/min/1.73m2. It is also associated with markers of obesity and inflammation. PMID- 27776153 TI - Correlating Tumor Stiffness with Immunohistochemical Subtypes of Breast Cancers: Prognostic Value of Comb-Push Ultrasound Shear Elastography for Differentiating Luminal Subtypes. AB - PURPOSE: The purpose of our study is to correlate quantitatively measured tumor stiffness with immunohistochemical (IHC) subtypes of breast cancer. Additionally, the influence of prognostic histologic features (cancer grade, size, lymph node status, and histological type and grade) to the tumor elasticity and IHC profile relationship will be investigated. METHODS: Under an institutional review board (IRB) approved protocol, B-mode ultrasound (US) and comb-push ultrasound shear elastography (CUSE) were performed on 157 female patients with suspicious breast lesions. Out of 157 patients 83 breast cancer patients confirmed by pathology were included in this study. The association between CUSE mean stiffness values and the aforementioned prognostic features of the breast cancer tumors were investigated. RESULTS: Our results demonstrate that the most statistically significant difference (p = 0.0074) with mean elasticity is tumor size. When considering large tumors (size >= 8mm), thus minimizing the statistical significance of tumor size, a significant difference (p< 0.05) with mean elasticity is obtained between luminal A of histological grade I and luminal B (Ki-67 > 20%) subtypes. CONCLUSION: Tumor size is an independent factor influencing mean elasticity. The Ki-67 proliferation index and histological grade were dependent factors influencing mean elasticity for the differentiation between luminal subtypes. Future studies on a larger group of patients may broaden the clinical significance of these findings. PMID- 27776154 TI - Non-Conventional Yeast Strains Increase the Aroma Complexity of Bread. AB - Saccharomyces cerevisiae is routinely used yeast in food fermentations because it combines several key traits, including fermentation efficiency and production of desirable flavors. However, the dominance of S. cerevisiae in industrial fermentations limits the diversity in the aroma profiles of the end products. Hence, there is a growing interest in non-conventional yeast strains that can help generate the diversity and complexity desired in today's diversified and consumer-driven markets. Here, we selected a set of non-conventional yeast strains to examine their potential for bread fermentation. Here, we tested ten non-conventional yeasts for bread fermentation, including two Saccharomyces species that are not currently used in bread making and 8 non-Saccharomyces strains. The results show that Torulaspora delbrueckii and Saccharomyces bayanus combine satisfactory dough fermentation with an interesting flavor profile. Sensory analysis and HS-SPME-GC-MS analysis confirmed that these strains produce aroma profiles that are very different from that produced by a commercial bakery strain. Moreover, bread produced with these yeasts was preferred by a majority of a trained sensory panel. These results demonstrate the potential of T. delbrueckii and S. bayanus as alternative yeasts for bread dough leavening, and provide a general experimental framework for the evaluation of more yeasts and bacteria. PMID- 27776156 TI - Reconsideration of the Effects of Age on Proximal Femur Structure: Implications for Joint Replacement and Hip Fracture. AB - OBJECTIVES: In recent years quantitative computed tomography (QCT) has allowed precise non-invasive, three dimensional, in vivo measurement of hip structure in large numbers of individuals. The effects of ageing on proximal femur structure are reported and implications for the prevention of hip prosthesis loosening and hip fracture considered. DESIGN, SETTING AND PARTICIPANTS: An observational cross sectional study of proximal femur QCT in 719 unselected female European descent aged 20 to 89 years recruited from US and Australian populations. MAIN OUTCOMES MEASURES: QCT scans were obtained using software that separates cortical and cancellous bone by a thresholding technique. Voxel based mineral volume and mass was computed for the integral (external), cancellous and cortical compartments of 1 mm wide sections through the femoral neck (FN), trochanter (TR) and intertrochanter (IT) regions. RESULTS: Over the adult life span total integral volumes at the FN, TR and IT sites expand linearly by between 18 and 37% at the same time as bone mass decreased by 22 to 25% resulting in massive reductions in true volumetric BMD (vBMD) of 40 to 50%. Cancellous volume expansion was larger at 65 to 79% at the three sites. Between the ages of 65 and 75 the average increase in cancellous volume at the IT site was 3.74 cm3 (12.1%). Voxel determined FN cortical volume decreased linearly by 43%, as did cortical bone mass so that vBMD did not change substantially. TR and IT cortical volumes decreased 54 and 28% respectively, small reductions in TR and IT cortical vBMD also occurred. CONCLUSIONS: Large endosteal expansion in the area in which hip replacement stem placement occurs may contribute to loosening. Regarding the propensity to hip fracture, periosteal expansion contributes to increased resistance to bending but cortical thinning contributes to loss of bone to resistance to bending forces. Understanding individual hip structure may contribute to individualisation of risk and subsequent targeting of management using pharmaceutical agents. PMID- 27776155 TI - Eye Contact Affects Object Representation in 9-Month-Old Infants. AB - Social cues in interaction with others enable infants to extract useful information from their environment. Although previous research has shown that infants process and retain different information about an object depending on the presence of social cues, the effect of eye contact as an isolated independent variable has not been investigated. The present study investigated how eye contact affects infants' object processing. Nine-month-olds engaged in two types of social interactions with an experimenter. When the experimenter showed an object without eye contact, the infants processed and remembered both the object's location and its identity. In contrast, when the experimenter showed the object while making eye contact with the infant, the infant preferentially processed object's identity but not its location. Such effects might assist infants to selectively attend to useful information. Our findings revealed that 9 month-olds' object representations are modulated in accordance with the context, thus elucidating the function of eye contact for infants' object representation. PMID- 27776157 TI - Fear Expression Suppresses Medial Prefrontal Cortical Firing in Rats. AB - The medial prefrontal cortex (mPFC) plays a crucial role in emotional learning and memory in rodents and humans. While many studies suggest a differential role for the prelimbic (PL) and infralimbic (IL) subdivisions of mPFC, few have considered the relationship between neural activity in these two brain regions recorded simultaneously in behaving animals. Importantly, how concurrent PL and IL activity relate to conditioned freezing behavior is largely unknown. Here we used single-unit recordings targeting PL and IL in awake, behaving rats during the acquisition and expression of conditioned fear. On Day 1, rats received either signaled or unsignaled footshocks in the recording chamber; an auditory conditioned stimulus (CS) preceded signaled footshocks. Twenty-four hours later, animals were returned to the recording chamber (modified to create a novel context) where they received 5 CS-alone trials. After fear conditioning, both signaled and unsignaled rats exhibited high levels of post-shock freezing that was associated with an enduring suppression of mPFC spontaneous firing, particularly in the IL of signaled rats. Twenty-four hours later, CS presentation produced differential conditioned freezing in signaled and unsignaled rats: freezing increased in rats that had received signaled shocks, but decreased in animals in the unsignaled condition (i.e., external inhibition). This group difference in CS-evoked freezing was mirrored in the spontaneous firing rate of neurons in both PL and IL. Interestingly, differences in PL and IL firing rate highly correlated with freezing levels. In other words, in the signaled group IL spontaneous rates were suppressed relative to PL, perhaps limiting IL-mediated suppression of fear and allowing PL activity to dominate performance, resulting in high levels of freezing. This was not observed in the unsignaled group, which exhibited low freezing. These data reveal that the activity of mPFC neurons is modulated by both associative and nonassociative stimuli that regulate conditioned fear. PMID- 27776158 TI - Both IIC and IID Components of Mannose Phosphotransferase System Are Involved in the Specific Recognition between Immunity Protein PedB and Bacteriocin-Receptor Complex. AB - Upon exposure to exogenous pediocin-like bacteriocins, immunity proteins specifically bind to the target receptor of the mannose phosphotransferase system components (man-PTS IIC and IID), therefore preventing bacterial cell death. However, the specific recognition of immunity proteins and its associated target receptors remains poorly understood. In this study, we constructed hybrid receptors to identify the domains of IIC and/or IID recognized by the immunity protein PedB, which confers immunity to pediocin PA-1. Using Lactobacillus plantarum man-PTS EII mutant W903, the IICD components of four pediocin PA-1 sensitive strains (L. plantarum WQ0815, Leuconostoc mesenteroides 05-43, Lactobacillus salivarius REN and Lactobacillus acidophilus 05-172) were respectively co-expressed with the immunity protein PedB. Well-diffusions assays showed that only the complex formed by LpIICD from L. plantarum WQ0815 with pediocin PA-1 could be recognized by PedB. In addition, a two-step PCR approach was used to construct hybrid receptors by combining LpIIC or LpIID recognized by PedB with the other three heterologous IID or IIC compounds unrecognized by PedB, respectively. The results showed that all six hybrid receptors were recognized by pediocin PA-1. However, when IIC or IID of L. plantarum WQ0815 was replaced with any corresponding IIC or IID component from L. mesenteroides 05-43, L. salivarius REN and L. acidophilus 05-172, all the hybrid receptors could not be recognized by PedB. Taken altogether, we concluded that both IIC and IID components of the mannose phosphotransferase system play an important role in the specific recognition between the bacteriocin-receptor complex and the immunity protein PedB. PMID- 27776159 TI - Marked Body Shape Concerns in Female Patients Suffering from Eating Disorders: Relevance of a Clinical Sub-Group. AB - Concerns about body shape and weight are core diagnostic criteria for eating disorders although intensity varies between patients. Few studies have focused on the clinical differences relative to the intensity of these concerns. Nonetheless, they might have a prognostic value. This study was aimed at identifying the characteristics associated with marked body shape concerns in patients with an eating disorder. Data was collected from a systematic and standardized clinical assessment of outpatients seeking treatment in our department for eating disorders. Only female patients, suffering from anorexia nervosa or bulimia nervosa, and with "no / mild" or "marked" body shape concerns according to the Body Shape Questionnaire, were included for the present study. We focused on sociodemographic characteristics, eating disorder characteristics, axis 1 disorders, types of attachment, self-esteem and dissociation. A multiple logistic regression was performed to identify factors related to "marked" body shape concerns. In our sample (123 participants, with a mean age of 24.3 years [range 16-61]), 56.9% had marked concerns with body shape. Marked body shape concerns were associated with a major depressive episode (OR = 100.3), the use of laxatives (OR = 49.8), a high score on the item "body dissatisfaction" of the Eating Disorders Inventory scale (OR = 1.7), a higher minimum body mass index (OR = 1.73), and a high score on the item "loss of control over behavior, thoughts and emotions" from the dissociation questionnaire (OR = 10.74). These results are consistent with previous studies, and highlight the importance of denial. PMID- 27776160 TI - Differential Responses of Dinitrogen Fixation, Diazotrophic Cyanobacteria and Ammonia Oxidation Reveal a Potential Warming-Induced Imbalance of the N-Cycle in Biological Soil Crusts. AB - N2 fixation and ammonia oxidation (AO) are the two most important processes in the nitrogen (N) cycle of biological soil crusts (BSCs). We studied the short term response of acetylene reduction assay (ARA) rates, an indicator of potential N2 fixation, and AO rates to temperature (T, -5 degrees C to 35 degrees C) in BSC of different successional stages along the BSC ecological succession and geographic origin (hot Chihuahuan and cooler Great Basin deserts). ARA in all BSCs increased with T until saturation occurred between 15 and 20 degrees C, and declined at 30-35 degrees C. Culture studies using cyanobacteria isolated from these crusts indicated that the saturating effect was traceable to their inability to grow well diazotrophically within the high temperature range. Below saturation, temperature response was exponential, with Q10 significantly different in the two areas (~ 5 for Great Basin BSCs; 2-3 for Chihuahuan BSCs), but similar between the two successional stages. However, in contrast to ARA, AO showed a steady increase to 30-35 degrees C in Great Basin, and Chihuhuan BSCs showed no inhibition at any tested temperature. The T response of AO also differed significantly between Great Basin (Q10 of 4.5-4.8) and Chihuahuan (Q10 of 2.4-2.6) BSCs, but not between successional stages. Response of ARA rates to T did not differ from that of AO in either desert. Thus, while both processes scaled to T in unison until 20 degrees C, they separated to an increasing degree at higher temperature. As future warming is likely to occur in the regions where BSCs are often the dominant living cover, this predicted decoupling is expected to result in higher proportion of nitrates in soil relative to ammonium. As nitrate is more easily lost as leachate or to be reduced to gaseous forms, this could mean a depletion of soil N over large landscapes globally. PMID- 27776161 TI - Minimum Acceptable Diet at 9 Months but Not Exclusive Breastfeeding at 3 Months or Timely Complementary Feeding Initiation Is Predictive of Infant Growth in Rural Bangladesh. AB - The association between suboptimal infant feeding practices and growth faltering is well-established. However, most of this evidence comes from cross-sectional studies. To prospectively assess the association between suboptimal infant feeding practices and growth faltering, we interviewed pregnant women at 28-32 weeks' gestation and followed-up their offspring at postnatal months 3, 9, 16 and 24 months in rural Bangladesh. Using maternal recall over the past 24 hours, exclusive breastfeeding (EBF) status at 3 months, age at complementary feeding (CF) initiation, and receipt of minimum acceptable diet (MAD; as defined by WHO) at 9 months were assessed. Infant length and weight measurements were used to produce length-for-age (LAZ) and weight-for-length (WLZ) z-scores at each follow up. Generalized estimating equations were used to estimate associations of LAZ and WLZ with infant feeding practices. All models were adjusted for baseline SES, infant sex, maternal height, age, literacy and parity. Follow-up was completed by 2189, 2074, 1969 and 1885 mother-child dyads at 3, 9, 16 and 24 months, respectively. Stunting prevalence increased from 28% to 57% between infant age 3 and 24 months. EBF at 3 months and age at CF initiation were not associated with linear infant growth, but receipt of MAD at 9 months was. By age 24 months, infants receiving MAD had attained a higher LAZ compared to infants who did not receive MAD (adjusted beta = 0.25, 95% CI: 0.13-0.37). Although prevalence of stunting was already high at age 3 months, ensuring infants receive a diverse, high quality diet from 6 months onwards may reduce rates of stunting in the second year of life. PMID- 27776162 TI - Incidence, Clinical Outcome and Risk Factors of Intensive Care Unit Infections in the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. AB - BACKGROUND: Infections are common complications in critically ill patients with associated significant morbidity and mortality. AIM: This study determined the prevalence, risk factors, clinical outcome and microbiological profile of hospital-acquired infections in the intensive care unit of a Nigerian tertiary hospital. MATERIALS AND METHODS: This was a prospective cohort study, patients were recruited and followed up between September 2011 and July 2012 until they were either discharged from the ICU or died. Antimicrobial susceptibility testing of isolates was done using CLSI guidelines. RESULTS: Seventy-one patients were recruited with a 45% healthcare associated infection rate representing an incidence rate of 79/1000 patient-days in the intensive care unit. Bloodstream infections (BSI) 49.0% (22/71) and urinary tract infections (UTI) 35.6% (16/71) were the most common infections with incidence rates of 162.9/1000 patient-days and 161.6/1000 patient-days respectively. Staphylococcus aureus was the most common cause of BSIs, responsible for 18.2% of cases, while Candida spp. was the commonest cause of urinary tract infections, contributing 25.0% of cases. Eighty percent (8/10) of the Staphylococcus isolates were methicillin-resistant. Gram negative multidrug bacteria accounted for 57.1% of organisms isolated though they were not ESBL-producing. Use of antibiotics (OR = 2.98; p = 0.03) and surgery (OR = 3.15, p< 0.05) in the month preceding ICU admission as well as urethral catheterization (OR = 5.38; p<0.05) and endotracheal intubation (OR = 5.78; p< 0.05) were risk factors for infection. CONCLUSION: Our findings demonstrate that healthcare associated infections is a significant risk factor for ICU-mortality and morbidity even after adjusting for APACHE II score. PMID- 27776164 TI - Risk of Premenopausal and Postmenopausal Breast Cancer among Multiple Sclerosis Patients. AB - OBJECTIVE: To investigate risk of premenopausal and postmenopausal breast cancer among Multiple Sclerosis (MS) patients, considering tumor stage. METHODS: The Swedish Patient Register identified 19,330 women with MS between 1968 and 2012, matched individually with a cohort of 193,458 without MS. Matching variables were year of birth, sex, region of residence and vital status at the time of diagnosis. The cancer register identified 471 and 5,753 breast cancer cases among the MS and non-MS cohorts, respectively. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal and postmenopausal breast cancer. RESULTS: Overall risk of postmenopausal breast cancer was 13% higher among MS patients compared with women without MS (HR = 1.13, 95% CI 1.02-1.26). Stratified analyses showed that the risk was statistically significantly increased in women diagnosed between 1968 and 1980 and those who were diagnosed at age 65 or older age. We observed a non statistically significant risk only for stage 0-1 postmenopausal breast cancer (HR = 1.17, 95% CI 0.93-1.48). MS was not associated with premenopausal breast cancer. CONCLUSION: The modest increased risk of postmenopausal breast cancer in women with MS may be due to surveillance bias, where contact with health services for one disease increases the risk of a second diagnosis being recorded. PMID- 27776163 TI - Potential Use of Autologous Renal Cells from Diseased Kidneys for the Treatment of Renal Failure. AB - Chronic kidney disease (CKD) occurs when certain conditions cause the kidneys to gradually lose function. For patients with CKD, renal transplantation is the only treatment option that restores kidney function. In this study, we evaluated primary renal cells obtained from diseased kidneys to determine whether their normal phenotypic and functional characteristics are retained, and could be used for cell therapy. Primary renal cells isolated from both normal kidneys (NK) and diseased kidneys (CKD) showed similar phenotypic characteristics and growth kinetics. The expression levels of renal tubular cell markers, Aquaporin-1 and E Cadherin, and podocyte-specific markers, WT-1 and Nephrin, were similar in both NK and CKD kidney derived cells. Using fluorescence- activated cell sorting (FACS), specific renal cell populations were identified and included proximal tubular cells (83.1% from NK and 80.3% from CKD kidneys); distal tubular cells (11.03% from NK and 10.9% from CKD kidneys); and podocytes (1.91% from NK and 1.78% from CKD kidneys). Ultra-structural analysis using scanning electron microscopy (SEM) revealed microvilli on the apical surface of cultured cells from NK and CKD samples. Moreover, transmission electron microscopy (TEM) analysis showed a similar organization of tight junctions, desmosomes, and other intracellular structures. The Na+ uptake characteristics of NK and CKD derived renal cells were also similar (24.4 mmol/L and 25 mmol/L, respectively) and no significant differences were observed in the protein uptake and transport characteristics of these two cell isolates. These results show that primary renal cells derived from diseased kidneys such as CKD have similar structural and functional characteristics to their counterparts from a normal healthy kidney (NK) when grown in vitro. This study suggests that cells derived from diseased kidney may be used as an autologous cell source for renal cell therapy, particularly in patients with CKD or end-stage renal disease (ESRD). PMID- 27776166 TI - Glucosamine Downregulates the IL-1beta-Induced Expression of Proinflammatory Cytokine Genes in Human Synovial MH7A Cells by O-GlcNAc Modification-Dependent and -Independent Mechanisms. AB - Osteoarthritis (OA) is one of the major joint diseases, and the synovial inflammation is involved in the pathogenesis and progression of OA. Glucosamine (GlcN) is widely used as a dietary supplement for OA, and is expected to exert the antiinflammatory action in OA. However, the detailed mechanism for the antiinflammatory action of GlcN remains poorly understood. In this study, to elucidate the molecular mechanism involved in the GlcN-medicated regulation of synovial cell activation, we comprehensively analyzed the effect of GlcN on the gene expression using a human synovial cell line MH7A by DNA microarray. The results indicated that GlcN significantly downregulates the expression of 187 genes (<=1/1.5-fold) and upregulates the expression of 194 genes (>=1.5-fold) in IL-1beta-stimulated MH7A cells. Interestingly, pathway analysis indicated that among the 10 pathways into which the GlcN-regulated genes are categorized, the 4 pathways are immune-related. Furthermore, GlcN suppressed the expression of proinflammatory cytokine genes (such as IL-6, IL-8, IL-24 and TNF-alpha genes). In addition, GlcN-mediated O-GlcNAc modification was involved in the downregulation of TNF-alpha and IL-8 genes but not IL-6 and IL-24 genes, based on the effects of alloxan, an O-GlcNAc transferase inhibitor. Thus, GlcN likely exerts an antiinflammatroy action in OA by suppressing the expression of proinflammatory cytokine genes in synovial MH7A cells by O-GlcNAc modification dependent and -independent mechanisms. PMID- 27776165 TI - Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity. AB - Hexanucleotide repeat expansions in C9orf72 are the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansions elicit toxicity in part through repeat-associated non-AUG (RAN) translation of the intronic (GGGGCC)n sequence into dipeptide repeat-containing proteins (DPRs). Little is known, however, about the structural characteristics and aggregation propensities of the dipeptide units comprising DPRs. To address this question, we synthesized dipeptide units corresponding to the three sense strand RAN translation products, analyzed their structures by circular dichroism, electron microscopy and dye binding assays, and assessed their relative toxicity when applied to primary cortical neurons. Short, glycine-arginine (GR)3 dipeptides formed spherical aggregates and selectively reduced neuronal survival compared to glycine-alanine (GA)3 and glycine-proline (GP)3 dipeptides. Doubling peptide length had little effect on the structure of GR or GP peptides, but (GA)6 peptides formed beta-sheet rich aggregates that bound thioflavin T and Congo red yet lacked the typical fibrillar morphology of amyloids. Aging of (GA)6 dipeptides increased their beta-sheet content and enhanced their toxicity when applied to neurons. We also observed that the relative toxicity of each tested dipeptide was proportional to peptide internalization. Our results demonstrate that different C9orf72-related dipeptides exhibit distinct structural properties that correlate with their relative toxicity. PMID- 27776167 TI - Birth Weights in Sickle Cell Disease Pregnancies: A Cohort Study. AB - Pregnancy in women with Sickle Cell Disease (SCD) has been linked with an increased incidence of adverse foetal outcomes when compared to women without haemoglobinopathies (HbAA). There's a paucity of data into foetal outcomes for infants born to women with SCD. Customised growth charts have been demonstrated to be better than population-based growth charts at identifying unhealthy small babies. We analysed the mean birth weight and customised birth weight centiles of infants born to mothers with SCD versus mothers with HbAA genotype, to quantify the risk of having a smaller baby. Birth weight and birth weight centiles were analysed for 88 women with SCD (50 HbSS; 38 HbSC) and 176 controls (HbAA). Statistically significant differences were seen in the mean birth weight (P value = 0.004) and the mean birth weight centiles (P value = 0.016). We conclude that SCD is a risk factor for having a smaller baby. PMID- 27776168 TI - An Automated Recording Method in Clinical Consultation to Rate the Limp in Lower Limb Osteoarthritis. AB - For diagnosis and follow up, it is important to be able to quantify limp in an objective, and precise way adapted to daily clinical consultation. The purpose of this exploratory study was to determine if an inertial sensor-based method could provide simple features that correlate with the severity of lower limb osteoarthritis evaluated by the WOMAC index without the use of step detection in the signal processing. Forty-eight patients with lower limb osteoarthritis formed two severity groups separated by the median of the WOMAC index (G1, G2). Twelve asymptomatic age-matched control subjects formed the control group (G0). Subjects were asked to walk straight 10 meters forward and 10 meters back at self-selected walking speeds with inertial measurement units (IMU) (3-D accelerometers, 3-D gyroscopes and 3-D magnetometers) attached on the head, the lower back (L3-L4) and both feet. Sixty parameters corresponding to the mean and the root mean square (RMS) of the recorded signals on the various sensors (head, lower back and feet), in the various axes, in the various frames were computed. Parameters were defined as discriminating when they showed statistical differences between the three groups. In total, four parameters were found discriminating: mean and RMS of the norm of the acceleration in the horizontal plane for contralateral and ipsilateral foot in the doctor's office frame. No discriminating parameter was found on the head or the lower back. No discriminating parameter was found in the sensor linked frames. This study showed that two IMUs placed on both feet and a step detection free signal processing method could be an objective and quantitative complement to the clinical examination of the physician in everyday practice. Our method provides new automatically computed parameters that could be used for the comprehension of lower limb osteoarthritis. It may not only be used in medical consultation to score patients but also to monitor the evolution of their clinical syndrome during and after rehabilitation. Finally, it paves the way for the quantification of gait in other fields such as neurology and for monitoring the gait at a patient's home. PMID- 27776170 TI - Submergence Causes Similar Carbohydrate Starvation but Faster Post-Stress Recovery than Darkness in Alternanthera philoxeroides Plants. AB - Carbon assimilation by submerged plants is greatly reduced due to low light levels. It is hypothesized that submergence reduces carbohydrate contents and that plants recover from submergence in the same way as darkness-treated plants. To test this hypothesis, the responses of plants to submergence and darkness were studied and compared. Plants of a submergence-tolerant species, Alternanthera philoxeroides, were exposed to well drained and illuminated conditions, complete submergence conditions or darkness conditions followed by a recovery growth period in a controlled experiment. The biomass maintenance and accumulation, carbohydrate content dynamics and respiration rate in the plants were assessed to quantify the carbohydrate utilization rate and regrowth. The submerged plants maintained higher chlorophyll contents, more green leaf tissue and more biomass; recovered more quickly; and accumulated more carbohydrates and biomass than darkness-treated plants. The respiration rate was continuously reduced in the same pattern under both stress conditions but was maintained at a significantly lower level in the submerged plants; the total soluble sugar and total fructan contents were decreased at approximately the same rate of decrease, reaching similar low levels, in the two stress treatments. The A. philoxeroides plants were more tolerant of submergence than darkness. The faster recovery of desubmerged plants could not be explained by the similar carbohydrate contents at the start of recovery. Other types of carbon reserves besides carbohydrates or other mechanisms such as higher post-stress photosynthetic performance might be involved. PMID- 27776169 TI - Hepatitis C virus Broadly Neutralizing Monoclonal Antibodies Isolated 25 Years after Spontaneous Clearance. AB - Hepatitis C virus (HCV) is world-wide a major cause of liver related morbidity and mortality. No vaccine is available to prevent HCV infection. To design an effective vaccine, understanding immunity against HCV is necessary. The memory B cell repertoire was characterized from an intravenous drug user who spontaneously cleared HCV infection 25 years ago. CD27+IgG+ memory B cells were immortalized using BCL6 and Bcl-xL. These immortalized B cells were used to study antibody mediated immunity against the HCV E1E2 glycoproteins. Five E1E2 broadly reactive antibodies were isolated: 3 antibodies showed potent neutralization of genotype 1 to 4 using HCV pseudotyped particles, whereas the other 2 antibodies neutralized genotype 1, 2 and 3 or 1 and 2 only. All antibodies recognized non-linear epitopes on E2. Finally, except for antibody AT12-011, which recognized an epitope consisting of antigenic domain C /AR2 and AR5, all other four antibodies recognized epitope II and domain B. These data show that a subject, who spontaneously cleared HCV infection 25 years ago, still has circulating memory B cells that are able to secrete broadly neutralizing antibodies. Presence of such memory B cells strengthens the argument for undertaking the development of an HCV vaccine. PMID- 27776171 TI - Analysis of Research Activity in Gastroenterology: Pancreatitis Is in Real Danger. AB - OBJECTIVE: Biomedical investment trends in 2015 show a huge decrease of investment in gastroenterology. Since academic research usually provides the basis for industrial research and development (R&D), our aim was to understand research trends in the field of gastroenterology over the last 50 years and identify the most endangered areas. METHODS: We searched for PubMed hits for gastrointestinal (GI) diseases for the 1965-2015 period. Overall, 1,554,325 articles were analyzed. Since pancreatology was identified as the most endangered field of research within gastroenterology, we carried out a detailed evaluation of research activity in pancreatology. RESULTS: In 1965, among the major benign GI disorders, 51.9% of the research was performed on hepatitis, 25.7% on pancreatitis, 21.7% on upper GI diseases and only 0.7% on the lower GI disorders. Half a century later, in 2015, research on hepatitis and upper GI diseases had not changed significantly; however, studies on pancreatitis had dropped to 10.7%, while work on the lower GI disorders had risen to 23.4%. With regard to the malignant disorders (including liver, gastric, colon, pancreatic and oesophageal cancer), no such large-scale changes were observed in the last 50 years. Detailed analyses revealed that besides the drop in research activity in pancreatitis, there are serious problems with the quality of the studies as well. Only 6.8% of clinical trials on pancreatitis were registered and only 5.5% of these registered trials were multicentre and multinational (more than five centres and nations), i.e., the kind that provides the highest level of impact and evidence level. CONCLUSIONS: There has been a clear drop in research activity in pancreatitis. New international networks and far more academic R&D activities should be established in order to find the first therapy specifically for acute pancreatitis. PMID- 27776172 TI - Fatal Cases of Seasonal Influenza in Russia in 2015-2016. AB - The influenza epidemic in 2015-2016 in Russia is characterized by a sharp increase of influenza cases (beginning from the second week of 2016) with increased fatalities. Influenza was confirmed in 20 fatal cases registered among children (0-10 years), in 5 cases among pregnant women, and in 173 cases among elderly people (60 years and older). Two hundred and ninety nine people died from influenza were patients with some chronic problems. The overwhelming majority among the deceased (more than 98%) were not vaccinated against influenza. We isolated 109 influenza A(H1N1)pdm09 and one A(H3N2) virus strains from 501 autopsy material samples. The antigenic features of the strains were similar to the vaccine strains. A phylogenic analysis of hemagglutinin revealed that influenza A(H1N1)pdm09 virus strains belonged to 6B genetic group that had two main dominant subgroups during the 2015-2016 season. In Russia strains of the first group predominated. We registered an increased proportion of strains with D222G mutation in receptor-binding site. A herd immunity analysis carried out immediately prior to the epidemic showed that 34.4% blood sera samples collected in different regions of Russia were positive to A/California/07/09(H1N1)pdm09. We came to a conclusion that public awareness enhancement is necessary to reduce unreasonable refusals of vaccination. PMID- 27776173 TI - The MADS Box Genes ABS, SHP1, and SHP2 Are Essential for the Coordination of Cell Divisions in Ovule and Seed Coat Development and for Endosperm Formation in Arabidopsis thaliana. AB - Seed formation is a pivotal process in plant reproduction and dispersal. It begins with megagametophyte development in the ovule, followed by fertilization and subsequently coordinated development of embryo, endosperm, and maternal seed coat. Two closely related MADS-box genes, SHATTERPROOF 1 and 2 (SHP1 and SHP2) are involved in specifying ovule integument identity in Arabidopsis thaliana. The MADS box gene ARABIDOPSIS BSISTER (ABS or TT16) is required, together with SEEDSTICK (STK) for the formation of endothelium, part of the seed coat and innermost tissue layer formed by the maternal plant. Little is known about the genetic interaction of SHP1 and SHP2 with ABS and the coordination of endosperm and seed coat development. In this work, mutant and expression analysis shed light on this aspect of concerted development. Triple tt16 shp1 shp2 mutants produce malformed seedlings, seed coat formation defects, fewer seeds, and mucilage reduction. While shp1 shp2 mutants fail to coordinate the timely development of ovules, tt16 mutants show less peripheral endosperm after fertilization. Failure in coordinated division of the innermost integument layer in early ovule stages leads to inner seed coat defects in tt16 and tt16 shp1 shp2 triple mutant seeds. An antagonistic action of ABS and SHP1/SHP2 is observed in inner seed coat layer formation. Expression analysis also indicates that ABS represses SHP1, SHP2, and FRUITFUL expression. Our work shows that the evolutionary conserved Bsister genes are required not only for endothelium but also for endosperm development and genetically interact with SHP1 and SHP2 in a partially antagonistic manner. PMID- 27776174 TI - Unsteady MHD Mixed Convection Slip Flow of Casson Fluid over Nonlinearly Stretching Sheet Embedded in a Porous Medium with Chemical Reaction, Thermal Radiation, Heat Generation/Absorption and Convective Boundary Conditions. AB - Numerical results are presented for the effect of first order chemical reaction and thermal radiation on mixed convection flow of Casson fluid in the presence of magnetic field. The flow is generated due to unsteady nonlinearly stretching sheet placed inside a porous medium. Convective conditions on wall temperature and wall concentration are also employed in the investigation. The governing partial differential equations are converted to ordinary differential equations using suitable transformations and then solved numerically via Keller-box method. It is noticed that fluid velocity rises with increase in radiation parameter in the case of assisting flow and is opposite in the case of opposing fluid while radiation parameter has no effect on fluid velocity in the forced convection. It is also seen that fluid velocity and concentration enhances in the case of generative chemical reaction whereas both profiles reduces in the case of destructive chemical reaction. Further, increase in local unsteadiness parameter reduces fluid velocity, temperature and concentration. Over all the effects of physical parameters on fluid velocity, temperature and concentration distribution as well as on the wall shear stress, heat and mass transfer rates are discussed in detail. PMID- 27776175 TI - Systematic Review with Network Meta-Analysis: Comparative Efficacy of Biologics in the Treatment of Moderately to Severely Active Ulcerative Colitis. AB - BACKGROUND: Biological therapies are increasingly used to treat ulcerative colitis (UC). AIM: To compare the efficacy of biologics in adults with moderately to-severely active UC, stratified by prior exposure to anti-tumour necrosis factor (anti-TNF) therapy. METHODS: A systematic literature review was undertaken to identify studies of biologics approved for UC. Network meta-analysis was conducted for endpoints at induction and maintenance. RESULTS: Seven studies were included in the meta-analysis of induction treatment for anti-TNF therapy-naive patients. All biologics were more effective than placebo in inducing clinical response, clinical remission, and mucosal healing. Infliximab demonstrated a statistically significant improvement over adalimumab in clinical response (odds ratio [OR] [95% credible interval (CrI)]: 2.19 [1.35-3.55]), clinical remission (OR [95% CrI]: 2.81 [1.49-5.49]), and mucosal healing (OR [95% CrI]: 2.23 [1.21 4.14]); there were no other significant differences between biologics for induction efficacy. Five studies were included in the meta-analysis of maintenance treatment, two studies rerandomised responder patients at end of induction, and three followed the same patients 'straight through'. To account for design differences, the number of responders at end of induction was assumed to be equivalent to the number rerandomised. Vedolizumab showed significantly different durable clinical response from comparators (OR [95% CrI] infliximab 3.18 [1.14-9.20], golimumab 2.33 [1.04-5.41], and adalimumab 3.96 [1.67-9.84]). In anti-TNF therapy-experienced patients, only vedolizumab and adalimumab could be compared. At induction, no significant differences in efficacy were seen. During maintenance, vedolizumab showed significantly improved rates of mucosal healing versus adalimumab (OR [95% CrI]: 6.72 [1.36-41.0]). CONCLUSIONS: This study expands the understanding of comparative efficacies of biologic treatments for UC, encompassing outcomes and populations not previously studied. All biologic treatments were effective for UC during induction. Vedolizumab demonstrated possible clinical benefits in the maintenance setting versus all comparators, irrespective of prior anti-TNF exposure and after adjusting for differences in study design. PMID- 27776176 TI - Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma. AB - BACKGROUND: Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo. METHODS AND RESULTS: A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of 125I labeled OI-3 antibody variants was compared with 125I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI 3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, 177Lu, and their biodistributions were studied in the nude mouse model. The 177Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant. CONCLUSION: Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies. PMID- 27776177 TI - Correction: High-Resolution Spatial Distribution and Estimation of Access to Improved Sanitation in Kenya. AB - [This corrects the article DOI: 10.1371/journal.pone.0158490.]. PMID- 27776178 TI - Molecular Study of the Amazonian Macabea Cattle History. AB - Macabea cattle are the only Bos taurus breed that have adapted to the wet tropical conditions of the Amazon. This breed has integrated into the culture of the indigenous Shuar-Asuar nations probably since its origins, being one of the few European zoogenetic resources assimilated by the deep-jungle Amazon communities. Despite its potential for local endogenous sustainable development, this breed is currently endangered. The present study used molecular genetics tools to investigate the within- and between-breeds diversity, in order to characterize the breed population, define its associations with other breeds, and infer its origin and evolution. The within-breed genetic diversity showed high values, as indicated by all genetic parameters, such as the mean number of alleles (MNA = 7.25+/-2.03), the observed heterozygosity (Ho = 0.72+/-0.02) and the expected heterozygosity (He = 0.72+/-0.02). The between-breeds diversity analysis, which included factorial correspondence analysis, Reynolds genetic distance, neighbor-joining analysis, and genetic structure analysis, showed that the Macabea breed belongs to the group of the American Creoles, with a Southern Spain origin. Our outcomes demonstrated that the Macabea breed has a high level of purity and null influences of exotic cosmopolitan breeds with European or Asiatic origin. This breed is an important zoogenetic resource of Ecuador, with relevant and unique attributes; therefore, there is an urgent need to develop conservation strategies for the Macabea breed. PMID- 27776179 TI - 3D Real-Time Echocardiography Combined with Mini Pressure Wire Generate Reliable Pressure-Volume Loops in Small Hearts. AB - BACKGROUND: Pressure-volume loops (PVL) provide vital information regarding ventricular performance and pathophysiology in cardiac disease. Unfortunately, acquisition of PVL by conductance technology is not feasible in neonates and small children due to the available human catheter size and resulting invasiveness. The aim of the study was to validate the accuracy of PVL in small hearts using volume data obtained by real-time three-dimensional echocardiography (3DE) and simultaneously acquired pressure data. METHODS: In 17 piglets (weight range: 3.6-8.0 kg) left ventricular PVL were generated by 3DE and simultaneous recordings of ventricular pressure using a mini pressure wire (PVL3D). PVL3D were compared to conductance catheter measurements (PVLCond) under various hemodynamic conditions (baseline, alpha-adrenergic stimulation with phenylephrine, beta adrenoreceptor-blockage using esmolol). In order to validate the accuracy of 3D volumetric data, cardiac magnetic resonance imaging (CMR) was performed in another 8 piglets. RESULTS: Correlation between CMR- and 3DE-derived volumes was good (enddiastolic volume: mean bias -0.03ml +/-1.34ml). Computation of PVL3D in small hearts was feasible and comparable to results obtained by conductance technology. Bland-Altman analysis showed a low bias between PVL3D and PVLCond. Systolic and diastolic parameters were closely associated (Intraclass-Correlation Coefficient for: systolic myocardial elastance 0.95, arterial elastance 0.93, diastolic relaxation constant tau 0.90, indexed end-diastolic volume 0.98). Hemodynamic changes under different conditions were well detected by both methods (ICC 0.82 to 0.98). Inter- and intra-observer coefficients of variation were below 5% for all parameters. CONCLUSIONS: PVL3D generated from 3DE combined with mini pressure wire represent a novel, feasible and reliable method to assess different hemodynamic conditions of cardiac function in hearts comparable to neonate and infant size. This methodology may be integrated into clinical practice and cardiac catheterization programs and has the capability to contribute to clinical decision making even in small hearts. PMID- 27776180 TI - Investigating the Interaction of Fe Nanoparticles with Lysozyme by Biophysical and Molecular Docking Studies. AB - Herein, the interaction of hen egg white lysozyme (HEWL) with iron nanoparticle (Fe NP) was investigated by spectroscopic and docking studies. The zeta potential analysis revealed that addition of Fe NP (6.45+/-1.03 mV) to HEWL (8.57+/-0.54 mV) can cause to greater charge distribution of nanoparticle-protein system (17.33+/-1.84 mV). In addition, dynamic light scattering (DLS) study revealed that addition of Fe NP (92.95+/-6.11 nm) to HEWL (2.68+/-0.37 nm) increases suspension potential of protein/nanoparticle system (51.17+/-3.19 nm). Fluorescence quenching studies reveled that both static and dynamic quenching mechanism occur and hydrogen bond and van der Waals interaction give rise to protein-NP system. Synchronous fluorescence spectroscopy of HEWL in the presence of Fe NP showed that the emission maximum wavelength of tryptophan (Trp) residues undergoes a red-shift. ANS fluorescence data indicated a dramatic exposure of hydrophobic residues to the solvent. The considerable reduction in melting temperature (T(m)) of HEWL after addition of Fe NP determines an unfavorable interaction system. Furthermore circular dichoroism (CD) experiments demonstrated that, the secondary structure of HEWL has not changed with increasing Fe NP concentrations; however, some conformational changes occur in tertiary structure of HEWL. Moreover, protein-ligand docking study confirmed that the Fe NP forms hydrogen bond contacts with HEWL. PMID- 27776182 TI - The Effect of Diurnal Fluctuation in Intraocular Pressure on the Evaluation of Risk Factors of Progression in Normal Tension Glaucoma. AB - PURPOSE: To investigate whether diurnal fluctuation in intraocular pressure (IOP) can influence the result of the correlations between IOP-related factors and progression of normal tension glaucoma (NTG). METHODS: Glaucoma progression was defined as visual field (VF) progression and changes in the optic disc and/or retinal nerve fiber layer (RNFL). Two different methods were used to evaluate the impact of the diurnal fluctuation in IOP. 'Conventional method' used in previous studies included all IOP measurements during the follow up time. 'Time adjusted method' was used to adjust diurnal fluctuation in IOP with the preferred time. Mean IOP, long term IOP fluctuation and the difference between the lowest and highest IOP were calculated using both methods. Cox regression analyses were performed to evaluate the association between IOP-related factors and NTG progression. RESULTS: One hundred and forty eyes of 140 patients with NTG were included in this study. 41% (58 of 140 eyes) of eyes underwent NTG progression. Long term IOP variation calculated by conventional method was not a significant risk factor for NTG progression (hazard ratio[HR], 0.311; 95% confidence interval[CI], 0.056-1.717; P = 0.180). Long term IOP variation calculated by time adjusted method, however, was related to progression, with an HR of 5.260 (95% CI,1.191-23.232; P = 0.029). CONCLUSION: Although having the same IOP-related factors, if diurnal fluctuation is included, different results may be found on the relationship between IOP-related factors and NTG progression. Based on our results, diurnal fluctuation in IOP should be considered when IOP-related factors are studied in the future. PMID- 27776181 TI - Biological Interactions and Simulated Climate Change Modulates the Ecophysiological Performance of Colobanthus quitensis in the Antarctic Ecosystem. AB - Most climate and environmental change models predict significant increases in temperature and precipitation by the end of the 21st Century, for which the current functional output of certain symbioses may also be altered. In this context we address the following questions: 1) How the expected changes in abiotic factors (temperature, and water) differentially affect the ecophysiological performance of the plant Colobanthus quitensis? and 2) Will this environmental change indirectly affect C. quitensis photochemical performance and biomass accumulation by modifying its association with fungal endophytes? Plants of C. quitensis from King George Island in the South Shetland archipelago (62 degrees 09' S), and Lagotellerie Island in the Antarctic Peninsula (65 degrees 53' S) were put under simulated abiotic conditions in growth chambers following predictive models of global climate change (GCC). The indirect effect of GCC on the interaction between C. quitensis and fungal endophytes was assessed in a field experiment carried out in the Antarctica, in which we eliminated endophytes under contemporary conditions and applied experimental watering to simulate increased precipitation input. We measured four proxies of plant performance. First, we found that warming (+W) significantly increased plant performance, however its effect tended to be less than watering (+W) and combined warming and watering (+T degrees +W). Second, the presence of fungal endophytes improved plant performance, and its effect was significantly decreased under experimental watering. Our results indicate that both biotic and abiotic factors affect ecophysiological performance, and the directions of these influences will change with climate change. Our findings provide valuable information that will help to predict future population spread and evolution through using ecological niche models under different climatic scenarios. PMID- 27776184 TI - Deoxyarbutin Possesses a Potent Skin-Lightening Capacity with No Discernible Cytotoxicity against Melanosomes. AB - Safe and effective ingredients capable of removing undesired hyperpigmentation from facial skin are urgently needed for both pharmaceutical and cosmetic purposes. Deoxyarbutin (4-[(tetrahydro-2H-pyran-2-yl) oxy] phenol, D-Arb) is a glucoside derivative of hydroquinone. Here, we investigated the toxicity and efficacy of D-Arb at the sub-cellular level (directly on melanosomes) and skin pigmentation using in vivo and in vitro models to compare with its parent compound hydroquinone (1,4-benzenediol, HQ). At first, we examined the ultrastructural changes of melanosomes in hyperpigmented guinea pig skin induced by 308-nm monochromatic excimer lightand/or treated with HQ and D-Arb using transmission electron microscopy. The results showed that prominent changes in the melanosomal membrane, such as bulb-like structure and even complete rupture of the outer membranes, were found in the skin after topical application of 5% HQ for 10 days. These changes were barely observed in the skin treated with D-Arb. To further clarify whether membrane toxicity of HQ was a direct result of the compound treatment, we also examinedultrastructural changes of individual melanosomes purified from MNT1 human melanoma cells. Similar observations were obtained from the naked melanosome model in vitro. Finally, we determined the effects of melanosomal fractions exposed to HQ or D-Arb on hydroxyl radical generation in the Fenton reaction utilizing an electron spin resonance assay. D Arb-treated melanosomesexhibit a moderate hydroxyl radical-scavenging activity, whereas HQ-treated melanosomessignificantly generate more hydroxyl free radicals. This study suggests that D-Arb possesses a potent ability in skin lightening and antioxidation with less melanosome cytotoxicity. PMID- 27776183 TI - Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model. AB - Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERalpha and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERalpha and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis. PMID- 27776186 TI - Serum Reactive Oxygen Metabolite Levels Predict Severe Exacerbations of Asthma. AB - BACKGROUND AND PURPOSE: Bronchial asthma (BA) is a chronic airway disease characterized by airway hyperresponsiveness and remodeling, which are intimately linked to chronic airway inflammation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells that are involved in the pathogenesis of BA. However, the role of ROS in the management of BA patients is not yet clear. We attempted to determine the role of ROS as a biomarker in the clinical setting of BA. SUBJECTS AND METHODS: We enrolled patients with BA from 2013 through 2015 and studied the degrees of asthma control, anti-asthma treatment, pulmonary function test results, fractional exhaled nitric oxide (FeNO), serum reactive oxygen metabolite (ROM) levels, and serum levels of interleukin (IL)-6 and IL-8. RESULTS: We recruited 110 patients with BA. Serum ROM levels correlated with white blood cell (WBC) count (rs = 0.273, p = 0.004), neutrophil count (rs = 0.235, p = 0.014), CRP (rs = 0.403, p < 0.001), and IL-6 (rs = 0.339, p < 0.001). Serum ROM levels and IL-8 and CRP levels negatively correlated with %FEV1 (rs = -0.240, p = 0.012, rs = -0.362, p < 0.001, rs = 0.197, p = 0.039, respectively). Serum ROM levels were significantly higher in patients who experienced severe exacerbation within 3 months than in patients who did not (339 [302-381] vs. 376 [352-414] CARR U, p < 0.025). Receiver-operating characteristics analysis showed that ROM levels correlated significantly with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597 0.801, p = 0.025). CONCLUSIONS: Serum levels of ROM were significantly associated with the degrees of airway obstruction, WBC counts, neutrophil counts, IL-6, and severe exacerbations. This biomarker may be useful in predicting severe exacerbations of BA. PMID- 27776187 TI - Epidemiological and Clinical Features of Severe Fever with Thrombocytopenia Syndrome in Japan, 2013-2014. AB - Although severe fever with thrombocytopenia syndrome (SFTS) was first reported from Japan in 2013, the precise clinical features and the risk factors for SFTS have not been fully investigated in Japan. Ninety-six cases of severe fever with thrombocytopenia syndrome (SFTS) were notified through the national surveillance system between April 2013 and September 2014 in Japan. All cases were from western Japan, and 82 cases (85%) had an onset between April and August. A retrospective observational study of the notified SFTS cases was conducted to identify the clinical features and laboratory findings during the same period. Of 96 notified cases, 49 (51%) were included in this study. Most case-patients were of advanced age (median age 78 years) and were retired or unemployed, or farmers. These case-patients had a history of outdoor activity within 2 weeks before the onset of illness. The median serum C-reactive protein concentration was slightly elevated at admission. Fungal infections such as invasive aspergilosis were found in 10% of these case-patients. Hemophagocytosis was observed in 15 of the 18 case patients (83%) whose bone marrow samples were available. Fifteen cases were fatal, giving a case-fatality proportion of 31%. The proportion of neurological abnormalities and serum concentrations of lactate dehydrogenase and aspartate aminotransferase were significantly higher in the fatal cases than in the nonfatal cases during hospitalization. Appearance of neurological abnormality may be useful for predicting the prognosis in SFTS patients. PMID- 27776185 TI - Computational Analysis of G-Quadruplex Forming Sequences across Chromosomes Reveals High Density Patterns Near the Terminal Ends. AB - G-quadruplex structures (G4) are found throughout the human genome and are known to play a regulatory role in a variety of molecular processes. Structurally, they have many configurations and can form from one or more DNA strands. At the gene level, they regulate gene expression and protein synthesis. In this paper, chromosomal-level patterns of distribution are analyzed on the human genome to identify high-level distribution patterns potentially related to global functional processes. Here we show unique high density banding patterns on individual chromosomes that are highly correlated, appearing in a mirror pattern, across forward and reverse DNA strands. The highest density of G4 sequences occurs within four megabases of one end of most chromosomes and contains G4 motifs that bind with zinc finger proteins. These findings suggest that G4 may play a role in global chromosomal processes such as those found in meiosis. PMID- 27776188 TI - Analysis of Macular Drusen and Blood Test Results in 945 Macaca fascicularis. AB - Age-dependent formation of macular drusen caused by the focal accumulation of extracellular deposits beneath the retinal pigment epithelium precede the development of age-related macular degeneration (AMD), one of the leading causes of blindness worldwide. It is established that inflammation contributes to the pathogenesis of drusen and AMD. However, development of a preemptive therapeutic strategy targeting macular drusen and AMD has been impeded by the lack of relevant animal models because most laboratory animals lack macula, an anatomic feature present only in humans and a subset of monkeys. Reportedly, macular drusen and macular degeneration develop in monkeys in an age-dependent manner. In this study, we analyzed blood test results from 945 Macaca fascicularis, 317 with and 628 without drusen. First, a trend test for drusen frequency (the Cochran Armitage test) was applied to the quartile data for each parameter. We selected variables with an increasing or decreasing trend with higher quartiles at P < 0.05, to which multivariate logistic regression analysis was applied. This revealed a positive association of age (odds ratio [OR]: 1.10 per year, 95% confidence interval [CI]: 1.07-1.12) and white blood cell count (OR: 1.01 per 1 * 103/MUl, 95% CI: 1.00-1.01) with drusen. When the monkeys were divided by age, the association between drusen and white blood cell count was only evident in younger monkeys (OR: 1.01 per 1 * 103/MUl, 95% CI: 1.00-1.02). In conclusion, age and white blood cell count may be associated with drusen development in M. fascicularis. Systemic inflammation may contribute to drusen formation in monkeys. PMID- 27776189 TI - The Tax-Inducible Actin-Bundling Protein Fascin Is Crucial for Release and Cell to-Cell Transmission of Human T-Cell Leukemia Virus Type 1 (HTLV-1). AB - The delta-retrovirus Human T-cell leukemia virus type 1 (HTLV-1) preferentially infects CD4+ T-cells via cell-to-cell transmission. Viruses are transmitted by polarized budding and by transfer of viral biofilms at the virological synapse (VS). Formation of the VS requires the viral Tax protein and polarization of the host cytoskeleton, however, molecular mechanisms of HTLV-1 cell-to-cell transmission remain incompletely understood. Recently, we could show Tax dependent upregulation of the actin-bundling protein Fascin (FSCN-1) in HTLV-1 infected T-cells. Here, we report that Fascin contributes to HTLV-1 transmission. Using single-cycle replication-dependent HTLV-1 reporter vectors, we found that repression of endogenous Fascin by short hairpin RNAs and by Fascin-specific nanobodies impaired gag p19 release and cell-to-cell transmission in 293T cells. In Jurkat T-cells, Tax-induced Fascin expression enhanced virus release and Fascin-dependently augmented cell-to-cell transmission to Raji/CD4+ B-cells. Repression of Fascin in HTLV-1-infected T-cells diminished virus release and gag p19 transfer to co-cultured T-cells. Spotting the mechanism, flow cytometry and automatic image analysis showed that Tax-induced T-cell conjugate formation occurred Fascin-independently. However, adhesion of HTLV-1-infected MT-2 cells in co-culture with Jurkat T-cells was reduced upon knockdown of Fascin, suggesting that Fascin contributes to dissemination of infected T-cells. Imaging of chronically infected MS-9 T-cells in co-culture with Jurkat T-cells revealed that Fascin's localization at tight cell-cell contacts is accompanied by gag polarization suggesting that Fascin directly affects the distribution of gag to budding sites, and therefore, indirectly viral transmission. In detail, we found gag clusters that are interspersed with Fascin clusters, suggesting that Fascin makes room for gag in viral biofilms. Moreover, we observed short, Fascin containing membrane extensions surrounding gag clusters and clutching uninfected T-cells. Finally, we detected Fascin and gag in long-distance cellular protrusions. Taken together, we show for the first time that HTLV-1 usurps the host cell factor Fascin to foster virus release and cell-to-cell transmission. PMID- 27776190 TI - Antennal Transcriptome and Differential Expression Analysis of Five Chemosensory Gene Families from the Asian Honeybee Apis cerana cerana. AB - Chemosensory genes play a central role in sensing chemical signals and guiding insect behavior. The Chinese honeybee, Apis cerana cerana, is one of the most important insect species in China in terms of resource production, and providing high-quality products for human consumption, and also serves as an important pollinator. Communication and foraging behavior of worker bees is likely linked to a complex chemosensory system. Here, we used transcriptome sequencing on adult A. c. cerana workers of different ages to identify the major chemosensory gene families and the differentially expressed genes(DEGs), and to investigate their expression profiles. A total of 109 candidate chemosensory genes in five gene families were identified from the antennal transcriptome assemblies, including 17 OBPs, 6 CSPs, 74 ORs, 10 IRs, and 2SNMPs, in which nineteen DEGs were screened and their expression values at different developmental stages were determined in silico. No chemosensory transcript was specific to a certain developmental period. Thirteen DEGs were upregulated and 6were downregulated. We created extensive expression profiles in six major body tissues using qRT-PCR and found that most DEGs were exclusively or primarily expressed in antennae. Others were abundantly expressed in the other tissues, such as head, thorax, abdomen, legs, and wings. Interestingly, when a DEG was highly expressed in the thorax, it also had a high level of expression in legs, but showed a lowlevel in antennae. This study explored five chemoreceptor superfamily genes using RNA-Seq coupled with extensive expression profiling of DEGs. Our results provide new insights into the molecular mechanism of odorant detection in the Asian honeybee and also serve as an extensive novel resource for comparing and investigating olfactory functionality in hymenopterans. PMID- 27776191 TI - Shifting Stakes: Understanding the Dynamic Roles of Individuals and Organizations in Social Media Protests. AB - In this paper we examine two protests characterized by substantial social media presence and distributed participation frameworks via two core questions: what roles did organizations and individuals play, and how did participants' social interactions change over the course of the protests? To answer these questions, we analyzed a large Twitter activity dataset for the #YoSoy132 student uprising in Mexico and Brazil's "bus rebellion." Results indicate that individuals initially took prominence at the protests but faded in importance as the movements dwindled and organizations took over. Regarding the dynamics and structure of the interactions, we found that key time points with unique social structures often map to exogenous events such as coordinated protests in physical locations. Our results have important consequences for the visibility of such social movements and their ability to attract continued participation by individuals and organizations. PMID- 27776193 TI - The role of the 5' terminal region of p53 mRNA in the p53 gene expression. AB - The p53 tumour suppressor protein is one of the major factors responsible for cell cycle regulation and protection against cancer development. This is why it is often referred to as "the guardian of the genome". On the other hand, mutations in the p53 gene are connected with more than 50% of tumours of various types. The thirty-six years of extensive research on the p53 gene and its protein products have shown how sophisticated the p53-based cell system control is. An additional level of complexity of the p53 research is connected with at least twelve p53 isoforms which have been identified in the cell. Importantly, disturbance of the p53 isoforms' expression seems to play a key role in tumorigenesis, cell differentiation and cell response to pathogenic bacteria, and RNA and DNA viruses. Expression of various p53 isoforms results from the usage of different transcription promoters, alternative splicing events and translation initiation from alternative AUG codons. The importance of the 5'-terminal regions of different p53 mRNA transcripts in the multi-level regulation of the p53 gene has recently been documented. In this review we focus on the structural features of these regions and their specific role in the p53 translation initiation process. PMID- 27776192 TI - Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure. AB - BACKGROUNDS & AIMS: We aimed to clarify the characteristics of resistance associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection. METHODS: This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing. RESULTS: The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients. CONCLUSION: Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors. PMID- 27776194 TI - RNA-Seq-based analysis of differential gene expression associated with hepatitis C virus infection in a cell culture. AB - Hepatitis C virus (HCV) infection is one of the major causes of chronic liver diseases. Unfortunately, the mechanisms of HCV infection-induced liver injury and host-virus interactions are still not well recognized. To better understand these processes we determined the changes in the host gene expression that occur during HCV infection of Huh-7.5 cells. As a result, we identified genes that may contribute to the immune and metabolic cellular responses to infection. Pathway enrichment analysis indicated that HCV induced an increased expression of genes involved in mitogen-activated protein kinases signaling, adipocytokine signaling, cell cycle and nitrogen metabolism. In addition, the enrichment analyses of processes and molecular functions revealed that the up-regulated genes were mainly implicated in the negative regulation of phosphorylation. Construction of the pathway-gene-process network enabled exploration of a much more complex landscape of molecular interactions. Consequently, several essential processes altered by HCV infection were identified: negative regulation of cell cycle, response to endoplasmic reticulum stress, response to reactive oxygen species, toll-like receptor signaling and pattern recognition receptor signaling. The analyses of genes whose expression was decreased upon HCV infection showed that the latter were engaged in the metabolism of lipids and amino acids. Moreover, we observed disturbance in the cellular antiviral defense. Altogether, our results demonstrated that HCV infection elicits host response that includes a very wide range of cellular mechanisms. Our findings significantly broaden the understanding of complex processes that accompany HCV infection. Consequently, they may be used for developing new host-oriented therapeutic strategies. PMID- 27776195 TI - Bone turnover markers in the obese children - relation to gender, body composition and leptin level. PMID- 27776196 TI - Postprandial sRAGE levels in type 1 diabetes mellitus in children and adolescents. PMID- 27776198 TI - Autoimmune gastritis among T1D individuals - important association? PMID- 27776197 TI - [Risk of cerebral edema in children with diabetic ketoacidosis in the course of type 1 diabetes]. PMID- 27776199 TI - [Fibroblast growth factor 21 - current point of view on its role in physiology of the organism and the pathogenesis of diabetes mellitus and obesity]. PMID- 27776200 TI - Role of gluten-free diet in pathogenesis of type 1 diabetes - what new? PMID- 27776201 TI - Evaluating the Impact of a Multistrategy Inference Intervention for Middle-Grade Struggling Readers. AB - Purpose: We examined the effectiveness of a multistrategy inference intervention designed to increase inference making and reading comprehension for middle-grade struggling readers. Method: A total of 66 middle-grade struggling readers were randomized to treatment (n = 33) and comparison (n = 33) conditions. Students in the treatment group received explicit instruction in 4 inference strategies (i.e., clarification using text clues; activating and using prior knowledge; understanding character perspectives and author's purpose; answering inferential questions). In addition, narrative and informational texts were carefully chosen and sequenced to build requisite background knowledge to form inferences. Intervention was delivered in small groups of 3 students for 10 days of instruction. Results: One-way analysis of covariance models on outcome measures with the respective pretest scores as a covariate revealed significant gains on a proximal measure of Egyptian-content knowledge (g = 1.37) and on a standardized measure of reading comprehension-i.e., Wechsler Individual Achievement Test-Third Edition Reading Comprehension (g = 0.46). Conclusion: The moderate effect on a standardized measure of reading comprehension provides preliminary evidence for the effectiveness of this multistrategy inference intervention in improving reading comprehension of middle-grade struggling readers. PMID- 27776202 TI - Uncertainties of testing methods: What do we (want to) know about carcinogenicity? AB - An approach to systematically describe the uncertainties and complexity of the standard animal testing and assessment approach for carcinogenicity is explored by using a OECD Guidance Document that was originally developed for reporting defined in vitro approaches to testing and assessment. The format is suitable for this re-purposing and it appears that the potential multitude of approaches for integrating and interpreting data from standard animal testing may ultimately be conceptually similar to the challenge of integrating relevant in vitro and in silico data. This structured approach shall allow 1) fostering interest in developing improved defined in silico and in vitro approaches; 2) the definition of what type of effects should be predicted by the new approach; 3) selection of the most suitable reference data and assessments; 4) definition of the weight that the standard animal reference data should have compared to human reference data and mechanistic information in the context of assessing the fitness of the new in vitro and in silico approach; 5) definition of a benchmark for the minimum performance of the new approach, based on a conceptual recognition that correlation of alternative assessment results with reference animal results is limited by the uncertainties and complexity of the latter. A longer term perspective is indicated for evolving the definition of adversity for classification and regulatory purposes. This work will be further discussed and developed within the OECD expert group on non-genotoxic carcinogenicity IATA development. PMID- 27776203 TI - Obesogens and male fertility. AB - In the last decades, several studies evidenced a decrease in male fertility in developed countries. Although the aetiology of this trend in male reproductive health remains a matter of debate, environmental compounds that predispose to weight gain, namely obesogens, are appointed as contributors because of their action as endocrine disruptors. Obesogens favour adipogenesis by an imbalance of metabolic processes and can be found virtually everywhere. These compounds easily accumulate in tissues with high lipid content. Obesogens change the functioning of male reproductive axis, and, consequently, the testicular physiology and metabolism that are pivotal for spermatogenesis. The disruption of these tightly regulated metabolic pathways leads to adverse reproductive outcomes. Notably, adverse effects of obesogens may also promote disturbances in the metabolic performance of the following generations, through epigenetic modifications passed by male gametes. Thus, unveiling the molecular pathways by which obesogens induce toxicity that may end up in epigenetic modifications is imperative. Otherwise, a transgenerational susceptibility to metabolic diseases may be favoured. We present an up-to-date overview of the impact of obesogens on testicular physiology, with a particular focus on testicular metabolism. We also address the effects of obesogens on male reproductive parameters and the subsequent consequences for male fertility. PMID- 27776205 TI - Investigations on 16-Arylideno Steroids as a New Class of Neuroprotective Agents for the Treatment of Alzheimer's and Parkinson's Diseases. AB - Neuroinflammatory mechanisms mediated by activated glial and cytokines (TNF alpha, IL-1beta) might contribute to neuronal degeneration leading to Alzheimer's (AD) and Parkinson's disease (PD). Lipopolysaccharide (LPS) is an inflammogen derived from the cell wall of Gram-negative bacteria, which promotes neuroinflammation and subsequent neurodegeneration. Dehydroepiandrosterone (DHEA) and testosterone have been reported as neuroprotective steroids useful for the treatment of various neurodegenerative disorders. In the present study, several 16-arylidene steroidal derivatives have been evaluated as neuroprotective agents in LPS-treated animal models. It was observed that 16-arylidene steroidal derivatives 1a-d and 6a-h considerably improve LPS-induced learning, memory, and movement deficits in animal models. Biochemical estimations of brain serum of treated animals revealed suppression of oxidative and nitrosative stress, acetylcholinesterase activity, and reduction in TNF-alpha levels, which were induced through LPS mediated neuroinflammatory mechanisms leading to neurodegeneration of brain. Of all the steroidal derivatives, 16-(4-pyridylidene) steroid 1c and its 4-aza analogue 6c were found to be the most active neuroprotective agents and produced effects comparable to standard drug celecoxib at a much lower dose and better than dexamethasone at the same dose in terms of behavioral, biochemical, and molecular aspects. PMID- 27776207 TI - Carbonized Electrospun Nanofiber Sheets for Thermophones. AB - Thermoacoustic performance of thin freestanding sheets of carbonized poly(acrylonitrile) and polybenzimidazole nanofibers are studied as promising candidates for thermophones. We analyze thermodynamic properties of sheets using transport parameters of single nanofibers and their aligned and randomly electrospun thin film assemblies. The electrical and thermal conductivities, thermal diffusivity, heat capacity, and infrared blackbody radiation are investigated to extract the heat exchange coefficient and enhance the energy conversion efficiency. Spectral and power dependencies of sound pressure in air are compared with carbon nanotube sheets and theoretical prediction. Despite lower thermoacoustic performance compared to that of CNT sheets, the mechanical strength and cost-effective production technology of thermophones make them very attractive for large-size sound projectors. The advantages of carbonized electrospun polymer nanofiber sheets are in the low frequency domain (<1000 Hz), where the large thermal diffusion length diminishes the thermal inertia of thick (~200 nm) nonbundled fibers and the high intrinsic thermal conductivity of fibers enhances the heat exchange coefficient. Applications of thermoacoustic projectors for loudspeakers, high power SONAR arrays, and sound cancellation are discussed. PMID- 27776206 TI - Unexpected Trend in Stability of Xe-F Compounds under Pressure Driven by Xe-Xe Covalent Bonds. AB - Xenon difluoride is the first and the most stable of hundreds of noble-gas (Ng) compounds. These compounds reveal the rich chemistry of Ng's. No stable compound that contains a Ng-Ng bond has been reported previously. Recent experiments have shown intriguing behaviors of this exemplar compound under high pressure, including increased coordination numbers and an insulator-to-metal transition. None of the behaviors can be explained by electronic-structure calculations with fixed stoichiometry. We therefore conducted a structure search of xenon-fluorine compounds with various stoichiometries and studied their stabilities under pressure using first-principles calculations. Our results revealed, unexpectedly, that pressure stabilizes xenon-fluorine compounds selectively, including xenon tetrafluoride, xenon hexafluoride, and the xenon-rich compound Xe2F. Xenon difluoride becomes unstable above 81 GPa and yields metallic products. These compounds contain xenon-xenon covalent bonds and may form intercalated graphitic xenon lattices, which stabilize xenon-rich compounds and promote the decomposition of xenon difluoride. PMID- 27776204 TI - Mean platelet volume: a potential biomarker of the risk and prognosis of heart disease. AB - Platelets are essential for progression of atherosclerotic lesions, plaque destabilization, and thrombosis. They secrete and express many substances that are crucial mediators of coagulation, inflammation, and atherosclerosis. Mean platelet volume (MPV) is a precise measure of platelet size, and is routinely reported during complete blood count analysis. Emerging evidence supports the use of MPV as a biomarker predicting the risk of ischemic stroke in patients with atrial fibrillation, and as a guide for prescription of anticoagulation and rhythm-control therapy. In addition, MPV may predict the clinical outcome of percutaneous coronary intervention (PCI) in patients with coronary artery disease and indicate whether additional adjunctive therapy is needed to improve clinical outcomes. This review focuses on the current evidence that MPV may be a biomarker of the risk and prognosis of common heart diseases, particularly atrial fibrillation and coronary artery disease treated via PCI. PMID- 27776208 TI - Thermoresponsive Delivery of Paclitaxel by beta-Cyclodextrin-Based Poly(N isopropylacrylamide) Star Polymer via Inclusion Complexation. AB - Paclitaxel (PTX), a hydrophobic anticancer drug, is facing several clinical limitations such as low bioavailability and drug resistance. To solve the problems, a well-defined beta-cyclodextrin-poly(N-isopropylacrylamide) star polymer was synthesized and used as a nanocarrier to improve the water solubility and aim to thermoresponsive delivery of PTX to cancer cells. The star polymer was able to form supramolecular self-assembled inclusion complex with PTX via host guest interaction at room temperature, which is below the low critical solution temperature (LCST) of the star polymer, significantly improving the solubilization of PTX. At body temperature (above LCST), the phase transition of poly(N-isopropylacrylamide) segments induced the formation of nanoparticles, which greatly enhanced the cellular uptake of the polymer-drug complex, resulting in efficient thermoresponsive delivery of PTX. In particular, the polymer-drug complex exhibited better antitumor effects than the commercial formulation of PTX in overcoming the multi-drug resistance in AT3B-1 cells. PMID- 27776209 TI - Electrochemical Investigations of the Mechanism of Assembly of the Active-Site H Cluster of [FeFe]-Hydrogenases. AB - Protein film electrochemistry (PFE) has been used to study the assembly of the complex 6Fe active site of [FeFe]-hydrogenases (known as the H-cluster) from its precursors-the [4Fe-4S] domain that is already coordinated within the host, and the 2Fe domain that is presented as a synthetic water-soluble complex stabilized by an additional CO. Not only does PFE allow control of redox states via the electrode potential but also the immobilized state of the enzyme facilitates control of extremely low concentrations of the 2Fe complex. Results for two enzymes, CrHydA1 from Chlamydomonas reinhardtii and CpI from Clostridium pasteurianum, are very similar, despite large differences in size and structure. Assembly begins with very tight binding of the 34-valence electron 2Fe complex to the apo-[4Fe-4S] enzyme, well before the rate-determining step. The precursor is trapped under highly reducing conditions (<-0.5 V vs SHE) that prevent fusion of the [4Fe-4S] and 2Fe domains (via cysteine-S) since the immediate product would be too electron-rich. Relaxing this condition allows conversion to the active H cluster. The intramolecular steps are relevant to the final stage of biological H cluster maturation. PMID- 27776210 TI - Intrinsic and Extrinsic Stability of Formamidinium Lead Bromide Perovskite Solar Cells Yielding High Photovoltage. AB - We report on both the intrinsic and the extrinsic stability of a formamidinium lead bromide [CH(NH2)2PbBr3 = FAPbBr3] perovskite solar cell that yields a high photovoltage. The fabrication of FAPbBr3 devices, displaying an outstanding photovoltage of 1.53 V and a power conversion efficiency of over 8%, was realized by modifying the mesoporous TiO2-FAPbBr3 interface using lithium treatment. Reasons for improved photovoltaic performance were revealed by a combination of techniques, including photothermal deflection absorption spectroscopy (PDS), transient-photovoltage and charge-extraction analysis, and time-integrated and time-resolved photoluminescence. With lithium-treated TiO2 films, PDS reveals that the TiO2-FAPbBr3 interface exhibits low energetic disorder, and the emission dynamics showed that electron injection from the conduction band of FAPbBr3 into that of mesoporous TiO2 is faster than for the untreated scaffold. Moreover, compared to the device with pristine TiO2, the charge carrier recombination rate within a device based on lithium-treated TiO2 film is 1 order of magnitude lower. Importantly, the operational stability of perovskites solar cells examined at a maximum power point revealed that the FAPbBr3 material is intrinsically (under nitrogen) as well as extrinsically (in ambient conditions) stable, as the unsealed devices retained over 95% of the initial efficiency under continuous full sun illumination for 150 h in nitrogen and dry air and 80% in 60% relative humidity (T = ~60 degrees C). The demonstration of high photovoltage, a record for FAPbBr3, together with robust stability renders our work of practical significance. PMID- 27776211 TI - Sulfoglucosides as Novel Modified Forms of the Mycotoxins Alternariol and Alternariol Monomethyl Ether. AB - The mycotoxins alternariol and alternariol-9-O-methyl ether have recently been reported to be extensively conjugated with glucose and malonyl glucose in tobacco suspension cells. However, only trace amounts of glucosylated conjugates were detected in tomatoes inoculated with Alternaria alternata in the present study. Instead, mostly sulfate conjugates were observed. In studies using cultures of A. alternata and incubations of alternariol and alternariol-9-O-methyl ether with tomato tissue in the absence of the fungus, it was clarified that sulfate conjugates were produced by the fungus, whereas tomato tissues converted alternariol and alternariol-9-O-methyl ether to glucosylated metabolites. Alternariol-3-sulfate, alternariol-9-sulfate, and alternariol-9-O-methyl ether-3 sulfate were unambiguously identified as fungal metabolites using MS and 1H and 13C NMR spectroscopy. When these sulfate conjugates were incubated with tobacco suspension cells or ex planta tomato tissues, three sulfoglucosides of alternariol and one sulfoglucoside of alternariol-9-O-methyl ether were formed. Using NMR spectroscopy, the chemical structures of alternariol-3-sulfate-9 glucoside, alternariol-9-sulfate-3-glucoside, and alternariol-9-O-methyl ether-3 sulfate-7-glucoside were established. These conjugates were also detected in the A. alternata-inoculated tomato. This is the first report on a mixed sulfate/glucoside diconjugate of a mycotoxin. Diconjugates of this novel type may be formed by all mycotoxins and their phase I metabolites with two or more hydroxyl groups and should be taken into account in the future analysis of modified mycotoxins. PMID- 27776212 TI - Kinetics of Oil Exchange in Nanoemulsions Prepared with the Phase Inversion Concentration Method. AB - Nanoemulsions (NEs) are metastable emulsions with droplet sizes between 20 and 100 nm and with a wide range of applications, for example, in polymerization, in pharmaceutical and cosmetic formulations, and as drug delivery systems. Even though they are not in thermodynamic equilibrium, they can be metastable over relatively long times and have the advantage that they can be formed easily by low energy input methods. In particular, the phase inversion concentration (PIC) method allows the formation of NEs by the dilution of a suitable mixture of oil and surfactants with water. In this paper, we investigate the kinetics of the oil exchange process of NEs formed by the PIC method by looking at the exchange of different hydrophobic oils and by employing contrast variation stopped flow small angle neutron scattering. These experiments demonstrate that this exchange becomes substantially slower by increasing the chain length of the alkane. This indicates a mechanism where monomer exchange is relevant, which would indicate also that for aging one would expect Ostwald ripening to be the determining factor. Such investigations can be carried out in a unique fashion by means of neutron scattering, and the results have important implications for the optimization of NE formulations. PMID- 27776213 TI - Primary Fibril Nucleation of Aggregation Prone Tau Fragments PHF6 and PHF6. AB - We performed replica exchange molecular dynamics and forward flux sampling simulations of hexapeptide VQIINK and VQIVYK systems, also known as, respectively, fragments PHF6* and PHF6 from the tau protein. Being a part of the microtubule binding region, these fragments are known to be aggregation prone, and at least one of them is a prerequisite for fibril formation of the tau protein. Using a coarse-grained force field, we establish the phase behavior of both fragments, and investigate the nucleation kinetics for the conversion into a beta-sheet fibril. As the conversion is, in principle, a reversible process, we predict the rate constants for both the fibril formation and melting, and examine the corresponding mechanisms. Our simulations indicate that, while both fragments form disordered aggregates, only PHF6 is able to form beta-sheet fibrils. This observation provides a possible explanation for the lack of available steric zipper crystal structures for PHF6*. PMID- 27776214 TI - Advances in Molecular Modeling of Nanoparticle-Nucleic Acid Interfaces. AB - Nanoparticles (NPs) play increasingly important roles in nanotechnology and nanomedicine in which nanoparticle surface chemistry allows for control over interactions with other nanoparticles and biomolecules. In particular, for applications in drug and gene delivery, a fundamental understanding of the NP nucleic acid interface allows for development of more efficient and effective nanoparticle carriers. Computational modeling can provide insights of processes occurring at the inorganic NP-nucleic interface in detail that is difficult to access by experimental methods. With recent advances such as the use of graphics processing units (GPUs) for simulations, computational modeling has the potential to give unprecedented insight into inorganic-biological interfaces via the examination of increasingly large and complex systems. In this Topical Review, we briefly review computational methods relevant to the interactions of inorganic NPs and nucleic acids and highlight recent insights obtained from various computational methods that were applied to studies of inorganic nanoparticle nanoparticle and nanoparticle-nucleic acid interfaces. PMID- 27776216 TI - Direct Evaluation of Protein-Lipid Contacts Reveals Protein Membrane Immersion and Isotropic Bicelle Structure. AB - The solvation of membrane proteins by both lipids and water makes their membrane immersion difficult to predict and the choice of a membrane mimic challenging. To characterize protein-lipid contacts and bicelle membrane mimics, we examined protein-lipid cross-relaxation of integrin alphaIIb and beta3(A711P) transmembrane helices in isotropic phospholipid bicelles (q = 0.5 and 0.7). Long chain bicelle lipids dominated contacts with central helix segments, whereas both short- and long-chain lipids contacted the terminal turns of each helix in corroboration of the mixed bicelle model. The saturation transfer profiles from long-chain lipids directly established helix midpoints in the lipid bilayer. Lipid headgroups and water molecules engaged the side chains of buried serine and threonine in competition with intrahelical hydrogen bonding, illustrating that polar side chains seek the most favorable electrostatic contacts. PMID- 27776215 TI - Iron Oxide Nanoparticle Based Contrast Agents for Magnetic Resonance Imaging. AB - Magnetic iron oxide nanoparticles (MIONs) have attracted enormous attention due to their wide applications, including for magnetic separation, for magnetic hyperthermia, and as contrast agents for magnetic resonance imaging (MRI). This review article introduces the methods of synthesizing MIONs, and their application as MRI contrast agents. Currently, many methods have been reported for the synthesis of MIONs. Herein, we only focus on the liquid-based synthesis methods including aqueous phase methods and organic phase methods. In addition, the MIONs larger than 10 nm can be used as negative contrast agents and the recently emerged extremely small MIONs (ES-MIONs) smaller than 5 nm are potential positive contrast agents. In this review, we focus on the ES-MIONs because ES MIONs avoid the disadvantages of MION-based T2- and gadolinium chelate-based T1 weighted contrast agents. PMID- 27776217 TI - A randomised, double-blind, placebo-controlled clinical study: the effects of a synbiotic, Lepicol, in adults with chronic, functional constipation. AB - The study objective was to evaluate the safety and effects of Lepicol(r) (pysllium fibre, inulin and 5 probiotic strains) in adults with chronic, functional constipation during a 4 week intervention. 69 subjects with functional constipation according to Rome III criteria were randomised to receive Lepicol (n = 35) or placebo (n = 34) daily. Both groups had improved frequency of bowel movements, with an increase of 1.082 bowel movements in the Lepicol group over placebo after one week, and 1.079 more than placebo after week 2, but with no significant difference at week 4. Both groups showed significant improvements in quality of life scores at 4 weeks, with the average score being 12.033% better in the Lepicol group, which also had 15.2% improvement in intensity of symptoms and 28.5% increase in satisfaction with quality of life compared to the placebo. Symptoms of constipation improved to a greater degree and there was a significant reduction in laxative use in the Lepicol group. PMID- 27776219 TI - Preoperative Cleft Lip Measurements and Maxillary Growth in Patients With Unilateral Cleft Lip and Palate. AB - OBJECTIVE: Maxillary growth in patients with cleft lip and palate is highly variable. The authors' aim was to investigate associations between preoperative cleft lip measurements and maxillary growth determined cephalometrically in patients with complete unilateral cleft lip and palate (cUCLP). DESIGN: Retrospective cross-sectional study. PATIENTS: Children with cUCLP. METHODS: Preoperative cleft lip measurements were made at the time of primary cheiloplasty and available for each patient. Maxillary growth was evaluated on lateral cephalometric radiographs taken prior to any orthodontic treatment and alveolar bone grafting (8.5 +/- 0.7 years). The presence of associations between preoperative cleft lip measurements and cephalometric measures of maxillary growth was determined using regression analyses. RESULTS: In the 58 patients included in the study, the cleft lateral lip element was deficient in height in 90% and in transverse width in 81% of patients. There was an inverse correlation between cleft lateral lip height and transverse width with a beta coefficient of 0.382 (P = .003). Patients with a more deficient cleft lateral lip height displayed a shorter maxillary length (beta coefficient = 0.336; P = .010), a less protruded maxilla (beta coefficient = .334; P = .008), and a shorter anterior maxillary height (beta coefficient = 0.306; P = .020) than those with a less deficient cleft lateral lip height. CONCLUSIONS: Patients with cUCLP present with varying degrees of lateral lip hypoplasia. Preoperative measures of lateral lip deficiency are related to later observed deficiencies of maxillary length, protrusion, and height. PMID- 27776221 TI - Establishment of reference intervals for procalcitonin in healthy pregnant women of Chinese population. AB - OBJECTIVE: To establish reference intervals (RIs) for procalcitonin (PCT) in healthy pregnant women of Chinese population. METHODS: Serum PCT levels were measured by electrochemiluminescence immunoassay (ECLIA) in 1246 healthy Chinese women, including 124 cases in the first trimester, 128 cases in the second trimester, 125 cases in the third trimester, 125 cases of vaginal delivery, 124 cases at the 3rd day after vaginal delivery, 122 cases at the 10th day after vaginal delivery, 126 cases with Cesarean delivery, 126 cases at the 3rd day after Cesarean delivery, 124 cases at the 10th day after Cesarean delivery, and 122 cases involving non-pregnant women. All cases were independent. The RIs for PCT were defined using nonparametric 95% intervals. RESULTS: The RIs for PCT were 0.018-0.051MUg/L for the first and second trimester; 0.020-0.152MUg/L for the third trimester; 0.022-0.195MUg/L for vaginal delivery; 0.019-0.021MUg/L for Cesarean delivery; 0.049-5.537MUg/L and 0.020-0.148MUg/L for 3rd and 10th days after vaginal delivery, respectively; 0.022-0.724MUg/L and 0.024-0.129MUg/L for the 3rd and 10th days after Cesarean delivery, respectively; and 0.015-0.061MUg/L for non-pregnant healthy women. CONCLUSION: The RIs for PCT in pregnant women by trimester, days postpartum, and mode of delivery were established, thus providing a clinical reference for doctors. PMID- 27776222 TI - Neck Dissection's Burden on the Patient: Functional and Psychosocial Aspects in 1,652 Patients With Oral Squamous Cell Carcinomas. AB - PURPOSE: In this study of patients with oral squamous cell carcinoma, the authors sought to clarify the functional and psychosocial harms of neck dissection (ND), which lessens quality of life. MATERIALS AND METHODS: The study included questionnaire responses from patients with oral squamous cell carcinoma (n = 1,652) and clinicians (n = 1,489), as collected in the DOSAK Rehab Study. Psychosocial and functional factors were assessed. Functional and psychosocial outcomes in patients who did not receive ND were compared with those in patients who underwent selective supraomohyoid ND (SND), modified radical ND (MND), and radical ND (RND). RESULTS: Patients with ND had lower quality of life than those without ND. Burdens after SND (n = 923) were generally lesser than those after MND (n = 301) or RDN (n = 678). There were meaningful differences between the SND, MND, and RND and without-ND groups in impairments in speech intelligibility for strangers and familiar persons, ingestion and swallowing, tongue mobility, opening of the mouth, lower jaw mobility, neck mobility, and shoulder and arm movement (P < .05). Many patients with ND faced a lower functional status and negative professional and financial consequences. CONCLUSIONS: Because of the burdens associated with ND, the decision to perform this treatment for oral squamous cell carcinoma should incorporate information on health-related quality of life and survival rates. PMID- 27776224 TI - From face processing to face recognition: Comparing three different processing levels. AB - Verifying that a face is from a target person (e.g. finding someone in the crowd) is a critical ability of the human face processing system. Yet how fast this can be performed is unknown. The 'entry-level shift due to expertise' hypothesis suggests that - since humans are face experts - processing faces should be as fast - or even faster - at the individual than at superordinate levels. In contrast, the 'superordinate advantage' hypothesis suggests that faces are processed from coarse to fine, so that the opposite pattern should be observed. To clarify this debate, three different face processing levels were compared: (1) a superordinate face categorization level (i.e. detecting human faces among animal faces), (2) a face familiarity level (i.e. recognizing famous faces among unfamiliar ones) and (3) verifying that a face is from a target person, our condition of interest. The minimal speed at which faces can be categorized (~260ms) or recognized as familiar (~360ms) has largely been documented in previous studies, and thus provides boundaries to compare our condition of interest to. Twenty-seven participants were included. The recent Speed and Accuracy Boosting procedure paradigm (SAB) was used since it constrains participants to use their fastest strategy. Stimuli were presented either upright or inverted. Results revealed that verifying that a face is from a target person (minimal RT at ~260ms) was remarkably fast but longer than the face categorization level (~240ms) and was more sensitive to face inversion. In contrast, it was much faster than recognizing a face as familiar (~380ms), a level severely affected by face inversion. Face recognition corresponding to finding a specific person in a crowd thus appears achievable in only a quarter of a second. In favor of the 'superordinate advantage' hypothesis or coarse-to-fine account of the face visual hierarchy, these results suggest a graded engagement of the face processing system across processing levels as reflected by the face inversion effects. Furthermore, they underline how verifying that a face is from a target person and detecting a face as familiar - both often referred to as "Face Recognition" - in fact differs. PMID- 27776223 TI - The substrate binding domains of human SIAH E3 ubiquitin ligases are now crystal clear. AB - BACKGROUND: Seven in absentia homologs (SIAHs) comprise a family of highly conserved E3 ubiquitin ligases that play an important role in regulating signalling pathways in tumorigenesis, including the DNA damage repair and hypoxia response pathways. SIAH1 and SIAH2 have been found to function as a tumour repressor and a proto-oncogene, respectively, despite the high sequence identity of their substrate binding domains (SBDs). Ubiquitin-specific protease USP19 is a deubiquitinase that forms a complex with SIAHs and counteracts the ligase function. Much effort has been made to find selective inhibitors of the SIAHs E3 ligases. Menadione was reported to inhibit SIAH2 specifically. METHODS: We used X ray crystallography, peptide array, bioinformatic analysis, and biophysical techniques to characterize the structure and interaction of SIAHs with deubiquitinases and literature reported compounds. RESULTS: We solved the crystal structures of SIAH1 in complex with a USP19 peptide and of the apo form SIAH2. Phylogenetic analysis revealed the SIAH/USP19 complex is conserved in evolution. We demonstrated that menadione destabilizes both SIAH1 and SIAH2 non-specifically through covalent modification. CONCLUSIONS: The SBDs of SIAH E3 ligases are structurally similar with a subtle stability difference. USP19 is the only deubiquitinase that directly binds to SIAHs through the substrate binding pocket. Menadione is not a specific inhibitor for SIAH2. GENERAL SIGNIFICANCE: The crystallographic models provide structural insights into the substrate binding of the SIAH family E3 ubiquitin ligases that are critically involved in regulating cancer-related pathways. Our results suggest caution should be taken when using menadione as a specific SIAH2 inhibitor. PMID- 27776220 TI - Using evolution to generate sustainable malaria control with spatial repellents. AB - Evolution persistently undermines vector control programs through insecticide resistance. Here we propose a novel strategy which instead exploits evolution to generate and sustain new control tools. Effective spatial repellents are needed to keep vectors out of houses. Our approach generates such new repellents by combining a high-toxicity insecticide with a candidate repellent initially effective against only part of the vector population. By killing mosquitoes that enter treated properties the insecticide selects for vector phenotypes deflected by the repellent, increasing efficacy of the repellent against the target vector population and in turn protecting the insecticide against the spread of insecticide resistance. Using such evolved spatial repellents offers an evolutionarily sustainable, 'double-dip' system of disease control combining mortality and repellence. We formalize this idea using models which explore vector population genetics and disease transmission probabilities and show that using evolved spatial repellents is theoretically achievable, effective and sustainable. PMID- 27776226 TI - The OH-initiated atmospheric chemical reactions of polyfluorinated dibenzofurans and polychlorinated dibenzofurans: A comparative theoretical study. AB - The atmospheric chemical reactions of some polyfluorinated dibenzofurans (PFDFs) and polychlorinated dibenzofurans (PCDFs), initiated by OH radical, were investigated by performing theoretical calculations using density functional theory (DFT) and B3LYP/6-311++G(2df,p) method. The obtained results indicate that OH addition reactions of PFDFs and PCDFs occurring at C1~4 and CA sites are thermodynamic spontaneous changes and the branching ratio of the PF(C)DF-OH adducts is decided primarily by kinetic factor. The OH addition reactions of PFDFs taking place at fluorinated C1~4 positions are kinetically comparable with those occurring at nonfluorinated C1~4 positions, while OH addition reactions of PCDFs occurring at chlorinated C1~4 sites are negligible. The total rate constants of the addition reactions of PFDFs or PCDFs become smaller with consecutive fluorination or chlorination, and substituting at C1 position has more adverse effects than substitution at other sites. The succedent O2 addition reactions of PF(C)DF-OH adducts are thermodynamic nonspontaneous processes under the atmospheric conditions, and have high Gibbs free energies of activation (DeltarG?). The substituted dibenzofuranols are the primary oxidation products for PCDFs under the atmospheric conditions. However, other oxidative products may also be available for PFDFs besides substituted dibenzofuranols. PMID- 27776225 TI - Acute respiratory response to traffic-related air pollution during physical activity performance. AB - BACKGROUND: Physical activity (PA) has beneficial, whereas exposure to traffic related air pollution (TRAP) has adverse, respiratory effects. Few studies, however, have examined if the acute effects of TRAP upon respiratory outcomes are modified depending on the level of PA. OBJECTIVES: The aim of our study was to disentangle acute effects of TRAP and PA upon respiratory outcomes and assess the impact of participants TRAP pre-exposure. METHODS: We conducted a real-world crossover study with repeated measures of 30 healthy adults. Participants completed four 2-h exposure scenarios that included either rest or intermittent exercise in high- and low-traffic environments. Measures of respiratory function were collected at three time points. Pre-exposure to TRAP was ascertained from land-use-modeled address-attributed values. Mixed-effects models were used to estimate the impact of TRAP and PA on respiratory measures as well as potential effect modifications. RESULTS: We found that PA was associated with a statistically significant increases of FEV1 (48.5mL, p=0.02), FEV1/FVC (0.64%, p=0.005) and FEF25-75% (97.8mL, p=0.02). An increase in exposure to one unit (1MUg/m3) of PMcoarse was associated with a decrease in FEV1 (-1.31mL, p=0.02) and FVC (-1.71mL, p=0.01), respectively. On the other hand, for an otherwise equivalent exposure an increase of PA by one unit (1%Heart rate max) was found to reduce the immediate negative effects of particulate matter (PM) upon PEF (PM2.5, 0.02L/min, p=0.047; PM10, 0.02L/min p=0.02; PMcoarse, 0.03L/min, p=0.02) and the several hours delayed negative effects of PM upon FVC (PMcoarse, 0.11mL, p=0.02). The negative impact of exposure to TRAP constituents on FEV1/FVC and PEF was attenuated in those participants with higher TRAP pre-exposure levels. CONCLUSIONS: Our results suggest that associations between various pollutant exposures and respiratory measures are modified by the level of PA during exposure and TRAP pre-exposure of participants. PMID- 27776228 TI - Chemical composition and bioaccumulation ability of Boletus badius (Fr.) Fr. collected in western Poland. AB - : The aim of the study was to determine content of 17 elements (Co, Cd, Cu, Cr, Ni, Pb, Zn, Mn, Fe, Mg, Na, Ca, K, N, C, S and P) and their bioaccumulation factors (BCF) in bay bolete (Boletus badius (Fr.) Fr.) fruiting bodies (caps and stalks) and underneath soil samples collected from forest sites in lubuskie voivodeship in Poland. Forty-eight samples of Boletus badius (Fr.) Fr. fruiting bodies and the same number of underneath soil substrate samples were collected in forest sites of Sulecin Forest District in western Poland. Copper and zinc were absorbed most strongly from soil substrate, which is performed by bioaccumulation factors (BCFCap/Soil = 16.57 and 11.60, respectively), wherein Pb, Co, Cr, Fe and Mn were excluded from bioaccumulation (BCF < 1.0). The mean content of Cd in caps and stalks was 1.44 +/- 0.88 and 2.01 +/- 1.26 mg kg-1 dry weight, respectively and in contrary to Pb (~3.00 +/- 2.66 and 2.01 +/- 1.26 mg kg-1 d. w.) this metal is strongly accumulated from subsoil (BCFCap/Soil = 11.12 and BCFStipe/Soil = 10.83). The fruiting bodies of Boletus badius were distinguished by elevated content of Cr, Zn, Pb and Cd. Few statistically significant metal-to-metal correlations were observed. The correlation between forest habitat types and metals concentrations was also analysed. An attempt of estimation of Pb and Cd safe dose for human consumption was made. IN CONCLUSION: mushrooms can be a good source of some micro- and macroelements, but they also contain a great amount of toxic heavy metals. PMID- 27776229 TI - A novel forward osmosis system in landfill leachate treatment for removing polycyclic aromatic hydrocarbons and for direct fertigation. AB - Landfill leachate (LL) is harmful to aquatic environment because it contains high concentrations of dissolved organic matter, inorganic components, heavy metals, and other xenobiotics. Thus, the remediation of LL is crucial for environmental conservation. Here, a potential application of the forward osmosis (FO) filtration process with ammonium bicarbonate (NH4HCO3) as a draw solution (DS) was investigated to remediate membrane bioreactor-treated LL (M-LL). After the leachate treatment, the toxicity and removal efficiencies of polycyclic aromatic hydrocarbons (PAHs) were evaluated using zebrafish and cultured human cells. The water recovery rate was improved using the current protocol up to 86.6% and 91.6% by both the pressure retarded osmosis (PRO) mode and the forward osmosis (FO) mode. Water flux increased with the increasing DS concentrations, but solution velocities decreased with the operation time. Toxicity tests revealed that the M LL treated by NH4HCO3 had no toxic effect on zebrafish and human cells. Moreover, green fluorescent protein (GFP) expression in the transgenic zebrafish Tg(cyp1a:gfp) induced by PAHs was very weak compared to the effects induced by untreated M-LL. Since the diluted DS met local safety requirements of liquid fertilizer, it could be directly applied as the liquid fertilizer for fertigation. In conclusion, this novel FO system using NH4HCO3 as the DS provides a cheap and efficient protocol to effectively remove PAHs and other pollutants in LL, and the diluted DS can be directly applied to crops as a liquid fertilizer, indicating that this technique is effective and eco-friendly for the treatment of different types of LL. PMID- 27776227 TI - Analysis of perfluorinated compounds in human serum from the general population in Shanghai by liquid chromatography-tandem mass spectrometry (LC-MS/MS). AB - Perfluorinated compounds (PFCs) have potential health risk to human. In this paper, human serum samples collected from Jiading District, Shanghai aged from 23 to 87 years old (12 male and 33 female) were analyzed for 17 perfluorinated compounds (PFCs). A novel method for the elimination of background contamination of perfluorooctanoic acid (PFOA) generated from instrument by the modification of high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has also been developed and validated. The limit of detection (LOD) for all monitored PFCs range from 0.02 to 0.18 ng mL-1. The limit of quantitation (LOQ) for PFOS and PFOA was 2.23 and 1.60 ng mL-1, respectively, and for other PFCs it ranged from 0.04 to 0.88 ng mL-1. Of the 17 PFCs analyzed in Shanghai serum, eleven were found. The dominating PFCs in all samples were perfluorooctanesulfonate (PFOS) and PFOA with a fraction of 49.5%, 34.2%, respectively. The median total concentration of each serum samples was 53.43 ng mL-1 with a range from =19h was associated with a greater likelihood of abstinence at the 4 and 12 week post-quit visits (aOR=1.81, 95% CI:1.01-3.22; aOR=2.18, 95% CI:1.03-4.63). CONCLUSIONS: Greater adherence to the nicotine patch early in a quit attempt may increase the likelihood of smoking cessation among socioeconomically disadvantaged adults. PMID- 27776248 TI - Protein-protein interaction and molecular dynamics analysis for identification of novel inhibitors in Burkholderia cepacia GG4. AB - The lack of complete treatments and appearance of multiple drug-resistance strains of Burkholderia cepacia complex (Bcc) are causing an increased risk of lung infections in cystic fibrosis patients. Bcc infection is a big risk to human health and demands an urgent need to identify new therapeutics against these bacteria. Network biology has emerged as one of the prospective hope in identifying novel drug targets and hits. We have applied protein-protein interaction methodology to identify new drug-target candidates (orthologs) in Burkhloderia cepacia GG4, which is an important strain for studying the quorum sensing phenomena. An evolutionary based ortholog mapping approach has been applied for generating the large scale protein-protein interactions in B. Cepacia. As a case study, one of the identified drug targets; GEM_3202, a NH (3) dependent NAD synthetase protein has been studied and the potential ligand molecules were screened using the ZINC database. The three dimensional structure (NH (3)-dependent NAD synthetase protein) has been predicted from MODELLERv9.11 tool using multiple PDB templates such as 3DPI, 2PZ8 and 1NSY with sequence identity of 76%, 50% and 50% respectively. The structure has been validated with Ramachandaran plot having 100% residues of NadE in allowed region and overall quality factor of 81.75 using ERRAT tool. High throughput screening and Vina resulted in two potential hits against NadE such as ZINC83103551 and ZINC38008121. These molecules showed lowest binding energy of -5.7kcalmol-1 and high stability in the binding pockets during molecular dynamics simulation analysis. The similar approach for target identification could be applied for clinical strains of other pathogenic microbes. PMID- 27776247 TI - Delay discounting in opioid use disorder: Differences between heroin and prescription opioid users. AB - BACKGROUND: Among those with opioid use disorder, heroin use is associated with poorer prognosis relative to use of prescription opioids alone. However, relatively little is known about distinguishing features between those who use heroin relative to those who use prescription opioids. In the present study we evaluated differences in delay discounting in those with opioid use disorder based on primary opioid of use. Delay discounting is associated with a range of negative outcomes and is an important therapeutic target in this population. METHODS: Treatment-seeking adults with opioid dependence completed self-report measures including past-month opioid use and the Monetary Choice Questionnaire (Kirby and Marakovic, 1996; Kirby et al., 1999), a measure of delay discounting. Participants were divided into two groups based on whether they used any heroin in the past 30days or only prescription opioids, and delay discounting scores were compared between the groups. Group differences in sociodemographic or clinical variables were included in the analysis as covariates. RESULTS: Results from a forward stepwise linear regression indicated that heroin use was associated with significantly higher delay discounting (B=-0.99, SEB=0.34, t= 2.88, p=0.005), even when considering covariates. CONCLUSIONS: Adults with opioid dependence who exclusively used prescription opioids had lower delay discounting relative to those who used heroin. This finding contributes further to the literature suggesting that heroin use is associated with greater clinical severity among those with opioid use disorder. PMID- 27776249 TI - Non-thyroidal illness syndrome in patients with cardiovascular diseases: A systematic review and meta-analysis. AB - BACKGROUND: Non-thyroidal illness syndrome (NTIS) is characterized by decreased serum triiodothyronine level without increased thyroid-stimulating hormone level during critical illness. The summary data on the prevalence of NTIS in cardiovascular patients are lacking, and its prognostic role in cardiovascular patients is also unclear. METHODS: We performed a systematic review and meta analysis to comprehensively determine the prevalence and the prognostic role of NTIS in cardiovascular patients. The prevalence of NTIS was pooled using random effect meta-analysis and the hazard ratios (HRs) for all-cause mortality, cardiac mortality and major adverse cardiovascular events (MACE) were also pooled. RESULTS: Forty-one studies were finally included. The pooled prevalence of NTIS in cardiovascular patients was 21.7% (95% CI 18.4%-25.3%). Subgroup by the types of cardiovascular diseases showed the prevalence of NTIS was highest in patients with heart failure (24.5%), followed by acute myocardial infarction (18.9%) and acute coronary syndrome (17.1%). Meta-analysis of studies using strict diagnostic criteria of NITS showed that the pooled prevalence of NTIS in cardiovascular patients was 17.6% (95% CI 14.5%-21.2%). NTIS was independently associated with increased risks of all-cause mortality (HR=2.52, 95% CI 1.87-3.40, P<0.001) and cardiac mortality (HR=2.06, 95% CI 1.58-2.69, P<0.001) in cardiovascular patients. NTIS was also an independent predictor of MACE in cardiovascular patients (HR=1.73, 95% CI 1.32-2.26, P<0.001). CONCLUSION: NTIS is very common in patients with cardiovascular diseases. NTIS is an independent prognostic factor in cardiovascular patients and is associated with increased risks of all-cause mortality, cardiac mortality and MACE. PMID- 27776250 TI - Atrial fibrillation in highly trained endurance athletes - Description of a syndrome. AB - Atrial fibrillation (AF) is the most common heart arrhythmia, the risk of which typically increases with age. This condition is commonly associated with major cardiovascular diseases and structural heart damage, while it is rarely observed in healthy young people. However, increasing evidence indicates that paroxysmal AF can also onset in young or middle-aged and otherwise healthy endurance athletes (e.g., cyclists, runners and cross-country skiers). Here we review the topic of AF associated with strenuous endurance exercise (SEE), for example cycling, running and cross-country skiing, especially at a competitive level, and we propose the definition of a new syndrome based on the accumulating data in the literature: SEE-related AF under the acronym of 'PAFIYAMA' ('paroxysmal AF in young and middle-aged athletes'). Special emphasis is given to the proper differentiation of PAFIYAMA from 'classical AF' regarding pathophysiology, diagnosis and medical management. PMID- 27776252 TI - The role of spinal interleukin-1beta and astrocyte connexin 43 in the development of mirror-image pain in an inflammatory pain model. AB - Although we have recently demonstrated that carrageenan-induced inflammation upregulates the expression of spinal interleukin (IL)-1beta, which inhibits spinal astrocyte activation and results in the delayed development of Mirror Image Pain (MIP), little is known regarding the mechanisms that underlie how spinal IL-1beta inhibits the astrocyte activation. In this study, we examined the effect of spinal IL-1beta on astrocyte gap junctions (GJ) and the development of MIP. Following unilateral carrageenan (CA) injection, mechanical allodynia (MA) was evaluated at various time points. Immunohistochemistry and Western blot analysis were used to determine changes in the expression of GFAP and connexins (Cx) in the spinal cord dorsal horn. Carrageenan rats showed a delayed onset of contralateral MA, which mimicked the temporal expression pattern of spinal Cx43 (an astrocyte gap junctional protein) and GFAP. Intrathecal administration of an interleukin-1 receptor antagonist (IL-1ra) twice-a-day on post-carrageenan injection days 0 to 3 caused a significant increase in contralateral MA and spinal Cx43 and GFAP expression. In addition, co-administration of IL-1beta with IL-1ra blocked the IL-1ra-induced increase in contralateral MA and the upregulated expression of spinal Cx43 and GFAP. Finally, co-administration of carbenoxolone (CBX; a GJ decoupler) or Gap26 (a specific Cx43 mimetic blocking peptide) with IL-1ra significantly blocked the IL-1ra-induced early development of contralateral MA and the associated upregulation of spinal Cx43 and GFAP expression. These results demonstrate that spinal IL-1beta suppresses Cx43 expression and astrocyte activation during the early phase of CA-induced inflammation resulting in the delayed onset of contralateral MA. These findings imply that spinal IL-1beta can inhibit astrocyte activation and regulate the time of induction of contralateral MA through modulation of spinal Cx43 expression. PMID- 27776251 TI - The effects of exenatide twice daily compared to insulin lispro added to basal insulin in Latin American patients with type 2 diabetes: A retrospective analysis of the 4B trial. AB - AIMS: Socioeconomic changes in Latin American countries have led to an increased prevalence of type 2 diabetes (T2D). We examined the effects of exenatide twice daily (BID) or insulin lispro, each added to insulin glargine, in Latin American patients with T2D. METHODS: This was a subgroup analysis of patients from Argentina and Mexico in the 4B study (N=114). Patients with glycated hemoglobin (HbA1c) of 7.0-10.0% (53-86mmol/mol) after 12weeks of intensive basal insulin optimization were randomized to exenatide BID or thrice-daily insulin lispro added to insulin glargine and metformin. RESULTS: After 30weeks, addition of exenatide BID or insulin lispro resulted in significant (P<0.0001) reductions in HbA1c (exenatide BID: -0.9% [-10mmol/mol]; insulin lispro: -1.2% [-13mmol/mol]). Weight was stable in the exenatide BID group (-0.1kg) and increased significantly (+3.4kg; P<0.0001) with insulin lispro. Major and minor hypoglycemia occurred less frequently (40 vs. 253 events) with exenatide BID compared with insulin lispro. Gastrointestinal adverse events of nausea, diarrhea, and vomiting occurred more frequently with exenatide BID than with insulin lispro. CONCLUSIONS: Both exenatide BID and prandial insulin lispro, each added to basal insulin glargine, were effective at reducing HbA1c in Latin American patients. Treatment with exenatide BID resulted in stable weight but more gastrointestinal adverse events. Treatment with insulin lispro resulted in weight gain and an increased risk of hypoglycemia. These findings support the addition of exenatide BID to insulin glargine as an option for Latin American patients unable to achieve glycemic control on basal insulin alone. PMID- 27776253 TI - Only minor changes in thrombin generation of children and adolescents with type 1 diabetes mellitus - A case-control study. AB - BACKGROUND: Micro- and macrovascular diseases are frequent complications in patients with diabetes. Hypercoagulability may contribute to microvascular alterations. OBJECTIVE: In this study, we investigated whether type 1 diabetes in children is associated with a hypercoagulable state by performing a global function test of coagulation - the thrombin generation assay. SUBJECTS: 75 patients with type 1 diabetes aged between 2 and 19years were compared to an age matched healthy control group. Diabetes patients were divided into high-dose and low-dose insulin cohorts with a cut-off at 0.8Ukg-1d-1. METHODS: Measurements were performed with platelet poor plasma using Calibrated Automated Thrombography and 1 pM or 5 pM tissue factor. Additionally, we quantified prothrombin fragments F1+2, thrombin-antithrombin complex, prothrombin, tissue factor pathway inhibitor, and antithrombin. RESULTS: Patients with type 1 diabetes exhibited a significantly shorter of lag time as well as decreased thrombin peak and endogenous thrombin potential compared to control subjects with 5 pM but not with 1 pM tissue factor. In high-dose insulin patients peak thrombin generation was higher and time to peak shorter than in low-dose patients. Thrombin-antithrombin complex was decreased in patients with type 1 diabetes, whereas prothrombin fragments F1+2 was comparable in both groups. Thrombin generation parameters did not correlate with parameters of metabolic control and the duration of diabetes. CONCLUSIONS: Taken together, we found only minor changes of thrombin generation in children and adolescents with type 1 diabetes which - in contrast to type 2 diabetes - do not argue for a hypercoagulable state. PMID- 27776255 TI - Does the measure matter? On the association between disgust proneness and OCD symptoms. AB - Although some studies suggest that the association between disgust proneness (DP) and obsessive-compulsive symptoms (OCS) is specific to the contamination subtype, others suggest that DP is associated with OCS more broadly. To examine if the discrepant findings may partially reflect differences in self-report measures used, this investigation employed structural equation modeling to examine the association between DP and OCS in three samples that completed different combinations of measures of DP, OCS, and anxiety/negative affect. In Study 1 (n=626), the path from DP to contamination-based OCS was significantly stronger than the path from DP to non-contamination OCS when controlling for anxiety sensitivity. In Study 2 (n=403), the results showed that the path from DP to contamination-based OCS did not significantly differ from the path from DP to non contamination OCS when controlling for negative affect. Lastly, Study 3 (n=296) showed that the path from DP to contamination-based OCS was significantly weaker than the path from DP to non-contamination OCS. These findings highlight that the self-report measures employed is an important moderator when making inferences about the association between DP and contamination-based OCS and non contamination OCS. PMID- 27776254 TI - Concentrations of arsenic, cadmium and lead in human hair and typical foods in eleven Chinese cities. AB - Concentrations of arsenic (As), cadmium (Cd) and lead (Pb) were determined in 384 human hair samples and 445 purchased food samples from 11 cities in China. The mean concentrations of hair As, Cd and Pb were 0.23, 0.062 and 2.45mgkg-1, respectively. The As, Cd and Pb concentrations in different foods were lower than the national maximum allowable contaminant levels. By comparison, males had higher hair As concentrations but lower Cd concentrations than females. When the interaction effects of gender and age were considered, males had the higher hair As, Cd and Pb concentrations in the 51-65 year-old age group. Residents of rural areas had higher hair As, Cd and Pb concentrations than people living in urban areas. Further analysis indicates that hair As, Cd and Pb concentrations and their changes with biological and environmental factors cannot be satisfactorily explained by the estimated intakes from purchased food. PMID- 27776256 TI - An initial psychometric assessment of an ICD-11 based measure of PTSD and complex PTSD (ICD-TQ): Evidence of construct validity. AB - Among the conditions following exposure to traumatic life events proposed by ICD 11 are Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD). The primary aim of this study was to provide an assessment of the reliability and validity of a newly developed self-report measure of ICD-11 PTSD and CPTSD: the ICD-11 Trauma Questionnaire (ICD-TQ). Participants in this study were a sample of individuals who were referred for psychological therapy to a National Health Service (NHS) trauma centre in Scotland (N=193). Participants completed the ICD-TQ and measures of traumatic life events, DSM-5 PTSD, emotion dysregulation, self-esteem, and interpersonal difficulties. Confirmatory factor analysis results supported the factorial validity of the ICD-TQ with results in line with ICD-11 proposals. The ICD-TQ demonstrated satisfactory internal reliability, and correlation results indicated that the scale exhibited convergent and discriminant validity. Current results provide initial support for the psychometric properties of this initial version of the ICD-TQ. Future theoretical and empirical work will be required to generate a final version of the ICD-TQ that will match the diagnostic structure of PTSD and CPTSD when ICD-11 is published. PMID- 27776257 TI - Fatal coronary sinus thrombosis due to hypercoagulability in Crohn's disease. AB - A 27-year-old male, admitted to hospital for a psoas muscle abscess secondary to Crohn's disease, suddenly died while in hospital. A medicolegal autopsy showed coronary sinus thrombosis. Coronary sinus thrombosis is rare and is usually associated with invasive cardiac procedures. Coronary sinus thrombosis associated with Crohn's disease has not been reported. Autopsy examination of the coronary sinus is advocated, especially in individuals with hypercoagulable states. PMID- 27776259 TI - Photo-catalytic polymerization of catechin molecules in alkaline aqueous. AB - Polyphenols are associated with a wide range of physiological properties. Catechin is a flavan-3-ol with five phenolic hydroxyl groups. After blue light illumination, the transparent solution of catechin became yellowish. The effects of visible light illumination (400-800nm) were investigated on molecular structures and antioxidant capacities of catechin. Under the neutral or alkaline aqueous with the illumination of blue light, the photolysis and polymerization of catechin were observed in this study. A chromogenic catechin dimer was separated and identified as a proanthocyanidin by the chromatographic technique and mass spectrometry. For quantitative evaluation, the signal intensities of the catechin and the photochemical product show a negative correlation in the liquid chromatograms. The oligomer of flavan-3-ols (catechin dimer) is suggested as a dimeric B type proanthocyanidin, which has the molecular formula C30H26O12 and 578.14g/mol in exact mass. The mass spectrum of catechin dimer had characteristic ion signals in m/z 577, 560, 439Da. However, the total phenolic contents and scavenging O2- activity of catechin treated by blue light illumination are not changed significantly at the neutral or alkaline aqueous. Our results of photocatalytic oligomers of catechin provide a novel way to explain the sensory changes of green tea and a biochemical mechanism under the irradiation environments. PMID- 27776258 TI - Atherosclerosis of aberrant arteries from the left gastric artery into the right intralobar pulmonary sequestration complicated by mycobacterial epithelioid cell granuloma. AB - Vascular changes observed in intralobar pulmonary sequestration (PS) have been reported to be similar to those observed in pulmonary hypertension (PH). However, atherosclerosis in the pulmonary artery, which is one of the characteristic arterial changes of PH, has scarcely been reported in PS. Here, we report this unique manifestation in a 66-year-old man, in whom an intralobar PS fed by an aberrant artery branching from the left gastric artery had been identified 10 years earlier, and who was diagnosed with pneumonia after having symptoms of fever and cough. He was treated by lobectomy of the lower lobe of his right lung. Subsequently, a culture test of the fluid from the sequestrated lung was performed, which identified Mycobacterium avium. Subsequent pathological examination of the sequestrated lung demonstrated multiple epithelioid cell granulomas. Furthermore, atherosclerosis of the aberrant artery was also found, which may be associated with his advanced age. This is an extremely rare case of right intralobar PS supplied by aberrant artery with atherosclerosis originating from left gastric artery passing over the diaphragm. PMID- 27776260 TI - Studies on the efficient dual performance of Mn1-xNixFe2O4 spinel nanoparticles in photodegradation and antibacterial activity. AB - The present work describes the successful synthesize of spinel magnetic ferrite Mn1-xNixFe2O4 (x=0.0, 0.1, 0.2, 0.3, 0.4 & 0.5) nanoparticles via a simple microwave combustion method which was then evaluated for its photocatalytic activity in the degradation of indigo carmine (IC) synthetic dye, a major water pollutant. Our results reveal that the synthesized of Ni2+ doped MnFe2O4 nanoparticles possess well-crystalline pure cubic spinel phase, exhibit excellent optical and magnetic properties. Further, the photocatalytic performance of the synthesized nanoparticles at different concentration ratios of Ni2+ ions was monitored by photocatalytic degradation of indigo carmine synthetic dye under UV (lambda=365nm) light irradiation. In order to get maximum photocatalytic degradation (PCD) efficiency, we have optimized various parameters, which include catalyst dosage, initial dye concentration, pH and Ni2+ dopant content. It was found that the reaction was facilitated with optimum catalyst dose of 50mg/100mL, high dye concentrations of 150mg/L and acidic pH and among all the synthesized samples, Mn0.5Ni0.5Fe2O4 exhibit superior performance of photocatalytic activity on the degradation of indigo carmine synthetic dye. These results highlighted the potential use of effective, low-cost and easily available photocatalysts for the promotion of wastewater treatment and environmental remediation. In addition, the antibacterial activity of spinel magnetic Mn1-xNixFe2O4 nanoparticles against two Gram positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram negative bacteria (Pseudomonas aeruginosa and Escherichia coli) was also examined. Our antibacterial activity results are comparable with the results obtained using the antibiotic, streptomycin. PMID- 27776261 TI - Biosynthesis of palladium nanoparticles by using Moringa oleifera flower extract and their catalytic and biological properties. AB - The biosynthesis of nanostructured biopalladium nanoparticles (PdNPs) from an aqueous solution of crystalline palladium acetate is reported. For the synthesised PdNPs in solution, an agroforest biomass waste petal of Moringa oleifera derived bis-phthalate was used as natural reducing and biocapping agents. Continuous absorption in the UV region and subsequent brown colour change confirmed the formation of PdNPs. A strong surface plasmon peak for PdNPs occurred at 460nm. PdNPs were characterized by SEM with EDX, FTIR, TEM and DLS. The chemical composition of the aqueous extract was determined by GC-MS coupled with FTIR and 1NMR. The catalytic degradation effect by PdNPs on industrial organic toxic effluents p-nitrophenol (PNP) and methylene blue dye was monitored by UV Spectroscopy. On the other hand PdNPs catalysed the base mediated suzuki coupling reaction for biphenyl synthesis, in water. Moreover, PdNPs were found to be reusable catalysts. Toxicity studies of PdNPs showed that the death of brine shrimp to be <50%. Therefore, PdNPs displayed potential for further anticancer studies via tumour cell lines. The in vitro cytotoxicity evaluation of the extract capped nanoparticles was carried out using human lung carcinoma cells (A549) and peripheral lymphocytes normal cells by MTT cell viability assay. Also, PdNPs showed antibacterial activity against Enterococcus faecalis among the different tested strains, including Bacillus cereus, Staphylococcus aureus, Esherichia coli and Candida albicans, Candida utilis. PMID- 27776262 TI - Cortical gray and subcortical white matter associations in Parkinson's disease. AB - Cortical atrophy has been documented in both Parkinson's disease (PD) and healthy aging, but its relationship to changes in subcortical white matter is unknown. This was investigated by obtaining T1- and diffusion-weighted images from 76 PD and 70 controls at baseline and 18 and 36 months, from which cortical volumes and underlying subcortical white matter axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) were determined. Twelve of 69 cortical subregions had significant group differences, and for these, underlying subcortical white matter was explored. At baseline, higher cortical volumes were significantly correlated with lower underlying subcortical white matter AD, RD, and higher FA (ps <= 0.017) in PD. Longitudinally, higher rates of cortical atrophy in PD were associated with increased rates of change in AD RD, and FA values (ps <= 0.0013) in 2 subregions explored. The significant gray-white matter associations were not found in controls. Thus, unlike healthy aging, cortical atrophy and subcortical white matter changes may not be independent events in PD. PMID- 27776263 TI - Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. AB - The pathway leading from amyloid-beta deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer's disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1beta, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-alpha]; anti-inflammatory cytokines: IL-4, IL-10, IL 13) in cognitively impaired patients with (n = 40, Amy+) and with no brain amyloidosis (n = 33, Amy-) and also in a group of controls (n = 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1beta) compared with both controls and with Amy- patients. A reduction of the anti-inflammatory cytokine IL 10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of E. rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC = -9.6, p < 0.001 and FC = +12.8, p < 0.001, respectively) and to Amy- (FC = -7.7, p < 0.001 and FC = +7.4, p = 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1beta, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho = 0.60, p < 0.001; rho = 0.57, p < 0.001; and rho = 0.30, p = 0.007, respectively) and a negative correlation with the anti-inflammatory E. rectale (rho = -0.48, p < 0.001; rho = -0.25, p = 0.024; rho = -0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation. PMID- 27776264 TI - Memory-related white matter tract integrity in amyotrophic lateral sclerosis: an advanced neuroimaging and neuropsychological study. AB - We aimed to investigate structural changes in vivo in memory-related white matter tracts (i.e., perforant pathway zone [PPZ]; uncinate fasciculus [UF]; fornix) using diffusion tensor tractography and evaluate possible associations with memory performance in nondemented patients with amyotrophic lateral sclerosis (ALS). Forty-two ALS patients and 25 healthy controls (HCs) underwent a 30 directional diffusion-weighted imaging on a 3T MR scanner, followed by tractography of PPZ, UF, and fornix and analysis of fractional anisotropy (FA), axial diffusivity and radial diffusivity (Dr). Patients were administered neuropsychological measures of verbal (list learning via Rey Auditory Verbal Learning Test [RAVLT] and prose memory via Babcock Story Recall Test) and nonverbal (Rey's Complex Figure Test) episodic memory. After correcting for multiple comparisons, ALS patients showed increased Dr in the left PPZ compared to HC. We then fitted a multivariate general linear model within ALS patients with neuropsychological measures as dependent variables and age, age2, gender, verbal IQ, and diffusion tensor tractography metrics with at least medium effect size differences between ALS and HC as independent variables. We found that (1) left PPZ FA, gender, and verbal IQ contributed to RAVLT-Total Learning; (2) left PPZ FA, left UF Dr, and gender contributed to RAVLT-Immediate Recall; and (3) left PPZ FA and left UF axial diffusivity contributed to Babcock Story Recall Test-Immediate and Delayed Recall. Advanced neuroimaging techniques verified in this study previously reported neuropathological findings regarding PPZ degeneration in ALS. We also detected a unique contribution of microstructural changes in hippocampal and frontotemporal white matter tracts on patients' memory profile. PMID- 27776265 TI - Epigenetic regulation of estrogen receptor alpha contributes to age-related differences in transcription across the hippocampal regions CA1 and CA3. AB - The expression of estrogen receptor alpha (ERalpha) varies across brain regions and changes with age and according to the previous history of estradiol exposure. ERalpha is regulated by a number of mechanisms including the level of mRNA (Esr1) expression. For this study, we took advantage of regional differences in hippocampal ERalpha expression to investigate DNA ERalpha promoter methylation at CpG dinucleotide sites as a potential epigenetic mechanism for regulating gene expression. Young and aged female Fischer 344 rats were ovariectomized, and Esr1 expression and ERalpha promoter methylation were examined in hippocampal regions CA1 and CA3, either 3 or 14 weeks following surgery. The results indicate that reduced Esr1 expression in region CA1 relative to CA3 was associated with an increase in DNA methylation in region CA1, particularly for the first CpG site. Additionally, differential methylation of distal CpG sites, 11-17, was associated with altered Esr1 expression during aging or following long-term hormone deprivation. The results support the idea that methylation of site 1 may be the primary regulatory region for cross-regional patterns in ERalpha expression, while distal sites are modifiable across the life span and may act as a feedback mechanism for ERalpha activity. PMID- 27776267 TI - Facebook dethroned: Revealing the more likely social media destinations for college students' depictions of underage drinking. AB - Studies examining representations of college drinking on social media have almost exclusively focused on Facebook. However, recent research suggests college students may be more influenced by peers' alcohol-related posts on Instagram and Snapchat, two image-based platforms popular among this demographic. One potential explanation for this differential influence is that qualitative distinctions in the types of alcohol-related content posted by students on these three platforms may exist. Informed by undergraduate focus groups, this study examined the hypothesis that, of the three platforms, students tend to use Instagram most often for photos glamourizing drinking and Snapchat for incriminating photos of alcohol misuse and negative consequences. Undergraduate research assistants aided investigators in developing hypothetical vignettes and photographic examples of posts both glamorizing and depicting negative consequences associated with college drinking. In an online survey, vignette and photo stimuli were followed by counterbalanced paired comparisons that presented each possible pair of social media platforms. Undergraduates (N=196) selected the platform from each pair on which they would be more likely to see each post. Generalized Bradley-Terry models examined the probabilities of platform selections. As predicted, Instagram was seen as the most probable destination (and Facebook least probable) for photos depicting alcohol use as attractive and glamorous. Conversely, Snapchat was selected as the most probable destination (and Facebook least probable) for items depicting negative consequences associated with heavy drinking. Results suggest researchers aiming to mitigate the potential influences associated with college students' glamorous and consequential alcohol-related photos posted social media posts should shift their focus from Facebook to Instagram and Snapchat. PMID- 27776266 TI - Abeta vaccination in combination with behavioral enrichment in aged beagles: effects on cognition, Abeta, and microhemorrhages. AB - Beta-amyloid (Abeta) immunotherapy is a promising intervention to slow Alzheimer's disease. Aging dogs naturally accumulate Abeta and show cognitive decline. An active vaccine against fibrillar Abeta 1-42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain Abeta. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in Abeta. We hypothesized cognitive outcomes could be improved by combining VAC with ENR in aged dogs. Aged dogs (11-12 years) were placed into 4 groups: (1) control/control (C/C); (2) control/VAC (C/V); (3) ENR/control (E/C); and (4) ENR/VAC (E/V) and treated for 20 months. VAC decreased brain Abeta, pyroglutamate Abeta, increased cerebrospinal fluid Abeta 42 and brain-derived neurotrophic factor RNA levels but also increased microhemorrhages. ENR reduced brain Abeta and prevented microhemorrhages. The combination treatment resulted in a significant maintenance of learning over time, reduced Abeta, and increased brain derived neurotrophic factor mRNA despite increased microhemorrhages; however, there were no benefits to memory. These results suggest that the combination of immunotherapy with behavioral enrichment leads to cognitive maintenance associated with reduced neuropathology that may benefit people with Alzheimer's disease. PMID- 27776268 TI - Is the Gambling Motives Questionnaire really three-dimensional? A proposition of a four-dimensional Gambling Motives Questionnaire - Revised. AB - The aim of the present study was to improve the weaknesses of the three dimensional Gambling Motives Questionnaire and to examine the psychometric properties and factor structure of the Gambling Motives Questionnaire-Revised. The Gambling Motives Questionnaire was administered to a sample of 418 gamblers (92% men, mean age 19.5years). Participants completed the Gambling Motives Questionnaire and an additional item tapping boredom, as well as a variety of measures of gambling behavior and gambling problems as criterion measures. Results showed that the Gambling Motives Questionnaire-Revised is better represented as a four-factor structure tapping the following four gambling motives factors; enhancement, coping, social, and self-gratification, Deltachi2 Delta(df)=24.76 (3), p<0.001. Removing two problematic items from the Gambling Motives Questionnaire and adding an extra item tapping boredom also improved the fit of the Gambling Motives Questionnaire-Revised. The subscales enhancement, social, and coping were all significant predictors of variety of gambling behaviors (p<0.05), whereas enhancement, coping, and self-gratification predicted frequency of gambling behaviors (p<0.01). Coping and self-gratification predicted loss of control (p<0.01), whereas self-gratification predicted gambling problems (p<0.001). The Gambling Motives Questionnaire - Revised, consisting of the four dimensions enhancement motives, social motives, coping motives and self gratification motives, is a reliable and valid instrument to measuring gambling motives. PMID- 27776270 TI - Validity and sensitivity of the longitudinal asymmetry index to detect gait asymmetry using Microsoft Kinect data. AB - Gait asymmetry information is a key point in disease screening and follow-up. Constant Relative Phase (CRP) has been used to quantify within-stride asymmetry index, which requires noise-free and accurate motion capture, which is difficult to obtain in clinical settings. This study explores a new index, the Longitudinal Asymmetry Index (ILong) which is derived using data from a low-cost depth camera (Kinect). ILong is based on depth images averaged over several gait cycles, rather than derived joint positions or angles. This study aims to evaluate (1) the validity of CRP computed with Kinect, (2) the validity and sensitivity of ILong for measuring gait asymmetry based solely on data provided by a depth camera, (3) the clinical applicability of a posteriorly mounted camera system to avoid occlusion caused by the standard front-fitted treadmill consoles and (4) the number of strides needed to reliably calculate ILong. The gait of 15 subjects was recorded concurrently with a marker-based system (MBS) and Kinect, and asymmetry was artificially reproduced by introducing a 5cm sole attached to one foot. CRP computed with Kinect was not reliable. ILong detected this disturbed gait reliably and could be computed from a posteriorly placed Kinect without loss of validity. A minimum of five strides was needed to achieve a correlation coefficient of 0.9 between standard MBS and low-cost depth camera based ILong. ILong provides a clinically pragmatic method for measuring gait asymmetry, with application for improved patient care through enhanced disease, screening, diagnosis and monitoring. PMID- 27776269 TI - Coping strategies as a mediator of internet-delivered psychosocial treatment: Secondary analysis from a NIDA CTN multisite effectiveness trial. AB - OBJECTIVE: Coping strategies are a predictor of abstinence among patients with substance use disorders. However, little is known regarding the role of coping strategies in the effectiveness of the Community Reinforcement Approach (CRA). Using data from a 12week randomized control trial assessing the effectiveness of the Therapeutic Education System (TES), an internet-delivered version of the CRA combined with contingency management, we tested the role of coping strategies as a mediator of treatment effectiveness. METHODS: 507 participants entering 10 outpatient addiction treatment programs received either treatment-as-usual (TAU), a counselor-delivered treatment (Arm 1), or reduced TAU plus TES wherein 2h of TAU per week were replaced by TES (Arm 2). Abstinence from drugs and alcohol was evaluated using urine toxicology and self-report. Coping strategies were measured using the Coping Strategies Scale-Brief Version. Mediation analyses were done following Baron and Kenny's and path analysis approaches. RESULTS: The average baseline coping strategies scores were not significantly different between the two treatment arms. Overall, TES intervention was significantly associated with higher coping strategies scores when accounting for baseline scores (F1,1342=8.3, p=0.004). Additionally, higher coping strategies scores at week 12 were associated with an increased likelihood of abstinence during the last 4weeks of the treatment, while accounting for treatment assignment and baseline abstinence. The effect of TES intervention on abstinence was no longer significant after controlling for coping strategies scores at week 12. CONCLUSION: Our results support the importance of coping skills as a partial mediator of the effectiveness of an internet-version of the CRA combined with contingency management. PMID- 27776271 TI - Gait Profile Score in multiple sclerosis patients with low disability. AB - BACKGROUND: Gait abnormalities are subtle in multiple sclerosis (MS) patients with low disability and need to be better determined. As a biomechanical approach, the Gait Profile Score (GPS) is used to assess gait quality by combining nine gait kinematic variables in one single value. This study aims i) to establish if the GPS can detect gait impairments and ii) to compare GPS with discrete spatiotemporal and kinematic parameters in low-disabled MS patients. METHOD: Thirty-four relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score <=2 (mean age 36.32+/-8.72 years; 12 men, 22 women; mean EDSS 1.19+/-0.8) and twenty-two healthy controls (mean age 36.85+/-7.87 years; 6 men, 16 women) matched for age, weight, height, body mass index and gender underwent an instrumented gait analysis. RESULTS: No significant difference in GPS values and in spatiotemporal parameters was found between patients and controls. However patients showed a significant alteration at the ankle and pelvis level. CONCLUSION: GPS fails to identify gait abnormalities in low-disabled MS patients, although kinematic analysis revealed subtle gait alterations. Future studies should investigate other methods to assess gait impairments with a gait score in low-disabled MS patients. PMID- 27776272 TI - Mature Let-7 miRNAs fine tune expression of LIN28B in pluripotent human embryonic stem cells. AB - MicroRNAs (miRNA) are central regulators of diverse biological processes and are important in the regulation of stem cell self-renewal. One of the widely studied miRNA-protein regulators is the Lin28-Let-7 pair. In this study, we demonstrate that contrary to the well-established models of mouse ES cells (mESC) and transformed human cancer cells, the pluripotent state of human ES cells (hESC) involves expression of mature Let-7 family miRNAs with concurrent expression of all LIN28 proteins. We show that mature Let-7 miRNAs are regulated during hESC differentiation and have opposite expression profile with LIN28B. Moreover, mature Let-7 miRNAs fine tune the expression levels of LIN28B protein in pluripotent hESCs, whereas silencing of LIN28 proteins have no effect on mature Let-7 levels. These results bring novel information to the highly complex network of human pluripotency and suggest that maintenance of hESC pluripotency differs greatly from the mESCs in regard to LIN28-Let-7 regulation. PMID- 27776273 TI - IGFBP-2 and -3 co-ordinately regulate IGF1 induced matrix mineralisation of differentiating human dental pulp cells. AB - Human dental pulp cells (DPCs), which are known to contain a subset of stem cells capable of reforming a dentin and pulp-like complex upon in vivo transplantation, were isolated from third molars of three healthy donors and differentiated to a matrix mineralisation phenotype using by culture in dexamethasone and l-ascorbic acid. qRT-PCR analysis of insulin-like growth factor ( IGF) axis gene expression indicated that all genes, except insulin-like growth factor 1 (IGF1) and insulin like growth factor binding protein-1 ( IGFBP-1), were expressed in DPCs. During differentiation upregulation of insulin-like growth factor binding protein-2 (IGFBP-2) and downregulation of insulin-like growth factor binding protein-3 (IGFBP-3) expression was observed. Changes in IGFBP-2 and IGFBP-3 mRNA expression were confirmed at the protein level by ELISA of DPC conditioned medium functional analysis indicated that IGF1 stimulated the differentiation of DPCs and that the activity of the growth factor was enhanced by pre-complexation with IGFBP-2 but inhibited by pre-complexation with IGFBP-3. Therefore changes in IGFBP-2 and -3 expression during differentiation form part of a co-ordinated functional response to enhance the pro-differentiative action of IGF1 and represent a novel mechanism for the regulation of DPC differentiation. PMID- 27776274 TI - Discovery, structure-activity relationship studies, and anti-nociceptive effects of N-(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)benzamides as novel opioid receptor agonists. AB - MU-Opioid receptor (MOR) agonists are analgesics used clinically for the treatment of moderate to severe pain, but their use is associated with severe adverse effects such as respiratory depression, constipation, tolerance, dependence, and rewarding effects. In this study, we identified N-({2-[(4-bromo-2 trifluoromethoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-1 isoquinolinyl}methyl)cyclohexanecarboxamide (1) as a novel opioid receptor agonist by high-throughput screening. Structural modifications made to 1 to improve potency and blood-brain-barrier (BBB) penetration resulted in compounds 45 and 46. Compound 45 was a potent MOR/KOR (kappa-opioid receptor) agonist, and compound 46 was a potent MOR and medium KOR agonist. Both 45 and 46 demonstrated a significant anti-nociceptive effect in a tail-flick test performed in wild type (WT) B6 mice. The ED50 value of 46 was 1.059 mg/kg, and the brain concentrations of 45 and 46 were 7424 and 11696 ng/g, respectively. Accordingly, compounds 45 and 46 are proposed for lead optimization and in vivo disease-related pain studies. PMID- 27776276 TI - Band structure analysis of leaky Bloch waves in 2D phononic crystal plates. AB - A hybrid Finite Element-Plane Wave Expansion method is presented for the band structure analysis of phononic crystal plates with two dimensional lattice that are in contact with acoustic half-spaces. The method enables the computation of both real (propagative) and imaginary (attenuation) components of the Bloch wavenumber at any given frequency. Three numerical applications are presented: a benchmark dispersion analysis for an oil-loaded Titanium isotropic plate, the band structure analysis of a water-loaded Tungsten slab with square cylindrical cavities and a phononic crystal plate composed of Aurum cylinders embedded in an epoxy matrix. PMID- 27776275 TI - War and remembrance: Combat exposure in young adulthood and memory function sixty years later. AB - OBJECTIVE: Identifying adaptive ways to cope with extreme stress is essential to promoting long-term health. Memory systems are highly sensitive to stress, and combat exposure during war has been shown to have deleterious effects on cognitive processes, such as memory, decades later. No studies have examined coping styles used by combat veterans and associations with later-life cognitive functioning. Defenses are coping mechanisms that manage difficult memories and feelings, with some more closely related to memory processes (e.g., suppression, repression). Utilizing a longitudinal database, we assessed how reliance on certain defense mechanisms after World War II combat exposure could affect cognitive health 60years later. METHOD: Data spanning 75years were available on 71 men who had post-war assessment of combat exposure, defense mechanism ratings (ages 19-50), and late-life neuropsychological testing. Interaction models of combat exposure with defenses predicting late-life memory were examined. RESULTS: In bivariate analyses, greater reliance on suppression correlated with worse memory performance (r=-0.30, p=.01), but greater reliance on repression did not. Greater reliance on suppression strengthened the link between combat exposure and worse memory in late life (R2=0.24, p<.001). In contrast, greater reliance on repression attenuated the link between combat exposure and poorer late-life memory (R2=0.19, p<.001). CONCLUSIONS: Results suggest that coping styles may affect the relationship between early-adult stress and late-life cognition. Findings highlight the importance of understanding how coping styles may impact cognitive functioning as people move through adult life. PMID- 27776278 TI - A survey of extraction solvents in the forensic analysis of textile dyes. AB - The characterization and identification of dyes in fibers can be used to provide investigative leads and strengthen associations between known and questioned items of evidence. The isolation of a dye from its matrix (e.g., a textile fiber) permits detailed characterization, comparison and, in some cases, identification using methods such as thin layer chromatography in conjunction with infrared and Raman spectroscopy. A survey of dye extraction publications reveals that pyridine:water (4:3) is among the most commonly cited extraction solvent across a range of fiber and dye chemistries. Here, the efficacy of this solvent system has been evaluated for the extraction of dyes from 172 commercially prevalent North American textile dyes. The evaluated population represents seven dye application classes, 18 chemical classes, and spans nine types of commercial textile fibers. The results of this survey indicate that ~82% of the dyestuffs studied are extractable using this solvent system. The results presented here summarize the extraction efficacy by class and fiber type and illustrate that this solvent system is applicable to a wider variety of classes and fibers than previously indicated in the literature. While there is no universal solvent for fiber extraction, these results demonstrate that pyridine:water represents an excellent first step for extracting unknown dyes from questioned fibers in forensic casework. PMID- 27776277 TI - Interleukin-33 induces mucin gene expression and goblet cell hyperplasia in human nasal epithelial cells. AB - We investigated whether IL-33 is involved in mucus overproduction and goblet cell hyperplasia in eosinophilic chronic rhinosinusitis (ECRS). IL-33 mRNA was significantly higher in the eosinophilic CRS group than in the non-eosinophilic CRS group from human nasal polyps. IL-33 induced MUC5AC mRNA and MUC5AC protein, and also goblet cell hyperplasia at air liquid interface culture in human nasal epithelial cells. In addition to that, IL-33 induced MUC5B and FOXA3, and reduces FOXJmRNA. In conclusion, our present study demonstrated that the direct evidence of IL-33 which lead to increase mucin gene and protein expression, as well as goblet cell hyperplasia. This study provides novel insights into the role of IL 33 on mucus overproduction in eosinophilic inflammation of human airways. PMID- 27776279 TI - The role of body image psychological flexibility on the treatment of eating disorders in a residential facility. AB - OBJECTIVE: The purpose of this study was to test whether pre-treatment levels of psychological flexibility would longitudinally predict quality of life and eating disorder risk in patients at a residential treatment facility for eating disorders. METHOD: Data on body image psychological flexibility, quality of life, and eating disorder risk were collected from 63 adolescent and 50 adult, female, residential patients (N=113) diagnosed with an eating disorder. These same measures were again collected at post-treatment. Sequential multiple regression analyses were performed to test whether pre-treatment levels of psychological flexibility longitudinally predicted quality of life and eating disorder risk after controlling for age and baseline effects. RESULTS: Pre-treatment psychological flexibility significantly predicted post-treatment quality of life with approximately 19% of the variation being attributable to age and pre treatment psychological flexibility. Pre-treatment psychological flexibility also significantly predicted post-treatment eating disorder risk with nearly 30% of the variation attributed to age and pre-treatment psychological flexibility. DISCUSSION: This study suggests that levels of psychological flexibility upon entering treatment for an eating disorder longitudinally predict eating disorder outcome and quality of life. PMID- 27776280 TI - Development of self-report scales measuring collaborative vs. directive support: Assessing beliefs and behaviors in carers of adults with eating disorders. AB - Collaboration is more acceptable and likely to produce favorable outcomes when providing care to individuals with eating disorders compared to directive care. We developed two self-report instruments that assess the extent to which carers (e.g., family, friends) of individuals with eating disorders provide collaborative vs. directive support (Support Behaviors Scale; SBH) and the extent to which carers believe that such approaches are helpful (Support Beliefs Scale; SBL). Participants were mothers, fathers, partners, friends and siblings (N=141) of eating disorder patients in hospital or residential treatment. Confirmatory factor analyses were used to test measurement models comprising collaborative and directive approaches identified in previous research. A 19-item three-factor model exhibited best fit for each scale and included three distinct caregiving approaches: two that were collaborative (encouraging, concerned), and one that was directive. The scales exhibited acceptable internal consistency. Reported caregiving behaviors (SBH) were correlated with beliefs about caregiving (SBL). The scales can be used to assess caregiving stance and outcomes for interventions aimed at promoting collaboration in carers. PMID- 27776281 TI - Abstract knowledge versus direct experience in processing of binomial expressions. AB - We ask whether word order preferences for binomial expressions of the form A and B (e.g. bread and butter) are driven by abstract linguistic knowledge of ordering constraints referencing the semantic, phonological, and lexical properties of the constituent words, or by prior direct experience with the specific items in questions. Using forced-choice and self-paced reading tasks, we demonstrate that online processing of never-before-seen binomials is influenced by abstract knowledge of ordering constraints, which we estimate with a probabilistic model. In contrast, online processing of highly frequent binomials is primarily driven by direct experience, which we estimate from corpus frequency counts. We propose a trade-off wherein processing of novel expressions relies upon abstract knowledge, while reliance upon direct experience increases with increased exposure to an expression. Our findings support theories of language processing in which both compositional generation and direct, holistic reuse of multi-word expressions play crucial roles. PMID- 27776283 TI - Hydrophilic and hydrophobic modifications of colloidal silica particles for Pickering emulsions. AB - Colloidal silica particles, functionalized with hydrophilic and hydrophobic groups, have been studied for utilization in particle-stabilized emulsions, so called Pickering emulsions. The amounts of attached groups have been characterized using NMR spectroscopy and elemental analysis. A range of particles were prepared, with sizes from around 13 to 70nm in diameter. Hydrophilic functionalization of the silica sols was achieved by attaching methyl poly(ethylene glycol) (mPEG) silane to the silica particle surface. This provides a reduction of surface charge density, a pH dependent and controllable flocculation behavior and surface activity. The hydrophobic functionalization of the silica sols was accomplished by attaching organosilanes containing mainly propyl and methyl groups. The emulsification abilities were evaluated by preparing Pickering emulsions using particles, with varying degrees and combinations of surface functionalization, as stabilizers and comparing the obtained emulsion droplet size distributions. It was found that colloidal silica functionalized with hydrophobic groups produced emulsions with smaller droplets compared to using unmodified silica. The emulsification performance was further improved by the combination of both hydrophilic and hydrophobic groups. All particles having this heterogeneous modification were found to generate emulsions with high stability towards coalescence (from five weeks to 1.5 years). PMID- 27776284 TI - Visible photocatalytic and photoelectrochemical activities of TiO2 nanobelts modified by In2O3 nanoparticles. AB - Novel In2O3 nanoparticle/TiO2 nanobelt heterostructures with enhanced visible light photocatalytic and photoelectrochemical (PEC) performance were successfully prepared via a facile hydrothermal method. Well-dispersed In2O3 nanoparticles with small sizes are uniformly attached on the surface of TiO2 nanobelts to form In2O3 nanoparticle/TiO2 nanobelt heterostructures. The TiO2 nanobelts as backbones restrict the aggregation of In2O3 nanoparticles, resulting in the formation of smaller In2O3 nanoparticles with more interaction sites for pollutants. The visible photocatalytic activity of as-prepared heterostructures for degradation of methyl blue (MB) is higher than those of TiO2 nanobelts and In2O3 nanoparticles alone. Moreover, the In2O3 nanoparticle/TiO2 nanobelt heterostructure shows an enhanced PEC performance under irradiation of visible light. The enhanced photocatalytic and PEC activities are mainly ascribed to the synergic effect of efficient charge separation of heterostructure, visible-light harvesting ability of In2O3, and the formation of preferential adsorption sites by the small size of In2O3 nanoparticles. Finally, based on the experimental results of Mott-Schottky, UV-vis DRS, photocurrent and open-circuit voltage response, a possible photocatalytic mechanism over the In2O3 nanoparticle/TiO2 nanobelt heterostructure is proposed. PMID- 27776282 TI - Nanoassemblies from amphiphilic cytarabine prodrug for leukemia targeted therapy. AB - The anti-leukemia effect of cytarabine (Ara-C) is severely restricted by its high hydrophilic properties and rapid plasma degradation. Herein, a novel amphiphilic small molecular prodrug of Ara-C was developed by coupling a short aliphatic chain, hexanoic acid (HA) to 4-NH2 of the parent drug. Based on the amphiphilic nature, the resulting bioconjugate (HA-Ara) could spontaneously self-assemble into stable spherical nanoassemblies (NAs) with an extremely high drug loading (~71wt%). Moreover, folate receptor (FR)-targeting NAs with high grafting efficient folic acid - bovine serum albumin (FA-BSA) conjugate immobilized on the surface (NAs/FA-BSA) was prepared. The results of MTT assays on FR-positive K562 cells and FR-negative A549 cells demonstrated higher cytotoxicity of HA-Ara NAs than the native drug. Especially, the IC50 values revealed that NAs/FA-BSA was 3 and 2-fold effective than non-targeted NAs after 24 and 48h treatment with K562 cells, respectively indicating FR-mediated enhanced anti-tumor efficacy. In vitro cellular uptake, larger accumulation of HA-Ara NAs were observed in comparative with the free FITC and the results further confirmed the selective uptake of NAs/FA-BSA in folate receptor enriched cancer cells. Above all, self-assembled HA Ara NAs exhibited potential superiority for Ara-C delivery and FA-modified NAs would be an excellent candidate for targeting leukemia therapy. PMID- 27776285 TI - Oxygen-generating hybrid nanoparticles to enhance fluorescent/photoacoustic/ultrasound imaging guided tumor photodynamic therapy. AB - Photodynamic therapy (PDT) is a promising tumor treatment modality that can convert oxygen into cytotoxic singlet oxygen (SO) via photosensitizer to ablate tumor growth. However, the uncontrolled cancer cell proliferation during tumor development and the oxygen consumption during PDT always result in an insufficient oxygen level in tumors, which can adversely affect the PDT efficiency in turn. We designed an oxygen-generating PDT nanocomplex by encapsulating a manganese dioxide nanoparticle (MnO2 NP) in an indocyanine green (ICG) modified hyaluronic acid nanoparticle (HANP) to overcome this limitation. Because of the excellent fluorescent and photoacoustic properties, the tumor accumulation of the ICG-HANP/MnO2 (IHM) nanocomplex was monitored by fluorescent imaging and photoacoustic imaging after intravenous administration into the SCC7 tumor-bearing mouse model. Both high fluorescent and photoacoustic signals were detected and found peak at 6 h post-injection (tumor-muscle ratio: 4.03 +/- 0.36 for fluorescent imaging and 2.93 +/- 0.13 for photoacoustic imaging). In addition, due to the high reactivity of MnO2 NP to H2O2, an unfavorable tumor cell metabolic, the oxygen content in the tumor is elevated 2.25 +/- 0.07 times compared to that without IHM treatment as ultrasound imaging confirmed. After laser irradiation, significant tumor growth inhibition was observed in the IHM treated group compared to the ICG-HANP-treated group, attributed to the beneficial oxygen-generating property of IHM for PDT. It is expected that the design of IHM will provide an alternative way of improving clinical PDT efficacy and will be widely applied in cancer theranostics. PMID- 27776286 TI - Inventory of oral anticancer agents: Pharmaceutical formulation aspects with focus on the solid dispersion technique. AB - Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and with that suboptimal or even failing therapy. This review discusses pharmaceutical formulation aspects and absorption pharmacokinetics of currently licensed orally administered oncolytics. In nearly half of orally dosed oncolytics poor dissolution is likely to play a major role in low and unpredictable absorption. Dissolution-limited drug absorption can be improved with a solid dispersion which is a formulation method that induces super-saturated drug dissolution and with that it enhances in vivo absorption. This review discusses formulation principles with focus on the solid dispersion technology and how it works to enhance drug absorption. There are currently three licensed orally dosed oncolytics formulated as a solid dispersion (everolimus, vemurafenib and regorafenib) and these formulations result in remarkably improved dissolution and absorption compared to what can be achieved with conventional formulations of the respective oncolytics. Because of the successful implementation of these three solid dispersion formulations, we encourage the application of this formulation method for poorly soluble oral oncolytics. PMID- 27776287 TI - Antimicrobial effect of the Tunisian Nana variety Punica granatum L. extracts against Salmonella enterica (serovars Kentucky and Enteritidis) isolated from chicken meat and phenolic composition of its peel extract. AB - Punica granatum L. is widely recognized for its potency against a broad spectrum of bacterial pathogens. The purpose of this study was to explore the inhibitory and the bactericidal activities of Punica granatum against Salmonella strains. The effect of extracts obtained from different parts (peels, seeds, juice and flowers) of pomegranate and using different solvents against Salmonella enterica serovars Kentucky and Enteritidis isolated from chicken meat was thus investigated. Salmonella strains were identified with the standard API-20E system and confirmed by real time PCR. The obtained results showed that the highest antibacterial activity against Salmonella strains was observed with the peels ethanolic extract giving MIC values ranging from 10.75 to 12.5mg/mL. The ethanolic extract of P. granatum Nana peels at 0.8 and 1.6mg/g significantly inhibited the growth of Salmonella Kentucky in chicken meat stored at 4 degrees C. The phenolic composition of the ethanolic peel extract was explored by HPLC coupled to both DAD and ESI/TOF-MS detections. The obtained results allowed the detection of 21 phytochemical compounds among which various phenolic compounds have been identified on the basis of their UV and MS spectra as well as with literature data. Among the detected compounds, anthocyanins, ellagitannins, ellagic acid derivatives and flavanols were further characterized through MS-MS analysis. Our results showed thus that the Tunisian variety Nana pomegranate constitutes a good source of bioactive compounds with potent antimicrobial activity on the growth of Salmonella strains suggesting that the studied pomegranate cultivar could be a natural remedy to minimize the emergence of Salmonella enterica strains which is often involved in food borne illness. PMID- 27776289 TI - Why do subjects on clinical trials discontinue therapy? Do we really know? PMID- 27776288 TI - Hyaluronic acid on collagen membranes: An experimental study in rats. AB - OBJECTIVE: The aim of this study was to evaluate the effect of hyaluronic acid (HA) in the structure and degradation patterns of BioGide(r) and OsseoGuardTM collagen membranes. HA mediates inflammation and acts in cell migration, adhesion, and differentiation, benefitting tissue remodeling and vascularization. These are desirable effects in guided regeneration procedures, but it is still unknown whether HA alters the barrier properties of absorbable membranes. DESIGN: Bone defects were created in the calvaria of rats, which were treated with HA gel 1% (HA group) or simply filled with blood clot (control group), and covered with BioGide(r) or OsseoGuardTM. The animals were euthanized after 1, 30, and 60days, and their calvarias were processed for histological analysis. RESULTS: BioGide(r), in both HA and control groups, showed vascularization, intense cell colonization, bone formation, and tissue integration at 30 and 60days. In contrast, OsseoguardTM presented minimal cellular colonization, and inflammatory reaction associated to foreign body reaction in both time points and groups. The HA group of BioGide(r) showed higher cell colonization (574.9+/-137.6) than the control group (269.1+/-70.83) at 60days (p<0.05). Despite this finding, the structure and degradation pattern were similar for BioGide(r) and OsseoguardTM in the HA and control groups. CONCLUSION: The results suggest that HA did not interfere with tissue integration and structural degradation of BioGide(r) and OsseoguardTM membranes. PMID- 27776290 TI - Good riddance to the term "refractory anemia" in myelodysplastic syndromes. AB - The term "refractory anemia" was used in 1937 by Cornelius Parker Rhoads to describe patients whose anemia did not improve after treatment with liver extract or iron salts, and this term has been used to denote patients with certain subtypes of myelodysplastic syndromes (MDS) since the 1976 and 1982 French American-British (FAB) classifications of acute leukemias and MDS. In 2016, the World Health Organization (WHO) proposed elimination of "refractory anemia" in a more general proposal for reclassification of myeloid neoplasia. A scandal relating to Dr. Rhoads' possibly unethical medical experiments on anemic patients in Puerto Rico in 1931 and a racially offensive letter he wrote during that period prompted an international incident and Congressional-level inquiry. This dark history, as well as continued terminological problems with refractory anemia, suggest that this hoary term has indeed worn out its usefulness. This article reviews the history of "refractory anemia" and evolution in its use over the past 80 years. Rhoads' personal history, the potentially confusing nature of "refractory anemia", and the fact that it is possible none of the 100 patients Rhoads described in 1937 actually had MDS all support the new WHO reclassification proposal to eliminate this term. PMID- 27776291 TI - Structure and elevator mechanism of the Na+-citrate transporter CitS. AB - The recently determined crystal structure of the bacterial Na+-citrate symporter CitS provides unexpected structural and mechanistic insights. The protein has a fold that has not been seen in other proteins, but the oligomeric state, domain organization and proposed transport mechanism strongly resemble those of the sodium-dicarboxylate symporter vcINDY, and the putative exporters YdaH and MtrF, thus hinting at convergence in structure and function. CitS and the related proteins are predicted to translocate their substrates by an elevator-like mechanism, in which a compact transport domain slides up and down through the membrane while the dimerization domain is stably anchored. Here we review the large body of available biochemical data on CitS in the light of the new crystal structure. We show that the biochemical data are fully consistent with the proposed elevator mechanism, but also demonstrate that the current structural data cannot explain how strict coupling of citrate and Na+ transport is achieved. We propose a testable model for the coupling mechanism. PMID- 27776292 TI - When less is more - Implicit preference for incomplete bodies in xenomelia. AB - Individuals with xenomelia identify with an amputated rather than with their physically complete, healthy body. They often mimic amputees and show a strong admiration of and sexual attraction towards them. Here we investigated for the first time empirically whether such unusual preference for amputated bodies is present also on an implicit level. Using the well-validated Implicit Association Test we show that individuals with xenomelia manifested a stronger implicit and explicit preference for amputated bodies than a normally-limbed control group and a group of involuntary amputees did. Interestingly, the two latter groups did not differ in their implicit and explicit preference for complete versus amputated bodies. These findings are an important step in understanding how deeply rooted attitudes about a socially normative body appearance may be influenced by a developmentally disordered experience of one's own bodily self. We conclude that this is the first behavioral evidence demonstrating a conflict of self identification on an implicit level and this enriches current understandings of xenomelia as a primarily neurological disorder. PMID- 27776294 TI - Do aromatase inhibitors increase cardiovascular risk? Piecing together the evidence. PMID- 27776295 TI - Behavioral responses of Arctica islandica (Bivalvia: Arcticidae) to simulated leakages of carbon dioxide from sub-sea geological storage. AB - Sub-sea geological storage of carbon dioxide (CO2) provides a viable option for the Carbon Capture and Storage (CCS) approach for reducing atmospheric emissions of this greenhouse gas. Although generally considered to offer a low risk of major leakage, it remains relevant to establish the possible consequences for marine organisms that live in or on sediments overlying these storage areas if such an event may occur. The present study has used a series of laboratory exposures and behavioral bioassays to establish the sensitivity of Arctica islandica to simulated leakages of CO2. This long-lived bivalve mollusc is widely distributed throughout the North Sea, an area where geological storage is currently taking place and where there are plans to expand this operation significantly. A recently published model has predicted a maximum drop of 1.9pH units in seawater at the point source of a substantial escape of CO2 from sub-sea geological storage in this region. Valve movements of A. islandica exposed to reduced pH seawater were recorded continuously using Hall effect proximity sensors. Valve movement regulation is important for optimising the flow of water over the gills, which supplies food and facilitates respiration. A stepwise reduction in seawater pH showed an initial increase in both the rate and extent of valve movements in the majority of individuals tested when pH fell to 6.2 units. Exposing A. islandica to pH 6.2 seawater continuously for seven days resulted in a clear increase in valve movements during the first 40h of exposure, followed by a gradual reduction in activity intensity over the subsequent five days, suggesting acclimation. The ability of both exposed and control bivalves to burrow successfully into sediment on completion of this exposure was very similar. A final exposure trial, testing whether increased valve movements initiated by reduced pH were related to foot extension during attempted burrowing, found no such association. In summary, significant changes in valve behavior did not occur until seawater pH fell to 6.2 units. The response took the form of an increase in valve activity rather than closure. The absence of foot extension coincident with increased valve movements indicates A. islandica were not attempting to burrow, leaving the possibility that valve movements are supporting a respiratory response to hypercapnia. In conclusion, A. islandica appears to be tolerant of reductions in seawater pH equivalent to those predicted for substantial losses of CO2 through leakage from sub-sea geological storage. PMID- 27776296 TI - Transcriptional and cellular effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in experimentally exposed mussels, Mytilus galloprovincialis. AB - The aim of the present investigation was to provide new insights on accumulation and possible adverse effects of various non-steroidal anti-inflammatory drugs (NSAIDs) in mussels, Mytilus galloprovincialis, exposed to an environmentally realistic concentration (0.5MUg/L) of individual compounds, Acetaminophen (AMP), Diclofenac (DIC), Ibuprofen (IBU), Ketoprofen (KET) or Nimesulide (NIM). The measurement of drugs in mussel tissues was integrated with both functional alterations at cellular level and transcriptomic responses. Results indicated the capability of mussels to accumulate DIC and NIM, while AMP, IBU and KET were always below detection limit. A large panel of ecotoxicological biomarkers revealed the early onset of alterations induced by tested NSAIDs on immunological responses, lipid metabolism and DNA integrity. The gene transcription analysis through DNA microarrays, supported cellular biomarker results, with clear modulation of a large number of genes involved in the arachidonic acid and lipid metabolism, immune responses, cell cycle and DNA repair. The overall results indicated an ecotoxicological concern for pharmaceuticals in M. galloprovincialis, with transcriptional responses appearing as sensitive exposure biomarkers at low levels of exposure: such changes, however, are not always paralleled by corresponding functional effects, suggesting caution when interpreting observed effects in terms of perturbed cellular pathways. Fascinating similarities can also be proposed in the mode of action of NSAIDs between bivalves and vertebrate species. PMID- 27776297 TI - The new approach to epilepsy classification: Cognition and behavior in adult epilepsy syndromes. AB - The revised terminology and concepts for the organization of seizures and epilepsy proposed by the ILAE Commission on Classification and Terminology in 2010 allows for a number of new opportunities in the study of cognition and behavior in adults. This review examines the literature that has looked for behavioral and cognitive correlates of the newly recognized genetic epilepsies in adults. While some studies report clear cognitive phenotypes associated with specific genetic mutations in adults with epilepsy, others report remarkable clinical heterogeneity. In the second part of this review, we discuss some of the factors that may influence the findings in this literature. Cognitive function is the product of both genetic and environmental influences. Neuropsychological phenotypes under direct genetic influence may be wider and more subtle than specific deficits within discreet cognitive domains and may be reflected in broader, multidimensional measures of cognitive function than those tapped by scores on standardized tests of function. Future studies must be carefully designed to reflect these factors. It is also imperative that studies with negative findings are assigned as much value as those with positive results and published accordingly. This article is part of a Special Issue titled "The new approach to classification: Rethinking cognition and behavior in epilepsy. PMID- 27776298 TI - Neurologists can identify diagnostic linguistic features during routine seizure clinic interactions: results of a one-day teaching intervention. AB - The diagnostic distinction between epilepsy and psychogenic nonepileptic seizures (PNES) can be challenging. Previous studies have demonstrated that experts in conversation analysis can identify linguistic and interactional features in transcripts and recordings of interviews with patients that reliably distinguish between epilepsy and PNES. In this study, ten senior neurology trainees took part in a one-day intervention workshop about linguistic and interactional differences in the conversation behavior of patients with epilepsy and those with PNES. Participants were familiarized with a 12-item questionnaire designed to capture their conversational observations immediately after talking to a patient with seizures. After the intervention, 55 initial outpatient visits of patients referred to seizure clinics were video and audio recorded. All medical diagnoses were confirmed two years after initial presentation on the basis of a chart review (including MRI and EEG findings) by a fully trained epilepsy expert. Postvisit questionnaires relating to patients confirmed to have epilepsy (n=20) or PNES (n=13) were analyzed. Doctors' mean responses to 6 of the 12 questions about linguistic and interactional observations differed significantly between the groups with epilepsy and PNES. Receiver operating curve analysis showed that a summation scale based on items demonstrating significant between-group differences correctly classified 81.8% of patients as having epilepsy or PNES. This study shows that a brief Conversation Analytic teaching intervention can enable neurologists to identify linguistic and interactional features supporting the differentiation of epilepsy and PNES as they take their patients' history in routine seizure clinic consultations, potentially improving diagnostic accuracy. PMID- 27776293 TI - Converging effects of diverse treatment modalities on frontal cortex in schizophrenia: A review of longitudinal functional magnetic resonance imaging studies. AB - OBJECTIVES: A variety of treatment options exist for schizophrenia, but the effects of these treatments on brain function are not clearly understood. To facilitate the development of more effective treatment strategies, it is important to identify how brain function in schizophrenia patients is affected by the diverse therapeutic approaches that are currently available. The aim of the present article is to systematically review the evidence for functional brain changes associated with different treatment modalities for schizophrenia. METHODS: We searched PubMed for longitudinal functional MRI (fMRI) studies reporting on the effects of antipsychotic medications (APM), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), cognitive remediation therapy (CRT) and cognitive behavioral therapy for psychosis (CBTp) on brain function in schizophrenia. RESULTS: Thirty six studies fulfilled the inclusion criteria. Functional alterations were observed in diverse brain regions. Across intervention modalities, changes in fMRI parameters were reported most commonly in frontal brain regions including prefrontal cortex, anterior cingulate and inferior frontal cortex. CONCLUSIONS: We conclude that current treatments for schizophrenia commonly induce functional brain alterations in frontal brain regions. However, interpretability is limited by inconsistency in task and region of interest selection, and failures to replicate. Further task independent fMRI studies examining treatment effects with whole brain analysis are needed to deepen our insights. PMID- 27776299 TI - Effects of different physical exercise programs on susceptibility to pilocarpine induced seizures in female rats. AB - In epilepsy, the most common serious neurological disorder worldwide, several investigations in both humans and animals have shown the effectiveness of physical exercise programs as a complementary therapy. Among the benefits demonstrated, regular exercise can decrease the number of seizures as well as improve cardiovascular and psychological health in people with epilepsy. While many studies in animals have been performed to show the beneficial effects of exercise, they exclusively used male animals. However, females are also worthy of investigation because of their cyclical hormonal fluctuations and possible pregnancy. Considering the few animal studies concerning seizure susceptibility and exercise programs in females, this study aimed to verify whether exercise programs can interfere with seizure susceptibility induced by pilocarpine in adult female Wistar rats. Animals were randomly divided into three groups: control, forced, and voluntary (animals kept in a cage with a wheel). After the final exercise session, animals received a pilocarpine hydrochloride (350 mg/kg i.p.; Sigma) injection to induce seizures. To measure the intensity of pilocarpine-induced motor signs, we used a scale similar to that developed by Racine (1972) in the kindling model. During a 4-h period of observation, we recorded latency for first motor signs, latency for reaching SE, number of animals that developed SE, and intensity of pilocarpine-induced motor signs. No difference was observed among groups in latency for first motor signs and in the number of animals that developed SE. Although the voluntary group presented more intense motor signs, an increased latency for developing SE was observed compared with that in forced and control groups. Our behavioral results are not enough to explain physiological and molecular pathways, but there are mechanisms described in literature which may allow us to propose possible explanations. Voluntary exercise increased latency to SE development. Further investigation is necessary to elucidate the pathways involved in these results, while more studies should be performed regarding gender specific differences. PMID- 27776301 TI - Investigation of the effect of mobile phase composition on selectivity using a solvent-triangle based approach in achiral SFC. AB - Defining a method development methodology for achiral drug impurity profiling in SFC requires a number of steps. Initially, diverse stationary phases are characterized and a small number of orthogonal or dissimilar phases are selected for further method development. In this paper, we focus on a next step which is the investigation of the modifier composition on chromatographic selectivity. A solvent-triangle based approach is used in which blends of organic solvents, mainly ethanol (EtOH), propanol (PrOH), acetonitrile (ACN) and tetrahydrofuran (THF) mixed with methanol (MeOH) are tested as modifiers on six dissimilar stationary phases. The tested modifier blends were composed to have equal eluotropic strengths as calculated on bare silica. The modifier leads to minor changes in terms of elution order, retention and mixture resolution. However, varying only the modifier composition on a given stationary phase does not lead to the creation of dissimilar systems. Therefore the modifier composition is an optimization parameter, with the stationary phase being the factor determining most the selectivity of a given mixture in achiral SFC. PMID- 27776300 TI - Disease externalities and net nutrition: Evidence from changes in sanitation and child height in Cambodia, 2005-2010. AB - Child height is an important indicator of human capital and human development, in large part because early life health and net nutrition shape both child height and adult economic productivity and health. Between 2005 and 2010, the average height of children under 5 in Cambodia significantly increased. What contributed to this improvement? Recent evidence suggests that exposure to poor sanitation - and specifically to widespread open defecation - can pose a critical threat to child growth. We closely analyze the sanitation height gradient in Cambodia in these two years. Decomposition analysis, in the spirit of Blinder-Oaxaca, suggests that the reduction in children's exposure to open defecation can statistically account for much or all of the increase in average child height between 2005 and 2010. In particular, we see evidence of externalities, indicating an important role for public policy: it is the sanitation behavior of a child's neighbors that matters more for child height rather than the household's sanitation behavior by itself. Moving from an area in which 100% of households defecate in the open to an area in which no households defecate in the open is associated with an average increase in height-for-age z-score of between 0.3 and 0.5. Our estimates are quantitatively robust and comparable with other estimates in the literature. PMID- 27776302 TI - Urine metabolomics of high-fat diet induced obesity using UHPLC-Q-TOF-MS. AB - Obesity has become a global epidemic and public health challenge which associates with serious health issues including diabetes, cardiovascular disease, stroke, arthritis, and some types of cancer. To better understand obesity and obesity related dysfunction, a high-fat diet (HFD) induced obese model was developed on Sprague-Dawley rats. Metabolomics based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q TOF-MS) was untilized to identify and analyze obesity related metabolites in rat urine samples. Multivariate analyses were applied to differentiate metabolite patterns between HFD group and normal group. The study successfully identified 20 altered urine metabolites that correlated with obesity. These metabolites are mainly involved in tryptophan metabolism, phenylalanine and tyrosine metabolism, gut microbiota metabolism and insulin resistance related metabolism. They could serve as potential biomarkers to diagnose the development of obesity. PMID- 27776303 TI - Solid lipid nanoparticles affect microbial colonization and enzymatic activity throughout the decomposition of alder leaves in freshwater microcosms. AB - Solid lipid nanoparticles (SLNs) are used as carriers for drug delivery, and are high biocompatible and designed to endure in the host organism. Despite its current industrial production is low, many of these substances are available on the market, and much more are in the production pipeline. As a result, many of them will end in aquatic systems raising the question whether they can pose a risk to aquatic biota and the associated ecological processes. Microbial decomposers of plant litter, play a key role in forested streams being responsible for the energy flow between terrestrial and aquatic environments. Here, we investigated the effects of SLNs on alder leaf litter decomposition by aquatic microbes. Alder leaves were immersed in a stream of Northeast Portugal to allow microbial colonization before being exposed in microcosms of two types of SLNs at two concentrations for 42 days. Results showed that rates of leaf decomposition decreased with exposure to SLNs. Bacterial biomass was not inhibited by SLNs, and cultivable fungi densities remained constant (SLN-A) or increased (SLN-C) compared with control microcosms. The type and concentration of SLNs influenced differently the leaf colonization by fungi as well as fungal sporulation rate. These effects were accompanied by changes in the community extraenzymatic profile: the activities of alkaline phosphatase, acidic phosphatase, Naphthol-AS-BI-phosphohydrolase (P cycle) and lipases increased in the SLNs microcosms. This study provided the first evidence of the adverse effects of the release of SLNs to streams on leaf litter decomposition. Those effects seem to depend on the composition and concentration of SLNs, as well on the microbial target group, or enzyme. Thus, prior to massive industrial production of these nanomaterials, some measures should be taken to avoid environmental impact affecting the microbial communities responsible for detritus decomposition. PMID- 27776304 TI - Trajectories of body dissatisfaction among South Korean youth: Findings from a nationally representative sample. AB - The present study aimed to identify qualitatively different classes of growth trajectories of body dissatisfaction and to investigate the antecedents associated with the classes. The survey included a nationally representative sample of 2844 Korean children who started Grade 4 (younger cohort) and 3449 adolescents who began Grade 8 (older cohort) at baseline. Participants completed self-report surveys across five or six measurement periods separated by 1year each. General growth mixture modeling was used and results revealed several distinct longitudinal patterns. Findings from this study clearly suggest the importance of early intervention efforts. Interventions aimed at boosting autonomy may be valuable in reducing body dissatisfaction among children. The findings also highlight the critical importance of parent-child connectedness and friendship closeness in the success of the intervention. PMID- 27776306 TI - Compact secondary treatment train combining a lab-scale moving bed biofilm reactor and enhanced flotation processes. AB - High-rate wastewater processes are receiving a renewed interest to obtain energy positive/efficient water resource recovery facilities. An innovative treatment train combining a high-rate moving bed biofilm reactor (HR-MBBR) with an enhanced flotation process was studied. The two objectives of this work were 1) to maximize the conversion of soluble organics to particulate matter in an HR-MBBR and 2) to maximize the particulate matter recovery from the HR-MBBR effluent by green chemicals to enhance biogas production by anaerobic digestion. To achieve these objectives, lab-scale MBBRs fed with synthetic soluble wastewater were operated at organic loading rates (OLRs) between 4 and 34 kg COD m-3 reactor d-1 corresponding to hydraulic retention times (HRTs) between 6 and 54 min. Colloidal and soluble chemical oxygen demand (COD) removal efficiency in the HR-MBBR increased with HRT to reach a plateau of 85% at an HRT longer than 27 min. Carrier clogging observed at an OLR higher than 16 kg COD m-3 d-1 (HRT < 13 min) resulted in about 23% loss in colloidal and soluble COD removal efficiency. Thus, the recommended parameters were between 22 and 37 min and between 6 and 10 kg COD m-3 d-1 for the HRT and the OLR, respectively, to maximize the conversion of soluble organics to particulate matter. Total suspended solids (TSS) recovery of 58-85% and 90-97% were achieved by enhanced flotation using green and unbiodegradable chemicals, respectively, corresponding to a TSS effluent concentration below 14 and 7 mg TSS/L. Among the synthetic polymers tested, a high molecular weight and low charge density cationic polyacrylamide was found to give the best results with less than 2 mg TSS/L in the clarified effluent (97% TSS recovery). Green chemicals, although performing slightly less for solids separation than unbiodegradable chemicals, achieved a mean TSS concentration of 10 +/- 3 mg/L in the clarified effluent. PMID- 27776305 TI - Perfluoroalkyl substances (PFASs) in wastewater treatment plants and drinking water treatment plants: Removal efficiency and exposure risk. AB - Perfluoroalkyl substances (PFASs) are a group of chemicals with wide industrial and commercial applications, and have been received great attentions due to their persistence in the environment. The information about their presence in urban water cycle is still limited. This study aimed to investigate the occurrence and removal efficiency of eighteen PFASs in wastewater treatment plants (WWTPs) and drinking water plants (DWTPs) with different treatment processes. The results showed that both perfluorobutane sulfonic acid (PFBS) and perfluorooctane sulfonic acid (PFOS) were the predominant compounds in the water phase of WWTPs and DWTPs, while PFOS was dominant in dewatered sludge of WWTPs. The average total PFASs concentrations in the three selected WWTPs were 19.6-232 ng/L in influents, 15.5-234 ng/L in effluents, and 31.5-49.1 ng/g dry weight in sludge. The distribution pattern of PFASs differed between the wastewater and sludge samples, indicating strong partition of PFASs with long carbon chains to sludge. In the WWTPs, most PFASs were not eliminated efficiently in conventional activated sludge treatment, while the membrane bio-reactor (MBR) and Unitank removed approximately 50% of long chain (C >= 8) perfluorocarboxylic acids (PFCAs). The daily mass loads of total PFASs in WWTPs were in the range of 1956 24773 mg in influent and 1548-25085 mg in effluent. PFASs were found at higher concentrations in the wastewater from plant A with some industrial wastewater input than from the other two plants (plant B and plant C) with mainly domestic wastewater sources. Meanwhile, the average total PFASs concentrations in the two selected DWTPs were detected at 4.74-14.3 ng/L in the influent and 3.34-13.9 ng/L in the effluent. In DWTPs, only granular activated carbon (GAC) and powder activated carbon (PAC) showed significant removal of PFASs. The PFASs detected in the tap water would not pose immediate health risks in the short term exposure. The findings from this study showed that effective treatment technology should be applied to eliminate this group of chemicals in the urban water cycle based on the precautionary principle. PMID- 27776307 TI - Co-occurrence of mobile genetic elements and antibiotic resistance genes in municipal solid waste landfill leachates: A preliminary insight into the role of landfill age. AB - Since municipal solid waste (MSW) landfill harbours miscellaneous wastes, pollutants and microorganisms, it gradually becomes a huge potential reservoir for breeding antibiotic resistance genes (ARGs). The objective of this study was to determine the prevalence and diversity of ARGs associated with various mobile genetic elements (MGEs) in MSW landfill leachates. The relationship of ARGs with leachate characteristics was also studied to explore the influence of landfill age. Seven sulfonamides (sulfapyridine, sulfadiazine, sulfathiazole, sulfamethoxazole, sulfamerazine, sulfamethazine and sulfaquinoxaline), three encoded ARGs (sul-I, sul-II and sul-III) and four types of MGEs (plasmids, transposons, integrons and insertion sequences) were quantified in leachates with landfill ages ranging from 3 months-6 years. ARGs increased to an absolute concentration of 106 copies/MUL and were positively correlated (p < 0.05) to MGEs. Significant correlations (p < 0.05) were also discovered among ARGs and the increasing humic acids, heavy metals (Zn, Cu and Co) and antibiotics (except for sulfathiazole and sulfaquinoxaline), implying landfilling might contribute to the enrichment of ARGs in the long-term. Non-target full scans revealed the role of persistent unknown compounds in stimulating the ARGs dissemination. Overall, this study demonstrates the exacerbation of ARGs pollution in landfill environment and a detailed delineation of the complex inter-relationships between ARGs and the substances harbouring in landfills is badly required. PMID- 27776308 TI - Characteristics of iron corrosion scales and water quality variations in drinking water distribution systems of different pipe materials. AB - Interaction between old, corroded iron pipe surfaces and bulk water is crucial to the water quality protection in drinking water distribution systems (WDS). Iron released from corrosion products will deteriorate water quality and lead to red water. This study attempted to understand the effects of pipe materials on corrosion scale characteristics and water quality variations in WDS. A more than 20-year-old hybrid pipe section assembled of unlined cast iron pipe (UCIP) and galvanized iron pipe (GIP) was selected to investigate physico-chemical characteristics of corrosion scales and their effects on water quality variations. Scanning Electron Microscope (SEM), Energy Dispersive X-ray Spectroscopy (EDS), Inductively Coupled Plasma (ICP) and X-ray Diffraction (XRD) were used to analyze micromorphology and chemical composition of corrosion scales. In bench testing, water quality parameters, such as pH, dissolved oxygen (DO), oxidation reduction potential (ORP), alkalinity, conductivity, turbidity, color, Fe2+, Fe3+ and Zn2+, were determined. Scale analysis and bench-scale testing results demonstrated a significant effect of pipe materials on scale characteristics and thereby water quality variations in WDS. Characteristics of corrosion scales sampled from different pipe segments show obvious differences, both in physical and chemical aspects. Corrosion scales were found highly amorphous. Thanks to the protection of zinc coatings, GIP system was identified as the best water quality stability, in spite of high zinc release potential. It is deduced that the complicated composition of corrosion scales and structural break by the weld result in the diminished water quality stability in HP system. Measurement results showed that iron is released mainly in ferric particulate form. PMID- 27776310 TI - Thermal stability of the complex formed between carotenoids from sea buckthorn (Hippophae rhamnoides L.) and bovine beta-lactoglobulin. AB - Sea buckthorn has gained importance as a versatile nutraceutical, due to its high nutritive value in terms of carotenoids content. beta-Lactoglobulin (beta-LG) is a natural carrier for various bioactive compounds. In this study, the effect of thermal treatment in the temperature range of 25 to 100 degrees C for 15min on the complex formed by beta-LG and carotenoids from sea buckthorn was reported, based on fluorescence spectroscopy, molecular docking and molecular dynamics simulation results. Also, the berries extracts were analyzed for their carotenoids content. The chromatographic profile of the sea buckthorn extracts revealed the presence of zeaxanthin and beta-carotene, as major compounds. The Stern-Volmer constants and binding parameters between beta-LG and beta-carotene were estimated based on quenching experiments. When thermally treating the beta LG-carotenoids mixtures, an increase in intrinsic and extrinsic fluorescence intensity up to 90 degrees C was observed, together with blue-shifts in maximum emission in the lower temperature range and red-shifts at higher temperature. Based on fluorescence spectroscopy results, the unfolding of the protein molecules at high temperature was suggested. Detailed information obtained at atomic level revealed that events taking place in the complex heated at high temperature caused important changes in the beta-carotene binding site, therefore leading to a more thermodynamically stable assembly. This study can be used to understand the changes occurring at molecular level that could help food operators to design new ingredients and functional foods, and to optimize the processing methods in order to obtain healthier food products. PMID- 27776311 TI - An insight into the photophysical properties of amide hydrogen bonded N (benzo[d]thiazol-2-yl) acetamide crystals. AB - Three distinct, hydrogen bond associated N-(benzo[d]thiazol-2-yl) acetamides were synthesized by refluxing benzothiazoles with acetic acid. The nature of the assemblies was characteristic to the substituent in the benzothiazole moiety. In N-(benzo[d]thiazol-2-yl)acetamide, water acts as a bridge for forming three hydrogen bonds, as an acceptor to amide NH, and donors to carbonyl of amide and thiazole nitrogen assembles of three different N-(benzo[d]thiazol-2-yl)acetamide molecules. The N-(6-methylbenzo[d]thiazol-2-yl)acetamide formed a (amide) N-H...N (thiazole) bonded R22(8) molecular dimers by two homo-intermolecular hydrogen bonding interactions. N-(6-methoxybenzo[d]thiazol-2-yl)acetamide formed (amide)N H...O (acid) & (acid)O-H...N (thiazole) interactions with the acetic acid, forming a R22(8) hydrogen-bonded ring by two hetero-intermolecular hydrogen bonding interactions. PMID- 27776309 TI - Serious injury prediction algorithm based on large-scale data and under-triage control. AB - The present study was undertaken to construct an algorithm for an advanced automatic collision notification system based on national traffic accident data compiled by Japanese police. While US research into the development of a serious injury prediction algorithm is based on a logistic regression algorithm using the National Automotive Sampling System/Crashworthiness Data System, the present injury prediction algorithm was based on comprehensive police data covering all accidents that occurred across Japan. The particular focus of this research is to improve the rescue of injured vehicle occupants in traffic accidents, and the present algorithm assumes the use of an onboard event data recorder data from which risk factors such as pseudo delta-V, vehicle impact location, seatbelt wearing or non-wearing, involvement in a single impact or multiple impact crash and the occupant's age can be derived. As a result, a simple and handy algorithm suited for onboard vehicle installation was constructed from a sample of half of the available police data. The other half of the police data was applied to the validation testing of this new algorithm using receiver operating characteristic analysis. An additional validation was conducted using in-depth investigation of accident injuries in collaboration with prospective host emergency care institutes. The validated algorithm, named the TOYOTA-Nihon University algorithm, proved to be as useful as the US URGENCY and other existing algorithms. Furthermore, an under-triage control analysis found that the present algorithm could achieve an under-triage rate of less than 10% by setting a threshold of 8.3%. PMID- 27776312 TI - Phosphorescence detection of manganese(VII) based on Mn-doped ZnS quantum dots. AB - The phosphorescent l-cysteine modified manganese-doped zinc sulfide quantum dots (l-cys-MnZnS QDs) was developed for a highly sensitive detection of permanganate anions (MnO4-). l-cys-MnZnS QDs, which were easily synthesized in aqueous media using safe and low-cost materials, can emit intense phosphorescence even though the solution was not deoxygenated. However, the phosphorescence of l-cys-Mn-ZnS QDs was strongly quenched by MnO4- ascribed to the oxidation of l-cys and the increase of surface defects on l-cys-MnZnS QDs. Under the optimal conditions, l cys-MnZnS QDs offer high selectivity over other anions for MnO4- determination, and good linear Stern-Volmer equation was obtained for MnO4- in the range of 0.5 100MUM with a detection limit down to 0.24MUM. The developed method was finally applied to the detection of MnO4- in water samples, and the spike-recoveries fell in the range of 95-106%. PMID- 27776313 TI - Competitive binding of (-)-epigallocatechin-3-gallate and 5-fluorouracil to human serum albumin: A fluorescence and circular dichroism study. AB - Combination therapy with more than one therapeutic agent can improve therapeutic efficiency and decrease drug resistance. In this study, the interactions of human serum albumin (HSA) with individual or combined anticancer drugs, (-) epigallocatechin-3-gallate (EGCG) and 5-fluorouracil (FU), were investigated by fluorescence and circular dichroism (CD) spectroscopy. The results demonstrated that the interaction of EGCG or FU with HSA is a process of static quenching and EGCG formed a more stable complex. The competitive experiments of site markers suggested that both anti-carcinogens mainly bound to site I (subdomain IIA). The interaction forces which play important roles in the binding process were discussed based on enthalpy and entropy changes. Moreover, the competition binding model for a ternary system was proposed so as to precisely calculate the binding parameters. The results demonstrated that one drug decreased the binding affinity of another drug with HSA, resulting in the increasing free drug concentration at the action sites. CD studies indicated that there was an alteration in HSA secondary structure due to the binding of EGCG and FU. It can be concluded that the combination of EGCG with FU may enhance anticancer efficacy. This finding may provide a theoretical basis for clinical treatments. PMID- 27776314 TI - Comparison of the interaction between lactoferrin and isomeric drugs. AB - The binding properties of pentacyclic triterpenoid isomeric drugs, i.e. ursolic acid (UA) and oleanolic acid (OA), to bovine lactoferrin (BLF) have been studied by molecule modeling, fluorescence spectroscopy, UV-visible absorbance spectroscopy and infrared spectroscopy (IR). Molecular docking, performed to reveal the possible binding mode or mechanism, suggested that hydrophobic interaction and hydrogen bonding play important roles to stabilize the complex. The results of spectroscopic measurements showed that the two isomeric drugs both strongly quenched the intrinsic fluorescence of BLF through a static quenching procedure although some differences between UA and OA binding strength and non radiation energy transfer occurred within the molecules. The number of binding sites was 3.44 and 3.10 for UA and OA, respectively, and the efficiency of Forster energy transfer provided a distance of 0.77 and 1.21nm for UA and OA, respectively. The conformation transformation of BLF affected by the drugs conformed to the "all-or-none" pattern. In addition, the changes of the ratios of alpha-helices, beta-sheets and beta-turns of BLF during the process of the interaction were obtained. The results of the experiments in combination with the calculations showed that there are two modes of pentacyclic triterpenoid binding to BLF instead of one binding mode only governed by the principle of the lowest bonding energy. PMID- 27776315 TI - IR-ATR investigation of surface anisotropy in silicate glasses. AB - Several samples of flat soda-lime silicate glass were investigated by the Infrared Attenuated Total Reflection (IR-ATR) spectroscopy technique. The specular reflectance spectra together with the results of the performed dispersion analysis and the generated reflectance spectra, using Fresnel equations, suggest that the samples are isotropic. In contrast, spectra recorded by the ATR technique suggest an anisotropic structure on the surface of the specimen different from that in the bulk. This is established through differences in the s- and p-polarized IR-ATR spectra, which cannot be simply transformed into one another employing Fresnel formula for an isotropic case. It appears that this thin film having a structure different from the bulk is larger than the ATR effective penetration depth of the evanescent ray for each incidence angle above the critical one. The investigation suggests C2 symmetry of the SiO4 unit. PMID- 27776317 TI - Facile synthesis of a water-soluble fluorescence sensor for Al3+ in aqueous solution and on paper substrate. AB - In this study, a facile water-soluble fluorescence sensor 2-((2 hydroxybenzylidene)-amino)-2-(hydroxymethyl)propane-1,3-diol (ST) was synthesized via one-step reaction, and its fluorescence sensing performance for Al3+ both in aqueous solution and on paper substrate was evaluated. The results showed that ST exhibited an specific fluorescence "turn-on" response to Al3+ over other cations in aqueous solution as well as on the test paper. The limit of detection was found to be 3.2*10-7M, which revealed that the obtained Schiff-base based fluorescence chemosensor ST possessed a great potential for the rapid, quantitative and qualitative detection of Al3+. PMID- 27776316 TI - Vibrational spectroscopy of the double complex salt Pd(NH3)4(ReO4)2, a bimetallic catalyst precursor. AB - Tetraamminepalladium(II) perrhenate, a double complex salt, has significant utility in PdRe catalyst preparation; however, the vibrational spectra of this readily prepared compound have not been described in the literature. Herein, we present the infrared (IR) and Raman spectra of tetraamminepalladium(II) perrhenate and several related compounds. The experimental spectra are complemented by an analysis of normal vibrational modes that compares the experimentally obtained spectra with spectra calculated using DFT (DMol3). The spectra are dominated by features due to the ammine groups and the ReO stretch in Td ReO4-; lattice vibrations due to the D4h Pd(NH3)42+ are also observed in the Raman spectrum. Generally, we observe good agreement between ab initio calculations and experimental spectra. The calculated IR spectrum closely matches experimental results for peak positions and their relative intensities. The methods for calculating resonance Raman intensities are implemented using the time correlator formalism using two methods to obtain the excited state displacements and electron-vibration coupling constants, which are the needed inputs in addition to the normal mode wave numbers. Calculated excited state energy surfaces of Raman-active modes correctly predict relative intensities of the peaks and Franck-Condon activity; however, the position of Raman bands are predicted at lower frequencies than observed. Factor group splitting of Raman peaks observed in spectra of pure compounds is not predicted by DFT. PMID- 27776318 TI - Onsite-detection of barium and nickel from river, pond and tap water samples using gold nanoparticles as a chemical sensor. AB - We report a simple, selective and sensitive colorimetric assay for onsite determination of Ni(II) and Ba(II) from river, pond and tap water samples using the localized surface plasmon resonance (LSPR) of malonate capped gold nanoparticles (AuNPs) as a chemical sensor. The method is based on the color change and red shift of LSPR absorption band in visible region that caused by the aggregation of NPs because of the coordination complex between Ba(II) and Ni(II) with carboxylate ions of malonate capped AuNPs. The determination of Ba(II) and NI(II) in a same sample was performed by masking one of the analyte at a time, EDTA was used to mask Ni(II) for detection of Ba(II) and dilute H2SO4 was used to mask the Ba(II) for detection of Ni(II). The linear range for quantitative determination of Ba(II) and NI(II) were found in the range of 15-500 and 10 500ngmL-1 with a limit of detection of 5 and 3ngmL-1, respectively. The advantages of the AuNPs based chemical sensor is found to be simple, rapid and sensitive as well as it can be applied at the sample source for trace detection of Ba(II) and Ni(II) in various environmental samples. PMID- 27776319 TI - Medium dependent dual turn on/turn off fluorescence sensing for Cu2+ ions using AMI/SDS assemblies. AB - Behavior of Amiloride (AMI) as a metal ion sensor in anionic surfactant assemblies of varying concentrations at different pH is depicted in this work. From a non-sensor fluorophore, AMI has been transformed in to a tunable fluorosensor for Cu2+ ions in various SDS concentrations. At premicellar concentration of SDS, ion-pair complex is expected to be formed between AMI and SDS due to electrostatic interactions between them. However at CMC concentrations of SDS, fluorescence intensity of AMI is greatly enhanced with red shift in emission, due to the incorporation of AMI molecule in the hydrophobic micellar interface. The behavior of metal sensing by AMI-SDS assemblies gives rise to several interesting observations. Micellation of SDS has been greatly enhanced by increasing copper ion concentrations, as these counter ions screens the charge on monomers of SDS which lead to the aggregation at premicellar concentrations only. Concentrations and pH dependent discrete trends of interactions between SDS-AMI and SDS-Cu2+ ions, have given tunable fluorescence responses (fluorescence turn on/turn off) of AMI for added Cu2+ ions. The electrostatic interaction between the metal cations and the anionic surfactants is the driving force for bringing the metal ions near to the vicinity of micelle where AMI resides. Thus, a comprehensive understanding of the mechanism related to the 'turn on-turn off' fluorescence response of AMI with respect to pH and SDS concentration for effective Cu2+ ion sensing is illustrated in this work. PMID- 27776320 TI - Assessment of mechanical behavior of PLA composites reinforced with Mg micro particles through depth-sensing indentations analysis. AB - This work deals with the mechanical characterization by depth-sensing indentation (DSI) of PLLA and PLDA composites reinforced with micro-particles of Mg (up to 15wt%), which is a challenging task since the indented volume must provide information of the bulk composite, i.e. contain enough reinforcement particles. The composites were fabricated by combining hot extrusion and compression moulding. Physico-chemical characterization by TGA and DSC indicates that Mg anticipates the thermal degradation of the polymers but does not compromise their stability during processing. Especial emphasis is devoted to determine the effect of strain rate and Mg content on mechanical behavior, thus important information about the visco-elastic behavior and time-dependent response of the composites is obtained. Relevant for the intended application is that Mg addition increases the elastic modulus and hardness of the polymeric matrices and induces a higher resistance to flow. The elastic modulus obtained by DSI experiments shows good agreement with that obtained by uniaxial compression tests. The results indicate that DSI experiments are a reliable method to calculate the modulus of polymeric composites reinforced with micro-particles. Taking into consideration the mechanical properties results, PLA/Mg composite could be used as substitute for biodegradable monolithic polymeric implants already in the market for orthopedics (freeform meshes, mini plates, screws, pins, ...), craniomaxillofacial, or spine. PMID- 27776321 TI - Biomechanical investigation of the effect of extracorporeal irradiation on resected human bone. AB - Extra Corporeal irradiation and Reimplantation Therapy (ECRT) is an established biological reconstruction technique of limb salvage surgery for malignant bone tumor. Several studies have focused on clinical outcome of the procedure, but biomechanical changes post ECRT procedure are not well established. The present study investigates changes in strength, deformation, and composition of cortical bone obtained post en block resection from five patients suffering from ECRT, and the results are verified against age-match control specimen from cadaver. For pre irradiated sample, average indentation modulus varied from 11.1GPa to 15.8GPa, and hardness from 0.36GPa to 0.48GPa. Post 50Gy irradiation, we observed an overall increase in deformation, viscous response, and energy dissipation across all samples, together with reduction in indentation modulus and hardness. These changes in strength and deformation were found to be consistent with compositional investigations via Raman spectroscopy, where mineralization and amount of calcium content was found to be decreased. The study thus quantifies the effect of extra corporeal irradiation on bone mechanical and compositional response, which in turn can provide clinicians much needed insight into the mechanism of bone healing and repair post ECRT to guide follow-up care and recovery. PMID- 27776322 TI - Comparison of specimen-specific vertebral body finite element models with experimental digital image correlation measurements. AB - The purpose of this study was to load cadaveric vertebral bodies (n=6) in compression and compare the response, measured with digital image correlation (DIC) on the cortex, with the predicted response from specimen-specific vertebral finite element (FE) models. Five modulus-density relationships were evaluated, and for the strongest modulus-density relationship, the correlation between the DIC and FE displacements had R2 values from 0.75 to 0.93. The stiffnesses derived from the DIC measurements were strongly predicted by the FE stiffnesses (R2=0.90). DIC provides full-field measurements of surface displacement, eliminating the influence of system compliance, for validation of specimen specific models. PMID- 27776323 TI - Report of a case with gallbladder carcinoma: P53 expression of the peritumor epithelium might predict biliary tract recurrence. AB - INTRODUCTION: The over-expression of P53 protein in gallbladder carcinoma is a biomarker correlating with a poor survival. However, the significance of P53 expression in peritumor tissues is unknown. We experienced a case of gallbladder carcinoma where the operative specimen showed over-expression of P53 on the peritumor epithelium, and early recurrence developed at the biliary tract. PRESENTATION OF CASE: A 74-year-old female patient was referred to our hospital due to wall thickening of the gallbladder on ultrasonography. Radiographic examinations revealed wall thickening at the fundus of gallbladder and no abnormalities of the biliary tract or surrounding lymph nodes. We performed open cholecystectomy and lymph node dissection without extrahepatic bile duct resection, as a frozen section of the surgical stump of the cystic duct was cancer-free. However, a pathological examination revealed over-expression of P53 protein in the epithelium of the peritumor to the cystic duct, which were diagnosed as normal on hematoxylin eosin staining. The patient developed bile duct metastases, two and half years after the operation. She underwent endoscopic stenting for the obstruction of bile duct with no additional therapy, and died 6 months later. DISCUSSION AND CONCLUSION: The immunohistochemical staining of the GB wall or surgical stump for a surgical specimen of GBC may be crucial to predict the bile duct recurrence. PMID- 27776324 TI - Ewing sarcoma/primitive neuroectodermal tumor of the kidney: A report of three cases. AB - INTRODUCTION: Ewing sarcoma/Primitive neuroectodermal tumor of the kidney (ES/PNET) is a member of Ewing's sarcoma family, occurring in young adults and has aggressive clinical behavior and poor prognosis. However, its discrimination from the renal cell carcinoma (RCC) is very difficult preoperatively. We present three cases of this rare disease that were managed in two academic centers. PRESENTATION OF CASES: Herein we report three cases of ES/PNET of the kidney, 2 young men complaining of right flank pain and gross hematuria and one young woman complaining of left subcostal pain. In two cases computerized tomography (CT) scan revealed huge renal masses which were excised by radical nephrectomy. Microscopic examination of the nephrectomy specimen showed primitive neuroectodermal tumor features which confirmed by immunohistochemistry (IHC). Two of 3 patients were treated with adjuvant chemotherapy and the third patient with neoadjuvant chemotherapy. They were symptom-free until now. DISCUSSION: The clinical course and prognosis of ES/PNET are different from renal cell carcinoma (RCC) and definite pathologic diagnosis is necessary for optimum treatment. For definite diagnosis, in addition to cytogenetic analysis; other techniques may be needed; such as fluorescent in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR) of the t (11; 22) translocation or the EWS-FLI and related gene fusions [1]. CONCLUSION: Up to our knowledge and search in English literature, this is the first case series that was reported from a major referral center from our country, Iran. PMID- 27776325 TI - Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure based virtual screening. AB - Hand, foot and mouth disease (HFMD) is a serious, highly contagious disease. HFMD caused by Enterovirus 71 (EV71), results in severe complications and even death. The pivotal role of EV71 3Cpro in the viral life cycle makes it an attractive target for drug discovery and development to treat HFMD. In this study, we identified novel EV71 3Cpro inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3Cpro. The best inhibitor DC07090 exhibited the inhibition potency with an IC50 value of 21.72 +/- 0.95 MUM without apparent toxicity (CC50 > 200 MUM). To explore structure-activity relationship of DC07090, 15 new derivatives were designed, synthesized and evaluated in vitro enzyme assay accordingly. Interestingly, four compounds showed inhibitory activities against EV71 3Cpro and only DC07090 inhibited EV71 replication with an EC50 value of 22.09 +/- 1.07 MUM. Enzyme inhibition kinetic experiments showed that the compound was a reversible and competitive inhibitor. The Ki value was determined to be 23.29 +/- 12.08 MUM. Further molecular docking, MD simulation and mutagenesis studies confirmed the binding mode of DC07090 and EV71 3Cpro. Besides, DC07090 could also inhibit coxsackievirus A16 (CVA16) replication with an EC50 value of 27.76 +/- 0.88 MUM. Therefore, DC07090 represents a new non-peptidyl small molecule inhibitor for further development of antiviral therapy against EV71 or other picornaviruses. PMID- 27776326 TI - Hyperactivity in boys with attention-deficit/hyperactivity disorder: The influence of underlying visuospatial working memory and self-control processes. AB - Changes in motor activity were examined across control and executive function (EF) tasks that differ with regard to demands placed on visuospatial working memory (VS-WM) and self-control processes. Motor activity was measured via actigraphy in 8- to 12-year-old boys with (n=15) and without (n=17) attention deficit/hyperactivity disorder (ADHD) during the completion of VS-WM, self control, and control tasks. Results indicated that boys with ADHD, relative to typically developing boys, exhibited greater motor activity across tasks, and both groups' activity was greater during EF tasks relative to control tasks. Lastly, VS-WM performance, relative to self-control performance, accounted for significantly more variance in activity across both VS-WM and self-control tasks. Collectively, findings suggest that ADHD-related hyperactivity is positively related to increased cognitive demands and appears to be better explained by deficient VS-WM rather than insufficient self-control. PMID- 27776327 TI - Component analysis and target cell-based neuroactivity screening of Panax ginseng by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. AB - Ginseng is one of the most widely used natural medicines in the world. Recent studies have suggested Panax ginseng has a wide range of beneficial effects on aging, central nervous system disorders, and neurodegenerative diseases. However, knowledge about the specific bioactive components of ginseng is still limited. This work aimed to screen for the bioactive components in Panax ginseng that act against neurodegenerative diseases, using the target cell-based bioactivity screening method. Firstly, component analysis of Panax ginseng extracts was performed by UPLC-QTOF-MS, and a total of 54 compounds in white ginseng were characterized and identified according to the retention behaviors, accurate MW, MS characteristics, parent nucleus, aglycones, side chains, and literature data. Then target cell-based bioactivity screening method was developed to predict the candidate compounds in ginseng with SH-SY5Y cells. Four ginsenosides, Rg2, Rh1, Ro, and Rd, were observed to be active. The target cell-based bioactivity screening method coupled with UPLC-QTOF-MS technique has suitable sensitivity and it can be used as a screening tool for low content bioactive constituents in natural products. PMID- 27776328 TI - Determination of trimethylamine, trimethylamine N-oxide, and taurine in human plasma and urine by UHPLC-MS/MS technique. AB - BACKGROUND: Trimethylamine-N-oxide (TMAO) is produced in the liver from trimethylamine (TMA) and is an important cellular osmolyte and potential atherogenic factor. Taurine is involved in cholesterol metabolism and also serves as a cellular osmolyte. Given their significant biological functions, the development of reliable measurement techniques is crucial to further study their role in health and disease METHODS: A new ultrahigh performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of TMA, TMAO, and taurine in plasma and urine. The method consisted of a deproteinization step using methanol/acetonitrile (15:85) that contained 0.2% formic acid and isotope-labeled internal standards. Samples were separated by centrifugation and injected into the UHPLC system. Quantification was conducted using a triple-quadrupole mass spectrometer detector with electrospray ionization interface in positive mode. RESULTS: The limits of detection ranged from 0.08 to 0.12MUmol/L. The calibration curves were linear (r>=0.999) over the range examined (0.15-400MUmol/L) for all compounds. The inter and intra-day coefficients of variations were<=14.5% for TMA and <=8% for TMAO and taurine. TMAO and taurine were found to be stable in EDTA plasma for at least 14 months at -70 degrees C. Mean recoveries ranged from 95% to 109% and the relative matrix effects were<=4.0%. The method was applied to study physiological and pre-analytical factors in plasma and urine samples. CONCLUSIONS: The new UHPLC-MS/MS method has good accuracy, precision, and recovery. The assay combines simple sample processing with a short run time, making it well suited for high throughput routine clinical or research purposes. PMID- 27776329 TI - Amphetamine and derivatives in natural weight loss pills and dietary supplements by capillary electrophoresis-tandem mass spectrometry. AB - A capillary electrophoresis-tandem mass spectrometry (CE-MS/MS) method for amphetamine (AM), phentermine (PTM), methamphetamine (MAM), methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), and methylenedioxyethylamphetamine (MDEA) in commercial samples of homeopathic and phytotherapic medicines and dietary supplements is presented. The samples were submitted to a modified QuEChERS extraction procedure (at apparent pH 13) followed by electrophoretic separation in 0.1molL-1 formic acid electrolyte (pH 2.4) and detection by ESI-MS/MS. A polyvinyl alcohol coated capillary was employed to prevent the adsorption of the analytes to the capillary wall. The limits of detection and quantitation were from 0.02 to 0.06MUgL-1 and from 0.06 to 0.21MUgL-1, respectively, with recovery ranging from 85 to 123% and the standard deviations were not greater than 6.1%. In addition, the separation occurs in less than six minutes. PMID- 27776330 TI - RP-HPLC detection and dosage method for acrylic monomers and degradation products released from implanted medical devices. AB - Acrylic copolymers are useful in medical therapeutics. As in dental implants or intraocular lenses, acrylics are present in many medical devices or drug adjuvants. Industrial using of acrylics is still important in painting or textile manufacturing. Scientific research background has proved that acrylic suffer for depolymerized and cross-linking mechanisms under heating and photo-oxidative conditions. Those aging processes could lead to release of unreacted monomers and degradation products. We developed a new RP-HPLC method with good resolution, recovery, linearity, detection and quantification limits that is efficient for acrylic monomers quantification in in vitro and in vivo saline solution matrices. This method allows the detection of copolymer and medical devices degradation products too. Both the limit of quantification and the limit of detection for monomers and degradation products are above cytotoxic concentrations for human epithelial cells. Those biological results confirm the interest of the method for dosage of unreacted acrylics after polymerization and for the research of degradation products in body fluids as aqueous humor. PMID- 27776331 TI - Margaret Archer, modes of reflexivity: The structured agency of nursing action. PMID- 27776332 TI - Exercise for adults with depressive symptoms: Beyond the weight loss paradigm. PMID- 27776333 TI - Large scale accelerator production of 225Ac: Effective cross sections for 78 192MeV protons incident on 232Th targets. AB - Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225Ac range from 3.6 to 16.7mb in the incident proton energy range of 78-192MeV. Based on these data, production of curie quantities of 225Ac is possible by irradiating a 5.0gcm-2 232Th target for 10 days in either BNL or LANL proton irradiation facilities. PMID- 27776334 TI - Improved controlled release of protein from expanded-pore mesoporous silica nanoparticles modified with co-functionalized poly(n-isopropylacrylamide) and poly(ethylene glycol) (PNIPAM-PEG). AB - Novel pore-expanded mesoporous silica nanoparticles (MSNs) with pore sizes of approximately 11nm were synthesized and modified with thermoresponsive, poly(n isopropylacrylamide) (PNIPAM) gating groups on the nanoparticle exterior surface and in addition with poly(ethylene-glycol) (PEG) within the porous interior to minimize protein adsorption. PEG traditionally has been grafted to the nanoparticle exterior to minimize non-specific binding and interactions with the biological environment, but due to the templating mechanism of MSN synthesis, both the pore interior and nanoparticle surface can be separately modified. Here, an improved control release behavior of bovine hemoglobin (BHb) was observed after PEGylating the interior porous framework, compared to the release BHb from unmodified MSNs. This can be attributed to the reduced protein denaturation on PEGylated silica that was observed using circular dichroism spectroscopy. PMID- 27776335 TI - Peripartum cardiomyopathy, place of drug therapy, assist devices, and outcome after left ventricular assistance. AB - Peripartum cardiomyopathy remains a challenging obstetric and cardiologic emergency. We report 5 interesting cases of peripartum cardiomyopathy with different clinical courses, with 3 patients requiring left ventricular assist device implantation. One patient underwent pump explantation and aortic balloon valvuloplasty postsurgery. Two patients improved with the medical treatment alone without the need of assistance. We will review main important related issues. PMID- 27776336 TI - Role of statins in delirium prevention in critical ill and cardiac surgery patients: A systematic review and meta-analysis. AB - BACKGROUND: The data evaluating the role of statins in delirium prevention in the intensive care unit are conflicting and limited. METHODS: We performed a systematic review and meta-analysis of literature from 1975 to 2015. All English language adult studies evaluating delirium incidence in statin and statin nonusers were included and studies without a control group were excluded. Mantel Haenszel model was used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Statistical significance was defined as CI not including unity and P value less than .05. RESULTS: Of a total 57 identified studies, 6 were included. The studies showed high heterogeneity (I2 = 73%) for all and moderate for cardiac surgery studies (I2 = 55%). Of 289 773 patients, statins were used in 22 292 (7.7%). Cardiac surgery was performed in 4382 (1.5%) patients and 2321 (53.0%) used statins. Delirium was noted in 710 (3.2%) and 3478 (1.3%) of the patients in the statin and nonstatin groups, respectively, with no difference between groups in the total cohort (RR, 1.05 [95% CI, 0.85-1.29]; P = .56) or in cardiac surgery patients (RR, 1.03 [95% CI, 0.68-1.56]; P = .89). CONCLUSIONS: In critically ill and cardiac surgery patients, this meta-analysis did not show a benefit with statin therapy in the prevention of delirium. PMID- 27776337 TI - Secreted protein acidic and rich in cysteine (SPARC) induces lipotoxicity in neuroblastoma by regulating transport of albumin complexed with fatty acids. AB - SPARC is a matrix protein that mediates interactions between cells and the microenvironment. In cancer, SPARC may either promote or inhibit tumor growth depending upon the tumor type. In neuroblastoma, SPARC is expressed in the stromal Schwannian cells and functions as a tumor suppressor. Here, we developed a novel in vivo model of stroma-rich neuroblastoma using non-tumorigenic SHEP cells with modulated levels of SPARC, mixed with tumorigenic KCNR cells. Tumors with stroma-derived SPARC displayed suppressed growth, inhibited angiogenesis and increased lipid accumulation. Based on the described chaperone function of SPARC, we hypothesized that SPARC binds albumin complexed with fatty acids and transports them to tumors. We show that SPARC binds albumin with Kd=18.9+/-2.3 uM, and enhances endothelial cell internalization and transendothelial transport of albumin in vitro. We also demonstrate that lipids induce toxicity in neuroblastoma cells and show that lipotoxicity is increased when cells are cultured in hypoxic conditions. Studies investigating the therapeutic potential of SPARC are warranted. PMID- 27776339 TI - Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies. AB - Immunotherapy of B-cell leukemia and lymphoma with CD20-targeting monoclonal antibodies (mAbs) has demonstrated clinical efficacy. However, the emergence of unresponsive disease due to low or absent cell surface CD20 urges the need to develop additional strategies. In contrast to mAbs, T-cells via their T-cell receptor (TCR) can recognize not only extracellular but also intracellular antigens in the context of HLA molecules. We hypothesized that T-cells equipped with high affinity CD20-targeting TCRs would be able to recognize B-cell malignancies even in the absence of extracellular CD20. We isolated CD8+ T-cell clones binding to peptide-MHC-tetramers composed of HLA-A*02:01 and CD20-derived peptide SLFLGILSV (CD20SLF) from HLA-A*02:01neg healthy individuals to overcome tolerance towards self-antigens such as CD20. High avidity T-cell clones were identified that readily recognized and lysed primary HLA-A2pos B-cell leukemia and lymphoma in the absence of reactivity against CD20-negative but HLA-A2pos healthy hematopoietic and nonhematopoietic cells. The T-cell clone with highest avidity efficiently lysed malignant cell-lines that had insufficient extracellular CD20 to be targeted by CD20 mAbs. Transfer of this TCR installed potent CD20-specificity onto recipient T-cells and led to lysis of CD20low malignant cell-lines. Moreover, our approach facilitates the generation of an off the-shelf TCR library with broad applicability by targeting various HLA alleles. Using the same methodology, we isolated a T-cell clone that efficiently lysed primary HLA-B*07:02pos B-cell malignancies by targeting another CD20-derived peptide. TCR gene transfer of high affinity CD20-specific TCRs can be a valuable addition to current treatment options for patients suffering from CD20low B-cell malignancies. PMID- 27776338 TI - PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials. AB - In this study, we examined PD-L1 expression by immunohistochemistry in 99 patients with tonsillar cancer and known human papillomavirus (HPV) status to assess its clinical significance. We showed that the pattern of PD-L1 expression is strongly related to HPV status. The PD-L1 positivity rate was 83.3% in HPV positive cases and 56.9% in HPV-negative cases (p < 0.05). Patients with HPV positive/PD-L1-positive cancer had significantly better event free survival and overall survival compared with patients with HPV-negative/PD-L1-negative cancer. Relative to those patients with HPV-negative/PD-L1-negative disease who had the highest risk of death, patients with HPV-positive/PD-L1-positive cancers had a 2.85 fold lower risk of developing an event (HR 0.35, 95% CI: 0.16-0.79) and a 4.5 fold lower risk of death (HR =0.22, 95% CI: 0.09-0.53). Our findings will help to guide future clinical trial design in immunotherapy based on PD-L1 expression in tonsillar cancer. PMID- 27776340 TI - Babao Dan attenuates hepatic fibrosis by inhibiting hepatic stellate cells activation and proliferation via TLR4 signaling pathway. AB - Babao Dan (BBD), a traditional Chinese medicine, has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the protective effect of BBD on rat hepatic fibrosis induced by diethylnitrosamine (DEN) and explore it possible mechanism. BBD was administrated while DEN was given. After eight weeks, values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicated that BBD significantly protected liver from damaging by DEN and had no obvious side effect on normal rat livers. Meanwhile, BBD attenuated hepatic inflammation and fibrosis in DEN-induced rat livers through histopathological examination and hepatic hydroxyproline content. Furthermore, we found that BBD inhibited hepatic stellate cells activation and proliferation without altering the concentration of lipopolysaccharide (LPS) in portal vein. In vitro study, serum from BBD treated rats (BBD-serum) could also significantly suppress LPS-induced HSCs activation through TLR4/NF-kappaB pathway. In addition, BBD-serum also inhibited the proliferation of HSCs by regulating TLR4/ERK pathway. Our study demonstrated that BBD may provide a new therapy strategy of hepatic injury and hepatic fibrosis. PMID- 27776341 TI - Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer. AB - Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/beta-catenin signaling and its downstream pathway, epithelial-to mesenchymal transition (EMT), play a key role in ovarian cancer metastasis and chemoresistance. To study the clinical implications of FILIP1L in regulating the WNT/beta-catenin pathway, the expression of FILIP1L, beta-catenin, SNAIL and SLUG was analyzed by immunohistochemistry on tissue microarrays of 369 ovarian samples ranging from normal to metastatic. In addition, the results were validated in mouse model and in vitro cell culture. In the present study, we demonstrated that FILIP1L expression was inversely correlated with poor prognosis, stage and chemoresistance in ovarian cancer. Notably, low FILIP1L expression was independent negative prognostic factor with respect to overall and disease-free survival. FILIP1L inhibited peritoneal metastases in orthotopic mouse model. FILIP1L knockdown induced chemoresistance in ovarian cancer cells and this phenotype was rescued by simultaneous knockdown of FILIP1L and SLUG, an EMT activator. We also demonstrated that FILIP1L regulates beta-catenin degradation. FILIP1L co-localizes with phospho-beta-catenin and increases phospho-beta-catenin at the centrosomes, destined for proteosomal degradation. Finally, we showed that FILIP1L regulates EMT. Overall, these findings suggest that FILIP1L promotes beta catenin degradation and suppresses EMT, thereby inhibiting metastases and chemoresistance. Our study provides the first clinical relevance of FILIP1L in human cancer, and suggests that FILIP1L may be a novel prognostic marker for chemotherapy in ovarian cancer patients. Further, the modulation of FILIP1L expression may have the potential to be a target for cancer therapy. PMID- 27776342 TI - Application of intensity-modulated radiotherapy in unresectable poorly differentiated thyroid carcinoma. AB - Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive malignancy with high rates of invasion and distant metastasis. This study was to explore the ability of intensity-modulated radiotherapy (IMRT) combined with chemotherapy to manage unresectable PDTC. Between February 2011 and April 2012, 5 patients with unresectable PDTC were treated by IMRT at our institution and were included in this analysis. The median radiotherapy dose to the gross tumor volume (GTV) was 66 Gy/33 fractions/6.4 weeks. All patients received chemotherapy, and one patient with tumor compression symptoms had a tracheotomy before treatment. The mean survival time of the 5 patients was 41.6 months. The direct causes of death were distant metastases (40%) and progression of the locoregional disease (20%). In conclusion, IMRT combined with chemotherapy for unresectable PDTC might be beneficial to improve locoregional control. Further new therapies are needed to control metastases. PMID- 27776344 TI - Baicalein protects against oxLDL-caused oxidative stress and inflammation by modulation of AMPK-alpha. AB - Atherosclerosis is considered to be a form of chronic inflammation and a disorder of lipid metabolism. Oxidative transformations in the lipid and apolipoprotein B (Apo B) constituent of low density lipoprotein drive the initial step in atherogenesis due to macrophage scavenger receptors identify oxidized LDL (oxLDL) but non-oxidized LDL. The human vascular endothelial cells fact a critical role in vasodilation, provides a nonadhesive surface for circulation, reduces vascular smooth muscle proliferation, inflammation, thrombus formation and platelet aggregation. Assembly of oxLDL contribute to stimulation of endothelial cells with up-regulation of adhesion molecules, increase oxidative stress to the vascular endothelium and inhibition of NO-mediated vasodilation. When adhesion molecules are over-expressed on the surface of endothelial cells under oxLDL stimulation, it will recruit monocytes to the arterial wall. Then adherent monocytes will migrate into the subendothelial space and subsequently differentiate into macrophages. In the subendothelial space, oxLDL will be taken up by macrophages, thereby causing the substantial cholesterol accumulation and the foam cells production. PMID- 27776345 TI - Quantitative proteomics reveals Piccolo as a candidate serological correlate of recovery from Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an autoimmune-mediated peripheral neuropathy of unknown cause. However, about a quarter of GBS patients have suffered a recent bacterial or viral infection, and axonal forms of the disease are especially common in these patients. Proteomics is a good methodological approach for the discovery of disease biomarkers. Until recently, most proteomics studies of GBS and other neurodegenerative diseases have focused on the analysis of the cerebrospinal fluid (CSF). However, serum represents an attractive alternative to CSF because it is easier to sample and has potential for biomarker discovery. The goal of this research was the identification of serum biomarkers associated with recovery from GBS. To address this objective, a quantitative proteomics approach was used to characterize differences in the serum proteome between a GBS patient and her healthy identical twin in order to lessen variations due to differences in genetic background, and with additional serum samples collected from unrelated GBS (N = 3) and Spinal Cord Injury (SCI) (N = 3) patients with similar medications. Proteomics results were then validated by ELISA using sera from additional GBS patients (N = 5) and healthy individuals (N = 3). All GBS and SCI patients were recovering from the acute phase of the disease. The results showed that Piccolo, a protein that is essential in the maintenance of active zone structure, constitutes a potential serological correlate of recovery from GBS. These results provided the first evidence for the Piccolo's putative role in GBS, suggesting a candidate target for developing a serological marker of disease recovery. PMID- 27776343 TI - Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone. AB - Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRalpha) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRalpha expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRalpha in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFbeta1 were upregulated by ERRalpha in tumor cells and all of these factors also significantly and positively correlated withERRalpha expression in CRPC patient specimens. Finally, high levels of ERRalpha in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRalpha regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRalpha is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRalpha may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID- 27776347 TI - SIRT1 suppresses adipogenesis by activating Wnt/beta-catenin signaling in vivo and in vitro. AB - Sirtuin 1 (SIRT1) regulates adipocyte and osteoblast differentiation. However, the underlying mechanism should be investigated. This study revealed that SIRT1 acts as a crucial repressor of adipogenesis. RNA-interference-mediated SIRT1 knockdown or genetic ablation enhances adipogenic potential, whereas SIRT1 overexpression inhibits adipogenesis in mesenchymal stem cells (MSCs). SIRT1 also deacetylates the histones of sFRP1, sFRP2, and Dact1 promoters; inhibits the mRNA expression of sFRP1, sFRP2, and Dact1; activates Wnt signaling pathways; and suppresses adipogenesis. SIRT1 deacetylates beta-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis. In mice, the partial absence of SIRT1 promotes the formation of white adipose tissues without affecting the development of the body of mice. Our study described the regulatory role of SIRT1 in Wnt signaling and proposed a regulatory mechanism of adipogenesis. PMID- 27776346 TI - Highly aligned stromal collagen is a negative prognostic factor following pancreatic ductal adenocarcinoma resection. AB - Risk factors for pancreatic ductal adenocarcinoma (PDAC) progression after surgery are unclear, and additional prognostic factors are needed to inform treatment regimens and therapeutic targets. PDAC is characterized by advanced sclerosis of the extracellular matrix, and interactions between cancer cells, fibrillar collagen, and other stromal components play an integral role in progression. Changes in stromal collagen alignment have been shown to modulate cancer cell behavior and have important clinical value in other cancer types, but little is known about its role in PDAC and prognostic value. We hypothesized that the alignment of collagen is associated with PDAC patient survival. To address this, pathology-confirmed tissues from 114 PDAC patients that underwent curative intent surgery were retrospectively imaged with Second Harmonic Generation (SHG) microscopy, quantified with fiber segmentation algorithms, and correlated to patient survival. The same tissue regions were analyzed for epithelial-to mesenchymal (EMT), alpha-SMA, and syndecan-1 using complimentary immunohistostaining and visualization techniques. Significant inter-tumoral variation in collagen alignment was found, and notably high collagen alignment was observed in 12% of the patient cohort. Stratification of patients according to collagen alignment revealed that high alignment is an independent negative factor following PDAC resection (p = 0.0153, multivariate). We also found that epithelial expression of EMT and the stromal expression of alpha-SMA and syndecan 1 were positively correlated with collagen alignment. In summary, stromal collagen alignment may provide additional, clinically-relevant information about PDAC tumors and underscores the importance of stroma-cancer interactions. PMID- 27776348 TI - Prognostic value of vascular mimicry in patients with urothelial carcinoma of the bladder after radical cystectomy. AB - Vascular mimicry (VM) refers to the plasticity of aggressive cancer cells forming de novo vascular networks, which promoted tumor metastasis. The aim of this study was evaluate the impact of VM on recurrence-free survival (RFS) in urothelial carcinoma of the bladder (UCB). Records from 202 patients treated with radical cystectomy (RC) for UCB at Zhongshan Hospital between 2002 and 2014 were reviewed. The presence of VM was identified by CD31-PAS double staining. Positive VM staining occurred in 19.3% (39 of 202) UCB cases, and it was associated with increased risks of recurrence (Log-Rank p<0.001). VM was identified as an independent prognostic factor (p=0.002). In the cohort with MIBC, patients with VM negative got CSS benefit from the use of ACT (p = 0.048). As for lung metastasis, the combination of VM and TNM stage (AUC 0.792) showed a better prognostic value than TNM stage alone (AUC 0.748, p = 0.008) or VM alone (AUC 0.714, p = 0.023). Vascular mimicry could be a potential prognosticator for recurrence-free survival in patients with UCB after RC. Vascular mimicry seems to predict risk of developing lung metastases after RC. The presence of VM identified a subgroup of patients with MIBC who appeared to benefit from adjuvant chemotherapy. PMID- 27776349 TI - Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a Caucasian family. AB - Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes.In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree.From the analysis of the pedigree, we were able to identify a "protective" haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model. PMID- 27776351 TI - Second-line ramucirumab therapy for advanced hepatocellular carcinoma (REACH): an East Asian and non-East Asian subgroup analysis. AB - PURPOSE: REACH investigated second-line ramucirumab therapy for advanced hepatocellular carcinoma. RESULTS: Median overall survival was 8.2 months for ramucirumab and 6.9 months for placebo (HR, 0.835; 95% CI, 0.634-1.100; p = 0.2046) for East Asians, and 10.1 months for ramucirumab and 8.0 months for placebo (HR, 0.895; 95% CI, 0.690-1.161; p = 0.4023) for non-East Asians. Median overall survival in patients with baseline alpha-fetoprotein >= 400 ng/mL was 7.8 months for ramucirumab and 4.2 months for placebo (HR, 0.749; 95% CI, 0.519 1.082; p = 0.1213) for East Asians (n = 139), and 8.2 months for ramucirumab and 4.5 months for placebo (HR, 0.579; 95% CI, 0.371-0.904; p = 0.0149) for non-East Asians (n = 111). The most common grade >= 3 treatment-emergent adverse events in East Asians and non-East Asians included hypertension and malignant neoplasm progression. MATERIALS AND METHODS: A post-hoc analysis of East Asians (N = 252) and non-East Asians (N = 313) in the intent-to-treat population was performed. CONCLUSIONS: In East Asians and non-East Asians, ramucirumab did not significantly prolong overall survival. In patients with baseline alpha fetoprotein >= 400 ng/mL, a potentially larger survival benefit was observed in both subgroups. Safety for East Asians was similar to non-East Asians. PMID- 27776350 TI - Focal adhesion molecule Kindlin-1 mediates activation of TGF-beta signaling by interacting with TGF-betaRI, SARA and Smad3 in colorectal cancer cells. AB - Kindlin-1, an integrin-interacting protein, has been implicated in TGF-beta/Smad3 signaling. However, the molecular mechanism underlying Kindlin-1 regulation of TGF-beta/Smad3 signaling remains elusive. Here, we reported that Kindlin-1 is an important mediator of TGF-beta/Smad3 signaling by showing that Kindlin-1 physically interacts with TGF-beta receptor I (TbetaRI), Smad anchor for receptor activation (SARA) and Smad3. Kindlin-1 is required for the interaction of Smad3 with TbetaRI, Smad3 phosphorylation, nuclear translocation, and finally the activation of TGF-beta/Smad3 signaling pathway. Functionally, Kindlin-1 promoted colorectal cancer (CRC) cell proliferation in vitro and tumor growth in vivo, and was also required for CRC cell migration and invasion via an epithelial to mesenchymal transition. Kindlin-1 was found to be increased with the CRC progression from stages I to IV. Importantly, raised expression level of Kindlin 1 correlates with poor outcome in CRC patients. Taken together, we demonstrated that Kindlin-1 promotes CRC progression by recruiting SARA and Smad3 to TbetaRI and thereby activates TGF-beta/Smad3 signaling. Thus, Kindlin-1 is a novel regulator of TGF-beta/Smad3 signaling and may also be a potential target for CRC therapeutics. PMID- 27776352 TI - The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer. AB - BACKGROUND: Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance. RESULTS: We completed an Agena MassArray screen of 10 ERBB-family single nucleotide polymorphisms (SNPs) in 194 adjuvant trastuzumab treated HER2-positive BC patients. SNPs in EGFR genes have a significant association with RFS and OS. Patients with the minor allele of EGFR N158N had significantly worse OS (hazard ratio (HR) = 4.01, (confidence interval (CI) = 1.53- 10.69), p = 0.05) relative to those with either the heterozygous or wild-type (WT) allele. Patients with the minor allele of EGFR T903T (HR = 3.52, (CI = 1.38- 8.97), p = 0.05) had worse RFS relative to those with either the heterozygous or WT allele. PATIENTS AND METHODS: Using next generation sequencing (NGS) we identified ERBB-family (EGFR, HER2, HER3 and HER4) single nucleotide polymorphisms (SNPs) that occurred in 2 or more patients of a 32 HER2-positive BC patient cohort. Agena MassArray analysis confirmed the frequency of these SNPs in 194 women with HER2-positive BC who received trastuzumab in the adjuvant setting. Using Kaplan-Meier estimates and Cox regression analysis we correlated the presence of ERBB-family SNPs with both RFS and OS. CONCLUSIONS: The presence of germline ERBB-family SNPs may play an important role in how a patient responds to adjuvant trastuzumab, and clinical assessment of these SNPs by targeted genetic screening of patients' blood may be important to stratify patients for treatment. PMID- 27776353 TI - Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside. AB - The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been approved for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Acquired resistance to ibrutinib due to BTK C481S mutation has been reported. Mutations in PLCgamma2 can also mediate resistance to ibrutinib. Untoward effects due to off-target effects are also disadvantages of ibrutinib. More selective and potent BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being investigated. This review summarized the preclinical research and clinical data of ONO/GS-4059. PMID- 27776354 TI - Defining synonymous codon compression schemes by genome recoding. AB - Synthetic recoding of genomes, to remove targeted sense codons, may facilitate the encoded cellular synthesis of unnatural polymers by orthogonal translation systems. However, our limited understanding of allowed synonymous codon substitutions, and the absence of methods that enable the stepwise replacement of the Escherichia coli genome with long synthetic DNA and provide feedback on allowed and disallowed design features in synthetic genomes, have restricted progress towards this goal. Here we endow E. coli with a system for efficient, programmable replacement of genomic DNA with long (>100-kb) synthetic DNA, through the in vivo excision of double-stranded DNA from an episomal replicon by CRISPR/Cas9, coupled to lambda-red-mediated recombination and simultaneous positive and negative selection. We iterate the approach, providing a basis for stepwise whole-genome replacement. We attempt systematic recoding in an essential operon using eight synonymous recoding schemes. Each scheme systematically replaces target codons with defined synonyms and is compatible with codon reassignment. Our results define allowed and disallowed synonymous recoding schemes, and enable the identification and repair of recoding at idiosyncratic positions in the genome. PMID- 27776355 TI - Atomic model for the membrane-embedded VO motor of a eukaryotic V-ATPase. AB - Vacuolar-type ATPases (V-ATPases) are ATP-powered proton pumps involved in processes such as endocytosis, lysosomal degradation, secondary transport, TOR signalling, and osteoclast and kidney function. ATP hydrolysis in the soluble catalytic V1 region drives proton translocation through the membrane-embedded VO region via rotation of a rotor subcomplex. Variability in the structure of the intact enzyme has prevented construction of an atomic model for the membrane embedded motor of any rotary ATPase. We induced dissociation and auto-inhibition of the V1 and VO regions of the V-ATPase by starving the yeast Saccharomyces cerevisiae, allowing us to obtain a ~3.9-A resolution electron cryomicroscopy map of the VO complex and build atomic models for the majority of its subunits. The analysis reveals the structures of subunits ac8c'c"de and a protein that we identify and propose to be a new subunit (subunit f). A large cavity between subunit a and the c-ring creates a cytoplasmic half-channel for protons. The c ring has an asymmetric distribution of proton-carrying Glu residues, with the Glu residue of subunit c" interacting with Arg735 of subunit a. The structure suggests sequential protonation and deprotonation of the c-ring, with ATP hydrolysis-driven rotation causing protonation of a Glu residue at the cytoplasmic half-channel and subsequent deprotonation of a Glu residue at a luminal half-channel. PMID- 27776358 TI - Colorectal Cancer Screening in the United States: What Is the Best FIT? PMID- 27776356 TI - Olfactory receptor pseudo-pseudogenes. AB - Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes. Although certain pseudogene-derived RNAs have regulatory roles, and some pseudogene fragments are translated, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid-a chemical cue important for locating fermenting food found only at trace levels in Morinda fruit-D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such 'pseudo-pseudogenes' could represent a widespread phenomenon. PMID- 27776357 TI - Amazon boundary layer aerosol concentration sustained by vertical transport during rainfall. AB - The nucleation of atmospheric vapours is an important source of new aerosol particles that can subsequently grow to form cloud condensation nuclei in the atmosphere. Most field studies of atmospheric aerosols over continents are influenced by atmospheric vapours of anthropogenic origin (for example, ref. 2) and, in consequence, aerosol processes in pristine, terrestrial environments remain poorly understood. The Amazon rainforest is one of the few continental regions where aerosol particles and their precursors can be studied under near natural conditions, but the origin of small aerosol particles that grow into cloud condensation nuclei in the Amazon boundary layer remains unclear. Here we present aircraft- and ground-based measurements under clean conditions during the wet season in the central Amazon basin. We find that high concentrations of small aerosol particles (with diameters of less than 50 nanometres) in the lower free troposphere are transported from the free troposphere into the boundary layer during precipitation events by strong convective downdrafts and weaker downward motions in the trailing stratiform region. This rapid vertical transport can help to maintain the population of particles in the pristine Amazon boundary layer, and may therefore influence cloud properties and climate under natural conditions. PMID- 27776359 TI - Exciting Changes Coming to LSHSS! You Are Invited to Participate! AB - Purpose: In this editorial, the Editor of Language, Speech, and Hearing Services in Schools (LSHSS) describes important changes coming to LSHSS and all ASHA journals and calls for readers to voice their opinion regarding important topics and formats they would like to see included in future LSHSS volumes. PMID- 27776360 TI - Motion-induced position shift in stereoscopic and dichoptic viewing. AB - The static envelope of a Gabor patch with a moving sinusoidal carrier appears shifted in the direction of the carrier motion (De Valois & De Valois, 1991). This phenomenon is called motion-induced position shift. Although several motion processing stages, ranging from low- to high-level processes, may contribute to position estimation, it is unknown whether a binocular matching stage or an even earlier stage exerts an influence. To elucidate this matter, we investigated the disparity tuning of this illusion by manipulating the binocular disparities of the carrier and the envelope. If the mechanisms underlying the illusion have disparity selectivity, the illusory shift should disappear when the carrier and envelope have sufficiently different disparities. We conducted an experiment in which a sinusoidal grating inside a Gaussian envelope had a crossed or uncrossed disparity and the background was filled with static random noise; each subject correctly judged whether the grating was in front of or behind the fixation plane. Position shift occurred even when the moving carrier had a vastly different disparity from that of the envelope, suggesting that one of the mechanisms responsible for the phenomenon exists at a monocular visual stage. To confirm this, in the next experiment we examined whether depth perception can be produced by an illusory disparity due to illusory position shifts in opposite directions between eyes. Two Gabor-like patches moving in opposite directions were presented at the same retinal position dichoptically. We found that when each monocular patch had a soft edge in its contrast envelope, the depth perception of such a patch was biased toward the depth consistent with the illusory crossed or uncrossed disparity, whereas depth perception of a stimulus with a hard edge was less biased. We suggest that the underlying mechanisms of motion-induced position shift are present at an early stage of monocular visual processing, and that the altered positions are represented in the left-eye and right-eye monocular pathways in a way that allows them to function as tokens of binocular matching. PMID- 27776361 TI - Calcium Supplements and Cardiovascular Disease Risk: What Do Clinicians and Patients Need to Know? PMID- 27776362 TI - Lack of Evidence Linking Calcium With or Without Vitamin D Supplementation to Cardiovascular Disease in Generally Healthy Adults: A Clinical Guideline From the National Osteoporosis Foundation and the American Society for Preventive Cardiology. AB - Description: Calcium is the dominant mineral present in bone and a shortfall nutrient in the American diet. Supplements have been recommended for persons who do not consume adequate calcium from their diet as a standard strategy for the prevention of osteoporosis and related fractures. Whether calcium with or without vitamin D supplementation is beneficial or detrimental to vascular health is not known. Methods: The National Osteoporosis Foundation and American Society for Preventive Cardiology convened an expert panel to evaluate the effects of dietary and supplemental calcium on cardiovascular disease based on the existing peer reviewed scientific literature. The panel considered the findings of the accompanying updated evidence report provided by an independent evidence review team at Tufts University. Recommendation: The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time. In light of the evidence available to date, calcium intake from food and supplements that does not exceed the tolerable upper level of intake (defined by the National Academy of Medicine as 2000 to 2500 mg/d) should be considered safe from a cardiovascular standpoint. PMID- 27776363 TI - Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. AB - Background: Conflicting evidence exists regarding potential cardiovascular risks associated with high levels of calcium intake. Purpose: To update and reanalyze 2 systematic reviews to examine the effects of calcium intake on cardiovascular disease (CVD) among generally healthy adults. Data Sources: MEDLINE; Cochrane Central Register of Controlled Trials; Scopus, including EMBASE; and previous evidence reports from English-language publications from 1966 to July 2016. Study Selection: Randomized trials and prospective cohort and nested case-control studies with data on dietary or supplemental intake of calcium, with or without vitamin D, and cardiovascular outcomes. Data Extraction: Study characteristics and results extracted by 1 reviewer were confirmed by a second reviewer. Two raters independently assessed risk of bias. Data Synthesis: Overall risk of bias was low for the 4 randomized trials (in 10 publications) and moderate for the 27 observational studies included. The trials did not find statistically significant differences in risk for CVD events or mortality between groups receiving supplements of calcium or calcium plus vitamin D and those receiving placebo. Cohort studies showed no consistent dose-response relationships between total, dietary, or supplemental calcium intake levels and cardiovascular mortality and highly inconsistent dose-response relationships between calcium intake and risks for total stroke or stroke mortality. Limitations: CVD disease outcomes were secondary end points in all trials. Dose-response metaregression analysis of cohort studies was limited by potential confounding, ecological bias, and imprecise measures of calcium exposures. Data were scarce regarding very high calcium intake-that is, beyond recommended tolerable upper intake levels. Conclusion: Calcium intake within tolerable upper intake levels (2000 to 2500 mg/d) is not associated with CVD risk in generally healthy adults. Primary Funding Source: National Osteoporosis Foundation. PMID- 27776365 TI - SMFM 2016 Archive: Hypertension-Part 1 (Podcast). PMID- 27776364 TI - Infant Mortality and Obstetric Assistance's Quality. PMID- 27776366 TI - Effect of Piperine on the Metabolism and Pharmacokinetics of Carbamazepine in Healthy Volunteers. AB - Carbamazepine (CBZ) is a widely used antiepileptic drug with narrow therapeutic window and it may be prone to drug interactions. The purpose of present study was to investigate the effect of PIP on metabolism and pharmacokinetics of CBZ in healthy volunteers. An open-label, 2 period, sequential study was conducted in 12 healthy volunteers. PIP 20 mg was administered once daily for 10 days during treatment phase. A single dose of CBZ 200 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected after CBZ dosing at predetermined time intervals and analyzed by LC-MS/MS method. Treatment with PIP significantly enhanced maximum plasma concentration (Cmax), area under the curve (AUC) and half life (T1/2) of CBZ by 68.7, 47.9 and 43.2%, respectively as compared to control. On the other hand, elimination rate constant (Kel) and apparent oral clearance (CL/F) of CBZ were significantly decreased by 23.8 and 38.9%, respectively upon PIP treatment as compared to control. Furthermore, PIP treatment significantly decreased metabolic (CBZE/CBZ) ratios of Cmax and AUC, indicating the decreased formation of CBZ to CBZE. The results suggest that the altered CYP3A4 enzyme activity and pharmacokinetics of CBZ might be attributed to PIP mediated inhibition of CYP3A4 enzyme. Thus, there is a potential pharmacokinetic interaction present between PIP and CBZ. Accordingly, caution should be taken when PIP is used in combination with therapeutic drugs metabolized by CYP3A4 in addition to CBZ. PMID- 27776368 TI - Erratum: Research in Osteochondritis Dissecans of the Knee: 2016 Update. PMID- 27776367 TI - Transoral Atlantoaxial Release and Posterior Reduction by Occipitocervical Plate Fixation for the Treatment of Basilar Invagination with Irreducible Atlantoaxial Dislocation. AB - Background Prior studies have mainly assessed transoral odontoidectomy for basilar invagination with irreducible atlantoaxial dislocation. However, studies evaluating transoral release and posterior reduction with occipitocervical fixation in this setting are scarce. Methods From 2008 to 2013, 11 patients (6 men and 5 women; 23-67 years of age) with basilar invagination and irreducible atlantoaxial dislocation underwent surgery. They presented signs and symptoms of myelopathy or significant spinal cord injury, and were treated by transoral soft tissue release without odontoidectomy, under skull traction with heavy weight and by posterior reduction with occipitocervical plate fixation. Results Patients were followed up for 10 to 42 months (average: 25.4 months). All achieved bony fusion; radiologically complete reduction was achieved in 10 cases, and partial reduction in 1. All patients showed an improved postoperative neurologic condition, indicated by increased muscle strength and decreased or now absent pathologic symptoms. The average Japanese Orthopaedic Association preoperative score of 10.5 points increased to 15.5 points postoperatively. These findings indicated an improvement rate of 76.1%. The efficiency rate was 90.9%. Conclusions Anterior transoral atlantoaxial release without odontoidectomy and posterior fixation is an efficient treatment of basilar invagination with irreducible atlantoaxial dislocation. PMID- 27776369 TI - Detection of Total Knee Arthroplasties at Airport Security Checkpoints: How Do Updated Security Measures Affect Patients? AB - Airport security measures continue to be updated with the incorporation of the new body scanners and automatic target recognition software. The purpose of this study was analyze the incidence of: (1) triggering the security alarm; (2) extra security searches; (3) perceived inconvenience; and (4) presence of other surgical hardware in those who underwent total knee arthroplasty (TKA) and passed through airport security. A questionnaire was given to 125 consecutive patients with a TKA. Those who passed through airport security after January 2014 were considered for inclusion. A questionnaire was administered that addressed the number of encounters with airport security, metal detector activation, additional screening procedures, and perceived inconvenience. Out of the 125 patients, 53 met inclusion criteria. Out of the 53 patients, 20 (38%) reported that their prosthesis triggered a metal detector. Out of the 20 patients, 8 (40%) who reported triggering of metal detectors also reported the presence of surgical hardware elsewhere in the body. Eighteen of the 53 patients (34%) believed having a TKA was inconvenient for airplane travel. Compared with the historical cohort, alarms were triggered in 70 of 97 patients (p = 0.0001) and 50 of 97 reported inconvenience when traveling (n = 50 of 97 patients; p = 0.04). The incidences of those who underwent TKA triggering alarms and perceiving inconvenience when passing through airport security have decreased from previously published studies. This is most likely due to the recent updates and modifications to screening. As these security measures are modified and implant designs continue to evolve, this is an area of investigation that should continue. PMID- 27776370 TI - Complications Related to Implant Fixation of Patellar Fractures: Comparison of Ring Pins versus Bent K-Wires. AB - Patellar fractures are characterized by injuries to the extensor and typically require surgical fixation. Among the methods used for fixation, the most common is the modified AO tension-band wiring technique. However, using this technique, implant migration occurs due to the lack of connections between the K-wires and the tension-band wire, which causes irritation and reduces fracture stability. Recently, new methods for tension-band wiring have been developed in which tension bands lock the K-wires through an attached "ring" to prevent migration. The purpose of this study was to compare the clinical outcomes when either the conventional or novel technique was used for tension-band wiring. This was a retrospective study involving 48 patients who underwent tension-band wiring to correct a patellar fracture. Patients in group 1 (n = 23) were treated between December 2010 and February 2012 using conventional tension-band wiring, while patients in group 2 (n = 25) were treated between March 2012 and May 2014 using the novel ring pin method. Different surgeons performed the operations in the two groups, while all other conditions were consistent. The surgical outcomes were assessed according to the level of implant migration, irritation, and implant removal procedures. All patients in group 2 achieved a union of the patella, while two patients in group 1 did not. These two patients underwent partial patellectomy within 1 year of the initial surgery. Implant migration and removal were significantly more common among patients in group 1 (p = 0.0038 and 0.011, respectively), with the implant removal period being significantly shorter as well (p = 0.005). The novel ring pin method was superior to the conventional method in terms of preventing implant migration, removal, or other secondary operations for the correction of complications. PMID- 27776371 TI - Total Knee Arthroplasty in the Younger Patient. AB - The rate of total knee arthroplasty (TKA) utilization in younger patients (< 65 years old) is increasing. Little is known regarding demographics and in-hospital outcomes in this population. The National Hospital Discharge Survey (NHDS) database was searched using International Classification of Diseases, Ninth Revision (ICD-9) procedure codes for patients admitted to U.S. hospitals for unilateral primary TKA between 2001 and 2010. Patients were separated into young (< 65 years of age) and senior cohorts (>= 65 years of age). ICD-9 diagnosis and procedure codes were used to identify demographics, hospital length of stay, in hospital adverse events, mortality, and discharge disposition. Trends were evaluated by linear regression with Pearson correlation coefficient (r) and statistical comparisons were made using Student t-test and chi-square analysis. The young cohort accounted for 38.4% of TKAs performed from 2001 to 2005, increasing to 42.7% of TKAs from 2006 to 2010. They had a higher percentage of males (36.4 vs. 34.2%, p < 0.001). Rates of obesity (11.1 vs. 6.0%, p < 0.001) and morbid obesity (5.8 vs. 1.9%, p < 0.001) were significantly higher, yet they had less comorbidities (4.7 vs. 5.2, p < 0.001), and lower rates of transfusion (12.2 vs. 19.8%, p < 0.001), pulmonary embolism (PE) (0.31 vs. 0.49%, p < 0.020), and mortality (0.03 vs. 0.18%, p < 0.001). Patients < 65 years old undergoing TKA have almost double the rate of obesity of patients >= 65 years old. This could explain the higher rates of periprosthetic infection and aseptic mechanical failure seen in younger patients. However, the young cohort had a more favorable discharge disposition and lower mortality and risk of PE than elderly patients. PMID- 27776373 TI - Arthroplasty Registries: Improving Clinical and Economic Outcomes. AB - With renewed focus on achieving value for patients in total hip and knee arthroplasty, payors, hospitals, and physicians strive to provide quality care while minimizing cost. Large registry datasets have gained popularity in the United States to track implant survivorship and outcomes after joint replacement. Partnerships among surgeons, insurers, and health systems have improved on earlier administrative datasets from Medicare to measure quality and outcomes. Participation in state and national registries can help surgeons and hospitals gain a financial advantage in several insurers' quality programs and alternative payment models. Although large dataset analysis has its limitations, all health care stakeholders will become increasingly dependent on arthroplasty registries to improve quality and control costs. PMID- 27776372 TI - Early Removal of Drainage Tube after Fast-Track Primary Total Knee Arthroplasty. AB - There is no consensus as to whether drainage tube should be used and how long it should remain in use after primary total knee arthroplasty (TKA). As fast-track (FT) program has been implemented in TKA, whether drainage tube could be removed early, and the ideal timing for removal after FT primary TKA has been a new topic. The purpose of this prospective cohort study was to evaluate the safety and feasibility of early removal of drainage tube when FT program was implemented in primary TKA. A total of 101 patients undergoing FT primary TKA were prospectively allocated into three groups. Patients in group A (31 patients) indwelled wound drainage tube for 6 hours after surgery while group B (34 patients) for 12 hours and group C (36 patients) for 18 hours. The knee circumference, resting and moving visual analogue score (VAS), hemoglobin (Hb), hematocrit, white blood count (WBC), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), interleukin-6 (IL-6), the volume of blood loss and drainage, and postoperative length of stay (LOS) among three groups were recorded and compared. There was no statistically significant difference in the volume of total and hidden blood loss among three groups (p > 0.05), but as the time of drainage prolonged, total volume of drainage and dominant blood loss increased gradually (p < 0.01). The knee circumference, the mean of resting and moving VAS, Hb, WBC, ESR, CRP, and IL-6 of three groups were similar preoperatively and on postoperative day 1 and 3 (p > 0.05), the decrease of Hb in the perioperative period and postoperative LOS as well. Early removal of wound drainage tube could drain the hematocele and reduce the risk of infection, and it doesn't increase the sense of pain, inflammatory reaction, limb swelling, and total blood loss. It's safe and feasible to remove the drainage tube within 6 to 12 hours after FT primary TKA. PMID- 27776374 TI - Investigation of Mammal Arginase Inhibitory Properties of Natural Ubiquitous Polyphenols by Using an Optimized Colorimetric Microplate Assay. AB - Polyphenols are plant secondary metabolites which possess many positive effects on human health. Although these beneficial effects could be mediated through an increase in nitric oxide synthase activity, little is known regarding the inhibitory effect of polyphenols on mammal arginase, an enzyme which competes with nitric oxide synthase for their common substrate, L-arginine. The aim of the present study was to determine the potential of a series of polyphenols as mammalian arginase inhibitors and to identify some structure-activity relationships. For this purpose, we first developed a simple and cost-effective in vitro colorimetric microplate method using commercially-available mammal bovine liver arginase (b-ARG 1). Among the ten tested polyphenolic compounds [chlorogenic acid, piceatannol, resveratrol, (-)-epicatechin, taxifolin, quercetin, fisetin, caffeic acid, quinic acid, and kaempferol], cholorogenic acid and piceatannol exhibited the highest inhibitory activities (IC50 = 10.6 and 12.1 uM, respectively) but were however less active as (S)-(2-Boronoethyl)-L-cysteine (IC50 = 3.3 uM), used as reference compound. Enzyme kinetic studies showed that both chlorogenic acid and piceatannol are competitive arginase inhibitors. Structural data identified the importance of the caffeoyl (3,4 dihydroxycinnamoyl)-part and of the catechol function in the inhibitory activity of the tested compounds. These results identified chlorogenic acid and piceatannol as two potential core structures for the design of new arginase inhibitors. PMID- 27776375 TI - Investigation of the Lignan Content in Extracts from Linum, Callitris and Juniperus Species in Relation to Their In Vitro Antiproliferative Activities. AB - Podophyllotoxin, a lignan still extracted from the rhizomes of Podophyllum hexandrum (Berberidaceae), is the starting molecule for the semisynthesis of widely used anticancer drugs such as etoposide. However, this source is threatened by the over-collection of P. hexandrum. Plants belonging to the Linaceae and Cupressaceae families could be attractive alternative sources with species that contain the lignan podophyllotoxin or its precursors and derivatives. Wild flax species, such as Linum flavum, as well as some Juniperus and Callitris species were investigated for their lignan content, and the in vitro antiproliferative capacity of their extracts was assayed on four tumor cell lines. Some of the lignans were detected by LC-HRMS for the first time in these extracts.In addition, lignans purified from these plants and compounds semisynthesized from commercially available podophyllotoxin were tested in terms of their in vitro antiproliferative activity. The genus Juniperus was the most promising given its in vitro antiproliferative effects, which were also observed with extracts from L. flavum and Callitris species.The in vitro antiproliferative effect of the plant extracts studied here appears to correlate well with the contents of the aryltetralin lignan podophyllotoxin and its glycoside as well as with deoxypodophyllotoxin and 6-methoxypodophyllotoxin. The strongest correlation between the lignan content of the extracts and the antiproliferative activity was observed for 6-methoxypodophyllotoxin. Regarding the possibility of producing large renewable amounts of 6-methoxypodophyllotoxin, this molecule could be of interest to produce new anticancer drugs and to bypass the resistance mechanisms against podophyllotoxin-derived drugs. PMID- 27776376 TI - Single-Laboratory Validation for the Determination of Flavonoids in Hawthorn Leaves and Finished Products by LC-UV. AB - Suitably validated analytical methods that can be used to quantify medicinally active phytochemicals in natural health products are required by regulators, manufacturers, and consumers. Hawthorn (Crataegus) is a botanical ingredient in natural health products used for the treatment of cardiovascular disorders. A method for the quantitation of vitexin-2"-O- rhamnoside, vitexin, isovitexin, rutin, and hyperoside in hawthorn leaf and flower raw materials and finished products was optimized and validated according to AOAC International guidelines. A two-level partial factorial study was used to guide the optimization of the sample preparation. The optimal conditions were found to be a 60-minute extraction using 50 : 48 : 2 methanol : water : acetic acid followed by a 25 minute separation using a reversed-phased liquid chromatography column with ultraviolet absorbance detection. The single-laboratory validation study evaluated method selectivity, accuracy, repeatability, linearity, limit of quantitation, and limit of detection. Individual flavonoid content ranged from 0.05 mg/g to 17.5 mg/g in solid dosage forms and raw materials. Repeatability ranged from 0.7 to 11.7 % relative standard deviation corresponding to HorRat ranges from 0.2 to 1.6. Calibration curves for each flavonoid were linear within the analytical ranges with correlation coefficients greater than 99.9 %. Herein is the first report of a validated method that is fit for the purpose of quantifying five major phytochemical marker compounds in both raw materials and finished products made from North American (Crataegus douglasii) and European (Crataegus monogyna and Crataegus laevigata) hawthorn species. The method includes optimized extraction of samples without a prolonged drying process and reduced liquid chromatography separation time. PMID- 27776377 TI - Saponins and Flavonoids from an Infusion of Herniaria hirsuta. AB - Stone diseases present a major health problem in the Western society, since both urinary and biliary stones occur with a relatively high prevalence of 10-12 % and 10-20 %, respectively, and demonstrate a high recurrence rate. At the moment treatment is mainly based on interventional procedures, or prophylactic and dissolution therapy. However, many of the current drugs cause severe side effects, and therefore, there is an increasing interest in natural medicines. At the moment no registered herbal medicinal products are available for treatment of gallstones. Since an infusion of Herniaria hirsuta L. has a proven efficacy against urolithiasis and cholelithiasis, its phytochemical composition has been investigated. Two previously undescribed triterpene saponins, 28-O-{[beta-D xylopyranosyl-(1 -> 4)-alpha-L-rhamnopyranosyl-(1 -> 2)]-[beta-D-glucopyranosyl (1-6)]-beta-D-glucopyranosyl}-medicagenic acid and 3-O-[alpha-L-rhamnopyranosyl (1 -> 3)-beta-D-glucuronopyranosyl]-28-O-{[beta-D-glucopyranosyl-(1 -> 3)-beta-D xylopyranosyl-(1 -> 4)]-[beta-D-apiofuranosyl-(1 -> 3)]-alpha-L-rhamnopyranosyl (1 -> 2)-beta-D-fucopyranosyl}-medicagenic acid and three known flavonoids, quercetin-3-O-(2"-O-alpha-L-rhamnopyranosyl)-beta-D-glucuronopyranoside, rutin, and narcissin (isorhamnetin-3-O-rutinoside), were isolated using flash chromatography and successive semi-preparative HPLC and were well characterized by MS and 1D and 2D NMR spectroscopic techniques. These findings could contribute to the development of a standardized extract that can be used in prophylaxis and treatment of gall and kidney stones. PMID- 27776378 TI - Thrombosis and Hemostasis Related Issues in Women and Pregnancy. PMID- 27776379 TI - Endoscopic Treatment of Renal Hydatid Cyst with Percutaneous Access through an All Seeing Needle. AB - A 44-year-old woman, who had had left flank pain for the previous 3 months, was treated successfully for renal hydatid cyst disease by using an endoscopic technique with percutaneous access through an all seeing needle. Abdominal ultrasonography showed a Gharbi type III cyst in the lower pole of the left kidney. Computerised tomography of the abdomen revealed a bulky solid-cystic mass with calcified and well-defined wall and daughter cyst without contrast enhancement. The patient, who refused any renal operation, underwent a percutaneous intervention with access through an all seeing needle access. There were no intraoperative or early postoperative complications. To our knowledge, this is the first published report of this minimally invasive percutaneous access technique through an all seeing needle. PMID- 27776380 TI - SANIST: optimization of a technology for compound identification based on the European Union directive with applications in forensic, pharmaceutical and food analyses. AB - Electrospray Ionization and collision induced dissociation tandem mass spectrometry are usually employed to obtain compound identification through a mass spectra match. Different algorithms have been developed for this purpose (for example the nist match algorithm). These approaches compare the tandem mass spectra of the unknown analyte with the tandem mass spectra spectra of known compounds inserted in a database. The compounds are usually identified on the basis of spectral match value associated with a probability of recognition. However, this approach is not usually applied to multiple reaction monitoring transition spectra achieved by means of triple quadrupole apparatus, mainly due to the lack of a transition spectra database. The Surface Activated Chemical Ionization-Electrospray-NIST Bayesian model database search (SANIST) platform has been recently developed for new potential metabolite biomarker discovery, to confirm their identity and to use them for clinical and diagnostic applications. Here, we present an improved version of the SANIST platform that extends its application to forensic, pharmaceutical, and food analysis studies, where the compound identification rules are strict. The European Union (EU) has set directives for compound identification (EU directive 2002/657/EC). We have applied the SANIST method to identification of 11-nor-9-carboxytetrahydro cannabinol in urine samples (an example of a forensic application), circulating levels of the immunosuppressive drug tacrolimus in blood (an example of a pharmaceutical application) and glyphosate in fruit juice (an example of a food analysis application) that meet the EU directive requirements. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27776381 TI - Molecular targets of developmental exposure to bisphenol A in diabesity: a focus on endoderm-derived organs. AB - Several studies associate foetal human exposure to bisphenol A (BPA) to metabolic/endocrine diseases, mainly diabesity. They describe the role of BPA in the disruption of pancreatic beta cell, adipocyte and hepatocyte functions. Indeed, the complexity of the diabesity phenotype is due to the involvement of different endoderm-derived organs, all targets of BPA. Here, we analyse this point delineating a picture of different mechanisms of BPA toxicity in endoderm derived organs leading to diabesity. Moving from epidemiological data, we summarize the in vivo experimental data of the BPA effects on endoderm-derived organs (thyroid, pancreas, liver, gut, prostate and lung) after prenatal exposure. Mainly, we gather molecular data evidencing harmful effects at low-dose exposure, pointing to the risk to human health. Although the fragmentation of molecular data does not allow a clear conclusion to be drawn, the present work indicates that the developmental exposure to BPA represents a risk for endoderm derived organs development as it deregulates the gene expression from the earliest developmental stages. A more systematic analysis of BPA impact on the transcriptomes of endoderm-derived organs is still missing. Here, we suggest in vitro toxicogenomics approaches as a tool for the identification of common mechanisms of BPA toxicity leading to the diabesity in organs having the same developmental origin. PMID- 27776382 TI - Randomized controlled pilot trial of naloxone-on-release to prevent post-prison opioid overdose deaths. AB - BACKGROUND AND AIMS: Naloxone is an opioid antagonist used for emergency resuscitation following opioid overdose. Prisoners with a history of heroin injection have a high risk of drug-related death soon after release from prison. The NALoxone InVEstigation (N-ALIVE) pilot trial (ISRCTN34044390) tested feasibility measures for randomized provision of naloxone-on-release (NOR) to eligible prisoners in England. DESIGN: Parallel-group randomized controlled pilot trial. SETTING: English prisons. PARTICIPANTS: A total of 1685 adult heroin injectors, incarcerated for at least 7 days pre-randomization, release due within 3 months and more than 6 months since previous N-ALIVE release. INTERVENTION: Using 1 : 1 minimization, prisoners were randomized to receive on release a pack containing either a single 'rescue' injection of naloxone or a control pack with no syringe. MEASUREMENTS: Key feasibility outcomes were tested against prior expectations: on participation (14 English prisons; 2800 prisoners), consent (75% for randomization), returned prisoner self-questionnaires (RPSQs: 207), NOR carriage (75% in first 4 weeks) and overdose presence (80%). FINDINGS: Prisons (16) and prisoners (1685) were willing to participate [consent rate, 95% confidence interval (CI) = 70-74%]; 218 RPSQs were received; NOR-carriage (95% CI = 63-79%) and overdose presence (95% CI = 75-84%) were as expected. We randomized 842 to NOR and 843 to control during 30 months but stopped early, because only one-third of NOR administrations were to the ex-prisoner. Nine deaths within 12 weeks of release were registered for 1557 randomized participants released before 9 December 2014. CONCLUSIONS: Large randomized trials are feasible with prison populations. Provision of take-home emergency naloxone prior to prison release may be a life-saving interim measure to prevent heroin overdose deaths among ex prisoners and the wider population. PMID- 27776383 TI - Clozapine Monitoring in Clinical Practice: Beyond the Mandatory Requirement. AB - Clozapine is effective in treatment resistant schizophrenia; however, it is underutilised probably because of its side effects. The side effects are also the potential reasons for clozapine discontinuation. A mandatory requirement for its use is regular monitoring of white blood cell count and absolute neutrophil count. However there are many side effects that need monitoring in clinical practice considering their seriousness. This article tries to summarise the clinical concerns surrounding the serious side effects of clozapine some of which are associated with fatalities and presents a comprehensive way to monitor patients on clozapine in clinical practice. It emphasizes the need to broaden the monitoring beyond the mandatory investigations. This may help in improving the safety in clinical practice and increasing clinician confidence for greater and appropriate use of this effective intervention. PMID- 27776384 TI - Neuro-stimulation Techniques for the Management of Anxiety Disorders: An Update. AB - Neuro-stimulation techniques have gradually evolved over the decades and have emerged potential therapeutic modalities for the treatment of psychiatric disorders, especially treatment refractory cases. The neuro-stimulation techniques involves modalities like electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS) and others. This review discusses the role of neuro-stimulation techniques in the treatment of anxiety disorders. The various modalities of neuro-stimulation techniques are briefly discussed. The evidence base relating to use of these techniques in the treatment of anxiety disorders is discussed further. The review then highlights the challenges in conducting research in relation to the use of neuro-stimulation techniques with reference to patients with anxiety disorders. The review provides the future directions of research and aimed at expanding the evidence base of treatment of anxiety disorders and providing neuro-stimulation techniques as promising effective and acceptable alternative in select cases. PMID- 27776385 TI - Valproic Acid Exposure during Early Postnatal Gliogenesis Leads to Autistic-like Behaviors in Rats. AB - Objective: We reported that postnatal exposure of rats to valproic acid (VPA) stimulated proliferation of glial precursors during cortical gliogenesis. However, there are no reports whether enhanced postnatal gliogenesis affects behaviors related to neuropsychiatric disorders. Methods: After VPA treatment during the postnatal day (PND) 2 to PND 4, four behavioral test, such as open field locomotor test, elevated plus maze test, three-chamber social interaction test, and passive avoidance test, were performed at PND 21 or 22. Results: VPA treated rats showed significant hyperactive behavior in the open field locomotor test (p<0.05). Moreover, the velocity of movement in the VPA group was increased by 69.5% (p<0.01). In the elevated plus maze test, VPA exposed rats expressed significantly lower percentage of time spent on and of entries into open arms more than the control group (p<0.05). Also, both sociability and social preference indices with strangers in the three-chamber social interaction test were significantly lower in the VPA exposed rats (p<0.05). Conclusion: Our results suggest that altered glial cell development is another locus at which pathogenetic factors can operate to contribute to the neurodevelopmental disorder. PMID- 27776386 TI - Evaluation of Paraoxonase, Arylesterase and Malondialdehyde Levels in Schizophrenia Patients Taking Typical, Atypical and Combined Antipsychotic Treatment. AB - Objective: Human serum paraoxonase (PON1) prevents lipids from peroxidation and functions as an antioxidant mechanism. Malonyldialdehyde (MDA) is the final product of lipid peroxidation and can be used as an indicator of oxidative stress. The aim of this study was to investigate PON1, MDA, and arylesterase (ARY) levels in schizophrenic patients who are taking typical, atypical, or combined (typical and atypical) antipsychotic drug treatment, with respect to those of healthy controls. Methods: We evaluated 41 patients (11 taking typical antipsychotics, 19 taking atypical antipsychotics, 11 taking combined antipsychotics) and 43 healthy controls. Results: MDA levels were higher in schizophrenic patients taking typical antipsychotics compared with healthy controls (p=0.001). ARY levels were higher in patients taking atypical antipsychotics compared with healthy controls (p=0.005). PON1 activity was similar in all groups. Conclusion: Our results indicate that treatment with typical antipsychotic drugs could be related to increased MDA levels; and antipsychotic medication may increase PON1 levels in schizophrenic patients. PMID- 27776387 TI - Agomelatine versus Sertraline: An Observational, Open-labeled and 12 Weeks Follow up Study on Efficacy and Tolerability. AB - Objective: In this open-labeled, 12 weeks follow-up study, we aimed to compare the efficacy and tolerability of agomelatine with sertraline. Methods: The outpatients of adult psychiatry clinic who have a new onset of depression and diagnosed as 'major depressive episode' by clinician according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition and prescribed agomelatine (25 mg/day) or sertraline (50 mg/day) were included in the study. Results: The decline of mean Montgomery-Asberg Depression Rating Scale (MADRS) scores of agomelatine group was significantly higher than the sertraline group at the end of 2nd week; however, the difference was not significant at the end of 3 months. Mean Clinical Global Impression-Improvement scale (CGI-I) scores of agomelatine group was lower than sertraline group at first week. Mean CGI-Severity scale and CGI-I scores were favour to sertraline group at the end of the study. Remission rates were 46.7% for sertraline group and 33.3% for agomelatine group while response rates were 76.7% for both groups. Any patient from agomelatine group dropped-out due to adverse effects. The amount of side effects was also less with agomelatine. Conclusion: Agomelatine has a rapid onset efficacy on depressive symptoms and this can be beneficial for some critical cases. Considering MADRS scores, agomelatine seems to have similar efficacy with sertraline but we also point the need for long term studies since CGI scores were favour to sertraline group at the end of the study. Agomelatine has a favourable tolerability profile both in terms of discontinuation and the amount of side effects compared to sertraline. PMID- 27776388 TI - The Effects of Equine-assisted Activities and Therapy on Resting-state Brain Function in Attention-deficit/Hyperactivity Disorder: A Pilot Study. AB - Objective: Equine-assisted activities and therapy (EAA/T) have been used as adjunct treatment options for physical and psychosocial rehabilitation. However, the therapeutic effects on resting-state brain function have not yet been studied. The aim of this study is to investigate the effects of EAA/T on participants with attention-deficit/hyperactivity disorder (ADHD) by comparing resting-state functional magnetic resonance imaging (rs-fMRI) signals and their clinical correlates. Methods: Ten participants with ADHD participated in a 12 week EAA/T program without any medication. Two rs-fMRIs were acquired for all participants before and after EAA/T. For estimating therapeutic effect, the regional homogeneity (ReHo) method was applied to capture the changes in the regional synchronization of functional signals. Results: After the EAA/T program, clear symptom improvement was found even without medication. Surface-based pairwise comparisons revealed that ReHo in the right precuneus and right pars orbitalis clusters had significantly diminished after the program. Reduced ReHo in the right precuneus cluster was positively correlated with changes in the scores on DuPaul's ADHD Rating Scale-Korean version. Conclusion: Our results indicate that EAA/T is associated with short-range functional connectivity in the regions related to the default mode network and the behavioral inhibition system, which are associated with symptom improvement. PMID- 27776389 TI - Arterial Stiffness in Patients Taking Second-generation Antipsychotics. AB - Objective: That treatment with second-generation antipsychotics (SGAs) causes metabolic side effects and atherosclerosis in patients with schizophrenia and bipolar disorder (BD) is well-known. Increased arterial stiffness is an important marker of arteriosclerosis and has been identified as an independent risk factor for cardiovascular diseases. We measured pulse wave velocity (PWV) as a marker of arteriosclerosis in patients with schizophrenia and BD who use SGAs. Methods: Patients and controls were collected from our psychiatry outpatient clinics or family medicine. Mental illness was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Mean age, gender, systolic and diastolic blood pressure, body mass index, Framingham risk score (FRS), etc. were determined. Simultaneous electrocardiography and pulse wave were recorded with an electromyography device. The photo-plethysmographic method was used to record the pulse wave. Inclusion criteria included use of SGAs for at least the last six months. Patients with diseases that are known to cause stiffness and the use of typical antipsychotics were excluded. Results: Ninety-six subject (56 patients, 40 controls) were included in our study. There were 49 females, 47 males. Patients had schizophrenia (n=17) and BD (n=39). Their treatments were quetiapine (n=15), risperidone (n=13), olanzapine (n=15), and aripiprazole (n=13). Although differences in mean age, gender, and FRS in the patient and control groups were not statistically significant (p=1), PWV was greater in patients in the antipsychotic group (p=0.048). Conclusion: This study supported the liability to stiffness in patients with schizophrenia and BD. Using SGAs may contribute to arterial stiffness in these patients. PMID- 27776390 TI - Amisulpride Switching in Schizophrenic Patients Who Showed Suboptimal Effect and/or Tolerability to Current Antipsychotics in a Naturalistic Setting: An Explorative Study. AB - Objective: Despite numerous atypical antipsychotics (AAP) available, many patients with schizophrenia still experience lack of efficacy and persistent side effects. Switching from one AAP to another with a different side-effect profile has become a common clinical strategy. We aimed to investigate effect of switching to amisulpride in patients who showed suboptimal effect and /or tolerability to current antipsychotics treatment. Methods: This was a 6-week, prospective, multicenter, open-label, flexible-dose study in patients with schizophrenia. Switching to amisulpride was achieved using cross-titration within 7 days (day 1: 300 mg on day 1 then flexibly dosed 400-800 mg/day). The primary end-point measure was proportion of patients achieving improvement in clinical benefit at week 6 based on Clinical Global Impressions-Clinical Benefit (CGI-CB). Secondary endpoints included change in scores in CGI-CB, CGI-Severity (CGI-S), Subjective Satisfaction Scores (SSS), Brief Psychiatric Rating Scale (BPRS), and Simpson and Angus Rating Scale. Results: Among 37 patients switched to amisulpride, 76% completed study and 56.8% had clinical benefit measure by CGI CB. CGI-CB and CGI-S scores showed significant improvement at week 6 compared to baseline (mean changes of CGI-CB and CGI-S scores: -1.7+1.0, p<0.0001 and -0.6+/ 0.0, p=0.001, respectively). SSS scores also improved significantly (mean change: 2.1+/-2.6, p<0.0001). Mean weight of patients significantly lowered compared to baseline (mean change: -1.2+/-2.0, p<0.0001). Conclusion: Patients with schizophrenia who showed suboptimal efficacy or tolerability with their current antipsychotics and thereby switched to amisulpride resulted in clinical benefit in terms of both improved efficacy and tolerability. The small sample size limits generalizability of the study results. PMID- 27776391 TI - Association between Cerebral Amyloid Deposition and Clinical Factors Including Cognitive Function in Geriatric Depression: Pilot Study Using Amyloid Positron Emission Tomography. AB - The purpose of this study was to explore the relationship between cerebral amyloid deposition and overall clinical factors including cognitive functions in geriatric depression by using 18F-florbetaben positron emission tomography. Thirteen subjects aged over 60 years who had a history of major depressive disorder and also had subjective memory complaint were included. Of all subjects, 3 subjects judged as amyloid positive, and the others judged as amyloid negative. Their memory, visuospatial functions and attention abilities were negatively correlated with amyloid deposition in specific brain regions, but their language and recognition abilities were not correlated with any region. The amyloid deposition of the whole brain region was significantly negatively correlated with immediate memory. PMID- 27776392 TI - Predictors of Suicide Attempts in Clinically Depressed Korean Adolescents. AB - We examined predictors of suicide attempts in clinically depressed adolescents in Korea and gender differences in suicidal behavior. In total, 106 adolescents diagnosed with depressive disorder were recruited in South Korea. We assessed various variables that might affect suicide attempts, and used a structured interview for the diagnosis of depression and comorbidities and to evaluate suicidality. Demographic and clinical characteristics of the subjects were compared between suicide attempt and non-suicide attempt groups and we examined significant predictors of suicide attempts. Gender differences in suicidal ideation and suicidal behavior were also analyzed. Among 106 depressed participants, 50 (47.2%) adolescents were classified in the suicide attempt group. Generally, the suicide attempt and non-suicide attempt group shared similar clinical characteristics. The suicide attempt group had more females, more major depressive disorder diagnoses, more depressive episodes, and higher suicidal ideation than the non-suicide attempt group. Suicidal ideation was the only significant predictor of suicidal attempt, regardless of gender. Higher suicidal ideation frequency scores and more non-suicidal self-injurious behaviors were shown in the female suicide attempt group than the male suicide attempt group. It is recommended that suicidal ideation be assessed regularly and managed rigorously to decrease suicide risks in depressive adolescents. PMID- 27776393 TI - Serotonin Syndrome after Clomipramine Overdose in a Child. AB - Serotonin syndrome (SS) is a potentially life-threatening condition associated with increased serotonergic activity in central nervous system and may occur during the use of serotonergic drugs. Although increasing frequency of serotonergic drug use in children, pediatricians, emergency medicine and pediatric intensive care specialists have not enough knowledge and experience about SS that is a potentially life-threatening condition. A 12-year-old girl patient was admitted to our emergency room with the history of involuntary contractions on her extremities and alteration of consciousness. Her physical examination showed agitation, hyperthermia, dilated pupils, tremor, increased deep tendon reflexes, positive spontaneous clonus, agitation, flushed skin and diaphoresis, excessive perspiration, and continuous horizontal ocular movements. The patient diagnosed as SS by clinical history, physical and laboratory findings. In this paper, we will discuss SS occurred in a 12-year-old girl after concurrent clomipramine and risperidone use. PMID- 27776394 TI - Efficacy of Adenine in the Treatment of Leukopenia and Neutropenia Associated with an Overdose of Antipsychotics or Discontinuation of Lithium Carbonate Administration: Three Case Studies. AB - Because adenine is effective for managing cases of radiation-induced and drug induced leukopenia, it may be effective in cases of antipsychotic-induced leukopenia and neutropenia. Here, we report our experience with patients with leukopenia and neutropenia caused by an antipsychotic overdose or discontinuation of lithium carbonate, in whom adenine administration ameliorated the white blood cell and neutrophil counts. The progress of patients suggests that adenine is effective in cases of leukopenia and neutropenia associated with lithium carbonate discontinuation and an antipsychotic overdose. PMID- 27776395 TI - Recurrence of Panic Attacks after Influenza Vaccination: Two Case Reports. AB - Human influenza is a contagious respiratory illness caused by the influenza virus. The influenza vaccination is recommended annually, but several adverse effects related to allergic reactions have been reported. Panic attacks are also known to occur, but no case of a panic attack adverse effect has been reported in South Korea. We present two cases of panic disorder patients whose symptoms were aggravated by the influenza vaccination. We assumed that dysregulation of T lymphocytes in panic disorder patients could have a role in activating various kinds of cytokines and chemokines, which then can lead to panic attack aggravation. PMID- 27776396 TI - Venous Thromboembolism Following Dantrolene Treatment for Neuroleptic Malignant Syndrome. AB - Neuroleptic malignant syndrome (NMS) is one of the most severe iatrogenic emergencies in clinical service. The symptoms including sudden consciousness change, critical temperature elevation and electrolytes imbalance followed by mutli-organ system failure were common in NMS. In addition to aggressive interventions with intravenous fluid resuscitation and antipyretics, several antidotes have been suggested to prevent further progression of the muscle damage. Dantrolene has been reported to be one of the most effective treatments for NMS. However, the adverse effects of dantrolene treatment for NMS have not yet been evaluated thoroughly. Here we report a young male patient with bipolar I disorder who developed NMS after rapid tranquilization with haloperidol. Dantrolene was given intravenously for the treatment of NMS. However, fever accompanied with local tenderness, hardness with clear border and swelling with heat over the patient's left forearm occurred on the sixth day of dantrolene treatment. Venous thromboembolism (VTE) over intravenous indwelling site at the patient's forearm was noted and confirmed by Doppler ultrasound. The patient's VTE recovered after heparin and warfarin thrombolytic therapy. To our knowledge, this is the first case report demonstrating the possible relationship between dantrolene use and VTE in a patient with antipsychotic treatment. Although the causal relationship and the underlying pathogenesis require further studies, dantrolene should be used with caution for patients with NMS. PMID- 27776397 TI - Modafinil Dependence and Hypersexuality: A Case Report and Review of the Evidence. AB - Apart from sleep wake disorders, nowadays, modafinil is being prescribed for several psychiatric disorders including depression. Despite being reported as to be having very low abuse potential, cases of modafinil dependence had come to the limelight. In this case report, we describe a 35 year old man with bipolar affective disorder while in remission who developed modafinil dependence and later on, had hypersexuality when he increased the dose of modafinil from 400 to 1,000 mg/day. Existing literature suggests that modafinil when taken above prescribed doses can cause many side effects ranging from nausea, vomiting to psychotic exacerbation and mania. However, hypersexuality as a side effect of modafinil overuse is not commonly seen. The exact pathophysiological mechanism of modafinil induced hypersexuality is not clear. Clinicians should be aware of possibility of modafinil leading to dependence and this rare significant side effect of modafinil. PMID- 27776398 TI - The Relief Effects of Ramelteon on Refractory Chronic Migraine: A Case Report. AB - The selective melatonin receptor agonism effect of ramelteon is useful for insomnia. Here we wanted to present a refractory chronic migraine case, who had significant improvements in migraine after using ramelteon. The possible mechanism for the ramelteon in the migraine relief might be related to melatonin effects. PMID- 27776399 TI - Hallucinations after Ingesting a High Dose of Benzydamine Hydrochloride. PMID- 27776400 TI - Effects of an integrated geriatric group balance class within an entry-level Doctorate of Physical Therapy program on students' perceptions of geriatrics and geriatric education in the United States. AB - This study was aimed at determining the effect of an integrated group balance class for community-dwelling older adults within entry-level physical therapist coursework on student perceptions of geriatric physical therapy and geriatric physical therapy education. Twenty-nine Doctor of Physical Therapy (DPT) students, 21-33 years old, in their second year of coursework in 2012, participated in an integrated clinical experience with exposure to geriatric patients at an outpatient facility at the Louis Stokes Cleveland Department of Veterans Affairs Medical Center in Akron, Ohio, USA. Student perceptions were collected before and after participation in the 8-week balance class. The Wilcoxon sign-ranked test was used to identify differences in perceptions after participation in the group balance class. Cohen's d values were calculated to measure the size of the pre-participation to post-participation effect for each measure. At the conclusion of the group class, the DPT students demonstrated an increase in positive perceptions of geriatric physical therapy in 8 measures, with small effect sizes (d=0.15-0.30). Two perceptions of geriatric physical therapy demonstrated a significant positive increase (P<.05) with moderate effect sizes (d=0.47 and d=0.50). The students' perceptions of geriatric education in the curriculum demonstrated a large positive effect for quality (d=1.68) and enjoyment (d=1.96). Positive changes were found in most of the perceptions of geriatrics and geriatric education after participation, suggesting that integrated clinical experiences with geriatric patients are an effective way to positively influence perceptions of physical therapist practice with older adults. PMID- 27776402 TI - The value of intraoperative ultrasonography during the resection of relapsed irradiated malignant gliomas in the brain. AB - PURPOSE: The aim of this study was to investigate whether intraoperative ultrasonography (IOUS) helped the surgeon navigate towards the tumor as seen in preoperative magnetic resonance imaging and whether IOUS was able to distinguish between tumor margins and the surrounding tissue. METHODS: Twenty-five patients suffering from high-grade gliomas who were previously treated by surgery and radiotherapy were included. Intraoperatively, two histopathologic samples were obtained a sample of unequivocal tumor tissue (according to anatomical landmarks and the surgeon's visual and tactile impressions) and a small tissue sample obtained using a navigated needle when the surgeon decided to stop the resection. This specimen was considered to be a boundary specimen, where no tumor tissue was apparent. The decision to take the second sample was not influenced by IOUS. The effect of IOUS was analyzed semi-quantitatively. RESULTS: All 25 samples of unequivocal tumor tissue were histopathologically classified as tumor tissue and were hyperechoic on IOUS. Of the boundary specimens, eight were hypoechoic. Only one harbored tumor tissue (P=0.150). Seventeen boundaries were moderately hyperechoic, and these samples contained all possible histological results (i.e., tumor, infiltration, or no tumor). CONCLUSION: During surgery performed on relapsed, irradiated, high-grade gliomas, IOUS provided a reliable method of navigating towards the core of the tumor. At borders, it did not reliably distinguish between remnants or tumor-free tissue, but hypoechoic areas seldom contained tumor tissue. PMID- 27776401 TI - Assessing the blood pressure waveform of the carotid artery using an ultrasound image processing method. AB - PURPOSE: The aim of this study was to introduce and implement a noninvasive method to derive the carotid artery pressure waveform directly by processing diagnostic sonograms of the carotid artery. METHODS: Ultrasound image sequences of 20 healthy male subjects (age, 36+/-9 years) were recorded during three cardiac cycles. The internal diameter and blood velocity waveforms were extracted from consecutive sonograms over the cardiac cycles by using custom analysis programs written in MATLAB. Finally, the application of a mathematical equation resulted in time changes of the arterial pressure. The resulting pressures were calibrated using the mean and the diastolic pressure of the radial artery. RESULTS: A good correlation was found between the mean carotid blood pressure obtained from the ultrasound image processing and the mean radial blood pressure obtained using a standard digital sphygmomanometer (R=0.91). The mean absolute difference between the carotid calibrated pulse pressures and those measured clinically was -1.333+/-6.548 mm Hg. CONCLUSION: The results of this study suggest that consecutive sonograms of the carotid artery can be used for estimating a blood pressure waveform. We believe that our results promote a noninvasive technique for clinical applications that overcomes the reproducibility problems of common carotid artery tonometry with technical and anatomical causes. PMID- 27776403 TI - Fructosazine, a Polyhydroxyalkylpyrazine with Antimicrobial Activity: Mechanism of Inhibition against Extremely Heat Resistant Escherichia coli. AB - Fructosazine is a polyhydroxyalkylpyrazine recently reported to have antimicrobial activity against heat-resistant Escherichia coli AW 1.7. This study investigated fructosazine's antimicrobial mechanism of action and compared it to that of riboflavin. Fructosazine-acetic acid was effective in permeabilizing the outer membrane based on an evaluation of bacterial membrane integrity using 1-N phenyl-1-naphthylamine and propidium iodide. The uptake of fructosazine by E. coli was pH-dependent with a greater uptake at pH 5 compared to pH 7 for all times throughout 16 h, except 2, 3, and 10 h. Fructosazine generates 1O2, which is partially why it damages E. coli. DNA fragmentation was confirmed by fluorescence microscopy, and the fructosazine-acetic acid was the second most intense treatment after riboflavin-acetic acid. Electron microscopy revealed membrane structural damage by fructosazine at pH 5 and 7. This study provides evidence that fructosazine exerts antimicrobial action by permeabilizing the cell membrane, damaging membrane integrity, and fragmenting DNA. PMID- 27776405 TI - Comment on "Nanohole-Structured and Palladium-Embedded 3D Porous Graphene for Ultrahigh Hydrogen Storage and CO Oxidation Multifunctionalities". PMID- 27776406 TI - ChemRXiv: A Chemistry Preprint Server. PMID- 27776404 TI - Curcumin Inhibits Protein Kinase Calpha Activity by Binding to Its C1 Domain. AB - Curcumin is a polyphenolic nutraceutical that acts on multiple biological targets, including protein kinase C (PKC). PKC is a family of serine/threonine kinases central to intracellular signal transduction. We have recently shown that curcumin selectively inhibits PKCalpha, but not PKCepsilon, in CHO-K1 cells [Pany, S. (2016) Biochemistry 55, 2135-2143]. To understand which domain(s) of PKCalpha is responsible for curcumin binding and inhibitory activity, we made several domain-swapped mutants in which the C1 (combination of C1A and C1B) and C2 domains are swapped between PKCalpha and PKCepsilon. Phorbol ester-induced membrane translocation studies using confocal microscopy and immunoblotting revealed that curcumin inhibited phorbol ester-induced membrane translocation of PKCepsilon mutants, in which the epsilonC1 domain was replaced with alphaC1, but not the PKCalpha mutant in which alphaC1 was replaced with the epsilonC1 domain, suggesting that alphaC1 is a determinant for curcumin's inhibitory effect. In addition, curcumin inhibited membrane translocation of PKCepsilon mutants, in which the epsilonC1A and epsilonC1B domains were replaced with the alphaC1A and alphaC1B domains, respectively, indicating the role of both alphaC1A and alphaC1B domains in curcumin's inhibitory effects. Phorbol 13-acetate inhibited the binding of curcumin to alphaC1A and alphaC1B with IC50 values of 6.27 and 4.47 MUM, respectively. Molecular docking and molecular dynamics studies also supported the higher affinity of curcumin for alphaC1B than for alphaC1A. The C2 domain-swapped mutants were inactive in phorbol ester-induced membrane translocation. These results indicate that curcumin binds to the C1 domain of PKCalpha and highlight the importance of this domain in achieving PKC isoform selectivity. PMID- 27776407 TI - Reply to "Comment on 'Nanohole-Structured and Palladium-Embedded 3D Porous Graphene for Ultrahigh Hydrogen Storage and CO Oxidation Multifunctionalities'". PMID- 27776408 TI - An Emerging Grip on the Growth of Grounded Bacteria. AB - Understanding the mechanisms that are involved in determining bacterial growth rates is fundamental to infection biology, yet the factors that influence bacterial growth variation on surfaces are largely unknown. In this issue of ACS Nano, Lee et al. track individual bacteria on surfaces for several generations to discover systematic differences in growth rate variation between cells that disperse from surfaces and cells that remain attached to surfaces. These growth rate distributions were shown to be strongly influenced by extracellular motility appendages. We provide a perspective on these results and discuss prospects for future work on the interactions between bacteria and surfaces. PMID- 27776410 TI - Live Cell Electron Microscopy Is Probably Impossible. AB - Electron microscopy of biological cells in liquid provides unique nanoscale information. A highly attractive idea is the capability to also study physiological processes of live cells with electron microscopy. However, this idea seems unrealistic because the minimal needed electron dose to obtain contrast is already many orders of magnitude above the lethal dose known to cause reproductive-cell death. We show here that claims of electron microscopy of viable cells in recent reports are based on a questionable interpretation of the used fluorescence live/dead assay. A practical alternative to study biological processes is correlative light and electron microscopy. PMID- 27776411 TI - Quasi-Flat Plasmonic Bands in Twisted Bilayer Graphene. AB - The charge susceptibility of twisted bilayer graphene is investigated in the Dirac cone, respectively, random-phase approximation. For small enough twist angles theta ? 2 degrees , we find weakly Landau damped interband plasmons, that is, collective excitonic modes that exist in the undoped material with an almost constant energy dispersion. In this regime, the loss function can be described as a Fano resonance, and we argue that these excitations arise from the interaction of quasi-localized states with the incident light field. These predictions can be tested by nanoinfrared imaging and possible applications include a "perfect" lens without the need of left-handed materials. PMID- 27776412 TI - Molecular Dynamics Analysis of 4E-BP2 Protein Fold Stabilization Induced by Phosphorylation. AB - Protein phosphorylation can affect the interaction with partner proteins but can also induce conformational transitions. In case of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) threonine (Thr) phosphorylation at two turn motifs results in transition from a disordered to a folded structure. In order to elucidate the stabilizing mechanism we employed comparative molecular dynamics (MD) free energy simulations on the turn motifs indicating that Thr phosphorylation favors a folded whereas dephosphorylation or substitution by Glu residues destabilizes the turn structure. In multiple unrestrained MD simulations at elevated temperature of the 4E-BP2 domain only the double phosphorylated variant remained close to the folded structure in agreement with experiment. Three surface Arg residues were identified as additional key elements for the tertiary structure stabilization of the whole phosphorylated domain. In addition to the local turn structure double phosphorylation also leads to an overall electrostatic stabilization of the folded form compared to wild type and other investigated variants of 4E-BP2. The principles of phosphorylation mediated fold stabilization identified in the present study may also be helpful for identifying other structural motifs that can be affected by phosphorylation or provide a route to design such motifs. PMID- 27776413 TI - Characterization and Quantitation of Vitamin B12 Compounds in Various Chlorella Supplements. AB - Vitamin B12 was determined and characterized in 19 dried Chlorella health supplements. Vitamin contents of dried Chlorella cells varied from <0.1 MUg to approximately 415 MUg per 100 g of dry weight. Subsequent liquid chromatography/electrospray ionization-tandem mass spectrometry analyses showed the presence of inactive corrinoid compounds, a cobalt-free corrinoid, and 5 methoxybenzimidazolyl cyanocobamide (factor IIIm) in four and three high vitamin B12-containing Chlorella tablets, respectively. In four Chlorella tablet types with high and moderate vitamin B12 contents, the coenzyme forms of vitamin B12 5' deoxyadenosylcobalamin (approximately 32%) and methylcobalamin (approximately 8%) were considerably present, whereas the unnaturally occurring corrinoid cyanocobalamin was present at the lowest concentrations. The species Chlorella sorokiniana (formerly Chlorella pyrenoidosa) is commonly used in dietary supplements and did not show an absolute requirement of vitamin B12 for growth despite vitamin B12 uptake from the medium being observed. In further experiments, vitamin B12-dependent methylmalonyl-CoA mutase and methionine synthase activities were detected in cell homogenates. In particular, methionine synthase activity was significantly increased following the addition of vitamin B12 to the medium. These results suggest that vitamin B12 contents of Chlorella tablets reflect the presence of vitamin B12-generating organic ingredients in the medium or the concomitant growth of vitamin B12-synthesizing bacteria under open culture conditions. PMID- 27776414 TI - Mechanism of Arachidonic Acid Accumulation during Aging in Mortierella alpina: A Large-Scale Label-Free Comparative Proteomics Study. AB - Arachidonic acid (ARA) is an important polyunsaturated fatty acid having various beneficial physiological effects on the human body. The aging of Mortierella alpina has long been known to significantly improve ARA yield, but the exact mechanism is still elusive. Herein, multiple approaches including large-scale label-free comparative proteomics were employed to systematically investigate the mechanism mentioned above. Upon ultrastructural observation, abnormal mitochondria were found to aggregate around shrunken lipid droplets. Proteomics analysis revealed a total of 171 proteins with significant alterations of expression during aging. Pathway analysis suggested that reactive oxygen species (ROS) were accumulated and stimulated the activation of the malate/pyruvate cycle and isocitrate dehydrogenase, which might provide additional NADPH for ARA synthesis. EC 4.2.1.17-hydratase might be a key player in ARA accumulation during aging. These findings provide a valuable resource for efforts to further improve the ARA content in the oil produced by aging M. alpina. PMID- 27776415 TI - Side-Chain Isomerization on an n-type Organic Semiconductor ITIC Acceptor Makes 11.77% High Efficiency Polymer Solar Cells. AB - Low bandgap n-type organic semiconductor (n-OS) ITIC has attracted great attention for the application as an acceptor with medium bandgap p-type conjugated polymer as donor in nonfullerene polymer solar cells (PSCs) because of its attractive photovoltaic performance. Here we report a modification on the molecular structure of ITIC by side-chain isomerization with meta-alkyl-phenyl substitution, m-ITIC, to further improve its photovoltaic performance. In a comparison with its isomeric counterpart ITIC with para-alkyl-phenyl substitution, m-ITIC shows a higher film absorption coefficient, a larger crystalline coherence, and higher electron mobility. These inherent advantages of m-ITIC resulted in a higher power conversion efficiency (PCE) of 11.77% for the nonfullerene PSCs with m-ITIC as acceptor and a medium bandgap polymer J61 as donor, which is significantly improved over that (10.57%) of the corresponding devices with ITIC as acceptor. To the best of our knowledge, the PCE of 11.77% is one of the highest values reported in the literature to date for nonfullerene PSCs. More importantly, the m-ITIC-based device shows less thickness-dependent photovoltaic behavior than ITIC-based devices in the active-layer thickness range of 80-360 nm, which is beneficial for large area device fabrication. These results indicate that m-ITIC is a promising low bandgap n-OS for the application as an acceptor in PSCs, and the side-chain isomerization could be an easy and convenient way to further improve the photovoltaic performance of the donor and acceptor materials for high efficiency PSCs. PMID- 27776417 TI - Redox-Active Carbohydrate-Coated Nanoparticles: Self-Assembly of a Cyclodextrin Polystyrene Glycopolymer with Tetrazine-Naphthalimide. AB - The controlled self-assembly of precise and well-defined photochemically and electrochemically active carbohydrate-coated nanoparticles offers the exciting prospect of biocompatible catalysts for energy storage/conversion and biolabeling applications. Here an aqueous nanoparticle system has been developed with a versatile outer layer for host-guest molecule encapsulation via beta-cyclodextrin inclusion complexes. A beta-cyclodextrin-modified polystyrene polymer was first obtained by copper nanopowder click chemistry. The glycopolymer enables self assembly and controlled encapsulation of tetrazine-naphthalimide, as a model redox-active agent, into nanoparticles via nanoprecipitation. Cyclodextrin host guest interactions permit encapsulation and internanoparticle cross-linking for the formation of fluorescent compound and clustered self-assemblies with chemically reversible electroactivity in aqueous solution. Light scattering experiments revealed stable particles with hydrodynamic diameters of 138 and 654 nm for nanoparticles prepared with tetrazine, of which 95% of the nanoparticles represent the smaller objects by number. Dynamic light scattering revealed differences as a function of preparation method in terms of size, 3-month stability, polydispersity, radius of gyration, and shape factor. Individual self assemblies were visualized by atomic force microscopy and fluorescence microscopy and monitored in real-time by nanoparticle tracking analysis. UV-vis and fluorescence spectra provided insight into the optical properties and critical evidence for host-guest encapsulation as evidenced by solvachromatism and enhanced tetrazine uptake. Cyclic voltammetry was used to investigate the electrochemical properties and provided further support for encapsulation and an estimate of the tetrazine loading capacity in tandem with light scattering data. PMID- 27776416 TI - TiO2-ZnS Cascade Electron Transport Layer for Efficient Formamidinium Tin Iodide Perovskite Solar Cells. AB - Achieving high open-circuit voltage (Voc) for tin-based perovskite solar cells is challenging. Here, we demonstrate that a ZnS interfacial layer can improve the Voc and photovoltaic performance of formamidinium tin iodide (FASnI3) perovskite solar cells. The TiO2-ZnS electron transporting layer (ETL) with cascade conduction band structure can effectively reduce the interfacial charge recombination and facilitate electron transfer. Our best-performing FASnI3 perovskite solar cell using the cascaded TiO2-ZnS ETL has achieved a power conversion efficiency of 5.27%, with a higher Voc of 0.380 V, a short-circuit current density of 23.09 mA cm-2, and a fill factor of 60.01%. The cascade structure is further validated with a TiO2-CdS ETL. Our results suggest a new approach for further improving the performance of tin-based perovskite solar cells with a higher Voc. PMID- 27776418 TI - Twenty-five years on: outcomes of a longitudinal evaluation of the NSW Rural Resident Medical Officer Cadetship Program. AB - INTRODUCTION: The New South Wales Rural Resident Medical Officer Cadetship Program began in 1988 as a strategy to increase the numbers of junior doctors in rural hospitals. This article outlines the results of an evaluation undertaken in 2014. Specifically, it will look at where former cadets who entered the program between 1989 and 2010 were working in 2014, what training programs they chose and their attitudes toward the program. METHOD: Data were collected using a semi structured questionnaire sent to all the former cadets who entered the program from 1989 until 2010. This included self-administered questions relating to background (where the majority of the students' primary schooling was undertaken), vocational training, current role, current work location and attitudes towards the cadetship. Responses were received from 142 of the 211 cadets in the study (67%). RESULTS: Of the 142 former cadets who responded to the questionnaire, 90 had completed a vocational training program and were working as fully qualified medical practitioners. A further 44 were trainees, six were non specialist hospital doctors and two were no longer practising. Overall, the most popular vocational training programs among fully qualified doctors and trainees combined were general practice, anaesthetics/intensive care and emergency medicine. Over half of the cadets included in the analysis (n=74, 53%) were working in rural areas (Australian Standard Geographical Classification Remoteness Areas 2-5) in 2014 and practice location was significantly (p<0.001) influenced by career choice. Of the cadets working in rural locations, the majority (58%) were working as general practitioners while 38% had chosen other specialties and 4% were working as hospital non-specialists. An equal proportion of cadets came from urban and rural backgrounds while a small proportion grew up overseas. The cadets with rural backgrounds were more likely to choose general practice than those from urban backgrounds. A similar analysis of cadets comparing geographic background and practice location showed cadets of rural background were more likely to be working in a rural location than cadets of urban background. CONCLUSIONS: The cadetship is an effective link between medical school and rural practice. The success of the program relies in part on the mentoring, networking and other educational opportunities available to cadets, which serve to foster their interest and provide a structured pathway to long-term rural practice. It has been demonstrated that targeted incentive based scholarship schemes with a return-of-service component can be beneficial, particularly where they include ongoing support and reinforcement throughout the transition from undergraduate to postgraduate training. PMID- 27776419 TI - Panobinostat for the management of multiple myeloma. AB - Multiple myeloma (MM) is the second most common blood cancer following non Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM. PMID- 27776420 TI - Using two web-based addiction Stroops to measure the attentional bias in adults with Internet Gaming Disorder. AB - Background and aims People with substance abuse and pathological gamblers show an attentional bias. In a laboratory setting, we found an attentional bias using an addiction Stroop in adults with Internet Gaming Disorder (IGD). We aimed at investigating this effect using two web-based experiments. Methods Study 1: Gamers with IGD, casual gamers, and non-gamers (N = 81, 28.1 +/- 7.8 years) completed a web-based addiction Stroop with a fully randomized word order. They saw computer-related and neutral words in four colors and indicated the word color via keypress. Study 2: Gamers with IGD, casual gamers, and non-gamers (N = 87, 23.4 +/- 5.1 years) completed a web-based addiction Stroop and a classical Stroop (incongruent color and neutral words), which both had a block design. We expected that in both studies, only the gamers with IGD would react more slowly to computer-related words in the addiction Stroop. All groups were expected to react more slowly to incongruent color words in the classical Stroop. Results In neither study did the gamers with IGD differ in their reaction times to computer related words compared to neutral words. In Study 2, all groups reacted more slowly to incongruent color words than to neutral words confirming the validity of the online reaction time assessment. Discussion Gamers with IGD did not show a significant attentional bias. IGD may differ from substance abuse and pathological gambling in this respect; alternatively experimenting on the Internet may have introduced error variance that made it harder to detect a bias. PMID- 27776421 TI - Research note: attitudes of teachers and undergraduate students regarding three augmentative and alternative communication modalities. AB - The social validity of different communication modalities is a potentially important variable to consider when designing augmentative and alternative communication (AAC) interventions. To assess the social validity of three AAC modes (i.e., manual signing, picture exchange, and an iPad(r)-based speech generating device), we asked 59 undergraduate students (pre-service teachers) and 43 teachers to watch a video explaining each mode. They were then asked to nominate the mode they perceived to be easiest to learn as well as the most intelligible, effective, and preferred. Participants were also asked to list the main reasons for their nominations and report on their experience with each modality. Most participants (68-86%) nominated the iPad-based speech-generating device (SGD) as easiest to learn, as well as the most intelligible, effective, and preferred. This device was perceived to be easy to understand and use and to have familiar and socially acceptable technology. Results suggest that iPad-based SGDs were perceived as more socially valid among this sample of teachers and undergraduate students. Information of this type may have some relevance to designing AAC supports for people who use AAC and their current and future potential communication partners. PMID- 27776422 TI - What is competent communication behaviour of patients in physician consultations? - Chronically-ill patients answer in focus groups. AB - Many desirable outcomes depend on good patient-physician communication. Patient based perspectives of what constitutes competent communication behavior with physicians are needed for patient-oriented health care. Therefore it was our main aim to identify competent patient communication skills from the patient's perspective. We also wanted to reveal any differences in opinion among various groups (chronic ischemic heart disease, chronic low back pain, breast cancer). This study examined nine guideline-supported focus groups in rehabilitation centers. The criterion for study inclusion was any one of the three diagnoses. Enrolled in the study were N = 49 patients (32 women) aged M = 60.1 (SD = 12.8). The interview recordings were transcribed and subjected to content analysis. We documented 396 commentaries in these interviews that were allocated to 82 different codes; these in turn resulted in the formation of 12 main topics. Examples are: posing questions, being an active and participatory patient, being aware of emotions and communicating them. This study represents stage two ('documentation of patient and clinician views') in the seven-stage model of communication research. Findings reveal that chronically-ill patients name behaviours that contribute to successful discussion with a physician. These enable us to develop communication trainings and design-measuring tools used for patient-based communication skills. PMID- 27776423 TI - MRI-guided focal therapy of prostate cancer. AB - With the advent of focal therapy as a recognized treatment option for men with prostate cancer, there are a host of emerging interventions that take advantage of MRI for image guidance. Focal therapy affords a middleground option for patients with low- to intermediate-grade prostate cancer by providing a means of keeping their cancer at bay while avoiding the negative consequences of radical therapies. However, the practice of focal treatment is far from straightforward, with some believing focal treatment errs on the side of overtreatment among patients with low-grade cancer; others worry it is undertreatment in potentially significant multifocal disease. Further research is necessary, both relating to focal therapy in general and to the utility of each MRI-guided focal treatment discussed. PMID- 27776424 TI - Tentacle-type immobilized metal affinity cryogel for invertase purification from Saccharomyces cerevisiae. AB - The aim of this study is to investigate the usability of cryogel columns for the purification of invertase from Saccharomyces cerevisiae. Poly(2-hydroxyethyl methacrylate) monolithic columns were produced via cryogelation. Ester groups of the poly(2-hydroxyethyl methacrylate) structure were then converted to imine groups by the reaction with poly(ethylene imine) in the presence of NaHCO3. Transition metal ions, Cu(II), Co(II), and Ni(II), were chelated on the PEI modified cryogel columns. Purification of invertase from natural source namely S. cerevisiae was also studied, and the purification fold values were obtained as 41.350, 44.714, and 30.302 for Cu(II)-chelated, Co(II)-chelated, and Ni(II) chelated PHEMA/PEI columns, respectively. PMID- 27776425 TI - Preparation and in vitro study of hydrochloric norvancomycin encapsulated poly (d,l-lactide-co-glycolide, PLGA) microspheres for potential use in osteomyelitis. AB - HNV-loaded PLGA microspheres (HNV-PLGA MSs) were prepared by water-in-oil-in water (w/o/w) double emulsion solvent evaporation technique. The surface of prepared HNV-PLGA MSs is smooth and nonporous with an average diameter of 69.9 MUm. The drug-loading rate and encapsulation rate of HNV-PLGA MSs are 4.40 +/- 0.26% and 48.51 +/- 14.83%, respectively. Additionally, 43.36% of HNV was released from PLGA MSs after seven days of incubation. The antibacterial effects of HNV released from PLGA were as good as the pure HNV. HNV-loaded PLGA microspheres were successfully prepared using double emulsion solvent evaporation technique and their properties met the requirements for local anti-infection. PMID- 27776426 TI - Tetrahydroxystilbene Glucoside Inhibits Excessive Autophagy and Improves Microvascular Endothelial Dysfunction in Prehypertensive Spontaneously Hypertensive Rats. AB - Autophagy exists in vascular endothelial cells, but the relationship between autophagy and blood vessel dysfunction in hypertension remains elusive. This study aimed to investigate role of autophagy in vascular endothelial dysfunction in prehypertension and hypertension and the underlying mechanisms involved. Furthermore, we sought to determine if and how tetrahydroxystilbene glucoside (TSG), a resveratrol analogue and active ingredient of Polygonum multiflorum Thunb used for its cardiovascular protective properties in traditional Chinese medicine, influences vascular endothelial function. Male spontaneously hypertensive rats (SHRs) aged 4 weeks (young) and 12 weeks (adult) were studied and the vascular function of isolated aorta and mesenteric artery was assessed in vitro. Compared with Wistar Kyoto rats (WKY), young and adult SHRs showed endothelial dysfunction of the aorta and mesenteric artery, along with decreased pAkt, pmTOR, and autophagic marker protein p62 and increased LC3 II/I in microvascular but not aortic tissues. TSG administration for 14 days significantly improved mesenteric vascular endothelial function, increased levels of pAkt and pmTOR, and decreased autophagy. Pretreatment of young SHRs with the mTOR inhibitor rapamycin blocked the antiautophagic and vasodilative effects of TSG. Moreover, TSG significantly activated Akt-mTOR signaling in HUVECs and reduced the autophagic levels in vitro, which were almost completely blocked by rapamycin. In summary, mesenteric endothelial dysfunction in prehypertensive SHRs was at least partly attributable to excessive autophagy in vascular tissues. TSG partly restored microvascular endothelial dysfunction through activating the Akt/mTOR pathway, which consequently suppressed autophagy, indicating that TSG could be potentially applied to protect vascular function against subclinical changes in prehypertension. PMID- 27776427 TI - Phyllanthus urinaria's Inhibition of Human Osteosarcoma Xenografts Growth in Mice is Associated with Modulation of Mitochondrial Fission/Fusion Machinery. AB - Osteosarcoma is an aggressive bone cancer arising from primitive transformed cells of mesenchymal origin to form malignant osteoid. Phyllanthus urinaria [Formula: see text]P. urinaria[Formula: see text] is a widely used folk medicine in cancer treatment, however the mechanism of P. urinaria inhibited human osteosarcoma is unclear. The present study was aimed at investigating the antitumoral effects of an aqueous P. urinaria on human osteosarcoma in vivo and the related underlying mechanisms, mainly focusing on mitochondrial dynamic dysfunction. Our results showed that oral administration of P. urinaria to mice led to significant inhibition of tumor development without substantial changes to body weight or major organs. Histological examinations with H&E, Giemsa, and Masson trichrome stains confirmed inhibition of tumor growth by the P. urinaria treatment. Immunohistochemical staining of proliferation markers antigen KI-67 (Ki67) and proliferating cell nuclear antigen (PCNA), as well as a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated a decrease of tumor proliferation and an increase of apoptosis, which was associated with the modulation of B-cell lymphoma 2 (Bcl-2) family activating the caspase cascade in the P. urinaria-treated mice. The neovascularization marker cluster of differentiation 31 (CD31) was inhibited in P. urinaria-treated xenografts, implicating the potential anti-angiogenic effect of P. urinaria. P. urinaria treatment resulted in a significant decrease in the mitochondrial fusion proteins, including mitofusin 1/2 (Mfn1/2) and optic atrophy type 1 (Opa1), as well as an increase in the fission protein dynamin-related protein 1 (Drp1). The results of this study suggest mitochondrial dysfunction is associated with dynamic change that is involved in the apoptosis and anti-angiogenesis elicited by P. urinaria. PMID- 27776428 TI - Coriandrum sativum Suppresses Abeta42-Induced ROS Increases, Glial Cell Proliferation, and ERK Activation. AB - Alzheimer's disease (AD), the most common neurodegenerative disease, has a complex and widespread pathology that is characterized by the accumulation of amyloid [Formula: see text]-peptide (A[Formula: see text]) in the brain and various cellular abnormalities, including increased oxidative damage, an amplified inflammatory response, and altered mitogen-activated protein kinase signaling. Based on the complex etiology of AD, traditional medicinal plants with multiple effective components are alternative treatments for patients with AD. In the present study, we investigated the neuroprotective effects of an ethanol extract of Coriandrum sativum (C. sativum) leaves on A[Formula: see text] cytotoxicity and examined the molecular mechanisms underlying the beneficial effects. Although recent studies have shown the benefits of the inhalation of C. sativum oil in an animal model of AD, the detailed molecular mechanisms by which C. sativum exerts its neuroprotective effects are unclear. Here, we found that treatment with C. sativum extract increased the survival of both A[Formula: see text]-treated mammalian cells and [Formula: see text]42-expressing flies. Moreover, C. sativum extract intake suppressed [Formula: see text]-induced cell death in the larval imaginal disc and brain without affecting A[Formula: see text]42 expression and accumulation. Interestingly, the increases in reactive oxygen species levels and glial cell number in AD model flies were reduced by C. sativum extract intake. Additionally, C. sativum extract inhibited the epidermal growth factor receptor- and A[Formula: see text]-induced phosphorylation of extracellular signal-regulated kinase (ERK). The constitutively active form of ERK abolished the protective function of C. sativum extract against the [Formula: see text]-induced eye defect phenotype in Drosophila. Taken together, these results suggest that C. sativum leaves have antioxidant, anti-inflammatory, and ERK signaling inhibitory properties that are beneficial for patients with AD. PMID- 27776429 TI - Effects of 5,6-Dihydroxy-2,4-Dimethoxy-9,10-Dihydrophenanthrene on G2/M Cell Cycle Arrest and Apoptosis in Human Lung Carcinoma Cells. AB - 5,6-dihydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene (HMP) is an active compound isolated from the rhizome extracts of Dioscorea membranacea Pierre, a Thai medicinal plant. This study aimed to investigate the growth-inhibitory and apoptosis-inducing effects of HMP in human lung cancer A549 cells. The antiproliferative and cytotoxic effects of HMP were analyzed by a Sulforhodamine B assay. Cell division, cell cycle distribution and membrane asymmetry changes were each performed with different fluorescent dyes and then analyzed by flow cytometry. Real-time PCR and immunoblotting were used to detect cell cycle- and apoptosis-related mRNA levels and proteins, respectively. The nuclear morphology of the cells stained with DAPI and DNA fragmentation were detected by fluorescence microscopy and gel electrophoresis, respectively. The results showed that HMP exerted strong antiproliferative and cytotoxic activities in A549 cells with the highest selectivity index. It halted the cell cycle in [Formula: see text]/M phase via down-regulation of the expression levels of regulatory proteins Cdc25C, Cdk1 and cyclinB1. In addition, HMP induced early apoptotic cells with externalized phosphatidylserine and subsequent apoptotic cells in sub-[Formula: see text] phase. HMP increased caspase-3 activity and levels of the cleaved (active) form of caspase-3 whose actions were supported by the cleavage of its target PARP, nuclear condensation and DNA apoptotic ladder. Moreover, HMP significantly increased the mRNA and protein levels of proapoptotic Bax as well as promoted subsequent caspase-9 activation and BID cleavage, indicating HMP induced apoptosis via both intrinsic and extrinsic pathways. These data support, for the first time, the potential role of HMP as a cell-cycle arrest and apoptosis-inducing agent for lung cancer treatment. PMID- 27776430 TI - Baicalein Promotes Angiogenesis and Odontoblastic Differentiation via the BMP and Wnt Pathways in Human Dental Pulp Cells. AB - Baicalein is an active flavonoid extracted from the root of Scutellaria baicalensis that has anticancer and anti-inflammatory properties; its effects on osteoblastic and angiogenic potential are controversial. The aim of this study was to investigate the effects of baicalein on odontoblastic differentiation and angiogenesis and the underlying mechanism in human dental pulp cells (HDPCs). Baicalein (1-10[Formula: see text][Formula: see text]M) had no cytotoxic effects and promoted alkaline phosphatase (ALP) activity, mineralization assayed by Alizarin Red-S staining, and the mRNA expression of marker genes, in a concentration-dependent manner. In addition, baicalein upregulated angiogenic factors and increased in vitro capillary-like tube formation. Moreover, baicalein upregulated bone morphogenetic protein (BMP)-2 mRNA and phosphorylation of Smad 1/5/8 and Wnt ligand mRNA, glycogen synthase kinase-3, and nuclear [Formula: see text]-catenin. The odontogenic and angiogenic effects of baicalein were abolished by the BMP antagonist noggin and the Wnt/[Formula: see text]-catenin receptor antagonist DKK-1. These results demonstrate that baicalein promoted odontoblastic differentiation and angiogenesis of HDPCs by activating the BMP and Wnt/[Formula: see text]-catenin signal pathways. Our findings suggest that baicalein may contribute to dental pulp repair and regenerative endodontics. PMID- 27776431 TI - Safflower Yellow Prevents Pulmonary Metastasis of Breast Cancer by Inhibiting Tumor Cell Invadopodia. AB - Carthamus tinctorius L. is a traditional Chinese medicine that activates blood circulation and dissipates blood stasis, and has been extensively used as antitumor treatment in a clinical setting in single or in compound preparation form. However, empirical evidence and a better understanding of the possible mechanisms involved are still required. Here, we investigated the role of safflower yellow (SY), the active ingredient of C. tinctorius, in the pulmonary metastasis of breast cancer, and the underlying mechanism of action. EGF meditated time- and dose-dependent cell response profiles were applied to screen for the activity of SY in vitro, while orthotopic lung metastasis and intravenous injection were used to evaluate the antimetastatic role of SY in vivo. SY could dose-dependently inhibit EGF-mediated time- and dose-dependent cell response profiles by inhibiting cytoskeletal rearrangement. We also found that SY significantly inhibited the migration of breast cancer cells in vitro and pulmonary metastasis of breast cancer cells in vivo. Consistent with these phenotypes, formation of invadopodia and the expression of MMP-9 and p-Src proteins were decreased after EGF stimulation in MBA-MD-231 cells treat with SY, as well as in lung metastatic foci. Additionally, circulating tumor cells retained in lung capillaries were also reduced. These results suggest that the antimetastatic effect of SY is due to its inhibition of invadopodia formation, which occurs mainly through Src-dependent cytoskeleton rearrangement. We suggest that SY should be considered as a potential novel therapeutic agent for the treatment of breast cancer. PMID- 27776432 TI - Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium. AB - In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS. PMID- 27776433 TI - Inhibition of the heme-induced hemolysis of red blood cells by thechlorite-based drug WF10. AB - Excessive release of hemoglobin from red blood cells markedly disturbs the health status of patients due to cytotoxic effects of free hemoglobin and heme. The latter component is able to initiate novel hemolytic events in unperturbed red blood cells. We modeled this process by incubation of ferric protoporphyrin IX with freshly isolated red blood cells from healthy volunteers. The heme-induced hemolysis was inhibited in a concentration-dependent manner by the chlorite-based drug WF10, whereby the hemolysis degree was totally abolished at a molar ratio of 1:2 between chlorite and heme. Upon incubation of heme with WF10, the ultraviolet visible spectrum changed, whereas the release of iron from heme and the appearance of fluorescent breakdown products of the porphyrin ring were negligible at this ratio, but increased with increasing excess of chlorite over heme. Thus, inhibition of hemolysis by WF10 takes already place at those chlorite concentrations, where no degradation of the porphyrin ring occurs. As WF10 is applied in form of an intravenous infusion to patients with severe inflammatory states, these data support the hypothesis that the beneficial WF10 effects are closely associated with inactivation of free heme. PMID- 27776434 TI - Codon usage bias and phylogenetic analysis of mitochondrial ND1 gene in pisces, aves, and mammals. AB - The mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT ND1) gene is a subunit of the respiratory chain complex I and involved in the first step of the electron transport chain of oxidative phosphorylation (OXPHOS). To understand the pattern of compositional properties, codon usage and expression level of mitochondrial ND1 genes in pisces, aves, and mammals, we used bioinformatic approaches as no work was reported earlier. In this study, a perl script was used for calculating nucleotide contents and different codon usage bias parameters. The codon usage bias of MT-ND1 was low but the expression level was high as revealed from high ENC and CAI value. Correspondence analysis (COA) suggests that the pattern of codon usage for MT-ND1 gene is not same across species and that compositional constraint played an important role in codon usage pattern of this gene among pisces, aves, and mammals. From the regression equation of GC12 on GC3, it can be inferred that the natural selection might have played a dominant role while mutation pressure played a minor role in influencing the codon usage patterns. Further, ND1 gene has a discrepancy with cytochrome B (CYB) gene in preference of codons as evident from COA. The codon usage bias was low. It is influenced by nucleotide composition, natural selection, mutation pressure, length (number) of amino acids, and relative dinucleotide composition. This study helps in understanding the molecular biology, genetics, evolution of MT-ND1 gene, and also for designing a synthetic gene. PMID- 27776436 TI - Disclosing negative trial results - procedure. PMID- 27776435 TI - The effect of histopathologic and clinical features on allograft survival in renal transplant patients with antibody-mediated rejection. AB - BACKGROUND: Antibody-mediated rejection is a frequent cause of graft failure; however, prognostic indications of this complication have not been well defined. The aim of this study was to evaluate the association of histopathological and clinical features and to determine the effect of these findings on allograft survival in patients with AMR. METHODS: Fifty-two patients suffered from AMR (30 male; mean age 39 +/- 11 years) were included in the study. Data were investigated retrospectively and graft survival was analyzed. All transplant biopsies were evaluated according to Banff 2009 classification. RESULTS: Of the 52 cases, 45 were transplanted from living-donors. Twenty-one patients were diagnosed in the first 3-months after transplantation. Graft survival was 65% at 12 months and 54% at 36 months. Mean serum creatinine at time of biopsy was 3.8 +/- 3.6 mg/dL. Thirty-five of the 52 cases showed diffuse C4d positivity, 12 cases showed focal and 5 remained C4d negative. One of the patients died, 13 experienced graft loss and 38 survived with functioning grafts. Serum creatinine levels at time of biopsy were correlated with graft survival (p = .021: OR = 1.10: 95 % CI = 1.015-1.199). In terms of the impact of pathological findings; tubulitis (p=.007: OR = 2.62: 95 % CI = 1.301-5.276), intimal arteritis (p=.017: OR = 2.85: 95% CI = 1.205-6.744) and interstitial infiltration (p=.004: OR = 3.37: 95% CI = 1.465-7.752) were associated with graft survival. CONCLUSIONS: Serum creatinine at time of biopsy, tubulitis, intimal arteritis and interstitial infiltration were significantly associated with graft survival. Antibody-mediated rejection is associated with reduced long-term graft survival. PMID- 27776437 TI - Statistical Performance Analysis of Data-Driven Neural Models. AB - Data-driven model-based analysis of electrophysiological data is an emerging technique for understanding the mechanisms of seizures. Model-based analysis enables tracking of hidden brain states that are represented by the dynamics of neural mass models. Neural mass models describe the mean firing rates and mean membrane potentials of populations of neurons. Various neural mass models exist with different levels of complexity and realism. An ideal data-driven model-based analysis framework will incorporate the most realistic model possible, enabling accurate imaging of the physiological variables. However, models must be sufficiently parsimonious to enable tracking of important variables using data. This paper provides tools to inform the realism versus parsimony trade-off, the Bayesian Cramer-Rao (lower) Bound (BCRB). We demonstrate how the BCRB can be used to assess the feasibility of using various popular neural mass models to track epilepsy-related dynamics via stochastic filtering methods. A series of simulations show how optimal state estimates relate to measurement noise, model error and initial state uncertainty. We also demonstrate that state estimation accuracy will vary between seizure-like and normal rhythms. The performance of the extended Kalman filter (EKF) is assessed against the BCRB. This work lays a foundation for assessing feasibility of model-based analysis. We discuss how the framework can be used to design experiments to better understand epilepsy. PMID- 27776438 TI - Independent Component Analysis-Support Vector Machine-Based Computer-Aided Diagnosis System for Alzheimer's with Visual Support. AB - Computer-aided diagnosis (CAD) systems constitute a powerful tool for early diagnosis of Alzheimer's disease (AD), but limitations on interpretability and performance exist. In this work, a fully automatic CAD system based on supervised learning methods is proposed to be applied on segmented brain magnetic resonance imaging (MRI) from Alzheimer's disease neuroimaging initiative (ADNI) participants for automatic classification. The proposed CAD system possesses two relevant characteristics: optimal performance and visual support for decision making. The CAD is built in two stages: a first feature extraction based on independent component analysis (ICA) on class mean images and, secondly, a support vector machine (SVM) training and classification. The obtained features for classification offer a full graphical representation of the images, giving an understandable logic in the CAD output, that can increase confidence in the CAD support. The proposed method yields classification results up to 89% of accuracy (with 92% of sensitivity and 86% of specificity) for normal controls (NC) and AD patients, 79% of accuracy (with 82% of sensitivity and 76% of specificity) for NC and mild cognitive impairment (MCI), and 85% of accuracy (with 85% of sensitivity and 86% of specificity) for MCI and AD patients. PMID- 27776439 TI - Introduction. PMID- 27776440 TI - Correction to: Synthesis, antitumor screening and cell cycle analysis of novel benzothieno[3,2-b]pyran derivatives. PMID- 27776441 TI - Nivolumab in melanoma. AB - INTRODUCTION: The treatment of melanoma is evolving rapidly over the past few years. Areas covered: We conducted a comprehensive review of the literature on the role of nivolumab in melanoma Expert commentary: Nivolumab is approved by FDA and EMA for the treatment of patients with metastatic melanoma. Nivolumab is superior to chemotherapy and to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of an increase in grade 3-4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients most likely to benefit from this combination and its pharmacoeconomics are to be elucidated. Prospectively validated predictive markers are lacking. Of particular interest are immune related adverse events which should be managed according to published guidelines. PMID- 27776442 TI - 6-mo aerobic exercise intervention enhances the lipid peroxide transport function of HDL. AB - During acute exercise, the concentration of oxidized high-density lipoprotein (HDL) lipids (ox-HDL) is reported to increase suggesting that HDL may function in decreasing the concentration of oxidized low-density lipoprotein (LDL) lipids. However, the effect of exercise intervention on the lipid peroxide transport function of HDL is unknown. A randomized controlled trial with sedentary women (N = 161), aged 43-63, with no current use of hormone therapy, were randomized into a 6-month (mo) exercise group and a control group. During the 6-mo intervention, the concentration of ox-HDL increased in the exercise group by 5% and decreased in the control group by 2% (p = .003). Also, the ratio of ox-HDL to HDL cholesterol increased by 5% in the exercise group and decreased by 1.5% in the control group (p = .036). The concentrations of cholesteryl ester transfer protein (CETP) and adiponectin did not change during the intervention. The concentration of serum triglycerides trended to decrease by 6% in the intervention group (p = .051). We found that the concentration of ox-HDL increased during the 6-mo aerobic exercise intervention, but the increase was not related to changes in the levels of CETP or adiponectin. These results, together with earlier studies, suggest that HDL has an active role in the reverse transport of lipid peroxides. PMID- 27776443 TI - Purification of polluted water with spent mushroom (Agaricus bisporus) substrate: from agricultural waste to biosorbent of phenanthrene, Cd and Pb. AB - The present research was aimed to (i) report the recycling of spent A. bisporus substrate (SAS) to remove heavy metals (Cd and Pb) and phenanthrene (Phe) from polluted water and (ii) assess the possibility to use the treated water for irrigation. Batch experiments were carried out to assess, firstly, the effect of interaction time between pollutants with SAS and, secondly, the pH of the polluted water. Then a biofilter was designed by using pressurized glass columns. Chemical parameters such as pH, electrical conductivity and content of Pb, Cd, Phe, nutrients (NPK) and Cl- were determined. Equilibrium for contaminants was quickly reached (1-2 h). The pH of the polluted water was the key factor for pollutants' adsorption. The polluted water's pH was increased after biofilter interaction. Phe was not detected in any fraction. Pb and Cd sorption rates were higher than 99%. The pollutant concentrations were within the permitted range to be used for agriculture purposes. Purified water showed significant concentrations of NPK, indicating its potential use as fertilizer. The SAS shows potential to be used as Phe, Pb and Cd biosorbent and the resulting treated water can be used for irrigation according to pollutant contents and agronomical evaluation. PMID- 27776445 TI - Treatment of florfenicol of synthetic trout fish farm wastewater through nanofiltration and photocatalyst oxidation. AB - The aquaculture system is a potential significant source of antibacterial agents. The removal of florfenicol (Flo) antibiotic from synthetic aqueous wastewater is performed by applying a commercial thin film composite polyamide nanofilter (NF). For concentrated wastewater treatment, the advanced oxidation process (AOP) is applied. The effects of pH, pressure and Flo concentration on removal efficiency of NF and the effects of pH, Flo concentration and dosage of hydrogen peroxide and contact time on the AOP are assessed. In the nanofiltration system, it is found that an increase in pH enhances the removal efficiency up to 99%. In this membrane, an increase of pressure between 4 and 7 bar would increase the removal percentage, followed by a decrease from 7 to 10 bar. In AOP, it is observed that the degradation efficiency of Flo increases by both an increase in its initial concentration up to values above 50 ppm and contact time. The degradation efficiency of Flo is at its highest in the pH range of 7-10. With increasing H2O2 dosage, from 0 to 500 ppm, the removal efficiency increases. The results of this study indicate that a combination of a polyamide nanofilteration together with an AOP introduces an effective manner of removing Flo antibiotic from synthetic trout fish farm wastewater. PMID- 27776444 TI - Impact of acute kidney injury on renal allograft survival. AB - BACKGROUND: Acute kidney injury (AKI) is one of the major determinants of graft survival in kidney transplantation (KTx). Renal Transplant recipients are more vulnerable to develop AKI than general population. AKI in the transplant recipient differs from community acquired, in terms of risk factors, etiology and outcome. Our aim was to study the incidence, risk factors, etiology, outcome and the impact of AKI on graft survival. METHODS: A retrospective analysis of 219 renal transplant recipients (both live and deceased donor) was done. RESULTS: AKI was observed in 112 (51.14%) recipients, with mean age of 41.5 +/- 11.2 years during follow-up of 43.2 +/- 12.5 months. Etiologies of AKI were infection (47.32%), rejection (26.78%), calcineurin inhibitor (CNI) toxicity (13.39%), and recurrence of native kidney disease (NKD) (4.46%). New Onset Diabetes After Transplant (NODAT) and deceased donor transplant were the significant risk factors for AKI. During follow-up 70.53% (p = .004) of AKI recipients progressed to chronic kidney disease (CKD) in contrast to only 11.21% (p = .342) of non AKI recipients. Risk factors for CKD were AKI within first year of transplant (HR: 7.32, 95%CI: 4.37-15.32, p = .007), multiple episodes of AKI (HR: 6.92, 95%CI: 3.92-9.63, p = .008), infection (HR: 3.62, 95%CI: 2.8-5.75, p = .03) and rejection (HR: 9.92 95%CI: 5.56-12.36, p = .001). CONCLUSION: Renal transplant recipients have high risk for AKI and it hampers long-term graft survival. PMID- 27776446 TI - Inhaled phage therapy: a promising and challenging approach to treat bacterial respiratory infections. AB - INTRODUCTION: Bacterial respiratory tract infections (RTIs) are increasingly difficult to treat due to evolving antibiotic resistance. In this context, bacteriophages (or phages) are part of the foreseen alternatives or combination therapies. Delivering phages through the airways seems more relevant to accumulate these natural antibacterial viruses in proximity to their bacterial host, within the infectious site. Areas covered: This review addresses the potential of phage therapy to treat RTIs and discusses preclinical and clinical results of phages administration in this context. Recent phage formulation and aerosolization attempts are also reviewed, raising technical challenges to achieve efficient pulmonary deposition via inhalation. Expert opinion: Overall, the inhalation of phages as antibacterial treatment seems both clinically relevant and technically feasible. Several crucial points still need to be investigated, such as phage product pharmacokinetics and immunogenicity. Furthermore, given phage-specific features, appropriate regulatory and manufacturing guidelines will need to be defined. Finally, randomized controlled clinical trials should be carried out to establish phage therapy's clinical positioning in the antimicrobial arsenal against RTIs. PMID- 27776447 TI - AHP-based approach for optimization of waste disposal method in urban functional zone. AB - In this study, the municipal solid waste (MSW) is considered as one kind of energy source in urban planning scheme instead of a trash stream. Considering the characteristics of MSW from different urban functional zones and the current energy supply modes, an evaluation model for waste-to-energy (WtE) method was set up based on the analytical hierarchy process technique. The model consists of three layers: 15 fundamental indices, 4 influencing factors based on fundamental indices and the target functions supported by influencing factors. Taking an urban functional region of a city in north China as the research object, 4 alternatives are compared according to their weights and the sensitivities of the influencing factors are analyzed. The result will provide guide for the disposal method of WtE in new urban district planning and old urban redevelopment. PMID- 27776448 TI - Platelet-derived growth factor-BB attenuates titanium-particle-induced osteolysis in vivo. AB - Inflammation and osteoclastogenesis play critical roles in wear-particle-induced periprosthetic osteolysis (WPO). Platelet-derived growth factor-BB (PDGF-BB) could promote osteogenesis and inhibit inflammatory response. The aim of this study was to investigate the impact of PDGF-BB on WPO. Mice were divided into four groups, namely, sham, vehicle, low-, and high-dose PDGF-BB groups. Mice in the rhPDGF-BB groups were treated with PDGF-BB at 0.25 or 1 mg/ml/kg/day. Mice in the sham and vehicle groups received PBS daily. Two weeks after surgery, calvariae were harvested. Immunohistochemical analysis and MU-CT showed that PDGF BB significantly reduced osteoclast formation and bone resorption. ELISA showed that rhPDGF-BB decreased the secretion of TNF-alpha, IL-1beta, and IL-6. Western blotting revealed that rhPDGF-BB stimulated the expression of osteocalcin and osteoprotegerin. Furthermore, more VEGF and CD31 proteins were observed due to PDGF-BB by immunofluorescence. In conclusion, these findings suggest that rhPDGF BB represents a potential treatment for WPO. PMID- 27776449 TI - Caries status in young Colombian children expressed by the ICCMSTM visual/radiographic combined caries staging system. AB - OBJECTIVE: To report (1) the caries experience prevalence and mean, and the caries severity and distribution patterns, expressed clinically and combined with radiographs with the conventional and ICCMSTM systems in young children from Bogota, Colombia; (2) the contribution of including radiographs to the clinical caries scoring and (3) in which surfaces the radiograph adds to the clinical caries registration. MATERIAL AND METHODS: Six hundred children from kindergartens/schools were enrolled: Cohort A: 2-year (n = 200), Cohort B: 4-year (n = 200) and Cohort C: 6-year (n = 200) olds. Radiographs were taken of the 4- and 6- year olds. Children were examined clinically using the Clinical (C) and Radiographic (R) ICCMSTM-epi Caries Scoring Systems, staging caries lesions (d) as: Initial (Cepi/RA), Moderate (CM/RB) or Extensive (CE/RC). Caries experience including missing (m) and filled (f) surfaces was expressed as follows: clinical conventional (CdMEmfs); clinical ICCMSTM (CdepiMEmfs); combined conventional (C + RdMEmfs) and combined ICCMSTM (C + RdepiMEmfs). RESULTS: The prevalence of CdMEmfs was: Cohort A: 32%; Cohort B: 59%; Cohort C: 67.5%, increasing to 73.5%, 99.8% and 100%, respectively, with the C + R depiMEmfs. The CdMEmfs means doubled when initial caries lesions (Cdepi) and radiographs (R) were included. The d component corresponded to over two-thirds of the caries experience. Findings on the radiographs significantly raised caries experience prevalence and means (p < .02), detecting primarily approximal lesions. Surfaces with highest caries frequency were occlusal/approximal of molar teeth and buccal of upper incisor teeth. CONCLUSION: Participants' caries experience was high. The radiographic assessment significantly contributed to caries experience. Molar and upper incisor teeth were most prone to caries. PMID- 27776450 TI - The isoflavone fraction from soybean presents mRNA maturation inhibition activity. AB - Recent findings indicate that mRNA splicing inhibitors can be potential anticancer candidates. We have previously established a screening system which monitors mRNA processing in order to identify mRNA processing inhibitors. Among a number of dietary resources, isoflavone fractions showed an inhibitory effect of mRNA processing. These findings demonstrate that a variety of dietary sources have an impact on mRNA biogenesis. PMID- 27776451 TI - Lutein, a carotenoid, suppresses osteoclastic bone resorption and stimulates bone formation in cultures. AB - Lutein, a member of the xanthophyll family of carotenoids, suppressed IL-1 induced osteoclast differentiation and bone resorption. The survival of mature osteoclasts was also suppressed by lutein in cultures. When lutein was added to the cultures of osteoblasts, lutein enhanced the formation of mineralized bone nodules by elevating BMP2 expression and inhibiting sclerostin expression. Lutein may be beneficial for bone health. PMID- 27776452 TI - The long and winding road to IgA deficiency: causes and consequences. AB - INTRODUCTION: The most common humoral immunodeficiency is IgA deficiency. One of the first papers addressing the cellular and molecular mechanisms underlying IgA deficiency indicated that immature IgA-positive B-lymphocytes are present in these patients. This suggests that the genetic background for IgA is still intact and that class switching can take place. At this moment, it cannot be ruled out that genetic as well as environmental factors are involved. Areas covered: A clinical presentation, the biological functions of IgA, and the management of IgA deficiency are reviewed. In some IgA deficient patients, a relationship with a loss-of-function mutation in the TACI (transmembrane activator and calcium modulating cyclophilin ligand interaction) gene has been found. Many other genes also have been associated. Gut microbiota are an important environmental trigger for IgA synthesis. Expert commentary: Expression of IgA deficiency is due to both genetic and environmental factors and a role for gut microbiota cannot be excluded. PMID- 27776453 TI - Individualized, patient-centered use of lixisenatide for the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease associated with hyperglycemia, which can lead to serious vascular complications. Current treatment guidelines place particular emphasis on personalization of therapy. Within this guidance, the use of various second-line therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), is recommended under certain circumstances. Areas covered: Factors influencing glucose homeostasis, including gastric emptying and the associated cardiovascular (CV) risk when homeostasis is not maintained, are reviewed. Physiology relating to the mechanism of action of GLP-1 RAs is summarized, with a particular focus on lixisenatide. In addition, an overview of efficacy and safety data for lixisenatide is presented and the CV effects of GLP-1 RAs are examined. Finally, the rationale and clinical data supporting the combination of lixisenatide and basal insulin are explored. Expert opinion: GLP-1 analogs meet a need for better glycemic control, with the added benefits of reduced hypoglycemic risk and body weight. The combination of a short-acting GLP-1 RA, such as lixisenatide, with a basal insulin, exploits the complementary effects of both of these therapies and seems well suited for the treatment of T2DM. However, further studies are needed to establish the associated CV risks and/or benefits of GLP-1 RAs. PMID- 27776454 TI - Shedding light on photo-switchable analgesics for pain. PMID- 27776455 TI - Introduction to the special issue on the legacy of M. P. Bryden. PMID- 27776456 TI - Laterality Prize Winners 5th North Sea Meeting on Brain Asymmetries (NSM 2016). PMID- 27776457 TI - Homologous recombination preferentially repairs heat-induced DNA double-strand breaks in mammalian cells. AB - PURPOSE: Heat shock induces DNA double-strand breaks (DSBs), but the precise mechanism of repairing heat-induced damage is unclear. Here, we investigated the DNA repair pathways involved in cell death induced by heat shock. MATERIALS AND METHODS: B02, a specific inhibitor of human RAD51 (homologous recombination; HR), and NU7026, a specific inhibitor of DNA-PK (non-homologous end-joining; NHEJ), were used for survival assays of human cancer cell lines with different p53-gene status. Mouse embryonic fibroblasts (MEFs) lacking Lig4 (NHEJ) and/or Rad54 (HR) were used for survival assays and a phosphorylated histone H2AX at Ser139 (gammaH2AX) assay. MEFs lacking Rad51d (HR) were used for survival assays. SPD8 cells were used to measure HR frequency after heat shock. RESULTS: Human cancer cells were more sensitive to heat shock in the presence of B02 despite their p53 gene status, and the effect of B02 on heat sensitivity was specific to the G2 phase. Rad54-deficient MEFs were sensitive to heat shock and showed prolonged gammaH2AX signals following heat shock. Rad51d-deficient MEFs were also sensitive to heat shock. Moreover, heat shock-stimulated cells had increased HR. CONCLUSIONS: The HR pathway plays an important role in the survival of mammalian cells against death induced by heat shock via the repair of heat-induced DNA DSBs. PMID- 27776458 TI - The effects of exercise on mastalgia. AB - OBJECTIVE: Mastalgia is often ignored by physicians although it is the most common breast-related complaint among women. The effectiveness of exercise therapy for mastalgia is unclear. The aim of this study is to investigate the effects of exercise on mastalgia. METHODS: A randomized controlled trial was conducted with twenty women with complaints of mastalgia fulfilling the inclusion and exclusion criteria. Patients were randomly assigned to the control group and to the exercise group. Sports brassiere, refraining from caffeine- and methylxanthine-containing foods, and simple analgesics were recommended for two groups. In the exercise group, an exercise program was conducted three times a week for 6 weeks. Participants in both groups were evaluated for breast pain and using the Short-Form Health Survey (SF-36) questionnaire before and six weeks after study. Serum cytokine levels were also collected and analyzed. RESULTS: No significant differences were detected with respect to age, body mass index, menopausal status, psychiatric condition, and existence of unexplained pain syndromes between the groups. Total breast pain scores were similar in both groups. The sensory component of breast pain questionnaire and visual analogue scale values significantly improved via exercise in only exercise group (p = 0.012 and p = 0.016). There was no significant difference between groups in serum levels of cytokines. SF-36 subscale scores for general health and social functioning significantly improved in the control group and scores for role physical, bodily pain, and social functioning improved in exercise group. CONCLUSIONS: Based on our preliminary findings, exercise treatment is beneficial for patients with mastalgia and it can be suggested by clinicians. PMID- 27776459 TI - Plant sterol-enriched soy milk consumption modulates 5-lipoxygenase, 12 lipoxygenase, and myeloperoxidase activities in healthy adults - a randomized controlled trial. AB - A randomized, double blind, placebo-controlled and crossover study was conducted to simultaneously measure the effects, after 3-h and 4-week daily exposure to plant sterols-enriched food product, on inflammation, oxidative status, 5 lipoxygenase, 12-lipoxygenase, and myeloperoxidase activities in healthy adults. Eighteen healthy participants (67% female, 35.3 (mean) +/- 9.5 (SD) years, mean body mass index 22.8 kg m-2) received two soy milk (20g) treatments daily: placebo and one containing 2.0 g free plant sterols equivalent of their palmitates (beta-sitosterol, 55%; campesterol, 29%; stigmasterol, 23%). F2 isoprostanes, leukotriene B4, sitosterol, campesterol, and stigmasterol concentrations were measured in the blood plasma and urine, using stable isotope labeled gas chromatography-mass spectrometry. High-sensitivity c-reactive protein, tumor necrosis factor-alpha, and lipoxin A4 concentrations in blood serum were measured using commercially available enzyme immunoassays. Myeloperoxidase activity, serum lipid hydroperoxides, plasma and urinary F2 isoprostanes, plasma and urinary leukotriene B4, and plasma high-sensitivity c reactive protein concentrations were significantly reduced, while circulating lipoxin A4 concentrations were significantly elevated after 4-week plant sterols treatment. Plant sterols treatment decreased plasma leukotriene B4 and increased plasma lipoxin A4 concentrations acutely. Total plant sterols, beta-sitosterol, campesterol, and stigmasterol concentrations were significantly elevated after 4 week treatments compared with the pre-treatment concentrations. Our results suggest that dietary plant sterols, in the combination used, can alleviate lipid peroxidation and inflammatory events in vivo. These effects are possibly exerted via the modulation of myeloperoxidase, 5-lipoxygenase, and 12-lipoxygenase activities. PMID- 27776460 TI - The influence of antioxidants in the thiyl radical induced lipid peroxidation and geometrical isomerization in micelles of linoleic acid. AB - The biomimetic model of micelles of linoleic acid containing 2-mercaptoethanol and the antioxidant was examined under gamma irradiation up to 400 Gy in aerobic or deoxygenated conditions where thiyl radicals are the main reactive species. Lipid peroxidation was retarded by ascorbic acid and alpha-tocopherol, whereas this process was strongly inhibited by resveratrol as effectively as the ascorbic acid/alpha-tocopherol mixture. Furthermore, antioxidants have a much stronger inhibitory effect on the peroxidation in the presence of 2-mercaptoethanol, and at the same time show protective properties of the double bond, decreasing the cis-trans isomerization. Under anaerobic conditions, cis-trans isomerization occurred and antioxidants efficiency increased along the series: resveratrol < alpha-tocopherol < ascorbic acid. This result is explained taking into account the double bond localization in the hydrophobic core of the micelle and the need of co-localization of the antioxidant in order to get an anti-isomerizing activity and protection of the natural lipid geometry. PMID- 27776462 TI - Neural Substrates of Antisocial Personality Disorder: Current State and Future Directions. PMID- 27776463 TI - A novel de novo mutation in the TSC2 gene in a Chinese patient with tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC), a multisystem genetic syndrome, often affects the central nervous system. The age of onset of TSC ranges from 0 to 15 years. The clinical features manifest as a combination of seizures, mental retardation, facial angiofibroma, renal angiomyolipoma, and cardiac rhabdomyoma. Most cases of TSC are caused by mutations of the TSC1 or TSC2 genes. We characterized a Chinese patient with a novel de novo mutation in the TSC2 gene associated with the TSC detected by next-generation sequencing. PMID- 27776464 TI - Extraction of rare earth elements from a contaminated cropland soil using nitric acid, citric acid, and EDTA. AB - Rare earth elements (REEs) contamination to the surrounding soil has increased the concerns of health risk to the local residents. Soil washing was first attempted in our study to remediate REEs-contaminated cropland soil using nitric acid, citric acid, and ethylene diamine tetraacetic acid (EDTA) for soil decontamination and possible recovery of REEs. The extraction time, washing agent concentration, and pH value of the washing solution were optimized. The sequential extraction analysis proposed by Tessier was adopted to study the speciation changes of the REEs before and after soil washing. The extract containing citric acid was dried to obtain solid for the X-ray fluorescence (XRF) analysis. The results revealed that the optimal extraction time was 72 h, and the REEs extraction efficiency increased as the agent concentration increased from 0.01 to 0.1 mol/L. EDTA was efficient to extract REEs over a wide range of pH values, while citric acid was around pH 6.0. Under optimized conditions, the average extraction efficiencies of the major REEs in the contaminated soil were 70.96%, 64.38%, and 62.12% by EDTA, nitric acid, and citric acid, respectively. The sequential extraction analyses revealed that most soil-bounded REEs were mobilized or extracted except for those in the residual fraction. Under a comprehensive consideration of the extraction efficiency and the environmental impact, citric acid was recommended as the most suitable agent for extraction of the REEs from the contaminated cropland soils. The XRF analysis revealed that Mn, Al, Si, Pb, Fe, and REEs were the major elements in the extract indicating a possibile recovery of the REEs. PMID- 27776465 TI - The effects of physicochemical wastewater treatment operations on forward osmosis. AB - Raw municipal wastewater from a full-scale wastewater treatment plant was physicochemically pretreated in a large pilot-scale system comprising coagulation, flocculation, microsieve and microfiltration operated in various configurations. The produced microsieve filtrates and microfiltration permeates were then concentrated using forward osmosis (FO). Aquaporin InsideTM FO membranes were used for both the microsieve filtrate and microfiltration permeates, and Hydration Technologies Inc.-thin-film composite membranes for the microfiltration permeate using only NaCl as the draw solution. The FO performance was evaluated in terms of the water flux, water flux decline and solute rejections of biochemical oxygen demand, and total and soluble phosphorus. The obtained results were compared with the results of FO after only mechanical pretreatment. The FO permeates satisfied the Swedish discharge demands for small and medium-sized wastewater treatment plants. The study demonstrates that physicochemical pretreatment can improve the FO water flux by up to 20%. In contrast, the solute rejection decreases significantly compared to the FO-treated wastewater with mechanical pretreatment. PMID- 27776466 TI - Persistent orofacial muscle pain: Its synonymous terminology and presentation. AB - OBJECTIVE: The purpose of the present paper is to describe the presentation of persistent orofacial muscle pain, also commonly referred to as myofascial temporomandibular disorder. METHODS: In this practice survey, the authors reviewed the demographic and clinical features of 34 patients who were evaluated and diagnosed personally. RESULTS: The majority of the 34 patients were women (82.4%), and their age at consultation averaged 44.6 +/- 12.6 (SD) years. The median pain duration was 4.0 years (range: 0.2-34 years). In 97.1% of patients, the pain occurred daily and continuously, and in 51.9% it was unilateral. Chewing or eating made the pain worse in 50% of the patients, and talking in 29.4%. On examination, tightness of the masseter muscle(s) was present in 58.8%, and tenderness in 58.8%. CONCLUSIONS: Persistent orofacial muscle pain mostly affects women, generally occurs daily and continuously, and is equally often unilateral and bilateral. Chewing, eating, and talking are the most common aggravating factors, and tightness or tenderness of the masseter muscle(s) is often found on examination. PMID- 27776467 TI - Response to letter: Wenle Zhao and Vance W. Berger, Better alternatives to permuted block randomization for clinical trials with unequal allocation. PMID- 27776468 TI - The cost of warfarin treatment for stroke prevention in patients with non valvular atrial fibrillation in Mexico from a collective perspective. AB - AIMS: To describe the collective costs of vitamin K antagonist (VKA) treatment for stroke prevention in non-valvular atrial fibrillation (NVAF). VKA drug costs are relatively low, but they necessitate frequent international normalized ratio (INR) monitoring. There are currently minimal data describing the economic impact of this in Mexico. MATERIALS AND METHODS: Cardiologists provided data on their NVAF patients (n = 400) to quantify direct medical costs (INR testing, appointments, drug costs). A sub-set of patients (n = 301) completed a patient questionnaire providing data to calculate direct non-medical costs (travel and other expenses for attendance at VKA-associated appointments) and indirect costs (opportunity cost and reduced work productivity associated with VKA treatment). RESULTS: Estimated annual direct medical costs totaled $753.6 per patient. Annual direct non-medical and indirect costs were USD$149.8 and $132.1, respectively. LIMITATIONS: Recruited patients were those who consulted with a cardiologist during the study period and selected due to inclusion criteria. All had received uninterrupted treatment for 12-24 months. Consequently, the results are not fully generalizable to all VKA treated NVAF patients. CONCLUSIONS: The true cost of VKA treatment cannot be appreciated by a consideration of drug costs alone. Ongoing monitoring appointments incur additional expenses for both patients and the healthcare system. PMID- 27776469 TI - Evaluation of the mercaptobenzothiazole degradation by combined adsorption process and Fenton reaction using iron mining residue. AB - The present study investigated the degradation of mercaptobenzothiazole (MBT), evaluating homogeneous and heterogeneous systems. An iron mineral residue from the desliming step of iron mining was used as a source in the Fenton-like reaction (advanced oxidation process). A granulometric analysis of the residue was performed and yielded fractions with high hematite (Fe2O3) and low quartz content in sieves from 74 to below 44 mm. In this particle size range, the hematite content from 58.9% to 67.4% and the Brunauer-Emmett-Teller area from 0.1345 to 1.3137 m2 g-1 were obtained. The zeta potential curves as a function of pH were obtained for the residue, the MBT solution and mixtures thereof. The adsorption of MBT in the residue and its degradation through the Fenton-like reaction were investigated. Adsorption tests and the Fenton-like reaction were carried out, where the MBT species and the residue are oppositely charged, yielding, respectively, 10% MBT adsorption on the surface of the residue and 100% MBT degradation by the Fenton-like reaction at pH 3, hydrogen peroxide concentration of 25 mg L-1, residue concentration of 3 g L-1, 200 rpm and 25 degrees C, from a 100 mg L-1 MBT solution. MBT degradation was found to occur mainly by the heterogeneous Fenton-like process. PMID- 27776470 TI - Editorial (Thematic Issue: Ferid Murad, at 80: A Legacy of Science, Medicine, and Mentorship). PMID- 27776471 TI - Reflecting Back to Bring Nitric Oxide Research to the Laboratory. AB - Professor Ferid Murad has been a remarkable colleague and a mentor. During our very first meeting, he not only shared unresolved puzzles in Nitric Oxide (NO) research but also listened to my questions pointing to protein nitration and nitrosylation. This was start of a new avenue in my laboratory involving protein nitration, inducible nitric oxide synthase and nitrite production in the context of signaling and gene expression in cancer cells. Dynamic changes in the cytoskeleton remodeling in response to the cell membrane generated signals are regulated by p21-activated kinase 1 (PAK1) which also feed into microtubules (MT) dynamic via phosphorylating Tubulin Cofactor B (CoB) on serine 65 and serine 128. While While searching for the mechanism through which MT biogenesis might be counteracted for the purpose of maintaining the balance in MT dynamic, we explored the possibility of nitration of tyrosine residues in TCoB. We found that TCoB is nitrated on tyrosine 64 and tyrosine 98 and that nitrated TCoB inhibits TCoB phosphorylation and that intact PAK1 phosphorylation sites are also essential for the ability of TCoB to undergo nitration. We suggested a model wherein TCoB nitration acts as a feedback mechanism to counteract PAK1- signaling dependent microtubule dynamics, and thus, revealed an inherent regulatory coordination of growth factor and nitric oxide signaling in microtubule dynamics. In addition, cytoskeleton remodeling and NO production and resulting post translational modifications in signaling modules serve as important modifiers of cellular processes. Here, I will discuss the cascade of events leading to my first meeting with Professor Murad, the development of scientific interactions, the recognition of our overlapping scientific interests in NO Signaling in cancer cells, and how these interactions have allowed us to connect NO - Cytoskeleton Signaling in cancer cells. PMID- 27776472 TI - Physiological Functions of NO-Sensitive Guanylyl Cyclase Isoforms. AB - NO-sensitive guanylyl cyclase (NO-GC) acts as the receptor for nitric oxide and by the increase in cGMP executes most of the NO effects in the cardiovascular and neuronal system. Two isoforms of NO-GC exist whose existence has not been paid much attention to probably because they reveal comparable regulatory and catalytic properties and therefore cannot be differentiated in vivo. Analysis of mice in which either one of the isoforms has been genetically deleted unequivocally establishes the coexpression of NO-GC1 and NOGC2 in any tissue tested to date with the exception of platelets. In tissues other than brain and platelets, no particular function could be ascribed to a specific NO-GC isoform so far. In contrast, NO-GC1 and NO-GC2 serve different functions in the central nervous system. With NO-GC1's presynaptic role and NO-GC2's postsynaptic action, two NO/cGMP pathways have been shown to exist that enhance the strength of synaptic transmission on either side of the synaptic cleft. PMID- 27776473 TI - An Update on the Role of Nitric Oxide in the Neurodegenerative Processes of Parkinson's Disease. AB - BACKGROUND: The pathogenesis of Parkinson's disease (PD) is not fully understood. Together with some important physiological functions in the Central Nervous System (CNS), nitric oxide (NO) can have both, neuroprotective or neurotoxic actions, depending on its redox state. An important body of evidence suggests the involvement of NO in many of the processes leading to neurodegeneration in several neurological disorders including PD. OBJECTIVE: The main aim of this review is to update the data regarding the possible involvement of NO in the pathogenesis of PD. METHODS: We performed a literature review on neuropathological, biochemical and genetic studies in PD patients and in several experimental models of parkinsonism and role of NO in these models. RESULTS: Results: Both studies in humans and in experimental models of parkinsonism give support to the contribution of NO in excitotoxicity, inflammation, oxidative stress, mitochondrial function impairment, DNA damage, and Snitrosylation of diverse proteins. The interaction of these mechanisms leads finally to neuronal death. The fact that selective of specific inhibitors of NO synthase (NOS, the enzyme responsible of NO synthesis) should prevent neuronal death through their actions of these pathogenic mechanisms supports the role of NO on PD as well. CONCLUSIONS: NO participates in the pathogenesis of PD by multiple mechanisms described in this review. PMID- 27776474 TI - The Role of Nitric Oxide Synthase Inhibitors in Schizophrenia. AB - Close to 1% of the world population suffer from schizophrenia. Current medications for this chronic mental disorder have greatly improved treatment over the last half century or more, but, the newer atypical antipsychotics have proven to be disappointing, and enormous challenges remain. The negative symptoms and cognitive dysfunction in schizophrenia which greatly affect overall morbidity call for better treatments. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of schizophrenia, so excessive NO production might contribute to the pathology. This implies that it might be useful to reduce nitrergic activity, so molecules aiming to decrease NO production such as NO synthase (NOS) inhibitors might be candidates. Here, I critically review advances in research on these emerging molecules which hold promise although a note of caution is required on account of their potential neurotoxicity and narrow therapeutic window. PMID- 27776475 TI - Multiple Means by Which Nitric Oxide can Antagonize Photodynamic Therapy. AB - Photodynamic therapy (PDT) is a unique site-specific treatment for eradicating a variety of solid tumors, including prostate, lung, bladder, and brain tumors. PDT is a three-component modality involving (i) administration of a photosensitizing agent (PS), (ii) PS photoexcitation by visible or near-infrared light, and (iii) molecular oxygen. Upon photoexcitation, PS gives rise to tumor-damaging reactive oxygen species, most prominently singlet oxygen (1O2). Previous studies revealed that endogenous nitric oxide (NO) in various mouse tumor models significantly reduced PDT effectiveness. Recent studies in the authors' laboratory indicated that NO produced by photostressed tumor cells per se can elicit anti-PDT effects. For example, breast cancer COH-BR1 and prostate cancer PC3 cells exhibited a rapid and prolonged upregulation of inducible nitric oxide synthase (iNOS) after sensitization with 5- aminolevulinic acid (ALA)-induced protoporphyrin-IX, followed by broad-band visible irradiation. Use of iNOS inhibitors and NO scavengers demonstrated that iNOS/NO played a key role in cell resistance to apoptotic photokilling. Moreover, cells surviving an ALA/light challenge proliferated, migrated, and invaded more rapidly than controls, again in iNOS/NOdependent fashion. Thus, NO was found to play a crucial role in various manifestations of enhanced aggressiveness exhibited by remaining live cells. Recent work has revealed that induced NO in PDT-targeted PC3 cells can also translocate and increase aggressiveness of non-targeted bystander cells. These negative and potentially tumor-promoting side effects of NO in PDT may be averted through use of iNOS inhibitors as adjuvants. Each of the above aspects of PDT antagonism by NO will be discussed in this review. PMID- 27776476 TI - Targeting NO/cGMP Signaling in the CNS for Neurodegeneration and Alzheimer's Disease. AB - cAMP-response element-binding protein (CREB) plays a central role in various aspects of central nervous system (CNS) function, ranging from the developmental stages to neuronal plasticity and survival in adult brain. Activation of CREB plays a crucial role in learning and memory and is at the convergence of multiple intracellular signaling cascades including CAMKII and MAPK. This review focuses on the important functions of nitric oxide (NO) in activating CREB via the NO receptor, soluble guanylyl cyclase (sGC), and production of the second messenger, cGMP. The involvement of the NO/cGMP signaling pathway in synaptic plasticity suggests several avenues for therapeutic intervention, and targeting early synaptic degeneration could be an attractive approach for the development of novel disease-modifying approaches to treat cognition and memory dysfunction in neurodegenerative diseases. PMID- 27776477 TI - Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression. AB - BACKGROUND: Astronauts are exposed to 56Fe ions that may pose a significant health hazard during and following prolonged missions in deep space. We showed previously that object recognition requiring the hippocampus, a structure critical for cognitive function, is affected in 2-month-old mice irradiated with 56Fe ions. Here we examined object recognition in 6-month-old mice irradiated with 56Fe ions, a biological age more relevant to the typical ages of astronauts. Moreover, because the mechanisms mediating the detrimental effects of 56Fe ions on hippocampal function are unclear, we examined changes in hippocampal networks involved in synaptic plasticity and memory, gene expression, and epigenetic changes in cytosine methylation (5mC) and hydroxymethylation (5hmC) that could accompany changes in gene expression. We assessed the effects of whole body 56Fe ion irradiation at early (2 weeks) and late (20 weeks) time points on hippocampus dependent memory and hippocampal network stability, and whether these effects are associated with epigenetic changes in hippocampal DNA methylation (both 5mC and 5hmC) and gene expression. RESULTS: At the two-week time point, object recognition and network stability were impaired following irradiation at the 0.1 and 0.4 Gy dose, but not following irradiation at the 0.2 Gy dose. No impairments in object recognition or network stability were seen at the 20-week time point at any irradiation dose used. Consistent with this pattern, the significance of pathways for gene categories for 5hmC was lower, though not eliminated, at the 20 week time point compared to the 2-week time point. Similarly, significant changes were observed for 5mC gene pathways at the 2-week time point, but no significant gene categories were observed at the 20-week time point. Only the 5hmC changes tracked with gene expression changes. CONCLUSIONS: Dose- and time-dependent epigenomic remodeling in the hippocampus following 56Fe ion exposure correlates with behavioral changes. PMID- 27776478 TI - Results on the spatial resolution of repetitive transcranial magnetic stimulation for cortical language mapping during object naming in healthy subjects. AB - BACKGROUND: The spatial resolution of repetitive navigated transcranial magnetic stimulation (rTMS) for language mapping is largely unknown. Thus, to determine a minimum spatial resolution of rTMS for language mapping, we evaluated the mapping sessions derived from 19 healthy volunteers for cortical hotspots of no-response errors. Then, the distances between hotspots (stimulation points with a high error rate) and adjacent mapping points (stimulation points with low error rates) were evaluated. RESULTS: Mean distance values of 13.8 +/- 6.4 mm (from hotspots to ventral points, range 0.7-30.7 mm), 10.8 +/- 4.8 mm (from hotspots to dorsal points, range 2.0-26.5 mm), 16.6 +/- 4.8 mm (from hotspots to apical points, range 0.9-27.5 mm), and 13.8 +/- 4.3 mm (from hotspots to caudal points, range 2.0-24.2 mm) were measured. CONCLUSIONS: According to the results, the minimum spatial resolution of rTMS should principally allow for the identification of a particular gyrus, and according to the literature, it is in good accordance with the spatial resolution of direct cortical stimulation (DCS). Since measurement was performed between hotspots and adjacent mapping points and not on a finer grained basis, we only refer to a minimum spatial resolution. Furthermore, refinement of our results within the scope of a prospective study combining rTMS and DCS for resolution measurement during language mapping should be the next step. PMID- 27776479 TI - Enhanced metabolic process to indole alkaloids in Clematis terniflora DC. after exposure to high level of UV-B irradiation followed by the dark. AB - BACKGROUND: Indole alkaloids, which characteristically contain an indole nucleus, have pharmaceutical potential in a diverse range of applications. UV-B can elicit the accumulation of indole alkaloids. The indole alkaloid (6-hydroxyl-1H-indol-3 yl) carboxylic acid methyl ester with cytotoxic activity was found to accumulate in Clematis terniflora DC. leaves after exposure to high level of UV-B irradiation and the dark. However, a more in-depth analysis of the process behind this response has not yet been performed. Therefore, an integrated approach involving metabolomic, proteomic, and transcriptomic analyses is essential to detail the biosynthetic mechanisms of the regulation of indole alkaloid under binary stress. RESULTS: Indole alkaloid (6-hydroxyl-1H-indol-3-yl) carboxylic acid methyl ester was found to increase 7-fold in C. terniflora leaves post treatment with high level of UV-B irradiation followed by an incubation in the dark compared with pre-treatment. Analysis by proteomics and metabolomics indicates a decrease in photosynthesis and carbohydrate metabolism, respectively. By contrast, amino acid metabolism was activated by this binary stress, and, specifically, the genes involved in the metabolic pathway converting shikimate to L-tryptophan were concurrently upregulated. Metabolites involved in indole biosynthesis (shikimate metabolic) pathway were anthranilate, indole, and L tryptophan, which increased 2-, 441-, and 1-fold, respectively. In addition, there was an increase of 2- and 9-fold in L-serine deaminase (L-SD) and L tryptophan synthase activity in C. terniflora leaves after exposure to high level of UV-B irradiation and the dark. CONCLUSIONS: (6-hydroxyl-1H-indol-3-yl) carboxylic acid methyl ester was found to increase in response to high level of UV-B irradiation followed by an incubation in the dark, implying that indole alkaloid biosynthesis was activated in C. terniflora leaves. Analysis of perturbations in metabolism in these leaves demonstrated that amino acid metabolism was specifically activated by this binary stress. In addition, an enhancement in serine level and L-SD activity was noted, which likely leads to an accumulation of pyruvate that, in turn, supplies shikimate metabolic pathway. The genes, metabolites, and L-tryptophan synthase activity that are involved in the metabolic pathway leading from shikimate to L-tryptophan all increased under the experimental binary stress, resulting in an enhancement of indole biosynthesis (shikimate metabolic) pathway. Therefore, the metabolic process to indole alkaloids in C. terniflora was enhanced after exposure to high level of UV-B irradiation followed by the dark. PMID- 27776481 TI - Mitochondrial genome sequences from wild and cultivated barley (Hordeum vulgare). AB - BACKGROUND: Sequencing analysis of mitochondrial genomes is important for understanding the evolution and genome structures of various plant species. Barley is a self-pollinated diploid plant with seven chromosomes comprising a large haploid genome of 5.1 Gbp. Wild barley (Hordeum vulgare ssp. spontaneum) and cultivated barley (H. vulgare ssp. vulgare) have cross compatibility and closely related genomes, although a significant number of nucleotide polymorphisms have been reported between their genomes. RESULTS: We determined the complete nucleotide sequences of the mitochondrial genomes of wild and cultivated barley. Two independent circular maps of the 525,599 bp barley mitochondrial genome were constructed by de novo assembly of high-throughput sequencing reads of barley lines H602 and Haruna Nijo, with only three SNPs detected between haplotypes. These mitochondrial genomes contained 33 protein coding genes, three ribosomal RNAs, 16 transfer RNAs, 188 new ORFs, six major repeat sequences and several types of transposable elements. Of the barley mitochondrial genome-encoded proteins, NAD6, NAD9 and RPS4 had unique structures among grass species. CONCLUSIONS: The mitochondrial genome of barley was similar to those of other grass species in terms of gene content, but the configuration of the genes was highly differentiated from that of other grass species. Mitochondrial genome sequencing is essential for annotating the barley nuclear genome; our mitochondrial sequencing identified a significant number of fragmented mitochondrial sequences in the reported nuclear genome sequences. Little polymorphism was detected in the barley mitochondrial genome sequences, which should be explored further to elucidate the evolution of barley. PMID- 27776480 TI - Immune genes and divergent antimicrobial peptides in flies of the subgenus Drosophila. AB - BACKGROUND: Drosophila is an important model for studying the evolution of animal immunity, due to the powerful genetic tools developed for D. melanogaster. However, Drosophila is an incredibly speciose lineage with a wide range of ecologies, natural histories, and diverse natural enemies. Surprisingly little functional work has been done on immune systems of species other than D. melanogaster. In this study, we examine the evolution of immune genes in the speciose subgenus Drosophila, which diverged from the subgenus Sophophora (that includes D. melanogaster) approximately 25-40 Mya. We focus on D. neotestacea, a woodland species used to study interactions between insects and parasitic nematodes, and combine recent transcriptomic data with infection experiments to elucidate aspects of host immunity. RESULTS: We found that the vast majority of genes involved in the D. melanogaster immune response are conserved in D. neotestacea, with a few interesting exceptions, particularly in antimicrobial peptides (AMPs); until recently, AMPs were not thought to evolve rapidly in Drosophila. Unexpectedly, we found a distinct diptericin in subgenus Drosophila flies that appears to have evolved under diversifying (positive) selection. We also describe the presence of the AMP drosocin, which was previously thought to be restricted to the subgenus Sophophora, in the subgenus Drosophila. We challenged two subgenus Drosophila species, D. neotestacea and D. virilis with bacterial and fungal pathogens and quantified AMP expression. CONCLUSIONS: While diptericin in D. virilis was induced by exposure to gram-negative bacteria, it was not induced in D. neotestacea, showing that conservation of immune genes does not necessarily imply conservation of the realized immune response. Our study lends support to the idea that invertebrate AMPs evolve rapidly, and that Drosophila harbor a diverse repertoire of AMPs with potentially important functional consequences. PMID- 27776482 TI - Ecological conditions determine extinction risk in co-evolving bacteria-phage populations. AB - BACKGROUND: Antagonistic coevolution between bacteria and their viral parasites, phage, drives continual evolution of resistance and infectivity traits through recurrent cycles of adaptation and counter-adaptation. Both partners are vulnerable to extinction through failure of adaptation. Environmental conditions may impose unequal abiotic selection pressures on each partner, destabilising the coevolutionary relationship and increasing the extinction risk of one partner. In this study we explore how the degree of population mixing and resource supply affect coevolution-induced extinction risk by coevolving replicate populations of Pseudomonas fluorescens SBW25 with its associated lytic phage SBW25F2 under four treatment regimens incorporating low and high resource availability with mixed or static growth conditions. RESULTS: We observed an increased risk of phage extinction under population mixing, and in low resource conditions. High levels of evolved bacterial resistance promoted phage extinction at low resources under both mixed and static conditions, whereas phage populations could survive when phage susceptible bacterial genotypes rose to high frequency. CONCLUSIONS: These findings demonstrate that phage extinction risk is influenced by multiple abiotic conditions, which together act to destabilise the bacteria-phage coevolutionary relationship. The risk of coevolution-induced extinction is therefore dependent on the ecological context. PMID- 27776483 TI - Induced abortion - impact on a subsequent pregnancy in first-time mothers: a registry-based study. AB - BACKGROUND: To date, several studies concerning the effects of induced abortion (IA) on women's later psychosocial well-being and future delivery complications have been published. However, the lack of reports on woman's physical well-being during their first full-term pregnancy occurring after IA is what inspired the current study. Here, we evaluate the physical well-being and use of maternity services of first-time mothers with a history of IA. METHODS: Finnish National Birth Registry data from 2008 to 2010 were linked with the Induced Abortion Registry data from 1983 to 2007. After excluding first-time mothers with a history of miscarriage, ectopic pregnancy or delivery, 57,406 mothers were eligible for the study, with 5,167 (9.0 %) having experienced prior IA. Data from the pregnancy follow-up visits were evaluated and compared between IA mothers and primiparous mothers. RESULTS: Women with IA had higher rates of smoking after the first trimester and were more likely to be overweight (body mass index >25 kg/m2) than the control group mothers. A higher use of maternity health clinic (MHC) services, thrombosis prophylaxis and participation in a second trimester ultrasound and amniotic fluid sample testing were evident in IA mothers, whereas the likelihood of assisted fertilisation procedure(s) was elevated in the control group. A shorter interpregnancy interval (IPI) seemed to contribute to a late first MHC visit and first trimester serum screening test participation, a higher incidence of placenta samples and an increased presence of preeclampsia and maternal care for poor foetal growth. CONCLUSIONS: IA is associated with being overweight before the subsequent pregnancy and with smoking after the first trimester. More frequent pregnancy follow-up visits in the IA group may be due to greater participation in the placenta sample testing and use of thrombosis prophylaxis. No association between IA and preeclampsia, hypertension, gestational diabetes or preterm premature rupture of membranes was evident in the pregnancy parameters. According to our findings, experiencing IA decreased the need for fertilisation procedures before the next pregnancy when compared to primiparous mothers. Among the IA mothers, the short IPI seemed to contribute to the higher risk for preeclampsia and maternal care for poor foetal growth. However, more research is needed around the IPI before establishing its effect on later pregnancy. PMID- 27776484 TI - Characterization of pneumococcal Ser/Thr protein phosphatase phpP mutant and identification of a novel PhpP substrate, putative RNA binding protein Jag. AB - BACKGROUND: Reversible protein phosphorylation catalyzed by protein kinases and phosphatases is the primary mechanism for signal transduction in all living organisms. Streptococcus pneumoniae encodes a single Ser/Thr protein kinase, StkP, which plays a role in virulence, stress resistance and the regulation of cell wall synthesis and cell division. However, the role of its cognate phosphatase, PhpP, is not well defined. RESULTS: Here, we report the successful construction of a DeltaphpP mutant in the unencapsulated S. pneumoniae Rx1 strain and the characterization of its phenotype. We demonstrate that PhpP negatively controls the level of protein phosphorylation in S. pneumoniae both by direct dephosphorylation of target proteins and by dephosphorylation of its cognate kinase, StkP. Catalytic inactivation or absence of PhpP resulted in the hyperphosphorylation of StkP substrates and specific phenotypic changes, including sensitivity to environmental stresses and competence deficiency. The morphology of the DeltaphpP cells resembled the StkP overexpression phenotype and conversely, overexpression of PhpP resulted in cell elongation mimicking the stkP null phenotype. Proteomic analysis of the phpP knock-out strain permitted identification of a novel StkP/PhpP substrate, Spr1851, a putative RNA-binding protein homologous to Jag. Here, we show that pneumococcal Jag is phosphorylated on Thr89. Inactivation of jag confers a phenotype similar to the phpP mutant strain. CONCLUSIONS: Our results suggest that PhpP and StkP cooperatively regulate cell division of S. pneumoniae and phosphorylate putative RNA binding protein Jag. PMID- 27776485 TI - The antioxidant N-acetyl cysteine suppresses lidocaine-induced intracellular reactive oxygen species production and cell death in neuronal SH-SY5Y cells. AB - BACKGROUND: The local anesthetic lidocaine can affect intra- and extra-cellular signaling pathways in both neuronal and non-neuronal cells, resulting in long term modulation of biological functions, including cell growth and death. Indeed, lidocaine was shown to induce necrosis and apoptosis in vitro. While several studies have suggested that lidocaine-induced apoptosis is mitochondrial pathway dependent, it remains unclear whether reactive oxygen species (ROS) are involved in this process and whether the observed cell death can be prevented by antioxidant treatment. METHODS: The effects of lidocaine and antioxidants on cell viability and death were evaluated using SH-SY5Y cells, HeLa cells, and HeLa cell derivatives. Cell viability was examined via MTS/PES ([3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt]/phenazine ethosulfate) assay. Meanwhile, cell apoptosis and necrosis were evaluated using a cell death detection assay with Annexin V-FITC and PI staining, as well as by assaying for caspase-3/7 and caspase-9 activity, and by measuring the release of lactate dehydrogenase, respectively. Mitochondrial transmembrane potential (DeltaPsim) was assessed using the fluorescent probe tetramethylrhodamine ethyl ester. RESULTS: Lidocaine treatment resulted in suppression of the mitochondrial electron transport chain and subsequent attenuation of mitochondrial membrane potential, as well as enhanced ROS production, activation of caspase-3/7 and caspase-9, and induction of apoptosis and necrosis in SH-SY5Y cells in a dose- and time-dependent manner. Likewise, the anesthetics mepivacaine and bupivacaine also induced apoptosis in SH-SY5Y cells. Notably, the antioxidants N-acetyl cysteine (NAC) and Trolox successfully scavenged the mitochondria-derived ROS and suppressed local lidocaine-induced cell death. CONCLUSIONS: Our findings demonstrate that the local anesthetics lidocaine, mepivacaine, and bupivacaine inhibited the activity of mitochondria and induced apoptosis and necrosis in a dose-dependent manner. Furthermore, they demonstrate that treatment with the antioxidants NAC, Trolox, and GGA resulted in preservation of mitochondrial voltage and inhibition of apoptosis via suppression of caspase activation. PMID- 27776486 TI - Bleeding 'downhill' esophageal varices associated with benign superior vena cava obstruction: case report and literature review. AB - BACKGROUND: Proximal or 'downhill' esophageal varices are a rare cause of upper gastrointestinal hemorrhage. Unlike the much more common distal esophageal varices, which are most commonly a result of portal hypertension, downhill esophageal varices result from vascular obstruction of the superior vena cava (SVC). While SVC obstruction is most commonly secondary to malignant causes, our review of the literature suggests that benign causes of SVC obstruction are the most common cause actual bleeding from downhill varices. Given the alternative pathophysiology of downhill varices, they require a unique approach to management. Variceal band ligation may be used to temporize acute variceal bleeding, and should be applied on the proximal end of the varix. Relief of the underlying SVC obstruction is the cornerstone of definitive treatment of downhill varices. CASE PRESENTATION: A young woman with a benign superior vena cava stenosis due to a tunneled internal jugular vein dialysis catheter presented with hematemesis and melena. Urgent upper endoscopy revealed multiple 'downhill' esophageal varices with stigmata of recent hemorrhage. As there was no active bleeding, no endoscopic intervention was performed. CT angiography demonstrated stenosis of the SVC surrounding the distal tip of her indwelling hemodialysis catheter. The patient underwent balloon angioplasty of the stenotic SVC segment with resolution of her bleeding and clinical stabilization. CONCLUSION: Downhill esophageal varices are a distinct entity from the more common distal esophageal varices. Endoscopic therapies have a role in temporizing active variceal bleeding, but relief of the underlying SVC obstruction is the cornerstone of treatment and should be pursued as rapidly as possible. It is unknown why benign, as opposed to malignant, causes of SVC obstruction result in bleeding from downhill varices at such a high rate, despite being a less common etiology of SVC obstruction. PMID- 27776488 TI - Midazolam plasma concentration after anesthesia premedication in clinical routine - an observational study : Midazolam plasma concentration after anesthesia premedication. AB - BACKGROUND: Midazolam is commonly used as a pre-anesthesia anxiolytic. It's elimination may not be fast enough for short procedures. In orally premedicated patients we obtained midazolam plasma concentrations at the end of surgical procedures and compared those to concentrations at anesthesia induction. METHODS: The study was conducted prospectively with consent of the local ethics committee (Ethikkomission Kanton Thurgau, Switzerland) and carried out with written informed consent of each patient. Female patients aged 20 to 60 years undergoing elective procedures with general anesthesia were included, and were divided in two groups according to the planned surgical time: group S (<30 min) and group L (90-120 min), respectively. All patients received 7.5 mg Midazolam po as premedication. Blood samples were drawn at anesthesia induction, and at the end of surgery. Data were compared with t-test (independent samples; significance level p <0.05). RESULTS: Twenty-five patients per group were included. Four patients were excluded from analysis, since midazolam was not detectable in any samples. Time of premedication to the 1st blood sample was not statistically different between groups, neither were Midazolam plasma levels at this time point (p = 0.94). None of the patients from group L (n = 24), but five patients in group S (n = 22) did have a higher plasma level of Midazolam at the end of the case compared to the beginning. CONCLUSIONS: The elimination half-life of oral Midazolam can lead to higher plasma levels at the end of a short procedure compared to those at induction of anesthesia. TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien), DRKS00005429 ; date of registration 3rd January 2014. PMID- 27776487 TI - The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection. AB - BACKGROUND: Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens. Host-directed immune modulating therapies have been suggested as adjunctive treatment to TB antibiotics. Upregulated cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) signaling pathway may cause a dysfunctional immune response that favors survival and replication of Mycobacterium tuberculosis (Mtb). METHODS: Blood samples were obtained from patients with latent TB (n = 9) and active TB (n = 33) before initiation of anti TB chemotherapy. COX-2 expression in monocytes and ESAT-6 and Ag85 specific T cell cytokine responses (TNF-alpha, IFN-gamma, IL-2), proliferation (carboxyfluorescein succinimidyl ester staining) and regulation (FOXP3+ T regulatory cells) were analysed by flow cytometry and the in vitro effects of the COX-1/2 inhibitor indomethacin were measured. RESULTS: We demonstrate that indomethacin significantly down-regulates the fraction of Mtb specific FOXP3+ T regulatory cells (ESAT-6; p = 0.004 and Ag85; p < 0.001) with a concomitant reduction of Mtb specific cytokine responses and T cell proliferation in active TB. Although active TB tend to have higher levels, there are no significant differences in COX-2 expression between unstimulated monocytes from patients with active TB compared to latent infection. Monocytes in both TB groups respond with a significant upregulation of COX-2 after in vitro stimulation. CONCLUSIONS: Taken together, our in vitro data indicate a modulation of the Th1 effector and T regulatory cells in Mtb infection in response to the COX-1/2 inhibitor indomethacin. The potential role as adjunctive host-directed therapy in TB disease should be further evaluated in both animal studies and in human clinical trials. PMID- 27776489 TI - Respiratory microbes present in the nasopharynx of children hospitalised with suspected pulmonary tuberculosis in Cape Town, South Africa. AB - BACKGROUND: Lower respiratory tract infection in children is increasingly thought to be polymicrobial in origin. Children with symptoms suggestive of pulmonary tuberculosis (PTB) may have tuberculosis, other respiratory tract infections or co-infection with Mycobacterium tuberculosis and other pathogens. We aimed to identify the presence of potential respiratory pathogens in nasopharyngeal (NP) samples from children with suspected PTB. METHOD: NP samples collected from consecutive children presenting with suspected PTB at Red Cross Children's Hospital (Cape Town, South Africa) were tested by multiplex real-time RT-PCR. Mycobacterial liquid culture and Xpert MTB/RIF was performed on 2 induced sputa obtained from each participant. Children were categorised as definite-TB (culture or qPCR [Xpert MTB/RIF] confirmed), unlikely-TB (improvement of symptoms without TB treatment on follow-up) and unconfirmed-TB (all other children). RESULTS: Amongst 214 children with a median age of 36 months (interquartile range, [IQR] 19-66 months), 34 (16 %) had definite-TB, 86 (40 %) had unconfirmed-TB and 94 (44 %) were classified as unlikely-TB. Moraxella catarrhalis (64 %), Streptococcus pneumoniae (42 %), Haemophilus influenzae spp (29 %) and Staphylococcus aureus (22 %) were the most common bacteria detected in NP samples. Other bacteria detected included Mycoplasma pneumoniae (9 %), Bordetella pertussis (7 %) and Chlamydophila pneumoniae (4 %). The most common viruses detected included metapneumovirus (19 %), rhinovirus (15 %), influenza virus C (9 %), adenovirus (7 %), cytomegalovirus (7 %) and coronavirus O43 (5.6 %). Both bacteria and viruses were detected in 73, 55 and 56 % of the definite, unconfirmed and unlikely-TB groups, respectively. There were no significant differences in the distribution of respiratory microbes between children with and without TB. Using quadratic discriminant analysis, human metapneumovirus, C. pneumoniae, coronavirus 043, influenza virus C virus, rhinovirus and cytomegalovirus best discriminated children with definite-TB from the other groups of children. CONCLUSIONS: A broad range of potential respiratory pathogens was detected in children with suspected TB. There was no clear association between TB categorisation and detection of a specific pathogen. Further work is needed to explore potential pathogen interactions and their role in the pathogenesis of PTB. PMID- 27776490 TI - Neonatal bloodstream infections in a Ghanaian Tertiary Hospital: Are the current antibiotic recommendations adequate? AB - BACKGROUND: Diagnosis of bloodstream infections (BSI) in neonates is usually difficult due to minimal symptoms at presentation; thus early empirical therapy guided by local antibiotic susceptibility profile is necessary to improve therapeutic outcomes. METHODS: A review of neonatal blood cultures submitted to the microbiology department of the Korle-Bu Teaching Hospital was conducted from January 2010 through December 2013. We assessed the prevalence of bacteria and fungi involved in BSI and the susceptibility coverage of recommended empiric antibiotics by Ghana Standard Treatment guidelines and the WHO recommendations for managing neonatal sepsis. The national and WHO treatment guidelines recommend either ampicillin plus gentamicin or ampicillin plus cefotaxime for empiric treatment of neonatal BSI. The WHO recommendations also include cloxacillin plus gentamicin. We described the resistance profile over a 28-day neonatal period using multivariable logistic regression analysis with linear or restricted cubic splines. RESULTS: A total of 8,025 neonatal blood culture reports were reviewed over the four-year period. Total blood culture positivity was 21.9 %. Gram positive organisms accounted for most positive cultures, with coagulase negative staphylococci (CoNS) being the most frequently isolated pathogen in early onset infections (EOS) (59.1 %) and late onset infections (LOS) (52.8 %). Susceptibility coverage of early onset bacterial isolates were 20.7 % to ampicillin plus cefotaxime, 32.2 % to the combination of ampicillin and gentamicin, and 71.7 % to cloxacillin plus gentamicin. For LOS, coverage was 24.6 % to ampicillin plus cefotaxime, 36.2 % to the combination ampicillin and gentamicin and 63.6 % to cloxacillin plus gentamicin. Cloxacillin plus gentamicin remained the most active regimen for EOS and LOS after exclusion of BSI caused by CoNS. For this regimen, the adjusted odds of resistance decreased between 12-34 % per day from birth to day 3 followed by the slowest rate of resistance increase, compared to the other antibiotic regimen, thereafter until day 28. The trend in resistance remained generally unchanged after excluding data from CoNS. Multidrug resistant isolates were significantly (p-value <0.001) higher in LOS (62.4 %, n = 555/886) than in EOS (37.3 %, n = 331/886). CONCLUSIONS: There is low antibiotic susceptibility coverage for organisms causing neonatal bloodstream infections in Korle-Bu Teaching Hospital when the current national and WHO recommended empiric antibiotics were assessed. A continuous surveillance of neonatal BSI is required to guide hospital and national antibiotic treatment guidelines for neonatal sepsis. PMID- 27776491 TI - The incidence of increased ICP in ICU patients with non-traumatic coma as diagnosed by ONSD and CT: a prospective cohort study. AB - BACKGROUND: Unexplained coma after critical illness can be multifactorial. We evaluated the diagnostic ability of bedside Optic Nerve Sheath Diameter [ONSD] as a screening test for non-traumatic radiographic cerebral edema. METHODS: In a prospective study, mixed medical-surgical intensive care units [ICU] patients with non-traumatic coma [GCS < 9] underwent bedside ultrasonographic ONSD measurements. Non-traumatic radiographic cerebral edema [NTRCE] was defined as > 5 mm midline shift, cisternal, sulcal effacement, or hydrocephalus on CT. RESULTS: NTRCE was identified in 31 of 102 patients [30.4 %]. The area under the ROC curve for detecting radiographic edema by ONSD was 0.785 [95 % CI 0.695 0.874, p <0.001]. ONSD diameter of 0.57 cm was found to be the best cutoff threshold with a sensitivity 84 % and specificity 71 %, AUC 0.785 [95 % CI 0.695 0.874, p <0.001]. Using ONSD as a bedside test increased the post-test odds ratio [OR] for NTRCE by 2.89 times [positive likelihood ratio], whereas post-test OR for NTRCE decreased markedly given a negative ONSD test [ONSD measurement less than 0.57 cm]; negative likelihood ratio 0.22. CONCLUSIONS: The use of ONSD as a bedside test in patients with non-traumatic coma has diagnostic value in identifying patients with non-traumatic radiographic cerebral edema. PMID- 27776492 TI - Australian black field crickets show changes in neural gene expression associated with socially-induced morphological, life-history, and behavioral plasticity. AB - BACKGROUND: Ecological and evolutionary model organisms have provided extensive insight into the ecological triggers, adaptive benefits, and evolution of life history driven developmental plasticity. Despite this, we still have a poor understanding of the underlying genetic changes that occur during shifts towards different developmental trajectories. The goal of this study is to determine whether we can identify underlying gene expression patterns that can describe the different life-history trajectories individuals follow in response to social cues of competition. To do this, we use the Australian black field cricket (Teleogryllus commodus), a species with sex-specific developmental trajectories moderated by the density and quality of calls heard during immaturity. In this study, we manipulated the social information males and females could hear by rearing individuals in either calling or silent treatments. We next used RNA-Seq to develop a reference transcriptome to study changes in brain gene expression at two points prior to sexual maturation. RESULTS: We show accelerated development in both sexes when exposed to calling; changes were also seen in growth, lifespan, and reproductive effort. Functional relationships between genes and phenotypes were apparent from ontological enrichment analysis. We demonstrate that increased investment towards traits such as growth and reproductive effort were often associated with the expression of a greater number of genes with similar effect, thus providing a suite of candidate genes for future research in this and other invertebrate organisms. CONCLUSIONS: Our results provide interesting insight into the genomic underpinnings of developmental plasticity and highlight the potential of a genomic exploration of other evolutionary theories such as condition dependence and sex-specific developmental strategies. PMID- 27776493 TI - Survey of the perceptions of key stakeholders on the attributes of the South African Notifiable Diseases Surveillance System. AB - BACKGROUND: An effective and efficient notifiable diseases surveillance system (NDSS) is essential for a rapid response to disease outbreaks, and the identification of priority diseases that may cause national, regional or public health emergencies of international concern (PHEICs). Regular assessments of country-based surveillance system are needed to enable countries to respond to outbreaks before they become PHEICs. As part of a broader evaluation of the NDSS in South Africa, the aim of the study was to determine the perceptions of key stakeholders on the national NDSS attributes of acceptability, flexibility, simplicity, timeliness and usefulness. METHODS: During 2015, we conducted a nationally representative cross-sectional survey of communicable diseases coordinators and surveillance officers, as well as members of NDSS committees. Individuals with less than 1 year experience of the NDSS were excluded. Consenting participants completed a self-administered questionnaire. The questionnaire elicited information on demographic information and perceptions of the NDSS attributes. Data were analysed using descriptive statistics and the unconditional logistic regression model. RESULTS: Most stakeholders interviewed (53 %, 60/114) were involved in disease control and response. The median number of years of experience with the NDSS was 11 years (inter-quartile range (IQR): 5 to 20 years). Regarding the NDSS attributes, 25 % of the stakeholders perceived the system to be acceptable, 51 % to be flexible, 45 % to be timely, 61 % to be useful, and 74 % to be simple. Health management stakeholders perceived the system to be more useful and timely compared to the other stakeholders. Those with more years of experience were less likely to perceive the NDSS system as acceptable (OR 0.91, 95 % CI: 0.84-1.00, p = 0.041); those in disease detection were less likely to perceive it as timely (OR 0.10, 95 % CI: 0.01-0.96, p = 0.046) and those participating in National Outbreak Response Team were less likely to perceive it as useful (OR 0.38, 95 % CI: 0.16-0.93, p = 0.034). CONCLUSION: The overall poor perceptions of key stakeholder on the system attributes are a cause for concern. The study findings should inform the revitalisation and reform of the NDSS in South Africa, done in consultation and partnership with the key stakeholders. PMID- 27776494 TI - Moxibustion treatment for diarrhea-predominant irritable bowel syndrome: study protocol for a randomized controlled trial. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a worldwide disease with high morbidity. The effect of current treatment with Western medicine is not satisfactory. Although moxibustion treatment is widely used for gastrointestinal diseases, randomized controlled trials on the use of this treatment for IBS are limited. This study aims to evaluate the clinical efficacy and safety of moxibustion treatment in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS/DESIGN: A multi-center, randomized, single-blind and placebo-controlled trial is employed. 104 cases will be divided into two groups: (1) a mild-warm moxibustion group in which moxa stick is 3-5 cm away from acupuncture points and the skin temperature is maintained at 43 +/- 1 degrees C; and (2) a placebo moxibustion group in which moxa stick is 8-10 cm away from acupuncture points and the skin temperature is maintained at 37 +/- 1 degrees C. Moxibustion is performed on bilateral ST25 and ST36 in the two groups for 30 min each time, three times a week for 6 weeks. The patients are followed up at the 12th and 18th weeks. Adequate relief is used as a primary outcome measure; IBS symptom severity score, Bristol stool form scale, IBS quality-of-life questionnaire, and hospital anxiety and depression scale are used as secondary outcome measures. DISCUSSION: This study aims to demonstrate the safety and efficacy of moxibustion treatment for IBS-D, which may validate moxibustion as an effective therapy for treating IBS-D. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02421627 (8 April 2015). PMID- 27776495 TI - Lessons learned from the PMTCT program in Swaziland: challenges with accepting lifelong ART for pregnant and lactating women - a qualitative study. AB - BACKGROUND: Swaziland has one of the highest HIV prevalence rates in sub-Saharan Africa, 26 % of the adult population is infected with HIV. The prevalence is highest among pregnant women, at 41.1 %. According to Swaziland's prevention of mother-to-child transmission (PMTCT) guidelines, approximately 50 % of pregnant women are eligible for antiretroviral therapy (ART) by CD4 criteria (<350 cells/ml). Studies have shown that most mother-to-child transmission and postnatal deaths occur among women who are eligible for ART. Therefore, ensuring that ART eligible women are initiated on ART is critical for PMTCT and for mother and baby survival. This study provides insight into the challenges of lifelong ART initiation among pregnant women under Option A in Swaziland. We believe that these challenges and lessons learned from initiating women on lifelong ART under Option A are relevant and important to consider during implementation of Option B+. METHODS: HIV-positive, treatment-eligible, postpartum women and nurses were recruited within maternal and child health (MCH) units using convenience and purposive sampling. Participants came from both urban and rural areas. Focus group discussions (FGDs) and structured interviews using a short answer questionnaire were conducted to gain an understanding of the challenges experienced when initiating lifelong ART. Seven FGDs (of 5-11 participants) were conducted, four FGDs with nurses, two FGDs with women who initiated ART, and one FGD with women who did not initiate ART. A total of 83 interviews were conducted; 50 with women who initiated ART and 33 with women who did not initiate. Data collection with the women was conducted in the local language of SiSwati and data collection with the nurses was done in English. FGDs were audio-recorded and simultaneously transcribed and translated into English. Analysis was conducted using thematic analysis. Transcripts were coded by two researchers in the qualitative software program MAXqda v.10. Thematic findings were illustrated using verbatim quotes which were selected on the basis of being representative of a specific theme. The short-answer interview questionnaire included specific questions about the different steps in the woman's experience initiating ART; therefore the responses for each question were analyzed separately. RESULTS: Findings from the study highlight women feeling overwhelmed by the lifetime commitment of ART, feeling "healthy" when asked to initiate ART, preference for short-course prophylaxis and fear of side effects (body changes). Also, the preference for nurses to determine on an individual basis the number of counseling appointments a woman needs before initiating ART, more information about HIV and ART needed at the community level, and the need to educate men about HIV and ART. CONCLUSION: Women face a myriad of challenges initiating lifelong ART. Understanding women's concerns will aid in developing effective counseling messages, designing appropriate counseling structures, understanding where additional support is needed in the process of initiating ART, and knowing who to target for community level messages. PMID- 27776497 TI - Development, genetic mapping and QTL association of cotton PHYA, PHYB, and HY5 specific CAPS and dCAPS markers. AB - BACKGROUND: Among SNP markers that become increasingly valuable in molecular breeding of crop plants are the CAPS and dCAPS markers derived from the genes of interest. To date, the number of such gene-based markers is small in polyploid crop plants such as allotetraploid cotton that has A- and D-sub-genomes. The objective of this study was to develop and map new CAPS and dCAPS markers for cotton developmental-regulatory genes that are important in plant breeding programs. RESULTS: Gossypium hirsutum and G. barbadense, are the two cultivated allotetraploid cotton species. These have distinct fiber quality and other agronomic traits. Using comparative sequence analysis of characterized GSTs of the PHYA1, PHYB, and HY5 genes of G. hirsutum and G. barbadense one PHYA1 specific Mbo I/Dpn II CAPS, one PHYB-specific Alu I dCAPS, and one HY5-specific Hinf I dCAPS cotton markers were developed. These markers have successfully differentiated the two allotetraploid genomes (AD1 and AD2) when tested in parental genotypes of 'Texas Marker-1' ('TM-1'), 'Pima 3-79' and their F1 hybrids. The genetic mapping and chromosome substitution line-based deletion analyses revealed that PHYA1 gene is located in A-sub-genome chromosome 11, PHYB gene is in A-sub-genome chromosome 10, and HY5 gene is in D-sub-genome chromosome 24, on the reference 'TM-1' x 'Pima 3-79' RIL genetic map. Further, it was found that genetic linkage map regions containing phytochrome and HY5-specific markers were associated with major fiber quality and flowering time traits in previously published QTL mapping studies. CONCLUSION: This study detailed the genome mapping of three cotton phytochrome genes with newly developed CAPS and dCAPS markers. The proximity of these loci to fiber quality and other cotton QTL was demonstrated in two A-subgenome and one D-subgenome chromosomes. These candidate gene markers will be valuable for marker-assisted selection (MAS) programs to rapidly introgress G. barbadense phytochromes and/or HY5 gene (s) into G. hirsutum cotton genotypes or vice versa. PMID- 27776496 TI - Health promoting practices and personal lifestyle behaviors of Brazilian health professionals. AB - BACKGROUND: This study was conducted to examine the lifestyle behaviors and health promoting practices of physicians, nurses, and community health workers in Brazil. METHODS: A random sample of primary health care units in Brazil was selected, and a pretested questionnaire was administered via phone interviews, in 2011, to 182 physicians, 347 nurses, and 269 community health workers, totaling 798 health professionals. The total initial sample included 1600 eligible health professionals. Variables measured included physical activity, alcohol intake, hours of sleep, diet, and perceived self-efficacy to provide preventive counseling on related lifestyle behaviors. RESULTS: More than 25 % of physicians, nurses, and community health workers reported eating 0-2 portions of fruits and vegetables per day. In terms of cervical and breast cancer, nurses reported to be 'very prepared' to advise patients on these topics more frequently than physicians. The prevalence of smoking ranged from 4.9 % among nurses to 7.4 % among community health workers. The proportion of physical inactivity ranged from 40.3 % among nurses to 52.1 % among community health workers. CONCLUSION: A reasonably high proportion of physicians, nurses, and community health workers report not engaging in healthy lifestyle behaviors that impact chronic diseases, thus, they may be less likely to encourage such behaviors in their patients. PMID- 27776498 TI - Cyclooxygenase-2 inhibitor celecoxib attenuates joint contracture following immobilization in rat knees. AB - BACKGROUND: The aim of this study is to clarify the following two points: First, whether a cyclooxygenase-2 mediated pathway is involved in the formation of immobilization-induced joint contracture and, second, the effectiveness of oral administration of non-steroidal anti-inflammatory drug celecoxib (CBX) for the prevention of myogenic and arthrogenic contracture following immobilization in a rat model. METHODS: Thirty male rats were randomly divided into three groups: immobilization (Im), Im + CBX, and control (n = 10 each). External fixation immobilized the right knee joint of Im and Im + CBX groups in flexion for 3 weeks. 50 mg/kg of CBX was administrated daily to the Im + CBX group during this period. The passive range of motion (ROM) of knee joints was measured before and after transection of knee flexor muscles and myogenic and arthrogenic ROM restrictions were calculated. The semitendinosus muscles and knee joints were investigated histologically to elucidate factors responsible for contracture. RESULTS: Myogenic ROM restrictions were exhibited both in Im and Im + CBX groups (44 +/- 5 and 36 +/- 8 degrees , respectively), but restrictions significantly decreased in the Im + CBX group compared to the Im group. Significant reductions of the muscle length ratios (Rt/Lt) and sarcomere number ratios (Rt/Lt) in knee flexor semitendinosus muscle, which are responsible for myogenic contracture, were also seen both in Im group (92 +/- 5 and 92 +/- 4 %, respectively) and Im + CBX group (97 +/- 3 and 97 +/- 3 %, respectively), but were inhibited by CBX administration (P < 0.05). Im and Im + CBX groups exhibited arthrogenic ROM restrictions with no significant differences (82 +/- 3 and 83 +/- 5 degrees , respectively). Posterior synovial length shortening and pathological changes (hemorrhage in joint cavities and capsule edema) in the knee joints were comparable between Im and Im + CBX groups. CONCLUSIONS: Oral administration of celecoxib partially reduced myogenic ROM restriction concomitantly with knee flexor muscle shortening following immobilization. These results imply that inflammation and nociception are involved in myogenic contracture formation independently of joint immobilization, and that CBX is effective in preventing joint contracture following immobilization in rats. PMID- 27776499 TI - Does the recent intensification of nationalistic and xenophobic attitudes in Eastern European countries adversely affect public mental health? AB - BACKGROUND: The authors postulate that the recent intensification of the nationalist and xenophobic attitude in Poland and other Eastern European countries is detrimental to public mental health. The xenophobic attitude is accompanied by a higher incidence of anxiety and depression, disputes due to the polarization of opinions, a sense of embarrassment and a sense of contradictions with so-called Christian values, unfavorable demographic predictions and reduced life satisfaction. DISCUSSION: The authors attempt to describe the sequence of adverse events that led to the intensification of xenophobia and characterize the current state of public mental health in European countries. They formulate and propose possible actions which could counteract the consequences of that transformation. SHORT CONCLUSION: The actions which may be undertaken to counteract the deterioration of public mental health can be based on the recommendations of so-called 'positive psychology' and 'positive psychiatry' as well as the principles of strengthening local social capital. PMID- 27776500 TI - Under-five mortality rate variation between the Health and Demographic Surveillance System (HDSS) and Demographic and Health Survey (DHS) approaches. AB - BACKGROUND: Several low and middle-income countries (LMIC) use Demographic and Health Surveys (DHS) and/or Health and Demographic Surveillance System (HDSS) to monitor the health of their population. The level and trends of under-five mortality rates could be different in the HDSS sites compared to the DHS reports. In this study, we investigated the change in under-five mortality rates overtime in the HDSS sites and the corresponding DHS reports in eight countries and 13 sites. METHODS: Under-five mortality rates in the HDSS sites were determined using number of under-five deaths (numerator) and live births (denominator). The trends and annualized rate of change (ARC) of under-five mortality rates in the HDSS sites and the DHS reports were compared by fitting exponential function. RESULTS: Under-five mortality rates declined substantially in most of the sites during the last 10-15 years. Ten out of 13 (77 %) HDSS sites have consistently lower under-five mortality rates than the DHS under-five mortality rates. In the Kilifi HDSS in Kenya, under-five mortality rate declined by 65.6 % between 2003 and 2014 with ARC of 12.2 % (95 % CI: 9.4-15.0). In the same period, the DHS under-five mortality rate in the Coastal region of Kenya declined by 50.8 % with ARC of 6 % (95 % CI: 2.0-9.0). The under-five mortality rate reduction in the Mlomp (78.1 %) and Niakhar (80.8 %) HDSS sites in Senegal during 1993-2012 was significantly higher than the mortality decline observed in the DHS report during the same period. On the other hand, the Kisumu HDSS in Kenya had lower under-five mortality reduction (15.8 %) compared to the mortality reduction observed in the DHS report (27.7 %) during 2003-2008. Under-five mortality rate rose by 27 % in the Agincourt HDSS in South Africa between 1998 to 2003 that was contrary to the 18 % under-five mortality reduction in the DHS report during the same period. CONCLUSIONS: The inconsistency between HDSS and DHS approaches could have global implication on the estimation of child mortality and ethical issues on mortality inequalities. Further studies should be conducted to investigate the reasons of child mortality variation between the HDSS and the DHS approaches. PMID- 27776501 TI - The feasibility and acceptability of short-term, individual existential behavioural therapy for informal caregivers of patients recruited in a specialist palliative care unit. AB - BACKGROUND: Existential behavioural therapy (EBT) is a recently developed intervention to support informal caregivers of patients in a specialist palliative care unit and was initially established as a six-session group programme. This pilot study aimed to test the feasibility and acceptability of an adapted short-term, individual approach of EBT in preparation for a randomized controlled trial (RCT). METHODS: The study was conducted in a prospective, mixed methods design including four quantitiative assessments with embedded qualitative interviews at one assessment. The intervention offered two one-hour therapeutic sessions focusing on (1) mindfulness and (2) existential meaning-in-life as a source of strength provided by a trained psychotherapist. To test the feasibility of the intervention, doubling of the participation rate, compared to the previous group study (13,6 %) as well as an attrition rate of less than 30 % were set as thresholds. To test the acceptability of the intervention, self-rated usefulness of individual aspects of the intervention and the frequency of implementing therapeutic elements by the carers were set as criteria. Acceptability testing also included the number of participants who completed both sessions, where we expected more than 75 % as a criterion for acceptability. Return rates of quantitative questionnaires were set as criteria for the feasibility of data collection (<33 % loss expected within the study period). Qualitative interviews were used to collect additional data on feasibililty and acceptability and to explore potential harms and benefits of the intervention. RESULTS: 44/102 (43,1 %) of eligible informal caregivers agreed to participate in the study. Due to attrition of 13 caregivers (attrition rate: 29,5 %), 31 caregivers were included in the trial. Self-rated usefulness showed sufficiant results for all but one individual aspect. Frequency of implementing therapeutic elements showed wide inter-item as well as inter-participant ranges and decreased over the study period. All participants completed both sessions. Return rates of the questionnaires were within the expected range. According to the interviews, the intervention was associated with several participant-identified benefits. No severe adverse effects were observed. CONCLUSIONS: Findings suggest that the short-term, individual EBT proved feasible and mostly acceptable. PMID- 27776502 TI - A quasi-experimental cross-disciplinary evaluation of the impacts of education outside the classroom on pupils' physical activity, well-being and learning: the TEACHOUT study protocol. AB - BACKGROUND: Education Outside the Classroom (EOTC) is a teaching method that aims to promote schoolchildren's learning, physical activity (PA), social relations, motivation, and well-being. EOTC activities are characterized by teachers using the local environment in their teaching, and involve innovative teaching methods, child-led approaches to problem-solving, experimentation, cooperation, PA, and play. EOTC has become common practice for many teachers in Scandinavia; however, only case studies have evaluated its impacts. The TEACHOUT study aims to evaluate the impacts of EOTC on Danish schoolchildren's PA, social relations, motivation, well-being, and learning. METHODS: TEACHOUT is a quasi-experimental, cross disciplinary study. Sixteen schools participated, containing 19 EOTC school classes and 19 parallel non-EOTC classes, with a total of 834 children aged 9 to 13 years. Measures of the children's social relations, motivation for school, well-being, and academic performance were collected at the beginning and end of the school year. Data on PA levels were collected over ten-day periods during the school year using accelerometers. The amount and characteristics of the actual EOTC provided in both EOTC and non-EOTC classes were monitored day-to-day throughout the school year, using an online teacher survey platform. The effects of EOTC are mainly analysed by comparing EOTC pupils to non-EOTC (i.e. control) pupils based on their scores on the outcome variables (i.e. school performance, well-being, motivation, and social relations) at the end of the school year, adjusting for the baseline values (from the beginning of the year). The impacts of EOTC on PA are evaluated by comparing the total as well as context-specific amounts of PA of children participating in EOTC to those of children in their parallel non-EOTC classes. Furthermore, the interdependencies between PA, social relations, well-being, motivation, and learning are explored using path analysis. To help describe and understand the processes that have led to the quantitative outcomes, qualitative case observations of children's practices and interactions in EOTC as well as classroom teaching were carried out and combined with qualitative interviews about children's perceptions of these practices. DISCUSSION: The TEACHOUT study represents a holistic multidisciplinary approach to educational and school health-promotion research through its study design and combination of scientific disciplines and methods, as well as its focus on the interdependent relations between learning, PA, social relations, well-being, and motivation. This will result in a comprehensive picture of school health promotion and children's health and well-being, which will broaden the understanding of the potential benefits of EOTC in school health promotion and primary education. These results can be used to inform and guide future policy and practice. PMID- 27776503 TI - Identification of a novel GLA mutation (Y88C) in a Korean family with Fabry nephropathy: a case report. AB - BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. With the advancement of molecular diagnostic tools, more disease-causing mutations in alpha-galactosidase A (GLA) have been identified in Fabry disease. We found a novel mutation in a Korean family with predominant renal manifestations of the disease. CASE PRESENTATION: A 24-year-old man who wanted to donate a kidney to his 28-year-old brother with end-stage renal disease of unknown cause was evaluated. The 24-year-old man underwent percutaneous renal biopsy because of an accidentally found proteinuria. Electron microscopy of his renal biopsy showed numerous electron-dense multi-lamellar inclusions in the epithelial cytoplasm, typical for Fabry disease. Clinical and laboratory evaluation including the assessment of GLA enzyme activity and direct DNA sequencing in four members of the family were performed. Renal biopsy findings in the two affected male patients were described. Re-evaluation of a renal biopsy specimen of his 28-year-old brother obtained when he was diagnosed with renal failure revealed a very focal area of suspicious multilamellated structures in the Bowman's space. DNA sequencing on the young man, his brother, and his mother revealed a novel GLA gene mutation, c.263A > G (p.Tyr88Cys). The three all showed decreased alpha-galactosidase A activity. CONCLUSION: A novel GLA mutation, c.263A > G (p.Tyr88Cys), was found in a Korean family with predominant renal manifestations of Fabry disease. PMID- 27776504 TI - A quasi-randomized feasibility pilot study of specific treatments to improve emotion recognition and mental-state reasoning impairments in schizophrenia. AB - BACKGROUND: Impaired ability to make inferences about what another person might think or feel (i.e., social cognition impairment) is recognised as a core feature of schizophrenia and a key determinant of the poor social functioning that characterizes this illness. The development of treatments to target social cognitive impairments as a causal factor of impaired functioning in schizophrenia is of high priority. In this study, we investigated the acceptability, feasibility, and limited efficacy of 2 programs targeted at specific domains of social cognition in schizophrenia: "SoCog" Mental-State Reasoning Training (SoCog MSRT) and "SoCog" Emotion Recognition Training (SoCog-ERT). METHOD: Thirty-one participants with schizophrenia or schizoaffective disorder were allocated to either SoCog-MSRT (n = 19) or SoCog-ERT (n = 12). Treatment comprised 12 twice weekly sessions for 6 weeks. Participants underwent assessments of social cognition, neurocognition and symptoms at baseline, post-training and 3-months after completing training. RESULTS: Attendance at training sessions was high with an average of 89.29 % attendance in the SoCog-MSRT groups and 85.42 % in the SoCog-ERT groups. Participants also reported the 2 programs as enjoyable and beneficial. Both SoCog-MSRT and SoCog-ERT groups showed increased scores on a false belief reasoning task and the Reading the Mind in the Eyes test. The SoCog MSRT group also showed reduced personalising attributional biases in a small number of participants, while the SoCog-ERT group showed improved emotion recognition. CONCLUSIONS: The results are promising and support the feasibility and acceptability of the 2 SoCog programs as well as limited efficacy to improve social cognitive abilities in schizophrenia. There is also some evidence that skills for the recognition of basic facial expressions need specific training. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000978763 . Retrospectively registered 3/09/2013. PMID- 27776505 TI - Health-seeking behaviours of older black women living with non-communicable diseases in an urban township in South Africa. AB - BACKGROUND: Various studies have shown that non-communicable diseases (NCDs) especially diabetes and hypertension are prevalent among older women living in South African urban areas, placing a heavy burden on the healthcare system. This study aimed to understand the health-seeking behaviour, healthcare practices and prevalence of traditional herbal medicine (THM) use among older women self reporting NCDs from the Prospective Urban Rural Epidemiology study (PURE). METHOD: A homogenous purposive sampling of PURE participants was used to recruit women who were 50 years or older (n = 250). Descriptive statistics were used to examine the number of NCDs reported by the study sample, health seeking behaviour and practices as well as THM use. Logistic regression was also employed to investigate possible associations between reported conditions and THM use or medical pluralism. RESULTS: Within the study sample, 72 % self-reported an NCD. Of those with self-reported NCDs, 46 % had one, and 54 % had two or more NCDs. Those with NCDs usually visited public clinics (80 %), relied on doctors (90 %) and nurses (85 %) for health information, and mostly used conventional medicine (CM) to manage high blood pressure (81 %). About 30 % of those with NCDs indicated using THM, of whom 29 (53 %) reported practicing medical pluralism. Participants with dental problems (OR: 3.24, 95 % CI: 1.30-8.20), headaches (OR: 2.42, 95 % CI: 1.24-4.94), heart burn (OR: 2.30, 95 % CI: 1.18-4.48) and severe tiredness (OR: 2.05, 95 % CI: 1.08-3.99) were more likely to use THM. Anxiety and allergies increased the likelihood to practise medical pluralism by five and 20 times, respectively. CONCLUSION: Self-reported NCD with co-morbidities was prevalent among the participants in the study. Most of the study participants utilized state-owned clinics and hospitals for the management of their chronic conditions. THM use was not very common. However, among those who used THM, medical pluralism was prevalent. Family history was the most common reason for THM use, with many THM patrons utilizing these for treatment of a health condition. Older black women with anxiety and allergies were more likely to practise medical pluralism. PMID- 27776506 TI - Background, design and conceptual model of the cluster randomized multiple component workplace study: FRamed Intervention to Decrease Occupational Muscle pain - "FRIDOM". AB - BACKGROUND: Several RCT studies have aimed to reduce either musculoskeletal disorders, sickness presenteeism, sickness absenteeism or a combination of these among females with high physical work demands. These studies have provided evidence that workplace health promotion (WHP) interventions are effective, but long-term effects are still uncertain. These studies either lack to succeed in maintaining intervention effects or lack to document if effects are maintained past a one-year period. This paper describes the background, design and conceptual model of the FRIDOM (FRamed Intervention to Decrease Occupational Muscle pain) WHP program among health care workers. A job group characterized by having high physical work demands, musculoskeletal disorders, high sickness presenteeism - and absenteeism. METHODS: FRIDOM aimed to reduce neck and shoulder pain. Secondary aims were to decrease sickness presenteeism, sickness absenteeism and lifestyle-diseases such as other musculoskeletal disorders as well as metabolic-, and cardiovascular disorders - and to maintain participation to regular physical exercise training, after a one year intervention period. The entire concept was tailored to a population of female health care workers. This was done through a multi-component intervention including 1) intelligent physical exercise training (IPET), dietary advice and weight loss (DAW) and cognitive behavioural training (CBT). DISCUSSION: The FRIDOM program has the potential to provide evidence-based knowledge of the pain reducing effect of a multi component WHP among a female group of employees with a high prevalence of musculoskeletal disorders and in a long term perspective evaluate the effects on sickness presenteeism and absenteeism as well as risk of life-style diseases. TRIAL REGISTRATION: NCT02843269 , 06.27.2016 - retrospectively registered. PMID- 27776507 TI - Geminin prevents DNA damage in vagal neural crest cells to ensure normal enteric neurogenesis. AB - BACKGROUND: In vertebrate organisms, the neural crest (NC) gives rise to multipotential and highly migratory progenitors which are distributed throughout the embryo and generate, among other structures, the peripheral nervous system, including the intrinsic neuroglial networks of the gut, i.e. the enteric nervous system (ENS). The majority of enteric neurons and glia originate from vagal NC derived progenitors which invade the foregut mesenchyme and migrate rostro caudally to colonise the entire length of the gut. Although the migratory behaviour of NC cells has been studied extensively, it remains unclear how their properties and response to microenvironment change as they navigate through complex cellular terrains to reach their target embryonic sites. RESULTS: Using conditional gene inactivation in mice we demonstrate here that the cell cycle dependent protein Geminin (Gem) is critical for the survival of ENS progenitors in a stage-dependent manner. Gem deletion in early ENS progenitors (prior to foregut invasion) resulted in cell-autonomous activation of DNA damage response and p53-dependent apoptosis, leading to severe intestinal aganglionosis. In contrast, ablation of Gem shortly after ENS progenitors had invaded the embryonic gut did not result in discernible survival or migratory deficits. In contrast to other developmental systems, we obtained no evidence for a role of Gem in commitment or differentiation of ENS lineages. The stage-dependent resistance of ENS progenitors to mutation-induced genotoxic stress was further supported by the enhanced survival of post gut invasion ENS lineages to gamma-irradiation relative to their predecessors. CONCLUSIONS: Our experiments demonstrate that, in mammals, NC-derived ENS lineages are sensitive to genotoxic stress in a stage-specific manner. Following gut invasion, ENS progenitors are distinctly resistant to Gem ablation and irradiation in comparison to their pre-enteric counterparts. These studies suggest that the microenvironment of the embryonic gut protects ENS progenitors and their progeny from genotoxic stress. PMID- 27776508 TI - Protective effects of Fraxinus xanthoxyloides (Wall.) leaves against CCl4 induced hepatic toxicity in rat. AB - BACKGROUND: Leaves and root bark of Fraxinus xanthoxyloides Wall. (Oleaceae) are used locally for the treatment of jaundice, malaria and pneumonia. Decoction of stem, twigs and bark is used in pain, internal injuries, rheumatism and in bone fracture. In this investigation we have evaluated the methanol extract of leaves for its hepatoprotective potential against CCl4 induced hepatic injuries in rat. METHODS: Powder of F. xanthoxyloides leaves was extracted with methanol (FXM) and subjected for the determination of polyphenolics through HPLC-DAD analysis. Sprague-Dawley (Rattus novergicus) male rats were divided into eight groups (six rats in each). Group I: non-treated control; Group II: vehicle treated (DMSO plus olive oil) while Group III- VI treated with 1 ml/kg body weight (bw) of CCl4 (30 % in olive oil) for 30 days (15 dosages) to induce the hepatic injuries. Group IV: treated with silymarin (100 mg/kg bw); Group V and VI with FXM (200, 400 mg/kg bw) on alternate days with CCl4 treatment. Group VII and VIII was administered with FXM (200, 400 mg/kg bw) alone (15 dosages). After 30 days the serum was evaluated for liver function enzymes and biochemical markers, liver samples for antioxidant enzymes, biochemical markers, comet assay and for histopathology. RESULTS: HPLC-DAD analysis of FXM revealed the existence of rutin and caffeic acid. In CCl4 treated rats the level of alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin was significantly increased while the albumin concentration in serum was decreased as compared to control group. The level of hepatic antioxidant enzymes, catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), glutathione-S-transferase (GST) and glutathione reductase (GSR) was significantly decreased against the control group. Further, significant decrease in GSH while increase in lipid peroxides (TBARS), H2O2, DNA damages and comet length was induced with CCl4 in hepatic tissues of rat. In contrast, co-administration of FXM and silymarin restored the biochemical and histopathological status of the liver. CONCLUSION: Results of present investigation revealed that F. xanthoxyloides leaves possibly protect the liver against CCl4 induced injuries like silymarin by its antioxidant constituents. PMID- 27776511 TI - Assimilating South African medical students trained in Cuba into the South African medical education system: reflections from an identity perspective. AB - BACKGROUND: In terms of the Nelson Mandela Fidel Castro Medical Collaboration programme, an agreement between the governments of South Africa and Cuba, cohorts of South African students receive their initial five years medical training at a Cuban university before returning to South Africa for a six to twelve months orientation before integration into the local final year class. It is common for these students to experience academic difficulty on their return. Frequently this is viewed merely as a matter of a knowledge deficit. DISCUSSION: We argue that the problem arises from a fundamental divergence in the outcomes of the Cuban and South African medical curricula, each of which is designed with a particular healthcare system in mind. Using the discrepancy theory of identity proposed by Higgins in 1987, we discuss the challenges experienced by the returning Nelson Mandela Fidel Castro Medical Collaboration students in terms of a potential crisis of identity and suggest interventions which may prove valuable in promoting academic success and successful integration. CONCLUSIONS: Though providing additional training to address the gap in skills and knowledge in returning students is an important part of their successful reintegration, this could be insufficient on its own and must be complemented by a range of measures designed to ameliorate the discrepancies in identity which arise from the transition from one educational model to another. PMID- 27776509 TI - Biofilm as a production platform for heterologous production of rhamnolipids by the non-pathogenic strain Pseudomonas putida KT2440. AB - BACKGROUND: Although a transition toward sustainable production of chemicals is needed, the physiochemical properties of certain biochemicals such as biosurfactants make them challenging to produce in conventional bioreactor systems. Alternative production platforms such as surface-attached biofilm populations could potentially overcome these challenges. Rhamnolipids are a group of biosurfactants highly relevant for industrial applications. However, they are mainly produced by the opportunistic pathogen Pseudomonas aeruginosa using hydrophobic substrates such as plant oils. As the biosynthesis is tightly regulated in P. aeruginosa a heterologous production of rhamnolipids in a safe organism can relive the production from many of these limitations and alternative substrates could be used. RESULTS: In the present study, heterologous production of biosurfactants was investigated using rhamnolipids as the model compound in biofilm encased Pseudomonas putida KT2440. The rhlAB operon from P. aeruginosa was introduced into P. putida to produce mono-rhamnolipids. A synthetic promoter library was used in order to bypass the normal regulation of rhamnolipid synthesis and to provide varying expression levels of the rhlAB operon resulting in different levels of rhamnolipid production. Biosynthesis of rhamnolipids in P. putida decreased bacterial growth rate but stimulated biofilm formation by enhancing cell motility. Continuous rhamnolipid production in a biofilm was achieved using flow cell technology. Quantitative and structural investigations of the produced rhamnolipids were made by ultra performance liquid chromatography combined with high resolution mass spectrometry (HRMS) and tandem HRMS. The predominant rhamnolipid congener produced by the heterologous P. putida biofilm was mono-rhamnolipid with two C10 fatty acids. CONCLUSION: This study shows a successful application of synthetic promoter library in P. putida KT2440 and a heterologous biosynthesis of rhamnolipids in biofilm encased cells without hampering biofilm capabilities. These findings expands the possibilities of cultivation setups and paves the way for employing biofilm flow systems as production platforms for biochemicals, which as a consequence of physiochemical properties are troublesome to produce in conventional fermenter setups, or for production of compounds which are inhibitory or toxic to the production organisms. PMID- 27776512 TI - Complementary and alternative medicine (CAM) as part of primary health care in Germany-comparison of patients consulting general practitioners and CAM practitioners: a cross-sectional study. AB - BACKGROUND: In Germany, complementary and alternative medicine (CAM) in primary health care is offered by general practitioners (GPs) and by natural health practitioners, so called 'Heilpraktiker' (HPs). Considering the steadily growing number of unregulated HPs, the aim of the study was to assess characteristics of patients consulting HPs in comparison to patients consulting GPs. METHODS: In a cross-sectional study, patients of randomly selected GPs and HPs were asked to complete a questionnaire about their health care status, health care behavior, and symptoms rated on the Measure Yourself Medical Outcome Profile (MYMOP-D). Patient groups were compared based on health care provider (HP, GP with high use of CAM (CAM-GP), and GP with no/little use of CAM (nCAM-GP)) using Kruskal-Wallis tests and analyses of variance (ANOVA). RESULTS: Altogether, 567 patients (91 of 11 HPs, 223 of 15 CAM-GPs, 253 of 19 nCAM-GPs) filled in the questionnaire. Patients of HPs had a higher education level and were more often female. The most common reason for encounter among all three groups were musculoskeletal problems (30.2-31.1 %). Patients seeing HPs reported more psychological (4.4 % vs. 17.8 %), but less respiratory problems (19.9 % vs. 7.8 %), and longer symptom duration (>5 years: 21.1 % vs. 40.7 %), than patients of nCAM-GPs. CONCLUSIONS: The high percentage of patients with psychological illness and chronic health problems consulting HPs demonstrates the urgent need for action with regard to CAM therapy in primary care and regulation of natural health practitioners. Appropriate measures with regard to quality and patient safety should be taken given the growing numbers of HPs and the absence of a regulatory body. PMID- 27776510 TI - Lung function reductions associated with motor vehicle density in chronic obstructive pulmonary disease: a cross-sectional study. AB - BACKGROUND: Motor vehicle-related air pollution can potentially impair lung function. The effect of pollution in people with compromised pulmonary function such as in COPD has not been previously investigated. To examine the association of lung function with motor vehicle density in people with spirometrically determined COPD in a cross-sectional study. METHODS: In 2004-06, The North West Adelaide Health Study (NWAHS), a biomedical cohort of adults assessed pre and post-bronchodilator spirometry (n = 3,103). Traffic density, obtained from the motor vehicle inventory maintained by the South Australian Environment Protection Authority, was expressed as the daily numbers of vehicles travelling within a 200 m diameter zone around participants' geocoded residences. RESULTS: In subjects with COPD (FEV1/FVC <0.7, n = 221, 7.1 %), increasing daily vehicle density was associated with statistically significant decreases in lung function parameters after adjustment for smoking and socio-economic variables. Mean (95 % CI) post bronchodilator % predicted FEV1 was 81 % (76-87) in the low (<=7179/day) compared with 71 % (67-75) in the high (>=15,270/day) vehicle exposure group (p < 0.05). Linear regression analysis in all subjects with COPD showed significant decrements in post-bronchodilator FEV1/FVC ratio and % predicted FEV1 of 0.03 and 0.05 % respectively per daily increase in 1000 vehicles. In men with COPD (n = 150), the corresponding reductions were 0.03 and 0.06 %. Smaller, non-significant decrements were seen in females. No difference was seen in those without COPD. CONCLUSIONS: Vehicle traffic density was associated with significant reductions in lung function in people with COPD. Urban planning should consider the health impacts for those with pre-existing respiratory conditions. PMID- 27776513 TI - The antifibrotic and fibrolytic properties of date fruit extract via modulation of genotoxicity, tissue-inhibitor of metalloproteinases and nuclear factor- kappa B pathway in a rat model of hepatotoxicity. AB - BACKGROUND: Hepatic fibrosis and its end point; cirrhosis, are the major cause of liver failure and death in patients with chronic liver disease. Therefore, the need for an effective treatment is evident. This study was designed to assess the potential effects of aqueous extract of date fruits, either flesh (DFE) or pits (DPE), on oxidative DNA damage and liver inflammation induced by carbon tetrachloride (CCl4) and whether they are related to inhibition of nuclear factor kappaB pathway. In addition, the fibrolytic potential was evaluated via measuring matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases -1 and -2. METHODS: Rats were divided into the following groups: normal control, model control (CCl4 only), CCl4 + DFE, CCl4 + DPE and CCl4 + coffee. Coffee was used as a positive control. Fibrosis was induced by chronic administration of CCl4 (0.4 ml/kg) 3* a week for 8 weeks, and rats were treated with 6 ml/kg/day of DFE or DPE for 8 weeks. Liver homogenate was prepared for evaluation of oxidative stress, DNA damage, inflammatory and fibrolytic markers. Data are analyzed using one-way analysis of variance followed by a Tukey-Kramer post hoc test. RESULTS: Both DFE and DPE significantly attenuated CCl4-induced oxidative damage as indicated by reducing lipid, protein and DNA oxidation in addition to increasing the levels of hepatic catalase activity. Both extracts blocked the accumulation of collagen I in the liver and ameliorated the increased expression of collagen III and alpha-smooth muscle actin suggesting suppression of profibrotic response induced by CCl4. DFE and DPE also upregulated the expression of heme oxygenase-1 and attenuated the nuclear factor-kappaB activation and cycloxygenase-2 expression reflecting their anti-inflammatory potential. Additionally, both flesh and pits extracts attenuated the increase in the tissue inhibitor of metalloproteinases -1 and -2 suggesting their fibrolytic activity. CONCLUSION: Our data suggest that DFE or DPE can prevent liver fibrosis by suppressing genotoxicity and nuclear factor-kappaB inflammatory pathway and by promoting collagen degradation. PMID- 27776514 TI - Optimal health and disease management using spatial uncertainty: a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia. AB - BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. METHODS: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. RESULTS: The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. CONCLUSION: This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas. PMID- 27776515 TI - Protective effects of hydroponic Teucrium polium on hippocampal neurodegeneration in ovariectomized rats. AB - BACKGROUND: The hippocampus is a target of ovarian hormones, and is necessary for memory. Ovarian hormone loss is associated with a progressive reduction in synaptic strength and dendritic spine. Teucrium polium has beneficial effects on learning and memory. However, it remains unknown whether Teucrium polium ameliorates hippocampal cells spike activity and morphological impairments induced by estrogen deficiency. METHODS: In the present study, we investigated the effects of hydroponic Teucrium polium on hippocampal neuronal activity and morpho-histochemistry of bilateral ovariectomized (OVX) rats. Tetanic potentiation or depression with posttetanic potentiation and depression was recorded extracellularly in response to ipsilateral entorhinal cortex high frequency stimulation. In morpho-histochemical study revealing of the activity of Ca2+-dependent acid phosphatase was observed. In all groups (sham-operated, sham + Teucrium polium, OVX, OVX + Teucrium polium), most recorded hippocampal neurons at HFS of entorhinal cortex showed TD-PTP responses. RESULTS: After 8 weeks in OVX group an anomalous evoked spike activity was detected (a high percentage of typical areactive units). In OVX + Teucrium polium group a synaptic activity was revealed, indicating prevention OVX-induced degenerative alterations: balance of types of responses was close to norm and areactive units were not recorded. All recorded neurons in sham + Teucrium polium group were characterized by the highest mean frequency background and poststimulus activity. In OVX+ Teucrium polium group the hippocampal cells had recovered their size and shape in CA1 and CA3 field compared with OVX group where hippocampal cells were characterized by a sharp drop in phosphatase activity and there was a complete lack of processes reaction. CONCLUSION: Thus, Teucrium polium reduced OVX-induce neurodegenerative alterations in entorhinal cortex-hippocamp circuitry and facilitated neuronal survival by modulating activity of neurotransmitters and network plasticity. PMID- 27776516 TI - Malaria diagnosis and mapping with m-Health and geographic information systems (GIS): evidence from Uganda. AB - BACKGROUND: Rural populations experience several barriers to accessing clinical facilities for malaria diagnosis. Increasing penetration of ICT and mobile-phones and subsequent m-Health applications can contribute overcoming such obstacles. METHODS: GIS is used to evaluate the feasibility of m-Health technologies as part of anti-malaria strategies. This study investigates where in Uganda: (1) malaria affects the largest number of people; (2) the application of m-Health protocol based on the mobile network has the highest potential impact. RESULTS: About 75% of the population affected by Plasmodium falciparum malaria have scarce access to healthcare facilities. The introduction of m-Health technologies should be based on the 2G protocol, as 3G mobile network coverage is still limited. The western border and the central-Southeast are the regions where m-Health could reach the largest percentage of the remote population. Six districts (Arua, Apac, Lira, Kamuli, Iganga, and Mubende) could have the largest benefit because they account for about 28% of the remote population affected by falciparum malaria with access to the 2G mobile network. CONCLUSIONS: The application of m-Health technologies could improve access to medical services for distant populations. Affordable remote malaria diagnosis could help to decongest health facilities, reducing costs and contagion. The combination of m-Health and GIS could provide real-time and geo-localized data transmission, improving anti-malarial strategies in Uganda. Scalability to other countries and diseases looks promising. PMID- 27776517 TI - The role of fibular for supramalleolar osteotomy in treatment of varus ankle arthritis: a biomechanical and clinical study. AB - BACKGROUND: Supramalleolar osteotomy (SMOT) is a well-accepted treatment method for mid-stage varus ankle osteoarthritis (OA). However, few studies have examined the role of fibular osteotomy in SMOT. The objective of the current study was to compare the biomechanical and clinical outcomes of SMOT with and without fibular osteotomy. METHODS: Eight cadaveric lower legs with 10 degrees varus/valgus SMOT models were tested using a Tekscan ankle sensor. Tibiotalar joint contact with and without fibular osteotomy conditions were compared. Forty-one varus ankle OA patients treated with SMOT were included; 22 underwent fibular osteotomy, and 19 did not. The Maryland foot score and radiological angles were used for clinical evaluation. RESULTS: The mean contact area and pressure did not differ significantly between normal and varus/valgus conditions with the fibula preserved. After fibular osteotomy, the mean contact area decreased and the mean contact pressure increased significantly in varus and valgus conditions (P < 0.01). The loading center moved to the opposite direction with and without fibular osteotomy in varus/valgus conditions. After a mean follow-up of 36.6 months (range 17-61), there was no significant difference in the Maryland scores of the two groups. However, in the fibular osteotomy group, the talar tilt angle decreased (P < 0.05), and the tibiocrural angle improved significantly (P < 0.01). CONCLUSIONS: Fibular osteotomy facilitates the translation of tibiotalar contact pressure and is helpful for varus ankle realignment in patients with large talar tilts and small tibiocrural angles. PMID- 27776518 TI - Evaluation of phytochemicals, antioxidant activity and amelioration of pulmonary fibrosis with Phyllanthus emblica leaves. AB - BACKGROUND: In the present study the antioxidant potential of a methanol extract of Phyllanthus emblica leaves (PELE) was determined by in vitro methods as well as by an in vivo animal model, along with HPLC-DAD screening for phyto constituents. METHODS: The in vitro antioxidant potential of PELE was assessed by scavenging of DPPH, nitric oxide and anti-lipid peroxidation assays. For in vivo evaluation, a 60-day experimental plan was followed in which Sprague Dawley rats were administered with 1 mL/kg of CCl4 (CCl4 : DMSO + Olive oil; 30 % v/v) alone or with different doses of PELE (200, 400 mg/kg p.o.). Silymarin (100 mg/kg) as standard drug was also administered to CCl4 treated rats. HPLC-DAD analysis was performed to quantify polyphenolic phytochemicals. RESULTS: PELE exhibited an appreciable in vitro antioxidant activity and scavenged the DPPH radical (IC50 = 39.73 +/- 2.12 MUg/mL) and nitric oxide (IC50 = 39.14 +/- 2.31 MUg/mL) while for anti-lipid peroxidation moderate antioxidant activity was noticed. Reduced levels of antioxidant enzyme activities viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and reduced glutathione (GSH) whereas enhanced levels of total extractable proteins, lipid peroxides (TBARS), nitrite and H2O2 were induced by CCl4 administration in lungs of rat. Co-administration of PELE to rats exhibited a dose dependent decline in the oxidative injuries induced in these parameters. Histopathological damages such as disrupted alveoli, infiltration of macrophages and modified architecture of Clara cells was reversed to the normal state with co-administration of PELE. HPLC-DAD analysis indicated the presence of gallic acid, rutin, kaempferol and caffeic acid in the PELE. CONCLUSION: The findings of this study demonstrate that presence of polyphenolics and other active constituents in PELE might play a significant role in repairing the pulmonary damages instigated with CCl4. PMID- 27776520 TI - Anatomical study of the coracoid process in Mongolian male cadavers using the Latarjet procedure. AB - BACKGROUND: The Latarjet procedure addresses recurrent anterior shoulder instability in the context of a significant bony defect. However, the bony and soft tissue anatomy of the coracoid in coracoid transfer procedures has not yet been defined in Mongolian men. The aims of this study were to describe the soft tissue attachments of the coracoid regarding the bony anatomy, define the average amount of bone available for coracoid transfer, analyze the characteristics of the pectoralis minor and coracoid, and study the relationship between the bony dimensions of the coracoid and body length in Mongolian men. METHODS: We dissected 30 shoulders from 15 male Mongolian cadavers, exposing the coracoid process and attached anatomical structures including the lateral clavicle and acromion, then measured the bony dimensions of the coracoid and the locations and sizes of the coracoid soft tissue footprints. RESULTS: The mean length of the coracoid available for transfer was 23.93 +/- 2.32 mm. The mean length of the coracoid was 42.10 +/- 2.3 mm, and the mean width and height of the coracoid midpoint were 15.29 +/- 1.70 mm and 11.61 +/- 1.98 mm, respectively. The pectoralis minor was part of the joint capsule and passed over the coracoid in some samples. The mutation rate of the pectoralis minor footprint, which was asymmetrical and irregular, was 23.33 %. Statistical analysis involved a multiple linear regression equation. CONCLUSIONS: The average amount of bone available for use in coracoid transfer in Mongolian men was less than that of other populations. Mutation of the pectoralis minor may induce intraoperative capsule injury because this muscle passes over the coracoid deep to the joint capsule of the glenohumeral joint and constitutes part of the shoulder joint, strengthening the joint. Statistically, higher coracoids appeared in shorter patients and longer coracoids appeared in taller patients. Surgically, great care should be taken to consider a patient's height to precisely implement the congruent-arc Latarjet technique. PMID- 27776521 TI - Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger. AB - BACKGROUND: Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether lumefantrine (AL) clinical efficacy in children with SAM compared to those without. METHODS: Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF - Plumpy'Nut(r)) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7. RESULTS: A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR corrected ACPR was 100 % (95 % CI, 96.8-100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4-99.7 %) at day 28 and 98.3 % (95.6-99.4 %) at day 42 in non SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04 4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049). CONCLUSIONS: This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958905 , registration date: October 7, 2013. PMID- 27776519 TI - Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. AB - BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer. PMID- 27776523 TI - In vitro anti-HIV and antioxidant activity of Hoodia gordonii (Apocynaceae), a commercial plant product. AB - BACKGROUND: Hoodia gordonii products are widely commercialized for anti-obesity purposes; however, minimal research is available on the other health properties demonstrated by this popular herbal plant. METHODS: H. gordonii crude extracts (ethanol and ethyl acetate) were assayed for in vitro anti-HIV-1 protease (PR), reverse transcriptase (RT) and integrase activity. The 2,2-diphenyl-1 picrylhydrazyl (DPPH) and reducing power assays were used for the antioxidant analysis. In addition, qualitative and quantitative phytochemical analyses of the extracts were determined using standard methods. RESULTS: H. gordonii extract demonstrated good inhibition against HIV RT with IC50 values of 73.55 +/- 0.04 and 69.81 +/- 9.45 MUg/mL for ethanol and ethyl acetate extracts, respectively. Both extracts also demonstrated inhibitory activity against HIV PR with IC50 values of 97.29 +/- 0.01 and 63.76 +/- 9.01 MUg/mL for ethanol and ethyl acetate extracts. In addition, H. gordonii also showed good antioxidant activity with IC50 values of 124.6 +/- 11.3 and 126.2 +/- 3.15 MUg/mL obtained for ethanol and ethyl acetate extracts, respectively. The reducing power of H. gordonii extracts increased as the concentration increased which confirmed the presence of antioxidants (reductants) in the extracts. Phytochemical screening of H. gordonii revealed the presence of phenolics, alkaloids, terpenes, steroids, cardiac glycosides and tannins in the ethanolic extract, while the ethyl acetate extract only showed the presence of phenolics, cardiac glycosides and steroids. The total phenolic content was 420 +/- 0.17 and 319.9 +/- 0.2 mg GAE/g for the ethanol and ethyl acetate extracts, respectively. The ethanol extract, which revealed the presence of tannins, had a tannin content of 330 +/- 0.2 mg TAE/g extract. CONCLUSION: This data suggests that H. gordonii has good in vitro inhibition against selected HIV-1 enzymes as well as antioxidant properties, suggesting new potential uses for this commercial plant. PMID- 27776524 TI - Pulsed high-dose dexamethasone modulates Th1-/Th2-chemokine imbalance in immune thrombocytopenia. AB - BACKGROUND: Chemokines and chemokine receptors play important roles in autoimmune diseases; however, their role in immune thrombocytopenia (ITP) is unclear. High dose dexamethasone (HD-DXM) may become a first-line therapy for adult patients with ITP, but the effect of HD-DXM on chemokines in ITP patients is unknown. Our aim was to investigate the mechanism of pulsed HD-DXM for management of ITP, specifically regarding the chemokine pathways. METHODS: Th1-/Th2-associated chemokine and chemokine receptor profiles in ITP patients before and after pulsed HD-DXM was studied. Plasma levels of CCL5 and CXCL11 (Th1-associated) and of CCL11 (Th2-associated) were determined by ELISA. Gene expression of these three chemokines and their corresponding receptors CCR5, CXCR3, and CCR3, in peripheral blood mononuclear cells (PBMCs) was determined by quantitative RT-PCR. RESULTS: Thirty-three of the thirty-eight ITP patients responded effectively to HD-DXM (oral, 40 mg/day, 4 days). In ITP patients, plasma CXCL11 levels increased, while CCL11 and CCL5 decreased compared to controls (P < 0.05). Similarly, gene expression of CXCL11 and its receptor CXCR3 increased, while CCL11 and CCR3 decreased (P < 0.05). CCL5 expression did not significantly change; however, expression of its receptor CCR5 increased (P < 0.05). Interestingly, in the patients who responded to pulsed HD-DXM, CXCL11 and CXCR3 expression was down regulated, while CCL11 and CCR3 expression was up-regulated (P < 0.05). Meanwhile, CCL5 expression was up-regulated and CCR5 was down-regulated by HD-DXM (P < 0.05). CONCLUSIONS: The abnormal profiles of Th1-/Th2-associated chemokines and chemokine receptors may play important roles in the pathogenesis of ITP. Importantly, regulating Th1 polarization by pulsed HD-DXM may represent a novel approach for immunoregulation in ITP. PMID- 27776522 TI - Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy. AB - BACKGROUND: Recently, we described a novel autoantibody, anti-Sj/ITPR1-IgG, that targets the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in patients with cerebellar ataxia. However, ITPR1 is expressed not only by Purkinje cells but also in the anterior horn of the spinal cord, in the substantia gelatinosa and in the motor, sensory (including the dorsal root ganglia) and autonomic peripheral nervous system, suggesting that the clinical spectrum associated with autoimmunity to ITPR1 may be broader than initially thought. Here we report on serum autoantibodies to ITPR1 (up to 1:15,000) in three patients with (radiculo)polyneuropathy, which in two cases was associated with cancer (ITPR1 expressing adenocarcinoma of the lung, multiple myeloma), suggesting a paraneoplastic aetiology. METHODS: Serological and other immunological studies, and retrospective analysis of patient records. RESULTS: The clinical findings comprised motor, sensory (including severe pain) and autonomic symptoms. While one patient presented with subacute symptoms mimicking Guillain-Barre syndrome (GBS), the symptoms progressed slowly in two other patients. Electrophysiology revealed delayed F waves; a decrease in motor and sensory action potentials and conduction velocities; delayed motor latencies; signs of denervation, indicating sensorimotor radiculopolyneuropathy of the mixed type; and no conduction blocks. ITPR1-IgG belonged to the complement-activating IgG1 subclass in the severely affected patient but exclusively to the IgG2 subclass in the two more mildly affected patients. Cerebrospinal fluid ITPR1-IgG was found to be of predominantly extrathecal origin. A 3H-thymidine-based proliferation assay confirmed the presence of ITPR1-reactive lymphocytes among peripheral blood mononuclear cells (PBMCs). Immunophenotypic profiling of PBMCs protein demonstrated predominant proliferation of B cells, CD4 T cells and CD8 memory T cells following stimulation with purified ITPR1 protein. Patient ITPR1-IgG bound both to peripheral nervous tissue and to lung tumour tissue. A nerve biopsy showed lymphocyte infiltration (including cytotoxic CD8 cells), oedema, marked axonal loss and myelin-positive macrophages, indicating florid inflammation. ITPR1-IgG serum titres declined following tumour removal, paralleled by clinical stabilization. CONCLUSIONS: Our findings expand the spectrum of clinical syndromes associated with ITPR1-IgG and suggest that autoimmunity to ITPR1 may underlie peripheral nervous system diseases (including GBS) in some patients and may be of paraneoplastic origin in a subset of cases. PMID- 27776525 TI - Douchi (fermented Glycine max Merr.) alleviates atopic dermatitis-like skin lesions in NC/Nga mice by regulation of PKC and IL-4. AB - BACKGROUND: Douchi (fermented Glycine max Merr.) is produced from fermented soybeans, which is widely used in traditional herbal medicine. In this study, we investigated whether Douchi attenuates protein kinase C (PKC) and interleukin (IL)-4 response and cutaneous inflammation in Atopic dermatitis (AD)-like NC/Nga mice. METHODS: To induce AD-like skin lesions, D. farinae antigen was applied to the dorsal skin of 3-week-old NC/Nga mice. After inducing AD, Douchi extract was administered 20 mg/kg daily for 3 weeks to the Douchi-treated mice group. We identified the changes of skin barrier and Th2 differentiation through PKC and IL 4 by immunohistochemistry. RESULTS: Douchi treatment of NC/Nga mice significantly reduced clinical scores (p < 0.01) and histological features. The levels of PKC and IL-4 were significantly reduced in the Douchi-treated group (p < 0.01). The reduction of IL-4 and PKC led to decrease of inflammatory factors such as substance P, inducible nitric oxide synthase (iNOS) and Matrix metallopeptidase 9 (MMP-9) (all p < 0.01). Douchi also down-regulated Th1 markers (IL-12, TNF-alpha) as well as Th2 markers (IL-4, p-IkappaB) (p < 0.01). CONCLUSION: Douchi alleviates AD-like skin lesions through suppressing of PKC and IL-4. These results also lead to diminish levels of substance P, iNOS and MMP-9 in skin lesions. Therefore, Douchi may have potential applications for the prevention and treatment of AD. PMID- 27776528 TI - Clinical characteristics of synchronous colorectal cancers in Japan. AB - BACKGROUND: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance. METHODS: We recruited 1005 patients with surgically resected CRCs between January 2007 and December 2011. The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression. RESULTS: Eighty-four patients (8.4 %) developed sCRCs, 16 of them (19.0 %) harboring three or more cancers. Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P = 0.62). CONCLUSIONS: Our results highlight the importance of perioperative colonoscopy examination to ensure the absence of sCRCs that, being small and early staged, are more difficult to detect. The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition. PMID- 27776526 TI - Association of metabolic syndrome and its components with arterial stiffness in Caucasian subjects of the MARK study: a cross-sectional trial. AB - BACKGROUND: The cardio-ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV) can reflect both central and peripheral arterial stiffness. Metabolic syndrome (MetS) and its components may increase arterial stiffness and the risk of cardiovascular diseases. However, the correlation of MetS and its components with arterial stiffness is still not clear. The primary aim of this study is thus the relationship using baPWV and CAVI in Caucasian adults with intermediate cardiovascular risk. The secondary aim is to analyze sex differences. METHODS: This study analyzed 2351 subjects aged 35-74 years (mean, 61.4 +/- 7.7 years) comprising 61.7 % males and enrolled in the improving interMediAte Risk management (MARK) study. CAVI was measured using a VaSera VS 1500 (r) device, and baPWV was calculated using a validated equation. MetS was defined based on the Joint Scientific Statement National Cholesterol Education Program III. Waist circumference, blood pressure, fasting plasma glucose, and lipid profile were measured. RESULTS: MetS was found in 51.9 % of the subjects. All MetS components except reduced HDL-cholesterol (p = 0.578) were associated with CAVI. High density lipoprotein cholesterol (p = 0.075) and waist circumference (p = 0.315) were associated with baPWV. The different MetS components that assess dyslipidemia using the stiffness measures show different associations according to patient sex. The high blood pressure component had a greater odds ratio (OR) for both baPWV >= 17.5 m/sec (OR = 6.90, 95 % CI 3.52 13.519) and CAVI >= 9 (OR = 2.20, 95 % CI 1.63-1.90). CONCLUSIONS: MetS and all its components (except HDL-cholesterol with baPWV and CAVI and WC with baPWV) were associated with baPWV and CAVI. However, there were sex differences in the association of MetS and its components with baPWV and CAVI. Data from this study suggest a greater association of CAVI and baPWV values with MetS components in males than in females and indicate greater arterial stiffness in the event of simultaneously elevated blood pressure, fasting plasma glucose, and waist circumference. Trial Registration Clinical Trials.gov Identifier: https://clinicaltrials.gov/ct2/show/ NCT01428934. Registered 2 September 2011. Last updated September 8, 2016. PMID- 27776527 TI - Real-time monitoring of the sugar sensing in Saccharomyces cerevisiae indicates endogenous mechanisms for xylose signaling. AB - BACKGROUND: The sugar sensing and carbon catabolite repression in Baker's yeast Saccharomyces cerevisiae is governed by three major signaling pathways that connect carbon source recognition with transcriptional regulation. Here we present a screening method based on a non-invasive in vivo reporter system for real-time, single-cell screening of the sugar signaling state in S. cerevisiae in response to changing carbon conditions, with a main focus on the response to glucose and xylose. RESULTS: The artificial reporter system was constructed by coupling a green fluorescent protein gene (yEGFP3) downstream of endogenous yeast promoters from the Snf3p/Rgt2p, SNF1/Mig1p and cAMP/PKA signaling pathways: HXT1p/2p/4p; SUC2p, CAT8p; TPS1p/2p and TEF4p respectively. A panel of eight biosensors strains was generated by single copy chromosomal integration of the different constructs in a W303-derived strain. The signaling biosensors were validated for their functionality with flow cytometry by comparing the fluorescence intensity (FI) response in the presence of high or nearly depleted glucose to the known induction/repression conditions of the eight different promoters. The FI signal correlated with the known patterns of the selected promoters while maintaining a non-invasive property on the cellular phenotype, as was demonstrated in terms of growth, metabolites and enzyme activity. CONCLUSIONS: Once verified, the sensors were used to evaluate the signaling response to varying conditions of extracellular glucose, glycerol and xylose by screening in 96-well microtiter plates. We show that these yeast strains, which do not harbor any recombinant pathways for xylose utilization, are lacking a signaling response for extracellular xylose. However, for the HXT2p/4p sensors, a shift in the flow cytometry population dynamics indicated that internalized xylose does affect the signaling. These results suggest that the previously observed effects of this pentose on the S. cerevisiae physiology and gene regulation can be attributed to xylose and not only to a lack of glucose. PMID- 27776529 TI - Biosynthesis of three N-acetylaminosugar-conjugated flavonoids using engineered Escherichia coli. AB - BACKGROUND: Nucleotide sugars serve as sugar donors for the synthesis of various glycones. The biological and chemical properties of glycones can be altered depending which sugar is attached. Bacteria synthesize unusual nucleotide sugars. A novel nucleotide sugar can be synthesized in Escherichia coli by introducing nucleotide biosynthetic genes from other microorganisms into E. coli. The engineered E. coli strains can be used as a platform for the synthesis of novel glycones. RESULTS: Four genes, Pdeg (UDP-N-acetylglucosamine C4,6-dehydratase), Preq (UDP-4-reductase), UDP-GlcNAc 6-DH (UDP-N-acetylglucosamine 6 dehydrogenase), and UXNAcS (UDP-N-acetylxylosamine synthase), were employed to synthesize UDP-quinovosamine, UDP-N-acetylglucosaminuronic acid, and UDP-N acetylxylosamine in E. coli. We engineered an E. coli nucleotide sugar biosynthetic pathway to increase the pool of substrate for the target nucleotide sugars. Uridine diphosphate dependent glycosyltransferase (UGT) was also selected and introduced into E. coli. Using engineered E. coli, high levels of three novel flavonoid glycosides were obtained; 158.3 mg/L quercetin 3-O-(N acetyl)quinovosamine, 172.5 mg/L luteolin 7-O-(N-acetyl)glucosaminuronic acid, and 160.8 mg/L quercetin 3-O-(N-acetyl)xylosamine. CONCLUSIONS: We reconstructed an E. coli nucleotide pathway for the synthesis of UDP-quinovosamine, UDP-N acetylglucosaminuronic acid and UDP-N-acetylxylosamine in an E. coli galU (UDP glucose 1-phosphate uridylyltransferase) or pgm (phosphoglucomutase) deletion mutant. Using engineered E. coli strains harboring a specific UGT, three novel flavonoids glycones were synthesized. The E. coli strains used in this study can be used for the synthesis of diverse glycones. PMID- 27776530 TI - Sequential Hybrid CryoMaze Ablation versus Surgical CryoMaze Alone for the Treatment of Atrial Fibrillation (SurHyb): study protocol for a randomized controlled trial. AB - BACKGROUND: Atrial fibrillation is common in patients with structural heart disease who are undergoing cardiac surgery. Surgical CryoMaze has been shown to be an effective treatment in several trials, but success rates have varied considerably, between 47-95 %. The sequential hybrid approach, combining surgical CryoMaze followed by radiofrequency catheter ablation, can achieve high freedom from atrial arrhythmias, even when rigorous methods to detect arrhythmias after the procedure are used. However, data from randomized trials comparing hybrid ablations to surgical ablations alone are lacking. METHODS/DESIGN: The SurHyb study is a prospective, multicenter, randomized study. Patients with persistent or long-standing persistent atrial fibrillation will be randomized to either surgical CryoMaze alone or surgical CryoMaze followed by catheter ablation 3 months post-surgery. The primary outcome measure is arrhythmia-free survival without class I or III antiarrhythmic drugs, which will be evaluated using 7-day ECG Holter monitoring at 24 months. A total of 260 patients will be investigated from three medical centers in the Czech Republic to obtain the relevant information. DISCUSSION: This is the first randomized study that compares surgical CryoMaze alone with the staged hybrid surgical CryoMaze followed by catheter ablation in patients with persistent or long-standing persistent atrial fibrillation. These results will contribute to the optimization of the treatment for these patients. TRIAL REGISTRATION: Czech Clinical Trials Registry, cz 301020151253 . Registered on 30 October 2015. PMID- 27776533 TI - Early antibiotic treatment for gradual ventilator-associated pneumonia: yes or no? PMID- 27776532 TI - Cadmium-induced apoptosis of Siberian tiger fibroblasts via disrupted intracellular homeostasis. AB - BACKGROUND: Heavy metals can cause great harm to Siberian tigers in the natural environment. Cadmium (Cd2+) is an environmental contaminant that affects multiple cellular processes, including cell proliferation, differentiation, and survival. It has been shown to induce apoptosis in a variety of cell types and tissues. RESULTS: We investigated the apoptotic effects of Cd2+ on Siberian tiger fibroblasts in vitro. Our research revealed the typical signs of apoptosis after Cd2+ exposure. Apoptosis was dose- (0-4.8 MUM) and duration-dependent (12-48 h), and proliferation was strongly inhibited. Cd2+ increased the activity of caspase 3, -8, and -9 and disrupted calcium homeostasis by causing oxidative stress and mitochondrial dysfunction. It also increased K+ efflux and altered the mRNA levels of Bax, Bcl-2, caspase-3, caspase-8, Fas, and p53. CONCLUSIONS: Our results suggest that Cd2+ triggers the apoptosis of Siberian tiger fibroblasts by disturbing intracellular homeostasis. These results will aid in our understanding of the effects of Cd2+ on Siberian tigers and in developing interventions to treat and prevent cadmium poisoning. PMID- 27776531 TI - Integrating precision cancer medicine into healthcare-policy, practice, and research challenges. AB - Precision medicine (PM) can be defined as a predictive, preventive, personalized, and participatory healthcare service delivery model. Recent developments in molecular biology and information technology make PM a reality today through the use of massive amounts of genetic, 'omics', clinical, environmental, and lifestyle data. With cancer being one of the most prominent public health threats in developed countries, both the research community and governments have been investing significant time, money, and efforts in precision cancer medicine (PCM). Although PCM research is extremely promising, a number of hurdles still remain on the road to an optimal integration of standardized and evidence-based use of PCM in healthcare systems. Indeed, PCM raises a number of technical, organizational, ethical, legal, social, and economic challenges that have to be taken into account in the development of an appropriate health policy framework. Here, we highlight some of the more salient issues regarding the standards needed for integration of PCM into healthcare systems, and we identify fields where more research is needed before policy can be implemented. Key challenges include, but are not limited to, the creation of new standards for the collection, analysis, and sharing of samples and data from cancer patients, and the creation of new clinical trial designs with renewed endpoints. We believe that these issues need to be addressed as a matter of priority by public health policymakers in the coming years for a better integration of PCM into healthcare. PMID- 27776534 TI - Coronary occlusion after the Manouguian procedure in a patient with a single coronary artery: a case report. AB - BACKGROUND: The association between the anatomy of a single coronary artery (SCA) and the surgical risk of aortic valve replacement (AVR) remains unclear due to a lack of studies on this topic. CASE PRESENTATION: A 73-year-old woman underwent AVR for aortic stenosis. Preoperative coronary angiography results showed a SCA arising from the left coronary sinus. The Manouguian procedure was performed for a small aortic annulus. Intraoperatively, an extracorporeal membrane oxygenator (ECMO) was needed for bypass weaning failure due to newly developed right ventricular dysfunction. Coronary angiography was performed on postoperative day 4, and the findings showed a right coronary artery occlusion just after its origin. After emergent coronary artery bypass surgery, she could be weaned from the ECMO. She was discharged on postoperative day 70 and followed up without complications for 12 months. CONCLUSIONS: AVR with the annular enlargement procedure in those with a SCA can result in an unexpected coronary artery occlusion, which should be, therefore, suspected when unexplained myocardial dysfunction occur. For reducing this risk, the use of a small prosthesis should be considered over the annular enlargement procedure when performing AVR in those with a small aortic annulus and a SCA. PMID- 27776535 TI - Microcirculatory assessment of patients under VA-ECMO. AB - BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an effective technique for providing emergency mechanical circulatory support for patients with cardiogenic shock. VA-ECMO enables a rapid restoration of global systemic organ perfusion, but it has not been found to always show a parallel improvement in the microcirculation. We hypothesized in this study that the response of the microcirculation to the initiation of VA-ECMO might identify patients with increased chances of intensive care unit (ICU) survival. METHODS: Twenty-four patients were included in this study. Sublingual microcirculation measurements were performed using the CytoCam-IDF (incident dark field) imaging device. Microcirculatory measurements were performed at baseline, after VA-ECMO insertion (T1), 48-72 h after initiation of VA-ECMO (T2), 5-6 days after (T3), 9 10 days after (T4), and within 24 h of VA-ECMO removal. RESULTS: Of the 24 patients included in the study population, 15 survived and 9 died while on VA ECMO. There was no significant difference between the systemic global hemodynamic variables at initiation of VA-ECMO between the survivors and non-survivors. There was, however, a significant difference in the microcirculatory parameters of both small and large vessels at all time points between the survivors and non survivors. Perfused vessel density (PVD) at baseline (survivor versus non survivor, 19.21 versus 13.78 mm/mm2, p = 0.001) was able to predict ICU survival on initiation of VA-ECMO; the area under the receiver operating characteristic curve (ROC) was 0.908 (95 % confidence interval 0.772-1.0). CONCLUSION: PVD of the sublingual microcirculation at initiation of VA-ECMO can be used to predict ICU mortality in patients with cardiogenic shock. PMID- 27776536 TI - Postprandial effect of breakfast glycaemic index on vascular function, glycaemic control and cognitive performance (BGI study): study protocol for a randomised crossover trial. AB - BACKGROUND: Postprandial glycaemic response affects cognitive and vascular function. The acute effect of breakfast glycaemic index on vascular parameters is not sufficiently known. Also, the influence of breakfasts with different glycaemic index on cognitive performance has been mostly studied in children and adolescents with varying results. Therefore, the purpose of this study is to analyse the postprandial effect of high and low glycaemic index breakfasts on vascular function and cognitive performance and their relationship with postprandial glycaemic response in healthy young adults. METHODS/DESIGN: This is a crossover clinical trial targeting adults (aged 20-40 years, free from cardiovascular disease) selected by consecutive sampling at urban primary care health clinics in Salamanca (Spain). Each subject will complete three interventions with a washout period of one week: a control condition (consisting of water); a low glycaemic index breakfast (consisting of dark chocolate, walnuts, yogurt and an apple, with an overall glycaemic index of 29.4 and an energy contribution of 1489 kJ); and a high glycaemic index breakfast (consisting of bread, grape juice and strawberry jam, with an overall glycaemic index of 64.0 and an energy contribution of 1318 kJ). The postprandial effect will be assessed at 60 and 120 minutes from each breakfast including blood sampling and cognitive performance evaluations. Measurements of arterial stiffness and central haemodynamic parameters will be taken at -10, 0, 15, 30, 45, 60, 75, 90, 105 and 120 minutes. DISCUSSION: The differences in postprandial glycaemic response due to breakfast glycaemic index could affect vascular parameters and cognitive performance with important applications and implications for the general population. This could provide necessary information for the establishment of new strategies in terms of nutritional education and work performance improvement. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02616276 . Registered on 19 November 2015. PMID- 27776537 TI - Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study. AB - BACKGROUND: Ventriculitis is a complication of temporary intraventricular drains. The limited penetration of meropenem into the cerebrospinal fluid (CSF) is well known. However, ventricular CSF pharmacokinetic data in patients with ventriculitis are lacking. The aim of this study was to evaluate meropenem pharmacokinetics in the serum and CSF of neurocritical care patients with proven or suspected ventriculitis. METHODS: We conducted an observational pharmacokinetic study of neurocritical care patients with proven or suspected ventriculitis receiving meropenem. Multiple blood and CSF samples were taken and were described using nonparametric pharmacokinetic modelling with Pmetrics. RESULTS: In total, 21 patients (median age 52 years, median weight 76 kg) were included. The median (range) of peak and trough concentrations in serum were 20.16 (4.40-69.00) mg/L and 2.54 (0.00-31.40) mg/L, respectively. The corresponding peak and trough concentrations in CSF were 1.20 (0.00-6.20) mg/L and 1.28 (0.00-4.10) mg/L, respectively, with a median CSF/serum ratio (range) of 0.09 (0.03-0.16). Median creatinine clearance ranged from 60.7 to 217.6 ml/minute (median 122.5 ml/minute). A three-compartment linear population pharmacokinetic model was most appropriate. No covariate relationships could be supported for any of the model parameters. Meropenem demonstrated poor penetration into CSF, with a median CSF/serum ratio of 9 % and high interindividual pharmacokinetic variability. CONCLUSIONS: Administration of higher-than-standard doses of meropenem and therapeutic drug monitoring in both serum and CSF should be considered to individualise meropenem dosing in neurocritical care patients with ventriculitis. PMID- 27776538 TI - Clusterflock: a flocking algorithm for isolating congruent phylogenomic datasets. AB - BACKGROUND: Collective animal behavior, such as the flocking of birds or the shoaling of fish, has inspired a class of algorithms designed to optimize distance-based clusters in various applications, including document analysis and DNA microarrays. In a flocking model, individual agents respond only to their immediate environment and move according to a few simple rules. After several iterations the agents self-organize, and clusters emerge without the need for partitional seeds. In addition to its unsupervised nature, flocking offers several computational advantages, including the potential to reduce the number of required comparisons. FINDINGS: In the tool presented here, Clusterflock, we have implemented a flocking algorithm designed to locate groups (flocks) of orthologous gene families (OGFs) that share an evolutionary history. Pairwise distances that measure phylogenetic incongruence between OGFs guide flock formation. We tested this approach on several simulated datasets by varying the number of underlying topologies, the proportion of missing data, and evolutionary rates, and show that in datasets containing high levels of missing data and rate heterogeneity, Clusterflock outperforms other well-established clustering techniques. We also verified its utility on a known, large-scale recombination event in Staphylococcus aureus. By isolating sets of OGFs with divergent phylogenetic signals, we were able to pinpoint the recombined region without forcing a pre-determined number of groupings or defining a pre-determined incongruence threshold. CONCLUSIONS: Clusterflock is an open-source tool that can be used to discover horizontally transferred genes, recombined areas of chromosomes, and the phylogenetic 'core' of a genome. Although we used it here in an evolutionary context, it is generalizable to any clustering problem. Users can write extensions to calculate any distance metric on the unit interval, and can use these distances to 'flock' any type of data. PMID- 27776539 TI - CLIP-GENE: a web service of the condition specific context-laid integrative analysis for gene prioritization in mouse TF knockout experiments. AB - MOTIVATION: Transcriptome data from the gene knockout experiment in mouse is widely used to investigate functions of genes and relationship to phenotypes. When a gene is knocked out, it is important to identify which genes are affected by the knockout gene. Existing methods, including differentially expressed gene (DEG) methods, can be used for the analysis. However, existing methods require cutoff values to select candidate genes, which can produce either too many false positives or false negatives. This hurdle can be addressed either by improving the accuracy of gene selection or by providing a method to rank candidate genes effectively, or both. Prioritization of candidate genes should consider the goals or context of the knockout experiment. As of now, there are no tools designed for both selecting and prioritizing genes from the mouse knockout data. Hence, the necessity of a new tool arises. RESULTS: In this study, we present CLIP-GENE, a web service that selects gene markers by utilizing differentially expressed genes, mouse transcription factor (TF) network, and single nucleotide variant information. Then, protein-protein interaction network and literature information are utilized to find genes that are relevant to the phenotypic differences. One of the novel features is to allow researchers to specify their contexts or hypotheses in a set of keywords to rank genes according to the contexts that the user specify. We believe that CLIP-GENE will be useful in characterizing functions of TFs in mouse experiments. AVAILABILITY: http://epigenomics.snu.ac.kr/CLIP-GENE REVIEWERS: This article was reviewed by Dr. Lee and Dr. Pongor. PMID- 27776540 TI - The alliance between genetic biobanks and patient organisations: the experience of the telethon network of genetic biobanks. AB - BACKGROUND: Rare diseases (RDs) are often neglected because they affect a small percentage of the population (6-8 %), which makes research and development of new therapies challenging processes. Easy access to high-quality samples and associated clinical data is therefore a key prerequisite for biomedical research. In this context, Genetic Biobanks are critical to developing basic, translational and clinical research on RDs. The Telethon Network of Genetic Biobanks (TNGB) is aware of the importance of biobanking as a service for patients and has started a dialogue with RD-Patient Organisations via promotion of dedicated meetings and round-tables, as well as by including their representatives on the TNGB Advisory Board. This has enabled the active involvement of POs in drafting biobank policies and procedures, including those concerning ethical issues. Here, we report on our experience with RD-Patient Organisations who have requested the services of existing biobanks belonging to TNGB and describe how these relationships were established, formalised and maintained. RESULTS: The process of patient engagement has proven to be successful both for lay members, who increased their understanding of the complex processes of biobanking, and for professionals, who gained awareness of the needs and expectations of the people involved. This collaboration has resulted in a real interest on the part of Patient Organisations in the biobanking service, which has led to 13 written agreements designed to formalise this process. These agreements enabled the centralisation of rare genetic disease biospecimens and their related data, thus making them available to the scientific community. CONCLUSIONS: The TNGB experience has proven to be an example of good practice with regard to patient engagement in biobanking and may serve as a model of collaboration between disease-oriented Biobanks and Patient Organisations. Such collaboration serves to enhance awareness and trust and to encourage the scientific community to address research on RDs. PMID- 27776541 TI - Course of disease in multifocal choroiditis lacking sufficient immunosuppression: a case report. AB - BACKGROUND: Multifocal choroiditis with panuveitis is a rare disease. The educational merit of this case presentation results from the good documentation and the impressive ocular fundus pictures. CASE PRESENTATION: We illustrate the 3 year course of disease in a 22-year-old myopic white woman with multifocal choroiditis with panuveitis and secondary choroidal neovascularization. The activity of the disease was evaluated clinically by optical coherence tomography and fluorescein angiography. Choroidal neovascularization was treated by intravitreal bevacizumab (2.5 mg/0.1 ml). Our patient lacked systemic therapy for the first 11 months because of noncompliance. CONCLUSIONS: The case is remarkable as the delayed onset of peripheral lesions and the additional existence of high myopia made diagnosis difficult. In addition, it demonstrates that full outbreak of disease with multiple central and peripheral fundus lesions and secondary choroidal neovascularization can develop without systemic treatment. PMID- 27776542 TI - Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. AB - BACKGROUND: In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self. This educational program is, to a large extent, mediated by medullary thymic epithelial cells that have a unique capacity to express, and subsequently present, a large fraction of body antigens. While the scope of promiscuously expressed genes by medullary thymic epithelial cells is well-established, relatively little is known about the expression of variants that are generated by co-transcriptional and post transcriptional processes. RESULTS: Our study reveals that in comparison to other cell types, medullary thymic epithelial cells display significantly higher levels of alternative splicing, as well as A-to-I and C-to-U RNA editing, which thereby further expand the diversity of their self-antigen repertoire. Interestingly, Aire, the key mediator of promiscuous gene expression in these cells, plays a limited role in the regulation of these transcriptional processes. CONCLUSIONS: Our results highlight RNA processing as another layer by which the immune system assures a comprehensive self-representation in the thymus which is required for the establishment of self-tolerance and prevention of autoimmunity. PMID- 27776543 TI - Measurement of HbA1c in multicentre diabetes trials - should blood samples be tested locally or sent to a central laboratory: an agreement analysis. AB - BACKGROUND: Glycated haemoglobin (HbA1c) is an important outcome measure in diabetes clinical trials. For multicentre designs, HbA1c can be measured locally at participating centres or by sending blood samples to a central laboratory. This study analyses the agreement between local and central measurements, using 1 year follow-up data collected in a multicentre randomised controlled trial (RCT) of newly diagnosed children with type I diabetes. METHODS: HbA1c measurements were routinely analysed both locally and centrally at baseline and then at 3, 6, 9 and 12 months and the data reported in mmol/mol. Agreement was assessed by calculating the bias and 95 % limits of agreement, using the Bland-Altman analysis method. A predetermined benchmark for clinically acceptable margin of error between measurements was subjectively set as +/-10 % for HbA1c. The percentage of pairs of measurements that were classified as clinically acceptable was calculated. Descriptive statistics were used to examine the agreement within centres. Treatment group was not considered. RESULTS: Five hundred and ninety pairs of measurement, representing 255 children and 15 trial centres across four follow-up time points, were compared. There was no significant bias: local measurements were an average of 0.16 mmol/mol (SD = 4.5, 95 % CI -0.2 to 0.5) higher than central. The 95 % limits of agreement were -8.6 to 9.0 mmol/mol (local minus central). Eighty percent of local measurements were within +/-10 % of corresponding central measurements. Some trial centres were more varied in the differences observed between local and central measurements: IQRs ranging from 3 to 9 mmol/mol; none indicated systematic bias. CONCLUSIONS: Variation in agreement between HbA1c measurements was greater than had been expected although no overall bias was detected and standard deviations were similar. Discrepancies were present across all participating centres. These findings have implications for the comparison of standards of clinical care between centres, the design of future multicentre RCTs and existing quality assurance processes for HbA1c measurements. We recommend that centralised HbA1c measurement is preferable in the multicentre clinical trial setting. TRIAL REGISTRATION: Eudract No. 2010 023792-25 , registered on 4 November 2010. PMID- 27776544 TI - Anti-N-methyl-D-aspartate receptor encephalitis with an imaging-invisible ovarian teratoma: a case report. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is a recently discovered disease entity of paraneoplastic limbic encephalitis. It largely affects young women and is often associated with an ovarian teratoma. It is a serious yet treatable condition if diagnosed early. Its remedy involves immunotherapy and surgical removal of the teratoma of the ovaries. This case of anti-N-methyl-D-aspartate receptor encephalitis involves an early surgical intervention with bilateral oophorectomy, despite negative imaging evidence of a teratoma. CASE PRESENTATION: A 25-year-old white woman with anti-N-methyl-D aspartate receptor encephalitis presented with behavioral changes and seizures that were confirmed to be secondary to anti-N-methyl-D-aspartate receptor encephalitis. She required an admission to our intensive care unit for ventilator support and received a number of immunological therapies. Multiple imaging investigations showed no evidence of an ovarian teratoma; she had a bilateral oophorectomy 29 days after admission. Ovarian histology confirmed the presence of a teratoma with neuronal cells. A few days after the operation she began to show signs of improvement and, apart from mild short-term memory loss, she returned to normal function. CONCLUSIONS: Our patient is an example of teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis, in which the teratoma was identified only microscopically. Her case highlights that even with negative imaging evidence of a teratoma, ovarian pathology should still be considered and explored. PMID- 27776545 TI - Epithelioid sarcoma with multiple lesions on the left arm: a case report. AB - BACKGROUND: Epithelioid sarcoma is a rare, high-grade malignant tumor of the soft tissue. The incidence of local recurrence, regional lymph node involvement, and distant metastases is high. Epithelioid sarcoma is most often seen in adolescents and young adults. In the early stage before the development of full clinical features, epithelioid sarcoma is often misdiagnosed as a benign disease such as granuloma. CASE PRESENTATION: We report a case of a 74-year-old Japanese woman whose epithelioid sarcoma was initially misdiagnosed as fungal infection. Rebiopsy revealed the proliferation of atypical polygonal or oval epithelioid cells in the dermis and lymphocyte infiltration through the dermis. Immunohistochemically, the tumor cells were positive for vimentin, cell adhesion molecule 5.2, epithelial membrane antigen, and E26-related gene. The nuclear expression of integrase interactor 1 was lost in the tumor cells. CONCLUSIONS: We encountered a rare case of epithelioid sarcoma and had difficulty in making the correct diagnosis. We suggest that in patients whose lesions are resistant to conventional treatments, repeat biopsy and immunohistochemical studies should be considered to rule out rare epithelioid sarcoma. PMID- 27776546 TI - Medicine and the future of health: reflecting on the past to forge ahead. AB - The development of new therapies has a rich history, evolves quickly with societal trends, and will have an exciting future. The last century has seen an exponential increase in complex interactions between medical practitioners, pharmaceutical companies, governments and patients. We believe technology and societal expectations will open up the opportunity for more individuals to participate as information becomes more freely available and inequality less acceptable. Corporations must recognize that usual market forces do not function ideally in a setting where health is regarded as a human right, and as modern consumers, patients will increasingly take control of their own data, wellbeing, and even the means of production for developing their own treatments. Ethics and legislation will increasingly impact the processes that facilitate drug development, distribution and administration. This article collection is a cross journal collaboration, between the Journal of Pharmaceutical Policy and Practice (JoPPP) and BMC Medicine that seeks to cover recent advances in drug development, medicines use, policy and access with high clinical and public health relevance in the future.The Medicine and the Future of Health article collection is a joint collection between BMC Medicine and Journal of Pharmaceutical Policy and Practice. Therefore, this Editorial by the guest editors has been published in both journals. PMID- 27776547 TI - Validation of the FASH (Functional Assessment Scale for Acute Hamstring Injuries) questionnaire for German-speaking football players. AB - BACKGROUND: The FASH (Functional Assessment Scale for Acute Hamstring Injuries) questionnaire has been recently developed as a disease-specific self-administered questionnaire for use in Greek, English, and German languages. Its psychometric qualities (validity and reliability) were tested only in Greek-speaking patients mainly representing track and field athletes. As hamstring injuries represent the most common football injury, we tested the validity and reliability of the FASH-G (G = German version) questionnaire in German-speaking footballers suffering from acute hamstring injuries. METHODS: The FASH-G questionnaire was tested for reliability and validity, in 16 footballers with hamstring injuries (patients' group), 77 asymptomatic footballers (healthy group), and 19 field hockey players (at-risk group). Known-group validity was tested by comparing the total FASH-G scores of the injured and non-injured groups. Reliability of the FASH-G questionnaire was analysed in 18 asymptomatic footballers using the intra-class coefficient. RESULTS: Known-group validity was demonstrated by significant differences between injured and non-injured participants (p < 0.001). The FASH-G exhibited very good test-retest reliability (intra-class correlation coefficient = 0.982, p < 0.001). Internal consistency was excellent (alpha = 0.938). Compared with the results presented in the original publication, no statistical differences were found between healthy athletes (p = 0.257), but patients' groups and at-risk groups presented scoring differences (p = 0.040 and <0.001, respectively). CONCLUSIONS: The FASH-G is a valid and reliable instrument to assess and determine the severity of hamstring injuries in German footballers. PMID- 27776549 TI - Increasing understanding of the relationship between geographic access and gendered decision-making power for treatment-seeking for febrile children in the Chikwawa district of Malawi. AB - BACKGROUND: This study used qualitative methods to investigate the relationship between geographic access and gendered intra-household hierarchies and how these influence treatment-seeking decision-making for childhood fever within the Chikwawa district of Malawi. Previous cross-sectional survey findings in the district indicated that distance from facility and associated costs are important determinants of health facility attendance in the district. This paper uses qualitative data to add depth of understanding to these findings by exploring the relationship between distance from services, anticipated costs and cultural norms of intra-household decision-making, and to identify potential intervention opportunities to reduce challenges experienced by those in remote locations. Qualitative data collection included 12 focus group discussions and 22 critical incident interviews conducted in the local language, with primary caregivers of children who had recently experienced a febrile episode. RESULTS: Low geographic accessibility to facilities inhibited care-seeking, sometimes by extending the 'assessment period' for a child's illness episode, and led to delays in seeking formal treatment, particularly when the illness occurred at night. Although carers attempted to avoid incurring costs, cash was often needed for transport and food. Whilst in all communities fathers were normatively responsible for treatment costs, mothers generally had greater access to and control over resources and autonomy in decision-making in the matrilineal and matrilocal communities in the central part of the district, which were also closer to formal facilities. CONCLUSIONS: This study illustrates the complex interplay between geographic access and gender dynamics in shaping decisions on whether and when formal treatment is sought for febrile children in Chikwawa District. Geographic marginality and cultural norms intersect in remote areas both to increase the logistical and anticipated financial barriers to utilising services and to reduce caretakers' autonomy to act quickly once they recognize the need for formal care. Health education campaigns should be based within communities, engaging all involved in treatment-seeking decision-making, including men and grandmothers, and should aim to promote the ability of junior women to influence the treatment seeking process. Both mothers' financial autonomy and fathers financial contributions are important to enable timely access to effective healthcare for children with malaria. PMID- 27776548 TI - Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. AB - BACKGROUND: Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined. METHODS: Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR-/-) mice and infected with neurotropic flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. RESULTS: Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post infection is already protective. CONCLUSIONS: These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of flavivirus replication in the CNS. PMID- 27776550 TI - Euphorbia humifusa Willd exerts inhibition of breast cancer cell invasion and metastasis through inhibition of TNFalpha-induced MMP-9 expression. AB - BACKGROUND: Breast cancer is the most common type of malignancy in women worldwide. Euphorbia humifusa Willd (EuH) is a plant that is widely used as a traditional medicine. However, no systemic studies on the anti-cancer effects of EuH have been reported. The aim of this study is to evaluate the anti-metastatic effect of the EuH. METHODS: Ethyl acetate fraction was prepared from EuH methanol extracts (EA/EuH). Inhibitory effect of EA/EuH on cell migration was determined using an in vitro scratch-wound healing assay. The anti-invasive activity was determined by in vitro three-dimensional spheroid culture system and in vivo syngenic experimental lung metastasis experiment. Gene expression profiles were analyzed by using RT-PCR, real-time PCR, and luciferase reporter assay systems. RESULTS: Ethyl acetate fraction from the EuH extract (EA/EuH) inhibited the migration and invasive capabilities of highly metastatic MDA-MB-231 breast cancer cells and attenuated syngeneic lung metastasis of mouse 4 T1 breast cancer cells in vivo. Mechanistically, EA/EuH decreased tumor necrosis factor alpha (TNFalpha) induced matrix metalloproteinase (MMP)-9 mRNA expression through the inhibition of NF-kappaB activity in MDA-MB-231 cells. CONCLUSION: EuH may be beneficial in the prevention of invasion and metastasis of early stage breast cancer and can be served as an anti-metastatic agent or adjuvant therapy against metastatic breast cancer. PMID- 27776552 TI - Scleroderma and dentistry: Two case reports. AB - BACKGROUND: Scleroderma is a chronic connective tissue disorder with unknown etiology. It is characterized by excessive deposition of extracellular matrix in the connective tissues causing vascular disturbances which can result in tissue hypoxia. These changes are manifested as atrophy of the skin and/or mucosa, subcutaneous tissue, muscles, and internal organs. Such changes can be classified into two types, namely, morphea (localized) and diffuse (systemic). Morphea can manifest itself as hemifacial atrophy (Parry-Romberg syndrome) although this remains debatable. Hence, we present a case of morphea, associated with Parry Romberg syndrome, and a second case with the classical signs of progressive systemic sclerosis. CASE PRESENTATION: Case one: A 20-year-old man of Dravidian origin presented to our out-patient department with a complaint of facial asymmetry, difficulty in speech, and loss of taste sensation over the last 2 years. There was no history of facial trauma. After physical and radiological investigations, we found gross asymmetry of the left side of his face, a scar on his chin, tongue atrophy, relative microdontia, thinning of the ramus/body of his mandible, and sclerotic lesions on his trunk. Serological investigations were positive for antinuclear antibody for double-stranded deoxyribonucleic acid and mitochondria. A biopsy was suggestive of morphea. Hence, our final diagnosis was mixed morphea with Parry-Romberg syndrome. Case two: A 53-year-old woman of Dravidian origin presented to our out-patient department with a complaint of gradually decreasing mouth opening over the past 7 years. Her medical history was noncontributory. On clinical examination, we found her perioral, neck, and hand skin to be sclerotic. Also, her fingers exhibited bilateral telangiectasia. An oral examination revealed completely edentulous arches as well as xerostomia and candidiasis. Her serological reports were positive for antinuclear antibodies against centromere B, Scl-70, and Ro-52. A hand and wrist radiograph revealed acro-osteolysis of the middle finger on her right hand. Hence, our final diagnosis was progressive systemic sclerosis. CONCLUSION: Through this article, we have tried to emphasize the importance of a general examination when diagnosing rare systemic diseases such as scleroderma and the role of the general dentist when caring for such patients, even though they can be quite rare in general practice. PMID- 27776551 TI - Molecular characterization and multilocus genotypes of Enterocytozoon bieneusi among horses in southwestern China. AB - BACKGROUND: Enterocytozoon bieneusi is one of the most prevalent causative species of diarrhea and enteric diseases in various hosts. E. bieneusi has been identified in humans, mammals, birds, rodents and reptiles in China, but few studies have reported E. bieneusi in horses. Therefore, the present study was conducted to assess the prevalence, molecular characteristics and zoonotic potential of E. bieneusi among horses in southwestern China. FINDINGS: Three hundred and thirty-three fecal specimens were collected from horses on five farms in the Sichuan and Yunnan provinces of southwestern China. The prevalence of E. bieneusi was 22.5 % (75/333), as determined by nested polymerase chain reaction and sequencing analysis of the internal transcribed spacer region of the ribosomal RNA gene of E. bieneusi. Altogether, 10 genotypes were identified among the 75 E. bieneusi-positive samples: four of these genotypes were known (horse1, horse2, SC02 and D) and six were novel (SCH1-4 and YNH1-2). Multilocus sequence typing using three microsatellites (MS1, MS3 and MS7) and one minisatellite (MS4) revealed three, two, three and three genotypes at these four loci, respectively. In phylogenetic analysis, all the genotypes of E. bieneusi obtained in this study were clustered into three distinct groups: D, SC02 and SCH1-3 were clustered into group 1 (zoonotic potential); SCH4 was clustered into group 2 (cattle-hosted); whereas horse2, YNH1 and YNH2 were clustered into group 6 (unclear zoonotic potential). CONCLUSIONS: This is the first report of E. bieneusi among horses in southwestern China. This is also the first multilocus genotyping analysis using microsatellite and minisatellite markers of E. bieneusi in horses. The presence of genotype D, which was previously identified in humans, and genotypes SC02 and SCH1-3, which belong to potential zoonotic group 1, these results indicate that horses are a potential source of human E. bieneusi infections in China. PMID- 27776553 TI - Effects of a job crafting intervention program on work engagement among Japanese employees: a pretest-posttest study. AB - BACKGROUND: Job crafting, an employee-initiated job design/redesign, has become important for employees' well-being such as work engagement. This study examined the effectiveness of a newly developed job crafting intervention program on work engagement (as primary outcome), as well as job crafting and psychological distress (as secondary outcomes), using a pretest-posttest study design among Japanese employees. METHODS: Participants were managers of a private company and a private psychiatric hospital in Japan. The job crafting intervention program consisted of two 120-min sessions with a two-week interval between them. Outcomes were assessed at baseline (Time 1), post-intervention (Time 2), and a one-month follow-up (Time 3). The mixed growth model analyses were conducted using time (Time 1, Time 2, and Time 3) as an indicator of intervention effect. Effect sizes were calculated using Cohen's d. RESULTS: The program showed a significant positive effect on work engagement (t = 2.20, p = 0.03) in the mixed growth model analyses, but with only small effect sizes (Cohen's d = 0.33 at Time 2 and 0.26 at Time 3). The program also significantly improved job crafting (t = 2.36, p = 0.02: Cohen's d = 0.36 at Time 2 and 0.47 at Time 3) and reduced psychological distress (t = -2.06, p = 0.04: Cohen's d = -0.15 at Time 2 and -0.31 at Time 3). CONCLUSIONS: The study indicated that the newly developed job crafting intervention program was effective in increasing work engagement, as well as in improving job crafting and decreasing psychological distress, among Japanese managers. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000024062 . Retrospectively registered 15 September 2016. PMID- 27776554 TI - S100A8/A9, a potent serum and molecular imaging biomarker for synovial inflammation and joint destruction in seronegative experimental arthritis. AB - BACKGROUND: Seronegative joint diseases are characterized by a lack of well defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. In this study, we investigated the biomarker potential of systemic and local levels of these S100 proteins to assess joint inflammation and joint destruction in an experimental model for seronegative arthritis. METHODS: Serum levels of S100A8/A9 and various cytokines were monitored during disease development in interleukin-1 receptor antagonist (IL-1Ra)-/- mice using ELISA and multiplex bead-based immunoassay, and were correlated to macroscopic and microscopic parameters for joint inflammation, bone erosion, and cartilage damage. Local expression of S100A8 and S100A9 and matrix metalloproteinase (MMP)-mediated cartilage damage in the ankle joints were investigated by immunohistochemistry. In addition, local S100A8 and activated MMPs were monitored in vivo by optical imaging using anti S100A8-Cy7 and AF489-Cy5.5, a specific tracer for activated MMPs. RESULTS: Serum levels of S100A8/A9 were significantly increased in IL-1Ra-/- mice and correlated with macroscopic joint swelling and histological inflammation, while serum levels of pro-inflammatory cytokines did not correlate with joint swelling. In addition, early serum S100A8/A9 levels were prognostic for disease outcome at a later stage. The increased serum S100A8/A9 levels were reflected by an increased expression of S100A8 and S100A9 within the ankle joint, as visualized by molecular imaging. Next to inflammatory processes, serum S100A8/A9 also correlated with histological parameters for bone erosion and cartilage damage. In addition, arthritic IL-1Ra-/- mice with increased synovial S100A8 and S100A9 expression showed increased cartilage damage that coincided with MMP-mediated neoepitope expression and in vivo imaging of activated MMPs. CONCLUSIONS: Expression of S100A8 and S100A9 in IL-1Ra-/- mice strongly correlates with synovial inflammation, bone erosion, and cartilage damage, underlining the potential of S100A8/A9 as a systemic and local biomarker in seronegative arthritis not only for assessing inflammation but also for assessing severity of inflammatory joint destruction. PMID- 27776556 TI - Alkaloids from piper longum protect dopaminergic neurons against inflammation mediated damage induced by intranigral injection of lipopolysaccharide. AB - BACKGROUND: Alkaloids from Piper longum (PLA), extracted from P. longum, have potent anti-inflammatory effects. The aim of this study was to investigate whether PLA could protect dopaminergic neurons against inflammation-mediated damage by inhibiting microglial activation using a lipopolysaccharide (LPS) induced dopaminergic neuronal damage rat model. METHODS: The animal behaviors of rotational behavior, rotarod test and open-field test were investigated. The survival ratio of dopaminergic neurons and microglial activation were examined. The dopamine (DA) and its metabolite were detected by high performance liquid chromatography (HPLC). The effects of PLA on the expression of interleukin (IL) 6, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha were detected by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and nitric oxide (NO) were also estimated. RESULTS: We showed that the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and DA content in the striatum were reduced after a single intranigral dose of LPS (10 MUg) treatment. The survival rate of TH-ir neurons in the SNpc and DA levels in the striatum were significantly improved after treatment with PLA for 6 weeks. The over-activated microglial cells were suppressed by PLA treatment. We also observed that the levels of inflammatory cytokines, including TNF-alpha, IL-6 and IL-1beta were decreased and the excessive production of ROS and NO were abolished after PLA treatment. Therefore, the behavioral dysfunctions induced by LPS were improved after PLA treatment. CONCLUSION: This study suggests that PLA plays a significant role in protecting dopaminergic neurons against inflammatory reaction induced damage. PMID- 27776555 TI - Pure and multi metal oxide nanoparticles: synthesis, antibacterial and cytotoxic properties. AB - Th antibacterial activity of metal oxide nanoparticles has received marked global attention as they can be specifically synthesized to exhibit significant toxicity to bacteria. The importance of their application as antibacterial agents is evident keeping in mind the limited range and effectiveness of antibiotics, on one hand, and the plethora of metal oxides, on the other, along with the propensity of nanoparticles to induce resistance being much lower than that of antibiotics. Effective inhibition against a wide range of bacteria is well known for several nano oxides consisting of one metal (Fe3O4, TiO2, CuO, ZnO), whereas, research in the field of multi-metal oxides still demands extensive exploration. This is understandable given that the relationship between physicochemical properties and biological activity seems to be complex and difficult to generalize even for metal oxide nanoparticles consisting of only one metal component. Also, despite the broad scope that metal oxide nanoparticles have as antibacterial agents, there arise problems in practical applications taking into account the cytotoxic effects. In this respect, the consideration of polymetallic oxides for biological applications becomes even greater since these can provide synergetic effects and unify the best physicochemical properties of their components. For instance, strong antibacterial efficiency specific of one metal oxide can be complemented by non-cytotoxicity of another. This review presents the main methods and technological advances in fabrication of nanostructured metal oxides with a particular emphasis to multi-metal oxide nanoparticles, their antibacterial effects and cytotoxicity. PMID- 27776558 TI - Characterization and history of arterial hypertension leading to inpatient treatment. AB - BACKGROUND AND AIMS: Arterial hypertension is a major cause of death worldwide. For the most part, treatment for hypertension can be performed on an outpatient basis. However, some patients also require inpatient treatment, and the contributing factors for this remain unknown. Therefore, the primary objective of the present study was to determine which patient characteristics are associated with inpatient treatment for arterial hypertension. METHODS: Here, we conducted a mono-centric study of 103 hypertensive subjects, who were treated as inpatients in the Department of Nephrology and rheumatology of the university medical faculty of Gottingen. Therapies were not altered, and data collection was performed retrospectively. In addition to epidemiological information, the following data were recorded: patient symptoms, blood pressure (BP), anti hypertensive therapy, and concomitant diseases (e.g., renal and cardiovascular conditions). RESULTS: Approximately half (53 %) of all subjects treated on an inpatient basis displayed elevated BP (>140/90 mmHg), while the remaining 47 % of patients showed normotensive readings (<140/90 mmHg) following admission. Moreover, 34 % of patients could be classified as therapy refractory. The main reasons for hospital admission were hypertension-related symptoms, including shortness of breath, dizziness, and headache (69 %). These patients were multi morbid, with approximately 60 % displaying a secondary form of hypertension. Indeed, over half of the subjects showed renoparenchymatous forms of hypertension, and a large percentage of patients received hypertension-inducing drugs (32 %). Moreover, a high proportion of inpatients were treated with reserve antihypertensives, with the most commonly used drug being Moxonidin. CONCLUSION: The majority of hypertensive patients were hospitalized due to their clinical symptoms and not as a result of BP values alone. The high proportion of patients with secondary forms of hypertension or treated with BP-boosting medications was striking. PMID- 27776557 TI - Mammographically dense human breast tissue stimulates MCF10DCIS.com progression to invasive lesions and metastasis. AB - BACKGROUND: High mammographic density (HMD) not only confers a significantly increased risk of breast cancer (BC) but also is associated with BCs of more advanced stages. However, it is unclear whether BC progression and metastasis are stimulated by HMD. We investigated whether patient-derived HMD breast tissue could stimulate the progression of MCF10DCIS.com cells compared with patient matched low mammographic density (LMD) tissue. METHODS: Sterile breast specimens were obtained immediately after prophylactic mastectomy from high-risk women (n = 10). HMD and LMD regions of each specimen were resected under radiological guidance. Human MCF10DCIS.com cells, a model of ductal carcinoma in situ (DCIS), were implanted into silicone biochambers in the groins of severe combined immunodeficiency mice, either alone or with matched LMD or HMD tissue (1:1), and maintained for 6 weeks. We assessed biochamber weight as a measure of primary tumour growth, histological grade of the biochamber material, circulating tumour cells and metastatic burden by luciferase and histology. All statistical tests were two-sided. RESULTS: HMD breast tissue led to increased primary tumour take, increased biochamber weight and increased proportions of high-grade DCIS and grade 3 invasive BCs compared with LMD. This correlated with an increased metastatic burden in the mice co-implanted with HMD tissue. CONCLUSIONS: Our study is the first to explore the direct effect of HMD and LMD human breast tissue on the progression and dissemination of BC cells in vivo. The results suggest that HMD status should be a consideration in decision-making for management of patients with DCIS lesions. PMID- 27776560 TI - Adjunctive memantine in clozapine-treated refractory schizophrenia: an open-label 1-year extension study. AB - BACKGROUND: In a recent placebo-controlled, double-blind crossover trial (n = 52), significant beneficial effects on memory (d = 0.30) and negative symptoms (d = 0.29) were found after 12 weeks of memantine augmentation in patients with clozapine-refractory schizophrenia. In this open-label 1-year extension study we report the long-term effects and tolerability of memantine add-on therapy to clozapine. METHOD: Completers of the first trial who experienced beneficial effects during 12 weeks of memantine treatment received memantine for 1 year. Primary endpoints were memory and executive function using the Cambridge Neuropsychological Test Automated Battery, the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Severity Scale (CGI-S). RESULTS: Of 31 randomized controlled trial completers who experienced beneficial effects from memantine, 24 received memantine for 1 year. The small improvement in memory found in the memantine condition in the placebo-controlled trial remained stable in the extension study. Executive function did not improve. After 26 weeks of memantine add-on therapy to clozapine, PANSS negative symptoms (r = 0.53), PANSS positive symptoms (r = 0.50) and PANSS total symptoms (r = 0.54) significantly improved. Even further significant improvement in all these measures was observed between 26 weeks and 52 weeks of memantine, with effect sizes varying from 0.39 to 0.51. CGI-S showed a non-significant moderate improvement at 26 weeks (r = 0.36) and 52 weeks (r = 0.34). Memantine was well tolerated without serious adverse effects. CONCLUSIONS: In the 1-year extension phase the favourable effect of adjunctive memantine on memory was sustained and we observed further improvement of negative, positive and overall symptoms in patients with clozapine-treated refractory schizophrenia. PMID- 27776559 TI - Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway. AB - BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. METHODS: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. RESULTS: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual gamma/delta inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. CONCLUSIONS: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients. PMID- 27776561 TI - Prenatal exposure to very severe maternal obesity is associated with adverse neuropsychiatric outcomes in children. AB - BACKGROUND: Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress. METHOD: We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ?40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively. RESULTS: Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression. CONCLUSIONS: Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood. PMID- 27776562 TI - Clinical anxiety promotes excessive response inhibition. AB - BACKGROUND: Laboratory tasks to delineate anxiety disorder features are used to refine classification and inform our understanding of etiological mechanisms. The present study examines laboratory measures of response inhibition, specifically the inhibition of a pre-potent motor response, in clinical anxiety. Data on associations between anxiety and response inhibition remain inconsistent, perhaps because of dissociable effects of clinical anxiety and experimentally manipulated state anxiety. Few studies directly assess the independent and interacting effects of these two anxiety types (state v. disorder) on response inhibition. The current study accomplished this goal, by manipulating state anxiety in healthy and clinically anxious individuals while they complete a response inhibition task. METHOD: The study employs the threat-of-shock paradigm, one of the best-established manipulations for robustly increasing state anxiety. Participants included 82 adults (41 healthy; 41 patients with an anxiety disorder). A go/nogo task with highly frequent go trials was administered during alternating periods of safety and shock threat. Signal detection theory was used to quantify response bias and signal-detection sensitivity. RESULTS: There were independent effects of anxiety and clinical anxiety on response inhibition. In both groups, heightened anxiety facilitated response inhibition, leading to reduced nogo commission errors. Compared with the healthy group, clinical anxiety was associated with excessive response inhibition and increased go omission errors in both the safe and threat conditions. CONCLUSIONS: Response inhibition and its impact on go omission errors appear to be a promising behavioral marker of clinical anxiety. These results have implications for a dimensional view of clinical anxiety. PMID- 27776563 TI - Precuneus functioning differentiates first-episode psychosis patients during the fantasy movie Alice in Wonderland. AB - BACKGROUND: While group-level functional alterations have been identified in many brain regions of psychotic patients, multivariate machine-learning methods provide a tool to test whether some of such alterations could be used to differentiate an individual patient. Earlier machine-learning studies have focused on data collected from chronic patients during rest or simple tasks. We set out to unravel brain activation patterns during naturalistic stimulation in first-episode psychosis (FEP). METHOD: We recorded brain activity from 46 FEP patients and 32 control subjects viewing scenes from the fantasy film Alice in Wonderland. Scenes with varying degrees of fantasy were selected based on the distortion of the 'sense of reality' in psychosis. After cleaning the data with a novel maxCorr method, we used machine learning to classify patients and healthy control subjects on the basis of voxel- and time-point patterns. RESULTS: Most (136/194) of the voxels that best classified the groups were clustered in a bilateral region of the precuneus. Classification accuracies were up to 79.5% (p = 5.69 * 10-8), and correct classification was more likely the higher the patient's positive-symptom score. Precuneus functioning was related to the fantasy content of the movie, and the relationship was stronger in control subjects than patients. CONCLUSIONS: These findings are the first to show abnormalities in precuneus functioning during naturalistic information processing in FEP patients. Correlational findings suggest that these alterations are associated with positive psychotic symptoms and processing of fantasy. The results may provide new insights into the neuronal basis of reality distortion in psychosis. PMID- 27776564 TI - Food-based solutions for vitamin D deficiency: putting policy into practice and the key role for research. AB - Recent re-evaluations of dietary reference values (DRV) for vitamin D have established intake requirements between 10 and 20 ug/d. National nutrition surveys indicate that habitual mean intakes of vitamin D in the population are typically in the range 3-7 ug/d. As vitamin D supplementation will not be effective at a population level because the uptake is generally low, creative food-based solutions are needed to bridge the gap between current intakes and these new requirement values. The overarching aim of this review is to highlight how food-based solutions can have an important role in bridging this gap and counteracting vitamin D inadequacy in Europe and elsewhere. The present review initially briefly overviews very recent new European DRV for vitamin D and, while not in agreement on requirement estimates, how they point very clearly to the need for food-based solutions. The review discusses the need for traditional fortification of foods in the dairy and other sectors, and finally overviews recent advances in the area of biofortification of food with vitamin D. In conclusion, increasing vitamin D intakes across the population distribution is important from a public health perspective to reduce the high degree of inadequacy of vitamin D intake in Europe. Fortification, including biofortification, of a wider range of foods, which accommodate diversity, is likely to have the potential to increase vitamin D intakes across the population distribution. Research has had, and will continue to have, a key role in terms of developing food-based solutions and tackling vitamin D deficiency. PMID- 27776565 TI - Validity of recalled v. recorded birth weight: a systematic review and meta analysis. AB - Low birth weight is associated with adverse health outcomes. If birth weight records are not available, studies may use recalled birth weight. It is unclear whether this is reliable. We performed a systematic review and meta-analysis of studies comparing recalled with recorded birth weights. We followed the Meta Analyses of Observational Studies in Epidemiology (MOOSE) statement and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) to May 2015. We included studies that reported recalled birth weight and recorded birth weight. We excluded studies investigating a clinical population. Two reviewers independently reviewed citations, extracted data, assessed risk of bias. Data were pooled in a random effects meta-analysis for correlation and mean difference. In total, 40 studies were eligible for qualitative synthesis (n=78,997 births from 78,196 parents). Agreement between recalled and recorded birth weight was high: pooled estimate of correlation in 23 samples from 19 studies (n=7406) was 0.90 [95% confidence interval (CI) 0.87 0.93]. The difference between recalled and recorded birth weight in 29 samples from 26 studies (n=29,293) was small [range -86-129 g; random effects estimate 1.4 g (95% CI -4.0-6.9 g)]. Studies were heterogeneous, with no evidence for an effect of time since birth, person reporting, recall bias, or birth order. In post-hoc subgroup analysis, recall was higher than recorded birth weight by 80 g (95% CI 57-103 g) in low and middle income countries. In conclusion, there is high agreement between recalled and recorded birth weight. If birth weight is recalled, it is suitable for use in epidemiological studies, at least in high income countries. PMID- 27776566 TI - Social support as a mediator variable of the relationship between depression and life satisfaction in a sample of Saudi caregivers of patients with Alzheimer's disease. AB - BACKGROUND: Caring for someone with Alzheimer's disease (AD) is very challenging. Social support may play a crucial role in helping caregivers to adapt better to their caregiving role. The aim of this study is to explore the role of social support as a moderator variable of the relationship between depression and life satisfaction in caregivers for patients with AD in Saudi Arabia. METHODS: In this cross-sectional study, 122 caregivers for patients with AD completed questionnaires assessing informal social support, depressive symptoms, and general life satisfaction. RESULTS: The demographic characteristics showed that 79% (n = 96) of caregivers were females and between the ages of 20 and 50. Higher levels of social support positively correlated with reported higher levels of life satisfaction (r = 0.483, p < 0.001). Depression was negatively correlated with social support (r = -0.418, p < 0.001) and life satisfaction scores (r = 0.553, p = < 0.001). Social support was found to be a partial mediator variable, mediating approximately 23.05% of the total effect of depression on life satisfaction (Sobel = -3.065, p = 0.002). CONCLUSION: Informal social support can act as a mediator variable in the relationship of depression and life satisfaction in caregivers of AD patients. Improving the informal social support networks may help in coping with caregiving burden and better quality of life. PMID- 27776567 TI - Use of antidepressants in patients with depression and comorbid diabetes mellitus: a systematic review. AB - OBJECTIVE: Depression may be difficult to treat and with comorbid diabetes mellitus (DM) it is an even bigger challenge. This article aims to evaluate antidepressants most suitable for patients with depression and comorbid DM. Design and methods Initially we searched for randomised, controlled double-blind trials of treatment with antidepressants in depressed with DM but there were only a few studies and many of them were small trials. Thus, we decided to include studies that were not only randomised-controlled trials. In total, we ended up with 18 articles for our purposes. RESULTS: The combination of depression and DM may be harmful as depression has a strong impact on psychosocial and medical outcomes in patients with DM. Almost all of the trials in this review showed a reduction in depressive symptoms after treatment with an antidepressant in the acute as well as during maintenance phase. It showed that depression improvement had a favourable effect on glycaemic control that was weight independent. Some studies included only subjects with minor depression or with suboptimal controlled diabetes making it difficult to show an effect. CONCLUSION: From these data, we will recommend choosing an selective serotonin reuptake inhibitor (SSRI) if possible to treat a depression among patients with diabetes. If treatment with a tricyclic antidepressant is needed, closer glycaemic monitoring is recommended. Bear in mind that there is a possible risk of hypoglycemia when using SSRIs. Agomelatine and bupropion have shown promising results, but need to be investigated in more trials. PMID- 27776568 TI - Relationship of Lutein and Zeaxanthin Levels to Neurocognitive Functioning: An fMRI Study of Older Adults. AB - OBJECTIVES: It is well known that the carotenoids lutein (L) and zeaxanthin (Z) improve eye health and an accumulating evidence base suggests cognitive benefits as well. The present study investigated underlying neural mechanisms using functional magnetic resonance imaging (fMRI). It was hypothesized that lower L and Z concentrations would be associated with neurobiological inefficiency (i.e., increased activation) during cognitive performance. METHODS: Forty-three community-dwelling older adults (mean age=72 years; 58% female; 100% Caucasian) were asked to learn and recall pairs of unrelated words in an fMRI-adapted paradigm. L and Z levels were measured in retina (macular pigment optical density) and serum using validated procedures. RESULTS: Following first-level contrasts of encoding and retrieval trials minus control trials (p<.05, family wise error corrected, minimum voxel cluster=8), L and Z were found to significantly and negatively relate to blood-oxygen-level-dependent signal in central and parietal operculum cortex, inferior frontal gyrus, supramarginal gyrus, planum polare, frontal and middle temporal gyrus, superior parietal lobule, postcentral gyrus, precentral gyrus, occipital cortex bilaterally, and cerebellar regions. CONCLUSIONS: To the authors' knowledge, the present study represents the first attempt to investigate neural mechanisms underlying the relation of L and Z to cognition using fMRI. The observed results suggest that L and Z promote cognitive functioning in old age by enhancing neural efficiency. (JINS, 2017, 23, 11-22). PMID- 27776569 TI - Twinning and Multiple Birth Rates According to Maternal Age in the City of Sao Paulo, Brazil: 2003-2014. AB - The present study investigates the twinning rates in the city of Sao Paulo, Brazil, during the years 2003-2014. The data were drawn from the Brazilian Health Department database of Sistema de Informacoes de Nascidos Vivos de Sao Paulo SINASC (Live Births Information System of Sao Paulo). In general, more information is available on the incidence of twinning in developed countries than in developing ones. A total of 24,589 twin deliveries and 736 multiple deliveries were registered in 140 hospitals of Sao Paulo out of a total of 2,056,016 deliveries during the studied time period. The overall average rates of singleton, twin, and multiple births per 1,000 maternities (0/00) were 987.43, 11.96 (dizygotic (DZ) rate was 7.15 and monozygotic (MZ) 4.42), and 0.36, respectively. We further regressed maternal age and historical time period on percentage of singleton, twin, and multiple birth rates. Our results indicated that maternal age strongly positively predicted twin and multiple birth rates, and negatively predicted singleton birth rates. The historical time period also positively, although weakly, predicted twin birth rates, and had no effect on singleton or multiple birth rates. Further, after applying Weinberg's differential method, we computed regressions separately for the estimated frequencies of DZ and MZ twin rates. DZ twinning was strongly positively predicted by maternal age and, to a smaller degree, by time period, while MZ twinning increased marginally only with higher maternal age. Factors such as increasing body mass index or air pollution can lead to the slight historical increase in DZ twinning rates. Importantly, consistent with previous cross cultural and historical research, our results support the existence of an age dependent physiological mechanism that leads to a strong increase in twinning and multiple births, but not singleton births, among mothers of higher age categories. From the ultimate perspective, twinning and multiple births in later age can lead to higher individual reproductive success near the end of the reproductive career of the mother. PMID- 27776570 TI - Determination of the Effective Detector Area of an Energy-Dispersive X-Ray Spectrometer at the Scanning Electron Microscope Using Experimental and Theoretical X-Ray Emission Yields. AB - A method is proposed to determine the effective detector area for energy dispersive X-ray spectrometers (EDS). Nowadays, detectors are available for a wide range of nominal areas ranging from 10 up to 150 mm2. However, it remains in most cases unknown whether this nominal area coincides with the "net active sensor area" that should be given according to the related standard ISO 15632, or with any other area of the detector device. Moreover, the specific geometry of EDS installation may further reduce a given detector area. The proposed method can be applied to most scanning electron microscope/EDS configurations. The basic idea consists in a comparison of the measured count rate with the count rate resulting from known X-ray yields of copper, titanium, or silicon. The method was successfully tested on three detectors with known effective area and applied further to seven spectrometers from different manufacturers. In most cases the method gave an effective area smaller than the area given in the detector description. PMID- 27776571 TI - Common pattern of gray-matter abnormalities in drug-naive and medicated first episode schizophrenia: a multimodal meta-analysis. AB - Studies of schizophrenia at drug-naive state and on antipsychotic medication have reported a number of regions of gray-matter (GM) abnormalities but the reports have been inconsistent. The aim of this study was to conduct multimodal meta analysis to compare the cross-sectional voxel-based morphometry studies of brain GM in antipsychotic-naive first-episode schizophrenia (AN-FES) and those with antipsychotic treatment within 1 year (AT-FES) to determine the similarities and differences in these groups. We conducted two separate meta-analyses containing 24 studies with a sample size of 801 patients and 957 healthy controls. A multimodal meta-analysis method was used to compare the findings between AN-FES and AT-FES. Meta-regression analyses were done to determine the influence of different variables including age, duration of illness, and positive and negative symptom scores. Finally, jack-knife analyses were done to test the robustness of the results. AN-FES and AT-FES showed common patterns of GM abnormalities in frontal (gyrus rectus), superior temporal, left hippocampal and insular cortex. GM in the left supramarginal gyrus and left middle temporal gyrus were found to be increased in AN-FES but decreased in AT-FES, whereas left median cingulate/paracingulate gyri and right hippocampus GM was decreased in AN-FES but increased in AT-FES. Findings suggest that both AN-FES and AT-FES share frontal, temporal and insular regions as common anatomical regions to be affected indicating these to be the primary regions of GM abnormalities in both groups. PMID- 27776573 TI - Morphological and molecular characterization of cucullanid nematodes including Cucullanus opisthoporus n. sp. in freshwater fish from the Brazilian Amazon. AB - Molecular and morphological characterization of two species of Cucullanidae from freshwater fish in Brazil are provided, one of which represented an undescribed taxon. Cucullanus opisthoporus n. sp. was collected in Cichla melaniae from River Xingu, State of Para, and in C. pinima from River Jamari, State of Rondonia. Nematodes referable to Cucullanus grandistomis were collected in Oxydoras niger from River Xingu. The new species has an appendage in the tail tip, ventrally covered by small spines, which is an exclusive feature of Cucullanus tucunarensis. However, C. tucunarensis differs from C. opisthoporus n. sp. based upon the relative position of deirids and the excretory pore, which are more posterior from the oesophageal end in the new species. Observations of C. tucunarensis type specimens also revealed features that were wrongly or not reported in the original description. Type specimens of C. grandistomis were observed, although they were poorly preserved. After evaluation of newly collected specimens of C. grandistomis, features unreported in the original description were observed for the first time, including the presence of an intestinal caecum. Thus, C. grandistomis was transferred to Dichelyne. Sequences of the 18S and 28S rRNA genes revealed high genetic similarity between the specimens of C. opisthoporus n. sp. from the two different hosts as well as their genetic distance from Dichelyne grandistomis n. comb. Phylogenetic reconstructions using representatives of Cucullanidae suggested the artificiality of the current morphological system adopted to separate the genera, since most genera were not monophyletic, although the availability of genetic data is still fragmented. PMID- 27776572 TI - Mismatch negativity and P3a amplitude in young adolescents with first-episode psychosis: a comparison with ADHD. AB - BACKGROUND: Deficient mismatch negativity (MMN) has been proposed as a candidate biomarker in schizophrenia and may therefore be potentially useful in early identification and intervention in early onset psychosis. In this study we explored whether deficits in the automatic orienting and reorienting responses, measured as MMN and P3a amplitude, are present in young adolescents with first episode psychosis (FEP) and whether findings are specific to psychosis compared to young adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: MMN and P3a amplitude were assessed in young adolescents (age 12-17 years) with either FEP (N = 27) or ADHD (N = 28) and age- and gender-matched healthy controls (N = 43). The MMN paradigm consisted of a four-tone auditory oddball task with deviant stimuli based on frequency, duration and their combination. RESULTS: Significantly less MMN was found in patients with psychosis compared to healthy controls in response to frequency and duration deviants. MMN amplitudes in the group of patients with ADHD were not significantly different from patients with psychosis or healthy controls. No significant group differences were found on P3a amplitude. CONCLUSION: Young adolescents with FEP showed impaired MMN compared to healthy controls while intermediate and overlapping levels of MMN were observed in adolescents with ADHD. The findings suggest that young FEP patients already exhibit pre-attentive deficits that are characteristic of schizophrenia albeit expressed on a continuum shared with other neuropsychiatric disorders. PMID- 27776574 TI - Empathy and aversion: the neural signature of mentalizing in Tourette syndrome. AB - BACKGROUND: Previous studies suggest that adults with Tourette syndrome (TS) can respond unconventionally on tasks involving social cognition. We therefore hypothesized that these patients would exhibit different neural responses to healthy controls in response to emotionally salient expressions of human eyes. METHOD: Twenty-five adults with TS and 25 matched healthy controls were scanned using fMRI during the standard version of the Reading the Mind in the Eyes Task which requires mental state judgements, and a novel comparison version requiring judgements about age. RESULTS: During prompted mental state recognition, greater activity was apparent in TS within left orbitofrontal cortex, posterior cingulate, right amygdala and right temporo-parietal junction (TPJ), while reduced activity was apparent in regions including left inferior parietal cortex. Age judgement elicited greater activity in TS within precuneus, medial prefrontal and temporal regions involved in mentalizing. The interaction between group and task revealed differential activity in areas including right inferior frontal gyrus. Task-related activity in the TPJ covaried with global ratings of the urge to tic. CONCLUSIONS: While recognizing mental states, adults with TS exhibit greater activity than controls in brain areas involved in the processing of negative emotion, in addition to reduced activity in regions associated with the attribution of agency. In addition, increased recruitment of areas involved in mental state reasoning is apparent in these patients when mentalizing is not a task requirement. Our findings highlight differential neural reactivity in response to emotive social cues in TS, which may interact with tic expression. PMID- 27776575 TI - Understanding the use of emergency department and urgent care services by diabetic patients of a Family Medicine Health Team: a retrospective observational study. AB - : Aim To understand the frequency, urgency, and rationale of emergency department and urgent care (ED/UC) use by diabetic patients of a Family Medicine Health Team (FHT). METHODS: A retrospective, observational study with comparison control groups was conducted from 1 January 2013 to 31 December 2014. A total of 693 diabetic patients were compared with two, age-standardized non-diabetic groups: one with a higher disease burden based on International Classification of Diseases 9 diagnoses and the other from a randomized patient pool. Findings The diabetic group utilized ED/UC services 1.25 and 1.92 times more often than the two control populations, consistent with that observed in other studies. Canadian Triage and Acuity Scale scores were essentially the same for the diabetic population. Only 3.1% of visits were for diabetic related emergencies, in contrast to the expected 23% by surveyed physicians of the FHT. Diabetic patient's sought treatment for cellulitis, wounds, abscesses, and infections more often than the control populations. PMID- 27776576 TI - Overwhelming post-splenectomy sepsis in patients with asplenia and hyposplenia: a retrospective cohort study. AB - Overwhelming post-splenectomy infection (OPSI) is a serious complication of asplenia and is associated with encapsulated organisms, most commonly Streptococcus pneumoniae, but also Haemophilus influenzae and Neisseria meningitidis. We aimed to estimate the risk of infection in this patient group. We reviewed data collected by the Victorian Spleen Registry in Australia. On registration, all patients are asked about significant infections requiring admission to hospital for intravenous antibiotics; those requiring admission to ICU were defined as OPSI. In the 3274 asplenic patients registered 492 patients reported at least one episode of infection. There were 47 episodes of OPSI requiring intensive care (incidence rate 1.11/1000 patient-years). The risk of OPSI was highest in older patients, and there were no statistically significant differences in incidence by reason for splenectomy except for a higher rate in patients with medical hyposplenia. This study reinforces that post-splenectomy infection is a clinically significant but uncommon complication, and that fulminant infection requiring intensive care is a minority of all infections. PMID- 27776577 TI - Wide exposure to Coxiella burnetii in ruminant and feline species living in a natural environment: zoonoses in a human-livestock-wildlife interface. AB - Assessment of the role of wild and domestic hosts as potential reservoirs of misdiagnosed zoonoses, such as Q fever by Coxiella burnetii, is an important public health issue today both for wildlife conservation and management of disease in human-livestock-wildlife interface. This study used ELISA, an indirect antibody, to research (2003-2013) C. burnetii infection in seven free-living wild and domestic ruminant species and in European wildcats (Felis silvestris). The animals studied were 0 European wildcats, 21 Spanish ibex (Capra pyrenaica), 314 red deer (Cervus elaphus), 556 fallow deer (Dama dama), 211 European mouflon (Ovis aries musimon), eight roe deer (Capreolus capreolus), 407 bovines (Bos taurus) and 3739 sheep (Ovis aries). All the animals shared the same habitat in the Serrania de Cuenca Natural Park (Castile-La Mancha, Spain). The study area is an example of human-domestic-wildlife interface where people and domestic animals live in close proximity to wildlife. Observed C. burnetii seropositive frequencies were: 33.3% European wildcats, 23.8% Spanish ibex, 22.5% domestic sheep 1.5% red deer, 1.4% European mouflon, 0.24% cattle, 0.18% fallow deer and 0% roe deer. The study found a wide C. burnetii prevalence of previous and present exposure in wild and domestic ruminant hosts in the Serrania de Cuenca Natural Park and reports the first evidence of C. burnetii exposure in free living European wildcats. PMID- 27776578 TI - Children with TB: neglected no more . . .. PMID- 27776580 TI - Need for combined interventions and operational research to tackle tuberculous meningitis. PMID- 27776579 TI - TB and HIV co-infection in children: do we know enough? PMID- 27776581 TI - Public-private mix for tuberculosis care and prevention. What progress? What prospects? AB - BACKGROUND: Public-private mix (PPM) for tuberculosis (TB) care implies working with all relevant public and private health care providers to ensure that high quality TB care is offered to all who need it. Despite significant global progress in PPM expansion and in TB control in general, a large proportion of care providers in high-incidence countries remain unengaged, and one third of the estimated TB cases go unnotified or undetected. OBJECTIVE: To present a global perspective on the progress and prospects of expanding PPM for TB care and prevention. DISCUSSION: People with TB in high-incidence countries approach diverse care providers. Productive working collaborations between national TB programmes and other care providers have been scaled up in many countries. However, a large proportion of private providers still do not participate in collaboration or follow recommended TB management practices. Persisting challenges include weak commitment and capacity to work together within both public and private sectors, poor enforcement of essential regulations and inadequate investments. CONCLUSION: Scaling up PPM programmes is critical to ending the TB epidemic. Investing in implementing bold policies that harness public and private sector capacity, combine collaborative and regulatory approaches and promote modern digital tools to simplify care delivery is the logical way forward. PMID- 27776582 TI - E-cigarettes: a need to broaden the debate. AB - The unregulated market for e-cigarettes continues to grow, with debates on their efficacy and impact on global public health. E-cigarettes, or electronic nicotine delivery systems (ENDs), are marketed as a 'safe' alternative to tobacco products and a tool for 'harm reduction'. Some public health experts are calling it a 'game changer' and favour the 'harm reduction' strategy, while others dispute this claim. In our opinion, the debate needs to be broadened to encompass other related concerns and effects on non-users and affected stakeholders. As with tobacco control, a holistic approach is needed to build a raft of policies that effectively address the issue from all angles and look beyond the direct health implications of e-cigarette use to explore the social, economic, political and environmental aspects of this debate, putting 'harm reduction' in context. PMID- 27776583 TI - Carbapenems against Mycobacterium tuberculosis: a review of the evidence. AB - Carbapenems, a more recent beta-lactam class, represent a unique anti tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium tuberculosis cell wall and beta-lactamase. This provides a potentially new agent against M. tuberculosis, in particular for multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), where options are limited. In this review, we examine the current evidence on the activity of carbapenems against M. tuberculosis. The predominance of work is in vitro, and suggests that carbapenems kill M. tuberculosis at least in the active phase, with possible greater potency with the addition of a beta-lactamase inhibitor. The few in vivo and clinical studies suggest that there are benefits and that they are generally tolerated, although the variability in duration, dosing, and background regimen and lack of pharmacokinetic analyses limit interpretation of efficacy. We outline further areas of research to better understand the role of carbapenems to add a needed new agent to the treatment of MDR- and XDR-TB. PMID- 27776585 TI - Incidence of tuberculosis meningitis in a high HIV prevalence setting: time series analysis from 2006 to 2011. AB - SETTING: This study was undertaken at a tertiary hospital in Soweto, a peri-urban low-middle income setting. Mycobacterium tuberculosis meningitis (TBM) is a severe manifestation of extra-pulmonary tuberculosis. OBJECTIVE: To describe the incidence, mortality and clinical features of TBM in human immunodeficiency virus (HIV) infected and non-infected children in South Africa from 2006 to 2011. DESIGN: A retrospective, cross-sectional descriptive study. METHODS: Electronic databases and individual patient records of all children with a discharge diagnosis of TBM were reviewed to yield incidence rate ratios (IRR) in HIV infected and non-infected children. Clinical, laboratory and radiological characteristics were compared between HIV-infected and non-infected children with TBM. RESULTS: Overall TBM incidence per 100 000 population in 2006 was 6.9 (95%CI 4.4-10.3) and 9.8 (95%CI 6.9-13.6) in 2009, but had subsequently declined to 3.1 (95%CI 1.6-5.5) by 2011. There was a significant reduction in the IRR of TBM among HIV-infected children (IRR 0.916, P = 0.036). The overall case fatality ratio was 6.7%. Clinical features, cerebrospinal fluid and computed tomography brain findings were similar in HIV-infected and non-infected children. CONCLUSION: TBM incidence decreased over the study period from 2006 to 2011, and was temporally associated with an increase in the uptake of antiretroviral treatment in HIV-infected individuals. PMID- 27776584 TI - Tuberculosis in HIV-infected children in Europe, Thailand and Brazil: paediatric TB-HIV EuroCoord study. AB - SETTING: Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil. OBJECTIVE: To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children. DESIGN: Observational study of TB diagnosed in HIV-infected children in 2011-2013. RESULTS: Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0-11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes. CONCLUSION: Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention. PMID- 27776586 TI - Controversies in tuberculous infection among pediatric infectious disease specialists in North America. AB - OBJECTIVE: To evaluate the extent to which advancements in the diagnosis and treatment of latent tuberculous infection (LTBI) have been integrated into practice by pediatric infectious disease (PID) specialists. DESIGN: We conducted an online survey of the Infectious Diseases Society of America's Emerging Infections Network (EIN) membership. RESULTS: Of the 323 members, 197 (61%) responded: 7% cared for ?5 children with TB disease and 34% for ?5 children with LTBI annually. We identified substantial variations in the use of interferon gamma release assays (IGRAs) based upon age, immune status, and TB risk factors. In addition, tuberculin skin test (TST) use was three times more common in younger children. Variations existed in managing children with discordant TST and IGRA results. Less variation existed in LTBI treatment, with 86% preferring a 9 month course of isoniazid; few other, newer regimens were used routinely. CONCLUSION: Substantial variations exist in LTBI management; uptake of newer diagnostic tools and treatment regimens has been slow. Variations in practice and the lag time to integrating new data into practice may indicate the relative infrequency with which providers encounter LTBI. Our findings reflect the need for increased visibility of existing TB guidelines and resources for expert consultation for scenarios not covered by guidelines. PMID- 27776587 TI - Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children. AB - SETTING: Isoniazid-resistant rifampicin-susceptible (HRRS) tuberculosis (TB) is the most prevalent form of drug-resistant TB globally, and may be a risk factor for poor outcomes, but has been poorly described in children. OBJECTIVE: To characterise the clinical presentation, treatment, and clinical and microbiological outcomes among children with culture-confirmed HRRS TB. DESIGN: Retrospective hospital-based cohort study. RESULTS: Of the 72 children included in the study, the median age was 50.1 months (IQR 21.5-102.5); 42% were male. Forty-four (51%) had a potential source case; only 13 were confirmed HRRS TB. Of 66 tested, 12 (17%) were human immunodeficiency virus (HIV) infected, and 36 (60%) of the 60 with pulmonary TB (PTB) had severe disease. Seventy children had treatment data; the median total duration of treatment was 11.3 months (IQR 9 12.3); 25 (36%) initiated treatment with a three-drug intensive phase; 52 (74%) received a fluoroquinolone. Of 63 children with known outcomes, 55 (88%) had a favourable outcome, 1 died and 3 had treatment failure. Ten had positive follow up cultures at ?2 months after starting treatment. Older age (P = 0.008), previous anti-tuberculosis treatment (P = 0.023) and severe PTB (P = 0.018) were associated with failure to culture-convert at ?2 months. CONCLUSIONS: Although overall outcomes were good, prolonged culture positivity and cases of treatment failure emphasise the need for additional attention to the management of children with HRRS TB. PMID- 27776588 TI - Treatment outcomes of drug-resistant tuberculosis patients in Kenya. AB - SETTING: Successful treatment of drug-resistant tuberculosis (DR-TB) is crucial in preventing disease transmission and reducing related morbidity and mortality. A standardised DR-TB treatment regimen is used in Kenya. Although patients on treatment are monitored, no evaluation of factors affecting treatment outcomes has yet been performed. OBJECTIVE: To analyse treatment outcomes of DR-TB patients in Kenya and factors associated with successful outcome. DESIGN: Retrospective analysis of secondary data from Kenya's National Tuberculosis, Leprosy and Lung disease programme. DR-TB data from the national database for January to December 2012 were reviewed. RESULTS: Of 205 DR-TB patients included in the analysis, 169 (82.4%) had a successful treatment outcome, 18 (9%) died and 18 (9%) were lost to follow-up. Only sex (P = 0.006) and human immunodeficiency virus (HIV) status (P = 0.008) were predictors of successful treatment. Females were more likely to attain treatment success (OR 3.86, 95%CI 1.47-10.12), and HIV negative status increased the likelihood of successful treatment (OR 3.53, 95%CI 1.4-8.9). CONCLUSION: Treatment success rates were higher than World Health Organization targets. Targeted policies for HIV-positive patients and males will improve treatment outcomes in these groups. PMID- 27776589 TI - Provider perspectives on drug-resistant tuberculosis and human immunodeficiency virus care in South Africa: a qualitative case study. AB - OBJECTIVE: To examine influences on health care workers' (HCWs') capacity to deliver health care for multi- and/or extensively drug-resistant tuberculosis (MDR/XDR-TB) and human immunodeficiency virus (HIV) infection in South Africa. DESIGN: Qualitative data were collected via group and individual interviews with a purposive sample of 17 HCWs at a centralised, tertiary TB facility and analysed using grounded theory. RESULTS: Four themes were identified: 1) personal infection control practices among HCWs may be weakened by a workplace culture comprising low motivation, disparate risk perceptions and practices across workforce hierarchies, physical discomfort, and problems managing patients with treatment-induced hearing loss. 2) Patient-provider interactions are likely stronger among nurses, and in HIV vs. MDR/XDR-TB service delivery, due to greater attention to patient empowerment and support. Stigma associated with MDR/XDR-TB, considered worse than HIV, may be perpetuated within non-specialised facilities less familiar with MDR/XDR-TB. 3) HCWs who struggle with the daily tedium of MDR/XDR-TB treatment supervision are becoming increasingly supportive of treatment literacy and self-administration. 4) Effective integration of HIV and MDR/XDR-TB services may be impeded by administrative restrictions, workplace norms and provider mindsets. CONCLUSION: Comprehensive, decentralised management of MDR/XDR-TB and HIV coinfection requires the creation of patient-provider trust and treatment literacy in MDR/XDR-TB programmes, and defying workplace norms that could provoke nosocomial TB exposure and fragmented service provision. PMID- 27776590 TI - Epidemiology of tuberculosis in Cameroon as mirrored in notification data, 2006 2014. AB - SETTING: The Cameroonian National Tuberculosis Programme. OBJECTIVES: To assess case surveillance data for the 9-year period between January 2006 and December 2014. DESIGN: Retrospective descriptive analysis of tuberculosis (TB) case finding in Cameroon using routine surveillance data. Data on sociodemographic characteristics, disease category, clinical and laboratory variables, and geographic regions were analysed. RESULTS: The absolute number of TB cases (all forms) notified increased from 24 878 in 2006 to 26 517 in 2014; however, the population-adjusted annual case notification rate (CNR) of TB (all forms) as well as that of new smear-positive pulmonary TB cases decreased significantly, from 139 to 121 (P < 0.001) and from 77 to 70/100 000 population (P < 0.02), respectively. The human immunodeficiency virus (HIV) infection rate reported among all TB cases (39% in 2014) remained stable from 2009. The male-to-female ratio also remained stable, with a slight shift towards older age. There was a CNR gradient from the north to the south that appears to be related to HIV infection rates, population density and access to health services. CONCLUSIONS: TB CNRs in Cameroon for the 2006-2014 period show a slow but steady decrease, and there are indications that the trend reflects incidence. However, there is evidence to suggest that TB transmission is still ongoing. PMID- 27776591 TI - Surveillance for tuberculosis in a rural community in The Philippines. AB - SETTING: Estimates of the tuberculosis (TB) burden in the Philippines are largely dependent on prevalence surveys. OBJECTIVE: To conduct a prospective community based survey to generate epidemiological data on TB among patients seeking care in public health centres in a rural municipality in the Philippines. DESIGN: Prospective surveillance and follow-up of presumptive TB cases from May 2013 to July 2015. RESULTS: Of 1622 participants with presumptive TB, 468 (28.8%) (95%CI 26.6-31.1) were diagnosed with TB. The annual TB case notification rate in San Juan was 212 (95%CI 184-242) per 100 000 population. There were nine TB attributable deaths during the study period. Only 8.8% (95%CI 6.2-11.32) of the cases were children aged <15 years; 274 (58.5%) cases were bacteriologically confirmed. Of 210 isolates tested for antimicrobial resistance, 49 (23.3%, 95%CI 17.58-29.02) were resistant. Resistance to isoniazid (INH) was common (n = 33, 15.7%); multidrug-resistant TB was 1.9%. CONCLUSION: TB remains an important health problem in the Philippines. We identified low case detection of TB in children and high INH resistance rates in this rural community. PMID- 27776592 TI - Evaluating the impact of health resource reconstruction on improving spatial accessibility of tuberculosis care. AB - SETTING: In Japan, a decline in tuberculosis (TB) notification rates and shortening of duration of hospitalisation have led to a drastic decrease in the number of hospital beds for TB patients (TB beds), causing severe undersupply in certain regions. OBJECTIVE: To assess the current status of spatial access to TB beds in Japan and evaluate the potential impact of health resource reconstruction in mitigating undersupply of TB beds. DESIGN: A cross-sectional study was conducted whereby a two-step floating catchment area (2SFCA) method was used to calculate an 'accessibility score' to evaluate spatial accessibility of TB beds in the regions classified by four levels of urbanisation. The impact of introducing 'potential TB beds' was assessed via the changes in the proportion of undersupplied regions and TB patients notified from undersupplied regions. RESULTS: Undersupplied regions were characterised by 'very low', 'low' and 'moderate' level of urbanisation. By introducing 'potential TB beds', the proportion of both undersupplied regions and TB patients could be significantly reduced, especially in less urbanised regions. CONCLUSION: Our results may be used to guide future decision-making over resource allocation of TB care in Japan. The 2SFCA method may be applied to other countries using appropriate demand and supply variables. PMID- 27776593 TI - Epidemiological study of hepatitis B virus among prisoners with active tuberculosis in Central Brazil. AB - BACKGROUND: Due to environmental and social conditions inherent to incarceration, tuberculosis (TB) and hepatitis B virus (HBV) are major diseases among prison inmates. OBJECTIVE: To determine overall and occult HBV infection (OBI) prevalence rates, risk factors and genotype distribution among inmates with active TB. STUDY DESIGN: A cross-sectional study was conducted among 216 inmates with active TB recruited at the largest prisons in Campo Grande, Mato Grosso do Sul, Central Brazil. The participants were interviewed and tested for the presence of serological markers for HBV infection. RESULTS: The overall prevalence of HBV infection (total hepatitis B core antibodies) was 10.2% (95%CI 6.2-14.2). HBV surface antigen (HBsAg) prevalence was 1.4% (3/216). HBV DNA was detected in all three HBsAg-positive samples and in 10.5% (2/19) of the anti-HBc positive samples (OBI), giving a HBV-TB co-infection prevalence of 2.3% (5/216). A multivariate analysis of risk factors showed that history of sharing cutting instruments, length of incarceration and homosexual sex were associated with HBV infection. CONCLUSION: Our findings indicate that HBV remains an important public health concern among prison inmates and active TB-HBV co-infection needs to be addressed for effective treatment. PMID- 27776594 TI - Outcomes of standard and tailored anti-tuberculosis regimens in patients with tuberculous pleural effusion. AB - BACKGROUND: In an era of increasing concerns about drug resistance, there are limited data on treatment outcomes and recurrence rates after standard short course anti-tuberculosis treatment in patients with culture-negative tuberculous pleural effusion (TPE). OBJECTIVE: To compare treatment outcomes and recurrence rates between a standard anti-tuberculosis regimen with negative culture and unavailable drug susceptibility testing (DST) data, and a tailored anti tuberculosis regimen based on individual DST data. DESIGN: We analysed the data of all patients with TPE from the TB registry database at Kyungpook National University Hospital, South Korea, during 2008-2012. The study population was divided into two groups according to regimen. RESULTS: Standard and tailored anti tuberculosis regimens were administered to respectively 124 and 146 patients with TPE. Drug resistance was detected in 10% of patients with TPE, about a quarter of whom were multidrug-resistant. The treatment completion rate was not significantly different between the two groups (91% vs. 93%). During a median 20 month follow-up, the recurrence rate was also similar in both groups (1% vs.1%). CONCLUSIONS: Despite limited statistical power, these preliminary results support the hypothesis that immunocompetent patients with culture-negative TPE can be appropriately managed with a standard short-course anti-tuberculosis regimen, even in this era of increasing concerns about drug resistance. PMID- 27776595 TI - Treatment of non-cavitary pulmonary tuberculosis with shortened fluoroquinolone based regimens: a meta-analysis. AB - SETTING: Several recent trials evaluating 4-month fluoroquinolone (FQ) containing regimens found that none of the experimental regimens were non-inferior to standard 6-month therapy in treating patients with drug-susceptible pulmonary tuberculosis (PTB). OBJECTIVE: To answer whether FQ-containing duration-shortened regimens are non-inferior to standard therapy in the treatment of patients with non-cavitary PTB. DESIGN: Systematic review of all randomized and quasi randomized trials that substituted an FQ into standard therapy for less than 6 months' duration to treat drug-susceptible, non-cavitary PTB. Non-inferiority was based on a 6% margin of difference. RESULTS: Of 4594 total participants in the three trials that met the inclusion criteria, 1066 patients had non-cavitary disease. The pooled difference in unfavorable outcomes was 5% (95%CI -3 to 13) in patients with non-cavitary disease treated with FQ-containing regimens vs. standard therapy. In subgroup analyses, the pooled difference in unfavorable outcomes was 1% (95%CI -3 to 5) when comparing the daily form of intervention regimen with standard therapy, and -1% (95%CI -5 to 4) between regimens replacing ethambutol (EMB) with an FQ and standard therapy. No difference in risk of adverse events was noted. CONCLUSION: Daily administered 4-month regimens with substitution of EMB by an FQ may be non-inferior to standard therapy in patients with culture-confirmed, non-cavitary, drug-susceptible PTB. PMID- 27776596 TI - Molecular typing of mycobacteria isolated from tuberculous lymphadenitis cases in Addis Ababa, Ethiopia. AB - BACKGROUND: In Ethiopia, one of the world's 22 high tuberculosis (TB) burden countries, one third of the tuberculosis (TB) cases are attributed to tuberculosis lymphadenitis (TBLN). However, information on the molecular type of the mycobacterial species and strains that cause TBLN in the country is scarce. OBJECTIVE: To identify the species and strains of mycobacteria that cause TBLN in Ethiopia. METHODS AND RESULTS: A cross-sectional study was conducted among 206 presumed TBLN cases to characterise positive culture isolates. Mycobacterium tuberculosis complex species and strains were identified using region of difference 9 deletion and SITVIT WEB, respectively. Of the 206 fine-needle aspirate samples collected, 74 (36%) were culture-positive: 73 (98.6%) of the isolates were M. tuberculosis, and the remaining 1.4% were M. bovis. Further characterisation of the 73 M. tuberculosis isolates led to 26 distinct spoligotype international types (SITs) and 13 newly identified patterns. The most prevalent strains were SIT149, SIT53, SIT26 and SIT37 of sublineages T3-ETH, T1, CASI-DELHI and T3, respectively; these accounted for 52.6% of the total number of strains. CONCLUSION: TBLN was mainly caused by M. tuberculosis and highly clustered strains SIT149, SIT53, SIT26 and SIT37 of sublineages T3-ETH, T1, CASI DELHI and T3, respectively. PMID- 27776597 TI - Pyrazinamide susceptibility testing in Mycobacterium tuberculosis using the fast resazurin microtiter assay plate. AB - SETTING: Department of Clinical Analysis and Biomedicine, State University of Maringa, Maringa, PR, Brazil. OBJECTIVE: To evaluate the performance of the resazurin microtiter assay (REMA) plate at pH 5.5 in detecting Mycobacterium tuberculosis susceptibility to pyrazinamide (PZA). DESIGN: The minimal inhibitory concentration (MIC) of PZA in M. tuberculosis H37Rv and M. bovis AN5 reference strains and in 34 clinical M. tuberculosis isolates (26 PZA-susceptible and eight PZA-resistant) was determined using REMA at pH 5.5 and compared to REMA at pH 6.0. RESULTS: REMA at pH 5.5 was helpful in discriminating PZA-susceptible from resistant M. tuberculosis isolates when ?50 MUg/ml PZA was considered as the cut off for PZA susceptibility. Furthermore, it provided results in 8 days. However, two PZA-resistant isolates failed to grow at pH 5.5. CONCLUSION: As the REMA method is rapid, inexpensive, easy to perform and read, it would be of great usefulness in low-income countries for detecting PZA-resistant M. tuberculosis. REMA at pH 5.6-5.9 should be evaluated on an extended panel of clinical M. tuberculosis isolates with a greater range of MIC values in different laboratories for a better understanding of its utility in differentiating PZA resistant from PZA-susceptible isolates. PMID- 27776598 TI - Endobronchial valve treatment of destructive multidrug-resistant tuberculosis. AB - BACKGROUND: In accordance with the existing hypothesis, the application of an endobronchial valve (EbV) leads to selective curative atelectasis of the affected part of the lung, contributing to early closure of cavities. OBJECTIVE: To assess the effect of EbV treatment on the course of tuberculosis (TB). METHODS: We compared the efficacy of EbV treatment and complex second-line treatment in treating patients with destructive pulmonary multidrug-resistant TB (MDR-TB). Bacteriological conversion and closure of cavities were selected as criteria to assess the effectiveness of EbV application. A total of 102 patients with destructive MDR-TB were enrolled into the study and randomly divided into two groups: 49 patients had an EbV installed (intervention group) and 53 patients received complex second-line treatment (control group). Complex chemotherapy was administered to both groups throughout the study period. RESULTS: The cure rate in the short- and long-term follow-up periods in the intervention group was shown to be much higher, 95.9% by bacteriological conversion and 67.3% by cavity closure. On comparison with the control group, this was respectively 37.7% and 20.7% (P < 0.0001). CONCLUSIONS: The application of EbV treatment can significantly improve the effectiveness of second-line chemotherapy regimens in MDR-TB patients. PMID- 27776599 TI - Comparative utility of interferon-gamma release assay, QuantiFERON(r) TB-GIT and T-SPOT(r).TB in rheumatoid arthritis. AB - SETTING: National hospital for tuberculosis (TB) and rheumatoid arthritis (RA) in Japan. OBJECTIVE: To compare two interferon-gamma release assays (IGRAs), QuantiFERON(r)-TB Gold In-Tube (QFT) and T-SPOT(r).TB (T-SPOT), in RA patients for detecting latent tuberculous infection (LTBI). DESIGN: QFT and T-SPOT were conducted concurrently in 230 prospectively enrolled RA patients. RESULTS: There were no active TB patients. The percentage of QFT- and T-SPOT-positive patients was respectively 8.3% and 5.7%. In patients aged ?60 years, these proportions were respectively 12.3% and 7.2%. The percentage of QFT positivity and T-SPOT positivity at age <60 years was respectively 2.2% and 3.3%. After multivariate logistic analysis for QFT positivity, age ?60 years and TB suspected based on chest X-ray were selected as independent factors, with adjusted odds ratios of respectively 4.73 and 3.25. No factors were selected for T-SPOT positivity. CONCLUSION: QFT had a higher positivity rate. In the light of the previous estimated rate of LTBI in Japan, both IGRAs underestimate LTBI, and neither IGRA has enough capability to detect LTBI. PMID- 27776601 TI - Active tuberculosis case finding in a migrant slum community, Mumbai, India. PMID- 27776600 TI - Blood and urine inducible protein 10 as potential markers of disease activity. AB - SETTING: Blood interferon-gamma inducible protein 10 (IP-10) has been proposed as a biomarker of disease activity for both tuberculosis (TB) and human immunodeficiency virus (HIV) infection. Urine IP-10 has been detected in adults with active TB, and its level decreases after successful anti-tuberculosis treatment. OBJECTIVE: To evaluate blood and urine IP-10 as biomarker of disease activity. DESIGN: Patients with HIV-TB and active TB were enrolled. Individuals with HIV infection only and healthy donors were included as controls. Blood and urine IP-10 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Of 39 active TB patients enrolled, 24 were HIV-infected and 15 were HIV uninfected. Of 87 control subjects without active TB, 54 were HIV-infected and 33 were HIV-uninfected. IP-10 analysis was performed in patients with concomitant blood and urine sample collection. Blood IP-10 was associated with active TB, regardless of HIV infection status; urine IP-10 levels were increased in active TB patients, although the difference was significant in HIV-infected individuals only. Finally, in HIV-infected patients, both blood and urine IP-10 levels were inversely correlated with CD4 T-cell counts. CONCLUSION: These findings suggest that IP-10 could be used as a biomarker for disease activity (inflammation). PMID- 27776602 TI - Cue-exposure software for the treatment of bulimia nervosa and binge eating disorder. AB - BACKGROUND: Cue-exposure therapy (CET) has proven its efficacy in treating patients with bulimia nervosa and binge eating disorder who are resistant to standard treatment. Furthermore, incorporating virtual reality (VR) technology is increasingly considered a valid exposure method that may help to increase the efficacy of standard treatments in a variety of eating disorders. Although immersive displays improve the beneficial effects, expensive technology is not always necessary. METHOD: We aimed to assess whether exposure to food related virtual environments could decrease food craving in a non-clinical sample. In addition, we specifically compared the effects of two VR systems (one non immersive and one immersive) during CET. We therefore applied a one-session CET to 113 undergraduate students. RESULTS: Decreased food craving was found during exposure to both VR environments compared with pre-treatment levels, supporting the efficacy of VR-CET in reducing food craving. We found no significant differences in craving between immersive and non-immersive systems. CONCLUSIONS: Low-cost non-immersive systems applied through 3D laptops can improve the accessibility of this technique. By reducing the costs and improving the usability, VR-CET on 3D laptops may become a viable option that can be readily applied in a greater range of clinical contexts. PMID- 27776603 TI - Prevalence of strategies for coping with daily stress in children. AB - BACKGROUND: The study of coping strategies in children guarantees quality of life from childhood onwards. The present paper aims to determine the prevalence of coping strategies for three everyday problems in children, while examining sociodemographic variables, context variables, and teacher assessment. METHOD: The sample is composed of 7,058 school children aged between 8 and 13 years old. RESULTS: Results show a higher prevalence of the Active Solution strategy at home and in school contexts compared with the health area, where the Active Solutionis the least prevalent strategy, and Concealing the Problem the most widely used, followed by Passivity. Other highly prevalent strategies in the school context include Search for Information, Emotion, and Social Support. In general, regardless of the context, Behavioural Avoidance and Passivity are theleast prevalent strategies, whereas Active Solution is the most prevalent one, followed by Emotion. The last two-Active Solution and Emotion - are part of two main coping styles suggested in a number of studies on which these results are based, which will be compared and discussed in this study. CONCLUSIONS: The present study allows us to extract relevant epidemiological information on strategies used to cope with everyday problems related to health, family, and school, in a sample of socially well-adapted and psychologically healthy Spanish school children. The data obtained can be useful in an increasing number of situations and contexts, both for diagnostic purposes and for psycho-educational orientation and intervention. PMID- 27776604 TI - Negative affect, perceived health, and endocrine and immunological levels in caregivers of offspring with schizophrenia. AB - BACKGROUND: Negative affect (NA) and chronic stress are separately associated with health imbalances, and the interaction between the two aspects remains unclear. Care of relatives with long-term pathologies could be a likely model in the study of this issue, as caregivers frequently report chronic stress and health complaints. The aim of this study is examine the role of NA on psychophysiological stress-induced response and health in schizophrenia caregivers. METHOD: Forty-one caregivers were distributed into two groups accordingly to their scores in NA. Thirteen non-caregivers were included as a control group. Participants were exposed to a repeated acute psychosocial stress while salivary cortisol, immunoglobulin A (IgA), and skin conductance level (SCL) were measured before, during, and after stress. Mood, state-anxiety, care conditions and perceived general health were also assessed. RESULTS: Caregivers with higher NA reported negative perceptions, worse health, and greater decreases in cortisol and IgA response than caregivers with low NA and than non-caregivers. CONCLUSIONS: NA could reduce the capability to develop adaptive psychophysiological stress responses. From a preventive view, the evaluation of NA could be useful to detect and assist high-risk individuals in potentially chronically stressed populations. PMID- 27776605 TI - Emotion awareness, mood and personality as predictors of somatic complaints in children and adults. AB - BACKGROUND: The relationships among somatic complaints, emotion awareness and mood have been observed in late childhood and adolescence, but very few studies have been carried out in adult populations like this work. This study also incorporates personality dimensions that can exacerbate or reduce the emergence of somatic complaints. Therefore, the aim of this study is to analyse the combined contribution of emotion awareness, mood, and personality to healthy children and adults’ somatic complaints. METHOD: Self-reported questionnaires about emotion awareness, mood, personality, and somatic complaints were administered to 1,476 children (7-14 years old) and 479 adults (27-56 years old). RESULTS: Emotion awareness and mood were the strongest predictors of somatic complaints (ΔR 2 = .32 for children; ΔR 2 = .36 for adults), and the contribution of personality dimensions was not so relevant (ΔR 2 = .07 for children; ΔR 2 = .12 for adults). CONCLUSIONS: Emotional and personality factors must be addressed in health-promotion programmes, tailored differently according to whether they are to be used with children or with adults. PMID- 27776606 TI - Stress in Spanish police force depending on occupational rank, sex, age and work shift. AB - BACKGROUND: In the police force, some variables such as occupational rank, sex, age and work-shift are associated with stress in workers. The aim of this paper was to determine possible differences in the perception of occupational stress at work depending on rank, sex, age and work-shift of police agents in the Community of Madrid, Spain. METHOD: A cross-sectional study was conducted in 24 municipalities of the Community of Madrid. A total number of 565 police agents participated. The ranks of the police agents were: constable, corporal, sergeant and police chief. Occupational stress (psychosocial risk factors at work) was assessed with the DECORE Questionnaire. RESULTS: All police agents perceived psychosocial risk factors adversely; especially agents of lesser rank perceived less control, fewer rewards and scarce support. There were significant differences in the perception of insufficient rewards between constables and other categories; and between constables and corporals in the perception of insufficient organisational support. No significant differences were found in the perception of psychosocial risk factors in relation to the rest of variables. CONCLUSIONS: The police rank should be taken into account for the development of preventive measures to reduce stress. PMID- 27776607 TI - Bio-psycho-social correlates of the perceived crowding in different contexts. AB - BACKGROUND: This paper analyzes the experience of crowding through a biopsychosocial approach to human behavior which empirically joins different dimensions that the literature has analyzed separately. The main aim consists of identifying factors involved in perceived crowding from (a) the emotional response and affective meaning (BIO dimension); (b) the perception of psychological well-being and personality traits (PSYCHO dimension), and (c) sociodemographic characteristics (SOCIO dimension). METHOD: 761 adults completed an online questionnaire that included an assessment of images representing four high- and low-density functional and residential contexts. The data were analyzed through four hierarchical regressions, one for each spatial context. RESULTS: Although the results vary depending on the contexts analyzed, the prevalence of the variables from the BIO dimension in functional contexts, as opposed to residential contexts, is highlighted. The latter spaces show greater heterogeneity regarding the explanatory power of the experience of crowding. CONCLUSIONS: The response to crowding experienced in residential environments shows a greater range of variables involved, supporting the idea of these spaces’ greater complexity, insofar as they are psychologically adaptive. PMID- 27776608 TI - A predictive study of antecedent variables of workaholism. AB - BACKGROUND: Recent studies have pointed to a relationship between personality variables, engagement, and the lifestyle of workers with workaholism. Our goal in the present study is to carry out a predictive study of the pre-existing variables for workaholism. Method : The study sample participants were 513 workers (48.1 % men, 51.9 % women), obtained through non-probability sampling. The programmes used were FACTOR (7.2 version) and SPSS 20.0. RESULTS: We found that personality variables such as engagement, self-efficacy, obsessive compulsive component (ICO), satisfaction with life and lifestyle were predictive of workaholism. CONCLUSIONS: Workaholism can, in fact, be predicted through certain variables (personality, engagement, self-efficacy, ICO, satisfaction with life and lifestyle) and hence, the present study contributes to a better understanding of workaholism and to furthering a healthy life style which may be affected by workaholism. PMID- 27776609 TI - Gender differences in mental health during the economic crisis. AB - BACKGROUND: Economic crises have a negative effect on mental health. Little evidence has been published on the impact of economic downturns on male and female. The aim of the study was to analyze gender differences in specific mental disorders in primary care during the current economic recession in Spain. METHOD: A total of 7,914 patients in 2006 and 5,876 patients in 2010 were recruited to collect sociodemographic data and the Primary Care Evaluation of Mental Disorders. RESULTS: Between 2006 and 2010 the prevalence of Major Depressive Disorder increased 155.7% in men and 104.9% in women; Generalized Anxiety Disorder increased 98.3% in men and 71.3% in women; and Multisomatoform Disorder increased 100.05% in men and 37% in women. The effect of the Employment confounder was significant across all comparisons: Major Depressive Disorder Generalized Odds Ratio=2.557 for Men (p<.001), 2.046 for Women (p=.002); Generalized Anxiety Disorder Generalized Odds Ratio= 2.153 (p<.001) for Men, 1.546 for Women (p<.001); and for Non-specific Multisomatoform Disorder Generalized Odds Ratio=1.680 for Men (p<.001) and 1.301 for women (p=.014). CONCLUSION: Overall prevalence of mental disorders increased significantly between 2006 and 2010, especially in males, who are more sensitive to the effect of the current economic recession than women. PMID- 27776610 TI - Testing the alleged superiority of the indulgent parenting style among Spanish adolescents. AB - BACKGROUND: While international studies have reported the superiority of the authoritative style (which combines parental involvement with demandingness), some studies in Spain and in other countries have found that the indulgent style (involvement without demandingness) might be just as good or even better. This study aims to discern whether the differences are cultural or methodological. METHOD: 306 adolescents from high schools in Madrid and Valencia (Spain) answered a questionnaire that included two parenting style instruments (SOC-30 and PSI), together with a self-esteem scale (AF5) and a question on academic performance. RESULTS: Concordance between the two instruments assessing parenting styles was poor. When associating parenting styles (according to the SOC-30) with outcomes (self-esteem and academic achievement), results were similar to previous studies in Spain. But if we use the PSI, results were similar to studies in Anglophone countries: the authoritative style achieved the best outcomes. CONCLUSIONS: The discrepancies found between studies carried out in Spain and in Anglophone countries do not seem to be due to differences between cultures, but to methodological differences (i.e., differences between the instruments used). If we use the same instruments that were used in Anglophone countries, the most effective parenting style is still the authoritative. PMID- 27776611 TI - Alcohol seeking by rats becomes habitual after prolonged training. AB - BACKGROUND: This study examines the effect of the amount of training on alcohol seeking behavior in rats. Contemporary theories of instrumental learning suggest that habit learning processes are involved in the development of the compulsive drug seeking that characterizes addiction. METHOD: Wistar rats were trained to perform an instrumental response for a solution of ethanol. In Experiment 1, the rats received 2 instrumental training sessions, whereas animals in Experiment 2 received 2, 8, or 16 sessions. An aversion was then conditioned to ethanol by pairing it with LiCl, and the performance in extinction was subsequently tested. RESULTS: Instrumental responding showed variable sensitivity to outcome devaluation as a function of the length of training. After 2 and 8 training sessions, but not after 16 sessions, drug seeking was influenced by a change in the value of ethanol. CONCLUSIONS: The results suggest that alcohol seeking is more flexible and goal-directed in early stages of training, but it becomes habitual and less governed by its consequences with more extended training. PMID- 27776612 TI - Psychopathic traits mediate the effects of neighbourhood risk on juvenile antisocial behaviour. AB - BACKGROUND: Research of the indirect effects of neighbourhood risk through psychopathic personality traits (i.e., impulsiveness, narcissism and callous unemotional traits) on juvenile antisocial behaviour has become relevant. METHODS: In the current study, mediation effects were assessed using a sample composed of 406 young people between 14 and 21 years old, 82.7% males, from juvenile centres in Galicia and Andalucía (Spain). RESULTS: The results showed significant mediation effects of neighbourhood risk on antisocial behaviour through impulsiveness and callous-unemotional traits. Conclusions: The implications of the mediation effects for prevention, risk assessment, and risk management in juvenile offenders are discussed. PMID- 27776613 TI - Do dichromats see colours in this way? Assessing simulation tools without colorimetric measurements. AB - BACKGROUND: Simulcheck evaluates Colour Simulation Tools (CSTs, they transform colours to mimic those seen by colour vision deficients). Two CSTs (Variantor and Coblis) were used to know if the standard Simulcheck version (direct measurement based, DMB) can be substituted by another (RGB values based) not requiring sophisticated measurement instruments. METHOD: Ten normal trichromats performed the two psychophysical tasks included in the Simulcheck method. The Pseudoachromatic Stimuli Identification task provided the h uv (hue angle) values of the pseudoachromatic stimuli: colours seen as red or green by normal trichromats but as grey by colour deficient people. The Minimum Achromatic Contrast task was used to compute the L R (relative luminance) values of the pseudoachromatic stimuli. RESULTS AND CONCLUSIONS: Simulcheck DMB version showed that Variantor was accurate to simulate protanopia but neither Variantor nor Coblis were accurate to simulate deuteranopia. Simulcheck RGB version provided accurate h uv values, so this variable can be adequately estimated when lacking a colorimeter —an expensive and unusual apparatus—. Contrary, the inaccuracy of the L R estimations provided by Simulcheck RGB version makes it advisable to compute this variable from the measurements performed with a photometer, a cheap and easy to find apparatus. PMID- 27776614 TI - Stevia preferences in Wistar rats. AB - BACKGROUND: The Stevia rebaudiana plant is likely to become a major source of high-potency sweetener for the growing natural-food market. S. rebaudiana is the source of a number of sweet diterpenoid glycosides, but the major sweet constituents are rebaudioside A and stevioside. These two constituents have similar pharmacokinetic and metabolic profiles in rats and humans, and thus, studies carried out with either steviol glycoside are relevant to both. Other studies illustrate the diversity of voluntary sweet intake in mammals. METHOD: This study was done using a series of two-bottle tests that compared a wide range of sweetener concentrations versus saccharin concentrations and versus water. RESULTS: Wistar rats displayed preferences for stevia extract and pure rebaudioside A solutions over water at a range of concentrations (0.001% to 0.3%), and their intake peak occurred at 0.1% concentration. They also preferred solutions prepared with a commercial rebaudioside A plus erythritol mixture to water, and their peak was at 2% concentration. CONCLUSIONS: The present study provides new information about the responses of Wistar rats to stevia compounds and commercial stevia products such as Truvia. These results could help with the appropriate dosage selection for focused behavioral and physiological studies on stevia. PMID- 27776615 TI - Knowledge level of effect size statistics, confidence intervals and meta-analysis in Spanish academic psychologists. AB - BACKGROUND: The statistical reform movement and the American Psychological Association (APA) defend the use of estimators of the effect size and its confidence intervals, as well as the interpretation of the clinical significance of the findings. METHOD: A survey was conducted in which academic psychologists were asked about their behavior in designing and carrying out their studies. The sample was composed of 472 participants (45.8% men). The mean number of years as a university professor was 13.56 years (SD= 9.27). RESULTS: The use of effect size estimators is becoming generalized, as well as the consideration of meta analytic studies. However, several inadequate practices still persist. A traditional model of methodological behavior based on statistical significance tests is maintained, based on the predominance of Cohen’s d and the unadjusted R2/η2, which are not immune to outliers or departure from normality and the violations of statistical assumptions, and the under-reporting of confidence intervals of effect-size statistics. CONCLUSION: The paper concludes with recommendations for improving statistical practice. PMID- 27776616 TI - Adherence to healthy diet and physical activity in clinical patients. AB - BACKGROUND: The aim of this study is to explore the psychometric properties of the Motiva.Diaf questionnaire, which assesses the adherence to healthy diet and physical activity in clinical patients. METHOD: Participants were 230 patients, who attended hospital services, with a mean age of 49.28 years (SD = 12.34). Women constituted 55.7% of the patients. Two weeks after initial administration, 40 participants, from those who had another hospital appointment scheduled, were selected at random to complete again the questionnaire in order to assess test–retest reliability. Results: the accuracy of the scores is adequate both in terms of internal consistency (α = .802; Ω = .776) and temporal stability ( r = .786). The test’s structure is essentially one dimensional, and the scores in this dimension converge with other necessary basic psychological measurements ( r Diet = .294; r Physical Activity = .359) and perceived health ( r = .266). In addition, a relatively moderate relationship was found with the Body Mass Index ( r = - .129). CONCLUSIONS: The test has shown adequate reliability and validity for evaluating adherence to healthy habits. The availability of an instrument with these characteristics has significant implications for evaluating behaviour, designing and implementing behavioural interventions. PMID- 27776617 TI - How response bias affects the factorial structure of personality self-reports. AB - BACKGROUND: Various studies have shown that acquiescence can distort the factor structure of personality questionnaires based on the five-factor model. In the present study, we analysed how acquiescence and social desirability affect the factor structure of a measure based on this personality model and a measure of aggression. METHOD: We analysed the factor structures of both tests before and after removing both biases in a sample of 532 adolescents aged between 11 and 18 (M= 14.75, SD= 2.1). RESULTS: The factor structure of both tests presented a worse fit to the expected model when response bias was not controlled, and the congruence indexes for the personality and aggression measures showed a moderate (from C= .948 to C= .872) or great (from C= .931 to C= .475) decrease, respectively. Furthermore, acquiescence was largely responsible for these effects, and social desirability effects were only shown on the aggression measure. CONCLUSIONS: Response bias, and especially acquiescence, should be controlled during the development of personality measures to avoid distorting them, especially with samples of people with a high level of acquiescence (for example, those with little education, the young or the elderly). Furthermore, the use of response bias loadings as a criterion for choosing the items minimizes those distortions. PMID- 27776618 TI - A computerized adaptive test for enterprising personality assessment in youth. AB - : Backgound : Assessing specific personality traits has shown better predictive power of enterprising personality than have broad personality traits. Hitherto, there have been no instruments that evaluate the combination of specific personality traits of enterprising personality in an adaptive format. So, the aim was to develop a Computerized Adaptive Test (CAT) to assess enterprising personality in young people. METHODS: A pool of 161 items was developed and applied to two sets of participants (n 1 = 357 students, M age = 17.89; SD age = 3.26; n 2 = 2,693 students; M age = 16.52, SD age = 1.38) using a stratified sampling method. RESULTS: 107 items that assess achievement motivation, risk taking, innovativeness, autonomy, self-efficacy, stress tolerance, internal locus of control, and optimism were selected. The assumption of unidimensionality was tested. The CAT demonstrated high precision for a wide range of q, using a mean of 10 items and demonstrating a relatively low Standard Error (0.378). CONCLUSIONS: A brief, valid, and precise instrument was obtained with relevant implications for educational and entrepreneurial contexts. PMID- 27776619 TI - Coping assessment from the perspective of the person-situation interaction: Development and validation of the Situated Coping Questionnaire for Adults (SCQA). AB - BACKGROUND: Although coping strategies are considered to contribute to resilience to adversity, their use is not stable, but varies depending on the specific adversity. However, to date, most of the questionnaires assessing coping do not consider its situational character. The objective of this study is to develop and validate the Situated Coping Questionnaire for Adults (SCQA), which assesses coping in the face of five different kinds of adverse contexts to take into account its situational dimension. METHODS: A total of 430 Spanish adults (256 from the general population, 77 people suffering from cancer or HIV, and 97 parents of children with cancer or developmental problems) completed the SCQA and two resilience questionnaires (the Brief Resilience Scale and the 10-item Connor Davidson Resilience Scale) for validation purposes. RESULTS: Confirmatory factor analyses showed the superiority of the person-situation model; the situation influences the degree to which people use specific coping strategies; however, coping is also stable to some extent. Regression analyses showed that coping strategies contribute to predict resilience, supporting the validity of the SCQA. The questionnaire and its sub-scales showed adequate reliability. CONCLUSION: The SCQA is deemed a reliable and valid means of situated coping assessment for use in several populations. PMID- 27776620 TI - Spanish adaptation of social withdrawal motivation and frequency scales. AB - OBJECTIVE: To adapt into Spanish three scales measuring frequency (SWFS) and motivation for social withdrawal (CSPS and SWMS) and to develop a scale capable of assessing the five motivations for social withdrawal. METHOD: Participants were 1,112 Spanish adolescents, aged 12-17 years. The sample was randomly split into two groups in which exploratory and confirmatory (CFA) factor analyses were performed separately. A sample of adolescents in residential care (n = 128) was also used to perform discriminant validity analyses. RESULTS: SWFS was reduced to eight items that account for 40% of explained variance (PVE), and its reliability is high. SWMS worked adequately in the original version, according to CFA. Some items from the CSPS were removed from the final Spanish version. The newly developed scale (SWMS-5D) is composed of 20 items including five subscales: Peer Isolation, Unsociability, Shyness, Low Mood and Avoidance. Analyses reveal adequate convergent and discriminant validities. CONCLUSIONS: The resulting SWFS 8 and SWMS-5D could be considered useful instruments to assess frequency and motivation for social withdrawal in Spanish samples. PMID- 27776621 TI - The factor structure of the Posttraumatic Growth Inventory in parents of critically ill children. AB - BACKGROUND: Posttraumatic growth (PTG) was conceptualized as consisting of changes in three broad dimensions; Self, interpersonal relationships, and philosophy of life. The aim of this study is to analyze the factor structure of the Posttraumatic Growth Inventory (PTGI) in a sample of parents whose children had survived a critical hospitalization in order to consider the structural validity of the PTGI scores for this population and to report our understanding of PTG as a construct. METHODS: 143 parents completed the PTGI 6 months after their child’s discharge from pediatric intensive care. The PTGI scores’ factor structure was studied through confirmatory factor analyses (CFA) of different models supported in prior research, followed by an exploratory principal component analysis (PCA). RESULTS: Prior models tested through CFA did not provide an acceptable fit for our data. Through exploratory PCA, three components emerged that explained 73.41% of the variance; personal growth, interpersonal growth and transpersonal growth. Subsequent CFAs on this three factor model showed that a bifactor model had the best fit. CONCLUSION: Although the PTGI scores have shown slightly different factor structures among diverse populations, the three dimensions initially theorized appear to be robust, which supports the structural validity of its scores. PMID- 27776622 TI - Yoga in Women With Abdominal Obesity?a Randomized Controlled Trial. AB - BACKGROUND: Abdominal obesity is a major risk factor for morbidity and mortality. The aim of this study was to investigate the effect of yoga on waist circumference and other anthropometric and self-reported variables in women with abdominal obesity. METHODS: 60 women with abdominal obesity (waist circumference >= 88 cm; body-mass index [BMI] >= 25) were randomly allocated in a 2:1 ratio to either a 12-week yoga intervention (n = 40) or a waiting list (n = 20). The waist circumference was the primary endpoint. Secondary (exploratory) endpoints included the waist/hip ratio, body weight, BMI, body fat percentage, body muscle mass percentage, blood pressure, health-related quality of life, self-esteem, subjective stress, body awareness, and body responsiveness, and the safety of the intervention. The persons assessing the outcomes were blinded to the group to which the patients belonged. RESULTS: The patients in the yoga group participated in a mean of 30.2+/-9.2 (maximum, 42) hours of supervised yoga practice. Their abdominal circum - ference was significantly reduced in comparison to the participants on the waiting list, with an intergroup difference of -3.8 cm (95% confidence interval [-6.1; -1,.5]; p = 0.001). There were further, moderate intergroup differences in the waist/hip ratio, body weight, BMI, body fat percentage, body muscle mass percentage, mental and physical well-being, self esteem, subjective stress, body awareness, and trust in bodily sensations (all p<0.05). There were no serious adverse events. None of the participants embarked on a low-calorie diet while participating in the study. CONCLUSION: The 12-week yoga intervention had moderately strong positive effects on anthropometric and self-reported variables in women with abdominal obesity. Yoga is safe in this population and can be recommended as a technique for combating abdominal obesity in women. PMID- 27776624 TI - Possible Overcoding. PMID- 27776623 TI - Evidence-based Treatment Options in Cannabis Dependency. AB - BACKGROUND: Now that the consumption of natural and synthetic cannabinoids is becoming more widespread, the specific treatment of cannabis-related disturbances is an increasingly important matter. There are many therapeutic options, and it is not always clear which ones are evidence-based and appropriate for use in a given clinical situation. METHODS: This review is based on reports of pertinent randomized and controlled trials (RCTs) that were retrieved by a selective search in the PubMed and Cochrane databases. RESULTS: Cognitive behavior therapy (CBT) combined with other techniques has been found to have a moderate to large effect (Cohen's d = 0.53-0.9) on the amount of cannabis consumed as well as on the level of psychosocial functioning or the dependence syndrome. Systemic multidimensional family therapy (MDFT) has been found beneficial for younger adolescents who consume large amounts of cannabis and have psychiatric comorbidities. Short-term interventions with motivational talk therapy have been found effective for patients with or without an initial desire to achieve cannabis abstinence. All of these psychotherapeutic interventions are effective at evidence level Ia. The administration of gabapentin had a weak effect (d = 0.26) on the quantity consumed and on abstinence (evidence level Ib). Withdrawal symptoms can be alleviated with cannabinoid-receptor antagonists (d = 0.223 and 0.481) (evidence level Ib). On the other hand, there is evidence that serotonergic antidepressants can worsen withdrawal manifestations and increase the likelihood of relapse. CONCLUSION: Psychotherapeutic techniques remain the foundation of treatment for cannabis dependence. No drug has yet been approved for the treatment of cannabis dependence because of the lack of scientific evidence. The rates of abstinence that are currently achieved, even with psychotherapy, are still only moderate. Further clinical studies are needed for the evaluation of combinations of various treatments that can meet the needs of individual patients. PMID- 27776625 TI - In Reply. PMID- 27776626 TI - Making the Most of Yoga in the Individual Setting. PMID- 27776627 TI - Further Areas of Application. PMID- 27776628 TI - In Reply. PMID- 27776629 TI - A 28-Year-Old Man with Impaired Vision. PMID- 27776630 TI - Seeing is believing. AB - A small transparent crustacean called Parhyale hawaiensis has become a powerful model system for the study of limb and appendage regeneration. PMID- 27776631 TI - Distinct neural mechanisms underlie the success, precision, and vividness of episodic memory. AB - A network of brain regions have been linked with episodic memory retrieval, but limited progress has been made in identifying the contributions of distinct parts of the network. Here, we utilized continuous measures of retrieval to dissociate three components of episodic memory: retrieval success, precision, and vividness. In the fMRI scanner, participants encoded objects that varied continuously on three features: color, orientation, and location. Participants' memory was tested by having them recreate the appearance of the object features using a continuous dial, and continuous vividness judgments were recorded. Retrieval success, precision, and vividness were dissociable both behaviorally and neurally: successful versus unsuccessful retrieval was associated with hippocampal activity, retrieval precision scaled with activity in the angular gyrus, and vividness judgments tracked activity in the precuneus. The ability to dissociate these components of episodic memory reveals the benefit afforded by measuring memory on a continuous scale, allowing functional parcellation of the retrieval network. PMID- 27776632 TI - Live imaging reveals the progenitors and cell dynamics of limb regeneration. AB - Regeneration is a complex and dynamic process, mobilizing diverse cell types and remodelling tissues over long time periods. Tracking cell fate and behaviour during regeneration in active adult animals is especially challenging. Here, we establish continuous live imaging of leg regeneration at single-cell resolution in the crustacean Parhyale hawaiensis. By live recordings encompassing the first 4-5 days after amputation, we capture the cellular events that contribute to wound closure and morphogenesis of regenerating legs with unprecedented resolution and temporal detail. Using these recordings we are able to track cell lineages, to generate fate maps of the blastema and to identify the progenitors of regenerated epidermis. We find that there are no specialized stem cells for the epidermis. Most epidermal cells in the distal part of the leg stump proliferate, acquire new positional values and contribute to new segments in the regenerating leg. PMID- 27776634 TI - Facile synthesis of a boronate affinity sorbent from mesoporous nanomagnetic polyhedral oligomeric silsesquioxanes composite and its application for enrichment of catecholamines in human urine. AB - A boronate-decorated nanomagnetic organic-inorganic hybrid material was facilely synthesized by utilizing the nanomagnetic polyhedral oligomeric silsesquioxanes (POSS) composite (Fe3O4@POSS) as the base platform. A simple copolymerization occurred between 3-acrylamidophenylboronic acid (AAPBA) and the residual end vinyl groups supplied by the substrate. Here the special emphasis was placed on the octavinyl POSS, which not only acted as the building blocks for a hybrid architecture but also facilitated the process of grafting boronate groups onto the surface of POSS based nanomagnetic composite (Fe3O4@POSS). The successful immobilization of affinity ligand-AAPBA on the Fe3O4@POSS was confirmed by Fourier transform infrared (FT-IR), elemental analysis, inductively coupled plasma atomic emission spectrometer (ICP-AES), field emission scanning electron microscope. A magnetic solid-phase extraction (MSPE) for cis-diols enrichment was developed using the as-prepared Fe3O4@POSS-AAPBA material as an affinity sorbent and three catecholamines (CAs), namely noradrenaline, epinephrine and isoprenaline, as model analytes. Under the optimal extraction conditions, sensitive and simultaneous analysis of three CAs from the urine sample was achieved by high-performance liquid chromatography with UV detection (HPLC-UV). The limits of detection (LOD, S/N = 3) and the limits of quantitation (LOQ, S/N = 10) for the target analytes were 0.81-1.32 ng mL-1 and 2.70-4.40 ng mL-1, respectively. Also good recoveries (85.5-101.7%) and repeatability (RSD<=10.1%) were obtained by this method. This work not only showed a facility for the utilization of Fe3O4@POSS as a substrate for constructing a boronate functionalized nanomagnetic sorbent, but also demonstrated the capability of the derived material for recognition of trace amount of cis-diols biomolecules presented in complicated biological matrices. PMID- 27776633 TI - Unexpected arousal modulates the influence of sensory noise on confidence. AB - Human perception is invariably accompanied by a graded feeling of confidence that guides metacognitive awareness and decision-making. It is often assumed that this arises solely from the feed-forward encoding of the strength or precision of sensory inputs. In contrast, interoceptive inference models suggest that confidence reflects a weighted integration of sensory precision and expectations about internal states, such as arousal. Here we test this hypothesis using a novel psychophysical paradigm, in which unseen disgust-cues induced unexpected, unconscious arousal just before participants discriminated motion signals of variable precision. Across measures of perceptual bias, uncertainty, and physiological arousal we found that arousing disgust cues modulated the encoding of sensory noise. Furthermore, the degree to which trial-by-trial pupil fluctuations encoded this nonlinear interaction correlated with trial level confidence. Our results suggest that unexpected arousal regulates perceptual precision, such that subjective confidence reflects the integration of both external sensory and internal, embodied states. PMID- 27776635 TI - Univariate analytical calibration methods and procedures. A review. AB - An original focus on univariate calibration as an experimental process of quantitative analysis is presented. A novel classification system is introduced against the background of the present situation concerning nomenclature of calibration methods. Namely, it has been revealed that four methods well-known in analytical chemistry: the conventional method, the internal standard method, the indirect method and the dilution method, can be split into those carried out in both the interpolative and the extrapolative mode. It is then shown that the basic procedures of all these methods can be modified including different approaches, such as matrix-matched technique, spiking the sample with a reactant, bracketing calibration, and others. For the first time (as compared to monographies dealing with univariate calibration) it is reviewed how the methods are mixed and integrated with one another thereby creating new calibration strategies of extended capabilities in terms of enhanced resistance to the interference and non-linear effects - as the main sources of systematic calibration errors. As additional novelty, rationally possible combinations of the calibration methods - not met hitherto in the literature - have been predicted. Finally, some general rules relating to calibration are formulated and the main calibration problems that still need to be solved are displayed. PMID- 27776636 TI - A novel quantitation method for phthalates in air using a combined thermal desorption/gas chromatography/mass spectrometry application. AB - In this study, a novel quantitation method was developed to facilitate the simple and effective sampling and analysis of phthalates in air based on a sorbent tube thermal desorption-gas chromatography-mass spectrometry system combination. The performance of the thermal desorption-based analysis was assessed using three different sorbent combinations [1]: quartz wool (QW) [2], glass wool (GW), and [3] quartz wool plus Tenax TA (QWTN) in terms of relative recovery in reference to a direct injection method. There was no significant difference in the average recovery rate for seven target phthalates based on sorbent tube type (QW, 70.2 +/ 4.28; GW, 73.2 +/- 8.8; and QWTN, 72.5 +/- 5.02%). However, the recovery rate of phthalates in each sorbent tube type was distingusihed by physicochemical properties of the target compound (e.g., molecular weight and boiling point). The recovery rate of the QW tube was high for dimethyl phthalate and diethyl phthalate compared to other sorbent tubes, while that of the GW tube exhibited greater values for dibutyl phthalate, benzyl butyl phthalate, di(2-ethylhexyl) adipate, di(2-ethylhexyl) phthalate, and di-n-octyl phthalate. The simple sorbent tube-thermal desorption approach is feasible for the quantitation of seven phthalates present at 0.45-24.5 ng m-3 levels in actual air samples (20 L). PMID- 27776637 TI - Untargeted screening of unknown xenobiotics and potential toxins in plasma of poisoned patients using high-resolution mass spectrometry: Generation of xenobiotic fingerprint using background subtraction. AB - A novel analytical workflow was developed and applied for the detection and identification of unknown xenobiotics in biological samples. High-resolution mass spectrometry (HRMS)-based data-independent MSE acquisition was employed to record full scan MS and fragment spectral datasets of test and control samples. Then, an untargeted data-mining technique, background subtraction, was utilized to find xenobiotics present only in test samples. Structural elucidation of the detected xenobiotics was accomplished by database search, spectral interpretation, and/or comparison with reference standards. Application of the workflow to analysis of unknown xenobiotics in plasma samples collected from four poisoned patients led to generation of xenobiotic profiles, which were regarded as xenobiotic fingerprints of the individual samples. Among 19 xenobiotics detected, 11 xenobiotics existed in a majority of the patients' plasma samples, thus were considered as potential toxins. The follow-up database search led to the tentative identification of azithromycin (X5), alpha-chaconine (X9) and penfluridol (X12). The identity of X12 was further confirmed with its reference standard. In addition, one xenobiotic component (Y5) was tentatively identified as a penfluridol metabolite. The remaining unidentified xenobiotics listed in the xenobiotic fingerprints can be further characterized or identified in retrospective analyses after their spectral data and/or reference compounds are available. This HRMS-based workflow may have broad applications in the detection and identification of unknown xenobiotics in individual biological samples, such as forensic and toxicological analysis and sport enhancement drug screening. PMID- 27776638 TI - Determination of 236U in environmental samples by single extraction chromatography coupled to triple-quadrupole inductively coupled plasma-mass spectrometry. AB - In order to measure trace 236U and 236U/238U in environmental samples with a high matrix effect, a novel and simple method was developed that makes the digestion and purification procedures compatible with advanced triple-quadrupole inductively coupled plasma-mass spectrometry. A total dissolution of sample with HF + HNO3 + HClO4 was followed by chromatographic separation with a single resin column containing normal type DGA resin (N,N,N',N'-tetra-n-octyldiglycolamide) as the extractant system. The analytical accuracy and precision of 236U/238U ratios, measured as 236U16O+/238U16O+, were examined by using the reference materials IAEA-135, IAEA-385, IAEA-447, and JSAC 0471. The low method detection limit (3.50 * 10-6 Bq kg-1) makes it possible to perform routine monitoring of environmental 236U due to global fallout combined with the Fukushima Daiichi Nuclear Power Plant accident fallout (>10-5 Bq kg-1). Finally, the developed method was successfully applied to measure 236U/238U ratios and 236U activities in soil samples contaminated by the accident. The low 236U/238U atom ratios ((1.50-13.5) * 10-8) and 236U activities ((2.25-14.1) * 10-2 mBq kg-1) indicate 236U contamination was mainly derived from global fallout in the examined samples. PMID- 27776639 TI - A simple, fast and low-cost turn-on fluorescence method for dopamine detection using in situ reaction. AB - A simple, fast and low-cost method for dopamine (DA) detection based on turn-on fluorescence using resorcinol is developed. The rapid reaction between resorcinol and DA allows the detection to be performed within 5 min, and the reaction product (azamonardine) with high quantum yield generates strong fluorescence signal for sensitive optical detection. The detection exhibits a high sensitivity to DA with a wide linear range of 10 nM-20 MUM and the limit of detection is estimated to be 1.8 nM (S/N = 3). This approach has been successfully applied to determine DA concentrations in human urine samples with satisfactory quantitative recovery of 97.84%-103.50%, which shows great potential in clinical diagnosis. PMID- 27776640 TI - A novel method for serum lipoprotein profiling using high performance capillary isotachophoresis. AB - A new capillary isotachophoresis (cITP) method for lipoprotein profiling with superior lipoprotein coverage compared to previous methods has been developed, resolving twice as many lipoprotein species (18 peaks/fractions) in serum or plasma in less than 9.5 min. For this, a novel mixture of 24 spacers, including amino acids, dipeptides and sulfonic acids, was developed and fine-tuned, using predictive software (PeakMaster) and testing of spiked serum samples. Lipoprotein peaks were identified by serum-spiking with reference lipoproteins. Compatibility with common lipophilic stains for selective lipoprotein detection with either UV/Vis or laser-induced fluorescence was demonstrated. A special new capillary with a neutral coating (combining water-compatible OV1701-OH deactivation and methylation) was used for the first time for electrodriven separations, allowing very stable separations in a pH 8.8-9.4 gradient system, being functional for more than 100 injections. Excellent reproducibility was achieved, with coefficients of variation lower than 2.6% for absolute migration times. Comparison was performed with human plasma samples analyzed by NMR, leading to similar results with cITP after multivariate statistics, regarding group clustering and lipoprotein species correlation. The new cITP method was applied to the analysis of serum samples from a LDL receptor knock-out mice model fed either a normal diet or a western-type diet. Differences in the lipoprotein levels and in the sublipoprotein types were detected, showing a shift to more atherogenic particles due to the high cholesterol diet. In summary, this novel method will allow more detailed and informative profiling of lipoprotein particle subtypes for cardiovascular disease research. PMID- 27776641 TI - Synthesis of novel chiral imidazolium stationary phases and their enantioseparation evaluation by high-performance liquid chromatography. AB - Two novel chiral stationary phases (CSPs) were prepared by bonding chiral imidazoliums on the surface of silica gel. The chiral imidazoles were derivatized from chiral amines, 1-phenylethylamine and 1-(1-naphthyl)ethylamine. The obtained CSPs were characterized by Fourier Transform Infrared (FT-IR) spectroscopy and elemental analysis (EA), demonstrating the bonding densities of CSP 1 and CSP 2 were 0.43 mmol g-1 and 0.40 mmol g-1, respectively. These two CSPs could be used to availably separate 8 pharmaceuticals, 7 mandelic acid/its derivatives, 2 1 phenylethylamine derivatives, 1 1,1'-bi-2-naphthol, and 1 camphorsulfonic acid in high-performance liquid chromatography (HPLC). It is found that CSP 1 could effectively enantioseparate most chiral analytes, especially the acidic components, while CSP 2 could enantiorecognize all chiral analytes, although a number of components did not achieve baseline separation. Additionally, the effects of mobile phase composition, mobile phase pH and salt content, chiral selector structures, and analyte structures on the enantiorecognitions of the two CSPs were investigated. It is found that high acetonitrile content in mobile phases was conducive to enantiorecognition. Mobile phase pH and salt content could alter the retention behaviors of different enantiomers of the same chiral compound, resulting in better enantioresolution. Moreover, both chiral selector structures and substituted groups of analytes played a significant role in the separation of chiral solutes. PMID- 27776642 TI - Type A aortic dissection: Are there CT signs suggestive of valvular involvement? AB - AIM: To identify the predictive signs of aortic valve involvement on the non electrocardiogram (ECG)-gated admission computed tomography (CT) of patients with Type A aortic dissection (AD) according to the Stanford classification. MATERIALS AND METHODS: We retrospectively analyzed the non-ECG-gated CT examinations of patients admitted to the emergency department who underwent surgery for Type A AD over a period of 4 years. The diameter of the following structures was calculated as the mean of the smallest and largest diameters (mm) measured in two different planes: aortic annulus, sinus of Valsalva, sinotubular junction, and proximal ascending aorta. These parameters were compared against operative reports in order to determine whether they were predictive of aortic valve involvement. RESULTS: In total, 20 patients (13 men and 7 women) of a mean age of 59.5 years (29-80) were included, 55% of patients (11/20) having surgically proven valvular involvement. The mean diameters (inmm) of the aortic annulus, sinus of Valsalva, sinotubular junction and proximal ascending aorta in the group with (and without, respectively) valvular involvement was 27.7 (26.7), 44.3 (38.1), 42.6 (36.6), and 47.8 (45.9). Only the measurement of the mean diameter of the sinuses of Valsalva was significantly predictive (p=0.02) of aortic valve involvement. CONCLUSION: Our findings suggest that measuring the diameter of the sinuses of Valsalva on non-ECG-gated admission CT examinations allows for predicting aortic valve involvement in Type A AD patients. PMID- 27776644 TI - Hybrid imaging for detection of carcinoma of unknown primary: A preliminary comparison trial of whole-body PET/MRI versus PET/CT. AB - PURPOSE: The aim of this study is to evaluate and compare the diagnostic potential of integrated whole-body [18F]FDG-PET/MRI to [18F]FDG-PET/CT for detection of a potential primary cancer and metastases in patients suspected for cancer of unknown primary (CUP). METHODS: A total of 20 patients (15 male, 5 female, age 53+/-13 years) suspect for CUP underwent a dedicated head and neck & whole-body [18F]FDG-PET/CT (Biograph mCT 128, Siemens Healthcare) and a subsequent simultaneous [18F]FDG-PET/MRI examination (Biograph mMR, Siemens Healthcare). Two readers rated the datasets (PET/CT; PET/MRI) regarding the detection of the primary cancer and metastases, lesion conspicuity (4-point ordinal scale) and diagnostic confidence (3-point ordinal scale). PET analysis comprised the assessment of maximum standardized uptake values (SUVmax) of all PET-positive lesions using volume of interest (VOI) analysis derived from the PET/CT and PET/MR datasets. All available data considering histology and imaging including prior and clinical follow-up examinations served as reference standard. Statistical analysis included comparison of mean values using Mann-Whitney U test and correlation of SUVmax using Pearson's correlation. RESULTS: In 14 out of 20 patients 49 malignant lesions were present. The primary cancer could be correctly identified in 11/20 patients with both PET/CT and PET/MRI. PET/CT enabled the detection of a total 38 metastases, PET/MR respectively of 37 metastases (one lung metastasis <5mm was missed). PET/CT and PET/MRI showed comparably high lesion conspicuity (2.6+/-0.6 each), with superior assessment of cervical lesions in PET/MRI and an indicated superior assessment of pulmonary lesions in PET/CT. Diagnostic confidence was rated comparably high in PET/CT and PET/MRI (2.7+/-0.5 each). The mean values of SUVmax of all PET-positive lesions (PET/MRT 7.9+/-4.2 vs. PET/CT 7.2+/-3.5) showed a strong positive correlation between the SUVs derived from both hybrid imaging systems (Pearson's correlation r=0.927). CONCLUSIONS: Both hybrid imaging techniques provide a comparable diagnostic ability for detection of primary cancer and metastases in patients with CUP, with comparably high lesion conspicuity and diagnostic confidence, offering superior assessment of cervical lesions in PET/MRI and potentially of pulmonary lesions in PET/CT. Furthermore, due to the significantly lower dose of ionizing radiation, PET/MRI may serve as a powerful alternative to PET/CT, particularly for therapy monitoring and/or surveillance considering the long-term cumulative dose. PMID- 27776643 TI - Clinical and CT characteristics of surgically resected lung adenocarcinomas harboring ALK rearrangements or EGFR mutations. AB - PURPOSE: To determine if clinical and CT characteristics of surgically resected lung adenocarcinomas can distinguish those harboring ALK rearrangements from EGFR mutations. MATERIALS AND METHODS: Patients who had surgical resection and histologically confirmed lung adenocarcinoma were enrolled, including 41 patients with ALK rearrangements and 66 patients with EGFR mutations. Eighteen categorical and six quantitative CT characteristics were used to evaluate the tumors. Differences in clinical and CT characteristics between the two groups were investigated. RESULTS: Age (P=0.003), histological subtypes (P<0.001), pathological stage (P=0.007), and five CT characteristics, including size (P<0.001), GGO (P=0.001), bubble-like lucency (P=0.048), lymphadenopathy (P=0.001), and tumor shadow disappearance rate (P=0.005) were significantly different between patients harboring ALK rearrangements compared to patients with EGFR mutations. When we compared histologic components, a solid pattern was more common (P=0.009) in tumors with ALK rearrangements, and lepidic and acinar patterns were more common (P<0.001 and P=0.040, respectively) in those with EGFR mutations. Backward elimination analyses revealed that age (OR=0.93; 95% CI 0.89 0.98), GGO (OR=0.14; 95% CI 0.03-0.67), and lymphadenopathy (OR=4.15; 95% CI 1.49 11.60) were significantly associated with ALK rearrangement status. CONCLUSION: Our analyses revealed that clinical and CT characteristics of lung adenocarcinomas harboring ALK rearrangements were significantly different, compared with those with EGFR mutations. These differences may be related to the molecular pathology of these diseases. PMID- 27776645 TI - Simultaneous multi-slice echo planar diffusion weighted imaging of the liver and the pancreas: Optimization of signal-to-noise ratio and acquisition time and application to intravoxel incoherent motion analysis. AB - PURPOSE: To optimize and test a diffusion-weighted imaging (DWI) echo-planar imaging (EPI) sequence with simultaneous multi-slice (SMS) excitation in the liver and pancreas regarding acquisition time (TA), number of slices, signal-to noise ratio (SNR), image quality (IQ), apparent diffusion coefficient (ADC) quantitation accuracy, and feasibility of intravoxel incoherent motion (IVIM) analysis. MATERIALS AND METHODS: Ten healthy volunteers underwent DWI of the upper abdomen at 3T. A SMS DWI sequence with CAIPIRINHA unaliasing technique (acceleration factors 2/3, denoted AF2/3) was compared to standard DWI-EPI (AF1). Four schemes were evaluated: (i) reducing TA, (ii) keeping TA identical with increasing number of averages, (iii) increasing number of slices with identical TA (iv) increasing number of b-values for IVIM. Acquisition schemes i-iii were evaluated qualitatively (reader score) and quantitatively (ADC values, SNR). RESULTS: In scheme (i) no differences in SNR were observed (p=0.321-0.038) with reduced TA (AF2 increase in SNR/time 75.6%, AF3 increase SNR/time 102.4%). No SNR improvement was obtained in scheme (ii). Increased SNR/time could be invested in acquisition of more and thinner slices or higher number of b-values. Image quality scores were stable for AF2 but decreased for AF3. Only for AF3, liver ADC values were systematically lower. CONCLUSION: SMS-DWI of the liver and pancreas provides substantially higher SNR/time, which either may be used for shorter scan time, higher slice resolution or IVIM measurements. PMID- 27776646 TI - Prediction of post-operative pulmonary function after lobectomy for primary lung cancer: A comparison among counting method, effective lobar volume, and lobar collapsibility using inspiratory/expiratory CT. AB - PURPOSE: To compare the predictabilities of postoperative pulmonary function after lobectomy for primary lung cancer among counting method, effective lobar volume, and lobar collapsibility. METHODS: Forty-nine patients who underwent lobectomy for primary lung cancer were enrolled. All patients underwent inspiratory/expiratory CT and pulmonary function tests 2 weeks before surgery and postoperative pulmonary function tests 6-7 months after surgery. Pulmonary function losses (DeltaFEV1.0 and DeltaVC) were calculated from the pulmonary function tests. Predictive postoperative pulmonary function losses (ppoDeltaFEV1.0 and ppoDeltaVC) were calculated using counting method, effective volume, and lobar collapsibility. Correlations and agreements between DeltaFEV1.0 and ppoFEV1.0 and those between DeltaVC and ppoDeltaVC were tested among three methods using Spearman's correlation coefficient and Bland-Altman plots. RESULTS: DeltaFEV1.0 and ppoDeltaFEV1.0insp-exp were strongly correlated (r=0.72), whereas DeltaFEV1.0 and ppoDeltaFEV1.0count and DeltaFEV1.0 and Pred. DeltaFEV1.0eff.vol. were moderately correlated (r=0.50, 0.56). DeltaVC and ppoDeltaVCeff.vol. (r=0.71) were strongly correlated, whereas DeltaVC and ppoDeltaVCcount, and DeltaVC and ppoDeltaVC insp-exp were moderately correlated (r=0.55, 0.42). CONCLUSIONS: Volumetry from inspiratory/expiratory CT data could be useful to predict postoperative pulmonary function after lobectomy for primary lung cancer. PMID- 27776647 TI - Proportion of false-positive lesions at interim and end-of-treatment FDG-PET in lymphoma as determined by histology: Systematic review and meta-analysis. AB - PURPOSE: To systematically review and meta-analyze the proportion of false positive lesions at interim and end-of-treatment 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in lymphoma using biopsy as reference standard. MATERIALS AND METHODS: Medline was searched for original studies. Methodological quality of included studies was evaluated, and results were meta analytically summarized using random effects (in case of interstudy heterogeneity [I2<=50%]) or fixed effects (in case of no interstudy heterogeneity [I2>50%]). RESULTS: Eleven studies, comprising 139 patients who underwent biopsy of an FDG avid lesion during or after completion of antilymphoma treatment, were included. Overall methodological quality was moderate. The proportion of false-positive results among all biopsied FDG-avid lesions at PET performed during of after completion of treatment ranged between 7.7% and 90.5% (the vast majority was due to inflammatory changes), with a weighted summary proportion (random effects, I2=75.7%) of 55.7% (95% confidence interval [CI]: 32.6-76.6%). There were no available studies on interim FDG-PET in Hodgkin lymphoma. The pooled summary false-positive proportions were 83.0% (95% CI: 72.0%-90.2%) for interim FDG-PET in non-Hodgkin lymphoma (fixed effects, I2=27.7%), 23.1% (95% CI: 4.7%-64.5%) for end-of-treatment FDG-PET in Hodgkin lymphoma (random effects; I2=67.1%), and 31.5% (95% CI: 3.9%-83.9%) for end-of-treatment FDG-PET in non-Hodgkin lymphoma (random effects, I2=68.3%). CONCLUSION: Both interim and end-of-treatment FDG-PET scans in patients with lymphoma suffer from a very high number of false-positive FDG-avid lesions. This finding, in combination with the previously reported high number of false-negative FGD-PET scans for residual disease detection, suggests that the role of interim and end-of-treatment FDG-PET should be reconsidered. PMID- 27776648 TI - Comparison of image quality and visibility of normal and abnormal findings at submillisievert chest CT using filtered back projection, iterative model reconstruction (IMR) and iDose4TM. AB - OBJECTIVE: To compare both image quality and visibility of normal and abnormal findings at submillisievert chest CT (smSv-CT) using filtered back projection (FBP) and the two different iterative reconstruction (IR) techniques iterative model reconstruction (IMR) and iDose4TM. MATERIALS AND METHODS: This institutional review board approved study was based on retrospective interpretation of clinically indicated acquired data. The requirement to obtain informed consent was waived. 81 patients with suspected pneumonia underwent smSv CT (Brilliance iCT, Philips Healthcare; mean effective dose: 0.86+/-0.2mSv). Data were reconstructed using FBP and two different IR techniques iDose4TM and IMR (Philips Healthcare) at various iteration levels. Objective image noise (OIN) was measured. Two experienced readers independently assessed all images for image noise, image appearance and visibility of normal anatomic and abnormal findings. A random intercept model was used for statistical analysis. RESULTS: Compared to FBP and iDose4TM, IMR reduced OIN up to 88% and 72%, respectively (p<0.001). A mild blotchy image appearance was seen in IMR images, affecting diagnostic confidence. iDose4TM images provided satisfactory to good image quality for visibility of normal and abnormal findings and were superior to FBP (p<0.001). IMR images were significantly inferior for visibility of normal structures compared to iDose4TM, while being superior for visibility of abnormal findings except for reticular pattern (p<0.001). CONCLUSION: IMR results for visibility of normal and abnormal lung findings are heterogeneous, indicating that IMR may not represent a priority technique for clinical routine. iDose4TM represents a suitable method for evaluation of lung tissue at submillisievert chest CT. PMID- 27776649 TI - Differentiation grade for extrahepatic bile duct adenocarcinoma: Assessed by diffusion-weighted imaging at 3.0-T MR. AB - PURPOSE-: To assess the pathological differentiation grade in the patients with extrahepatic bile duct adenocarcinoma (EBDA) using diffusion-weighted imaging (DWI) at 3.0-T MR. METHODS-: Sixty-eight patients who were clinically and histologically diagnosed with EBDA underwent abdominal DWI within 2 weeks before surgery. The lesion signal intensity, signal intensity ratio of the lesion and hepar (SIR-LH) value, and apparent diffusion coefficient (ADC) value in patients with EBDA were retrospectively analysed. RESULTS: -In the 68 patients, 22 well differentiated, 36 moderately-differentiated, and 10 poorly-differentiated EBDAs were histopathological confirmed. These EBDAs exhibited hyper-intensity on DWI in 95.59% of patients. Hyper-intensity lesions were found in 90.91% of patients with good-differentiation, in 97.22% with moderate-differentiation and in 100% with poor-differentiation. There showed no statistical difference for the lesion signal intensity (P=0.426) and SIR-LH value (P=0.766) on DWI among three groups. The median ADC value of the well-differentiated, moderately-differentiated and poorly-differentiated EBDAs were 1.506*10-3mm2/s, 1.275*10-3mm2/s and 1.154*10 3mm2/s, respectively. As the pathological differentiation grade decreased, the lesion ADC value of EBDA gradually declined (x2=51.220, P=0.000). The ADC value <1.184*10-3mm2/s can predict the poorly-differentiated EBDA with a sensitivity of 100% and a specificity of 94.83%. The ADC value >1.316*10-3mm2/s can forecast the well-differentiated EBDA with a sensitivity of 100% and a specificity of 84.78%. CONCLUSIONS-: The histopathological differentiation grade of EBDA can be detected non-invasively using DWI at 3.0-T MR. PMID- 27776650 TI - Assessment of glioma response to radiotherapy using 3D pulsed-continuous arterial spin labeling and 3D segmented volume. AB - BACKGROUND: Gliomas are the most common primary brain tumors in adults, in some cases, radiotherapy may be the preferred treatment option especially for elderly people who cannot endure surgery. Therefore, it is necessary to evaluate the effects of radiotherapy on glioma. Arterial spin labeling (ASL) is an MR imaging technique that allows for a quantitative determination of cerebral blood flow (CBF) noninvasively. Tumor volume is still an important determinant for evaluating treatment response. The purpose of this study was to investigate the relationship between the tumor perfusion parameters and tumor volume and assess the effects of radiotherapy on glioma using pulsed-continuous arterial spin labeling (pcASL) technique. METHODS: 35 patients with gliomas, histologically classified as low-grade group (n=16) and high-grade group (n=19), treated with radiotherapy only or before using other therapies were included in this study. MR examinations, including T1 weighted image and pcASL, were performed before and 4, 8, 12, 16 weeks after radiotherapy. Regional CBF of normal tissue, mean tumor blood flow (TBFmean), maximum tumor blood flow (TBFmax), and tumor volume were evaluated at each time point. Both the percentage change in CBF (CBF ratio), TBFmean (TBFmean ratio), TBFmax (TBFmax ratio) and the percentage change in tumor volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and CBF ratio, TBFmean ratio, TBFmax ratio was assessed using linear regression analysis and Pearson's correlation. RESULTS: The TBFmean and TBFmax of high-grade gliomas were significantly higher than that of low-grade group. In high-grade group, a strong correlation was demonstrated between the tumor volume and the TBFmax before radiotherapy (R2=0.35, rs=0.59, p<0.05). There was also a significant correlation between the TBFmax before radiotherapy and the tumor volume ratio before and 8 weeks after radiotherapy (R2=0.56, rs=-0.74, p<0.05). CONCLUSION: The TBFmax measured using pcASL could assess tumoral grade and also could become a potential tool for evaluating the therapeutic effects of radiation. PMID- 27776651 TI - Double contrast-enhanced ultrasonography in the detection of periampullary cancer: Comparison with B-mode ultrasonography and MR imaging. AB - PURPOSE: To investigate the value of double contrast-enhanced ultrasonography (DCEUS) in the detection of periampullary cancer. MATERIALS AND METHODS: Ninety nine patients with surgery or biopsy-proven periampullary cancer who underwent both DCEUS and magnetic resonance imaging (MRI) examinations before operation were enrolled in our study. DCEUS in which intravenous microbubbles were used in combination with oral contrast agent and MRI were performed preoperatively to make a detection diagnosis of periampullary cancer. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of DCEUS, B-mode ultrasonography (BUS) and MRI were calculated and compared. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy of BUS, DCEUS and MRI in the detection. Stratified analyses were performed for different pathological types and different sizes of periampullary lesions. The inter- and intra-observer reliability of DCEUS for cancer detection was also investigated. RESULT: There were no significant differences in sensitivity, specificity, PPV, NPV or accuracy between DCEUS and MRI (all P>0.05). ROC analysis showed that the accuracy of DCEUS or MRI was higher than that of BUS (P<0.001), while no significant differences were noted in the accuracy between DCEUS and MR. In the 76 cases of periampullary cancer, DCEUS appeared to be superior to BUS for ampullary carcinoma, duodenum carcinoma and for lesions with an average diameter of less than 3cm. DCEUS appeared equal to BUS in other groups. No significant differences were noted between DCEUS and MRI in the stratified analysis. A considerably well agreement between DCEUS and MRI was obtained using Kappa analysis (k=0.649, P<0.001). The intra- and inter-observer reproducibility were both good for detection of periampullary cancer by DCEUS, with a Kappa values of 0.783 (P<0.01) and 0.732 (P<0.01), respectively. CONCLUSION: DCEUS provides an available and useful imaging modality in the detection of periampullary cancer. This technique can aid in displaying the invisible periampullary region in BUS and may also become an effective supplemental method to MRI. PMID- 27776652 TI - Biliary tract enhancement in gadoxetic acid-enhanced MRI correlates with liver function biomarkers. AB - PURPOSE: To evaluate the association between gadoxetic-acid-enhanced magnetic resonance (MR) imaging measurements and laboratory and clinical biomarkers of liver function and fibrosis. MATERIALS AND METHODS: One hundred thirty nine consecutive patients with suspected liver disease or liver tumor underwent gadoxetic-acid-enhanced MR imaging. MR imaging measurements during the hepatobiliary phase included biliary tract structure-to-muscle signal intensity ratio (SIR). These measurements were compared with Child-Pugh classification, end stage liver disease (MELD) score, and aspartate aminotransferase-to-platelet ratio index (APRI). RESULTS: The SIRs of cystic duct and common bile duct were significantly correlated with Child-Pugh classification (P=0.012 for cystic duct and P<0.0001 for common bile duct), MELD score (P=0.0016 and P=0.0033), and APRI (P=0.0022 and P=0.0015). The sensitivity, specificity, and area under the receiver-operating-characteristic curve were: (74%, 88%, 0.86) with the SIR of common bile duct for the detection of patients with Child-Pugh class B or C; (100%, 87%, 0.94) with the SIR of cystic duct for MELD score (>10); (65%, 76%, 0.70) with the SIR of common bile duct for APRI (>1.5). CONCLUSION: Gadoxetic acid contrast enhancement of cystic duct and common bile duct could be used as biomarkers to assess liver function. PMID- 27776653 TI - Follow-up of CT-derived airway wall thickness: Correcting for changes in inspiration level improves reliability. AB - OBJECTIVES: Airway wall thickness (AWT) is affected by changes in lung volume. This study evaluated whether correcting AWT on computed tomography (CT) for differences in inspiration level improves measurement agreement, reliability, and power to detect changes over time. METHODS: Participants of the Dutch-Belgian lung cancer screening trial who underwent 3-month repeat CT for an indeterminate pulmonary nodule were included. AWT on CT was calculated by the square root of the wall area at a theoretical airway with an internal perimeter of 10mm (Pi10). The scan with the highest lung volume was labelled as the reference scan and the scan with the lowest lung volume was labelled as the comparison scan. Pi10 derived from the comparison scan was corrected by multiplying it with the ratio of CT lung volume of the comparison scan to CT lung volume on the reference scan. Agreement of uncorrected and corrected Pi10 was studied with the Bland-Altman method, reliability with intra-class correlation coefficients (ICC), and power to detect changes over time was calculated. RESULTS: 315 male participants were included. Limit of agreement and reliability for Pi10 was -0.61 to 0.57mm (ICC=0.87), which improved to -0.38 to 0.37mm (ICC=0.94) after correction for inspiration level. To detect a 15% change over 3 months, 71 subjects are needed for Pi10 and 26 subjects for Pi10 adjusted for inspiration level. CONCLUSIONS: Correcting Pi10 for differences in inspiration level improves reliability, agreement, and power to detect changes over time. PMID- 27776654 TI - MDCT of acute pancreatitis: Intraindividual comparison of single-phase versus dual-phase MDCT for initial assessment of acute pancreatitis using different CT scoring systems. AB - OBJECTIVES: The purpose of the retrospective study was to evaluate the additional value of dual-phase multidetector computed tomography (MDCT) protocols over a single-phase protocol on initial MDCT in patients with acute pancreatitis using three CT-based pancreatitis severity scores with regard to radiation dose. METHODS: In this retrospective, IRB approved study MDCT was performed in 102 consecutive patients (73 males; 55years, IQR48-64) with acute pancreatitis. Inclusion criteria were CT findings of interstitial edematous pancreatitis (IP) or necrotizing pancreatitis (NP) and a contrast-enhanced dual-phase (arterial phase and portal-venous phase) abdominal CT performed at >=72h after onset of symptoms. The severity of pancreatic and extrapancreatic changes was independently assessed by 2 observers using 3 validated CT-based scoring systems (CTSI, mCTSI, EPIC). All scores were applied to arterial phase and portal venous phase scans and compared to score results of portal venous phase scans, assessed >=14days after initial evaluation. For effective dose estimation, volume CT dose index (CTDIvol) and dose length product (DLP) were recorded in all examinations. RESULTS: In neither of the CT severity scores a significant difference was observed after application of a dual-phase protocol compared with a single-phase protocol (IP: CTSI: 2.7 vs. 2.5, p=0.25; mCTSI: 4.0 vs. 4.0, p=0.10; EPIC: 2.0 vs. 2.0, p=0.41; NP: CTSI: 8.0 vs. 7.0, p=0.64; mCTSI: 8.0 vs. 8.0, p=0.10; EPIC: 3.0 vs. 3.0, p=0.06). The application of a single-phase CT protocol was associated with a median effective dose reduction of 36% (mean dose reduction 31%) compared to a dual-phase CT scan. CONCLUSIONS: An initial dual-phase abdominal CT after >=72h after onset of symptoms of acute pancreatitis was not superior to a single-phase protocol for evaluation of the severity of pancreatic and extrapancreatic changes. However, the effective radiation dose may be reduced by 36% using a single-phase protocol. PMID- 27776655 TI - Abnormal resting-state functional connectivity study in unilateral pulsatile tinnitus patients with single etiology: A seed-based functional connectivity study. AB - OBJECTIVE: Previous studies demonstrated altered regional neural activations in several brain areas in patients with pulsatile tinnitus (PT), especially indicating an important role of posterior cingulate cortex (PCC). However, few studies focused on the degree of functional connectivity (FC) of this area in PT patients. In this study, we will compare the FC of PCC in patients affected with this condition and normal controls by using resting-state functional magnetic resonance imaging (fMRI). METHODS: Structural and functional MRI data were obtained from 36 unilateral PT patients with single etiology and 36 matched healthy controls. FC feature of the region of interest (PCC) were characterized using a seed-based correlation method with the voxels in the whole-brain. RESULTS: Compared with healthy controls, patients showed significant decreased FC to the right middle temporal gyrus (MTG), right thalamus and bilateral insula. By contrast, PCC demonstrated increased functional connectivity between the precuneus, bilateral inferior parietal lobule and middle occipital gyrus. We also found correlations between the disease duration of PT and FC of PCC-right MTG (r= 0.616, p<0.001). CONCLUSIONS: Unilateral PT patients could have abnormal FC to the PCC bilaterally in the brain. PCC, as a highly integrated brain area, is an example of nucleus that was involved in mediation between different neural networks. It might be a modulation core between visual network and auditory network. The decreased FC of MTG to PCC may indicate a down regulation of activity between PCC and auditory associated brain cortex. Decreased FC between limbic system (bilateral AI) and PCC may reflect the emotional message control in patient group. This study facilitated understanding of the underlying neuropathological process in patients with pulsatile tinnitus. PMID- 27776656 TI - Characterization of atherosclerotic disease in thoracic aorta: A 3D, multicontrast vessel wall imaging study. AB - PURPOSE: To investigate the characteristics of plaque in the thoracic aorta using three dimensional multicontrast magnetic resonance imaging. MATERIALS AND METHODS: Elderly subjects (>=60years) were recruited in this study. Thoracic aorta was imaged on a 3.0T MR scanner by acquiring multicontrast sequences. The plaque burden was evaluated by measuring lumen area, wall area, wall thickness, and normalized wall index. The presence or absence of plaque and intraplaque hemorrhage (IPH)/mural thrombus (MT) were identified. The characteristics of atherosclerosis among different thoracic aorta segments (AAO: ascending aorta; AOA: aortic arch, and DOA: descending aorta) were determined. RESULTS: Of 66 recruited subjects (mean age 72.3+/-6.2years, 30 males), 55 (83.3%) had plaques in the thoracic aorta. The prevalence of plaque in AAO, AOA, and DAO was 5.4%, 72.7%, and 71.2%, respectively. In addition, 21.2% of subjects were found to have lesions with IPH/MT in the thoracic aorta. The prevalence of IPH/MT in segment of AAO, AOA and DAO was 0%, 13.6%, and 12.1%, respectively. The aortic wall showed the highest NWI in DAO (34.1%+/-4.8%), followed by AOA (31.2%+/-5%), and AAO (26.8%+/-3.3%) (p<0.001). CONCLUSION: Three dimensional multicontrast MR imaging is capable of characterizing atherosclerotic plaques in the thoracic aorta. The findings of high prevalence of plaques and the presence of high risk plaques in the thoracic aorta suggest early screening for aortic vulnerable lesions in the elderly. PMID- 27776658 TI - Replacing single-view mediolateral oblique (MLO) digital mammography (DM) with synthesized mammography (SM) with digital breast tomosynthesis (DBT) images: Comparison of the diagnostic performance and radiation dose with two-view DM with or without MLO-DBT. AB - OBJECTIVES: To evaluate the diagnostic performance and radiation dose of single view cranio-caudal (CC) digital mammography (DM) plus mediolateral oblique (MLO) digital breast tomosynthesis (DBT) combined with synthesized mammography (SM) in comparison with two-view DM with or without DBT. MATERIAL AND METHODS: This study was approved by our institutional review board, and informed consent was obtained from 130 women. Paired two-view DM and single MLO-DBT with SM images were acquired, and four independent retrospective reading sessions of different combinations of DM, SM and DBT were performed for the presence of malignant tumors using jackknife alternative free-response receiver operator curve (JAFROC) methods. The diagnostic performances and average glandular dose (AGD) were compared between different combinations of DM, SM and DBT. RESULTS: Of 159 lesions in 130 patients, 27 were malignant. When using MLO-DBT with SM instead of MLO-DM, a significantly higher sensitivity (P=0.016) and specificity (P=0.012) were noted than with two-view DM, and comparable figure of merit (FOM), sensitivity, and specificity to two-view DM with DBT were noted. The mean AGD of CC-DM plus MLO-DBT with SM was 5.78mGy+/-1.06 per patient, which was significantly lower than that with two-view DM with MLO-DBT (8.45mGy+/-1.32; P <0.001) and slightly higher than that with two-view DM (5.30mGy+/-0.63). CONCLUSIONS: The combined use of CC-DM plus MLO-DBT with SM showed higher sensitivity and specificity to two-view DM with a smaller AGD increment and comparable diagnostic performance to that of two-view DM with MLO-DBT with a significantly lower mean AGD. PMID- 27776657 TI - VEGFR-2 expression in HCC, dysplastic and regenerative liver nodules, and correlation with pre-biopsy Dynamic Contrast Enhanced CT. AB - PURPOSE: To evaluate whether VEGFR-2-expression in hepatocellular carcinoma (HCC), dysplastic (DLN) and regenerative liver nodules (RLN) correlates with pre histology, in vivo Dynamic Contrast Enhanced-Computed Tomography (DCE-CT) data as VEGFR-2-expression affects prognosis and therapeutic options. MATERIALS AND METHODS: 34 patients (63.6+/-8.9years, 7 females) underwent liver biopsy or surgery due to suspected HCC or dysplastic nodules after DCE-CT between 2009 and 2015 with no previous chemo- or interventional therapy. Immunohistochemistry staining for VEGFR-2 was performed using Immunoreactive-Remmele-Stegner-Score (IRS) for quantification. A 128-row CT-scanner was used for DCE-CT with assessment of perfusion parameters blood flow (BF), blood volume (BV), arterial liver perfusion (ALP), portal venous perfusion (PVP), and hepatic perfusion index (HPI). RESULTS: Histology confirmed HCC (n=10), DLN (n=7) and RLN (n=34). Mean IRS for VEGFR-2 in HCCs was 9.1+/-3.0, 7.3+/-1.6 for DLN and 5.2+/-2.8 for RLN (p=0.0004 for HCC vs. RLN). Perfusion values varied significantly between all three groups for BF and HPI (p<0.001 and p<0.0001) and for BV in HCC vs. RLN (p<0.0001) and DLN vs. RLN (p=0.0019). Strong correlations between VEGFR-2-IRS and perfusion parameters were observed for BF in HCC (r=0.88, p<0.01) and HPI in HCC and DLN (r=0.85, p<0.04; r=0.9, p<0.01). CONCLUSION: Immunostaining revealed different VEGFR-2-expression levels in HCC, dysplastic and regenerative liver nodules. Perfusion markers blood flow, blood volume and hepatic perfusion index correlated well with VEGFR-2-immunostaining. This non-invasive discrimination between regenerative and dysplastic/HCC nodules might open new perspectives for diagnosis, therapy planning, and anti-VEGFR therapy monitoring. PMID- 27776659 TI - CT pulmonary angiography of adult pulmonary vascular diseases: Technical considerations and interpretive pitfalls. AB - Computed tomography pulmonary angiography (CTPA) has become the primary imaging modality for evaluating the pulmonary arteries. Although pulmonary embolism is the primary indication for CTPA, various pulmonary vascular abnormalities can be detected in adults. Knowledge of these disease entities and understanding technical pitfalls that can occur when performing CTPA are essential to enable accurate diagnosis and allow timely management. This review will cover a spectrum of acquired abnormalities including pulmonary embolism due to thrombus and foreign bodies, primary and metastatic tumor involving the pulmonary arteries, pulmonary hypertension, as well as pulmonary artery aneurysms and stenoses. Additionally, methods to overcome technical pitfalls and interventional treatment options will be addressed. PMID- 27776660 TI - MRI of ovarian torsion: Correlation of imaging features with the presence of perifollicular hemorrhage and ovarian viability. AB - PURPOSE: The purpose of our study is to test for: (a) correlation between the presence of a perifollicular T2-hypointense rim on MRI with the presence of perifollicular hemorrhage on histology; and (b) correlation between this finding and diminished ovarian viability after intra-operative detorsion. METHODS AND MATERIALS: Our IRB-approved, retrospective study evaluated 780 patients between August 2012 and February 2016 with ovarian torsion as a diagnostic consideration on the emergency department note. Patients were included if they had preoperative MRI and intraoperatively confirmed case of ovarian torsion. MRIs were retrospectively reviewed for presence of perifollicular T2 hypointense rim in the torsed ovary. Two arms of analysis were performed: (a) assessment of perifollicular hemorrhage on histological exam; and (b) assessment of ovarian viability after intra-operative detorsion. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI for predicting ovarian viability in the setting of torsion was performed. kappa test assessed level of agreement between readers. RESULTS: 24 patients included in one of the two arms; 20 in viability analysis and 12 in perifollicular hemorrhage analysis (8 in both). The presence of T2-hypointense rim on MRI demonstrated 88.9% sensitivity and 66.7% specificity for the diagnosis of perifollicular hemorrhage on histology, and 91.7% sensitivity and 100% specificity for predicting intraoperative viability. CONCLUSION: The presence of a perifollicular T2 hypointense rim on MRI in the setting of ovarian torsion correlates with perifollicular hemorrhage on histopathologic exam, and may also be a useful predictor of ovarian viability in patients presenting with ovarian torsion. PMID- 27776661 TI - Non-palpable incidentally found testicular tumors: Differentiation between benign, malignant, and burned-out tumors using dynamic contrast-enhanced MRI. AB - PURPOSE: To evaluate qualitative, semi-quantitative, and quantitative parameters obtained by dynamic contrast-enhanced (DCE)-MRI for the characterization of histologically proven, non-palpable, incidentally found intratesticular tumors. MATERIALS AND METHODS: From 2006 to 2014, we included men with non-palpable, incidentally found testicular tumors on ultrasound, normal tumoral marker levels,referred for surgery. DCE-MRI data were analyzed retrospectively and independently by two radiologists blinded to the histological diagnosis. The visual enhancement patterns, time-signal intensity curves, shape of the curves (type 0-3), maximal relative enhancement (Peak), initial enhancement slope (IS), time to peak (TTP), as well as transfer constants Ktrans and Kep were compared between the tumors. The interobserver correlation was evaluated. Receiver Operating Characteristic (ROC) curves and areas under the curve (AUC) were extracted. RESULTS: Thirty-one patients (mean age of 37.3 years) were included. Tumor mean size was 1.2+/-0.77 cm (min=0.3cm, max=2.8cm). Regarding the histology results, three groups were defined: Twelve stromal "benign tumors" (BT) exhibited more type 2 and type 3 curves than 12 "malignant tumors" (MT) and 7 "burned-out tumors" (BOT) (p<0.0001). BT had a higher peak (96 vs. 54 and 17%), shorter TTP (215 vs. 412 and 692 sec), higher IS (73 vs. 12 and 2 arbitrary units), higher Ktrans (255 vs. 88 and 14min-1*1000) and higher Kep (554 vs. 159 and 48min 1*1000) than MT and BOT, respectively (p<0.0001, p=0.0003, p<0.0001, p<0.0001 and p<0.0001, respectively). The agreement coefficient values and the AUC extracted after gathering MT with BOT varied from 0.83 to 0.96 and from 0.868 to 0.978, respectively. CONCLUSION: DCE-MRI may assist in differentiating between benign intratesticular stromal tumors,malignant and burned-out tumors. PMID- 27776662 TI - Microwave treatment of renal cell carcinoma adjacent to renal sinus. AB - PURPOSE: To evaluate the efficacy and safety of ultrasound (US)-guided percutaneous microwave ablation (MWA) for renal cell carcinoma (RCC) adjacent to renal sinus. MATERIALS AND METHODS: This retrospective study included 41 patients who underwent US-guided percutaneous MWA of 41 RCCs adjacent to the renal sinus from April 2006 to December 2015. Contrast-enhanced images of US and computed tomography (CT) or magnetic resonance (MR) imaging were performed at pre-ablation and 1day, 1 month, 3 months, and every 6 months after ablation. Initial ablation success (IAS), disease-free survival (DFS), RCC-related survival (RRS), and overall survival (OS) were recorded at the follow-up visits. RESULTS: IAS was achieved in 92.7% (38/41) of the study subjects. The IAS significantly differed between patients with RCCs <=4cm (100%, 29/29) and RCCs >4cm (75%, 9/12, p=0.021). During the median follow-up of 37.6 (range, 3.0-97.3) months, the estimated 1-, 3-, and 5-year DFS of patients with an initial tumor of <=4cm were 100%, 89.7%, and 81.5%, respectively. The 1-, 3-, and 5-year RRS were 100%, 93.3%, and 93.3%, respectively. The 1-, 3-, and 5-year OS were 97.1%, 87.8%, and 83.6%, respectively. The multivariate analysis using the Cox proportional hazard model revealed no independent predictor of recurrence among all the variables. There were no MWA-related deaths among the study subjects. One patient developed a retroperitoneal abscess after ablation. CONCLUSION: US-guided percutaneous MWA appears to be a promising method for RCCs adjacent to renal sinus, especially for tumors <=4cm. PMID- 27776663 TI - Superb microvascular imaging technology for ultrasound examinations: Initial experiences for hepatic tumors. AB - PURPOSE: To explore whether superb microvascular imaging (SMI) technology could be helpful for the evaluation of hepatic tumors. MATERIALS AND METHODS: Our institutional review board approved this study, and informed consent was obtained from all of the patients. Twenty-three patients with 29 hepatic tumors were enrolled in our study. The tumors consisted of hemangiomas (n=15), focal nodular hyperplasias (FNHs) (n=7), and hepatocellular carcinomas (n=7). All lesions were pathologically (n=2) or radiologically (n=27) confirmed. The mean tumor diameter was 1.9cm (range, 0.9cm to 5.0cm). Using SMI technology, all lesions were scanned and categorized into subgroups according to the flow pattern on the SMI. RESULTS: The hemangiomas exhibited nodular rim patterns (33%) and spotty dot-like patterns (20%), and both of these findings were very specific for the diagnosis of hemangioma. The FNHs exhibited spoke-wheel patterns (43%) and radiating vessel patterns (29%) that were very specific findings for the diagnosis of FNH. The other tumors did not exhibit any specific patterns on SMI. CONCLUSION: Evaluations of the inner vascularities of hepatic tumors with the SMI technique were feasible, and the SMI features were significantly different between the different types of hepatic tumors. These differences could aid the diagnoses of hepatic tumors with US. PMID- 27776664 TI - Subchondral insufficiency fracture of the knee: A recognizable associated soft tissue edema pattern and a similar distribution among men and women. AB - OBJECTIVE: Primary: to describe the presence and pattern of soft tissue edema in subchondral insufficiency fractures of the knee (SIFK). Secondary: to investigate the gender distribution and identify factors associated with disease progression. METHODS: MR images of 74 SIFKs in 74 patients were retrospectively reviewed for soft tissue edema presence and location, meniscal tears and extrusion and synovitis. The clinical records were reviewed for age, gender, and BMI. Follow up examinations were reviewed to assess for progression. Data were analyzed for gender distribution and for association between each imaging finding as a predictor of SIFK location and progression. RESULTS: Soft tissue edema was present in 89% (66/74) of SIFK. It was located around the MCL in 78% (58/74), posterior to and abutting on the posterior distal femur in 68% (50/74), around to the tibia in only 18% (13/74), but when present it strongly predicted the presence of a medial tibial plateau SIFK (p=5.6*10^-12). Edema extended to the vastus medialis fascia in 51% (38/74) and vastus lateralis fascia in 24% (18/74). Gender distribution was 1:1 (males=38, females=36), most common in the 6th decade (29/74, 39%). Lesion progression showed a trend towards being more common in females (8/9, 89%) compared to males (9/16, 56%), and in patients with meniscal extrusion (>=3mm) (13/14, 93%) compared to those with no extrusion (2/7, 29%). CONCLUSION: A recognizable soft tissue edema pattern is seen in SIFK and may have an important role in early diagnosis. Also, SIFK may affect equally males and females in the 6th decade and may progress more in females. Meniscal extrusion may predispose to disease progression. PMID- 27776665 TI - Image quality of mean temporal arterial and mean temporal portal venous phase images calculated from low dose dynamic volume perfusion CT datasets in patients with hepatocellular carcinoma and pancreatic cancer. AB - PURPOSE: Dynamic volume perfusion CT (dVPCT) provides valuable information on tissue perfusion in patients with hepatocellular carcinoma (HCC) and pancreatic cancer. However, currently dVPCT is often performed in addition to conventional CT acquisitions due to the limited morphologic image quality of dose optimized dVPCT protocols. The aim of this study was to prospectively compare objective and subjective image quality, lesion detectability and radiation dose between mean temporal arterial (mTA) and mean temporal portal venous (mTPV) images calculated from low dose dynamic volume perfusion CT (dVPCT) datasets with linearly blended 120-kVp arterial and portal venous datasets in patients with HCC and pancreatic cancer. MATERIALS AND METHODS: All patients gave written informed consent for this institutional review board-approved HIPAA compliant study. 27 consecutive patients (18 men, 9 women, mean age, 69.1 years+/-9.4) with histologically proven HCC or suspected pancreatic cancer were prospectively enrolled. The study CT protocol included a dVPCT protocol performed with 70 or 80kVp tube voltage (18 spiral acquisitions, 71.2s total acquisition times) and standard dual-energy (90/150kVpSn) arterial and portal venous acquisition performed 25min after the dVPCT. The mTA and mTPV images were manually reconstructed from the 3 to 5 best visually selected single arterial and 3 to 5 best single portal venous phases dVPCT dataset. The linearly blended 120-kVp images were calculated from dual energy CT (DECT) raw data. Image noise, SNR, and CNR of the liver, abdominal aorta (AA) and main portal vein (PV) were compared between the mTA/mTPV and the linearly blended 120-kVp dual-energy arterial and portal venous datasets, respectively. Subjective image quality was evaluated by two radiologists regarding subjective image noise, sharpness and overall diagnostic image quality using a 5-point Likert Scale. In addition, liver lesion detectability was performed for each liver segment by the two radiologists using the linearly blended120-kVp arterial and portal venous datasets as the reference standard. RESULTS: Image noise, SNR and CNR values of the mTA and mTPV were significantly higher when compared to the corresponding linearly blended arterial and portal venous 120-kVp datasets (all p<0.001) except for image noise within the PV in the portal venous phases (p=0.136). OBJECTIVE: image quality of mTA and mTPV were rated significantly better when compared to the linearly blended 120-kVp arterial and portal venous datasets. Both readers were able to detect all liver lesions found on the linearly blended 120-kVp arterial and portal venous datasets using the mTA and mTPV datasets. The effective radiation dose of the dVPCT was 27.6mSv for the 80kVp protocol and 14.5mSv for the 70kVp protocol. The mean effective radiation dose for the linearly blended 120-kVp arterial and portal venous CT protocol together of the upper abdomen was 5.60mSv+/-1.48mSv. CONCLUSION: Our preliminary data suggest that subjective and objective image quality of mTA and mTPV datasets calculated from low-kVp dVPCT datasets is non-inferior when compared to linearly blended 120-kVp arterial and portal venous acquisitions in patients with HCC and pancreatic cancer. Thus, dVPCT could be used as a stand alone imaging technique without additionally performed conventional arterial and portal venous CT acquisitions. PMID- 27776667 TI - Dynamic contrast-enhanced case-control analysis in 3T MRI of prostate cancer can help to characterize tumor aggressiveness. AB - PURPOSE: The aim of this work is to establish normality and tumor tissue ranges for perfusion parameters from dynamic contrast-enhanced (DCE) MR of the peripheral prostate at 3T and to compare the diagnostic performance of quantitative and semi-quantitative parameters. MATERIALS AND METHODS: Thirty-six patients with prostate carcinomas (18 Gleason-6, 15 Gleason-7, and 3 Gleason-8) and 33 healthy subjects were included. Image analysis workflow comprised four steps: manual segmentation of whole prostate and lesions, series registration, voxelwise T1 mapping and calculation of pharmacokinetic and semi-quantitative parameters. RESULTS: Ktrans, ve, upslope and AUC60 showed statistically significant differences between healthy peripheral areas and tumors. Curve type showed no association with healthy/tumor peripheral areas (chi-square=0.702). Areas under the ROC curves were 0.64 (95% CI: 0.54-0.75), 0.70 (0.60-0.80), 0.62 (0.51-0.72) and 0.63 (0.52-0.74) for Ktrans, ve, upslope and AUC60, respectively. The optimal cutoff values were: Ktrans=0.21min-1 (sensitivity=0.61, specificity=0.64), ve=0.36 (0.63, 0.71), upslope=0.59 (0.59, 0.59) and AUC60=2.4 (0.63, 0.64). Significant differences were found between Gleason scores 6 and 7 for normalized Ktrans, upslope and AUC60, with good diagnostic accuracy (area under ROC curve 0.80, 95% CI: 0.60-1.00). CONCLUSION: Quantitative (Ktrans and ve) and semi-quantitative (upslope and AUC60) perfusion parameters showed significant differences between tumors and control areas in the peripheral prostate. Normalized Ktrans, upslope and AUC60 values might characterize tumor aggressiveness. PMID- 27776666 TI - Can quantitative contrast-enhanced ultrasonography predict cervical tumor response to neoadjuvant chemotherapy? AB - OBJECTIVE: To evaluate the feasibility of quantitative contrast-enhanced ultrasonography (CEUS) for predicting and assessing cervical tumor response to neoadjuvant chemotherapy (NACT). METHODS: Thirty-eight cases with stage IB2 or IIA cervical cancer were studied using CEUS before and after one cycle of NACT. The quantitative CEUS parameters maximum intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (MTT) were compared between cervical tumors and myometrium (reference zone) using Sonoliver software. Absolute and relative changes in quantitative CEUS parameters were also compared among complete response, partial response, and non-responsive groups. Correlations between pre treatment IMAX and changes in quantitative parameters were assessed after one cycle of NACT. RESULTS: There were significant changes in cervical tumor IMAX (P<0.001), RT (P<0.05), and TTP (P<0.05) after one cycle of NACT. According to the Response Evaluation Criteria In Solid Tumors guidelines, the enrollments were divided into complete response, partial response, stable disease and progressive disease groups. There were no significant differences in quantitative CEUS parameters among complete response, partial response, and non-responsive groups (P>0.05). In the stable disease group (n=17), cervical tumor IMAX, RT, and TTP decreased significantly after NACT (P<0.001). The absolute and percentage changes in IMAX were positively correlated with pre-treatment IMAX in all 38 patients (r=0.576, P<0.001 and r=0.429, P<0.001). CONCLUSION: Quantitative CEUS analysis can reveal changes in tumor perfusion following NACT. Tumor perfusion values changes likely precede size changes during the NACT course, and pre-treatment IMAX may be a valuable predictor of cervical tumor perfusion response to NACT with a great decrease in IMAX correlated with better perfusion response. PMID- 27776668 TI - Cooled microwave ablation of thyroid nodules: Initial experience. AB - OBJECTIVE: To evaluate if internally cooled microwave ablation (cMWA) is a safe and effective method for treatment of benign and malign thyroid nodules. METHODS: 9 patients with 11 symptomatic cold benign thyroid nodules and 1 recurrent thyroid carcinoma ranging in volume from 9.1 to 197ml (mean size 52+/- 57ml) were treated with cMWA. The mean age of the patients was 59 years. Pain during the treatment was measured on a 10-point scale. Side effects revealed by ultrasound or patients' complaints were documented. Periablative efficacy was measured 24h after cMWA as change (Delta) in serum thyreoglobulin (Tg). Nodule elasticity was measured on a 4-point scale, blood circulation and echogenicity on a 3-point scale. RESULTS: All patients tolerated cMWA well. Median pain intensity averaged 2.1+/-0.8 (range: 1-3). Postablative hematoma was observed in all cases. In no cases ablation led to hoarseness, superficial burns, nodule ruptures, vagal reactions or dysphagia. cMWA lead to a significant decrease of blood circulation, nodule echogenicity and a significant increase of elasticity (Delta = 1.1 +/- 0.33; 0.8 +/- 0.4 and 1.1 +/- 0.6 points)(p<0.05). An average increase of 4495ng/ml Tg was measured (p<0.05). CONCLUSIONS: cMWA is an effective and secure method for treatment of thyroid nodules. PMID- 27776669 TI - Spring ligament complex: Illustrated normal anatomy and spectrum of pathologies on 3T MR imaging. AB - The spring (plantar calcaneonavicular) ligament complex connects the calcaneus and navicular bone of the foot and serves as the primary static stabilizer of the medial longitudinal arch of the foot. In this article, we describe the normal anatomy of the spring ligament complex, illustrate 3T magnetic resonance imaging appearances in its normal and abnormal states, and discuss the pathological associations with relevant case examples. PMID- 27776670 TI - Quantitative computed tomography measurements to evaluate airway disease in chronic obstructive pulmonary disease: Relationship to physiological measurements, clinical index and visual assessment of airway disease. AB - PURPOSE: To correlate currently available quantitative CT measurements for airway disease with physiological indices and the body-mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: This study was approved by our institutional review board (IRB number 2778). Written informed consent was obtained from all subjects. The subjects included 188 current and former cigarette smokers from the COPDGene cohort who underwent inspiratory and expiratory CT and also had physiological measurements for the evaluation of airflow limitation, including FEF25-75%, airway resistance (Raw), and specific airway conductance (sGaw). The BODE index was used as the index of clinical symptoms. Quantitative CT measures included % low attenuation areas [% voxels<=950 Hounsfield unit (HU) on inspiratory CT, %LAA-950ins], percent gas trapping (% voxels<=-856HU on expiratory CT, %LAA -856exp), relative inspiratory to expiratory volume change of voxels with attenuation values from -856 to -950HU [Relative Volume Change (RVC)-856 to -950], expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD), Pi10, and airway wall thickness (WT), luminal diameter (LD) and airway wall area percent (WA%) in the segmental, subsegmental and subsubsegmental bronchi on inspiratory CT. Correlation coefficients were calculated between the QCT measurements and physiological measurements in all subjects and in the subjects with mild emphysema (%LAA-950ins <10%). Univariate and multiple variable analysis for the BODE index were also performed. Adjustments were made for age, gender, smoking pack years, FEF25-75%, Raw, and sGaw. RESULTS: Quantitative CT measurements had significant correlations with physiological indices. Among them, E/I-ratio MLD had the strongest correlations with FEF25-75% (r=-0.648, <0.001) and sGaw (r=-0.624, <0.001) while in the subjects with mild emphysema subsegmental WA% and segmental WA% had the strongest correlation with FEF25-75% (r=-0.669, <0.001) and sGaw (r=-0.638, <0.001), respectively. The multiple variable analyses showed that RVC-856 to -950 was an independent predictor of the BODE index showing the highest R2 (0.468) as an independent variable among the QCT measurements. CONCLUSION: Quantitative CT measurements of gas trapping such as E/I-ratio MLD, correlate better with physiological indices for airway disease than those of airway such as WA% or LD. In mild emphysema, however, quantitative CT measurements of airway correlate better with the physiological indices. RVC-856 to -950 is a predictor of the BODE index. PMID- 27776671 TI - Submillisievert coronary calcium quantification using model-based iterative reconstruction: A within-patient analysis. AB - PURPOSE: To determine the effect of model-based iterative reconstruction (IR) on coronary calcium quantification using different submillisievert CT acquisition protocols. METHODS: Twenty-eight patients received a clinically indicated non contrast-enhanced cardiac CT. After the routine dose acquisition, low-dose acquisitions were performed with 60%, 40% and 20% of the routine dose mAs. Images were reconstructed with filtered back projection (FBP), hybrid IR (HIR) and model based IR (MIR) and Agatston scores, calcium volumes and calcium mass scores were determined. RESULTS: Effective dose was 0.9, 0.5, 0.4 and 0.2mSv, respectively. At 0.5 and 0.4mSv, differences in Agatston scores with both HIR and MIR compared to FBP at routine dose were small (-0.1 to -2.9%), while at 0.2mSv, differences in Agatston scores of -12.6 to -14.6% occurred. Reclassification of risk category at reduced dose levels was more frequent with MIR (21-25%) than with HIR (18%). CONCLUSIONS: Radiation dose for coronary calcium scoring can be safely reduced to 0.4mSv using both HIR and MIR, while FBP is not feasible at these dose levels due to excessive noise. Further dose reduction can lead to an underestimation in Agatston score and subsequent reclassification to lower risk categories. Mass scores were unaffected by dose reductions. PMID- 27776672 TI - A Review of Methamphetamine Dependence and Withdrawal Treatment: A Focus on Anxiety Outcomes. AB - Rates of anxiety disorders among individuals who use methamphetamine are estimated to be as high as 30.2%. The presence of an anxiety disorder in methamphetamine users is associated with higher rates of relapse, non-adherence to treatment and poorer outcomes relative to methamphetamine users without an anxiety disorder. A review investigating current treatment options for methamphetamine dependence or withdrawal from methamphetamine was conducted using PubMed, CINAHL and PsycINFO. The focus of the review was trials that utilized an intervention and collected anxiety as an outcome measure. Seven studies were included in the review, and five of these studies examined a pharmacotherapy option, one studied a psychosocial intervention and one study investigated exercise as an intervention. Some of the pharmacotherapy studies and the study of exercise were associated with improvements in mood and/or a reduction in methamphetamine use. Concerns of sample size and measurement of anxiety were raised. Future well-designed research with large sample sizes is warranted to examine how to manage anxiety among methamphetamine users. PMID- 27776673 TI - READY or Not: Findings From a School-Based MI Intervention for Adolescent Substance Use. AB - We aimed to examine the impact of a school-based Motivational Interviewing (MI) intervention, Project READY, on reducing adolescent substance use. We randomly assigned students (N = 244) to receive the intervention immediately (READY First) or to be in a waitlist control group (WLC). Those in WLC received the intervention once those in READY First had completed the intervention. Our hypotheses were: (1) adolescents in READY First would make greater initial reductions in their alcohol and marijuana use compared to adolescents assigned to WLC, (2) adolescents in READY First would make greater initial reductions in their alcohol and marijuana-related consequences compared to adolescents assigned to WLC, and (3) upon completing treatment, adolescents assigned to WLC would yield substance-related outcomes comparable to their peers in the READY First group. We found that those in READY First made greater initial decreases in their marijuana use and substance-related consequences upon completing treatment than participants in WLC, during the first phase of the study. Once both groups had completed the active intervention, those in the WLC had comparable marijuana use to those in READY First. At enrollment, daily marijuana users were equally represented in both groups. Post-treatment, significantly fewer participants reported daily marijuana use in the READY First group, prior to treatment initiation for WLC. Comparable reductions were observed once WLC began treatment. Those in WLC were observed to make reductions in their alcohol use at the same rate as those in READY First, prior to treatment initiation. Participants were not observed to make differential reductions in alcohol use based on group assignment. The findings from this study support the effectiveness of school based MI interventions for adolescent marijuana use and provide evidence that MI is a critical and effective component within such interventions. PMID- 27776675 TI - Structure of Problem Recognition Questionnaire with Hispanic/Latino Adolescents. AB - Motivation is a prominent target for substance use interventions because it is theorized to increase engagement in therapy and predict treatment outcomes. Establishing the validity of measures relevant to motivation among Hispanic/Latino adolescents will improve the resources available for screening and measuring change processes in a multicultural population. We examined the structure of the Problem Recognition Questionnaire (PRQ; Cady, Winters, Jordan, Solberg, & Stinchfield, 1996) with Hispanic/Latino adolescents. Participants were adolescents (n=191) in a randomized controlled trial for substance abuse. Data were collected during a baseline pre-treatment time point and post-treatment time point that was four-months post-baseline. Confirmatory factor analysis (CFA) showed that the three-factor structure proposed by Cady et al. (1996) had a poor fit with pre-treatment data. Follow-up exploratory analyses with principal axis factoring identified an alternate three-factor structure with pre-treatment data (problem recognition, readiness, and treatment resistance). A second CFA showed this three-factor model fit data from participants at the post-treatment time point (n=155). The results provide preliminary evidence for using our proposed factor structure for the PRQ subscales with Hispanic/Latino adolescents. We discuss the dimensions we identified in the context of similar measures and the implications for measuring problem recognition, readiness, and treatment resistance. PMID- 27776674 TI - Identifying and Addressing the Unmet Health Care Needs of Drug Court Clients. AB - Drug courts address issues such as employment and housing but largely miss the opportunity to address important health care issues. The current study examined the prevalence and correlates of chronic medical conditions among a sample of drug court clients who were participating in a clinical trial of an intervention to reduce HIV risk. A total of 256 clients completed a health survey at entry into the drug court program and 9 months post-entry. The baseline health survey included a comprehensive list of chronic medical conditions, and participants were asked to indicate which, if any, they had ever been diagnosed as having. They were also asked to indicate whether or not they were currently receiving treatment for each chronic condition that they endorsed. The follow-up survey was identical to the baseline survey, with the exception that it contained items reflecting (1) whether or not any member of the drug court team engaged in discussion with the client about each of the chronic conditions reported and (2) whether the client received a referral to medical care for endorsed conditions while in the drug court program. Results indicated that over 50% of clients reported at least one chronic condition and 21% reported more than one condition. Among those with chronic conditions, 71% reported having chronic conditions for which they were not currently receiving treatment. Unfortunately, drug court clients reported that the drug court team did little to address these unmet health needs. Findings from this study suggest that clients could benefit if drug court programs began to widen their focus to include addressing health-related issues. PMID- 27776676 TI - Stressful Events and Other Predictors of Remission from Drug Dependence in the United States: Longitudinal Results from a National Survey. AB - This study examined stressful life events and other predictors associated with remission from DSM-IV drug dependence involving cannabis, cocaine, hallucinogens, heroin, inhalants, non-heroin opioids, sedatives, stimulants, tranquilizers, or other drugs. Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were used to examine the prevalence and predictors of past year remission status. Among U.S. adults with previous (i.e., prior-to-past-year) drug dependence (n=921) at baseline (wave 1), the prevalence of past-year remission status at wave 1 was: abstinence (60.5%), asymptomatic drug use (18.8%), partial remission (7.1%), and still drug dependent (13.5%). Similarly, the prevalence of past-year remission status three years after baseline at wave 2 was: abstinence (69.1%), asymptomatic drug use (15.5%), partial remission (8.4%), and still drug dependent (7.0%). Remission three years after baseline at wave 2 was much more likely among formerly drug dependent U.S. adults who abstained from drug use at baseline (wave 1) relative to those who reported asymptomatic drug use, partial remission, or remained drug dependent. Design-based weighted multinomial logistic regression analysis showed that relative to abstinence, past year stressful events at baseline (wave 1) predicted higher odds of partial remission and drug dependence at both waves 1 and 2. This is the first national study to examine the potential role of stressful life events associated with remission from drug dependence. Although the majority of those who reported previous drug dependence transitioned to full remission, a sizeable percentage were either still drug dependent or in partial remission. Higher levels of stressful life events appear to create barriers to remission and should remain a focus for relapse prevention programs. PMID- 27776678 TI - Cognitive Behavioral Therapy Improves Treatment Outcomes for Prescription Opioid Users in Primary Care Buprenorphine Treatment. AB - To determine whether treatment outcomes differed for prescription opioid and heroin use disorder patients, we conducted a secondary analysis of a 24-week (N=140) randomized trial of physician management (PM) or PM plus cognitive behavioral therapy (CBT) in primary care buprenorphine/naloxone treatment. Self reported opioid use and urine toxicology analyses were obtained weekly. We examined baseline demographic differences between primary prescription opioid use patients (n=49) and primary heroin use patients (n=91) and evaluated whether treatment response differed by assigned condition. Compared to primary heroin use patients, primary prescription opioid use patients had marginally fewer years of opioid use, were less likely to have had a previous drug treatment or detoxification, and were less likely to report injection drug use. Although opioid abstinence only, and treatment retention did not differ by opioid use group, opioid category moderated the effect of CBT on urine samples negative for all drugs. Primary prescription opioid use patients assigned to PM-CBT had more than twice the mean number of weeks of abstinence for all drugs (7.6) than those assigned to PM only (3.6; p=.02), while primary heroin use patients did not differ by treatment. Findings suggest that examination of other factors that may predict response to behavioral interventions is warranted. PMID- 27776677 TI - From Long-Term Injecting to Long-Term Non-Injecting Heroin and Cocaine Use: The Persistence of Changed Drug Habits. AB - OBJECTIVES: Transitioning from injecting to non-injecting routes of drug administration can provide important individual and community health benefits. We assessed characteristics of persons who had ceased injecting while continuing to use heroin and/or cocaine in New York City. METHODS: We recruited subjects entering Mount Sinai Beth Israel detoxification and methadone maintenance programs between 2011 and 2015. Demographic information, drug use histories, sexual behaviors, and "reverse transitions" from injecting to non-injecting drug use were assessed in structured face-to-face interviews. There were 303 "former injectors," operationally defined as persons who had injected at some time in their lives, but had not injected in at least the previous 6 months. Serum samples were collected for HIV and HCV testing. RESULTS: Former injectors were 81% male, 19% female, 17% White, 43% African-American, and 38% Latino/a, with a mean age of 50 (SD=9.2), and were currently using heroin and/or cocaine. They had injected drugs for a mean of 14 (SD=12.2) years before ceasing injection, and a mean of 13 (SD=12) years had elapsed since their last injection. HIV prevalence among the sample was 13% and HCV prevalence was 66%. The former injectors reported a wide variety of reasons for ceasing injecting. Half of the group appeared to have reached a point where relapse back to injecting was no longer problematic: they had not injected for three or more years, were not deliberately using specific techniques to avoid relapse to injecting, and were not worried about relapsing to injecting. CONCLUSIONS: Former injectors report very-long term behavior change toward reduced individual and societal harm while continuing to use heroin and cocaine. The behavior change appears to be self-sustaining, with full replacement of an injecting route of drug administration by a non-injecting route of administration. Additional research on the process of long-term cessation of injecting should be conducted within a "combined prevention and care" approach to HIV and HCV infection among persons who use drugs. PMID- 27776679 TI - Association Between Utilization of Quitline Services and Probability of Tobacco Abstinence in Low-Income Smokers. AB - INTRODUCTION: Quitlines (QL) are an effective means for smoking cessation, but a paucity of data exist examining the dose-response relationship between use of QL services and quit rates, especially among low-income smokers. The purpose of this study was to study the relationship between tobacco abstinence and use of QL services among low-income smokers. METHODS: Secondary analysis of a randomized trial of every- or some-day smokers aged 18 years or older visiting an urban emergency department. Inclusion criteria included self-pay or Medicaid insurance, as a proxy for low-income and low socioeconomic status. Intervention participants received a motivational interview, 6 weeks of nicotine patches and gum, a referral faxed to the state-sponsored QL, a booster call, and a quitline brochure. Control participants received the brochure. Smoking status was assessed by phone at 1 and 3 months, with confirmation via exhaled carbon monoxide testing at 3 months for those reporting abstinence. QL usage was obtained by utilization data from the QL database. RESULTS: Of 778 subjects, 197 (25.3%) reported any use of QL services at 3 months. Participants were trichotomized: no QL usage, 1 call only, and >1 call (583, 99, and 98 participants, respectively). Quit rates at 3 months in these no, low-, and high-use groups were, respectively, 7.2%, 9.1%, and 15.3% (P=0.03). Participants who used the QL had a median of 28 total minutes of telephone contact. CONCLUSION: Among low-income smokers, greater use of QL services is associated with higher abstinence. Whether this resulted from a direct effect of the QL, or greater motivation among smokers using QL services cannot be determined from these data. PMID- 27776680 TI - Medication-Assisted Treatment Improves Child Permanency Outcomes for Opioid-Using Families in the Child Welfare System. AB - Parents who use opioids and are involved in the child welfare system are less likely to retain custody of their children than parents who use other drugs. No previous studies have described medication-assisted treatment (MAT) utilization and child permanency outcomes for this population. The Sobriety Treatment and Recovery Team (START) model is a child welfare-based intervention focused on families with co-occurring substance use and child abuse / neglect issues. This study examined the prevalence and correlates of MAT utilization among parents in the START program with a history of opioid use, and compared child outcomes for families who received MAT services to those who did not. Of the 596 individuals with a history of opioid use in the START program, 55 (9.2%) received MAT. Receipt of MAT services did not differ by gender, age, county of residence, or drug use, though individuals who identified as White were more likely to participate in MAT. In a multiple logistic regression model, additional months of MAT increased the odds of parents retaining custody of their children. To address barriers to MAT, results-focused educational interventions may be needed for the child welfare workforce, as well as programs to improve collaboration and decision-making between the child welfare workforce, court personnel, and drug addiction treatment providers. PMID- 27776681 TI - Typologies of Individuals Attending an Addiction Rehabilitation Center Based on Diagnosis of Mental Disorders. AB - OBJECTIVES: This study aimed to: (1) identify clusters based on the diagnostic status of mental disorders among individuals with problematic substance use treated in an addiction rehabilitation center (ARC), and (2) characterize these clusters according to socio-demographic variables, neighborhood characteristics, and health service utilization. METHODS: Data were compiled for 4526 individuals with problematic substance use who received services from an ARC in 2004. The data were compiled by merging four databases: the ARC data registry, the Quebec Health Insurance Board database, the Quebec provincial database for hospitalizations, and the Quebec National Institute of Public Health database. A two-step cluster analysis was performed to generate distinct groups based on diagnostic categories of mental disorders. Complementary comparative analyses were conducted to test differences among the clusters. RESULTS: Three clusters were identified. The first cluster consisted of individuals who did not receive any diagnosis of a mental disorder, including substance use disorders (SUDs), and who were low users of health services. The second cluster was composed of individuals who received a diagnosis of mental disorder, but not of SUD, and who primarily used mental health services. The third cluster included individuals who had a dual diagnosis (co-occurring SUD and mental disorder), and who were high users of acute care services. CONCLUSIONS: This study highlights the heterogeneity of individuals with problematic substance use treated in an ARC. Treatment will be more effective, overall, if tailored to the varying needs of individuals with problematic substance use. Recommendations of the study geared toward improving the effectiveness of care for this population include systematic diagnostic screening for SUDs by physicians, developing strong primary care for individuals with problematic substance use, and ensuring a continuing care model for individuals with a dual diagnosis. PMID- 27776682 TI - Hazardous Alcohol Drinking as Predictor of Smoking Relapse (3-, 6-, and 12-Months Follow-Up) by Gender. AB - Diverse studies have found a relation between alcohol consumption and smoking relapse. Few studies have analyzed the relation of smoking relapse with pretreatment alcohol consumption and gender differences. The main purpose of this study is to analyze the influence of alcohol consumption in smoking relapse over 12 months (3-, 6-, and 12-months follow-up) and to determine possible gender differences. The sample included 374 smokers who quit smoking by participating in a psychological smoking cessation treatment. We assessed hazardous pretreatment alcohol drinking (AUDIT), cigarette consumption (FTND; number of cigarettes) and sociodemographic variables. Higher scores on hazardous pretreatment alcohol drinking predict smoking relapse at 3-, 6-, and 12-months after smoking cessation. In males, higher scores on hazardous pretreatment alcohol drinking predict relapse at 6 and at 12 months. In females, higher scores on hazardous pretreatment alcohol drinking predict tobacco relapse at 3 months. Hazardous pretreatment alcohol drinking predicts relapse at all intervals after smoking cessation (3-, 6-, and 12-months follow-up). However, the influence of hazardous pretreatment alcohol drinking on smoking relapse differs as a function of gender, as it is a short-term predictor in women (3 months) and a long-term predictor in men (6 and 12 months). PMID- 27776683 TI - Social Ecological Determinants of Substance Use Treatment Entry Among Serious Juvenile Offenders From Adolescence Through Emerging Adulthood. AB - PURPOSE: To examine the social-ecological determinants of substance use treatment entry among serious juvenile offenders over a 7 year period. Using the social ecological framework, relevant predictors of substance use from the literature were used to assess risk (and protective) factors at the individual, parental, peer and neighborhood level. METHOD: Serious juvenile offenders (N=1354, Mage baseline=16.0 years, SD=1.14) were prospectively followed over 7 years (Mage Conclusion=23.0 years, SD=1.15). Cox regression with time invariant and time varying predictors was used to predict time to first substance use treatment entry. RESULTS: Results for each dimension, separately, varied slightly from the full model. In the full model peer delinquency, peer arrests, post-traumatic stress disorder (PTSD), impulse control, temperament, and emotional regulation remained salient risk (and protective) factors for treatment entry. CONCLUSION: Associating with more deviant peers and having more of your peers arrested over the 7 year study period was associated with substantial increase in time to treatment entry. Furthermore, one of the strongest risk factors for treatment entry was a PTSD diagnosis. Treatment implications are discussed regarding peer affiliation and PTSD symptomology as well as potential neurological and biological contributors to increased risk for treatment entry. PMID- 27776684 TI - Corrigendum to "How do Mindfulness-Based Cognitive Therapy and Mindfulness-Based Stress Reduction Improve Mental Health and Wellbeing? A Systematic Review and Meta-Analysis of Mediation Studies" [Clinical Psychology Review 37 (2015) 1-12]. PMID- 27776685 TI - Erratum to "Adopting a population-level approach to parenting and family support interventions" [Clinical Psychology Review 27 (2007) 739-749]. PMID- 27776686 TI - Lanthanum nitrate genotoxicity evaluation: Ames test, mouse micronucleus assay, and chromosome aberration test. AB - The increasing use of rare-earth elements (REE) and their compounds has led to their accumulation in the environment and has raised concern about their safety. The toxic effects of REE such as lanthanum are largely unknown; genotoxicity studies have been limited and results are controversial. We evaluated the genotoxicity of lanthanum nitrate (La(NO3)3) in several in vitro and in vivo tests, including bacterial reverse mutation assay (Ames test), mouse bone marrow micronucleus assay, and chromosome aberration assay. La(NO3)3 was not mutagenic in the Ames test. La(NO3)3 did not increase the frequencies of bone marrow micronuclei or chromosome aberration in the mouse after repeated treatments at oral doses up to 735 (females) and 855mg/kg (males). The compound did not increase the frequency of chromosome aberrations in CHO cells in vitro. These results indicate that lanthanum is not a genotoxic hazard. PMID- 27776687 TI - The Vitotox and ToxTracker assays: A two-test combination for quick and reliable assessment of genotoxic hazards. AB - To ensure safety for humans, it is essential to characterize the genotoxic potential of new chemical entities, such as pharmaceutical and cosmetic substances. In a first tier, a battery of in vitro tests is recommended by international regulatory agencies. However, these tests suffer from inadequate specificity: compounds may be wrongly categorized as genotoxic, resulting in unnecessary, time-consuming, and expensive in vivo follow-up testing. In the last decade, novel assays (notably, reporter-based assays) have been developed in an attempt to overcome these drawbacks. Here, we have investigated the performance of two in vitro reporter-based assays, Vitotox and ToxTracker. A set of reference compounds was selected to span a variety of mechanisms of genotoxic action and applicability domains (e.g., pharmaceutical and cosmetic ingredients). Combining the performance of the two assays, we achieved 93% sensitivity and 79% specificity for prediction of gentoxicity for this set of compounds. Both assays permit quick high-throughput analysis of drug candidates, while requiring only small quantities of the test substances. Our study shows that these two assays, when combined, can be a reliable method for assessment of genotoxicity hazard. PMID- 27776688 TI - Cytogenetic status and oxidative stress parameters in patients with thyroid diseases. AB - Since the incidence of cancer has increased over the years, adequate prevention programmes are needed. Thyroid cancer is one of the fastest growing cancer types in the world. In this study we performed a case-control study of 100 untreated patients with thyroid diseases (papillary thyroid cancer, follicular thyroid adenoma, and other thyroid diseases) and 100 control volunteers. Oxidative status differed among the two investigated groups. The patients' group had 1.60-fold higher concentrations of malondialdehyde and 1.26-fold higher concentrations of protein carbonyls. At the same time, the concentrations of glutathione and catalase activity were by 32% and 35% lower, respectively. A similar effect was observed for the cytogenetic status where higher comet assay tail intensity (1.84 fold) and the total numbers of chromosome aberrations (1.47-fold), micronuclei (2.32-fold), nucleoplasmic bridges (3.98-fold), and nuclear buds (2.34-fold) were detected. As for protein expression in thyroid tissue, 97.89% were positive for either B-Raf or Ret. Interestingly, the papillary thyroid cancer patients more frequently expressed B-Raf proteins compared to the follicular thyroid adenoma patients and patients with other thyroid diseases. Human biomonitoring studies enable a risk assessment of general population, such data could be used to identify risk subgroups. PMID- 27776689 TI - Dose-dependent de novo germline mutations detected by whole-exome sequencing in progeny of ENU-treated male gpt delta mice. AB - Germline mutations are an important component of genetic toxicology; however, mutagenicity tests of germline cells are limited. Recent advances in sequencing technology can be used to detect mutations by direct sequencing of genomic DNA (gDNA). We previously reported induced de novo mutations detected using whole exome sequencing in the offspring of N-ethyl-N-nitrosourea (ENU)-treated mice in a single-dose experiment (85mg/kg, i.p., weekly on two occasions). In this study, two lower doses (10 and 30mg/kg) were added, and dose-response of inherited germline mutations was analyzed. Male gpt delta transgenic mice treated with ENU in three dose groups were mated with untreated females 10 weeks after the last treatment, and offspring were obtained. The ENU-treated male mice showed dose dependent increases in gpt mutant frequencies in their sperm, testis, and liver. gDNA of one family (parents and four offspring) from each dose group was used for whole-exome sequencing, and unique de novo mutations in the offspring were detected. Frequencies of inherited mutations increased with dosage more than 25 fold in the highest dose group. The mutation spectrum of the inherited mutations showed characteristics of ENU-induced mutations, such as A:T base substitutions. No confirmed mutations were observed in the control group. Filtering using the alternate reads ratio resulted in the mutation frequencies and spectra similar to those obtained by the Sanger sequencing confirmation. These results suggest that direct sequencing analysis may be a useful tool to investigate inherited germline mutations induced by environmental mutagens. PMID- 27776690 TI - Protective effect and induction of DNA repair by Myrciaria cauliflora seed extract and pedunculagin on cyclophosphamide-induced genotoxicity. AB - Ellagitannins are well-known antioxidants in medicinal plants, foods, and edible fruits, particularly in Myrciaria cauliflora (jabuticaba). Thus, this study aimed to evaluate the protective effects of jabuticaba seed extract (JSE) and pedunculagin using in vivo micronucleus test and comet assay in mouse bone marrow cells, in combination with cyclophosphamide (CP), a bioreductive alkylating agent. The ellagitannin composition of JSE was determined by HPLC/PDA, with castalagin, vescalagin, and pedunculagin as the main compounds (124.4, 45.5, and 15.6mg/g dw, respectively). Results from pre- and co- treatments with JSE or pedunculagin clearly showed their protective action against CP-induced micronuclei and DNA damage. The effects of both tannins in post-treatments with CP suggested they influence DNA repair systems. These findings indicate that JSE and pedunculagin possess chemopreventive as well as DNA repair-inducing properties. PMID- 27776691 TI - Combination of tacrolimus and mycophenolate mofetil induces oxidative stress and genotoxicity in spleen and bone marrow of Wistar rats. AB - Tacrolimus (TAC) and mycophenolate mofetil (MMF) are common immunosuppressive drugs used to avoid immunological rejection of transplanted organs. The risk of developing cancer is the most critical complication in organ transplant recipients undergoing immunosuppressive therapy. This study aims to explore the cytotoxic and genotoxic effects of TAC and MMF alone or combined orally administrated on spleen and bone marrow of Wistar rats. Our results showed that TAC (2.4; 24 and 60mg/kg) and MMF (5; 50 and 125mg/kg) induced a genotoxic effect on rat bone marrow. Moreover, the co-treatment with the TAC/MMF (2.4/5mg/kg b.w.; 2.4/50mg/kg b.w. and 60/50mg/kg b.w.) produce a genotoxicity as measured by micronuclei (MN) frequencies, chromosomal aberrations (CA) rates and DNA damage levels. Furthermore, the TAC and MMF-treated animals developed oxidative stress in spleen, indicated by a significant increase of malondialdehyde (MDA), protein oxidation and decrease of anti-oxidant enzymes levels such as catalase (CAT) and superoxide dismutase (SOD). This damage was associated with an increase of DNA fragmentation. Co-treatment with TAC/MMF synergistically induced markers of oxidative stress in rat splenic tissue. In conclusion, TAC/MMF associated induction in oxidative stress plays a role in the splenic and bone marrow toxicity and enhances the different endpoints of genotoxicity, suggesting its mutagenic action in vivo. PMID- 27776692 TI - Biological and health effects of radiofrequency fields: Good study design and quality publications. AB - During recent decades, researchers have used several different parameters to evaluate the biological and health effects of in vitro and in vivo exposure to non-ionizing radiofrequency fields in animals, humans and their isolated cells. The data reported in many of publications in peer-reviewed scientific journals were reviewed by the international and national expert groups of scientists for human risk assessment of exposure to radiofrequency fields. The criteria used for such assessment depended on the study design, methodology and reporting of the data in the publication. This paper describes the requirements for good study design and quality publications, and provides guidance and a checklist for researchers studying radiofrequency fields and other environmental agents. PMID- 27776693 TI - Introduction to the HUPO 2015 Special Issue. PMID- 27776694 TI - [Editorial]. PMID- 27776695 TI - We care. PMID- 27776696 TI - Preservation of hypogastric flow and control of iliac aneurysm size in the treatment of aortoiliac aneurysms using the Nellix EndoVascular Aneurysm Sealing endograft. AB - OBJECTIVE: The purpose of this study was to determine the long-term effectiveness of endovascular aneurysm sealing (EVAS) in the treatment of complex aortoiliac aneurysms with preservation of hypogastric artery flow. METHODS: We reviewed all patients with abdominal aortic aneurysms (AAAs) and common iliac aneurysms (CIAs) enrolled and treated in prospective studies of EVAS using the Nellix endograft (Endologix, Irvine, Calif) at two centers from 2008 to 2014. Patients with 1 year or more of computed tomography follow-up underwent quantitative morphometric assessment by two independent vascular radiologists blinded to clinical outcome results. Hypogastric patency and CIA diameter changes over time were assessed and compared in three treatment groups: totally excluded CIA, partially excluded CIA, and untreated CIA. RESULTS: Among 125 patients with EVAS, 68 patients (mean age, 75 +/- 8 years; 79% men) had both AAA (mean diameter, 55.8 +/- 2.0 mm) and CIA (median diameter, 23.4; interquartile range, 21.3-27.0 mm), with bilateral CIAs in 33 patients. Treatment of 101 CIAs included complete CIA exclusion in 40 (39.6%), partial CIA exclusion in 33 (32.7%), and no CIA treatment in 28 (27.7%), with successful AAA exclusion in all patients. Internal iliac flow was preserved in all 122 hypogastric arteries that were patent before treatment (14 hypogastric arteries were occluded at baseline). During the 5-year follow-up period (median follow-up, 24.7 months; range, 11.5-61.7 months), three patients required secondary treatment with hypogastric occlusion and graft extension to the external iliac. Thus, internal iliac flow was maintained in 98% of at-risk hypogastric arteries. There were no aneurysm-related clinical events, except for the three secondary treatments. Totally excluded iliac aneurysms did not change in diameter over time (P = .85), whereas untreated CIAs enlarged at a rate of 0.16 mm/y (95% confidence interval, 0.09-0.23; P < .0001). Partially excluded CIAs enlarged at a higher rate of 0.59 mm/y (95% confidence interval, 0.47-0.71; P < .0001). Enlargement >=3 mm occurred only in partially treated CIAs larger than 3 cm. CONCLUSIONS: EVAS was effective in treating aortoiliac aneurysms with preservation of internal iliac patency in most cases. Complete CIA exclusion prevented aneurysm enlargement over time, whereas partial exclusion did not prevent continued CIA enlargement, particularly in larger aneurysms. PMID- 27776697 TI - Perioperative and long-term impact of chronic kidney disease on carotid artery interventions. AB - OBJECTIVE: Chronic kidney disease (CKD) increases morbidity and mortality after vascular procedures and adversely affects late survival of patients. The presence of CKD also confers increased risk of stroke in patients with asymptomatic carotid stenosis. Patients undergoing carotid intervention in the Vascular Study Group of New England database were stratified by CKD status referable to periprocedural and late outcomes. METHODS: All carotid artery stenting and carotid endarterectomies (CEAs) performed from 2003 to 2013 were stratified by CKD severity as mild (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2), moderate (eGFR 30-59), and severe (eGFR <30). The impact of CKD on outcomes of carotid procedures was evaluated using univariate and multivariate methods. RESULTS: Of 12,568 patients identified, 11,746 (93%) underwent CEA and 822 (7%) underwent carotid artery stenting. Procedures were performed for symptomatic disease in 40%. CKD severity was mild in 58%, moderate in 35%, and severe in 7%. The 30-day stroke rate was very low across all CKD groups (1.76% mild vs 1.84% moderate and 1.34% severe; P = .009). The 30-day mortality increased with worsening renal function (0.4% mild vs 0.9% moderate and 0.9% severe; P = .01). Independent predictors of 30-day stroke or death included American Society of Anesthesiologists (ASA) class 4 or 5 (odds ratio, 2.3; 95% confidence interval [CI], 1.5-3.4; P = .0001). Multivariable Cox hazards regression showed that severe CKD (hazard ratio [HR], 1.8; 95% CI, 1.3-2.6), ASA class 4 or 5 (HR, 1.7; 95% CI, 1.3-2.2), preoperative cortical symptoms (HR, 1.5; 95% CI, 1.2-1.8), history of diabetes (HR, 1.4; 95% CI, 1.1-1.7), and age (HR, 1.03/y; 95% CI, 1.02 1.04) independently (all P < .01) predicted neurologic events or death at median follow-up of 12.7 months (interquartile range, 10.3-15.2 months). CKD did not increase the risk of neurologic events at 1-year follow-up. Predictors (P < .05) of late death included moderate CKD (HR, 1.3; 95% CI, 1.01-1.7), severe CKD (HR, 2.2; 95% CI, 1.6-2.9), ASA class 4 or 5 (HR, 1.6; 95% CI, 1.2-2.0), history of diabetes (HR, 1.4; 95% CI, 1.2-1.7), chronic obstructive pulmonary disease (HR, 1.4; 95% CI, 1.1-1.8), and cortical symptoms (HR, 1.3; 95% CI, 1.05-1.6). The 1-, 5-, and 10-year survival rates decreased with worsening renal function (log-rank test, P < .001), but patients with severe CKD maintained a 71% survival at 5 years. CONCLUSIONS: CKD severity increases risk of perioperative mortality as well as late mortality. Patients with CKD benefit from stroke-free survival especially after CEA. Unlike patients with peripheral arterial occlusive disease, for whom severe CKD reduces median survival to ~2.5 years, patients with CKD and carotid disease exhibit much longer survival. This suggests that carotid interventions have utility in carefully selected patients with moderate and severe CKD, particularly in symptomatic disease. PMID- 27776699 TI - Invited commentary. PMID- 27776698 TI - Ethyl pyruvate modulates delayed paralysis following thoracic aortic ischemia reperfusion in mice. AB - OBJECTIVE: Delayed paralysis is an unpredictable problem for patients undergoing complex repair of the thoracic/thoracoabdominal aorta. These experiments were designed to determine whether ethyl pyruvate (EP), a potent anti-inflammatory and antioxidant agent, might ameliorate delayed paralysis following thoracic aortic ischemia reperfusion (TAR). METHODS: C57BL6 mice were subjected to 5 minutes of thoracic aortic ischemia followed by reperfusion for up to 48 hours. Mice received either 300 mg/kg EP or lactated ringers (LR) at 30 minutes before ischemia and 3 hours after reperfusion. Neurologic function was assessed using an established rodent scale. Spinal cord tissue was analyzed for markers of inflammation (keratinocyte chemoattractant [KC], interleukin-6 [IL-6]), microglial activation (ionized calcium-binding adapter molecule-1 [Iba-1]), and apoptosis (Bcl-2, Bax, and terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL] staining) at 24 and 48 hours after TAR. Nissl body stained motor neurons were counted in the anterior horns sections from L1-L5 segments. RESULTS: Ninety-three percent of the LR mice developed dense delayed paralysis between 40 and 48 hours after TAR, whereas only 39% of EP mice developed delayed paralysis (P < .01). Bcl-2 expression was higher (P < .05) and Iba-1 expression was lower (P < .05) in the EP group only at 24 hours reperfusion. At 48 hours, the number of motor neurons was higher (P < .01) and the number and TUNEL-positive cells was lower (P < .001) in the EP-treated mice. EP decreased the expression of KC (P < .01) and IL-6 (P < .001) at 48 hours after TAR. CONCLUSIONS: The protection provided by EP against delayed paralysis correlated with preservation of motor neurons, higher expression of antiapoptotic molecules, decreased microglial cell activation, and decreased spinal cord inflammation. EP may be a treatment for humans at risk for delayed paralysis. PMID- 27776700 TI - Invited commentary. PMID- 27776701 TI - A tricky nontraumatic pseudoaneurysm of the posterior tibial artery. PMID- 27776702 TI - Chronic anastomotic pseudoaneurysm on a polytetrafluoroethylene axillobifemoral bypass graft. PMID- 27776703 TI - Hybrid endovascular treatment for an asymptomatic Kommerell diverticulum at the right aortic arch. PMID- 27776704 TI - Technical options for treatment of in-stent restenosis after carotid artery stenting. AB - OBJECTIVE: This review summarizes the available evidence and analyzes the current trends on treatments for carotid in-stent restenosis (ISR) after carotid artery stenting (CAS). METHODS: An update of a 2010 review of the literature (which included 20 articles) was conducted using PubMed and Embase. All studies published from inception until January 2016 reporting original data on ISR treatments were included. Treatment trends before and after 2005 were compared. RESULTS: We found 22 new articles reporting ISR treatments in 138 patients, of which two (case series) were published before 2005. With the inclusion of the 20 articles of the 2010 report (n = 96 patients), a total of 42 articles were included (23 case reports and 19 case series) reporting 239 interventions for ISR in 234 patients. Of these 42 studies, 14 (including 10 case series) were published before 2005. The interventions were percutaneous transluminal angioplasty (PTA) in 136, repeat CAS in 51, carotid endarterectomy in 39, carotid artery bypass in 10, or brachytherapy in 3. Compared with the articles published before 2005, PTA with regular balloon remains the most practiced treatment (26% before 2005, 40% after 2005). PTA with drug-coated balloons started after 2005. Carotid endarterectomy with stent removal was the second most reported treatment before 2005 but moved to the third place of reported interventions after 2005 owing to an increase in repeat CAS treatment. Of the treated patients, 140 were asymptomatic, 72 were symptomatic, and for 22 the symptomology was unclear. ISR treatment averaged 18 months after CAS, and the follow-up thereafter was 16 months. Treatment for recurrent ISR was performed in 48 of 239 treated arteries, mostly after PTA (n = 35) and repeat CAS (n = 8). CONCLUSIONS: The available evidence for ISR treatment is still limited owing to methodologic heterogeneity; therefore, no recommendation on the optimal intervention can be provided. Although PTA is the common treatment for ISR, recurrent ISR seems to limit the durability, leading to recurrent interventions and cost implications. A uniform definition for ISR is needed with a standardized workup to compare the treatment options based on individual patient data analysis. Drug-eluting techniques are emerging and may become the preferred treatment option, but long-term follow-up is needed to evaluate their efficacy. Further study and understanding of the effect of drug-eluting technologies on the brain and neurologic function is warranted. PMID- 27776705 TI - Regarding "Retrograde stenting of proximal lesions with carotid endarterectomy increases risk". PMID- 27776706 TI - Reply. PMID- 27776707 TI - Regarding "A comparison of revision using distal inflow and distal revascularization interval ligation for the management of severe access-related hand ischemia". PMID- 27776708 TI - Regarding "Morphologic findings and management strategy of spontaneous isolated dissection of the celiac artery". PMID- 27776709 TI - Reply. PMID- 27776710 TI - Regarding "Autonomic outcome is better after endarterectomy than after stenting in patients with asymptomatic carotid stenosis". PMID- 27776711 TI - Reply. PMID- 27776712 TI - Correction. PMID- 27776713 TI - Missed Appointments in a Breast Clinic: Patient-Related Factors. AB - BACKGROUND: Missed appointments are problematic because they occupy an appointment that could have been used by another patient and represent lost resources for the hospital system. The objective of this study was to determine patient-related factors associated with missed appointments. METHODS: Totally, 1,624 patients were seen from January 14, 2010 to January 16, 2012. Sociodemographic variables were collected including health literacy assessment, electronic medical record system-collected scheduled appointments and missed appointments for each patient. Patients were also asked for their preferred method of contact. RESULTS: From January 1, 2009 to January 16, 2012 the 1,624 patients had 21,648 scheduled appointments in the hospital system. Overall 3,633 (16.8%) of the appointments were missed. Insurance status, income, education and primary language were not significant predictors for missed appointments. Limited health literacy was associated with increased rate of missed appointments (adequate health literacy 13.4% versus limited health literacy 17.2%, P = 0.0009). Current smokers had higher rates of missed appointments than nonsmokers (18.5% versus 16.1%, P = 0.025). Patients who underwent screening mammography were also less likely to miss appointments (odds ratio = 0.78, P < 0.0001). The preferred method of contact was via mobile phone; however, this was only 42%. CONCLUSIONS: Patients with limited health literacy and current smokers had higher rates of missed appointments. In addition, patients who were compliant with screening mammography were also more likely to be compliant with appointments. Appointment reminders should be kept simple to accommodate the rapidly growing population with limited health literacy. PMID- 27776714 TI - Assessment for Pulmonary Artery Hypertension Using Clinical and Echocardiographic Criteria in Patients With Systemic Sclerosis. AB - BACKGROUND: Prognosis of systemic sclerosis (SSc) is affected by pulmonary artery hypertension (PAH). METHODS: Among 202 patients (mean age: 46.1 +/- 13.3 years; 177 women) with SSc, those with a tricuspid regurgitation (TR) jet maximal velocity at 2D-echocardiography (2DE) < 2.8m/second were not considered at high risk for PAH, whereas those with a TR velocity >3m/second or between 2.8 and 3m/second and associated with dyspnea were. RESULTS: Among 22 patients at risk, 15 (mean age: 50.4 +/- 14.3 years) had definite precapillary PAH on right heart catheterization (RHC). The delay period between recognitions of SSc and PAH was 12.9 +/- 5.2 years. Dyspnea was present in all 15 patients, 11 (73.3%) being in the New York Heart Association class III or IV. The 2DE showed normal left ventricular geometrics and function (n = 15), enlargement of the right-sided cardiac chambers (n = 12), increased pulmonary arterial resistances with a TR velocity to pulmonary time-velocity integral ratio of > 0.2 (n = 15) and impaired right ventricle function (n = 15). RHC showed severe PAH in all 15 patients (mean pulmonary artery pressure: 48 +/- 17mmHg and mean right atrial pressure: 11.8 +/- 4.4mmHg) and a reduced cardiac index (2.2L/m2). There was no statistical difference between patients with and without PAH regarding age, sex ratio, duration from onset of disease, diffuse or cutaneous limited type of SSc, Rodnan severity score and presence of digital ulcerations or autoantibodies. Telangiectasia (P = 0.01) and New York Heart Association class III or IV heart failure (P = 0.001) were more frequent in patients with PAH. CONCLUSION: A combined clinical and Doppler-coupled 2DE screening of PAH risk in patients with SSc is useful to select those who can undergo RHC. PMID- 27776715 TI - Characterization of Lipoprotein-associated Phospholipase A2 in Serum in Patients With Stage 3-5 Chronic Kidney Disease. AB - BACKGROUND: This study aims to test the lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity in patients with chronic kidney disease (CKD) and to analyze their connection of Lp-PLA2 with the development of disease and with the occurrence of atherosclerosis in this population. MATERIALS AND METHODS: In total, 59 patients older than 18 years and with a diagnosis of CKD were recruited. Kidney function was evaluated by serum creatinine, serum urea and estimated glomerular filtration rate according to Chronic Kidney Disease Epidemiology Collaboration formula and clinical data were collected. A total of 24 healthy volunteers served as healthy controls. Lp-PLA2 mass is measured by enzyme-linked immunosorbent assay. Lp-PLA2 activity is determined by an enzymatic platelet-activating factor acetylhydrolase assay. RESULTS: Serum mass and activity of Lp-PLA2 were higher in patients with CKD compared with healthy controls (P < 0.001 and P = 0.031). There was a positive linear relationship betweenLp-PLA2 mass and activity in the patients with CKD (r = 0.586, P < 0.001). The similar result was observed in the healthy controls (r = 0.585, P = 0.003). However, the ratio of Lp-PLA2 mass to activity in the patients with CKD was significantly higher than those of healthy controls (P < 0.001). Lp-PLA2 mass and activity were correlated with low-density lipoprotein (r = 0.366 and r = 0.303, P = 0.004 and P = 0.02). CONCLUSIONS: Lp-PLA2 mass and activity increase in patients with CKD. Elevated mass and activity of Lp-PLA2 related to inflammation and atherosclerosis may take part in the development of kidney injury and atherosclerosis in patients with CKD. PMID- 27776716 TI - Assessment of Apelin Serum Levels in Persistent Atrial Fibrillation and Coronary Artery Disease. AB - BACKGROUND: Apelin, the endogenous ligand of orphan receptor APJ (gene symbol APLNR), is an adipokine that was suggested to have a direct correlation with obesity. This peptide might play a role in obesity-related disorders, especially in the cardiovascular system. Currently, few data are available on levels and potential metabolic functions of apelin in different cardiac diseases including atrial fibrillation (AF) and coronary artery disease (CAD), which have common underlying pathophysiological mechanisms. This study aimed to investigate apelin levels in patients with AF and CAD that were overweight or obese, as well as its relationship with anthropometry and metabolic profile. METHODS: This preliminary investigation was compromised of 41 patients with AF and 39 with CAD aged > 50 years and body mass index (BMI) > 25kg/m2. Serum levels of apelin, fasting plasma glucose, insulin, homeostatic model assessment, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and very-low-density lipoprotein were measured. RESULTS: The apelin serum levels were not statistically different between patients with AF and CAD. A negative correlation was observed between apelin with weight (r = -0.257, P = 0.023) and BMI (r = -0.258, P = 0.023). Moreover, apelin showed an inverse correlation with insulin (r =-0.227, P = 0.045) and marginally with homeostatic model assessment (r = -0.21, P = 0.066). There was a negative association between apelin and triglyceride (r = -0.238, P = 0.036) and very-low-density lipoprotein (r = -0.25, P = 0.027). CONCLUSIONS: Apelin serum levels were not significantly different among patients with AF and CAD. The unexpected inverse correlation of apelin with weight and BMI might indicate the dominant effects of pathophysiological conditions such as AF and CAD on serum levels of apelin compared with BMI and adipose tissue. Understanding the precise role of apelin in modulating obesity induced disorders including AF and CAD requires further studies. PMID- 27776717 TI - Metabolically Obese Individuals of Normal Weight Have a High Risk of 25 Hydroxyvitamin D Deficiency. AB - BACKGROUND: Vitamin D status is related to obesity-related metabolic disorders. We investigated the risk of 25-hydroxyvitamin D [25(OH)D] deficiency among different metabolic phenotypes. METHODS: This prospective cross-sectional study evaluated 1,292 individuals who were >=40 years old. Participants were classified as metabolically healthy and normal weight (MHNW), metabolically obese but normal weight (MONW), metabolically healthy but obese (MHO) or metabolically unhealthy and obese (MUO). The demographic and clinical characteristics, as well as plasma 25(OH)D levels, were compared between the 4 groups. RESULTS: The prevalences of MHNW, MONW, MHO and MUO were 32.1%, 19.3%, 17.9% and 30.7%, respectively. Approximately 58.5% participants had vitamin D deficiency, and vitamin D deficiency was more common in the MONW (68.7%) and MUO (73.6%) groups (MHNW, 42.7 and MHO, 50.2%). The MONW and MUO groups had lower 25(OH)D levels (versus the MHNW and the MHO groups). Among vitamin D-deficient participants, the MONW group exhibited increased risks of abdominal obesity (odds ratio [OR]: 3.28, P = 0.005), hypertension (OR: 3.08, P = 0.003) and elevated C-reactive protein (OR: 1.97, P = 0.03). In addition, the MUO group exhibited increased risks of hypertriglyceridemia (OR: 2.57, P = 0.001), insulin resistance (OR: 2.37, P = 0.001) and elevated C-reactive protein level (OR: 2.09, P = 0.003). CONCLUSIONS: Individuals who were MONW and MUO had increased risks of vitamin D deficiency (versus MHNW and MHO), and individuals with vitamin D deficiency had worse metabolic status. Vitamin D supplementation may improve the metabolic status of individuals who are MONW or MUO. PMID- 27776720 TI - Identifying Different Causes of Hyponatremia With Fractional Excretion of Uric Acid. AB - BACKGROUND: There is controversy over the prevalence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral or renal salt wasting (RSW), 2 syndromes with identical common clinical and laboratory parameters but different therapies. The traditional approach to the hyponatremic patient relies on volume assessment, but there are limitations to this method. METHODS: We used an algorithm that relies on fractional excretion of urate (FEurate) to evaluate patients with hyponatremia and present 4 illustrative cases. RESULTS: Overall, 2 patients had increased FEurate [normal: 4-11%], as is seen in SIADH and RSW. A diagnosis of SIADH was made in 1 patient by correcting the hyponatremia with 1.5% saline and observing a characteristic normalization of an elevated FEurate that is characteristic of SIADH as compared to FEurate being persistently increased in RSW. A patient with T-cell lymphoma had symmetrical leg edema due to lymphomatous obstruction of the inferior vena cava, postural hypotension, pleural effusion, ascites, decreased cardiac output and urine sodium level of 10mmol/L. Saline-induced excretion of dilute urines and undetectable plasma antidiuretic hormone were consistent with RSW. Furosemide, given for presumed heart failure, induced a profound diuresis that required large volumes of fluid resuscitation. A normal FEurate identified a reset osmostat in a transplant patient with a slowly developing pneumocystis carinii pneumonia. A volume-depleted hyponatremic patient with Addison's disease had a low FEurate of 1.4%. CONCLUSIONS: These illustrative cases suggest that an approach to hyponatremia using FEurate may be a useful alternative to traditional volume based approaches. PMID- 27776719 TI - Cone Beam Computed Tomography Analysis of Upper Airway Measurements in Patients With Obstructive Sleep Apnea. AB - PURPOSE: To explore the validity of cone beam computed tomography (CBCT) as one of many predictive tools that can be used (alone or in conjunction) to help in identifying high-risk cases of obstructive sleep apnea (OSA) that should get the earliest possible referral to a sleep specialist for standard diagnostic polysomnography, and to identify imaging airway parameters that may be predictive of OSA severity. METHODS: Using a case-control design, 45 subjects matched by age and sex (22 OSA cases and 23 controls) were included in this study. Subjects were assigned as cases depending on a sleep study with apnea-hypopnea index (AHI)>5 and as controls depending on a Berlin questionnaire score identifying low risk or no risk of OSA. All subjects had CBCT scans. Airway and craniofacial parameters as assessed by CBCT were compared between the 2 groups. Significant CBCT variables were entered into a logistic regression model to identify risk factors of OSA and the correlations of variables with AHI were evaluated using multiple linear regression. For all tests P <= 0.05 was considered statistically significant. RESULTS: OSA cases had larger body mass index and neck circumference than controls. OSA cases showed significantly smaller airway narrowest cross sectional areas (CSAs) (P < 0.05) and larger posterior nasal spine and the second cervical vertebrae distances (P < 0.001) than those in controls. Airway narrowest CSA showed a significant negative correlation with AHI (r = -0.653, P = 0.001) and was a significant variable for predicting the AHI of OSA cases in multiple regression analysis. CONCLUSIONS: The importance of the narrowest CSA and posterior nasal spine and the second cervical vertebrae distance in the pathogenesis of OSA has been highlighted in the present study. We can conclude that CBCT can provide findings that entail earlier referral of suspected patients with OSA for further assessment. PMID- 27776718 TI - Maternal Alcohol Use During Pregnancy and Associated Morbidities in Very Low Birth Weight Newborns. AB - BACKGROUND: We hypothesized that maternal alcohol use occurs in pregnancies that end prematurely and that in utero alcohol exposure is associated with an increased risk of morbidities of premature newborns. METHODS: In an observational study of mothers who delivered very low birth weight newborns (VLBW) <=1,500 g, maternal alcohol use was determined via a standardized administered questionnaire. We compared the effect of maternal drinking on the odds of developing late-onset sepsis (LOS), bronchopulmonary dysplasia (BPD), death, BPD or death, days on oxygen or any morbidity (either LOS, BPD or death). The effect of drinking amounts (light versus heavy) was also evaluated. RESULTS: A total of 129 subjects who delivered 143 VLBW newborns were enrolled. Approximately 1 in 3 (34%) subjects reported drinking alcohol during the first trimester ("exposed"). Within the exposed group, 15% reported drinking >=7drinks/week ("heavy") and 85% of the subjects reported drinking <7drinks/week ("light"). When controlling for maternal age, drug or tobacco use during pregnancy and neonatal gestational age, any drinking increased the odds of BPD or death and any morbidity. Furthermore, light or heavy drinking increased the odds of BPD or death and any morbidity, whereas heavy drinking increased the odds of LOS. CONCLUSIONS: In utero alcohol exposure during the first trimester occurred in 34% of VLBW newborns. Maternal drinking in the first trimester was associated with significantly increased odds of neonatal morbidity. Further studies are warranted to determine the full effect of in utero alcohol exposure on the adverse outcomes of VLBW premature newborns. PMID- 27776721 TI - Primary Aldosteronism: Diagnosis and Management. AB - Primary aldosteronism (PA) is an important and commonly unrecognized cause of secondary hypertension. Idiopathic hyperaldosteronism and aldosterone-producing adenomas account for more than 95% of PA and are characterized, respectively, by bilateral or unilateral involvement of the adrenal glands. When there is suspicion for the presence of PA, a plasma aldosterone to renin ratio should be obtained initially. Localization to determine adrenal gland involvement is done by imaging, with computerized tomography or magnetic resonance imaging. After imaging, adrenal vein sampling is done to establish treatment options. Patients with unilateral disease, who are good surgical candidates, are most appropriately managed with adrenalectomy. A biochemical cure is almost certain following adrenalectomy; however, only 30-50% of patients would show adequate blood pressure improvement. Patients with bilateral adrenal disease and those believed not to be surgical candidates are managed with mineralocorticoid antagonists. PMID- 27776724 TI - Booker T. Washington and the Secret of Hypertension in African Americans. AB - Booker T. Washington rose from slavery to become one of the most admired Americans of his time. He died of long-standing malignant hypertension on November 14, 1915. At that time the medical profession was just beginning to recognize the importance of hypertension as a risk factor for cardiovascular disease. In spite of intensive research fueled by ongoing speculation, why Washington might have been predisposed to the ravages of hypertension, and African Americans continue to be so predisposed, is a secret yet to be told. PMID- 27776722 TI - Infectious Diseases and the Criminal Justice System. AB - The United States leads the world in incarceration, which disproportionately affects disadvantaged individuals, including those who are mentally ill, poor, homeless and racial minorities. Incarceration is disruptive to families and communities and contributes to health disparities in sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). The objective of this grand rounds is to review (1) the epidemiology of incarceration in the United States, (2) the social factors which contribute to high rates of STIs in incarcerated individuals and (3) the HIV care cascade in incarcerated and recently released individuals. Routine screening and treatment for STIs and HIV in the criminal justice system can identify many new infections and has the potential to both improve individual outcomes and reduce transmission to others. Increased collaboration between the department of health and department of corrections, as well as partnerships between academic institutions and the criminal justice system, have the potential to improve outcomes in this vulnerable population. PMID- 27776723 TI - High-density Lipoprotein and Inflammation and Its Significance to Atherosclerosis. AB - Great advances are being made in the understanding of the structural and functional diversity of high-density lipoprotein at the mechanistic level. High density lipoprotein possesses numerous physiological activities, the most studied of which is the ability to promote excess cholesterol efflux from peripheral tissues to the liver for excretion via a mechanism believed to confer protection against atherosclerosis. Accumulating evidence has demonstrated that atherosclerosis is a chronic inflammatory response. Recent studies have suggested that high-density lipoprotein possesses anti-inflammatory properties and regulates both innate and adaptive immune responses. However, further complicating this very complex system is the finding that inflammation, via alteration of the proteomic and lipidomic composition of high-density lipoprotein species, can modulate at least some of their functional activities. Modified high density lipoprotein exhibits a reduced ability to mediate cholesterol efflux from peripheral tissues and to inhibit cytokine-induced adhesion molecule expression and even promotes the occurrence of inflammation. This review focuses on the underlying mechanism of the interaction between high-density lipoprotein and inflammation to clarify the pathologic process of atherosclerosis. PMID- 27776725 TI - Electronic Cigarettes for Smoking Cessation. AB - The use of electronic cigarettes (e-cigarettes) is increasing, but their use as a smoking-cessation aid is controversial. The reporting of e-cigarette studies on cessation is variable and inconsistent. To date, only 1 randomized clinical trial has included an arm with other cessation methods (nicotine patches). The cessation rates for available clinical trials are difficult to compare given differing follow-up periods and broad ranges (4% at 12 months with non-nicotine e cigarettes to 68% at 4 weeks with concomitant nicotine e-cigarettes and other cessation methods). The average combined abstinence rate for included prospective studies was 29.1% (combination of 6-18 months' rates). There are few comparable clinical trials and prospective studies related to e-cigarettes use for smoking cessation, despite an increasing number of citations. Larger randomized clinical trials are essential to determine whether e-cigarettes are effective smoking cessation devices. PMID- 27776727 TI - Depressed Myocardial Contractility: Can It Be Rescued? AB - Current dogma suggests patients with advanced systolic heart failure have an irreversible depression in myocardial contractility. Recent experience with improved ventricular function during continuous flow ventricular assist devices used as destination therapy would suggest otherwise. Herein, cellular and molecular signaling involved in reversing depressed myocardial contractility would be addressed. This includes cardiomyocyte thyroid hormone signaling responsible for the reexpression of fetal gene program that preserves cell efficiency (work and energy consumed) and the rescue of an endogenous population of atrophic myocytes bordering on microdomains of fibrosis to improve contractile mass. PMID- 27776726 TI - Synchronous Primary Lung Cancer With Adenocarcinoma and Squamous Cell Carcinoma in the Right Upper Lobe. PMID- 27776728 TI - Value of Polymerase Chain Reaction in Diagnosis of Streptococcus pneumoniae Valve Endocarditis. PMID- 27776730 TI - Sinonasal Neuroendocrine Tumor With Head Lump and Seizures. PMID- 27776729 TI - Right Atrial Angiosarcoma Diagnosed by Cardiac Magnetic Resonance Imaging. PMID- 27776731 TI - Gastric Mucosa-associated Lymphoid Tissue Lymphoma: Posttransplant Lymphopoliferative Disorder. PMID- 27776732 TI - Tissue fibroblasts: From bystanders to proactive modulators of homeostasis and disease. PMID- 27776733 TI - [National patient follow-up care logbook: Guidelines by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. AB - In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country. Our article discusses the updates and modifications for the 2016 version of the national patient follow-up care logbook. PMID- 27776735 TI - Reply to: Neuroclinical Assessment of Addiction Needs to Incorporate Decision Making Measures and Ecological Validity. PMID- 27776736 TI - Neuroclinical Assessment of Addiction Needs to Incorporate Decision-Making Measures and Ecological Validity. PMID- 27776734 TI - Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice. AB - BACKGROUND: Adverse childhood experiences (ACEs) are one of the greatest predictors of affective disorders for women. Periods of dynamic hormonal flux, including pregnancy, exacerbate the risk for affective disturbance and promote hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a key feature of affective disorders. Little is understood as to how stress experienced in late childhood, defined as preadolescence, alters the programming unique to this period of brain maturation and its interaction with the hormonal changes of pregnancy and postpartum. METHODS: Preadolescent female mice were exposed to chronic stress and examined for changes in their HPA axis during pregnancy and postpartum, including assessment of maternal-specific stress responsiveness and transcriptomics of the paraventricular nucleus of the hypothalamus. Translationally, pregnant women with low or high ACEs were examined for their maternal stress responsiveness. RESULTS: As predicted, preadolescent stress in mice resulted in a significant blunting of the corticosterone response during pregnancy. Transcriptomic analysis of the paraventricular nucleus revealed widespread changes in expression of immediate early genes and their targets, supporting the likely involvement of an upstream epigenetic mechanism. Critically, in our human studies, the high ACE women showed a significant blunting of the HPA response. CONCLUSIONS: This unique mouse model recapitulates a clinical outcome of a hyporesponsive HPA stress axis, an important feature of affective disorders, during a dynamic hormonal period, and suggests involvement of transcriptional regulation in the hypothalamus. These studies identify a novel mouse model of female ACEs that can be used to examine how additional life adversity may provoke disease risk or resilience. PMID- 27776737 TI - Abnormal placentation: the role of MRI in diagnosis and therapeutic planning. AB - AIM: To evaluate the role of magnetic resonance imaging (MRI) for diagnosis and therapeutic planning in patients with abnormal placentation (AP). MATERIALS AND METHODS: Overall, 168 consecutive patients with suspected placenta previa and AP were referred for MRI before caesarean section (CS). The ability of MRI to properly detect and assess abnormal placentation was correlated with findings at CS, which were considered the reference standard diagnostic tool. For each patient, MRI was used to determine whether the AP was suitable for complete/incomplete delivery, hysterectomy, or conservative treatment. Treatment planning with MRI was prospectively compared with the actual treatment that had been carried out in each patient decided at CS. RESULTS: Placenta previa was detected at MRI in 63 patients and AP in 105 patients; 16 patients had false positive MRI findings, and three had false-negative findings. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI compared to findings at CS were 88.9% (149 of 168), 96.7% (89 of 92), 78.9% (60 of 76), 84.8% (89 of 105), and 95.2% (60 of 63), respectively. Treatment planning could be correctly made on the basis of MRI with accuracy, sensitivity, specificity, PPV, and NPV of 97%, 100%, 92.6%, 95.2%, and 100%, respectively. CONCLUSIONS: MRI offers high diagnostic accuracy in the detection of AP, and it may be helpful in the detailed planning of treatment. PMID- 27776738 TI - Bone marrow-derived innate macrophages attenuate oxazolone-induced colitis. AB - Previous studies have shown that a subpopulation of granulocyte macrophage colony stimulating factor (GM-CSF)-dependent F4/80high CD11bhigh innate macrophages could be derived from bone marrow cells by continuous in vitro culturing. These cells could be induced to differentiate into M1 or M2 macrophages in vitro. In the current study, we sought to determine whether bone marrow cell-derived innate macrophages (BMIMs) could be used to fulfill an anti-inflammatory purpose by intravenous transplantation in vivo after being stimulated to differentiate into M2 macrophages. Because Th2 cytokines, such as interleukin IL-4 and IL-13, can induce macrophage polarization into M2 macrophages, we treated the BMIMs with IL 4 and IL-13 in vitro. Next, the M2 macrophages were intravenously transplanted into a typical Th2-mediated inflammatory disease model, oxazolone (OXZ)-induced colitis, to assess the anti-inflammatory activity of BMIM-derived M2 macrophages (BMIM-M2Ms) in vivo. After transplantation, the severity of intestinal inflammation was attenuated. In addition, colon lengths and mouse body weights were noticeably improved. F4/80+ CD206+ double-positive cells (displaying the markers of M2 macrophages) had accumulated in the colon tissue of BMIM-M2M transplanted mice. This evidence demonstrated that bone marrow-derived BMIM-M2Ms could be used to alleviate OXZ-induced Th2-mediated inflammation in a mouse model in vivo. PMID- 27776739 TI - Deleterious effects in reproduction and developmental immunity elicited by pulmonary iron oxide nanoparticles. AB - With the extensive application of iron oxide nanoparticles (FeNPs), attention about their potential risks to human health is also rapidly raising, particularly in sensitive subgroups such as pregnant women and babies. In this study, we a single instilled intratracheally FeNPs (1, 2, and 4mg/kg) to the male and female parent mice, mated, then assessed reproductive toxicity according to the modified OECD TG 421. During the pre-mating period (14 days), two female parent mice died at 4mg/kg dose, and the body weight gain dose-dependently decreased in male and female parent mice exposed to FeNPs. Additionally, iron accumulation and the enhanced expression of MHC class II molecules were observed in the ovary and the testis of parent mice exposed to the highest dose of FeNPs, and the total sex ratio (male/female) of the offspring mice increased in the groups exposed to FeNPs. Following, we a single instilled intratracheally to their offspring mice with the same doses and evaluated the immunotoxic response on day 28. The increased mortality and significant hematological- and biochemical- changes were observed in offspring mice exposed at 4mg/kg dose, especially in female mice. More interestingly, balance of the immune response was shifted to a different direction in male and female offspring mice. Taken together, we conclude that the NOAEL for reproductive and developmental toxicity of FeNPs may be lower than 2mg/kg, and that female mice may show more sensitive response to FeNPs exposure than male mice. Furthermore, we suggest that further studies are necessary to identify causes of both the alteration in sex ratio of offspring mice and different immune response in male and female offspring mice. PMID- 27776741 TI - Mechanical properties and composition of carotid and femoral atherosclerotic plaques: A comparative study. AB - This study compares the mechanical properties of excised carotid and femoral human plaques and also develops a predictor of these properties based on plaque composition. Circumferential planar tension tests were performed on 24 carotid and 16 femoral plaque samples. Composition was characterised using Fourier Transform Infrared spectroscopy. Stretch at failure, strength, and stiffness are significantly higher in the carotid group (P=.012, P<.001 and P=.002, respectively). The ratio of calcified to lipid plaque content demonstrates the strongest correlation with the stretch at failure and strength (R2=.285, P<.001 and R2=.347, P<.001). No composition based parameter correlates significantly with stiffness. The significantly different mechanical properties of the two groups aids in explaining the varying endovascular treatment outcomes clinically observed in these vessels. Furthermore, determining the ratio of calcified to lipid plaque content may be useful in predicting individual plaque mechanical response to endovascular treatment. PMID- 27776740 TI - Estimating the gravity induced three dimensional deformation of the breast. AB - As human breast tissue is continuously deformed by gravity, it is difficult to identify the non-loaded neutral breast position from which to take measurements. To estimate the neutral nipple position, this study proposed a simple novel method to counteract the three dimensional effect of gravity on the breast using the buoyant forces from water and soybean oil (rhoWATER = 994kgm-3; rhoOIL = 909kgm-3). Fourteen female participants with breast sizes ranging from 30 to 34in. under band and B to E cup size took part in this study. Each participant had their static gravity-loaded nipple position measured and their neutral nipple position estimated (as the midpoint between the nipple position during water and soybean oil immersion). Participants were asked to sit in each fluid and fully submerge their torso and breasts. The mean gravity-induced nipple displacements from the neutral nipple position were 15.3mm in the posterior direction, 7.4mm in the lateral direction, and 25.7mm in the inferior direction. Gravity had a significant (p < 0.05, r > 0.82) measurable effect on the static nipple position, particularly in the inferior and posterior directions. Furthermore the density difference between water and soybean oil produced a significant difference (p < 0.05, r = 0.72) in superior-inferior nipple position (5.6mm). These findings suggest that neglect of gravity-induced breast deformations may lead to errors when assessing breast position and its relationship to possible breast pain, and that water alone may not be sufficient to estimate the neutral nipple position. PMID- 27776742 TI - Set-membership methodology for model-based prognosis. AB - This paper addresses model-based prognosis to predict Remaining Useful Life (RUL) of a class of dynamical systems. The methodology is based on singular perturbed techniques to take into account the slow behavior of degradations. The full-order system is firstly decoupled into slow and fast subsystems. An interval observer is designed for both subsystems under the assumption that the measurement noise and the disturbances are bounded. Then, the degradation is modeled as a polynomial whose parameters are estimated using ellipsoid algorithms. Finally, the RUL is predicted based on an interval evaluation of the degradation model over a time horizon. A numerical example illustrates the proposed technique. PMID- 27776743 TI - Open airway reconstruction in adults: Outcomes and prognostic factors. AB - PURPOSE: The purpose was to assess the success of open tracheal resection and re anastomosis for non-malignant tracheal stenosis in adults. Successful operations were defined as T-tube or tracheostomy-free status by 6months post-operatively. MATERIALS AND METHODS: Retrospective chart review was performed and data were recorded in a de-identified manner. The primary outcome was T-tube or tracheostomy-free status by 6months following tracheal resection. Clinical and demographic characteristics were evaluated as potential prognostic variables. RESULTS: Thirty-two patients met inclusion criteria, with a median age of 46. Seven patients underwent tracheal resection with primary closure, without stenting. Successful tracheal resection was defined as tracheostomy or T-tube free by 6months post-operation, and this was possible in 21 patients (66%). Eighty-two percent of patients with cricoid cartilage-sparing tracheal resection had a successful outcome, versus 30% of patients who underwent cricoid cartilage resection (HR 5.02, 95% CI 1.46-17.3; p=0.011). Patients with a history of tracheostomy-dependence were four times more likely to remain tube-dependent at 6months (HR 4.15, 95% CI 1.56-10.86; p=0.004). CONCLUSIONS: Tracheal stenosis remains a very difficult problem to treat. In our series, we confirm that patients with cricoid involvement or with a history of tracheostomy were more likely to be tube dependent at 6-months post-operation. PMID- 27776744 TI - Late-stage pharmaceutical R&D and pricing policies under two-stage regulation. AB - We present a model combining the two regulatory stages relevant to the approval of a new health technology: the authorisation of its commercialisation and the insurer's decision about whether to reimburse its cost. We show that the degree of uncertainty concerning the true value of the insurer's maximum willingness to pay for a unit increase in effectiveness has a non-monotonic impact on the optimal price of the innovation, the firm's expected profit and the optimal sample size of the clinical trial. A key result is that there exists a range of values of the uncertainty parameter over which a reduction in uncertainty benefits the firm, the insurer and patients. We consider how different policy parameters may be used as incentive mechanisms, and the incentives to invest in R&D for marginal projects such as those targeting rare diseases. The model is calibrated using data on a new treatment for cystic fibrosis. PMID- 27776745 TI - Musculoskeletal Dysfunctions in Patients With Chronic Pelvic Pain: A Preliminary Descriptive Survey. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of musculoskeletal dysfunctions based on a standardized clinical examination of patients with chronic pelvic pain (CPP) who were referred to a specialized tertiary care center for laparoscopic examination. In addition, we stratified levels of self-reported pelvic pain, self-rated health, education, and work status based on musculoskeletal dysfunction status. METHODS: This study used a cross-sectional design to determine the prevalence of musculoskeletal dysfunctions in women with CPP who were referred to a tertiary care center specializing in care of women with CPP. The women completed a questionnaire and underwent a blinded systematic objective clinical examination of the musculoskeletal system by a doctor of chiropractic who then categorized the patients as having or not having musculoskeletal dysfunction. RESULTS: Ninety four patients returned the questionnaire, completed the clinical examination, and fulfilled the inclusion criteria. More than half of the referred patients with CPP (48 out of 94) had musculoskeletal dysfunctions in the lumbar/pelvic region. No statistically significant differences were found between the groups with respect to self-rated health, education, work status, and pain level. Pain location was significantly different after Bonferroni correction in 1 out of the 36 aspects. CONCLUSIONS: In this sample of CPP patients, 51% were categorized as having a musculoskeletal dysfunction. Overall, CPP patients were similar with respect to certain characteristics, such as age, body mass index, and pain level, regardless of their classification; however, patients with musculoskeletal dysfunction tended to report more pain in the front and back of the lower limbs. PMID- 27776746 TI - Trends in the use of mechanical circulatory support as a bridge to heart transplantation across different age groups. AB - INTRODUCTION: Numerous cohort analyses suggest rapidly increasing use of mechanical circulatory support (MCS) as a bridge to heart transplantation (HTx), but the role of age in selection for MCS remains unknown. METHODS: We assessed adult HTx in the International Society for Heart And Lung Transplantation Registry between 2005 and 2013 and we determined MCS use by recipient age group and transplant year. Multivariable logistic regression models were constructed to identify variables associated with continuous flow (CF) left ventricular assist device (LVAD) use within each age group. RESULTS: Among 16,480 HTx recipients the percentage of overall MCS use increased from 23% to 38%, 21% to 41%, and 17% to 42% in age groups 18-39 years, 40-59 years and over 60 years, respectively. This effect was mainly due to an increase in CF LVAD use and primarily in HTx recipients aged over 60. In multivariable analyses, male gender and blood group O were significantly associated with CF LVAD use in all age groups. CONCLUSIONS: Bridge to transplant MCS use increased dramatically between 2005 and 2013 primarily due to increased use of CF LVAD and primarily in higher ages. Pre-HTx CF LVAD use was more frequent in men and blood group O. PMID- 27776748 TI - Does prostate volume has an impact on biochemical failure in patients with localized prostate cancer treated with HDR boost? AB - PURPOSE: To compare biochemical failure free survival (BFFS) of patients with small and large prostate glands treated with external beam radiation therapy (EBRT) and HDR (high dose rate) brachytherapy boost. MATERIALS AND METHODS: Between 2002 and 2012, 548 patients were treated with EBRT followed by HDR boost. The effect of covariates and prostate volume on biochemical failure was analyzed by survival analysis and Cox regression model. RESULTS: The median follow-up and age were not different between the two groups. The mean prostate gland volume at the time of CT planning was 48.1 and 76.0cc in small (<60cc) and large (? 60cc) prostate volume, respectively (p<0.001). When PSA bounces were excluded, there was no significant difference between the two groups with a 5-years BFFS of 95.8% vs 92.3%, p=0.094. There were no significant differences between the two groups for urinary symptoms (IPSS) as well as acute and late GI toxicities. CONCLUSIONS: This study showed that a HDR brachytherapy boost in large prostate gland cases is feasible at the price of increased PSA bounces. When the benign bounces are excluded, there is no significant difference between the two groups for tumor control and toxicity. Therefore, in our experience, there is no rational precluding the use of HDR boost in patients with a prostate size of 60 cc or more so long as an adequate dosimetry is achievable. PMID- 27776747 TI - Dose-dependent white matter damage after brain radiotherapy. AB - BACKGROUND AND PURPOSE: Brain radiotherapy is limited in part by damage to white matter, contributing to neurocognitive decline. We utilized diffusion tensor imaging (DTI) with multiple b-values (diffusion weightings) to model the dose dependency and time course of radiation effects on white matter. MATERIALS AND METHODS: Fifteen patients with high-grade gliomas treated with radiotherapy and chemotherapy underwent MRI with DTI prior to radiotherapy, and after months 1, 4 6, and 9-11. Diffusion tensors were calculated using three weightings (high, standard, and low b-values) and maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda?), and radial diffusivity (lambda?) were generated. The region of interest was all white matter. RESULTS: MD, lambda?, and lambda? increased significantly with time and dose, with corresponding decrease in FA. Greater changes were seen at lower b-values, except for FA. Time-dose interactions were highly significant at 4-6months and beyond (p<.001), and the difference in dose response between high and low b-values reached statistical significance at 9-11months for MD, lambda?, and lambda? (p<.001, p<.001, p=.005 respectively) as well as at 4-6months for lambda? (p=.04). CONCLUSIONS: We detected dose-dependent changes across all doses, even <10Gy. Greater changes were observed at low b-values, suggesting prominent extracellular changes possibly due to vascular permeability and neuroinflammation. PMID- 27776749 TI - alpha-Synuclein-Based Animal Models of Parkinson's Disease: Challenges and Opportunities in a New Era. AB - In recent years, a new generation of animal models of Parkinson's disease (PD) based on ectopic expression, overexpression, or intracerebral injection of the protein alpha-synuclein have emerged. Critically, these models develop inclusions of aggregated alpha-synuclein and/or alpha-synuclein-mediated neuronal loss replicating the defining pathological hallmarks of PD and driving significant advances in the understanding of the pathogenic mechanisms underpinning PD. Here, we provide a comprehensive review of this new generation of animal models of PD, ranging from invertebrate to rodent to nonhuman primate. We focus on their strengths and limitations with respect to their highly anticipated contribution to the further understanding of alpha-synuclein pathobiology and the future testing of novel disease-modifying therapeutics. PMID- 27776750 TI - Intravenous Ferric Carboxymaltose in Children with Iron Deficiency Anemia Who Respond Poorly to Oral Iron. AB - OBJECTIVE: To assess the benefits and risks of intravenous (IV) ferric carboxymaltose (FCM) in children with iron deficiency anemia (IDA). STUDY DESIGN: In a retrospective cohort study of patients seen at our center, we identified all FCM infusions in children with IDA over a 12-month period through a query of pharmacy records. Clinical data, including hematologic response and adverse effects, were extracted from the electronic medical record. RESULTS: A total of 116 IV FCM infusions were administered to 72 patients with IDA refractory to oral iron treatment (median age, 13.7 years; range, 9 months to 18 years). Median preinfusion and postinfusion hemoglobin values were 9.1 g/dL and 12.3 g/dL, respectively (at 4-12 weeks after the initial infusion; n = 53). Sixty-five patients (84%) experienced no adverse effects. Minor transient complications were encountered during or immediately after 7 infusions. CONCLUSION: FCM administered as a short IV infusion without a test dose proved to be safe and highly effective in a small yet diverse population of infants, children, and adolescents with IDA refractory to oral iron therapy. PMID- 27776751 TI - Eyelid Mass Secondary to T-Cell Lymphoma in a Child: A Rare Presentation and Literature Review. PMID- 27776752 TI - Acute Perinatal Sentinel Events, Neonatal Brain Injury Pattern, and Outcome of Infants Undergoing a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. AB - : Infants with perinatal sentinel events in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Hypothermia for Encephalopathy Trial had more basal ganglia and thalamus lesions on brain magnetic resonance imaging but similar neurodevelopmental outcomes at 18 months of age than infants without perinatal sentinel events. Outcomes correlated with the neonatal magnetic resonance imaging findings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005772. PMID- 27776753 TI - Comparison of Methods of Initial Ascertainment in 58 Cases of Propionic Acidemia Enrolled in the Inborn Errors of Metabolism Information System Reveals Significant Differences in Time to Evaluation and Symptoms at Presentation. AB - OBJECTIVES: To compare time to evaluation and symptoms at diagnosis of propionic acidemia (PA) by method of ascertainment, and to explore correlations between genotype and biochemical variables. STUDY DESIGN: Clinical symptoms, genotype, and biochemical findings were analyzed retrospectively in 58 individuals with PA enrolled in the Inborn Errors of Metabolism Information System (IBEM-IS) based on the type of initial ascertainment: abnormal newborn screening (NBS), clinical presentation (symptomatic), or family history. RESULTS: The average age at initial evaluation and treatment was significantly younger in patients ascertained via abnormal NBS compared with those referred for clinical symptoms. Furthermore, the majority of individuals ascertained because of abnormal NBS were asymptomatic at diagnosis, compared with a minority of clinical presentations. A notable difference in the frequency of metabolic acidosis at initial presentation was observed between those with abnormal NBS (12.5%; 2 of 16) and those with an abnormal clinical presentation (79%; 19 of 24). The frequency of hyperammonemia was similar in the 2 groups. CONCLUSION: Our data support the continued value of NBS to identify individuals with PA, who are diagnosed and treated earlier than for other modes of ascertainment. There were no statistically significant correlations between genotype and NBS for C3 acylcarnitines. Although expanded use of NBS has allowed for early diagnosis and treatment, long-term outcomes of individuals with PA, especially with respect to mode of ascertainment, remain unclear and would benefit from a longitudinal study. PMID- 27776754 TI - Nosocomial outbreaks in Brazil: can they be controlled? PMID- 27776755 TI - Multicenter proficiency benchmarks for advanced laparoscopic suturing tasks. AB - BACKGROUND: Advanced laparoscopic suturing (LS) tasks were developed based on a needs assessment. Initial validity evidence has been shown. The purpose of this multicenter study was to determine expert proficiency benchmarks for these tasks. METHODS: 6 tasks were included: needle handling (NH), offset-camera forehand suturing (OF), offset-camera backhand suturing (OB), confined space suturing (CF), suturing under tension (UT), and continuous suturing (CS). Minimally invasive surgeons experienced in LS completed the tasks twice. Mean time and median accuracy scores were used to establish the benchmarks. RESULTS: Seventeen MIS surgeons enrolled, from 7 academic centers. Mean (95% CI) time in seconds to complete each task was: NH 169 (149-189), OF 158 (134-181), OB 189 (154-224), CF 181 (156-205), UT 379 (334-423), and CS 416 (354-477). Very few errors in accuracy were made by experts in each of the tasks. CONCLUSIONS: Time- and accuracy-based proficiency benchmarks for 6 advanced LS tasks were established. These benchmarks will be included in an advanced laparoscopic surgery curriculum currently under development. PMID- 27776756 TI - Psychometric properties of the Global Operative Assessment of Laparoscopic Skills (GOALS) using item response theory. AB - BACKGROUND: The extent to which each item assessed using the Global Operative Assessment of Laparoscopic Skills (GOALS) contributes to the total score remains unknown. The purpose of this study was to evaluate the level of difficulty and discriminative ability of each of the 5 GOALS items using item response theory (IRT). METHODS: A total of 396 GOALS assessments for a variety of laparoscopic procedures over a 12-year time period were included. Threshold parameters of item difficulty and discrimination power were estimated for each item using IRT. RESULTS: The higher slope parameters seen with "bimanual dexterity" and "efficiency" are indicative of greater discriminative ability than "depth perception", "tissue handling", and "autonomy". CONCLUSIONS: IRT psychometric analysis indicates that the 5 GOALS items do not demonstrate uniform difficulty and discriminative power, suggesting that they should not be scored equally. "Bimanual dexterity" and "efficiency" seem to have stronger discrimination. Weighted scores based on these findings could improve the accuracy of assessing individual laparoscopic skills. PMID- 27776757 TI - Utilization of iron (III)-doped nanoshells for in vivo marking of nonpalpable tumors using a VX2 rabbit model. AB - BACKGROUND: We aimed to evaluate the potential for ultrasound (US) visible biodegradable nanoshells (NS) as an alternative to wire-guided localization for nonpalpable tumors in vivo. METHODS: VX2 tumor was injected in bilateral thighs of 22 New Zealand rabbits and after 5 to 10 days, 1 tumor was marked with a wire as a control and the contralateral tumor was injected with 1 mL of 500 nm gas filled silica NS under Doppler US. Tumors were excised after 24 hours. Chi-square was used for significance, P = .05. RESULTS: One rabbit was excluded on postoperative day 1 due to equipment failure, no ill effects were observed from the NS. The NS were used to localize and resect 100% of marked tissue, 4/21 wires were displaced (P < .05). CONCLUSIONS: We have shown that preoperatively injected US visible silica NS can be successfully used to mark nonpalpable tumors in vivo more consistently than WL. PMID- 27776758 TI - It depends on your perspective: Resident satisfaction with operative experience. AB - INTRODUCTION: Resident satisfaction is a key performance metric for surgery programs; we studied factors influencing resident satisfaction in operative cases, and the concordance of faculty and resident perceptions on these factors. METHODS: Resident and faculty were separately queried on satisfaction immediately following operative cases. Statistical significance of the associations between resident and faculty satisfaction and case-related factors were tested by Chi square or Fisher's exact test. RESULTS: Residents and faculty were very satisfied in 56/87 (64%) and 36/87 (41%) of cases respectively. Resident satisfaction was associated with their perceived role as surgeon (p < 0.04), performing >50% of the case (p < 0.01), autonomy (p < 0.03), and PGY year 4-5(p < 0.02). Faculty taking over the case was associated with both resident and faculty dissatisfaction. Faculty satisfaction was associated with resident preparation (p < 0.01), faculty perception of resident autonomy (p < 0.01), and faculty familiarity with resident's skills (p < 0.01). CONCLUSIONS: Resident and faculty satisfaction are associated with the resident's competent performance of the case, suggesting interventions to optimize resident preparation for a case or faculty's ability to facilitate resident autonomy will improve satisfaction with OR experience. PMID- 27776759 TI - Acupuncture: Health and Well-being. PMID- 27776760 TI - Types of Control in Acupuncture Clinical Trials Might Affect the Conclusion of the Trials: A Review of Acupuncture on Pain Management. AB - Analgesic effects of acupuncture have been extensively studied in various clinical trials. However, the conclusion remains controversial, even among large scale randomized controlled trials. This study aimed to evaluate the association between the conclusion of the trials and the types of control used in those trials via systematic review. Published randomized controlled trials of acupuncture for pain were retrieved from electronic databases (Medline, AMED, Cochrane libraries, EMBASE, PsycINFO, Clinicaltrials.gov, and CAB Abstracts) using a prespecified search strategy. One hundred and thirty-nine studies leading to 166 pairs of acupuncture-control treatment effect comparisons (26 studies comprised of 53 intervention-control pairs) were analyzed based on the proportion of positive conclusions in different control designs. We found that treatment effects of acupuncture compared with nontreatment controls had the highest tendency to yield a positive conclusion (84.3%), compared with nonneedle insertion controls (53.3%). Whereas with needle-insertion controls, the lowest tendency of positive conclusions was observed (37.8%). Consistently, in studies reporting successful blinding, a higher tendency of positive findings on the treatment effect of acupuncture was found in the noninsertion sham controls compared with that in the insertion sham controls. We conclude that the type of control is likely to affect the conclusion in acupuncture analgesic trials. Appropriate control should be chosen according to the aims of studies. PMID- 27776761 TI - Intraoperative Low-frequency Electroacupuncture under General Anesthesia Improves Postoperative Recovery in a Randomized Trial. AB - Neuronal stimulation improves physiological responses to infection and trauma, but the clinical potential of this strategy is unknown. We hypothesized that transdermal neural stimulation through low-frequency electroacupuncture might control the immune responses to surgical trauma and expedite the postoperative recovery. However, the efficiency of electroacupuncture is questioned due to the placebo effect. Here, electroacupuncture was performed on anesthetized patients to avoid any placebo. This is a prospective double-blinded pilot trial to determine whether intraoperative electroacupuncture on anesthetized patients improves postoperative recovery. Patients with electroacupuncture required 60% less postoperative analgesic, even they had pain scores similar to those in the control patients. Electroacupuncture prevented postoperative hyperglycemia and attenuated serum adrenocorticotropic hormone in the older and heavier group of patients. From an immunological perspective, electroacupuncture did not affect the protective immune responses to surgical trauma, including the induction of interleukin-6 and interleukin-10. The most significant immunological effect of electroacupuncture was enhancing transforming growth factor-beta1 production during surgery in the older and lighter group of patients. These results suggest that intraoperative electroacupuncture on anesthetized patients can reduce postoperative use of analgesics and improve immune and stress responses to surgery. PMID- 27776762 TI - Soluble N-ethylmaleimide-sensitive Factor Attachment Receptor (SNARE) Protein Involved in the Remission of Depression by Acupuncture in Rats. AB - This study aims to investigate the molecular mechanisms of acupuncture in the remission of depression. A depressive disorder model was induced by exposing Sprague-Dawley rats to chronic unpredictable stress. The rats were divided into five groups: healthy (blank group) and stressed rats (model group), and stressed rats treated with acupuncture (acupuncture group), riluzole (riluzole group), acupuncture combined with botulinum toxin A (BTX-A) injection (acupuncture+BTX-A group) or riluzole combined with BTX-A injection (riluzole+BTX-A group). Behavioral analysis showed significant differences in sucrose consumption, weight, and horizontal or vertical movements between the model and both the riluzole and acupuncture groups. No obvious differences between the riluzole+BTX A and acupuncture+BTX-A groups were found. Moreover, no significance differences in glutamate content in the hippocampus were found among the riluzole+BTX-A, acupuncture+BTX-A and model groups (p>0.05). Western blots and reverse transcription polymerase chain reactions were employed to detect protein and mRNA expressions of VGLUT2, SNAP25, VAMP1, VAMP2, VAMP7, and syntaxin1; no obvious differences among the riluzole+BTX-A, acupuncture+BTX-A and model groups were found. These data suggest that soluble N-ethylmaleimide-sensitive factor attachment receptor proteins are involved in the remission of depression in rats treated with acupuncture. PMID- 27776763 TI - Unilateral and Immediate Stimulation of Acupuncture Points Xiaohai (SI8) and Jianwaishu (SI14) of the Small Intestine Meridian Increases Electromyographic Activity and Strength in the Ipsilateral and Contralateral Upper Trapezius Muscle. AB - We previously showed that a yin meridian of the upper limb decreased electromyographic activity (root mean square) and muscle strength ipsilateral and contralateral to the side of stimulation. Here, we tested the upper trapezius (UT) muscle response after stimulation of a yang meridian of the upper limb, the small intestine (SI). Thirty-eight healthy volunteers were randomized into the following groups: UT muscle (SI14), distant of the UT muscle (SI8), without stimulation (CG), and sham (R3). An acupuncturist certificated by the Brazilian Society of Physical Therapists and Acupuncturists performed the needle insertion. Each volunteer received only one stimulation to the right upper limb. The evaluation occurred before, 5 minutes after, and 20 minutes after needle withdrawal. The root mean square activity increased on the right side in the UT muscle for the SI8 and SI14 groups (F3,37 = 4.67; p < 0.025) at the 20-minute evaluation. The most vigorous response occurred on the contralateral side because the effects were maintained for 5 minutes after withdrawal (F3,37 = 4.52; p < 0.025). Both groups showed an increase in the UT muscle strength at the 20-minute evaluation (F3,37 = 3.41; p < 0.025). The CG and R3 groups did not show any changes. Our data indicate that SI a yang meridian increases the UT muscle response. PMID- 27776764 TI - Comparison of the Effects of Manual Acupuncture, Laser Acupuncture, and Electromagnetic Field Stimulation at Acupuncture Point BL15 on Heart Rate Variability. AB - The aim of this study was to compare the influences of manual acupuncture, laser acupuncture, and electromagnetic field stimulation on the autonomic nervous system. We monitored the heart rate variability before and after stimulation to check the influence on the autonomic nervous system. The heart rate variabilities at low frequency (LF; 0.04-0.15 Hz) and high frequency (HF; 0.15-0.4 Hz) were analyzed to acquire LF/HF ratio. Xinshu (BL15) was selected as the stimulation point. Methods included manual acupuncture with a 1-cm depth and laser acupuncture at a wavelength of 660 nm and output power of 50 mW. An electromagnetic field of 2 Hz and 460 gauss (46 mT) was chosen. The LF and the LF/HF ratio were found to be lower in the manual acupuncture and the electromagnetic field groups, but to be higher in the laser acupuncture group. The HF was found to be lower in the laser acupuncture group, but higher in the manual acupuncture and the electromagnetic field groups. In conclusion, we found that manual acupuncture and electromagnetic field stimulation at BL15 activated the parasympathetic nervous system, whereas laser acupuncture at BL15 activated the sympathetic nervous system. PMID- 27776765 TI - Evaluation of the Effectiveness of Acupuncture Therapy by Verbal Pain Scale in Patients with Abdominal Pain of Familial Mediterranean Fever. AB - In this study, we evaluated the effectiveness of acupuncture therapy based on Verbal Pain Scale (VPS) scores in familial Mediterranean fever (FMF) patients admitted to the emergency department with attacks of abdominal pain. This observational study was conducted in Erzurum Regional Training and Research Hospital between August 2014 and December 2014. Twenty patients admitted to the emergency department with FMF attacks were included in the study. Acupuncture therapy was applied to three points including LI4 (Hegu), ST25 (Tianshu), and Ren12 (Zhongwan). The VPS test was applied to the patients before and after the treatment. Average VPS scores were found to be 8.45+/-0.75 before the treatment and 2.10+/-0.85 after the treatment. The difference of the VPS scores before and after treatment was statistically significant (p=0.001). To our knowledge, this is the first study evaluating the effectiveness of acupuncture therapy in the treatment of FMF attacks. Our results suggest that acupuncture therapy can be used as an effective treatment method in patients with FMF attacks. PMID- 27776766 TI - Amblyopia: Can Laser Acupuncture be an Option? AB - This paper describes the results of the treatment of amblyopia in young patients using an unconventional laser-acupuncture technique. After obtaining satisfactory results in the treatment of a 14-year-old amblyopic girl, the treatment was applied to 13 amblyopic children aged 3-11 years, with an encouraging outcome. An ultralow-light-intensity laser with a square-wave modulated emission was applied over a sequence of acupuncture points. Each session lasted < 15 minutes, and the treatment was performed once a week in 6-week cycles. Patients were followed for several years to evaluate the long-term results and/or to extend the treatment. All except two of the treated patients showed a rapid increase in visual acuity after several treatment sessions. Some required retreatment for regressions in visual acuity. The need for medium-term treatment cycles seems, however, to suggest that results may not be stable for all individuals. Although acupuncture has already been proved to be effective in the treatment of amblyopia, the results reported in this paper suggest that laser acupuncture at ultra-low-light intensity levels can provide similar, if not better, results to conventional acupuncture stimulation, but with higher patient compliance. PMID- 27776767 TI - A Case Report on the Effect of Sham Acupuncture. AB - When nausea, an extremely unpleasant symptom, is experienced during dental treatment, it generates disorders and obstacles for both the patient and the professional, compromising the good quality of dental care. Clinical studies have confirmed the antiemetic action of acupuncture and shown its use for the treatment of nausea and vomiting. In the scientific literature there are several recent studies that address the placebo effect of acupuncture. The aim of this manuscript is to present a case report of a 46-year-old Caucasian male patient, who had severe symptoms of nausea while undergoing dental care. Treatment with sham acupuncture (acupuncture simulation) obtained a positive result of nausea prevention. We will discuss three possible hypotheses concerning this result: (1) there was action of Deqi; (2) high expectations of the patient; and (3) association with specific learned response. The patient in this case report received nonpenetrating sham acupuncture at acupoint Neiguan (PC6), which resulted in the complete remission of nausea during an intra-oral impression taking procedure, but it is unclear whether the placebo effect was triggered by the action of Deqi, the high expectations of the patient, an association with a learned response, or by the interaction of all these factors. PMID- 27776768 TI - The Use of Bile Salt Micelles for the Prediction of Human Intestinal Absorption. AB - Human intestinal absorption (HIA) will dictate biopharmaceutical performance through its influence on absorption, distribution, metabolism, and elimination and can vary significantly depending upon the nature of the compound under consideration. In this study, an in vitro assay method is proposed for the prediction of HIA through the measurement of drug solubility in an aqueous phase containing micellar bile salt, namely sodium deoxycholate. A series of twenty compounds, displaying a range of physicochemical properties and known HIA values, were analyzed using UV spectroscopy to determine a solubilization ratio for each compound. A micelle/water partition coefficient (Kxm/a) was calculated and then used to develop an equation through simple linear regression; logit HIA = -0.919 + 0.4618 logKxm/a (R2 = 0.85). From this equation, a value for % HIA was determined which compared well with literature. Furthermore, 4 additional drugs were then analyzed using the developed equation and found to match well with literature, confirming the suitability of the method. Using a simple, economic, and robust UV bile salt assay allows prediction of HIA and avoids many of the disadvantages of other techniques, such as animal-based methods. PMID- 27776769 TI - Host-Guest Complexes of Carboxylated Pillar[n]arenes With Drugs. AB - Pillar[n]arenes are a new family of nanocapsules that have shown application in a number of areas, but because of their poor water solubility their biomedical applications are limited. Recently, a method of synthesizing water-soluble pillar[n]arenes was developed. In this study, carboxylated pillar[n]arenes (WP[n], n = 6 or 7) have been examined for their ability to form host-guest complexes with compounds relevant to drug delivery and biodiagnostic applications. Both pillar[n]arenes form host-guest complexes with memantine, chlorhexidine hydrochloride, and proflavine by 1H nuclear magnetic resonance and modeling. Binding is stabilized by hydrophobic effects within the cavities, and hydrogen bonding and electrostatic interactions at the portals. Encapsulation within WP[6] results in the complete and efficient quenching of proflavine fluorescence, giving rise to "on" and "off" states that have potential in biodiagnostics. The toxicity of the pillar[n]arenes was examined using in vitro growth assays with the OVCAR-3 and HEK293 cell lines. The pillar[n]arenes are relatively nontoxic to cells except at high doses and after prolonged continuous exposure. Overall, the results show that there could be a potentially large range of medical applications for carboxylated pillar[n]arene nanocapsules. PMID- 27776770 TI - Control of Globular Protein Thermal Stability in Aqueous Formulations by the Positively Charged Amino Acid Excipients. AB - The positively charged amino acids are commonly used excipients in biopharmaceutical formulations for stabilization of therapeutic proteins, yet the mechanisms for their modulation of protein stability are poorly understood. In this study, both lysine and histidine are shown to affect the thermal stability of myoglobin, bovine serum albumin, and lysozyme through a combination of mechanisms governed by their respective functional side chains and glycine, similar to arginine. This study provides evidence that at low concentrations, lysine and histidine interact with proteins by a combination of (1) direct electrostatic interactions with negatively charged side chains, (2) possible binding to high-affinity hydrophobic binding sites, and (3) glycine-mediated weak interactions with peptide backbone and polar side chains. At high concentrations, lysine and histidine act via (4) glycine-mediated competition for water between the unfolding protein and the excipient and (5) sidechain-mediated interaction with apolar regions exposed during unfolding (histidine). Lysine and histidine are useful for biopharmaceutical formulations as they were less destabilizing of the protein structures tested than arginine at concentrations above 100 mM. PMID- 27776771 TI - Determination of particulate phase polycyclic aromatic hydrocarbons and their nitrated and oxygenated derivatives using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. AB - An analytical method has been developed for the quantitative determination of polycyclic aromatic hydrocarbons (PAHs) and their nitrated and oxygenated derivatives (nitro- and oxy-PAHs respectively) in particulate matter (PM) samples. The sample preparation procedure included only a simple and quick sonication-assisted extraction step, clean-up based on addition of water and centrifugation as well as pre-concentration under N2 stream. The determination of 16 PAHs and 4 oxy-PAHs was carried out by gas chromatography-mass spectrometry, while liquid chromatography-tandem mass spectrometry was used in the case of the 11 investigated nitro-PAHs. The optimized method was fully evaluated in terms of trueness, precision (repeatability), limit of detection (LOD), limit of quantification (LOQ), sensitivity and linearity. The LOQ values ranged at pgm-3 level for the investigated PAHs (42pgm-3), oxy-PAHs (either 42 or 83pgm-3) and nitro-PAHs (either 83 or 167pgm-3) as well. The developed method was applied for the quantitative determination of PAHs, nitro- and oxy-PAHs in urban PM2.5 (particles with aerodynamic diameter smaller than 2.5MUm) samples (n=36) collected in Budapest, Hungary. Almost 100% of the PM2.5 samples contained the investigated PAHs and oxy-PAHs in detectable and quantifiable amounts; however, the concentration of the nitro-PAHs was generally lower than the corresponding LOD/LOQ values. According to our results, during the 3-year long sampling campaign the concentration of benzo(a)pyrene never exceeded the limit value (1ngm 3) set by the European Commission. PMID- 27776772 TI - Preparation of a boronate affinity silica stationary phase with enhanced binding properties towards cis-diol compounds. AB - In this study, a boronate affinity silica stationary phase with enhanced binding properties towards cis-diol compounds was prepared through the combination of surface-initiated atom transfer radical polymerization (SI-ATRP) with a Wulff type boronate as affinity ligand. The stationary phase showed good hydrophilicity and improved binding strength toward adenosine, with binding constant to be as low as 2.38*10-4M. The column exhibited excellent binding specificity, low binding pH (>=5.5) and high binding capacities (80.1MUmol adenosine g-1 at pH 7.0 and 45.2MUmol adenosine g-1 at pH 5.5, respectively). The stationary phase was applied as adsorbent for the selective extraction of nucleosides in human urine with excellent specificity and high enrichment efficiency. These results demonstrated that this stationary phase could be favorably applied for selective capture and enrichment of cis-diol compounds in complex samples. PMID- 27776773 TI - A coacervative extraction based on single-chain and double-chain cationic surfactants. AB - A coacervative extraction (CAE) with the common cationic surfactants dodecyltrimethylammonium bromide (DTAB) and didodecyldimethylammonium bromide (DDAB) was firstly developed. Notable characteristics of the CAE was the use of low concentration of salt (0.1molL-1 NaBr) at ambient temperature and without the requirement of organic solvent. The CAE was based on phase separation due to the neutralization of the surface charge of the micelle by electrostatic interaction with the predominant common counter ion (bromide). The coacervative phase was subjected to an optimized micellar liquid chromatography with UV (MLC-UV) method without any treatments. The method was applied to the determination of penicillins including amoxicillin, ampicillin, penicillin-G, oxacillin, and cloxacillin in milk samples. Method detection limits (MDLs) from standard were 0.5-2ngmL-1, and 40-80-fold analyte enrichment were obtained. The CAE-MLC-UV has shown to be of high potential for the analysis of five penicillins in milk with recoveries >90%. PMID- 27776774 TI - Development and validation of ultra-high-performance liquid chromatography-tandem mass spectrometry methods for the simultaneous determination of beauvericin, enniatins (A, A1, B, B1) and cereulide in maize, wheat, pasta and rice. AB - Rapid and accurate UPLC-MS/MS methods for the simultaneous determination of beauvericin and the related enniatins (A, A1, B, B1), together with cereulide were successfully developed and validated in cereal and cereal-based food matrices such as wheat, maize, rice and pasta. Although these emerging foodborne toxins are of different microbial origin, the similar structural, toxicological and food safety features provided rationale for their concurrent detection in relevant food matrices. A Waters Acquity UPLC system coupled to a Waters Quattro Premier XETM Mass Spectrometer operating in ESI+ mode was employed. Sample pretreatment involved a fast and simple liquid extraction of the target toxins without any further clean-up step. For all toxins the sample preparation resulted in acceptable extraction recoveries with values of 85-105% for wheat, 87-106% for maize, 84-106% for rice and 85-105% for pasta. The efficient extraction protocol, together with a fast chromatographic separation of 7min allowed substantial saving costs and time showing its robustness and performance. The validation of the developed method was performed based on Commission Decision 2002/657/EC. The obtained limits of detection ranged from 0.1 to 1.0MUgkg-1 and the limits of quantification from 0.3 to 2.9MUgkg-1 for the targeted toxins in the selected matrices. The obtained sensitivities allow detection of relevant toxicological concentrations. All relative standard deviations for repeatability (intra-day) and intermediate precision (inter-day) were lower than 20%. Trueness, expressed as the apparent recovery varied from 80 to 107%. The highly sensitive and repeatable validated method was applied to 57 naturally contaminated samples allowing detection of sub-clinical doses of the toxins. PMID- 27776775 TI - Microcrystalline cellulose based matrix solid phase dispersion microextration for isomeric triterpenoid acids in loquat leaves by ultrahigh-performance liquid chromatography and quadrupole time-of-flight mass spectrometry. AB - An analytical procedure based on matrix solid phase dispersion (MSPD) microextration and ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was developed for the determination of isomeric triterpenoid acids (maslinic acid, corosolic acid, oleanolic acid and ursolic acid) in loquat leaves. Microcrystalline cellulose was used for the first time as a solid sorbent in MSPD microextration. Compared with the traditional extraction methods, the proposed method possessed the advantages of shorter extraction time, and lower consumption of sample, sorbent and organic solvent. The MSPD parameters that influenced the extraction efficiency of isomeric analytes were investigated and optimized in detail. Under the optimized conditions, good linearity was obtained with correlation coefficients higher than 0.9990. The limits of detection and quantification were 19.6-51.6MUg/kg and 65.3 171.8MUg/kg, respectively. Meanwhile, the recoveries obtained for all the analytes were ranging from 90.1% to 107.5%. Finally, the optimized method was successfully applied for analyzing these isomeric acids in loquat leaves samples obtained from different cultivated areas. PMID- 27776776 TI - 7th International Water and Health Seminar. PMID- 27776778 TI - Mobile Transcripts and Intercellular Communication in Plants. AB - Phloem serves as a highway for mobile signals in plants. Apart from sugars and hormones, proteins and RNAs are transported via the phloem and contribute to the intercellular communication coordinating growth and development. Different classes of RNAs have been found mobile and in the phloem exudate such as viral RNAs, small interfering RNAs (siRNAs), microRNAs, transfer RNAs, and messenger RNAs (mRNAs). Their transport is considered to be mediated via ribonucleoprotein complexes formed between phloem RNA-binding proteins and mobile RNA molecules. Recent advances in the analysis of the mobile transcriptome indicate that thousands of transcripts move along the plant axis. Although potential RNA mobility motifs were identified, research is still in progress on the factors triggering siRNA and mRNA mobility. In this review, we discuss the approaches used to identify putative mobile mRNAs, the transport mechanism, and the significance of mRNA trafficking. PMID- 27776777 TI - Bacteria in the respiratory tract-how to treat? Or do not treat? AB - BACKGROUND: Acute and chronic respiratory tract infections are a common cause of inappropriate antimicrobial prescription. Antimicrobial therapy leads to the development of resistance and the emergence of opportunistic pathogens that substitute the indigenous microbiota. METHODS: This review explores the major challenges and lines of research to adequately establish the clinical role of bacteria and the indications for antimicrobial treatment, and reviews novel therapeutic approaches. RESULTS: In patients with chronic pulmonary diseases and structural disturbances of the bronchial tree or the lung parenchyma, clinical and radiographic signs and symptoms are almost constantly present, including a basal inflammatory response. Bacterial adaptative changes and differential phenotypes are described, depending on the clinical role and niche occupied. The respiratory tract has areas that are potentially inaccessible to antimicrobials. Novel therapeutic approaches include new ways of administering antimicrobials that may allow intracellular delivery or delivery across biofilms, targeting the functions essential for infection, such as regulatory systems, or the virulence factors required to cause host damage and disease. Alternatives to antibiotics and antimicrobial adjuvants are under development. CONCLUSIONS: Prudent treatment, novel targets, and improved drug delivery systems will contribute to reduce the emergence of antimicrobial resistance in lower respiratory tract infections. PMID- 27776779 TI - Receptor-Like Kinases and Regulation of Plant Innate Immunity. AB - Plants are sessile organisms exposed constantly to potential virulent microbes seeking for full pathogenesis in hosts. Different from animals employing both adaptive and innate immune systems, plants only rely on innate immunity to detect and fight against pathogen invasions. Plant innate immunity is proposed to be a two-tiered immune system including pathogen-associated molecular pattern (PAMP) triggered immunity (PTI) and effector-triggered immunity. In PTI, PAMPs, the elicitors derived from microbial pathogens, are perceived by cell surface localized proteins, known as pattern recognition receptors (PRRs), including receptor-like kinases (RLKs) and receptor-like proteins (RLPs). As single-pass transmembrane proteins, RLKs and RLPs contain an extracellular domain (ECD) responsible for ligand binding. Recognitions of signal molecules by PRR-ECDs induce homo- or heterooligomerization of RLKs and RLPs to trigger corresponding intracellular immune responses. RLKs possess a cytoplasmic Ser/Thr kinase domain that is absent in RLPs, implying that protein phosphorylations underlie key mechanism in transducing immunity signalings and that RLPs unlikely mediate signal transduction independently, and recruitment of other patterns, such as RLKs, is required for the function of RLPs in plant immunity. Receptor-like cytoplasmic kinases, resembling RLK structures but lacking the ECD, act as immediate substrates of PRRs, modulating PRR activities and linking PRRs with downstream signaling mediators. In this chapter, we summarize recent discoveries illustrating the molecular machines of major components of PRR complexes in mediating pathogen perception and immunity activation in plants. PMID- 27776780 TI - The Plastid Terminal Oxidase is a Key Factor Balancing the Redox State of Thylakoid Membrane. AB - Mitochondria possess oxygen-consuming respiratory electron transfer chains (RETCs), and the oxygen-evolving photosynthetic electron transfer chain (PETC) resides in chloroplasts. Evolutionarily mitochondria and chloroplasts are derived from ancient alpha-proteobacteria and cyanobacteria, respectively. However, cyanobacteria harbor both RETC and PETC on their thylakoid membranes. It is proposed that chloroplasts could possess a RETC on the thylakoid membrane, in addition to PETC. Identification of a plastid terminal oxidase (PTOX) in the chloroplast from the Arabidopsis variegation mutant immutans (im) demonstrated the presence of a RETC in chloroplasts, and the PTOX is the committed oxidase. PTOX is distantly related to the mitochondrial alternative oxidase (AOX), which is responsible for the CN-insensitive alternative RETC. Similar to AOX, an ubiquinol (UQH2) oxidase, PTOX is a plastoquinol (PQH2) oxidase on the chloroplast thylakoid membrane. Lack of PTOX, Arabidopsis im showed a light dependent variegation phenotype; and mutant plants will not survive the mediocre light intensity during its early development stage. PTOX is very important for carotenoid biosynthesis, since the phytoene desaturation, a key step in the carotenoid biosynthesis, is blocked in the white sectors of Arabidopsis im mutant. PTOX is found to be a stress-related protein in numerous research instances. It is generally believed that PTOX can protect plants from various environmental stresses, especially high light stress. PTOX also plays significant roles in chloroplast development and plant morphogenesis. Global physiological roles played by PTOX could be a direct or indirect consequence of its PQH2 oxidase activity to maintain the PQ pool redox state on the thylakoid membrane. The PTOX-dependent chloroplast RETC (so-called chlororespiration) does not contribute significantly when chloroplast PETC is normally developed and functions well. However, PTOX-mediated RETC could be the major force to regulate the PQ pool redox balance in the darkness, under conditions of stress, in nonphotosynthetic plastids, especially in the early development from proplastids to chloroplasts. PMID- 27776781 TI - Histone Acetylation and Plant Development. AB - Reversible histone acetylation and deacetylation at the N-terminus of histone tails play a crucial role in regulation of gene activity. Hyperacetylation of histones relaxes chromatin structure and is associated with transcriptional activation, whereas hypoacetylation of histones induces chromatin compaction and gene repression. Histone acetylation and deacetylation are catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Emerging evidences revealed that plant HATs and HDACs play essential roles in regulation of gene expression in plant development and plant responses to environmental stresses. Furthermore, HATs and HDACs were shown to interact with various chromatin-remodeling factors and transcription factors involved in transcriptional regulation of multiple developmental processes. PMID- 27776782 TI - Plant Stress Responses Mediated by CBL-CIPK Phosphorylation Network. AB - At any given time and location, plants encounter a flood of environmental stimuli. Diverse signal transduction pathways sense these stimuli and generate a diverse array of responses. Calcium (Ca2+) is generated as a second messenger due to these stimuli and is responsible for transducing the signals downstream in the pathway. A large number of Ca2+ sensor-responder components are responsible for Ca2+ signaling in plants. The sensor-responder complexes calcineurin B-like protein (CBL) and CBL-interacting protein kinases (CIPKs) are pivotal players in Ca2+-mediated signaling. The CIPKs are the protein kinases and hence mediate signal transduction mainly by the process of protein phosphorylation. Elaborate studies conducted in Arabidopsis have shown the involvement of CBL-CIPK complexes in abiotic and biotic stresses, and nutrient deficiency. Additionally, studies in crop plants have also indicated their role in the similar responses. In this chapter, we review the current literature on the CBL and CIPK network, shedding light into the enzymatic property and mechanism of action of CBL-CIPK complexes. We also summarize various reports on the functional modulation of the downstream targets by the CBL-CIPK modules across all plant species. PMID- 27776783 TI - Modulation of Host Endocycle During Plant-Biotroph Interactions. AB - Recent studies have revealed that several mutualistic and parasitic biotrophic microbes induce a cell cycle variant termed the endocycle in host cells to support their growth and reproduction. Endoreduplication is a process in which cells successively replicate their genomes without mitosis resulting in an increase in nuclear DNA ploidy. Depending on the interaction, endoreduplication can support biotroph colonization and feeding structure initiation/development, and/or serve as a mechanism to support enhanced metabolic demands of the microbe. When endoreduplication is inhibited in these interactions, biotroph growth or development is compromised. In this review, we summarize the molecular machinery known to mediate endocycle control in plants and highlight the role of these core components in feeding site establishment and/or nutrient acquisition for a diverse set of plant biotrophs. PMID- 27776784 TI - Preface. PMID- 27776785 TI - Has the rescheduling of hydrocodone changed ED prescribing practices? AB - OBJECTIVE: The objective was to examine the effect of hydrocodone-containing product (HCP) rescheduling on the proportion of prescriptions for HCPs given to patients discharged from the emergency department (ED). METHODS: Electronic queries of ED records were used to identify patients aged 15 years and older discharged with a pain-related prescription in the 12 months before and after HCP rescheduling. Prescriptions were classified as HCPs; other Schedule II medications (eg, oxycodone products); other Schedule III medications (eg, codeine products); and non-Schedule II/III products (eg, nonsteroidal anti-inflammatory drugs). We compared the proportions of patients receiving each type of prescription before and after rescheduling using chi2 analysis and used logistic regression to explore the relationship between prescription type and time period while controlling for age, sex, race, and ethnicity. RESULTS: Before rescheduling, 58.1% (95% confidence interval [CI], 57.4-58.7) of patients receiving a pain-related prescription received an HCP; after rescheduling, 13.2% (95% CI, 12.7-13.7) received an HCP (P < .001). Concurrently, other Schedule III prescriptions increased (pre: 11.7% [CI, 11.3-12.2] vs post: 44.9% [CI, 44.2 45.6], P < .001)), as did non-Schedule II/III prescriptions (pre: 51.8% [CI, 51.2 52.5] vs post: 59.3% [CI, 58.6-60.0], P < .001). When controlling for demographic characteristics, patients remained less likely to receive an HCP after rescheduling (adjusted odds ratio [AOR], 0.11; CI, 0.10-0.11) and more likely to receive other Schedule III (AOR, 6.1; CI, 5.8-6.5) and non-Schedule II/III (AOR, 1.4; CI, 1.3-1.4) products. CONCLUSION: Rescheduling HCPs from Schedule III to Schedule II led to a substantial decrease in HCP prescriptions in our ED and an increase in prescriptions for other Schedule III and non-Schedule II/III products. PMID- 27776787 TI - Molecular characterization of ESBL-producing Escherichia coli isolates from hospital- and community-acquired infections in NW Mexico. AB - We investigated the molecular characteristics of ESBL-producing E. coli (ESBL PEc) isolates from two hospitals and community settings in Ciudad Obregon, Sonora, Mexico. Between 2011 and 2014, thirty-seven ESBL-PEc isolates were collected. The major encoded ESBL was the blaCTX-M-15 gene (97%); followed by 13.5% of the blaSHV-12 gene, and 5.5% encoded the blaTLA-1 gene. The PMQR gene aac(6')-Ib-cr was detected in 97% of the isolates and the qnrB gene, in one isolate. The ESBL-PEc isolates corresponded to phylogenetic group B2, ST131. Our results highlight the dissemination of ESBL-PEc isolates in northwest Mexico (Ciudad Obregon, Sonora). PMID- 27776786 TI - Preventing falls in assisted living: Results of a quality improvement pilot study. AB - Residents of assisted living (AL) communities are at high risk for falls, which result in negative outcomes and high health care costs. Adapting effective falls prevention programs for AL quality improvement (QI) has the potential to reduce falls, improve resident quality of life, and reduce costs. This project tested the feasibility and outcomes of an evidence-based multi-component QI program, the Assisted Living Falls Prevention and Monitoring Program (AL-FPMP). Resident posture and gait improved, likely due to exercise and/or physical therapy. Effective falls prevention QI programs can be implemented in AL, and are advised to (1) establish and maintain a falls team to create a culture focused on the reduction of falls risk; (2) teach staff to assess residents using the Morse Falls Scale to increase their awareness of residents' falls risk and improvement; and (3) modify existing exercise programs to address balance and lower body strength. PMID- 27776788 TI - Diversity of polymyxin resistance mechanisms among Acinetobacter baumannii clinical isolates. AB - Polymyxins have become drugs of last resort for treatment of multi-drug resistant (MDR) Gram-negative infections. However, the mechanisms of resistance to this compound have not been completely elucidated. In this study, we evaluated the mechanisms of resistance to this antimicrobial in two A. baumannii clinical isolates, respectively, susceptible (A027) and resistant (A009) to polymyxin B before and after polymyxin B exposure (A027ind and A009ind). The pmrAB and lpxACD were sequenced and their transcriptional levels were analyzed by qRT-PCR. The bacterial cell morphology was evaluated by transmission electronic microscopy (TEM) and the membrane potential was measured using Zeta-potential analyzer. The virulence of strains was studied using a Caenorhabditis elegans model. Both clinical isolates exhibited an elevation of the polymyxin B MIC after exposure to this compound. On the other hand, A027ind showed decreased values of MIC for beta lactams, aminoglycosides, vancomycin, teicoplanin, oxacillin and erythromycin. A027ind harbored two mutations in pmrB and the ISAba125 disrupting the lpxA. In contrast, A009ind strain exhibited increase of pmrB transcriptional level, after polymyxin B exposure, despite the absence of mutations in the pmrAB genes. The TEM images revealed a thicker and more electron-dense peptidoglycan layer for A009 than that of A027. The exposure to polymyxin B induced a strong condensation and darkening of intracellular material, mainly in A009ind. In addition, the surface charge of A009 was significantly less negative than the one of A027. Using the C. elegans model, only A027ind strain showed a reduction on virulence. The diversity of polymyxin B resistance mechanisms among A. baumannii strains evaluated in this study confirms the complexity of these mechanisms, which may vary depending of the background of each strain. PMID- 27776789 TI - Preferences and needs of patients with a rheumatic disease regarding the structure and content of online self-management support. AB - OBJECTIVE: Aim of this study was to investigate preferences and needs regarding the structure and content of a person-centered online self-management support intervention for patients with a rheumatic disease. METHODS: A four step procedure, consisting of online focus group interviews, consensus meetings with patient representatives, card sorting task and hierarchical cluster analysis was used to identify the preferences and needs. RESULTS: Preferences concerning the structure involved 1) suitability to individual needs and questions, 2) fit to the life stage 3) creating the opportunity to share experiences, be in contact with others, 4) have an expert patient as trainer, 5) allow for doing the training at one's own pace and 6) offer a brief intervention. Hierarchical cluster analysis of 55 content needs comprised eleven clusters: 1) treatment knowledge, 2) societal procedures, 3) physical activity, 4) psychological distress, 5) self-efficacy, 6) provider, 7) fluctuations, 8) dealing with rheumatic disease, 9) communication, 10) intimate relationship, and 11) having children. CONCLUSION: A comprehensive assessment of preferences and needs in patients with a rheumatic disease is expected to contribute to motivation, adherence to and outcome of self-management-support programs. PRACTICE IMPLICATIONS: The overview of preferences and needs can be used to build an online-line self-management intervention. PMID- 27776790 TI - The association of health literacy and blood pressure reduction in a cohort of patients with hypertension: The heart healthy lenoir trial. AB - OBJECTIVE: Lower health literacy is associated with poorer health outcomes. Few interventions poised to mitigate the impact of health literacy in hypertensive patients have been published. We tested if a multi-level quality improvement intervention could differentially improve Systolic Blood Pressure (SBP) more so in patients with low vs. higher health literacy. METHODS: We conducted a non randomized prospective cohort trial of 525 patients referred with uncontrolled hypertension. Stakeholder informed and health literacy sensitive strategies were implemented at the practice and patient level. Outcomes were assessed at 0, 6, 12, 18 and 24 months. RESULTS: At 12 months, the low and higher health literacy groups had statistically significant decreases in mean SBP (6.6 and 5.3mmHg, respectively), but the between group difference was not significant (Delta 1.3mmHg, P=0.067). At 24 months, the low and higher health literacy groups reductions were 8.1 and 4.6mmHg, respectively, again the between group difference was not significant (Delta 3.5mmHg, p=0.25). CONCLUSIONS/PRACTICE IMPLICATIONS: A health literacy sensitive multi-level intervention may equally lower SBP in patients with low and higher health literacy. Practical health literacy appropriate tools and methods can be implemented in primary care settings using a quality improvement approach. PMID- 27776791 TI - What is the mechanism of the second tachycardia? PMID- 27776792 TI - In Memoriam-Dr. Bernard Kosowsky. PMID- 27776793 TI - How accurately does high tibial osteotomy correct the mechanical axis of an arthritic varus knee? A systematic review. AB - BACKGROUND: The aim of this study was to give an overview of the accuracy of coronal limb alignment correction after high tibial osteotomy (HTO) for the arthritic varus knee by performing a systematic review of the literature. METHODS: The databases PubMed, MEDLINE and Cochrane Library were screened for relevant articles. Only prospective clinical studies with the accuracy of alignment correction by performing HTO as primary or secondary objective were included. RESULTS: Fifteen studies were included in this systematic review and were subdivided in 23 cohorts. A total of 966 procedures were considered. Nine cohorts used computer navigation during HTO and the other 14 cohorts used a conventional method. In seven computer navigation cohorts, at least 75% of the study population fell into the accepted "range of accuracy" (AR) as proposed by the different studies, but only six out of 14 conventional cohorts reached this percentage. Four out of eight conventional cohorts that provided data on under- and overcorrection, had a tendency to undercorrection. CONCLUSIONS: The accuracy of coronal alignment corrections using conventional HTO falls short. The number of procedures outside the proposed AR is surprising and exposes a critical concern for modern HTO. Computer navigation might improve the accuracy of correction, but its use is not widespread among orthopedic surgeons. Although HTO procedures have been shown to be successful in the treatment of unicompartmental knee arthritis when performed accurately, the results of this review stress the importance of ongoing efforts in order to improve correction accuracy in modern HTO. PMID- 27776794 TI - Oncolytic influenza A virus expressing interleukin-15 decreases tumor growth in vivo. AB - BACKGROUND: Interleukin-15 has become a promising molecule in the context of eliciting an effective, antitumor immune response because it is able to stimulate cells of the innate and adaptive immune system. METHODS: We generated an interleukin-15-expressing oncolytic influenza A virus for the treatment of an established murine tumor model. RESULTS: Our oncolytic influenza A virus produced large amounts of interleukin-15 and induced proliferation and activation of human T cells in vitro. Intraperitoneal administration increased the amount of mouse natural killer cells and effector memory T cells, as well as T cell reactivity in vivo. Moreover, intratumoral injection induced a profound decrease in growth of established tumors in mice and increased the amount of tumor-infiltrating T cells and natural killer cells. CONCLUSION: We established a stable, IL-15-producing oncolytic influenza A virus with promising immunostimulatory and antitumor attributes. PMID- 27776796 TI - Improving access to cognitive behavioral therapy for insomnia (CBT-I). PMID- 27776797 TI - [Patterns of prescription of opioid analgesics in Hotel-Dieu de France of Beyrouth]. AB - OBJECTIVES: Use of chronic opioid therapy has increased substantially over the past few years, even though opioid therapy is associated with potentially serious harms, including opioid-related adverse effects and outcomes. Prescription of opioids for chronic pain, particularly nonmalignant chronic pain, remains controversial. In the midst of this controversy, patterns of actual prescription and influences on these patterns are not well understood. This study aims to describe the frequency of prescription of opioid analgesics in a university hospital, the attitudes of doctors towards this category of drugs, and the follow up modalities of patients taking these drugs. The study also explores the association between the practitioners' characteristics and the modalities of prescription. DESIGN AND METHODS: A survey was delivered to 112 doctors and surgeons in the hospital during the four months between August and December 2013 and it was returned by 55 (49.0%). The survey consists of three parts. The first part addresses the frequency and reluctance of doctors' prescription of opioids and other analgesics for acute and chronic pain. The second part studies the doctors' attitudes and concerns towards opioids. It explores the belief of the doctors in the efficacy of this category of drugs, their confidence in prescribing such medications and the eventual side effects they might worry about. The third part of the survey studies the modalities of evaluation prior to the prescription and the modalities of follow-up of the patients receiving a long term opioid treatment. RESULTS: Overall, 76.4% of doctors reported they sometimes, frequently, or always, prescribe opioids, which, using the Wilcoxon test, proved to be a significantly lower frequency than for prescribing of minor analgesics or nonsteroidal anti-inflammatory drugs (NSAIDS). Similarly, 60.1% reported a reluctance to prescribe opioids for chronic nonmalignant pain, which was a significantly greater reluctance than for cancer pain. The age and sex of the participants were unrelated to prescribing, but those with specialty training and use of practice guidelines were more likely to prescribe opioids and were less reluctant to do so. A majority of practitioners felt that opioids are effective for the treatment of chronic nonmalignant pain and that they have the sufficient training to prescribe them adequately; however, they still worry about the long-term prescription of opioids, particularly fearing the psychological dependence this treatment might cause. Using a series of Spearman correlation tests, we found that practitioners who thought they were adequately trained and who believed in the efficacy of long-term opioid treatment were more likely to prescribe them but that the worries about side effects decreased the frequency of prescription. A significant proportion of practitioners do not evaluate addiction risk factors of patients before prescribing opioids. The results concerning the modalities of follow-up of prescription were very heterogeneous with 87% of practitioners not explaining and 65% not screening for adverse effects. We similarly found that the frequency of follow-up and the management of patients who were exhibiting signs of dependence were very diverse. CONCLUSION: The results of this study were compatible with those of other recent studies about opioid prescription. The doctors practicing in the university hospital Hotel-Dieu de France de Beyrouth present comparable prescription patterns, independent of their personal or professional characteristics, and they are more confident in their prescription when professionally trained for it. However, they exhibit a notable heterogeneity in their attitudes towards opioids and in their modalities of evaluating patients receiving long-term treatment. These results suggest a need for additional training in the management of this category of drugs. PMID- 27776798 TI - Percutaneous Coronary Intervention as a Trigger for Stroke. AB - Percutaneous coronary intervention (PCI) is a plausible triggering factor for stroke, yet the magnitude of this excess risk remains unclear. This study aimed to quantify the transient change in risk of stroke for up to 12 weeks after PCI. We applied the case-crossover method, using data from the Norwegian Patient Register on all hospitalizations in Norway in the period of 2008 to 2014. The relative risk (RR) of ischemic stroke was highest during the first 2 days after PCI (RR 17.5, 95% confidence interval [CI] 4.2 to 72.8) and decreased gradually during the following weeks. The corresponding RR was 2.0 (95% CI 1.2 to 3.3) 4 to 8 weeks after PCI. The RR for women was more than twice as high as for men during the first 4 postprocedural weeks, RR 10.5 (95% CI 3.8 to 29.3) and 4.4 (95% CI 2.7 to 7.2), respectively. Our results were compatible with an increased RR of hemorrhagic stroke 4 to 8 weeks after PCI, but the events were few and the estimates were very imprecise, RR 3.0 (95% CI 0.8 to 11.1). The present study offers new knowledge about PCI as a trigger for stroke. Our estimates indicated a substantially increased risk of ischemic stroke during the first 2 days after PCI. The RR then decreased gradually but stayed elevated for 8 weeks. Increased awareness of this vulnerable period after PCI in clinicians and patients could contribute to earlier detection and treatment for patients suffering a postprocedural stroke. PMID- 27776795 TI - Early plasma transfusion is associated with improved survival after isolated traumatic brain injury in patients with multifocal intracranial hemorrhage. AB - BACKGROUND: Plasma-based resuscitation improves outcomes in trauma patients with hemorrhagic shock, while large-animal and limited clinical data suggest that it also improves outcomes and is neuroprotective in the setting of combined hemorrhage and traumatic brain injury. However, the choice of initial resuscitation fluid, including the role of plasma, is unclear for patients after isolated traumatic brain injury. METHODS: We reviewed adult trauma patients admitted from January 2011 to July 2015 with isolated traumatic brain injury. "Early plasma" was defined as transfusion of plasma within 4 hours. Purposeful multiple logistic regression modeling was performed to analyze the relationship of early plasma and inhospital survival. After testing for interaction, subgroup analysis was performed based on the pattern of brain injury on initial head computed tomography: epidural hematoma, intraparenchymal contusion, subarachnoid hemorrhage, subdural hematoma, or multifocal intracranial hemorrhage. RESULTS: Of the 633 isolated traumatic brain injury patients included, 178 (28%) who received early plasma were injured more severely coagulopathic, hypoperfused, and hypotensive on admission. Survival was similar in the early plasma versus no early plasma groups (78% vs 84%, P = .08). After adjustment for covariates, early plasma was not associated with improved survival (odds ratio 1.18, 95% confidence interval 0.71-1.96). On subgroup analysis, multifocal intracranial hemorrhage was the largest subgroup with 242 patients. Of these, 61 (25%) received plasma within 4 hours. Within-group logistic regression analysis with adjustment for covariates found that early plasma was associated with improved survival (odds ratio 3.34, 95% confidence interval 1.20-9.35). CONCLUSION: Although early plasma transfusion was not associated with improved in-hospital survival for all isolated traumatic brain injury patients, early plasma was associated with increased in-hospital survival in those with multifocal intracranial hemorrhage. PMID- 27776799 TI - Relation Between Clinical Best Practices and 6-Month Outcomes After Transcatheter Aortic Valve Implantation With CoreValve (from the ADVANCE II Study). AB - Best practices for transcatheter aortic valve implantation with CoreValve include patient screening and valve size selection using multislice computed tomography, adherence to manufacturer recommendations for oversizing, control of implant depth to 6 mm or less, and management of conduction disturbances according to international guidelines. The ADVANCE II study implemented these strategies and demonstrated their relation to clinical outcomes. From October 2011 to April 2013, 200 patients with severe aortic stenosis were enrolled, and 194 were implanted. All imaging and electrocardiographic data were analyzed by an independent core laboratory, and adverse events were adjudicated to valve academic research consortium-2 definitions. The mean age was 80.2 +/- 6.7 years and the mean Society of Thoracic Surgeons Predicted Risk of Mortality was 7.2 +/- 6.8% for the enrolled patients. At 6 months, all-cause mortality was 9.2%, stroke was 2.6%, and permanent pacemaker implantation was 19.2% for class I and II indications. In patients with implant depth <=6 mm, both mortality and permanent pacemaker implantation were lower than in patients with depth >6 mm (2.5% vs 14.5%, p <0.01 and 18.1% vs 31.7%, p = 0.03, respectively). The rate of moderate and severe paravalvular leak was 9.8% at 7 days after transcatheter aortic valve implantation, decreasing to 4.3% at 6 months (p = 0.02). Valves were significantly more oversized in patients with mild or less paravalvular leak at day 7 compared with those with moderate or severe (15.8 +/- 8.0% vs 11.8 +/- 4.9%, p = 0.01). In conclusion, findings from the ADVANCE II study reinforce that adherence to best clinical practices improves patient outcomes. PMID- 27776800 TI - Influence of Myocardial Ischemia Extent on Left Ventricular Global Longitudinal Strain in Patients After ST-Segment Elevation Myocardial Infarction. AB - Two-dimensional echocardiographic left ventricular (LV) global longitudinal strain (GLS) after ST-segment elevation myocardial infarction (STEMI) is moderately correlated with infarct size and reflects the residual LV systolic function. This correlation may be influenced by the presence of myocardial ischemia. The present study investigated how myocardial ischemia modulates the correlation between LV GLS and infarct size determined with single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in patients with first STEMI treated with primary coronary intervention. A total of 1,128 patients (age 60 +/- 11 years) who underwent SPECT MPI for the evaluation of infarct size and residual ischemia were evaluated. LV GLS was measured on transthoracic echocardiography. The time interval between echocardiography and SPECT MPI was 1 +/- 1 month. A moderate correlation between echocardiographic LV GLS and infarct size on SPECT MPI was observed (r = 0.58, p <0.001). This correlation was weakened by the presence or extent of ischemia; in the group of patients without ischemia, the correlation between LV GLS and infarct size on SPECT MPI was r = 0.66 (p <0.001), whereas in patients with mild or moderate-to severe ischemia, the correlations were r = 0.56 and 0.38, respectively (both p <0.001). Moderate-to-severe myocardial ischemia was independently associated with more impaired LV GLS after adjusting for infarct size, age, diabetes mellitus, and hypertension (beta 0.60, 95% confidence interval 013 to 1.06). In conclusion, the presence of myocardial ischemia after STEMI impacts on the correlation between echocardiographic LV GLS and infarct size measured on SPECT MPI. Residual ischemia is independently associated with more impaired LV GLS. PMID- 27776802 TI - Bone Anchored Hearing Aid (BAHA) in children: Experience of a tertiary referral centre in Portugal. AB - OBJECTIVES: The aim of this study is to describe the experience of a tertiary referral centre in Portugal, of the placement of BAHA in children. METHODS: The authors performed a retrospective analysis of all children for whom hearing rehabilitation with BAHA was indicated at a central hospital, between January 2003 and December 2014. RESULTS: 53 children were included. The most common indications for placement of BAHA were external and middle ear malformations (n=34, 64%) and chronic otitis media with difficult to control otorrhea (n=9, 17%). The average age for BAHA placement was 10.66+/-3.44 years. The average audiometric gain was 31.5+/-7.20dB compared to baseline values, with average hearing threshold with BAHA of 19.6+/-5.79dB. The most frequent postoperative complications were related to the skin (n=15, 28%). There were no major complications. CONCLUSIONS: This study concludes that BAHA is an effective and safe method of hearing rehabilitation in children. PMID- 27776801 TI - Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients With Asymptomatic Heart Failure. AB - Patients with asymptomatic heart failure (HF; stage A and B) are characterized by maladaptive left ventricular (LV) remodeling. Classic 4-group classification of remodeling considers only LV mass index and relative wall thickness as variables. Complex remodeling classification (CRC) includes also LV end-diastolic volume index. Main aim was to assess the prognostic impact of CRC in stage A and B HF. A total of 1,750 asymptomatic subjects underwent echocardiographic examination as a screening evaluation in the presence of cardiovascular risk factors. LV dysfunction, both systolic (ejection fraction) and diastolic (transmitral flow velocity pattern), was evaluated, together with LV remodeling. We considered a composite end point: all-cause death, myocardial infarction, coronary revascularizations, cerebrovascular events, and acute pulmonary edema. CRC was suitable for 1,729 patients (men 53.6%; age 58.3 +/- 13 years). Two hundred thirty-eight patients presented systolic dysfunction (ejection fraction <50%) and 483 diastolic dysfunction. According to the CRC, 891 patients were normals or presented with physiologic hypertrophy, 273 concentric remodeling, 47 eccentric remodeling, 350 concentric hypertrophy, 29 mixed hypertrophy, 86 dilated hypertrophy, and 53 eccentric hypertrophy. Age and gender distribution was noticed (p <0.001). After a median follow-up of 21 months, Kaplan-Meier analysis showed different survival distribution (p <0.001) of the CRC patterns. In multivariate Cox regression (adjusted for age, gender, history of stable ischemic heart disease, classic remodeling classification, systolic, and diastolic dysfunction), CRC was independent predictor of primary end point (p = 0.044, hazard ratio 1.101, 95% CI 1.003 to 1.21), confirmed in a logistic regression (p <0.03). In conclusion, CRC could help physicians in prognostic stratification of patients in stage A and B HF. PMID- 27776803 TI - Hypoparathyroidism following thyroidectomy: Predictive factors. AB - OBJECTIVE: To evaluate the incidence and predictive factors for transient and permanent hypocalcemia and hypoparathyroidism following thyroidectomy. METHOD: We studied all the 162 patients that underwent thyroid surgery in the ENT department of the Centro Hospitalar Vila Nova Gaia/Espinho from January 2005 to December 2014. We reviewed pre-operative, 6h and 12h after surgery ionized calcium and PTH levels. All patients were reviewed and evaluated according to the following criteria: gender, age, thyroid function, histologic diagnosis of the specimen, surgery extension and presence or absence of hypoparathyroidism. RESULTS: There were 31 (19.1%) cases of transient hypoparathyroidism and 8 (5%) of permanent hypoparathyroidism. No significant difference was found for transient hypoparathyroidism when patients were analyzed by gender. However, all cases of permanent hypoparathyroidism were observed in female individuals. Comparing hemithyroidectomy with all other surgical procedures, we found that extension of surgery was a great predictor of transient (p=0.0001) and permanent (p=0.001) hypoparathyroidism. Diagnosis of malignancy was a strong predictor of transient hypoparathyroidism (p=0.002). It was also associated with permanent hypoparathyroidism, although differences did not reach statistical significance (p=0.096). CONCLUSION: Extension of surgery (total thyroidectomy) and diagnosis of malignancy are predictors of transient and permanent hypoparathyroidism. PMID- 27776804 TI - Nasal agenesis and other facial malformations: Report of a case of congenital anomaly and literature review. PMID- 27776805 TI - Is the nasal airway the main mode of transmission for pharyngeal tuberculosis? PMID- 27776806 TI - Spontaneous laryngeal abscess causing dysphagia. PMID- 27776807 TI - Intranasal ectopic tooth. PMID- 27776809 TI - [Metameric macular and papular skin mastocytosis]. AB - BACKGROUND: Mastocytosis is characterised by the presence of abnormal quantities of mastocytes in one or more organs. Although it occurs in systemic forms of mastocytosis, isolated skin involvement is the predominant presentation, particularly in children, in the form of more or less extensive though non systematic lesions. Herein, we report a case of maculopapular cutaneous mastocytosis that is unusual in terms of its metameric topography. PATIENTS AND METHODS: A 16-year-old youth presented with an erythematous maculopapular rash of 18 months' duration and involving pruritic inflammatory episodes strictly localised in segment T8 to the left. The skin biopsy showed a significant increase in the number of dermal mastocytes (CD117+). No KIT mutations were found in the skin lesions nor in the unimpaired skin of the opposite side. Further investigations ruled out systemic mastocytis. DISCUSSION: Herein, we report a case of cutaneous mastocytosis that is unusual in terms of its metameric disposition. There have been only two previous reports of segmental cutaneous mastocytis. The two pathological hypotheses involved precessional dermatitis that renders the skin surface susceptible to homing, and somatic mosaicism (type 1) with local mastocyte proliferation. PMID- 27776808 TI - Evaluation of family history of permanent hearing loss in childhood as a risk indicator in universal screening. AB - INTRODUCTION AND OBJECTIVE: Sixty percent of prelingual hearing loss is of genetic origin. A family history of permanent childhood hearing loss is a risk factor. The objective of the study is to determine the relationship between this risk factor and hearing loss. We have evaluated clinical and epidemiological characteristics and related nonsyndromic genetic variation. MATERIAL AND METHOD: This was a retrospective, descriptive and observational study of newborns between January 2007 and December 2010 with family history as risk factor for hearing loss using transient evoked otoacoustic emissions and auditory brainstem response. RESULTS: A total of 26,717 children were born. Eight hundred and fifty seven (3.2%) had family history. Fifty-seven(0.21%) failed to pass the second test. A percentage of 29.1 (n=16) had another risk factor, and 17.8% (n=9) had no classical risk factor. No risk factor was related to the hearing loss except heart disease. Seventy-six point four percent had normal hearing and 23.6% hearing loss. The mean of family members with hearing loss was 1.25. On genetic testing, 82.86% of homozygotes was normal, 11.43% heterozygosity in Connexin 26 gene (35delG), 2.86% R143W heterozygosity in the same gene and 2.86% mutant homozygotes (35delG). We found no relationship between hearing loss and mutated allele. CONCLUSIONS: The percentage of children with a family history and hearing loss is higher than expected in the general population. The genetic profile requires updating to clarify the relationship between hearing loss and heart disease, family history and the low prevalence in the mutations analyzed. PMID- 27776811 TI - [Prevention of STD/STI]. PMID- 27776810 TI - [Management following sexual exposure to HIV, HVB and HVC]. PMID- 27776812 TI - [Mucopurulent cervicitis]. PMID- 27776813 TI - [Male urethritis]. PMID- 27776814 TI - [Genital ulcers]. PMID- 27776815 TI - [Vaccinations]. PMID- 27776816 TI - [STD in pregnancy]. PMID- 27776817 TI - [Assessment of the medico-economic characteristics of inpatient dermatological consultations at the Hopital Nord Franche-Comte: A prospective survey]. PMID- 27776818 TI - [STD in MSM]. PMID- 27776819 TI - Automated hand hygiene auditing with and without an intervention. AB - BACKGROUND: Daily feedback from continuous automated auditing with a peer reminder intervention was used to improve compliance. Compliance rates from covert and overt automated auditing phases with and without intervention were compared with human mandatory audits. METHODS: An automated system was installed to covertly detect hand hygiene events with each depression of the alcohol-based handrub dispenser for 5 months. The overt phase included key clinicians trained to share daily rates with clinicians, set compliance goals, and nudge each other to comply for 6 months. During a further 6 months, the intervention continued without being refreshed. Hand Hygiene Australia (HHA) human audits were performed quarterly during the intervention in accordance with the World Health Organization guidelines. Percentage point (PP) differences between compliance rates were used to determine change. RESULTS: HHA rates for June 2014 were 85% and 87% on the medical and surgical wards, respectively. These rates were 55 PPs and 38 PPs higher than covert automation rates for June 2014 on the medical and surgical ward at 30% and 49%, respectively. During the intervention phase, average compliance did not change on the medical ward from their covert rate, whereas the surgical ward improved compared with the covert phase by 11 PPs to 60%. On average, compliance during the intervention without being refreshed did not change on the medical ward, whereas the average rate on the surgical ward declined by 9 PPs. CONCLUSIONS: Automation provided a unique opportunity to respond to daily rates, but compliance will return to preintervention levels once active intervention ceases or human auditors leave the ward, unless clinicians are committed to change. PMID- 27776821 TI - Occupational health risks associated with use of environmental surface disinfectants in health care. PMID- 27776820 TI - Designing for cleanability: The effects of material, surface roughness, and the presence of blood test soil and bacteria on devices. AB - Cleaning reusable medical devices removes organic and inorganic soil, which allows for effective disinfection and sterilization. However, it is not always clear what variables to consider when validating cleaning. This study compared the ability of 3 different cleaning agents (ie, water, alcohol, and bleach) to remove bacteria (ie, vegetative and spores) and artificial blood test soil from 2 common device materials: polypropylene and ultra-high-molecular-weight polyethylene. There was a complex interaction between bacteria, soil, and surface roughness. PMID- 27776822 TI - Endorsing reporting guidelines: Infection control literature gets ahead of the game. PMID- 27776823 TI - Zika virus pandemic-analysis of Facebook as a social media health information platform. AB - The arrival of Zika virus in the United States has generated a lot of activity on social media focusing on the algorithmic increase in the spread of the disease and its concerning complications. Accurate and credible dissemination of correct information about the arbovirus could help in decreasing the pandemic spread and associated apprehension in the population. Our study examined the effective use of the social media site Facebook (Facebook Inc, Menlo Park, CA) as an information source for the Zika virus pandemic. We found that the misleading posts were far more popular than the posts dispersing accurate, relevant public health information about the disease. PMID- 27776825 TI - Review of single-port laparoscopic sleeve gastrectomy as a routine procedure in 1000 patients. PMID- 27776824 TI - A descriptive case study of the changing nature of nurses' work: The impact of managing infectious diseases requiring isolation. AB - Methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and Clostridium difficile have increased in health care facilities worldwide. The complexity of caring for patients with infectious comorbidities has impacted nurses' daily work. A mixed-methods study at 1 community hospital in Ontario, Canada, demonstrated the cumulative effect of additional time spent on infection prevention and control measures resulted in trade-offs, cutting corners, and raised concerns about the quality and continuity of care. PMID- 27776827 TI - Intranasal Dexmedetomidine Sedation as Adjuvant Therapy in Acute Asthma Exacerbation With Marked Anxiety and Agitation. AB - We describe 2 patients with acute asthma exacerbation who were admitted to the emergency department (ED) with severe agitation and restlessness as a prominent finding, for which bedside asthma treatment sedation with intranasal dexmedetomidine was performed. In both cases, dexmedetomidine allowed the patients to rest and improved tolerance to treatment. Dexmedetomidine is a unique sedative with an excellent safety profile and minimal effect on respiratory function. These properties render it particularly promising for the management of severe agitation in children admitted to the ED with acute asthma exacerbation. PMID- 27776829 TI - Comparative study of profiling post-translational modifications of a circulating antibody drug in human with different capture reagents. AB - Capture reagents are critical to affinity-based bioanalytical methods. The potential bias of capture reagents, for or against certain subpopulations of the target of interest, may lead to inaccurate quantitation. This issue is more profound for sensitive measurements, such as post-translational modification (PTM) profiling of therapeutic proteins from complex matrix. Here, a recently developed affinity purification coupled mass spectrometric method was utilized to assess the full sequence of a circulating therapeutic aglycosylated IgG1 (MAB3) in human subject, using two different capture reagents. We monitored all PTMs known to be related to MAB3 drug quality (three representative PTMs are shown in this paper). The results validated the comparability of these two reagents. PMID- 27776830 TI - Assessment of Multiple Co-Occurring Cancer Symptoms in the Clinical Setting. AB - OBJECTIVES: To discuss multiple co-occurring cancer symptoms, review symptom assessment instruments, identify innovative methods to integrate symptom assessment and management in the clinical setting, and examine barriers and facilitators for implementation of symptom assessment and use of clinical practice guidelines. DATA SOURCES: Peer-reviewed articles, guidelines, systematic reviews, and web-based resources. CONCLUSION: Despite the availability of brief, reliable, and valid instruments, symptom assessment has not been integrated as a routine aspect of clinical care. New technologies and changes in health policy provide an optimal environment to integrate electronic symptom assessment and management into cancer care. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses play a key role in early identification and management of distressing symptoms. PMID- 27776828 TI - Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array. AB - We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration. PMID- 27776831 TI - Defining the Symptom Cluster: How Far Have We Come? AB - OBJECTIVES: To examine the evolution of the concept of the symptom cluster through literature synthesis and identify knowledge gaps. DATA SOURCES: Published literature. CONCLUSION: A robust body of research has developed showing that clusters of symptoms can be identified empirically with modest evidence of convergence across methods. The science would benefit from a coordinated effort of qualitative studies to ensure that appropriate symptoms are evaluated; empirical symptom cluster identification studies building upon qualitative work; and subgroup identification studies based on empirically defined symptom clusters. IMPLICATIONS FOR NURSING PRACTICE: Work is needed to demonstrate the value of symptom cluster identification in guiding symptom assessment and management for cancer patients and survivors. PMID- 27776833 TI - Future Directions in Symptom Cluster Research. AB - OBJECTIVES: To consider future directions for symptom cluster research. These considerations are organized using the two main conceptual approaches for symptom cluster research (ie, "de novo" identification of symptom clusters, and identification of subgroups of patients with distinct symptom experiences with a prespecified symptom cluster). DATA SOURCES: Peer-reviewed journals and guidelines from professional organizations. CONCLUSION: Research on symptom clusters in oncology patients is growing at an exponential rate. However, numerous studies are needed to increase the growth of symptom management research. IMPLICATIONS FOR NURSING PRACTICE: Findings from this area of symptom management science have the potential to improve the management of multiple co occurring symptoms in oncology patients. In addition, mechanistic-based studies hold great promise to identify new biological and behavioral targets that will form the basis for subsequent intervention studies. PMID- 27776832 TI - Biological Basis for the Clustering of Symptoms. AB - OBJECTIVES: Identification of biologic pathways of symptom clusters is necessary to develop precision therapies for distressing symptoms. This review examined extant literature evaluating relationships between biomarkers and symptom clusters in cancer survivors. DATA SOURCES: PubMed, CINAHL, Web of Science and Cochrane Library were searched using terms "biological markers" or "biomarkers" and "symptom cluster" or "symptom complex" or "multiple symptoms." CONCLUSION: Biomarkers related to inflammation (eg, cytokines) were the most studied and showed the most significant relationships with clusters of symptoms. This review suggests that clustering of symptoms related to cancer or cancer therapy is linked to immune/inflammatory pathways. IMPLICATIONS FOR NURSING PRACTICE: Understanding the etiology of symptom clusters may guide future nursing interventions for symptom management. PMID- 27776834 TI - Symptom Clusters in Children and Adolescents with Cancer. AB - OBJECTIVE: To report evidence regarding assessment methods and management strategies for symptom clusters among children and adolescents with cancer. DATA SOURCES: Published research and clinical guidelines. CONCLUSION: Although a number of studies have identified multiple co-occurring symptoms in children and adolescents with cancer, only a few have included analyses aimed at identifying symptom clusters. Evidence is limited for symptom cluster management strategies. IMPLICATIONS FOR NURSING PRACTICE: Researchers and clinicians need to employ mechanisms that support children and adolescents to: 1) fully express multiple, co-occurring symptoms; 2) identify symptom clusters within specific developmental and diagnostic groups; and 3) develop and evaluate interventions targeting symptom clusters. PMID- 27776836 TI - Symptom Clusters. PMID- 27776837 TI - RNA-Targeting Therapies: Translating Hope. PMID- 27776835 TI - Exercise Recommendations for the Management of Symptoms Clusters Resulting From Cancer and Cancer Treatments. AB - OBJECTIVE: To review existing exercise guidelines for cancer patients and survivors for the management of symptom clusters. DATA SOURCES: Review of PubMed literature and published exercise guidelines. CONCLUSION: Cancer and its treatments are responsible for a copious number of incapacitating symptoms that markedly impair quality of life. The exercise oncology literature provides consistent support for the safety and efficacy of exercise interventions in managing cancer- and treatment-related symptoms, as well as improving quality of life in cancer patients and survivors. IMPLICATIONS FOR NURSING PRACTICE: Effective management of symptoms enhances recovery, resumption of normal life activities and quality of life for patients and survivors. Exercise is a safe, appropriate, and effective therapeutic option before, during, and after the completion of treatment for alleviating symptoms and symptom clusters. PMID- 27776838 TI - Indocyanine green fluorescence imaging of lymph nodes during robotic-assisted laparoscopic operation for endometrial cancer. A prospective validation study using a sentinel lymph node surgical algorithm. AB - OBJECTIVE: A sentinel lymph node (SLN) strategy may have particular value in endometrial cancer (EC) because a therapeutic effect of lymphadenectomy per se is unproven. The aim was to evaluate indocyanine green (ICG) and near-infrared (NIR) fluorescence mapping using a surgical algorithm. METHODS: From November 2012 through December 2015, women with apparently early stage EC underwent robot assisted laparoscopic hysterectomy including ICG fluorescence SLN mapping following the Memorial Sloane Kettering Cancer Center (MSKCC) surgical algorithm. RESULTS: Among 108 patients included, >=1 SLNs was identified in 104 (96%), bilaterally in 84 (78%) and unilaterally in 20 patients (18%). Four patients failed SLN mapping. All SLN-positive patients had pelvic SLNs. Median number of nodes were 4.0 and 6.0 (p<0.001), when SLNs only and SLNs plus non-SLNs were removed, respectively. Lymph node metastases were detected in 17 patients (16%). One patient who failed SLN mapping had a non-SLN metastasis. The remaining 16 patients had metastases in SLNs, 12 in SLNs only and four in both SLNs and non SLNs. Routine pathology detected 75% of patients with cancer positive SLNs while 25% were based on extended pathology. Lymph node metastases were found among 9% with low-, 11% with intermediate- and 32% with high-risk profiles, respectively. CONCLUSIONS: We have reproduced the high total and bilateral SLN mapping using cervical ICG injection and NIR fluorescence. Practical application of the MSKCC algorithm allowed high lymph node metastasis detection in combination with a low extent of lymph node removal. PMID- 27776839 TI - Kidney Function After the First Kidney Stone Event. AB - OBJECTIVE: To determine whether there is a persistent decline in kidney function after the first kidney stone event. PATIENT AND METHODS: Incident symptomatic stone formers and age- and sex-matched controls underwent 2 study visits 90 days apart to assess kidney function, complete a survey, and have their medical records reviewed. Kidney function was compared between stone formers and controls adjusting for clinical, blood, and urine risk factors. RESULTS: There were 384 stone formers and 457 controls. At visit 1, a median of 104 days after the stone event, stone formers compared with controls had similar serum creatinine (0.86 vs 0.84 mg/dL; P=.23), higher serum cystatin C (0.83 vs 0.72 mg/L; P<.001), higher urine protein (34.2 vs 19.7 mg/24 h; P<.001) levels, and were more likely to have albuminuria (24 h urine albumin >30 mg: 5.4% vs 2.2%; P=.02). Findings were similar after adjustment for risk factors and at visit 2, a median of 92 days after visit 1. In the 173 stone formers with serum creatinine levels from care before study participation, the mean serum creatinine level was 0.84 mg/dL before the stone event, increased to 0.97 mg/dL (P<.001) at the stone event, but returned to 0.85 mg/dL (P=.38) after the stone event (visit 1). CONCLUSIONS: Incident symptomatic stone formers have a rise in serum creatinine levels that resolves. However, stone formers have sustained higher cystatin C levels and proteinuria that may affect long-term risk of chronic kidney disease. PMID- 27776841 TI - Setting the record straight. PMID- 27776840 TI - Association of Physical Activity and Inflammation With All-Cause, Cardiovascular Related, and Cancer-Related Mortality. AB - OBJECTIVE: To investigate the association between physical activity (PA) and risk of mortality in a large middle-aged cohort stratified by inflammatory status. PATIENTS AND METHODS: A total of 336,560 individuals (mean age, 39.7 years; 58% male) who underwent comprehensive health screenings were enrolled in this prospective cohort study. They were grouped according to self-reported PA level using a questionnaire: no regular PA with a sedentary lifestyle, regular but insufficient PA (below the guidelines), sufficient PA (concordant with the guidelines), and health-enhancing PA. Inflammation was assessed via high sensitivity C-reactive protein (hsCRP) level. Study end points were all-cause, cardiovascular-related, and cancer-related mortality. RESULTS: During the 1,976,882 person-years of follow-up (median follow-up duration, 6.17 years), 2062 deaths occurred. Compared with a sedentary lifestyle, the hazard ratios (95% CIs) on the multivariable Cox proportional hazards regression analyses for all-cause mortality by PA level were 0.95 (0.84-1.07), 0.85 (0.72-0.99), and 0.75 (0.60 0.93) (P for trend=.003), and those for cardiovascular- and cancer-related mortality were 0.95, 0.80, and 0.55 (P for trend=.05) and 0.82, 0.83, and 0.78 (P for trend=.01), respectively. Compared with participants with low hsCRP levels and any regular PA, those with high hsCRP levels and no regular PA had a significantly higher risk of mortality (1.59 [1.38-1.84]). CONCLUSION: Higher PA levels were associated with a dose-dependent reduced risk of cardiovascular related, cancer-related, and all-cause mortality. Individuals with high hsCRP levels and no regular PA had the highest risk of mortality. PMID- 27776842 TI - Personalised therapy for localised gastric and gastro-oesophageal adenocarcinoma. PMID- 27776844 TI - Gross alpha and beta activity and annual committed effective dose due to natural radionuclides in some water spinach (ipomoea aquatica Forssk) samples in Ho Chi Minh City, Vietnam. AB - The results of gross alpha and beta radioactivity measurement in water spinach samples from some districts in Ho Chi Minh City, Vietnam are presented in this paper. The measurements were performed using a low-background proportional counters LB4200 manufactured by Canberra Company, Inc. Mean concentrations of gross alpha and beta activity were found to be 1.50 +/- 0.38 Bq kg-1 to 84.25 +/- 8.67 Bq kg-1. In order to keep the recommended dose level, a recommended maximum intake of water spinach was proposed to be 6 kg fresh per year. The total annual committed effective dose due to natural radionuclides in water spinach samples was then found in range from 0.07 mSv y-1 to 0.82 mSv y-1. The dose from 26.32% of samples exceeds the exemption mean dose criterion of 0.3 mSv y-1 but complies with the upper dose principle of 1 mSv y-1 provided in UNSCEAR 2008 report. The estimated soil-to-plant transfer factors for gross alpha and beta for water spinach samples were also presented. PMID- 27776843 TI - Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open label, randomised phase 2/3 trial. AB - BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. METHODS: In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0.02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). INTERPRETATION: Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. FUNDING: None. PMID- 27776845 TI - [The use of progestatives for the prevention of spontaneous preterm birth]. AB - OBJECTIVES: To identify clinical situations in which progestatives used to reduce the risk of spontaneous preterm delivery and/or reduced adverse neonatal outcomes have been evaluated and identify situations in which 17OHPC or vaginal progesterone might be recommended. METHODS: Bibliographic searches were performed in the Medline and Cochrane databases with the use of a combination of keywords and text words related to "progesterone", "tocolysis", and "preterm labor" from 1956 through July 2016. RESULTS: 17OHPC administrated after 16 weeks gestational age is not associated with an increased risk of birth defect (LE3). Because of discrepancies on the risk associated with first trimester utilization, it is recommended not to use it before 16 weeks (grade C). Utilization of 17OHPC and vaginal progesterone during both second and third trimester is not associated with an increased risk of congenital abnormalities and developmental adverse outcomes (LE3). Utilization of progestatives is not associated with an increased risk of intrahepatic cholestasis of pregnancy (LE3) and gestational diabetes (LE3). 17OHPC is not recommended as a primary prevention of preterm delivery in a population of women with monofetal pregnancy without history of preterm delivery (grade C). Although systematic screening of short cervix is not recommended (Professional consensus), the discovery of a short cervix (<20mm) between 16 and 24 weeks in an asymptomatic woman with monofetal pregnancy without history of preterm delivery indicates the daily administration of vaginal progesterone until 36 weeks gestational age (grade B). In a randomized controlled trial, 17OHPC is associated with a decreased risk of preterm delivery before 34 weeks gestationnal age (LE2) and with a reduction of neonatal morbidity (LE3) in women with at least one previous preterm delivery before 34 weeks gestationnal age. It is not possible to recommend the systematic use of 17OHPC on the basis of this sole trial with limited external validity (Professional consensus). Vaginal progesterone do not seem to be associated with a decreased risk of preterm delivery before 34 weeks (LE3), a better neonatal outcome (LE3) or a better cognitive development at the age of two (LE3) among asymptomatic patients with an history of preterm delivery (Professional consensus). Utilization of 17OHPC (LE2) in patients with monofetal pregnancy, a short cervix (<25mm) and a history of preterm delivery is not associated with reduced risk of preterm delivery. The utilization of 17OHPC is not recommended in this clinical context (grade B). In this context, vaginal progesterone may be associated with a decreased risk of preterm delivery (NP3) but further studies are needed to recommend its utilization (Professional consensus). Although some studies suggest a tocolytic effect of progestatives in case of preterm labor, qualitative scientific data are lacking to recommend this treatment in this situation (Professional consensus). Utilization of 17OHPC or vaginal progesterone after arrested preterm labor is not associated with a reduction of the risk of preterm delivery (LE1). Utilization of progestatives is not recommended after arrested preterm labor (grade A). In asymptomatic patients with twin pregnancies and normal or unknown cervix length, 17OHPC and vaginal progesterone are not associated with a reduction of the risk of preterm delivery (LE2). The utilization of progestatives is not recommended in this context (grade B). In patients with twin pregnancies with a short cervix (<25mm), the utilization of 17OHPC (LE1) and vaginal progesterone (LE3) is not associated with a reduction of the risk of preterm delivery and better perinatal outcome. The utilization of 17OHPC (grade A) or vaginal progesterone (grade C) is not recommended in this context. Utilization of 17OHPC progesterone is not associated with beneficial effect in patients with triple pregnancy (LE2). The utilization of 17OHPC is not recommended in this context (grade B). CONCLUSION: Asymptomatic women with monofetal pregnancy without history of preterm delivery and a short cervix between 16 and 24 weeks is the only population in which vaginal progesterone is recommended. PMID- 27776846 TI - [Prevention of preterm birth complications by antenatal corticosteroid administration]. AB - OBJECTIVE: To evaluate short- and long-term benefits and risks associated with antenatal administration of a single course of corticosteroids and the related strategies: multiple and rescue courses. METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: Antenatal administration of a single course of corticosteroids before 34 weeks of gestation is associated in the neonatal period with a significant reduction of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC) and death (LE1), and in possibly childhood with a reduction of cerebral palsy and increased psychomotor development index and intact survival (LE3). However, this treatment is associated with alterations of the HPA axis response persisting until 8 weeks after birth (LE2) and possibly with insulin resistance in adulthood (LE3). Antenatal corticosteroid administration after 34 weeks is associated, with high number needed to treat, with reduced respiratory morbidity (LE2), with no significant effect on neurological (LE2) or digestive (LE2) morbidities. Because of a very favourable benefit/risk balance, antenatal administration of a single course of corticosteroids is recommended for women at risk of preterm delivery before 34 weeks (grade A). The minimum gestational age for treatment will depend on the threshold chosen to start neonatal intensive care in maternity units and perinatal networks (Professional consensus). After 34 weeks, evidences are not consistent enough to recommend systematic antenatal corticosteroid treatment (grade B), however, a course might be indicated in the clinical situations associated with the higher risk of "severe" RDS, mainly in case of planned cesarean delivery (gradeC). In case of imminent preterm birth, pre-empting the second betamethasone injection is not recommended (gradeC), because this policy might be associated with increased rates of NEC (LE3). Repeated antenatal corticosteroid administration is associated in the neonatal period with respiratory benefits (LE1) but decreased birth weight (LE1) and, in childhood, with possible neurological impairment (LE2). Therefore, this strategy is not recommended (grade A). Rescue courses are only associated with neonatal respiratory benefits (LE2). Because of the possible adverse effects associated with this strategy when delivery occurs during the 24hours following the first injection and because of the doubts raised by repeated courses, rescue courses are not recommended (Professional consensus). It is not possible to recommend one corticosteroid (betamethasone or dexamethasone) over another (Professional consensus). In case of contraindication for the intramuscular (IM) route, the intravenous route might be proposed (Professional consensus). The oral route is not recommended (grade A) because of increased rates of IVH and neonatal sepsis in comparison with the IM route (LE1). Either betamethasone as 2 injections of 12mg 24hours apart or dexamethasone as 4 injections of 6mg 12hours apart is recommended (grade A). Antenatal corticosteroid-induced alterations of fetal heart rate and movements should be recognized by the care providers of women at risk of preterm birth to avoid unjustified decision of labor induction or cesarean (Professional consensus). Gestational diabetes and pre-existing diabetes are not contraindication to antenatal corticosteroid therapy (Professional consensus). However, caution should be exercised in women with poorly controlled type 1 diabetes (Professional consensus). The apprehension to provoke maternal or neonatal infection should not delay antenatal corticosteroid administration even in case of preterm premature rupture of membranes (grade A). CONCLUSION: Antenatal corticosteroid administration is recommended to every woman at risk of preterm delivery before 34 weeks of gestation (grade A). Repeated courses of antenatal corticosteroids are not recommended (grade A). Rescue courses are not recommended (Professional consensus). PMID- 27776847 TI - [Mode of delivery in spontaneous preterm birth]. AB - OBJECTIVE: To evaluate the benefit/risk balance of way of birth according to fetal presentation, to assess monitoring during preterm labor, to discuss method of delivery and practice of delayed cord clamping in case of spontaneous preterm birth. METHODS: Bibliographic research from the Pubmed database and recommendations issued by the main scientific societies, and assignment of a level of evidence and a recommendation grade. RESULTS: In case of vertex presentation, no studies suggest that cesarean section improve neonatal outcome during spontaneous preterm birth (LE4). Nevertheless, cesarean is associated with higher maternal morbidity than vaginal delivery. Thus, routine cesarean is not recommended simply because of a spontaneous preterm labor (professional consensus). The available data do not allow specific recommendations about the choice of mode of delivery for preterm breech presentation in view of the low levels of proof (Professional consensus). Fetal rate monitoring is necessary during preterm labor (Professional consensus). Current data about second lines method for fetal surveillance (fetal scalp blood for pH or lactates) are insufficient to recommend their use before 34 WG (Professional consensus). Systematic assisted vaginal delivery is not recommended during preterm birth (Professional consensus). Use of vacuum is possible after 34 WG when cranial vertex ossification is considered satisfactory (Professional consensus). Systematic use of episiotomy in case of preterm birth is not recommended (Professional consensus). A delayed cord clamping is possible if the neonatal or maternal state so permits (Professional consensus). The available data are insufficient to recommend a systematic use of this procedure (LE3). CONCLUSION: In case of preterm delivery, the available data do not allow specific recommendations about the choice of mode of delivery regardless of fetal presentation. PMID- 27776848 TI - [Clinical practice guidelines: Synthesis of the guidelines for the surgical treatment of primary pelvic organ prolapse in women by the AFU, CNGOF, SIFUD-PP, SNFCP, and SCGP]. AB - OBJECTIVE: Develop guidelines for surgery for primary pelvic organ prolapse (POP). METHODS: Literature review, establishment of levels of evidence, external review, and grading of recommendations by 5 French academic societies: Association Francaise d'Urologie, College National des Gynecologues et Obstetriciens Francais, Societe Interdisciplinaire d'Urodynamique et de Pelvi Perineologie, Societe Nationale Francaise de Colo-proctologie, and Societe de Chirurgie Gynecologique et Pelvienne. RESULTS: It is useful to evaluate symptoms, their impact, women's expectations, and to describe the prolapse prior to surgery (grade C). In the absence of any spontaneous or occult urinary sign, there is no reason to perform urodynamics (grade C). When a sacrocolpopexy is indicated, laparoscopy is recommended (grade B). A bowel preparation before vaginal (grade B) or abdominal surgery (grade C) is not recommended. There is no argument to systematically use a rectovaginal mesh to prevent rectocele (grade C). The use of a vesicovaginal mesh by vaginal route should be discussed taking into account an uncertain long-term risk-benefit ratio (grade B). Levator myorrhaphy is not recommended as a first-line rectocele treatment (grade C). There is no indication for a vaginal mesh as a first-line rectocele treatment (grade C). There is no reason to systematically perform a hysterectomy during prolapse repair (grade C). It is possible to not treat stress incontinence at the time of prolapse repair, if the woman is advised of the possibility of a 2-step surgical treatment (grade C). PMID- 27776849 TI - Activation of persulfate by Fe(III) species: Implications for 4-tert-butylphenol degradation. AB - In this study, the activation of persulfate induced by Fe(III) species, including 5 kinds of iron oxhydroxides (IOs) and dissolved Fe3+ under dark condition were investigated. Ferrihydrite (FH) and akaganeite (AK) showed the highest activity in 4-tert-butylphenol (4tBP) removal. The 4tBP degradation rate constant decreased as the solution pH increased from pH 3.2 to 7.8 in FH/S2O82- system. However, the pH value had no significant effect on the 4tBP degradation in AK/S2O82- system. The degradation of 4tBP in Fe3+/S2O82- system was also performed to investigate the role of ferric species in persulfate activation. The pH dependency of 4tBP degradation rate was closely related to the speciation of FeIII, whereas the Fe(H2O)63+ was found to be the most active soluble iron complex form in the activation of S2O82-. 4tBP degradation was mainly due to the SO4- in IOs/S2O82- system, while SO4- and HO2 both had great contribution on 4tBP degradation in Fe3+/S2O82- system. Further investigations showed clearly that 4tBP degradation efficiency was decreased significantly due to the trapping of SO4- by chloride. This finding may have promising implications in developing a new technology for the treatment of contaminated waters and soils, especially where Fe3+ species are naturally occurring. PMID- 27776850 TI - Electrochemical reduction of nalidixic acid at glassy carbon electrode modified with multi-walled carbon nanotubes. AB - The aqueous phase electrochemical degradation of nalidixic acid (NAL) is studied in this work, using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) as instrumental techniques. The promotional effect of multi-walled carbon nanotubes (MWCNT) on the performance of glassy carbon electrodes is demonstrated, being observed that these materials catalyze the NAL reduction. The effect of surface functional groups on MWCNT -MWCNT-COOH and MWCNT-NH2-was also studied. The modification of glassy carbon electrode (GCE) with MWCNT leads to an improved performance for NAL reduction following the order of MWCNT>MWCNT-NH2>MWCNT-COOH. The best behavior at MWCNT-GCE is mainly due to both the increased electrode active area and the enhanced MWCNT adsorption properties. The NAL degradation was carried out under optimal conditions (pH=5.0, deposition time=20s and volume of MWCNT=10MUL) using MWCNT-GCE obtaining an irreversible reduction of NAL to less toxic products. Paramaters as the number of DPV cycles and the volume/area (V/A) ratio were optimized for maximize pollutant degradation. It was observed that after 15 DPV scans and V/A=8, a complete reduction was obtained, obtaining two sub-products identified by liquid chromatography-mass spectrometry (LC-MS). PMID- 27776851 TI - Optimization of Fenton treatment process for degradation of refractory organics in pre-coagulated leachate membrane concentrates. AB - Untreated leachate membrane concentrates are a threat to the environment. In our study, effective removal of contaminants in pre-coagulated leachate membrane concentrates was achieved using the Fenton process. The Fenton process was optimized using the response surface method, and the maximum total organic carbon (TOC), chemical oxygen demand (COD), and chromaticity reduction efficiencies reached 68.9%, 69.6%, and 100% under the conditions pH 2, H2O2 concentration 1mol/L, and Fe2+ concentration 17.5mmol/L. The COD concentration was reduced from 1120 to 340mg/L. The H2O2 concentration was the key factor affecting the TOC removal efficiency. Slow, continuous addition of the Fenton reagents improved the H2O2 utilization rate, which improved the TOC removal efficiency. Fourier transform infrared and three-dimensional fluorescence spectroscopy showed that the majority compound of the removed organic material was humic acid. Our study provides guidelines for the treatment of leachate membrane concentrates in engineering applications. PMID- 27776853 TI - Phosphorus-containing polymers from THPS. IV: Synthesis and properties of phosphorus-containing polybenzoxazines as a green route for recycling toxic phosphine (PH3) tail gas. AB - A convenient route to convert the highly toxic phosphine (PH3) tail gas into high performance polybenzoxazines was first described in this paper. Two aliphatic polyamines, namely tris(aminomethyl)phosphine oxide and bis(aminomethyl)phenylphosphine oxide, were synthesized from tetrakis(hydroxymethyl)phosphonium sulfate (THPS), a green derivative of PH3 tail gas. And then two novel phosphorus-containing benzoxazine monomers, tris(3,4 dihydro-2H-1,3-benzoxazin-3-yl-methyl)phosphine oxide (TBOz) and benzylbis(3,4 dihydro-2H-1,3-benzoxazin-3-yl-methyl) phosphine oxide (BBOz) were prepared by three-steps procedure. FT-IR and DSC technologies were adopted to study the thermal-initiated polymerization behaviors of two benzoxazine monomers. Thermal properties of these crosslinked polymers were studied by TGA and DMA. The results display that the polybenzoxazines (PTBOz and PBBOz) exhibite good thermal stabilities and high glass transition temperatures. The char yield of polybanzoxazine is high as 47% and indiactes that phosphorus-containing polybenzoxazines show high fire-retardancy. The surface free energies of the PTBOz and PBBOz are 37.1 and 40.4mJm-2 by Owens two-liquid method. The dielectric properties of the PTBOz and PBBOz remaine near constant in the experimental frequency range. PMID- 27776852 TI - Hormetic effects of metal ions upon V. fischeri and the application of a new parameter for the quantitative assessment of hormesis. AB - Hormesis is an intriguing phenomenon that is characterized by low dose stimulation and high dose inhibition. Several traditional parameters, such as the concentration of the zero equivalent point (ZEP) and the maximal stimulatory effect (Ymax), have been used to characterize the zone of hormesis or the extent of the stimulatory effect. However, the characteristics of hormesis for chemicals cannot be quantified completely by one parameter, which is important to accurately compare the hormetic effects of chemicals and to describe the combined effects of chemical mixtures at low doses. In the present study, a novel parameter, termed the relative standard area of hormetic zone (HorAreaR), was developed and proposed to quantify the hormetic effects (24h exposure) of nine metal ions (Cr3+, Cu2+, Mg2+, Cd2+, Fe3+, Ni2+, Zn2+, Co2+, Cs+) towards Vibrio fischeri, both individually and as binary mixtures. The results indicate that HorAreaR can be used not only to accurately assess the hormetic effects and its relationship with structural characteristics but also to conveniently describe the combined effects of interactive mixtures at low dose. Thus, the HorAreaR parameter can quantitatively assess the hormetic effects and can offer a useful approach to perform environmental risk assessments of chemicals at low doses. PMID- 27776854 TI - Study on non-isothermal kinetics of the thermal desorption of mercury from spent mercuric chloride catalyst. AB - Kinetics of the thermal desorption of mercury from spent mercury chloride catalysts were investigated using non-isothermal thermal analysis technique. Complex mercury species absorbed on waste catalysts were revealed by sequential extraction procedure. A scheme of six reactions was applied to elucidate mercury desorption kinetics. Activation energy estimated by model-free isoconversional methods is a slightly increasing function of conversion, implying a variation in the mechanism controlling mercury desorption. Average value of apparent activation energy (116.32kJ/mol) calculated by isoconversional Starink method was used to determine reaction mechanism using model-fitting and z(alpha) master method. One dimensional diffusion appears to govern mercury desorption process in the conversion range of 10%-40%, and then the reaction kinetic is controlled by two and three dimensional diffusion at greater conversion. PMID- 27776855 TI - Magnetic graphene based nanocomposite for uranium scavenging. AB - Magnetic graphene based ferberite nanocomposite was tailored by simple, green, low cost and industrial effective method. The microstructure and morphology of the designed nanomaterials were examined via XRD, Raman, FTIR, TEM, EDX and VSM. The prepared nanocomposites were introduced as a novel adsorbent for uranium ions scavenging from aqueous solution. Different operating conditions of time, pH, initial uranium concentration, adsorbent amount and temperature were investigated. The experimental data shows a promising adsorption capacity. In particular, a maximum value of 455mg/g was obtained within 60min at room temperature with adsorption efficiency of 90.5%. The kinetics and isotherms adsorption data were fitted with the pseudo-second order model and Langmuir equation, respectively. Finally, the designed nanocomposites were found to have a great degree of sustainability (above 5 times of profiteering) with a complete maintenance of their parental morphology and adsorption capacity. PMID- 27776856 TI - Graphene oxide-mediated rapid dechlorination of carbon tetrachloride by green rust. AB - Graphene-based nanomaterials can mediate environmentally relevant abiotic redox reactions of chlorinated aliphatic hydrocarbons. In this study as low amounts as ~0.007 % of graphene oxide (GO) was found to catalyze the reduction of carbon tetrachloride by layered Fe(II)-Fe(III) hydroxide (Green Rust, GR) in aqueous solutions with chloroform being the reduction product. On the basis of sorption studies of carbon tetrachloride onto the GO surface it is suggested that it is the amphiphilicity of GO, which initiates the reaction by providing a suitable reaction platform for the reagents. This study indicates that traces of graphene oxide can affect reaction pathways as well as kinetics for dechlorination processes in anoxic sediments by facilitating a partial dechlorination. PMID- 27776857 TI - Adsorption of benzotriazole and benzimidazole from water over a Co-based metal azolate framework MAF-5(Co). AB - Benzotriazole (BTA) and benzimidazole (BZI) are regarded as water pollutants because of their extensive uses in industry and appreciable water solubility. The adsorption of both BTA and BZI from water over a newly synthesized metal-organic framework, MAF-5(Co), was investigated and compared with zeolitic imidazole frameworks (ZIFs), such as ZIF-8(Zn) and ZIF-67(Co), as well as commercial activated carbon. MAF-5(Co) had the highest adsorption capacities for both BTA and BZI. The maximum adsorption capacities of MAF-5(Co) for BTA and BZI were 389 and 175mgg-1, respectively. Hydrophobic and pi-pi interactions between the aromatic adsorbate BTA and MAF-5(Co) were suggested as a plausible mechanism. Based on the zeta potential of MAF-5(Co) and effects of pH on the BTA adsorption, electrostatic interactions between the MAF-5(Co) and BTA species might also affect the adsorption of BTA over MAF-5(Co). MAF-5(Co) can be recycled for adsorptive removal of BTA by simple ethanol washing. Therefore, MAF-5(Co) is suggested as a promising adsorbent for the removal of BTA and BZI from water. PMID- 27776858 TI - Bioinspired synthesis of high-performance nanocomposite imprinted membrane by a polydopamine-assisted metal-organic method. AB - Significant efforts have been focused on the functionalization and simplification of membrane-associated molecularly imprinted materials, which can rapidly recognize and separate specific compound. However, issues such as low permselectivity and unstable composite structures are restricting it from developing stage to a higher level. In this work, with the bioinspired design of polydopamine (pDA)-assisted inorganic film, we present a novel molecular imprinting strategy to integrate multilevel nanocomposites (Ag/pDA) into the porous membrane structure. The molecularly imprinted nanocomposite membranes were then obtained through an in situ photoinitiated ATRP method by using tetracycline (TC) as the template molecule. Importantly, attributing to the formation of the Ag/pDA-based TC-imprinted layers, largely enhance TC-rebinding capacity (35.41mg/g), adsorption selectivity and structural stability (still maintained 92.1% of the maximum adsorption capacity after 10 cycling operations) could been easily achieved. Moreover, largely enhanced permselectivity performance toward template molecule (the permeability factor beta values were also more than 5.95) was also obtained. Finally, all synthesis methods were conducted in aqueous solution at ambient temperature, which was environmental friendly for scaling up without causing pollution. PMID- 27776859 TI - Assessment of exposure to polycyclic aromatic hydrocarbons in preschool children: Levels and impact of preschool indoor air on excretion of main urinary monohydroxyl metabolites. AB - The present work aimed to assess exposure of preschool children to polycyclic aromatic hydrocarbons (PAHs) by environmental monitoring (eighteen compounds in air) and biomonitoring (six urinary biomarkers of exposure (OH-PAHs)). The impact of preschool indoor air on excretion of urinary monohydroxyl metabolites was also evaluated. Gaseous and particulate-bound PAHs were simultaneously collected indoors and outdoors in two Portuguese preschools. PAHs and OH-PAHs were quantified by high-performance liquid chromatography with fluorescence and photodiode array detection. Total air (gaseous+total suspended particles) levels of PAHs (SigmaPAHs) were higher indoors than outdoors. Gaseous phase (composed by >=98% of 2-3 rings compounds) and particulate-bound PAHs (90-99% of 5-6 rings) accounted for 93-95% and 5-7% of SigmaPAHs in indoor air, respectively. Total (including probable/possible) carcinogenic PAHs represented 26-45% of SigmaPAHs; naphthalene and dibenz[a,h]anthracene were the strongest contributors. A similar distribution profile was observed between airborne PAHs and urinary OH-PAHs. Urinary 1-hydroxynaphthalene+1-hydroxyacenaphthene represented more than 78% of SigmaOH-PAHs, being followed by 2-hydroxyfluorene, 1-hydroxypyrene, and 1 hydroxyphenanthrene. 3-hydroxybenzo[a]pyrene (PAH biomarker of carcinogenicity) was not detected. Results suggest that children had preschool indoor air as their major exposure source of naphthalene and acenaphthene, while no conclusion was reached regarding fluorene, phenanthrene and pyrene. PMID- 27776860 TI - Multi-responsive, tough and reversible hydrogels with tunable swelling property. AB - A novel family of multi-responsive, tough, and reversible hydrogels were prepared by the combination of dipole-dipole interaction, hydrogen bonding interaction and slightly chemical cross-linking, using monomers of acrylonitrile, sodium allylsulfonate and itaconic acid. Reversible gel-sol transition was achieved by the flexible conversion of the dipole-dipole interactions between acrylonitrile acrylonitrile and acrylonitrile-sodium thiocyanate, and the hydrogels could freely form desired shapes. The dipole-dipole and hydrogen bonding interactions improved the mechanical strength of the hydrogels with a compressive stress of 2.38MPa. Meanwhile, the hydrogels sustained cyclic compressive tests with 60% strain, and exhibited excellent elastic property. The hydrogels were sensitive to pH and ionic strength, and could keep their perfect spherical structures without any obvious cracks even after immersing in strong ionic strength (or pH) solution for several reversible cycles. Furthermore, the hydrogels were recycled for environmental pollution remediation, and showed great potential to be applied in water treatments and other related fields. PMID- 27776861 TI - Removal of arsenic(III) from water by magnetic binary oxide particles (MBOP): Experimental studies on fixed bed column. AB - Magnetic binary oxide particles (MBOP) were prepared by template method using chitosan in the laboratory for the removal of As(III) from water. The prepared MBOP has super paramagnetic property which is sufficient for magnetic separation. Column study was performed at two different flow rates of 2.0ml/min and 5.0ml/min and comparison was made with regenerated MBOP, commercial activated carbon and commercial activated alumina. It is observed that fresh MBOP has higher breakthrough time and capacity than regenerated MBOP by a factor of 1.25 and 1.37 respectively. In Logit method, the values of K (adsorption rate constant) and N (adsorption capacity coefficient) were obtained as 0.2066 (L/mgh) and 1014(mg/L) for 5.0ml/min flow rate. All the drinking water parameters are within the limit of BIS 10500-2012. Toxicity characteristic leaching procedure (TCLP) and semi dynamic tests were performed for the mix ratios of 01:02:01, 01:02:05 and 01:02:10 and were found safe for the disposal. PMID- 27776862 TI - Degradation of tetracycline by immobilized laccase and the proposed transformation pathway. AB - Magnetic cross-linked enzyme aggregates (M-CLEAs) were prepared for Cerrena laccase and used in antibiotic treatment. Of the seven antibiotics examined in this study, Cerrena laccase M-CLEAs were most effective in degradation of tetracycline (TC) and oxytetracycline (OTC), followed by ampicillin, sulfamethoxazole and erythromycin. The redox mediator ABTS was not able to improve efficiencies of degradation of TC and OTC. Cerrena laccase at 40U/mL eliminated 100MUg/mL TC at pH 6 and 25 degrees C in 48h in the absence of a redox mediator, with over 80% degradation occurring within the first 12h. Laccase treatment also significantly suppressed the antimicrobial activity of TC and OTC. Three TC transformation products, the levels of which initially increased and subsequently decreased during laccase treatment were identified by using LC-TOF MS. A mechanism of laccase-mediated TC oxidation was proposed based on the identified intermediates. PMID- 27776863 TI - Fabrication of Ce/N co-doped TiO2/diatomite granule catalyst and its improved visible-light-driven photoactivity. AB - Eliminating antibiotic remnants in aquatic environment has become one of the hottest topics among current research works. Thus, we prepared Ce, N co-doped TiO2/diatomite granule (CNTD-G) catalyst to provide a new method. As one typical antibiotics, oxytetracycline (OTC) was selected as the target pollutant to be degradated under visible light irradiation. The carrier diatomite helped the spread of TiO2 nanoparticles onto its surface, and inhibited their agglomeration. The synergy of Ce and N dopants highly improved the visible-light-driven photoactivity of TiO2. The optimal doping amount and degradation conditions were determined. Besides, the effects of impurity ions were also investigated, including cations: Ca2+, Mg2+; or anions: NO3-, SO42- and PO43-. The intermediates generated during degradation process were studied, and the mechanism of the photodegradation process was proposed. CNTD-G could be easily collected from the reactor, and showed excellent recyclability. PMID- 27776864 TI - Heterogeneous activation of peroxymonosulfate by amorphous boron for degradation of bisphenol S. AB - Recently, tremendous efforts have been devoted to developing carbon-based metal free catalysts as an alternative to metal-based catalysts for remediation of emerging contaminants. However, further investigations have demonstrated that the durability of carbocatalysts is poor. Therefore, it is extremely desirable to seek a novel metal-free catalyst with high efficiency and superb stability. Herein, we first discovered that amorphous boron (A-boron) can be used as a metal free catalyst for peroxymonosulfate (PMS) activation to produce free radicals for effective degradation of bisphenol S (BPS), which is a newly-occurring estrogenic endocrine-disrupting chemical. It exhibited outstanding catalytic activity and superior stability as comparing to metal-based and metal-free carbon-based catalysts. Moreover, many other typical organic pollutants in water such as bisphenol F, sulfamethoxazole, rhodamine B and methyl orange can also be effectively decomposed in A-boron/PMS oxidative system. The effects of reaction parameters on BPS degradation were systematically investigated. The catalytic oxidation mechanism was proposed. The intriguing catalytic feature of A-boron discovered in this study will provide new opportunities for the future development of A-boron based materials with promising applications in water remediation. PMID- 27776865 TI - Iron bound to soil organic matter catalyzes H2O2 to oxidize crude oil in soil. AB - Under the action of hydrogen peroxide, soil organic matter (SOM) can transform dissolved iron (Fe2+) into the solid phase. Solid iron is bound to SOM (Fe-SOM), and two components are included: iron oxides bound to SOM (Fe-SOM oxides) and organic iron bound to SOM (organic Fe-SOM). In oil-contaminated soil samples with Fe-SOM, total petroleum hydrocarbon (TPH) was degraded by 67%; however, in oil contaminated soil samples without Fe-SOM, the degradation of TPH was only 6%. In oil-contaminated soil samples with Fe-SOM, 73-86% of the primary alkanes (C14-C22 composed 67.5% of TPH) were removed, whereas only 45-65% of the C12-C13 and C22 C30 alkanes were removed. The 11 types of alkanes (C12-C13 and C22-C30) accounted for only 32.5% of TPH. Obviously, the degradation of TPH by Fe-SOM is independent of its hydrophobicity in the solid phase. The results also demonstrated that at a higher content of Fe-SOM, more hydroxyl radical (OH) was produced in the solid phase and more TPH was degraded. A large number of OH are generated near iron-SOM oil interface. PMID- 27776866 TI - Effect of controlled release formulations of diuron and alachlor herbicides on the biochemical activity of agricultural soils. AB - The use of pesticides in agriculture is essential because it reduces the economic losses caused by pests, improving crop yields. In spite of the growing number of studies concerning the development and application of controlled release formulations (CRFs) of pesticides in agricultural soils, there are no studies about the effects of such formulations on the biochemical properties. In this paper the dissipation of diuron and alachlor in three agricultural soils for 127days, applied either as commercial or CRFs, was determined as well as their concomitant effects on soil biochemical properties. Dehydrogenase, urease, beta glucosidase and phosphatase activities were measured thought the experimental period. The application of alachlor as CRF increases its half-life time in soils, whereas no differences were noticed between diuron formulations due to its slower degradation, which takes longer than its release from the CRF. At the end of the incubation period, the enzymatic activities were the same after the use of diuron either as commercial or CRF, recovering the soil previous status. For alachlor formulations, no differences in enzymatic activities were again observed between both formulations, but their levels in soils were enhanced. Therefore, the use of these CRFs does not adversely affect the soil biochemical properties. PMID- 27776867 TI - Amorphous boron-doped sodium titanates hydrates: Efficient and reusable adsorbents for the removal of Pb2+ from water. AB - Amorphous titanium hydroxide and boron-doped (B-doped) sodium titanates hydrates were synthetized and used as adsorbents for the removal of Pb2+ from water. The use of sodium borohydride (NaBH4) and titanium(IV) isopropoxide (TTIP) as precursors permits a very easy synthesis of B-doped adsorbents at 298K. The new adsorbent materials were first chemically characterized (XRD, XPS, SEM, DRIFT and elemental analysis) and then tested in Pb2+ adsorption batch experiments, in order to define kinetics and equilibrium studies. The nature of interaction between such sorbent materials and Pb2+ was also well defined: besides a pure adsorption due to hydroxyl interaction functionalities, there is also an ionic exchange between Pb2+ and sodium ions even working at pH 4.4. Langmuir model presented the best fitting with a maximum adsorption capacity up to 385mg/g. The effect of solution pH and common ions (i.e. Na+, Ca2+ and Mg2+) onto Pb2+ sorption were also investigated. Finally, recovery was positively conducted using EDTA. Very efficient adsorption (>99.9%) was verified even using tap water spiked with traces of Pb2+ (50ppb). PMID- 27776868 TI - UV/persulfate preoxidation to improve coagulation efficiency of Microcystis aeruginosa. AB - The performance of UV-activated persulfate (UV/PS) technology as preoxidation process to enhance Microcystis aeruginosa removal by subsequent coagulation sedimentation was firstly evaluated. The results demonstrate that UV/PS preoxidation could successfully promote coagulation of algae cells through the effective neutralization of zeta potential, which was caused by the changes of cell morphology, size distribution and surface properties after simultaneous UV irradiation and formed reactive species (i.e. SO4- and HO) oxidation. Since excessive oxidation would cause cell rupture along with the release of organics, which could deteriorate coagulation efficiency, optimal PS dose (60mg/L) and UV dose (375mJ/cm2) were proposed to exist in this study. The concentrations of extracellular algal organic matter (AOM) sharply increased by 48.2% during the preoxidation period, while gradually decreased in the following coagulation and sedimentation. Most of the concerned disinfection by-products (DBPs) monotonically decreased or followed fluctuant reduction with increasing PS doses, whereas the trichloromethane, trichloroacetic acid and dichloroacetonitrile persistently increased, which was inferred to be related to the variation of AOM. This study suggests that UV/PS might be a potential pretreatment process to assist coagulation on the removal of algae. PMID- 27776869 TI - Removal of copper from water using a thermally regenerative electrodeposition battery. AB - A thermally regenerative ammonia battery (TRAB) recently developed for electricity generation using waste heat was adapted and used here as a treatment process for solutions containing high concentrations of copper ions. Copper removal reached a maximum of 77% at an initial copper concentration (Ci) of 0.05M, with a maximum power density (P) of 31Wm-2-electrode area. Lowering the initial copper concentration decreased the percentage of copper removal from 51% (Ci=0.01M, P=13Wm-2) to 2% (Ci=0.002M, P=2Wm-2). Although the final solution may require additional treatment, the adapted TRAB process removed much of the copper while producing electrical power that could be used in later treatment stages. These results show that the adapted TRAB can be a promising technology for removing copper ions and producing electricity by using waste heat as a highly available and free source of energy at many industrial sites. PMID- 27776870 TI - Ion-recognizable hydrogels for efficient removal of cesium ions from aqueous environment. AB - At present, selective and efficient removal of cesium ions (Cs+) from nuclear waste is of significant importance but still challenging. In this study, an easy to-get and low-cost hydrogel adsorbent has been developed for effective adsorption and removal of Cs+ from aqueous environment. The novel Cs+ recognizable poly(acrylic acid-co-benzo-18-crown-6-acrylamide) (poly(AAc-co B18C6Am)) hydrogel is specifically designed with a synergistic effect, in which the AAc units are designed to attract Cs+ via electrostatic attraction and the B18C6Am units are designed to capture the attracted Cs+ by forming stable 2:1 "sandwich" complexes. The poly(AAc-co-B18C6Am) hydrogels are simply synthesized by thermally initiated free-radical copolymerization and display excellent Cs+ adsorption from commonly coexisting metal ions. Important parameters affecting the adsorption are investigated comprehensively, and the adsorption kinetics and adsorption isotherms are also discussed systematically. The poly(AAc-co-B18C6Am) hydrogels exhibit rapid Cs+ adsorption within 30min and the adsorption process is governed by the pseudo-second order model. Adsorption isotherm results demonstrate that the equilibrium data are well fitted by the Langmuir isotherm model, indicating that the Cs+ adsorption is probably a monolayer adsorption process. Such Cs+-recognizable hydrogel materials based on the host-guest complexation are promising as efficient and feasible candidates for adsorption and removal of radioactive Cs+ from nuclear contaminants. PMID- 27776871 TI - Combined genotoxicity of chlorinated products from tyrosine and benzophenone-4. AB - The toxicity of disinfection by-products (DBPs) from a single precursor was studied intensively. Here we examined the genotoxicity when two precursors (tyrosine (Tyr) and benzophenone-4 (BP-4)) were chlorinated together and separately. We sought to examine whether the genotoxicity of the mixture (GCM) could be estimated from the sum of the genotoxicities of the individual precursors (GCI), which were chlorinated separately. We determined the genotoxicity using the SOS/umu test. The results revealed that GCM was not identical to GCI. The difference in genotoxicity between GCM and GCI (GDelta) was observed to decrease with increasing pH. GCM was higher than GCI (GDelta>0) at pH 5.0-6.1, and lower than GCI (GDelta<0) at pH 6.3-8.0. We found that nitrogen containing DBPs played a dominant role in determining GCM and GCI. We propose that the total organic nitrogen (TON) ratio, TON(chlorinatedmixture)/TON(thesumofchlorinatedindividuals), is useful to estimate GDelta. PMID- 27776872 TI - Mechanical investigation of U(VI) on pyrrhotite by batch, EXAFS and modeling techniques. AB - The interaction mechanism of U(VI) on pyrrhotite was demonstrated by batch, spectroscopic and modeling techniques. Pyrite was selected as control group in this study. The removal of U(VI) on pyrite and pyrrhotite significantly decreased with increasing ionic strength from 0.001 to 0.1mol/L at pH 2.0-6.0, whereas the no effect of ionic strength was observed at pH >6.0. The maximum removal capacity of U(VI) on pyrite and pyrrhotite calculated from Langmuir model was 10.20 and 21.34mgg-1 at pH 4.0 and 333K, respectively. The XPS analysis indicated the U(VI) was primarily adsorbed on pyrrhotite and pyrite and then approximately 15.5 and 9.8% of U(VI) were reduced to U(IV) by pyrrhotite and pyrite after 20 days, respectively. Based on the XANES analysis, the adsorption edge of uranium containing pyrrhotite located between UIVO2(s) and UVIO22+ spectra. The EXAFS analysis demonstrated the inner-sphere surface complexation of U(VI) on pyrrhotite due to the occurrence of U-S shell, whereas the U-U shell revealed the reductive co-precipitates of U(VI) on pyrrhotite/pyrite with increasing reaction times. The surface complexation modeling showed that outer- and inner-surface complexation dominated the U(VI) removal at pH<4 and pH>5.0, respectively. The findings presented herein play a crucial role in the removal of radionuclides on iron sulfide in environmental cleanup applications. PMID- 27776873 TI - H2O2 and/or TiO2 photocatalysis under UV irradiation for the removal of antibiotic resistant bacteria and their antibiotic resistance genes. AB - Inactivating antibiotic resistant bacteria (ARB) and removing antibiotic resistance genes (ARGs) are very important to prevent their spread into the environment. Previous efforts have been taken to eliminate ARB and ARGs from aqueous solution and sludges, however, few satisfying results have been obtained. This study investigated whether photocatalysis by TiO2 was able to reduce the two ARGs, mecA and ampC, within the host ARB, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, respectively. The addition of H2O2 and matrix effect on the removal of ARB and ARGs were also studied. TiO2 thin films showed great effect on both ARB inactivation and ARGs removal. Approximately 4.5 5.0 and 5.5-5.8 log ARB reductions were achieved by TiO2 under 6 and 12mJ/cm2 UV254 fluence dose, respectively. For ARGs, 5.8 log mecA reduction and 4.7 log ampC reduction were achieved under 120mJ/cm2 UV254 fluence dose in the presence of TiO2. Increasing dosage of H2O2 enhanced the removal efficiencies of ARB and ARGs. The results also demonstrated that photocatalysis by TiO2 was capable of removing both intracellular and extracellular forms of ARGs. This study provided a potential alternative method for the removal of ARB and ARGs from aqueous solution. PMID- 27776875 TI - Reply by Authors. PMID- 27776874 TI - Innovative combination of Fe2+-BAF and ozonation for enhancing phosphorus and organic micropollutants removal treating petrochemical secondary effluent. AB - Two sets of BAF - ozonation systems, with (System-A) and without (System-B) Fe2+ dosing into BAF, were used for organic micropollutants (OMPs) and phosphorus removal in the advanced treatment of petrochemical secondary effluent. Pilot scale study showed that when the influent COD, TP and TSS were 73.0, 1.40 and 24.6mgL-1, the effluent COD, TP and TSS were 48.9, 0.32, 7.78mgL-1 for System-A with the ozone and Fe2+ dosage of 25mgL-1 and 0.08mmolL-1, and 60.2, 1.16, 6.44mgL-1 for System-B with the ozone dosage of 25mgL-1. The dosage of Fe2+ into the BAF significantly enhanced the TP and OMPs removal ability. Exactly, the residual Fe2+ in the BAF-A effluent stimulated the catalytic ozonation in the following ozone unit. Therefore, the OMPs removal in System-A was obviously better than that in System-B. The dosage of Fe2+ from 0.02 to 0.10mmolL-1 had slight adverse effect on the biofilm activity in BAF. Based on the TP and OMPs removal ability, the System-B is selected as a proposed process for the advanced treatment of petrochemical secondary effluent. PMID- 27776876 TI - Comparison of the Potential Discoloration Effect of Bioaggregate, Biodentine, and White Mineral Trioxide Aggregate on Bovine Teeth: In Vitro Research. AB - INTRODUCTION: Tricalcium silicate cements can be used for pulp capping, pulpotomies, apical barrier formation in teeth with open apices, repair of root perforations, regenerative endodontics, and root canal filling. The aim of this study was to evaluate and compare the discoloration potential of 3 different tricalcium cements using a bovine tooth model. METHODS: Forty bovine anterior teeth have been used for the study. Crowns separated from the roots were randomly divided into 4 groups: the BioAggregate (IBC, Vancouver, Canada) group, the Biodentine (Septodont, Saint Maur des Fosses, France) group, the mineral trioxide aggregate Angelus (Angelus, Londrina, PR, Brazil) group, and the only blood group. Materials have been placed to the standardized cavities on the lingual surfaces of the crowns, and their contact with blood has been provided. The color values of the samples were measured with a digital tooth shade determinator (VITA Easyshade; VITA Zahnfabrik, Bad Sackingen, Germany) before the placement of the materials, after the placement of the materials, in the 24th hour, in the first week, in the first month, in the third month, and in the first year. The mean value of all groups was compared using the Tukey multiple comparison test (alpha = 0.05). RESULTS: All groups displayed increasing discoloration during a period of the first year. The "only blood group" showed the highest color change values, and it was followed as BioAggregate, mineral trioxide aggregate Angelus, and Biodentine, respectively. Statistically significant differences were found for Biodentine when compared with the only blood and BioAggregate groups (P < .05). CONCLUSIONS: Considering the results of the study, Biodentine is found to have the least discoloration potential among the tested materials. PMID- 27776877 TI - Influence of Warm Vertical Compaction Technique on Physical Properties of Root Canal Sealers. AB - INTRODUCTION: The aim of this study was to evaluate the influence of warm vertical compaction on the physical properties of root canal sealers. METHODS: The physical properties of 4 sealers (zinc oxide -eugenol [ZOE], AH Plus [Dentsply International, York, PA], RoekoSeal [Roeko/Coltene/Whaledent, Langenau, Germany], and iRoot SP [Innovative Bioceramix, Vancouver, Canada]) were tested. The setting time and flow of these sealers were measured at standard and high temperatures using ISO 6876 (2012) specifications. The percentage of voids in each sealer after complete setting at 37 degrees C and 140 degrees C was analyzed under a stereoscopic microscope. RESULTS: The setting time of ZOE sealer increased significantly from 144.0 +/- 4.1 minutes to 274.2 +/- 7.4 minutes when the temperature increased from 37 degrees C to 140 degrees C, whereas there was a significant reduction in the other 3 sealers. At 37 degrees C, the setting time of AH Plus, iRoot SP, and RoekoSeal was 543.8 +/- 16.4, 245.8 +/- 15.9, and 49.3 +/- 1.5 minutes, and at 140 degrees C the setting time decreased significantly to 12.9 +/- 0.7, 14.2 +/- 0.6, and 2.7 +/- 0.4 minutes (P < .05). The flow of AH Plus increased when the temperature changed from 25 degrees C to 140 degrees C (P < .05), whereas the flow reduced for RoekoSeal and iRoot SP (for RoekoSeal from 24.8 +/- 0.9 to 12.4 +/- 1.3 mm and for iRoot SP from 22.9 +/- 0.9 to 13.3 +/- 1.5 mm) (P < .05). However, the flow of ZOE sealer was unaffected by the high temperature. ZOE sealer and iRoot SP exhibited a reduction of porosity at a high temperature (P < .05). CONCLUSIONS: Warm vertical compaction influenced some properties (the setting time, flow, and porosity) of 4 sealers. A significant reduction of setting time and flow was found in RoekoSeal and iRoot SP sealers at a high temperature. PMID- 27776878 TI - Evaluation of the Cyclic Fatigue and Torsional Resistance of Novel Nickel Titanium Rotary Files with Various Alloy Properties. AB - INTRODUCTION: The purpose of this study was to evaluate the cyclic fatigue and torsional resistance of Hyflex EDM, ProTaper Gold (PTG), and ProTaper Universal (PTU) instruments. METHODS: For the cyclic fatigue test, 10 instruments from each group were tested by using a stainless steel block with 1.5-mm diameter and 3-mm radius of 60 degrees angle of curvature. The instruments were allowed to rotate by using a low-torque motor, and number of cycles from the beginning to the fracture was recorded. Torsional resistance of the instruments (n = 10) was evaluated according to ISO 3630-1. The rotational speed of the instruments was set in the clockwise direction at 2 rpm. The maximum torque and angular deflection until fracture of the instrument were recorded. The data were analyzed by using one-way analysis of variance followed by post hoc Tukey test (P = .05). RESULTS: HyFlex EDM instruments exhibited the highest cyclic fatigue resistance and were followed by PTG and PTU groups, respectively. The mean fragment length for PTU instruments was significantly shorter than that for Hyflex EDM and PTG instruments. PTG instruments demonstrated significantly higher torsional resistance than HyFlex EDM files (P = .025), and the distortion angle of the instruments ranged as follows: PTU < PTG < Hyflex EDM files. CONCLUSIONS: Hyflex EDM files demonstrated significantly higher cyclic fatigue resistance. Although PTG and PTU have similar cross-sectional design, PTG instruments presented higher cyclic fatigue and torsional resistance than PTU instruments. The enhanced alloy properties of PTG might be considered as the main reason for those differences. PMID- 27776879 TI - Expression Profiles of Inflammation-associated microRNAs in Periapical Lesions and Human Periodontal Ligament Fibroblasts Inflammation. AB - INTRODUCTION: microRNAs (miRNAs) have been identified to be closely related to inflammatory diseases. The aim of our study was to identify expression profiles of miRNAs associated with inflammation in apical periodontitis (AP) lesions and human periodontal ligament fibroblasts (HPDLFs) inflammation. METHODS: Total RNAs were extracted from 10 AP lesions, 6 control tissues, and HPDLFs using lysis buffer. Expressions of miRNAs (miR-29b, 106b, 125b, 143, 155, and 198) were detected by real-time polymerase chain reaction. The dual luciferase assay was used to test miR-155 directly targeted semaphorein3a (SEMA3A). Western Blot and the enzyme-linked immunosorbent assay were used to detect the protein expressions of SEMA3A and proinflammatory cytokines, respectively. All experiments were repeated at least 3 times. Data were analyzed using the independent sample t test. RESULTS: The previously mentioned miRNAs were all significantly up regulated in AP lesions (P < .05), whereas they were not in HPDLFs inflammation, in which miR-29b, 106b, 125b, and 198 were down-regulated (P < .05) and miR-143 and 155 were unchanged (P > .05). Overexpression of miR-155 induced proinflammatory phenotype, and down-regulation reduced the other miRNAs in HPDLFs (P < .05). Moreover, miR-155 directly targeted SEMA3A, which was significantly up regulated (increased) in acute HPDLFs inflammation and down-regulated (decreased) in AP lesions (P < .05). Knockdown of SEMA3A led to induction of the proinflammatory phenotype; down-regulation of miR-29b, 106b, 125b, 143, and 198 (P < .05); and, more importantly, up-regulation of miR-155 (P < .01). CONCLUSIONS: Our study showed that the expression profiles of inflammation associated miRNAs associated with inflammation in AP lesions and HPDLFs inflammation were different. miR-155 may play a crucial role in apical periodontitis progression by directly inhibiting SEMA3A. PMID- 27776880 TI - Guided Autotransplantation of Teeth: A Novel Method Using Virtually Planned 3 dimensional Templates. AB - INTRODUCTION: The aim of this study was to introduce an innovative method for autotransplantation of teeth using 3-dimensional (3D) surgical templates for guided osteotomy preparation and donor tooth placement. METHODS: This report describes autotransplantation of immature premolars as treatment of an 11-year old boy having suffered severe trauma with avulsion of permanent maxillary incisors. This approach uses modified methods from guided implant surgery by superimposition of Digital Imaging and Communications in Medicine files and 3D data sets of the jaws in order to predesign 3D printed templates with the aid of a fully digital workflow. RESULTS: The intervention in this complex case could successfully be accomplished by performing preplanned virtual transplantations with guided osteotomies to prevent bone loss and ensure accurate donor teeth placement in new recipient sites. Functional and esthetic restoration could be achieved by modifying methods used in guided implant surgery and prosthodontic rehabilitation. The 1-year follow-up showed vital natural teeth with physiological clinical and radiologic parameters. CONCLUSIONS: This innovative approach uses the latest diagnostic methods and techniques of guided implant surgery, enabling the planning and production of 3D printed surgical templates. These accurate virtually predesigned surgical templates could facilitate autotransplantation in the future by full implementation of recommended guidelines, ensuring an atraumatic surgical protocol. PMID- 27776881 TI - Anxiety Related to Nonsurgical Root Canal Treatment: A Systematic Review. AB - INTRODUCTION: Anxiety is an emotion characterized by feelings of tension, worried thoughts, and physical changes. Dental anxiety has been associated with pain, fear, care avoidance, and more invasive treatments including nonsurgical root canal treatment (NSRCT). The very words root canal are deeply embedded in societal consciousness. Better understanding of dental anxiety may prevent treatment avoidance. The purpose of this study was to conduct a systematic review of NSRCT-associated anxiety. METHODS: Inclusion/exclusion criteria defined MEDLINE, Cochrane Library, psychINFO, manual, and citation searches. Title lists and abstracts were read to determine utility; data were extracted, summarized, and compiled into an evidence table, and meta-analyses were performed. RESULTS: Defined searching produced 835 titles; 36 articles were included, mostly representing modern populations from countries with very high human development indices. Major sources of heterogeneity included differing study aims, outcome measures, clinical settings, locations, operators, sample selection, and sample size. Meta-analysis of 18 articles including 1989 subjects gave a pretreatment anxiety rating of 39 (standard deviation, 9) on a normalized 100-point scale. Meta-analysis of 4 articles including 232 subjects gave a post-treatment anxiety rating of 27 (standard deviation, 5) on a normalized 100-point scale, representing a 30% reduction. A L'Abbe plot of 5 studies also showed that anxiety decreased after NSRCT. Limited data indicated that gender, age, and prior NSRCT experience influenced NSRCT-associated anxiety. NSRCT-associated anxiety was ranked high among dental treatments, often close to oral surgery. CONCLUSIONS: NSRCT-associated anxiety was generally moderate. Anxiety decreased after NSRCT. Limited evidence suggested that anxiety is influenced by patient and treatment factors. PMID- 27776882 TI - Zinc Oxide Nanoparticles Enhance Physicochemical Characteristics of Grossman Sealer. AB - INTRODUCTION: Metallic antibacterial nanoparticles have been shown to provide distinct antibacterial advantage and antibiofilm efficacy when applied in infected root canals. The purpose of this study was to evaluate the influence of incorporating zinc oxide nanoparticles (ZnO-Np) on the physicochemical properties of Grossman sealer. METHODS: Grossman sealer was prepared according to its original formula. Additionally, 4 experimental sealers were prepared by replacing the zinc oxide component of the powder with ZnO-Np (average size of 20 nm) in different amounts (25%, 50%, 75%, and 100%). Characterization of the setting time, flow, solubility, dimensional changes, and radiopacity were performed according to American National Standards Institute (ANSI)/American Dental Association (ADA) Specification 57. Scanning electron microscopic and energy dispersive X-ray spectroscopic analyses were conducted to assess the ultrastructural and chemical characteristics of experimental sealers subjected to the solubility test. Statistical analyses were performed with analysis of variance and post hoc Tukey-Kramer tests with a significance level of 5%. RESULTS: A statistically significant difference in the setting time was observed among groups (P < .05), but only 25% ZnO-Np sealer complied with ANSI/ADA requirements. There was a significant difference in the flow characteristics between the control and 25% and 75% ZnO-Np experimental sealers (P < .05), but all sealers conformed to ANSI/ADA standardization; 25% ZnO-Np sealer showed significantly less solubility (1.81% +/- 0.31%) and dimensional change (-0.34% +/ 0.12%) than other sealers (P < .05). All sealers showed ultrastructural changes with increasing solubility. CONCLUSIONS: ZnO-Np decreased the setting time and dimensional changes characteristic of Grossman sealer; 25% ZnO-Np improved the physicochemical properties of Grossman sealer in accordance with ANSI/ADA requirements. PMID- 27776883 TI - Gene Expression Profiling and Molecular Signaling of Various Cells in Response to Tricalcium Silicate Cements: A Systematic Review. AB - INTRODUCTION: The aim of this study was to present a systematic review investigating the gene expression of various cells (other than dental pulp cells) in response to different variants of tricalcium silicate cements (TSCs). METHODS: A systematic search of the literature was performed by 2 independent reviewers followed by article selection and data extraction. Studies analyzing any cell type except dental pulp stem cells and any variant of tricalcium silicate cement either as the experimental or as the control group were included. RESULTS: A total of 41 relevant articles were included in this review. Among the included studies, ProRoot MTA (Dentsply, Tulsa, OK) was the most commonly studied (69.1%) TSC variant, and 11 cell types were identified, with 13 articles investigating gene expression in osteoblasts. A total of 39 different genes/molecules expressed were found in the selected studies. The experimental group (irrespective of the TSC variant) was identified to express significantly increased gene expression compared with the control group (untreated) in all included studies. Recent studies have provided useful insight into the gene expression and molecular signaling of various cells in response to TSCs, and new elements have been supplied on the pathways activated in this process. CONCLUSIONS: TSCs are capable of eliciting a favorable cellular response in periapical regeneration. PMID- 27776885 TI - Understanding External Cervical Resorption in Vital Teeth. AB - INTRODUCTION: The aim of this study was to investigate the 3-dimensional (3D) structure and the cellular and tissue characteristics of external cervical resorption (ECR) in vital teeth and to understand the phenomenon of ECR by combining histomorphological and radiographic findings. METHODS: Twenty-seven cases of vital permanent teeth displaying ECR were investigated. ECR diagnosis was based on clinical and radiographic examination with cone-beam computed tomographic imaging. The extracted teeth were further analyzed by using nanofocus computed tomographic imaging, hard tissue histology, and scanning electron microscopy. RESULTS: All examined teeth showed some common characteristics. Based on the clinical and experimental findings, a 3-stage mechanism of ECR was proposed. At the first stage (ie, the initiation stage), ECR was initiated at the cementum below the gingival epithelial attachment. At the second stage (ie, the resorption stage), the resorption invaded the tooth structure 3-dimensionally toward the pulp space. However, it did not penetrate the pulp space because of the presence of a pericanalar resorption-resistant sheet. This layer was observed to consist of predentin, dentin, and occasionally reparative mineralized (bonelike) tissue, having a fluctuating thickness averaging 210 MUm. At the last advanced stage (ie, the repair stage), repair took place by an ingrowth and apposition of bonelike tissue into the resorption cavity. During the reparative stage, repair and remodeling phenomena evolve simultaneously, whereas both resorption and reparative stages progress in parallel at different areas of the tooth. CONCLUSIONS: ECR is a dynamic and complex condition that involves periodontal and endodontic tissues. Using clinical, histologic, radiographic, and scanning microscopic analysis, a better understanding of the evolution of ECR is possible. Based on the experimental findings, a 3-stage mechanism for the initiation and growth of ECR is proposed. PMID- 27776884 TI - Antimicrobial Activity and Physicochemical Properties of Calcium Hydroxide Pastes Used as Intracanal Medication. AB - INTRODUCTION: The aim of the present study was to evaluate the pH, calcium release, solubility, and antimicrobial action against biofilms of calcium hydroxide + saline solution, Calen (SS White Artigos Dentarios Ltd, Rio de Janeiro, Brazil) (CH/P), Calen camphorated paramonochlorophenol (CMCP) (CH/CMPC), and calcium hydroxide + chlorhexidine (CH/CHX) pastes. METHODS: The pH of the pastes was determined with a calibrated pH meter placed in direct contact with each paste. The root canals of acrylic teeth (N = 10) were filled with the previously mentioned intracanal dressings and immersed in ultrapure water to measure hydroxyl (pH meter) and calcium ion release (atomic absorption spectrophotometer) at time intervals of 3, 7, 15, and 30 days. To assess solubility, the root canals of acrylic teeth (N = 10) were filled with the previously mentioned pastes and scanned by micro-computed tomographic imaging before (initial) and after 7, 15, and 30 days of immersion in ultrapure water. The solubility of each specimen was the difference between the initial and final volume scanning. For antimicrobial analysis, monospecies and dual-species biofilms were in vitro induced on dentin blocks (N = 20). Afterward, they were treated with the pastes for 7 days. Live/dead dye and a confocal microscope were used to measure the percentage of living cells. Data were statistically compared (P < .05). RESULTS: The highest OH- ion release values were found in 3 and 30 days. Ca2+ releases were greater in CH/CMCP. CH/P and CH/CMCP showed a higher percentage of volume loss values. CH/CHX presented the greatest antimicrobial action. CONCLUSIONS: CH/P and CH/CMPC showed higher solubility values in the period analyzed. Seven days of contact may be insufficient for calcium hydroxide + saline solution, CH/P, and CH/CMCP pastes to kill bacterial cells in the biofilms studied. Chlorhexidine added to CH favored greater effectiveness against the previously mentioned bacterial biofilms. PMID- 27776887 TI - Response to 'Re. Surgery in disorders of sex development (DSD) with a gender issue: If (why), when, and how?' PMID- 27776886 TI - Bending Resistance and Cyclic Fatigue Life of Reciproc, Unicone, and WaveOne Reciprocating Instruments. AB - INTRODUCTION: This study evaluated the bending resistance and cyclic fatigue life of a new single-file reciprocating instrument (Unicone; Medin, Nove Mesto na Morave, Czech Republic). Reciproc (VDW, Munich, Germany) and WaveOne (Dentsply Maillefer) instruments were used as references for comparison. METHODS: Flexibility was determined by 45 degrees bending tests using a universal testing machine. The cyclic fatigue test was performed using a custom-made device. For this test, an artificial canal with a 60 degrees angle and a 5-mm radius of curvature was used. Scanning electron microscopic analysis was performed to determine the mode of fracture and possible deformations at the helical shaft. Statistical analysis for the bending resistance test was performed using parametric methods (ie, 1-way analysis of variance). Post hoc pair-wise comparisons were performed using the Tukey test for multiple comparisons (P < .05). Weibull analysis was used to calculate the mean life, beta, and eta parameters. RESULTS: Reciproc presented significantly lower bending resistance than the other tested systems (P < .05), whereas no differences were observed between WaveOne and Unicone (P > .05). When mean life was compared among the brands, Reciproc lasted longer than WaveOne with a probability of 99.9%, longer than Unicone in the "RECIPROC ALL" mode with a probability of 99.9%, and longer than Unicone in the "WAVEONE ALL" mode with a probability of 99.9% (all statistically significant). Moreover, WaveOne lasted longer than Unicone in the "RECIPROC ALL" mode with a probability of 98.5% and longer than Unicone in the "WAVEONE ALL" mode with a probability of 99.8% (all statistically significant). Finally, Unicone in the "RECIPROC ALL" mode lasted longer than Unicone in the "WAVEONE ALL" mode with a probability of 95.3% (statistically significant). CONCLUSIONS: The new reciprocating instrument Unicone showed lower cyclic fatigue resistance compared with Reciproc R25 and WaveOne Primary files. PMID- 27776889 TI - A new target for Parkinson's disease: Small molecule SERCA activator CDN1163 ameliorates dyskinesia in 6-OHDA-lesioned rats. AB - Endoplasmic reticulum (ER) stress is intimately linked to Parkinson's disease (PD) pathophysiology. Disrupted intracellular calcium homeostasis is a major cause of the ER stress seen in dopaminergic neurons, leading to the cell death and subsequent loss of movement and coordination in patients. Dysfunctional calcium handling proteins play a major role in the promulgation of ER stress in PD. Specifically, compromised sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been identified as a major cause of ER stress and neuron loss in PD. We have identified a small molecule activator of SERCA that increases ER calcium content, rescues neurons from ER stress-induced cell death in vitro, and shows significant efficacy in the rat 6-hydroxydopamine (6-OHDA) model of PD. Together, these results support targeting SERCA activation as a viable strategy to develop disease-modifying therapeutics for PD. PMID- 27776888 TI - Polyfluorinated salicylic acid derivatives as analogs of known drugs: Synthesis, molecular docking and biological evaluation. AB - We have developed the convenient methods for synthesis of polyfluorosalicylic acids and their derivatives. For the first time the biological properties of polyfluorosalicylates were investigated in vitro (permeability through the biological membranes, COX-1 inhibitory action) and in vivo (anti-inflammatory, analgesic activities, acute toxicity). Molecular docking of polyfluorinated salicylates confirmed in vitro and in vivo experiments. PMID- 27776890 TI - Modulating amyloid-beta aggregation: The effects of peptoid side chain placement and chirality. AB - Alzheimer's disease (AD) is characterized by the buildup of insoluble aggregated amyloid-beta protein (Abeta) into plaques that accumulate between the neural cells in the brain. AD is the sixth leading cause of death in the United States and is the only cause of death among the top ten that cannot currently be treated or cured (Alzheimer's Association, 2011; Selkoe, 1996). Researchers have focused on developing small molecules and peptides to prevent Abeta aggregation; however, while some compounds appear promising in vitro, the research has not resulted in a viable therapeutic treatment. We previously reported a peptoid-based mimic (JPT1) of the peptide KLVFF (residues 16-20 of Abeta) that modulates Abeta40 aggregation, specifically reducing the total number of fibrillar, beta-sheet structured aggregates formed. In this study, we investigate two new variants of JPT1 that probe the importance of aromatic side chain placement (JPT1s) and side chain chirality (JPT1a). Both JPT1s and JPT1a modulate Abeta40 aggregation by reducing total beta-sheet aggregates. However, JPT1a also has a pronounced effect on the morphology of fibrillar Abeta40 aggregates. These results suggest that Abeta40 aggregation may follow a different pathway in the presence of peptoids with different secondary structures. A better understanding of the interactions between peptoids and Abeta will allow for improved design of AD treatments. PMID- 27776891 TI - Mortality and Cardiovascular Risk of Sulfonylureas in South Asian, Chinese and Other Canadians with Diabetes. AB - OBJECTIVES: Sulfonylureas have been inconsistently associated with increased cardiovascular mortality in patients with type 2 diabetes mellitus. However, there are no existing studies of long-term risk in South Asian and Chinese populations. Our objective was to determine whether sulfonylureas are associated with increased mortality or cardiovascular disease in a population cohort of South Asian, Chinese and other Canadian patients with incident diabetes. METHODS: We studied a population-based cohort of adults 35 years of age or older who had diabetes and had been diagnosed between April 2004 and March 2014 by using administrative databases from British Columbia. The primary outcome was time to death from any cause or from a major cardiovascular event (MACE) with sulfonylurea treatment within each ethnicity. Propensity score modelling was applied using inverse probability of treatment weights. Results were stratified by agent and adjusted for age, sex, comorbidities, income and other medications. RESULTS: We included 208 870 patients: 13 755 South Asians, 22 871 Chinese, 172 244 other Canadians. Mortality and MACEs were higher in other Canadian patients for whom sulfonylureas had been prescribed (adjusted HR = 2.0; 95% confidence interval 1.9 to 2.2; and HR = 1.9, 1.7 to 2.2). Among Chinese and South Asian patients who had been prescribed sulfonylureas, mortality (HR = 2.6, 2.0 to 3.5; and HR = 2.4, 1.7 to 3.4, respectively) and MACEs (HR = 2.3; 1.4 to 4.0; and HR = 2.0, 1.2 to 3.2, respectively) were elevated. CONCLUSIONS: Considering the widespread use of sulfonylureas, there is a significant signal for increased mortality in all patients. In particular, increased mortality and MACEs were observed in South Asian and Chinese patients. These results should be confirmed in other studies, and patients of Asian descent should be included in clinical trials concerning diabetes. PMID- 27776892 TI - Computed Tomography Perfusion Deficits during the Baseline Period in Aneurysmal Subarachnoid Hemorrhage Are Predictive of Delayed Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a frequent and fearful complication following aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study is to assess the diagnostic accuracy of computed tomography perfusion (CTP) during an admission baseline period for the prediction of DCI. METHODS: Fifty four aSAH cases were screened by baseline CTP within 3 days after aSAH and were reexamined with CTP 7-17 days after aSAH. Relative cerebral blood volume, relative cerebral blood flow (CBF), and relative mean transit time were measured. DCI was confirmed by a combination of noncontrast CT, CTP reexamination, and clinical assessment of neurologic deficits. Quantitative baseline and reexamination CTP data for all patients were compared between DCI and without DCI groups using Student's t-tests. The quantitative baseline and reexamination CTP data of DCI patients were compared using paired Student's t-tests. The chi2 test was used to evaluate incidences of DCI between different baseline relative CBF levels. The optimal cutoff value for each parameter was established by receiver operating characteristic curve analysis. RESULTS: Of the patients included in this study, 33.3% (18 of 54) developed DCI. There was a significant difference in the incidence of DCI among different baseline relative CBF subsets (chi2 = 38.00, P < .05). A relative CBF of .84 had the highest specificity and sensitivity of predicting DCI. CONCLUSION: CTP parameters during the baseline period can be helpful for the early identification of aSAH patients who are at high risk for DCI. PMID- 27776893 TI - Is spinal cord stimulation safe? A review of 13 years of implantations and complications. AB - OBJECTIVE: The aim of this review was to evaluate the complications of spinal cord stimulation (SCS) for chronic pain. METHODS: This was a retrospective case series of 212 patients treated with SCS for chronic lower-limb neuropathic pain between March 2002 and February 2015 in a Reims academic hospital. All patients received a surgically implanted paddle-type electrode. Complications with this technique are here described and analyzed, and other treatment and preventative methods proposed. RESULTS: The major indication was 'failed back surgery syndrome', and 74 (35%) patients experienced complications, of which 57% were benign, while 42% required invasive treatment. Most frequent complications (n=22, 10%) were hardware malfunctions. There were two cases (0.9%) of postoperative neurological deficit and nine (4.2%) with postoperative infections. All patients received the appropriate treatment for their complication. CONCLUSION: Despite the presence of complications, SCS is still a safe technique, although careful patient selection and proper surgical technique can help to avoid major complications. PMID- 27776894 TI - End-of-life, euthanasia, and assisted suicide: An update on the situation in France. AB - On February 2, 2016, the French parliament adopted legislation creating new rights for the terminally ill. The text modifies and reinforces the rights of patients to end-of-life care and strengthens the status of surrogate decision makers. Under the new regulations, advance directives become legally binding though not unenforceable. Two types of advance directives are distinguished depending on whether the person is suffering or not from a serious illness when drafting them. The attending physician must abide by the patient's advance directives except in three situations: there is a life-threatening emergency; the directives are manifestly inappropriate; the directives are not compatible with the patient's medical condition. There is no time limit on the validity of advance directives. They are to be written in concordance with a model elaborated by the French superior health authority. This model takes into account the person's knowledge (or not) of having a serious illness when drafting his/her advance directives. In all likelihood, physicians will be called upon to help patients elaborate their advance directives. The law also has a provision for a national registry - potentially the shared medical file - to be designed as a reference source to facilitate storage, accessibility and safety of advance directives. The law introduces the right to continuous deep sedation until death in three specific situations: (i) at the patient's request when the short-term prognosis is death and continuous deep sedation is the only alternative for relieving the patient's suffering or one or more otherwise uncontrollable symptoms; (ii) at the patient's request when the patient chooses to withdraw artificial life-sustaining treatment and such withdrawal would be rapidly life shortening and susceptible to cause unbearable suffering; (iii) when the patient is unable to express his/her wishes and the collegiate medical decision is to withdraw aggressive futile life-sustaining treatment; continuous deep sedation is mandatory when the patient presents signs of suffering or when the patient's suffering cannot be evaluated due to the patient's cerebral or cognitive state. The law stipulates prior control of such practices, implying the development of a new type of collegiate procedure for medical decision-making. Satisfactory application of this new law will depend greatly on the implementing decrees. It will also depend on the implementation of a genuine policy for the development of palliative care. Professional guidelines will be needed. Several issues relevant to the field of neurology remain unresolved or are introduced by the new regulations. Further in-depth reflection and research are need. PMID- 27776896 TI - Transcatheter arterial embolization with ethylene vinyl alcohol copolymer (Onyx) for the treatment of hemorrhage due to uterine arteriovenous malformations. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of ethylene vinyl alcohol copolymer (Onyx) as a single embolic agent for percutaneous arterial treatment of hemorrhage due to uterine arteriovenous malformations (AVMs). MATERIALS AND METHODS: Twelve women (mean age, 33 years) with metrorrhagia due to uterine AVMs who were treated by percutaneous arterial embolization using Onyx as a single embolic agent were retrospectively included. The diagnosis of uterine AVM was suggested by pelvic ultrasound and/or magnetic resonance imaging findings and further confirmed by angiography. Clinical files and angiographic examinations were reviewed for angiographic findings, technical and clinical success, procedure complication and further pregnancies. Clinical success was defined by absence of metrorrhagia at 1 month following embolization. RESULTS: Sixteen arterial embolization procedures were performed. Angiographically, 6 women had high flow AVM and 6 had low flow AVM. The rate of technical and clinical success was 92% (11/12 patients). One woman with early repeat hemorrhage underwent two embolization procedures and further hysterectomy. No severe complications were observed after embolization. Three women (3/12; 25%) became pregnant following embolization including one full term pregnancy. CONCLUSION: In women with metrorrhagia due to AVM, arterial embolization with Onyx is effective and safe. Additional research is needed to confirm the possibility of future pregnancy after Onyx embolization. PMID- 27776895 TI - Evidence in immunotherapy for paediatric respiratory allergy: Advances and recommendations. AB - Allergic respiratory diseases are major health problems in paediatric population due their high level of prevalence and chronicity, and to their relevance in the costs and quality of life. One of the most important risk factors for the development of airway diseases in children and adolescents is atopy. The mainstays for the treatment of these diseases are avoiding allergens, controlling symptoms, and preventing them through sustained desensitization by allergen immunotherapy (AIT). AIT is a treatment option that consists in the administration of increasing amounts of allergens to modify the biological response to them, inducing long-term tolerance even after treatment has ended. This treatment approach has shown to decrease symptoms and improve quality of life, becoming cost effective for a large number of patients. In addition, it is considered the only treatment that can influence the natural course of the disease by targeting the cause of the allergic inflammatory response. The aim of this publication is to reflect the advances of AIT in the diagnosis and treatment of allergic respiratory diseases in children and adolescents reviewing articles published since 2000, establishing evidence categories to support the strength of the recommendations based on evidence. The first part of the article covers the prerequisite issues to understand how AIT is effective, such as the correct etiologic and clinical diagnosis of allergic respiratory diseases. Following this, the article outlines the advancements in understanding the mechanisms by which AIT achieve immune tolerance to allergens. Administration routes, treatment regimens, dose and duration, efficacy, safety, and factors associated with adherence are also reviewed. Finally, the article reviews future advances in the research of AIT. PMID- 27776897 TI - Measurement of parent satisfaction in the paediatric intensive care unit - Translation, cultural adaptation and psychometric equivalence for the French speaking version of the EMPATHIC-65 questionnaire. AB - INTRODUCTION: Within paediatric intensive care units (PICUs), only a few parent satisfaction instruments are validated and none are available for French-speaking parents. The aims of the study were to translate and culturally adapt the Dutch EMPATHIC-65 questionnaire into a French version and to test its psychometric equivalence. METHODS: Two French-speaking PICUs in Switzerland and France participated. The questionnaire was translated using a standardised method and parents with PICU experience were interviewed to assess clarity of the translated version. Secondly, parents of children hospitalised for at least 24 hours and who were fluent in French, were invited to complete the French translated version of the EMPATHIC-65 questionnaire. Reliability and validity measures were used to examine its psychometric equivalence. RESULTS: The overall mean clarity agreement reached 90.2% by 17 French-speaking parents. Eight unclear items have subsequently been reworded. One hundred seventy-two parents completed the French version questionnaire. Reliability and convergent validity have been confirmed by an adequate internal consistency (0.59-0.89) and convergent validity (rs 0.25 0.63, p<0.01). CONCLUSION: Psychometric equivalence of the French EMPATHIC-65 questionnaire highlights the appropriateness of relying on available valid instrument to expand the availability of health instrument measure in French. PMID- 27776898 TI - Cementless Porous Tantalum Monoblock Tibia vs Cemented Modular Tibia in Primary Total Knee Arthroplasty: A Meta-Analysis. AB - BACKGROUND: With the introduction of new fixation systems and designs, there has been a recent reemergence of interest in cementless fixation of the tibial component in total knee arthroplasty. However, little is known regarding the clinical features and survivorship of the cementless porous tantalum monoblock tibial component compared to the conventional cemented modular tibial component. METHODS: We conducted a literature search of multiple databases for comparative studies published before June 2015 that investigated the outcomes of cementless porous tantalum monoblock tibia vs conventional cemented modular tibia. A pooled analysis was performed. The outcomes of interest were postoperative functional score, range of motion, Western Ontario and McMaster University Osteoarthritis Index, total complications, reoperation, radiolucent lines, loosening of the tibial component, and length of operation. RESULTS: Six studies involving 977 patients were eligible for the meta-analysis. The use of a cementless porous tantalum monoblock tibial component may associate with a slightly higher functional score, fewer radiolucent lines, and shorter operation. No significant difference was seen in regard to the range of motion, Western Ontario and McMaster University Osteoarthritis Index, total complications, reoperation, and loosening of the component between the 2 groups. CONCLUSION: However, due to variation among the included studies, the use of cementless porous tantalum monoblock tibia seems to achieve no substantial superiority over that of the conventional cemented modular tibia at 5-year follow-up. Data concerning the long term prognosis of this novel implant should continue to be collected and analyzed. PMID- 27776899 TI - The Association Between Hospital Length of Stay and 90-Day Readmission Risk Within a Total Joint Arthroplasty Bundled Payment Initiative. AB - BACKGROUND: To curb the unsustainable rise in health care expenses, health care payers are developing programs to incentivize hospitals and physicians to improve the value of care delivered to patients. Payers are utilizing various metrics, such as length of stay (LOS) and unplanned readmissions, to track progression of quality metrics. Relevant to orthopedic surgeons, the Centers for Medicare and Medicaid Services announced in 2015 the Comprehensive Care for Joint Replacement Payment Model-a program aimed at improving the quality of health care delivered to patients by shifting more of the financial risk of patient care onto providers. METHODS: We analyzed the medical records of 1329 consecutive lower extremity total joint patients enrolled in Centers for Medicare and Medicaid Services' Bundled Program for Care Improvement treated over a 21-month period. The goal of this study was to ascertain if hospital LOS is associated with unplanned readmissions within 90 days of admission for a total hip or knee arthroplasty. RESULTS: After controlling for multiple demographic variables including sex, age, comorbidities and discharge location, we found that hospital LOS greater than 4 days is a significant risk factor for unplanned readmission within 90 days (odd ratio = 1.928, P = .010). Total knee arthroplasty (TKA) and discharge to a location other than home are also independent risk factors for 90 day readmission. CONCLUSION: Our results demonstrate that increased LOS is a significant risk factor for readmission within 90 days of admission for a hip or knee arthroplasty in the Medicare population. PMID- 27776900 TI - Effect of Body Mass Index on Digital Templating for Total Hip Arthroplasty. AB - BACKGROUND: Digital templating is becoming more prevalent in orthopedics. Recent investigations report high accuracy using digital templating in total hip arthroplasty (THA); however, the effect of body mass index (BMI) on templating accuracy is not well described. METHODS: Digital radiographs of 603 consecutive patients (645 hips) undergoing primary THA by a single surgeon were digitally templated using OrthoView (Jacksonville, FL). A 25-mm metallic sphere was used as a calibration marker. Preoperative digital hip templates were compared with the final implant size. Hips were stratified into groups based on BMI: BMI <30 (315), BMI 30-35 (132), BMI 35-40 (97), and BMI >40 (101). RESULTS: Accuracy between templating and final size did not vary by BMI for acetabular or femoral components. Digital templating was within 2 sizes of the final acetabular and femoral implants in 99.1% and 97.1% of cases, respectively. CONCLUSION: Digital templating is an effective means of predicting the final size of THA components. BMI does not appear to play a major role in altering THA digital templating accuracy. PMID- 27776901 TI - Bilateral Total Hip Arthroplasty: 1-Stage or 2-Stage? A Meta-Analysis. AB - BACKGROUND: Total hip arthroplasty (THA) is one of the most successful orthopedic surgeries performed in the last 50 years. However, controversies still exist between conducting 1- or 2-stage bilateral THA. METHODS: Using PubMed, Ovid, Embase, and Cochrane library databases, we searched for papers written between January 1995 and October 2015 that contained the following search terms: "one stage or two-stage" or "simultaneous or staged," and "hip" and "arthroplasty or replacement." A meta-analysis was conducted with the collected pooled data about major and minor systemic complications, surgical complications, and other perioperative data associated with 1- and 2-stage bilateral THA. Statistical analysis was performed by the Mantel-Haenszel method, and the fixed effect model was used to analyze data. RESULTS: There were 13 studies with 17,762 patients who underwent 1-stage bilateral THA and 46,147 patients who underwent 2-stage bilateral THA. One-stage bilateral THA had a lower risk of major systemic complications, less deep venous thrombosis, and shorter operative time compared with 2-stage bilateral THA. There were no significant differences in death, pulmonary embolism, cardiovascular complication, infections, minor complications, and other surgical complications between procedures. CONCLUSION: One-stage bilateral THA was superior to 2-stage bilateral THA in terms of major systemic complication, deep venous thrombosis, and surgical time compared with 2-stage bilateral THA. However, this study does not encourage performing 1-stage over 2 stage bilateral THA. Higher evidence level studies are necessary for further analysis. PMID- 27776902 TI - Reply to Letter to the Editor on 'The Effects of a Hospitalist Comanagement Model for Joint Arthroplasty Patients in a Teaching Facility'. PMID- 27776903 TI - Delayed Total Hip Arthroplasty for Failed Acetabular Fractures: The Influence of Initial Fracture Management on Outcome After Arthroplasty. AB - BACKGROUND: Total hip arthroplasty (THA) provides a successful salvage option for failed acetabular fractures. The complexity of arthroplasty for a failed acetabular fracture will depend on the fracture pattern and the initial management of the fracture. Our objective was to compare the midterm outcome of THA between patients who presented with failed acetabular fractures following initial surgical or nonsurgical treatment. METHODS: Forty-seven patients underwent cementless THA +/- acetabular reconstruction following failed treatment of acetabular fractures. Twenty-seven were initially treated by surgery (group A) and 20 had nonsurgical treatment (group B). Intraoperative measures, preoperative and follow-up clinical, radiological, and functional outcomes were compared between the 2 groups. RESULTS: The mean surgical time, blood loss, and need for blood transfusion were significantly less in group A (P < .05). Acetabular reconstruction to address cavitary or segmental defects was needed in a significantly higher number of patients in group B (P = .006). Significant improvement in modified Merle d'Aubigne and Oxford scores was seen postsurgery in both groups. Acetabular component survival with aseptic loosening as end point was 98%. Overall survival rate with infection, revision, or loosening as end point was 93% at a mean follow-up of 7 years +/- 17 months. CONCLUSION: THA for a failed acetabular fracture is greatly facilitated by initial surgical treatment. Although functional results and survivorship were similar in both groups, failed nonsurgical treatment in complex fractures is associated with migrated femoral head and extensive acetabular defects requiring complex acetabular reconstruction. PMID- 27776904 TI - Prevalence of Venous Thromboembolic Events Is Low in Asians After Total Knee Arthroplasty Without Chemoprophylaxis. AB - BACKGROUND: This retrospective cohort study was designed to establish the prevalence of clinically significant venous thromboembolic events (VTE) in our patients undergoing total knee arthroplasty (TKA) without chemoprophylaxis. METHODS: A single-surgeon cohort of patients who underwent TKA from 2006 to 2014 were included. All patients had a pneumatic tourniquet applied and a drain inserted postoperatively. Tranexamic acid was not used perioperatively. All patients were under a standardized postoperative protocol with routine mechanical prophylaxis against VTE. None of the patients received prophylactic anticoagulation. All patients ambulated on the second postoperative day. Only symptomatic patients were referred for radiological examination to exclude VTE. We evaluated the patient demographics and calculated the prevalence of VTE in our cohort. RESULTS: A total of 966 patients were reviewed. Mean age was 66.1 +/- 7.8 years. Mean body mass index was 28.2 +/- 4.7 kg/m2. Mean tourniquet time was 53 +/- 23 minutes. Patients stayed in hospital for a mean of 5.4 +/- 3.1 days. There was 100% compliance to mechanical prophylaxis. And 11.1% of our patients were on concomitant antiplatelet or anticoagulant use. There were 8 patients with clinically significant VTE. This translates to a prevalence of 0.82%. Seven patients developed deep vein thrombosis and 1 patient died from massive pulmonary embolism. CONCLUSION: The prevalence of clinically significant VTE in our patients who underwent TKA without routine chemoprophylaxis is 0.82%. With proper patient selection, risk stratification, and stringent perioperative protocols, routine chemoprophylaxis may not be necessary in Asians undergoing TKA. PMID- 27776905 TI - Silver-Impregnated Occlusive Dressing Reduces Rates of Acute Periprosthetic Joint Infection After Total Joint Arthroplasty. AB - BACKGROUND: Commercial silver-impregnated occlusive dressings (such as AQUACEL(r) Ag SURGICAL Cover Dressing) have been touted as antimicrobial dressings to be used following total joint arthroplasty. Given the increased cost of an AQUACEL(r) Ag SURGICAL Cover Dressing over a standard dressing for total joint arthroplasty, the objective of this study was to determine whether AQUACEL(r) Ag SURGICAL Cover Dressing is effective in reducing the rates of acute periprosthetic joint infection (PJI) compared to standard sterile dressing. METHODS: We retrospectively reviewed the charts of 1173 consecutive patients who underwent a total knee or total hip arthroplasty between 2007 and 2015 by 1 surgeon. The surgeon switched from using a standard xeroform/gauze dressing to an AQUACEL(r) Ag SURGICAL Cover Dressing in June 2011, with no other major changes in antimicrobial management. Charts were reviewed for evidence of acute PJI (within 3 months of surgery). RESULTS: There were a total of 11 cases of acute PJI in this patient cohort (0.94%). The incidence of acute PJI for patients managed with a sterile xeroform dressing was 1.58% (9 of 568 patients), compared to 0.33% (2 of 605 patients) with the use of AQUACEL(r) Ag SURGICAL Cover Dressing. Univariate analysis showed this to be statistically significant (P = .03), and a multiple logistic regression model supported AQUACEL(r) Ag SURGICAL Cover Dressing as a protective factor with an odds ratio of 0.092 (95% confidence interval, 0.017-0.490; P = .005). CONCLUSION: This 4-fold decrease in acute PJI with the use of AQUACEL(r) Ag SURGICAL Cover Dressing supports the use of silver impregnated occlusive dressings for the reduction of acute PJI. PMID- 27776906 TI - The Anteroposterior Axis of the Proximal Tibia Can Change After Tibial Resection in Total Knee Arthroplasty: Computer Simulation Using Asian Osteoarthritis Knees. AB - BACKGROUND: We evaluated the effect of cutting surface on the anteroposterior (AP) axis of the proximal tibia using a 3-dimensional (3D) bone model to ensure proper tibial rotational alignment in total knee arthroplasty. METHODS: 3D bone models were reconstructed from the preoperative computed tomography data of 93 Japanese osteoarthritis knees with varus deformity. The AP axis was defined as the perpendicular bisector of the medial and lateral condylar centers in a 3D coordinate system. Bone cutting of the proximal tibia was performed with various tibial posterior slopes (0 degrees , 3 degrees , 7 degrees ) to the mechanical axis, and we compared the AP axes before and after bone cutting. RESULTS: The AP axis before bone cutting crossed a point at about 16% (one-sixth) of the distance from the medial edge of the patellar tendon at its tibial attachment. The AP axis after bone cutting was significantly internally rotated at all posterior slopes: 4.1 degrees at slope 0 degrees , 3.0 degrees at slope 3 degrees , and 2.1 degrees at slope 7 degrees . The percentages of cases with differences of more than 3 degrees or 5 degrees were 66.7% and 34.4% at slope 0 degrees , 53.8% and 24.7% at slope 3 degrees , and 38.3% and 11.8% at slope 7 degrees , respectively. CONCLUSION: The AP axis of the proximal tibia may be rotated internally after resection of the proximal tibia in total knee arthroplasty. Hence, surgeons should recognize the effect of changes in the cutting surface on rotational alignment of the proximal tibia. PMID- 27776907 TI - Sensitivity and Specificity of Metal Ion Levels in Predicting "Pseudotumors" due to Taper Corrosion in Patients With Dual Taper Modular Total Hip Arthroplasty. AB - BACKGROUND: Currently, no serum metal ion threshold exists to identify adverse tissue reactions in total hip arthroplasty (THA) patients with taper corrosion. Our study aims to investigate the sensitivity and specificity of serum metal ions in detecting taper corrosion related pseudotumors in patients with dual taper modular THA. METHODS: A total of 148 patients with dual taper modular THA were investigated: (1) 90 patients with pseudotumors detected with metal artifact reduction sequence-magnetic resonance imaging (MARS-MRI) and (2) 58 patients without pseudotumors on MARS-MRI. Receiver operating characteristic curves were constructed to determine the sensitivity and specificity using different metal ion thresholds. The severity of intraoperative tissue damage was correlated with preoperative metal ion levels. RESULTS: Pseudotumor was associated with higher cobalt (5.0 MUg/L vs 3.7 MUg/L, P < .01) and Co/Cr ratio (6.0 vs 3.7, P < .01). The sensitivity and specificity for cobalt level of 2.8 MUg/L and Co/Cr ratio of 3.8 in detecting taper corrosion-related pseudotumors on MARS-MRI was 88% and 32% and 70% and 50%, respectively. Higher intraoperative tissue damage grades demonstrated significantly higher Co/Cr ratios (8.6 vs 3.4, P = .03). CONCLUSION: Although metal ion levels alone should not be relied on as the sole parameter to determine revision surgery, cobalt level >2.8 MUg/L and the Co/Cr ratio >3.8 are useful clinical diagnostic adjuncts in the systematic clinical evaluation for taper corrosion-related adverse tissue reactions in patients with dual modular taper THA. PMID- 27776908 TI - The High Value Healthcare Collaborative: Observational Analyses of Care Episodes for Hip and Knee Arthroplasty Surgery. AB - BACKGROUND: Broader use of value-based reimbursement models will require providers to transparently demonstrate health care value. We sought to determine and report cost and quality data for episodes of hip and knee arthroplasty surgery among 13 members of the High Value Healthcare Collaborative (HVHC), a consortium of health care systems interested in improving health care value. METHODS: We conducted a retrospective, cross-sectional observational cohort study of 30-day episodes of care for hip and knee arthroplasty in fee-for-service Medicare beneficiaries aged 65 or older who had hip or knee osteoarthritis and used 1 of 13 HVHC member systems for uncomplicated primary hip arthroplasty (N = 8853) or knee arthroplasty (N = 16,434), respectively, in 2012 or 2013. At the system level, we calculated: per-capita utilization rates; postoperative complication rates; standardized total, acute, and postacute care Medicare expenditures for 30-day episodes of care; and the modeled impact of reducing episode expenditures or per-capita utilization rates. RESULTS: Adjusted per capita utilization rates varied across HVHC systems and postacute care reimbursements varied more than 3-fold for both types of arthroplasty in both years. Regression analysis confirmed that total episode and postacute care reimbursements significantly differed across HVHC members after considering patient demographic differences. Potential Medicare cost savings were greatest for knee arthroplasty surgery and when lower total reimbursement targets were achieved. CONCLUSION: The substantial variation that we found offers opportunities for learning and collaboration to collectively improve outcomes, reduce costs, and enhance value. Ceteris paribus, reducing per-episode reimbursements would achieve greater Medicare cost savings than reducing per capita rates. PMID- 27776909 TI - Acetic Acid as Part of a Debridement Protocol During Revision Total Knee Arthroplasty. AB - BACKGROUND: Thorough debridement is mandatory in revision for infected total knee arthroplasties (TKA). We investigated a novel adjuvant chemical debridement strategy using acetic acid (AA) that seeks to create a hostile environment for microorganisms. We report the first orthopedic in vivo series using an AA soak in infected TKAs. We also investigated the in vitro efficacy of AA against bacteria isolated from these knees. METHODS: Twenty-three patients with infected TKA were treated with a standard debridement protocol and chemical debridement with a 20 minute AA soak. In parallel, bacteria from infected TKAs were cultured for in vitro susceptibility testing with AA solutions of different concentrations to understand its potential mechanism of action. RESULTS: Intraoperatively, there were no physiological responses during the AA soak or on release of the tourniquet. Postoperatively, there was no increase in analgesic requirements or wound or soft-tissue complications. Clinical follow-up continued for 24 months to monitor recurrent infection. In vitro, zones of inhibition were formed on less than 40% of the organisms, demonstrating that AA was not directly bactericidal against the majority of the isolates. However, when cultured in a bacterial suspension, AA completely inhibited the growth of the isolates at concentrations as low as 0.19% vol/vol. CONCLUSION: This study has shown that the use of 3% AA soak, as part of a debridement protocol is safe in patients. While the exact mechanism of action is yet to be determined, AA concentrations as low as 0.19% vol/vol in vitro are sufficient to completely inhibit bacterial growth. PMID- 27776912 TI - Discussion. PMID- 27776910 TI - The Outcomes Following Revision of Monoblock Metal on Metal Acetabular Components for Painful Micromotion in the Absence of Adverse Local Tissue Reaction to Metal. AB - BACKGROUND: Revision hip arthroplasty for metal-on-metal arthroplasty (MOMA) in the presence of an adverse local tissue reaction (ALTR) has been associated with compromised outcomes. We hypothesized that revision of MOMA for painful micromotion of the cup, in the absence of ALTR, would have a more favorable outcome. METHODS: We reviewed our database for Durom acetabular shell revision with minimum 24 months (24 months to 8 years) follow-up. Patients with a diagnosis of painful micromotion in the absence of pseudotumor was identified. RESULTS: At mid-term follow-up, 71 patients had undergone revision of a Durom MOMA. Twenty-seven of these (38%) were for painful micromotion (9 total hip arthroplasty, 18 hip resurfacing) of the cup alone. Following revision surgery, all patients reported resolution of the preoperative pain, as well as satisfactory outcome measures (mean scores: The Western Ontario and McMaster Universities Arthritis Index [WOMAC] 84.6, oxford hip score 84.7, Short Form Health Survey (SF-16) 51, University of California, Los Angeles (UCLA) 7.3). Radiologically, all cases demonstrated osseointegration of the revision shells; 1 case had zone-3 radiolucency that was nonprogressive. One patient had a dislocation treated by closed reduction at 10 weeks. CONCLUSION: Revision MOMA for painful micromotion of the shell in the absence of ALTR is not similar to revision for ALTR and is associated with predictable improvement in pain and quality of life. PMID- 27776911 TI - Genomic characterization of a fructophilic bee symbiont Lactobacillus kunkeei reveals its niche-specific adaptation. AB - Lactobacillus kunkeei is classified as a sole obligate fructophilic lactic acid bacterium that is found in fructose-rich niches, including the guts of honeybees. The species is differentiated from other lactobacilli based on its poor growth with glucose, enhanced growth in the presence of oxygen and other electron acceptors, and production of high concentrations of acetate from the metabolism of glucose. These characteristics are similar to phylogenetically distant Fructobacillus spp. In the present study, the genomic structure of L. kunkeei was characterized by using 16 different strains, and it had significantly less genes and smaller genomes when compared with other lactobacilli. Functional gene classification revealed that L. kunkeei had lost genes specifically involved in carbohydrate transport and metabolism. The species also lacked most of the genes for respiration, although growth was enhanced in the presence of oxygen. The adhE gene of L. kunkeei, encoding a bifunctional alcohol dehydrogenase (ADH)/aldehyde dehydrogenase (ALDH) protein, lacked the part encoding the ADH domain, which is reported here for the first time in lactic acid bacteria. The deletion resulted in the lack of ADH activity, implying a requirement for electron acceptors in glucose assimilation. These results clearly indicated that L. kunkeei had undergone a specific reductive evolution in order to adapt to fructose-rich environments. The reduction characteristics were similar to those of Fructobacillus spp., but distinct from other lactobacilli with small genomes, such as Lactobacillus gasseri and Lactobacillus vaginalis. Fructose-richness thus induced an environment-specific gene reduction in phylogenetically distant microorganisms. PMID- 27776914 TI - The fate of small-size pericardial heart valve prostheses in an older patient population. AB - BACKGROUND: Structural valve deterioration (SVD) is the Achilles' heel of bioprostheses. Its correlation with younger age is well known. In recent years we exclusively reserved use of small-size Mitroflow valve prostheses (LivaNova, London, United Kingdom) to an older patient population with small aortic annuli. This study aimed to assess the incidence of SVD and its effect on patient survival and need for reoperation. MATERIALS AND METHODS: Two hundred five patients (aged 75.9 +/- 5.3 years; range, 62-92 years) underwent aortic valve replacement with a 19-mm or 21-mm Mitroflow valve prosthesis between 2005 and 2011. The great majority was female (n = 170; 83%). In half of patients it was an isolated procedure. All valve prostheses were implanted in a supra-annular position using pledgeted sutures. A 19-mm valve was implanted in 93 patients (45.3%), whereas in 112 patients (54.6%) a 21-mm valve was used. RESULTS: Twenty three patients (11.2%) were diagnosed with early SVD by echocardiography. Average time from surgery to diagnosis of SVD was 64.3 +/- 26.8 months. Ten patients needed a reoperation for SVD. Average time from surgery to a second operation was 45.7 +/- 35.7 months. Overall survival was 64.5% and 42.3% at 5 and 9 years, respectively. Cumulative freedom from SVD at 5 and 9 years was 94.8% +/- 1.6% and 77.4% +/- 5.4%, respectively. In 4 patients death was linked to the presence of SVD. There were no differences in mortality, reoperation, or SVD between the 2 Mitroflow valve sizes. CONCLUSIONS: Small-size Mitroflow pericardial valve prostheses have shown a worrisome incidence of SVD even in patients aged >70 years. Based on this experience we have discontinued their use. PMID- 27776913 TI - How successful is successful? Aortic arch shape after successful aortic coarctation repair correlates with left ventricular function. AB - OBJECTIVES: Even after successful aortic coarctation repair, there remains a significant incidence of late systemic hypertension and other morbidities. Independently of residual obstruction, aortic arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch 3 dimensional shape features with functional data obtained from cardiac magnetic resonance scans. METHODS: Three-dimensional aortic arch shape models of 53 patients (mean age, 22.3 +/- 5.6 years) 12 to 38 years after aortic coarctation repair were reconstructed from cardiac magnetic resonance data. A novel validated statistical shape analysis method computed a 3-dimensional mean anatomic shape of all aortic arches and calculated deformation vectors of the mean shape toward each patient's arch anatomy. From these deformations, 3-dimensional shape features most related to left ventricular ejection fraction, indexed left ventricular end-diastolic volume, indexed left ventricular mass, and resting systolic blood pressure were extracted from the deformation vectors via partial least-squares regression. RESULTS: Distinct arch shape features correlated significantly with left ventricular ejection fraction (r = 0.42, P = .024), indexed left ventricular end-diastolic volume (r = 0.65, P < .001), and indexed left ventricular mass (r = 0.44, P = .014). Lower left ventricular ejection fraction, larger indexed left ventricular end-diastolic volume, and increased indexed left ventricular mass were identified with an aortic arch shape that has an elongated ascending aorta with a high arch height-to-width ratio, a relatively short proximal transverse arch, and a relatively dilated descending aorta. High blood pressure seemed to be linked to gothic arch shape features, but this did not achieve statistical significance. CONCLUSIONS: Independently of hemodynamically important arch obstruction or residual aortic coarctation, specific aortic arch shape features late after successful aortic coarctation repair seem to be associated with worse left ventricular function. Analyzing 3 dimensional shape information via statistical shape modeling can be an adjunct to long-term risk assessment in patients after aortic coarctation repair. PMID- 27776915 TI - Reduction in ins-7 gene expression in non-neuronal cells of high glucose exposed Caenorhabditis elegans protects from reactive metabolites, preserves neuronal structure and head motility, and prolongs lifespan. AB - BACKGROUND: Glucose derived metabolism generates reactive metabolites affecting the neuronal system and lifespan in C. elegans. Here, the role of the insulin homologue ins-7 and its downstream effectors in the generation of high glucose induced neuronal damage and shortening of lifespan was studied. RESULTS: In C. elegans high glucose conditions induced the expression of the insulin homologue ins-7. Abrogating ins-7 under high glucose conditions in non-neuronal cells decreased reactive oxygen species (ROS)-formation and accumulation of methylglyoxal derived advanced glycation endproducts (AGEs), prevented structural neuronal damage and normalised head motility and lifespan. The restoration of lifespan by decreased ins-7 expression was dependent on the concerted action of sod-3 and glod-4 coding for the homologues of iron-manganese superoxide dismutase and glyoxalase 1, respectively. CONCLUSIONS: Under high glucose conditions mitochondria-mediated oxidative stress and glycation are downstream targets of ins-7. This impairs the neuronal system and longevity via a non-neuronal/neuronal crosstalk by affecting sod-3 and glod-4, thus giving further insight into the pathophysiology of diabetic complications. PMID- 27776916 TI - Acute Rheumatic Fever: Global Persistence of a Preventable Disease. AB - The persistence of acute rheumatic fever continues to be seen globally. Once thought to be eradicated in various parts of the world, the disease came back with a vengeance secondary to a lack of diligence on the part of providers. Today, the global burden of group A streptococcal infection, the culprit of the numerous sequelae manifested in acute rheumatic fever, is considerable. Although a completely preventable disease, rheumatic fever continues to exist. It is a devastating disease that involves long-term, multisystem treatment and monitoring for patients who were unsuccessful at eradicating the precipitating group A streptococcal infection. Prevention is the key to resolving the dilemma of the disease's global burden, yet the method to yield its prevention still remains unknown. Thus, meticulous attention to implementing proper treatment is the mainstay and remains a top priority. PMID- 27776918 TI - Chronic kidney disease and high eGFR according to body composition phenotype in adults with normal BMI. AB - BACKGROUND AND AIMS: Body composition contributes to the risk of chronic kidney disease (CKD) and glomerular hyperfiltration. In adults with normal body mass index (BMI), the relationships of body composition with CKD and high estimated glomerular filtration rate (eGFR) are largely unknown. METHODS AND RESULTS: We analyzed 10,734 adults from the Korean National Health and Nutrition Examination Survey (KNHANES), whose body mass index (BMI) was within the normal range (18.5 24.9 kg/m2). Body composition was categorized into four phenotypes (normal, sarcopenia alone, obesity alone, and sarcopenic obesity) based on appendicular lean mass index (ALMI) and total body fat percentage (TBF%) measured by dual energy X-ray absorptiometry (DXA). We examined the relationship of CKD and high eGFR (eGFR >= 120 ml/min per 1.73 m2) with body composition phenotypes. Sarcopenia alone (14.3%), obesity alone (16.0%), and sarcopenic obesity (10.7%) were prevalent. The association between sarcopenia alone and eGFR was J-shaped, while that between sarcopenic obesity and eGFR was U-shaped. In multivariate logistic regression analysis compared with the normal phenotype, sarcopenic obesity had an elevated odds ratio (OR) for CKD (OR: 1.59, 95% CI: 1.16-2.19). Sarcopenia alone (OR: 1.87; 95% CI: 1.41-2.47) and sarcopenic obesity (OR: 2.37, 95% CI: 1.68-3.36) had elevated OR for high eGFR. CONCLUSION: These findings suggest that decreased muscle mass and coexistence with excess adiposity show associations with CKD and high eGFR even in adults with normal BMI. Body composition measured by DXA could provide information on the relationship of body composition with CKD and high eGFR. PMID- 27776917 TI - Which is the main molecular target responsible for the cardiovascular benefits in the EMPA-REG OUTCOME trial? A journey through the kidney, the heart and other interesting places. AB - BACKGROUND: The results of the EMPA-REG-OUTCOME trial on type 2 diabetic patients at high risk for prior cardiovascular events showed that empagliflozin produces a remarkable reduction in the rates of hospitalization for heart failure (35%), cardiovascular death (38%), and all-cause death (32%). This unexpected cardio protective action cannot be accounted for by the improvement of "classical" cardiovascular risk factors. AIMS: This review aims at summarizing current knowledge on the cardiovascular action of SGLT2 inhibitors and discuss the different hypotheses formulated to explain the results of the EMPA-REG-OUTCOME study. DATA SYNTHESIS: We discuss in detail the major cardiovascular outcomes of the study in the light of the potential systemic and myocardial mechanisms of action of the drug. In addition, we propose and speculate on a direct effect of empagliflozin on cardiomyocytes. CONCLUSIONS: The available evidence is insufficient to establish any of the proposed mechanisms of cardiovascular action of empagliflozin. While awaiting for the results of ongoing clinical studies with other SGLT2 inhibitors, the most promising putative mechanisms still deserve to be confirmed with specifically designed, yet unavailable, pre-clinical studies. PMID- 27776919 TI - Ischemic stroke in a patient with moderate to severe inherited factor VII deficiency. AB - Thrombosis is known to occur in patients with rare inherited bleeding disorders, usually in the presence of a thrombotic risk factor such as surgery and/or factor replacement therapy, but sometimes spontaneously. We present the case of a 72 year-old African American male diagnosed with congenital factor VII (FVII) deficiency after presenting with ischemic stroke, presumably embolic, in the setting of atherosclerotic carotid artery stenosis. The patient had an international normalized ratio (INR) of 2.0 at presentation, with FVII activity of 6% and normal Extem clotting time in rotational thromboelastometry. He was treated with aspirin (325 mg daily) and clopidogrel (75 mg daily) with no additional bleeding or thrombotic complications throughout his admission. This case provides further evidence that moderate to severe FVII deficiency does not protect against thrombosis. PMID- 27776920 TI - Addressing potential pitfalls of reproductive life planning with patient-centered counseling. AB - Engaging women in discussions about reproductive goals in health care settings is increasingly recognized as an important public health strategy to reduce unintended pregnancy and improve pregnancy outcomes. "Reproductive life planning" has gained visibility as a framework for these discussions, endorsed by public health and professional organizations and integrated into practice guidelines. However, women's health advocates and researchers have voiced the concern that aspects of the reproductive life planning framework may have the unintended consequence of alienating rather than empowering some women. This concern is based on evidence indicating that women may not hold clear intentions regarding pregnancy timing and may have complex feelings about achieving or avoiding pregnancy, which in turn may make defining a reproductive life plan challenging or less meaningful. We examine potential pitfalls of reproductive life planning counseling and, based on available evidence, offer suggestions for a patient centered approach to counseling, including building open and trusting relationships with patients, asking open-ended questions, and prioritizing information delivery based on patient preferences. Research is needed to ensure that efforts to engage women in conversations about their reproductive goals are effective in both achieving public health objectives and empowering individual women to achieve the reproductive lives they desire. PMID- 27776921 TI - Changes in Resilience Predict Function in Adults With Physical Disabilities: A Longitudinal Study. AB - OBJECTIVES: (1) To determine if resilience exhibits similar stability across time as depression, fatigue, and sleep quality; and (2) to determine if changes in resilience over a period of 1 year are associated with changes in depression, fatigue, sleep quality, and physical function over the same time period. DESIGN: Observational longitudinal survey study with measures administered 2 times, 1 year apart. SETTING: Community-based population sample. PARTICIPANTS: Adults with physical disabilities (N=893). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Primary outcomes were measures of resilience (Connor-Davidson Resilience Scale), depression (Patient Health Questionnaire-9), fatigue (Patient Reported Outcomes Measurement Information System [PROMIS] Fatigue Short Form), sleep quality (PROMIS Sleep Disturbance), and physical function (8-item PROMIS Physical Functioning). RESULTS: Resilience (r=.71, P<.001) exhibited similar stability over 1 year to depression (r=.71, P<.001), fatigue (r=.79, P<.001), and sleep quality (r=.68, P<.001). A decrease in resilience was associated with an increase in depression (F1,885=70.23; P<.001; R2=.54) and fatigue (F1,885=25.66; P<.001; R2=.64), and an increase in resilience was associated with improved sleep quality (F1,885=30.76; P<.001; R2=.48) and physical function (F1,885=16.90; P<.001; R2=.86) over a period of 1 year, while controlling for age, sex, and diagnosis. CONCLUSIONS: Resilience exhibits similar test-retest stability as other important domains that are often treatment targets. Changes in resilience were associated with changes in depression, fatigue, sleep quality, and physical functioning over the course of 1 year. Further longitudinal and experimental research is warranted to investigate the potential causal effect of changes in resilience on quality of life in individuals with physical disabilities. PMID- 27776922 TI - Management of oromandibular dystonia with botulinum A toxin: a series of cases. AB - Oromandibular dystonia is a disorder of movement that is often misdiagnosed. We present our experience of six patients treated with botulinum A toxin, for whom we recorded the symptoms, the group of muscles targeted, and the quantity of botulinum toxin used. We used the Glasgow Benefit Inventory (GBI) questionnaire to record and analyse outcomes after treatment. Five of the six patients had a good outcome as recorded by the GBI, the mean (SD) score of which was +40 (28), which reflected that the patients were well satisfied. The overall improvement in the categories of general health, social health, and physical health were 82%, 37%, and 31%, respectively. Botulinum type A toxin is an effective treatment of oromandibular dystonia. It is important for clinicians to recognise the condition, as treatment is well-tolerated and can improve quality of life. PMID- 27776923 TI - Intraoral ultrasonography with wrapped acoustic coupling medium. PMID- 27776924 TI - In vitro evaluation of the resistance of three types of fixation to treat fractures of the mandibular angle. AB - The purpose of this study was to compare the mechanical resistance of three different plates used to treat fractures of the mandibular angle: a regular 4 hole plate, a longer 4-hole plate (both positioned using the Champy technique), and a 3-dimensional plate positioned over the oblique line. Three equal groups of replicas of human dentate mandibles made out of polyurethane resin were used (n=21 in each group). The force was applied perpendicular to the occlusal plane at a rate of 2mm/minute at three different points: the first molar on the sectioned side; the first molar on the contralateral side; and between the central incisors. This was followed by a resistance-to-load test. The two varying factors (type of plate and site-of-load application) were tested by analysis of variance, and probabilities of less than 0.05 were accepted as significant. There were no significant differences between the subgroups, or between the mean values of the different types of plates (p=0.925). The three types of plates showed similar mechanical behaviour, which showed that the 3-dimensional plates positioned over the oblique line can produce mechanical scores similar to those of conventional plates. PMID- 27776925 TI - Carbohydrate and protein intake and risk of ulcerative colitis: Systematic review and dose-response meta-analysis of epidemiological studies. AB - BACKGROUND & AIM: Dietary carbohydrate and protein intake is generally thought as risk factors for onset of ulcerative colitis (UC), while epidemiological data had been controversial. This study aimed to evaluate the role of carbohydrate and protein intake in the development of UC. METHODS: Comprehensive search in PubMed and Embase was conducted to identify all relevant studies, and the role of carbohydrate and protein intake in the development of UC was quantitatively assessed by dose-response meta-analysis. RESULTS: Nine studies (5 case-control and 4 prospective cohort) were identified with a total of 975 UC cases and 239352 controls. The summary relative risks (RR) for per 10 g increment/day were 1.005 (95%CI: 0.991-1.019, I2 = 31.5%, n = 5) for total carbohydrate intake, 1.001 (95%CI: 0.971-1.032, I2 = 0.0%, n = 7) for the subtype of fiber intake, 1.029 (95%CI: 0.962-1.101, I2 = 68.9%, n = 2) for the subtype of sugar intake, and 1.010 (95%CI: 0.975-1.047, I2 = 12.4%, n = 7) for total protein intake. Among sugar subtypes, only sucrose intake was found positively related with UC risk (RR for per 10 g increment/day: 1.098, 95%CI: 1.024-1.177, I2 = 0.0%, n = 3). No evidence of a non-linear dose-response association was found between the nutrient intake and UC risk, except for the subtype of sucrose (P for non-linear trend = 0.032). Subgroup analyses showed consistent results. CONCLUSIONS: This meta analysis suggested a lack of association between dietary carbohydrate or protein intake and the risk of UC, except for the subtype of sucrose which played a significant role in the development of UC. Large-scale prospective designed studies are needed to confirm our findings. PMID- 27776926 TI - Ultrasound evaluation of the subacromial space in healthy subjects performing three different positions of shoulder abduction in both loaded and unloaded conditions. AB - BACKGROUND: Subacromial space (SS) narrowing may result in unsafe contact of rotator cuff tendons and bursa with the acromion, possibly promoting rotator cuff pathologies and pain. We measured SS in asymptomatic subjects after three movements employed for shoulder muscles' training. PARTICIPANTS AND MAIN OUTCOME MEASURES: Twenty-five males (age 24+/-5years; stature 175+/-8 cm; body mass 74+/ 12 kg) underwent SS ultrasound evaluation while executing with (WL) and without (NL) 4-kg load: 90 degrees shoulder abduction (SA) without humerus rotation (90 degrees neutral); 90 degrees SA maximal humeral external rotation (90 degrees er); maximum SA (above 90 degrees ) during upright row (UR). For inter-operator reliability analysis, a subset of 12 subjects was assessed by two operators. RESULTS: Intra/inter-operator reliability coefficients were high (ICC>0.87; standard error of measurement range: 0.23-0.51 mm; minimum detectable change range: 0.61-1.79 mm). ANOVA revealed significant differences between loads (p = 0.003, eta2 = 0.37) and angles (p < 0.001, eta2 = 0.72), and interaction (p = 0.004, eta2 = 0.45). Normalized SS values WL were higher at 90 degrees er vs. 90 degrees neutral and UR (p < 0.001 for both). Differences in NL were found between 90 degrees neutral and both 90 degrees er (p = 0.002) and UR (p = 0.009). CONCLUSIONS: When holding a 4-kg load, SS is larger at 90 degrees er than at 90 degrees neutral and UR shoulder abduction positions. In unloaded condition, SS at 90 degrees neutral is reduced compared to 90 degrees er and UR. PMID- 27776927 TI - The energetic cost of gait retraining: A pilot study of the acute effect. AB - OBJECTIVE: To investigate the acute effect of gait retraining aimed at reducing tibial peak positive acceleration (PPA) on energetic cost (VO2). DESIGN: Intervention with a pre/post-test design. SETTING: University biomechanics laboratory. PARTICIPANTS: 12 healthy male runners (23.4 +/- 5.3 years, 179.7 +/- 4.3 cm, 75.6 +/- 9.2 kg). MAIN OUTCOME MEASURES: Tibial PPA and oxygen consumption (VO2) were measured after a five minute baseline run and at the end of a gait retraining session aimed at minimizing tibial PPA. RESULTS: Tibial PPA significantly decreased between baseline and after gait retraining (32.6%, p = 0.007). VO2 significantly increased between the two time periods (9.3%, p = 0.008). There was no correlation between change in tibial PPA and change in VO2 (p = 0.956, r = 0.018). CONCLUSION: Practitioners who aim to reduce injury risk by minimizing tibial PPA in runners need to consider the possible acute effect on performance as a result of changes in VO2. Further investigation is warranted to understand the energetic cost of different kinematic strategies used by individuals. PMID- 27776929 TI - Kidney transplantation for HIV-positive patients. AB - HIV+ patients are at increased risk for end-stage renal disease, but HIV infection was once considered a contraindication to renal transplantation. However, contemporary studies from the United States and Europe have now demonstrated that renal transplantation is a safe and effective treatment for end stage renal disease in HIV patients, with equivalent patient and allograft survival to those uninfected. Broader experience in transplantation in HIV+ patients has identified unique challenges including high rates of acute rejection, delayed graft function, and significant drug-drug interactions. Kidney transplantation in HIV-infected patients is an active area of clinical research and trials of HIV+ to HIV+ transplantation in the United States are underway. PMID- 27776928 TI - The SAM domain inhibits EphA2 interactions in the plasma membrane. AB - All members of the Eph receptor family of tyrosine kinases contain a SAM domain near the C terminus, which has been proposed to play a role in receptor homotypic interactions and/or interactions with binding partners. The SAM domain of EphA2 is known to be important for receptor function, but its contribution to EphA2 lateral interactions in the plasma membrane has not been determined. Here we use a FRET-based approach to directly measure the effect of the SAM domain on the stability of EphA2 dimers on the cell surface in the absence of ligand binding. We also investigate the functional consequences of EphA2 SAM domain deletion. Surprisingly, we find that the EphA2 SAM domain inhibits receptor dimerization and decreases EphA2 tyrosine phosphorylation. This role is dramatically different from the role of the SAM domain of the related EphA3 receptor, which we previously found to stabilize EphA3 dimers and increase EphA3 tyrosine phosphorylation in cells in the absence of ligand. Thus, the EphA2 SAM domain likely contributes to a unique mode of EphA2 interaction that leads to distinct signaling outputs. PMID- 27776930 TI - Discrepancy between cervical disc prostheses and anatomical cervical dimensions. AB - OBJECTIVE: The aim of this study was to assess appropriateness of the sizes of available cervical disc prostheses based on tomographic measurement of human cervical vertebrae. METHODS: The anatomic dimensions of the C3-C7 segments were measured on 50 patients (age range 26-47 years) with computerized tomography scan and compared with the sizes of the popular cervical total disc prostheses (CTDP) at the market [Bryan (Medtronic), Prodisc-C (Synthes), Prestige LP (Medtronic), Discover (DePuy)]. The mediolateral and anteriorposterior diameters of the upper and lower endplates were measured with a digital measuring system. RESULTS: Overall, 43.7% of the largest implant footprints were smaller in the anterior posterior diameter and 42.6% in the mediolateral diameter were smaller than cervical endplate measurements. Discrepancy of the level C5/C6 and C6/C7 was calculated as 56.2% at the anteroposterior diameter and 43.8% at the center of mediolateral diameter. CONCLUSION: Large disparity has been found between the sizes of devices and cervical anatomic data. Companies that produce CTDP should take care of the anatomical dimensions and generate different sizes of CTDP. Spine surgeon should be familiar with the size mismatch in CTDP that may affect the clinical and radiological outcome of the surgery. PMID- 27776931 TI - Molecular Evolution of Grass Stomata. AB - Grasses began to diversify in the late Cretaceous Period and now dominate more than one third of global land area, including three-quarters of agricultural land. We hypothesize that their success is likely attributed to the evolution of highly responsive stomata capable of maximizing productivity in rapidly changing environments. Grass stomata harness the active turgor control mechanisms present in stomata of more ancient plant lineages, maximizing several morphological and developmental features to ensure rapid responses to environmental inputs. The evolutionary development of grass stomata appears to have been a gradual progression. Therefore, understanding the complex structures, developmental events, regulatory networks, and combinations of ion transporters necessary to drive rapid stomatal movement may inform future efforts towards breeding new crop varieties. PMID- 27776932 TI - Human biomonitoring reference values for metals and trace elements in blood and urine derived from the Canadian Health Measures Survey 2007-2013. AB - Human biomonitoring reference values are statistical estimates that indicate the upper margin of background exposure to a given chemical at a given time. Nationally representative human biomonitoring data on 176 chemicals, including several metals and trace elements, are available in Canada from 2007 to 2013 through the Canadian Health Measures Survey (CHMS). In this work, we used a systematic approach based on the reference interval concept proposed by the International Federation of Clinical Chemistry and Laboratory Medicine and the International Union of Pure and Applied Chemistry to derive reference values (RV95s) for metals and trace elements. These RV95s were derived for blood and urine matrices in the general Canadian population based on the latest biomonitoring data from the CHMS. Biomarkers were chosen based on specific selection criteria, including widespread detection in Canadians (>=66% detection rate). Reference populations were created for each biomarker by applying appropriate exclusion criteria. Age and sex were evaluated as possible partitioning criteria and separate RV95s were derived for the sub-populations in cases where partitioning was deemed necessary. The RV95s for metals and trace elements in blood ranged from 0.18MUg/L for cadmium in young children aged 3-5 years to 7900MUg/L for zinc in males aged 20-79 years. In the case of urinary biomarkers, the RV95s ranged from 0.17MUg/L for antimony in the total population aged 3-79 years to 1400mg/L for fluoride in adults aged 20-79 years. These RV95s represent the first set of reference values for metals and trace elements in the general Canadian population. We compare the RV95s from other countries where available and discuss factors that could influence such comparisons. PMID- 27776933 TI - Amidst the excitement: A cautionary tale of immunotherapy, pseudoprogression and head and neck squamous cell carcinoma. PMID- 27776934 TI - The antiphospholipid syndrome in patients with systemic lupus erythematosus. AB - The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the occurrence of venous and/or arterial thrombosis and pregnancy morbidity in the presence of pathogenic autoantibodies known as antiphospholipid antibodies (aPL). APS may be associated with other diseases, mainly systemic lupus erythematosus (SLE). The presence or absence of SLE might modify the clinical or serological expression of APS. Apart from the classical manifestations, APS patients with associated SLE more frequently display a clinical profile with arthralgias, arthritis, autoimmune hemolytic anemia, livedo reticularis, epilepsy, glomerular thrombosis, and myocardial infarction. The management of patients with SLE and APS/aPL should include an accurate stratification of vascular risk factors. Low dose aspirin and hydroxychloroquine should be considered as primary prophylaxis. In high risk situations, such as surgery, prolonged immobilization, and puerperium, the prophylaxis should be potentiated with low molecular weight heparin. The challenge of treating patients with a previous vascular event (secondary prophylaxis) is the choice of treatment (anti-platelet agents, anticoagulation with vitamin K antagonists or combined therapy) and its duration, based on individual risk stratification and the site of vascular presentation. The role of novel anticoagulants in APS patients is still to be clearly defined. Novel approaches are needed since the prognosis of SLE patients with APS/aPL is still worse than that of SLE patients with negative aPL. The goal for the future is to improve the outcome of these patients by means of early recognition and optimal preventative treatment. PMID- 27776935 TI - Traumatic lung hernia. PMID- 27776936 TI - Compliance-guided versus FiO2-driven positive-end expiratory pressure in patients with moderate or severe acute respiratory distress syndrome according to the Berlin definition. AB - OBJECTIVE: To study the effect of setting positive end-expiratory pressure (PEEP) in an individualized manner (based on highest static compliance) compared to setting PEEP according to FiO2 upon mortality at 28 and 90 days, in patients with different severity acute respiratory distress syndrome (ARDS). SETTING: A Spanish medical-surgical ICU. DESIGN: A post hoc analysis of a randomized controlled pilot study. PATIENTS: Patients with ARDS. INTERVENTIONS: Ventilation with low tidal volumes and pressure limitation at 30cmH2O, randomized in two groups according to the method used to set PEEP: FiO2-guided PEEP group according to FiO2 applied and compliance-guided group according to the highest compliance. PRIMARY VARIABLES OF INTEREST: Demographic data, risk factors and severity of ARDS, APACHE II and SOFA scores, daily Lung Injury Score, ventilatory measurements, ICU and hospital stay, organ failure and mortality at day 28 and 90 after inclusion. RESULTS: A total of 159 patients with ARDS were evaluated, but just 70 patients were included. Severe ARDS patients showed more organ dysfunction-free days at 28 days (12.83+/-10.70 versus 3.09+/-7.23; p=0.04) and at 90 days (6.73+/-22.31 vs. 54.17+/-42.14, p=0.03), and a trend toward lower 90 days mortality (33.3% vs. 90.9%, p=0.02), when PEEP was applied according to the best static compliance. Patients with moderate ARDS did not show these effects. CONCLUSIONS: In patients with severe ARDS, individualized PEEP selection based on the best static compliance was associated to lower mortality at 90 days, with an increase in organ dysfunction-free days at 28 and 90 days. PMID- 27776937 TI - Real-time random safety audits: A transforming tool adapted to new times. AB - Real-time random safety audits constitute a tool designed to transfer knowledge from the sources of scientific evidence to the patient bedside. It has proven useful in critically ill patients, improving safety in the process of critical patient care, turning unsafe situations into safe ones in daily practice, and ensuring adherence to scientific evidence. In parallel, the design and methodology involved affords process indicators that will make it possible to know how we provide care for our patients, evolution over time (with regular feedback for professionals), the impact of our interventions, and benchmarking. PMID- 27776938 TI - [Erratum to "Temporomandibular joint (TMJ): Condyle hyperplasia and condylectomy" [Rev. Stomatol. Chir. Maxillofac. Chir. Orale 117 (2016) 259-65]]. PMID- 27776939 TI - Development of Collaterals to the Spinal Cord after Endovascular Stent Graft Repair of Thoracic Aneurysms. AB - OBJECTIVES: In thoracic and thoraco-abdominal aortic aneurysm repair, spinal cord injury (SCI) is devastating. Detection of the Adamkiewicz artery might be important for preventing SCI. Although thoracic endovascular stent grafts often occlude the segmental artery, the incidence of SCI in thoracic endovascular aortic repair is thought to be low compared with open repair. This study aimed to evaluate how the Adamkiewicz artery is supplied after segmental arteries are occluded by stent grafts. METHODS: From March 2007 to August 2015, 32 patients were enrolled whose segmental arteries that were connected to the Adamkiewicz arteries were occluded by stent grafts. Segmental arteries, Adamkiewicz arteries, collateral circulation into the Adamkiewicz arteries, and anterior spinal arteries were pre- and post-operatively evaluated by computed tomography angiography. RESULTS: Post-operatively, Adamkiewicz arteries were detected in 24 (75%) patients, except for two patients with paraplegia and six without paraplegia. Post-operative Adamkiewicz arteries were the same as pre-operative Adamkiewicz arteries, except for one Adamkiewicz artery that was located at two vertebral levels below the pre-operative level. SCI occurred in two (6.3%) patients. The distribution of feeding arteries into the Adamkiewicz artery post operatively was divided into three patterns as follows: a segmental artery below the distal landing zone of the stent graft (53%), branches of the left subclavian artery (33%), and a branch of the left external iliac artery (13%). CONCLUSIONS: The length of the stent graft should be as short as possible. Blood supply to the left subclavian artery should be maintained because segmental arteries below the segmental artery occluded by the stent graft and branches of the left subclavian artery can become collaterals post-operatively. PMID- 27776940 TI - Psoas Muscle Area Predicts All-Cause Mortality After Endovascular and Open Aortic Aneurysm Repair. AB - OBJECTIVE: Psoas muscle area (PMA) is a validated surrogate for muscle mass that can be easily measured from a clinical CT scan. This study sought to determine whether PMA was associated with post-operative mortality after endovascular or open aortic aneurysm repair. METHODS: A retrospective review was undertaken of patients who underwent elective endovascular or open aortic aneurysm repair between 2010 and 2015 at a tertiary vascular center in Montreal, Quebec, Canada. Pre-operative CT scan images were analyzed with the CoreSlicer.com software tool to measure PMA at the axial level of the L4 vertebrae. Measurements were made by two independent observers blinded to clinical data. The primary endpoint was all cause mortality. RESULTS: The cohort consisted of 149 patients with a mean age of 75.6 +/- 8.8 years. The mean PMA was 24.0 +/- 5.8 cm2 in males, and 14.3 +/- 3.1 cm2 in females. There were 31 deaths over a mean follow-up of 22.4 months. After adjusting for age, sex, revised cardiac risk index, and surgical approach, Cox regression revealed a graded association between PMA and all-cause mortality with a hazard ratio of 0.86 per cm2 (95% CI 0.79-0.93). Addition of PMA to the model with the clinical covariates resulted in an improvement in C-statistic from 0.57 to 0.67, and BIC from 307 to 301 (with lower BIC values preferred). CONCLUSIONS: PMA is independently associated with all-cause mortality after elective endovascular and open aortic aneurysm repair, and may be integrated into the pre operative risk assessment to optimize care in high-risk frail patients. PMID- 27776941 TI - Current controversies on sentinel node biopsy in thin and thick cutaneous melanoma. PMID- 27776942 TI - National trends in immediate and delayed post-mastectomy reconstruction procedures in England: A seven-year population-based cohort study. AB - INTRODUCTION: Little is known about post-mastectomy reconstruction procedural trends in women diagnosed with breast cancer in England. Our aim was to examine patterns of immediate and delayed reconstruction procedures over time and within regions. METHODS: Women with breast cancer who underwent unilateral index immediate or delayed post-mastectomy reconstruction between 2007 and 2014 were identified using the National Hospital Episode Statistics database. Women were grouped into categories based on the type of reconstruction procedure. Adjusted rates of implant and free flap reconstructions were then calculated across regional Cancer Networks using a regression model to adjust for age, disease, comorbidities, ethnicity, and deprivation. RESULTS: Between 2007 and 2014, 21 862 women underwent immediate reconstruction and 8653 delayed reconstruction. Immediate implant reconstruction increased from 30% to 54%, and immediate free flap reconstruction from 17% to 21%. Adjusted immediate implant and free flap proportions ranged from 17 to 68% and 9-63%, respectively, across regions. Free flaps became more common in the delayed setting, rising from 25% to 42%. However, adjusted rates ranged from 23% to 74% across regions. Networks with high/low rates of free flaps for immediate tended to have high/low rates for delayed reconstruction. CONCLUSION: There has been a substantial increase in the use of immediate implant reconstruction in England. In comparison, there has been an increasing use of autologous free flap reconstruction for delayed procedures. Significant regional variation exists in the type of reconstruction performed, and these patterns need to be examined to determine if variation is related to service provision and/or capacity barriers. PMID- 27776943 TI - Focused parathyroidectomy without intraoperative parathormone testing is safe after pre-operative localization with 18F-Fluorocholine PET/CT. AB - A focused surgical approach based on pre-operative localization replaced the classical four-gland exploration in patients with primary hyperparathyroidism (PHP). Sestamibi scanning and ultrasound are most often used localization modalities with reported sensitivity of 54-100% for identification of single gland disease. The aim of this study was to analyze the results of pre-operative localization with 18F-Fluorocholine PET/CT (FCh-PET) in patients with PHP. A retrospective review of 151 patients with PHP who underwent surgery after pre operative localization with FCh-PET was performed. Only a focused parathyroidectomy without ioPTH testing had been done in patients with single adenoma on FCh-PET. Primary outcome was operative failure, defined as persistent PHP. According to pre-operative FCh-PET 126 (83,4%) patients had single adenoma, 22 (14,5%) multiglandular disease and the test was negative in only two patients. Intraoperative failure experienced 4/126 patients (3,3%) with single adenoma. Removed parathyroid glands were normal in three and hyperplastic in one patient with intraoperative failure. A limited bilateral neck exploration with ioPTH testing was used in 14/22 patients with double adenoma and a classical four-gland exploration without ioPTH testing was used in 8/22 patients with more than two pathological glands according to pre-operative FCh-PET. Intraoperative failure experienced 2/22 patients (9,1%). In two patients with negative FCh-PET a classical four-gland exploration without ioPTH testing was used and one experienced intraoperative failure. A preoperative localization with FCh-PET is a reliable test in patients with PHP. Patients with a single adenoma on FCh-PET can safely undergo a focused parathyroidectomy without ioPTH testing. PMID- 27776944 TI - [An "allergy" triggered by the use of an obstructive sleep apnea device in a type 2 diabetes patient]. PMID- 27776945 TI - [Current situation of primary prophylaxis with isoniazid (INH) in children who are contacts of patients with bacillary pulmonary tuberculosis in Abidjan (Cote d'Ivoire)]. AB - INTRODUCTION: The National tuberculosis program (NTP) in Ivory Coast recommends that children under 5 years living in a family environment with contagious tuberculosis patients, should receive Prophylactic treatment with INH (PTI), whatever the result of the tuberculin skin test (positive or negative) and their BCG status (vaccinated or not), at a dose of 5mg/kg/day for 6 months. We conducted this study to check the implementation of this recommendation in three support services of tuberculosis in Abidjan, the economic capital. MATERIAL AND METHOD: We conducted a multicenter, cross-sectional and descriptive study over 3 years (2011-2013), on consented patients, adolescents and adults aged at least 15 years, with a first episode of infectious pulmonary tuberculosis, in order to look for information on the INH prophylaxis in children under 5 years living under the same roof. We made patients interviews during their visit for bacteriological sputum controls at the second month of TB treatment. RESULTS: Of a total of 412 patients (53% males and 47% females) with a mean age of 34.5 years and with a low level of instruction (66.5%), we noticed 639 children under 5 years living under the same roof with them. Information on the screening of contact children was given to 71% of interviewed patients (291/412). Of the 339 children examined among 639 contacts, 234 (69%) had received only an intradermoreaction (IDR) and PTI was finally administered to 64% of them (217/339). CONCLUSION: High proportion of contact children under 5 not examined is a major concern for the NTP and a missed opportunity to prevent additional cases of tuberculosis among children. PMID- 27776946 TI - [Survival of malignant and paramalignant pleural effusions in Ouagadougou]. AB - This study aimed to present the survival of patients with malignant and paramalignant pleural effusion (MPE) in a context of resource-limited countries. We retrospectively studied patients received for malignant and paramalignant pleural effusion in three health facilities in Ouagadougou from 1st August 2009 to 30 July 2015. Survival was analyzed according to various characteristics related to patients and disease. Eighty patients with a mean age of 54 years were selected. The sex-ratio was 0.9. Sixteen patients had comorbidities. Pleural effusion was revealing, synchronous and metachronous in respectively 55 %, 26.3 % and 17.5 % of cases. Lung cancer was the most common cause of MPE (27.5 %), followed by breast cancer (18.7 %). The median overall survival was 3 months; it varied between primary cancers: 5 months for primary cancer unknown, 4 months for lung cancers and 2 months for breast cancers. Sex and the presence of comorbidities were independent factors influencing survival of patients. In this study, patient survival length is strongly compromised by inadequacies of medical technical equipment. PMID- 27776947 TI - [Paradoxical reaction following antituberculosis therapy in immunocompetent patient]. AB - INTRODUCTION: The features of paradoxical reactions (PR) that occurred in non-HIV infected patients are rare and not well known. CASE REPORT: The authors reported the case of a 21years old, non-immunocompromised, and HIV negative patient treated for disseminated tuberculosis. PR occurred after 8months after initiation of antituberculous treatment. PR presented as left cervical lymphadenopathy, pulmonary, pleural, costal and spinal location of the tuberculosis. The antituberculous drugs were prolonged. Patient's clinical symptoms improved initially. However, left inguinal lymphadenopathy appeared after 20months of antituberculous therapy. Inguinal lymph node biopsy revealed tuberculous lymphadenitis. The patient has a good compliance to the treatment. The patient was continued on same antituberculous treatment for a total of 28months. The cervical and inguinal lymphadenopathy disappeared and CT scan showed regression of thoracic, abdominal, costal and spinal lesions. CONCLUSION: PR during antituberculous treatment must be considered after exclusion of other causes. No consensus on the therapeutic management of this entity has been developed to date. PMID- 27776948 TI - [What place for the thoracostomy-thoracmyoplasty in the management of the chronic pleural empyema?] AB - INTRODUCTION: The occurrence of empyema after pneumonectomy or in suites with chronic pleural pocket is a dreaded complication. The management is long and difficult. The authors report their experience before this complication including infection control by an emptying of the pleural pocket percutaneous drainage or thoracostomy which will be complemented by a thoracomyoplasty the aim to erase the pleural pocket. MATERIALS AND METHODS: This is a retrospective study conducted between 2009 and 2015 concerning the records of 9 patients treated for empyema or in the aftermath of a lung resection or as part of a chronic pleural pocket and calcific. RESULTS: We had identified all 9 male patients aged 30 to 67 years. This was pyothorax complicating pneumonectomy in 4 patients and 1 pyothorax after a left upper lobectomy in 1 case. For the other 4 patients, there was a post-tuberculous pleural pocket, calcified chronic and whose attempts to decortication seemed impossible. We observed 3 cases of bronchopleural fistula. All patients had received evacuation of the contents of the pleural drainage bag is either thoracostomy laying the bed of a possible filling thoracomyoplasty. The evolution of pleural cavities after thoracostomy was favorable on septic map leading to a retraction of the pleural cavity and its spontaneous closure in 1 patient. In 6 patients, filling the cavity with thoracomyoplasty was necessary. The evolution immediate postoperative was favorable in all patients and no deaths were noted in connection with this technique. CONCLUSION: Pyothorax on pneumonectomy cavity and chronic pleural calcified pockets are serious complications whose management is long and delicate. The thoracomyoplastie is a real alternative to the filling of the cavity in fragile patients with significant operational risk. The results are satisfactory in the hands of a broken team this technique. PMID- 27776949 TI - Behcet's disease? and familial Mediterranean fever: Two sides of the same coin or just an association? A cross-sectional study?. AB - BACKGROUND: Familial Mediterranean fever (FMF) is a genetic disease, characterized by attacks of fever, arthritis, serositis and pain. Behcet's disease (BD) is an inflammatory disorder with a genetic basis, characterized by oral and genital ulcers, uveitis, pustular erythematous cutaneous lesions, arthritis, central nervous system involvement and possible vascular manifestations such as venous thrombosis, arteritis and aneurysms. OBJECTIVES: To investigate the association and actual differentiation between these two entities in a large-scale population-based study. METHODS: Data for this study was collected from the databases of "Clalit Health Services", the largest state mandated health service organization in Israel. All adult members diagnosed with BD were included (n=892) and as well as their age- and sex-matched controls (n=4444), creating a cross-sectional population-based study. Medical records of all subjects were analyzed for documented FMF. A logistic regression model was done to estimate how BD, age, gender, BMI, ethnicity and socioeconomic status contributed as risk factors for FMF. RESULTS: The proportion of FMF in patients with BD increased compared with those reported in controls (5.83% and 0.23%, respectively, P<0.001). This coexistence was prominent among both sex groups but was much stronger among female BD patients (females with OR of 177 and of 8.4 in males, P<0.001). In a multivariate analysis, BD was identified as an independent risk factor for FMF (OR 25.16, 95% CI 13-53.3). CONCLUSION: BD diagnosis was found to be independently associated with higher incidence of FMF, especially in females, people of Arab descent and BMI>30. Our data imply that understating the differentiation between FMF and BD is not evident and clear in a real-life population of patients with BD. PMID- 27776950 TI - Weak associations between the daily number of suicide cases and amount of daily sunlight. AB - Several environmental factors with periodic changes in intensity during the calendar year have been put forward to explain the increase in suicide frequency during spring and summer. In the current study we investigated the effect of averaged daily sunshine duration of periods with different lengths and 'lags' (i.e. the number of days between the last day of the period for which the averaged sunshine duration was calculated and the day of suicide) on suicide risk. We obtained data on daily numbers of suicide cases and daily sunshine duration in Hungary from 1979 to 2013. In order to remove the seasonal components from the two time series (i.e. numbers of suicide and sunshine hours) we used the differencing method. Pearson correlations (n=22,950) were calculated to reveal associations between sunshine duration and suicide risk. The final sample consisted of 122,116 suicide cases. Regarding the entire investigated period, after differencing, sunshine duration and number of suicides on the same days showed a distinctly weak, but highly significant positive correlation in the total sample (r=0.067; p=1.17*10-13). Positive significant correlations (p?0.0001) between suicide risk on the index day and averaged sunshine duration in the previous days (up to 11days) were also found in the total sample. Our results from a large sample strongly support the hypothesis that sunshine has a prompt, but very weak increasing effect on the risk of suicide (especially violent cases among males). The main limitation is that possible confounding factors were not controlled for. PMID- 27776951 TI - Urbanized South Asians' susceptibility to coronary heart disease: The high-heat food preparation hypothesis. AB - OBJECTIVE: Known risk factors do not fully explain the comparatively high susceptibility to coronary heart disease (CHD) in South Asians (Indian, Pakistani, Bangladeshi, and Sri Lankan populations in South Asia and overseas). The search for explanatory hypotheses and cofactors that raise susceptibility of South Asians to CHD continues. The aim of this study was to propose "the high heat food preparation hypothesis," where neo-formed contaminants (NFCs) such as trans-fatty acids (TFAs) and advanced glycation end-products (AGEs) are the cofactors. METHODS: We reviewed the actions of AGEs and TFAs, the burden of these products in tissues and blood in South Asians, the relationship between these products and CHD, the effects of preparing food and reheating oils at high temperatures on NFCs, and the foods and mode of preparation in South Asian and Chinese cuisines. RESULTS: Animal and human studies show NFCs increase the risk for CHD. Evidence on the consumption and body burden of these products across ethnic groups is not available, and comparable data on the NFC content of the cuisine of South Asians and potential comparison populations (e.g., the Chinese with lower CHD rates) are limited. South Asians' cuisine is dominated by frying and roasting techniques that use high temperatures. South Asian foods have high TFA content primarily through the use of partially hydrogenated fats, reheated oils, and high-heat cooking. Reheating oils greatly increases the TFA content. In comparison, Chinese cuisine involves mostly braising, steaming, and boiling rather than frying. CONCLUSION: We hypothesize that South Asians' susceptibility to CHD is partly attributable to high-heat treated foods producing high NFCs. Research to accrue direct evidence is proposed. PMID- 27776953 TI - Association between DBH 19bp insertion/deletion polymorphism and cognition in schizophrenia with and without tardive dyskinesia. AB - Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5' insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5' Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention. PMID- 27776954 TI - Serum gamma-glutamyltransferase is associated with future risk of psychosis - A prospective cohort study. PMID- 27776952 TI - Prolactin gene polymorphism (-1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics. AB - BACKGROUND: Antipsychotic drugs can cause hyperprolactinemia. However, hyperprolactinemia was also observed in treatment-naive patients with a first schizophrenic episode. This phenomenon might be related to the role of prolactin as a cytokine in autoimmune diseases. Extrapituitary prolactin production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism -1149 G/T (rs1341239). We examined whether this polymorphism was associated with hyperprolactinemia in patients with schizophrenia. METHOD: We recruited 443 patients with schizophrenia and 126 healthy controls. The functional polymorphism -1149 G/T (rs1341239) in the prolactin gene was genotyped with multiplexed primer extension, combined with MALDI-TOF mass spectrometry. Genotype and allele frequencies were compared between groups with the chi2 test and logistic regression models adjusting for covariates. RESULTS: The frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects. A comparison between patients with schizophrenia with and without hyperprolactinemia revealed significantly higher frequency of the G allele in patients with hyperprolactinemia than in patients without it (chi2=7.25; p=0.007; OR=1.44 [1.10 1.89]). Accordingly, patients with hyperprolactinemia carried the GG genotype more frequently than patients without hyperprolactinemia (chi2=9.49; p=0.009). This association remained significant after adjusting the estimates for such covariates as sex, age, duration of the diseases and the dose of chlorpromazine equivalents. CONCLUSION: This study revealed a significant association between the polymorphic variant rs1341239 and the development of hyperprolactinemia in patients with schizophrenia. The serum prolactin concentration in patients with schizophrenia treated with antipsychotics may provide an indication of the activity of the gene that regulates extrapituitary prolactin production which is believed to play a role in the immune system. PMID- 27776955 TI - External validation of the A2SD2 and ISAN scales for predicting infectious respiratory complications of ischaemic stroke. AB - BACKGROUND AND PURPOSE: Pneumonia as a complication of stroke is associated with poor outcomes. The A2DS2 and ISAN scales were developed by German and English researchers, respectively, to predict in-hospital stroke-associated pneumonia. We conducted an external validation study of these scales in a series of consecutive patients admitted to our hospital due to ischaemic stroke. METHOD: These predictive models were applied to a sample of 340 consecutive patients admitted to hospital in 2015 due to stroke. Discrimination was assessed by calculating the area under the ROC curve for diagnostic efficacy. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test and graphing the corresponding curve. Logistic regression analysis was performed to determine the independent predictors of respiratory infection secondary to stroke. RESULTS: We included 285 patients, of whom 45 (15.8%) had respiratory infection after stroke according to the study criteria. Mean age was 71.01+/-12.62 years; men accounted for 177 of the patients (62.1%). Seventy-two patients (25.3%) had signs or symptoms of dysphagia, 42 (14.7%) had atrial fibrillation, and 14 (4.9%) were functionally dependent before stroke; the median NIHSS score was 4 points. Mean scores on A2DS2 and ISAN were 3.25+/-2.54 and 6.49+/-3.64, respectively. Our analysis showed that higher A2DS2 scores were associated with an increased risk of infection (OR=1.576; 95% CI: 1.363-1.821); the same was true for ISAN scores (OR=1.350; 95% CI: 1.214-1.501). CONCLUSION: High scores on A2DS2 and ISAN were found to be a strong predictor of respiratory infection associated with acute stroke in a cohort of consecutive patients with stroke. These easy-to-use scales are promising tools for predicting this complication in routine clinical practice. PMID- 27776956 TI - Longitudinal extensive transverse myelitis and Zika virus: A diagnostic challenge in a hospital in Colombia. PMID- 27776957 TI - Neuroimmunological interactions in stroke. AB - INTRODUCTION: Stroke is one of the leading causes of death in the world; its incidence is increasing due to increased life expectancy. However, treatment options for these patients are limited since no clinically effective drugs have been developed to date. DEVELOPMENT: According to clinical evidence, a number of neurochemical changes take place after stroke, including energy depletion, increased free radical synthesis, calcium accumulation, neurotransmitter imbalance, excitotoxicity, and, at a later stage, immune system activation leading to inflammation. Immune response has been shown to be a major factor in disease progression. The release of proinflammatory cytokines such as TNF increase brain damage secondary to excitotoxicity and calcium accumulation, and promote free radical synthesis and cell death through various mechanisms. On the other hand, certain anti-inflammatory cytokines, such as IL-10 and IL-4, have been shown to have a neuroprotective effect and even promote neurogenesis and synapse remodeling, which makes immune modulation a promising treatment approach. CONCLUSIONS: Understanding the relationship between the immune system and the nervous system not only deepens our knowledge of stroke but also provides new diagnostic, prognostic, and therapeutic strategies that may increase the quality of life of stroke patients. PMID- 27776958 TI - Trends in stroke hospitalisation rates in Extremadura between 2002 and 2014: Changing the notion of stroke as a disease of the elderly. AB - BACKGROUND: The incidence of stroke in Spain has been evaluated in several studies, whose results are highly variable and not comparable. No studies of stroke have analysed epidemiological changes in younger patients. METHOD: We conducted a retrospective observational study using the Spanish health system's Minimum Data Set and included all patients older than 19 hospitalised due to stroke (ICD-9-CM codes 434.01, 434.11, 434.91, 430, 431, 432.9, 436, and 435) between 2002 and 2013. The analysis was performed using joinpoint regression. RESULTS: A total of 39,321 patients were identified (47.25% were women); 3.73% were aged 20-44, 6.29% were 45-54, 11.49% were 55-64, 23.89% were 65-74, and 54.60% were > 74 years. The hospitalisation rate due to ischaemic stroke has increased significantly in men aged 45-54 (+6.7%; 95% CI, 3.3-10.2) and in women aged 20-44 and 45-54 (+6.1%; 95% CI, 0.8-11.7 and +5.7%; 95% CI, 3.0-8.4, respectively). We also observed a significant increase in the rate of hospitalisation due to ischaemic stroke in men aged over 74 (+4.2%; 95% CI, 1.3 7.2). The rate of hospitalisations due to transient ischaemic attack has also increased significantly whereas the rate of hospitalisations due to brain haemorrhage has stabilised over time. CONCLUSIONS: Our results provide indirect evidence that the epidemiological profile of stroke is changing based on the increase in hospitalisation rates in young adults. PMID- 27776959 TI - Longus colli tendinitis: An unusual stroke mimic. PMID- 27776960 TI - Peripheral nerve stimulation: An effective treatment alternative for refractory pain. PMID- 27776961 TI - Early and recurrent macular oedema in a patient treated with fingolimod. PMID- 27776962 TI - Diagnosis of POEMS syndrome in a patient with long-standing neuropathy. PMID- 27776963 TI - Isolated hypoglossal nerve palsy. PMID- 27776964 TI - Energy drinks as a trigger factor for seizures in paediatric patients: A case report. PMID- 27776965 TI - Experience with botulinum toxin in chronic migraine. AB - OBJECTIVE: The purposes of this study were to describe our 16-month experience with onabotulinumtoxinA (OnabotA) for the treatment of chronic migraine (CM) in the Spanish province of Segovia, evaluate its benefits, and determine clinical markers of good response to treatment. PATIENTS AND METHODS: Prospective study of patients with CM who received OnabotA for 16 months. The effectiveness of OnabotA was evaluated based on the reduction in the number of headache days, pain intensity, and side effects. We used two-way analysis of variance (ANOVA) to assess the effects of treatment according to the time factor. We studied the correlation between treatment effects and other variables using a linear regression model to establish the clinical markers of good response to treatment. RESULTS: We included 69 patients who met the diagnostic criteria for CM. Patients underwent an average of 2 infiltrations. Mean age was 43 years; 88.4% were women. The number of headache days and pain intensity decreased significantly (P < .005); improvements remained over time. We found a negative correlation between the reduction in pain intensity and the number of treatments before OnabotA. CONCLUSION: The beneficial effects of OnabotA for CM continue over time. OnabotA is a safe and well-tolerated treatment whose use for refractory CM should not be delayed since early treatment provides greater benefits. PMID- 27776966 TI - Hemifacial spasm and vestibular paroxysmia: Co-presence of two neurovascular compression syndromes in a patient. PMID- 27776967 TI - Posterior reversible encephalopathy syndrome: A case report. PMID- 27776968 TI - Downregulation of long non-coding RNAs JPX and XIST is associated with the prognosis of hepatocellular carcinoma. AB - BACKGROUND: The expression profiles and biological relevance of long non-coding RNA XIST and its activator JPX in hepatocellular carcinoma (HCC) are not well elucidated. We measured JPX and XIST expression levels in HCC, evaluated their clinical significance in HCC progression, and verified their potential as biomarkers for diagnosing HCC. METHODS: JPX and XIST expression in 68 HCC tissues and adjacent normal tissues were evaluated by quantitative reverse transcription PCR (qRT-PCR); their association with pathologic features and overall survival was analyzed. Plasma JPX/XIST levels in 42 patients with HCC and 68 healthy controls were measured by qRT-PCR to determine their potential as biomarkers. RESULTS: JPX and XIST levels were significantly decreased in HCC and associated with histological grade and tumor-node-metastasis stage (P<0.05). Low JPX and XIST expression resulted in significantly poor overall survival of HCC. Multivariate Cox regression analysis demonstrated that JPX/XIST expression levels were independent prognostic factors for HCC overall survival rates. Moreover, plasma JPX levels in patients were lower than that in controls; JPX yielded an area under the receiver operating characteristic curve of 0.814 and the combination of JPX and AFP possessed a promoted ability for discrimination between HCC patients and controls (AUC 0.905, 72.2% specificity, 97.1% sensitivity). CONCLUSIONS: Downregulated JPX and XIST may serve as novel biomarkers of poor prognosis in HCC. PMID- 27776969 TI - Predictors of Clinical Outcomes in Patients With Stable Coronary Artery Disease. PMID- 27776970 TI - [Evaluation of educational interventions with dialysis patient]. AB - The treatment of end-stage renal disease requires a significant number of drug treatments. At patient level, daily management is somewhat difficult: Number of prescribed pills, medication side effects, treatment of asymptomatic diseases... The objective of the study was to investigate the effect of guidance tailored to each patient receiving hemodialysis, performed by the pharmacist (educational interventions). Adult haemodialysis patients with hyperphosphatemia despite phosphate binders were eligible for study entry. The study was controlled with a retrospective group. The primary end point was a change in serum phosphate levels. The secondary end points were therapy adherence, knowledge regarding phosphate management and patient satisfaction with the programme. Sixteen patients in each group participated in the study. The mean serum phosphate level at endpoint was decreased by 0.25 mmol/L in the intervention group (0.41 mmol/L for patients with expectancy for this reduction) and by 0.11 mmol/L in the control group. Five patients normalized their serum phosphate level in the intervention group against three patients in the control group. The mean score of adherence decreased from 1.75 to 1.50. The main factors affecting adherence were forgetfulness or carelessness in taking medications and number of daily doses. This study showed the feasibility of an improvement in serum phosphate level and adherence driven by therapeutic education, though effect was highly amplified by the motivation induced by pharmaceutical guidance. Patients emphasize the importance of the involvement of pharmacist in their care. PMID- 27776971 TI - Association between vascular calcification assessed by simple radiography and non fatal cardiovascular events in hemodialysis patients. AB - BACKGROUND: Vascular calcification (VC) is one of the factors associated with cardiovascular mortality in hemodialysis (HD) patients. Recommendations concerning screening for VC differ. Possible ability to prevent and reversibility of VC are major subjects on debate whether screening for VC could improve outcomes of renal patients. The objective of the study was to evaluate the significance of simple vascular calcification score (SVCS) based on plane radiographic films and to test its association with non-fatal cardiovascular events in patients on chronic HD. METHODS: A study population consisted of 95 prevalent HD patients in the HD unit of Hospital of Lithuanian University of Health sciences Kaunas Clinics. Clinical data and laboratory tests information were collected from medical records. SVCS was evaluated as it is described by Adragao et al. After measurement of VC, HD patients were observed for novel non fatal cardiovascular events. RESULTS: Patients were divided into two groups: SVCS>=3 (57 patients [60%]) and <3 (38 patients [40%]). The Kaplan-Meier survival curves show a significant difference in non-fatal cardiovascular events in the group with SVCS>=3 vs. <3 group (26.3% vs. 7.8%; log rank 5,49; P=0.018). Multivariate Cox regression analysis confirmed a negative impact of VC, hyperphosphatemia, and lower ejection fraction on cardiovascular events. No statistically significant differences were observed comparing parameters of Ca-P metabolism disorders between groups with different SVCS. On separate analysis, the presence of VC in hands was also associated with higher rate of novel cardiovascular events (score 0 goup-5 events [10.6%] vs. score>=1 group-13 events [27%], log rank P=0.035). CONCLUSION: VC assessed by simple and inexpensive radiological method was an independent predictor of novel non-fatal cardiovascular events in HD patients. PMID- 27776972 TI - Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis. AB - TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21Cip-1, PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems. PMID- 27776974 TI - The significance of the 1-kinase/1-phosphatase activities of the PPIP5K family. AB - The inositol pyrophosphates (diphosphoinositol polyphosphates), which include 1 InsP7, 5-InsP7, and InsP8, are highly 'energetic' signaling molecules that play important roles in many cellular processes, particularly with regards to phosphate and bioenergetic homeostasis. Two classes of kinases synthesize the PP InsPs: IP6Ks and PPIP5Ks. The significance of the IP6Ks - and their 5-InsP7 product - has been widely reported. However, relatively little is known about the biological significance of the PPIP5Ks. The purpose of this review is to provide an update on developments in our understanding of key features of the PPIP5Ks, which we believe strengthens the hypothesis that their catalytic activities serve important cellular functions. Central to this discussion is the recent discovery that the PPIP5K is a rare example of a single protein that catalyzes a kinase/phosphatase futile cycle. PMID- 27776973 TI - PLC-beta1 and cell differentiation: An insight into myogenesis and osteogenesis. AB - Phosphoinositide-phospholipase C-beta1 (PLC-beta1) plays a crucial role in the initiation of the genetic program responsible for muscle differentiation and osteogenesis. During myogenic differentiation of murine C2C12 myoblasts, PLC beta1 signaling pathway involves the Inositol Polyphosphate Multikinase (IPMK) and beta-catenin as downstream effectors. By means of c-jun binding to cyclin D3 promoter, the activation of PLC-beta1 pathway determines cyclin D3 accumulation. However, osteogenesis requires PLC-beta1 expression and up-regulation but it does not affect cyclin D3 levels, suggesting that the two processes require the activation of different mediators. PMID- 27776975 TI - Machineries regulating the activity of the small GTPase Arf6 in cancer cells are potential targets for developing innovative anti-cancer drugs. AB - The Small GTPase ADP-ribosylation factor 6 (Arf6) functions as the molecular switch in cellular signaling pathways by cycling between GDP-bound inactive and GTP-bound active form, which is precisely regulated by two regulators, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Numerous studies have shown that these machineries play critical roles in tumor angiogenesis/growth and cancer cell invasion/metastasis through regulating the cycling of Arf6. Here, we summarize accumulating knowledge for involvement of Arf6 GEFs/GAPs and small molecule inhibitors of Arf6 signaling/cycling in cancer progression, and discuss possible strategies for developing innovative anti cancer drugs targeting Arf6 signaling/cycling. PMID- 27776976 TI - Production of uracil from methane by a newly isolated Methylomonas sp. SW1. AB - Methane is an abundant, inexpensive one-carbon feedstock and one of the most powerful greenhouse gases. Because it does not compete with food demand, it is considered a promising carbon feedstock for the production of valuable products using methanotrophic bacteria. Here, we isolated a novel methanotrophic bacterium, Methylomonas sp. SW1, from a sewage sample obtained from Wonju City Water Supply Drainage Center, Republic of Korea. The conditions for uracil production by Methylomonas sp. SW1, such as Cu2+ concentration and temperature were investigated and optimized. As a result, Methylomonas sp. SW1 produced uracil from methane as a sole carbon source with a titer of 2.1mg/L in 84h without genetic engineering under the optimized condition. The results in this study demonstrate the feasibility of using Methylomonas sp. SW1 for the production of uracil from methane. This is the first report of uracil production from gas feedstock by methanotrophic bacteria. PMID- 27776977 TI - Emerging role of checkpoint inhibition in localized bladder cancer. AB - OBJECTIVE: Checkpoint inhibitors have rapidly become a standard treatment option for metastatic urothelial carcinoma. A wave of enthusiasm for these drugs has pushed them also into the setting of localized bladder cancer, including both non muscle-invasive bladder cancer (NMIBC) and muscle-invasive disease bladder cancer (MIBC). Here, we aimed to review the emerging role of checkpoint inhibition in localized bladder cancer. METHODS: We reviewed the current treatment landscape for both NMIBC and MIBC and established a significant unmet clinical need for novel therapies. We have compiled the evidence that supports the investigation of checkpoint blockade in localized bladder cancer and have reviewed the corresponding clinical trial's landscape. RESULTS: The success of checkpoint inhibitors in metastatic bladder cancer offers the most compelling rationale for testing checkpoint blockade in localized disease. The established benefit of intravesical Bacillus Calmette-Guerin provides precedent for immune therapy in bladder cancer. Immune dysfunction has been described in bladder cancer, and we know that checkpoint molecules are expressed in these tumors. Furthermore, the high neoantigen burden of bladder cancer and results from preclinical studies suggest that checkpoint blockade deserves testing in earlier stage disease. Multiple trials are either planned or underway in almost all bladder cancer disease states. CONCLUSION: Ongoing trials would determine in the next several years whether checkpoint inhibitors can have a similar effect in localized disease as they have had in metastatic bladder cancer. They would also determine if patients with earlier disease would tolerate the toxicity of systemic therapy. The future holds promise for predictive biomarkers to guide individualized use of these agents and for effective combination therapies to overcome resistances. PMID- 27776978 TI - Partial nephrectomy vs. radical nephrectomy for renal tumors: A meta-analysis of renal function and cardiovascular outcomes. AB - OBJECTIVES: The widespread use of partial nephrectomy (PN) has led to the preservation of functional renal parenchyma. However, the benefits of PN on renal function and cardiovascular outcomes remain controversial. Thus, a meta-analysis was performed to reconcile the conflicting results. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library were searched from inception to August 2015, and databases with all relevant comparative studies were included. The Mantel-Haenszel method with random-effects models was used to determine the pooled hazard ratios (HRs) for each outcome. RESULTS: In total, 26 studies were pooled for new-onset chronic kidney disease, and 6 studies were pooled for cardiovascular outcomes. According to the pooled estimates, PN correlated with a 73% risk reduction of new-onset chronic kidney disease in all included patients (HR = 0.27, P<0.0001) and a 65% risk reduction in patients with tumors>4cm (HR = 0.35, P<0.0001) compared with radical nephrectomy. There were no significant differences between groups regarding postsurgery cardiovascular events (HR = 0.86, P = 0.238) and cardiovascular death (HR = 0.79, P = 0.196). Despite inherent selection biases, the pooled estimates were robust in sensitivity and subgroup analyses. CONCLUSIONS: Our findings suggest that PN lowers the postoperative risk of new-onset chronic kidney disease. Nevertheless, the protection of renal function by PN did not reduce the risk of cardiovascular outcomes. However, this result remains controversial, and additional large-scale evaluations are warranted. PMID- 27776979 TI - Chronic kidney disease impairs renal nerve and haemodynamic reflex responses to vagal afferent input through a central mechanism. AB - We investigated age- and sex-related changes in reflex renal sympathetic nerve activity (RSNA) and haemodynamic responses to vagal afferent stimulation in a rodent model of chronic kidney disease (CKD). Using anaesthetised juvenile (7 8weeks) and adult (12-13weeks) Lewis Polycystic Kidney (LPK) and Lewis control rats of either sex (n=63 total), reflex changes in RSNA, heart rate (HR) and mean arterial pressure (MAP) to vagal afferent stimulation (5-s train, 4.0V, 2.0-ms pulses, 1-16Hz) were measured. In all groups, stimulation of the vagal afferents below 16Hz produced frequency-dependent reductions in RSNA, HR and MAP, while a 16Hz stimulus produced an initial sympathoinhibition followed by sympathoexcitation. In juvenile LPK versus age-matched Lewis, sympathoinhibition was reduced when responses were expressed as % baseline (P<0.05), but not as microvolts, while bradycardic responses were greater. Reflex depressor responses were greater (P=0.015) only in juvenile female LPK. In adult LPK, reflex sympathoinhibition (%) was blunted (P<0.05), and an age-related decline apparent (when expressed as microvolts). Reflex reductions in HR and MAP were only diminished (P<0.05) in adult female LPK versus age-matched Lewis. Peak reflex sympathoexcitation at 16Hz did not differ between groups; however, area under the curve values were greater in the LPK versus Lewis (overall, 9+/-1 versus 19+/ 3MUVs, P<0.05) irrespective of age, suggestive of enhanced sympathoexcitatory drive in the LPK. Our data demonstrates a progressive deficit in the central processing of vagal afferent input and a differential sex influence on reflex regulation of autonomic function and blood pressure homeostasis in CKD. PMID- 27776980 TI - Why are we waiting? Patients' perspectives for accessing emergency department services with non-urgent complaints. AB - [Background] Emergency departments world-wide report service demands which exceed resource availability. Themes such as crowding, non-urgent presentations, ambulance diversion and access block have been linked to complications in care, poorer patient outcomes, increased morbidity and staff burnout. People attending the emergency department with problems perceived as non-urgent are frequently attributed blame for increased service demand, yet little is known from the patients' perspective. [Method] This project utilised a descriptive cross sectional waiting room survey of non-urgent patients to identify factors contributing to their decision making process to access ED services at a regional hospital in Tasmania, Australia. Data were analysed using a statistical software package and comparison made between the sample and population groups to determine broad representation. [Results] Patients' decision making processes were found to be influenced by convenience, perceived need and referral by a health care provider. Cost did not present as a significant factor. A high incidence of patients under 25years of age were identified and musculoskeletal complaints were the most common complaint across all age groups. [Conclusion] Further consideration is required to determine how to best meet service demand to facilitate the provision of the right service at the right time to the right patient. PMID- 27776982 TI - Percutaneous Thermal Ablation for Small-Cell Lung Cancer: Initial Experience with Ten Tumors in Nine Patients. AB - PURPOSE: To evaluate outcomes in a small cohort of patients with local or disseminated small-cell lung cancer (SCLC) who received percutaneous thermal ablation therapy. MATERIALS AND METHODS: Ten biopsy-proven SCLC tumors in 9 consecutive patients (5 men, 4 women; average age, 73.8 y +/- 12.4) were retrospectively evaluated. Average tumor sizes were 1.8 cm +/- 0.5 and 2.6 cm +/- 1.2 among patients with local and disseminated disease, respectively. Microwave and radiofrequency ablation were each used for 5 tumors. None of the patients with local SCLC received adjuvant therapy following thermal ablation. Median follow-up duration was 16 months (range, 2-48 mo). Median and 1-year overall survival (OS) were compared for patients in the local and disseminated disease groups. RESULTS: Median and 1-year OS were better among patients treated for local SCLC compared with disseminated disease (47.0 vs 5.5 mo and 3 [100%] vs 2 [40%], respectively). Pneumothorax occurred in 5 patients (55.6%), and 3 patients received successful outpatient thoracostomy tube placement. No patients were hospitalized, and there were no major complications. CONCLUSIONS: This preliminary analysis suggests favorable outcomes in selected patients with local SCLC who undergo percutaneous thermal ablation without adjuvant therapy. PMID- 27776983 TI - Doxycycline Sclerotherapy Is Superior in the Treatment of Pediatric Lymphatic Malformations. AB - PURPOSE: To evaluate efficacy of sclerotherapy with doxycycline versus sodium tetradecyl sulfate (STS) for treatment of macrocystic and mixed lymphatic malformations (LMs). MATERIALS AND METHODS: This single-center retrospective review identified 41 children (17 boys; 24 girls; age range, 1 month to 15.4 y) who underwent sclerotherapy with doxycycline (n = 32) or STS (n = 9) for macrocystic (n = 31) or mixed (n = 10) LMs. There were 114 treatments performed, averaging 2.8 treatments (range, 1-8 treatments) per patient. Average follow-up time was 10 months (range, 1-59 months). Clinical response was deemed excellent or moderate if > 90% or > 50% of LMs resolved based on visual estimate. RESULTS: With doxycycline, 87% of patients (28 of 32) had excellent or moderate response with an average of 2.8 treatments (range, 1-7 treatments); 13% required subsequent resection. With 3% STS monotherapy, only 55% of patients (5 of 9) had excellent or moderate response with an average of 2.8 treatments (range, 1-8 treatments), and 33% required subsequent resection. Significantly fewer patients treated with STS responded well compared with patients treated with doxycycline (P = .03). Patients treated with STS had significantly longer follow-up than patients treated with doxycycline (27 months vs 6 months, P = .0001). CONCLUSIONS: Doxycycline monotherapy resulted in a high rate of excellent clinical outcomes after a few treatments without increased need for subsequent operative resection. These results support use of doxycycline sclerotherapy as primary treatment for macrocystic and mixed LMs in children. PMID- 27776981 TI - Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic. AB - Asthma is a complex disease well-suited to metabolomic profiling, both for the development of novel biomarkers and for the improved understanding of pathophysiology. In this review, we summarize the 21 existing metabolomic studies of asthma in humans, all of which reported significant findings and concluded that individual metabolites and metabolomic profiles measured in exhaled breath condensate, urine, plasma, and serum could identify people with asthma and asthma phenotypes with high discriminatory ability. There was considerable consistency across the studies in terms of the reported biomarkers, regardless of biospecimen, profiling technology, and population age. In particular, acetate, adenosine, alanine, hippurate, succinate, threonine, and trans-aconitate, and pathways relating to hypoxia response, oxidative stress, immunity, inflammation, lipid metabolism and the tricarboxylic acid cycle were all identified as significant in at least two studies. There were also a number of nonreplicated results; however, the literature is not yet sufficiently developed to determine whether these represent spurious findings or reflect the substantial heterogeneity and limited statistical power in the studies and their methods to date. This review highlights the need for additional asthma metabolomic studies to explore these issues, and, further, the need for standardized methods in the way these studies are conducted. We conclude by discussing the potential of translation of these metabolomic findings into clinically useful biomarkers and the crucial role that integrated omics is likely to play in this endeavor. PMID- 27776984 TI - Understanding Mortality of Femoral Fractures Following Low-Impact Trauma in Persons With and Without Care Need. AB - OBJECTIVES: Persons with osteoporotic fracture history are subject to an increased risk for subsequent fractures and mortality. The aim of this retrospective study was to investigate the impact of a previous osteoporotic low impact (fragility) index fracture (eg, forearm, lower leg) on mortality of a subsequent femoral fracture. DESIGN: Retrospective cohort study. PARTICIPANTS/MEASUREMENTS: Claims data of a German health insurance agency including >1.2 million insurants aged 65 years or older and observed between 2004 and 2009. METHODS: A multistate model was developed handling index fractures and care need as time-dependent exposures, while age was chosen as the underlying time scale. Excess risks were expressed as differences in cause-specific hazards. Nelson-Aalen estimates were used for their nonparametric estimation. Time simultaneous statistical inference was based on confidence bands provided by wild bootstrap resampling. RESULTS: Excess femoral fracture risk increased with progressive age and was highest in persons with care need. It was observed starting from an age of 79 years in women and 85 years in men onward. A prior index fracture increased mortality after a femoral fracture by increasing femoral fracture risk, while leaving the hazard of death after a subsequent femoral fracture unchanged. CONCLUSIONS: The results indicated that increased mortality of a subsequent femoral fracture is not triggered by an intrinsically increased mortality hazard but an increased femoral fracture incidence. PMID- 27776985 TI - Depression Among Nonfrail Old Men Is Associated With Reduced Physical Function and Functional Capacity After 9 Years Follow-up: The Health in Men Cohort Study. AB - BACKGROUND: Older adults with depression have increased risk of frailty and death. OBJECTIVE: To determine if history of depression hinders future physical and functional capacity. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study of 1148 men aged 70-87 years who were living in the Perth metropolitan community in 2001-2004 and completed a follow-up assessment of physical and functional capacity in 2011-2012. MAIN OUTCOME AND MEASURES: Outcomes were collected in 2011-2012 and included 4 measures of physical function (timed up-and-go, timed sit-to-stand, functional reach, and step test) and the assessment of basic (activities of daily living) and instrumental activities of daily living. We also collected information on depression and frailty [using the FRAIL (fatigue resistance ambulation illness, and loss of weight) scale] in 2001 2004 and 2011-2012. Frail men at the 2001-2004 were excluded from the analyses. RESULTS: Men with history of depression at the 2001-2004 assessment showed significantly worse performance than their counterparts in the timed sit-to-stand and step tests 9 years later. They also had approximately twice the risk of attaining the lowest decile of performance in both tests (analyses adjusted for age, education, and prevalent depressive symptoms). In addition, the adjusted risk ratio of impaired instrumental activities of daily living was 58% (95% confidence interval 15%, 116%) greater for men with than without history of past depression. These associations were particularly robust for men with current depression at the 2001-2004 assessment. CONCLUSIONS: Nonfrail older men with history of current or past depression showed greater impairment of physical and functional capacity 9 years later. Older men with history of depression may benefit from regular monitoring of physical and occupational function and should be targeted by preventive trials designed to improve function and decrease frailty. PMID- 27776986 TI - Reliability and Validity of the Resistiveness to Care Scale Among Cognitively Impaired Older Adults. AB - BACKGROUND: Resistiveness to care is behavior that prevents or interferes with caregivers' performing or assisting with activities of daily living and puts residents at risk for inappropriate use of antipsychotic drugs, other restraining interventions, social isolation, and physical abuse. The purpose of this study was to establish the psychometric properties of a previously developed Resistiveness to Care measure. PROCEDURES: This was a descriptive study using baseline data from an ongoing randomized controlled trial testing a Function and Behavior Focused Care (FBFC) intervention. Residents were eligible to participate if they were 55 years of age or older, had a Mini-Mental State Exam (MMSE) score of 15 or less, and were not enrolled in hospice or admitted for subacute care. Descriptive information included age, race, gender, cognitive status, and marital status. In addition to the Resistance to Care Scale, the Barthel Index, the Physical Activity Survey in Long Term Care (PAS-LTC), and the Cohen-Mansfield Agitation Inventory (CMAI) were completed. Psychometric testing was done using Rasch analysis and the Winsteps statistical program. MAIN FINDINGS: The participants were moderate to severely cognitively impaired (MMSE of 7.23), functionally dependent (Barthel Index 47.31, SD 27.59), and engaged in only 134.17 (SD = 207.32) minutes of physical activity daily. Reliability was supported based on a Cronbach alpha of 0.84 and the DIF analysis, as there was no difference in function of the items between male and female participants. Validity was supported as all items fit the measurement model based on INFIT and OUTFIT statistics. CONCLUSIONS: The findings support the reliability and validity of the Resistiveness to Care Scale for use with older adults with dementia in nursing home settings. Future work with the measure may benefit from the addition of items that are easier to endorse with regard to resistiveness to care (shutting eyes or spitting out food may be useful additions). PMID- 27776987 TI - Endocrinology of Aging From a Muscle Function Point of View: Results From the Toledo Study for Healthy Aging. AB - INTRODUCTION: Aging is a process that involves a reduction in muscle strength and anabolic hormone concentrations, which impacts significantly on health. AIM: To study the hormone/total strength (H/TS) ratio as a proxy of anabolic insensitivity status in elders, and its relationship with disability, hospitalization, and mortality risk. DESIGN: A total of 1462 persons aged >=65 years from the Toledo Study of Healthy Aging participated in this study. Serum concentrations of insulin like growth factor 1, total and free testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and 17beta-estradiol were measured. Total maximal voluntary isometric strength was obtained (handgrip, shoulder, hip, and knee) using standardized techniques and equipment. Physical activity was recorded by physical activity scale for the elderly questionnaire. Associations of the H/TS ratio with hospitalization and mortality were assessed using logistic regression models, and participants stratified into quartiles for each H/TS ratio. RESULTS: In women, all individual ratio H/TS models showed a strong to moderate increased risk for death and hospitalization. In men, all models revealed a significant positive association of the ratio H/TS with mortality rate but not for hospitalization (P < .01). Participants who have 2 or more H/TS ratios in the worst quartile increased the risk of hospitalization and mortality at least by 2-fold. CONCLUSIONS: We demonstrate the main role that muscle function plays in the relationship between the hormonal status and hospitalization and mortality risk; this could be taken into consideration as a way to classify patients for hormonal therapy. PMID- 27776988 TI - Impact of aortic valve closure on adverse events and outcomes with the HeartWare ventricular assist device. AB - BACKGROUND: This study examined whether aortic valve opening (AVO) and other echocardiographic parameters influence outcomes in patients on left ventricular (LV) assist device (LVAD) support. Pump thrombosis (PT) and ischemic stroke (IS) are known complications of LVAD, but mechanisms that could influence them are not completely understood. METHODS: This was a retrospective analysis of 147 patients who received a HeartWare Ventricular Assist Device ( HeartWare International) as a bridge to transplant or to candidacy between July 2009 and August 2015, of whom 126 had at least 30 days of follow-up before the first event (30-days-out cohort). Outcomes included survival, PT, IS, and PT+IS (combined thrombotic event; CTE). RESULTS: Median time on support was 518 days. Of the 30-days-out cohort, 29% had a first PT and 19% a first IS. AVO was associated with longer survival on device (1,081 vs 723 days; p = 0.01) in the entire cohort. In the 30 days-out cohort, the aortic valve was more frequently closed in patients with lower ejection fractions on support (14% +/- 6% vs 18% +/- 9%; p = 0.009), more dilated pre-event echocardiogram (LV end-diastolic diameter, 66 +/- 12 mm vs 62 +/- 10 mm; p = 0.04), and pre-implant LV end-diastolic diameter (70 +/- 10 mm vs 66 +/- 9 mm; p = 0.06). CTE-free survival on the device was lower with a closed aortic valve (897 vs 1,314 days; p = 0.003) as was PT-free survival on the device (1,070 vs 1,457 days; p = 0.02). Cox regression analysis showed that AVO was an independent predictor of CTE (p = 0.03) CONCLUSIONS: Thrombotic events are relatively frequent in patients on long-term LVAD support. A closed aortic valve was associated with decreased overall survival, thrombosis-free survival, and poorer LV function on support. These are high-risk patients, so whether they require more intense anti-coagulation or prioritizing for transplantation requires further research. PMID- 27776989 TI - Extinction of Fear Generalization: A Comparison Between Fibromyalgia Patients and Healthy Control Participants. AB - : Fear learning deficiencies might contribute to the development and maintenance of chronic pain disability. Fear is often not restricted to movements (conditioned stimulus [CS+]) originally associated with pain (unconditioned stimulus), but expands to similar movements (generalization stimuli [GSs]). This spreading of fear becomes dysfunctional when overgeneralization to safe stimuli occurs. More importantly, persistence of pain-related fear to GSs despite corrective feedback might even be more debilitating and maintain long-term chronic pain disability. Yet, research on this topic is lacking. Using a voluntary joystick movement paradigm, we examined (extinction of) pain-related fear generalization in fibromyalgia patients (FM) and healthy control participants (HC). During acquisition, one movement (CS+) predicted pain; another did not (CS-). We tested (extinction of) fear generalization to 5 GSs varying in similarity with the CS+ and CS-. Results revealed flatter pain expectancy generalization gradients in FM than in HC due to elevated responses to GSs more similar to the CS-; the fear generalization gradients did not differ. Although pain-related fear and expectancy to the GSs decreased during extinction, responses to the GSs remained higher for FM than HC, suggesting that extinction of generalization is impaired in chronic pain patients. Persistence of excessive protective responses may contribute to maintaining long-term chronic pain disability. PERSPECTIVE: Pain-related fear and expectancy to movements-varying in similarity with the original painful and nonpainful movement-decrease during extinction in HC and FM. Yet, conditioned responses remain elevated in patients despite corrective feedback, indicating impaired extinction of generalization. Persistent excessive protective responses may contribute to preserving pain disability. PMID- 27776990 TI - Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury. AB - : At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI. PERSPECTIVE: At-level hypersensitivity after complete thoracic SCI is associated with neuropathic below level pain if evoked by clinical sensory stimuli. QST, LEP, and electrically induced axon reflex flare sizes did not indicate somatosensory deafferentation in SCIHs. PMID- 27776991 TI - [Factors influencing the quality of clinical practice guidelines in ovarian cancer]. AB - OBJECTIVE: To identify the characteristics of the published clinical practice guidelines for the management of epithelial ovarian cancer that suggest a good methodological quality. MATERIAL AND METHODS: A literature review was performed on 25 clinical practice guidelines for epithelial ovarian cancer that were identified in different databases (MEDLINE, Guidelines International Network, National Guidelines Clearing house) published between 2007 and 2014. The quality of the guidelines was evaluated using the Appraisal of Guidelines Research and Evaluation II tool. Descriptive and bivariate analyses were performed to assess the association between the quality of the guidelines and of some of their features and their developers. RESULTS: Just under half (48%) of the guidelines were rated as low quality. Scientific societies or independent centres and private funding, or under-reporting the source of funding, were statistically associated with lower quality of clinical practice guidelines (P<.01). The guidelines developed by National Program Guidelines had a median of consistently higher scores in all domains of the Appraisal of Guidelines Research and Evaluation II, with significant differences in the definition of scope and objectives, the participation of stakeholders, the methodological rigour of development, and applicability to the context. CONCLUSIONS: Features such as the nature of the developer and funding of the guidelines are predictors of quality that should be taken into account prior to the use of the recommendations of a document. PMID- 27776992 TI - Routine enema before urodynamics has no impact on the quality of abdominal pressure curves: Results of a prospective controlled study. AB - AIMS: The presence of stools in the rectum might affect the quality of the abdominal pressure curve during filling cystometry, but, to date, no study has evaluated the impact of bowel preparation before urodynamics. We evaluated the influence of a sodium phosphate enema before urodynamics on the quality of the abdominal pressure curve. METHODS: A prospective, controlled, single-blind study was conducted in a single center from May to June 2013. The patients were divided into 2 consecutive groups: patients seen in outpatient clinics during the first 6 weeks (group A) who underwent urodynamics without bowel preparation and patients seen in outpatient clinics during the second 6 weeks (group B) who had a prescription of sodium phosphate enema before urodynamics. The primary endpoint was the quality of the abdominal pressure curve evaluated independently by three physicians who were blinded to the study group. The following data were also collected: age, gender, the presence of a neurological disorder, complicated nature of urodynamics and bother related to preparation for it, assessed using a Likert scale (0 to 10), and the equipment used. A per protocol analysis and an intent-to-treat analysis were conducted. RESULTS: One hundred and thirty-nine patients were included: 54 in group A and 85 in group B. One-third of patients had neurological conditions. 14 patients in group B did not perform their scheduled enema. Thus, 68 patients performed an enema before urodynamics and 71 did not. There was no difference between groups A and B regarding the complicated nature of urodynamics (Likert scale: 3.12 vs. 3.18; P=0.91) or bother related to preparation for it (Likert scale: 3.46 vs. 2.97; P=0.43). In the per protocol analysis, the abdominal pressure curve was considered perfectly interpretable (PI) in 69% of patients who did not receive an enema before urodynamics and in 65% of patients who did (P=0.61). The between-group difference was not statistically significant in intent-to-treat analysis (P=0.99). In patients who did not receive an enema before urodynamics, the only factors statistically associated with better quality of abdominal pressure curves were age <60years (P=0.001) and the urodynamic equipment used (Dantec(r)>Laborie(r); P=0.01). CONCLUSION: In this prospective study, routine enema before urodynamics did not improve the quality of the abdominal pressure curve and did not increase the complicated nature of urodynamics or the bother of preparation for it. LEVEL OF EVIDENCE: 3. PMID- 27776993 TI - Lixisenatide attenuates the detrimental effects of amyloid beta protein on spatial working memory and hippocampal neurons in rats. AB - Type 2 diabetes mellitus(T2DM) is a risk factor of Alzheimer's disease (AD), which is most likely linked to impairments of insulin signaling in the brain. Hence, drugs enhancing insulin signaling may have therapeutic potential for AD. Lixisenatide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analogue, facilitates insulin signaling and has neuroprotective properties. We previously reported the protective effects of lixisenatide on memory formation and synaptic plasticity. Here, we describe additional key neuroprotective properties of lixisenatide and its possible molecular and cellular mechanisms against AD related impairments in rats. The results show that lixisenatide effectively alleviated amyloid beta protein (Abeta) 25-35-induced working memory impairment, reversed Abeta25-35-triggered cytotoxicity on hippocampal cell cultures, and prevented against Abeta25-35-induced suppression of the Akt-MEK1/2 signaling pathway. Lixisenatide also reduced the Abeta25-35 acute application induced intracellular calcium overload, which was abolished by U0126, a specific MEK1/2 inhibitor. These results further confirmed the neuroprotective and cytoprotective action of lixisenatide against Abeta-induced impairments, suggesting that the protective effects of lixisenatide may involve the activation of the Akt-MEK1/2 signaling pathway and the regulation of intracellular calcium homeostasis. PMID- 27776994 TI - Combined effects of antiorthostatic suspension and ionizing radiation on the behaviour and neurotransmitters changes in different brain structures of rats. AB - Space flight factors (SFF) significantly affect the operating activity of astronauts during deep space missions. In contrast to an orbital flight, leaving the Earth's magnetic field is fraught with the dangers of exposure to ionizing radiation and more specifically, the high-energy nuclei component of galactic cosmic rays. Microgravity, just another critical non-radiation factor, significantly affects the normal functioning of the CNS. Some morphological structures of the brain, such as the prefrontal cortex and the hippocampus, that are rich in monoaminergic and acetylcholinergic neurones, are the most sensitive to the effects of ionizing radiation and non-radiation spaceflight factors (SFF). In this work we have studied the combined effects of microgravity (in antiorthostatic suspension model, AS) and irradiation (gamma-ray and protons in spread-out Bragg peak) on the behaviour, cognitive abilities, and metabolism of monoamines and acetylcholine in the key structures of the rat's brain. Irradiation (as independently as combined with AS) resulted in the decrease of thigmotaxis in rats. Learning problems, caused by the malfunctioning of the working memory but not the spatial memory, were observed in response to AS as well as to the SFF in combination. Analysis of monoamines metabolism showed that the serotoninergic system was the most affected by the SFF. Concentration of acetylcholine in the hippocampus significantly increased in the groups of irradiated rats, and in the groups which were exposed to the SFF in combination, compared to the rats exposed only to AS. PMID- 27776995 TI - ST2 from rainbow trout quenches TLR signalling, localises at the nuclear membrane and allows the nuclear translocation of MYD88. AB - The mammalian interleukin 1 receptor-like 1 receptor (IL1RL1), commonly known as ST2, is thought to downregulate TLR signalling by sequestering the signalling adapter MYD88 (myeloid differentiation primary response protein 88). ST2 sequences are known in several fish species, but none of them have functionally been examined. We characterised ST2 from rainbow trout (Oncorhynchus mykiss) and the structure of its encoding gene. The primary sequence of ST2 is only weakly conserved from fish to human. However, the amino acid sequences forming the interfaces for ST2 and MYD88 interaction are well conserved throughout evolution. High similarity of the gene segmentation unambiguously proves the common ancestry of fish and mammalian ST2. Trout ST2 and trout MYD88 genes were constitutively expressed in embryonic, larval and adult trout. In vivo infection with Aeromonas salmonicida did not modulate the mRNA levels of both factors. Overexpressing trout ST2 in the mammalian HEK-293 reconstitution system of TLR2 signalling quenched the Escherichia coli-induced activation of NF-kappaB and SAA promoters in a dose-dependent fashion. The expression of GFP-tagged trout ST2 in human HEK 293 or trout CHSE-214 cells surprisingly revealed that (i) ST2 localised abundantly at the nuclear membrane rather than at the cell membrane and (ii) the coexpression of both ST2 and MYD88 allowed the translocation of trout MYD88 from cytoplasm to nucleus, as assessed using confocal microscopy and Western blotting. Hence, we validated that trout ST2 is a dampener of TLR signalling and interacts with MYD88. The spatial distribution of these factors raises questions about how this repressive mechanism functions. PMID- 27776997 TI - Does biomass production correlate with metabolic activity in Staphylococcus aureus? AB - We assessed agreement between the crystal violet binding assay and the XTT assay in the classification of biofilm production in 492 Staphylococcus aureus strains from bacteremic patients. We found that the overall correlation between the procedures was 46.5%. Biomass production and metabolic activity must be assessed simultaneously. PMID- 27776998 TI - Fighting Small Numbers. PMID- 27776996 TI - Contrasting expression of immune genes in scaled and scaleless skin of Atlantic salmon infected with young stages of Lepeophtheirus salmonis. AB - Atlantic salmon skin tissues with and without scales were taken from two preferred sites of salmon louse (Lepeophtheirus salmonis) attachment, behind the dorsal fin (scaled) and from the top of the head (scaleless), respectively. Tissues were profiled by qPCR of 32 genes to study responses to copepodids, 4 days post infection (dpi), and during the moult of copepodids to the chalimus stage, at 8 dpi. Basal/constitutive differences were found for many immune related genes between the two skin sites; e.g., mannose binding protein C was over 100 fold higher expressed in the scaled skin from the back in comparison to the skin without scales from the head. With lice-infection, at 4 dpi most genes in both tissues showed lower values than in the non-infected control. By 8 dpi, the majority of responses increased towards the control levels, including cytokines of Th1, Th17 and Th2 pathways. Immunohistochemistry of three immune factors revealed an even distribution of MHC class II positive cells throughout epidermis, including the top layer of keratinocytes, marked compartmentalization of Mx+ and CD8alpha+ cells close to stratum basale, and an increase in numbers of CD8alpha+ cells in response to infection. In conclusion, suppression of immune genes during the copepodid stage likely sets off a beneficial situation for the parasite. At the moult to chalimus stage 8 dpi, only few genes surpassed the non infected control levels, including CD8alpha. The gene expression pattern was reflected in the increased number of CD8alpha expressing cells, thus revealing a relatively minor activation of skin T-cell defenses in Atlantic salmon in response to L. salmonis infection. PMID- 27776999 TI - First detection of Allobilharzia visceralis (Schistosomatidae, Trematoda) from Cygnus cygnus in Japan. AB - Adult schistosomes were detected in the veins or capillaries of the large intestine, mesentery, liver, and adrenal glands in eight of 13 whooper swans (Cygnus cygnus) examined in Iwate Prefecture, Japan. However, neither eggs nor severe tissue injuries were observed in any of the swans. The schistosomes were definitively identified as Allobilharzia visceralis based on the nucleotide sequences of the ribosomal internal transcribed spacer (ITS) region. Allobilharzia visceralis infections have been reported in whooper swan in Iceland and tundra swan (Cygnus columbianus) in North America. These detections suggest that A. visceralis is distributed extensively along the swan flyways because the swans are migratory birds. To the best of our knowledge, this is the first report of A. visceralis infection in Asia. PMID- 27777000 TI - Fast and robust segmentation of the striatum using deep convolutional neural networks. AB - BACKGROUND: Automated segmentation of brain structures is an important task in structural and functional image analysis. We developed a fast and accurate method for the striatum segmentation using deep convolutional neural networks (CNN). NEW METHOD: T1 magnetic resonance (MR) images were used for our CNN-based segmentation, which require neither image feature extraction nor nonlinear transformation. We employed two serial CNN, Global and Local CNN: The Global CNN determined approximate locations of the striatum. It performed a regression of input MR images fitted to smoothed segmentation maps of the striatum. From the output volume of Global CNN, cropped MR volumes which included the striatum were extracted. The cropped MR volumes and the output volumes of Global CNN were used for inputs of Local CNN. Local CNN predicted the accurate label of all voxels. Segmentation results were compared with a widely used segmentation method, FreeSurfer. RESULTS: Our method showed higher Dice Similarity Coefficient (DSC) (0.893+/-0.017 vs. 0.786+/-0.015) and precision score (0.905+/-0.018 vs. 0.690+/ 0.022) than FreeSurfer-based striatum segmentation (p=0.06). Our approach was also tested using another independent dataset, which showed high DSC (0.826+/ 0.038) comparable with that of FreeSurfer. Comparison with existing method Segmentation performance of our proposed method was comparable with that of FreeSurfer. The running time of our approach was approximately three seconds. CONCLUSION: We suggested a fast and accurate deep CNN-based segmentation for small brain structures which can be widely applied to brain image analysis. PMID- 27777001 TI - Implantable RF-coil with multiple electrodes for long-term EEG-fMRI monitoring in rodents. AB - BACKGROUND: Simultaneous EEG-fMRI is a valuable tool in the clinic as it provides excellent temporal and spatial information about normal and diseased brain function. In pre-clinical research with small rodents, obtaining simultaneous EEG fMRI in longitudinal studies faces a number of challenges, including issues related to magnetic susceptibility artifacts. NEW METHOD: Here, we demonstrate a method for permanent MRI RF-coil and EEG electrode implantation in rats that is suitable for long-term chronic follow-up studies in both stimulus and resting state fMRI paradigms. RESULTS: Our findings showed that the screw-free implantation method is well suited for long-term follow-up studies in both freely moving video-EEG settings and fMRI without causing MRI susceptibility artifacts. Furthermore, the results demonstrated that a multimodal approach can be used to track the progression of structural and functional changes. COMPARISON WITH EXISTING METHODS: The quality of both MRI and EEG data were comparable to those obtained with traditional methods with the benefit of combining them into artifact-free simultaneous recordings. The signal-to-noise ratios of the MRI images obtained with the implanted RF-coil were similar to those using a quadrature coil and were therefore suitable for resting-state fMRI experiments. Similarly, EEG data collected with the RF-coil/electrode set-up were comparable to EEG recorded with traditional epidural screw electrodes. CONCLUSION: This new multimodal EEG-fMRI approach provides a novel tool for concomitant analysis and follow-up of anatomic and functional MRI, as well as electrographic changes in a preclinical research. PMID- 27777002 TI - Structural Basis of Novel Iron-Uptake Route and Reaction Intermediates in Ferritins from Gram-Negative Bacteria. AB - Iron and oxygen chemistry is mediated by iron proteins for many biological functions. Carboxylate-bridged diiron enzymes including ferritin have the common mechanism of oxygen activation via peroxodiferric intermediates. However, the route for iron uptake and the structural identification of intermediates still remain incomplete. The 4-fold symmetry channel of Helicobacter pylori ferritin was previously proposed as the iron-uptake route in eubacteria, but the amino acid residues at the 4-fold channel are not highly conserved. Here, we show evidence for a short path for iron uptake from His93 on the surface to the ferroxidase center in H. pylori ferritin and Escherichia coli ferritin. The amino acid residues along this path are highly conserved in Gram-negative bacteria and some archaea, and the mutants containing S20A and H93L showed significantly decreased iron oxidation. Surprisingly, the E. coli ferritin S20A crystal structure showed oxygen binding and side-on, symmetric MU-eta2:eta2 peroxodiferric and oxodiferric intermediates. The results provide the structural basis for understanding the chemical nature of intermediates in iron oxidation in bacteria and some of archaea. PMID- 27777003 TI - A two-step strategy to radiolabel choline phospholipids with 99mTc in S180 cell membranes via strain-promoted cyclooctyne-azide cycloaddition reaction. AB - As tumor markers, the radiolabeling of choline (Cho)-containing phospholipids in cellular membranes with 99mTc is a challenge. The conventional strategy to combine the metallic radionuclide with Cho by large ligand damages the bioactivity of Cho, resulting in low tumor-to-nontumor ratios. Pretargeting strategy based on strain-promoted cyclooctyne-azide cycloaddition (SPAAC) reaction was applied to solve this general problem. Functional click synthons were synthesized as pretargeting components: azidoethyl-choline (AECho) serves as tumor marker and azadibenzocyclooctyne (ADIBO) conjugated to bis(2-pieolyl) amine (BPA) ligand (ADIBO-BPA) as 99mTc(CO)3-labeling and azido-binding group. Both in vitro cell experiment and in vivo biodistribution experiment indicate that it is versatile to radiolabel Cho in cellular membranes via this two-step pretargeting strategy. We believe that this pretargeting strategy can indeed enhance the target-specificity and also reduce background signals to optimize imaging quality. PMID- 27777004 TI - Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles. AB - This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490-525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6 arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and gamma-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ~50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate. PMID- 27777005 TI - Dihydrostilbenes and diarylpropanes: Synthesis and in vitro pharmacological evaluation as potent nitric oxide production inhibition agents. AB - An efficient synthesis of dihydrostilbenes (1-5) and diarylpropanes (6-10) is achieved from the commercially available starting materials and Wittig-Horner reaction, Claisen-Schmidt condensation and hydrogenation as key steps. Later, their nitric oxide (NO) production inhibition effects were evaluated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages as an indicator of anti inflammatory activity. All the tested compounds significantly decreased NO production in a concentration-dependent manner except compounds 2, 6 and 8 and did not show notable cytotoxicity except compound 1. Two compounds i.e., compound 9 (hindsiipropane B) (100%; IC50=1.84MUM) possessed the most potent NO inhibitory activity which was even stronger than the positive control, L-NMMA (90.1%; IC50=2.73MUM) followed by compound 4 (75.5%; IC50=2.98MUM) at 10MUM concentration and this finding was also further correlated by suppressed expression of LPS stimulated inducible NO synthase. Our study revealed that compound 9, a 1,3 diarylpropane scaffold with 3",4"-dimethoxyphenyl and 3',4'-dihydroxy-2' methoxyphenyl motifs could be considered as potential compound or lead compound for further development of NO production-targeted anti-inflammatory agents. PMID- 27777006 TI - Inhibition of plasma lipid oxidation induced by peroxyl radicals, peroxynitrite, hypochlorite, 15-lipoxygenase, and singlet oxygen by clinical drugs. AB - With increasing evidence showing the involvement of oxidative stress in the pathogenesis of various diseases, the effects of clinical drugs possessing antioxidant functions have received much attention. The unregulated oxidative modification of biological molecules leading to diseases is mediated by multiple oxidants including free radicals, peroxynitrite, hypochlorite, lipoxygenase, and singlet oxygen. The capacity of antioxidants to scavenge or quench oxidants depends on the nature of oxidants. In the present study, the antioxidant effects of several clinical drugs against plasma lipid oxidation induced by the aforementioned five kinds of oxidants were investigated from the production of lipid hydroperoxides, which have been implicated in the pathogenesis of various diseases. Troglitazone acted as a potent peroxyl radical scavenger, whereas probucol and edaravone showed only moderate reactivity and carvedilol, pentoxifylline, and ebselen did not act as radical scavenger. Probucol and edaravone suppressed plasma oxidation mediated by peroxynitrite and hypochlorite. Troglitazone and edaravone inhibited 15-lipoxygenase mediated plasma lipid oxidation, the IC50 being 20 and 34MUM respectively. None of the drugs used in this study suppressed plasma lipid oxidation by singlet oxygen. This study shows that the antioxidant effects of drugs depend on the nature of oxidants and that antioxidants against multiple oxidants are required to cope with oxidative stress in vivo. PMID- 27777007 TI - The synthesis and antistaphylococcal activity of dehydroabietic acid derivatives: Modifications at C-12. AB - A series of 12-oxime and O-oxime ether derivatives of dehydroabietic acid were synthesized and investigated for the antibacterial activity against Staphylococcus aureus Newman strain and five multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The aromatic oximate derivative 11a showed the highest activity with MIC of 0.39-0.78MUg/mL against S. aureus Newman. Of note, compounds 10b, 11 and 14 showed the most potent antibacterial activity against five multidrug-resistant S. aureus with MIC values of 1.25-3.13MUg/mL. These results offered useful information for further strategic optimization in search of the antibacterial candidates against infection of multidrug-resistant Gram-positive bacteria. PMID- 27777009 TI - Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit. AB - Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC 3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50 values of 0.56+/-0.83MUM, 3.88+/-1.03MUM and 3.15+/-0.81MUM, which were 1.03-6.14-fold more active than sorafenib (3.44+/-1.50MUM, 3.18+/-1.43MUM, 3.24+/-0.45MUM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50 value was 0.72MUM. Structure-activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4 F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity. PMID- 27777008 TI - Syntheses, cytotoxic activity evaluation and HQSAR study of 1,2,3-triazole-linked isosteviol derivatives as potential anticancer agents. AB - A series of novel 1,2,3-triazole-linked isosteviol derivatives were designed and synthesized via Huisgen-click reaction. Their cytotoxicities in vitro against HCT 116 and JEKO-1 cells were screened. The preliminary bioassays indicated that most of the title compounds exhibited noteworthy cytotoxic activities. Particularly, the compound 10b revealed the most potent inhibitory activities against HCT-116 cells with IC50 value of 2.987+/-0.098MUM, which was better than that (3.906+/ 0.261MUM) of positive control cisplatin. On the basis of these bioactivity data, hologram quantitative structure-activity relationship (HQSAR) was performed, and a statistically reliable model with good predictive power (r2=0.848, q2=0.544 and R2pred=0.982) was achieved. Additionally, the contribution maps derived from the optimal model explained the individual atomic contributions to the activity for each molecule. PMID- 27777010 TI - Mesoionic pyrido[1,2-a]pyrimidinones: A novel class of insecticides inhibiting nicotinic acetylcholine receptors. AB - A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species, particularly hemiptera and lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors (nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of this class of chemistry. Our efforts in structure-activity relationship elucidation and biological activity evaluation are also presented. PMID- 27777011 TI - Variation of the aryl substituent on the piperazine ring within the 4-(piperazin 1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold unveils potent, non-competitive inhibitors of the inflammatory caspases. AB - The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1-41 displaying low nanomolar Ki values across this family of caspases. Three analogs were nearly 10 fold selective for caspase-5 over caspase-1 and -4. The compounds display non-competitive, time dependent inhibition profiles. To our knowledge, this series is the first example of small molecule inhibitors of all three inflammatory caspases. PMID- 27777012 TI - Characterization of rhizobia isolates obtained from nodules of wild genotypes of common bean. AB - This study aimed to evaluate the tolerance to salinity and temperature, the genetic diversity and the symbiotic efficiency of rhizobia isolates obtained from wild genotypes of common bean cultivated in soil samples from the States of Goias, Minas Gerais and Parana. The isolates were subjected to different NaCl concentrations (0%, 1%, 2%, 4% and 6%) at different temperatures (28 degrees C, 33 degrees C, 38 degrees C, 43 degrees C and 48 degrees C). Genotypic characterization was performed based on BOX-PCR, REP-PCR markers and 16S rRNA sequencing. An evaluation of symbiotic efficiency was carried out under greenhouse conditions in autoclaved Leonard jars. Among 98 isolates about 45% of them and Rhizobium freirei PRF81 showed a high tolerance to temperature, while 24 isolates and Rhizobium tropici CIAT899 were able to use all of the carbon sources studied. Clustering analysis based on the ability to use carbon sources and on the tolerance to salinity and temperature grouped 49 isolates, R. tropici CIAT899 and R. tropici H12 with a similarity level of 76%. Based on genotypic characterization, 65% of the isolates showed an approximately 66% similarity with R. tropici CIAT899 and R. tropici H12. About 20% of the isolates showed symbiotic efficiency similar to or better than the best Rhizobium reference strain (R. tropici CIAT899). Phylogenetic analysis of the 16S rRNA revealed that two efficient isolates (ALSG5A1 and JPrG6A8) belong to the group of strains used as commercial inoculant for common bean in Brazil and must be assayed in field experiments. PMID- 27777013 TI - Potential for biocontrol of melanized fungi by actinobacteria isolated from intertidal region of Ilha Do Mel, Parana, Brazil. AB - Actinobacteria occur in many environments and have the capacity to produce secondary metabolites with antibiotic potential. Identification and taxonomy of actinobacteria that produce antimicrobial substances is essential for the screening of new compounds, and sequencing of the 16S region of ribosomal DNA (rDNA), which is conserved and present in all bacteria, is an important method of identification. Melanized fungi are free-living organisms, which can also be pathogens of clinical importance. This work aimed to evaluate growth inhibition of melanized fungi by actinobacteria and to identify the latter to the species level. In this study, antimicrobial activity of 13 actinobacterial isolates from the genus Streptomyces was evaluated against seven melanized fungi of the genera Exophiala, Cladosporium, and Rhinocladiella. In all tests, all actinobacterial isolates showed inhibitory activity against all isolates of melanized fungi, and only one actinobacterial isolate had less efficient inhibitory activity. The 16S rDNA region of five previously unidentified actinobacterial isolates from Ilha do Mel, Parana, Brazil, was sequenced; four of the isolates were identified as Streptomyces globisporus subsp. globisporus, and one isolate was identified as Streptomyces aureus. This work highlights the potential of actinobacteria with antifungal activity and their role in the pursuit of novel antimicrobial substances. PMID- 27777014 TI - Semisynthetic flavonoid 7-O-galloylquercetin activates Nrf2 and induces Nrf2 dependent gene expression in RAW264.7 and Hepa1c1c7 cells. AB - The natural flavonoid quercetin is known to activate the transcription factor Nrf2, which regulates the expression of cytoprotective enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, a novel semisynthetic flavonoid 7-O-galloylquercetin (or quercetin-7-gallate, 3) was prepared by direct galloylation of quercetin, and its effect on the Nrf2 pathway was examined. A luciferase reporter assay showed that 7-O galloylquercetin, like quercetin, significantly activated transcription via the antioxidant response element in a stably transfected human AREc32 reporter cell line. In addition, 7-O-galloylquercetin caused the accumulation of Nrf2 and induced the expression of HO-1 at both the mRNA and protein levels in murine macrophage RAW264.7 cells. The induction of HO-1 by 7-O-galloylquercetin was significantly suppressed by N-acetyl-l-cysteine and SB203580, indicating the involvement of reactive oxygen species and p38 mitogen-activated protein kinase activity, respectively. HPLC/MS analyses also showed that 7-O-galloylquercetin was not degalloylated to quercetin, but it was conjugated with glucuronic acid and/or methylated in RAW264.7 cells. Furthermore, 7-O-galloylquercetin was found to increase the protein levels of Nrf2 and HO-1, and also the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. Taken together, we conclude that 7-O galloylquercetin increases Nrf2 activity and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells. PMID- 27777015 TI - High-resolution fMRI investigations of the fingertip somatotopy and variability in BA3b and BA1 of the primary somatosensory cortex. AB - The fingertip somatotopy in BA1 and BA3b of monkeys exhibits characteristic differences with a more discrete separation of the body parts in BA3b and a continuous orientation column-like structure in BA1. We present evidence for similar differences in the human somatotopy using BOLD fMRI for the investigations. Though the variability between the individual maps was large, we found a group-wide somatotopic representation in BA3b and BA1. The variability due to anatomical differences was small in our sample. This was demonstrated by comparing exact shortest distances in the individual brains and after nonlinear normalization to the group space template, for the removal of the individual anatomical variability. Distance mapping along Dijkstra paths was found to be a valid approximation to exact shortest paths only in the individual brains. The degree of fine-scale detail mapping was improved if valid surface distances instead of 3D Euclidean distances were applied. A further improvement was achieved by mapping the distances between all neighboring fingertips instead of only the outer fingertips. Taking into account all optimizations we found mirror symmetry of the somatotopy with respect to the interhemispheric gap. PMID- 27777016 TI - Physiological and molecular responses of juvenile shortnose sturgeon (Acipenser brevirostrum) to thermal stress. AB - The shortnose sturgeon (Acipenser brevirostrum LeSueur, 1818) is a vulnerable species that is found along the eastern coast of North America. Little is known about temperature tolerance in this species and with a rapidly changing global climate, it becomes increasingly important to define the thermal tolerance of this species to better predict population distribution. Using a modified critical thermal maximum test (CTMax), the objectives of this study were to determine the impact of heating rate (0.1, 0.2 and 0.25 degrees Cmin-1) on the thermal tolerance, associated hematological responses, and oxygen consumption in juvenile sturgeon. In addition, transcripts associated with physiological stress and heat shock (i.e., heat shock proteins) were also measured. Heating rate did not alter the CTMax values of shortnose sturgeon. Neither heating rate nor thermal stress affected plasma sodium and chloride levels, nor the expression of transcripts that included catalase, glucocorticoid receptor, heat shock protein70 (hsp70), heat shock protein 90alpha (hsp90alpha) and cytochrome P450 1a (cyp1a). However, regardless of heating rate, thermal stress increased both plasma potassium and lactate concentrations. Glucose levels were increased at heating rates of 0.2 and 0.25 degrees Cmin-1, but not at 0.1 degrees Cmin-1. Overall, oxygen consumption rates increased with thermal stress, but the response patterns were not affected by heating rate. These data support the hypothesis that shortnose sturgeon can tolerate acute heat stress, as many physiological and molecular parameters measured here were non-responsive to the thermal stress. PMID- 27777017 TI - Economic preferences and fast food consumption in US adults: Insights from behavioral economics. AB - OBJECTIVE: To examine the relationship between economic time preferences and frequency of fast food and full-service restaurant consumption among U.S. adults. METHODS: Participants included 5871U.S. adults who responded to a survey conducted in 2011 pertaining to the lifestyle behaviors of families and the social context of these behaviors. The primary independent variable was a measure of time preferences, an intertemporal choice assessing delay discounting. This was elicited via responses to preferences for an immediate dollar amount or a larger sum in 30 (30-day time horizon) or 60days (60-day time horizon). Outcomes were the frequency of fast food and full-service restaurant consumption. Ordered logistic regression was performed to examine the relationship between time preferences and food consumption while adjusting for covariates (e.g. socio demographics). RESULTS: Multivariable analysis revealed that higher future time preferences were significantly related to less frequent fast food intake for both the 30- and 60-day time horizon variables (P for linear trend <0.05; both). Notably, participants with the highest future time preference were significantly less likely to consume fast food than those with very low future time preferences (30-day: OR=0.74, 95%CI: 0.62-0.89; and 60-day: OR=0.86, 95%CI: 0.74-1.00). In comparison, higher future time preferences were not significantly associated with full-service restaurant intake (30-day: p for linear trend=0.73; 60-day: p for linear trend=0.83). CONCLUSIONS: Higher future time preferences were related to a lower frequency of fast food consumption. Utilizing concepts from behavioral economics (e.g. pre-commitment contracts) to facilitate more healthful eating is warranted using experimental studies. PMID- 27777018 TI - Successful derivation of xeno-free mesenchymal stem cell lines from endometrium of infertile women. AB - Transplantation of mesenchymal stem cells (MSC) can effectively repair endometrial deficiencies, including infertile patients with a problem of inadequate endometrium thickness. Although, MSC derived from different organ sources have a similarity of MSC specific characteristics, endometrial stem cells (EMSC) are temporally regulated throughout the menstrual cycle in a micro environmental niche found only in endometrial tissue. Given the micro-environment niche, developing treatments for endometrial disorders with EMSC should be a top priority. To provide EMSC that afford safety for therapeutic usage, we have established a completely xeno-free EMSC line derivation protocol using human allogenic umbilical cord serum instead of animal derived reagents, and proved that it is feasible to generate xeno-free EMSC lines from infertile patient donors using these conditions. Our results demonstrate the successful derivation of xeno-free EMSC lines from 10 out of 10 infertile patients. The resultant xeno free EMSC lines showed typical MSC morphology, phenotypic markers, differentiation capacity, telomere length and normal karyotypes. They showed superior proliferation capability, but lower expression of proto-oncogenes, to the lines generated under standard (animal derived reagents) culture. Biosafety of xeno-free EMSC lines also displayed in retention of immunosuppressive ability, epigenetic stability by imprinted genes expression, proto-oncogenes expression and no mutation of specific codon on p53 tumor suppressor gene. Taken together, these data indicate that our cells may be safe for clinical use. In conclusion, we have succeeded in establishing completely xeno-free EMSC lines and demonstrate for the first time that autogenic and xeno-free EMSC lines can be generated from infertile women. PMID- 27777019 TI - Chest pain, dysphagia and hematemesis in a new mother. PMID- 27777021 TI - Clinical heterogeneity in familial Alzheimer's disease. PMID- 27777020 TI - Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). AB - BACKGROUND: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. METHODS: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. FINDINGS: The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer's disease, including visual agnosia (55.1%, 95% CI 45.7-64.6), aphasia (57.9%, 48.6-67.3), and behavioural changes (61.7%, 51.5-70.0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5.6%, 3.9 7.2], aphasia [23.0%, 20.0-26.0], and behavioural changes [31.7%, 28.4-35.1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9.3%, 95% CI 3.8-15.0), and seizures (2.8%, 0.5-5.9) and moderate for parkinsonism (11.2%, 5.3-17.1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19.4%, 16.6-22.2 and 15.0%, 12.5-17.6, respectively), parkinsonism (12.5%, 10.1 15.0), and seizures (20.3%, 17.4-23.2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1.09 per 1 year increase in age of onset, 95% CI 1.04-1.14, p=0.0003); and motor symptoms were more common at younger age of onset (myoclonus 0.93, 0.90-0.97, p=0.0007; seizures 0.95, 0.92-0.98, p=0.0018; corticobulbar deficits 0.91, 0.86-0.96, p=0.0012; and cerebellar ataxia 0.82, 0.74-0.91, p=0.0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. INTERPRETATION: The non-cognitive clinical manifestations of Alzheimer's disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer's disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. FUNDING: National Institutes of Health and German Center for Neurodegenerative Diseases. PMID- 27777022 TI - Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. AB - BACKGROUND: The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). METHODS: We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. FINDINGS: Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43.6 years [SD 7.2] vs 50.4 years [SD 5.2], respectively, p<0.0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0.037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0.001 for PSEN1; p=0.036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs. INTERPRETATION: ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. FUNDING: Medical Research Council and National Institute for Health Research. PMID- 27777023 TI - [Rituximab therapy for refractory thrombocytopenia in patients with antiphospholipid antibodies]. PMID- 27777024 TI - [Elevated thyroid hormone levels following low molecular weight heparin administration]. PMID- 27777025 TI - Treacher Collins syndrome: New insights from animal models. AB - Treacher Collins syndrome (TCS, OMIM: 154500), an autosomal-dominant craniofacial developmental syndrome that occurs in 1 out of every 50,000 live births, is characterized by craniofacial malformation. Mutations in TCOF1, POLR1C, or POLR1D have been identified in affected individuals. In addition to established mouse models, zebrafish models have recently emerged as an valuable method to study facial disease. In this report, we summarized the two updated articles working on the pathogenesis of the newly identified polr1c and polr1d TCS mutations (Lau et al., 2016; Noack Watt et al., 2016) and discussed the possibility of using the anti-oxidants to prevent or rescue the TCS facial phenotype (Sakai et al., 2016). Taken together, this article provides an update on the disease from basic information to pathogenesis, and further summarizes the suggested therapies from recent laboratory research. PMID- 27777027 TI - Role of pelvic radiotherapy for locally advanced rectal cancer and synchronous unresectable distant metastases. AB - PURPOSE: To evaluate the efficacy and safety of pelvic irradiation combined systematic chemotherapy in patients with locally advanced (cT3-T4 and/or cN+) rectal cancer and synchronous unresectable distant metastases. PATIENTS AND METHODS: A total of 76 eligible patients who received pelvic radiotherapy and concurrent capecitabine-based chemotherapy were retrospectively reviewed. Patients survival curves were constructed using the Kaplan-Meier method, and a multivariate analysis was performed to identify independent prognostic factors. RESULTS: Most of the adverse events were mild during the period of combined chemoradiotherapy. Twenty-two patients experienced resection of primary tumour and 16 patients underwent radical surgery of all lesions. Only five patients had pelvic progression during the follow-up period. The median progression-free survival and median overall survival were 13 and 30 months, respectively. Radical surgery of all lesions following chemoradiotherapy was found to be an independent prognostic factor according to multivariate analysis. CONCLUSIONS: Pelvic irradiation combined with systematic chemotherapy in patients with locally advanced rectal cancer and synchronous unresectable distant metastases is effective and tolerable, both for pelvic and distant control. A curative resection following chemoradiotherapy was associated with prolonged survival. PMID- 27777026 TI - Analysis of RNA structure using small-angle X-ray scattering. AB - In addition to their role in correctly attaching specific amino acids to cognate tRNAs, aminoacyl-tRNA synthetases (aaRS) have been found to possess many alternative functions and often bind to and act on other nucleic acids. In contrast to the well-defined 3D structure of tRNA, the structures of many of the other RNAs recognized by aaRSs have not been solved. Despite advances in the use of X-ray crystallography (XRC), nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy (cryo-EM) for structural characterization of biomolecules, significant challenges to solving RNA structures still exist. Recently, small-angle X-ray scattering (SAXS) has been increasingly employed to characterize the 3D structures of RNAs and RNA-protein complexes. SAXS is capable of providing low-resolution tertiary structure information under physiological conditions and with less intensive sample preparation and data analysis requirements than XRC, NMR and cryo-EM. In this article, we describe best practices involved in the process of RNA and RNA-protein sample preparation, SAXS data collection, data analysis, and structural model building. PMID- 27777028 TI - [1896: How nascent radiotherapy gathered Roentgen, Pasteur and the Lumiere brothers]. AB - On the 4th July, 1896, in his medical office of Les Echelles (Savoie, France), Victor Despeignes performed the very first radiotherapy against cancer, documented by indisputable proofs. However, the intellectual and practical approach that leads to this first radiotherapy may appear unexpected to date. Indeed, it is likely that the treatment that Despeignes applied to his neighbour, who did not suffer from stomach cancer, was born with the indirect support of the Lumiere brothers, on the basis of a biological theory (the parasitory theory of cancer) that is irrelevant today, with an experimental protocol based on experiments performed on tuberculosis et in a bifractionated model linked by the constraints of a district medical doctor. PMID- 27777029 TI - Global malaria importations. PMID- 27777031 TI - Excess mortality associated with loiasis: a retrospective population-based cohort study. AB - BACKGROUND: The burden of loiasis has received limited attention and loiasis is still considered a benign condition. To assess whether loiasis bears any excess mortality, we did a retrospective cohort study in Cameroon. METHODS: In 2001, 3627 individuals living in 28 villages were examined for Loa loa infection. In 2016, these villages were revisited and the vital status was determined for 3301 individuals (91%). The data were analysed at community level to assess the relation between the level of L loa infection in 2001 and standardised mortality rates (SMRs), and at individual level to assess the excess mortality relative to the 2001 microfilaraemia and to calculate the population-attributable fraction of mortality associated with L loa microfilaraemia. FINDINGS: 915 deaths occurred during the follow-up time (mean time of 12.5 years [IQR 10.2-14.9]) between April, 2001, and March 22, 2016. Crude mortality rate was 20.3 deaths per 1000 person-years. SMRs increased by 4.1% when the proportion of participants infected with greater than 30 000 microfilariae per mL increased by 1% (p=0.030). People aged older than 25 years with greater than 30 000 microfilariae per mL in 2001 died significantly earlier than did amicrofilaraemic people (time ratio 0.67, 95% CI 0.48-0.95, p=0.024). The population-attributable fraction of mortality associated with presence of L loa microfilaraemia was 14.5% (95% CI 6.5-21.8, p=0.001). INTERPRETATION: High-grade L loa microfilaraemia is associated with an increased mortality risk, suggesting that loiasis is not a benign condition and merits more attention because of its effect on onchocerciasis and lymphatic control strategies. Loiasis should be considered for inclusion in the WHO's list of neglected tropical diseases. FUNDING: Drugs for Neglected Diseases initiative. PMID- 27777032 TI - Filarial infection deserves attention as neglected tropical disease. PMID- 27777030 TI - The geography of imported malaria to non-endemic countries: a meta-analysis of nationally reported statistics. AB - BACKGROUND: Malaria remains a problem for many countries classified as malaria free through cases imported from endemic regions. Imported cases to non-endemic countries often result in delays in diagnosis, are expensive to treat, and can sometimes cause secondary local transmission. The movement of malaria in endemic countries has also contributed to the spread of drug resistance and threatens long-term eradication goals. Here we focused on quantifying the international movements of malaria to improve our understanding of these phenomena and facilitate the design of mitigation strategies. METHODS: In this meta-analysis, we studied the database of publicly available nationally reported statistics on imported malaria in the past 10 years, covering more than 50 000 individual cases. We obtained data from 40 non-endemic countries and recorded the geographical variations. FINDINGS: Infection movements were strongly skewed towards a small number of high-traffic routes between 2005 and 2015, with the west Africa region accounting for 56% (13 947/24 941) of all imported cases to non-endemic countries with a reported travel destination, and France and the UK receiving the highest number of cases, with more than 4000 reported cases per year on average. Countries strongly linked by movements of imported cases are grouped by historical, language, and travel ties. There is strong spatial clustering of plasmodium species types. INTERPRETATION: The architecture of the air network, historical ties, demographics of travellers, and malaria endemicity contribute to highly heterogeneous patterns of numbers, routes, and species compositions of parasites transported. With global malaria eradication on the international agenda, malaria control altering local transmission, and the threat of drug resistance, understanding these patterns and their drivers is increasing in importance. FUNDING: Bill & Melinda Gates Foundation, National Institutes of Health, UK Medical Research Council, UK Department for International Development, Wellcome Trust. PMID- 27777033 TI - Development of a hybrid model to predict construction and demolition waste: China as a case study. AB - Construction and demolition waste (C&DW) is currently a worldwide issue, and the situation is the worst in China due to a rapid increase in the construction industry and the short life span of China's buildings. To create an opportunity out of this problem, comprehensive prevention measures and effective management strategies are urgently needed. One major gap in the literature of waste management is a lack of estimations on future C&DW generation. Therefore, this paper presents a forecasting procedure for C&DW in China that can forecast the quantity of each component in such waste. The proposed approach is based on a GM SVR model that improves the forecasting effectiveness of the gray model (GM), which is achieved by adjusting the residual series by a support vector regression (SVR) method and a transition matrix that aims to estimate the discharge of each component in the C&DW. Through the proposed method, future C&DW volume are listed and analyzed containing their potential components and distribution in different provinces in China. Besides, model testing process provides mathematical evidence to validate the proposed model is an effective way to give future information of C&DW for policy makers. PMID- 27777034 TI - Impact of sodium lauryl sulfate in oral liquids on e-tongue measurements. AB - During development of oral liquid medicines taste assessment is often required to evaluate taste and taste masking. Electronic tongue analysis can provide taste assessment of medicinal products but should only be conducted with medicines that interact with the instrument without damaging the sensor membranes or interfering with their electrical output so that robust data is generated. To explore the impact of a substance deemed unsuitable for electronic tongue analysis the influence of the anionic surfactant sodium lauryl sulfate (SLS), on the performance of the electronic tongue was conducted using electronic tongues equipped with self-developed PVC based sensors. The results showed a significant impact of SLS on all applied sensor types and an alteration of the sensor's sensitivity. Nevertheless, concentration dependent sensor responses could still be obtained and the sensor performance was not impacted negatively. Assessment of unsuitable substances should therefore be evaluated prior to performing electronic tongue analysis so that their impact is understood fully. PMID- 27777035 TI - The phospholipase C (FgPLC1) is involved in regulation of development, pathogenicity, and stress responses in Fusarium graminearum. AB - Phospholipase C (PLC) is an important phospholipid hydrolase that plays critical roles in various biological processes in eukaryotic cells. To elucidate the functions of PLC in morphogenesis and pathogenesis in Fusarium graminearum, deletion mutants were constructed of all six FgPLC genes identified in this study. Deletion of FgPLC1, but not the other five FgPLC genes, affected hyphal growth and conidiation. The FgPLC1 deletion mutant (Deltaplc1) also was defective in conidium germination and germ tube growth. It was sterile in selfing crosses and had increased sensitivities to hyperosmotic and cell wall stresses. The Deltaplc1 mutant showed reduced DON production and virulence during infection in flowering wheat heads. Deletion of FgPLC1 decreased the phosphorylation levels of both Gpmk1 and Mgv1 MAP kinases. qRT-PCR analysis showed that several genes related to defective phenotypes were down-regulated in the Deltaplc1 mutant. Taken together, these results indicated that FgPLC1 is important for hyphal growth, plant infection, and sexual or asexual reproduction, and it may be functionally related to MAP kinases in F. graminearum. PMID- 27777036 TI - Heterologous expression of an active chitin synthase from Rhizopus oryzae. AB - Chitin synthases are highly important enzymes in nature, where they synthesize structural components in species belonging to different eukaryotic kingdoms, including kingdom Fungi. Unfortunately, their structure and the molecular mechanism of synthesis of their microfibrilar product remain largely unknown, probably because no fungal active chitin synthases have been isolated, possibly due to their extreme hydrophobicity. In this study we have turned to the heterologous expression of the transcript from a small chitin synthase of Rhizopus oryzae (RO3G_00942, Chs1) in Escherichia coli. The enzyme was active, but accumulated mostly in inclusion bodies. High concentrations of arginine or urea solubilized the enzyme, but their dilution led to its denaturation and precipitation. Nevertheless, use of urea permitted the purification of small amounts of the enzyme. The properties of Chs1 (Km, optimum temperature and pH, effect of GlcNAc) were abnormal, probably because it lacks the hydrophobic transmembrane regions characteristic of chitin synthases. The product of the enzyme showed that, contrasting with chitin made by membrane-bound Chs's and chitosomes, was only partially in the form of short microfibrils of low crystallinity. This approach may lead to future developments to obtain active chitin synthases that permit understanding their molecular mechanism of activity, and microfibril assembly. PMID- 27777037 TI - A model for the 77K excited state dynamics in Chlamydomonas reinhardtii in state 1 and state 2. AB - The regulatory mechanism of state transitions was studied in Chlamydomonas reinhardtii (C.r.) wild type (WT) as well as mutant strains deficient in the photosystem I (PSI) or the photosystem II (PSII) core. Time-resolved fluorescence measurements were obtained on instantly frozen cells incubated beforehand in the dark in aerobic or anaerobic conditions which leads to state 1 (S1) or state 2 (S2). WT data contains information on the light-harvesting complex (LHC) connected to PSI and PSII. The mutants' data contain information on either LHCII LHCI-PSI or LHCII-PSII, plus information on LHC antennas devoid of a PS core. In a simultaneous analysis of the data from all strains under S1 or S2 conditions a unified model for the excited state dynamics at 77K was created. This yielded the completely resolved LHCII-LHCI-PSI and LHCII-PSII dynamics and quantified the state transitions. In WT cells the fraction of light absorbed by LHCII connected to PSII decreases from 45% in S1 to 29% in S2, while it increases from 0% to 16% for LHCII connected to PSI. Thus (16/45=) 36% of all LHCII is involved in the state transition. In the mutant strains deficient in the PSI core, the red most species peaking at 716nm disappears completely, indicating that this far red Chl pigment is located in the PSI core. In the mutant strain deficient in the PSII core, red shifted species with maxima at 684 and 686nm appear in the LHCII antenna. LHCII-684 is quenched and decays with a rate of (310ps)-1. PMID- 27777038 TI - Acute effects on cognitive performance following bouts of standing and light intensity physical activity in a simulated workplace environment. AB - OBJECTIVES: To compare acute cognitive effects following bouts of standing (STAND), cycling (CYCLE) and walking (WALK) to a sit-only (SIT) condition. DESIGN: Randomized cross-over full-factorial study. METHODS: Nine overweight (BMI=29+/-3kg/m2) adults (30+/-15years; 7 females, 2 males) completed four conditions (SIT, STAND, WALK and CYCLE) across a 6h period with a 7days washout period between conditions. SIT consisted of uninterrupted sitting. Experimental conditions included intermittent bouts of standing (STAND), cycling (CYCLE) and walking (WALK). A cognitive performance battery (Cogstate) was completed twice in a seated position following bouts of standing and light-intensity physical activity. Mixed-effects models compared between-condition differences in standardized score (z-score), accuracy (%), and speed (log10ms). RESULTS: Cognitive performance z-score and accuracy measures were higher during STAND, CYCLE and WALK (P<0.05) conditions compared to the SIT condition. CYCLE was better than other experimental conditions. CONCLUSIONS: Compared to uninterrupted sitting, short bouts of standing or light-intensity cycling and walking may improve acute cognitive performance. PMID- 27777039 TI - Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes. AB - The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers. PMID- 27777040 TI - Uterine leiomyosarcoma metastatic to thyroid shown by 18F-FDG PET/CT imaging. AB - About one third of focal thyroid uptakes in a fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) study are malignant, the most frequent histological type being papillary carcinoma. Metastases to the thyroid account for approximately 7.5% of thyroid malignancies and come mainly from kidney, lung, head and neck, and breast cancers. We report the case of a 64 year-old woman presenting a fast growing thyroid nodule whose primitive or metastatic origin was not obvious, for which 18F-FDG PET/CT helped in the diagnostic process and in the later management of the patient. Histopathologic findings finally revealed a metastasis of uterine leiomyosarcoma. PMID- 27777041 TI - Cytomegalovirus as an oncomodulatory agent in the progression of glioma. AB - Glioblastoma multiforme (GBM) is the most aggressive neoplastic brain tumor in humans with a median survival of less than 2 years. It is therefore critical to understand the mechanism of glioma progression and to identify future targets for intervention. We investigate the mechanisms of cytomegalovirus as an oncomodulatory agent implicated in glioma progression, as well as immunosuppression. This review provides a comprehensive evaluation of recent investigative developments concerning the role of CMV in cellular processes during glioma growth. The manners in which CMV and its viral products interact with regulatory cellular signaling pathways in the host are of primary interest. Here, we examine some of the most significant oncomodulatory effects that CMV can confer in brain tumors, including the inhibition of apoptosis and promoting the growth of glioma stem cells, which are tightly linked to tumor survival and recurrence. PMID- 27777042 TI - The steroid hormone 20-hydroxyecdysone promotes switching from autophagy to apoptosis by increasing intracellular calcium levels. AB - Autophagy regulates cell survival (or cell death in several cases), whereas apoptosis regulates cell death. However, the relationship between autophagy and apoptosis and the regulative mechanism is unclear. We report that steroid hormone 20-hydroxyecdysone (20E) promotes switching from autophagy to apoptosis by increasing intracellular calcium levels in the midgut of the lepidopteran insect Helicoverpa armigera. Autophagy and apoptosis sequentially occurred during midgut programmed cell death under 20E regulation, in which lower concentrations of 20E induced microtubule-associated protein 1 light chain 3-phosphatidylethanolamine (LC3-II, also known as autophagy-related gene 8, ATG8) expression and autophagy. High concentrations of 20E induced cleavage of ATG5 to NtATG5 and pro-caspase-3 to active caspase-3, which led to a switch from autophagy to apoptosis. Blocking autophagy by knockdown of ATG5, ATG7, or ATG12, or with the autophagy inhibitor 3 methyladenine, inhibited 20E-induced autophagy and apoptosis. Blocking apoptosis by using the apoptosis inhibitor Ac-DEVD-CHO did not prevent 20E-induced autophagy, suggesting that apoptosis relies on autophagy. ATG5 knockdown resulted in abnormal pupation and delayed pupation time. High concentrations of 20E induced high levels of intracellular Ca2+, NtATG5, and active caspase-3, which mediated the switch from autophagy to apoptosis. Blocking 20E-mediated increase of cellular Ca2+ caused a decrease of NtATG5 and active caspase-3 and repressed the transformation from autophagy to apoptosis, thereby promoting cell survival. 20E induces an increase in the concentration of intracellular Ca2+, thereby switching autophagic cell survival to apoptotic cell death. PMID- 27777043 TI - Trends in Hospitalization and Mortality of Venous Thromboembolism in Hospitalized Patients With Colon Cancer and Their Outcomes: US Perspective. AB - INTRODUCTION: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients with colon cancer. We assessed nationwide population-based trends in rates of hospitalization and mortality from VTE among patients with colon cancer to determine its impact. METHODS: We queried the Nationwide Inpatient Sample (NIS) database entries from 2003 to 2011 to identify patients with colon cancer. Bivariate group comparisons between hospitalized patients with colon cancer with VTE to those without VTE were made. Multivariate logistic regression analysis was used to obtain adjusted odds ratios. The Cochrane-Armitage test for linear trend was used to assess occurrences of VTE and mortality rates among patients with colon cancer. RESULTS: The total number patients with colon cancer was 1,502,743, of which 41,394 (2.75%) had VTE. The median age of the study population was 69 years; 51.5% were women. After adjusting for potential confounders, compared with those without VTE, patients with colon cancer with VTE had significantly higher inpatient mortality (6.26% vs. 5.52%, OR 1.15, P < .001) and greater disability at discharge (OR 1.38, P < .001), but were not associated with longer length of stay (LOS) or cost of hospitalization. From 2003 to 2011, despite an increase in hospitalization rate with VTE in patients with colon cancer, their mortality steadily declined. CONCLUSION: VTE in hospitalized patients with colon cancer is associated with a significantly higher inpatient mortality and greater disability, but not with longer LOS or cost of hospitalization. Furthermore, even though there has been a trend toward more frequent hospitalizations in this patient population, their mortality continues to decline. PMID- 27777044 TI - Renin Angiotensin Aldosterone System Inhibitors in Hypertension: Is There Evidence for Benefit Independent of Blood Pressure Reduction? AB - The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the pathogenesis of hypertension (HTN). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are first line anti-HTN drug classes that are potent, effective and largely safe. Direct renin inhibitors (DRIs) have shown similar blood pressure (BP) reduction but more side effects. The efficacy of ACEIs and ARBs (for cardiovascular, cerebrovascular and renal protection) has been promoted to extend beyond what could be explained by BP reduction alone. In the current review, we will briefly discuss the (1) pathophysiology of renin-angiotensin-aldosterone system (RAAS) system, (2) clinical evidence for ACEIs, ARBs and DRIs in HTN, (3) comparison of ACEIs vs. ARBs and combination therapy, (4) role of RAAS inhibitors in specific patient populations, (5) safety profile of RAAS inhibitors, and (6) guideline recommendations and future perspectives. Closer scrutiny of outcome data shows little, if any, evidence that the efficacy of RAAS blockers in HTN extends beyond BP reduction. PMID- 27777045 TI - Playful activity post-learning improves training performance in Labrador Retriever dogs (Canis lupus familiaris). AB - Situations that are emotional and arousing have an effect on cognitive performance. It is thought that beta adrenergic activation and the release of stress hormones enhance memory consolidation and lead to an increase in memorability of emotional events. This beneficial effect has been shown in humans, non-human primates and rodents. Techniques which could enhance memory for learning specific tasks would be highly valuable, especially in dogs, which are extensively trained to aid humans. A pseudo-randomized, counterbalanced, between subject study designs was utilised and 16 Labrador Retrievers ranging from 1 to 9years of age were trained in a 2-choice discrimination paradigm. After task acquisition, either a playful activity intervention (N=8) or a resting period (N=8) took place, lasting for 30min. A range of factors including age, sex, training experience and trials to criterion on each day was subjected to a multiple factor/covariate General Linear Model analysis. The results show that playful activity post-learning improved training performance evidenced by fewer trials needed to re-learn the task 24h after initial acquisition (playful activity group: mean number of trials 26, SD 6; resting group: mean number of trials 43, SD 19, effect size 1.2). Average heart rate, as a measure of arousal, during the intervention was significantly higher in the playful activity group (143beats/min, SD 16) versus the resting group (86beats/min, SD 19, P<0.001). Salivary cortisol did not significantly differ between groups during training, however a significant decrease (T: -4.1 P<0.01) was seen after the playful activity. To our knowledge this is the first evidence that posttraining activity may influence training performance in dogs. PMID- 27777047 TI - Acute ACTH-induced elevations of circulating cortisol do not affect hair cortisol concentrations in calves. AB - In recent times, the detection of cortisol in hair is intended to be used as an animal-based indicator for the assessment of chronic stress. However, the relationship between the ability to report average values of long-term circulating cortisol concentrations and the sensitivity to acute peaks of cortisol is still unclear. To gain insight into this relationship, 24 Holstein Friesian bull calves under the same management conditions were used in this study. Two injections of ACTH (at D0 and D7) were administrated to twelve animals with the aim to create two acute increases of serum cortisol concentrations. Blood samples were taken in order to determine the duration of serum cortisol peaks and to confirm a mediated response by the administration of ACTH. Cortisol concentrations from 14-day-old white hair samples collected from forehead and hip were analysed separately by EIA and compared with those from the control group. Serum cortisol analyses revealed an acute increase of cortisol concentrations for approximately three hours after each ACTH administration. Concentrations of hair cortisol from forehead and hip locations showed no differences between ACTH administrated and control animals. Hair cortisol concentrations from 14-day old samples were not altered by two acute elevations of serum cortisol suggesting that hair cortisol is not masked by short and non-recurrent moments of stress. These results are a step forward in the validation of hair cortisol detection as a robust integrative measure of serum cortisol concentrations from an extended period of time. PMID- 27777046 TI - CRH peptide evolution occurred in three phases: Evidence from characterizing sea lamprey CRH system members. AB - The corticotropin releasing hormone (CRH) system, which includes the CRH family of peptides, their receptors (CRHRs) and a binding protein (CRHBP), has been strongly conserved throughout vertebrate evolution. The identification of invertebrate homologues suggests this system evolved over 500 million years ago. However, the early vertebrate evolution of the CRH system is not understood. Current theory indicates that agnathans (hagfishes and lampreys) are monophyletic with a conservative evolution over the past 500million years and occupy a position at the root of vertebrate phylogeny. We isolated the cDNAs for three CRH family members, two CRHRs and a CRHBP from the sea lamprey, Petromyzon marinus. Two of the CRH peptides are related to the CRH/urotensin-1 (UI) lineage, whereas the other is a urocortin (Ucn) 3 orthologue. The predicted amino acid identity of CRH and UI is 61% but they possess distinct motifs indicative of each peptide, suggesting an early divergence of the two genes. Based on our findings we propose the CRH peptides evolved in at least 3 distinct phases. The first occurring prior to the agnathans gave rise to the CRH/UI-like and Ucn2/3-like paralogous lineages. The second was a partial sub-genomic duplication of the ancestral CRH/UI-like gene, but not the Ucn2/3-like gene, giving rise to the CRH and UI (Ucn) lineages. The third event which resulted in the appearance of Ucn2 and Ucn3 must have occurred after the evolution of the cartilaginous fishes. Interestingly, unlike other vertebrate CRHRs, we were unable to classify our two P. marinus receptors (designated CRHRalpha and CRHRbeta) as either type 1 or type 2, indicating that this split evolved later in vertebrate evolution. A single CRHBP gene was found suggesting that either this gene has not been affected by the vertebrate genome duplications or there have been a series of paralogous gene deletions. This study suggests that P. marinus possess a functional CRH system that differs from that of the gnathostomes and may represent a model for the earliest functioning CRH system in vertebrates. PMID- 27777048 TI - Analysis of a growth model inspired by Gompertz and Korf laws, and an analogous birth-death process. AB - We propose a new deterministic growth model which captures certain features of both the Gompertz and Korf laws. We investigate its main properties, with special attention to the correction factor, the relative growth rate, the inflection point, the maximum specific growth rate, the lag time and the threshold crossing problem. Some data analytic examples and their performance are also considered. Furthermore, we study a stochastic counterpart of the proposed model, that is a linear time-inhomogeneous birth-death process whose mean behaves as the deterministic one. We obtain the transition probabilities, the moments and the population ultimate extinction probability for this process. We finally treat the special case of a simple birth process, which better mimics the proposed growth model. PMID- 27777049 TI - Molecular changes in appearance of a cancer cell among normal HEK293T cells. AB - In very early stages of cancer development, one or a few cells expressing cancer associated genes appear among a much larger number of surrounding normal cells. To analyze the molecular changes induced by this co-existence, we artificially prepared transformed cells with complete loss of tumor suppressor gene, SCRIB, among normal human embryonic kidney (HEK293T) cells. A cell strain with SCRIB knockout was successfully constructed by using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease system and co-cultured with normal cells. By measuring the time-course changes in cell numbers when SCIRB knockout cells (cancer model) or cells with normal level of SCRIB expression were respectively co-cultured with wild-type normal HEK293T cells, it was shown that the SCRIB-knockout strain was beneficial for proliferation when mixed together with normal cells. Moreover, as a result of proteome analysis on wild-type cells separated from co-culture with SCRIB-knockout cells, a total of 843 proteins were identified, among which 139 proteins were specific. Among the specifically identified proteins, 22 proteins were annotated to be involved in cytoskeletons including microtubule motor activity-associated proteins. It was implied that molecular changes in cytoskeletons occurred in normal cells when co-cultured with SCRIB knockout cells, but the SCRIB knockout might affect proliferation of the transformed cells with SCRIB knockout by defensive or offensive mechanism of surrounding normal cells. PMID- 27777050 TI - Localisation of an occult thyrotropinoma with 11C-methionine PET-CT before and after somatostatin analogue therapy. PMID- 27777051 TI - Patient-reported outcomes after lumbar epidural steroid injection for degenerative spine disease in depressed versus non-depressed patients. AB - BACKGROUND CONTEXT: Medical interventional modalities such as lumbar epidural steroid injections (LESIs) are often used in the setting of lumbar spine disorders where other conservative measures have failed. Concomitant depression can lead to worse outcomes in lumbar spine pathology. A number of studies have demonstrated an association between preoperative depression and poor outcomes following surgery, but the effect of depression on outcomes following medical interventional modalities is poorly understood. PURPOSE: To evaluate the differences in patient-reported outcomes (PROs) between depressed and non depressed patients undergoing LESI. STUDY DESIGN/SETTING: This study is an analysis of a prospective longitudinal registry database at a single academic institution. PATIENT SAMPLE: All patients undergoing LESI from 2012 to 2014 were eligible for enrollment into a prospective, web-based registry. Eligible patients had radicular pain, correlative imaging findings of degenerative pathology, and failed 6 weeks of conservative care. OUTCOME MEASURES: The PROs measured included the (1) numeric rating scale for back pain (NRS-BP), (2) numeric rating scale for leg pain (NRS-LP), (3) disease-specific physical disability-Oswestry Disability Index (ODI), and (4) preference-based health status-EuroQol-5D (EQ-5D). MATERIALS AND METHODS: Patients who met the inclusion criteria underwent LESI. Patient reported outcomes were collected at baseline and at 12 months following treatment. Based on previously validated values for the Zung Depression Scale (ZDS) as a screening tool for depression, patients were dichotomized into non depressed (ZDS score <=33) and depressed (ZDS score >33). The PRO change scores from baseline to 12 months were calculated. The mean absolute and change scores between the groups were compared using Student t test. Multivariable linear regression analysis for ODI, EQ-5D, NRS-LP, and NRS-BP was performed. RESULTS: A total of 161 patients with complete 12-month follow-up were included. Seventy-one patients (44%) were classified as depressed and 90 patients (56%) were classified as non-depressed. The mean baseline PRO scores were significantly worse in depressed patients compared with non-depressed patients: ODI (p<.001), NRS-BP (p=.013), NRS-LP (p<.001), and EQ-5D (p=.001). The mean absolute scores at 12 months were significantly lower in the depressed versus non-depressed patients: ODI (p<.001), NRS-BP (p=.001), NRS-LP (p=.05), and EQ-5D (p=.003). However, there was no difference in mean change scores observed at 12 months between the depressed and non-depressed cohorts: ODI (p=.42), NRS-BP (p=.31), NRS-LP (p=.25), EQ-5D (p=.14). Adjusting for pre-procedure variables, the higher ZDS score was associated with higher disability (ODI) at 12 months. CONCLUSIONS: Depression led to worse absolute scores for PROs and is associated with higher disability following LESI. However, patients with depressive symptoms can expect similar improvement in PROs at 12 months. PMID- 27777052 TI - Spinal intraoperative three-dimensional navigation: correlation between clinical and absolute engineering accuracy. AB - BACKGROUND CONTEXT: Spinal intraoperative computer-assisted navigation (CAN) may guide pedicle screw placement. Computer-assisted navigation techniques have been reported to reduce pedicle screw breach rates across all spinal levels. However, definitions of screw breach vary widely across studies, if reported at all. The absolute quantitative error of spinal navigation systems is theoretically a more precise and generalizable metric of navigation accuracy. It has also been computed variably and reported in less than a quarter of clinical studies of CAN guided pedicle screw accuracy. PURPOSE: This study aimed to characterize the correlation between clinical pedicle screw accuracy, based on postoperative imaging, and absolute quantitative navigation accuracy. DESIGN/SETTING: This is a retrospective review of a prospectively collected cohort. PATIENT SAMPLE: We recruited 30 patients undergoing first-time posterior cervical-thoracic-lumbar sacral instrumented fusion+/-decompression, guided by intraoperative three dimensional CAN. OUTCOME MEASURES: Clinical or radiographic screw accuracy (Heary and 2 mm classifications) and absolute quantitative navigation accuracy (translational and angular error in axial and sagittal planes). METHODS: We reviewed a prospectively collected series of 209 pedicle screws placed with CAN guidance. Each screw was graded clinically by multiple independent raters using the Heary and 2 mm classifications. Clinical grades were dichotomized per convention. The absolute accuracy of each screw was quantified by the translational and angular error in each of the axial and sagittal planes. RESULTS: Acceptable screw accuracy was achieved for significantly fewer screws based on 2 mm grade versus Heary grade (92.6% vs. 95.1%, p=.036), particularly in the lumbar spine. Inter-rater agreement was good for the Heary classification and moderate for the 2 mm grade, significantly greater among radiologists than surgeon raters. Mean absolute translational-angular accuracies were 1.75 mm-3.13 degrees and 1.20 mm-3.64 degrees in the axial and sagittal planes, respectively. There was no correlation between clinical and absolute navigation accuracy. CONCLUSIONS: Radiographic classifications of pedicle screw accuracy vary in sensitivity across spinal levels, as well as in inter-rater reliability. Correlation between clinical screw grade and absolute navigation accuracy is poor, as surgeons appear to compensate for navigation registration error. Future studies of navigation accuracy should report absolute translational and angular errors. Clinical screw grades based on postoperative imaging may be more reliable if performed in multiple by radiologist raters. PMID- 27777053 TI - Are pedicle screw perforation rates influenced by distance from the reference frame in multilevel registration using a computed tomography-based navigation system in the setting of scoliosis? AB - BACKGROUND CONTEXT: Pedicle screw fixation is commonly employed for the surgical correction of scoliosis but carries a risk of serious neurovascular or visceral structure events during screw insertion. To avoid these complications, we have been using a computed tomography (CT)-based navigation system during pedicle screw placement. As this could also prolong operation time, multilevel registration for pedicle screw insertion for posterior scoliosis surgery was developed to register three consecutive vertebrae in a single time with CT-based navigation. The reference frame was set either at the caudal end of three consecutive vertebrae or at one or two vertebrae inferior to the most caudal registered vertebra, and then pedicle screws were inserted into the three consecutive registered vertebrae and into the one or two adjacent vertebrae. OBJECTIVES: This study investigated the perforation rates of vertebrae at zero, one, two, three, or four or more levels above or below the vertebra at which the reference frame was set. STUDY DESIGN: This is a retrospective, single-center, single-surgeon study. PATIENT SAMPLE: One hundred sixty-one scoliosis patients who had undergone pedicle screw fixation were reviewed. OUTCOME MEASURES: Screw perforation rates were evaluated by postoperative CT. MATERIALS AND METHODS: We evaluated 161 scoliosis patients (34 boys and 127 girls; mean+/-standard deviation age: 14.6+/-2.8 years) who underwent pedicle screw fixation guided by a CT-based navigation system between March 2006 and December 2015. RESULTS: A total of 2,203 pedicle screws were inserted into T2-L5 using multilevel registration with CT-based navigation. The overall perforation rates for Grade 1, 2, or 3, Grade 2 or 3 (major perforations), and Grade 3 perforations (violations) were as follows: vertebrae at which the reference frame was set: 15.9%, 6.1%, and 2.5%; one vertebra above or below the reference frame vertebra: 16.5%, 4.0%, and 1.2%; two vertebrae above or below the reference frame vertebra: 20.7%, 8.7%, and 2.3%; three vertebrae above or below the reference frame vertebra: 23.8%, 7.9%, and 3.5%; and four vertebrae or more above/below the reference frame vertebra: 25.4%, 9.5%, and 4.1%, respectively. Fisher exact test was performed to detect significant differences among the above five groups. With regard to Grade 1, 2, or 3 perforations, the rates of screw perforation for three and four vertebrae or more above or below the reference frame vertebra were significantly larger than that for vertebrae at the reference frame (both p<.01). No significant differences were found for Grade 3 perforations (violations) among the groups. CONCLUSIONS: In multilevel registration of three consecutive vertebrae, the accuracy of screw insertion into vertebrae at which the reference frame was not set was not significantly inferior to that in vertebrae at which the reference frame was set with regard to major perforation rate. Including minor perforations, however, a distance of three vertebrae or more above or below the reference frame vertebra produced significantly more frequent perforations. PMID- 27777054 TI - Risk factors and correlation of secondary adjacent vertebral compression fracture in percutaneous kyphoplasty. AB - BACKGROUND: To analyze risk factors and correlation of secondary adjacent vertebral compression fracture in percutaneous kyphoplasty. MATERIALS AND METHODS: A total of 139 patients underwent PKP in our hospital for osteoporotic vertebral compression fracture between January 2013 and December 2014 and had completed follow-up data more than one year were selected randomly. Participants were divided into two groups in accordance with whether adjacent vertebral compression fracture occurred. The gender, age, body mass index, smoking history, bone mineral density, bone metabolic markers and affected vertebra number preoperative, balloon volume, cement volume, recovery rate of vertebral height, bone cement leakage intraoperative and anti-osteoporosis treatment postoperative, oswestry disability index and visual analog scale in the first three days after surgery were observed. RESULTS: There was a statistically significant difference (P < 0.05) in bone mineral density value, balloon volume, cement volume, recovery rate of vertebral height and bone cement leakage between two groups. CONCLUSION: Patients with a lower bone mineral density value preoperative, larger balloon volume, cement volume, recovery rate of vertebral height and bone cement leakage intraoperative have an increased risk of adjacent vertebral compression fracture after percutaneous kyphoplasty. PMID- 27777055 TI - Laboratory Evaluation of Vocal Fold Paralysis and Paresis. AB - OBJECTIVES: This study aimed to assess the value of comprehensive laboratory evaluation in patients with vocal fold paralysis or paresis. STUDY DESIGN: This is a retrospective chart review. METHODS: Records of 231 patients with vocal fold paralysis or paresis were reviewed to determine whether there is a significant increase in the number of abnormal test results compared with rates of abnormal results for these tests in the general population and whether testing resulted in clinically important diagnosis. Laboratory data were collected from charts from initial visits from 2010 to 2014 and compared with national data. RESULTS: When controlled for age and sex, white blood cell count was found to have a significantly higher rate of abnormal test results (P < 0.001) in patients with vocal fold paralysis or paresis than the general population. Although hemoglobin, thyroid-stimulating hormone, and thyroid antibody tests were more likely to be abnormal in our patient population, the trend was not statistically significant. Further, the prevalence of syphilis and myasthenia gravis was found to be higher in these subjects than their respective national prevalences, and the incidence of Lyme disease was found to be higher than the national prevalence of Lyme disease. Several patients were diagnosed with medically important conditions such as diabetes, thyroid dysfunction, syphilis, myasthenia gravis, and Lyme disease based on these tests. CONCLUSION: This study suggests that comprehensive testing of patients with vocal fold movement disorders results in diagnoses that would be missed without a comprehensive evaluation, some of which are important medically, although their causal relationship to vocal fold paralysis or paresis was not investigated or established. PMID- 27777056 TI - Validity and Reliability of the Filipino Reflux Symptom Index. AB - OBJECTIVES: This study aimed to establish validity and reliability of the Filipino Reflux Symptom Index (FRSI) and to test it among patients with laryngopharyngeal reflux (LPR) before and after 6 months' trial of rabeprazole. STUDY DESIGN: A case-control study was carried out. METHODS: There were 35 LPR patients and 30 controls who were twice-administered the FRSI and Filipino Voice Handicap Index (FVHI) for test-retest reliability, and videostroboscopy was performed to obtain baseline reflux finding scores (RFSs). Patients took rabeprazole 20 mg twice daily for 6 months. The FRSI and FVHI were readministered a third time, repeat videostroboscopy was performed, and repeat RFS was obtained. Reliability, validity, and internal consistency were computed. RESULTS: A total of 58 participants, 29 patients and controls each, aged 22-65 years completed the study. FVHI 2:1 and FRSI 2:1 significantly correlated with no significant differences between FRSI 2:1. FRSI had good item-total correlations indicating psychometrically sound items. There were significant differences between patients and controls for FRSI scores and mean scores. FRSI 3 scores were significantly lower than FRSI 1 scores, suggesting symptoms improved after treatment. There were no significant differences between RFS 2 and 1. Significant differences between FRSI 3 and 1, but not between FVHI 3 and 1, suggest the FRSI was more sensitive to changes in reflux after 6 months' intervention than the FVHI. CONCLUSIONS: The FRSI is a valid and reliable tool for assessing LPR symptoms and may be used for primary care screening among Filipinos. Initial response to a 2 week empirical proton pump inhibitor trial may support an impression of LPR; non response warrants specialist referral for further investigation. PMID- 27777057 TI - Perturbation Measurements on the Degree of Naturalness of Synthesized Vowels. AB - OBJECTIVE: To determine the impact of jitter and shimmer on the degree of naturalness perception of synthesized vowels produced by acoustical simulation with glottal pulses (GP) and with solid model of the vocal tract (SMVT). STUDY DESIGN: Prospective study. METHODS: Synthesized vowels were produced in three steps: 1. Eighty GP were developed (20 with jitter, 20 with shimmer, 20 with jitter+shimmer, 20 without perturbation); 2. A SMVT was produced based on magnetic resonance imaging (MRI) from a woman during phonation-/epsilon/ and using rapid prototyping technology; 3. Acoustic simulations were performed to obtain eighty synthesized vowels-/epsilon /. Two experiments were performed. First Experiment: three judges rated 120 vowels (20 humans+80 synthesized+20% repetition) as "human" or "synthesized". Second Experiment: twenty PowerPoint slide sequences were created. Each slide had 4 synthesized vowels produced with the four perturbation condition. Evaluators were asked to rate the vowels from the most natural to the most artificial. RESULTS: First Experiment: all the human vowels were classified as human; 27 out of eighty synthesized vowels were rated as human, 15 of those were produced with jitter+shimmer, 10 with jitter, 2 without perturbation and none with shimmer. Second Experiment: Vowels produced with jitter+shimmer were considered as the most natural. Vowels with shimmer and without perturbation were considered as the most artificial. CONCLUSIONS: The association of jitter and shimmer increased the degree of naturalness of synthesized vowels. Acoustic simulations performed with GP and using SMVT demonstrated a possible method to test the effect of the perturbation measurements on synthesized voices. PMID- 27777058 TI - Voice Habits and Behaviors: Voice Care Among Flamenco Singers. AB - PURPOSE: The purpose of this study is to analyze the vocal behavior of flamenco singers, as compared with classical music singers, to establish a differential vocal profile of voice habits and behaviors in flamenco music. METHOD: Bibliographic review was conducted, and the Singer's Vocal Habits Questionnaire, an experimental tool designed by the authors to gather data regarding hygiene behavior, drinking and smoking habits, type of practice, voice care, and symptomatology perceived in both the singing and the speaking voice, was administered. We interviewed 94 singers, divided into two groups: the flamenco experimental group (FEG, n = 48) and the classical control group (CCG, n = 46). Frequency analysis, a Likert scale, and discriminant and exploratory factor analysis were used to obtain a differential profile for each group. RESULTS: The FEG scored higher than the CCG in speaking voice symptomatology. The FEG scored significantly higher than the CCG in use of "inadequate vocal technique" when singing. Regarding voice habits, the FEG scored higher in "lack of practice and warm-up" and "environmental habits." A total of 92.6% of the subjects classified themselves correctly in each group. CONCLUSIONS: The Singer's Vocal Habits Questionnaire has proven effective in differentiating flamenco and classical singers. Flamenco singers are exposed to numerous vocal risk factors that make them more prone to vocal fatigue, mucosa dehydration, phonotrauma, and muscle stiffness than classical singers. Further research is needed in voice training in flamenco music, as a means to strengthen the voice and enable it to meet the requirements of this musical genre. PMID- 27777059 TI - Metabolic Mechanisms of Vocal Fatigue. AB - OBJECTIVE: This study aimed to identify potential metabolic mechanisms including (1) neuromuscular inefficiency, (2) cardiovascular recovery deficits, or (3) both, in individuals with complaints of vocal fatigue. STUDY DESIGN: Within- and between-subjects group design was used in this study. METHODS: Three groups of women participated in the study, including (1) individuals with complaints of vocal fatigue; (2) vocally healthy sedentary individuals; and (3) vocally healthy, cardiovascularly conditioned individuals. Group assignment was based on results from the Vocal Fatigue Index, laryngeal examination, and self-report regarding exercise regimens. Metabolic profiles were obtained using gas exchange measures monitored during vocal task performance (reading) at two different loudness levels, and during recovery from reading. RESULTS: Statistical analyses did not reveal reliable group differences in metabolic cost for or recovery from vocal tasks. However, descriptive review of oxygen uptake and recovery kinetics revealed patterns indicating reliance on differential energy resources for the vocal task in individuals with vocal fatigue compared with cardiovascularly trained, vocally healthy individuals in particular. Slow oxygen uptake kinetics at task onset was a characteristic of the vocal fatigue group, indicating a general reliance on anaerobic resources to meet the demands of the vocal task, pointing to possible neuromuscular inefficiency. Individuals with vocal fatigue also demonstrated an increase in oxygen consumption following vocal task compared with cardiovascularly trained individuals, suggesting possible cardiovascular recovery deficits. CONCLUSION: This study provides initial data relevant to possible metabolic mechanisms of vocal fatigue and the potential relevance of aerobic conditioning in individuals with such fatigue. PMID- 27777060 TI - Adverse Reaction to Hyaluronic Acid Injection Laryngoplasty: A Case Report. AB - INTRODUCTION: Injection laryngoplasty using hyaluronic acid is a safe procedure commonly performed on patients with glottic insufficiency. STUDY DESIGN: This is a descriptive study of a case of adverse reaction to hyaluronic acid in a patient who underwent injection laryngoplasty for the treatment of unilateral vocal cord paralysis. DISCUSSION: The patient was treated with antibiotics and corticosteroids and had a full recovery. The authors recommend close observation following injection laryngoplasty using hyaluronic acid and diligent investigation of persistent postoperative laryngopharyngeal symptoms. PMID- 27777061 TI - An exploratory clinical trial to evaluate the efficacy of an experimental dentifrice formulation in the relief of dentine hypersensitivity. AB - OBJECTIVES: This study aimed to investigate whether addition of an octadecene/maleic anhydride copolymer (O/MA) to a potassium nitrate (KNO3) dentifrice could facilitate delivery of potassium to dentine and enhance its efficacy in dentine hypersensitivity relief. METHODS: This was a randomised, examiner-blind, controlled, parallel group study in 139 healthy subjects with at >=2 sensitive teeth. Assessment of dentine hypersensitivity to tactile (Yeaple probe) and evaporative (air) stimuli (Schiff Sensitivity Scale, visual analogue scale [VAS]) was carried out at baseline and after 1, 2, 4 and 8 weeks twice daily treatment with an experimental 5% KNO3/3% O/MA dentifrice, a comparator 5% KNO3 dentifrice (active comparator), a 0% KNO3/3% O/MA dentifrice (placebo) and a regular fluoride dentifrice (negative control). This study was not powered to detect statistically significant differences between treatments. RESULTS: Across the treatment period an improvement in sensitivity to evaporative air stimulus was observed for all products and to a tactile stimulus for the potassium containing treatments, with the greatest reductions for the experimental dentifrice (5% KNO3/3% O/MA). Reductions in sensitivity observed for the potassium-containing dentifrices compared to the placebo and negative control dentifrices were statistically significantly for Schiff sensitivity score and tactile threshold at all time-points and for VAS at Weeks 4 and 8. Trends in the study data also favoured the experimental dentifrice, compared to the active comparator dentifrice, for all clinical measures. Study treatments were generally well tolerated. CONCLUSION: This study provides initial clinical evidence to suggest that addition of a polymer excipient may enhance the anti-sensitivity efficacy of potassium-containing dentifrices. CLINICAL SIGNIFICANCE: Daily use potassium-containing dentifrices are established as efficacious for the relief of dentine hypersensitivity. Inclusion of a polymer excipient in such formulations may facilitate delivery of potassium to the dentine surface and so enhance clinical efficacy. Further clinical studies are required to confirm this hypothesis. PMID- 27777062 TI - Effectiveness, efficiency and efficacy in the multidimensional treatment of schizophrenia: Rethinking project. AB - Schizophrenia is a clinically heterogeneous syndrome affecting multiple dimensions of patients' life. Therefore, its treatment might require a multidimensional approach that should take into account the efficacy (the ability of an intervention to get the desired result under ideal conditions), the effectiveness (the degree to which the intended effect is obtained under routine clinical practice conditions or settings) and the efficiency (value of the intervention as relative to its cost to the individual or society) of any therapeutic intervention. In a first step of the process, a group of 90 national experts from different areas of health-care and with a multidimensional and multidisciplinary perspective of the disease, defined the concepts of efficacy, effectiveness and efficiency of established therapeutic interventions within 7 key dimensions of the illness: symptomatology; comorbidity; relapse and adherence; insight and subjective experience; cognition; quality of life, autonomy and functional capacity; and social inclusion and associated factors. The main conclusions and recommendations of this stage of the work are presented herein. PMID- 27777063 TI - Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway. AB - Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3-100 nmol/L) in the presence of PA (0.5mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4 diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-l-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism. PMID- 27777065 TI - Reply. PMID- 27777064 TI - Carnosine ameliorates cognitive deficits in streptozotocin-induced diabetic rats: Possible involved mechanisms. AB - Diabetic patients are at increased risk to develop cognitive deficit and senile dementia. This study was planned to assess the benefits of chronic carnosine administration on prevention of learning and memory deterioration in streptozotocin (STZ)-diabetic rats and to explore some of the involved mechanisms. Rats were divided into 5 groups: i.e., control, carnosine100-treated control, diabetic, and carnosine-treated diabetics (50 and 100mg/kg). Carnosine was injected i.p. at doses of 50 or 100mg/kg for 7 weeks, started 1 week after induction of diabetes using streptozotocin. Treatment of diabetic rats with carnosine at a dose of 100mg/kg at the end of the study lowered serum glucose, improved spatial recognition memory in Y maze, improved retention and recall in elevated plus maze, and prevented reduction of step-through latency in passive avoidance task. Furthermore, carnosine at a dose of 100mg/kg reduced hippocampal acetylcholinesterase (AChE) activity, lowered lipid peroxidation, and improved superoxide dismutase (SOD) activity and non-enzymatic antioxidant defense element glutathione (GSH), but not activity of catalase. Meanwhile, hippocampal level of nuclear factor-kappaB (NF-kappaB), tumor necrosis factor alpha (TNF-alpha), and glial fibrillary acidic protein (GFAP) decreased and level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) increased upon treatment of diabetic group with carnosine at a dose of 100mg/kg. Taken together, chronic carnosine treatment could ameliorate learning and memory disturbances in STZ-diabetic rats through intonation of NF-kappaB/Nrf2/HO-1 signaling cascade, attenuation of astrogliosis, possible improvement of cholinergic function, and amelioration of oxidative stress and neuroinflammation. PMID- 27777066 TI - Psoralen loaded liposomal nanocarriers for improved skin penetration and efficacy of topical PUVA in psoriasis. AB - Psoralen in combination with ultraviolet A radiation (PUVA) is an FDA recommended therapy for clinical application in the management of severe recalcitrant psoriasis. Psoralen acts by intercalation of DNA and upon exposure to UV-A, it forms monoadducts which in turn induce apoptosis. Poor skin deposition, weak percutaneous permeability of psoralen and adverse effects of severe burning, blisters, pigmentation associated with conventional topical psoralen vehicles hinders the therapeutic efficacy and safety of topical PUVA. The aim of the present study is to formulate psoralen loaded liposomal nanocarriers for enhanced skin penetration, safety and efficacy of topical PUVA in psoriasis. Two different liposomal compositions i.e., cationic liposomes composed of DC-Chol, cholesterol and anionic liposomes composed of egg lecithin, cholesterol, tetramyristoyl cardiolipin were prepared for the topical delivery of psoralen. Liposomal carriers were characterized with respect to size, zeta potential, entrapment efficiency, stability, in vitro drug release and in vivo studies. Both liposomes were prepared with particle size of nearly 100nm. Zeta potential and entrapment efficiency of cationic liposomes were +25.8mV, 75.12% and anionic liposomes were 28.5mV, 60.08% respectively. Liposomal dermal distribution demonstrated higher penetration of both liposomal carriers over solution. Similarly, skin permeation study indicated 5 fold increase in permeation of psoralen with liposomal carriers. Topical application of psoralen liposomal gels on imiquimod induced psoriatic plaque model reduced the symptoms of psoriasis and levels of key psoriatic cytokines such as tumor necrosis factor-alpha, IL-17 and IL-22. In conclusion, the developed liposomal carriers of psoralen were found to be promising and can find application for optimal safety and efficacy of topical PUVA in psoriasis. PMID- 27777067 TI - Securinine disturbs redox homeostasis and elicits oxidative stress-mediated apoptosis via targeting thioredoxin reductase. AB - Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug. PMID- 27777069 TI - Insulin as a weapon. AB - The discovery of insulin and its use for the treatment of diabetes is undoubtedly one of the true successes of modern medicine. Injectable insulin would prove the first effective treatment for a previously incurable and usually fatal disease. Soon after however, the powerful effects of insulin overdose would be reported, and subsequently exploited for dubious medical and sometimes nefarious purposes. In this article we describe the discovery that certain venomous marine snails of the genus Conus also exploit the powerful effects of insulin overdose, employing it as a weapon for prey capture. PMID- 27777068 TI - Exploring the developmental mechanisms underlying Wolf-Hirschhorn Syndrome: Evidence for defects in neural crest cell migration. AB - Wolf-Hirschhorn Syndrome (WHS) is a neurodevelopmental disorder characterized by mental retardation, craniofacial malformation, and defects in skeletal and heart development. The syndrome is associated with irregularities on the short arm of chromosome 4, including deletions of varying sizes and microduplications. Many of these genotypic aberrations in humans have been correlated with the classic WHS phenotype, and animal models have provided a context for mapping these genetic irregularities to specific phenotypes; however, there remains a significant knowledge gap concerning the cell biological mechanisms underlying these phenotypes. This review summarizes literature that has made recent contributions to this topic, drawing from the vast body of knowledge detailing the genetic particularities of the disorder and the more limited pool of information on its cell biology. Finally, we propose a novel characterization for WHS as a pathophysiology owing in part to defects in neural crest cell motility and migration during development. PMID- 27777070 TI - Analysis of correlation between height of residual ridge and bone density of residual ridge crest at edentulous mandible using computed tomography. AB - PURPOSE: The aim of this study was to investigate the correlation between bone density of the edentulous mandibular ridge crest and residual bone height in edentulous subjects using multidetector computed tomography (MDCT) images. METHODS: A total of 194 bilateral MDCT images from 97 individuals with an edentulous mandible were selected for analysis. The residual ridge ratio (RRR), the CT values at the residual ridge crest, and the CT values at the lowest point of the mandible measured from MDCT images at molar region. RRR was classified into the three groups (Group 1: >2.0, Group 2: 1.5-2.0, Group 3: <1.5). Bone density at the residual ridge crest was evaluated by calculating the ratio of the CT value at the lowest point of the mandible and the CT value of the residual ridge crest ("ratio of CT values"). The relationship between the height of the residual ridge and the bone density of the residual ridge crest was evaluated by ratio of CT values. RESULTS: Median ratio of CT values was 0.62 in Group 1, 0.70 in Group 2, and 0.84 in Group 3, indicating significant differences between all 3 groups (p<0.05). The correlation coefficient for RRR and residual ridge crest bone density was -0.54 in males and -0.55 in females, implying a moderate correlation for both males and females. CONCLUSIONS: The present results suggest a negative correlation between residual bone height and the bone density of the edentulous mandibular ridge crest. PMID- 27777071 TI - Effect of phytic acid etchant on resin-dentin bonding: Monomer penetration and stability of dentin collagen. AB - PURPOSE: Phytic acid (IP6) works well as an etchant in dentin bonding to remove the smear layer due to its acidity and chelating effect. This study compared the etching effect of IP6 with phosphoric acid (PA) and ethylenediaminetetraacetic acid (EDTA) on resin-dentin bond strength, micromorphology of the etched dentin surface and nanoleakage formation along resin-dentin interfaces and compared the protecting effect against collagen degradation. METHODS: Dentin disks and flat dentin surfaces were obtained from extracted human teeth. Specimens were etched with 35% PA (15s), 0.5M EDTA (30s) or 1% IP6 (30s). The surfaces and longitudinal sections of the etched dentin disks were observed using field emission scanning electron microscope (FE-SEM). An etch-and-rinse adhesive was used to create composite build up-specimens for microtensile bond strength (MUTBS) testing and nanoleakage observation. To evaluate the effect on collagen degradation, demineralized bovine root dentin blocks were challenged with bacterial collagenase and then observed under light microscope. RESULTS: PA- and EDTA- treated groups showed significantly lower MUTBS when compared to IP6-treated group. PA showed distinct nanoleakage and severe collagen degradation. Only slight nanoleakage was detected in IP6 group. IP6 showed better effect than EDTA in preventing collagen degradation induced by bacterial collagenase. CONCLUSIONS: IP6 effectively removed the smear layer and etched dentin, providing high bond strength values and causing minimal nanoleakage and slight collagen degradation. PMID- 27777073 TI - mTORC2 activation is regulated by the urokinase receptor (uPAR) in bladder cancer. AB - Mammalian target of rapamycin complex 2 (mTORC2) has been identified as a major regulator of bladder cancer cell migration and invasion. Upstream pathways that mediate mTORC2 activation remain poorly defined. Urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored membrane protein and known activator of cell-signaling. We identified increased uPAR expression in 94% of invasive human bladder cancers and in 54-71% of non-invasive bladder cancers, depending on grade. Normal urothelium was uPAR-immunonegative. Analysis of publicly available datasets identified uPAR gene amplification or mRNA upregulation in a subset of bladder cancer patients with reduced overall survival. Using biochemical approaches, we showed that uPAR activates mTORC2 in bladder cancer cells. Highly invasive bladder cancer cell lines, including T24, J82 and UM-UC-3 cells, showed increased uPAR mRNA expression and protein levels compared with the less aggressive cell lines, UROtsa and RT4. uPAR gene-silencing significantly reduced phosphorylation of Serine-473 in Akt, an mTORC2 target. uPAR gene-silencing also reduced bladder cancer cell migration and Matrigel invasion. S473 phosphorylation was observed by immunohistochemistry in human bladder cancers only when the tumors expressed high levels of uPAR. S473 phosphorylation was not controlled by uPAR in bladder cancer cell lines that are PTEN-negative; however, this result probably did not reflect altered mTORC2 regulation. Instead, PTEN deficiency de repressed alternative kinases that phosphorylate S473. Our results suggest that uPAR and mTORC2 are components of a single cell-signaling pathway. Targeting uPAR or mTORC2 may be beneficial in patients with bladder cancer. PMID- 27777074 TI - Impact of a telephonic outreach program on medication adherence in Medicare Advantage Prescription Drug (MAPD) plan beneficiaries. AB - OBJECTIVES: To determine the impact of a telephone call reminder program provided by a campus-based medication therapy management call center on medication adherence in Medicare Advantage Part D (MAPD) beneficiaries with hypertension. METHODS: The reminder call services were offered to eligible MAPD beneficiaries, and they included a live interactive conversation with patients to assess the use of their medications. This study used a quasi-experimental design for comparing the change in medication adherence between the intervention and matched control groups. Adherence, defined by proportion of days covered (PDC), was measured using incurred medication claims 6 months before and after the adherence program was implemented. A difference-in-differences approach with propensity score matching was used. RESULTS: After propensity score matching, paired samples included 563 patients in each of the intervention and control groups. The mean PDC (standard deviation) increased significantly during postintervention period by 17.3% (33.6; P <0.001) and 13.8% (32.3; P <0.001) for the intervention and the control groups, respectively; the greater difference-in-differences increase of 3.5% (36.3) in the intervention group over the control group was statistically significant (P = 0.022). A generalized estimating equation model adjusting for covariates further confirmed that the reminder call group had a significant increase in pre-post PDC (P = 0.021), as compared with the control group. CONCLUSIONS: Antihypertensive medication adherence increased in both reminder call and control groups, but the increase was significantly higher in the intervention group. A telephonic outreach program was effective in improving antihypertensive medication adherence in MAPD beneficiaries. PMID- 27777072 TI - Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling. AB - Mutations in KIT or PDGFRA are responsible for >85% of gastrointestinal stromal tumors. The introduction of imatinib in the GIST therapy scheme revolutionized the patient outcome. Unfortunately, the therapy allows the disease stabilization instead of curation. Furthermore the resistance to the inhibitor arises in most cases within two first years of therapy. A thorough investigation of the signalling pathways activated by the major PDGFRA and KIT mutants encountered in the GIST landscape allowed to identify striking differences between the two receptor tyrosine kinases. PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a high constitutive kinase activity. In contrast, all KIT mutants retained, in addition to their constitutive activation, the ability to be stimulated by their ligand. Kit mutants displayed a lower intrinsic kinase activity relative to PDGFRA mutants, while the KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity among KIT mutants. At the transcriptomic level, the MAPK pathway was established as the most prominent activated pathway, which is commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway, using the MEK inhibitor PD0325901, reduced the proliferation of GIST primary cells at nanomolar concentrations. Altogether, our data demonstrate the high value of MEK inhibitors for combination therapy in GIST treatment and more importantly the interest of evaluating the SCF expression profile in GIST patients presenting KIT mutations. PMID- 27777075 TI - Influences on the frequency and type of community pharmacy services. AB - OBJECTIVES: To describe services provided by community pharmacies and to identify factors associated with services being provided in community pharmacies. DESIGN: Cross-sectional national mail survey. SETTING AND PARTICIPANTS: Pharmacists actively practicing in community pharmacies (independent, chain, mass merchandisers, and supermarkets). OUTCOME MEASURES: Frequency and type of pharmacy services available in a community pharmacy, including medication therapy management, immunization, adjusting medication therapy, medication reconciliation, disease state management, health screening or coaching, complex nonsterile compounding, and point-of-care testing. RESULTS: With a 48.4% response rate, the survey showed that community pharmacies offered on average 3 of the 8 services studied. Pharmacy chains and supermarket pharmacies reported providing significantly more services than did mass merchandise pharmacies. The number of pharmacy services provided was positively associated with involvement in an interprofessional care team, innovativeness, and perceived workload. The number of pharmacy services was negatively correlated with having 3.5 or more pharmacy technicians on duty. CONCLUSION: Pharmacy chains and supermarkets are providing the most pharmacy services among community pharmacy settings. The number of services provided was associated with innovativeness, technician staffing, and perceived workload. Also, involvement with an interprofessional care team supported greater service delivery. Community pharmacies vary in their provision of services beyond dispensing. PMID- 27777076 TI - Addressing low health literacy with "Talking Pill Bottles": A pilot study in a community pharmacy setting. AB - OBJECTIVES: To test the effect of "Talking Pill Bottles" on medication self efficacy, knowledge, adherence, and blood pressure readings among hypertensive patients with low health literacy and to assess patients' acceptance of this innovation. DESIGN: Longitudinal nonblinded randomized trial with standard treatment and intervention arms. SETTING AND PARTICIPANTS: Two community pharmacies serving an ethnically diverse population in the Pacific Northwest. Participants were consented patients with antihypertension prescriptions who screened positive for low health literacy based on the Test of Functional Health Literacy Short Form. Participants in the intervention arm received antihypertensive medications and recordings of pharmacists' counseling in Talking Pill Bottles at baseline. Control arm participants received antihypertensive medications and usual care instructions. MAIN OUTCOME MEASURES: Comparison and score changes between baseline and day 90 for medication knowledge test, Self Efficacy for Appropriate Medication Use Scale (SEAMS), Morisky Medication Adherence Scale (MMAS-8), blood pressure, and responses to semistructured exit interviews and Technology Acceptance Model surveys. RESULTS: Of 871 patients screened for health literacy, 134 eligible participants were enrolled in the trial. The sample was elderly, ethnically diverse, of low income, and experienced regarding hypertension and medication history. In both arms, we found high baseline scores in medication knowledge test, SEAMS, and MMAS-8 and minimal changes in these measures over the 90-day study period. Blood pressure decreased significantly in the intervention arm. Acceptability scores for the Talking Pill Bottle technology were high. CONCLUSION: Our results suggest that providing audio assisted medication instructions in Talking Pill Bottles positively affected blood pressure control and was well accepted by patients with low health literacy. Further research involving newly diagnosed patients is needed to mitigate possible ceiling effects that we observed in an experienced population. PMID- 27777077 TI - ISG12a inhibits HCV replication and potentiates the anti-HCV activity of IFN alpha through activation of the Jak/STAT signaling pathway independent of autophagy and apoptosis. AB - Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) signaling pathways in host innate immunity. ISG12a can be induced by IFN-alpha. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway, apoptosis and autophagy in Huh7.5.1 cells transiently transfected with ISG12a over-expression plasmid. Interestingly, we found that ISG12a inhibited HCV replication in both Con1b replicon and the HCV JFH1-based cell culture system and potentiated the anti-HCV activity of IFN-alpha. ISG12a promoted the production of IFN alpha/beta and activated the type I IFN signaling pathway as shown by increased p-STAT1 level, higher Interferon sensitive response element (ISRE) activity and up-regulated ISG levels. However, ISG12a over-expression did not affect cell autophagy and apoptosis. Data from our current study collectively indicated that ISG12a inhibited HCV replication and potentiated the anti-HCV activity of IFN-alpha possibly through induced production of type I IFNs and activation of Jak/STAT signaling pathway independent of autophagy and cell apoptosis. PMID- 27777079 TI - Chitosan nanoparticles enhances the anti-quorum sensing activity of kaempferol. AB - Quorum sensing (QS) is a cell density dependent expression of species in bacteria mediated by compounds called autoinducers (AI). Several processes responsible for successful establishment of bacterial infection are mediated by QS. Inhibition of QS is therefore being considered as a new target for antimicrobial chemotherapy. Flavonoid compounds are strong antioxidant and antimicrobial agents but their applications are limited due to their poor dissolution and bioavailability. Our objective was to investigate the effect of kaempferol loaded chitosan nanoparticles on modulating QS mediated by AI in model bioassay test systems. For this purpose, kaempferol loaded nanoparticles were synthesized and characterized in terms of hydrodynamic diameter, hydrogen bonding, amorphous transformation and antioxidant activity. QS inhibition in time dependent manner of nanoparticles was measured in violacein pigment producing using the biosensor strain Chromobacterium violaceum CV026 mediated by AI known as acylated homoserine lactone (AHL). Our results indicated that the average kaempferol loaded chitosan/TPP nanoparticle size and zeta potential were 192.27+/-13.6nm and +35mV, respectively. The loading and encapsulation efficiency of kaempferol into chitosan/TPP nanoparticles presented higher values between 78 and 93%. Kaempferol loaded chitosan/TPP nanoparticle during the 30 storage days significantly inhibited the production of violacein pigment in Chromobacterium violaceum CV026. The observation that kaempferol encapsulated chitosan nanoparticles can inhibit QS related processes opens up an exciting new strategy for antimicrobial chemotherapy as stable QS-based anti-biofilm agents. PMID- 27777078 TI - Field-based evaluation of a male-specific (F+) RNA coliphage concentration method. AB - Fecal contamination of water poses a significant risk to public health due to the potential presence of pathogens, including enteric viruses. Therefore, sensitive, reliable and easy to use methods for the concentration, detection and quantification of microorganisms associated with the safety and quality of water are needed. In this study, we performed a field evaluation of an anion exchange resin-based method to concentrate male-specific (F+) RNA coliphages (FRNA), fecal indicator organisms, from diverse environmental waters that were suspected to be contaminated with feces. In this system, FRNA coliphages are adsorbed to anion exchange resin and direct nucleic acid isolation is performed, yielding a sample amenable to real-time reverse transcriptase (RT)-PCR detection. Matrix-dependent inhibition of this method was evaluated using known quantities of spiked FRNA coliphages belonging to four genogroups (GI, GII, GII and GIV). RT-PCR-based detection was successful in 97%, 72%, 85% and 98% of the samples spiked (106 pfu/l) with GI, GII, GIII and GIV, respectively. Differential FRNA coliphage genogroup detection was linked to inhibitors that altered RT-PCR assay efficiency. No association between inhibition and the physicochemical properties of the water samples was apparent. Additionally, the anion exchange resin method facilitated detection of naturally present FRNA coliphages in 40 of 65 environmental water samples (61.5%), demonstrating the viability of this system to concentrate FRNA coliphages from water. PMID- 27777080 TI - Fabrication and characterization of PVA/Gum tragacanth/PCL hybrid nanofibrous scaffolds for skin substitutes. AB - In this work three dimensional biodegradable nanofiberous scaffolds containing poly(epsilon-caprolactone) (PCL), poly(vinyl alcohol) (PVA) and gum tragacanth (GT) were successfully fabricated through two nozzles electrospinning process. For this purpose, PVA/GT blend (Blend: B) solution (60:40wt%) was injected from one syringe and poly(epsilon-caprolactone) solution from the other one. Presence of PVA and PCL in the formulation improved the electrospinning process of GT solution and mechanical properties of the fabricated nanofibers. Scanning electron microscopy (SEM) results showed uniform PVA/GT-PCL blend-hybrid (Blend Hybrid: B-H) nanofibers with the diameter ranging about 132+/-27nm. Hybrid nanofibers were evaluated by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) tests. The antibacterial activities of the PVA/GT-PCL (B-H) nanofibers were conducted against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus and results indicated that the hybrid nanofibers were 95.19% antibacterial against S. aureus bacterium. NIH 3T3 fibroblast cells growth and MTT assay were carried out on the scaffolds. Hydrophilicity nature, favorable mechanical properties of the fabricated hybrid nanofibers, along with their structure in biological media, biocompatibility, as well as antibacterial property indicate scaffolds prepared are suitable for tissue engineering. PMID- 27777081 TI - Novel biocomposite of carboxymethyl chitosan and pineapple peel carboxymethylcellulose as sunscreen carrier. AB - This study aims to prepare of biocomposite of carboxymethyl chitosan (CM chitosan) and carboxymethylcellulose (CMC) from Ananas comosus (pineapple) peel for use as broad spectrum sunscreen carrier. Biocomposite was produced by using ferulic acid (FA), a plant extract, as crosslinker with the optimal ratio of CMC: CM-chitosan: FA at 1:2:4%w. FT-IR technique demonstrated that crosslinking may occur at amine group of CM-chitosan and carboxyl group of FA and hydrogen bonding between hydroxyl group of CMC and carboxyl group of FA. Biocomposite is pale yellow powder and present fibre bundle-like surface in the SEM image. DSC, TGA and XRD results indicated that new compound was formed. The particle size of biocomposite is 626nm determined by using Zetasizer. Hydrophilic TiO2 and phenylbenzimidazole sulphonic acid (PBSA) were used as sunscreen agent at ratio of TiO2: PBSA at 2:1%w. The biocomposite sunscreen possesses the SPF value of 2.47 with boost star rating of 3 at 2% compound. The results obtained indicate that the biocomposite was successfully prepared from CM-chitosan and pineapple peel CMC and the system can be used as matrix delivery system for hydrophilic sunscreens. PMID- 27777082 TI - Some aspects of space-charge effect calculation in high-resolution mass spectrometry. AB - A variational 3D approach to the problem of simulating stationary distributions of ions in the radiofrequency low-vacuum ion traps with regard to Coulomb interaction and collisions of ions with buffer gas molecules is proposed. The software developed in the course of this work is employed to study the structure of stationary ion ensembles in the radiofrequency ion traps of various types. The effect of high-frequency and constant voltages, space-charge density, and buffer gas temperature on the formation of stationary distributions in the radiofrequency ion traps and their limiting capacitance is investigated. It is shown that the use of electrodes with a constant voltage in the presence of high enough ion density allows pre-filtering of ions directly in a high-frequency trap accumulator. PMID- 27777084 TI - Crosstalk between the gut and the liver via susceptibility loci: Novel advances in inflammatory bowel disease and autoimmune liver disease. AB - Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-alpha, GPR35, MST1R, CARD9, IL2/IL21/IL2R, BACH2, TNFRSF14, MAdCAM-1, and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or Treg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review. PMID- 27777085 TI - Suitability of cholinesterase of polychaete Diopatra neapolitana as biomarker of exposure to pesticides: In vitro characterization. AB - Cholinesterases of Diopatra neapolitana were characterized for their activity in whole body and different body segments (apical, intermediate, posterior), substrate affinity (acetyl-, butyryl-, propionylthiocholine), kinetic parameters (Km and Vmax) and in vitro response to model inhibitors (eserine hemisulfate, isoOMPA, BW284C51) and carbamates (carbofuran, methomyl, aldicarb and carbaryl). Results showed that the rate of hydrolysis for acetyl- and propionylthiocholine was higher in the posterior segment than the apical/intermediate segments and whole body. Cholinesterases of D. neapolitana showed a substrate preference for acetylthiocholine followed by propionylthiocholine; butyrylthioline was poorly hydrolyzed indicating, together with the absence of inhibition by the specific inhibitor and the absence of reactive bands in native electrophoresis, a lack of an active butyrylcholinesterase, differently than that observed in other Annelida species. The degree of inhibition by selected carbamates of cholinesterase activity with propionylthiocholine as substrate was higher than that observed with ATChI-ChE activity; aldicarb showed the highest inhibitory effect. PMID- 27777083 TI - Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy. AB - Various preclinical studies have demonstrated that the success of immunotherapeutic strategies in inhibiting tumor progression in animal models of Glioblastoma multiforme (GBM). It is also evident that tumor-induced immune suppression drastically impacts the efficacy of immune based therapies. Among the mechanisms employed by GBM to induce immunosuppression is the accumulation of regulatory T cells (Tregs) and Myeloid derived suppressor cells (MDSCs). Advancing our understanding about the pathways regulating the expansion, accumulation and activity of MDSCs will allow for the development of therapies aimed at abolishing the inhibitory effect of these cells on immunotherapeutic approaches. In this review, we have focused on the origin, expansion and immunosuppressive mechanisms of MDSCs in animal models and human cancer, in particular GBM. PMID- 27777086 TI - Interdomain interactions rearrangements control the reaction steps of a thermostable DNA alkyltransferase. AB - BACKGROUND: Alkylated DNA-protein alkyltransferases (AGTs) are conserved proteins that repair alkylation damage in DNA by using a single-step mechanism leading to irreversible alkylation of the catalytic cysteine in the active site. Trans alkylation induces inactivation and destabilization of the protein, both in vitro and in vivo, likely triggering conformational changes. A complete picture of structural rearrangements occurring during the reaction cycle is missing, despite considerable interest raised by the peculiarity of AGT reaction, and the contribution of a functional AGT in limiting the efficacy of chemotherapy with alkylating drugs. METHODS: As a model for AGTs we have used a thermostable ortholog from the archaeon Sulfolobus solfataricus (SsOGT), performing biochemical, structural, molecular dynamics and in silico analysis of ligand free, DNA-bound and mutated versions of the protein. RESULTS: Conformational changes occurring during lesion recognition and after the reaction, allowed us to identify a novel interaction network contributing to SsOGT stability, which is perturbed when a bulky adduct between the catalytic cysteine and the alkyl group is formed, a mandatory step toward the permanent protein alkylation. CONCLUSIONS: Our data highlighted conformational changes and perturbation of intramolecular interaction occurring during lesion recognition and catalysis, confirming our previous hypothesis that coordination between the N- and C-terminal domains of SsOGT is important for protein activity and stability. GENERAL SIGNIFICANCE: A general model of structural rearrangements occurring during the reaction cycle of AGTs is proposed. If confirmed, this model might be a starting point to design strategies to modulate AGT activity in therapeutic settings. PMID- 27777087 TI - Small femoral offset is a risk factor for lateral femoral cutaneous nerve injury during total hip arthroplasty using a direct anterior approach. AB - INTRODUCTION: Lateral femoral cutaneous nerve (LFCN) injury is a risk specific to the direct anterior approach (DAA) for total hip arthroplasty (THA). However, prevention strategies have not been established. This study aimed to identify the predisposing factors determining LFCN injury during THA via a DAA. HYPOTHESIS: Patients with LFCN injury after THA via DAA would demonstrate predisposing factors. MATERIAL AND METHODS: LFCN injury was identified using a patient questionnaire. Potential factors predisposing to LFCN injury were identified in four categories in patient records: patient factors (age, sex, BMI, diagnosis and range of hip motion), surgical factors (surgical time and surgeon's experience of the DAA), preoperative radiographic factors (neck-shaft angle, femoral offset, acetabular offset, total offset and length of muscle on computed tomography axial image) and radiographic changes (differences between each offset pre- and post surgery). Multivariate analysis was performed to identify risk factors for LFCN injury during this surgery. RESULTS: After application of inclusion and exclusion criteria, 102 hips (28 with LFCN injury; 74 without) in 102 patients (17 males, 85 females; mean age 66.0 years [range, 26-88 years]) were included. Univariate analysis of patients with and without LFCN injury revealed that small preoperative femoral offset and short preoperative long axis of the tensor fascia lata were statistically significant risk factors for LFCN injury (P=0.004, and P=0.01, respectively). Multivariate analysis showed that small preoperative femoral offset was the only independent risk factor for LFCN injury (odds ratio, 0.895; 95% Confidence Interval, 0.817-0.981; P=0.0018). DISCUSSION: Smaller femoral offset was a significant risk factor for LFCN injury following THA via a DAA. Our recommendations are that careful attention should be paid to the skin fascia incision and subcutaneous exposure, and that excessive retraction of the sartorius muscle and tensor fascia lata should be avoided, to reduce the risk of LFCN injury in patients with a small femoral offset. LEVEL OF EVIDENCE: IV, retrospective historical cohort study. PMID- 27777088 TI - IL-15 receptor alpha as the magic wand to boost the success of IL-15 antitumor therapies: The upswing of IL-15 transpresentation. AB - Interleukin (IL)-15 as a stand-alone therapy can activate the antitumor functions of immune effector cells resulting in significant tumor regression. Interestingly, combining IL-15 with the alpha-moiety of its receptor (IL 15Ralpha), also called IL-15 transpresentation, increases the in vivo half-life of IL-15 and enhances binding of IL-15 with cells expressing the IL-15Rbetagamma, such as NK cells and CD8+ T cells. These features enlarge the signal transmission of IL-15, resulting in improved proliferation and antitumor activities of both NK cells and CD8+ T cells, eventually leading to enhanced killing of tumor cells. In this review, we discuss the antitumor strategies in which this IL-15 transpresentation mechanism is implemented, that are currently under preclinical investigation. Furthermore, we give an overview of the studies in which the IL 15/IL-15Ralpha complexes are combined with other antitumor therapies. The promising results in these preclinical studies have incited several clinical trials to test the safety and efficacy of IL-15 transpresentation strategies to treat both hematological and advanced solid tumors. PMID- 27777089 TI - Prevalence of human immune deficiency virus in immigrants crossing to Europe from North and Sub-Saharan Africa. PMID- 27777090 TI - How low an effect of a preventive measure against diarrhoea are travellers willing to pay for?: A survey of Norwegian travellers. AB - BACKGROUND: Traveller's diarrhoea (TD) is the most common infectious problem for travellers, and we lack effective ways of preventing it, apart from antibiotic prophylaxis. This study aims to quantify the risk reduction of a hypothetic TD vaccine Norwegian travellers are willing to pay for. METHODS: 1204 clients at Reiseklinikken responded to a questionnaire asking what level of effectiveness would be required of a hypothetical vaccine against TD costing US$65. RESULTS: 18.7% of the respondents would buy the vaccine even if it was only 20% effective. Among respondents older than 50 years, the proportion was 28.8%. CONCLUSIONS: Our findings should encourage the development of vaccines and other preventive measures against travellers' diarrhoea. PMID- 27777091 TI - Clinical metagenomic analysis of bacterial communities in breast abscesses of granulomatous mastitis. AB - BACKGROUND: Granulomatous mastitis (GM) is a chronic inflammatory breast lesion. Its etiology remains incompletely defined. Although mounting evidence suggests the involvement of Corynebacterium in GM, there has been no systematic study of GM bacteriology using -omics technology. METHODS: The bacterial diversity and relative abundances in breast abscesses from 19 women with GM were investigated using 16S rDNA metagenomic sequencing and Sanger sequencing. A quantitative PCR (qPCR) assay was also developed to identify Corynebacterium kroppenstedtii. RESULTS: A bioinformatic analysis revealed that Corynebacterium was present in the 19 GM patients, with abundances ranging from 1.1% to 58.9%. Of note, Corynebacterium was the most abundant taxon in seven patients (more than a third of the subjects). The predominance of Corynebacterium kroppenstedtii infection (11 of 19 patients, 57.9%) was confirmed with Sanger sequencing and the qPCR assay. CONCLUSIONS: This study profiled the microbiota of patients with GM and indicated an important role for Corynebacterium, and in particular C. kroppenstedtii, in the pathogenesis of this disease. PMID- 27777092 TI - Drivers of earlier infectious disease outbreak detection: a systematic literature review. AB - BACKGROUND: The early detection of infectious disease outbreaks can reduce the ultimate size of the outbreak, with lower overall morbidity and mortality due to the disease. Numerous approaches to the earlier detection of outbreaks exist, and methods have been developed to measure progress on timeliness. Understanding why these surveillance approaches work and do not work will elucidate key drivers of early detection, and could guide interventions to achieve earlier detection. Without clarity about the conditions necessary for earlier detection and the factors influencing these, attempts to improve surveillance will be ad hoc and unsystematic. METHODS: A systematic review was conducted using the PRISMA framework (Preferred Reporting Items for Systematic Reviews and Meta-analyses) to identify research published between January 1, 1990 and December 31, 2015 in the English language. The MEDLINE (PubMed) database was searched. Influencing factors were organized according to a generic five-step infectious disease detection model. RESULTS: Five studies were identified and included in the review. These studies evaluated the effect of electronic-based reporting on detection timeliness, impact of laboratory agreements on timeliness, and barriers to notification by general practitioners. Findings were categorized as conditions necessary for earlier detection and factors that influence whether or not these conditions can be in place, and were organized according to the detection model. There is some evidence on reporting, no evidence on assessment, and speculation about local level recognition. CONCLUSION: Despite significant investment in early outbreak detection, there is very little evidence with respect to factors that influence earlier detection. More research is needed to guide intervention planning. PMID- 27777093 TI - Prevalence of Spirometra mansoni in dogs, cats, and frogs and its medical relevance in Guangzhou, China. AB - BACKGROUND: Sparganosis is an important parasitic disease in Guangzhou and is mainly acquired through the consumption of frog meat or contact with fresh frogs infected by larval stages (spargana) of the tapeworm species Spirometra mansoni. METHODS: In this study, the prevalence of intestinal S. mansoni infections (with adult parasites) in dogs and cats and of extraintestinal S. mansoni infections (with spargana) in frogs was assessed. In addition, a questionnaire survey was carried out among residents in Guangzhou City in order to evaluate their awareness about the medical and epidemiological relevance of Spirometra and sparganosis. RESULTS: In total, the feces of 229 dogs and 116 cats were examined for eggs, and 1949 frogs were examined for spargana. Sixty-three dogs (27.5%) and 47 cats (40.5%) had eggs in their feces. Two hundred and sixteen out of 416 wild Rana tigrina rugulosa Wiegmann frogs examined were sparganum-positive, with an infection rate of 51.9%, while the infection rate in Rana limnocharis Boie was 35.1% (13/37). None of the tested farmed frogs (including R. tigrina rugulosa and Rana catesbeiana) was positive (0/1382). Analysis of the questionnaire revealed the following results: (1) about 41.0% of residents in Guangzhou had some knowledge of sparganosis or sparganum infection, and information in TV programs was the most important way that residents learned about sparganosis. (2) About 59.9% of the residents ate frog meat. Eating the meat, viscera, or blood of animals, e.g., frogs, snakes, pigs, chicken, mice, and birds, in an improper way might be the main means by which residents acquire the infection. (3) The risk of sparganum infection was higher in males than in females. CONCLUSIONS: A high sparganum infection rate was observed in the wild frogs sold in agricultural product markets in Guangzhou. The infection was also serious in cats and dogs in Guangdong Province. With lifestyles and eating habits resulting in sparganum infection, it is necessary to focus on market management and community education in order to prevent the transmission of this disease in Guangzhou. PMID- 27777094 TI - Dietary nitrate supplementation improves sprint and high-intensity intermittent running performance. AB - : The influence of dietary nitrate (NO3-) supplementation on indices of maximal sprint and intermittent exercise performance is unclear. PURPOSE: To investigate the effects of NO3- supplementation on sprint running performance, and cognitive function and exercise performance during the sport-specific Yo-Yo Intermittent Recovery level 1 test (IR1). METHODS: In a double-blind, randomized, crossover study, 36 male team-sport players received NO3--rich (BR; 70 mL.day-1; 6.4 mmol of NO3-), and NO3--depleted (PL; 70 mL.day-1; 0.04 mmol NO3-) beetroot juice for 5 days. On day 5 of supplementation, subjects completed a series of maximal 20-m sprints followed by the Yo-Yo IR1. Cognitive tasks were completed prior to, during and immediately following the Yo-Yo IR1. RESULTS: BR improved sprint split times relative to PL at 20 m (1.2%; BR 3.98 +/- 0.18 vs. PL 4.03 +/- 0.19 s; P < 0.05), 10 m (1.6%; BR 2.53 +/- 0.12 vs. PL 2.57 +/- 0.19 s; P < 0.05) and 5 m (2.3%; BR 1.73 +/- 0.09 vs. PL 1.77 +/- 0.09 s; P < 0.05). The distance covered in the Yo-Yo IR1 test improved by 3.9% (BR 1422 +/- 502 vs. PL 1369 +/- 505 m; P < 0.05). The reaction time to the cognitive tasks was shorter in BR (615 +/- 98 ms) than PL (645 +/- 120 ms; P < 0.05) at rest but not during the Yo-Yo IR1. There was no difference in response accuracy. CONCLUSIONS: Dietary NO3- supplementation enhances maximal sprint and high-intensity intermittent running performance in competitive team sport players. Our findings suggest that NO3- supplementation has the potential to improve performance in single-sprint or multiple-sprint (team) sports. PMID- 27777095 TI - From the Burning Platform to the Beautiful Island: Clinicians Can Envision the Way to Value-Based Care. PMID- 27777096 TI - Impact of Fibromyalgia in the Sit-to-Stand-to-Sit Performance Compared With Healthy Controls. AB - BACKGROUND: Fibromyalgia is associated with a reduction in the ability to perform activities of daily living. Sit-to-stand-to-sit performance is one of the most common activities of daily living and often is evaluated by counting the number of repetitions of the 30-second chair-stand test. No study, however, has examined the performance over the 30 seconds of this test of female patients with fibromyalgia on a phase-by-phase basis. OBJECTIVE: To evaluate the impact of fibromyalgia on performance of the 30-second chair-stand test and to analyze how the kinematic performance changed over the 30-second test period. DESIGN: A cross sectional study. SETTING: Local association of fibromyalgia. PARTICIPANTS: Fifteen females with fibromyalgia and nine healthy female controls. INTERVENTION: Participants performed the 30-second chair-stand test while wearing a motion capture device. MAIN OUTCOME MEASURE: Duration of each sit-to-stand-to-sit phase within the 30-second time limit was compared between groups using repeated measures analysis of variance. The association between duration of phases and scores from the revised version of the Fibromyalgia Impact Questionnaire was tested using bivariate correlations. RESULTS: The duration of impulse and sit-to stand phases were gradually increased over the 30 seconds of the chair-stand test for women with fibromyalgia compared with healthy controls (P = .04 and P = .02, respectively). The mean duration of these 2 phases was associated with symptom duration and the function domain of the revised version of the Fibromyalgia Impact Questionnaire (P < .05). Also, stiffness was directly associated with the duration of the stand-up phase (P = .04). CONCLUSION: Kinematic performance during the 30-second chair-stand test differed between women with fibromyalgia and healthy controls. Since sit-to-stand from a chair is a common daily activity, women with fibromyalgia may require specific exercises to improve performance of this task. LEVEL OF EVIDENCE: Not applicable. PMID- 27777097 TI - Auditing the Physical Activity and Parkinson Disease Literature Using the Behavioral Epidemiologic Framework. AB - : Motor and nonmotor symptoms associated with Parkinson disease place individuals at greater risk of sedentary behaviors and comorbidities. Physical activity is one modifiable means of improving health and reducing the risk of morbidity. We applied a behavioral framework to classify existing research on physical activity and Parkinson disease to describe the current evolution and inform knowledge gaps in this area. Research placed in phase 1 establishes links between physical activity and health-related outcomes; phase 2 develops approaches to quantify physical activity behavior; phase 3 identifies factors associated with implementation of physical activity behaviors; phase 4 assesses the effectiveness of interventions to promote activity; and phase 5 disseminates evidence-based recommendations. Peer-reviewed literature was identified by searching PubMed, Google Scholar, and EBSCO-host. We initially identified 287 potential articles. After further review, we excluded 109 articles, leaving 178 included articles. Of these, 75.84% were categorized into phase 1 (n = 135), 10.11% in phase 2 (n = 18), 9.55% into phase 3 (n = 17), 3.37% into phase 4 (n = 6), and 1.12% into phase 5 (n = 2). By applying the behavioral framework to the physical activity literature for people with Parkinson disease, we suggest this area of research is nascent with more than 75% of the literature in phase 1. LEVEL OF EVIDENCE: III. PMID- 27777098 TI - It's high time to follow DNA repair in Routine Labs. PMID- 27777099 TI - Longevity study with low doses of selegiline/(-)-deprenyl and (2R)-1-(1 benzofuran-2-yl)-N-propylpentane-2-amine (BPAP). AB - AIMS: The first longevity study demonstrating that rats treated with the MAO-B inhibitory dose of (-)-deprenyl (0.25mg/kg) lived significantly longer than their saline-treated peers was published in 1988, and corroborated in many papers. The recent findings that (-)-deprenyl is primarily a PEA-derived synthetic catecholaminergic activity enhancer substance; (2R)-1-(1-benzofuran-2-yl)-N propylpentane-2-amine (BPAP) is a tryptamine-derived synthetic enhancer substance, initiated our first longevity study on rats with low enhancer doses of (-)-deprenyl and BPAP to test the enhancer effect's role in life extension. MAIN METHODS: We used the shuttle box technique for selecting the optimum doses of (-) deprenyl and BPAP. (-)-Deprenyl exerts in rats in 0.001mg/kg its 'specific' enhancer effect and in 0.1mg/kg its 'non-specific' enhancer effect. BPAP exerts its 'specific' enhancer effect in 0.0001mg/kg and its 'non-specific' enhancer effect in 0.05mg/kg. Groups of male Wistar rats (N=40) were treated subcutaneously from their 10th week until death, three times weekly, with saline (0.5ml/kg), and the selected doses of (-)-deprenyl or BPAP, respectively. As an indicator of aging we tested the age-related changes in their learning ability. KEY FINDINGS: Rats treated with 0.0001 or 0.05mg/kg BPAP lived significantly longer than their saline treated peers (P<0.02) and BPAP was more potent in extending rats' lifespan than (-)-deprenyl. 18-month-old rats treated with 0.0001mg/kg BPAP were as good learners as 3-month-old saline treated rats. SIGNIFICANCE: The study revealed that the enhancer effect is responsible for life extension. PMID- 27777100 TI - Corrected Fructosamine improves both correlation with HbA1C and diagnostic performance. AB - AIMS: There is increasing interest in using fructosamine measurements in screening for or managing diabetes, yet uncertainty remains as to whether these measurements should be corrected for variation in serum protein concentrations. METHODS: We considered all sets of simultaneous measurements of fructosamine, albumin, total serum protein (TP), fasting plasma glucose (FPG) and HbA1C recorded in our laboratory over 10years. The relationships between fructosamine and other variables were studied by multivariate linear regression and other analyses, and receiver operating curves (ROCs) were analysed to compare the diabetes screening performance of uncorrected fructosamine to those of albumin corrected fructosamine (FAAlb) and TP-corrected fructosamine (FATP). RESULTS: 40,938 sets of measurements were collected from 20,114 patients. Though correlation between fructosamine and serum proteins was strongest among patients with HbA1C <6.5% (48mmol/mol), it was also significant in the whole sample (r=0.193 for albumin, r=0.213 for TP). With diabetes defined by HbA1C >=6.5% (48mmol/mol), the areas under the ROCs of FAAlb (0.905) and FATP (0.895) were both significantly greater (P<0.001) than that of uncorrected fructosamine (0.878). Correction of fructosamine for albumin or TP slightly improved its correlation with HbA1C. There was no correlation of protein (albumin or TP) with log(fructosamine/protein). CONCLUSIONS: Fructosamine concentration correlates significantly with albumin and total protein concentrations throughout their ranges. Correction of fructosamine improves its correlation with HbA1C and its performance in detecting diabetes. PMID- 27777101 TI - Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis. AB - Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-beta signaling in dermal fibroblasts through the down regulation of thrombospondin 1, a latent transforming growth factor-beta receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc. PMID- 27777102 TI - Atypical microglial response to biodiesel exhaust in healthy and hypertensive rats. AB - Accumulating evidence suggests a deleterious role for urban air pollution in central nervous system (CNS) diseases and neurodevelopmental disorders. Microglia, the resident innate immune cells and sentinels in the brain, are a common source of neuroinflammation and are implicated in air pollution-induced CNS effects. While renewable energy, such as soy-based biofuel, is of increasing public interest, there is little information on how soy biofuel may affect the brain, especially in people with preexisting disease conditions. To address this, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were exposed to 100% Soy-based Biodiesel Exhaust (100SBDE; 0, 50, 150 and 500MUg/m3) by inhalation, 4h/day for 4 weeks (5 days/week). Ionized calcium binding adapter molecule-1 (IBA-1) staining of microglia in the substantia nigra revealed significant changes in morphology with 100SBDE exposure in rats from both genotypes, where SHR were less sensitive. Aconitase activity was inhibited in the frontal cortex and cerebellum of WKY rats exposed to 100SBDE. No consistent changes occurred in pro-inflammatory cytokine expression, nitrated protein, or arginase1 expression in brain regions from either rat strain exposed to 100SBDE. However, while IBA-1 mRNA expression was not modified, CX3CR1 mRNA expression was lower in the striatum of 100SBDE exposed rats regardless of genotype, suggesting a downregulation of the fractalkine receptor on microglia in this brain region. Together, these data indicate that while microglia are detecting and responding to 100SBDE exposure with changes in morphology, there is reduced expression of CX3CR1 regardless of genetic background and the activation response is atypical without traditional inflammatory markers of M1 or M2 activation in the brain. PMID- 27777103 TI - Resource competition amid overlapping territories: The territorial raider model applied to multi-group interactions. AB - Many organisms maintain collective territories and compete on behalf of the fitness of the overall group. Inspired by this concept, the territorial raider model is a graph-based resource competition in which populations have fixed home locations and a limited range of sites accessible for raiding. In our present extension of the model, groups control "colonies" or "armies" which can be divided across multiple locations. We present Nash equilibria for games played on both regular graphs and regular bipartite graphs, and we also examine differences that emerge when populations are composed of discrete units (pack scale) or when they are continuously divisible (colony scale). Reliance upon defense over aggressive raiding is greater here than in the original model where populations had to totally commit to a singular action. This defensive posture increases with the advantage of the local population and also varies with the degree of the graph's connectivity. When discrete units are employed, multiple strategies emerge. PMID- 27777104 TI - West Nile virus 'circulation' in Vojvodina, Serbia: Mosquito, bird, horse and human surveillance. AB - Efforts to detect West Nile virus (WNV) in the Vojvodina province, northern Serbia, commenced with human and mosquito surveillance in 2005, followed by horse (2009) and wild bird (2012) surveillance. The knowledge obtained regarding WNV circulation, combined with the need for timely detection of virus activity and risk assessment resulted in the implementation of a national surveillance programme integrating mosquito, horse and bird surveillance in 2014. From 2013, the system showed highly satisfactory results in terms of area specificity (the capacity to indicate the spatial distribution of the risk for human cases of West Nile neuroinvasive disease - WNND) and sensitivity to detect virus circulation even at the enzootic level. A small number (n = 50) of Culex pipiens (pipiens and molestus biotypes, and their hybrids) females analysed per trap/night, combined with a high number of specimens in the sample, provided variable results in the early detection capacity at different administrative levels (NUTS2 versus NUTS3). The clustering of infected mosquitoes, horses, birds and human cases of WNND in 2014-2015 was highly significant, following the south-west to north-east direction in Vojvodina (NUTS2 administrative level). Human WNND cases grouped closest with infected mosquitoes in 2014, and with wild birds/mosquitoes in 2015. In 2014, sentinel horses showed better spatial correspondence with human WNND cases than sentinel chickens. Strong correlations were observed between the vector index values and the incidence of human WNND cases recorded at the NUTS2 and NUTS3 levels. From 2010, West Nile virus was detected in mosquitoes sampled at 43 different trap stations across Vojvodina. At 14 stations (32.56%), WNV was detected in two different (consecutive or alternate) years, at 2 stations in 3 different years, and in 1 station during 5 different years. Based on these results, integrated surveillance will be progressively improved to allow evidence based adoption of preventive public health and mosquito control measures. PMID- 27777105 TI - Effects of occupational exposure to poorly soluble forms of beryllium on biomarkers of pulmonary response in exhaled breath of workers in machining industries. AB - OBJECTIVE: To analyze the effects of occupational exposure to poorly soluble forms of beryllium (Be) on biomarkers of pulmonary inflammation using exhaled breath condensate (EBC) in workers employed in machining industries. METHODS: Twenty machining operators were compared to 16 controls. The individual exposure to Be was assessed from the work history with several indices of exposure calculated on the basis of task-exposures matrices developed for each plant using historical air measurements. Clinical evaluation consisted in a medical questionnaire, measurements of biomarkers in EBC (tumor necrosis factor alpha (TNF-alpha), total nitrogen oxides (NOx)), measurement of the fraction of exhaled nitric oxide (FeNO) and resting spirometry. Adjusted multiple linear regressions were used to study the effect of the exposure to Be on inflammatory biomarkers. RESULTS: Levels of TNF-alpha and NOx in EBC were not statistically different between exposed and controls. We found a statistically significant relationship between levels of TNF-alpha in EBC and both index of cumulative exposure and duration of exposure to Be. No other statistically significant relationships were found between exposure to Be and pulmonary response. CONCLUSION: Our results suggest that machining-related exposure to Be is related to pulmonary inflammation involving TNF-alpha. These findings must be confirmed by larger studies. PMID- 27777106 TI - In vitro modulation of Drimys winteri bark extract and the active compound polygodial on Salmo salar immune genes after exposure to Saprolegnia parasitica. AB - The rapid development of the aquaculture industry has global concerns with health management and control strategies to prevent and/or treat diseases and increase sustainability standards. Saprolegniosis is a disease caused by Saprolegnia parasitica, and is characterized by promoting an immunosuppression in the host. This study evaluated in vitro the extract and one active compound (polygodial) of Drimys winteri, a Chilean medicinal tree as a potential early immunostimulatory aid in Saprolegniosis control. Atlantic salmon (Salmo salar) head kidney cells (ASK-1) were incubated with both extract and pure polygodial before exposure to S. parasitica mycelium, and the expression of the immune-related genes interleukin 1beta (IL-1beta), interferon alpha (IFNalpha), and major histocompatibility complex II (MHCII) was evaluated. Both evidenced immunomodulatory capacities by increasing gene expressions. This immunomodulation related to a mitigatory action counteracting the immunosuppressing effects of S. parasitica. Despite that most immune-related genes were up-regulated, the down regulation of MHCII, characteristic of S. parasitica infection, was lessened by pre-incubation with the compounds. This study provides the first insight on the potential of D. winteri bark extract as a possible immunomodulatory and defensive strategy against this oomycete infection in fish. PMID- 27777107 TI - The first discovery of RNA interference by RNA restriction enzymes to inhibit protein synthesis. AB - In this article, I review how an RNA restriction enzyme, a highly sequence specific endoribonuclease, was for the first time discovered in 2003 and how the concept of RNA interference using RNA restriction enzymes or mRNA interferases has been developed. PMID- 27777108 TI - Conditional tenomodulin overexpression favors tenogenic lineage differentiation of transgenic mouse derived cells. AB - Tenomodulin (TNMD) is a type II transmembrane protein that is widely expressed in a variety of avascular connective tissues and fat tissue. Its function remains largely unknown except for a marker for mature tenocytes. This study reports the generation of tetracycline (Tet)-on driven conditional TNMD overexpressing mice and thus to provide a tool for systemic investigation of its role in regulating functions of various tissues. The current study focuses on in vitro comparison of tenogenic differentiation potentials induced by doxycycline (Dox) treatment among bone marrow derived stem cells (BMSCs), adipose derived stem cells (ASCs), dermal fibroblasts (DFs) and tenocytes (TCs) of the same transgenic mice. The results showed that BMSCs exhibited the best tenogenic potential than other three cell types (p<0.05 for majority of markers), whereas ASCs and DFs revealed similar potentials (p>0.05 for majority of markers). TCs were found the least capable of being induced for tenogenic gene expression. In addition, TNMD overexpression also significantly inhibited the differentiation towards osteogenic and chondrogenic lineages in both BMSCs and ASCs (p<0.05). However, the inhibition of adipogenic differentiation was not observed in ASCs (p>0.05), suggesting different gene regulation mechanisms may involve in different tissue types and thus leading to different functions, which is likely to be revealed with a transgenic mouse model. PMID- 27777109 TI - In silico analysis of differential gene expressions in biliary stricture and hepatic carcinoma. AB - In-silico attempt was made to identify the key hub genes which get differentially expressed in biliary stricture and hepatic carcinoma. Gene expression data, GSE34166, was downloaded from the GEO database, which contains 10 biliary stricture samples (4 benign control and 6 malignant carcinoma), for screening of key hub genes associated with the disease. R packages scripts were identified 85 differentially expressed genes. Further these genes were uploaded in WebGestalt database and identified nine key genes. Using STRING database and Gephi software, the protein-protein interaction networks were constructed and also studied gene ontology through WebGestalt. Finally, we identified four key genes (CXCR4, ADH1C, ABCB1 and ADH1A) are associated with liver carcinoma and further cross-validated with Liverome, Protein Atlas database and bibliography. In addition, transcription factors and their binding sites also studied. These identified hub genes and their transcription factors are the probable potential targets for possible future drug design. PMID- 27777110 TI - Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model. AB - Polycystic ovary syndrome (PCOS) causes female subfertility with ovarian disorders and may be associated with increased rate of early-pregnancy failure. Rat PCOS models were established using letrozole to understand the uterine pathogenesis of PCOS. The differential expression of microRNAs (miRNAs) was observed in rat uterus with PCOS. After estrous cycles were disrupted, significantly abnormal ovarian morphology and hormone level were observed in rats with PCOS. A total of 148 miRNAs differentially expressed were identified in the uterus from the letrozole-induced rat model compared with the control. These miRNAs included 111 upregulated miRNAs and 37 downregulated miRNAs. The differential expression of miR-484, miR-375-3p, miR-324-5p, and miR-223-3p was further confirmed by quantitative reverse transcription polymerase chain reaction. Bioinformatic analysis showed that these four miRNAs were predicted to regulate a large number of genes with different functions. Pathway analysis supported that target genes of miRNAs were involved in insulin secretion and signaling pathways, such as wnt, AMPK, PI3K-Akt, and Ras. These data indicated that miRNAs differentially expressed in rat uterus with PCOS may be associated with PCOS pathogenesis in the uterus. Our findings can help clarify the mechanism of uterine defects in PCOS. PMID- 27777111 TI - The first demonstration of the existence of reverse transcriptases in bacteria. AB - It has been long thought that reverse transcriptases are unique to the eukaryotes. However, through our research on a peculiar single stranded DNA called msDNA in Myxococcus xanthus, it was predicted that its synthesis requires reverse transcriptases. Subsequently, Lim and Maas as well as our group demonstrated the existence of reverse transcriptases for the production of msDNA. In this review, I describe how the discovery of msDNA led to the discovery of reverse transcriptases in bacteria and discuss the evolutionary significance of the discovery of revise transcriptases in bacteria. PMID- 27777112 TI - Stereological investigation of the CA1 pyramidal cell layer in untreated and lithium-treated 3xTg-AD and wild-type mice. AB - Pyramidal neuron loss in the hippocampal CA1 region is a very early hallmark of Alzheimer disease (AD). Lithium might be a therapeutic strategy for AD due to its neuroprotective and neurotrophic properties. This study used modern stereological techniques to investigate possible CA1 pyramidal neuron loss in 11-month-old triple transgenic AD (3xTg-AD) mice, and also the effects of therapeutic and subtherapeutic lithium doses on the number and density of CA1 pyramidal neurons and volume of CA1 pyramidal layer in 3xTg-AD and wild-type mice treated from 3 to 11 months of age. 3xTg-AD mice displayed CA1 pyramidal layer atrophy that is likely due to reduced neuronal volume because of the absence of neuronal loss. Both lithium treatments of 3xTg-AD mice, which already expressed AD-like pathology, had no effect on CA1 atrophy. However, lithium treatment of wild-type mice, at low (subtherapeutic) doses, induced a significant increase in total CA1 pyramidal neuron number that led to a significant increase in total CA1 pyramidal layer volume. The lithium-induced increase in CA1 neuron number is highly consistent with previous evidence that adult neurogenesis can be exogenously induced in the CA1 pyramidal layer with impact on total CA1 neuron number, thus raising the possibility of the chronic use of low-dose lithium as a strategy to help compensate for neuronal loss in CA1 and perhaps other typically non neurogenic brain regions in various neurological diseases. With regard to AD, low dose lithium intervention must be initiated as early as possible in the course of neuropathology for beneficial effects to occur. PMID- 27777113 TI - Subsets of telocytes: Myocardial telocytes. AB - Telocytes (TCs) are morphologically defined as small-sized cells with long, thin, moniliform processes called telopodes (Tps). Numerous papers imply that TCs are a distinctive cell type, and that transmission electron microscopy (TEM) is the gold standard tool for their identification. We aimed to reproduce previous studies on myocardial TCs to check their validity. For this purpose we performed an immunohistochemical study on human cardiac samples from six autopsied donor cadavers, using antibodies against CD10, CD31, CD34, CD146, Ki67, alpha-smooth muscle actin (alpha-SMA), Platelet-Derived Growth Factor Receptor-alpha (PDGFRalpha) and laminin. Additionally we performed a TEM study on cardiac samples from three human autopsied donor cadavers and five adult Sprague-Dawley rats. We found endothelial cells (ECs), cords, and filopodia-projecting endothelial tip cells (ETCs) that expressed CD10, CD31, CD34, CD146, and PDGFR alpha. Often, endothelial cells closely neighbored the sarcolemmal basal laminae. Endothelial progenitor cells, as well as nascent capillaries, were CD31+/CD34+. Proliferative endothelial cells expressed Ki67. In larger vessels we found pericytes that expressed CD146 and alpha-SMA; scarce alpha-SMA-expressing spindle shaped cells lining cardiomyocytes were suggestive of a pericytic role in angiogenic sprout guidance. The TEM study showed that endothelial tubes are almost exclusively found in the narrow myocardial interstitia. ECs that built them up appeared identical to the cells that previous TEM studies have suggested to be myocardial telocytes. A subset of stromal cells with TC-like phenotype and telopodes-like processes actually seem to configure blood vessels, and therefore belong to the endothelial lineage. This study shows that data presented in previous studies on myocardial telocytes is not enough to allow the reproducibility of the results. At least a subset of cells considered to be TCs might belong to the endothelial lineage. PMID- 27777114 TI - Myocardial bridges, neither rare nor isolated-Autopsy study. AB - PURPOSE: Myocardial bridge is a congenital anomaly with a markedly variable reported incidence on autopsy (4.7%-86%), likely related to geographical regions. Our previous retrospective study showed a prevalence of 0.8%, which we doubted to be the true one in the examined sample of the Serbian population. To assess the importance of the phenomenon we conducted a 2-year prospective study at the same institution. METHODS: Ninety-six cadaver hearts from adult individuals of both genders (51 men, 45 women) who died from natural causes underwent special dissection. Tunneled coronary arteries and myocardium were examined using light microscopy. RESULTS: A total of 14 myocardial bridges were found in 13 (13.54%) hearts. This anomaly was insignificantly more common in men (13.72% vs. 13.33%, p>0.05). In one heart we noted two myocardial bridges (the left anterior interventricular artery and left marginal artery were overbridged). None of the myocardial bridges had been diagnosed during life. The most common causes of death were cardiac related. Myocardial bridges were located in the following areas: left anterior interventricular (50%), left circumflex artery (28.6%), left marginal artery (14.3%), and right coronary artery (7.1%). In 92.3% of cases, the right coronary artery was dominant. The only heart with a balanced-type had two bridges. Most of the myocardial bridges were long and deep. All tunneled coronary arteries, and although surrounded by "coronary cushion," were not protected from atherosclerosis. In 30.8% of hearts with myocardial bridges, we found additional coronary artery anomalies. CONCLUSION: Myocardial bridges were not rare in the examined sample of the Serbian population and were often associated with other coronary artery anomalies, rendering the carriers at higher risk. PMID- 27777115 TI - Scanning electron microscopy study of new bone formation following small and large defects preserved with xenografts supplemented with pamidronate-A pilot study in Fox-Hound dogs at 4 and 8 weeks. AB - The aim of the present study was to evaluate the feasibility of SEM and EDX microanalysis on evaluating the effect of porcine xenografts (MP3(r)) supplemented with pamidronate during socket healing. Mandibular second premolars (P2) and first molars (M1) were extracted from six Beagle dogs. P2 were categorized as small defects (SD) and M1 as large defects (LD). Four random groups were created: SC (small control defects with MP3(r)), ST (small test defects MP3(r)+pamidronate), LC (large control defects with MP3(r)), and LT (large test defects MP3(r)+pamidronate). At four and eight weeks of healing the samples were evaluated fisically through scanning electron microscopy (SEM), and chemical element mapping was carried out by Energy dispersive X-ray spectroscopy (EDX). After four weeks of healing, SEM and EDX analysis revealed more mineralized bone in ST and LT groups compared with control groups (p<0.05). After eight weeks, Ca/P ratios were slightly higher for small defects (groups SC and ST); in SEM description, in both control and test groups, trabecular bone density was similar to the adjacent mineralized cortical bone. Within the limitations of this experimental study, SEM description and EDX elemental microanalysis have demonstrated to be useful techniques to assess bone remodelling of small and large defects. Both techniques show increased bone formation in test groups (MP3(r) modified with pamidronate) after four and eight weeks of healing. PMID- 27777116 TI - Digital preservation of anatomical variation: 3D-modeling of embalmed and plastinated cadaveric specimens using uCT and MRI. AB - Anatomy educators have an opportunity to teach anatomical variations as a part of medical and allied health curricula using both cadaveric and three-dimensional (3D) digital models of these specimens. Beyond published cadaveric case reports, anatomical variations identified during routine gross anatomy dissection can be powerful teaching tools and a medium to discuss several anatomical sub disciplines from embryology to medical imaging. The purpose of this study is to document how cadaveric anatomical variation identified during routine dissection can be scanned using medical imaging techniques to create two-dimensional axial images and interactive 3D models for teaching and learning of anatomical variations. Three cadaveric specimens (2 formalin embalmed, 1 plastinated) depicting anatomical variations and an embryological malformation were scanned using magnetic resonance imaging (MRI) and micro-computed tomography (MUCT) for visualization in cross-section and for creation of 3D volumetric models. Results provide educational options to enable visualization and facilitate learning of anatomical variations from cross-sectional scans. Furthermore, the variations can be highlighted, digitized, modeled and manipulated using 3D imaging software and viewed in the anatomy laboratory in conjunction with traditional anatomical dissection. This study provides an example for anatomy educators to teach and describe anatomical variations in the undergraduate medical curriculum. PMID- 27777117 TI - A viscoelastic analysis of the P56 mouse brain under large-deformation dynamic indentation. AB - : The brain is a complex organ made up of many different functional and structural regions consisting of different types of cells such as neurons and glia, as well as complex anatomical geometries. It is hypothesized that the different regions of the brain exhibit significantly different mechanical properties which may be attributed to the diversity of cells within individual brain regions. The regional viscoelastic properties of P56 mouse brain tissue, up to 70MUm displacement, are presented and discussed in the context of traumatic brain injury, particularly how the different regions of the brain respond to mechanical loads. Force-relaxation data obtained from micro-indentation measurements were fit to both linear and quasi-linear viscoelastic models to determine the time and frequency domain viscoelastic response of the pons, cortex, medulla oblongata, cerebellum, and thalamus. The damping ratio of each region was also determined. Each region was found to have a unique mechanical response to the applied displacement, with the pons and thalamus exhibiting the largest and smallest force-response, respectively. All brain regions appear to have an optimal frequency for the dissipation of energies which lies between 1 and 10Hz. STATEMENT OF SIGNIFICANCE: We present the first mechanical characterization of the viscoelastic response for different regions of mouse brain. Force-relaxation tests are performed under large strain dynamic micro indentation, and viscoelastic models are used subsequently, providing time dependent mechanical properties of brain tissue under loading conditions comparable to what is experienced in TBI. The unique mechanical properties of different brain regions are highlighted, with substantial variations in the viscoelastic properties and damping ratio of each region. Cortex and pons were the stiffest regions, while the thalamus and medulla were most compliant. The cerebellum and thalamus had highest damping ratio values and those of the medulla were lowest. The reported material parameters can be implemented into finite element computer models of the mouse to investigate the effects of trauma on individual brain regions. PMID- 27777118 TI - The occurrence of infective endocarditis with Staphylococcus lugdunensis bacteremia: A retrospective cohort study and systematic review. AB - BACKGROUND: Staphylococcus lugdunensis is a coagulase-negative staphylococcus with similar virulence characteristics as Staphylococcus aureus. Whether S. lugdunensis causes infective endocarditis (IE) in a similar proportion of cases as S. aureus (reported to be 12.6% in a definitive multicenter prospective study) is unclear. METHODS: We conducted a retrospective cohort study of adult patients with at least one blood culture positive for S. lugdunensis at our institution from January 2006 to December 2014. We examined microbiology data, ascertained disease severity and determined the proportion of patients with definite or possible IE based on the 2000 Modified Duke Criteria. Because coagulase-negative staphylococci were routinely identified to the species level at our institution from 2012 onwards, we determined the proportion of patients with definite or possible IE before and after implementation of routine speciation. We also compared our results with reported proportions of IE among patients with S. lugdunensis bacteremia (SLB) in other institutions by conducting a systematic review of the scientific literature. Nonparametric bootstrapping methods were performed to determine 95% confidence intervals (CI) for proportions of IE in patients with SLB. RESULTS: Seventy-four patients with SLB were identified, of whom 64% (47/74) had sepsis by SIRS criteria, and 18% (13/74) had severe illness by Pittsburgh bacteremia score (PBS). Kaplan-Meier survival analysis showed that one-year survival among patients with severe illness was worse than patients with non-severe illness (p = 0.02). Fifteen percent (11/74) of patients had definite or possible IE (95% CI 6.8-23.0%). The proportion of SLB patients with definite or possible IE was 15.8% (6/38, 95% CI 5.3-28.9%) prior to routine speciation and 13.9% (5/36, 95% CI 2.8-27.8%) after routine speciation (p = 0.71). Among patients with at least two positive blood cultures for S. lugdunensis, 25% (10/40, 95% CI 12.5-40.0%) had IE. Systematic review of the literature yielded eight relevant retrospective studies. Of studies that included patients with one or more positive blood cultures for S. lugdunensis, the proportion of IE ranged from 6.3% to 27.0%. CONCLUSION: The proportion of definite or possible IE among patients with SLB is similar to the proportion of IE among patients with S. aureus bacteremia. The proportions of IE among patients with SLB at other institutions fall within the 95% CI yielded by bootstrapping. Our findings suggest that growth of S. lugdunensis in two separate blood cultures should prompt consideration of workup for IE. PMID- 27777119 TI - Focal osteoporosis defects play a key role in hip fracture. AB - BACKGROUND: Hip fractures are mainly caused by accidental falls and trips, which magnify forces in well-defined areas of the proximal femur. Unfortunately, the same areas are at risk of rapid bone loss with ageing, since they are relatively stress-shielded during walking and sitting. Focal osteoporosis in those areas may contribute to fracture, and targeted 3D measurements might enhance hip fracture prediction. In the FEMCO case-control clinical study, Cortical Bone Mapping (CBM) was applied to clinical computed tomography (CT) scans to define 3D cortical and trabecular bone defects in patients with acute hip fracture compared to controls. Direct measurements of trabecular bone volume were then made in biopsies of target regions removed at operation. METHODS: The sample consisted of CT scans from 313 female and 40 male volunteers (158 with proximal femoral fracture, 145 age-matched controls and 50 fallers without hip fracture). Detailed Cortical Bone Maps (c.5580 measurement points on the unfractured hip) were created before registering each hip to an average femur shape to facilitate statistical parametric mapping (SPM). Areas where cortical and trabecular bone differed from controls were visualised in 3D for location, magnitude and statistical significance. Measures from the novel regions created by the SPM process were then tested for their ability to classify fracture versus control by comparison with traditional CT measures of areal Bone Mineral Density (aBMD). In women we used the surgical classification of fracture location ('femoral neck' or 'trochanteric') to discover whether focal osteoporosis was specific to fracture type. To explore whether the focal areas were osteoporotic by histological criteria, we used micro CT to measure trabecular bone parameters in targeted biopsies taken from the femoral heads of 14 cases. RESULTS: Hip fracture patients had distinct patterns of focal osteoporosis that determined fracture type, and CBM measures classified fracture type better than aBMD parameters. CBM measures however improved only minimally on aBMD for predicting any hip fracture and depended on the inclusion of trabecular bone measures alongside cortical regions. Focal osteoporosis was confirmed on biopsy as reduced sub-cortical trabecular bone volume. CONCLUSION: Using 3D imaging methods and targeted bone biopsy, we discovered focal osteoporosis affecting trabecular and cortical bone of the proximal femur, among men and women with hip fracture. PMID- 27777120 TI - A homozygous intronic branch-point deletion in the ALPL gene causes infantile hypophosphatasia. AB - Hypophosphatasia (HPP) is a multi-systemic inborn disease with an extraordinary spectrum of severity, ranging from the absence of mineralization to high lethality and it involves different organs including bone, muscle, kidney, lung, gastrointestinal tract and the nervous system. The disease is characterized by low levels of serum alkaline phosphatase, caused by loss-of-function mutations within the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP. Here we present the functional characterization of a gene mutation, detected in intron 7 of the ALPL gene of a boy with infantile HPP in whom routine sequencing of the coding region failed to detect any mutation. The homozygous c.793del-14_33 mutation results in the loss of the branch-point motif, relevant for correct ALPL pre-mRNA splicing. The main transcript skips exon 8 and codes for a C-terminally truncated TNAP protein of 275 amino acids, which was detected in peripheral blood mononuclear cells and serum from the patient. The functional characterization of recombinant TNAP275 revealed no enzymatic activity nor any dominant-negative effect, relevant for the heterozygous parents. Nevertheless correct pre-mRNA splicing can take place without the branch-point sequence to a limited extend, as concluded from the ALPL cDNA, obtained from patient's PBMC, and from the low serum AP activity. These data reaffirm that in clear cut clinical cases, where conventional sequencing including the coding sequence and direct exon-intron-boundaries fails to detect mutations, deeper analyses of regulatory important motifs like branch-point sequences are required to establish a genetic diagnosis. PMID- 27777121 TI - Efficacy of a new topical cationic emulsion of cyclosporine A on dry eye clinical signs in an experimental mouse model of dry eye. AB - Dry eye disease (DED) is a complex, multifactorial pathology characterized by corneal epithelium lesions and inflammation. The aim of the present study was to evaluate the efficacy of a cationic emulsion of cyclosporine A (CsA) in a mouse model that mimics severe dry eye. Eight to 12-week-old female C57BL/6N mice with tail patches of scopolamine were housed in controlled environment chambers to induce dry eye. At day three, following dry eye confirmation by corneal fluorescein staining (CFS, score 0-15) and phenol red thread (PRT) lacrimation test, the mice (n = 10/gp) were either treated 3 times a day in both eyes with drug-free cationic emulsion, a 0.1% CsA cationic emulsion, or 1% methylprednisolone (positive control), or non-treated. Aqueous tear production and CFS scores were evaluated at baseline and throughout the treatment period. The lacrimation test confirmed the scopolamine-induced decrease in aqueous production by the lacrimal gland. A reduction of 59% in induced-CFS was observed following topical treatment with 0.1% CsA. The beneficial effect of the cationic emulsion vehicle itself on keratitis was also clearly evidenced by its better performance over 1% methylprednisolone, -36%, vs. -28% on the CFS scores, respectively. This study indicates that the cationic emulsion of CsA (0.1%) was a very effective formulation for the management of corneal epithelium lesions in a severe DED mouse model. In addition, it performed better than a potent glucocorticosteroid (1% methylprednisolone). This cationic emulsion of CsA (0.1%), combining CsA and a tear film oriented therapy (TFOT), i.e. with vehicle properties that mechanically stabilize the tear film, represents a promising new treatment strategy for the management of the signs of dry eye. PMID- 27777122 TI - Mapping wild-type and R345W fibulin-3 intracellular interactomes. AB - Fibulin-3 (F3) is an important, disulfide-rich, extracellular matrix glycoprotein that has been associated with a number of diseases ranging from cancer to retinal degeneration. An Arg345Trp (R345W) mutation in F3 causes the rare, autosomal dominant macular dystrophy, Malattia Leventinese. The purpose of this study was to identify and validate novel intracellular interacting partners of wild-type (WT) and R345W F3 in retinal pigment epithelium cells. We used stable isotope labeling by amino acids in cell culture (SILAC) to generate 'heavy' and 'light' isotopically labeled ARPE-19 cell populations which were subsequently infected with adenovirus encoding for FLAG-tagged WT or R345W F3. After immunoprecipitation, interacting proteins were identified by multidimensional protein identification technology (MudPIT). We identified sixteen new intracellular F3 interacting partners, the vast majority of which are involved in protein folding and/or degradation in the endoplasmic reticulum (ER). Eight of these interactions (ANXA5, ERdj5, PDIA4, P4HB, PDIA6, RCN1, SDF2L1, and TXNDC5) were verified at the western blotting level. These F3 interactome results can serve as the basis for pursuing targeted genetic or pharmacologic approaches in an effort to alter the fate of either WT or mutant F3. PMID- 27777123 TI - Descemet membrane adhesion strength is greater in diabetics with advanced disease compared to healthy donor corneas. AB - Descemet membrane endothelial keratoplasty (DMEK) is an increasingly popular surgical procedure for treating ocular diseases that require a corneal transplant. Previous studies have found that tissue tearing during surgical preparation is more likely elevated in eyes from donors with a history of diabetes mellitus. To quantify these potential differences, we established an experimental technique for quantifying the force required to separate the endothelium-Descemet membrane complex (EDM) from stroma in human donor corneal tissue, and we assessed differences in adhesion strength between diabetic and non diabetic donor corneas. Transplant suitable corneas were obtained from 23 donors 50-75 years old with an average preservation to assay time of 11.5 days. Corneas were classified from a medical records review as non-diabetic (ND, n = 9), diabetic without evidence of advanced disease (NAD, n = 8), or diabetic with evidence of advanced disease (AD, n = 10). Corneas were sectioned into 3 mm wide strips and the EDM peeled from the stroma. Using the force-extension data obtained from mechanical peel testing, EDM elastic peel tension (TE), elastic stiffness (SE), average delamination tension (TD), and maximum tension (TMAX) were calculated. Mean TE, SE, TD, and TMAX values for ND corneas were 0.78 +/- 0.07 mN/mm, 0.37 +/- 0.05 mN/mm/mm, 0.78 +/- 0.08 mN/mm, and 0.94 +/- 0.17 mN/mm, respectively. NAD values did not differ significantly. However, AD values for TE (1.01 +/- 0.18 mN/mm), TD (1.09 +/- 0.21 mN/mm), and TMAX (1.37 +/- 0.24 mN/mm) were greater than ND and NAD corneas (P < 0.05). SE did not differ significantly between groups. These findings provide proof of the concept that chronic hyperglycemia from diabetes mellitus results in a phenotypically more adhesive interface between Descemet membrane and the posterior stroma in donor corneal tissue. Results of this study provide a foundation for further investigations into the impact of diabetes on the posterior cornea, eye banking, and keratoplasty. PMID- 27777124 TI - Effect of pharmacologically induced retinal degeneration on retinal autofluorescence lifetimes in mice. AB - Fluorescence lifetime imaging ophthalmoscopy (FLIO) was used to investigate retinal autofluorescence lifetimes in mouse models of pharmacologically induced retinal degeneration over time. Sodium iodate (NaIO3, 35 mg/kg intravenously) was used to induce retinal pigment epithelium (RPE) degeneration with subsequent loss of photoreceptors (PR) whereas N-methyl-N-nitrosourea (MNU, 45 mg/kg intraperitoneally) was employed for degeneration of the photoreceptor cell layer alone. All mice were measured at day 3, 7, 14, and 28 after the respective injection of NaIO3, MNU or NaCl (control). Fluorescence lifetime imaging was performed using a fluorescence lifetime imaging ophthalmoscope (Heidelberg Engineering, Heidelberg, Germany). Fluorescence was excited at 473 nm and fluorescence lifetimes were measured in a short and a long spectral channel (498 560 nm and 560-720 nm). Corresponding optical coherence tomography (OCT) images were consecutively acquired and histology was performed at the end of the experiments. Segmentation of OCT images and histology verified the cell type specific degeneration process over time. Retinal autofluorescence lifetimes increased from day 3 to day 28 in mice after NaIO3 treatment. Finally, at day 28, fluorescence lifetimes were prolonged by 8% in the short and 61% in the long spectral channel compared to control animals (p = 0.21 and p = 0.004, respectively). In mice after MNU treatment, the mean retinal autofluorescence lifetimes were already decreased at day 3 and retinal lifetimes were finally shortened by 27% in the short and 51% in the long spectral channel at day 28 (p = 0.0028). In conclusion, degeneration of the RPE with subsequent photoreceptor degeneration by NaIO3 lead to longer mean fluorescence lifetimes of the retina compared to control mice, whereas during specific degeneration of the photoreceptor layer induced by MNU shorter lifetimes were measured. Therefore, short retinal fluorescence lifetimes may originate from the RPE and may be modified by the overlaying retinal layers. PMID- 27777125 TI - Dynamic Changes of IsiA-Containing Complexes during Long-Term Iron Deficiency in Synechocystis sp. PCC 6803. AB - Iron stress-induced protein A (IsiA), a major chlorophyll-binding protein in the thylakoid membrane, is significantly induced under iron deficiency conditions. Using immunoblot analysis and 77 K fluorescence spectroscopy combined with sucrose gradient fractionation, we monitored dynamic changes of IsiA-containing complexes in Synechocystis sp. PCC 6803 during exposure to long-term iron deficiency. Within 3 days of exposure to iron deficiency conditions, the initially induced free IsiA proteins preferentially conjugated to PS I trimer to form IsiA18-PS I trimers, which serve as light energy collectors for efficiently transmitting energy to PS I. With prolonged iron deficiency, IsiA proteins assembled either into IsiA aggregates or into two other types of IsiA-PS I supercomplexes, namely IsiA-PS I high fluorescence supercomplex (IHFS) and IsiA PS I low fluorescence supercomplex (ILFS). Further analysis revealed a role for IsiA as an energy dissipater in the IHFS and as an energy collector in the ILFS. The trimeric structure of PS I mediated by PsaL was found to be indispensable for the formation of IHFS/ILFS. Dynamic changes in IsiA-containing complexes in cyanobacteria during long-term iron deficiency may represent an adaptation to iron limitation stress for flexible light energy distribution, which balances electron transfer between PS I and PS II, thus minimizing photooxidative damage. PMID- 27777126 TI - Design of a long-term follow-up effectiveness, immunogenicity and safety study of women who received the 9-valent human papillomavirus vaccine. AB - The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16-26years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare. PMID- 27777127 TI - The electronic medication complete communication (EMC2) study: Rationale and methods for a randomized controlled trial of a strategy to promote medication safety in ambulatory care. AB - BACKGROUND: Adverse drug events (ADEs) affect millions of patients annually and place a significant burden on the healthcare system. The Food and Drug Administration (FDA) has developed patient safety information for high-risk medications that pose serious public health concerns. However, there are currently few assurances that patients receive this information or are able to identify or respond correctly to ADEs. OBJECTIVE: To evaluate the effectiveness of the Electronic Medication Complete Communication (EMC2) Strategy to promote safe medication use and reporting of ADEs in comparison to usual care. METHODS: The automated EMC2 Strategy consists of: 1) provider alerts to counsel patients on medication risks, 2) the delivery of patient-friendly medication information via the electronic health record, and 3) an automated telephone assessment to identify potential medication concerns or ADEs. The study will take place in two community health centers in Chicago, IL. Adult, English or Spanish-speaking patients (N=1200) who have been prescribed a high-risk medication will be enrolled and randomized to the intervention arm or usual care based upon practice location. The primary outcomes of the study are medication knowledge, proper medication use, and reporting of ADEs; these will be measured at baseline, 4weeks, and three months. Intervention fidelity as well as barriers and costs of implementation will be evaluated. CONCLUSIONS: The EMC2 Strategy automates a patient-friendly risk communication and surveillance process to promote safe medication use while minimizing clinic burden. This trial seeks to evaluate the effectiveness and feasibility of this strategy in comparison to usual care. PMID- 27777128 TI - Learning about Activity and Understanding Nutrition for Child Health (LAUNCH): Rationale, design, and implementation of a randomized clinical trial of a family based pediatric weight management program for preschoolers. AB - Obesity affects nearly 2 million preschool age children in the United States and is not abating. However, research on interventions for already obese preschoolers is limited. To address this significant gap in the literature, we developed an intervention targeting obesity reduction in 2 to 5year olds, Learning about Activity and Understanding Nutrition for Child Health (LAUNCH). This paper describes the rationale, design, participant enrollment, and implementation of a 3-arm randomized, parallel-group clinical trial comparing LAUNCH to a motivational-interviewing intervention (MI) and standard care (STC), respectively. Whereas LAUNCH was designed as a skills based intervention, MI focused on addressing the guardian's motivation to make changes in diet and activity and providing tools to do so at the guardian's level of readiness to implement changes. Child body mass index z-score was the primary outcome, assessed at pretreatment, posttreatment (Month 6), and 6 and 12month follow-ups (Months 12 and 18). Mechanisms of weight change (e.g., dietary intake, physical activity) and environmental factors associated with weight (e.g., foods available in the home, caregiver diet) were also assessed. This study is unique because it is one of the few randomized controlled trials to examine a developmentally informed, clinic and home skills based behavioral family intervention for preschoolers who are already obese. Being obese during the preschool years increases the likelihood of remaining obese as an adult and is associated with serious health conditions; if this intervention is successful, it has the potential to change the health trajectories for young children with obesity. PMID- 27777130 TI - ATB-346, a novel hydrogen sulfide-releasing anti-inflammatory drug, induces apoptosis of human melanoma cells and inhibits melanoma development in vivo. AB - Inflammation plays a key role in tumor promotion and development. Indeed, cyclooxygenase-2 (COX-2) expression is strongly associated with different types of cancer. An emerging class of compounds with significant anti-inflammatory properties is the hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs). They consist of a traditional NSAID to which an H2S-releasing moiety is covalently attached. We have recently demonstrated that H2S donors inhibit melanoma cell proliferation. In the current study, we evaluated the potential beneficial effects of a new H2S-releasing derivative of naproxen, ATB 346 [2-(6-methoxynapthalen-2-yl)-propionic acid 4-thiocarbamoyl phenyl ester] which inhibits COX activity but also releases H2S. We used cell culture and a mouse melanoma model to evaluate the effect of ATB-346 on: i) in vitro growth of human melanoma cells; ii) in vivo melanoma development in mice. Cell culture studies demonstrated that ATB-346 reduced the in vitro proliferation of human melanoma cells and this effect was associated to induction of apoptosis and inhibition of NF-kappaB activation. Moreover, ATB-346 had novel Akt signaling inhibitory properties. Daily oral dosing of ATB-346 (43MUmol/kg) significantly reduced melanoma development in vivo. This study shows that ATB-346, a novel H2S NSAID, inhibits human melanoma cell proliferation by inhibiting pro-survival pathways associated with NF-kappaB and Akt activation. Furthermore, oral treatment with ATB-346 inhibits melanoma growth in mice. In conclusion, the combination of inhibition of cyclooxygenase and delivery of H2S by ATB-346 may offer a promising alternative to existing therapies for melanoma. PMID- 27777131 TI - Incorporating imaging into personalized medicine for the detection of prostate cancer: Pharmacological research-Urogenital pharmacology. AB - Imaging has played an important role in the administration of personalized medicine. From diagnosing diseases to guiding therapies, imaging has become an all-encompassing modality. With respect to prostate cancer, personalized management of the disease has been transformed by imaging. Specifically, multiparametric magnetic resonance imaging has emerged as a vital player in the detection, characterization, and localization of the disease thus making the incorporation of imaging in personalized prostate cancer management integral. In this review, the current role of imaging in personalized medicine for the management of prostate cancer is discussed. PMID- 27777132 TI - Reply to: Agonism at delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. PMID- 27777129 TI - ADD-ASPIRIN: A phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours. AB - BACKGROUND: There is a considerable body of pre-clinical, epidemiological and randomised data to support the hypothesis that aspirin has the potential to be an effective adjuvant cancer therapy. METHODS: Add-Aspirin is a phase III, multi centre, double-blind, placebo-controlled randomised trial with four parallel cohorts. Patients who have undergone potentially curative treatment for breast (n=3100), colorectal (n=2600), gastro-oesophageal (n=2100) or prostate cancer (n=2120) are registered into four tumour specific cohorts. All cohorts recruit in the United Kingdom, with the breast and gastro-oesophageal cohort also recruiting in India. Eligible participants first undertake an active run-in period where 100mg aspirin is taken daily for approximately eight weeks. Participants who are able to adhere and tolerate aspirin then undergo a double-blind randomisation and are allocated in a 1:1:1 ratio to either 100mg aspirin, 300mg aspirin or a matched placebo to be taken daily for at least five years. Those participants >=75years old are only randomised to 100mg aspirin or placebo due to increased toxicity risk. RESULTS: The primary outcome measures are invasive disease-free survival for the breast cohort, disease-free survival for the colorectal cohort, overall survival for the gastro-oesophageal cohort, and biochemical recurrence free survival for the prostate cohort, with a co-primary outcome of overall survival across all cohorts. Secondary outcomes include adherence, toxicity including serious haemorrhage, cardiovascular events and some cohort specific measures. CONCLUSIONS: The Add-Aspirin trial investigates whether regular aspirin use after standard therapy prevents recurrence and prolongs survival in participants with four non-metastatic common solid tumours. PMID- 27777133 TI - Callviminols A-E, new terpenoid-conjugated phloroglucinols from the leaves of Callistemon viminalis. AB - Callviminols A-E (1-5), five rare phloroglucinols bearing a framework embodying a hexahydrodibenzo[b,d]furan or 2-phenylcyclohexanol nucleus derived from a phloroglucinol-monoterpene adduct, were isolated from the leaves of Callistemon viminalis. Their structures were established via extensive spectroscopic measurements, with the absolute configuration of 5 determined by electronic circular dichroism (ECD) calculations. The plausible biogenetic pathway suggested that a unique oxidative radical addition and classic cationic cyclization were key biosynthetic steps. PMID- 27777135 TI - [Evaluation of the management of soft tissue sarcomas in Franche-Comte since the establishment of a multidisciplinary meeting at University Hospital. About 47 cases]. AB - GOALS OF STUDY: A multidisciplinary meeting (RCP) dedicated to the treatment of sarcoma was established in Franche-Comte in 2010. The goals of the study are: (a) To evaluate the treatment of sarcomas by confrontation with the existing literature; (b) To evaluate the influence of the multidisciplinary meeting on the management of sarcomas by hospitals at the regional level. MATERIALS AND METHODS: This is a retrospective single center study from 2010 to 2015 on patients with sarcoma and peripheral soft tissue drawn from a Netsarc database (National Network of sarcomas) and communicating cancer record. A database Cleanweb especially dedicated is created. RESULTS: Forty-seven patients were included: ten sarcomas at the upper member 26 to the lower limbs, 11 on the trunk. Forty patients were operated on: ten out of the university hospital, 28 at the university hospital and two in a coordinating center. Ninety percent of patients treated at the university hospital were in accordance with the recommandations. None of the patients operated out of the university hospital benefited from medical care in accordance to the recommendations. There is an increase in the number of files sent by the hospitals out of the university hospital discussed in multidisciplinary meeting, before treatment. CONCLUSION: The creation of a dedicated multidisciplinary meeting sarcoma improves the medical management of these tumors and decreases inappropriate medical managements thanks to a better education of the regional physicians. PMID- 27777134 TI - Is there any place for spontaneous healing in deep palmar burn of the child? AB - Child palm burns arise by contact and are often deep. The singular difficulty of such a disease comes from the necessity of the child growth and from the potential occurrence of constricted scars. In order to avoid sequelae, the actual gold standard is to practice an early excision of the burn, followed by a skin graft. The aim of this study is to evaluate the results of spontaneous healing combined with rehabilitation versus early skin grafting and rehabilitation concerning the apparition of sequelae. We performed a retrospective study in two burn centers and one rehabilitation hospital between 1995 and 2010. Eighty-seven hands have been included in two groups: one group for spontaneous healing and the other group for excision and skin grafting. Every child benefited from a specific rehabilitation protocol. The two main evaluation criteria were the duration of permanent splint wearing and the number of reconstructive surgery for each child. The median follow-up duration is about four years. The two groups were comparable. For the early skin grafting group, the splint wearing duration was 1/3 longer than for the spontaneous healing group. Concerning the reconstructive surgery, half of the grafted hands needed at least one procedure versus 1/5 of spontaneous healing hands. Our results show the interest of spontaneous healing in palmar burn in child, this observation requires a specific and intense rehabilitation protocol. PMID- 27777136 TI - Sex differences of hemispheric lateralization for faces and Chinese characters in early perceptual processing. AB - Previous event-related potential studies showed that the N170 response is left lateralized for words and right-lateralized for faces. Using a one-back repetition task, this study aimed to clarify sex differences in hemispheric specialization for both faces and words in early visual processing. We found that the N170 amplitude elicited by faces in males was right-lateralized, while in females it was bilateral. Interestingly, the N170 amplitude elicited by Chinese characters in males was bilateral, whereas in females it was left-lateralized. The N170 latency for faces was shorter in females than in males, whereas the N170 latency for Chinese characters was similar in females and males. The degree of lateralization of faces was significantly related to the degree of lateralization of Chinese characters in both the female and male groups. Therefore, sex differences in N170 hemispheric lateralization for faces are different from those for Chinese characters, and there are some links between the two categories of objects of expertise in early perceptual processing. PMID- 27777137 TI - Autosomal dominant Parkinson's disease: Incidence of mutations in LRRK2, SNCA, VPS35 and GBA genes in Brazil. AB - INTRODUCTION: Amongst Parkinson's disease (PD) genetic factors, mutations in LRRK2, SNCA, VPS35 and GBA genes are recognized causes of PD. Nonetheless, few genetic screenings have been conducted in families with a history of PD consistent with autosomal dominant inheritance (ADPD), and their relevance to the etiology of PD has been poorly explored in Latin American populations, such as the Brazilian one, with a high degree of admixture. METHODS: In order to assess the contribution of specific mutations in LRRK2, SNCA, VPS35 and GBA genes to ADPD in Brazil, we conducted the first molecular evaluation in a cohort of 141 index cases from families with ADPD. Genomic DNA was isolated from peripheral blood or saliva, and the molecular analysis was performed by TaqMan allelic discrimination assays or bidirectional sequencing. RESULTS: Heterozygous mutations in LRRK2 and GBA genes were identified in 10 (7.0%) probands, and all presented typical signs of classical PD. No mutations were found in SNCA or VPS35 genes. CONCLUSION: Our findings in a representative series of index cases from families with ADPD emphasize the important contribution of LRRK2 G2019S and GBA (L444P and N370S) mutations to parkinsonism in Brazilian families. The absence of mutations in VPS35 and SNCA genes reveals that they are uncommon causes of PD in Brazil, corroborating previous studies that also failed to detect these genetic variants in PD patients from other populations. Recent discoveries of novel causative genes of autosomal dominant forms of PD expand the investigative possibilities and should be targeted on future studies. PMID- 27777138 TI - Effects of 4-phenyl butyric acid on high glucose-induced alterations in dorsal root ganglion neurons. AB - Mechanisms and pathways involving in diabetic neuropathy are still not fully understood but can be unified by the process of overproduction of reactive oxygen species (ROS) such as superoxide, endoplasmic reticulum (ER) stress, downstream intracellular signaling pathways and their modulation. Susceptibility of dorsal root ganglion (DRG) to internal/external hyperglycemic environment stress contributes to the pathogenesis and progression of diabetic neuropathy. ER stress leads to abnormal ion channel function, gene expression, transcriptional regulation, metabolism and protein folding. 4-phenyl butyric acid (4-PBA) is a potent and selective chemical chaperone; which may inhibit ER stress. It may be hypothesized that 4-PBA could attenuate via channels in DRG in diabetic neuropathy. Effects of 4-PBA were determined by applying different parameters of oxidative stress, cell viability, apoptosis assays and channel expression in cultured DRG neurons. Hyperglycemia-induced apoptosis in the DRG neuron was inhibited by 4-PBA. Cell viability of DRG neurons was not altered by 4-PBA. Oxidative stress was significantly blocked by the 4-PBA. Sodium channel expression was not altered by the 4-PBA. Our data provide evidence that the hyperglycemia-induced alteration may be reduced by the 4-PBA without altering the sodium channel expression. PMID- 27777139 TI - Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Myelodysplastic Syndrome Harboring Trisomy 8. AB - Trisomy 8 (+8) is 1 of the most common cytogenetic abnormalities in adult patients with myelodysplastic syndrome (MDS). However, the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with MDS harboring +8 remains unclear. To evaluate the outcome and prognostic factors in patients with MDS harboring +8 as the sole cytogenetic abnormality or in association with other abnormalities, we retrospectively analyzed the Japanese registration data of 381 adult patients with MDS harboring +8 treated with allogeneic HSCT between 1990 and 2013. With a median follow-up period of 53 months, the probability of overall survival and cumulative incidence of relapse at 4 years were 51% and 22%, respectively. In the multivariate analysis, age > 50 years, 2 or more additional cytogenetic abnormalities, and a high risk at the time of HSCT according to the FAB/WHO classification were significantly associated with a higher overall mortality. Nevertheless, no significant impact of the outcome was observed in patients with 1 cytogenetic abnormality in addition to +8. Although 221 patients (58%) had advanced MDS at the time of HSCT, allogeneic HSCT offered a curative option for adult patients with MDS harboring +8. PMID- 27777140 TI - Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis. AB - Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% +/- 3% and of 4-year chronic GVHD was 13% +/- 2%. CIF of 1-year transplant-related mortality was 23% +/- 3% and of 4-year relapse was 27% +/- 3%. Leukemia-free survival (LFS) at 4 years was 50% +/- 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL. PMID- 27777142 TI - Targeting Integrin alpha4beta7 in Steroid-Refractory Intestinal Graft-versus-Host Disease. AB - Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin alpha4beta7, in 6 patients. All patients responded, and 4 of 6 patients are alive with a median follow-up of 10 months. PMID- 27777143 TI - The influence of photodynamic therapy with 5-aminolevulinic acid on senescent skin cancer cells. AB - BACKGROUND: Senescent cells, which are resistant to apoptosis, accumulate with age and after ultraviolet (UV) radiation, chemotherapy and radiation therapy. Preventing or eliminating senescent cells may be crucial for protection against skin cancer development and improving tumour treatment. The aim of the present study was to investigate the potential of photodynamic therapy (PDT) with 5 aminolevulinic acid (ALA) to induce senescence in skin cancer cells and to eliminate senescent cells induced by chemotherapy (bleomycin) or UVA (315-400nm) exposure. METHODS: WM115 and A431 cells were incubated with 1mM ALA for 2 and 4h, respectively, before exposure to blue light (10mW/cm2, 0-80s, 0-0.8J/cm2). WM115 cells were treated once with 106J/cm2 (58.4mW/cm2, 30.25min) UVA 6days before ALA PDT or with 0.24IU/ml bleomycin for 7days to induce senescence before ALA-PDT. Cell viability was monitored by the MTT colorimetric assay. Senescent cells were detected using senescence-associated-beta-galactosidase (SA-beta-Gal) staining and morphological changes (enlarged, flat cells). RESULTS: ALA-PDT caused a light dose dependent increase in senescence. ALA-PDT induced senescence very effectively only in WM115 cells but not in A431 cells, while similar cytotoxic effects were observed in both cell lines. After ALA-PDT with 0.4J/cm2 around 70% of survived WM115 cells were senescent, while only around 5% of A431 cells were senescent after ALA-PDT with 0.8J/cm2. CONCLUSION: ALA-PDT can induce premature senescence and kill senescent cells induced by ALA-PDT itself, UVA and chemotherapy (bleomycin). Light doses must be properly chosen to photoinactivate ALA-PDT-induced senescent cells. PMID- 27777141 TI - Angiogenic Factors Correlate with T Cell Immune Reconstitution and Clinical Outcomes after Double-Unit Umbilical Cord Blood Transplantation in Adults. AB - Umbilical cord blood (UCB) is a valuable graft source for allogeneic hematopoietic stem cell transplantation (HSCT) in patients who lack adult donors. UCB transplantation (UCBT) in adults results in delayed immune reconstitution, leading to high infection-related morbidity and mortality. Angiogenic factors and markers of endothelial dysfunction have biologic and prognostic significance in conventional HSCT, but their role in UCBT has not been investigated. Furthermore, the interplay between angiogenesis and immune reconstitution has not been studied. Here we examined whether angiogenic cytokines, angiopoietin-1 (ANG-1) and vascular endothelial growth factor (VEGF), or markers of endothelial injury, thrombomodulin (TM) and angiopoietin-2 (ANG-2), associate with thymic regeneration as determined by T cell receptor excision circle (TREC) values and recovery of T cell subsets, as well as clinical outcomes in adult recipients of UCBT. We found that plasma levels of ANG-1 significantly correlated with the reconstitution of naive CD4+CD45RA+ and CD8+CD45RA+ T cell subsets, whereas plasma levels of VEGF displayed a positive correlation with CD4+CD45RO+ T cells and regulatory T cells and a weak correlation with TRECs. Assessment of TM and ANG-2 revealed a strong inverse correlation of both factors with naive T cells and TRECs. The angiogenic capacity of each patient's plasma, as determined by an in vitro angiogenesis assay, positively correlated with VEGF levels and with reconstitution of CD4+ T cell subsets. Higher VEGF levels were associated with worse progression-free survival and higher risk of relapse, whereas higher levels of TM were associated with chronic graft-versus-host disease and nonrelapse mortality. Thus, angiogenic factors may serve as valuable markers associated with T cell reconstitution and clinical outcomes after UCBT. PMID- 27777144 TI - Over expression of 5-aminolevulinic acid synthase 2 increased protoporphyrin IX in nonerythroid cells. AB - Protoporphyrin IX has been used as an efficient sensitizer in photodynamic diagnosis, photodynamic therapy, and sonodynamic therapy. The level of protoporphyrin IX is very important for diagnostic or therapy effects. 5 aminolevulinic acid synthase 2 (ALAS2) is the key enzyme upstream of protoporphyrin IX synthesis. To increase protoporphyrin IX accumulation, ALAS2 over-expression transgenic mice were generated. Plasmid containing alas2 gene was transfected in colonic carcinoma cell lines. Both in tissues of transgenic mice and in colonic carcinoma cells, the amount of protoporphyrin IX accumulation did increase. In addition, the level of heme, which is down stream of protoporphyrin IX did not change. Overexpression ALAS2 in nonerythriod cells may become a novel approach to cause protoporphyrin IX accumulation. PMID- 27777145 TI - Characterisation of Lesions after Stereotactic Radiosurgery for Brain Metastases: Impact of Delayed Contrast Magnetic Resonance Imaging. AB - AIMS: To investigate if brain metastases and radiation injuries after stereotactic radiosurgery (SRS) have different signal intensity (SI) time courses up to 55 min after contrast agent application and if delayed contrast magnetic resonance imaging (MRI) contributes to improve diagnostic accuracy. MATERIALS AND METHODS: Thirty-four consecutive patients treated with SRS for cerebral metastases were prospectively enrolled in the study. T1-weighted images were acquired on a 3-Tesla MR unit at three time points, at 2 (TP1), 15 (TP2) and 55 (TP3) min after administering contrast agent. A simultaneous, matched-pairs approach was used for region of interest analysis of the entire contrast enhancing lesion (SI-e), the centre (SI-c), the border of the lesion (SI-b) and the adjacent non-contrast-enhancing tissue (SI-p). SIs of brain metastases and radiation injuries after SRS were compared using a two-level, linear, mixed effects regression model. RESULTS: In total, 41 lesions were analysed: 16 metastases and 25 radiation injuries. The SI time course of SI-e, SI-c and SI-b proved to be significantly different for both entities (P < 0.001) from TP2 to TP3. The SI of 39/41 lesions increased from TP1 to TP2 for the three parameters. Radiation injuries showed a further signal increase at least for SI-c from TP2 to TP3, whereas for all the three parameters SI decreased in all metastases. CONCLUSION: Brain metastases and radiation injuries after SRS have a characteristic and statistically significantly different SI time course on sequential gadolinium enhancement MRI when late MR studies are included. PMID- 27777146 TI - The Rapid Access Palliative Ambulatory Radiotherapy Clinic as an Educational Tool - Experience of Leeds Cancer Centre. PMID- 27777147 TI - Hypofractionation for Prostate Cancer: Time to Change. PMID- 27777148 TI - Eleclazine, an inhibitor of the cardiac late sodium current, is superior to flecainide in suppressing catecholamine-induced ventricular tachycardia and T wave alternans in an intact porcine model. AB - BACKGROUND: The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented. OBJECTIVE: The effectiveness of the novel cardiac late sodium inhibitor eleclazine in suppressing catecholamine-induced VT in a large animal model was compared with that of flecainide. METHODS: In 13 closed-chest anesthetized Yorkshire pigs, spontaneous VT and surges in T-wave alternans (TWA) level measured using the Modified Moving Average method were induced by epinephrine (2.0 ug/kg, i.v., bolus over 1 minute). Effects of eleclazine (0.3 mg/kg, i.v., infused over 15 minutes; n = 6) or flecainide (1 mg/kg, i.v., bolus over 2 minutes followed by 1 mg/kg/hr, i.v., for 1 hour; n = 7) on VT incidence and TWA level were measured from right intraventricular electrogram recordings. RESULTS: Epinephrine reproducibly elicited hemodynamically significant spontaneous VT in all 13 pigs and increased TWA level by 33-fold compared to baseline (P < .001). Eleclazine reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 51% (from 31.3 +/- 1.91 to 15.2 +/- 5.08 episodes; P = .038) and the incidence of 3- to 7-beat VT by 56% (from 10.8 +/- 3.45 to 4.7 +/- 3.12 episodes; P = .004). Concurrently, the drug reduced the peak epinephrine-induced TWA level by 64% (from 217 +/- 22.2 to 78 +/- 15.3 uV; P < .001). Flecainide also reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 53% (from 40.4 +/- 6.37 to 19.0 +/- 2.73 episodes; P = .024) but did not affect the incidence of VT (from 15.0 +/- 3.08 to 11.6 +/- 2.93 episodes; P = .29) or the peak TWA level (from 207 +/- 30.6 to 172 +/- 26.2 uV; P = .34). CONCLUSION: Selective inhibition of cardiac late sodium current with eleclazine is more effective than flecainide in reducing catecholamine-induced VT and TWA in an intact porcine model. PMID- 27777149 TI - Ruptured Wide-Necked Aneurysms: Is Stent-Assisted Coiling During Posthemorrhage Days 4-10 Safe and Efficient? AB - BACKGROUND: Recent studies have reported the use of stent-assisted coiling (SAC) for wide-necked aneurysms in patients with acute subarachnoid hemorrhage (SAH). This study attempted to determine whether it is safe and efficient to use SAC for wide-necked aneurysms during post-SAH days 4-10. METHODS: We reviewed 126 consecutive patients with ruptured wide-necked aneurysms who underwent SAC. The patients were classified into the early cohort (SAC was performed within post-SAH days 0-3) and late cohort (SAC was performed within post-SAH days 4-10). Intergroup differences in patients' demographics, aneurysm features, angiographic vasospasm, periprocedural complications, and clinical and angiographic outcomes were analyzed. RESULTS: Of the 126 study patients, there were 70 (55.6%) in the early cohort and 56 (44.4%) in the late cohort. Angiographic vasospasm was significantly more likely to occur in patients treated in the late cohort (P < 0.05). No difference (P > 0.05) in age, sex, hypertension, dichotomized Fisher grade, dichotomized Hunt-Hess score, aneurysm features, aneurysm location, or periprocedural complications was found between the cohorts. We followed up 112 patients, in whom clinical and angiographic results showed no statistical significance (P > 0.05) between the 2 cohorts. When the patients were divided based on the dichotomized modified Rankin Scale into the "good outcome" and "poor outcome" groups at 6 months follow-up, higher Hunt-Hess scores (P < 0.001) were the only independent risk factors for poor outcome on multivariate logistic regression analysis. CONCLUSIONS: Patients with ruptured wide-necked aneurysms treated on posthemorrhage days 4-10 did not appear to have worse outcomes compared to patients treated on posthemorrhage days 0-3. PMID- 27777150 TI - Risk Factors of Preoperative and Early Postoperative Seizures in Patients with Meningioma: A Retrospective Single-Center Cohort Study. AB - OBJECTIVE: Well-defined risk factors for the identification of patients with meningioma who might benefit from preoperative or early postoperative seizure prophylaxis are unknown. We investigated and quantified risk factors to determine individual risks of seizure occurrence in patients with meningioma. METHODS: A total of 634 adult patients with meningioma were included in this retrospective cohort study. Patient gender and age, tumor location, grade and volume, usage of antiepileptic drugs (AEDs) and extent of resection were determined. RESULTS: Preoperative and early postoperative seizures occurred in 15% (n = 97) and 5% (n = 21) of the patients, respectively. Overall, 502 and 418 patients were eligible for multivariate logistic regression analyses of preoperative and early postoperative seizures, respectively. Male gender (odds ratio [OR], 2.06; P = 0.009), a non-skull base location (OR, 4.43; P < 0.001), and a tumor volume of >8 cm3 (OR, 3.05; P = 0.002) were associated with a higher risk of preoperative seizures and were used to stratify the patients into 3 prognostic groups. The high-risk subgroup of patients with meningioma showed a seizure rate of >40% (OR, 9.8; P < 0.001). Only a non-skull base tumor location (OR, 2.61; P = 0.046) was identified as a significant risk factor for early postoperative seizures. AEDs did not reduce early postoperative seizure occurrence. CONCLUSIONS: Seizure prophylaxis might be considered for patients at high risk of developing seizures who are for other reasons being considered for watchful waiting instead of resection. In contrast, our data do not provide any evidence of the efficacy of perioperative AEDs in patients with meningioma. PMID- 27777151 TI - Management of Patients with Primary Intramedullary Spinal Cord Glioblastoma. AB - BACKGROUND: Primary intramedullary spinal cord glioblastomas are very rare tumors of the spinal cord. They imply a very poor prognosis because complete surgical resection is not possible as the result of the infiltrative growth of these tumors. The aim of this study is to present our data achieved with an aggressive multimodality treatment. METHODS: We retrospectively reviewed our clinical database. All patients with histologically proven intramedullary spinal cord glioblastoma treated in our department were included in this study. RESULTS: Four patients with intramedullary spinal cord glioblastoma were identified between 2006 and 2015, all of whom were female. Mean age at the time of surgery was 33.5 years (range 14-50 years). Tumors were located in the cervical region in 2 patients and in the thoracic region in 2 patients. All 4 patients underwent microsurgical biopsy of the tumor. After surgery, all patients received radiation and temozolomide treatment. One patient underwent additional therapy with Bevacizumab, another patient received Rapamycin and Sunitinib, and the third patient received Chlorethyl-cyclohexyl-nitroso-urea and Etoposide as additional therapy after tumor regrowth. Tumor progression occurred in a mean time of 18.2 months (6-32 months). In this series, all patients died as the result of progression of the malignancy; median survival after diagnosis was 32.5 months. CONCLUSIONS: The surgical outcome of intramedullary spinal cord glioblastoma still remains poor. Severe disability and amelioration of the neurologic status lead to reduced quality of life; however, an aggressive multimodal and interdisciplinary treatment for the disease may be associated with longer survival. PMID- 27777152 TI - Prophylactic Antiepileptic Drug Use in Patients with Brain Tumors Undergoing Craniotomy. AB - BACKGROUND: Prophylactic use of antiepileptic drugs (AEDs) for patients undergoing brain tumor surgery is common practice despite lack of clear evidence. We hypothesized that prophylactic AED (pAED) use did not affect seizure rates in patients with brain tumor who underwent craniotomy for tumor resection. METHODS: A retrospective review was performed of 606 patients who underwent surgery for brain tumors from 2006 to 2013 at the University of Florida, excluding patients with preexisting seizure condition before tumor diagnosis. Data were analyzed to determine seizure incidence, AED use, and AED toxicities. RESULTS: Most patients (81%) had no seizure on presentation. Eight patients did not present with seizure but had seizure postoperatively, and 9 patients did not present with seizure or have seizure postoperatively but did have seizure on follow-up. Despite not presenting with a seizure preoperatively, 208 patients (43%) were placed on pAED preoperatively, 313 patients (64%) were on AED in the postoperative period, and 274 patients (56%) remained on AED at discharge. The pAED use odds ratio for seizures was 1.3 (95% confidence interval, 0.5-3.4; P = 0.599). At last follow up, 34% of patients with no seizure on presentation remained on pAEDs. CONCLUSIONS: pAEDs did not significantly reduce postoperative seizures in patients with brain tumor in this analysis. In addition, pAED was often continued once prescribed even if the patient remained seizure free. PMID- 27777153 TI - Hypofractionated Stereotactic Radiosurgery and Radiotherapy to Large Resection Cavity of Metastatic Brain Tumors. AB - OBJECTIVE: To evaluate the efficacy of postoperative fractionated stereotactic radiosurgery (FSRS) and hypofractionated stereotactic radiotherapy (SRT) to large surgical cavities after gross total resection of brain metastases. METHODS: A retrospective analysis of 41 patients who had received tumor-bed FSRS (5 fractions) or SRT (10 fractions) after resection of brain metastasis between 2005 and 2015 was performed. All resection cavities were treated with a frameless linear accelerator-based system. Patients who underwent subtotal resection, single-dose SRS to the resection cavity, or were treated with a fractionation schedule other than 5 or 10 fractions, were excluded. RESULTS: Twenty-six patients were treated with 5 fractions and 15 patients with 10 fractions. The median planning target volume was 19.78 cm3 (12.3-28 cm3) to the 5-fraction group and 29.79 cm3 (26.3-47.6 cm3) to the 10-fraction group (P = 0.020). The 1-year and 2-year local control rates for all patients were 89.4% and 77.1%, respectively, and 89.6% and 78.6% were free from distant intracranial progression, respectively. No difference was observed in local control or freedom from distant intracranial progression between the 5-fraction or 10-fraction groups. The median overall survival was 28.27 months (95% confidence interval, 19.42-37.12) for all patients. No patient developed necrosis at the resection cavity. CONCLUSIONS: Fractionation offers the potential to exploit the different biological responses between neoplastic and normal tissues to ionizing radiation. The use of 5 daily doses of 5-6 Gy or 10 daily doses of 3 Gy is a good strategy to have a reasonable local control and avoid neurotoxicity. PMID- 27777155 TI - Shunting of Syringomyelic Cavities by Using a Myringotomy Tube: Technical Note and Long-Term Results. AB - BACKGROUND: Syringomyelia is a progressive cerebrospinal fluid disorder that can lead to irreversible spinal cord injury. To date, the optimal management of syringomyelic cavities remains controversial. Multiple studies have emphasized the importance of the craniocervical decompression or shunting procedures; however, except for syrinx related to Chiari malformation, nearly one-half of patients need to undergo reoperation. The purpose of the present study was to describe a simple and efficient surgical technique and to report the long-term radioclinical outcomes. MATERIAL AND METHODS: We report a series of 17 consecutive patients (10 male, 7 female) with symptomatic syringomyelia treated by myringotomy tube between January 1999 and January 2014. The mean follow-up was 43.6 months (5-118). For each case, a laminectomy was carried out at the level of the most expanded part of the syrinx. The myringotomy tube was then placed through a puncture myelotomy. RESULTS: Clinical examination showed disappearance of symptoms in 3 cases, a significant improvement in 8 cases, stabilization in 5 patients, and continuation of neurologic deterioration in 1 case. Thus, favorable long-term outcomes were observed in two-thirds of patients. No permanent postoperative complication was reported. The postoperative imaging showed complete or almost complete disappearance of the syrinx in 11 cases and a reduction over 80% in 4 cases. In 2 cases, the cavity remained stable. Moreover, just 2 patients had to undergo reoperation with the placement of a syringoperitoneal shunt. CONCLUSION: A myringotomy tube is a simple surgical technique that seems to be an efficient and safe treatment for syringomyelic cavities. PMID- 27777154 TI - A Retrospective Analysis of Vision-Impairing Tumors Among 467 Patients with Neurofibromatosis Type 2. AB - BACKGROUND: Vision is important for patients with hearing loss caused by neurofibromatosis type 2 (NF2). Tumors adjacent to the anterior visual pathway can potentially impair the vision. Only a few case reports and small-series studies have been reported. OBJECTIVE: To evaluate the clinical features of tumors adjacent to the anterior visual pathway in a large series of patients with NF2. METHODS: Seventy-three patients with potentially vision-impairing tumors were carefully screened from among 467 patients with NF2. RESULTS: Among the 73 patients, 31 had intraorbital tumors, 21 had suprasellar meningiomas, and 21 had medial sphenoid ridge meningiomas. Of the 31 patients with intraorbital tumors, 17 had optic nerve sheath meningiomas, 9 had intraorbital schwannomas, 3 had spheno-orbital meningiomas, 1 had an anterior cranial fossa-orbital meningioma, and 1 had a cranio-orbital schwannoma. To the date of the last follow-up, 43 patients (58.9%) experienced visual loss. In most cases, hearing loss tended to occur earlier than visual loss. Six patients underwent early operations, and they recovered well without any further vision damage. Six other patients underwent operations after having no functional visual ability in the affected eyes, and their visual ability was not saved. CONCLUSIONS: Tumors adjacent to the anterior visual pathway, although uncommon in patients with NF2, can cause progressive visual loss. Early surgical intervention seems to be the primary treatment strategy, except for in patients' optic nerve sheath meningiomas. If patients adopt a wait and see policy, regular visual examination seems to be mandatory. PMID- 27777156 TI - The Role of ABO Blood Group in Cerebral Vasospasm, Associated Intracranial Hemorrhage, and Delayed Cerebral Ischemia in 470 Patients with Subarachnoid Hemorrhage. AB - OBJECTIVE: Rupture of an intracranial aneurysm usually presents with an acute onset and requires multidisciplinary intensive care treatment and the overall death and disability rates are high. The ABO blood type is known to play an important role in hemostasis, thrombosis, and vascular NO response. The aspect of ABO blood type in onset, clinical progress, and outcome after subarachnoid hemorrhage (SAH) is largely unexplored. We conducted this study to elucidate the association of ABO blood type with the occurrence and outcome of aneurysmal SAH. METHODS: In our retrospective study, 470 patients with aneurysmal SAH treated at our institution were included. We performed a chi2 test for comparison between blood types and World Federation of Neurosurgical Societies admission status, cerebral vasospasm, delayed infarction, associated intracerebral hemorrhage and Fisher grade for analysis for their association with SAH. RESULTS: No significant difference between blood type and the reviewed variables for SAH outcome were identified: World Federation of Neurosurgical Societies admission status (odds ratio, 1.12; 95% confidence interval [CI], 0.7-1.6; P = 0.56); SAH-associated intracerebral hemorrhage (odds ratio, 0.81; 95% CI, 0.5-1.3; P = 0.36); cerebral vasospasm (odds ratio, 1.08; 95% CI, 0.7-1.6; P = 0.71); DCI (odds ratio, 1.23; 95% CI, 0.8-1.8; P = 0.30); Fisher grade (odds ratio, 1.13; 95% CI, 0.7-1.6; P = 0.19). CONCLUSIONS: Although a possible relationship between the ABO blood group and the clinical course of patients with SAH was hypothesized, our study showed no significant influence of patient's ABO blood type on cerebral vasospasm onset, SAH-associated intracerebral hemorrhage, or delayed infarction. PMID- 27777157 TI - Gamma Knife Radiosurgery for Residual and Recurrent Vestibular Schwannomas After Previous Surgery: Clinical Results in a Series of 90 Patients and Review of the Literature. AB - OBJECTIVE: Complete removal of vestibular schwannomas (VS) is not always achievable without any risk of disabling postoperative complications, especially in terms of facial nerve function. Moreover, even after gross total removal, a relevant rate of recurrence has been reported. The aim of this study is to validate Gamma Knife radiosurgery (GKRS) as an effective strategy to treat tumor regrowth after previous surgery. METHODS: Ninety patients treated with GKRS for VS after previous microsurgery were included in the present study. GKRS was performed at a median of 31 months (range, 4-174 months) postoperatively. Mean tumor volume was 3.35 cm3 (median, 2.5 cm3; range, 0.027-13 cm3) and median marginal dose was 13 Gy. RESULTS: At a mean follow-up of 77.2 months, tumor control was achieved in 90% of patients: 2 patients underwent repeated GKRS, and 7 patients underwent further microsurgery. Tumor shrinkage at last follow-up was recorded in 80.3% of cases. The complication rate was low and many consisted of a transient worsening of preexisting symptoms. The overall incidence of persisting facial nerve deficit and trigeminal nerve impairment was, in both cases, 3.3%. Two of 5 patients (40%) preserved functional hearing at last follow-up. One patient (1.1%) underwent ventriculoperitoneal shunting 12 months after GKRS. CONCLUSIONS: GKRS is a safe and effective treatment for growing residual and recurrent VSs, with tumor control obtained in 90% of cases and a low morbidity rate. Moreover, the possibility of treating patients with major medical comorbidities constitutes a significant advantage over repeated surgery. PMID- 27777158 TI - Cyclic Sciatica and Back Pain Responds to Treatment of Underlying Endometriosis: Case Illustration. AB - BACKGROUND: Multiple causes outside the spine can mimic spinal back pain. Endometriosis is an important gynecologic disorder, which commonly affects the lower region of the female pelvis and less frequently the spine and soft tissues. The lumbosacral trunk is vulnerable to pressure from any abdominal mass originating from the uterus and the ovaries. Therefore symptoms of endometriosis include severe reoccurring pain in the pelvic area as well as lower back and abdominal pain. CASE DESCRIPTION: We report on a 39-year-old gymnast with cyclic sciatica and back pain, whose initial presentation initially led to a spinal fusion at L4/5 and L5/S1, but that procedure did not change her symptoms. Her diagnosis of endometriosis was not made until 2 years after her spinal fusion. Ultimately, once diagnosed with endometriosis of the retroperitoneal spinal and neural elements, her back and leg pain responded completely to hormonal therapy and then to a hysterectomy and a bilateral salpingo-oophorectomy. Because her true diagnosis of endometriosis was unknown and she had some degenerative changes in her spine, she underwent a spinal fusion that would probably not have been done if the diagnosis of endometriosis had been suggested. CONCLUSIONS: It is critical for any clinician who deals with back pain to at least consider the diagnosis of endometriosis in female patients who have a history of pelvic pain. The diagnosis of endometriosis should be considered in candidate patients by asking whether there is a significant hormonal cyclic nature to the symptoms, to prevent such unnecessary surgical adventures. PMID- 27777159 TI - Cervical Osteochondroma Causing Myelopathy in Adults: Management Considerations and Literature Review. AB - BACKGROUND: Osteochondromas are the most frequent benign bone tumors but only rarely occur along the spinal column and even more rarely induce symptoms from spinal cord compression. CASE DESCRIPTIONS: We report 2 adult patients, both with a history of hereditary multiple exostoses, who presented with cervical myelopathy secondary to osteochondromas. The first patient is a 22-year-old man with numbness and weakness of his right upper limb and neck pain. Radiologic images showed a bony tumor arising from the C3 lamina with evidence of severe spinal cord compression. The second patient is a 20-year-old woman with weakness of her left upper and lower limbs and progressive numbness of the left hand, as well as neck and back pain. Radiologic images showed a bony tumor arising from the C4 lamina with evidence of significant spinal cord compression and cord signal abnormality. Both patients underwent surgical excision of the epidural mass and pathology confirmed a diagnosis of osteochondroma. CONCLUSIONS: We discuss the role of surgical intervention, management, and postoperative follow up in adult patients with cervical osteochondromas. Recommended management includes radiographic imaging and surgical intervention, particularly when evidence of spinal cord impingement occurs. Consistent postoperative follow-up is necessary to ensure appropriate recovery of neurologic function. Surgical management of cervical osteochondromas typically results in excellent and stable clinical outcomes with rare recurrence. PMID- 27777160 TI - Growth Dynamics of Intracranial Tumors in Patients with Neurofibromatosis Type 2. AB - OBJECTIVE: Patients with neurofibromatosis type 2 (NF2) are prone to develop multiple intracranial neoplasms, such as schwannomas of the cranial nerves and meningiomas. The aim of our study was to investigate 1) the median growth rate per year, 2) the growth-free interval, and 3) the growth patterns of NF2 associated intracranial tumors. METHODS: All available magnetic resonance (MR) images of patients from the regional neurofibromatosis center were collected. The depicted tumors' volumes were then calculated if the tumors met the following inclusion criteria: contrast enhanced T1-weighted MRI datasets had to be available from at least two investigations and tumors had to be measurable on at least two slices. RESULTS: One-hundred and eighty-eight tumors from 52 patients (20 male, 32 female) met the inclusion criteria for volumetric analysis. Overall, the median follow-up time was 76.5 months per patient (range 13-199 months). After 5 years, the median tumor size was 196% +/- 338% for vestibular schwannomas (VS), 204% +/- 702% meningiomas (M), 128% +/- 64.9% for non-vestibular schwannomas (NVS) and 139% +/- 270% for pre-operated tumors of the cerebellopontine angle (TX), respectively. The median time to 20% tumor progression was 21 months for VS, NVS and TX, and 17 months for M. Overall, saltatory growth was the most common growth pattern (46.9%). CONCLUSIONS: Most NF2-associated tumors display a saltatory growth pattern. Meningiomas and untreated vestibular schwannomas grow rapidly and overall at similar rates. Tumors of the CPA that have been operated on and non-vestibular schwannomas show less relative growth per year. PMID- 27777161 TI - Oblique Lumbar Interbody Fusion: Technical Aspects, Operative Outcomes, and Complications. AB - OBJECTIVE: Anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) are commonly used approaches for lumbar spine fusion surgery, each with their own unique advantages and disadvantages. ALIF requires mobilization of the great vessels and peritoneum, and dissection of the psoas muscle in the LLIF technique is associated with postoperative neurologic complications in the proximal lower limb. The anterior-to-psoas (ATP) or oblique lumbar interbody fusion (OLIF) technique is the proposed solution to accessing the L1-L5 levels without the issues encountered with ALIF and LLIF. In this review, the technical nuances, operative outcomes, and complications with the ATP/OLIF technique in the current literature are summarized. METHODS: A systematic search of the literature was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data collected included operative time, blood loss, postoperative hospital stay, and complications, which were then pooled together. RESULTS: From the 16 studies selected, the mean blood loss was 109.9 mL, average operating time was 95.2 minutes, and mean postoperative hospital stay was 6.3 days. Fusion was achieved in 93% of levels operated. Incidence of intraoperative and postoperative complications was 1.5% and 9.9%, respectively. Transient thigh pain and/or numbness and hip flexion weakness occurred in 3.0% and 1.2% of patients, respectively. CONCLUSIONS: Early results on the ATP/OLIF technique are promising and warrant further investigation with well-designed prospective randomized studies to provide high-level evidence of the potential advantages over the ALIF and LLIF approaches. PMID- 27777162 TI - Safety and Efficacy of Noncompliant Balloon Angioplasty for the Treatment of Subarachnoid Hemorrhage-Induced Vasospasm: A Multicenter Study. AB - OBJECTIVE: Cerebral vasospasm following subarachnoid hemorrhage is the most important cause of neurologic decline after successful treatment of the ruptured aneurysm. We report safety and efficacy of noncompliant balloon angioplasty for treatment of cerebral vasospasm. METHODS: Three major U.S. academic institutions provided data on cerebral vasospasm treated with noncompliant balloon angioplasty between October 2004 and February 2016. Baseline characteristics, procedure details, and radiographic and clinical outcome data were collected and analyzed. RESULTS: There were 52 patients (median age 50 years; range, 27-73 years) who underwent 165 noncompliant balloon angioplasty procedures. Balloon angioplasty was performed most frequently in the middle cerebral artery (MCA) (49.1%) followed by the internal carotid artery (27.2%). Improvement in vasospasm severity occurred in 160 arteries (97.0%) without procedure-related complications. No independent predictor of angioplasty success was identified on multivariate analysis. Delayed cerebral ischemia occurred in 24 patients (46.2%) encompassing 36 vascular territories. The rate of delayed cerebral ischemia in territories supplied by vessels that underwent angioplasty at least once was 29.4%, 24.2%, 19.3%, and 0% for the anterior cerebral artery (ACA) territory, internal carotid artery territory (ACA, ACA/MCA watershed, or MCA), MCA territory, and posterior circulation. CONCLUSIONS: Our data suggest that noncompliant balloon angioplasty for treatment of subarachnoid hemorrhage-induced cerebral vasospasm is safe and effective. No predictors of angioplasty success were identified. The rate of delayed cerebral ischemia in territories supplied by vessels that underwent angioplasty was highest in the ACA territory and lowest in the posterior circulation. PMID- 27777163 TI - Comparative Study of 2 Skin Incisions for Microscopic Lumbar Discectomy. AB - OBJECTIVE: Microscopic lumbar discectomy is a common minimally invasive surgery. A transverse skin incision has sound theoretical cosmetic advantages compared with the classic vertical incision. We compared transverse and vertical skin incisions for microscopic discectomy regarding cosmetic outcome, postoperative pain, and the provided surgical cutaneous inlet. METHODS: This prospective study enrolled 86 patients who were randomly assigned to a vertical incision group or a transverse incision group. The maximum surgical cutaneous inlet provided was measured in 2 diameters. Pain was recorded on postoperative days 1, 3, and 7 using a numeric patient rating scale from 0 to 10 with 0 indicating no pain. The cosmetic appearance of the wound was evaluated by a plastic surgeon and by the patients as excellent, very good, good, fair, and poor. RESULTS: Compared with vertical incisions, transverse incisions provide similar surgical cutaneous inlets, cause higher pain scores on postoperative days 1 and 3 but a similar score on postoperative day 7, and ensure significantly better wound cosmesis. CONCLUSIONS: Transverse skin incision for microscopic lumbar discectomy is an applicable alternative to classic midline or paramedian vertical incision with better esthetic results. PMID- 27777164 TI - Upfront Gamma Knife Surgery for Giant Central Neurocytoma. AB - BACKGROUND: In this report, we present the results of using upfront Gamma Knife surgery (GKS) in the management of giant central neurocytoma (CNC) (volume >50 mL) without the initial removal of the tumor mass. CASE DESCRIPTIONS: Two patients underwent GKS for histologically proven CNC. Clinical and imaging studies were performed to evaluate the response to treatment. GKS involved delivery doses of 12 or 13 Gy to the tumor margin at the isodose line of 50%. Tumor response to GKS appeared as early as 4-6 months after GKS, at which point a dramatic reduction in volume was observed. No adverse effects of radiation or new neurologic deficits were observed in either of the cases. In case 1, we observed a reduction in tumor volume from 69 to 20 mL at 6 months and a further reduction to 10.3 mL at 86 months. In case 2, we observed a reduction in tumor volume from 62 to 31 mL at 4 months with a further reduction to 22.5 mL at 30 months. The female patient (case 1) showed mild weakness in the right lower limb after the minimal surgical removal of tumor using the cortical approach. No additional neurologic deficits were observed after GKS. The young male patient (case 2) presented a complete recovery without any signs of headache at 3 months after GKS. CONCLUSIONS: Based on this initial experience, it appears that GKS is an effective treatment for CNC and may be used for upfront management in cases of indolent clinical symptoms, even when the tumor is very large. PMID- 27777165 TI - Seven Cerebral Aneurysms: A Challenging Case from the Andean Slopes Managed with 1-Stage Surgery. AB - BACKGROUND: Treatment of multiple intracranial aneurysms is particularly demanding and even more so in a developing country where access to specialized centers may be prevented by different factors. METHODS: Single-stage surgical treatment of 7 cerebral aneurysms was performed in a 58-year-old woman from the northern Peruvian Andes. RESULTS: All 7 aneurysms were successfully and safely clipped through 2 lateral supraorbital craniotomies. The double clip technique was used in 3 aneurysms to prevent any residual aneurysmal neck. CONCLUSIONS: Good teamwork and correct application of microsurgical principles may allow effective treatment in complex neurosurgical cases even in resource-challenged environments. PMID- 27777166 TI - Rathke Cleft Cyst with Evidence of Rupture into Subarachnoid Space. AB - BACKGROUND: A Rathke cleft cyst (RCC) with nonhemorrhagic rupture mimicking pituitary apoplexy has been reported rarely. CASE DESCRIPTION: A 52-year-old woman, previously diagnosed with asymptomatic RCC, came to us with a severe headache, along with visual dysfunction and symptoms of pituitary insufficiency. Fluid-attenuated inversion recovery magnetic resonance imaging demonstrated diffuse hyperintensity in the cerebral cisterns, whereas watery clear cerebrospinal fluid was obtained by lumbar puncture. Surgery performed 1 month after onset revealed a nonhemorrhagic lesion, with a final diagnosis of nonhemorrhagic RCC rupture. CONCLUSIONS: We conclude that nonhemorrhagic RCC rupture and subsequent leakage of the contents into subarachnoid space were the underlying pathogenesis in the present case of RCC resembling apoplexy. PMID- 27777168 TI - Extramedullary hematopoiesis with spinal cord compression in pachydermoperiostosis. PMID- 27777167 TI - Zanthoxylum piperitum reversed alveolar bone loss of periodontitis via regulation of bone remodeling-related factors. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum piperitum (ZP) has been used to prevent toothache in East Asia. AIM OF STUDY: In this study, we investigated the effects of ZP on periodontitis along with alveolar bone loss. MATERIALS AND METHODS: Twenty-eight male Sprague-Dawley rats were assigned into 4 groups; non ligated (NOR), ligated and treated vehicle (CTR), ligated and treated 1mg/mL ZP (ZP1), and ligated and treated 100mg/mL ZP (ZP100). Sterilized 3-0 nylon ligature was placed into the subgingival sulcus around the both sides of mandibular first molar. After topical application of 1 and 100mg/mL ZP for 2 weeks, mandibles was removed for histology. In addition, SaOS-2 osteoblast cells were treated 1, 10 and 100MUg/mL ZP for 24h to analyze the expressions of alveolar bone-related markers. RESULTS: Several alveolar bone resorption pits, which indicate cementum demineralization were decreased by ZP treatment. Topical ZP treatment inhibited periodontitis-induced alveolar bone loss. In addition, there were significant reduction of osteoclastic activities following topical ZP treatment in periodontium. The expression of RANKL was decreased in SaOS-2 osteoblast cells by treating ZP, while that of OPG was increased. ZP treatment increased the expressions of Runx2 and Osterix in SaOS-2 cells. CONCLUSION: In summary, ZP treatment inhibited alveolar bone loss as well as maintained the integrity of periodontal structures via regulation of bone remodeling. ZP may be a therapeutic target for treating periodontitis. PMID- 27777169 TI - Ultrasound and follow-up of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is chronic rheumatic disorder leading to joint inflammation and potential structural damages. This destruction occurs early in the disease outcome leading to the concept of window of opportunity. New diagnosis RA criteria have been proposed to allow an earlier diagnosis and subsequently a better management of the disease. Moreover, tight control of the disease was able to improve the prognosis of RA. For this, rheumatologists need routinely feasible tools and ultrasound (US) appears as the ideal imaging modality. US is superior to clinical exam for the detection of subclinical synovitis. US has a good correlation with clinical findings and markers of inflammation. US persistence of synovitis is associated with higher rate of relapse and more radiographic progression. However, standardization of scoring and settings procedures is necessary before being universally accepted as a marker of disease activity. Finally, US did not improve the tight control strategy and did not replace clinical exam for RA management. PMID- 27777170 TI - Rheumatoid arthritis, insulin resistance, and diabetes. AB - Recent progress in the management of rheumatoid arthritis (RA) is turning attention toward comorbidities, such as diabetes. The objectives of this review are to clarify the links between RA and diabetes and to assess potential effects of disease-modifying antirheumatic drugs (DMARDs) on diabetes. The increased insulin resistance seen in RA is closely linked to the systemic inflammation induced by certain proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin-6. The prevalence of type 2 diabetes is increased in patients with RA. Furthermore, certain DMARDs including hydroxychloroquine, methotrexate, TNFalpha antagonist, and interleukin-1beta antagonists seem to improve the markers of glucose metabolism. In contrast, glucocorticoids tend to adversely affect glycemic control, particularly when taken chronically. Consequently, a crucial yet insufficiently applied rule is that cardiovascular risk factors must be sought and treated routinely, particularly as the choice of the DMARD may affect glucose metabolism. PMID- 27777171 TI - Effects of autophagy on joint inflammation. PMID- 27777172 TI - Seeing it all: Convolutional network layers map the function of the human visual system. AB - Convolutional networks used for computer vision represent candidate models for the computations performed in mammalian visual systems. We use them as a detailed model of human brain activity during the viewing of natural images by constructing predictive models based on their different layers and BOLD fMRI activations. Analyzing the predictive performance across layers yields characteristic fingerprints for each visual brain region: early visual areas are better described by lower level convolutional net layers and later visual areas by higher level net layers, exhibiting a progression across ventral and dorsal streams. Our predictive model generalizes beyond brain responses to natural images. We illustrate this on two experiments, namely retinotopy and face-place oppositions, by synthesizing brain activity and performing classical brain mapping upon it. The synthesis recovers the activations observed in the corresponding fMRI studies, showing that this deep encoding model captures representations of brain function that are universal across experimental paradigms. PMID- 27777173 TI - Continuous infusion of manganese improves contrast and reduces side effects in manganese-enhanced magnetic resonance imaging studies. AB - The ability to administer systemically high doses of manganese as contrast agent while circumventing its toxicity is of particular interest for exploratory MRI studies of the brain. Administering low doses either repeatedly or continuously over time has been shown to enable the acquisition of satisfactory MRI images of the mouse brain without apparent side effects. Here we have systematically compared the obtained MRI contrast and recorded potential systemic side effects such as stress response and muscle strength impairment in relation to the achieved contrast. We show in mice that administering MnCl2 via osmotic infusion pumps allows for a side-effect free delivery of a high cumulative dose of manganese chloride (480mg/kg bodyweight in 8 days). High contrast in MRI was achieved while we did not observe the weight loss or distress seen in other studies where mice received manganese via fractionated intraperitoneal injections of lower doses of manganese. As the normal daily conduct of the mice was not affected, this new manganese delivery method might be of particular use to study brain activity over several days. This may facilitate the phenotyping of new transgenic mouse models, the study of chronic disease models and the monitoring of changes in brain activity in long-term behavioral studies. PMID- 27777175 TI - Discrepancies between biopsy and formal excision histology of non-melanoma skin cancer. PMID- 27777174 TI - Chronnectomic patterns and neural flexibility underlie executive function. AB - Despite extensive research into executive function (EF), the precise relationship between brain dynamics and flexible cognition remains unknown. Using a large, publicly available dataset (189 participants), we find that functional connections measured throughout 56min of resting state fMRI data comprise five distinct connectivity states. Elevated EF performance as measured outside of the scanner was associated with greater episodes of more frequently occurring connectivity states, and fewer episodes of less frequently occurring connectivity states. Frequently occurring states displayed metastable properties, where cognitive flexibility may be facilitated by attenuated correlations and greater functional connection variability. Less frequently occurring states displayed properties consistent with low arousal and low vigilance. These findings suggest that elevated EF performance may be associated with the propensity to occupy more frequently occurring brain configurations that enable cognitive flexibility, while avoiding less frequently occurring brain configurations related to low arousal/vigilance states. The current findings offer a novel framework for identifying neural processes related to individual differences in executive function. PMID- 27777176 TI - When should axillary drains be removed? A meta-analysis of time-limited versus volume controlled strategies for timing of drain removal following axillary lymphadenectomy. AB - BACKGROUND: Despite numerous studies over the past few decades, the optimum strategy for deciding when to remove drains following axillary lymphadenectomy remains unknown. This meta-analysis aims to compare time-limited and volume controlled strategies for drain removal. METHODS: A total of 584 titles were identified following a systematic literature search of EMBASE, MEDLINE, Cinahl and the Cochrane library; 6 titles met our eligibility criteria. Data were extracted and independently verified by two authors. Time-limited drain removal was defined as drain removal at <5 days; volume-controlled strategies ranged from <20 ml/24 h to <50 ml/24 h. RESULTS: In all the studies, the time-limited approach resulted in earlier drain removal. Development of a seroma is 2.54 times more likely with early drain removal (Mantel-Haenszel Fixed Odds Ratio (OR) 2.54, p < 0.00001). However, there is no difference in infection rates between early and late drain removal (OR = 1.07, p = 0.76). CONCLUSIONS: This meta-analysis demonstrates that a strategy of early drain removal following axillary lymphadenectomy is safe, with no difference in infection rates; however, the incidence of seroma is significantly higher, which may necessitate more demanding outpatient care. There is a need for further well-designed clinical trials to address the clinical equipoise in this common area of surgical practice. PMID- 27777177 TI - Management of chest deformity caused by microtia reconstruction: Comparison of autogenous diced cartilage versus cadaver cartilage graft partial filling techniques. AB - BACKGROUND: Efforts to prevent chest wall deformity after costal cartilage graft are ongoing. In this study, we introduce a new method to prevent donor site deformation using irradiated cadaver cartilage (ICC) and compare this method to the autogenous diced cartilage (ADC) technique. METHODS: Forty-two pediatric patients comprised the ADC group (n = 24) and the ICC group (n = 18). After harvesting costal cartilage, the empty perichondrial space was filled with autologous diced cartilage in the ADC group and cadaver cartilage in the ICC group. Digital photographs and rib cartilage three-dimensional computed tomography (CT) data were analyzed to compare the preventive effect of donor site deformity. We compared the pre- and postoperative costal cartilage volumes using 3D-CT and graded the volumes (grade I: 0%-25%, grade II: 25%-50%, grade III: 50% 75%, and grade IV: 75%-100%). RESULTS: The average follow-up period was 20 and 24 months in the ADC and ICC groups, respectively. Grade IV maintenance of previous costal cartilage volume was evident postoperatively in 22% of patients in the ADC group and 82% of patients in the ICC group. Intercostal space narrowing and chest wall depression were less in the ICC group. There were no complications or severe resorption of cadaver cartilage. CONCLUSIONS: ICC support transected costal ring and prevented stability loss by acting as a spacer. The ICC technique is more effective in preventing intercostal space narrowing and chest wall depression than the ADC technique. CLINICAL TRIAL REGISTRY: Samsung Medical Center Institution Review Board, Unique protocol ID: 2009-10-006-008. This study is also registered on PRS (ClinicalTrials.gov Record 2009-10-006). PMID- 27777178 TI - Proteomic analysis of venom variability and ontogeny across the arboreal palm pitvipers (genus Bothriechis). AB - : Bothriechis is a genus of eleven currently recognized slender and arboreal venomous snakes, commonly called palm-pitvipers that range from southern Mexico to northern South America. Despite dietary studies suggesting that palm-pitvipers are generalists with an ontogenetic shift toward endothermic prey, venom proteomic analyses have revealed remarkable divergence between the venoms of the Costa Rican species, B. lateralis, B. schlegelii, B. supraciliaris, and B. nigroviridis. To achieve a more complete picture of the venomic landscape across Bothriechis, the venom proteomes of biodiversity of the northern Middle American highland palm-pitvipers, B. thalassinus, B. aurifer, and B. bicolor from Guatemala, B. marchi from Honduras, and neonate Costa Rican B. lateralis and B. schlegelii, were investigated. B. thalassinus and B. aurifer venoms are comprised by similar toxin arsenals dominated by SVMPs (33-39% of the venom proteome), CTLs (11-16%), BPP-like molecules (10-13%), and CRISPs (5-10%), and are characterized by the absence of PLA2 proteins. Conversely, the predominant (35%) components of B. bicolor are D49-PLA2 molecules. The venom proteome of B. marchi is similar to B. aurifer and B. thalassinus in that it is rich in SVMPs and BPPs, but also contains appreciable amounts (14.3%) of PLA2s. The major toxin family found in the venoms of both neonate B. lateralis and B. schlegelii, is serine proteinase (SVSP), comprising about 20% of their toxin arsenals. The venom of neonate B. schlegelii is the only palm-pitviper venom where relative high amounts of Kunitz type (6.3%) and gammaPLA2 (5.2%) inhibitors have been identified. Despite notable differences between their proteomes, neonate venoms are more similar to each other than to adults of their respective species. However, the ontogenetic changes taking place in the venom of B. lateralis strongly differ from those that occur in the venom of B. schlegelii. Thus, the ontogenetic change in B. lateralis produces a SVMP-rich venom, whereas in B. schlegelii the age-dependent compositional shift generates a PLA2-rich venom. Overall, genus-wide venomics illustrate the high evolvability of palm-pitviper venoms. The integration of the pattern of venom variation across Bothriechis into a phylogenetic and biogeographic framework may lay the foundation for assessing, in future studies, the evolutionary path that led to the present-day variability of the venoms of palm-pitvipers. SIGNIFICANCE: Bothriechis represents a monophyletic basal genus of eleven arboreal palm-pitvipers that range from southern Mexico to northern South America. Despite palm-pitvipers' putative status as diet generalists, previous proteomic analyses have revealed remarkable divergence between the venoms of Costa Rican species, B. lateralis, B. schlegelii, B. supraciliaris, and B. nigroviridis. Our current proteomic study of Guatemalan species, B. thalassinus, B. aurifer, and B. bicolor, Honduran B. marchi, and neonate B. lateralis and B. schlegelii from Costa Rica was undertaken to deepen our understanding of the evolutionary pattern of venom proteome diversity across Bothriechis. Ancestral characters are often, but not always, preserved in an organism's development. Venoms of neonate B. lateralis and B. schlegelii are more similar to each other than to adults of their respective species, suggesting that the high evolvability of palm-pitviper venoms may represent an inherent feature of Bothriechis common ancestor. Our genus-wide data identified four nodes of venom phenotype differentiation across the phylogeny of Bothriechis. Integrated into a phylogenetic and biogeographic framework, the pattern of venom variation across Bothriechis may lay the groundwork to establish whether divergence was driven by selection for efficient resource exploitation in arboreal 'islands', thereby contributing to the ecological speciation of the genus. PMID- 27777179 TI - Thiol oxidation and di-tyrosine formation in human plasma proteins induced by inflammatory concentrations of hypochlorous acid. AB - : In this study, we assessed the oxidative damage occurring in plasma proteins when human blood was exposed to inflammatory concentrations of hypochlorous acid (HOCl). We used specific thiol labelling and Western blot analyses to determine protein thiol oxidation, as well as analytical gel filtration HPLC coupled to fluorescence detection to explore formation of high molecular weight (HMW) protein aggregates. Thiol-containing proteins oxidized by HOCl were identified by redox proteomics. Mass spectrometry (MS) analysis was performed to elucidate the protein composition of HMW aggregates. alpha1-antitrypsin, transthyretin, and haptoglobin showed thiol oxidation at HOCl concentrations higher than those causing complete oxidation of albumin. At the highest HOCl concentrations, formation of carbonylated and di-tyrosine cross-linked HMW protein aggregates also occurred. MS analysis identified fibrinogen, complement C3 and apolipoprotein A-I as components of HMW protein aggregates. These results could be relevant for human diseases characterized by inflammatory conditions in which myeloperoxidase and HOCl are involved. BIOLOGICAL SIGNIFICANCE: In this study we evaluated the oxidative damage occurring on plasma proteins when reconstituted human blood was exposed to inflammatory concentrations of hypochlorous acid (HOCl). Pathophysiological concentrations of HOCl are able to induce different modifications on plasma proteins such as carbonylation, sulfhydryl oxidation and formation of high molecular weight (HMW) protein aggregates characterized by di tyrosine fluorescence. There are two relevant aspects emerging from this paper. The first one consists on identifying low abundant proteins undergoing sulfhydryl oxidation by biotin-maleimide derivatization followed by MALDI-TOF mass spectrometry. This approach suggests three low-abundant proteins undergoing HOCl induced oxidation: transthyretin, alpha1-antitrypsin, and haptoglobin. In addition, we analysed HMW protein aggregates forming after HOCl exposure. These aggregates are characterized by carbonylation, intra- and/or intermolecular di tyrosine bridges. After their isolation from SDS-PAGE gel electrophoresis, using electrospray tandem mass spectrometry coupled to reversed-phase nanoscale capillary liquid chromatography, we identified some protein constituents of these HMW aggregates such as alpha, beta, gamma fibrinogen chains, apolipoprotein A-I and complement C3. In particular, our work highlights how fibrinogen is an important constituent of HOCl-induced HMW protein aggregates validating the mass spectrometry result with additional experiments. Further investigations are required in order to evaluate the possibility to use carbonylated and di-Tyr cross-linked HMW protein aggregates as (early) biomarkers for disease progression in inflammatory conditions in which myeloperoxidase and HOCl are involved. PMID- 27777181 TI - Home visits are needed to address asthma health disparities in adults. AB - Research on asthma frequently recruits patients from clinics because the ready pool of patients leads to easy access to patients in office waiting areas, emergency departments, or hospital wards. Patients with other chronic conditions, and with mobility problems, face exposures at home that are not easily identified at the clinic. In this article, we describe the perspective of the community health workers and the challenges they encountered when making home visits while implementing a research intervention in a cohort of low-income, minority patients. From their observations, poor housing, often the result of poverty and lack of social resources, is the real elephant in the chronic asthma room. To achieve a goal of reduced asthma morbidity and mortality will require a first hand understanding of the real-world social and economic barriers to optimal asthma management and the solutions to those barriers. PMID- 27777182 TI - Autoimmune chronic spontaneous urticaria: What we know and what we do not know. AB - Chronic spontaneous urticaria (CSU) is a mast cell-driven skin disease characterized by the recurrence of transient wheals, angioedema, or both for more than 6 weeks. Autoimmunity is thought to be one of the most frequent causes of CSU. Type I and II autoimmunity (ie, IgE to autoallergens and IgG autoantibodies to IgE or its receptor, respectively) have been implicated in the etiology and pathogenesis of CSU. We analyzed the relevant literature and assessed the existing evidence in support of a role for type I and II autoimmunity in CSU with the help of Hill's criteria of causality. For each of these criteria (ie, strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy), we categorized the strength of evidence as "insufficient," "low," "moderate," or "high" and then assigned levels of causality for type I and II autoimmunity in patients with CSU from level 1 (causal relationship) to level 5 (causality not likely). Based on the evidence in support of Hill's criteria, type I autoimmunity in patients with CSU has level 3 causality (causal relationship suggested), and type II autoimmunity has level 2 causality (causal relationship likely). There are still many aspects of the pathologic mechanisms of CSU that need to be resolved, but it is becoming clear that there are at least 2 distinct pathways, type I and type II autoimmunity, that contribute to the pathogenesis of this complex disease. PMID- 27777183 TI - Food sources of vitamin D and their association with 25-hydroxyvitamin D status in Dutch older adults. AB - Various populations are at increased risk of developing a low vitamin D status, in particular older adults. Whereas sun exposure is considered the main source of vitamin D, especially during summer, dietary contributions should not be underestimated. This study aims to identify food sources of vitamin D that associate most strongly with serum vitamin D concentration. Data of 595 Dutch adults, aged >=65 years, were analysed. Vitamin D intake was assessed with a food frequency questionnaire and 25-hydroxyvitamin D (25(OH)D) was determined in serum. Associations of total vitamin D intake and vitamin D intake from specific food groups with serum 25(OH)D status were examined by P-for trend analyses over tertiles of vitamin D intake, prevalence ratios (PRs), and spline regression. The prevalence of vitamin D deficiency was high, with 36% of the participants having a 25(OH)D status <50nmol/L. Participants with adequate 25(OH)D concentrations were more likely to be men and more likely to be younger than participants with vitamin D deficiency. Total median vitamin D intake was 4.3MUg/day, of which 4.0MUg/day was provided by foods. Butter and margarine were the leading contributors to total vitamin D intake with 1.8MUg/day, followed by the intake of fish and shellfish with 0.56MUg/day. Participants with higher intakes of butter and margarine were 21% more likely to have a sufficient 25(OH)D status after adjustment for covariates (T1 vs. T3: PR 1.0 vs. 1.21 (95%CI: 1.03-1.42), P-for trend 0.02). None of the other food groups showed a significant association with the probability of having a sufficient 25(OH)D status. This study shows that vitamin D intake was positively associated with total serum 25(OH)D concentration, with butter and margarine being the most important contributors to total vitamin D intake. PMID- 27777184 TI - A case of antisynthetase syndrome with elevated serum CA19-9 associated with interstitial lung disease. PMID- 27777180 TI - Individualized therapy for persistent asthma in young children. AB - BACKGROUND: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications. METHODS: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response. RESULTS: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/MUL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments. CONCLUSIONS: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression. PMID- 27777185 TI - Problems associated with the microbiological control of the breast milk from hospital milk bank units. AB - The microbiological tests on breast milk performed when samples of pasteurized breast milk are added to hospital milk banks are covered by French regulations dating from December 3rd 2007. They involve counts of the aerobic total flora and of Staphylococcus aureus in a sample of milk before pasteurization, and culture after pasteurization to check that the treated milk is sterile. The regulations specify the nature of the agar plates to be used, together with the conditions for plating and incubation, but they lack detail in other areas. We developed a quality assurance system, modified our process to meet the statutory requirements, prepared for COFRAC certification of the laboratory for this parameter, and proposed solutions to overcome the inadequacies of the regulations. The modifications of the process associated with the quality approach led to a successful initial certification visit. However, the preparation for this certification highlighted other inadequacies of the regulations that might affect the final results obtained for total flora and S. aureus counts. We think that the text should be modified to overcome these problems and to ensure high-quality counting such that those running hospital milk banks can have confidence in the laboratory results they receive. PMID- 27777186 TI - Bullous pemphigoid during ustekinumab therapy in a psoriatic patient. PMID- 27777187 TI - Lichenoid drug eruption caused by adalimumab: a case report and literature review. PMID- 27777188 TI - Persistent elevation of serum interleukin-6 and serum amyloid A levels in patients with recessive dystrophic epidermolysis bullosa. PMID- 27777189 TI - [Diversity of intestinal microflora in patients with depression after stroke]. AB - OBJECTIVE: To investigate the changes in the population and distribution intestinal microflora and their relationship with depression in post-stroke patients. METHODS: Fecal specimens were obtained from 32 patients with post stroke depression and 30 healthy adults for gene sequencing of 16S RNA V3 region of the intestinal microorganism using Roche/45 high-throughput sequencing platform. RESULTS: The genus and species of intestinal bacteria showed significant differences between the post-stroke patients and health adults. CONCLUSION: Significant changes in the structure of intestinal flora occur in patients with post-stroke depression. PMID- 27777190 TI - [Correlation analysis of fetal middle cerebral artery peak systolic velocity, cardiothoracic ratio and crown-rump length in early pregnancy]. AB - OBJECTIVE: To explore the pattern of variations in middle cerebral artery peak systolic velocity (MCA PSV) and cardiothoracic ratio (CTR) during early pregnancy, establish their reference ranges and explore their correlation with the crown-rump length (CRL). METHODS: A total of 522 pregnant women with normal findings in antenatal examinations underwent routine color Doppler ultrasound examination to collect the data of MCA PSV, CTR and CRL. The reference ranges of MCA PSV and CTR for different CRL levels were established, and the correlation of MCA PSV and CTR with CRL was analyzed. RESULTS: During the first trimester, MCA PSV and CRL showed a moderate positive correlation with a correlation coefficient of 0.426 (P<0.001), while CTR and CRL showed no significant correlation (0.168, P<0.001). The reference range of MCA PSV was 14.35 (14.08-14.62) cm/s and that of CTR was 0.34 (0.33-0.34) during early pregnancy. CONCLUSION: Color Doppler ultrasound is a safe and feasible modality to assess fetal MCA PSV and CTR for detecting fetal growth abnormalities in early pregnancy. The established reference ranges of MCA PSV and CTR offer a clinical theoretical basis for detecting alpha-thalassemia in early pregnancy. PMID- 27777191 TI - [Effect of implantation of cardiosphere-derived cells combined with rat heart tissue-derived extracellular matrix on acute myocardial infarction in rats]. AB - OBJECTIVE: To investigate whether heart tissue-derived extracellular matrix (ECM) promotes the differentiation of cardiosphere-derived cells (CDCs) implanted in rat infracted myocardium to improve the cardiac structure and function. METHODS: Rat CDCs were cultured by cardiac explant methods, and ECM was prepared by decelluariztion method. In a Wistar rat model of acute myocardial infarction established by ligating the left anterior descending branch, IMDM solution, ECM suspension, 106 CDCs in IMDM solution, or 106 CDCs in ECM suspension were injected into the infracted rat myocardium (6 rats in each group). The cardiac function of the rats was evaluated by cardiac ultrasonography, and the percentage of positive heart fibrosis area after infarction was determined with Masson staining. The differentiation of implanted CDCs in the infarcted myocardium was detected using immunofluorescence assay for the markers of cardiac muscle cells (alpha-SA), vascular endothelial cells (vWF) and smooth muscle cells (alpha-SMA). RESULTS: Three weeks after acute myocardial infarction, the rats with injection of CDCs in ECM showed the highest left ventricular ejection fraction (LVEF) and percentage of fraction shortening with the lowest percentage of positive heart fibrosis area; implantation of CDCs with ECM resulted in significantly higher rates of CDC differentiation into cardiac muscle cells, vascular endothelial cells and smooth muscle cell (P<0.05). CONCLUSION: Heart-tissue derived ECM significantly promotes the differentiation of CDCs implanted in the infracted myocardium into cardiac muscle cells, vascular endothelial cells and smooth muscle cells to improve the cardiac structure and cardiac functions in rats. PMID- 27777192 TI - [Ulinastatin inhibits hypoxia-induced phenotype modulation of pulmonary artery smooth muscle cells by up-regulating PPAR-gamma expression]. AB - OBJECTIVE: To evaluate the effect of ulinastatin on hypoxia-induced phenotype modulation of pulmonary artery smooth muscle cells (PASMCs) and explore the underlying mechanism. METHODS: Cultured PASMCs from SD rats were exposed to normoxic condition, normoxia with ulinastatin treatment, hypoxia, or hypoxia with ulinastatin treatment. After 24 h of exposures, the cells were examined for SM alpha-actin and caplonin expressions with immunofluorescence assay and for cell migration with CCK-8 and 3H-TdR assays. Western blotting was used for detecting the expressions of PPAR-gamma in the cells, and PPAR-gamma-responsive firefly luciferase reporter was employed for measuring the transcriptional activity of PPAR-gamma. The PPAR-gamma inhibitor GW9662 was used to explore the mechanism of the inhibitory effect of ulinastatin on hypoxia induced-phenotype modulation of PASMCs by measuring the changes in cell proliferation and migration. RESULTS: Ulinastatin obviously enhanced the expressions of SM-alpha-actin and calponin (P<0.05), inhibited the proliferation and migration (P<0.05), and up-regulated the expression of PPAR-gamma in PASMCs exposed to hypoxia (P<0.05). Pretreatment of the cells with GW9662 abolished the effect of ulinastatin on hypoxia-induced phenotype modulation of PASMCs and enhanced the cell proliferation and migration (P<0.05). CONCLUSION: Ulinastatin inhibits hypoxia-induced phenotype modulation of PASMCs from rats possibly by up-regulating the expression of PPAR-gamma. PMID- 27777193 TI - [Analysis of causes and whole microbial structure in a case of rampant caries]. AB - OBJECTIVE: To analyze the whole microbial structure in a case of rampant caries to provide evidence for its prevention and treatment. METHODS: Clinical samples including blood, supragingival plaque, plaque in the caries cavity, saliva, and mucosal swabs were collected with the patient's consent. The blood sample was sent for routine immune test, and the others samples were stained using Gram method and cultured for identifying colonies and 16S rRNA sequencing. DNA was extracted from the samples and tested for the main cariogenic bacterium (Streptococcus mutans) with qPCR, and the whole microbial structure was analyzed using DGGE. RESULTS: The patient had a high levels of IgE and segmented neutrophils in his blood. Streptococci with extremely long chains were found in the saliva samples under microscope. Culture of the samples revealed the highest bacterial concentration in the saliva. The relative content of hemolytic bacterium was detected in the samples, the highest in the caries cavity; C. albicans was the highest in the dental plaque. In addition, 33 bacterial colonies were identified by VITEK system and 16S rDNA sequence phylogenetic analysis, and among them streptococci and Leptotrichia wade were enriched in the dental plaque sample, Streptococcus mutans, Fusobacterium nucleatum, and Streptococcus tigurinus in the caries cavity, and Lactobacillus in the saliva. S. mutans was significantly abundant in the mucosal swabs, saliva and plaque samples of the caries cavity as shown by qPCR. Compared to samples collected from a healthy individual and another two patients with rampant caries, the samples from this case showed a decreased bacterial diversity and increased bacterial abundance shown by PCR-DGGE profiling, and multiple Leptotrichia sp. were detected by gel sequencing. CONCLUSION: The outgrowth of such pathogenic microorganisms as S. mutans and Leptotrichia sp., and dysbiosis of oral microbial community might contribute to the pathogenesis of rampant caries in this case. PMID- 27777194 TI - [Tumor necrosis factor-alpha-induced protein 8 like-2 promotes apoptosis of CD4+ T lymphocytes in mice with severe burn injury]. AB - OBJECTIVE: To investigate the effect of tumor necrosis factor-alpha-induced protein 8 like-2 (TIPE2) on apoptosis of CD4+ T lymphocytes in a murine model of severe burn injury. METHODS: A total of 140 male mice were randomly allocated into 6 groups. Small RNA interference technique was used to construct a siTIPE2 overexpressing lentivirus, and severe burn injury models were established in the mice. CD4+ T cells were purified from spleen of the mice, and the expressions of TIPE2, Smad2/Smad3, P-Smad2/P-Smad3 and Bcl-2/Bimprotein in CD4+ Tregs were detected. The changes in mitochondrial membrane potential and cytochrome C in CD4+ T cells were detected, and the activities of caspase-3, caspase-8, and caspase-9 were analyzed. RESULTS: Down-regulation of TIPE2 promoted the apoptosis of CD4+ T lymphocytes in siTIPE2-burn group, in which the protein expressions of P-smad2/P-Smad3 decreased, Bcl-2 expression increased and Bim expression decreased significantly as compared with the other groups (P<0.01 or 0.05). The mitochondrial membrane potential and cytochrome C expression in CD4+ T cells were down-regulated in siTIPE2-burn group (P<0.05) with a lowered caspase-3 activity compared with TIPE2-burn group (P<0.01) and decreased caspase-8 and caspase-9 compared with the other groups (P<0.05). The apoptosis rate was the highest in TIPE2-burn group, whose Smad2/Smad3 was higher than that in the sham group (P<0.05) and the expression of P-smad2/P-Smad3 significantly increased compared with the other groups (P<0.05). In TIPE2-burn group, the mitochondrial membrane potential in CD4+ T cells was decreased (P<0.01), the expression of cytochrome C increased markedly (P<0.01), and the activities of caspase-3, caspase-8, and caspase-9 were all obviously higher than those in the other groups (P<0.05). CONCLUSION: As an important immunoregulatory molecule, TIPE2 can promote the apoptosis of CD4+T lymphocyte in mice with sever burn injury. PMID- 27777195 TI - [Correlation among serum MBL, MASP-2, HsCRP and C3 levels in rheumatoid arthritis]. AB - OBJECTIVE: To investigate the correlation among serum levels of manning-binding lectin (MBL), MBL-associated serine proteases-2 (MASP-2), complement C3 and high sensitive C reactive protein (HsCRP) in patients with rheumatoid arthritis (RA). METHODS: Fasting venous blood were collected from 50 RA patients (25 in active stage and 25 in remission) and 40 healthy subjects for detecting serum levels of MBL, MASP-2, complement C3 and HsCRP using enzyme-linked immunosorbent assay (ELISA) and immune turbidity assay. RESULTS: The serum levels of MBL and MASP-2 were significantly lower and HsCRP level was significantly higher in patients with RA (in both acute stage and remission) than in the healthy control group (P<0.05), but complement C3 level was similar between the RA patients and control group. Bivariate Pearson correlation analysis showed that in RA patients, MBL was positively correlated with MASP-2 level (r=0.550, P=0.001) and negatively with HsCRP (r=-0.323, P=0.022) but not correlated with C3 (r=-0.022, P=0.882); MASP-2 was negatively correlated with HsCRP (r=0.453, P=0.453) and was not correlated with C3 (r=0.049, P=0.738). ROC curve analysis revealed the largest area under curve (AUC) of HsCRP (0.844, P=0.001) and smaller AUCs of MBL (0.025, P=0.001) and MASP-2 (0.266, P=0.001). HsCRP had a much higher sensitivity (84%) than MBL (10%) and MASP-2 (40%) in the diagnosis of RA. CONCLUSION: In RA patients, MBL and MASP-2 are negatively correlated with HsCRP level. Serum MBL and MASP-2 levels decrease with the progression of joint injury in RA patients, suggesting their involvement in the pathological process of RA; but due to their low sensitivity, they are not appropriate indicators for evaluating the disease activity of RA. PMID- 27777196 TI - [Glucagon-like peptide 1 improves learning and memory abilities of rats with type 2 diabetes]. AB - OBJECTIVE: To investigate the effect of glucagon-like peptide 1 (GLP-1) on cognitive dysfunction in diabetic rats. METHODS: Male SD rats were randomly divided into normal control group, diabetes mellitus (DM) group, and GLP-1 treatment group. Rat models of type 2 diabetes were established by high-sugar and high-fat feeding and streptozotocin (STZ) injection, and 25 days after the onset of diabetes, GLP-1 was infused in GLP-1 treatment group at the rate of 30 pmol.kg 1.min-1 via a subcutaneous osmotic pump for 7 days. The learning and cognitive ability of the rats was assessed with Morris water maze test, and the expression of cognition-related genes in the hippocampus tissue was detected with real-time PCR, Western blotting and immunohistochemical staining. RESULTS: Compared with the normal control group, the diabetic rats showed significantly decreased learning and memory abilities (P<0.05) with increased hippocampal expressions of APP, BACE1, Arc, ERK1/2, PKA, and PKC mRNAs (P<0.05) and Arc protein. Compared with diabetic rats, GLP-1-treated rats showed significantly improvements in the learning and memory function (P<0.05) with decreased expressions of APP, BACE1, Arc, ERK1/2, and PKA mRNAs (P<0.05) and Arc protein. CONCLUSION: GLP-1 can improve cognitive dysfunctions in diabetic rats possibly by regulating the PKC, PKA, and ERK1/2 pathways and inhibiting Arc expression in the hippocampus. PMID- 27777197 TI - [Effect of low-dose focused ultrasound pre-irradiation versus microbubbles for enhancing high-intensity focused ultrasound ablation of VX2 hepatic tumor in rabbits]. AB - OBJECTIVE: To compare the effect of low-dose focused ultrasound pre-irradiation and microbubbles for enhancing the ablation effect of high intensity focused ultrasound (HIFU) on VX2 hepatic tumor in rabbits. METHODS: Fifty-five rabbits bearing VX2 hepatic tumor were randomly divided into low-dose pre-irradiation + HIFU ablation group, microbubbles+HIFU ablation group, and HIFU ablation group for corresponding treatments. The pathological changes in the tumors after low dose irradiation, time for HIFU ablation, tumor volume with coagulative necrosis, energy efficiency factor (EEF), pathological changes in the ablated tumor, and sound channel of HIFU ablation were observed. RESULTS: Tumor cell edema, vacuolar changes in the cytoplasm and tumor interstitial vascular congestion were observed 24 h after low-dose pre-irradiation. The ablation time were significantly shorter, coagulative necrosis volume was larger, and EEF was lower in low-dose irradiation + HIFU ablation group and microbubbles+HIFU ablation group than in simple HIFU ablation group (P<0.05), but the differences between the former two groups were not significant. The effectiveness and stability of the synergistic effect of low-dose pre-irradiation were inferior to microbubbles, but the former ensured a better safety of the sound channel. CONCLUSION: Low-dose irradiation has comparable synergistic effect in HIFU with microbubbles with such advantages as non-invasiveness, high concentration and good safety, and can be a potentially new method to enhance the efficiency of HIFU. PMID- 27777198 TI - [Effect of low-selenium diet on expressions of CCR7, CD206 and CD163 in the liver and kidney of rats]. AB - OBJECTIVE: To investigate the effect of low-selenium diet on the liver and kidneys of rats and explore the role of macrophage polarization into M1 and M2 phenotypes in liver and kidney injuries. METHODS: Twenty-four rats (12 female and 12 male) were randomly divided into control group and low-selenium group and fed with normal chow (dietary selenium of 0.18 mg/kg) and low-selenium diet (dietary selenium of 0.02 mg/kg) for 109 days. After the feeding, the rats were sacrificed for HE staining to observe liver and kidney pathologies, and immunohistochemistry was performed for analyzing CCR7, CD206, CD163-positive cell numbers in the liver and kidneys. RESULTS: The rats in low-selenium group showed severer fibrosis in the liver and kidney than the control group. In either male or female rats in low selenium group, CCR7 and CD206 expressions in the liver were comparable with those in control group, but CD163 expression was lower than that in the control group (P<0.05 for both female and male rats). In the kidney, the proximal tubule showed a slightly higher while the distal tubule showed a slightly lower CCR7 expression in low selenium group than in the control group (P>0.05). In low selenium group, a significantly lower CD163 expression in the distal tubule and a significantly higher CD206 expression in the proximal tubule were noted as compared with the control group (P<0.05 in both female and male rats). Compared with the control rats, the male rats in low-selenium group, but not the female rats, showed a significantly lower CD163 expression in the proximal tubule of the kidney (P<0.05); the female but not the male rats in low-selenium group show a higher CD206 expression in the distal tubule (P<0.05). CONCLUSION: Low-selenium diet can cause liver and kidney fibrosis in rats and may inhibit macrophage activation into the M2 phenotype. PMID- 27777199 TI - [Expression of microRNA-155 in papillary thyroid carcinoma and its clinical significance]. AB - OBJECTIVE: To investigate the correlation of microRNA-155 (miR-155) expression with clinicopathological features of patients with papillary thyroid carcinoma (PTC) and explore the value of miR-155 in prognostic assessment of PTC. METHODS: We collected 86 pairs of fresh PTC and adjacent tissues to examine the expression of miR-155 using fluorescent quantitative PCR. miR-155 expressions in the tissues were analyzed in relation to the clinicopathological features of the patients. RESULTS: Compared with the paired adjacent tissues, 69.8% (60/86) of the PTC tissues showed up-regulated miR-155 expression by 2.63?2.73 folds. Up-regulated miR-155 expressions were associated with a larger tumor size (1.66?0.96 vs 1.19?0.52 cm, P=0.021), a higher likeliness of extrathyroid invasion (56.7% vs 23.1%, P=0.004), a higher rate of lymph node metastasis (70% vs 46.2%, P=0.036), a more advanced TNM stage, and a higher rate of III-IV stage of the tumor (20% vs 0%, P=0.014). The expression level of miR-155 in PTC tissues was positively correlated with lymph node metastasis (r=0.531, P=0.001). CONCLUSION: PTC patients with miR-155 over-expression tend to have a greater tumor size, a greater likeliness of extrathyroid involvement, a higher rate of cervical lymph node metastasis and a more advanced TNM stage. The high expression of miR-155 in the tumor may indicate a poor prognosis of PTC patients. PMID- 27777200 TI - [Effect of hypobaric hypoxic preconditioning on surgically induced endometriosis by allotransplant of uterine tissue in rats]. AB - OBJECTIVE: To determine the effects of hypobaric hypoxia pretreatment on surgically induced endometriosis in rats. METHODS: Six rats were randomized into 2 groups and exposed to hypoxia (8% O2) and normoxia (21% O2) for 8 h. The uterine endometrium was intraperitoneally implanted into estrogen-treated ovariectomized Lewis rat, and the growth and quality of the implants were measured. The changes in apoptosis, protein and gene expressions in the serum, abdominis effusion fluids and implants were tested by ELISA, immunohistochemical staining, TUNNEL assay, Western blotting and RT-PCR. RESULTS: The volume of the implants in the hypoxic pretreatment group was significantly increased compared with the normoxia group. High expressions of Ki67, CD31, VEGF, and HIF-1alpha and lowered cell apoptosis were found in the hypoxia-pretreated implants compared with the normoxic group. VEGF level in the serum and peritoneal fluid were increased in hypoxia-pretreated group, but TNFalpha level was comparable between the 2 groups. CONCLUSION: Hypoxia play an important role in the occurrence and progression of endometriosis by increasing cell proliferation and angiogenesis and decreasing cell apoptosis in the implants in the rat model. PMID- 27777201 TI - [Efficacy of intracutaneous methylene blue injection for moderate to severe acute thoracic herpes zoster pain and prevention of postherpetic neuralgia in elderly patients]. AB - OBJECTIVE: To evaluate the clinical efficacy of intradermal injection of methylene blue for treatment of moderate to severe acute thoracic herpes zoster and prevention of postherpetica neuralgia in elderly patients. METHODS: Sixty four elderly patients with herpes zoster were randomized to receive a 10-day course of intradermal injection of methylene blue and lidocaine plus oral valaciclovir (group A, 32 cases) and intradermal injection of lidocaine plus oral valaciclovir (group B).Herpes evaluation index, pain rating index, incidence of postherpetic neuralgia, and comprehensive therapeutic effect were compared between the two groups at 11, 30 and 60 days after the treatment. RESULTS: The baseline characteristics were comparable between the two groups (all P>0.05). Compared with that in group B, the time for no new blister formation, blister incrustation and decrustation, and pain relief was significantly shortened in group A (P<0.05) with also obviously lower pain intensity after the treatment. The incidence of postherpetic neuralgia was significantly lower in group A than in group B at 30 days (P<0.05), but not at 60 and 90 days after the treatment. The total clinical response rate was 93.8% in group A, much higher than that in group B (62.5%, P<0.05). CONCLUSION: Intradermal injection of methylene blue can effectively shorten the disease course, reduce the pain intensity and prevent the development of postherpetic neuralgia in elderly patients with herpes zoster. PMID- 27777202 TI - [Serum non-esterified fatty acids to albumin ratio increased significantly in children with nephrotic syndrome]. AB - OBJECTIVE: To analyze serum levels of non-esterified fatty acids (NEFA) and albumin (ALB) in children with nephrotic syndrome (NS) and investigate the clinical significance of altered serum NEFA to ALB ratio in children with NS in acute and remission phases. METHODS: Serum levels of NEFA and ALB were measured in 55 NS children in acute phase, in 33 NS children in remission and in 122 healthy control children, and the ratio of NEFA to ALB was calculated. The other lipid/lipoprotein and renal function parameters were also analyzed in these children. RESULTS: Compared with the healthy control children, children with NS had a significantly decreased serum ALB level (t=11.152, P<0.001) and a significantly increased NEFA to ALB ratio (t=4.991, P<0.001). Compared with NS children in remission, those in acute phase showed a significantly decreased ALB (Z=7.822, P<0.001) and an increased NEFA to ALB ratio (t=4.991, P<0.001). In all the NS children, NEFA to ALB ratio was positively correlated with the levels of TC (r=0.564, P<0.001), TG (r=0.444, P<0.001), LDL-C (r=0.625, P<0.001), urea (r=0.437, P<0.001), creatinine (r=0.278, P=0.013), and uric acid (r=0.397, P<0.001), while negatively correlated with the level of total protein (r=-0.461, P<0.001). Multiple linear regression analyses showed that NEFA to ALB ratio was independently associated with serum urea levels (beta=0.703, P=0.001; adjusted R2=0.494) after adjustment of other related factors. CONCLUSION: Serum NEFA to ALB ratio is significantly increased in NS children in close association with impaired kidney function, and may function as a novel parameter for assessing the development of NS. PMID- 27777203 TI - [Clinical significance of serum carbohydrate antigen 125 in acute exacerbation of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To study the serum level of carbohydrate antigen 125 (CA125) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and its relation with pulmonary hypertension. METHODS: Forty-six patients with AECOPD complicated by pulmonary hypertension, 46 with AECOPD and 38 healthy control subjects were examined for their clinical data, pulmonary function, echocardiographic findings, and serum levels of lung tumor markers and brain natriuretic peptide (BNP). RESULTS: Compared with the healthy control group, COPD patients with or without pulmonary hypertension showed significantly decreased pulmonary function (P<0.05), especially in those with AECOPD and concurrent pulmonary hypertension (P<0.05). Serum CA125 level was obviously higher in AECOPD group than in the healthy control group, and further increased in AECOPD patients with pulmonary hypertension (P<0.05). The levels of lung tumor markers (CEA, NSE, CYFRA and PROGRP) were similar among the 3 groups (P>0.05). The serum level of BNP in patients with AECOPD and concurrent pulmonary hypertension was significantly higher than that in patients with AECOPD (P<0.05). Pearson linear correlation analysis showed that serum CA125 was positively correlated with pulmonary artery systolic pressure and BNP in AECOPD patients with pulmonary hypertension (P<0.01). CONCLUSION: Serum CA125 may serve as a serological index to identify AECOPD patients with pulmonary hypertension. PMID- 27777204 TI - [Expression of ALDH1, CXCR4 and E-cadherin in castric carcinoma and their roles in lymphatic metastasis]. AB - OBJECTIVE: To investigate the expression of ALDH1, CXCR4 and E-cadherin in gastric carcinoma and their roles in lymphatic metastasis. METHODS: Surgical specimens from 127 cases of gastric carcinoma were examined for expressions of ALDH1, CXCR4 and E-cadherin immuohistochemistry with 60 adjacent tissues as control. The associations of ALDH1, CXCR4 and E-cadherin with the clinicopathological pfeatures, 5-year survival rate and lymph node metastasis of the patients were analyzed. RESULTS: ALDH1, CXCR4 and E-cadherin were positive in 57.5% (73/127), 63.8% (81/127), and 36.2% (46/127) of the gastric carcinoma tissues, respectively, showing significant differences from the rates in the adjacent tissues (P<0.05). The expression of ALDH1 was significantly correlated with TNM stage and lymph node metastasis (P<0.05), CXCR4 was significantly correlated with the invasion depth, differentiation, TNM stage and lymph node metastasis of the tumor (P<0.05), and E-cadherin was significantly correlated with the invasion depth, differentiation and lymph node metastasis (P<0.05). The positivity rates of ALDH1, CXCR4 and E-cadherin were higher in cases with lymph node metastasis than in those without metastasis. E-cadherin expression was inversely correlated with ALDH1 and CXCR4 expression, and the latter two were positively correlated (P<0.001). Overexpressions of ALDH1 and CXCR4 and a decreased expression of E-cadherin were all related to a poor prognosis of the patients (P<0.05). The expressions ofALDH1, CXCR4 and E-cadherin were all independent prognostic factors of gastric carcinoma. CONCLUSION: The expressions of ALDH1, CXCR4 and E-cadherin are associated with the invasion, metastasis and prognosis of gastric carcinoma, and their combined detection provides important evidence for predicting the progression and prognosis of gastric carcinoma. PMID- 27777205 TI - [Pharmacokinetics of a cisatracurium dose according to fat-free mass for anesthesia induction in morbidly obese patients]. AB - OBJECTIVE: To compare the pharmacokinetics of cisatracurium between normal weight patients and morbidly obese patients. METHODS: Twelve obese ASA I-II patients (BMI>=35 kg/m2) undergoing laparoscopic Roux-en-Y gastric bypass and 12 normal weight ASA I-II patients (BMI of 18.5-24 kg/m2) undergoing laparoscopic surgery were enrolled. The obese patients were given a cisatracurium dose of 0.15 mg/kg according to the fat-free mass (FFM), and the non-obese patients received a dose of 0.15 mg/kg according to the total body weight. Plasma concentrations of cisatracurium was monitored in the patients with high-performance liquid chromatography (HPLC) before anesthetic induction and at 1, 2, 4, 6, 8, 10, 12, 15, and 20 min after cisatracurium administration and the pharmacokinetic parameters were computed. SBP, DBP, HR, MAP, SpO2 and PetCO2 were recorded before anesthetic induction (T0) and at 1 min (T1), 2 min (T2), 4 min (T3) after cisatracurium administration. RESULTS: Compared with those measured at T0, SBP, DBP and MAP in the 2 groups were significantly decreased at the time points of T1 3 (P<0.05). Compared with the non-obese patients, the obese patients showed significantly increased Hct level (P<0.05). The total clearance, apparent volume of distribution, and distribution and elimination half-life of the drug were similar between the 2 groups (P>0.05). The plasma concentration of cisatracurium at T1-2 was significantly decreased in the obese patients compared with that in the non-obese patients (P<0.05). CONCLUSION: Cisatracurium doses according to fat free mass is clinically reasonable for inducing anesthesia in morbidly obese patients, but due to a prolonged muscle relax onset time, the timing of tracheal intubation should be delayed by 1-2 min. PMID- 27777206 TI - [Role of serotoninergic/melatoninergic system in melanin metabolism in melanocytes exposed to serum of rabbits fed with Liuwei Dihuang decoction]. AB - OBJECTIVE: To investigate the effects of Liuwei Dihuang (LWDH) decoction on serotonine (5-HTs), melatonin and the activity of the rate-limiting enzymes ANNAT and HIOMT in cultured human melanocytes and in melanocytes co-cultured with keratinocytes. METHODS: CCK-8 assay was used to assess the proliferation of melanocytes and melanocytes co-cultured with keratinocytes after treatment with the serum from rabbits fed with LWDH decoction. High-performance liquid chromatography was used to determine 5-HT and melatonin contents, and real-time fluorescent PCR was employed to evaluate the ANNAT and HIOMT activities in the cell cultures. RESULTS: The serum from rabbits fed with LWDH Decoction at low doses did not affect the proliferation of melanocytes co-cultured with keratinocytes, but at the concentrations of 20%-40%, the serum significantly inhibited the proliferation of melanocytes, and the effect was optimal with a concentration of 40% (P<0.05). 5-HT and melatonin contents in the cell culture decreased as the serum concentration increased (P<0.05), which was the most obvious with a serum concentration of 40% (P<0.01). Exposure of the cells to low and moderate doses of the serum caused a dose-dependent decrease in AANAT activity (P<0.05), but the serum produced no significant changes in the level of HIOMT mRNA expression in the cells. COUCLUSIONS: The serotoninergic/melatoninergic system mediate the regulation of melanin metabolism by LWDH Decoction, the mechanism of which may involve 5-HTs, melatonin and ANNAT. PMID- 27777207 TI - [Clinical value of detecting serum soluble CD163 level in patients with atrial fibrillation]. AB - OBJECTIVE: To investigate the relationship between atrial fibrillation (AF) and serum soluble CD163. METHODS: A total of 336 patients with heart valve disease were included in this study, including 167 with AF and 169 with sinus rhythm. The clinical data were compared between the two grops, and Logistic regression analysis was used to identify the risk factors associated with AF. RESULTS: The levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor (TNF), interleukin-6 (IL - 6), high-sensitivity C-reactive protein (hs-CRP) and left atrial diameter (LAD) all differed significantly between the two groups (P<0.05). Serum soluble CD163 levels in AF patients were significantly higher than those in patients with sinus rhythm (P<0.05). Serum soluble CD163 was positively correlated with TNF (r=0.244, P=0.244), IL-6 (r=0.186, P=0.186), hs-CRP (r=0.183, P=0.183) and LAD (r=0.194, P=0.194) in patients with AF. Logistic regression analysis showed that LAD, IL-6, TNF, hs-CRP and CD163 were all associated with AF. ROC curve analysis showed that the area under curve of serum soluble CD163 was 0.861 in patients with AF (CI 95%: 0.820-0.901, P<0.01) with a sensitivity and a specificity of 80.8 and 76.9%, respectively. CONCLUSION: Serum soluble CD163 level may be a risk factor for AF, and an increased soluble CD163 level may indicate active inflammation in AF patients. PMID- 27777208 TI - [Anlysis of foot biomechanics characteristic in 303 patients with type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate foot biomechanics characteristic of patients with type 2 diabetes mellitus. METHODS: This study was conducted among 303 patients with type 2 diabetes. The whole foot was divided into 10 regions, namely the first toe (T1); the second to fifth toes (T2-5); the first, second, third, fourth, and fifth metatarsals (M1, M2, M3, M4, and M5, respectively); midfoot (MF), and the heel medial (HM). Foot arch index, foot angle and maximum peak pressure (MPP) of the 10 regions were measured using a Footscan gait system. RESULTS: The maximum peak pressure of 10 regions decreased in the order of M3>M2>HM>M4>HL>M1>M5>T1>ML>T2-5 for the left foot, and in the order of M3>M2>HM>M4>HL>M1>M5>T1>ML>T2-5 for the right foot. The MPP in M1 region was higher in the right than in the left foot (P<0.05). The MPP in M3, M4, M5, and MF was higher in the left than in the right foot (P<0.05). The percentage of high risk foot (defined by a total plantar pressure >=70 N/cm2) was 34% on the left and 17.7% on the right. An increased BMI was associated with a significant increase in high-risk foot, but not for the right foot in underweight patients. Foot flat phase was extended and forefoot push-off phase shortened in stance phase in the patients. Compared with the right foot, the left foot showed a significantly increased foot arch index and increased low and high arch rates with a decreased normal arch rate. Total plantar pressure was higher in of the left high arch foot than in normal arch foot. The foot angle was significantly larger on the right than on the left. The bilateral total plantar pressures were significantly greater in male patients (P<0.05) and increased with age but were not associated with the duration of DM, foot angle, or glycosylated hemoglobin level. CONCLUSION: Diabetic patients have obvious alterations in foot biomechanics with abnormalities of the plantar pressure, and the percentage of high-risk foot increases in overweight and obese patients, suggesting the need of body weight control in these patients when administering offloading treatment for prevention of diabetic foot ulcer. PMID- 27777209 TI - [Effect of diallyl disulfide on learning and memory abilities and hippocampal synapses in mouse models of Alzheimer's disease]. AB - OBJECTIVE: To explore the effect of diallyl disulfide (DADS) on hippocampal synapses and learning and memory abilities in a mouse model of A1zheimer's disease (AD). METHODS: Mouse models of AD established by agglutinated Abeta1-42 injection in the lateral cerebral ventricle were randomized into 4 groups and treated with DADS at the daily doses of 0, 10, 50 and 100 mg/kg by gavage for 30 consecutive days. The learning and memory abilities of the mice were assessed with Morris water maze test; the structures of the dendritic spines and synapses in CA1 region of the hippocampus were observed under transmission electron microscope with silver staining; PSD95 and SYP protein and mRNA expressions in the hippocampus were detected with Western blotting and RT-PCR. RESULTS: Compared with the AD model mice, the mice treated with 50 and 100 mg/kg DADS showed enhanced learning and memory abilities in Morris water maze test. The dendritic spines and synapses in CA1 region of the hippocampus increased obviously and hippocampal expressions of PSD95 and SYP were enhanced in mice treated with 50 and 100 mg/kg DADS. CONCLUSION: DADS at the daily doses of 50 and 100 mg/kg can improve the learning and memory abilities and increase the number of dendritic spines and synapses in the hippocampus in mouse models of AD. PMID- 27777210 TI - [RITA combined with temozolomide inhibits the proliferation of human glioblastoma U87 cells]. AB - OBJECTIVE: To observe the effect of RITA, a small molecule that targets p53, combined with temozolomide (TMZ) on proliferation, colony formation and apoptosis of human glioblastoma U87 cells and explore the underlying mechanism. METHODS: Cultured U87 cells were treated with RITA (1, 5, 10, 20 umol/L), TMZ, or RITA+TMZ (half dose) for 24, 48 or 72 h. MTS assay were used to detect the cell proliferation, and the cell proliferation rate and inhibitory rate were calculated. The effect of combined treatments was evaluated by the q value. The expressions of p53, p21 and other apoptosis-associated genes were detected by qRT PCR and Western blotting; cell apoptosis was assayed using flow cytometry with Annexin V/PI double staining; colony formation of the cells was detected with crystal violet staining. RESULTS: MTS assay showed that RITA at the 4 doses more potently inhibited U87 cell viability than TMZ at 72 h (P=0.000) with inhibitory rates of 25.94%-41.38% and 3.84%-8.20%, respectively. RITA combined with TMZ caused a more significant inhibition of U87 cells (29.21%-52.11%) than RITA (P<0.01) and TMZ (P=0.000) alone. At the doses above 5 umol/L, the combined treatments with RITA+TMZ for 48 h resulted in q values exceeding 1.2 and showed an obvious synergistic effect of the drugs. Both RITA and TMZ, especially the latter, significantly increased the expressions of p53, p21, puma, and other apoptosis-associated genes to accelerate apoptosis and inhibit the growth and colony formation of U87 cells, and the effect was more obvious with a combined treatment. CONCLUSION: RITA inhibits the growth of human glioblastoma cells and enhance their sensitivity to TMZ by up-regulating p53 expression, and when combined, RITA and TMZ show a synergistic effect to cause a stronger cell inhibition. PMID- 27777211 TI - [Development of laparoscopic technology in biliary surgery in the past 23 years: a single-center experience]. AB - OBJECTIVE: To summarize the 23-year experience of laparoscopic biliary surgery in General Hospital of PLA and evaluate the application of laparoscopic surgery in the treatment of biliary diseases. METHODS: We retrospectively analyzed the clinical data of 11 419 consecutive patients with biliary diseases undergoing laparoscopic surgery from April, 1992 and December, 2014. The disease spectrum was compared between patients treated before December 31, 2003 and those treated after the time point. RESULTS: The 11419 patients receiving laparoscopic surgery accounted for 56.3% of the total patients undergoing biliary surgeries during the 23 years, including 4701 male and 6718 female patients with a mean age of 50.9?13.2 years (6-93 years). Most (80.83%) of the patients received laparoscopic surgery for gallbladder stones, and 12.53% patients had the operation for gallbladder polyps. The laparoscopic operation rate was 84.81% in patients with gallbladder stones and 34.91% in patients with extrahepatic bile duct stones, but remained low in patients with biliary carcinoma. In laparoscopic operations, laparoscopic cholecystectomy was the most frequent (96.18%) followed by operations for extrahepatic bile duct stones, in which primary suture accounted for 1.38%, traditional T tube drainage for 0.90% and laparoscopic transcystic duct exploration for 0.72%. For malignant tumors, laparoscopic technique was used mainly for the purpose of exploration (0.34%). The application of laparoscopic technique in biliary surgery tended to increase after the year 2004, especially for benign gallbladder diseases and extrahepatic bile duct stones (P<0.05). CONCLUSION: Laparoscopic technique in biliary surgery is gradually replacing the traditional open operation and becomes the gold standard for the treatment of benign biliary diseases. PMID- 27777212 TI - [Effect of Klebsiella pneumoniae KbvR regulator on bacterial biofilm formation and capsular synthesis]. AB - OBJECTIVE: To construct the KbvR gene of LuxR family deletion mutant and complementation strains from Klebsiella pneumoniae NTUH-K2044 and analyze the effect of KbvR on bacterial growth, biofilm formation and capsular synthesis. METHODS: A KbvR gene deletion mutant strain was constructed using the suicide vector pKO3-Km, and the gene fragment including KbvR coding region, promoter area and transcription termination area were amplified and cloned into pGEM-T-easy plasmid to construct KbvR complementation strain. The growth curves of the wild type strain, KbvR gene deletion mutant strain and complementation strain were observed to assess the effect of KbvR on bacterial growth. Crystal violet staining method was used to measure the effect of KbvR on biofilm formation; the effect of KbvR on capsular synthesis was detected using string test, centrifugal test and RT-PCR. RESULTS: The KbvR deletion mutant and complementation strains were constructed successfully. KbvR gene did not affect the growth of the bacteria, but biofilm formation and capsular synthesis were attenuated in KbvR deletion mutant strain. CONCLUSION: As a transcription factor of the LuxR family orphans of the quorum sensing system, KbvR positively regulates bacterial biofilm formation by affecting capsular synthesis. PMID- 27777213 TI - [Logistic regression analysis of risk factors of serious complications related with double-J ureteral stenting following percutaneous nephrolithotomy]. AB - OBJECTIVE: To investigate the risk factors of the serious complications related with double-J ureteral stent placement following percutaneous nephrolithotomy (PCNL). METHODS: Clinical data were reviewed for 272 patients treated with PCNL and indwelling double-J stents between January, 2014 and April, 2016. The risk factors of serious complications were identified using univariate and multivariate logistic regression analysis. RESULTS: Serious complications of double-J ureteral stenting occurred in 63 patients (23.1%). Univariate and multivariate logistic regression analysis indicated that the ureter abnormalities (beta=1.735, P=0.000, OR=5.670), stent indwelling duration (beta=1.206, P=0.028, OR=3.340), gender (beta=0.895, P=0.016, OR=2.446), preoperative urinary tract infection (beta=0.849, P=0.020 , OR=2.338) and stent size (beta=0.847, P=0.011, OR=2.333) were all risk factors of serious complications related with the procedure. CONCLUSION: Male patients are exposed to a higher risk of serious complications following PCNL. Effective management of urinary tract infection and choice of appropriate stent size in cases of ureteral abnormalities help to reduce these complications. The double-J stent should be withdrawn as soon as possible in patients with good postoperative recovery. PMID- 27777214 TI - [Effect of covered stent length in portal and hepatic veins on long-term clinical efficacy of transjugular intrahepatic portosystemic shunt]. AB - OBJECTIVE: To evaluate the effect of the length of covered stents in the portal and hepatic veins on long-term clinical efficacy of transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We retrospectively reviewed 53 cases receiving TIPSs between January, 2008 and December, 2011. All the shunts were created with Fluency stents (8 mm in diameter). Bare metal grafts of the same diameter were implanted to extend the length in the portal and hepatic veins as deemed necessary according to angiographic images. The primary patency, hepatic encephalopathy and patient survival were evaluated during the follow up. The length of the covered stents within the hepatic vein (X1) and in the portal vein (X2), and the total length of stents placed in the hepatic vein (X3) and the portal vein (X4) were measured and their effects on primary patency and the patients'outcomes were evaluated. RESULTS: The procedures were completed successfully in all the patients and the mean portosystemic pressure decreased from 29.80?4.83 mmHg to 19.00?3.92 mmHg (t=13.44, P<0.01) after the procedure. The patients were followed up for a median of 64 months (3 to 89 months, 39 months on average). Hepatic encephalopathy occurred in 23% (12/53) of the patients after TIPS. Shunt dysfunction occurred in 16 cases, and the cumulative primary patency rates at 1 to 5 years were 83%, 75%, 63%, 62%, and 54%, respectively. The cumulative survival rates of the patients at 1 to 5 years were 79%, 72%, 72%, 69%, and 69%, respectively. Cox proportional regression analysis showed a significant association between the length of covered-stent in the hepatic vein and the primary patency (OR=0.42, P<0.01), and there was a significant association between the length of stent in the portal vein and the patient survival. No significant correlation was found between these parameters and hepatic encephalopathy. CONCLUSION: Increasing the length of the covered stent in the hepatic vein and decreasing the stent length in the portal vein can improve the primary patency and the patient survival receiving TIPS. PMID- 27777215 TI - "When 'Bad' is 'Good'": Identifying Personal Communication and Sentiment in Drug Related Tweets. AB - BACKGROUND: To harness the full potential of social media for epidemiological surveillance of drug abuse trends, the field needs a greater level of automation in processing and analyzing social media content. OBJECTIVES: The objective of the study is to describe the development of supervised machine-learning techniques for the eDrugTrends platform to automatically classify tweets by type/source of communication (personal, official/media, retail) and sentiment (positive, negative, neutral) expressed in cannabis- and synthetic cannabinoid related tweets. METHODS: Tweets were collected using Twitter streaming Application Programming Interface and filtered through the eDrugTrends platform using keywords related to cannabis, marijuana edibles, marijuana concentrates, and synthetic cannabinoids. After creating coding rules and assessing intercoder reliability, a manually labeled data set (N=4000) was developed by coding several batches of randomly selected subsets of tweets extracted from the pool of 15,623,869 collected by eDrugTrends (May-November 2015). Out of 4000 tweets, 25% (1000/4000) were used to build source classifiers and 75% (3000/4000) were used for sentiment classifiers. Logistic Regression (LR), Naive Bayes (NB), and Support Vector Machines (SVM) were used to train the classifiers. Source classification (n=1000) tested Approach 1 that used short URLs, and Approach 2 where URLs were expanded and included into the bag-of-words analysis. For sentiment classification, Approach 1 used all tweets, regardless of their source/type (n=3000), while Approach 2 applied sentiment classification to personal communication tweets only (2633/3000, 88%). Multiclass and binary classification tasks were examined, and machine-learning sentiment classifier performance was compared with Valence Aware Dictionary for sEntiment Reasoning (VADER), a lexicon and rule-based method. The performance of each classifier was assessed using 5-fold cross validation that calculated average F-scores. One tailed t test was used to determine if differences in F-scores were statistically significant. RESULTS: In multiclass source classification, the use of expanded URLs did not contribute to significant improvement in classifier performance (0.7972 vs 0.8102 for SVM, P=.19). In binary classification, the identification of all source categories improved significantly when unshortened URLs were used, with personal communication tweets benefiting the most (0.8736 vs 0.8200, P<.001). In multiclass sentiment classification Approach 1, SVM (0.6723) performed similarly to NB (0.6683) and LR (0.6703). In Approach 2, SVM (0.7062) did not differ from NB (0.6980, P=.13) or LR (F=0.6931, P=.05), but it was over 40% more accurate than VADER (F=0.5030, P<.001). In multiclass task, improvements in sentiment classification (Approach 2 vs Approach 1) did not reach statistical significance (eg, SVM: 0.7062 vs 0.6723, P=.052). In binary sentiment classification (positive vs negative), Approach 2 (focus on personal communication tweets only) improved classification results, compared with Approach 1, for LR (0.8752 vs 0.8516, P=.04) and SVM (0.8800 vs 0.8557, P=.045). CONCLUSIONS: The study provides an example of the use of supervised machine learning methods to categorize cannabis- and synthetic cannabinoid-related tweets with fairly high accuracy. Use of these content analysis tools along with geographic identification capabilities developed by the eDrugTrends platform will provide powerful methods for tracking regional changes in user opinions related to cannabis and synthetic cannabinoids use over time and across different regions. PMID- 27777217 TI - Correlating Ratings of Health Insurance Plans to Their Providers' Attributes. AB - BACKGROUND: There is a push towards quality measures in health care. As a consequence, the National Committee for Quality Assurance (NCQA) has been publishing insurance plan quality measures. OBJECTIVE: The objective of this study was to examine the relationship between insurance plan quality measures and the participating providers (doctors). METHODS: We collected and analyzed provider and insurance plan data from several online sources, including provider directories, provider referrals and awards, patient reviewing sites, and hospital rankings. The relationships between the provider attributes and the insurance plan quality measures were examined. RESULTS: Our analysis yielded several findings: (1) there is a moderate Pearson correlation (r=.376) between consumer satisfaction insurance plan scores and review ratings of the member providers, (2) referral frequency and provider awards are negligibly correlated to consumer satisfaction plan scores (correlations of r=.031 and r=.183, respectively), (3) there is weak positive correlation (r=.266) between the cost charged for the same procedures and consumer satisfaction plan scores, and (4) there is no significant correlation between member specialists' review ratings and specialty-specific insurance plan treatment scores for most specialties, except a surprising weak negative correlation for diabetes treatment (r=-.259). CONCLUSIONS: Our findings may be used by consumers to make informed choices about their insurance plans or by insurances to understand the relationship between patients' satisfaction and their network of providers. PMID- 27777216 TI - Game On? Smoking Cessation Through the Gamification of mHealth: A Longitudinal Qualitative Study. AB - BACKGROUND: Finding ways to increase and sustain engagement with mHealth interventions has become a challenge during application development. While gamification shows promise and has proven effective in many fields, critical questions remain concerning how to use gamification to modify health behavior. OBJECTIVE: The objective of this study is to investigate how the gamification of mHealth interventions leads to a change in health behavior, specifically with respect to smoking cessation. METHODS: We conducted a qualitative longitudinal study using a sample of 16 smokers divided into 2 cohorts (one used a gamified intervention and the other used a nongamified intervention). Each participant underwent 4 semistructured interviews over a period of 5 weeks. Semistructured interviews were also conducted with 4 experts in gamification, mHealth, and smoking cessation. Interviews were transcribed verbatim and thematic analysis undertaken. RESULTS: Results indicated perceived behavioral control and intrinsic motivation acted as positive drivers to game engagement and consequently positive health behavior. Importantly, external social influences exerted a negative effect. We identified 3 critical factors, whose presence was necessary for game engagement: purpose (explicit purpose known by the user), user alignment (congruency of game and user objectives), and functional utility (a well-designed game). We summarize these findings in a framework to guide the future development of gamified mHealth interventions. CONCLUSIONS: Gamification holds the potential for a low-cost, highly effective mHealth solution that may replace or supplement the behavioral support component found in current smoking cessation programs. The framework reported here has been built on evidence specific to smoking cessation, however it can be adapted to health interventions in other disease categories. Future research is required to evaluate the generalizability and effectiveness of the framework, directly against current behavioral support therapy interventions in smoking cessation and beyond. PMID- 27777219 TI - Prostate Cancer and Socioeconomic Status in the Finnish Randomized Study of Screening for Prostate Cancer. AB - Prostate cancer (PC) screening remains controversial. We investigated whether screening reduces the difference in prostate cancer risk by socioeconomic status (SES). In 1996-2011, a total of 72,139 men from the Finnish Randomized Study of Screening for Prostate Cancer were analyzed. Outcome measures were PC incidence, mortality, and participation in screening. SES indicators were educational level, income, and home ownership status (data obtained from the Statistics Finland registry). The mean duration of follow-up was 12.7 years. Higher SES was associated with a higher incidence of low- to moderate-risk PC but with a lower risk of advanced PC. Higher education was associated with significantly lower PC mortality in both control and screening arms (risk ratio = 0.48-0.69; P < 0.05). Higher income was also associated with lower PC mortality but only in the control arm (risk ratio = 0.45-0.73; P < 0.05). There were no significant differences in SES gradient by arm (Pinteraction = 0.33 and Pinteraction = 0.47 for primary vs. secondary education and primary vs. tertiary education, respectively; Pinteraction = 0.65 and Pinteraction = 0.09 for low vs. intermediate income and low vs. high income, respectively; and Pinteraction = 0.27 among home ownership status strata). Substantial gradients by SES in PC incidence and mortality were observed in the control arm. Higher SES was associated with overdiagnosis of low risk PC and, conversely, lower risk of incurable PC and lower PC mortality. Special attention should be directed toward recruiting men with low SES to participate in population-based cancer screening. PMID- 27777218 TI - A Multimedia Child Developmental Screening Checklist: Design and Validation. AB - BACKGROUND: Identifying disability early in life confers long-term benefits for children. The Taipei City Child Development Screening tool, second version (Taipei II) provides checklists for 13 child age groups from 4 months to 6 years. However, the usability of a text-based screening tool largely depends on the literacy level and logical reasoning ability of the caregivers, as well as language barriers caused by increasing numbers of immigrants. OBJECTIVE: The objectives of this study were to (1) design and develop a Web-based multimedia version of the current Taipei II developmental screening tool, and (2) investigate the measurement equivalence of this multimedia version to the original paper-based version. METHODS: To develop the multimedia version of Taipei II, a team of experts created illustrations, translations, and dubbing of the original checklists. The developmental screening test was administered to a total of 390 primary caregivers of children aged between 4 months and 6 years. RESULTS: Psychometric testing revealed excellent agreement between the paper and multimedia versions of Taipei II. Good to excellent reliabilities were demonstrated for all age groups for both the cross-mode similarity (mode intraclass correlation range 0.85-0.96) and the test-retest reliability (r=.93). Regarding the usability, the mean score was 4.80 (SD 0.03), indicating that users were satisfied with their multimedia website experience. CONCLUSIONS: The multimedia tool produced essentially equivalent results to the paper-based tool. In addition, it had numerous advantages, such as it can facilitate active participation and promote early screening of target populations. CLINICALTRIAL: Clinicaltrials.gov NCT02359591; https://clinicaltrials.gov/ct2/show/NCT02359591 (Archived by WebCite at http://www.webcitation.org/6l21mmdNn). PMID- 27777220 TI - What Level of Risk Compensation Would Offset the Preventive Effect of Early Antiretroviral Therapy? Simulations From the TEMPRANO Trial. AB - Whether risk compensation could offset the preventive effect of early initiation of antiretroviral therapy (ART) on human immunodeficiency virus (HIV) transmission remains unknown. Using virological and behavioral data collected 12 months after inclusion in the TEMPRANO randomized trial of early ART (Abidjan, Cote d'Ivoire, 2009-2012), we estimated the risk of HIV transmission and compared it between the intervention (early ART; n = 490) and control (deferred ART; n = 467) groups. We then simulated increases in various sexual risk behaviors in the intervention group and estimated the resulting preventive effect. On the basis of reported values of sexual behaviors, we estimated that early ART had an 89% (95% confidence interval: 81, 95) preventive effect on the cumulative risk of HIV transmission over a 1-month period. This preventive effect remained significant for a wide range of parameter combinations and was offset (i.e., nonsignificant) only for dramatic increases in different sexual behaviors simulated simultaneously. For example, when considering a 2-fold increase in serodiscordance and the frequency of sexual intercourse together with a 33% decrease in condom use, the resulting preventive effect was 47% (95% confidence interval: -3, 74). An important reduction of HIV transmission may thus be expected from the scale-up of early ART, even in the context of behavioral change. PMID- 27777221 TI - Is this trial misreported? Truth seeking in the burgeoning age of trial transparency. PMID- 27777222 TI - Comprehensive assessment and performance improvement of effector protein predictors for bacterial secretion systems III, IV and VI. AB - Bacterial effector proteins secreted by various protein secretion systems play crucial roles in host-pathogen interactions. In this context, computational tools capable of accurately predicting effector proteins of the various types of bacterial secretion systems are highly desirable. Existing computational approaches use different machine learning (ML) techniques and heterogeneous features derived from protein sequences and/or structural information. These predictors differ not only in terms of the used ML methods but also with respect to the used curated data sets, the features selection and their prediction performance. Here, we provide a comprehensive survey and benchmarking of currently available tools for the prediction of effector proteins of bacterial types III, IV and VI secretion systems (T3SS, T4SS and T6SS, respectively). We review core algorithms, feature selection techniques, tool availability and applicability and evaluate the prediction performance based on carefully curated independent test data sets. In an effort to improve predictive performance, we constructed three ensemble models based on ML algorithms by integrating the output of all individual predictors reviewed. Our benchmarks demonstrate that these ensemble models outperform all the reviewed tools for the prediction of effector proteins of T3SS and T4SS. The webserver of the proposed ensemble methods for T3SS and T4SS effector protein prediction is freely available at http://tbooster.erc.monash.edu/index.jsp. We anticipate that this survey will serve as a useful guide for interested users and that the new ensemble predictors will stimulate research into host-pathogen relationships and inspiration for the development of new bioinformatics tools for predicting effector proteins of T3SS, T4SS and T6SS. PMID- 27777224 TI - Novel Concept of Discrimination of 1,2,4-Triazole-3-thione and 3-Thiol Tautomers. AB - Till now, three major spectroscopic techniques, fourier transform infrared (FT IR), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, have been used for determination of thiol-thione tautomeric forms. Therefore, a novel analytical concept of discrimination of 1,2,4-triazole-3-thione and 3-thiol tautomers using two high-resolution mass spectrometers has been proposed. It comprises the high-performance liquid chromatography (HPLC) hyphenated with electrospray ionization (ESI)-time-of-flight mass spectrometry (ESI-TOF-MS, positive ion mode) followed by in-source collision-induced dissociation (CID) and low-energy CID-tandem mass spectrometry (MS/MS) analysis measured with a Quadruple-TOF-MS instrument. The HPLC column was a Zorbax Stable Bond RP-18 and a rapid isocratic elution. Selected 3-thione and 3-thiol tautomers were rapidly separated, within 6 min and detected both by in-source CID ESI(+)-TOF-MS and CID ESI(+)-QTOF-MS with a high mass accuracy and high sensitivity. The method limits of detection were of 2.8-5.6 pg/MUl (at S/N 3:1) for ESI-TOF-MS and 0.25-0.55 pg/MUl for ESI-QTOF-MS. The tautomeric form could be easily discriminated by both methods and by the different gas-phase fragmentation patterns. Differences and similarities between in-source CID MS and CID MS/MS spectra have also been presented. These findings were also supported by recorded FT-IR spectra in solid state. The developed methodology using both the high-resolution MS systems is considerably the most sensitive among the others. PMID- 27777223 TI - CONSORT 2010 statement: extension to randomised pilot and feasibility trials. PMID- 27777225 TI - Wide-Bore Columns of Poly(Glycidyl Methacrylate-Co-Divinylbenzene)-Based Monolithic Beds for Reversed-Phase and Anion-Exchange Chromatographic Separation of Biomolecules. AB - Three monoliths based on poly(glycidyl methacrylate-co-divinylbenzene) were prepared in the confines of borosilicate glass columns (100 * 3 mm I.D.). The first monolith was applied for analysis of proteins by reversed-phase high performance liquid chromatography. It furnished a fast base-line separation for four proteins (ribonuclease A, cytochrome c, alpha-lactalbumin and myoglobin) in <80 s, with optimum resolution range of 2.11-2.84, and extremely small values of peak width at half height with a range of 1.0-1.6 s. The second and third monoliths were surface-modified into weak and strong anion-exchangers, respectively, and were investigated for anion-exchange (AE) high-performance liquid chromatography of four proteins with acidic isoelectronic points (bovine carbonic anhydrase, conalbumin, ovalbumin and soybean trypsin inhibitor) and of 5 phosphorylated oligodeoxythymidylic acids fragments [d(pT)12-18]. The weak AE monolith experienced complete elution of the four proteins applying a basic Tris HCl buffer (0.02 M, pH 8.9); however, the strong AE monolith established a base line separation of these proteins in ~14 min. Both monoliths showed base-line separation of the seven fragments of d(pT)12-18 in ~6 min. The ion-exchange capacity determined by frontal and elemental analyses was comparable for the weak AE monolith (0.75 and 0.80 meq/g) and for the strong AE monolith (0.81 and 0.87 meq/g), respectively. Finally, a run-to-run and monolith-to-monolith reproducibility showed a relative standard deviation in retention time of d(pT)12 18 fragments of <2%. PMID- 27777226 TI - The computer will assess you now. PMID- 27777227 TI - Conflicts of interest compromise US public health agency's mission, say scientists. PMID- 27777228 TI - Medical director of Cornwall trust is first to be struck off for management failings. PMID- 27777229 TI - Margaret McCartney: Cameras and complaints. PMID- 27777230 TI - Opportunities for primary care to reduce hospital admissions: a cross-sectional study of geographical variation. AB - BACKGROUND: Reducing unplanned hospital admissions is a key priority within the UK. Substantial interpractice variation in admission rates for ambulatory care sensitive conditions (ACSC) suggests that decreases might be possible. AIM: To identify the clinical areas and patient subgroups where the greatest opportunities exist for GPs to improve ACSC care. DESIGN AND SETTING: Cross sectional study using routine hospital data from patients registered at 8123 English GP practices during 2011 and 2012. METHOD: The authors used random effects Poisson models to estimate interpractice variation after adjusting for several drivers of healthcare need and availability of local hospital services. Interpractice variation was contrasted across patient subgroups based on age. RESULTS: There were 1.8 million hospital admissions. Overall, high-utilisation practices had ACSC admission rates that were 55% (95% CI = 53 to 56) greater than low-utilisation practices. Differences of 67% (95% CI = 65 to 69) were found for chronic ACSCs, which was much larger than the 51% (95% CI = 49 to 52) difference exhibited by acute presentations. At least two-fold differences were found for 15 (54%) ACSCs, although large interpractice variations were not ubiquitous. Admission rates were consistently more variable among younger-than-average patients. The most variable conditions tended to disproportionately affect deprived patients. CONCLUSION: Substantial interpractice variation suggests that current efforts to standardise primary care have had a limited effect on unplanned hospital admissions. GPs and healthcare commissioners should ensure they are offering best practice care for the most variable clinical areas and patient subgroups identified in the study, particularly in adults aged <70 years with chronic conditions. PMID- 27777231 TI - Investigating the relationship between consultation length and patient experience: a cross-sectional study in primary care. AB - BACKGROUND: Longer consultations in primary care have been linked with better quality of care and improved health-related outcomes. However, there is little evidence of any potential association between consultation length and patient experience. AIM: To examine the relationship between consultation length and patient-reported communication, trust and confidence in the doctor, and overall satisfaction. DESIGN AND SETTING: Analysis of 440 videorecorded consultations and associated patient experience questionnaires from 13 primary care practices in England. METHOD: Patients attending a face-to-face consultation with participating GPs consented to having their consultations videoed and completed a questionnaire. Consultation length was calculated from the videorecording. Linear regression (adjusting for patient and doctor demographics) was used to investigate associations between patient experience (overall communication, trust and confidence, and overall satisfaction) and consultation length. RESULTS: There was no evidence that consultation length was associated with any of the three measures of patient experience (P >0.3 for all). Adjusted changes on a 0-100 scale per additional minute of consultation were: communication score 0.02 (95% confidence interval [CI] = -0.20 to 0.25), trust and confidence in the doctor 0.07 (95% CI = -0.27 to 0.41), and satisfaction -0.14 (95% CI = -0.46 to 0.18). CONCLUSION: The authors found no association between patient experience measures of communication and consultation length, and patients may sometimes report good experiences from very short consultations. However, longer consultations may be required to achieve clinical effectiveness and patient safety: aspects also important for achieving high quality of care. Future research should continue to study the benefits of longer consultations, particularly for patients with complex multiple conditions. PMID- 27777233 TI - Poorest urban areas face highest rates of psychosis, study finds. PMID- 27777232 TI - Cytology in the diagnosis of cervical cancer in symptomatic young women: a retrospective review. AB - BACKGROUND: Cervical cancer in young women presents a diagnostic challenge because gynaecological symptoms are common but underlying disease is rare. AIM: To explore the potential for using cytology as a diagnostic aid for cervical cancer in young women. DESIGN AND SETTING: Retrospective review of primary care records and cytology data from the national cervical screening database and national audit of cervical cancers. METHOD: Four datasets of women aged 20-29 years in England were examined: primary care records and national screening data from an in-depth study of cervical cancers; cytology from the national audit of cervical cancers; whole-population cytology from the national screening database; and general-population primary care records from the Clinical Practice Research Datalink. The authors explored the sensitivity and positive predictive value (PPV) of symptomatic cytology (earliest <12 months before diagnosis) to cervical cancer. RESULTS: The estimated prevalence of cervical cancer among symptomatic women was between 0.4% and 0.9%. The sensitivity of moderate dyskaryosis (high grade squamous intraepithelial lesion [HSIL]) or worse in women aged 20-29 years was 90.9% to 96.2% across datasets, regardless of symptom status. The PPV was estimated to be between 10.0% and 30.0%. For women aged 20-24 years, the PPV of '?invasive squamous carcinoma' was 25.4%, and 2.0% for severe or worse cytology. CONCLUSION: Cytology has value beyond screening, and could be used as a diagnostic aid for earlier detection of cervical cancer in young women with gynaecological symptoms by ruling in urgent referral. PMID- 27777236 TI - Babies should sleep in parents' bedroom for as long as a year, says US guidance. PMID- 27777235 TI - Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention. AB - Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as alpha-tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative Risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90-1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared with placebo (RR = 1.03; 95% CI, 0.96-1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention. Cancer Prev Res; 10(1); 45-54. (c)2016 AACR. PMID- 27777234 TI - Evaluation of computed tomography in patients with atypical angina or chest pain clinically referred for invasive coronary angiography: randomised controlled trial. AB - OBJECTIVE: To evaluate whether invasive coronary angiography or computed tomography (CT) should be performed in patients clinically referred for coronary angiography with an intermediate probability of coronary artery disease. DESIGN: Prospective randomised single centre trial. SETTING: University hospital in Germany. PARTICIPANTS: 340 patients with suspected coronary artery disease and a clinical indication for coronary angiography on the basis of atypical angina or chest pain. INTERVENTIONS: 168 patients were randomised to CT and 172 to coronary angiography. After randomisation one patient declined CT and 10 patients declined coronary angiography, leaving 167 patients (88 women) and 162 patients (78 women) for analysis. Allocation could not be blinded, but blinded independent investigators assessed outcomes. MAIN OUTCOME MEASURE: The primary outcome measure was major procedural complications within 48 hours of the last procedure related to CT or angiography. RESULTS: Cardiac CT reduced the need for coronary angiography from 100% to 14% (95% confidence interval 9% to 20%, P<0.001) and was associated with a significantly greater diagnostic yield from coronary angiography: 75% (53% to 90%) v 15% (10% to 22%), P<0.001. Major procedural complications were uncommon (0.3%) and similar across groups. Minor procedural complications were less common in the CT group than in the coronary angiography group: 3.6% (1% to 8%) v 10.5% (6% to 16%), P=0.014. CT shortened the median length of stay in the angiography group from 52.9 hours (interquartile range 49.5 76.4 hours) to 30.0 hours (3.5-77.3 hours, P<0.001). Overall median exposure to radiation was similar between the CT and angiography groups: 5.0 mSv (interquartile range 4.2-8.7 mSv) v 6.4 mSv (3.4-10.7 mSv), P=0.45. After a median follow-up of 3.3 years, major adverse cardiovascular events had occurred in seven of 167 patients in the CT group (4.2%) and six of 162 (3.7%) in the coronary angiography group (adjusted hazard ratio 0.90, 95% confidence interval 0.30 to 2.69, P=0.86). 79% of patients stated that they would prefer CT for subsequent testing. The study was conducted at a University hospital in Germany and thus the performance of CT may be different in routine clinical practice. The prevalence was lower than expected, resulting in an underpowered study for the predefined primary outcome. CONCLUSIONS: CT increased the diagnostic yield and was a safe gatekeeper for coronary angiography with no increase in long term events. The length of stay was shortened by 22.9 hours with CT, and patients preferred non-invasive testing.Trial registration ClinicalTrials.gov NCT00844220. PMID- 27777237 TI - Spice and all things nasty: the challenge of synthetic cannabinoids. PMID- 27777241 TI - We want the best doctors in Wales, wherever they come from, says first minister. PMID- 27777239 TI - TGF-beta inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors. AB - Burst-forming unit erythroid progenitors (BFU-Es) are so named based on their ability to generate in methylcellulose culture large colonies of erythroid cells that consist of "bursts" of smaller erythroid colonies derived from the later colony-forming unit erythroid progenitor erythropoietin (Epo)-dependent progenitors. "Early" BFU-E cells forming large BFU-E colonies presumably have higher capacities for self-renewal than do "late" BFU-Es forming small colonies, but the mechanism underlying this heterogeneity remains unknown. We show that the type III transforming growth factor beta (TGF-beta) receptor (TbetaRIII) is a marker that distinguishes early and late BFU-Es. Transient elevation of TbetaRIII expression promotes TGF-beta signaling during the early BFU-E to late BFU-E transition. Blocking TGF-beta signaling using a receptor kinase inhibitor increases early BFU-E cell self-renewal and total erythroblast production, suggesting the usefulness of this type of drug in treating Epo-unresponsive anemias. PMID- 27777238 TI - Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. AB - Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kalpha, PI3Kdelta, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0% 99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated. PMID- 27777240 TI - Inherited Chromosomally Integrated Human Herpesvirus 6 and Breast Cancer. AB - Background: Inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) is a condition observed in approximately 1% of the population. Whether such a genetic alteration predisposes to cancer development in currently unknown. Two studies were conducted to determine whether iciHHV-6 is associated with cancer development.Methods: First, a screen of 19,597 people from the province of Quebec (Canada) was conducted. A replication test, using data from a population-based case-control study of 1,090 women with incident breast cancer and 1,053 controls from British Columbia and Ontario (Canada) was conducted. DNA samples were analyzed by qPCR and droplet digital PCR to identify iciHHV-6+ carriers.Results: In the initial study, a potential association between iciHHV-6 positivity and breast cancer was identified [OR = 2.66; 95% confidence interval (CI), 0.95 7.44]. In the replication dataset, no association was found between iciHHV-6 positivity in women and breast cancer (OR = 0.87; 95% CI, 0.35-2.15).Conclusions: We found no statistically significant associations between inherited chromosomally integrated HHV-6 and breast cancer in women.Impact: These results do not provide evidence to suggest that iciHHV-6 is a risk factor for breast cancer. Cancer Epidemiol Biomarkers Prev; 26(3); 425-7. (c)2016 AACR. PMID- 27777242 TI - Scottish court gives go-ahead to minimum alcohol pricing. PMID- 27777243 TI - Antimicrobial susceptibility of long term care facility and general practice urine samples in patients 65 years and older: an observational study. AB - Background: Antimicrobial resistance in long-term care facilities (LTCFs) poses a risk to elderly residents. The aim of this observational study was to investigate recent patterns of antimicrobial susceptibility in urine samples submitted to the Microbiology Laboratory at Cork University Hospital (CUH) from LTCFs in the greater Cork region. The antimicrobial susceptibilities of LTCF and General Practitioner (GP) urine samples sent to CUH, for patients aged over 65 years of age, were compared. Methods: A retrospective analysis of the antimicrobial susceptibilities of urine samples submitted to the microbiology laboratory at CUH in quarter one of 2011-2014 was conducted. LTCF and GP urine sample susceptibilities, for patients over 65 years of age, were compared using Chi square statistics. Results: Overall, the LTCF urine samples were less susceptible than GP urine samples to the antimicrobials recommended in the national urinary tract infection guidelines; trimethoprim, nitrofurantoin, cephalexin, co amoxiclav, ciprofloxacin and amoxicillin ( P < 0.001). Important trends in antimicrobial susceptibility over the time period were noted. A significant reduction in susceptibility to co-amoxiclav was found between Q1 2011 and Q1 2014 in both settings (GP P = 0.013, LTCF P = 0.005). This study provides important information which will contribute to the revision of antimicrobial prescribing guidelines in the future. Conclusion: This study highlights the need for continuous surveillance of antimicrobial susceptibility trends in LTCFs. Antimicrobial stewardship strategies are urgently required to address antimicrobial resistance and appropriate antimicrobial prescribing in the LTCF setting. PMID- 27777244 TI - Disease named entity recognition by combining conditional random fields and bidirectional recurrent neural networks. AB - The recognition of disease and chemical named entities in scientific articles is a very important subtask in information extraction in the biomedical domain. Due to the diversity and complexity of disease names, the recognition of named entities of diseases is rather tougher than those of chemical names. Although there are some remarkable chemical named entity recognition systems available online such as ChemSpot and tmChem, the publicly available recognition systems of disease named entities are rare. This article presents a system for disease named entity recognition (DNER) and normalization. First, two separate DNER models are developed. One is based on conditional random fields model with a rule-based post processing module. The other one is based on the bidirectional recurrent neural networks. Then the named entities recognized by each of the DNER model are fed into a support vector machine classifier for combining results. Finally, each recognized disease named entity is normalized to a medical subject heading disease name by using a vector space model based method. Experimental results show that using 1000 PubMed abstracts for training, our proposed system achieves an F1-measure of 0.8428 at the mention level and 0.7804 at the concept level, respectively, on the testing data of the chemical-disease relation task in BioCreative V.Database URL: http://219.223.252.210:8080/SS/cdr.html. PMID- 27777245 TI - Subacute Sclerosing Panencephalitis in a Child with Human Immunodeficiency Virus Co-Infection. AB - Subacute sclerosing panencephalitis is a fatal infectious disease of childhood caused by persistence of the measles virus in the brain. The effect of human immunodeficiency virus (HIV) co-infection on subacute sclerosing panencephalitis remains elusive and rare. We report a child who developed subacute sclerosing panencephalitis following a short latency period and a rapidly progressive course with HIV co-infection. PMID- 27777246 TI - Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach. AB - Induction of cytochrome P450 (P450) can impact the efficacy and safety of drug molecules upon multiple dosing with coadministered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of P450 induction are related to these enzymes. However, the in vitro evaluation of induction is applicable to other P450 enzymes; however, the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the preclinical phase, compounds are screened using pregnane X receptor reporter gene assay, and if necessary structure-activity relationships (SAR) are developed. When projects progress toward the clinical phase, induction studies in a hepatocyte-derived model using HepaRG cells will generate enough robust data to assess the compound's induction liability in vivo. The sensitive CYP3A biomarker 4beta-hydroxycholesterol is built into the early clinical phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts from the currently used in vitro methods. Using this model, the AstraZeneca induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data that support the validity of both the in vitro models and the use of the biomarker can be found in the scientific literature. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission. PMID- 27777248 TI - Letter in reply to 'Evidence pyramids' from Dr Kaufmann. PMID- 27777247 TI - AMP-Activated Protein Kinase alpha2 in Neutrophils Regulates Vascular Repair via Hypoxia-Inducible Factor-1alpha and a Network of Proteins Affecting Metabolism and Apoptosis. AB - RATIONALE: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia, and although the AMPKalpha1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPKalpha2 subunit in vascular repair. OBJECTIVE: To determine the role of the AMPKalpha2 subunit in vascular repair. METHODS AND RESULTS: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPKalpha2-/- versus wild-type mice, a phenotype reproduced in mice lacking AMPKalpha2 in myeloid cells (AMPKalpha2DeltaMC). Three days after ligation, neutrophil infiltration into ischemic limbs of AMPKalpha2DeltaMC mice was lower than that in wild-type mice despite being higher after 24 hours. Neutrophil survival in ischemic tissue is required to attract monocytes that contribute to the angiogenic response. Indeed, apoptosis was increased in hypoxic neutrophils from AMPKalpha2DeltaMC mice, fewer monocytes were recruited, and gene array analysis revealed attenuated expression of proangiogenic proteins in ischemic AMPKalpha2DeltaMC hindlimbs. Many angiogenic growth factors are regulated by hypoxia-inducible factor, and hypoxia-inducible factor-1alpha induction was attenuated in AMPKalpha2-deficient cells and accompanied by its enhanced hydroxylation. Also, fewer proteins were regulated by hypoxia in neutrophils from AMPKalpha2DeltaMC mice. Mechanistically, isocitrate dehydrogenase expression and the production of alpha-ketoglutarate, which negatively regulate hypoxia-inducible factor-1alpha stability, were attenuated in neutrophils from wild-type mice but remained elevated in cells from AMPKalpha2DeltaMC mice. CONCLUSIONS: AMPKalpha2 regulates alpha-ketoglutarate generation, hypoxia-inducible factor-1alpha stability, and neutrophil survival, which in turn determine further myeloid cell recruitment and repair potential. The activation of AMPKalpha2 in neutrophils is a decisive event in the initiation of vascular repair after ischemia. PMID- 27777249 TI - Where should preappraised evidence summaries and guidelines place in a pyramid? PMID- 27777250 TI - Letter in reply to 'Evidence pyramids' from Dr Kaufmann. PMID- 27777251 TI - Evidence pyramids. PMID- 27777253 TI - Mouth and throat cancers from HPV on rise in men. PMID- 27777252 TI - Predicting the presence of bacterial pathogens in the airways of primary care patients with acute cough. AB - BACKGROUND: Bacterial testing of all patients who present with acute cough is not feasible in primary care. Furthermore, the extent to which easily obtainable clinical information predicts bacterial infection is unknown. We evaluated the diagnostic value of clinical examination and testing for C-reactive protein and procalcitonin for bacterial lower respiratory tract infection. METHODS: Through a European diagnostic study, we recruited 3104 adults with acute cough (<= 28 days) in primary care settings. All of the patients underwent clinical examination, measurement of C-reactive protein and procalcitonin in blood, and chest radiography. Bacterial infection was determined by conventional culture, polymerase chain reaction and serology, and positive results were defined by the presence of Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Bordetella pertussis or Legionella pneumophila. Using multivariable regression analysis, we examined the association of diagnostic variables with the presence of bacterial infection. RESULTS: Overall, 539 patients (17%) had bacterial lower respiratory tract infection, and 38 (1%) had bacterial pneumonia. The only item with diagnostic value for lower respiratory tract infection was discoloured sputum (area under the receiver operating characteristic [ROC] curve 0.56, 95% confidence interval [CI] 0.54-0.59). Adding C-reactive protein above 30 mg/L increased the area under the ROC curve to 0.62 (95% CI 0.59-0.65). For bacterial pneumonia, comorbidity, fever and crackles on auscultation had diagnostic value (area under ROC curve 0.68, 95% CI 0.58-0.77). Adding C-reactive protein above 30 mg/L increased the area under the ROC curve to 0.79 (95% CI 0.71 0.87). Procalcitonin did not add diagnostic information for any bacterial lower respiratory tract infection, including bacterial pneumonia. INTERPRETATION: In adults presenting with acute lower respiratory tract infection, signs, symptoms and C-reactive protein showed diagnostic value for a bacterial cause. However, the ability of these diagnostic indicators to exclude a bacterial cause was limited. Procalcitonin added no clinically relevant information. PMID- 27777254 TI - Mycobacterium chelonae bacteremia in a patient taking infliximab and prednisone. PMID- 27777255 TI - Uncertainty over MAiD likely to continue. PMID- 27777256 TI - An older patient with diabetes and severe foot pain. PMID- 27777257 TI - Canada Health Act needs bite. PMID- 27777259 TI - Assisted-dying demand concentrated in four provinces. PMID- 27777258 TI - Diagnosis and management of supraventricular tachycardias. PMID- 27777261 TI - Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients: an acute and 12-week randomised, double-blind, placebo-controlled trial. AB - OBJECTIVE: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. DESIGN: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. METHODS: In total, 57 type 2 diabetes patients (mean +/- s.d. age: 62.8 +/ 6.9 years; BMI: 31.8 +/- 4.1 kg/m2; HbA1c: 7.3 +/- 0.6%), treated with metformin and/or sulfonylureas, were included between July 2013 and August 2015. In the acute study, the GLP-1 receptor agonist exenatide (n = 29) or placebo (saline 0.9%; n = 28) was infused intravenously. Subsequently, patients were again randomised to receive the GLP-1 receptor agonist liraglutide (n = 19) or matching placebo (n = 17) for 12 weeks. RHR and blood pressure (BP) were measured by oscillometric technique, systemic haemodynamics by finger photoplethysmography, sympathetic nervous system (SNS) activity by heart rate variability and arterial stiffness by applanation tonometry. This trial was registered at ClinicalTrials.gov (Nbib1744236). RESULTS: Exenatide-infusion increased RHR (mean +/- s.e.m. +7.5 +/- 0.9 BPM, P < 0.001), and systolic and diastolic BP (both P < 0.05), compared with placebo. Vascular resistance increased during exenatide infusion, whereas stroke volume and arterial stiffness decreased (P < 0.05). SNS activity and cardiac output were unaffected. Twelve-week treatment with liraglutide increased RHR (+6.6 +/- 2.1 BPM), while reducing systolic BP (-12.6 +/- 4.7 mmHg) and stroke volume (all P < 0.01). Cardiac output, vascular resistance, arterial stiffness and SNS activity remained unchanged (all P > 0.05). CONCLUSIONS: RHR acceleration with acute and 12-week GLP-1 receptor agonist treatment in type 2 diabetes patients is not explained by changes in SNS activity, and our data argue against vasodilation. In line with pre-clinical data, direct sino-atrial stimulation may be involved. PMID- 27777262 TI - New Insights into the Roles of Host Gene-Necrotrophic Effector Interactions in Governing Susceptibility of Durum Wheat to Tan Spot and Septoria nodorum Blotch. AB - Tan spot and Septoria nodorum blotch (SNB) are important diseases of wheat caused by the necrotrophic fungi Pyrenophora tritici-repentis and Parastagonospora nodorum, respectively. The P. tritici-repentis necrotrophic effector (NE) Ptr ToxB causes tan spot when recognized by the Tsc2 gene. The NE ToxA is produced by both pathogens and has been associated with the development of both tan spot and SNB when recognized by the wheat Tsn1 gene. Most work to study these interactions has been conducted in common wheat, but little has been done in durum wheat. Here, quantitative trait loci (QTL) analysis of a segregating biparental population indicated that the Tsc2-Ptr ToxB interaction plays a prominent role in the development of tan spot in durum. However, analysis of two biparental populations indicated that the Tsn1-ToxA interaction was not associated with the development of tan spot, but was strongly associated with the development of SNB. Pa. nodorum expressed ToxA at high levels in infected Tsn1 plants, whereas ToxA expression in P. tritici-repentis was barely detectable, suggesting that the differences in disease levels associated with the Tsn1-ToxA interaction were due to differences in pathogen expression of ToxA These and previous results together indicate that: (1) the effects of Tsn1-ToxA on tan spot in common wheat can range from nonsignificant to highly significant depending on the host genetic background; (2) Tsn1-ToxA is not a significant factor for tan spot development in durum wheat; and (3) Tsn1-ToxA plays a major role in SNB development in both common and durum wheat. Durum and common wheat breeders alike should strive to remove both Tsc2 and Tsn1 from their materials to achieve disease resistance. PMID- 27777263 TI - Comparison of neutralizing antibody titers against outbreak-associated measles genotypes (D4, H1 and B3) in Iran. AB - Despite the accessibility of a promising vaccine, outbreaks of the measles virus (MV) take place even in well-vaccinated populations. D4, H1 and B3 genotypes have been detected regularly in different regions of Iran. These observations highlight the necessity of evaluating the protective efficacy of the vaccine against currently circulating MV genotypes during the elimination phase. A focus reduction neutralization test has been developed to measure the neutralizing antibodies against different genotypes of MV, such as H1, D4, B3 and vaccine strain (A), in children after second doses of measles vaccine. The geometric mean titer (GMT) rates of the sera against D4, H1, B3 and A genotypes were 95.9, 90.5, 32.0 and 76.1, respectively. Low GMTs of antibody against the B3 genotype compared with the other genotypes were indicated. Based on the current study results, the MV antibody titers in the sera of vaccinated cases are sufficient to neutralize all circulating genotypes in Iran; however, neutralizing antibody titers were lower for the B3 genotype than for the H1, D4 and A genotypes. The heterogeneous nature of MV, for instance the nucleotide sequence diversity between different strains, necessitates the evaluation of the protective efficacy of the vaccine against measles B3 genotype in countries where this virus has been the most commonly identified circulating genotype. PMID- 27777260 TI - Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast. AB - Pontocerebellar hypoplasia type 1b (PCH1b) is an autosomal recessive disorder that causes cerebellar hypoplasia and spinal motor neuron degeneration, leading to mortality in early childhood. PCH1b is caused by mutations in the RNA exosome subunit gene, EXOSC3 The RNA exosome is an evolutionarily conserved complex, consisting of nine different core subunits, and one or two 3'-5' exoribonuclease subunits, that mediates several RNA degradation and processing steps. The goal of this study is to assess the functional consequences of the amino acid substitutions that have been identified in EXOSC3 in PCH1b patients. To analyze these EXOSC3 substitutions, we generated the corresponding amino acid substitutions in the Saccharomyces cerevisiae ortholog of EXOSC3, Rrp40 We find that the rrp40 variants corresponding to EXOSC3-G31A and -D132A do not affect yeast function when expressed as the sole copy of the essential Rrp40 protein. In contrast, the rrp40-W195R variant, corresponding to EXOSC3-W238R in PCH1b patients, impacts cell growth and RNA exosome function when expressed as the sole copy of Rrp40 The rrp40-W195R protein is unstable, and does not associate efficiently with the RNA exosome in cells that also express wild-type Rrp40 Consistent with these findings in yeast, the levels of mouse EXOSC3 variants are reduced compared to wild-type EXOSC3 in a neuronal cell line. These data suggest that cells possess a mechanism for optimal assembly of functional RNA exosome complex that can discriminate between wild-type and variant exosome subunits. Budding yeast can therefore serve as a useful tool to understand the molecular defects in the RNA exosome caused by PCH1b-associated amino acid substitutions in EXOSC3, and potentially extending to disease-associated substitutions in other exosome subunits. PMID- 27777264 TI - Cell coupling mediated by connexin 26 selectively contributes to reduced adhesivity and increased migration. AB - Gap junction proteins (connexins) have crucial effects on cell motility in many systems, from migration of neural crest cells to promotion of metastatic invasiveness. Here, we show that expression of Cx26 (also known as GJB2) in HeLa cells specifically enhances cell motility in scrape wounding and sparse culture models. This effect is dependent on gap junction channels and is isotype specific [Cx26 enhances motility, whereas Cx43 (also known as GJA1) does not and Cx32 (also known as GJB1) has an intermediate effect]. The increased motility is associated with reduced cell adhesiveness, caused by loss of N-cadherin protein and RNA at the wound edge. This in turn causes a redistribution of N-cadherin binding proteins (p120 catenin and beta-catenin) to the cytosol and nucleus, respectively. The former activates Rac-1, which mediates cytoskeletal rearrangements needed for filopod extension. The latter is associated with increased expression of urokinase plasminogen activating receptor (an activator of extracellular proteases) and secretion of extracellular matrix components like collagen. Although these effects were dependent on Cx26-mediated coupling of the cells, they are not mediated by the same signal (i.e. cAMP) through which Cx26 has been shown to suppress proliferation in the same system. PMID- 27777267 TI - Incidence rate for prostate cancer in Japanese in Japan and in the United States from the Cancer Incidence in Five Continents. PMID- 27777265 TI - Prenatal sex selection and female infant mortality are more common in India after firstborn and second-born daughters. AB - BACKGROUND: The Indian sex ratio has become highly male-biased in recent decades. This may be attributed to prenatal sex selection (PSS) and excess female infant mortality. However, the question of whether these factors are related has not been adequately studied. Here we examine whether increased use of PSS may offset excess female infant mortality, by reducing the number of 'unwanted' daughters being born. METHODS: We analyse the National Family Health Survey (NHFS) data sets for India, which contain nationally representative samples of birth histories for women aged 15-49, interviewed in 1992-1993, 1998-1999 and 2005 2006. We test for missing female births at the second and third birth order, by analysis of the frequencies of sibling sex combinations, and examine the mortality differential between male and female infants, controlling for household wealth and sex(es) of older siblings. RESULTS: PSS was used most in wealthier households at the second and third birth order, when the firstborn, or firstborn and second-born, siblings were female. Having preceding female siblings was a significant risk factor for female infant mortality, but was not correlated with household wealth. CONCLUSIONS: PSS and female infant mortality increase with the presence of older female siblings, yet we find no evidence that increasing use of PSS prevents female infant mortality, because PSS and the proportion of female infant mortality attributable to having older sisters increased over the study period. Increased pressure on higher birth order females caused by the trend towards smaller family sizes may explain this. PMID- 27777266 TI - A Proposal for a Serology-Based Approach to Membranous Nephropathy. AB - Primary membranous nephropathy (MN) is an autoimmune disease mainly caused by autoantibodies against the recently discovered podocyte antigens: the M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R antibodies are commercially available, but a semiquantitative test to detect anti-THSD7A antibodies has been only recently developed. The presence or absence of anti PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Persistence or reappearance of anti-PLA2R antibodies after kidney transplant predicts development of recurrent disease. We propose that an individualized serology-based approach to MN, used to complement and refine the traditional proteinuria-driven approach, will improve the outcome in this disease. PMID- 27777268 TI - Immunoglobulin G4-related disease presenting as an intrapericardial tumor. PMID- 27777269 TI - Randomised placebo-controlled trials of surgery: ethical analysis and guidelines. AB - Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: (1) the presence of equipoise, defined as a lack of unbiased evidence for efficacy of an intervention; (2) clinically important research question; (3) the risk to patients is minimised and reasonable; (4) there is uncertainty about treatment allocation rather than deception; (5) there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and (6) ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial (1) should be sufficiently powered and (2) standardised so that its results are valid, (3) consent should be valid, (4) the standard treatment or rescue medication should be provided if possible, and (5) after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association. PMID- 27777270 TI - A gene-centered C. elegans protein-DNA interaction network provides a framework for functional predictions. AB - Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein-DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we delineated the largest gene-centered metazoan PDI network to date by examining interactions between 90% of C. elegans TFs and 15% of gene promoters. We used this network as a backbone to predict TF binding sites for 77 TFs, two-thirds of which are novel, as well as integrate gene expression, protein-protein interaction, and phenotypic data to predict regulatory and biological functions for multiple genes and TFs. PMID- 27777271 TI - Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance. AB - The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b-/- versus wild-type mice. The liver to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2-/- mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin. PMID- 27777273 TI - Good News? A Longitudinal Analysis of Newspaper Portrayals of Mental Illness in Canada 2005 to 2015. AB - OBJECTIVES: The overarching aim of this article is to assess media portrayals of mental illness in Canada. We hypothesise that portrayals have improved over time, related to the various antistigma activities of organisations such as the Mental Health Commission of Canada (MHCC). Specific objectives are to assess 1) overall tone and content of newspaper articles, 2) change over time, and 3) variables associated with positive or negative content. METHODS: We collected newspaper articles from print and online editions of over 20 best-selling Canadian newspapers from 2005 to 2015 ( N = 24,570) that mentioned key search terms such as mental illness or schizophrenia. These were read by research assistants, who assessed tone and content for each article using preassigned codes and categories. Data were subjected to chi-squared and trend analysis. RESULTS: Over the study period, 21% of the articles had a positive tone and 28% had stigmatising content. Trend analysis suggested significantly improved coverage over 11 years ( P < 0.001). For example, articles with a positive tone had almost doubled from 2005 (18.9%) to 2015 (34.8%), and articles with stigmatising content had reduced by a third (22.3% vs 32.7%). Analysis also suggested that articles on the front page, as well as articles in broadsheet newspapers, had significantly more positive coverage. CONCLUSIONS: The study indicates that news media coverage related to mental illness has improved over the past decade. This may be related to the concerted efforts of the MHCC, which has executed a targeted strategy aimed at reducing stigma and improving media coverage since 2007. PMID- 27777274 TI - Involuntary Outpatient Commitment and the Elusive Pursuit of Violence Prevention. AB - OBJECTIVE: Involuntary outpatient commitment (OPC)-also referred to as 'assisted outpatient treatment' or 'community treatment orders'-are civil court orders whereby persons with serious mental illness and repeated hospitalisations are ordered to adhere to community-based treatment. Increasingly, in the United States, OPC is promoted to policy makers as a means to prevent violence committed by persons with mental illness. This article reviews the background and context for promotion of OPC for violence prevention and the empirical evidence for the use of OPC for this goal. METHOD: Relevant publications were identified for review in PubMed, Ovid Medline, PsycINFO, personal communications, and relevant Internet searches of advocacy and policy-related publications. RESULTS: Most research on OPC has focussed on outcomes such as community functioning and hospital recidivism and not on interpersonal violence. As a result, research on violence towards others has been limited but suggests that low-level acts of interpersonal violence such as minor, noninjurious altercations without weapon use and arrests can be reduced by OPC, but there is no evidence that OPC can reduce major acts of violence resulting in injury or weapon use. The impact of OPC on major violence, including mass shootings, is difficult to assess because of their low base rates. CONCLUSIONS: Effective implementation of OPC, when combined with intensive community services and applied for an adequate duration to take effect, can improve treatment adherence and related outcomes, but its promise as an effective means to reduce serious acts of violence is unknown. PMID- 27777275 TI - Human Error as an Emergent Property of Action Selection and Task Place-Holding. AB - OBJECTIVE: A computational process model could explain how the dynamic interaction of human cognitive mechanisms produces each of multiple error types. BACKGROUND: With increasing capability and complexity of technological systems, the potential severity of consequences of human error is magnified. Interruption greatly increases people's error rates, as does the presence of other information to maintain in an active state. METHOD: The model executed as a software instantiated Monte Carlo simulation. It drew on theoretical constructs such as associative spreading activation for prospective memory, explicit rehearsal strategies as a deliberate cognitive operation to aid retrospective memory, and decay. RESULTS: The model replicated the 30% effect of interruptions on postcompletion error in Ratwani and Trafton's Stock Trader task, the 45% interaction effect on postcompletion error of working memory capacity and working memory load from Byrne and Bovair's Phaser Task, as well as the 5% perseveration and 3% omission effects of interruption from the UNRAVEL Task. CONCLUSION: Error classes including perseveration, omission, and postcompletion error fall naturally out of the theory. APPLICATION: The model explains post-interruption error in terms of task state representation and priming for recall of subsequent steps. Its performance suggests that task environments providing more cues to current task state will mitigate error caused by interruption. For example, interfaces could provide labeled progress indicators or facilities for operators to quickly write notes about their task states when interrupted. PMID- 27777276 TI - Improving Health Care Quality and Patient Safety Through Peer-to-Peer Assessment: Demonstration Project in Two Academic Medical Centers. AB - Despite decades of investment in patient safety, unintentional patient harm remains a major challenge in the health care industry. Peer-to-peer assessment in the nuclear industry has been shown to reduce harm. The study team's goal was to pilot and assess the feasibility of this approach in health care. The team developed tools and piloted a peer-to-peer assessment at 2 academic hospitals: Massachusetts General Hospital and Johns Hopkins Hospital. The assessment evaluated both the institutions' organizational approach to quality and safety as well as their approach to reducing 2 specific areas of patient harm. Site visits were completed and consisted of semistructured interviews with institutional leaders and clinical staff as well as direct patient observations using audit tools. Reports with recommendations were well received and each institution has developed improvement plans. The study team believes that peer-to-peer assessment in health care has promise and warrants consideration for wider adoption. PMID- 27777277 TI - The impact of mild cognitive impairment on the self-regulation process: A comparison study of persons with mild cognitive impairment and cognitively healthy older adults. AB - This study examined whether mild cognitive impairment affects the associations between personal expectations (i.e. optimism and self-efficacy), illness-related coping, and quality of life. In total, two groups of older adults participated: 127 persons diagnosed with mild cognitive impairment and 225 cognitively healthy older persons (cognitively non-impaired group). Several significant relationships observed in the cognitively non-impaired group did not reach significance among mild cognitive impairment patients, with the opposite trend noted for others (e.g. between palliative coping and physical health). These findings indicate that mild cognitive impairment may lead to problems in the self-regulation process and highlight the significance of the interplay between neurocognitive and psychosocial aspects of self-regulation. PMID- 27777278 TI - Duration of Prehospital Cardiopulmonary Resuscitation and Favorable Neurological Outcomes for Pediatric Out-of-Hospital Cardiac Arrests: A Nationwide, Population Based Cohort Study. AB - BACKGROUND: The appropriate duration of cardiopulmonary resuscitation (CPR) for pediatric out-of-hospital cardiac arrests (OHCAs) remains unclear and may differ based on initial rhythm. We aimed to determine the relationship between the duration of prehospital CPR by emergency medical services (EMS) personnel and post-OHCA outcomes. METHODS: We analyzed the records of 12 877 pediatric patients who experienced OHCAs (<18 years of age). Data were recorded in a nationwide Japanese database between 2005 and 2012. Study end points were 30-day survival and 30-day survival with favorable neurological outcomes (Cerebral Performance Category [CPC] scale 1-2). Prehospital EMS-initiated CPR duration was defined as the time from CPR initiation by EMS personnel to prehospital return of spontaneous circulation (ROSC) or to hospital arrival when prehospital ROSC was not achieved during prehospital CPR efforts. RESULTS: The rates of 30-day survival and 30-day CPC 1 to 2 were 9.1% (n=1167) and 2.5% (n=325), respectively. Prehospital EMS-initiated CPR duration was significantly and inversely associated with 30-day outcomes (adjusted odds ratio for 1-minute increments: 0.94, 95% confidence interval: 0.93-0.95 for survival; adjusted odds ratio: 0.90, 95% confidence interval: 0.88-0.92 for CPC 1-2). The duration of prehospital EMS initiated CPR, beyond which the chance for favorable outcomes diminished to <1%, was 42 minutes for each key outcome, 30-day survival, and 30-day survival with CPC 1 to 2. When categorized by initial rhythm, the prehospital EMS-initiated CPR durations beyond which the chance for 30-day survival with CPC 1 to 2 diminished to <1% were 39 minutes for shockable rhythms, 42 minutes for pulseless electric activity, and 46 minutes for asystole, respectively. In patients with bystander initiated CPR, the prehospital CPR duration, beyond which the chance for favorable outcome diminished to <1%, was 46 minutes from call receipt. CONCLUSIONS: Prehospital EMS-initiated CPR duration for pediatric OHCAs was independently and inversely associated with 30-day favorable outcomes. The duration of prehospital EMS-initiated CPR, beyond which the chance for 30-day favorable outcomes diminished to <1%, was 42 minutes. However, the CPR duration to achieve this proportion of outcomes differed based on initial rhythm. Further research is required to elucidate appropriate CPR duration for pediatric OHCAs, including in-hospital CPR time. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02432196. PMID- 27777280 TI - Ground zero: Ontology, recognition, and the elusiveness of care in American eating disorders treatment. AB - This paper reflects upon questions of ontological contingency when the stark, visceral reality of a person's relentless self-destruction unfolds within institutional mechanisms that systematically withhold certain kinds of care. I consider these issues through the lens of "manipulation" as it is elaborated within an American eating disorders treatment center, where the notion of manipulation does particular kinds of affective and pragmatic work. Specifically, it serves to render clients as, paradoxically, both hyper-agentic and "agentically challenged" in ways that legitimate the withholding of their recognition as full subjects and therefore deserving of care. I propose that the ontological perspectives of the treatment center are ill-equipped for accounting for such dynamics and, in fact, carry certain risks when employed in the consideration of psychiatric conditions where they can even become coopted in unintended ways. This carries special importance when working with people whose ontological status is, in a very real (and not just theoretical) sense, teetering on the brink of the void. PMID- 27777279 TI - Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control. AB - BACKGROUND: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin. METHODS: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses. RESULTS: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions. CONCLUSIONS: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513. PMID- 27777281 TI - Hand Pain in a Golfer: A Case Report of a Metacarpal Stress Injury and a Review of the Literature Regarding Return to Play in Grip Athletes. AB - A 19-year-old golfer presented to the sports clinic with a 2-week history of dominant-hand pain after several months of daily golf. He had a metacarpal stress fracture. This case discusses the athlete's return-to-play timeline as well as reviews the current limited literature guiding return to play in grip athletes. PMID- 27777282 TI - Diagnosis delay and duration of hospitalisation of patients with Buruli ulcer in Nigeria. AB - BACKGROUND: Delayed diagnosis of Buruli ulcer can worsen clinical presentation of the disease, prolong duration of management, and impose avoidable additional costs on patients and health providers. We investigated the profile, delays in diagnosis, duration of hospitalisation, and associated factors among patients with Buruli ulcer in Nigeria. METHODS: This was a prospective cohort study of patients with Buruli ulcer who were identified from a community-based survey. Data on the patients' clinical profile, delays in diagnosis and duration of hospitalisation were prospectively collected. RESULTS: Of 145 patients notified, 125 (86.2%) were confirmed by one or more laboratory tests (81.4% by PCR). The median age of the patients was 20 years, 88 (60.7%) were >15years old and 85 (58.6%) were females. In addition, 137 (94.5%) were new cases, 119 (82.1%) presented with ulcers and 110 (75.9%) had lower limb lesions. The mean time delay to diagnosis was 50.6 (+/-101.9) weeks. The mean duration of hospitalisation was 108 (+/-60) days. Determinants of time delay to diagnosis were higher disease category (p=0.001) and laboratory confirmation of disease (p=0.02). Determinants of longer hospitalisation were; multiple lesions (p=0.035), and having functional limitation at diagnosis and undertaking surgery (p=0.003). CONCLUSIONS: Patients with Buruli ulcer have very long time delays to diagnosis and long hospitalisation during treatment. This calls for early case-finding and improved access to Buruli ulcer services in Nigeria. PMID- 27777283 TI - Parallel Evolution of Cold Tolerance within Drosophila melanogaster. AB - Drosophila melanogaster originated in tropical Africa before expanding into strikingly different temperate climates in Eurasia and beyond. Here, we find elevated cold tolerance in three distinct geographic regions: beyond the well studied non-African case, we show that populations from the highlands of Ethiopia and South Africa have significantly increased cold tolerance as well. We observe greater cold tolerance in outbred versus inbred flies, but only in populations with higher inversion frequencies. Each cold-adapted population shows lower inversion frequencies than a closely-related warm-adapted population, suggesting that inversion frequencies may decrease with altitude in addition to latitude. Using the FST-based "Population Branch Excess" statistic (PBE), we found only limited evidence for parallel genetic differentiation at the scale of ~4 kb windows, specifically between Ethiopian and South African cold-adapted populations. And yet, when we looked for single nucleotide polymorphisms (SNPs) with codirectional frequency change in two or three cold-adapted populations, strong genomic enrichments were observed from all comparisons. These findings could reflect an important role for selection on standing genetic variation leading to "soft sweeps". One SNP showed sufficient codirectional frequency change in all cold-adapted populations to achieve experiment-wide significance: an intronic variant in the synaptic gene Prosap. Another codirectional outlier SNP, at senseless-2, had a strong association with our cold trait measurements, but in the opposite direction as predicted. More generally, proteins involved in neurotransmission were enriched as potential targets of parallel adaptation. The ability to study cold tolerance evolution in a parallel framework will enhance this classic study system for climate adaptation. PMID- 27777284 TI - Spontaneous Mutation Accumulation in Daphnia pulex in Selection-Free vs. Competitive Environments. AB - Understanding the rates, spectra, and fitness effects of spontaneous mutations is fundamental to answering key questions in evolution, molecular biology, disease genetics, and conservation biology. To estimate mutation rates and evaluate the effect of selection on new mutations, we propagated mutation accumulation (MA) lines of Daphnia pulex for more than 82 generations and maintained a non-MA population under conditions where selection could act. Both experiments were started with the same obligate asexual progenitor clone. By sequencing 30 genomes and implementing a series of validation steps that informed the bioinformatic analyses, we identified a total of 477 single nucleotide mutations (SNMs) in the MA lines, corresponding to a mutation rate of 2.30 * 10-9 (95% CI 1.90-2.70 * 10 9) per nucleotide per generation. The high overall rate of loss of heterozygosity (LOH) of 4.82 * 10-5 per site per generation was due to a large ameiotic recombination event spanning an entire arm of a chromosome (~6 Mb) and several hemizygous deletion events spanning ~2 kb each. In the non-MA population, we found significantly fewer mutations than expected based on the rate derived from the MA experiment, indicating purifying selection was likely acting to remove new deleterious mutations. We observed a surprisingly high level of genetic variability in the non-MA population, which we propose to be driven by balancing selection. Our findings suggest that both positive and negative selection on new mutations is powerful and effective in a strictly clonal population. PMID- 27777285 TI - Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations. AB - In the majority of gastrointestinal stromal tumors (GIST), oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in patient-derived xenograft (PDX) models of GIST, carrying different KIT mutations. NMRI nu/nu mice (n = 52) were bilaterally transplanted with human GIST: UZLX-GIST4 (KIT exon 11 mutation, imatinib sensitive), UZLX GIST2 (KIT exon 9, imatinib dose-dependent resistance), or UZLX-GIST9 (KIT exon 11 and 17 mutations, imatinib resistant). Mice were grouped as control (untreated), imatinib (50 mg/kg/bid), and cabozantinib (30 mg/kg/qd) and treated orally for 15 days. Cabozantinib resulted in significant tumor regression in UZLX GIST4 and -GIST2 and delayed tumor growth in -GIST9. In all three models, cabozantinib inhibited the proliferative activity, which was completely absent in UZLX-GIST4 and significantly reduced in -GIST2 and -GIST9. Increased apoptotic activity was observed only in UZLX-GIST4. Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. In conclusion, cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models. Mol Cancer Ther; 15(12); 2845-52. (c)2016 AACR. PMID- 27777287 TI - Circulation's Vision for Cardiac Surgery. PMID- 27777288 TI - Introduction to the Cardiovascular Surgery Themed Issue of Circulation. PMID- 27777286 TI - Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis. AB - Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here, we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101-induced cell death and reactivates effector caspase mediated apoptosis in U251 glioma cells with high BAG3 expression, whereas these sensitizing effects were less pronounced in U343 cells expressing lower BAG3 levels. KRIBB11 decreased protein levels of HSP70, BAG3, and the antiapoptotic Bcl-2 protein Mcl-1, and both KRIBB11 and YM-1 elicited significantly increased mitochondrial dysfunction, effector caspase activity, and apoptotic cell death after combined treatment with AT-101 and ABT-737. Depletion of BAG3 also led to a pronounced loss of cell-matrix adhesion, FAK phosphorylation, and in vivo tumor growth in an orthotopic mouse glioma model. Furthermore, it reduced the plating efficiency of U251 cells in three-dimensional clonogenic assays and limited clonogenic survival after short-term treatment with AT-101. Collectively, our data suggest that the HSF1/HSP70/BAG3 pathway plays a pivotal role for overexpression of prosurvival Bcl-2 proteins and cell death resistance of glioma. They also support the hypothesis that interference with BAG3 function is an effective novel approach to prime glioma cells to anoikis. Mol Cancer Ther; 16(1); 156-68. (c)2016 AACR. PMID- 27777289 TI - The Evolution of Coronary Bypass Surgery Will Determine Its Relevance as the Standard of Care for the Treatment for Multivessel Coronary Artery Disease. PMID- 27777290 TI - Long-Term Survival and Freedom From Reintervention After Off-Pump Coronary Artery Bypass Grafting: A Propensity-Matched Study. AB - BACKGROUND: The long-term outcomes of off-pump coronary artery bypass grafting (CABG) are the subject of speculation. Our institution has >15 years of experience performing CABG both off-pump (OPCAB) and on cardiopulmonary bypass (CPB). Our null hypothesis was that there would be no difference in a long-term composite of death and revascularisation between the 2 methods. METHODS: We performed a retrospective cohort study of all isolated CABG at our institution from 2001 to 2015. We used an intention-to-treat analysis, performing risk adjustment with adjustment for and matching to propensity score. In total, 13 226 patients had CABG: 5882 had OPCAB and 7344 had CPB, with a median follow-up of 6.2 years. RESULTS: Of the 5882 OPCAB, 76 (1.3%) converted to CPB. One-, 5-, and 10-year survivals in each group were similar (OPCAB vs CPB: 96.7%, 87.9%, 72.1% vs 96.2%, 87.4%, 72.8%). No difference was found in long-term survival (adjusted hazards ratio [HR] 1.03; 95% confidence interval [CI]: 0.94-1.11 for OPCAB vs CPB; P=0.56) or freedom from death and reintervention (HR 0.98; 95% CI: 0.92-1.06 for OPCAB vs CPB; P=0.23). Patients receiving OPCAB had higher EuroSCOREs (median [quartiles]: 2.81 [1.53-5.57] vs 2.73 [1.51-5.22]; P=0.01), fewer grafts (mean+/ SD: 3.0+/-0.9 vs 3.3+/-0.9; P<0.001), but more total arterial grafting (45.9% vs 8.4%; P<0.001). OPCAB also had more trainee first operators (15.3% vs 12.5%), lower cardiac enzyme rise, shorter length of stay, and fewer complications (such as myocardial infarction). CONCLUSIONS: OPCAB is associated with similar long term outcomes to CABG performed on CPB in our institution. Our low conversion rate to CPB, while training junior surgeons, demonstrates that OPCAB can be taught safely. The number of grafts performed between the 2 approaches is clinically comparable, if statistically different, and appears to provide equal benefits to survival and freedom from reintervention as on-pump CABG. PMID- 27777291 TI - Tailoring Operations to the Patient Is Always Best. PMID- 27777292 TI - Temporal Trends in Predictors of Early and Late Mortality After Emergency Coronary Artery Bypass Grafting for Cardiogenic Shock Complicating Acute Myocardial Infarction. AB - BACKGROUND: Cardiogenic shock after acute myocardial infarction is an indication for emergent coronary artery bypass grafting in patients not amenable to percutaneous coronary intervention. Our study aimed to evaluate and identify risk factors for early and long-term outcomes in such patients. METHODS: A total of 508 patients who underwent coronary artery bypass grafting for cardiogenic shock complicating acute myocardial infarction between January 2000 and June 2014 were divided into 3 time cohorts: 2000 to 2004 (n=204), 2005 to 2009 (n=166), and 2010 to 2014 (n=138). Predictors of in-hospital mortality for each time cohort and long-term mortality for all patients were identified by logistic and Cox regression analyses, respectively. RESULTS: Mean age was 68.3+/-9.8 years. Of the 508 patients, 78.5% had 3-vessel and 47.1% had left main disease. Left ventricular function <30% was observed in 44.1% of patients, with 30.4%, 37.9%, 52.9%, and 3.1% requiring preoperative resuscitation, ventilation, intra-aortic balloon pump, and extracorporeal membrane oxygenation support, respectively. Overall in-hospital mortality was 33.7%; declined from 42.2% to 30.7% to 24.6%, respectively, for the 3 time cohorts (P=0.02); and was independently predicted by serum lactate >4 mmol/L (odds ratio [OR], 4.78; 95% confidence interval, 2.88 7.95; P<0.0001), ST-segment-elevation myocardial infarction (OR, 2.10; 95% confidence interval, 1.36-3.26; P=0.001), age >75 years (OR, 2.01; 95% confidence interval, 1.06-3.85; P=0.03), and left ventricular ejection fraction <30% (OR, 1.83; 95% confidence interval, 1.15-2.91; P=0.01). Cumulative survival was 42.6+/ 2.0% and 33.4+/-2.0% at 5 and 10 years, respectively, and correspondingly improved to 64.3+/-3.0% and 49.8+/-3.0% in hospital survivors. Serum lactate >4 mmol/L (OR, 2.2; P<0.0001), incremental age (OR, 1.05; P<0.0001), New York Heart Association class IV (OR, 1.33; P=0.02), diabetes mellitus (OR, 1.39; P=0.005), and preoperative inotropic (OR, 2.61; P=0.001) and extracorporeal membrane oxygenation (OR, 1.68; P=0.05) support predicted late mortality. CONCLUSIONS: Emergency coronary artery bypass grafting in patients with acute myocardial infarction complicated by cardiogenic shock is associated with a high in-hospital mortality, which showed a significant decline with time. Hospital survivors have good long-term outcomes, which demonstrate the beneficial effect of surgical revascularization. Preoperative serum lactate >4 mmol/L is a strong predictor of both early and late mortality. PMID- 27777295 TI - Single-Ventricle Outcomes After Neonatal Palliation of Severe Ebstein Anomaly With Modified Starnes Procedure. AB - BACKGROUND: We have previously shown that neonates in profound cardiogenic shock caused by a severe Ebstein anomaly can be successfully salvaged with fenestrated right ventricular exclusion and systemic to pulmonary shunt (modified Starnes procedure). The long-term outcome of single-ventricle management in these patients is not known. METHODS: We retrospectively reviewed the records of patients who underwent neonatal Starnes procedure between 1989 and 2015. Patient demographics, clinical variables, and outcome data were collected. RESULTS: Twenty-seven patients (13, 48% boys) underwent the Starnes procedure at 7 (5-9) days of life. All were intubated and on prostaglandin, 24 (89%) were inotrope dependent, and 22 (81%) had no antegrade flow from the right ventricle. Three patients underwent nonfenestrated right ventricular exclusion, 2 (67%) of whom died. Of the remaining 24, 3 (13%) died during the same hospitalization. The 22 neonatal survivors have been followed for 7 (6-8) years: 1 patient is awaiting a Glenn procedure; 1 died after undergoing a Glenn procedure; and the remaining 20 patients have successfully undergone Fontan completion. Their indexed pulmonary vascular resistance was 1.8 (1.2-2.3) W/m2, and mean pulmonary pressure was 12 (9 18) mm Hg. At last follow-up, 1 patient had died, and the remaining patients had normal left ventricular function, and all but 1 have New York Heart Association class I symptoms. Two patients have required pacemaker implantation, whereas the rest are in sinus rhythm. Survival for the entire cohort at 1, 5, and 10 years is 81+/-4%, 81+/-5%, and 76+/-3%, respectively, whereas for those with fenestrated right ventricular exclusion, survival at 1, 5, and 10 years is 87+/-2%, 87+/-2%, and 81+/-4%, respectively. CONCLUSIONS: Long-term single-ventricle outcomes among neonatal survivors of the modified Starnes procedure are excellent. There is reliable remodeling of the excluded right ventricle and good function of the left ventricle. PMID- 27777294 TI - Impact of Left Ventricular to Mitral Valve Ring Mismatch on Recurrent Ischemic Mitral Regurgitation After Ring Annuloplasty. AB - BACKGROUND: In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty. METHODS: Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size). RESULTS: At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (P=0.02) and LVESd/ring size (P=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05 4.62; P=0.038) remained significantly associated with 1-year MR recurrence. CONCLUSIONS: LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone. CLINICAL TRIAL REGISTRATION: URL:http://clinicaltrials.gov. Unique identifiers: NCT00806988 and NCT00807040. PMID- 27777293 TI - Coronary Artery Bypass Graft Versus Percutaneous Coronary Intervention: Meds Matter: Impact of Adherence to Medical Therapy on Comparative Outcomes. AB - BACKGROUND: Multiple studies have compared coronary artery bypass graft (CABG) with percutaneous coronary interventions (PCI) for coronary revascularization. There is considerable evidence that adherence to medical therapy can affect the outcomes of therapeutic interventions. However, the long-term influence of compliance with recommended medical therapy on the comparative outcomes of CABG versus PCI remains to be defined. METHODS: All non-ST-segment-elevation myocardial infarction patients undergoing coronary revascularization in an 8 hospital network were followed for up to 8 years to determine medication history and major adverse cardiac events: all-cause mortality, nonfatal myocardial infarction, and reintervention. All mortalities were checked against the Social Security Death Index. Survival curves were derived with Kaplan-Meier methods; hazard ratios were calculated with the Cox proportional hazard model; and propensity score matching was used to account for differences in patient selection. RESULTS: Among the 973 CABG and 2255 PCI patients, Kaplan-Meier major adverse cardiac event-free survival curves demonstrated a significant benefit for antiplatelet, lipid-lowering, and beta-blocker therapy in both the CABG and PCI groups (P=0.001 for all 3 medications). Cox regression identified compliance with optimal medical therapy as a more powerful predictor of major adverse cardiac event-free survival than choice of therapy (hazard ratio for noncompliance=2.79; 95% confidence limits, 2.19-3.54; P<0.001; hazard ratio for PCI versus CABG=1.68, 95% confidence limits, 138-2.04; P<0.001). In propensity-matched patients, CABG outcomes were superior to PCI outcomes in patients nonadherent to optimal medical therapy (P=0.001) but were not different in patients adherent to optimal medical therapy (P=0.574). CONCLUSIONS: Regardless of coronary revascularization strategy, medication adherence has a dramatic effect on long-term outcome. Among comparable patients who adhere to optimal medical therapy, outcomes of PCI and CABG may not differ; however, among nonadherent patients, CABG affords better major adverse cardiac event-free survival. Therefore, patient compliance with medical therapy may inform clinical decision making and should be incorporated into all future comparative studies of comparative coronary revascularization strategies. PMID- 27777297 TI - Surgical Management of Infective Endocarditis Complicated by Embolic Stroke: Practical Recommendations for Clinicians. AB - There has been an overall improvement in surgical mortality for patients with infective endocarditis (IE), presumably because of improved diagnosis and management, centered around a more aggressive early surgical approach. Surgery is currently performed in approximately half of all cases of IE. Improved survival in surgery-treated patients is correlated with a reduction in heart failure and the prevention of embolic sequelae. It is reported that between 20% and 40% of patients with IE present with stroke or other neurological conditions. It is for these IE patients that the timing of surgical intervention remains a point of considerable discussion and debate. Despite evidence of improved survival in IE patients with earlier surgical treatment, a significant proportion of patients with IE and preexisting neurological complications either undergo delayed surgery or do not have surgery at all, even when surgery is indicated and guideline endorsed. Physicians and surgeons are caught in a common conundrum where the urgency of the heart operation must be balanced against the real or perceived risks of neurological exacerbation. Recent data suggest that the risk of neurological exacerbation may be lower than previously believed. Current guidelines reflect a shift toward early surgery for such patients, but there continue to be important areas of clinical equipoise. Individualized clinical assessment is of major importance for decision making, and, as such, we emphasize the need for the functioning of an endocarditis team, including cardiac surgeons, cardiologists, infectious diseases specialists, neurologists, neurosurgeons, and interventional neuroradiologists. Here, we present 2 illustrative cases, critically review contemporary data, and offer conceptual and practical suggestions for clinicians to address this important, common, and often fatal cardiac condition. PMID- 27777298 TI - Management of Systemic Right Ventricular Failure in Patients With Congenitally Corrected Transposition of the Great Arteries. AB - In recent decades, significant progress has been made in the diagnosis and management of congenitally corrected transposition of the great arteries (ccTGA). Nevertheless, gradual dysfunction and failure of the right ventricle (RV) in the systemic circulation remain the main contributors to mortality and disability for patients with ccTGA, especially after adolescence. Anatomic repair of ccTGA effectively resolves the problem of failure of the systemic RV and has good early and midterm results. However, this strategy is applicable primarily in infants and children up to their teens and has associated risks and limitations, and new challenges can arise in the late postoperative period. Patients with ccTGA manifesting progressive systemic RV dysfunction beyond adolescence represent the major challenge. Several palliative options such as cardiac resynchronization therapy, tricuspid valve repair or replacement, pulmonary artery banding, and implantation of an assist device into the systemic RV can be used to improve functional status and to delay the progression of ventricular dysfunction in patients who are not suitable for anatomic correction of ccTGA. For adult patients with severe systemic RV failure, heart transplantation currently remains the only long-term lifesaving procedure, although donor organ availability remains one of the most limiting factors in this type of therapy. This review focuses on current surgical and medical strategies and interventional options for the prevention and management of systemic RV failure in adults and children with ccTGA. PMID- 27777296 TI - Current Therapy for Hypoplastic Left Heart Syndrome and Related Single Ventricle Lesions. AB - Universally fatal only 4 decades ago, the progress in the 3-stage palliation of hypoplastic left heart syndrome and related single right ventricular lesions has drastically improved the outlook for these patients. Although the stage II operation (hemi-Fontan or bidirectional Glenn) and stage III Fontan procedure have evolved into relatively low-risk operations, the stage I Norwood procedure remains one of the highest-risk and costliest common operations performed in congenital heart surgery. Yet, despite this fact, experienced centers now report hospital survivals of >90% for the Norwood procedure. This traditional 3-stage surgical palliation has seen several innovations in the past decade aimed at improving outcomes, particularly for the Norwood procedure. One significant change is a renewed interest in the right ventricle-to-pulmonary artery shunt as the source of pulmonary blood flow, rather than the modified Blalock-Taussig shunt for the Norwood. The multi-institutional Single Ventricle Reconstruction trial randomly assigned 555 patients to one or the other shunt, and these subjects continue to be followed closely as they now approach 10 years postrandomization. In addition to modifications to the Norwood procedure, the hybrid procedure, a combined catheter-based and surgical approach, avoids the Norwood procedure in the newborn period entirely. The initial hybrid procedure is then followed by a comprehensive stage II, which combines components of both the Norwood and the traditional stage II, and later completion of the Fontan. Proponents of this approach hope to improve not only short-term survival, but also potentially longer-term outcomes, such as neurodevelopment, as well. Regardless of the approach, traditional surgical staged palliation or the hybrid procedure, survivals have vastly improved, and large numbers of these patients are surviving not only through their Fontan in early childhood, but also into adolescence and young adulthood. As this population grows, it becomes increasingly important to understand the longer-term outcomes of these Fontan patients, not only in terms of survival, but also in terms of the burden of disease, neurodevelopmental outcomes, psychosocial development, and quality of life. PMID- 27777299 TI - High on Aspirin Platelet Reactivity in Pediatric Patients Undergoing the Fontan Procedure. PMID- 27777300 TI - Front-end genomics: using an alternative approach for the recovery of high quality DNA from core needle biopsies. AB - AIMS: Determine whether a simple prewash step will provide adequate amounts of high-quality DNA from core needle biopsies for molecular sequencing studies. METHODS: The quantitative and qualitative metrics of DNA recovered from core needle biopsies processed either by 1) formalin fixation and paraffin embedding (FFPE), 2) cells recovered after the core needle biopsy was washed, and 3) frozen sections of the core needle biopsy tissue were evaluated and compared to one another. RESULTS: Fairly equivalent amounts of DNA can be obtained from cells recovered from a prewash step relative to the FFPE and frozen section samples. The number of amplifiable DNA in the wash sample was greater than that from the FFPE samples. The average molecular size of DNA in the wash sample was greater than that of both the FFPE and frozen samples. CONCLUSIONS: Although more starting material in terms of the number of cells was present in both the FFPE and frozen section samples than the wash samples, equivalent to better results were obtained from the latter with regard to quality. This approach may be a means to better aliquot the diminutive amounts of tissue associated with core needle biopsies, allowing dissociated cells to be dedicated for molecular studies while keeping the tissue intact for morphological studies. PMID- 27777301 TI - Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up regulation of the von Hippel-Lindau Gene (VHL). AB - FOXO3a, a member of the forkhead homeobox type O (FOXO) family of transcriptional factors, regulates cell survival in response to DNA damage, caloric restriction, and oxidative stress. The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of the E3 ubiquitin ligase complex that mediates hypoxia-inducible factor alpha degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown. Here we show that FOXO3a directly binds to the VHL promoter and up-regulates VHL expression. Using a zebrafish model, we confirmed the up-regulation of vhl by foxo3b, an ortholog of mammalian FOXO3a Furthermore, by employing the clustered regularly interspaced short palindromic repeats (CRISPR)-associated RNA-guided endonuclease Cas9 (CRISPR/Cas9) technology, we deleted foxo3b in zebrafish and determined that expression of hypoxia-inducible genes was affected under hypoxia. Moreover, foxo3b-null zebrafish exhibited impaired acute hypoxic tolerance, resulting in death. In conclusion, our findings suggest that, by modulating hypoxia-inducible factor activity via up-regulation of VHL, FOXO3a (foxo3b) plays an important role in survival in response to hypoxic stress. PMID- 27777302 TI - Alkaline Response of a Halotolerant Alkaliphilic Halomonas Strain and Functional Diversity of Its Na+(K+)/H+ Antiporters. AB - Halomonas sp. Y2 is a halotolerant alkaliphilic strain from Na+-rich pulp mill wastewater with high alkalinity (pH >11.0). Transcriptome analysis of this isolate revealed this strain may use various transport systems for pH homeostasis. In particular, the genes encoding four putative Na+/H+ antiporters were differentially expressed upon acidic or alkaline conditions. Further evidence, from heterologous expression and mutant studies, suggested that Halomonas sp. Y2 employs its Na+/H+ antiporters in a labor division way to deal with saline and alkaline environments. Ha-NhaD2 displayed robust Na+(Li+) resistance and high transport activities in Escherichia coli; a DeltaHa-nhaD2 mutant exhibited growth inhibition at high Na+(Li+) concentrations at pH values of 6.2, 8.0, and 10.0, suggesting its physiological role in osmotic homeostasis. In contrast, Ha-NhaD1 showed much weaker activities in ion exporting and pH homeostasis. Ha-Mrp displayed a combination of properties similar to those of Mrp transporters from some Bacillus alkaliphiles and neutrophiles. This conferred obvious Na+(Li+, K+) resistance in E. coli-deficient strains, as those ion transport spectra of some neutrophil Mrp antiporters. Conversely, similar to the Bacillus alkaliphiles, Ha-Mrp showed central roles in the pH homeostasis of Halomonas sp. Y2. An Ha-mrp-disrupted mutant was seriously inhibited by high concentrations of Na+(Li+, K+) but only under alkaline conditions. Ha-NhaP was determined to be a K+/H+ antiporter and shown to confer strong K+ resistance both at acidic and alkaline stresses. PMID- 27777303 TI - HIV-1 Reverse Transcriptase Polymerase and RNase H (Ribonuclease H) Active Sites Work Simultaneously and Independently. AB - HIV reverse transcriptase plays a central role in viral replication and requires coordination of both polymerase and RNase H activities. Although this coordination is crucial in viral replication, whether a DNA/RNA hybrid can simultaneously engage both active sites has yet to be determined as structural and kinetic analyses have provided contradictory results. Single nucleotide incorporation and RNase H cleavage were examined using presteady-state kinetics with global data analysis. The results revealed three interconverting reverse transcriptase-DNA/RNA species; 43% were active for both sites simultaneously, 27% showed only polymerase activity, and the remaining 30% were nonproductive. Our data clearly demonstrated that the DNA/RNA hybrid could contact both active sites simultaneously, although the single nucleotide incorporation (105 s-1) was ~5 fold faster than the cleavage (23 s-1). By using a series of primers with different lengths, we found that a string of at least 4-6 nucleotides downstream of the cleaving site was required for efficient RNA cleavage. This was corroborated by our observations that during processive nucleotide incorporation, sequential rounds of RNA cleavage occurred each time after ~6 nucleotides were incorporated. More importantly, during processive primer extension, pyrophosphate (PPi) release was rate-limiting so that the average rate of nucleotide incorporation (~28 s-1) was comparable with that of net RNA cleavage (~27 nucleotides(s)). Although polymerization is efficient and processive, RNase H is inefficient and periodic. This combination allows the two catalytic centers of HIVRT to work simultaneously at similar speeds without being tightly coupled. PMID- 27777304 TI - Rate-limiting Pyrophosphate Release by HIV Reverse Transcriptase Improves Fidelity. AB - Previous measurements of the rates of polymerization and pyrophosphate release with DNA templates showed that pyrophosphate (PPi) dissociation was fast after nucleotide incorporation so that it did not contribute to enzyme specificity (kcat/Km). Here, kinetic parameters governing nucleotide incorporation and PPi release were determined using an RNA template. Compared with a DNA template of the same sequence, the rate of chemistry increased by up to 10-fold (250 versus 24 s-1), whereas the rate of PPi release decreased to approximately 58 s-1 so that PPi release became the rate-limiting step. During processive nucleotide incorporation, the first nucleotide (TTP) was incorporated at a fast rate (152 s 1), whereas the rates of incorporation of remaining nucleotides (CGTCG) were much slower with an average rate of 24 s-1, suggesting that sequential incorporation events were limited by the relatively slow PPi release step. The accompanying paper shows that slow PPi release allows polymerization and RNase H to occur at comparable rates. Although PPi release is the rate-determining step, it is not the specificity-determining step for correct incorporation based on our current estimates of the rate of reversal of the chemistry step (3 s-1). In contrast, during misincorporation, PPi release became extremely slow, which we estimated to be ~0.002 s-1 These studies establish the mechanistic basis for DNA polymerase fidelity during reverse transcription and provide a free energy profile. We correct previous underestimates of discrimination by including the slow PPi release step. Our current estimate of 2.4 * 106 is >20-fold greater than estimated previously. PMID- 27777305 TI - Expansion of Lysine-rich Repeats in Plasmodium Proteins Generates Novel Localization Sequences That Target the Periphery of the Host Erythrocyte. AB - Repetitive low complexity sequences, mostly assumed to have no function, are common in proteins that are exported by the malaria parasite into its host erythrocyte. We identify a group of exported proteins containing short lysine rich tandemly repeated sequences that are sufficient to localize to the erythrocyte periphery, where key virulence-related modifications to the plasma membrane and the underlying cytoskeleton are known to occur. Efficiency of targeting is dependent on repeat number, indicating that novel targeting modules could evolve by expansion of short lysine-rich sequences. Indeed, analysis of fragments of GARP from different species shows that two novel targeting sequences have arisen via the process of repeat expansion in this protein. In the protein Hyp12, the targeting function of a lysine-rich sequence is masked by a neighboring repetitive acidic sequence, further highlighting the importance of repetitive low complexity sequences. We show that sequences capable of targeting the erythrocyte periphery are present in at least nine proteins from Plasmodium falciparum and one from Plasmodium knowlesi We find these sequences in proteins known to be involved in erythrocyte rigidification and cytoadhesion as well as in previously uncharacterized exported proteins. Together, these data suggest that expansion and contraction of lysine-rich repeats could generate targeting sequences de novo as well as modulate protein targeting efficiency and function in response to selective pressure. PMID- 27777306 TI - A Critical Role for beta-Catenin in Modulating Levels of Insulin Secretion from beta-Cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization. AB - The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic beta-cells are only partly understood. Here we investigate the involvement of beta-catenin in these processes. Reducing beta catenin levels using siRNA knockdown attenuated GSIS in a range of beta-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both beta-cell models and isolated islets by short-term exposure to the beta-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases beta-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that beta-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional co-activator of beta-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating beta-catenin from the plasma membrane pool to the nucleus. We show that beta-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that beta-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that beta catenin levels modulate Ca2+-dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion. PMID- 27777308 TI - Molecular Determinants of Scaffold-induced Linear Ubiquitinylation of B Cell Lymphoma/Leukemia 10 (Bcl10) during T Cell Receptor and Oncogenic Caspase Recruitment Domain-containing Protein 11 (CARD11) Signaling. AB - The activation of NF-kappaB downstream of T cell receptor (TCR) engagement is a key signaling step required for normal lymphocyte function during the adaptive immune response. During TCR signaling, the adaptor protein Bcl10 is inducibly recruited to the CARD11 scaffold protein as part of a multicomponent complex that induces IkappaB kinase (IKK) activity and NF-kappaB activation. Here, we show that a consequence of this recruitment is the TCR-induced conjugation of Bcl10 with linear-linked polyubiquitin chains to generate the signaling intermediate Lin(Ub)n-Bcl10, which is required for the association of Bcl10 with the NEMO subunit of the IKK complex. The TCR-induced generation of Lin(Ub)n-Bcl10 requires Bcl10 lysines 17, 31, and 63, CARD11, MALT1, and the HOIP subunit of the linear ubiquitin chain assembly complex (LUBAC) but not the HOIP accessory protein SHARPIN. CARD11 promotes signal-induced Lin(Ub)n-Bcl10 generation by co recruiting Bcl10 with HOIP, thereby bringing substrate to enzyme. The CARD11-HOIP interaction is rendered TCR-inducible by the four autoinhibitory repressive elements in the CARD11 inhibitory domain and involves the CARD11 coiled-coil domain and two independent regions of HOIP. Interestingly, oncogenic CARD11 variants associated with diffuse large B cell lymphoma spontaneously induce Lin(Ub)n-Bcl10 production to extents that correlate with their abilities to activate NF-kappaB and with their enhanced abilities to bind HOIP and Bcl10. Our results define molecular determinants that control the production of Lin(Ub)n Bcl10, an important signaling intermediate in TCR and oncogenic CARD11 signaling. PMID- 27777307 TI - Structural Analysis of the Catalytic Mechanism and Substrate Specificity of Anabaena Alkaline Invertase InvA Reveals a Novel Glucosidase. AB - Invertases catalyze the hydrolysis of sucrose to glucose and fructose, thereby playing a key role in primary metabolism and plant development. According to the optimum pH, invertases are classified into acid invertases (Ac-Invs) and alkaline/neutral invertases (A/N-Invs), which share no sequence homology. Compared with Ac-Invs that have been extensively studied, the structure and catalytic mechanism of A/N-Invs remain unknown. Here we report the crystal structures of Anabaena alkaline invertase InvA, which was proposed to be the ancestor of modern plant A/N-Invs. These structures are the first in the GH100 family. InvA exists as a hexamer in both crystal and solution. Each subunit consists of an (alpha/alpha)6 barrel core structure in addition to an insertion of three helices. A couple of structures in complex with the substrate or products enabled us to assign the subsites -1 and +1 specifically binding glucose and fructose, respectively. Structural comparison combined with enzymatic assays indicated that Asp-188 and Glu-414 are putative catalytic residues. Further analysis of the substrate binding pocket demonstrated that InvA possesses a stringent substrate specificity toward the alpha1,2-glycosidic bond of sucrose. Together, we suggest that InvA and homologs represent a novel family of glucosidases. PMID- 27777309 TI - Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex: IMPLICATION OF A NOVEL MDMX SER-314 PHOSPHOSITE. AB - Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes. Using a phospho-proteomics approach, we functionally identified a novel Her4-induced posttranslational modification on MDMX at Ser-314, a putative phosphorylation site for the CDK4/6 kinase. Remarkably, inhibition of Ser-314 phosphorylation either with Ser-to-Ala substitution or with a specific inhibitor of CDK4/6 kinase blocked Her4-induced stabilization of MDMX-MDM2 and rescued p53 activity. Our study offers insights into the mechanisms of deregulated RTK induced carcinogenesis and provides the basis for the use of inhibitors targeting RTK-mediated signals for p53 restoration. PMID- 27777310 TI - Distinct Roles of Transcription Factors KLF4, Krox20, and Peroxisome Proliferator Activated Receptor gamma in Adipogenesis. AB - Much of our knowledge on adipogenesis comes from cell culture models of preadipocyte differentiation. Adipogenesis is induced by treating confluent preadipocytes with the adipogenic cocktail, which activates transcription factors (TFs) glucocorticoid receptor (GR) and CREB within minutes and increases expression of TFs C/EBPbeta, C/EBPdelta, KLF4, and Krox20 within hours. All of these TFs have been shown to be capable of promoting adipogenesis in culture when they are overexpressed. However, it has remained unclear whether endogenous KLF4 and Krox20 are required for adipogenesis in culture and in vivo Using conditional knockout mice and derived white and brown preadipocytes, we show that endogenous KLF4 and Krox20 are dispensable for adipogenesis in culture and for brown adipose tissue development in mice. In contrast, the master adipogenic TF peroxisome proliferator-activated receptor gamma (PPARgamma) is essential. These results challenge the existing model on transcriptional regulation in the early phase of adipogenesis and highlight the need of studying adipogenesis in vivo. PMID- 27777311 TI - Glucocorticoid Receptor Accelerates, but Is Dispensable for, Adipogenesis. AB - Dexamethasone (DEX), a synthetic ligand for glucocorticoid receptor (GR), is routinely used to stimulate adipogenesis in culture. GR-depleted preadipocytes show adipogenesis defects 1 week after induction of differentiation. However, it has remained unclear whether GR is required for adipogenesis in vivo By deleting GR in precursors of brown adipocytes, we found unexpectedly that GR is dispensable for brown adipose tissue development in mice. In culture, GR deficient primary or immortalized white and brown preadipocytes showed severely delayed adipogenesis 1 week after induction of differentiation. However, when differentiation was extended to 3 weeks, GR-deficient preadipocytes showed levels of adipogenesis marker expression and lipid accumulation similar to those of the wild-type cells, indicating that DEX-bound GR accelerates, but is dispensable for, adipogenesis. Consistently, DEX accelerates, but is dispensable for, adipogenesis in culture. We show that DEX-bound GR accelerates adipogenesis by directly promoting the expression of adipogenic transcription factors CCAAT/enhancer-binding protein alpha (C/EBPalpha), C/EBPbeta, C/EBPdelta, KLF5, KLF9, and peroxisome proliferator-activated receptor gamma (PPARgamma) in the early phase of differentiation. Mechanistically, DEX-bound GR recruits histone H3K27 acetyltransferase CBP to promote activation of C/EBPbeta-primed enhancers of adipogenic genes. These results clarify the role of GR in adipogenesis in vivo and demonstrate that DEX-mediated activation of GR accelerates, but is dispensable for, adipogenesis. PMID- 27777313 TI - The Effect of Operating Lamps on the Protected Area of a Unidirectional Down Flow (UDF) System. AB - BACKGROUND: Operating lamps are often seen as the most disruptive factors within the protective area in the operating theater (OT). The effect of the operation lamps (with different shapes) should be demonstrated in an OT by trial, since research on the effects of the lamps is still limited. OBJECTIVES: The main aim of this study was to determine the effects of a skirt, different lamps, and the position of the lamp on the protected area. METHODS: The concentration of airborne particles was measured under different circumstances, in order to determine the size and quality of the protected area. This entrainment/segregation test is based on the deliberate and controlled emission of particles outside the zone that is protected. FINDINGS AND CONCLUSIONS: The degree of protection (DP) at the center of the protected area was higher for the case with the skirt. This skirt stimulates more down flow and prevents the early entry of particles into the protected area. It can also be concluded that Lamp Y, due to its open shape, has the most positive effect on the DP at the center. It has also been shown that the position of the lamp has an effect on the protected area. PMID- 27777312 TI - MBD4 Facilitates Immunoglobulin Class Switch Recombination. AB - Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when Mbd4 exons 6 to 8 are deleted in a switching B cell line, DSB formation is severely reduced and CSR frequency is impaired. Impaired CSR can be rescued by ectopic expression of Mbd4 Mbd4 deficiency yields a deficit in DNA end processing similar to that found in MutS homologue 2 (Msh2)- and Mlh1-deficient B cells. We demonstrate that microhomology rich S-S junctions are enriched in cells in which Mbd4 is deleted. Our studies suggest that Mbd4 is a component of MMR-directed DNA end processing. PMID- 27777314 TI - Integrating Lean Exploration Loops Into Healthcare Facility Design. AB - PURPOSE: To explore how Lean can add value during the schematic phase of design through providing additional resources and support to project leadership and the architectural design team. BACKGROUND: This case study-based research took place at one large academic hospital during design efforts of surgical tower to house 19 operating rooms (ORs) and support spaces including pre- and post-op, central processing and distribution, and materials management. Surgical services project leadership asked for Lean practitioners' support during the design process. METHODS: Lean Exploration Loops (LELs) were conducted to generate evidence to support stakeholders, as they made important decisions about the new building design. The analyses conducted during LELs during the schematic phase were primarily conducted using express workouts (EWOs) and were focused on the flow of patients, staff, and family throughout the pavilion. RESULTS: LELs resulted in recommendations for key design features (e.g., number of pre- and post-op bays per OR floor, location of doors, scrub sinks, stretcher alcoves, equipment storage, and sterile core areas). Two-sided pre- and post-op bays with an inner clinical workspace and an outer patient transport corridor were recommended. Communicating elevator and a centrally located stairwell for staff to alleviate stress on the main bank of elevators at peak usage times were also suggested. CONCLUSIONS: We found Lean tools and methods to be of most value during schematic phase when focused on detailed process and layout analysis, while acknowledging the usefulness of focused EWOs to generate the evidence needed for the decision making. PMID- 27777315 TI - Epigenome-wide association study of triglyceride postprandial responses to a high fat dietary challenge. AB - Postprandial lipemia (PPL), the increased plasma TG concentration after consuming a high-fat meal, is an independent risk factor for CVD. Individual responses to a meal high in fat vary greatly, depending on genetic and lifestyle factors. However, only a few loci have been associated with TG-PPL response. Heritable epigenomic changes may be significant contributors to the unexplained inter individual PPL variability. We conducted an epigenome-wide association study on 979 subjects with DNA methylation measured from CD4+ T cells, who were challenged with a high-fat meal as a part of the Genetics of Lipid Lowering Drugs and Diet Network study. Eight methylation sites encompassing five genes, LPP, CPT1A, APOA5, SREBF1, and ABCG1, were significantly associated with PPL response at an epigenome-wide level (P < 1.1 * 10-7), but no methylation site reached epigenome wide significance after adjusting for baseline TG levels. Higher methylation at LPP, APOA5, SREBF1, and ABCG1, and lower methylation at CPT1A methylation were correlated with an increased TG-PPL response. These PPL-associated methylation sites, also correlated with fasting TG, account for a substantially greater amount of phenotypic variance (14.9%) in PPL and fasting TG (16.3%) when compared with the genetic contribution of loci identified by our previous genome-wide association study (4.5%). In summary, the epigenome is a large contributor to the variation in PPL, and this has the potential to be used to modulate PPL and reduce CVD. PMID- 27777317 TI - Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years. AB - Blood concentrations of triglycerides are influenced by genetic factors as well as a number of environmental factors, including adiposity and glucose homeostasis. The aim was to investigate the association between a serum triglyceride weighted genetic risk score (wGRS) and changes in fasting serum triglyceride level over 5 years and to test whether the effect of the wGRS was modified by 5 year changes of adiposity, insulin resistance, and lifestyle factors. A total of 3,474 nondiabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5 year follow-up physical examinations and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex, and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years [per allele effect = 1.3% (1.0-1.6%); P = 1.0 * 10-17]. This triglyceride-increasing effect of the wGRS interacted with changes in insulin resistance (Pinteraction = 1.5 * 10-6). This interaction indicated that the effect of the wGRS was stronger in individuals who became more insulin resistant over 5 years. In conclusion, our findings suggest that increased genetic risk load is associated with a larger increase in fasting serum triglyceride levels in nondiabetic individuals during 5 years of follow-up. This effect of the wGRS is accentuated by increasing insulin resistance. PMID- 27777316 TI - The panorama of familial hypercholesterolemia in Latin America: a systematic review. AB - The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified. PMID- 27777318 TI - Understanding mouse bile acid formation: Is it time to unwind why mice and rats make unique bile acids? PMID- 27777322 TI - The potential toxicological insights about the anti-HIV drug azidothymidine derived monoselenides in human leukocytes: Toxicological insights of new selenium azidothymidine analogs. AB - Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5'-Se-(phenyl)zidovudine; 5'-Se-(1,3,5-trimethylphenyl)zidovudine; 5'-Se-(1-naphtyl)zidovudine; 5'-Se-(4-chlorophenyl)zidovudine) (C4); 5'-Se-(4 methylphenyl)zidovudine (C5); and 5'-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 uM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 uM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se containing analogs of AZT. PMID- 27777319 TI - Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte hepatocyte axis. AB - Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance and mediating suppression of fatty acid synthase activity. Feeding C57BL/6J male mice with a high-fat (HF) diet for 3-4 weeks triggered a >60% decrease in hepatic CEACAM1 levels to subsequently impair insulin clearance and cause systemic insulin resistance and hepatic steatosis. This study aimed at investigating whether lipolysis drives reduction in hepatic CEACAM1 and whether this constitutes a key mechanism leading to diet-induced metabolic abnormalities. Blocking lipolysis with a daily intraperitoneal injection of nicotinic acid in the last two days of a 30-day HF feeding regimen demonstrated that white adipose tissue (WAT)-derived fatty acids repressed hepatic CEACAM1-dependent regulation of insulin and lipid metabolism in 3-month-old male C57BL/6J mice. Adenoviral-mediated CEACAM1 redelivery countered the adverse metabolic effect of the HF diet on insulin resistance, hepatic steatosis, visceral obesity, and energy expenditure. It also reversed the effect of HF diet on inflammation and fibrosis in WAT and liver. This assigns a causative role for lipolysis-driven decrease in hepatic CEACAM1 level and its regulation of insulin and lipid metabolism in sustaining systemic insulin resistance, hepatic steatosis, and other abnormalities associated with excessive energy supply. PMID- 27777320 TI - Associations of genetic variants for adult lipid levels with lipid levels in children. The Generation R Study. AB - Lipid concentrations are heritable traits. Recently, the number of known genetic loci associated with lipid levels in adults increased from 95 to 157. The effects of these 157 loci have not been tested in children. Considering that lipid levels track from childhood to adulthood, we studied to determine whether these variants already affected lipid concentrations in a large group of 2,645 children with a median age of 6.0 years (95% range 5.7-7.3 years) from the population-based Generation R Study. Twenty-eight SNPs associated with TGs, 39 SNPs associated with total cholesterol (TC), 28 SNPs associated with LDL cholesterol (LDL-C), and 56 SNPs associated with HDL cholesterol (HDL-C) were analyzed individually and combined into genetic risk scores (GRSs). All risk scores were associated with their specific outcomes. The differences in mean absolute lipid and lipoprotein values between the 10% of children with the highest lipid or lipoprotein GRS versus the 10% with the lowest score were 0.28, 0.25, 0.32, and 0.30 mmol/l for TGs, TC, LDL-C, and HDL-C, respectively. In conclusion, we show for the first time that GRSs based on 157 SNPs associated with adult lipid concentrations are associated with lipid levels in children. The genetic background of these phenotypes at least partly overlaps between children and adults. PMID- 27777323 TI - A single dose of allopregnanolone affects the ovarian morphology and steroidogenesis. AB - Allopregnanolone, a progesterone metabolite, is one of the best characterized neurosteroids. In a dose that mimics serum levels during stress, allopregnanolone inhibits sexual receptivity and ovulation and induces a decrease in luteinizing hormone levels. The aim of this work was to examine the effect of an intracerebroventricular administration of allopregnanolone on ovarian morphophysiology, serum and tissue levels of progesterone and estrogen, and enzymatic activity of 3beta-hydroxysteroid dehydrogenase, 20alpha-hydroxysteroid dehydrogenase and 3alpha-hydroxysteroid oxido-reductase in the ovary and in the medial basal hypothalamus on the morning of estrus. Ovarian morphology was analyzed under light microscopy. The hormone assays were performed by radioimmunoassay. The enzymatic activities were measured by spectrophotometric analysis. The morphometric analysis revealed that, in allopregnanolone-treated animals, the number of secondary and Graafian follicles was decreased while that of atretic follicles and cysts was significantly increased. Some cysts showed luteinized unruptured follicles. There were no differences in the number of tertiary follicles or corpora lutea in comparison with the corresponding control groups. In allopregnanolone-treated animals, progesterone serum levels were increased, while ovarian progesterone levels were decreased. Moreover, 3beta-HSD and 3alpha-HSOR enzymatic activities were increased in the medial basal hypothalamus while ovarian levels were decreased. The enzyme 20alpha hydroxysteroid dehydrogenase showed the opposite profile. The results of this study showed that allopregnanolone interferes on ovarian steroidogenesis and ovarian morphophysiology in rats, providing a clear evidence for the role of this neurosteroid in the control of reproductive function under stress situations. PMID- 27777325 TI - Remarkable motor recovery after riboflavin therapy in adult-onset Brown-Vialetto Van Laere syndrome. AB - The clinical diagnosis of Brown-Vialetto-Van Laere syndrome in this woman with rapidly progressive pontobulbar palsy led to empirical high-dose oral riboflavin (1200 mg/day) therapy. This resulted in a dramatic improvement in her motor function from being anarthric, dysphagic, tetraparetic and in ventilatory failure to living independently with mild dysarthria and distal limb weakness. DNA sequencing of the SLC52A3 gene found compound heterozygous C-terminus mutations, V413A1/D461Y, consistent with recent reports of mutations within the riboflavin transporter genes (SLC52A2 and SLC52A3) in this condition. Early diagnosis and empirical riboflavin therapy can lead to major motor recovery in this condition, that can be sustained with long-term maintenance therapy. PMID- 27777324 TI - The prognostic effect of cardiac rehabilitation in the era of acute revascularisation and statin therapy: A systematic review and meta-analysis of randomized and non-randomized studies - The Cardiac Rehabilitation Outcome Study (CROS). AB - Background The prognostic effect of multi-component cardiac rehabilitation (CR) in the modern era of statins and acute revascularisation remains controversial. Focusing on actual clinical practice, the aim was to evaluate the effect of CR on total mortality and other clinical endpoints after an acute coronary event. Design Structured review and meta-analysis. Methods Randomised controlled trials (RCTs), retrospective controlled cohort studies (rCCSs) and prospective controlled cohort studies (pCCSs) evaluating patients after acute coronary syndrome (ACS), coronary artery bypass grafting (CABG) or mixed populations with coronary artery disease (CAD) were included, provided the index event was in 1995 or later. Results Out of n = 18,534 abstracts, 25 studies were identified for final evaluation (RCT: n = 1; pCCS: n = 7; rCCS: n = 17), including n = 219,702 patients (after ACS: n = 46,338; after CABG: n = 14,583; mixed populations: n = 158,781; mean follow-up: 40 months). Heterogeneity in design, biometrical assessment of results and potential confounders was evident. CCSs evaluating ACS patients showed a significantly reduced mortality for CR participants (pCCS: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20-0.69; rCCS: HR 0.64, 95% CI 0.49-0.84; odds ratio 0.20, 95% CI 0.08-0.48), but the single RCT fulfilling Cardiac Rehabilitation Outcome Study (CROS) inclusion criteria showed neutral results. CR participation was also associated with reduced mortality after CABG (rCCS: HR 0.62, 95% CI 0.54-0.70) and in mixed CAD populations. Conclusions CR participation after ACS and CABG is associated with reduced mortality even in the modern era of CAD treatment. However, the heterogeneity of study designs and CR programmes highlights the need for defining internationally accepted standards in CR delivery and scientific evaluation. PMID- 27777326 TI - Smoking as an 'informed choice': implications for endgame strategies. AB - OBJECTIVE: Tobacco companies often assert that adults should be free to make an 'informed choice' about smoking; this argument influences public perceptions and shapes public health policy agendas by promoting educative interventions ahead of regulation. Critically analysing 'informed choice' claims is pivotal in countries that have set endgame goals and require new, more effective policies to achieve their smoke-free aims. METHODS: In-depth interviews with 15 New Zealand politicians, policy analysts and tobacco control advocates examined how they interpreted 'informed choice' arguments. We used a thematic analysis approach to review and explicate interview transcripts. RESULTS: Participants thought 'informed choice' implied that people make an active decision to smoke, knowing and accepting the risks they face; they rejected this assumption and saw it as a cynical self-justification by tobacco companies. Some believed this rhetoric had countered calls for stronger policies and thought governments used 'informed choice' arguments to support inaction. Several called on the government to stop allowing a lethal product to be widely sold while simultaneously advising people not to use it. CONCLUSIONS: 'Informed choice' arguments allow the ubiquitous availability of tobacco to go unquestioned and create a tension between endgame goals and the strategies used to achieve these. Reducing tobacco availability would address this anomaly by aligning government's actions with its advice. PMID- 27777327 TI - Wiedemann-Steiner Syndrome With 2 Novel KMT2A Mutations. AB - Wiedemann-Steiner syndrome is a rare genetic disorder characterized by short stature, hairy elbows, facial dysmorphism, and developmental delay. It can also be accompanied by musculoskeletal anomalies such as muscular hypotonia and small hands and feet. Mutations in the KMT2A gene have only recently been identified as the cause of Wiedemann-Steiner syndrome; therefore, only 16 patients from 15 families have been described, and new phenotypic features continue to be added. In this report, we describe 2 newly identified patients with Wiedemann-Steiner syndrome who presented with variable severity. One girl exhibited developmental dysplasia of the hip and fibromatosis colli accompanied by other clinical features, including facial dysmorphism, hypertrichosis, patent ductus arteriosus, growth retardation, and borderline intellectual disability. The other patient, a boy, showed severe developmental retardation with automatic self-mutilation, facial dysmorphism, and hypertrichosis at a later age. Exome sequencing analysis of these patients and their parents revealed a de novo nonsense mutation, p.Gln1978*, of KMT2A in the former, and a missense mutation, p.Gly1168Asp, in the latter, which molecularly confirmed the diagnosis of Wiedemann-Steiner syndrome. PMID- 27777328 TI - Focal Seizures in Patients With SCN1A Mutations. AB - The SCN1A gene has been implicated in the etiology of various forms of epilepsy. New research has linked this gene to specific types of epilepsy, all of which present in infancy or early childhood. This study examines the time course and pathology of pediatric patients who have a mutation in the SCN1A gene in order to open a discussion regarding the key trends of this form of epilepsy as well as important clinical considerations in management for patients who present with symptoms relating to the SCN1A mutations. We retrospectively examined 20 patients who presented to the clinic with focal seizures, as well as were positive for an SCN1A genetic mutation. Despite the small sample size, we were able to find important trends in the time course of the disorder as well as important areas of clinical practice that must be taken into consideration for these patients. PMID- 27777329 TI - Concordance Between Self-Reported Childhood Maltreatment Versus Case Record Reviews for Child Welfare-Affiliated Adolescents. AB - The present study used data from an ongoing longitudinal study of the effects of maltreatment on adolescent development to (1) describe rates of maltreatment experiences obtained from retrospective self-report versus case record review for adolescents with child welfare-documented maltreatment histories, (2) examine self-reported versus child welfare-identified maltreatment in relation to mental health and risk behavior outcomes by maltreatment type, and (3) examine the association between the number of different types of maltreatment and mental health and risk behavior outcomes. Maltreatment was coded from case records using the Maltreatment Case Record Abstraction Instrument (MCRAI) and participants were asked at mean age = 18.49 about childhood maltreatment experiences using the Comprehensive Trauma Interview (CTI). Results showed that an average of 48% of maltreatment found by the MCRAI for each type of maltreatment were unique cases not captured by the CTI, whereas an average of 40% self-reported maltreatment (CTI) was not indicated by the MCRAI. Analyses with outcomes showed generally, self-reported maltreatment, regardless of concordance with MCRAI, was related to the poorest outcomes. The difference in associations with the outcomes indicates both self-report and case record review data may have utility depending on the outcomes being assessed. PMID- 27777330 TI - Child Maltreatment and Risky Sexual Behavior. AB - Risky sexual behavior is a serious public health problem. Child sexual abuse is an established risk factor, but other forms of maltreatment appear to elevate risky behavior. The mechanisms by which child maltreatment influence risk are not well understood. This study used data from 859 high-risk youth, followed through age 18. Official reports of each form of maltreatment were coded. At age 16, potential mediators (trauma symptoms and substance use) were assessed. At age 18, risky sexual behavior (more than four partners, unprotected sex, unassertiveness in sexual refusal) was assessed. Neglect significantly predicted unprotected sex. Substance use predicted unprotected sex and four or more partners but did not mediate the effects of maltreatment. Trauma symptoms predicted unprotected sex and mediated effects of emotional maltreatment on unprotected sex and on assertiveness in sexual refusal and the effects of sexual abuse on unprotected sex. Both neglect and emotional maltreatment emerged as important factors in risky sexual behavior. Trauma symptoms appear to be an important pathway by which maltreatment confers risk for risky sexual behavior. Interventions to reduce risky sexual behavior should include assessment and treatment for trauma symptoms and for history of child maltreatment in all its forms. PMID- 27777331 TI - Pseudolipomatosis in Endometrial Specimens Does Not Represent Uterine Perforation. AB - BACKGROUND: Specimens of endometrial biopsies can sometimes present with an artifact within blood, composed of optically clear vacuoles mimicking adipose tissue, pseudolipomatosis. This artifact can be mistaken for adipose tissue and lead to an overdiagnosis of uterine perforation. CASE: We describe the case of pseudolipomatosis seen within the evacuated products of conception from a missed abortion. RESULTS: Areas of vacuolization in the blood clot mimicked adipose tissue. However, the vacuoles varied in size and did not contain adipocytes. CONCLUSION: Familiarity with this artifact will lead to avoidance of overdiagnosis of adipose tissue and uterine perforation in curettage specimens. PMID- 27777332 TI - What Do Domestic Violence and Sexual Assault Service Providers Need to Know About Survivors to Deliver Services? AB - Using survey data, we investigate perspectives of 80 program directors of domestic violence and/or sexual assault agencies regarding whether gathering specific information at intake is helpful in determining survivors' needs for five service areas: legal advocacy, medical advocacy, support group, counseling, and shelter. We explore whether directors' opinions of information-type usefulness differ by type of service agency (single- or dual-focus). Findings show directors perceive the information most helpful to early service provision includes survivors' goals, experiences of violence and trauma, and health status. MANOVA results show no significant differences among directors from single- or dual-focus agencies. PMID- 27777333 TI - Low-Dose Isotretinoin for Seborrhoeic Dermatitis. PMID- 27777334 TI - Secondary Merkel Cell Carcinoma Arising From a Graft Donor Site. AB - Merkel cell carcinoma (MCC) is a highly aggressive cutaneous neuroendocrine tumour that is increasing in incidence. We report a case of a 92-year-old white man on long-term immunosuppression for temporal arteritis who presented with a Merkel cell tumour on his left cheek. A wide local excision was performed and the defect was reconstructed with a full-thickness skin graft. Four years later, the patient re-presented with a Merkel cell tumour arising from the right supraclavicular donor site. To our knowledge, this is the first report of a recurrence of MCC into a donor site. This has important implications as a reminder of planning fresh surgical instruments and needle inoculation for reconstruction if there is any clinical suspicion of MCC to prevent iatrogenic spread. PMID- 27777335 TI - Complexities of Introducing Group Medical Visits With Nurse Practitioners in British Columbia. AB - In Canada, increasing numbers of people with chronic conditions have prompted calls for innovative approaches to delivering primary care. These approaches may include group medical visits (GMVs) and the introduction of nurse practitioners (NPs). We examined why NPs in the province of British Columbia were not using GMVs. This case study is part of a larger research project that examined the impact of GMVs with NPs for patients with chronic conditions. We completed open ended interviews with seven NPs working in primary care. Interviews were audiotaped and transcribed. Data were analyzed using interpretive descriptive approaches. Three major themes emerged: (a) advantages of GMVs, (b) questioning the fit of GMVs in current practice contexts, and (c) navigating scope of practice and role constraints that affect NPs' ability to use GMVs. Power dynamics and hierarchies may influence NPs' ability to adapt to GMVs. Consideration of practice environments and structures that enable the NPs ability to diffuse and utilize health-care innovative care delivery methods is needed. PMID- 27777336 TI - Evaluation of the suitability and performance of cassava waste (peel) extracts in a microbial fuel cell for supplementary and sustainable energy production. AB - In a number of energy-poor nations, peel from cassava processing represents one of the most abundant sources of lignocellulosic biomass. This peel is mostly discarded indiscriminately and eventually constitutes a problem to the environment. However, energy can be extracted from this peel in a microbial fuel cell. In this study, the viability of cassava peel extract as a substrate in a single-chamber air cathode microbial fuel cell is demonstrated, and optimum performance conditions are explored. The effects of different pretreatments on the extract are also discussed in the context of observed changes in the internal resistances, conductivity and Coulombic efficiencies. At the best conditions examined, the extract from cassava peel fermented for 168 h and adjusted to a pH of 7.63 attained a peak voltage of 687 mV +/- 21 mV, a power density of 155 mW m 3 of reactor volume and a Coulombic efficiency of 11 %. Although this energy is limited to direct use, systems exist that can effectively harvest and boost the energy to levels sufficient for supplementary energy usage in cassava producing regions. PMID- 27777338 TI - Association Between the IL-6 rs1800795 Polymorphism and the Risk of Cervical Cancer: A Meta-Analysis of 1210 Cases and 1525 Controls. AB - Cervical cancer is the second most common cancer and the third leading cause of cancer-related death among females in less developed countries. Studies have shown that the single-nucleotide polymorphisms of interleukin 6 might be associated with cervical cancer risk. A total of 710 articles from EMBASE, EBSCO, Web of science, PubMed, Springer link, and Chinese National Knowledge Infrastructure databases were reviewed in our study. A meta-analysis on the associations between interleukin 6 rs1800795 polymorphism and cervical cancer risk was carried out by comparison using 5 genetic models. In this systematic review, 5 studies were analyzed. The pooled population included 2735 participants (1210 cases and 1525 controls). The overall odds ratio (G vs C alleles) using fixed-effects model was 0.85 (95% confidence interval 0.75-0.97), P = .02. Our results show that the C genotype of interleukin 6 rs1800795 is associated with higher cervical cancer risk. Our results indicate that interleukin 6 rs1800795 polymorphism might be associated with susceptibility to cervical cancer. PMID- 27777339 TI - Assessing genotoxicity of diuron on Drosophila melanogaster by the wing-spot test and the wing imaginal disk comet assay. AB - The aim of this study was to evaluate the genotoxicity of the herbicide diuron in the wing-spot test and a novel wing imaginal disk comet assay in Drosophila melanogaster. The wing-spot test was performed with standard (ST) and high bioactivation (HB) crosses after providing chronic 48 h treatment to third instar larvae. A positive dose-response effect was observed in both crosses, but statistically reduced spot frequencies were registered for the HB cross compared with the ST. This latter finding suggests that metabolism differences play an important role in the genotoxic effect of diuron. To verify diuron's ability to produce DNA damage, a wing imaginal disk comet assay was performed after providing 24 h diuron treatment to ST and HB third instar larvae. DNA damage induced by the herbicide had a significantly positive dose-response effect even at very low concentrations in both strains. However, as noted for the wing-spot test, a significant difference between strains was not observed that could be related to the duration of exposure between both assays. A positive correlation between the comet assay and the wing-spot test was found with regard to diuron genotoxicity. PMID- 27777337 TI - Blindsight and Unconscious Vision: What They Teach Us about the Human Visual System. AB - Damage to the primary visual cortex removes the major input from the eyes to the brain, causing significant visual loss as patients are unable to perceive the side of the world contralateral to the damage. Some patients, however, retain the ability to detect visual information within this blind region; this is known as blindsight. By studying the visual pathways that underlie this residual vision in patients, we can uncover additional aspects of the human visual system that likely contribute to normal visual function but cannot be revealed under physiological conditions. In this review, we discuss the residual abilities and neural activity that have been described in blindsight and the implications of these findings for understanding the intact system. PMID- 27777340 TI - Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells. AB - Each year over 90 million units of blood are transfused worldwide. Our dependence on this blood supply mandates optimized blood management and storage. During storage, red blood cells undergo degenerative processes resulting in altered metabolic characteristics which may make blood less viable for transfusion. However, not all stored blood spoils at the same rate, a difference that has been attributed to variable rates of energy usage and metabolism in red blood cells. Specific metabolite abundances are heritable traits; however, the link between heritability of energy metabolism and red blood cell storage profiles is unclear. Herein we performed a comprehensive metabolomics and proteomics study of red blood cells from 18 mono- and di-zygotic twin pairs to measure heritability and identify correlations with ATP and other molecular indices of energy metabolism. Without using affinity-based hemoglobin depletion, our work afforded the deepest multi-omic characterization of red blood cell membranes to date (1280 membrane proteins and 330 metabolites), with 119 membrane protein and 148 metabolite concentrations found to be over 30% heritable. We demonstrate a high degree of heritability in the concentration of energy metabolism metabolites, especially glycolytic metabolites. In addition to being heritable, proteins and metabolites involved in glycolysis and redox metabolism are highly correlated, suggesting that crucial energy metabolism pathways are inherited en bloc at distinct levels. We conclude that individuals can inherit a phenotype composed of higher or lower concentrations of these proteins together. This can result in vastly different red blood cells storage profiles which may need to be considered to develop precise and individualized storage options. Beyond guiding proper blood storage, this intimate link in heritability between energy and redox metabolism pathways may someday prove useful in determining the predisposition of an individual toward metabolic diseases. PMID- 27777342 TI - The Neurology Resident & Fellow Section: Year in review. PMID- 27777341 TI - Identification of Novel Biomarkers for Behcet Disease Diagnosis Using Human Proteome Microarray Approach. AB - Behcet disease (BD) is a chronic systemic vasculitis and considered as an autoimmune disease. Although rare, BD can be fatal due to ruptured vascular aneurysms or severe neurological complications. To date, no known biomarker has been reported for this disease, making it difficult to diagnosis in the clinics. To undertake this challenge, we employed the HuProt arrays, each comprised of ~20,000 unique human proteins, to identify BD-specific autoantibodies using a Two Phase strategy established previously. In Phase I, we profiled the autoimmunity on the HuProt arrays with 75 serum samples collected from 40 BD patients, 15 diagnosed autoimmune patients who suffer from Takayasu arteritis (TA; n = 5)), ANCA associated vasculitis (AAV; n = 5), and Sjogren's syndrome (SS; n = 5), and 20 healthy subjects, and identified 20 candidate autoantigens that were significantly associated with BD. To validate these candidates, in Phase II we constructed a focused array with these 20 candidate BD-associated antigens, and use it to profile a much larger cohort, comprised of serum samples collected from 130 BD patients, 103 autoimmune patients (i.e. 40TA, 40 AAV and 23 SS), and 110 healthy controls. This allowed us to validate CTDP1 (RNA polymerase II subunit A C-terminal domain phosphatase)as a BD-specific autoantigen. The association of anti-CTDP1 with BD patients was further validated using the traditional Western blotting analysis. In conclusion, anti-CTDP1 antibody serves a novel autoantibody for Behcet disease and is expected to help more accurate clinical diagnosis. PMID- 27777344 TI - Tuberculous optochiasmatic arachnoiditis and vision loss. PMID- 27777343 TI - Evidence of association between sleep quality and APOE epsilon4 in healthy older adults: A pilot study. AB - BACKGROUND: It has been estimated that the prevalence of Alzheimer disease (AD) and related dementias will triple by 2035, unless effective interventions or treatments are found for the neurodegenerative disease. Understanding sleep changes as a marker for both AD risk and progression is a burgeoning area of investigation. Specifically, there is emerging evidence that both sleep disturbances and the APOE epsilon4 allele are associated with increased dementia risk. Previous research has suggested that in AD, individuals carrying the APOE epsilon4 allele have decreased sleep quality compared to individuals without the APOE epsilon4 allele. This observational trial aimed to determine if healthy older adults with the risk allele (APOE epsilon4+) have more sleep complaints or evidence of objective sleep disruption compared to healthy older adults without the risk allele (APOE epsilon4-). METHODS: Within the larger Brain in Motion study, a subset of participants completed at-home polysomnography (PSG) and actigraphy sleep assessment. Subjective sleep complaints were determined using the Pittsburgh Sleep Quality Index. RESULTS: This investigation found a significant relationship between presence of APOE epsilon4 allele and objective sleep disturbances measured by both actigraphy and PSG, but not subjective sleep complaints in a healthy population screened for dementia. CONCLUSIONS: These data suggest that the influence of APOE epsilon4 allele on objective sleep quality may precede subjective sleep complaints in individuals at increased risk for dementia. PMID- 27777345 TI - Limb shaking: Video EEG report in a patient with neurolupus but no carotid stenosis. PMID- 27777346 TI - The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. PMID- 27777347 TI - Mystery Case: Acute clot within P1 segment mimicking cisternal hemorrhage in Percheron infarction. PMID- 27777348 TI - Teaching NeuroImages: Acute neurologic deficits due to surfer's myelopathy. PMID- 27777349 TI - Teaching NeuroImages: Stroke mimicking thalamotomy: Cessation of tremor following ventrolateral thalamic ischemia. PMID- 27777350 TI - Teaching Video NeuroImages: Video-ophthalmoscopy: Nystagmus from the inside. PMID- 27777351 TI - Antiepileptic drugs: Are generics as effective as brand name? PMID- 27777353 TI - Correction. PMID- 27777354 TI - Correction. PMID- 27777355 TI - Analgesia in the surgical intensive care unit. AB - Critically ill patients are a heterogeneous group with diverse comorbidities and physiological derangements. The management of pain in the critically ill population is emerging as a standard of care in the intensive care unit (ICU). Pain control of critically ill patients in the ICU presents numerous challenges to intensivists. Inconsistencies in pain assessment, analgesic prescription and variation in monitoring sedation and analgesia result in suboptimal pain management. Inadequate pain control can have deleterious effects on several organ systems in critically ill patients. Therefore, it becomes incumbent on physicians and nurses caring for these patients to carefully evaluate their practice on pain management and adopt an optimal pain management strategy that includes a reduction in noxious stimuli, adequate analgesia and promoting education regarding sedation and analgesia to the ICU staff. Mechanistic approaches and multimodal analgesic techniques have been clearly demonstrated to be the most effective pain management strategy to improve outcomes. For example, recent evidence suggests that the use of short acting analgesics and analgesic adjuncts for sedation is superior to hypnotic based sedation in intubated patients. This review will address analgesia in the ICU, including opioid therapy, adjuncts, regional anaesthesia and non-pharmacological options that can provide a multimodal approach to treating pain. PMID- 27777357 TI - Sex Differences in Hypertension: Recent Advances. PMID- 27777358 TI - Management of Masked Hypertension: Why Are We Still Sitting on the Fence? PMID- 27777356 TI - Prolonged Baroreflex Activation Abolishes Salt-Induced Hypertension After Reductions in Kidney Mass. AB - Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated for therapy in patients with resistant hypertension. However, patients with significant impairment of renal function have been largely excluded from clinical trials. Thus, there is little information on blood pressure and renal responses to baroreflex activation in subjects with advanced chronic kidney disease, which is common in resistant hypertension. Changes in arterial pressure and glomerular filtration rate were determined in 5 dogs after combined unilateral nephrectomy and surgical excision of the poles of the remaining kidney to produce ~70% reduction in renal mass. After control measurements, sodium intake was increased from ~45 to 450 mol/d. While maintained on high salt, animals experienced increases in mean arterial pressure from 102+/-4 to 121+/-6 mm Hg and glomerular filtration rate from 40+/-2 to 45+/-2 mL/min. During 7 days of baroreflex activation, the hypertension induced by high salt was abolished (103+/-6 mm Hg) along with striking suppression of plasma norepinephrine concentration from 139+/-21 to 81+/-9 pg/mL, but despite pronounced blood pressure lowering, there were no significant changes in glomerular filtration rate (43+/-2 mL/min). All variables returned to prestimulation values during a recovery period. These findings indicate that after appreciable nephron loss, chronic suppression of central sympathetic outflow by baroreflex activation abolishes hypertension induced by high salt intake. The sustained antihypertensive effects of baroreflex activation occur without significantly compromising glomerular filtration rate in remnant nephrons. PMID- 27777359 TI - Cardiovascular Risk Factors and Masked Hypertension: The Jackson Heart Study. AB - Masked hypertension is associated with increased risk for cardiovascular disease. Identifying modifiable risk factors for masked hypertension could provide approaches to reduce its prevalence. Life's Simple 7 is a measure of cardiovascular health developed by the American Heart Association that includes body mass index, physical activity, diet, cigarette smoking, blood pressure (BP), cholesterol, and glucose. We examined the association between cardiovascular health and masked daytime hypertension in the Jackson Heart Study, an exclusively African American cohort. Life's Simple 7 factors were assessed during a study visit and categorized as poor, intermediate, or ideal. Ambulatory BP monitoring was performed after the study visit. Using BP measured between 10:00 am and 8:00 pm on ambulatory BP monitoring, masked daytime hypertension was defined as mean clinic systolic BP/diastolic BP <140/90 mm Hg and mean daytime systolic BP/diastolic BP >=135/85 mm Hg. Among the 758 participants with systolic BP/diastolic BP <140/90 mm Hg, 30.5% had masked daytime hypertension. The multivariable-adjusted prevalence ratios for masked daytime hypertension comparing participants with 2, 3, and >=4 versus <=1 ideal Life's Simple 7 factors were 0.99 (95% confidence interval [CI], 0.74-1.33), 0.77 (95% CI, 0.57 1.03), and 0.51 (95% CI, 0.33-0.79), respectively. Masked daytime hypertension was less common among participants with ideal versus poor levels of physical activity (ratio, 0.74; 95% CI, 0.56-1.00), ideal or intermediate levels pooled together versus poor diet (prevalence ratio, 0.73; 95% CI, 0.58-0.91), ideal versus poor levels of cigarette smoking (prevalence ratio, 0.61; 95% CI, 0.46 0.82), and ideal versus intermediate levels of clinic BP (prevalence ratio, 0.28, 95% CI, 0.16-0.48). Better cardiovascular health is associated with a lower preva lence of masked hypertension. PMID- 27777360 TI - Trends in Antihypertensive Medication Use Among US Patients With Resistant Hypertension, 2008 to 2014. AB - Little is known of US trends in antihypertensive drug use for patients with treatment-resistant hypertension (TRH). We analyzed antihypertensive use among patients with TRH (treated with >=4 antihypertensive drugs concurrently) from July 2008 through December 2014 using Marketscan administrative data. We included adults aged 18 to 65 years, with >=6 months of continuous enrollment, a hypertension diagnosis, and >=1 episode of overlapping use of >=4 antihypertensive drugs; patients with heart failure were excluded. We identified 411 652 unique TRH episodes from 261 652 patients with a mean age of 55.9 years. From 2008 to 2014, we observed an increased prevalence, among TRH episodes, of beta-blockers (+6.8% [79% to 85.8%]) and dihydropyridine calcium antagonists (+8.1% [69.1% to 77.2%]), and a decreased prevalence of angiotensin-converting enzyme inhibitors (-12.5% [60.4% to 47.9%]) and nondihydropyridine calcium antagonists (-5.0% [15% to 10%]). The prevalence of most other classes changed by <5% from 2008 to 2014. Thiazide diuretic use was largely unchanged from 2008 to 2014, with hydrochlorothiazide being by far the most prevalent thiazide diuretic; chlorthalidone use increased only modestly (+2.6% [3.8% to 6.4%]). Aldosterone antagonist use increased only modestly (+2.9% [7.3% to 10.2%]). Use of optimal regimens increased steadily (+13.8% [50.8% to 64.6%]) during the study period, whereas combined angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use declined (-11.4% [17.7% to 6.3%]). Our results highlight the persistent infrequent use of recommended therapies in TRH, including spironolactone and chlorthalidone, and suggest a need for better efforts to increase the use of such approaches in light of recent evidence demonstrating their efficacy. PMID- 27777361 TI - Resistant Hypertension: Is the Number of Drugs a Reliable Marker of Resistance? PMID- 27777362 TI - Associations Between Fetal Imprinted Genes and Maternal Blood Pressure in Pregnancy. AB - In addition to maternal genes and environmental exposures, variation in fetal imprinted genes could also affect maternal blood pressure during pregnancy. Our objective was to test the associations between polymorphic variants in 16 imprinted genes and maternal mean arterial blood pressures in 1160 DNA trios from 2 established birth cohorts (the Cambridge Baby Growth and Wellbeing Studies) and seek replication in 1367 Hyperglycemia and Adverse Pregnancy Outcome Study participants. Significant univariate associations, all independent of fetal sex, were observed in the Cambridge cohorts, including FAM99A rs1489945 transmitted from the mother (P=2*10-4), DLK1 rs10139403 (mother; P=9*10-4), DLK1 rs12147008 (mother; P=1*10-3), H19 rs217222 (father; P=1*10-3), SNRPN rs1453556 (father; P=1*10-3), IGF2 rs6356 (father; P=1*10-3), and NNAT rs6066671 (father; P=1*10-3). In meta-analysis including additional independent Hyperglycemia and Adverse Pregnancy Outcome Study data, the association with maternally transmitted fetal DLK1 rs10139403 reached genome-wide significance (P=6.3*10-10). With the exception of fetal rs1489945 and rs217222, all of other associations were unidirectional and most were statistically significant. To further explore the significance of these relationships, we developed an allele score based on the univariate findings. The score was strongly associated with maternal blood pressure at 31 weeks (P=4.1*10-8; adjusted r2=5.6%) and 37 weeks of pregnancy (P=1.1*10-4; r2=3.6%), and during the last 2 weeks before parturition (P=1.1*10 10; r2=8.7%). It was also associated with gestational hypertension (odds ratio, 1.54 [range, 1.14-2.09] per allele; P=0.005; 45 cases and 549 controls). These data support the concept that fetal imprinted genes are related to the development of gestational hypertension. PMID- 27777364 TI - Changes in the self-rated well-being of people who move from congregated settings to personalized arrangements and group home placements. AB - A natural experiment contrasted the self-rated well-being of people with intellectual disabilities ( n = 75) and those with enduring mental health problems ( n = 44) after they moved to new accommodation and support options, while others remained in congregated settings or living in the family home. Most support staff also provided well-being ratings. In personalized arrangements, personal well-being was significantly higher than in congregated settings; particularly for people with intellectual disability who had higher support needs compared to people with mental health problems. Moving to a group home also brought some improvement in the well-being ratings of people with intellectual disability but only for those with higher support needs. Such moves seemed to lead to a decline in well-being for those with mental health problems. There were marked discrepancies between ratings given by the person with those of staff. The well-being measure shows promise for use in further comparative and longitudinal studies. PMID- 27777363 TI - Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone Producing Human Tissues. AB - Primary aldosteronism is present in ~10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1) mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism. PMID- 27777365 TI - Fluorophore ligand binding and complex stabilization of the RNA Mango and RNA Spinach aptamers. AB - The effective tracking and purification of biological RNAs and RNA protein complexes is currently challenging. One promising strategy to simultaneously address both of these problems is to develop high-affinity RNA aptamers against taggable small molecule fluorophores. RNA Mango is a 39-nucleotide, parallel stranded G-quadruplex RNA aptamer motif that binds with nanomolar affinity to a set of thiazole orange (TO1) derivatives while simultaneously inducing a 103-fold increase in fluorescence. We find that RNA Mango has a large increase in its thermal stability upon the addition of its TO1-Biotin ligand. Consistent with this thermal stabilization, RNA Mango can effectively discriminate TO1-Biotin from a broad range of small molecule fluorophores. In contrast, RNA Spinach, which is known to have a substantially more rigid G-quadruplex structure, was found to bind to this set of fluorophores, often with higher affinity than to its native ligand, 3,5-difluoro-4-hydroxybenzylidene imidazolinone (DFHBI), and did not exhibit thermal stabilization in the presence of the TO1-Biotin fluorophore. Our data suggest that RNA Mango is likely to use a concerted ligand-binding mechanism that allows it to simultaneously bind and recognize its TO1-Biotin ligand, whereas RNA Spinach appears to lack such a mechanism. The high binding affinity and fluorescent efficiency of RNA Mango provides a compelling alternative to RNA Spinach as an RNA reporter system and paves the way for the future development of small fluorophore RNA reporter systems. PMID- 27777366 TI - Effect of Crc and Hfq proteins on the transcription, processing, and stability of the Pseudomonas putida CrcZ sRNA. AB - In Pseudomonas putida, the Hfq and Crc proteins regulate the expression of many genes in response to nutritional and environmental cues, by binding to mRNAs that bear specific target motifs and inhibiting their translation. The effect of these two proteins is antagonized by the CrcZ and CrcY small RNAs (sRNAs), the levels of which vary greatly according to growth conditions. The crcZ and crcY genes are transcribed from promoters PcrcZ and PcrcY, respectively, a process that relies on the CbrB transcriptional activator and the RpoN sigma factor. Here we show that crcZ can also be transcribed from the promoter of the immediate upstream gene, cbrB, a weak constitutive promoter. The cbrB-crcZ transcript was processed to render a sRNA very similar in size to the CrcZ produced from promoter PcrcZ The processed sRNA, termed CrcZ*, was able to antagonize Hfq/Crc because, when provided in trans, it relieved the deregulated Hfq/Crc-dependent hyperrepressing phenotype of a DeltacrcZDeltacrcY strain. CrcZ* may help in attaining basal levels of CrcZ/CrcZ* that are sufficient to protect the cell from an excessive Hfq/Crc-dependent repression. Since a functional sRNA can be produced from PcrcZ, an inducible strong promoter, or by cleavage of the cbrB-crcZ mRNA, crcZ can be considered a 3'-untranslated region of the cbrB-crcZ mRNA. In the absence of Hfq, the processed form of CrcZ was not observed. In addition, we show that Crc and Hfq increase CrcZ stability, which supports the idea that these proteins can form a complex with CrcZ and protect it from degradation by RNases. PMID- 27777367 TI - Artificial "ping-pong" cascade of PIWI-interacting RNA in silkworm cells. AB - PIWI-interacting RNAs (piRNAs) play essential roles in the defense system against selfish elements in animal germline cells by cooperating with PIWI proteins. A subset of piRNAs is predicted to be generated via the "ping-pong" cascade, which is mainly controlled by two different PIWI proteins. Here we established a cell based artificial piRNA production system using a silkworm ovarian cultured cell line that is believed to possess a complete piRNA pathway. In addition, we took advantage of a unique silkworm sex-determining one-to-one ping-pong piRNA pair, which enabled us to precisely monitor the behavior of individual artificial piRNAs. With this novel strategy, we successfully generated artificial piRNAs against endogenous protein-coding genes via the expected back-and-forth traveling mechanism. Furthermore, we detected "primary" piRNAs from the upstream region of the artificial "ping-pong" site in the endogenous gene. This artificial piRNA production system experimentally confirms the existence of the "ping-pong" cascade of piRNAs. Also, this system will enable us to identify the factors involved in both, or each, of the "ping" and "pong" cascades and the sequence features that are required for efficient piRNA production. PMID- 27777368 TI - Mycotic aneurysm of the ascending aorta in a child with bicuspid aortic valve. PMID- 27777369 TI - The Effects of Exposure to Psychological Violence in the Workplace on Commitment and Turnover Intentions: The Moderating Role of Social Support and Role Stressors. AB - Exposure to workplace violence has been identified as a serious and universal issue facing modern organizations. The present study focuses more specifically on exposure to psychological violence, and its association with turnover intentions as mediated by workplace affective commitment. In addition, we also explore the moderating role of various facets of job demands (role stressors) and resources (social support) on the aforementioned relations. Data collected from 1,228 university employees indicated that experiencing psychological violence at work was associated with lower levels of workplace affective commitment and higher levels of turnover intentions, and that the relation between psychological violence and turnover intentions was partially mediated by commitment. Furthermore, role stressors and social support were found to moderate the negative relation between exposure to psychological violence and workplace affective commitment, as well as between commitment and turnover intentions, but not the direct relation between psychological violence and turnover intentions. Theoretical and research implications for the literature on psychological violence and practical suggestions for minimizing its damaging consequences are proposed. PMID- 27777370 TI - Differences in Abuse, Neglect, and Exposure to Community Violence in Adolescents With and Without PTSD and Depression. AB - South African adolescents are exposed to high levels of violence and trauma, including community violence, abuse, and neglect. Violence and trauma are associated with negative mental health outcomes, including posttraumatic stress disorder (PTSD) and depression. Demographic characteristics, additional exposure to trauma, community violence, and types of childhood abuse and neglect may place adolescents at greater risk of developing PTSD. This study aimed to first assess the weighted contribution of demographic factors, trauma load, community violence, and types of abuse and neglect in predicting PTSD symptom severity. Second, we aimed to determine group differences in demographic factors, trauma load, community violence, and types of abuse and neglect among participants with no disorder, PTSD only, PTSD and depression, and depression only. Participants were 215 adolescents identified with emotional and/or behavioral problems and referred to an adolescent trauma clinic from schools in the Western Cape region of South Africa. Clinical assessments were undertaken to assess community violence exposure; physical, sexual, and emotional abuse; physical and emotional neglect; and a clinical diagnosis of PTSD and comorbidity. Trauma-exposed adolescents with PTSD and depression reported significantly higher levels of emotional abuse and community violence exposure in comparison with trauma-exposed adolescents without a disorder. Emotional abuse, community violence exposure, and female gender were significant predictors of PTSD in regression analysis. These findings underscore the contribution of different types of trauma in the development of PTSD. Interventions focused on preventing trauma, PTSD, and depression should be multifaceted and be targeted at various levels, for example, individual/interpersonal level (reduce abuse in the household and immediate environment) and community/societal level (reduce crime rates in communities and strengthen conviction policies). Traumatized youth should routinely be screened for a history of abuse and particularly exposure to community violence, given their strong association with PTSD. PMID- 27777371 TI - Ambulatory Glucose Profile Applied to Flash Glucose Monitoring in Real Life: An Expert Opinion. PMID- 27777374 TI - Perceptions of Older Residents and Their Adult Children Regarding Continuing Care Retirement Community Staff. AB - This study examined the perspectives of continuing care retirement community (CCRC) residents and their adult children regarding services provided by staff in the CCRC. The study is based on semistructured qualitative interviews with 49 residents and their 34 adult children from 11 CCRCs. Transcripts were analyzed using qualitative content analysis. Three major themes emerged: (a) "Reliance on the CCRC staff," (b) "Dissatisfaction with the CCRC staff," and (c) "Disregard to the CCRC staff." Findings suggest that staff should maintain constant contact with all residents, including those who are not satisfied with staff's function and those who do not use staff services, to identify and respond to the residents' changing needs. Attention should be paid in meeting residents' physical needs prior to meeting their social and emotional needs, as these tend to be the most urgent. PMID- 27777372 TI - Current best practice in the evaluation and management of malignant pleural effusions. AB - Malignant pleural effusions (MPEs) are an important cause of cancer-related mortality and morbidity. It is a heterogeneous group of conditions, which leads to debilitating symptoms and confers a poor prognosis. Recent well-designed randomized trials have provided a broader evidence base for an expanding range of treatment options. Together, with new prognostic scoring systems and a greater understanding of how different patient phenotypes respond to treatment, this allows greater personalization of management. This article will discuss the current evidence on evaluation and management of MPEs. PMID- 27777373 TI - Occupational exposures and chronic obstructive pulmonary disease (COPD): comparison of a COPD-specific job exposure matrix and expert-evaluated occupational exposures. AB - OBJECTIVES: To compare the occupational exposure levels assigned by our National Institute for Occupational Safety and Health chronic obstructive pulmonary disease-specific job exposure matrix (NIOSH COPD JEM) and by expert evaluation of detailed occupational information for various jobs held by members of an integrated health plan in the Northwest USA. METHODS: We analysed data from a prior study examining COPD and occupational exposures. Jobs were assigned exposure levels using 2 methods: (1) the COPD JEM and (2) expert evaluation. Agreement (Cohen's kappa coefficients), sensitivity and specificity were calculated to compare exposure levels assigned by the 2 methods for 8 exposure categories. RESULTS: kappa indicated slight to moderate agreement (0.19-0.51) between the 2 methods and was highest for organic dust and overall exposure. Sensitivity of the matrix ranged from 33.9% to 68.5% and was highest for sensitisers, diesel exhaust and overall exposure. Specificity ranged from 74.7% to 97.1% and was highest for fumes, organic dust and mineral dust. CONCLUSIONS: This COPD JEM was compared with exposures assigned by experts and offers a generalisable approach to assigning occupational exposure. PMID- 27777375 TI - Reminders of Social Connection Can Attenuate Anthropomorphism. AB - It is a fundamental human need to secure and sustain a sense of social belonging. Previous research has shown that individuals who are lonely are more likely than people who are not lonely to attribute humanlike traits (e.g., free will) to nonhuman agents (e.g., an alarm clock that makes people get up by moving away from the sleeper), presumably in an attempt to fulfill unmet needs for belongingness. We directly replicated the association between loneliness and anthropomorphism in a larger sample ( N = 178); furthermore, we showed that reminding people of a close, supportive relationship reduces their tendency to anthropomorphize. This finding provides support for the idea that the need for belonging has causal effects on anthropomorphism. Last, we showed that attachment anxiety-characterized by intense desire for and preoccupation with closeness, fear of abandonment, and hypervigilance to social cues-was a stronger predictor of anthropomorphism than loneliness was. This finding helps clarify the mechanisms underlying anthropomorphism and supports the idea that anthropomorphism is a motivated process reflecting the active search for potential sources of connection. PMID- 27777376 TI - Issues using linkage of hospital records and death certificate data to determine the size of a potential palliative care population. AB - BACKGROUND: Studies aiming to identify palliative care populations have used data from death certificates and in some cases hospital records. The size and characteristics of the identified populations can show considerable variation depending on the data sources used. It is important that service planners and researchers are aware of this. AIM: To illustrate the differences in the size and characteristics of a potential palliative care population depending on the differential use of linked hospital records and death certificate data. DESIGN: Retrospective cohort study. SETTING/PARTICIPANTS: The cohort consisted of 23,852 people aged 20 years and over who died in Western Australia between 1 January 2009 and 31 December 2010 after excluding deaths related to pregnancy or trauma. Within this cohort, the number, proportion and characteristics of people who died from one or more of 10 medical conditions considered amenable to palliative care were identified using linked hospital records and death certificate data. RESULTS: Depending on the information source(s) used, between 43% and 73% of the 23,852 people who died had a condition potentially amenable to palliative care identified. The median age at death and the sex distribution of the decedents by condition also varied with the information source. CONCLUSION: Health service planners and researchers need to be aware of the limitations when using hospital records and death certificate data to determine a potential palliative care population. The use of Emergency Department and other administrative data sources could further exacerbate this variation. PMID- 27777377 TI - Severe edentulism is a major risk factor influencing stroke incidence in rural Ecuador (The Atahualpa Project). AB - Background There is no information on stroke incidence in rural areas of Latin America, where living conditions and cardiovascular risk factors are different from urban centers. Aim Using a population-based prospective cohort study design, we aimed to assess risk factors influencing stroke incidence in community dwelling adults living in rural Ecuador. Methods First-ever strokes occurring from 1 June 2012 to 31 May 2016, in Atahualpa residents aged >=40 years, were identified from yearly door-to-door surveys and other overlapping sources. Poisson regression models adjusted for demographics, cardiovascular risk factors, edentulism and the length of observation time per subject were used to estimate stroke incidence rate ratio as well as factors influencing such incidence. Results Of 807 stroke-free individuals prospectively enrolled in the Atahualpa Project, follow-up was achieved in 718 (89%), contributing 2,499 years of follow up (average 3.48 +/- 0.95 years). Overall stroke incidence rate was 2.97 per 100 person-years of follow-up (95% CI: 1.73-4.2), which increased to 4.77 (95% CI: 1.61-14.1) when only persons aged >=57 years were considered. Poisson regression models, adjusted for relevant confounders, showed that high blood pressure (IRR: 5.24; 95% CI: 2.55-7.93) and severe edentulism (IRR: 5.06; 95% CI: 2.28-7.85) were the factors independently increasing stroke incidence. Conclusions Stroke incidence in this rural setting is comparable to that reported from the developed world. Besides age and high blood pressure, severe edentulism is a major factor independently predicting incident strokes. Public awareness of the consequences of poor dental care might reduce stroke incidence in rural settings. PMID- 27777378 TI - Two decades of nation-wide community-based stroke support - The Singapore National Stroke Association. AB - The Singapore National Stroke Association, registered in 1996, offers support and information to stroke survivors and caregivers, and aims to raise public stroke awareness. In the last 20 years, we have developed programs to equip stroke survivors and caregivers with knowledge, life skills, comfort, and opportunities for socialization and reintegration. We have on-going public education and advocacy initiatives. Obtaining funding, member recruitment, volunteer retention, and leadership renewal are on-going challenges. Singapore National Stroke Association will continue to strive for the betterment of stroke survivors, their caregivers, and the public. PMID- 27777379 TI - Impaired autophagy activity is linked to elevated ER-stress and inflammation in aging adipose tissue. AB - Adipose tissue dysfunction in aging is associated with inflammation, metabolic syndrome and other diseases. We propose that impaired protein homeostasis due to compromised lysosomal degradation (micro-autophagy) might promote aberrant ER stress response and inflammation in aging adipose tissue. Using C57BL/6 mouse model, we demonstrate that adipose tissue-derived stromal vascular fraction (SVF) cells from old (18-20 months) mice have reduced expression of autophagy markers as compared to the younger (4-6 months) cohort. Elevated expressions of ER-stress marker CHOP and autophagy substrate SQSTM1/p62 are observed in old SVFs compared to young, when treated with either vehicle or with thapsigargin (Tg), an ER stress inducer. Treatment with bafilomycin A1 (Baf), a vacuolar-type H (+) ATPase, or Tg elevated expressions of CHOP, and SQSTM1/p62 and LC-3-II, in 3T3-L1 preadipocytes. We also demonstrate impaired autophagy activity in old SVFs by analyzing increased accumulation of autophagy substrates LC3-II and p62. Compromised autophagy activity in old SVFs is correlated with enhanced release of pro-inflammatory cytokines IL-6 and MCP-1. Finally, SVFs from calorie restricted old mice (CR-O) have shown enhanced autophagy activity compared to ad libitum fed old mice (AL-O). Our results support the notion that diminished autophagy activity with aging contributes to increased adipose tissue ER stress and inflammation. PMID- 27777381 TI - A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation. AB - Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to alpha,beta-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug. PMID- 27777380 TI - Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction. AB - Post-myocardial infarction (MI), overactive inflammation is the hallmark of aging, however, the mechanism is unclear. We hypothesized that excess influx of omega 6 fatty acids may impair resolution, thus impacting the cardiosplenic and cardiorenal network post-MI. Young and aging mice were fed on standard lab chow (LC) and excess fatty acid (safflower oil; SO)-enriched diet for 2 months and were then subjected to MI surgery. Despite similar infarct areas and left ventricle (LV) dysfunction post-MI, splenic mass spectrometry data revealed higher levels of arachidonic acid (AA) derived pro-inflammatory metabolites in young-SO, but minimal formation of docosanoids, D- and E- series resolvins in SO fed aged mice. The aged mice receiving excess intake of fatty acids exhibit; 1) decreased lipoxygenases (5-,12-, and 15) in the infarcted LV; 2) lower levels of 14HDHA, RvD1, RvD5, protectin D1, 7(S)maresin1, 8-,11-,18-HEPE and RvE3 with high levels of tetranor-12-HETEs; 3) dual population of macrophages (CD11blow/F480high and CD11bhigh/F480high) with increased pro-inflammatory (CD11bp+F4/80+Ly6Chi) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-alpha and IL-1beta indicating MI-induced non-resolving response compared with LC-group. Thus, excess fatty acid intake magnifies the post-MI chemokine signaling and inflames the cardiosplenic and cardiorenal network towards a non resolving microenvironment in aging. PMID- 27777382 TI - Prenatal hyperbaric normoxia treatment improves healthspan and regulates chitin metabolic genes in Drosophila melanogaster. AB - Aging is a universal, irreversible process accompanied by physiological declines that culminate in death. Rapid progress in gerontology research has revealed that aging can be slowed through mild stress-induced hormesis. We previously reported that hyperbaric normoxia (HN, 2 atm absolute pressure with 10% O2) induces a cytoprotective response in vitro by regulating fibronectin. In the present study, we investigated the hormetic effects of prenatal HN exposure on Drosophila healthspan related to molecular defense mechanisms. HN exposure had no disruptive effect on developmental rate or adult body weight. However, lifespan was clearly enhanced, as was resistance to oxidative and heat stress. In addition, levels of reactive oxygen species were significantly decreased and motor performance was increased. HN stress has been shown to trigger molecular changes in the heat shock response and ROS scavenging system, including hsp70, catalase, glutathione synthase, and MnSOD. Furthermore, to determine the hormetic mechanism underlying these phenotypic and molecular changes, we performed a genome-wide profiling in HN-exposed and control flies. Genes encoding chitin metabolism were highly up regulated, which could possibly serve to scavenge free radicals. These results identify prenatal HN exposure as a potential hormetic factor that may improve longevity and healthspan by enhancing defense mechanisms in Drosophila. PMID- 27777383 TI - MicroRNA-346 facilitates cell growth and metastasis, and suppresses cell apoptosis in human non-small cell lung cancer by regulation of XPC/ERK/Snail/E cadherin pathway. AB - Determinants of growth and metastasis in cancer remain of great interest to define. MicroRNAs (miRNAs) have frequently emerged as tumor metastatic regulator by acting on multiple signaling pathways. Here we report the definition of miR 346 as a novel oncogenic microRNA that facilitates non-small cell lung cancer (NSCLC) cell growth and metastasis. XPC, an important DNA damage recognition factor in nucleotide excision repair was defined as a target for down-regulation by miR-346, functioning through direct interaction with the 3'-UTR of XPC mRNA. Blocking miR-346 by an antagomiR was sufficient to inhibit NSCLC cell growth and metastasis, an effect that could be phenol-copied by RNAi-mediated silencing of XPC. In vivo studies established that miR-346 overexpression was sufficient to promote tumor growth by A549 cells in xenografts mice, relative to control cells. Overall, our results defined miR-346 as an oncogenic miRNA in NSCLC, the levels of which contributed to tumor growth and invasive aggressiveness. PMID- 27777384 TI - Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non small cell lung cancer via the ERK1/2/MMP9 pathway. AB - Sirtuin6 (SIRT6), a member of the sirtuins protein family, plays multiple complex roles in cancer. Here, we report that elevated SIRT6 expression was correlated with clinicopathological parameters such as T and N classification in non-small cell lung cancer (NSCLC) patient tumors. SIRT6 overexpression in NSCLC cell lines increased extracellular signal-regulated kinase (p-ERK)1/2 phosphorylation, activated matrix metalloproteinase 9 (MMP9) and promoted tumor cell migration and invasion. Upon treatment with a specific mitogen-activated protein kinase (MEK) 1/2 inhibitor, these effects were abolished. Our results demonstrate SIRT6 upregulation in NSCLC for the first time and suggest a functional role for SIRT6 in promoting migration and invasion through ERK1/2/MMP9 signaling. SIRT6 may serve as a potential therapeutic target in NSCLC and its utility as a prognostic indicator warrants further study. PMID- 27777386 TI - [Physiolgically-based pharmacokinetics:Theory and examples.] AB - Pharmacological outcome and a certain side effects of therapeutic drugs generally depend on concentration of the drugs and/or their active metabolites in the body. Physiologically-based pharmacokinetics is quantitative tool to understand the drug concentration in the body. Drug efficacy is sometimes affected by subjective factors and cannot be clearly quantified. Even in such cases, it could be possible to quantitatively understand possible pharmacological events occurred in the patients by understanding pharmacokinetics of the corresponding drug. Here, we have attempted to summarize the basis of physiologically-based pharmacokinetics to understand which factors will determine drug concentration in the body and how to predict/speculate the drug concentration in the body in a quantitative manner. For easier understanding by the readers, we introduce some examples of pharmacokinetic property of several osteoporosis drugs. PMID- 27777387 TI - [Effect of impaired tissue function on pharmacokinetics of anti-osteoporotic drugs.] AB - It is necessary to achieve pharmacotherapy appropriate to individual patient with respect to effectiveness and safety. Since drugs are given to patients with various kinds of diseases and conditions, in which pharmacokinetics greatly changes, we need to understand the relationship between pharmacokinetics and patient's condition, minimizing the individual differences in drug efficacy and toxicity. In this report, I outline the alteration of pharmacokinetics of anti osteoporotic drugs in patients with various diseases and conditions. PMID- 27777385 TI - Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria. AB - Telomerase in its canonical function maintains telomeres in dividing cells. In addition, the telomerase protein TERT has non-telomeric functions such as shuttling to mitochondria resulting in a decreased oxidative stress, DNA damage and apoptosis. TERT protein persists in adult neurons and can co-localise to mitochondria under various stress conditions. We show here that TERT expression decreased in mouse brain during aging while release of reactive oxygen species (ROS) from the mitochondrial electron transport chain increased. Dietary restriction (DR) caused accumulation of TERT protein in mouse brain mitochondria correlating to decreased ROS release and improved learning and spatial short-term memory. Decreased mTOR signalling is a mediator of DR. Accordingly, feeding mice with rapamycin increased brain mitochondrial TERT and reduced ROS release. Importantly, the beneficial effects of rapamycin on mitochondrial function were absent in brains and fibroblasts from first generation TERT -/- mice, and when TERT shuttling was inhibited by the Src kinase inhibitor bosutinib. Taken together, our data suggests that the mTOR signalling pathway impinges on the mitochondrial localisation of TERT protein, which might in turn contribute to the protection of the brain by DR or rapamycin against age-associated mitochondrial ROS increase and cognitive decline. PMID- 27777388 TI - [Clinical Pharmacokinetics of Active Vitamin D3 and its derivatives, and Vitamin K2(Menatetrenone).] AB - Active vitamin D3(calcitriol)and its derivatives(alfacalcidol, eldecalcitol), and vitamin K2(menatetrenone)are used as the therapeutic medicines for osteoporosis in Japan. Active vitamin D3 and its derivatives have their own feature of pharmacokinetics, due to differences in binding affinity for carrier protein such as vitamin D binding protein and in metabolism. Menatetrenone is easily absorbed from intestine, and distribute to bone higher than other natural vitamin K homologues. PMID- 27777389 TI - [Pharmacokinetics of bisphosphonate.] AB - The objective of treating osteoporosis is to prevent fractures. Bisphosphonates inhibit bone resorption and increase bone density, thereby suppressing the occurrence of fractures. Bisphosphonates have a high affinity for hydroxyapatite. About 20-80%of bisphosphonates absorbed in vivo is adsorbed onto the bone surface. However, the absorption rates of orally ingested bisphosphonates are less than 1%. Bisphosphonates adhered to the bone surface are specifically incorporated into cells upon bone resorption by osteoclasts. Thus, the cytoskeleton of osteoclasts is destroyed, and apoptosis is induced to suppress bone resorption. This article overviews the mechanisms of action and pharmacokinetics of bisphosphonates. PMID- 27777390 TI - [Pharmacokinetics of selective estrogen receptor modulators(SERMs).] AB - Selective estrogen receptor modulators(SERMs), or estrogen receptor agonists/antagonists(ERAAs), are a class of compounds that function as estrogen receptor(ER)agonists or antagonists tissue-dependently. Two types of SERMs are currently used in Japan to treat osteoporosis, raloxifene(RLX:Evista)and bazedoxifene(BZA:Viviant). This article describes the pharmacokinetics of these two drugs. PMID- 27777391 TI - [Relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during treatment with anabolic agents;Teriparatide daily and once weekly subcutaneous injections.] AB - Teriparatide(recombinant human PTH1-34, 20 MUg daily subcutaneous injection)has been approved for osteoporosis patients at high risk of fracture in many countries including Japan. Teriparatide daily injection therapy has been reported to increase BMD, improve microarchitecture of bone, and reduce the risk of new vertebral fractures and that of non-vertebral fractures. Pharmakokinetic(PK)study after a single Teriparatide injection of the daily dose in healthy Japanese postmenopausal women(n=18)revealed very rapid achievement of peak blood level(median of tmax=0.25 hr)followed by fast disappearance from the blood(mean t1/2=0.708 hr, n=17). Consistent with these PK characteristics, a rapid increase in bone formation marker and later increase in bone resorption marker has previously been observed, which was described as a bone anabolic window. More recently, once weekly subcutaneous injection of teriparatide acetate(56.5 MUg)has been reported to reduce the risk of new vertebral fractures compared with placebo and has been approved in Japan. PK study after injection of the higher weekly dose in healthy Japanese postmenopausal women(n=10)revealed a relatively slow achievement of the peak blood level(mean tmax=0.875 hr)compared to daily injections, followed by relatively slow disappearance from the blood(mean t1/2=1.295 hr). Consistent with these PK characteristics, an initial(<24 hr)transient decrease of bone formation markers(serum osteocalcin and P1NP)and transient increase of bone resorption markers(serum NTX and urinary CTX)were observed. However, afterword, the bone formation and resorption markers were increased and decreased, respectively, for longer than 1 week from the baseline levels. The relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during daily versus weekly teriparatide treatment needs to be clarified. PMID- 27777392 TI - [Pharmacokinetics of anti-RANKL antibody drugs:Denosumab.] AB - Antibody drug is a kind of glycoprotein which molecular weight is over one hundred thousand. The number of pharmaceutical approval of antibody drug has been increasing in recent years. In terms of a working mechanism and pharmacokinetics, antibody drug is markedly different from existing low molecular weight drugs. In prospect, about body kinetics is the same. This paper describes general features of antibody drug mainly about internal kinetics in the first half. In the last half, body kinetics of human anti-RANKL monoclonal antibody called Denosumab and body kinetics changes in special population are outlined. PMID- 27777393 TI - [Pharmacokinetics of Zoledronic acid[once-yearly bisphosphonate(intravenous infusion)].] AB - Zoledronic acid hydrate(zoledronic acid)is an osteoporosis therapeutic agent which shows the fracture suppression effect with once-yearly intravenous infusion. Although zoledronic acid is quickly disappeared from the blood after intravenous infusion, it is taken into the bone immediately and incorporated into the bone tissue. In addition, zoledronic acid shows the potent suppression effect on bone resorption by inhibiting farnesyl diphosphate synthase of the mevalonate pathway(FPPS)strongly. In vivo study, the single intravenous administration of zoledronic acid to the mature ovariectomized(OVX)rats demonstrated to suppress the decreasing bone strength dose-dependently in 32 weeks, corresponding to more than one year in human. Changes in bone resorption markers in the study of Japanese osteoporosis patients(ZONE Study)indicated that bone resorption inhibition action was maintained also over one year. The fracture suppression and increase of bone density with once-yealy administration was demonstrated in clinical trials in the osteoporosis patients in Japan and other countries, and zoledronic acid was currently approved for osteoporosis in September 2016 in Japan. Zoledronic acid is expected to contribute to the treatment of osteoporosis as a new bisphosphonate with once-yearly administration. PMID- 27777394 TI - Systemic Lupus Erythematosus Presenting as Refractory Thrombotic Thrombocytopenic Purpura: A Diagnostic and Management Challenge. A Case Report and Concise Review of the Literature. AB - BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is one of the thrombotic microangiopathic (TMA) syndromes, caused by severely reduced activity of the vWF cleaving protease ADAMTS13. Systemic lupus erythematosus (SLE), on the other hand, is an autoimmune disease that affects various organs in the body, including the hematopoietic system. SLE can present with TMA, and differentiating between SLE and TTP in those cases can be very challenging, particularly in patients with no prior history of SLE. Furthermore, an association between these 2 diseases has been described in the literature, with most of the TTP cases occurring after the diagnosis of SLE. In rare cases, TTP may precede the diagnosis of SLE or occur concurrently. CASE REPORT We present a case of a previously healthy 34-year-old female who presented with dizziness and flu-like symptoms and was found to have thrombocytopenia, hemolytic anemia, and schistocytes in the peripheral smear. She was subsequently diagnosed with TTP and started on plasmapheresis and high-dose steroids, but without a sustained response. A diagnosis of refractory TTP was made, and she was transferred to our facility for further management. Initially, the patient was started on rituximab, but her condition continued to deteriorate, with worsening thrombocytopenia. Later, she also fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria for diagnosis of SLE. Treatment of TTP in SLE patients is generally similar to that in the general population, but in refractory cases there are few reports in the literature that show the efficacy of cyclophosphamide. We started our patient on cyclophosphamide and noticed a sustained improvement in the platelet count in the following weeks. CONCLUSIONS Thrombotic thrombocytopenic purpura is a life-threatening hematological emergency which must be diagnosed and treated in a timely manner. Refractory cases of TTP have been described in the literature, but without clear evidence-based guidelines for its management, and is solely based on expert opinion and previous case reports. Further studies are needed to establish guidelines for its management. We present this case to highlight the role that cyclophosphamide might carry in those cases and to be a foundation for these future studies. PMID- 27777395 TI - Diagnostic Role of Blood Tumor Markers in Predicting Hepatocellular Carcinoma in Liver Cirrhosis Patients Undergoing Liver Transplantation. AB - BACKGROUND The aim of this study was to investigate the diagnostic role of alpha fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in predicting hepatocellular carcinoma (HCC) in patients with advanced liver cirrhosis (LC) awaiting liver transplantation (LT). MATERIAL AND METHODS During a study period of 10 years, 2074 adult LT recipients were identified. They were divided into 2 groups: HCC (n=970; 46.8%) and non-HCC (n=1104; 53.2%). They were stratified into 5 categories according to model for end-stage liver disease (MELD) scores: <10 (n=464), >=10 and <15 (n=632), >=15 and <20 (n=355), >=20 and <30 (n=340), and >=30 (n=283). RESULTS Median pretransplant AFP vs. DCP levels were 11.3 ng/mL vs. 26 mAU/mL and 4.2 ng/mL vs. 22 mAU/mL in the HCC and non-HCC groups, respectively. Receiver-operator characteristic (ROC) curve analyses showed that area under the curve (AUC) of AFP was 0.693, having a crossing-point cutoff at 6.8 ng/mL with sensitivity of 64.5% and specificity of 64.5%. AUC of AFP was inversely correlated with MELD score. AUC of DCP was 0.546, having a crossing point cutoff at 25 mAU/mL with sensitivity of 53.1% and specificity of 51.8%. AUC of DCP was <0.6 except in MELD score >=30. CONCLUSIONS Diagnostic predictability of AFP was reliably associated with MELD score but that of DCP was not. The sensitivity of AFP and DCP is not high enough, especially in patients with MELD score >=20. Thus, thorough HCC screening with imaging studies should be conducted during the waiting period for LT and pretransplant assessment. PMID- 27777396 TI - Incidence of Posttraumatic Shoulder Dislocation in Poland. AB - BACKGROUND The incidence of shoulder joint dislocation has been estimated at 11 26 per 100 000 population per year. In our opinion, basic epidemiological data need to be continually updated in studies of large populations. To study the incidence of posttraumatic dislocation of the shoulder joint in the Polish population. MATERIAL AND METHODS We retrospectively investigated the entire Polish population between 1 January 2010 and 1 January 2015. To identify the study group, data collected in the electronic database of the National Health Fund were used. The study group was divided into subgroups to detect possible differences in the incidence of shoulder dislocation with regard to age, sex, and season of the year (month) when the dislocation occurred. RESULTS The cumulative size of the study sample was 192.72 million over the 5 years of the study. We identified 51 409 patients with first posttraumatic shoulder dislocation, at a mean age of 50.83 years (SD 21.12), from 0 to 104 years. The incidence of traumatic shoulder dislocations for the entire study group ranged from 24.75/100 000/year (number of posttraumatic shoulder dislocations per 100 000 persons per year) to 29.09/100 000/year, for a mean of 26.69/100 000/year. CONCLUSIONS In this study, the overall incidence of first-time posttraumatic shoulder dislocations in the Polish general population was 26.69 per 100 000 persons per year. These results are higher than estimates presented by other authors. It is necessary to study, regularly update, and monitor this problem in the general population. PMID- 27777397 TI - Evaluation of the Maintained Effect of 3% Hypertonic Saline Solution in an Animal Model of Intracranial Hypertension. AB - BACKGROUND Current clinical treatment methods for refractory intracranial hypertension include elevation of the decubitus, ventilation adjustment, and use of hypertonic solutions such as hypertonic saline and mannitol solutions. Previous studies have shown that hypertonic solutions are particularly effective. Although several concentrations of saline solution have been proposed, a 3% solution is the most widely used. The aim of this study was to evaluate the maintained efficacy of a 3% hypertonic saline solution in an experimental model of intracranial hypertension. MATERIAL AND METHODS A porcine model of reversible intracranial hypertension was created by inserting a balloon catheter into the brain parenchyma, which was inflated and deflated to simulate intracranial hypertension and its surgical correction. The experiment included 3 groups of animals (A, B, and C) with different balloon inflation volumes. In group B, balloons were inflated 2 times to simulate reexpansion. A 20 mL/kg bolus of 3% saline solution was infused using a pump 90 minutes after the start of balloon inflation, and the effects of intracranial pressure were evaluated 60 minutes after infusion. RESULTS No increases outside of the normal range were observed in mean serum sodium concentrations (p=0.09). In addition, we identified no differences within each group in serum sodium levels measured during hypertonic saline infusion (p=0.21). No significant reductions in intracranial pressure were observed in any of the 3 groups. CONCLUSIONS Bolus infusion of 3% hypertonic saline solution with the aid of a pump does not significantly reduce intracranial pressure in an animal model of intracranial hypertension. PMID- 27777398 TI - Chitosan Hydrogel Structure Modulated by Metal Ions. AB - As one of the most important polysaccharide, chitosan (CS) has generated a great deal of interest for its desirable properties and wide applications. In the utilization of CS materials, hydrogel is a major and vital branch. CS has the ability to coordinate with many metal ions by a chelation mechanism. While most researchers focused on the applications of complexes between CS and metal ions, the complexes can also influence gelation process and structure of CS hydrogel. In the present work, such influence was studied with different metal ions, revealing two different kinds of mechanisms. Strong affinity between CS and metal ions leads to structural transition from orientation to multi-layers, while weak affinity leads to composite gel with in-situ formed inorganic particles. The study gave a better understanding of the gelation mechanism and provided strategies for the modulation of hydrogel morphology, which benefited the design of new CS-based materials with hierarchical structure and facilitated the utilization of polysaccharide resources. PMID- 27777400 TI - Beyond particle physics. PMID- 27777399 TI - Label-free detection of microRNA based on coupling multiple isothermal amplification techniques. AB - MicroRNA (miRNA) was a promising class of cancer biomarkers. Here we developed a label-free method for sensitive measurement of let-7d miRNA based on multiple amplification techniques. The primer will bind to the duplex strand DNA that was formed by stem-loop template and target let-7d to initiate strand displacement amplification (SDA) in tandem. The released single strand DNA will be a primer to bind the circular template to initiate rolling circle amplification (RCA). The products based on multiple amplifications will be detected by a standard fluorimeter with N-methyl mesoporphyrin IX (NMM) as the fluorescent indicator. The proposed method exhibited excellent selectivity and high sensitivity with a detection limit of as low as 1.5 * 10-13 M. Moreover, this methodology was used for the determination of biomolecules in real serum samples with satisfying results. PMID- 27777401 TI - Colloidal crystals: Stresses come to light. PMID- 27777402 TI - Weyl semimetals, Fermi arcs and chiral anomalies. PMID- 27777403 TI - Topological semimetals. PMID- 27777404 TI - Material witness: Searching the web. PMID- 27777405 TI - Weyl semimetals: Magnetically induced. PMID- 27777406 TI - Zebrafish as a new model to study effects of periodontal pathogens on cardiovascular diseases. AB - Porphyromonas gingivalis (Pg) is a keystone pathogen in the aetiology of chronic periodontitis. However, recent evidence suggests that the bacterium is also able to enter the bloodstream, interact with host cells and tissues, and ultimately contribute to the pathogenesis of cardiovascular disease (CVD). Here we established a novel zebrafish larvae systemic infection model showing that Pg rapidly adheres to and penetrates the zebrafish vascular endothelium causing a dose- and time-dependent mortality with associated development of pericardial oedemas and cardiac damage. The in vivo model was then used to probe the role of Pg expressed gingipain proteases using systemically delivered gingipain-deficient Pg mutants, which displayed significantly reduced zebrafish morbidity and mortality compared to wild-type bacteria. In addition, we used the zebrafish model to show efficacy of a gingipain inhibitor (KYT) on Pg-mediated systemic disease, suggesting its potential use therapeutically. Our data reveal the first real-time in vivo evidence of intracellular Pg within the endothelium of an infection model and establishes that gingipains are crucially linked to systemic disease and potentially contribute to CVD. PMID- 27777407 TI - 'The story behind NICU reading programs'. PMID- 27777408 TI - Extended-interval gentamicin administration in neonates: an over-simplified approach. PMID- 27777409 TI - Response to "Extended-interval gentamicin administration in neonates: an over simplified approach". PMID- 27777411 TI - Laboratory Investigation web focus on China. AB - The vast growth of China's publishing output is a reflection of the increasing strength of Chinese science. The editors of Laboratory Investigation (LI) present a collection of papers that showcases research by authors from institutions across China, highlighting the significant contributions of Chinese scientists to the journal. PMID- 27777413 TI - In Memorium: Nathan Kaufman. PMID- 27777410 TI - Red blood cell thickness is evolutionarily constrained by slow, hemoglobin restricted diffusion in cytoplasm. AB - During capillary transit, red blood cells (RBCs) must exchange large quantities of CO2 and O2 in typically less than one second, but the degree to which this is rate-limited by diffusion through cytoplasm is not known. Gas diffusivity is intuitively assumed to be fast and this would imply that the intracellular path length, defined by RBC shape, is not a factor that could meaningfully compromise physiology. Here, we evaluated CO2 diffusivity (DCO2) in RBCs and related our results to cell shape. DCO2 inside RBCs was determined by fluorescence imaging of [H+] dynamics in cells under superfusion. This method is based on the principle that H+ diffusion is facilitated by CO2/HCO3- buffer and thus provides a read-out of DCO2. By imaging the spread of H+ ions from a photochemically-activated source (6-nitroveratraldehyde), DCO2 in human RBCs was calculated to be only 5% of the rate in water. Measurements on RBCs containing different hemoglobin concentrations demonstrated a halving of DCO2 with every 75 g/L increase in mean corpuscular hemoglobin concentration (MCHC). Thus, to compensate for highly restricted cytoplasmic diffusion, RBC thickness must be reduced as appropriate for its MCHC. This can explain the inverse relationship between MCHC and RBC thickness determined from >250 animal species. PMID- 27777417 TI - Studying schizophrenia in the post-genomic era: perspectives from the 2016 summer Banbury Workshop at Cold Spring Harbor Laboratory. PMID- 27777414 TI - Microparticles in the blood of patients with systemic lupus erythematosus (SLE): phenotypic characterization and clinical associations. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS-), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2-10 times more abundant in SLE blood compared to controls. PS- MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS- MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS- MPs, suggests a generalized disturbance in SLE. MPs may be regarded as "liquid biopsies" to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis. PMID- 27777416 TI - AP2gamma controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior. AB - Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2gamma (AP2gamma, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2gamma is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2gamma in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2gamma-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2gamma deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and depressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain. PMID- 27777415 TI - Brain structure in pediatric Tourette syndrome. AB - Previous studies of brain structure in Tourette syndrome (TS) have produced mixed results, and most had modest sample sizes. In the present multicenter study, we used structural magnetic resonance imaging (MRI) to compare 103 children and adolescents with TS to a well-matched group of 103 children without tics. We applied voxel-based morphometry methods to test gray matter (GM) and white matter (WM) volume differences between diagnostic groups, accounting for MRI scanner and sequence, age, sex and total GM+WM volume. The TS group demonstrated lower WM volume bilaterally in orbital and medial prefrontal cortex, and greater GM volume in posterior thalamus, hypothalamus and midbrain. These results demonstrate evidence for abnormal brain structure in children and youth with TS, consistent with and extending previous findings, and they point to new target regions and avenues of study in TS. For example, as orbital cortex is reciprocally connected with hypothalamus, structural abnormalities in these regions may relate to abnormal decision making, reinforcement learning or somatic processing in TS. PMID- 27777418 TI - The PHF21B gene is associated with major depression and modulates the stress response. AB - Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD. PMID- 27777420 TI - Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy. AB - Here, we report a novel target of the drug memantine, ATP-sensitive K+ (KATP) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of KATP channels. Memantine also inhibited Kir6.1 and Kir6.2 KATP channels and elevated intracellular Ca2+ concentrations in neuro2A cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. Finally, we confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. Altogether, our studies show that memantine modulates Kir6.2 activity, and that the Kir6.2 channel is a novel target for therapeutics to improve memory impairment in Alzheimer disease patients. PMID- 27777419 TI - Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. AB - Recent data suggest that intraneuronal accumulation of metabolites of the amyloid beta-precursor protein (APP) is neurotoxic. We observed that transgenic mice overexpressing in neurons a human APP gene harboring the APPE693Q (Dutch) mutation have intraneuronal lysosomal accumulation of APP carboxylterminal fragments (APP-CTFs) and oligomeric amyloid beta (oAbeta) but no histological evidence of amyloid deposition. Morphometric quantification using the lysosomal marker protein 2 (LAMP-2) immunolabeling showed higher neuronal lysosomal counts in brain of 12-months-old APPE693Q as compared with age-matched non-transgenic littermates, and western blots showed increased lysosomal proteins including LAMP 2, cathepsin D and LC3. At 24 months of age, these mice also exhibited an accumulation of alpha-synuclein in the brain, along with increased conversion of LC3-I to LC3-II, an autophagosomal/autolysosomal marker. In addition to lysosomal changes at 12 months of age, these mice developed cholinergic neuronal loss in the basal forebrain, GABAergic neuronal loss in the cortex, hippocampus and basal forebrain and gliosis and microgliosis in the hippocampus. These findings suggest a role for the intraneuronal accumulation of oAbeta and APP-CTFs and resultant lysosomal pathology at early stages of Alzheimer's disease-related pathology. PMID- 27777422 TI - Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice. PMID- 27777421 TI - Glutathione peroxidase 4: a new player in neurodegeneration? AB - Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme reported as an inhibitor of ferroptosis, a recently discovered non-apoptotic form of cell death. This pathway was initially described in cancer cells and has since been identified in hippocampal and renal cells. In this Perspective, we propose that inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration. In addition, we suggest that selenium deficiency enhances susceptibility to ferroptotic processes, as well as other programmed cell death pathways due to a reduction in GPx4 activity. We review recent studies of GPx4 with an emphasis on neuronal protection, and discuss the relevance of selenium levels on its enzymatic activity. PMID- 27777424 TI - The Clinical Application of Hydrogen as a Medical Treatment. AB - In recent years, it has become evident that molecular hydrogen is a particularyl effective treatment for various disease models such as ischemia-reperfusion injury; as a result, research on hydrogen has progressed rapidly. Hydrogen has been shown to be effective not only through intake as a gas, but also as a liquid medication taken orally, intravenously, or locally. Hydrogen's effectiveness is thus multifaceted. Herein we review the recent research on hydrogen-rich water, and we examine the possibilities for its clinical application. Now that hydrogen is in the limelight as a gaseous signaling molecule due to its potential ability to inhibit oxidative stress signaling, new research developments are highly anticipated. PMID- 27777425 TI - Quantitative Analysis of the Effects of a Bangerter Filter on Gross Stereopsis in Experimental Models of Reduced Visual Acuity. AB - Although a 0.3 Bangerter filter, which reduces visual acuity, is frequently used for treating moderate amblyopia, the effects on gross stereopsis are not well known. This study quantitatively evaluated whether gross stereopsis is degraded by a Bangerter filter. Seven healthy subjects (median age: 29 years) participated in this psychophysical study. Targets with crossed disparities of 1 degrees , 2 degrees , 3 degrees , 4 degrees , and 5 degrees were randomly presented on a three-dimensional television display. The subjects indicated the point at which the targets popped out from the television screen (matching method). The distance from the screen to the point was defined as the degree of stereopsis. This experiment was performed with and without a 0.3 Bangerter filter. The corrected monocular visual acuities were decreased to about 20/63 by the filter in all subjects. No significant difference was observed for any of the disparities (1 degrees -5 degrees ), between the degree of stereopsis visualized with and without filters for either the dominant or the non-dominant eye. The degree of stereopsis was not degraded by the reduced visual acuity induced by the use of 0.3 Bangerter filters. In this regard, the use of 0.3 Bangerter filters may be considered safer than occlusion eye patches for the patients with normal binocular vision. PMID- 27777423 TI - Characterization and transplantation of enteric neural crest cells from human induced pluripotent stem cells. AB - The enteric nervous system (ENS) is recognized as a second brain because of its complexity and its largely autonomic control of bowel function. Recent progress in studying the interactions between the ENS and the central nervous system (CNS) has implicated alterations of the gut/brain axis as a possible mechanism in the pathophysiology of autism spectrum disorders (ASDs), Parkinson's disease (PD) and other human CNS disorders, whereas the underlying mechanisms are largely unknown because of the lack of good model systems. Human induced pluripotent stem cells (hiPSCs) have the ability to proliferate indefinitely and differentiate into cells of all three germ layers, thus making iPSCs an ideal source of cells for disease modelling and cell therapy. Here, hiPSCs were induced to differentiate into neural crest stem cells (NCSCs) efficiently. When co-cultured with smooth muscle layers of ganglionic gut tissue, the NCSCs differentiated into different subtypes of mature enteric-like neurons expressing nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), choline acetyltransferase (ChAT) or calretinin with typical electrophysiological characteristics of functional neurons. Furthermore, when they were transplanted into aneural or aganglionic chick, mouse or human gut tissues in ovo, in vitro or in vivo, hiPSC-derived NCSCs showed extensive migration and neural differentiation capacity, generating neurons and glial cells that expressed phenotypic markers characteristic of the enteric nervous system. Our results indicate that enteric NCSCs derived from hiPSCs supply a powerful tool for studying the pathogenesis of gastrointestinal disorders and brain/gut dysfunction and represent a potentially ideal cell source for enteric neural transplantation treatments. PMID- 27777426 TI - Survival and Neurodevelopmental Outcomes of Very Low Birth Weight Infants in a Regional Core Hospital in Kochi, Japan. AB - We sought to clarify the survival and neurodevelopmental outcomes of very low birth weight infants (VLBWIs) and to identify risk factors for death or neurodevelopmental impairment (NDI) in VLBWIs at our hospital. The total study population was 217 infants born in 2005-2012 weighing 1,500 g. We compared their outcomes with those from previous reports analyzed the causes of death. Risk factors for death after discharge or NDI were evaluated by a multivariate logistic regression analysis. The incidences of death or NDI reported revealed in this study and the database of Neonatal Research Network of Japan were 25.3% and 19.6% (p=0.039), respectively. The main causes of death before discharge were intraventricular hemorrhage, sepsis, and persistent pulmonary hypertension of the newborn. The significant risk factors for death after discharge or NDI were early gestational age (weeks) and periventricular leukomalacia (adjusted odds ratio [95% confidence interval, p-value], 0.72 [0.54-0.94, 0.017] and 6.90 [1.35-38.25, 0.021], respectively). These factors must be addressed in order to improve treatment strategies for VLBWIs. PMID- 27777427 TI - Relationship between Changes in Physical Activity and Changes in Health-related Quality of Life in Patients on Chronic Hemodialysis with 1-Year Follow-up. AB - In a longitudinal study, we examined the link between changes in physical activity and changes in health-related quality of life (HRQOL) in patients on chronic hemodialysis. Seventy-one patients (43 males, 28 females; aged 70.9+/ 10.6 years) on chronic hemodialysis in September 2013 were enrolled. The data of the 43 patients whose complete measurements were taken again in September 2014 were used for the longitudinal analysis. Clinical parameters including age, height, dry weight, duration of hemodialysis, blood pressure (BP), blood triglyceride and HDL cholesterol levels, physical activity, and HRQOL were evaluated. Physical activity was measured by a tri-accelerometer, and HRQOL was evaluated by the EuroQol questionnaire (EQ-5D). In the first cross-sectional analysis, EQ-5D scores were significantly correlated with daily step counts (steps per day) on all days and non-hemodialysis days. In the second longitudinal analysis, in the women, changes in EQ-5D scores were positively correlated with changes in daily step counts on all days. In all patients, changes in EQ-5D were weakly and negatively correlated with changes in physical activity (1-3 METs: min per day) on hemodialysis days. Promoting daily physical activity may improve the HRQOL in patients on chronic hemodialysis, especially in women. PMID- 27777428 TI - Sarcopenia and American Society of Anesthesiologists Physical Status in the Assessment of Outcomes of Hepatocellular Carcinoma Patients Undergoing Hepatectomy. AB - Sarcopenia following liver surgery has been reported as a predictor of poor prognosis. Here we investigated predictors of outcomes in patients with hepatocellular carcinoma (HCC) and attempted to establish a new comprehensive preoperative assessment protocol. We retrospectively analyzed the cases of 254 patients who underwent curative hepatectomy for HCC with Child-Pugh classification A at our hospital between January 2007 and December 2013. Sarcopenia was evaluated by computed tomography measurement. The influence of sarcopenia on outcomes was evaluated. We used multivariate analyses to assess the impact of prognostic factors associated with outcomes, including sarcopenia. Of the 254 patients, 118 (46.5% ) met the criteria for sarcopenia, and 32 had an American Society of Anesthesiologists (ASA) physical status 3. The sarcopenic group had a significantly lower 5-year overall survival rate than the non sarcopenic group (58.2% vs. 82.4% , p=0.0002). In multivariate analyses of prognostic factors, sarcopenia was an independent predictor of poor survival (hazard ratio [HR]=2.28, p=0.002) and poor ASA status (HR=3.17, p=0.001). Sarcopenia and poor ASA status are independent preoperative predictors for poor outcomes after hepatectomy. The preoperative identification of sarcopenia and ASA status might enable the development of comprehensive approaches to assess surgical eligibility. PMID- 27777429 TI - The Anticonvulsant Zonisamide Inhibits Hydroxyl Radical Generated from Methylguanidine. AB - Methylguanidine (MG) is a known nephrotoxin and neurotoxin, and an intracisternal injection of MG can induce convulsions in experimental animals. In this in vitro study, we examined the inhibitory effects of the antiepileptic agent zonisamide (ZNS) on hydroxyl radicals (*OH) generated from MG by using an electron spin resonance (ESR) technique. ZNS scavenged *OH generated from MG in a dose dependent manner through direct scavenging during the auto-oxidation of MG. The rate constant of ZNS reacting with the *OH was at a near diffusion-controlled rate. These findings indicate that ZNS might detoxify MG and could thus protect against convulsive disorders. PMID- 27777430 TI - A Case of Streptobacillus moniliformis Infection with Cutaneous Leukocytoclastic Vasculitis. AB - A 71-year-old man presented with a high fever, polyarthralgia, petechiae and palpable purpura accompanied by livedoid change on his legs and feet. Histopathological findings of the purpura revealed perivascular infiltration of neutrophils, mononuclear cells, and nuclear debris, and extravasation of red cells mainly in the upper dermis: all signs consistent with leukocytoclastic vasculitis. Small vessel thrombi, which are characteristic features of septic vasculopathy, were also observed. Direct immunofluorescence showed negative results. Blood culture revealed the growth of gram-negative bacilli. Subsequently, 16S rRNA sequencing of DNA confirmed the organism as Streptobacillus moniliformis, which is the causative pathogen of rat-bite fever. He had frequently encountered wild rats in his house although there was no evidence of rat bite on his body. Empiric therapy with intravenous administration of ceftriaxone in combination with azithromycin hydrate led to a prompt resolution of the symptoms. Precise history-taking related to contact with rats and detection of skin eruptions suggestive of leukocytoclastic vasculitis on the extremities, especially on the feet, can be clues to Streptobacillus moniliformis infection. Familiarity with its cutaneous features is important for early diagnosis; the evidence herein may also help in understanding its underlying pathogenesis. PMID- 27777431 TI - Kikuchi-Fujimoto Disease Complicated with Reactive Hemophagocytic Lymphohistiocytosis. AB - Kikuchi-Fujimoto disease (KFD) is a benign cause of self-limiting subacute necrotizing lymphadenitis. KFD is rarely complicated with reactive hemophagocytic lymphohistiocytosis (HLH), and the clinical features of the simultaneous occurrence of these conditions are uncertain. A 30-year-old Japanese man with a persistent fever and sore throat presented to our hospital for treatment. Laboratory analysis showed bicytopenia, and radiological studies showed systemic lymphadenopathy accompanied by splenomegaly. A bone marrow examination showed hemophagocytic macrophages, suggesting HLH. Malignant lymphoma was suspected as a possible underlying disease, but the histology of the lymph nodes led to a final diagnosis of KFD and treatment with prednisolone (1 mg/kg/day), resulting in clinical improvement. This case highlighted the importance and difficulty of differentiating KFD from malignant lymphoma as an underlying condition of HLH. The literature review showed that patients with HLH-associated KFD may have higher serum ferritin and lactate dehydrogenase levels compared to typical KFD cases. Definite diagnosis based on pathological examination is essential for a better understanding of this rare disease. The presence of systemic lymphadenopathy does not exclude the possibility of KFD. This case serves to remind physicians that KFD is a potential etiology of HLH. PMID- 27777432 TI - Case of 24-week Fetus Delivered from Mother on Life Support with Brain-death from Suicide Attempt: Ethical Issues Associated with Severe Complications. AB - Advances in critical care medicine have made it possible to sustain vital organ systems in brain-dead patients. One clinical scenario besides donor organ retrieval in which a benefit may be gained from continuing life support is pregnancy. A pregnant woman in her late 30's at 23 weeks gestation exhibiting worsening depression was referred to the Department of Psychiatry. One day after admission she attempted suicide by hanging and suffered a cardiopulmonary arrest. A fetal heart beat and fetal motion was confirmed immediately after resuscitation. Three days after admission, an emergency Cesarean section (CS) was performed because of her unstable hemodynamic situation. The baby was born and the mother died after delivery. The baby presented neurological complications. Such a case should be managed collaboratively among professional experts in several medical teams. Consensus and recommendations for the management of similar scenarios may also be adjusted. PMID- 27777433 TI - Granulocyte Colony-Stimulating Factor-Producing Gallbladder Cancer. AB - We report a case of a granulocyte colony-stimulating factor (G-CSF)-producing gallbladder tumor associated with fever in a middle-aged female. Preoperative blood analysis showed leukocytosis with elevated levels of C-reactive protein and G-CSF. We resected the liver at S4a+S5, with regional lymph node dissection and partial resection of the duodenum. Histology revealed undifferentiated carcinoma with spindle and giant cells and papillary adenocarcinoma. Immunohistochemistry revealed Stage IIIB G-CSF-producing gallbladder cancer. Postoperatively, leukocyte and serum G-CSF levels decreased to within normal limits. Adjuvant gemcitabine chemotherapy was administered for 16 months, and she has been recurrence-free for 48 months. PMID- 27777434 TI - Feasibility of Repairing Defects Followed by Treatment with Pulmonary Hypertension-specific Drugs (Repair and Treat) in Patients with Pulmonary Hypertension Associated with Atrial Septal Defect: Study Protocol for Interventional Trial. AB - A treatment strategy for patients with pulmonary hypertension (PH) and atrial septal defect (ASD) remains unclear. This study was designed to evaluate the effects of initial repair of ASD followed by treatment with PH-specific drugs in patients with PH and ASD. Eligible patients receive transcatheter ASD closure followed by treatment with bosentan and sildenafil. Right heart catheterization is performed at baseline and at 12, 24 and 48 weeks. The primary endpoint is change in pulmonary artery pressure and pulmonary vascular resistance from baseline to follow-up. This study should provide valuable information to establish a therapeutic strategy for PH and ASD. PMID- 27777435 TI - A Phase II Clinical Trial of the Efficacy and Safety of Short-term (3 days) Enoxaparin for the Prevention of Venous Thromboembolism after Gastric Cancer Surgery. AB - Although intermittent pneumatic compression (IPC) has become common as perioperative prophylaxis for venous thromboembolism (VTE) consisting of pulmonary thromboembolism (PE) and deep vein thrombosis (DVT), the prophylactic effect against VTE, especially lethal PE, is not yet satisfactory. Therefore, pharmacologic prophylaxis, such as with enoxaparin, is desirable. While the efficacy and safety of enoxaparin have been proven in several clinical trials, concern about bleeding with longterm (at least 7 days) use have potentially decreased its widespread adoption. We have launched a phase II study to evaluate the efficacy and safety of short-term (3 days) enoxaparin, in which a total of 70 gastric cancer patients undergoing gastrectomy will be recruited, and the primary endpoint is the incidence of DVT. This study could contribute to making pharmacologic prophylaxis for VTE more common. PMID- 27777437 TI - An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease. AB - Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD. PMID- 27777436 TI - A Multicenter, Prospective, Randomized Controlled Trial Evaluating the Efficacy of Rectal Diclofenac and Sublingual Nitroglycerin as a Combined Prophylactic Treatment for Post-ERCP Pancreatitis. AB - Acute pancreatitis is the major complication of endoscopic retrograde cholangiopancreatography (ERCP). A preliminary research suggested that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) with nitroglycerin might reduce the incidence of post-ERCP pancreatitis (PEP) more effectively than NSAIDs alone. We conduct a two-arm, multicenter, prospective, randomized, superiority trial to evaluate the additional effect of nitroglycerin for prevention of PEP. A total of 900 patients randomly receive 50 mg diclofenac suppository either alone or with 5 mg isosorbide dinitrate sublingual tablet. The primary endpoint is the occurrence of PEP. This study will clarify whether NSAIDs plus nitroglycerin can prevent PEP. PMID- 27777438 TI - A Single-center, Open-label, Randomized Controlled Clinical Trial to Evaluate the Efficacy and Safety of the Indirect Bonding Technique. AB - Although accurate bracket placement is essential for orthodontic treatment, many practitioners apply brackets indiscriminately with direct or indirect bonding techniques. Nonetheless, there have been few prospective clinical comparisons of the 2 techniques. We will therefore conduct a single-center, randomized control trial in 100 patients aged 12 years and diagnosed with malocclusion. All patients will receive orthodontic treatment using brackets with direct or indirect bonding techniques. The primary endpoints will be the total treatment time, occlusal index, discomfort at bonding, and oral hygiene after bonding. This study will clarify whether indirect bonding can improve the efficiency of orthodontic treatment. PMID- 27777439 TI - A Prospective Randomized Controlled Study Comparing EUS Sonopsy CY(R) and 22 gauge Biopsy Needles for Endoscopic Ultrasound-guided Fine-Needle Aspiration of Solid Pancreatic Mass Lesions. AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a standard procedure for precise histological diagnosis of pancreas tumors, but it is sometimes difficult to obtain adequate specimens. EUS Sonopsy CY(r) is a newly designed needle with original features. This randomized study will compare the tissue collection rate of EUS Sonopsy CY(r) to that of a conventional needle in EUS-FNA. The major eligibility criteria are as follows: Patients with a pancreatic mass referred for EUSFNA; age 20 years, and performance status<4. The primary outcome is the tissue collection rate. This study will elucidate the efficacy of EUS Sonopsy CY(r). PMID- 27777440 TI - Balloon-expandable Metallic Stents for Airway Diseases. AB - Stent placement is an essential treatment for airway diseases. Although self expandable metallic stents and silicone stents are commonly applied for the treatment of airway diseases, these stents are unsuitable for the treatment of small airway diseases encountered in pediatric patients and lung transplant recipients with airway complications. Currently, only vascular balloon-expandable metallic stents are available for the treatment of small airway diseases; however, little research has been conducted on the use of these stents in this field. We have launched a prospective feasibility study to clarify the safety and efficacy of balloon-expandable metallic stents for the treatment of airway diseases. PMID- 27777441 TI - A Phase I Trial of 100 mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer. AB - Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer. PMID- 27777442 TI - Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease. AB - Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT. PMID- 27777444 TI - Exploring Electron/Proton Transfer and Conformational Changes in the Nitrogenase MoFe Protein and FeMo-cofactor Through Cryoreduction/EPR Measurements. AB - We combine cryoreduction/annealing/EPR measurements of nitrogenase MoFe protein with results of earlier investigations to provide a detailed view of the electron/proton transfer events and conformational changes that occur during early stages of [e-/H+] accumulation by the MoFe protein. This includes reduction of (i) the non-catalytic state of the iron-molybdenum cofactor (FeMo-co) active site that is generated by chemical oxidation of the resting-state cofactor (S = 3/2)) within resting MoFe (E0), and (ii) the catalytic state that has accumulated n =1 [e-/H+] above the resting-state level, denoted E1(1H) (S >= 1) in the Lowe Thorneley kinetic scheme. FeMo-co does not undergo a major change of conformation during reduction of oxidized FeMo-co. In contrast, FeMo-co undergoes substantial conformational changes during the reduction of E0 to E1(1H), and of E1(1H) to E2(2H) (n = 2; S = 3/2). The experimental results further suggest that the E1(1H) -> E2(2H) step involves coupled delivery of a proton and electron (PCET) to FeMo co of E1(H) to generate a non-equilibrium S = 1/2 form E2(2H)*. This subsequently undergoes conformational relaxation and attendant change in FeMo-co spin state, to generate the equilibrium E2(2H) (S = 3/2) state. Unexpectedly, these experiments also reveal conformational coupling between FeMo-co and P-cluster, and between Fe protein binding and FeMo-co, which might play a role in gated ET from reduced Fe protein to FeMo-co. PMID- 27777443 TI - Best Practices for Biostatistical Consultation and Collaboration in Academic Health Centers. AB - Given the increasing level and scope of biostatistics expertise needed at academic health centers today, we developed best practices guidelines for biostatistics units to be more effective in providing biostatistical support to their institutions, and in fostering an environment in which unit members can thrive professionally. Our recommendations focus on the key areas of: 1) funding sources and mechanisms; 2) providing and prioritizing access to biostatistical resources; and 3) interacting with investigators. We recommend that the leadership of biostatistics units negotiate for sufficient long-term infrastructure support to ensure stability and continuity of funding for personnel, align project budgets closely with actual level of biostatistical effort, devise and consistently apply strategies for prioritizing and tracking effort on studies, and clearly stipulate with investigators prior to project initiation policies regarding funding, lead time, and authorship. PMID- 27777445 TI - Antimicrobial peptides as natural bio-preservative to enhance the shelf-life of food. AB - Antimicrobial peptides (AMPs) are diverse group of natural proteins present in animals, plants, insects and bacteria. These peptides are responsible for defense of host from pathogenic organisms. Chemical, enzymatic and recombinant techniques are used for the synthesis of antimicrobial peptides. These peptides have been found to be an alternative to the chemical preservatives. Currently, nisin is the only antimicrobial peptide, which is widely utilized in the preservation of food. Antimicrobial peptides can be used alone or in combination with other antimicrobial, essential oils and polymeric nanoparticles to enhance the shelf life of food. This review presents an overview on different types of antimicrobial peptides, purification techniques, mode of action and application in food preservation. PMID- 27777446 TI - Transformation of food packaging from passive to innovative via nanotechnology: concepts and critiques. AB - In recent decades, there is a global advancement in manufacturing industry due to increased applications of nanotechnology. Food industry also has been tremendously changing from passive packaging to innovative packaging, to cope with global trends, technological advancements, and consumer preferences. Active research is taking place in food industry and other scientific fields to develop innovative packages including smart, intelligent and active food packaging for more effective and efficient packaging materials with balanced environmental issues. However, in food industry the features behind smart packaging are narrowly defined to be distinguished from intelligent packaging as in other scientific fields, where smart materials are under critical investigations. This review presents some scientific concepts and features pertaining innovative food packaging. The review opens new research window in innovative food packaging to cover the existing disparities for further precise research and development of food packaging industry. PMID- 27777447 TI - Plant-based milk alternatives an emerging segment of functional beverages: a review. AB - Plant-based or non-dairy milk alternative is the fast growing segment in newer food product development category of functional and specialty beverage across the globe. Nowadays, cow milk allergy, lactose intolerance, calorie concern and prevalence of hypercholesterolemia, more preference to vegan diets has influenced consumers towards choosing cow milk alternatives. Plant-based milk alternatives are a rising trend, which can serve as an inexpensive alternate to poor economic group of developing countries and in places, where cow's milk supply is insufficient. Though numerous types of innovative food beverages from plant sources are being exploited for cow milk alternative, many of these faces some/any type of technological issues; either related to processing or preservation. Majority of these milk alternatives lack nutritional balance when compared to bovine milk, however they contain functionally active components with health promoting properties which attracts health conscious consumers. In case of legume based milk alternatives, sensory acceptability is a major limiting factor for its wide popularity. New and advanced non-thermal processing technologies such as ultra high temperature treatment, ultra high pressure homogenization, pulsed electric field processing are being researched for tackling the problems related to increase of shelf life, emulsion stability, nutritional completeness and sensory acceptability of the final product. Concerted research efforts are required in coming years in functional beverages segment to prepare tailor-made newer products which are palatable as well as nutritionally adequate. PMID- 27777448 TI - Implementing principles of traditional concentrated grape must fermentation to the production of new generation balsamic vinegars. Starter selection and effectiveness. AB - In an effort to implement principles of traditional concentrated grape must fermentation to the production of new generation balsamic vinegars (BVs), the specific goals of the study were the isolation and molecular identification of the predominant yeasts in concentrated grape must (cv. Xinomavro), their technological characterization and the evaluation of the fermentative aptitude of the selected strains. Tolerance against 5-hydroxymethyl-furfural (HMF) and furfural, acetic acid and glucose concentration was examined by appropriate methods and tests. The enological characteristics studied were acetic acid and H2S production, foaming and flocculation ability and key enzymatic activity. PCR RFLP analysis revealed only the presence of Saccharomyces cerevisiae and Hanseniaspora uvarum among the 14 predominant osmophilic yeast isolates. Tolerance to both HMF and furfural was found strain- and dose-dependent and was suggested as a critical factor in the pre-selection of yeast starters. The most tolerant yeasts to these stress factors, a S. cerevisiae and a non-Saccharomyces strains, showed satisfactory growth in the presence of high glucose and acetic acid content (up to 600 g/L and 2 % w/w, respectively) and desirable enological characteristics. Results from the comparative evaluation of the fermentative aptitude of these strains with a commercial wine strain highlighted that the isolates had glucophilic behaviour and ability to produce desirable amounts of ethanol (100-120 g/kg) in short time (~20 d). The key volatiles useful for varietal discrimination and differentiation between the BVs and the traditional ones were also evaluated. PMID- 27777449 TI - 3-Butenyl isothiocyanate: a hydrolytic product of glucosinolate as a potential cytotoxic agent against human cancer cell lines. AB - The present study envisages the cytotoxic potential of 3-butenyl isothiocyanate isolated from Brassica juncea L. Czern var. Pusa Jaikisan against the human cancer cell lines viz. prostate, bone osteosarcoma, cervical, liver, neuroblastoma and breast cancer. As the compound was observed to be more effective against prostate cancer cell line, therefore, this cell line was further used to study the mechanism of cell death using neutral red assay, reactive oxygen species assay, mitochondrial membrane potential assay, microscopic and cell cycle analysis. The mechanistic analysis indicated that it induced the cell death of prostate cancer cells via apoptosis and hence made it an excellent choice as an effective anticancer compound. PMID- 27777450 TI - Effect of incorporation of Cyperus rotundus L. rhizome powder on quality attributes of minced beef meat. AB - The primary objective of this study was to investigate the biological effectiveness of C. rotundus rhizome powder (CRRP) in improving the quality, storability, and safety of minced beef meat. CRRP was analyzed for its flavonoid and polyphenol content, antioxidants and antimicrobial activity, and its effect on the chemical properties, microbiological and sensory quality of minced beef meat. The results revealed that CRRP had a flavonoid and polyphenol contents of 24.30 mg CE/g and 353.10 mg GAE/g, respectively. The aqueous extract of CRRP showed inhibition zones of 16.3 and 11.7 mm against E. coli and S. aureus, respectively. The CRRP exhibited greater increase in TRPA, chelation of Fe2+ ions, and scavenging of H2O2 with the increase in CRRP extract concentration. Incorporation of various concentration of CRRP in minced beef meat significantly affected the physicochemical properties, microbial load, and sensory quality of the product. The effect was concentration dependent, and the highest level of CRRP (5 %) was more effective in retarding microbial growth and reducing peroxidation, but it negatively affected the sensory quality of the product. Therefore, CRRP at 2.5 % concentration was recommended as a functional additive to preserve minced meat. PMID- 27777451 TI - Effect of removal of phenolic compounds on structural and thermal properties of sunflower protein isolate. AB - The present study evaluated the effect of removal of polyphenols on the structural properties of protein isolates extracted from sunflower seed and kernel. The structural and thermal changes in protein upon phenolic interaction were studied using circular dichroism, differential scanning calorimetry, thermal gravimetric analysis, X-ray diffraction, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and Fourier Transform Infrared (FT-IR) spectroscopy. Presence of phenolic compounds in proteins decreased the ordered structure content with parallel increase in unordered structure content. Denaturation temperature was higher for protein isolates with phenolic compounds while, enthalpy decreased upon phenolic interaction. In the presence of phenolic compounds, higher mass loss was observed upon heating. Crystalinity and crystal size got increased after removal of phenolic compounds. Protein isolates from kernels had higher percentage of crystalinity and crystal size as compared to seed protein isolates. Higher molecular weights were observed for protein isolates with phenolic compounds. Presence of polyphenols reduced the hydrophobicity as well the sulfhydryl content and increased the particle size of proteins. PMID- 27777452 TI - UV-C and hyperoxia abiotic stresses to improve healthiness of carrots: study of combined effects. AB - Phenolic compounds are phytochemicals with high health-promoting properties. Carrot is a vegetable highly worldwide consumed although its phenolic content is low compared to other plant products. The aim of this work was to evaluate changes in phenolic compounds in carrots caused by abiotic stresses. The phenylalanine ammonia-lyase (PAL) activity, phenolic compounds and total antioxidant capacity (TAC) changes during storage up to 72 h at 15 degrees C after wounding (shredding), 9 kJ UV-C m-2 pretreatment and hyperoxia (80 kPa) conditions of carrots were studied. Shredding and hyperoxia storage induced the highest phenolic compounds and TAC enhancements. Accumulation of phenolic compounds in shredded carrots could be structured in the following phases: 1st phase (<24 h): unchanged phenolic compounds levels with minimum PAL activity; 2nd phase (24-48 h): moderate phenolic increases (~600-700 mg CAE kg-1 accumulated in 24 h) concurring with the greatest increase of PAL activity; 3nd phase (48-72 h): high phenolic increases (~1600-2700 mg CAE kg-1, accumulated in 24 h) while a moderate increment of PAL activity was registered. Although UV-C pretreatment of shreds reduced phenolic accumulation, 600 % increments were still registered in those samples stored under hyperoxia conditions for 72 h. However, the contents of chlorogenic acid at 72 h were 1.4-fold higher in irradiated shreds under hyperoxia compared to the same samples under air conditions. PMID- 27777453 TI - Development and quality assessment of carrageenan incorporated low fat chevon patties. AB - The present study was conducted to develop and assess the quality of carrageenan incorporated chevon patties with the objective of reducing fat content. Efficacy of carrageenan as fat replacers (0.3, 0.6 & 0.9 %) was assessed for development of low fat chevon patties. Emulsion stability and cooking yield increased with the increase in levels of carrageenan. Significantly (P < 0.05) lower fat and cholesterol contents and higher moisture and fat retention were observed in formulation with carrageenan. No significant difference in the mineral content in either of the treatment was recorded. Incorporation of fat replacer in chevon patties demonstrated significant effect on all the textural parameters except adhesiveness. Results of color value illustrated that lightness (L*) value differ significantly. Sensory scores were higher or comparable for patties containing 0.6 % carrageenan as compared to control. Hence, carrageenan was observed to be suitable as fat replacer for producing low fat chevon meat patties. PMID- 27777454 TI - Preparation of gluten-free rice spaghetti with soy protein isolate using twin screw extrusion. AB - The objective of this study was to investigate the effect of soy protein isolate on functional properties and consumer acceptance of gluten-free rice spaghetti (GFRS) made from rice flour. Dry-milled high-amylose (Chai Nat 1) rice flour was premixed with dry-milled waxy (RD 6) rice flour at a ratio of 90:10 (w/w) with the soy protein isolate (SPI) concentration varying between 0, 2.5, 5.0, 7.5, 10.0 %, db. The GFRS formulation was processed using a co-rotating twin-screw extruder up to 95 degrees C with a screw speed of 220 rpm, 32 % moisture content, and then dried at 40 degrees C. The GFRS samples were analyzed by differential scanning calorimetry (DSC), X-ray diffraction, scanning electron microscopy (SEM) and texture parameters. Increasing SPI decreased the starch retrogradation of GFRS, whereas the enthalpy change of the amylose-lipid complex increased and crystallinity decreased. SEM revealed that the surface of GFRS containing SPI was much more porous than that of GFRS without SPI. The cooked GFRS containing 5.0 % SPI showed the best eating quality with increased firmness and tensile strength, and decrease stickiness. The GFRS samples were evaluated on the bases of cooking qualities and sensory evaluation. The results showed that the GFRS containing 5.0 % SPI decrease the cooking time from 17.6 to 13.7 min and cooking loss from 25.4 to 17.0 %. Overall acceptability of cooked GFRS containing 5.0 % SPI was the highest among all GFRS samples. PMID- 27777455 TI - Effect of microwave drying and oven drying on the water activity, color, phenolic compounds content and antioxidant activity of coconut husk (Cocos nucifera L.). AB - The coconut (Cocos nucifera L.) husk is basically composed by fiber and pith material and remained under-utilized. This is an important source of phenolic compounds that could be used as functional ingredients. The aim of this study was to determine the effect of: oven-drying (OD) and microwave drying (MD), on the water activity, color, phenolic compound content and antioxidant activity of coconut husk. The OD was performed at 60 degrees C for 12 h and MD was performed at 900 W for 10 min. The total phenolic content (TPC) in fresh coconut husk was 64.2 mg GAE/g dry wt and significant higher than observed after OD and MD of 35.8 and 45.5 mg GAE/g dry wt, respectively. Ten phenols were identified in fresh and dehydrated coconut husks. The husk MD showed an increase in the content of gallic, 4-hydroxybenzoic, ferulic and syringic acids and epicatechin compared with the fresh; while coconut husk OD and MD, showed a decrease in the content of vanillic acid, vanillin, catequin and kaempferol. The antioxidant activity decreased after both OD and MD. However, MD resulted in a better antioxidant activity in husk than OD. MD of husk resulted into better retention of preserved color, TPC and TFC than OD. PMID- 27777456 TI - Emerging technique for healthier frying for production of reduced-fat beetroot (Beta vulgaris) chips. AB - In the present work, the processing variables were optimized to retain betalain compound and their effect on quality attributes (oil content, breaking force and color) of fried beetroot chips. The beetroot slices were fried in lab scale vacuum fryer. Experimental design with temperature (86-153 degrees C), absolute pressure (1.3-9.7 kPa) and frying time (2.6-9.4 min) as independent variables which produced 20 different combinations, were studied using response surface methodology to study the effect of these variables on product responses. Multiple regression equations were obtained to describe the effects of each variable on product responses. Results predicted that optimum frying conditions namely temperature ranging from 101 to 110 degrees C, pressure ranging from 2.9 to 4.4 kPa and time 6.0 min required for preparing beetroot chips with oil content (Y1) <= 15.7, breaking force (Y2) <= 11.53, L* value (Y3) >= 27.94, a* value (Y4) <= 17.87, b* value (Y5) >= 6.46, betalain content (Y6) >= 13.05 (mg/l) and overall acceptability (Y7) >= 7.5. Further results showed that traditionally fried beetroot chips contain 2.6 mg/l betalain, 19.68 N breaking force, 21.1 L*, 15.18 a*, 2.38 b*, overall acceptability 6.0 and 38.41 % oil content. PMID- 27777457 TI - Instant vegetable from osmo-air drying of jimikand (A. campanulatus) in NaCl solution: nutritional, functional, micro-structural and other quality aspects. AB - The aim of this work was to study the effect of osmotic dehydration on the quality of jimikand which can be used as an instant vegetable to get its nutritional and functional benefits. Osmotic dehydration was applied as pre treatment to hot-air drying for increasing palatability, mass transfer improvement and minimizing nutritional losses. To see the effect of osmotic dehydration on various quality parameters, conditions of osmotic dehydration selected were osmotic solution concentrations (5, 10 and 15 % w/w) and temperatures (40, 50 and 60 degrees C) for constant process time (80 min) on the basis of mass transfer analysis. The observed values of hardness, oxalate content and water activity of osmo-dried samples varied from 66.04 +/- 14.5 to 79.12 +/- 14.8 N, 60.0 +/- 0.40 to 69.1 +/- 0.65 mg/100 g, 0.911 +/- 0.001 to 0.826 +/- 0.001, respectively, and found less as compared to fresh sample, i.e. 131.12 +/- 9.5 N, 110.5 +/- 0.78 mg/100 g and 0.990 +/- 0.00 respectively. Rehydration ratio of fresh sample was 3.52 +/- 0.03 and varied from 2.82 +/- 0.06 to 3.57 +/- 0.10 for osmo-dried samples being higher at lower concentrations and temperatures. The best conditions of osmotic dehydration found were 10 % NaCl, 50 degrees C temperature and 80 min duration on the basis of appreciable mass transfer, lowest oxalate content, water activity, better rehydration, textural and sensory quality. The selected osmo-dried sample was better due to low anti-nutritional content, less micro-structural damage and appreciably comparable to fresh hot-air dried in terms of total phenol, antioxidant activity, and other quality parameters. PMID- 27777459 TI - Gluten-free starch noodles from sweet potato with reduced starch digestibility and enhanced protein content. AB - Sweet potato starch (SPS) noodles despite being gluten-free, has low nutritional value as it lacks proteins, minerals, vitamins etc. The objective of this study was to develop gluten-free starch noodles from sweet potato with enhanced protein content through fortification with whey protein concentrate (WPC) and to study the effect of protein fortification and blending SPS with banana (BS), cassava (CS) and mung bean (MBS) starches and annealed cassava starch (ACS) in reducing the starch digestibility. The highest protein retention in cooked noodles was obtained for 20 % WPC fortification, while the lowest starch digestibility was observed for 40 % BS fortified noodles followed by 50 % ACS fortified noodles. The highest resistant starch (RS) retention was for BS and ACS fortified noodles, which also had medium glycemic index of 66.3 (BS) and 67.2 (ACS). High sensory scores were obtained for the BS and 20 % WPC fortified noodles. The study showed that protein and/or BS fortification with SPS could enhance the acceptability as well as functional value of SPS noodles. PMID- 27777458 TI - Antioxidant properties and UPLC-MS/MS profiling of phenolics in jacquemont's hazelnut kernels (Corylus jacquemontii) and its byproducts from western Himalaya. AB - A rapid and selective analytical method was developed to simultaneously quantify seven polyphenolic compounds (gallic acid, catechin, epicatechin, quercetin, kaempferol, syringic acid and p-coumaric acid). 15 phenolics of diverse groups in 80 % ethanolic extracts of jacquemont's hazelnut (Corylus jacquemontii) kernels and its byproducts from western Himalaya using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) were identified. The developed analytical method showed excellent linearity, repeatability and accuracy. Total phenols concentrations were found to be 4446, 1199 and 105 mg gallic acid equivalent (GAE)/Kg of dried extract for jacquemont's hazelnut skin, hard shell and kernels respectively. Antioxidant potential of defatted, raw jacquemont's hazelnut skin, hard shell and kernel extracts assessed by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), 2,2'-diphenyl-1-picrylhydrazyl (DPPH) methods were increased in a dose dependent manner. The IC50 values were observed as 23.12, 51.32, 136.46 and 45.73, 63.65, 169.30 MUg/ml for jacquemont's hazelnut skin, hard shell, kernels by DPPH and ABTS assays, respectively. The high phenolic contents in jacquemont's hazelnut skin contributed towards their free radical scavenging capacities. PMID- 27777460 TI - Transfer of HMW glutenin subunits from Aegilops kotschyi to wheat through radiation hybridization. AB - High molecular weight glutenin subunits (HMWGS) are responsible for dough elasticity and bread making quality of bread wheat. Related wild non-progenitor species, Aegilops kotschyi possesses higher molecular weight x and y glutenin subunits than the bread wheat cultivars. A wheat-Aegilops substitution line with 1U chromosome was used for the transfer of (HMWGS) of 1U to wheat by using pollen radiation hybridization approach. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiling showed different patterns of allelic variations with either the presence or absence of HMWGS, Glu-1A (1, null), Glu-1B (7, 7 + 8, 17 + 18) and Glu-1D (5 + 10, 2 + 12, null). The pollen irradiated wheat-Aegilops derivatives, B-56-1-4-2, B-56-1-4-3, B-14-1 and B-14-2 with Glu1Ux and 1Uy and absence or presence of some Glu-1A and Glu-1B HMWGS showed high micro SDS sedimentation test (MST) values while B-16-1 and B-16-2 had moderate MST values and high protein content. However, B-58-3 with transfer of Glu-1Ux + 1Uy for Glu 1D showed very low MST values indicating that Glu-1Ux + 1Uy enhance MST value only in the presence of Glu1D HMWGS. The transfer/substitution of alien HMW-GS for Glu-1A and or Glu-1B loci only can lead to improved bread making quality of wheat. PMID- 27777461 TI - Consumer acceptance test and some related properties of selected KDML 105 rice mutants. AB - Comparative analysis of the Kao Dawk Mali 105 (KDML 105) premium rice variety, and its six mutants, obtained after low energy ion bombardment, was carried out for sensory and other consumer acceptance related important properties. Consumer acceptance test (n = 200), colour parameters (L*, a*, b*), grain length, and texture parameters of cooked rice and 2-Acetyl-1-pyrroline (2AP), amylose, fat, and protein contents of polished rice were determined. The consumer acceptance test showed that HyKOS3-1 and KDML 105 were equally accepted for every attribute, while HyKOS16 had lower colour liking than KDML 105. Other mutants of KDML 105 were less accepted than KDML 105. Preference mapping (PCA bi-plot) showed that the overall liking of cooked rice was positively correlated to 2AP and fat content and negatively correlated to hardness, cohesiveness, springiness, chewiness, amylose and protein contents. Consumers preferred cooked rice which has good aroma and soft texture. However, only 2AP content might be not enough to explain aroma liking of cooked rice and rice with different texture could be accepted in the same level of KDML 105. PMID- 27777462 TI - Effect of maceration duration on physicochemical characteristics, organic acid, phenolic compounds and antioxidant activity of red wine from Vitis vinifera L. Karaoglan. AB - Effects of different maceration times (5, 10 and 15 days) on composition, phenolic compounds and antioxidant activities of red wines made from the Vitis vinifera L. Karaoglan grown in Malatya were investigated. Maceration duration changed some chemical constituents and color of Karaoglan red wines. A linear relationship was observed between antioxidant activity of wine and maceration duration. Major organic acid was tartaric acid which was at the highest concentration in wine macerated for 10 days. A total of 25 phenolic compounds was determined in wine samples. Within these phenolics; procyanidin B2, trans caftaric acid, gallic acid, trans-caffeic acid, (+) catechin, (-) epicatechin and quercetin-3-O-glucoside were the most abundant phenolics regardless of maceration duration. In general, extended maceration duration resulted in increase in the concentration of phenolic compounds, reflecting the antioxidant activities of wine. In conclusion, the highest concentrations of total and individual phenolic compounds as well as antioxidant activities were found in wines macerated for 15 days. PMID- 27777463 TI - Comparative analysis of mozzarella cheeses fortified with whey protein hydrolysates, diverse in hydrolysis time and concentrations. AB - The objective of the present study was to improve the quality of mozzarella cheese using whey protein concentrates (WPCs) hydrolyzed for varying lengths of time (1 and 3 h). Four types of cheeses were made incorporating hydrolyzed WPCs in milk 3 and 6 % level and evaluated for nutritional, structural, and functional properties during 28 days storage at 4 degrees C. Whey protein hydrolysates (WPHs) incorporation increased protein, lactose, minerals, water-soluble-protein, non-protein-nitrogen. Mozzarella incorporated with WPHs hydrolyzed for 3 h had higher fat contents, favorable meltability and lower browning effect, stretchability, brittleness, springiness, and cohesiveness compared to mozzarella fortified with WPHs hydrolyzed for 1 h. The incorporation of hydrolyzed WPCs significantly influenced rheological and functional characteristics of mozzarella cheese. The cheeses made with hydrolyzed WPCs showed fewer changes in whiteness than control during storage. It was observed that both extent of hydrolysis and levels of WPHs incorporation had significant effect on the characteristics of mozzarella cheeses. PMID- 27777464 TI - Sustainable use of silver warehou (Seriollela punctata): effects of storage, processing conditions and simulated gastrointestinal digestion on selected in vitro bioactivities. AB - Australian underutilised fish species may serve as a potential source of valuable proteins and potent bioactive peptides. This novel research is the first to investigate the effects of storage-processing conditions and an in-vitro simulated gastrointestinal digestion (pepsin-pancreatin) on bioactive peptides' release during storage of fish fillet, derived from Australian silver warehou (Seriolella punctata). In-vitro bioactivities including angiotensin-converting enzyme and trypsin inhibitory and antioxidant activities were analysed. The antioxidant power was evaluated by DPPH free radical scavenging activity, Cu2+ chelating and Fe3+ reducing abilities. Fillets were stored at chilled (4 and 6 degrees C) and freezing (-18 degrees C) temperatures for 7 and 28 days, respectively. Results indicated that during postmortem storage, endogenous enzymes released from fillets an array of polypeptides during storage. The demonstrated physiological activities were further increased during simulated digestion. Bioactivities were greater at 4 degrees C, increasing over 7 days as compared to at 6 and -18 degrees C. An increase by 2 degrees C for chilled temperature was enough to cause significant changes in activities. The crude extracts obtained by pancreatin treatment demonstrated the highest metal chelating activities at 4 degrees C (86.3 +/- 0.1 % on day 7). Physiological potency, especially metal chelating activity, of fillets obtained from silver warehou may be manipulated by storage conditions that would consequently be further enhanced during simulated digestion. PMID- 27777465 TI - Effect of maltodextrin on characteristics and antioxidative activity of spray dried powder of gelatin and gelatin hydrolysate from scales of spotted golden goatfish. AB - Characteristics and antioxidative activity of gelatin and gelatin hydrolysate powders from scale of spotted golden goatfish using maltodextrin as a carrier agent at different ratios [1:0, 2:1, 1:1 and 1:2 (w/w)] were investigated. Gelatin hydrolysates with 40 % degree of hydrolysis exhibited the highest antioxidative activity. With increasing maltodextrin proportions, the resulting powders showed an increase in yields, total sugar content and whiteness with coincidental decrease in [Formula: see text], [Formula: see text]-values and browning intensity. Solubility of gelatin powder increased with increase in maltodextrin proportion. Gelatin powder was spherical with smooth surface of hydrolysate varied, regardless of maltodextrin levels. Gelatin hydrolysate powder form, uniform agglomerates when maltodextrin was incorporated. DPPH and ABTS radical scavenging activities and ferric-reducing antioxidant power of gelatin and gelatin hydrolysate decreased when maltodextrin was used as a carrier agent. Thus, maltodextrin levels directly affected characteristics and antioxidative activity of gelatin and gelatin hydrolysate powders. PMID- 27777466 TI - Identification of peptides, metal binding and lipid peroxidation activities of HPLC fractions of hydrolyzed oat bran proteins. AB - The aim of this study was to evaluate metal binding and antioxidant activities of hydrolyzed oat bran proteins followed by the determination of peptide sequences. Protamex oat bran protein hydrolysates (OBPH) were separated by reverse-phase HPLC into eight peptide fractions (F1-F8) and their abilities to either chelate metals (Fe2+, Ca2+) or prevent the oxidation of lipids were investigated. In the Fe2+ chelation assay, OBPH had significantly (p < 0.05) higher activity (39.7 %) than the best performed fraction F7 (22.8 %). The second most active was F5 with 12.1 % chelating activity and this was higher than the activity of the tripeptide glutathione (5.8 %) used as control. The two most Fe2+ chelating fractions (F5, F7) however had weak calcium binding (0.6-1.0 %) properties at peptide concentration ranging from 0.2 to 1.0 mg/mL. In the lipid peroxidation assay, OBPH and all HPLC fractions prevented the oxidation of linoleic acid. More than 60 peptides mainly derived from globulin and avenin proteins were identified using tandem mass spectrometry. PMID- 27777467 TI - Characterization of swiftlet edible bird nest, a mucin glycoprotein, and its adulterants by Raman microspectroscopy. AB - Edible bird's nest (EBN) is made from the glutinous salivary secretion of highly concentrated mucin glycoprotein by swiftlets (genus Aerodramus or Collocalia) native to the Indo-Pacific region. The unique Raman spectrum of EBN has vibrational lines that can be assigned to peptides and saccharides in the glycoprotein, and it can be used to screen for adulteration. The common edible adulterants classified into two types. Type I adulterants, such as fish bladder, pork skin, karaya gum, coralline seaweed, agar strips, and tremella fungus, were solids which adhered externally on the surface of the EBN cement. They can usually be detected with a microscope based on differences in the surface structure. Type II adulterants were water soluble substances such as saccharides (e.g., glucose, sucrose), polypeptides (e.g., hydrolyzed collagen) and salts (e.g. monosodium glutamate) which can be readily soaked up by the EBN hydrogel when moist and adsorbed internally in the EBN cement matrix forming a composite upon drying, making them difficult to detect visually. The present study showed that Raman microspectroscopy offers a rapid, non-invasive, and label free technique to detect both Type I and II adulterants in EBN. PMID- 27777468 TI - Effect of small chain N acyl homoserine lactone quorum sensing signals on biofilms of food-borne pathogens. AB - Quorum sensing or cell to cell communication which includes inter- and intra cellular communication has been implicated in the production of virulence factor and formation of biofilm in food-borne pathogens. In the present study, the effect of quorum sensing signals on the biofilms of food-borne pathogens has been elucidated. N-butryl homoserine lactone and N-hexanoyl homoserine lactone belonging to acyl homoserine lactone (AHL) family of signaling molecules were investigated for their effect on the biofilm formation (attachment and exopolymeric substance production) in the food-borne pathogens Escherichia coli, Salmonella enterica serovar Typhimurium and Vibrio parahemolyticus. The signaling molecules at a concentration of 1 uM were capable of increasing biofilm formation in all the tested pathogens. There was an increase in the attachment of the bacterial cells and biomass as observed by microtiter plate assay and exopolymeric substances production in the biofilms in presence of the AHLs. Further, it needs to be elucidated if the effect of AHLS on the biofilms of E. coli and S. enterica serovar Typhimurium is SdiA dependent. PMID- 27777469 TI - Comparative study on antioxidant activity of hydrolysates from splendid squid (Loligo formosana) gelatin and protein isolate prepared using protease from hepatopancreas of Pacific white shrimp (Litopenaeus vannamei). AB - Antioxidative activities of splendid squid gelatin hydrolysate (SGH) and squid mantle protein isolate hydrolysate (SMPIH) with different DHs (10-50 %) prepared using crude protease from hepatopancreas of Pacific white shrimp were comparatively studied. At the same DH, SGH had higher FRAP and metal chelating activity and SMPIH showed higher ABTS radical scavenging activities. However, SMPIH had higher ABTS radical scavenging activity than SGH at all DHs tested. SMPIH showed higher DPPH radical scavenging activities than SGH when DHs were up to 30 % DH. However, the former had the lower activity as DHs were 40 and 50 %. ABTS radical scavenging activity of SGH and SMPIH with 50 % DH in gastrointestinal model system increased in the duodenal condition, while SGH showed higher activity in stomach condition than SMPIH. SGH and SMPIH (500, 1000 and 2000 mg/L) could retard lipid oxidation in a lecithin liposome system in a dose dependent manner. Based on Sephadex G-25 column chromatography, the fraction with ABTS radical scavenging activity had MW of 283 and 1381 Da, respectively. Therefore, both hydrolysates from squid gelatin and mantle protein isolate could be used as the alternative natural antioxidants. PMID- 27777470 TI - Effects of salts on the freeze-thaw stability, gel strength and rheological properties of potato starch. AB - The objective of this study was to evaluate the effects of different salts (NaF, NaCl, NaBr, NaI, K2SO4, KCl, KNO3, KSCN, LiCl) on freeze-thaw stability, gel strength and rheological properties of potato starch. Addition of the structure making (salting-out) ions, such as F- and SO42-, decreased freeze-thaw stability and increased gel strength, maximal storage modulus (G') and maximal loss modulus (G") of potato starch, due to a stronger three-dimensional network by promoting the starch retrogradation and inhibiting starch gelatinization. Shear stress versus shear rate of all samples at 25 degrees C was well fitted to the simple power-law model with high determination coefficients (R2 = 0.9863-0.9990). Flow behavior index (n), consistency index (K) and apparent viscosities increased with adding salting-out ions. However, the structure-breaking (salting-in) ions had reverse effects on freeze-thaw stability, gel strength and rheological characteristics of potato starch. The addition of structure-breaking ions, such as Br-, NO3-, I-, SCN-, Na+ and Li+, decreased gel strength, G' and G" values and increased freeze-thaw stability. Salts could significantly influence on the retrogradation of potato starch, generally following the ion order: F- > SO42- > Cl- > Br- > NO3- > I- > SCN- for anions and K+ > Na+ > Li+ for cations, consistent with the Hofmeister series. PMID- 27777471 TI - Minimax Rate-optimal Estimation of High-dimensional Covariance Matrices with Incomplete Data. AB - Missing data occur frequently in a wide range of applications. In this paper, we consider estimation of high-dimensional covariance matrices in the presence of missing observations under a general missing completely at random model in the sense that the missingness is not dependent on the values of the data. Based on incomplete data, estimators for bandable and sparse covariance matrices are proposed and their theoretical and numerical properties are investigated. Minimax rates of convergence are established under the spectral norm loss and the proposed estimators are shown to be rate-optimal under mild regularity conditions. Simulation studies demonstrate that the estimators perform well numerically. The methods are also illustrated through an application to data from four ovarian cancer studies. The key technical tools developed in this paper are of independent interest and potentially useful for a range of related problems in high-dimensional statistical inference with missing data. PMID- 27777472 TI - Pulmonary infection caused by Mycobacterium kansasii: findings on computed tomography of the chest. AB - OBJECTIVE: To describe the main tomography findings in patients diagnosed with pulmonary infection caused by Mycobacterium kansasii. MATERIALS AND METHODS: Retrospective study of computed tomography scans of 19 patients with pulmonary infection by M. kansasii. RESULTS: Of the 19 patients evaluated, 10 (52.6%) were male and 9 (47.4%) were female. The mean age of the patients was 58 years (range, 33-76 years). Computed tomography findings were as follows: architectural distortion, in 17 patients (89.5%); reticular opacities and bronchiectasis, in 16 (84.2%); cavities, in 14 (73.7%); centrilobular nodules, in 13 (68.4%); small consolidations, in 10 (52.6%); atelectasis and large consolidations, in 9 (47.4%); subpleural blebs and emphysema, in 6 (31.6%); and adenopathy, in 1 (5.3%). CONCLUSION: There was a predominance of cavities, as well as of involvement of the small and large airways. The airway disease was characterized by bronchiectasis and bronchiolitis presenting as centrilobular nodules. PMID- 27777473 TI - Changes seen on computed tomography of the chest in mildly symptomatic adult patients with sickle cell disease. AB - OBJECTIVE: To describe and quantify the main changes seen on computed tomography of the chest in mildly symptomatic adult patients with sickle cell disease, as well as to evaluate the radiologist accuracy in determining the type of hemoglobinopathy. MATERIALS AND METHODS: A prospective study involving 44 adult patients with sickle cell disease who underwent inspiration and expiration computed tomography of the chest. The frequency of tomography findings and the extent of involvement are reported. We also calculated radiologist accuracy in determining the type of hemoglobinopathy by analyzing the pulmonary alterations and morphology of the spleen. RESULTS: The changes found on computed tomography scans, in descending order of frequency, were as follows: fibrotic opacities (81.8%); mosaic attenuation (56.8%); architectural distortion (31.8%); cardiomegaly (25.0%); lobar volume reduction (18.2%); and increased caliber of peripheral pulmonary arteries (9.1%). For most of the findings, the involvement was considered mild, five or fewer lung segments being affected. The accuracy in determining the type of hemoglobinopathy (HbSS group versus not HbSS group) was 72.7%. CONCLUSION: In adult patients with sickle cell disease, the main tomography findings reflect fibrotic changes. In addition, computed tomography can be helpful in differentiating among hemoglobinopathies. PMID- 27777474 TI - Magnetic resonance imaging evaluation of meniscoid superior labrum: normal variant or superior labral tear. AB - OBJECTIVE: The objective of this study was to determine the incidence of a "meniscoid" superior labrum. MATERIALS AND METHODS: This was a retrospective analysis of 582 magnetic resonance imaging examinations of shoulders. Of those 582 examinations, 110 were excluded, for a variety of reasons, and the final analysis therefore included 472 cases. Consensus readings were performed by three musculoskeletal radiologists using specific criteria to diagnose meniscoid labra. RESULTS: A meniscoid superior labrum was identified in 48 (10.2%) of the 472 cases evaluated. Arthroscopic proof was available in 21 cases (43.8%). In 10 (47.6%) of those 21 cases, the operative report did not include the mention a superior labral tear, thus suggesting the presence of a meniscoid labrum. In only one of those cases were there specific comments about a mobile superior labrum (i.e., meniscoid labrum). In the remaining 11 (52.4%), surgical correlation demonstrated superior labral tears. CONCLUSION: A meniscoid superior labrum is not an infrequent finding. Depending upon assumptions and the requirement of surgical proof, the prevalence of a meniscoid superior labrum in this study was between 2.1% (surgically proven) and 4.8% (projected). However, superior labral tears are just as common and are often confused with meniscoid labra. PMID- 27777475 TI - Ultrasound evaluation of the morphometric patterns of lymph nodes of the head and neck in young and middle-aged individuals. AB - OBJECTIVE: To show the morphometric patterns of lymph nodes of the head and neck, evaluating their number, shape, dimensions, hilum, and cortex, through the use of ultrasound examination of the neck. MATERIALS AND METHODS: We analyzed 400 right and left lymph nodes in a group of 20 healthy young and middle-aged individuals of both genders. RESULTS: In the ultrasound examination, we observed the following lymph nodes: mastoid; parotid (superficial, extraglandular, and intraglandular); submandibular (preglandular, retroglandular, and intracapsular); submental; and cervical (anterior and posterior). Although some individuals had up to seven lymph nodes in the same region, most had only two to three per region. The smallest lymph node diameter observed was 0.4 cm, and the largest was 2.7 cm. Most lymph nodes showed an elongated or oval shape. Most of the lymph node hila were echogenic, although a few were hyperechoic. However, the cortex was clearly hypoechoic in all of the lymph nodes evaluated. CONCLUSION: Ultrasound examination of healthy individuals allowed the characteristics of the lymph nodes of the head and neck to be observed clearly, which could provide a basis for the analysis of patients with diseases of these lymph nodes. PMID- 27777476 TI - Duplex ultrasound and computed tomography angiography in the follow-up of endovascular abdominal aortic aneurysm repair: a comparative study. AB - OBJECTIVE: To compare duplex ultrasound and computed tomography (CT) angiography in terms of their performance in detecting endoleaks, as well as in determining the diameter of the aneurysm sac, in the postoperative follow-up of endovascular abdominal aortic aneurysm repair. MATERIALS AND METHODS: This was a prospective study involving 30 patients who had undergone endovascular repair of infrarenal aortoiliac aneurysms. Duplex ultrasound and CT angiography were performed simultaneously by independent radiologists. Measurements of the aneurysm sac diameter were assessed, and the presence or absence of endoleaks was determined. RESULTS: The average diameter of the aneurysm sac, as determined by duplex ultrasound and CT angiography was 6.09 +/- 1.95 and 6.27 +/- 2.16 cm, respectively. Pearson's correlation coefficient showing a statistically significant correlation (R = 0.88; p < 0.01). Comparing the duplex ultrasound and CT angiography results regarding the detection of endoleaks, we found that the former had a negative predictive value of 92.59% and a specificity of 96.15%. CONCLUSION: Our results show that there is little variation between the two methods evaluated, and that the choice between the two would have no significant effect on clinical management. Duplex ultrasound could replace CT angiography in the postoperative follow-up of endovascular aneurysm repair of the infrarenal aorta, because it is a low-cost procedure without the potential clinical complications related to the use of iodinated contrast and exposure to radiation. PMID- 27777477 TI - Study of scattered radiation during fluoroscopy in hip surgery. AB - OBJECTIVE: To measure the scattered radiation dose at different positions simulating hip surgery. MATERIALS AND METHODS: We simulated fluoroscopy-assisted hip surgery in order to study the distribution of scattered radiation in the operating room. To simulate the patient, we used a anthropomorphic whole-body phantom, and we used an X-ray-specific detector to quantify the radiation. Radiographs were obtained with a mobile C-arm X-ray system in continuous scan mode, with the tube at 0o (configuration 1) or 90o (configuration 2). The operating parameters employed (voltage, current, and exposure time) were determined by a statistical analysis based on the observation of orthopedic surgical procedures involving the hip. RESULTS: For all measurements, higher exposures were observed in configuration 2. In the measurements obtained as a function of height, the maximum dose rates observed were 1.167 (+/- 0.023) uSv/s and 2.278 (+/- 0.023) uSv/s in configurations 1 and 2, respectively, corresponding to the chest level of health care professionals within the operating room. Proximal to the patient, the maximum values were recorded in the position occupied by the surgeon. CONCLUSION: We can conclude that, in the scenario under study, health care professionals workers are exposed to low levels of radiation, and that those levels can be reduced through the use of personal protective equipment. PMID- 27777478 TI - Clinical and radiological correlations in patients with gestational trophoblastic disease. AB - Gestational trophoblastic disease is an abnormality of pregnancy that encompasses a group of diseases that differ from each other in their propensity for regression, invasion, metastasis, and recurrence. In the past, it was common for patients with molar pregnancy to present with marked symptoms: copious bleeding; theca lutein cysts; uterus larger than appropriate for gestational age; early preeclampsia; hyperemesis gravidarum; and hyperthyroidism. Currently, with early diagnosis made by ultrasound, most patients are diagnosed while the disease is still in the asymptomatic phase. In cases of progression to trophoblastic neoplasia, staging-typically with Doppler flow studies of the pelvis and chest X ray, although occasionally with computed tomography or magnetic resonance imaging is critical to the choice of an appropriate antineoplastic therapy regimen. Because it is an unusual and serious disease that affects women of reproductive age, as well as because its appropriate treatment results in high cure rates, it is crucial that radiologists be familiar with gestational trophoblastic disease, in order to facilitate its early diagnosis and to ensure appropriate follow-up imaging. PMID- 27777479 TI - Acquired portosystemic collaterals: anatomy and imaging. AB - Portosystemic shunts are enlarged vessels that form collateral pathological pathways between the splanchnic circulation and the systemic circulation. Although their causes are multifactorial, portosystemic shunts all have one mechanism in common-increased portal venous pressure, which diverts the blood flow from the gastrointestinal tract to the systemic circulation. Congenital and acquired collateral pathways have both been described in the literature. The aim of this pictorial essay was to discuss the distinct anatomic and imaging features of portosystemic shunts, as well as to provide a robust method of differentiating between acquired portosystemic shunts and similar pathologies, through the use of illustrations and schematic drawings. Imaging of portosystemic shunts provides subclinical markers of increased portal venous pressure. Therefore, radiologists play a crucial role in the identification of portosystemic shunts. Early detection of portosystemic shunts can allow ample time to perform endovascular shunt operations, which can relieve portal hypertension and prevent acute or chronic complications in at-risk patient populations. PMID- 27777480 TI - Abdominal vascular syndromes: characteristic imaging findings. AB - Abdominal vascular syndromes are rare diseases. Although such syndromes vary widely in terms of symptoms and etiologies, certain imaging findings are characteristic. Depending on their etiology, they can be categorized as congenital-including blue rubber bleb nevus syndrome, Klippel-Trenaunay syndrome, and hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)-or compressive-including "nutcracker" syndrome, median arcuate ligament syndrome, Cockett syndrome (also known as May-Thurner syndrome), and superior mesenteric artery syndrome. In this article, we aimed to illustrate imaging findings that are characteristic of these syndromes, through studies conducted at our institution, as well as to perform a brief review of the literature on this topic. PMID- 27777481 TI - Right aortic arch with aberrant left innominate artery arising from Kommerell's diverticulum. AB - We report a case of an uncommon thoracic aorta anomaly-right aortic arch with aberrant left innominate artery arising from Kommerell's diverticulum-that went undiagnosed until adulthood. PMID- 27777483 TI - Anterior cerebral artery aneurysm rupture presenting as hemorrhage in the splenium of the corpus callosum. PMID- 27777482 TI - Hemichorea-hemiballism: the role of imaging in diagnosing an unusual disorder in patients with nonketotic hyperglycemia. PMID- 27777484 TI - Fat necrosis associated with the use of oral anticoagulant therapy: atypical mammographic findings. PMID- 27777485 TI - Intestinal malrotation associated with duodenal obstruction secondary to Ladd's bands. PMID- 27777486 TI - Pulse granuloma: a rare condition mimicking a gastric tumor. PMID- 27777487 TI - Caseous calcification of the mitral annulus: computed tomography features. PMID- 27777488 TI - Aortic arch anomaly in an adult patient: a case of right aortic arch with aberrant left subclavian artery and Kommerell's diverticulum. PMID- 27777489 TI - Rosai-Dorfman disease affecting the nasal cavities and paranasal sinuses. PMID- 27777490 TI - The importance of computed tomography of the chest in cases of suspected infection with nontuberculous mycobacteria (Mycobacterium kansasii). PMID- 27777491 TI - Anatomic variations of the renal arteries, as characterized by computed tomography angiography: rule or exception? Its usefulness in surgical plannning. PMID- 27777492 TI - The Bodymind Model: A platform for studying the mechanisms of change induced by art therapy. AB - This paper introduces the Bodymind model of Art Therapy and delineates the processes through which it has salutary effects on individuals coping with a variety of health related challenges. The goal of this model is to articulate how activation, reorganization, growth and reintegration of the self can emerge from bodymind processes activated by art therapy. It provides a framework for the conduct of research that will test the key theoretical mechanisms through which art therapy benefits clients. We expect this model to be a spring board for discussion, debate and development of the profession of art therapy. Furthermore, we hope readers can use this model to conduct sound mechanistic studies. This paper can inform social scientists and medical professionals on the manner in which art making can contribute to health. PMID- 27777494 TI - Singing together or apart: The effect of competitive and cooperative singing on social bonding within and between sub-groups of a university Fraternity. AB - Singing together seems to facilitate social bonding, but it is unclear whether this is true in all contexts. Here we examine the social bonding outcomes of naturalistic singing behaviour in a European university Fraternity composed of exclusive 'Cliques': recognised sub-groups of 5-20 friends who adopt a special name and identity. Singing occurs frequently in this Fraternity, both 'competitively' (contests between Cliques) and 'cooperatively' (multiple Cliques singing together). Both situations were re-created experimentally in order to explore how competitive and cooperative singing affects feelings of closeness towards others. Participants were assigned to teams of four and were asked to sing together with another team either from the same Clique or from a different Clique. Participants (N = 88) felt significantly closer to teams from different Cliques after singing with them compared to before, regardless of whether they cooperated with (singing loudly together) or competed against (trying to singing louder than) the other team. In contrast, participants reported reduced closeness with other teams from their own Clique after competing with them. These results indicate that group singing can increase closeness to less familiar individuals regardless of whether they share a common motivation, but that singing competitively may reduce closeness within a very tight-knit group. PMID- 27777493 TI - miR-1 Inhibits Cell Growth, Migration, and Invasion by Targeting VEGFA in Osteosarcoma Cells. AB - microRNAs (miRNAs) are small noncoding RNAs and have been shown to play a crucial role in the osteosarcoma (OS) tumorigenesis and progression. VEGFA is a key regulator of angiogenesis and plays an important role in regulation of tumor metastasis. The objective of this study was to determine whether VEGFA was involved in miR-1-mediated suppression of proliferation, migration, and invasion of OS cells. The expression levels of miR-1 were significantly lower in OS tumor tissues than those in adjacent normal tissues and in SAOS-2 and U2OS cell lines compared to a normal osteoblast (NHOst) cell line. VEGFA was upregulated in OS tumor tissues and SAOS-2 and U2OS cell lines. The results of CCK-8 assay and transwell assay showed that miR-1 acted as a tumor suppressor by inhibiting cell proliferation, migration, and invasion in U2OS cells. Dual luciferase reporter assay demonstrated that VEGFA was a direct and functional target gene of miR-1. miR-1 directly inhibits the protein expression of VEGFA via its 3'-UTR. Knockdown of VEGFA by siRNA inhibited proliferation, migration, and invasion of U2OS cells. Our study suggested the potential inhibitory function of miR-1 in OS cell proliferation, migration, and invasion via inhibiting VEGFA. PMID- 27777495 TI - Dancing the Two-Step in Ontario's Long-term Care Sector: More Deterrence-oriented Regulation = Ownership and Management Consolidation. AB - This paper explores shifts in public and private delivery over time through an analysis of Ontario's approach to LTC funding and regulation in relation to other jurisdictions in Canada and abroad. The case of Ontario's long-term care (LTC) policy evolution - from the 1940s until early 2013 -- shows how moving from compliance to deterrence oriented regulation can support consolidation of commercial providers' ownership and increase the likelihood of non-profit and public providers outsourcing their management. PMID- 27777496 TI - Effects of induced orthographic and semantic knowledge on subsequent learning: A test of the partial knowledge hypothesis. AB - Word learning can build the high-quality word representations that support skilled reading and language comprehension. According to the partial knowledge hypothesis, words that are partially known, also known as "frontier words" (Durso & Shore, 1991), may be good targets for instruction precisely because they are already familiar. However, studies investigating this question have produced mixed findings, and individual differences in baseline knowledge have complicated results both within and across studies. We present two studies that took a different approach, controlling both familiarity and the nature of the familiarizing episode. We controlled familiarity with novel words through pre exposure ("pre-familiarization") in isolation, to induce form-based familiarity, or in sentences that provided few clues to meaning, to induce partial semantic knowledge. The number of pre-exposures varied (0, 1, or 4). After the pre familiarization phase, we presented the words in several highly informative sentences to support meaning acquisition. Participants included both adults and typically developing children, ages 9-12. Participants' self-rated familiarity with target words, and their knowledge of the words' meanings and orthography were each measured at baseline, immediately after learning, and one week later. Orthographic and semantic word learning showed contrasting effects of pre familiarization. For orthographic learning, it was the number, rather than the type, of pre-familiarizations that mattered most. By contrast, the number of pre familiarizations had little impact on word semantic learning; further, pre familiarization in low-constraint sentences did not consistently boost subsequent learning. These findings suggest that familiarity with a word prior to instruction does not necessarily improve word-learning outcomes, and they highlight the importance of repeated exposures to high quality contexts for robust word learning. PMID- 27777498 TI - The Role of Endocrine System in the Inflammatory Process. PMID- 27777497 TI - Effects of Glutamate and Aspartate on Serum Antioxidative Enzyme, Sex Hormones, and Genital Inflammation in Boars Challenged with Hydrogen Peroxide. AB - Background. Oxidative stress is associated with infertility. This study was conducted to determine the effects of glutamate and aspartate on serum antioxidative enzymes, sex hormones, and genital inflammation in boars suffering from oxidative stress. Methods. Boars were randomly divided into 4 groups: the nonchallenged control (CON) and H2O2-challenged control (BD) groups were fed a basal diet supplemented with 2% alanine; the other two groups were fed the basal diet supplemented with 2% glutamate (GLU) or 2% aspartate (ASP). The BD, GLU, and ASP groups were injected with hydrogen peroxide (H2O2) on day 15. The CON group was injected with 0.9% sodium chloride solution on the same day. Results. Dietary aspartate decreased the malondialdehyde (MDA) level in serum (P < 0.05) compared with the BD group. Additionally, aspartate maintained serum luteinizing hormone (LH) at a relatively stable level. Moreover, glutamate and aspartate increased transforming growth factor-beta1 (TGF-beta1) and interleukin-10 (IL-10) levels in the epididymis and testis (P < 0.05) compared with the BD group. Conclusion. Both glutamate and aspartate promoted genital mRNA expressions of anti-inflammatory factors after oxidative stress. Aspartate more effectively decreased serum MDA and prevented fluctuations in serum sex hormones after H2O2 challenge than did glutamate. PMID- 27777499 TI - Minilaparoscopy For Inguinal Hernia Repair. AB - BACKGROUND AND OBJECTIVES: Inguinal hernia repair is among the most common procedures performed worldwide and the laparoscopic totally extraperitoneal (TEP) approach is a recognized and effective surgical technique. Although technically advantageous because of the option of no mesh fixation and no need for creation of a peritoneal flap resulting, in less postoperative pain and faster recovery, TEP has not achieved the popularity it deserves, mainly because of its complexity and steep learning curve. Minilaparoscopy was first described in the 1990s and has recently gained significantly from better instrumentation that may increase TEP's effectiveness and acceptance. We performed a prospective study, to analyze the outcomes of minilaparoscopy in pain and operative time when compared to the conventional laparoscopic technique in hernia repair. METHODS: Fifty-eight laparoscopic inguinal hernia repairs were performed: 36 by traditional laparoscopic technique and 22 by minilaparoscopic instruments (mini). A study protocol was applied prospectively for data collection. Variables analyzed were early postoperative pain (at hour 6 after procedure), pain at discharge, use of on-demand analgesics, and operative time. RESULTS: The mini group presented reduced early postoperative pain and operative time. The present study also suggests less postoperative pain at discharge with mini procedures, although this difference was not statistically significant. No difference between the groups regarding on-demand use of analgesics was found. CONCLUSIONS: This study corroborates findings in previously published papers that have shown the feasibility of minilaparoscopy in laparoscopic TEP hernia repair and its benefits regarding postoperative pain, operative time, and aesthetic outcomes. PMID- 27777500 TI - Immediate Continence Rates in RALRP: A Comparison of Three Techniques. AB - BACKGROUND AND OBJECTIVES: Robot-assisted laparoscopic radical prostatectomy (RALRP) is said to provide excellent long-term continence. In this study, we compared the early incontinence outcomes of our patients, who had undergone no reconstruction, posterior reconstruction only, or total anatomic restoration and posterior reconstruction. METHODS: We retrospectively analyzed the patients who underwent RALRP for localized prostate cancer by a single surgeon in our clinic from January 1, 2009-February 1, 2016. Continence was defined as no leakage or use of a safety pad for minimal leakage. The main outcome measure was continence at postoperative week 1 and months 1, 6, and 12. RESULTS: Between 2009 and 2016, 239 patients underwent RALRP for localized prostate disease. Seventy-four patients underwent a standard approach (group 1), 88 had posterior reconstruction (group 2), and 77 had posterior reconstruction with total anatomic restoration (group 3). After 1 week, 24.3% of the patients in group 1 (18/74), 31.8% in group 2 (28/88), and 45.8% in group 3 (33/72) were continent (P = .02). One month after the surgery, continence rates for groups 1, 2, and 3 were 56.7, 67, and 75%, respectively (0.065). After 6 and 12 months, continence rates for groups 1, 2, and 3 were 72.9 and 87.8%, 81.8 and 89.7%, and 84.7 and 91.6%, respectively (P = .178 and .7484). CONCLUSION: Anatomic restoration improves continence rates in the early period after RALRP. Even though other parameters were higher in the total restoration group, immediate continence (at 1 week) was significantly better. PMID- 27777501 TI - Human postmortem lacrimal and submandibular glands stored in RNAlater are suitable for molecular, biochemical, and cell biological studies. AB - PURPOSE: Gene expression and protein analysis studies require high-quality human tissue which is a challenge and difficult to obtain through live human biopsies. Human postmortem lacrimal gland (LG) and submandibular gland (SMG) tissues have the potential to provide an invaluable source for studying the mechanisms involved in LG and SMG dysfunction. Therefore, we aimed to test the suitability of post-mortem LG and SMG for molecular, biochemical, and cell biological studies. METHODS: LG and SMG tissue from healthy donors was collected and immediately placed in RNAlater solution and then shipped overnight at 4 degrees C. After receipt, each gland was divided into three pieces for RNA, protein, and histological analysis, respectively. Total RNA isolated from each LG and SMG was analyzed for RNA integrity using an Agilent Bioanalyzer and reverse transcription PCR (RT-PCR). For histology, tissues were embedded in paraffin and stained with hematoxylin and eosin. For protein analysis, lysates were prepared and processed for sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. RESULTS: When the LG and SMG samples were preserved in RNAlater, the RNA integrity number (RIN) values from the LG and SMG were >7.0 from all three donors, while the RNAs from tissue not preserved in RNAlater were of poorer quality. The gene and/or protein expression of E-cadherin, aquaporin 5, alpha-smooth muscle actin (alpha-SMA), beta-actin, and GAPDH was preserved in all samples. In addition, histological analyses showed normal tubuloacinar structures of all glands with serous and mucous producing acini within lobules interspersed with adipose fat. CONCLUSIONS: In this study, we determined that RNA, protein, and histological sections obtained from postmortem human LG and SMG tissue preserved in RNAlater were of high quality. This would provide a viable source of human LG and SMG tissue suitable for studies of diseases that affect these glands, such as Sjogren's syndrome. PMID- 27777502 TI - Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes. AB - PURPOSE: The CYP1B1 gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in CYP1B1 have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG). METHODS: We examined CYP1B1 in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG negative controls (288) was examined. RESULTS: Recessive pathogenic variants in CYP1B1 were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with CYP1B1. Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the CYP1B1-positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles in CYP1B1 within the POAG cases compared to the controls. CONCLUSIONS: In summary, these data expand the mutational and phenotypic spectra of CYP1B1 to include two novel alleles and additional developmental ocular phenotypes. The contribution of CYP1B1 to POAG is less clear, but loss-of-function variants in CYP1B1, especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG. PMID- 27777503 TI - North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene. AB - PURPOSE: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). METHODS: A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. RESULTS: Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13. The duplication creates a partial copy of CCNC and a complete copy of PRDM13. The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. CONCLUSIONS: The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13, not CCNC, is the cause of NCMD mapped to the MCDR1 locus. PMID- 27777504 TI - Optimizing rejection readouts in a corneal allograft transplantation model. AB - PURPOSE: To evaluate the feasibility of anterior segment spectral domain optic coherence tomography (ASOCT) as rejection readout in a keratoplasty mouse model and to compare ASOCT against the current standard (i.e., a clinical score system). Furthermore, to compare both approaches with respect to intra- and inter individual observer variability and to calculate a critical point that distinguishes between rejection and non-rejection in ASOCT analysis. METHODS: Allogeneic penetrating keratoplasties (PKs) were performed using C3H/He donor mice and BALB/c recipient mice; syngeneic transplantations served as controls using BALB/c donors and recipients. Corneal graft rejection was determined with a clinical score. ASOCT was used to determine the central thickness of the corneal grafts in the same animals. The rejection status was corroborated with histopathological examination. RESULTS: The median survival time (MST) of the corneal allografts in the wild-type BALB/c mice was 12 days. Allogeneic transplantation led to a 100% rejection rate, whereas signs of rejection after syngeneic transplantation appeared in up to 20% of the mice. Central corneal thickness (CCT) determination via customized software revealed a direct correlation with the clinical score. Receiver operating curve (ROC) analysis confirmed CCT as a valid surrogate for rejection. Calculation of the area under the curve (AUC) revealed a value of 0.88 with an optimal cut-off at 267 pixels. CONCLUSIONS: An increase in the CCT during acute allogeneic corneal graft rejection significantly correlated with the clinical surrogate parameter "corneal opacity." ASOCT not only generates source data, but also analysis of the ASOCT data shows lower readout variability and fewer interpreter variations than the clinical score commonly used to define the time point of graft rejection in mice. PMID- 27777505 TI - Plasma endothelin-1 and single nucleotide polymorphisms of endothelin-1 and endothelin type A receptor genes as risk factors for normal tension glaucoma. AB - PURPOSE: The purpose of this study was to determine whether four single nucleotide polymorphisms (SNPs) of endothelin and endothelin receptor type A genes can constitute a risk factor for normal tension glaucoma (NTG) and high tension glaucoma (HTG). METHODS: The study included 160 patients with NTG, 124 patients with HTG, and 165 healthy controls. To analyze the frequency of polymorphic variants of the endothelin EDN gene (K198N) and the endothelin receptor type A gene EDN RA (C1222T, C70G, G231A), DNA was isolated from peripheral blood, and SNP genotyping was performed using the real-time PCR (RT PCR) method. Plasma endothelin (ET) concentrations were detected using an enzyme immunoassay. Endothelin levels were compared with genotype and allele distributions, patients' clinical status, and various risk factors for NTG. RESULTS: There was a significant difference between the patients with NTG and HTG and the controls (p = 0.035, p = 0.008) regarding the genotype of the C1222T and C70G polymorphism. Plasma concentrations of ET did not differ between the NTG and HTG groups, and no significant correlation with intraocular pressure (IOP), best corrected visual acuity (BCVA), and the cup to disc ratio (c/d ratio) was seen in patients with NTG. Plasma endothelin levels showed a noticeably positive correlation with age in the NTG group (R = 0.249, p = 0.042). Higher endothelin levels corresponded to more advanced visual field damage. No statistical difference was observed between variant genotypes of K198N and the ET-1 plasma concentration in patients with NTG, whereas a slightly higher ET level was observed in the patients with HTG with the GT genotype in comparison to those with the GG genotype (p = 0.001). The C1222T polymorphism significantly affected the plasma ET level in patients with NTG. The TT genotype carriers had the highest ET level, and the CC genotype carriers the lowest (p = 0.034). The AA variant genotype of the G231A polymorphism exhibited the highest ET level, while the GG variant genotype represented the lowest level (p = 0.033). No significant differences were observed regarding the endothelin levels and the frequency of notches, peripapillary atrophy, low blood pressure, cold extremities, or migraine in the two groups studied. Slightly lower endothelin plasma levels were observed in patients with optic disc hemorrhages in the NTG group (p = 0.05). CONCLUSIONS: Polymorphic variants of endothelin EDN (K198N) and endothelin receptor type A genes EDN RA (C1222T, C70G, G231A) affected ET plasma concentrations. There was no association between the plasma endothelin levels and the risk factors for NTG. According to these results, plasma endothelin concentrations do not appear to be a marker for NTG. PMID- 27777507 TI - Fully Covered Metallic Stents for the Treatment of Benign Airway Stenosis. AB - Introduction. We herein report our experience with new fully covered self expanding metallic stents in the setting of inoperable recurrent benign tracheobronchial stenosis. Methods. Between May 2010 and July 2014, 21 Micro Tech(r) FC-SEMS (Nanjing Co., Republic of Korea) were placed in our hospital in 16 patients for inoperable, recurrent (after dilatation), and symptomatic benign airway stenosis. Their medical files were retrospectively reviewed in December 2014, with focus on stent's tolerance and durability data. Results. Twenty-one stents were inserted: 13 for posttransplant left main bronchus anastomotic stricture, seven for postintubation tracheal stenosis, and one for postlobectomy anastomotic stricture. Positioning was easy for all of them. Stents were in place for a mean duration of 282 days. The most common complications were granulation tissue development (35%), migration (30%), and sputum retention (15%). Fifty-five % of the stents (11/20) had to be removed because of various complications, without difficulty for all of them. None of the patients had life-threatening complications. Conclusion. Micro-Tech FC-SEMS were easy to position and to remove. While the rate of complications requiring stent removal was significant, no life-threatening complication occurred. Further studies are needed to better define their efficacy and safety in the treatment of benign airway disease. PMID- 27777508 TI - Pathogenic potential and growth kinetics of Muko virus in mice and human-derived cells. AB - BACKGROUND: Ticks have been long known as vectors of various pathogens, some of which can cause high fatality rates among infected individuals. Our enhanced tick surveillance around Nagasaki, Japan, led to the isolation and identification of a new strain of a recently identified Orbivirus, Muko virus (MUV). The orbiviruses have a wide host range, including humans, and is related to a spectrum of clinical outcomes. However, the zoonotic potential of some members of the genus, although reported, were not clearly elucidated. Hence, it is imperative to characterize newly isolated orbiviruses and investigate its ability to endanger public health. METHODS: In this study, we explored the in vivo pathogenicity of a newly isolated MUV strain (MUV-Hay) using a mouse model and demonstrated its growth kinetics in human-derived cells. RESULTS: Our results showed the ability of MUV-Hay to propagate in human neuronal and renal cells with some cytopathic effect. Furthermore, intracerebral inoculation of our new isolate caused high mortality in adult A129 mice. CONCLUSION: Our study provided a first step to experimentally test the hypothesis, that MUV can replicate and produce cytopathic effect in human cells and demonstrate virulence in adult mice. PMID- 27777506 TI - The Influence of Prenatal Exercise on Offspring Health: A Review. AB - Research has continued to demonstrate that exercise during pregnancy is safe. Growing evidence supports that exercise during pregnancy is beneficial for mother and fetus during gestation, with benefits persisting for the child into adulthood. Regardless of income or socioeconomic status, exercise during pregnancy is associated with increased incidence of full-term delivery. Additionally, normalization of birth measures, such as birth weight, occurs when women perform regular exercise throughout gestation. Measures of growth and development further indicate that exercise during pregnancy does not harm and may stimulate healthy growth throughout childhood. Measures of cognition and intelligence demonstrate that exercise during pregnancy causes no harm and may be beneficial. Overall, the benefits of exercise during pregnancy decrease the risk of chronic disease for both mother and child. PMID- 27777509 TI - CINGLE-trial: cochlear implantation for siNGLE-sided deafness, a randomised controlled trial and economic evaluation. AB - BACKGROUND: Individuals with single-sided deafness (SSD) have problems with speech perception in noise, localisation of sounds and with communication and social interaction in their daily life. Current treatment modalities (Contralateral Routing of Sound systems [CROS] and Bone Conduction Devices [BCD]) do not restore binaural hearing. Based on low level of evidence studies, CROS and BCD do not improve speech perception in noise or sound localisation. In contrast, cochlear implantation (CI) may overcome the limitations of CROS and BCD, as binaural input can be restored. Promising results have previously been achieved on speech perception in noise, sound localisation, tinnitus and quality of life. METHODS AND DESIGN: A single-center Randomised Controlled Trial (RCT) was designed to compare all treatment strategies for SSD. One hundred and twenty adult single-sided deaf patients (duration of deafness >3 months and maximum 10 years; pure tone average at 0.5, 1, 2, 4 kHz, deaf ear: threshold equal to or more than 70 dB, better ear: threshold of maximum 30 dB) will be included in this trial and randomised to CI, 'first BCD, then CROS' or 'first CROS, then BCD' groups. After the trial period, patients in the two latter groups may choose with which treatment option they continue. Outcomes of interest are speech perception in noise, sound localization, tinnitus and quality of life. These outcomes will be measured during a baseline visit and at follow up visits, which will take place at 6, 12, 18, 24, 36, 48 and 60 months after onset of treatment. Furthermore, an economic evaluation will be performed and adverse events will be monitored. DISCUSSION: This RCT allows for a comparison between the two current treatment modalities for single-sided deafness and a new promising treatment strategy, CI, on a range of health outcomes: speech perception in noise, sound localization, tinnitus and quality of life. Additionally, we will be able to answer the question if the additional costs of CI are justified by increased benefits, when compared to current treatment strategies. This study will inform health policy makers with regard to reimbursement of CI. TRIAL REGISTRATION: Netherlands Trial Register (www.trialregister.nl): NTR4580. PMID- 27777510 TI - Dealing with professional misconduct by colleagues in home care: a nationwide survey among nursing staff. AB - BACKGROUND: Professional misconduct in healthcare, a (generally) lasting situation in which patients are at risk or actually harmed, can jeopardise the health and well-being of patients and the quality of teamwork. Two types of professional misconduct can be distinguished: misconduct associated with incompetence and that associated with impairment. This study aimed to (1) quantify home-care nursing staff's experiences with actual or possible professional misconduct; (2) provide insight into the difficulty home-care nursing staff experience in reporting suspicions of professional misconduct within the organisation and whether this is related to the individual characteristics of nursing staff; and (3) show which aspects of professional practice home-care nursing staff consider important in preventing professional misconduct. METHODS: A questionnaire survey was held among registered nurses and certified nursing assistants employed in Dutch home-care organisations in 2014. The 259 respondents (60 % response rate; mean age of 51; 95 % female) were members of the Dutch Nursing Staff Panel, a nationwide group of nursing staff members in various healthcare settings. RESULTS: Forty-two percent of the nursing staff in home care noticed or suspected professional misconduct by another healthcare worker during the previous year, predominantly a nursing colleague. Twenty to 52 % of the nursing staff experience difficulty in reporting suspicions of different forms of incompetence or impairment. This is related to educational level (in the case of incompetence), and managerial tasks (both in the case of incompetence and of impairment). Nursing staff consider a positive team climate (75 %), discussing incidents (67 %) and good communication between healthcare workers (57 %) most important in preventing professional misconduct among nursing staff. CONCLUSIONS: Suspicions of professional misconduct by colleagues occur quite frequently among nursing staff. However, many nursing staff members experience difficulty in reporting suspicions of professional misconduct, especially in the case of suspected impairment. Home-care employers and professional associations should eliminate the barriers that nursing staff may encounter when they attempt to raise an issue. Furthermore, advocating a positive team climate within nursing teams, encouraging nursing staff to discuss incidents and facilitating this, and promoting good communication between healthcare workers may be appropriate strategies that help reduce professional misconduct by nursing staff. PMID- 27777511 TI - Expression of microtubule-associated protein TPX2 in human gastric carcinoma and its prognostic significance. AB - BACKGROUND: The molecular mechanisms underlying the development and progression of gastric carcinoma remain poorly understood. The main objective of this study was to investigate the expression level of targeting protein for Xenopus kinesin like protein 2 (TPX2) and its clinical significance in human gastric carcinoma. METHODS: Real-time quantitative polymerase chain reaction (RT-PCR) and western blotting were used to determine the mRNA and protein levels of TPX2 in 20 paired gastric carcinoma tissues and the adjacent normal tissues, and the expression of TPX2 protein in 106 specimens of a gastric carcinoma tissue microarray was determined by immunohistochemistry. The associations of TPX2 expression with the clinicopathological features were analyzed, and the prognosis of gastric carcinoma patients was evaluated. RESULTS: The results showed that the expression of TPX2 mRNA was significantly higher in gastric carcinoma than in the adjacent normal tissues in 20 paired samples. Western blotting analysis revealed that TPX2 protein was differentially increased in 17 of 20 specimens from primary human gastric carcinoma tissues compared with those from adjacent non-tumor tissues. Immunohistochemical staining showed that TPX2 over-expression was significantly associated with advanced age (P = 0.001) and tumor T stage (P = 0.003). In addition, TPX2 was an independent prognostic factor for overall survival (OS) in the multivariate analysis [hazard ratio (HR) 0.001; 95 % confidence interval (CI) 2.626-7.198; P = 0.001]. CONCLUSIONS: TPX2 is up-regulated in gastric carcinoma and is associated with old age and tumor T stage. TPX2 may serve as a good prognostic indicator in patients with gastric carcinoma. PMID- 27777513 TI - Multi-omics analysis on the pathogenicity of Enterobacter cloacae ENHKU01 isolated from sewage outfalls along the Ningbo coastline. AB - BACKGROUND: The acquisition of iron is important for the pathogenicity of bacteria and blood. Three different culture environments (Fe stimulation, blood agar plate and normal plate) were used to stimulate Enterobacter cloacae, and their respective pathogenicities were compared at the proteomic, mRNA and metabolomic levels. METHODS: 2D-DIGE combined with MALDI-TOF-MS/MS, RT-PCR and 1H NMR were used to analyze the differential expression levels of proteins, mRNA and metabolites. RESULTS: A total of 109 proteins were identified by 2D-DIGE and mass spectrometry after pairwise comparison within three culture environments, clustered into 3 classes and 183 functional categories, which were involved in 23 pathways. Based on the 2D-DIGE results, multiple proteins were selected for verification by mRNA expression. These results confirmed that most of the proteins were regulated at the transcriptional level. Thirty-eight metabolites were detected by NMR, which correlated with the differentially expressed proteins under different treatment conditions. CONCLUSIONS: The results show that culture in a blood agar plate and a suitable concentration of iron promote the pathogenicity of E. cloacae and that high iron concentrations may have adverse effects on growth and iron uptake and utilization by E. cloacae. PMID- 27777512 TI - Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer. AB - BACKGROUND: Many long non coding RNAs have been identified as key modulators in cancer development. A lncRNA, DBCCR1-003, derived from the locus of tumor suppressor gene DBCCR1 (deleted in bladder cancer chromosome region 1), has unknown function. In the present study, we explored function and molecular mechanism of DBCCR1-003 in bladder cancer (BC) development. METHODS: We evaluated the expression levels of DBCCR1-003 in tissues and cells with western blot and quantitative real-time polymerase chain reaction. Multiple approaches including chromatin immunoprecipitation assay and RNA immunoprecipitation were used to confirm the direct binding of DBCCR1-003 to DNMT1. The recombinant vector overexpressing DBCCR1-003 was constructed. Cell proliferation assay, colony formation assay and flow cytometric analysis were employed to measure the role of DBCCR1-003 in regulation of cell proliferation, cycle and apoptosis. RESULTS: Firstly we detected the expression of DBCCR1-003, DBCCR1, DNMT1 (DNA methyltransferase 1) and DNA methylation in the promoter of DBCCR1. We found low expression of DBCCR1-003, same as DBCCR1, while high expression of DNMT1 and hypermethylation of DBCCR1 gene promoter in BC tissues and T24 cells line. Further studies revealed that treatment of DNMT inhibitor, 5-aza-2 deoxycytidine(DAC), or overexpression of DBCCR1-003 led to increased DBCCR1 expression by reversion of promoter hypermethylation and DNMT1 binding to DBCCR1 promoter in T24 cells. Importantly, RNA immunoprecipitation (RIP) showed that DBCCR1-003 physically associates with DNMT1. The binding of them was increased with the inhibition of DBCCR1 promoter methylation, indicating that DBCCR1-003 may bind to DNMT1 and prevent DNMT1-mediated the methylation of DBCCR1. Furthermore, overexpression of DBCCR1-003 resulted in significant inhibition of T24 cells growth through the inducing G0/G1 arrest and apoptosis. CONCLUSIONS: Taken together, these findings demonstrated that a novel tumor suppressor DBCCR1 003 regulates the expression of DBCCR1 via binding to DNMT1 and preventing DNMT1 mediated the methylation of DBCCR1 in BC. LncRNA DBCCR1-003 may serve as a novel biomarker and therapeutic target for BC in future cancer clinic. PMID- 27777515 TI - Thirty-Three Years of Dizzy Medical Writing and Editing: A Meta-Analysis and the Hall of Shame. PMID- 27777514 TI - Dynamic denominators: the impact of seasonally varying population numbers on disease incidence estimates. AB - BACKGROUND: Reliable health metrics are crucial for accurately assessing disease burden and planning interventions. Many health indicators are measured through passive surveillance systems and are reliant on accurate estimates of denominators to transform case counts into incidence measures. These denominator estimates generally come from national censuses and use large area growth rates to estimate annual changes. Typically, they do not account for any seasonal fluctuations and thus assume a static denominator population. Many recent studies have highlighted the dynamic nature of human populations through quantitative analyses of mobile phone call data records and a range of other sources, emphasizing seasonal changes. In this study, we use mobile phone data to capture patterns of short-term human population movement and to map dynamism in population densities. METHODS: We show how mobile phone data can be used to measure seasonal changes in health district population numbers, which are used as denominators for calculating district-level disease incidence. Using the example of malaria case reporting in Namibia we use 3.5 years of phone data to investigate the spatial and temporal effects of fluctuations in denominators caused by seasonal mobility on malaria incidence estimates. RESULTS: We show that even in a sparsely populated country with large distances between population centers, such as Namibia, populations are highly dynamic throughout the year. We highlight how seasonal mobility affects malaria incidence estimates, leading to differences of up to 30 % compared to estimates created using static population maps. These differences exhibit clear spatial patterns, with likely overestimation of incidence in the high-prevalence zones in the north of Namibia and underestimation in lower-risk areas when compared to using static populations. CONCLUSION: The results here highlight how health metrics that rely on static estimates of denominators from censuses may differ substantially once mobility and seasonal variations are taken into account. With respect to the setting of malaria in Namibia, the results indicate that Namibia may actually be closer to malaria elimination than previously thought. More broadly, the results highlight how dynamic populations are. In addition to affecting incidence estimates, these changes in population density will also have an impact on allocation of medical resources. Awareness of seasonal movements has the potential to improve the impact of interventions, such as vaccination campaigns or distributions of commodities like bed nets. PMID- 27777516 TI - Caring for the Courageous. PMID- 27777517 TI - Detecting Acute Myocardial Infarction by Diffusion-Weighted versus T2-Weighted Imaging and Myocardial Necrosis Markers. AB - We used a porcine model of acute myocardial infarction to study the signal evolution of ischemic myocardium on diffusion-weighted magnetic resonance images (DWI). Eight Chinese miniature pigs underwent percutaneous left anterior descending or left circumflex coronary artery occlusion for 90 minutes followed by reperfusion, which induced acute myocardial infarction. We used DWI preprocedurally and hourly for 4 hours postprocedurally. We acquired turbo inversion recovery magnitude T2-weighted images (TIRM T2WI) and late gadolinium enhancement images from the DWI slices. We measured the serum myocardial necrosis markers myoglobin, creatine kinase-MB isoenzyme, and cardiac troponin I at the same time points as the magnetic resonance scanning. We used histochemical staining to confirm injury. All images were analyzed qualitatively. Contrast-to noise ratio (the contrast between infarcted and healthy myocardium) and relative signal index were used in quantitative image analysis. We found that DWI identified myocardial signal abnormity early (<4 hr) after acute myocardial infarction and identified the infarct-related high signal more often than did TIRM T2WI: 7 of 8 pigs (87.5%) versus 3 of 8 (37.5%) (P=0.046). Quantitative image analysis yielded a significant difference in contrast-to-noise ratio and relative signal index between infarcted and normal myocardium on DWI. However, within 4 hours after infarction, the serologic myocardial injury markers were not significantly positive. We conclude that DWI can be used to detect myocardial signal abnormalities early after acute myocardial infarction-identifying the infarction earlier than TIRM T2WI and widely used clinical serologic biomarkers. PMID- 27777520 TI - Seventeenth Symposium on Cardiac Arrhythmias In Honor of Dr. Ali Massumi: ? CME Information. PMID- 27777518 TI - Long-Term Follow-Up Study of Temporary Tricuspid Valve Detachment as Approach to VSD Repair without Consequent Tricuspid Dysfunction. AB - Temporary tricuspid valve detachment improves the operative view of certain congenital ventricular septal defects (VSDs), but its long-term effects on tricuspid valve function are still debated. From 2002 through 2012, we performed a prospective study of 68 children (mean age, 1.28 +/- 1.01 yr) who underwent transatrial closure of VSDs following temporary tricuspid valve detachment. Sixty patients had conoventricular and 8 had mid-muscular VSDs. All were in sinus rhythm. Seventeen patients had systemic pulmonary artery pressures. Preoperative echocardiograms showed trivial-to-mild tricuspid regurgitation in 62 patients and tricuspid dysplasia with severe regurgitation in 6 patients. Patients were clinically and echocardiographically monitored at 30 postoperative days, 3 months, 6 months, every 6 months thereafter for the first 2 years, and then once a year. No in-hospital or late death was observed at the median follow-up evaluation of 5.9 years. Mean intensive care unit and hospital stays were 1.6 +/- 1.1 and 7.3 +/- 2.7 days, respectively. Residual small VSDs occurred in 3 patients, and temporary atrioventricular block in one. After VSD repair, 62 patients (91%) had trivial or mild tricuspid regurgitation, and 6 moderate. Five of these last had severe tricuspid regurgitation preoperatively and had undergone additional tricuspid valve repair during the procedure. The grade of residual tricuspid regurgitation remained stable postoperatively, and no tricuspid stenosis was documented. All patients were in New York Heart Association class I at follow-up. Temporary tricuspid valve detachment is a simple and useful method for a complete visualization of certain VSDs without incurring substantial tricuspid dysfunction. PMID- 27777519 TI - Incidence, Predictors, and Impact of Postoperative Atrial Fibrillation after Coronary Artery Bypass Grafting in Military Veterans. AB - Little is known about the frequency and clinical implications of postoperative atrial fibrillation in military veterans who undergo coronary artery bypass grafting (CABG). We examined long-term survival data, clinical outcomes, and associated risk factors in this population. We retrospectively reviewed baseline, intraoperative, and postoperative data from 1,248 consecutive patients with similar baseline risk profiles who underwent primary isolated CABG at a Veterans Affairs hospital from October 2006 through March 2013. Multivariable logistic regression identified predictors of postoperative atrial fibrillation. Kaplan Meier analysis was used to evaluate long-term survival (the primary outcome measure), morbidity, and length of hospital stay. Postoperative atrial fibrillation occurred in 215 patients (17.2%). Independent predictors of this sequela were age >=65 years (odds ratios [95% confidence intervals], 1.7 [1.3 2.4] for patients of age 65-75 yr and 2.6 [1.4-4.8] for patients >75 yr) and body mass index >=30 kg/m2 (2.0 [1.2-3.2]). Length of stay was longer for patients with postoperative atrial fibrillation than for those without (12.7 +/- 6.6 vs 10.3 +/- 8.9 d; P <=0.0001), and the respective 30-day mortality rate was higher (1.9% vs 0.4%; P=0.014). Seven-year survival rates did not differ significantly. Older and obese patients are particularly at risk of postoperative atrial fibrillation after CABG. Patients who develop the sequela have longer hospital stays than, but similar long-term survival rates to, patients who do not. PMID- 27777521 TI - Introduction to the Seventeenth Symposium on Cardiac Arrhythmias: Words in Honor of Dr. Ali Massumi. PMID- 27777522 TI - Catheter Ablation of Ventricular Tachycardia: Moving Beyond Palliation? PMID- 27777524 TI - Update on Atrial Fibrillation. PMID- 27777523 TI - Electrophysiology Updates in Adult Congenital Heart Disease. PMID- 27777525 TI - Pacemaker Troubleshooting: Common Clinical Scenarios. PMID- 27777527 TI - CME Assessment Questions. PMID- 27777526 TI - What's New in Anticoagulation. PMID- 27777528 TI - Staged High-Risk Percutaneous Coronary Intervention with Impella Support after On Pump Transcatheter Aortic Valve Replacement. AB - The management of concomitant obstructive coronary artery disease and severe aortic stenosis in poor surgical candidates is an evolving topic. Although the typical current practice is to perform percutaneous revascularization before transcatheter aortic valve replacement (TAVR), some data have emerged regarding revascularization after performing TAVR. We present the case of a 90-year-old man with multivessel coronary artery disease who was at prohibitive risk for surgical aortic valve replacement. We first performed TAVR with use of hemodynamic support, then Impella-assisted multivessel percutaneous coronary intervention on the patient's unprotected left main coronary artery. We describe this complex case and review the medical literature on percutaneous coronary intervention after TAVR. PMID- 27777529 TI - Repair of Multiple Subclavian and Axillary Artery Aneurysms in a 58-Year-Old Man with Marfan Syndrome. AB - Dilation of the ascending aorta and aortic dissections are often seen in Marfan syndrome; however, true aneurysms of the subclavian and axillary arteries rarely seem to develop in patients who have this disease. We present the case of a 58 year-old man with Marfan syndrome who had undergone a Bentall procedure and thoracoabdominal aortic repair for an aortic dissection and who later developed multiple aneurysmal dilations of his right subclavian and axillary arteries. The aneurysms were successfully repaired by means of a surgical bypass technique in which a Dacron graft was placed between the carotid and brachial arteries. We also discuss our strategy for determining the optimal surgical approach in these patients. PMID- 27777530 TI - Venous Myocardial Infarction in an Infant with Obstructed Totally Anomalous Pulmonary Venous Drainage and Coronary Sinus Ostial Atresia. AB - We report a rare causal association between obstructed supracardiac totally anomalous pulmonary venous drainage and coronary sinus ostial atresia. Our 12 week-old patient developed venous myocardial infarction secondary to coronary venous hypertension because her sole route of coronary venous drainage was obstructed. She recovered after the obstruction was relieved by balloon dilation. Surgical repair then included anastomosis of the pulmonary venous confluence to the left atrium, ligation of the vertical vein, and unroofing of the coronary sinus. Coronary sinus ostial atresia is rarely diagnosed before autopsy. PMID- 27777531 TI - Contained Rupture of Sinus of Valsalva Aneurysm in a 64-Year-Old Man. AB - We report a contained rupture of a right coronary sinus of Valsalva aneurysm, in which repair resulted in symptomatic improvement. Patients often present with symptoms secondary to rupture of the sinus of Valsalva aneurysm into one of the cardiac chambers, or secondary to the compression of adjacent structures. Whereas sinus of Valsalva aneurysms and their rupture are well reported in the literature, contained ruptures have been described only rarely. In those cases, symptoms often arose from compression of adjacent structures. Although transesophageal echocardiography is considered to be the diagnostic method of choice, cardiac magnetic resonance imaging and computed tomography can be equally helpful in establishing the diagnosis and delineating the lesion. Diagnosis and prompt repair in our 64-year-old patient resulted in the rapid resolution of his symptoms. PMID- 27777532 TI - Asymptomatic Interrupted Aortic Arch, Severe Tricuspid Regurgitation, and Bicuspid Aortic Valve in a 76-Year-Old Woman. AB - Interrupted aortic arch is a rare congenital abnormality with a high infancy mortality rate. The principal finding is loss of luminal continuity between the ascending and descending portions of the aorta. Because of the high mortality rate in infancy, interrupted aortic arch is very rare among adults. In this report, we describe the case of a 76-year-old woman with asymptomatic interrupted aortic arch, severe tricuspid regurgitation, and bicuspid aortic valve. To our knowledge, she is the oldest patient ever reported with this possibly unique combination of pathologic conditions. In addition to reporting her case, we review the relevant medical literature. PMID- 27777533 TI - Delayed-Onset Left Main Coronary Artery Obstruction More than 24 Hours after Balloon-Expandable Transcatheter Aortic Valve Replacement. AB - Coronary obstruction during or after transcatheter aortic valve replacement is a rare and catastrophic sequela that occurs most frequently just after valve implantation. Even rarer is the delayed clinical presentation, in some few patients, of coronary obstruction on the day after self-expandable valve implantation. Here we describe a case of balloon-expandable (not self-expandable) transcatheter aortic valve replacement, followed by partial obstruction of the left main coronary artery on the day after that procedure in a 93-year-old man, despite normal left ventricular contraction just after valve implantation. Visual evaluation of the echocardiogram for left ventricular wall motion was not sufficient, by itself, to achieve early diagnosis of the obstruction. We performed emergency percutaneous coronary intervention. Ninety days after the procedure, the patient was in New York Heart Association functional class I. PMID- 27777534 TI - Long-Term Survival on Medical Therapy Alone after Blunt-Trauma Aortic Regurgitation: Report of a New Case with Summary of 95 Others. AB - Aortic regurgitation resulting from blunt chest trauma has been reported only 95 times, to our knowledge. The noncoronary and right coronary cusps are the cardiac structures most often injured. Although the aortic leaflets can appear to be undamaged after nonpenetrating trauma, they can have pathologic abnormalities and insufficient function. Some cases of posttraumatic aortic regurgitation progress slowly. Aortic valve replacement is the optimal treatment. We present the case of a then-62-year-old man who has lived more than 5 years after blunt-trauma aortic regurgitation. His is the only case of long-term survival on medical therapy alone among the 96 cases summarized in this report. PMID- 27777536 TI - Ewing Sarcoma in the Right Ventricle. AB - Ewing sarcoma is the second most prevalent malignant primary bone tumor but constitutes only a small proportion of cardiac metastases. We present a case of asymptomatic Ewing sarcoma metastatic to the right ventricle. A 36-year-old man presented for evaluation and resection of a pedunculated right ventricular cardiac tumor. Three years before, he had been diagnosed with translocation negative Ewing sarcoma, for which he had undergone chemotherapy and amputation of the left leg below the knee. We resected the right ventricular tumor. Analysis of the resected mass supported the diagnosis of metastatic Ewing sarcoma. Postoperative transthoracic echocardiograms showed normal biventricular size and function. One year later, the patient had no recurrence of the sarcoma. In addition to discussing this case, we review the relevant medical literature. PMID- 27777535 TI - Open Conversion after Aortic Endograft Infection Caused by Colistin-Resistant, Carbapenemase-Producing Klebsiella pneumoniae. AB - A 62-year-old man presented with fever, abdominal pain, and malaise 13 months after emergency endovascular aortic repair. Computed tomographic angiograms showed a periprosthetic fluid and gas collection, so infection was diagnosed. Open conversion was performed, involving endograft explantation and in situ aortic reconstruction. Cultures and the explanted prosthesis were positive for carbapenemase-producing Klebsiella pneumoniae, resistant to colistin. Because of the sparse data on endograft infections caused by this pathogen, we placed the patient on an empiric double-carbapenem regimen for 4 weeks. Symptomatic recovery occurred after 21 days. On the 30th day, we deployed a stent to treat a new pseudoaneurysm. Three years later, the patient had no signs of persistent or recurrent infection. We think that this is the first report of aortic endograft infection caused by colistin-resistant, carbapenemase-producing K. pneumoniae. PMID- 27777537 TI - Giant Cardiac Lipoma: Refined Hypothesis Proposes Invagination from Extracardiac to Intracardiac Sites. AB - Cardiac lipomas are rare and usually present as benign, encapsulated masses outside the heart; however, they can also be found within the atria. No single theory-including molecular genetic mutation-adequately explains why this occurs. Extensive career experience and broadened knowledge in embryology and cardiac physiology have helped us to develop a hypothesis based on invagination of extracardiac tumors. This report describes a vexing case of a giant right atrial lipoma, from 1985, in which the diagnosis was made incidentally during management of a patient's acute limb ischemia. In addition, we discuss the imaging and treatment of cardiac lipoma. PMID- 27777538 TI - To Pace or Not to Pace? PMID- 27777539 TI - SPECT Myocardial Perfusion Imaging in the Diagnosis of Apical Hypertrophic Cardiomyopathy. PMID- 27777540 TI - Giant Left Atrium Causing Dysphagia. PMID- 27777541 TI - Evidence inconclusive - comment on article by Schoenfeld et al. AB - This article comments on the study by Schoenfeld, et al. entitled "The effect of protein timing on muscle strength and hypertrophy: a meta-analysis" and discusses how the methodology led to inconclusive results. PMID- 27777542 TI - Gender differences and access to a sports dietitian influence dietary habits of collegiate athletes. AB - BACKGROUND: Limited research exists on the effect of a sports dietitian (SD) on athletes' dietary habits and nutrient periodization, which is the deliberate manipulation of macronutrient intake to match training goals. Further, the difference in dietary habits between men and women collegiate athletes has been understudied. A survey questionnaire examining dietary habits and practices was administered to athletes at two universities that employed a full time SD. Not all athletes used the SD as their primary source for nutritional guidance. The purposes were to examine the effect of a SD as a primary source of nutrition information, and the effect of gender on dietary habits in collegiate athletes. METHODS: Three hundred eighty-three women (n = 240) and men (n = 143) student athletes (mean +/- SD: age = 19.7 +/- 1.4 years) from 10 collegiate sports took a 15-min survey consisting of questions on dietary habits and practices. Topics queried included eating habits, breakfast habits, hydration habits, nutritional supplementation use, pre-workout nutrition, post-workout nutrition, nutrition during team trips, and nutrient timing. Data were sorted by the athlete's source of nutritional information (i.e., sport dietitian, other). Data analysis consisted of descriptive statistics and 2-way Pearson X2 analyses (p <= 0.10). RESULTS: When a SD was indicated as the primary nutrition information source, athletes appeared to have a greater understanding of nutrient periodization (47.12 % vs. 32.85 %), were more likely to have school-provided boxed meals while on team trips (21.29 % vs. 6.77 %), and also less likely to consume fast food while on team trips (9.90 % vs. 19.55 %). Men athletes consumed fast food or restaurant meals more frequently, had higher weekly and more frequent alcohol intake during the competitive season. Women athletes were more likely to prepare meals, eat breakfast 7 days a week, and have school-provided boxed meals. CONCLUSIONS: Positive effects on dietary habits were observed when a SD was the primary nutrition information source. Practitioners should be aware of the gender differences in alcohol intake, fast food consumption, and knowledge of nutrient periodization. Collegiate athletes and athletic staff members could benefit from SD access to safeguard against dietary habits detrimental to performance. PMID- 27777543 TI - ? AB - Hand burns in children are common and may lead to debilitating sequelae. Therefore, full functional restoration of the hand is the goal of treatment. To assess the epidemiological, clinical and development aspects of the burns, we conducted a retrospective study over 4 years, from January 2011 to January 2015. It evaluated 313 children suffering from burns and treated at the National Burn and Plastic Surgery Unit of Ibn Richd Teaching Hospital in Casablanca. Most patients were aged 3-6 years (70%), with a slight male predominance. Scalds accounted for 62% of the causes of burns, flames 33% and electricity 4.5%. Chemical and contact-related burns were anecdotal (1 case of each). Seventy-two per cent of the patients had partial thickness burns, which healed spontaneously. Awareness of and education on these accidents should be part of the school curriculum in order to reduce the incidence of burns in childhood. PMID- 27777544 TI - Qualitative analysis of emergency department reports applied to a pilot project for the prevention of pediatric burns. AB - Accidents and burns are a major problem in Italy and in industrialized countries, due to the consequences they have on health, especially in children aged 0-4 years. In Italy, about 400 people die each year from burns, with over 70% of these occurring in the home. In the European Union, burns are one of the top five causes of death from accidents, accounting for 3% of all deaths from accidents and violence in those age groups. One percent of all deaths in children are due to burns. In this paper, we illustrate the results of qualitative analysis, conducted according to the methodology of content analysis, on narratives included in the anamnesis of clinical papers at the ED in 738 cases of burns in children (0-14 years) observed in a sample of Emergency Departments in the years 2005-2009. The results of content analysis show that the most frequent mechanism that leads to burns is contact with hot liquids and heating surfaces. Much of preventive action should be directed at controlling the child. The accidental event descriptions for the younger age group (0-4 years) reveal an unequivocal responsibility of the parents. The qualitative analysis of narratives was carried out to produce scientific evidence to identify the more frequent and severe burn accidents for specific target/age groups and to establish specific preventive measures. The study of qualitative analysis of burns observed at the ED was introductory to the pilot project PRIUS (Preventing burns among school-aged children). The objective of PRIUS is to increase awareness of the risks of burns in children and adults through a learning path tailored towards their prevention, and the promotion of appropriate standards of personal safe behaviour and first aid actions. PMID- 27777545 TI - Childhood burns: an analysis of 124 admissions in the Gaza Strip. AB - Burns are a serious public health problem among paediatrics. Little is known about the epidemiological profile and outcomes of hospitalized paediatric burns in the Gaza Strip. A cross-sectional retrospective review was conducted of medical records of patients aged 15 years and below, admitted to the Al Alamy burn centre in the Al Shifa Medical Complex from 30 June, 2013 to 01 July, 2014. There were 189 admissions; 124 (65.6%) of them were below 15 years, their mean age +/- SD being 4.02 +/- 2.85 years. 72 of these cases (58.1%) were males, giving a male to female ratio of 1.6:1. 89.5% of the injuries were accidents and 96% were home-located. Scalds, which were a common cause of burns, represented 83.9% of cases. Mean TBSA was 10.72 +/- 8.15%: half of the patients (50.8%) sustained second-degree burns, while 34.7% were a mix of second- and third degree. Mean length of hospital stay was 10.23 +/- 10.60 days. Only two children died during the study period, giving a case fatality rate and total mortality rate of 1.6% and 1.0% respectively. In conclusion, there is a need to focus on home safety and parents' education as a means of reducing childhood burns. PMID- 27777546 TI - Pre-burn centre management of the airway in patients with face burns. AB - Face burns expose patients to a higher respiratory risk, and early prophylactic intubation before they enter the burn unit might be life-saving. However, unnecessary intubation may compromise their clinical evolution. Hence, the decision to perform pre-burn centre endotracheal intubation remains a clinical challenge. A retrospective study was developed to characterize the experience of the tertiary burn unit of the Hospital da Prelada with face burn patients arriving endotracheally-intubated between January 2009 and September 2013. Specific goals included assessment of whether these intubations were clinically appropriate and if these procedures determined significant changes in clinical course and outcome. A total of 136 patients were admitted to our burn centre with facial burns. 38.2% (n=52) of them arrived endotracheally-intubated, with 75% (n=39) intubated at the scene of the burn injury and 25% (n=13) in the emergency room because of the suspicion of smoke inhalation injury. In only 23% of the cases (n=12) was the lesion confirmed by bronchoscopy. The overall mortality rate was 12.5% (n=17): 3.6% (n=3) were patients who had not been subjected to pre-burn centre intubation, and 27% (n=14) were in the group of patients arriving intubated. A face burn is a warning sign of a possible upper airway injury, and pre-burn centre prophylactic intubation might be life-saving. However, unnecessary intubation may impair clinical evolution. Therefore, it is imperative that updated practice guidelines for pre-burn centre airway management are adhered to, and that these guidelines are subject to revision in order to improve airway management in burn patients. PMID- 27777547 TI - Minimally invasive burn care: a review of seven clinical studies of rapid and selective debridement using a bromelain-based debriding enzyme (Nexobrid(r)). AB - Current surgical and non-surgical eschar removal-debridement techniques are invasive or ineffective. A bromelainbased rapid and selective enzymatic debriding agent was developed to overcome these disadvantages and compared with the standard of care (SOC). The safety and efficacy of a novel Debriding Gel Dressing (DGD) was determined in patients with deep partial and full thickness burns covering up to 67% total body surface area (TBSA). This review summarizes data from seven studies, four of which were randomized clinical trials that included a SOC or control vehicle. DGD eschar debridement efficacy was >90% in all studies, comparable to the SOC and significantly greater than the control vehicle. The total area excised was less in patients treated with DGD compared with the control vehicle (22.9% vs. 73.2%, P<0.001) or the surgical/non-surgical SOC (50.5%, P=0.006). The incidence of surgical debridement in patients treated with DGD was lower than the SOC (40/163 [24.5%] vs. 119/170 [70.0%], P0.001). Less autografting was used in all studies. Long-term scar quality and function were similar in DGD- and SOCtreated. DGD is a safe and effective method of burn debridement that offers an alternative to surgical and non-surgical SOC. PMID- 27777548 TI - ? AB - Le crush syndrome se definit comme l'ensemble des manifestations locales et generales secondaires a une rhabdomyolyse traumatique avec ischemie de grosses masses musculaires par compression prolongee, a l'origine d'un syndrome compartimental ou syndrome des loges. Rarement isole, il peut passer inapercu dans les 24 a 48 premieres heures de la phase aigue d'un traumatisme severe quand les principales preoccupations medicales sont la sauvegarde des fonctions vitales. La souffrance musculaire liee au syndrome compartimental entraine la liberation de myoglobine dans la circulation generale. La precipitation de la myoglobine dans les tubules renaux est un facteur de tubulopathie, s'ajoutant a l'atteinte ischemique eventuelle, concomitante du traumatisme initial. Il s'ensuit une insuffisance renale aigue avec, entre autres, acidose et hyperkaliemie. Le crush syndrome constitue une urgence medico-chirurgicale, recurrente et d'actualite lors des catastrophes, mettant en exergue tous les problemes de prise en charge de ce syndrome. Le remplissage precoce et important, vise a restaurer et maintenir une normovolemie et un debit urinaire de 1 a 2 ml/kg/h, en s'aidant au besoin de diuretiques et de bicarbonate afin d'eviter l'emission d'urines acides, dans le but d'eviter la precipitation de myoglobine et l'apparition de l'insuffisance renale. Si celle-ci survient, l'usage precoce de l'Epuration Extra Renale (EER " prophylactique ") peut permettre une realimentation rapide, adaptee au traumatisme initial ou de necessite en vue d'une alimentation equilibree. La levee chirurgicale (aponevrotomie) de la compression musculo-vasculo-nerveuse est une urgence vitale pour le membre concerne. Le syndrome de revascularisation lors de la decompression (par levee de garrot ou post chirurgicale) peut entrainer un arret cardiaque irreversible par hyperkaliemie sur terrain hypovolemique et choque. PMID- 27777550 TI - Benefits of an outreach education coordinator: a burn center's experience. AB - Education of first responders and referring medical professionals is considered vital to high-quality burn care. Prior to 1999, the community education program at The Burn Center of MedStar Washington Hospital Center (MWHC) was staffed by ICU nurses who volunteered their time. As the program became more popular in the mid-1990s, the requests for lectures exceeded the capacity of a volunteer program. A request to hospital administration for a full-time education coordinator position was rejected in the climate of budget cut-backs and declining reimbursement. A business-oriented proposal, ultimately accepted, promised an increase in admissions, an improved payor mix, and an annual review of data to demonstrate the cost/benefit advantage. To advertise the creation of the coordinator position and education programs, letters were mailed to local fire departments, nursing schools and emergency departments. The response was positive, and, with a full-time coordinator, the requests were accommodated in a timely manner. Community education programs increased almost four-fold. Average annual admissions increased initially from 292 to 374 and have continued to increase, rising to 812 in fiscal year 2008. As expected, the average percent total body surface area burns decreased (from 10.8% to 6.9%), reflecting increased referral of smaller burns and, inferentially and per analysis, an improved payor mix. Most impressive was the increase in charitable donations, from an annual average of $27,500 before the position was created to an average of $183,000 annually thereafter. From this experience as well as the experience discovered by a national survey, there are desirable side effects of a full-time community burn education program coordinator, and the cost for The Burn Center at MWHC has been more than balanced by the benefits. PMID- 27777549 TI - Burn injuries and soft tissue traumas complicated by mucormycosis infection: a report of six cases and review of the literature. AB - Mucor fungus infection is a rare opportunistic infection, rapidly progressive and often fatal in immunocompromised patients, or in patients with chronic debilitating diseases. We report six cases of trauma patients with mucormycosis. Three had severe thermal burns, one of them with a medical history of diabetes mellitus. The other three patients suffered from severe soft tissue injuries caused by traffic accidents. In all cases there had been spontaneous exposure and contact of the wounds with soil. During hospitalization, fungi cultures and/or biopsies of all wounds were performed and all resulted positive. The patients were treated with Amphotericin B (AmB) and surgical debridement. Two of them died and the other four were fully healed and discharged. Mucormycosis should be considered in any case of aggressive skin tissue necrosis with a history of soiled wounds. We suggest that mucormycosis is treated by intravenous and local administration of AmB, extensive and repeated debridement and cautious coverage of the wound. The plastic surgeon must wait for negative swab cultures and biopsies before covering the defects with skin grafts or flaps. Reconstruction may be challenging, depending on the extent, depth, location and special indications of the affected site and the donor site availability. PMID- 27777551 TI - ? AB - Chaque annee, le congres de la SFB est l'occasion d'une mise au point sur un theme (" table ronde ".) Celui choisi en 2015 etait la nutrition. Huit orateurs se sont succedes, faisant le point sur les donnees actuelles de la science, les pratiques dans les centres, et les recommandations actuelles, datant de 2013. Cet article se propose de diffuser les interventions. PMID- 27777553 TI - ? PMID- 27777552 TI - Financial burden of burn injuries in iran: a report from the burn registry program. AB - Understanding the cost of burn treatment is very important for patients, their families, governmental authorities and insurance companies. It alleviates patient and familial stress, provides a framework for better use of resources, and facilitates better performance between burn centers. Hospital burn costs can provide a basis for authorities to budget for acute burn treatment, for further management of chronic complications, and for planning prevention and public educational programs in Iran. To identify costs we used data from our burn registry program. Over the two-year assessment period, we treated roughly 28,700 burn patients, 1,721 of whom were admitted, with a mortality rate of 5.9%. The male to female ratio was 1.7:1 (63% male; 37% female). Flame burns were most frequent (49.8%) followed by scalds (35.7%). Mean hospital stay was 14.41 days (range 0-64 days). Mean TBSA was 17.39%. Skin grafts were carried out in 65.4% of the patients, with a mean of 5.2 surgeries per patient. The total cost of all patient admissions over the two years was US$ 4,835,000. The maximum treatment cost for one patient was US$ 91,000. The mean cost per patient was US$ 2,810 (29,500,000 Rials). The mean cost for each percent of burn was US$ 162. The mean cost for a one-day stay in hospital was US$ 195. The mean cost of each operation was US$ 540. Patients who contracted infections endured longer hospital stays, meaning increased costs of US$ 195 per day. With comparable outcome and results, the cost of burn treatment in Iran is cheaper than in the US and Europe. PMID- 27777554 TI - Whole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System. AB - The basal forebrain cholinergic system (BFCS) robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum, central amygdala, paraventricular nucleus of hypothalamus, dorsal raphe, and parabrachial nucleus. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal-hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function. PMID- 27777555 TI - The Predictive Processing Paradigm Has Roots in Kant. AB - Predictive processing (PP) is a paradigm in computational and cognitive neuroscience that has recently attracted significant attention across domains, including psychology, robotics, artificial intelligence and philosophy. It is often regarded as a fresh and possibly revolutionary paradigm shift, yet a handful of authors have remarked that aspects of PP seem reminiscent of the work of 18th century philosopher Immanuel Kant. To date there have not been any substantive discussions of how exactly PP links back to Kant. In this article, I argue that several core aspects of PP were anticipated by Kant (1996/1787) in his works on perception and cognition. Themes from Kant active in PP include: (1) the emphasis on "top-down" generation of percepts; (2) the role of "hyperpriors"; (3) the general function of "generative models"; (4) the process of "analysis-by synthesis"; and (5) the crucial role of imagination in perception. In addition to these, I also point out that PP echoes Kant's general project in that it aims to explain how minds track causal structure in the world using only sensory data, and that it uses a reverse-engineer or "top-down" method of analysis. I then locate a possible source of Kant's influence on PP by tracing the paradigm back to Hermann von Helmholtz, who saw himself as providing a scientific implementation of Kant's conclusions. I conclude by arguing that PP should not be regarded as a new paradigm, but is more appropriately understood as the latest incarnation of an approach to perception and cognition initiated by Kant and refined by Helmholtz. PMID- 27777558 TI - Pre-Activation Negativity (PrAN) in Brain Potentials to Unfolding Words. AB - We describe an event-related potential (ERP) effect termed the "pre-activation negativity" (PrAN), which is proposed to index the degree of pre-activation of upcoming word-internal morphemes in speech processing. Using lexical competition measures based on word-initial speech fragments (WIFs), as well as statistical analyses of ERP data from three experiments, it is shown that the PrAN is sensitive to lexical competition and that it reflects the degree of predictive certainty: the negativity is larger when there are fewer upcoming lexical competitors. PMID- 27777557 TI - Snap Your Fingers! An ERP/sLORETA Study Investigating Implicit Processing of Self vs. Other-Related Movement Sounds Using the Passive Oddball Paradigm. AB - So far, neurophysiological studies have investigated implicit and explicit self related processing particularly for self-related stimuli such as the own face or name. The present study extends previous research to the implicit processing of self-related movement sounds and explores their spatio-temporal dynamics. Event related potentials (ERPs) were assessed while participants (N = 12 healthy subjects) listened passively to previously recorded self- and other-related finger snapping sounds, presented either as deviants or standards during an oddball paradigm. Passive listening to low (500 Hz) and high (1000 Hz) pure tones served as additional control. For self- vs. other-related finger snapping sounds, analysis of ERPs revealed significant differences in the time windows of the N2a/MMN and P3. An subsequent source localization analysis with standardized low resolution brain electromagnetic tomography (sLORETA) revealed increased cortical activation in distinct motor areas such as the supplementary motor area (SMA) in the N2a/mismatch negativity (MMN) as well as the P3 time window during processing of self- and other-related finger snapping sounds. In contrast, brain regions associated with self-related processing [e.g., right anterior/posterior cingulate cortex (ACC/PPC)] as well as the right inferior parietal lobule (IPL) showed increased activation particularly during processing of self- vs. other-related finger snapping sounds in the time windows of the N2a/MMN (ACC/PCC) or the P3 (IPL). None of these brain regions showed enhanced activation while listening passively to low (500 Hz) and high (1000 Hz) pure tones. Taken together, the current results indicate (1) a specific role of motor regions such as SMA during auditory processing of movement-related information, regardless of whether this information is self- or other-related, (2) activation of neural sources such as the ACC/PCC and the IPL during implicit processing of self-related movement stimuli, and (3) their differential temporal activation during deviance (N2a/MMN ACC/PCC) and target detection (P3 - IPL) of self- vs. other-related movement sounds. PMID- 27777556 TI - Attention Performance Measured by Attention Network Test Is Correlated with Global and Regional Efficiency of Structural Brain Networks. AB - Functional neuroimaging studies have indicated the involvement of separate brain areas in three distinct attention systems: alerting, orienting, and executive control (EC). However, the structural correlates underlying attention remains unexplored. Here, we utilized graph theory to examine the neuroanatomical substrates of the three attention systems measured by attention network test (ANT) in 65 healthy subjects. White matter connectivity, assessed with diffusion tensor imaging deterministic tractography was modeled as a structural network comprising 90 nodes defined by the automated anatomical labeling (AAL) template. Linear regression analyses were conducted to explore the relationship between topological parameters and the three attentional effects. We found a significant positive correlation between EC function and global efficiency of the whole brain network. At the regional level, node-specific correlations were discovered between regional efficiency and all three ANT components, including dorsolateral superior frontal gyrus, thalamus and parahippocampal gyrus for EC, thalamus and inferior parietal gyrus for alerting, and paracentral lobule and inferior occipital gyrus for orienting. Our findings highlight the fundamental architecture of interregional structural connectivity involved in attention and could provide new insights into the anatomical basis underlying human behavior. PMID- 27777559 TI - Curcumin Represses NLRP3 Inflammasome Activation via TLR4/MyD88/NF-kappaB and P2X7R Signaling in PMA-Induced Macrophages. AB - Aims: In the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome is closely related to the progression of atherosclerosis. This study aimed to assess the effects of curcumin on NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages and explore its underlying mechanism. Methods: Human monocytic THP-1 cells were pretreated with curcumin for 1 h and subsequently induced with PMA for 48 h. Total protein was collected for Western blot analysis. Cytokine interleukin (IL)-1beta release and nuclear factor kappa B (NF-kappaB) p65 translocation were detected by ELISA assay and cellular NF-kappaB translocation kit, respectively. Results: Curcumin significantly reduced the expression of NLRP3 and cleavage of caspase-1 and IL 1beta secretion in PMA-induced macrophages. Moreover, Bay (a NF-kappaB inhibitor) treatment considerably suppressed the expression of NLRP3 inflammasome in PMA induced THP-1 cells. Curcumin also markedly inhibited the upregulation of toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphorylation level of IkappaB-alpha, and activation of NF-kappaB in PMA induced macrophages. In addition, purinergic 2X7 receptor (P2X7R) siRNA was administered, and it significantly decreased NLRP3 inflammasome expression in PMA induced macrophages. Furthermore, curcumin reversed PMA-stimulated P2X7R activation, which further reduced the expression of NLRP3 and cleavage of caspase 1 and IL-1beta secretion. Silencing of P2X7R using siRNA also suppressed the activation of NF-kappaB pathway in PMA-induced macrophages, but P2X7R-silenced cells did not significantly decrease the expression of TLR4 and MyD88. Conclusion: Curcumin inhibited NLRP3 inflammasome through suppressing TLR4/MyD88/NF-kappaB and P2X7R pathways in PMA-induced macrophages. PMID- 27777560 TI - Changes in the Influence of Alcohol-Paired Stimuli on Alcohol Seeking across Extended Training. AB - Previous work has demonstrated that goal-directed control of alcohol-seeking and other drug-related behaviors is reduced following extended self-administration and drug exposure. Here, we examined how the magnitude of stimulus influences on responding changes across similar training and drug exposure. Rats self administered alcohol or sucrose for 2 or 8 weeks. Previous work has shown that 8 weeks, but not 2 weeks of self-administration produces habitual alcohol seeking. Next, all animals received equivalent Pavlovian conditioning sessions where a discrete stimulus predicted the delivery of alcohol or sucrose. Finally, the impact of the stimuli on ongoing instrumental responding was examined in a Pavlovian-instrumental transfer (PIT) test. While a significant PIT effect was observed following 2 weeks of either alcohol or sucrose self-administration, the magnitude of this effect was greater following 8 weeks of training. The specificity of the PIT effect appeared unchanged by extended training. While it is well established that evaluation of the outcome of responding contributes less to behavioral control following extended training and/or drug exposure, our data indicate that reward-predictive stimuli have a stronger contribution to responding after extended training. Together, these findings provide insight into the factors that control behavior after extended drug use, which will be important for developing effective methods for controlling and ideally reducing these behaviors. PMID- 27777561 TI - The Non-linear Trajectory of Change in Play Profiles of Three Children in Psychodynamic Play Therapy. AB - Aim: Even though there is substantial evidence that play based therapies produce significant change, the specific play processes in treatment remain unexamined. For that purpose, processes of change in long-term psychodynamic play therapy are assessed through a repeated systematic assessment of three children's "play profiles," which reflect patterns of organization among play variables that contribute to play activity in therapy, indicative of the children's coping strategies, and an expression of their internal world. The main aims of the study are to investigate the kinds of play profiles expressed in treatment, and to test whether there is emergence of new and more adaptive play profiles using dynamic systems theory as a methodological framework. Methods and Procedures: Each session from the long-term psychodynamic treatment (mean number of sessions = 55) of three 6-year-old good outcome cases presenting with Separation Anxiety were recorded, transcribed and coded using items from the Children's Play Therapy Instrument (CPTI), created to assess the play activity of children in psychotherapy, generating discrete and measurable units of play activity arranged along a continuum of four play profiles: "Adaptive," "Inhibited," "Impulsive," and "Disorganized." The play profiles were clustered through K-means Algorithm, generating seven discrete states characterizing the course of treatment and the transitions between these states were analyzed by Markov Transition Matrix, Recurrence Quantification Analysis (RQA) and odds ratios comparing the first and second halves of psychotherapy. Results: The Markov Transitions between the states scaled almost perfectly and also showed the ergodicity of the system, meaning that the child can reach any state or shift to another one in play. The RQA and odds ratios showed two trends of change, first concerning the decrease in the use of "less adaptive" strategies, second regarding the reduction of play interruptions. Conclusion: The results support that these children express different psychic states in play, which can be captured through the lens of play profiles, and begin to modify less dysfunctional profiles over the course of treatment. The methodology employed showed the productivity of treating psychodynamic play therapy as a complex system, taking advantage of non-linear methods to study psychotherapeutic play activity. PMID- 27777562 TI - Bariatric Surgery Patients' Perceptions of Weight-Related Stigma in Healthcare Settings Impair Post-surgery Dietary Adherence. AB - Background: Weight-related stigma is reported frequently by higher body-weight patients in healthcare settings. Bariatric surgery triggers profound weight loss. This weight loss may therefore alleviate patients' experiences of weight-related stigma within healthcare settings. In non-clinical settings, weight-related stigma is associated with weight-inducing eating patterns. Dietary adherence is a major challenge after bariatric surgery. Objectives: (1) Evaluate the relationship between weight-related stigma and post-surgical dietary adherence; (2) understand if weight loss reduces weight-related stigma, thereby improving post-surgical dietary adherence; and (3) explore provider and patient perspectives on adherence and stigma in healthcare settings. Design: This mixed methods study contrasts survey responses from 300 postoperative bariatric patients with ethnographic data based on interviews with 35 patients and extensive multi-year participant-observation within a clinic setting. The survey measured experiences of weight-related stigma, including from healthcare professionals, on the Interpersonal Sources of Weight Stigma scale and internalized stigma based on the Weight Bias Internalization Scale. Dietary adherence measures included patient self-reports, non-disordered eating patterns reported on the Disordered Eating after Bariatric Surgery scale, and food frequencies. Regression was used to assess the relationships among post-surgical stigma, dietary adherence, and weight loss. Qualitative analyses consisted of thematic analysis. Results: The quantitative data show that internalized stigma and general experiences of weight-related stigma predict worse dietary adherence, even after weight is lost. The qualitative data show patients did not generally recognize this connection, and health professionals explained it as poor patient compliance. Conclusion: Reducing perceptions of weight-related stigma in healthcare settings and weight bias internalization could enhance dietary adherence, regardless of time since patient's weight-loss surgery. PMID- 27777563 TI - Grounding Abstractness: Abstract Concepts and the Activation of the Mouth. AB - One key issue for theories of cognition is how abstract concepts, such as freedom, are represented. According to the WAT (Words As social Tools) proposal, abstract concepts activate both sensorimotor and linguistic/social information, and their acquisition modality involves the linguistic experience more than the acquisition of concrete concepts. We report an experiment in which participants were presented with abstract and concrete definitions followed by concrete and abstract target-words. When the definition and the word matched, participants were required to press a key, either with the hand or with the mouth. Response times and accuracy were recorded. As predicted, we found that abstract definitions and abstract words yielded slower responses and more errors compared to concrete definitions and concrete words. More crucially, there was an interaction between the target-words and the effector used to respond (hand, mouth). While responses with the mouth were overall slower, the advantage of the hand over the mouth responses was more marked with concrete than with abstract concepts. The results are in keeping with grounded and embodied theories of cognition and support the WAT proposal, according to which abstract concepts evoke linguistic-social information, hence activate the mouth. The mechanisms underlying the mouth activation with abstract concepts (re-enactment of acquisition experience, or re-explanation of the word meaning, possibly through inner talk) are discussed. To our knowledge this is the first behavioral study demonstrating with real words that the advantage of the hand over the mouth is more marked with concrete than with abstract concepts, likely because of the activation of linguistic information with abstract concepts. PMID- 27777564 TI - Contextual Positive Psychology: Policy Recommendations for Implementing Positive Psychology into Schools. AB - There has been a rapid growth in positive psychology, a research and intervention approach that focuses on promoting optimal functioning and well-being. Positive psychology interventions are now making their way into classrooms all over the world. However, positive psychology has been criticized for being decontextualized and coercive, and for putting an excessive emphasis on positive states, whilst failing to adequately consider negative experiences. Given this, how should policy be used to regulate and evaluate these interventions? We review evidence that suggests these criticisms may be valid, but only for those interventions that focus almost exclusively on changing the content of people's inner experience (e.g., make it more positive) and personality (improving character strength), and overemphasize the idea that inner experience causes action. We describe a contextualized form of positive psychology that not only deals with the criticisms, but also has clear policy implications for how to best implement and evaluate positive education programs so that they do not do more harm than good. PMID- 27777565 TI - Competitiveness and the Process of Co-adaptation in Team Sport Performance. AB - An evolutionary psycho-biological perspective on competitiveness dynamics is presented, focusing on continuous behavioral co-adaptations to constraints that arise in performance environments. We suggest that an athlete's behavioral dynamics are constrained by circumstances of competing for the availability of resources, which once obtained offer possibilities for performance success. This defines the influence of the athlete-environment relationship on competitiveness. Constraining factors in performance include proximity to target areas in team sports and the number of other competitors in a location. By pushing the athlete beyond existing limits, competitiveness enhances opportunities for co-adaptation, innovation and creativity, which can lead individuals toward different performance solutions to achieve the same performance goal. Underpinned by an ecological dynamics framework we examine whether competitiveness is a crucial feature to succeed in team sports. Our focus is on intra-team competitiveness, concerning the capacity of individuals within a team to become perceptually attuned to affordances in a given performance context which can increase their likelihood of success. This conceptualization implies a re-consideration of the concept of competitiveness, not as an inherited trait or entity to be acquired, but rather theorizing it as a functional performer-environment relationship that needs to be explored, developed, enhanced and maintained in team games training programs. PMID- 27777566 TI - Softening the Blow of Social Exclusion: The Responsive Theory of Social Exclusion. AB - Social exclusion is an interactive process between multiple people, yet previous research has focused almost solely on the negative impacts on targets. What advice is there for people on the other side (i.e., sources) who want to minimize its negative impact and preserve their own reputation? To provide an impetus for research on the interactive nature of exclusion, we propose the Responsive Theory of Social Exclusion. Our theory postulates that targets and sources' needs are better maintained if sources use clear, explicit verbal communication. We propose that sources have three options: explicit rejection (clearly stating no), ostracism (ignoring), and ambiguous rejection (being unclear). Drawing on psychology, sociology, communications, and business research, we propose that when sources use explicit rejection, targets' feelings will be less hurt, their needs will be better protected, and sources will experience less backlash and emotional toil than if sources use ambiguous rejection or ostracism. Finally, we propose how the language of rejections may impact both parties. PMID- 27777567 TI - Distribution of 5-HT1F Receptors in Monkey Vestibular and Trigeminal Ganglion Cells. AB - BACKGROUND: Evidence of serotonergic involvement in vestibular pathway contributions to migraine and balance disorders is compelling. Serotonergic 5 HT1B and 5-HT1D receptors are expressed extensively in inner ear ganglia of monkeys and rats. The serotonergic 5-HT1F receptor is also a target of triptans. This study describes its distribution in vestibular and trigeminal ganglia of monkeys. METHODS: Using primary polyclonal antibodies raised against oligopeptides specific for the human 5-HT1F receptor, neuronal somatic area and intensity of immunoreactive vestibular and trigeminal ganglia were quantified. RESULTS AND DISCUSSION: Virtually all vestibular and considerable trigeminal ganglia showed positive 5-HT1F receptor immunoreactivity. Inferior and superior vestibular ganglia staining appeared confined to distinct cell regions, varying considerably among cells of different sizes: more intense in small, punctate in some medium and regionally polarized in some large cells. Analyses of average somatic vestibular neuronal immunoreactive intensity identified mainly medium sized cells with high standard deviation of intensity corresponding to punctately stained cells. Less variability occurred in somatic intensity staining and cellular distribution among 5-HT1F receptor immunopositive trigeminal ganglia. Most exhibited similar punctate staining patterns, higher mean somatic immunoreactive intensity and larger neuronal somatic size proportions per size distribution subpopulation compared to vestibular ganglia size distribution populations. Centrally directed vestibular ganglion neuronal processes, cochlear inner hair cells, vestibular hair cells and blood vessels in vestibular maculae and cristae were immunoreactive. The 5-HT1F receptor expression in vestibular ganglia shows complex variable staining intensity patterns associated with cell size of immunopositive neurons, not seen in immunopositive trigeminal ganglia and not previously evident with 5-HT1B and 5-HT1D receptor subtype immunoreactivity in vestibular ganglia. These data motivate exploration of 5-HT1 receptor oligomerization and ligand functional selectivity in differential serotonergic involvement in co-morbidity of migraine and balance disorders. Similar findings in cochlear inner hair cell afferents are applicable to migraine-related tinnitus or hypercusis (phonophobia). PMID- 27777568 TI - Growth Hormone-Releasing Hormone in Diabetes. AB - Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggest that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications. PMID- 27777571 TI - Live Attenuated Vaccine Based on Duck Enteritis Virus against Duck Hepatitis A Virus Types 1 and 3. AB - As causative agents of duck viral hepatitis, duck hepatitis A virus type 1 (DHAV 1) and type 3 (DHAV-3) causes significant economic losses in the duck industry. However, a licensed commercial vaccine that simultaneously controls both pathogens is currently unavailable. Here, we generated duck enteritis virus recombinants (rC-KCE-2VP1) containing both VP1 from DHAV-1 (VP1/DHAV-1) and VP1 from DHAV-3 (VP1/DHAV-3) between UL27 and UL26. A self-cleaving 2A-element of FMDV was inserted between the two different types of VP1, allowing production of both proteins from a single open reading frame. Immunofluorescence and Western blot analysis results demonstrated that both VP1 proteins were robustly expressed in rC-KCE-2VP1-infected chicken embryo fibroblasts. Ducks that received a single dose of rC-KCE-2VP1 showed potent humoral and cellular immune responses and were completely protected against challenges of both pathogenic DHAV-1 and DHAV-3 strains. The protection was rapid, achieved as early as 3 days after vaccination. Moreover, viral replication was fully blocked in vaccinated ducks as early as 1 week post-vaccination. These results demonstrated, for the first time, that recombinant rC-KCE-2VP1 is potential fast-acting vaccine against DHAV-1 and DHAV 3. PMID- 27777570 TI - Interactions between Obesity Status and Dietary Intake of Monounsaturated and Polyunsaturated Oils on Human Gut Microbiome Profiles in the Canola Oil Multicenter Intervention Trial (COMIT). AB - Long-term dietary fatty acid intake is believed to induce changes in the human gut microbiome which might be associated with human health or obesity status; however, considerable debate remains regarding the most favorable ratios of fatty acids to optimize these processes. The objective of this sub-study of a double blinded randomized crossover clinical study, the canola oil multi-center intervention trial, was to investigate effects of five different novel oil blends fed for 30 days each on the intestinal microbiota in 25 volunteers with risk of metabolic syndrome. The 60 g treatments included three MUFA-rich diets: (1) conventional canola oil (Canola); (2) DHA-enriched high oleic canola oil (CanolaDHA); (3) high oleic canola oil (CanolaOleic); and two PUFA-rich diets: (4) a blend of corn/safflower oil (25:75) (CornSaff); and (5) a blend of flax/safflower oil (60:40) (FlaxSaff). Stool samples were collected at the end of each period. DNA was extracted and amplified for 16S rRNA gene pyrosequencing. A total of 17 phyla and 187 genera were identified. While five novel oil treatments failed to alter bacterial phyla composition, obese participants resulted in a higher proportion of Firmicutes to Bacteroidetes than overweight or normal weight groups (P = 0.01). Similarly at the genus level, overall bacterial distribution was highly associated with subjects' body mass index (BMI). Treatment effects were observed between MUFA- and PUFA-rich diets, with the three MUFA diets elevating Parabacteroides, Prevotella, Turicibacter, and Enterobacteriaceae's populations, while the two PUFA-rich diets favored the higher abundance of Isobaculum. High MUFA content feedings also resulted in an increase of Parabacteroides and a decrease of Isobaculum in obese, but not overweight subjects. Data suggest that BMI is a predominant factor in characterization of human gut microbiota profile, and that MUFA-rich and PUFA-rich diets impact the composition of gut microbiota at lower taxonomical levels mainly in obese subjects. PMID- 27777569 TI - Evolution and Application of Inteins in Candida species: A Review. AB - Inteins are invasive intervening sequences that perform an autocatalytic splicing from their host proteins. Among eukaryotes, these elements are present in many fungal species, including those considered opportunistic or primary pathogens, such as Candida spp. Here we reviewed and updated the list of Candida species containing inteins in the genes VMA, THRRS and GLT1 and pointed out the importance of these elements as molecular markers for molecular epidemiological researches and species-specific diagnosis, since the presence, as well as the size of these inteins, is polymorphic among the different species. Although absent in Candida albicans, these elements are present in different sizes, in some environmental Candida spp. and also in most of the non-albicans Candida spp. considered emergent opportunistic pathogens. Besides, the possible role of these inteins in yeast physiology was also discussed in the light of the recent findings on the importance of these elements as post-translational modulators of gene expression, reinforcing their relevance as alternative therapeutic targets for the treatment of non-albicans Candida infections, because, once the splicing of an intein is inhibited, its host protein, which is usually a housekeeping protein, becomes non-functional. PMID- 27777572 TI - Role of yqiC in the Pathogenicity of Salmonella and Innate Immune Responses of Human Intestinal Epithelium. AB - The yqiC gene of Salmonella enterica serovar Typhimurium (S. Typhimurium) regulates bacterial growth at different temperatures and mice survival after infection. However, the role of yqiC in bacterial colonization and host immunity remains unknown. We infected human LS174T, Caco-2, HeLa, and THP-1 cells with S. Typhimurium wild-type SL1344, its yqiC mutant, and its complemented strain. Bacterial colonization and internalization in the four cell lines significantly reduced on yqiC depletion. Post-infection production of interleukin-8 and human beta-defensin-3 in LS174T cells significantly reduced because of yqiC deleted in S. Typhimurium. The phenotype of yqiC mutant exhibited few and short flagella, fimbriae on the cell surface, enhanced biofilm formation, upregulated type-1 fimbriae expression, and reduced bacterial motility. Type-1 fimbriae, flagella, SPI-1, and SPI-2 gene expression was quantified using real-time PCR. The data show that deletion of yqiC upregulated fimA and fimZ expression and downregulated flhD, fliZ, invA, and sseB expression. Furthermore, thin-layer chromatography and high-performance liquid chromatography revealed the absence of menaquinone in the yqiC mutant, thus validating the importance of yqiC in the bacterial electron transport chain. Therefore, YqiC can negatively regulate FimZ for type-1 fimbriae expression and manipulate the functions of its downstream virulence factors including flagella, SPI-1, and SPI-2 effectors. PMID- 27777573 TI - Artery Tertiary Lymphoid Organs: Powerhouses of Atherosclerosis Immunity. AB - Artery tertiary lymphoid organs (ATLOs) are atherosclerosis-associated lymphoid aggregates with varying degrees of complexity ranging from small T/B-cell clusters to well-structured lymph node-like though unencapsulated lymphoid tissues. ATLOs arise in the connective tissue that surrounds diseased arteries, i.e., the adventitia. ATLOs have been identified in aged atherosclerosis-prone hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice: they are organized into distinct immune cell compartments, including separate T-cell areas, activated B cell follicles, and plasma cell niches. Analyses of ATLO immune cell subsets indicate antigen-specific T- and B-cell immune reactions within the atherosclerotic arterial wall adventitia. Moreover, ATLOs harbor innate immune cells, including a large component of inflammatory macrophages, B-1 cells, and an aberrant set of antigen-presenting cells. There is marked neoangiogenesis, irregular lymphangiogenesis, neoformation of high endothelial venules, and de novo synthesis of lymph node-like conduits. Molecular mechanisms of ATLO formation remain to be identified though media vascular smooth muscle cells may adopt features of lymphoid tissue organizer-like cells by expressing lymphorganogenic chemokines, i.e., CXCL13 and CCL21. Although these data are consistent with the view that ATLOs participate in primary T- and B-cell responses against elusive atherosclerosis-specific autoantigens, their specific protective or disease-promoting roles remain to be identified. In this review, we discuss what is currently known about ATLOs and their potential impact on atherosclerosis and make attempts to define challenges ahead. PMID- 27777574 TI - Phenotypic and Functional Dysregulated Blood NK Cells in Colorectal Cancer Patients Can Be Activated by Cetuximab Plus IL-2 or IL-15. AB - The clinical outcome of colorectal cancer (CRC) is associated with the immune response; thus, these tumors could be responsive to different immune therapy approaches. Natural killer (NK) cells are key antitumor primary effectors that can eliminate CRC cells without prior immunization. We previously determined that NK cells from the local tumor environment of CRC tumors display a profoundly altered phenotype compared with circulating NK cells from healthy donors (HD). In this study, we evaluated peripheral blood NK cells from untreated patients and their possible role in metastasis progression. We observed profound deregulation in receptor expression even in early stages of disease compared with HD. CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-gamma production. We also determined that NKp30 and NKp46 are the key receptors involved in detriment of CRC-NK cells' antitumor activity. Moreover, NKp46 expression correlated with relapse-free survival of CRC patients with a maximum follow-up of 71 months. CRC-NK cells also exhibited altered antibody-dependent cellular cytotoxicity function responding poorly to cetuximab. IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity. These results show potential strategies to enhance CRC-NK cell activity. PMID- 27777576 TI - Neutrophil Extracellular Traps Form a Barrier between Necrotic and Viable Areas in Acute Abdominal Inflammation. AB - Neutrophils form neutrophil extracellular traps (NETs) of decondensed DNA and histones that trap and immobilize particulate matter and microbial pathogens like bacteria. NET aggregates reportedly surround and isolate large objects like monosodium urate crystals, which cannot be sufficiently cleared from tissues. In the setting of acute necrotizing pancreatitis, massive tissue necrosis occurs, which is organized as pancreatic pseudocysts (1). In contrast to regular cysts, these pseudocysts are not surrounded by epithelial layers. We hypothesize that, instead, the necrotic areas observed in necrotizing pancreatitis are isolated from the surrounding healthy tissues by aggregated NETs. These may form an alternative, putatively transient barrier, separating necrotic areas from viable tissue. To test this hypothesis, we investigated histological samples from the necropsy material of internal organs of two patients with necrotizing pancreatitis and peritonitis accompanied by multiple organ failure. Tissues including the inflammatory zone were stained with hematoxylin and eosin and evaluated for signs of inflammation. Infiltrating neutrophils and NETs were detected by immunohistochemistry for DNA, neutrophil elastase (NE), and citrullinated histone H3. Interestingly, in severely affected areas of pancreatic necrosis or peritonitis, chromatin stained positive for NE and citrullinated histone H3, and may, therefore, be considered NET-derived. These NET structures formed a layer, which separated the necrotic core from the areas of viable tissue remains. A condensed layer of aggregated NETs, thus, spatially shields and isolates the site of necrosis, thereby limiting the spread of necrosis-associated proinflammatory mediators. We propose that necrotic debris may initiate and/or facilitate the formation of the NET-based surrogate barrier. PMID- 27777575 TI - Activation of Human Complement System by Dextran-Coated Iron Oxide Nanoparticles Is Not Affected by Dextran/Fe Ratio, Hydroxyl Modifications, and Crosslinking. AB - While having tremendous potential as therapeutic and imaging tools, the clinical use of engineered nanoparticles has been associated with serious safety concerns. Activation of the complement cascade and the release of proinflammatory factors C3a and C5a may contribute to infusion-related reactions, whereas opsonization with C3 fragments promotes rapid recognition and clearance of nanomaterials by mononuclear phagocytes. We used dextran-coated superparamagnetic iron oxide nanoparticles (SPIO), which are potent activators of the complement system, to study the role of nanoparticle surface chemistry in inciting complement in human serum. Using complement inhibitors and measuring levels of fluid phase markers (sC5b-9, C5a, and Bb), we found that the majority of human complement activation by SPIO is through the alternative pathways (AP). SPIO prepared with high dextran/iron ratio showed some complement activation via calcium-sensitive pathways, but the AP was responsible for the bulk of complement activation and amplification. Activation via the AP required properdin, the positive regulator of the alternative C3bBb convertase. Modification of sugar alcohols of dextran with alkylating, acylating, or crosslinking agents did not overcome complement activation and C3 opsonization. These data demonstrate that human complement activation is independent of dextran modification of SPIO and suggest a crucial role of the AP in immune recognition of nano-assemblies in human serum. PMID- 27777579 TI - The Hygroscopic Opening of Sesame Fruits Is Induced by a Functionally Graded Pericarp Architecture. AB - To enhance the distribution of their seeds, plants often utilize hygroscopic deformations that actuate dispersal mechanisms. Such movements are based on desiccation-induced shrinkage of tissues in predefined directions. The basic hygroscopic deformations are typically actuated by a bi-layer configuration, in which shrinking of an active tissue layer is resisted by a stiff layer, generating a set of basic movements including bending, coiling, and twisting. In this study, we investigate a new type of functionally graded hygroscopic movement in the fruit (capsule) of sesame (Sesamum indicum L.). Microscopic observations of the capsules showed that the inner stiff endocarp layer is built of a bilayer of transverse (i.e., circumferential) and longitudinal fiber cells with the layers positioned in a semi-circle, one inside the other. The outer mesocarp layer is made of soft parenchyma cells. The thickness of the fibrous layers and of the mesocarp exhibits a graded architecture, with gradual changes in their thickness around the capsule circumference. The cellulose microfibrils in the fiber cell walls are lying parallel to the cell long axis, rendering them stiff. The outer mesocarp layer contracted by 300% as it dried. Removal of this outer layer inhibited the opening movement, indicating that it is the active tissue. A biomechanical hygro-elastic model based on the relative thicknesses of the layers successfully simulated the opening curvature. Our findings suggest that the sesame capsules possess a functionally graded architecture, which promotes a non uniform double-curvature hygroscopic bending movement. In contrast to other hygroscopic organs described in the literature, the sesame capsule actuating and resisting tissues are not uniform throughout the device, but changing gradually. This newly described mechanism can be exploited in bio-inspired designs of novel actuating platforms. PMID- 27777578 TI - Charophytes: Evolutionary Giants and Emerging Model Organisms. AB - Charophytes are the group of green algae whose ancestral lineage gave rise to land plants in what resulted in a profoundly transformative event in the natural history of the planet. Extant charophytes exhibit many features that are similar to those found in land plants and their relatively simple phenotypes make them efficacious organisms for the study of many fundamental biological phenomena. Several taxa including Micrasterias, Penium, Chara, and Coleochaete are valuable model organisms for the study of cell biology, development, physiology and ecology of plants. New and rapidly expanding molecular studies are increasing the use of charophytes that in turn, will dramatically enhance our understanding of the evolution of plants and the adaptations that allowed for survival on land. The Frontiers in Plant Science series on "Charophytes" provides an assortment of new research reports and reviews on charophytes and their emerging significance as model plants. PMID- 27777580 TI - Redox Signaling and CBF-Responsive Pathway Are Involved in Salicylic Acid Improved Photosynthesis and Growth under Chilling Stress in Watermelon. AB - Salicylic acid (SA) plays an important role in plant response to abiotic stresses. This study investigated the potential role of SA in alleviating the adverse effects of chilling stress on photosynthesis and growth in watermelon (Citrullus lanatus). Chilling stress induced the simultaneous accumulation of free and conjugated SA in watermelon plants, and the chilling-induced SA production was attributed to the phenylalanine ammonia-lyase pathway. Applying SA at moderate concentrations induced chilling tolerance, whereas inhibition of SA biosynthesis by L-alpha-aminooxy-beta-phenylpropionic acid (AOPP) increased the photooxidation of PS II under chilling stress in watermelon, resulting in reduced photosynthesis and growth. Chilling induced a transient increase in the ratios of reduced to oxidized glutathione and reduced ascorbate to dehydroascorbate. Then, the expression of antioxidant genes was upregulated, and the activities of antioxidant enzymes were enhanced. Furthermore, SA-induced chilling tolerance was associated with cellular glutathione and ascorbate homeostasis, which served as redox signals to regulate antioxidant metabolism under chilling stress. AOPP treatment stimulated the chilling-induced expression of cold-responsive genes, particularly via C-repeat binding factors CBF3 and CBF4. These results confirm the synergistic role of SA signaling and the CBF-dependent responsive pathway during chilling stress in watermelon. PMID- 27777581 TI - Trichoderma harzianum T-22 Induces Systemic Resistance in Tomato Infected by Cucumber mosaic virus. AB - Understanding the induction of plant defenses against viruses using biocontrol agents is essential for developing new strategies against these pathogens, given the ineffectiveness of chemical treatments. The ability of Trichoderma harzianum, strain T-22 (T22) to control Cucumber mosaic virus (CMV) in Solanum lycopersicum var. cerasiforme plants and the changes in the physiology of tomato treated/infected with T22/CMV were examined. Plant growth-promoting effects, photosynthetic performance, reactive oxygen species scavenging enzymes, and phytohormones were investigated. T22 improved tomato growth in terms of plant height and improved photosynthesis, total chlorophyll content and plant gas exchange. In contrast, CMV induced a negative effect on dry matter accumulation and inhibited the photosynthetic capacity. The analysis of plant hormones demonstrated that treating with T22 before or simultaneously to CMV infection, led to a systemic resistance by jasmonic acid/ethylene and salicylic acid signaling pathways. Conversely, systemic resistance was abscissic acid-dependent when T22 treatment was administered after the CMV infection. In conclusion, the data reported here indicate that the T22-based strategy may be the most effective measure against CMV. PMID- 27777577 TI - Moving through the Stressed Genome: Emerging Regulatory Roles for Transposons in Plant Stress Response. AB - The recognition of a positive correlation between organism genome size with its transposable element (TE) content, represents a key discovery of the field of genome biology. Considerable evidence accumulated since then suggests the involvement of TEs in genome structure, evolution and function. The global genome reorganization brought about by transposon activity might play an adaptive/regulatory role in the host response to environmental challenges, reminiscent of McClintock's original 'Controlling Element' hypothesis. This regulatory aspect of TEs is also garnering support in light of the recent evidences, which project TEs as "distributed genomic control modules." According to this view, TEs are capable of actively reprogramming host genes circuits and ultimately fine-tuning the host response to specific environmental stimuli. Moreover, the stress-induced changes in epigenetic status of TE activity may allow TEs to propagate their stress responsive elements to host genes; the resulting genome fluidity can permit phenotypic plasticity and adaptation to stress. Given their predominating presence in the plant genomes, nested organization in the genic regions and potential regulatory role in stress response, TEs hold unexplored potential for crop improvement programs. This review intends to present the current information about the roles played by TEs in plant genome organization, evolution, and function and highlight the regulatory mechanisms in plant stress responses. We will also briefly discuss the connection between TE activity, host epigenetic response and phenotypic plasticity as a critical link for traversing the translational bridge from a purely basic study of TEs, to the applied field of stress adaptation and crop improvement. PMID- 27777582 TI - Mycobacterium genavense infection in two species of captive snakes. AB - BACKGROUND: Mycobacterium is an important zoonotic agent with companion, livestock and wildlife animals reportedly playing a role as reservoirs. Although its association with reptiles has been described, the disease cycle remains to be fully established, particularly in snakes. Accordingly, this study aimed to report the occurrence of mycobacteriosis with clinical pneumonia in one exotic python snake (Python molurus) and one native green snake (Philodryas olfersii) from the Sorocaba Zoo, Sao Paulo state, Brazil. METHODS: Diagnosis was based on necropsy, histopathological examination, Ziehl-Neelsen stain and immunohistochemistry. RESULTS: Using a nested PCR followed by DNA sequencing and bioinformatics analysis, the causative Mycobacterium species was identified as Mycobacterium genavense. CONCLUSION: Mycobacterium genavense is an infectious zoonotic agent of animal and public health concerns. PMID- 27777583 TI - Laparoscopic Surgery Can Reduce Postoperative Edema Compared with Open Surgery. AB - Aim. The study aimed to investigate the impact of laparoscopic surgery and open surgery on postoperative edema in Crohn's disease. Methods. Patients who required enterectomy were divided into open group (Group O) and laparoscopic group (Group L). Edema was measured using bioelectrical impedance analysis preoperatively (PRE) and on postoperative day 3 (POD3) and postoperative day 5 (POD5). The postoperative edema was divided into slight edema and edema by an edema index, defined as the ratio of total extracellular water to total body water. Results. Patients who underwent laparoscopic surgery had better clinical outcomes and lower levels of inflammatory and stress markers. A total of 31 patients (26.05%) developed slight edema and 53 patients (44.54%) developed edema on POD3. More patients developed postoperative edema in Group O than in Group L on POD3 (p = 0.006). The value of the edema index of Group O was higher than that of Group L on POD3 and POD5 (0.402 +/- 0.010 versus 0.397 +/- 0.008, p = 0.001; 0.401 +/- 0.009 versus 0.395 +/- 0.007, p = 0.039, resp.). Conclusions. Compared with open surgery, laparoscopic surgery can reduce postoperative edema, which may contribute to the better outcomes of laparoscopic surgery over open surgery. PMID- 27777584 TI - Noninferiority and Equivalence Evaluation of Clinical Performance among Computed Radiography, Film, and Digitized Film for Telemammography Services. AB - Objective. The aim of this study was to evaluate and compare the clinical performance of different alternatives to implement low-cost screening telemammography. We compared computed radiography, film printed images, and digitized films produced with a specialized film digitizer and a digital camera. Material and Methods. The ethics committee of our institution approved this study. We assessed the equivalence of the clinical performance of observers for cancer detection. The factorial design included 70 screening patients, four technological alternatives, and cases interpreted by seven radiologists, for a total of 1,960 observations. The variables evaluated were the positive predictive value (PPV), accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curves (AUC). Result. The mean values for the observed variables were as follows: accuracy ranged from 0.77 to 0.82, the PPV ranged from 0.67 to 0.68, sensitivity ranged from 0.64 to 0.74, specificity ranged from 0.87 to 0.90, and the AUC ranged from 0.87 to 0.90. At a difference of 0.1 to claim equivalence, all alternatives were equivalent for all variables. Conclusion. Our findings suggest that telemammography screening programs may be provided to underserved populations at a low cost, using a film digitizer or a digital camera. PMID- 27777585 TI - Time Trends and Predictors of Abnormal Postoperative Body Temperature in Infants Transported to the Intensive Care Unit. AB - Background. Despite increasing adoption of active warming methods over the recent years, little is known about the effectiveness of these interventions on the occurrence of abnormal postoperative temperatures in sick infants. Methods. Preoperative and postoperative temperature readings, patient characteristics, and procedural factors of critically ill infants at a single institution were retrieved retrospectively from June 2006 until May 2014. The primary endpoints were the incidence and trend of postoperative hypothermia and hyperthermia on arrival at the intensive care units. Univariate and adjusted analyses were performed to identify factors independently associated with abnormal postoperative temperatures. Results. 2,350 cases were included. 82% were normothermic postoperatively, while hypothermia and hyperthermia each occurred in 9% of cases. During the study period, hypothermia decreased from 24% to 2% (p < 0.0001) while hyperthermia remained unchanged (13% in 2006, 8% in 2014, p = 0.357). Factors independently associated with hypothermia were higher ASA status (p = 0.02), lack of intraoperative convective warming (p < 0.001) and procedure date before 2010 (p < 0.001). Independent associations for postoperative hyperthermia included lower body weight (p = 0.01) and procedure date before 2010 (p < 0.001). Conclusions. We report an increase in postoperative normothermia rates in critically ill infants from 2006 until 2014. Careful monitoring to avoid overcorrection and hyperthermia is recommended. PMID- 27777586 TI - Structural Stability, Transitions, and Interactions within SoxYZCD-Thiosulphate from Sulfurimonas denitrificans: An In Silico Molecular Outlook for Maintaining Environmental Sulphur Cycle. AB - Thiosulphate oxidation (an essential mechanism) serves to maintain the global sulphur cycle. Earlier experimental and computational studies dealt with environmental thiosulphate oxidation but none dealt with thiosulphate oxidation from deep ocean belts. Wet-laboratory experimental research shows that epsilon proteobacteria Sulfurimonas denitrificans possess sox (sulphur-oxidizing) operon and perform thiosulphate oxidation efficiently underneath the oceans. From this specific sox operon, SoxCD complex recycles the thiosulphate-bound SoxY from SoxYZ complex to balance the environmental sulphur cycle. So, four chief proteins were variedly modeled and relevant simulated interactive structures were obtained. The final simulated tetraprotein complex (SoxYZCD) from docked SoxYZ and SoxCD complexes was disclosed to be a highly interactive one with predominant ionic residues. Free energy of folding, solvent accessibility, and conformational shifts (coil-like conformation to helices and sheets) were observed in SoxYZ complex after interacting with SoxCD. The stability of the complex (SoxYZCD) after simulation was also observed through the electrostatic surface potential values. These evaluations were rationalized via biostatistics. This aids SoxCD for recycling SoxY along with thiosulphate, which remains interconnected by four H-bonds with SoxY. Therefore, this novel exploration is endowed with the detailed molecular viewpoint for maintaining the sulphur cycle (globally) including the ocean belts. PMID- 27777587 TI - Myoinositol Improves Embryo Development in PCOS Patients Undergoing ICSI. AB - The aim of this study was to investigate the activity of myoinositol, in a court of 217 PCOS women undergoing intracytoplasmic sperm injection (ICSI), on pregnancy rate, embryo development, estradiol, and progesterone concentration in blood serum, superoxide dismutase (SOD), and catalase (CAT) in follicular fluid. Concerning the court of patient, 112 (groups I and II) out of 217 were PCOS women, whereas group III consisted of healthy subjects (not PCOS). Group I patients were treated with 400 MUg of folic acid per day for 3 months before ICSI, whereas group II patients received 4000 mg of myoinositol and 400 MUg of folic acid per day for 3 months before ICSI. Group II revealed a shorter embryo/blastocyst development period between microinjection and 5-cell stage compared to group I. The difference in SOD concentration between groups I and II and between groups II and III was statistically significant. In group II, 34.62% of pregnancies were obtained, whereas in group I this number reached 20% (NS). Myoinositol increased embryo development dynamics and accelerated blastocyst stage reaching time; however, no effect was shown on clinical pregnancy. Furthermore, it restored SOD concentration, lowered in PCOS women, but did not exert any effect on CAT concentration. PMID- 27777589 TI - Spirulina Supplements Improved the Nutritional Status of Undernourished Children Quickly and Significantly: Experience from Kisantu, the Democratic Republic of the Congo. AB - Aim. Despite high levels of malnutrition, there is still very little information on the nutritional benefits of Spirulina, a natural alga that provides essential amino acids, rare essential lipids, and numerous minerals and vitamins, to undernourished children in the world. Methods. We carried out a prospective study of 50 children aged between six and 60 months. The intervention group consisted of 16 children who received 10 g of Spirulina daily, as well as the local diet administered by the nutritional centre, and the control group of 34 children who just received the local diet. Both groups of children were assessed on day zero, day 15, and day 30. Results. After treatment, the weight-for-age Z scores and weight-for-height Z scores increased significantly in the intervention group. At day 15, there was a statistically significant difference between the mean corpuscular volume, total proteins, and albumin (p < 0.05) in both groups, in favour of the intervention group, and at day 30, this difference extended to all of the studied parameters (p < 0.05). Conclusion. This study found that the nutritional status of undernourished children who received Spirulina supplements as well as the local diet administered by the nutritional centre improved quickly and significantly. PMID- 27777588 TI - A Transcriptomic Signature of Mouse Liver Progenitor Cells. AB - Liver progenitor cells (LPCs) can proliferate extensively, are able to differentiate into hepatocytes and cholangiocytes, and contribute to liver regeneration. The presence of LPCs, however, often accompanies liver disease and hepatocellular carcinoma (HCC), indicating that they may be a cancer stem cell. Understanding LPC biology and establishing a sensitive, rapid, and reliable method to detect their presence in the liver will assist diagnosis and facilitate monitoring of treatment outcomes in patients with liver pathologies. A transcriptomic meta-analysis of over 400 microarrays was undertaken to compare LPC lines against datasets of muscle and embryonic stem cell lines, embryonic and developed liver (DL), and HCC. Three gene clusters distinguishing LPCs from other liver cell types were identified. Pathways overrepresented in these clusters denote the proliferative nature of LPCs and their association with HCC. Our analysis also revealed 26 novel markers, LPC markers, including Mcm2 and Ltbp3, and eight known LPC markers, including M2pk and Ncam. These markers specified the presence of LPCs in pathological liver tissue by qPCR and correlated with LPC abundance determined using immunohistochemistry. These results showcase the value of global transcript profiling to identify pathways and markers that may be used to detect LPCs in injured or diseased liver. PMID- 27777590 TI - Women in Saudi Arabia and the Prevalence of Cardiovascular Risk Factors: A Systematic Review. AB - Background. Cardiovascular disease (CVD) is one of the leading causes of death in Saudi Arabia. Saudi women in particular are more susceptible as there are sociocultural restrictions on female physical activities that may lead to high prevalence of CVD risks, especially obesity, and physical inactivity. This study aims to systematically review the published articles related to the prevalence of CVD risk among women in Saudi Arabia. The search strategy covers all published articles that assess the risk factor of CVD in Saudi Arabia from January 2000 to December 2015, using the following sources: Medline, Embase, and PsycINFO. A total of 61 studies were included. Results. Prevalence among Saudi women of smoking ranged from 1.1% to 9.1%, hypertension was 21.8%, diabetes ranged from 9.6% to 27.6%, overweight was 27%, and obesity was 40.23%, and physical inactivity ranged from 53.2% to 98.1%. Hypercholesterolemia prevalence on Saudi women on average was 24.5%, while metabolic syndrome ranged from 13.6% to 40.3%. Conclusion. The prevalence of CVD risk factors is high among women in Saudi Arabia especially in obesity and physical inactivity. Public health authorities must implement solutions from a gender specific aspect to reverse the trend and decrease the prevalence of CVDs among Saudi women. PMID- 27777591 TI - Interacting effects of obesity, race, ethnicity and sex on the incidence and control of adult-onset asthma. AB - BACKGROUND: To improve care and control for patients with adult-onset asthma, a better understanding of determinants of their risk and outcomes is important. We investigated how associations between asthma, asthma control and obesity may be modified by patient demographic characteristics. METHODS: This retrospective study of adults enrolled in several health plans across the U.S. (n = 2,860,305) examined the interacting effects of obesity, age, race, and sex on adult-onset asthma and asthma control. Multivariable adjusted Cox and logistic regression models estimated hazard ratios (HR), and 95 % confidence intervals (CI) for the associations between body mass index (BMI) and study outcomes, and interactions of BMI with demographic characteristics. RESULTS: Compared with individuals who had a BMI <25 kg/m2, the hazard of adult-onset asthma progressively increased with increasing BMI, from a 12 % increase among persons with a BMI of 25.0-29.9 kg/m2 (HR 1.12, 95 % CI 1.10, 1.14) to an almost 250 % increase among persons with a BMI >=50 kg/m2 (HR 2.49, 95 % CI 2.38, 2.60). The magnitude of the association between obesity and asthma risk was greater for women (compared with men) and lower for Blacks (compared with non-Hispanic Whites). Among individuals with asthma, obesity was associated with poorly controlled and high-risk asthma. CONCLUSIONS: The present study demonstrates that the magnitude of the associations between obesity and adult-onset asthma incidence and control are modified by race, age, and sex. Understanding the role of obesity in the development of adult-onset asthma will help to improve asthma treatment algorithms and to develop targeted interventions. PMID- 27777592 TI - Air pollution, epigenetics, and asthma. AB - Exposure to traffic-related air pollution (TRAP) has been implicated in asthma development, persistence, and exacerbation. This exposure is highly significant as large segments of the global population resides in zones that are most impacted by TRAP and schools are often located in high TRAP exposure areas. Recent findings shed new light on the epigenetic mechanisms by which exposure to traffic pollution may contribute to the development and persistence of asthma. In order to delineate TRAP induced effects on the epigenome, utilization of newly available innovative methods to assess and quantify traffic pollution will be needed to accurately quantify exposure. This review will summarize the most recent findings in each of these areas. Although there is considerable evidence that TRAP plays a role in asthma, heterogeneity in both the definitions of TRAP exposure and asthma outcomes has led to confusion in the field. Novel information regarding molecular characterization of asthma phenotypes, TRAP exposure assessment methods, and epigenetics are revolutionizing the field. Application of these new findings will accelerate the field and the development of new strategies for interventions to combat TRAP-induced asthma. PMID- 27777594 TI - Clinical validation of controlled exposure to birch pollen in the Environmental Exposure Unit (EEU). AB - BACKGROUND: The Environmental Exposure Unit (EEU) in Kingston, Ontario, Canada is a controlled allergen challenge facility (CACF) that has been previously clinically validated for the use of ragweed and grass pollen in clinical studies. In this study we aim to validate the use of birch pollen to challenge allergic participants. METHODS: A total of 59 volunteers were screened and 38 birch allergic participants and ten non-allergics completed the study, outside of tree pollen season. Participants had to have a minimum of 2-year history of allergic rhinoconjunctivitis during the typical tree pollen season and have a positive skin prick test to birch allergen >=5 mm from the control. Qualified participants were exposed to birch (Betula pendula) pollen for 4 h in the EEU and recorded their symptoms of sneezing, rhinorrhea, nasal congestion, nasal itch which comprised the total nasal symptom score (TNSS), as well as itchy/watery eyes, red/burning eyes and itching of ears/palate/throat which along with the TNSS comprised the total rhinoconjunctival symptom score (TRSS) along with Peak Nasal Inspiratory Flow (PNIF) at baseline and at 30 min intervals for the duration of exposure, then hourly for up to 12 h from the start of exposure. RESULTS: Allergic participants reported a gradual rise in TNSS and TRSS, reaching a mean and standard error of the mean of 7.08 +/- 0.45 and 11.58 +/- 0.93 respectively by 180 min from the start of exposure. Symptoms gradually declined to near baseline values following departing from the unit, reaching 1.9 and 2.7 by 450 min. Allergic participants reported significantly higher TNSS than non-allergics starting from 30 min (p < 0.01, two-way ANOVA with Bonferroni corrections), maintaining maximum significance from 60 to 300 min (p < 0.0001) and losing significance by 420 min. TRSS and PNIF followed similar trends as those seen with TNSS. Participants were phenotyped using previously published definitions using the TNSS into Early Phase Responders (EPR, 57.8 %), protracted EPR (pEPR, 39.5 %), and Dual Phase Responders (DPR, 2.7 %). CONCLUSIONS: The EEU can competently challenge birch allergic participants and achieve statistically significant changes in symptoms and nasal airflow, while such changes are not reported in non allergic controls. Trial registration NCT02351830 clinicaltrials.gov. PMID- 27777595 TI - Soshiho-Tang Aqueous Extract Exerts Antiobesity Effects in High Fat Diet-Fed Mice and Inhibits Adipogenesis in 3T3-L1 Adipocytes. AB - Soshiho-tang (SST; sho-saiko-to in Japanese; xiaochaihu-tang in Chinese) has generally been used to improve liver fibrosis- and cirrhosis-related symptoms in traditional Korean medicine. Although many studies have investigated the pharmacological properties of SST, its antiobesity effect has not been elucidated. Thus, our present study was carried out to evaluate the antiobesity effect of SST using a high fat diet- (HFD) induced obese mouse model and 3T3-L1 adipose cells. C57BL/6J mice were randomly divided into four groups (n = 6/group), normal diet (ND), HFD-fed group, and HFD- and SST-fed groups (S200: 200 mg/kg of SST; S600: 600 mg/kg of SST) and given HFD with or without SST extract for 8 weeks. 3T3-L1 preadipocytes were differentiated into adipocytes for 8 days with or without SST. In the HFD-fed obese mice, body weight and fat accumulation in adipose tissue were significantly reduced by SST administration. Compared with control-differentiated adipocytes, SST significantly inhibited lipid accumulation by decreasing the triglyceride (TG) content and leptin concentration in 3T3-L1 adipocytes. SST also decreased the expression of adipogenesis-related genes including lipoprotein lipase (LPL), fatty acid binding protein 4 (FABP4), CCAAT/enhancer-binding protein-alpha (C/EBP-alpha), and peroxisome proliferator activated receptor-gamma (PPAR-gamma). Our findings suggest that SST has potential as a nontoxic antiobesity medication. PMID- 27777596 TI - Acmella oleracea and Achyrocline satureioides as Sources of Natural Products in Topical Wound Care. AB - The Brazilian forests have one of the world's biggest biodiversities. Achyrocline satureioides (macela) and Acmella oleracea (jambu) are native species from Brazil with a huge therapeutic potential, with proved anti-inflammatory and anesthetic action, respectively. The jambu's crude extract after depigmentation with activated charcoal and macela's essential oil were incorporated in a film made with hydroxyethyl cellulose. Those films were evaluated by mechanical test using a texturometer and anti-inflammatory and anesthetic activities by in vivo tests: wound healing and antinociceptive. The film containing the highest concentration of depigmented jambu's extract and macela's essential oil obtained an anesthesia time of 83.6 (+/-28.5) min longer when compared with the positive control EMLA(r); the same occurred with the wound healing test; the film containing the highest concentration had a higher wound contraction (62.0% +/- 12.1) compared to the positive control allantoin and the histopathological analysis demonstrated that it increases collagen synthesis and epidermal thickening. The results demonstrate that the films have a potential use in skin wounds, pressure sore, and infected surgical wounds treatment. PMID- 27777597 TI - The Effects of Yoga on Pain, Mobility, and Quality of Life in Patients with Knee Osteoarthritis: A Systematic Review. AB - Objective. To systematically assess the effects of yoga on pain, mobility, and quality of life in patients with knee osteoarthritis. Methods. Pubmed, Medline, EMBASE, the Cochrane Central Register of Controlled Trials, Physiotherapy Evidence Database (PEDro), and other sources were searched systematically in this study. Two reviewers identified eligible studies and extracted data independently. Downs and Black's Quality Index were used to evaluate the methodological quality of the included studies. Results. A total of 9 articles (6 studies) involving 372 patients with knee osteoarthritis met the inclusion criteria. The most common yoga protocol is 40~90 minutes/session, lasting for at least 8 weeks. The effect of yoga on pain relief and function improvement could be seen after two-week intervention. Conclusion. This systematic review showed that yoga might have positive effects in relieving pain and mobility on patients with KOA, but the effects on quality of life (QOL) are unclear. Besides, more outcome measure related to mental health of yoga effects on people with KOA should be conducted. PMID- 27777593 TI - Genetic and epigenetic studies of atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory disease caused by the complex interaction of genetic, immune and environmental factors. There have many recent discoveries involving the genetic and epigenetic studies of AD. METHODS: A retrospective PubMed search was carried out from June 2009 to June 2016 using the terms "atopic dermatitis", "association", "eczema", "gene", "polymorphism", "mutation", "variant", "genome wide association study", "microarray" "gene profiling", "RNA sequencing", "epigenetics" and "microRNA". A total of 132 publications in English were identified. RESULTS: To elucidate the genetic factors for AD pathogenesis, candidate gene association studies, genome wide association studies (GWAS) and transcriptomic profiling assays have been performed in this period. Epigenetic mechanisms for AD development, including genomic DNA modification and microRNA posttranscriptional regulation, have been explored. To date, candidate gene association studies indicate that filaggrin (FLG) null gene mutations are the most significant known risk factor for AD, and genes in the type 2 T helper lymphocyte (Th2) signaling pathways are the second replicated genetic risk factor for AD. GWAS studies identified 34 risk loci for AD, these loci also suggest that genes in immune responses and epidermal skin barrier functions are associated with AD. Additionally, gene profiling assays demonstrated AD is associated with decreased gene expression of epidermal differentiation complex genes and elevated Th2 and Th17 genes. Hypomethylation of TSLP and FCER1G in AD were reported; and miR-155, which target the immune suppressor CTLA-4, was found to be significantly over-expressed in infiltrating T cells in AD skin lesions. CONCLUSIONS: The results suggest that two major biologic pathways are responsible for AD etiology: skin epithelial function and innate/adaptive immune responses. The dysfunctional epidermal barrier and immune responses reciprocally affect each other, and thereby drive development of AD. PMID- 27777598 TI - The Effect of Chinese Herbal Medicine Gualouxiebaibanxia Decoction for the Treatment of Angina Pectoris: A Systematic Review. AB - We systematically assess the current clinical evidence of Gualouxiebaibanxia (GLXBBX) decoction for the treatment of angina pectoris (AP). We included RCTs testing GLXBBX against conventional drugs and GLXBBX combined with conventional drugs versus conventional drugs. 19 RCTs involving 1730 patients were finally identified, and the methodological quality was evaluated as generally low. The results of the meta-analysis showed that GLXBBX alone had significant effect on improving angina symptoms (RR: 1.24, 95% CI 1.14 to 1.35; P < 0.00001), ECG (RR: 1.28 [1.13,1.44]; P < 0.0001), and HDL-C (MD: 0.56 [0.54,0.58]; P < 0.00001) compared with anti-arrhythmic drugs. A significant improvement in angina symptoms (RR: 1.17 [1.12,1.22]; P < 0.00001) and ECG (RR = 1.22; 95% CI = [1.14,1.30]; P < 0.00001) was observed for GLXBBX plus conventional drugs when compared with conventional drugs. Eight trials reported adverse events without serious adverse effects. GLXBBX appears to have beneficial effects on improvement of ECG and reduction of angina symptoms in participants with AP. However, the evidence remains weak due to the poor methodological quality of the included studies. More rigorous trials are needed to confirm the results. PMID- 27777599 TI - Frailty has a stronger association with inflammation than age in older veterans. AB - BACKGROUND: Upregulation of pro-inflammatory cytokines has not only been associated with increased morbidity and mortality in older adults but also has been linked to frailty. In the current study we aimed to compare the relative relationship of age and frailty on inflammation and thrombosis in older veterans. RESULTS: We analyzed 117 subjects (age range 62-95 years; median 81) divided into 3 cohorts: non-frail, pre-frail and frail based on the Fried phenotype of frailty. Serum inflammatory markers were determined using commercially available ELISA kits. Frail and pre-frail (PF) subjects had higher levels than non-frail (NF) subjects of IL-6 (NF vs. PF: p = 0.002; NF vs. F: p < 0.001), TNFR1 (NF vs. F: p = 0.012), TNFRII (NF vs. F: 0.002; NF vs. PF: p = 0.005) and inflammatory index: = 0.333*log(IL-6) + 0.666*log(sTNFR1) (NF vs. F: p = 0.009; NF vs. PF: p < 0.001). Frailty status explained a greater percent of variability in markers of inflammation than age: IL-6 (12 % vs. 0.3 %), TNFR1 (5 % vs. 4 %), TNFR2 (11 % vs. 6 %), inflammatory index (16 % vs. 8 %). Aging was significantly associated with higher fibrinogen (p = 0.04) and D-dimer levels (p = 0.01) but only among NF subjects. CONCLUSION: In conclusion, these data suggest that among older veterans, frailty status has a stronger association with inflammation and the inflammatory index than age does. Larger studies, in more diverse populations are needed to confirm these findings. PMID- 27777600 TI - Effects of recall time on cause-of-death findings using verbal autopsy: empirical evidence from rural South Africa. AB - BACKGROUND: Verbal autopsy (VA) is a widely used technique for assigning causes to non-medically certified deaths using information gathered from a close caregiver. Both operational and cultural factors may cause delays in follow-up of deaths. The resulting time lag-from death to VA interview-can influence ways in which terminal events are remembered, and thus affect cause-of-death assignment. This study investigates the impact of recall period on causes of death determined by VA. METHODS: A total of 10,882 deaths from the Agincourt Health and Demographic Surveillance System (HDSS) with complete VAs, including recall period, were incorporated in this study. To measure seasonal effect, cause specific mortality fractions (CSMFs) were calculated and compared by every cause for VAs undertaken within six months of death and those undertaken from six to 12 months of death. All causes were classified into eight broad categories and entered in a multiple logistic regression to explore outcome by recall period in relation to covariates. RESULTS: The majority of deaths (83 %) had VAs completed within 12 months. There was a tendency towards longer recall periods for deaths of those under one year or over 65 years of age. Only the acute respiratory, diarrhoeal and other unspecified non-communicable disease groups showed a CSMF ratio significantly different from unity at the 99 % confidence level between the two recall periods. Only neonatal deaths showed significantly different OR for recall exceeding 12 months (OR 1.69; p value = 0.004) and this increased when adjusting for background factors (OR 2.58; p value = 0.000). CONCLUSION: A recall period of up to one year between death and VA interview did not have any consequential effects on the cause-of-death patterns derived, with the exception of neonatal causes. This is an important operational consideration given the planned widespread use of the VA approach in civil registration, HDSS sites and occasional surveys. PMID- 27777601 TI - Energy state affects exploratory behavior of tree sparrows in a group context under differential food-patch distributions. AB - BACKGROUND: When facing a novel situation, animals can retreat or leave to avoid risks, but will miss potential resources and opportunities. Alternatively they may reduce environmental uncertainty by exploration, while risking no energy rewards and exposure to hazards, and use the information retrieved for subsequent decision making. When exploring, however, animals may adopt different tactics according to individual states. RESULTS: We tested that energy states will affect exploratory behavior by experimenting with wild-caught untrained Eurasian tree sparrows (Passer montanus) in fasted or fed states exploring in a novel space with hidden food supply in different patch distribution patterns. Our data revealed that fasted sparrows risked being earlier explorers more often, initiated more exploratory bouts before patches were found, and stayed longer on the ground under both patch patterns. Fasted sparrows discovered more patches and consumed more food than fed sparrows in dispersed, but not necessary so in clumped, patch patterns; whereas fed birds also increased patch finding to a certain level in dispersed patterns. Sparrows of both energy states, however, did not differ in feeding rates in either patch pattern. CONCLUSIONS: Exploratory behavior of tree sparrows is state-dependent, which supports our prediction that birds with an energy shortage will be risk-prone and explore more readily. Our study also indicates a game nature of tree sparrow exploratory behavior in a group context when explorers are in different energy states and are exposed to different patch distributions. Birds of lower energy state adopting an active exploring tactic may be favored by obtaining higher energy gains in dispersed patch patterns with lower patch richness. More satiated birds, however, achieved a similar feeding rate by lowered exposure time. PMID- 27777602 TI - Dietary green-plant thylakoids decrease gastric emptying and gut transit, promote changes in the gut microbial flora, but does not cause steatorrhea. AB - Green-plant thylakoids increase satiety by affecting appetite hormones such as ghrelin, cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). The objective of this study was to investigate if thylakoids also affect gastrointestinal (GI) passage and microbial composition. To analyse the effects on GI passage, 16 rats were gavage-fed a control or thylakoid-supplemented high-fat diet (HFD) 30 min before receiving Evans blue. Another 16 rats were fed a control HFD or thylakoid HFD for two weeks prior to the intragastric challenge with Evans blue. The amount of Evans blue in the stomach and the distance of migration in the intestines after 30 min were used as a measurement of gastric emptying and intestinal transit. These were reduced by thylakoid supplementation in the acute study, and however not significantly also after the two-week diet study. The second aim of the study was to investigate if thylakoid-supplementation affects the gut microbiota and amount of faecal fat in healthy human volunteers (n = 34) receiving thylakoid or placebo treatments for three months. Microbiota was analysed using 16S rRNA gene sequencing and qPCR, and faecal fat was extracted by dichloromethane. The total bacteria, and specifically the Bacteriodes fragilis group, were increased by thylakoid treatment versus placebo, while thylakoids did not cause steatorrhea. Dietary supplementation with thylakoids thus affects satiety both via appetite hormones and GI fullness, and affects the microbial composition without causing GI adverse effects such as steatorrhea. This suggests thylakoids as a novel agent in prevention and treatment of obesity. PMID- 27777603 TI - Angiotensin-converting enzyme insertion/deletion polymorphism association with obesity and some related disorders in Egyptian females: a case-control observational study. AB - BACKGROUND: According to the WHO report in 2015, obesity is the fifth leading cause of death worldwide, and the prevalence of Egyptian female obesity is 37.5 %. Since obesity is highly influenced by genetics, and adipose tissue renin angiotensin system is over-activated in obesity, the effect of angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism on obesity and related disorders was studied in several populations, because of its effect on ACE activity. Our objective was to study the association of ACE I/D polymorphism with obesity and certain related disorders, namely hypertension, insulin resistance and metabolic syndrome, in Egyptian females. METHODS: Eighty female volunteers were recruited, blood pressure and body measurements were recorded and a fasting blood sample was obtained for the quantitation of glucose, lipid profile, insulin, leptin and identification of ACE I/D polymorphs. Subjects were grouped based on hypertension and obesity states. Comparisons of continuous parameters were made with independent sample t-test between two groups. The frequencies of ACE genotypes and alleles, and the association between gene polymorphism and metabolic parameters were assessed using chi-square or Fisher's exact test. RESULTS: Genotype frequencies were in Hardy-Weinberg equilibrium for all groups. Genotype distribution did not differ significantly between controls and cases of all the studied disorders. Although DD carriers had apparently higher parameters of blood pressure, lipid profile and insulin resistance, only diastolic blood pressure was almost significant (p = 0.057). I-carriers were significantly less susceptible to hypertension than DD carriers having normal waist/hip ratio (p = 0.007, OR = 17.29, CI = 1.81-164.96) and normal conicity index (p = 0.024, OR = 7.00, CI = 1.36-35.93). In DD genotype carriers, a significant association was found between insulin resistance and high body mass index (p = 0.004, OR = 8.89, CI = 1.94-40.71), waist circumference (p = 0.003, OR = 9.63, CI = 2.14-43.36) and waist/height ratio (p = 0.034, OR = 6.86, CI = 1.25 37.61), although the variations in percentages between DD and I-carriers were not high enough to conclude an effect of ACE I/D on such an association. CONCLUSIONS: In this sample of Egyptian females, ACE I/D polymorphism was not significantly associated with obesity nor with any of its related disorders studied. The I allele seemed protective against hypertension in subjects with normal, not high, waist/hip ratio and conicity index compared to DD genotype carriers. PMID- 27777604 TI - Comparison of maternal isocaloric high carbohydrate and high fat diets on osteogenic and adipogenic genes expression in adolescent mice offspring. AB - BACKGROUND: Maternal high fat/high calorie diet leads to adiposity and bone fracture in offspring. However, the effects of macronutrient distribution in maternal isocaloric diet have not been studied. The present study was designed to test the hypothesis that maternal isocaloric pair-fed high-carbohydrate diet will increase osteoblastic and decrease osteoclastic and adipogenic gene expression compared with high-fat diet in adolescent mice offspring. METHODS: Virgin female C57BL/6 mice were impregnated and fed either the AIN 93G isocaloric pair-fed high carbohydrate (LF-HCD) or a high fat (HF-LCD) diet from the time of vaginal plug confirmation until the offspring was weaned. RESULTS: After adjusting for the sex of offspring, osteoprotegrin (OPG) and Ctnnb1 (beta-catenin) genes expression were significantly reduced by 98 % and 97 % in the bone of offspring born from the HF-LCD compared with the LF-HCD-fed mothers (p < 0.001 and p < 0.001, respectively). Peroxisome proliferator-activated receptor gamma-2 (PPAR gamma2) gene expression in the bone of offspring born from the HF-LCD was 7.1-folds higher than the LF-HCD-fed mothers (p = 0.004). In the retroperitoneal fat mass of offspring born from HF-LCD, AdipoQ and LPL genes expression were respectively up-regulated 15.8 and 4.2-folds compared with the LF-HCD-fed mothers (p < 0.001 and p = 0.03, respectively). CONCLUSIONS: Maternal isocaloric pair-fed high carbohydrate diet enhances osteoblastogenesis and inhibits adipogenesis compared with high-fat diet in adolescent mice offspring. PMID- 27777605 TI - Metabolic response of glioblastoma cells associated with glucose withdrawal and pyruvate substitution as revealed by GC-MS. AB - BACKGROUND: Tumor cells are highly dependent on glucose even in the presence of oxygen. This concept called the Warburg effect is a hallmark of cancer and strategies are considered to therapeutically exploit the phenomenon such as ketogenic diets. The success of such strategies is dependent on a profound understanding of tumor cell metabolism. With new techniques it is now possible to thoroughly analyze the metabolic responses to the withdrawal of substrates and their substitution by others. In the present study we used gas chromatography coupled to mass spectrometry (GC-MS) to analyze how glioblastoma brain tumor cells respond metabolically when glucose is withdrawn and substituted by pyruvate. METHODS: Glioblastoma brain tumor cells were cultivated in medium with high (25 mM), medium (11 mM) or low (5.5 mM) glucose concentration or with pyruvate (5 mM). After 24 h GC-MS metabolite profiling was performed. RESULTS: The abundances of most metabolites were dependent on the supply of glucose in tendency but not in a linear manner indicating saturation at high glucose. Noteworthy, a high level of sorbitol production and release was observed at high concentrations of glucose and high release of alanine, aspartate and citrate were observed when glucose was substituted by pyruvate. Intermediates of the TCA cycle were present under all nutritional conditions and evidence was found that cells may perform gluconeogenesis from pyruvate. CONCLUSIONS: Our experiments reveal a high plasticity of glioblastoma cells to changes in nutritional supply which has to be taken into account in clinical trials in which specific diets are considered for therapy. PMID- 27777606 TI - Hormonal responses to non-nutritive sweeteners in water and diet soda. AB - BACKGROUND: Non-nutritive sweeteners (NNS), especially in form of diet soda, have been linked to metabolic derangements (e.g. obesity and diabetes) in epidemiologic studies. We aimed to test acute metabolic effects of NNS in isolation (water or seltzer) and in diet sodas. METHODS: We conducted a four period, cross-over study at the National Institutes of Health Clinical Center (Bethesda, Maryland). Thirty healthy adults consumed 355 mL water with 0 mg, 68 mg, 170 mg, and 250 mg sucralose, and 31 individuals consumed 355 mL caffeine free Diet Rite ColaTM, Diet Mountain DewTM (18 mg sucralose, 18 mg acesulfame potassium, 57 mg aspartame), and seltzer water with NNS (68 mg sucralose and 41 mg acesulfame-potassium, equivalent to Diet Rite ColaTM) in randomized order, prior to oral glucose tolerance tests. Blood samples were collected serially for 130 min. Measures included GLP-1, GIP, glucose, insulin, C-peptide, glucose absorption, gastric emptying, and subjective hunger and satiety ratings. RESULTS: Diet sodas augmented active GLP-1 (Diet Rite ColaTM vs. seltzer water, AUC, p = 0.039; Diet Mountain DewTM vs. seltzer water, AUC, p = 0.07), but gastric emptying and satiety were unaffected. Insulin concentrations were nominally higher following all NNS conditions without altering glycemia. Sucralose alone (at any concentration) did not affect metabolic outcomes. CONCLUSIONS: Diet sodas but not NNS in water augmented GLP-1 responses to oral glucose. Whether the trends toward higher insulin concentrations after NNS are of clinical importance remains to be determined. Our findings emphasize the need to test metabolic effects of NNS after chronic consumption. TRIAL REGISTRATION: The data for this manuscript were gathered from clinical trial #NCT01200940. PMID- 27777607 TI - Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial. AB - BACKGROUND: This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. METHODS: We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a >=50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. RESULTS: Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P < 0.001; and 12.5 vs. 81.8 %, P = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased (chi2 = 8.5, df = 3, P = 0.036) and serum mature BDNF levels were temporarily significantly decreased (F = 3.5, df = 2.4, P = 0.027) in the responders of both groups at week 24. CONCLUSION: This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled. PMID- 27777608 TI - Personality traits, gender roles and sexual behaviours of young adult males. AB - BACKGROUND: Previous studies have shown that personality characteristics affect sexual functioning. The aim of this exploratory study was to assess and describe the relationship between global personality traits and the stereotypical femininity and masculinity levels with the broad aspects of sexual behaviours and attitudes in the group of 97 heterosexual young adult men aged 19-39 and living in Poland. METHODS: The 'Big Five' personality traits were measured with the NEO FFI questionnaire; stereotypical femininity and masculinity with the Bem sex role inventory (BSRI); sexual disorders with the International index of erectile function (IIEF); socio-epidemiological data, sexual behaviours and attitudes towards sexuality with a self-constructed questionnaire. RESULTS: We identified weak to moderate associations with particular sexual behaviours and attitudes. Neuroticism correlated positively with lower sexual satisfaction, self-acceptance and more negative attitudes towards sexuality; extraversion with higher desire, frequency of sexual intercourses, their diversity, sexual satisfaction, masculinity level and lower report of erectile problems; openness to experience with better quality of partnership, more positive attitudes towards sexual activity and masculinity level; conscientiousness with later sexual initiation age, more frequent and diverse sexual behaviours (but lower interest in masturbation and coitus interruptus), overall sexual satisfaction, satisfaction with one's body and femininity level; agreeableness with a better quality of relationship with a partner, satisfaction from body, lower number of previous partners and more frequent sexual encounters (but less masturbation). Stereotypical masculinity, more so than femininity, was related to a wide range of positive aspects of sexuality. CONCLUSIONS: The Big Five personality traits and stereotypical femininity/masculinity dimensions were found to have a noticeable, but weak to moderate influence on sexual behaviour in young adult males. PMID- 27777609 TI - Perceptions related to breastfeeding and the early introduction of complementary foods amongst migrants in Cape Town, South Africa. AB - BACKGROUND: Infant feeding recommendations are of health importance, yet the extent to which migrant communities in low- and middle-income countries know or implement these recommendations is poorly understood. This study explores the perspectives of infant feeding amongst cross-border migrants in Cape Town, South Africa. METHODS: Between February and October 2013, semi-structured in-depth interviews (n = 23) were conducted face-to-face with Congolese, Somali and Zimbabwean mothers living in Cape Town. To assess commonly identified narratives of infant feeding, nine focus group discussions (three with men and six with women) were conducted with migrant Somalis, Congolese, and Zimbabweans. RESULTS: Three dominant themes framed infant feeding. 1) Pragmatism in feeding choices drove responses to baby's cues, including cries, sleeping patterns, and weight gain (2). Formula feeding was normative in the South African context, whereas lack of commercial infant milk back home was described in terms of expense (3). Low rates of breastfeeding were explained in terms of work responsibilities including household work and lack of breastmilk supply resulting from stress and poor diet. However, women participants typically did not consider their feeding choices to negatively affect their baby's health. CONCLUSIONS: The reasons for early introduction of both commercial infant milk and solid foods were complex. Breastfeeding was not prioritized despite an awareness of medical recommendations. Rather than emphasizing specific breastfeeding intentions, participants favoured an approach that reacted to their baby's perceived changing needs. The practical challenges of breastfeeding described by cross-border migrant women reflect one way in which socio-economic and health inequalities may currently be perpetuated for marginalised populations. PMID- 27777611 TI - What inhibits working women with mental disorders from returning to their workplace?-A study of systematic re-employment support in a medical institution. AB - BACKGROUND: It has been customary for working women in Japan to retire when they marry and to devote themselves to household work as well as having children. However, according to a report published by the Ministry of Internal Affairs and Communications in 2013, the number of working women has increased consistently. As more women are advancing into society, they have more options with respect to lifestyle but may encounter new psychological burdens. Therefore, we reviewed trends among participants in a re-work day care program (hereinafter referred to as "re-work program") to clarify various problems encountered by working women and the prevalence of mental disorders. METHODS: A total of 454 participants (352 males, mean age 46.5 +/- 9.4 years; 102 females, mean age 39.8 +/- 9.4 years) who participated in our re-work program were included in this study. We reviewed their basic characteristics: life background, clinical diagnoses, outcomes after use of the re-work program, and reasons for failing to return to the workplace or start working where applicable. RESULTS: The number of female participants was small and accounted for less than one fourth of all participants. As many as 67.3 % of the males succeeded in returning to the workplace, but only 48.0 % of the females were successful. The most common reason for failing to return to the workplace in both sexes was the exacerbation of symptoms; among females, other reasons, such as pregnancy, marriage, and family circumstances, were observed occasionally, but these reasons were not reported by the males. CONCLUSIONS: We found that female-specific problems were not the only issue, but rather work-life balance, relationships in the workplace, and gender differences in work roles could also trigger psychiatric disorders. A deeper understanding of the problems encountered by women in the workforce is important for the treatment of their psychiatric disorders. Therefore, it is considered essential for family members, co-workers, medical staff, and others to understand the various problems encountered by working women. Coping with these problems appropriately will aid in treating mental disorders and creating an environment suitable to prevent their development among women. PMID- 27777610 TI - Infiltration-RNAseq: transcriptome profiling of Agrobacterium-mediated infiltration of transcription factors to discover gene function and expression networks in plants. AB - BACKGROUND: Transcription factors (TFs) coordinate precise gene expression patterns that give rise to distinct phenotypic outputs. The identification of genes and transcriptional networks regulated by a TF often requires stable transformation and expression changes in plant cells. However, the production of stable transformants can be slow and laborious with no guarantee of success. Furthermore, transgenic plants overexpressing a TF of interest can present pleiotropic phenotypes and/or result in a high number of indirect gene expression changes. Therefore, fast, efficient, high-throughput methods for assaying TF function are needed. RESULTS: Agroinfiltration is a simple plant biology method that allows transient gene expression. It is a rapid and powerful tool for the functional characterisation of TF genes in planta. High throughput RNA sequencing is now a widely used method for analysing gene expression profiles (transcriptomes). By coupling TF agroinfiltration with RNA sequencing (named here as Infiltration-RNAseq), gene expression networks and gene function can be identified within a few weeks rather than many months. As a proof of concept, we agroinfiltrated Medicago truncatula leaves with M. truncatula LEGUME ANTHOCYANIN PRODUCITION 1 (MtLAP1), a MYB transcription factor involved in the regulation of the anthocyanin pathway, and assessed the resulting transcriptome. Leaves infiltrated with MtLAP1 turned red indicating the production of anthocyanin pigment. Consistent with this, genes encoding enzymes in the anthocyanin biosynthetic pathway, and known transcriptional activators and repressors of the anthocyanin biosynthetic pathway, were upregulated. A novel observation was the induction of a R3-MYB transcriptional repressor that likely provides transcriptional feedback inhibition to prevent the deleterious effects of excess anthocyanins on photosynthesis. CONCLUSIONS: Infiltration-RNAseq is a fast and convenient method for profiling TF-mediated gene expression changes. We utilised this method to identify TF-mediated transcriptional changes and TF target genes in M. truncatula and Nicotiana benthamiana. This included the identification of target genes of a TF not normally expressed in leaves, and targets of TFs from other plant species. Infiltration-RNAseq can be easily adapted to other plant species where agroinfiltration protocols have been optimised. The ability to identify downstream genes, including positive and negative transcriptional regulators, will result in a greater understanding of TF function. PMID- 27777612 TI - Factors associated with pain level in non-cardiac chest pain patients with comorbid panic disorder. AB - BACKGROUND: Panic disorder (PD) is highly prevalent in patients with non-cardiac chest pain (NCCP). This study aims to explore the role of psychological factors (PD intensity, anxiety sensitivity, heart-related fear, attention and avoidance) common to NCCP and PD in predicting chest pain levels in patients with both conditions. METHODS: This association was investigated in emergency department patients with NCCP and PD receiving either evidence-based treatment of PD or treatment as usual. Patients were assessed at baseline and 14 weeks later for post-treatment. RESULTS: Only heart-focused fear and attention for cardiac sensations independently explained a significant portion of the variance in baseline pain (n = 66). At 3 months follow-up (n = 53), changes in heart-related fear was the only factor independently associated with changes in chest pain intensity. Even in patients with PD, fear specific to cardiac sensations seems to play a central role in determining NCCP intensity. CONCLUSION: These results suggest that the efficacy of intervention for patients with PD and comorbid NCCP could be improved by targeting heart-related fear and attention. TRIAL REGISTRATION: NCT00736346. PMID- 27777613 TI - Prevalence, care-seeking, and health service utilization for non-communicable diseases among Syrian refugees and host communities in Lebanon. AB - BACKGROUND: Given the large burden of non-communicable diseases (NCDs) among both Syrian refugees and the host communities within which they are settled, humanitarian actors and the government of Lebanon face immense challenges in addressing health needs. This study assessed health status, unmet needs, and utilization of health services among Syrian refugees and host communities in Lebanon. METHODS: A cross-sectional survey of Syrian refugees and host communities in Lebanon was conducted using a two-stage cluster survey design with probability proportional to size sampling. To obtain information on chronic NCDs, respondents were asked a series of questions about hypertension, cardiovascular disease, diabetes, chronic respiratory disease, and arthritis. Differences in household characteristics by care-seeking for these conditions were examined using chi-square, t-test, and adjusted logistic regression methods. RESULTS: Over half (50.4 %) of refugee and host community households (60.2 %) reported a member with one of the five NCDs. Host community prevalence rates were significantly higher than refugees for all conditions except chronic respiratory diseases (p = 0.08). Care-seeking for NCDs among refugees and host community households was high across all conditions with 82.9 and 97.8 %, respectively, having sought care in Lebanon for their condition. Refugees utilized primary health care centers (PHCC) (57.7 %) most often while host communities sought care most in private clinics (62.4 %). Overall, 69.7 % of refugees and 82.7 % of host community members reported an out-of-pocket consultation payment (p = 0.041) with an average payment of US$15 among refugees and US$42 for the host community (p <0.001). CONCLUSIONS: Given the protracted nature of the Syrian crisis and the burden on the Lebanese health system, implications for both individuals with NCDs and Lebanon's health system are immense. The burden of out of pocket expenses on persons with NCDs are also substantial, especially given the tenuous economic status of many refugees and the less affluent segments of the Lebanese population. Greater investment in the public sector health system could benefit all parties. Efforts to improve quality of care for NCDs at the primary care level are also a critical component of preventing adverse outcomes and lowering the overall cost of care for NCDs. PMID- 27777615 TI - Erratum to: Pathways to psychiatric care for mental disorders: a retrospective study of patients seeking mental health services at a public psychiatric facility in Ghana. AB - [This corrects the article DOI: 10.1186/s13033-016-0095-1.]. PMID- 27777614 TI - Knowledge evaluation in dementia care networks: a mixed-methods analysis of knowledge evaluation strategies and the success of informing family caregivers about dementia support services. AB - BACKGROUND: In general, most people with dementia living in the community are served by family caregivers at home. A similar situation is found in Germany. One primary goal of dementia care networks is to provide information on support services available to these caregiving relatives of people with dementia via knowledge management. The evaluation of knowledge management tools and processes for dementia care networks is relevant to their performance in successfully achieving information goals. One goal of this paper was the analysis of knowledge evaluation in dementia care networks, including potential barriers and facilitators, across Germany within the DemNet-D study. Additionally, the impact of highly formalized and less formalized knowledge management performed in dementia care networks was analyzed relative to family caregivers' feelings of being informed about dementia support services. METHODS: Qualitative data were collected through interviews with and semi-standardized questionnaires administered to key persons from 13 dementia care networks between 2013 and 2014. Quantitative data were collected using standardized questionnaires. A structured content analysis and a mixed-methods analysis were conducted. RESULTS: The analyses indicated that the development of knowledge goals is important for a systematic knowledge evaluation process. Feedback from family caregivers was found to be beneficial for the target-oriented evaluation of dementia care network services. Surveys and special conferences, such as quality circles, were used in certain networks to solicit this feedback. Limited resources can hinder the development of formalized knowledge evaluation processes. More formalized knowledge management processes in dementia care networks can lead to a higher level of knowledge among family caregivers. CONCLUSIONS: The studied tools, processes and potential barriers related to knowledge evaluation contribute to the development and optimization of knowledge evaluation strategies for use in dementia care networks. Furthermore, the mixed-methods results indicate that highly formalized dementia care networks are especially successful in providing information to family members caring for people with dementia via knowledge management. PMID- 27777616 TI - Significantly enhancing recombinant alkaline amylase production in Bacillus subtilis by integration of a novel mutagenesis-screening strategy with systems level fermentation optimization. AB - BACKGROUND: Alkaline amylase has significant potential for applications in the textile, paper and detergent industries, however, low yield of which cannot meet the requirement of industrial application. In this work, a novel ARTP mutagenesis screening method and fermentation optimization strategies were used to significantly improve the expression level of recombinant alkaline amylase in B. subtilis 168. RESULTS: The activity of alkaline amylase in mutant B. subtilis 168 mut-16# strain was 1.34-fold greater than that in the wild-type, and the highest specific production rate was improved from 1.31 U/(mg.h) in the wild-type strain to 1.57 U/(mg.h) in the mutant strain. Meanwhile, the growth of B. subtilis was significantly enhanced by ARTP mutagenesis. When the agitation speed was 550 rpm, the highest activity of recombinant alkaline amylase was 1.16- and 1.25-fold of the activities at 450 and 650 rpm, respectively. When the concentration of soluble starch and soy peptone in the initial fermentation medium was doubled, alkaline amylase activity was increased 1.29-fold. Feeding hydrolyzed starch and soy peptone mixture or glucose significantly improved cell growth, but inhibited the alkaline amylase production in B. subtilis 168 mut-16#. The highest alkaline amylase activity by feeding hydrolyzed starch reached 591.4 U/mL, which was 1.51 fold the activity by feeding hydrolyzed starch and soy peptone mixture. Single pulse feeding-based batch feeding at 10 h favored the production of alkaline amylase in B. subtilis 168 mut-16#. CONCLUSION: The results indicated that this novel ARTP mutagenesis-screening method could significantly improve the yield of recombinant proteins in B. subtilis. Meanwhile, fermentation optimization strategies efficiently promoted expression of recombinant alkaline amylase in B. subtilis 168 mut-16#. These findings have great potential for facilitating the industrial-scale production of alkaline amylase and other enzymes, using B. subtilis cultures as microbial cell factories. PMID- 27777618 TI - Efficient hydrolysis of raw starch and ethanol fermentation: a novel raw starch digesting glucoamylase from Penicillium oxalicum. AB - BACKGROUND: Starch is a very abundant and renewable carbohydrate and is an important feedstock for industrial applications. The conventional starch liquefaction and saccharification processes are energy-intensive, complicated, and not environmentally friendly. Raw starch-digesting glucoamylases are capable of directly hydrolyzing raw starch to glucose at low temperatures, which significantly simplifies processing and reduces the cost of producing starch based products. RESULTS: A novel raw starch-digesting glucoamylase PoGA15A with high enzymatic activity was purified from Penicillium oxalicum GXU20 and biochemically characterized. The PoGA15A enzyme had a molecular weight of 75.4 kDa, and was most active at pH 4.5 and 65 degrees C. The enzyme showed remarkably broad pH stability (pH 2.0-10.5) and substrate specificity, and was able to degrade various types of raw starches at 40 degrees C. Its adsorption ability for different raw starches was consistent with its degrading capacities for the corresponding substrate. The cDNA encoding the enzyme was cloned and heterologously expressed in Pichia pastoris. The recombinant enzyme could quickly and efficiently hydrolyze different concentrations of raw corn and cassava flours (50, 100, and 150 g/L) with the addition of alpha-amylase at 40 degrees C. Furthermore, when used in the simultaneous saccharification and fermentation of 150 g/L raw flours to ethanol with the addition of alpha-amylase, the ethanol yield reached 61.0 g/L with a high fermentation efficiency of 95.1 % after 48 h when raw corn flour was used as the substrate. An ethanol yield of 57.0 g/L and 93.5 % of fermentation efficiency were achieved with raw cassava flour after 36 h. In addition, the starch-binding domain deletion analysis revealed that SBD plays a very important role in raw starch hydrolysis by the enzyme PoGA15A. CONCLUSIONS: A novel raw starch-digesting glucoamylase from P. oxalicum, with high enzymatic activity, was biochemically, molecularly, and genetically identified. Its efficient hydrolysis of raw starches and its high efficiency during the direct conversion of raw corn and cassava flours via simultaneous saccharification and fermentation to ethanol suggests that the enzyme has a number of potential applications in industrial starch processing and starch-based ethanol production. PMID- 27777617 TI - Metabolic engineering of oleaginous yeast Yarrowia lipolytica for limonene overproduction. AB - BACKGROUND: Limonene, a monocyclic monoterpene, is known for its using as an important precursor of many flavoring, pharmaceutical, and biodiesel products. Currently, d-limonene has been produced via fractionation from essential oils or as a byproduct of orange juice production, however, considering the increasing need for limonene and a certain amount of pesticides may exist in the limonene obtained from the citrus industry, some other methods should be explored to produce limonene. RESULTS: To construct the limonene synthetic pathway in Yarrowia lipolytica, two genes encoding neryl diphosphate synthase 1 (NDPS1) and limonene synthase (LS) were codon-optimized and heterologously expressed in Y. lipolytica. Furthermore, to maximize limonene production, several genes involved in the MVA pathway were overexpressed, either in different copies of the same gene or in combination. Finally with the optimized pyruvic acid and dodecane concentration in flask culture, a maximum limonene titer and content of 23.56 mg/L and 1.36 mg/g DCW were achieved in the final engineered strain Po1f-LN-051, showing approximately 226-fold increase compared with the initial yield 0.006 mg/g DCW. CONCLUSIONS: This is the first report on limonene biosynthesis in oleaginous yeast Y. lipolytica by heterologous expression of codon-optimized tLS and tNDPS1 genes. To our knowledge, the limonene production 23.56 mg/L, is the highest limonene production level reported in yeast. In short, we demonstrate that Y. lipolytica provides a compelling platform for the overproduction of limonene derivatives, and even other monoterpenes. PMID- 27777620 TI - An enclosed rotating floating photobioreactor (RFP) powered by flowing water for mass cultivation of photosynthetic microalgae. AB - BACKGROUND: The design of photobioreactor (PBR) for outdoor mass cultivation of microalgae determines the distribution of solar irradiance among cells in the culture, mode of agitation, mass transfer efficacy, and energy consumption, thus determines the productivity of the system and the cost of production. In this study, the concept of a floating photobioreactor with rotation function is proposed. Dunaliella tertiolecta, a model microalga, cultured in the attached vessels was evaluated. RESULTS: The rotation of the photobioreactor was powered by flowing water, in this case waves generated through a paddle wheel in an outdoor raceway pond for proof of concept. The rotating floating PBR (RFP) could be powered by natural flowing stream, river, and tidal waves, thus there could be no energy cost for agitation of the cultures in maintaining the cells in suspension. This RFP is characterized by its energy-saving and temperature control properties as well as more homogenous light distribution in the culture as compared to conventional culture systems, such as raceway pond. Maximal cell concentration of 8.38 * 106 cells mL-1, biomass productivity of 3.10 g m-2 day-1, and photosynthetic efficiency of 4.61 % (PAR) were achieved. In addition, satisfactory productivities of D. tertiolecta metabolites including carotenoids, mycosporine-like amino acids and lipids were also obtained. CONCLUSIONS: The RFP, powered by flowing water, creates an innovative culture technology for economical cultivation of microalgal cells and production of microalgal metabolites. PMID- 27777619 TI - Synergetic effect of dilute acid and alkali treatments on fractional application of rice straw. AB - BACKGROUND: The biorefinery based on an effective and economical process is to fractionate the three primary constituents (cellulose, hemicelluloses, and lignin) from lignocellulosic biomass, in which the constituents can be respectively converted into high-value-added products. In this study, a successive treatment with dilute acid (0.25-1.0 % aqueous H2SO4, 100-150 degrees C, 0.5-3.0 h) and alkali (1.5 % aqueous NaOH, 80 degrees C, 3 h) was performed to produce xylooligosaccharides (XOS), high-purity lignin, and cellulose-rich substrates to produce glucose for ethanol production from rice straw (RS). RESULTS: During the dilute acid pretreatment, the maximum production of XOS (12.8 g XOS/100 g RS) with a relatively low level of byproducts was achieved at a relatively low temperature (130 degrees C) and a low H2SO4 concentration (0.5 %) for a reaction time of 2.0 h. During the alkali post-treatment, 14.2 g lignin with a higher purity of 99.2 % and 30.3 g glucose with a higher conversion rate by enzymatic hydrolysis were obtained from the successively treated substrates with 100 g RS as starting material. As the pretreatment temperature, H2SO4 concentration, or time increased, more beta-O-4 linkages in lignins were cleaved, which resulted in an increase of phenolic OH groups in lignin macromolecules. The signal intensities of G2 and G6 in HSQC spectra gradually reduced and vanished, indicating that a condensation reaction probably occurred at C-2 and C-6 of guaiacyl with the side chains of other lignin. CONCLUSIONS: The present study demonstrated that the successive treatments with dilute acid and alkali had a synergetic effect on the fractionation of the three main constituents in RS. It is believed that the results obtained will enhance the availability of the combined techniques in the lignocellulosic biorefinery for the application of the main components, cellulose, hemicelluloses, and lignin as biochemical and biofuels. PMID- 27777621 TI - Genome editing of Clostridium autoethanogenum using CRISPR/Cas9. AB - BACKGROUND: Impactful greenhouse gas emissions abatement can now be achieved through gas fermentation using acetogenic microbes for the production of low carbon fuels and chemicals. However, compared to traditional hosts like Escherichia coli or yeast, only basic genetic tools exist for gas-fermenting acetogens. To advance the process, a robust genetic engineering platform for acetogens is essential. RESULTS: In this study, we report scarless genome editing of an industrially used model acetogen, Clostridium autoethanogenum, using the CRISPR/Cas9 system. Initial efforts to retrofit the CRISPR/Cas9 system for C. autoethanogenum resulted in poor efficiency likely due to uncontrolled expression of Cas9. To address this, we constructed and screened a small library of tetracycline-inducible promoters that can also be used to fine-tune gene expression. With a new inducible promoter, the efficiency of CRISPR/Cas9-mediated desired gene deletion in C. autoethanogenum was improved to over 50 %, making it a viable tool for engineering C. autoethanogenum. CONCLUSIONS: Addition of both an inducible promoter library and a scarless genome editing tool is an important expansion to the genetic tool box of industrial C. autoethanogenum strain. PMID- 27777622 TI - Comprehensive investigations of biobutanol production by a non-acetone and 1,3 propanediol generating Clostridium strain from glycerol and polysaccharides. AB - BACKGROUND: Low-cost feedstocks, a single product (butanol), and a high butanol titer are three key points for establishing a sustainable and economically viable process for biological butanol production. Here, we comprehensively investigated the butanol production from mono-substrates, mainly glycerol and polysaccharides, mainly starch and xylan by a newly identified wild-type Clostridium pasteurianum GL11. RESULTS: Strain GL11 produced 14.7 g/L of butanol with a yield of 0.41 g/g from glycerol in the batch mode without formation of by-products of acetone and 1,3-propanediol (1,3-PDO). With in situ extraction with biodiesel, the amount of butanol was finally improved to 28.8 g/L in the fed-batch mode. Genomic and enzymatic analysis showed that the deficiency of key enzymes involved in acetone and 1,3-PDO pathway within strain GL11 led to the elimination of these by products, which may also greatly simplify downstream separation. The elimination of acetone and 1,3-PDO and high butanol tolerance contributed to its high butanol production yield from glycerol. More importantly, strain GL11 could directly convert polysaccharides, such as xylan and starch to butanol with secretion of xylanase and amylase via consolidated bioprocessing. CONCLUSIONS: The wild-type strain GL11 was found to be particularly advantageous due to its capability of efficient butanol production from glycerol and polysaccharides with elimination of acetone and 1,3-PDO formation. And the high butanol production with in situ extraction by using biodiesel would significantly enhance the economic feasibility of fermentative production of butanol from glycerol. These unique features of C. pasteurianum GL11 open the door to the possibility of cost effective biofuels production in large scale. PMID- 27777624 TI - Process design of SSCF for ethanol production from steam-pretreated, acetic-acid impregnated wheat straw. AB - BACKGROUND: Pretreatment is an important step in the production of ethanol from lignocellulosic material. Using acetic acid together with steam pretreatment allows the positive effects of an acid catalyst to be retained, while avoiding the negative environmental effects associated with sulphuric acid. Acetic acid is also formed during the pretreatment and hydrolysis of hemicellulose, and is a known inhibitor that may impair fermentation at high concentrations. The purpose of this study was to improve ethanol production from glucose and xylose in steam pretreated, acetic-acid-impregnated wheat straw by process design of simultaneous saccharification and co-fermentation (SSCF), using a genetically modified pentose fermenting yeast strain Saccharomyces cerevisiae. RESULTS: Ethanol was produced from glucose and xylose using both the liquid fraction and the whole slurry from pretreated materials. The highest ethanol concentration achieved was 37.5 g/L, corresponding to an overall ethanol yield of 0.32 g/g based on the glucose and xylose available in the pretreated material. To obtain this concentration, a slurry with a water-insoluble solids (WIS) content of 11.7 % was used, using a fed-batch SSCF strategy. A higher overall ethanol yield (0.36 g/g) was obtained at 10 % WIS. CONCLUSIONS: Ethanol production from steam-pretreated, acetic-acid impregnated wheat straw through SSCF with a pentose fermenting S. cerevisiae strain was successfully demonstrated. However, the ethanol concentration was too low and the residence time too long to be suitable for large-scale applications. It is hoped that further process design focusing on the enzymatic conversion of cellulose to glucose will allow the combination of acetic acid pretreatment and co-fermentation of glucose and xylose. PMID- 27777623 TI - Aquatic plant Azolla as the universal feedstock for biofuel production. AB - BACKGROUND: The quest for sustainable production of renewable and cheap biofuels has triggered an intensive search for domestication of the next generation of bioenergy crops. Aquatic plants which can rapidly colonize wetlands are attracting attention because of their ability to grow in wastewaters and produce large amounts of biomass. Representatives of Azolla species are some of the fastest growing plants, producing substantial biomass when growing in contaminated water and natural ecosystems. Together with their evolutional symbiont, the cyanobacterium Anabaena azollae, Azolla biomass has a unique chemical composition accumulating in each leaf including three major types of bioenergy molecules: cellulose/hemicellulose, starch and lipids, resembling combinations of terrestrial bioenergy crops and microalgae. RESULTS: The growth of Azolla filiculoides in synthetic wastewater led up to 25, 69, 24 and 40 % reduction of NH4-N, NO3-N, PO4-P and selenium, respectively, after 5 days of treatment. This led to a 2.6-fold reduction in toxicity of the treated wastewater to shrimps, common inhabitants of wetlands. Two Azolla species, Azolla filiculoides and Azolla pinnata, were used as feedstock for the production of a range of functional hydrocarbons through hydrothermal liquefaction, bio-hydrogen and bio-ethanol. Given the high annual productivity of Azolla, hydrothermal liquefaction can lead to the theoretical production of 20.2 t/ha-year of bio-oil and 48 t/ha-year of bio-char. The ethanol production from Azolla filiculoides, 11.7 * 103 L/ha-year, is close to that from corn stover (13.3 * 103 L/ha-year), but higher than from miscanthus (2.3 * 103 L/ha-year) and woody plants, such as willow (0.3 * 103 L/ha-year) and poplar (1.3 * 103 L/ha-year). With a high C/N ratio, fermentation of Azolla biomass generates 2.2 mol/mol glucose/xylose of hydrogen, making this species a competitive feedstock for hydrogen production compared with other bioenergy crops. CONCLUSIONS: The high productivity, the ability to grow on wastewaters and unique chemical composition make Azolla species the most attractive, sustainable and universal feedstock for low cost, low energy demanding, near zero maintenance system for the production of a wide spectrum of renewable biofuels. PMID- 27777625 TI - Long-term variability in sugarcane bagasse feedstock compositional methods: sources and magnitude of analytical variability. AB - BACKGROUND: In an effort to find economical, carbon-neutral transportation fuels, biomass feedstock compositional analysis methods are used to monitor, compare, and improve biofuel conversion processes. These methods are empirical, and the analytical variability seen in the feedstock compositional data propagates into variability in the conversion yields, component balances, mass balances, and ultimately the minimum ethanol selling price (MESP). We report the average composition and standard deviations of 119 individually extracted National Institute of Standards and Technology (NIST) bagasse [Reference Material (RM) 8491] run by seven analysts over 7 years. Two additional datasets, using bulk extracted bagasse (containing 58 and 291 replicates each), were examined to separate out the effects of batch, analyst, sugar recovery standard calculation method, and extractions from the total analytical variability seen in the individually extracted dataset. We believe this is the world's largest NIST bagasse compositional analysis dataset and it provides unique insight into the long-term analytical variability. Understanding the long-term variability of the feedstock analysis will help determine the minimum difference that can be detected in yield, mass balance, and efficiency calculations. RESULTS: The long term data show consistent bagasse component values through time and by different analysts. This suggests that the standard compositional analysis methods were performed consistently and that the bagasse RM itself remained unchanged during this time period. The long-term variability seen here is generally higher than short-term variabilities. It is worth noting that the effect of short-term or long-term feedstock compositional variability on MESP is small, about $0.03 per gallon. CONCLUSIONS: The long-term analysis variabilities reported here are plausible minimum values for these methods, though not necessarily average or expected variabilities. We must emphasize the importance of training and good analytical procedures needed to generate this data. When combined with a robust QA/QC oversight protocol, these empirical methods can be relied upon to generate high-quality data over a long period of time. PMID- 27777626 TI - Directed plant cell-wall accumulation of iron: embedding co-catalyst for efficient biomass conversion. AB - BACKGROUND: Plant lignocellulosic biomass is an abundant, renewable feedstock for the production of biobased fuels and chemicals. Previously, we showed that iron can act as a co-catalyst to improve the deconstruction of lignocellulosic biomass. However, directly adding iron catalysts into biomass prior to pretreatment is diffusion limited, and increases the cost of biorefinery operations. Recently, we developed a new strategy for expressing iron-storage protein ferritin intracellularly to accumulate iron as a catalyst for the downstream deconstruction of lignocellulosic biomass. In this study, we extend this approach by fusing the heterologous ferritin gene with a signal peptide for secretion into Arabidopsis cell walls (referred to here as FerEX). RESULTS: The transgenic Arabidopsis plants. FerEX. accumulated iron under both normal and iron fertilized growth conditions; under the latter (iron-fertilized) condition, FerEX transgenic plants showed an increase in plant height and dry weight by 12 and 18 %, respectively, compared with the empty vector control plants. The SDS- and native-PAGE separation of cell-wall protein extracts followed by Western blot analyses confirmed the extracellular expression of ferritin in FerEX plants. Meanwhile, Perls' Prussian blue staining and X-ray fluorescence microscopy (XFM) maps revealed iron depositions in both the secondary and compound middle lamellae cell-wall layers, as well as in some of the corner compound middle lamella in FerEX. Remarkably, their harvested biomasses showed enhanced pretreatability and digestibility, releasing, respectively, 21 % more glucose and 34 % more xylose than the empty vector control plants. These values are significantly higher than those of our recently obtained ferritin intracellularly expressed plants. CONCLUSIONS: This study demonstrated that extracellular expression of ferritin in Arabidopsis can produce plants with increased growth and iron accumulation, and reduced thermal and enzymatic recalcitrance. The results are attributed to the intimate colocation of the iron co-catalyst and the cellulose and hemicellulose within the plant cell-wall region, supporting the genetic modification strategy for incorporating conversion catalysts into energy crops prior to harvesting or processing at the biorefinery. PMID- 27777627 TI - FEDRR: fast, exhaustive detection of redundant hierarchical relations for quality improvement of large biomedical ontologies. AB - BACKGROUND: Redundant hierarchical relations refer to such patterns as two paths from one concept to another, one with length one (direct) and the other with length greater than one (indirect). Each redundant relation represents a possibly unintended defect that needs to be corrected in the ontology quality assurance process. Detecting and eliminating redundant relations would help improve the results of all methods relying on the relevant ontological systems as knowledge source, such as the computation of semantic distance between concepts and for ontology matching and alignment. RESULTS: This paper introduces a novel and scalable approach, called FEDRR - Fast, Exhaustive Detection of Redundant Relations - for quality assurance work during ontological evolution. FEDRR combines the algorithm ideas of Dynamic Programming with Topological Sort, for exhaustive mining of all redundant hierarchical relations in ontological hierarchies, in O(c.|V|+|E|) time, where |V| is the number of concepts, |E| is the number of the relations, and c is a constant in practice. Using FEDRR, we performed exhaustive search of all redundant is-a relations in two of the largest ontological systems in biomedicine: SNOMED CT and Gene Ontology (GO). 372 and 1609 redundant is-a relations were found in the 2015-09-01 version of SNOMED CT and 2015-05-01 version of GO, respectively. We have also performed FEDRR on over 190 source vocabularies in the UMLS - a large integrated repository of biomedical ontologies, and identified six sources containing redundant is-a relations. Randomly generated ontologies have also been used to further validate the efficiency of FEDRR. CONCLUSIONS: FEDRR provides a generally applicable, effective tool for systematic detecting redundant relations in large ontological systems for quality improvement. PMID- 27777628 TI - High-throughput assessment of context-dependent effects of chromatin proteins. AB - BACKGROUND: Chromatin proteins control gene activity in a concerted manner. We developed a high-throughput assay to study the effects of the local chromatin environment on the regulatory activity of a protein of interest. The assay combines a previously reported multiplexing strategy based on barcoded randomly integrated reporters with Gal4-mediated tethering. We applied the assay to Drosophila heterochromatin protein 1a (HP1a), which is mostly known as a repressive protein but has also been linked to transcriptional activation. RESULTS: Recruitment to over 1000 genomic locations revealed that HP1a is a potent repressor able to silence even highly expressing reporter genes. However, the local chromatin context can modulate HP1a function. In pericentromeric regions, HP1a-induced repression was enhanced by twofold. In regions marked by a H3K36me3-rich chromatin signature, HP1a-dependent silencing was significantly decreased. We found no evidence for an activating function of HP1a in our experimental system. Furthermore, we did not observe stable transmission of repression over mitotic divisions after loss of targeted HP1a. CONCLUSIONS: The multiplexed tethered reporter assay should be applicable to a large number of chromatin proteins and will be a useful tool to dissect combinatorial regulatory interactions in chromatin. PMID- 27777630 TI - The emergence of Klebsiella pneumoniae liver abscess in non-diabetic patients and the distribution of capsular types. AB - BACKGROUND: Klebsiella pneumoniae is the most common pathogen of community acquired pyogenic liver abscess in East Asia. Diabetes mellitus (DM) is a well established risk factor for K. pneumoniae liver abscess (KPLA). However, reports regarding the emergence of KPLA in non-diabetic patients are limited. RESULTS: A total 230 patients with KPLA from a medical center in Taiwan were identified retrospectively. The rate of DM in patients with KPLA was 44.4 % in 2011, 57.9 % in 2012, 44.9 % in 2013, 35.0 % in 2014, and 53.5 % in 2015. Diabetic patients had higher rate of gas-forming abscesses than non-diabetic patients, but the clinical outcomes were not different. The six virulent capsular types (K1, K2, K5, K20, K54, and K57) accounted for 90.2 % of all K. pneumoniae isolates, and were more prevalent in non-diabetic than diabetic patients (93.9 vs 85.9 %, P = 0.048). The six virulent capsular types were also more prevalent in the group with optimal glycemic levels (Non-DM and DM with HbA1c level <7 %) than the DM group with HbA1c level >=7 % (93.9 vs 84.3 %, P = 0.022). CONCLUSION: Klebsiella pneumoniae liver abscess has emerged in non-diabetic patients in Taiwan. Diabetic patients were at higher risk of acquiring gas-forming abscesses. Non diabetic patients and diabetic patients with optimal glycemic levels are more susceptible to the virulent capsular types of K. pneumoniae. PMID- 27777629 TI - An H4K16 histone acetyltransferase mediates decondensation of the X chromosome in C. elegans males. AB - BACKGROUND: In C. elegans, in order to equalize gene expression between the sexes and balance X and autosomal expression, two steps are believed to be required. First, an unknown mechanism is hypothesized to upregulate the X chromosome in both sexes. This mechanism balances the X to autosomal expression in males, but creates X overexpression in hermaphrodites. Therefore, to restore the balance, hermaphrodites downregulate gene expression twofold on both X chromosomes. While many studies have focused on X chromosome downregulation, the mechanism of X upregulation is not known. RESULTS: To gain more insight into X upregulation, we studied the effects of chromatin condensation and histone acetylation on gene expression levels in male C. elegans. We have found that the H4K16 histone acetyltransferase MYS-1/Tip60 mediates dramatic decondensation of the male X chromosome as measured by FISH. However, RNA-seq analysis revealed that MYS-1 contributes only slightly to upregulation of gene expression on the X chromosome. These results suggest that the level of chromosome decondensation does not necessarily correlate with the degree of gene expression change in vivo. Furthermore, the X chromosome is more sensitive to MYS-1-mediated decondensation than the autosomes, despite similar levels of H4K16ac on all chromosomes, as measured by ChIP-seq. H4K16ac levels weakly correlate with gene expression levels on both the X and the autosomes, but highly expressed genes on the X chromosome do not contain exceptionally high levels of H4K16ac. CONCLUSION: These results indicate that H4K16ac and chromosome decondensation influence regulation of the male X chromosome; however, they do not fully account for the high levels of gene expression observed on the X chromosomes. PMID- 27777631 TI - Functional opsin retrogene in nocturnal moth. AB - BACKGROUND: Retrotransposed genes are different to other types of genes as they originate from a processed mRNA and are then inserted back into the genome. For a long time, the contribution of this mechanism to the origin of new genes, and hence to the evolutionary process, has been questioned as retrogenes usually lose their regulatory sequences upon insertion and generally decay into pseudogenes. In recent years, there is growing evidence, notably in mammals, that retrotransposition is an important process driving the origin of new genes, but the evidence in insects remains largely restricted to a few model species. FINDINGS: By sequencing the messenger RNA of three developmental stages (first and fifth instar larvae and adults) of the pest Helicoverpa armigera, we identified a second, intronless, long-wavelength sensitive opsin (that we called LWS2). We then amplified the partial CDS of LWS2 retrogenes from another six noctuid moths, and investigate the phylogenetic distribution of LWS2 in 15 complete Lepidoptera and 1 Trichoptera genomes. Our results suggests that LWS2 evolved within the noctuid. Furthermore, we found that all the LWS2 opsins have an intact ORF, and have an omega-value (omega = 0.08202) relatively higher compared to their paralog LWS1 (omega = 0.02536), suggesting that LWS2 opsins were under relaxed purifying selection. Finally, the LWS2 shows temporal compartmentalization of expression. LWS2 in H. armigera in adult is expressed at a significantly lower level compared to all other opsins in adults; while in the in 1st instar stage larvae, it is expressed at a significantly higher level compared to other opsins. CONCLUSIONS: Together the results of our evolutionary sequence analyses and gene expression data suggest that LWS2 is a functional gene, however, the relatively low level of expression in adults suggests that LWS2 is most likely not involved in mediating the visual process. PMID- 27777632 TI - The effect of maternal undernutrition on the rat placental transcriptome: protein restriction up-regulates cholesterol transport. AB - BACKGROUND: Fetal exposure to a maternal low protein diet during rat pregnancy is associated with hypertension, renal dysfunction and metabolic disturbance in adult life. These effects are present when dietary manipulations target only the first half of pregnancy. It was hypothesised that early gestation protein restriction would impact upon placental gene expression and that this may give clues to the mechanism which links maternal diet to later consequences. METHODS: Pregnant rats were fed control or a low protein diet from conception to day 13 gestation. Placentas were collected and RNA sequencing performed using the Illumina platform. RESULTS: Protein restriction down-regulated 67 genes and up regulated 24 genes in the placenta. Ingenuity pathway analysis showed significant enrichment in pathways related to cholesterol and lipoprotein transport and metabolism, including atherosclerosis signalling, clathrin-mediated endocytosis, LXR/RXR and FXR/RXR activation. Genes at the centre of these processes included the apolipoproteins ApoB, ApoA2 and ApoC2, microsomal triglyceride transfer protein (Mttp), the clathrin-endocytosis receptor cubilin, the transcription factor retinol binding protein 4 (Rbp4) and transerythrin (Ttr; a retinol and thyroid hormone transporter). Real-time PCR measurements largely confirmed the findings of RNASeq and indicated that the impact of protein restriction was often striking (cubilin up-regulated 32-fold, apoC2 up-regulated 17.6-fold). The findings show that gene expression in specific pathways is modulated by maternal protein restriction in the day-13 rat placenta. CONCLUSIONS: Changes in cholesterol transport may contribute to altered tissue development in the fetus and hence programme risk of disease in later life. PMID- 27777633 TI - Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high resolution analysis of copy number variation. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. METHODS: We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD. RESULTS: We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 * 10-03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4. CONCLUSIONS: Our findings suggest that rare CNVs may contribute to the etiology of OCD. PMID- 27777634 TI - Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome. AB - BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. MECP2-null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABAARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABAARs, there is a group of GABAARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT. METHODS: Wild-type and MECP2-null mice were randomly divided into four groups, receiving the extrasynaptic GABAAR agonist 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology. RESULTS: With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of MECP2-null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression. CONCLUSIONS: THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms in MECP2-null mice and perhaps in people with RTT as well. PMID- 27777635 TI - Global DNA methylation profiling reveals new insights into epigenetically deregulated protein coding and long noncoding RNAs in CLL. AB - BACKGROUND: Methyl-CpG-binding domain protein enriched genome-wide sequencing (MBD-Seq) is a robust and powerful method for analyzing methylated CpG-rich regions with complete genome-wide coverage. In chronic lymphocytic leukemia (CLL), the role of CpG methylated regions associated with transcribed long noncoding RNAs (lncRNA) and repetitive genomic elements are poorly understood. Based on MBD-Seq, we characterized the global methylation profile of high CpG rich regions in different CLL prognostic subgroups based on IGHV mutational status. RESULTS: Our study identified 5800 hypermethylated and 12,570 hypomethylated CLL-specific differentially methylated genes (cllDMGs) compared to normal controls. From cllDMGs, 40 % of hypermethylated and 60 % of hypomethylated genes were mapped to noncoding RNAs. In addition, we found that the major repetitive elements such as short interspersed elements (SINE) and long interspersed elements (LINE) have a high percentage of cllDMRs (differentially methylated regions) in IGHV subgroups compared to normal controls. Finally, two novel lncRNAs (hypermethylated CRNDE and hypomethylated AC012065.7) were validated in an independent CLL sample cohort (48 samples) compared with 6 normal sorted B cell samples using quantitative pyrosequencing analysis. The methylation levels showed an inverse correlation to gene expression levels analyzed by real time quantitative PCR. Notably, survival analysis revealed that hypermethylation of CRNDE and hypomethylation of AC012065.7 correlated with an inferior outcome. CONCLUSIONS: Thus, our comprehensive methylation analysis by MBD-Seq provided novel hyper and hypomethylated long noncoding RNAs, repetitive elements, along with protein coding genes as potential epigenetic-based CLL-signature genes involved in disease pathogenesis and prognosis. PMID- 27777638 TI - A multivariate geostatistical methodology to delineate areas of potential interest for future sedimentary gold exploration. AB - This paper describes a multivariate geostatistical methodology to delineate areas of potential interest for future sedimentary gold exploration, with an application to an abandoned sedimentary gold mining region in Portugal. The main challenge was the existence of only a dozen gold measurements confined to the grounds of the old gold mines, which precluded the application of traditional interpolation techniques, such as cokriging. The analysis could, however, capitalize on 376 stream sediment samples that were analyzed for twenty two elements. Gold (Au) was first predicted at all 376 locations using linear regression (R2=0.798) and four metals (Fe, As, Sn and W), which are known to be mostly associated with the local gold's paragenesis. One hundred realizations of the spatial distribution of gold content were generated using sequential indicator simulation and a soft indicator coding of regression estimates, to supplement the hard indicator coding of gold measurements. Each simulated map then underwent a local cluster analysis to identify significant aggregates of low or high values. The one hundred classified maps were processed to derive the most likely classification of each simulated node and the associated probability of occurrence. Examining the distribution of the hot-spots and cold-spots reveals a clear enrichment in Au along the Erges River downstream from the old sedimentary mineralization. PMID- 27777636 TI - Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. AB - BACKGROUND: Environmental perturbation of epigenetic mechanisms is linked to a growing number of diseases. Characterizing the role environmental factors play in modifying the epigenome is important for disease etiology. Vitamin D is an essential nutrient affecting brain, bone, heart, immune and reproductive health. Vitamin D insufficiency is a global issue, and the role in maternal and child health remains under investigation. METHODS: We used Collaborative Cross (CC) inbred mice to characterize the effect of maternal vitamin D depletion on offspring phenotypic and epigenetic outcomes at imprinted domains (H19/Igf2, Snrpn, Dlk1/Gtl2, and Grb10) in the soma (liver) and germline (sperm). We assessed outcomes in two generations of offspring to determine heritability. We used reciprocal crosses between lines CC001/Unc and CC011/Unc to investigate parent of origin effects. RESULTS: Maternal vitamin D deficiency led to altered body weight and DNA methylation in two generations of offspring. Loci assayed in adult liver and sperm were mostly hypomethylated, but changes were few and small in effect size (<7 % difference on average). There was no change in total expression of genes adjacent to methylation changes in neonatal liver. Methylation changes were cell type specific such that changes at IG-DMR were present in sperm but not in liver. Some methylation changes were distinct between generations such that methylation changes at the H19ICR in second-generation liver were not present in first-generation sperm or liver. Interestingly, some diet-dependent changes in body weight and methylation were seemingly influenced by parent of origin such that reciprocal crosses exhibited inverse effects. CONCLUSIONS: These findings demonstrate that maternal vitamin D status plays a role in determining DNA methylation state in the germline and soma. Detection of methylation changes in the unexposed second-generation demonstrates that maternal vitamin D depletion can have long-term effects on the epigenome of subsequent generations. Differences in vitamin D-dependent epigenetic state between cell types and generations indicate perturbation of the epigenetic landscape rather than a targeted, locus-specific effect. While the biological importance of these subtle changes remains unclear, they warrant an investigation of epigenome-wide effects of maternal vitamin D depletion. PMID- 27777637 TI - Integrating DNA methylation and microRNA biomarkers in sputum for lung cancer detection. AB - BACKGROUND: Abnormal microRNA (miRNA) expressions and promoter methylation of genes detected in sputum may provide biomarkers for non-small lung cancer (NSCLC). Here, we evaluate the individual and combined analysis of the two classes of sputum molecular biomarkers for NSCLC detection. RESULTS: We analyze expression of 3 miRNAs (miR-21, miR-31, and miR-210) and methylation of 3 genes (RASSF1A, PRDM14, and 3OST2), which were previously identified as potential biomarkers for NSCLC, in sputum of a set of 117 stage I NSCLC patients and 174 cancer-free smokers. The results are validated in a different set of 144 stage I NSCLC patients and 171 controls. The panel of 3 miRNA biomarkers has 81.5 % sensitivity and 85.9 % specificity; the panel of 3 methylation biomarkers displays 82.9 % sensitivity and 76.4 % specificity for NSCLC detection. Integrated analysis of 2 miRNAs (miR-31 and miR-210) and 2 genes (RASSF1A and 3OST2) yields higher sensitivity (87.3 %) and specificity (90.3 %) compared with the individual panels of the biomarkers (P < 0.05). Combined analysis of all the 3 miRNAs and 3 genes does not have performance superior to that of the panel of 2 miRNAs and 2 genes (P > 0.05). The performance of combined use of the two classes of biomarkers was confirmed in the validation set. CONCLUSIONS: The integration of two different classes of biomarkers synergistically improves both the sensitivity and the specificity for the early detection of NSCLC. PMID- 27777639 TI - Differences in neuropsychological and behavioral parameters and brain structure in patients with familial adenomatous polyposis: a sibling-paired study. AB - BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colon cancer syndrome caused by mutations in adenomatous polyposis coli (APC) with both colonic and extra-colonic manifestations. Case reports have noted an association with FAP and intellectual disability and animal studies have shown that APC is implicated in neural development and function, but no studies have investigated neuropsychological, behavioral, or structural brain characteristics of patients with FAP. METHODS: We undertook a pilot, sibling-pair study comparing three patients with FAP to their sex-matched siblings without FAP. Each sibling pair underwent neuropsychological testing by a blinded examiner, high resolution brain MRI scans, and the mother of each pair rated her children's adaptive life skills and behavioral and emotional characteristics. Given the small number of study participants in this pilot study, quantitative comparisons of results were made by subtracting the score of the non-FAP sibling from the FAP patient on the various neuropsychological tests and parent rating questionnaires to calculate a difference, which was then divided by the standard deviation for each individual test to determine the difference, corrected for the standard deviation. Diffusion numbers in multiple regions of the brain as assessed by MRI were calculated for each study participant. RESULTS: We found similarity between siblings in all three pairs on a wide range of neuropsychological measures (general intelligence, executive function, and basic academic skills) as tested by the psychologist as well as in descriptions of adaptive life skills as rated by mothers. However, mothers' ratings of behavioral and emotional characteristics of two of the three pairs showed differences between the siblings, specifically that the patients with FAP were found to have more behavioral and emotional problems compared to their siblings. No differences in brain structure were identified by MRI. CONCLUSION: We report the first study exploring neuropsychological, behavioral, emotional, and structural brain characteristics of patients with FAP and found subjective differences as assessed by maternal perception in behavioral and emotional characteristics in patients with FAP compared to their siblings. Larger studies are needed to elucidate the relationship, if any, between FAP and brain function. PMID- 27777641 TI - Heated egg yolk challenge predicts the natural course of hen's egg allergy: a retrospective study. AB - BACKGROUND: Children do not always outgrow hen's egg allergies in early childhood. Because egg yolks are less allergenic than egg whites, we performed an oral food challenge with heated egg yolk slightly contaminated with egg white (EYSEW OFC) in infants allergic to hen's egg. We hypothesized that the EYSEW OFC results would predict the egg allergy's natural course. METHODS: We retrospectively reviewed participants with hen's egg allergy who underwent their first EYSEW OFC at 12-23 months of age between 2004 and 2010. Participants who passed the first EYSEW OFC were defined as EYSEW-tolerant, and participants who failed the OFC were defined as EYSEW-reactive. Participants who passed the EYSEW OFC underwent an OFC with half of a heated whole egg (WE OFC). Participants who passed a WE OFC were defined to be heated hen's egg-tolerant. Participants who failed the EYSEW OFC or the WE OFC underwent another OFC at least 6 months later. We compared tolerance to heated hen's egg at 36 months after the first EYSEW OFC between EYSEW-tolerant and EYSEW-reactive participants. Univariate and multivariate logistic regression analyses were conducted. RESULTS: Of the 197 included participants (median age: 18.3 months; range: 12.1-23.8 months), 179 (90.9 %) were EYSEW tolerant and 18 (9.1 %) were EYSEW reactive. At 36 months after the first EYSEW OFC, 164 EYSEW-tolerant (91.6 %) and 12 EYSEW-reactive participants (66.7 %) achieved heated hen's egg tolerance. In the univariate logistic regression analyses, EYSEW-reactive participants (crude odds ratio [OR], 5.5 [95 % confidence intervals [CI], 1.8-16.6]; p = 0.003) and those with baseline egg white sIgE levels (crude OR: 3.9 per ten-fold increase [95 % CI, 1.5 10.2]; p = 0.005) had greater odds of persistent allergy to hen's egg at 36 months after the first EYSEW OFC. In a multivariate logistic regression analysis after adjustment for baseline egg white sIgE, EYSEW-reactive participants had greater odds of persistent allergy to hen's egg than EYSEW-tolerant participants (adjusted OR: 4.6 [95 % CI, 1.5-15.0]; p = 0.003). CONCLUSIONS: Classifying infants who are allergic to hen's egg into EYSEW tolerant and EYSEW reactive groups was useful in determining prognosis. PMID- 27777640 TI - Neuromimetic Event-Based Detection for Closed-Loop Tactile Feedback Control of Upper Limb Prostheses. AB - Upper limb amputees lack the valuable tactile sensing that helps provide context about the surrounding environment. Here we utilize tactile information to provide active touch feedback to a prosthetic hand. First, we developed fingertip tactile sensors for producing biomimetic spiking responses for monitoring contact, release, and slip of an object grasped by a prosthetic hand. We convert the sensor output into pulses, mimicking the rapid and slowly adapting spiking responses of receptor afferents found in the human body. Second, we designed and implemented two neuromimetic event-based algorithms, Compliant Grasping and Slip Prevention, on a prosthesis to create a local closed-loop tactile feedback control system (i.e. tactile information is sent to the prosthesis). Grasping experiments were designed to assess the benefit of this biologically inspired neuromimetic tactile feedback to a prosthesis. Results from able-bodied and amputee subjects show the average number of objects that broke or slipped during grasping decreased by over 50% and the average time to complete a grasping task decreased by at least 10% for most trials when comparing neuromimetic tactile feedback with no feedback on a prosthesis. Our neuromimetic method of closed-loop tactile sensing is a novel approach to improving the function of upper limb prostheses. PMID- 27777644 TI - Gasotransmitters in Biology and Medicine: Molecular Mechanisms and Drug Targets. PMID- 27777643 TI - The Overexpression of NALP3 Inflammasome in Knee Osteoarthritis Is Associated with Synovial Membrane Prolidase and NADPH Oxidase 2. AB - Osteoarthritis is characterized by the presence of proinflammatory cytokines and reactive oxygen species. We aimed to clarify the role of prooxidant enzyme content at the synovial membrane level and how it correlates with the inflammatory process in patients with knee osteoarthritis (KOA). In synovial membranes from KOA patients and control group, we analyzed the protein content of prooxidant enzymes such as Nox2, xanthine oxidase (XO), and prolidase as well as the proinflammatory NALP3. Results show that protein content of prolidase and Nox2 increased 4.8- and 8.4-fold, respectively, and XO showed an increasing trend, while the NALP3 inflammasome increased 5.4-fold with respect to control group. Levels of prolidase and XO had a positive correlation between the levels of NALP3 and Nox2. By principal component analysis the protein expression pattern by study groups was evaluated. Three clusters were identified; protein expression patterns were higher for clusters two (prolidase) and three (XO and Nox2) between KOA patients and controls. Data suggest that prooxidant enzymes increase in synovial membrane of KOA patients and may contribute to the inflammatory state and degradation of the articular cartilage. PMID- 27777646 TI - A draft genome sequence of Pseudomonas veronii R4: a grapevine (Vitis vinifera L.) root-associated strain with high biocontrol potential. AB - A new plant commensal Pseudomonas veronii isolate (strain R4) was identified from a Xiphinema index biocontrol screen. Isolated from grapevine roots from vineyards in central Chile, the strain R4 exhibited a slower yet equivalently effective nematicide activity as the well-characterized P. protegens CHA0. Whole genome sequencing of strain R4 and comparative analysis among the available Pseudomonas spp. genomes allowed for the identification of gene clusters that encode putative extracellular proteases and lipase synthesis and secretion systems, which are proposed to mediate-at least in part-the observed nematicidal activity. In addition, R4 strain presented relevant gene clusters related to metal tolerance, which is typical in P. veronii. Bioinformatics analyses also showed gene clusters associated with plant growth promoting activity, such as indole-3-acetic acid synthesis. In addition, the strain R4 genome presented a metabolic gene clusters associated with phosphate and ammonia biotransformation from soil, which could improve their availability for plants. PMID- 27777647 TI - Erratum to: Permanent draft genome of Thermithiobacillus tepidarius DSM 3134T, a moderately thermophilic, obligately chemolithoautotrophic member of the Acidithiobacillia. AB - [This corrects the article DOI: 10.1186/s40793-016-0188-0.]. PMID- 27777648 TI - MIxS-HCR: a MIxS extension defining a minimal information standard for sequence data from environments pertaining to hydrocarbon resources. AB - Here we introduce a MIxS extension to facilitate the recording and cataloguing of metadata from samples related to hydrocarbon resources. The proposed MIxS-HCR package incorporates the core features of the MIxS standard for marker gene (MIMARKS) and metagenomic (MIMS) sequences along with a hydrocarbon resources customized environmental package. Adoption of the MIxS-HCR standard will enable the comparison and better contextualization of investigations related to hydrocarbon rich environments. The insights from such standardized way of reporting could be highly beneficial for the successful development and optimization of hydrocarbon recovery processes and management of microbiological issues in petroleum production systems. PMID- 27777645 TI - Targeting Glial Mitochondrial Function for Protection from Cerebral Ischemia: Relevance, Mechanisms, and the Role of MicroRNAs. AB - Astrocytes and microglia play crucial roles in the response to cerebral ischemia and are effective targets for stroke therapy in animal models. MicroRNAs (miRs) are important posttranscriptional regulators of gene expression that function by inhibiting the translation of select target genes. In astrocytes, miR expression patterns regulate mitochondrial function in response to oxidative stress via targeting of Bcl2 and heat shock protein 70 family members. Mitochondria play an active role in microglial activation, and miRs regulate the microglial neuroinflammatory response. As endogenous miR expression patterns can be altered with exogenous mimics and inhibitors, miR-targeted therapies represent a viable intervention to optimize glial mitochondrial function and improve clinical outcome following cerebral ischemia. In the present article, we review the role that astrocytes and microglia play in neuronal function and fate following ischemic stress, discuss the relevance of mitochondria in the glial response to injury, and present current evidence implicating miRs as critical regulators in the glial mitochondrial response to cerebral ischemia. PMID- 27777649 TI - Genome sequences and annotation of two urinary isolates of E. coli. AB - The genus Escherichia includes pathogens and commensals. Bladder infections (cystitis) result most often from colonization of the bladder by uropathogenic E. coli strains. In contrast, a poorly defined condition called asymptomatic bacteriuria results from colonization of the bladder with E. coli strains without symptoms. As part of an on-going attempt to identify and characterize the newly discovered female urinary microbiota, we report the genome sequences and annotation of two urinary isolates of E. coli: one (E78) was isolated from a female patient who self-reported cystitis; the other (E75) was isolated from a female patient who reported that she did not have symptoms of cystitis. Whereas strain E75 is most closely related to an avian extraintestinal pathogen, strain E78 is a member of a clade that includes extraintestinal strains often found in the human bladder. Both genomes are uncommonly rich in prophages. PMID- 27777642 TI - Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement. AB - One of the major concerns in the practice of allergy is related to the safety of procedures for the diagnosis and treatment of allergic disease. Management (diagnosis and treatment) of hypersensitivity disorders involves often intentional exposure to potentially allergenic substances (during skin testing), deliberate induction in the office of allergic symptoms to offending compounds (provocation tests) or intentional application of potentially dangerous substances (allergy vaccine) to sensitized patients. These situations may be associated with a significant risk of unwanted, excessive or even dangerous reactions, which in many instances cannot be completely avoided. However, adverse reactions can be minimized or even avoided if a physician is fully aware of potential risk and is prepared to appropriately handle the situation. Information on the risk of diagnostic and therapeutic procedures in allergic diseases has been accumulated in the medical literature for decades; however, except for allergen specific immunotherapy, it has never been presented in a systematic fashion. Up to now no single document addressed the risk of the most commonly used medical procedures in the allergy office nor attempted to present general requirements necessary to assure the safety of these procedures. Following review of available literature a group of allergy experts within the World Allergy Organization (WAO), representing various continents and areas of allergy expertise, presents this report on risk associated with diagnostic and therapeutic procedures in allergology and proposes a consensus on safety requirements for performing procedures in allergy offices. Optimal safety measures including appropriate location, type and required time of supervision, availability of safety equipment, access to specialized emergency services, etc. for various procedures have been recommended. This document should be useful for allergists with already established practices and experience as well as to other specialists taking care of patients with allergies. PMID- 27777650 TI - Complete genome sequence of Methanoculleus bourgensis strain MAB1, the syntrophic partner of mesophilic acetate-oxidising bacteria (SAOB). AB - Methanoculleus bourgensis strain MAB1 has been identified as the hydrogenotrophic partner of mesophilic acetate-oxidising bacteria, a syntrophic relationship operating close to the thermodynamic equilibrium and of considerable importance in ammonia-rich engineered biogas processes. Methanoculleus bourgensis strain MAB1 belongs to the order Methanomicrobiales, family Methanomicrobiaceae, within the phylum Euryarchaeota. The genome shows a total size of 2,859,299 bp encoding 3450 predicted protein-encoding genes, of which only 1472 (43 %) have been assigned tentative functions. The genome encodes further 44 tRNA genes and three rRNA genes (5S, 16S and 23S rRNA). This study presents assembling and annotation features as well as genomic traits related to ammonia tolerance and methanogenesis. PMID- 27777651 TI - Draft genome sequence of the marine Rhodobacteraceae strain O3.65, cultivated from oil-polluted seawater of the Deepwater Horizon oil spill. AB - The marine alphaproteobacterium strain O3.65 was isolated from an enrichment culture of surface seawater contaminated with weathered oil (slicks) from the Deepwater Horizon (DWH) oil spill and belongs to the ubiquitous, diverse and ecological relevant Roseobacter group within the Rhodobacteraceae. Here, we present a preliminary set of physiological features of strain O3.65 and a description and annotation of its draft genome sequence. Based on our data we suggest potential ecological roles of the isolate in the degradation of crude oil within the network of the oil-enriched microbial community. The draft genome comprises 4,852,484 bp with 4,591 protein-coding genes and 63 RNA genes. Strain O3.65 utilizes pentoses, hexoses, disaccharides and amino acids as carbon and energy source and is able to grow on several hydroxylated and substituted aromatic compounds. Based on 16S rRNA gene comparison the closest described and validated strain is Phaeobacter inhibens DSM 17395, however, strain O3.65 is lacking several phenotypic and genomic characteristics specific for the genus Phaeobacter. Phylogenomic analyses based on the whole genome support extensive genetic exchange of strain O3.65 with members of the genus Ruegeria, potentially by using the secretion system type IV. Our physiological observations are consistent with the genomic and phylogenomic analyses and support that strain O3.65 is a novel species of a new genus within the Rhodobacteraceae. PMID- 27777652 TI - Draft genome of Prochlorothrix hollandica CCAP 1490/1T (CALU1027), the chlorophyll a/b-containing filamentous cyanobacterium. AB - Prochlorothrix hollandica is filamentous non-heterocystous cyanobacterium which possesses the chlorophyll a/b light-harvesting complexes. Despite the growing interest in unusual green-pigmented cyanobacteria (prochlorophytes) to date only a few sequenced genome from prochlorophytes genera have been reported. This study sequenced the genome of Prochlorothrix hollandica CCAP 1490/1T (CALU1027). The produced draft genome assembly (5.5 Mb) contains 3737 protein-coding genes and 114 RNA genes. PMID- 27777653 TI - 7 Deadly Sins in Educational Research. PMID- 27777654 TI - A Mile Wide but 1 Cell Thick: The Need to Prioritize Learning in Graduate Medical Education. PMID- 27777656 TI - Nurturing the Healers: A Unique Program to Support Residents. PMID- 27777655 TI - Achieving Career Satisfaction: Personal Goal Setting and Prioritizing for the Clinician Educator. PMID- 27777657 TI - Clinic First: 6 Actions to Transform Ambulatory Residency Training. PMID- 27777658 TI - Assessing the Reliability of Performance Assessment Scores: Some Considerations in Selecting an Appropriate Framework. PMID- 27777659 TI - Questions Program Directors Need to Answer Before Using Resident Clinical Performance Data. PMID- 27777660 TI - A Narrative Review and Novel Framework for Application of Team-Based Learning in Graduate Medical Education. AB - BACKGROUND : Team-based learning (TBL) promotes problem solving and teamwork, and has been applied as an instructional method in undergraduate medical education with purported benefits. Although TBL curricula have been implemented for residents, no published systematic reviews or guidelines exist for the development and use of TBL in graduate medical education (GME). OBJECTIVE : To review TBL curricula in GME, identify gaps in the literature, and synthesize a framework to guide the development of TBL curricula at the GME level. METHODS : We searched PubMed, MEDLINE, and ERIC databases from 1990 to 2014 for relevant articles. References were reviewed to identify additional studies. The inclusion criteria were peer-reviewed publications in English that described TBL curriculum implementation in GME. Data were systematically abstracted and reviewed for consensus. Based on included publications, a 4-element framework-system, residents, significance, and scaffolding-was developed to serve as a step-wise guide to planning a TBL curriculum in GME. RESULTS : Nine publications describing 7 unique TBL curricula in residency met inclusion criteria. Outcomes included feasibility, satisfaction, clinical behavior, teamwork, and knowledge application. CONCLUSIONS : TBL appears feasible in the GME environment, with learner reactions ranging from positive to neutral. Gaps in the literature occur within each of the 4 elements of the suggested framework, including: system, faculty preparation time and minimum length of effective TBL sessions; residents, impact of team heterogeneity and inconsistent attendance; significance, comparison to other instructional methods and outcomes measuring knowledge retention, knowledge application, and skill development; and scaffolding, factors that influence the completion of preparatory work. PMID- 27777661 TI - Physician Retention in the Same State as Residency Training: Data From 1 Michigan GME Institution. AB - BACKGROUND : In a time of threats to the funding for graduate medical education (GME) and projected physician shortages, drawing attention to the value of physician training programs may be useful. One approach is to study the number and percentage of physicians who enter practice in the state in which they trained. OBJECTIVE : We sought to examine the percentage of graduates from a single Michigan-based GME institution over a 15-year period, who practiced medicine in Michigan during their career. METHODS : We performed a retrospective review of historical data for all graduates currently in practice, derived from 18 GME training programs from 2000 through 2014. Practice location data were collected and confirmed using multiple sources for accuracy. RESULTS : Data were available for 1168 graduates. The average age at the time of graduation was 32.6 +/- 4.4 years (mean and standard deviation [SD]), and 60.2% were men (703 of 1168). There were 546 graduates (46.7%) who practiced in Michigan after graduation. Almost 80% of the graduates (279 of 358) who completed medical school and GME in Michigan also practiced in Michigan. Of those, 87.8% (245 of 279) also completed a bachelor's degree in Michigan. CONCLUSIONS : The findings show that graduates from our GME programs were highly likely to practice in Michigan if they completed their pre-GME education in Michigan. PMID- 27777662 TI - Rounds Today: A Qualitative Study of Internal Medicine and Pediatrics Resident Perceptions. AB - BACKGROUND : Attending rounds is a key component of patient care and education at teaching hospitals, yet there is an absence of studies addressing trainees' perceptions of rounds. OBJECTIVE : To determine perceptions of pediatrics and internal medicine residents about the current and ideal purposes of inpatient rounds on hospitalist services. METHODS : In this multi-institutional qualitative study, the authors conducted focus groups with a purposive sample of internal medicine and pediatrics residents at 4 teaching hospitals. The constant comparative method was used to identify themes and codes. RESULTS : The study identified 4 themes: patient care, clinical education, patient/family involvement, and evaluation. Patient care included references to activities on rounds that forwarded care of the patient. Clinical education pertained to teaching/learning on rounds. Patient/family involvement encompassed comments about incorporating patients and families on rounds. Evaluation described residents demonstrating skill for attendings. CONCLUSIONS : Resident perceptions of the purposes of rounds aligned with rounding activities described by prior observational studies of rounds. The influence of time pressures and the divergent needs of participants on today's rounds placed these identified purposes in tension, and led to resident dissatisfaction in the achievement of all of them. Suboptimal congruency exists between perceived resident clinical education and specialty-specific milestones. These findings suggest a need for education of multiple stakeholders by (1) enhancing faculty teaching strategies to maximize clinical education while minimizing inefficiencies; (2) informing residents about the value of patient interactions and family-centered rounds; and (3) educating program directors in proper alignment of inpatient rotational objectives to the milestones. PMID- 27777664 TI - Can Item Keyword Feedback Help Remediate Knowledge Gaps? AB - BACKGROUND : In graduate medical education, assessment results can effectively guide professional development when both assessment and feedback support a formative model. When individuals cannot directly access the test questions and responses, a way of using assessment results formatively is to provide item keyword feedback. OBJECTIVE : The purpose of the following study was to investigate whether exposure to item keyword feedback aids in learner remediation. METHODS : Participants included 319 trainees who completed a medical subspecialty in-training examination (ITE) in 2012 as first-year fellows, and then 1 year later in 2013 as second-year fellows. Performance on 2013 ITE items in which keywords were, or were not, exposed as part of the 2012 ITE score feedback was compared across groups based on the amount of time studying (preparation). For the same items common to both 2012 and 2013 ITEs, response patterns were analyzed to investigate changes in answer selection. RESULTS : Test takers who indicated greater amounts of preparation on the 2013 ITE did not perform better on the items in which keywords were exposed compared to those who were not exposed. The response pattern analysis substantiated overall growth in performance from the 2012 ITE. For items with incorrect responses on both attempts, examinees selected the same option 58% of the time. CONCLUSIONS : Results from the current study were unsuccessful in supporting the use of item keywords in aiding remediation. Unfortunately, the results did provide evidence of examinees retaining misinformation. PMID- 27777663 TI - Factors Associated With Resident Continuity in Ambulatory Training Practices. AB - BACKGROUND : Continuity of care is a critical element of residents' educational experience in primary care programs. OBJECTIVE : We examined how continuity in resident practices compares to nonteaching practices, identified factors associated with increased continuity, and explored the association between continuity and quality measures. METHODS : We analyzed 117 235 patient visits to 4 resident practices (26 resident teams in internal medicine, pediatrics, family medicine, and medicine-pediatrics) and 270 242 visits to nonteaching community practices between July 2013 and May 2014. We defined continuity from both clinician and patient perspectives, and used logistic regression models to examine the influence of factors on continuity while controlling for postgraduate year, patient age, gender, race, and insurance. RESULTS : Continuity was greater at nonteaching sites compared to resident practices (87.3% versus 56.2%, P < .001). Resident continuity ranged from 33.1% to 83.7% among resident sites. Factors associated with improved resident continuity included absence of advanced practice providers (71.5% versus 52.3%); consistent use of scheduling protocols (77.5% versus 33.1%); rescheduling policies (71.5% versus 41.3%); increased faculty clinical time (71.5% versus 46.3%); and dismissal policies for excessive missed appointments (71.5% versus 62.5%, P < .001 for all). Increased continuity was associated with improved rates of diabetic control (62.8% versus 54.6%); hypertension control (82.8% versus 57.5%); screening colonoscopy (69.2% versus 31.9%); and mammography (74.8% versus 38.2%, P < .001 for all). CONCLUSIONS : Increased clinical faculty time, scheduling protocols, and absence of advanced practice providers were most strongly associated with increasing continuity. Increased continuity was associated with improved quality measures. PMID- 27777665 TI - The Role of Generic Competencies in the Entrustment of Professional Activities: A Nationwide Competency-Based Curriculum Assessed. AB - BACKGROUND : Entrustable professional activities (EPAs) seek to translate essential physician competencies into clinical practice. Until now, it is not known whether EPA-based curricula offer enhanced assessment and feedback to trainees. OBJECTIVE : This study examined program directors' and senior residents' justifications for entrustment decisions and what role generic, cross specialty competencies (such as communication skills, collaboration, and understanding health care systems) play in these decisions. METHODS : Entrustment decisions for all Dutch obstetrics and gynecology residents between January 2010 and April 2014 were retrieved from their electronic portfolios. Justifications for entrustment were divided into 4 categories: the resident's experience, his or her technical performance, the presence of a generic competency, and training. Template analysis was used to analyze in depth the types of justifications, which play a role in entrustment decisions. RESULTS : A total of 5139 entrustment decisions for 375 unique residents were extracted and analyzed. In 59% of all entrustment decisions, entrusting a professional task to a resident was justified by the experience of the resident. Generic competencies were mentioned in 0.5% of all entrustment decisions. Template analysis revealed that the amount of exposure and technical skills are leading factors, while the quality of the performance was not reported to be of any influence. CONCLUSIONS : Entrustment decisions only rarely are based on generic competencies, despite the introduction of competency frameworks and EPAs. For program directors, a leading factor in entrustment decisions is a resident's exposure to an activity, and the quality of a resident's performance appears to play only a minor role. PMID- 27777666 TI - Internal Medicine Residents' Retention of Knowledge and Skills in Bedside Ultrasound. AB - BACKGROUND : The long-term retention of knowledge and skills in bedside ultrasound by internal medicine residents after ultrasound training is not well understood. OBJECTIVE : We sought to determine whether knowledge and skills acquired from focused training in bedside ultrasound are retained over time, and whether retention is related to independent practice. METHODS : We conducted a prospective observational trial of 101 internal medicine residents at an academic medical center who participated in a bedside ultrasound workshop followed by 12 months of independent practice. Performance was measured on image-based knowledge and skills assessment using direct observation, both before the workshop and 12 months later. Individual usage data were obtained along with a survey on attitudes toward bedside ultrasound. RESULTS : Participants' mean knowledge assessment score increased from a baseline of 63.7% to 84.5% immediately after training (P < .001). At 12 months, mean knowledge score fell to 73.0%, significantly different from both prior assessments (P < .001). Despite knowledge decline, the mean skills assessment score improved from a baseline of 30.5% to 50.4% at 12 months (P < .001). Residents reporting more ultrasound use (> 25 examinations) had higher scores in baseline knowledge and skills assessments than those with lower usage (< 25 examinations). Change in knowledge and image acquisition skills between assessments was equal in both subgroups. CONCLUSIONS : Residents' knowledge of ultrasound improved after brief training but decayed over time, whereas skills showed marginal improvement over the study, with minimal support. Growth and retention of ultrasound abilities were not impacted by usage rates. PMID- 27777667 TI - The Relationship Between ACGME Duty Hour Requirements and Performance on the American Board of Emergency Medicine Qualifying Examination. AB - BACKGROUND : In 2003, the Accreditation Council for Graduate Medical Education (ACGME) instituted requirements that limited the number of hours residents could spend on duty, and in 2011, it revised these requirements. OBJECTIVE : This study explored whether the implementation of the 2003 and 2011 duty hour limits was associated with a change in emergency medicine residents' performance on the American Board of Emergency Medicine (ABEM) Qualifying Examination (QE). METHODS : Beginning with the 1999 QE and ending with the 2014 QE, candidates for whom all training occurred without duty hour requirements (Group A), candidates under the first set of duty hour requirements (Group C), and candidates under the second set of duty hour requirements (Group E) were compared. Comparisons included mean scores and pass rates. RESULTS : In Group A, 5690 candidates completed the examination, with a mean score of 82.8 and a 90.2% pass rate. In Group C, 8333 candidates had a mean score of 82.4 and a 90.5% pass rate. In Group E, there were 1269 candidates, with a mean score of 82.5 and an 89.4% pass rate. There was a small but statistically significant decrease in the mean scores (0.04, P < .001) after implementation of the first duty hour requirements, but this difference did not occur after implementation of the 2011 standards. There was no difference among pass rates for any of the study groups (chi2 = 1.68, P = .43). CONCLUSIONS : We did not identify an association between the 2003 and 2011 ACGME duty hour requirements and performance of test takers on the ABEM QE. PMID- 27777668 TI - Clinical and Educational Outcomes of an Integrated Inpatient Quality Improvement Curriculum for Internal Medicine Residents. AB - BACKGROUND : Integrating teaching and hands-on experience in quality improvement (QI) may increase the learning and the impact of resident QI work. OBJECTIVE : We sought to determine the clinical and educational impact of an integrated QI curriculum. METHODS : This clustered, randomized trial with early and late intervention groups used mixed methods evaluation. For almost 2 years, internal medicine residents from Dartmouth-Hitchcock Medical Center on the inpatient teams at the White River Junction VA participated in the QI curriculum. QI project effectiveness was assessed using statistical process control. Learning outcomes were assessed with the Quality Improvement Knowledge Application Tool-Revised (QIKAT-R) and through self-efficacy, interprofessional care attitudes, and satisfaction of learners. Free text responses by residents and a focus group of nurses who worked with the residents provided information about the acceptability of the intervention. RESULTS : The QI projects improved many clinical processes and outcomes, but not all led to improvements. Educational outcome response rates were 65% (68 of 105) at baseline, 50% (18 of 36) for the early intervention group at midpoint, 67% (24 of 36) for the control group at midpoint, and 53% (42 of 80) for the late intervention group. Composite QIKAT-R scores (range, 0-27) increased from 13.3 at baseline to 15.3 at end point (P < .01), as did the self-efficacy composite score (P < .05). Satisfaction with the curriculum was rated highly by all participants. CONCLUSIONS : Learning and participating in hands-on QI can be integrated into the usual inpatient work of resident physicians. PMID- 27777669 TI - Learnings From the Pilot Implementation of Mobile Medical Milestones Application. AB - BACKGROUND : Implementation of the educational milestones benefits from mobile technology that facilitates ready assessments in the clinical environment. We developed a point-of-care resident evaluation tool, the Mobile Medical Milestones Application (M3App), and piloted it in 8 North Carolina family medicine residency programs. OBJECTIVE : We sought to examine variations we found in the use of the tool across programs and explored the experiences of program directors, faculty, and residents to better understand the perceived benefits and challenges of implementing the new tool. METHODS : Residents and faculty completed presurveys and postsurveys about the tool and the evaluation process in their program. Program directors were interviewed individually. Interviews and open-ended survey responses were analyzed and coded using the constant comparative method, and responses were tabulated under themes. RESULTS : Common perceptions included increased data collection, enhanced efficiency, and increased perceived quality of the information gathered with the M3App. Residents appreciated the timely, high-quality feedback they received. Faculty reported becoming more comfortable with the tool over time, and a more favorable evaluation of the tool was associated with higher utilization. Program directors reported improvements in faculty knowledge of the milestones and resident satisfaction with feedback. CONCLUSIONS : Faculty and residents credited the M3App with improving the quality and efficiency of resident feedback. Residents appreciated the frequency, proximity, and specificity of feedback, and faculty reported the app improved their familiarity with the milestones. Implementation challenges included lack of a physician champion and competing demands on faculty time. PMID- 27777670 TI - Association of Resident Duty Hour Restrictions on Mortality of Nervous System Disease and Disorder. AB - BACKGROUND : The impact of the 2003 residency duty hour reform on patient care remains a debated issue. OBJECTIVE : Determine the association between duty hour limits and mortality in patients with nervous system pathology. METHODS : Via a retrospective cohort study using the Nationwide Inpatient Sample from 2000-2010, the authors evaluated in-hospital mortality status in those with a primary discharge level diagnosis of disease or disorder of the nervous system. Odds ratios were calculated, and Bonferroni corrected P values and confidence intervals were determined to account for multiple comparisons relating in hospital mortality with teaching status of the hospital by year. RESULTS : The pre-reform (2000-2002) and peri-reform (2003) periods revealed no significant difference between teaching and nonteaching hospital mortality (P > .99). The post-reform period (2004-2010) was dominated by years of significantly higher mortality rates in teaching hospitals compared to nonteaching hospitals: 2004 (P < .001); 2006 (P = .043); 2007 (P = .042); and 2010 (P = .003). However, data for 2005 (P >= .99), 2008 (P = .80), and 2009 (P = .09) did not show a significant difference in mortality. CONCLUSIONS : Teaching and nonteaching hospital mortality was similar in patients with nervous system pathology prior to the duty hour reform. While nonteaching institutions demonstrated steadily declining mortality over the decade, teaching hospital mortality spiked in 2004 and declined at a more restricted rate. The timing of these changes could suggest a negative correlation of duty hour restrictions on outcomes of patients with nervous system pathology. PMID- 27777671 TI - Developing Teaching Strategies in the EHR Era: A Survey of GME Experts. AB - BACKGROUND : There is limited information on the impact of widespread adoption of the electronic health record (EHR) on graduate medical education (GME). OBJECTIVE : To identify areas of consensus by education experts, where the use of EHR impacts GME, with the goal of developing strategies and tools to enhance GME teaching and learning in the EHR environment. METHODS : Information was solicited from experienced US physician educators who use EPIC EHR following 3 steps: 2 rounds of online surveys using the Delphi technique, followed by telephone interviews. The survey contained 3 stem questions and 52 items with Likert-scale responses. Consensus was defined by predetermined cutoffs. A second survey reassessed items for which consensus was not initially achieved. Common themes to improve GME in settings with an EHR were compiled from the telephone interviews. RESULTS : The panel included 19 physicians in 15 states in Round 1, 12 in Round 2, and 10 for the interviews. Ten items were found important for teaching and learning: balancing focus on EHR documentation with patient engagement achieved 100% consensus. Other items achieving consensus included adequate learning time, balancing EHR data with verbal history and physical examination, communicating clinical thought processes, hands-on EHR practice, minimizing data repetition, and development of shortcuts and templates. Teaching strategies incorporating both online software and face-to-face solutions were identified during the interviews. CONCLUSIONS : New strategies are needed for effective teaching and learning of residents and fellows, capitalizing on the potential of the EHR, while minimizing any unintended negative impact on medical education. PMID- 27777672 TI - Leadership for All: An Internal Medicine Residency Leadership Development Program. AB - BACKGROUND : Developing effective leadership skills in physicians is critical for safe patient care. Few residency-based models of leadership training exist. OBJECTIVE : We evaluated residents' readiness to engage in leadership training, feasibility of implementing training for all residents, and residents' acceptance of training. METHODS : In its fourth year, the Leadership Development Program (LDP) consists of twelve 90-minute modules (eg, Team Decision Making and Bias, Leadership Styles, Authentic Leadership) targeting all categorical postgraduate year (PGY) 1 residents. Modules are taught during regularly scheduled educational time. Focus group surveys and discussions, as well as annual surveys of PGY-1s assessed residents' readiness to engage in training. LDP feasibility was assessed by considering sustainability of program structures and faculty retention, and resident acceptance of training was assessed by measuring attendance, with the attendance goal of 8 of 12 modules. RESULTS : Residents thought leadership training would be valuable if content remained applicable to daily work, and PGY 1 residents expressed high levels of interest in training. The LDP is part of the core educational programming for PGY-1 residents. Except for 2 modules, faculty presenters have remained consistent. During academic year 2014-2015, 45% (13 of 29) of categorical residents participated in at least 8 of 12 modules, and 72% (21 of 29) participated in at least 7 of 12. To date, 125 categorical residents have participated in training. CONCLUSIONS : Residents appeared ready to engage in leadership training, and the LDP was feasible to implement. The attendance goal was not met, but attendance was sufficient to justify program continuation. PMID- 27777673 TI - Evaluating the Evaluators: Implementation of a Multi-Source Evaluation Program for Graduate Medical Education Program Directors. AB - BACKGROUND: Multi-source evaluation has demonstrated value for trainees, but is not generally provided to residency or fellowship program directors (PDs). OBJECTIVE: To develop, implement, and evaluate a PD multi-source evaluation process. METHODS: Tools were developed for PD evaluation by trainees, department chairs, and graduate medical education (GME) leadership. Evaluation questions were based on PD responsibilities, including Accreditation Council for Graduate Medical Education (ACGME) requirements. A follow-up survey assessed the process. RESULTS: Evaluation completion rates were as follows: trainees in academic year 2012-2013, 53% (958 of 1824), and in academic year 2013-2014, 42% (800 of 1898); GME directors in 2013-2014, 100% (95 of 95); and chairs/chiefs in 2013-2014, 92% (109 of 118). Results of a follow-up survey of PDs (66%, 59 of 90) and chairs (74%, 48 of 65) supports the evaluations' value, with 45% of responding PDs (25 of 56) and 50% of responding chairs (21 of 42) characterizing them as "extremely" or "quite" useful. Most indicated this was the first written evaluation they had received (PDs 78%, 46 of 59) or provided (chairs 69%, 33 of 48) regarding the PD role. More than 60% of PD (30 of 49) and chair respondents (24 of 40) indicated trainee feedback was "extremely" or "quite" useful, and nearly 50% of PDs (29 of 59) and 21% of chairs (10 of 48) planned changes based on the results. Trainee response rates improved in 2014-2015 (52%, 971 of 1872) and 2015-2016 (69%, 1276 of 1837). CONCLUSIONS: In our institution, multi-source evaluation of PDs was sustained over 4 years with acceptable and improving evaluation completion rates. The process and assessment tools are potentially transferrable to other institutions. PMID- 27777674 TI - The Effect of Burnout on Medical Errors and Professionalism in First-Year Internal Medicine Residents. AB - BACKGROUND : Burnout is a common issue in internal medicine residents, and its impact on medical errors and professionalism is an important subject of investigation. OBJECTIVE : To evaluate differences in medical errors and professionalism in internal medicine residents with and without burnout. METHODS : A single institution observational cohort study was conducted between June 2011 and July 2012. Burnout was measured using the Maslach Burnout Inventory to generate subscores for the following 3 domains: emotional exhaustion, depersonalization, and sense of personal accomplishment. By convention, burnout was defined as a high emotional exhaustion or depersonalization subscore. Medication prescription error rate was the chosen measure of medical errors. Professionalism was measured cumulatively through examining discharge summaries completed within 48 hours, outpatient charts completed within 72 hours, and the average time to review outpatient laboratory tests. RESULTS : Of a total of 54 eligible first-year residents, 53 (98%) and 32 (59%) completed the initial and follow-up surveys, respectively. Residents with year-end burnout had a lower rate of medication prescription errors (0.553 versus 0.780, P = .007). Discharge summaries completed within 48 hours of discharge (83.8% versus 84.0%, P = .93), outpatient charts completed within 72 hours of encounter (93.7% versus 94.3%, P = .31), and time (minutes) to review outpatient laboratory test results (72.3 versus 26.9, P = .28) were similar between residents with and without year-end burnout. CONCLUSIONS : This study found a small decrease in medical errors in residents with year-end burnout compared to burnout-free residents and no difference in selected measures of professionalism. PMID- 27777675 TI - Daily Encounter Cards-Evaluating the Quality of Documented Assessments. AB - BACKGROUND : Concerns over the quality of work-based assessment (WBA) completion has resulted in faculty development and rater training initiatives. Daily encounter cards (DECs) are a common form of WBA used in ambulatory care and shift work settings. A tool is needed to evaluate initiatives aimed at improving the quality of completion of this widely used form of WBA. OBJECTIVE : The completed clinical evaluation report rating (CCERR) was designed to provide a measure of the quality of documented assessments on in-training evaluation reports. The purpose of this study was to provide validity evidence to support using the CCERR to assess the quality of DEC completion. METHODS : Six experts in resident assessment grouped 60 DECs into 3 quality categories (high, average, and poor) based on how informative each DEC was for reporting judgments of the resident's performance. Eight supervisors (blinded to the expert groupings) scored the 10 most representative DECs in each group using the CCERR. Mean scores were compared to determine if the CCERR could discriminate based on DEC quality. RESULTS : Statistically significant differences in CCERR scores were observed between all quality groups (P < .001). A generalizability analysis demonstrated the majority of score variation was due to differences in DECs. The reliability with a single rater was 0.95. CONCLUSIONS : The CCERR is a reliable and valid tool to evaluate DEC quality. It can serve as an outcome measure for studying interventions targeted at improving the quality of assessments documented on DECs. PMID- 27777676 TI - How to Utilize Blogs for Residency Education. PMID- 27777677 TI - Recognizing and Responding to Ethically Important Moments in Qualitative Research. PMID- 27777678 TI - Homegrown = Home-Served: The Power of Local Training. PMID- 27777679 TI - Attending Rounds: The HumptyDumptification of Medical Discourse. PMID- 27777680 TI - Continuity: A Central Principle of Primary Care. PMID- 27777681 TI - Reality Doesn't Bite: Improving Education and Outcomes Through Innovations That Enhance Resident Continuity of Care. PMID- 27777682 TI - The Motor in the Machine: A Lesson in Surgical Processing. PMID- 27777683 TI - Improving Patient Safety by Combating Alert Fatigue. PMID- 27777684 TI - Impact of ACGME Accreditation Process on Quality of Program and Patient Care in the Community. PMID- 27777685 TI - Disparate Perceptions of Resident Physicians, Faculty Physicians, and Program Directors on the 2011 ACGME Work Hour Regulations. PMID- 27777686 TI - Is It Inappropriate for Attendings and Residents to be Friends on Facebook and Other Social Media Accounts? PMID- 27777687 TI - Alliance of Independent Academic Medical Centers Outstanding Resident Poster: Effect of Ethnic Disparities on the Outcome of Stage III Colon Cancer Patients. PMID- 27777688 TI - Listening in the "Hear and Now". PMID- 27777689 TI - About Losing a Resident. PMID- 27777690 TI - How Residents Say They Learn: A National, Multi-Specialty Survey of First- and Second-Year Residents. AB - Relatively little is known about how, from whom, and under what conditions residents say they most effectively learn. We examined the relationships between residents' self-reported ratings of 11 different sources of learning and a number of empirical variables, using a national, random sample of postgraduate year (PGY) 1 and PGY-2 residents in the 1998-1999 training year. Residents were surveyed by mail. Completed surveys were received from 64.2% of 5616 residents contacted. The most often reported sources of learning were other residents and attending physicians. Ratings varied by specialty, level of training, and US medical graduates (USMGs) versus international medical graduates (IMGs). Factor analysis identified 3 primary modes of learning: faculty-organized, peer oriented, and self-directed. Residents in different specialties varied in their use of these 3 sources of learning. IMG residents reported significantly less learning from peers and more self-directed learning. Increased resident duty hours were associated with a decrease in faculty-organized and self-directed learning, and an increase in peer-oriented learning. PMID- 27777691 TI - Current Attitudes Toward the ACGME and Its Role: Perspectives of a National Multi Specialty Panel of Residents and Fellows. AB - BACKGROUND : Resident attitudes toward the Accreditation Council for Graduate Medical Education (ACGME) likely influence the ACGME's effectiveness in its role of ensuring compliance with its requirements. Beyond perceptions of duty hour limits and their enforcement, there is a lack of data on resident perceptions of the ACGME and its role. OBJECTIVE : We explored resident attitudes toward the ACGME and developed recommendations for improved outreach to the resident community to improve perceptions. METHODS : A multi-specialty, nationally representative group of residents and fellows conducted a 3-part structured exercise that (1) described current trainee impressions of the ACGME; (2) evaluated the value of the ACGME engaging residents; and (3) recommended ways to improve communication between the ACGME and residents. RESULTS : Most residents are only vaguely familiar with the role of the ACGME and generally have a negative impression regarding ACGME accreditation functions. This contrasts with the attitudes of the residents more closely involved with the ACGME through its Review Committees. There is value in engaging residents in the mission of the ACGME, and outreach efforts across multiple modalities could more closely align ACGME values and resident impressions of the organization and its role. CONCLUSIONS : A multifaceted effort to engage residents in the mission and goals of the ACGME would augment both ACGME and trainee efforts to improve graduate medical education. PMID- 27777692 TI - Prevalence of physical inactivity in Iran: a systematic review. AB - Introduction: Physical inactivity is one of the most important risk factors for chronic diseases, including cardiovascular disease, cancer, and stroke. We aim to conduct a systematic review of the prevalence of physical inactivity in Iran. Methods: We searched international databases; ISI, PubMed/Medline, Scopus, and national databases Irandoc, Barakat knowledge network system, and Scientific Information Database (SID). We collected data for outcome measures of prevalence of physical inactivity by sex, age, province, and year. Quality assessment and data extraction has been conducted independently by two independent research experts. There were no limitations for time and language. Results: We analyzed data for prevalence of physical inactivity in Iranian population. According to our search strategy we found 254 records; of them 185 were from international databases and the remaining 69 were obtained from national databases after refining the data, 34 articles that met eligible criteria remained for data extraction. From them respectively; 9, 20, 2 and 3 studies were at national, provincial, regional and local levels. The estimates for inactivity ranged from approximately 30% to almost 70% and had considerable variation between sexes and studied sub-groups. Conclusion: In Iran, most of studies reported high prevalence of physical inactivity. Our findings reveal a heterogeneity of reported values, often from differences in study design, measurement tools and methods, different target groups and sub-population sampling. These data do not provide the possibility of aggregation of data for a comprehensive inference. PMID- 27777693 TI - Comparison of end-tidal carbon dioxide and arterial blood bicarbonate levels in patients with metabolic acidosis referred to emergency medicine. AB - Introduction: The routine and gold standard method to diagnose of acid - base disturbance is arterial blood gas (ABG) sampling. Capnography could be used to measure the end-tidal carbon dioxide (ETCO2) levels and ETco2 has a close correlation with the PaCo2. The aim of this study was comparison the ETco2 and arterial blood bicarbonate levels in patients with metabolic acidosis. Methods: In a descriptive-analytical study that performed in Emergency Department of Emam Reza Medical Research and Training Hospital of Tabriz on patients with metabolic acidosis, ETco2 level and blood bicarbonate levels in 262 patients were evaluated. Results: Mean of ETco2 and Hco3 levels in patients with metabolic acidosis were 22.29 +/- 4.15 and 12.78 +/- 3.83, respectively. In all patients, the significant direct linear relationship was found between ETco2 with Hco3 (r = 0.553, P < 0.001). We had 4 groups of patients with metabolic acidosis, also there is a significant direct linear relationship between the ETCo2 and the Hco3 level of arterial blood in patients with renal failure (P < 0.001 and r = 0.551), sepsis (P < 0.001 and r = 0.431), drug toxicity (P < 0.001 and r = 0.856), and ketoacidosis (DKA) (P < 0.001 and r = 0.559). Conclusion: According to the results of this study, capnography can be used for primary diagnosis of metabolic acidosis in spontaneously breathing patients who referred to the emergency wards, however, the ABG must be considered as the gold standard tool for diagnosis and guiding the treatment. PMID- 27777694 TI - A reversal of age-dependent proliferative capacity of endothelial progenitor cells from different species origin in in vitro condition. AB - Introduction: A large number of cardiovascular disorders and abnormalities, notably accelerated vascular deficiencies could be related to aging changes and increased length of life. During the past decades, the discovery of different stem cells facilitates ongoing attempts for attenuating many disorders, especially in vascular beds. Endothelial progenitor cells (EPCs) are a subtype of stem cells that have potent capacity to differentiate into mature endothelial cells (ECs). However, some documented studies reported an age-related decline in proliferation and function of many stem cells. There is no data on aging effect upon proliferation and morphological feature of EPCs. Methods: To show aging effect on EPCs proliferation and multipotentiality, bone marrow samples were provided from old and young cases in three different species; human, mouse and dog. After 7 days of culture, the cell morphology and clonogenic capacity were evaluated. We also calculated the mean number of colonies both in bone marrow samples from old and young subjects. To confirm the cell phenotype, isolated cells were immune-phenotyped by a panel of antibodies against Tie-2, CD133 and CD309 markers. Results: Our results showed that EPCs exhibited prominent spindle form in all bone marrow samples from young cases while the cell shape became more round by aging. Notably, the number of colonies was reduced in aged samples as compared to parallel young subject samples (P < 0.05). We also detected that the expression of endothelial related markers diminished by aging. Conclusion: The results of this study suggest that the age-related vascular abnormalities could be presumably related to the decline in stemness capacity of EPCs. PMID- 27777695 TI - Association of ghrelin with cardiometabolic risk factors in Iranian adolescents: the CASPIAN-III study. AB - Introduction: Current evidence suggests that ghrelin could contribute to the development of metabolic syndrome (MetS) in adults, but limited experience exists in adolescents. This study aims to explore the association of ghrelin levels with the MetS components among Iranian adolescents. Methods: In this case-control study, 32 adolescents with MetS and 148 healthy controls were selected randomly from the childhood and Adolescence Surveillance and Prevention of Adult Non communicable disease (CASPIAN-III) study. MetS was defined according to the Adult Treatment Panel III (ATP III) criteria modified for children and adolescents. Anthropometric measures (including body mass index [BMI], waist circumference [WC] and waist to height ratio [WHtR]), blood pressure (BP) and biochemical data (including fasting blood sugar [FBS], triglyceride [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC] and gerlin) were measured. Results: Total ghrelin level was significantly higher in students without MetS compared to those with MetS (748.89 +/- 85.04 vs. 728.72 +/- 90.36 [pg/mL]; P < 0.001). Significant negative correlations were seen between ghrelin levels and BMI, WC, WHtR, TG, and TC. Ghrelin had also relatively strong inverse correlations with FBS (r = -0.59, P< 0.001), LDL-C (r = -0.56, P < 0.001), and positive correlation with HDL-C (r = 0.60, P < 0.001). Compared with the children with MetS, in those without MetS, ghrelin was significantly associated with HDL-C and LDL-C. A decreasing trend was observed in the mean ghrelin level across increasing number of MetS components (P for trend <0.001). Conclusion: We observed a relationship between ghrelin concentration and MetS components in adolescents. PMID- 27777696 TI - Effect of remote ischemic post-conditioning on oxidative stress in blood of STEMI patients treated with primary angioplasty. AB - Introduction: This study designed to use remote ischemic post conditioning (RIPC) as a protective strategy during percutaneous coronary intervention (PCI) in patients with ST segment elevation myocardial infarction (STEMI) to reduce myocardial cells damage due to reperfusion injury. Methods: Sixty-one patients were divided into test group (32 patients) receiving RIPC and control group (29 patients). Patients were included with first MI who had 20-80 years old. The RIPC protocol was applied on patients arm in three successive episodes during the opening of infarct-related artery (IRA). Whole blood sample were taken from patients after the first episode before IRA opening and after the third episode after IRA opening. The serums were extracted and stored in the freezer -70C to determine the levels of glutathione peroxidase (GPX), superoxide dismutase (SOD), total antioxidant capacity (TAC) and malondialdehyde (MDA). Results: The levels of GPX and SOD after the first episode of RIPC were significantly higher in test group than control group (P < 0.001). Similar alterations of these enzymes were obtained after IRA opening (after third episode). In addition, the levels of TAC remained unchanged in control patients but it was significantly increased after the third episode of RIPC in test patients (P < 0.001). Finally, the MDA level was increased in control group in comparison with test group, and administration of RIPC in test group prevented the enhancement of MDA levels significantly (P < 0.001). Conclusion: The results indicated that RIPC protocol has protective properties in patients with STEMI through enhancing the antioxidant potentials and decreasing lipid peroxidation. PMID- 27777697 TI - Study of the normal heart size in Northwest part of Iranian population: a cadaveric study. AB - Introduction: The heart is in a muscular organ in the middle mediastinum. According to our knowledge, there is no standard data about the anthropologic parameters of normal Iranian hearts. Hence, the aim of the present study was to investigate the normal heart size in Iranian cadavers. Methods: In a cross sectional study, 550 cadavers (104 female/446 male) from June 2014 to July 2015 in the Razavi Khorasan province of Iran were included in the study. After approval of the Ethical Committee, cadavers were divided into 10 groups based on age groups. Length, width, weight, chordae tendineae, papillary muscles, and heart valves were measured using vernier caliper. Finally, data were analyzed using SPSS software. Results: The mean values of the demographic data were as follows: age= 42.12 +/- 21.34 years; weight = 60.38 +/- 15.32 kg; height = 158.14 +/- 23.77 cm; and BMI = 24.66 +/- 17.60 kg/m2. The mean values of the heart length, width, chordae tendineae, pupillary muscles, weight, and index of the heart were 11.41 +/- 2.15 cm, 8.21 +/- 4.38 cm, 19.41 +/- 6.70, 5.74 +/- 1.96, 247.78 +/- 62.27 grams, and 5.74 +/- 1.96, respectively. In addition, the circumference of the tricuspid valve, circumference of the mitral valves, and tricuspid and mitral areas were 8.80 +/- 1.11 cm, 9.43 +/- 1.44 cm, 4.11 +/- 0.71 cm2, and 4.50 +/- 0.90 cm2, respectively. Conclusion: Mean values of the heart's length and width was similar to previous reports from western population. The circumference of the tricuspid valve was less than the textbook's data, while circumference of the mitral valves was more than it. The study findings provide valuable information about standard data of the heart in the Iranian population, which is useful for surgeons as well as anthropologists. However, multi-center studies with a larger sample size are required to complete data about anatomical characteristics of normal hearts. PMID- 27777698 TI - Poor outcome following percutaneous balloon mitral valvotomy in patients with atrial fibrillation. AB - Introduction: Atrial fibrillation (AF) is the most common arrhythmia in patients with mitral stenosis (MS) and it may increase complications and decreases success rates of percutaneous balloon mitral valvotomy (PBMV). This study aimed to investigate the short and long term results of PBMV in patients with AF compared to sinus rhythm (SR). Methods: In this cross sectional study, 1000 patients with MS who had undergone PBMV between 1999 and 2013 were enrolled including 585 and 415 patients with AF and SR respectively. Patients were followed for a mean of 7.27 +/- 3.16 years. Clinical, echocardiographic and hemodynamic data were collected. Procedure success, in-hospital and long-term outcome were evaluated. Results: Patients with AF were older and had greater symptoms, mitral regurgitation, mitral echocardiographic score, and mitral pressure gradient before PBMV. PBMV success rate were significantly lower in AF group (P < 0.001). In-hospital complications, including severe mitral regurgitation, emergency mitral valve surgery, peripheral embolism and long-term complications, including mortality, re-valvotomy, mitral replacement surgery and peripheral embolism/stroke were significantly higher in patients with AF. Conclusion: AF leads to worse in-hospital and long-term outcome and lower PBMV success rate. Repeated assessment and early decision to PBMV in patients with MS to reduce AF and AF related complication seems necessary. PMID- 27777699 TI - Tetralogy of Fallot and pheochromocytoma in a situs inversus totalis: An unusual association. AB - Introduction: Situs inversus totalis is an uncommon anomaly which exist a complete transposition of organs and it's occasionally associated with congenital heart diseases, such as tetralogy of fallot. Pheochromocytoma is a rare neuroendocrine tumor with an annual incidence of 2-8 cases per million people and for years has been studied its relationship with the hypoxic pathway. Case Report: A 29 year old male with a history of tetralogy of fallot corrected at 10 years and situs inversus totalis. He was admitted to hospital with a progressive story of four months of constipation, palpitations, headache, dyspnea and sweating. Physical examination revealed a thinned man with peripheral cyanosis, clubbing and signs of decompensated congestive heart failure as hepatomegaly, legs edema, multifocal systodiastolic murmurs, abdominal distension and jugular venous distention. The echocardiogram shows severe right ventricular dysfunction and severe pulmonary hypertension. Furthermore, abdominal computed tomography shows right adrenal mass. Elevated metanephrines and catecholamines confirmed the diagnosis of pheochromocytoma. Surgical removal is decided and preoperative management begins with alpha-adrenergic blockade, however the patient had a hemodynamic decompensation with an unfavorable evolution. Discussion: In conclusion, there are few reports of cyanotic congenital heart disease with pheochromocytoma. Several studies show a significant association between both of them due to chronic hypoxia leads sustained hyperresponsiveness in adrenal medulla and it would cause the tumor. Special preoperative management of pheochromocytoma is recommended when there underlying heart disease and congestive heart failure. We present the first international report of tetralogy of fallot and pheochromocytoma in a patient with situs inversus totalis. PMID- 27777700 TI - Spontaneous multi-focal coronary artery spasm: a case report. AB - Spontaneous coronary artery vasospasm is one of the important causes of acute chest pain syndromes. The diagnosis of diffuse multifocal spasm can be quite challenging and it could be easily mistaken for diffuse coronary artery disease. The use of intracoronary nitroglycerin can relieve spasm and reveal the real extent of coronary artery disease. Herein we present a case presenting with acute myocardial infarction due to severe coronary artery spasm that had even received fibrinolytic therapy. Multiple narrowing was shown during coronary angiography and the patient was scheduled for percutaneous coronary intervention (PCI). But after intracoronary (IC) injection of nitroglycerin, all of lesions disappeared completely and the diagnosis of coronary spasm was confirmed. PMID- 27777701 TI - The Role of DNA Amplification and Cultural Growth in Complicated Acute Appendicitis. AB - Bacterial growth of peritoneal fluid specimens obtained during surgical procedures for acute appendicitis may be useful to optimize further antibiotic therapy in complicated cases. DNA amplification represents a fast technique to detect microbial sequences. We aimed to compare the potential of DNA amplification versus traditional bacterial growth culture highlighting advantages and drawbacks in a surgical setting. Peritoneal fluid specimens were collected during surgery from 36 children who underwent appendectomy between May and December 2012. Real-time polymerase chain reaction (RT-PCR) and cultures were performed on each sample. RT-PCR showed an amplification of 16S in 18/36 samples, Escherichia coli (in 7 cases), Pseudomonas aeruginosa (3), Fusobacterium necrophorum (3), Adenovirus (2), E.coli (1), Klebsiella pneumoniae (1), Serratia marcescens/Enterobacter cloacae (1). Bacterial growth was instead observed only in four patients (3 E.coli and 1 P.aeruginosa and Bacteroides ovatus). Preoperative C-reactive protein and inflammation degree, the most reliable indicators of bacterial translocation, were elevated as expected. DNA amplification was a quick and useful method to detect pathogens and it was even more valuable in detecting aggressive pathogens such as anaerobes, difficult to preserve in biological cultures; its drawbacks were the lack of biological growths and of antibiograms. In our pilot study RT-PCR and cultures did not influence the way patients were treated. PMID- 27777702 TI - Bruises Around the Umbilicus in an Infant. AB - The most common causes of umbilical discharge in infancy are infection and umbilical granuloma that may be treated by antibiotics and topical application of silver nitrate subsequently. If the umbilical discharge persists or if there is any abnormal discoloration around the umbilicus, it is important to investigate for underlying congenital abnormality that may be cured by surgical intervention. Unusual presentation of omphalomesenteric duct cyst has been reported in literature. We report, for the first time as far as our search is concerned, a case of a 16-month-old infant who presented initially with persistent umbilical discharge and finally with bruising around the umbilicus in keeping with Cullen's sign. A diagnosis of omphalomesenteric duct cyst containing pancreatic tissue was made on histopathological examination. This case emphasizes that, a persistent umbilical discharge and or discoloration around the umbilicus should be further investigated and an omphalomesenteric duct cyst can present as Cullen's sign. PMID- 27777703 TI - Mild Encephalopathy with Reversible Lesions in the Splenium of Corpus Callosum and Bilateral Cerebral Deep White Matter in Identical Twins. AB - Identical twin brothers developed mild encephalopathy at the age of 7.0 and 9.7 years (Patient 1) and 10.7 years (Patient 2). Patient 1 had influenza A at the time of his second episode, but triggering agents were not evident at the first episode. The triggering agents in Patient 2 were unclear. The neurological features of both patients included transient facial numbness, left arm paresis, dysarthria, and gait disturbance. Diffusion-weighted images from magnetic resonance imaging showed high signal levels at the splenium of corpus callosum and in the bilateral cerebral deep white matter. These results are characteristic of mild encephalitis/encephalopathy with a reversible isolated splenium of corpus callosum lesion. All three episodes were treated with a methylprednisolone pulse. Acyclovir was also administered to Patient 2 and to Patient 1 during his first episode. Patient 1 received an anti-influenza agent and intravenous immunoglobulin during his second episode. Both patients recovered completely without sequelae. Genetic factors, which may predispose identical twins to develop encephalopathy, are discussed. PMID- 27777704 TI - Sternal Osteomyelitis after Bacillus Calmette-Guerin Vaccination. AB - Presented here is the case of a nine-month-old boy with the osteomyelitis of the upper area sternum caused by bacillus Calmette-Guerin (BCG), the Danish 1331 strain vaccine against tuberculosis. Upon examination, a swelling of approximately 2*3 cm diameter was observed in the upper sternal area. The mass was hard, fixed and sensitive to palpation with no local skin hyperaemia. Chest X rays revealed a round mass anterior to the sternum, suggesting a diagnosis of osteomyelitis. A consequent sternal biopsy was performed and Mycobacterium bovis BCG was identified by a positive growth culture. PMID- 27777705 TI - Post Discharge Formula Fortification of Maternal Human Milk of Very Low Birth Weight Preterm Infants: An Introduction of a Feeding Protocol in a University Hospital. AB - The objective of this study is to determine the growth parameters and nutritional biochemical markers and complications of fortification of human milk by post discharge formula of preterm very low birth weight newborns (VLBW). Fifty preterm infants less than 37 weeks with weight less than 1500 g were enrolled in the study. They received parental nutrition and feeding according to our protocol. When enteral feeding reached 100 cc/kg/day, infants were randomized into two groups: group I, Cases, n=25, where post discharge formula (PDF) was used for fortification, group II, Controls, n=25 with no fortification. Infants of both groups were given 50% of required enteral feeding as premature formula. This protocol was used until infants' weight reached 1800 g. Daily weight, weekly length and head circumference were recorded. Hemoglobin, albumin (Alb), electrolytes, blood urea nitrogen (BUN) and clinical complications were documented. Human milk fortification with PDF resulted in better growth with increase in weight 16.8 and 13.78 g/kg/day (P=0.0430), length 0.76 and 0.58 cm/week (P=0.0027), and head circumference of 0.59 and 0.5 cm/week (P=0.0217) in cases and controls respectively. Duration of hospital stay was less in cases (22.76 versus 28.52 days in Controls), P=0.02. No significant changes were found in serum electrolytes, BUN, or Alb between both groups. Hemoglobin was significantly higher in Cases, P=0.04. There were no significant clinical complications. Our feeding protocol of fortification of human milk with PDF in preterm very low birth weight newborns resulted in better growth and decrease in length of hospital stay. The use of PDF could be an alternative option for fortification of mothers' milk for preterm VLBW infants in developing countries with low resources. PMID- 27777706 TI - Swyer-James Syndrome in a 7-Year-Old Female. AB - Swyer-James syndrome is a rare syndrome that occurs as a result of repeated bronchiolitis and pneumonitis in childhood. Most cases are asymptomatic, and subsequent diagnosis may not occur until adulthood. We present the case of a 7 year-old female with Swyer-James syndrome, which was initially diagnosed and treated as asthma. The patient developed respiratory distress and atelectasis which were treated with biphasic cuirass ventilation. This case suggests that Swyer-James syndrome should be a concern in patients with chronic cough and wheezing, and highlights the importance of taking a careful history and appropriate radiological investigations for diagnosis. Once Swyer-James syndrome is diagnosed, prophylaxis and appropriate management of respiratory infections becomes important. PMID- 27777707 TI - Multiple Esophageal Foreign Bodies in an Infant: A Rare Case of Serious Parental Neglect. AB - A case of multiple esophageal foreign bodies, which were retrieved successfully by rigid esophagoscopy in a 1-year old child is being reported. There are few cases of multiple esophageal foreign bodies in children reported in the literature; this case was unique in presentation as there was no history of foreign body ingestion. This case also highlights the serious neglect present in our society towards children of lower socio-economic strata despite this child being the 1st child in the family. PMID- 27777708 TI - Persistent Hyperinsulinism in Kabuki Syndrome 2: Case Report and Literature Review. AB - Kabuki syndrome is a clinically and genetically heterogeneous congenital malformation syndrome with protean clinical manifestations. This reflects the important epigenetic role in embryonic development of the two genes currently known to be associated with Kabuki syndrome i.e., KMT2D and KDM6A, which are responsible for Kabuki syndrome 1 and Kabuki syndrome 2, respectively. Hypoglycemia is thought to be a rare manifestation of Kabuki syndrome; however it may be under diagnosed. Herein we describe the case of a 5-year-old girl with Kabuki syndrome 2 in whom persistent hyperinsulinism was diagnosed at 4 years of age. We postulate an epigenetic mechanism for hyperinsulinism where specific loss KDM6A demethylation of the H3K27me3/me2 mark may lead to deregulated pancreatic beta-cell development. PMID- 27777709 TI - Genetic Counseling for a Prenatal Diagnosis of Structural Chromosomal Abnormality with High-Resolution Analysis Using a Single Nucleotide Polymorphism Microarray. AB - A 41-year old pregnant woman underwent amniocentesis to conduct a conventional karyotyping analysis; the analysis reported an abnormal karyotype: 46, XY, add(9)(p24). Chromosomal microarray analysis (CMA) is utilized in prenatal diagnoses. A single nucleotide polymorphism microarray revealed a male fetus with balanced chromosomal translocations on 9p and balanced chromosomal rearrangements, but another chromosomal abnormality was detected. The fetus had microduplication. The child was born as a phenotypically normal male. CMA is a simple and informative procedure for prenatal genetic diagnosis. CMA is the detection of chromosomal variants of unknown clinical significance; therefore, genetic counseling is important during prenatal genetic testing. PMID- 27777710 TI - Oromandibular Dystonia: A Case Report of the Lateral Pterygoid Muscle Involvement and Treatment with Botulinum Toxin A. AB - The objective of the present case report is to punctuate the importance of individualized therapy procedures and the accurate diagnosis of the muscles involved in oromandibular dystonia and underline the role of electromyography (EMG). We report a woman who presented sustained jaw movement towards the left, severe difficulty in jaw opening and jaw protrusion. The patient was treated with injections of botulinum A toxin in lateral pterygoid, masseter, platysma, sternoclidomastoid, temporalis muscles with EMG guidance. She experienced an 80% reduction of her symptoms after the first injection. In jaw deviation dystonia symptoms impressively respond to botulinum toxin treatment of the pterygoid muscle. Individualized therapy procedures are necessitated. PMID- 27777711 TI - Cocaine Use and Splenic Rupture: A Rare Yet Serious Association. AB - Cocaine abuse is frequent in patients visiting the emergency department. The knowledge of the cardiovascular complications of cocaine is excellent among physicians. However the awareness regarding its abdominal complications, the most important of which include gastroduodenal perforation, bowel ischemia and splenic rupture is less adequate. We report a 58-year-old with cocaine use who presents with upper abdominal pain and a rapidly worsening clinical status. He was found to have atraumatic splenic rupture causing a hemoperitoneum that was managed by intervention radiology guided splenic artery embolization. Splenic hemorrhage and rupture need timely recognition, as they are difficult to diagnose clinically and can be potentially fatal. In the encounter of patients with cocaine use who present with chest or upper abdominal pain, clinicians should consider imaging to look for splenic rupture as it is often masked or overlooked due to the complicated clinical picture. PMID- 27777712 TI - Midterm Results of Consecutive Periprosthetic Femoral Fractures Vancouver Type A and B. AB - Surgical treatment of periprosthetic femoral fractures has a high complication and mortality rate of more than 10%. The aim of this study is to report the outcome of a consecutive single center patient group. Thirty-four consecutive patients (mean age 81.2+/-8.5 years, 14 male, 20 female) with a periprosthetic femoral fracture Vancouver type A (n=5) or type B (n=29) were followed-up after 43.2 months, none of the patients were lost to follow-up. Nineteen of the patients were treated through change of the stem and cerclage fixation, five by plates and ten by cerclage cables. One successfully treated infection was observed. No further complications have been reported peri- or postoperatively, therefore resulting in 2.9% overall complication rate. These results demonstrate that precisely selected revision surgery protocol following periprosthetic femoral fractures within elderly multimorbid patients may lead to beneficial outcomes at a low risk of complications. PMID- 27777713 TI - Medication Error When Switching from Warfarin to Rivaroxaban Leading to Spontaneous Large Ecchymosis of the Abdominal and Chest Wall. AB - Non-vitamin K oral anticoagulant (NOAC) therapy may be inappropriate if prescription was incorrect, the patient's physiological parameters change, or interacting concomitant medications are erroneously added. The aim of this report was to illustrate inappropriate NOAC prescription in a 78-year-old woman with non valvular atrial fibrillation and borderline renal dysfunction who was switched from warfarin to rivaroxaban and subsequently developed bruising with hemorrhagic shock and acute on chronic renal failure. Administration of 4-factor prothrombin complex concentrate effectively reversed coagulopathy and stopped bleeding. Retrospective determination of circulating plasma levels of rivaroxaban and warfarin confirmed that excessive anticoagulation was likely due to warfarin that the patient probably continued to take although rivaroxaban was initiated. Pharmacodynamic interaction between rivaroxaban and warfarin may not only be additive but synergistic. In patients at high risk of complications, judicious prescribing and dosing of NOACs, and regular monitoring of concomitant medications and renal function are highly recommended. PMID- 27777714 TI - Giant Adrenal Cavernous Hemangioma in a Patient with Familial Adenomatous Polyposis. AB - Adrenal hemangioma is an uncommon benign vascular tumor that is often discovered incidentally. It has never been reported in association with familial adenomatous polyposis. We report a case of a 60-year old man with a history of familial adenomatous polyposis, in whom a huge retroperitoneal cyst of 18x17 cm was discovered during routine radiologic evaluation. Because of the impossibility of ruling out the presence of malignancy, surgical cystectomy was performed, associated to a scheduled total colectomy. Pathological examination revealed that the cyst corresponded to an adrenal cavernous hemangioma. Colonic adenomas did not show signs of degeneration. Screening for adenomatous polyposis coli (APC) gene mutation was not carried out. As familial adenomatous polyposis is known to involve a variety of extracolonic manifestations, this finding raises the suspicion of a possible variant of this syndrome including adrenal hemangioma. An extensive study based on a larger patient series with genetic exploration is necessary. PMID- 27777715 TI - Bifid Mandibular Canal: A Rare or Underestimated Entity? AB - One of the rare anatomical variations that can be of significant importance for the dentist is the bifid mandibular canal. Many complications can occur from this condition such as failure of anesthesia when performing inferior alveolar nerve block, difficulties during the surgical extraction of the third mandibular molar, and during implants placement. Therefore, good knowledge of this condition is essential. In this report, we describe the radiographic finding of a unilateral bifid mandibular canal. PMID- 27777717 TI - Outcome and the effect of age and socioeconomic status in 1318 patients with synovial sarcoma in the English National Cancer Registry: 1985-2009. AB - BACKGROUND: The role of age as a prognostic factor has been examined in single institutional studies and in larger data sets from the SEER database, showing a survival advantage for younger versus adult patients with synovial sarcoma (SS). To further assess the role of age, socioeconomic status and other prognostic factors on outcome for SS, we analysed a contemporary all-age population-based cohort of patients with SS registered in England. METHODS: The data on 1318 synovial sarcomas diagnosed in England between 1985 and 2009 were retrospectively analysed for incidence, and the effect of age, patient characteristics and deprivation on outcome using both univariate and multivariate analysis. RESULTS: The incidence of SS increased to 1.4 per million over the time period, the numbers diagnosed in patients under 10 years of age were small. The site or incidence of metastases did not vary between age groups. There were, however, significant differences (p < 0.05) in the 5-year relative survival rates between patients aged 0-19 years and those >=20 years of age, 76 % and 53 % respectively. Survival was better in localised tumours at an extremity site. In multivariate analysis higher mortality occurred in older patients, non-extremity site, presence of metastases, female adults and a higher deprivation score. CONCLUSIONS: Synovial sarcoma in children/teenagers compared with adults, have a similar clinical presentation in this population-based series, but a superior outcome. The finding of socioeconomic deprivation affecting outcome in SS needs further exploration in a complete and contemporary dataset, where all prognostic variables are present. PMID- 27777716 TI - Emotional decision-making in autism spectrum disorder: the roles of interoception and alexithymia. AB - The way choices are framed influences decision-making. These "framing effects" emerge through the integration of emotional responses into decision-making under uncertainty. It was previously reported that susceptibility to the framing effect was reduced in individuals with autism spectrum disorder (ASD) due to a reduced tendency to incorporate emotional information into the decision-making process. However, recent research indicates that, where observed, emotional processing impairments in ASD may be due to co-occurring alexithymia. Alexithymia is thought to arise due to impaired interoception (the ability to perceive the internal state of one's body), raising the possibility that emotional signals are not perceived and thus not integrated into decision-making in those with alexithymia and that therefore reduced framing effects in ASD are a product of co-occurring alexithymia rather than ASD per se. Accordingly, the present study compared framing effects in autistic individuals with neurotypical controls matched for alexithymia. Results showed a marked deviation between groups. The framing effect was, in line with previous data, significantly smaller in autistic individuals, and there was no relationship between alexithymia or interoception and decision making in the ASD group. In the neurotypical group, however, the size of the framing effect was associated with alexithymia and interoception, even after controlling for autistic traits. These results demonstrate that although framing effects are associated with interoception and alexithymia in the neurotypical population, emotional and interoceptive signals have less impact upon the decision-making process in ASD. PMID- 27777719 TI - After the games are over: life-history trade-offs drive dispersal attenuation following range expansion. AB - Increased dispersal propensity often evolves on expanding range edges due to the Olympic Village effect, which involves the fastest and fittest finding themselves together in the same place at the same time, mating, and giving rise to like individuals. But what happens after the range's leading edge has passed and the games are over? Although empirical studies indicate that dispersal propensity attenuates following range expansion, hypotheses about the mechanisms driving this attenuation have not been clearly articulated or tested. Here, we used a simple model of the spatiotemporal dynamics of two phenotypes, one fast and the other slow, to propose that dispersal attenuation beyond preexpansion levels is only possible in the presence of trade-offs between dispersal and life-history traits. The Olympic Village effect ensures that fast dispersers preempt locations far from the range's previous limits. When trade-offs are absent, this preemptive spatial advantage has a lasting impact, with highly dispersive individuals attaining equilibrium frequencies that are strictly higher than their introduction frequencies. When trade-offs are present, dispersal propensity decays rapidly at all locations. Our model's results about the postcolonization trajectory of dispersal evolution are clear and, in principle, should be observable in field studies. We conclude that empirical observations of postcolonization dispersal attenuation offer a novel way to detect the existence of otherwise elusive trade-offs between dispersal and life-history traits. PMID- 27777720 TI - Climate change is the primary driver of white-tailed deer (Odocoileus virginianus) range expansion at the northern extent of its range; land use is secondary. AB - Quantifying the relative influence of multiple mechanisms driving recent range expansion of non-native species is essential for predicting future changes and for informing adaptation and management plans to protect native species. White tailed deer (Odocoileus virginianus) have been expanding their range into the North American boreal forest over the last half of the 20th century. This has already altered predator-prey dynamics in Alberta, Canada, where the distribution likely reaches the northern extent of its continuous range. Although current white-tailed deer distribution is explained by both climate and human land use, the influence each factor had on the observed range expansion would depend on the spatial and temporal pattern of these changes. Our objective was to quantify the relative importance of land use and climate change as drivers of white-tailed deer range expansion and to predict decadal changes in white-tailed deer distribution in northern Alberta for the first half of the 21st century. An existing species distribution model was used to predict past decadal distributions of white-tailed deer which were validated using independent data. The effects of climate and land use change were isolated by comparing predictions under theoretical "no-change between decades" scenarios, for each factor, to predictions under observed climate and land use change. Climate changes led to more than 88%, by area, of the increases in probability of white-tailed deer presence across all decades. The distribution is predicted to extend 100 km further north across the northeastern Alberta boreal forest as climate continues to change over the first half of the 21st century. PMID- 27777718 TI - Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis. AB - Somatic mutations of KIT are frequently found in mastocytosis and gastrointestinal stromal tumor (GIST), while germline mutations of KIT are rare, and only found in few cases of familial GIST and mastocytosis. Although ligand independent activation is the common feature of KIT mutations, the phenotypes mediated by various germline KIT mutations are different. Germline KIT mutations affect different tissues such as interstitial cells of Cajal (ICC), mast cells or melanocytes, and thereby lead to GIST, mastocytosis, or abnormal pigmentation. In this review, we summarize germline KIT mutations in familial mastocytosis and GIST and discuss the possible cellular context dependent transforming activity of KIT mutations. PMID- 27777721 TI - Correlated evolution between targets of pre- and postcopulatory sexual selection across squamate reptiles. AB - Sexual selection reflects the joint contributions of precopulatory selection, which arises from variance in mating success, and postcopulatory selection, which arises from variance in fertilization success. The relative importance of each episode of selection is variable among species, and comparative evidence suggests that traits targeted by precopulatory selection often covary in expression with those targeted by postcopulatory selection when assessed across species, although the strength and direction of this association varies considerably among taxa. We tested for correlated evolution between targets of pre- and postcopulatory selection using data on sexual size dimorphism (SSD) and testis size from 151 species of squamate reptiles (120 lizards, 31 snakes). In squamates, male-male competition for mating opportunities often favors large body size, such that the degree of male-biased SSD is associated with the intensity of precopulatory selection. Likewise, competition for fertilization often favors increased sperm production, such that testis size (relative to body size) is associated with the intensity of postcopulatory selection. Using both conventional and phylogenetically based analyses, we show that testis size consistently decreases as the degree of male-biased SSD increases across lizards and snakes. This evolutionary pattern suggests that strong precopulatory selection may often constrain the opportunity for postcopulatory selection and that the relative importance of each selective episode may determine the optimal resolution of energy allocation trade-offs between traits subject to each form of sexual selection. PMID- 27777722 TI - Nuclear-mitochondrial epistasis: a gene's eye view of genomic conflict. AB - We use population genetic models to investigate the cooperative and conflicting synergistic fitness effects between genes from the nucleus and the mitochondrion. By varying fitness parameters, we examine the scope for conflict relative to cooperation among genomes and the utility of the "gene's eye view" analytical approach, which is based on the marginal average fitness of specific alleles. Because sexual conflict can maintain polymorphism of mitochondrial haplotypes, we can explore two types of evolutionary conflict (genomic and sexual) with one epistatic model. We find that the nuclear genetic architecture (autosomal, X linked, or Z-linked) and the mating system change the regions of parameter space corresponding to the evolution by sexual and genomic conflict. For all models, regardless of conflict or cooperation, we find that population mean fitness increases monotonically as evolution proceeds. Moreover, we find that the process of gene frequency change with positive, synergistic fitnesses is self accelerating, as the success of an allele in one genome or in one sex increases the frequency of the interacting allele upon which its success depends. This results in runaway evolutionary dynamics caused by the positive intergenomic associations generated by selection. An inbreeding mating system tends to further accelerate these runaway dynamics because it maintains favorable host-symbiont or male-female gene combinations. In contrast, where conflict predominates, the success of an allele in one genome or in one sex diminishes the frequency of the corresponding allele in the other, resulting in considerably slower evolutionary dynamics. The rate of change of mean fitness is also much faster with positive, synergistic fitnesses and much slower where conflict is predominant. Consequently, selection rapidly fixes cooperative gene combinations, while leaving behind a slowing evolving residue of conflicting gene combinations at mutation-selection balance. We discuss how an emphasis on marginal fitness averages may obscure the interdependence of allelic fitness across genomes, making the evolutionary trajectories appear independent of one another when they are not. PMID- 27777724 TI - Heading for the hills? Evaluating spatial distribution of woodland caribou in response to a growing anthropogenic disturbance footprint. AB - Anthropogenic landscape change (i.e., disturbance) is recognized as an important factor in the decline and extirpation of wildlife populations. Understanding and monitoring the relationship between wildlife distribution and disturbance is necessary for effective conservation planning. Many studies consider disturbance as a covariate explaining wildlife behavior. However, we propose that there are several advantages to considering the spatial relationship between disturbance and wildlife directly using utilization distributions (UDs), including objective assessment of the spatially explicit overlap between wildlife and disturbance, and the ability to track trends in this relationship over time. Here, we examined how central mountain woodland caribou (Rangifer tarandus caribou) distribution changed over time in relation to (i) anthropogenic disturbance, baseline range (defined using telemetry data from 1998 to 2005), and alpine habitat; and (ii) interannual climate variation (North Pacific Index; NPI). We developed seasonal UDs for caribou in west-central Alberta and east-central British Columbia, Canada, monitored with GPS collars between 1998 and 2013. We mapped the cumulative annual density of disturbance features within caribou range and used indices of overlap to determine the spatial relationship and trend between caribou UDs, anthropogenic disturbance, baseline range, alpine habitat, and the NPI. Anthropogenic disturbance increased over time, but the overlap between caribou UDs and disturbance did not. Caribou use of alpine habitat during spring, fall, and late winter increased over time, concurrent with a decrease in use of baseline range. Overlap between caribou UDs and disturbance increased during spring and fall following relatively cold, snowy winters (high NPI), but overall, climate did not explain changes in caribou distribution over time. We provide evidence supporting the hypothesis that caribou populations adjust their spatial distribution in relation to anthropogenic landscape change. Our findings could have implications for population persistence if distributional shifts result in greater use of alpine habitat during winter. Monitoring long-term changes in the distribution of populations is a valuable component of conservation planning for species at risk in disturbed landscapes. PMID- 27777723 TI - Attack of the clones: reproductive interference between sexuals and asexuals in the Crepis agamic complex. AB - Negative reproductive interactions are likely to be strongest between close relatives and may be important in limiting local coexistence. In plants, interspecific pollen flow is common between co-occurring close relatives and may serve as the key mechanism of reproductive interference. Agamic complexes, systems in which some populations reproduce through asexual seeds (apomixis), while others reproduce sexually, provide an opportunity to examine effects of reproductive interference in limiting coexistence. Apomictic populations experience little or no reproductive interference, because apomictic ovules cannot receive pollen from nearby sexuals. Oppositely, apomicts produce some viable pollen and can exert reproductive interference on sexuals by siring hybrids. In the Crepis agamic complex, sexuals co-occur less often with other members of the complex, but apomicts appear to freely co-occur with one another. We identified a mixed population and conducted a crossing experiment between sexual diploid C. atribarba and apomictic polyploid C. barbigera using pollen from sexual diploids and apomictic polyploids. Seed set was high for all treatments, and as predicted, diploid-diploid crosses produced all diploid offspring. Diploid-polyploid crosses, however, produced mainly polyploidy offspring, suggesting that non-diploid hybrids can be formed when the two taxa meet. Furthermore, a small proportion of seeds produced in open-pollinated flowers was also polyploid, indicating that polyploid hybrids are produced under natural conditions. Our results provide evidence for asymmetric reproductive interference, with pollen from polyploid apomicts contributing to reduce the recruitment of sexual diploids in subsequent generations. Existing models suggest that these mixed sexual-asexual populations are likely to be transient, eventually leading to eradication of sexual individuals from the population. PMID- 27777725 TI - Ecological niche modeling for conservation planning of an endemic snail in the verge of becoming a pest in cardamom plantations in the Western Ghats biodiversity hotspot. AB - Conservation managers and policy makers are often confronted with a challenging dilemma of devising suitable strategies to maintain agricultural productivity while conserving endemic species that at the early stages of becoming pests of agricultural crops. Identification of environmental factors conducive to species range expansion for forecasting species distribution patterns will play a central role in devising management strategies to minimize the conflict between the agricultural productivity and biodiversity conservation. Here, we present results of a study that predicts the distribution of Indrella ampulla, a snail endemic to the Western Ghats biodiversity hotspot, which is becoming a pest in cardamom (Ellettaria cardamomum) plantations. We determined the distribution patterns and niche overlap between I. ampulla and Ellettaria cardamomum using maximum entropy (MaxEnt) niche modeling techniques under current and future (2020-2080) climatic scenarios. The results showed that climatic (precipitation of coldest quarter and isothermality) and soil (cation exchange capacity of soil [CEC]) parameters are major factors that determine the distribution of I. ampulla in Western Ghats. The model predicted cardamom cultivation areas in southern Western Ghats are highly sensitive to invasion of I. ampulla under both present and future climatic conditions. While the land area in the central Western Ghats is predicted to become unsuitable for I. ampulla and Ellettaria cardamomum in future, we found 71% of the Western Ghats land area is suitable for Ellettaria cardamomum cultivation and 45% suitable for I. ampulla, with an overlap of 35% between two species. The resulting distribution maps are invaluable for policy makers and conservation managers to design and implement management strategies minimizing the conflicts to sustain agricultural productivity while maintaining biodiversity in the region. PMID- 27777726 TI - Seed set variation in wild Clarkia populations: teasing apart the effects of seasonal resource depletion, pollen quality, and pollen quantity. AB - In habitats where resource availability declines during the growing season, selection may favor early-flowering individuals. Under such ephemerally favorable conditions, late-blooming species (and individuals) may be particularly vulnerable to resource limitation of seed production. In California, a region prone to seasonal drought, members of the annual genus Clarkia are among the last to flower in the spring. We compared pollen limitation (PL) of seed set and outcrossing rates between early- and late-flowering individuals in two mixed mating Clarkia taxa to detect whether flowering time is associated with changes in seed set due to resource depletion, PL, or increased selfing. In 2008-2010, we hand-pollinated one flower on a total of 1855 individual plants either Early (near the onset of flowering) or Late (near the end of flowering) in the flowering season and compared seed set to adjacent, open-pollinated flowers on the same stem. To assess the contribution of pollen quality to reproduction, we first (2008) used allozymes to estimate outcrossing rates of seeds produced by Early and Late open-pollinated flowers. Second (2009), we conducted an anther removal experiment to estimate self-pollen deposition. Seed set in Clarkia unguiculata was not pollen-limited. Clarkia xantiana ssp. xantiana was pollen limited in 2008 and 2010, but not 2009. PL did not differ between Early and Late treatments. In both taxa, seed set of Early flowers was greater than Late flowers, but not due to PL in the latter. Reproduction was generally pollinator dependent. Most pollen deposition was xenogamous, and outcrossing rates were >0.7 - and similar between Early and Late periods. These results suggest that pollen receipt and pollen quality remain seasonally consistent. By contrast, the resources necessary to provision seeds decline, reducing the fitness benefits associated with resource allocation to ovules. PMID- 27777727 TI - Stress-induced peak (but not resting) metabolism correlates with mating display intensity in male guppies. AB - Recent empirical and conceptual papers have highlighted the potential for metabolism to act as a proximate mechanism for behavior that could explain animal personality (consistency over time). Under this hypothesis, individuals with consistently high levels of behavioral activity should also have high resting metabolic rate (RMR) as it can reflect capacity to process food and generate energy. We tested for the predicted positive covariance between RMR and three behaviors that differ in energy demands in 30 male guppies, using multivariate mixed models; we repeatedly measured their activity (10 times each), courtship displays (nine times), voracity (10 times), and metabolism (four-times). Resting metabolic rate (measured overnight in respirometry trials) did not consistently differ among males, whereas initial peak metabolism measured during those same trials (R = 0.42), and all behaviors were repeatable (R = 0.33-0.51). RMR declined over time suggesting habituation to the protocol, whereas peak metabolism did not. Initial peak metabolism was negatively correlated with courtship display intensity, and voracity was positively correlated with activity, but all other among-individual correlations were not significant. We conclude that RMR does not provide a proximate explanation for consistent individual differences in behavior in male guppies, and therefore the potential for independent evolution of these physiological and behavioral traits seems possible. Finally, we identify peak metabolism as a potential measure of the stress response to confinement, which highlights the value of considering various aspects of metabolic rates recording during respirometry trials. PMID- 27777728 TI - Effect of acute stressor on reproductive behavior differs between urban and rural birds. AB - The life-history trade-off between self-maintenance and reproduction posits that investment in one function decreases investment in the other. Manipulating the costs and benefits of functions involved in a trade-off may alter this interaction. Here we ask whether investment in self-maintenance during a stress response alters territorial behavior in wild Dark-eyed Juncos and whether rural and urban birds, which are known to differ in the magnitude of the stress response (greater in rural), also differ in the degree to which stress reduces territorial behavior. In rural and urban habitats, we measured territorial behavior using song playback, followed by either an acute stressor (capture and collection of a blood sample) or a nonstressful control situation. The following day, we again measured territorial behavior, predicting greater reduction in territorial behavior in individuals exposed to the stressor but a lesser reduction in territorial behavior in the urban as compared to the rural environment. We further assessed individual and population differences in response to stressors by measuring flight initiation distance, breath rate, and corticosterone levels in the blood. The rural population had a higher physiological and behavioral stress response than the urban population, and acute capture stress had a lasting (24 h) negative effect on territorial behavior, but only in the rural habitat. However, individual-level differences in measures of the stress response did not explain variation in the impact of stress on territorial behavior. Our findings show that stressors can have a negative effect on territorial behavior, but that this effect may differ between populations that vary in their stress ecology. PMID- 27777729 TI - Metabolic adaptations in a range-expanding arthropod. AB - Despite an increasing number of studies documenting life-history evolution during range expansions or shifts, we lack a mechanistic understanding of the underlying physiological processes. In this explorative study, we used a metabolomics approach to study physiological changes associated with the recent range expansion of the two-spotted spider mite (Tetranychus urticae). Mite populations were sampled along a latitudinal gradient from range core to edge and reared under benign common garden conditions for two generations. Using gas chromatography-mass spectrometry, we obtained metabolic population profiles, which showed a gradual differentiation along the latitudinal gradient, indicating (epi)genetic changes in the metabolome in association with range expansion. These changes seemed not related with shifts in the mites' energetic metabolism, but rather with differential use of amino acids. Particularly, more dispersive northern populations showed lowered concentrations of several essential and nonessential amino acids, suggesting a potential downregulation of metabolic pathways associated with protein synthesis. PMID- 27777730 TI - Evidence for ecological speciation via a host shift in the holly leaf miner, Phytomyza glabricola (Diptera: Agromyzidae). AB - Evolutionary radiations have been well documented in plants and insects, and natural selection may often underly these radiations. If radiations are adaptive, the diversity of species could be due to ecological speciation in these lineages. Agromyzid flies exhibit patterns of repeated host-associated radiations. We investigated whether host-associated population divergence and evidence of divergent selection exist in the leaf miner Phytomyza glabricola on its sympatric host plants, the holly species, Ilex coriacea and I. glabra. Using AFLPs and nuclear sequence data, we found substantial genetic divergence between host associated populations of these flies throughout their geographic range. Genome scans using the AFLP data identified 13 loci under divergent selection, consistent with processes of ecological speciation. EF-1alpha data suggest that I. glabra is the original host of P. glabricola and that I. coriacea is the novel host, but the AFLP data are ambiguous with regard to directionality of the host shift. PMID- 27777731 TI - Plasticity of fertilization rates under varying temperature in the broadcast spawning mussel, Mytilus galloprovincialis. AB - Oceans are a huge sink for the increased heat associated with anthropogenic climate change, and it is vital to understand the heat tolerance of marine organisms at all life stages to accurately predict species' responses. In broadcast spawning marine invertebrates, reproduction is a vulnerable process in which sperm and eggs are released directly into the open water. Gametes are then exposed to fluctuating environmental conditions that may impact their fertilizing capacity. Using the broadcast spawning Mediterranean mussel, Mytilus galloprovincialis, as a model species, we performed blocks of factorial mating crosses to assess the variance in fertilization rates among individuals under both ambient and elevated temperatures. Overall, we found a small, but significant decline in fertilization rates with elevated temperatures. However, there was substantial plasticity in responses, with particular mussels having increased fertilization under elevated temperatures, although the majority showed decreased fertilization rates. Our results suggest possible future reproductive costs to ocean warming in M. galloprovincialis, although it is also possible that genetic variation for thermal sensitivity may allow for adaptation to changing environmental conditions. PMID- 27777732 TI - Landscape-scale deforestation decreases gene flow distance of a keystone tropical palm, Euterpe edulis Mart (Arecaceae). AB - Habitat loss represents one of the main threats to tropical forests, which have reached extremely high rates of species extinction. Forest loss negatively impacts biodiversity, affecting ecological (e.g., seed dispersal) and genetic (e.g., genetic diversity and structure) processes. Therefore, understanding how deforestation influences genetic resources is strategic for conservation. Our aim was to empirically evaluate the effects of landscape-scale forest reduction on the spatial genetic structure and gene flow of Euterpe edulis Mart (Arecaceae), a palm tree considered a keystone resource for many vertebrate species. This study was carried out in nine forest remnants in the Atlantic Forest, northeastern Brazil, located in landscapes within a gradient of forest cover (19-83%). We collected leaves of 246 adults and 271 seedlings and performed genotyping using microsatellite markers. Our results showed that the palm populations had low spatial genetic structure, indicating that forest reduction did not influence this genetic parameter for neither seedlings nor adults. However, forest loss decreased the gene flow distance, which may negatively affect the genetic diversity of future generations by increasing the risk of local extinction of this keystone palm. For efficient strategies of genetic variability conservation and maintenance of gene flow in E. edulis, we recommend the maintenance of landscapes with intermediary to high levels of forest cover, that is, forest cover above 40%. PMID- 27777733 TI - The proportion of impervious surfaces at the landscape scale structures wild bee assemblages in a densely populated region. AB - Given the predicted expansion of cities throughout the world, understanding the effect of urbanization on bee fauna is a major issue for the conservation of bees. The aim of this study was to understand how urbanization affects wild bee assemblages along a gradient of impervious surfaces and to determine the influence of landscape composition and floral resource availability on these assemblages. We chose 12 sites with a proportion of impervious surfaces (soil covered by parking, roads, and buildings) ranging from 0.06% to 64.31% within a 500 m radius. We collected using pan trapping and estimated the landscape composition of the sites within a 500 m radius and the species richness of plant assemblages within a 200 m radius. We collected 1104 bees from 74 species. The proportion of impervious surfaces at the landscape scale had a negative effect on wild bee abundance and species richness, whereas local flower composition had no effect. Ground-nesting bees were particularly sensitive to the urbanization gradient. This study provides new evidences of the impact of urbanization on bee assemblages and the proportion of impervious surfaces at the landscape scale emerged as a key factor that drives those assemblages. PMID- 27777734 TI - Why fly the extra mile? Latitudinal trend in migratory fuel deposition rate as driver of trans-equatorial long-distance migration. AB - Trans-equatorial long-distance migrations of high-latitude breeding animals have been attributed to narrow ecological niche widths. We suggest an alternative hypothesis postulating that trans-equatorial migrations result from a possible increase in the rate at which body stores to fuel migration are deposited with absolute latitude; that is, longer, migrations away from the breeding grounds surpassing the equator may actually enhance fueling rates on the nonbreeding grounds and therewith the chance of a successful, speedy and timely migration back to the breeding grounds. To this end, we first sought to confirm the existence of a latitudinal trend in fuel deposition rate in a global data set of free-living migratory shorebirds and investigated the potential factors causing this trend. We next tested two predictions on how this trend is expected to impact the migratory itineraries on northward migration under the time minimization hypothesis, using 56 tracks of high-latitude breeding shorebirds migrating along the East Asian-Australasian Flyway. We found a strong positive effect of latitude on fuel deposition rate, which most likely relates to latitudinal variations in primary productivity and available daily foraging time. We next confirmed the resulting predictions that (1) when flying from a stopover site toward the equator, migrants use long jumps that will take them to an equivalent or higher latitude at the opposite hemisphere; and (2) that from here onward, migrants will use small steps, basically fueling only enough to make it to the next suitable staging site. These findings may explain why migrants migrate "the extra mile" across the equator during the nonbreeding season in search of better fueling conditions, ultimately providing secure and fast return migrations to the breeding grounds in the opposite hemisphere. PMID- 27777735 TI - Genetic signatures of a range expansion in natura: when clones play leapfrog. AB - The genetic consequences of range expansions have generally been investigated at wide geographical and temporal scales, long after the colonization event. A unique ecological system enabled us to both monitor the colonization dynamics and decipher the genetic footprints of expansion over a very short time period. Each year an epidemic of the poplar rust (Melampsora larici-populina) expands clonally and linearly along the Durance River, in the Alps. The colonization dynamics observed in 2004 showed two phases with different genetic outcomes. Upstream, fast colonization maintained high genetic diversity. Downstream, the colonization wave progressively faltered, diversity eroded, and differentiation increased, as expected under recurrent founder events. In line with the high dispersal abilities of rust pathogens, we provide evidence for leapfrog dispersal of clones. Our results thus emphasize the importance of colonization dynamics in shaping spatial genetic structure in the face of high gene flow. PMID- 27777736 TI - Phylogeographic structure in long-tailed voles (Rodentia: Arvicolinae) belies the complex Pleistocene history of isolation, divergence, and recolonization of Northwest North America's fauna. AB - Quaternary climate fluctuations restructured biodiversity across North American high latitudes through repeated episodes of range contraction, population isolation and divergence, and subsequent expansion. Identifying how species responded to changing environmental conditions not only allows us to explore the mode and tempo of evolution in northern taxa, but also provides a basis for forecasting future biotic response across the highly variable topography of western North America. Using a multilocus approach under a Bayesian coalescent framework, we investigated the phylogeography of a wide-ranging mammal, the long tailed vole, Microtus longicaudus. We focused on populations along the North Pacific Coast to refine our understanding of diversification by exploring the potentially compounding roles of multiple glacial refugia and more recent fragmentation of an extensive coastal archipelago. Through a combination of genetic data and species distribution models (SDMs), we found that historical climate variability influenced contemporary genetic structure, with multiple isolated locations of persistence (refugia) producing multiple divergent lineages (Beringian or northern, southeast Alaska or coastal, and southern or continental) during glacial advances. These vole lineages all occur along the North Pacific Coast where the confluence of numerous independent lineages in other species has produced overlapping zones of secondary contact, collectively a suture zone. Finally, we detected high levels of neoendemism due to complex island geography that developed in the last 10,000 years with the rising sea levels of the Holocene. PMID- 27777737 TI - Marine reserves indirectly affect fine-scale habitat associations, but not overall densities, of small benthic fishes. AB - Many large, fishery-targeted predatory species have attained very high relative densities as a direct result of protection by no-take marine reserves. Indirect effects, via interactions with targeted species, may also occur for species that are not themselves targeted by fishing. In some temperate rocky reef ecosystems, indirect effects have caused profound changes in community structure, notably the restoration of predator-urchin-macroalgae trophic cascades. Yet, indirect effects on small benthic reef fishes remain poorly understood, perhaps because of behavioral associations with complex, refuge-providing habitats. Few, if any, studies have evaluated any potential effects of marine reserves on habitat associations in small benthic fishes. We surveyed densities of small benthic fishes, including some endemic species of triplefin (Tripterygiidae), along with fine-scale habitat features in kelp forests on rocky reefs in and around multiple marine reserves in northern New Zealand over 3 years. Bayesian generalized linear mixed models were used to evaluate evidence for (1) main effects of marine reserve protection, (2) associations with habitat gradients, including complexity, and (3) differences in habitat associations inside versus outside reserves. No evidence of overall main effects of marine reserves on species richness or densities of fishes was found. Both richness and densities showed strong associations with gradients in habitat features, particularly habitat complexity. In addition, some species exhibited reserve-by-habitat interactions, having different associations with habitat gradients inside versus outside marine reserves. Two species (Ruanoho whero and Forsterygion flavonigrum) showed stronger positive associations with habitat complexity inside reserves. These results are consistent with the presence of a behavioral risk effect, whereby prey fishes are more strongly attracted to habitats that provide refuge from predation in areas where predators are more abundant. This work highlights the importance of habitat structure and the potential for fishing to affect behavioral interactions and the interspecific dynamic attributes of community structure beyond simple predator-prey consumption and archetypal trophic cascades. PMID- 27777738 TI - Coastal connectivity and spatial subsidy from a microbial perspective. AB - The transfer of organic material from one coastal environment to another can increase production in recipient habitats in a process known as spatial subsidy. Microorganisms drive the generation, transformation, and uptake of organic material in shallow coastal environments, but their significance in connecting coastal habitats through spatial subsidies has received limited attention. We address this by presenting a conceptual model of coastal connectivity that focuses on the flow of microbially mediated organic material in key coastal habitats. Our model suggests that it is not the difference in generation rates of organic material between coastal habitats but the amount of organic material assimilated into microbial biomass and respiration that determines the amount of material that can be exported from one coastal environment to another. Further, the flow of organic material across coastal habitats is sensitive to environmental change as this can alter microbial remineralization and respiration rates. Our model highlights microorganisms as an integral part of coastal connectivity and emphasizes the importance of including a microbial perspective in coastal connectivity studies. PMID- 27777739 TI - Changes in distribution of waterbirds following prolonged drought reflect habitat availability in coastal and inland regions. AB - Provision of suitable habitat for waterbirds is a major challenge for environmental managers in arid and semiarid regions with high spatial and temporal variability in rainfall. It is understood in broad terms that to survive waterbirds must move according to phases of wet-dry cycles, with coastal habitats providing drought refugia and inland wetlands used during the wet phase. However, both inland and coastal wetlands are subject to major anthropogenic pressures, and the various species of waterbird may have particular habitat requirements and respond individualistically to spatiotemporal variations in resource distribution. A better understanding of the relationships between occurrence of waterbirds and habitat condition under changing climatic conditions and anthropogenic pressures will help clarify patterns of habitat use and the targeting of investments in conservation. We provide the first predictive models of habitat availability between wet and dry phases for six widely distributed waterbird species at a large spatial scale. We first test the broad hypothesis that waterbirds are largely confined to coastal regions during a dry phase. We then examine the contrasting results among the six species, which support other hypotheses erected on the basis of their ecological characteristics. There were large increases in area of suitable habitat in inland regions in the wet year compared with the dry year for all species, ranging from 4.14% for Australian White Ibis to 31.73% for Eurasian Coot. With over half of the suitable habitat for three of the six species was located in coastal zones during drought, our study highlights the need to identify and conserve coastal drought refuges. Monitoring of changes in extent and condition of wetlands, combined with distribution modeling of waterbirds, will help support improvements in the conservation and management of waterbirds into the future. PMID- 27777740 TI - Eutrophication strengthens the response of zooplankton to temperature changes in a high-altitude lake. AB - To assess whether and how zooplankton communities respond to variations in temperature and how these assemblages change with eutrophication, we performed a large-scale, monthly survey from August 2011 to July 2012 to determine the seasonal and spatial variations in these communities in a high-altitude lake. A detrended correspondence analysis and a path analysis demonstrated that temperature and chlorophyll a were important factors influencing zooplankton. The path diagram showed that Daphnia was negatively affected directly by chlorophyll a and indirectly by temperature, whereas Bosmina was directly and positively affected by temperature. Daphnia spp. decreased in both absolute and relative biomass during warm seasons, whereas Bosmina spp. showed the opposite trend. Moreover, the lowest Daphnia spp. biomass was observed in the southern region, which was the most eutrophic. Our results indicate that increasing temperatures will continue to shift the dominant genus from Daphnia to Bosmina, and this change will be exacerbated by eutrophication. In addition, the zooplankton of Lake Erhai have shifted to smaller species over time as temperature and eutrophication have increased, which implies that zooplankton succession to small cladocerans may be markedly accelerated under further climate change and the increased eutrophication that has been observed in recent decades. PMID- 27777741 TI - Livestock guardian dogs as surrogate top predators? How Maremma sheepdogs affect a wildlife community. AB - Use of livestock guardian dogs (LGDs) to reduce predation on livestock is increasing. However, how these dogs influence the activity of wildlife, including predators, is not well understood. We used pellet counts and remote cameras to investigate the effects of free ranging LGDs on four large herbivores (eastern gray kangaroo, common wombat, swamp wallaby, and sambar deer) and one mesopredator (red fox) in Victoria, Australia. Generalized mixed models and one- and two-species detection models were used to assess the influence of the presence of LGDs on detection of the other species. We found avoidance of LGDs in four species. Swamp wallabies and sambar deer were excluded from areas occupied by LGDs; gray kangaroos showed strong spatial and temporal avoidance of LGD areas; foxes showed moderately strong spatial and temporal avoidance of LGD areas. The effect of LGDs on wombats was unclear. Avoidance of areas with LGDs by large herbivores can benefit livestock production by reducing competition for pasture and disease transmission from wildlife to livestock, and providing managers with better control over grazing pressure. Suppression of mesopredators could benefit the small prey of those species. Synthesis and applications: In pastoral areas, LGDs can function as a surrogate top-order predator, controlling the local distribution and affecting behavior of large herbivores and mesopredators. LGDs may provide similar ecological functions to those that in many areas have been lost with the extirpation of native large carnivores. PMID- 27777742 TI - Phylogenetic comparisons of pedestrian locomotion costs: confirmations and new insights. AB - The energetic costs for animals to locomote on land influence many aspects of their ecology. Size accounts for much of the among-species variation in terrestrial transport costs, but species of similar body size can still exhibit severalfold differences in energy expenditure. We compiled measurements of the (mass-specific) minimum cost of pedestrian transport (COTmin, mL/kg/m) for 201 species - by far the largest sample to date - and used phylogenetically informed comparative analyses to investigate possible eco-evolutionary differences in COTmin between various groupings of those species. We investigated number of legs, ectothermy and endothermy, waddling, and nocturnality specifically in lizards. Thus, our study primarily revisited previous theories about variations in COTmin between species, testing them with much more robust analyses. Having accounted for mass, while residual COTmin did not differ between bipedal and other species, specifically waddling bipeds were found to have relatively high COTmin. Furthermore, nocturnal lizards have relatively low COTmin although temperature does not appear to affect COTmin in ectotherms. Previous studies examining across-species variation in COTmin from a biomechanical perspective show that the differences between waddling birds and nonwaddling species, and between nocturnal lizards and other ecotherms, are likely to be attributable to differences in ground reaction forces, posture, and effective limb length. PMID- 27777743 TI - Diploid male production correlates with genetic diversity in the parasitoid wasp Venturia canescens: a genetic approach with new microsatellite markers. AB - Sex determination is ruled by haplodiploidy in Hymenoptera, with haploid males arising from unfertilized eggs and diploid females from fertilized eggs. However, diploid males with null fitness are produced under complementary sex determination (CSD), when individuals are homozygous for this locus. Diploid males are expected to be more frequent in genetically eroded populations (such as islands and captive populations), as genetic diversity at the csd locus should be low. However, only a few studies have focused on the relation between population size, genetic diversity, and the proportion of diploid males in the field. Here, we developed new microsatellite markers in order to assess and compare genetic diversity and diploid male proportion (DMP) in populations from three distinct habitat types - mainland, island, or captive -, in the parasitoid wasp Venturia canescens. Eroded genetic diversity and higher DMP were found in island and captive populations, and habitat type had large effect on genetic diversity. Therefore, DMP reflects the decreasing genetic diversity in small and isolated populations. Thus, Hymenopteran populations can be at high extinction risk due to habitat destruction or fragmentation. PMID- 27777744 TI - Bacteria-type-specific biparental immune priming in the pipefish Syngnathus typhle. AB - The transfer of acquired and specific immunity against previously encountered bacteria from mothers to offspring boosts the immune response of the next generation and supports the development of a successful pathogen defense. While most studies claim that the transfer of immunity is a maternal trait, in the sex role-reversed pipefish Syngnathus typhle, fathers nurse the embryos over a placenta-like structure, which opens the door for additional paternal immune priming. We examined the potential and persistence of bacteria-type-specific parental immune priming in the pipefish S. typhle over maturation time using a fully reciprocal design with two different bacteria species (Vibrio spp. and Tenacibaculum maritimum). Our results suggest that S. typhle is able to specifically prime the next generation against prevalent local bacteria and to a limited extent even also against newly introduced bacteria species. Long-term protection was thereby maintained only against prevailing Vibrio bacteria. Maternal and paternal transgenerational immune priming can complement each other, as they affect different pathways of the offspring immune system and come with distinct degree of specificity. The differential regulation of DNA-methylation genes upon parental bacteria exposure in premature pipefish offspring indicates that epigenetic regulation processes are involved in transferring immune-related information across generations. The identified trade-offs between immune priming and reproduction determine TGIP as a costly trait, which might constrain the evolution of long-lasting TGIP, if parental and offspring generations do not share the same parasite assembly. PMID- 27777745 TI - Heterotrophy mitigates the response of the temperate coral Oculina arbuscula to temperature stress. AB - Anthropogenic increases in atmospheric carbon dioxide concentration have caused global average sea surface temperature (SST) to increase by approximately 0.11 degrees C per decade between 1971 and 2010 - a trend that is projected to continue through the 21st century. A multitude of research studies have demonstrated that increased SSTs compromise the coral holobiont (cnidarian host and its symbiotic algae) by reducing both host calcification and symbiont density, among other variables. However, we still do not fully understand the role of heterotrophy in the response of the coral holobiont to elevated temperature, particularly for temperate corals. Here, we conducted a pair of independent experiments to investigate the influence of heterotrophy on the response of the temperate scleractinian coral Oculina arbuscula to thermal stress. Colonies of O. arbuscula from Radio Island, North Carolina, were exposed to four feeding treatments (zero, low, moderate, and high concentrations of newly hatched Artemia sp. nauplii) across two independent temperature experiments (average annual SST (20 degrees C) and average summer temperature (28 degrees C) for the interval 2005-2012) to quantify the effects of heterotrophy on coral skeletal growth and symbiont density. Results suggest that heterotrophy mitigated both reduced skeletal growth and decreased symbiont density observed for unfed corals reared at 28 degrees C. This study highlights the importance of heterotrophy in maintaining coral holobiont fitness under thermal stress and has important implications for the interpretation of coral response to climate change. PMID- 27777746 TI - Dermatosparaxis in two Limousin calves. AB - BACKGROUND: An unusual presentation of skin disease was identified in two related neonatal Pedigree Limousin calves presented to University Veterinary Hospital, University College Dublin, following detailed post mortem examination a diagnosis of dermatosparaxis was made. Dermatosparaxis in animals or Ehlers Danlos Syndrome, which is the analogous condition seen in humans, is a connective tissue disorder characterised by extreme skin fragility. To the authors' knowledge this is the first report of such a diagnosis in the Limousin breed and the features of this lethal phenotype were severe in comparison to previous reports of the condition. CASE PRESENTATION: Two calves, which were full siblings, a pedigree Limousin bull (Calf A) and pedigree Limousin heifer (Calf B) were examined clinically after presenting collapsed since birth, both had grossly abnormal skin with multiple skin fissures visible and both calves were subsequently euthanised. Both calves underwent gross post mortem examination, after which histological samples were reviewed and electron microscopical examination of selected skin samples was carried out. Histological features of dysplastic dermal collagen were identified. The diagnosis of dermatosparaxis in the Limousin breed was confirmed. Genetic testing was conducted to determine if the current cases had the same mutation as has previously been described in Belgian Blue cattle. Some common parentage was traced but genetic testing did not show a similar mutation to that previously described in cattle. The specific genetic cause in this case is unknown. CONCLUSIONS: This is the first report of dermatosparaxis in the Limousin and the presentation of the dermatosparaxis phenotype has some noteworthy features thus further genetic testing is required to pinpoint the causative mutation or other genetic defect. Given the popularity of the breed and the lethal nature of the phenotype in this case it is important to raise awareness of the condition. PMID- 27746907 TI - Whose sample is it anyway? Widespread misannotation of samples in transcriptomics studies. AB - Concern about the reproducibility and reliability of biomedical research has been rising. An understudied issue is the prevalence of sample mislabeling, one impact of which would be invalid comparisons. We studied this issue in a corpus of human transcriptomics studies by comparing the provided annotations of sex to the expression levels of sex-specific genes. We identified apparent mislabeled samples in 46% of the datasets studied, yielding a 99% confidence lower-bound estimate for all studies of 33%. In a separate analysis of a set of datasets concerning a single cohort of subjects, 2/4 had mislabeled samples, indicating laboratory mix-ups rather than data recording errors. While the number of mixed up samples per study was generally small, because our method can only identify a subset of potential mix-ups, our estimate is conservative for the breadth of the problem. Our findings emphasize the need for more stringent sample tracking, and that re-users of published data must be alert to the possibility of annotation and labelling errors. PMID- 27777750 TI - In conversation with...Thomas Frederic Hornbein. AB - Whilst attending a conference in the not too distant past, I was fortunate enough to be seated at lunch next to a very eminent octogenarian academic. Conversation ensued, and I was instantly captivated by his stories. These were not narratives filled with scientific facts, but rather anecdotes of his life and the pathways he had taken to get where he was today. Fascinated by such accounts, I set about the task of interviewing persons of scientific acclaim, to learn more about their life stories and unwritten tales. 'In conversation with...' therefore offers readers a chance to share an abridged version of these conversations. (In view of the need to condense 4 h of conversation, the original interview text has been abridged, and then reviewed, revised, and approved by TFH.). PMID- 27746904 TI - Using diverse U.S. beef cattle genomes to identify missense mutations in EPAS1, a gene associated with pulmonary hypertension. AB - The availability of whole genome sequence (WGS) data has made it possible to discover protein variants in silico. However, existing bovine WGS databases do not show data in a form conducive to protein variant analysis, and tend to under represent the breadth of genetic diversity in global beef cattle. Thus, our first aim was to use 96 beef sires, sharing minimal pedigree relationships, to create a searchable and publicly viewable set of mapped genomes relevant for 19 popular breeds of U.S. cattle. Our second aim was to identify protein variants encoded by the bovine endothelial PAS domain-containing protein 1 gene ( EPAS1), a gene associated with pulmonary hypertension in Angus cattle. The identity and quality of genomic sequences were verified by comparing WGS genotypes to those derived from other methods. The average read depth, genotype scoring rate, and genotype accuracy exceeded 14, 99%, and 99%, respectively. The 96 genomes were used to discover four amino acid variants encoded by EPAS1 (E270Q, P362L, A671G, and L701F) and confirm two variants previously associated with disease (A606T and G610S). The six EPAS1 missense mutations were verified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays, and their frequencies were estimated in a separate collection of 1154 U.S. cattle representing 46 breeds. A rooted phylogenetic tree of eight polypeptide sequences provided a framework for evaluating the likely order of mutations and potential impact of EPAS1 alleles on the adaptive response to chronic hypoxia in U.S. cattle. This public, whole genome resource facilitates in silico identification of protein variants in diverse types of U.S. beef cattle, and provides a means of translating WGS data into a practical biological and evolutionary context for generating and testing hypotheses. PMID- 27703669 TI - Factors affecting stone free rate of primary percutaneous nephrolithotomy on staghorn calculi: a single center experience of 15 years. AB - Objectives: Percutaneous nephrolithotomy on staghorn calculi is challenging for urologists because it is difficult to remove all of the stones. The purpose of this study was to evaluate the associated factors of stone-free rate after primary percutaneous nephrolithotomy on staghorn calculi in a large series of patients at a single, tertiary referral, endourologic stone center. Methods: We collected data from medical record between January 2000 and December 2015. A total of 345 primary percutaneous nephrolithotomy procedures were performed for patients with staghorn calculi. This study included both and made no distinction between partial and complete staghorn calculi. Stone-free is defined as the absence of residual stones after undergoing percutaneous nephrolithotomy for the first time. Significant factors from univariate analysis that correlated with stone-free rate after primary percutaneous nephrolithotomy of staghorn stone were further analyzed using multivariate regression analysis. Results: The mean patient age was 52.23+/-10.38 years. The stone-free rate of percutaneous nephrolithotomy monotherapy was 62.6%. The mean operating time was 79.55+/-34.46 minutes. The mean length of stay in hospital was 4.29+/-3.00 days. Using the chi square test, history of ipsilateral open renal stone surgery ( p = 0.01), stone burden ( p = < 0.001), and type of anesthesia ( p = 0.04) had a significant impact on the stone-free. From multivariate analysis, the history of ipsilateral open renal stone surgery [OR 0.48; 95% CI 0.28-0.81; p 0.01] and the stone burden [OR 0.28; 95% CI 0.18-0.45; p 0.00] were significant independent risk factors for stone-free. PMID- 27777751 TI - Evidence-Based Perioperative Medicine comes of age: the Perioperative Quality Initiative (POQI): The 1st Consensus Conference of the Perioperative Quality Initiative (POQI). AB - The 1st POQI Consensus Conference occurred in Durham, NC, on March 4-5, 2016, and was supported by the American Society of Enhanced Recovery (ASER) and Evidence Based Perioperative Medicine (EBPOM). The conference focused on enhanced recovery for colorectal surgery and discussed four topics-perioperative analgesia, perioperative fluid management, preventing nosocomial infection, and measurement and quality in enhanced recovery pathways. PMID- 27777752 TI - A case management report: a collaborative perioperative surgical home paradigm and the reduction of total joint arthroplasty readmissions. AB - BACKGROUND: Efforts to mitigate costs while improving surgical care quality have received much scrutiny. This includes the challenging issue of readmission subsequent to hospital discharge. Initiatives attempting to preclude readmission after surgery require planned and unified efforts extending throughout the perioperative continuum. Patient optimization prior to discharge, enhanced disease monitoring, and seamless coordination of care between hospitals and community providers is integral to this process. The perioperative surgical home (PSH) has been proposed as a model to improve the delivery of perioperative healthcare via patient-centered risk stratification strategies that emphasize value and evidence-based processes. RESULTS: This case report seeks to specifically describe implementation of readmission reduction strategies via a PSH paradigm during total joint arthroplasty (TJA) procedures at the University of California Irvine (UCI) Health. An orthopedic surgeon open to collaborate within a PSH paradigm for TJA procedures was recruited to UCI Health in October of 2012. Institution specific data was then prospectively collected for 2 years post implementation of the novel program. A total of 328 unilateral, elective primary TJA (120 hip, 208 knee) procedures were collectively performed. Demographic analysis reveals the following: mean age of 64 +/- 12; BMI of 28.5 +/ 6.2; ASA Score distribution of 0.3 % class 1, 23 % class 2, 72 % class 3, and 4.3 % class 4; and 62.5 % female patients. In all, a 30-day unplanned readmission rate of 2.1 % (95 % CI 0.4-3.8) was observed during the study period. As a limitation of this case report, this reported rate does not reflect readmissions that may have occurred at facilities outside UCI Health. CONCLUSIONS: As healthcare evolves to emphasize value over volume, it is integral to invest efforts in longitudinal patient outcomes including patient disposition subsequent to hospital discharge. As outlined by this case management report, the PSH provides an institution-led means to implement a series of care initiatives that optimize the important metric of readmission following TJA, potentially adding further value to patients, surgical colleagues, and health systems. PMID- 27777753 TI - Coagulative safety of epidural catheters after major upper gastrointestinal surgery: advanced and routine coagulation analysis in 38 patients. AB - BACKGROUND: The risk of spinal haematoma in patients receiving epidural catheters is estimated using routine coagulation tests, but guidelines are inconsistent in their recommendations on what to do when results indicate slight hypocoagulation. Postoperative patients are prone to thrombosis, and thromboelastometry has previously shown hypercoagulation in this setting. We aimed to better understand perioperative haemostasis by comparing results from routine and advanced tests, hypothesizing that patients undergoing major upper gastrointestinal surgery would be deficient in vitamin K-dependent coagulation factors because of malnutrition, or hypocoagulative because of accumulation of low molecular weight heparin (LMWH). METHODS: Thirty-eight patients receiving epidural analgesia for major upper gastrointestinal surgery were included. We took blood at the time of preoperative epidural catheterization and at catheter withdrawal. Prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) and platelet count (Plc) were analysed, and also albumin, proteins induced by vitamin K absence (PIVKA-II), rotational thromboelastometry (ROTEM(r)), multiple electrode aggregometry (Multiplate(r)) and activities of factors II, VII, IX, X, XI, XII and XIII. RESULTS: Postoperative coagulation was characterized by thrombocytosis and hyperfibrinogenaemia. Mean PT-INR increased significantly from 1.0 +/- 0.1 to 1.2 +/- 0.2 and mean aPTT increased significantly from 27 +/- 3 to 30 +/- 4 s. Activity of vitamin K-dependent factors did not decrease significantly: FIX and FX activity increased. FXII and FXIII decreased significantly. Mean Plc increased from 213 +/- 153 * 106/L while all mean ROTEM-MCFs (maximal clot firmnesses) especially FIBTEM-MCF increased significantly to above the reference interval. All mean ROTEM(r) clotting times were within their reference intervals both before and after surgery. ROTEM(r) (HEPTEM minus INTEM) results were spread around 0. There were significant correlations between routine tests and the expected coagulation factors, but not any of the viscoelastic parameters or PIVKA-II. Multiplate(r) area under curve and EXTEM-MCF correlated significantly to Plc as did EXTEM-MCF to fibrinogen, FIX, FX and FXIII; and FIBTEM-MCF to Plc, FII, FXI and FXIII. CONCLUSIONS: The increase in PT-INR may be caused by decreased postoperative FVII while the elevated aPTT may be caused by low FXII. The mild postoperative hypocoagulation indicated by routine tests is not consistent with thromboelastometry. The relevance of ROTEM(r) and Multiplate(r) in the context of moderately increased routine tests remains unclear. Trial registration number is not applicable since this is not a clinical trial. PMID- 27777754 TI - Associations between ASA Physical Status and postoperative mortality at 48 h: a contemporary dataset analysis compared to a historical cohort. AB - BACKGROUND: In this study, we examined the association between American Society of Anesthesiologists Physical Status (ASA PS) designation and 48-h mortality for both elective and emergent procedures in a large contemporary dataset (patient encounters between 2009 and 2014) and compared this association with data from a landmark study published by Vacanti et al. in 1970. METHODS: Patient history, hospital characteristics, anesthetic approach, surgical procedure, efficiency and quality indicators, and patient outcomes were prospectively collected for 732,704 consecutive patient encounters between January 1, 2009, and December 31, 2014, at 233 anesthetizing locations across 19 facilities in two US states and stored in the QuantumTM Clinical Navigation System (QCNS) database. The outcome (death within 48 h of procedure) was tabulated against ASA PS designations separately for patients with and without "E" status labels. To maintain consistency with the historical cohort from the landmark study performed by Vacanti et al. on adult men at US naval hospitals in 1970, we then created a comparison cohort in the contemporary dataset that consisted of 242,103 adult male patients (with/without E designations) undergoing elective and emergent procedures. Differences in the relationship between ASA PS and 48-h mortality in the historical and contemporary cohorts were assessed for patients undergoing elective and emergent procedures. RESULTS: As reported nearly five decades ago, we found a significant trend toward increased mortality with increasing ASA PS for patients undergoing both elective and emergent procedures in a large contemporary cohort (p < 0.0001). Additionally, the overall mortality rate at 48 h was significantly higher among patients undergoing emergent compared to elective procedures in the large contemporary cohort (1.27 versus 0.03 %, p < 0.0001). In the comparative analysis with the historical cohort that focused on adult males, we found the overall 48-h mortality rate was significantly lower among patients undergoing elective procedures in the contemporary cohort (0.05 % now versus 0.24 % in 1970, p < 0.0001) but not significantly lower among those undergoing emergent procedures (1.88 % now versus 1.22 % in 1970, p < 0.0001). CONCLUSIONS: The association between increasing ASA PS designation (1-5) and mortality within 48 h of surgery is significant for patients undergoing both elective and emergent procedures in a contemporary dataset consisting of over 700,000 patient encounters. Emergency surgery was associated with a higher risk of patient death within 48 h of surgery in this contemporary dataset. These data trends are similar to those observed nearly five decades ago in a landmark study evaluating the association between ASA PS and 48-h surgical mortality on adult men at US naval hospitals. When a comparison cohort was created from the contemporary dataset and compared to this landmark historical cohort, the absolute 48-h mortality rate was significantly lower in the contemporary cohort for elective procedures but not significantly lower for emergency procedures. The underlying implications of these findings remain to be determined. PMID- 27777755 TI - Serious electronic games as behavioural change interventions in healthcare associated infections and infection prevention and control: a scoping review of the literature and future directions. AB - BACKGROUND: The uptake of improvement initiatives in infection prevention and control (IPC) has often proven challenging. Innovative interventions such as 'serious games' have been proposed in other areas to educate and help clinicians adopt optimal behaviours. There is limited evidence about the application and evaluation of serious games in IPC. The purposes of the study were: a) to synthesise research evidence on the use of serious games in IPC to support healthcare workers' behaviour change and best practice learning; and b) to identify gaps across the formulation and evaluation of serious games in IPC. METHODS: A scoping study was conducted using the methodological framework developed by Arksey and O'Malley. We interrogated electronic databases (Ovid MEDLINE, Embase Classic + Embase, PsycINFO, Scopus, Cochrane, Google Scholar) in December 2015. Evidence from these studies was assessed against an analytic framework of intervention formulation and evaluation. RESULTS: Nine hundred sixty five unique papers were initially identified, 23 included for full-text review, and four finally selected. Studies focused on intervention inception and development rather than implementation. Expert involvement in game design was reported in 2/4 studies. Potential game users were not included in needs assessment and game development. Outcome variables such as fidelity or sustainability were scarcely reported. CONCLUSIONS: The growing interest in serious games for health has not been coupled with adequate evaluation of processes, outcomes and contexts involved. Explanations about the mechanisms by which game components may facilitate behaviour change are lacking, further hindering adoption. PMID- 27777756 TI - First hospital outbreak of the globally emerging Candida auris in a European hospital. AB - BACKGROUND: Candida auris is a globally emerging multidrug resistant fungal pathogen causing nosocomial transmission. We report an ongoing outbreak of C. auris in a London cardio-thoracic center between April 2015 and July 2016. This is the first report of C. auris in Europe and the largest outbreak so far. We describe the identification, investigation and implementation of control measures. METHODS: Data on C. auris case demographics, environmental screening, implementation of infection prevention/control measures, and antifungal susceptibility of patient isolates were prospectively recorded then analysed retrospectively. Speciation of C. auris was performed by MALDI-TOF and typing of outbreak isolates performed by amplified fragment length polymorphism (AFLP). RESULTS: This report describes an ongoing outbreak of 50 C. auris cases over the first 16 month (April 2015 to July 2016) within a single Hospital Trust in London. A total of 44 % (n = 22/50) patients developed possible or proven C. auris infection with a candidaemia rate of 18 % (n = 9/50). Environmental sampling showed persistent presence of the yeast around bed space areas. Implementation of strict infection and prevention control measures included: isolation of cases and their contacts, wearing of personal protective clothing by health care workers, screening of patients on affected wards, skin decontamination with chlorhexidine, environmental cleaning with chorine based reagents and hydrogen peroxide vapour. Genotyping with AFLP demonstrated that C. auris isolates from the same geographic region clustered. CONCLUSION: This ongoing outbreak with genotypically closely related C. auris highlights the importance of appropriate species identification and rapid detection of cases in order to contain hospital acquired transmission. PMID- 27777757 TI - A quasi-experimental study to determine the effects of a multifaceted educational intervention on hand hygiene compliance in a radiography unit. AB - BACKGROUND: Whilst numerous studies have investigated nurses' compliance with hand hygiene and use of alcohol-based hand rub (ABHR), limited attention has been paid to these issues in allied health staff. Reports have linked infections to breaches in infection control in the radiography unit (RU). With advances in medical imaging, a higher proportion of patients come into contact with RU staff increasing the need for good hand hygiene compliance. This study aimed to evaluate effectiveness on compliance of an intervention to improve awareness of hand hygiene in the RU of a district hospital. METHODS: A quasi-experimental study design including questionnaires assessing knowledge and attitudes of hand hygiene and direct observation of participants was used to evaluate an educational programme on hand hygiene of the RU of a large district hospital. All healthcare workers (HCW), comprising 76 radiographers, 17 nurses, and nine healthcare assistants (HCA), agreed to participate in the study. Of these, 85 completed the initial and 76 the post-test anonymous questionnaire. The hand hygiene compliance of all 102 HCW was observed over a 3-week period prior to and after the intervention. The 2-month intervention consisted of talks on hand hygiene and benefits of ABHR, provision of visual aids, wall-mounted ABHR dispensers, and personal bottles of ABHR. RESULTS: Before the intervention, overall hand hygiene compliance was low (28.9 %). Post-intervention, compliance with hand hygiene increased to 51.4 %. This improvement was significant for radiographers and HCA. Additionally, knowledge and attitudes improved in particular, understanding that ABHR can largely replace handwashing and there is a need to perform hand hygiene after environmental contact. The increased use of ABHR allowed HCW to feel they had enough time to perform hand hygiene. CONCLUSIONS: The educational intervention led to increased awareness of hand hygiene opportunities and better acceptance of ABHR use. The reduced time needed to perform hand rubbing and improved access to dispensers resulted in fewer missed opportunities. Although radiographers and other allied HCW make frequent contact with patients, these may be mistakenly construed as irrelevant with respect to healthcare associated infections. Stronger emphasis on hand hygiene compliance of these staff may help reduce infection risk. PMID- 27777758 TI - E. coli bacteremia in comparison to K. pneumoniae bacteremia: influence of pathogen species and ESBL production on 7-day mortality. AB - In a previous study, we demonstrated prolonged length of hospital stay in cases of extended-spectrum beta-lactamase (ESBL)-positive K. pneumoniae bacteremia compared to bacteremia cases due to E. coli (ESBL-positive and -negative) and ESBL-negative K. pneumoniae. The overall mortality was significantly higher in bacteremia cases resulting from ESBL-positive pathogens but also in K. pneumoniae cases disregarding ESBL-production. In order to examine whether pathogen species rather than multidrug resistance might affect mortality risk, we reanalyzed our dataset that includes 1.851 cases of bacteremia. PMID- 27777760 TI - A mixed methods study to understand patient expectations for antibiotics for an upper respiratory tract infection. AB - BACKGROUND: Antimicrobial resistance is a public health challenge supplemented by inappropriate prescribing, especially for an upper respiratory tract infection in primary care. Patient/carer expectations have been identified as one of the main drivers for inappropriate antibiotics prescribing by primary care physicians. The aim of this study was to understand who is more likely to expect an antibiotic for an upper respiratory tract infection from their doctor and the reasons underlying it. METHODS: This study used a sequential mixed methods approach: a nationally representative cross sectional survey (n = 1509) and four focus groups. The outcome of interest was expectation and demand for an antibiotic from a doctor when presenting with a cold or flu. RESULTS: The study found 19.5 % of survey respondents reported that they would expect the doctor to prescribe antibiotics for a cold or flu. People younger than 65 years of age, those who never attended university and those speaking a language other than English at home were more likely to expect or demand antibiotics for a cold or flu. People who knew that 'antibiotics don't kill viruses' and agreed that 'taking an antibiotic when one is not needed means they won't work in the future' were less likely to expect or demand antibiotics. The main reasons for expecting antibiotics were believing that antibiotics are an effective treatment for a cold or flu and that they shortened the duration and potential deterioration of their illness. The secondary reason centered around the value or return on investment for visiting a doctor when feeling unwell. CONCLUSION: Our study found that patients do not appear to feel they have a sufficiently strong incentive to consider the impact of their immediate use of antibiotics on antimicrobial resistance. The issue of antibiotic resistance needs to be explained and reframed as a more immediate health issue with dire consequences to ensure the success of future health campaigns. PMID- 27777759 TI - Regional variations in fluoroquinolone non-susceptibility among Escherichia coli bloodstream infections within the Veterans Healthcare Administration. AB - OBJECTIVES: We sought to define regional variations in fluoroquinolone non susceptibility (FQ-NS) among bloodstream isolates of Escherichia coli across the Veterans Health Administration (VHA) in the United States. METHODS: We analyzed a retrospective cohort of patients managed at 136 VHA hospitals who had a blood culture positive for E.coli between 2003 and 2013. Hospitals were classified based on US Census Divisions, and regional variations in FQ-NS were analyzed. RESULTS: Twenty-four thousand five hundred twenty-three unique E.coli bloodstream infections (BSIs) were identified between 2003 and 2013. 53.9 % of these were community-acquired, 30.7 % were healthcare-associated, and 15.4 % were hospital onset BSIs. The proportion of E.coli BSIs with FQ-NS significantly varied across US Census Divisions (p < 0.001). During 2003-2013, the proportion of E.coli BSIs with FQ-NS was highest in the West South-Central Division (32.7 %) and lowest in the Mountain Division (20.0 %). Multivariable analysis showed that there were universal secular trends towards higher FQ-NS rates (p < 0.001) with significant variability of slopes across US Census Divisions (p < 0.001). CONCLUSION: There has been a universal increase in FQ-NS among E.coli BSIs within VHA, but the rate of increase has significantly varied across Census Divisions. The reasons for this variability are unclear. These findings reinforce the importance of using local data to develop and update local antibiograms and antibiotic-prescribing guidelines. PMID- 27777761 TI - A pilot study to assess use of fluorescent lotion in patient care simulations to illustrate pathogen dissemination and train personnel in correct use of personal protective equipment. AB - BACKGROUND: Simulations using fluorescent tracers can be useful in understanding the spread of pathogens and in devising effective infection control strategies. METHODS: During simulated patient care interactions in which providers wore gloves and gowns, we evaluated environmental and personnel dissemination of fluorescent lotion and bacteriophage MS2 from a contaminated mannequin. The frequency of skin and clothing contamination after removal of personal protective equipment (PPE) was compared before versus after an intervention that included education and practice in PPE donning and doffing. RESULTS: Ten healthcare personnel participated in 30 pre-intervention and 30 post-intervention patient care simulations. Fluorescent lotion and bacteriophage MS2 were rapidly disseminated to touched surfaces throughout the room; there was no difference in the frequency of contamination before versus after the PPE training intervention. After the intervention, there was a decrease in skin and/or clothing contamination with fluorescent lotion (9/30, 30 % versus 1/30, 3 %; P = 0.01) and bacteriophage MS2 (8/30, 27 % versus 2/30, 7 %; P = 0.08) and there was a significant reduction in the concentration of bacteriophage MS2 recovered from hands (0.31 versus 0.07 log10plaque-forming units; P < 0.01). CONCLUSIONS: Our findings suggest that simulations with fluorescent lotion can be a useful teaching tool to illustrate the spread of pathogens and provide further evidence that simple PPE training interventions can be effective in reducing contamination of personnel. PMID- 27777762 TI - Evaluation of a laying-hen tracking algorithm based on a hybrid support vector machine. AB - BACKGROUND: Behavior is an important indicator reflecting the welfare of animals. Manual analysis of video is the most commonly used method to study animal behavior. However, this approach is tedious and depends on a subjective judgment of the analysts. There is an urgent need for automatic identification of individual animals and automatic tracking is a fundamental part of the solution to this problem. RESULTS: In this study, an algorithm based on a Hybrid Support Vector Machine (HSVM) was developed for the automated tracking of individual laying hens in a layer group. More than 500 h of video was conducted with laying hens raised under a floor system by using an experimental platform. The experimental results demonstrated that the HSVM tracker outperformed the Frag (fragment-based tracking method), the TLD (Tracking-Learning-Detection), the PLS (object tracking via partial least squares analysis), the MeanShift Algorithm, and the Particle Filter Algorithm based on their overlap rate and the average overlap rate. CONCLUSIONS: The experimental results indicate that the HSVM tracker achieved better robustness and state-of-the-art performance in its ability to track individual laying hens than the other algorithms tested. It has potential for use in monitoring animal behavior under practical rearing conditions. PMID- 27777764 TI - Physical and chemical changes of rapeseed meal proteins during toasting and their effects on in vitro digestibility. AB - BACKGROUND: Toasting during the production of rapeseed meal (RSM) decreases ileal crude protein (CP) and amino acid (AA) digestibility. The mechanisms that determine the decrease in digestibility have not been fully elucidated. A high protein quality, low-denatured, RSM was produced and toasted up to 120 min, with samples taken every 20 min. The aim of this study was to characterize secondary structure and chemical changes of proteins and glucosinolates occurring during toasting of RSM and the effects on its in vitro CP digestibility. RESULTS: The decrease in protein solubility and the increase of intermolecular beta-sheets with increasing toasting time were indications of protein aggregation. The contents of NDF and ADIN increased with increasing toasting time. Contents of arginine, lysine and O-methylisourea reactive lysine (OMIU-RL) linearly decreased with increasing toasting time, with a larger decrease of OMIU-RL than lysine. First-order reactions calculated from the measured parameters show that glucosinolates were degraded faster than lysine, OMIU-RL and arginine and that physical changes to proteins seem to occur before chemical changes during toasting. Despite the drastic physical and chemical changes noticed on the proteins, the coefficient of in vitro CP digestibility ranged from 0.776 to 0.750 and there were no effects on the extent of protein hydrolysis after 120 min. In contrast, the rate of protein hydrolysis linearly decreased with increasing toasting time, which was largely correlated to the decrease in protein solubility, lysine and OMIU-RL observed. Rate of protein hydrolysis was more than 2-fold higher for the untoasted RSM compared to the 120 min toasted material. CONCLUSIONS: Increasing the toasting time for the production of RSM causes physical and chemical changes to the proteins that decrease the rate of protein hydrolysis. The observed decrease in the rate of protein hydrolysis could impact protein digestion and utilization. PMID- 27777763 TI - Dietary stimulation of the endogenous somatotropic axis in weaner and grower finisher pigs using medium chain triglycerides and cysteamine hydrochloride. AB - BACKGROUND: Three experiments were conducted to examine the overall hypothesis that addition of medium chain triglycerides (MCT) and cysteamine hydrochloride (CSH) into the diets of young and growing pigs would stimulate the endogenous somatotropic axis to improve growth and performance. RESULTS: In Experiment 1, weaner pigs were given either a 5 d dietary supplement of 5 % MCT (n = 8) or a control diet (n = 8). MCT increased the plasma concentration of growth hormone (GH; P < 0.05) and the GH secretagogue, ghrelin (P < 0.05). Additionally, the MCT treatment reduced scouring (P < 0.05), maintained villous height in the small intestine (P < 0.05) and stabilised daily weight gain (P < 0.05), compared to the controls. Experiment 2 compared the effects of 4 levels (0, 1, 3 and 6 % v/v) of MCT supplementation in grower-finisher male pigs, of approximately 35 kg live weight (n = 15 per treatment). Blood samples taken after 7 wk of treatment showed that the MCT supplementation increased circulating ghrelin (P < 0.001), GH (P < 0.01) and insulin (P < 0.05) concentrations in a dose-dependent manner. Daily weight gain, feed intake and feed conversion ratio were not affected by the MCT diets. In Experiment 3, 64 female pigs of approximately 60 kg live weight were allocated to one of three dietary treatments: control (n = 20); 6 % MCT (n = 21); and 70 mg/kg CSH (n = 21). After 3 wk of supplementation, the MCT treated pigs had a higher plasma concentration of ghrelin compared to the control and CSH pigs (P < 0.05). Plasma concentrations of GH and weight were not affected by any of the dietary treatments. CONCLUSIONS: Evidence is provided in Experiment 1 to support the use of dietary MCT supplements, perhaps acting via stimulation of somatotropic endocrine pathways, to minimise weaning-associated disorders such as slowing of growth and diarrhoea. In Experiments 2 and 3, although there was no effect on weight gain or feed conversion ratio in either experiment, MCT and CSH increased endocrine components of the somatotropic axis. PMID- 27777765 TI - Epithelial-mesenchymal transition induction is associated with augmented glucose uptake and lactate production in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy with dismal prognosis. Metastatic spread and therapeutic resistance, the main causes of PDAC-related mortalities, are both partially underlined by the epithelial mesenchymal transition (EMT) of PDAC cells. While the role of Warburg metabolism has been recognized in supporting rapid cellular growth and proliferation in many cancer types, less is known about the metabolic changes occurring during EMT, particularly in the context of PDAC. RESULTS: In the current study, experimental models of EMT were established in the Panc-1 cell line of human PDAC via exposure to two physiologically relevant EMT inducers (tumor necrosis factor-alpha and transforming growth factor-beta) and the metabolic consequences examined. The two EMT models displayed similar alterations in the general metabolic profile including augmented glucose uptake and lactate secretion as well as the lack of change in oxidative metabolism. Examination of molecular markers revealed differences in the pathways underlying the metabolic rewiring. 13C-Glucose tracer data confirmed that a major portion of accumulated lactate was derived from glucose, but subsequent flux analysis suggested involvement of non-canonical pathways towards lactate production. CONCLUSIONS: Our results characterize the metabolic reprogramming occurring during PDAC cell EMT and highlight the common changes of increased glucose uptake and lactate secretion under different EMT conditions. Such insight is urgently required for designing metabolic strategies to selectively target cells undergoing EMT in PDAC. PMID- 27777767 TI - Erratum to: Open-source, small-animal magnetic resonance-guided focused ultrasound system. AB - [This corrects the article DOI: 10.1186/s40349-016-0066-7.]. PMID- 27777766 TI - Physical activity and sedentary behavior in Belgium (BNFCS2014): design, methods and expected outcomes. AB - BACKGROUND: There is strong evidence to indicate that regular moderate intensity physical activity is associated with health benefits. Furthermore, sedentary behavior has been related with an increased risk for all-cause mortality. The accurate measurement of physical activity and sedentary behavior is therefore vital to evaluate their health impact and provide evidence for the development of public health recommendations. This paper describes the methodology used for assessing physical activity and sedentary behavior in the Belgian population in the context of the Belgian National Food Consumption Survey 2014 (BNFCS2014). RESULTS: Data about physical activity and sedentary behavior were collected as part of the cross-sectional BNFCS2014 between February 2014 and May 2015. A nationally-representative sample of children (3-9 years) and adolescents (10-17 years) were asked to wear an accelerometer (Actigraph(r) GT3X) during their waking hours for 7 consecutive days. Data were recorded in 15-second epochs and respondents with at least 2 valid week days (i.e., 10 h of wear-time) and 1 valid week-end day (i.e., 8 h of wear-time) were retained for the analyses. The Evenson cut points were used to assess the time spent in each physical activity intensity level: sedentary, low, moderate and vigorous. Complementary, diaries were provided to register the activities performed when the accelerometer was removed; these activities were added to the measures provided by the accelerometers. In addition, age-specific self-reported questionnaires (ToyBox and FPAQ) were completed to provide contextual information about the type of activities performed. Due to financial constraints, physical activity in adults (18-64 years) was assessed and described through the self-reported International Physical Activity Questionnaire (IPAQ long version) only. CONCLUSION: Data were collected in the context of the BNFCS2014 to provide a comprehensive picture of the physical activity and sedentary behavior in the Belgian population, with a special focus on children (3-9 years) and adolescents (10-17 years). Levels of physical activity and sedentary behavior can be compared to international guidelines and analyzed according to several background variables, such as age, gender, Body Mass Index, education level and region. Such results are aimed to underpin future policies in the field of physical activity. PMID- 27777768 TI - JAK2 V617F mutation, multiple hematologic and non-hematologic processes: an association? AB - BACKGROUND: Population studies showed that patients with JAK2 V617F mutation had increased mortality, and increased risk of any cancer, hematologic cancer, and myeloproliferative disease. CASE PRESENTATION: A 68-year-old Asian male with JAK2 V617F mutation developed four different hematologic and non-hematologic neoplastic processes. In 2009, he was diagnosed with stage IA lung adenocarcinoma and also noted to have worsening leukocytosis and thrombocytosis with peak platelet count of 1,054,000/mL). Bone marrow biopsy was consistent with myeloproliferative neoplasm. His monocyte percentage increased in 2011 and met criteria for chronic myelomonocytic leukemia. In 2013, he was admitted for proximal small bowel obstruction, with biopsy confirming stage IE diffuse large B cell lymphoma. In 2014, a bone marrow biopsy performed for worsening leukocytosis was consistent with acute myeloid leukemia with monocytic differentiation. CONCLUSION: This is a rare case depicting the association of JAK2 V617F mutation with myeloproliferative, lymphoproliferative and solid neoplasms. PMID- 27777769 TI - Clinical significance of tumor-infiltrating lymphocytes in breast cancer. AB - Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer. Triple negative breast cancers (TN) are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL. The majority of HER2+ breast cancers have similar level of immune infiltrate as TN breast cancer yet the presence of TILs has not shown the same survival benefit. For HER2+ breast cancers, type 1 T-cells, either increased TBET+ tumor infiltration or increased type 1 HER2-specific CD4+ T-cells in the peripheral blood, are associated with better outcomes. Hormone receptor positive HER2 negative tumors tend to have the least immune infiltrate yet are the only breast cancer subtype to show worse prognosis with increased FOXP3 regulatory T-cell infiltrate. Notably, all breast cancer subtypes have tumors with low, intermediate, or high TIL infiltrate. Tumors with high TILs may also have increased PD-L1 expression which might be the reason that TN breast cancer seems to demonstrate the most robust clinical response to immune checkpoint inhibitor therapy but further investigation is needed. Tumors with intermediate or low levels of pre-treatment immune infiltrate, on the other hand, may benefit from an intervention that may increase TIL, particularly type 1 T-cells. Examples of these interventions include specific types of cytotoxic chemotherapy, radiation, or vaccine therapy. Therefore, the systematic evaluation of TIL and specific populations of TIL may be able to both guide prognosis and the appropriate sequencing of therapies in breast cancer. PMID- 27777770 TI - Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. AB - BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced malignancies. Patients with baseline organ dysfunction are largely excluded from clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or effective in this setting. Further, these patients are often not candidates for other anti-cancer therapies, highlighting their need for active treatment options. METHODS: We performed a retrospective analysis of patients from multiple centers with advanced solid tumors and baseline organ dysfunction who received anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular ejection fraction <=45 %), renal (creatinine >=2 mg/dL or GFR <=30 ml/min) or hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin >=3x ULN). We assessed change in organ dysfunction, immune related adverse events (irAEs), response rate, progression free survival (PFS) and overall survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4). Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective response or stable disease) at data collection (48 %). Eleven patients had primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial responses (15 %), and one had a complete response (4 %). Overall, median PFS was 168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable irAEs and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring. PMID- 27777772 TI - Urothelial carcinoma of donor origin in a kidney transplant patient. AB - BACKGROUND: Malignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication. Herein, we review our patient history and discuss diagnostic strategies and the implications of immunosuppression for donor-derived malignancy. CASE PRESENTATION: This is a 69-year-old man with post renal-transplant urothelial carcinoma determined to be of donor origin. His course was complicated by BK virus at six years post-transplant; urothelial carcinoma was identified nine years post-transplant. Cystectomy was performed, but because of immunosuppression and underlying chronic kidney disease, the patient was considered ineligible for adjuvant chemotherapy. Two years after resection, screening MRI demonstrated retroperitoneal lymphadenopathy and a right upper pole mass in the transplanted kidney. Urine cytology confirmed the presence of malignant cells; FISH showed 2-8 copies of the X chromosome and no Y chromosome consistent with female origin of the malignant cells. CT-guided renal mass and paraaortic lymph node biopsies demonstrated that about 50 % of cells had an XY complement, while the remainder showed a XX genotype by chromosomal SNP microarray analysis. Immunosuppression was discontinued and the donor kidney removed. X/Y FISH of the urothelial carcinoma identified in the explanted kidney confirmed that the malignant cells were of female donor origin. Follow-up at 3, 6 and 12 months after discontinuation of immunosuppression and surgery demonstrated normalization of the lymphadenopathy and absence of new lesions. CONCLUSIONS: Immunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment in our case. PMID- 27777771 TI - Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors. AB - BACKGROUND: We evaluated whether tumor infiltrating lymphocytes (TIL) could be expanded from surgically resected tumors from pancreatic cancer patients. METHODS: Tumors were resected from pancreatic cancer patients. Tumors were minced into fragments and cultured in media containing high dose interleukin-2 (IL-2) for up to 6 weeks. T cell phenotype, activation markers, and reactivity were measured. RESULTS: TIL expansion was measured in 19 patient samples. The majority of these TIL were CD4+ T cells and were highly activated. Purified CD8+ T cells produced IFN-gamma in response to HLA-matched pancreatic tumor targets. PD-1 blockade and 4-1BB stimulation were demonstrated as effective strategies to improve effective TIL yield, including the production of tumor-reactive pancreatic TIL. CONCLUSIONS: TIL expanded from pancreatic tumors are functional and able to respond to pancreatic tumor associated antigens. PD-1 blockade, 41BB stimulation, and CD8+ T cell enrichment are effective strategies to improve TIL yield and tumor reactivity. These results support the development of adoptive cell therapy strategies using TIL for the treatment of pancreatic cancer. PMID- 27777773 TI - Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. AB - BACKGROUND: Nivolumab (OpdivoTM) is a novel IgG4 subclass programmed death-1 (PD 1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer. CASE PRESENTATION: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient's immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response. CONCLUSIONS: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis. PMID- 27777774 TI - 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers. AB - BACKGROUND: Resistance to chemotherapy is a major obstacle in the effective treatment of cancer patients. B7-homolog 1, also known as programmed death ligand 1 (PD-L1), is an immunoregulatory protein that is overexpressed in several human cancers. Interaction of B7-H1 with programmed death 1 (PD-1) prevents T-cell activation and proliferation, sequestering the T-cell receptor from the cell membrane, inducing T-cell apoptosis, thereby leading to cancer immunoresistance. B7-H1 upregulation contributes to chemoresistance in several types of cancer, but little is known with respect to changes associated with 5-fluorouracil (5-FU) or gastrointestinal cancers. METHODS: HCT 116 p53+/+, HCT 116 p53-/- colorectal cancer (CRC) and OE33 esophageal adenocarcinoma (EAC) cells were treated with increasing doses of 5-FU (0.5 uM, 5 uM, 50 uM, 500 uM) or interferon gamma (IFN gamma, 10 ng/mL) in culture for 24 h and B7-H1 expression was quantified using flow cytometry and western blot analysis. We also evaluated B7-H1 expression, by immunohistochemistry, in tissue collected prior to and following neoadjuvant therapy in 10 EAC patients. RESULTS: B7-H1 expression in human HCT 116 p53+/+ and HCT 116 p53-/- CRC cells lines, while low at baseline, can be induced by treatment with 5-FU. OE33 baseline B7-H1 expression exceeded CRC cell maximal expression and could be further increased in a dose dependent manner following 5 FU treatment in the absence of immune cells. We further demonstrate tumor B7-H1 expression in esophageal adenocarcinoma patient-derived pre-treatment biopsies. While B7-H1 expression was not enhanced in post-treatment esophagectomy specimens, this may be due to the limits of immunohistochemical quantification. CONCLUSIONS: B7-H1/PD-L1 expression can be increased following treatment with 5 FU in gastrointestinal cancer cell lines, suggesting alternative mechanisms to classic immune-mediated upregulation. This suggests that combining 5-FU treatment with PD-1/B7-H1 blockade may improve treatment in patients with gastrointestinal adenocarcinoma. PMID- 27777775 TI - Acute visual loss after ipilimumab treatment for metastatic melanoma. AB - BACKGROUND: Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs). CASE PRESENTATION: Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs. CONCLUSIONS: This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab. PMID- 27777776 TI - High-dose interleukin2 - a 10-year single-site experience in the treatment of metastatic renal cell carcinoma: careful selection of patients gives an excellent outcome. AB - BACKGROUND: VEGF-targeted therapy has become the mainstay of treatment for majority of mRCC patients. For most patients, benefit is short-lived and therefore treatment remains palliative in intent. HD IL2 is an effective immunotherapy treatment capable of durable remission in some patients but its unselected use has been difficult due to its modest response rate and considerable adverse effects. Using set pathology criteria as a selection tool in clinical practice, we have been able to show improved outcomes in our previous report. Here, we present an updated and extended report of this treatment and seek to explore any pathological, clinical and treatment variables likely to predict better outcomes. METHODS: This is an extension of a previously reported clinical audit, which includes mRCC cases treated with HD IL2 between 2003 and 2013. Since 2006, tumour specimens of potential candidates were routinely reviewed prospectively and stratified into Favourable or Other categories based on constitution of histological growth pattern, namely alveolar or solid versus papillary and/or sarcomatoid architecture; clear cell versus granular cell cytoplasmic morphology. HD IL2 was preferentially offered to patients with Favourable pathology. Outcome evaluation includes response rates, survival, and treatment tolerance. Multivariate analysis was performed to explore potential prognostic and predictive factors. RESULTS: Among prospectively selected patients with Favourable pathology (n = 106), overall response rate was 48.1 % (51/106) with CR rate of 21.6 % (23/106). Median OS was 58.1 months. Factors associated with significantly better response and/or survival includes favourable pathology pattern, higher cycle 1 tolerance and lower number of metastatic organ sites (<3). CAIX (Carbonic anhydrase 9) has prognostic value but is not predictive of response. Toxicities were those expected of IL2 but were manageable on general medical wards, with no treatment-related death. Importantly most complete responses were durable with 76 % (23/30) cases remained relapse-free (median 39 months follow up) and 2 of the seven who relapsed had had long-term disease free survival after resection of oligometastatic relapse. CONCLUSIONS: Our experience shows that HD IL2 remains an effective and safe treatment in well-selected cases of mRCC. The result in this single-institution patient series confirms similar outcomes to our previously reported retrospective series. Given the prospect of long-term remission, fit patients with Favourable histology and low disease burden should be considered for HD IL2 in an experienced centre. Better understanding has been gained from this in-depth analysis especially the examination of possible response predictors and strategies that can improve treatment outcome. PMID- 27777778 TI - To be or not to be [fertile], that is the question. AB - BACKGROUND: According to our literature analysis, there are no data focused on spermatozoa emotional representations in childless men and data on the emotional repercussions of a diagnosis of infertility on men are still scarce. Thus, in this work, we investigated what the presence or absence of spermatozoa in the semen symbolize for men. MATERIAL AND METHODS: To answer this question, 441 childless heterosexual men participated in an anonymous, prospective, Internet based survey. RESULTS: In response to the question "What would having a high or normal sperm count symbolize for you?" the most frequent answer was "ability to father a child". Men living with a partner were significantly more likely than single men to answer "ability to father a child" (p < 0.05) and less likely to answer "virility" and/or "ability to have an erection/ejaculation" (p = 0.001). In response to the question "If you found out that you had a low sperm count or no spermatozoa at all, how would you feel?", most of the men stated that they would be disappointed. Men living with a partner were more likely to state that they would feel ashamed (p < 0.05) or guilty with regard to their partner (p < 0.0001). CONCLUSIONS: These preliminary results should help us to improve (i) the way that male infertility is announced (it is easier to find the right words if one understands the possible importance of having a high sperm count) and (ii) the psychological, marital and sexual counselling provided to men with a diagnosis of infertility. PMID- 27777777 TI - Anti-PD-1 increases the clonality and activity of tumor infiltrating antigen specific T cells induced by a potent immune therapy consisting of vaccine and metronomic cyclophosphamide. AB - BACKGROUND: Future cancer immunotherapies will combine multiple treatments to generate functional immune responses to cancer antigens through synergistic, multi-modal mechanisms. In this study we explored the combination of three distinct immunotherapies: a class I restricted peptide-based cancer vaccine, metronomic cyclophosphamide (mCPA) and anti-PD-1 treatment in a murine tumor model expressing HPV16 E7 (C3). METHODS: Mice were implanted with C3 tumors subcutaneously. Tumor bearing mice were treated with mCPA (20 mg/kg/day PO) for seven continuous days on alternating weeks, vaccinated with HPV16 E749-57 peptide antigen formulated in the DepoVax (DPX) adjuvanting platform every second week, and administered anti-PD-1 (200 MUg/dose IP) after each vaccination. Efficacy was measured by following tumor growth and survival. Immunogenicity was measured by IFN-gamma ELISpot of spleen, vaccine draining lymph nodes and tumor draining lymph nodes. Tumor infiltration was measured by flow cytometry for CD8alpha+ peptide-specific T cells and RT-qPCR for cytotoxic proteins. The clonality of tumor infiltrating T cells was measured by TCRbeta sequencing using genomic DNA. RESULTS: Untreated C3 tumors had low expression of PD-L1 in vivo and anti-PD-1 therapy alone provided no protection from tumor growth. Treatment with DPX/mCPA could delay tumor growth, and tri-therapy with DPX/mCPA/anti-PD-1 provided long term control of tumors. We found that treatment with DPX/mCPA/anti-PD-1 enhanced systemic antigen-specific immune responses detected in the spleen as determined by IFN-gamma ELISpot compared to those in the DPX/mCPA group, but immune responses in tumor-draining lymph nodes were not increased. Although no increases in antigen-specific CD8alpha+ TILs could be detected, there was a trend for increased expression of cytotoxic genes within the tumor microenvironment as well as an increase in clonality in mice treated with DPX/mCPA/anti-PD-1 compared to those with anti-PD-1 alone or DPX/mCPA. Using a library of antigen-specific CD8alpha+ T cell clones, we found that antigen-specific clones were more frequently expanded in the DPX/mCPA/anti-PD-1 treated group. CONCLUSIONS: These results demonstrate how the efficacy of anti-PD-1 may be improved by combination with a potent and targeted T cell activating immune therapy. PMID- 27777779 TI - A systematic review on the relationship between antisocial, borderline and narcissistic personality disorder diagnostic traits and risk of violence to others in a clinical and forensic sample. AB - Risk assessments identify the presence of a Personality Disorder diagnosis as relevant to future violence. At present, risk assessments focus on the presence of the disorder rather than identifying key traits related to risk. Systematic searches of three databases were conducted from January 2000 until August 2014. Of 92,143, 15 studies met the inclusion criteria. A lack of empirical research was found focusing on individual traits; instead most considered PD diagnosis as a sole entity. A preliminary model has been developed detailing the link between potential interactions of diagnostic traits and risk of violence. Recommendations for future research are made. PMID- 27777781 TI - Impact of pharmacists as immunizers on influenza vaccination coverage in the community-setting in Nova Scotia, Canada: 2013-2015. AB - BACKGROUND: Annual immunization is the most effective way to prevent influenza and its associated complications. However, optimal immunization rates are not being met in Nova Scotia, Canada. Additional providers, such as pharmacists, may improve access and convenience to receive vaccines. Pharmacists began immunizing patients 5 years of age and older within the publicly funded universal influenza vaccination program during the 2013-2014 influenza season. The objective of this study was to evaluate influenza immunization coverage rates before and after pharmacists in Nova Scotia gained authority to immunize as part of the publicly funded universal influenza vaccination program. METHODS: Influenza immunization data was obtained from the Department of Health and Wellness from 2010 to 2015. Data included billing data from physicians and pharmacists, and local public health data. Vaccination coverage was calculated as proportion of vaccinations received in comparison to the total population. RESULTS: Prior to pharmacists immunizing, overall vaccination coverage for Nova Scotia residents 6 months of age and older was 35.8 % in 2012-2013, increasing to 41.8 % coverage in 2013-2014 the year pharmacists began immunizing. A decrease of 1.9 to 39.9 % was observed in 2014-2015. In patients 65 years of age and older living in the community, coverage has increased from 61.8 % in 2012-2013 to 71.6 % in 2013-2014, and again to 73.3 % in 2014-2015 with the addition of pharmacists immunizing. Prior to pharmacists immunizing the highest coverage noted for this portion of the population was 61.8 %. CONCLUSIONS: The addition of pharmacists as immunizers within a publicly funded universal influenza vaccination program was found to increase overall vaccination coverage in the first year and to maintain higher coverage rates in the second year than those observed before pharmacists began immunizing. Increases in coverage in both years were observed in the elderly. Future research will be required to determine the ongoing impact of the addition of pharmacists as immunizers and other strategies to improve vaccination coverage. PMID- 27777780 TI - Initial central venous pressure could be a prognostic marker for hemodynamic improvement of polymyxin B direct hemoperfusion: a retrospective cohort study. AB - BACKGROUND: Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX DHP) could improve the hemodynamic status of septic shock patients. As PMX-DHP is an invasive and costly procedure, it is desirable to estimate the therapeutic effect before performing the therapy. However, it is still unclear when this therapy should be started and what type of sepsis it should be employed for. In this study, we retrospectively examined the clinical effect of patients treated with PMX-DHP by using central venous pressure (CVP). METHODS: Seventy patients who received PMX-DHP for septic shock during the study period were recruited and divided into a low CVP group (n = 33, CVP < 12 mmHg) and a high CVP group (n = 37, CVP?12 mmHg). The primary endpoint was vasopressor dependency index at 24 hours after starting PMX-DHP, and the secondary endpoint was the 28-day survival rate. Additionally, we performed a multivariate linear regression analysis on the difference in the vasopressor dependency index. RESULTS: The vasopressor dependency index significantly improved at 24 h in the low CVP group (0.33 to 0.16 mmHg-1; p < 0.01) but not in the high CVP group (0.43 to 0.34 mmHg-1; p = 0.41), and there was a significant difference between the two groups in the index at 24 h (p = 0.02). The 28-day survival rate was higher in the low CVP group (79 vs. 43 %; p < 0.01). Multivariate linear regression analysis showed that CVP (p = 0.04) was independently associated with the difference in the vasopressor dependency index. CONCLUSIONS: Our study indicates that the clinical effect of PMX-DHP for septic shock patients with higher CVP (?12 mmHg) might be limited and that the initial CVP when performing PMX-DHP could function as an independent prognostic marker for the hemodynamic improvement. PMID- 27777782 TI - Self-resilience as a protective factor against development of post-traumatic stress disorder symptoms in police officers. AB - BACKGROUND: This study was conducted to check whether self-resilience, one of the characteristics known to affect the occurrence of post-traumatic stress disorder (PTSD) symptoms after experiencing traumatic events, could serve as a protective factor for police officers whose occupational factors are corrected. METHODS: We conducted a cross-sectional study in which 112 male police officers in Gangwon Province participated. They visited the Wonju Severance Christian Hospital Occupational Environment Center for medical check-ups from June to December 2015. Their general characteristics were identified using structured questionnaires, and they were asked to fill in the Korean Occupational Stress Scale-Short Form (KOSS-SF). Further, the Center for Epidemiologic Studies-Depression Scale (CES D), Connor-Davidson Resilience Scale-Korean (CD-RI-K), and Impact of Event Scale Revised-Korean version (IES-R-K) were used to evaluate their job stress, depression, self-resilience, and PTSD symptoms. Logistic regression analysis was conducted to correct their personal, occupational, and psychological factors to analyze the relationship between self-resilience and PTSD symptoms. RESULTS: Among 112 respondents who experienced a traumatic event, those with low self resilience had significantly higher rate of PTSD symptoms than those with high self-resilience even after correcting for the covariate of general, occupational, and psychological characteristics (odds ratio [OR] 3.51; 95 % CI: 1.06-19.23). CONCLUSIONS: Despite several limitations, these results suggest that a high degree of self-resilience may protect police officers from critical incident related PTSD symptoms. PMID- 27777783 TI - Relationship of workplace violence and perpetrators on sleep disturbance-data from the 4th Korean working conditions survey. AB - OBJECTIVE: The present study analyzed relationship of workplace violence and perpetrators of violence on sleep disturbance among wage workers in Korea. METHODS: The present study used data from the 4th Korean Working Conditions Survey (KWCS) of 2014 in selecting a total of 25,138wage workers as the study population, which excluded those who failed or refused to respond to questions required for the present study. The workplace violence experience group included people who satisfied at least one of six relevant criteria (verbal abuse, unwanted sexual attention, threatening or humiliating behavior, physical violence, bullying/harassment, and sexual harassment) and the group was divided according to whether the perpetrator of violence was a client or colleague. Presence of sleep disturbance was determined based on subjective symptoms felt within the past 12 months by each individual. A multiple logistic regression analysis was performed to identify the effects on sleep distance according to general, occupational, and psychosocial characteristics, as well as the types of workplace violence and perpetrators of violence. RESULTS: Workplace violence was found as a factor affecting sleep disturbance (OR = 3.773, 95 % CI = 3.058 4.655), and with respect to perpetrators of violence, complaint of sleep disturbance symptoms was higher when the perpetrator was a colleague or boss (OR = 5.688, 95 % CI 4.189-7.723) than a client (OR = 2.992, 95 % CI 2.301-3.890). CONCLUSION: Workplace violence had an effect on occurrence of sleep disturbance and when the perpetrators of violence was a boss or colleague at work, the risk for symptoms such as sleep disturbance increased, which indicated the need for appropriate intervention from a workplace healthcare perspective, including preventive education of workplace violence among employees. PMID- 27777784 TI - Relating factors to wearing personal radiation protectors among healthcare professionals. AB - BACKGROUND: With increasing use of medical radiologic procedures, wearing proper protector should be emphasized to reduce occupational radiation exposures. This research describes the rates of lead apron wearing for radiation protection and assessed occupational factors related to wearing rates for various types of healthcare professionals. METHODS: We conducted a self-administered questionnaire survey through a website, on-site visits, fax, and mail. Of the 13,489 participants, 8858 workers who could not completely separate themselves from radiological procedure areas. Their general characteristics (sex and age), work history (job title, duration of employment, and hospital type), and practices (frequency of radiation procedures, ability to completely separate from radiation, and frequency of wearing protective lead aprons) were examined. RESULTS: The mean rate of lead apron wearing during radiologic procedures was 48.0 %. The rate was different according to sex (male: 52.9 %, female: 39.6 %), hospital type (general hospital: 63.0 %, hospital: 51.3 %, clinic: 35.6 %, dental hospital/clinic: 13.3 %, public health center: 22.8 %), and job title (radiologic technologist: 50.3 %, doctor: 70.3 %, dentist/dental hygienist: 15.0 %, nurse/nursing assistant: 64.5 %) (p < 0.001). By logistic regression analysis stratified by job title, use of lead aprons by radiologic technologists and nurses/nursing assistants was associated with hospital type and exposure frequency score. For doctors, apron wearing was associated with employment duration. For dentists/dental hygienists, apron wearing was associated with the exposure frequency score. CONCLUSIONS: To improve working environments for healthcare professionals exposed to radiation, it is necessary to consider related factors, such as job title, duration of employment, and hospital type, when utilizing a planning and management system to prevent radiation-related health problems. PMID- 27777785 TI - Descriptive study of claims for occupational mental disorders or suicide. AB - BACKGROUND: This study aimed to identify the characteristics of claimed mental disorders. Because the workers believed the cause of the mental disorders was work-related stress or a specific event, we could identify the major work-related stressor for claimed cases. METHODS: We included claimed cases of occupational mental disorder or suicide reported during 2010-2014 to the Korea Workers Compensation and Welfare Service (KCOMWEL), established by Industrial Accidents Insurance (IACI) Act. We conducted qualitative analysis using a form specifically developed for this study as well as a quantitative analysis. RESULTS: Of the 569 claimed cases, 142 cases were recognized as occupational mental disorder or suicide. The approval rate was 24.9 %. Suicide was the most commonly approved mental disorder (23.0 %), followed by major depressive disorder (14.9 %). Regarding profession, 109 workers were managers, and 95 workers were office clerks. The main work-related stressors of the approved cases were acute stressful events (76 cases), long working hours (12 cases), and changes in workload (6 cases). The primary stressful events were work-related legal problems, workplace violence, and employment status-related issues. CONCLUSION: Claims due to mental disorders or suicide increased during the 5-year study period, and the approval rate was approximately 33 %, and the main stressor of the claimed cases was an acute stressful event such as physiologic trauma, employment-related issues, fear of legal or financial responsibility, abrupt change in organizational responsibility, or workplace violence. PMID- 27777787 TI - Practical alignment method for X-ray spectral measurement in micro-CT system based on 3D printing technology. AB - This study presents a practical alignment method for X-ray spectral measurement in a rotating gantry based micro-computed tomography (micro-CT) system using three-dimensional (3D) printing technology. In order to facilitate the spectrometer placement inside the gantry, supporting structures including a cover and a stand were dedicatedly designed and printed using a 3D printer. According to the relative position between the spectrometer and the stand, the upright projection of the spectrometer collimator onto the stand was determined and then marked by a tungsten pinhole. Thus, a visible alignment indicator of the X-ray central beam and the spectrometer collimator represented by the pinhole was established in the micro-CT live mode. Then, a rough alignment could be achieved through repeatedly adjusting and imaging the stand until the pinhole was located at the center of the acquired projection image. With the spectrometer being positioned back onto the stand, the precise alignment was completed by slightly translating the spectrometer-stand assembly around the rough location, until finding a "sweet spot" with the highest photon rate and proper distribution of the X-ray photons in the resultant spectrum. The spectra were acquired under precise alignment and misalignment of approximately 0.2, 0.5, and 1.0mm away from the precise alignment position, and then were compared in qualitative and quantitative analyses. Qualitative analysis results show that, with slight misalignment, the photon rate is reduced from 1302 to 1098, 1031, and 416 photons/second (p/s), respectively, and the characteristic peaks in the acquired spectra are gradually deteriorated. Quantitative analysis indicates that the energy resolutions for characteristic peak of Kalpha1 were calculated as 1.56% for precise alignment, while were 1.84% and 2.40% for slight misalignment of 0.2mm and 0.5mm. The mean energies were reduced from 43.93keV under precise alignment condition to 40.97, 39.63 and 37.78keV when misaligned. Accurate spectral measurements in micro-CT systems are significantly influenced by the alignment precision. This practical alignment method using 3D printing technology could be readily applied to other rotating gantry based micro-CT systems with modified design of the supporting structures and careful considerations of the spectrometer and gantry dimensions. PMID- 27777786 TI - Progressive cerebellar degeneration revealing Primary Sjogren Syndrome: a case report. AB - BACKGROUND: Cerebellar ataxia represents a rare and severe complication of Sjogren syndrome (SS), especially with a progressive onset and cerebellar atrophy on imaging. CASE PRESENTATION: We report the case of a 30-year-old woman, with a past history of dry eyes and mouth, who presented a severe cerebellar ataxia worsening over 4 years associated with tremor of the limbs and the head. Brain MRI showed bilateral hyperintensities on T2 and FLAIR sequences, affecting periventricular white matter, with marked cerebellar atrophy. Complementary investigations confirmed the diagnosis of primary SS (pSS). The patient was treated by methylprednisolone, Cyclophosphamid and Azathioprine. Her clinical and radiological states are stabilized after 2 years of following. Primary cerebellar degeneration is extremely rarely associated with pSS. Few cases of isolated cerebellar ataxia or belonging to a multifocal disease were reported in the literature, most of them characterized by an acute or rapidly progressive onset. Cerebellar atrophy was described in only three patients. There have been few clarifications of the pathogenesis of the neurological manifestations in pSS. Treatment is based on corticosteroids and immunosuppressive agents with no consensus of a specific therapy. CONCLUSIONS: Cerebellar ataxia due to pSS may exceptionally mimic a degenerative cerebellar ataxia, especially when the onset is progressive, which represents the particularity of our observation. The role of brain MRI and antibodies remains important for the differential diagnosis. PMID- 27777788 TI - A novel ligand of calcitonin receptor reveals a potential new sensor that modulates programmed cell death. AB - We have discovered that the accumulation of an anti-calcitonin receptor (anti CTR) antibody conjugated to a fluorophore (mAb2C4:AF568) provides a robust signal for cells undergoing apoptotic programmed cell death (PCD). PCD is an absolute requirement for normal development of metazoan organisms. PCD is a hallmark of common diseases such as cardiovascular disease and tissue rejection in graft versus host pathologies, and chemotherapeutics work by increasing PCD. This robust signal or high fluorescent events were verified by confocal microscopy and flow cytometry in several cell lines and a primary culture in which PCD had been induced. In Jurkat cells, GBM-L2 and MG63 cells, the percentage undergoing PCD that were positive for both mAb2C4:AF568 and annexin V ranged between 70 and >90%. In MG63 cells induced for the preapoptotic cell stress response (PACSR), the normal expression of alpha-tubulin, a key structural component of the cytoskeleton, and accumulation of mAb2C4:AF568 were mutually exclusive. Our data support a model in which CTR is upregulated during PACSR and recycles to the plasma membrane with apoptosis. In cells committed to apoptosis (alpha-tubulin negative), there is accumulation of the CTR-ligand mAb2C4:AF568 generating a high fluorescent event. The reagent mAb2C4:AF568 effectively identifies a novel event linked to apoptosis. PMID- 27777790 TI - Utilization of Public Health Service Increased Risk Donors Yields Equivalent Outcomes in Liver Transplantation. AB - Background. The PHS increased risk donor (IRD) is underutilized in liver transplantation. We aimed to examine the posttransplant outcomes in recipients of increased-risk organs. Methods. We analyzed 228,040 transplants in the Organ Procurement and Transplantation Network database from 2004 to 2013. Endpoints were graft failure and death. Results were controlled for demographics and comorbidities. Statistical analysis utilized Fisher's test and logistic regression. Results. 58,816 patients were identified (5,534 IRD, 53,282 non-IRD). IRDs were more frequently male (69.2% versus 58.3%, p < 0.001), younger (34 versus 39, p < 0.001), and less likely to have comorbidities (p < 0.001). Waitlist time was longer for IRD graft recipients (254 versus 238 days, p < 0.001). All outcomes were better in the IRD group. Graft failure (23.6 versus 27.3%, p < 0.001) and mortality (20.4 versus 22.3%, p = 0.001) were decreased in IRD graft recipients. However, in multivariate analysis, IRD status was not a significant indicator of outcomes. Conclusion. This is the first study to describe IRD demographics in liver transplantation. Outcomes are improved in IRD organ recipients; however, controlling for donor and recipient comorbidities, ischemia time, and MELD score, the differences lose significance. In multivariate analysis, use of IRD organs is noninferior, with similar graft failure and mortality despite the infectious risk. PMID- 27777789 TI - FoxO1 interacts with transcription factor EB and differentially regulates mitochondrial uncoupling proteins via autophagy in adipocytes. AB - Mitochondrial uncoupling proteins (UCPs) are inducible and play an important role in metabolic and redox homeostasis. Recent studies have suggested that FoxO1 controls mitochondrial biogenesis and morphology, but it remains largely unknown how FoxO1 may regulate mitochondrial UCPs. Here we show that FoxO1 interacted with transcription factor EB (Tfeb), a key regulator of autophagosome and lysosome, and mediated the expression of UCP1, UCP2 and UCP3 differentially via autophagy in adipocytes. UCP1 was down-regulated but UCP2 and UCP3 were upregulated during adipocyte differentiation, which was associated with increased Tfeb and autophagy activity. However, inhibition of FoxO1 suppressed Tfeb and autophagy, attenuating UCP2 and UCP3 but increasing UCP1 expression. Pharmacological blockade of autophagy recapitulated the effects of FoxO1 inhibition on UCPs. Chromatin immunoprecipitation assay demonstrated that FoxO1 interacted with Tfeb by directly binding to its promoter, and silencing FoxO1 led to drastic decrease in Tfeb transcript and protein levels. These data provide the first line of evidence that FoxO1 interacts with Tfeb to regulate autophagy and UCP expression in adipocytes. Dysregulation of FoxO1->autophagy->UCP pathway may account for metabolic changes in obesity. PMID- 27777791 TI - Intravitreal Conbercept Injection with and without Grid Laser Photocoagulation in the Treatment of Diffuse Diabetic Macular Edema in Real-Life Clinical Practice. AB - Purpose. To evaluate the efficacy of intravitreal conbercept (IVC) plus modified grid laser photocoagulation (MGP) versus IVC alone for treatment of diffuse diabetic macular edema (DDME). Methods. In this retrospective study, 51 DDME patients were treated with either IVC alone (IVC group) or IVC plus MGP (combined group) with 12 months of follow-up. The clinical records of those patients were reviewed. Results. 26 patients (31 eyes) received IVC alone and 25 patients (30 eyes) received combined therapy. At month 12, the mean best-corrected visual acuity (BCVA) letter score improvement was 9.1 +/- 4.5 and 7.5 +/- 4.2 in the IVC group and the combined group and the mean central retinal thickness (CRT) reduction was 145.1 +/- 69.9 MUm and 168.5 +/- 53.6 MUm, respectively. There was no statistically significant difference of improvement in BCVA (P = 0.164) and decrease in CRT (P = 0.149) between the two groups. The mean number of injections delivered was significantly higher (P < 0.001) in the IVC group (5.6 +/- 0.8 per eye) than in the combined group (3.3 +/- 1.2 per eye). Conclusions. IVC alone or combined with MGP appeared to be effective for treatment of DDME, achieving the similar clinical efficacy. Moreover, MGP helps to reduce the number of injections. PMID- 27777793 TI - Visual Impairment among Older Adults in a Rural Community in Eastern China. AB - Purpose. To determine the prevalence, causes, and associations of visual impairment (VI) among participants aged 60 years or older in a rural community in China. Methods. A community-based survey was undertaken in a rural town located in Eastern China and 4579 people aged 60 years or older participated in the study. Presenting visual acuity was assessed using a Snellen chart with tumbling E optotypes and anterior segment was examined using a slit-lamp. VI was defined as presenting VA <6/18 and it included moderate VI (<6/18 to 6/60) and blindness (<6/60). Results. The prevalence of VI was 5.4% (95% confidence interval [CI] 4.7 6.0). In multivariate analysis, the presence of VI was positively associated with increasing age (odds ratio [OR] = 1.12, 95% CI 1.10-1.16, per year increase), female gender (OR = 2.33, 95% CI 1.53-3.55), the presence of hypertension (OR = 1.31, 95% CI 1.001-1.85), living alone (OR = 1.52, 95% CI 1.08-2.62), and increased sleeping hours (OR = 1.10, 95% CI 1.001-1.22). Drinking 3 or more glasses of green tea per day was inversely associated with VI (OR = 0.79, 95% CI 0.63-0.98). Conclusion. VI was less prevalent in this community compared with previous report in other areas in China. PMID- 27777792 TI - The Role of E-Cadherin in Maintaining the Barrier Function of Corneal Epithelium after Treatment with Cultured Autologous Oral Mucosa Epithelial Cell Sheet Grafts for Limbal Stem Deficiency. AB - The role of E-cadherin in epithelial barrier function of cultured autologous oral mucosa epithelial cell sheet (CAOMECS) grafts was examined. CAOMECS were cultured on a temperature-responsive surface and grafted onto rabbit corneas with Limbal Stem Cell Deficiency (LSCD). E-cadherin levels were significantly higher in CAOMECS compared to normal and LSCD epithelium. Beta-catenin colocalized with E cadherin in CAOMECS cell membranes while phosphorylated beta-catenin was significantly increased. ZO-1, occludin, and Cnx43 were also strongly expressed in CAOMECS. E-cadherin and beta-catenin localization at the cell membrane was reduced in LSCD corneas, while CAOMECS-grafted corneas showed a restoration of E cadherin and beta-catenin expression. LSCD corneas did not show continuous staining for ZO-1 or for Cnx43, while CAOMECS-grafted corneas showed a positive expression of ZO-1 and Cnx43. Cascade Blue(r) hydrazide did not pass through CAOMECS. Because E-cadherin interactions are calcium-dependent, EGTA was used to chelate calcium and disrupt cell adhesion. EGTA-treated CAOMECS completely detached from cell culture surface, and E-cadherin levels were significantly decreased. In conclusion, E cadherin high expression contributed to CAOMECS tight and gap junction protein recruitment at the cell membrane, thus promoting cellular adhesion and a functional barrier to protect the ocular surface. PMID- 27777794 TI - Molecular Analysis of CYP21A2 Gene Mutations among Iraqi Patients with Congenital Adrenal Hyperplasia. AB - Congenital adrenal hyperplasia is a group of autosomal recessive disorders. The most frequent one is 21-hydroxylase deficiency. Analyzing CYP21A2 gene mutations was so far not reported in Iraq. This work aims to analyze the spectrum and frequency of CYP21A2 mutations among Iraqi CAH patients. Sixty-two children were recruited from the Pediatric Endocrine Consultation Clinic, Children Welfare Teaching Hospital, Baghdad, Iraq, from September 2014 till June 2015. Their ages ranged between one day and 15 years. They presented with salt wasting, simple virilization, or pseudoprecocious puberty. Cytogenetic study was performed for cases with ambiguous genitalia. Molecular analysis of CYP21A2 gene was done using the CAH StripAssay (ViennaLab Diagnostics) for detection of 11 point mutations and >50% of large gene deletions/conversions. Mutations were found in 42 (67.7%) patients; 31 (50%) patients were homozygotes, 9 (14.5%) were heterozygotes, and 2 (3.2%) were compound heterozygotes with 3 mutations, while 20 (32.3%) patients had none of the tested mutations. The most frequently detected mutations were large gene deletions/conversions found in 12 (19.4%) patients, followed by I2Splice and Q318X in 8 (12.9%) patients each, I172N in 5 (8.1%) patients, and V281L in 4 (6.5%) patients. Del 8 bp, P453S, and R483P were each found in one (1.6%) and complex alleles were found in 2 (3.2%). Four point mutations (P30L, Cluster E6, L307 frameshift, and R356W) were not identified in any patient. In conclusion, gene deletions/conversions and 7 point mutations were recorded in varying proportions, the former being the commonest, generally similar to what was reported in regional countries. PMID- 27777795 TI - Limited Effects of Endurance or Interval Training on Visceral Adipose Tissue and Systemic Inflammation in Sedentary Middle-Aged Men. AB - Purpose. Limited data exists for the effects of sprint-interval training (SIT) and endurance training (ET) on total body composition, abdominal visceral adipose tissue, and plasma inflammation. Moreover, whether "active" or "passive" recovery in SIT provides a differential effect on these measures remains uncertain. Methods. Sedentary middle-aged men (n = 62; 49.5 +/- 5.8 y; 29.7 +/- 3.7 kg.m2) underwent abdominal computed tomography, dual-energy X-ray absorptiometry, venepuncture, and exercise testing before and after the interventions, which included the following: 12 wks 3 d.wk-1 ET (n = 15; 50-60 min cycling; 80% HRmax), SIT (4-10 * 30 s sprint efforts) with passive (P-SIT; n = 15) or active recovery (A-SIT; n = 15); or nonexercise control condition (CON; n = 14). Changes in cardiorespiratory fitness, whole-body and visceral fat mass, and plasma systemic inflammation were examined. Results. Compared to CON, significant increases in interpolated power output (P-SIT, P < 0.001; ET, P = 0.012; A-SIT, P = 0.041) and test duration (P-SIT, P = 0.001; ET, P = 0.012; A-SIT, P = 0.046) occurred after training. Final VO2 consumption was increased after P-SIT only (P < 0.001). Despite >90% exercise compliance, there was no change in whole-body or visceral fat mass or plasma inflammation (P > 0.05). Conclusion. In sedentary middle-aged men, SIT was a time-effective alternative to ET in facilitating conditioning responses yet was ineffective in altering body composition and plasma inflammation, and compared to passive recovery, evidenced diminished conditioning responses when employing active recovery. PMID- 27777796 TI - Objectively Quantified Physical Activity and Sedentary Behavior in Predicting Visceral Adiposity and Liver Fat. AB - Objective. Epidemiologic studies suggest an inverse relationship between nonalcoholic fatty liver disease (NAFLD), visceral adipose tissue (VAT), and self reported physical activity levels. However, subjective measurements can be inaccurate and prone to reporter bias. We investigated whether objectively quantified physical activity levels predicted liver fat and VAT in overweight/obese adults. Methods. Habitual physical activity was measured by triaxial accelerometry for four days (n = 82). Time spent in sedentary behavior (MET < 1.6) and light (MET 1.6 < 3), moderate (MET 3 < 6), and vigorous (MET 6 < 9) physical activity was quantified. Magnetic resonance imaging and spectroscopy were used to quantify visceral and liver fat. Bivariate correlations and hierarchical multiple regression analyses were performed. Results. There were no associations between physical activity or sedentary behavior and liver lipid. Sedentary behavior and moderate and vigorous physical activity accounted for just 3% of variance for VAT (p = 0.14) and 0.003% for liver fat (p = 0.96). Higher levels of VAT were associated with time spent in moderate activity (r = 0.294, p = 0.007), but there was no association with sedentary behavior. Known risk factors for obesity-related NAFLD accounted for 62% and 40% of variance in VAT and liver fat, respectively (p < 0.01). Conclusion. Objectively measured levels of habitual physical activity and sedentary behavior did not influence VAT or liver fat. PMID- 27777798 TI - Mentoring Nurses in Political Skill to Navigate Organizational Politics. AB - Objective. The aim of this study was to describe and analyze the correlations between mentoring functions and political skill development among nurses who have earned or are candidates for a Ph.D. or doctorate of nursing practice (DNP) degree. Background. The healthcare system is in flux; future generations of Ph.D. and DNP nurse leaders will be required to demonstrate political acumen. Political skill to navigate organizational politics has had limited research within nursing. Methods. A cross-sectional research design using a web-based survey of 222 nurses who have earned or are candidates for a Ph.D. or DNP. This study utilized two validated tools to measure mentoring functions and political skill. Results. The response rate was 52% (n = 115) of which 86 were Ph.D. and 29 were DNPs. An informal mentoring relationship was described by 62% of the respondents and formal mentoring by 35% of the proteges; only 25% (n = 74) established a mentoring contract. Mentoring score showed significance for total political skill and moderate effect on the networking ability. The mentoring functions of advocacy, career development facilitation, learning facilitation, and friendship were found to correlate significantly with total political skill scores. Conclusions. This study established a benefit for nurses who have earned or are candidates for a Ph.D. or DNP from mentoring to support political skill development. PMID- 27777799 TI - New Possible Surgical Approaches for the Submammary Adipofascial Flap Based on Its Arterial Supply. AB - Introduction. Submammary adipofascial flap (SMAF) is a valuable option for replacement of the inferior portion of the breast. It is particularly useful for reconstruction of partial mastectomy defects. It is also used to cover breast implants. Most surgeons base this flap cranially on the submammary skin crease, reflecting it back onto the breast. The blood vessels supplying this flap are not well defined, and the harvest of the flap may be compromised due to its uncertain vascularity. The aim of the work was to identify perforator vessels supplying SMAF and define their origin, site, diameter, and length. Materials and Methods. The flap was designed and dissected on both sides in 10 female cadavers. SMAF outline was 10 cm in length and 7 cm in width. The flap was raised carefully from below upwards to identify the perforator vessels supplying it from all directions. These vessels were counted and the following measurements were taken using Vernier caliper: diameter, total length, length inside the flap, and distance below the submammary skin crease. Conclusions. The perforators at the lateral part of the flap took origin from the lateral thoracic, thoracodorsal, and intercostal vessels. They were significantly larger, longer, and of multiple origins than those on the medial part of the flap and this suggests that laterally based flaps will have better blood supply, better viability, and more promising prognosis. Both approaches, medially based and laterally based SMAF, carry a better prognosis and lesser chance for future fat necrosis than the classical cranially based flap. PMID- 27777800 TI - Adaptation and Plasticity of Breathing during Behavioral and Cognitive Tasks. PMID- 27777797 TI - Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals. AB - Neurological complications associated with the human immunodeficiency virus (HIV) are a matter of great concern. While antiretroviral (ARV) drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity. PMID- 27777801 TI - Neural Plasticity on Body Representations: Advancing Translational Rehabilitation. PMID- 27777802 TI - TAFRO Syndrome Associated with EBV and Successful Triple Therapy Treatment: Case Report and Review of the Literature. AB - TAFRO syndrome is a rare constellation of symptoms: thrombocytopenia, anasarca, reticulin fibrosis of the bone marrow, renal dysfunction, and organomegaly. Its pathogenesis involves an excessive and inappropriate cytokine storm, most notably from IL-6, causing multiorgan failure; however, its etiology is undetermined. Starting in 2012, TAFRO syndrome was first identified in Japan as an atypical variant of Castleman's disease. Previous reports include various different treatment protocols with inconsistent survival outcomes. Here we report the first known American, EBV positive but HIV and HHV-8 negative, male with TAFRO syndrome. He was successfully treated with an unusual three-drug regimen including tocilizumab, etoposide, and rituximab. We review the literature of TAFRO syndrome, discuss its possible viral etiology, and propose an original treatment regimen. PMID- 27777803 TI - A Case of De Novo CD5+ Disseminated Intravascular Large B-Cell Lymphoma Presenting as Multiorgan Failure. AB - Intravascular large B-cell lymphoma is an extremely rare extranodal lymphoma that proliferates in the lumen of the blood vessels while sparing the organ parenchyma. It usually presents with CNS and skin involvement. A 65-year-old Caucasian female presented with fevers and chills of 3-4 months' duration. Bone marrow biopsy done 3 months prior showed no significant myelodysplasia or lymphoid aggregates. The patient later died due to multiorgan failure. A bone marrow biopsy showed 20-30% CD5+ B cells consistent with infiltrative large B cell lymphoma. An autopsy performed revealed diffuse intravascular invasion by lymphoma cells. Multiorgan involvement by intravascular B-cell lymphoma is very rare. Based on our literature review and to the best of our knowledge, there are only 5 case reports describing the presentation of this lymphoma with multiorgan failure. The immunophenotypic studies performed revealed that our patient had de novo CD5+ intravascular large B-cell lymphoma which is known to be aggressive with very poor prognosis. Although it is an extremely rare lymphoma, it should be considered as a potential cause of multiorgan failure when no other cause has been identified. A prompt tissue diagnosis and high-dose chemotherapy followed by ASCT can sometimes achieve remission. PMID- 27777804 TI - Detection of the Dimorphic Phases of Mucor circinelloides in Blood Cultures from an Immunosuppressed Female. AB - Mucormycosis fungemia is rarely documented since blood cultures are nearly always negative. We describe a case of Mucor circinelloides fungemia in a patient with a history of a sinus infection, sarcoidosis, and IgG deficiency. The identity of the isolate was supported by its microscopic morphology and its ability to convert into yeast forms under anaerobic conditions. The early detection, initiation of liposomal amphotericin B treatment, and reversal of underlying predisposing risk factors resulted in a good outcome. PMID- 27777805 TI - Two Cases of Human T-Lymphotropic Virus Type I-Associated Myelopathy/Tropical Spastic Paraparesis Caused by Living-Donor Renal Transplantation. AB - In rare instances, recipients of organ transplants from human T-lymphotropic virus type I- (HTLV-I-) positive donors reportedly developed neurologic symptoms due to HTLV-I-associated myelopathy (HAM). We present herein two cases of HAM associated with renal transplantation from HTLV-I seropositive living-donors. The first patient was a 42-year-old woman with chronic renal failure for twelve years and seronegative for HTLV-I. She underwent renal transplantation with her HTLV-I seropositive mother as the donor, and she developed HAM three years after the transplantation. The second patient was a 65-year-old man who had been suffering from diabetic nephropathy. He was seronegative for HTLV-I and underwent renal transplantation one year previously, with his HTLV-I seropositive wife as the donor. He developed HAM eight months after renal transplantation. Both cases showed neurological improvements after the immunomodulating therapies. We tried to shed some light on the understanding of immunological mechanisms of transplantation-associated HAM, focusing on therapeutic strategies based on the immunopathogenesis of the condition. PMID- 27777806 TI - Ochrobactrum anthropi Keratitis with Focal Descemet's Membrane Detachment and Intracorneal Hypopyon. AB - Purpose. To describe a unique case of O. anthropi keratitis associated with a rare manifestation of Descemet's membrane detachment and intracorneal hypopyon and to discuss challenges in diagnosis and management. Methods. Best-corrected visual acuity was measured with Snellen letters. Corneal scrapings were performed and aerobic, viral, herpetic, acid-fast bacilli, Acanthamoeba, and fungal stains and cultures were obtained. Following evisceration, tissue was evaluated for histologic features and again stained for bacteria, mycobacteria, Acanthamoeba, fungi, and viral particles. Results. Initial presentation to our institute was notable for a corneal ulcer, focal Descemet's membrane detachment, and intracorneal hypopyon. Speciation of initial corneal scrapes revealed Ochrobactrum anthropi and initial management included fortified tobramycin. Despite medical therapy, the patient developed a corneal perforation and required subsequent evisceration. Conclusion. O. anthropi is an emerging ocular pathogen that has not been previously reported in cases of keratitis. As this pathogen becomes increasingly recognized as a source of ocular infections, it is important to identify and treat aggressively to avoid vision-threatening disease. PMID- 27777807 TI - Synthetic Cannabis Overdose and Withdrawal in a Young Adult: A Case Report, Commentary on Regulation, and Review of the Literature. AB - Introduction. Marijuana has been used for its psychotropic effects including enhanced relaxation and perceptual alterations. However, the use of synthetic marijuana (SM) leads to more frequent and drastic side effects than the typical use of regular marijuana, owing to the fact that SM has a shorter duration and an earlier peak of action. Despite all the potential adverse health effects associated with SM use, current health policies on SM are very limited. It is believed that the popularity of SM has increased, due to its easy accessibility in the US and lack of detection in typical urine drug screens for THC. Case Report. One case presented is of a young adult patient, with histories of recurrent synthetic cannabis and recreational cannabis use, who had developed drastic physiological and psychiatric symptoms, including the development of acute-onset psychosis. Conclusion/Discussion. This case, as many others nationwide, exemplifies the impact of synthetic cannabinoid use and abuse in adolescents. Side effects and adverse health consequences of synthetic cannabinoid use warrant stricter regulations and policies in order to decrease psychiatric hospital admissions and associated healthcare costs. PMID- 27777808 TI - Chronic Intussusception Associated with Malrotation in a Child: A Variation of Waugh's Syndrome? AB - Chronic intussusception is a relatively uncommon disease most commonly observed in older children. Waugh's syndrome represents a rare entity characterized by intestinal malrotation and acute intussusception. We report a very unusual case of intestinal malrotation associated with chronic intussusception. Clinical presentation, radiological findings, and managing of this association are discussed in the light of the available literature. PMID- 27777810 TI - Low Density of Top Predators (Seabirds and Marine Mammals) in the High Arctic Pack Ice. AB - The at-sea distribution of top predators, seabirds and marine mammals, was determined in the high Arctic pack ice on board the icebreaker RV Polarstern in July to September 2014. In total, 1,620 transect counts were realised, lasting 30 min each. The five most numerous seabird species represented 74% of the total of 15,150 individuals registered: kittiwake Rissa tridactyla, fulmar Fulmarus glacialis, puffin Fratercula arctica, Ross's gull Rhodostethia rosea, and little auk Alle alle. Eight cetacean species were tallied for a total of 330 individuals, mainly white-beaked dolphin Lagenorhynchus albirostris and fin whale Balaenoptera physalus. Five pinniped species were represented by a total of 55 individuals and the polar bear Ursus maritimus was represented by 12 individuals. Four main geographical zones were identified: from Tromso to the outer marginal ice zone (OMIZ), the Arctic pack ice (close pack ice, CPI), the end of Lomonosov Ridge off Siberia, and the route off Siberia and northern Norway. Important differences were detected between zones, both in species composition and in individual abundance. Low numbers of species and high proportion of individuals for some of them can be considered to reflect very low biodiversity. Numbers encountered in zones 2 to 4 were very low in comparison with other European Arctic seas. The observed differences showed strong patterns. PMID- 27777809 TI - Patients' Views on a Combined Action Observation and Motor Imagery Intervention for Parkinson's Disease. AB - Background. Action observation and motor imagery activate neural structures involved in action execution, thereby facilitating movement and learning. Although some benefits of action observation and motor imagery have been reported in Parkinson's disease (PD), methods have been based on stroke rehabilitation and may be less suitable for PD. Moreover, previous studies have focused on either observation or imagery, yet combining these enhances effects in healthy participants. The present study explores the feasibility of a PD-specific home based intervention combining observation, imagery, and imitation of meaningful everyday actions. Methods. A focus group was conducted with six people with mild to moderate PD and two companions, exploring topics relating to the utility and feasibility of a home-based observation and imagery intervention. Results. Five themes were identified. Participants reported their experiences of exercise and use of action observation and motor imagery in everyday activities, and the need for strategies to improve movement was expressed. Motivational factors including feedback, challenge, and social support were identified as key issues. The importance of offering a broad range of actions and flexible training was also highlighted. Conclusions. A home-based intervention utilising action observation and motor imagery would be useful and feasible in mild to moderate PD. PMID- 27777811 TI - A Review on Recent Developments for Detection of Diabetic Retinopathy. AB - Diabetic retinopathy is caused by the retinal micro vasculature which may be formed as a result of diabetes mellitus. Blindness may appear as a result of unchecked and severe cases of diabetic retinopathy. Manual inspection of fundus images to check morphological changes in microaneurysms, exudates, blood vessels, hemorrhages, and macula is a very time-consuming and tedious work. It can be made easily with the help of computer-aided system and intervariability for the observer. In this paper, several techniques for detecting microaneurysms, hemorrhages, and exudates are discussed for ultimate detection of nonproliferative diabetic retinopathy. Blood vessels detection techniques are also discussed for the diagnosis of proliferative diabetic retinopathy. Furthermore, the paper elaborates a discussion on the experiments accessed by authors for the detection of diabetic retinopathy. This work will be helpful for the researchers and technical persons who want to utilize the ongoing research in this area. PMID- 27777812 TI - Heavy metal and junk DNA. PMID- 27777813 TI - The Etiology and Pathogenesis of Kienbock Disease. AB - Kienbock disease is a condition that typically occurs in the "at-risk" patient, in the "at-risk" aspect of the proximal condyle of the "at-risk" lunate. In the active male, repetitive loading causes the stress fracture that commences in the single layer proximal subchondral bone plate. The lunate fracture commences at the point the lunate cantilevers over the edge of the distal radius, and then takes on the shape of the radius. We postulate that the stress fracture violates the parallel veins of the venous subarticular plexus-leading to localized venous hypertension and subsequent ischemia and edema of the fatty marrow. The increased osseous compartment pressure further potentiates the venous obstruction, producing avascular necrosis. If the fracture remains localized, it can heal or settle into a stable configuration, so that the wrist remains functional. Fractures of the subchondral bone plate produce irregularity of the lunate articular surfaces and secondary "kissing lesions" of the lunate facet and capitate, and subsequent degeneration. The lunate collapses when the fracture is comminuted, or there is disruption of the spanning trabeculae or a coronal fracture. The secondary effect of the lunate collapse is proximal migration of the capitate between the volar and dorsal fragments, producing collapse of the entire central column. The proximal carpal row is now unstable, and is similar to scapholunate instability, where the capitate migrates between the scaphoid and lunate. The scaphoid is forced into flexion by the trapezium, however, degeneration of the scaphoid and scaphoid facet only occurs in late disease or following failed surgery. In Kienbock disease, the secondary effects of the collapsing lunate are a "compromised" wrist, including: deformity and collapse of the central column, degeneration of the central column (perilunate) articulations, proximal row instability (i.e., between the central and radial columns), and degeneration of the radial column. PMID- 27777814 TI - Kienbock Disease and Arthroscopy: Assessment, Classification, and Treatment. AB - The assessment and management of Kienbock Disease (KD) has always been a conundrum. The Lichtman classification has traditionally been used to guide treatment based on imaging. Arthroscopy provides a direct visualization of the articular surface, allows probing of the surfaces, and enables minimally invasive techniques to be performed. The Lichtman-Bain classification is a new classification that takes into account the osseous, vascular, and cartilage aspects of the lunate and the secondary effects on the wrist. It identifies the important prognostic factors including age, the status of the lunate, and the status of the wrist. With arthroscopy, the articular surfaces of the lunate can be assessed to better understand the status of the lunate. The lunate can be defined as intact, compromised, or not reconstructable. If the lunate is intact then lunate decompression (forage) and arthroscopic assisted bone grafting can be performed. If the lunate facet and capitate are functional, then a proximal carpectomy can be performed. This can be performed as an arthroscopic procedure. Assessment of the wrist includes assessment of the adjacent articular surfaces of the central column articulations (radiocarpal and midcarpal articulations). Instability of the proximal carpal row can also be assessed. The radioscaphoid articulation is often preserved except in late KD, which allows the scaphocapitate fusion to be a good surgical option. This can now be performed as an arthroscopic procedure. Once the radioscaphoid articulation is degenerate, a salvage procedure is required. PMID- 27777815 TI - The Prevalence of Pisotriquetral Arthritis in the Setting of Scapholunate Advanced Collapse. AB - Background Previous authors have reported pisotriquetral pain and subsequent pisiform excision following partial or total wrist fusion in patients with scapholunate advanced collapse (SLAC). Prior studies have not considered the potential role of SLAC biomechanics on pisotriquetral osteoarthritis (PT OA) development preoperatively. Purpose To determine the prevalence and severity of PT OA in patients with SLAC as compared with a control population. Patients and Methods Magnetic resonance imaging (MRI) studies of 24 patients with SLAC wrist and 24 sex- and age-matched control patients were analyzed. Patients with SLAC wrist were selected from a database of all wrist MRI studies performed at our institution from 2006 to 2015, excluding those with inflammatory arthritis, chondrocalcinosis, and incomplete or atraumatic scapholunate interosseous ligament rupture. Control patients underwent MRI for nonarthritic clinical indications and were chosen in an age- and sex-matched fashion. Patients undergoing MRI for triangular fibrocartilage complex injury, extensor carpi ulnaris tendinopathy, or ulnar-sided wrist pain were excluded from the control cohort. MRI grading of arthritic change at the pisotriquetral joint was assessed by a blinded musculoskeletal radiologist according to a four-category scale, with grade 4 indicating the greatest arthritic severity. Results The prevalence of PT OA in the control cohort was found to be 37.5% compared with 41.7% in the SLAC cohort. The prevalence of greatest arthritic severity (grade 4) at the pisotriquetral joint was found to be 4.2% in the control cohort, compared with 16.7% in the SLAC cohort. Conclusion We conclude that the overall prevalence of chondral wear at the pisotriquetral joint in SLAC wrist does not differ significantly from that found in control populations. We did identify a fourfold (but not statistically significant) increased prevalence of end-stage arthritis in patients with SLAC. Given reports of symptomatic PT OA developed following four-corner arthrodesis, we recommend preoperative vigilance for pisotriquetral pain in patients with SLAC arthritis. Level of Evidence Prognostic level III. PMID- 27777816 TI - Stage III Advanced Wrist Collapse Treatment Options: A Cadaveric Study. AB - Background Scapholunate advanced collapse and scaphoid nonunion advanced collapse result in high morbidity and pose significant challenges for active patients. Multiple treatment options have been proposed to yield satisfactory results; however, restoration of physiological wrist motion remains an issue. Questions/Purposes The objective of this study was to compare wrist mobility after four different treatment methods for grade III wrist collapse: (1) no treatment, (2) scaphoidectomy and lunate-capitate arthrodesis, (3) scaphoidectomy, lunate-capitate arthrodesis, and triquetrum-hamate arthrodesis, and (4) scaphoidectomy, lunate-capitate arthrodesis, and triquetrum excision. Methods Four paired (n = 8) fresh-frozen human cadaveric upper limbs were used in this controlled laboratory study. Computed tomography scans were collected at all testing states and measurements were made to evaluate midcarpal joint mobility and alignment. Results A significant decrease in wrist extension was observed for all treatments. Middle column and two-column arthrodesis demonstrated no significant differences for carpal alignment and mobility. No significant differences were observed for triquetrum-hamate mobility or wrist extension between the partial and two-column arthrodesis. Triquetrum excision significantly improved ulnar deviation. Conclusion The most important finding of this study was that the one-column arthrodesis has comparable carpal alignment and range of motion to that of bi-column arthrodesis. Clinical Relevance The results of this study suggest that a stage III advanced wrist collapse can be treated by isolated lunate-capitate arthrodesis with scaphoidectomy. Fusion between the remaining carpal bones may not be necessary because the carpal alignment and range of motion of the remaining joints were not significantly different in the present study. PMID- 27777817 TI - Accessory Slip of the Extensor Carpi Ulnaris: A Cadaveric Assessment. AB - Background An accessory slip arising from the extensor carpi ulnaris (ECU) tendon that inserts on the fifth metacarpal bone has been identified. We describe the frequency of this accessory slip arising from the ECU tendon and provide both qualitative and quantitative description of the slip via cadaveric examination. Methods Fifty (28 males and 22 females) cadaveric upper extremity specimens were examined after loupe-aided dissection of the dorsoulnar wrist and hand with identification of the ECU tendon. The presence of an accessory slip arising from the ECU tendon was noted. The insertion and morphology of the accessory slip was also described. Results An accessory slip arising from the ECU tendon at the level of the radiocarpal joint was found to insert on the fifth metacarpal bone in 11 (22%) specimens. Nine accessory slips inserted at the base of the fifth metacarpal (Nakashima Type A) and two inserted at the fifth metacarpal head (Nakashima Type C). Mean width of the accessory slip was 1.2 +/- 0.4 mm. No evidence of sexual dimorphism was found regarding the morphology of the accessory slip. Conclusion The current study demonstrates the relative frequency and morphology of the accessory slip arising from the ECU tendon. This variant should be of diagnostic consideration in ailments of the dorsoulnar wrist and hand. Hand surgeons should be aware of this anatomic variant and its potential for clinical manifestation. PMID- 27777818 TI - Trapeziometacarpal Ligaments Biomechanical Study: Implications in Arthroscopy. AB - Purpose In the presence of early osteoarthritis, changes to the trapeziometacarpal joint (TMJ) often result in pain and is associated with joint instability and a tendency of dorsoradial subluxation. In these instances, arthroscopy may be indicated to: (1) assess the extent of cartilage disease and the laxity of ligaments and to (2) treat TMJ instability. The purpose of our study was to biomechanically analyze which ligaments are the primary stabilizers of the TMJ. Methods Overall, 11 fresh-frozen human cadaver specimens were dissected and attached to a testing device with the thumb positioned in neutral abduction, neutral flexion, and neutral opposition. The four extrinsic and five intrinsic muscle tendons acting on the TMJ were simultaneously loaded with weights proportional to their physiological cross-sectional area. The dorsal, volar, and ulnar groups of ligaments were dissected. A motion-tracking device, FasTrak (Polhemus Inc., Colchester, VT), was used to study the spatial position of the base of the first metacarpal bone (MC1), before and after random sectioning of each of the ligaments. Statistical analysis of the MC1 translation along the transverse XY plane was performed using one-way analysis of variance and a paired t-test, with a significance level of p < 0.05. Results After isolated sectioning of the volar or the ulnar ligaments, the MC1 moved dorsoradially with an average of 0.150 mm (standard deviation [SD]: 0.072) and 0.064 mm (SD: 0.301), respectively. By contrast, the destabilization of the MC1 after sectioning of the dorsal ligaments was substantially larger (0.523 mm; SD: 0.0512; p = 0.004). Conclusion Sectioning of the dorsal ligament group resulted in the greatest dorsoradial translation of the MC1. Consequently, the dorsal ligaments may be regarded as the primary TMJ stabilizers. Clinical Relevance This study suggests that stabilizing arthroscopic shrinkage of the TMJ should be targeted toward the dorsal TMJ ligaments. PMID- 27777819 TI - Influence of Plate Size and Design upon Healing of Ulna-Shortening Osteotomies. AB - Purpose Ulna-shortening osteotomy is one of the most established and most frequent operations in hand surgery. However, bone union is not always achieved and the use of plates implies potential risks and problems. The traditional points of criticism are the duration of bone healing, the incidence of nonunion, and the necessity of hardware removal due to the soft tissue irritation by the plate or the screws. These shortcomings have been addressed by an increasing standardization of the procedure and finally specific instruments and implants. The aim of this retrospective study was to compare a new LCP (locking compression plate) Ulna Osteotomy System 2.7 mm (Synthes, Paoli, PA) with the former 3.5-mm LCDCP (limited-contact dynamic compression plate) (Synthes) regarding consolidation, complications, and rate of plate removal. Methods To investigate the effect of an implant and technique specifically designed for this purpose, we have compared the course of healing and the result in 72 patients who have undergone ulnar shortening osteotomy using general instruments and applying a standard osteosynthesis plate (Synthes, 3.5-mm LCDCP) to a consecutive cohort of 40 patients who had ulnar shortening using the new dedicated ulna-shortening osteotomy system plate (Synthes, 2.7-mm LCP). Clinical and radiologic evaluation was performed 8 weeks, 3 months, 6 months, and 1 year postoperatively in all patients. Results The latter displayed shorter bone healing time, suggesting an advantage of an oblique osteotomy. There was no significant difference in rate of plate removal. Ultimate complication and consolidation rate was not different. Conclusion Using the new LCP 2.7 implant, time to consolidation was shorter and oblique osteotomies healed faster than transverse ones. However, in spite of the smaller plate, screws, and tapered design, the plate did not cause less local problems and failed to decrease the necessity of plate removal. Furthermore, the cost of the implant is higher than the LCDPC 3.5. Type of Study Retrospective comparative study. Therapeutic evidence Level III. PMID- 27777820 TI - Midterm Results of Semiconstrained Distal Radioulnar Joint Arthroplasty and Analysis of Complications. AB - Range of motion and stability are important outcome parameters to assess function of the distal radioulnar joint (DRUJ), in particular pronation, supination, and weight-lifting capacity. The DRUJ semiconstrained implant developed by Scheker et al is intended to reproduce all the functions of the triangular fibrocartilage complex and the DRUJ. The aim of the study was to investigate the subjective, clinical, and radiographic results in 10 patients after primary implantation of the semiconstrained DRUJ arthroplasty following DRUJ derangement and painful instability, with an average follow-up of 3 years with a special focus on the complications. Standardized preoperative and postoperative evaluation included assessment of pain by a visual analog scale, radiographic examination, range of motion measurements, lifting capacity, and grip strength. The patient-perceived function was investigated using clinical score charts. Compared with the preoperative status, range of motion showed little change, while grip strength, lifting capacity, pain score, and patient-perceived functions improved significantly. One patient developed an ulna stem loosening, while two patients had to be reoperated because of an irritation of the extensor tendons and the superficial radial nerve at the first dorsal compartment of the wrist. In this study, arthroplasty of the DRUJ using the semiconstrained DRUJ arthroplasty was found to result in satisfactory outcome. Level of evidence: Level IV. PMID- 27777821 TI - Development of a Protocol for SPECT/CT in the Assessment of Wrist Disorders. AB - Background Single-photon emission computed tomography and computed tomography (SPECT/CT) is a hybrid diagnostic imaging modality that allows clinicians to integrate their diagnostic evaluations and deliver a definitive diagnosis in musculoskeletal disorders. Specifically, in identification of osseous pathology, the conventional bone scan delivers greater specificity compared with magnetic resonance imaging (MRI). However, use of SPECT/CT enhances the sensitivity and specificity. Use of this modality denotes the possibility to specify the lesion more accurately and precisely while grading the activity according to osseous structural changes. Purpose This study aimed to evaluate the clinical utility of SPECT/CT in the diagnoses and management of osseous wrist disorders. The objectives were to examine the value of SPECT/CT in the diagnosis of osseous related wrist pain and whether the findings altered management. Patients and Methods A retrospective cohort study of 20 patients with such wrist pain was conducted. SPECT/CT was used in the diagnostic process for these patients. Results Following SPECT/CT imaging, the common final diagnoses were osteoarthritis (10; 50%) and avascular necrosis (5; 25%). Less common diagnoses included ulnar carpal impact syndrome, infection, malunion, complex regional pain syndrome, and carpal boss. Some presented with multiple pathologies. SPECT/CT changed the final diagnosis in 11 cases, resulting in nonoperative treatment (7; 63%) or surgery (4; 37%). Conclusion Findings from this study and the literature demonstrate the clinical utility of SPECT/CT in the assessment of osseous-related wrist disorders. We present an algorithm for the assessment of wrist pain with osseous pathology. This commences with clinical assessment and plane radiographs (first-line investigation). Some cases will require a second-line investigation (ultrasound, CT, and/or MRI). If the diagnosis remains unclear, SPECT/CT is recommended as a third-line investigation. PMID- 27777823 TI - Ulnar-Sided Wrist Pain due to Long Ulnar Styloid: A Case Report. AB - Ulnar styloid impaction syndrome involves repetitive friction between an excessively long ulnar styloid and the carpus, resulting in chondromalacia, synovitis, and pain. The arthroscopic diagnosis, evaluation, and management of this syndrome are not well characterized. We present a patient with chronic wrist pain of unknown origin, culminating with arthroscopic findings demonstrating substantial loss of articular cartilage on both the lunate and triquetrum. The patient successfully underwent operative ulnar styloid excision, ultimately resolving chronic wrist pain symptomology. PMID- 27777822 TI - The Role of Dynamic (4D) CT in the Detection of Scapholunate Ligament Injury. AB - Background Scapholunate (SL) interosseus ligament injuries detected at an early stage could allow the surgeon to prevent progression through the spectrum of injury that leads to instability, and eventually osteoarthritis. We contend that early instability following injury can be detected by visualizing the relative motions and distances between the involved carpal bones (scaphoid and lunate) during wrist movement in vivo. The purpose of this study is to demonstrate the utility of dynamic CT (i.e., 4DCT) in diagnosing SL interosseus ligament injuries in two patients with clinical suspicion of SL interosseus ligament injury during flexion-extension (FE), radial-ulnar (RU) deviation, and dart thrower's (DT) motions. Case Description 4DCT images obtained from two individual cases were analyzed to assess the proximity between the scaphoid and lunate during wrist motion using standard image processing techniques. Proximity maps representing the distances between the scaphoid and lunate bones during each phase of wrist motion were determined. These maps provide insight into the severity of diastasis (large separation) and location of diastasis at the SL joint. The patients' proximity maps indicated dorsal diastasis and subtle uniform diastasis. Literature Review Complex musculoskeletal abnormalities, such as wrist joint instabilities, elude diagnosis during 2D fluoroscopy due to the 3D geometry of the anatomy and the inherent 3D nature of the bony kinematics. Even the most recent advances with MR arthrography lack good correlation with wrist arthroscopy. Wrist arthroscopy remains the gold standard for diagnosis to assess for intercarpal laxity. However, arthroscopy is an invasive procedure subjecting patients to the risk of infection, nerve injury, pain, and stiffness. Clinical Relevance 4DCT allows noninvasive characterization of where ligament injuries likely occur; this may allow for a more selective surgical treatment directed at the specific location of the tear. PMID- 27777824 TI - The Course of the Terminal Posterior Interosseous Nerve and Its Relationship with Wrist Arthroscopy Portals. AB - Purpose The terminal branches of the posterior interosseous nerve (PIN) are the main articular branch on the dorsal aspect of the wrist. Its relationship to dorsal wrist arthroscopic portals has not yet been elucidated. The purpose of this study was to quantitatively describe the anatomical relationships between the dorsal wrist arthroscopic portals and the PIN. Methods Dorsal wrist arthroscopic portals were established in 28 cadaver extremities, after which the limbs were dissected. Measurements were taken from the portals to the PIN. Results The PIN passed ulnar to the 3/4 portal with a mean distance of 4.8 mm (range: 1.2-12.0, standard deviation [SD] = 2.6). The PIN passed radial to the 4/5 portal with a mean interval of 9.0 mm (range: 3.8-12.7, SD = 2.3). The main trunk of PIN or its closest terminal branch was a mean of 7.2 mm (range: 0.0-13.2 mm, SD = 3.1) radial to the midcarpal radial (MCR) portal. In 2 of the 28 specimens, one terminal branch of PIN lay directly over this portal. The distance between the midcarpal ulnar (MCU) portal and the PIN or its closest terminal branch was only a mean of 1.6 mm (range: 0-6.4 mm, SD = 2.0). In 15 of the 28 specimens, the PIN lay directly over the MCU portal, or the portal was located between the terminal branches of PIN. Conclusion The MCU portal was the most precarious, due to the close proximity of PIN and its terminal branches. The 3/4 and MCR portals were also at risk, while the 4/5 portal was relatively safe for the PIN. PMID- 27777826 TI - Lunate Fragments in Unstable Scaphoid Nonunion Wrists: Affect or Effect? PMID- 27777825 TI - Complications of Wrist Arthroscopy: A Multicenter Study Based on 10,107 Arthroscopies. AB - Background Wrist arthroscopy is now a routine procedure, regarded as safe. Complications are reported in the literature as being rare and mostly minor. Purpose The two goals of this study were to evaluate the incidence and nature of complications based on a very large multicenter retrospective study, and to investigate about a potential learning curve. Methods The authors sent a detailed questionnaire to all members of the European Wrist Arthroscopy Society (EWAS), inquiring about the number and types of complications encountered during their practice of wrist arthroscopy, and about their experience with the technique. Results A total of 36 series comprising 10,107 wrist arthroscopies were included in the study. There were 605 complications (5.98% of the cases), of which 5.07% were listed as serious and 0.91% as minor. The most frequent ones were failure to achieve the procedure (1.16%), and nerve lesions (1.17%). Cartilage lesions and complex regional pain syndrome each occurred in 0.50% cases. Other complications (wrist stiffness, loose bodies, hematomas, tendon lacerations) were less frequent. Breaking down of the data according to each surgeon's experience of the technique showed a significant relationship with the rate of complications, the threshold for a lower complication rate being approximately 25 arthroscopies a year and/or greater than 5 years of experience. Conclusion Although the global incidence of complications was in keeping with the literature, the incidence of serious complications was much higher than previously reported. There is a significant learning curve with the technique of wrist arthroscopy, both in terms of volume and experience. PMID- 27777827 TI - Quantitative Evaluation of Microdistortions in Bowman's Layer and Corneal Deformation after Small Incision Lenticule Extraction. AB - PURPOSE: To quantitatively evaluate microdistortions in Bowman's layer and change in corneal stiffness after small incision lenticule extraction (SMILE). METHODS: This was a prospective, longitudinal, and interventional study. Thirty eyes of 30 patients were screened preoperatively and underwent SMILE for treatment of myopia with astigmatism. Visual acuity, refraction, optical coherence tomography (OCT; Bioptigen, Inc., Morrisville, NC) imaging of the layer and air-puff applanation (Corvis-ST, OCULUS Optikgerate Gmbh, Germany) was performed before and after surgery (1 day, 1 week, and 1 month). The Bowman's Roughness Index (BRI) was defined as the enclosed area between the actual and an ideal smooth layer to quantify the microdistortions. A viscoelastic model was used to quantify the change in corneal stiffness using applanation. RESULTS: Uncorrected distance visual acuity improved (P < 0.001) and refractive error decreased (P < 0.0001) after SMILE. BRI increased from preoperative levels (1.81 * 10-3 mm2) to 1 week (3.14 * 10-3 mm2) after SMILE (P < 0.05) and then decreased up to a month (2.43 * 10-3 mm2; P < 0.05). Increase in the magnitude of the index correlated positively with refractive error (P = 0.02). However, corneal stiffness reduced after SMILE (105.86 +/- 1.4 N/m versus 97.97 +/- 1.21 N/m at 1 month, P = 0.001). The decrease in corneal stiffness did not correlate with refractive error (P = 0.61). CONCLUSIONS: BRI correlated positively the magnitude of refractive error. However, decrease in corneal stiffness, assessed by air-puff applanation, may not be related to microdistortions after SMILE. TRANSLATIONAL RELEVANCE: An objective method of quantification of Bowman's layer microdistortions using OCT was developed to monitor corneal wound healing and improve lenticule extraction methods. PMID- 27777828 TI - Psychophysical Vision Simulation of Diffractive Bifocal and Trifocal Intraocular Lenses. AB - PURPOSE: The visual performance of monofocal, bifocal, and trifocal intraocular lenses was evaluated by human individuals using a vision simulator device. This allowed investigation of the visual impression after cataract surgery, without the need actually to implant the lenses. METHODS: The randomized, double-masked, three-way cross-over study was conducted on 60 healthy male and female subjects aged between 18 and 35 years. Visual acuity (Early Treatment Diabetic Retinopathy Study; ETDRS) and contrast sensitivity tests (Pelli-Robson) under different lighting conditions (luminosities from 0.14-55 cd/m2, mesopic to photopic) were performed at different distances. RESULTS: Visual acuity tests showed no difference for corrected distance visual acuity data of bi- and trifocal lens prototypes (P = 0.851), but better results for the trifocal than for the bifocal lenses at distance corrected intermediate (P = 0.021) and distance corrected near visual acuity (P = 0.044). Contrast sensitivity showed no differences between bifocal and trifocal lenses at the distant (P = 0.984) and at the near position (P = 0.925), but better results for the trifocal lens at the intermediate position (P = 0.043). Visual acuity and contrast sensitivity showed a strong dependence on luminosity (P < 0.001). CONCLUSIONS: At all investigated distances and all lighting conditions, the trifocal lens prototype often performed better, but never worse than the bifocal lens prototype. TRANSLATIONAL RELEVANCE: The vision simulator can fill the gap between preclinical lens development and implantation studies by providing information of the perceived vision quality after cataract surgery without implantation. This can reduce implantation risks and promotes the development of new lens concepts due to the cost effective test procedure. PMID- 27777829 TI - Non-Invasive Neuromodulation Using Time-Varying Caloric Vestibular Stimulation. AB - Caloric vestibular stimulation (CVS) to elicit the vestibulo-ocular reflex has long been used in clinical settings to aid in the diagnosis of balance disorders and to confirm the absence of brainstem function. While a number of studies have hinted at the potential therapeutic applications of CVS, the limitations of existing devices have frustrated that potential. Current CVS irrigators use water or air during short-duration applications; however, this approach is not tenable for longer duration therapeutic protocols or home use. Here, we describe a solid state CVS device we developed in order to address these limitations. This device delivers tightly controlled time-varying thermal waveforms, which can be programmed through an external control unit. It contains several safety features, which limit patients to the prescribed waveform and prevent the potential for temperature extremes. In this paper, we provide evidence that CVS treatment with time-varying, but not constant temperature waveforms, elicits changes in cerebral blood flow physiology consistent with the neuromodulation of brainstem centers, and we present results from a small pilot study, which demonstrate that the CVS can safely and feasibly be used longitudinally in the home setting to treat episodic migraine. Together, these results indicate that this solid-state CVS device may be a viable tool for non-invasive neuromodulation. PMID- 27777832 TI - Spotlights on our sister journals: ChemistryOpen 5/2016. PMID- 27777831 TI - Acid-Responsive Absorption and Emission of 5-N-Arylaminothiazoles: Emission of White Light from a Single Fluorescent Dye and a Lewis Acid. AB - The front cover artwork is provided by the group of Toshiaki Murai at Gifu University (Japan). The image shows structures of the key compounds and the change of the fluorescence. Although electron-donating and -accepting groups are not in the same plane, they show relatively strong fluorescence from blue to orange. For more details, read the full text of the Communication at 10.1002/open.201600059. PMID- 27777834 TI - Acid-Responsive Absorption and Emission of 5-N-Arylaminothiazoles: Emission of White Light from a Single Fluorescent Dye and a Lewis Acid. AB - Solutions of 5-N-arylaminothiazoles containing pyridyl groups exhibited clear halochromism and halofluorism upon addition of Bronsted and Lewis acids. The addition of triflic acid to solutions of 5-N-arylaminothiazoles in Et2O induced bathochromic shifts of the absorption and emission bands. DFT calculations suggested that the spectral changes arise from the protonation of the pyridyl group of the thiazoles in Et2O. Single-crystal X-ray diffraction analysis of a thiazole and its protonated form revealed the change of the conformation around the thiazole ring. The emission of white light was accomplished from a single fluorescent dye by adjusting the ratio of dye and B(C6F5)3, whereby the International Commission on Illumination coordinates showed a linear change from blue to orange. PMID- 27777835 TI - Induction of an Infinite Periodic Minimal Surface by Endowing An Amphiphilic Zwitterion with Halogen-Bond Ability. AB - We have designed an amphiphilic zwitterion with an iodine-substituted imidazolium cation. Although it forms a layered assembly with flat interfaces, the addition of an equimolar amount of bis(trifluoromethane)sulfonimide results in the formation of a bicontinuous cubic liquid-crystalline assembly with a primitive type infinite periodic minimal surface, where its zwitterionic headgroup sits regularly. IR measurements revealed that halogen bond between the iodine atoms on the imidazolium cation and the anions is involved in its molecular-assembly behavior. The present results clearly indicate the potential utility of halogen bonding to control the dimensionality and continuity of the ionic/nonionic interface of amphiphiles in bulk and consequent mesophase patterns, which may be a significant new molecular technology for precisely arranging functional molecules on a 3D continuous interfaces. PMID- 27777836 TI - Affinity Capturing and Surface Enrichment of a Membrane Protein Embedded in a Continuous Supported Lipid Bilayer. AB - Investigations of ligand-binding kinetics to membrane proteins are hampered by their poor stability and low expression levels, which often translates into sensitivity-related limitations impaired by low signal-to-noise ratios. Inspired by affinity capturing of water-soluble proteins, which utilizes water as the mobile phase, we demonstrate affinity capturing and local enrichment of membrane proteins by using a fluid lipid bilayer as the mobile phase. Specific membrane protein capturing and enrichment in a microfluidic channel was accomplished by immobilizing a synthesized trivalent nitrilotriacetic acid (tris-NTA)-biotin conjugate. A polymer-supported lipid bilayer containing His6-tagged beta secretase (BACE) was subsequently laterally moved over the capture region by using a hydrodynamic flow. Specific enrichment of His6-BACE in the Ni2+-NTA modified region of the substrate resulted in a stationary three-fold increase in surface coverage, and an accompanied increase in ligand-binding response. PMID- 27777837 TI - Synthesis of Functional Fluorescent BODIPY-based Dyes through Electrophilic Aromatic Substitution: Straightforward Approach towards Customized Fluorescent Probes. AB - Fluorescent materials are widely used in biological and material applications as probes for imaging or sensing; however, their customization is usually complicated without the support of an organic chemistry laboratory. Here, we present a straightforward method for the customization of BODIPY cores, which are among the most commonly used fluorescent probes. The method is based on the formation of a new C-C bond through Friedel-Crafts electrophilic aromatic substitution carried out at room temperature. The method presented can be used to obtain completely customized fluorescent materials in one or two steps from commercially available compounds. Examples of the preparation of fluorescent materials for cell staining and functionalization of silica colloids are also presented. PMID- 27777838 TI - Elucidation of the Enantiodiscrimination Properties of a Nonracemic Chiral Alignment Medium through Gel-based Capillary Electrochromatography: Separation of the Mefloquine Stereoisomers. AB - Enantiodiscrimination and enantioseparation are two highly important processes in chemistry, often performed by using NMR spectroscopy and chromatography. For a better understanding of the mechanistic details, the same system should be studied by both methods. In addition, isotropic and anisotropic NMR parameters should be obtained, the latter using alignment media so that residual dipolar couplings and chemical-shift anisotropies can be measured. Consequently, a chiral alignment medium was used for the first time in chiral gel-based capillary electrochromatography with the four stereoisomers of the antimalaria drug mefloquine as test compounds. Chromatographic data verify that enantiodiscrimination obtained with this alignment gel is caused by differences in the equilibrium constants related to associate formation. Hence, the chromatographic separation provides physicochemical data that form a basis for the understanding and optimization of alignment processes, and vice versa. PMID- 27777833 TI - Chemical O-Glycosylations: An Overview. AB - The development of glycobiology relies on the sources of particular oligosaccharides in their purest forms. As the isolation of the oligosaccharide structures from natural sources is not a reliable option for providing samples with homogeneity, chemical means become pertinent. The growing demand for diverse oligosaccharide structures has prompted the advancement of chemical strategies to stitch sugar molecules with precise stereo- and regioselectivity through the formation of glycosidic bonds. This Review will focus on the key developments towards chemical O-glycosylations in the current century. Synthesis of novel glycosyl donors and acceptors and their unique activation for successful glycosylation are discussed. This Review concludes with a summary of recent developments and comments on future prospects. PMID- 27777839 TI - Ionic Liquid Solvation versus Catalysis: Computational Insight from a Multisubstituted Imidazole Synthesis in [Et2NH2][HSO4]. AB - The mechanisms of a tetrasubstituted imidazole [2-(2,4,5-triphenyl-1 H-imidazol-1 yl)ethan-1-ol] synthesis from benzil, benzaldehyde, ammonium acetate, and ethanolamine in [Et2NH2][HSO4] ionic liquid (IL) are studied computationally. The effects of the presence of the cationic and anionic components of the IL on transition states and intermediate structures, acting as a solvent versus as a catalyst, are determined. In IL-free medium, carbonyl hydroxylation when using a nucleophile (ammonia) proceeds with a Gibbs free energy (DeltaG?) barrier of 49.4 kcal mol-1. Cationic and anionic hydrogen-bond solute-solvent interactions with the IL decrease the barrier to 35.8 kcal mol-1. [Et2NH2][HSO4] incorporation in the reaction changes the nature of the transition states and decreases the energy barriers dramatically, creating a catalytic effect. For example, carbonyl hydroxylation proceeds via two transition states, first proton donation to the carbonyl (DeltaG?=9.2 kcal mol-1) from [Et2NH2]+, and then deprotonation of ammonia (DeltaG?=14.3) via Et2NH. Likewise, incorporation of the anion component [HSO4]- of the IL gives comparable activation energies along the same reaction route and the lowest transition state for the product formation step. We propose a dual catalytic IL effect for the mechanism of imidazole formation. The computations demonstrate a clear distinction between IL solvent effects on the reaction and IL catalysis. PMID- 27777840 TI - Mechanistic Investigation into Olefin Epoxidation with H2O2 Catalyzed by Aqua Coordinated Sandwich-Type Polyoxometalates: Role of the Noble Metal and Active Oxygen Position. AB - Aqua-coordinated sandwich-type polyoxometalates (POMs), {[WZnTM2(H2O)2](ZnW9O34)2} n- (TM=RhIII, PdII, and PtII), catalyze olefin epoxidation with hydrogen peroxide and have been well established, and they present an advance toward the utilization of olefins. To elucidate the epoxidation mechanism, we systematically performed density functional calculations. The reaction proceeds through a two-step mechanism: activation of H2O2 and oxygen transfer. The aqua-coordinated complexes show two distinct H2O2 activation pathways: "two-step" and "concerted". The concerted processes are more facile and proceed with similar and rate-determining energy barriers at the Rh-, Pd-, and Pt-containing transition states, which agrees well with the experimental results. Next, the resulting TM-OH-(MU-OOH) intermediate transfers an O atom to olefin to form an epoxide. The higher reactivity of the Rh-containing POM is attributed to more interactions between the Rh and hydroperoxo unit. We also calculated all active oxygen positions to locate the most favorable pathway. The higher reactivity of the two-metal-bonded oxygen position is predominantly ascribed to its lower stereoscopic hindrance. Furthermore, the presence of one and two explicit water solvent molecules significantly reduces the energy barriers, making these sandwich POMs very efficient for the olefin epoxidation with H2O2. PMID- 27777841 TI - Synthesis of a New Series of Sialylated Homo- and Heterovalent Glycoclusters by using Orthogonal Ligations. AB - The synthesis of heteroglycoclusters (hGCs) is being subjected to rising interest, owing to their potential applications in glycobiology. In this paper, we report an efficient and straightforward convergent protocol based on orthogonal chemoselective ligations to prepare structurally well-defined cyclopeptide-based homo- and heterovalent glycoconjugates displaying 5-N-acetyl neuraminic acid (Neu5Ac), galactose (Gal), and/or N-acetyl glucosamine (GlcNAc). We first used copper-catalyzed azide-alkyne cycloaddition and/or thiol-ene coupling to conjugate propargylated alpha-sialic acid 3, beta-GlcNAc thiol 5, and beta-Gal thiol 6 onto cyclopeptide scaffolds 7-9 to prepare tetravalent homoglycoclusters (10-12) and hGCs (13-14) with 2:2 combinations of sugars. In addition, we have demonstrated that 1,2-diethoxycyclobutene-3,4-dione can be used as a bivalent linker to prepare various octavalent hGCs (16, 19, and 20) in a controlled manner from these tetravalent structures. PMID- 27777842 TI - Regioselective Synthesis of a Family of beta-Lactams Bearing a Triazole Moiety as Potential Apoptosis Inhibitors. AB - Apoptosis is a biological process important to several human diseases; it is strongly regulated through protein-protein interactions and complex formation. We previously reported the synthesis of apoptosis inhibitors bearing an exocyclic triazole amide isoster by using an Ugi four-component coupling reaction (Ugi 4CC), followed by a base-promoted intramolecular cyclization. Depending on the substitution patterns and the reaction conditions, this cyclization forms the six or four-membered ring. Two compounds bearing the beta-lactam scaffold turned out to be the most potent inhibitors. This encouraged us to optimize the modulation of the cyclization, and prepare a library of 15 beta-lactams with total regioselectivity. Moreover, we aimed to improve the bioavailability of these compounds through the introduction of diversity at different substitution positions. The activity of these compounds as apoptosis inhibitors in cellular extracts has been evaluated, showing an increase in their potency. PMID- 27777843 TI - Catalytic Degradation of Benzene over Nanocatalysts containing Cerium and Manganese. AB - A Ce-Mn composite oxide possessing a rod-like morphology (with a fixed molar ratio of Ce/Mn=3:7) was synthesized through a hydrothermal method. Mn ions were doped into a CeO2 framework to replace Ce ions, thereby increasing the concentration of oxygen vacancies. The formation energies of O vacancies for the Ce-Mn composite oxide were calculated by applying density functional theory (DFT). The data showed that it was easier to form an O vacancy in the composite. The catalytic behavior of the Ce-Mn composite oxide for benzene degradation was researched in detail, which exhibited a higher activity than the pure phases. Based on this, the Ce-Mn composite oxide was chosen as a supporter to load PdO nanoparticles. The activity was enhanced further compared with that of the supporter alone (for the supporter, the reaction rate R214 degrees C=0.68*10-4 mol gcat-1 s-1 and apparent activation energy Ea=12.75 kJ mol-1; for the supporting catalyst, R214 degrees C=1.46*10-4 mol gcat-1 s-1, Ea=10.91 kJ mol 1). The corresponding catalytic mechanism was studied through in situ Raman and FTIR spectroscopy, which indicated that the process of benzene oxidation was related to different types of oxygen species existing at the surface of the catalysts. PMID- 27777845 TI - Aggregation operators of neutrosophic linguistic numbers for multiple attribute group decision making. AB - Based on the concept of neutrosophic linguistic numbers (NLNs) in symbolic neutrosophic theory presented by Smarandache in 2015, the paper firstly proposes basic operational laws of NLNs and the expected value of a NLN to rank NLNs. Then, we propose the NLN weighted arithmetic average (NLNWAA) and NLN weighted geometric average (NLNWGA) operators and discuss their properties. Further, we establish a multiple attribute group decision-making (MAGDM) method by using the NLNWAA and NLNWGA operators under NLN environment. Finally, an illustrative example on a decision-making problem of manufacturing alternatives in the flexible manufacturing system is given to show the application of the proposed MAGDM method. PMID- 27777846 TI - The impact of women's education, workforce experience, and the One Child Policy on fertility in China: a census study in Guangdong, China. AB - The impact of women's education on fertility is of interest to researchers, particularly in China. However, few studies have provided well-founded assessments of how women's education, workforce experience, and birth control policy jointly affect fertility in China. This study, conducted in Guangdong Province, aimed to analyze how these three factors influenced the timing of births and affected women at different stages of their reproductive lives. We used census data for Guangdong Province (1990, 2000, and 2010) to make cross sectional age-specific comparisons to examine the effects of women's education and workforce participation on fertility outcomes under China's One Child Policy. We found that: (1) under circumstances of low fertility, women tend to have more children with greater educational attainment; (2) the impact of women's education and workforce experience on fertility varied across age groups, with the effect of education showing a bimodal curve peaking at 25-29 years and 40-44 years, and a workforce experience effect at 25-34 years; and (3) the fertility time-squeeze effect by educational attainment was relatively small, the effect by workforce participation was larger, and the most important effect was birth control policy and its implementation. These results suggest that educational attainment and workforce experience have a substantial effect on women's fertility, and a tradeoff between them is unavoidable. China's 2015 birth control policy adjustment should be considered in planning future services to accommodate anticipated increases in the birth rate. More attention should be directed to the causal mechanism (women's preference and selection effects) behind the factors analyzed in this study. PMID- 27777847 TI - Jacobi spectral collocation method for the approximate solution of multidimensional nonlinear Volterra integral equation. AB - We present in this paper the convergence properties of Jacobi spectral collocation method when used to approximate the solution of multidimensional nonlinear Volterra integral equation. The solution is sufficiently smooth while the source function and the kernel function are smooth. We choose the Jacobi Gauss points associated with the multidimensional Jacobi weight function [Formula: see text] (d denotes the space dimensions) as the collocation points. The error analysis in [Formula: see text]-norm and [Formula: see text]-norm theoretically justifies the exponential convergence of spectral collocation method in multidimensional space. We give two numerical examples in order to illustrate the validity of the proposed Jacobi spectral collocation method. PMID- 27777848 TI - Antibacterial and antioxidant activity of Portuguese Lavandula luisieri (Rozeira) Rivas-Martinez and its relation with their chemical composition. AB - Lavandula luisieri (Rozeira) Rivas-Martinez is an endemic aromatic Labiatae the Iberian Peninsula, common in semi-arid regions of southern Portugal and southwestern Spain, that produces an active antibacterial essential oil from the leaves and flowers. This work presents the study of the chemical variation in various stages of growth of leaves and flowers of L. luisieri. It has been found that the essential oils are mainly constituted by 1,8-cineol, camphor, linalool and trans-alpha-necrodil acetate. It was also studied the total phenol content and the antioxidant activity on leaves and flowers. The ethanol extraction from de leaves contents the highest total phenol, important factor for the antioxidant activity of the plant, extract. It has been studied too, the antibacterial activity against Escherichia coli, Salmonella spp. and Staphylococcus aureus. In accordance with the obtained results, the antibacterial activities stand out against Staphylococcus, of the oil of L. luisieri (leaves and flowers). PMID- 27777849 TI - Living with idiopathic basal ganglia calcification 3: a qualitative study describing the lives and illness of people diagnosed with a rare neurological disease. AB - PURPOSE: Idiopathic basal ganglia calcification (IBGC) is a rare, intractable disease with unknown etiology. IBGC3 is a familial genetic disease defined by genetic mutations in the major causative gene (SLC20A2). People with IBGC3 experience distress from the uncommon nature of their illness and uncertainty about treatment and prognoses. The present study aimed to describe the lives and illness of people with IBGC3. METHODS: Participants were recruited from patients aged 20 years or older enrolled in a genetic study, who were diagnosed with IBGC3 and wanted to share their experiences. In-depth semi-structured interviews were conducted with six participants. Interviews were conducted between December 2012 and February 2014, and were recorded and transcribed verbatim. Qualitative data analysis was performed to identify categories and subcategories. Efforts were made to ensure the credibility, transferability, dependability, conformability, and validity of the data. RESULTS: Six thematic categories, 17 subcategories, and 143 codes emerged. The six categories were: (1) Frustration and anxiety with progression of symptoms without a diagnosis; (2) Confusion about diagnosis with an unfamiliar disease; (3) Emotional distress caused by a genetic disease; (4) Passive attitude toward life, being extra careful; (5) Taking charge of life, becoming active and engaged; and (6) Requests for healthcare. CONCLUSIONS: The qualitative data analysis indicated a need for genetic counseling, access to disease information, establishment of peer and family support systems, mental health services, and improvement in early intervention and treatment for the disease. PMID- 27777850 TI - Blind image quality assessment via probabilistic latent semantic analysis. AB - We propose a blind image quality assessment that is highly unsupervised and training free. The new method is based on the hypothesis that the effect caused by distortion can be expressed by certain latent characteristics. Combined with probabilistic latent semantic analysis, the latent characteristics can be discovered by applying a topic model over a visual word dictionary. Four distortion-affected features are extracted to form the visual words in the dictionary: (1) the block-based local histogram; (2) the block-based local mean value; (3) the mean value of contrast within a block; (4) the variance of contrast within a block. Based on the dictionary, the latent topics in the images can be discovered. The discrepancy between the frequency of the topics in an unfamiliar image and a large number of pristine images is applied to measure the image quality. Experimental results for four open databases show that the newly proposed method correlates well with human subjective judgments of diversely distorted images. PMID- 27777851 TI - Several types of groupoids induced by two-variable functions. AB - In this paper, we introduce the concept of several types of groupoids related to semigroups, viz., twisted semigroups for which twisted versions of the associative law hold. Thus, if [Formula: see text] is a groupoid and if [Formula: see text] is a function [Formula: see text], then [Formula: see text] is a left twisted semigroup with respect to [Formula: see text] if for all [Formula: see text], [Formula: see text]. Other types are right-twisted, middle-twisted and their duals, a dual left-twisted semigroup obeying the rule [Formula: see text] for all [Formula: see text]. Besides a number of examples and a discussion of homomorphisms, a class of groupoids of interest is the class of groupoids defined over a field [Formula: see text] via a formula [Formula: see text], with [Formula: see text], fixed structure constants. Properties of these groupoids as twisted semigroups are discussed with several results of interest obtained, e.g., that in this setting simultaneous left-twistedness and right-twistedness of [Formula: see text] implies the fact that [Formula: see text] is a semigroup. PMID- 27777853 TI - Callogenesis and cell suspension establishment of tropical highland blackberry (Rubus adenotrichos Schltdl.) and its microscopic analysis. AB - Blackberries are fruits produced worldwide, with 25 % of their production centered in Mexico, Central and South America. Tropical highland blackberry is a fruit that can potentially enhance human health, due to their high content in phenolic compounds, which include anthocyanins, phenolic acids, tannins (gallotannins and elagitannins) and flavonoids. Therefore, the overall aim of this study is the development of a callus induction protocol, the establishment of blackberry cell suspensions (Rubus adenotrichos Schltdl.) and their cell analysis through optical microscopy and TEM, for the potential production of phenolic compounds. In order to produce callogenesis, segments of blackberry leaves were disinfected and placed in different concentrations of 2,4-D and the control media (0; 0.5; 1.0; 1.5; 2.0; 2.5 and 3.0 mg/l of 2,4-D); obtaining the higher size of calli in the medium with 1.5 mg/l of 2,4-D. After this determination, and for this specific treatment, a growth curve was performed through the use of fresh and dry weight parameters, in order to identify each of the growth stages. Furthermore, the calli obtained from the 1.5 mg/l of 2,4-D treatment were placed in two different culture media (MS and MS supplemented with 1.5 mg/l of 2,4-D) in order to establish the cell suspensions and the growth curve. To the best treatment, the total polyphenols were also quantified. It was determined that the MS medium is ideal for the growth and disintegration of the cell suspensions, obtaining 0.0256 mg of gallic acid/g of fresh sample. Finally, a cell callus and cell suspension analysis was performed through OM and TEM, evidencing a higher hystological differentiation in the calli, as well as the observation of antioxidant storage in the plastids. PMID- 27777852 TI - Endobronchial ultrasound versus conventional transbronchial needle aspiration in the diagnosis of mediastinal lymphadenopathy: a meta-analysis. AB - Currently, whether endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is superior to conventional TBNA (cTBNA) in the diagnosis of mediastinal lymphadenopathy remains controversial. We undertook a meta analysis of randomized controlled trials (RCTs) to evaluate the diagnostic yield of EBUS-TBNA versus cTBNA in the diagnosis of mediastinal lymphadenopathy, both in benign and malignant etiologies. Computer-based retrieval was performed on PubMed and EMBASE. The quality was evaluated according to the quality assessment of diagnostic accuracy studies-2, and Meta-Disc was adopted to perform meta analysis. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with 95 % confidence intervals (CIs) were calculated. The summary receiving operating characteristic curve as well as the areas under curve (AUC) was measured. Four studies with a total of 440 patients met the inclusion criteria. Our results showed that the pooled sensitivity was 0.90 (95 % CI 0.85-0.94) and 0.76 (95 % CI 0.68-0.82), pooled specificity was 0.75 (95 % CI 0.60-0.87) and 0.94 (95 % CI 0.86-0.98), DOR was 75.38 (95 % CI 16.38-346.97) and 108.17 (95 % CI 13.84-845.35), and AUC was 0.9339 and 0.9732 for EBUS-TBNA group and cTBNA group, respectively. Although EBUS-TBNA with a higher sensitivity performs better than cTBNA, there is lack of enough evidence regarding EBUS-TBNA being superior to cTBNA in the diagnosis of mediastinal lymphadenopathy. Considering the limitations of methodology and limited data, further robust RCTs are needed to verify the current findings and investigate the optimal choice in patients receiving TBNA. PMID- 27777854 TI - Multimodal approach to rehabilitation of the patients with lateral epicondylosis: a case series. AB - PURPOSE: The objective of this study was to evaluate the effectiveness of mobilization with movement and kinesiotherapy in the treatment of patients with lateral epicondylosis. METHODS: This cases series included eight volunteers who had chronic lateral epicondylosis. The patients were treated with stretching, massage deep transverse at the lateral epicondyle and mobilization with movement associated with eccentric exercise. The mobilization with movement that consisted of a force of lateral glide of the proximal forearm. We performed twelve sessions, twice a week for 45 min/session. All patients underwent an evaluation with a visual analog scale and functional assessment through questionnaires patient-rated tennis elbow evaluation (PRTEE) and disabilities of the arm, shoulder and hand (DASH), before and after the treatment. Data were analyzed by student's t test (p < 0.05). RESULTS: The results showed statistical differences in pain symptoms before and after treatment, in the analysis and functional assessment through both questionnaires comparing the pre and post treatment. CONCLUSION: The data obtained in this study demonstrates improvement of the function and pain status of the sample investigated. PMID- 27777856 TI - To be objective in Experimental Phenomenology: a Psychophysics application. AB - BACKGROUND: Several scientific psychologists consider the approach for the study of perceptive problems of the Experimental Phenomenology is problematic, namely that the phenomenological demonstrations are subjectively based and they do not produce quantifiable results. AIM: The aim of this study is to show that Experimental Phenomenology can lead to conclusions objective and quantifiable and propose a procedure allowing to obtain objective measuring using the Rasch mathematical model able to describe the experimental data gathered in Experimental Phenomenology procedures. METHOD: In order to demonstrate this, a Psychophysics simulated study is proposed. RESULTS/CONCLUSIONS: It is possible to carry out a fundamental measurement starting from Experimental Phenomenology by way of the Theory of Conjoint Measurement. PMID- 27777855 TI - Telbivudine for the treatment of chronic hepatitis B in HBeAg-positive patients in China: a health economic analysis. AB - BACKGROUND: Nucleos(t)ide analogs (NUCs) are the standard of care for chronic hepatitis B (CHB). The present analysis aimed to determine the cost effectiveness of NUCs in Chinese healthcare settings. METHODS: A Markov model was used to simulate two therapeutic strategies for a hypothetical patient cohort diagnosed with hepatitis B e antigen-positive CHB, unwilling or unable to receive interferon therapy, and about to start treatment with any NUC. The first strategy included NUC monotherapy without sequencing (telbivudine [LDT], entecavir [ETV], tenofovir [TDF], lamivudine [LAM], adefovir dipivoxil [ADV], and combination therapies of either LDT and ADV or LDT and TDF, followed by best supportive care [BSC]). The second strategy included sequential therapies of individual NUCs: LAM -> ADV, ADV -> LAM, LDT -> ADV, and ETV -> ADV, followed by BSC. The analysis included two scenarios: with and without costs due to nephrotoxicity. Renal impact was quantified as costs alone, without consideration for quality of life decrements. RESULTS: When renal impact was not considered, without treatment sequencing, LDT was cost effective compared with other NUCs. Amongst the strategies with sequencing, LDT -> ADV was cost effective. The results were similar when renal impact was considered. However, LDT strategy demonstrated better cost effectiveness. In probabilistic sensitivity analysis, in both scenarios, LDT -> ADV sequence was cost effective with 51 % probability even at willingness to pay of $20,000. CONCLUSION: Use of LDT, as compared with other NUCs, is cost effective in CHB treatment in Chinese healthcare settings. Considering the detrimental renal impact, overall costs for all treatment options were increased. However, the increase for LDT was comparatively small. PMID- 27777857 TI - Long noncoding RNA MALAT1 can serve as a valuable biomarker for prognosis and lymph node metastasis in various cancers: a meta-analysis. AB - BACKGROUND: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a newly discovered long intergenic noncoding RNA (lincRNA), has been reported to be aberrantly expressed in various cancers, and may serve as a novel potential biomarker for cancer prognosis. This meta-analysis was conducted to investigate the effects of MALAT1 on cancer prognosis and lymph node metastasis. METHODS: A quantitative meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science databases to identify eligible papers on prognostic value of MALAT1 in cancers. The pooled hazard ratios (HRs) or odds ratios (OR) with a 95 % confidence interval (95 % Cl) were calculated to evaluate its prognostic value. RESULTS: A total of 2094 patients from 17 studies between 2003 and 2016 were included. The results revealed that elevated MALAT1 expression was significantly associated with poor overall survival (OS) in 11 types of cancers (HR = 1.91, 95 % CI 1.49-2.34). Furthermore, subgroup analysis indicated that region of study (Germany, Japan or China), cancer type (digestive system cancers, urinary system cancers or respiratory system cancers) and sample size (more or less than 100) did not alter the significant predictive value of MALAT1 in OS from various types of cancer. In addition, upregulation of MALAT1 expression was significantly associated with poor disease-free survival (HR = 2.29, 95 % CI 1.24 3.35), and recurrence-free survival (HR = 2.09, 95 % CI 0.81-3.37). The results showed that the incidence of lymph node metastasis was higher in high MALAT1 expression group than that in low MALAT1 expression group (OR = 1.67, 95 % CI 1.30-2.15). CONCLUSIONS: This meta-analysis revealed that elevated MALAT1 expression may serve as a novel predictive biomarker for poor survival and lymph node metastasis in different types of cancer. PMID- 27777859 TI - A new multi-step technique with differential transform method for analytical solution of some nonlinear variable delay differential equations. AB - This work presents an analytical solution of some nonlinear delay differential equations (DDEs) with variable delays. Such DDEs are difficult to treat numerically and cannot be solved by existing general purpose codes. A new method of steps combined with the differential transform method (DTM) is proposed as a powerful tool to solve these DDEs. This method reduces the DDEs to ordinary differential equations that are then solved by the DTM. Furthermore, we show that the solutions can be improved by Laplace-Pade resummation method. Two examples are presented to show the efficiency of the proposed technique. The main advantage of this technique is that it possesses a simple procedure based on a few straight forward steps and can be combined with any analytical method, other than the DTM, like the homotopy perturbation method. PMID- 27777858 TI - Meta-analysis of randomized clinical trials comparing fistulectomy versus fistulotomy for low anal fistula. AB - OBJECTIVE: We evaluated the efficacy of fistulectomy compared to fistulotomy, and which procedure was the best procedure for patients with low anal fistula. METHODS: The literature search included PubMed, EMBASE, Cochrane library, Google original studies and a manual search of reference on the topic of fistulectomy compared to fistulotomy for anal fistula that had a deadline for publication by June 2016. Randomized controlled trials studies were included in the review. The outcome variables were analyzed which including operative time, healing time, postoperative complications, recurrence and incontinence. RESULTS: Six randomized controlled trials (fistulectomy = 280, fistulotomy = 285) were considered suitable for the meta-analysis, with a total of 565 patients. The result of meta analysis indicated no statistically significant difference in operative time [OR 4.74, 95 % CI -2.74, 12.23, p = 0.21] and healing time [OR -3.32, 95 % CI -19.86, 13.23, p = 0.69] between the fistulectomy and fistulotomy procedures. Three main postoperative complications were included, and the combined result indicated no statistically significant difference in overall complications [OR 1.39, 95 % CI 0.51, 3.78, p = 0.52] and subgroup complication. At the end of follow up, two kinds of surgical methods have the same low recurrence rate and faecal incontinence. The result revealed that there was no significant difference in rate of fistula recurrence between the fistulectomy and the fistulotomy [OR 1.39, 95 % CI 0.70, 2.73, p = 0.34]. CONCLUSION: The meta-analysis indicates that there is no conclusive evidence if fistulectomy or fistulotomy procedure is better in the treatment of low anal fistula. PMID- 27777860 TI - The study of statistical methods for evaluating the comparability of routine chemistry analytes among 3 routine laboratory measurement systems in China. AB - BACKGROUND: Clinical laboratory tests are important for clinicians to make diagnostic decisions, but discrepancies may directly lead to incorrect diagnosis. We would like to introduce some statistical methods to evaluate the comparability of chemistry analytes while comparing the performances of different measurement systems. METHODS: We used a panel of 10 fresh-frozen single donation serum samples to assess assays for the measurement of glucose and other 13 analytes. Statistical methods used in this article include traditional statistical analysis, robust statistics, regression analysis and differences on medical decision levels (MDL). All the statistical analysis results would be evaluated. 20 Chinese tertiary hospitals accredited to ISO 15189 took part in this work. The commercial random access platforms included: Olympus (8 labs), Hitachi (6 labs) and Roche (6 labs). To compare the acceptable rates, Chi square test was used. RESULTS: The statistical analysis results are as follows: (1) Coefficient of variations are between 2.8 and 3.9 %, with the slopes and intercepts of regression functions between 0.928 to 1.064 and -0.174 to 0.630, respectively. (2) The percentage of robust z-scores between -2 and 2 is bigger than 90 %. (3) The total percentages of differences on all the MDLs are: less than optimal was 31.7 % (19/60); less than desirable was 60.0 % (36/60); less than minimum was 65.0 % (39/60); more than minimum was 35.0 % (21/60). In this study, 2 laboratories (Nos. 8 and 16) were considered as poor performance by z-scores. 10 laboratories (Nos. 4, 5, 7, 8, 9, 10, 11, 14, 16 and 19) have unacceptable measurement errors on MDLs. 10 laboratories (Nos. 1, 2, 3, 6, 12, 13, 15, 17, 18, 20) can achieve mutual recognition of serum glucose testing results, including: 5 (5/8) Olympus, 2 (2/6) Hitachi and 3 (3/6) Roche. There was no significant difference among acceptable rates of the three measurements systems for the serum glucose assay. CONCLUSIONS: Traditional statistical analysis, robust statistics and robust z-score, fitting linear regression equations and calculating differences on different MDLs can be used on studying the comparability and mutual recognition of clinical chemistry analytes among hospitals or laboratories in China. The mutual recognition and interchangeability of results remains jeopardized even among tertiary hospitals in China. More works and efforts should be done for improvement of the current situation of interchangeability of results in clinical laboratories in China. PMID- 27777861 TI - Syphilitic aortic aneurysm with a pulmonary lesion: a case report and literature view. AB - INTRODUCTION: Syphilitic aortic aneurysm (SAA) is caused by tertiary stage of syphilis infection. As the wide application of penicillin, this complication is becoming rarer than before. The SAA with lung cancer is a very rare disease in patient. CASE DESCRIPTION: A 55-year-old male was admitted to the hospital complaining "progressive hoarseness for 3 months" and the patient has been diagnosed with syphilis after specific blood exams, computed tomography angiography (CTA) and 3dimensional (3D) reconstructions of cardiac vessels. Chest computed tomography displayed an anomalous soft tissue mass with slightly lobular borders in the peripheral segment of the left lower lobe. According to the aneurysm's and lung neoplasm's location, several procedures could be selected such as aneurysm resection with artificial graft replacement or endovascular stenting under angiography. Then, the lesion was removed by lobectomy using video assisted thoracic surgery. DISCUSSION AND EVALUATION: Cardiovascular syphilis remains a major cause of ascending aortic aneurysm. The clinical manifestations of patients with syphilis aortic aneurysm could vary. Aortic imaging is necessary to confirm the diagnosis and to determine the anatomic extent of the aneurysm. The differential diagnosis of the lesion in the pulmonary is mostly the tumor like pulmonary lesion, Pulmonary syphilis. Some studies showed that thoracic aortic aneurysm has been reduced by using penicillin. However, penicillin therapy alone is not always sufficient in recent years. The serologic response to treatment is more significant and faster in patients treated with the enhanced regimen compared to patients treated with the standard penicillin regimen. CONCLUSIONS: Syphilitic aortic aneurysm with lung cancer is a rare disease in patient. Chest CT and CTA scans are able to indicate the presence of SAA. Pathological analysis is an effective method to clarify the diagnosis of the lung lesion. The interventional therapy and surgery are regular treatment method for SAA and pulmonary neoplasm. PMID- 27777862 TI - Availability and cost of major and first-line antiepileptic drugs: a comprehensive evaluation in the capital of Madagascar. AB - BACKGROUND: The prevalence of epilepsy is high in Madagascar (23.5/1000), as is the treatment gap (estimated at 92 %). The health system of the country is underfunded; some AEDs are used, and the national drug policy does not encourage price regulation or the administration of generic agents. We conducted a cross sectional study to assess the availability and cost of solid oral AED formulations in Antananarivo, capital of Madagascar. Data were gathered from all officially registered pharmacies (according to the drug agency list, updated in 2015) by means of telephone interviews lasting no more than 10 min and conducted by a native Malagasy speaker. With regard to other sources (hospitals, illicit sales) data were obtained at specific visits. The study received ethical approval from the Madagascar Ministry of Health. FINDINGS: A total of 91 of 100 pharmacies (the nine not included were because of an inoperative phone number), two of three public hospitals, and two illegal outlets were investigated. Sodium valproate was available in 84.6 % of the pharmacies, while carbamazepine and phenobarbital were available in 68.1 % and 36.3 % of the pharmacies, respectively, but phenytoin was not available in any supply chain. There were more originator brands than generic formulations, with a higher cost (range 20.3-81.1 %, median 40.7 %) compared to the equivalent generic. The public system had only a very limited choice of AED, but offered the lowest costs. Illicit sources were more expensive by 54.3 % for carbamazepine and 62.5 % for phenobarbital. Concerning the annual cost of treatment, the average percentage of the gross national income per capita based on the purchasing power parity was 29.8 %/19.0 % (brand/generic) for sodium valproate, 16.4 %/7.3 % (brand/generic) for carbamazepine, 8.9 %/5.1 % (brand/generic) for phenobarbital. CONCLUSIONS: The main sources of AEDs were private pharmacies, but the stocks held were low. The financial burden was still important in the capital of Madagascar, mainly the consequence of a highly developed private sector at the expense of the public sector. Although sodium valproate remains the most expensive solution, it still remains the most available instead of phenobarbital. The most striking feature of this study concerns the cost of AEDs in the informal sector, mostly used because they are deemed to provide less costly drugs, the opposite was observed there. The assessment of the cost and availability of medicines was easily and quickly implemented. It provided a relevant focus of the situation in areas difficult to investigate, in terms of road network and geographical situation. PMID- 27777863 TI - Bounds for the Z-spectral radius of nonnegative tensors. AB - In this paper, we have proposed some new upper bounds for the largest Z eigenvalue of an irreducible weakly symmetric and nonnegative tensor, which improve the known upper bounds obtained in Chang et al. (Linear Algebra Appl 438:4166-4182, 2013), Song and Qi (SIAM J Matrix Anal Appl 34:1581-1595, 2013), He and Huang (Appl Math Lett 38:110-114, 2014), Li et al. (J Comput Anal Appl 483:182-199, 2015), He (J Comput Anal Appl 20:1290-1301, 2016). PMID- 27777864 TI - Macrobrachium rosenbergii nodavirus infection in a giant freshwater prawn hatchery in Indonesia. AB - A pathogen of giant freshwater prawn, Macrobrachium rosenbergii, was recently recorded in a hatchery in Yogyakarta. The clinical symptom in post-larvae (PL) was a whitish appearance of the muscles in the tail. Histological examination revealed myonecrosis with massive infiltration of myonuclei and hemocytes. RT-PCR products of 850 bp were obtained when using RNA from diseased PL as a template. The clinical signs and RT-PCR amplicon were reproduced in M. rosenbergii inoculated with bacteria-free inocula. Electron microscopy demonstrated that the M. rosenbergii nodavirus (MrNV) was icosahedral in shape and 28.12 +/- 2.31 nm in diameter. RT-PCR products of the RNA-dependent RNA polymerase gene (RNA-1) and capsid protein gene (RNA-2) of MrNV were obtained using designed primer pairs, cloned into pBluescript-KS, and sequenced. The 1312 nucleotide (nt) sequence of MrNV RNA-1 revealed 98.0 % identity with isolates from China and India. Additionally, the 1112 nt sequence of MrNV RNA-2 displayed 98.0 % identity with isolates from China and Taiwan. Disease control efforts involving disinfection of PL, broodstocks, water media, tanks, equipment and ponds successfully eradicated white tail disease from the hatchery. This study is the first report on white tail disease and the isolation and characterization of MrNV in Indonesia. PMID- 27777865 TI - Factors associated with time provided to children for physical activity in family child care: a cross-sectional study. AB - Childhood obesity has increased in the past 30 years, and physical inactivity is a major contributor. Factors related to physical activity promotion in the family child care context are understudied. A convenience sample of participants in a mid-sized city in the Midwestern U.S. was recruited through the local child care resource and referral agency and were invited through flyers and emails to take part in an online or paper survey. Survey results in a sample of 107 family child care providers indicate that many did not meet physical activity recommendations and are missing the opportunity to enable children's physical activity via important practices and resources. Provider self-efficacy about being physically active, and indoor physical activity space positively associated with time provided for child physical activity. Health training is negatively associated with time provided for child physical activity. Practice implications include: (1) develop activities that promote physical activity in the tight confines of family child care homes and yard; (2) develop trainings that can influence the integration of suitable portable play equipment in the space constraints of family child care homes (3) Propose creative ideas for active free play even when in a shared space; (4) prioritize providing separate play areas by age group and strategize ways to do this in family child care contexts (for example, alternate access to spaces by age); (5) engage providers and children in joint activities that increase provider physical activity efficacy and physical activity time as well as that of children; (6) promote health and physical activity among family child care providers themselves. PMID- 27777866 TI - Hydrological impacts of precipitation extremes in the Huaihe River Basin, China. AB - Precipitation extremes play a key role in flooding risks over the Huaihe River Basin, which is important to understand their hydrological impacts. Based on observed daily precipitation and streamflow data from 1958 to 2009, eight precipitation indices and three streamflow indices were calculated for the study of hydrological impacts of precipitation extremes. The results indicate that the wet condition intensified in the summer wet season and the drought condition was getting worse in the autumn dry season in the later years of the past 50 years. The river basin had experienced higher heavy rainfall-related flooding risks in summer and more severe drought in autumn in the later of the period. The extreme precipitation events or consecutive heavy rain day events led to the substantial increases in streamflow extremes, which are the main causes of frequent floods in the Huaihe River Basin. The large inter-annual variation of precipitation anomalies in the upper and central Huaihe River Basin are the major contributor for the regional frequent floods and droughts. PMID- 27777868 TI - Injuries and home advantage in the NFL. AB - BACKGROUND: In the first decade of this century players in the National Football League, the NFL community, fans, even the public at large, became aware that multiple concussions, heretofore considered inconsequential, could have devastating consequences later in life. RESULTS: Since 1978, each one of the 32 teams in the NFL plays 16 games in the regular season. In the 25 years from 1978 to 2004 home advantage in the regular season tended to increase with Game Number (1-16). Then in the following decade (2005-2014) it changed direction and tended clearly to decrease. The change in direction was highly reliable statistically. DISCUSSION: The result reported in this paper is an association in time between two striking events, a new consciousness regarding the long-term consequences of concussions in football, and a change in the course of home advantage in the regular season. The paper then advances a possible explanation for this association. The home advantage may be equally well treated as an away disadvantage, the disadvantage being that away players tend to feel on the defensive, that both the hometown crowd and the officials are against them. Injuries put players on both teams on the defensive. The higher the percentage of players on a team who are injured or playing hurt (injury prevalence) the less likely it is that as-yet-uninjured players will adopt an attacking style of play. Injury prevalence increases linearly with Game Number. It turns out, however, that formal considerations require that injury prevalence be the same or close to it for teams playing at home and teams playing away. Therefore, the away disadvantage in total defensiveness (defensiveness due to playing away plus defensiveness due to injury) starts at 1 in the first game of the season, decreases steeply at first, and then decelerates as it approaches .5. This downward course of the away disadvantage in total defensiveness leads directly to a corresponding downward course of the home advantage in game outcome (by the teamwork theory of home advantage). CONCLUSIONS: Further research on the reported association or its explanation may be complicated by continued change in the association itself. PMID- 27777867 TI - Multivariate analysis and molecular interaction of curcumin with PPARgamma in high fructose diet induced insulin resistance in rats. AB - To investigate the effect of curcumin on the multivariate and docking analysis on peroxisome proliferator activated receptor-gamma, the rats were fed with high fructose diet (Group 2) to induce insulin resistance and curcumin was co administered orally (Group 4) for a period of 8 weeks and measured the biochemical parameters in blood, kidney and liver tissues. The results showed a significant (p <= 0.05) increase in the level of creatinine, glucose, insulin, low density lipoprotein, total cholesterol, triglyceride, urea, uric acid, very low density lipoprotein and decreased albumin, high density lipoprotein and total protein level in the blood of Group 2 when compared with Group 1 control rats. Further, analysis on liver and kidney tissues showed a significant decrease in antioxidants, hexokinase and increased glucose 6-phosphatase and fructose 1,6 bisphosphatase, hydroperoxides and TBARS in Group 2 rats. Furthermore, the multivariate and loading coefficient analysis showed that albumin, HDL, catalase, glutathione reductase, hexokinase and vitamin E are the most contributing factors in blood, liver and kidney. Subsequently, molecular docking was carried out to determine the binding efficiency of curcumin as agonist of PPARgamma showed high affinity compared to pioglitazone. The histology of liver and kidney were also studied and the administration of curcumin along with fructose protects the organs from the abnormal changes and also prevents the fat accumulation. Overall, these results demonstrate the preventive role of curcumin on diet induced insulin resistant in rats by ameliorating the altered levels of metabolic changes and potential binding of curcumin with PPARgamma as agonist in the treatment of insulin resistance. PMID- 27777869 TI - Applying a punch with microridges in multistage deep drawing processes. AB - The developers of high aspect ratio components aim to minimize the processing stages in deep drawing processes. This study elucidates the application of microridge punches in multistage deep drawing processes. A microridge punch improves drawing performance, thereby reducing the number of stages required in deep forming processes. As an example, the original eight-stage deep forming process for a copper cylindrical cup with a high aspect ratio was analyzed by finite element simulation. Microridge punch designs were introduced in Stages 4 and 7 to replace the original punches. In addition, Stages 3 and 6 were eliminated. Finally, these changes were verified through experiments. The results showed that the microridge punches reduced the number of deep drawing stages yielding similar thickness difference percentages. Further, the numerical and experimental results demonstrated good consistency in the thickness distribution. PMID- 27777870 TI - Color demosaicking via fully directional estimation. AB - Given a natural image from the single sensor, the key task is to properly reconstruct the full color image. This paper presents an effectively demosaicking algorithm based on fully directional estimation using Bayer color filter array pattern. The proposed method smoothly keeps access to current reconstruction implementations, and outperforms the horizontal and vertical estimating approaches in terms of the perceptual quality. To analyze the target of existing methods, the proposed algorithm use the multiscale gradients in single green channels as the diagonal information for the auxiliary interpolation. Furthermore, two group of weights (one is from the horizontal and vertical directions, another is from the diagonal and anti-diagonal directions) are built. Combinational weight is better suited for representing neighbor information. Another contribution is to better use the prior result. While calculating the same type of color difference, we divide all the color difference values into two interleaved parts. Estimated value in the first part will guide the subsequent color difference in the second part. It less brings the artifact of the interpolation procedure. Experimental results show that this adaptive algorithm is efficient both in the objective and subjective output measures. PMID- 27777871 TI - Combined spinal-epidural anesthesia for radical hysterectomy in a patient with Sjogren syndrome with progressive interstitial lung disease. AB - INTRODUCTION: Interstitial lung disease (ILD), which is the most common form of respiratory involvement of Sjogren syndrome (SS), is highly associated with postoperative pulmonary complications after surgery. We report the successful anesthetic management of a cervical cancer patient with SS and ILD under combined spinal-epidural anesthesia (CSE) to avoid postoperative pulmonary complications. CASE DESCRIPTION: A 41-year-old woman with SS complicated by recently progressive ILD was scheduled for an elective radical hysterectomy under the diagnosis of cervical cancer. We performed CSE with separate needle technique (SNT) using two different interspaces. An epidural catheter was inserted at T11-T12 before administration of spinal medication at L3-L4. We could achieve successful anesthetic management for radical hysterectomy, maintaining stable hemodynamic variables. Postoperative analgesia, using epidural catheter, was effective and devoid of any postoperative pulmonary morbidity. DISCUSSION AND EVALUATION: CSE could offer a high level of sensory blockade, profound muscular blockade, longer duration of surgical anesthesia, excellent postoperative pain control, and reduction in the incidence of pulmonary morbidity. Therefore it would be excellent anesthetic option for the patients with pulmonary impairment. CONCLUSION: CSE with SNT may be particularly advantageous in patients with pulmonary impairment such as progressive ILD when general anesthesia is associated with high risk of postoperative complications. PMID- 27777872 TI - Sodium channel Nav1.7 expression is upregulated in the dorsal root ganglia in a rat model of paclitaxel-induced peripheral neuropathy. AB - Paclitaxel-induced peripheral neuropathy is not completely known. Since the sodium channel Nav1.7 has been implicated in pain perception, and is upregulated in pain disorders, we investigated the effect of paclitaxel on Nav1.7 expression in rat dorsal root ganglion (DRG) neurons. Thirty Sprague-Dawley rats were administered either 2 mg/kg paclitaxel or vehicle on days 0, 2, 4 and 6. To evaluate nociceptive responses, paw withdrawal threshold (PWT) was measured by von Frey anesthesiometer on days 7, 14 and 21 after first paclitaxel administration. Expression of Nav1.7 in DRG was measured by real-time RT-PCR and Western blot. PWT was also measured in rats that received dorsal root ganglionic injection of either Nav1.7 antibody, neutralized Nav1.7 antibody or no injection (sham surgery) (n = 5/group). Average PWT was lower in animals administered paclitaxel than those administered vehicle at days 7 (P < 0.05), 14 (P < 0.01), and 21 (P < 0.01). DRG Nav1.7 mRNA and protein levels were higher in animals administered paclitaxel than those administered vehicle on days 7, 14 and 21 (all P < 0.05). PWT decrease was significantly correlated with increased Nav1.7 protein levels on days 7 (r = -0.88, P = 0.04), 14 (r = -0.46, P = 0.03) and 21 (r = -0.27, P = 0.01) after first paclitaxel administration. In animals that received sham surgery, neutralized Nav1.7 antibody or Nav1.7 antibody, PWTs were significantly reduced 7 days after first paclitaxel administration (all P < 0.05), but PWTs of animals that received Nav1.7 antibody were higher than those that received neutralized Nav1.7 antibody (P < 0.05). These results indicate that increased DRG Nav1.7 expression may be partially responsible for paclitaxel induced peripheral neuropathy. PMID- 27777874 TI - Long term observation of MRSA prevalence in a German rehabilitation center: risk factors and variability of colonization rate. AB - Background: Data on MRSA prevalence in rehabilitation centers are sparse. Methods: We screened more than 18,000 patients with neurological, cardiac/pulmonary or orthopedic diagnoses treated in three German rehabilitation centers and documented potential risk factors in almost 1,500 of them. Results: 2.1% were MRSA positive (CI 1.9%-2.4%). Prevalence was higher in neurologic patients (3.7%) and lower in orthopedic patients (0.9%). While the overall MRSA situation was stable over two years, the weekly MRSA rate fluctuated strongly (0.0% to 8.0%). We confirmed five risk factors in our study population. A risk adapted screening strategy derived from our data had a significance of 74% and a positive predictive value of only 2.2%. Conclusion: MRSA positivity is a rare and highly variable event, requiring a huge sample size to generate robust data. The benefit of a risk-adapted screening strategy over a general screening should be questioned in each individual setting. PMID- 27777873 TI - Bipolar versus monopolar resection of benign prostate hyperplasia: a comparison of plasma electrolytes, hemoglobin and TUR syndrome. AB - BACKGROUND: Bipolar and monopolar transurethral resection of prostate (TURP) are both widely used for surgical treatment of benign prostatic hyperplasia. Systemic absorption of irrigation fluids during TURP operations leads to variations in blood chemistry. The aim of this prospective clinical study was to compare two different surgical techniques and the systemic effects of irrigation solutions (5 % mannitol vs. 0.9 % sodium chloride) under standardized anesthesia care. METHODS: Fifty-two patients who were scheduled for elective TURP were enrolled in the study. Patients were divided into two groups; the group M; 5 % mannitol was used for irrigation and the group B; 0.9 % sodium chloride was used for irrigation. Spinal anesthesia was performed to all patients. The patients' demographics, prostate volumes, hemodynamic parameters, volumes of irrigation, and IV fluids were recorded. Serum electrolytes (Na+, K+) and hemoglobin (Hb) were analyzed in blood samples taken before the operation (control), at the 45th min of the operation (1st measurement), and 1 h after the end of the surgery (2nd measurement) and recorded. RESULTS: The Na+ value of group M was significantly lower in both the 1st and 2nd measurements compared with the control value (p < 0.001 and p < 0.001). Na+ values of group M were also significantly lower than group B in both the 1st and 2nd measurements (p < 0.001 and p < 0.001). The change in Na+ levels was found to be statistically significant (p < 0.001) in group M, whereas the intergroup changes were not statistically significant in group B. CONCLUSION: Our results demonstrated that bipolar resection coupled with 0.9 % sodium chloride has minimal effects on serum sodium levels compared with monopolar resection. Clinicaltrials.gov identifier NCT02681471. PMID- 27777875 TI - Predictors of low prevalence of latent tuberculosis infection among Egyptian health care workers at intensive care and bronchoscopy units. AB - Aim: Latent tuberculosis infections (LTBI) contain a significant reservoir for future epidemics. Screening of health care workers (HCWs) in a high-risk tuberculosis (TB) environment is an important strategy in TB control. The study aimed to assess the prevalence of LTBI among high risk Egyptian HCWs and to assess infection associated risk factors. Methods: Fifty-two HCWs who work at intensive care unit (ICU), bronchoscopy unit, and chest diseases department were tested for LTBI using both tuberculin skin test (TST) and Quantiferon TB Gold in tube test (QFT). Risk factors for infection, knowledge of HCWs towards different aspects of TB infection and agreement between TST and QFT were also evaluated. Results: Prevalence of LTBI in this study was 13.5% by QFT and TST. It was 13.6% by TST alone and 10.3% by QFT alone. There was good concordance between both tests (Kappa=0.713). There was a statistically significant association between prevalence of LTBI and age of staff >=30 yr (p=0.002), period of working experience (p=0.006) and working at the Bronchoscopy Unit (p=0.001). The total knowledge of HCWs towards different aspects of TB infection was generally good. Conclusion: Although the participants in the current study were among high risk HCWs, the prevalence of LTBI was low. Bacille Calmette-Guerin (BCG) vaccination, young age, short employment duration, good knowledge and a good infection control were the predictors of low risk of contracting TB at our hospitals. The risk of TB infection in resource-limited countries can be reduced with simple continuous educational and administrative infection control programmes. PMID- 27777876 TI - Transanal total mesorectal excision: Myths and reality. AB - Transanal total mesorectal excision (TaTME) is a new and promising approach for the treatment of rectal cancer. Whilst the experience is still limited, there are growing evidences that this approach might overcome the limits of standard low anterior resection. TaTME might help to decrease the conversion rate especially in difficult patients, and to improve the pathological results, while preserving the urogenital function. Evaluation of data from large registries and randomized studies should help to draw firmer conclusions. Beyond these technical considerations, the next challenge seems to be clearly the safe introduction of this approach, motivating the development of dedicated courses. PMID- 27777877 TI - Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer. AB - Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade. PMID- 27777879 TI - Accelerated partial breast irradiation: Past, present, and future. AB - Accelerated partial breast irradiation (APBI) focuses higher doses of radiation during a shorter interval to the lumpectomy cavity, in the setting of breast conserving therapy for early stage breast cancer. The utilization of APBI has increased in the past decade because of the shorter treatment schedule and a growing body of outcome data showing positive cosmetic outcomes and high local control rates in selected patients undergoing breast conserving therapy. Technological advances in various APBI modalities, including intracavitary and interstitial brachytherapy, intraoperative radiation therapy, and external beam radiation therapy, have made APBI more accessible in the community. Results of early APBI trials served as the basis for the current consensus guidelines, and multiple prospective randomized clinical trials are currently ongoing. The pending long term results of these trials will help us identify optimal candidates that can benefit from ABPI. Here we provide an overview of the clinical and cosmetic outcomes of various APBI techniques and review the current guidelines for selecting suitable breast cancer patients. We also discuss the impact of APBI on the economics of cancer care and patient reported quality of life. PMID- 27777880 TI - Granulocyte colony-stimulating factor-producing hepatocellular carcinoma with abrupt changes. AB - Granulocyte colony-stimulating factor (G-CSF)-producing tumor is one of the rare types of cancer clinically characterized by an elevated fever and white blood cell (WBC) increment. Although G-CSF producing tumors have been reported in several types of cancer including those of the lungs, cervix and bladder, G-CSF producing hepatocellular carcinoma is extremely rare. Here, we report the case of a rapidly growing and poorly differentiated hepatocellular carcinoma producing G CSF. The patient showed symptoms of continuous high fever, stomach pain and cough, and high serum WBC counts, C-reactive protein (CRP) and G-CSF levels were found in laboratory tests. After a radical hepatectomy, the patient completely recovered from the above symptoms and inflammatory state. The serum levels of G CSF were reduced to normal levels after radical surgery. An immunohistochemical analysis revealed the overexpression of G-CSF in the cytoplasm of certain hepatocellular carcinoma (HCC) cell. The patient's serum WBC, CRP and G-CSF levels remained within normal levels in the six months after surgery without recurrence. This is the 9th case report of G-CSF producing hepatocellular carcinoma in English literature. We review the clinical characteristics of the G CSF producing HCC and discuss a possible treatment strategy. PMID- 27777878 TI - Role of Akt signaling in resistance to DNA-targeted therapy. AB - The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients. PMID- 27777881 TI - Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy. AB - AIM: To determine influence of neoadjuvant-chemotherapy (NAC) over tumor infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC). METHODS: TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS: Higher TIL evaluated in full face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) (P = 0.0251) and outcome (P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR (P = 0.6331). NAC produced a TIL decrease in full-face sections (P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR. CONCLUSION: TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related. PMID- 27777883 TI - Factors associated with cervical cancer screening in a safety net population. AB - AIM: To identify factors associated with Papanicolaou-smear (Pap-smear) cervical cancer screening rates in a safety net population. METHODS: From January 2012 to May 2013, the use of Pap-smear was determined for all patients seen at the breast clinic in a safety net hospital. Health literacy assessment was performed using the validated Newest Vital Sign. The records of patients were reviewed to determine if they had undergone Pap-smears for cervical cancer screening. Sociodemographic information was collected included age, education, monthly income, race/ethnicity, employment, insurance status, and primary care provider of the patient. Logistic regression analysis was then performed to determine factors associated with utilization of Pap-smears. Crude and adjusted odds ratios derived from multivariate logistic regression models were calculated as well as the associated 95%CIs and P-values. RESULTS: Overall, 39% had Pap-smears in the prior 15 mo, 1377 consecutive women were seen during the study period and their records were reviewed. Significantly more patients with adequate health literacy underwent Pap-smears as compared to those with limited health literacy (59% vs 34%, P < 0.0001). In multivariate analysis, patients with adequate health literacy, younger patients, and those with later age of first live birth were more likely to undergo Pap-smears. Patients whose primary care providers were gynecologists were also significantly more likely to have Pap-smears compared to other specialties (P < 0.0001). Patients younger than 21 years or older than 65 years underwent screening less frequently (11% and 11%, respectively) than those 21-64 years (41%, P < 0.0001). Race, ethnicity, language, and insurance status were not associated with Pap-smear screening rates. CONCLUSION: Patient health literacy and primary care physician were associated with Pap-smear utilization. Development of interventions to target low health literacy populations could improve cervical cancer screening. PMID- 27777882 TI - Cigarette smoking, dietary habits and genetic polymorphisms in GSTT1, GSTM1 and CYP1A1 metabolic genes: A case-control study in oncohematological diseases. AB - AIM: To analyze the association between oncohematological diseases and GSTT1/GSTM1/CYP1A1 polymorphisms, dietary habits and smoking, in an argentine hospital-based case-control study. METHODS: This hospital-based case-control study involved 125 patients with oncohematological diseases and 310 control subjects. A questionnaire was used to obtain sociodemographic data and information about habits. Blood samples were collected, and DNA was extracted using salting out methods. Deletions in GSTT1 and GSTM1 (null genotypes) were addressed by PCR. CYP1A1 MspI polymorphism was detected by PCR-RFLP. Odds ratio (OR) and 95%CI were calculated to estimate the association between each variable studied and oncohematological disease. RESULTS: Women showed lower risk of disease compared to men (OR 0.52, 95%CI: 0.34-0.82, P = 0.003). Higher levels of education (> 12 years) were significantly associated with an increased risk, compared to complete primary school or less (OR 3.68, 95%CI: 1.82-7.40, P < 0.001 adjusted for age and sex). With respect to tobacco, none of the smoking categories showed association with oncohematological diseases. Regarding dietary habits, consumption of grilled/barbecued meat 3 or more times per month showed significant association with an increased risk of disease (OR 1.72, 95%CI: 1.08 2.75, P = 0.02). Daily consumption of coffee also was associated with an increased risk (OR 1.77, 95%CI: 1.03-3.03, P = 0.03). Results for GSTT1, GSTM1 and CYP1A1 polymorphisms showed no significant association with oncohematological diseases. When analyzing the interaction between polymorphisms and tobacco smoking or dietary habits, no statistically significant associations that modify disease risk were found. CONCLUSION: We reported an increased risk of oncohematological diseases associated with meat and coffee intake. We did not find significant associations between genetic polymorphisms and blood cancer. PMID- 27777884 TI - Bone and soft tissue tumors presenting as sciatic notch dumbbell masses: A critical differential diagnosis of sciatica. AB - AIM: To study the clinical findings and characteristic features in sciatic notch dumbbell tumors (SNDTs). METHODS: We retrospectively reviewed the clinical outcomes and characteristic features of consecutive cases of SNDTs (n = 8). RESULTS: Buttock masses occurred in three patients with SNDT (37.5%). Severe buttock tenderness and pain at rest were observed in seven patients with SNDTs (87.5%). Remarkably, none of the patients with SNDTs experienced back pain. Mean tumor size was 8.4 +/- 2.0 cm (range, 3.9 to 10.6 cm) and part of the tumor mass was detected in 2 patients in the sagittal view of lumbar magnetic resonance imaging (MRI). CONCLUSION: The clinical information regarding to SNDTs is scarce. The authors consider that above mentioned characteristic findings may facilitate the suspicion of pelvic pathology and a search for SNDT by MRI or computed tomography should be considered in patients presenting with sciatica without evidence of spinal diseases. PMID- 27777885 TI - Male papillary breast cancer treated by wide resection and latissimus dorsi flap reconstruction: A case report and review of the literature. AB - Breast cancer (BC) in men represents between 0.5% and 1% of all BC diagnosed each year. We report a case of advanced BC in a 62-year-old male treated at our interdisciplinary Breast Cancer Center. The patient presented with a newly diagnosed large, symptomatic mass in his left breast. Clinical examination showed a not movable mass of 16 cm diameter, deforming the whole breast; the overlying skin was livid and hypervascularized. Enlarged lymph nodes were palpable in the axillary pit. He had no concomitant diseases at time of presentation. He denied any first- or second degree family medical history of cancer of any type and he never received radiotherapy. Ultrasound guided minimal-invasive 14-gauge core biopsy revealed a moderately differentiated encapsulated papillary carcinoma with high expression of estrogen and progesterone receptors (both > 80%, IRS 12) and HER2-negative. Because of the tumor size a mastectomy with axillary dissection and chest wall reconstruction using a latissimus dorsi flap was performed. Histological analysis showed invasive growth besides typical (non-invasive) papillary carcinoma and was classified as invasive solid papillary carcinoma; pT3 (10 cm), pN0 (0/15), M0, R0; OncotypeDX Recurrence Score indicated low risk (RS: 2). After discussion in the interdisciplinary tumor board meeting, radiation therapy and tamoxifen were recommended. The patient had an uneventful recovery and is disease-free after two years of follow-up. Male BC is typically diagnosed at an advanced stage, most likely due to a lack of awareness that men can develop BC. Therefore, in case of a large tumor, a flap-based thoracic reconstruction may be required. PMID- 27777886 TI - Underutilization of Living Donor Liver Transplantation in the United States: Bias against MELD 20 and Higher. AB - Background and Aims: Utilization of living donor liver transplantation (LDLT) and its relationship with recipient Model for End-Stage Liver Disease (MELD) needs further evaluation in the United States (U.S.). We evaluated the association between recipient MELD score at the time of surgery and survival following LDLT. Methods: All U.S. adult LDLT recipients with MELD < 25 were evaluated using the 1995-2012 United Network for Organ Sharing registry. Survival following LDLT was stratified into three MELD categories (MELD < 15 vs. MELD 15-19 vs. MELD 20-24) and evaluated using Kaplan-Meier methods and multivariate Cox proportional hazards models. Results: Overall, 2,258 patients underwent LDLT. Compared to patients with MELD < 15, overall 5-year survival following LDLT was similar among patients with MELD 15-19 (80.9% vs. 80.3%, p = 0.77) and MELD 20-24 (81.2% vs. 80.3%, p = 0.73). When compared to patients with MELD < 15, there was no significant difference in long-term post-LDLT survival among those with MELD 15 19 (HR: 1.11, 95% CI: 0.85-1.45, p = 0.45) and a non-significant trend towards lower survival in patients with MELD 20-24 (HR: 1.28, 95% CI: 0.91-1.81, p = 0.16). Only 14% of LDLTs were performed in patients with MELD 20-24 and the remaining 86% in patients with MELD < 20. Conclusion: LDLT is underutilized in patients with MELD 20 and higher. PMID- 27777887 TI - PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum. AB - Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease. Methods: Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) and NAFLD were included. Pooled data are reported as odds ratios (ORs) with 95% confidence intervals. Results: Of 393 potentially relevant studies, 35 on NAFLD were included in the analysis. Compared to healthy controls, the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL) were 1.46 (1.16-1.85) and 2.76 (2.30-3.13), and were 1.75 (1.24-2.46) and 4.44 (2.92-6.76) among patients with non-alcoholic steatohepatitis respectively. The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90-6.13) and 5.05 (1.47-17.29) when comparing non-alcoholic hepatocellular carcinoma to NAFL patients. Among the NAFLD patients, the ORs for G allele frequency when comparing steatosis grade 2-3 to grade 0-1 NAFL, when comparing the NAFLD activity score of >= 4 to score <= 3, when comparing NASH to NAFLD, when comparing the presence of lobular inflammation to absence, and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43-3.80), 1.80 (1.36-2.37), 1.66 (1.42-1.94), 1.58 (1.19-2.10), and 2.63 (1.87-3.69) respectively. Subgroup analysis based on ethnicity showed similar results. Conclusions:PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs. PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD. PMID- 27777888 TI - Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review. AB - Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited to minor gastrointestinal complaints (most often, diarrhea) and did not occur at increased frequency as compared to controls. As administration of bile acids was often limited to durations of 12 months or less, long-term side effects for non-cholestatic indications cannot be excluded. Conclusions: Based on the available literature, bile acids cannot be widely recommended for non-cholestatic liver diseases at present. PMID- 27777891 TI - HIV/HCV Antiviral Drug Interactions in the Era of Direct-acting Antivirals. AB - Therapy for human immunodeficiency virus (HIV) and chronic hepatitis C has evolved over the past decade, resulting in better control of infection and clinical outcomes; however, drug-drug interactions remain a significant hazard. Joint recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America regarding drug-drug interactions between HIV antiretroviral agents and direct-acting antiviral agents for treatment of hepatitis C virus (HCV) infection are reviewed here. This review is oriented to facilitate appropriate selection of an antiviral therapy regimen for HCV infection based on the choice of antiretroviral therapy being administered and, if necessary, switching antiretroviral regimens. PMID- 27777890 TI - Supplementing Conventional Treatment with Pycnogenol(r) May Improve Hepatitis C Virus-Associated Type 2 Diabetes: A Mini Review. AB - Hepatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM) present a significant health burden, with increasing complications and mortality rates worldwide. Pycnogenol(r) (PYC), a natural product, possesses antidiabetic and antiviral properties that may improve HCV-associated T2DM. In this review, we present previously published data on the effectiveness of PYC against HCV replication and T2DM. We believe that supplementing conventional treatment with PYC may improve the current HCV therapy, attenuate HCV-associated T2DM, and reduce the risk of complications such as cirrhosis or hepatocellular carcinoma and cardiovascular disease. PMID- 27777889 TI - Treatment of Hepatitis C in Patients Undergoing Immunosuppressive Drug Therapy. AB - With 185 million people chronically infected globally, hepatitis C is a leading bloodborne infection. All-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more tolerable. However, trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ transplantation. Yet, these patients-most often suffering from malignancy or autoimmune diseases-could stand to benefit from these treatments. In this study, we systematically review the literature on the treatment of hepatitis C in these neglected populations. Research on patients with organ transplants is more robust and this literature is reviewed here non-systematically. Our systematic review produced 2273 unique works, of which 56 met our inclusion criteria and were used in our review. The quality of data was low; only 3 of the 56 studies were randomized controlled trials. Sustained virologic response was reported sporadically. Interferon-containing regimens achieved this end-point at rates comparable to that in immunocompetent individuals. Severe adverse effects and death were rare. Data on all-oral regimens were sparse, but in the most robust study, rates of sustained virologic response were again comparable to immunocompetent individuals (40/41). Efficacy and safety of interferon-containing regimens and all-oral regimens were similar to rates in immunocompetent individuals; however, there were few interventional trials. The large number of case reports and case series makes conclusions vulnerable to publication bias. While firm conclusions are challenging, given the dearth of high-quality studies, our results demonstrate that antiviral therapy can be safe and effective. The advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side effects. Preliminary data reveal that these regimens may confer such benefits in immunosuppressed individuals as well. More prospective interventional trials would greatly benefit the many patients with chronic hepatitis C on immunosuppressive therapies. PMID- 27777892 TI - Hepatitis B Management in the Pregnant Patient: An Update. AB - Chronic hepatitis B is a worldwide disease, with significant burden on health care systems. While universal vaccination programs have led to an overall decrease in incidence of transmission of hepatitis B, unfortunately, there remain large areas in the world where vaccination against hepatitis B is not practiced. In addition, vertical transmission of hepatitis B persists as a major concern. Hepatitis B treatment of the pregnant patient requires a thorough assessment of disease activity and close monitoring for flares, regardless of initiation of antiviral therapy. We discuss, in this article, the current and emergent strategies which aim to reduce the rate of transmission of hepatitis B from the pregnant mother to the infant and we review the updated guidelines regarding management of liver disease in pregnant women with hepatitis B. PMID- 27777894 TI - Pulmonary Manifestations among Patients with Primary Biliary Cirrhosis. AB - Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease caused by diffuse inflammation, destruction and fibrosis of the intrahepatic bile ducts, ultimately leading to cirrhosis, portal hypertension and liver failure. The pathogenesis of PBC is incompletely understood, but current data suggest roles for genetic susceptibility and environmental factors. PBC is often thought of as an organ-specific autoimmune disease, which mainly targets the liver; however, lung tissue is also a site for autoimmune involvement of PBC. The pulmonary manifestations of PBC include abnormalities in gas transfer and pulmonary function, subclinical alveolitis, interstitial lung disease, granulomatous lung disease, airway disease, pulmonary hypertension, pulmonary hemorrhage and pleural effusion. PMID- 27777893 TI - Inhibitor-Based Therapeutics for Treatment of Viral Hepatitis. AB - Viral hepatitis remains a significant worldwide threat, in spite of the availability of several successful therapeutic and vaccination strategies. Complications associated with acute and chronic infections, such as liver failure, cirrhosis and hepatocellular carcinoma, are the cause of considerable morbidity and mortality. Given the significant burden on the healthcare system caused by viral hepatitis, it is essential that novel, more effective therapeutics be developed. The present review attempts to summarize the current treatments against viral hepatitis, and provides an outline for upcoming, promising new therapeutics. Development of novel therapeutics requires an understanding of the viral life cycles and viral effectors in molecular detail. As such, this review also discusses virally-encoded effectors, found to be essential for virus survival and replication in the host milieu, which may be utilized as potential candidates for development of alternative therapies in the future. PMID- 27777895 TI - Hypoxic Hepatitis: A Review and Clinical Update. AB - Hypoxic hepatitis (HH), also known as ischemic hepatitis or shock liver, is characterized by a massive, rapid rise in serum aminotransferases resulting from reduced oxygen delivery to the liver. The most common predisposing condition is cardiac failure, followed by circulatory failure as occurs in septic shock and respiratory failure. HH does, however, occur in the absence of a documented hypotensive event or shock state in 50% of patients. In intensive care units, the incidence of HH is near 2.5%, but has been reported as high as 10% in some studies. The pathophysiology is multifactorial, but often involves hepatic congestion from right heart failure along with reduced hepatic blood flow, total body hypoxemia, reduced oxygen uptake by hepatocytes or reperfusion injury following ischemia. The diagnosis is primarily clinical, and typically does not require liver biopsy. The definitive treatment of HH involves correction of the underlying disease state, but successful management includes monitoring for the potential complications such as hypoglycemia, hyperglycemia, hyperammonemia and hepatopulmonary syndrome. Prognosis of HH remains poor, especially for cases in which there was a delay in diagnosis. The in-hospital mortality rate is >50%, and the most frequent cause of death is the predisposing condition and not the liver injury itself. PMID- 27777897 TI - Chronic Cholestatic Liver Injury Attributable to Vedolizumab. AB - Drug-induced liver injury is a rare but clinically important diagnosis. Vedolizumab is an alpha4beta7 integrin inhibitor recently approved for use in patients with moderate-to-severe inflammatory bowel disease. Cases of hepatoxicity due to vedolizumab in the pre-marketing stage were rare, and all cases resolved upon drug withdrawal. We present here the first reported case of hepatotoxicity attributable to vedolizumab, which despite drug cessation persisted with chronic cholestatic liver injury. PMID- 27777896 TI - Epidemiology of Hepatitis E in Pregnant Women and Children in Iran: A General Overview. AB - From an epidemiological point of view, hepatitis E is an old infection in Iran, but only recently has its importance as a public health concern been considered from research and public health standpoints. As such, there is still a long road ahead to clarify the real burden of hepatitis E virus (HEV) infection in Iran. According to the available epidemiological studies, the seroprevalence of HEV infection among pregnant women is between 3.6% and 7.4%, and among Iranian children is between 0.9% to 8.5%, varying by geographic regions within the country and directly dependent upon the sanitary status of each. In addition to evaluating the sanitation level of a society, community-based seroprevalence studies of HEV infection demonstrate the most prevalent risk factors, the major routes of transmission, and the epidemiological patterns of HEV among that country's population. In this review, the current knowledge about the pathogenesis and epidemiology of HEV infection in pregnant women and children in Iran, as well as the recent advances in diagnosis, prevention and treatment of HEV infection have been summarized. PMID- 27777898 TI - Skeletal Metastasis as Detected by 18F-FDG PET with Negative CT of the PET/CT: Frequency and Impact on Cancer Staging and/or Management. AB - OBJECTIVES: The aim of our study is to assess the frequency of detection of PET positive computed tomography (CT)-negative skeletal metastases (SM) and determine the impact of such detection on staging and/or management in patients who had FDG PET/CT as part of the cancer work-up. METHODS: We retrospectively reviewed 2000 18F-FDG PET/CT scans of known cancer patients. A log was kept to record cases of suspected SM with or without bone changes from the low-dose non-contrast CT. The presence or absence of SM was evaluated based on available pathological and clinical data. The impact of detection of such lesions on cancer staging and/or management was evaluated by a board certified oncologist. RESULTS: Of the 2000 cases, 18F-FDG PET/CT suggested SM in 146/2000 (7.3%). Of those 146 cases, 105 (72%) were positive on both PET and CT. The remaining 41 (28%) had PET-positive CT-negative bone lesions. SM was confirmed in 36/41 (88%) PET-positive/CT negative cases. This was based on biopsy, imaging, or clinical follow-up. The detection of PET-positive CT-negative SM did not change staging or management in 7/36 (19.4%). However, staging and/or management was affected in 29/36 (80.6%). CONCLUSION: SM is not uncommon in 18F-FDG PET/CT, as it accounts for 146/2000 (7.3%) of cases. PET demonstrated FDG-avid SM without a CT abnormality in at least 36/146 (25%). Patients staging and/or management changed in 29/36 (80.5%). We concluded that 18F-FDG PET is sensitive in the detection of SM with significant impact on staging and/or management. PMID- 27777901 TI - Excess weight gain during insulin pump therapy is associated with higher basal insulin doses. AB - BACKGROUND: While higher total daily dose (TDD) of insulin has been associated with excess weight gain on insulin pump therapy, the role of higher total basal dose (TBD) of insulin on weight gain has not been studied. We evaluated the impact of higher TBD on weight gain in relationship to glycosylated hemoglobin (HbA1c), hypoglycemic episodes, and change in body mass index (BMI) z score in a group of pediatric patients with type 1 diabetes mellitus (T1DM). METHODS: One year data from 91 (54 Female/37 Male) patients (2.3-17.8 years of age), transitioned from basal-bolus regimen to insulin pump therapy were reviewed. Patients were divided into two groups based on changes in BMI z score: Group 1 (no change or decrease) and Group 2 (increase). RESULTS: Thirty-three patients in Group 1 and 58 patients in Group 2. The two groups had similar TDD (0.9 +/- 0.2 vs. 0.8 +/- 0.2 U/kg/day), however Group 1 had a higher bolus: basal insulin ratio (1.8 +/- 0.6 vs. 1.5 +/- 0.6, p < 0.05). While Groups 1 and 2 had similar HbA1c values (7.7 +/- 0.7 vs. 7.70 +/- 0.6 %; p = 0.79) and activity levels (2.2 +/- 0.6 vs. 2.2 +/- 0.7; p = 0.15), Group 2 had higher rates of hypoglycemic episodes (1.0 +/- 0.4 vs. 1.5 +/- 0.9, p < 0.01). CONCLUSION: Excess weight gain was associated with lower bolus to basal insulin ratios independent of glycemic control and activity level. Evaluation of bolus and basal insulin doses during insulin therapy is warranted in order to avoid excess weight gain. PMID- 27777900 TI - Circulating angiogenic factors in diabetes patients in a tertiary hospital in Ghana. AB - BACKGROUND: Impaired angiogenesis is amongst the underlining mechanisms of organ damage in diabetes and hypertensive patients. In diabetes and hypertensive patients without proteinuria and overt CVDs, we studied the levels of angiogenic growth factors, angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF), and the relationship between these angiogenic growth factors and renal function, measured as estimated glomerular filtration rate (eGFR). METHOD: In a case control design, 107 type 2 diabetes (T2DM) patients and 93 non-diabetes controls were recruited into the study. Levels of plasma glucose, lipids, creatinine and angiogenic growth factors; Ang-1, Ang-2 and VEGF measured from fasting blood samples. Estimated glomerular filtration rate (eGFR) was computed using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm and eGFR < 60 ml/min/1.73 m2 was considered to be low. Multivariable logistic regression was used to assess the odds of change in angiogenic growth factors among patients with diabetes and hypertension, and patients with low eGFR, compared to those without these conditions. RESULTS: In a total of 200 participants with 49 % females and mean age of 54.1 +/- 10.2 years, 22.7 % of T2DM patients and 13.3 % of non-diabetes participant had low eGFR. The levels of Ang-1 and Ang-2 were highest in hypertensive T2DM patients, followed by patients with either T2DM or hypertension alone, with the controls having the lowest levels. The odds of change in circulating Ang-2 levels increased in patients with both diabetes and hypertension [11.76 (7.97-16.63), p < 0.01] compared to patients with either diabetes [5.45 (3.31-9.71), p = 0.02] or hypertension [5.45 (3.31-9.71), p = 0.02] alone. Compared to those with normal eGFR, the odds of change in serum Ang-2 levels were increased in patients with low eGFR in both the crude [1.26 (1.08-2.110), p = 0.023] and adjusted [1.14 (1.03-2.34), p = 0.043] regression models. CONCLUSION: In our study population, having diabetes and hypertension increased the levels of Ang-1 and Ang-2. Also, low eGFR status was associated with increased levels of Ang-2 after adjustment for other risk factors. PMID- 27777899 TI - Helicobacter pylori Infection Is Associated with Decreased Expression of SLC5A8, a Cancer Suppressor Gene, in Young Children. AB - Background:Helicobacter pylori infects half of the world's population and causes gastric cancer in a subset of infected adults. Previous blood microarray findings showed that apparently healthy children, persistently infected with H. pylori have differential gene expression compared to age-matched, non-infected children. SLC5A8, a cancer suppressor gene with decreased expression among infected children, was chosen for further study based on bioinformatics analysis. Methods: A pilot study was conducted using specific qRT-PCR amplification of SLC5A8 in blood samples from H. pylori infected and non-infected children, followed by a larger, blinded, case-control study. We then analyzed gastric tissue from H. pylori infected and non-infected children undergoing endoscopy for clinical purposes. Results: Demographics, clinical findings, and family history were similar between groups. SLC5A8 expression was decreased in infected vs. non infected children in blood, 0.12 (IQR: 0-0.89) vs. 1.86 (IQR: 0-8.94, P = 0.002), and in gastric tissue, 0.08 (IQR: 0.04-0.15) vs. 1.88 (IQR: 0.55-2.56; P = 0.001). Children who were both stool positive and seropositive for H. pylori had the lowest SLC5A8 expression levels. Conclusions:H. pylori infection is associated with suppression of SCL5A8, a cancer suppressor gene, in both blood and tissue samples from young children. Key Points: Young children, persistently infected with Helicobacter pylori show decreased expression of SLC5A8 mRNA in both blood and tissue samples as compared to non-infected children. PMID- 27777902 TI - Prevalence of dyslipidemia and its association with other coronary artery disease risk factors among urban population in Southeast of Iran: results of the Kerman coronary artery disease risk factors study (KERCADRS). AB - BACKGROUND: Despite the importance of identifying and screening dyslipidemia to prevent coronary artery diseases CAD(Coronary Artery Disease), little information is available on dyslipidemia in our large area. So the present study aimed to assess the management status of lipid abnormalities and its association with other CAD risk factors in an urban population of southeast of Iran. METHODS: This cross-sectional study was a part of the Kerman coronary artery disease risk factor study KERCADRS (Kerman coronary artery disease risk study) as a population based, epidemiological research among 5900 individuals aged 15 to 75 years who were residents of Kerman city, the largest city in Southeast of Iran. Lipid profile was assessed using enzymatic laboratory methods. RESULTS: In total, 5558 persons from 5899 participants were assessed in whom 45.1 % were male and 54.9 % female. Overall 20.9 % had borderline level of cholesterol (200-239 mg/dl) and 8.7 % suffered from hypercholesterolemia (>=240 mg/dl). The prevalence of undiagnosed dyslipidemia (UDL) was 16.8 % and of diagnosed dyslipidemia (DDL) was 13.2 % that both UDL and DDL were more prevalent in women. Also, UDL was more revealed in third and fourth age decades. Advanced age, anxiety, obesity (BMI >=30 Kg/m2), and family history of dyslipidemia predicted dyslipidemia in study population. CONCLUSION: The overall prevalence of UDL was higher than of DDL, and was significantly influenced by advanced age, anxiety, obesity, and family history of dyslipidemia. The data showed that our health care management system should improve its strategies to reduce the burden of this important CAD risk factor. PMID- 27777903 TI - Exosomes as the source of biomarkers of metabolic diseases. AB - Exosomes are extracellular vesicles that contain molecules that regulate the metabolic functions of adjacent or remote cells. Recent in vitro, in vivo and clinical studies support the hypothesis that exosomes released from various cell types play roles in the progression of metabolic disorders including type 2 diabetes. Based on this concept and advances in other diseases, the proteins, mRNA, microRNA and lipids in exosomes isolated from biological fluids have been proposed as biomarkers in metabolic disorders. However, several problems with the development of clinically applicable biomarkers have not been resolved. In this review, the biologic functions of exosomes are briefly introduced, and we discuss the technical and practical pros and cons of different methods of exosome isolation for the identification of exosomal biomarkers of metabolic disorders. Standardization of preanalytical variables and isolation of high-purity exosomes from fully characterized biological fluids will be necessary for the identification of useful exosomal biomarkers that can provide insights into the pathogenic mechanisms of complications of metabolic syndrome and of whole-body metabolism. PMID- 27777905 TI - Etiology and therapeutic outcomes of children with gonadotropin-independent precocious puberty. AB - PURPOSE: This study was performed to investigate the etiology, clinical features, and outcomes of patients with gonadotropin-independent precocious puberty (GIPP). METHODS: The study included 16 patients (14 female and 2 male patients) who manifested secondary sexual characteristics, elevated sex hormones, or adrenal androgens with prepubertal luteinizing hormone levels after gonadotropin releasing hormone stimulation diagnosed between May 1994 and December 2015. Patients with congenital adrenal hyperplasia were excluded. Clinical features, laboratory findings, treatment modalities, and outcomes were retrospectively reviewed. RESULTS: The median age at diagnosis was 2.6 years (range, 0.7-7.9 years) and median follow-up duration was 4.6 years (range, 1 month-9.8 years). Patients with McCune-Albright syndrome (n=5) and functional ovarian cysts (n=4) presented with vaginal bleeding and elevated estradiol levels (23.3+/-17.5 pg/mL); adrenocortical tumors (n=4) with premature pubarche and elevated dehydroepiandrosterone sulfate levels (87.2-6,530 ug/dL); and human chorionic gonadotropin (hCG)-producing tumor (n=1) with premature pubarche and elevated beta-human chorionic gonadotropin levels (47.4 mIU/mL). Two patients were idiopathic. Six patients transited to gonadotropin-dependent precocious puberty median 3.3 years (range, 0.3-5.1 years) after the onset of GIPP. Initial and follow-up height standard deviation scores (0.99+/-0.84 vs. 1.10+/-1.10, P=0.44) and bone age advancement (1.49+/-1.77 years vs. 2.02+/-1.95 years, P=0.06) were not significantly different. CONCLUSION: The etiologies of GIPP are heterogeneous, and treatment and prognosis is quite different according to the etiology. Efficacy of treatment with aromatase inhibitors needs to be evaluated after long-term follow-up. PMID- 27777904 TI - Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome. AB - The Prader-Willi syndrome (PWS) is a human imprinting disorder resulting from genomic alterations that inactivate imprinted, paternally expressed genes in human chromosome region 15q11-q13. This genetic condition appears to be a contiguous gene syndrome caused by the loss of at least 2 of a number of genes expressed exclusively from the paternal allele, including SNRPN, MKRN3, MAGEL2, NDN and several snoRNAs, but it is not yet well known which specific genes in this region are associated with this syndrome. Prader-Will-Like syndrome (PWLS) share features of the PWS phenotype and the gene functions disrupted in PWLS are likely to lie in genetic pathways that are important for the development of PWS phenotype. However, the genetic basis of these rare disorders differs and the absence of a correct diagnosis may worsen the prognosis of these individuals due to the endocrine-metabolic malfunctioning associated with the PWS. Therefore, clinicians face a challenge in determining when to request the specific molecular test used to identify patients with classical PWS because the signs and symptoms of PWS are common to other syndromes such as PWLS. This review aims to provide an overview of current knowledge relating to the genetics of PWS and PWLS, with an emphasis on identification of patients that may benefit from further investigation and genetic screening. PMID- 27777906 TI - The cutoff values of indirect indices for measuring insulin resistance for metabolic syndrome in Korean children and adolescents. AB - PURPOSE: The prevalence rates of metabolic syndrome (MetS) and percentile distribution of insulin resistance (IR) among Korean children and adolescents were investigated. The cutoff values of IR were calculated to identify high-risk MetS groups. METHODS: Data from 3,313 Korean subjects (1,756 boys and 1,557 girls, aged 10-18 years) were included from the Korean National Health and Nutrition Examination Survey conducted during 2007-2010. Three different sets of criteria for MetS were used. Indirect measures of IR were homeostasis model assessment (HOMA-IR) and triglyceride and glucose (TyG) index. The cutoff values of the HOMA-IR and TyG index were obtained from the receiver operation characteristic curves. RESULTS: According to the MetS criteria of de Ferranti el al., Cook et al., and the International Diabetes Federation, the prevalence rates in males and females were 13.9% and 12.3%, 4.6% and 3.6%, and 1.4% and 1.8%, respectively. Uses these 3 criteria, the cutoff values of the HOMA-IR and TyG index were 2.94 and 8.41, 3.29 and 8.38, and 3.54 and 8.66, respectively. The cutoff values using each of the 3 criteria approximately corresponds to the 50th 75th, 75th, and 75th-90th percentiles of normal HOMA-IR and TyG index levels. CONCLUSION: This study describes the prevalence rates of MetS in Korean children and adolescents, an index of IR, and the cutoff values for MetS with the aim of detecting high-risk groups. The usefulness of these criteria needs to be verified by further evaluation. PMID- 27777908 TI - Body image and depression in girls with idiopathic precocious puberty treated with gonadotropin-releasing hormone analogue. AB - PURPOSE: Precocious puberty (PP) is associated with psychological and behavioral problems. This study aimed to evaluate the perception of body image and depression in girls with PP receiving gonadotropin-releasing hormone (GnRH) analogue therapy. METHODS: From March to August 2013, 82 girls with PP receiving GnRH analogue therapy were enrolled. Height, weight, body mass index, and stages of pubertal development were assessed. Participants completed a series of questionnaires on their body image perception and pubertal self-assessment. The depression score was calculated using the Korean Kovacs' Children's Depression Inventory. RESULTS: The patients perceived their body to be more obese than the controls did. The mean depression score did not differ between the patients and controls. The mean depression scores according to Tanner stages (1: prepubertal, 2: early pubertal, and 3-5: mid to late pubertal stage) by self-assessment were 5.2+/-3.6, 6.8+/-4.9, and 11.4+/-10.1 (P<0.05), respectively. The perception of overall body build and figure (%) and the mean depression scores in patients were: dissatisfied (25.6%, 9.7+/-7.8) and satisfied (74.4%, 5.5+/-3.4) (P<0.05). In multiple linear regression analysis, self-T3 (Tanner stage 3-5 by self awareness) and dissatisfaction about overall body build and figure were found to significantly affect the depression score(P<0.05). CONCLUSION: The perception of pubertal status and satisfaction about height or weight are unrelated to objective physical findings. Patients with PP are prone to distorted perception about their body image and breast development. Such incorrect body image seems to contribute to depression score. PMID- 27777907 TI - Vitamin D deficiency in children aged 6 to 12 years: single center's experience in Busan. AB - PURPOSE: This study investigated the prevalence and risk factors associated with vitamin D deficiency in children. METHODS: We analyzed the medical records of 330 patients from the age of 6 to 12, who visited the endocrinology clinic of the Department of Pediatrics at Pusan National University Hospital, from September, 2013 to May, 2014. According to their serum 25-hydroxyvitamin D (25(OH)D) levels, the patients were grouped into either the deficiency group (25(OH)D<20 ng/mL), or the sufficiency group (25(OH)D>=20 ng/mL). The differences between the 2 groups were compared. RESULTS: There were 195 patients (59.1%) who had vitamin D deficiency. Their mean serum 25(OH)D level was 14.86+/-3.20 ng/mL. The differences in sex, age, and pubertal status between the 2 groups were not statistically significant. Weight standard deviation score (SDS), and body mass index SDS, were significantly higher in the vitamin D deficiency group (P=0.002 for each), compared to the sufficiency group. Compared with Autumn, both Spring (odds ratio [OR], 9.7; 95% confidence interval [CI], 4.3-22.0), and Winter (OR, 5.9; 95% CI, 3.5-10.0), were risk factors for vitamin D deficiency. In multiple logistic regression analysis, only seasonal differences have been confirmed to have an effect on vitamin D deficiency. CONCLUSION: Vitamin D deficiency in children aged 6 to 12 years is very common. Spring and Winter are the most important risk factors for vitamin D deficiency. We suggest that it is necessary to supplement the guideline for the vitamin D intake according to our situation. PMID- 27777909 TI - A baby with congenital hypothyroidism born to a hypothyroid mother who expressed undiagnosed thyroid stimulation blocking antibody. AB - In adults, hypothyroidism caused by thyroid stimulation blocking antibody (TSB Ab) is rare, and confirmed cases are even fewer, as TSB Ab levels are rarely assayed. However, this may create problems in babies, as the transplacental passage of maternal TSB Ab can cause a rare type of hypothyroidism in the infant. Prompt levothyroxine replacement for the baby starting immediately after birth is important. We describe a congenital hypothyroid baby born to a hypothyroid mother who was not aware of the cause of her hypothyroid condition, which turned out to be associated with the expression of TSB Ab. This cause was confirmed in both the infant and mother using a series of thyroid function tests and measurements of autoantibody levels, including TSB Ab. During periodic follow-up, the TSB Ab and thyroid stimulating hormone receptor antibody titers became negative in the baby at 8 months of age, but remained positive in the mother. Evaluation of hypothyroidism and its cause in mothers during pregnancy is important for both maternal and child health. PMID- 27777910 TI - Diagnostic difficulties by the unusual presentations in children and adolescents with Hashimoto thyroiditis. AB - Complex clinical presentation with diverse timing of particular symptoms may cause diagnostic difficulties, especially in children and adolescents. This paper presents diagnostic difficulties and pitfalls in 3 children with acquired primary hypothyroidism due to Hashimoto's thyroiditis (HT) presenting with unusual manifestations. We described 3 children with acquired primary hypothyroidism due to HT. One of our patients had musculoskeletal pain and was diagnosed and treated as having connective tissue disease. Another patient presented with chest pain, dyspnea, and swelling in the abdomen. She had a massive pericardial effusion (PE). Two patients had severe growth failure. A third patient with Down syndrome had a small PE. Her complaint was dyspnea during sleep. All patients improved with thyroxin therapy. Patients with hypothyroidism due to HT who have complicated clinical manifestations were misdiagnosed and mismanaged at childhood and adolescence. Growth failure is an important sign in children and adolescents. In the presence of complicated manifestations in children and adolescents, thyroid dysfunction must be considered in differential diagnosis. PMID- 27777911 TI - Long-term clinical outcome and the identification of homozygous CYP27B1 gene mutations in a patient with vitamin D hydroxylation-deficient rickets type 1A. AB - Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is an autosomal recessively-inherited disorder caused by mutations in CYP27B1 encoding the 1alpha hydroxylase enzyme. We report on a female patient with VDDR1A who presented with hypocalcemic seizure at the age of 13 months. The typical clinical and biochemical features of VDDR1A were found, such as hypocalcemia, increased alkaline phosphatase, secondary hyperparathyroidism and normal 25-hydroxyvitamin D3 (25(OH)D3). Radiographic images of the wrist showed metaphyseal widening with cupping and fraying of the ulna and distal radius, suggesting rickets. A mutation analysis of the CYP27B1 gene identified a homozygous mutation of c.589+1G>A in the splice donor site in intron 3, which was known to be pathogenic. Since that time, the patient has been under calcitriol and calcium treatment, with normal growth and development. During the follow-up period, she did not develop genu valgum, scoliosis, or nephrocalcinosis. PMID- 27777912 TI - Endocrine complications during and after adolescence in a patient with cystinosis. AB - Cystinosis is a rare disease characterized by abnormal lysosomal cystine accumulation of cystine due to impaired lysosomal transport. We previously reported the first case of cystinosis in Korea in a 12-year-old boy with short stature, general weakness, and photophobia. The diagnosis was confirmed based on ophthalmic findings and biochemical analyses (serum leukocyte cystine measurement). Major endocrine manifestations at diagnosis included hypothyroidism, growth retardation, and hypogonadism. Despite oral cysteamine administration and renal replacement therapy, multiple complications including both endocrine and nonendocrine disorders developed during and after adolescence. In this report, we review the presenting features and factors related to the long term complications in a patient with cystinosis. PMID- 27777914 TI - On the Occasion of PMC Registration of Hip & Pelvis. PMID- 27777913 TI - Retraction: Mixed gonadal dysgenesis in 45,X Turner syndrome with SRY gene. AB - [This retracts the article on p. 226 in vol. 20, PMID: 26817010.]. PMID- 27777915 TI - Current Concepts of Using Large Femoral Heads in Total Hip Arthroplasty. AB - Instability and dislocation after total hip arthroplasty are the most common causes of revisions and major complications for failure of inserted prostheses, leading to a reduction in quality of life. Because the use of artificial femoral head sizes smaller than patient's own size is the important cause for dislocation, the use of large femoral head have increased. Femoral head sizes greater than 32 mm offer multiple advantages in physical function and activity levels of patients by improving hip stability, decreasing dislocation rate and increasing range of motion. However, various concerns are encountered including wear debris generation at the trunnion-bore interface and increases in frictional torque and stress over the component-bone interface when using larger head sizes. So, the use of femoral head sizes less than 40 mm is recommended. PMID- 27777916 TI - Result of Modular Necks in Primary Total Hip Arthroplasty with a Average Follow up of Four Years. AB - PURPOSE: This study aimed to investigate the outcomes of modular neck-utilization in primary total hip arthroplasty (THA). MATERIALS AND METHODS: Thirty patients (34 hips) who had modular stem THA between April 2011 and January 2013 were evaluated. There were 19 men and 11 women with a mean age of 61.2 years at the time of surgery. There were 20 cases of osteonecrosis of femoral head, 7 cases of osteoarthritis, 6 cases of femur neck fracture, and 1 case of rheumatoid arthritis. No patients presented with anatomical deformity of hip. Patients were operated on using a modified Watson-Jones anterolateral approach. All patients underwent clinical and radiological follow-up at 6 weeks, 3, 6, and 12 months, and every year postoperatively. The mean duration of follow-up was 48.2 months (range, 39 to 59 months). RESULTS: The average Harris hip score improved from 63.7 to 88.1 at the final follow-up. Radiographically, mean acetabular cup inclination was 45.3 degrees (range, 36 degrees -61 degrees ) and anteversion was 21.7 degrees (range, 11 degrees -29 degrees ). All were neutral-positioned stems except 5 which were varus-positioned stems. In only 3 cases (8.8%), varus or valgus necks were required. A case of linear femoral fracture occurred intraoperatively and 1 case of dislocation occurred at postoperative 2 weeks. No complications at modular junction were occurred. CONCLUSION: Our study shows that the use of modular necks had favorable clinical and radiographic results. This suggests that the use of modular neck in primary THA without anatomical deformity is safe at a follow-up of 39 months. PMID- 27777917 TI - Adjuvant Teriparatide Therapy for Surgical Treatment of Femoral Fractures; Does It Work? AB - PURPOSE: Atypical femoral fracture (AFF), periprosthetic femoral fracture (PPFF) and femoral nonunion (FNU) are recalcitrant challenges for orthopedic surgeons. Teriparatide (TPTD) had been demonstrated to have anabolic effects on bone in various studies. We postulated that adjuvant TPTD after operation would enhance biologic stimulation for bone formation. We investigated (1) whether the adjuvant TPTD could achieve satisfactory union rate of surgically challenging cases such as displaced AFF, PPFF and FNU; (2) whether the adjuvant TPTD could promote development of abundant callus after surgical fixation; (3) whether the adjuvant TPTD had medically serious adverse effects. MATERIALS AND METHODS: Thirteen patients who agreed to off label use of TPTD in combination of operation were included in this retrospective case series. Median patients' age was 68.7 years, and there were three male and ten female patients. Their diagnoses were nonunion in six patients and acute fracture in seven. Medical records and radiographic images were reviewed. RESULTS: Twelve of thirteen fractures were united both clinically and radiologically within a year after adjuvant TPTD. Union completed radiologically median 5.4 months and clinically 5.7 months after the medication, respectively. Callus appeared abundantly showing median 1.4 of fracture healing response postoperatively. There was no serious adverse reaction of medication other than itching, muscle cramp, or nausea. CONCLUSION: Even appropriate surgical treatment is a mainstay of treatment for AFF, PPFF, and FNU, the current report suggested that adjuvant TPTD combined with stable fixation results in satisfactory outcome for the challenging fractures of femur. PMID- 27777918 TI - Analysis of the Korean Orthopedic In-Training Examination: The Hip and Pelvis Section. AB - PURPOSE: The purpose of this study was to analyze the questions in the hip and pelvis section of the Korean Orthopaedic In-Training Examination (KOITE). MATERIALS AND METHODS: We analyzed all KOITE questions pertaining to hip and pelvis surgery between 2010 and 2014. A thorough analysis of the contents was performed after categorizing as tested topics, imaging modalities used, taxonomic classification, and recommended references. We also analyzed the scores of the hip and pelvis section of the KOITE. RESULTS: Seventy-five of five-hundred questions (weight, 15.0%) were related to the hip and pelvis. Trauma including fracture and dislocation (26/75, 34.7%) was asked more commonly than disease and basics. The description-only questions (65/75, 86.7%) were the most frequently asked. According to taxonomic classification, taxonomy 3 (decision; 39/75, 52.0%) was most frequently asked. Campbell's Operative Orthopedics (52/75, 69.3%) was the reference that covered most of the questions. CONCLUSION: This analysis of the hip and pelvis section of KOITE could be used for resident training programs in teaching hospitals. PMID- 27777919 TI - Hip Arthroscopy for Incarcerated Acetabular Labrum following Reduction of Traumatic Hip Dislocation: Three Case Reports. AB - Traumatic hip fracture-dislocations are associated with chondral and labral pathology as well as loose bodies that can be incarcerated in the hip joint. Incarceration, such as interposed labrum between acetabulum and femoral head that is not readily visualized preoperatively, is a rare but important cause of pain and can potentially be a source for early degeneration and progression to osteoarthritis. We present three cases, arthroscopic surgery of incarcerated acetabular osseo-labral fragment following reduction of traumatic hip fracture dislocation. PMID- 27777920 TI - Bilateral Femoral Neck Stress Fracture in Child: A Case Report. AB - A femoral neck stress fracture in child is rare, particularly in bilateral case. It is easy to miss initially or may be misdiagnosed. The authors experienced a case of bilateral femoral neck stress fracture in a 10-year-old boy with bilateral hip. The patient was successfully healed by conservative treatment. We report this rare case with a review of the literature. A femoral neck stress fracture should be included in the differential diagnosis in children who present with sustained hip or groin pain. PMID- 27777921 TI - Pathologic Fracture of the Femur in Brown Tumor Induced in Parathyroid Carcinoma: A Case Report. AB - Brown tumor refers to a change of skeletones that develops as a complication of hyperparathyroidism. As osteoclast is activated to stimulate reabsorption and fibrosis of bone, it causes a cystic change of the bone. Parathyroid carcinoma is being reported as a tumor that induces primary hyperparathyroidism. It causes excessive secretion of the parathyroid hormone and increases the blood parathyroid hormone and calcium. Bone deformation due to brown tumor is known to be naturally recovered through the treatment for hyperparathyroidism. However, there is no clearly defined treatment for lesions that can induce pathological fractures developing in lower extremities. We experienced a case where brown tumor developed in the proximal femur of a 57-year-old female patient due to parathyroid carcinoma. In this case, spontaneous fracture occurred without any trauma, and it was cured by performing intramedullary nailing fixation and parathyroidectomy. We report the treatment results along with a literature review. PMID- 27777922 TI - Abductor Reconstruction with Gluteus Maximus Transfer in Primary Abductor Deficiency during Total Hip Arthroplasty. AB - Abductor deficiency in native hip joint may cause severe limping and pain. It is more serious situation in case of arthroplasty due to instability and recurrent dislocation. Well-known causes of abductor deficiency are repeated surgery, chronic trochanteric bursitis, superior gluteal nerve injury, failure of repair of abductor tendon insertion to the greater trochanter. Author had experienced primary abductor deficiency during total hip replacement and treated successfully with the transfer of gluteus maximus. We'd like to introduce the operation technique with the review of literature. PMID- 27777923 TI - Primary Intraosseus Xanthoma Involving the Proximal Femur in a Normolipidemic Patient: A Case Report. AB - We report the case of a 25-year-old woman presenting with left hip pain. A lesion was found in the proximal femoral metaphysis. Benign bone tumor, such as intraosseous lipoma or liposclerosing myxofibrous tumor, was suspected based on simple radiographs and magnetic resonance images. Curettage of the lesion and bone grafting was performed. Histologic findings reflected primary intraosseous xanthoma of the proximal femur. Laboratory tests revealed the patient to be normolipidemic, while immunoelectrophoretic fractionation of lipoproteins revealed normal values for alpha, pre-beta, beta, and chylomicrons. At the one year follow-up, there was no evidence of local recurrence. This is the first reported case of primary intraosseous xanthoma of the proximal femur in a normolipidemic patient. PMID- 27777924 TI - Ischial Tuberosity Avulsion Stress Fracture after Short Period of Repetitive Training. AB - Fatigue fracture of the pelvis is the form of fracture due to repetitive micro stress accumulation, can be affected by a number of factors such as patient's nutritional status, biomechanics, social status and so on. Still there is no study about precise standard degree of external force that lead to stress fracture, but it may caused by compression force, traction force or complex force and others. Avulsion stress to ischial tuberosity or anterior superior iliac spine by attached muscle is known as the main factor for the avulsion fracture. This report will deal with 19 years old conscripted policeman who occurred ischial tuberosity avulsion fracture after training of 6-hour running for 5 days accompanying hip hyper-flexion motion. This reports aims to provide case study of stress fracture occurred after 5 days of exercise which is relatively short period who had no specific trauma history or pain. PMID- 27777925 TI - The Effect of Bariatric Surgery on the Spectrum of Fatty Liver Disease. AB - Nonalcoholic fatty liver disease is becoming one of the most common causes of liver disease in the western world. The most significant risk factors are obesity and the metabolic syndrome for which bariatric surgery has been shown to be an effective treatment. However, the effects of bariatric surgery on nonalcoholic fatty liver disease, specifically liver fibrosis and cirrhosis, are not well established. We review published bariatric surgery outcomes with respect to nonalcoholic liver disease. On the basis of this review we suggest that bariatric surgery may provide a viable treatment option for the treatment of nonalcoholic fatty liver disease, including patients with fibrosis and compensated cirrhosis, and that this topic should be a target of future investigation. PMID- 27777926 TI - Effects of the West Africa Ebola Virus Disease on Health-Care Utilization - A Systematic Review. AB - Significant efforts were invested in halting the recent Ebola virus disease outbreak in West Africa. Now, studies are emerging on the magnitude of the indirect health effects of the outbreak in the affected countries, and the aim of this study is to systematically assess the results of these publications. The methodology for this review adhered to the Prisma guidelines for systematic reviews. A total of 3354 articles were identified for screening, and while 117 articles were read in full, 22 studies were included in the final review. Utilization of maternal health services decreased during the outbreak. The number of cesarean sections and facility-based deliveries declined and followed a similar pattern in Guinea, Liberia, and Sierra Leone. A change in the utilization of antenatal and postnatal care and family planning services was also seen, as well as a drop in utilization of children's health services, especially in terms of vaccination coverage. In addition, the uptake of HIV/AIDS and malaria services, general hospital admissions, and major surgeries decreased as well. Interestingly, it was the uptake of health service provision by the population that decreased, rather than the volume of health service provision. Estimates from the various studies suggest that non-Ebola morbidity and mortality have increased after the onset of the outbreak in Sierra Leone, Guinea, and Liberia. Reproductive, maternal, and child health services were especially affected, and the decrease in facility deliveries, cesarean sections, and volume of antenatal and postnatal care visits might have significant adverse effects on maternal and newborn health. The impact of Ebola stretches far beyond Ebola cases and deaths. This review indicates that indirect health service effects are substantial and both short and long term, and highlights the importance of support to maintain routine health service delivery and the maintenance of vaccination programs as well as preventative and curative malaria programs, both in general but especially in times of a disaster. PMID- 27777927 TI - Mechanobiology in Cardiovascular Disease Management: Potential Strategies and Current Needs. PMID- 27777928 TI - Cervicovaginal Fluid Acetate: A Metabolite Marker of Preterm Birth in Symptomatic Pregnant Women. AB - Changes in vaginal microbiota that is associated with preterm birth (PTB) leave specific metabolite fingerprints that can be detected in the cervicovaginal fluid (CVF) using metabolomics techniques. In this study, we characterize and validate the CVF metabolite profile of pregnant women presenting with symptoms of threatened preterm labor (PTL) by both 1H-nuclear magnetic resonance spectroscopy (NMR) and enzyme-based spectrophotometry. We also determine their predictive capacity for PTB, singly, and in combination, with current clinical screening tools - cervicovaginal fetal fibronectin (FFN) and ultrasound cervical length (CL). CVF was obtained by high-vaginal swabs from 82 pregnant women with intact fetal membranes presenting between 24 and 36 weeks gestation with symptoms of threatened, but not established, PTL. Dissolved CVF samples were scanned with a 400 MHz NMR spectrometer. Acetate and other metabolites were identified in the NMR spectrum, integrated for peak area, and normalized to the total spectrum integral. To confirm and validate our observations, acetate concentrations (AceConc) were also determined from a randomly-selected subset of the same samples (n = 57), by spectrophotometric absorption of NADH using an acetic acid assay kit. CVF FFN level, transvaginal ultrasound CL, and vaginal pH were also ascertained. Acetate normalized integral and AceConc were significantly higher in the women who delivered preterm compared to their term counterparts (P = 0.002 and P = 0.006, respectively). The 1H-NMR-derived acetate integrals were strongly correlated with the AceConc estimated by spectrophotometry (r = 0.69; P < 0.0001). Both methods were equally predictive of PTB <37 weeks (acetate integral: AUC = 0.75, 95% CI = 0.60-0.91; AceConc: AUC = 0.74, 95% CI = 0.57-0.90, optimal predictive cutoff of >0.53 g/l), and of delivery within 2 weeks of the index assessment (acetate integral: AUC = 0.77, 95% CI = 0.58-0.96; AceConc: AUC = 0.68, 95% CI = 0.5-0.9). The predictive accuracy of CVF acetate was similar to CL and FFN. The combination of CVF acetate, FFN, and ultrasound CL in a binary logistic regression model improved the prediction of PTB compared to the three markers individually, but CVF acetate offered no predictive improvement over ultrasound CL combined with CVF FFN. Elevated CVF acetate in women with symptoms of PTL appears predictive of preterm delivery, as well as delivery within 2 weeks of presentation. An assay of acetate in CVF may prove of clinical utility for predicting PTB. PMID- 27777931 TI - Mitochondrial ROS versus ER ROS: Which Comes First in Myocardial Calcium Dysregulation? PMID- 27777929 TI - Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain. AB - Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent (cp) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous (cp/cp) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the "thrifty gene" hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS). PMID- 27777932 TI - Multi-Biomarker Profiling and Recurrent Hospitalizations in Heart Failure. AB - BACKGROUND: Despite advances in pharmacologic therapy and devices, patients with heart failure (HF) continue to have significant rehospitalization rates and risk prediction remains challenging. We sought to explore the value of a multi biomarker panel [including NT-proBNP, high-sensitivity cardiac troponin T (hs TnT), and ST2] on top of clinical assessment for long-term prediction of recurrent hospitalizations in HF. METHODS AND RESULTS: NT-proBNP, hs-TnT, and ST2 (suppression of tumorigenicity-2) levels were measured in 891 consecutive ambulatory HF patients. The independent association between the multi-biomarker panel and recurrent hospitalizations was assessed through a multivariable negative binomial regression and expressed as incidence rates ratios. McFadden pseudo-R2 and goodness-of-fit measures were also used. The total number of unplanned hospitalizations [all-cause, cardiovascular (CV)-, and HF-related] were selected as the primary endpoints. At a mean follow-up of 4.2 +/- 2.1 years, 1623 all-cause hospitalizations in 498 patients (55.9%), 710 CV-related hospitalizations in 331 patients (37.2%), and 444 HF-related hospitalizations in 214 patients (24.1%) were registered. The crude incidence of all-cause, CV-, and HF-related recurrent hospitalizations was significantly higher for patients with the multi-biomarker panel above the cut-point (hs-TnT > 14 ng/L, NT-proBNP > 1000 ng/L, and ST2 > 35 ng/mL) (all P < 0.001). For all-cause, CV-, and HF-related recurrent hospitalizations, the McFadden R2, Akaike information criterion, and Bayesian information criterion supported the superiority of incorporating the multi-biomarker panel into a clinical predictive model. CONCLUSION: A multi biomarker approach based on NT-proBNP, hs-TnT, and ST2 better identifies HF patients at risk for recurrent hospitalizations as compared to approaches entailing just one or two of these biomarkers. Elucidation of new biophysiological predictors for recurrent hospitalizations may identify patient profiles for focused intervention. PMID- 27777930 TI - Characterization of AQPs in Mouse, Rat, and Human Colon and Their Selective Regulation by Bile Acids. AB - In normal individuals, the epithelium of the colon absorbs 1.5-2 l of water a day to generate dehydrated feces. However, in the condition of bile acid malabsorption (BAM), an excess of bile acids in the colon results in diarrhea. Several studies have attempted to address the mechanisms contributing to BAM induced by various bile acids. However, none have addressed a potential dysregulation of aquaporin (AQP) water channels, which are responsible for the majority of transcellular water transport in epithelial cells, as a contributing factor to the onset of diarrhea and the pathogenesis of BAM. In this study, we aimed to systematically analyze the expression of AQPs in colonic epithelia from rat, mouse, and human and determine whether their expression is altered in a rat model of BAM. Mass spectrometry-based proteomics, RT-PCR, and western blotting identified various AQPs in isolated colonic epithelial cells from rats (AQP1, 3, 4, 7, 8) and mice (AQP1, 4, 8). Several AQPs were also detected in human colon (AQP1, 3, 4, 7-9). Immunohistochemistry localized AQP1 to the apical plasma membrane of epithelial cells in the bottom of the crypts, whereas AQP3 (rat, human) and AQP4 (mice, human) were localized predominantly in the basolateral plasma membrane. AQP8 was localized intracellularly and at the apical plasma membrane of epithelial cells. Rats fed sodium cholate for 72 h had significantly increased fecal water content, suggesting development of BAM-associated diarrhea. Colonic epithelial cells isolated from this model had significantly altered levels of AQP3, 7, and 8, suggesting that these AQPs may be involved in the pathogenesis of bile acid-induced diarrhea. PMID- 27777933 TI - Simulating the Epidemiological and Economic Impact of Paratuberculosis Control Actions in Dairy Cattle. AB - We describe a new mechanistic bioeconomic model for simulating the spread of Mycobacterium avium subsp. paratuberculosis (MAP) within a dairy cattle herd. The model includes age-dependent susceptibility for infection; age-dependent sensitivity for detection; environmental MAP build up in five separate areas of the farm; in utero infection; infection via colostrum and waste milk, and it allows for realistic culling (i.e., due to other diseases) by including a ranking system. We calibrated the model using a unique dataset from Denmark, including 102 random farms with no control actions against spread of MAP. Likewise, four control actions recommended in the Danish MAP control program were implemented in the model based on reported management strategies in Danish dairy herds in a MAP control scheme. We tested the model parameterization in a sensitivity analysis. We show that a test-and-cull strategy is on average the most cost-effective solution to decrease the prevalence and increase the total net revenue on a farm with low hygiene, but not more profitable than no control strategy on a farm with average hygiene. Although it is possible to eradicate MAP from the farm by implementing all four control actions from the Danish MAP control program, it was not economically attractive since the expenses for the control actions outweigh the benefits. Furthermore, the three most popular control actions against the spread of MAP on the farm were found to be costly and inefficient in lowering the prevalence when used independently. PMID- 27777934 TI - Direct conversion of fibroblasts traces the way back to our first organ-the placenta. PMID- 27777935 TI - Maintenance of hematopoietic stem cell dormancy: yet another role for the macrophage. PMID- 27777936 TI - Divergent lncRNAs take the lead on pluripotent cell differentiation. PMID- 27777937 TI - Mesenchymal stem cell therapy for refractory scleroderma: a report of 2 cases. AB - We treated 2 patients with progressive, refractory scleroderma with a combined immunotherapy approach using plasmapheresis followed by rituximab and then intravenous umbilical-cord-derived allogeneic mesenchymal stem cells (MSCs). Both patients improved subjectively and objectively for over a year. Upon recurrence of their symptoms, the patients were treated again with allogeneic MSCs alone with a very good response. The combination was well tolerated and effective suggesting a large scale study may be warranted in progressive, refractory Scleroderma. PMID- 27777938 TI - Intestinal stem cell resurgence by enterocyte precursors. PMID- 27777939 TI - TET2 mutations were predictive of inferior prognosis in the presence of ASXL1 mutations in patients with chronic myelomonocytic leukemia. AB - BACKGROUND: Somatic mutations involving epigenetic regulators, histone modification and chromatin regulation, splicing components, transcription factors and signaling regulator genes are common in chronic myelomonocytic leukemia (CMML) patients. It has been consensus that ASXL1 mutations have adversely impact on overall survival (OS), while the effect of TET2 mutations remains controversial and undefined. METHODS: ASXL1 and TET2 mutations were analyzed in 141 patients with CMML using Sanger sequencing, with the aim to identify the interplay of ASXL1 and TET2 mutations in the prognosis of CMML. RESULTS: Sixty five (46.1%) of the CMML patients harbored ASXL1 mutations (frameshift and nonsense), and 46 (32.6%) had TET2 mutations (frame shift, nonsense and missense). In a separate multivariable analysis that included the Mayo Prognostic Model as a single variable along with ASXL1wt/TET2wt, the respective hazard ratios of ASXL1mut/TET2mut, ASXL1mut/TET2wt and ASXL1wt/TET2mut were 4.7 (95% CI, 2.2-10.3; P<0.001), 2.2 (95% CI, 1.1-4.2; P=0.025) and 1.3 (95% CI, 0.6-2.5; P=0.521). CONCLUSIONS: Our study showed that ASXL1 mutations predict inferior OS, and additional TET2 mutations were associated with poor survival in the presence of ASXL1 mutations of CMML patients. PMID- 27777940 TI - Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications. AB - Colorectal carcinogenesis is a multi-step process. While ~25% of colorectal cancers (CRCs) arise in patients with a family history (genetic predisposition), ~75% of CRCs are due to age-associated accumulation of epigenetic alterations which can result in the suppression of key tumor suppressor genes leading to mutations and activation of oncogenic pathways. Sporadic colon-carcinogenesis is facilitated by many molecular pathways of genomic instability which include chromosomal instability (CIN), micro-satellite instability (MSI) and CpG island methylator phenotype (CIMP), leading towards loss of homeostasis and onset of neoplastic transformation. The unopposed activation of Wnt/beta-catenin pathways, either due to loss of APC function or up-regulation of related stimulatory pathways, results in unopposed hyperproliferation of colonic crypts, considered the single most important risk factor for colon carcinogenesis. Hypermethylation of CpG islands within the promoters of specific genes can potentially inactivate DNA repair genes and/or critical tumor suppressor genes. Recently, CpG methylation of the 5' promoter of human (h) DCLK1 gene was reported in many human epithelial cancers, including colorectal cancers (CRCs), resulting in the loss of expression of the canonical long isoform of DCLK1 (DCLK1-L) in hCRCs. Instead, a shorter isoform of DCLK1 (DCLK1-S) was discovered to be expressed in hCRCs, from an alternate beta promoter of DCLKL1-gene; the clinical and biological implications of these novel findings, in relation to recent publications is discussed. PMID- 27777942 TI - In vivo reprogramming of hepatic myofibroblasts into hepatocytes attenuates liver fibrosis: back to the future? PMID- 27777943 TI - Noncoding RNAs as therapeutics for acetaminophen-induced liver injury. PMID- 27777941 TI - A review of Rett syndrome (RTT) with induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs. For these reasons, hiPSCs have huge potential in translational medicine such as disease modeling, drug screening, and cellular therapy. Indeed, patient-specific hiPSCs have been generated for a multitude of diseases, including many with a neurological basis, in which disease phenotypes have been recapitulated in vitro and proof-of-principle drug screening has been performed. As the techniques for generating hiPSCs are refined and these cells become a more widely used tool for understanding brain development, the insights they produce must be understood in the context of the greater complexity of the human genome and the human brain. Disease models using iPS from Rett syndrome (RTT) patient's fibroblasts have opened up a new avenue of drug discovery for therapeutic treatment of RTT. The analysis of X chromosome inactivation (XCI) upon differentiation of RTT-hiPSCs into neurons will be critical to conclusively demonstrate the isolation of pre-XCI RTT-hiPSCs in comparison to post-XCI RTT hiPSCs. The current review projects on iPSC studies in RTT as well as XCI in hiPSC were it suggests for screening new potential therapeutic targets for RTT in future for the benefit of RTT patients. In conclusion, patient-specific drug screening might be feasible and would be particularly helpful in disorders where patients frequently have to try multiple drugs before finding a regimen that works. PMID- 27777944 TI - Phytochemical Screening and Antinociceptive and Antidiarrheal Activities of Hydromethanol and Petroleum Benzene Extract of Microcos paniculata Barks. AB - Introduction. Microcos paniculata is traditionally used for treating diarrhea, wounds, cold, fever, hepatitis, dyspepsia, and heat stroke. Objective. To investigate the qualitative phytochemical constituents of hydromethanol (HMPB) and petroleum benzene extract of Microcos paniculata barks (PBMPB) and to evaluate their antinociceptive and antidiarrheal activities. Methods. Phytochemical constituents and antinociceptive and antidiarrheal activities were determined and evaluated by different tests such as Molisch's, Fehling's, Mayer's, Wagner's, Dragendorff's, frothing, FeCl3, alkali, Pew's, and Salkowski's test, general test of glycosides, Baljet and NH4OH test, formalin-induced paw licking, acetic acid-induced writhing, tail immersion, and hot plate tests, and castor oil and MgSO4 induced diarrheal tests. Results. These extracts revealed the presence of saponins, flavonoids, and triterpenoids and significantly (*P < 0.05, versus control) reduced paw licking and abdominal writhing of mice. At 30 min after their administration, PBMPB revealed significant increase in latency (*P < 0.05, versus control) in tail immersion test. In hot plate test, HMPB and PBMPB 200 mg/kg showed significant increase in response latency (*P < 0.05, versus control) at 30 min after their administration. Moreover, both extracts significantly (*P < 0.05, versus control) inhibited percentage of diarrhea in antidiarrheal models. Conclusion. Study results indicate that M. paniculata may provide a source of plant compounds with antinociceptive and antidiarrheal activities. PMID- 27777945 TI - The Effects of Agave fourcroydes Powder as a Dietary Supplement on Growth Performance, Gut Morphology, Concentration of IgG, and Hematology Parameters in Broiler Rabbits. AB - This study was conducted to determine the effects of Agave fourcroydes powder as a dietary supplement on the growth performance, gut morphology, serum concentration of IgG, and the hematology parameters of broiler rabbits. A total of 32 rabbits [New Zealand * Californian] were weaned at 35 days. They were randomly selected for two dietary treatments (eight repetitions per treatment), which consisted of a basal diet and a basal diet supplemented with 1.5% dried stem powder of A. fourcroydes. On day 60 from the initiation of treatment, gut histomorphology (duodenum and cecum), serum concentration of IgG, and hematology parameters were all measured. The results showed that A. fourcroydes powder supplementation improved (P < 0.05) the ADFI, ADG, and final BW. Correspondingly, this treatment increased (P < 0.05) the muscle and mucosa thickness and height and width of villi. However, duodenum crypts depth was lower (P < 0.05) when rabbits were fed with this natural product, compared with the basal diet treatment. Results also indicated that the A. fourcroydes powder increased (P < 0.05) the serum concentration of IgG but did not change the hematology parameters. This data indicates that A. fourcroydes powder, as a supplement, had beneficial effects on increasing the growth performance and serum concentration of IgG, as well as improving the gut morphology without affecting the hematology parameters in broiler rabbits. PMID- 27777946 TI - The Effects of Diabetes Mellitus in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting. AB - Objective. To investigate the effects of diabetes mellitus (DM) in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Method. A total of 728 patients with DM and 1380 patients without DM who underwent OPCAB treatment from March 2012 to April 2015 were reviewed. The effects of DM on intraoperative variables and postoperative complications were determined using propensity score analysis. Results. Two well-matched subgroups were selected using propensity score analysis (DM = 728, no-DM = 728) to compare the perioperative outcome. The duration of the ICU stay, in hours (55.2 +/- 53.0 versus 49.29 +/- 51.30, P < 0.05), postoperative new-onset atrial fibrillation (20.9% versus 14.97%, P < 0.05), and postoperative infection (9.2% versus 4.67%, P < 0.05) were greater in DM patients, as indicated by univariate analysis. Conclusion. OPCAB was found to be effective in DM patients, but postoperative infection and postoperative new onset atrial fibrillation were found to be more likely to occur in DM patients than in other patients. DM was found to be a powerful risk factor for postoperative infection and postoperative new-onset atrial fibrillation. PMID- 27777947 TI - Expansion of Submucosal Bladder Wall Tissue In Vitro and In Vivo. AB - In order to develop autologous tissue engineering of the whole wall in the urinary excretory system, we studied the regenerative capacity of the muscular bladder wall. Smooth muscle cell expansion on minced detrusor muscle in vitro and in vivo with or without urothelial tissue was studied. Porcine minced detrusor muscle and urothelium were cultured in vitro under standard culture conditions for evaluation of the explant technique and in collagen for tissue sectioning and histology. Autografts of minced detrusor muscle with or without minced urothelium were expanded on 3D cylinder moulds by grafting into the subcutaneous fat of the pig abdominal wall. Moulds without autografts were used as controls. Tissue harvesting, mincing, and transplantation were performed as a one-step procedure. Cells from minced detrusor muscle specimens migrated and expanded in vitro on culture plastic and in collagen. In vivo studies with minced detrusor autografts demonstrated expansion and regeneration in all specimens. Minced urothelium autografts showed multilayered transitional urothelium when transplanted alone but not in cotransplantation with detrusor muscle; thus, minced bladder mucosa was not favored by cografting with minced detrusor. No regeneration of smooth muscle or epithelium was seen in controls. PMID- 27777948 TI - The Role of Obesity in Sepsis Outcome among Critically Ill Patients: A Retrospective Cohort Analysis. AB - Background. The objective of this study was to assess the correlation between sepsis, obesity, and mortality of patients admitted to an Intensive Care Unit (ICU). Subjects and Methods. Data of all patients admitted to the ICU of a tertiary hospital during a 28-month period were retrospectively analyzed and included in the study. Results. Of 834 patients included, 163 (19.5%) were obese, while 25 (3.0%) were morbidly obese. Number of comorbidities (P < 0.001), bloodstream infection (P 0.033), and carbapenemase-producing Klebsiella pneumoniae colonization during ICU stay (P 0.005) were significantly associated with obesity, while nonobese patients suffered more frequently from spontaneous intracranial hemorrhage (P 0.038). Total ICU mortality was 22.5%. Increased mortality among obese ICU patients was observed. Sepsis was the main condition of admission for which obese patients had statistically lower survival than normal weight subjects (76.3% versus 43.7%; P 0.001). Mortality of septic patients upon admission was independently associated with SOFA score upon ICU admission (P 0.003), obesity (P 0.014), pneumonia (P 0.038), and development of septic shock (P 0.015). Conclusions. Our study revealed that sepsis upon ICU admission is adversely influenced by obesity but further studies are needed in order to assess the role of obesity in sepsis outcome. PMID- 27777949 TI - Predictors of Survival in Esophageal Squamous Cell Carcinoma with Pathologic Major Response after Neoadjuvant Chemoradiation Therapy and Surgery: The Impact of Chemotherapy Protocols. AB - Tumor recurrence is an important problem threatening esophageal cancer patients after surgery, even when they achieve a pathologic major response (pMR) after neoadjuvant concurrent chemoradiation therapy (CCRT). The predictors related to overall survival and disease progression for these patients remain elusive. We aimed to identify factors that predict disease progression and overall survival in esophageal squamous cell carcinoma (SCC) patients who achieve a pMR after neoadjuvant CCRT followed by surgery. We conducted a retrospective study to analyze the factors influencing survival and disease progression after esophagectomy for esophageal cancer patients who had a major response to CCRT, which is defined by complete pathological response or microscopic residual disease without lymph node metastasis. From our study cohort, 285 patients underwent CCRT and subsequent esophagectomy; 171 (60%) of these patients achieved pMR. After excluding patients with lymph node metastases, incomplete clinical data, and adenocarcinomas, we enrolled 117 patients in this study. We found that the CCRT regimen was the only factor that influenced overall survival. The overall survival of the patients receiving taxane-incorporated CCRT was superior to that of patients receiving traditional cisplatin and 5-fluorouracil (PF) (P = 0.011). The CCRT regimen can significantly influence the clinical outcome of esophageal SCC patients who achieve pMR after neoadjuvant CCRT and esophagectomy. Incorporation of taxanes into cisplatin-based CCRT may be associated with prolonged survival. PMID- 27777950 TI - Epidemiology of American Tegumentary Leishmaniasis and Trypanosoma cruzi Infection in the Northwestern Argentina. AB - Background. Endemic areas of tegumentary leishmaniasis (TL) in Salta, Argentina, present some overlap zones with the geographical distribution of Chagas disease, with mixed infection cases being often detected. Objectives. The purpose of this study was to determine the magnitude of Leishmania sp. infection and potential associated risk factors, the serologic prevalence of T. cruzi, and the presence of T. cruzi-Leishmania sp. mixed infection in a region of the northwest of Argentina. Methods. Cross-sectional studies were conducted to detect TL prevalence and T. cruzi seroprevalence. A case-control study was conducted to examine leishmaniasis risk factors. Results. Prevalence of TL was 0.17%, seroprevalence of T. cruzi infection was 9.73%, and mixed infection proportion within the leishmaniasic patients group-was 16.67%. The risk factors associated with TL transmission were sex, age, exposure to bites at work, staying outdoors more than 10 hours/day, bathing in the river, and living with people who had lesions or were infected during the study. Discussion. The endemic pattern of TL seems to involve exposure of patients to vectors in wild as well as peridomestic environment. Cases of T. cruzi infection are apparently due to migration. Therefore, a careful epidemiological surveillance is necessary due to the contraindication of antimonial administration to chagasic patients. PMID- 27777951 TI - Optimization of a Coastal Environmental Monitoring Network Based on the Kriging Method: A Case Study of Quanzhou Bay, China. AB - Environmental monitoring is fundamental in assessing environmental quality and to fulfill protection and management measures with permit conditions. However, coastal environmental monitoring work faces many problems and challenges, including the fact that monitoring information cannot be linked up with evaluation, monitoring data cannot well reflect the current coastal environmental condition, and monitoring activities are limited by cost constraints. For these reasons, protection and management measures cannot be developed and implemented well by policy makers who intend to solve this issue. In this paper, Quanzhou Bay in southeastern China was selected as a case study; and the Kriging method and a geographic information system were employed to evaluate and optimize the existing monitoring network in a semienclosed bay. This study used coastal environmental monitoring data from 15 sites (including COD, DIN, and PO4-P) to adequately analyze the water quality from 2009 to 2012 by applying the Trophic State Index. The monitoring network in Quanzhou Bay was evaluated and optimized, with the number of sites increased from 15 to 24, and the monitoring precision improved by 32.9%. The results demonstrated that the proposed advanced monitoring network optimization was appropriate for environmental monitoring in Quanzhou Bay. It might provide technical support for coastal management and pollutant reduction in similar areas. PMID- 27777952 TI - Abdominal Aortic Aneurysm Repair: Results from a Series of Young Patients. AB - Objectives. To compare durability and survival after endovascular aneurysm repair (EVAR) and open repair (OR) of abdominal aortic aneurysms (AAAs) in young patients. Material and Methods. A retrospective study was conducted between 2005 and 2014 on all consecutive patients of 60 years of age or younger. Measures considered for analysis were reintervention related to AAA, laparotomy and access vessel injury during EVAR, and all-cause mortality during hospitalization and follow-up. Results. Seventy out of 119 patients were treated by OR (58.8%) and 49 (41.2%) by EVAR, 9 in off-label fashion (18.3%). Technical success was achieved in all cases. No AAA-related death was recorded. Overall in-hospital mortality was zero and the reintervention rate was 2.5% (3/119: 1/70 OR, 2/49 EVAR, p = 0.36). There is no death at 30-day or 1-year follow-up. Thirty-day reintervention rate was 1.6% (2/119; 0/70 OR, 2/49 EVAR, p = 0.16), while the 1-year rate was 2.5% (3/119; 1/70 OR, 2/49 EVAR, p = 0.36). At the mean follow-up of 56.8 +/- 42.7 months, mortality and reintervention rates were 5.8% (7/119; 3/70 OR, 4/49 EVAR, p = 0.38) and 10% (12/119; 8/70 OR, 4/49 EVAR, p = 0.39), respectively. The overall reintervention rate, mortality, and freedom from adverse events did not differ between the two groups. No differences in outcome were recorded between patients treated by EVAR in on-label versus off-label fashion. Conclusion. Our (albeit limited) experience suggests that, in an unselected young patient population undergoing elective AAA repair, OR or EVAR can be performed safely with similar immediate and long term outcomes. PMID- 27777953 TI - Brain-Computer Interface for Control of Wheelchair Using Fuzzy Neural Networks. AB - The design of brain-computer interface for the wheelchair for physically disabled people is presented. The design of the proposed system is based on receiving, processing, and classification of the electroencephalographic (EEG) signals and then performing the control of the wheelchair. The number of experimental measurements of brain activity has been done using human control commands of the wheelchair. Based on the mental activity of the user and the control commands of the wheelchair, the design of classification system based on fuzzy neural networks (FNN) is considered. The design of FNN based algorithm is used for brain actuated control. The training data is used to design the system and then test data is applied to measure the performance of the control system. The control of the wheelchair is performed under real conditions using direction and speed control commands of the wheelchair. The approach used in the paper allows reducing the probability of misclassification and improving the control accuracy of the wheelchair. PMID- 27777954 TI - Bioguided Fraction and Isolation of the Antitumor Components from Phyllanthus niruri L. AB - Phyllanthus niruri L., a well-known medicinal plant, has been used as a folk antitumor remedy in the worldwide scale. However, the antitumor components in P. niruri have not been reported. In order to verify the antitumor components of P. niruri and the plants which have the high content of these components, we isolated the antitumor components with bioguided fraction and isolation, by different chromatographic methods from the ethyl acetate fraction of P. niruri., and identified them as ethyl brevifolincarboxylate and corilagin by 1H-NMR, 13C NMR, 2D-NMR, and mass spectrometric analyses. Cell cytotoxicity assays showed that corilagin has broad-spectrum antitumor activity, a better antitumor potential, and lower toxicity in normal cells. Besides, the coefficient of drug interaction (CDI) of 10 MUM corilagin and 20 MUM cDDP reached up to 0.77, which means corilagin can promote the antitumor activity of cDDP. Furthermore, by the extensive screening among 10 species of plants reported to contain corilagin, we found that Dimocarpus longan Lour. has the maximum content of corilagin. In conclusion, corilagin is the major active antitumor composition in P. niruri. L. on HCC cells and has high content in D. longan. PMID- 27777955 TI - Bioactive Natural Products 2016. PMID- 27777956 TI - Sequestration and Distribution Characteristics of Cd(II) by Microcystis aeruginosa and Its Role in Colony Formation. AB - To investigate the sequestration and distribution characteristics of Cd(II) by Microcystis aeruginosa and its role in Microcystis colony formation, M. aeruginosa was exposed to six different Cd(II) concentrations for 10 days. Cd(II) exposure caused hormesis in the growth of M. aeruginosa. Low concentrations of Cd(II) significantly induced formation of small Microcystis colonies (P < 0.05) and increased the intracellular polysaccharide (IPS) and bound extracellular polysaccharide (bEPS) contents of M. aeruginosa significantly (P < 0.05). There was a linear relationship between the amount of Cd(II) sequestrated by algal cells and the amount added to cultures in the rapid adsorption process that occurred during the first 5 min of exposure. After 10 d, M. aeruginosa sequestrated nearly 80% of 0.2 mg L-1 added Cd(II), while >93% of Cd(II) was sequestrated in the groups with lower added concentrations of Cd(II). More than 80% of the sequestrated Cd(II) was bioadsorbed by bEPS. The Pearson correlation coefficients of exterior and interior factors related to colony formation of M. aeruginosa revealed that Cd(II) could stimulate the production of IPS and bEPS via increasing Cd(II) bioaccumulation and bioadsorption. Increased levels of cross-linking between Cd(II) and bEPS stimulated algal cell aggregation, which eventually promoted the formation of Microcystis colonies. PMID- 27777957 TI - Optimal Revascularization Strategy on Medina 0,1,0 Left Main Bifurcation Lesions in Type 2 Diabetes. AB - Aim. Diabetes mellitus (DM) is a major risk factor for cardiovascular disease. The implications of a diagnosis of DM are as severe as the diagnosis of coronary artery disease. For many patients with complex coronary artery disease, optimal revascularization strategy selection and optimal medical therapy are equally important. In this study, we compared the hemodynamic results of different stenting techniques for Medina 0,1,0 left main bifurcation lesions. Methods. We use idealized left main bifurcation models and computational fluid dynamics analysis to evaluate hemodynamic parameters which are known to affect the risk of restenosis and thrombosis at stented bifurcation. The surface integrals of time averaged wall shear stress (TAWSS) and oscillatory shear index (OSI) at bifurcation site were quantified. Results. Crossover stenting without final kissing balloon angioplasty provided the most favorable hemodynamic results (integrated values of TAWSS = 2.96 * 10-4 N, OSI = 4.75 * 10-6 m2) with bifurcation area subjected to OSI values >0.25, >0.35, and >0.45 calculated as 0.39 mm2, 0.06 mm2, and 0 mm2, respectively. Conclusion. Crossover stenting only offers hemodynamic advantages over other stenting techniques for Medina 0,1,0 left main bifurcation lesions and large bifurcation angle is associated with unfavorable flow profiles. PMID- 27777958 TI - Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity. AB - Ceramide and diacylglycerol (DAG) may be involved in the early phase of insulin resistance but data are inconsistent in man. We evaluated if an increase in insulin sensitivity after endurance training was accompanied by changes in these lipids in skeletal muscle. Nineteen first-degree type 2 diabetes Offsprings (Offsprings) (age: 33.1 +/- 1.4 yrs; BMI: 26.4 +/- 0.4 kg/m2) and sixteen matched Controls (age: 31.3 +/- 1.5 yrs; BMI: 25.3 +/- 0.7 kg/m2) performed 10 weeks of endurance training three times a week at 70% of VO2max on a bicycle ergometer. Before and after the intervention a hyperinsulinemic-euglycemic clamp and VO2max test were performed and muscle biopsies obtained. Insulin sensitivity was significantly lower in Offsprings compared to control subjects (p < 0.01) but improved in both groups after 10 weeks of endurance training (Off: 17 +/- 6%; Con: 12 +/- 9%, p < 0.01). The content of muscle ceramide, DAG, and their subspecies were similar between groups and did not change in response to the endurance training except for an overall reduction in C22:0-Cer (p < 0.05). Finally, the intervention induced an increase in AKT protein expression (Off: 27 +/- 11%; Con: 20 +/- 24%, p < 0.05). This study showed no relation between insulin sensitivity and ceramide or DAG content suggesting that ceramide and DAG are not major players in the early phase of insulin resistance in human muscle. PMID- 27777960 TI - The Type 2 Deiodinase Thr92Ala Polymorphism Is Associated with Worse Glycemic Control in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta Analysis. AB - Objective. Type 2 deiodinase (Dio2) is an enzyme responsible for the conversion of T4 to T3. The Thr92Ala polymorphism has been shown related to an increased risk for developing type 2 diabetes mellitus (T2DM). The aim of this study is to assess the association between this polymorphism and glycemic control in T2DM patients as marked by the HbA1C levels. Design and Methods. The terms "rs225014," "thr92ala," "T92A," or "dio2 a/g" were used to search for eligible studies in the PubMed, Embase, and Cochrane databases and Google Scholar. A systematic review and meta-analysis of studies including both polymorphism testing and glycated hemoglobin (HbA1C) assays were performed. Results. Four studies were selected, totaling 2190 subjects. The pooled mean difference of the studies was 0.48% (95% CI, 0.18-0.77%), indicating that type 2 diabetics homozygous for the Dio2 Thr92Ala polymorphism had higher HbA1C levels. Conclusions. Homozygosity for the Dio2 Thr92Ala polymorphism is associated with higher HbA1C levels in T2DM patients. To confirm this conclusion, more studies of larger populations are needed. PMID- 27777959 TI - Changes of Regulatory T Cells and of Proinflammatory and Immunosuppressive Cytokines in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta Analysis. AB - Objective. The aim of this study was to investigate the changes of regulatory T cells (Treg), interleukin-6 (IL-6), IL-10, transforming growth factor-beta (TGF beta), and tumor necrosis factor-alpha (TNF-alpha) in patients with type 2 diabetes mellitus (T2DM). Methods. We performed a comprehensive search up to July 2016 for all clinical studies about the changes of Treg, IL-6, IL-10, IL-17, TGF beta, and TNF-alpha in T2DM patients versus healthy controls. Results. A total of 91 articles (5642 cases and 7378 controls) were included for this meta-analysis. Compared with the controls (all p < 0.001), the patients had increased serum levels of IL-6, TGF-beta, and TNF-alpha but decreased the percentage of peripheral CD4+CD25+Foxp3+Treg and serum IL-10 level. Furthermore, the percentage of peripheral CD4+CD25+Foxp3+Treg (p < 0.001) and serum IL-10 level (p = 0.033) were significantly lower in the patients with complication and in the patients without complication, respectively. No significant changes about the percentage of CD4+CD25+Treg (p = 0.360) and serum IL-17 level (p = 0.459) were found in T2DM patients. Conclusions. T2DM patients have decreased the percentage of peripheral CD4+CD25+Foxp3+Treg and levels of serum IL-10 but elevated serum levels of IL-6, TGF-beta, and TNF-alpha. Presence of diabetic complications further lowers the peripheral CD4+CD25+Foxp3+Treg number. PMID- 27777961 TI - Sweet Bones: The Pathogenesis of Bone Alteration in Diabetes. AB - Diabetic patients have increased fracture risk. The pathogenesis underlying the status of bone alterations in diabetes mellitus is not completely understood but is multifactorial. The major deficits appear to be related to a deficit in mineralized surface area, a decrement in the rate of mineral apposition, deceased osteoid surface, depressed osteoblast activity, and decreased numbers of osteoclasts due to abnormal insulin signaling pathway. Other prominent features of diabetes mellitus are an increased urinary excretion of calcium and magnesium, accumulation of advanced glycation end products, and oxidative stress leading to sweet bones (altered bone's strength, metabolism, and structure). Every diabetic patient should be assessed for risk factors for fractures and osteoporosis. The pathogenesis of the bone alterations in diabetes mellitus as well as their molecular mechanisms needs further study. PMID- 27777962 TI - The Polymorphism -308G/A of Tumor Necrosis Factor-alpha Gene Modulates the Effect of Immunosuppressive Treatment in First Kidney Transplant Subjects Who Suffer an Acute Rejection. AB - The -308G/A SNP of tumor necrosis factor-alpha (TNF-alpha) gene affects TNF-alpha production. As its impact on transplant outcome remains open to debate, we decided to genotype it in a cohort of transplant subjects. A retrospective analysis of 439 first kidney recipients randomly divided into two subgroups (discovery and validation cohorts) was performed to identify the best predictors of acute rejection (AR). The effect on transplant outcome was analyzed by an adjusted logistic regression model. Carriers of the A allele, associated with elevated TNF-alpha production, presented a higher risk of AR (OR = 2.78; 95% CI = 1.40-5.51). Logistic regression analyses for AR showed an interaction between the polymorphism and treatment with thymoglobulin (p-interaction = 0.03). In recipients who did not receive thymoglobulin, carriers of A allele had higher risk of AR (OR = 4.05; 95% CI = 1.76-9.28). Moreover, carriers of A allele not treated with thymoglobulin presented higher risk of AR than those who received thymoglobulin (OR = 13.74; 95% CI = 1.59-118.7). The AUC of the model in the discovery cohort was 0.70 and in the validation cohort was 0.69. Our findings indicate that the -308G/A TNF-alpha polymorphism is associated with AR risk and it modulates the effectiveness of thymoglobulin treatment. This pharmacogenetic effect lets us propose this SNP as a useful predictor biomarker to tailor immunosuppressive regimens. PMID- 27777965 TI - Behavioral factors predicting response to employment-based reinforcement of cocaine abstinence in methadone patients. AB - We sought to identify behavioral factors associated with response to an employment-based intervention, in which participants had to provide drug-free urine samples to gain access to paid employment. The present secondary analysis included data from a randomized clinical trial. The trial evaluated whether employment-based reinforcement could decrease cocaine use in community methadone patients. Participants (N=56) in the trial worked in a model workplace for 4 hr every weekday and earned about $10 per hr. After a 4-week baseline, participants were randomly assigned to an Abstinence & Work (n = 28) or Work Only (n = 28) condition and could work for an additional 26 weeks. Abstinence & Work participants had to provide cocaine-negative urine samples to work and maintain maximum pay. Work Only participants only had to work to earn pay. For Work Only participants, cocaine abstinence during baseline and the intervention period were significantly (rs = .72, p <.001) correlated. For Abstinence & Work participants, baseline opiate abstinence was significantly correlated (rs = .59, p <.001) and workplace attendance was marginally correlated (rs = .32, p = .098) with cocaine abstinence during the intervention period. Furthermore, participants who provided over 60% cocaine-negative urine samples during the intervention period (i.e., responders) had significantly higher baseline rates of opiate abstinence (p <.0001) and workplace attendance (p = .042) than non-responders. Employment-based reinforcement of cocaine abstinence may be improved by increasing opiate abstinence and workplace attendance prior to initiating the cocaine-abstinence intervention. PMID- 27777964 TI - A Review of the Literature on Remote Monitoring Technology in Incentive-Based Interventions for Health-Related Behavior Change. AB - Use of technology (e.g., Internet, cell phones) to allow remote implementation of incentives interventions for health-related behavior change is growing. To our knowledge, there has yet to be a systematic review of this literature reported. The present report provides a systematic review of the controlled studies where technology was used to remotely implement financial incentive interventions targeting substance use and other health behaviors published between 2004 and 2015. For inclusion in the review, studies had to use technology to remotely accomplish one of the following two aims alone or in combination: (a) monitor the target behavior, or (b) deliver incentives for achieving the target goal. Studies also had to examine financial incentives (e.g., cash, vouchers) for health related behavior change, be published in peer-reviewed journals, and include a research design that allowed evaluation of the efficacy of the incentive intervention relative to another condition (e.g., non-contingent incentives, treatment as usual). Of the 39 reports that met inclusion criteria, 18 targeted substance use, 10 targeted medication adherence or home-based health monitoring, and 11 targeted diet, exercise, or weight loss. All 39 (100%) studies used technology to facilitate remote monitoring of the target behavior, and 26 (66.7%) studies also incorporated technology in the remote delivery of incentives. Statistically significant intervention effects were reported in 71% of studies reviewed. Overall, the results offer substantial support for the efficacy of remotely implemented incentive interventions for health-related behavior change, which have the potential to increase the cost-effectiveness and reach of this treatment approach. PMID- 27777966 TI - The Therapeutic Utility of Employment in Treating Drug Addiction: Science to Application. AB - Research on a model Therapeutic Workplace has allowed for evaluation of the use of employment in the treatment of drug addiction. Under the Therapeutic Workplace intervention, adults with histories of drug addiction are hired and paid to work. To promote drug abstinence or adherence to addiction medications, participants are required to provide drug-free urine samples or take prescribed addiction medications, respectively, to gain access to the workplace and/or to maintain their maximum rate of pay. Research has shown that the Therapeutic Workplace intervention is effective in promoting and maintaining abstinence from heroin, cocaine and alcohol and in promoting adherence to naltrexone. Three models could be used to implement and maintain employment-based reinforcement in the treatment of drug addiction: A Social Business model, a Cooperative Employer model, and a Wage Supplement model. Under all models, participants initiate abstinence in a training and abstinence initiation phase (Phase 1). Under the Social Business model, Phase 1 graduates are hired as employees in a social business and required to maintain abstinence to maintain employment and/or maximum pay. Under the Cooperative Employer model, cooperating community employers hire graduates of Phase 1 and require them to maintain abstinence to maintain employment and/or maximum pay. Under the Wage Supplement Model, graduates of Phase 1 are offered abstinence-contingent wage supplements if they maintain competitive employment in a community job. Given the severity and persistence of the problem of drug addiction and the lack of treatments that can produce lasting effects, continued development of the Therapeutic Workplace is warranted. PMID- 27777963 TI - Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer. AB - The tumour microenvironment consists of malignant cells, stroma, and immune cells. Prominent tumour-infiltrating lymphocytes (TILs) in breast cancer are associated with a good prognosis and are predictors of a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC). The contribution of different T effector/regulatory cells and cytokines to tumour cell death with NAC requires further characterisation and was investigated in this study. Breast tumours from 33 women with large and locally advanced breast cancers undergoing NAC were immunohistochemically (intratumoural, stromal) assessed for T cell subsets and cytokine expression using labelled antibodies, employing established semiquantitative methods. Prominent levels of TILs and CD4+, CD8+, and CTLA-4+ (stromal) T cells and CD8+ : FOXP3+ ratios were associated with a significant pCR; no association was seen with FOXP3+, CTLA-4+ (intratumoural), and PD-1+ T cells. NAC significantly reduced CD4+, FOXP3+, CTLA-4+ (stromal) (concurrently blood FOXP3+, CTLA-4+ Tregs), and PD-1+ T cells; no reduction was seen with CD8+ and CTLA-4+ (intratumoural) T cells. High post-NAC tumour levels of FOXP3+ T cells, IL-10, and IL-17 were associated with a failed pCR. Our study has characterised further the contribution of T effector/regulatory cells and cytokines to tumour cell death with NAC. PMID- 27777968 TI - Adaptability and Stability Study of Selected Sweet Sorghum Genotypes for Ethanol Production under Different Environments Using AMMI Analysis and GGE Biplots. AB - The genotype and environment interaction influences the selection criteria of sorghum (Sorghum bicolor) genotypes. Eight sweet sorghum genotypes were evaluated at five different locations in two growing seasons of 2014. The aim was to determine the interaction between genotype and environment on cane, juice, and ethanol yield and to identify best genotypes for bioethanol production in Kenya. The experiments were conducted in a randomized complete block design replicated three times. Sorghum canes were harvested at hard dough stage of grain development and passed through rollers to obtain juice that was then fermented to obtain ethanol. Cane, juice, and ethanol yield was analyzed using the additive main effect and multiplication interaction model (AMMI) and genotype plus genotype by environment (GGE) biplot. The combined analysis of variance of cane and juice yield of sorghum genotypes showed that sweet sorghum genotypes were significantly (P < 0.05) affected by environments (E), genotypes (G) and genotype by environment interaction (GEI). GGE biplot showed high yielding genotypes EUSS10, ACFC003/12, SS14, and EUSS11 for cane yield; EUSS10, EUSS11, and SS14 for juice yield; and EUSS10, SS04, SS14, and ACFC003/12 for ethanol yield. Genotype SS14 showed high general adaptability for cane, juice, and ethanol yield. PMID- 27777967 TI - NOD-Like Receptor Protein 3 Inflammasome Priming and Activation in Barrett's Epithelial Cells. AB - BACKGROUND & AIMS: Microbial molecular products incite intestinal inflammation by activating Toll-like receptors (TLRs) and inflammasomes of the innate immune system. This system's contribution to esophageal inflammation is not known. Gram negative bacteria, which dominate the esophageal microbiome in reflux esophagitis, produce lipopolysaccharide (LPS), a TLR4 ligand. TLR4 signaling produces pro-interleukin (IL)1beta, pro-IL18, and NOD-like receptor protein 3 (NLRP3), which prime the NLRP3 inflammasome. Subsequent NLRP3 inflammasome activation cleaves caspase-1, inducing secretion of proinflammatory cytokines and pyroptosis (inflammatory cell death). We explored LPS effects on NLRP3 inflammasome priming and activation in esophageal cells. METHODS: We exposed esophageal squamous and Barrett's epithelial cells to LPS and measured the following: (1) TLR4, pro-IL1beta, pro-IL18, and NLRP3 expression; (2) caspase-1 activity; (3) tumor necrosis factor-alpha, IL8, IL1beta, and IL18 secretion; (4) lactate dehydrogenase (LDH) release (a pyroptosis marker); and (5) mitochondrial reactive oxygen species (ROS). As inhibitors, we used acetyl-Tyr-Val-Ala-Asp-CHO for caspase-1, small interfering RNA for NLRP3, and (2-(2,2,6,6, Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride for mitochondrial ROS. RESULTS: Squamous and Barrett's cells expressed similar levels of TLR4, but LPS induced TLR4 signaling that increased tumor necrosis factor-alpha and IL8 secretion only in Barrett's cells. Barrett's cells treated with LPS showed increased expression of pro-IL18, pro-IL1beta, and NLRP3, and increased mitochondrial ROS levels, caspase-1 activity, IL1beta and IL18 secretion, and LDH release. Acetyl-Tyr-Val-Ala-Asp-CHO, NLRP3 small interfering RNA, and Mito-TEMPO all blocked LPS-induced IL1beta and IL18 secretion and LDH release. CONCLUSIONS: In Barrett's cells, LPS both primes and activates the NLRP3 inflammasome, causing secretion of proinflammatory cytokines and pyroptosis. By triggering molecular events promoting inflammation, the esophageal microbiome might contribute to inflammation-mediated carcinogenesis in Barrett's esophagus. PMID- 27777969 TI - A Study to Analyze Different Patterns of Quid Usage among Subjects with Oral Submucous Fibrosis in Mangalore Population. AB - Aim and Objectives. Oral submucous fibrosis (OSF) is a potentially malignant disorder associated with the usage of areca nut. Usage of processed forms of areca nut is popular among the youth and its carcinogenic effects are not well known. Due to large immigrant population, various patterns of areca nut usage are seen. The aim of this study is to assess the various quid chewing patterns and their association with severity of OSF. Materials and Methods. A cross-sectional study was carried out with 250 cases clinically and histologically diagnosed as having OSF lesion that were selected and subjected to a detailed habit history which was recorded through preformed questionnaire. The data obtained was statistically analyzed. Results. Among the 250 subjects, males were seen to be affected more than females within the age group of 26-35 years and were having clinical stage I OSF. A combination of processed areca nut and processed tobacco was used by the majority of the subjects with duration of 1 to 5 years, at a frequency of 3 to 5 quids per day. Conclusion. The present study confirms the association between oral submucous fibrosis and the quid containing processed areca nut and processed tobacco and also highlights the increasing youth population using the processed forms of areca nut. PMID- 27777970 TI - PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. AB - Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished bone resorption by osteoclasts. PLEKHM1 binds to RAB7 and is critical for lysosome trafficking. However, the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways remain unknown. Here, we generated germline and conditional Plekhm1-deficient mice. These mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Furthermore, loss of PLEKHM1 abrogated the peripheral distribution of lysosomes and bone resorption in osteoclasts. Mechanistically, we indicated that DEF8 interacts with PLEKHM1 and promotes its binding to RAB7, whereas the binding of FAM98A and NDEL1 with PLEKHM1 connects lysosomes to microtubules. Importantly, suppression of these proteins results in lysosome positioning and bone resorption defects similar to those of Plekhm1-null osteoclasts. Thus, PLHKEM1, DEF8, FAM98A, and NDEL1 constitute a molecular complex that regulates lysosome positioning and secretion through RAB7. PMID- 27777971 TI - Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues. AB - There continues to be a need for immunotherapies to treat type 1 diabetes in the clinic. We previously reported that nondepleting anti-CD4 and -CD8 Ab treatment effectively reverses diabetes in new-onset NOD mice. A key feature of the induction of remission is the egress of the majority of islet-resident T cells. How this occurs is undefined. Herein, the effects of coreceptor therapy on islet T cell retention were investigated. Bivalent Ab binding to CD4 and CD8 blocked TCR signaling and T cell cytokine production, while indirectly downregulating islet chemokine expression. These processes were required for T cell retention, as ectopic IFN-gamma or CXCL10 inhibited Ab-mediated T cell purging. Importantly, treatment of humanized mice with nondepleting anti-human CD4 and CD8 Ab similarly reduced tissue-infiltrating human CD4+ and CD8+ T cells. These findings demonstrate that Ab binding of CD4 and CD8 interrupts a feed-forward circuit by suppressing T cell-produced cytokines needed for expression of chemotactic cues, leading to rapid T cell egress from the islets. Coreceptor therapy therefore offers a robust approach to suppress T cell-mediated pathology by purging T cells in an inflammation-dependent manner. PMID- 27777973 TI - Systems biology analysis reveals role of MDM2 in diabetic nephropathy. AB - To derive new insights in diabetic complications, we integrated publicly available human protein-protein interaction (PPI) networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy. We focused on the participating proteins in the network that were computationally predicted to connect the urine metabolites. MDM2 had the highest significant number of PPI connections. As validation, significant downregulation of MDM2 gene expression was found in both glomerular and tubulointerstitial compartments of kidney biopsy tissue from 2 independent cohorts of patients with diabetic nephropathy. In diabetic mice, chemical inhibition of MDM2 with Nutlin-3a led to reduction in the number of podocytes, increased blood urea nitrogen, and increased mortality. Addition of Nutlin-3a decreased WT1+ cells in embryonic kidneys. Both podocyte- and tubule-specific MDM2-knockout mice exhibited severe glomerular and tubular dysfunction, respectively. Interestingly, the only 2 metabolites that were reduced in both podocyte and tubule-specific MDM2-knockout mice were 3-methylcrotonylglycine and uracil, both of which were also reduced in human diabetic kidney disease. Thus, our bioinformatics tool combined with multi omics studies identified an important functional role for MDM2 in glomeruli and tubules of the diabetic nephropathic kidney and links MDM2 to a reduction in 2 key metabolite biomarkers. PMID- 27777974 TI - Lymphocyte activation gene 3 and coronary artery disease. AB - BACKGROUND: The lipoprotein scavenger receptor BI (SCARB1) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 (LAG3), and atherosclerosis. METHODS: In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein. Fasting plasma LAG3 protein was measured in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants. RESULTS: In comparison with rs10846744 reference (GG homozygous) cells, LAG3 protein levels by flow cytometry (P < 0.001), in lipid rafts stimulated and unstimulated (P = 0.03), and phosphosignaling downstream of B cell receptor engagement of CD79A (P = 0.04), CD19 (P = 0.04), and LYN (P = 0.001) were lower in rs10846744 risk (CC homozygous) cells. Overexpressing LAG3 protein in risk cells and silencing LAG3 in reference cells confirmed its importance in phosphosignaling. Secretion of TNF alpha was higher (P = 0.04) and IL-10 was lower (P = 0.04) in risk cells. Plasma LAG3 levels were lower in HALP carriers of the CC allele (P < 0.0001) and by race (P = 0.004). In MESA, race (P = 0.0005), age (P = 0.003), lipid medications (P = 0.03), smoking history (P < 0.0001), and rs10846744 genotype (P = 0.002) were independent predictors of plasma LAG3. In multivariable regression models, plasma LAG3 was significantly associated with HDL-cholesterol (HDL-C) (P = 0.007), plasma IL-10 (P < 0.0001), and provided additional predictive value above the Framingham risk score (P = 0.04). In MESA, when stratified by high HDL-C, plasma LAG3 was associated with coronary heart disease (CHD) (odds ratio 1.45, P = 0.004). CONCLUSION: Plasma LAG3 is a potentially novel independent predictor of HDL-C levels and CHD risk. FUNDING: This work was supported by an NIH RO1 grant (HL075646), the endowed Linda and David Roth Chair for Cardiovascular Research, and the Harold S. Geneen Charitable Trust Coronary Heart Disease Research award to Annabelle Rodriguez. MESA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC 95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01 HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Cardiometabochip genotyping data for the MESA samples was supported in part by grants and contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50 ES015915. PMID- 27777972 TI - Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy. AB - Current antiangiogenesis therapy relies on inhibiting newly developed immature tumor blood vessels and starving tumor cells. This strategy has shown transient and modest efficacy. Here, we report a better approach to target cancer associated endothelial cells (ECs), reverse permeability and leakiness of tumor blood vessels, and improve delivery of chemotherapeutic agents to the tumor. First, we identified deregulated microRNAs (miRs) from patient-derived cancer associated ECs. Silencing these miRs led to decreased vascular permeability and increased maturation of blood vessels. Next, we screened a thioaptamer (TA) library to identify TAs selective for tumor-associated ECs. An annexin A2 targeted TA was identified and used for delivery of miR106b-5p and miR30c-5p inhibitors, resulting in vascular maturation and antitumor effects without inducing hypoxia. These findings could have implications for improving vascular targeted therapy. PMID- 27777975 TI - The role for neutrophil extracellular traps in cystic fibrosis autoimmunity. AB - While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by Pseudomonas aeruginosa, no single factor predicts the extent of lung damage in CF. To elucidate other causes, we studied the autoantibody profile in CF and rheumatoid arthritis (RA) patients, given the similar association of airway inflammation and autoimmunity in RA. Even though we observed that bactericidal permeability-increasing protein (BPI), carbamylated proteins, and citrullinated proteins all localized to the neutrophil extracellular traps (NETs), which are implicated in the development of autoimmunity, our study demonstrates striking autoantibody specificity in CF. Particularly, CF patients developed anti-BPI autoantibodies but hardly any anti citrullinated protein autoantibodies (ACPA). In contrast, ACPA-positive RA patients exhibited no reactivity with BPI. Interestingly, anti-carbamylated protein autoantibodies (ACarPA) were found in both cohorts but did not cross react with BPI. Contrary to ACPA and ACarPA, anti-BPI autoantibodies recognized the BPI C-terminus in the absence of posttranslational modifications. In fact, we discovered that P. aeruginosa-mediated NET formation results in BPI cleavage by P. aeruginosa elastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence of P. aeruginosa on sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function. PMID- 27777976 TI - Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome. AB - Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-beta production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-beta in myeloid cells or of TGF-beta signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-beta, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling. PMID- 27777977 TI - IP3 receptors regulate vascular smooth muscle contractility and hypertension. AB - Inositol 1, 4, 5-trisphosphate receptor-mediated (IP3R-mediated) calcium (Ca2+) release has been proposed to play an important role in regulating vascular smooth muscle cell (VSMC) contraction for decades. However, whether and how IP3R regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle-specific IP3R triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IP3R-mediated Ca2+ release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction. We demonstrated that deletion of IP3Rs significantly reduced aortic contractile responses to vasoconstrictors, including phenylephrine, U46619, serotonin, and endothelin 1. Deletion of IP3Rs also dramatically reduced the phosphorylation of MLC20 and MYPT1 induced by U46619. Furthermore, although the basal blood pressure of smTKO mice remained similar to that of wild-type controls, the increase in systolic blood pressure upon chronic infusion of angiotensin II was significantly attenuated in smTKO mice. Taken together, our results demonstrate an important role for IP3R-mediated Ca2+ release in VSMCs in regulating vascular contractility and hypertension. PMID- 27777978 TI - Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection. AB - Adaptive changes in the genome of a locally predominant clinical isolate of the multidrug-resistant Klebsiella pneumoniae ST258 (KP35) were identified and help to explain the selection of this strain as a successful pulmonary pathogen. The acquisition of 4 new ortholog groups, including an arginine transporter, enabled KP35 to outcompete related ST258 strains lacking these genes. KP35 infection elicited a monocytic response, dominated by Ly6Chi monocytic myeloid-derived suppressor cells that lacked phagocytic capabilities, expressed IL-10, arginase, and antiinflammatory surface markers. In comparison with other K. pneumoniae strains, KP35 induced global changes in the phagocytic response identified with proteomics, including evasion of Ca2+ and calpain activation necessary for phagocytic killing, confirmed in functional studies with neutrophils. This comprehensive analysis of an ST258 K. pneumoniae isolate reveals ongoing genetic adaptation to host microenvironments and innate immune clearance mechanisms that complements its repertoire of antimicrobial resistance genes and facilitates persistence in the lung. PMID- 27777980 TI - Ly6Chi monocytes regulate T cell responses in viral hepatitis. AB - Viral hepatitis remains a global health challenge despite recent progress in the development of more effective therapies. Although virus-specific CD8+ and CD4+ T cell responses are essential for viral clearance, it remains largely unknown what regulates T cell-mediated viral clearance. Thus, a better understanding of the regulation of anti-viral T cell immunity would be critical for the design of more effective therapies for viral hepatitis. Using a model of adenovirus-induced hepatitis, here we showed that adenoviral infection induced recruitment of Ly6Chi monocytes to the liver in a CCR2-dependent manner. These recruited Ly6Chi monocytes suppressed CD8+ and CD4+ T cell responses to adenoviral infection, leading to a delay in viral clearance. In vivo depletion of Ly6Chi monocytes markedly enhanced anti-viral T cell responses and promoted viral clearance. Mechanistically, we showed that induction of iNOS and the production of NO by Ly6Chi monocytes are critical for the suppression of T cell responses. In addition, a contact-dependent mechanism mediated by PD-1 and PD-L1 interaction is also required for T cell suppression by Ly6Chi monocytes. These findings suggest a critical role for Ly6Chi monocytes in the regulation of T cell immunity in viral hepatitis and may provide new insights into development of more effective therapies for treating viral hepatitis based on targeting the immunosuppressing monocytes. PMID- 27777979 TI - The head and neck cancer immune landscape and its immunotherapeutic implications. AB - Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV+ and HPV- HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8+ T cell ratio and the highest levels of CD56dim NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8+ T cell infiltration and CD56dim NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV+ and HPV- HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti-PD 1 in the treatment of advanced HNSCC. PMID- 27777981 TI - Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. AB - Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection. PMID- 27777982 TI - A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22. AB - A unique feature of rheumatoid arthritis (RA) is the presence of anti citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increase the expression or activity of peptidyl arginine deiminases (PADs), which catalyze citrullination and, when dysregulated, can result in hypercitrullination. However, the consequence of hypercitrullination is unknown and the function of each PAD has yet to be defined. Th cells of RA patients are hypoglycolytic and hyperproliferative due to impaired expression of PFKFB3 and ATM, respectively. Here, we report that these features are also observed in peripheral blood mononuclear cells (PBMCs) from healthy at-risk individuals (ARIs). PBMCs of ARIs are also hypercitrullinated and produce more IL-2 and Th17 cytokines but fewer Th2 cytokines. These abnormal features are due to impaired induction of PTPN22, a phosphatase that also suppresses citrullination independently of its phosphatase activity. Attenuated phosphatase activity of PTPN22 results in aberrant expression of IL-2, ATM, and PFKFB3, whereas diminished nonphosphatase activity of PTPN22 leads to hypercitrullination mediated by PADs. PAD2- or PAD4-mediated hypercitrullination reduces the expression of Th2 cytokines. By contrast, only PAD2-mediated hypercitrullination can increase the expression of Th17 cytokines. Taken together, our data depict a molecular signature of preclinical RA that is triggered by impaired induction of PTPN22. PMID- 27777983 TI - Shewanella baltica Ecotypes Have Wide Transcriptional Variation under the Same Growth Conditions. AB - In bacterial populations, subtle expressional differences may promote ecological specialization through the formation of distinct ecotypes. In a barrier-free habitat, this process most likely precedes population divergence and may predict speciation events. To examine this, we used four sequenced strains of the bacterium Shewanella baltica, OS155, OS185, OS195, and OS223, as models to assess transcriptional variation and ecotype formation within a prokaryotic population. All strains were isolated from different depths throughout a water column of the Baltic Sea, occupying different ecological niches characterized by various abiotic parameters. Although the genome sequences are nearly 100% conserved, when grown in the laboratory under standardized conditions, all strains exhibited different growth rates, suggesting significant expressional variation. Using the Ecotype Simulation algorithm, all strains were considered to be discrete ecotypes when compared to 32 other S. baltica strains isolated from the same water column, suggesting ecological divergence. Next, we employed custom microarray slides containing oligonucleotide probes representing the core genome of OS155, OS185, OS195, and OS223 to detect natural transcriptional variation among strains grown under identical conditions. Significant transcriptional variation was noticed among all four strains. Differentially expressed gene profiles seemed to coincide with the metabolic signatures of the environment at the original isolation depth. Transcriptional pattern variations such as the ones highlighted here may be used as indicators of short-term evolution emerging from the formation of bacterial ecotypes. IMPORTANCE Eukaryotic studies have shown considerable transcriptional variation among individuals from the same population. It has been suggested that natural variation in eukaryotic gene expression may have significant evolutionary consequences and may explain large-scale phenotypic divergence of closely related species, such as humans and chimpanzees (M.-C. King and A. C. Wilson, Science 188:107-116, 1975, http://dx.doi.org/10.1126/science.1090005; M. F. Oleksiak, G. A. Churchill, and D. L. Crawford, Nat Genet 32:261-266, 2002, http://dx.doi.org/10.1038/ng983). However, natural variation in gene expression is much less well understood in prokaryotic organisms. In this study, we used four sequenced strains of the marine bacterium Shewanella baltica to better understand the natural transcriptional divergence of a stratified prokaryotic population. We found substantial low-magnitude expressional variation among the four S. baltica strains cultivated under identical laboratory conditions. Collectively, our results indicate that transcriptional variation is an important factor for ecological speciation. PMID- 27777984 TI - Molecular Epidemiology of Colonizing and Infecting Isolates of Klebsiella pneumoniae. AB - Klebsiella pneumoniae is among the most common causes of hospital-acquired infections and has emerged as an urgent threat to public health due to carbapenem antimicrobial resistance. K. pneumoniae commonly colonizes hospitalized patients and causes extraintestinal infections such as urinary tract infection, bloodstream infection (septicemia), and pneumonia. If colonization is an intermediate step before infection, then detection and characterization of colonizing isolates could enable strategies to prevent or empirically treat K. pneumoniae infections in hospitalized patients. However, the strength of the association between colonization and infection is unclear. To test the hypothesis that hospitalized patients become infected with their colonizing strain, 1,765 patients were screened for rectal colonization with K. pneumoniae, and extraintestinal isolates from these same patients were collected over a 3-month period in a cohort study design. The overall colonization prevalence was 23.0%. After adjustment for other patient factors, colonization was significantly associated with subsequent infection: 21 of 406 (5.2%) colonized patients later had extraintestinal infection, compared to 18 of 1,359 (1.3%) noncolonized patients (adjusted odds ratio [OR], 4.01; 95% confidence interval, 2.08 to 7.73; P < 0.001). Despite a high diversity of colonizing isolates, 7/7 respiratory, 4/4 urinary, and 2/5 bloodstream isolates from colonized patients matched the patient corresponding rectal swab isolates, based on wzi capsular typing, multilocus sequence typing (MLST), and whole-genome sequence analysis. These results suggest that K. pneumoniae colonization is directly associated with progression to extraintestinal infection. IMPORTANCE K. pneumoniae commonly infects hospitalized patients, and these infections are increasingly resistant to carbapenems, the antibiotics of last resort for life-threatening bacterial infections. To prevent and treat these infections, we must better understand how K. pneumoniae causes disease and discover new ways to predict and detect infections. This study demonstrates that colonization with K. pneumoniae in the intestinal tract is strongly linked to subsequent infection. This finding helps to identify a potential time frame and possible approach for intervention: the colonizing strain from a patient could be isolated as part of a risk assessment, and antibiotic susceptibility testing could guide empirical therapy if the patient becomes acutely ill. PMID- 27777985 TI - Norovirus Polymerase Fidelity Contributes to Viral Transmission In Vivo. AB - Intrahost genetic diversity and replication error rates are intricately linked to RNA virus pathogenesis, with alterations in viral polymerase fidelity typically leading to attenuation during infections in vivo. We have previously shown that norovirus intrahost genetic diversity also influences viral pathogenesis using the murine norovirus model, as increasing viral mutation frequency using a mutagenic nucleoside resulted in clearance of a persistent infection in mice. Given the role of replication fidelity and genetic diversity in pathogenesis, we have now investigated whether polymerase fidelity can also impact virus transmission between susceptible hosts. We have identified a high-fidelity norovirus RNA-dependent RNA polymerase mutant (I391L) which displays delayed replication kinetics in vivo but not in cell culture. The I391L polymerase mutant also exhibited lower transmission rates between susceptible hosts than the wild type virus and, most notably, another replication defective mutant that has wild type levels of polymerase fidelity. These results provide the first experimental evidence that norovirus polymerase fidelity contributes to virus transmission between hosts and that maintaining diversity is important for the establishment of infection. This work supports the hypothesis that the reduced polymerase fidelity of the pandemic GII.4 human norovirus isolates may contribute to their global dominance. IMPORTANCE Virus replication fidelity and hence the intrahost genetic diversity of viral populations are known to be intricately linked to viral pathogenesis and tropism as well as to immune and antiviral escape during infection. In this study, we investigated whether changes in replication fidelity can impact the ability of a virus to transmit between susceptible hosts by the use of a mouse model for norovirus. We show that a variant encoding a high fidelity polymerase is transmitted less efficiently between mice than the wild type strain. This constitutes the first experimental demonstration that the polymerase fidelity of viruses can impact transmission of infection in their natural hosts. These results provide further insight into potential reasons for the global emergence of pandemic human noroviruses that display alterations in the replication fidelity of their polymerases compared to nonpandemic strains. PMID- 27777987 TI - Clinical Neurophysiological Evaluation for Simple Motor Tics. AB - Simple motor tics are sudden, nonrhythmic jerk like movements that are often preceded by premonitory urge and can be voluntarily suppressed. Some clinical characteristic of tics such as variability of movement, distractibility and fluctuating course can mimic functional movement disorders. Here we report a case of motor tics where the physiological approach in addition to careful clinical assessments is helpful to support the diagnosis of tic. PMID- 27777986 TI - Transcription factor Dlx3 induces aryl hydrocarbon receptor promoter activity. AB - The Distal-less (Dlx) homeobox transcription factors (TFs) play a prominent role in regulating multiple facets of vertebrate biology. Though widely studied as mediators of tissue development, recent work has uncovered a role for this TF family in modulating the vertebrate hematopoietic compartment. Pertinent to our study, murine Dlx1-3 are expressed in an innate lymphocyte population known as natural killer (NK) cells, and they are implicated to assume a functional role in the NK cell maturation pathway. However, Dlx target genes are poorly understood. In Drosophila, the invertebrate Dlx ortholog Distal-less (Dll) regulates another transcription factor called Spineless (ss), which is critical for specifying distal antennal segments. Importantly, the vertebrate ortholog of ss is the aryl hydrocarbon receptor (AhR), a transcription factor recently shown to be important in the regulation of a number of immune cell subsets, including NK cells. Given these findings, we investigated whether Dlx TF family members might analogously regulate AhR in an NK cell context. Our results demonstrate that Dlx3 is constitutively co-expressed with AhR in murine and human CD127+ NK cells. Critically, we show that Dlx3 induces AhR promoter activity by binding to a regulatory region that resides ~5.5 kb upstream of the transcriptional start site. This mechanism is functionally relevant, as Dlx3 expression in human NK cells significantly enhances TF activity at AhR DNA-binding elements (Xenobiotic Responsive Elements, XREs). Thus, our study defines Dlx3 as a positive regulator of the aryl hydrocarbon receptor. PMID- 27777988 TI - Investigation of helium at a Y2Ti2O7 nanocluster embedded in a BCC Fe matrix. AB - Nanostructured ferritic alloys (NFAs) are prime candidates for structural and first wall components of fission and fusion reactors. The main reason for this is their ability to effectively withstand high concentrations of the transmutation product helium. A high number density of oxide nanoclusters dispersed throughout a BCC Fe matrix act as trapping sites for helium and prevent its eventual delivery to high risk nucleation sites. The current study uses density functional theory to investigate the helium trapping mechanisms at the boundary between BCC iron and Y2Ti2O7, a common stoichiometry of the oxide nanoclusters in NFAs. The investigation is carried out on a structure matched oxide nanocluster that is embedded within a BCC Fe supercell. Investigation of the electronic structure and a mapping of the potential energy landscape reveals that the localized iono covalent bonds present within the oxides create a potential energy-well within the metallically bonded BCC Fe matrix, so that trapping of helium at the oxide nanocluster is thermodynamically and kinetically favorable. PMID- 27777989 TI - Salt gradient driven ion transport in solid-state nanopores: the crucial role of reservoir geometry and size. AB - Modern applications of nanotechnology such as salinity gradient power and ionic diodes usually involve the transport of ionic species in a system comprising a nanopore connecting two large reservoirs. The charge properties on the nanopore surface plays a key role, and they need to be estimated by fitting a mathematical model for the system to measurable quantities such as ionic current or conductance. This model can also be used to simulate the system behavior under various conditions. However, the large difference between the linear size of a nanopore and that of a reservoir makes relevant analyses difficult. Considering numerical efforts, the impact of the computational domain for the reservoir geometry and size on the system behavior is almost always overlooked in previous studies, where the computational domain for a reservoir is often assumed to have a relatively small size. Taking salinity gradient ionic current as an example, we show for the first time that the performance of a reservoir-nanopore-reservoir system is influenced appreciably by the computational domain for the reservoir geometry and size, especially when a voltage bias is not applied. Using the reported experimental data for the osmotic current in a single boron nitride nanopore, we show that its surface charge density can be estimated realistically by choosing an appropriate computational domain for reservoir geometry and size. Numerical simulation also reveals that choosing appropriate reservoir geometry and size is necessary; otherwise, the results obtained might be unreliable, or even misleading. To avoid this, we suggest that for the nanopore with the pore length smaller than 1000 nm, the size of the computational domain of a reservoir, (length * radius), with equal length and radius, should exceed 800 * 800 nm. PMID- 27777990 TI - Conformational features of the Abeta42 peptide monomer and its interaction with the surrounding solvent. AB - Accumulation of the amyloid beta (Abeta) peptide in the brain is responsible for debilitating neurodegenerative diseases, such as Alzheimer's disease (AD). We have carried out atomistic molecular dynamics simulations of the full-length Abeta42 peptide monomer with a wide range of conformations at room temperature. Efforts have been made to probe the conformational features of different segments of the peptide, namely the two terminal segments (N-term and C-term), the central hydrophobic regions (hp1 and hp2) and the central turn region joining hp1 and hp2, and their nonuniform influence on the spatial arrangements and binding energies of the surrounding water molecules. Our calculations reveal fluctuating conformations of the monomers with the formation and breaking of different secondary structural elements. In particular, it is noticed that the Abeta monomers exhibit a propensity to either retain or transform into a helical form toward the N-term region and a beta-strand-like form near the C-term segment. Besides, heterogeneous conformational flexibility of the Abeta monomers has been found to be correlated with the corresponding nonuniform entropy gains. Additionally, our calculation further reveals a heterogeneous hydration environment around the peptide. It is found that irrespective of the Abeta peptide conformations and their nonuniform fluctuations, water molecules around the hydrophobic hp1 and hp2 segments are relatively weakly bound. This is an important observation, as in the presence of other monomers such weakly bound water molecules around hp1 and hp2 are expected to be easily displaced during the hydrophobic collapse that leads to Abeta aggregation. PMID- 27777991 TI - Magnetic anisotropy of a CoII single ion magnet with distorted trigonal prismatic coordination: theory and experiment. AB - The single ion magnetic properties of Co(ii) are affected by the details of the coordination geometry of the ion. Here we show that a geometry close to trigonal prismatic which arises when the ligand 6,6'-((1Z)-((piperazine-1,4 diylbis(propane-3,1-diyl))bis(azanylylidene))bis(methanylylidene))bis(2 methoxyphenol) coordinates to Co(ii) does indeed lead to enhanced single-ion behaviour as has previously been predicted. Synthesis of the compound, structural information, and static as well as dynamic magnetic data are presented along with an analysis using quantum chemical ab initio calculations. Though the complex shows a slight deviation from an ideal trigonal prismatic coordination, the zero field splitting as well as the g-tensor are strongly axial with D = -41 cm-1 and E < 0.01 cm-1. For the lowest Kramers doublet (S = 1/2) g? = 7.86 and g? < 0.05 were found. In contrast, the second Kramers doublet possesses a rhombic g-tensor with g? = 2.75 and g? = 4.35. Due to large spin-orbit coupling resulting in very different g tensors, it is not possible to simulate the temperature dependence of the magnetic susceptibility with a spin Hamiltonian of the form H = D(Sz2 - S(S + 1)/3) + E(Sx2 - Sy2) + MUBgS.B using an effective spin S = 3/2. Calculations on model complexes show the influence of the coordinating atoms and the deviation from the ideal trigonal prismatic coordination. As the distortion is reduced towards idealised D3h, the zero field splitting increases and the g-tensor of the second Kramers doublet also becomes axial. PMID- 27777992 TI - Transition-metal-free three-component reaction of cyclopropenes, aldehydes and amines. AB - A transition-metal-free three-component reaction of cyclopropenes, aldehydes and amines is reported. The reaction is a new demonstration of formal [3+2] cycloaddition triggered by ring-opening of cyclopropenes bearing electron withdrawing substituents. The reaction provides a unique method for the construction of cyclopentene structures. PMID- 27777998 TI - Deprotonation of formic acid in collisions with a liquid water surface studied by molecular dynamics and metadynamics simulations. AB - Deprotonation of organic acids at aqueous surfaces has important implications in atmospheric chemistry and other disciplines, yet it is not well-characterized or understood. This article explores the interactions of formic acid (FA), including ionization, in collisions at the air-water interface. Ab initio molecular dynamics simulations with dispersion-corrected density functional theory were used. The 8-50 picosecond duration trajectories all resulted in the adsorption of FA within the interfacial region, with no scattering, absorption into the bulk or desorption into the vapor. Despite the known weak acidity of FA, spontaneous deprotonation of the acid was observed at the interface on a broad picosecond timescale, ranging from a few picoseconds typical for stronger acids to tens of picoseconds. Deprotonation occurred in 4% of the trajectories, and was followed by Grotthuss proton transfer through adjacent water molecules. Both sequential and ultrafast concerted proton transfer were observed. The formation of contact ion pairs and solvent-separated ion pairs, and finally the reformation of neutral FA, both trans and cis conformers, occurred in different stages of the dynamics. To better understand the deprotonation mechanisms at the interface compared with the process in bulk water, we used well-tempered metadynamics to obtain deprotonation free energy profiles. While in bulk water FA deprotonation has a free energy barrier of 14.8 kJ mol-1, in fair agreement with the earlier work, the barrier at the interface is only 7.5 kJ mol-1. Thus, at the air-water interface, FA may dissociate more rapidly than in the bulk. This finding can be rationalized with reference to the dissimilar aqueous solvation and hydrogen bonding environments in the interface compared to those in bulk liquid water. PMID- 27777999 TI - A combined UHV-STM-flow cell set-up for electrochemical/electrocatalytic studies of structurally well-defined UHV prepared model electrodes. AB - We describe the construction and discuss the performance of a novel combined ultrahigh vacuum (UHV)-electrochemistry set-up, allowing the controlled preparation and structural characterization of complex nanostructured electrode surfaces by high resolution scanning tunnelling microscopy (STM) under UHV conditions on the one hand and, after electrode transfer under clean conditions, electrochemical measurements under continuous, controlled electrolyte mass transport conditions on the other. Electrochemical measurements can be coupled with online product detection, either using an additional collector electrode or by differential electrochemical mass spectrometry (DEMS). The potential of the set-up will be illustrated in two electrocatalytic reactions on complex, but structurally well-defined bimetallic electrode surfaces, O2 reduction on PtxAg1 x/Pt(111) monolayer surface alloys and bulk CO oxidation on Pt monolayer island modified Ru(0001) electrodes. We will particularly demonstrate the importance of structural characterization after the electrochemical measurements for identifying structural modifications induced by the electrochemical environment and thus avoiding misleading conclusions about the structure-activity relationships. PMID- 27778000 TI - Improving selectivity in catalytic hydrodefluorination by limiting SNV reactivity. AB - Catalytic hydrodefluorination of perfluoroallylbenzene with Cp2TiH in THF is unselective and yields a variety of previously unknown compounds, predominantly activated in the allylic position. Several different mechanisms have been examined in detail using solvent corrected (THF) DFT(M06-2X) calculations for the archetypal perfluorinated olefin perfluoropropene and perfluoroallylbenzene: (a) single electron transfer, (b) hydrometallation/fluoride elimination, (c) sigma bond metathesis (allylic or vinylic), and (d) nucleophilic vinylic substitution (SNV, w/o Ti-F contacts in the TS). SNV is shown to be a competitive mechanism to hydrometallation and proceeds via ionic species from which F-elimination is facile and unselective leading to low selectivity in polar solvents. Subsequent experiments show that selectivity can be increased in a non-polar solvent. PMID- 27778001 TI - Revisiting oxo-centered carbonyl-triruthenium clusters: investigating CO photorelease and some spectroscopic and electrochemical correlations. AB - We synthesized and characterized a series of oxo-centered carbonyl-triruthenium complexes with the general formula [Ru3O(CH3COO)6(L)2(CO)], where L = 2,6 dimethylpyrazine (dmpz) (1), isonicotinamide (adpy) (2), 4-acetylpyridine (acpy) (3), 3-methylpyridine (3-pic) (4), 4-methylpyridine (4-pic) (5), 4-tert butylpyridine (4-tbpy) (6), 4-(dimethyl)aminopyridine (dmap) (7), or 4 aminopyridine (ampy) (8); we also investigated the photoreactivity of these complexes. Single-crystal X-ray diffraction helped to elucidate the structures of 1.H2O, 7.C2H4Cl2, and 8. The unit cell of 8 is composed of four cluster units; the hydrogen bonds between the amino groups of the terminal ligand of a neighboring molecule and the oxygen atoms of CO or acetate bridging ligands hold these cluster units together. The spectroscopic (NMR, UV-visible, and IR) and the electrochemical properties (cyclic voltammetry) of these complexes correlated with the ancillary ligands in terms of their sigma-donating and pi-accepting characteristics. The molecular orbital and the electronic localized description of the [Ru3O]-CO unit helped to rationalize the correlations. The photoreactivity of compounds 1-8 was investigated by laser excitation at 377 nm. Given the CO photorelease quantum yields, sigma-donor ligands and aqueous medium (more polar) stabilized the charge-transfer excited state that culminated in CO photosubstitution, leading to higher Phi values. PMID- 27778002 TI - Novel magnetic relaxation nanosensors: an unparalleled "spin" on influenza diagnosis. AB - Rapid detection and diagnosis of pathogenic strains of influenza is necessary for expedited treatment and quicker resolutions to the ever-rising flu pandemics. Considering this, we propose the development of novel magnetic relaxation nanosensors (MRnS) for the rapid detection of influenza through targeted binding with hemagglutinin. 2,6- and 2,3-sialic acid ligands and entry blocker peptides are conjugated to iron oxide nanoparticles to create functional MRnS. Positive detection of various hemagglutinin variants (H1 and H5) is possible with protein concentrations as little as 1.0 nM. Most importantly, detection using functional MRnS is achieved within minutes and differentiates between influenza subtypes. This specificity allows mixtures of MRnS to screen for multiple pathogens at once, discarding the need to conduct multiple individual tests. Current methods used to diagnose influenza, such as RT-PCR and viral culturing, while largely effective, are complex, time-consuming and costly. As well, they are not as sensitive or specific, and have been known to produce false-positive results. In contrast to these methods, targeted MRnS are robust, point-of-care diagnostic tools featuring simple, rapid and low-cost procedures. These qualities, as well as high sensitivity and specificity, and low turnaround times, make a strong case for the diagnostic application of MRnS in clinical settings. PMID- 27778003 TI - Time-gated luminescence bioimaging with new luminescent nanocolloids based on [Mo6I8(C2F5COO)6]2- metal atom clusters. AB - Bioimaging and cell labeling using red or near infrared phosphors emitting in the "therapeutic window" of biological tissues have recently become some of the most active research fields in modern medical diagnostics. However, because organic and inorganic autofluorophores are omnipresent in nature, very often the background signal from fluorochromes other than targeted probes has to be eliminated. This discrimination could be available using a time-gated luminescence microscopy (TGLM) technique associated with long lifetime phosphorescent nanocomposites. Here, we report new SiO2 nanostructured particle (50 nm in diameter) embedded luminescent nanosized [Mo6I8(C2F5COO)6]2- metal atom clusters (1 nm in diameter), successfully prepared by the microemulsion technique. This combination provides new physical insight and displays red emission in biological based solution under UV-Vis excitation with long lifetimes of around 17 and 84 MUs. Moreover, the nanoparticles can be internalized by cancer cells after surface functionalization by transferrin protein and clearly imaged by TGLM under excitation at 365 nm. The nanocomposites have been mainly characterized by scanning and transmission electron microscopies (SEM and HAADF STEM), UV-Vis and photoluminescence (PL) spectroscopies. PMID- 27778004 TI - Single ion magnets based on lanthanoid polyoxomolybdate complexes. AB - Polyoxometalate (POM) chemistry has recently offered excellent examples of single ion magnets (SIMs) and molecular spin qubits. Compared with conventional coordination compounds, POMs provide rigid and highly symmetric coordination sites. However, all POM-based SIMs reported to date exhibit a very limited range of possibilities for chemical processability. We present herein two new families of POM-based SIMs which are soluble in organic solvents: [Ln(beta-Mo8O26)2]5- {LnIII = Tb, Dy, Ho, Er, Tm and Yb} and the functionalised POMs [Ln{Mo5O13(OMe)4NNC6H4-p-NO2}2]3- {LnIII = Tb, Dy, Ho, Er, Yb and Nd}. In addition, these two families represent the first SIMs based on polyoxomolybdates. A magneto-structural analysis of these families is presented, which is based on an effective crystal field model, and compared with the results reported in analogous lanthanoid SIMs based on polyoxotungstates. PMID- 27778005 TI - A scanning tunneling microscopy study of the electronic and spin states of bis(phthalocyaninato)terbium(iii) (TbPc2) molecules on Ag(111). AB - In this article, we investigate a single molecule magnet bis(phthalocyaninato)terbium(iii) (TbPc2) molecule film by using low temperature STM. In order to investigate the effect of molecule-substrate interaction on the electronic and spin properties of the adsorbed molecule, we tune the molecule substrate coupling by switching the substrate between Au(111) and Ag(111), the latter of which provides stronger interaction with the molecule than the former. Despite the enhanced chemical reactivity of the Ag(111) surface compared with Au(111), a well-organized pseudo-square film is formed. In addition, a checker board type contrast variation is identified, which is well explained by the existence of two types of molecules whose rotational angle between the top and bottom Pc is theta = 45 degrees (bright molecule) and theta = 30 degrees (dark molecule). The expected stronger molecule-substrate interaction, however, appears as an intriguing dI/dV mapping image which reveals the spatial distribution of the density of states (DOS). We identify the contrast reversal in the dI/dV mapping for the molecules of theta = 45 degrees and theta = 30 degrees at the sample voltages of V = 0.7 eV and 1.1 eV. Combined with the density functional theory (DFT) calculation, we attribute this change to the shift of an electronic state due to the rotation of the mutual angle between the top and bottom Pc. For the spin behavior, we previously observed a Kondo resonance for the TbPc2 molecule adsorbed on the Au(111) surface. On the Ag(111) surface, the Kondo resonance is hardly observed, which is due to the annihilation of the pi radical spin by the charge transfer from the substrate to the molecule. Instead we observe a Kondo peak for the molecule on the second layer, for which the spin recovers due to the reduction of the coupling with the substrate. In addition, when a magnetic field of 2 T normal to the surface is applied, the second layer molecule shows a sharp dip at the Fermi level. We attribute this to the inelastic tunneling feature caused by the spin flipping. This feature is not observed for the TbPc2/Au(111) system, suggesting that the decoupling between the TbPc2 molecule and Ag(111) by the presence of the first layer produces an inelastic feature in the tunneling spectra. PMID- 27778006 TI - Controllable lasing performance in solution-processed organic-inorganic hybrid perovskites. AB - Solution-processed organic-inorganic perovskites are fascinating due to their remarkable photo-conversion efficiency and great potential in the cost-effective, versatile and large-scale manufacturing of optoelectronic devices. In this paper, we demonstrate that the perovskite nanocrystal sizes can be simply controlled by manipulating the precursor solution concentrations in a two-step sequential deposition process, thus achieving the feasible tunability of excitonic properties and lasing performance in hybrid metal-halide perovskites. The lasing threshold is at around 230 MUJ cm-2 in this solution-processed organic-inorganic lead-halide material, which is comparable to the colloidal quantum dot lasers. The efficient stimulated emission originates from the multiple random scattering provided by the micro-meter scale rugged morphology and polycrystalline grain boundaries. Thus the excitonic properties in perovskites exhibit high correlation with the formed morphology of the perovskite nanocrystals. Compared to the conventional lasers normally serving as a coherent light source, the perovskite random lasers are promising in making low-cost thin-film lasing devices for flexible and speckle-free imaging applications. PMID- 27778007 TI - Tuning of quantum entanglement in molecular quantum cellular automata based on mixed-valence tetrameric units. AB - In this article we consider two coupled tetrameric mixed-valence (MV) units accommodating electron pairs, which play the role of cells in molecular quantum cellular automata. It is supposed that the Coulombic interaction between instantly localized electrons within the cell markedly inhibits the transfer processes between the redox centers. Under this condition, as well as due to the vibronic localization of the electron pair, the cell can encode binary information, which is controlled by neighboring cells. We show that under certain conditions the two low-lying vibronic spin levels of the cell (ground and first excited states) can be regarded as originating from an effective spin-spin interaction. This is shown to depend on the internal parameters of the cell as well as on the induced polarization. Within this simplified two-level picture we evaluate the quantum entanglement in the system represented by the two electrons in the cell and show how the entanglement within the cell and concurrence can be controlled via polarization of the neighboring cells and temperature. PMID- 27778008 TI - High performance triboelectric nanogenerators with aligned carbon nanotubes. AB - As the essential element of a triboelectric nanogenerator (TENG), friction layers play key roles that determine the device performance, which can be enhanced by material selection and surface modification. In this work, we have embedded aligned carbon nanotubes (CNTs) on the polydimethylsiloxane (PDMS) surface as the effective dielectric layer to donate electrons. This layer not only increases the electron generation for the output, but also shows notable stretchability. The length and the properties of the aligned CNTs can be controlled precisely. Using the 40 MUm CNT as an example, the fabricated CNT-PDMS TENG shows an output voltage of 150 V and a current density of 60 mA m-2, which are 250% and 300% enhancement compared to the TENG using directly doped PDMS/multiwall carbon nanotubes, respectively. The maximum power density of this TENG reaches 4.62 W m 2 at an external load of 30 MOmega. The TENG has demonstrated superior stability during cyclic measurement of over 12 000 cycles. Besides, the aligned CNT-PDMS film shows superhydrophobicity (154 degrees ) and good sheet resistance of 280 Omega sq-1. This stretchable aligned CNT-PDMS film can be universally utilized as a positive triboelectric layer pairing with polymeric materials such as polyethylene terephthalate, polyimide, PDMS and polytetrafluoroethylene for TENGs. This work provides an effective method of structure design for flexible and stretchable nanogenerators. PMID- 27778009 TI - Numerical simulation of micro-particle rotation by the acoustic viscous torque. AB - We present the first numerical simulation setup for the calculation of the acoustic viscous torque on arbitrarily shaped micro-particles inside general acoustic fields. Under typical experimental conditions, the particle deformation plays a minor role. Therefore, the particle is modeled as a rigid body which is free to perform any time-harmonic and time-averaged translation and rotation. Applying a perturbation approach, the viscoacoustic field around the particle is resolved to obtain the time-averaged driving forces for a subsequent acoustic streaming simulation. For some acoustic fields, the near-boundary streaming around the fluid-suspended particle induces surface forces on the nonrotating particle that integrate into a non-zero acoustic viscous torque. In the equilibrium state, this torque is compensated by an equal and opposite drag torque due to the particle rotation. The rotation-induced flow field is superimposed on the acoustic streaming field to obtain the total fluid motion around the rotating particle. In this work, we only consider cases within the Rayleigh limit even though the presented numerical model is not strictly limited to this regime. After a validation by analytical solutions, the numerical model is applied to challenging experimental cases. For an arbitrary particle density, we consider particle sizes that can be comparable to the viscous boundary layer thickness. This important regime has not been studied before because it lies beyond the validity limits of the available analytical solutions. The detailed numerical analysis in this work predicts nonintuitive phenomena, including an inversion of the rotation direction. Our numerical model opens the door to explore a wide range of experimentally relevant cases, including non-spherical particle rotation. As a step toward application fields such as micro-robotics, the rotation of a prolate ellipsoid is studied. PMID- 27778010 TI - DNA biosensor combining single-wavelength colorimetry and a digital lock-in amplifier within a smartphone. AB - Smartphone camera based gold nanoparticle colorimetry (SCB-AuNP colorimetry) has shown good potential for point-of-care applications. However, due to the use of a camera as a photo-detector, there are major limitations to this technique such as a low bit resolution (~8 bits mainstream) and a low data acquisition rate. These issues have limited the ultimate sensitivity of smartphone based colorimetry as well as the possibility to integrate efficiently a more sensitive approach such as detection based on a lock-in amplifier (LIA). In this paper, we improve the metrological performance of the smartphone to overcome existing issues by adding the LIA capability to AuNP sensing. In this work, instead of using the camera as a photo-detector, the audio jack is used as a photo-detector reader and function generator for driving a laser diode in order to achieve a smartphone based digital lock-in amplifier AuNP colorimetric (SBLIA-AuNP colorimetry) system. A full investigation on the SBLIA design, parameters and performance is comprehensively provided. It is found that the SBLIA can reduce most of the noise and provides a detection noise-to-signal ratio down to -63 dB, which is much better than the -49 dB of the state-of-the-art SCB based method. A DNA detection experiment is demonstrated to reveal the efficacy of the proposed metrological method. The results are compared to UV-visible spectrometry, which is the gold standard for colorimetric measurement. Based on our results, the SBLIA-AuNP colorimetric system has a detection limit of 0.77 nM on short strand DNA detection, which is 5.7 times better than the 4.36 nM limit of a commercial UV visible spectrometer. Judging from the results, we believe that the sensitive SBLIA would be further extended to other optical diagnostic tools in the near future. PMID- 27778011 TI - Glucose-bearing biodegradable poly(amino acid) and poly(amino acid)-poly(ester) conjugates for controlled payload release. AB - The glucoseamine-initiated ring-opening polymerisation of amino acid N carboxyanhydrides and O-carboxanhydrides to yield amphiphilic block copolymers that are capable of self-assembly in aqueous solution to form well-defined, glucose-presenting, particles is reported. The particles formed are susceptible to enzyme-mediated (lipase and protease) and pH-induced degradation, and can selectively bind the lectin concanavalin A. Consequently, such glycoparticles are of significance for the controlled release of payload molecules in response to an acidic environment, for instance cancerous tissue, and upon interaction with target enzymes. PMID- 27778012 TI - Dual-band moire metasurface patches for multifunctional biomedical applications. AB - There has been strong interest in developing multi-band plasmonic metasurfaces for multiple optical functions on single platforms. Herein, we developed Au moire metasurface patches (AMMP), which leverage the tunable multi-band responses of Au moire metasurfaces and the additional field enhancements of the metal-insulator metal configuration to achieve dual-band plasmon resonance modes in near-infrared and mid-infrared regimes with high field enhancement. Furthermore, we demonstrate the multifunctional applications of AMMP, including surface-enhanced infrared spectroscopy, optical capture and patterning of bacteria, and photothermal denaturation of proteins. With their multiple functions of high performance, in combination with cost-effective fabrication using moire nanosphere lithography, the AMMP will enable the development of highly integrated biophotonic platforms for a wide range of applications in disease theranostics, sterilization, and the study of microbiomes. PMID- 27778013 TI - A field effect glucose sensor with a nanostructured amorphous In-Ga-Zn-O network. AB - Amorphous indium gallium zinc oxide (IGZO) field effect transistors (FETs) are a promising technology for a wide range of electronic applications. Herein, we fabricated and characterized FETs with a nanostructured IGZO network as a sensing transducer. The IGZO was patterned using colloidal lithography and electrohydrodynamic printing, where an 8 MUm wide nanostructured close-packed hexagonal IGZO network was obtained. Electrical characterization of the nanostructured IGZO network FET demonstrated a drain-source current on-off ratio of 6.1 * 103 and effective electron mobilities of 3.6 cm2 V-1 s-1. The nanostructured IGZO network was functionalized by aminosilane groups with cross linked glucose oxidase. The devices demonstrated a decrease in drain-source conductance and a more positive VON with increasing glucose concentration. These changes are ascribed to the acceptor-like surface states associated with positively charged aminosilane groups attached to the nanostructured IGZO surface. Continuous monitoring of the drain-source current indicates a stepwise and fully reversible response to glucose concentrations with a short response time. The specific catalytic reaction between the GOx enzyme and glucose eliminates interference from acetaminophen/ascorbic acid. We demonstrate that nanostructured IGZO FETs have improved sensitivity compared to non-nanostructured IGZO for sensing glucose and can be potentially extended to other biosensor technologies. PMID- 27778014 TI - A solution processed nanostructured p-type NiO electrode for efficient inverted perovskite solar cells. AB - Here we report a solution processed nanostructured NiO as a hole transport layer (HTL) for efficient inverted MAPb(I1-xBrx)3 (x = 0.3) perovskite solar cells (PSCs). The best performing p-i-n PSC exhibits 15.35% power conversion efficiency with a current density (JSC) of 19.85 mA cm-2, an open circuit voltage (VOC) of 1.056 V and a fill factor (FF) of 0.73. The developed method is simple and cost effective. PMID- 27778016 TI - Path-selective lasing in nanostructures based on molecular control of localized surface plasmons. AB - We propose a new type of nanodevice, capable of both path-selectivity and anisotropic lasing, that is based on loss-compensation and amplification by a localized plasmon polariton. The nanodevice is a Y-shaped plasmonic nanostructure embedded in an anisotropic host medium with gain. The anisotropy leads to path selectivity, an effect which is more pronounced once gain is included. Such a device is potentially realizable via bottom-up techniques. The path-selectivity may be coupled with activation of a rotation of the anisotropic host medium for inducing a light-guiding switching functionality. PMID- 27778015 TI - Crossover between superconductivity and magnetism in SrRuO3 mesocrystal embedded YBa2Cu3O7-x heterostructures. AB - The competition between superconductivity and ferromagnetism poses great challenges and has attracted renewed interest for applications in novel spintronic devices. In order to emphasize their interactions, we fabricated a heterostructure composed of superconducting YBa2Cu3O7-delta (YBCO) film embedded with itinerant ferromagnetic SrRuO3 (SRO) mesocrystals. Starting from a doping concentration of 10 vol% of SRO mesocrystal in a YBCO matrix, corresponding to the density of SRO nanocrystals ~5 * 109 cm-2, which exhibits the typical characteristic of a metal-superconductor transition, and then increasing the magnetic interactions as a function of SRO embedment, the electronic correlation and the interplay between superconductivity and magnetism throughout the temperature regime were investigated. A metal-insulator transition in the normal state of YBCO and a crossover between superconductivity and magnetism at low temperatures were found upon increasing the density of nano-size SRO crystallites in the YBCO matrix as a consequence of competing interactions between these two ordered phases. PMID- 27778017 TI - Hiding and unveiling trans-chalcone in a constrained derivative of 4',7 dihydroxyflavylium in water: a versatile photochromic system. AB - A structurally constrained derivative of 4',7-dihydroxyflavylium was studied in aqueous solution and in CTAB micelles by pH jumps, flash photolysis and continuous irradiation with spectroscopic details assessed as well by theoretical calculations. In water, up to pH = 8, the compound shows only acid base chemistry with deprotonation of the flavylium cation to form a quinoidal base that further deprotonates with pKas of 4.8 and 7.4. In the basic region, unprotonated trans chalcones are formed. No neutral trans-chalcone (Ct) is formed in water preventing the establishment of the well-known photochromism involving photoisomerization of this species with subsequent formation of the flavylium cation. Addition of 0.02 M CTAB drastically changes the mole fraction distribution of species, leading to the formation of Ct (chiCt = 1 at pH = 5) and unveiling a photochromic behavior with a pH-tunable colour contrast in a large pH range (2 < pH < 8). The Ct species can be hidden again (irreversibly) upon addition of alpha-cyclodextrin that disrupts the CTAB micelles, reverting the system to its initial mole fraction distribution of species. These supramolecular inputs work atop the molecular reaction networks by modifying their species' mole fraction distribution. PMID- 27778018 TI - Neuronal ceroid lipofuscinosis in an adult American Staffordshire Terrier. AB - A female, 5-year-old American Staffordshire Terrier with severe progressive neurological deficits, particularly in terms of ataxia and keeping balance, was examined pathomorphologically and a genetic analysis was performed. In neurons of various localizations of the central nervous system an accumulation of a finely granular pale eosinophilic or light brown material was found. In addition, the cerebellum revealed marked degeneration and loss of Purkinje and inner granule cells. The accumulated PAS-positive, argyrophilic, autofluorescent material showed ultrastructurally a lamellar appearance suggestive of lipofuscin. Genetic analysis revealed the presence of a sequence variant in the ARSG gene encoding the lysosomal enzyme arylsulfatase G. This case report describes an adult-onset of a neuronal ceroid lipofuscinosis that shows similarities with a human disorder termed Kufs disease. PMID- 27778019 TI - Multiple thoracolumbar partial lateral corpectomies in 17 dogs. AB - OBJECTIVE: To report feasibility and outcome of multiple thoracolumbar partial lateral corpectomies (TLPLCs) in dogs with predominantly ventral spinal cord compression caused by intervertebral disc disease (IVDD) in the light of reported decreased spinal stability following single TLPLC. Material und methods: In a retrospective study the records of dogs treated by multiple TLPLCs for ventral spinal cord compression caused by Hansen type I or type II IVDD were reviewed. Presurgical spinal cord compression and postsurgical decompression, as well as slot dimensions were determined based on computed tomography (CT)-myelography images. Neurological outcome was assessed based on repetitive examinations applying a modified Frankel Score as well as on an owner questionnaire. RESULTS: Seventeen dogs with a mean body weight of 20.3 kg (range 4.0-49.0 kg) were included. Fourteen dogs had two TLPLCs, two dogs had three TLPLCs and one dog had four TLPLCs performed. The mean slot depth was 63% of entire vertebral body width, the mean slot height was 29% of the entire vertebral body height, the mean slot length was 25% of the entire vertebral body length and the mean residual vertebral interslot length between two adjacent TLPLCs was 55% of the vertebral body length. At reevaluation 4 weeks after surgery, 6/17 dogs (35.3%) had the same modified Frankel Score as before surgery, whereas 11/17 dogs (64.7%) showed a neurological improvement. According to the owners 78.5% of dogs were walking normally within 6 months after surgery. The mean survival time of 16 dogs, where follow-up was available, was 951 days. CONCLUSION AND CLINICAL RELEVANCE: Multiple spinal cord compressions caused by IVDD can be eliminated by multiple, even consecutive, TLPLCs without the risk of a clinically significant risk of spinal instability. PMID- 27778020 TI - Developmental programming of the metabolic syndrome: Next-generation sequencing analysis of transcriptome expression in a rat model of maternal high fructose intake. AB - Excessive fructose intake is related to a high prevalence of metabolic syndrome, while little attention has been paid to the impact of maternal high-fructose (HF) intake on the development of metabolic syndrome and organ-specific transcriptome alterations in the offspring. We utilized RNA next-generation sequencing (NGS) technology to analyze the transcriptome expression in four organs (kidney, brain, heart, and urinary bladder) from 1-day, 3-week, and 3-month-old male offspring exposed to maternal HF diet. Maternal HF induced various phenotypes of metabolic syndrome in adult male offspring. We observed that maternal HF exposure induces long-term alterations of gene expression in the brain, heart, kidney, and urinary bladder in adult offspring. Different organs do not respond similarly to maternal HF intake. We found that changes in expression of Errfi1 and Ctgf were shared by four organs at 1 day of age. Also, a number of genes regulating fructose metabolism, glycolysis/gluconeogenesis, fatty acid metabolism, and insulin signalling appear to be regulated by maternal HF intake in different organs at 1 day of age. Our NGS results are of significance to the development of maternal interventions in the prevention of maternal HF-induced organ-specific programming, in order to reduce the global burden of metabolic syndrome. PMID- 27778021 TI - [Proanthocyanidin protects H9C2 cells against hypoxia/reoxygenation injury via JAK2/STAT3 signaling pathway]. AB - The present study was aimed to investigate the underlying mechanisms of the protective effect of proanthocyanidin (Pro) against hypoxia/reoxygenation (H/R) injury in H9C2 cells with a focus on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. H9C2 cells were randomly assigned to 5 groups, including the control group (Con), the H/R-injured group (H/R), the Pro-treated group (H/R+Pro), the JAK2 siRNA-treated group (H/R+Pro+JAK2 siRNA) and the JAK2 siRNA control group (H/R+JAK2 siRNA). The cells were pretreated with Pro (40 umol/L) for 8 h before 2 h of hypoxia and 4 h of reoxygenation. Cellular viability and apoptosis rate were detected by MTT and TUNEL methods, and superoxide generation was measured. JAK2/STAT3 signaling, oxidative stress markers and endoplasmic reticulum stress markers were also detected by Western blot. We found that Pro treatment significantly improved cellular viability and reduced apoptosis rate in H/R-treated H9C2 cells. In addition, Pro treatment significantly up-regulated the phosphorylation levels of JAK2 and STAT3, down-regulated the superoxide generation, gp91phox, glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 expression. However, these protective effects of Pro were all attenuated by JAK2 siRNA administration. Taken together, we demonstrated that Pro protects H9C2 cells against H/R-induced oxidative stress and endoplasmic reticulum stress injury via JAK2/STAT3 signaling pathway. PMID- 27778022 TI - Upregulation of cystathionine beta-synthetase in the arcuate nucleus produces pain hypersensitivity via PKC upregulation and GluN2B phosphorylation in rats with chronic pancreatitis. AB - Hydrogen sulfide (H2S) contributes to visceral hyperalgesia in primary sensory neurons, but its role in central nervous system remains largely unknown. This study was to investigate the roles and underlying mechanisms of H2S and its endogenous synthesis enzymes in the arcuate nucleus (ARC) in rat pancreatic hyperalgesia. Chronic pancreatitis (CP) was induced in male adult Sprague-Dawley rats by intra-pancreatic ductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Western blot analysis was performed to detect protein expression in the ARC. CP markedly upregulated cystathionine beta synthetase (CBS) expression but did not alter cystathionine-gamma-lyase level in the ARC at 4 weeks after TNBS injection. Although the expression of total GluN2B was not altered, CP greatly enhanced the phosphorylation level of GluN2B in the ARC when compared with age- and sex-matched control rats. CP also significantly increased expression of protein kinase Cgamma (PKCgamma) in the ARC. Arcuate microinjection of O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA, an inhibitor of CBS) significantly attenuated abdominal pain in CP rats in a dose dependent manner and reversed the CP-induced upregulation of p-GluN2B and PKCgamma in the ARC. Furthermore, the GluN2B inhibitor or specific PKC inhibitor chelerythrine significantly attenuated abdominal hyperalgesia in CP rats. The p GluN2B expression was also suppressed by PKC inhibitor. Taken together, our results suggest that the upregulation of CBS in the ARC leads to an activation of GluN2B via PKCgamma, which may play an important role in generation of pain hypersensitivity of CP. PMID- 27778023 TI - Icariin protects against MPP+-induced neurotoxicity in MES23.5 cells. AB - Icariin is the major bioactive component of Epimedium and has been demonstrated to be a potential drug for age-related diseases. The present study was aimed to investigate the neuroprotective properties of icariin against 1-methyl-4 phenylpyridinium ion (MPP+)-induced neurotoxicity in MES23.5 cells and the possible mechanisms. MTT assay showed that treatment with MPP+ attenuated the cell viability in a dose-dependent manner in MES23.5 cells. Icariin pretreatment resulted in an enhancement of survival. Immunocytochemistry analysis revealed that icariin treatment attenuated MPP+-induced loss of tyrosine hydroxylase (TH) positive cells. Meanwhile, Western blot confirmed MPP+ significantly decreased the TH protein expression, and icariin pretreatment could reverse the toxic effect of MPP+. Moreover, flow cytometry showed that MPP+-induced decrease of the mitochondrial membrane potential could be partly restored by icariin. Furthermore, real-time RT-PCR and Western blot analysis demonstrated that icariin treatment restored the MPP+-induced up-regulation of Bax and down-regulation of Bcl-2 mRNA and protein expressions. Western blot data also revealed the inhibitory effect of icariin on MPP+-induced up-regulation of cleaved caspase-3. These findings provide the evidence that icariin has neuroprotective properties against MPP+-induced neurotoxicity in MES23.5 cells and the mechanism might be related to the anti-apoptotic action of icariin. PMID- 27778024 TI - [The mechanisms of medial vascular calcification]. AB - Vascular calcification is an active, invertible and highly regulated pathophysiological process, characterized by the deposition of hydroxyapatite crystal in vascular wall. Vascular calcification is classified into two types based on the sites of calcification: intimal atherosclerotic calcification and Monckeberg's medial calcification. Medial vascular calcification is a pathological phenomenon commonly existed in diabetes, chronic kidney failure and aging. The current review summarizes the mechanisms of medial vascular calcification. PMID- 27778025 TI - Gas transmitters in female reproductive system. AB - Nitric oxide, carbon monoxide and hydrogen sulfide synthesized endogenously in living organisms produce an array of disparate biological effects, so as to be considered as gas transmitters. These three gaseous molecules play important roles in many physiological and pathological processes in the bodies, such as the regulation of vascular tone and inflammatory responses as well as reproductive function. This review mainly focuses on the distribution and biological functions of these three gas transmitters in female reproductive tissues. PMID- 27778026 TI - [Physiological and pathophysiological meanings of gastrointestinal smooth muscle motor unit SIP syncytium]. AB - Gastrointestinal smooth muscle layer contains two kinds of interstitial cells with special differentiation, i.e., interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRalpha+) cells. The ICC and PDGFRalpha+ cells contact with smooth muscle cells (SMCs) by gap junctions and regulate contractive function of the SMCs. Therefore, these three kinds of cells constitute a functional syncytium, i.e., the SMC, ICC and PDGFRalpha+ cells syncytium (SIP syncytium). Various neurotransmitters, humoral factors, endogenous bioactive molecules, as well as drugs regulate gastrointestinal motility through the SIP syncytium. In this review, we introduce the concept of SIP syncytium and summarize functions of the syncytium, as well as its physiological and pathological significances. PMID- 27778027 TI - [Research progress of visual prosthesis]. AB - Vision is one of the most important human sensations about the surrounding world. Visual deprivation not only markedly affects the life of blind people, but also gives a heavy burden to their family and the society. A visual prosthesis is an electronic device that helps the blinds to regain visual perception by directly stimulating the visual pathway using the microelectrodes implanted into the body. In recent years, visual prostheses have been developed rapidly and some devices have already become clinically available. In this paper, we reviewed the history of visual prosthesis, introduced different visual prostheses classified according to the location of the implanted stimulating electrodes. Clinical study results as well as the functional status of the currently available visual prosthesis devices were also summarized. PMID- 27778028 TI - Effect of estrogen on iron metabolism in mammals. AB - Estrogen is a steroid hormone produced mainly by the ovaries. It combines with the nuclear receptors to exert the biological effects influencing the metabolism of body. Elevated levels of estrogen are often associated with altered iron levels in mammals. Furthermore, the findings of estrogen response element (ERE) have demonstrated that estrogen affects iron metabolism directly in peripheral tissues. In this review, we will briefly summarize the effect of estrogen on iron metabolism in mammals, and discuss recent progress in the mechanisms of estrogen on some iron related proteins in order to provide guidance for clinical use of estrogen. Estrogen and iron metabolism are closely related, but the exact regulatory mechanisms still need further exploration. PMID- 27778029 TI - [Advances in the association of ATP-sensitive potassium channels and Parkinson's disease]. AB - ATP-sensitive potassium channels (KATP), as an inward rectifying potassium channel, are widely distributed in many types of tissues. KATP are activated by the depletion of ATP level and the increase in oxidative stress in cells. The activity of KATP couples cell metabolism with electrical activity and results in membrane hyperpolarization. KATP are ubiquitously distributed in the brain, including substantia nigra, hippocampus, hypothalamus, cerebral cortex, dorsal nucleus of vagus and glial cells, and participate in neuronal excitability, mitochondria homeostasis and neurotransmitter release. Accumulating lines of evidence suggest that KATP are the major contributing factors in the pathogenesis of Parkinson's disease (PD). This review discussed the association of KATP with the pathogenic processes of PD by focusing on the roles of KATP on the degeneration of dopaminergic neurons, the functions of mitochondria, the firing pattern of dopaminergic neurons in the substantia nigra, the alpha-synuclein secretion from striatum, and the microglia activation. PMID- 27778030 TI - [An overview on autophagy in neural stem cells]. AB - Neural stem cells (NSCs) offer great promise for the treatment of multiple neurodegenerative diseases. However, the survival and differentiation rates of grafted cells in the host brain need to be enhanced. In this regard, understanding of the underlying mechanism of NSCs survival and death is of great importance for the implications of stem cell-based therapeutic application in the treatments of neurological disorders. Autophagy is a conserved proteolytic mechanism required for maintaining cellular homeostasis, which can affect NSCs fate through regulating their biological behaviors, such as survival and proliferation. In this mini-review, we will summarize the effects of autophagy on NSCs fate including survival, apoptosis, proliferation and differentiation, as well as the underlying mechanisms. PMID- 27778031 TI - [Application of optogenetic technique in pain research]. AB - Chronic pain represents a major clinical issue which so far is still in shortage of selective and effective treatment. Multiple components are involved in the pain processing, including peripheral, spinal and supraspinal levels of the nervous system. The core to fight the pain problem effectively is to have a good understanding of nociceptive mechanism and the neurobiology of pain perception. Optogenetic technique allows selective activation of subpopulation neurons and provides possibility for better understanding of complex pathway and modulation mechanism in nervous system. Here we review the researches to date that used optogenetic tools for studying pain pathway, and we also provide a brief overview of some new development in optogenetic techniques that may have great potentials in pain research. PMID- 27778032 TI - Activation of necroptosis in a rat model of acute respiratory distress syndrome induced by oleic acid. AB - The present study was aimed to investigate the role of necroptosis in the pathogenesis of acute respiratory distress syndrome (ARDS). The rat model of ARDS was induced by intravenous injection of oleic acid (OA), and observed for 4 h. The lung injury was evaluated by arterial blood gas, lung wet-dry weight ratio (W/D) and histological analyses. Simultaneously, bronchoalveolar lavage fluid (BALF) was collected for total and differential cell analysis and total protein determination. Tumor necrosis factor alpha (TNF-alpha) level in BALF was determined with a rat TNF-alpha ELISA kit. Expressions of receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL) in lung tissue were determined by Western blot and immunohistochemical staining. The interaction between RIPK1 and RIPK3 was explored by immunoprecipitation. The results showed that, compared with those in control group, total white blood cells count (WBC), polymorphonuclear percentage (PMN%), total protein concentration, TNF-alpha level in BALF, W/D, and the alveolar arterial oxygen tension difference (P(A-a)O2) in OA group were significantly increased at 4 h after OA injection. Western blot and immunostaining further showed remarkably increased expressions of RIPK1, RIPK3 and MLKL in lung tissue from OA group. Additionally, immunoprecipitation results indicated an enforced interaction between RIPK1 and RIPK3 in OA group. Collectively, the TNF-alpha level in BALF and the RIPK1-RIPK3-MLKL signaling pathway in lung tissue were found to be upregulated and activated with the process of ARDS. These findings implicate that RIPK1/RIPK3-mediated necroptosis plays a possible role in the pathogenesis of ARDS, which may provide a new idea to develop novel drugs for the therapy of ARDS. PMID- 27778033 TI - Mitochondrial division inhibitor Mdivi-1 ameliorates angiotensin II-induced endothelial dysfunction. AB - Mitochondrial fission can occur via activation of dynamin-related protein 1 (Drp1), which participates in the mitochondrial membrane scission process. The present study was designed to investigate the effect of angiotensin II (AngII) on mitochondrial fission and fusion in human umbilical vascular endothelial cells (HUVECs). And we further inquire into whether Mdivi-1, a newly identified pharmacological inhibitor of Drp1, can prevent endothelial dysfunction induced by AngII. The HUVECs were treated with AngII alone or in combination with Mdivi-1. Western blot was used to detect protein expressions of Drp1, endothelial nitric oxide synthase (eNOS) and apoptosis-related enzymes. MitoTracker Red and JC-1 dye were used to detect mitochondrial morphology and membrane potential, respectively. DCFH-DA probe was used to access intracellular reactive oxygen species (ROS) generation. Transwell assay was used to evaluate cell migration. Annexin V/PI staining was used to assess cellular apoptosis. The results showed that, in cultured HUVECs, AngII (1 * 10-7 mol/L, 12 h) treatment significantly upregulated the expression of Drp1 followed by increased apoptosis and decreased eNOS expression. The treatment of AngII resulted in a change in mitochondrial morphology from elongated to uniformly punctate organelles, which was accompanied by decreased mitochondrial membrane potential. Furthermore, Mdivi-1 significantly protected against AngII-induced endothelial dysfunction, as shown by increased mitochondrial membrane potential and eNOS expression, reduced ROS level, decreased apoptosis and migration ability. Taking together, our data suggest that inhibition of Drp1 with Mdivi-1 can restore AngII-induced endothelial dysfunction. PMID- 27778034 TI - [Injurious effect of zinc deficiency on cardiomyocytes]. AB - The aim of the present study was to investigate the effect of zinc deficiency on cardiomyocyte survival and the underlying mechanisms. Simulated zinc deficiency model was developed in H9c2 cardiac cells with zinc chelator N, N, N', N' tetrakis (2-pyridylmethyl) ethylenediamine (TPEN). MTT assay was used to evaluate cell viability. Morphological changes of the cells were observed by optical microscope. Lacate dehydrogenase (LDH) levels of the cells were determined with LDH assay kit. Mitochondrial membrane potential (DeltaPsi) was measured with confocal microscope using JC-1 dye. Intracellular reactive oxygen species (ROS) levels were determined by DCFH-DA staining. PD98059 (an inhibitor of ERK), SNAP, which can activate ERK, and the ROS scavenger, MPG, were respectively used to investigate mechanism of signal transduction. The phosphorylation of ERK was detected by Western blot. The results showed that TPEN significantly induced the cell morphological damage and the loss of DeltaPsi, increased LDH leakage, and promoted ROS generation. In the H9c2 cells, TPEN significantly inhibited ERK phosphorylation and decreased cell viability, which was potentiated by PD98059, whereas both SNAP and MPG reversed the inhibitory effects of TPEN. These data suggest that zinc deficiency leads to the injury in H9c2 cardiac cells through down-regulating ERK pathway. Increased intracellular ROS may account for the effect of zinc deficiency. PMID- 27778035 TI - [Aliskiren inhibits proliferation of cardiac fibroblasts in AGT-REN double transgenic hypertensive mice in vitro]. AB - The purpose of the present study is to explore the effect of aliskiren on the proliferation of cardiac fibroblasts (CFs) in AGT-REN double transgenic hypertensive (dTH) mice. The cultured CFs from AGT-REN dTH mice were divided into AGT-REN group (dTH) and aliskiren group (ALIS). Cultured CFs from C57B6 mice were served as control (WT). The effect of different concentration of aliskiren (1 * 10-6, 1 * 10-7, 1 * 10-8, 1 * 10-9 mol/L) on CFs proliferation was determined by MTT assay. After treatment with 1 * 10-7 mol/L aliskiren for 24 h, alpha-SMA, collagen I, III and NADPH oxidase (NOX) protein expression in CFs of AGT-REN dTH mice were detected by Western blot. The collagen synthesis in CFs was assessed by hydroxyproline kit. The expression of ROS was determined by DHE. Results showed that the blood pressure and plasma Ang II levels were significantly increased and CFs proliferation was significantly increased as well in AGT-REN dTH mice compared with WT group. However, aliskiren intervention decreased CFs proliferation, myofibroblast transformation, as well as the collagen I and III synthesis in CFs of AGT-REN dTH mice. Meanwhile, aliskiren inhibited ROS content and NOX2/NOX4 protein expression in CFs of AGT-REN dTH mice. These results suggest that aliskiren decreases the cell proliferation, myofibroblast transformation and collagen production in CFs of AGT-REN dTH mice, which might be through inhibition of oxidative stress response. PMID- 27778036 TI - [Biological characteristics of mesenchymal stem cell and hematopoietic stem cell in the co-culture system]. AB - The aim of the present study was to obtain the qualified hematopoietic stem/progenitor cells (HSC/HPC) and human umbilical cord-mesenchymal stem cells (MSC) in vitro in the co-culture system. Cord blood mononuclear cells were separated from umbilical cord blood by Ficoll lymphocyte separation medium, and then CD34+ HSC was collected by MACS immunomagnetic beads. The selected CD34+ HSC/HPC and MSC were transferred into culture flask. IMDM culture medium with 15% AB-type cord plasma supplemented with interleukin-3 (IL-3), IL-6, thrombopoietin (TPO), stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (Flt-3L) factors were used as the co-culture system for the amplification of HSC/HPC and MSC. The cellular growth status and proliferation on day 6 and 10 after co culture were observed by using inverted microscope. The percentage of positive expression of CD34 in HSC/HPC, as well as the percentages of positive expressions of CD105, CD90, CD73, CD45, CD34 and HLA-DR in the 4th generation MSC, was tested by flow cytometry. Semisolid colony culture was used to test the HSC/HPC colony forming ability. The osteogenic, chondrogenesis and adipogenic ability of the 4th generation MSC were assessed. The karyotype analysis of MSC was conducted by colchicines. The results demonstrated that the HSC/HPC of co-culture group showed higher ability of amplification, CFU-GM and higher CD34+ percentage compared with the control group. The co-cultured MSC maintained the ability to differentiate into bone cells, fat cells and chondrocytes. And the karyotype stability of MSC remained normal. These results reveal that the appropriate co-culture system for MSC and HSC is developed, and via this co-culture system we could gain both two kinds of these cells. The MSCs under the co-culture system maintain the biological characteristics. The CFU-GM ability, cell counting and the flow cytometry results of HSC/HPC under the co-culture system are conform to the criterion, showing that the biological functions of HSC/HPC are maintained. PMID- 27778037 TI - Direct modulation of firing activity by dopamine D2 like receptors in the globus pallidus of both normal and parkinsonian rats. AB - The globus pallidus occupies a critical position in the indirect pathway of the basal ganglia circuit, which regulates movement under both normal and pathological conditions. Previous studies have shown that the globus pallidus receives dopaminergic innervation from the axonal collaterals of nigrostriatal fibers. Both dopamine D1 and D2 like receptors are expressed in the globus pallidus. The present study was aimed to investigate the direct in vivo electrophysiological effects of dopamine D2 like receptors in the globus pallidus of both normal and parkinsonian rats. Extracellular recordings of multi-barreled microelectrode were used in the present study. In normal rats, micro-pressure ejection of dopamine D2 like receptor agonist quinpirole induced different effects on the firing rate of globus pallidus neurons. In 24 out of the 61 pallidal neurons, quinpirole significantly increased the firing rate by (62.7 +/- 11.2)%. In another 16 neurons, quinpirole decreased the spontaneous firing rate by (37.5 +/- 2.9)%. Furthermore, co-application of dopamine D2 like receptor antagonist, sulpride, blocked quinpirole-induced modulation of the firing rate of pallidal neurons. On the 6-hydroxydopamine (6-OHDA) lesioned side of parkinsonian rats, quinpirole increased the firing rate in 25 out of the 47 pallidal neurons by (64.2 +/- 10.1)%, while decreased the firing rate in 11 neurons by (51.9 +/- 6.2)%. Our findings suggest that activation of pallidal dopamine D2 like receptors may bidirectionally modulate the spontaneous firing of globus pallidus neurons in both normal and parkinsonian rats. PMID- 27778038 TI - Erratum to: Aurantibacter crassamenti gen. nov., sp. nov., a bacterium isolated from marine sediment. PMID- 27778039 TI - Variation in practice preferences in management of open injuries of extremities an international survey by SICOT research academy. AB - PURPOSE: Open fractures are challenging injuries and there is a lot of variation in practice preferences which may reflect the wide variations in outcome in different units across the world. A survey was done amongst the international community of SICOT membership to document the practice preferences and variations. METHODS: An online questionnaire containing 23 questions which were sub-divided into three sections covering the various aspects of open injury management was sent by email to orthopaedic trauma surgeons across the world. A total of 358 responses were evaluated and presented in this manuscript. RESULTS: The SICOT study confirmed wide variation in practice protocols. About 94.7 % of orthopaedic surgeons around the world use the Gustillo Anderson scoring system for assessment of open injury and 50.6 % of surgeons prefer lavage in operation theatre. For lavage, 84.6 % of surgeons preferred normal saline and for antibiotic prophylaxis, 48.3 % used a combination of second generation cephalosporin, metronidazole and an aminoglycoside for a minimum of three to five days. In 88 % of patients, orthopaedic surgeons performed the initial debridement and 69.2 % surgeons aimed for debridement within six hours. Regarding wound management, 43.9 % units preferred and were capable of soft tissue cover within 72 hours and about 26.3 % surgeons combined definitive fixation along with plastic procedure. CONCLUSION: Our study documented wide variations in practice preferences across the world and showed that information and awareness about current guidelines and practices will help many to update themselves in terms of basic questions about open fracture care. PMID- 27778040 TI - Modern American scurvy - experience with vitamin C deficiency at a large children's hospital. AB - BACKGROUND: Until recently scurvy has been viewed in developed countries as a disease of the past. More recently there have been reports of case series of children with scurvy who have had a delayed diagnosis after an extensive diagnostic workup that included imaging. Most of these children have had underlying neurologic conditions such as autism. OBJECTIVE: To review the medical records of children diagnosed with vitamin C (ascorbic acid) deficiency based on serum ascorbic acid levels at a large pediatric health care system, to determine imaging findings and utility of imaging in management, and to identify at-risk pediatric populations. MATERIALS AND METHODS: We retrospectively identified cases of vitamin C deficiency in children tested for serum ascorbic acid levels during the last 5 years. We used the criteria of normal ascorbic acid >23 MUmol/L and included children with ascorbic acid levels <23 MUmol/L. We evaluated their clinical history, underlying medical condition, imaging studies obtained and imaging findings. RESULTS: We identified 32 children with vitamin C deficiency. All of these children had underlying medical conditions, most commonly iron overload from multiple transfusions related to sickle cell anemia or thalassemia (20), neurologic disorders (4) and bone marrow transplant/chemotherapy (3). No cases of scurvy from dietary deficiency in otherwise normal children were identified. All except two children had multiple imaging studies, primarily related to their underlying conditions. Three of these children had extensive imaging workups related to diffuse musculoskeletal pain. Imaging findings included ill-defined sclerotic and lucent metaphyseal bands (mainly at the knee) on radiography and MRI studies that showed diffuse increased T2-weighted signal in the bilateral lower-extremity long-bone metaphyses, periosteal reaction and adjacent soft-tissue edema. CONCLUSION: Vitamin C deficiency is not uncommon in large pediatric health care facilities, and it is frequently missed on clinical evaluation and diagnostic imaging. At-risk populations include those with iron overload, neurologic conditions and history of chemotherapy. Scurvy related to dietary deficiency in otherwise normal children was not encountered. When characteristic MRI findings are seen, particularly in children with a predisposing condition for vitamin C deficiency, scurvy should be considered and a serum ascorbic acid level checked to potentially confirm a diagnosis prior to further invasive tests. PMID- 27778042 TI - [PROKOMB - prostate-cooperative MRI project Berlin-study AP 95/16 of the AUO]. PMID- 27778041 TI - Acute ACL reconstruction in patients over 40 years of age. AB - PURPOSE: The purpose of this study is to compare the clinical outcome of ACL reconstructions in patients older than 40 years of age to younger subjects. It has been hypothesized that patients older than 40 years of age achieve comparable clinical outcomes following acute ACL reconstruction using a hamstring tendon autograft than younger patients. METHODS: Patients with an isolated ACL tear without any concomitant injuries and subsequent ACL reconstruction within 48 h from injury were included in this prospective study. According to patients' age, subjects were assigned to two groups: (A) 18-40 years and (B) 40-60 years. Functional outcomes, pain, post-operative radiographs and return to sports were recorded and analysed. The follow-up period was 24 months. RESULTS: A total of 59 patients were included in the study. Group A consisted of 39 patients (14 women, 25 men; median 27 years), group B of 20 patients (12 women, 8 men; median 45 years) respectively. At final follow-up, the Lysholm score showed no significant difference between group A (median 90; range 68-100) and group B (median 94.5; range 63-100) (n.s.). The final Tegner score showed a significant difference between group A (median 6; range 2-9) and group B (median 5.5; range 3-8) (p < 0.05). The mean VAS pain score was 1.3 (range 0-6) in group A and 1 (range 0-7) in group B, respectively (n.s.). Both groups returned to their pre-injury activity level and did not significantly change their activity in respect of pivoting sports and sports frequency at final follow-up (n.s.). According to the IKDC score, all except one of the patients in group A and all patients in group B had a normal or nearly normal final outcome (n.s.). CONCLUSION: Patients older than 40 years of age achieve comparable clinical outcomes following acute ACL reconstruction using a hamstring tendon autograft than younger patients. LEVEL OF EVIDENCE: Cohort study, Level III. PMID- 27778043 TI - [Erratum to: Generation Y - problem or solution in daily clinical practice]. PMID- 27778044 TI - Clusters of ineffective efforts during mechanical ventilation: impact on outcome. AB - PURPOSE: The aim of this study was to investigate the role of ineffective efforts (IEs), specifically clusters of IEs, during mechanical ventilation on the outcome of critically ill patients. METHODS: In a prospective observational study, 24-h recordings were obtained in 110 patients on the 1st day of assisted ventilation (pressure support or proportional assist), using a prototype monitor validated to identify IEs. Patients remaining on assisted ventilation were studied again on the 3rd day (n = 37) and on the 6th day (n = 13). To describe the clusters of IEs, the concept of an IEs event was developed, defined as a 3-min period of time containing more than 30 IEs. Along with all patient data, to minimize selection bias by time of recording, analysis was performed only on 1st day data of patients with >=16 h of recording (1st day group). RESULTS: The analysis included 2931 h of assisted ventilation and 4,456,537 breaths. Neither the IEs index (IEs as a percentage of total breaths) in general nor a value above 10 % was correlated with patient outcome. Overall, IEs events were identified in 38 % of patients. In multivariate analysis, the presence of events in the 1st day group (n = 79) was associated with the risk of being on mechanical ventilation >=8 days after first recording [odds ratio 6.4, 95 % confidence interval (1.1-38.30)] and hospital mortality [20 (2.3-175)]. Analysis of the data for all patients revealed similarly increased risks for prolonged ventilation [3.4 (1.1-10.7)] and mortality [4.9 (1.3-18)]. CONCLUSIONS: Clusters of IEs are often present in mechanically ventilated critically ill patients and are associated with prolonged mechanical ventilation and increased mortality. Studies to find ways of improving patient-ventilator interaction are warranted. PMID- 27778045 TI - Sepsis: find me, manage me, and stop me! PMID- 27778046 TI - Kinetics of Deposition, Acute Toxicity and Bioaccumulation of Copper in some Freshwater Organisms. AB - Experiments with environmentally relevant concentrations of Cu in glass aquaria revealed that Cu was quickly removed from water. Cubic regression of Cu concentration against time showed that maximum rate of removal was around 69.34 72.11 h irrespective of treatment. The 96 h LC50 value of Cu was respectively 0.18, 0.19 and 0.35 mg/L for fish Cyprinus carpio, crustacean Diaptomus forbesi and worm Branchiura sowerbyi. Normalizing the lethal values and plotting them against time it was observed that there was sharp differences in mortality over time between the organisms and 96 h lethal values could misrepresent susceptibility of the organisms to Cu. Treatment of 0.1 mg/L of Cu in water resulted in accumulation of 10.57, 4.38, 1.46 and 2.44 ug/g of Cu, respectively in sediment, worm, crustacean zooplankton and whole body of fish. But, Cu deposited in high concentrations in gut and liver of fish indicating that Cu was principally accumulated through food. PMID- 27778047 TI - Relative contributions of spatial weighting, explicit knowledge and proprioception to hand localisation during positional ambiguity. AB - When vision and proprioception are rendered incongruent during a hand localisation task, vision is initially weighted more than proprioception in determining location, and proprioception gains more weighting over time. However, it is not known whether, under these incongruency conditions, particular areas of space are also weighted more heavily than others, nor whether explicit knowledge of the sensory incongruence (i.e. disconfirming the perceived location of the hand) modulates the effect. Here, we hypothesised that both non-informative inputs coming from one side of space and explicit knowledge of sensory incongruence would modulate perceived location of the limb. Specifically, we expected spatial weighting to shift hand localisation towards the weighted area of space, and we expected greater weighting of proprioceptive input once perceived location was demonstrated to be inaccurate. We manipulated spatial weighting using an established auditory cueing paradigm (Experiment 1, n = 18) and sensory incongruence using the 'disappearing hand trick' (Experiment 2, n = 9). Our first hypothesis was not supported-spatial weighting did not modulate hand localisation. Our second hypothesis was only partially supported disconfirmation of hand position did lead to more accurate localisations, even if participants were still unaware of their hand position. This raised the possibility that rather than disconfirmation, a simple movement of the hand in view could update the sensory-motor system, by immediately increasing the weighting of proprioceptive input relative to visual input. This third hypothesis was then confirmed (Experiment 3, n = 9). These results suggest that hand localisation is robust in the face of differential weighting of space, but open to modulation in a modality-specific manner, when one sense (vision) is rendered inaccurate. PMID- 27778049 TI - Geographic location is an important determinant of risk factors for stone disease. AB - Some regions are known to have an increased burden of urolithiasis. Urolithiasis is known to be affected by weather patterns, particularly high ambient temperatures. To identify geographic differences in risk factors, we compared metabolic information for 1254 patients in two geographically distinct regions, New York and Florida, with per sample adjustment for ambient weather. We observed that patients in New York were more likely to have low urine volume, but also lower total urinary calcium (168 vs 216 mg, p = 0.005), urate (376 vs 678 mg, p < 0.001), and phosphate (0.8 vs 0.9 g, p 0.007). Temperature was a predictor of urine pH (B = -0.07, p = 0.024). Geographic region was a predictive factor (p < 0.01) for urine calcium, volume, serum bicarbonate, and anion gap. Increased anion gap and serum HCO3- were also predicted by temperature (B = 0.065, p = 0.035). Interestingly, urine volume was not affected by temperature. Our finding that temperature is a determining factor of urine pH and anion gap may help to explain the finding that hot weather is associated with increases in urolithiasis. Anion gap has also been previously associated with poor health measures and represents an interesting target for future research. Geographic location may independently contribute to urine composition, through regional diets, sun exposure, and groundwater. This study highlights the impact geographic location plays in determining risk factors for stone disease and the value of regional knowledge to the treating physician in preventing stone disease. PMID- 27778048 TI - Optimality and stability of intentional and unintentional actions: II. Motor equivalence and structure of variance. AB - We address the nature of unintentional changes in performance in two papers. This second paper tested hypotheses related to stability of task-specific performance variables estimated using the framework of the uncontrolled manifold (UCM) hypothesis. Our first hypothesis was that selective stability of performance variables would be observed even when the magnitudes of those variables drifted unintentionally because of the lack of visual feedback. Our second hypothesis was that stability of a variable would depend on the number of explicit task constraints. Subjects performed four-finger isometric pressing tasks that required the accurate production of a combination of total moment and total force with natural or modified finger involvement under full visual feedback, which was removed later for some or all of the salient variables. We used inter-trial analysis of variance and drifts in the space of finger forces within the UCM and within the orthogonal to the UCM space. The two variance components were used to estimate a synergy index stabilizing the force/moment combination, while the two drift components were used to estimate motor equivalent and non-motor equivalent force changes, respectively. Without visual feedback, both force and moment drifted toward lower absolute magnitudes. The non-motor equivalent component of motion in the finger force space was larger than the motor equivalent component for variables that stopped receiving visual feedback. In contrast, variables that continued to receive visual feedback showed larger motor equivalent component, compared to non-motor equivalent component, over the same time interval. These data falsified the first hypothesis; indeed, selective stabilization of a variable over the duration of a trial allows expecting comparably large motor equivalent components both with and without visual feedback. Adding a new constraint (presented as a target magnitude of middle finger force) resulted in a drop in the synergy index in support of the second hypothesis. We interpret the force drift as a natural relaxation process toward states with lower potential energy in the physical (physiological) system involved in the task. The results show that presenting sensory feedback on a performance variable makes synergies stabilizing that variable dependent on that particular sensory feedback. PMID- 27778050 TI - [Pharmacokinetics and pharmacodynamics of antibiotics in intensive care]. AB - Optimized dosage regimens of antibiotics have remained obscure since their introduction. During the last two decades pharmacokinetic(PK)-pharmacodynamic(PD) relationships, originally established in animal experiments, have been increasingly used in patients. The action of betalactams is believed to be governed by the time the plasma concentration is above the minimum inhibitory concentration (MIC). Aminoglycosides act as planned when the peak concentration is a multiple of the MIC and vancomycin seems to work best when the area under the plasma vs. time curve (AUC) to MIC has a certain ratio. Clinicians should be aware that these relationships can only be an indication in which direction dosing should go. Larger studies with sufficiently high numbers of patients and particularly severely sick patients are needed to prove the concepts. In times where all antibiotics can be measured with new technologies, the introduction of therapeutic drug monitoring (TDM) is suggested for ICUs (Intensive Care Unit). The idea of a central lab for TDM of antibiotics such as PEAK (Paul Ehrlich Antibiotika Konzentrationsmessung) is supported. PMID- 27778051 TI - Patient survey on Invisalign(r) treatment comparen the SmartTrack(r) material to the previous aligner material. AB - OBJECTIVES: In 2013, a novel material SmartTrack(r) was introduced to replace the previous material used for Invisalign(r) aligners. We conducted this study to test how this transition was accepted by patients during ongoing Invisalign(r) treatment. METHODS: We surveyed a total of 72 patients (68 % women, 32 % men, mean age: 29.3 +/- 9.2 years) who had worn the new material for a mean of 6 months. They completed a questionnaire with 25 items that compared both materials in terms of pain, pressure upon insertion, comfort, mucosal irritation, phonetics, discoloration, and taste. RESULTS: On a numerical rating scale (NRS) ranging from 0 to 10, the new aligner material was rated by the respondents to cause significantly (p < 0.001) less maximum pain than the old material (2.8 vs. 3.8). Significant reductions were obtained for duration of pain (p < 0.001) and duration of pressure (2.5 vs. 1.9 days; p = 0.001) upon insertion of the aligners. Over 90 % of the respondents indicated less or equal pain during eating, felt that the new material offered a tighter fit, and provided more favorable ratings for impairment, durability, and discoloration. Improved comfort was reported by 50 % of the respondents. CONCLUSIONS: The new material was favorably rated by the patients and showed significant reductions in pain intensity, pain duration, and pressure upon insertion. Important clinical parameters like overall comfort and impairment also were improved. The clinical effectiveness of the new material remains to be investigated. PMID- 27778053 TI - Effects of Suspended Sediment on Early Life Stages of Smallmouth Bass (Micropterus dolomieu). AB - The resuspension of sediments caused by activities, such as dredging operations, is a concern in Great Lakes harbors where multiple fish species spawn. To address such concerns, smallmouth bass (Micropterus dolomieu) were exposed to uncontaminated suspended sediment (nominally 0, 100, 250, and 500 mg/L) continuously for 72 h to determine the effects on egg-hatching success and swim up fry survival and growth. The test sediments were collected from two harbors: (1) fine-grained sediment in Grand Haven Harbor, Lake Michigan, and (2) coarser grained sediment in Fairport Harbor, Lake Erie. Eggs exposed to total suspended solids (TSS) concentrations >100 mg/L resulted in decreased survival of post hatch larval fish. Fry survival was >90 % at the highest exposure concentration (500 mg/L), but growth was decreased when the exposure concentration was >100 mg/L. Growth and survival of swim-up fry held for a 7- and 26-day post-exposure the grow-out period was variable suggesting that the sediment grain size and strain of fish may influence lingering effects after the cessation of exposure. The results suggest that exposed eggs hatched normally; however, newly hatched larvae, which are temporarily immobile, are more vulnerable to the effects of suspended sediment. The swim-up fry were found to be more sensitive to high TSS concentrations in sandy relative to silty sediment. These data represent a conservative exposure scenario that can be extrapolated to high-energy systems in the field to inform management decisions regarding the necessity for dredging windows or need to implement controls to protect M. dolomieu. PMID- 27778052 TI - Stereotactic body radiotherapy for renal cell cancer and pancreatic cancer : Literature review and practice recommendations of the DEGRO Working Group on Stereotactic Radiotherapy. AB - PURPOSE: This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a literature review and practice recommendations for stereotactic body radiotherapy (SBRT) of primary renal cell cancer and primary pancreatic cancer. METHODS: A literature search on SBRT for both renal cancer and pancreatic cancer was performed with focus on prospective trials and technical aspects for clinical implementation. RESULTS: Data on renal and pancreatic SBRT are limited, but show promising rates of local control for both treatment sites. For pancreatic cancer, fractionated SBRT should be preferred to single-dose treatment to reduce the risk of gastrointestinal toxicity. Motion-compensation strategies and image guidance are paramount for safe SBRT delivery in both tumor entities. CONCLUSION: SBRT for renal cancer and pancreatic cancer have been successfully evaluated in phase I and phase II trials. Pancreatic SBRT should be practiced carefully and only within prospective protocols due to the risk of severe gastrointestinal toxicity. SBRT for primary renal cell cancer appears a viable option for medically inoperable patients but future research needs to better define patient selection criteria and the detailed practice of SBRT. PMID- 27778054 TI - [Comment on: Andexanet alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.] PMID- 27778055 TI - [Necessitas not habet legem? : The physician's tension between professional ethics and patient wishes]. PMID- 27778056 TI - [Unilateral spinal anesthesia : Literature review and recommendations]. AB - Unilateral spinal anesthesia is a cost-effective and rapidly performed anesthetic technique. An exclusively unilateral block only affects the sensory, motor and sympathetic functions on one side of the body and offers the advantages of a spinal block without the typical adverse side effects seen with a bilateral block. The lack of hypotension, in particular, makes unilateral spinal anesthesia suitable for patients with cardiovascular risk factors e. g. aortic valve stenosis or coronary artery disease. Increasing numbers of surgical procedures are now being performed on an outpatient basis. Until now, spinal anesthesia has been considered unsuitable for this, not only because of the high incidence of intraoperative hypotension and postoperative urinary retention but also because of the prolonged postoperative stay before home discharge. This is not the case with unilateral spinal anesthesia: motor function returns rapidly, the incidence of urinary retention is extremely low, and patients are usually eligible for home discharge sooner than after bilateral spinal anesthesia or general anesthesia. The success of the technique depends on a number of factors. In addition to the local anesthetic, its concentration and dose, and the baricity of the injected solution, the shape of the spinal needle, the injection speed, the patient's position during injection, and the time the patient remains in this position after injection are equally important parameters. A number of intrathecally applied adjuvant drugs are used to give a more intense and/or longer-lasting block. For this review, we collated the published data on unilateral spinal anesthesia from journals with an impact factor greater than 1.0 and defined an optimized method for performing the technique. In order to achieve an exclusively unilateral block one should use 0.5 % hyperbaric bupivacaine injected at a rate of 0.33 ml/min or slower. During the injection and the following 20 min the patient should lie in the lateral decubitus position on the side intended for surgery with knees drawn to the chest. An injection of 5 mg (1 ml) hyperbaric bupivacaine 0.5 % provides an hour-long block to T 12, and a dose of 7.5 to 10 mg (1.5-2.0 ml) extends the block to T 6. Adding clonidine (0.5 to 1.0 ug/kg BW) to the injection prolongs the duration of the block to approximately two to three hours. During the 20-minute fixation period, the cephalad spread of the block can be influenced to a certain extent by raising or lowering the head of the table. PMID- 27778059 TI - [Intelligent operating room suite : From passive medical devices to the self thinking cognitive surgical assistant]. AB - Modern operating room (OR) suites are mostly digitally connected but until now the primary focus was on the presentation, transfer and distribution of images. Device information and processes within the operating theaters are barely considered. Cognitive assistance systems have triggered a fundamental rethinking in the automotive industry as well as in logistics. In principle, tasks in the OR, some of which are highly repetitive, also have great potential to be supported by automated cognitive assistance via a self-thinking system. This includes the coordination of the entire workflow in the perioperative process in both the operating theater and the whole hospital. With corresponding data from hospital information systems, medical devices and appropriate models of the surgical process, intelligent systems could optimize the workflow in the operating theater in the near future and support the surgeon. Preliminary results on the use of device information and automatically controlled OR suites are already available. Such systems include, for example the guidance of laparoscopic camera systems. Nevertheless, cognitive assistance systems that make use of knowledge about patients, processes and other pieces of information to improve surgical treatment are not yet available in the clinical routine but are urgently needed in order to automatically assist the surgeon in situation-related activities and thus substantially improve patient care. PMID- 27778057 TI - Potential role for ET-2 acting through ETA receptors in experimental colitis in mice. AB - OBJECTIVE AND DESIGN: This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB receptors in mouse models of colitis. MATERIALS AND METHODS: Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors. RESULTS: Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1beta, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ETA and ETB receptors mRNA were increased at 24, 48 and 72 h after colitis induction. CONCLUSIONS: Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS treated mice, suggesting that ETA receptors might be a potential target for inflammatory bowel diseases. PMID- 27778061 TI - [Impact of weather, time of day and season on the admission and outcome of major trauma patients]. AB - BACKGROUND AND OBJECTIVES: The potential association of external factors such as time of day, lunar phases or specific weather conditions on the daily management and outcome of trauma emergencies remains under debate. We undertook this trauma centre investigation to detect possible worthwhile factors of influence in order to optimize the organizational structure of trauma admissions. MATERIALS AND METHODS: Retrospective cohort analysis over the years 2010-2013, including all emergency trauma admissions with a new injury severity score (NISS) >=8 (major trauma) treated in a teaching hospital in the lowland of Switzerland (uni- and multivariable analysis; p < 0.05). RESULTS: During the study period, 1178 major trauma patients were admitted to the hospital. The mean age of trauma victims was 53 +/- 23 and the average ISS was 14 +/- 8. More patients arrived within the summer months than during the rest of the year (p < 0.001). Higher energy trauma was found to correlate with higher daytime temperature, longer duration of sunshine (each p < 0.001), and change in weather conditions (p = 0.008). In contrast, snowfall and lunar phases did not demonstrate any association with the number or characteristics of trauma admissions. Multivariable analysis demonstrated that altogether longer sunshine, higher minimum daytime temperature and lower air humidity, compared to the previous day, accounted for 31 % of major trauma admissions. We could not find any impact of the investigated external factors on the outcome of patients. CONCLUSIONS: The study shows a significant relationship between specific weather conditions, such as higher daytime temperature or change in circulation, and the admission of major trauma patients. Due to the small effect in our setting, our results do not implicate any according change in the management of resources. Nevertheless, for hospitals in other geographic or more exposed weather regions, such effects could indeed be relevant and therefore should be tested. PMID- 27778058 TI - [Closure of pancreas stump after distal and segmental resection : Suture, stapler, coverage or anastomosis?] AB - Postoperative pancreatic fistulas represent the most frequent complication after distal and segmental pancreatectomy and occur with a frequency of up to 50 %. There are many technical variations of pancreatic stump treatment for reduction of fistula rates after distal resection. Most of these techniques have only been analyzed in retrospective studies and the evidence for or against a specific technique is low. Several retrospective trials have been conducted with good results to compare suturing with stapled closure of the remnant and to assess the effect of a vascularized falciform ligament patch in reducing postoperative pancreatic fistula; however, in a recently published randomized trial, which analyzed closure of the remnant with a pancreaticojejunostomy compared to standard closure, these results could not be confirmed. Because stapler resection and closure is the most commonly used technique in laparoscopic distal pancreatectomy, there are a large number of studies which assessed various novel methods of improving stapling. Extended stapler compression time and mesh augmentation of the stapler line can be valid methods to reduce fistula rates. Central pancreatectomy is a relatively rarely used procedure where the right sided pancreatic remnant is closed in the same fashion as during distal pancreatectomy and the left-sided remnant is connected to the intestines with a pancreaticojejunostomy or pancreaticogastrostomy. In conclusion, postoperative pancreatic fistula rates are still a relevant clinical problem after distal pancreatectomy and further studies on potentially improved novel techniques are required. PMID- 27778060 TI - The role of oral antibiotics prophylaxis in prevention of surgical site infection in colorectal surgery. AB - BACKGROUND: Surgical site infection (SSI) continues to be a challenge in colorectal surgery. Over the years, various modalities have been used in an attempt to reduce SSI risk in elective colorectal surgery, which include mechanical bowel preparation before surgery, oral antibiotics and intravenous antibiotic prophylaxis at induction of surgery. Even though IV antibiotics have become standard practice, there has been a debate on the exact role of oral antibiotics. AIM: The primary aim was to identify the role of oral antibiotics in reduction of SSI in elective colorectal surgery. The secondary aim was to explore any potential benefit in the use of mechanical bowel preparation (MBP) in relation to SSI in elective colorectal surgery. METHODS: Medline, Embase and the Cochrane Library were searched. Any randomised controlled trials (RCTs) or cohort studies after 1980, which investigated the effectiveness of oral antibiotic prophylaxis and/or MBP in preventing SSIs in elective colorectal surgery were included. RESULTS: Twenty-three RCTs and eight cohorts were included. The results indicate a statistically significant advantage in preventing SSIs with the combined usage of oral and systemic antibiotic prophylaxis. Furthermore, our analysis of the cohort studies shows no benefits in the use of MBP in prevention of SSIs. CONCLUSIONS: The addition of oral antibiotics to systemic antibiotics could potentially reduce the risk of SSIs in elective colorectal surgery. Additionally, MBP does not seem to provide a clear benefit with regard to SSI prevention. PMID- 27778063 TI - Forecasting Urban Forest Ecosystem Structure, Function, and Vulnerability. AB - The benefits derived from urban forest ecosystems are garnering increasing attention in ecological research and municipal planning. However, because of their location in heterogeneous and highly-altered urban landscapes, urban forests are vulnerable and commonly suffer disproportionate and varying levels of stress and disturbance. The objective of this study is to assess and analyze the spatial and temporal changes, and potential vulnerability, of the urban forest resource in Toronto, Canada. This research was conducted using a spatially explicit, indicator-based assessment of vulnerability and i-Tree Forecast modeling of temporal changes in forest structure and function. Nine scenarios were simulated for 45 years and model output was analyzed at the ecosystem and municipal scale. Substantial mismatches in ecological processes between spatial scales were found, which can translate into unanticipated loss of function and social inequities if not accounted for in planning and management. At the municipal scale, the effects of Asian longhorned beetle and ice storm disturbance were far less influential on structure and function than changes in management actions. The strategic goals of removing invasive species and increasing tree planting resulted in a decline in carbon storage and leaf biomass. Introducing vulnerability parameters in the modeling increased the spatial heterogeneity in structure and function while expanding the disparities of resident access to ecosystem services. There was often a variable and uncertain relationship between vulnerability and ecosystem structure and function. Vulnerability assessment and analysis can provide strategic planning initiatives with valuable insight into the processes of structural and functional change resulting from management intervention. PMID- 27778062 TI - Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice. AB - BACKGROUND: Cytisine (CYT) is a partial agonist of brain alpha4beta2 nicotinic acetylcholine receptors widely used in Central/Eastern Europe for smoking cessation. OBJECTIVES: This study evaluated the effect of CYT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz test, a model of psychomotor seizures in mice thought as a model of drug resistant seizures. RESULTS: CYT administered intraperitoneally (i.p.) in a dose of 2 mg kg-1 significantly inhibited the anticonvulsant activity of lacosamide, levetiracetam, and pregabalin, increasing their median effective doses 50 (ED50) values from 6.88 to 10.52 mg kg-1 (P < 0.05) for lacosamide, from 22.08 to 38.26 mg kg-1 (P < 0.05) for levetiracetam, and from 40.48 to 64.61 mg kg-1 (P < 0.01) for pregabalin, respectively. There were no significant changes in total brain concentrations of lacosamide, levetiracetam, and pregabalin following CYT i.p. administration. CYT administered in a dose of 2 mg kg-1 failed to change the protective action of clobazam, clonazepam, phenobarbital, tiagabine, and valproate in the 6-Hz test. Neither CYT (2 mg kg-1) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. CONCLUSION: CYT-evoked alterations in the protection provided by some antiepileptic drugs against seizures can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to lacosamide, levetiracetam, and pregabalin, resulting in possible breakthrough seizure attacks. PMID- 27778064 TI - Climate Trends and Farmers' Perceptions of Climate Change in Zambia. AB - A number of studies use meteorological records to analyze climate trends and assess the impact of climate change on agricultural yields. While these provide quantitative evidence on climate trends and the likely effects thereof, they incorporate limited qualitative analysis of farmers' perceptions of climate change and/or variability. The present study builds on the quantitative methods used elsewhere to analyze climate trends, and in addition compares local narratives of climate change with evidence found in meteorological records in Zambia. Farmers offer remarkably consistent reports of a rainy season that is growing shorter and less predictable. For some climate parameters-notably, rising average temperature-there is a clear overlap between farmers' observations and patterns found in the meteorological records. However, the data do not support the perception that the rainy season used to begin earlier, and we generally do not detect a reported increase in the frequency of dry spells. Several explanations for these discrepancies are offered. Further, we provide policy recommendations to help farmers adapt to climate change/variability, as well as suggestions to shape future climate change policies, programs, and research in developing countries. PMID- 27778065 TI - A Holistic Approach Including Biological and Geological Criteria for Integrative Management in Protected Areas. AB - Biodiversity hotspots and geosites are indivisible parts of natural heritage. Therefore, an adequate spatial delimitation and understanding of both and their linkages are necessary in order to be able to establish conservation policies. Normally, biodiversity hotspots are a typical target for those policies but, generally, geosites are not taken into account. Thus, this paper aims to fill this gap by providing an easily replicable method for the identification and integration of the geosites and the biodiversity hotspots in a Network for Integrative Nature Conservation that highlights their linkages. The method here presented has been applied to Urdaibai Biosphere Reserve situated in southeastern of the Bay of Biscay. The obtained results indicate that some geosites that are not directly related with biodiversity hotspots remain unprotected. Thus, from the study carried out, it can be stated that we conserving just the biodiversity hotspots is not enough to conserve the whole natural heritage of a protected area, as some plots interesting due to their relevant geoheritage remain unprotected. Therefore, it is necessary to fully integrate geosites into the planning documents of protected areas as a part of an ecosystem approach. The ecosystem approach recognizes the integrity of abiotic and biotic elements in nature conservation policies. Moreover, the proposed framework and the innovative methodology can be used as an easy input to identify priority areas for conservation, to improve the protected areas conservation planning, and to demonstrate the linkages between biodiversity hotspots and geosites. PMID- 27778066 TI - Deforestation and Carbon Stock Loss in Brazil's Amazonian Settlements. AB - We estimate deforestation and the carbon stock in 2740 (82 %) of the 3325 settlements in Brazil's Legal Amazonia region. Estimates are made both using available satellite data and a carbon map for the "pre-modern" period (prior to 1970). We used data from Brazil's Project for Monitoring Deforestation in Amazonia updated through 2013 and from the Brazilian Biomes Deforestation Monitoring Project (PMDBBS) updated through 2010. To obtain the pre-modern and recent carbon stocks we performed an intersection between a carbon map and a map derived from settlement boundaries and deforestation data. Although the settlements analyzed occupied only 8 % of Legal Amazonia, our results indicate that these settlements contributed 17 % (160,410 km2) of total clearing (forest + non-forest) in Legal Amazonia (967,003 km2). This represents a clear-cutting of 41 % of the original vegetation in the settlements. Out of this total, 72 % (115,634 km2) was in the "Federal Settlement Project" (PA) category. Deforestation in settlements represents 20 % (2.6 Pg C) of the total carbon loss in Legal Amazonia (13.1 Pg C). The carbon stock in remaining vegetation represents 3.8 Pg C, or 6 % of the total remaining carbon stock in Legal Amazonia (58.6 Pg C) in the periods analyzed. The carbon reductions in settlements are caused both by the settlers and by external actors. Our findings suggest that agrarian reform policies contributed directly to carbon loss. Thus, the implementation of new settlements should consider potential carbon stock losses, especially if settlements are created in areas with high carbon stocks. PMID- 27778067 TI - Cost-effectiveness of clinical remission by treat to target strategy in established rheumatoid arthritis: results of the CREATE registry. AB - To analyse the cost-effectiveness, in daily clinical practice, of the strategy of treating to the target of clinical remission (CR) in patients with established rheumatoid arthritis (RA), after 2 years of treatment with biological therapy. Adult patients with established RA were treated with biological therapy and followed up for 2 years by a multidisciplinary team responsible for their clinical management. Treatment effectiveness was evaluated by the DAS28 score. The direct costs incurred during this period were quantified from the perspective of the healthcare system. We calculated the cost-effectiveness of obtaining a DAS28 < 2.6, considered as CR. The study included 144 RA patients treated with biological therapies. After 2 years of treatment, 32.6% of patients achieved CR. The mean cost of achieving CR at 2 years was 79,681 +/- 38,880 euros. The strategy of treatment to the target of CR is considered the most effective, but in actual clinical practice in patients with established RA, it has a high cost. PMID- 27778068 TI - Association between the body mass index and the clinical findings in patients with acute heart failure: evaluation of the obesity paradox in patients with severely decompensated acute heart failure. AB - Obesity is known to be associated with the development of heart failure (HF). However, the relationship between the body mass index (BMI) and acute HF (AHF) remains to be elucidated. Eight hundred and eight AHF patients were enrolled in this study. The patients were assigned to four groups according to their BMI values: severely thin (n = 11, BMI <16), normal/underweight (n = 579, 16 <= BMI <25), overweight (n = 178, 25 <= BMI <30) and obese (n = 40, BMI >=30). The patients in the severely thin group were more likely to be female, have systolic blood pressure (SBP) <100 mmHg and have valvular disease than normal/underweight patients. The patients in the overweight group were significantly younger than those in the normal/underweight, and those in the overweight group were more likely to have SBP >=140 mmHg and hypertensive heart disease and less likely to have valvular disease than the patients in the normal/underweight group. The prognosis, including all-cause death, was significantly poorer among patients who were severely thin than those who were normal/underweight, overweight and significantly better among those who were overweight than those who were normal/underweight, severely thin and obese patients. A multivariate Cox regression model identified that severely thin [HR: 3.372, 95% confidence interval (CI) 1.362-8.351] and overweight (HR: 0.615, 95% CI 0.391-0.966) were independent predictors of 910-day mortality as the reference of normal/underweight. Overweight patients tended to have SBP >=140 mmHg and be relatively young, while severely thin patients tended to have SBP <100 mmHg and be female. These factors were associated with a better prognosis of overweight patients and adverse outcomes in severely thin patients. These factors may contribute to the "obesity paradox" in severely decompensated AHF patients. PMID- 27778069 TI - Behavioral responses of zebrafish depend on the type of threatening chemical cues. AB - In fish, defensive reactions are induced by different chemical cues that emanate from sense-related stresses [physical, chemical, and visual (visual contact with predator)] or food stresses (acute fasting and chronic food restriction). Using a shuttle box with a two-chamber unmixed laminar flow that allowed fish to remain or flee from a chemical cue, we showed that the avoidance response depended on the type of the chemical cue. We show that zebrafish (Danio rerio) retreated from water conditioned with chemical cues released by chemically or physically stressed fish and acutely fasted fish, but not from water with cues from fish experiencing visual contact with predatory fish or fish suffering from chronic food restriction. Our data reinforced the hypothesis that fish use a combination of information and the context of the situation to determine their evasion strategy. PMID- 27778070 TI - Active salvage chemotherapy versus best supportive care for patients with recurrent or metastatic squamous cell carcinoma of the esophagus refractory or intolerable to fluorouracil, platinum, and taxane. AB - PURPOSE: The survival benefit of chemotherapy (CTx) compared with best supportive care (BSC) is unclear in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC) previously treated with fluorouracil (FU), platinum (PT), and taxane (TAX). PATIENTS AND METHODS: The data of 283 consecutive patients with R/M-ESCC, who could not tolerate or whose tumor was refractory to all three agents (FU, PT, and TAX) between March 2003 and November 2014, were retrospectively reviewed. Patient selection criteria were as follows: age 20-75 years, performance status 0-2, and preserved organ function. Prognostic factors for overall survival (OS), defined as survival time from the last administration of all three agents, were analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: Of the 283 patients, 147 received BSC and 136 received CTx (PT-containing regimen 37, investigative new drugs 28, irinotecan-containing regimen 29, TAX alone 25, FU alone 16, others 4). Most patients' tumors were refractory to all three agents. The median OS of BSC and CTx patients was 4.2 and 7.8 months (hazard ratio 0.41; 95% confidence interval 0.31-0.54), respectively. Multivariate analysis with or without propensity score matching indicated that BSC, metastatic sites other than lung, liver, or bone, and hemoglobin <10 g/dL were associated with poor prognosis. CONCLUSION: CTx might provide a survival benefit over BSC even for patients with R/M-ESCC who cannot tolerate or whose tumor is refractory to all three agents. PMID- 27778071 TI - Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation. AB - PURPOSE: The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination. METHODS: Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single-dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing, and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined. RESULTS: Of the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% SolutolTM was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro. CONCLUSIONS: Rapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation. PMID- 27778072 TI - Robotic Site Adjusted Levator Transection for Carcinoma of the Rectum: A Modification of the Existing Cylindrical Abdominoperineal Resection for Eccentrically Located Tumors. AB - BACKGROUND: Today, extralevator abdominoperineal resection is the standard of care for low rectal cancers with sphincter involvement or location precluding anastomosis. This procedure, while effective from an oncologic point of view, is morbid, with a high incidence of wound complications and genitourinary, and sexual dysfunction. We present a modification of this procedure via a robotic approach, which maintains the radicality while reducing the soft tissue loss and potentially the morbidity. METHODS: Over a 2-year period, five patients (four men and one woman) with eccentric low rectal cancers following neoadjuvant chemoradiation underwent a robot-assisted modified abdominoperineal resection with wide levator transection on the tumor side and conservative levator division on the opposite side. These patients were prospectively followed. Perioperative outcomes, pathologic specimen measures, wound-related problems, and local and systemic recurrences were documented and analyzed. RESULTS: All procedures were successfully completed without conversion. Average body mass index was 32 kg/m2. The mean operative time and blood loss were 370 min and 130 ml, respectively. All specimens had an intact mesorectal envelope with no tumor perforations, and the mean lymph node yield was 16. There were no urinary complications or perineal wound infections. At a median follow-up of 14 months, all patients remain disease free. CONCLUSIONS: Modified robotic cylindrical abdominoperineal resection with site adjusted levator transection for rectal cancer is an oncologically sound operation in eccentrically located tumors. It maintains the radicality of conventional extralevator abdominoperineal resection, while also reducing the soft tissue loss and thereby potentially the morbidity. PMID- 27778073 TI - Prognostic Impact of Further Treatments on Distant Metastasis in Patients with Minimally Invasive Follicular Thyroid Carcinoma: Verification Using Inverse Probability of Treatment Weighting. PMID- 27778074 TI - Chylous Ascites Management After Pancreatic Surgery. AB - BACKGROUND: Postoperative chylous ascites (CA) following pancreatic surgery is uncommon. If left untreated, it leads to malnutrition, immunodeficiency and increased postoperative morbidity and mortality. The aim of this study was to seek out risk factors associated with CA onset and conservative treatment (CT) failure in order to determine better management of CA following pancreatic resection. MATERIALS AND METHODS: All consecutive patients who underwent pancreatic surgery between 2004 and 2014 were reviewed retrospectively. Main demographic, clinical and pathological data were searched for CA risk factors. Patients with CA successfully treated with CT alone were compared to those requiring additional bipedal lymphangiography (BPLAG) in order to seek out risk factors associated with CT failure. RESULTS: Fifteen patients (2.4 %) developed CA after pancreatic surgery. Para-aortic lymph node sampling and early enteral feeding were found to be independent risk factors for postoperative CA (OR 6.36, p = 0.024 and OR 12.18, p = 0.02, respectively). CT was successful in ten patients, and five patients required additional BPLAG to achieve CA resolution. Statistical analysis revealed no significant risk factors for CT failure, including total lymph node count (p = 0.196), para-aortic lymph node sampling (p = 0.661) or maximum chyle loss per day (p = 0.758). CONCLUSIONS: Owing to postoperative CA rarity, there is no consensus in treatment. Early on, CT should be attempted in all patients with CA. BPLAG is a safe and efficient procedure that should be discussed earlier in the step-up therapeutic management. PMID- 27778075 TI - Risk Factors for Anastomotic Stricture Post-esophagectomy with a Standardized Sutured Anastomosis. AB - BACKGROUND: Benign anastomotic strictures occur frequently after esophagectomy, and impact on postoperative recovery, nutritional status, and quality of life. This large cohort study explored the incidence of stricture after transthoracic (2- and 3-stage) and transhiatal resections with uniform single-layer sutured anastomotic technique, and aimed to identify independent risk factors. METHODS: Patients undergoing esophagectomy with gastric conduit reconstruction between February 2001 and October 2014 were studied prospectively. Symptomatic anastomotic stricture was defined as dysphagia requiring endoscopic dilatation, and refractory strictures as those requiring >5 dilatations. Multivariable logistic regression was performed to determine factors independently associated with stricture development. RESULTS: Five-hundred and twenty-four patients, 77 % with adenocarcinoma, underwent esophagectomy [2-stage, n = 328 (62.6 %); 3-stage, n = 129 (23.3 %); transhiatal, n = 74 (14.1 %)], with an overall inhospital mortality rate of 2.7 %. 58.5 % of patients received neoadjuvant therapy [chemotherapy only, n = 119 (22.7 %); chemoradiation, n = 188 (35.9 %)]. Anastomotic stricture developed in 125 patients (24.5 %), was refractory in 20 (3.9 %) and required a median of 2 dilatations (range 1-18). On multivariable analysis, ASA grade (P < 0.05), cervical anastomosis (P < 0.001), and a significant postoperative cardiac event (P < 0.05) were independently associated with stricture risk. Refractory strictures were independently associated with anastomotic leak (P = 0.01) and transhiatal resections (P < 0.001). CONCLUSION: Benign anastomotic strictures are common, particularly with cervical reconstruction, and after transhiatal resection. Refractory strictures are rare. Where fitness and oncologic equivalence apply, a thoracic anastomosis provides significant advantages compared with a cervical anastomosis in terms of anastomotic stricture risk. PMID- 27778077 TI - Plate Fixation Versus Intramedullary Nailing for Both-Bone Forearm Fractures: A Meta-analysis of Randomized Controlled Trials and Cohort Studies. AB - OBJECTIVE: The aim of this study was to compare the radiographic and functional outcomes of operative intervention in patients with both-bone forearm fractures treated by open reduction and internal fixation (ORIF) with plates or intramedullary (IM) nailing. METHODS: Studies published in PubMed, EMBASE, Web of Science, SinoMed (Chinese BioMedical Literature Service System, China), and CNKI (China National Knowledge Infrastructure, China) were systematically searched. The main outcomes included time to union, union rate, operation time, magnitude and location of radial bow, loss of forearm rotation, and complication rates. Results were expressed with weighted mean difference or risk ratio with 95 % confidence intervals. Pooled estimates were calculated using a fixed-effects or random-effects model according to the heterogeneity among studies. RESULTS: A total of 13 studies met the inclusion criteria and were included in this meta analysis. Compared with ORIF, IM nailing significantly reduced the operation time and complication rate. However, no significant differences were observed between the two surgical techniques in several outcomes, including time to union, union rate, radial bow magnitude, and loss of forearm rotation. Except in complications, these findings were consistent across the subgroup analysis of children and adult patients. CONCLUSION: IM nailing is associated with shorter operation time and lower complication rate compared with ORIF. It is an effective and safe treatment option for children and adults with both forearm fractures. However, considering the limitations in this study, large-scale, high-quality randomized controlled trials are needed to indentify these findings. PMID- 27778076 TI - A Retrospective One-Year Estimation of the Volume and Nature of Surgical and Anaesthetic Services Delivered to the Populations of the Fako Division of the South-West Region of Cameroon: An Urgent Call for Action. AB - BACKGROUND: Surgery-related conditions account for the majority of admissions in primary referral hospitals in Sub-Saharan Africa. The role of surgery in the reduction of global disease burden is well recognized, but there is a great qualitative and quantitative disparity in the delivery of surgical and anaesthetic services between countries. This study aims at estimating the nature and volume of surgery delivered in an entire administrative division of Cameroon. METHODS: In this retrospective survey conducted during the year 2013, we used a standard tool to analyse the infrastructure and human resources involved in the delivery of surgical and anaesthetic services in the Fako division in the south west region of Cameroon. We also estimated the nature and volume of surgical services as a rate per catchment population. RESULTS: Public, private and mission hospital contributed equally to the delivery of surgical services in the Fako. For every 100,000 people, there were <5 operative rooms. A total of 2460 surgical interventions were performed by 2.2 surgeons, 1.1 gynaecologists and 0.3 anaesthetists. These surgical interventions consisted mostly of minor and emergency procedures. Neurosurgery, paediatric, thoracic and endocrine surgery were almost non-existent. CONCLUSIONS: The volume of surgery delivered in the Fako is far below the minimum rates required to meet up with the most basic requirements of the populations. It is likely that most of these surgical needs are left unattended. A community-based assessment of unmet surgical needs is necessary to accurately estimate the magnitude of the problem and guide surgical capacity improvements. PMID- 27778078 TI - Development and health: keeping hope alive in the midst of irrationality. PMID- 27778081 TI - ? PMID- 27778080 TI - ? AB - The German Committee on Indoor Guide Values issues indoor air guide values to protect public health. For health evaluation of inhaled toluene a number of valid studies in humans is available. Toluene is a neurotoxic substance and the guide values are based on deficits in neurobehavioural tests observed at workers with chronic exposure of 337 mg toluene/m3. For the derivation of guide values the assumed continuous exposure is considered by a factor of 4.2, the interindividual variability by a factor of 10 and the elevated respiratory rate in children as compared to adults by a factor of 2. The resulting health hazard guide value (guide value II) is 4 mg toluene/m3. As the difference to the former indoor air guide value of 1996 for toluene is only caused by the slightly changed extrapolation factor for continuous exposure, the committee maintains the guide value II of 3 mg toluene/m3 and the precautionary guide value (guide value I) of 0.3 mg toluene/m3 indoor air. As all C7-C8 alkylbenzenes are neurotoxic the committee evaluates toluene, ethylbenzene and the xylenes as a group. In order to achieve a total evaluation the ratios of concentration and respective guide value of each compound were added. The total guide values I and II are regarded to be complied with if the corresponding sum falls below 1. PMID- 27778082 TI - ? PMID- 27778083 TI - [First ciguatera outbreak in Germany in 2012]. AB - In November 2012, 23 cases of ciguatera with typical combinations of gastrointestinal and neurological symptoms occurred in Germany after consumption of imported tropical fish (Lutjanus spp.). A questionnaire was used to gather information on the disease course and fish consumption. All patients suffered from pathognomonic cold allodynia. Aside from two severe courses of illness, all other cases showed symptoms of moderate intensity. During a three-year follow-up, seven patients reported prolonged paresthesia for more than one year. Two of them reported further neuropathies over almost three years. This is the first time that long-term persistence of symptoms has been documented in detail. Outbreak cases were allocated to eight clusters in seven German cities. A further cluster was prevented by the successful recall of ciguatoxic fish. Three clusters were confirmed by the detection of ciguatoxin in samples of suspicious and recalled fish. An extrapolation on the basis of ciguatoxic samples revealed twenty prevented cases of ciguatera. Further officially unknown cases should be assumed. During the outbreak investigations, inadvertently falsely labelled fish species and fishing capture areas on import and retail level documents were observed. The ascertainment of cases and the outbreak investigations proved to be difficult due to inconsistent case reports to poisons centers, local health and veterinary authorities. In Germany, many physicians are unaware of the disease pattern of ciguatera and the risks caused by tropical fish. The occurrence of further outbreaks during the following years emphasizes the increasing significance of ciguatera in Germany. PMID- 27778084 TI - [Antibiotic consumption surveillance - state of implementation in Munich hospitals : Latest survey by the Munich public health department on the implementation of S 23 Infection protection act]. AB - BACKGROUND: On 4 August 2011 a modification of the infection protection act became law, meaning that antibiotic consumption surveillance and evaluation of data on the local resistance situation became obligatory for hospitals. Four years after the modification of the infection protection act became law, the Munich public health department aimed to evaluate the state of implementation of antibiotic consumption surveillance in Munich hospitals and to ascertain which antibiotic stewardship (ABS) structures have already been established. METHODS: A questionnaire was sent to Munich hospitals about their antibiotic management structural data and state of implementation of legal requirements. RESULTS: Only 32 % of the hospitals have qualified ABS-experts available. In 76 % of the hospitals persons responsible for antibiotic consumption surveillance are appointed, while in 12 % persons responsible for antibiotic consumption surveillance are at least partly released from their normal work for this activity. Twenty-one hospitals (21 %) conduct antibiotic consumption surveillance taking into account all antiinfective agents mentioned in the Robert Koch Institute (RKI) guidelines. Of these, 19 (76 %) did this on basis of World Health Organizations ATC/DDD-system (anatomical therapeutic chemical [ATC] classification system which uses defined daily doses [DDD]). The data on antibiotic consumption is evaluated in 72 % of the hospitals, 68 % take account of the local resistance situation. In 96 %, in-house lists of antiinfectives are available; in 80 %, in-house guidelines for antibiotic treatment are available. Fourty-four percent of the hospitals take part in a national surveillance. CONCLUSIONS: For the first time data were collected on implementation of antibiotic consumption surveillance in hospitals, which has been required by law since 2011. An incomplete implementation of legal requirements was demonstrated. It was found that structural and personnel prerequisites are often missing, that release from normal work for this additional duty is rarely granted and that the evaluation of data is often either missing or does not correspond to the legal requirements by omitting to take account of the local resistance situation. The hygienic control of hospitals by the public health service was extended by an additional subject. To carry out this very specialized task in a competent way, an ABS-qualification for public health staff is essential from the perspective of the authors. PMID- 27778085 TI - [The waterpipe (shisha) - indoor air quality, human biomonitoring, and health effects]. AB - Waterpipe (WP) smoking, also known as shisha or hookah smoking, is growing in western countries as an alternative to cigarette smoking, especially in younger age groups. A majority of smokers mistakenly believe that shisha smoking is a social entertainment practice that leads to more social behavior and relaxation and that this type of smoking is safe or less harmful and less addictive than cigarette smoking.In reality, WP smokers are exposed to hundreds of toxic substances that include well-known carcinogens. High exposures to carbon monoxide and nicotine are major health threats. There is growing evidence that WP smoke causes adverse effects on the pulmonary and cardiovascular systems and there are indications that WP smoke is associated with cancer. Persons exposed to secondhand WP smoke are also at risk.More research on the health effects of WP is urgently needed and more preventive measures for public health protection. Moreover, public WP facilities should be implemented under specific nonsmoker protection laws and consequently controlled.This review summarizes recent data on exposure to WP smoking in indoor environments, the results of biomonitoring data, and the known health effects based on currently available toxicological or epidemiological studies. PMID- 27778086 TI - [On-site detection of bioterrorism-relevant agents : Rapid detection methods for viruses, bacteria and toxins - capabilities and limitations]. AB - In Europe, besides the threat of terrorist attacks involving conventional methods such as explosive devices and automatic weapons, there is also a potential threat of terrorist groups using non-conventional material like biological agents in the scope of future attacks. Consequently, rapid and reliable detection systems for biological agents are being developed and tested continuously to inform crisis management. For environmental detection, a broad spectrum of different laboratory based techniques has been developed for relevant biological agents. However for environmental samples, fast and reliable on-site detection methods are desired by first responders for rapid assessment.Based on different functional principles, generic, immunological and nucleic-acid-based on-site detection methods can be distinguished. Those should be facile, fast, sensitive, and specific. However, commercially available kits usually have limited sensitivity and often have not been validated independently. Furthermore in this context, the multitude of relevant biological agents that potentially have to be considered present in complex environmental matrices poses a serious challenge for reliable detection. Therefore, detailed knowledge of the specific scope of applications and the limitations of different analytical systems is necessary to evaluate the results obtained purposefully.The aim of this article is to provide an overview of the analytical principles, benefits and limitations of prevailing on-site environmental detection systems for bioterrorism-relevant viruses, bacteria and toxins. Despite promising developments the informative value of currently available on-site tests is still limited. Thus, expert laboratories have to conduct confirmatory testing. PMID- 27778087 TI - [Improving drug licensing for children and adolescents : Position paper from the More Medicines for Minors Symposion 8 June 2015 in Bonn]. AB - In Germany and throughout Europe, medicinal products for adults have been developed and evaluated systematically for decades. Medicinal products for children and adolescents, however, have only been researched for the past ten years. As a result, many medicinal products have been administered to children without systematic clinical trials, for example regarding dosage or pharmaceutical form.EU Regulation 1901/2006 aimes to close the gaps in the medical treatment of children and adolescents. In order to do so, the regulation provides for paediatric use marketing authorisations (PUMA) for previously authorised products no longer covered by intellectual property rights and also grants holders of such PUMA licenses further property rights. However, only two PUMA licenses have been applied for. Thus, the PUMA license instrument is hardly being used despite the fact that many medicinal products have a great potential for closing medical gaps for children and adolescents.In order to improve the situation regarding medicinal products for children and adolescents, this scientific symposium "More Medicines for Minors" intended to promote dialogue among the parties involved and to provide an opportunity to discuss reasons for the reluctance to apply for PUMA licenses. Speakers specialised in paediatric and adolescent medicine as well as those from licensing authorities, the Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA), the pharmaceutical industry and the federal ministries presented problems and possible solutions from their point of view with the aim of making the PUMA license instrument more attractive. PMID- 27778088 TI - Association between full breastfeeding, timing of complementary food introduction, and iron status in infancy in Germany: results of a secondary analysis of a randomized trial. AB - PURPOSE: Considering the low content in breast milk breastfed infants might be at particular risk for depleted iron stores after the first months of life. This study evaluates the association of the mode of milk feeding and the timing of complementary food (CF) introduction with parameters of iron status in term healthy infants in Germany. METHODS: In this secondary analysis of a randomized controlled trial, parents recorded all foods consumed by their infants from the age of 8 weeks onwards. Mothers were advised on the German food-based dietary guidelines for infants. Accordingly, CF was introduced between the fifth and seventh month of age. Blood samples were taken at 4 and at 10 months of age for analyses of iron status parameters. Iron depletion was defined as serum ferritin <12 ng/mL. RESULTS: The iron intake was lower in breastfed infants (n = 50) than in formula fed (n = 23) with decreasing differences during the course of infancy. At 10 months of age, most iron parameters were not associated with the mode of milk feeding or the timing of CF introduction. At this age, the iron depletion prevalence was >34% without general differences according to the mode of milk feeding or the timing of CF introduction. CONCLUSION: The high prevalence of depleted iron stores observed in both breastfed and formula-fed infants illustrates the need for further studies to improve our understanding of the optimal iron intake and sensitive parameters of iron status in infancy. PMID- 27778089 TI - Comparison of initial and tertiary centre second opinion reads of multiparametric magnetic resonance imaging of the prostate prior to repeat biopsy. AB - OBJECTIVES: To investigate the value of second-opinion evaluation of multiparametric prostate magnetic resonance imaging (MRI) by subspecialised uroradiologists at a tertiary centre for the detection of significant cancer in transperineal fusion prostate biopsy. METHODS: Evaluation of prospectively acquired initial and second-opinion radiology reports of 158 patients who underwent MRI at regional hospitals prior to transperineal MR/untrasound fusion biopsy at a tertiary referral centre over a 3-year period. Gleason score (GS) 7 10 cancer, positive predictive value (PPV) and negative (NPV) predictive value (+/-95 % confidence intervals) were calculated and compared by Fisher's exact test. RESULTS: Disagreement between initial and tertiary centre second-opinion reports was observed in 54 % of cases (86/158). MRIs had a higher NPV for GS 7-10 in tertiary centre reads compared to initial reports (0.89 +/- 0.08 vs 0.72 +/- 0.16; p = 0.04), and a higher PPV in the target area for all cancer (0.61 +/- 0.12 vs 0.28 +/- 0.10; p = 0.01) and GS 7-10 cancer (0.43 +/- 0.12 vs 0.2 3 +/- 0.09; p = 0.02). For equivocal suspicion, the PPV for GS 7-10 was 0.12 +/- 0.11 for tertiary centre and 0.11 +/- 0.09 for initial reads; p = 1.00. CONCLUSIONS: Second readings of prostate MRI by subspecialised uroradiologists at a tertiary centre significantly improved both NPV and PPV. Reporter experience may help to reduce overcalling and avoid overtargeting of lesions. KEY POINTS: * Multiparametric MRIs were more often called negative in subspecialist reads (41 % vs 20 %). * Second readings of prostate mpMRIs by subspecialist uroradiologists significantly improved NPV and PPV. * Reporter experience may reduce overcalling and avoid overtargeting of lesions. * Greater education and training of radiologists in prostate MRI interpretation is advised. PMID- 27778090 TI - Radiomic features from the peritumoral brain parenchyma on treatment-naive multi parametric MR imaging predict long versus short-term survival in glioblastoma multiforme: Preliminary findings. AB - OBJECTIVE: Despite 90 % of glioblastoma (GBM) recurrences occurring in the peritumoral brain zone (PBZ), its contribution in patient survival is poorly understood. The current study leverages computerized texture (i.e. radiomic) analysis to evaluate the efficacy of PBZ features from pre-operative MRI in predicting long- (>18 months) versus short-term (<7 months) survival in GBM. METHODS: Sixty-five patient examinations (29 short-term, 36 long-term) with gadolinium-contrast T1w, FLAIR and T2w sequences from the Cancer Imaging Archive were employed. An expert manually segmented each study as: enhancing lesion, PBZ and tumour necrosis. 402 radiomic features (capturing co-occurrence, grey-level dependence and directional gradients) were obtained for each region. Evaluation was performed using threefold cross-validation, such that a subset of studies was used to select the most predictive features, and the remaining subset was used to evaluate their efficacy in predicting survival. RESULTS: A subset of ten radiomic 'peritumoral' MRI features, suggestive of intensity heterogeneity and textural patterns, was found to be predictive of survival (p = 1.47 * 10-5) as compared to features from enhancing tumour, necrotic regions and known clinical factors. CONCLUSION: Our preliminary analysis suggests that radiomic features from the PBZ on routine pre-operative MRI may be predictive of long- versus short-term survival in GBM. KEY POINTS: * Radiomic features from peritumoral regions can capture glioblastoma heterogeneity to predict outcome. * Peritumoral radiomics along with clinical factors are highly predictive of glioblastoma outcome. * Identifying prognostic markers can assist in making personalized therapy decisions in glioblastoma. PMID- 27778091 TI - Delayed graft function and its management in children. AB - Delayed graft function (DGF) is commonly defined as the requirement for dialysis within the first 7 days following renal transplantation. The major underlying mechanism is related to ischaemia/reperfusion injury, which includes microvascular inflammation and cell death and apoptosis, and to the regeneration processes. Several clinical factors related to donor, recipient and organ procurement/transplantation procedures may increase the risk of DGF, including donor cardiovascular instability, older donor age, donor creatinine concentration, long cold ischaemia time and marked body mass index of both the donor and recipient. Some of these parameters have been used in specific predictive formulas created to assess the risk of DGF. A variety of other pre-, intra- and post-transplant clinical factors may also increase the risk of DGF, such as potential drug nephrotoxicity, surgical problems and/or hyperimmunization of the recipient. DGF may decrease the long-term graft function, but data on this effect are inconsistent, partially due to the many different types of organ donation. Relevant management strategies may be classified into the classic clinical approach, which has the aim of minimizing the individual risk factors of DGF, and specific pharmacologic strategies, which are designed to prevent or treat ischaemia/reperfusion injury. Both strategies are currently being evaluated in clinical trials. PMID- 27778092 TI - Epidemiology of idiopathic nephrotic syndrome in children: endemic or epidemic? AB - BACKGROUND: The etiology of idiopathic nephrotic syndrome (INS) remains partially unknown. Viral infections have been reported to be associated with INS onset and relapse. The aim of this study was to describe the epidemiology of a population based cohort of children with INS and propose a spatiotemporal analysis. METHODS: All children aged 6 months to 15 years with INS onset between December 2007 and May 2010 and living in the Paris area were included in a prospective multicenter study. Demographic and clinical features at diagnosis and 2 years were collected. RESULTS: INS was diagnosed in 188 children, 93 % of whom were steroid sensitive. Annual incidence was 3.35/100,000 children. Standardized incidence ratio (SIR) was higher in one of the eight counties: Seine-Saint-Denis, with SIR 1.43 [95 % confidence interval (CI) 1.02-1.95]. A spatial cluster was further identified with higher SIR 1.36 (95 % CI 1.09-1.67). Temporal analysis within this overincidence area showed seasonal variation, with a peak during the winter period (p <0.01). In addition, partition of the Paris area into quintiles of the population showed that the average delay of occurrence, with regard to the first study case, followed a longitudinal progression (p <0.0001). CONCLUSION: The clustering of cases, the seasonal variation within this particular area, and the progression over the Paris area altogether suggest that INS may occur on an epidemic mode. PMID- 27778093 TI - First record of Rhizoscyphus ericae in Southern Hemisphere's Ericaceae. AB - Ericoid mycorrhiza is arguably the least investigated mycorrhizal type, particularly when related to the number of potential hosts and the ecosystems they inhabit. Little is known about the global distribution of ericoid mycorrhizal (ErM) fungi, and this holds true even for the prominent ErM mycobiont Rhizoscyphus ericae. Earlier studies suggested R. ericae might be low in abundance or absent in the roots of Southern Hemisphere's Ericaceae, and our previous investigations in two Argentine Patagonian forests supported this view. Here, we revisited the formerly investigated area, albeit at a higher altitude, and screened fungi inhabiting hair roots of Gaultheria caespitosa and Gaultheria pumila at a treeless alpine site using the same methods as previously. We obtained 234 isolates, most of them belonging to Ascomycota. In contrast to previous findings, however, among 37 detected operational taxonomic units (OTUs), OTU 1 (=R. ericae s. str.) comprised the highest number of isolates (87, ~37 %). Most of the OTUs and isolates belonged to the Helotiales, and 82.5 % of isolates belonged to OTUs shared between both Gaultheria species. At the alpine site, ericoid mycorrhizal fungi dominated, followed by dark septate endophytes and aquatic hyphomycetes probably acting as root endophytes. Our results suggest that the distribution of R. ericae is influenced, among others, by factors related to altitude such as soil type and presence/absence and type of the neighboring vegetation. Our study is the first report on R. ericae colonizing Ericaceae roots in the Southern Hemisphere and extends the known range of this prominent ErM species to NW Patagonia. PMID- 27778094 TI - Tumor enucleation specimens of small renal tumors more frequently have a positive surgical margin than partial nephrectomy specimens, but this is not associated with local tumor recurrence. AB - Approaches to nephron-sparing surgeries (NSS) of renal lesions include partial nephrectomy (PN) and tumor enucleation (TE). Our objective was to examine the pathology of the pseudocapsule and status of the surgical margin in small renal masses treated by NSS and to correlate these findings with the surgical and oncological outcomes. All consecutive renal TE and PN specimens obtained during the period between January 2012 and December 2014, of which clinical follow-up was available, were included in this study. Pathologic features and clinical data were reviewed and analyzed. A total of 117 NSS specimens (59 EN, 58 PN) were reviewed. Clear cell renal cell carcinomas and paraganglioma had the thickest pseudocapsules (0.36 mm), while angiomyolipomas did not form a well-defined pseudocapsule. Other tumors were intermediate in their characteristics. The positive margin rate for TE and PN was 17.2 and 0 %, respectively. Compared to PN, TE involved a significantly shorter procedure time, less blood loss, and fewer post-operative complications. None of the patients from either group was found to have a local recurrence after follow-up imaging. Although positive surgical margins were more frequently seen in TE specimens, local tumor recurrence was comparable to PN. Thus, TE is a reasonable choice for pT1 renal tumors, especially for those without a prominent infiltrative growth pattern. PMID- 27778095 TI - Impacts of meteorological and environmental factors on allergic rhinitis in children. AB - Meteorological and environmental factors influence the pathogenesis of allergic rhinitis (AR). An understanding of the risk factors will facilitate the development of diagnostic and preventative tools for AR children and improve their quality of life. However, research on the impact of these factors on subjective symptoms in AR children remains scarce. This study explored the relationships between subjective symptoms in pollen and dust mite positive AR children, and meteorological and environmental factors. Using a linear mixed effect model, we analyzed the correlations between monthly data on the subjective symptoms of 351 AR children (from the Shanghai Children's Medical Center) and meteorological and environmental factors during 2013. The monthly meteorological and environmental data were provided by the Shanghai Meteorological Service and Shanghai Environmental Protection Bureau. Temperature and humidity were negatively correlated with the subjective symptom score, with a 0.04 point increase observed for every 1 degrees C decrease in temperature (P < 0.0001) or 10 % decline in humidity (P = 0.0412). The particulate matter (PM) 10 and PM2.5 concentrations were positively correlated with the subjective symptom score, with a 10 MUg/m3 increase in PM10 and PM2.5 yielding a 0.02 (P = 0.0235) and 0.03 (P = 0.0281) increase in the subjective symptom score, respectively. In conclusion, meteorological and environmental factors were correlated with subjective symptoms in AR children. Low temperatures, lower humidity, and high PM10 and PM2.5 concentrations aggravated subjective symptoms in AR children. PMID- 27778096 TI - The dimeric form of HLA-G molecule is associated with the response of early rheumatoid arthritis (ERA) patients to methotrexate. AB - A growing body of evidence indicates a possible involvement of HLA (human leukocyte antigen)-G antigens in rheumatoid arthritis (RA), mainly in the HLA-G dimeric isoform, the most active HLA-G form with the strongest immunosuppression, that showed an excellent anti-inflammatory effect in collagen-induced arthritis model mice. However, the relevance of HLA-G dimers in RA response to methotrexate (MTX) treatment is still unknown. We analyzed the HLA-G dimers' amount in plasma samples from early rheumatoid arthritis (ERA) patients before MTX therapy and evaluated the role of these molecules as biomarker of the different response to the treatment. Plasma sHLA-G levels were detected by ELISA, and HLA-G dimeric and monomeric forms were revealed by Western blot in 12 MTX responder (reaching DAS28 remission <2.6) and 8 MTX non-responder (DAS28 >=5.1) patients before the therapy. The response to MTX was evaluated after 6 months of treatment. All ERA patients reaching remission showed higher plasma sHLA-G levels and the 78 kDa HLA G dimeric form. Unresponsive ERA patients were characterized by lower plasma sHLA G levels, and only one patient presented the 78 kDa HLA-G dimeric form (DAS28 5.1). Our preliminary results support the hypothesis that in ERA patients, sHLA-G and, in particular, the presence of the dimeric form in plasma samples before MTX therapy could be an a priori biomarker for the response to MTX treatment. PMID- 27778097 TI - Sulfasalazine induced immune thrombocytopenia in a patient with rheumatoid arthritis. AB - Sulfasalazine has long been used for the treatment of rheumatoid arthritis and is often chosen as a first-line treatment. Here, we report a case of sulfasalazine induced autoimmune thrombocytopenia and review the mechanisms behind drug-induced immune thrombocytopenia (DITP) and the approach to its diagnosis and management. PMID- 27778098 TI - Status of rheumatology practice and professional training courses in rural areas of China-an ILAR project. AB - With the financial support from International League of Associations for Rheumatology (ILAR), we held a rheumatologic care education project in Xishuang Ban'na, a remote district in southern China. During 2014-2015, our project devoted to improve rheumatologic care skills of local clinical practitioners and basic rheumatologic knowledge tothe public. This paper summarizes the undeveloped conditions of rheumatology and our effort in Xishuang Ban'na. PMID- 27778100 TI - Internally coupled ears: mathematical structures and mechanisms underlying ICE. AB - In internally coupled ears (ICE), the displacement of one eardrum creates pressure waves that propagate through air-filled passages in the skull, causing a displacement of the opposing eardrum and vice versa. In this review, a thorough mathematical analysis of the membranes, passages, and propagating pressure waves reveals how internally coupled ears generate unique amplitude and temporal cues for sound localization. The magnitudes of both of these cues are directionally dependent. On the basis of the geometry of the interaural cavity and the elastic properties of the two eardrums confining it at both ends, the present paper reviews the mathematical theory underlying hearing through ICE and derives analytical expressions for eardrum vibrations as well as the pressures inside the internal passages, which ultimately lead to the emergence of highly directional hearing cues. The derived expressions enable one to explicitly see the influence of different parts of the system, e.g., the interaural cavity and the eardrum, on the internal coupling, and the frequency dependence of the coupling. The tympanic fundamental frequency segregates a low-frequency regime with constant time difference magnification (time dilation factor) from a high-frequency domain with considerable amplitude magnification. By exploiting the physical properties of the coupling, we describe a concrete method to numerically estimate the eardrum's fundamental frequency and damping solely through measurements taken from a live animal. PMID- 27778099 TI - Brain structural profile of multiple system atrophy patients with cognitive impairment. AB - Current consensus diagnostic criteria for multiple system atrophy (MSA) consider dementia a non-supporting feature, although cognitive impairment and even frank dementia are reported in clinical practice. Mini-Mental State Examination (MMSE) is a commonly used global cognitive scale, and in a previous study, we established an MSA-specific screening cut-off score <27 to identify cognitive impairment. Finally, MSA neuroimaging findings suggest the presence of structural alterations in patients with cognitive deficits, although the extent of the anatomical changes is unclear. The aim of our multicenter study is to better characterize anatomical changes associated with cognitive impairment in MSA and to further investigate cortical and subcortical structural differences versus healthy controls (HC). We examined retrospectively 72 probable MSA patients [50 with normal cognition (MSA-NC) and 22 cognitively impaired (MSA-CI) based on MMSE <27] and compared them to 36 HC using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to HC, MSA patients showed widespread cortical (bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white-matter alterations. However, MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These results suggest only a marginal contribution of cortical pathology to cognitive deficits. We believe that cognitive dysfunction is driven by focal fronto-striatal degeneration in line with the concept of "subcortical cognitive impairment". PMID- 27778101 TI - Discovery of herpesviruses in Canadian wildlife. AB - Herpesviruses (HVs) have a wide range of hosts in the animal kingdom. The result of infection with HVs can vary from asymptomatic to fatal diseases depending on subtype, strain, and host. To date, little is known about HVs naturally circulating in wildlife species and the impact of these viruses on other species. In our study, we used genetic and comparative approaches to increase our understanding of circulating HVs in Canadian wildlife. Using nested polymerase chain reaction targeting a conserved region of the HV DNA polymerase gene, we analyzed material derived from wildlife of western and northern Canada collected between February 2009 and Sept 2014. For classification of new virus sequences, we compared our viral sequences with published sequences in GenBank to identify conserved residues and motifs that are unique to each subfamily, alongside phylogenetic analysis. All alphaherpesviruses shared a conserved tryptophan (W856) and tyrosine (Y880), betaherpesviruses all shared a serine (S836), and gammaherpesviruses had a conserved glutamic acid (E835). Most of our wildlife HV sequences grouped together with HVs from taxonomically related host species. From Martes americana, we detected previously uncharacterized alpha- and beta herpesviruses. PMID- 27778102 TI - Genomic skimming for identification of medium/highly abundant transposable elements in Arundo donax and Arundo plinii. AB - Transposable elements (TEs) are the most abundant genetic material for almost all eukaryotic genomes. Their effects on the host genomes range from an extensive size variation to the regulation of gene expression, altering gene function and creating new genes. Because of TEs pivotal contribute to the host genome structure and regulation, their identification and characterization provide a wealth of useful data for gaining an in-depth understanding of host genome functioning. The giant reed (Arundo donax) is a perennial rhizomatous C3 grass, octadecaploid, with an estimated nuclear genome size of 2744 Mbp. It is a promising feedstock for second-generation biofuels and biomethane production. To identify and characterize the most repetitive TEs in the genomes of A. donax and its ancestral A. plinii species, we carried out low-coverage whole genome shotgun sequencing for both species. Using a de novo repeat identification approach, 33,041 and 28,237 non-redundant repetitive sequences were identified and characterized in A. donax and A. plinii genomes, representing 37.55 and 31.68% of each genome, respectively. Comparative phylogenetic analyses, including the major TE classes identified in A. donax and A. plinii, together with rice and maize TE paralogs, were carried out to understand the evolutionary relationship of the most abundant TE classes. Highly conserved copies of RIRE1-like Ty1-Copia elements were discovered in two Arundo spp. in which they represented nearly 3% of each genomic sequence. We identified and characterized the medium/highly repetitive TEs in two unexplored polyploid genomes, thus generating useful information for the study of the genomic structure, composition, and functioning of these two non-model species. We provided a valuable resource that could be exploited in any effort aimed at sequencing and assembling these two genomes. PMID- 27778104 TI - Armored brain in a young girl with a syndromal hydrocephalus. AB - The authors present a case of a young girl affected by a syndromal hydrocephalus who developed a bilateral ossified chronic subdural hematoma with the typical radiological appearance of "the armored brain". Bilateral calcified chronic subdural hematoma is a rare complication of ventriculoperitoneal shunt. There is controversy in the treatment, but most published literature discourages a surgical intervention to remove the calcifications. PMID- 27778103 TI - Is routine abdominal drainage necessary after liver resection? AB - PURPOSE: Prophylactic abdominal drainage is performed routinely after liver resection in many centers. The aim of this study was to examine the safety and validity of liver resection without abdominal drainage and to clarify whether routine abdominal drainage after liver resection is necessary. METHODS: Patients who underwent elective liver resection without bilio-enteric anastomosis between July, 2006 and June, 2012 were divided into two groups, based on whether surgery was performed before or after, we adopted the no-drain strategy. The "former group" comprised 256 patients operated on between July, 2006 and June, 2009 and the "latter group" comprised 218 patients operated between July, 2009 and June, 2012. We compared the postoperative complications, percutaneous drainage, and postoperative hospital stay between the groups, retrospectively. RESULTS: There were no significant differences in the rates of postoperative bleeding, intraabdominal infection, or bile leakage between the groups. Drain insertion after liver resection did not reduce the rate of percutaneous drainage. Postoperative hospital stay was significantly shorter in the latter group. CONCLUSION: Routine abdominal drainage is unnecessary after liver resection without bilio-enteric anastomosis. PMID- 27778105 TI - Can early clinical parameters predict post-traumatic pituitary dysfunction in severe traumatic brain injury? AB - BACKGROUND: Post-traumatic hypopituitarism is a major complication after severe head trauma. The aim of our study was to evaluate the possible role of early clinical parameters in the development of endocrine deficits. METHODS: Data on endocrine function, on-admission clinical-, laboratory-, and ICU-monitored parameters were available in 63 patients of the surviving 86 severe head injury patients (post-resuscitation GCS under 8) treated at one neurosurgical center during a 10-year period. RESULTS: Hypopituitarism was diagnosed in 68.3 % of the patients. The most frequently affected pituitary axis was the growth hormone (GH): GH deficiency or insufficiency was present in 50.8 %. Central hypogonadism affected 23.8 % of male patients; hypothyroidism and secondary adrenal failure were found in 22.2 and 9.5 % of the investigated population, respectively. Early onset (within 1 year of brain injury) hypopituitarism was found in 24 patients. No connection was found between the development of hypopituitarism and any of the clinical parameters assessed on-admission or at ICU. Significant correlations were found between early endocrine dysfunctions and surgical intervention (OR: 4.64) and the diagnosis of subdural hematoma (OR: 12). In our population, after road traffic accidents, the development of late-onset hypopituitarism was less prevalent (OR: 0.22). CONCLUSIONS: Since our results do not indicate any reliable predictive parameter for the development of endocrine dysfunction in a cohort of patients with severe traumatic brain injury, regular endocrine screening of this specific patient population seems obligatory. PMID- 27778106 TI - The telencephalon of the Gottingen minipig, cytoarchitecture and cortical surface anatomy. AB - During the last 20 years pigs have become increasingly popular in large animal translational neuroscience research as an economical and ethical feasible substitute to non-human primates. The anatomy of the pig telencephalon is, however, not well known. We present, accordingly, a detailed description of the surface anatomy and cytoarchitecture of the Gottingen minipig telencephalon based on macrophotos and consecutive high-power microphotographs of 15 MUm thick paraffin embedded Nissl-stained coronal sections. In 1-year-old specimens the formalin perfused brain measures approximately 55 * 47 * 36 mm (length, width, height) and weighs around 69 g. The telencephalic part of the Gottingen minipig cerebrum covers a large surface area, which can be divided into a neocortical gyrencephalic part located dorsal to the rhinal fissure, and a ventral subrhinal part dominated by olfactory, amygdaloid, septal, and hippocampal structures. This part of the telencephalon is named the subrhinal lobe, and based on cytoarchitectural and sulcal anatomy, can be discerned from the remaining dorsally located neocortical perirhinal/insular, pericallosal, frontal, parietal, temporal, and occipital lobes. The inner subcortical structure of the minipig telencephalon is dominated by a prominent ventricular system and large basal ganglia, wherein the putamen and the caudate nucleus posterior and dorsally are separated into two entities by the internal capsule, whereas both structures ventrally fuse into a large accumbens nucleus. The presented anatomical data is accompanied by surface renderings and high-power macrophotographs illustrating the telencephalic sulcal pattern, and the localization of the identified lobes and cytoarchitectonic areas. Additionally, 24 representative Nissl-stained telencephalic coronal sections are presented as supplementary material in atlas form on http://www.cense.dk/minipig_atlas/index.html and referred to as S1-S24 throughout the manuscript. PMID- 27778107 TI - A Bowman-Birk protease inhibitor purified, cloned, sequenced and characterized from the seeds of Maclura pomifera (Raf.) Schneid. AB - MAIN CONCLUSION: A new BBI-type protease inhibitor with remarkable structural characteristics was purified, cloned, and sequenced from seeds of Maclura pomifera , a dicotyledonous plant belonging to the Moraceae family. In this work, we report a Bowman-Birk inhibitor (BBI) isolated, purified, cloned, and characterized from Maclura pomifera seeds (MpBBI), the first of this type from a species belonging to Moraceae family. MpBBI was purified to homogeneity by RP HPLC, total RNA was extracted from seeds of M. pomifera, and the 3'RACE-PCR method was applied to obtain the cDNA, which was cloned and sequenced. Peptide mass fingerprinting (PMF) analysis showed correspondence between the in silico translated protein and MpBBI, confirming that it corresponds to a new plant protease inhibitor. The obtained cDNA encoded a polypeptide of 65 residues and possesses 10 cysteine residues, with molecular mass of 7379.27, pI 6.10, and extinction molar coefficient of 9105 M-1 cm-1. MpBBI inhibits strongly trypsin with K i in the 10-10 M range and was stable in a wide array of pH and extreme temperatures. MpBBI comparative modeling was applied to gain insight into its 3D structure and highlighted some distinguishing features: (1) two non-identical loops, (2) loop 1 (CEEESRC) is completely different from any known BBI, and (3) the amount of disulphide bonds is also different from any reported BBI from dicot plants. PMID- 27778108 TI - Seroprevalence of five parasitic pathogens in pregnant women in ten Caribbean countries. AB - To date, published epidemiological studies of parasitic infections in humans in the Caribbean region are very limited. Here, we report the seroprevalence of five parasitic pathogens, including Ascaris lumbricoides, Entamoeba histolytica, Giardia lamblia, Schistosoma mansoni, and Toxocara canis in 435 serum samples collected between 2008 and 2011 from pregnant women in ten Caribbean islands. We tested the serum samples for IgG antibodies against the five parasites by enzyme linked immunosorbent assay (ELISA). Among them, 66.2 % were serologically positive for at least one parasite. The most prevalent parasite was G. lamblia (40.5 %), followed by A. lumbricoides (37.9 %), T. canis (14.5 %), E. histolytica (6.7 %), and S. mansoni (3.0 %). Evidence of infections of G. lamblia and A. lumbricoides were detected in all ten Caribbean countries. Seroprevalence estimates significantly differed between countries for A. lumbricoides, E. histolytica, and T. canis (p values <0.001). For S. mansoni, significance was observed by Fisher's exact test (p = 0.013) but not by multiple comparisons. The prevalence of G. lamblia was not significantly different between countries (p = 0.089). A significant negative correlation between the gross domestic product (GDP) per capita and overall seroprevalence by country was also observed (Pearson's r = -0.9202, p = 0.0002). The data strongly indicates that neglected parasitic infections remain a significant health burden on people in these countries. Thus, justification has been provided to regional health planners to enhance existing public health surveillance programs on parasitic diseases and to heighten the public's awareness through education and outreach programs on how they can minimize the occurrence of parasitic infections. PMID- 27778109 TI - A novel myxosporean parasite Myxobolus klamathellus n. sp. (Cnidaria: Myxosporea) from native blue chub (Gila coerulea) in Klamath Lake, Oregon. AB - Blue chub, Gila coerulea Girard, 1856 is a freshwater cyprinid fish native to inland drainages of western North America. It has not previously been recorded as a host of any myxosporean parasite (Cnidaria: Myxosporea), despite myxosporeans being cosmopolitan in freshwater and marine fishes worldwide and sympatric with this host. Herein, we describe a novel myxosporean from subcutaneous cysts in native blue chub from Klamath Lake, Oregon. Myxospores were consistent with genus Myxobolus, being obovoid but compressed in thickness, length 14.3 +/- 0.4 (13-15) MUm, width 9.7 +/- 0.4 (9-10) MUm, thickness 7.7 +/- 0.3 (7-8) MUm; two polar capsules ovoid slightly dissimilar in size, length 6.4 +/- 0.4 (6-7) MUm, width 3.8 +/- 0.3 (3-4) MUm, with four (3-5) turns of the polar filament (tubule); capsule openings apical, one in each valve cell. The small subunit ribosomal DNA sequence was up to 97 % similar to Myxobolus spp. from other cyprinids from North America and Europe. Given the novel host, unique myxospore morphometrics, and DNA sequence, we describe this as Myxobolus klamathellus n. sp. PMID- 27778110 TI - Surface proteome mining for identification of potential vaccine candidates against Campylobacter jejuni: an in silico approach. AB - Campylobacter jejuni remains a major cause of human gastroenteritis with estimated annual incidence rate of 450 million infections worldwide. C. jejuni is a major burden to public health in both socioeconomically developing and industrialized nations. Virulence determinants involved in C. jejuni pathogenesis are multifactorial in nature and not yet fully understood. Despite the completion of the first C. jejuni genome project in 2000, there are currently no vaccines in the market against this pathogen. Traditional vaccinology approach is an arduous and time extensive task. Omics techniques coupled with sequencing data have engaged researcher's attention to reduce the time and resources applied in the process of vaccine development. Recently, there has been remarkable increase in development of in silico analysis tools for efficiently mining biological information obscured in the genome. In silico approaches have been crucial for combating infectious diseases by accelerating the pace of vaccine development. This study employed a range of bioinformatics approaches for proteome scale identification of peptide vaccine candidates. Whole proteome of C. jejuni was investigated for varied properties like antigenicity, allergenicity, major histocompatibility class (MHC)-peptide interaction, immune cell processivity, HLA distribution, conservancy, and population coverage. Predicted epitopes were further tested for binding in MHC groove using computational docking studies. The predicted epitopes were conserved; covered more than 80 % of the world population and were presented by MHC-I supertypes. We conclude by underscoring that the epitopes predicted are believed to expedite the development of successful vaccines to control or prevent C. jejuni infections albeit the results need to be experimentally validated. PMID- 27778113 TI - Effect of passive transport of water through plasma membrane in production of extracellular enzyme. AB - In this article, availability and control of water in solid-state fermentation (SSF) were investigated. Based on passive transport of water through plasma membranes, a new model was proposed for calculation and control of water activities in the mixture of solids. The validity of theoretical model and accuracy of the proposed model were proved by experimental data. This model was used for production of pectinases via mixed-SSF with the aid of a rotary drum bioreactor. It was found that in case of extracellular enzyme production, the new model is in good agreement with experimental data for the control of water activities in the mixed-SSF. Exact control of water activity in SFF, the production of endo- and exo-pectinases was relatively enhanced. Based on theoretical view point, the prominence of this new model in control of water activity was also proved. PMID- 27778112 TI - Anti-N-methyl-D-aspartate receptor encephalitis associated with intracranial Angiostrongylus cantonensis infection: a case report. AB - Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a recently described paraneoplastic syndrome with prominent neuropsychiatric symptoms. Many of these cases are associated with neoplasma especially teratoma. In addition, a few of cases with anti-NMDAR antibodies triggered by viral infection have been reported, but never by parasitic infection. Here, we report a novel case of NMDA receptor encephalitis in a 51-year-old male related to the development of anti-NMDAR antibodies triggered by Angiostrongylus cantonensis infection. PMID- 27778111 TI - Alr2954 of Anabaena sp. PCC 7120 with ADP-ribose pyrophosphatase activity bestows abiotic stress tolerance in Escherichia coli. AB - In silico derived properties on experimental validation revealed that hypothetical protein Alr2954 of Anabaena sp. PCC7120 is ADP-ribose pyrophosphatase, which belongs to nudix hydrolase superfamily. Presence of ADP ribose binding site was attested by ADP-ribose pyrophosphatase activity (K m 44.71 +/- 8.043 mM, V max 7.128 +/- 0.417 MUmol min-1 mg protein-1, and K cat/K m 9.438 * 104 MUM-1 min-1). Besides ADP-ribose, the enzyme efficiently hydrolyzed various nucleoside phosphatases such as 8-oxo-dGDP, 8-oxo-dADP, 8-oxo-dGTP, 8-oxo dATP, GDP-mannose, ADP-glucose, and NADH. qRT-PCR analysis of alr2954 showed significant expression under different abiotic stresses reconfirming its role in stress tolerance. Thus, Alr2954 qualifies to be a member of nudix hydrolase superfamily, which serves as ADP-ribose pyrophosphatase and assists in multiple abiotic stress tolerance. PMID- 27778114 TI - ASER core curriculum illustration project: aortic intramural hematoma (IMH). AB - This is the 23rd installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at http://www.aseronline.org/curriculum/toc.htm . PMID- 27778115 TI - Influence of dentin thickness on intrapulpal temperature under simulated pulpal pressure during Nd:YAG laser irradiation. AB - The aim of this study was to evaluate the effects of dentin thickness and pulpal pressure simulation (PPS) on the variation of intrapulpal temperature (?T) when submitted to an adhesive technique using laser irradiation. Sixty sound human molars were sectioned and randomly divided into two groups (n = 30): group 1-1 mm of dentin thickness; group 2-2 mm of dentin thickness. Each group was divided into two subgroups (n = 15): subgroup A-absence of PPS; subgroup P-presence of PPS (15 cm H2O), sequentially treated with the following: 37 % phosphoric acid, adhesive system (Adper Single Bond), irradiation with Nd:YAG laser (1064 nm, 10 Hz, 60 s) using 60, 80, and 100 mJ/pulse energy parameters and light-curing (10 s). The ?T was evaluated during the laser irradiation with a digital thermometer. Data were analyzed by three-way ANOVA and Tukey tests (p < 0.05). Three-way ANOVA revealed no significant differences for dentin thickness (p = 0.6512) on ?T. PPS significantly reduced ?T (p = 0.0001). The laser energy parameters (p = 0.0027) indicated that 100 mJ presented with significantly greater ?T when compared to the groups irradiated with 80 and 60 mJ. Dentin thickness did not affect ?T. The presence of PPS reduced the mean temperature values. The Nd:YAG laser energy parameters had a negative influence on the variation of temperature in the absence of PPS. In the presence of PPS, there was no risk to the pulp, since this study obtained temperature increases below 5.5 degrees C for all energy parameters, showing the technical viability for in vivo conditions. PMID- 27778116 TI - The effectiveness of the Erbium:Yttrium aluminum garnet PIPS technique in comparison to different chemical solutions in removing the endodontic smear layer an in vitro profilometric study. AB - This study evaluated the degree of endodontic smear layer removal using the Er:YAG PIPS technique (2.94 MUm) in comparison with different irrigants. Sixty four single-rooted teeth were endodontically prepared up to size #40 and were divided into 8 groups (a-h) (n = 8). Groups a, b, c, and d were irrigated with (3 % NaOCl + 20 % EDTA), (0.9 % NaCl), (3 % NaOCl), and (20 % EDTA), respectively. Groups e, f, g, and h were treated with (3 % NaOCl + 20 % EDTA + PIPS), (0.9 % NaCl + PIPS), (3 % NaOCl + PIPS), and (20 % EDTA + PIPS), respectively. The settings of the Er:YAG PIPS technique were (0.3 W, 20 mJ, 15 Hz, 50 MUs, no water and air). The root canals were examined under a profilometer to evaluate the degree of smear layer removal using Hulsmann scores. The smear layer was present in the coronal, middle, and apical thirds of groups b, c, f, and g. Groups a, d, e, and h exhibited open dentinal tubules in the coronal and middle thirds. However, none of the apical thirds showed open dentinal tubules. No significant difference was observed between the groups treated only with irrigants and those treated with Er:YAG PIPS and the same irrigants (p >= 0.0018). The Er:YAG PIPS technique did not show any improved results in removing the smear layer when compared to the irrigants alone. Moreover, the open dentinal tubules in some groups were a result of the chelating action of 20 % EDTA. PMID- 27778117 TI - A comparison of clinical outcomes between three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer. AB - BACKGROUND: Intensity-modulated radiation therapy (IMRT) reduces the dose delivered to organs at risk. However, there have been few direct comparisons of IMRT with conventional three-dimensional conformal radiotherapy (3DCRT). The aim of this study was to evaluate the clinical benefit of IMRT in terms of toxicity and biochemical control. METHODS: The medical records of 203 consecutive patients with localized to non-metastatic (stage T1a-T3bN0M0) prostate cancer between 2007 and 2011 were retrospectively reviewed. The prescribed dose was 76 Gy delivered in 38 fractions in both the 3DCRT and IMRT treatment groups. The frequency of grade 2 or greater late gastrointestinal (GI) and genitourinary toxicity and biochemical control were estimated by the log-rank test and Cox proportional hazards model with and without adjustment by the propensity score for treatment choice. RESULTS: A total of 159 patients were included in the study (3DCRT: 70 patients, IMRT: 89 patients). The median follow-up period was 4.7 years. The estimated 5-year cumulative risk of late GI toxicity was significantly lower in the IMRT group than in the 3DCRT group (3.6 vs 13.2%, respectively, p = 0.022). After adjustment by propensity score, IMRT remained associated with a lower risk of late GI toxicity (hazard ratio 0.22; 95% confidence interval 0.058-0.85; p = 0.028). The 5-year biochemical failure-free rate was 93.2% in the 3DCRT group and 95.4% in the IMRT group (non-significant difference). CONCLUSIONS: The incidence of late GI toxicity was significantly lower in the IMRT group than in the 3DCRT group, while the biochemical control rates were no different between the two groups. These clinical data suggest the benefit of IMRT in the reduction of late GI toxicity. PMID- 27778118 TI - A panel of autoantibodies as potential early diagnostic serum biomarkers in patients with breast cancer. AB - BACKGROUND: Specific circulating autoantibodies are produced by host immune systems to respond to antigens that arise during tumorigenesis. To achieve auxiliary diagnosis, the present study was designed to test whether circulating autoantibodies against tumor-associated antigens (TAAs) were altered in early breast cancer. METHODS: A total of 102 breast cancer patients and 146 age-matched healthy volunteers were recruited to participate in this study. Autoantibody expression was tested using in-house developed enzyme-linked immunosorbent assay (ELISA) with linear peptide envelope antigens derived from TAAs. RESULTS: Student's t tests showed that expression of autoantibodies against the panel (p16, c-myc, TP53, and ANXA-1) was significantly higher in the breast cancer group, stage I and II breast cancer group, and stage III and IV breast cancer group than in the healthy control group (p < 0.001, p < 0.001, p < 0.001). The sensitivities of detection of the panel (90% specificity) in these groups were 33.3%, 31.7%, and 33.3%, respectively, significantly higher than that of any single autoantibody. CONCLUSION: The panel of autoantibodies is more sensitive than single TAA autoantibody detection and may be used as biomarkers for early diagnosis of breast cancer. PMID- 27778119 TI - Identification of Mitochondrial Genome-Encoded Small RNAs Related to Egg Deterioration Caused by Postovulatory Aging in Rainbow Trout. AB - Many factors have been reported to affect rainbow trout egg quality, among which, postovulatory aging is one of the most significant causes as reared rainbow trout do not usually volitionally oviposit the ovulated eggs. In order to uncover the genetic regulation underling egg deterioration caused by postovulatory aging in rainbow trout, mitochondrial genome-encoded small RNA (mitosRNAs) were analyzed from unfertilized eggs on Days 1, 7, and 14 postovulation with fertilization rates of 91.8, 73.4, and less than 50 %, respectively. A total of 248 mitosRNAs were identified from Illumina high-throughput sequencing of the small RNA libraries derived from the eggs of ten females. Ninety-eight of the small RNAs exhibited more than a threefold difference in expression between eggs from females exhibiting high fertilization rates at Day 1 and low fertilization rates at Day 14. The differentially expressed mitosRNAs were predominantly derived from mitochondrial D-loop, tRNA, rRNA, COII, and Cytb gene regions. Real-time quantitative PCR analysis was carried out for 14 differentially expressed mitosRNAs, of which, 12 were confirmed to be consistent with the sequencing reads. Further characterization of the differentially expressed mitosRNAs may lead to the development of new biomarkers for egg quality in rainbow trout. PMID- 27778120 TI - Monitoring of abdominal Staphylococcus aureus infection using magnetic resonance imaging: a murine animal model for hepatic and renal abscesses. AB - To establish a routine workflow for in vivo magnetic resonance imaging (MRI) of mice infected with bacterial biosafety level 2 pathogens and to generate a mouse model for systemic infection with Staphylococcus aureus suitable for monitoring by MRI. A self-contained acrylic glass animal bed complying with biosafety level 2 requirements was constructed. After intravenous infection with 105 colony forming units (CFU) (n = 3), 106 CFU (n = 11) or 107 CFU (n = 6) of S. aureus strain Newman, female Balb/c mice were whole-body scanned by 7T MRI. Abdominal infections such as abscesses were visualized using a standard T2-weighted scan. Infection monitoring was performed for each animal by measurements at 1, 3, and 7 days after infection. Intravenous pathogen application led to a dose-dependent decrease in survival probability (p = 0.03). In the group with the highest infectious dose the 7-day survival rate was 33 %. An intermediate S. aureus dose showed a survival rate of 80 %, whereas at the lowest infection dose, none of the animals died. All animals with the highest infection dose exhibited hepatic abscesses 4 days after inoculation, 80 % developed renal abscesses on the 3rd day. Mice obtaining the intermediate S. aureus load reached a plateau at day 4 with 72 % liver and 60 % renal abscess probability. No abscesses were observed in other abdominal organs at any time point. The implemented experimental setup provides a suitable and reliable in vivo MRI method to study murine abdominal infection models using BSL-2 pathogen. Systemic Staphylococcus aureus infection leads to a dose-dependent development of hepatic and renal abscesses. PMID- 27778121 TI - The effect of vitreous on proliferative diabetic retinopathy and the response to panretinal photocoagulation. PMID- 27778122 TI - FK962 induces neurite outgrowth in cultured monkey trigeminal ganglion cells. AB - PURPOSE: Corneal sensation, cell proliferation, and wound healing all depend on adequate corneal innervation. Disruption of corneal innervation can lead to dry eye and delayed wound healing. Our studies in rats and rabbits show that the substituted fluorobenzamide drug FK962 accelerates the extension of neuronal processes and recovery of corneal sensitivity. The purpose of the present study was 1) to determine whether FK962 induces sprouting and elongation of neurites in cultured monkey trigeminal ganglion cells, and 2) to investigate the involvement of the neurotrophic peptide GDNF in FK962-induced neurite elongation. METHODS: Dissociated, cultured trigeminal ganglion cells, containing neuronal and Schwann cells were cultured for 48 h with or without FK962. Neuronal elongation was evaluated by immunostaining with a neurofilament-specific antibody. Culture with or without GDNF, or with antibody against GDNF, was used to determine the role of GDNF in FK962-induced neurite elongation. RESULTS: FK962 or GDNF were found to significantly induce neurite elongation. The GDNF antibody significantly inhibited elongation induced by FK962. CONCLUSION: GDNF was found to be a mediator of FK962-induced neurite elongation in a relevant primate model. FK962 may be a candidate drug for treatment of neurotrophic disorders in the human cornea. PMID- 27778123 TI - Spatial attention across perception and action. AB - We hypothesize that a shared spatial attention mechanism is used for both perception and action. To this end we created a new dual-task version of the classical Simon task. In one task, the spatial-input task, associated with input spatial attention, participants named one shape out of two bilaterally presented colored shapes. In a second task, the spatial-output task, associated with output spatial attention, participants discriminated between high and low pitch tones by pressing either a left or a right key. In Experiment 1, input for both tasks appeared simultaneously, and participants were instructed not to prioritize either task. A between tasks Simon-like effect was found for responses to both tasks. Reaction times were shorter when the side of the relevant shape in the spatial-input task and the side of the correct response in the spatial-output task were congruent. In Experiment 2, we manipulated the stimulus-onset asynchrony (SOA) between the inputs for the two tasks and showed that the Simon like effect remained intact at all SOAs. Experiment 3 was similar to Experiment 1 except that the vocal response for the spatial-input task was not speeded. A Simon-like effect was still observed. Experiment 4 was the same as Experiment 3 except that the non-speeded response for the spatial-input task was manual rather than vocal. No Simon-like effect was observed in this experiment. Our results support a shared spatial attention mechanism involved in the Simon effect and indicate that this spatial attention mechanism is shared by perception and action. PMID- 27778124 TI - Early detection of nonperitoneal recurrence may contribute to survival benefit after curative gastrectomy for gastric cancer. AB - BACKGROUND: There is no evidence that strict follow-up using cross-sectional imaging after curative gastrectomy benefits survival; however, nonperitoneal recurrence detected early might be treated with additional surgery. The present study examined whether early detection of recurrence by imaging modalities could increase survival, particularly in patients with nonperitoneal recurrence. METHODS: We retrospectively analyzed 218 patients with recurrent gastric cancer after curative gastrectomy performed from 2002 to 2014. The patients were divided into an asymptomatic group (n = 117) and a symptomatic group (n = 101), according to the presence of symptoms at the time of recurrence, to compare clinicopathological characteristics and long-term survival. RESULTS: Peritoneal recurrence was less frequent in the asymptomatic group (22.2%) than in the symptomatic group (62.4%), the median time to recurrence was shorter (12.7 months vs 18.9 months; P < 0.001), and the median survival time after recurrence was longer (18.7 months vs 7.5 months; P < 0.001). In the asymptomatic group, 10 of 117 patients (8.5%) received additional curative surgery after recurrence. Median overall survival after gastrectomy was not significantly different between the groups (30.1 months for the asymptomatic group vs 30.0 months for the symptomatic group; P = 0.132); however, it was significantly longer among asymptomatic patients with nonperitoneal recurrence compared with symptomatic patients (35.9 months vs 24.0 months; P = 0.039). CONCLUSIONS: The presence of symptoms at recurrence did not affect survival in patients with recurrent gastric cancer. However, detection of nonperitoneal recurrence before the appearance of symptoms may provide survival benefit. Therefore, regular follow-up, including use of imaging modalities, is recommended. PMID- 27778127 TI - Race Is a Risk for Lymph Node Metastasis in Patients With Gastric Cancer. AB - BACKGROUND: The frequency of lymph node metastasis in each T stage of gastric cancer has not been as well described for Western populations as it has for Asian populations. This study aimed to determine these frequencies and to investigate risk factors associated with lymph node metastases in a racially diverse U.S. POPULATION: METHODS: A prospectively maintained database of 8260 patients with gastric or gastroesophageal junction adenocarcinoma treated at our institution from 1995 to 2013 was reviewed to identify those who underwent surgical resection without preoperative therapy. Associations between clinicopathologic variables and lymph node metastasis were tested with uni- and multivariate analyses. RESULTS: The study identified 218 patients with a pathologic diagnosis of gastric adenocarcinoma who underwent upfront gastrectomy. These study subjects included 115 white (53 %), 19 black (9 %), and 41 Asian (19 %) patients. At least 15 lymph nodes were examined in 148 (68 %) of the patients. The lymph node metastasis rates were 10 % for stage T1a, 34 % for stage T1b, 44 % for stage T2, 73 % for stage T3, and 95 % for stage T4 tumors. Univariate analysis showed that submucosal invasion, race, 15 or more lymph nodes examined, and lymphovascular invasion were associated with lymph node metastasis in T1 and T2 tumors. The multivariate analysis showed all but lymphovascular invasion to be independent risk factors for nodal metastasis. CONCLUSIONS: The rates of lymph node metastasis observed in this study were higher than those reported in Asian reports. Race was an independent risk factor for lymph node metastasis. Caution is therefore needed when evidence from Asian countries is extrapolated to more racially diverse Western countries. PMID- 27778126 TI - Reconfiguration of NKT Cell Subset Compartment Is Associated with Plaque Development in Patients with Carotid Artery Stenosis. AB - Accumulating evidence shows that immune cells play an important role in carotid atherosclerotic plaque development. In this study, we assessed the association of 6 different natural killer T (NKT) cell subsets, based on CD57 and CD8 expression, with risk for development of carotid atherosclerotic plaque (CAP). Molecular expression by peripheral NKT cells was evaluated in 13 patients with high-risk CAP and control without carotid stenosis (n = 18). High-risk CAP patients, compared with healthy subjects, had less percentage of CD57+CD8- NKT cell subsets (8.64 +/- 10.15 versus 19.62 +/- 10.8 %; P = 0.01) and CD57+CD8int NKT cell subsets (4.32 +/- 3.04 versus 11.87 +/- 8.56 %; P = 0.002), with a corresponding increase in the CD57-CD8high NKT cell subsets (33.22 +/- 11.87 versus 18.66 +/- 13.68 %; P = 0.007). Intracellular cytokine staining showed that CD8+ NKT cell subset was the main cytokine-producing NKT cell. Cytokine production in plasma was measured with Bio-Plex assay. The expression levels of pro-inflammatory mediators (IFN-gamma, IL-17, IP-10) were significantly higher in CAP patients as compared to that from controls. These data provide evidence that NKT cell subset compartment reconfiguration in patients with carotid stenosis seems to be associated with the occurrence of carotid atherosclerotic plaque and suggest that both pathogenic and protective NKT cell subsets exist. PMID- 27778125 TI - Ten-Eleven Translocation 1 and 2 Confer Overlapping Transcriptional Programs for the Proliferation of Cultured Adult Neural Stem Cells. AB - Adult neurogenesis originates from neural stem cells (NSCs) in specific regions of the adult brain. The molecular mechanisms that control the self-renewal and multipotency of NSCs have not been fully elucidated. In recent years, emerging evidence has revealed that ten-eleven translocation (TET) family DNA dioxygenases TET1 and TET2 play important roles in the central nervous system. Here, I present evidence that Tet1 and Tet2 are expressed in cultured NSCs derived from adult mouse brain and play an important role in the proliferative self-renewal of NSCs in an undifferentiated state. The investigation of intracellular molecular networks involving both Tet1 and Tet2 by gene knockdown and comprehensive genetic analyses showed that overlapping molecular mechanisms involving TET1 and TET2 regulate the expression of at least 16 genes required for DNA replication and cell cycle control. Interestingly, transcriptional regulation of the selected gene through TET1 and TET2 did not correlate with direct CpG demethylation of the gene promoter. These findings suggest that TET1 and TET2 play an important role in the proliferation of NSCs in the adult mouse brain by specifically regulating common genes for DNA replication and the cell cycle. PMID- 27778128 TI - Robotic Versus Open Hepatectomy for Hepatocellular Carcinoma: A Matched Comparison. AB - BACKGROUND: Robotic hepatectomy has been suggested to be a safe and effective approach for liver disease; however, studies comparing robotic hepatectomy with the conventional open approach regarding oncologic outcomes for hepatocellular carcinoma (HCC) are limited. Accordingly, we performed a matched comparison of surgical and oncological outcomes between robotic and open hepatectomy. METHODS: Between January 2012 and October 2015, a total of 183 patients underwent robotic hepatectomy and 275 patients underwent open hepatectomy by the same surgical team in our center. Eighty-one newly diagnosed HCC cases in each group were compared under propensity score matching (PSM) in a 1:1 ratio. RESULTS: With robotic hepatectomy, the conversion rate was 1.6 % and the complication rate was 4.4 %. On PSM, the groups had a comparable percentage of major liver resections (41.9 vs. 39.5 %) and liver cirrhosis (45.7 vs. 46.9 %). Compared with the open group, the robotic group required longer operation times (343 vs. 220 min), shorter hospital stays (7.5 vs. 10.1 days), and lower dosages of postoperative patient controlled analgesia (350 vs. 554 ng/kg). The 3-year disease-free survival of the robotic group was comparable with that of the open group (72.2 % vs. 58.0 %; p = 0.062), as was the 3-year overall survival (92.6 vs. 93.7 %; p = 0.431). CONCLUSIONS: This is the first oncological study comparing robotic liver resection for HCC with open resection. Robotic hepatectomy can be applied for challenging major resections in patients with cirrhotic liver disease with less postoperative pain and shorter hospital stays without compromising oncological outcomes. PMID- 27778129 TI - Robotic Hepatectomy: A New Paradigm in the Management of Hepatocellular Carcinoma? PMID- 27778133 TI - The Chronophilia Conundrum: Continuum or Epiphenomenon? PMID- 27778132 TI - Insights on the involvement of (-)-epigallocatechin gallate in ER stress-mediated apoptosis in age-related macular degeneration. AB - Endoplasmic reticulum (ER) stress-mediated apoptosis is a well-known factor in the pathogenesis of age-related macular degeneration (AMD). ER stress leads to accumulation of misfolded proteins, which in turn activates unfolded protein response (UPR) of the cell for its survival. The prolonged UPR of ER stress promotes cell death; however, the transition between adaptation and ER stress induced apoptosis has not been clearly understood. Hence, the present study investigates the regulatory effect of (-)-epigallocatechin gallate (EGCG) on ER stress-induced by hydrogen peroxide (H2O2) and disturbance of calcium homeostasis by thapsigargin (TG) in mouse retinal pigment epithelial (MRPE) cells. The oxidant molecules influenced MRPE cells showed an increased level of intracellular calcium [Ca2+]i in ER and transferred to mitochondria through ER mitochondrial tether site then increased ROS production. EGCG restores [Ca2+]i homeostasis by decreasing ROS production through inhibition of prohibitin1 which regulate ER-mitochondrial tether site and inhibit apoptosis. Effect of EGCG on ER stress-mediated apoptosis was elucidated by exploring the UPR signalling pathways. EGCG downregulated GRP78, CHOP, PERK, ERO1alpha, IRE1alpha, cleaved PARP, cleaved caspase 3, caspase 12 and upregulated expression of calnexinin MRPE cells. In addition to this, inhibition of apoptosis by EGCG was also confirmed with expression of proteins Akt, PTEN and GSK3beta. MRPE cells with EGCG upregulates phosphorylation of Akt at ser473 and phospho ser380 of PTEN, but phosphorylation at ser9 of GSK3beta was inhibited. Further, constitutively active (myristoylated) CA-Akt transfected in MRPE cells had an increased Akt activity in EGCG influenced cells. These findings strongly suggest that antioxidant molecules inhibit cell death through the proper balancing of [Ca2+]i and ROS production in order to maintain UPR of ER in MRPE cells. Thus, modulation of UPR signalling may provide a potential target for the therapeutic approaches of AMD. PMID- 27778131 TI - The role of heparins and nano-heparins as therapeutic tool in breast cancer. AB - Glycosaminoglycans are integral part of the dynamic extracellular matrix (ECM) network that control crucial biochemical and biomechanical signals required for tissue morphogenesis, differentiation, homeostasis and cancer development. Breast cancer cells communicate with stromal ones to modulate ECM mainly through release of soluble effectors during cancer progression. The intracellular cross-talk between cell surface receptors and estrogen receptors is important for the regulation of breast cancer cell properties and production of ECM molecules. In turn, reorganized ECM-cell surface interface modulates signaling cascades, which regulate almost all aspects of breast cell behavior. Heparan sulfate chains present on cell surface and matrix proteoglycans are involved in regulation of breast cancer functions since they are capable of binding numerous matrix molecules, growth factors and inflammatory mediators thus modulating their signaling. In addition to its anticoagulant activity, there is accumulating evidence highlighting various anticancer activities of heparin and nano-heparin derivatives in numerous types of cancer. Importantly, heparin derivatives significantly reduce breast cancer cell proliferation and metastasis in vitro and in vivo models as well as regulates the expression profile of major ECM macromolecules, providing strong evidence for therapeutic targeting. Nano formulations of the glycosaminoglycan heparin are possibly novel tools for targeting tumor microenvironment. In this review, the role of heparan sulfate/heparin and its nano-formulations in breast cancer biology are presented and discussed in terms of future pharmacological targeting. PMID- 27778134 TI - Determination of ligand binding modes in weak protein-ligand complexes using sparse NMR data. AB - We describe a general approach to determine the binding pose of small molecules in weakly bound protein-ligand complexes by deriving distance constraints between the ligand and methyl groups from all methyl-containing residues of the protein. We demonstrate that using a single sample, which can be prepared without the use of expensive precursors, it is possible to generate high-resolution data rapidly and obtain the resonance assignments of Ile, Leu, Val, Ala and Thr methyl groups using triple resonance scalar correlation data. The same sample may be used to obtain Met epsilonCH3 assignments using NOESY-based methods, although the superior sensitivity of NOESY using [U-13C,15N]-labeled protein makes the use of this second sample more efficient. We describe a structural model for a weakly binding ligand bound to its target protein, DsbA, derived from intermolecular methyl-to-ligand nuclear Overhauser enhancements, and demonstrate that the ability to assign all methyl resonances in the spectrum is essential to derive an accurate model of the structure. Once the methyl assignments have been obtained, this approach provides a rapid means to generate structural models for weakly bound protein-ligand complexes. Such weak complexes are often found at the beginning of programs of fragment based drug design and can be challenging to characterize using X-ray crystallography. PMID- 27778135 TI - Effect of adhesive system application for cavities prepared with erbium, chromium: yttrium scandium gallium garnet laser on rat dental pulp tissue. AB - We examined the effects of adhesive systems under study applied for a laser-cut cavity using an Er,Cr:YSGG laser on rat dental pulp at 24 h and 14 days postoperatively. Group 1, laser-cut cavities were treated with a self-etching primer and bonding agent; group 2, pretreated with a phosphoric-acid, and then treated with a self-etching-primer and bonding agent; group 3, pretreated with a phosphoric-acid and sodium-hypochlorite, and then treated with a self-etching primer and bonding agent; and group 4, treated with an all-in-one adhesive. A flowable resin composite was used as filling material for each cavity treated with each group. A glass-ionomer-cement was used as a control. The following items were evaluated: pulp-tissue-disorganization (PTD), inflammatory-cell infiltration (ICI), tertiary-dentin-formation (TDF), and bacterial-penetration (BP). The results were statistically analyzed using the Kruskal-Wallis test and Mann-Whitney U test. No significant differences were observed among the experimental groups for all parameters after 24 h and 14 days (P > 0.05). The majority of the specimens showed PTD with edema formation after 24 h; however, all the specimens demonstrated pulpal healing with TDF after 14 days. On the parameter of TDF, all groups showed significant differences between the two postoperative periods (P < 0.01). On the parameter of ICI, a significant difference was found between the two postoperative periods in group 4 (P < 0.05). No specimens showed BP. The pretreatment on the cavity prepared with the laser using phosphoric-acid or sodium-hypochlorite did not affect the dental pulp healing of rat tooth. PMID- 27778136 TI - Dietary flavones counteract phorbol 12-myristate 13-acetate-induced SREBP-2 processing in hepatic cells. AB - Consumption of fruits and vegetables is generally regarded as beneficial to plasma lipid profile. The mechanism by which the plant foods induce desirable lipid changes remains unclear. SREBP-2 is crucial in cholesterol metabolism, and it is a major regulator of the cholesterol biosynthesis enzyme HMGCR. Our lab has previously illustrated that apigenin and luteolin could attenuate the nuclear translocation of SREBP-2 through an AMPK-dependent pathway. In the present study, these two flavones were studied for their ability to deter the same in an AMPK independent signaling route. The processing of SREBP-2 protein was promoted by phorbol 12-myristate 13-acetate (PMA) in the hepatic cells WRL and HepG2, and the increased processing was reversed by apigenin or luteolin co-administration. EMSA results demonstrated that the PMA-induced DNA-binding activity was weakened by the flavones. The increased amount of nuclear SREBP-2 in cells was attenuated by the flavonoid as shown by immunocytochemical imaging. Quantitative reverse transcriptase-polymerase chain reaction assay demonstrated that the transcription of HMGCR under both flavone treatments was reduced. However, apigenin appeared to be stronger than luteolin in restraining PMA-induced HMGCR mRNA expression. Since PMA is a diacylglycerol analog, these findings might have some physiological implications. PMID- 27778138 TI - Relationships Between Integration and Drug Use Among Deported Migrants in Tijuana, Mexico. AB - Deported migrants face numerous challenges which may elevate their risk for drug use. We examined relationships between integration and drug use among deported migrants in Tijuana, Mexico. A cross-sectional survey conducted at a free health clinic included 255 deported Mexican-born migrants residing in Tijuana >=6 months. Multivariable logistic regression examined associations between variables across four integration domains (public participation, social connections, macro level facilitators and foundations) and recent (past 6-month) drug use. The prevalence of recent drug use was 46 %. Having sought work in Tijuana in the past 6 months, greater household affluence, lifetime history of incarceration in both US and Mexico, and lacking health insurance were independently associated with recent drug use. Policies that support access to employment, adequate housing and healthcare in Mexico, particularly for justice-involved deportees, may facilitate successful integration and reduce potential stressors that may contribute to drug use. PMID- 27778139 TI - Variation in Human Papillomavirus Vaccine Uptake and Acceptability Between Female and Male Adolescents and Their Caregivers. AB - HPV vaccination coverage is suboptimal. Previous research largely focused on vaccinating girls. This study aimed to identify factors associated with HPV vaccination among male and female adolescents. We conducted secondary analyses using the National Immunization Survey-Teen. We specified parallel logistic models to examine associations of adolescent, caregiver, and provider characteristics with vaccination status among boys and girls. The primary outcome was HPV vaccination status defined as unvaccinated, initiated, or completed. Additionally, we analyzed caregivers' intent to initiate or complete the three dose series. The vaccination completion rate was 26 %. Among teens aged 13-17 years, 19 % initiated, but did not complete the vaccine. Additionally, 14 % of males completed the 3-dose series as compared to 38 % of females. Vaccination rates were higher among teens receiving a provider recommendation [girls: adjusted odds ratio (AOR) = 3.33, 95 % confidence interval (CI) (2.44, 4.55); boys: AOR = 10.0, 95 % CI (7.69, 12.5)]. Moreover, provider recommendation was associated with caregivers' intent to initiate vaccination [girls: AOR = 2.32, 95 % CI (1.77, 3.02); boys: AOR = 2.76, 95 % CI (2.22, 3.43)]. Other associations differed by gender. Higher vaccine initiation rates were associated with younger age and residing in the mid-west for girls and racial/ethnic minority and eligibility for the "Vaccine for Children" program for boys. Provider recommendation for vaccination was the strongest predictor for both genders; however, it is insufficient to achieve high coverage rates, especially among boys. Factors associated with HPV vaccination were different for males and females. These findings suggest providers should consider gender bias with regard to HPV vaccination. PMID- 27778140 TI - Nitrogen deprivation of microalgae: effect on cell size, cell wall thickness, cell strength, and resistance to mechanical disruption. AB - Nitrogen deprivation (N-deprivation) is a proven strategy for inducing triacylglyceride accumulation in microalgae. However, its effect on the physical properties of cells and subsequently on product recovery processes is relatively unknown. In this study, the effect of N-deprivation on the cell size, cell wall thickness, and mechanical strength of three microalgae was investigated. As determined by analysis of micrographs from transmission electron microscopy, the average cell size and cell wall thickness for N-deprived Nannochloropsis sp. and Chlorococcum sp. were ca. 25% greater than the N-replete cells, and 20 and 70% greater, respectively, for N-deprived Chlorella sp. The average Young's modulus of N-deprived Chlorococcum sp. cells was estimated using atomic force microscopy to be 775 kPa; 30% greater than the N-replete population. Although statistically significant, these microstructural changes did not appear to affect the overall susceptibility of cells to mechanical rupture by high pressure homogenisation. This is important as it suggests that subjecting these microalgae to nitrogen starvation to accumulate lipids does not adversely affect the recovery of intracellular lipids. PMID- 27778141 TI - Assessment of the construct validity and responsiveness of preference-based quality of life measures in people with Parkinson's: a systematic review. AB - PURPOSE: Generic preference-based quality of life (PbQoL) measures are sometimes criticized for being insensitive or failing to capture important aspects of quality of life (QoL) in specific populations. The objective of this study was to systematically review and assess the construct validity and responsiveness of PbQoL measures in Parkinson's. METHODS: Ten databases were systematically searched up to July 2015. Studies were included if a PbQoL instrument along with a common Parkinson's clinical or QoL measure was used, and the utility values were reported. The PbQoL instruments were assessed for construct validity (discriminant and convergent validity) and responsiveness. RESULTS: Twenty-three of 2758 studies were included, of which the majority evidence was for EQ-5D. Overall good evidence of discriminant validity was demonstrated in the Health Utility Index (HUI)-3, EQ-5D-5L, EQ-5D-3L, 15D, HUI-2, and Disability and Distress Index (DDI). Nevertheless, HUI-2 and EQ-5D-3L were shown to be less sensitive among patients with mild Parkinson's. Moderate to strong correlations were shown between the PbQoL measures (EQ-5D-3L, EQ-5D-5L, 15D, DDI, and HUI-II) and Parkinson's-specific measures. Twelve studies provided evidence for the assessment of responsiveness of EQ-5D-3L and one study for 15D, among which six studies reached inconsistent results between EQ-5D-3L and the Parkinson's specific measures in measuring the change overtime. CONCLUSIONS: The construct validity of the PbQoL measures was generally good, but there are concerns regarding their responsiveness to change. In Parkinson's, the inclusion of a Parkinson's-specific QoL measure or a generic but broader scoped mental and well being focused measure to incorporate aspects not included in the common PbQoL measures is recommended. PMID- 27778142 TI - Effect of stocking rate and supplementation on performance of dairy cows grazing native grassland in small-scale systems in the highlands of central Mexico. AB - The use and management of native grassland for dairy production during the rainy season was studied on two small-scale dairy farms in the highlands of central Mexico. Two stocking rates (2 and 4 cows/ha) and two levels of supplementation with commercial concentrate (4 and 6 kg/cow/day) under grazing were given to 12 milking Holstein cows in a 4 * 4 Latin square design replicated three times in a factorial arrangement. Net herbage accumulation (NHA), sward height, chemical composition, and in vitro digestibility of organic matter were recorded for the grassland, as well as vegetation cover and herbage mass 12 weeks post experiment. Animal performance variables were milk yield and composition, live weight, and body condition score. A partial budget analysis of feeding costs, returns, and margins was calculated. There were no differences between periods for NHA and herbage height and between plots for chemical composition (P > 0.05). However, there were highly significant differences among periods (P < 0.01) for organic matter, neutral detergent fibre (NDF), acid detergent fibre, in vitro organic matter digestibility (IVOMD), and estimated metabolisable energy (eME), with highly significant plot * period interactions (P < 0.01) for NDF, IVOMD, and eME. There were no statistical differences (P > 0.05) between treatments for milk yield, chemical composition of milk, live weight, or body condition score. Post experimental vegetation cover was 72 % for both stocking rates, indicating there was no degradation of the grassland. Lower feeding costs were for the low supplementation treatments. It is concluded that a high stocking rate in studied native grasslands of 4 cows/ha with moderate concentrate supplementation supports a mean milk yield of 11.9 kg/cow/day during the rainy season without deleterious effects on the grassland. PMID- 27778145 TI - Splenic rupture and mediastinal mass associated with rare TdT-negative T-LBL/T ALL lead to sudden death of a juvenile. PMID- 27778144 TI - Encapsulation of eptifibatide in RGD-modified nanoliposomes improves platelet aggregation inhibitory activity. AB - Eptifibatide is an antiplatelet drug used for the treatment of thrombosis. However, as a result of its accumulation in non-targeted tissues and short half life, it has a limited efficacy. In this study, RGD-modified nano-liposomes (RGD MNL) were prepared as carriers for the targeted delivery of eptifibatide to activated platelets. The nano-liposomes were about 90 +/- 10 nm in size, with an encapsulation efficiency of 37 +/- 5 % and a good stability during 21 days, with a negligible change in the size of nanoliosomes. The in vitro cytotoxicity of nanoliposomes was examined using MTT assay. The results obtained from the ex vivo study showed that the antiplatelet activity of eptifibatide encapsulated nanoliposomes was higher in comparison with the free drug (81.63 vs. 46.17 % for RGD-MNL) and (66.67 vs. 46.17 % for UNL), and this increase was more significant for nanoliposomes targeted with RGD peptide (81.63 %; p < 0.05). The results indicated that RGD-MNL encapsulated eptifibatide had no significant cytotoxic effect on cells. In conclusion, the present nanoliposome formulation can be regarded as a new delivery system for protection and enhancement of the antiplatelet activity of eptifibatide. PMID- 27778143 TI - Extranodal NK/T Cell Lymphoma, Nasal Type (ENKTL-NT): An Update on Epidemiology, Clinical Presentation, and Natural History in North American and European Cases. AB - PURPOSE OF REVIEW: Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is an aggressive extranodal non-Hodgkin lymphoma most commonly occurring in East Asia and Latin America but with increasing incidence in the United States. Data on epidemiology, disease presentation, and outcome for European and North American ("Western") cases are very limited. We review published landmark clinical studies on ENKTL-NT in the West and report in detail recent data, including our institutional experience. RECENT FINDINGS: We highlight key observations in its epidemiology, natural history, and trends in clinical management. In the USA, ENKTL-NT is more common among Asian Pacific Islanders (API) and Hispanics compared to non-Hispanic whites. Published studies indicate less heterogeneity in clinical presentation in Western ENKTL-NT compared to Asian patients. While there is variation in age at diagnosis, presence of antecedent lymphoproliferative disorders, and outcomes among racial/ethnic groups, the universal association of ENKTL-NT with EBV and the poor response of this neoplasm to anthracycline-based therapy is consistent across all geographic areas. Data on epidemiology, disease presentation, and clinical outcomes in mature T cell and NK cell (T/NK cell) neoplasms, including ENKTL-NT, in Europe and North America are very limited. As the classification and diagnostic characterization of the currently recognized T/NK cell lymphoma disease entities continue to evolve, gaps and inconsistencies in data reporting across different studies are being recognized. Despite these limitations, several studies from the USA suggest that the incidence of ENKTL-NT is higher in Asian Pacific Islanders (API) and non-white Hispanics and that outcomes may be worse in non-whites. However, the universal association of ENKTL NT with Epstein-Barr virus (EBV) across all ethnic groups suggests a common pathogenesis. Given the overlap between the entities included in the category of T/NK cell neoplasms, there is a need to further define biological and clinical differences that may affect diagnosis, treatment, and outcome. PMID- 27778146 TI - Fluid content in the pleural cavity protects internal structures against heat. AB - PURPOSE: In this paper we present a case report of two people who were found dead in a holiday cottage after a fire. The cause of death in these cases was clarified by the presence of blood in the left pleural cavity in both bodies. METHODS: An inspection of the bodies at the scene of the fire and subsequent examination by a medical examiner suggested the deaths were accidental. RESULTS: An autopsy showed that the bodies were those of a man and a woman with severe carbonization of the skin, soft tissues, brain, and some organs of the thoracic and abdominal cavities. There were also isolated stab injuries to the chest, as well as injuries to skeletal structures and intrathoracic organs. The accumulated blood in the pleural cavity had protected the internal organs against thermal destruction and preserved the traumatic findings. CONCLUSION: To the best of our knowledge this is the first description of the protective effect of hemothorax against thermal damage of the intrathoracic organs. PMID- 27778147 TI - Effects of Acute Carbon Monoxide Poisoning on ECG and Echocardiographic Parameters in Children. AB - The aim of the current study is to investigate the effects of CO (carbon monoxide) on the cardiovascular system via electrocardiographic, echocardiographic and biochemical findings in children. This prospective study included 22 children with CO poisoning and 24 healthy children as a control group. The CO-intoxicated children were evaluated via electrocardiography and echocardiography 1 h after admission to the emergency department and daily until their discharge from the hospital. Blood gasses, complete blood account, troponin I and creatinine kinase-MB(CK-MB) were assessed daily. Tpeak-end (p:0.001), QTc durations (p:0.02), Tpeak-end dispersion (p:0.001) and Tpeak-end/QT ratio (p:0.001) of CO-intoxicated patients were significantly higher than those in the control group. Mitral E duration (p:0.001), mitral E/A ratio (p:0.001) and left ventricle contractile fraction (p:0.023) at admission were significantly lower, and left ventricle myocardial performance index was higher (p:0.001) in the CO poisoning group. Troponin I and CK-MB levels were higher at admission in 6 (27 %) and 4 (18 %) patients, respectively. The heart is the most critical organ in pediatric CO poisoning. These children present subclinical systolic and diastolic left ventricle dysfunction even in mild cases. Although, in children with acute CO-intoxication ventricular repolarization is impaired, it seems to be reversible like other findings. PMID- 27778148 TI - Suicide and filicide in postpartum psychosis. AB - This paper reviews the frequency of suicide and filicide in a literature of over 4000, and personal series of 321, childbearing psychoses. Suicide is rare during the acute episode, but the rate is high later in the mother's life and in first degree relatives. The filicide rate is high in depressive psychoses (4.5 %), but lower in episodes without overt depression (less than 1 %), and some of these appear to be accidental, without intent to kill. PMID- 27778149 TI - The Stafford Interview : A comprehensive interview for mother-infant psychiatry. AB - This article describes an interview exploring the social, psychological and psychiatric events in a single pregnancy and puerperium. It has been in development since 1992 and is now in its 6th edition. It takes approximately 2 h to administer and has 130 compulsory probes and 185 ratings. It is suitable for clinical practice, teaching and research. PMID- 27778150 TI - Perceived stress, depressive symptoms, and suicidal ideation in undergraduate women with varying levels of mindfulness. AB - Research has demonstrated that perceived stress and depression are risk factors for suicidal ideation in young adults, particularly women attending college. Female undergraduate students (N = 928) were administered measures assessing their levels of stress, depressive symptoms, suicidal thoughts, and mindfulness. A moderated-mediation analysis was conducted to examine the complex associations among these variables. Results indicated that mindfulness moderated the mediated effect of depressive symptoms on perceived stress and suicidal ideation. Specifically, the indirect effect was stronger in college women with lower levels of mindfulness as compared to those students who reported higher mindfulness. Thus, teaching mindfulness techniques on college campuses may be an important strategy for preventing suicide, especially among young adult women experiencing stress and depressive symptoms. PMID- 27778151 TI - Data from Controlled Metabolic Ward Studies Provide Guidance for the Determination of Status Indicators and Dietary Requirements for Magnesium. AB - Determination of whether magnesium (Mg) is a nutrient of public health concern has been hindered by questionable Dietary Recommended Intakes (DRIs) and problematic status indicators that make Mg deficiency assessment formidable. Balance data obtained since 1997 indicate that the EAR and RDA for 70-kg healthy individuals are about 175 and 250 mg/day, respectively, and these DRIs decrease or increase based on body weight. These DRIs are less than those established for the USA and Canada. Urinary excretion data from tightly controlled metabolic unit balance studies indicate that urinary Mg excretion is 40 to 80 mg (1.65 to 3.29 mmol)/day when Mg intakes are <250 mg (10.28 mmol)/day, and 80 to 160 mg (3.29 to 6.58 mmol)/day when intakes are >250 mg (10.28 mmol)/day. However, changing from low to high urinary excretion with an increase in dietary intake occurs within a few days and vice versa. Thus, urinary Mg as a stand-alone status indicator would be most useful for population studies and not useful for individual status assessment. Tightly controlled metabolic unit depletion/repletion experiments indicate that serum Mg concentrations decrease only after a prolonged depletion if an individual has good Mg reserves. These experiments also found that, although individuals had serum Mg concentrations approaching 0.85 mmol/L (2.06 mg/dL), they had physiological changes that respond to Mg supplementation. Thus, metabolic unit findings suggest that individuals with serum Mg concentrations >0.75 mmol/L (1.82 mg/L), or as high as 0.85 mmol/L (2.06 mg/dL), could have a deficit in Mg such that they respond to Mg supplementation, especially if they have a dietary intake history showing <250 mg (10.28 mmol)/day and a urinary excretion of <80 mg (3.29 mmol)/day. PMID- 27778152 TI - Date Fruits-Assisted Synthesis and Biocompatibility Assessment of Nickel Oxide Nanoparticles Anchored onto Graphene Sheets for Biomedical Applications. AB - Nanographene- and graphene-based nanohybrids have garnered attention in the biomedical community owing to their biocompatibility, excellent aqueous processability, ease of cellular uptake, facile surface functionalization, and thermal and electrical conductivities. NiO nanoparticle-graphene nanohybrid (G NiO) was synthesized by first depositing Ni(OH)2 onto the surface of graphene oxide (GO) sheets. The Ni(OH)2-GO hybrids were then reduced to G-NiO using date palm syrup at 85 degrees C. The prepared G-NiO nanohybrids were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy (EDX). The NiO nanoparticles, with a diameter of approximately 20-30 nm, were uniformly dispersed over the surface of the graphene sheets. The G-NiO hybrids exhibit biocompatibility in human mesenchymal stem cells (hMSCs) up to 100 MUg/mL. The nanohybrids do not cause any significant changes in cellular and nuclear morphologies in hMSCs. The as-synthesized nanohybrids show excellent biocompatibility and could be a promising material for biomedical applications. PMID- 27778154 TI - ST2-Based Precision Medicine in Device Management: the Next Frontier Beyond MADIT CRT? PMID- 27778153 TI - Phenotypic characterization of a novel HO-1 depletion model in the rat. AB - Although the protective role of HO-1 induction in various forms of kidney disease is well established, mechanisms other than heme catabolism to biliverdin, bilirubin and carbon monoxide have recently been identified. Unraveling these mechanisms requires the generation of appropriate animal models. The present study describes the generation of a HO-1 deficient Hmox1 -/- rat model and characterizes its renal and extrarenal phenotype. Hmox1 -/- rats had growth retardation and splenomegaly compared to their Hmox1 +/+ littermates. Focal segmental glomerulosclerosis-type lesions and interstitial inflammatory infiltrates were prominent morphologic findings and were associated with increased blood urea nitrogen, serum creatinine and albuminuria. There was no increase in iron deposition in glomeruli, tubules or interstitium. Iron deposition in spleen and liver was reduced. Electron microscopic examination of glomeruli revealed edematous podocytes with scant areas of foot process effacement but otherwise well preserved processes and slit-diaphragms. Of the filtration barrier proteins examined, beta-catenin expression was markedly reduced both in glomeruli and extrarenal tissues. Since the rat is the preferred laboratory animal in experimental physiology and pathophysiology, the rat model of HO-1 deficiency may provide a novel tool for investigation of the role of this enzyme in renal function and disease. PMID- 27778155 TI - Current management of aneurysmal bone cysts. AB - Aneurysmal bone cysts (ABCs) are benign bone lesions arising predominantly in the pediatric population that can cause local pain, swelling, and pathologic fracture. Primary lesions, which constitute roughly two thirds of all ABCs, are thought to be neoplastic in nature, with one third of ABCs arising secondary to other tumors. Diagnosis is made with various imaging modalities, which exhibit characteristic features such as "fluid-fluid levels," although biopsy is critical, as telangiectatic osteosarcoma cannot be excluded based on imaging alone. Currently, the standard of care and most widely employed treatment is intralesional curettage. However, tumor recurrence with curettage alone is common and has driven some to propose a multitude of adjuvants with varying efficacy and risk profiles. Historically, therapies such as en bloc resection or radiation therapy were utilized as an alternative to decrease the recurrence rate, but these therapies imposed high morbidity. As a result, modern techniques now seek to simultaneously reduce morbidity and recurrence, the pursuit of which has produced preliminary study into minimally invasive percutaneous treatments and medical management. PMID- 27778156 TI - Factors predicting survival in ALS: a multicenter Italian study. AB - The aim of this multicenter, retrospective study is to investigate the role of clinical characteristics and therapeutic intervention on ALS prognosis. The study included patients diagnosed from January 1, 2009 to December 31, 2013 in 13 Italian referral centers for ALS located in 10 Italian regions. Caring neurologists collected a detailed phenotypic profile and follow-up data until death into an electronic database. One center collected also data from a population-based registry for ALS. 2648 incident cases were collected. The median survival time from onset to death/tracheostomy was 44 months (SE 1.18, CI 42-46). According to univariate analysis, factors related to survival from onset to death/tracheostomy were: age at onset, diagnostic delay, site of onset, phenotype, degree of certainty at diagnosis according to revised El Escorial criteria (R-EEC), presence/absence of dementia, BMI at diagnosis, patients' provenance. In the multivariate analysis, age at onset, diagnostic delay, phenotypes but not site of onset, presence/absence of dementia, BMI, riluzole use, R-EEC criteria were independent prognostic factors of survival in ALS. We compared patients from an ALS Registry with patients from tertiary centers; the latter ones were younger, less frequently bulbar, but more frequently familial and definite at diagnosis. Our large, multicenter study demonstrated the role of some clinical and demographic factors on ALS survival, and showed some interesting differences between referral centers' patients and the general ALS population. These results can be helpful for clinical practice, in clinical trial design and to validate new tools to predict disease progression. PMID- 27778157 TI - Magnetic resonance imaging of the proximal upper extremity musculature in boys with Duchenne muscular dystrophy. AB - There is a pressing need for biomarkers and outcomes that can be used across disease stages in Duchenne muscular dystrophy (DMD), to facilitate the inclusion of a wider range of participants in clinical trials and to improve our understanding of the natural history of DMD. Quantitative magnetic resonance imaging (qMRI) and spectroscopy (MRS) biomarkers show considerable promise in both the legs and forearms of individuals with DMD, but have not yet been examined in functionally important proximal upper extremity muscles such as the biceps brachii and deltoid. The primary objective of this study was to examine the feasibility of implementing qMRI and MRS biomarkers in the proximal upper extremity musculature, and the secondary objective was to examine the relationship between MR measures of arm muscle pathology and upper extremity functional endpoints. Biomarkers included MRS and MRI measures of fat fraction and transverse relaxation time (T 2). The MR exam was well tolerated in both ambulatory and non-ambulatory boys. qMR biomarkers differentiated affected and unaffected participants and correlated strongly with upper extremity function (r = 0.91 for biceps brachii T 2 versus performance of upper limb score). These qMR outcome measures could be highly beneficial to the neuromuscular disease community, allowing measurement of the quality of functionally important muscles across disease stages to understand the natural history of DMD and particularly to broaden the opportunity for clinical trial participation. PMID- 27778159 TI - The role of sleep on cognition and functional connectivity in patients with multiple sclerosis. AB - Sleep disturbances are common in multiple sclerosis (MS), but its impact on cognition and functional connectivity (FC) of the hippocampus and thalamus is unknown. Therefore, we investigated the relationship between sleep disturbances, cognitive functioning and resting-state (RS) FC of the hippocampus and thalamus in MS. 71 MS patients and 40 healthy controls underwent neuropsychological testing and filled out self-report questionnaires (anxiety, depression, fatigue, and subjective cognitive problems). Sleep disturbances were assed with the five item version of the Athens Insomnia Scale. Hippocampal and thalamic volume and RS FC of these regions were determined. Twenty-three patients were categorized as sleep disturbed and 48 as normal sleeping. No differences were found between disturbed and normal sleeping patients concerning cognition and structural MRI. Sleep disturbed patients reported more subjective cognitive problems, and displayed decreased FC between the thalamus and middle and superior frontal gyrus, inferior frontal operculum, anterior cingulate cortex, inferior parietal gyrus, precuneus, and angular gyrus compared to normal sleeping patients. We conclude that sleep disturbances in MS are not (directly) related to objective cognitive functioning, but rather to subjective cognitive problems. In addition, sleep disturbances in MS seem to coincide with a specific pattern of decreased thalamic FC. PMID- 27778158 TI - Neurorehabilitation: applied neuroplasticity. AB - The prevalence of disability due to neurological conditions is escalating worldwide. Neurological disorders have significant disability-burden with long term functional and psychosocial issues, requiring specialized rehabilitation services for comprehensive management, especially treatments tapping into brain recovery 'neuroplastic' processes. Neurorehabilitation is interdisciplinary and cross-sectorial, requiring coordinated effort of diverse sectors, professions, patients and community to manage complex condition-related disability. This review provides evidence for a range of neurorehabilitation interventions for four common neurological conditions: multiple sclerosis (MS), stroke, traumatic brain injury and Parkinson's disease using the Grade of Recommendation, Assessment, Development and Evaluation tool for quality of evidence. Although, existing best-evidence for many interventions is still sparse, the overall findings suggest 'strong' evidence for physical therapy and psychological intervention for improved patient outcomes; and. 'moderate' evidence for multidisciplinary rehabilitation for longer term gains at the levels of activity (disability) and participation in MS and stroke population. The effect of other rehabilitation interventions is inconclusive, due to a paucity of methodologically robust studies. More research is needed to improve evidence-base for many promising rehabilitation interventions. PMID- 27778160 TI - New evidence for involvement of ESR1 gene in susceptibility to Chinese migraine. AB - Migraine is a common and disabling nervous system disease with a significant genetic predisposition. The sex hormones play an important role in the pathogenesis of migraine. However, the conclusions of the previous genetic relation studies are conflicting. The aim of this study is to determine whether variants in genes involved in estrogen receptor and estrogen hormone metabolism are related to Chinese migraine. By employing a case-control approach, 8 SNPs in the ESR1, ESR2, and CYP19A1 genes are studied in a cohort of 494 migraine cases and 533 controls. In addition, genotyping is performed using Sequenom MALDI-TOF mass spectrometry iPLEX platform. Univariate and multivariate analyses are carried out by logistic regression. The corresponding haplotypes are studied with the Haploview software and gene-gene interaction is assessed using the Generalized Multifactor Dimensionality Reduction (GMDR) analysis. There are significant differences in allelic distributions for rs2234693 and rs9340799 in ESR1 gene between patients with migraine and control subjects. Univariate logistic analysis shows that rs2234693 and rs9340799 are risk factors for migraine, but multivariate analysis reveals that only rs2234693 is significant associated with migraine. In the subgroup analysis, rs2234693 in ESR1 gene is found associated with menstrually related migraine. Further haplotypic analysis shows that rs2234693-rs9340799 TA haplotype serves as risk haplotype for migraine. The GMDR analysis identifies rs2234693 in ESR1 alone to be a crucial candidate in migraine susceptibility. This study is in agreement with the previous studies that variants in the ESR1 gene are associated with migraine suggesting that it plays a role in the migraine process. PMID- 27778162 TI - Low testosterone and myasthenia gravis in males: a national record-linkage study. PMID- 27778161 TI - Brain plasticity in Parkinson's disease with freezing of gait induced by action observation training. AB - Gait disorders represent a therapeutic challenge in Parkinson's disease (PD). This study investigated the efficacy of 4-week action observation training (AOT) on disease severity, freezing of gait and motor abilities in PD, and evaluated treatment-related brain functional changes. 25 PD patients with freezing of gait were randomized into two groups: AOT (action observation combined with practicing the observed actions) and "Landscape" (same physical training combined with landscape-videos observation). At baseline and 4-week, patients underwent clinical evaluation and fMRI. Clinical assessment was repeated at 8-week. At 4 week, both groups showed reduced freezing of gait severity, improved walking speed and quality of life. Moreover, AOT was associated with reduced motor disability and improved balance. AOT group showed a sustained positive effect on motor disability, walking speed, balance and quality of life at 8-week, with a trend toward a persisting reduced freezing of gait severity. At 4-week vs. baseline, AOT group showed increased recruitment of fronto-parietal areas during fMRI tasks, while the Landscape group showed a reduced fMRI activity of the left postcentral and inferior parietal gyri and right rolandic operculum and supramarginal gyrus. In AOT group, functional brain changes were associated with clinical improvements at 4-week and predicted clinical evolution at 8-week. AOT has a more lasting effect in improving motor function, gait and quality of life in PD patients relative to physical therapy alone. AOT-related performance gains are associated with an increased recruitment of motor regions and fronto-parietal mirror neuron and attentional control areas. PMID- 27778164 TI - Effect of a Pre-Treatment Educational Video in Improving Patient Satisfaction with 5-Fluorouracil Treatment for Actinic Keratoses: A Randomized Controlled Trial. AB - INTRODUCTION: Patient treatment satisfaction and adherence may be affected by the initial understanding of outcomes in the treatment of actinic keratoses with 5 fluorouracil 5% cream (5-FU). Pre-treatment educational videos may optimize this understanding. The objective of this study was to determine whether prospective patient viewing of an educational video delineating treatment effects and expectations improves patient satisfaction and treatment completion rates for the treatment of actinic keratoses with 5-FU. METHODS: Forty-four participants were recruited to the UC Davis Dermatology outpatient clinic. Each participant was randomized to the video (group A) or control group (group B), and topical 5-FU cream treatment was conducted for 2 weeks in both groups. RESULTS: A follow-up questionnaire was performed to assess patient satisfaction and adherence to the treatment regimen. The results of these questions were analyzed using the Mann Whitney test. One item on the questionnaire asked the patient to rate their overall level of satisfaction on a score of 0-100. The results of this question were analyzed using the unpaired t test. The results of the statistical analysis show no significant difference between the patient group that viewed the video and the patient group that did not view the video. CONCLUSIONS: We speculate that this study may establish a foundation for subsequent studies that may affect the broader medical community and promote development of educational videos. PMID- 27778163 TI - Alzheimer's disease in people with Down's syndrome: the prospects for and the challenges of developing preventative treatments. AB - People with Down's syndrome (DS) are at high risk for developing Alzheimer's disease (AD) at a relatively young age. This increased risk is not observed in people with intellectual disabilities for reasons other than DS and for this reason it is unlikely to be due to non-specific effects of having a neurodevelopmental disorder but, instead, a direct consequence of the genetics of DS (trisomy 21). Given the location of the amyloid precursor protein (APP) gene on chromosome 21, the amyloid cascade hypothesis is the dominant theory accounting for this risk, with other genetic and environmental factors modifying the age of onset and the course of the disease. Several potential therapies targeting the amyloid pathway and aiming to modify the course of AD are currently being investigated, which may also be useful for treating AD in DS. However, given that the neuropathology associated with AD starts many years before dementia manifests, any preventative treatment must start well before the onset of symptoms. To enable trials of such interventions, plasma, CSF, brain, and retinal biomarkers are being studied as proxy early diagnostic and outcome measures for AD. In this systematic review, we consider the prospects for the development of potential preventative treatments of AD in the DS population and their evaluation. PMID- 27778165 TI - A review of the immunomodulatory role of dietary tryptophan in livestock and poultry. AB - Tryptophan, a nutritionally essential amino acid, is active in the regulation of immune responses in animals. The products of tryptophan metabolism, such as indoleamine 2,3-dioxygenase, kynurenine, quinolinic acid, and melatonin, may improve immunity in an organism and induce anti-inflammatory responses. The immune tolerance processes mediated by tryptophan metabolites are not well understood. Recent studies have reported that the enzymes that break down tryptophan through the kynurenine metabolic pathway are found in numerous cell types, including immunocytes. Moreover, some tryptophan metabolites have been shown to play a role in the inhibition of T lymphocyte proliferation, elevation of immunoglobulin levels in the blood, and promotion of antigen-presenting organization in tissues. This review summarizes the effects and mechanisms of tryptophan and metabolites in immune functions in livestock and poultry. It also highlights the areas in which our understanding of the role(s) of tryptophan is incomplete and suggests possible future research that might prove of benefit to livestock and poultry producers. PMID- 27778166 TI - Isoleucine/leucine residues at "a" and "d" positions of a heptad repeat sequence are crucial for the cytolytic activity of a short anticancer lytic peptide. AB - Many lytic peptides contain a heptad sequence with leucine or isoleucine residues at "a" and "d" positions. However, their roles in the peptide-induced cytolytic process remain unclear. We have recently reported an anticancer lytic peptide ZXR 2 (FKIGGFIKKLWRSLLA), which contains a shortened zipper-like sequence with Ile/Leu at "a" and "d" positions. To understand the roles of these Ile/Leu residues, a series of analogs were constructed by sequentially replacing the Ile or Leu residue with alanine (Ala). Significant reduction of the cytolytic activity was observed when the Ile (3rd and 7th) and Leu (10th and 14th) residues at the "a" and "d" positions were substituted, while the replacement of the separate Leu (15th) residue had less effect. Based on the quenching of the intrinsic fluorescence of the peptides and their induced surface pressure changes of lipid monolayer, it was conjectured that the peptide ZXR-2 might insert into cell membranes from the C-terminal and to a depth of the W11 position. Accordingly, I3, I7, and L10 residues which mainly exposed in aqueous solution were more responsible for the peptide self-association on cell membranes, while L14, together with L15, might help peptide insert and anchor to cell membranes. These results are significant to elucidate the crucial roles of such Ile/Leu residues at "a" and "d" positions in peptide-peptide and peptide-membrane interactions to exert the membrane disruption activity of lytic peptides. With further understanding about the structure-activity relationship of lytic peptides, it would be helpful for designing novel anticancer lytic peptides. PMID- 27778167 TI - Structural classification of proteins using texture descriptors extracted from the cellular automata image. AB - Nowadays, having knowledge about cellular attributes of proteins has an important role in pharmacy, medical science and molecular biology. These attributes are closely correlated with the function and three-dimensional structure of proteins. Knowledge of protein structural class is used by various methods for better understanding the protein functionality and folding patterns. Computational methods and intelligence systems can have an important role in performing structural classification of proteins. Most of protein sequences are saved in databanks as characters and strings and a numerical representation is essential for applying machine learning methods. In this work, a binary representation of protein sequences is introduced based on reduced amino acids alphabets according to surrounding hydrophobicity index. Many important features which are hidden in these long binary sequences can be clearly displayed through their cellular automata images. The extracted features from these images are used to build a classification model by support vector machine. Comparing to previous studies on the several benchmark datasets, the promising classification rates obtained by tenfold cross-validation imply that the current approach can help in revealing some inherent features deeply hidden in protein sequences and improve the quality of predicting protein structural class. PMID- 27778168 TI - Visceral to subcutaneous fat ratio predicts acuity of diverticulitis. AB - INTRODUCTION: There is an association between obesity and more complicated diverticular disease. We hypothesize that this link may be due to an increased level of visceral fat rather than an elevated body mass index alone. Adipose tissue secretes inflammatory cytokines, and chronic inflammation may account for the link between obesity and a more severe presentation of diverticular disease. We have applied a quantitative measure of visceral fat content in a series of patients admitted with diverticulitis, comparing those who required emergent versus elective surgical procedures for diverticulitis. METHODS: We performed a retrospective review of all adult patients who underwent emergent or elective surgery at our institution for diverticulitis from 2010 to 2014. Data were collected on demographics, comorbidities, operative findings, complications, and length of stay. Radiologic measurements of adiposity were obtained from preoperative CT scans. Visceral fat areas and subcutaneous fat areas were measured, and the V/S ratio was calculated. RESULTS: Thirty-four patients underwent emergent and 32 patients underwent elective surgery. The mean age was 66.3 years for the emergent and 57.11 for the elective group (p = 0.04178). The perinephric, visceral, subcutaneous fat, and V/S ratio for the emergent group were 1.71, 185.22, 338.22, and 0.56 and were 1.11, 127.18, 295.28, and 0.46 for the elective group. The difference between the V/S ratio for each group was significant (p = 0.0238). The emergent group had an average LOS of 16.11 days compared to 5.15 for the elective group (p = <0.00001). The complication rate was significantly higher (p = 0.024) in the emergent group (n = 12, 35.2 %) compared to the elective group (n = 4, 12.5 %). CONCLUSION: Our study demonstrates a clinically significant link between visceral fat and severity of presentation of diverticulitis. Patients with higher V/S fat ratios were more likely to require emergency surgery and have more complications and a longer LOS. PMID- 27778169 TI - Laparoscopic colorectal cancer resections in the obese: a systematic review. AB - BACKGROUND: Laparoscopic colorectal cancer operations in obese patients pose technical challenges that may negatively impact oncologic adequacy. A meta analysis was performed to assess the oncologic outcomes of laparoscopic colorectal cancer resections in obese compared to non-obese patients. Short- and long-term outcomes were assessed secondarily. METHODS: A systematic literature search was conducted from inception until October 01, 2014. Studies that compared outcomes of laparoscopic colorectal malignant neoplasms in obese and non-obese patients were selected for meta-analysis. Studies that defined obesity as body mass index (BMI) >= 30 kg/m2 were included. Oncologic, operative, and postoperative outcomes were evaluated. Pooled odds ratios (OR) and weighted mean differences (WMD) with 95 % confidence intervals (CI) were calculated using fixed effects models. For oncologic and survival outcomes, a subgroup analysis was conducted for rectal cancer and a secondary analysis was conducted for Asian studies that used a BMI cutoff of 25 kg/m2. RESULTS: Thirteen observational studies with a total of 4550 patients were included in the meta-analysis. Lymph node retrieval, distal, and circumferential margins, and 5-year disease-free and overall survival were similar in the obese and non-obese groups. Conversion rate (OR 2.11, 95 % CI 1.58-2.81), postoperative morbidity (OR 1.54, 95 % CI 1.21 1.97), wound infection (OR 2.43, 95 % CI 1.46-4.03), and anastomotic leak (OR 1.65, 95 % CI 1.01-2.71) were all significantly increased in the obese group. CONCLUSIONS: Laparoscopic colorectal cancer operations in obese patients pose an increased technical challenge as demonstrated by higher conversion rates and higher risk of postoperative complications compared to non-obese patients. Despite these challenges, oncologic adequacy of laparoscopic colorectal cancer resections is comparable in both groups. PMID- 27778170 TI - Fluorescent incisionless cholangiography as a teaching tool for identification of Calot's triangle. AB - BACKGROUND: Intraoperative incisionless fluorescent cholangiogram (IOIFC) has been demonstrated to be a useful tool to increase the visualization of Calot's triangle. This study evaluates the identification of extrahepatic biliary structures with IOIFC by medical students and surgery residents. METHODS: Two pictures were taken, one with xenon light and one with near-infrared (NIR) light, at the same stage during dissection of Calot's triangle in ten different cases of laparoscopic cholecystectomy (LC). All twenty pictures were organized in a random fashion to remove any imagery bias. Twenty students and twenty residents were asked to identify the biliary anatomy. RESULTS: Medical students were able to accurately identify the cystic duct on an average 33.8 % under the xenon light versus 86 % under NIR light (p = 0.0001), the common hepatic duct (CHD) on an average 19 % under the xenon light versus 88.5 % under NIR light (p = 0.0001), and the junction on an average 24 % under xenon light versus 80.5 % under NIR light (p = 0.0001). Surgery residents were able to accurately identify the cystic duct on an average 40 % under the xenon light versus 99 % under NIR light (p = 0.0001), the CHD on an average 35 % under the xenon light versus 96 % under NIR light (p = 0.0001), and the junction on an average 24 % under the xenon light versus 95.5 % under NIR light (p = 0.0001). CONCLUSIONS: IOIFC increases the visualization of Calot's triangle structures when compared to xenon light. IOIFC may be a useful teaching tool in residency programs to teach LC. PMID- 27778172 TI - Participation of Canadian anesthesiology departments in undergraduate medical education. AB - PURPOSE: Historically, anesthesiology departments have played a small role in teaching the pre-clerkship component of undergraduate medical education (UGME). The purpose of this study was to measure the current participation of Canadian anesthesiologists in UGME with a focus on pre-clerkship. METHODS: Three surveys were developed in collaboration with the Association of Canadian Departments of Anesthesia. After an initial series of validation procedures, the surveys were distributed to anesthesia department heads, UGME directors, and associate deans at the 17 Canadian medical schools. RESULTS: The median [interquartile range (IQR)] percentage of anesthesiologists with teaching roles in pre-clerkship was 10.0 [3.4-21]%. The median [IQR] hours taught per anesthesiologist during pre clerkship was 2.2 [0.4-6.1] hr.yr-1, representing an 817% increase over the last 15 years. Eleven of 17 departments contributed at a level less than expected based on their proportional faculty size, and 6 of 17 departments contributed less than 1% of pre-clerkship hours. Anesthesiology departments thought more strongly than associate deans that their contributions were limited by a lack of teaching opportunities (P = 0.01) and that their contributions were indispensable (P = 0.033). Only 12 of 17 schools had mandatory anesthesia clerkships, with a median [IQR] duration of 10 [10-11] days. CONCLUSION: The contribution of anesthesiology departments to pre-clerkship has increased over the past fifteen years but remains much less than expected based on proportional faculty size. While the increase is encouraging, the relatively poor engagement is concerning, representing not only a missed opportunity but also a possible threat to the academic standing of the profession. PMID- 27778173 TI - Real-time physiologic monitoring and physician feedback: Are we ready? PMID- 27778171 TI - Multi-port versus single-port cholecystectomy: results of a multi-centre, randomised controlled trial (MUSIC trial). AB - BACKGROUND: Single-port laparoscopic surgery as an alternative to conventional laparoscopic cholecystectomy for benign disease has not yet been accepted as a standard procedure. The aim of the multi-port versus single-port cholecystectomy trial was to compare morbidity rates after single-access (SPC) and standard laparoscopy (MPC). METHODS: This non-inferiority phase 3 trial was conducted at 20 hospital surgical departments in six countries. At each centre, patients were randomly assigned to undergo either SPC or MPC. The primary outcome was overall morbidity within 60 days after surgery. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov (NCT01104727). RESULTS: The study was conducted between April 2011 and May 2015. A total of 600 patients were randomly assigned to receive either SPC (n = 297) or MPC (n = 303) and were eligible for data analysis. Postsurgical complications within 60 days were recorded in 13 patients (4.7 %) in the SPC group and in 16 (6.1 %) in the MPC group (P = 0.468); however, single-access procedures took longer [70 min (range 25-265) vs. 55 min (range 22-185); P < 0.001]. There were no significant differences in hospital length of stay or pain VAS scores between the two groups. An incisional hernia developed within 1 year in six patients in the SPC group and in three in the MPC group (P = 0.331). Patients were more satisfied with aesthetic results after SPC, whereas surgeons rated the aesthetic results higher after MPC. No difference in quality of life scores, as measured by the gastrointestinal quality of life index at 60 days after surgery, was observed between the two groups. CONCLUSIONS: In selected patients undergoing cholecystectomy for benign gallbladder disease, SPC is non-inferior to MPC in terms of safety but it entails a longer operative time. Possible concerns about a higher risk of incisional hernia following SPC do not appear to be justified. Patient satisfaction with aesthetic results was greater after SPC than after MPC. PMID- 27778174 TI - Pre-clerkship teaching: Are we missing an opportunity? PMID- 27778175 TI - An easily assembled phantom for teaching ultrasound-guided vascular access. PMID- 27778188 TI - Changes in intraocular pressure during cardiopulmonary bypass. AB - PURPOSE: The aim of the present study was to investigate the changes in intraocular pressures (IOP) in patients who underwent pulsatile and non-pulsatile cardiopulmonary bypass (CPB). METHODS: A total of 42 patients operated for elective coronary bypass surgery (CABG) on CPB were randomly allocated to pulsatile (Group P) and non-pulsatile (Group N) groups. Pulsatile flow was applied to Group P patients during crops-clamp period. The IOP measurements were made before and after the induction of anesthesia, before the onset of CPB, on the 5th, 15th, 30th, 45th, and 60th min of CPB, after CPB and at the end of the operation. The results of repetitive measurements were analyzed at different intervals and in two groups. RESULTS: The second IOP measurements of right and left eyes displayed statistically significant decreases from the baseline level [11.9 +/- 2.9 (p = 0.0001) and 12.5 +/- 3.2 (p = 0.0001), respectively]. The significant decrease in the IOP values persisted in the repeated measurements except for the 5th min of CPB values [17.0 +/- 3.5 (p = 0.346) and 16.7 +/- 3.6 (p = 0.399)]. Comparison of two groups demonstrated significant differences at pre-CPB (right 12.8 +/- 2.3 vs. 10.8 +/- 2.4; p = 0.013 and left 13.3 +/- 2.4 vs. 11.5 +/- 2.5; p = 0.023), and 5th min of CPB measurements (right 18.5 +/- 3.1 vs. 15.9 +/- 3.4; p = 0.015; left 18.2 +/- 3.0 vs. 15.7 +/- 3.6; p = 0.019). CONCLUSION: We noted a steady decrease in repeated IOP measurements except for the transient increase in CPB values on 5th min. The IOP values were higher in pulsatile CPB group in pre-CPB and 5th min of CPB measurements; however, the difference was not significant in the repeated measurements. PMID- 27778189 TI - C-reactive protein and complement factor H polymorphism interaction in advanced exudative age-related macular degeneration. AB - PURPOSE: To determine the association of C-reactive protein (CRP) and complement factor H (CFH) gene with exudative age-related macular degeneration (AMD) and any possible interaction among these factors. METHODS: In this case-control study, 139 unrelated patients with exudative AMD and 123 non-AMD controls were recruited. Blood sample was taken for analysis of the CRP levels and DNA testing. DNA fragments of CFH gene variants containing 4 single nucleotide polymorphisms including rs800292, rs1061170, rs2274700, and rs3753395 were assessed. A CRP level of >=3 mg/L was considered as elevated. The association of elevated CRP and CFH gene variants polymorphism with exudative AMD was compared between the groups. RESULTS: Mean age was 72.6 +/- 6.4 for controls and 74.9 +/- 7.4 for case group (P = 0.006). The difference between CRP levels in cases and controls was not statistically significant (P = 0.055). However, Y402H variant of CFH in both homozygous and heterozygous carriers C allele was significantly more frequent among exudative AMD patients than controls, 32.1 versus 6.5 % (P < 0.001). Evaluating various CRP levels in patients with CC and non-CC genotypes disclosed that in CC genotype group, higher CRP level (>3 mg/L) was associated with higher risk of developing exudative AMD (OR = 12.0, CI: 1.5-98.8) compared with the control group. CONCLUSION: This study disclosed no difference in CRP levels per se between exudative AMD patients with control group. However, higher levels of CRP in the presence of C allele of Y402H might confer more risk for the development of exudative AMD. PMID- 27778192 TI - Therapeutic Targeting of Cellular Stress to Prevent Cardiovascular Disease: A Review of the Evidence. AB - The availability of effective drugs targeting the major risk factors of cardiovascular disease (CVD) has reduced morbidity and mortality. Cumulative relative risk of CVD events can be reduced by 75 % with a combination of aspirin, a beta-adrenoceptor antagonist (beta-blocker), an HMG-CoA reductase inhibitor (statin), and an angiotensin-converting enzyme inhibitor. The principal pharmacodynamics of these drugs cannot explain the entirety of their cardioprotective action, as other drugs with similar pharmacologic targets have not been associated with favorable clinical effects. This raises the possibility that the cardioprotective drugs have a unique pleiotropic activity that contributes to their clinical efficacy. Recent data suggest that reducing cellular stress such as oxidative, inflammatory, and endoplasmic reticulum stress, might be a common denominator of the drugs with proven efficacy in reducing CVD risk. In this communication, the evidence in favor of this hypothesis is discussed, and ongoing trials with therapeutic agents targeting cellular stresses are reviewed. PMID- 27778191 TI - Impact of Adding Eicosapentaenoic Acid to Statin Therapy on Plasma Pentraxin 3 Level in Patients with Stable Coronary Artery Disease: A 6-Month, Randomized Controlled Study. AB - BACKGROUND: We hypothesized that the additional administration of eicosapentaenoic acid (EPA) in patients with stable coronary artery disease (CAD) receiving statin has the potential to lower the serum pentraxin 3 (PTX3) level, an indicator of plaque stabilization. METHODS: We randomly assigned CAD patients already receiving statin therapy to an EPA group (1800 mg/day, n = 53) or control group (n = 53). RESULTS: No significant difference was found in the change in the plasma PTX3 level between the groups. However, in a subgroup analysis, a significant percentage reduction in the plasma PTX3 level was observed in patients receiving strong statin compared with the patients receiving moderate statin in the EPA group (-5.6 vs. 14.7 %, p = 0.0082), while no such difference in the percentage change in the plasma PTX3 level was noted between the two same statin subgroups in the control group. A multiple logistic regression analysis identified the addition of EPA to ongoing strong statin treatment as an independent predictor of PTX3 level reduction. Furthermore, even in patients with relatively well-controlled serum lipid levels, pretreatment with EPA added to ongoing statin therapy reduced serum non-high-density lipoprotein cholesterol and triglyceride-rich lipoproteins as residual risk factors. CONCLUSION: Through this study design, the results could not support the hypothesis that adding EPA in patients with stable CAD receiving varying degrees of statin treatment reduces the plasma PTX3 level comprehensively. However, addition of EPA to ongoing strong statin treatment, but not ongoing moderate statin treatment, may reduce the plasma PTX3 level, possibly leading to coronary plaque stabilization. CLINICAL TRIAL REGISTRATION INFORMATION: UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010452. PMID- 27778190 TI - Synchronous multifocal necrotizing fasciitis prognostic factors: a retrospective case series study in a single center. AB - PURPOSE: No reports have been published on synchronous multifocal necrotizing fasciitis (SMNF), a multifocal presence of necrotizing fasciitis in different extremities. We evaluated the clinical characteristics and outcomes of SMNF. METHODS: Eighteen patients (14 men, 4 women; mean age: 59 years) diagnosed with SMNF of the extremities between January 2004 to December 2012 were enrolled and evaluated. RESULTS: Vibrio species were the most commonly (78%; n = 14) isolated; others were two cases (11%) of Aeromonas spp., one case (6%) of group A beta hemolytic streptococcus, and one case of coagulase-negative staphylococcus. SMNF was in the bilateral lower limbs (72%; n = 13), bilateral upper limbs (17%; n = 3), and one patient with one upper and one lower limb (11%). Non-surviving patients had more bilateral lower limb involvement and thrombocytopenia. CONCLUSIONS: Most patients with SMNF were male and had bilateral lower limb and marine Gram-negative bacteria involvement. The mortality of SMNF remained extremely high in patients with involvement of bilateral lower limb and initial thrombocytopenia. PMID- 27778193 TI - Evaluation of Quality of Life in Patients With Narcolepsy Treated With Sodium Oxybate: Use of the 36-Item Short-Form Health Survey in a Clinical Trial. AB - INTRODUCTION: The present post hoc analysis was designed to evaluate health related quality of life (HRQoL) using the 36-item Short Form Health Status Survey (SF-36) during an 8-week trial of sodium oxybate (SXB). METHODS: SF-36 was assessed in a phase 3 placebo-controlled trial in patients with narcolepsy (N = 228) randomized to placebo or SXB in doses of 4.5, 6, or 9 g nightly for 8 weeks. Changes from baseline in SF-36 (last observation carried forward) were compared between SXB and placebo, and effect sizes (ES) were estimated. RESULTS: Baseline SF-36 values were lower than normative values for the US general population. After 8 weeks of treatment, mean (+/-standard deviation) improvement from baseline on the Physical Component Summary (PCS) was significantly greater with SXB 9 g/night than placebo (6.3 +/- 9.1 vs. 1.5 +/- 6.2; p = 0.005), with moderate ES; no significant difference was found between the SXB and placebo groups on the Mental Component Summary. SXB 9 g/night resulted in significantly (p < 0.05) greater improvements than placebo in Physical Functioning (4.4 +/- 9.2 vs. 1.0 +/- 8.0), General Health (GH; 3.1 +/- 7.0 vs. 0.4 +/- 6.8), and Social Functioning (6.8 +/- 16.8 vs. 1.1 +/- 9.6). All SXB doses resulted in significant improvement (p < 0.05) relative to placebo for Vitality, with moderate ES. No significant differences versus placebo were observed for Role-Physical, Role Emotional, or Mental Health domains. CONCLUSION: Treatment with SXB was associated with a dose-dependent improvement in HRQoL, with the 9-g nightly dose demonstrating a positive impact on PCS and individual SF-36 domains of Vitality, GH, and Physical and Social Functioning. TRIAL REGISTRATION: NCT00049803. FUNDING: Jazz Pharmaceuticals. PMID- 27778194 TI - Intra-articular Injection of Urinary Bladder Matrix Reduces Osteoarthritis Development. AB - Micronized porcine urinary bladder matrix (UBM) is an extracellular matrix biomaterial that has immunomodulatory and pro-regenerative properties. The objective of this study was to assess the ability of UBM to alter disease progression in a mouse model of post-traumatic osteoarthritis (OA). Ten-week-old wild-type C57BL/6 male mice underwent anterior cruciate ligament transection (ACLT) to induce OA. Two weeks after ACLT, UBM (50 mg/mL) or saline was injected into the mouse joint. At 4 and 8 weeks post-ACLT, cartilage integrity was assessed using OARSI scoring of histology, pain was evaluated, and joints were harvested for quantitative RT-PCR analysis of cartilage-specific and inflammatory gene expression. UBM-treated animals showed improved cartilage integrity at 4 and 8 weeks and reduced pain at 4 weeks compared to saline-injected mice. Animals injected with UBM expressed higher levels of genes encoding structural cartilage proteins, such as collagen2alpha1 and aggrecan, as well as anti-inflammatory cytokines, including interleukins 10 and 4. UBM decreased cartilage degeneration in the murine ACLT model of OA, which may be due to reduced inflammation in the joint and maintenance of high expression levels of proteoglycans. PMID- 27778195 TI - Adjusting foraging strategies: a comparison of rural and urban common mynas (Acridotheres tristis). AB - Establishment in urbanized environments is associated with changes in physiology, behaviour, and problem-solving. We compared the speed of learning in urban and rural female common mynas, Acridotheres tristis, using a standard visual discrimination task followed by a reversal learning phase. We also examined how quickly each bird progressed through different stages of learning, including sampling and acquisition within both initial and reversal learning, and persistence following reversal. Based on their reliance on very different food resources, we expected urban mynas to learn and reversal learn more quickly but to sample new contingencies for proportionately longer before learning them. When quantified from first presentation to criterion achievement, urban mynas took more 20-trial blocks to learn the initial discrimination, as well as the reversed contingency, than rural mynas. More detailed analyses at the level of stage revealed that this was because urban mynas explored the novel cue-outcome contingencies for longer, and despite transitioning faster through subsequent acquisition, remained overall slower than rural females. Our findings draw attention to fine adjustments in learning strategies in response to urbanization and caution against interpreting the speed to learn a task as a reflection of cognitive ability. PMID- 27778196 TI - Orthorexic eating behaviour as a coping strategy in patients with anorexia nervosa. AB - PURPOSE: Orthorexia nervosa is defined as the fixation on health-conscious eating behaviour and has recently been discussed as a new variant of disordered eating. The aim of the present study was to analyse orthorexic eating behaviour in an inpatient treatment sample of female anorexics to investigate the relation between anorexic and orthorexic eating behaviour. METHOD: Female anorexic patients with low (n = 29) and pronounced (n = 13) orthorexic eating behaviour as well as a matched control group composed of healthy females (n = 30) were compared with regard to several aspects of disordered eating, hypochondriacal traits, food consumption frequency and fulfilment of basic psychological needs in terms of eating. Orthorexic eating behaviour was assessed using the Dusseldorfer Orthorexie Skala. RESULTS: Fulfilment of basic psychological needs with respect to autonomy and competence is higher in anorexic individuals with pronounced orthorexic eating behaviour compared to patients with low orthorexic eating behaviour. Furthermore, patients with pronounced orthorexic eating behaviour state eating healthy food regardless of calorie content more often. No difference was found for hypochondriacal traits and eating disordered symptoms in general. CONCLUSIONS: Orthorexic eating behaviour enhances self-perception of eating behaviour as autonomous and competent, indicating that it might serve as a coping strategy in anorexic individuals. Further research is needed to investigate if this tendency in food selection strategy leads to positive effects in the long term. PMID- 27778199 TI - The Watson-Forbes Biogeographical Controversy Untangled 170 Years Later. AB - Hewett Cottrell Watson and Edward Forbes were two naturalists of the Victorian age. They were protagonists on a dispute that generated comment and serves as an illuminating case study of misunderstanding in priority issues. Watson accused Forbes of having plagiarized his original classification of the British plants into groups on the basis of their geographical distribution. This controversy originated mostly from a so-far-ignored basic difference in Watson's and Forbes' ideas about biogeographical regionalization. Watson's classification of the British flora into groups of species with similar distribution was probably the first application of the concept of "regional chorotype." By contrast, the biogeographical classification of the British flora proposed by Forbes belongs to the concept of "element," because it was based on assumed species history (i.e. colonization routes). The two approaches may produce similar outcomes, but remain conceptually different. Although personal reasons may have contributed to exacerbate the Watson-Forbes controversy, failure in recognizing this distinction by its actors and their contemporaries, such as Hooker and Darwin, was the most important cause. PMID- 27778197 TI - Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment. AB - BACKGROUND: Activating mutations of the receptor tyrosine kinase FLT3 (fms related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy. PATIENTS AND METHODS: We retrospectively analyzed the response to induction chemotherapy and the outcome of 76 patients with FLT3-ITD-positive AML including 50 patients who underwent allogeneic SCT. Furthermore, efficacy of TKI treatment was evaluated in 18 patients (median age 54 years, range 21-74) with relapsed or refractory FLT3 ITD-positive AML. RESULTS: Response to induction chemotherapy in 76 FLT3-ITD positive AML patients was characterized by a complete remission (CR) rate of 68%. In total, 50 of 76 patients (66%) underwent allogeneic SCT including 40 patients (80%) in CR. Relapse of AML was observed in 21 of 47 patients (45%) after allogeneic SCT with a median relapse-free survival (RFS) of 13 months (range 3 224) for patients with CR prior to or at day +30 after SCT. Myeloablative conditioning resulted in an improved median RFS of 29 months (4-217) as compared to a reduced intensity conditioning protocol prior to allogeneic SCT with a RFS of 8 months (1-197, P = 0.048), respectively. Median OS of FLT3-ITD-positive AML was 17 months (5-225) for patients who received an allogeneic SCT as compared to 9 months (1-184) for patients who did not undergo SCT. Response of FLT3-ITD positive AML to sorafenib was characterized by only 3 of 18 patients achieving a bone marrow response (17%), while there was no response to second-line treatment with ponatinib. CONCLUSION: This "real-life" data reflect the continuing challenge of FLT3-ITD-positive AML and confirm the poor outcome even after allogeneic SCT. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML is still limited and requires substantial improvement, e.g., by the introduction of second-generation inhibitors targeting constitutively active FLT3. PMID- 27778200 TI - Ameliorating chronic pain: opioids, adjunct and alternative therapies. PMID- 27778198 TI - Left-sided laterality of Merkel cell carcinoma in a German population: more than just sun exposure. AB - BACKGROUND: Lateral distribution of cancer has been observed previously. Most evident is this laterality in ultraviolet (UV)-induced skin cancer, based on an unequally distributed UV exposure. OBJECTIVES: The aim of this study was to explore whether patients from Germany also show asymmetrical lateral distribution of Merkel cell carcinoma (MCC). METHODS: In total, 115 patients with MCC were studied for laterality of the primary tumour. Correlation of clinical variables with lateral distribution of MCC was investigated as well. RESULTS: In 64/115 (55.7%) patients, primary tumours were present on the left side, in 37/115 (32.2%) on the right side, and in 14/115 (12.2%) in the midline (P < 0.0001). Excluding the latter localization occurrence of left-sided MCCs (64 of 101/63.4%) was significantly (P = 0.0072) more often observed (1.73-fold) when compared to right-sided tumours (37 of 101/36.6%). The excess of left-sided tumours was found on the head with a left-right ratio of 1.8, trunk of 8, arm of 1.2, and leg of 1.8. There was no significant association between laterality and gender, age, MCPyV status, and anatomic localization of primary tumours including the occurrence in sun-exposed sites. CONCLUSIONS: Occurrence of left-sided MCCs was significantly more often observed when compared to right-sided tumours. Laterality was not associated with tumour presentation at chronically ultraviolet exposed sites. Hence, the reason for laterality in MCC remains obscure, but likely goes beyond UV exposure. PMID- 27778201 TI - Secrets of Lecturing: How I Learned to Talk the Talk. PMID- 27778202 TI - Profiles: Raymond S. Koff, MD. PMID- 27778203 TI - Tissue Transglutaminase Levels Are Not Sufficient to Diagnose Celiac Disease in North American Practices Without Intestinal Biopsies. AB - BACKGROUND: Celiac serology is crucial for the diagnosis of celiac disease in children. The American guideline for celiac disease in children suggested that positive serology should be followed by confirmatory intestinal histology. The relationship between high tissue transglutaminase titers and celiac disease in children has not been well investigated in children from North America. AIMS: In the present study, we investigated whether different tissue transglutaminase titers in symptomatic children could predict celiac disease without the confirmation of intestinal histology. METHODS: Data from biopsy confirmed celiac children were collected from four different clinics in North America. Clinical, serological, histological, and follow-up data were collected. The accuracy rates of various tissue transglutaminase titers to predict celiac disease in children were calculated. RESULTS: The data from 240 children were calculated. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of tissue transglutaminase titers at >=10* upper limit of normal were 75.4, 48.8, 87.7, 29.0, and 70.8 %, respectively. Similar data were noted in the other tissue transglutaminase titers (>=3* upper limit of normal, >100 U/ml, or >100 U/ml and >10* upper limit of normal). CONCLUSIONS: The positive predictive value of tissue transglutaminase titers at >=3* upper limit of normal or higher was too low to predict celiac disease in children. Our data suggested that in routine clinical practice, high titers of tissue transglutaminase are not sufficient to diagnose celiac disease in North American children without intestinal biopsies. PMID- 27778204 TI - Rates and Predictors of Endoscopic and Clinical Recurrence After Primary Ileocolic Resection for Crohn's Disease. AB - BACKGROUND AND AIMS: The utility of postoperative medical prophylaxis (POMP) and the treatment of mild endoscopic recurrence remain controversial. METHODS: This study is a retrospective review of patients undergoing a primary ileocolic resection for CD at a single academic center. Endoscopic recurrence (ER) was defined using the Rutgeerts score (RS), and clinical recurrence (CR) was defined as symptoms of CD with endoscopic or radiologic evidence of neo-terminal ileal disease. RESULTS: There were 171 patients who met inclusion criteria. The cumulative probability of ER (RS >= i-1) at 1, 2, and 5 years was 29, 51, and 77 %, respectively. The only independent predictors of ER were the absence of POMP (HR 1.50; P = 0.03) and penetrating disease behavior (HR 1.50; P = 0.05). The cumulative probability of CR at 1, 2, and 5 years was 8, 13, and 27 %, respectively. There was a higher rate of clinical recurrence in patients with RS 2 compared to RS-1 on the initial postoperative endoscopy (HR 2.50; P = 0.02). In 11 patients not exposed to POMP with i-1 on initial endoscopy, only 2 patients (18 %) progressed endoscopically during the study period while 5 patients (45 %) regressed to i-0 on subsequent endoscopy without treatment. CONCLUSIONS: Postoperative medical prophylaxis decreased the likelihood of ER while certain phenotypes of CD appear to increase the risk of developing ER and CR. There may be a role for watchful waiting in patients with mild endoscopic recurrence on the initial postoperative endoscopy. PMID- 27778206 TI - A prospective study of peripheral blood DNA methylation at RPTOR, MGRN1 and RAPSN and risk of breast cancer. PMID- 27778207 TI - Estimation of breathing rate in thermal imaging videos: a pilot study on healthy human subjects. AB - Diverse studies have demonstrated the importance of monitoring breathing rate (BR). Commonly, changes in BR are one of the earliest and major markers of serious complications/illness. However, it is frequently neglected due to limitations of clinically established measurement techniques, which require attachment of sensors. The employment of adhesive pads or thoracic belts in preterm infants as well as in traumatized or burned patients is an additional paramount issue. The present paper proposes a new robust approach, based on data fusion, to remotely monitor BR using infrared thermography (IRT). The algorithm considers not only temperature modulation around mouth and nostrils but also the movements of both shoulders. The data of these four sensors/regions of interest need to be further fused to reach improved accuracy. To investigate the performance of our approach, two different experiments (phase A: normal breathing, phase B: simulation of breathing disorders) on twelve healthy volunteers were performed. Thoracic effort (piezoplethysmography) was simultaneously acquired to validate our results. Excellent agreements between BR estimated with IRT and gold standard were achieved. While in phase A a mean correlation of 0.98 and a root-mean-square error (RMSE) of 0.28 bpm was reached, in phase B the mean correlation and the RMSE hovered around 0.95 and 3.45 bpm, respectively. The higher RMSE in phase B results predominantly from delays between IRT and gold standard in BR transitions: eupnea/apnea, apnea/tachypnea etc. Moreover, this study also demonstrates the capability of IRT to capture varied breathing disorders, and consecutively, to assess respiratory function. In summary, IRT might be a promising monitoring alternative to the conventional contact-based techniques regarding its performance and remarkable capabilities. PMID- 27778205 TI - Association Between Body Mass Index and Clinical and Endoscopic Features of Eosinophilic Esophagitis. AB - BACKGROUND: Because eosinophilic esophagitis (EoE) causes dysphagia, esophageal narrowing, and strictures, it could result in low body mass index (BMI), but there are few data assessing this. AIM: To determine whether EoE is associated with decreased BMI. METHODS: We conducted a prospective study at the University of North Carolina from 2009 to 2013 enrolling consecutive adults undergoing outpatient EGD. BMI and endoscopic findings were recorded. Incident cases of EoE were diagnosed per consensus guidelines. Controls had either reflux or dysphagia, but not EoE. BMI was compared between cases and controls and by endoscopic features. RESULTS: Of 120 EoE cases and 297 controls analyzed, the median BMI was lower in EoE cases (25 vs. 28 kg/m2, p = 0.002). BMI did not differ by stricture presence (26 vs. 26 kg/m2, p = 0.05) or by performance of dilation (26 vs. 27 kg/m2 for undilated; p = 0.16). However, BMI was lower in patients with narrow caliber esophagus (24 vs. 27 kg/m2, p < 0.001). EoE patients with narrow caliber esophagus also had decreased BMI compared to controls with narrow caliber esophagi (24 vs. 27 kg/m2, p = 0.001). On linear regression after adjustment for age, race, and gender, narrowing decreased BMI by 2.3 kg/m2 [95% CI -4.1, -0.6]. CONCLUSIONS: BMI is lower in EoE cases compared to controls, and esophageal narrowing, but not focal stricture, is associated with a lower BMI in patients with EoE. Weight loss or low BMI in a patient suspected of having EoE should raise concern for esophageal remodeling causing narrow caliber esophagus. PMID- 27778208 TI - Frequency-domain vs continuous-wave near-infrared spectroscopy devices: a comparison of clinically viable monitors in controlled hypoxia. AB - The Near-infrared spectroscopy (NIRS) has not been adopted as a mainstream monitoring modality in acute neurosurgical care due to concerns about its reliability and consistency. However, improvements in NIRS parameter recovery techniques are now available that may improve the quantitative accuracy of NIRS for this clinical context. Therefore, the aim of this study was to compare the abilities of a continuous-wave (CW) NIRS device with a similarly clinically viable NIRS device utilising a frequency-domain (FD) parameter recovery technique in detecting changes in cerebral tissue saturation during stepwise increases of experimentally induced hypoxia. Nine healthy individuals (6M/3F) underwent a dynamic end-tidal forced manipulation of their expiratory gases to induce a stepwise induced hypoxia. The minimum end-tidal oxygen partial pressure (EtO2) achieved was 40 mm Hg. Simultaneous neurological and extra-cranial tissue NIRS reading were obtained during this protocol by both tested devices. Both devices detected significant changes in cerebral tissue saturation during the induction of hypoxia (CW 9.8 +/- 2.3 %; FD 7.0 +/- 3.4 %; Wilcoxon signed rank test P < 0.01 for both devices). No significant difference was observed between the saturation changes observed by either device (P = 0.625). An observably greater degree of noise was noticed in parameters recovered by the FD device, and both demonstrated equally variable baseline readings (Coefficient of variance 8.4 and 9.7 % for the CW and FD devices, respectively) between individuals tested. No advantageous difference was observed in parameters recovered from the FD device compared with those detected by CW. PMID- 27778209 TI - Prediction of inspired oxygen fraction for targeted arterial oxygen tension following open heart surgery in non-smoking and smoking patients. AB - Simple and accurate expressions describing the PaO2-FiO2 relationship in mechanically ventilated patients are lacking. The current study aims to validate a novel mathematical expression for accurate prediction of the fraction of inspired oxygen that will result in a targeted arterial oxygen tension in non smoking and smoking patients receiving mechanical ventilation following open heart surgeries. One hundred PaO2-FiO2 data pairs were obtained from 25 non smoking patients mechanically ventilated following open heart surgeries. One data pair was collected at each of FiO2 of 40, 60, 80, and 100% while maintaining same mechanical ventilation support settings. Similarly, another 100 hundred PaO2-FiO2 data pairs were obtained from 25 smoking patients mechanically ventilated following open heart surgeries. The utility of the new mathematical expression in accurately describing the PaO2-FiO2 relationship in these patients was assessed by the regression and Bland-Altman analyses. Significant correlations were seen between the true and estimated FiO2 values in non-smoking (r2 = 0.9424; p < 0.05) and smoking (r2 = 0.9466; p < 0.05) patients. Tight biases between the true and estimated FiO2 values for non-smoking (3.1%) and smoking (4.1%) patients were observed. Also, significant correlations were seen between the true and estimated PaO2/FiO2 ratios in non-smoking (r2 = 0.9530; p < 0.05) and smoking (r2 = 0.9675; p < 0.05) patients. Tight biases between the true and estimated PaO2/FiO2 ratios for non-smoking (-18 mmHg) and smoking (-16 mmHg) patients were also observed. The new mathematical expression for the description of the PaO2-FiO2 relationship is valid and accurate in non-smoking and smoking patients who are receiving mechanical ventilation for post cardiac surgery. PMID- 27778210 TI - Surgical resection of fourth ventricular ependymomas: case series and technical nuances. AB - Ependymomas are rare neuroepithelial tumors which may arise anywhere along the ventricular system. Tumors arising in the fourth ventricle present unique challenges. Complete tumor resection favors prolonged survival, but may result in inadvertent injury of surrounding neural structures-such as cranial nerve (CN) nuclei. Here, our institutional experience with surgical resection of fourth ventricular ependymomas is described. A single institution, retrospective analysis of consecutive case series of adult surgically resected fourth ventricular ependymomas with the bilateral telovelar approach. Extent of resection, outcomes and postoperative complications are statistically analyzed. From January 2000 to April 2016, 22 fourth ventricular ependymomas underwent surgical resection. Gross total resection was achieved in 18 of 22 cases (82 %). There were six postoperative CN palsies-3 lower CN palsies (IX, X, or XI), 1 CN VII palsy, 1 CN IV palsy, and 1 CN VI palsy. No deaths or cerebellar mutism occurred. Two of 6 CN deficits resolved and the rate of permanent neurologic deficit was 18 %. A CN deficit was not statistically associated with prolonged hospital stay or functional outcome. With exception of one patient, all patients functionally improved or remained unchanged following surgery. Postoperative complications included one wound infection (4.5 %) and four pseudomeningoceles (18 %). The rate of shunt-dependent hydrocephalus was 18 %. Tumors adherence to the fourth ventricular floor is not an absolute contraindication for complete resection. Intraoperative neuro-monitoring is essential, and the development of sustained, but not transient CN activity, and/or hemodynamically significant bradycardia should limit the extent of resection. PMID- 27778211 TI - Resection of falx and parasagittal meningioma: complication avoidance. AB - Falx and parasagittal meningiomas are common locations for meningiomas of the cranial vault. Many of these tumors are now discovered incidentally during cranial imaging for other reasons. Therefore, in the calculation of the risks and benefits of surgery it behooves the surgeon to do all he/she can to avoid surgical complications. This is a heavily experience based article based off the senior author's experience with over 1200 intracranial meningiomas. We present three cases to illustrate some of the decision-making and techniques used to reduce complications in the management of these cases treated with an open operation. PMID- 27778212 TI - Survival after chemotherapy and stem cell transplant followed by delayed craniospinal irradiation is comparable to upfront craniospinal irradiation in pediatric embryonal brain tumor patients. AB - Pediatric embryonal brain tumor patients treated with craniospinal irradiation (CSI) are at risk for adverse effects, with greater severity in younger patients. Here we compare outcomes of CSI vs. high-dose chemotherapy (HD), stem cell transplant (SCT) and delayed CSI in newly diagnosed patients. Two hundred one consecutive patients treated for medulloblastoma (72 %), supratentorial primitive neuroectodermal tumor (sPNET; 18 %) or pineoblastoma (10 %) at two institutions between 1988 and 2014 were retrospectively identified. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank tests. Adjuvant CSI regimens were used for 56 % of patients (upfront-CSI), and HD/SCT regimens were used in 32 % of patients. HD/SCT patients were significantly younger than those receiving upfront-CSI (2.9 vs. 7.8 years; P < 0.0001). There were no differences in metastases, extent of resection, or CSI dose between upfront-CSI and HD/SCT patients, but median follow-up was shorter in the HD/SCT group (6.2 vs. 3.9 years; P = 0.007). There were no significant outcome differences between upfront-CSI and HD/SCT patients who received CSI as a prophylaxis or following relapse (OS 66 % vs. 61 %, P = 0.13; PFS 67 % vs. 62 %, P = 0.12). Outcomes were equivalent when restricting analyses to HD/SCT patients who received prophylactic CSI prior to relapse (OS 66 % vs. 65 %, P = 0.5; PFS 67 % vs. 74 %, P = 0.8). At last follow-up, 48 % of HD/SCT patients had received neither definitive nor salvage radiotherapy. In this retrospective cohort, outcomes with adjuvant HD/SCT followed by delayed CSI are comparable to upfront CSI for carefully surveyed pediatric embryonal brain tumor patients. Future prospective studies are required to validate this finding, and also to assess the impact of delayed CSI on neurocognitive outcomes. PMID- 27778213 TI - Lessons Learned from a Middle-Aged Man with Testicular Pain: Exercises in Clinical Reasoning. PMID- 27778214 TI - The Evolution of General Internal Medicine (GIM)in Canada: International Implications. AB - General internal medicine (GIM), like other generalist specialties, has struggled to maintain its identity in the face of mounting sub-specialization over the past few decades. In Canada, the path to licensure for general internists has been through the completion of an extra year of training after three core years of internal medicine. Until very recently, the Royal College of Physicians and Surgeons of Canada (RCPSC) did not recognize GIM as a distinct entity. In response to a societal need to train generalist practitioners who could care for complex patients in an increasingly complex health care setting, the majority of universities across Canada voluntarily developed structured GIM training programs independent of RCPSC recognition. However, interest amongst trainees in GIM was declining, and the GIM workforce in Canada, like that in many other countries, was in danger of serious shortfalls. After much deliberation and consultation, in 2010, the RCPSC recognized GIM as a distinct subspecialty of internal medicine. Since this time, despite the challenges in the educational implementation of GIM as a distinct discipline, there has been a resurgence of interest in this field of medicine. This paper outlines the journey of the Canadian GIM to educational implementation as a distinct discipline, the impact on the discipline, and the implications for the international GIM community. PMID- 27778216 TI - Mine dewatering and impact assessment in an arid area: Case of Gulf region. AB - Analytical and empirical solution coupled with water balance method were used to predict the ground water inflow to a mine pit excavated below the water table, final pit lake level/recovery and radius of influence, through long-term and time variant simulations. The solution considers the effect of decreased saturated thickness near the pit walls, distributed recharge to the water table and upward flow through the pit bottom. The approach is flexible to accommodate the anisotropy/heterogeneity of the real world. Final pit void water level was assessed through scenarios to know whether it will be consumed by evaporation and a shallow lake will form or not. The optimised radius of influence was estimated which is considered as crucial information in relation to the engineering aspects of mine planning and sustainable development of the mine area. Time-transient inflow over a period of time was estimated using solutions, including analytical element method (AEM). Their primary value is in providing estimates of pit inflow rates to be used in the mine dewatering. Inflow estimation and recovery helps whether there is water to supplement the demand and if there is any recovery issue to be dealt with in relation to surface and groundwater quality/eco-system, environmental evaluations and mitigation. Therefore, this method is good at informing decision makers in assessing the effects of mining operations and developing an appropriate water management strategy. PMID- 27778215 TI - A Cross-Sectional Online Survey of HIV Pre-Exposure Prophylaxis Adoption Among Primary Care Physicians. AB - BACKGROUND: Among health care providers, prescription of HIV pre-exposure prophylaxis (PrEP) has been low. Little is known specifically about primary care physicians (PCPs) with regard to PrEP awareness and adoption (i.e., prescription or referral), and factors associated with adoption. OBJECTIVE: To assess PrEP awareness, PrEP adoption, and factors associated with adoption among PCPs. DESIGN: Cross-sectional online survey conducted in April and May 2015. RESPONDENTS: Members of a national professional organization for academic primary care physicians (n = 266). MAIN MEASURES: PrEP awareness, PrEP adoption (ever prescribed or referred a patient for PrEP [yes/no]), provider and practice characteristics, and self-rated knowledge, attitudes, and beliefs associated with adoption. KEY RESULTS: The survey response rate was 8.6 % (266/2093). Ninety three percent of respondents reported prior awareness of PrEP. Of these, 34.9 % reported PrEP adoption. In multivariable analysis of provider and practice characteristics, compared with non-adopters, adopters were more likely to provide care to more than 50 HIV-positive patients (vs. 0, aOR = 6.82, 95 % CI 2.06 22.52). Compared with non-adopters, adopters were also more likely to report excellent, very good, or good self-rated PrEP knowledge (15.1 %, 33.7 %, 30.2 % vs. 2.5 %, 18.1 %, 23.8 %, respectively; p < 0.001) and to perceive PrEP as extremely safe (35.1 % vs. 10.7 %; p = 0.002). Compared with non-adopters, adopters were less likely to perceive PrEP as being moderately likely to increase risk behaviors ("risk compensation") (12.8 % vs. 28.8 %, p = 0.02). CONCLUSIONS: While most respondents were aware of PrEP, only one-third of PrEP-aware PCPs reported adoption. Adopters were more likely to have experience providing HIV care and to perceive PrEP as extremely safe, and were less likely to perceive PrEP use as leading to risk compensation. To enhance PCP adoption of PrEP, educational efforts targeting PCPs without HIV care experience should be considered, as well as training those with HIV care experience to be PrEP "clinical champions". Concerns about safety and risk compensation must also be addressed. PMID- 27778217 TI - Variation of biomass and carbon pool with NDVI and altitude in sub-tropical forests of northwestern Himalaya. AB - In the present study, forests at three altitudes, viz., A1 (600-900 m), A2 (900 1200 m) and A3 (1200-1500 m) above mean sea level having normalised differential vegetation index (NDVI) values of N1 (0.0-0.1), N2 (0.1-0.2), N3 (0.2-0.3), N4 (0.3-0.4) and N5 (0.4-0.5) were selected for studying their relationship with the biomass and carbon pool in the state of Himachal Pradesh, India. The study reported maximum stem density of (928 trees ha-1) at the A2 altitude and minimum in the A3 and A1 with 600 trees ha-1 each. The stem densities in relation to NDVIs were observed in the order N5 > N3 > N4 > N1 > N2 and did not show any definite trend with increasing altitude. Highest stem volume (295.7 m3 ha-1) was observed in N1 NDVI and minimum (194.1 m3 ha-1) in N3 index. The trend observed for stem biomass at different altitudes was A3 > A1 > A2 and for NDVIs, it was N5 > N1 > N4 > N2 > N3. Maximum aboveground biomass (265.83 t ha-1) was recorded in the 0.0-0.1 NDVI and minimum (169.05 t ha-1) in 0.2-0.3 NDVI index. Significantly, maximum total soil carbon density (90.82 t C ha-1) was observed in 0.4-0.5 NDVI followed by 0.3-0.4 NDVI (77.12 t C ha-1). The relationship between soil carbon and other studied parameters was derived through different functions simultaneously. Cubic function showed highest r 2 in most cases, followed by power, inverse and exponential function. The relationship with NDVI showed highest r 2 (0.62) through cubic functions. In relationship between ecosystem carbon with other parameters of different altitudinal gradient and NDVI, only one positively significant relation was formed with total density (0.579) through cubic function. The present study thus reveals that soil carbon density was directly related to altitude and NDVIs, but the vegetation carbon density did not bear any significant relation with altitude and NDVI. PMID- 27778218 TI - Preventive services use among female survivors of adolescent and young adult cancer. AB - PURPOSE: Examine preventive services utilization among female survivors of adolescent and young adult (AYA) cancer compared with women without cancer in the USA. METHODS: A total of 1017 women diagnosed with cancer at AYA ages (15-39 years) who were at least 5 years since diagnosis were identified from 2008 to 2012 Medical Expenditure Panel Surveys. A comparison group without cancer was matched on age and other characteristics. General preventive services included dental, medical, blood pressure, and cholesterol checkups, and flu shots in the previous year. Cancer-related services included pap smear and mammography. Preventive services and covariates (demographics, socioeconomics, and health status) were compared between groups using chi 2 tests. Ordinal logistic regression identified covariates associated with general preventive services use. RESULTS: Female survivors reported dental checkups less often (57.8 vs. 72.4 %, p < 0.001) than the comparison group and checked their blood pressure (90 vs. 86.7 %, p = 0.045) and cholesterol (67.5 vs. 61.7 %, p = 0.045) more often. No differences were found in flu shots, medical checkups, and cancer-related services. Survivors without insurance were less likely to use general preventive services (odds ratio [OR] = 0.2, 95 % confidence interval [CI] 0.12-0.35, p < 0.001). Older survivors (OR = 3.09, 95 % CI 1.69-5.62, p < 0.001) and those who speak Spanish or other languages at home (OR = 3.19, 95 % CI 1.33-7.67, p = 0.01) were more likely to use general prevention than their counterparts. CONCLUSION: Overall, female survivors were as likely as the comparison group to use preventive services, except dental services, blood pressure, and cholesterol checks. IMPLICATIONS FOR CANCER SURVIVORS: Survivors may require support to use recommended preventive services more effectively, especially the younger and uninsured who may be at greater risk for underuse. PMID- 27778221 TI - Hydrogen sulfide: the shutter button of stomata in plants. PMID- 27778220 TI - Intimate Partner Violence and HIV-Risk Behaviors: Evaluating Avoidant Coping as a Moderator. AB - Women who experience intimate partner violence (IPV) report higher rates of HIV risk behaviors. However, few studies have examined factors that may influence the strength of the link between IPV and HIV-risk behaviors. The goal of the current study was to extend extant research by evaluating the potential moderating role of avoidant coping in this relation. Participants were 212 women currently experiencing IPV (M age = 36.63, 70.8 % African American) who were recruited from the community. Significant positive associations were found between physical, psychological, and sexual IPV severity and both avoidant coping and HIV-risk behaviors. Avoidant coping moderated the relations between both physical and psychological IPV severity and HIV-risk behaviors, such that physical and psychological IPV severity were significantly associated with HIV-risk behaviors when avoidant coping was high (but not low). Findings underscore avoidant coping as an important factor in identifying and subsequently treating IPV-victimized women vulnerable to HIV-risk behaviors. PMID- 27778222 TI - Strategies for efficient and economical 2,3-butanediol production: new trends in this field. AB - 2,3-Butanediol (2,3-BD) is a promising bulk chemical with a potentially wide range of applications e.g., in the manufacture of printing inks, perfumes, synthetic rubber, fumigants, antifreeze agents, fuel additives, foodstuffs and pharmaceuticals. Its high heating value and ability to increase the octane number of fuels make 2,3-BD a promising drop-in fuel. It can also be converted to methyl ethyl ketone (MEK), which is considered an effective liquid fuel additive. After combination with MEK and hydrogenation reaction, 2,3-BD can be converted to octane, which is used to produce high-quality aviation fuel. Currently 2,3-BD is mainly produced on an industrial scale by chemical methods. However, microbiological production of 2,3-BD offers a less expensive and more environmentally friendly alternative to traditional synthesis. This alcohol is generated from hexoses and pentoses mainly by bacterial strains of the genera Klebsiella, Bacillus, Serratia, and Enterobacter, which can convert waste products (such as glycerol and agricultural residues) and excess biomass (such as wood hydrolysates) to 2,3-BD. Recently, a significant improvement in microbial production has been achieved by the screening of efficient natural microbial strains, the application of alternative cost-effective substrates, and the genetic improvement of microbial producers. Furthermore, Klebsiella strains, which are regarded the most efficient natural 2,3-BD producers, have been subjected to genetic modifications aiming at the removal of pathogenic factors and the development of avirulent strains that could be used for the safe production of the diol. This review summarizes existing knowledge and experience concerning various strategies for efficient and economical microbial production of 2,3-BD. PMID- 27778224 TI - Erratum to: Thoracic and cardiovascular surgery in Japan during 2007 : Annual report by the Japanese Association for Thoracic Surgery. PMID- 27778223 TI - Mini review: surgical management of primary chest wall tumors. AB - Primary chest wall tumors (PCWTs) are relatively rare entities, and their clinical characteristics as well as appropriate treatments are not fully known. Previously reported studies, including ours, are reviewed here, taking into account the clinical approach and findings in Japan for the diagnosis, distribution of histological types, surgical procedures, and prognosis of these entities. Surgery for PCWTs comprised that approximately 0.7 % of surgeries in 2012 in Japan and 28.3 % of PCWTs were malignant with an extremely low rate of mortality within 30 days from surgery. Surgical biopsy is recommended for the differential diagnosis of chest wall tumors to determine if they are primary, metastatic, benign, or malignant lesions. Of the 297 PCWT cases reported in nine published studies, neurogenic tumors were the most common benign PCWT, and chondrosarcoma was the most common malignant PCWT. Reconstruction of the resected chest wall was performed for 41.3 % of cases, and the materials used were e-PTFE or polypropylene. The prognosis of patients with benign tumors is usually good if complete resection is achieved; however, the 5-year recurrence rate and disease related mortality were approximately 22.5 and 18.1 %, respectively, for patients with malignant tumors. Surgery for PCWTs is safe; however, surgical treatment for patients with malignant PCWTs remains challenging, and multimodal treatments for each histological tumor type should be considered. PMID- 27778225 TI - Ultra-miniature ultra-compliant neural probes with dissolvable delivery needles: design, fabrication and characterization. AB - Stable chronic functionality of intracortical probes is of utmost importance toward realizing clinical application of brain-machine interfaces. Sustained immune response from the brain tissue to the neural probes is one of the major challenges that hinder stable chronic functionality. There is a growing body of evidence in the literature that highly compliant neural probes with sub-cellular dimensions may significantly reduce the foreign-body response, thereby enhancing long term stability of intracortical recordings. Since the prevailing commercial probes are considerably larger than neurons and of high stiffness, new approaches are needed for developing miniature probes with high compliance. In this paper, we present design, fabrication, and in vitro evaluation of ultra-miniature (2.7 MUm x 10 MUm cross section), ultra-compliant (1.4 * 10-2 MUN/MUm in the axial direction, and 2.6 * 10-5 MUN/MUm and 1.8 * 10-6 MUN/MUm in the lateral directions) neural probes and associated probe-encasing biodissolvable delivery needles toward addressing the aforementioned challenges. The high compliance of the probes is obtained by micron-scale cross-section and meandered shape of the parylene-C insulated platinum wiring. Finite-element analysis is performed to compare the strains within the tissue during micromotion when using the ultra compliant meandered probes with that when using stiff silicon probes. The standard batch microfabrication techniques are used for creating the probes. A dissolvable delivery needle that encases the probe facilitates failure-free insertion and precise placement of the ultra-compliant probes. Upon completion of implantation, the needle gradually dissolves, leaving behind the ultra-compliant neural probe. A spin-casting based micromolding approach is used for the fabrication of the needle. To demonstrate the versatility of the process, needles from different biodissolvable materials, as well as two-dimensional needle arrays with different geometries and dimensions, are fabricated. Further, needles incorporating anti-inflammatory drugs are created to show the co-delivery potential of the needles. An automated insertion device is developed for repeatable and precise implantation of needle-encased probes into brain tissue. Insertion of the needles without mechanical failure, and their subsequent dissolution are demonstrated. It is concluded that ultra-miniature, ultra compliant probes and associated biodissolvable delivery needles can be successfully fabricated, and the use of the ultra-compliant meandered probes results in drastic reduction in strains imposed in the tissue as compared to stiff probes, thereby showing promise toward chronic applications. PMID- 27778219 TI - Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. AB - Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 MUmol/L. Nevertheless, we recommend keeping the concentration below 100 MUmol/L because levels fluctuate and the complications associated with high levels are so serious. PMID- 27778226 TI - In vitro clearance of doxorubicin with a DNA-based filtration device designed for intravascular use with intra-arterial chemotherapy. AB - To report a novel method using immobilized DNA within mesh to sequester drugs that have intrinsic DNA binding characteristics directly from flowing blood. DNA binding experiments were carried out in vitro with doxorubicin in saline (PBS solution), porcine serum, and porcine blood. Genomic DNA was used to identify the concentration of DNA that shows optimum binding clearance of doxorubicin from solution. Doxorubicin binding kinetics by DNA enclosed within porous mesh bags was evaluated. Flow model simulating blood flow in the inferior vena cava was used to determine in vitro binding kinetics between doxorubicin and DNA. The kinetics of doxorubicin binding to free DNA is dose-dependent and rapid, with 82 96 % decrease in drug concentration from physiologic solutions within 1 min of reaction time. DNA demonstrates faster binding kinetics by doxorubicin as compared to polystyrene resins that use an ion exchange mechanism. DNA contained within mesh yields an approximately 70 % decrease in doxorubicin concentration from solution within 5 min. In the IVC flow model, there is a 70 % drop in doxorubicin concentration at 60 min. A DNA-containing ChemoFilter device can rapidly clear clinical doses of doxorubicin from a flow model in simple and complex physiological solutions, thereby suggesting a novel approach to reduce the toxicity of DNA-binding drugs. PMID- 27778227 TI - High tech or high risk? An analysis of media reports about robotic surgery. AB - Robotic surgery continues to increase in popularity and prevalence. The adoption of robotic technology has generated controversy and frequent media coverage. We evaluate recent reports of surgical robotics in the lay press to characterize its objectivity. LexisNexis and Factiva consumer news databases were queried for articles pertaining to robotic surgery published during 2010-2015 in the three highest circulation national (US) newspapers as well as New England regional newspapers. Two independent reviewers performed content analysis and assessed headline bias with strong reliability (mean kappa = 0.96). 82 articles met inclusion criteria. Urological and gynecologic procedures were the most cited (54 and 57%, respectively). Commonly discussed aspects of robotic surgery included increased cost (45 articles, 55%), increased complications (38 articles, 43%), and easier recovery (32 articles, 39%). A minority of headlines (45%) had a neutral or unbiased tone. National newspapers were significantly more likely to report robotic surgery unfavorably by discussing disadvantages of the technology, only quoting surgeons with negative opinions, or citing scientific studies discrediting the robot (all p < 0.05). Of the 27 news articles that referenced published research studies, all 27 quoted studies reported the disadvantages of robotic surgery, while only 7 (26%) cited findings favoring robotic approaches. News reports about robotic surgery in the popular press contain a high proportion of negative bias. Non-neutral headlines and emphasis on research unfavorable to robotics were common. Clinicians should be aware of these reporting biases, which may affect patients' perceptions of robotic surgery. PMID- 27778228 TI - Comparison of in vitro invasiveness of high- and low-metastatic triple-negative human breast cancer visualized by color-coded imaging. PMID- 27778229 TI - Production of endothelial progenitor cells from skin fibroblasts by direct reprogramming for clinical usages. AB - Endothelial progenitor cells (EPCs) play an important role in angiogenesis. However, they exist in limited numbers in the human body. This study was aimed to produce EPCs, for autologous transplantation, using direct reprogramming of skin fibroblasts under GMP-compliant conditions. Fibroblasts were collected and cultured from the skin in DMEM/F12 medium supplemented with 5% activated platelet rich plasma and 1% antibiotic-antimycotic solution. They were then transfected with mRNA ETV2 and incubated in culture medium under hypoxia (5% oxygen) for 14 d. Phenotype analysis of transfected cells confirmed that single-factor ETV2 transfection successfully reprogrammed dermal fibroblasts into functional EPCs. Our results showed that ETV2 mRNA combined with hypoxia can give rise to functional EPCs. The cells exhibited functional phenotypes similar to endothelial cells derived from umbilical cord vein; they expressed CD31 and VEGFR2, and formed capillary-like structures in vitro. Moreover, these EPCs could significantly improve hindlimb ischemia in mouse models. Although the direct conversion efficacy was low (3.12 +/- 0.98%), altogether our study demonstrates that functional EPCs can be produced from fibroblasts and can be used in clinical applications. PMID- 27778230 TI - An iron-deficient diet during development induces oxidative stress in relation to age and gender in Wistar rats. AB - Iron is a trace element and a structural part of antioxidant enzymes, and its requirements vary according to age and gender. We hypothesized that iron deficiency (ID) leads to an increase in free radicals which mainly affect the brain, and the severity of damage would therefore be dependent on age and gender. Two groups of Wistar rats were evaluated evolutionarily: 100 rats (50 males; 50 females) with ID diet and 100 rats (50 males; 50 females) with standard diet. Both groups were offspring from mothers who were previously under the same dietary intervention. The ages studied roughly correspond to stages of human development: birth (0 postnatal day "PND" in rats), childhood (21 PND), early adolescence (42 PND), late adolescence (56 PND), and adulthood (70 PND). The following biomarkers in the brain, blood, and liver were analyzed: lipid peroxidation products (LPO), protein carbonyl content and activity of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. It was demonstrated that ID subjects are born with high levels of LPO in the brain and low antioxidant activity, the damage being more severe in males. After birth, antioxidant defense focuses on the central level (brain) in ID females and on the peripheral level (blood and liver) in ID males. In two critical stages of development, birth and late adolescence, antioxidant protection is insufficient to counteract oxidative damage in ID subjects. Moreover, we observed that the variability of results in the literature on oxidative stress and ID comes from gender and age of the subjects under study. With this, we can establish patterns and exact moments to carry out studies or treatments. PMID- 27778231 TI - Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia. AB - Response to dexamethasone (DEXA), as a hallmark drug in the treatment of childhood acute lymphoblastic leukemia (ALL), is one of the pivotal prognostic factors in the prediction of outcome in ALL. Identification of predictive markers of chemoresistance is beneficial to selecting of the best therapeutic protocol with the lowest effect adverse. Hence, we aimed to find drug targets using the 2DE/MS proteomics study of a DEXA-resistant cell line (REH) as a model for poor DEXA responding patients before and after drug treatment. Using the proteomic methods, three differentially expressed proteins were detected, including voltage dependent anion channel 1 (VDAC1), sorting Nexin 3 (SNX3), and prefoldin subunit 6 (PFDN6). We observed low expression of three proteins after DEXA treatment in REH cells. We subsequently verified low expression of resulted proteins at the mRNA level using the quantitative PCR method. These proteins are promising proteins because of their important roles in drug resistance and regulation of apoptosis (VDAC1), protein trafficking (SNX3), and protein folding (PFDN6). Additionally, mRNA expression level of these proteins was assessed in 17 bone marrow samples from children with newly diagnosed ALL and 7 non-cancerous samples as controls. The results indicated that independent of the molecular subtypes of leukemia, mRNA expression of VDAC1, SNX3, and PFDN6 decreased in ALL samples compared with non-cancerous samples particularly in VDAC1 (p < 0.001). Additionally, mRNA expression of three proteins was also declined in high-risk samples compared with standard risk cases. These results demonstrated diagnostic and prognostic value of these proteins in childhood ALL. Furthermore, investigation of protein-protein interaction using STRING database indicated that these proteins involved in the signaling pathway of NR3C1 as dexamethasone target. In conclusion, our proteomic study in DEXA resistant leukemic cells revealed VDAC1, SNX3, and PFDN6 are promising proteins that might serve as potential biomarkers of prognosis and chemotherapy in childhood ALL. PMID- 27778234 TI - Erratum to: miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma. PMID- 27778232 TI - A Computational Systems Biology Approach for Identifying Candidate Drugs for Repositioning for Cardiovascular Disease. AB - We report an in silico method to screen for receptors or pathways that could be targeted to elicit beneficial transcriptional changes in a cellular model of a disease of interest. In our method, we integrate: (1) a dataset of transcriptome responses of a cell line to a panel of drugs; (2) two sets of genes for the disease; and (3) mappings between drugs and the receptors or pathways that they target. We carried out a gene set enrichment analysis (GSEA) test for each of the two gene sets against a list of genes ordered by fold-change in response to a drug in a relevant cell line (HL60), with the overall score for a drug being the difference of the two enrichment scores. Next, we applied GSEA for drug targets based on drugs that have been ranked by their differential enrichment scores. The method ranks drugs by the degree of anti-correlation of their gene-level transcriptional effects on the cell line with the genes in the disease gene sets. We applied the method to data from (1) CMap 2.0; (2) gene sets from two transcriptome profiling studies of atherosclerosis; and (3) a combined dataset of drug/target information. Our analysis recapitulated known targets related to CVD (e.g., PPARgamma; HMG-CoA reductase, HDACs) and novel targets (e.g., amine oxidase A, delta-opioid receptor). We conclude that combining disease-associated gene sets, drug-transcriptome-responses datasets and drug-target annotations can potentially be useful as a screening tool for diseases that lack an accepted cellular model for in vitro screening. PMID- 27778235 TI - The long non-coding RNA maternally expressed gene 3 activates p53 and is downregulated in esophageal squamous cell cancer. AB - Esophageal squamous cell cancer (ESCC) is an aggressive malignancy with poor survival. Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression; hence, lncRNAs are also involved in the development and progression of ESCC. In this study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to investigate expression of lncRNA, maternally expressed gene 3 (MEG3) in ESCC. Ectopic expression of MEG3 was performed in ESCC cell lines. Proliferation and apoptosis of ESCC cell lines were analyzed after ectopic expression of MEG3. We found MEG3 was significantly downregulated in ESCC tissues compared with normal tissues by qRT-PCR. Low expression of MEG3 was correlated with lymph node metastasis and advanced TNM stages of ESCC patients and indicated shorter survival (HR = 0.471, 95 % CI 0.234-0.950, P = 0.035), which was confirmed by The Cancer Genome Atlas (TCGA) esophageal cancer dataset. DNA-demethylating agent (5-aza-2-deoxy-cytidine (5-aza-CdR)) treatment significantly increased MEG3 expression level in ESCC cells, and TCGA esophageal cancer dataset also showed that DNA methylation of MEG3 predicted survival. Ectopic expression of MEG3 in ESCC cells inhibited cell proliferation, promoted apoptosis, and suppressed metastasis. Further investigation showed enforced expression of MEG3 activated p53 and its target genes by downregulation of mouse double minute 2 homolog (MDM2). Overall, our study indicated that MEG3 expression loss is common in ESCC and MEG3 could activate p53 and predict prognosis in ESCC. PMID- 27778233 TI - Schools and Disasters: Safety and Mental Health Assessment and Interventions for Children. AB - This article draws on experiences and lessons from global disasters and utilizes the United Nations Comprehensive School Safety Framework to highlight the necessary role of safe schools in protecting children, as well as adult staff, from the immediate threats and long-term implications of disasters. Specifically, we focus on three well-established pillars of school safety: Pillar I: Safe Learning Facilities; Pillar II: Disaster Management; and Pillar III: Risk Reduction and Resilience Education. In addition, we propose a potential fourth pillar, which underscores the function of schools in postdisaster mental health assessment and intervention for children. We argue that schools offer a central location and trusted institutional space for mental health assessment and intervention after disasters. We also examine the important linkages between schools, child mental health, and household and family recovery. We conclude with recommendations for filling gaps in research and practice related to ensuring the safety of schools and the associated health and well-being of children in the face of future disasters. PMID- 27778236 TI - In Reply: "The Evolution of Recommended Naloxone Dosing for Opioid Overdose by Medical Specialty". PMID- 27778237 TI - In Response to: "The Evolution of Recommended Naloxone Dosing for Opioid Overdose by Medical Specialty". PMID- 27778238 TI - A livelihood in a risky environment: Farmers' preferences for irrigation with wastewater in Hyderabad, India. AB - Most cities in developing countries fail to treat their wastewater comprehensively. Consequently, farmers downstream use poor-quality water for irrigation. This practice implies risks for farmers, consumers and the environment. Conversely, this water supply supports the livelihood of these farmers and other stakeholders along the value chains. Linking safer options for wastewater management with irrigation could therefore be a win-win solution: removing the risks for society and maintaining the benefits for farmers. However, in developing countries, the high investment costs for the required treatment are problematic and the willingness of farmers to pay for the water (cost recovery) is often questionable. Using a choice experiment, this paper gives insight into farmers' preferences for wastewater use scenarios, quantifying their willingness to pay. The case study is Hyderabad, India. Farmers there prefer water treatment and are prepared to pay a surplus for this. Considering the cost-recovery challenge, this information could be valuable for planning small on site wastewater treatment systems. PMID- 27778239 TI - Three-dimensional conformal versus intensity modulated radiotherapy in breast cancer treatment: is necessary a medical reversal? AB - OBJECTIVES: Aim of the present study is to compare three-dimensional conformal RT (3D-CRT) and 4-fields intensity modulated radiation therapy (4f-IMRT) treatment plans, in terms of target dose coverage, integral dose and dose to Organs at risk (OARs) in early breast cancer (BC). METHODS: Twenty consecutive BC patients, after lumpectomy, were selected for the present analysis. A total dose of 50 Gy and a simultaneous dose of 60 Gy in 25 fractions was prescribed to Planning Target Volume of the whole breast (PTVbreast) and of the surgical bed, respectively. For each patient, a 3D-CRT plan and a sliding-window 4f-IMRT plan were generated. Conformity and homogeneity indexes (CI, HI) and various organ specific VxGy values were analyzed for PTVs, OARs and normal tissue (NT), respectively. RESULTS: In terms of HI, 4f-IMRT was superior to 3D-CRT for the PTVbreast (p < 0.0001), and a significant difference for CI was observed in favor of 4f-IMRT (p < 0.0001).In terms of dose to OARs, a superiority of 4f-IMRT was shown. For NT, all parameters are in favor of IMRT, except the V 5Gy for which the difference was not statistically significant. The average NT-Dmean was 2.7 +/ 0.7 for 3D-CRT and 1.8 +/- 0.5 for 4f-IMRT (p < 0.0001). CONCLUSIONS: 4f-IMRT technique significantly reduced the dose to OARs and NT, with a better target coverage compared to 3D-CRT. PMID- 27778240 TI - Economic Evaluations of Pharmaceuticals Granted a Marketing Authorisation Without the Results of Randomised Trials: A Systematic Review and Taxonomy. AB - BACKGROUND: Pharmaceuticals are usually granted a marketing authorisation on the basis of randomised controlled trials (RCTs). Occasionally the efficacy of a treatment is assessed without a randomised comparator group (either active or placebo). OBJECTIVE: To identify and develop a taxonomic account of economic modelling approaches for pharmaceuticals licensed without RCT data. METHODS: We searched PubMed, the websites of UK health technology assessment bodies and the International Society for Pharmacoeconomics and Outcomes Research Scientific Presentations Database for assessments of treatments granted a marketing authorisation by the US Food and Drug Administration or European Medicines Agency from January 1999 to May 2014 without RCT data (74 indications). The outcome of interest was the approach to modelling efficacy data. RESULTS: Fifty-one unique models were identified in 29 peer-reviewed articles, 30 health technology appraisals, and 15 International Society for Pharmacoeconomics and Outcomes Research abstracts concerning 30 indications (44 indications had not been modelled). We noted the high rate of non-submission to health technology assessment agencies (28/98). The majority of models (43/51) were based on 'historical controls'-comparisons to previous meta-analysis or pooling of trials (5), individual trials (16), registries/case series (15), or expert opinion (7). Other approaches used the patient as their own control, performed threshold analysis, assumed time on treatment was added to overall survival, or performed cost-minimisation analysis. CONCLUSIONS: There is considerable variation in the quality and approach of models constructed for drugs granted a marketing authorisation without a RCT. The most common approach is of a naive comparison to historical data (using other trials/registry data as a control group), which has considerable scope for bias. PMID- 27778241 TI - Monitoring Toxic Ionic Liquids in Zebrafish (Danio rerio) with Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI). AB - Ambient mass spectrometry imaging has become an increasingly powerful technique for the direct analysis of biological tissues in the open environment with minimal sample preparation and fast analysis times. In this study, we introduce desorption electrospray ionization mass spectrometry imaging (DESI-MSI) as a novel, rapid, and sensitive approach to localize the accumulation of a mildly toxic ionic liquid (IL), AMMOENG 130 in zebrafish (Danio rerio). The work demonstrates that DESI-MSI has the potential to rapidly monitor the accumulation of IL pollutants in aquatic organisms. AMMOENG 130 is a quaternary ammonium-based IL reported to be broadly used as a surfactant in commercialized detergents. It is known to exhibit acute toxicity to zebrafish causing extensive damage to gill secondary lamellae and increasing membrane permeability. Zebrafish were exposed to the IL in a static 96-h exposure study in concentrations near the LC50 of 1.25, 2.5, and 5.0 mg/L. DESI-MS analysis of zebrafish gills demonstrated the appearance of a dealkylated AMMOENG 130 metabolite in the lowest concentration of exposure identified by a high resolution hybrid LTQ-Orbitrap mass spectrometer as the trimethylstearylammonium ion, [C21H46N]+. With DESI-MSI, the accumulation of AMMOENG 130 and its dealkylated metabolite in zebrafish tissue was found in the nervous and respiratory systems. AMMOENG 130 and the metabolite were capable of penetrating the blood brain barrier of the fish with significant accumulation in the brain. Hence, we report for the first time the simultaneous characterization, distribution, and metabolism of a toxic IL in whole body zebrafish analyzed by DESI-MSI. This ambient mass spectrometry imaging technique shows great promise for the direct analysis of biological tissues to qualitatively monitor foreign, toxic, and persistent compounds in aquatic organisms from the environment. Graphical Abstract ?. PMID- 27778242 TI - Surgical margins for duodenopancreatectomy. AB - Microscopic residual tumor (R1) affects prognosis of resected pancreatic head cancer patients. Surgeon's ability, caseload and accuracy of pathological staging affect the rate of R1 resections. The goal of this study was to verify if a standardized histopathological workup of the specimen affects the rate of microscopic residual tumor after PD for cancer. Two groups of specimens were managed with (Group 1, Standardized Group, SG) or without (Group 2, Non Standardized Group, NSG) a standardized histopathological workup reported by the Royal College of Pathologists. Group 1 included 50 cases of PD for periampullary cancer treated between October 2010 and July 2012. Group 2 included 50 cases of PD for periampullary cancer treated between September 2005 and September 2010. The primary endpoint of the study was to verify the differences in terms of R1 rate in the two groups. Correlation between presence/absence of microscopic residual tumor status and local recurrence was also evaluated. The cohort of 100 patients consisted of 66 pancreatic ductal adenocarcinoma (PDAC) (SG: 35; NSG: 31), 15 distal common bile duct cancer (SG: 9; NSG: 6) and 19 cancer of the ampulla of Vater (SG: 6; NSG: 13). The rate of R1 resections resulted higher in the SG (66% vs 10%, p < 0.05). The rate of local recurrence did not differ in the two groups (NSG 23.4%, SG 27.6%). No relationships were found between R1 status and development of local recurrence in both groups. Local recurrence occurred in 20% of R1-NSG and in 34.3% of R1-SG. Our study showed that the standardized method determines a significant increase of R1 resection if compared with other non-standardized methods. This difference is due to the different definition of minimum clearance (0-mm- vs 1-mm rule). Even if not significantly, the standardized method seems to better discriminate the patients in terms of local recurrence risk after R1 vs R0 in SG (34 vs 11%) in comparison with R1 vs R0 in NSG (20 vs 27%). PMID- 27778243 TI - Activation of the nuclear factor E2-related factor 2/anitioxidant response element alleviates the nitroglycerin-induced hyperalgesia in rats. AB - BACKGROUND: Antioxidants have been proven to weaken hyperalgesia in neuropathic pain. Endogenous antioxidant defense system may have a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) pathway in regulating the activation of the trigeminovascular system (TGVS) and hypersensitivity in nitroglycerin (NTG)-induced hyperalgesia rats. METHODS: The expression levels of Nrf2, HO, HO1, and NQO1 in the trigeminal nucleus caudalis (TNC) were detected by western blot. Immunofluorescence was used to demonstrate the cell-specific localization of Nrf2 in TNC. Sulforaphane, a Nrf2 activator, was administered to NTG-induced rats. Then, the number of c-Fos- and nNOS immunoreactive neurons in TNC was evaluated using immunofluorescence, and c-Fos and nNOS protein levels were quantified using western blot. Von Frey hair testing was used to evaluate the tactile thresholds of rats at different time points in different groups. RESULTS: Total cellular and nuclear levels of the proteins Nrf2, HO1, and NQO1 were elevated in TNC after NTG injection, and Nrf2 was found to be located in the nucleus and cytoplasm of the neurons. Sulforaphane pretreatment significantly increased the nuclear Nrf2, HO1, and NQO1 levels in TNC. In addition, sulforaphane exposure effectively inhibited the expression of nNOS and c-Fos, reduced the number of nNOS and c-Fos immunoreactive neurons in TNC, and attenuated the tactile thresholds induced by NTG injection. CONCLUSION: Oxidative stress was involved in nitroglycerin-induced hyperalgesia. Activation of the Nrf2/ARE pathway inhibited the activation of TGVS and prevented the induction of hyperalgesia. Sulforaphane might therefore be an effective agent for hyperalgesia. Further studies are needed to discover the underlying mechanisms of the process. PMID- 27778245 TI - Unrecognized Interstitial Lung Disease as a Result of Chronic Nitrofurantoin Use. AB - Drug-induced interstitial lung disease is a rare condition attributed to several medications, including antimicrobial agents such as amphotericin B, anti inflammatory agents such as methotrexate, biologic agents such as bevacizumab, and cardiovascular agents and chemotherapeutic agents. We describe the case of a 73-year-old female who developed interstitial lung disease following chronic use of nitrofurantoin for a urinary tract infection (UTI). The patient was taking nitrofurantoin 100 mg capsules twice daily for approximately 3 years. She presented to the hospital with complaints of a persistent dry cough that started 2 years previously. Her chest radiograph revealed bilateral reticular opacities and some atelectasis. Computed tomography of the chest demonstrated development of subpleural reticular opacities with minimal honeycombing. The patient had a severe restrictive defect on her pulmonary function tests, with a significant reduction in her carbon monoxide diffusion capacity. Multiple infectious disease and autoimmune tests were negative. Utilizing the algorithm of Naranjo (score of 9), it was determined that chronic use of nitrofurantoin was the definite cause of the patient's interstitial lung disease. Nitrofurantoin was discontinued and she was treated with oxygen and started on an oral steroid, both of which were continued permanently once discharged. Upon discharge, the patient was maintained on 5 L of oxygen at rest and 10 L of oxygen when ambulating. Unfortunately, her lung disease ultimately resulted in her demise several months after her diagnosis. This case report illustrates the importance of rapid recognition of drug-induced lung injuries and discontinuation of the offending agent. PMID- 27778244 TI - Thalamo-cortical network activity between migraine attacks: Insights from MRI based microstructural and functional resting-state network correlation analysis. AB - BACKGROUND: Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks. METHODS: Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z scores. RESULTS: In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally. CONCLUSIONS: The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology. PMID- 27778247 TI - Effectiveness of Integrating Role Play with Didactic Lecture, Video Review, and Group Discussion in Enhancing Interview Skills of New Psychiatric Nurses. PMID- 27778248 TI - Analysis of the dynamics of temporal relationships of neural activities using optical imaging data. AB - The temporal relationship between the activities of neurons in biological neural systems is critically important for the correct delivery of the functionality of these systems. Fine measurement of temporal relationships of neural activities using micro-electrodes is possible but this approach is very limited due to spatial constraints in the context of physiologically valid settings of neural systems. Optical imaging with voltage-sensitive dyes or calcium dyes can provide data about the activity patterns of many neurons in physiologically valid settings, but the data is relatively noisy. Here we propose a numerical methodology for the analysis of optical neuro-imaging data that allows robust analysis of the dynamics of temporal relationships of neural activities. We provide a detailed description of the methodology and we also assess its robustness. The proposed methodology is applied to analyse the relationship between the activity patterns of PY neurons in the crab stomatogastric ganglion. We show for the first time in a physiologically valid setting that as expected on the basis of earlier results of single neuron recordings exposure to dopamine de synchronises the activity of these neurons. We also discuss the wider implications and application of the proposed methodology. PMID- 27778246 TI - Unravelling the Link Between Prenatal Stress, Dopamine and Substance Use Disorder. AB - Substance use disorder (SUD) refers to the detrimental use of psychoactive substances and it is related to a cluster of behavioural, cognitive and physiological dysfunctions indicating that the individual continues using the substance despite significant substance-related problems. Although it is one of the most prevalent neuropsychiatric diseases affecting society worldwide, the mechanism underlying the vulnerability of certain individuals is not well understood yet. It is now widely accepted that, in addition to genetic factors, environmental adversities during critical stages of development of an organism could also be considered as risk factors that contribute to SUD. It has been suggested that prenatal stress (PS) could play an important role in the causal mechanisms of SUD, since it was shown that PS leads individuals to poor stress management and behavioural problems, both of which increase the risk of SUD. It is widely accepted that gestational stress exposure in rats interferes with the correct progeny development. In particular, research in this field points out that the development of the mesocorticolimbic dopaminergic (DA) system is sensitive to disruption by exposure to early stressors. Interestingly, PS induces behavioural abnormalities that are similar to those observed in individuals that present SUD. Since dysfunction of mesocorticolimbic DA pathway has been reported in both prenatally stressed and SUD individuals, in this review we will summarise the current knowledge supporting that PS may serve as a strong candidate to explain the vulnerability of certain individuals to develop SUD following repeated drug exposure. We will also propose a mechanistic hypothesis to explain PS-induced changes on mesocorticolimbic DA system. PMID- 27778249 TI - Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema. AB - Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB 9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy. PMID- 27778250 TI - Metabolomic Biomarkers in the Progression to Type 1 Diabetes. AB - Metabolomics is the snapshot of all detectable metabolites and lipids in biological materials and has potential in reflecting genetic and environmental factors contributing to the development of complex diseases, such as type 1 diabetes. The progression to seroconversion to development of type 1 diabetes has been studied using this technique, although in relatively small cohorts and at limited time points. Overall, three observations have been consistently reported; phospholipids at birth are lower in children developing type 1 diabetes early in childhood, methionine levels are lower in children at seroconversion, and triglycerides are increased at seroconversion and associated to microbiome diversity, indicating an association between the metabolome and microbiome in type 1 diabetes progression. PMID- 27778252 TI - Successful Treatment of an Unusual Case of FPLD2: The Role of Roux-en-Y Gastric Bypass-Case Report and Literature Review. AB - Familial partial lipodystrophy type 2 (FPLD2) is a rare disorder associated with LMNA gene mutations. It is usually marked by loss of subcutaneous fat on the limbs and trunk and severe insulin resistance. Scattered reports have indicated that Roux-en-Y bypass helps to control the diabetes mellitus in these patients. We present here a very unusual patient with FPLD2 who had life-threatening retroperitoneal and renal fat accumulation accompanied by bilateral renal cancers. Following cryotherapy of one renal cancer and a contralateral nephrectomy with debulking of the retroperitoneal fat, Roux-en-Y gastric bypass (RYGB) has successfully controlled the disease for 3 years. The clinical presentations and causes of FPLD are reviewed and the role of RYGB is discussed. PMID- 27778251 TI - Biomarkers of Diabetic Retinopathy. AB - Diabetic retinopathy (DR), a leading cause of acquired vision loss, is a microvascular complication of diabetes. While traditional risk factors for diabetic retinopathy including longer duration of diabetes, poor blood glucose control, and dyslipidemia are helpful in stratifying patient's risk for developing retinopathy, many patients without these traditional risk factors develop DR; furthermore, there are persons with long diabetes duration who do not develop DR. Thus, identifying biomarkers to predict DR or to determine therapeutic response is important. A biomarker can be defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Incorporation of biomarkers into risk stratification of persons with diabetes would likely aid in early diagnosis and guide treatment methods for those with DR or with worsening DR. Systemic biomarkers of DR include serum measures including genomic, proteomic, and metabolomics biomarkers. Ocular biomarkers including tears and vitreous and retinal vascular structural changes have also been studied extensively to prognosticate the risk of DR development. The current studies on biomarkers are limited by the need for larger sample sizes, cross-validation in different populations and ethnic groups, and time efficient and cost-effective analytical techniques. Future research is important to explore novel DR biomarkers that are non-invasive, rapid, economical, and accurate to help reduce the incidence and progression of DR in people with diabetes. PMID- 27778253 TI - Emergency Versus Delayed Cholecystectomy After Percutaneous Transhepatic Gallbladder Drainage in Grade II Acute Cholecystitis Patients. AB - INTRODUCTION: In grade II acute cholecystitis patients presenting more than 72 h after onset of symptoms, we prospectively compared treatment with emergency (ELC) to delayed laparoscopic cholecystectomy performed 6 weeks after percutaneous transhepatic gallbladder drainage (PTGBD). METHODS: Four hundred ninety-five patients with acute cholecystitis were assessed for eligibility; 345 were excluded or declined to participate. One hundred fifty patients were treated after consent with either ELC or PTGBD. RESULTS: Both PTGBD and ELC were able to resolve quickly cholecystitis sepsis. ELC patients had a significantly higher conversion rate (24 vs. 2.7 %, P < 0.001), longer mean operative time (87.8 +/- 33.06 vs. 38.09 +/- 8.23 min, P < 0.001), higher intraoperative blood loss (41.73 +/- 51.09 vs. 26.33 +/- 23.86, P = 0.008), and longer duration of postoperative hospital stay (51.71 +/- 49.39 vs. 10.76 +/- 5.75 h, P < 0.001) than those in the PTGBD group. Postoperative complications were significantly more frequent in the ELC group (26.7 vs. 2.7 %, P < 0.001) with a significant increase in incidence (10.7 %) of bile leak (P = 0.006) compared to those in the PTGBD group. CONCLUSION(S): PTGBD and ELC are highly efficient in resolving cholecystitis sepsis. Delayed cholecystectomy after PTGBD produces better outcomes with a lower conversion rate, fewer procedure-related complications, and a shorter hospital stay than emergency cholecystectomy. PMID- 27778255 TI - Is Revision Surgery Justified for Symptomatic Pancreatico-enteric Anastomotic Stenosis in Long-term Survivors Following Pancreaticoduodenectomy for Malignancy? AB - BACKGROUND: Pancreatico-enteric anastomotic (PEA) stenosis is one of the late complications following pancreaticoduodenectomy (PD) and reported for benign diseases. Literature for PEA stenosis following PD for malignancy is very limited due to low survival. MATERIAL AND METHODS: Patients undergoing surgery for symptomatic, recurrent, obstructive pancreatitis due to PEA stenosis following PD for malignancy were retrospectively identified from the authors' prospective database between January 1997 and December 2014. RESULTS: Six patients with median age 56.5 years underwent revision surgery for PEA stenosis during this time period. At primary PD, all were node negative with T1/T2 disease. The primary PEA were pancreatico-jejunostomy (PJ) (n = 5) and pancreatico-gastrostomy (n = 1). Median time to develop symptoms was 62 months. At revision surgery, a Roux-en-Y longitudinal PJ (n = 5) and an end-to-side PJ (n = 1) were done. With a median follow-up of 36 months, pain relief was excellent (n = 5) to average (n = 1). CONCLUSION: With improving long-term survival in patients undergoing PD for malignancy more such patients will be identified in future. Patients with symptomatic PEA stenosis following PD for malignancy can be managed surgically, with excellent outcomes in centers of expertise in pancreatic surgery. PMID- 27778254 TI - Liver Transplantation After Transarterial Chemoembolization and Radiotherapy for Hepatocellular Carcinoma with Vascular Invasion. AB - PURPOSE: The study aims to analyze the oncologic outcomes of living donor liver transplantation (LDLT) after combined transarterial chemoembolization (TACE) and radiotherapy for hepatocellular carcinoma (HCC) with major vascular invasion. METHODS: We retrospectively reviewed 17 HCC patients with major vascular invasion who underwent LDLT after combined treatment modality between May 2007 and September 2014. The LDLT timing was determined by the surgeons depending on the disease status and liver function. The intrahepatic recurrence-free survival, disease-free survival (DFS), and overall survival (OS) rates were estimated from the date of the LDLT. RESULTS: The median follow-up period was 24.5 months (range, 6.4-66.0 months) after the LDLT. The interval between the combined treatment and the LDLT was a median of 5 months (range, 0.4-65.3 months). On the explanted liver, total necrosis was shown in five patients (29.4 %). The 1- and 3 year DFS rates were 70.6 and 57.8 %, respectively. The 1- and 3-year OS rates were 87.4 and 60.5 %, respectively. The major pattern of failure was distant metastasis (35.3 %), and intrahepatic recurrence occurred in three patients (17.6 %) who experienced distant metastasis. CONCLUSIONS: In the selected HCC patients with major vascular invasion, LDLT after combined TACE and radiotherapy showed acceptable oncologic outcomes. PMID- 27778256 TI - Comparative Study Between Trans-perineal Repair With or Without Limited Internal Sphincterotomy in the Treatment of Type I Anterior Rectocele: a Randomized Controlled Trial. AB - BACKGROUND AND AIM: Two types of rectocele exist; type I is characterized by relatively high resting anal pressures, whereas type II has lower resting anal pressures with associated pelvic organ prolapse. We compared trans-perineal repair (TPR) of rectocele with or without limited internal sphincterotomy (LIS) in the treatment of type I anterior rectocele. PATIENTS AND INTERVENTIONS: Consecutive patients with anterior rectocele were evaluated for inclusion. Sixty two female patients with type I anterior rectocele were randomized and equally allocated to receive TPR alone (group I) or TPR with LIS (group II). The primary outcome was the clinical improvement of constipation. Secondary outcomes were recurrence of rectocele, operative time, and postoperative complications including fecal incontinence (FI). RESULTS: Clinical improvement of constipation and patients' satisfaction were significantly higher in group II at 1 year of follow-up (93.3 versus 70 %). Constipation scores significantly decreased in both groups postoperatively with more reduction being observed in group II (11.1 +/- 2.1 in group I versus 8 +/- 1.97 in group II). Significant reduction in the resting anal pressure was noticed in group II. Recurrence was recorded in three (10 %) patients of group I and one patient of group II. No significant differences between the two groups regarding the operative time and hospital stay were noted. CONCLUSION: Adding LIS to TPR of type I rectocele achieved better clinical improvement than TPR alone. The only drawback of LIS was the development of a minor degree of FI, which was temporary in duration. PMID- 27778258 TI - Radiation Exposures Associated With Radial and Femoral Coronary Interventions. AB - OPINION STATEMENT: The volume of cardiac diagnostic procedures involving the use of ionizing radiation has increased rapidly in recent years, and the radiation exposure experienced by patients undergoing any medical imaging procedure has recently obtained a growing attention. Transradial (TR) access is being increasingly used worldwide for diagnostic coronary angiography (CA), and percutaneous coronary interventions, since it offers several benefits as compared to transfemoral (TF) access, such as by reducing hemostasis time and vascular complications, increased patient comfort, reduced hospital stay, and lower cost. In contrast, TR CA is thought to be associated with increased radiation exposure parameters compared with the traditional TF access. Although experienced operators may almost counterbalance this shortcoming, the increase in radiation exposure associated with TR approach seems not to be present in most clinical settings. PMID- 27778259 TI - How Do We Treat Complex Calcified Coronary Artery Disease? AB - OPINION STATEMENT: Despite significant advances in treatment of coronary artery disease and improvements in interventional devices and techniques, the subset of obstructive calcified coronary artery disease remains challenging to treat. Percutaneous treatment of these lesions results in increased rates of procedural complications, as well as a higher risk of stent underexpansion and malapposition. This is associated with higher rates of restenosis, target lesion revascularization (TLR), and major adverse cardiac events (MACE). Several interventional strategies and technologies have been developed to improve lesion preparation and successful stent implantation. This includes use of cutting and scoring balloons and atherectomy devices. Several intravascular imaging techniques have also shown to have value in the treatment of complex calcified coronary lesions. These advances have improved the treatment of patients with calcified coronary disease who are often difficult to treat and frequently excluded from large randomized trials. Thoughtful, and not routine, use of rotational atherectomy can be helpful in pre-treating severely calcified lesions to achieve successful stent delivery. Orbital atherectomy represents a newer advancement in the atherectomy approach that may be beneficial in the treatment of calcified coronary disease, but further trials are needed to support its routine use. PMID- 27778257 TI - Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience. AB - BACKGROUND: The purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to pancreatoduodenectomy (PD). METHODS: Consecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990-1999, 2000 2004, 2005-2009, 2010-2014) were evaluated and compared. RESULTS: The average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001). CONCLUSIONS: Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy. PMID- 27778260 TI - Acute cerebellar infarction complicated with multiple intracerebral hemorrhage treated by an integrated chinese and western medicine approach: A case report. PMID- 27778261 TI - Positive effects of Qing'e Pill () on trabecular microarchitecture and its mechanical properties in osteopenic ovariectomised mice. AB - OBJECTIVE: To investigate the impact of Qing'e Pill (, QEP) on the cancellous bone microstructure and its effect on the level of beta-catenin in a mouse model of postmenopausal osteoporosis. METHODS: Ninety-six 8-week-old specifific pathogen free C57BL/6 mice were randomly divided into 4 groups (24/group): sham, ovariectomised osteoporosis model, oestradiol-treated, and QEP-treated groups. Three months after surgery, the third lumbar vertebra and left femur of the animals were dissected and scanned using micro-computed tomography (micro-CT) to acquire three-dimensional (3D) parameters of their cancellous bone microstructure. The impact of ovariectomy, the effect of oestradiol and QEP intervention on cancellous bone microstructure, and the expression of beta catenin were evaluated. RESULTS: The oestradioland the QEP-treated groups exhibited a signifificant increase in the bone volume fraction, trabecular number, trabecular thicknebetas, bone surface to bone volume ratio (BS/BV), and beta-catenin expression compared with those of the model group (P <0.05). In contrast, the structure model index, trabecular separation, and BS/BV were signifificantly decreased compared with those of the ovariectomised osteoporosis model group (P <0.05). No differences were observed in the above parameters between animals of the QEP- and oestradiol-treated groups. CONCLUSIONS: The increased beta-catenin expression may be the mechanism underlying QEP's improvement of the cancellous bone microstructure in ovariectomised mice. Our fifindings provide a scientifific rationale for using QEP as a dietary supplement to prevent bone loss in postmenopausal women. PMID- 27778262 TI - How do precision medicine and system biology response to human body's complex adaptability? AB - In the field of life sciences, although system biology and "precision medicine" introduce some complex scientifific methods and techniques, it is still based on the "analysis-reconstruction" of reductionist theory as a whole. Adaptability of complex system increase system behaviour uncertainty as well as the difficulties of precise identifification and control. It also put systems biology research into trouble. To grasp the behaviour and characteristics of organism fundamentally, systems biology has to abandon the "analysis-reconstruction" concept. In accordance with the guidelines of complexity science, systems biology should build organism model from holistic level, just like the Chinese medicine did in dealing with human body and disease. When we study the living body from the holistic level, we will fifind the adaptability of complex system is not the obstacle that increases the diffificulty of problem solving. It is the "exceptional", "right-hand man" that helping us to deal with the complexity of life more effectively. PMID- 27778263 TI - Effects of electroacupuncture intervention on expression of cyclooxygenase 2 and microglia in spinal cord in rat model of neuropathic pain. AB - OBJECTIVE: To investigate the effect of electroacupuncture (EA) treatment on the expression of cyclooxygenase (COX) 2 and microglia in spinal cord by using rat model of neuropathic pain, and to probe into the relationship between COX 2 and microglia. METHODS: The rats were randomly divided into 6 groups, including normal control group, model group, sham group, EA 1 group (distant acupoints + local acupoints), EA 2 group (local acupoints), and EA 3 group (distant acupoints). Thermal withdrawal latencies were evaluated at 1 day preoperatively and 3, 5 and 7 days postoperatively. At 7 days postoperatively, the spinal COX 2 mRNA was detected by reverse-transcription polymerase chain reaction. Double immunofluorescent staining technology was applied to screen and verify the relationship between altered COX 2 and microglia. RESULTS: Compared with the model group, thermal withdrawal latencies increased after EA treatment (P<0.01). The expressions of COX 2 mRNA were up-regulated in spinal cord of rat on day 7 after surgery (P<0.05). Compared with the model group, EA stimulation (EA 1 and EA 2 groups) reversed the up-regulation of COX 2 mRNA expression (P<0.05). EA 1 and EA 2 groups might have better treatment effect compared with the EA 3 group. Fluorescent images displayed COX 2 and microglia expressed at common areas. CONCLUSIONS: EA was effective in analgesic and anti-inflammatory. EA has decreased the expression of spinal COX 2 mRNA in the trend of the therapeutic effect of "distant acupoints + local acupoints", and "local acupoints" intervention may be superior to that of "distant acupoints" intervention. Microglia may be related to the formation of COX 2. PMID- 27778264 TI - Long-term follow-up of Chinese herbal medicines combined with conventional treatment in patients with acute coronary syndrome after percutaneous coronary intervention: A multicenter randomized controlled trial. AB - OBJECTIVE: To evaluate the prognosis effect of Chinese herbal medicines (CHMs) for benefiting qi and activating blood circulation adjunctive to conventional treatment in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: A total of 702 patients with ACS who underwent PCI were enrolled and randomly assigned to receive conventional treatment plus CHMs for benefiting qi and activating blood circulation (treatment group, 351 cases) or conventional treatment alone (control group, 351 cases) for 6 months. Six months later, all patients received conventional treatment alone. Follow-ups were scheduled at 6th, 12th, 18th, 24th month after enrollment in April 2008, and the final follow-up visit was during September 2011 and November 2011. The primary endpoint was the composite of cardiac death, nonfatal myocardial infarction or revascularization (PCI or coronary artery bypass grafting); and the secondary endpoint was the composite of re-admission for ACS, congestive heart failure, nonfatal stroke or other thrombus events. RESULTS: A total of 621 (88.59%) patients completed 35.4+/-3.8 months follow-up, while 80 (11.41%) patients withdrew from the trial (41 in the treatment group and 39 in the control group). The incidence of primary endpoint was 5.7% (20 patients) in the treatment group versus 10.86% (38 patients) in the control group [relative risk (RR): 0.53; 95% confidence interval (CI): 0.30, 0.88; P=0.013; absolute risk reduction (ARR):-0.052, 95% CI: -0.06, 0.01]. The incidence of secondary endpoint was 5.98% (21 patients) in the treatment group versus 10.28% (36 patients) in control group (RR: 0.58, 95% CI: 0.33, 0.97, P=0.037; ARR: -0.043, 95% CI: 0.06, 0.01). Most of the primary and secondary endpoints were occurred in 18 months (84.50% in the treatment group versus 78.10% in the control group). CONCLUSION: CHMs for benefiting qi and activating blood circulation adjunctive to conventional treatment improved clinical outcomes for patients with ACS after PCI in long-term follow-up. PMID- 27778265 TI - Synchronous dynamic research on respiratory and intestinal microflora of chronic bronchitis rat model. AB - OBJECTIVES: To investigate the mechanism of the Chinese medicine theory that Fei (Lung) and Dachang (Large Intestine) are exteriorly and interiorly related via synchronous observation on the dynamic changes of the respiratory and intestinal microflora. METHODS: Forty specific pathogen free Sprague-Dawley rats were selected and randomly divided into blank (10 rats) and chronic bronchitis model groups (30 rats). The blank group rats were put into the smoke-free environment and the model group rats were put into the smoke environment in order to establish pulmonary disease (chronic bronchitis) model. Then the corresponding changes of the respiratory and intestinal microflflora of the model on 20th, 50th and 70th days were synchronously observed. RESULTS: The respiratory tract microflflora showed an increase in the total aerobic and Staphylococcus aureus and reduced anaerobic amount signifificantly on 20th day in the respiratory tract microflflora (P<0.05 or 0.01). On 50th day, total aerobic, total anaerobic amount and bififidobacterium signifificantly increased (P<0.05). On 70th day, Staphylococcus aureus reduced and lactobacillus increased signifificantly (P<0.01). The intestinal microflflora showed an increase in the total aerobic, Clostridium perfringens, enterobacter and enterococcus significantly increased on 20th day (P<0.05 or 0.01). Staphylococcus aureus on 50th day increased significantly (P<0.05). Total aerobic and enterococcus increased, total anaerobic and Clostridium perfringens reduced signifificantly on 70th day (P<0.05 or 0.01). CONCLUSION: The microecosystem of respiratory tract and intestine of rat model during the pathological process showed a dynamic disorder, indicating an interaction between the lung and large intestine which may be one of the connotations as they exteriorly and interiorly related. PMID- 27778266 TI - Therapeutic Role of Tangshenkang Granule () in Rat Model with Diabetic Nephropathy. AB - OBJECTIVE: To evaluate the renal protective effect of Tangshenkang Granule () in a rat model of diabetic nephropathy (DN). METHODS: Forty male Sprague-Dawley rats were randomly divided into control, DN, Tangshenkang and benazepril groups. DN model was established in the rats of DN, Tangshenkang and benazepril groups. Tangshenkang Granule solution and benazepril hydrochloride solution were intragastrically administered daily to the rats in the Tangshenkang and benazepril groups for 8 weeks, respectively. Urinary albumin and creatinine were detected. The albumin/creatinine (ACR) was calculated in addition to 24 h urinary protein (24-h UPr), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and creatinine clearance rate (Ccr). Right kidneys were harvested for pathological observation using periodic acid-silver methenamine Masson staining. The average glomerular diameter (DG), average glomerular (AG) and mesangial areas (AM) were measured. The thickness of glomerular basement membrane (TGBM) was detected using transmission electron microscope. RESULTS: Compared with rats in the control group, rats in the DN group showed significantly decreased body weight, increased hypertrophy index, 24-h urinary volume, 24-h UPr, ACR, Scr, BUN, Ccr, blood lipids as well as renal pathological indices including DG, AG, AM, AM/AG and TGBM (P <0.05). Compared with the DN group, the weights of rats in the Tangshenkang and benazepril groups were significantly increased, and the renal hypertrophy indices were significantly decreased (P <0.05). The 24-h urinary volumes, ACR, 24-h UPr, Scr, BUN, Ccr, LDL, DG, AG, AM and TGBM were obviously decreased (P <0.05). Compared with the benazepril group, the Tangshenkang group showed significantly decreased levels of ACR, 24-h UPr, AG and AM (P <0.05). CONCLUSIONS: Tangshenkang Granule decreased the urinary protein, attenuated the high glomerular filtration rate and improved lipid metabolism in DN rats, and prevented further injury induced by diabetic nephropathy. PMID- 27778268 TI - The influence of hydrous ferric oxide, earthworms, and a hypertolerant plant on arsenic and iron bioavailability, fate, and transport in soils. AB - Historic applications of lead arsenate pesticides and smelting activities have resulted in elevated concentrations of arsenic in Washington State soils. For example, old orchard topsoils in Washington have concentrations reaching upwards of 350 mg As/kg soil with an estimated 187,590 acres of arsenic contamination from pesticide application alone. Iron oxides have been indicated as a key factor in modulating the fate and transport of arsenic in the soil environment. We employed a factorial design to investigate the role of a specific iron oxide, hydrous ferric oxide (HFO), and terrestrial organisms on the mobility, bioavailability, and fate of arsenic and iron in locally collected soils. Earthworms in soils amended with both arsenic and HFO had 47.2 % lower arsenic tissue concentrations compared to those in soils only amended with arsenic. Similarly, arsenic leachate concentrations and plant tissue concentrations were lower when HFO was present, although this was with a reduced magnitude and was not consistently significant. A lack of significance of HFO in three of the linear models for leachate and plant bioavailability, however, indicates that the role of HFO in arsenic mobility, bioavailability, and fate is more complicated than can be explained by the simple addition or not of HFO. For example, our analyses showed that earthworms decreased pH and increased bioavailability for both arsenic and iron as demonstrated by increases in leachate and plant tissue concentrations. The mechanisms for this could include a biotransformation of earthworm-ingested arsenic combined with an earthworm-induced change in pH. We also found that arsenic amendments increased the mobility and bioavailability of iron, evidenced by increased iron concentrations in earthworms, plants, and leachate. A mechanistic explanation for this change in bioavailability is not readily apparent but does support a need for more work on bioavailability when mixtures are present. From these results, it is clear that a combination of biotic and abiotic factors influences metal/metalloid fate and transport in soils, with earthworms being one of the most important factors in our work. Study designs such as the factorial analysis can help to address the role each factor plays while efficiently generating new hypotheses and areas of inquiry; this approach can also bridge knowledge generated through reductionist and holistic approaches to complex environmental problems. PMID- 27778269 TI - Environmental quality benchmarks-the good, the bad, and the ugly. AB - Environmental quality benchmarks (EQBs) such as water or sediment quality guidelines comprise one line of evidence for assessing the potential harm from chemicals and other stressors (physical, biological). They are useful but not perfect tools, should not always be used, and should never be used alone for final decision-making. The "good" can be designed to be situation-specific and can provide understandable scientific input to decision-makers. The "bad" includes perception that they are absolutes (i.e., definitive binary decision points), no or limited adaptability based on good science or common sense, and protection of individual organisms not populations of organisms. The "ugly" includes benchmarks based on simplistic indices (information loss, misleading results), misuse of biomarkers, and misapplication of EQBs. Other factors to be considered include the following: appropriately deriving EQBs, uncertainty, the laboratory is not the field, contaminant uptake and cause-effect, and specifics regarding sediment quality benchmarks (i.e., their specific "good," "bad," and "ugly" components). EQBs are not always needed or useful. PMID- 27778267 TI - Arsenic, cadmium, lead and mercury levels in blood of Finnish adults and their relation to diet, lifestyle habits and sociodemographic variables. AB - The Northern Finland Birth Cohort program (NFBC) is the epidemiological and longitudinal prospective general population research program, which was established to promote health and wellbeing of the population in northern Finland. The aim of present study, as a part of the NFBC program, was to analyze the blood levels of arsenic (B-As), cadmium (B-Cd), lead (B-Pb), total mercury (B Hg) and selenium (B-Se); to compare these levels with threshold limits; to study sociodemographic factors; and to correlate these levels with calcium and haemoglobin. The study was comprised of 249 NFBC subjects, of which 123 were female and 126 were male (ages 31.1 +/- 0.3 and 31.1 +/- 0.4, respectively). All participants were asked to complete a questionnaire regarding diet and living habits. The geometric means (+/- SD) of B-As were 0.49 +/- 2.80 MUg/l and 0.44 +/ 2.72 MUg/l; B-Cd were 0.18 +/- 4.02 MUg/l and 0.12 +/- 3.21 MUg/l; B-Pb were 17.0 +/- 1.8 MUg/l and 9.06 +/- 2.20 MUg/l; B-Hg were 2.18 +/- 2.02 MUg/l and 1.85 +/- 1.78 MUg/l; and B-Se were 106.0 +/- 1.3 and 94.3 +/- 1.3 MUg/l in males and females, respectively. Among the subjects in the present analysis, 23 % of males and 17.1 % of females had B-As levels above the ATSDR normal human levels of B-As in unexposed individuals (1.0 MUg/l). The B-Pb geometric mean (12.44 MUg/l) was approximately one eighth the CDC toxicological cut-off point of 100 MUg/l. Twenty-one individuals (8.4 %) exceeded a B-Hg level of 5.8 MUg/l. Fifty eight females (47 %) had a B-Hg higher than 2.0 MUg/l, the German Federal Environmental Agency cut-off point for women (18-69 years) who consume fish at least three times/month; therefore, their babies could be at risk of adverse effects during development. PMID- 27778270 TI - Copper phytoextraction by Salvinia cucullata: biochemical and morphological study. AB - The present study investigated the effect of copper on photosynthesis, antioxidant potential, and anatomical response of aquatic fern, Salvinia cucullata, with a view to ascertain its phytoremediation potential. Plants were exposed in hydroponics for 21 days to different Cu concentrations (10, 15, 20, and 30 mg/L). Significant declines in chlorophyll, carotenoids, and soluble proteins, as a function of Cu proportion were observed. Lipid peroxidation was also evident, which implied reactive oxygen species (ROS) generation. However, both root and leaf tissues responded remarkably to the ROS produced, by inducing superoxide dismutase (1.6-6.5 times), catalase (1.5-5.4 times), guaicol peroxidase (1.5-7.2 times), and ascorbyl peroxidase (1.3-4.7 times) over the control. The plant showed best phytoremedial activity within Cu range of 10-15 mg/L, with maximum accumulation of 2956 +/- 82.6 MUg/g dw., at 15 mg Cu/L and showed efficient root to shoot translocation (translocation factor, TF > 1) at this range, which is the stipulated minimum requirement to be a hyperaccumulator. The capacity of metal extraction from environment to leaf (extraction coefficient, EC) was also high (EC = 73-197). However, at higher doses (20-30 mg/L), the plant resorted to an exclusion strategy, whereby, more metal accumulation was observed in root than in leaf. The plant conferred suitable remediation attributes by showing minimal root and leaf anatomical damages along with high Ca peaks in both the tissues, and rapid leaf stomatal closure, all of which probably helped in the Cu induced stress mitigation. Due to its widespread availability, fast growth, ability to grow in myriads of polluted environment, and having hardy physiology, this plant can be suggested for use as a suitable Cu phytoremediator. PMID- 27778271 TI - Preparation, characterization, and application of ZnO@SiO2 core-shell structured catalyst for photocatalytic degradation of phenol. AB - In the current study, ZnO@SiO2 core-shell structured catalyst was synthesized for photocatalytic degradation of phenol from aqueous samples. The synthesized catalyst was characterized by Fourier transform infrared spectra, X-ray diffraction, energy-dispersive X-ray spectroscopy, UV-Vis-NIR diffuse reflectance spectroscopy, transmission electron microscopy, BET surface area, zeta potential, and field emission scanning electron microscopy. The effect of catalyst loading, initial phenol concentration, pH, UV light intensity and weight ratio of ZnO/(SiO2 + ZnO) were studied towards photocatalytic degradation of phenol. Moreover, photocatalytic activities of bare ZnO and ZnO@SiO2 were compared. The results advocated that ZnO@SiO2 catalyst showed high photocatalytic performance for degradation of phenol (96 % after 120 min) at an initial pH of 5.9, catalyst loading of 0.5 g/L and initial phenol concentration of 25 mg/L. Increase in the weight ratio of ZnO/(SiO2 + ZnO) from 0.2 to 0.33 significantly enhanced the photodegradation of phenol from 84 to 94 %. It was also found that photocatalytic activity of ZnO@SiO2 was higher than bare ZnO nanoparticles. Graphical abstract ?. PMID- 27778272 TI - Urinary polyaromatic hydrocarbons are associated with adult emphysema, chronic bronchitis, asthma, and infections: US NHANES, 2011-2012. AB - Links between environmental chemicals and human health have emerged over the last few decades, but the effects from polyaromatic hydrocarbons were less studied, compared to other commonly known environmental chemicals such as heavy metals, phthalates, arsenic, phenols, pesticides, etc. Therefore, the aim of the study was to examine the relationships of urinary polyaromatic hydrocarbons and adult respiratory health conditions using a large human sample in a national and population-based setting in recent years. Data were retrieved from United States National Health and Nutrition Examination Surveys, 2011-2012 including demographics, self-reported health conditions, and urinary polyaromatic hydrocarbons. Statistical analyses including chi-square test, t test, and survey weighted logistic regression modeling were performed. Of 5560 American adults aged 20-80, urinary 2-hydroxyfluorene and 3-hydroxyfluorene were positively associated with emphysema (OR, 1.60, 95 % CI 1.26 to 2.03, P = 0.001 and OR, 1.42, 95 % CI 1.15 to 1.77, P = 0.003, respectively) and chronic bronchitis (OR, 1.42, 95 % CI 1.04 to 1.94, P = 0.031 and OR, 1.40, 95 % CI 1.03 to 1.91, P = 0.036, respectively), while 2-hydroxynaphthalene (2-naphthol) was likely to be borderline associated with emphysema and chronic bronchitis. Conversely, urinary 1-hydroxyphenanthrene, 3-hydroxyphenanthrene, 1-hydroxypyrene, and 4 hydroxyphenanthrene were inversely associated with asthma and infections. Urinary polyaromatic hydrocarbons are associated with adult respiratory health conditions, although the causality cannot be established. For future research, studies using large human sample across regions to longitudinally monitor would be suggested. For practice and policy-making, regulation on minimizing polyaromatic hydrocarbons exposure to protect respiratory health might need to be considered in future health and environmental policies and intervention programs. PMID- 27778273 TI - Investigations into Salmonella contamination in feed production chain in Karst rural areas of China. AB - In order to understand the status of Salmonella contamination of feed production chain in Karst rural areas, southwest of China, a total of 1077 feed samples including animal feed materials and feed products were randomly collected from different sectors of feed chain covering feed mills, farms, and feed sales in nine regions of Karst rural areas between 2009 and 2012, to conduct Salmonella test. The different positive rates with Salmonella contamination were detected, the highest was 4.7 % in 2009, the lowest was 0.66 % in 2011, while 4.3 % in 2010, 2.8 % in 2012, respectively. Twelve types of feed including concentrate, complete, self-made, and feed ingredients were inspected. Salmonella contamination mainly concentrated on animal protein material such as meat meal, meat and bone meal, feather meal, blood meal, and fish meal. No Salmonella contamination was detected in feed yeast, microbial protein, rapeseed, and soybean meal. Salmonella contamination existed in each sector of feed production chain. This investigation provided a basic reference for feed production management and quality control in feed production chain in Karst rural areas of China. PMID- 27778275 TI - Anti-septic effects of pelargonidin on HMGB1-induced responses in vitro and in vivo. AB - A certain nucleosomal protein-high mobility group box-1 (HMGB1)-has recently been established as a late mediator of sepsis, with a relatively wide therapeutic window for pharmacological intervention. Pelargonidin (PEL) is a well-known red pigment found in plants; it has important biological activities that are potentially beneficial for human health. In the present study, we investigated whether PEL can modulate HMGB1-mediated inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice. The anti-inflammatory activities of PEL were determined by measuring permeability, leukocyte adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice, as well as the beneficial effects of PEL on survival rate in the mouse sepsis model. The data showed that PEL had effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1 and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. Furthermore, PEL inhibited the HMGB1-mediated production of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), as well as the activation of nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Collectively, these results indicate that PEL could be used to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway. PMID- 27778274 TI - Moisturizing effect of serine-loaded solid lipid nanoparticles and polysaccharide rich extract of root Phragmites communis incorporated in hydrogel bases. AB - This study evaluated the moisturizing effect of serine-loaded solid lipid nanoparticles (serine-SLN) and polysaccharide-rich reed (Phragmites communis) root extract (RRE) incorporated in hydrogel bases. The hydrogels with serine-SLN and/or RRE were carefully applied on the volar forearm of human volunteers. Their moisturizing efficacy was evaluated by monitoring conductance values using a skin surface hygrometer. The values of the area under the normalized conductance-time curve (AUCC) were developed and compared as a parameter for the water holding capacity of the skin. Hydrogels with serine-SLN did not significantly moisturize the skin, while hydrogel containing 0.25% RRE produced a significant increase in the moisture content of the skin. However, adding more than 0.25% of RRE into the hydrogel base decreased the moisturizing effect due to the marked reduction of viscosity. Significantly enhanced moisturizing effect was observed with the hydrogel containing 0.25% RRE and 3% serine-SLN, with AUCC increased 2.21 times compared to than blank hydrogel. The results imply that effective delivery of serine into the skin is possible using lipid-based nanocarriers and RRE, which could be a promising strategy to moisturize the skin effectively. PMID- 27778276 TI - Transcriptional modulation of regulatory T cell development by novel regulators NR4As. AB - Regulatory T (Treg) cells with high expression of both CD25 and Foxp3 are developed in the thymus and also peripheral tissues. Treg cells suppress the activation and functions of effector T cells raised against specific antigens and are crucial for maintaining immune homeostasis. Treg cell development is associated with the induction of and epigenetic alterations of forkhead transcription factor Foxp3. Foxp3 expression is increased by the activation of several transcription factors including nuclear factor-kappa B (NF-kappaB), nuclear factor of activated T cells (NFAT), and Smad3 in response to various signals such as TGFbeta, retinoic acid, and rapamycin. Recently, the orphan nuclear receptor 4A proteins (NR4As) including NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor1) are reported to regulate Treg cell development through activation of Foxp3 and have therapeutic potentials in treating immune disorders. This review summarizes the function and regulatory mechanisms of Treg cells and also implicates current advances in immunomodulatory functions of NR4As and their therapeutic potentials in inflammation and cancer. PMID- 27778277 TI - Activity-Based Protein Profiling: From Chemical Novelty to Biomedical Stalwart. AB - Biological systems often respond to environmental changes by rapidly altering the activity of specific enzymes: for example through desequesterization of enzyme activities by dissociation from inhibitors, activation/deactivation through posttranslational modification, or relocation of the enzyme to different organelles. This means that expression levels of enzymes do not necessarily correlate with the activities observed for these enzymes. In this chapter we review some of the approaches used to selectively image only the active sub populations of given enzymes, the so-called activity-based protein profiling. A focus lies on recent developments that are taking this approach from chemical novelty to biochemical stalwart. PMID- 27778278 TI - A Quantitative Mass-Spectrometry Platform to Monitor Changes in Cysteine Reactivity. AB - Cysteine residues on proteins serve diverse functional roles in catalysis and regulation and are susceptible to numerous posttranslational modifications. Methods to monitor the reactivity of cysteines within the context of a complex proteome have facilitated the identification and functional characterization of cysteine residues on disparate proteins. Here, we describe the use of a cysteine reactive iodoacetamide probe coupled to isotopically labeled, cleavable linkers to identify and quantify cysteine-reactivity changes from two biological samples. PMID- 27778279 TI - Activity-Based Protein Profiling with Natural Product-Derived Chemical Probes in Human Cell Lysates. AB - Bioreactive natural products represent versatile starting points for the development of structurally unique activity-based probes. In the present protocol, we describe the workflow for an activity-based protein profiling (ABPP) experiment with an alkyne-tagged natural product derivative. Our protocol includes experimental procedures for in vivo labeling, sample preparation and 2 step (click chemistry) visualization and sample preparation for mass spectrometry based target identification. PMID- 27778280 TI - Inhibitor Discovery by Convolution ABPP. AB - Activity-based protein profiling (ABPP) has emerged as a powerful proteomic approach to study the active proteins in their native environment by using chemical probes that label active site residues in proteins. Traditionally, ABPP is classified as either comparative or competitive ABPP. In this protocol, we describe a simple method called convolution ABPP, which takes benefit from both the competitive and comparative ABPP. Convolution ABPP allows one to detect if a reduced signal observed during comparative ABPP could be due to the presence of inhibitors. In convolution ABPP, the proteomes are analyzed by comparing labeling intensities in two mixed proteomes that were labeled either before or after mixing. A reduction of labeling in the mix-and-label sample when compared to the label-and-mix sample indicates the presence of an inhibitor excess in one of the proteomes. This method is broadly applicable to detect inhibitors in proteomes against any proteome containing protein activities of interest. As a proof of concept, we applied convolution ABPP to analyze secreted proteomes from Pseudomonas syringae-infected Nicotiana benthamiana leaves to display the presence of a beta-galactosidase inhibitor. PMID- 27778281 TI - Activity-Based Protein Profiling in Bacteria. AB - Understanding the molecular mechanisms of bacterial pathogenesis and virulence is of great importance from both an academic and clinical perspective, especially in view of an alarming increase in bacterial resistance to existing antibiotics and antibacterial agents. Use of small molecules to dissect the basis of these dynamic processes is a very attractive approach due to their ability for rapid spatiotemporal control of specific biochemical functions. Activity-based protein profiling (ABPP), employing small molecule probes to interrogate enzyme activities in complex proteomes, has emerged as a powerful tool to study bacterial pathogenesis. In this chapter, we present a set of ABPP methods to identify and analyze enzymes essential for growth, metabolism and virulence of different pathogens including S. aureus and L. monocytogenes using natural product-inspired activity-based probes. PMID- 27778282 TI - Activity-Based Lipid Esterase Profiling of M. bovis BCG at Different Metabolic States Using Tetrahydrolipstatin (THL) as Bait. AB - This chapter provides a step-by-step protocol using activity-based protein profiling (ABPP) as a chemical-proteomic tool to survey the antibiotic properties of a small molecule. Here, we investigate the molecular mechanism behind the bactericidal activity of tetrahydrolipstatin (THL). ABPP relies on small molecule probes that target the active site of specific enzymes in complex proteomes. These probes in turn are equipped with a reporter tag that allows capturing, visualization, enrichment, identification, and quantification of its targets either in vitro or in situ. THL possesses bactericidal activities, but its precise spectrum of molecular targets is poorly characterized. Here, we used THL analogs functionalized to enable Huisgen-base cycloaddition, commonly known as "click chemistry," to identify target proteins after enrichment from mycobacterial cell lysates obtained from different physiological conditions. PMID- 27778283 TI - Comparative Activity-Based Flavin-Dependent Oxidase Profiling. AB - Activity-based protein profiling (ABPP) has become a powerful chemoproteomic technology allowing for the dissection of complex ligand-protein interactions in their native cellular environment. One of the biggest challenges for ABPP is the extension of the proteome coverage. In this chapter a new ABPP strategy dedicated to monoamine oxidases (MAO) is presented. These enzymes are representative examples of flavin-dependent oxidases, playing a crucial role in the regulation of nervous system signaling. PMID- 27778284 TI - Activity-Dependent Photoaffinity Labeling of Metalloproteases. AB - Metalloproteases, notably members of the matrix metalloprotease (MMP) and A Disintegrin And Metalloprotease (ADAM) families play crucial roles in tissue remodeling, the liberation of growth factors and cytokines from cell membranes (shedding) and cell-cell or cell-matrix interactions. Activity of MMPs or ADAMs must therefore be tightly controlled in time and space by activation of pro enzymes upon appropriate stimuli and inhibition by endogenous tissue inhibitors of metalloproteases (TIMPs) or alpha2-macroglobulin to prevent irreversible tissue damage due to excessive degradation or uncontrolled release of potent inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha).Although there is a wide range of methods to measure the amount of metalloproteases based on immunological approaches, relatively little is known about the activation status of a given enzyme at any given time and location. This information is, however, critical in order to understand the function and possible implication of these enzymes in disease. Since metalloproteases use an active-site bound water molecule to cleave the peptide bond, it is not possible to apply known active site-directed labeling approaches with electrophilic "warheads." We therefore developed novel metalloprotease inhibitors that contain a photoactivatable trifluoromethylphenyldiazirine group and show that such inhibitors are suitable for activity-dependent photoaffinity labeling of MMPs and ADAMs. PMID- 27778285 TI - Profiling the Activity of Deubiquitinating Enzymes Using Chemically Synthesized Ubiquitin-Based Probes. AB - Deubiquitinating enzymes (DUBs) are of interest as potential new targets for pharmacological intervention. Active-site-directed probes can be used for the accurate profiling of DUB activity as well as the identification of DUBs and DUB inhibitor selectivity. Previously, active-site directed DUB probes have been obtained using intein-based methods that have inherent limitations. Total chemical synthesis of ubiquitin allows for easy incorporation of different tags, such as fluorescent reporters, affinity tags, and cleavable linkers. Here, we describe the total chemical synthesis of a fluorescent active-site directed DUB probe, which facilitates fast, in-gel detection of active DUBs and circumvents the use of Western blot analysis. In addition, an in-gel activity-based DUB profiling assay is described in detail, in which the fluorescent DUB probe is used to visualize active DUBs in cell lysates. Finally, an inhibition assay is described in which the fluorescent probe is used to determine the specificity and potency of a small molecule DUB inhibitor. PMID- 27778286 TI - Biochemical and Mass Spectrometry-Based Approaches to Profile SUMOylation in Human Cells. AB - Posttranslational modification of proteins with the small ubiquitin-like modifier (SUMO) regulates protein function in the context of cell cycle and DNA repair. The occurrence of SUMOylation is less frequent as compared to protein modification with ubiquitin, and appears to be controlled by a smaller pool of conjugating and deconjugating enzymes. Mass spectrometry has been instrumental in defining specific as well as proteome-wide views of SUMO-dependent biological processes, and several methodological approaches have been developed in the recent past. Here, we provide an overview of the latest experimental approaches to the study of SUMOylation, and also describe hands-on protocols using a combination of biochemistry and mass spectrometry-based technologies to profile proteins that are SUMOylated in human cells. PMID- 27778287 TI - Live Cell Imaging and Profiling of Cysteine Cathepsin Activity Using a Quenched Activity-Based Probe. AB - Since protease activity is highly regulated by structural and environmental influences, the abundance of a protease often does not directly correlate with its activity. Because in most of the cases it is the activity of a protease that gives rise to its biological relevance, tools to report on this activity are of great value to the research community. Activity-based probes (ABPs) are small molecule tools that allow for the monitoring and profiling of protease activities in complex biological systems. The class of fluorescent quenched ABPs (qABPs), being intrinsically "dark" and only emitting fluorescence after reaction with the target protease, are ideally suited for imaging techniques such as small animal noninvasive fluorescence imaging and live cell fluorescence microscopy. An additional powerful characteristic of qABPs is their covalent and irreversible modification of the labeled protease, enabling in-depth target characterization. Here we describe the synthesis of a pan-cysteine cathepsin qABP BMV109 and the application of this probe to live cell fluorescence imaging and fluorescent SDS PAGE cysteine cathepsin activity profiling. PMID- 27778288 TI - Competitive ABPP of Serine Hydrolases: A Case Study on DAGL-Alpha. AB - Competitive activity-based protein profiling is a highly efficient chemical biology technique to determine target engagement and selectivity profiles of enzyme inhibitors in complex proteomes. Fluorophosphonate-based fluorescent inhibitors are widely used as broad-spectrum probes for serine hydrolases. However, diacylglycerol lipase-alpha is not labeled by fluorophosphonate-based probes. To overcome this problem, we have developed a tailor-made activity-based probe that reacts with diacylglycerol lipase-alpha. Here we describe a case study in which we apply competitive activity-based protein profiling using a broad spectrum and a tailor-made activity-based probe to establish selectivity and activity profiles of inhibitors targeting diacylglycerol lipase-alpha in the mouse brain proteome. PMID- 27778289 TI - A Protocol for Protein Profiling Using Chemoselective Cleavable Linker Probes in Semi-permeabilized Cells. AB - Activity-based protein profiling using activity-based probes (ABPs) resulted in the identification of various enzymes that are involved in the onset and progress of diseases. Detection of such proteins, often expressed at low abundance, is greatly enhanced by incorporating chemically cleavable linkers in the ABP of choice. Initial affinity purification, followed by tailored chemical cleavage of the linker, allows for specific release of the captured enzymes and their interaction partners. When the ABPs are delivered directly to semi-permeabilized cells, in contrast to a crude cell lysate, the sensitivity and efficacy of cell impermeable probes can be enhanced even further. PMID- 27778290 TI - Cleavable Linkers in Chemical Proteomics Applications. AB - The discovery of the protein targets of small molecule probes is a crucial aspect of activity-based protein profiling and chemical biology. Mass spectrometry is the primary method for target identification, and in the last decade, cleavable linkers have become a popular strategy to facilitate protein enrichment and identification. In this chapter, we provide an overview of cleavable linkers used in chemical proteomics approaches, discuss their different chemistries, and describe how they aid in protein identification. PMID- 27778291 TI - Two-Step Activity-Based Protein Profiling with the Proteasome System as Model of Study. AB - Activity-based protein profiling (ABPP) is a method to highlight enzymatic activities in a biological sample, which uses chemical probes that react covalently with the catalytic nucleophile of the enzyme. To circumvent disadvantages associated with the presence of reporter tags on chemical probes, the probe is equipped with a ligation handle to which the reporter can be reacted at the desired time and place in the ABPP workflow. This chapter demonstrates the power of a triple bioorthogonal ligation strategy which addresses the three activities of the proteasome: the beta5-subunit selective norbornene-tagged probe is reacted with fluorescent tetrazine, the beta1-selective azide-functionalized probe was addressed with a biotinylated phosphine, followed by an alkyne substituted pan-reactive probe to label the remaining beta2 activity to which an azide-coupled fluorophore was ligated. The result of the triple ligation was similar to each reaction performed separately demonstrating the value of the triple ligation strategy for a single experiment. PMID- 27778292 TI - The determinants of the choice of treatment of pregnant women in Cameroon. AB - This paper seeks to identify the determinants of the choice of treatment of pregnant women in Cameroon. Theoretically, the methodology is based on a discrete choice model with random utility. Empirically, the econometric specification is a Nested Multinomial Logit Model. The data used comes from the Demographic Health Survey (DHS) organized in 2011 by the National Institute of Statistics. The results reveal that uneducated women or those having only a primary education prefer to meet the traditional midwives than seek modern maternal health services. Moreover, the absence of a paid job for the pregnant woman, the large size of the household, Islamic or animist religion, poverty, high costs of healthcare and transportation are constraints which make the pregnant woman to prefer the services of traditional midwives to modern services of maternal health. The use of modern healthcare services by pregnant women in Cameroon can therefore be improved by at least two means: firstly, by improving on the level of education of women and economically empowering them. Secondly, in a context where the costs of healthcare services are paid directly by the pregnant women themselves or by their families, it is important to put in place health insurance schemes in order to guarantee proper follow-up of pregnant women until delivery as well as taking care of complicated cases. PMID- 27778294 TI - Global Neighborhoods: Beyond the Multiethnic Metropolis. AB - Neighborhoods where blacks and whites live in integrated settings alongside Hispanics and Asians represent a new phenomenon in the United States. These "global neighborhoods" have previously been identified in the nation's most diverse metropolitan centers. This study examines the full range of metropolitan areas to ask whether similar processes are occurring in other parts of the country. Is there evidence of stable racial integration in places that lack such diversity? What are the paths of neighborhood change in areas with few Hispanic or Asian residents, or areas where Hispanics are the principal minority group, or where there is no large minority presence at all? We distinguish four types of metropolitan regions: white, white/black, white/Hispanic/Asian, and multiethnic. These regions necessarily differ greatly in neighborhood composition, but some similar trajectories of neighborhood change are found in all of them. The results provide new evidence of the effect of Hispanic and Asian presence on black-white segregation in all parts of the country. PMID- 27778293 TI - Deep analysis of wild Vitis flower transcriptome reveals unexplored genome regions associated with sex specification. AB - KEY MESSAGE: RNA-seq of Vitis during early stages of bud development, in male, female and hermaphrodite flowers, identified new loci outside of annotated gene models, suggesting their involvement in sex establishment. The molecular mechanisms responsible for flower sex specification remain unclear for most plant species. In the case of V. vinifera ssp. vinifera, it is not fully understood what determines hermaphroditism in the domesticated subspecies and male or female flowers in wild dioecious relatives (Vitis vinifera ssp. sylvestris). Here, we describe a de novo assembly of the transcriptome of three flower developmental stages from the three Vitis vinifera flower types. The validation of de novo assembly showed a correlation of 0.825. The main goals of this work were the identification of V. v. sylvestris exclusive transcripts and the characterization of differential gene expression during flower development. RNA from several flower developmental stages was used previously to generate Illumina sequence reads. Through a sequential de novo assembly strategy one comprehensive transcriptome comprising 95,516 non-redundant transcripts was assembled. From this dataset 81,064 transcripts were annotated to V. v. vinifera reference transcriptome and 11,084 were annotated against V. v. vinifera reference genome. Moreover, we found 3368 transcripts that could not be mapped to Vitis reference genome. From all the non-redundant transcripts that were assembled, bioinformatics analysis identified 133 specific of V. v. sylvestris and 516 transcripts differentially expressed among the three flower types. The detection of transcription from areas of the genome not currently annotated suggests active transcription of previously unannotated genomic loci during early stages of bud development. PMID- 27778295 TI - Lymphocytic hypophysitis: modern day management with limited role for surgery. AB - PURPOSE: We set out to describe the modern day management of Lymphocytic hypophysitis (LH) with respect to its diagnosis, treatment and long-term endocrine and visual outcomes. We deliberately included patients with a clinical diagnosis of LH and compared them with those with a histological diagnosis following surgery. METHODS: A multi-centre observational study was performed. Twenty-two patients were included and studied over a mean follow-up period of 8.6 years (range 4-26 years). RESULTS: Patients presented with headache (N = 15; 68 %), visual field disturbances (N = 7; 32 %) or a combination of these symptoms (N = 5; 23 %). The time lag between onset of symptoms and diagnosis was <1 month, 1 6 months or >6 months in approximately a third of the patients each, respectively. In two-thirds of the patients (N = 14) LH was diagnosed based on their clinical, biochemical and radiological findings. The surgical cohort (N = 8) was statistically more likely to have presented with larger lesions, with suprasellar extension and greater visual field defects. During follow-up there was improvement in headaches and visual symptoms, but the rate of hypopituitarism as reflected by the need for on-going pituitary hormone replacement persisted. At the 1, 5 and 10 year follow-up there was no significant difference between the medically and surgically managed cohorts in terms of ongoing symptomatology or need for pituitary hormone replacement. CONCLUSIONS: In the modern era, most patients with LH are diagnosed by non-surgical means and managed medically. There remains a significant time lag between the onset of symptoms and the eventual diagnosis of LH. Despite the considerable morbidity attached to LH, overall prognosis is good. PMID- 27778296 TI - Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance. AB - INTRODUCTION: Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but they assure biochemical control of disease (and the possibility of an improvement of clinical symptoms and tumor shrinkage), only in a subset of patients. DISCUSSION: The mechanisms underlying the so called "SRL resistance" are various and involve in particular SST receptor expression and molecular pathways of signal transduction. Different predictors of SRL response have been reported, including clinical and biochemical features (gender, age, growth hormone and insulin-like growth factor-I levels at diagnosis), and tumor characteristic (both at preoperative magnetic resonance imaging study and histopathology) as well as expression of SST receptors. In some cases, only a "partial resistance" to SST can be detected, probably due to the presence of other impaired molecular mechanisms involved in signal transduction, which compromise specific pathways and not others. This may explain some cases of dissociated response between biochemical control and tumor shrinkage. PMID- 27778297 TI - Intrinsic Cell Stress is Independent of Organization in Engineered Cell Sheets. AB - Understanding cell contractility is of fundamental importance for cardiovascular tissue engineering, due to its major impact on the tissue's mechanical properties as well as the development of permanent dimensional changes, e.g., by contraction or dilatation of the tissue. Previous attempts to quantify contractile cellular stresses mostly used strongly aligned monolayers of cells, which might not represent the actual organization in engineered cardiovascular tissues such as heart valves. In the present study, therefore, we investigated whether differences in organization affect the magnitude of intrinsic stress generated by individual myofibroblasts, a frequently used cell source for in vitro engineered heart valves. Four different monolayer organizations were created via micro contact printing of fibronectin lines on thin PDMS films, ranging from strongly anisotropic to isotropic. Thin film curvature, cell density, and actin stress fiber distribution were quantified, and subsequently, intrinsic stress and contractility of the monolayers were determined by incorporating these data into sample-specific finite element models. Our data indicate that the intrinsic stress exerted by the monolayers in each group correlates with cell density. Additionally, after normalizing for cell density and accounting for differences in alignment, no consistent differences in intrinsic contractility were found between the different monolayer organizations, suggesting that the intrinsic stress exerted by individual myofibroblasts is independent of the organization. Consequently, this study emphasizes the importance of choosing proper architectural properties for scaffolds in cardiovascular tissue engineering, as these directly affect the stresses in the tissue, which play a crucial role in both the functionality and remodeling of (engineered) cardiovascular tissues. PMID- 27778298 TI - Important Considerations When Determining the Cost-effectiveness of Viscosupplements in the Treatment of Knee Osteoarthritis: Letter to the Editor regarding Rosen, J., Sancheti, P., Fierlinger, A. et al. Adv Ther (2016) 33: 998. doi:10.1007/s12325-016-0331-8. PMID- 27778299 TI - Response to: Important Considerations When Determining the Cost-effectiveness of Viscosupplements in the Treatment of Knee Osteoarthritis. PMID- 27778300 TI - Liver Perfusion Modifies Gd-DTPA and Gd-BOPTA Hepatocyte Concentrations Through Transfer Clearances Across Sinusoidal Membranes. AB - BACKGROUND AND OBJECTIVES: Gadobenate dimeglumine (Gd-BOPTA) is a commercialised hepatobiliary contrast agent used during liver magnetic resonance imaging (MRI) to detect liver diseases. It enters into human hepatocytes through organic anion transporting polypeptides (OATP1B1/B3) and crosses the canalicular transporter multiple resistance-associated protein 2 (MRP2) to be excreted into bile canaliculi. Gd-BOPTA can return to sinusoids via the sinusoidal transporters MRP3/MRP4. Hepatocyte concentrations of Gd-BOPTA depend on three clearances: the sinusoidal clearance or volume of sinusoidal blood cleared of drugs per unit of time and two hepatocyte clearances (into bile canaliculi or back to sinusoids) or volume of hepatocytes cleared of drugs per unit of time in the respective liver compartments. The present study investigates whether changing liver blood flow modifies hepatocyte concentrations when plasma concentrations do not change. METHODS: We perfused normal rat livers at various portal flow rates (24, 30, and 36 ml/min) with 200 uM Gd-BOPTA and measured sinusoidal clearances, hepatocyte clearances, and hepatocyte concentrations of Gd-BOPTA. RESULTS: We showed that varying portal flow rates changes the sinusoidal clearance of Gd-BOPTA despite its low extraction ratio. Portal flow rates do not modify Gd-BOPTA clearance from hepatocytes into bile canaliculi but can change hepatocyte clearance back to sinusoids. CONCLUSION: At a given perfused concentration, portal flow rates modify Gd-BOPTA hepatocyte concentrations, a result important to consider when interpreting liver imaging. PMID- 27778301 TI - Footbinding, Industrialization, and Evolutionary Explanation : An Empirical Illustration of Niche Construction and Social Inheritance. AB - The incorporation of niche construction theory (NCT) and epigenetics into an extended evolutionary synthesis (EES) increases the explanatory power of evolutionary analyses of human history. NCT allows identification of distinct social inheritance and cultural inheritance and can thereby account for how an existing-but-dynamic social system yields variable influences across individuals and also how these individuals' microlevel actions can feed back to alter the dynamic heterogeneously across time and space. An analysis of Chinese footbinding, as it was ending during the first half of the twentieth century and China was industrializing, illustrates the evolutionary dynamics of niche construction across inheritance tracks and explains regional heterogeneity as well as the persistence of a cultural belief that was socially inaccurate. Incorporating anthropological and sociological insights into an EES with NCT has the potential to proffer source laws for relationships between individual actions and macro-patterns in beliefs, structures, climate, and demography. PMID- 27778305 TI - Erratum to: 12th WINFOCUS world congress on ultrasound in emergency and critical care. PMID- 27778304 TI - Understanding the Mechanical forces of Self-Expandable Metal Stents in the Biliary Ducts. AB - Self-expandable metallic stent (SEMS) was an effective biliary endoprosthesis. Mechanical properties of SEMS, radial and axial force (RF, AF), may play important roles in the bile duct after placement. RF was well known dilation force and influenced on the occurrence of migration. AF, newly proposed by this author, was defined as the recovery force when the SEMS vended. AF was related with the cause of bile duct kinking, pancreatitis, and cholecystitis due to the compression of the bile duct, orifice of the cystic duct, and pancreatic orifice. Ideal SEMS may show high RF and low AF. PMID- 27778303 TI - Will the Conscious-Subconscious Pacing Quagmire Help Elucidate the Mechanisms of Self-Paced Exercise? New Opportunities in Dual Process Theory and Process Tracing Methods. AB - The extent to which athletic pacing decisions are made consciously or subconsciously is a prevailing issue. In this article we discuss why the one dimensional conscious-subconscious debate that has reigned in the pacing literature has suppressed our understanding of the multidimensional processes that occur in pacing decisions. How do we make our decisions in real-life competitive situations? What information do we use and how do we respond to opponents? These are questions that need to be explored and better understood, using smartly designed experiments. The paper provides clarity about key conscious, preconscious, subconscious and unconscious concepts, terms that have previously been used in conflicting and confusing ways. The potential of dual process theory in articulating multidimensional aspects of intuitive and deliberative decision-making processes is discussed in the context of athletic pacing along with associated process-tracing research methods. In attempting to refine pacing models and improve training strategies and psychological skills for athletes, the dual-process framework could be used to gain a clearer understanding of (1) the situational conditions for which either intuitive or deliberative decisions are optimal; (2) how intuitive and deliberative decisions are biased by things such as perception, emotion and experience; and (3) the underlying cognitive mechanisms such as memory, attention allocation, problem solving and hypothetical thought. PMID- 27778306 TI - Heat and Mass Transfer Analysis of MHD Nanofluid Flow with Radiative Heat Effects in the Presence of Spherical Au-Metallic Nanoparticles. AB - Energy generation is currently a serious concern in the progress of human civilization. In this regard, solar energy is considered as a significant source of renewable energy. The purpose of the study is to establish a thermal energy model in the presence of spherical Au-metallic nanoparticles. It is numerical work which studies unsteady magnetohydrodynamic (MHD) nanofluid flow through porous disks with heat and mass transfer aspects. Shaped factor of nanoparticles is investigated using small values of the permeable Reynolds number. In order to scrutinize variation of thermal radiation effects, a dimensionless Brinkman number is introduced. The results point out that heat transfer significantly escalates with the increase of Brinkman number. Partial differential equations that govern this study are reduced into nonlinear ordinary differential equations by means of similarity transformations. Then using a shooting technique, a numerical solution of these equations is constructed. Radiative effects on temperature and mass concentration are quite opposite. Heat transfer increases in the presence of spherical Au-metallic nanoparticles. PMID- 27778302 TI - Spotlight on the relevance of mtDNA in cancer. AB - The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer's biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA. PMID- 27778307 TI - Erratum to: Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future. PMID- 27778308 TI - Leukocyte recruitment in preterm and term infants. AB - Impaired cellular innate immune defense accounts for susceptibility to sepsis and its high morbidity and mortality in preterm infants. Leukocyte recruitment is an integral part of the cellular immune response and follows a well-defined cascade of events from rolling of leukocytes along the endothelium to firm adhesion and finally transmigration which is concerted by a variety of adhesion molecules. Recent analytical advances such as fetal intravital microscopy have granted new insights into ontogenetic regulation and maturation of fetal immune cell recruitment. Understanding the fetal innate immune system is essential for targeted prevention and therapy of premature infants with severe infections or disorders of the immune system. This review gives an overview of the basic principles of leukocyte recruitment, particularly neutrophil trafficking, and its development during early life and highlights technical limitations to our current knowledge. PMID- 27778309 TI - Infection prevention and ultrasound probe decontamination practices in Europe: a survey of the European Society of Radiology. AB - OBJECTIVES: Although ultrasound (US) is considered one of the safest imaging modalities, concerns have been raised regarding potential infection transmission risks through US procedures. A survey was undertaken by the European Society of Radiology (ESR) to establish infection prevention and control measures in US and to highlight the importance of good medical practice. METHODS: An online survey was sent to all 22,000 full ESR members. RESULTS: The response rate of completed surveys was 4.3 % (946 practitioners, 97 % of which were radiologists, mostly working in larger hospital settings). Among respondents, 29 %, 11 % and 6 % did not disinfect the US probe after every patient when performing standard surface US, endo-cavity US and interventional procedures, respectively. Eleven percent did not always use probe covers for endo-cavity US; for interventional procedures, the proportion was 23 %. A minority used sterile gel sachets in direct patient contact for endo-cavity scans (30 %), and 77.5 % used sterile gel for interventional procedures. CONCLUSIONS: The survey results highlight a wide range of practices throughout Europe and the need to raise awareness amongst practitioners regarding the importance of infection prevention and control measures. The development of European recommendations encompassing all US examinations, together with education is a priority. MAIN MESSAGES: * Transmission of infection through ultrasound procedures is possible. * There is a wide range of ultrasound probe decontamination practices in Europe. * Not all practitioners use probe covers for endo-cavity or interventional ultrasound. * Not all practitioners use sterile gel for internal and invasive procedures. * Currently there are no European recommendations encompassing all US examinations. PMID- 27778310 TI - The critical care response to a hospital outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection: an observational study. AB - BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) has caused several hospital outbreaks, including a major outbreak at King Abdulaziz Medical City, a 940-bed tertiary-care hospital in Riyadh, Saudi Arabia (August-September 2015). To learn from our experience, we described the critical care response to the outbreak. METHODS: This observational study was conducted at the Intensive Care Department which covered 5 ICUs with 60 single-bedded rooms. We described qualitatively and, as applicable, quantitatively the response of intensive care services to the outbreak. The clinical course and outcomes of healthcare workers (HCWs) who had MERS were noted. RESULTS: Sixty-three MERS patients were admitted to 3 MERS-designated ICUs during the outbreak (peak census = 27 patients on August 25, 2015, and the last new case on September 13, 2015). Most patients had multiorgan failure. Eight HCWs had MERS requiring ICU admission (median stay = 28 days): Seven developed acute respiratory distress syndrome, four were treated with prone positioning, four needed continuous renal replacement therapy and one had extracorporeal membrane oxygenation. The hospital mortality of ICU MERS patients was 63.4 % (0 % for the HCWs). In response to the outbreak, the number of negative-pressure rooms was increased from 14 to 38 rooms in 3 MERS-designated ICUs. Patients were managed with a nurse-to-patient ratio of 1:0.8. Infection prevention practices were intensified. As a surrogate, surface disinfectant and hand hygiene gel consumption increased by ~30 % and 17 N95 masks were used per patient/day on average. Family visits were restricted to 2 h/day. Although most ICU staff expressed concerns about acquiring MERS, all reported to work normally. During the outbreak, 27.0 % of nurses and 18.4 % of physicians working in the MERS-designated ICUs reported upper respiratory symptoms, and were tested for MERS-CoV. Only 2/196 (1.0 %) ICU nurses and 1/80 (1.3 %) physician tested positive, had mild disease and recovered fully. The total sick leave duration was 138 days for nurses and 30 days for physicians. CONCLUSIONS: Our hospital outbreak of MERS resulted in 63 patients requiring organ support and prolonged ICU stay with a high mortality rate. The ICU response required careful facility and staff management and proper infection control and prevention practices. PMID- 27778311 TI - Cryopreservation of primary human monocytes does not negatively affect their functionality or their ability to be labelled with radionuclides: basis for molecular imaging and cell therapy. AB - BACKGROUND: Circulating white blood cells crucially contribute to maintenance and repair of solid organs. Therefore, certain cell populations such as monocytes are attractive targets for use in molecular imaging and cell imaging, e.g. after labelling with radionuclides, as well as for cell therapies. However, the preparation of monocytes may require freezing and thawing to preserve cells for timely and standardised applications. Additional modifications of these cells such as radioisotope labelling are necessary prior to their application in vivo. We therefore tested the hypothesis whether cryopreservation of freshly isolated circulating human monocytes affects their functional phenotype or their suitability for radionuclide labelling. RESULTS: CD14+CD16- monocytes were isolated from human peripheral blood. They were either directly used for cellular assays and labelling or frozen down using cryoprotectants. In the latter case, cells were thawed prior to further use and analysed for survival, chemotactic responses to various growth factors and adhesion on endothelial cells. In addition, both fresh and cryopreserved monocytes were labelled with radiotracers followed by assessment of survival and chemotactic responses. In all functional assays performed, cryopreserved monocytes did not significantly differ from freshly isolated monocytes with regard to their functionality. Cryopreservation did not affect cell survival. There was no effect on the chemotactic response of monocytes towards different growth factors. Likewise, adhesion properties remained unchanged following cryopreservation. Moreover, the labelling efficiency was similar for freshly isolated and cryopreserved monocytes. Labelling did not negatively affect monocyte survival and function. CONCLUSIONS: Our data indicate that cryopreservation of freshly isolated human primary monocytes is feasible and does not negatively affect their functionality when used for labelling and functional assessment. PMID- 27778313 TI - Inbreeding depression and drift load in small populations at demographic disequilibrium. AB - Inbreeding depression is a major driver of mating system evolution and has critical implications for population viability. Theoretical and empirical attention has been paid to predicting how inbreeding depression varies with population size. Lower inbreeding depression is predicted in small populations at equilibrium, primarily due to higher inbreeding rates facilitating purging and/or fixation of deleterious alleles (drift load), but predictions at demographic and genetic disequilibrium are less clear. In this study, we experimentally evaluate how lifetime inbreeding depression and drift load, estimated by heterosis, vary with census (Nc ) and effective (estimated as genetic diversity, He ) population size across six populations of the biennial Sabatia angularis as well as present novel models of inbreeding depression and heterosis under varying demographic scenarios at disequilibrium (fragmentation, bottlenecks, disturbances). Our experimental study reveals high average inbreeding depression and heterosis across populations. Across our small sample, heterosis declined with He , as predicted, whereas inbreeding depression did not vary with He and actually decreased with Nc . Our theoretical results demonstrate that inbreeding depression and heterosis levels can vary widely across populations at disequilibrium despite similar He and highlight that joint demographic and genetic dynamics are key to predicting patterns of genetic load in nonequilibrium systems. PMID- 27778312 TI - Medication adherence in women with epilepsy who are planning pregnancy. AB - OBJECTIVE: This study examines medication adherence among women with epilepsy via use of an electronic diary, as part of a prospective multicenter observational study designed to evaluate fertility in women with epilepsy (WWE) versus age matched controls. METHODS: WWE and healthy age-matched controls, seeking pregnancy, were given an iPod Touch using a customized mobile application (the WEPOD App) for daily data tracking. Eighty-six WWE tracked seizures and antiepileptic drugs (AEDs). Tracking of nonepilepsy medications was optional. Diary data were counted from enrollment date until date of delivery, or up to 12 months if pregnancy was not achieved. Each day that subjects reported missing one or more AED was counted as nonadherence. Because adherence can only be determined in women who track consistently, we elected to include adherence data only for women who tracked >80% of days in the study. RESULTS: Approximately 75% of WWE tracked >80% of days and were included in medication adherence data analysis. In this group, medication adherence rate was 97.71%; 44% of women admitted to missing an AED on at least 1 day. Among the subgroup of WWE who recorded nonepilepsy medications, AED adherence rate was 98.56%, versus 93.91% for non AEDs. SIGNIFICANCE: The 75% compliance rate with an electronic diary suggests that it may be useful to track medication adherence in future studies and in the clinical setting. In those who tracked, the observed medication adherence rate was considerably higher than the 75% adherence rate seen in previous epilepsy studies. This might be explained in part by selection bias, but may also result from properties of the diary itself (daily reminders, real time feedback given to the provider). Women reported a higher rate of adherence to AEDs than to other prescribed medications and supplements, suggesting that perceived importance of medications likely influences medication adherence, and warrants future study. PMID- 27778314 TI - Disintegrating the fly: A mutational perspective on phenotypic integration and covariation. AB - The structure of environmentally induced phenotypic covariation can influence the effective strength and magnitude of natural selection. Yet our understanding of the factors that contribute to and influence the evolutionary lability of such covariation is poor. Most studies have either examined environmental variation without accounting for covariation, or examined phenotypic and genetic covariation without distinguishing the environmental component. In this study, we examined the effect of mutational perturbations on different properties of environmental covariation, as well as mean shape. We use strains of Drosophila melanogaster bearing well-characterized mutations known to influence wing shape, as well as naturally derived strains, all reared under carefully controlled conditions and with the same genetic background. We find that mean shape changes more freely than the covariance structure, and that different properties of the covariance matrix change independently from each other. The perturbations affect matrix orientation more than they affect matrix eccentricity or total variance. Yet, mutational effects on matrix orientation do not cluster according to the developmental pathway that they target. These results suggest that it might be useful to consider a more general concept of "decanalization," involving all aspects of variation and covariation. PMID- 27778315 TI - Divergent evolution of life span associated with mitochondrial DNA evolution. AB - Mitochondria play a key role in ageing. The pursuit of genes that regulate variation in life span and ageing have shown that several nuclear-encoded mitochondrial genes are important. However, the role of mitochondrial encoded genes (mtDNA) is more controversial and our appreciation of the role of mtDNA for the evolution of life span is limited. We use replicated lines of seed beetles that have been artificially selected for long or short life for >190 generations, now showing dramatic phenotypic differences, to test for a possible role of mtDNA in the divergent evolution of ageing and life span. We show that these divergent selection regimes led to the evolution of significantly different mtDNA haplotype frequencies. Selection for a long life and late reproduction generated positive selection for one specific haplotype, which was fixed in most such lines. In contrast, selection for reproduction early in life led to both positive selection as well as negative frequency-dependent selection on two different haplotypes, which were both present in all such lines. Our findings suggest that the evolution of life span was in part mediated by mtDNA, providing support for the emerging general tenet that adaptive evolution of life-history syndromes may involve mtDNA. PMID- 27778317 TI - Vulvar Langerhans cell histiocytosis and thalidomide: an effective treatment option. PMID- 27778316 TI - Testing the Replicability of a Successful Care Management Program: Results from a Randomized Trial and Likely Explanations for Why Impacts Did Not Replicate. AB - OBJECTIVES: To test whether a care management program could replicate its success in an earlier trial and determine likely explanations for why it did not. DATA SOURCES/SETTING: Medicare claims and nurse contact data for Medicare fee-for service beneficiaries with chronic illnesses enrolled in the trial in eastern Pennsylvania (N = 483). STUDY DESIGN: A randomized trial with half of enrollees receiving intensive care management services and half receiving usual care. We developed and tested hypotheses for why impacts declined. DATA EXTRACTION: All outcomes and covariates were derived from claims and the nurse contact data. PRINCIPAL FINDINGS: From 2010 to 2014, the program did not reduce hospitalizations or generate Medicare savings to offset program fees that averaged $260 per beneficiary per month. These estimates are statistically different (p < .05) from the large reductions in hospitalizations and spending in the first trial (2002-2010). The treatment-control differences in the second trial disappeared because the control group's risk-adjusted hospitalization rate improved, not because the treatment group's outcomes worsened. CONCLUSION: Even if demonstrated in a randomized trial, successful results from one test may not replicate in other settings or time periods. Assessing whether gaps in care that the original program filled exist in other settings can help identify where earlier success is likely to replicate. PMID- 27778318 TI - Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is defined as pneumonia developing in people who have received mechanical ventilation for at least 48 hours. VAP is a potentially serious complication in these patients who are already critically ill. Oral hygiene care (OHC), using either a mouthrinse, gel, toothbrush, or combination, together with aspiration of secretions, may reduce the risk of VAP in these patients. OBJECTIVES: To assess the effects of oral hygiene care on incidence of ventilator-associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs). SEARCH METHODS: We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 17 December 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 11), MEDLINE Ovid (1946 to 17 December 2015), Embase Ovid (1980 to 17 December 2015), LILACS BIREME Virtual Health Library (1982 to 17 December 2015), CINAHL EBSCO (1937 to 17 December 2016), Chinese Biomedical Literature Database (1978 to 14 January 2013), China National Knowledge Infrastructure (1994 to 14 January 2013), Wan Fang Database (January 1984 to 14 January 2013) and VIP Database (January 2012 to 4 May 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials to 17 December 2015. We placed no restrictions on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of OHC (mouthrinse, swab, toothbrush or combination) in critically ill patients receiving mechanical ventilation for at least 48 hours. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed search results, extracted data and assessed risk of bias in included studies. We contacted study authors for additional information. We pooled data from trials with similar interventions and outcomes. We reported risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, using random-effects models unless there were fewer than four studies. MAIN RESULTS: We included 38 RCTs (6016 participants). There were four main comparisons: chlorhexidine (CHX) mouthrinse or gel versus placebo/usual care; toothbrushing versus no toothbrushing; powered versus manual toothbrushing; and comparisons of oral care solutions. We assessed the overall risk of bias as low in five trials (13%), high in 26 trials (68%), and unclear in seven trials (18%). We did not consider the risk of bias to be serious when assessing the quality of evidence (GRADE) for VAP incidence, but we downgraded other outcomes for risk of bias.High quality evidence from 18 RCTs (2451 participants, 86% adults) shows that CHX mouthrinse or gel, as part of OHC, reduces the risk of VAP compared to placebo or usual care from 25% to about 19% (RR 0.74, 95% confidence intervals (CI) 0.61 to 0.89, P = 0.002, I2 = 31%). This is equivalent to a number needed to treat for an additional beneficial outcome (NNTB) of 17 (95% CI 10 to 33), which indicates that for every 17 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP would be prevented. There is no evidence of a difference between CHX and placebo/usual care for the outcomes of mortality (RR 1.09, 95% CI 0.96 to 1.23, P = 0.18, I2 = 0%, 15 RCTs, 2163 participants, moderate quality evidence), duration of mechanical ventilation (MD -0.09 days, 95% CI -1.73 to 1.55 days, P = 0.91, I2 = 36%, five RCTs, 800 participants, low quality evidence), or duration of intensive care unit (ICU) stay (MD 0.21 days, 95% CI -1.48 to 1.89 days, P = 0.81, I2 = 9%, six RCTs, 833 participants, moderate quality evidence). There is insufficient evidence to determine the effect of CHX on duration of systemic antibiotics, oral health indices, caregivers' preferences or cost. Only two studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.We are uncertain as to the effects of toothbrushing (+/- antiseptics) on the outcomes of VAP (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11, I2 = 64%, five RCTs, 889 participants, very low quality evidence) and mortality (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24, I2 = 0%, five RCTs, 889 participants, low quality evidence) compared to OHC without toothbrushing (+/- antiseptics). There is insufficient evidence to determine whether toothbrushing affects duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, adverse effects, caregivers' preferences or cost.Only one trial (78 participants) compared use of a powered toothbrush with a manual toothbrush, providing insufficient evidence to determine the effect on any of the outcomes of this review.Fifteen trials compared various other oral care solutions. There is very weak evidence that povidone iodine mouthrinse is more effective than saline/placebo (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, three studies, 356 participants, high risk of bias), and that saline rinse is more effective than saline swab (RR 0.47, 95% CI 0.37 to 0.62, P < 0.001, I2 = 84%, four studies, 488 participants, high risk of bias) in reducing VAP. Due to variation in comparisons and outcomes among trials, there is insufficient evidence concerning the effects of other oral care solutions. AUTHORS' CONCLUSIONS: OHC including chlorhexidine mouthwash or gel reduces the risk of developing ventilator-associated pneumonia in critically ill patients from 25% to about 19%. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence that OHC including both antiseptics and toothbrushing is different from OHC with antiseptics alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline/placebo, and saline rinse is more effective than saline swab in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. There is also insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects. PMID- 27778319 TI - Histological lymphovascular invasion is associated with nodal involvement, recurrence, and survival in patients with cutaneous malignant melanoma. AB - BACKGROUND: Invasion of the lymphatic or vascular vessels by the primary tumor is considered a sign of aggressive disease that leads to metastases to the regional lymph nodes and to distant sites. Although lymphovascular invasion (LVI) is one of the major characteristics of a primary melanoma tumor, its prognostic significance remains controversial. OBJECTIVE: The objective of this study was to determine the clinical significance of LVI in melanoma patients. METHODS: Outcomes in 705 patients with cutaneous melanoma were investigated retrospectively. RESULTS: The median age of the patients was 52 years (range: 16 104 years). Of the 705 patients, 624 (88.5%) did not have LVI and 81 (11.5%) patients did. Melanoma patients with LVI more frequently had nodular pathology (P = 0.001), invasion to an advanced Clark level (P = 0.000), greater Breslow thickness (P = 0.000), a high mitotic rate (P = 0.018), ulceration (P = 0.000), neurotropism (P = 0.000), lymph node involvement (P = 0.000), multiple lymph node involvement (P = 0.008), recurrent disease (P = 0.003), and metastatic disease (P = 0.008) than those without LVI. However, LVI was not significantly associated with age, gender, anatomic localization, tumor-infiltrating lymphocytes, vertical growth phase, a pre-existing melanocytic nevus, or type of distant metastasis. Lymphovascular invasion was significantly associated with both recurrence-free (P = 0.000) and overall (P = 0.000) survival. On multivariate analyses, although LVI was not independently associated with RFS (P = 0.134), it retained its significance for overall survival (P = 0.000). CONCLUSIONS: Lymphovascular invasion has significant prognostic impact on nodal involvement, recurrence, and overall survival in cutaneous melanoma. PMID- 27778320 TI - Association of classic lichen planus with human herpesvirus-7 infection. AB - BACKGROUND: Lichen planus is a mucocutaneous papulosquamous itchy disease with unknown etiology. A number of factors such as immune mechanisms, viral agents, and drugs have been implicated in pathogenesis of lichen planus. In recent years, several studies have indicated the role of viral agents in this disease, including human herpesvirus-7 (HHV-7). Studies have given contradictory results, which is why we decided to study the possible association between lichen planus with HHV-7. METHODS: In this case-control study, which was conducted on 60 cutaneous classic lichen planus samples as well as 60 healthy control skin samples after matching the two groups in terms of gender and age, tissue samples of patients and controls were studied by real time polymerase chain reaction to detect for HHV-7. RESULTS: According to this study, HHV-7 DNA was found in 18 samples of the case group (30.0%) and in six (10.0%) of the control group (P = 0.006). CONCLUSION: The results of this study support the likely role of HHV-7 in pathogenesis of lichen planus. As an exogenous antigen, this virus may be involved in cellular immune-mediated destruction of keratinocytes. PMID- 27778321 TI - Patients as Partners in Learning from Unexpected Events. AB - IMPORTANCE: Patient safety experts believe that patients/family members should be involved in adverse event review. However, it is unclear how aware patients/family members are about the causes of adverse events they experienced. OBJECTIVE: To determine whether patients/family members interviewed could identify at least one contributing factor for the event they experienced. Secondary objectives included understanding the way patients/family members became aware of adverse events, the types of contributing factors patients/family members identified for different types of adverse events, and recommendations provided by patients/family members to address the contributing factors. DESIGN: We interviewed patients/family members using semistructured interviews to understand their perceptions about why these adverse events occurred. The adverse events occurred between 1991 and 2014. SETTING: Participants described adverse events that occurred in various types of health care organizations (i.e., hospitals, ambulatory facilities/clinics, and dental clinics). PARTICIPANTS: We interviewed 72 patients and family members who each described a unique adverse event. Eligibility requirements were that patients/family members spoke English or Spanish and were aware of an adverse event that happened to them or a loved one. INTERVENTION(S) FOR CLINICAL TRIALS OR EXPOSURE(S) FOR OBSERVATIONAL STUDIES: N/A. MAIN OUTCOME(S) AND MEASURE(S): The main outcome was determining whether patients/family members could identify at least one contributing factor they perceived as related to the adverse event they described. RESULTS: Each participant identified at least one contributing factor and on average identified 3.67 contributing factors for their event. The most frequently mentioned contributing factors were Staff Qualifications/Knowledge (79 percent), Safety Policies/Procedures (74 percent), and Communication (64 percent). Participants knew about the contributing factors from personal observation only (32 percent), personal reasoning (11 percent), personal research (7 percent), record review (either their own medical records or reports they received in their own investigation; 6 percent), and being told by a physician (5 percent). Finally, patients/family members were able to provide recommendations that address each of the nine contributing factors we examined. CONCLUSIONS AND RELEVANCE: Patients/family members identified contributing factors related to their adverse event. Given that these contributing factors might not be known to health care organizations because most participants stated that they were not involved in the analysis process, opportunities for organizational learning from patients are potentially being missed. Health care organizations should interview patients/family about the event that harmed them to help ensure a full understanding of the causes of the event. PMID- 27778322 TI - Use of the term "rule out" in requisition forms may cause diagnostic delays in dermatopathology practice. AB - BACKGROUND: Timely pathologic diagnosis relies on the communication of specific clinical information in the requisition form (RF). Clinical information may use nonspecific terms such as "rule out", the use of which may result in diagnostic delays and the unnecessary application of pathology stains and sections. OBJECTIVE: This study was designed to evaluate the relationship between use of the term "rule out" and time to diagnosis, and the use of additional pathology stains and sections in integrated and non-integrated dermatopathology practices. METHODS: A retrospective double-cohort study of 475 RFs from the integrated practice (of which 182 used the term "rule out" [RO] and 293 did not [NRO]) and 412 RFs from the non-integrated practice (RO, n = 126; NRO, n = 286) was performed. RESULTS: No significant differences emerged between groups of patients with, respectively, RO and NRO RFs in the integrated practice with respect to time to diagnosis, and numbers of additional tissue sections or stains applied. By contrast, the use of RFs containing the term "rule out" was associated with significantly longer times to diagnosis and higher rates of use of pathology stains and sections in comparison with NRO RFs in the non-integrated practice. However, the study is limited by its status as a retrospective review of data sourced from a single institution. CONCLUSIONS: Use of the term "rule out" in RFs may not significantly impact key care delivery outcomes in an integrated practice. However, it may cause diagnostic delays and the use of unnecessary pathology services in a non-integrated practice. PMID- 27778323 TI - The incidence and mortality rates of neuroblastoma cases before and after the cessation of the mass screening program in Japan: A descriptive study. AB - In 2003, Japan's Ministry of Health, Labour and Welfare halted the neuroblastoma (NB) mass screening program, running since 1985. This study aimed to examine whether NB incidence and mortality changed before and after the program halted. This is a descriptive population-based study. We used data from the Monitoring of Cancer Incidence in Japan (MCIJ) project, Vital Statistics of Japan, and Japanese CANcer Survival Information for Society (J-CANSIS). Incidence rate, cumulative incidence rate, mortality rate, cumulative mortality rate, and relative 5-year survival for NB were calculated. Children were divided into two birth cohort groups, consisting of children born before, or after the cessation of the NB mass screening program. We compared the two cohorts, with regards to the cumulative incidence and mortality rates at 5 years old. The incidence rate was lower after the cessation of the NB mass screening program. There was no substantial change in the mortality rate, and no significant variation in the relative 5-year survival between groups. The cumulative incidence rate in the latter cohort was significantly lower than that in the former cohort (rate ratio: 0.39, 95% CI: 0.25-0.61, p < 0.001). No significant difference in the cumulative mortality rate between the two cohorts was observed (rate ratio: 0.99, 95% CI: 0.80-1.22, p = 0.93). The NB incidence rate decreased markedly and the mortality rate did not substantially change after the cessation of the NB mass screening program. The NB mass screening program probably caused overdiagnosis, and its effectiveness was not clear. PMID- 27778324 TI - Intraneural injection of a test dose of local anesthetic in peripheral nerves - does it induce histological changes in nerve tissue? AB - BACKGROUND & OBJECTIVES: Most anesthesiologists use the injection of a test dose of local anesthetic in order to evaluate the final needle tip position. Thus, the intraneural injection of a full dose can be avoided. The aim of this study was to analyze whether an intraneural injection of a test dose of bupivacaine could trigger histological changes. METHODS: Intraneural injections under direct vision were performed in 40 brachial plexus nerves in seven anesthetized pigs. Tibial nerves served as positive and negative controls. Two milliliter of bupivacaine 0.5% was injected in three nerves on the left brachial plexus. For control of local anesthetic's toxicity Ringer's solution was applied intraneurally on the right side. After maintaining 48 h of general anesthesia, the nerves were resected. The specimens were processed for histological examination and assessed for inflammation (hematoxylin and eosin stain, CD68-immunohistochemistry) and myelin damage (Kluver-Barrera stain). The degree of nerve injury was rated on a scale from 0 (no injury) to 4 (severe injury). RESULTS: Statistical analysis showed no significant differences between the bupivacaine group [median (interquartile range) 1 (1-1.5)] and the Ringer's solution group [1 (0.5-2) P = 0.772]. Mild myelin alteration was found in 12.5% of all specimens following intraneural injection, irrespective of the applied substance. CONCLUSIONS: "In our experimental study, intraneural injection of 2 ml of bupivacaine or Ringer's solution showed comparable mild inflammation. Nevertheless, inflammation can only be prevented by strictly avoiding nerve perforation followed by intraneural injection, as mechanical nerve perforation is a key factor for evolving inflammation. PMID- 27778325 TI - A possible link between famine exposure in early life and future risk of gastrointestinal cancers: Implications from age-period-cohort analysis. AB - The Chinese famine in 1958-1962 was one of the worst in human history, but its potential influence on cancer risks is uncertain. Using cancer incidence data in Shanghai, China, during 1983-2007, we calculated age-specific incidence rates of gastrointestinal cancers in birth cohorts exposed to the Chinese famine in different periods of life and a non-exposed reference cohort. Age-period-cohort regressions estimated the overall relative risks of gastrointestinal cancers in each birth cohort. A total of 212,098 new cases of gastrointestinal cancer were identified during the study period (129,233 males and 82,865 females), among whom 18,146 had esophageal cancer, 71,011 gastric cancer, 55,864 colorectal cancer, 42,751 liver cancer, 9,382 gallbladder cancer and 14,944 had pancreatic cancer. The risk of esophageal, gastric, colorectal and liver cancers was higher in cohorts exposed to the Chinese famine in early life than in the reference cohort, except for esophageal cancer in women. The risk of esophageal, liver and colorectal cancers was particularly high in men exposed to famine during early childhood (0-9 years). There were no clear associations between famine exposure and the risk of pancreatic or gallbladder cancer. This study suggests an increased risk of esophageal, gastric, liver and colorectal cancers associated with childhood exposure to the Chinese famine. These findings indicate a need for further investigations confirming the results and identifying the underlying mechanisms. PMID- 27778326 TI - Surgical treatment of polymicrogyria-related epilepsy. AB - OBJECTIVE: The role of resective surgery in the treatment of polymicrogyria (PMG) related focal epilepsy is uncertain. Our aim was to retrospectively evaluate the seizure outcome in a consecutive series of patients with PMG-related epilepsy who received, or did not receive, surgical treatment, and to outline the clinical characteristics of patients who underwent surgery. METHODS: We evaluated 64 patients with epilepsy associated with magnetic resonance imaging (MRI) documented PMG. After presurgical evaluation, 32 patients were excluded from surgical treatment and 32 were offered surgery, which was declined by 8 patients. Seizure outcome was assessed in the 40 nonsurgical and 24 surgical patients. RESULTS: Of 40 nonsurgical patients, 8 (20%) were seizure-free after a mean follow-up of 91.7 +/- (standard deviation) 59.5 months. None of the eight patients who declined surgical treatment was seizure-free (mean follow-up: 74.3 +/- 60.6 months). These seizure outcomes differ significantly (p = 0.000005 and p = 0.0003, respectively) from that of the 24 surgical patients, 18 of whom (66.7%) were Engel's class I postoperatively (mean follow-up: 66.5 +/- 54.0 months). Of the eight patients excluded from surgery for seizure control at first visit, two had seizure recurrence at last contact. At last contact, antiepileptic drugs (AEDs) had been withdrawn in 6 of 24 surgical and in one of 40 nonsurgical cases (p = 0.0092). SIGNIFICANCE: The present study indicates that, at least in a subset of adequately selected patients with PMG-related epilepsy, surgery may provide excellent seizure outcomes. Furthermore, it suggests that surgery is superior to AEDs for achieving seizure freedom in these cases. PMID- 27778327 TI - CD8+ and FoxP3+ T-cell infiltration in actinic cheilitis. AB - BACKGROUND: Differences in immune profile between actinic cheilitis (AC), a precursor of lip squamous cell carcinoma, and normal lip vermillion (NL) have not been elucidated. OBJECTIVES: To compare density, distribution, and ratios of CD8+ and FoxP3+ cells between AC and NL and assess their associations with clinicopathologic variables. METHODS: Samples of AC and NL obtained between 2001 and 2013 at the College of Dentistry of the University of Concepcion, Chile, were retrospectively analyzed for immunohistochemical detection of CD8+ and FoxP3+ cells. Differences between groups were tested by Mann-Whitney U and Fisher's exact tests. Independent effects of cell densities and CD8/FoxP3 ratio with AC were assessed by multiple logistic regression analysis after adjustment for potential confounding. RESULTS: A total of 62 AC and 24 NL biopsies were included. Densities of CD8+ and FoxP3+ cells in AC were significantly higher than in NL. Conversely, the CD8+/FoxP3+ ratio was significantly lower in AC as compared to NL. After adjustment for sun exposure, age, gender, and smoking status, a stromal FoxP3+ cell density higher than 0.35 cells/field was significantly associated with increased odds of AC (odds ratio [OR] = 5.01, 95% confidence interval [CI]: 1.18-21.31), while a stromal CD8+/FoxP3+ ratio higher than 5.91 was associated with decreased odds of AC (OR = 0.29, 95% CI: 0.08 1.08). CONCLUSIONS: AC is characterized by increased FoxP3+ cell infiltration and a reduced CD8/FoxP3 ratio as compared to NL. Therefore, increased infiltration of FoxP3+ cells relative to CD8+ cells may contribute to the transition from normal to preneoplastic stages in lip carcinogenesis. PMID- 27778328 TI - Low-dose oral isotretinoin for moderate to severe seborrhea and seborrheic dermatitis: a randomized comparative trial. AB - BACKGROUND: The efficacy of low-dose oral isotretinoin in the treatment of seborrhea and seborrheic dermatitis has been poorly investigated in randomized studies. OBJECTIVES: This study was designed to determine the efficacy and safety of low-dose oral isotretinoin in the treatment of moderate to severe seborrhea and seborrheic dermatitis on the scalp and/or face. METHODS: A randomized, comparative clinical trial, using two groups, was conducted over 6 months. Patients in Group ISO were treated with isotretinoin 10 mg every other day. In Group X, patients received antiseborrheic topical treatment. Patient opinion, investigator assessment, scalp pruritus, sebum production, and quality of life (QoL) comprised the efficacy outcomes. RESULTS: The intention-to-treat population comprised a total of 45 patients with mean +/- standard deviation ages of 28.7 +/ 5.8 years in Group ISO and 29.8 +/- 6.5 years in Group X. The rate of sebum production significantly decreased in Group ISO. Patient opinion, investigator, and QoL assessments improved in both groups. CONCLUSIONS: Low-dose oral isotretinoin can be a therapeutic modality for moderate to severe seborrhea and seborrheic dermatitis. PMID- 27778329 TI - Potential value of routine contralateral patent processus vaginalis repair in children with unilateral inguinal hernia. AB - BACKGROUND: The development of laparoscopy as a means of evaluation and treatment of inguinal hernia in children has raised the question of whether simultaneous closure of a contralateral patent processus vaginalis (CPPV) is justified. The present study aimed to determine the rate of metachronous inguinal hernia (MIH) in children with CPPV. METHODS: Children with unilateral inguinal hernia from two hospitals underwent either open or laparoscopic repair, and were followed up for MIH. The presence of CPPV was evaluated during laparoscopy and, if detected, the CPPV was closed. The relationship between CPPV and subsequent MIH was studied. RESULTS: The study included children who had complete follow-up (90.0 per cent of those having open repair and 92.2 per cent of those undergoing laparoscopic repair). Of 2538 children who had open hernia repair, 62 (2.4 per cent) developed MIH (30 on the right side and 32 on the left; P = 0.015). Among 2855 children who underwent laparoscopic repair, a CPPV was identified and closed in 1469 (51.5 per cent). The rate of MIH after negative laparoscopic evaluation for CPPV was three of 2855 (0.1 per cent). There were no significant differences in the rate of CPPV between sexes and either the right or left side (P = 0.072 and P = 0.099 respectively). Ipsilateral recurrence was less frequent after laparoscopic repair: seven (0.2 per cent) versus 26 (1.0 per cent) for open repair (P < 0.001). CONCLUSION: Laparoscopic inguinal hernia repair was associated with a lower recurrence rate than open repair. Routine repair of CPPV reduced the rate of subsequent MIH, but 21 CPPVs needed to be closed to prevent one MIH. PMID- 27778330 TI - Poor oral health is associated with an increased risk of esophageal squamous cell carcinoma - a population-based case-control study in China. AB - To further examine the association between oral hygiene and esophageal squamous cell carcinoma (ESCC) risk and the effect modification of other exposures, we conducted a population-based case-control study between 2010 and 2012 in Taixing, China, a high-risk area for ESCC. Cases were primarily recruited from endoscopy units at local hospitals, supplemented by linkage to the local Cancer Registry. Control subjects were frequency matched to cases by sex and age (5-year groups) and were randomly selected from the Taixing Population Registry. For the current analysis, data from 616 histopathologically confirmed cases and 770 controls with complete information on oral hygiene were analyzed. Unconditional logistic regression models, including oral hygiene indicators and potential behavioral confounders, were used to derive odds ratios (ORs) and 95% confidence intervals (CIs). Tooth loss was only marginally significantly associated with ESCC risk (yes vs. no, OR = 1.29, 95% CI 0.94-1.74). However, the excess risk increased with increasing numbers of lost teeth (more than 6 teeth lost vs. none, OR = 1.48, 95% CI 1.04-2.11). Tooth brushing once or less per day, compared with tooth brushing twice or more per day, was associated with a 1.81-fold increased risk of ESCC. In the stratification analyses, the increased risks associated with these indicators of oral health were more pronounced in older subjects (age >= 70 years), women, non-smokers, and non-drinkers. Further studies are warranted to verify these findings and to explore the underlying mechanisms, e.g., changed oral microbiota, associated with poor oral hygiene. PMID- 27778331 TI - Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo. AB - Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells. This effect was mediated by caspase activation, mainly caspase-2, and was partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma bearing mice significantly suppressed tumor growth in vivo. Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM. PMID- 27778332 TI - Cold-induced hyperhidrosis: possible association with hyper-IgE syndrome. PMID- 27778333 TI - Personalizing Nursing Home Compare and the Discharge from Hospitals to Nursing Homes. AB - OBJECTIVE: To test whether use of a personalized report card, Nursing Home Compare Plus (NHCPlus), embedded in a reengineered discharge process, can lead to better outcomes than the usual discharge process from hospitals to nursing homes. DATA SOURCES/SETTING: Primary data collected in the Departments of Medicine and Surgery at a University Medical Center between March 2014 and August 2015. STUDY DESIGN: A randomized controlled trial in which patients in the intervention group were given NHCPlus. Participants included 225 patients or their family members/surrogates. DATA COLLECTION: Key strokes of NHCPlus users were recorded to obtain information about usage. Users were surveyed about usability and satisfaction with NHCPlus. All participants were surveyed at discharge from the hospital. Survey data were merged with medical records. PRINCIPAL FINDINGS: About 85 percent of users indicated satisfaction with NHCPlus. Compared to controls, intervention patients were more satisfied with the choice process (by 40 percent of the standard deviation p < .01), more likely to go to higher ranked five-star nursing homes (OR = 1.8, p < .05), traveled to further nursing homes (IRR = 1.27, p < .10), and had shorter hospital stays (IRR = 0.84, p < .05). CONCLUSIONS: Personalizing report cards and reengineering the discharge process may improve quality and may lower costs compared to the usual discharge process. PMID- 27778335 TI - Neurobehaviour at term in infants born moderately and late preterm is associated with cognition at 2 years. PMID- 27778334 TI - Cognitive impairment and magnetic resonance imaging correlates in primary progressive multiple sclerosis. AB - OBJECTIVES: To characterize cognitive impairment in primary progressive multiple sclerosis (PPMS) and to correlate the pattern of cognitive deficits with brain magnetic resonance imaging (MRI) volumetric data. MATERIALS AND METHODS: In a multicenter cross-sectional study, we recruited consecutive patients with PPMS as well as age, sex, and education level-matched healthy controls (HC). All participants underwent neuropsychological (NP) assessment, and brain MRI was performed in patients with PPMS for analysis of lesion load, subcortical GM volumes, and regional cortical volumes. RESULTS: We recruited 55 patients with PPMS and 36 HC. Thirty-six patients were included in the MRI analysis. Patients with PPMS performed significantly worse than HC in all NP tests. Subcortical GM volume was significantly correlated with all NP tests, except for Stroop Test, with the largest effect for the thalamus (r=-.516 [BVMT-R DR, P=.016 FDR corrected] to r=.664 [SDMT, P<.001 FDR-corrected]). In the stepwise linear regression model, thalamic volume was the only predictor of performance in all NP tests. CONCLUSION: Cognitive impairment is common in PPMS and affects all evaluated cognitive domains. Subcortical GM volume, particularly of the thalamus, is a strong predictor of cognitive performance, suggesting it has a central role in the pathophysiology of PPMS-related cognitive dysfunction. PMID- 27778337 TI - Marker-assisted introgression of broad-spectrum blast resistance genes into the cultivated MR219 rice variety. AB - BACKGROUND: The rice cultivar MR219 is famous for its better yield and long and fine grain quality; however, it is susceptible to blast disease. The main objective of this study was to introgress blast resistance genes into MR219 through marker-assisted selection (MAS). The rice cultivar MR219 was used as the recurrent parent, and Pongsu Seribu 1 was used as the donor. RESULTS: Marker assisted foreground selection was performed using RM6836 and RM8225 to identify plants possessing blast resistance genes. Seventy microsatellite markers were used to estimate recurrent parent genome (RPG) recovery. Our analysis led to the development of 13 improved blast resistant lines with Piz, Pi2 and Pi9 broad spectrum blast resistance genes and an MR219 genetic background. The RPG recovery of the selected improved lines was up to 97.70% with an average value of 95.98%. Selected improved lines showed a resistance response against the most virulent blast pathogen pathotype, P7.2. The selected improved lines did not express any negative effect on agronomic traits in comparison with MR219. CONCLUSION: The research findings of this study will be a conducive approach for the application of different molecular techniques that may result in accelerating the development of new disease-resistant rice varieties, which in turn will match rising demand and food security worldwide. (c) 2016 Society of Chemical Industry. PMID- 27778336 TI - Hospital costs of colorectal cancer surgery for the oldest old: A Dutch population-based study. AB - : Background Due to increasing healthcare costs, discussions regarding increased hospital costs when operating on high-risk patients is rising. Therefore, the aim of this study was to analyze if oldest-old colorectal cancer patients have a greater impact on hospital costs than their younger counterparts. METHODS: All colorectal cancer procedures performed in 29 Dutch hospitals between 2010 and 2012 and listed in the Dutch Surgical Colorectal Audit were analyzed. Oldest-old patients (>=85 years) were compared to patients <85 years. Ninety-day hospital costs were measured uniformly in all hospitals based on time-driven activity based costs. RESULTS: Compared to <85-year-old patients (n = 9130), the oldest old (n = 783) had longer hospital stays (LOS) (11.3 vs. 13.2, P < 0.001), more severe complications (21.8% vs. 29.0%, P < 0.001), more failure to rescue (13.9% vs. 37.0%, P < 0.001) and higher mortality (3.0% vs. 10.7%, P < 0.001). Deceased oldest-old patients had significantly less LOS and less LOS ICU. Total hospital costs were 3% lower for oldest-old patients (?13,168) than for <85-year-old patients (?13,644, P < 0.001). In cases of severe complications or death, hospital costs for the oldest old were 25% and 31% lower than those of <85-year old patients (both P < 0.001). CONCLUSION: Although frequently assumed to be more expensive, operating on oldest-old patients with colorectal cancer does not increase hospital costs compared to younger patients. This was most likely due to faster deterioration or less aggressive treatment of oldest-old patients when (severe) complications occurred. J. Surg. Oncol. 2016;114:1009-1015. (c) 2016 Wiley Periodicals, Inc. PMID- 27778338 TI - Preliminary investigation of mineral content of pollen collected from different Serbian maize hybrids - is there any potential nutritional value? AB - BACKGROUND: Bee pollen has already proved to be a good supplement rich in iron and zinc. Studies on the application of flower pollen in the food industry and medicine have begun. Bearing in mind the prevalence of maize as a crop culture, its pollen will be easily available. The mineral composition of pollen of seven Serbian maize hybrids was analyzed in order to establish its nutritional value and the benefits of its implementation in the human diet using the inductively coupled plasma method. RESULTS: The presence of twenty four different macro- (nine) and micronutrients (fifteen) was detected. The most common minerals were phosphorus and potassium, while arsenic, cobalt, lead, nickel and molybdenum were found in some samples. CONCLUSION: Comparing the results obtained with recommended or tolerable dietary intake references for adults, it was found that maize pollen can be used as a very good source of zinc, iron, chromium and manganese for humans. With regard to selenium content, pollen samples proved to be moderately good source of this important micronutrient. Contents of some elements (Fe, Zn, Mn, Cr, Se, Al and V) showed significant differences depending on hybrid type. In some samples increased concentrations of aluminum and vanadium were recorded, which may pose a potential problem due to their toxicity. (c) 2016 Society of Chemical Industry. PMID- 27778339 TI - Permanent His-Bundle Pacing: An Adolescent with Promise. PMID- 27778341 TI - Geographic distribution and environmental control of vertebral count in Ammodytes spp. along the northern Pacific coast of Japan. AB - To examine species composition and population structures in sand lance (Ammodytidae) along the northern Pacific coast of Japan, genetic analysis were carried out for specimens collected in 2014 from Otsuchi Bay, Iwate, Ishinomaki Bay, Miyagi, off Soma, Fukushima and Ise-Mikawa Bays, Aichi. The samples consisted of Ammodytes japonicus and Ammodytes heian, of which the latter is a recently described species. Neither species exhibited significant genetic differences among localities. Only A. japonicus was found in the most southern locality at Aichi, but it decreased northward to <90% in Miyagi and Fukushima and the two species occurred almost evenly in Iwate suggesting a latitudinal cline in their species composition along the northern Pacific coast of Japan, off Tohoku. The vertebral counts differed between A. japonicus and A. heian with modes of 65 and 63, respectively, but this characteristic did not differ significantly within a locality (Iwate). This suggests that the vertebral counts of Ammodytes spp. in Japanese waters are probably strongly determined by the environment than by a species-specific genetic trait. PMID- 27778340 TI - Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring. AB - Early malnutrition is a risk factor for depression and schizophrenia. Since the offspring of malnourished dams exhibit increased brain levels of serotonin (5 HT), a tryptophan-derived neurotransmitter involved in the pathophysiology of these mental disorders, it is believed that the deleterious effects of early malnutrition on brain function are due in large part to altered serotoninergic neurotransmission resulting from impaired tryptophan (Trp) metabolism. However, tryptophan is also metabolized through the kynurenine (KYN) pathway yielding several neuroactive compounds including kynurenic (KA), quinolinic (QA) and xanthurenic (XA) acids. Nevertheless, the impact of perinatal malnutrition on brain kynurenine pathway metabolism has not been examined to date. Here, we used ultra-performance liquid chromatography-tandem mass spectrometry for the simultaneous quantification of tryptophan and a set of seven compounds spanning its metabolism through the serotonin and kynurenine pathways, in the brain of embryos and adult offspring of rat dams fed a protein-restricted (PR) diet. Protein-restricted embryos showed reduced brain levels of Trp, serotonin and KA, but not of KYN, XA, or QA. In contrast, PR adult rats exhibited enhanced levels of Trp in the brainstem and cortex along with increased concentrations of 5-HT, kynurenine and XA. The levels of XA and KA were also increased in the hippocampus of adult PR rats. These results show that early protein deficiency induces selective and long-lasting changes in brain kynurenine metabolism. Given the regulatory role of KYN pathway metabolites on brain development and function, these changes might contribute to the risk of developing psychiatric disorders induced by early malnutrition. PMID- 27778344 TI - Research Review: Neural response to threat in children, adolescents, and adults after child maltreatment - a quantitative meta-analysis. AB - BACKGROUND: Child maltreatment is common and has long-term consequences for affective function. Investigations of neural consequences of maltreatment have focused on the amygdala. However, developmental neuroscience indicates that other brain regions are also likely to be affected by child maltreatment, particularly in the social information processing network (SIPN). We conducted a quantitative meta-analysis to: confirm that maltreatment is related to greater bilateral amygdala activation in a large sample that was pooled across studies; investigate other SIPN structures that are likely candidates for altered function; and conduct a data-driven examination to identify additional regions that show altered activation in maltreated children, teens, and adults. METHODS: We conducted an activation likelihood estimation analysis with 1,733 participants across 20 studies of emotion processing in maltreated individuals. RESULTS: Maltreatment is associated with increased bilateral amygdala activation to emotional faces. One SIPN structure is altered: superior temporal gyrus, of the detection node, is hyperactive in maltreated individuals. The results of the whole-brain corrected analysis also show hyperactivation of the parahippocampal gyrus and insula in maltreated individuals. CONCLUSIONS: The meta-analysis confirms that maltreatment is related to increased bilateral amygdala reactivity and also shows that maltreatment affects multiple additional structures in the brain that have received little attention in the literature. Thus, although the majority of studies examining maltreatment and brain function have focused on the amygdala, these findings indicate that the neural consequences of child maltreatment involve a broader network of structures. PMID- 27778346 TI - Physiochemical, texture properties, and the microstructure of set yogurt using whey protein-sodium tripolyphosphate aggregates as thickening agents. AB - BACKGROUND: Polymerized whey protein-sodium tripolyphosphate can be induced to gel in an acidic environment provided during fermentation. The variety of thickening agent has an influence on texture that is an essential aspect of yogurt quality affecting consumer preference. Similar to polysaccharide stabilizers, the cold gelation properties of whey proteins can improve the body texture of yogurt products. Polymerized whey protein-sodium tripolyphosphate could be a favorable and interesting thickening agent for making set yogurt. RESULTS: The effects of whey protein isolate (WPI), heat-treated whey protein sodium tripolyphosphate (WPI-STPP), heat-treated WPI and pectin on the storage properties and microstructure of yogurt were investigated. All samples were analyzed for syneresis, pH, titratable acidity, viscosity, texture profile and microstructure during storage. The results showed that incorporating heat-treated WPI-STPP had a significant impact on syneresis (32.22 +/- 0.60), viscosity (10 956.67 +/- 962.1) and hardness (209.24 +/- 12.48) (p < 0.05) with uniform body texture. CONCLUSION: Yogurt fermented with modified WPI-STPP had higher levels of protein and better hardness compared with yogurt using pectin. The microstructure was observed to be a uniform and denser, complicated network. Heat-treated WPI STPP may be useful for improving yogurt texture. (c) 2016 Society of Chemical Industry. PMID- 27778342 TI - Do method and species lifestyle affect measures of maximum metabolic rate in fishes? AB - The rate at which active animals can expend energy is limited by their maximum aerobic metabolic rate (MMR). Two methods are commonly used to estimate MMR as oxygen uptake in fishes, namely during prolonged swimming or immediately following brief exhaustive exercise, but it is unclear whether they return different estimates of MMR or whether their effectiveness for estimating MMR varies among species with different lifestyles. A broad comparative analysis of MMR data from 121 fish species revealed little evidence of different results between the two methods, either for fishes in general or for species of benthic, benthopelagic or pelagic lifestyles. PMID- 27778343 TI - Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study. AB - Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. PMID- 27778345 TI - Evaluating organ preservation outcome as treatment endpoint for T1aN0 glottic cancer. AB - OBJECTIVES/HYPOTHESIS: Common endpoints in reporting the outcomes for early glottic cancer do not highlight the importance of organ preservation. We evaluated the treatment outcomes among patients with T1aN0 laryngeal cancer with laryngectomy-free disease-specific survival (LFS-DSS), which is defined as time to total laryngectomy or time to death from cancer cause, against all other endpoints. STUDY DESIGN: Outcome research on an institutional database. METHODS: A retrospective review covered all consecutive patients from 2003 to 2013. Patients with T1a laryngeal squamous cell carcinoma (SCC) were offered the options of either radiation treatment (RT) or transoral laser microsurgery (TLM). Tumor control, survival outcomes, standard definition laryngectomy-free survival (LFS), and LFS-DSS were calculated. RESULTS: There were 105 patients, of whom 53 were treated with TLM and 52 were treated with RT. There were 11 recurrences within the TLM group, of which four were successfully salvaged with repeated TLM and two were salvaged with RT. Among the four recurrences within the RT group, all four patients had salvage total laryngectomies. The 5-year overall survival for patients treated with TLM versus RT was 86% versus 85% (P = .887), disease free survival was 69% versus 78% (P = .151), LFS was 65% versus 77% (P = .198), LFS-DSS was 100% versus 88% (P = .030), and ultimate locoregional control was 100% in both groups. CONCLUSIONS: Patients with T1aN0 glottic SCC treated with RT or TLM have similar survival outcomes. Patients with T1a tumor treated with TLM have better organ preservation compared to RT, when measured with LFS-DSS. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1322-1327, 2017. PMID- 27778349 TI - Salvage esophagectomy after failure of definitive radiochemotherapy for esophageal cancer. AB - BACKGROUND: Definitive radiochemotherapy (dRCT) in locally advanced esophageal cancer is associated with a high rate of loco-regional recurrence. In this condition, salvage esophagectomy may be considered as a therapeutic option. The aim of this analysis is to evaluate the feasibility and the morbi-mortality of this strategy. METHODS: Between January 2006 and April 2014, 208 patients underwent esophagectomy for esophageal cancer at ULB-Erasme-Bordet. Thirty-two patients received a preoperative radiochemotherapy (pRCT) followed by planned esophagectomy (Group 1) for locally advanced disease. Sixteen patients underwent salvage esophagectomy for recurrence or failure after dRCT (Group 2). Data on post-operative morbidity and mortality and survival were collected and analyzed. RESULTS: An increase of overall morbidity was detected in Group 2 as compared to Group 1 (43% vs. 37.5%), mainly related to respiratory complications (35.5% vs. 28%) and anastomotic leak (25% vs. 3%). No 90-days mortality was observed in the two surgical groups. The 1, 2, and 3-year survival rates after surgery were respectively 89%, 80%, and 71% for Group1 and 84%, 73%, and 63% for Group 2. CONCLUSIONS: In our experience, both salvage esophagectomy and esophagectomy after pRCT showed good survival results with low postoperative morbidity and mortality. Salvage surgery remains a therapeutic indication in selected patients. J. Surg. Oncol. 2016;114:833-837. (c) 2016 2016 Wiley Periodicals, Inc. PMID- 27778347 TI - Hippocampal GABAergic transmission: a new target for adenosine control of excitability. AB - Physiological network functioning in the hippocampus is dependent on a balance between glutamatergic cell excitability and the activity of diverse local circuit neurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Tuners of neuronal communication such as adenosine, an endogenous modulator of synapses, control hippocampal network operations by regulating excitability. Evidence has been recently accumulating on the influence of adenosine on different aspects of GABAergic transmission to shape hippocampal function. This review addresses how adenosine, through its high-affinity A1 (A1 R) and A2A receptors (A2A R), interferes with different GABA-mediated forms of inhibition in the hippocampus to regulate neuronal excitability. Adenosine mediated modulation of phasic/tonic inhibitory transmission, of GABA transport mechanisms and its interference with other modulatory systems are discussed together with the putative implications for neuronal function in physiological and pathological conditions. This article is part of a mini review series: 'Synaptic Function and Dysfunction in Brain Diseases'. PMID- 27778352 TI - Long-Term Stability and Clinical Utility of Amplified Atrial Electrograms in a Single-Lead ICD System with Floating Atrial Electrodes. AB - BACKGROUND: Available atrial electrograms in implantable cardioverter defibrillators (ICDs) improve arrhythmia diagnosis, allow monitoring for atrial fibrillation, and may reduce the risk of inappropriate therapies. A recently introduced ICD system using a single-lead with floating atrial electrodes provides diagnostic capability of a dual-chamber system without placing an additional lead. Data on long-term clinical performance of this system are limited. METHODS: We retrospectively analyzed data from 35 consecutive patients implanted with Biotronik VR-T DX devices and LinoxSmart DX leads. (Biotronik, SE & Co., Berlin, Germany) RESULTS: Of 35 patients (77% male, age 52 +/- 11.28 years), 32 were followed for a mean of 432 +/- 197 days (range 56-765). During implantation, average preamplified and amplified sinus P-wave amplitudes were 2.61 +/- 1.39 mV (range 0.9-6.8 mV) and 8.7 +/- 4.51 mV (range 1.4-18 mV), respectively. Despite statistically significant variations, the amplified P-wave amplitude measurements (calculated mean values over 3 months) remained within a clinically acceptable range during follow-up (5.4-8.7 mV). R-wave amplitude and ventricular pacing threshold measurements were stable over time. A total of 13 stored arrhythmia events (three ventricular tachycardia, eight supraventricular tachycardia, two atrial fibrillation) were reviewed. All of them showed readily interpretable atrial electrograms. Eight out of 10 (80%) supraventricular events were correctly classified by the device. Three patients received inappropriate ICD therapies. CONCLUSION: The single-lead ICD system using a floating atrial dipole provides reliable recording of atrial signals during sinus rhythm and arrhythmias. Our data suggest that the system may offer diagnostic advantages of a dual-chamber device without potential risks of an additional atrial lead. PMID- 27778348 TI - Trends in childhood leukemia incidence over two decades from 1992 to 2013. AB - Incidence rates of childhood leukemia in the United States have steadily increased over the last several decades, but only recently have disparities in the increase in incidence been recognized. In the current analysis, Surveillance, Epidemiology and End Results (SEER) data were used to evaluate recent trends in the incidence of childhood leukemia diagnosed at age 0-19 years from 1992 to 2013, overall and by age, race/ethnicity, gender and histologic subtype. Hispanic White children were more likely than non-Hispanic White, non-Hispanic Black or non-Hispanic Asian children to be diagnosed with acute lymphocytic leukemia (ALL) from 2009 to 2013. From 1992 to 2013, a significant increase in ALL incidence was observed for Hispanic White children [annual percent change (APC)Hispanic = 1.08, 95% CI: 0.59, 1.58]; no significant increase was observed for non-Hispanic White, Black or Asian children. ALL incidence increased by about 3% per year from 1992 to 2013 for Hispanic White children diagnosed from 15 to 19 years (APC = 2.67; 95% CI: 0.88, 4.49) and by 2% for those 10-14 years (APC = 2.09; 95% CI: 0.57, 3.63), while no significant increases in incidence were observed in non Hispanic White, Black, or Asian children of the same age. Acute myeloid leukemia (AML) incidence increased among non-Hispanic White children under 1 year at diagnosis, and among Hispanic White children diagnosed at age 1-4. The increase in incidence rates of childhood ALL appears to be driven by rising rates in older Hispanic children (10-14, and 15-19 years). Future studies are needed to evaluate reasons for the increase in ALL among older Hispanic children. PMID- 27778351 TI - His-Bundle Pacing: Full Circle and Maybe a Bull's Eye. PMID- 27778350 TI - Cell-free DNA is higher and more fragmented in intrahepatic cholestasis of pregnancy. PMID- 27778354 TI - Leon Goldman: Dermatologist & surgeon; pioneer and leader in laser surgery and medicine (1905-1997). PMID- 27778353 TI - Rooting for cassava: insights into photosynthesis and associated physiology as a route to improve yield potential. AB - Contents 50 I. 50 II. 52 III. 54 IV. 55 V. 57 VI. 57 VII. 59 60 References 61 SUMMARY: As a consequence of an increase in world population, food demand is expected to grow by up to 110% in the next 30-35 yr. The population of sub Saharan Africa is projected to increase by > 120%. In this region, cassava (Manihot esculenta) is the second most important source of calories and contributes c. 30% of the daily calorie requirements per person. Despite its importance, the average yield of cassava in Africa has not increased significantly since 1961. An evaluation of modern cultivars of cassava showed that the interception efficiency (Ei ) of photosynthetically active radiation (PAR) and the efficiency of conversion of that intercepted PAR (Ec ) are major opportunities for genetic improvement of the yield potential. This review examines what is known of the physiological processes underlying productivity in cassava and seeks to provide some strategies and directions toward yield improvement through genetic alterations to physiology to increase Ei and Ec . Possible physiological limitations, as well as environmental constraints, are discussed. PMID- 27778355 TI - Skin pre-ablation and laser assisted microjet injection for deep tissue penetration. AB - BACKGROUND AND AIMS: For conventional needless injection, there still remain many unresolved issues such as the potential for cross-contamination, poor reliability of targeted delivery dose, and significantly painstaking procedures. As an alternative, the use of microjets generated with Er:YAG laser for delivering small doses with controlled penetration depths has been reported. In this study, a new system with two stages is evaluated for effective transdermal drug delivery. First, the skin is pre-ablated to eliminate the hard outer layer and second, laser-driven microjet penetrates the relatively weaker and freshly exposed epidermis. Each stage of operation shares a single Er:YAG laser that is suitable for skin ablation as well as for the generation of a microjet. METHODS: In this study, pig skin is selected for quantification of the injection depth based on the two-stage procedure, namely pre-ablation and microjet injection. The three types of pre-ablation devised here consists of bulk ablation, fractional ablation, and fractional-rotational ablation. The number of laser pulses are 12, 18, and 24 for each ablation type. For fractional-rotational ablation, the fractional beams are rotated by 11.25 degrees at each pulse. The drug permeation in the skin is evaluated using tissue marking dyes. The depth of penetration is quantified by a cross sectional view of the single spot injections. Multi-spot injections are also carried out to control the dose and spread of the drug. RESULTS: The benefits of a pre-ablation procedure prior to the actual microjet injection to the penetration is verified. The four possible combinations of injection are (a) microjet only; (b) bulk ablation and microjet injection; (c) fractional ablation and microjet injection; and (d) fractional-rotational ablation and microjet injection. Accordingly, the total depth increases with injection time for all cases. In particular, the total depth of penetration attained via fractional pre-ablation increased by 8 ~ 11% and that of fractional rotational pre-ablation increased by 13 ~ 33%, when compared with the no pre ablation or microjet only cases. A noticeable point is that the fraction rotational pre-ablation and microjet result is comparable to the bulk ablation and microjet result of 11 ~ 42%. The penetration depth underneath ablated stratum corneum (SC) is also measured in order to verify the pre-ablation effect. The penetration depths for each case are (a) 443 +/- 104 um; (b) 625 +/- 98 um; (c) 523 +/- 95 um; and (d) 595 +/- 141 um for microjet only, bulk ablation and microjet, fractional ablation and microjet, and fractional-rotational ablation and microjet, respectively. This is quite beneficial since any healing time associated with ablation is significantly reduced by avoiding hard-core bulk ablation. Thus the bulk pre-ablation and microjet may well be superseded by the less invasive fractiona-rotational ablation followed by the microjet injection. The density of micro-holes is 1.27 number/mm2 for fractional ablation and 4.84 number/mm2 for fractional-rotational ablation. The penetration depths measured underneath the ablated SC are 581 um (fractional ablation and microjet) and 691 um (fractional-rotational ablation and microjet). CONCLUSIONS: Fractional rotational ablation increases number of micro-holes in a unit area, enabling fast reepithelialization and high drug delivery efficiency. Optimization of system parameters such as ablation time, number of ablations, and injection time will eventually ensure a macromolecule delivery technique with the potential to include vaccines, insulins, and growth hormones, all of which require deeper penetration into the skin. Lasers Surg. Med. 49:387-394, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27778356 TI - Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid-beta (Abeta)42 peptides. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most frequent cause of dementia in the aged population. According to the amyloid hypothesis, the amyloid-beta (Abeta) peptide plays a key role in the pathogenesis of AD. Abeta is generated from the amyloidogenic processing of amyloid precursor protein and can aggregate to form oligomers, which have been described as a major synaptotoxic agent in neurons. Dysfunction of Wnt signaling has been linked to increased Abeta formation; however, several other studies have argued against this possibility. Herein, we use multiple experimental approaches to confirm that the inhibition of Wnt signaling promoted the amyloidogenic proteolytic processing of amyloid precursor protein. We also demonstrate that inhibiting Wnt signaling increases the production of the Abeta42 peptide, the Abeta42 /Abeta40 ratio, and the levels of Abeta oligomers such as trimers and tetramers. Moreover, we show that activating Wnt signaling reduces the levels of Abeta42 and its aggregates, increases Abeta40 levels, and reduces the Abeta42 /Abeta40 ratio. Finally, we show that the protective effects observed in response to activation of the Wnt pathway rely on beta-catenin-dependent transcription, which is demonstrated experimentally via the expression of various 'mutant forms of beta-catenin'. Together, our findings indicate that loss of the Wnt signaling pathway may contribute to the pathogenesis of AD. PMID- 27778357 TI - Patient selection for the surgical treatment of resectable colorectal liver metastases. AB - Advances in surgery and chemotherapy regimens have increased the long-term survival of patients with colorectal liver metastases (CRLM). Although liver resection remains an essential part of any curative strategy for resectable CRLM, chemotherapy regimens have also improved the long-term outcomes. However, the optimal timing for chemotherapy regimens remains unclear. Thus, this review addressed key points to aid the decision-making process regarding the timing of chemotherapy and surgery for patients with resectable CRLM. J. Surg. Oncol. 2017;115:213-220. (c) 2016 Wiley Periodicals, Inc. PMID- 27778358 TI - The role of attentional resources in explaining sex differences in object location memory. AB - Sex differences in object location memory have been widely studied, with mixed results. The role of attention in mediating the female advantage in object location memory has not been clearly understood yet. Two experiments, involving 181 participants and using an actual object array, were conducted in the present study to examine two learning conditions: incidental and intentional. In each experiment, participants were randomly assigned to divided versus full attention conditions. The study also examined memorizing location-maintained and location exchanged objects. In both experiments, in both incidental and intentional learning conditions, women outperformed men in memorizing location-exchanged objects in the full but not in the divided attention condition. These findings confirm and extend previous ones concerning the conditions under which the female advantage in the detection of change in an array of objects occurs. The findings are discussed within an evolutionary conceptual framework. PMID- 27778359 TI - Effects of species co-occurrence on the trophic-niche breadth of characids in Amazon forest streams. AB - This study assessed the width of the trophic niche of four characid species (Bryconops giacopinii, Bryconops inpai, Hyphessobrycon aff. melazonatus and Iguanodectes geisleri) found under different co-occurrence circumstances in Amazonian upland streams. The study was conducted during the rainy season of 2011 at eight sites of two micro-basins of the Ducke Reserve, Manaus, Amazonas, Brazil. The four species were studied in the following circumstances: only one of the species occurring in the stream; two species co-occurring; three species co occurring. The relative volume of the food items in the fish stomachs was used to calculate Hurlbert's trophic-niche breadth for the individuals of each species in the different co-occurrence circumstances. Hyphessobrycon aff. melazonatus changed their diet when occurring in syntopy with other characid species of similar feeding habits, as shown by a significant narrowing of its trophic niche. The opportunistic habits and great feeding flexibility of these characid species make the partitioning of food resources possible and act as an important ecological mechanism that facilitates the coexistence of different species, possibly by attenuating the effects of direct competition for food. In addition, the low carrying capacity of these upland forest streams may be an important environmental factor influencing the results of this study. PMID- 27778360 TI - Sentinel lymph node biopsy and aberrant lymphatic drainage in recurrent breast cancer: Findings likely to change treatment decisions. AB - BACKGROUND AND OBJECTIVES: It is not clear whether sentinel lymph node biopsy (SLNB) can be applied to patients with a second breast cancer or recurrence occurring at previously treated breast. The purpose of this study was to assess the feasibility of SLNB procedure in patients with recurrent breast cancer. METHODS: Patients with non-metastatic recurrent N0 breast cancer at ipsilateral breast were included. Patients were grouped according to their initial breast, axilla, and overall surgery. Presence of drainage and its pattern as well as SLNB success rate and overall axillary involvement rates were assessed. Findings were compared. RESULTS: Out of 75 patients, mean age was 52.5 years and disease-free interval was 82 (9-312) months. Lymphatic drainage was successful in 42 (56%) patients. Drainage positivity was more frequent in patients who were previously treated with SLNB (82.6%) than in patients who underwent axillary lymph node dissection (ALND) (44.2%; P = 0,002). Aberrant lymphatic drainage was detected in 64.3% of drainage positive patients. Success rate of reoperative SLNB was 92.9%. Adjuvant treatment plan was altered in 12 (16%) patients. In 15 patients, negative SLNB prevented axillary dissection. CONCLUSIONS: Reoperative SLNB seems to be technically feasible in N0 recurrent breast cancer patients. It may further avoid unnecessary ALND and lead changes in adjuvant treatment plans. J. Surg. Oncol. 2016;114:796-802. (c) 2016 2016 Wiley Periodicals, Inc. PMID- 27778361 TI - Are voiding parameters a marker for the severity of quality of life impairment in women with overactive bladder symptoms? AB - AIMS: There is evidence of an association between voiding parameters and the presence of overactive bladder symptoms. The aim of this study was to evaluate whether there is any association between pressure flow study parameters and the degree of health related quality of life impairment in women with OAB symptoms. The null hypothesis is that there is no significant correlation between quality of life domain scores and pressure flow study parameters. METHODS: One hundred and sixty-seven consecutive women with overactive bladder symptoms underwent evaluation with a quality of life assessment plus filling and voiding cystometry. These data were used to evaluate for any correlation between pressure flow study parameters and quality of life domain scores. RESULTS: Fifty-six out of 167 women had proven detrusor overactivity (DO). There were no differences in voiding parameters or quality of life scores between women with DO and women without DO. There was no consistent correlation identified between quality of life domain scores and pressure flow variables. CONCLUSIONS: There is no evidence of an association between increasing quality of life impairment and voiding parameters in this cohort. PMID- 27778362 TI - The Australian Pelvic Floor Questionnaire is a valid measure of pelvic floor symptoms in patients following surgery for colorectal cancer. AB - AIMS: This study evaluated the construct validity of the Australian Pelvic Floor Questionnaire against two alternative measures of the severity of bladder and bowel symptoms. METHODS: This was an exploratory analysis of data from two prospective studies. Patients who had undergone surgery for colorectal cancer were analysed. Bladder and bowel symptoms were measured using three validated questionnaires: the Australian Pelvic Floor Questionnaire, the International Consultation on Incontinence Questionnaire Short Form Questionnaire for urinary incontinence and the International Consultation on Incontinence Questionnaire Bowel Module post-cancer treatment. RESULTS: The study sample consisted of 44 participants, including 25 men and 19 women. The Australian Pelvic Floor Questionnaire bladder and bowel domain scores demonstrated moderate positive correlations with the International Consultation on Incontinence Questionnaire Short Form Questionnaire for urinary incontinence (r = 0.74, P < 0.01) and the International Consultation on Incontinence Questionnaire-Bowel Module (r = 0.69 0.78, P < 0.01). Similar results were obtained in each gender subgroup. CONCLUSIONS: This study suggested that the Australian Pelvic Floor Questionnaire may be a valid measurement tool for use in colorectal cancer populations in clinical trials and practice. Future research using larger cohorts is warranted. PMID- 27778364 TI - Primary dermal pleomorphic liposarcoma: utility of adipophilin and MDM2/CDK4 immunostainings. AB - Liposarcoma, usually arises in deep soft tissues and pleomorphic liposarcoma (PL), is the rarest histopathologic variant. However, 15 cases of entirely dermal PL have been reported. We describe a case of a 79-year-old man who developed a rapidly growing nodule on his thorax. Excisional biopsy was performed and immunohistochemical studies were carried. The lesion was a well-circumscribed dermal nodule composed of multivacuolated pleomorphic lipoblasts and atypical mitotic figures. Neoplastic cells expressed CD10 and resulted negative S100 protein, Melan-A, MITF-1, AE1/AE3, CD4, CD68 (PGM1), retinoblastoma gene family protein, pericentrine and lysozyme. Adipophilin stain showed the lipid contents in the cytoplasm of the neoplastic cells. MDM2 and CDK4 resulted both negative. A diagnosis of primary dermal PL was made. This case shows the utility of adipophilin immunostaining to prove the lipid contents in neoplastic cells, which has the advantage of using formalin-fixed paraffin-embedded tissue and making needless frozen sections and ultrastructural studies to show these findings. Negative MDM2/CDK4 staining in our case argues against the possibility of dedifferentiated liposarcoma and further supports the diagnosis of true PL. PMID- 27778363 TI - Review article: novel methods for the treatment of non-alcoholic steatohepatitis targeting the gut immune system to decrease the systemic inflammatory response without immune suppression. AB - BACKGROUND: The systemic immune system plays a role in inflammation and fibrogenesis associated with non-alcoholic steatohepatitis (NASH) and has become a potential target for drug development. In particular, the gut immune system has been suggested as a means for generating signals that can target the systemic immune system. AIM: To describe seven novel methods being developed for the treatment of NASH that target the gut immune system for alleviation of the systemic inflammatory response, including oral administration of fatty-liver derived proteins, anti-CD3 antibodies, tumour necrosis factor fusion protein, anti-lipopolysaccharide antibodies, glucosylceramide, delayed-release mercaptopurine, and soy-derived extracts. METHODS: A search for these methods for oral immunotherapy for NASH was conducted. RESULTS: Oral administration of these compounds provides an opportunity for immune modulation without immune suppression, with the advantage of being independent of a single molecular/inflammatory pathway. These modes of oral immune therapy demonstrate superior safety profiles, such that the patient is not exposed to general immune suppression. Moreover, these approaches target the whole spectrum of the disease and may serve as adjuvants to other therapies, such that they provide a platform for treatment of concomitant disorders in patients with NASH, including diabetes and hyperlipidaemia. Most of the compounds reviewed are currently in phase II trials, and it is anticipated that the acquisition of more clinical data in the next few years will enable the use of this new class of drugs for the treatment of NASH. CONCLUSION: Oral immunotherapy may provide a novel platform for the treatment of NASH. PMID- 27778365 TI - Moderate Prenatal Cadmium Exposure and Adverse Birth Outcomes: a Role for Sex Specific Differences? AB - BACKGROUND/AIM: Studies on the effects of moderate prenatal exposure to cadmium (Cd) on birth outcomes have been contradictory and it has been suggested that effects may be partly masked by sex-specific effects. Our aim was to examine the association of Cd exposure in a large group of pregnant women with birth outcomes in the whole group of participants and by sex. METHODS: Pregnant women were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood samples for singleton pregnancies with a live birth were analysed for Cd (n = 4191). Data collected on the infants included anthropometric variables and gestational age at delivery. Data were analysed using SPSS v18. RESULTS: There were adverse associations of maternal blood Cd level with birthweight (unstandardized B coefficient -62.7 g, 95% CI -107.0, -18.4) and crown-heel length (-0.28 cm, 95% CI -0.48, -0.07) in adjusted regression models. On stratification by sex, maternal blood Cd level was adversely associated with birthweight (-87.1 g, 95% CI -144.8, -29.4), head circumference (-0.22 cm, 95% CI -0.39, -0.04), and crown-heel length (-0.44 cm, 95% CI -0.71, -0.18) in girls but not in boys in adjusted regression models. CONCLUSION: In these pregnant women with moderate prenatal Cd exposure there evidence of adverse associations with birth anthropometry variables in the whole group. However, there was evidence of associations with anthropometric variables in girls that were not evident in boys. Sex-specific effects require further investigation in large cohorts as a possible contributor to the lack of associations generally found in mixed-sex studies. PMID- 27778366 TI - The relationship between different information sources and disease-related patient knowledge and anxiety in patients with inflammatory bowel disease. AB - BACKGROUND: Patient education forms a cornerstone of management of inflammatory bowel disease (IBD). The Internet has opened new avenues for information gathering. AIM: To determine the relationship between different information sources and patient knowledge and anxiety in patients with IBD. METHODS: The use of information sources in patients with IBD was examined via questionnaire. Anxiety was assessed with the hospital anxiety and depression scale and disease related patient knowledge with the Crohn's and colitis knowledge score questionnaires. Associations between these outcomes and demographics, disease related factors, and use of different information sources were analysed using linear regression analysis. RESULTS: Of 307 patients (165 Crohn's disease, 142 ulcerative colitis) 60.6% were female. Participants used the hospital IBD team (82.3%), official leaflets (59.5%), and official websites (53.5%) most frequently in contrast to alternative health websites (9%). University education (P < 0.001), use of immunosuppressants (P = 0.025), Crohn's and Colitis UK membership (P = 0.001), frequent use of the hospital IBD team (P = 0.032), and frequent use of official information websites (P = 0.005) were associated with higher disease related patient knowledge. Female sex (P = 0.004), clinically active disease (P < 0.001), frequent use of general practitioners (P = 0.014), alternative health websites (homoeopathy, nutritionists, etc.) (P = 0.004) and random links (P = 0.016) were independently associated with higher anxiety. CONCLUSIONS: Different patient information sources are associated with better knowledge or worse anxiety levels. Face-to-face education and written information materials remain the first line of patient education. Patients should be guided towards official information websites and warned about the association between the use of alternative health websites or random links and anxiety. PMID- 27778367 TI - Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH. PMID- 27778368 TI - A proposed classification for follicular involvement by melanoma. AB - BACKGROUND: Folliculotropism in melanoma is poorly characterized and standard categorization for follicular involvement by melanoma is unavailable. We propose a logical categorization system. METHODS: We conducted a search of our archives over a 24-year period for cases mentioning the terms follicle, follicular, folliculotropic, folliculocentric and melanoma. RESULTS: We identified 90 cases of melanoma with involvement of the hair follicle. Distinct patterns were identified. The invasive patterns were primary follicular, folliculotropic and invasive arising from melanoma in situ (MIS) with extensive follicular involvement. Follicular involvement by MIS was either lentiginous, nested or a combination of both. A total of 29 invasive melanomas were identified. Of these 12 had invasive melanoma around the hair follicle, 2 were primary follicular melanomas, 7 showed folliculotropism and 3 were invasive melanomas arising from MIS around the follicle. Seventeen invasive melanomas had follicles only involved by MIS (9 nested, 6 nested and lentiginous and 2 lentiginous). A total of 61 cases of MIS with follicular involvement were identified; of these 33 were lentiginous, 10 nested and 18 both lentiginous and nested. CONCLUSION: We propose that the three distinct patterns of follicular involvement by invasive melanoma and the three distinct patterns of MIS will be valuable for logically categorizing involvement of the hair follicle by melanoma. PMID- 27778369 TI - Is bladder neck and urethral mobility associated with urinary incontinence and mode of delivery 4 years after childbirth? AB - AIMS: To study changes in bladder neck, urethral mobility and urinary incontinence (UI) from pregnancy to 4 years postpartum and demonstrate any association to mode of delivery or presence of levator ani muscle (LAM) injury. Secondly, we aimed to correlate bladder neck and urethral mobility to UI symptoms. METHODS: Prospective study of 180 women, recruited in their first pregnancy and followed up 1 and/or 4 years postpartum. UI symptoms were assessed with a validated questionnaire. All underwent 4D transperineal ultrasound to assess LAM injury, bladder neck descent (BND), retrovesical angle at Valsalva (RVA), and urethral rotation between rest and Valsalva. A mixed model compared changes over time, different delivery modes, and women with and without LAM injury. Spearman's rank correlation tested the correlation of BND, RVA, and urethral rotation to UI symptoms. RESULTS: BND, RVA, and urethral rotation all increased following delivery. From 1 to 4 years postpartum, a larger increase in BND was found for women delivered vaginally with LAM injury, compared to women with intact LAM (P = 0.02) and women with cesarean section (P = 0.046). One year postpartum, BND and RVA correlated to UI symptoms, rs = 0.22, P = 0.01. Four years postpartum, RVA correlated to UI symptoms, rs = 0.19, P = 0.02. CONCLUSIONS: Although bladder neck and urethral mobility increased from pregnancy to 4 years postpartum irrespective of delivery mode, women with LAM injury had larger increase in BND, suggesting that this is important in the pathogenesis of bladder neck mobility and could lead to pelvic floor dysfunction in the long term. PMID- 27778370 TI - Test-retest repeatability of patterns of brain activation provoked by bladder filling. AB - OBJECTIVE: To assess short-term repeatability of an fMRI protocol widely used to assess brain control of the bladder. fMRI offers the potential to discern incontinence phenotypes as well as the mechanisms mediating therapeutic response. If so, this could enable more targeted efforts to enhance therapy. Such data, however, require excellent test-retest repeatability. METHODS: Fifty-nine older women (age >=60 years) with urgency incontinence underwent two fMRI scans within 5-10 min with a concurrent bladder infusion/withdrawal protocol. Activity in three brain regions relevant to bladder control was compared using paired t tests and intra-class correlation. RESULTS: There were no statistically significant differences in brain activity between the two consecutive scans in the regions of interest. Intra-class correlation was 0.19 in the right insula, 0.32 in the dorsal anterior cingulate cortex/supplementary motor area, and 0.44 in the medial pre-frontal cortex. Such correlations are considered fair or poor, but are comparable to those from studies of other repeated fMRI tasks. CONCLUSIONS: This is the first evaluation of the repeatability of a bladder fMRI protocol. The technique used provides a framework for comparing different fMRI protocols applied to brain-bladder research. Despite universal patient response to the stimulus, brain response had limited repeatability within individuals. Improvement of the investigational protocol should magnify brain response and reduce variability. These results suggest that although analysis of fMRI data among groups of subjects yields valuable insight into bladder control, fMRI is not yet appropriate for evaluation of the brain's role in continence on an individual level. PMID- 27778371 TI - Long-term course of sacral anterior root stimulation in spinal cord injured individuals: The fate of the detrusor. AB - AIMS: To investigate the long-term course of the detrusor pressure during sacral anterior root stimulation in spinal cord injury (SCI) patients. METHODS: Retrospective evaluation of 111 patients who had undergone sacral deafferentation and implantation of an anterior root stimulator at a single SCI rehabilitation center with a minimum follow-up time of 5 years. RESULTS: The median follow-up time was 11.7 years (range 5.0-24.9 years). The maximum detrusor pressure (Pdet_max) during stimulation was higher in men compared to women (P = 0.0004) and decreased over time (P = 0.0006). However, there were no significant (P >= 0.06) differences in the median Pdet_max during stimulation between the first measurement time point and any follow-up time point. The Pdet_max during stimulation decreased from 62 cmH2 O (95%CI 57-73 cmH2 O) to 53 cmH2 O (95%CI 47 69 cmH2 O) (P = 0.9). The time had also a significant effect on Pdet_max during the storage phase (P < 0.0001) and bladder compliance (P = 0.0007). The Pdet_max during the storage phase decreased, whereas bladder compliance increased during the follow-up period. There were no significant (P >= 0.1) changes over time in bladder capacity, the number of daily stimulations and the residual urine volume after voiding. CONCLUSIONS: The detrusor pressure during sacral anterior root stimulation decreases over time in SCI individuals. However, the changes do not seem to be clinically relevant during the first decade after surgery. PMID- 27778372 TI - Lumbosacral spinal segmental contributions to tibial and pudendal neuromodulation of bladder overactivity in cats. AB - AIMS: To determine the spinal segmental afferent contributions to tibial and pudendal inhibition of bladder overactivity. METHODS: Intravesical infusion of 0.5% acetic acid was used to irritate the bladder and induce bladder overactivity in anesthetized cats. Tibial or pudendal nerve stimulation was used to suppress the bladder overactivity and increase bladder capacity during cystometry. L5-S3 dorsal roots ipsilateral to the stimulation were exposed by a laminectomy and transected sequentially during the experiments to determine the role of individual dorsal roots in tibial or pudendal neuromodulation. RESULTS: Transection of L5 dorsal root had no effect. Transection of L6 dorsal root in four cats produced an average 18% reduction in tibial inhibition, which is not a significant change when averaged in the group of 10 cats. Transection of L7 dorsal root completely removed the tibial inhibition without changing reflex bladder activity or pudendal inhibition. Transection of S1 dorsal root reduced the pudendal inhibition, after which transection of S2 dorsal root completely removed the pudendal inhibition. Transection of S3 dorsal root had no effect. The control bladder capacity was increased only by transection of S2 dorsal root. CONCLUSIONS: This study in cats revealed that tibial and pudendal neuromodulation of reflex bladder overactivity depends on activation of primary afferent pathways that project into different spinal segments. This difference may be related to the recent observation in cats that the two types of neuromodulation have different mechanisms of action. PMID- 27778373 TI - Urinary incontinence, but not fecal incontinence, is a risk factor for admission to aged residential care of older persons in New Zealand. AB - AIMS: To determine if urinary incontinence (UI) and fecal incontinence (FI) were independent risk factors for aged resident care (ARC) admissions for older people, after controlling for confounders and applying apposite statistical methods. METHODS: Since 2012, all community care recipients in New Zealand have undergone a standardized needs assessment using the Home Care International Residential Assessment Instrument (interRAI-HC). The interRAI-HC instrument elicits information on 236 questions over 20 domains, including UI and FI frequency within the last 3 days. Those aged 65+ years with an interRAI-HC assessment between July 1, 2012 and May 31, 2014 were matched to national mortality and ARC databases, and competing-risk regression models applied to those without collection devices or indwelling catheters who were admitted to ARC or alive 30+ days after their interRAI-HC assessment. RESULTS: Overall, 32 285 people were eligible, with average age of 82.1 years (range 65, 105 years) of whom 20 627 (63.9%) were female. UI and FI was reported by 36.4% and 12.9% of people, respectively. By June 30, 2014, 5993 (18.6%) had an ARC admission and 5443 (16.9%) had died before any such admission. In the multivariable analysis, the subhazard ratio (SHR) for ARC admission was significant for UI (SHR = 1.11, 95%CI: 1.05, 1.18) but not for FI (SHR = 1.07, 95%CI: 0.99, 1.16). CONCLUSIONS: UI is a common, independent risk factor for ARC admissions. Identifying the extent of incontinence and its impact on ARC admissions is the first vital step in addressing the burgeoning need for better community continence services. PMID- 27778374 TI - Prevalence of drug-related problems associated with direct oral anticoagulants in hospitalized patients: a multicenter, cross-sectional study. AB - WHAT IS KNOWN AND OBJECTIVE: The complex dose regimens of the direct-acting oral anticoagulants (DOAC) make their appropriate prescribing highly challenging. Inappropriate prescribing of the DOAC remains poorly addressed. We studied the patterns of DOAC prescription and estimated the prevalence of drug-related problems (DRPs) associated with their use. METHODS: A cross-sectional study was conducted using data from medical records system of the Lyon teaching hospitals. DRPs, identified among patients who received a DOAC, between 1 January 2010 and 31 July 2013, were categorized according to the Pharmaceutical Care Network Europe Classification System. The prevalence of hospital stays with a DRP was estimated, and a subgroup analysis according to DOAC and their indication for use was provided. Clinical outcomes were not assessed. RESULTS: Of the 4154 hospital stays with at least one DOAC administration [3412 patients; median age (range): 71 years (14-98), 57% female], 70.8% were excluded from the analysis mainly due to missing information for renal function and/or patient weight. Of the 1188 hospital stays that were screened, 100 DRPs were identified (prevalence 8.4%; 95% CI, 6.8-10.0). The highest prevalence was found among patients who received rivaroxaban for atrial fibrillation (14.6%; 95% CI, 10.7-18.5). A too low drug dose was the most frequent DRP (n = 56; 4.7%), followed by a too high drug dose (n = 37; 3.1%), contraindication (n = 5; 0.4%), and pharmacokinetic problem requiring dose adjustment (n = 2; 0.2%). WHAT IS NEW AND CONCLUSION: Drug-related problems associated with the DOACs occur quite commonly among hospitalized patients. Although these DRPs were considered to be of minor severity, prescribing protocols to support better prescribing should be disseminated to reduce the risk to patients. Renal function and body weight data should be mandatory on prescriptions to allow cross-checking. PMID- 27778375 TI - Mycophenolate mofetil improves renal haemodynamics, microvascular oxygenation, and inflammation in a rat model of supra-renal aortic clamping-mediated renal ischaemia reperfusion injury. AB - Ischaemia/reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), which is characterized by sterile inflammation and oxidative stress. Immune cell activation can provoke overproduction of inflammatory mediators and reactive oxygen species (ROS), leading to perturbation of the microcirculation and tissue oxygenation associated with local and remote tissue injury. This study investigated whether the clinically employed immunosuppressant mycophenolate mofetil (MMF) was able to reduce I/R-induced renal oxygenation defects and oxidative stress by preventing sterile inflammation. Rats were divided into three groups (n=6/group): (1) a sham-operated control group; (2) a group subjected to renal I/R alone (I/R); and (3) a group subjected to I/R and MMF treatment (20 mg/kg prior to I/R) (I/R+MMF). Ischaemia was induced by a vascular occluder placed on the abdominal aorta for 30 minutes, followed by 120 minutes of reperfusion. Renal I/R deteriorated renal oxygenation (P<.001) and oxygen delivery (P<.01), reduced creatinine clearance (P<.01) and tubular sodium reabsorption (P<.001), and increased iNOS, renal tissue injury markers (P<.001), and IL-6 (P<.001). Oral MMF administration prior to insult restored renal cortical oxygenation (P<.05) and iNOS, renal injury markers, and inflammation parameters (P<.001) to near-baseline levels without affecting renal function. MMF exerted a prophylactic effect on renal microvascular oxygenation and abrogated tissue inflammation and renal injury following lower body I/R-induced AKI. These findings may have clinical implications during major vascular or renal transplant surgery. PMID- 27778376 TI - Post-injury bladder management strategy influences lower urinary tract dysfunction in the mouse model of spinal cord injury. AB - AIMS: To examine the effects of a different number of daily bladder squeezes on bladder dysfunction in mice with spinal cord injury (SCI). METHODS: Spinal cord was transected at the Th8/9 in female C57BL/6N mice. Their bladders were manually squeezed to eliminate urine inside every day for 4 weeks. The mice were divided into three groups depending on the number of bladder squeezes; A: once daily, B: twice daily, C: three times daily. Four weeks after transection, single-filling cystometry were performed under an awake condition. NGF in the bladder mucosa and mRNA expression of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured. RESULTS: Bladder weight in group C was less than that of group A. Bladder capacity, post-void residual, and the number of non-voiding contractions during the storage phase were significantly larger in group A compared to group B or C. The level of NGF in groups C were lower compared to group A or B. The expression of P2X3 and TRPA1 in groups B and C was decreased compared to group A. The expression of P2X2 was decreased in groups B compared to group A. CONCLUSION: The post-injury bladder management after SCI with an increased number of daily bladder emptying improves the storage and voiding bladder dysfunction associated with the reduction of NGF in the bladder as well as P2X and TRP transcripts in lumbosacral DRG. PMID- 27778377 TI - Dynamics of PDGFRbeta expression in different cell types after brain injury. AB - Platelet-derived growth factor receptor beta (PDGFRbeta) is upregulated after brain injury and its depletion results in the blood-brain barrier (BBB) damage. We investigated the time-window and localization of PDGFRbeta expression in mice with intrahippocampal kainic acid-induced status epilepticus (SE) and in rats with lateral fluid-percussion-induced traumatic brain injury (TBI). Tissue immunohistochemistry was evaluated at several time-points after SE and TBI. The distribution of PDGFRbeta was analyzed, and its cell type-specific expression was verified with double/triple-labeling of astrocytes (GFAP), NG2 cells, and endothelial cells (RECA-1). In normal mouse hippocampus, we found evenly distributed PDGFRbeta+ parenchymal cells. In double-labeling, all NG2+ and 40% 60% GFAP+ cells were PDGFRbeta+. After SE, PDGFRbeta+ cells clustered in the ipsilateral hilus (178% of that in controls at fourth day, 225% at seventh day, P < 0.05) and in CA3 (201% at seventh day, P < 0.05), but the total number of PDGFRbeta+ cells was not altered. As in controls, PDGFRbeta-immunoreactivity was detected in parenchymal NG2+ and GFAP+ cells. We also observed PDGFRbeta+ structural pericytes, detached reactive pericytes, and endothelial cells. After TBI, PDGFRbeta+ cells clustered in the perilesional cortex and thalamus, particularly during the first post-injury week. PDGFRbeta immunopositivity was observed in NG2+ and GFAP+ cells, structural pericytes, detached reactive pericytes, and endothelial cells. In some animals, PDGFRbeta vascular staining was observed around the cortical glial scar for up to 3 months. Our data revealed an acute accumulation of PDGFRbeta+ BBB-related cells in degenerating brain areas, which can be long lasting, suggesting an active role for PDGFRbeta signaling in blood vessel and post-injury tissue recovery. GLIA 2017;65:322-341. PMID- 27778379 TI - Controlling the BET Surface Area of Porous Carbon by Using the Cd/C Ratio of a Cd MOF Precursor and Enhancing the Capacitance by Activation with KOH. AB - Herein, four new cadmium metal-organic frameworks (Cd-MOFs), [Cd(bib)(bdc)]infinity (1), [Cd(bbib)(bdc)(H2 O)]infinity (2), [Cd(bibp)(bdc)]infinity (3), and [Cd2 (bbibp)2 (bdc)2 (H2 O)]infinity (4), have been constructed from the reaction of Cd(NO3 )2 ?4 H2 O with 1,4 benzenedicarboxylate (H2 bdc) and structure-related bis(imidazole) ligands (1,4 bis(imidazol-1-yl)benzene (bib), 1,4-bis(benzoimidazol-1-yl)benzene (bbib), 4,4' bis(imidazol-1-yl)biphenyl (bibp), and 4,4'-bis(benzoimidazol-1-yl)biphenyl (bbibp)) under solvothermal conditions. Cd-MOF 1 shows a 2D (4,4) lattice with parallel interpenetration, whereas 2 displays an interesting 3D interpenetrating dia network, 3 exhibits an unusual 3D interpenetrating dmp network, and 4 presents a 3D self-catenated pillar-layered framework with a Schafli symbol of [43 ?63 ]2 ?[46 ?616 ?86 ]. The structural diversity indicates that the backbone of the bis(imidazole) ligand (including the terminal group and spacer) plays a crucial role in the assembly of mixed-ligand frameworks. By using the pore forming effect of cadmium vapor, for the first time we have utilized these Cd MOFs as precursors to further prepare porous carbon materials (PCs) in a calcination-thermolysis procedure. These PCs show different porous features that correspond to the topological structures of Cd-MOFs. Significantly, it was found that the specific surface area and capacitance of PCs are tuned by the Cd/C ratio of the MOF. Furthermore, the as-synthesized PCs were processed with KOH to obtain activated porous carbon materials (APCs) with higher specific surface area and porosity, which greatly promoted the energy-storage capacity. After full characterization, we found that APC-bib displays the largest specific surface area (1290 m2 g-1 ) and total pore volume (1.37 cm3 g-1 ) of this series of carbon materials. Consequently, APC-bib demonstrates the highest specific capacitance of 164 F g-1 at a current density of 0.5 A g-1 , and also excellent retention of capacitance (~89.4 % after 5000 cycles at 1 A g-1 ). Therefore, APC bib has great potential as the electrode material in a supercapacitor. PMID- 27778380 TI - Precision Construction of 2D Heteropore Covalent Organic Frameworks by a Multiple Linking-Site Strategy. AB - Integrating different kinds of pores into one covalent organic framework (COF) endows it with hierarchical porosity and thus generates a member of a new class of COFs, namely, heteropore COFs. Whereas the construction of COFs with homoporosity has already been well developed, the fabrication of heteropore COFs still faces great challenges. Although two strategies have recently been developed to successfully construct heteropore COFs from noncyclic building blocks, they suffer from the generation of COF isomers, which decreases the predictability and controllability of construction of this type of reticular materials. In this work, this drawback was overcome by a multiple-linking-site strategy that offers precision construction of heteropore COFs containing two kinds of hexagonal pores with different shapes and sizes. This strategy was developed by designing a building block in which double linking sites are introduced at each branch of a C3 -symmetric skeleton, the most widely used scaffold to construct COFs with homogeneous porosity. This design provides a general way to precisely construct heteropore COFs without formation of isomers. Furthermore, the as-prepared heteropore COFs have hollow-spherical morphology, which has rarely been observed for COFs, and an uncommon staggered AB stacking was observed for the layers of the 2D heteropore COFs. PMID- 27778381 TI - Controlled Orthogonal Self-Assembly of Heterometal-Decorated Coordination Cages. AB - Multiple orthogonal coordinative interactions were utilized to construct heterometal-decorated tetrahedral cages from in situ formed trinuclear ZrIV clusters through the combination with other metal ions such as CuII or PdII . Through effective use of the hard/soft acid/base principle, the orthogonal self assembly process of Zr-bpydc-CuCl2 (H2 bpydc=2,2-bipyridine-5,5-dicarboxylic acid) can be finely controlled using three strategies: post-synthetic metallization, a stepwise metalloligand approach, or a one-pot reaction. PMID- 27778378 TI - Morphology of visual sector thalamic reticular neurons in the macaque monkey suggests retinotopically specialized, parallel stream-mixed input to the lateral geniculate nucleus. AB - The thalamic reticular nucleus (TRN) is a unique brain structure at the interface between the thalamus and the cortex. Because the TRN receives bottom-up sensory input and top-down cortical input, it could serve as an integration hub for sensory and cognitive signals. Functional evidence supports broad roles for the TRN in arousal, attention, and sensory selection. How specific circuits connecting the TRN with sensory thalamic structures implement these functions is not known. The structural organization and function of the TRN is particularly interesting in the context of highly organized sensory systems, such as the primate visual system, where neurons in the retina and dorsal lateral geniculate nucleus of the thalamus (dLGN) are morphologically and physiologically distinct and also specialized for processing particular features of the visual environment. To gain insight into the functional relationship between the visual sector of the TRN and the dLGN, we reconstructed a large number of TRN neurons that were retrogradely labeled following injections of rabies virus expressing enhanced green fluorescent protein (EGFP) into the dLGN. An independent cluster analysis, based on 10 morphological metrics measured for each reconstructed neuron, revealed three clusters of TRN neurons that differed in cell body shape and size, dendritic arborization patterns, and medial-lateral position within the TRN. TRN dendritic and axonal morphologies are inconsistent with visual stream specific projections to the dLGN. Instead, TRN neuronal organization could facilitate transmission of global arousal and/or cognitive signals to the dLGN with retinotopic precision that preserves specialized processing of foveal versus peripheral visual information. J. Comp. Neurol. 525:1273-1290, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27778382 TI - Merging elemental and macronutrient approaches for a comprehensive study of energy and nutrient flows. AB - Global warming and predation risk can have important impacts on animal physiology and life histories that can have consequences for ecosystem function. Zhang et al. () recently tested the separate and interactive effects of warming and predation risk on the body composition of Daphnia magna. By measuring both the elemental and biochemical composition of individuals, they showed that D. magna body elemental composition responded opposite to theoretical predictions and previous studies but that these changes were explained by adaptive life-history shifts in allocation to protein in eggs versus body lipid reserves. Photograph by Joachim Mergeay. Zhang, C., Jansen, M., De Meester, L. & Stoks, R. (2016) Energy storage and fecundity explain deviations from ecological stoichiometry predictions under global warming and size-selective predation. Journal of Animal Ecology 85, 1431-1441. Understanding the mechanisms through which energy and nutrients flow through ecosystems is critical to predicting and mitigating the consequences of climate change and other ecological disturbances. Ecological stoichiometry and nutritional geometry, using data on elements and macromolecules, respectively, have independently made major contributions towards this goal. Zhang et al. () provide data demonstrating that these two major frameworks can provide complementary insight into the consequences of global warming and predation risk for the physiology and life-history traits of a key aquatic herbivore, Daphnia magna. This study should catalyse further work to unite these two parallel and complementary frameworks. PMID- 27778383 TI - Natural history matters: how biological constraints shape diversified interactions in pollination networks. AB - Species-specific traits constrain the ways organisms interact in nature. Some pairwise interactions among coexisting species simply do not occur; they are impossible to observe despite the fact that partners coexist in the same place. The author discusses these 'forbidden links' of species interaction networks. Photo: a sphingid moth, Manduca sexta visiting a flower of Tocoyena formosa (Rubiaceae) in the Brazilian Cerrado; tongue and corolla tube lengths approximately 100 mm. Courtesy of Felipe Amorim. Sazatornil, F.D., More, M., Benitez-Vieyra, S., Cocucci, A.A., Kitching, I.J., Schlumpberger, B.O., Oliveira, P.E., Sazima, M. & Amorim, F.W. (2016) Beyond neutral and forbidden links: morphological matches and the assembly of mutualistic hawkmoth-plant networks. Journal of Animal Ecology, 85, 1586-1594. Species-specific traits and life history characteristics constrain the ways organisms interact in nature. For example, gape-limited predators are constrained in the sizes of prey they can handle and efficiently consume. When we consider the ubiquity of such constrains, it is evident how hard it can be to be a generalist partner in ecological interactions: a free-living animal or plant cannot simply interact with every available partner it encounters. Some pairwise interactions among coexisting species simply do not occur; they are impossible to observe despite the fact that partners coexist in the same place. Sazatornil et al. () explore the nature of such constraints in the mutualisms among hawkmoths and the plants they pollinate. In this iconic interaction, used by Darwin and Wallace to vividly illustrate the power of natural selection in shaping evolutionary change, both pollinators and plants are sharply constrained in their interaction modes and outcomes. PMID- 27778384 TI - Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the beta-Adrenoreceptor Antagonists Carazolol and Carvedilol. AB - We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the beta-adrenoreceptor antagonists (-)-(S)-carazolol (5) and (-)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5 hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent. PMID- 27778385 TI - Congenital Milium of the Nipple. AB - A 12-month-old girl presented with an asymptomatic, pearly nodule on the left nipple that had been present from birth and was currently 3 mm in diameter and growing. Assuming the diagnosis of congenital primary milium of the nipple, we took a "wait and see" approach. After 3 months, the pearl disappeared without any scarring. PMID- 27778386 TI - Case of Pediatric Bullous Systemic Lupus Erythematosus Treated with Intravenous Immunoglobulin. AB - This is a case report of a 16-year-old girl recently diagnosed with systemic lupus erythematosus (SLE) who presented with multiple blisters on the face, hands, arms, legs, trunk, and vaginal and oral mucosa. Skin biopsy was consistent with bullous SLE (BSLE). Dapsone is often the first-line treatment option for BSLE, but the patient's history of anemia and leukopenia and long-term immunosuppression requirement for her systemic symptoms raised concerns about dapsone and bone marrow toxicity, especially hemolytic anemia and agranulocytosis. She was started on intravenous immunoglobulin (IVIG), 2 g/kg divided over 3 days, with significant improvement in her cutaneous symptoms. IVIG is a treatment option for BSLE patients in whom agents such as dapsone are contraindicated. PMID- 27778387 TI - AIM-1: An Antibiotic-Degrading Metallohydrolase That Displays Mechanistic Flexibility. AB - Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo-beta-lactamases (MBL) have evolved to inactivate most of the commonly used beta-lactam antibiotics. AIM-1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM-1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors. PMID- 27778388 TI - Detrusor overactivity increases bladder wall thickness in male patients: A urodynamic multicenter cohort study. AB - AIMS: To evaluate the role of Bladder wall thickness (BWT) as a predictor of Detrusor overactivity (DO) in patients with Lower urinary tract symptoms (LUTS)/Benign prostatic enlargement without Bladder Outlet Obstruction. METHODS: From January 1996 to December 2000, each new patient, aged 45 years or older with LUTS, underwent standard diagnostic assessment, urodynamic studies (cystometry and pressure flow studies), and ultrasound measurements of the bladder wall thickness (BWT) in two centers. In order to exclude the possible effect of benign prostatic obstruction (BPO) on detrusor thickness, patients with a Schaefer class was >=2 were excluded from the study. The area under the receiver operating characteristics curve (AUC) quantified the predictive accuracy (PA) of BWT for the diagnosis of DO. RESULTS: Overall 195 patients were enrolled. DO was observed in 98/195 patients (50%). The BWT presented an AUC of 0.70; 95% CI: 0.62-0.77 for the diagnosis of DO. At the best cut-off value of 3.85 mm sensitivity was 73%; specificity was 59%; positive predictive value (64%, PPV). Negative predictive value (69%, NPV). CONCLUSIONS: Our study firstly showed, how BWT in male patients may be a consequence of DO other than BPO. Our finding, if confirmed in further studies, could limit the accuracy of BWT in patients with DO and BPO. PMID- 27778390 TI - Incarceration of Higher-Order Fullerenes within Cyclotriveratrylene-Based Hemicarcerands Allows Selective Isolation of C76 , C78 , and C84 from a Commercial Fullerene Mixture. AB - Size-complementary cyclotriveratrylene (CTV)-based hosts can incarcerate C76 , C78 , and C84 , thus allowing the selective isolation of these higher-order fullerenes from a commercially available mixture of fullerenes. The hemicarceplexes, formed after the encapsulation of the size-complementary fullerenes within the hosts, are isolated by column chromatography and released at elevated temperature, thereby leading to the isolation of C76 /C78 and C84 in good purities (up to 95 and 88 %, respectively). PMID- 27778389 TI - Beckwith-Wiedemann Syndrome and Primary Lymphedema of the Lower Extremity. AB - Beckwith-Wiedemann syndrome is the most common genetic overgrowth syndrome. Patients with Beckwith-Wiedemann syndrome may have hemihypertrophy, but their lymphatic vasculature is intact. We present a child with Beckwith-Wiedemann syndrome and lower extremity enlargement thought to be due to hemihypertrophy that was instead diagnosed with primary lymphedema. There are many causes of leg overgrowth in the pediatric population and misdiagnosis is common. While extremity enlargement secondary to hemihypertrophy may occur in 15% of patients with Beckwith-Wiedemann syndrome, progression and pitting edema only occur in primary lymphedema. This report highlights the importance of ensuring an accurate diagnosis so that patients are managed appropriately. PMID- 27778391 TI - Sclerotic Regressing Large Congenital Nevus. AB - Regression of congenital nevi is usually associated with loss of pigment or halo formation. In rare cases, regression is characterized by sclerosis and hair loss. We describe a rare case of a sclerotic hypopigmented large congenital melanocytic nevus in which a localized scleroderma-like reaction process of regression seemed to have started in utero and progressed throughout early childhood. PMID- 27778392 TI - Can positive inquiry strengthen obstetric referral systems in Cambodia? AB - Maternal death remains high in low resource settings. Current literature on obstetric referral that sets out to tackle maternal death tends to focus on problematization. We took an alternative approach and rather asked what works in contemporary obstetric referral in a low income setting to find out if positive inquiry could generate original insights on referral that could be transformative. We documented and analysed instances of successful referral in a rural province of Cambodia that took place within the last year. Thirty women, their families, healthcare staff and community volunteers were purposively sampled for in-depth interviews, conducted using an appreciative inquiry lens. We found that referral at its best is an active partnership between families, community and clinicians that co-constructs care for labouring women during referral and delivery. Given the short time frame of the project we cannot conclude if this new understanding was transformative. However, we can show that acknowledging positive resources within contemporary referral systems enables health system stakeholders to widen their understanding of the kinds of resources that are available to them to direct and implement constructive change for maternal health. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27778393 TI - Synthesis of Functional Bis(pentafluoroethyl)silanes (C2 F5 )2 SiX2 , with X=H, F, Cl, Br, OPh, and O2 CCF3. AB - As recently shown, the introduction of pentafluoroethyl functionalities into silicon compounds is of general interest due to an enhanced Lewis acidity of the resulting species. By this means, the synthesis of previously inaccessible hypervalent silicon derivatives is enabled. While an easy access to tris(pentafluoroethyl)silanes has already been published, synthetic strategies for the selective preparation of bis derivatives are yet unknown. In this contribution, a convenient protocol for the synthesis of functional bis(pentafluoroethyl)silicon compounds is presented. These compounds represent precursors for the synthesis of pentafluoroethylated polysiloxanes. Furthermore, they prove to be resistant to oxonium cations, which is a key feature for the preparation of stable pentafluoroethylsilic acids. Treatment of dichlorodiphenoxysilane with in situ generated pentafluoroethyl lithium leads to the corresponding bis(pentafluoroethyl)silane in high yields. (C2 F5 )2 Si(OPh)2 serves as a starting material for further functionalized bis(pentafluoroethyl)silanes. These silanes have been isolated and their reactivity towards N bases studied. The pronounced Lewis acidity of the obtained compounds has been documented by the formation of octahedral adducts with nitrogen donors such as 1,10-phenanthroline and acetonitrile. PMID- 27778394 TI - Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review. AB - New targeted cancer therapies such as bisphosphonates, denosumab, and bevacizumab are routinely used in adult for the past decades. Their introduction into pediatric medicine is more recent that means there is a paucity of data on long term effects on dental development and on the risk of osteonecrosis of jaw. This study aimed to outline adverse effects of new targeted cancer therapies on oral cavity including dental abnormalities observed in pediatric population treated with these molecules and the risk of osteonecrosis of the jaw (ONJ). The impact of bisphosphonates and denosumab on bone remodeling (inhibition of osteoclasts) could interfere with teeth exfoliation and eruption processes, causing a tooth eruption delay. This hypothesis was confirmed, bisphosphonate-treated rats presented tooth eruption delay, and bisphosphonate therapy was associated with a mean delay of 1.67 years in tooth eruption in children with osteogenesis imperfecta. Another study showed that the inhibition of RANK/RANKL by denosumab was associated with a lack of tooth eruption in animals. Several animal studies reported that bisphosphonate could also induce dental abnormalities including defective amelogenesis and dentinogenesis in rats, but there is no evidence of such effects in children; only one case of enamel hypoplasia in a child treated for idiopathic arterial calcification with bisphosphate was reported. To date, there has been no reported case of ONJ in children treated with bisphosphonates, denosumab, or bevacizumab. PMID- 27778396 TI - The European Young Chemists Award 2016. AB - The future is in good hands! The European Young Chemist Award for 2016 was awarded at the 6th EuCheMS Chemistry Congress in Seville. Reflections on the participants and their chemistry from the Convener of the event, Professor Bruno Pignataro, are given in the Guest Editorial. PMID- 27778395 TI - Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis. AB - Microglial clusters with C3d deposits are observed in the periplaque of multiple sclerosis (MS) brains and were proposed as early stage of lesion formation. As such they should appear in the brain of MS donors with acute disease but thus far this has not been shown. Using postmortem brain tissue from acute (n = 10) and chronic (n = 15) MS cases we investigated whether C3d+ microglial clusters are part of an acute attack against myelinated axons, which could have implications for disease pathogenesis. The specificity of our findings to MS was tested in ischemic stroke cases (n = 8) with initial or advanced lesions and further analyzed in experimental traumatic brain injury (TBI, n = 26), as both conditions are primarily nondemyelinating but share essential features of neurodegeneration with MS lesions. C3d+ microglial clusters were found in chronic but not acute MS. They were not associated with antibody deposits or terminal complement activation. They were linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production. C3d+ microglial clusters were not specific to MS as they were also found in stroke and experimental TBI. We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons. As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease. GLIA 2017;65:264-277. PMID- 27778397 TI - A Controlled Route to a Luminescent 3 d10 -5 d10 Sulfido Cluster Containing Unique AuCu2 (MU3 -S) Motifs. AB - The first examples of gold(I) trimethylsilylchalcogenolate complexes were synthesized and their reactivity showcased in the preparation of a novel gold copper-sulfur cluster [Au4 Cu4 S4 (dppm)2 ] (dppm=bis(diphenylphosphino)methane). The unprecedented structural chemistry of this compound gives rise to interesting optoelectronic properties, including long-lived orange luminescence in the solid state. Through time-dependent density functional theory calculations, this emission is shown to originate from ligand-to-metal charge transfer facilitated by Au???Cu metallophilic bonding. PMID- 27778398 TI - The Driving Force of Photoinduced Charge Separation in Metal-Cluster-Encapsulated Triphenylamine-[80]fullerenes. AB - Understanding photoinduced charge separation in fullerene-based dye-sensitized solar cells is crucial for the development of photovoltaic devices. We investigate here how the driving force of the charge separation process in conjugates of M@C80 (M=Sc3 N, Sc3 CH, Sc3 NC, Sc4 O2 , and Sc4 O3 ) with triphenylamine (TPA) depends on the nature of the metal cluster. Both singlet and triplet excited-state electron-transfer reactions are considered. These results based on TD-DFT calculations demonstrate that the driving force of charge separation in TPA-M@C80 can be tuned well by varying the structure of the metal cluster encapsulated inside the fullerene cage. PMID- 27778399 TI - Effect of Substituents and Initial Degree of Functionalization of Alkylated Single-Walled Carbon Nanotubes on Their Thermal Stability and Photoluminescence Properties. AB - Alkylated single-walled carbon nanotubes (SWNTs) have been thermally treated to determine the influence of substituents and the degree of functionalization on their thermal stability and photoluminescence (PL) properties. Alkylated SWNTs were prepared by treating SWNTs with sodium naphthalenide and alkyl bromide. The defunctionalization of the alkylated SWNTs was monitored by absorption and Raman spectra. Selective recovery of the characteristic absorption and radial breathing mode peaks was observed during the thermal treatment, which indicates that the thermal stability of the alkylated SWNTs decreases with increases in SWNT diameter and degree of functionalization. n-Butylated and phenethylated SWNTs showed higher thermal stability than sec-butylated and benzylated SWNTs for a similar degree of functionalization, respectively. The diameter selectivity and effect of substituents on the thermal elimination reaction were confirmed by density functional theory. In addition, it was shown that the initial degree of functionalization of the alkylated SWNTs, with the alkyl group and degree of functionalization being kept constant after thermal treatment, strongly affects their PL properties; Stokes shift, and PL peak intensity. PMID- 27778401 TI - Pilomatricoma Associated with Kabuki Syndrome. AB - We report three cases of pilomatricomas associated with Kabuki syndrome (KS), supporting the hypothesis proposed of an association between pilomatricomas and KS and suggesting a noncoincidental association, because the Wnt pathway mutations involved could affect both morphogenesis and tumorigenesis in these patients. PMID- 27778402 TI - Multiple Minute Digitate Hyperkeratosis in an Infant. AB - A distinct variant of multiple minute digitate hyperkeratoses in a healthy 4 month-old boy, exclusively located in the anogenital area and with a transitory character, is described. PMID- 27778403 TI - Azulene-Based Macrocyclic Receptors for Recognition and Sensing of Phosphate Anions. AB - Herein we report the synthesis and detailed studies of the anion-binding properties of two 20-membered macrocyclic tetramide receptors: one symmetrical, containing two identical azulene-based bisamide units, the other a hybrid, containing a dipicolinic bisamide unit and an azulene-based bisamide unit. Analysis of the crystal structures of the macrocyclic receptors revealed their preference for adopting similar well-preorganized bent-sheet conformations, both as free receptors and in their complexes with anions. Studies of the optical properties of both receptors revealed abilities to selectively sense phosphate anions (H2 PO4- , HP2 O73- ), allowing for naked-eye detection of the presence of these guests in DMSO. Binding studies in solution confirmed that the receptors bind strongly to a series of anions even in highly demanding media, such as mixtures of DMSO with water or with methanol. Comparison of the anion affinity of linear analogues with that of the macrocyclic receptors evidenced the importance of macrocyclic topology. Quantitative analysis revealed that the macrocyclic receptors are selective for H2 PO4- over other anions. The affinity to H2 PO4- seen for the symmetrical receptor, containing two azulene-based subunits, is much higher than for the hybrid macrocycle containing both the azulene-based and pyridine-derived subunits. This highlights that the azulene-based building block serves efficiently as both a binding site and a structure-preorganizing motif. PMID- 27778400 TI - Site-Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome. AB - The synthetic transformation of polypeptides with molecular accuracy holds great promise for providing functional and structural diversity beyond the proteome. Consequently, the last decade has seen an exponential growth of site-directed chemistry to install additional features into peptides and proteins even inside living cells. The disulfide rebridging strategy has emerged as a powerful tool for site-selective modifications since most proteins contain disulfide bonds. In this Review, we present the chemical design, advantages and limitations of the disulfide rebridging reagents, while summarizing their relevance for synthetic customization of functional protein bioconjugates, as well as the resultant impact and advancement for biomedical applications. PMID- 27778404 TI - Progranulin protects against exaggerated axonal injury and astrogliosis following traumatic brain injury. AB - In response to traumatic brain injury (TBI) microglia/macrophages and astrocytes release inflammatory mediators with dual effects on secondary brain damage progression. The neurotrophic and anti-inflammatory glycoprotein progranulin (PGRN) attenuates neuronal damage and microglia/macrophage activation in brain injury but mechanisms are still elusive. Here, we studied histopathology, neurology and gene expression of inflammatory markers in PGRN-deficient mice (Grn /- ) 24 h and 5 days after experimental TBI. Grn-/- mice displayed increased perilesional axonal injury even though the overall brain tissue loss and neurological consequences were similar to wild-type mice. Brain inflammation was elevated in Grn-/- mice as reflected by increased transcription of pro inflammatory cytokines TNFalpha, IL-1beta, IL-6, and decreased transcription of the anti-inflammatory cytokine IL-10. However, numbers of Iba1+ microglia/macrophages and immigrated CD45+ leukocytes were similar at perilesional sites while determination of IgG extravasation suggested stronger impairment of blood brain barrier integrity in Grn-/- compared to wild-type mice. Most strikingly, Grn-/- mice displayed exaggerated astrogliosis 5 days after TBI as demonstrated by anti-GFAP immunohistochemistry and immunoblot. GFAP+ astrocytes at perilesional sites were immunolabelled for iNOS and TNFalpha suggesting that pro-inflammatory activation of astrocytes was attenuated by PGRN. Accordingly, recombinant PGRN (rPGRN) attenuated LPS- and cytokine-evoked iNOS and TNFalpha mRNA expression in cultured astrocytes. Moreover, intracerebroventricular administration of rPGRN immediately before trauma reduced brain damage and neurological deficits, and restored normal levels of cytokine transcription, axonal injury and astrogliosis 5 days after TBI in Grn-/- mice. Our results show that endogenous and recombinant PGRN limit axonal injury and astrogliosis and suggest therapeutic potential of PGRN in TBI. GLIA 2017;65:278 292. PMID- 27778405 TI - A Dendritic Supramolecular Complex as Uniform Hybrid Micelle with Dual Structure for Bimodal In Vivo Imaging. AB - In this study, a uniform complex dual micelle bearing a gadolinium-substituted polyoxometalate core, a hydrophobic middle, and a biocompatible organic shell, which exhibits a uniform size and definite molecular weight and chemical composition, is constructed through a simple two-step process for use as a fluorescence and magnetic resonance imaging (MRI) contrast agent. A paramagnetic polyoxometalate cluster, K13 [Gd(beta2 -SiW11 O39 )2 ], is first encapsulated with a cationic 3-generation dendron (D-3) bearing triethylene glycol monomethyl ether terminal groups through ionic substitution. The formed electrostatic complex, (D-3)13 [Gd(beta2 -SiW11 O39 )2 ] (D-GdSiW), which displays an ambivalent micellar structure, is then demonstrated to act as a suitable carrier for the uptake of cationic fluorescent dyes, forming a loaded complex. The dye loaded complex D-GdSiW-D is thus proven to display high relaxivity as a contrast agent, maintaining its structural stability under physiological conditions with low cell cytotoxicity. Confocal laser scanning microscopic observation also demonstrates the fluorescence imaging property of the prepared complex upon consumption by MCF-7 cells. Both in vivo fluorescence imaging and MRI further confirm that the complex micelle with dual micellar structure may be a suitable liver-specific contrast agent for clinical diagnosis. PMID- 27778406 TI - Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. AB - WHAT IS KNOWN AND OBJECTIVE: Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide (NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of cebranopadol. METHODS: Published literature and Internet sources were searched to identify information related to the basic science (pharmacology and medicinal chemistry) and development (clinical trial) information on the mechanism of dual opioid and NOP receptor pharmacologic action in general, and for cebranopadol in particular. The identified sources were reviewed and the information synthesized. RESULTS: The preclinical testing of cebranopadol has characterized it as a dual opioid and NOP receptor agonist that displays antinociceptive and antihyperalgesic action in a variety of acute and chronic pain models in animals. Unlike most current traditional opioids, it is generally more potent against neuropathic than nociceptive pain. Several phase 2 clinical trials have been completed. WHAT IS NEW AND CONCLUSION: Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials. PMID- 27778408 TI - Development of Japanese version of King's Stigma Scale and its short version: Psychometric properties of a self-stigma measure. AB - AIM: The study aimed to develop two Japanese versions of King's Stigma Scale, a full version (KSS-J-1) and a short version (KSS-J-2), through psychometric property testing. METHODS: The sample included 112 people with mental illness. We tested the constructs of the scales using both confirmatory and exploratory factor analyses. Internal consistency and test-retest reliability were tested. We examined convergent validity with self-esteem or perceived stigma, and different group validity, using the Kessler Psychological Distress Scale (K6). RESULTS: Whereas a relatively weak model fit (comparative fit index = 0.66, Tucker-Lewis index = 0.63, root mean square error of approximation = 0.097) of KSS-J-1 (full version: 28 items) was found, KSS-J-2 (short version: 17 items), produced by exploratory factor analysis, had a moderate model fit (comparative fit index = 0.90, Tucker-Lewis index = 0.89, root mean square error of approximation = 0.063). High internal consistency (KSS-J-1, omega = 0.82-0.89; KSS-J-2, omega = 0.86-0.89) and moderate test-retest reliability (KSS-J-1, interclass correlation = 0.56-0.88; KSS-J-2, interclass correlation = 0.45-0.85) were reported. Some subscales and the entire scale of KSS-J-1 were significantly correlated with self esteem and perceived stigma. Conversely, only two subscales in KSS-J-2 were significantly correlated with self-esteem. The scores of each subscale and the entire score for both KSS-J-1 and KSS-J-2 in the high psychological distress group were higher than the low group (KSS-J-1, d = 0.61-0.83; KSS-J-2, d = 0.47 0.70), except for the Discrimination subscale in KSS-J-2. CONCLUSION: Both Japanese versions of King's Stigma Scale can be utilized depending on their intended use. PMID- 27778409 TI - Early and dynamic colonization of Central America drives speciation in Neotropical army ants. AB - The emergence of the Isthmus of Panama is one of the most important events in recent geological history, yet its timing and role in fundamental evolutionary processes remain controversial. While the formation of the isthmus was complete around 3 million years ago (Ma), recent studies have suggested prior intercontinental biotic exchange. In particular, the possibility of early intermittent land bridges facilitating colonization constitutes a potential mechanism for speciation and colonization before full closure of the isthmus. To test this hypothesis, we employed genomic methods to study the biogeography of the army ant genus Eciton, a group of keystone arthropod predators in Neotropical rainforests. Army ant colonies are unable to disperse across water and are therefore ideally suited to study the biogeographic impact of land bridge formation. Using a reduced representation genome sequencing approach, we show that all strictly Central American lineages of Eciton diverged from their respective South American sister lineage between 4 and 7 Ma, significantly prior to the complete closure of the isthmus. Furthermore, three of the lineage pairs form extensive and coincident secondary contact zones in Costa Rica and Nicaragua, with no evidence of gene flow. Such a discrete and repeated biogeographic pattern indicates at least two waves of army ant dispersal into Central America that were separated by significant genetic divergence times. Thus, by integrating phylogenomic, population genomic and geographic evidence, we show that early colonization of Central America across the emerging Isthmus of Panama drove parallel speciation in Eciton army ants. PMID- 27778407 TI - The effects of HIV and aging on subcortical shape alterations: A 3D morphometric study. AB - Standard volumetric neuroimaging studies have demonstrated preferential atrophy of subcortical structures among individuals with HIV. However, to our knowledge, no study has investigated subcortical shape alterations secondary to HIV and whether advancing age impacts that relationship. This study employed 3D morphometry to examine the independent and interactive effects of HIV and age on shape differences in nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus in 81 participants ranging in age from 24 to 76 including 59 HIV+ individuals and 22 HIV-seronegative controls. T1-weighted MRI underwent a preprocessing pipeline followed by automated subcortical segmentation. Parametric statistical analyses were used to determine independent effects of HIV infection and age on volume and shape in each region of interest (ROI) and the interaction between age and HIV serostatus in predicting volume/shape in each ROI. Significant main effects for HIV were found in the shape of right caudate and nucleus accumbens, left pallidum, and hippocampus. Age was associated with differences in shape in left pallidum, right nucleus accumbens and putamen, and bilateral caudate, hippocampus, and thalamus. Of greatest interest, an age * HIV interaction effect was found in the shape of bilateral nucleus accumbens, amygdala, caudate, and thalamus as well as right pallidum and putamen such that increasing age in HIV participants was associated with greater shape alterations. Traditional volumemetric analyses revealed main effects for both HIV and age but no age * HIV interaction. These findings may suggest that age and HIV infection conferred additional deleterious effects on subcortical shape abnormalities beyond the independent effects of these factors. Hum Brain Mapp 38:1025-1037, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27778411 TI - Low secondary leaf wax n-alkane synthesis on fully mature leaves of C3 grasses grown at controlled environmental conditions and variable humidity. AB - RATIONALE: Leaf wax n-alkanes are long-chained aliphatic compounds that are present in the cuticle of terrestrial plant leaves. Their delta2 H values are used for the reconstruction of past environments and for plant ecological investigations. The timing of n-alkane synthesis during leaf development and the rate of synthesis of secondary n-alkanes in fully matured leaves are still a matter of debate. METHODS: Using a 2 H-labeling approach we estimated secondary leaf wax n-alkane synthesis rates in mature leaf blades of six C3 grass species grown in climate chambers under controlled environmental conditions. RESULTS: We found that mature grass leaves continue the synthesis of leaf wax n-alkanes after leaf maturation. The rate of secondary n-alkanes synthesis was, however, relatively low and varied in response to atmospheric humidity and among species from 0.09 to 1.09% per day. CONCLUSIONS: Our investigation provides new evidence on the timing of cuticular wax synthesis in grass leaves and indicates that the majority of n-alkanes are synthesized during the initial development of the leaf. Our study will improve the interpretation of leaf wax n-alkane delta2 H values in environmental and geological studies as it suggests that secondary synthesis of leaf wax n-alkanes in grass leaves contributes only slightly to the geological record. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27778410 TI - Mendelian randomisation suggests no beneficial effect of moderate alcohol consumption on the severity of nonalcoholic fatty liver disease. AB - BACKGROUND: Previous epidemiological studies suggest that patients diagnosed with nonalcoholic fatty liver disease (NAFLD) who drink light to moderate amounts of alcohol (up to ~30 g per day) have less severe histological lesions compared with nondrinkers. However, while the cross-sectional nature of current evidence precludes assessment of causality, cumulative lifetime-exposure of moderate alcohol consumption on histological outcomes has never been evaluated. AIM: To overcome these limitations, a Mendelian randomisation study was performed using a validated genetic variant (rs1229984 A;G) in the alcohol dehydrogenase (ADH1B) gene as a proxy of long-term alcohol exposure. METHODS: We first assessed whether the instrumental variant (rs1229984) was associated with the amount of alcohol consumption in our cohort. We further explored the association between the variant and histological outcomes; a sample of 466 individuals, including 266 patients with NAFLD confirmed by liver biopsy, was studied. RESULTS: We found that carriers of the A-allele consumed significantly lower amounts of alcohol compared with noncarriers (2.3 +/- 5.3 vs. 8.18 +/- 21 g per day, mean +/- s.d., P = 0.03). The analysis of association with the disease severity showed that carriers of the A-allele had lower degree of histological steatosis (1.76 +/- 0.83 vs. 2.19 +/- 0.78, P = 0.03) and lower scores of lobular inflammation (0.54 +/- 0.65 vs. 0.95 +/- 0.92, P = 0.02) and NAFLD-Activity Score (2.9 +/- 1.4 vs. 3.7 +/- 1.4, P = 0.015) compared with noncarriers. CONCLUSION: Mendelian randomisation analysis suggests no beneficial effect of moderate alcohol consumption on NAFLD disease severity. PMID- 27778412 TI - Lipopolysaccharide increases IL-6 secretion via activation of the ERK1/2 signaling pathway to up-regulate RANKL gene expression in MLO-Y4 cells. AB - Lipopolysaccharide (LPS) plays an important role in bone resorption, which involves numerous cytokines through various signaling pathways. RANKL and interleukin (IL)-6 are two important cytokines that are involved in bone remodeling. The aim of this study was to evaluate the effect of LPS on RANKL and IL-6 gene expression, the relationship of RANKL and IL-6, and the role of extracellular signal-regulated kinases 1/2 (ERK1/2) on IL-6 secretion induced by LPS in MLO-Y4 cells. The cells were stimulated by LPS at different concentrations (1, 10, 100, 500, and 1000 ng/mL) for different durations (0.5, 1, 2, 4, and 8 h and 0.5, 1, 1.5, 2, and 4 h), and the mRNA expressions of RANKL and IL-6 were determined by PCR. In the presence of 100 ng/mL LPS at different time points (0.5, 1, 1.5, 2, and 4 h), IL-6 secretion and ERK1/2 phosphorylation in the cells were determined by ELISA and western blotting, respectively. STAT3 phosphorylation in cells simulated by 100 ng/mL LPS at different time points (0.5, 1, 2, 4, and 8 h) was assessed by western blotting. We found that LPS significantly up-regulated RANKL expression and activated the ERK1/2 pathway to induce IL-6 mRNA expression and protein synthesis in MLO-Y4 cells. However, the increased IL-6 was blocked by pre-treatment of MLO-Y4 cells with the ERK1/2 inhibitor U0126 (10 uM), and the enhanced RANKL was blocked by the STAT3 inhibitor S3I-201 (100 uM). Our results indicate that LPS up-regulates osteocyte expression of RANKL and IL-6, and the increased RANKL is associated with the up regulation of IL-6, which involves the ERK1/2 pathway. PMID- 27778414 TI - Dual-compartmental transcriptomic + proteomic analysis of a marine endosymbiosis exposed to environmental change. AB - As significant anthropogenic pressures are putting undue stress on the world's oceans, there has been a concerted effort to understand how marine organisms respond to environmental change. Transcriptomic approaches, in particular, have been readily employed to document the mRNA-level response of a plethora of marine invertebrates exposed to an array of simulated stress scenarios, with the tacit and untested assumption being that the respective proteins show a corresponding trend. To better understand the degree of congruency between mRNA and protein expression in an endosymbiotic marine invertebrate, mRNAs and proteins were sequenced from the same samples of the common, Indo-Pacific coral Seriatopora hystrix exposed to stable or upwelling-simulating conditions for 1 week. Of the 167 proteins downregulated at variable temperature, only two were associated with mRNAs that were also differentially expressed between treatments. Of the 378 differentially expressed genes, none were associated with a differentially expressed protein. Collectively, these results highlight the inherent risk of inferring cellular behaviour based on mRNA expression data alone and challenge the current, mRNA-focused approach taken by most marine and many molecular biologists. PMID- 27778413 TI - Altering Conventional to High Density Spinal Cord Stimulation: An Energy Dose Response Relationship in Neuropathic Pain Therapy. AB - OBJECTIVES: To examine whether converting from conventional Spinal Cord Stimulation (SCS) to High Density (HD) SCS reduces neuropathic pain over a period of 12 months in patients with failed SCS therapy. METHODS: Retrospective, open label, single center, consecutive case series of 30 neuropathic pain patients (Failed Back Surgery Syndrome [FBSS], Complex Regional Pain Syndrome [CRPS], and polyneuropathy [NP]). Patients with an initial adequate response to conventional SCS, but in whom pain increased over time, were included (Numeric Rating Scales [NRS] >6). These patients were stimulated with HD-SCS parameters and followed-up for 12 months. We report pain intensity, measured with NRS, before SCS implantation, 1 and 3 months after starting SCS with conventional stimulation, and after 1, 6, and 12 months of HD SCS. RESULTS: Pain reduction with conventional stimulation was initially adequate (NRS mean 8.6 to 5.3 at three months postimplant) but increased over time to a mean NRS of 7.7 at the time of reprogramming. NRS scores decreased significantly to 4.3 (p = 0.015) after reprogramming from conventional SCS (30 Hz, 300 usec, 3.0 V) to HD SCS (409 Hz, range 130-1000 Hz, 409 usec, 2.4V) in the patients still using HD-SCS at 12 months. In the nonresponders (patients who stopped HD-SCS for any reason), 76% had a diagnosis of FBSS. Almost half of the patients aborting HD-SCS preferred to feel paresthesias despite better pain relief. There was a significant difference between nonresponders and responders regarding the amount of electrical energy delivered to the spinal cord. CONCLUSION: Neuropathic pain suppression is significantly enhanced after converting from failed conventional SCS to HD SCS in patients with FBSS, CRPS, and NP over a measured period of 12 months. There appears to be a dose-related response between the amount of energy delivered to the spinal cord and clinical effect. PMID- 27778416 TI - Improved Antifouling Properties of Polydimethylsiloxane Films via Formation of Polysiloxane/Polyzwitterion Interpenetrating Networks. AB - Nonspecific adsorption of proteins is a challenging problem for the development of biocompatible materials, as well as for antifouling and fouling-release coatings, for instance for the marine industry. The concept of preparing amphiphilic systems based on low surface energy hydrophobic materials via their hydrophilic modification is being widely pursued. This work describes a novel two step route for the preparation of interpenetrating polymer networks of otherwise incompatible poly(dimethylsiloxane) and zwitterionic polymers. Changes in surface hydrophilicity as well as surface charge at different pH values are investigated. Characterization using atomic force microscopy provides thorough insight into surface changes upon hydrophilic modification. Protein fouling of the materials is assessed using fibrinogen as a model protein. PMID- 27778415 TI - Preliminary psychometrics of the Existential Distress Scale in patients with advanced cancer. AB - Existential distress is of clinical concern in patients with terminal illness. Although existential distress has been used to describe a broad spectrum of psychological disturbances, its narrower definition may be confined to distress that arises when the meaning and value of one's life is unclear, and is comorbid with feelings of loneliness and low self-worth. To promote further study, we developed and pilot-tested a 10-item Existential Distress Scale (EDS). Twenty-one patients with advanced cancer were recruited from a palliative care unit. Measures of existential distress, death anxiety, depression, performance status and physical symptom burden were collected. The EDS showed promising psychometric properties, including significant associations with death anxiety and depression. Thirty-eight per cent of the sample reported great or unbearable distress on at least one existential concern. The EDS may be administered to measure existential distress in patients with advanced cancer and clinicians may find the instrument useful to initiate a structured discussion about this symptom. PMID- 27778417 TI - Pregnancy alters the circulating B cell compartment in atopic asthmatic women, and transitional B cells are positively associated with the development of allergy manifestations in their progeny. AB - PROBLEM: Maternal atopy is a risk factor for allergy. B cells are poorly studied in reproduction and atopy. We aimed to assess how pregnancy affects B cells in atopic women and whether B cells relate to allergic manifestations in offspring. METHOD OF STUDY: Women with and without atopic asthma, pregnant and non-pregnant were enrolled for the study, and circulating B cells were evaluated by flow cytometry, using CD19, CD27, CD38, IgD, and IgM. RESULTS: Compared to healthy non pregnant, atopic asthmatic non-pregnant (ANP) women presented increased B cell counts, enlarged memory subsets, less transitional cells, and plasmablasts. Atopic asthmatic pregnant (AP) and healthy pregnant (HP) women showed similarities: reduced B cell counts and percentages, fewer memory cells, especially switched, and higher plasmablast percentages. Transitional B cell percentages were increased in AP women with allergic manifestations in their progeny. CONCLUSION: Atopic asthmatic non-pregnant women have a distinctive B cell compartment. B cells change in pregnancy, similarly in AP and HP women. The recognition that AP women with allergy in their progeny have a typical immune profile may help, in the future, the adoption of preventive measures to avoid the manifestation of allergic diseases in their newborns. PMID- 27778418 TI - Causes of homelessness prevalence: Relationship between homelessness and disability. AB - AIM: Many studies have reported that the prevalence of mental illness and cognitive disability is higher among homeless individuals compared to the general population, and the rates of mental illness among the homeless population have recently increased. This study: (i) compares causes of homelessness or barriers to escaping homelessness for people with/without mental illness/cognitive disability; (ii) reveals problems with the Japanese homeless policy; and (iii) proposes an effective and necessary support system. METHODS: The participants were 114 homeless individuals. A psychiatric diagnostic interview and the Wechsler Adult Intelligence Scale, version III were used to measure participants' mental health and cognitive abilities. A questionnaire was administered comprising 17 items related to the causes of their homelessness and barriers to escaping from it. Participants were divided into four groups - with/without mental illness or cognitive disability - and Fisher's exact test was used to compare the questionnaire results. RESULTS: Individuals with cognitive disabilities considered bad relationships with their family members to be the cause of their homelessness. Conversely, normal individuals considered their homelessness to be the result of debt more so than did individuals with mental problems. Individuals with mental illness had more difficulties escaping homelessness than did either normal individuals or individuals with cognitive disability. This tendency was observed most strongly among individuals with both mental illness and cognitive disability. CONCLUSION: Most homeless individuals considered economic problems to be the cause of their homelessness; however, difficulties with human relationships were also important factors and were more difficult for participants to acknowledge. Furthermore, these difficulties were exacerbated among those individuals with mental problems. PMID- 27778419 TI - Baseline impedance measured during high-resolution esophageal impedance manometry reliably discriminates GERD patients. AB - BACKGROUND: Baseline impedance measured with ambulatory impedance pH monitoring (MII-pH) and a mucosal impedance catheter detects gastroesophageal reflux disease (GERD). However, these tools are limited by cost or patient tolerance. We investigated whether baseline impedance measured during high-resolution impedance manometry (HRIM) distinguishes GERD patients from controls. METHODS: Consecutive patients with clinical HRIM and MII-pH testing were identified. Gastroesophageal reflux disease was defined by esophageal pH <4 for >=5% of both the supine and total study time, whereas controls had an esophageal pH <4 for <=3% of the study performed off PPI. Baseline impedance was measured over 15 seconds during the landmark period of HRIM and over three 10 minute intervals during the overnight period of MII-pH. KEY RESULTS: Among 29 GERD patients and 26 controls, GERD patients had a mean esophageal acid exposure time of 22.7% compared to 1.2% in controls (P<.0001). Mean baseline impedance during HRIM was lower in GERD (1061 Omega) than controls (2814 Omega) (P<.0001). Baseline mucosal impedance measured during HRIM and MII-pH correlated (r=0.59, P<.0001). High-resolution esophageal manometry baseline impedance had high diagnostic accuracy for GERD, with an area under the curve (AUC) of 0.931 on receiver operating characteristics (ROC) analysis. A HRIM baseline impedance threshold of 1582 Omega had a sensitivity of 86.2% and specificity of 88.5% for GERD, with a positive predictive value of 89.3% and negative predictive value of 85.2%. CONCLUSIONS & INFERENCES: Baseline impedance measured during HRIM can reliably discriminate GERD patients with at least moderate esophageal acid exposure from controls. This diagnostic tool may represent an accurate, cost-effective, and less invasive test for GERD. PMID- 27778420 TI - Urinary renalase concentration in patients with preserved kidney function undergoing coronary angiography. AB - AIM: The purpose of the study was to evaluate urinary renalase concentration before and after coronary angiography/percutaneous coronary interventions (CA/PCI) in patients with coronary artery disease (CAD) and preserved kidney function and verify its potential application as contrast-induced acute kidney injury (CI-AKI) diagnostic marker. METHODS: This prospective study comprised 95 consecutive patients (69.5% men; median age 65 years) with CAD submitted to elective or urgent CA/PCI. Data regarding 128 clinical variables were obtained. Urine samples were collected on admission and 6 h after CA/PCI and tested for urinary renalase using ELISA method, which was expressed as renalase-to creatinine ratio. The CI-AKI diagnosis was based on >=50% relative or >=0.3 mg/dl absolute increase of serum creatinine concentration 48 h following the procedure. RESULTS: Nine patients developed CI-AKI (9.5%). In comparison to baseline values, urinary renalase-to-creatinine ratio significantly decreased 6 h following CA/PCI, (2843.6 vs.1540.7 ng/mg, P < 0.0001). Nine patients developed CI-AKI (9.5%).The reduction of renalase level was profound both in CI-AKI (2709.7 vs. 1585.7 ng/mg, P = 0.007) and non-CI-AKI group (2814.9 vs.1561.8 ng/mg, P < 0.0001). There was a trend towards a greater relative decrease of urinary renalase in CI-AKI group (-57.3 vs.-41.8%, P = 0.10). Univariate analysis revealed that both pre- and post-procedural urinary renalase did not predict CI AKI onset; however, absolute decrease of renalase below 25 percentile was a predictor of CI-AKI (OR = 5.4, 95% CI:1.3-21.9, P = 0.027). CONCLUSION: Urinary renalase concentration is reduced in the aftermath of CA/PCI, which may be related to CI-AKI development. Further studies are warranted to elucidate the role of urinary renalase as a CI-AKI diagnostic marker. PMID- 27778421 TI - Does pediatric post-traumatic stress disorder alter the brain? Systematic review and meta-analysis of structural and functional magnetic resonance imaging studies. AB - Several studies have recently demonstrated that the volumes of specific brain regions are reduced in children and adolescents with post-traumatic stress disorder (PTSD) compared with those of healthy controls. Our study investigated the potential association between early traumatic experiences and altered brain regions and functions. We conducted a systematic review of the scientific literature regarding functional magnetic resonance imaging and a meta-analysis of structural magnetic resonance imaging studies that investigated cerebral region volumes in pediatric patients with PTSD. We searched for articles from 2000 to 2014 in the PsycINFO, PubMed, Medline, Lilacs, and ISI (Web of Knowledge) databases. All data regarding the amygdala, hippocampus, corpus callosum, brain, and intracranial volumes that fit the inclusion criteria were extracted and combined in a meta-analysis that assessed differences between groups. The meta analysis found reduced total corpus callosum areas and reduced total cerebral and intracranial volumes in the patients with PTSD. The total hippocampus (left and right hippocampus) and gray matter volumes of the amygdala and frontal lobe were also reduced, but these differences were not significant. The functional studies revealed differences in brain region activation in response to stimuli in the post-traumatic stress symptoms/PTSD group. Our results confirmed that the pediatric patients with PTSD exhibited structural and functional brain abnormalities and that some of the abnormalities occurred in different brain regions than those observed in adults. PMID- 27778422 TI - Facile Preparation of CO2 -Responsive Polymer Nano-Objects via Aqueous Photoinitiated Polymerization-Induced Self-Assembly (Photo-PISA). AB - Carbon dioxide (CO2 )-responsive polymer nano-objects are prepared by photoinitiated reversible addition-fragmentation chain transfer dispersion polymerization of 2-hydroxypropyl methacrylate and 2-(dimethylamino)ethyl methacrylate (DMAEMA) in water at room temperature using a poly(poly(ethylene glycol) methyl ether methacrylate) macromolecular chain transfer agent. Kinetic studies confirm that full monomer conversions are achieved in all cases within 10 min of visible-light irradiation (405 nm, 0.5 mW cm-2 ). The effect of DMAEMA on the polymerization is studied in detail, and pure higher order morphologies (worms and vesicles) are prepared by this particular formulation. Finally, CO2 responsive property of the obtained vesicles is investigated by dynamic light scattering, visual appearance, and transmission electron microscope. PMID- 27778423 TI - Prevalence and clinical correlates of flunitrazepam-related complex sleep behaviors. AB - AIM: Complex sleep behaviors (CSB) are often associated with the use of hypnotic drugs. This study investigated the prevalence and correlates of CSB among psychiatric patients who were given flunitrazepam. METHODS: From June 2011 to May 2012, a total of 268 psychiatric outpatients who had received flunitrazepam for at least 3 months were enrolled. Data on occurrence of CSB, demographic characteristics, flunitrazepam dosage and duration of use, psychiatric diagnoses, physical illnesses, and alcohol use were collected. Logistic regression analysis was used to examine the clinical correlates of CSB. RESULTS: Sixty-six participants (24.6%) reported experiencing CSB. Logistic regression analysis showed that a high dosage (>2 mg/day) of flunitrazepam (odds ratio [OR] = 1.941, 95% confidence interval [CI] = 1.090-3.455, P = 0.024) and alcohol use (OR = 1.948, 95%CI = 1.023-3.709, P = 0.042) were significantly associated with the occurrence of CSB. Sex, age, duration of flunitrazepam use, psychiatric diagnoses, and physical illnesses were not significantly associated with the occurrence of CSB. CONCLUSION: CSB among flunitrazepam users should be monitored routinely, especially among those receiving a high dosage who also consume alcohol. PMID- 27778424 TI - Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in New-incident and relapsing primary membranous nephropathy. AB - AIM: Primary membranous nephropathy is associated with progression to end stage renal diseasein some patients. Standard therapy with cyclical cyclophosphamide and corticosteroids can be associated with significant adverse effects. We aimed to assess immunological and clinical response with intravenous pulse cyclophosphamide and oral steroids in patients with severe nephrotic syndrome - in a prospective observational cohort study. METHODS: A total of 17 consecutive patients (nine new-incident and eight relapses) with severe nephrotic syndrome received monthly intravenous pulse cyclophosphamide and oral steroids after failure to achieve remission with supportive therapy. Immunosuppressive therapy was discontinued at 6 months or earlier if proteinuria regressed to <100 mg/mmol and patients were followed for 12 months. Achievement of partial remission was primary outcome; changes in clinical parameters and anti-PLA2 R were secondary outcomes. RESULTS: Dose of cyclophosphamide received was 5.4 g in New-incident patients and 4.2 g in patients with relapses. All 17 patients achieved partial remission within 6 months: proteinuria improved from 656 to 102 mg/mmol at 6 months and 55 mg/mmol at 12 months (P < 0.001); eGFR improved from 31 to 48 mL/min per 1.73 m2 at 6 months and 45 mL/min per 1.73 m2 at 12 months (P < 0.05). Anti-PLA2 R levels reduced from 244 to 10 U/L at 6 months and 10 U/L at 12 months (P < 0.001). Two out of nine patients in the New-incident group developed subsequent relapse. Cumulative doses of cyclophosphamide and steroids that patients received was about half of the standard regime. CONCLUSION: Pulse cyclophosphamide with oral steroids induced immunological and clinical partial remission at significantly reduced doses in primary membranous nephropathy. PMID- 27778425 TI - Contact Alopecia: Improvement of Alopecia with Discontinuation of Fluocinolone Oil in Individuals Allergic to Balsam Fragrance. AB - Inflammatory scalp dermatoses can be associated with alopecia, which is nonscarring and reversible in its early stages. This association has been described in seborrheic dermatitis, psoriasis, and atopic dermatitis. We describe three girls with alopecia aggravated by contact allergy to balsam fragrances. All three had complete resolution with avoidance of balsam of Peru and other balsam derivatives (including discontinuation of fluocinolone oil, which contains balsam of pine). PMID- 27778426 TI - Improving Quality of Life Outcomes in Supported Accommodation for People with Intellectual Disability: What Makes a Difference? AB - BACKGROUND: The quality of life (QOL) of people with intellectual disability living in supported accommodation services is variable, influenced by many possible factors. Various frameworks have attempted to identify these factors without assigning value, direction of influence or relative impact on outcomes. METHODS: A realist review of the literature aimed to expose different propositions about variables influencing QOL outcomes and review the strength of supporting evidence for these, to identify their relative influence. Evidence was reviewed for and against each of five clusters. RESULTS: Evidence was strongest for the presence of staff practices (use of Active Support), front-line management practice (use of practice leadership), culture (enabling and motivating), human resources policies and practice (that support front-line leaders and recruitment of staff with the right values), adequate resources, and small, dispersed and homelike settings. CONCLUSIONS: The evidence informs policy and practice but in some clusters remains limited, warranting further research which measures outcomes on all QOL domains. PMID- 27778427 TI - Drug Hypersensitivity Syndrome with Prolonged Course Complicated by Parvovirus Infection. AB - Drug hypersensitivity syndrome (DHS) is a severe medication reaction involving multiple organ systems that is characterized by rash, lymphadenopathy, and laboratory aberrations, including hepatic enzyme changes. Viral reactivation in the setting of DHS can significantly affect the course of disease. We report two children in whom parvovirus infection prolonged and complicated their course of DHS. Most other DHS-complicating viruses are herpesviruses; this report broadens the scope of DHS-modifying infections to include activation of Parvoviridae. PMID- 27778428 TI - Dispersion Forces, Disproportionation, and Stable High-Valent Late Transition Metal Alkyls. AB - The transition metal tetra- and trinorbornyl bromide complexes, M(nor)4 (M=Fe, Co, Ni) and Ni(nor)3 Br (nor=1-bicyclo[2.2.1]hept-1-yl) and their homolytic fragmentations were studied computationally using hybrid density functional theory (DFT) at the B3PW91 and B3PW91-D3 dispersion-corrected levels. Experimental structures were well replicated; the dispersion correction resulted in shortened M-C bond lengths for the stable complexes, and it was found that Fe(nor)4 receives a remarkable 45.9 kcal mol-1 stabilization from the dispersion effects whereas the tetragonalized Co(nor)4 shows stabilization of 38.3 kcal mol 1 . Ni(nor)4 was calculated to be highly tetragonalized with long Ni-C bonds, providing a rationale for its current synthetic inaccessibility. Isodesmic exchange evaluation for Fe(nor)4 confirmed that dispersion force attraction between norbornyl substituents is fundamental to the stability of these species. PMID- 27778430 TI - Published Only: Clinical diabetes/Therapeutics. PMID- 27778431 TI - Poster: Clinical Diabetes/Therapeutics. PMID- 27778432 TI - Oral Presentation: Clinical Diabetes/Therapeutics. PMID- 27778429 TI - Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. AB - BACKGROUND & AIMS: The diagnosis of non-alcoholic steatohepatitis and fibrosis staging are central to non-alcoholic fatty liver disease assessment. We evaluated multiparametric magnetic resonance in the assessment of non-alcoholic steatohepatitis and fibrosis using histology as standard in non-alcoholic fatty liver disease. METHODS: Seventy-one patients with suspected non-alcoholic fatty liver disease were recruited within 1 month of liver biopsy. Magnetic resonance data were used to define the liver inflammation and fibrosis score (LIF 0-4). Biopsies were assessed for steatosis, lobular inflammation, ballooning and fibrosis and classified as non-alcoholic steatohepatitis or simple steatosis, and mild or significant (Activity >=2 and/or Fibrosis >=2 as defined by the Fatty Liver Inhibition of Progression consortium) non-alcoholic fatty liver disease. Transient elastography was also performed. RESULTS: Magnetic resonance success rate was 95% vs 59% for transient elastography (P<.0001). Fibrosis stage on biopsy correlated with liver inflammation and fibrosis (rs =.51, P<.0001). The area under the receiver operating curve using liver inflammation and fibrosis for the diagnosis of cirrhosis was 0.85. Liver inflammation and fibrosis score for ballooning grades 0, 1 and 2 was 1.2, 2.7 and 3.5 respectively (P<.05) with an area under the receiver operating characteristic curve of 0.83 for the diagnosis of ballooning. Patients with steatosis had lower liver inflammation and fibrosis (1.3) compared to patients with non-alcoholic steatohepatitis (3.0) (P<.0001); area under the receiver operating characteristic curve for the diagnosis of non alcoholic steatohepatitis was 0.80. Liver inflammation and fibrosis scores for patients with mild and significant non-alcoholic fatty liver disease were 1.2 and 2.9 respectively (P<.0001). The area under the receiver operating characteristic curve of liver inflammation and fibrosis for the diagnosis of significant non alcoholic fatty liver disease was 0.89. CONCLUSIONS: Multiparametric magnetic resonance is a promising technique with good diagnostic accuracy for non alcoholic fatty liver disease histological parameters, and can potentially identify patients with non-alcoholic steatohepatitis and cirrhosis. PMID- 27778433 TI - Extending the Domain-Averaged Exchange-Correlation Energies Within the Context of the MC-QTAIM: Tracing Subtle Variations Induced by Isotope Substitution. AB - Recently, it has been demonstrated that the domain-averaged exchange-correlation energies, Vxc , are capable of tracing the covalent character of atom-atom interactions unequivocally and thus pave the way for detailed bonding analysis within the context of the quantum theory of atoms in molecules (QTAIM) [M. Garcia Revilla, E. Francisco, P. L. Popelier, A. Martin Pendas, ChemPhysChem 2013, 14, 1211-1218]. Herein, the concept of Vxc is extended within the context of the newly developed multicomponent QTAIM (MC-QTAIM). The extended version, Veexc , is capable of analyzing nonadiabatic wavefunctions and thus is sensitive to the mass of nuclei and can trace "locally" the subtle electronic variations induced by isotope substitution. To demonstrate this capability in practice, ab initio nonadiabatic wavefunctions for three isotopically substituted hydrogen cyanide molecules, in which the hydrogen nucleus was assumed to be a proton, deuterium, or tritium, were derived. The resulting wavefunctions were then used to compute Veexc and it emerged that for the hydrogen-carbon bond, the Veexc was distinct for each isotopic composition and varied in line with chemical expectations. Indeed, the introduction of Veexc paves the way for the investigation of vast numbers of structural and kinetic isotope effects within the context of the MC QTAIM. PMID- 27778434 TI - Optimization of home treatment in haemophilia: effects of transmural support by a haemophilia nurse on adherence and quality of life. AB - BACKGROUND: Transmural support by a haemophilia nurse may improve treatment and may empower parents and patients. AIM: To measure the effect of structured home visits by a haemophilia nurse in (parents of) patient on aspects of prophylactic home treatment. METHODS: A multicentre intervention study in two paediatric haemophilia treatment centres was performed. Primary outcome measures were: adherence to prescribed treatment, health-related quality of life and behavioural scores. Secondary outcome measures were: total clotting factor consumption, self efficacy and number of joint bleeds. RESULTS: Over a period of 22 months (median, IQR 21-23), four to seven home visits in 46 patients (mean age 9.4 +/- 4.2 years) were made. No difference in adherence to prescribed treatment was seen after the home visits when compared to baseline measurements. Both the Child Health Questionnaire (CHQ) scales on 'Role functioning - Emotional/Behavioural' (P = 0.02, d = 0.53) and 'Parental Time Impact' (P = 0.04, d = 0.33) were reduced after intervention. The disease-specific Haemo-QoL questionnaire showed improvement in domains: 'Family' (P = 0.04, d = -0.14), 'Friends' (P = 0.03, d = 0.29) and 'Perceived support' (P = 0.03, d = -0.37). Significant improvement was observed with regard to domain 'Communication' of the VERITAS-Pro scale (P = 0.03, d = -0.28). CONCLUSIONS: After a period of transmural care by a haemophilia nurse, significant but small positive effects were demonstrated with regard to communication and increase of perceived support between parents and haemophilia treatment centre. No improvement was observed in other outcome measures. PMID- 27778435 TI - Safety and efficacy of topical ketoprofen in transfersome gel in knee osteoarthritis: A systematic review. AB - PURPOSE: Topical ketoprofen in Transfersome gel has been used for the alleviation of symptoms in osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with various side effects. Topical NSAIDs are known to have a lower side-effect profile when compared with systemic administration. The present systematic review aimed to determine the safety and efficacy of topical ketoprofen in Transfersome gel in knee osteoarthritis (OA). METHODS: A systematic literature review was performed. The electronic databases EMBASE, MEDLINE, HealthStar and PubMed were searched from 1946 to June 2016. A screen of the reference sections of the included studies was also performed. Two blinded reviewers searched, screened, abstracted and evaluated the data quality using the Jadad scale. Studies were included if they contained: at least 50% of participants with knee OA, topical ketoprofen, human subjects and participants from North America or Europe. Study outcomes had to include patient-reported functional outcome scores. RESULTS: Five studies were included, with a total of 3619 participants, and a mean Jadad score of 3.4/5. Western Ontario McMaster Universities (WOMAC) Osteoarthritis Index was the only outcome measure consistent across all of the randomized controlled trials included in the present review (four of the five included studies). All topical ketoprofen in Transfersome gel groups (25 mg, 50 mg and 100 mg) had improvements in pain that were superior to all other treatment arms, and the 50 mg topical ketoprofen in Transfersome gel group had functional gains that were superior to all other treatment arms. The majority of the adverse events were non-serious and related to skin and subcutaneous tissue disorders, with erythema being the most common. The average of all adverse events and gastrointestinal (GI) adverse events was highest in the oral celecoxib group (47.1% and 15.1%, respectively). The average frequency of GI adverse events in the topical ketoprofen groups was comparable with that in the topical placebo treatment arm. A meta-analysis was not feasible due to the heterogeneity among the studies. CONCLUSIONS: Topical ketoprofen in Transfersome gel is an effective means of treating symptoms of knee OA, and is superior to oral celecoxib, oral placebo and topical placebo. The most commonly reported adverse events associated with the use of topical ketoprofen in Transfersome gel were non-severe skin and subcutaneous tissue disorders. Furthermore, as topical ketoprofen in Transfersome gel was associated with fewer adverse events when compared with oral celecoxib, and had rates of GI adverse events comparable with those of topical placebo, it may be ideal for those who are unable to take oral NSAIDs. PMID- 27778436 TI - Social capital strategies to enhance hepatitis C treatment awareness and uptake among men in prison. AB - Prisoner populations are characterized by high rates of hepatitis C (HCV), up to thirty times that of the general population in Australia. Within Australian prisons, less than 1% of eligible inmates access treatment. Public health strategies informed by social capital could be important in addressing this inequality in access to HCV treatment. Twenty-eight male inmates participated in qualitative interviews across three correctional centres in New South Wales, Australia. All participants had recently tested as HCV RNA positive or were receiving HCV treatment. Analysis was conducted with participants including men with experiences of HCV treatment (n=10) (including those currently accessing treatment and those with a history of treatment) and those who were treatment naive (n=18). Social capital was a resourceful commodity for inmates considering and undergoing treatment while in custody. Inmates were a valuable resource for information regarding HCV treatment, including personal accounts and reassurance (bonding social capital), while nurses a resource for the provision of information and care (linking social capital). Although linking social capital between inmates and nurses appeared influential in HCV treatment access, there remained opportunities for increasing linking social capital within the prison setting (such as nurse-led engagement within the prisons). Bonding and linking social capital can be valuable resources in promoting HCV treatment awareness, uptake and adherence. Peer-based programmes are likely to be influential in promoting HCV outcomes in the prison setting. Engagement in prisons, outside of the clinics, would enhance opportunities for linking social capital to influence HCV treatment outcomes. PMID- 27778437 TI - Increase of KCC2 in hippocampal synaptic plasticity disturbances after perinatal ethanol exposure. AB - Low to moderate perinatal ethanol exposure (PEE) may have disastrous consequences for the central nervous system resulting notably in permanent cognitive deficits. Learning and memory are mediated in the hippocampus by long-term potentiation (LTP) and long term depression (LTD), two forms of synaptic plasticity. PEE decreases LTP but also abnormally facilitates LTD (Kervern et al. ) through a presently unknown mechanism. We studied in rat hippocampus slice, the involvement of the chloride co-transporters NKCC1 and KCC2, in the role of GABAA inhibitions in facilitated LTD after moderate PEE. After PEE and in contrast to control slices, facilitated LTD in CA1 field was reduced by the GABAA receptor antagonist bicuculline with no changes in sensitivity to bicuculline and in GABA and benzodiazepine binding sites. Also, sensitivity to diazepam was unaltered, whereas aberrant LTD was blocked. Immunohistochemistry and protein analysis demonstrated an increase in KCC2 protein level at cell membrane in CA1 after PEE with no change in NKCC1 expression. Specifically, both monomeric and dimeric forms of KCC2 were increased in CA1. Bumetanide (10-100 MUM), a dose-dependent blocker of NKCC1 and KCC2, or VU0240551 (10 MUM) a specific antagonist of KCC2, corrected the enhanced LTD and interestingly bumetanide also restored the lower LTP after PEE. These results demonstrate for the first time an upregulation of the KCC2 co-transporter expression after moderate PEE associated with disturbances in GABAergic neurotransmission modulating bidirectional synaptic plasticity in the hippocampus. Importantly, bumetanide compensated deficits in both LTP and LTD, revealing its potential therapeutic properties. PMID- 27778438 TI - Direct Conversion of Nitriles into Alkene "Isonitriles". AB - The sequenced addition of RLi to nitriles, trapping with isopropylformate, and dehydration with phosphoryl chloride provides an efficient, direct synthesis of alkene isocyanides. The one-pot sequence involves a series of carefully orchestrated steps: addition, formylation, tautomerization, and dehydration, with CuCN catalyzing a key equilibration of a formyl imine to an N-formyl enamine. The resulting aromatic alkeneisocyanides, that are otherwise challenging to synthesize, engage in an unusual [4+2]-type cycloaddition/1,3-H shift/decyanation sequence to afford substituted naphthalenes. PMID- 27778439 TI - Von Willebrand factor and angiogenesis: basic and applied issues. AB - The recent discovery that von Willebrand factor (VWF) regulates blood vessel formation has opened a novel perspective on the function of this complex protein. VWF was discovered as a key component of hemostasis, capturing platelets at sites of endothelial damage and synthesized in megakaryocytes and endothelial cells (EC). In recent years, novel functions and binding partners have been identified for VWF. The finding that loss of VWF in EC results in enhanced, possibly dysfunctional, angiogenesis is consistent with the clinical observations that in some patients with von Willebrand disease (VWD), vascular malformations can cause severe gastrointestinal (GI) bleeding. In vitro and in vivo studies indicate that VWF can regulate angiogenesis through multiple pathways, both intracellular and extracellular, although their relative importance is still unclear. Investigation of these pathways has been greatly facilitated by the ability to isolate EC from progenitors circulating in the peripheral blood of normal controls and patients with VWD. In the next few years, these will yield further evidence on the molecular pathways controlled by VWF and shed light on this novel and fascinating area of vascular biology. In this article, we will review the evidence supporting a role for VWF in blood vessel formation, the link between VWF dysfunction and vascular malformations causing GI bleeding and how they may be causally related. Finally, we will discuss how these findings point to novel therapeutic approaches to bleeding refractory to VWF replacement therapy in VWD. PMID- 27778441 TI - Usefulness of mean platelet volume as a marker for clinical outcomes after out-of hospital cardiac arrest: reply. PMID- 27778440 TI - Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. AB - BACKGROUND: Direct-acting oral anticoagulants (DOACs) are used in patients with splanchnic vein thrombosis (SVT) and cirrhosis, but evidence for safety and efficacy in this setting is limited. Our aim was to identify indications and reasons for starting or switching to DOACs and to report adverse effects, complications and short-term outcome. METHODS: Data collection including demographic information, laboratory values, treatment and complications through the Vascular Liver Disease Interest Group Consortium. RESULTS: Forty-five centres (90%) of the consortium completed the initial eCRF. We report here a series of 94 patients from 17 centres. Thirty-six patients (38%) had cirrhosis. Child-Pugh score was 6 (range 5-8), and MELD score 10.2 (range 6-19). Indications for anticoagulation were splanchnic vein thrombosis (75%), deep vein thrombosis (5%), atrial fibrillation (14%) and others (6%). DOACs used were rivaroxaban (83%), dabigatran (11%) and apixaban (6%). Patients were followed up for a median duration of 15 months (cirrhotic) and 26.5 months (non-cirrhotic). Adverse events occurred in 17% of patients and included one case of recurrent portal vein thrombosis and five cases of bleeding. Treatment with DOACs was stopped in three cases. The major reasons for choosing DOACs were no need for monitoring or inadequacy of INR to guide anticoagulation in cirrhotic patients. Renal and liver function did not change during treatment. CONCLUSIONS: A consistent number of patients with SVT and/or cirrhosis are currently treated with DOACs, which seem to be effective and safe. These data provide a basis for performing randomized clinical trials of DOACs vs. low molecular weight heparin or vitamin K antagonists. PMID- 27778442 TI - Anionic Chains of Parent Pnictogenylboranes. AB - We report on the synthesis and structural characterization of unprecedented anionic parent compounds of mixed Group 13/15 elements. The reactions of the pnictogenylboranes H2 E-BH2 ?NMe3 (1 a=P, 1 b=As) with phosphorus and arsenic centered nucleophiles of the type [EH2 ]- (E=P, As) lead to the formation of compounds of the type [H2 E-BH2 -E'H2 ]- (2: E=E'=P; 3: E=E'=As; 4: E=P, E'=As) containing anionic pnictogen-boron chain-like units. Furthermore, a longer 5 membered chain species [H2 As-BH2 -PH2 -BH2 -AsH2 ]- (5) and a cyclic compound [NHCdipp -H2 B-PH2 -BH2 -NHCdipp ]+ [P5 B5 H19 ]- (6) containing a n butylcyclohexane-like anion were obtained. All the compounds have been characterized by X-ray structure analysis, multinuclear NMR spectroscopy, IR spectroscopy, and mass spectrometry. DFT calculations elucidate their high thermodynamic stability, the charge distribution, and give insight into the reaction pathway. PMID- 27778443 TI - Plasmapheresis exerts a long-lasting antipruritic effect in severe cholestatic itch. AB - BACKGROUND & AIMS: The amelioration of refractory cholestatic pruritus after plasmapheresis has been reported in single patients. Here, we analyse the efficacy of plasmapheresis in a cohort of patients with primary biliary cholangitis (PBC). METHODS: Seventeen consecutive patients with PBC (age range 39 85 years, 16 females, 9 with cirrhosis) and refractory pruritus underwent 129 plasmapheresis procedures during 40 admissions. Pruritus was quantified by the 10 point numeric rating scale (NRS) before and after plasmapheresis, as well as ~30 and ~90 days later. RESULTS: The mean pruritus before plasmapheresis did not differ between patients with and without cirrhosis (P>.05). Cirrhotics presented, however, with significantly higher serum alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and bilirubin before plasmapheresis. Plasmapheresis decreased itching to NRS<=5 in all but five admissions: Mean pruritus decreased from 8.3+/ 1.4 to 3.1+/-2.2 (P<.0001) in the entire cohort. It also led to a significant decrease in serum ALT, ALP, AST, GGT (all P<.001) and bilirubin (P=.002). Antipruritic effect persisted throughout the 90-days follow-up (P<.0001). The amelioration of pruritus was not affected by the presence of cirrhosis. CONCLUSIONS: Plasmapheresis is a promising method for reducing intractable itch in a significant proportion of PBC patients regardless of liver fibrosis. Long lasting improvement of symptoms requires repeated procedures. PMID- 27778444 TI - Using graphical representations to enhance the quality-of-care for colorectal cancer patients. AB - The study was to enhance adherence to quality-of-care guidelines for colorectal cancer (CRC) patients through plotting graphical representations. Rasch analysis was performed to examine the unidimensional measurement of the 13 core indicators. An author-made Excel module was applied to plot the so-called Wright map and KIDMAP in education field to report physicians' adherence to the quality of-life guidelines. We found that the scale of the quality-of-care guidelines for patients with colon cancer is unidimensional. A total of 15 (3.8%) and 14 (3.5%) persons' response patterns (i.e., Outfit MNSQs >2.0 and 4.0, respectively) are aberrantly dispersed from the majority of sample according to their estimated parameters of persons and indicators. It can be used for investigating the root cause of the 1ow measures and/or the most unexpected aberrant pattern of responses using Rasch analysis once any one indicator of unexpectedly aberrant treatment (p < .05) presents. The Rasch model can deal with these binary and/or missing data frequently seen in clinical settings. We confirm this computer module can contribute to ensuring that hospitals adhere to the treatment guidelines for patients with colon cancer. PMID- 27778445 TI - Simultaneous determination of seven multiclass veterinary antibiotics in surface water samples in the Republic of Korea using liquid chromatography with tandem mass spectrometry. AB - A simultaneous determination method using solid-phase extraction and liquid chromatography with tandem mass spectrometry was developed to detect and quantify the presence of seven multiclass veterinary antibiotics (13 compounds in total) in surface water samples, which included the effluents of livestock wastewater and sewage treatment plants, as well as the reservoir drainage areas from dense animal farms. The pH of all water samples was adjusted to 2 or 6 before solid phase extraction using Oasis HLB cartridges. The developed method was fully validated in terms of linearity, method detection limit, method quantitation limit, accuracy, and precision. The linearity of all tested drugs was good, with R2 determination coefficients >= 0.9931. The method detection limits and method quantitation limits were 0.1-74.3 and 0.5-236.6 ng/L, respectively. Accuracy and precision values were 71-120 and 1-17%, respectively. The determination method was successfully applied for monitoring water samples obtained from the Yeongsan River in 2015. The most frequently detected antibiotics were lincomycin (96%), sulfamethazine (90%), sulfamethoxazole (88%), and sulfathiazole (50%); the maximum concentrations of which were 398.9, 1151.3, 533.1, and 307.4 ng/L, respectively. Overall, the greatest numbers and concentrations of detected antibiotics were found in samples from the effluents of livestock wastewater, sewage treatment plants, and reservoir drainage areas. Diverse veterinary antibiotics were present, and their presence was dependent upon the commercial sales and environmental properties of the analytes, the geographical positions of the sampling points, and the origin of the water. PMID- 27778446 TI - Cataract surgery affects the pupil size and pupil constrictions, but not the late post-illumination pupil response. PMID- 27778447 TI - Distribution of intraocular pressure, central corneal thickness and vertical cup to-disc ratio in a healthy Iranian population: the Yazd Eye Study. AB - PURPOSE: To determine the distribution of intraocular pressure (IOP), central corneal thickness (CCT) and vertical cup-to-disc ratio (VCDR) in the healthy Iranian population. METHODS: This population-based, epidemiologic study evaluated Iranian aged 40-80 years, residing in Yazd, Iran, in 2010-2011. Eligible subjects were selected by cluster random sampling. Each participant underwent an interview and ophthalmologic examination including slit lamp examination, Goldmann applanation tonometry, binocular optic disc evaluation, stereoscopic fundus photography, ultrasonic pachymetry and visual field testing. RESULTS: Of 2320 eligible individuals, 2098 subjects (response rate of 90.4%) participated in the study. One eye from 1159 subjects (total of 2262 normal eyes) were randomly selected for the purpose of the study. Mean age was 53.1 +/- 9.6 years. Mean IOP, CCT and VCDR were 14.2 +/- 2.5 mmHg, 543 +/- 37 MUm and 0.32 +/- 0.14, respectively. Multiple regression analysis showed a significant correlation between IOP and age (regression coefficient = 0.02 per year, p = 0.015), CCT (regression coefficient = 0.02 per micron, p < 0.001), Spherical equivalent (regression coefficient = -0.15 per dioptre, p = 0.0.024) and smoking (regression coefficient = 0.89 higher for smokers, p = 0.009); it also showed a significant correlation between CCT with spherical equivalent (regression coefficient = 3.6 per dioptre, p = 0.002) and IOP (regression coefficient = 3.6 per mmHG, p < 0.001). There was no significant correlation with VCDR. CONCLUSIONS: Mean IOP, CCT and VCDR were 14.2 +/- 2.5 mmHg, 543 +/- 35 MUm and 0.32 +/- 0.14, respectively, in healthy Iranians that is different from other ethnicities. It seems advisable to pay attention to ethnicity for interpretation of each person's variables. PMID- 27778448 TI - Intestinal fatty acid binding protein Ala54Thr polymorphism is associated with peripheral atherosclerosis combined with type 2 diabetes mellitus. AB - BACKGROUND: Intestinal fatty acid-binding protein 2 (FABP2) is expressed in enterocytes and binds saturated and unsaturated long-chain fatty acids. The FABP2 Ala54Thr polymorphism has been reported to effect lipid metabolism. The aim of the present study was to assess the relationship between this polymorphism and peripheral atherosclerosis combined with type 2 diabetes mellitus (T2DM) in an Egyptian population. METHODS: The study was performed on 100 T2DM patients with peripheral atherosclerosis and 100 control subjects. The Ala54Thr polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism, whereas serum FABP2 levels were determined using ELISA. Fasting blood glucose, fasting serum insulin concentrations, HbA1c, lipid profile, body mass index (BMI) and systolic and diastolic blood pressure (SBP and DBP, respectively) were determined. RESULTS: There was a higher frequency of the Thr54 allele among the patient group (P = 0.002). In Ala54/Thr54 heterozygotes and carriers of the rare Thr54/Thr54 genotype, there were significant increases in BMI and FABP2. Those with the Thr54/Thr54 genotype had significantly decreased high-density lipoprotein cholesterol (HDL-C) concentrations; in addition, those with the Thr54/Thr54 genotype had significantly higher SBP and DBP than subjects with the Ala54/Ala54 and Ala54/Thr54 genotypes. There was a positive correlation between FABP2 levels and BMI, SBP and DBP, and a negative correlation with HDL-C. CONCLUSIONS: The Thr54 allele of the FABP2 Ala54Thr polymorphism was associated with an increased incidence of peripheral atherosclerosis combined with T2DM in the population studied. PMID- 27778449 TI - Dilated fundus exam and associated findings in spontaneous subconjunctival haemorrhage. PMID- 27778450 TI - Scattering the spotlight on microparticles. PMID- 27778451 TI - Management of extremely hard-to-heal extremity wounds with severe life threatening complications. AB - The introduction of neoadjuvant radiotherapy has allowed limb-preserving surgical treatment in patients with extremity soft tissue sarcoma, and the overall prognosis of this approach is similar to that of limb amputation. The benefits of this treatment, however, are often accompanied with a higher risk of major complications and blood vessel damage because of radiation-induced inflammation and necrosis of the vessel wall. In particular, it is associated with the rupture of large vessels like the femoral artery and more severe complications of wounds located in the proximal lower extremity. We present a series of four patients with soft tissue sarcoma of the thigh undergoing tumour removal and reconstruction of the defect after neoadjuvant radiotherapy. The post-operative outcome depended on the total dose of radiation used as well as the closing technique of the resulting wound. Major wound complications occurred when the irradiated skin was closed directly over the resection cavity or when local skin flaps were used. In one case, severe radiation-induced life-threatening multiple bleeding events occurred, which led to multiple flap failures. Even if the skin cover is not a problem, we propose a combined interdisciplinary approach involving immediate plastic surgical transfer of healthy, well-vascularised tissue into a defect resulting from oncological resection of sarcoma of the lower extremity following neoadjuvant radiotherapy in order to avoid secondary wound breakdown and severe bleeding complications. PMID- 27778452 TI - Improving clean-catch contamination rates: A prospective interventional cohort study. AB - OBJECTIVES: The clean-catch method of urine collection carries a high contamination rate. This study aims to evaluate the effects on contamination rate of providing a parent handout and pre-made urine collection pack for clean-catch urine collection. METHODS: We conducted a single-centre prospective cohort interventional study in a tertiary paediatric ED. All children younger than 24 months who presented from April 2013 to June 2014 requiring a urine sample to be obtained were included. The intervention was provision of a pre-made urine collection pack including a standardised information handout. The primary outcome measure was the difference in proportion of urine contamination in samples obtained via a clean-catch pre- and post-intervention. RESULTS: The total number of urine specimens included was 288 in the pre-intervention group and 333 in the post-intervention group. Contamination rates were 14.9% in the pre-intervention group and 11.4% in the post-intervention group. There was no statistically significant reduction in contamination (P = 0.19). The contamination rates appeared to be associated with gender, with (pooled) female contamination rates being 16.4% (44/269) and male contamination rates being 10.5% (37/352). Most specimens of urine were collected via the clean-catch method (81.2%), followed by catheter urine specimen (13.7%) and suprapubic aspirate (5.1%). The contamination rate in our study for clean-catch urine collectively was 13%, catheter urine specimen 3.8% and suprapubic aspirate 0%. CONCLUSION: The contamination rate of clean-catch urine did not improve with the implementation of a pre-made urine collection pack including standardised written instructions. PMID- 27778453 TI - Successful Recovery of Acute Renal Transplant Failure in Recurrent Hepatitis C Virus-Associated Membranoproliferative Glomerulonephritis. AB - Recurrence of hepatitis C virus (HCV)-associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct-acting antiviral agents (DAAs) allow a highly effective and interferon free treatment option for chronic HCV-infected patients. Data on the therapeutic safety and efficacy in HCV-infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63 year-old female HCV-positive renal transplant patient with biopsy-proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti-HCV-directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy-associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis-dependent renal transplant failure after treatment of recurrent HCV associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs. PMID- 27778454 TI - Quantification of fluid resorption from diabetic macular oedema with foveal serous detachment after dexamethasone intravitreal implant (Ozurdex(r) ) in a pregnant diabetic. AB - PURPOSE: To quantify the fluid resorption from the centre of the fovea in a pregnant woman with diabetic macular oedema by daily optical coherence tomography (OCT) measurements after the administration of intravitreal dexamethasone implant (Ozurdex(r) ). METHODS: A 36-year-old pregnant woman with type 1 diabetes for 33 years presented with diabetic macular oedema with foveal serous detachment and symptomatic vision loss at 16 gestational weeks. Best-corrected visual acuity (BCVA) in Snellen notation and central retinal volume assessed by optical coherence tomography (OCT, Topcon Corporation) were measured almost on a daily basis the first five weeks after implantation and then 2-3 times per month until childbirth. RESULTS: The pretreatment BCVA was 0.6/1.0, and pretreatment central retinal volume was 0.32 mm3 . Near elimination of the oedema was achieved 3 days after treatment. One week after treatment, BCVA improved to preconception level, and full regression of the oedema was achieved. The rate of fluid resorption from the centre of the fovea was highest 3 days after treatment 0.00139 MUL/hr and decreasing to 0.00065 MUL/hr 1 week after treatment. CONCLUSION: Intravitreal dexamethasone implant Ozurdex reduces promptly central retinal volume in diabetic macular oedema involving the centre of the fovea in pregnancy with highest rate of fluid resorption 3 days after treatment initiation. PMID- 27778455 TI - Wine microbiology is driven by vineyard and winery anthropogenic factors. AB - The effects of different anthropic activities (vineyard: phytosanitary protection; winery: pressing and sulfiting) on the fungal populations of grape berries were studied. The global diversity of fungal populations (moulds and yeasts) was performed by pyrosequencing. The anthropic activities studied modified fungal diversity. Thus, a decrease in biodiversity was measured for three successive vintages for the grapes of the plot cultivated with Organic protection compared to plots treated with Conventional and Ecophyto protections. The fungal populations were then considerably modified by the pressing clarification step. The addition of sulfur dioxide also modified population dynamics and favoured the domination of the species Saccharomyces cerevisiae during fermentation. The non-targeted chemical analysis of musts and wines by FT ICR-MS showed that the wines could be discriminated at the end of alcoholic fermentation as a function of adding SO2 or not, but also and above all as a function of phytosanitary protection, regardless of whether these fermentations took place in the presence of SO2 or not. Thus, the existence of signatures in wines of chemical diversity and microbiology linked to vineyard protection has been highlighted. PMID- 27778456 TI - Parinaud syndrome: a 25-year (1991-2016) review of 40 consecutive adult cases. AB - PURPOSE: To characterize the clinical features, aetiology and management of ophthalmic symptoms in adult patients with Parinaud syndrome. METHODS: This is a retrospective, non-comparative observational case series. We reviewed 40 consecutive charts of adult patients with the clinical diagnosis of Parinaud syndrome at the Royal Adelaide Hospital Department of Ophthalmology in Adelaide, South Australia, between 1991 and 2016. Charts were reviewed for the following: (1) demographic information, (2) clinical presentation, (3) neuro-ophthalmology signs, (4) aetiology of Parinaud syndrome, and (5) management. Examination findings were collected at initial evaluation, throughout the course of follow up, and at last follow-up. RESULTS: All the cases were assessed by one of the authors (JLC). The commonest presenting symptoms were diplopia (67.5%) and blurred vision (25%) followed by visual field defect (12.5%), ataxia (7.5%) and manifest squint (7.5%). The commonest presenting signs were vertical gaze palsy (100%), convergence-retraction nystagmus (87.5%) and light-near dissociation (65.0%). Only 65.0% patients had the classical triad of vertical gaze palsy, convergence-retraction nystagmus and light-near dissociation. Midbrain pathologies including haemorrhage (30.0%), infarction (20.0%) and tumour (15.0%) were the commonest aetiology. Pineal region tumours accounted for 30.0% of presentations. Symptoms were managed conservatively in 45% of cases with temporary occlusion, prisms or refractive correction, and observation in 42.5% of cases. Surgical intervention for refractory diplopia was required in 12.5% of cases, of which 80% reported symptom resolution following surgery. CONCLUSION: Our series highlights the variable clinical presentation of Parinaud syndrome. The classic triad of conjugate upgaze paralysis, convergence-retraction nystagmus and light-near dissociation was only present in 65% of cases. Pineal neoplasms remain an important aetiological consideration; however, primary midbrain pathology including infarction and haemorrhage constituted the majority of our cases and should be considered in all patients. Conservative management approaches for ocular symptoms are sufficient in most cases although surgical treatment of upgaze palsy can be a useful option in refractory cases. PMID- 27778457 TI - Comparison of Digital 12-Lead ECG and Digital 12-Lead Holter ECG Recordings in Healthy Male Subjects: Results from a Randomized, Double-Blinded, Placebo Controlled Clinical Trial. AB - BACKGROUND: Electrocardiogram (ECG) variability is greatly affected by the ECG recording method. This study aims to compare Holter and standard ECG recording methods in terms of central locations and variations of ECG data. METHODS: We used the ECG data from a double-blinded, placebo-controlled, randomized clinical trial and used a mixed model approach to assess the agreement between two methods in central locations and variations of eight ECG parameters (Heart Rate, PR, QRS, QT, RR, QTcB, QTcF, and QTcI intervals). RESULTS: A total of 34 heathy male subjects with mean age of 25.7 +/- 4.78 years were randomized to receive either active drug or placebo. Digital 12-lead ECG and digital 12-lead Holter ECG recordings were performed to assess ECG variability. There are no significant differences in least square mean between the Holter and the standard method for all ECG parameters. The total variance is consistently higher for the Holter method than the standard method for all ECG parameters except for QRS. The intraclass correlation coefficient (ICC) values for the Holter method are consistently lower than those for the standard method for all ECG parameters except for QRS, in particular, the ICC for QTcF is reduced from 0.86 for the standard method to 0.67 for the Holter method. CONCLUSIONS: This study suggests that Holter ECGs recorded in a controlled environment are not significantly different but more variable than those from the standard method. PMID- 27778458 TI - T-Wave Alternans, Heart Rate Turbulence, and Ventricular Ectopy in Standard versus Daily Hemodialysis: Results from the FHN Daily Trial. AB - BACKGROUND: Hemodialysis (HD) patients are at high risk of sudden cardiac death (SCD). HD 6-times/week (6x/wk) may reduce SCD risk compared to usual 3-times/week HD (3x/wk) by mechanisms unknown. T-wave alternans (TWA), heart rate turbulence (HRT), and ventricular ectopy (VE) are elevated in HD patients, but their response to 6x/wk HD has not been assessed. METHODS: Baseline and 1-year Holter recordings were analyzed from enrollees in the Frequent Hemodialysis Network Daily Trial, a randomized trial comparing 3x/wk to 6x/wk in 245 chronic HD patients. TWA, HRT, and VE were assessed using MARS software. RESULTS: Sixty eight patients (34 with 6x/wk) had complete baseline and 1-year Holter recordings. Mean age was 50 +/- 13 years and 38% were female. Maximum TWA in the 3x/wk and 6x/wk groups were 52.4 MUV at baseline and 51.2 MUV at 1-year versus 54.0 and 49.9 MUV, respectively (P = 0.28). The proportion of abnormal HRT (scores of 1 or 2) in the 3x/wk group decreased from 65% to 56% at 1-year versus 53% to 53% in the 6x/wk group (P = 0.58). Mean %VE changed from 1.6% to 2.9% in the 3x/wk group from baseline to 1-year and from 2.1% to 3.7% in the 6x/wk group (P = 0.85). CONCLUSIONS: There were no significant differences in HRT or VE at 1 year in chronic HD patients randomized to 6x/wk versus 3x/wk and a trend in TWA reduction. Additional studies are needed to evaluate the impact and mechanisms of SCD in HD. PMID- 27778459 TI - Infliximab equivalently suppresses oxidative stress compared to tocilizumab among well-controlled patients with rheumatoid arthritis. AB - AIM: This study was designed to investigate which biological agent, infliximab or tocilizumab, would more intensively keep suppressing oxidative stress among well controlled patients as C-reactive protein (CRP) levels normalized in rheumatoid arthritis (RA). In addition, it was intended to clarify indicative factors of oxidative stress among well-controlled patients with RA. METHODS: We recruited 61 well-controlled (CRP < 0.3 mg/dL within normal ranges) patients with RA using biological agents (infliximab n = 33; tocilizumab n = 28), active RA patients with CRP > 1.0 mg/dL (n = 10) and healthy subjects (n = 10) and examined the fraction of oxidized albumin (oxidized-albumin [%]) as a marker of oxidative stress in addition to inflammatory measures and disease activity scores such as CRP, erythrocyte sedimentation rate (ESR), matrix metalloproteinase 3 (MMP-3), serum amyloid A (SAA), Clinical Disease Activity Index, Simplified Disease Activity Index, visual analog scale (VAS), Disease Activity Index of 28 joints (DAS28)-CRP, DAS28-ESR and renal function (creatinine clearance [CCr]). RESULTS: Oxidized-albumin (%) was significantly elevated among active RA patients (33.83 +/- 5.31%) as compared with healthy subjects (23.00 +/- 2.56%). Although oxidized albumin (%) among well-controlled RA patients also increased, there was no difference with oxidized-albumin (%) between infliximab and tocilizumab groups (26.40 +/- 5.44% in infliximab; 26.62 +/- 4.53% in tocilizumab). In Pearson's correlation, oxidized-albumin (%) had significant correlations with CRP, MMP-3, ESR, SAA, age, CCr, VAS, DAS28-CRP and DAS28-ESR. With those variables, multiple stepwise forward regression analysis was conducted and revealed that CCr, DAS28 ESR and CRP are the statistically significant explanatory variables on oxidized albumin (%) among well-controlled RA patients. CONCLUSIONS: We demonstrated that there was no difference with infliximab and tocilizumab on oxidative stress and we clarified that CCr, DAS28-ESR and CRP become indicative factors of oxidative stress among well-controlled RA patients. PMID- 27778460 TI - Diabetes mellitus prevalence is increasing in South Asians but is stable in Chinese living in Singapore and Mauritius. AB - BACKGROUND: Asia is experiencing a type 2 diabetes epidemic, but prevalence differs by ethnicity and level of socioeconomic development. Singapore and Mauritius have implemented comprehensive campaigns to address this public health problem. We compared diabetes and obesity prevalence trends among Chinese and South Asians living in Singapore and Mauritius to determine the contribution of ethnicity and economic development to diabetes. METHODS: Age-specific data from serial national population-based surveys in Singapore and Mauritius between 1987 and 2010 were used to estimate age-standardized diabetes and obesity prevalence. Modified Breslow-Cox proportional hazard models were used to obtain rate ratios for diabetes risk factors. RESULTS: In Singapore, the age-standardized prevalence of diabetes remained stable for Chinese (men: 14% in 1992, 13% in 2010; women: 12% in 1992, 10% in 2010), but increases were observed for South Asians (men: 20% in 1992, 26% in 2010; women: 18% in 1992, 20% in 2010). There were similar patterns in Mauritius. In both countries, obesity prevalence trends were stable for Chinese women, but increased for Chinese men and South Asians. Associations between obesity and diabetes were stronger in Chinese than South Asians regardless of country. CONCLUSIONS: Despite different socioeconomic settings in Singapore and Mauritius, we observed rising diabetes prevalence among South Asians but stable prevalence in Chinese in both countries. This provides further evidence that ethnicity contributes to the development of diabetes, and that there should be an increased emphasis on future prevention strategies targeting South Asian populations in these countries. PMID- 27778461 TI - Retinal pigment epithelium wound healing after traumatic choroidal rupture. AB - PURPOSE: The aim of this study was to investigate wound healing in the retinal pigment epithelium (RPE) after traumatic indirect choroidal rupture using fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT). METHODS: A total of 14 eyes of 14 patients with traumatic indirect choroidal rupture were included. Baseline and last follow-up FAF images were compared to evaluate the extent of RPE healing after choroidal rupture, and associated morphologic characteristics were examined by SD-OCT. RESULTS: The size of the RPE lesion was reduced in five eyes. The change occurred in the fovea in four eyes and in the macula in three eyes. The change was noted in both the fovea and the macula in two eyes; in these cases, the changes were more prominent in the fovea than in the macula. Extra-macular lesions and lesions with deep choroidal involvement did not show any reduction in size. Choroidal neovascularization (CNV) developed in seven eyes. There was no extra-macular CNV. CONCLUSION: Retinal pigment epithelium (RPE) wound healing after traumatic choroidal rupture is affected by location and extent of the lesion. PMID- 27778462 TI - Laparoscopic gastric bypass surgery: a safe and effective operation for the >=60s? AB - BACKGROUND: The perceived benefits of Roux-en-Y laparoscopic gastric bypass (LRYGB) surgery in the >=60s are regarded as being significantly less than in the younger population. This study examined a New Zealand population who underwent LRYGB and analysed the mortality rate, complications and postoperative weight loss. METHODS: This was a retrospective cohort study of patients who underwent LRYGB over a 12-year period and had attended up to 1 year of follow-up clinic. The study population was from a single centre in New Zealand. RESULTS: A total of 1362 patients were eligible. Demographic analysis showed the <60 to have 83% female majority, mean age of 43 years and a mean body mass index of 46. The >=60 group had a 76% female majority, mean age of 63 years and a mean body mass index of 45. The % excess weight loss, % weight loss and weight loss at 1 year all showed a significant difference. Analysis of the % excess weight loss at 1 year in the >=60s showed a mean of 79% and a median of 78% (95% confidence interval: 69%, 85%). In the <60s the mean was 84% and the median 84% (95% confidence interval: 83%, 85%). Comparison between the groups showed a significant difference (Kruskal-Wallis test, P = 0.0064). The complication frequency of the groups was not significantly different (chi-square test, P = 0.7605). CONCLUSION: LRYGB is an effective weight loss operation in the <60s and >=60s. LRYGB is safe, with a low complication rate and 30-day postoperative mortality rate. LRYGB should not be restricted on the basis of age alone. PMID- 27778464 TI - Societal perceptions of male nurses in South Korea: A Q-methodological study. AB - AIM: One of the remarkable changes in today's nursing profession is the emergence of male nurses. In order to promote the development of nursing, it would be beneficial for a positive perception of male nurses to be established in society. This study identified the public perceptions of male nurses in South Korea by using Q methodology and offered basic strategies for enhancing the perception of male nurses. METHODS: A Q-methodological approach, suitable for subjective research, was used for a survey. Q statements were based on 600 Q concourses that were collected through a literature review and individual interviews. Thirty seven final Q statements were selected from those. The P sample was collected from 45 persons who were likely to represent a diverse range of views about male nurses. The collected data were analyzed with PQMethod software; a principal component factor analysis with varimax rotation was used to identify the patterns of the public's perception of male nurses. RESULTS: Four distinct perspectives were identified: progressive occupational; conservative occupational; negative occupational; and supportive occupational. CONCLUSION: This study provided strategies for improving the public's views of male nurses in a conservative country with gender stereotypes. These findings also could attract more male nurses into the profession and increase their retention. PMID- 27778463 TI - Detection of glaucoma progression by perimetry and optic disc photography at different stages of the disease: results from the Early Manifest Glaucoma Trial. AB - PURPOSE: To compare the earliest detection of progression in visual fields and monoscopic optic disc photographs at different stages of manifest glaucoma. METHODS: This study evaluated 306 eyes in 249 patients with manifest open-angle glaucoma included in the Early Manifest Glaucoma Trial (EMGT). All patients in the trial were followed up regularly by standard automated perimetry and monoscopic optic disc photography, and the median follow-up time was 8 years. Progression was assessed in series of optic disc photographs and in series of visual fields using glaucoma change probability maps and the predefined EMGT progression criterion. The proportion of progressions detected first in visual fields and the proportion detected first in optic disc photographs were compared at different stages of glaucoma severity defined by the perimetric mean deviation (MD) of the baseline visual field. RESULTS: Assessment of 210 eyes with early visual field loss, 83 eyes with moderate field loss, and 13 eyes with advanced field loss showed that, among the eyes exhibiting progression, the progression was detected first in the visual field in 80%, 79% and 100%, respectively. The predominance of visual field progressions at all stages was still apparent when using narrower (3-dB) MD intervals for staging. CONCLUSION: In the EMGT material on eyes with manifest open-angle glaucoma, the initial progression was detected much more often in the visual field series than in the optic disc photographs at all stages of disease. PMID- 27778465 TI - Improving the Health and Well-Being of Adults With Conditions of a Genetic Origin: Views from Professionals, Syndrome Support Groups and Parents. AB - BACKGROUND: Advances in medical genetics herald the possibility that health and social care services could be more responsive to the needs arising from a person's genotype. This development may be particularly important for those men and women whose learning disability (known internationally as intellectual disability) is linked to a neurodevelopmental condition of genetic origin. METHOD: This possibility is tested through interviews with samples of (i) professional 'opinion former' with nationally recognised clinical and/or academic interests in learning disabilities and genetics; (ii) representatives of syndrome organisations prompting the interests of families where someone has a neurodevelopmental condition, and parent-members of these same organisations. RESULTS: The reporting and discussion of the interview data considers the possibility that notwithstanding the successes of the social model of disability, the health and wellbeing of people whose learning disability is associated with a neurodevelopmental condition could be better served by a more medicalised approach to their interests. CONCLUSION: While a more medicalised approach to this populations' disabilities would appear to be beneficial, so long as it is focused on interventions to improve their lives rather than catalogues their deficiencies. PMID- 27778466 TI - A double chamber rotating bioreactor for enhanced tubular tissue generation from human mesenchymal stem cells: a promising tool for vascular tissue regeneration. AB - Cardiovascular diseases represent a major global health burden, with high rates of mortality and morbidity. Autologous grafts are commonly used to replace damaged or failing blood vessels; however, such approaches are hampered by the scarcity of suitable graft tissue, donor site morbidity and poor long-term stability. Tissue engineering has been investigated as a means by which exogenous vessel grafts can be produced, with varying levels of success to date, a result of mismatched mechanical properties of these vessel substitutes and inadequate ex vivo vessel tissue genesis. In this work, we describe the development of a novel multifunctional dual-phase (air/aqueous) bioreactor, designed to both rotate and perfuse small-diameter tubular scaffolds and encourage enhanced tissue genesis throughout such scaffolds. Within this novel dynamic culture system, an elastomeric nanofibrous, microporous composite tubular scaffold, composed of poly(caprolactone) and acrylated poly(lactide-co-trimethylene-carbonate) and with mechanical properties approaching those of native vessels, was seeded with human mesenchymal stem cells (hMSCs) and cultured for up to 14 days in inductive (smooth muscle) media. This scaffold/bioreactor combination provided a dynamic culture environment that enhanced (compared with static controls) scaffold colonization, cell growth, extracellular matrix deposition and in situ differentiation of the hMSCs into mature smooth muscle cells, representing a concrete step towards our goal of creating a mature ex vivo vascular tissue for implantation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27778468 TI - Public (Q)SAR Services, Integrated Modeling Environments, and Model Repositories on the Web: State of the Art and Perspectives for Future Development. AB - Thousands of (Quantitative) Structure-Activity Relationships (Q)SAR models have been described in peer-reviewed publications; however, this way of sharing seldom makes models available for the use by the research community outside of the developer's laboratory. Conversely, on-line models allow broad dissemination and application representing the most effective way of sharing the scientific knowledge. Approaches for sharing and providing on-line access to models range from web services created by individual users and laboratories to integrated modeling environments and model repositories. This emerging transition from the descriptive and informative, but "static", and for the most part, non-executable print format to interactive, transparent and functional delivery of "living" models is expected to have a transformative effect on modern experimental research in areas of scientific and regulatory use of (Q)SAR models. PMID- 27778467 TI - Association between vitamin D receptor gene polymorphism and ankylosing spondylitis in Han Chinese. AB - OBJECTIVES: To investigate whether vitamin D receptor (VDR) gene polymorphisms confer susceptibility to aankylosing spondylitis (AS) and study its polymorphisms in Han Chinese. METHODS: We screened single nucleotide polymorphisms (SNPs) in the VDR region through genome-wide genotyping chips in AS cases and healthy controls, then used the exome sequencing result to analyze all the potential AS associated SNPs in the VDR gene. RESULTS: Thirty-two SNPs were found in the VDR gene in the genome-wide genotyping chips and the logistic regression result showed no significant difference between AS cases and controls. A total of 46 SNPs in the VDR region were genotyped through exome sequencing, including four functional SNPs (rs731236 [TaqI], rs2228570 [FokI], rs7975232 [ApaI], rs1544410 [BsmI]) and two newly discovered SNPs (12:48259222 and 12:48276730). To note, rs731236 and rs2228570 locate in the exons of VDR, which cause synonymous and missense mutation. The association test showed there was no significant difference between AS cases and controls in the allele frequency distribution, but haplotype analysis of rs11168266-rs11168267 show nominal significance (P = 0.01268). CONCLUSION: Our preliminary study indicates the haplotypes (TG) of rs11168266-rs11168267 in the VDR gene confers susceptibility to AS, which is worth further research. PMID- 27778469 TI - Developing an Easy Read Version of the Adult Social Care Outcomes Toolkit (ASCOT). AB - BACKGROUND: This study reports the experiences of developing and pre-testing an Easy Read version of the Adult Social Care Outcomes Toolkit (ASCOT) for self report by people with intellectual disabilities. METHODS: The study has combined survey development and pre-testing methods with approaches to create accessible information for people with intellectual disabilities. A working group assisted researchers in identifying appropriate question formats, pictures and wording. Focus groups and cognitive interviews were conducted to test various iterations of the instrument. RESULTS: Substantial changes were made to the questionnaire, which included changes to illustrations, the wording of question stems and response options. CONCLUSIONS: The process demonstrated the benefits of involving people with intellectual disabilities in the design and testing of data collection instruments. Adequately adapted questionnaires can be useful tools to collect information from people with intellectual disabilities in survey research; however, its limitations must be recognized. PMID- 27778470 TI - Periodontal regeneration in aggressive periodontitis patients: A systematic review of the literature. AB - The aim of the present study was to systematically review the existing literature on periodontal regenerative procedures in individuals affected by aggressive periodontitis (AgP). An electronic and manual search was performed using an ad hoc prepared search string. All types of study designs were considered acceptable for inclusion. Data about treated patients, baseline clinical parameters, type of surgery, and outcomes were extracted and recorded. A narrative evaluation of the results was performed. After the article-selection process, a total of 22 full texts were included in the qualitative synthesis. Twelve papers were case reports; one was a retrospective study; six were non-randomized, comparative studies; and three papers were published on two randomized, controlled trials (RCT). Various biomaterials and surgical techniques were described in the included papers. Based on the existing literature, even considering the relatively low level of evidence, periodontal regenerative surgery could be successfully performed in patients affected by AgP. There is a substantial need of high-quality RCT to support this. PMID- 27778471 TI - Antibiotic-prescribing patterns of South African dental practitioners following tooth extractions. AB - AIM: In the present study, we assessed the patterns and types of antibiotics prescribed following tooth extractions, and the alignment of these practices with the evidence available. METHODS: The study used health insurance claim data from South African dental practitioners for 2013, analyzing the antibiotic prescribing patterns around tooth extractions, separately for four event types: exposed (simple) tooth extractions in: (a) healthy patients and (b) patients with chronic conditions; and impacted tooth extractions in (c) healthy patients and (d) patients with a chronic condition. RESULTS: More than 50 000 extraction events were analyzed. The findings show no consistency in prescribing patterns. The same percentage (10%) of the healthy and the chronically ill patients undergoing an exposed (simple) tooth extraction were prescribed antibiotics, while approximately 50% of both healthy and chronically ill patient groups undergoing an impacted tooth extraction received a prescription. Almost 81% of prescriptions were for narrow spectrum antibiotics, with few differences across the four event types. CONCLUSIONS: The antibiotic prescription patterns of dental practitioners reported in the present study do not appear to follow a coherent set of guidelines or meaningful indications for antibiotic use. The study highlights the need for explicit and more prudent guidelines for the use of antibiotics following tooth extractions, to reduce the risk of antibiotic resistance. PMID- 27778472 TI - Impedance technology reduces the enumeration time of Brettanomyces yeast during beer fermentation. AB - Brettanomyces yeasts are increasingly being used to produce lambic style beers and craft beers with unique flavors. Currently, the industry monitors Brettanomyces bruxellensis using time consuming plate counting. B. bruxellensis is a fastidious slow growing organism, requiring five days of incubation at 30 degrees C for visible growth on agar plates. Thus, a need exists to develop a quicker, feasible method to enumerate this yeast. The aim of this study was therefore to determine the feasibility of using the 'direct' and 'indirect' impedance methods for the enumeration of B. bruxellensis in beer and to monitor the growth of the yeast during fermentation. The impedance methods were able to decrease the incubation time of beer samples containing Brettanomyces from 120 h down to 2 and 84 h for samples containing 107 and 103 cfu/mL, respectively. The 'indirect' method was more successful than the 'direct' method, presenting a smaller error and wider detection range. Overall, the 'indirect' impedance method is a viable alternative to plate counting for the enumeration of yeasts in the brewing industry because it decreases preparation and incubation times, thereby increasing throughput and decreasing the chance of contamination. PMID- 27778473 TI - Creating an Efficient Methanol-Stable Biocatalyst by Protein and Immobilization Engineering Steps towards Efficient Biosynthesis of Biodiesel. AB - Two ternary sol-gel matrices, an octyltriethoxysilane-based aliphatic matrix and a phenyltriethoxysilane (PTEOS)-based aromatic matrix, were used to immobilize a methanol-stable variant of lipase from Geobacillus stearothermophilus T6 for the synthesis of biodiesel from waste oil. Superior thermal stability of the mutant versus the wildtype in methanol was confirmed by intrinsic protein fluorescence measurements. The influence of skim milk and soluble E. coli lysate proteins as bulking and stabilizing agents in conjunction with sol-gel entrapment were investigated. E. coli lysate proteins were better stabilizing agents of the purified lipase mutant than skim milk, as evidenced by reverse engineering of the aromatic-based system. This was also shown for commercial Candida antarctica lipase B (CaLB) and Thermomyces lanuginosus lipase (TLL). Uniform, dense, and nonaggregated particles imaged by scanning electron microscopy and a small particle size of 13 MUm pertaining to the system comprising PTEOS and E. coli lysate proteins correlated well with high esterification activity. Combining protein and immobilization engineering resulted in a durable biocatalyst with efficient recycling ability and high biodiesel conversion rates. PMID- 27778475 TI - Abstracts of the 25th Malaysian Urological Conference MUC 2016, Malaysia, 25 November 2016. PMID- 27778477 TI - Exploratory Population PK Analysis of Dupilumab, a Fully Human Monoclonal Antibody Against IL-4Ralpha, in Atopic Dermatitis Patients and Normal Volunteers. AB - An exploratory population pharmacokinetic model for functional dupilumab was developed. Data from healthy volunteers and patients with atopic dermatitis (AD) receiving intravenous or subcutaneous doses were integrated. The data included 197 participants (2,518 measurements of dupilumab in serum) from six phase I and II studies. The data were analyzed using stochastic approximation expectation maximization and importance sampling methods. The best structural model was a two compartment model with parallel linear and Michaelis-Menten elimination from the central compartment. Estimated parameters were: central volume 2.74 L, elimination rate 0.0459 d-1 , central-to-peripheral rate 0.0652 d-1 , peripheral to-central rate 0.129 d-1 , bioavailability 60.7%, maximal target-mediated elimination rate 0.968 mg/L/d, and Michaelis-Menten constant 0.01 mg/L. Body weight was a significant covariate of the central volume. No gender effect was observed when controlling for weight. No differences between healthy volunteers and patients with AD were found. The model adequately described dupilumab pharmacokinetics for intravenous and subcutaneous routes of administration. PMID- 27778478 TI - Istamycin aminoglycosides profiling and their characterization in Streptomyces tenjimariensis ATCC 31603 culture using high-performance liquid chromatography with tandem mass spectrometry. AB - A high-performance liquid chromatography with electrospray ionization ion trap tandem mass spectrometry method was developed and validated for the robust profiling and characterization of biosynthetic congeners in the 2-deoxy aminocyclitol istamycin pathway, from the fermentation broth of Streptomyces tenjimariensis ATCC 31603. Gradient elution on an Acquity CSH C18 column was performed with a gradient of 5 mM aqueous pentafluoropropionic acid and 50% acetonitrile. Sixteen natural istamycin congeners were profiled and quantified in descending order; istamycin A, istamycin B, istamycin A0 , istamycin B0 , istamycin B1 , istamycin A1 , istamycin C, istamycin A2 , istamycin C1 , istamycin C0 , istamycin X0 , istamycin A3 , istamycin Y0 , istamycin B3 , and istamycin FU-10 plus istamycin AP. In addition, a total of five sets of 1- or 3 epimeric pairs were chromatographically separated using a macrocyclic glycopeptide-bonded chiral column. The lower limit of quantification of istamycin A present in S. tenjimariensis fermentation was estimated to be 2.2 ng/mL. The simultaneous identification of a wide range of 2-deoxy-aminocyclitol-type istamycin profiles from bacterial fermentation was determined for the first time by employing high-performance liquid chromatography with tandem mass spectrometry analysis and the separation of istamycin epimers. PMID- 27778476 TI - A minimally invasive adjustable-depth blunt injector for delivery of pharmaceuticals into the posterior pole. AB - PURPOSE: To investigate the feasibility and safety of a novel minimally invasive adjustable-depth blunt injector for pharmaceuticals delivery into the posterior segment. METHODS: Indocyanine green (ICG), sodium fluorescein and iron oxide nanoparticles (IONPs) were injected using the new injector into the extravascular spaces of the choroid (EVSC) compartment of rabbits and cadaver pig eyes. Spectral domain optical coherence tomography (SD-OCT), fundus imaging and histology analysis were performed for assessment of injection safety and efficacy. RESULTS: Indocyanine green, fluorescein and IONPs were detected across the EVSC in rabbit eyes, covering over 80 per cent of the posterior eye surface. Injected IONPs were retained in the EVSC for at least 2 weeks following injection. No retinal detachment, choroidal haemorrhage or inflammation was detected in any of the injected eyes. In cadaver pig eyes, ICG was detected across the EVSC. CONCLUSIONS: This novel minimally invasive delivery system may be used to safely deliver large volumes of pharmaceuticals into a new treatment reservoir compartment - the EVSC which can serve as a depot, in close proximity to the retina, covering most of the surface of the back of the eye without insertion of surgical instruments under the central retina. This system is predicted to enhance the therapeutic effect of treatments for posterior eye disorders. PMID- 27778474 TI - Nitrosylation of Nitric-Oxide-Sensing Regulatory Proteins Containing [4Fe-4S] Clusters Gives Rise to Multiple Iron-Nitrosyl Complexes. AB - The reaction of protein-bound iron-sulfur (Fe-S) clusters with nitric oxide (NO) plays key roles in NO-mediated toxicity and signaling. Elucidation of the mechanism of the reaction of NO with DNA regulatory proteins that contain Fe-S clusters has been hampered by a lack of information about the nature of the iron nitrosyl products formed. Herein, we report nuclear resonance vibrational spectroscopy (NRVS) and density functional theory (DFT) calculations that identify NO reaction products in WhiD and NsrR, regulatory proteins that use a [4Fe-4S] cluster to sense NO. This work reveals that nitrosylation yields multiple products structurally related to Roussin's Red Ester (RRE, [Fe2 (NO)4 (Cys)2 ]) and Roussin's Black Salt (RBS, [Fe4 (NO)7 S3 ]. In the latter case, the absence of 32 S/34 S shifts in the Fe-S region of the NRVS spectra suggest that a new species, Roussin's Black Ester (RBE), may be formed, in which one or more of the sulfide ligands is replaced by Cys thiolates. PMID- 27778479 TI - Rapid discovery of absorbed constituents and metabolites in rat plasma after the oral administration of Zi Shen Wan using high-throughput UHPLC-MS with a multivariate analysis approach. AB - Zi Shen Wan is a typical formula consisting of three herbs, Phellodendri Amurensis Cortex, Rhizoma Anemarrhenae, and Cortex Cinnamomi, and has been widely used for treating prostatitis and infection diseases. However, it lacks in-depth research of the constituents of Zi Shen Wan in vivo and in vitro. In this work, ultra high performance liquid chromatography coupled with quadrupole-time-of flight mass spectrometry and MassLynx software was established to characterize the chemical compositions of Zi Shen Wan in vivo and in vitro. In total, 92 peaks were characterized in vitro and 33 peaks were characterized in vivo based on mass spectrometry and tandem mass spectrometry data. Among the 33 compounds characterized in rat plasma, 22 prototype components absorbed in rat serum and 11 metabolites were identified in vivo. This work was fully reports the chemical constituents of traditional Chinese formula of Zi Shen Wan, it demonstrated that ultra high performance liquid chromatography combined with quadrupole time-of flight mass spectrometry coupled to MassLynx software and multivariate data processing approach could be successfully applied for rapid screening and comprehensive analysis of chemical constituents in vitro and prototype components or metabolites in vivo of traditional Chinese medicine. PMID- 27778480 TI - Mechanisms of topiramate effects: refining medications development for alcoholism. PMID- 27778481 TI - Optical coherence tomography angiography in leber hereditary optic neuropathy. PMID- 27778482 TI - Circulating tumor cells as a potential biomarker in diagnosis of lung cancer: a systematic review and meta-analysis. AB - OBJECTIVES: Accumulating evidences demonstrated that circulating tumor cells (CTCs) show significant high concentration in plasma of lung cancer patients compared to control cohorts, suggesting that CTCs may be a promising biomarker for lung cancer. The meta-analysis was used to evaluate potential diagnostic value of CTCs in diagnosing lung cancer. METHODS: Relevant literatures were searched in PubMed, Embase, Cochrane Library, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP), and Wan Fang Data. Summary estimates were used to evaluate CTCs as the diagnostic standard for lung cancer using Meta-DiSc and STATA 12.0 statistical software. RESULTS: This meta-analysis included five studies with a total of 460 lung cancer patients and 239 benign controls. The sensitivity and specificity (95% confidence interval [CI]) of CTCs was 75% (95% CI: 54%-88%) and 92% (95%CI: 82%-97%), respectively. In addition, the area under the summary ROC curve (AUC) was 0.93. CONCLUSION: CTCs is a novel potential biomarker in the diagnosis of lung cancer, and more prospective are needed in the future. PMID- 27778483 TI - Comparing pattern scanning laser trabeculoplasty to selective laser trabeculoplasty: A randomized controlled trial. AB - PURPOSE: To compare safety, tolerability and intraocular pressure (IOP)-lowering efficacy of pattern scanning laser trabeculoplasty (PSLT) with selective laser trabeculoplasty (SLT) in fellow eyes of untreated patients with glaucoma. DESIGN: Randomized controlled trial. PARTICIPANTS: Twenty-nine patients (58 eyes) with primary and secondary open angle glaucoma (OAG) were randomized to undergo PSLT or SLT in each eye. METHODS: Pattern scanning laser trabeculoplasty was performed using the Pascal laser (Pascal Streamline 577; Topcon Inc., Tokyo, Japan). Patients' comfort level to treatment was assessed using a visual analogue scale (VAS). Follow-up visits were at week 1, month 1, 3 and 6. Success was defined as IOP reduction >=20%. MAIN OUTCOME MEASURES: Safety, tolerability and IOP reduction. RESULTS: The mean age of patients was 54.1 +/- 15.5 years. Baseline IOP was similar between both groups (PSLT, 17.3 +/- 4.0 mmHg; SLT, 16.8 +/- 3.6 mmHg, p > 0.05). In the PSLT group, the mean IOP at 1, 3 and 6 months was 14.2 +/ 3.5, 13.9 +/- 2.6 and 14.0 +/- 2.7 mmHg, respectively. In the SLT group, the mean IOP at 1, 3 and 6 months was 14.4 +/- 4.1, 13.7 +/- 3.2 and 13.7 +/- 3.1 mmHg, respectively. The IOP reduction in the PSLT group was greater than the SLT group at 1 month (p < 0.01) and 3 months (p < 0.01). VAS score was better in PSLT eyes: 23.9 +/- 20.5 (range, 0-82) than in SLT eyes: 50.4 +/- 25.3 (range, 0-98) (p < 0.001). No serious adverse events were recorded. CONCLUSIONS: Both laser modalities had similar safety and efficacy profiles while PSLT was better tolerated by patients. PMID- 27778484 TI - A k-Nearest Neighbours Approach Using Metabolism-related Fingerprints to Improve In Silico Metabolite Ranking. AB - The application of biotransformation dictionaries derived by expert evaluation of known metabolic pathways represents one approach to the prediction of both phase I and phase II xenobiotic metabolites. The ranking of metabolites generated by such dictionaries has previously been achieved through the use of qualitative reasoning rules and quantitative probability values. Using the biotransformation dictionary available in the Meteor expert system, we show that metabolite over prediction by both of these methods can be reduced by the adoption of a k-nearest neighbours methodology in which the likelihood of a predicted biotransformation is determined based on comparison of a query chemical with structurally-similar substrates with known experimental metabolic data which activate the same biotransformation. Optimal performance was achieved when similarity was defined in terms of a combination of two fingerprints, one describing the overall profile of biotransformations a structure can potentially undergo and the other describing the local environment around the predicted site of metabolism for the particular biotransformation under consideration. PMID- 27778485 TI - In vivo biocompatibility of p(HPMAm-lac)-PEG hydrogels hybridized with hyaluronan. AB - The present study reports on the biocompatibility in vivo after intramuscular and subcutaneous administration in Balb/c mice of vinyl sulphone bearing p(HPMAm-lac1 2)-PEG-p(HPMAm-lac1-2)/thiolated hyaluronic acid hydrogels, designed as novel injectable biomaterials for potential application in the fields of tissue engineering and regenerative medicine. Ultrasonography, used as a method to study hydrogel gelation and residence time in vivo, showed that, upon injection, the biomaterial efficiently formed a hydrogel by simultaneous thermal gelation and Michael Addition cross-linking forming a viscoelastic spherical depot at the injection site. The residence time in vivo (20 days) was found to be shorter than that observed in vitro (32 days), indicating that the injected hydrogel was resorbed not only by chemical hydrolysis but also by cellular metabolism and/or enzymatic activity. Systemic biocompatibility was tested by analysing routine haematological parameters at different time-points (7, 14 and 21 days after administration) and histology of the main organs, including the haematopoietic system. No statistically significant difference between parameters of the saline treated group and those of the hydrogel-treated group was found. Importantly, a time-dependent decrease of important pro-inflammatory cytokines (TREM1 (Triggering Receptor Expressed on Myeloid cells-1), tumour necrosis factor-alpha and interleukin-1beta) in cultured bone marrow cells extracted from hydrogel treated mice was observed, possibly correlated to the anti-inflammatory effect of hyaluronic acid released in time as hydrogel degraded. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27778486 TI - Percutaneous Retrograde Transhepatic Arterial Puncture to Regain Access in the True Lumen of the Dissected and Acutely Occluded Transplant Hepatic Artery. AB - Iatrogenic hepatic artery dissection is a serious complication that can progress to complete hepatic artery occlusion and graft loss. Restoration of arterial flow to the graft is urgent, but the severity and extent of the dissection may interfere with endovascular techniques. The authors describe a technique of percutaneous retrograde transhepatic arterial puncture to regain access into the true lumen of the dissected hepatic artery to restore in-line flow to the liver graft. PMID- 27778487 TI - Retro-1 Analogues Differentially Affect Oligonucleotide Delivery and Toxin Trafficking. AB - Retro-1 is a small molecule that displays two important biological activities: First, it blocks the actions of certain toxins by altering their intracellular trafficking. Second, it enhances the activity of oligonucleotides by releasing them from entrapment in endosomes. This raises the question of whether the two actions involve the same cellular target. Herein we report the effects of several Retro-1 analogues on both toxins and oligonucleotides. We found analogues that affect toxins but not oligonucleotides and vice-versa, while Retro-1 is the only compound that affects both. This indicates that the molecular target(s) involved in the two processes are distinct. PMID- 27778490 TI - Robotic pyelolithotomy in a congenital pelvic kidney: side docking and robotic prostatectomy port - site approach. AB - INTRODUCTION AND OBJECTIVES: Ectopic pelvic kidneys with renal stones are challenging to treat. We report our experience in managing a case of ectopic pelvic kidney with a pelvic stone by robotic pyelolithotomy after failure of flexible ureteroscopy. MATERIALS AND METHODS: A 46-year old male with 2 months history of vague lower abdominal pain was found to have on Computed Tomography scan a left ectopic pelvic kidney with a 12mm stone in an anomalous renal pelvis. Flexible ureteroscopy failed to reach the stone twice and a 4.7 French ureteric stent was placed. RESULTS: Side docking was utilized with the patient in supine Trendelenburg position. Port placements were similar to robotic assisted laparoscopic prostatectomy. Docking time was 35 minutes and console time was 150 minutes. Multiple attempts failed to follow the course of the ureter to the renal pelvis. Subsequently the renal pelvis was directly opened through the mesocolon and a flexible cystoscope was used to basket the stone out. Estimated Blood Loss was < 100ml. The patient was discharged 2 days postoperatively. CONCLUSION: Robotic pyelolithotomy is safe and feasible for management of ectopic pelvic kidneys with pelvic stones. The use of flexible cystoscopy helped in localizing and extracting the stone in our case. Detailed understanding of patient's anatomy helps in the success of this procedure. PMID- 27778491 TI - Feasibility of Robot - assisted Segmental Ureterectomy and Ureteroureterostomy in Patient with High Medical Comorbidity. AB - INTRODUCTION AND OBJECTIVES: Nephroureterectomy remains the gold standard treatment option for upper tract tumors. However, segmental ureterectomy may be another option in patients with single kidney, borderline renal function or high medical comorbidities. The aim of this video is to assess the feasibility of robotic surgery as a minimally invasive technique in treatment of a high comorbid patient with ureteric tumor. MATERIALS AND METHODS: Eighty-year old male patient, with a medical history of chronic hypertensive and uncontrolled Diabetes Mellitus, was referred to our department for treatment of ureteric tumor. Patient underwent robot-assisted radical prostatectomy 5 years ago. Patient's Charlson comorbidity index score was 9. Computed tomography showed a 2.5cm right ureteral luminal filling enhancing lesion at lower part of upper 1/3 ureter. We performed diagnostic flexible cystoscopy under local anesthesia to exclude associated lower urinary tract carcinoma, and bladder wash was negative for malignancy. Under general anesthesia patient underwent diagnostic flexible ureteroscopy to confirm mass location, and a retrograde pyelography to rule out additional tumors on the right collecting system. Then, the patient was placed in the full lateral flank position without Table flexion. Ports placement were inserted as follow: a "12mm" optical trocar at pararectal line superior and lateral to umbilicus, two "8mm" robotic trocars cranial and caudal to optical trocar (8cm distance), a "8mm" robotic trocar towards anterior superior ischial spine, and a "12mm" assistant trocar was inserted between umbilicus and pubic bone. The surgical steps are shown in the video. RESULTS: The procedure was performed easily. The total operative time and consol time were 100 and 60 minutes, respectively. Blood loss was 50ml. No reported intraoperative or postoperative complications. Notably, we took full precautions in case of intraoperative failure to complete the procedure successfully, nephroureterectomy was our second option. Postoperative serum creatinine was 1.2mg/dL and length of hospital stay was 2 days. The frozen biopsy showed that the tumor was resected with safe proximal and distal surgical margins. Final histopathology revealed high grade (G3) urothelial carcinoma (pT3), measures (1.3x1.2x0.2cm), associated with carcinoma in situ. CONCLUSION: We affirm that robotic segmental ureterectomy and ureteroureterostomy could be offered safely as a minimally invasive treatment for patients with ureteric tumors and high-risk medical comorbidities. It provides excellent perioperative outcomes and early oncological safety with regard to surgical margins. PMID- 27778492 TI - Laparoscopic partial nephrectomy for multiple (four) tumors. AB - BACKGROUND: Nephron sparing surgery (NSS) is well established as the standard of care for most surgical small renal tumors when technically feasible. While the majority of sporadic renal tumors are solitary, multifocal tumors have been reported in 5.4% to 25% of patients with tumors smaller than 5cm. We present a video where we approach, through laparoscopy, four tumors on the same kidney. CASE STUDY: Male, 58y, went through a routine abdominal ultrasound which showed a 5cm left kidney nodule. His MRI pointed a total of 4 nodules on his left kidney. The aspect suggested a papillary cancer due to high cellularity and low vascularization. The patient was submitted to partial nephrectomy under ischemia to remove the two largest tumors (in!ferior pole) and a resection without clamping of the other two ipsilateral tumors. RESULT: We performed the surgery in 2 stages. In the first one, we approached the 2 tumors located on the inferior pole inducing warm ischemia, whereas in the second stage we resected the 2 remaining tumors using the technique without clamping. The surgery lasted 220 minutes, with 800mL of blood loss, not requiring blood transfusion. Ischemia time was 35 minutes. The histopathological analysis confirmed that the 4 tumors were papillary cancer, with free margins. CONCLUSION: NSS can be performed and should be tried in patients with multiple kidney tumors, preferably through lapa!roscopy or assisted by robot. It can be made either using or not clamping of the pedicle, depending on the RENAL score. PMID- 27778495 TI - Laparoscopic Pyeloplasty in children with Horseshoe Kidney. AB - INTRODUCTION: Horseshoe kidney occurs in 1 per 400-800 live births and are more frequently observed in males (M:F 2:1). Ureteropelvic junction obstruction (UPJO) is commonly associated with horseshoe kidneys. The variable blood supply, presence of the isthmus and high insertion of the ureter contribute to this problem. CASE REPORT: An asymptomatic 6 year-old boy presented with antenatal hydronephrosis. Ultrasonography and CT scan demonstrated left UPJO associated with a horseshoe kidney. DMSA showed 33% of function on the left side. DTPA showed a flat curve and lack of washout. A left dismembered laparoscopic pyeloplasty was performed after identification of crossing vessels and abnormal implantation of the ureter. After one year, the child is asymptomatic. DTPA demonstrated a good washout curve. RESULTS: Our cohort consisted of six patients, five males and one female, with a mean age of 6 years (range 6m-17 years) and a mean follow-up of 3 years. Ureteropelvic junction obstruction was more common on the left side. Symptoms appeared only in 34% of the cases. Mean operative time was 198 minutes (range 120-270 minutes). Crossing vessels were common (observed in 50% patients). High implantation of ureter was seen in 67% patients and intrinsic obstruction in 83%. Surgical difficulties were found in two cases. Hospital stay was 4.3 days (3 to 6 days), with only one patient having a mild complication (pyelonephritis). All cases had clinical and radiologic improvement. CONCLUSION: Laparoscopic pyeloplasty is safe and feasible in children with UPJO in horseshoe kidneys, with good results and minimal morbidity. PMID- 27778499 TI - Inhibition and Promotion of Pyrolysis by Hydrogen Sulfide (H2S) and Sulfanyl Radical (SH). AB - This study resolves the interaction of sulfanyl radical (SH) with aliphatic (C1 C4) hydrocarbons, using CBS-QB3 based calculations. We obtained the C-H dissociation enthalpies and located the weakest link in each hydrocarbon. Subsequent computations revealed that, H abstraction by SH from the weakest C-H sites in alkenes and alkynes, except for ethylene, appears noticeably exothermic. Furthermore, abstraction of H from propene, 1-butene, and iso-butene displays pronounced spontaneity (i.e., DeltarG degrees < -20 kJ mol-1 between 300-1200 K) due to the relatively weak allylic hydrogen bond. However, an alkyl radical readily abstracts H atom from H2S, with H2S acting as a potent scavenger for alkyl radicals in combustion processes. That is, these reactions proceed in the opposite direction than those involving SH and alkene or alkyne species, exhibiting shallow barriers and strong spontaneity. Our findings demonstrate that the documented inhibition effect of hydrogen sulfide (H2S) on pyrolysis of alkanes does not apply to alkenes and alkynes. During interaction with hydrocarbons, the inhibitive effect of H2S and promoting interaction of SH radical depend on the reversibility of the H abstraction processes. For the three groups of hydrocarbon, Evans-Polanyi plots display linear correlations between the bond dissociation enthalpies of the abstracted hydrogens and the relevant activation energies. In the case of methane, we demonstrated that the reactivity of SH radicals toward abstracting H atoms exceeds that of HO2 but falls below those of OH and NH2 radicals. PMID- 27778498 TI - Injectable Self-Assembled Dipeptide-Based Nanocarriers for Tumor Delivery and Effective In Vivo Photodynamic Therapy. AB - Self-assembling peptide-based materials are playing an important role in fabricating drug delivery carriers; however, they are often limited by several challenges, such as precise structure modulation, desirable nanoscale size, and sufficient circulation lifetime in the body. To address this issue, herein one type of injectable dipeptide-based nanocarriers with well-modulated size and structure has been developed by adjusting glutaraldehyde (GA)-assisted cationic dipeptide (CDP) assembly. After loading a model photosensitive drug (Ce6) and further decorating CDP nanoparticles (NPs) with heparin polymers (Hep), the desired dipeptide-based NPs are achieved with an average diameter of 100 nm and surface charge of -25 mV, which are favorable for the enhanced permeability and retention effects. Significantly, the dipeptide-based NPs with Ce6 loading have a longer circulation lifetime against opsonization than free Ce6 solution, and subsequently, they achieve the best anticancer efficiency in vivo. They do not cause body weight loss or induce bad immune activation in organs, implying good biosafety of the designed carriers. Taken together, dipeptide-based delivery carriers through GA-assisted assembly may provide a new alternative for developing precisely controlled nanostructures toward effective antitumor therapy. PMID- 27778500 TI - Simultaneous Determination of Protein Kinase A and Casein Kinase II by Dual-Color Peptide Biomineralized Metal Nanoclusters. AB - We design two artificial substrate peptides to synthesize blue-emissive Cu nanoclusters and red-emissive Au nanoclusters, respectively. In addition to the biomineralization function, these two peptides retain the biological activity to be phosphorylated by protein kinase and digested by carboxypeptidase Y. In the absence of protein kinase, the peptides capped on the nanoclusters suffer consecutive exocleavage by carboxypeptidase Y, resulting in oxidation and thus fluorescence quenching of the nanoclusters due to the losing of peptide protection. In the presence of protein kinase A and casein kinase II, the phosphorylation modification on corresponding substrate peptides protects the peptides against carboxypeptidase Y digestion and then the fluorescence of the nanoclusters can be retained. Since a single excitation wavelength can excite the both nanoclusters, blue and red emissive signals can be collected at the same time and then the quantitative determination of protein kinase A and casein kinase II can be achieved simultaneously. PMID- 27778501 TI - How Oliceridine (TRV-130) Binds and Stabilizes a MU-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways. AB - Substantial attention has recently been devoted to G protein-biased agonism of the MU-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 MUs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand receptor interactions that are expected to inform the structure-based design of improved opioid analgesics. PMID- 27778503 TI - One-Pot Fabrication of Hollow and Porous Pd-Cu Alloy Nanospheres and Their Remarkably Improved Catalytic Performance for Hexavalent Chromium Reduction. AB - Noble metal nanostructures (NMNSs) play a crucial role in many heterogeneous catalytic reactions. Hollow and porous NMNSs possess generally prominent advantages over their solid counterparts due to their unordinary structural features. In this work, we describe a facial one-pot synthesis of hollow and porous Pd-Cu alloy nanospheres (Pd-Cu HPANSs) through a polyethylenimine (PEI) assisted oxidation-dissolution mechanism. The strong coordination interaction between CuII and PEI facilitates the oxidation-dissolution of the Cu2O nanospheres template under air conditions, which is responsible for the generation of the Pd-Cu alloy and the convenient removal of the Cu2O nanospheres template at room temperature. Compared to the commercial Pd black, the Pd-Cu HPANSs show remarkably improved catalytic activity for the reduction of K2Cr2O7 by HCOOH at room temperature, attributing to the enhanced catalytic activity of the Pd-Cu HPANSs for the dehydrogenation decomposition of HCOOH. PMID- 27778502 TI - Stereoselective Synthesis of Cyclic Guanidines by Directed Diamination of Unactivated Alkenes. AB - A method for a directed stereoselective guanidinylation of alkenes is described. The guanidine unit can be delivered as an intact fragment by a hydroxy or carboxy group, usually with a high level of stereocontrol. After the guanidine delivery, the directing group can be cleaved under exceptionally mild conditions, typically by alcoholysis in the presence of acetic acid. Broad functional group tolerance and mild reaction conditions for the cycloguanidilation suggest applications in medicinal chemistry and natural products synthesis. PMID- 27778504 TI - Characterization of the Reversed-Phase Chromatographic Behavior of PEGylated Peptides Based on the Poly(ethylene glycol) Dispersity. AB - The separation mechanism of PEGylated peptides in reversed-phase high-performance liquid chromatography (RP-HPLC) is complex, because the PEGylated molecules exhibit physicochemical properties that are different from those of the parent molecules and have heterogeneous structure. Since most separation studies have focused on the hydrophobicity of the peptide relative to poly(ethylene glycol) (PEG), the role of PEG in the separation of PEGylated peptides on RP-HPLC is not clear. To elucidate the effect of the attached PEG on the retention of PEGylated peptides on RP-HPLC, the mono-PEGylated forms of collagen pentapeptide and octreotide were fractionated drop-by-drop from the outlet of the HPLC system and each drop was subjected to matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS). This approach demonstrated that the dispersity of the attached PEG leads to the peak broadness of PEGylated peptides in RP-HPLC and the elution order inside the HPLC peak of PEGylated peptides was dependent on the attached PEG chain length. The retention time of PEGylated peptide increased as the attached PEG chain increased in length. When uniform PEG was conjugated to octreotide, its well-resolved positional isomers of the mono PEGylated forms showed narrow peaks comparable to native peptide peak under the same HPLC conditions, which confirmed the effect of the attached PEG dispersity on the chromatographic behavior of PEGylated peptides. In conclusion, this study indicates that the chromatographic behavior of PEGylated peptides is affected by the PEG chain length dispersity as well as the peptide's hydrophobicity. PMID- 27778506 TI - Observations of Atmospheric Delta14CO2 at the Global and Regional Background Sites in China: Implication for Fossil Fuel CO2 Inputs. AB - Six months to more than one year of atmospheric Delta14CO2 were measured in 2014 2015 at one global background site in Waliguan (WLG) and four regional background sites at Shangdianzi (SDZ), Lin'an (LAN), Longfengshan (LFS) and Luhuitou (LHT), China. The objectives of the study are to document the Delta14CO2 levels at each site and to trace the variations in fossil fuel CO2 (CO2ff) inputs at regional background sites. Delta14CO2 at WLG varied from 7.1 +/- 2.90/00 to 32.0 +/- 3.20/00 (average 17.1 +/- 6.80/00) in 2015, with high values generally in autumn/summer and low values in winter/spring. During the same period, Delta14CO2 values at the regional background sites were found to be significantly (p < 0.05) lower than those at WLG, indicating different levels of CO2ff inputs at those sites. CO2ff concentrations at LAN (12.7 +/- 9.6 ppm) and SDZ (11.5 +/- 8.2 ppm) were significantly (p < 0.05) higher than those at LHT (4.6 +/- 4.3 ppm) in 2015. There were no significant (p > 0.05) seasonal differences in CO2ff concentrations for the regional sites. Regional sources contributed in part to the CO2ff inputs at LAN and SDZ, while local sources dominated the trend observed at LHT. These data provide a preliminary understanding of atmospheric Delta14CO2 and CO2ff inputs for a range of Chinese background sites. PMID- 27778507 TI - Cobalt-Catalyzed Biaryl Couplings via C-F Bond Activation in the Absence of Phosphine or NHC Ligands. AB - A highly general and selective Co-catalyzed biaryl coupling through C-F cleavage under phosphine or NHC-free conditions was described. A broad range of aryl fluorides including unactivated fluorides as well as those with sensitive functionalities could couple with various Ti(OEt)4-mediated aryl Grignard reagents with high selectivity under the catalysis of CoCl2/DMPU. Importantly, selective C-F bond activation couplings between two types of fluorines (difluorinated aromatics and on two different coupling partners) and in the presence of C-Cl or C-Br bonds could also be achieved. PMID- 27778505 TI - Biomimetic Design of Mussel-Derived Bioactive Peptides for Dual-Functionalization of Titanium-Based Biomaterials. AB - Specific cell adhesion and osteogenicity are both crucial factors for the long term success of titanium implants. In this work, two mussel-derived bioactive peptides were designed to one-step dual-biofunctionalization of titanium implants via robust catechol/TiO2 coordinative interactions. The highly biomimetic peptides capped with integrin-targeted sequence or osteogenic growth sequence could efficiently improve the biocompatibilities of titanium implants and endow the implants with abilities to induce specific cell adhesion and enhanced osteogenicity. More importantly, rationally combined use of the two biomimetic peptides indicated an enhanced synergism on osteogenicity, osseointegration and finally the mechanical stability of Ti implants in vivo. Therefore, the highly biomimetic mussel-derived peptides and the dual-functional strategy in this study would provide a facile, safe, and effective means for improving clinical outcome of titanium-based medical implants. PMID- 27778508 TI - Laser Flash Photolysis of Au-PNIPAM Core-Shell Nanoparticles: Dynamics of the Shell Response. AB - Hydrophobic forces play a key role in the processes of collapse and reswelling of thermoresponsive polymers. However, little is known about the dynamics of these processes. Here, thermoresponsive poly(N-isopropylacrylamide)-encapsulated gold nanoparticles (Au-PNIPAM) are heated via nanosecond laser flash photolysis. Photothermal heating via excitation of the localized surface plasmon resonance of the Au nanoparticle cores results in rapid PNIPAM shell collapse within the 10 ns pulse width of the laser. Remarkably, reswelling of the polymer shell takes place in less than 100 ns. A clear pump fluence threshold for the collapse of the PNIPAM shell is demonstrated, below which collapse is not observed. Reswelling takes longer at higher laser intensities. PMID- 27778509 TI - Ultrafast Heating for Intrinsic Properties of Atomically Thin Two-Dimensional Materials on Plastic Substrates. AB - Despite recent progress in producing flexible and stretchable electronics based on two-dimensional (2D) nanosheets, their intrinsic properties are often degraded by the presence of polymeric residues that remain attached to the 2D nanosheet surfaces following fabrication. Further breakthroughs are therefore keenly awaited to obtain clean surfaces compatible with flexible applications. Here, we report a method that allows the 2D nanosheets to be intrinsically integrated onto flexible substrates. The method involves thermal decomposition of polymeric residues by microwave-induced ultrafast heating of the surface without affecting the underlying flexible substrate. Mapping the C?O stretching mode by Fourier transform infrared spectroscopy in combination with atomic force microscopy confirms elimination of the polymeric residues from the 2D nanosheet surface. Flexible devices prepared using microwave-cleaned 2D nanosheets show enhanced electrical, optical, and electrothermal performances. This simple technique is applicable to a wide range of 2D nanomaterials and represents an important advance in the field of flexible devices. PMID- 27778510 TI - Correlation of Emulsion Structure with Cellular Uptake Behavior of Encapsulated Bioactive Nutrients: Influence of Droplet Size and Interfacial Structure. AB - In this study, an in vitro Caco-2 cell culture assay was employed to evaluate the correlation between emulsion structure and cellular uptake of encapsulated beta carotene. After 4 h of incubation, an emulsion stabilized with whey protein isolate showed the highest intracellular accumulation of beta-carotene (1.06 MUg), followed by that stabilized with sodium caseinate (0.60 MUg) and Tween 80 (0.20 MUg), which are 13-, 7.5-, and 2.5-fold higher than that of free beta carotene (0.08 MUg), respectively. Emulsions with small droplet size (239 +/- 5 nm) showed a higher cellular uptake of beta-carotene (1.56 MUg) than emulsiond with large droplet size (489 +/- 9 nm) (0.93 MUg) (p < 0.01). The results suggested that delivery in an emulsion significantly improved the cellular uptake of beta-carotene and thus potentially its bioavailability; uptake was closely correlated with the interfacial composition and droplet size of emulsions. The findings support the potential for achieving optimal controlled and targeted delivery of bioactive nutrients by structuring emulsions. PMID- 27778511 TI - Reversible G Protein betagamma9 Distribution-Based Assay Reveals Molecular Underpinnings in Subcellular, Single-Cell, and Multicellular GPCR and G Protein Activity. AB - Current assays to measure the activation of G protein coupled receptors (GPCRs) and G proteins are time-consuming, indirect, and expensive. Therefore, an efficient method which directly measures the ability of a ligand to govern GPCR-G protein interactions can help to understand the molecular underpinnings of the associated signaling. A live cell imaging-based approach is presented here to directly measure ligand-induced GPCR and G protein activity in real time. The number of active GPCRs governs G protein heterotrimer (alphabetagamma) dissociation, thereby controlling the concentration of free betagamma subunits. The described gamma9 assay measures the GPCR activation-induced extent of the reversible betagamma9 subunit exchange between the plasma membrane (PM) and internal membranes (IMs). Confocal microscopy-based gamma9 assay quantitatively determines the concentration dependency of ligands on GPCR activation. Demonstrating the high-throughput screening (HTS) adaptability, the gamma9 assay performed using an imaging plate reader measures the ligand-induced GPCR activation. This suggests that the gamma9 assay can be employed to screen libraries of compounds for their ability to activate GPCRs. Together with subcellular optogenetics, the spatiotemporal sensitivity of the gamma9 assay permits experimental determination of the limits of spatially restricted activation of GPCRs and G proteins in subcellular regions of single cells. This assay works effectively for GPCRs coupled to alphai/o and alphas heterotrimers, including light-sensitive GPCRs. In addition, computational modeling of experimental data from the assay is used to decipher intricate molecular details of the GPCR-G protein activation process. Overall, the gamma9 assay provides a robust strategy for quantitative as well as qualitative determination of GPCR and G protein function on a single-cell, multicell, and subcellular level. This assay not only provides information about the inner workings of the signaling pathway, but it also strengthens GPCR deorphanization as well as drug discovery efforts. PMID- 27778512 TI - Multifunctional Gold Nanoclusters-Based Nanosurface Energy Transfer Probe for Real-Time Monitoring of Cell Apoptosis and Self-Evaluating of Pro-Apoptotic Theranostics. AB - Bioimaging probes for accurately monitoring apoptosis process have extensive significance for cell biological studies and clinical investigations. Herein, novel multifunctional peptide-tailored gold nanoclusters (AuNCs) have been developed for real-time imaging of caspase-indicated cell apoptosis. The AuNCs nanoprobe was facilely prepared by a one-step peptide-mediated biomineralization with the dye (TRAMA)-tagged peptides specific to caspase 3 as both template agents and the signal switch. Unlike conventional FRET-based fluorescent probes of caspase activity, these nanoprobes relied on the unique quenching effect of AuNCs through the nanosurface energy transfer (NSET) from dye to AuNCs. Intracellular caspase 3 activation cleaved the substrate peptide and released the dye from AuNCs, leading to a significant fluorescence lighting-up for sensitive and continuous analysis of caspase 3 activity in live cells, with a high signal background ratio, wide linear range (32 pM-10 nM), and ultralow detection limit (12 pM). Moreover, this versatile AuNCs nanoprobe can serve as a theranostic platform via codisplaying pro-apoptotic and detecting peptides, which allows in situ activation and real-time monitoring of apoptosis in cancer cells. These results indicate that the AuNCs nanoprobe provides a smart molecular imaging and therapeutic agent targeted to cell apoptosis, which has great potential for apoptosis-related diagnosis and precision chemotherapy. PMID- 27778513 TI - Trying to Make Regulation Something More Than Just a Burden: A Review of Excellence Beyond Compliance: Enhancing Animal Welfare Through the Constructive Use of the Animal Welfare Act, edited by James F. Gesualdi. PMID- 27778514 TI - Advanced heart failure: an appraisal of the potential of levosimendan in this end stage scenario and some related ethical considerations. AB - INTRODUCTION: The later stages of heart failure are characterized by a steady decline in quality of life. Clinical priorities should be to maintain functional capacity and quality of life. In the absence of sufficient organs for transplantation, options include left ventricular assist devices and inotropic support. Areas covered: We examined data published in the last two decades on the use of inotropes and inodilators in advanced heart failure. Expert commentary: In the literature, use of conventional inotropes, including adrenergic agonists and phosphodiesterase inhibitors, appears to be suboptimal for achieving the clinical priorities of late-stage heart failure. Evidence suggests instead that the calcium-sensitizing inodilator levosimendan, administered intermittently, delivers improvements in functional capacity and quality of life and does so with no adverse impact on life expectancy. At a terminal or near-terminal stage of heart failure, the therapeutic philosophy should shift towards meeting patients' existential priorities rather than traditional heart failure-centric targets. PMID- 27778515 TI - Characterization of titanium dioxide nanoparticles modified with polyacrylic acid and H2O2 for use as a novel radiosensitizer. AB - An induction of polyacrylic acid-modified titanium dioxide with hydrogen peroxide nanoparticles (PAA-TiO2/H2O2 NPs) to a tumor exerted a therapeutic enhancement of X-ray irradiation in our previous study. To understand the mechanism of the radiosensitizing effect of PAA-TiO2/H2O2 NPs, analytical observations that included DLS, FE-SEM, FT-IR, XAFS, and Raman spectrometry were performed. In addition, highly reactive oxygen species (hROS) which PAA-TiO2/H2O2 NPs produced with X-ray irradiation were quantified by using a chemiluminescence method and a EPR spin-trapping method. We found that PAA-TiO2/H2O2 NPs have almost the same characteristics as PAA-TiO2. Surprisingly, there were no significant differences in hROS generation. However, the existence of H2O2 was confirmed in PAA-TiO2/H2O2 NPs, because spontaneous hROS production was observed w/o X-ray irradiation. In addition, PAA-TiO2/H2O2 NPs had a curious characteristic whereby they absorbed H2O2 molecules and released them gradually into a liquid phase. Based on these results, the H2O2 was continuously released from PAA-TiO2/H2O2 NPs, and then released H2O2 assumed to be functioned indirectly as a radiosensitizing factor. PMID- 27778516 TI - Tyrosinase inhibitory components from Aloe vera and their antiviral activity. AB - A new compound, 9-dihydroxyl-2'-O-(Z)-cinnamoyl-7-methoxy-aloesin (1), and eight known compounds (2-9) were isolated from Aloe vera. Their structures were elucidated using 1D/2D nuclear magnetic resonance and mass spectra. Compound 9 exhibited reversible competitive inhibitory activity against the enzyme tyrosinase, with an IC50 value of 9.8 +/- 0.9 uM. A molecular simulation revealed that compound 9 interacts via hydrogen bonding with residues His244, Thr261, and Val283 of tyrosinase. Additionally, compounds 3 and 7 were shown by half-leaf assays to exhibit inhibitory activity towards Pepper mild mottle virus. PMID- 27778517 TI - Fertility-related knowledge and information-seeking behaviour among people of reproductive age: a qualitative study. AB - Some potentially modifiable factors adversely affect fertility and pregnancy health. To inform a fertility health promotion programme, this study investigated fertility knowledge and information-seeking behaviour among people of reproductive age. This was a qualitative study involving six focus group discussions with women and men who intended to have children in the future and eight paired interviews with couples who were actively trying to conceive. Participants (n = 74) themselves generally claimed 'low' to 'average' levels of knowledge about fertility. Most of them overestimated women's reproductive lifespan and had limited knowledge about the 'fertile window' of the menstrual cycle. The Internet was a common source of fertility-related information and social media was viewed as a potential effective avenue for dissemination of messages about fertility and how to protect it. Most participants agreed that primary health care providers, such as general practitioners (GPs), are well placed to provide information regarding fertility and pregnancy health. This study identified several gaps in knowledge among people of reproductive age about factors that influence fertility and pregnancy health negatively. Addressing these knowledge gaps in school curricula, primary care and health promotion would assist people to realize their reproductive goals and reduce the risk of infertility and adverse obstetric outcomes. PMID- 27778518 TI - Macrophage activation syndrome associated with tocilizumab treatment in adult onset Still's disease. PMID- 27778519 TI - Beyond academic performance: Practice implications for working with students following traumatic brain injury. AB - PURPOSE: Speech-language pathologists (SLPs) have a key role in supporting educational participation for secondary and tertiary students with traumatic brain injury (TBI). This article aims to (i) explore issues identified by students with TBI that affect educational participation beyond their academic performance, (ii) offer a framework based on research evidence to guide the practice of SLPs and (iii) explore strategies that may expand the traditional roles of SLPs to support students beyond academic performance. METHOD: Data were drawn from an earlier qualitative research project in which three adolescent males were interviewed about their experiences of returning to education after severe TBI. Interviews were recorded, transcribed verbatim and analysed using a grounded theory approach. RESULT: Six themes were identified that had a substantial impact beyond academic performance: poor community awareness of TBI, the invisible nature of TBI, getting back to everyday life, planning to return to education, being accepted and adjusting to long-term changes. Incorporating these factors, a clinical framework is put forward to guide SLPs in developing strategies for promoting positive educational participation. CONCLUSION: By considering factors beyond academic performance and addressing these in intervention, SLPs may significantly improve the overall educational success and wellbeing of students living with TBI. PMID- 27778520 TI - Bone marrow biopsies for staging of diffuse large B-cell lymphoma: are we looking too closely? PMID- 27778521 TI - Gender differences in perception of psychosocial distress and coping mechanisms among infertile men and women in Saudi Arabia. AB - The objective of the study was to evaluate the differences in psychosocial distress and coping mechanisms among infertile men and women in Saudi Arabia (SA). We performed a cross-sectional study of infertile patients (206 women and 200 men) attending infertility clinics in three referral hospitals in Riyadh, SA. A semi-structured questionnaire was developed to assess socio-demographic, clinical and psychosocial variables. Infertility-related psychosocial pressures were reported in 79 (39.7%) male and 97 (47.3%) female participants (p = 0.123). Males suffered more from intrusive questions and pressure to conceive, remarry or get divorced, while females were stressed more from psychological and emotional exhaustion, marital discord, attitudes of mothers-in-law or society, and persistent desire by the husband to have children. To cope with infertility, females engaged more in religious activities (p < 0.001) and spoke more to someone regarding their problems (p < 0.001). To solve their infertility problems, 50% tried to find solutions via the internet, and 38.5% of males and 51% of females reported using alternative medicines (p = 0.012). The patients with infertility in SA face multiple psychosocial stressors related to their infertility, and cope differently based on the gender and culture-specific knowledge of infertility. The female participants were significantly more affected from psychosocial stressors and the persistent desire by their spouse to have children. PMID- 27778522 TI - Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity. AB - A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC50 0.037, 0.044 and 0.042 MUM, respectively, while IC50 of thiourea is 20.9 MUM. PMID- 27778523 TI - The multifunctionality of berries toward blood platelets and the role of berry phenolics in cardiovascular disorders. AB - Diet and nutrition have an important influence on the prophylaxis and progression of cardiovascular disease; one example is the inhibition of blood platelet functions by specific components of fruits and vegetables. Garlic, onion, ginger, dark chocolate and polyunsaturated fatty acids all reduce blood platelet aggregation. A number of fruits contain a range of cardioprotective antioxidants and vitamins, together with a large number of non-nutrient phytochemicals such as phenolic compounds, which may possess both antioxidant properties and anti platelet activity. Fresh berries and berry extracts possess high concentrations of phenolic compounds, i.e. phenolic acid, stilbenoids, flavonoids and lignans. The aim of this review article is to provide an overview of current knowledge of the anti-platelet activity of berries, which form an integral part of the human diet. It describes the effects of phenolic compounds present in a number of berries, i.e. black chokeberries - aronia berries (Aronia melanocarpa), blueberries (Vaccinium myrtillus), cranberries (Vaccinium sect. Oxycoccus), sea buckthorn berries (Hippophae rhamnoides) and grapes (Vitis), as well as various commercial products from berries (i.e. juices), on platelets and underlying mechanisms. Studies show that the effects of berries on platelet activity are dependent on not only the concentrations of the phenolic compounds in the berries or the class of phenolic compounds, but also the types of berry and the form (fresh berry, juice or medicinal product). Different results indicate that berries may play a role in the prevention of cardiovascular disorders, but the development of well-controlled clinical studies with berries is encouraged. PMID- 27778524 TI - The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation. AB - A dynamic, properly organised actin cytoskeleton is critical for the production and haemostatic function of platelets. The Wiskott Aldrich Syndrome protein (WASp) and Actin-Related Proteins 2 & 3 Complex (Arp2/3 complex) are critical mediators of actin polymerisation and organisation in many cell types. In platelets and megakaryocytes, these proteins have been shown to be important for proper platelet production and function. The cortactin family of proteins (Cttn & HS1) are known to regulate WASp-Arp2/3-mediated actin polymerisation in other cell types and so here we address the role of these proteins in platelets using knockout mouse models. We generated mice lacking Cttn and HS1 in the megakaryocyte/platelet lineage. These mice had normal platelet production, with platelet number, size and surface receptor profile comparable to controls. Platelet function was also unaffected by loss of Cttn/HS1 with no differences observed in a range of platelet function assays including aggregation, secretion, spreading, clot retraction or tyrosine phosphorylation. No effect on tail bleeding time or in thrombosis models was observed. In addition, platelet actin nodules, and megakaryocyte podosomes, actin-based structures known to be dependent on WASp and the Arp2/3 complex, formed normally. We conclude that despite the importance of WASp and the Arp2/3 complex in regulating F-actin dynamics in many cells types, the role of cortactin in their regulation appears to be fulfilled by other proteins in platelets. PMID- 27778525 TI - In-stent thrombosis when switching ticagrelor to clopidogrel after percutaneous coronary intervention. AB - Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker has been proven to reduce subsequent cardiovascular events and in-stent thrombosis in patients undergoing percutaneous coronary intervention. Newer P2Y12 antagonists with faster onset and greater inhibition of platelet activity have improved cardiovascular outcomes but have created uncertainty with the appropriate dosing when switching between agents. Currently, there are no evidence-based guidelines to aid clinicians when switching between P2Y12 receptor blockers. Here we describe two patients that developed in-stent thrombosis when switching from ticagrelor to clopidogrel using a 300 mg clopidogrel loading dose. Both patients presented with ST elevation myocardial infarction and underwent stent placement but then developed in-stent thrombosis 48 hours after switching from ticagrelor to clopidogrel. These cases illustrate the severe consequences of suboptimal platelet inhibition and the need for prospective trials thoroughly powered to assess clinical outcomes in order to determine the most appropriate strategy when switching from ticagrelor to clopidogrel. PMID- 27778526 TI - The RENEB operational basis: complement of established biodosimetric assays. AB - PURPOSE: To set up an operational basis of the Realizing the European Network of Biodosimetry (RENEB) network within which the application of seven established biodosimetric tools (the dicentric assay, the FISH assay, the micronucleus assay, the PCC assay, the gamma-H2AX assay, electron paramagnetic resonance and optically stimulated luminescence) will be compared and standardized among the participating laboratories. METHODOLOGY: Two intercomparisons were organized where blood samples and smartphone components were irradiated, coded and sent out to participating laboratories for dosimetric analysis. Moreover, an accident exercise was organized during which each RENEB partner had the chance to practice the procedure of activating the network and to handle large amounts of dosimetric results. RESULTS: All activities were carried out as planned. Overall, the precision of dose estimates improved between intercomparisons 1 and 2, clearly showing the value of running such regular activities. CONCLUSIONS: The RENEB network is fully operational and ready to act in case of a major radiation emergency. Moreover, the high capacity for analyzing radiation-induced damage in cells and personal electronic devices makes the network suitable for large-scale analyses of low doses effects, where high numbers of samples must be scored in order to detect weak effects. PMID- 27778527 TI - A qualitative interview study into experiences of management of labor pain among women in midwife-led care in the Netherlands. AB - INTRODUCTION: Many pregnant women are concerned about the pain they will experience in labor and how to deal with this. This study's objective was to explore women's postpartum perception and view of how they dealt with labor pain. METHODS: Semistructured postpartum interviews were analyzed using the constant comparison method. Using purposive sampling, we selected 17 women from five midwifery practices across the Netherlands, from August 2009 to September 2010. RESULTS: Women reported that control over decision making during labor (about dealing with pain) helped them to deal with labor pain, as did continuous midwife support at home and in hospital, and effective childbirth preparation. Some of these women implicitly or explicitly indicated that midwives should know which method of pain management they need during labor and arrange this in good time. DISCUSSION: It may be difficult for midwives to discriminate between women who need continuous support through labor without pain medication and those who genuinely desire pain medication at a certain point in labor, and who will be dissatisfied postpartum if this need is unrecognized and unfulfilled. PMID- 27778528 TI - Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 6. Dental arch relationships in 5 year-olds. AB - BACKGROUND AND AIM: Good dentofacial growth is a major goal in the treatment of unilateral cleft lip and palate (UCLP). The aim was to evaluate dental arch relationships at age 5 years after four different protocols of primary surgery for UCLP. DESIGN: Three parallel randomised clinical trials were undertaken as an international multi-centre study by 10 cleft teams in five countries: Denmark, Finland, Sweden, Norway, and the UK. METHODS: Three different surgical procedures for primary palatal repair (Arms B, C, D) were tested against a common procedure (Arm A) in the total cohort of 448 children born with non-syndromic UCLP. Study models of 418 patients (273 boys) at the mean age of 5.1 years (range = 4.8-7.0) were available. Dental arch relationships were assessed using the 5-year index by a blinded panel of 16 orthodontists. Kappa statistics were calculated to assess reliability. The trials were tested statistically with t- and Chi-square tests. RESULTS: Good-to-very good levels of intra- and interrater reliability were obtained (0.71-0.94 and 0.70-0.87). Comparisons within each trial showed no statistically significant differences in the mean 5-year index scores or their distributions between the common method and the local team protocol. The mean index scores varied from 2.52 (Trial 2, Arm C) to 2.94 (Trial 3, Arm D). CONCLUSION: The results of the three trials do not provide statistical evidence that one technique is better than the others. Further analysis of the possible influence of individual surgical skill and learning curve are being pursued in this dataset. TRIAL REGISTRATION: ISRCTN29932826. PMID- 27778530 TI - GPVI modulation during platelet activation and storage: its expression levels and ectodomain shedding compared to markers of platelet storage lesion. AB - Platelet storage is associated with deleterious changes leading to the loss of platelet reactivity and response. During storage, platelets experience increased expression and shedding of P-selectin and CD40L as specific markers of platelet activation, whereas GPIbalpha decreases due to ectodomain shedding. As an important adhesive receptor, GPVI contributes significantly to thrombus formation while its expression and shedding levels during storage of platelet products have not been well characterized yet. This study investigated the modulation of GPVI during platelet storage. For this study, samples obtained from 10 PRP-platelet concentrates (PCs) were subjected to flow-cytometry analysis to examine the expression of platelet activation markers and GPVI on days 1, 3, and 5 post storage. To examine the levels of etcodomain shedding of these molecules, microparticle (MP)-free supernatants were also analyzed by either ELISA or Western blot methods. According to results, the expression levels of P-selectin and CD40L as well as the amounts of their soluble forms significantly increased during storage. The expression of GPIbalpha and GPVI decreased whereas their shedding significantly increased post-storage. The expression and shedding levels of these two receptors were significantly correlated. Negative correlations between the expressions of GPIbalpha or GPVI and P-selectin have been observed whereas their shedding levels were significantly relevant together. In a control study, the use of biotinylated platelet resuspended in Tyrode's buffer in the presence of ionophore with/without EDTA, confirmed the role of calcium in receptors shedding. In citrated PRP-PCs, recalcification of platelets also enhanced shedding levels of both GPIbalpha and GPVI. Intriguingly, the shedding levels of GPVI in stored PRP-PCs were much higher than those of ionophore-treated controls obtained from washed platelets. The ratios of sGPVI in stored platelet to ionophore-treated controls were also at least six times higher than those of GPIbalpha during storage. In conclusion, here we showed significant decreases of GPVI expression associated with its increasing levels of shedding during storage, suggesting GPVI as a valid marker of platelet storage lesion. Importantly, we found higher levels of GPVI shedding in stored platelets than those of ionophore treated non-stored control samples. This suggests whereas platelet receptor shedding is mainly modulated by calcium-dependent signals, either platelet surface interactions with the container walls during storage or induced shear stress under long-term agitation, might be also involved in the excessive shedding of GPVI during the storage of PCs. PMID- 27778529 TI - Residential radon and COPD. An ecological study in Galicia, Spain. AB - PURPOSE: Radon is a human lung carcinogen but it might be linked with other respiratory diseases. We aimed to assess the relationship between residential radon exposure and COPD (chronic obstructive pulmonary disease) prevalence and hospital admissions at a municipal level. MATERIALS AND METHODS: We designed an ecological study where we included those municipalities with at least three radon measurements. Using mixed Poisson regression models, we calculated the relative risk (RR) for COPD for each 100 Bq/m3 of increase in radon concentration and also the relative risk for COPD using a cut-off point of 50 Bq/m3. We did not have individual data on cigarette smoking and therefore we used a proxy (bladder cancer standardized mortality rate) that has proved to account for tobacco consumption. We performed separate analyses for sex and also sensitivity analysis considering age and rurality. RESULTS: A total of 3040 radon measurements and 49,393 COPD cases were included. The relative risk for COPD prevalence was 0.95 (95% CI: 0.92-0.97) while for hospital admissions the RR was 1.04 (95% CI: 1.00 1.10) for each 100 Bq/m3. Relative risks were higher for women compared to men. Using a categorical analysis with a cut-off point of 50 Bq/m3, the RR for COPD prevalence was 1.06 (95% CI: 1.02-1.10) and for hospital admissions it was 1.08 (95% CI: 1.00-1.17) for women living in municipalities with more than 50 Bq/m3. All risks were also higher for women. No relevant differences were observed for age, rurality or other categories for radon exposure. CONCLUSION: While the influence of radon on COPD prevalence is unclear depending on the approach used, it seems that residential radon might increase the risk of hospital admissions in COPD patients. Women have a higher risk than men in all situations. Since this is an ecological study, results should be interpreted cautiously. PMID- 27778531 TI - Basic mechanisms of platelet receptor shedding. AB - Proteolytic shedding of the extracellular ectodomain of platelet receptors provides a key mechanism for irreversible loss of ligand-binding capacity, and for regulating platelet function in health and disease. Platelets derived from megakaryocytes are small anucleate cells in peripheral blood, with the ability to rapidly adhere, become activated, and secrete an array of procoagulant and proinflammatory factors at sites of vascular injury or disease, and to form a platelet aggregate (thrombus) which is not only critical in normal hemostasis and wound healing, but in atherothrombotic diseases including myocardial infarction and ischemic stroke. Basic mechanisms of receptor shedding on platelets have important distinctions from how receptors on other cell types might be shed, in that shedding is rapidly initiated (within seconds to minutes) and occurs under altered shear conditions encountered in flowing blood or experimentally ex vivo. This review will consider the key components of platelet receptor shedding, that is, the receptor with relevant cleavage site, the (metallo)proteinase or sheddase and how its activity is regulated, and the range of known regulatory factors that control platelet receptor shedding including receptor-associated molecules such as calmodulin, factors controlling sheddase surface expression and activity, and other elements such as shear stress, plasma membrane properties, cellular activation status or age. Understanding these basic mechanisms of platelet receptor shedding is significant in terms of utilizing receptor surface expression or soluble proteolytic fragments as platelet-specific biomarkers and/or ultimately therapeutic targeting of these mechanisms to control platelet reactivity and function. PMID- 27778532 TI - 90th anniversary Collegiun Otorhinolaryngologicum Amicitiae Sacrum, Bordeaux, 28 31 August 2016: Opening session, Hommage to the Portmann family. PMID- 27778533 TI - Quality of life, clinical outcome, personality and coping in chronic hemodialysis patients. AB - RATIONAL: Our aim was to investigate the quality of life (QoL) in 103 patients undergoing chronic hemodialysis (HD) in an integrated assessment of clinical, personological, and adaptation parameters, also in a non-urban context. OBJECTIVES: We collected data from all chronic HD patients attending four HD units. Clinical status was assessed by Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and by Age-adjusted Charlson Comorbidity Index (ACCI). Patients completed the following questionnaires: Kidney Disease Quality of Life Short Form (KDQOL-SF), Pittsburgh Sleep Quality Index (PSQI). Personality profile and coping style were assessed by Temperament and Character Inventory (TCI) revised and Coping Inventory for Stressful Situation (CISS). Data were analyzed by conventional descriptive statistics. Multiple forward stepwise linear regression analyses were performed. MAIN FINDINGS: Variables significantly associated with physical and mental components of KDQOL-SF were: intact parathyroid hormone (iPTH) (p = .004; p = .0015), typology of cohabitant (family member or not) (p = .022; p = .007), years of dialysis (p = .022; p = .048). Variables associated with mental component of KDQOL-SF were: PSQI (p = .000), task-coping (p = .000), avoidance-coping (p = .003), work status (p = .021). Principle conclusions: Our results suggest the importance of an integrated and multidirectional management of patients chronically undergoing HD and living in a non-urban context. PMID- 27778639 TI - Hyperinsulinemia and Insulin Resistance in Dopamine beta-Hydroxylase Deficiency. AB - Context: Dopamine beta-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. Case Description: We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 MUU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. Conclusions: We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism. PMID- 27778640 TI - Normal Pubertal Development in Daughters of Women With PCOS: A Controlled Study. AB - Context: Daughters of women with polycystic ovary syndrome (PCOS) are thought to be at increased risk for developing stigmata of the syndrome, but the ontogeny during puberty is uncertain. Objective: We phenotyped daughters (n = 76) of mothers with PCOS and daughters (n = 80) from control mothers for reproductive and metabolic parameters characteristic of PCOS. Design, Setting, and Participants: We performed a matched case/control study at Penn State Hershey Medical Center that included non-Hispanic, white girls 4 to 17 years old. Intervention: We obtained birth history, biometric, ovarian ultrasounds, whole body dual-energy X-ray absorptiometry scan for body composition, 2-hour glucose challenged salivary insulin levels, and two timed urinary collections (12 hours overnight and 3 hours in the morning) for gonadotropins and sex steroids. Main Outcome Measures: We measured integrated urinary levels of adrenal (dehydroepiandrosterone sulfate) and ovarian [testosterone (TT)] steroids. Other endpoints included integrated salivary insulin levels and urinary luteinizing hormone levels. Results: There were no differences in detection rates or mean levels for gonadotropins and sex steroids in timed urinary collections between PCOS daughters and control daughters, nor were there differences in integrated salivary insulin levels. Results showed that 69% of Tanner 4/5 PCOS daughters vs 31% of control daughters had hirsutism defined as a Ferriman-Gallwey score >8 (P = 0.04). There were no differences in body composition as determined by dual energy X-ray absorptiometry between groups in the three major body contents (i.e., bone, lean body mass, and fat) or in ovarian volume between groups. Conclusions: Matched for pubertal stage, PCOS daughters have similar levels of urinary androgens and gonadotropins as well as glucose-challenged salivary insulin levels. PMID- 27778641 TI - Progesterone Resistance in Endometriosis Is Modulated by the Altered Expression of MicroRNA-29c and FKBP4. AB - Context: Endometriosis results in aberrant gene expression in the eutopic endometrium (EuE) and subsequent progesterone resistance. MicroRNA (miR) microarray data in a baboon model of endometriosis showed an increased expression of miR-29c. Objectives: To explore the role of miR-29c in progesterone resistance in a subset of women with endometriosis. Design: MiR-29c expression was analyzed in the endometrium of baboons and women with or without endometriosis. The role in progesterone resistance and decidualization was analyzed by transfecting human uterine fibroblast cells with miR-29c. Patients: Subjects diagnosed with deep infiltrative endometriosis (DIE) by transvaginal ultrasound with bowel preparation underwent surgical excision of endometriosis. Eutopic secretory endometrium was collected pre- and postoperatively. Women with normal EuE and without DIE served as controls. Results: Quantitative reverse transcription polymerase chain reaction demonstrated that miR-29c expression increased, while the transcript levels of its target, FK506-binding protein 4 (FKBP4), decreased in the EuE of baboons following the induction of endometriosis. FKBP4 messenger RNA and decidual markers were statistically significantly decreased in decidualized human uterine fibroblast cells transfected with a miR-29c mimic compared with controls. Human data corroborated our baboon data and demonstrated higher expression of miR-29c in endometriosis EuE compared with normal EuE. MiR 29c was significantly decreased in endometriosis EuE postoperatively compared with preoperative tissues, and FKBP4 showed an inverse trend following radical laparoscopic resection surgery. Conclusions: We demonstrate that miR-29c expression is increased in EuE of baboons and women with endometriosis, which might contribute to a compromised progesterone response by diminishing the levels of FKBP4. Resection of DIE is likely to reverse the progesterone resistance associated with endometriosis in women. PMID- 27778642 TI - Effects of Conjugated Linoleic Acid and Metformin on Insulin Sensitivity in Obese Children: Randomized Clinical Trial. AB - Context: Insulin resistance precedes metabolic syndrome abnormalities and may promote cardiovascular disease and type 2 diabetes in children with obesity. Results of lifestyle modification programs have been discouraging, and the use of adjuvant strategies has been necessary. Objective: This study aimed to evaluate the effects of metformin and conjugated linoleic acid (CLA) on insulin sensitivity, measured via euglycemic-hyperinsulinemic clamp technique and insulin pathway expression molecules in muscle biopsies of children with obesity. Design: A randomized, double-blinded, placebo-controlled clinical trial was conducted. Setting: Children with obesity were randomly assigned to receive metformin, CLA, or placebo. Results: Intervention had a positive effect in all groups. For insulin sensitivity Rd value (mg/kg/min), there was a statistically significant difference between the CLA vs placebo (6.53 +/- 2.54 vs 5.05 +/- 1.46, P = 0.035). Insulinemia and homeostatic model assessment of insulin resistance significantly improved in the CLA group (P = 0.045). After analysis of covariance was performed and the influence of body mass index, age, Tanner stage, prescribed diet, and fitness achievement was controlled, a clinically relevant effect size on insulin sensitivity remained evident in the CLA group (37%) and exceeded lifestyle program benefits. Moreover, upregulated expression of the insulin receptor substrate 2 was evident in muscle biopsies of the CLA group. Conclusions: Improvement of insulin sensitivity, measured via euglycemic hyperinsulinemic clamp and IRS2 upregulation, favored patients treated with CLA. PMID- 27778752 TI - Evaluation of quantitative glare technique based on the analysis of bio-signals. AB - This laboratory study evaluated the effect of glare source (halogen, HID and LED) and its illumination levels (0.7, 2 and 5 lx) using a quantitative methodology. Pupil diameter and electroencephalography were measured using FaceLab and Biopac systems, respectively. The discomfort glare was assessed subjectively with Borg's CR-10 scale. Twenty healthy subjects participated. Pupil size was significantly affected by the headlamp type and illumination condition. Pupil size was smaller when exposed to the LED headlamp than other headlamps (Halogen > HID > LED). In addition, when the illumination increased, pupil size decreased (0.7 lx > 2 lx > 5 lx). Also, driver's discomfort increased when pupil size was small, and theta waves were high. This discomfort may cause reduced attention and safety of the driver. These results can be applied to design and development of headlamps. Further investigation is necessary with adopted methodology to evaluate other headlamps in different illumination conditions. Practitioner Summary: This study evaluated pupil size and electroencephalography under different glare source (halogen, HID and LED) and illumination levels (0.7, 2 and 5 lx). Driver's discomfort increased when pupil size was small, and theta waves were high. This discomfort may cause reduced attention and safety of the driver. PMID- 27778643 TI - Effects of 12 Months of Caloric Restriction on Muscle Mitochondrial Function in Healthy Individuals. AB - Context: The effects of caloric restriction (CR) on in vivo muscle mitochondrial function in humans are controversial. Objective: We evaluated muscle mitochondrial function and associated transcriptional profiles in nonobese humans after 12 months of CR. Design: Individuals from an ancillary study of the CALERIE 2 randomized controlled trial were assessed at baseline and 12 months after a 25% CR or ad libitum (control) diet. Setting: The study was performed at Pennington Biomedical Research Center in Baton Rouge, LA. Participants: Study participants included 51 (34 female subjects, 25 to 50 years of age) healthy nonobese individuals randomized to 1 of 2 groups (CR or control). Intervention: This study included 12 months of a 25% CR or ad libitum (control) diet. Main Outcomes: In vivo mitochondrial function [maximal ATP synthesis rate (ATPmax), ATPflux/O2 (P/O)] was determined by 31P-magnetic resonance spectroscopy and optical spectroscopy, and body composition was determined by dual-energy X-ray absorptiometry. In a subset of individuals, a muscle biopsy was performed for transcriptional profiling via quantitative reverse transcription polymerase chain reaction and microarrays. Results: Weight, body mass index (BMI), fat, and fat free mass (P < 0.001 for all) significantly decreased at month 12 after CR vs control. In vivo ATPmax and P/O were unaffected by 12 months of CR. Targeted transcriptional profiling showed no effects on pathways involved in mitochondrial biogenesis, function, or oxidative stress. A subgroup analysis according to baseline P/O demonstrated that a higher (vs lower) P/O was associated with notable improvements in ATPmax and P/O after CR. Conclusions: In healthy nonobese humans, CR has no effect on muscle mitochondrial function; however, having a "more coupled" (versus "less coupled") phenotype enables CR-induced improvements in muscle mitochondrial function. PMID- 27778753 TI - Global-local processing impacts academic risk taking. AB - Research has shown that academic risk taking-the selection of school tasks with varying difficulty levels-affords important implications for educational outcomes. In two experiments, we explored the role of cognitive processes specifically, global versus local processing styles-in students' academic risk taking tendencies. Participants first read a short passage, which provided the context for their subsequent academic risk-taking decisions. Following which, participants undertook the Navon's task and attended to either global letters or local letters only, i.e., were either globally or locally primed. The effects of priming on academic risk taking were then assessed using a perception-based measure (Experiment 1) and a task-based measure (Experiment 2). Experiment 1 provided preliminary evidence, which Experiment 2 confirmed, that globally focused individuals took more academic risk than did locally focused individuals after controlling for participants' need for cognition (how much they enjoy effortful cognitive activities). Additionally, the inclusion of and comparisons with a control group in Experiment 2 revealed that locally focused participants drove the observed effects. The theory of predictive and reactive control systems (PARCS) provides a cogent account of our findings. Future directions and practical applications in education are discussed. PMID- 27778754 TI - Disjunction and conjunction fallacies in episodic memory. AB - It has recently been found that episodic memory displays analogues of the well known disjunction and conjunction fallacies of probability judgement. The aim of the present research was, for the first time, to study these memory fallacies together under the same conditions, and test theoretical predictions about the reasons for each. The focus was on predictions about the influence of semantic gist, target versus context recollection, and proactive versus retroactive interference. Disjunction and conjunction fallacies increased in conditions in which subjects were able to form semantic connections among list words. In addition, disjunction fallacies were increased by manipulations that minimised proactive interference, whereas conjunction fallacies were increased by manipulations that minimised retroactive interference. That pattern suggests that disjunction fallacies are more dependent on target recollection, whereas conjunction fallacies are more dependent on context recollection. PMID- 27778757 TI - An optimal sampling approach to modelling whole-body vibration exposure in all terrain vehicle driving. AB - Exposure to whole-body vibration (WBV) presents an occupational health risk and several safety standards obligate to measure WBV. The high cost of direct measurements in large epidemiological studies raises the question of the optimal sampling for estimating WBV exposures given by a large variation in exposure levels in real worksites. This paper presents a new approach to addressing this problem. A daily exposure to WBV was recorded for 9-24 days among 48 all-terrain vehicle drivers. Four data-sets based on root mean squared recordings were obtained from the measurement. The data were modelled using semi-variogram with spectrum analysis and the optimal sampling scheme was derived. The optimum sampling period was 140 min apart. The result was verified and validated in terms of its accuracy and statistical power. Recordings of two to three hours are probably needed to get a sufficiently unbiased daily WBV exposure estimate in real worksites. The developed model is general enough that is applicable to other cumulative exposures or biosignals. Practitioner Summary: Exposure to whole-body vibration (WBV) presents an occupational health risk and safety standards obligate to measure WBV. However, direct measurements can be expensive. This paper presents a new approach to addressing this problem. The developed model is general enough that is applicable to other cumulative exposures or biosignals. PMID- 27778758 TI - The time course from gender categorization to gender-stereotype activation. AB - Social categorization is the foundation of stereotype activation, and the process from social categorization to stereotype activation is rapid. However, the time from social categorization to stereotype activation is unknown. This study involves a real-time measurement of the time course of gender-stereotype activation beginning with gender categorization using event-related potential technology with a face as the priming stimulus. We found that 195 ms after a face stimulus was presented, brain waves stimulated by male or female gender categorization showed a clear separation, with male faces stimulating larger N200 waves. In addition, 475 ms after a face stimulus appeared or 280 ms after the gendercategorization process occurred, gender-stereotype-consistent and gender stereotype-inconsistent stimuli were distinct, with gender-stereotype inconsistent stimuli inducing larger N400 waves. These results indicate that during gender-stereotype activation by face perception, gender categorization occurs approximately 195 ms after seeing a face stimulus and a gender stereotype is activated at approximately 475 ms. PMID- 27778759 TI - The continuing struggle between career civil servants and political appointees in the development of government public health standards. PMID- 27778760 TI - Effect of flavonoids rich extract of Capparis spinosa on inflammatory involved genes in amyloid-beta peptide injected rat model of Alzheimer's disease. AB - OBJECTIVES: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Despite vast ongoing researches focusing on the area, little is known about novel treatments. In this study, we aimed to survey the effects of Capparis spinosa (C. spinosa) extract on amyloid-beta peptide (Abeta) injected rat. METHODS: For this purpose, hydroalcoholic extracts of caper leaf and fruit were prepared. Total phenolic content, DPPH, and FRAP assay were accomplished to determine antioxidant activity of C. spinosa. HPLC analysis was conducted to measure rutin and quercetin content of selected parts of the plant. Higher levels of flavonoids were observed in leaves of the plant. Twelve male Wistar Abeta-induced rats were randomly divided in four groups of (1) Abeta-/DW+: Sham-operated group (2) Abeta+/DW+: Abeta-injected group (3) Abeta+/RU+: Standard rutin treatment (4) Abeta+/CS+: C. spinosa extract treatment. After 6 weeks of oral administration, real-time qPCR were conducted to determine APP, BACE-1, PSEN 1, and PSEN-2 genes expression in the hippocampus of rats. RESULTS: HPLC analysis showed high levels of rutin and quercetin in leaves of Capparis. Rutin was 16939.2 +/- 0.01 and quercetin was 908.93 +/- 0.01 ug/g fresh weight. In fruit, 1019.52 +/- 0.01 rutin and 97.86 +/- 0.01 ug/g FW quercetin were measured. Expression of BACE-1, APP, PSEN-1, and PSEN-2 genes in comparison with the control group showed significant down regulation. DISCUSSION: Results of the study demonstrated that C. spinosa has the potential to down regulate inflammation-involved genes in AD, due to its high levels of flavonoids and could be beneficial as a dietary complement in AD patients. PMID- 27778761 TI - New reports from the NIOSH health hazard evaluation program. PMID- 27779078 TI - The Regulatory Roles of Mitogen-Activated Protein Kinase (MAPK) Pathways in Health and Diabetes: Lessons Learned from the Pancreatic beta-Cell. AB - BACKGROUND: Glucose-stimulated insulin secretion (GSIS) from the pancreatic beta cell involves several intracellular metabolic events which lead to the translocation of insulin granules towards the membrane for fusion and release. It is well established that loss of beta-cell function and decreased GSIS underlie the pathogenesis of diabetes. Evidence from several laboratories, including our own, demonstrated requisite roles of Rac1 and phagocyte-like NADPH oxidase (Nox2) derived reactive oxygen species (ROS) in optimal function of the pancreatic beta cell, including GSIS. However, it is becoming increasingly clear that prolonged exposure of beta-cells to hyperglycemic conditions, leads to sustained activation of Rac1-Nox2 signaling axis culminating in excessive generation of intracellular ROS (oxidative stress) and beta-cell dysregulation and demise. Such "cytotoxic" effects of ROS appear to be mediated via the stress-activated protein kinases/mitogen-activated protein kinases (SAPK/MAPK) signaling pathways. OBJECTIVE: This review discusses our current understanding of regulation and functions of the conventional MAPKs, namely, ERK1/2, JNK1/2 and p38MAPK. CONCLUSION: The MAPK pathways are activated in the presence of various stress stimuli including intracellular ROS, via distinct signaling cascades. Once activated, MAPKs participate in specific intracellular signaling processes via interaction with several downstream kinases including the MAPKactivated protein kinases (MAPKAPKs) and transcription factors including c-jun and p53. We have provided an overview of existing evidence in the islet beta-cell on the regulatory roles of these MAPKs in mediating cellular responses to alterations in intracellularly generated ROS, which is mediated by the Rac1-Nox2 signaling module. Additionally, we enlisted recent patents developed to improve beta-cell function in diabetes and novel pharmacological agents that target oxidative stress and MAPK pathways. PMID- 27779079 TI - The Role of PPARs in Pathological Cardiac Hypertrophy and Heart Failure. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the regulation of lipid metabolism, energy production, and inflammation. It is well established that all of the three isoforms of PPARs expressed in the cardiomyocytes, and that PPARs are closely involved in the regulation of lipid metabolism and energy homeostasis as well as many other different aspects in the heart. We think that PPARs are very important therapeutic targets for drug development, however, the drugs targeting at PPARs meet some trouble in clinical practice, especially the reported side effects related to heart failure. This review summarizes different functions and mechanisms of each isoform in cardiac hypertrophy and heart failure, for the reason that if more efforts are made to investigate the interactions among different isoforms, minimize the off-target effects, and avoid PPARs-independent side effects, we can develop safer and more effective PPAR agonists for the clinical practice in the near future. PMID- 27779080 TI - Efficacy of Ropinirole-Loaded PLGA Microspheres for the Reversion of Rotenone- Induced Parkinsonism. AB - A new controlled delivery system has been developed for ropinirole (RP) for the treatment of Parkinson's Disease (PD) consisting in PLGA microparticles (MPs) which exhibited in vitro constant release of RP (78.23 ug/day/10 mg MPs) for 19 days. The neuroprotective effects of RP released from MPs were evaluated in SKN AS cells after exposure to rotenone (20 uM). Cell apoptosis was significantly reduced by RP (100-120 uM). Daily doses of rotenone (2 mg/kg) given i.p. to rats induced neuronal and behavioral changes similar to those of PD. After 15 days, animals received RP in saline (1 mg/kg/day for 45 days) or as MPs at two dose levels (amount of MPs equivalent to 7.5 mg/kg or 15 mg/kg RP given on days 15 and 30). Brain immunochemistry (Nisslstaining, GFAP and TH immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that animals receiving RP either in solution or encapsulated within the MPs reverted the PD symptoms with the best results obtained in animals receiving RP microspheres at the highest dose assayed, thereby confirming the potential therapeutic interest of the new RP delivery system. PMID- 27779081 TI - Calixarene: A Versatile Material for Drug Design and Applications. AB - The therapy of various diseases by the drugs entrapped in calixarene derivatives is gaining attraction of researchers nowadays. Calixarenes are macrocyclic nano baskets which belong to cavitands class of host-guest chemistry. They are the marvelous hosts with distinct hydrophobic three dimensional cavities to entrap and encapsulate biologically active guest drugs. Calixarene and its derivatives develop inclusion complexes with various types of drugs and vitamins for their sustained/targeted release. Calixarene and its derivatives are used as carriers for anti-cancer, anti-convulsant, anti-hypertensive, anthelmentic, anti inflammatory, antimicrobial and antipsychotic drugs. They are the important biocompatible receptors to improve solubility, chemical reactivity and decrease cytotoxicity of poorly soluble drugs in supramolecular chemistry. This review focuses on the calixarene and its derivatives as the state-of-the-art in host guest interactions for important drugs. We have also critically evaluated calixarenes for the development of prodrugs. PMID- 27779082 TI - Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory Drugs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID-induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic. PMID- 27779083 TI - Severe Drug Hypersensitivity Reactions: Clinical Pattern, Diagnosis, Etiology and Therapeutic Options. AB - Severe cutaneous adverse reactions (SCAR) are known for a high morbidity and mortality. They may be life-threatening for the affected patient and difficult to accomplish for the patient's family and the treating physician. Such conditions include not only bullous reactions like toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), but also acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Since clinical pattern, etiology, prognosis and treatment differ among these severe skin reactions, a clear diagnosis based on a comprehensive clinical examination, skin biopsy, and specific laboratory tests is necessary. Because most of these reactions are caused by drug intake, a thorough history of medication use has to be obtained. However, there are cases with an infectious or idiopathic cause. In any case it is crucial to identify the most likely cause and rapidly discontinue the inducing agent, if a drug cause is suspected. This is associated with the patient's prognosis which is often poor for bullous reaction. In addition, patient's age, underlying conditions, and the extent of skin detachment play a major role in terms of prognosis. Severe cutaneous adverse reactions are T-cell-mediated reactions, and certain alleles of human leukocyte antigens (HLA) are involved in the activation of T-cells with cytotoxic effect. The therapeutic options depend on the clinical diagnosis. For all reactions a symptomatic and adequate supportive therapy is necessary, in some cases a systemic immunomodulating therapy can be useful. PMID- 27779084 TI - Mast Cell Disorders In Drug Hypersensitivity. AB - Mastocytosis is a clonal disease characterized by proliferation and accumulation of mast cells (MC) in different tissues, preferentially skin and bone marrow, leading to a wide variety of clinical manifestations, mainly caused by the inappropriate release of MC mediators. As a consequence, patients with mastocytosis may experience symptoms due to massive MC activation and release of mediators. Anaphylaxis is the most frequent manifestation of this phenomenon. Drugs are possible triggers of anaphylaxis in patients with mastocytosis, even though the association between mastocytosis and drug anaphylaxis does not appear to be as strong as anaphylaxis after hymenoptera sting; nevertheless, MC disorders might be ruled out in cases of severe systemic reactions to drugs. Moreover, the risk of perioperative anaphylaxis in adults appears high, mainly in patients with indolent systemic mastocytosis regardless of skin involvement. Such risk is probably lower in patients who have never experienced anaphylaxis and/or have tolerated previous general anaesthesia. However, data published about drug anaphylaxis in patients with MC disorders are scanty and currently it is not possible to provide clear recommendations. PMID- 27779085 TI - Development of a Novel Human scFv Against EGFR L2 Domain by Phage Display Technology. AB - Epidermal growth factor receptor (EGFR) as a transmembrane tyrosine kinase receptor frequently overexpresses in tumors with epithelial origin. The L2 domain from extracellular part of EGFR is involved in ligand binding and the blockage of this domain prevents activation of related signaling pathways. This study was aimed to develop a novel human scFv against EGFR L2 domain as a promising target for cancer therapy. The L2 recombinant protein was purified and used for panning a human scFv phage library (Tomlinson I). In this study, a novel screening strategy was applied to select clones with high binding and enrichment of rare specific phage clones of the L2 protein. After five biopanning rounds several specific clones were isolated which among them one phage clone with high binding was purified for further analysis. The specific interaction of selected clone against target antigen was confirmed by ELISA and western blotting. Immunofluorescence staining showed that purified scFv binds to A431 cells surface, displaying EGFR surface receptor. In the present study, we isolated for the first time a novel human scFv against EGFR L2 domain. This study can be the groundwork for developing more effective diagnostic and therapeutic agents against EGFR overexpressing cancers using this novel human anti-L2 ScFv. PMID- 27779086 TI - Genetic Predictors of Drug Hypersensitivity. AB - Our knowledge of genetic predisposing factors of drug hypersensitivity reactions (DHRs) is still scarce. The analysis of the genetic basis of these reactions may contribute to dissect the underlying mechanisms. We will outline current knowledge of the genetic predictors of most common DHRs, including reactions to betalactam antibiotics (BLs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biological agents. The predictors of DHRs to BLs are mostly linked to IgE-class switching, IgE pathway and atopy (IL4R, NOD2, LGALS3) in replicated candidate gene studies, and to antigen presentation (HLA-DRA) in the single replicated GWAS performed so far. The HLA-DRA variants are predictors of allergy to penicillins, but not to cephalosporins and they influence also the sensitization against prevalent allergens. The predictors of DHRs against NSAIDs are mostly linked to metabolism of eicosanoids (ALOX5, ALOX5AP, TBXAS1, PTGDR, CYSLTR1). Single nucleotide polymorphisms (SNPs) in genes involved in histamine biosynthesis and antigen presentation, HLA, could also have a role in DHRs against NSAIDs. The intriguing association of DHRs to NSAIDs with atopy should deserve further attention. Predictors of DHRs against asparaginase and other biological agents relate to antigen presentation (HLA-DRB1 and HLA-A alleles, respectively). The potential relationship of genetic predictors of DHRs with pathomechanisms also involved in environmental exposure and atopy highlights the need to perform GWAS in contrasted populations, taking into account world-wide variations of allele frequencies and contrasted situations of environmental exposure. PMID- 27779087 TI - Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies. AB - Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be lifethreatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, noncovalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies. PMID- 27779088 TI - Workplace nutrition knowledge questionnaire: psychometric validation and application. AB - Workplace dietary intervention studies in low- and middle-income countries using psychometrically sound measures are scarce. This study aimed to validate a nutrition knowledge questionnaire (NQ) and its utility in evaluating the changes in knowledge among participants of a Nutrition Education Program (NEP) conducted at the workplace. A NQ was tested for construct validity, internal consistency and discriminant validity. It was applied in a NEP conducted at six workplaces, in order to evaluate the effect of an interactive or a lecture-based education programme on nutrition knowledge. Four knowledge domains comprising twenty-three items were extracted in the final version of the NQ. Internal consistency of each domain was significant, with Kuder-Richardson formula values>0.60. These four domains presented a good fit in the confirmatory factor analysis. In the discriminant validity test, both the Expert and Lay groups scored>0.52, but the Expert group scores were significantly higher than those of the Lay group in all domains. When the NQ was applied in the NEP, the overall questionnaire scores increased significantly because of the NEP intervention, in both groups (P<0.001). However, the increase in NQ scores was significantly higher in the interactive group than in the lecture group, in the overall score (P=0.008) and in the healthy eating domain (P=0.009). The validated NQ is a short and useful tool to assess gain in nutrition knowledge among participants of NEP at the workplace. According to the NQ, an interactive nutrition education had a higher impact on nutrition knowledge than a lecture programme. PMID- 27779089 TI - Unusual Cause of Sphenoidal Sinus Mass: Extramedullary Plasmacytoma. PMID- 27779090 TI - A Novel Examination of Successful Aging Trajectories at the End of Life. AB - A successful aging (SA) index was captured in a longitudinal population-based cohort study of individuals aged 75 and older and examined longitudinally using growth mixture modelling (GMM) to identify groups with similar trajectories using decedents' (n = 1,015) last completed interview and up to four previous data collection waves before death. GMM identified a three-class model. Classes were high-functioning, no decline (HN); high-functioning, gradual decline (HG); and low-functioning, steep decline (LS). HN class individuals were significantly younger at death (p < 0.001) and at last interview (p < 0.001), consisted of more men (p < 0.001), and more likely to be married (p < 0.001) compared to HG and LS class individuals. These results demonstrate the different ways in which individuals can experience successful aging at the end of life. This study provides the framework for future research into life-course processes of aging, with important implications for policy and practice. PMID- 27779092 TI - Differential susceptibility to effects of maternal sensitivity? A study of candidate plasticity genes-CORRIGENDUM. PMID- 27779091 TI - Pupillary and affective responses to maternal feedback and the development of borderline personality disorder symptoms. AB - Etiological models propose that a biological vulnerability to emotional reactivity plays an important role in the development of borderline personality disorder (BPD). However, the physiological and phenomenological components of emotional reactivity that predict the course of BPD symptoms in adolescence are poorly understood. This prospective study examines pupillary and affective responses to maternal feedback as predictors of BPD symptom development in adolescent girls over 18 months. Fifty-seven 16-year-old girls completed a laboratory task in which they heard recorded clips of their own mothers making critical or praising statements about them, as well as neutral statements that did not pertain to them. Changes in girls' pupil dilation and subjective affect were assessed throughout the task. The results demonstrated that greater pupillary response to maternal criticism predicted increases in BPD symptoms over time. In addition, greater pupillary and positive affective responses to maternal praise were associated with higher BPD symptoms at age 16 and faster decreases in BPD symptoms over time, but only among girls who heard clips that were rated by independent observers as less praising. The results suggest that emotional reactivity can serve as either a risk or a protective factor depending on context, with differential effects of reactivity to criticism versus praise. PMID- 27779093 TI - MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. AB - Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) - a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice. PMID- 27779095 TI - Associations between diabetic retinopathy and systemic risk factors. AB - INTRODUCTION: Diabetes mellitus is a systemic disease with complications that include sight-threatening diabetic retinopathy. It is essential to understand the risk factors of diabetic retinopathy before effective prevention can be implemented. The aim of this review was to examine the association between diabetic retinopathy and systemic risk factors. METHODS: A PubMed literature search was performed up to May 2016 to identify articles reporting associations between diabetic retinopathy and systemic risk factors; only publications written in English were included. Relevant articles were selected and analysed. RESULTS: Patients with diabetic retinopathy were more likely to have poor glycaemic control as reflected by a higher glycated haemoglobin, longer duration of diabetes, and use of insulin therapy for treatment. For other systemic risk factors, hypertension was positively associated with prevalence and progression of diabetic retinopathy. No clear association between obesity, hyperlipidaemia, gender, or smoking with diabetic retinopathy has been established as studies reported inconsistent findings. Myopia was a protective factor for the development of diabetic retinopathy. Several genetic polymorphisms were also found to be associated with an increased risk of development of diabetic retinopathy. CONCLUSIONS: Good glycaemic and blood pressure control remain the most important modifiable risk factors to reduce the risk of progression of diabetic retinopathy and vision loss. PMID- 27779094 TI - Long non-coding RNA produced by RNA polymerase V determines boundaries of heterochromatin. AB - RNA-mediated transcriptional gene silencing is a conserved process where small RNAs target transposons and other sequences for repression by establishing chromatin modifications. A central element of this process are long non-coding RNAs (lncRNA), which in Arabidopsis thaliana are produced by a specialized RNA polymerase known as Pol V. Here we show that non-coding transcription by Pol V is controlled by preexisting chromatin modifications located within the transcribed regions. Most Pol V transcripts are associated with AGO4 but are not sliced by AGO4. Pol V-dependent DNA methylation is established on both strands of DNA and is tightly restricted to Pol V-transcribed regions. This indicates that chromatin modifications are established in close proximity to Pol V. Finally, Pol V transcription is preferentially enriched on edges of silenced transposable elements, where Pol V transcribes into TEs. We propose that Pol V may play an important role in the determination of heterochromatin boundaries. PMID- 27779096 TI - Sexual violence cases in a hospital setting in Hong Kong: victims' demographic, event characteristics, and management. AB - INTRODUCTION: Rainlily, the first one-stop crisis centre in Hong Kong, was set up in 2000 to protect female victims of sexual violence. This study aimed to analyse the characteristics of sexual assault cases and victims who presented to two hospitals in Hong Kong. The data are invaluable for health care professionals and policymakers to improve service provision to these victims. METHODS: This retrospective analysis of hospital records was conducted in two acute hospitals under the Hospital Authority in Hong Kong. Sexual assault victims who attended the two hospitals between May 2010 and April 2013 were included. Characteristics of the cases and the victims, the use of alcohol and drugs, involvement of violence, and the outcome of the victims were studied. RESULTS: During the study period, 154 sexual assault victims attended either one of the two hospitals. Their age ranged from 13 to 64 years. The time from assault to presentation ranged from 1 hour to more than 5 months. Approximately 50% of the assailants were strangers. Approximately 50% of victims presented with symptoms; the most common were pelvic and genitourinary symptoms. Those with symptoms (except pregnancy) presented earlier than those without. The use of alcohol and drugs was involved in 36.4% and 11.7% of cases, respectively. Approximately 10% of the screened victims were positive for Chlamydia trachomatis. There were 11 pregnancies with gestational age ranged from 6 weeks to 5 months at presentation. Less than half of the victims completed follow-up care. CONCLUSIONS: Involvement of alcohol and drugs is not uncommon in sexual assault cases. Efforts should be made to promote public education, enhance coordination between medical and social services, and improve the accessibility and availability of clinical care. Earlier management and better compliance with follow-up can minimise the health consequences and impact on victims. PMID- 27779097 TI - Factors affecting the deceased organ donation rate in the Chinese community: an audit of hospital medical records in Hong Kong. AB - INTRODUCTION: The number of actual donors per million population is the most commonly used metric to measure organ donation rates worldwide. It is deemed inadequate, however, because it does not take into account the potential donor pool. The aim of this study was to determine the true potential for solid organ donation from deceased brain-dead donors and the reasons for non-donation from potential donors in the Chinese community. METHODS: Medical records of all hospital deaths between 1 January and 31 December 2014 at a large regional hospital in Hong Kong were reviewed. Those who were on mechanical ventilation with documented brain injury and aged <=75 years were classified as possible organ donors. The reasons why some potential organ donors did not become utilised organ donors were recorded and evaluated. RESULTS: Among 3659 patient deaths, 121 were classified as possible organ donors. The mean age of the possible organ donors was 59.4 years and 72.7% of them were male. The majority (88%) were from non-intensive care units. Of the 121 possible organ donors, 108 were classified as potential organ donors after excluding 13 unlikely to fulfil brain death criteria. Finally 11 patients became actual organ donors with an overall conversion rate of 10%. Reasons for non-donation included medical contra indication (46%), failure to identify and inform organ donation coordinators (14%), failure of donor maintenance (11%), brain death diagnosis not established (18%), and refusal by relatives (11%). CONCLUSIONS: It is possible to increase the organ donation rate considerably by action at different stages of the donation process. Ongoing accurate audit of current practice is necessary. PMID- 27779098 TI - Effectiveness of proximal intra-operative salvage Palmaz stent placement for endoleak during endovascular aneurysm repair. AB - INTRODUCTION: The use of a proximal Palmaz stent is a well-recognised technique to treat proximal endoleak in endovascular aortic repair. This study aimed to report the effectiveness and safety of an intra-operative Palmaz stent for immediate type 1a endoleak in Hong Kong patients. METHODS: This case series was conducted at a tertiary hospital in Hong Kong. In a cohort of 494 patients who underwent infrarenal endovascular aortic repair from July 1999 to September 2015, 12 (2.4%) received an intra-operative proximal Palmaz stent for type 1a endoleak. Immediate and subsequent proximal endoleak on follow-up image was documented. RESULTS: Morphological review of the pre-repair aneurysm neck showed five conical, one funnel, five cylindrical and one undetermined short neck, with a median neck angle of 61 degrees (range, 19-109 degrees). Stent grafts used included seven Cook Zenith, one Cook Aorto-Uni-Iliac device, three Metronic Endurant, and one TriVascular Ovation. Eleven Palmaz stents were placed successfully as intended, but one of them was accidentally placed too low. Of the 12 type 1a endoleaks, postoperative imaging revealed immediate resolution of eight whilst four had improved. After a median follow-up of 16 (range, 1-59) months, none of the subsequent imaging showed a type 1a endoleak. The mean size of the aneurysm sac reduced from 7.4 cm preoperatively to 7.3 cm at 1 month, 6.9 cm at 6 months, 7.1 cm at 1 year, and 6.1 cm at 2 years postoperatively. None of these patients required aortic reintervention or had device-related early- or mid term mortality. One patient required delayed iliac re-interventions for an occluded limb at 10 days post-surgery. CONCLUSION: In our cohort, Palmaz stenting was effective and safe in securing proximal sealing and fixation. PMID- 27779099 TI - Ductal carcinoma in situ of breast: detection and treatment pattern in Hong Kong. AB - INTRODUCTION: The treatment of ductal carcinoma in situ has been widely reported in the western and other Asian countries, but the relevant data in Hong Kong are relatively limited. This study aimed to evaluate the latest detection and treatment pattern for ductal carcinoma in situ in Hong Kong so as to guide planning of future service provision. METHODS: This was a retrospective case series study. A total of 573 patients who registered with the Hong Kong Breast Cancer Registry, and were diagnosed and treated in Hong Kong from January 2001 to December 2011 were reviewed. RESULTS: Compared with invasive breast cancer patients, patients with ductal carcinoma in situ were younger (median, 48.6 vs 50.3 years; P<0.001), had a higher education level (P<0.001), had a higher total monthly family income (P<0.001), and more common breast-screening habits (P<0.001). Significantly more patients with ductal carcinoma in situ underwent breast-conserving surgery than their invasive cancer counterparts (55.8% vs 36.7%; P<0.001). The percentage of screen-detected ductal carcinoma in situ was relatively lower than that reported in other studies, but was still much higher than that in invasive breast cancer patients (29.0% vs 4.7%; P<0.001). Screen detected patients with ductal carcinoma in situ tended to choose a private hospital instead of a public hospital for treatment (P=0.05) and to undergo breast-conserving surgery (P=0.02). With a median follow-up of 3 years, the crude local recurrence rate after mastectomy and breast-conserving surgery was 0.4% and 3.3%, respectively; 44% of recurrent tumours had developed invasive components. No regional recurrence, distant recurrence, or cancer-related deaths were recorded. CONCLUSIONS: In the absence of a population-based breast screening programme in Hong Kong, ductal carcinoma in situ is more frequently found in the higher social classes and managed in the private sector. The clinical outcome of ductal carcinoma in situ is excellent and more than half of the patients can be successfully managed with breast-conserving surgery. PMID- 27779100 TI - Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-kappaB. AB - The molecular and cellular mechanisms behind the involvement of inflammation in melanoma have not been fully elucidated. In this study, knockdown of Hmgb1 expression increased apoptosis, reduced invasion and p-NF-kappaB expression, but increased Klotho protein level in melanoma tumor cells. The effect of Hmgb1 knockdown was overcome by LPS. Introduction of exogenous Hmgb1 significantly decreased apoptosis, increased invasion, elevated p-NF-kappaB, but lowered Klotho protein level in melanoma cells. The effect of exogenous Hmgb1 was agonized by NF kappaB inhibitor CAPE. Hmgb1 knockdown activated, but exogenous Hmgb1 inactivated, p-IGF1R/p-PI3K p-85/p-Akt/p-mTOR signaling. Knockdown of Klotho gene expression significantly decreased apoptosis, increased invasion in melanoma cells, and inhibited xenograft A375 tumor growth. A significantly high percentage of cells stained positive for p-NF-kappaB, but negative for Klotho, in melanoma tissues compared to normal and benign skin tissues. The positive p-NF-kappaB and negative Klotho protein expression correlated with poor prognosis in melanoma patients. Multivariate analysis revealed an independent association between p-NF kappaB / Klotho protein level and overall survival. In conclusion, Hmgb1 can inhibit Klotho gene expression and malignant phenotype in melanoma cells through activation of NF-kappaB signaling. PMID- 27779101 TI - A four-gene signature predicts survival in clear-cell renal-cell carcinoma. AB - Clear-cell renal-cell carcinoma (ccRCC) is the most common pathological subtype of renal cell carcinoma (RCC), accounting for about 80% of RCC. In order to find potential prognostic biomarkers in ccRCC, we presented a four-gene signature to evaluate the prognosis of ccRCC. SurvExpress and immunohistochemical (IHC) staining of tissue microarrays were used to analyze the association between the four genes and the prognosis of ccRCC. Data from TCGA dataset revealed a prognostic prompt function of the four genes (PTEN, PIK3C2A, ITPA and BCL3). Further discovery suggested that the four-gene signature predicted survival better than any of the four genes alone. Moreover, IHC staining demonstrated a consistent result with TCGA, indicating that the signature was an independent prognostic factor of survival in ccRCC. Univariate and multivariate Cox proportional hazard regression analysis were conducted to verify the association of clinicopathological variables and the four genes' expression levels with survival. The results further testified that the risk (four-gene signature) was an independent prognostic factors of both Overall Survival (OS) and Disease-free Survival (DFS) (P<0.05). In conclusion, the four-gene signature was correlated with the survival of ccRCC, and therefore, may help to provide significant clinical implications for predicting the prognosis of patients. PMID- 27779102 TI - The increased expression of fatty acid-binding protein 9 in prostate cancer and its prognostic significance. AB - In contrast to numerous studies conducted to investigate the crucial role of fatty acid binding protein 5 (FABP5) in prostate cancer, investigations on the possible involvement of other FABPs are rare. Here we first measured the mRNA levels of 10 FABPs in benign and malignant prostate cell lines and identified the differentially expressed FABP6 and FABP9 mRNAs whose levels in all malignant cell lines were higher than those in the benign cells. Thereafter we assessed the expression status of FABP6 and FABP9 in both prostate cell lines and in human tissues. FABP6 protein was overexpressed only in 1 of the 5 malignant cell lines and its immunostaining intensities were not significantly different between benign and malignant prostate tissues. In contrast, FABP9 protein was highly expressed in highly malignant cell lines PC-3 and PC3-M, but its level in the benign PNT-2 and other malignant cell lines was not detectable. When analysed in an archival set of human prostate tissues, immunohistochemical staining intensity for FABP9 was significantly higher in carcinomas than in benign cases and the increase in FABP9 was significantly correlated with reduced patient survival times. Moreover, the increased level of staining for FABP9 was significantly associated with the increased joint Gleason scores (GS) and androgen receptor index (AR). Suppression of FABP9 expression in highly malignant PC3-M cells inhibited their invasive potential. Our results suggest that FABP9 is a valuable prognostic marker to predict the outcomes of prostate cancer patients, perhaps by playing an important role in prostate cancer cell invasion. PMID- 27779103 TI - Functional variant of the P2X7 receptor gene is associated with human papillomavirus-16 positive cervical squamous cell carcinoma. AB - Human papillomavirus (HPV) infection and the fate of HPV infected cervical epithelial cells are strictly associated with cervical cancer development. P2X7 receptor has been implicated in both the regulation of immune responses and apoptosis of cervical cancer cells. The study aims to investigate if polymorphisms in the P2RX7 gene are associated with the risk of cervical cancer in Taiwanese women. P2RX7 253 T/C, 835 G/A, and 1513 A/C loss-of-function polymorphisms were genotyped in a hospital-based study of 507 women with cervical squamous cell carcinoma (CSCC) and 1619 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. The frequency of 253 C/C genotype was found to increase significantly in patients with HPV-16 positive CSCC compared with controls (odds ratio = 10.2, 95% confidence interval 1.39 87.8, Pc = 0.03). No significant associations were found for other 2 polymorphisms. Analysis of haplotypes also revealed no significant differences among women with CSCC, those with HPV-16 positive CSCC and controls. In conclusion, inheritance of the C/C genotype at position 253 in the P2RX7 gene may contribute to the risk of HPV-16 associated CSCC in Taiwanese women. PMID- 27779104 TI - TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of rheumatoid arthritis. AB - Accumulating evidences suggested that tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene rs10499194, rs13207033 polymorphisms may be associated with the risk of rheumatoid arthritis (RA). However, these studies yielded contradictory findings. To clarify convincing associations, we conducted a comprehensive meta-analysis by searching in PubMed, Embase, and the China Knowledge Resource Integrated Database. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using fixed-effect or random-effect models. A total of 13 case-control studies for rs10499194 polymorphism and 6 studies for rs13207033 polymorphism were included. Our data indicated that TNFAIP3 gene rs10499194, rs13207033 polymorphisms were associated with the decreased risk of RA. Stratification analyses of ethnicity indicated rs10499194, rs13207033 polymorphisms decreased the risk of RA among Caucasian populations, but not among Asian populations. In conclusion, this meta-analysis indicates that TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of RA, especially among Caucasian populations. PMID- 27779105 TI - Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis. AB - We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p=0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments. PMID- 27779106 TI - Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models. AB - The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the "undruggable" KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA 12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA 12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest.Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists. PMID- 27779107 TI - The components of Huang-Lian-Jie-Du-Decoction act synergistically to exert protective effects in a rat ischemic stroke model. AB - Huang-Lian-Jie-Du-Decoction (HLJDD, Oren-gedoku-to in Japanese) is commonly used in traditional Chinese medicine (TCM) to treat ischemic stroke. This study investigated the efficacy of various combinations of the major components of HLJDD, berberine (A), baicalin (B), and jasminoidin (C), on the treatment of ischemic stroke modeled by middle cerebral artery occlusion (MCAO) in rats. The effects of A, B and C individually and their combinations were investigated using proton nuclear magnetic resonance (1H NMR)-based metabolomics complemented with neurologic deficit scoring, infarct volume measurement, biochemistry, histopathology and immunohistochemistry, as well as quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Ischemic stroke produces severe oxidative stress, which induces further damage. Our results show that the ABC combination treatment increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 (Nrf2) signaling cascade. These protective effects were not observed with the other treatments. These results suggest that a combination of component herbs in HLJDD exhibit stronger effects than the individual herbs alone. Our integrated metabolomics approach also provides a tractable, powerful tool for understanding the science behind TCM formulations. PMID- 27779108 TI - RNAi screens identify CHD4 as an essential gene in breast cancer growth. AB - Epigenetic regulation plays an essential role in tumor development and epigenetic modifiers are considered optimal potential druggable candidates. In order to identify new breast cancer vulnerabilities and improve therapeutic chances for patients, we performed in vivo and in vitro shRNA screens in a human breast cancer cell model (MCF10DCIS.com cell line) using epigenetic libraries. Among the genes identified in our screening, we deeply investigated the role of Chromodomain Helicase DNA binding Protein 4 (CHD4) in breast cancer tumorigenesis. CHD4 silencing significantly reduced tumor growth in vivo and proliferation in vitro of MCF10DCIS.com cells. Similarly, in vivo breast cancer growth was decreased in a spontaneous mouse model of breast carcinoma (MMTV-NeuT system) and in metastatic patient-derived xenograft models. Conversely, no reduction in proliferative ability of non-transformed mammary epithelial cells (MCF10A) was detected. Moreover, we showed that CHD4 depletion arrests proliferation by inducing a G0/G1 block of cell cycle associated with up regulation of CDKN1A (p21). These results highlight the relevance of genetic screens in the identification of tumor frailties and the role of CHD4 as a potential pharmacological target to inhibit breast cancer growth. PMID- 27779111 TI - Ultrathin thermoacoustic nanobridge loudspeakers from ALD on polyimide. AB - The recent development of low-temperature (<200 degrees C) atomic layer deposition (ALD) for fabrication of freestanding nanostructures has enabled consideration of active device design based on engineered ultrathin films. This paper explores audible sound production from thermoacoustic loudspeakers fabricated from suspended tungsten nanobridges formed by ALD. Additionally, this paper develops an approach to lumped-element modeling for design of thermoacoustic nanodevices and relates the near-field plane wave model of individual transducer beams to the far-field spherical wave sound pressure that can be measured with standard experimental techniques. Arrays of suspended nanobridges with 25.8 nm thickness and sizes as small as 17 MUm * 2 MUm have been fabricated and demonstrated to produce audible sound using the thermoacoustic effect. The nanobridges were fabricated by ALD of 6.5 nm Al2O3 and 19.3 nm tungsten on sacrificial polyimide, with ALD performed at 130 degrees C and patterned by standard photolithography. The maximum observed loudspeaker sound pressure level (SPL) is 104 dB, measured at 20 kHz, 9.71 W input power, and 1 cm measurement distance, providing a loudspeaker sensitivity value of ~64.6 dB SPL/1 mW. Sound production efficiency was measured to vary proportional to frequency f 3 and was directly proportional to input power. The devices in this paper demonstrate industrially feasible nanofabrication of thermoacoustic transducers and a sound production mechanism pertinent to submicron-scale device engineering. PMID- 27779112 TI - Diazoketo-functionalized POSS resists for high performance replica molds of ultraviolet-nanoimprint lithography. AB - Novel polyhedral oligomeric silsesquioxane (POSS) resists, which are based on a new photo-crosslinking system via Wolff rearrangement, are developed as ideal replica mold materials for ultraviolet-nanoimprint lithography. These POSS resist materials are synthesized by incorporating diazoketo and hydroxyl groups into the POSS core. The resist materials have exhibited a variety of desirable properties as replica molds, such as high modulus, low shrinkage ratio, high transparency, low surface energy, and resistance to organic solvents. The resultant replica molds exhibit a high resolution patterning capacity. These economic fabrication methods of replica molds with high mechanical durability and good releasing properties are potentially useful for versatile applications in the area of mold based lithography. PMID- 27779113 TI - High performance FETs based on ZnO nanowires synthesized by low cost methods. AB - Single ZnO nanowires prepared by wet and dry methods are used as channels in high performance back-gated field effect transistors working in low power operation mode, with on-off ratios up to 105 and mobilities up to 167 cm2 V-1 s-1. The nanowires' properties, generated by the growth techniques, influence the parameters of the transistors, therefore a throughout comparison is made. PMID- 27779109 TI - Methylation of promoter of RBL1 enhances the radioresistance of three dimensional cultured carcinoma cells. AB - Three dimensional (3D) culture in vitro is a new cell culture model that more closely mimics the physiology features of the in vivo environment and is being used widely in the field of medical and biological research. It has been demonstrated that cancer cells cultured in 3D matrices are more radioresistant compared with cells in monolayer (2D). However, the mechanisms causing this difference remain largely unclear. Here we found that the cell cycle distribution and expression of cell cycle regulation genes in 3D A549 cells are different from the 2D. The higher levels of the promotor methylation of cell cycle regulation genes such as RBL1 were observed in 3D A549 cells compared with cells in 2D. The treatments of irradiation or 5-Aza-CdR activated the demethylation of RBL1 promotor and resulted in the increased expression of RBL1 only in 3D A549 cells. Inhibition of RBL1 enhanced the radioresistance and decreased the G2/M phase arrest induced by irradiation in 2D A549 and MCF7 cells. Overexpression of RBL1 sensitized 3D cultured A549 and MCF7 cells to irradiation. Taken together, to our knowledge, it is the first time to revealthat the low expression of RBL1 due to itself promotor methylation in 3D cells enhances the radioresistance. Our finding sheds a new light on understanding the features of the 3D cultured cell model and its application in basic research into cancer radiotherapy and medcine development. PMID- 27779114 TI - Novel one-pot and facile room temperature synthesis of gold nanodots and application as highly sensitive and selective probes for cyanide detection. AB - Highly fluorescent gold nanodots have been synthesized through a novel rapid, facile and one-pot room temperature route using trithiocyanuric acid as mild reducing agent and surface ligand. The proposed synthesis overcomes limitations of other synthetic routes in terms of cost, time, complexity and environmental risks, and gives rise to highly fluorescent gold nanodots within 10 min at room temperature, with a maximum emission wavelength at 623 nm and a large Stokes shift (213 nm). Moreover, the synthesized gold nanodots showed a large emission QY (9.62 * 10-2) and excellent photostability and colloidal properties during long periods. Increasing concentrations of CN- in aqueous solution progressively quenched the fluorescence emission and produced a slight blue shift of the synthesized gold nanodots. A good linear relationship was observed for CN- concentrations between 0.29 and 8.87 MUM, obtaining a detection limit estimated according to the 3s IUPAC criteria of 150 nM. Besides, the influence on the fluorescence signal of potential interferents at high concentrations (1000 MUM) was studied, including I-, F-, citrate, [Formula: see text] [Formula: see text] [Formula: see text] CH3COO-, EDTA, Br-, [Formula: see text] Cl- and S2- K+, Na+, Li+, Mg2+, Ca2+, Ba2+, Cu2+, Zn2+, Ni2+, Al3+, Fe2+, Fe3+, Pb2+, Cd2+, Hg2+ and Co2+. Results showed a high selectivity towards all the investigated ions, except for Pb2+, Cd2+ and Hg2+, although the use of glutathione and BSA as masking agents drastically minimized the effect of such cations at high concentrations. The synthesized gold nanodots were successfully evaluated as highly sensitive and selective probes for cyanide determination in environmental water samples, including tap, river, lake and sea water, indicating the validity of TCA-AuNDs for analytical CN- contamination control. PMID- 27779110 TI - The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? AB - Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes. We studied 583 consecutive patients from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-genes panel including 20 well-established high-risk cancer genes as well as more recently identified predisposing HBOC cancer. A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2%), ATM (n = 9; 1.5%), and PALB2 (n = 4; 0.6%). Three patients had a mutation in two different predisposing genes. The analysis of clinical actionability conducted in mutation-positive individuals revealed that additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone had been recommended in 69% of cases. In conclusion, multigene panel testing is a powerful tool to identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancers with these other genes are sometimes undefined, and further collaborative work is crucial to address this question. PMID- 27779115 TI - Structural fluctuations and thermal stability of proteins in crowded environments: effects of the excluded volume. AB - We perform molecular dynamics simulations for a simple coarse-grained model of a protein placed inside of a softly repulsive sphere of radius R. The protein is surrounded either by a number of same molecules or a number of spherical crowding particles that immitate other biomolecules such as the osmolytes. The two descriptions are shown to lead to distinct results when testing thermal stability as assessed by studying the unfolding times as a function of temperature. We consider three examples of proteins and show that crowding increases the thermal stability provided the inter-protein or protein-crowder interactions are repulsive. On the other hand, an introduction of attraction between the proteins is found to destabilize the proteins. Crowding by repulsive crowder particles is seen to enhance the RMSF in certain exposed regions. The effect grows on decreasing the size of the crowding particles. In the absence of crowding the RMSF anticorrelates with the coordination number related to the residue-residue interaction. PMID- 27779116 TI - Highly sensitive, direct and real-time detection of silver nanowires by using a quartz crystal microbalance. AB - For several decades, silver nanomaterials (AgNMs) have been used in various research areas and commercial products. Among the many AgNMs, silver nanowires (AgNWs) are one of the mostly widely used nanomaterials due to their high electrical and thermal conductivity. However, recent studies have investigated the toxicity of AgNWs. For this reason, it is necessary to develop a successful detection method of AgNWs for protecting human health. In this study, label-free, highly sensitive, direct, and real-time detection of AgNWs is performed for the first time. The detection mechanism is based on the resonance frequency shift upon the mass change from the hybridization between the probe DNA on the electrode and the linker DNA attached on AgNWs. The frequency shift is measured by using a quartz crystal microbalance. We are able to detect 1 ng ml-1 of AgNWs in deionized water in real-time. Moreover, our detection method can selectively detect AgNWs among other types of one-dimensional nanomaterials and can also be applied to detection in drinking water. PMID- 27779117 TI - Photothermal and mechanical stimulation of cells via dualfunctional nanohybrids. AB - Stimulating cells by light is an attractive technology to investigate cellular function and deliver innovative cell-based therapy. However, current techniques generally use poorly biopermeable light, which prevents broad applicability. Here, we show that a new type of composite nanomaterial, synthesized from multi walled carbon nanotubes, magnetic iron nanoparticles, and polyglycerol, enables photothermal and mechanical control of Ca2+ influx into cells overexpressing transient receptor potential vanilloid type-2. The nanohybrid is simply operated by application of highly biotransparent near-infrared light and a magnetic field. The technology may revolutionize remote control of cellular function. PMID- 27779118 TI - New approach for fabricating hybrid-structured metal mesh films for flexible transparent electrodes by the combination of electrospinning and metal deposition. AB - In this study, hybrid-structured metal mesh (HMM) films as potential flexible transparent electrodes, composed of aligned micro-sized metal fibers integrated into random network of metal nanofibers, were fabricated by the combination of electrospinning and metal deposition. These naturally fiber-bridged HMMs, with a gold layer thickness of 85 nm, exhibited a high transmittance of around 90% and a sheet resistance of approximately 10 Omega sq-1, as well as favorable mechanical stability under bending stress. These results demonstrate that the approach employed herein is a simple, highly efficient, and facile process for fabricating, uniform, interconnected fiber networks with potential for producing high-performance flexible transparent electrodes. PMID- 27779119 TI - Heterogeneous force network in 3D cellularized collagen networks. AB - Collagen networks play an important role in coordinating and regulating collective cellular dynamics via a number of signaling pathways. Here, we investigate the transmission of forces generated by contractile cells in 3D collagen-I networks. Specifically, the graph (bond-node) representations of collagen networks with collagen concentrations of 1, 2 and 4 mg ml-1 are derived from confocal microscopy data and used to model the network microstructure. Cell contraction is modeled by applying correlated displacements at specific nodes of the network, representing the focal adhesion sites. A nonlinear elastic model is employed to characterize the mechanical behavior of individual fiber bundles including strain hardening during stretching and buckling under compression. A force-based relaxation method is employed to obtain equilibrium network configurations under cell contraction. We find that for all collagen concentrations, the majority of the forces are carried by a small number of heterogeneous force chains emitted from the contracting cells, which is qualitatively consistent with our experimental observations. The force chains consist of fiber segments that either possess a high degree of alignment before cell contraction or are aligned due to fiber reorientation induced by cell contraction. The decay of the forces along the force chains is significantly slower than the decay of radially averaged forces in the system, suggesting that the fibreous nature of biopolymer network structure can support long-range force transmission. The force chains emerge even at very small cell contractions, and the number of force chains increases with increasing cell contraction. At large cell contractions, the fibers close to the cell surface are in the nonlinear regime, and the nonlinear region is localized in a small neighborhood of the cell. In addition, the number of force chains increases with increasing collagen concentration, due to the larger number of focal adhesion sites in collagen networks with high concentrations. PMID- 27779120 TI - Towards clinical application: prompt gamma imaging of passively scattered proton fields with a knife-edge slit camera. AB - Prompt gamma-ray imaging with a knife-edge shaped slit camera provides the possibility of verifying proton beam range in tumor therapy. Dedicated experiments regarding the characterization of the camera system have been performed previously. Now, we aim at implementing the prototype into clinical application of monitoring patient treatments. Focused on this goal of translation into clinical operation, we systematically addressed remaining challenges and questions. We developed a robust energy calibration routine and corresponding quality assurance protocols. Furthermore, with dedicated experiments, we determined the positioning precision of the system to 1.1 mm (2sigma). For the first time, we demonstrated the application of the slit camera, which was intentionally developed for pencil beam scanning, to double scattered proton beams. Systematic experiments with increasing complexity were performed. It was possible to visualize proton range shifts of 2-5 mm with the camera system in phantom experiments in passive scattered fields. Moreover, prompt gamma-ray profiles for single iso-energy layers were acquired by synchronizing time resolved measurements to the rotation of the range modulator wheel of the treatment system. Thus, a mapping of the acquired profiles to different anatomical regions along the beam path is feasible and additional information on the source of potential range shifts can be obtained. With the work presented here, we show that an application of the slit camera in clinical treatments is possible and of potential benefit. PMID- 27779121 TI - The effect of particle density on ultrasound-mediated transport of nanoparticles. AB - A significant barrier to successful drug delivery is the limited penetration of nanoscale therapeutics beyond the vasculature. Building on recent in vivo findings in the context of cancer drug delivery, the current study investigates whether modification of nanoparticle drug-carriers to increase their density can be used to enhance their penetration into viscoelastic materials under ultrasound exposure. A computational model is first presented to predict the transport of identically sized nanoparticles of different densities in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming and microstreaming. Experiments are then described in which near monodisperse (polydispersity index <0.2) nanoparticles of approximate mean diameter 200 nm and densities ranging from 1.01 g cm-3 to 5.58 g cm-3 were fabricated and delivered to a tissue mimicking material in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz and a peak negative pressure of 1 MPa. Both the theoretical and experimental results confirm that denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that density is a key consideration in the design of nanoscale therapeutics. PMID- 27779122 TI - Track-average LET of secondary electrons generated in LiF:Mg,Ti and liquid water by 20-300 kV x-ray, 137Cs and 60Co beams. AB - Electrons generated in matter by photons could be a fundamental basis for an adequate analysis of radiation effects and damage. We have studied separately the 'primary electrons' generated directly by photons from the 'secondary electrons' (SE) produced by electron-electron interactions. In this work, track-average linear energy transfer, [Formula: see text], of SE in LiF:Mg,Ti and liquid water produced by twelve photon energy beams from 20 kV x-ray to 60Co gamma rays have been investigated using the EGSnrc Monte Carlo Code. The exposure of LiF:Mg,Ti in different phantom materials has been considered. Depending on the photon energy, SE represent 40%-90% of the total electron fluence (TEF) between 1 keV and 10 keV, being higher when the photon energy increases. Independent of the medium, [Formula: see text] versus mean photon energy displays a local minimum at around 40 keV, followed by a local maximum at ~80 keV-100 keV. The [Formula: see text] of SE generated by the x-ray beams are of order of 11 keV um-1 to 19 keV um-1 in LiF:Mg,Ti and 5 keV um-1 to 9 keV um-1 in liquid water which represent 3-5 times those produced by 60Co gamma rays in both media. These values were considerably greater than those of TEF, by factors of 3-8. Furthermore, [Formula: see text] of SE generated in liquid water by 20 kV-200 kV x-rays are similar to those of 76 MeV-120 MeV 3He ions. Contrary to the TEF, where [Formula: see text] were independent of the phantom material, at low photon energies [Formula: see text] of SE was found to be sensitive to the surrounding medium showing higher values within the phantom than in air. This result, which agrees with published experimental results, implies the importance of the SE ionization density for an understanding of dosimeter response induced by photon beams. PMID- 27779123 TI - Quantifying hypoxia in human cancers using static PET imaging. AB - Compared to FDG, the signal of 18F-labelled hypoxia-sensitive tracers in tumours is low. This means that in addition to the presence of hypoxic cells, transport properties contribute significantly to the uptake signal in static PET images. This sensitivity to transport must be minimized in order for static PET to provide a reliable standard for hypoxia quantification. A dynamic compartmental model based on a reaction-diffusion formalism was developed to interpret tracer pharmacokinetics and applied to static images of FAZA in twenty patients with pancreatic cancer. We use our model to identify tumour properties-well-perfused without substantial necrosis or partitioning-for which static PET images can reliably quantify hypoxia. Normalizing the measured activity in a tumour voxel by the value in blood leads to a reduction in the sensitivity to variations in 'inter-corporal' transport properties-blood volume and clearance rate-as well as imaging study protocols. Normalization thus enhances the correlation between static PET images and the FAZA binding rate K 3, a quantity which quantifies hypoxia in a biologically significant way. The ratio of FAZA uptake in spinal muscle and blood can vary substantially across patients due to long muscle equilibration times. Normalized static PET images of hypoxia-sensitive tracers can reliably quantify hypoxia for homogeneously well-perfused tumours with minimal tissue partitioning. The ideal normalizing reference tissue is blood, either drawn from the patient before PET scanning or imaged using PET. If blood is not available, uniform, homogeneously well-perfused muscle can be used. For tumours that are not homogeneously well-perfused or for which partitioning is significant, only an analysis of dynamic PET scans can reliably quantify hypoxia. PMID- 27779125 TI - Novel crystal timing calibration method based on total variation. AB - A novel crystal timing calibration method based on total variation (TV), abbreviated as 'TV merge', has been developed for a high-resolution positron emission tomography (PET) system. The proposed method was developed for a system with a large number of crystals, it can provide timing calibration at the crystal level. In the proposed method, the timing calibration process was formulated as a linear problem. To robustly optimize the timing resolution, a TV constraint was added to the linear equation. Moreover, to solve the computer memory problem associated with the calculation of the timing calibration factors for systems with a large number of crystals, the merge component was used for obtaining the crystal level timing calibration values. Compared with other conventional methods, the data measured from a standard cylindrical phantom filled with a radioisotope solution was sufficient for performing a high-precision crystal level timing calibration. In this paper, both simulation and experimental studies were performed to demonstrate the effectiveness and robustness of the TV merge method. We compare the timing resolutions of a 22Na point source, which was located in the field of view (FOV) of the brain PET system, with various calibration techniques. After implementing the TV merge method, the timing resolution improved from 3.34 ns at full width at half maximum (FWHM) to 2.31 ns FWHM. PMID- 27779124 TI - Automated segmentation of liver and liver cysts from bounded abdominal MR images in patients with autosomal dominant polycystic kidney disease. AB - Liver and liver cyst volume measurements are important quantitative imaging biomarkers for assessment of disease progression in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD). To date, no study has presented automated segmentation and volumetric computation of liver and liver cysts in these populations. In this paper, we proposed an automated segmentation framework for liver and liver cysts from bounded abdominal MR images in patients with ADPKD. To model the shape and variations in ADPKD livers, the spatial prior probability map (SPPM) of liver location and the tissue prior probability maps (TPPMs) of liver parenchymal tissue intensity and cyst morphology were generated. Formulated within a three-dimensional level set framework, the TPPMs successfully captured liver parenchymal tissues and cysts, while the SPPM globally constrained the initial surfaces of the liver into the desired boundary. Liver cysts were extracted by combined operations of the TPPMs, thresholding, and false positive reduction based on spatial prior knowledge of kidney cysts and distance map. With cross-validation for the liver segmentation, the agreement between the radiology expert and the proposed method was 84% for shape congruence and 91% for volume measurement assessed by the intra-class correlation coefficient (ICC). For the liver cyst segmentation, the agreement between the reference method and the proposed method was ICC = 0.91 for cyst volumes and ICC = 0.94 for % cyst-to liver volume. PMID- 27779126 TI - MR-compatibility of a high-resolution small animal PET insert operating inside a 7 T MRI. AB - A full-ring PET insert consisting of 16 PET detector modules was designed and constructed to fit within the 114 mm diameter gradient bore of a Bruker 7 T MRI. The individual detector modules contain two silicon photomultiplier (SiPM) arrays, dual-layer offset LYSO crystal arrays, and high-definition multimedia interface (HDMI) cables for both signal and power transmission. Several different RF shielding configurations were assessed prior to construction of a fully assembled PET insert using a combination of carbon fibre and copper foil for RF shielding. MR-compatibility measurements included field mapping of the static magnetic field (B 0) and the time-varying excitation field (B 1) as well as acquisitions with multiple pulse sequences: spin echo (SE), rapid imaging with refocused echoes (RARE), fast low angle shot (FLASH) gradient echo, and echo planar imaging (EPI). B 0 field maps revealed a small degradation in the mean homogeneity (+0.1 ppm) when the PET insert was installed and operating. No significant change was observed in the B 1 field maps or the image homogeneity of various MR images, with a 9% decrease in the signal-to-noise ratio (SNR) observed only in EPI images acquired with the PET insert installed and operating. PET detector flood histograms, photopeak amplitudes, and energy resolutions were unchanged in individual PET detector modules when acquired during MRI operation. There was a small baseline shift on the PET detector signals due to the switching amplifiers used to power MRI gradient pulses. This baseline shift was observable when measured with an oscilloscope and varied as a function of the gradient duty cycle, but had no noticeable effect on the performance of the PET detector modules. Compact front-end electronics and effective RF shielding led to minimal cross-interference between the PET and MRI systems. Both PET detector and MRI performance was excellent, whether operating as a standalone system or a hybrid PET/MRI. PMID- 27779127 TI - Towards real-time MRI-guided 3D localization of deforming targets for non invasive cardiac radiosurgery. AB - Radiosurgery to the pulmonary vein antrum in the left atrium (LA) has recently been proposed for non-invasive treatment of atrial fibrillation (AF). Precise real-time target localization during treatment is necessary due to complex respiratory and cardiac motion and high radiation doses. To determine the 3D position of the LA for motion compensation during radiosurgery, a tracking method based on orthogonal real-time MRI planes was developed for AF treatments with an MRI-guided radiotherapy system. Four healthy volunteers underwent cardiac MRI of the LA. Contractile motion was quantified on 3D LA models derived from 4D scans with 10 phases acquired in end-exhalation. Three localization strategies were developed and tested retrospectively on 2D real-time scans (sagittal, temporal resolution 100 ms, free breathing). The best-performing method was then used to measure 3D target positions in 2D-2D orthogonal planes (sagittal-coronal, temporal resolution 200-252 ms, free breathing) in 20 configurations of a digital phantom and in the volunteer data. The 3D target localization accuracy was quantified in the phantom and qualitatively assessed in the real data. Mean cardiac contraction was ? 3.9 mm between maximum dilation and contraction but anisotropic. A template matching approach with two distinct template phases and ECG-based selection yielded the highest 2D accuracy of 1.2 mm. 3D target localization showed a mean error of 3.2 mm in the customized digital phantoms. Our algorithms were successfully applied to the 2D-2D volunteer data in which we measured a mean 3D LA motion extent of 16.5 mm (SI), 5.8 mm (AP) and 3.1 mm (LR). Real-time target localization on orthogonal MRI planes was successfully implemented for highly deformable targets treated in cardiac radiosurgery. The developed method measures target shifts caused by respiration and cardiac contraction. If the detected motion can be compensated accordingly, an MRI-guided radiotherapy system could potentially enable completely non-invasive treatment of AF. PMID- 27779128 TI - Photoluminescence of monolayer transition metal dichalcogenides integrated with VO2. AB - Integrating a phase transition material with two-dimensional semiconductors can provide a route towards tunable opto-electronic metamaterials. Here, we integrate monolayer transition metal dichalcogenides with vanadium dioxide (VO2) thin films grown via molecular beam epitaxy to form a 2D/3D heterostructure. Vanadium dioxide undergoes an insulator-to-metal transition at 60-70 degrees C, which changes the band alignment between MoS2 and VO2 from a semiconductor-insulator junction to a semiconductor-metal junction. By switching VO2 between insulating and metallic phases, the modulation of photoluminescence emission in the 2D semiconductors was observed. This study demonstrates the feasibility to combine TMDs and functional oxides to create unconventional hybrid optoelectronic properties derived from 2D semiconductors that are linked to functional properties of oxides through proximity coupling. PMID- 27779129 TI - Structure and dynamics in network-forming materials. AB - The study of the structure and dynamics of network-forming materials is reviewed. Experimental techniques used to extract key structural information are briefly considered. Strategies for building simulation models, based on both targeting key (experimentally-accessible) materials and on systematically controlling key model parameters, are discussed. As an example of the first class of materials, a key target system, SiO2, is used to highlight how the changing structure with applied pressure can be effectively modelled (in three dimensions) and used to link to both experimental results and simple structural models. As an example of the second class the topology of networks of tetrahedra in the MX2 stoichiometry are controlled using a single model parameter linked to the M-X-M bond angles. The evolution of ordering on multiple length-scales is observed as are the links between the static structure and key dynamical properties. The isomorphous relationship between the structures of amorphous Si and SiO2 is discussed as are the similarities and differences in the phase diagrams, the latter linked to potential polyamorphic and 'anomalous' (e.g. density maxima) behaviour. Links to both two-dimensional structures for C, Si and Ge and near-two-dimensional bilayers of SiO2 are discussed. Emerging low-dimensional structures in low temperature molten carbonates are also uncovered. PMID- 27779130 TI - Remarkably enhanced adhesion of coherently aligned catechol-terminated molecules on ultraclean ultraflat gold nanoplates. AB - We report the characterization and formation of catechol-terminated molecules immobilized on gold nanoplates (Au NPLs) using N-(3,4-dihydroxyphenethyl)-2 mercaptoacetamide (Cat-EAA-SH). Single-crystalline Au NPLs, synthesized using a one-step chemical vapor transport method, have ultraclean and ultraflat surfaces that make Cat-EAA-SH molecules aligned into a well-ordered network of a large scale. Topographic study of the catechol-terminated molecules on Au NPLs using atomic force microscopy showed more orderly orientation and higher density, leading to significantly higher adhesion as observed from local force-distance curves than those on other Au surfaces. These coherently aligned catechol terminated molecules on the atomically smooth gold surface led to significanty more reproducible and thus more physico-chemically meaningful measurements than was possible before by employing rough gold surfaces. PMID- 27779131 TI - Magnetic states, correlation effects and metal-insulator transition in FCC lattice. AB - The ground-state magnetic phase diagram (including collinear and spiral states) of the single-band Hubbard model for the face-centered cubic lattice and related metal-insulator transition (MIT) are investigated within the slave-boson approach by Kotliar and Ruckenstein. The correlation-induced electron spectrum narrowing and a comparison with a generalized Hartree-Fock approximation allow one to estimate the strength of correlation effects. This, as well as the MIT scenario, depends dramatically on the ratio of the next-nearest and nearest electron hopping integrals [Formula: see text]. In contrast with metallic state, possessing substantial band narrowing, insulator one is only weakly correlated. The magnetic (Slater) scenario of MIT is found to be superior over the Mott one. Unlike simple and body-centered cubic lattices, MIT is the first order transition (discontinuous) for most [Formula: see text]. The insulator state is type-II or type-III antiferromagnet, and the metallic state is spin-spiral, collinear antiferromagnet or paramagnet depending on [Formula: see text]. The picture of magnetic ordering is compared with that in the standard localized-electron (Heisenberg) model. PMID- 27779132 TI - Measurement of neural respiratory drive via parasternal intercostal electromyography in healthy adult subjects. AB - Neural respiratory drive, quantified by the parasternal intercostal muscle electromyogram (EMGpara), provides a sensitive measure of respiratory system load capacity balance. Reference values for EMGpara-based measures are lacking and the influence of individual anthropometric characteristics is not known. EMGpara is conventionally expressed as a percentage of that obtained during a maximal inspiratory effort (EMGpara%max), leading to difficulty in applying the technique in subjects unable to reliably perform such manoeuvres. To measure EMGpara in a large, unselected cohort of healthy adult subjects in order to evaluate relevant technical and anthropometric factors. Surface second intercostal space EMGpara was measured during resting breathing and maximal inspiratory efforts in 63 healthy adult subjects, median (IQR) age 31.0 (25.0-47.0) years, 28 males. Detailed anthropometry, spirometry and respiratory muscle strength were also recorded. Median (IQR EMGpara was 4.95 (3.35-6.93) uV, EMGpara%max 4.95 (3.39 8.65)% and neural respiratory drive index (NRDI, the product of EMGpara%max and respiratory rate) was 73.62 (46.41-143.92) %.breath/min. EMGpara increased significantly to 6.28 (4.26-9.93) uV (p < 0.001) with a mouthpiece, noseclip and pneumotachograph in situ. Median (IQR) EMGpara was higher in female subjects (5.79 (4.42-7.98) uV versus 3.56 (2.81-5.35) uV, p = 0.003); after controlling for sex neither EMGpara, EMGpara%max or NRDI were significantly related to anthropometrics, age or respiratory muscle strength. In subjects undergoing repeat measurements within the same testing session (n = 48) or on a separate occasion (n = 19) similar repeatability was observed for both EMGpara and EMGpara%max. EMGpara is higher in female subjects than males, without influence of other anthropometric characteristics. Reference values are provided for EMGpara-derived measures. Expressing EMGpara as a percentage of maximum confers no advantage with respect to measurement repeatability, expanding the potential application of the technique. Raw EMGpara is a useful marker of respiratory system load-capacity balance. PMID- 27779133 TI - Validity of a wearable accelerometer to quantify gait in spinocerebellar ataxia type 6. AB - Biomarkers are required to track disease progression and measure the effectiveness of interventions for people with spinocerebellar ataxia type-6 (SCA6). Gait is a potential biomarker that is sensitive to SCA6 which can be measured using wearable technology, reducing the need for expensive specialist facilities. However, algorithms used to calculate gait using data from wearables have not been validated in SCA6. This study sought to examine the validity of a single wearable for deriving 14 spatio-temporal gait characteristics in SCA6 and control cohorts. Participants performed eight intermittent walks along a 7 m instrumented walkway at their preferred walking pace while also wearing a single accelerometer-based wearable on L5. Gait algorithms previously validated in neurological populations and controls were used to derive gait characteristics. We assessed the bias, agreement and sensitivity of gait characteristics derived using the instrumented walkway and the wearable. Mean gait characteristics showed good to excellent agreement for both groups, although gait variability and asymmetry showed poor agreement between the two systems. Agreement improved considerably in the SCA6 group when people who used walking sticks were excluded from the analysis, suggesting poorer agreement in people with more severe gait impairment. Despite poor agreement for some characteristics, gait measured using the wearable was generally more sensitive to group differences than the instrumented walkway. Our findings indicate mean gait characteristics can be accurately measured using an accelerometer-based wearable in people SCA6 with mild-to-moderately severe gait impairment yet further development of algorithms are required for people with more severe symptoms. PMID- 27779134 TI - A numerical study on the oblique focus in MR-guided transcranial focused ultrasound. AB - Recent clinical data showing thermal lesions from treatments of essential tremor using MR-guided transcranial focused ultrasound shows that in many cases the focus is oblique to the main axis of the phased array. The potential for this obliquity to extend the focus into lateral regions of the brain has led to speculation as to the cause of the oblique focus, and whether it is possible to realign the focus. Numerical simulations were performed on clinical export data to analyze the causes of the oblique focus and determine methods for its correction. It was found that the focal obliquity could be replicated with the numerical simulations to within [Formula: see text] of the clinical cases. It was then found that a major cause of the focal obliquity was the presence of sidelobes, caused by an unequal deposition of power from the different transducer elements in the array at the focus. In addition, it was found that a 65% reduction in focal obliquity was possible using phase and amplitude corrections. Potential drawbacks include the higher levels of skull heating required when modifying the distribution of power among the transducer elements, and the difficulty at present in obtaining ideal phase corrections from CT information alone. These techniques for the reduction of focal obliquity can be applied to other applications of transcranial focused ultrasound involving lower total energy deposition, such as blood-brain barrier opening, where the issue of skull heating is minimal. PMID- 27779135 TI - An end-to-end assessment of range uncertainty in proton therapy using animal tissues. AB - Accurate assessment of range uncertainty is critical in proton therapy. However, there is a lack of data and consensus on how to evaluate the appropriate amount of uncertainty. The purpose of this study is to quantify the range uncertainty in various treatment conditions in proton therapy, using transmission measurements through various animal tissues. Animal tissues, including a pig head, beef steak, and lamb leg, were used in this study. For each tissue, an end-to-end test closely imitating patient treatments was performed. This included CT scan simulation, treatment planning, image-guided alignment, and beam delivery. Radio chromic films were placed at various depths in the distal dose falloff region to measure depth dose. Comparisons between measured and calculated doses were used to evaluate range differences. The dose difference at the distal falloff between measurement and calculation depends on tissue type and treatment conditions. The estimated range difference was up to 5, 6 and 4 mm for the pig head, beef steak, and lamb leg irradiation, respectively. Our study shows that the TPS was able to calculate proton range within about 1.5% plus 1.5 mm. Accurate assessment of range uncertainty in treatment planning would allow better optimization of proton beam treatment, thus fully achieving proton beams' superior dose advantage over conventional photon-based radiation therapy. PMID- 27779136 TI - PETPVC: a toolbox for performing partial volume correction techniques in positron emission tomography. AB - Positron emission tomography (PET) images are degraded by a phenomenon known as the partial volume effect (PVE). Approaches have been developed to reduce PVEs, typically through the utilisation of structural information provided by other imaging modalities such as MRI or CT. These methods, known as partial volume correction (PVC) techniques, reduce PVEs by compensating for the effects of the scanner resolution, thereby improving the quantitative accuracy. The PETPVC toolbox described in this paper comprises a suite of methods, both classic and more recent approaches, for the purposes of applying PVC to PET data. Eight core PVC techniques are available. These core methods can be combined to create a total of 22 different PVC techniques. Simulated brain PET data are used to demonstrate the utility of toolbox in idealised conditions, the effects of applying PVC with mismatched point-spread function (PSF) estimates and the potential of novel hybrid PVC methods to improve the quantification of lesions. All anatomy-based PVC techniques achieve complete recovery of the PET signal in cortical grey matter (GM) when performed in idealised conditions. Applying deconvolution-based approaches results in incomplete recovery due to premature termination of the iterative process. PVC techniques are sensitive to PSF mismatch, causing a bias of up to 16.7% in GM recovery when over-estimating the PSF by 3 mm. The recovery of both GM and a simulated lesion was improved by combining two PVC techniques together. The PETPVC toolbox has been written in C++, supports Windows, Mac and Linux operating systems, is open-source and publicly available. PMID- 27779137 TI - A general method to derive tissue parameters for Monte Carlo dose calculation with multi-energy CT. AB - To develop a general method for human tissue characterization with dual- and multi-energy CT and evaluate its performance in determining elemental compositions and quantities relevant to radiotherapy Monte Carlo dose calculation. Ideal materials to describe human tissue are obtained applying principal component analysis on elemental weight and density data available in literature. The theory is adapted to elemental composition for solving tissue information from CT data. A novel stoichiometric calibration method is integrated to the technique to make it suitable for a clinical environment. The performance of the method is compared with two techniques known in literature using theoretical CT data. In determining elemental weights with dual-energy CT, the method is shown to be systematically superior to the water-lipid-protein material decomposition and comparable to the parameterization technique. In determining proton stopping powers and energy absorption coefficients with dual-energy CT, the method generally shows better accuracy and unbiased results. The generality of the method is demonstrated simulating multi-energy CT data to show the potential to extract more information with multiple energies. The method proposed in this paper shows good performance to determine elemental compositions from dual-energy CT data and physical quantities relevant to radiotherapy dose calculation. The method is particularly suitable for Monte Carlo calculations and shows promise in using more than two energies to characterize human tissue with CT. PMID- 27779138 TI - Skeletonization algorithm-based blood vessel quantification using in vivo 3D photoacoustic imaging. AB - Blood vessels are the only system to provide nutrients and oxygen to every part of the body. Many diseases can have significant effects on blood vessel formation, so that the vascular network can be a cue to assess malicious tumor and ischemic tissues. Various imaging techniques can visualize blood vessel structure, but their applications are often constrained by either expensive costs, contrast agents, ionizing radiations, or a combination of the above. Photoacoustic imaging combines the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging, and image contrast depends on optical absorption. This enables the detection of light absorbing chromophores such as hemoglobin with a greater penetration depth compared to purely optical techniques. We present here a skeletonization algorithm for vessel architectural analysis using non-invasive photoacoustic 3D images acquired without the administration of any exogenous contrast agents. 3D photoacoustic images were acquired on rats (n = 4) in two different time points: before and after a burn surgery. A skeletonization technique based on the application of a vesselness filter and medial axis extraction is proposed to extract the vessel structure from the image data and six vascular parameters (number of vascular trees (NT), vascular density (VD), number of branches (NB), 2D distance metric (DM), inflection count metric (ICM), and sum of angles metric (SOAM)) were calculated from the skeleton. The parameters were compared (1) in locations with and without the burn wound on the same day and (2) in the same anatomic location before (control) and after the burn surgery. Four out of the six descriptors were statistically different (VD, NB, DM, ICM, p < 0.05) when comparing two anatomic locations on the same day and when considering the same anatomic location at two separate times (i.e. before and after burn surgery). The study demonstrates an approach to obtain quantitative characterization of the vascular network from 3D photoacoustic images without any exogenous contrast agent which can assess microenvironmental changes related to disease progression. PMID- 27779139 TI - Fast automated segmentation of multiple objects via spatially weighted shape learning. AB - Active shape models (ASMs) have proved successful in automatic segmentation by using shape and appearance priors in a number of areas such as prostate segmentation, where accurate contouring is important in treatment planning for prostate cancer. The ASM approach however, is heavily reliant on a good initialisation for achieving high segmentation quality. This initialisation often requires algorithms with high computational complexity, such as three dimensional (3D) image registration. In this work, we present a fast, self-initialised ASM approach that simultaneously fits multiple objects hierarchically controlled by spatially weighted shape learning. Prominent objects are targeted initially and spatial weights are progressively adjusted so that the next (more difficult, less visible) object is simultaneously initialised using a series of weighted shape models. The scheme was validated and compared to a multi-atlas approach on 3D magnetic resonance (MR) images of 38 cancer patients and had the same (mean, median, inter-rater) Dice's similarity coefficients of (0.79, 0.81, 0.85), while having no registration error and a computational time of 12-15 min, nearly an order of magnitude faster than the multi-atlas approach. PMID- 27779140 TI - Integral equations and boundary-element solution for static potential in a general piece-wise homogeneous volume conductor. AB - Boundary element methods (BEM) are used for forward computation of bioelectromagnetic fields in multi-compartment volume conductor models. Most BEM approaches assume that each compartment is in contact with at most one external compartment. In this work, I present a general surface integral equation and BEM discretization that remove this limitation and allow BEM modeling of general piecewise-homogeneous medium. The new integral equation allows positioning of field points at junctioned boundary of more than two compartments, enabling the use of linear collocation BEM in such a complex geometry. A modular BEM implementation is presented for linear collocation and Galerkin approaches, starting from the standard formulation. The approach and resulting solver are verified in four ways, including comparisons of volume and surface potentials to those obtained using the finite element method (FEM), and the effect of a hole in skull on electroencephalographic scalp potentials is demonstrated. PMID- 27779141 TI - Development and first use of a novel cylindrical ball bearing phantom for 9-DOF geometric calibrations of flat panel imaging devices used in image-guided ion beam therapy. AB - Image guidance during highly conformal radiotherapy requires accurate geometric calibration of the moving components of the imager. Due to limited manufacturing accuracy and gravity-induced flex, an x-ray imager's deviation from the nominal geometrical definition has to be corrected for. For this purpose a ball bearing phantom applicable for nine degrees of freedom (9-DOF) calibration of a novel cone-beam computed tomography (CBCT) scanner was designed and validated. In order to ensure accurate automated marker detection, as many uniformly distributed markers as possible should be used with a minimum projected inter-marker distance of 10 mm. Three different marker distributions on the phantom cylinder surface were simulated. First, a fixed number of markers are selected and their coordinates are randomly generated. Second, the quasi-random method is represented by setting a constraint on the marker distances in the projections. The third approach generates the ball coordinates helically based on the Golden ratio, phi. Projection images of the phantom incorporating the CBCT scanner's geometry were simulated and analysed with respect to uniform distribution and intra-marker distance. Based on the evaluations a phantom prototype was manufactured and validated by a series of flexmap calibration measurements and analyses. The simulation with randomly distributed markers as well as the quasi random approach showed an insufficient uniformity of the distribution over the detector area. The best compromise between uniform distribution and a high packing fraction of balls is provided by the Golden section approach. A prototype was manufactured accordingly. The phantom was validated for 9-DOF geometric calibrations of the CBCT scanner with independently moveable source and detector arms. A novel flexmap calibration phantom intended for 9-DOF was developed. The ball bearing distribution based on the Golden section was found to be highly advantageous. The phantom showed satisfying results for calibrations of the CBCT scanner and provides the basis for further flexmap correction and reconstruction developments. PMID- 27779142 TI - Retraction: Delleman syndrome: Report of a case in an adolescent boy. AB - [This corrects the article DOI: 10.4103/0378-6323.93662]. PMID- 27779143 TI - Primary cutaneous plasmablastic lymphoma presenting as perineal ulcero proliferative growth in a human immunodeficiency virus-seropositive patient. PMID- 27779145 TI - Nano-silver dressing in toxic epidermal necrolysis. PMID- 27779144 TI - B-cell chronic lymphocytic leukemia followed by mycosis fungoides in a psoriatic patient on long-term methotrexate therapy. PMID- 27779146 TI - Variables affecting interpretation of skin prick test results. AB - BACKGROUND: Both performer- and device-dependent variabilities have been reported in sizes of wheal responses to skin prick tests. OBJECTIVE: We aimed to evaluate whether or not variabilities in sizes of wheal responses influence the final interpretation of skin prick tests; in other words, the decision on whether or not there is an allergy to a given antigen. METHODS: Skin prick tests with positive and negative controls and extracts of Dermatophagoides farinae and Dermatophagoides pteronyssinus were done for 69 patients by two different persons, using two different puncturing devices- disposable 22-gauge hypodermic needles and metal lancets. RESULTS: Among four different skin prick tests, the average coefficients of variation in sizes of wheal responses were near to or higher than 20% for all of them. On the other hand, in the final interpretation of results, kappa values indicated substantial or almost perfect agreements between these tests. However, the frequency of establishing allergy to the house dust mites widely ranged in these tests (20.8-35.8% for D. farinae and 20.8-28.3% for D. pteronyssinus). LIMITATIONS: The conduction of the study in a single center and the comparisons of results of only two performers. CONCLUSION: We feel that variabilities in sizes of wheal responses of skin prick test can influence its categorical results. PMID- 27779147 TI - Lip swelling: An unusual presentation of post kala-azar dermal leishmaniasis. PMID- 27779148 TI - Giant eccrine hidrocystoma of the eyelid. PMID- 27779149 TI - Disseminated cryptococcosis presenting as cellulitis. PMID- 27779150 TI - Cutaneous epithelioid angiomatous nodule versus epithelioid hemangioma: A dilemma. PMID- 27779151 TI - Acral syringomas associated with hematological neoplasm. PMID- 27779152 TI - Role of demographic and job-related variables in determining work-related quality of life of hospital employees. AB - BACKGROUND: Considering a huge working population in health sector faced with stressful work life, limited autonomy in work and declining work contentment calls for an overemphasis on evaluating and monitoring their satisfaction associated with work-related quality of life (WRQoL). This study evaluates WRQoL of hospital employees and validates the bilingual (English and Marathi) version of WRQoL scale. METHODS: The study was conducted during March-April'2014 on employees of a corporate hospital of Pune, India after ethical approval and informed consent from employees. The bilingual WRQoL scale has been tested for reliability and validity, and WRQoL scores have been reported. RESULTS: A total of 132 hospital employees (mean age 31 [+/-8] years, 55% males) who participated in the study reported overall moderate WRQoL scores. The scale showed high internal consistency (Cronbach's alpha = 0.82, P < 0.0001) and moderate to high validity. WRQoL did not significantly vary across marital status, family size, and gender. "Stress at work" score of WRQoL increased with age of employees. Higher work experience, employment at higher positions and those working in clinical and diagnostic departments reported a higher WRQoL. CONCLUSION: WRQoL scale is a reliable and valid instrument. Better WRQoL in employees placed in higher organizational positions indicates a need for focused measures to enhance WRQoL of employees in lower hierarchical levels, especially in control at work and home life interface domains. WRQoL needs regular monitoring for employees in lower positions and aging employees. PMID- 27779153 TI - Cytohistological correlation in pituitary tumor and immunological assessment with the help of Ki-67. AB - BACKGROUND: Tumors of the pituitary gland and sellar region represent approximately 10-15% of all brain tumors. Pituitary adenoma (PA), the most common pathology of the pituitary gland, can be effectively subclassified only with the help of immunohistochemistry (IHC). This is important and needed for individual patient management. AIMS AND OBJECTIVES: The objective of the study was to analyze the importance of intraoperative imprint smear cytology and correlating with final histopathological diagnosis. Furthermore, to classify the different types of PA with the help of IHC, prolactin (PRL), adrenocorticotropic hormone (ACTH), and growth hormone (GH) and to predict the benign, atypical, or malignant nature of the tumor with the help of prognostic marker Ki-67. MATERIALS AND METHODS: A prospective study was done in 34 cases. The patients whose pituitary gland samples are referred from the endocrine and the neurosurgery department to the pathology department for histopathological examinations were selected. We have studied the clinical features, radiology and touch imprint cytology, histopathology, and IHC with the help of PRL, ACTH, GH, and Ki-67 of PA over 2 years. RESULTS: In our study, we had 32 cases of PA of 34 cases over a span of 2 years. We have seen that there is a correlation between cytological and histological diagnosis of the subtypes of PA in 62% cases, and the Kappa statistics show a moderate extent of agreement (Kappa - 0.320, 95% confidence interval = 0.031-0.609). Ki-67 when compared to the radiological grading showed a high degree of comparability (Chi-square test: P < 0.001). All cases with invasion had a higher Ki-67. On using the Fisher's exact test, we found that the Ki-67 expression with GH-producing adenomas and ACTH-producing adenomas was comparable (P = 1.000) while in PRL-producing adenomas too this was not significant (P = 0.269). CONCLUSION: PA can be effectively classified with the help of IHC. Intraoperative cytology is important in diagnosing PA, but histopathology remains the gold standard in diagnosing and differentiating PA from other pathologies of the pituitary gland. The radiological grading together with immunological classification and the prognostic markers of Ki-67 is important in deciding the benign or atypical nature of the adenomas thus helping in better patient management. PMID- 27779154 TI - Salmonella pyomyositis with concurrent sacroiliac osteomyelitis presenting as piriformis syndrome: A rare case. AB - A-21-year old male admitted with fever and piriformis syndrome, typically associated with gluteal region pain radiating down the thigh, was evaluated and found to have pyomyositis involving piriformis and osteomyelitis with sacroiliac joint affection on radiological imaging. Salmonella serotype typhi was isolated from blood culture. He was treated with intravenous Ceftriaxone for 6 weeks with signs of recovery documented clinically as well as on imaging studies. Salmonella pyomyositis with osteomyelitis in an immunocompetent patient with no previous hematological or endocrine disorder makes this case an unusual presentation. PMID- 27779155 TI - Minimally Invasive Reduction and Fixation in Orthopedic Trauma. PMID- 27779156 TI - Preoperative Measurement of Tibial Resection in Total Knee Arthroplasty Improves Accuracy of Postoperative Limb Alignment Restoration. AB - BACKGROUND: Accuracy of implant placement in total knee arthroplasty (TKA) is crucial. Traditional extramedullary alignment instruments are fairly effective for achieving the desired mean tibial component coronal alignment. We modified the traditional tibial plateau resection technique and evaluated its effect on alignment restoration. METHODS: Two hundred and eighty-two primary TKAs in our hospital between January 2013 and December 2014 were enrolled in this retrospective study. Group A consisted of 128 primary TKAs performed by one senior surgeon. Preoperative measurement of the tibial resection was conducted on radiographs, and the measured thicknesses of the lateral and medial plateau resection were used to place the tibial alignment guide. Group B consisted of 154 primary TKAs performed by the other senior surgeon, using a traditional tibial plateau resection technique. In all patients, an extramedullary guide was used for tibial resection, and preoperative and postoperative full-leg standing radiographs were used to assess the hip-knee-ankle angle (HKA), femoral component alignment angle (FA), and tibial component alignment angle (TA). A deviation >=3 degrees was considered unsatisfactory. Data were analyzed by unpaired Student's t-test. RESULTS: The mean postoperative HKA and TA angles were significantly different between Groups A and B (178.2 +/- 3.2 degrees vs. 177.0 +/- 3.0 degrees , t = 2.54, P = 0.01; 89.3 +/- 1.8 degrees vs. 88.3 +/- 2.0 degrees , t = 3.75, P = 0.00, respectively). The mean postoperative FA was 88.9 +/- 2.5 degrees in Group A and 88.9 +/- 2.6 degrees in Group B, and no significant difference was detected (t = 0.10, P = 0.92). There were 90 (70.3%) limbs with restoration of the mechanical axis to within 3 degrees of neutral alignment and 38 (29.7%) outliers (>3 degrees deviation) in Group A, whereas there were 89 (57.8%) limbs with restoration of the mechanical axis to within 3 degrees of neutral alignment and 65 (42.2%) outliers (>3 degrees deviation) in Group B. The severity of the preoperative alignment deformity was a strong predictor for postoperative alignment. CONCLUSIONS: Using conventional surgical instruments, preoperative measurement of resection thickness of the tibial plateau on radiographs could improve the accuracy of conventional surgical techniques. PMID- 27779157 TI - Delayed High-dose Methotrexate Excretion and Influencing Factors in Osteosarcoma Patients. AB - BACKGROUND: High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is "gold standard" therapy for osteosarcoma. Plasma concentrations of methotrexate (MTX) are closely related to its efficacy and toxicity. Delayed excretion of MTX can lead to serious adverse reactions that may result in treatment cessation, irreversible organ damage, and death. This study focused on the incidence of delayed excretion of MTX in Chinese osteosarcoma patients. METHODS: A total of 1277 osteosarcoma patients were treated with HD-MTX chemotherapy (4291 cycles) from 2010 to 2015. Factors that could influence delayed excretion of MTX (gender, age, number of chemotherapy cycles, and serum concentration of MTX) were analyzed. RESULTS: The incidence of delayed excretion of MTX (serum concentrations at 24 h [C24 h] >5 MUmol/L) and severe delayed excretion of MTX (C24 h >20 MUmol/L) were 6.19% and 0.86% per patient, and 2.31% and 0.26% per cycle of treatment, respectively. The incidence of severe delayed excretion of MTX was associated with gender, age, and C24 h. CONCLUSIONS: Precaution of delayed excretion of MTX is needed during osteosarcoma treatment using HD-MTX. An optimal individualized rescue strategy can be created with consideration of gender, age, and C24 h. PMID- 27779158 TI - Effect of Femoral Resection on Coronal Overall Alignment after Conventional Total Knee Arthroplasty. AB - BACKGROUND: A good postoperative alignment in total knee arthroplasty (TKA) is the key to achieving satisfactory results. We assessed the effect of femoral and tibial resection on the overall alignment after conventional TKA. METHODS: We conducted a retrospective analysis of 212 primary TKAs in 188 patients. Intramedullary (IM)-guided resection was applied on the femoral side while extramedullary (EM)-guided resection was used on the tibial side. Using full length X-ray, the preoperative femoral valgus angle and lower extremity alignment, as well as 2-week postoperative femoral and tibial prosthetic coronal alignment and overall lower extremity alignment, were measured. RESULTS: Postoperatively, good prosthetic alignment was achieved in 191 cases (90.1%) on the tibial side and in 144 cases (67.9%) on the femoral side (chi2 = 5.441, P = 0.02). Multiple linear regression analysis was used to assess the effect of different alignment sides on the overall alignment in the coronal plane. Data were divided into five subgroups based on the valgus or varus status of the prostheses. The standardized regression coefficients of the femoral and tibial prosthetic alignment on the overall alignment were 0.666 and 0.414, respectively; in varus on both sides were 0.658 and 0.377, respectively; in valgus, 0.555 and 0.030; femoral side varus and tibial side valgus, 0.702 and 0.211; femoral side valgus and tibial side varus, -0.416 and 0.287. The study showed that the overall low extremity alignment was statistically influenced by the prosthetic alignment, except for the tibial prosthetic alignment when femoral prosthesis was in valgus (P = 0.153). CONCLUSIONS: In conventional TKA, tibial side EM-guided resection may offer satisfactory postoperative alignment, and femoral resection relying on IM guide may lead to more undesirable results. Postoperative coronal alignment is mainly affected by the femoral resection. Therefore, femoral side operation should receive adequate attention from the surgeons. PMID- 27779159 TI - Narrow Intercondylar Notch and Anterior Cruciate Ligament Injury in Female Nonathletes with Knee Osteoarthritis Aged 41-65 Years in Plateau Region. AB - BACKGROUND: Few data are available concerning intercondylar notch dimensions in female nonathletes with knee osteoarthritis (OA) in plateau region. The aim of this study was to assess the relation of intercondylar notch morphology to anterior cruciate ligament (ACL) injuries in female nonathletes with knee OA aged 41-65 years from the Chinese Loess Plateau. METHODS: The study was conducted on 330 patients with ACL injury (aged 31-65 years; 159 males, 171 females), 141 patients with OA (aged 31-65 years; 59 males, 82 females), and 89 female healthy controls (aged 41-65 years), and this evaluation included identifying the distribution of patients with OA or ACL injury and measuring the intercondylar notch width indexes (NWIs). RESULTS: There was a significant rising trend in patients with OA (the Kellgren and Lawrence grade = 3) with ACL injury (OA-S + ACL) aged 41-65 years, especially in females. We found that the notches of OA-S + ACL had a smaller NWI compared with control and OA without ACL injury (OA-S-only, P = 0.000, 95% confidence interval [CI] = -0.059--0.030; P = 0.000, 95% CI = 0.049--0.016). A similar trend was found in notch shape index (NSI), but not in notch depth index and the cross-sectional area. The cutoff of NWI and NSI value was 0.26, and 0.65, and area under the receiver operating characteristic curve was 0.82, and 0.79, respectively. Further study displayed a significant correlation between a reduced NWI and NSI and OA-S + ACL (P = 0.000, chi2 = 14.012; P = 0.000, chi2 = 14.286). CONCLUSION: A narrower intercondylar notch and a plateau environment are risk factors of predisposing female nonathletes with knee OA to ACL injury aged 41-65 years. PMID- 27779160 TI - Relationship between Inflammatory Response and Estimated Complication Rate after Total Hip Arthroplasty. AB - BACKGROUND: After total hip arthroplasty (THA), there is a noteworthy inflammatory response. The inflammatory response is associated with postoperative recovery and complications. However, there had been few reports on the relationship between inflammatory response and postoperative complication rate. The aim of the present study was to investigate early inflammatory response in the first 3 days after THA, and to identify the relationship between inflammatory response and estimated complication rate after surgery. METHODS: It was a prospective, nonrandomized cohort study. There were 148 patients who underwent unilateral THA in our hospital enrolled. Blood samples were collected preoperatively in the morning of the surgery and at 24, 48, and 72 h after surgery. C-reactive protein (CRP) and interleukin-6 (IL-6) in peripheral blood were measured. The modified physiological and operative severity score for the enumeration of the morbidity (POSSUM) was recorded pre- and intra-operatively. Based on the score, estimated complication rate was calculated. Harris score was used to assess hip function before and after surgery. RESULTS: IL-6 levels reached the peak at 24 h after surgery and CRP at 48 h. After that, both of the levels decreased. The mean Harris scores significantly increased from 41.62 +/- 23.47 before surgery to 72.75 +/- 9.13 at 3 days after surgery. The Harris scores after surgery did not have a significant relation with either IL-6 or CRP peak levels (P = 0.165, P = 0.341, respectively). Both CRP and IL-6 peak levels significantly and positively correlated with estimated complication rate after surgery. The estimated complication rate calculated using the POSSUM system was 43 cases of 148 patients. Actually, there were only 28 cases that were observed to get postoperative complications during hospitalization. However, there was no significant difference between estimated and observed complication rates (P = 0.078). In the group with complications, the CRP and IL-6 peak levels were significantly higher than those in the group without complications (both P< 0.001). CONCLUSIONS: There were significantly positive relationships between both peak levels of CRP and IL-6 and estimated complication rate after THA. Inflammatory response could predict the incidence of complications after THA. PMID- 27779161 TI - Three-dimensional Fluoroscopy-based Navigation for the Pedicle Screw Placement in Patients with Primary Invasive Spinal Tumors. AB - BACKGROUND: Although pedicle screw placement (PSP) is a well-established technique for spine surgery, the treatment of patients with primary invasive spinal tumor (PIST) has high surgical risks secondary to destroyed pedicles. Intraoperative three-dimensional fluoroscopy-based navigation (ITFN) system permits safe and accurate instrumentation of the spine with the advantage of obtaining intraoperative real-time three-dimensional images and automatic registration. The aim of this study is to evaluate the feasibility and accuracy of PSP using ITFN system for patients afflicted with PIST in the thoracic spine. METHODS: Fifty-one patients diagnosed with PISTs were retrospectively analyzed, and 157 pedicles screws were implanted in 23 patients using the free-hand technique (free-hand group) and 197 pedicle screws were implanted in 28 patients using the ITFN system (ITFN group). Modified classification of Gertzbein and Robbins was used to evaluate the accuracy of PSP, and McCormick classification was applied for assessment of neurological function. Demographic data and factors affecting accuracy of screw insertion were compared using independent t-test while comparison of accuracy of screw insertion between the two groups was analyzed with Chi-square test. RESULTS: Of 51 patients, 39 demonstrated improved neurological status and the other 12 patients reported that symptoms remained the same. In the free-hand group, 145 screws (92.4%) were Grade I, 9 screws (5.7%) were Grade II, and 3 screws (1.9%) were Grade III. In the ITFN group, 192 screws (97.4%) were Grade I, 5 screws (2.6%) were Grade II, and no Grade III screw was detected. Statistical analysis showed that the accuracies of pedicle screws in the two groups are significantly different (chi2 = 4.981, P = 0.026). CONCLUSIONS: The treatments of PISTs include total tumor resection and reconstruction of spine stability. The ITFN system provides a high accuracy of pedicle screw placement. PMID- 27779162 TI - Local Administration of Bisphosphonate-soaked Hydroxyapatite for the Treatment of Osteonecrosis of the Femoral Head in Rabbit. AB - BACKGROUND: Systemic administration of bisphosphonates has shown promising results in the treatment of osteonecrosis of the femoral head (ONFH). However, few studies have evaluated the efficacy of local zoledronate (ZOL) administration in the treatment of ONFH. The purpose of this study was to investigate whether local administration of bisphosphonate-soaked hydroxyapatite (HA) could improve bone healing in an experimental rabbit model of ONFH. METHODS: This experimental study was conducted between October 2014 and June 2015. Forty-five rabbits underwent simulated ONFH surgery. Immediately following surgery, they were divided into three groups: model (untreated, n = 15), HA (treated with HA alone, n = 15), and HA + ZOL (treated with HA soaked in a low-dose ZOL solution, n = 15). Histological, immunohistochemical, and quantitative analyses were performed to evaluate bone formation and resorption 2, 4, and 8 weeks after surgery. RESULTS: Gross bone matrix and hematopoietic tissue formation were observed in the HA + ZOL group 4 weeks after surgery. The immunohistochemical staining intensities for 5-bromodeoxyuridine, runt-related transcription factor 2, osteocalcin, osteopontin, and osteoprotegerin were significantly higher in the HA + ZOL group than that in the model (P < 0.001, P< 0.001, P< 0.001, P< 0.001, and P = 0.018, respectively) and HA groups (P = 0.003, P = 0.049, P< 0.001, P = 0.020, and P = 0.019, respectively), whereas receptor activator of the nuclear factor-kappaB ligand staining intensity was significantly lower in the HA + ZOL group than that in the model and HA groups (P = 0.029 and P = 0.015, respectively) 4 weeks after surgery. No significant differences in bone formation or bone resorption marker expression were found between the three groups 2 or 8 weeks after surgery (P > 0.05). CONCLUSIONS: Local administration of HA soaked in a low-dose ZOL solution increased new bone formation while inhibiting bone resorption in an animal model of ONFH, which might provide new evidence for joint preserving surgery in the treatment of ONFH. PMID- 27779164 TI - Three-dimensional Printed Scaffolds with Gelatin and Platelets Enhance In vitro Preosteoblast Growth Behavior and the Sustained-release Effect of Growth Factors. AB - BACKGROUND: Three-dimensional (3D) printing technology holds great promise for treating diseases or injuries that affect human bones with enhanced performance over traditional techniques. Different patterns of design can lead to various mechanical properties and biocompatibility to various degrees. However, there is still a long way to go before we can fully take advantage of 3D printing technologies. METHODS: This study tailored 3D printed scaffolds with gelatin and platelets to maximize bone regeneration. The scaffolds were designed with special internal porous structures that can allow bone tissue and large molecules to infiltrate better into the scaffolds. They were then treated with gelatin and platelets via thermo-crosslinking and freeze-drying, respectively. Vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 were measured at different time points after the scaffolds had been made. Cell proliferation and cytotoxicity were determined via cell counting kit-8 (CCK-8) assay. RESULTS: There was a massive boost in the level of VEGF and TGF-beta1 released by the scaffolds with gelatin and platelets compared to that of scaffolds with only gelatin. After 21 days of culture, the CCK-8 cell counts of the control group and treated group were significantly higher than that of the blank group (P < 0.05). The cytotoxicity test also indicated the safety of the scaffolds. CONCLUSIONS: Our experiments confirmed that the 3D printed scaffolds we had designed could provide a sustained-release effect for growth factors and improve the proliferation of preosteoblasts with little cytotoxicity in vitro. They may hold promise as bone graft substitute materials in the future. PMID- 27779163 TI - Effects of Roughly Focused Extracorporeal Shock Waves Therapy on the Expressions of Bone Morphogenetic Protein-2 and Osteoprotegerin in Osteoporotic Fracture in Rats. AB - BACKGROUND: Roughly focused extracorporeal shock waves therapy (ESWT) is characterized by a wide focal area, a large therapy zone, easy positioning, and less pain during treatment. The purpose of this study was to investigate the effects of roughly focused ESWT on the expression of osteoprotegerin (OPG) and bone morphogenetic protein-2 (BMP-2) in osteoporotic fractures in rats. METHODS: Seventy-two female Sprague-Dawley (SD) rats, 3 months old, were divided into sham operated group (n = 6) and an ovariectomized (OVX) group (n = 66). Sixty OVX SD rats were used as a model of double proximal tibial osteotomy and inner fixation. The osteotomy site in the left tibia was treated with roughly focused ESWT once at an energy density of 0.26 mJ/mm2, 60 doses/min, and 2000 pact quantities. The contralateral right tibia was left untreated and served as a control. Expression of OPG and BMP-2 in the callus of the osteoporotic fracture area was assessed using immunohistochemistry, real-time polymerase chain reaction (PCR), and Western blotting analysis. RESULTS: Bone mineral density (BMD) at the proximal tibia, femur, and L5 spine was significantly reduced after ovariectomy. BMD of proximal tibia was 12.9% less in the OVX group than that in the sham-operated group. Meanwhile, bilateral oophorectomy resulted in a lower trabecular bone volume fraction (BV/TV) in the proximal tibia of the sham-OVX animals. Three months after bilateral oophorectomy, BV/TV was 14.29% of baseline BV/TV in OVX legs versus 45.91% in the sham-OVX legs (P < 0.001). These data showed that the SD rats became a suitable model of osteoporosis, 3 months after they were OVX. Immunohistochemical analysis showed higher levels of BMP-2 and OPG expression in the treatment group than those in the control group. Compared with the contralateral controls, decreased expression of OPG and BMP-2 at 3 days after roughly focused ESWT, followed by a later increase at 7 days, was indicated by real-time PCR and Western blotting analysis. The OPG messenger RNA (mRNA) expression levels peaked at 6 weeks after the shock wave treatment, paired with a much earlier (at 4 weeks) increase of BMP-2, and declined close to normal at 8 weeks. CONCLUSIONS: Roughly focused ESWT may promote the expression of OPG and BMP-2 in the osteoporotic fracture area in rats. BMP-2 and OPG may act synergistically and may lead to a significant enhancement of bone formation and remodeling. PMID- 27779165 TI - Independent Prognostic Value of High-sensitivity C-reactive Protein in Patients with Coronary Artery Ectasia. AB - BACKGROUND: Despite its severity, coronary artery ectasia (CAE) is still poorly understood. High-sensitivity C-reactive protein (hs-CRP) has been recognized as a prognostic factor in some cardiovascular diseases but not assessed in CAE. The aim of this observational study was to investigate the prognostic value of hs-CRP in CAE. METHODS: Our analysis evaluated the effect of the baseline hs-CRP on cardiovascular events (CVs) (cardiac death and nonfetal myocardial infarction) in consecutively enrolled stable CAE patients. We used the Cox proportional hazards regression models to examine the association between baseline hs-CRP level and follow-up CVs in CAE. The net reclassification improvement and integrated discrimination improvement (IDI) of hs-CRP were also assessed. RESULTS: We obtained the follow-up results of 540 patients over a median follow-up period of 36 (37.41 +/- 15.88) months. The multivariable Cox analysis showed that the hs CRP was a significant predictor of adverse outcomes in CAE (hazard ratio [HR]: 2.99, 95% confidence interval [CI]: 1.31-6.81, P = 0.0091). In Kaplan-Meier analysis, the group with hs-CRP >3 mg/L had a lower cumulative 66-month event free survival rate (log-rank test for trend, P = 0.0235) and a higher risk of CVs (HR = 2.66, 95% CI: 1.22-5.77, P = 0.0140) than the group with hs-CRP <=3 mg/L. Hs-CRP added predictive information beyond that given by the baseline model comprising the classical risk factors (P value for IDI = 0.0330). CONCLUSIONS: A higher level of hs-CRP was independently associated with cardiac death and nonfatal myocardial infarction in CAE patients. The hs-CRP level may therefore provide prognostic information for the risk stratification of CAE patients. PMID- 27779166 TI - Association of Plasma Pentraxin-3 Levels on Admission with In-hospital Mortality in Patients with Acute Type A Aortic Dissection. AB - BACKGROUND: Acute aortic dissection is a life-threatening cardiovascular emergency. Pentraxin-3 (PTX3) is proposed as a prognostic marker and found to be related to worse clinical outcomes in various cardiovascular diseases. This study sought to investigate the association of circulating PTX3 levels with in-hospital mortality in patients with acute Type A aortic dissection (TAAD). METHODS: A total of 98 patients with TAAD between January 2012 and December 2015 were enrolled in this study. Plasma concentrations of PTX3 were measured upon admission using a high-sensitivity enzyme-linked immunosorbent assay system. Patients were divided into two groups as patients died during hospitalization (Group 1) and those who survived (Group 2). The clinical, laboratory variables, and imaging findings were analyzed between the two groups, and predictors for in hospital mortality were evaluated using multivariate analysis. RESULTS: During the hospital stay, 32 (33%) patients died and 66 (67%) survived. The patients who died during hospitalization had significantly higher PTX3 levels on admission compared to those who survived. Pearson's correlation analysis demonstrated that PTX3 correlated positively with high-sensitivity C-reactive protein (hsCRP), maximum white blood cell count, and aortic diameter. Multivariate logistic regression analysis demonstrated that PTX3 levels, coronary involvement, cardiac tamponade, and a conservative treatment strategy are significant independent predictors of in-hospital mortality in patients with TAAD. The receiver operating characteristic curve analysis further illustrated that PTX3 levels on admission were strong predictors of mortality with an area under the curve of 0.89. A PTX3 level >=5.46 ng/ml showed a sensitivity of 88% and a specificity of 79%, and an hsCRP concentration >=9.5 mg/L had a sensitivity of 80% and a specificity of 69% for predicting in-hospital mortality. CONCLUSION: High PTX3 levels on admission are independently associated with the in-hospital mortality in patients with TAAD. PMID- 27779167 TI - A Missense Mutation in Epsilon-subunit of Acetylcholine Receptor Causing Autosomal Dominant Slow-channel Congenital Myasthenic Syndrome in a Chinese Family. AB - BACKGROUND: Congenital myasthenic syndromes are a group of rare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction. Here, we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome (SCCMS). METHODS: Clinical characteristics and electrophysiological features of three patients from a Chinese family were examined, and next-generation sequencing followed by direct sequencing was carried out. RESULTS: The patients revealed variability in clinical and electrophysiological features. However, weakness, scoliosis, and repetitive compound muscle action potential were found in all affected members in the family. A heterozygous C>T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit (CHRNE) gene that causes a leucine-to-phenylalanine substitution at position 289 (L289F) was found. CONCLUSIONS: We reported a SCCMS family of Chinese origin. In the family, classical clinical phenotype with phenotypic variability among different members was found. Genetic testing could help diagnose this rare disease. PMID- 27779168 TI - Porcine Small Intestinal Submucosa Mesh for Treatment of Pelvic Organ Prolapsed. AB - BACKGROUND: Pelvic organ prolapse (POP) is a major health concern that affects women. Surgeons have increasingly used prosthetic meshes to correct POP. However, the most common used is synthetic mesh, and absorbable mesh is less reported. This research aimed to evaluate the clinical effectiveness of porcine small intestinal submucosa (SIS). METHODS: Consecutive forty POP patients who met the inclusion criteria underwent pelvic reconstruction surgery with SIS between March 2012 and December 2013. The patients' clinical characteristics were recorded preoperatively. Surgical outcomes, measured by objective and subjective success rates, were investigated. We evaluated the quality of life (QOL) using the Pelvic Floor Distress Inventory-20 (PFDI-20) and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7). Sexual QOL was assessed by the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-12 (PISQ-12). RESULTS: At postoperative 12 months, the subjective recurrence rate (7.5%) was much lower than the objective recurrence rate (40.0%). Postoperatively, no erosion was identified. One underwent a graft release procedure because of urinary retention, and one had anus sphincter reconstruction surgery due to defecation urgency. Another experienced posterior vaginal wall infection where the mesh was implanted, accompanied by severe vaginal pain. Estrogen cream relieved the pain. One patient with recurrence underwent a secondary surgery with Bard Mesh because of stage 3 anterior vaginal wall prolapse. Scoring system of PFDI-20 was from 59.150 +/- 13.143 preoperatively to 8.400 +/- 4.749 postoperatively and PFIQ-7 was from 73.350 +/- 32.281 to 7.150 +/- 3.110, while PISQ-12 was from 15.825 +/- 4.050 to 12.725 +/- 3.471. CONCLUSIONS: QOL and the degree of subjective satisfaction were significantly improved postoperatively. Anterior repair deserves more attention because of the higher recurrence rate. The long-term follow-up of the patient is warranted to draw firm conclusion. PMID- 27779169 TI - Comparison of the 1-year Outcomes of Conbercept Therapy between Two Different Angiographic Subtypes of Polypoidal Choroidal Vasculopathy. AB - BACKGROUND: Polypoidal choroidal vasculopathy (PCV) is characterized by the presence of polyps with or without a branching vascular network and more prevalent among Asians. The aim of this study was to compare the outcomes of conbercept therapy between two different angiographic subtypes of PCV. METHODS: Fifty-eight patients of PCV were classified into two phenotypes according to indocyanine green angiography (ICGA). In Type 1, both feeder and draining vessels are visible on ICGA and network vessels are numerous. In Type 2, neither feeder nor draining vessels are detectable, and the number of network vessels is small. The patients were treated with intravitreal conbercept (IVC) for 3 months. Additional IVC was given at subsequent monthly visits, if needed. The patients were followed up for 12 months, and changes in mean best-corrected visual acuity (BCVA), central retinal thickness (CRT), subretinal fluid (SRF) thickness, pigmented epithelial detachment (PED), hemorrhage, and number of polypoidal lesions were evaluated. RESULTS: The mean BCVA in Type 2 PCV (15.92 +/- 9.76 letters) achieved a significantly greater improvement than that in the Type 1 (14.10 +/- 9.07 letters) at month 12 (t = 2.37, P< 0.01). Moreover, the mean CRT decrease was numerically greater in Type 2 (120.44 +/- 73.81 MUm) compared with Type 1 (106.48 +/- 72.33 MUm) at month 6 (t = 4.31, P< 0.01), and greater in Type 2 (130.21 +/- 76.28 MUm) compared with Type 1 (111.67 +/- 79.57 MUm) at month 9 (t = 1.87, P< 0.01). There was no significant difference between the two types for the decrease in SRF thickness, PED height, and regression of polyps from month 3 to 12 (t = 2.97, P > 0.05). CONCLUSION: Classification systems for PCV will show differences in presentation, natural history, or response to anti vascular endothelial growth factor treatment and might, therefore, provide a new key to the choice of treatment for the disease. PMID- 27779170 TI - In vivo Confocal Microscopy Evaluation of Meibomian Gland Dysfunction in Dry Eye Patients with Different Symptoms. AB - BACKGROUND: Dry eye patients suffer from all kinds of symptoms. Sometimes, the clinical signs evaluation does not disclose any obvious difference in routine examination; in vivo confocal microscopy (IVCM) is a powerful tool for ocular surface disease. This study aimed to clarify meibomian gland (MG) alterations in dry eye patients with different symptoms and to compare the findings using IVCM. METHODS: A total of sixty patients were recruited, all subjected to Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ), and questionnaires for the assessment of dry eye symptoms before clinical sign examinations were given to the patients. Finally, IVCM was applied to observe MG's structure. Statistical analysis was performed using the t-test, Mann-Whitney U-test and Spearman correlation analysis. The differences were statistically significant when P< 0.05. RESULTS: In the severe symptom group, OSDI and SEEQ scores were significantly higher (P< 0.05) compared with the mild symptoms group. All other clinical sign examinations had no statistical difference in the two groups (P> 0.05). However, all the IVCM-observed data showed that patients with severe symptoms had more significant fibrosis in MG (acinar unit area 691.87 +/- 182.01 MUm2 for the severe, 992.17 +/- 170.84 MUm2 for the mild; P< 0.05) and severer decrease in the size of MG acinar units than those observed in patients with mild symptoms (MG acinar unit density [MGAUD] 70.08 +/- 18.78 glands/mm2, MG acinar unit longest diameter [MGALD] 51.50 +/- 15.51 MUm, MG acinar unit shortest diameter [MGASD] 20.30 +/- 11.85 MUm for the severe, MGAUD 89.53 +/- 39.88 glands/mm2, MGALD 81.57 +/- 21.14 MUm, MGASD 42.37 +/- 14.55 MUm for the mild;P< 0.05). Dry eye symptoms were negatively correlated with MG confocal microscopic parameters and positively correlated with conjunctival inflammatory cells and Langerhans cells (P< 0.05). CONCLUSIONS: IVCM application provides a strong support to differentiate dry eye patients with different symptoms: meibomian gland dysfunction (MGD) plays a pivotal role in dry eye aggravation, and using IVCM to observe MG fibrosis, changes in size and density of MG as well as status of inflammation cells can help not only correctly diagnose the type and severity of dry eye, but also possibly prognosticate in routine eye examination in the occurrence of MGD. PMID- 27779171 TI - Knockdown of Decoy Receptor 3 Impairs Growth and Invasiveness of Hepatocellular Carcinoma Cell Line of HepG2. AB - BACKGROUND: Decoy receptor 3 (DcR3) binds to Fas ligand (FasL) and inhibits FasL induced apoptosis. The receptor is overexpressed in hepatocellular carcinoma (HCC), and it is associated with the growth and metastatic spread of tumors. DcR3 holds promises as a new target for the treatment of HCC, but little is known regarding the molecular mechanisms underlying the oncogenic properties of DcR3. The present work, therefore, examined the role of DcR3 in regulating the growth and invasive property of liver cancer cell HepG2. METHODS: HepG2 cells were stably transfected with lentivirus-based short hairpin RNA vector targeting DcR3. After the knockdown of DcR3 was confirmed, cell proliferation, clone formation, ability of migrating across transwell membrane, and wound healing were assessed in vitro. Matrix metalloproteinase-9 (MMP 9) and vascular epithelial growth factor (VEGF)-C and D expressions of the DcR3 knockdown were also studied. Comparisons between multiple groups were done using one-way analysis of variance (ANOVA), while pairwise comparisons were performed using Student's t test. P< 0.05 was regarded statistically significant. RESULTS: DcR3 was overexpressed in HepG2 compared to other HCC cell lines and normal hepatocyte Lo-2. Stable knockdown of DcR3 slowed down the growth of HepG2 (P < 0.05) and reduced the number of clones formed by 50% compared to those without DcR3 knockdown (P < 0.05). The knockdown also reduced the migration of HepG2 across transwell matrix membrane by five folds compared to the control (P < 0.05) and suppressed the closure of scratch wound (P < 0.05). In addition, the messenger RNA levels of MMP 9, VEGF-C, and VEGF-D were significantly suppressed by DcR3 knockdown by 90% when compared with the mock control (P < 0.05). CONCLUSIONS: Loss of DcR3 impaired the growth and invasive property of HCC cell line of HepG2. Targeting DcR3 may be a potential therapeutic approach for the treatment of HCC. PMID- 27779173 TI - Osteotomy Techniques for Spinal Deformity. PMID- 27779172 TI - Arthroplasty versus Internal Fixation for Displaced Intracapsular Femoral Neck Fracture in the Elderly: Systematic Review and Meta-analysis of Short- and Long term Effectiveness. AB - BACKGROUND: There is conflicting evidence as to whether the femoral head should be preserved or replaced in elderly patients with displaced intracapsular femoral neck fractures. In this article, we performed a systematic review and meta analysis to compare the short- and long-term effectiveness of arthroplasty (AR) and internal fixation (IF). METHODS: PubMed, Embase, and the Cochrane Library were searched systematically up to January 2016. All randomized controlled trials directly comparing the effectiveness of AR and IF for displaced intracapsular fracture were retrieved with no limitation on language or publication year. RESULTS: In total, eight prospective randomized studies involving 2206 patients were included. The results of our study showed that patients in the AR group reported significantly lower complication (risk ratio: 0.56, 95% confidence interval [CI] = 0.38-0.80), re-operation (risk ratio: 0.17, 95% CI = 0.13-0.22), revision rates (risk ratio: 0.11, 95% CI: 0.08-0.16), and better function compared with their IF counterparts, and they were less likely to suffer postoperative pain. No statistically significant differences for the rates of mortality, infection, and/or deep vein thrombosis between AR and IF were found. CONCLUSIONS: Based on our analysis, we recommend that AR should be used as the primary treatment for displaced intracapsular femoral neck fractures in the elderly. However, IF may be appropriate for those who are very frail. PMID- 27779174 TI - Angiosarcoma around Hip Joint Prosthesis. PMID- 27779175 TI - Three-dimensional Printed Patient-specific Drilling Templates for Expansive Open door Laminoplasty. PMID- 27779176 TI - Corrigendum: Multiple Functions of Ten-eleven Translocation 1 during Tumorigenesis. AB - [This corrects the article DOI: 10.4103/0366-6999.185873.]. PMID- 27779177 TI - Long-Term Alcohol-Induced Activation of Mammalian Target of Rapamycin is a Key Risk Factor of Epilepsy. AB - BACKGROUND The aim of this study was to determine whether activation of mammalian target of rapamycin (mTOR) is a key epileptogenic mechanism in the development of alcohol-related seizure. MATERIAL AND METHODS C57BL/6 mice were administered 10% ethanol in drinking water for 9 weeks. Video-electroencephalography (EEG) monitoring was then used to assess seizure frequency after alcohol and rapamycin treatment. In addition, mouse neuroblastoma NG108-15 cells were treated ethanol for 3 days and subsequently treated with AKT inhibitor LY294002 for 2-12 h. The in vitro kinase assay was performed for determining mTOR activity. Western blot analysis was used to determine the expression of P-AKT, P-S6K, and P-S6. RESULTS Long-term ethanol treatment markedly increased the seizure frequency of C57/BL6 mice over time. Moreover, ethanol treatment increased the expression level of P S6 over time. Ethanol-induced seizure can be reversed by rapamycin. In addition, the in vitro kinase assay showed mTOR activity was activated by ethanol. Compared with NG108-15 cells treated without both ethanol and LY294002, ethanol increased the expression level of P-AKT, P-S6K, and P-S6, whereas LY294002 had opposite effects on expression levels of these proteins. CONCLUSIONS Our findings indicate that long-term alcohol intake increases the risk of epilepsy via activation of mTOR signaling. Moreover, ethanol-induced mTOR activation may be dependent on the AKT-mTOR signaling pathway. The key molecules involved in AKT-mTOR signaling pathway may serve as potential targets in the treatment of epilepsy. PMID- 27779178 TI - [Aggressions towards Primary Health Care Workers in Madrid, Spain, 2011-2012]. AB - OBJECTIVE: The number of aggressions towards health care professionals has risen over the past few years. There are no previous studies in primary care covering an entire region and to all professional categories. The aim of this study was to characterize aggressions in Primary Care in the Community of Madrid. METHODS: Multicenter cross-sectional study. Analysis of a Registration System that reports any type of aggression suffered by Primary Care workers, in the Community of Madrid. The study variables included sociodemographic characteristics of the aggressor and the victim, the type of aggression (verbal or physical abuse), its causes and consequences. We described median, intercuartilic range and frequencies. Logistic regression was performed calculating odds ratio and their 95% confidence intervals. RESULTS: 1,157 assaults were reported, 53.07% suffered by doctors. Physical assault occurred in 4.7% of the cases. The main reason was dissatisfaction with the care (36.1%). The non-medical staff showed less risk of being physically assaulted (OR: 0.38; CI95%: 0.17-0.86). The perpetrator profile was male (56.8%), aged between 31-40 (26.8%) years. Health care victim profile was female (84%), aged between 45-60 years. 10% of professionals reported some form of aggression, 5,9% of aggression were submitted to court. CONCLUSIONS: The risk of assault is higher in health personnel, particularly physicians. There were significant differences by gender and age, both in the profile of the aggressor and the victim. PMID- 27779179 TI - Spatial and temporal movements in Pyrenean bearded vultures (Gypaetus barbatus): Integrating movement ecology into conservation practice. AB - Understanding the movement of threatened species is important if we are to optimize management and conservation actions. Here, we describe the age and sex specific spatial and temporal ranging patterns of 19 bearded vultures Gypaetus barbatus tracked with GPS technology. Our findings suggest that spatial asymmetries are a consequence of breeding status and age-classes. Territorial individuals exploited home ranges of about 50 km2, while non-territorial birds used areas of around 10 000 km2 (with no seasonal differences). Mean daily movements differed between territorial (23.8 km) and non-territorial birds (46.1 km), and differences were also found between sexes in non-territorial birds. Daily maximum distances travelled per day also differed between territorial (8.2 km) and non-territorial individuals (26.5 km). Territorial females moved greater distances (12 km) than males (6.6 km). Taking into account high-use core areas (K20), Supplementary Feeding Sites (SFS) do not seem to play an important role in the use of space by bearded vultures. For non-territorial and territorial individuals, 54% and 46% of their home ranges (K90), respectively, were outside protected areas. Our findings will help develop guidelines for establishing priority areas based on spatial use, and also optimize management and conservation actions for this threatened species. PMID- 27779180 TI - Elevated granzyme B+ B-cell level in SIV-infection correlate with viral load and low CD4 T-cell count. AB - Granzyme B-expressing (GrB+) B cells are thought to contribute to immune dysfunctions in HIV patients, but so far their exact role is unknown. This report demonstrates for the first time the existence of GrB+ B cells in SIV-infected rhesus macaques, which represent the most commonly used nonhuman primate model for HIV research. Similar to HIV patients, we found significantly higher frequencies of these cells in the blood of chronically SIV-infected rhesus monkeys compared with uninfected healthy ones. These frequencies correlated with plasma viral load and inversely with absolute CD4 T-cell counts. When investigating GrB+ B cells in different compartments, levels were highest in blood, spleen and bone marrow, but considerably lower in lymph nodes and tonsils. Analysis of expression of various surface markers on this particular B-cell subset in SIV-infected macaques revealed differences between the phenotype in macaques and in humans. GrB+ B cells in SIV-infected rhesus macaques exhibit an elevated expression of CD5, CD10, CD25 and CD27, while expression of CD19, CD185 and HLA-DR is reduced. In contrast to human GrB+ B cells, we did not observe a significantly increased expression of CD43 and CD86. B-cell receptor stimulation in combination with IL-21 of purified B cells from healthy animals led to the induction of GrB expression. Furthermore, initial functional analyses indicated a regulatory role on T-cell proliferation. Overall, our data pave the way for longitudinal analyses including studies on the functionality of GrB+ B cells in the nonhuman primate model for AIDS. PMID- 27779181 TI - Simulating the exchange of Majorana zero modes with a photonic system. AB - The realization of Majorana zero modes is in the centre of intense theoretical and experimental investigations. Unfortunately, their exchange that can reveal their exotic statistics needs manipulations that are still beyond our experimental capabilities. Here we take an alternative approach. Through the Jordan-Wigner transformation, the Kitaev's chain supporting two Majorana zero modes is mapped to the spin-1/2 chain. We experimentally simulated the spin system and its evolution with a photonic quantum simulator. This allows us to probe the geometric phase, which corresponds to the exchange of two Majorana zero modes positioned at the ends of a three-site chain. Finally, we demonstrate the immunity of quantum information encoded in the Majorana zero modes against local errors through the simulator. Our photonic simulator opens the way for the efficient realization and manipulation of Majorana zero modes in complex architectures. PMID- 27779183 TI - Surface uplift in the Central Andes driven by growth of the Altiplano Puna Magma Body. AB - The Altiplano-Puna Magma Body (APMB) in the Central Andes is the largest imaged magma reservoir on Earth, and is located within the second highest orogenic plateau on Earth, the Altiplano-Puna. Although the APMB is a first-order geologic feature similar to the Sierra Nevada batholith, its role in the surface uplift history of the Central Andes remains uncertain. Here we show that a long wavelength topographic dome overlies the seismically measured extent of the APMB, and gravity data suggest that the uplift is isostatically compensated. Isostatic modelling of the magmatic contribution to dome growth yields melt volumes comparable to those estimated from tomography, and suggests that the APMB growth rate exceeds the peak Cretaceous magmatic flare-up in the Sierran batholith. Our analysis reveals that magmatic addition may provide a contribution to surface uplift on par with lithospheric removal, and illustrates that surface topography may help constrain the magnitude of pluton-scale melt production. PMID- 27779182 TI - Dynamic microfluidic control of supramolecular peptide self-assembly. AB - The dynamic nature of supramolecular polymers has a key role in their organization. Yet, the manipulation of their dimensions and polarity remains a challenge. Here, the minimalistic diphenylalanine building block was applied to demonstrate control of nano-assemblies growth and shrinkage using microfluidics. To fine-tune differential local environments, peptide nanotubes were confined by micron-scale pillars and subjected to monomer flows of various saturation levels to control assembly and disassembly. The small-volume device allows the rapid adjustment of conditions within the system. A simplified kinetic model was applied to calculate parameters of the growth mechanism. Direct real-time microscopy analysis revealed that different peptide derivatives show unidirectional or bidirectional axial dimension variation. Atomistic simulations show that unidirectional growth is dictated by the differences in the axial ends, as observed in the crystalline order of symmetry. This work lays foundations for the rational control of nano-materials dimensions for applications in biomedicine and material science. PMID- 27779184 TI - Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1. AB - Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction (HJ) resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination (HR) in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling. Yen1, but not the HJ resolvases Slx1-Slx4 and Mus81-Mms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2. Post-replicative DNA damage checkpoint activation in Dna2 helicase-defective cells causes terminal G2/M arrest by precluding Yen1-dependent repair, whose activation requires progression into anaphase. These findings explain the exquisite replication stress sensitivity of Dna2 helicase-defective cells, and identify a non-canonical role for Yen1 in the processing of replication intermediates that is distinct from HJ resolution. The involvement of Dna2 helicase activity in completing replication may have implications for DNA2-associated pathologies, including cancer and Seckel syndrome. PMID- 27779185 TI - Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation. AB - The mammary gland undergoes significant proliferative stages after birth, but little is known about how the developmental changes impact DNA double-strand break (DSB) repair. Mutations in multiple genes involved in homology-directed repair (HDR), considered a particularly accurate pathway for repairing DSBs, are linked to breast cancer susceptibility, including BRCA2. Using reporter mice that express an inducible endonuclease, we find that HDR is particularly robust in mammary tissue during puberty and pregnancy, accounting for 34-40% of detected repair events, more than in other tissues examined. Brca2 hypomorphic mutation leads to HDR defects in mammary epithelium during puberty and pregnancy, including in different epithelial lineages. Notably, a similar dependence on Brca2 is observed in other proliferative tissues, including small intestine epithelium. Our results suggest that the greater reliance on HDR in the proliferating mammary gland, rather than a specific dependence on BRCA2, may increase its susceptibility to tumorigenesis incurred by BRCA2 mutation. PMID- 27779187 TI - The role of fivefold symmetry in suppressing crystallization. AB - Although long assumed to have an important role in the suppression of crystallization and the development of glassformers, the effect of local fivefold symmetry has never been directly tested. Here we consider whether such suppression of crystallization has a kinetic or thermodynamic nature and investigate its mechanism. We introduce a model in which the degree of fivefold symmetry can be tuned by favouring arrangements of particles in pentagonal bipyramids. We thus show that fivefold symmetry has both kinetic and thermodynamic effects on the mechanism of crystallization to a face-centred cubic crystal. Our results suggest that the mechanism of crystallization suppression is related to the surface tension between fluid and crystal. Interestingly, the degree of fivefold symmetry has little effect on crystal growth rate, suggesting that growth may be only weakly coupled to fluid structure in hard sphere like systems. Upon increasing the fivefold symmetry, we find a first-order transition to an alternative icosahedra-rich phase. At intermediate bias strengths we find a one-component glassformer. PMID- 27779186 TI - PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. AB - Sepsis, severe sepsis and septic shock are the main cause of mortality in non cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2 mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1beta, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2-EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis. PMID- 27779188 TI - Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARgamma signalling pathway. AB - Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPARgamma-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3beta. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPARgamma-antagonist (GW9662), whereas the treatment of PPARalpha antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPARgamma signalling pathway. PMID- 27779189 TI - Microtubule organization is determined by the shape of epithelial cells. AB - Interphase microtubule organization is critical for cell function and tissue architecture. In general, physical mechanisms are sufficient to drive microtubule organization in single cells, whereas cells within tissues are thought to utilize signalling mechanisms. By improving the imaging and quantitation of microtubule alignment within developing Drosophila embryos, here we demonstrate that microtubule alignment underneath the apical surface of epithelial cells follows cell shape. During development, epidermal cell elongation and microtubule alignment occur simultaneously, but by perturbing cell shape, we discover that microtubule organization responds to cell shape, rather than the converse. A simple set of microtubule behaviour rules is sufficient for a computer model to mimic the observed responses to changes in cell surface geometry. Moreover, we show that microtubules colliding with cell boundaries zip-up or depolymerize in an angle-dependent manner, as predicted by the model. Finally, we show microtubule alignment responds to cell shape in diverse epithelia. PMID- 27779190 TI - Single-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny. AB - The mammary gland undergoes cycles of growth and regeneration throughout reproductive life, a process that requires mammary stem cells (MaSCs). Whilst recent genetic fate-mapping studies using lineage-specific promoters have provided valuable insights into the mammary epithelial hierarchy, the true differentiation potential of adult MaSCs remains unclear. To address this, herein we utilize a stochastic genetic-labelling strategy to indelibly mark a single cell and its progeny in situ, combined with tissue clearing and 3D imaging. Using this approach, clones arising from a single parent cell could be visualized in their entirety. We reveal that clonal progeny contribute exclusively to either luminal or basal lineages and are distributed sporadically to branching ducts or alveoli. Quantitative analyses suggest that pools of unipotent stem/progenitor cells contribute to adult mammary gland development. Our results highlight the utility of tracing a single cell and reveal that progeny of a single proliferative MaSC/progenitor are dispersed throughout the epithelium. PMID- 27779191 TI - 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. AB - X-linked adrenoleukodystrophy (X-ALD), caused by an ABCD1 mutation, is a progressive neurodegenerative disorder associated with the accumulation of very long-chain fatty acids (VLCFA). Cerebral inflammatory demyelination is the major feature of childhood cerebral ALD (CCALD), the most severe form of ALD, but its underlying mechanism remains poorly understood. Here, we identify the aberrant production of cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol (25 HC) in the cellular context of CCALD based on the analysis of ALD patient-derived induced pluripotent stem cells and ex vivo fibroblasts. Intriguingly, 25-HC, but not VLCFA, promotes robust NLRP3 inflammasome assembly and activation via potassium efflux-, mitochondrial reactive oxygen species (ROS)- and liver X receptor (LXR)-mediated pathways. Furthermore, stereotaxic injection of 25-HC into the corpus callosum of mouse brains induces microglial recruitment, interleukin-1beta production, and oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner. Collectively, our results indicate that 25-HC mediates the neuroinflammation of X-ALD via activation of the NLRP3 inflammasome. PMID- 27779192 TI - tDCS over left M1 or DLPFC does not improve learning of a bimanual coordination task. AB - Previously, transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has resulted in improved performance in simple motor tasks. For a complex bimanual movement, studies using functional magnetic resonance imaging and transcranial magnetic stimulation indicated the involvement of the left dorsolateral prefrontal cortex (DLPFC) as well as left M1. Here we investigated the relative effect of up-regulating the cortical function in left DLPFC and left M1 with tDCS. Participants practised a complex bimanual task over four days while receiving either of five stimulation protocols: anodal tDCS applied over M1, anodal tDCS over DLPFC, sham tDCS over M1, sham tDCS over DLPFC, or no stimulation. Performance was measured at the start and end of each training day to make a distinction between acquisition and consolidation. Although task performance improved over days, no significant difference between stimulation protocols was observed, suggesting that anodal tDCS had little effect on learning the bimanual task regardless of the stimulation sites and learning phase (acquisition or consolidation). Interestingly, cognitive performance as well as corticomotor excitability did not change following stimulation. Accordingly, we found no evidence for behavioural or neurophysiological changes following tDCS over left M1 or left DLPFC in learning a complex bimanual task. PMID- 27779193 TI - Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. AB - The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases. Here we show that C57BL/6J mice have a defect in neutrophil recruitment to a range of inflammatory stimuli compared with the related C57BL/6N substrain. This immune perturbation is associated with a missense mutation in Nlrp12 in C57BL/6J mice. Both C57BL/6J and NLRP12-deficient mice have increased susceptibility to bacterial infection that correlates with defective neutrophil migration. C57BL/6J and NLRP12-deficient macrophages have impaired CXCL1 production and the neutrophil defect observed in C57BL/6J and NLRP12-deficient mice is rescued by restoration of macrophage NLRP12. These results demonstrate that C57BL/6J mice have a functional defect in NLRP12 and that macrophages require NLRP12 expression for effective recruitment of neutrophils to inflammatory sites. PMID- 27779194 TI - Development of Risk Prediction Model for Hepatocellular Carcinoma Progression of Indeterminate Nodules in Hepatitis B Virus-Related Cirrhotic Liver. AB - OBJECTIVES: This study was performed to evaluate long-term outcome of indeterminate nodules detected on cirrhotic liver and to develop risk prediction model for hepatocellular carcinoma (HCC) progression of indeterminate nodules on hepatitis B virus (HBV)-related cirrhotic liver. METHODS: Indeterminate nodules up to 2 cm with uncertain malignant potential detected on computed tomography of cirrhotic liver during HCC surveillance were analyzed retrospectively. HCC risk prediction model of indeterminate nodules in HBV-related cirrhotic liver was deduced based on result of Cox regression analysis. RESULTS: A total of 494 indeterminate nodules were included. Independent risk factors of HCC progression were old age, arterial enhancement, large nodule size, low serum albumin level, high serum alpha-fetoprotein (AFP) level, and prior HCC history in all included subjects. In subjects with chronic hepatitis B, old age (year; hazard ratio (HR)=1.06; P<0.001), arterial enhancement (HR=2.62; P=0.005), large nodule size (>1 cm; HR=7.34; P<0.001), low serum albumin level (<=3.5 g/dl; HR=3.57; P=0.001), high serum AFP level (>=100 ng/ml; HR=6.04; P=0.006), prior HCC history (HR=4.24; P=0.001), and baseline hepatitis B e antigen positivity (HR=2.31; P=0.007) were associated with HCC progression. We developed a simple risk prediction model using these risk factors and identified patients at low, intermediate, and high risk for HCC; 5-year cumulative incidences were 1%, 14.5%, and 63.1%, respectively. The developed risk score model showed good performance with area under the curve at 0.886 at 3 years, and 0.920 at 5 years in leave-one out cross-validation. CONCLUSIONS: We developed a useful and accurate risk score model for predicting HCC progression of indeterminate nodules detected on HBV related cirrhotic liver. PMID- 27779196 TI - Thyroid Dysfunction in Primary Biliary Cholangitis: A Comparative Study at Two European Centers. AB - OBJECTIVES: Primary biliary cholangitis (PBC) is often associated with other autoimmune diseases, but little is known about the influence of thyroid disease (TD) on the natural history of PBC. Our aim is to analyze the association between PBC and TD, and the latter's impact on the natural history of PBC at two European centers. METHODS: The study involved 921 PBC patients enrolled between 1975 and 2015 in Padova (376 patients) and Barcelona (545 patients), with a mean follow-up of 126.9+/-91.7 months. Data were recorded on patients' histological stage at diagnosis, biochemical data, associated extrahepatic autoimmune conditions, and clinical events, including hepatic decompensation. RESULTS: A total of 150 patients (16.3%) had TD, including 94 patients (10.2%) with Hashimoto's thyroiditis; 15 (1.6%) with Graves' disease; 22 (2.4%) with multinodular goiter; 7 (0.8%) with thyroid cancer; and 12 (1.3%) with other thyroid conditions. The prevalence of different types of TD was similar in Padova and Barcelona, except for Graves' disease and thyroid cancer, which were more frequent in the Padova cohort (15.7 vs. 5.0%, and 8.6 vs. 1.3%, respectively, P<0.05). Overall, there were no differences between PBC patients with and without TD in terms of their histological stage at diagnosis, hepatic decompensation events, occurrence of HCC, or liver transplantation rate. The presence of associated TD was not associated with lower survival for PBC patients in either cohort. CONCLUSIONS: TDs, and autoimmune TD like Hashimoto's thyroiditis in particular, are often associated with PBC, but the presence of TD does not influence the rate of hepatic complications or the natural history of PBC. PMID- 27779195 TI - Accuracy of CT Colonography for Detection of Polypoid and Nonpolypoid Neoplasia by Gastroenterologists and Radiologists: A Nationwide Multicenter Study in Japan. AB - OBJECTIVES: The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists. METHODS: This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms >=6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated. RESULTS: Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms >=6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms >=10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions >=10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists. CONCLUSIONS: CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms >=6 mm than did radiologists, although their interpretation time was longer than that of radiologists. PMID- 27779197 TI - Single 5 MUm diameter needle electrode block modules for unit recordings in vivo. AB - Investigations into mechanisms in various cortical areas can be greatly improved and supported by stable recording of single neuronal activity. In this study, fine silicon wire electrodes (diameter 3 MUm, length 160 MUm) are fabricated by vapor-liquid-solid (VLS) growth with the aim of stabilizing recording and reducing the invasiveness on the measurement procedure. The electrode is fabricated on a modular 1 * 1 mm2 conductive silicon block that can be assembled into a number of different device packages, for example on rigid or flexible printed circuit boards (PCB). After plating with a 5 MUm diameter platinum black, the needle exhibits an electrical impedance of ~100 kOmega at 1 kHz in saline. The in vivo recording capability of the device is demonstrated using mice, and spike signals with peak-to-peak amplitudes of 200-300 MUV in the range 0.5-3 kHz are stably detected, including single-unit activities in cortical layer 2/3. In addition, the device packaged with a flexible PCB shows stable unit recordings for 98.5 min (n = 4). Consequently, our modular, low-invasive needle electrode block devices present an effective route for single-unit recordings in vivo, as well as demonstrating adaptability in device design for a diverse range of experiments. PMID- 27779198 TI - Form, shape and function: segmented blood flow in the choriocapillaris. AB - The development of fluid transport systems was a key event in the evolution of animals and plants. While within vertebrates branched geometries predominate, the choriocapillaris, which is the microvascular bed that is responsible for the maintenance of the outer retina, has evolved a planar topology. Here we examine the flow and mass transfer properties associated with this unusual geometry. We show that as a result of the form of the choriocapillaris, the blood flow is decomposed into a tessellation of functional vascular segments of various shapes delineated by separation surfaces across which there is no flow, and in the vicinity of which the transport of passive substances is diffusion-limited. The shape of each functional segment is determined by the distribution of arterioles and venules and their respective relative flow rates. We also show that, remarkably, the mass exchange with the outer retina is a function of the shape of each functional segment. In addition to introducing a novel framework in which the structure and function of the metabolite delivery system to the outer retina may be investigated in health and disease, the present work provides a general characterisation of the flow and transfers in multipole Hele-Shaw configurations. PMID- 27779199 TI - Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves. AB - Individuals with a bicuspid aortic valve (BAV) are at significantly higher risk of developing aortic complications than individuals with tricuspid aortic valves (TAV) and defective signaling during the embryonic development and/or life time exposure to abnormal hemodynamic have been proposed as underlying factors. However, an explanation for the molecular mechanisms of aortopathy in BAV has not yet been provided. We combined proteomics, RNA analyses, immunohistochemistry, and electron microscopy to identify molecular differences in samples of non dilated ascending aortas from BAV (N = 62) and TAV (N = 54) patients. Proteomic analysis was also performed for dilated aortas (N = 6 BAV and N = 5 TAV) to gain further insight into the aortopathy of BAV. Our results collectively showed the molecular signature of an endothelial/epithelial-mesenchymal (EndMT/EMT) transition-like process, associated with instability of intimal cell junctions and activation of RHOA pathway in the intima and media layers of ascending aorta in BAV patients. We propose that an improper regulation of EndMT/EMT during the spatiotemporally related embryogenesis of semilunar valves and ascending aorta in BAV individuals may result in aortic immaturity and instability prior to dilation. Exasperation of EndMT/EMT state in post embryonic life and/or exposure to non-physiological hemodynamic could lead to the aneurysm of ascending aorta in BAV individuals. PMID- 27779200 TI - Prevalence of Integrase Strand Transfer Inhibitors (INSTI) Resistance Mutations in Taiwan. AB - Antiretroviral therapy containing an integrase strand transfer inhibitor (INSTI) plus two NRTIs has become the recommended treatment for antiretroviral-naive HIV 1-infected patients in the updated guidelines. We aimed to determine the prevalence of INSTI-related mutations in Taiwan. Genotypic resistance assays were performed on plasma from ARV-naive patients (N = 948), ARV-experienced but INSTI naive patients (N = 359), and raltegravir-experienced patients (N = 63) from 2006 to 2015. Major INSTI mutations were defined according to the IAS-USA list and other substitutions with a Stanford HIVdb score ? 10 to at least one INSTI were defined as minor mutations. Of 1307 HIV-1 samples from patients never exposed to INSTIs, the overall prevalence of major resistance mutations to INSTIs was 0.9% (n = 12), with an increase to 1.2% in 2013. Of these 12 sequences, 11 harboured Q148H/K/R, one Y143R, and none N155H. Of 30 sequences (47.6%) with INSTI resistant mutations from raltegravir-experienced patients, 17 harboured Q148H/K/R, 8 N155H, and 6 Y143C/R. Other than these major mutations, the prevalence of minor mutations were 5.3% and 38.1%, respectively, in ARV-naive and raltegravir-experienced patients. The overall prevalence of INSTI mutations remains low in Taiwan. Surveillance of INSTI resistance is warranted due to circulation of polymorphisms contributing to INSTI resistance and expected increasing use of INSTIs. PMID- 27779202 TI - The impact of local treatment of the primary tumor site in node positive and metastatic prostate cancer patients. AB - BACKGROUND: Surgical treatment of the primary tumor in patients with metastatic prostate cancer (mPCa) is gaining traction. We discuss the biological rational and the existing literature on this approach. METHODS: We reviewed the literature regarding surgical management of advanced and mPCa disease. RESULTS: Surgical removal of the primary tumor despite metastases is becoming a standard in an increasing number of malignancies. Basic science data support the use of surgical removal of the prostate in metastatic PCa. In addition, durable long-term survival has been reported in patients with node-positive PCa treated with radical prostatectomy (RP) as mono or multimodal approach. Based on these data, several groups have demonstrated the feasibility and safety of RP in the metastatic setting. Retrospective series have also reported an improvement in survival for metastatic patients treated with RP in addition to systemic treatment. CONCLUSIONS: Although no level I data exist at this time to support the use of RP in clinically node-positive or mPCa patients, retrospective data together with basic research data and experience from other malignancies suggest that treatment of the primary tumor, in form of a RP, is safe and could improve long-term quality of life and survival. However, prospective evaluations are requested to validate these findings before including in the standard clinical practice. PMID- 27779201 TI - Involvement of voltage-dependent anion channel (VDAC) in dengue infection. AB - During infection, dengue virus (DENV) proteins interact with host cellular constituents promoting the remodeling of the cell to facilitate virus production. While a number of interacting proteins have been identified for DENV non structural proteins, far fewer interacting partners have been identified for the DENV structural proteins. One protein that has been identified as a DENV E protein interacting protein is the cellular chaperone GRP78. GRP78 has been shown to have a number of cellular interacting partners including the voltage-dependent anion channel (VDAC). In this study we confirmed the interactions between GRP78 and DENV E protein and between GRP78 and VDAC. VDAC was shown to be re-localized during DENV infection, with no change in levels of protein expression. VDAC is predominantly located on the outer membrane of mitochondria and our result is consistent with movement of the mitochondria towards the ER during DENV infection. Down regulation of VDAC through siRNA significantly reduced DENV protein expression, as well as the percentage infection and output virus titer. Our results suggest that VDAC plays an important role in DENV infection. PMID- 27779203 TI - SOCS1 inhibits migration and invasion of prostate cancer cells, attenuates tumor growth and modulates the tumor stroma. AB - BACKGROUND: The suppressor of cytokine signaling 1 (SOCS1) gene is repressed in prostate cancer (PCa) by epigenetic silencing and microRNA miR30d. Increased expression of the SOCS1-targeting miR30d correlates with higher biochemical recurrence, suggesting a tumor suppressor role of SOCS1 in PCa, but the underlying mechanisms are unclear. We have shown that SOCS1 inhibits MET receptor kinase signaling, a key oncogenic pathway in cancer progression. Here we evaluated the role of SOCS1 in attenuating MET signaling in PCa cells and tumor growth in vivo. METHODS: MET-overexpressing human DU145 and PC3 PCa cell lines were stably transduced with SOCS1, and their growth, migration and invasion of collagen matrix were evaluated in vitro. Cells expressing SOCS1 or the control vector were evaluated for tumor growth in NOD.scid.gamma mice as xenograft or orthotopic tumors. RESULTS: HGF-induced MET signaling was attenuated in SOCS1 expressing DU145 and PC3 cells. Compared with vector control cells, SOCS1 expressing cells showed reduced proliferation and impaired migration following HGF stimulation. DU145 and PC3 cells showed marked ability to invade the collagen matrix following HGF stimulation and this was attenuated by SOCS1. As xenografts, SOCS1-expressing PCa cells showed significantly reduced tumor growth compared with vector control cells. In the orthotopic tumor model, SOCS1 reduced the growth of primary tumors and metastatic spread. Intriguingly, the SOCS1 expressing DU145 and PC3 tumors showed increased collagen deposition, associated with increased frequency of myofibroblasts. CONCLUSIONS: Our findings support the tumor suppressor role of SOCS1 in PCa and suggest that attenuation of MET signaling is one of the underlying mechanisms. SOCS1 in PCa cells also appears to prevent the tumor-promoting functions of cancer-associated fibroblasts. PMID- 27779206 TI - Context-Dependent Effects of Inflammation: Reduced Reward Responding is Not an Invariant Outcome of Sickness. PMID- 27779207 TI - HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression. AB - Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, >=5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection. Results showed double mutation A1762T/G1764A (TA) combined with other mutation(s) (TACO) in HBV genome and phosphorylated AKT (pAKT) were more common in PHCC than BHCC. TACO and pAKT levels correlated with proliferation and microvascularization but inversely correlated with apoptosis in HCC samples. These were more pronounced when TACO and pAKT co-expressed. Levels of p21 and p27 were decreased in TACO or pAKT overexpressing HCC due to SKP2 upregulation. Levels of E2F1 and both mRNA and protein of SKP2 were increased in TACO expressing HCC. Levels of 4EBP1/2 decreased and SKP2 mRNA level remained constant in pAKT-overexpressing HCC. Therefore, TACO and AKT are two independent predictors of postoperative survival in HCC. Their co-target, SKP2 may be a diagnostic or therapeutic marker. PMID- 27779205 TI - Linearized texture of three-dimensional extracellular matrix is mandatory for bladder cancer cell invasion. AB - In the fields of biomaterials and tissue engineering simulating the native microenvironment is of utmost importance. As a major component of the microenvironment, the extracellular matrix (ECM) contributes to tissue homeostasis, whereas modifications of native features are associated with pathological conditions. Furthermore, three-dimensional (3D) geometry is an important feature of synthetic scaffolds favoring cell stemness, maintenance and differentiation. We analyzed the 3D structure, geometrical measurements and anisotropy of the ECM isolated from (i) human bladder mucosa (basal lamina and lamina propria) and muscularis propria; and, (ii) bladder carcinoma (BC). Next, binding and invasion of bladder metastatic cell line was observed on synthetic scaffold recapitulating anisotropy of tumoral ECM, but not on scaffold with disorganized texture typical of non-neoplastic lamina propria. This study provided information regarding the ultrastructure and geometry of healthy human bladder and BC ECMs. Likewise, using synthetic scaffolds we identified linearization of the texture as a mandatory feature for BC cell invasion. Integrating microstructure and geometry with biochemical and mechanical factors could support the development of an innovative synthetic bladder substitute or a tumoral scaffold predictive of chemotherapy outcomes. PMID- 27779204 TI - Corrigendum: Determining crystal structures through crowdsourcing and coursework. PMID- 27779208 TI - Racial differences in microRNA and gene expression in hypertensive women. AB - Systemic arterial hypertension is an important cause of cardiovascular disease morbidity and mortality. African Americans are disproportionately affected by hypertension, in fact the incidence, prevalence, and severity of hypertension is highest among African American (AA) women. Previous data suggests that differential gene expression influences individual susceptibility to selected diseases and we hypothesized that this phenomena may affect health disparities in hypertension. Transcriptional profiling of peripheral blood mononuclear cells from AA or white, normotensive or hypertensive females identified thousands of mRNAs differentially-expressed by race and/or hypertension. Predominant gene expression differences were observed in AA hypertensive females compared to AA normotensives or white hypertensives. Since microRNAs play important roles in regulating gene expression, we profiled global microRNA expression and observed differentially-expressed microRNAs by race and/or hypertension. We identified novel mRNA-microRNA pairs potentially involved in hypertension-related pathways and differently-expressed, including MCL1/miR-20a-5p, APOL3/miR-4763-5p, PLD1/miR 4717-3p, and PLD1/miR-4709-3p. We validated gene expression levels via RT-qPCR and microRNA target validation was performed in primary endothelial cells. Altogether, we identified significant gene expression differences between AA and white female hypertensives and pinpointed novel mRNA-microRNA pairs differentially-expressed by hypertension and race. These differences may contribute to the known disparities in hypertension and may be potential targets for intervention. PMID- 27779210 TI - Dispersing upconversion nanocrystals in a single silicon microtube. AB - Nanocrystals of Ln3+ (Ln = Yb, Tm and Ho) doped beta-NaLuF4 with average diameter about 200 nm are dispersed in silica-based microtube (MT) by a simple flame heating method. The fabricated microtube has a diameter range from 2 MUm to 30 MUm and lengths up to hundreds microns. The fluorescence of upconversion nanocrystals (UCNCs) can propagate along a single MT and couple into another MT through evanescent field. The guiding performance of the single UCNCs doped MT is measured to prove that it can be used as an active waveguide. Moreover, optical temperature sensing based on the single UCNCs-MT is also demonstrated, and the sensitivity of UCNCs-MT is significantly enough for thermometry applications in the range of 298-383 K. PMID- 27779209 TI - Quantitative Relationship between Cadmium Uptake and the Kinetics of Phytochelatin Induction by Cadmium in a Marine Diatom. AB - Heavy metals activate the synthesis of phytochelatins (PCs), while the induced PCs might affect metal uptake via chelating intracellular free metals. However, the relationship of PCs to metal uptake is poorly understood. In this study, we examined the kinetics of cadmium (Cd) accumulation and the synthesis of PCs in a marine diatom, Thalassiosira weissflogii, under different irradiance levels. Irradiance alone could not change the concentrations of PCs in the Cd-free treatments, while higher irradiance accelerated the induction of intracellular PCs at the same [Cd2+] level. PC-SH (2 * PC2 + 3 * PC3 + 4 * PC4) was bound with Cd at a stoichiometric ratio of 2 to 49 in our short-term uptake experiments, indicating that PC induction is sufficient to serve as the first line of defense against Cd stress. A positive linear correlation between the induction rate of PCs and the Cd uptake rate was observed, while the ratio of the PC content to intracellular Cd varied greatly when the irradiance was increased several fold. Because metal uptake has been successfully used in predicting acute metal toxicity, our findings are helpful for understanding the role of PCs in metal detoxification and developing PCs as biomarkers for metal sensitivity. PMID- 27779211 TI - Brain responses to facial attractiveness induced by facial proportions: evidence from an fMRI study. AB - Brain responses to facial attractiveness induced by facial proportions are investigated by using functional magnetic resonance imaging (fMRI), in 41 young adults (22 males and 19 females). The subjects underwent fMRI while they were presented with computer-generated, yet realistic face images, which had varying facial proportions, but the same neutral facial expression, baldhead and skin tone, as stimuli. Statistical parametric mapping with parametric modulation was used to explore the brain regions with the response modulated by facial attractiveness ratings (ARs). The results showed significant linear effects of the ARs in the caudate nucleus and the orbitofrontal cortex for all of the subjects, and a non-linear response profile in the right amygdala for only the male subjects. Furthermore, canonical correlation analysis was used to learn the most relevant facial ratios that were best correlated with facial attractiveness. A regression model on the fMRI-derived facial ratio components demonstrated a strong linear relationship between the visually assessed mean ARs and the predictive ARs. Overall, this study provided, for the first time, direct neurophysiologic evidence of the effects of facial ratios on facial attractiveness and suggested that there are notable gender differences in perceiving facial attractiveness as induced by facial proportions. PMID- 27779212 TI - Variation in structure of proteins by adjusting reactive oxygen and nitrogen species generated from dielectric barrier discharge jet. AB - Over the last few years, the variation in liquid chemistry due to the development of radicals generated by cold atmospheric plasma (CAP) has played an important role in plasma medicine. CAP direct treatment or CAP activated media treatment in cancer cells shows promising anticancer activity for both in vivo and in vitro studies. However, the anticancer activity or antimicrobial activity varies between plasma devices due to the different abilities among plasma devices to generate the reactive oxygen and nitrogen species (RONS) at different ratios and in different concentrations. While the generation of RONS depends on many factors, the feeding gas plays the most important role among the factors. Hence, in this study we used different compositions of feeding gas while fixing all other plasma characteristics. We used Ar, Ar-O2 (at different ratios), and Ar-N2 (at different ratios) as the working gases for CAP and investigated the structural changes in proteins (Hemoglobin (Hb) and Myoglobin (Mb)). We then analyzed the influence of RONS generated in liquid on the conformations of proteins. Additionally, to determine the influence of H2O2 on the Hb and Mb structures, we used molecular dynamic simulation. PMID- 27779213 TI - Equatorial Pacific forcing of western Amazonian precipitation during Heinrich Stadial 1. AB - Abundant hydroclimatic evidence from western Amazonia and the adjacent Andes documents wet conditions during Heinrich Stadial 1 (HS1, 18-15 ka), a cold period in the high latitudes of the North Atlantic. This precipitation anomaly was attributed to a strengthening of the South American summer monsoon due to a change in the Atlantic interhemispheric sea surface temperature (SST) gradient. However, the physical viability of this mechanism has never been rigorously tested. We address this issue by combining a thorough compilation of tropical South American paleorecords and a set of atmosphere model sensitivity experiments. Our results show that the Atlantic SST variations alone, although leading to dry conditions in northern South America and wet conditions in northeastern Brazil, cannot produce increased precipitation over western Amazonia and the adjacent Andes during HS1. Instead, an eastern equatorial Pacific SST increase (i.e., 0.5-1.5 degrees C), in response to the slowdown of the Atlantic Meridional Overturning Circulation during HS1, is crucial to generate the wet conditions in these regions. The mechanism works via anomalous low sea level pressure over the eastern equatorial Pacific, which promotes a regional easterly low-level wind anomaly and moisture recycling from central Amazonia towards the Andes. PMID- 27779215 TI - The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese Leukoencephalopathies. AB - Leukoencephalopathies are diseases with high clinical heterogeneity. In clinical work, it's difficult for doctors to make a definite etiological diagnosis. Here, we designed a custom probe library which contains the known pathogenic genes reported to be associated with Leukoencephalopathies, and performed targeted gene capture and massively parallel sequencing (MPS) among 49 Chinese patients who has white matter damage as the main imaging changes, and made the validation by Sanger sequencing for the probands' parents. As result, a total of 40.8% (20/49) of the patients identified pathogenic mutations, including four associated with metachromatic leukodystrophy, three associated with vanishing white matter leukoencephalopathy, three associated with mitochondrial complex I deficiency, one associated with Globoid cell leukodystrophy (or Krabbe diseases), three associated with megalencephalic leukoencephalopathy with subcortical cysts, two associated with Pelizaeus-Merzbacher disease, two associated with X-linked adrenoleukodystrophy, one associated with Zellweger syndrome and one associated with Alexander disease. Targeted capture and MPS enables to identify mutations of all classes causing leukoencephalopathy. Our study combines targeted capture and MPS technology with clinical and genetic diagnosis and highlights its usefulness for rapid and comprehensive genetic testing in the clinical setting. This method will also expand our knowledge of the genetic and clinical spectra of leukoencephalopathy. PMID- 27779214 TI - Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice. AB - Disabled-2 (Dab2) is a widely expressed clathrin binding endocytic adaptor protein and known for the endocytosis of the low-density lipoprotein (LDL) family receptors. Dab2 also modulates endosomal Ras/MAPK (Erk1/2) activity by regulating the disassembly of Grb2/Sos1 complexes associated with clathrin-coated vesicles. We found that the most prominent phenotype of Dab2 knockout mice was their striking lean body composition under a high fat and high caloric diet, although the weight of the mutant mice was indistinguishable from wild-type littermates on a regular chow. The remarkable difference in resistance to high caloric diet induced weight gain of the dab2-deleted mice was presented only in juvenile but not in mature mice. Investigation using Dab2-deficient embryonic fibroblasts and mesenchymal stromal cells indicated that Dab2 promoted adipogenic differentiation by modulation of MAPK (Erk1/2) activity, which otherwise suppresses adipogenesis through the phosphorylation of PPARgamma. The results suggest that Dab2 is required for the excessive calorie-induced differentiation of an adipocyte progenitor cell population that is present in juvenile but depleted in mature animals. The finding provides evidence for a limited pre-adipocyte population in juvenile mammals and the requirement of Dab2 in the regulation of Ras/MAPK signal in the commitment of the precursor cells to adipose tissues. PMID- 27779217 TI - Responses of the summer Asian-Pacific zonal thermal contrast and the associated evolution of atmospheric circulation to transient orbital changes during the Holocene. AB - This study investigates the response of large-scale atmospheric circulation over the Asian-Pacific sector and precipitation over eastern China to transient orbital changes during the Holocene summer using an intermediate-complexity climate model. Corresponding to variations in the incoming solar radiation, the eddy sea level pressure (SLP) exhibited an out-of-phase relationship between the North Pacific and the Eurasian landmass that was similar to the present-day Asia Pacific Oscillation (APO) pattern and was defined as the paleo-APO. Its index presented an increasing trend, which implies the enhancement of a zonal thermal contrast between Asia and the North Pacific. Associated with the strengthening of the paleo-APO was the westward shift in North Pacific high pressure. Accordingly, there was less/more summer precipitation over both the middle reach of the Yangtze River and Southwest China/over North China. The high-resolution stalagmite delta18O records further support this decrease in the model precipitation. Along with the strengthening of paleo-APO from the early Holocene to the present, the eddy SLP anomalies exhibited a decreasing/increasing trend over the Eurasian landmass/the North Pacific, with a phase change of approximately 4.5 ka BP, and they both moved westward. Meanwhile, a less rainfall belt over eastern China exhibited northward propagation from southern China. PMID- 27779216 TI - Soluble P-selectin rescues viper venom-induced mortality through anti inflammatory properties and PSGL-1 pathway-mediated correction of hemostasis. AB - Venomous snakebites are lethal and occur frequently worldwide each year, and receiving the antivenom antibody is currently the most effective treatment. However, the specific antivenom might be unavailable in remote areas. Snakebites by Viperidae usually lead to hemorrhage and mortality if untreated. In the present study, challenges of rattlesnake (Crotalus atrox) venom markedly increased the circulating soluble P-selectin (sP-sel) level, but not P-selectin (P-sel, Selp-/-) mutants, in wild-type mice. Because sP-sel enhances coagulation through the P-selectin ligand 1 (PSGL-1, Selplg) pathway to produce tissue factor positive microparticles, we hypothesized that increasing the plasma sP-sel level can be a self-rescue response in hosts against snake venom-mediated suppression of the coagulation system. Confirming our hypothesis, our results indicated that compared with wild-type mice, Selp-/- and Selplg-/- mice were more sensitive to rattlesnake venom. Additionally, administration of recombinant sP-sel could effectively reduce the mortality rate of mice challenged with venoms from three other Viperidae snakes. The antivenom property of sP-sel is associated with improved coagulation activity in vivo. Our data suggest that the elevation of endogenous sP-sel level is a self-protective response against venom-suppressed coagulation. The administration of recombinant sP-sel may be developed as a new strategy to treat Viperidae snakebites. PMID- 27779221 TI - Flaw-induced plastic-flow dynamics in bulk metallic glasses under tension. AB - Inheriting amorphous atomic structures without crystalline lattices, bulk metallic glasses (BMGs) are known to have superior mechanical properties, such as high strength approaching the ideal value, but are susceptible to catastrophic failures. Understanding the plastic-flow dynamics of BMGs is important for achieving stable plastic flow in order to avoid catastrophic failures, especially under tension, where almost all BMGs demonstrate limited plastic flow with catastrophic failure. Previous findings have shown that the plastic flow of BMGs displays critical dynamics under compression tests, however, the plastic-flow dynamics under tension are still unknown. Here we report that power-law critical dynamics can also be achieved in the plastic flow of tensile BMGs by introducing flaws. Differing from the plastic flow under compression, the flaw-induced plastic flow under tension shows an upward trend in the amplitudes of the load drops with time, resulting in a stable plastic-flow stage with a power-law distribution of the load drop. We found that the flaw-induced plastic flow resulted from the stress gradients around the notch roots, and the stable plastic flow stage increased with the increase of the stress concentration factor ahead of the notch root. The findings are potentially useful for predicting and avoiding the catastrophic failures in tensile BMGs by tailoring the complex stress fields in practical structural-applications. PMID- 27779218 TI - A role for intestinal TLR4-driven inflammatory response during activity-based anorexia. AB - Anorexia nervosa (AN) is associated with low-grade systemic inflammation and altered gut microbiota. However, the molecular origin of the inflammation remains unknown. Toll-like receptors are key regulators of innate immune response and their activation seems also to be involved in the control of food intake. We used activity-based anorexia (ABA) model to investigate the role of TLR4 and its contribution in anorexia-associated low-grade inflammation. Here, we found that ABA affected early the intestinal inflammatory status and the hypothalamic response. Indeed, TLR4 was upregulated both on colonic epithelial cells and intestinal macrophages, leading to elevated downstream mucosal cytokine production. These mucosal changes occurred earlier than hypothalamic changes driving to increased levels of IL-1beta and IL-1R1 as well as increased levels of plasma corticosterone. Paradoxically, TLR4-deficient mice exhibited greater vulnerability to ABA with increased mortality rate, suggesting a major contribution of TLR4-mediated responses during ABA-induced weight loss. PMID- 27779219 TI - Establishment of a translational endothelial cell model using directed differentiation of induced pluripotent stem cells from Cynomolgus monkey. AB - Due to their broad differentiation potential, pluripotent stem cells (PSCs) offer a promising approach for generating relevant cellular models for various applications. While human PSC-based cellular models are already advanced, similar systems for non-human primates (NHPs) are still lacking. However, as NHPs are the most appropriate animals for evaluating the safety of many novel pharmaceuticals, the availability of in vitro systems would be extremely useful to bridge the gap between cellular and animal models. Here, we present a NHP in vitro endothelial cell system using induced pluripotent stem cells (IPSCs) from Cynomolgus monkey (Macaca fascicularis). Based on an adapted protocol for human IPSCs, we directly differentiated macaque IPSCs into endothelial cells under chemically defined conditions. The resulting endothelial cells can be enriched using immuno-magnetic cell sorting and display endothelial marker expression and function. RNA sequencing revealed that the differentiation process closely resembled vasculogenesis. Moreover, we showed that endothelial cells derived from macaque and human IPSCs are highly similar with respect to gene expression patterns and key endothelial functions, such as inflammatory responses. These data demonstrate the power of IPSC differentiation technology to generate defined cell types for use as translational in vitro models to compare cell type-specific responses across species. PMID- 27779220 TI - Two flagellar BAR domain proteins in Trypanosoma brucei with stage-specific regulation. AB - Trypanosomes are masters of adaptation to different host environments during their complex life cycle. Large-scale proteomic approaches provide information on changes at the cellular level, and in a systematic way. However, detailed work on single components is necessary to understand the adaptation mechanisms on a molecular level. Here, we have performed a detailed characterization of a bloodstream form (BSF) stage-specific putative flagellar host adaptation factor Tb927.11.2400, identified previously in a SILAC-based comparative proteome study. Tb927.11.2400 shares 38% amino acid identity with TbFlabarin (Tb927.11.2410), a procyclic form (PCF) stage-specific flagellar BAR domain protein. We named Tb927.11.2400 TbFlabarin-like (TbFlabarinL), and demonstrate that it originates from a gene duplication event, which occurred in the African trypanosomes. TbFlabarinL is not essential for the growth of the parasites under cell culture conditions and it is dispensable for developmental differentiation from BSF to the PCF in vitro. We generated TbFlabarinL-specific antibodies, and showed that it localizes in the flagellum. Co-immunoprecipitation experiments together with a biochemical cell fractionation suggest a dual association of TbFlabarinL with the flagellar membrane and the components of the paraflagellar rod. PMID- 27779223 TI - Prostate cancer: Proteomic assay predicts biochemical recurrence. PMID- 27779222 TI - Lead chromate detected as a source of atmospheric Pb and Cr (VI) pollution. AB - Spherical black carbon aggregates were frequently observed in dust dry deposition in Daejeon, Korea. They were tens of micrometers in diameter and presented a mixture of black carbon and several mineral phases. Transmission electron microscopy (TEM) observations with energy-dispersive X-ray spectroscopy (EDS) and selected area diffraction pattern (SADP) analyses confirmed that the aggregates were compact and included significant amounts of lead chromate (PbCrO4). The compositions and morphologies of the nanosized lead chromate particles suggest that they probably originated from traffic paint used in roads and were combined as discrete minerals with black carbon. Based on Pb isotope analysis and air-mass backward trajectories, the dust in Daejeon received a considerable input of anthropogenic pollutants from heavily industrialized Chinese cities, which implies that long-range transported aerosols containing PbCrO4 were a possible source of the lead and hexavalent chromium levels in East Asia. Lead chromate should be considered to be a source of global atmospheric Pb and Cr(VI) pollution, especially given its toxicity. PMID- 27779224 TI - Urinary incontinence: Interneuron precursors restore bladder function. PMID- 27779225 TI - Prostate cancer: N-Myc expression drives neuroendocrine disease. PMID- 27779226 TI - Kidney cancer: Classifying the unclassified - molecular analysis of uRCC. PMID- 27779227 TI - Prostate cancer: Exosomal AR-V7 is a marker of hormonal therapy resistance. PMID- 27779228 TI - Transplantation: Ex vivo model of penile transplantation developed. PMID- 27779229 TI - The management of neurogenic lower urinary tract dysfunction after spinal cord injury. AB - The management of patients with neurogenic bladder has changed substantially over the past decades. Obtaining balanced lower urinary tract function has become possible in most patients, although, urological complications remain among the most serious complications these patients are likely to have and, even today, these can have a negative effect on quality of life. To this extent, patients with spinal cord injury (SCI) are likely to develop neurogenic bladder, and data are available on most aspects of neurogenic bladder in these patients. Data on physiology and pathophysiology form the basis of our understanding of patients' symptoms, and also provide a basis for the management of these patients. The use of conservative, and/or more invasive treatment measures, their complications and measures to prevent these complications, are all important clinical aspects that merit discussion. Considerable progress has been made in the urological management of patients with SCI over the past decades, but opportunities remain to make diagnosis more accurate and therapy more successful. PMID- 27779231 TI - Prostate cancer: Analysis of progression through time and space. PMID- 27779230 TI - The current evidence on statin use and prostate cancer prevention: are we there yet? AB - An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate- cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects. The epidemiological evidence is supported by preclinical studies that show that statins directly inhibit prostate cancer development and progression in cell based and animal-based models. The antineoplastic effect of statins might arise from a number of cholesterol-mediated and non-cholesterol-mediated mechanisms that affect pathways essential for cancer formation and progression. Understanding these mechanisms is instrumental in drug discovery research for the development of future prostate cancer therapeutics, as well as in designing clinical trials to test a role for statins in prostate cancer prevention. Currently, sufficient data are lacking to support the use of statins for the primary prevention of prostate cancer and further research is clearly warranted. Secondary and tertiary prevention trials in men who have been diagnosed with prostate cancer might soon be performed. PMID- 27779232 TI - Network Consistency Projection for Human miRNA-Disease Associations Inference. AB - Prediction and confirmation of the presence of disease-related miRNAs is beneficial to understand disease mechanisms at the miRNA level. However, the use of experimental verification to identify disease-related miRNAs is expensive and time-consuming. Effective computational approaches used to predict miRNA-disease associations are highly specific. In this study, we develop the Network Consistency Projection for miRNA-Disease Associations (NCPMDA) method to reveal the potential associations between miRNAs and diseases. NCPMDA is a non parametric universal network-based method that can simultaneously predict miRNA disease associations in all diseases but does not require negative samples. NCPMDA can also confirm the presence of miRNAs in isolated diseases (diseases without any known miRNA association). Leave-one-out cross validation and case studies have shown that the predictive performance of NCPMDA is superior over that of previous method. PMID- 27779233 TI - MicroRNA-939 restricts Hepatitis B virus by targeting Jmjd3-mediated and C/EBPalpha-coordinated chromatin remodeling. AB - Multi-layered mechanisms of virus host interaction exist for chronic hepatitis B virus (HBV) infection, which have been typically manifested at the microRNA level. Our previous study suggested that miRNA-939 (miR-939) may play a potential role in regulating HBV replication. Here we further investigated the mechanism by which miR-939 regulates HBV life cycle. We found that miR-939 inhibited the abundance of viral RNAs without direct miRNA-mRNA base pairing, but via host factors. Expression profiling and functional validation identified Jmjd3 as a target responsible for miR-939 induced anti-HBV effect. Jmjd3 appeared to enhance the transcription efficiency of HBV enhancer II/core promoter (En II) in a C/EBPalpha-dependent manner. However, the demethylase activity of Jmjd3 was not required in this process. Rather, Jmjd3's transactivation activity depended on its interaction with C/EBPalpha. This coordinated action further recruited the Brm containing SWI/SNF chromatin remodeling complex which promoted the transcription of HBV RNAs. Taken together, we propose that the miR-939-Jmjd3 axis perturbs the accessibility of En II promoter to essential nuclear factors (C/EBPalpha and SWI/SNF complex) therefore leading to compromised viral RNA synthesis and hence restricted viral multiplication. PMID- 27779234 TI - ADAMTS-10 and -6 differentially regulate cell-cell junctions and focal adhesions. AB - ADAMTS10 and ADAMTS6 are homologous metalloproteinases with ill-defined roles. ADAMTS10 mutations cause Weill-Marchesani syndrome (WMS), implicating it in fibrillin microfibril biology since some fibrillin-1 mutations also cause WMS. However little is known about ADAMTS6 function. ADAMTS10 is resistant to furin cleavage, however we show that ADAMTS6 is effectively processed and active. Using siRNA, over-expression and mutagenesis, it was found ADAMTS6 inhibits and ADAMTS10 is required for focal adhesions, epithelial cell-cell junction formation, and microfibril deposition. Either knockdown of ADAMTS6, or disruption of its furin processing or catalytic sites restores focal adhesions, implicating its enzyme activity acts on targets in the focal adhesion complex. In ADAMTS10 depleted cultures, expression of syndecan-4 rescues focal adhesions and cell-cell junctions. Recombinant C-termini of ADAMTS10 and ADAMTS6, both of which induce focal adhesions, bind heparin and syndecan-4. However, cells overexpressing full length ADAMTS6 lack heparan sulphate and focal adhesions, whilst depletion of ADAMTS6 induces a prominent glycocalyx. Thus ADAMTS10 and ADAMTS6 oppositely affect heparan sulphate-rich interfaces including focal adhesions. We previously showed that microfibril deposition requires fibronectin-induced focal adhesions, and cell-cell junctions in epithelial cultures. Here we reveal that ADAMTS6 causes a reduction in heparan sulphate-rich interfaces, and its expression is regulated by ADAMTS10. PMID- 27779236 TI - In the news: From ESMO 2016. PMID- 27779237 TI - Lung cancer: Anti-PD-1 therapy in the frontline. PMID- 27779238 TI - Kidney cancer: New approaches for high-risk disease. PMID- 27779235 TI - One compound of saponins from Disocorea zingiberensis protected against experimental acute pancreatitis by preventing mitochondria-mediated necrosis. AB - Acute pancreatitis (AP) is a painful inflammatory disorder of the exocrine pancreas, ranking as the most common gastrointestinal reasons for hospitalization with no specific therapy currently. Diosgenyl saponins extracted from natural products and diosgenin or its derivatives have been shown to exert anti inflammatory effects in various diseases. However, the therapeutic effects of diosgenyl saponins from Dioscorea zingiberensis C. H. Wright in AP have not yet been determined. Five compounds were extracted and screened for taurocholate induced necrosis in mouse pancreatic acinar cells. Particularly, 26-O-beta-d glucopyranosyl-3beta, 22alpha, 26-trihydroxy-25(R)-furosta-5-en-3-O-[alpha-L rhamnopyranosyl-(1 -> 4)]-beta-d-glucopyranoside (compound 1) exhibited the best protective effects with no toxicity observed. Next, we showed compound 1 concentration-dependently inhibited necrotic cell death pathway activation and 2.5 mM compound 1 also prevented the loss of mitochondrial membrane potential, adenosine triphosphate production, and reactive oxygen species generation in mouse pancreatic acinar cells. Finally, we showed compound 1 protected against three clinically representative murine models of AP and significantly improved pancreatitis-associated acute lung injury. These data provide in vitro and in vivo evidence that one compound of diosgenyl saponins can be potential treatment for AP. This study suggests natural saponins may serve as fruitful sources for exploring/identifying potential therapies for inflammatory diseases. PMID- 27779239 TI - Critical scaling of icosahedral medium-range order in CuZr metallic glass-forming liquids. AB - The temperature evolution of icosahedral medium-range order formed by interpenetrating icosahedra in CuZr metallic glassforming liquids was investigated via molecular dynamics simulations. Scaling analysis based on percolation theory was employed, and it is found that the size distribution of clusters formed by the central atoms of icosahedra at various temperatures follows a very good scaling law with the cluster number density scaled by S-tau and the cluster size S scaled by |1 - Tc/T|-1/sigma, respectively. Here Tc is scaling crossover-temperature. tau and sigma are scaling exponents. The critical scaling behaviour suggests that there would be a structural phase transition manifested by percolation of locally favoured structures underlying the glass transition, if the liquid could be cooled slowly enough but without crystallization intervening. Furthermore, it is revealed that when icosahedral short-range order (ISRO) extends to medium-range length scale by connection, the atomic configurations of ISROs will be optimized from distorted ones towards more regular ones gradually, which significantly lowers the energies of ISROs and introduces geometric frustration simultaneously. Both factors make key impacts on the drastic dynamic slow-down of supercooled liquids. Our findings provide direct structure-property relationship for understanding the nature of glass transition. PMID- 27779240 TI - Specificity Evaluation and Disease Monitoring in Arthritis Imaging with Complement Receptor of the Ig superfamily targeting Nanobodies. AB - Single-photon emission computed tomography combined with micro-CT (SPECT/MUCT) imaging using Nanobodies against complement receptor of the Ig superfamily (CRIg), found on tissue macrophages such as synovial macrophages, has promising potential to visualize joint inflammation in experimental arthritis. Here, we further addressed the specificity and assessed the potential for arthritis monitoring. Signals obtained with 99mTc-labelled NbV4m119 Nanobody were compared in joints of wild type (WT) versus CRIg-/- mice with collagen-induced arthritis (CIA) or K/BxN serum transfer-induced arthritis (STIA). In addition, SPECT/MUCT imaging was used to investigate arthritis development in STIA and in CIA under dexamethasone treatment. 99mTc-NbV4m119 accumulated in inflamed joints of WT, but not CRIg-/- mice with CIA and STIA. Development and spontaneous recovery of symptoms in STIA was reflected in initially increased and subsequently reduced joint accumulation of 99mTc-NbV4m119. Dexamethasone treatment of CIA mice reduced 99mTc-NbV4m119 accumulation as compared to saline control in most joints except knees. SPECT/MUCT imaging with 99mTc-NbV4m119 allows specific assessment of inflammation in different arthritis models and provides complementary information to clinical scoring for quantitatively and non-invasively monitoring the pathological process and the efficacy of arthritis treatment. PMID- 27779241 TI - Comparative venomics of Psyttalia lounsburyi and P. concolor, two olive fruit fly parasitoids: a hypothetical role for a GH1 beta-glucosidase. AB - Venom composition of parasitoid wasps attracts increasing interest - notably molecules ensuring parasitism success on arthropod pests - but its variation within and among taxa is not yet understood. We have identified here the main venom proteins of two braconid wasps, Psyttalia lounsburyi (two strains from South Africa and Kenya) and P. concolor, olive fruit fly parasitoids that differ in host range. Among the shared abundant proteins, we found a GH1 beta glucosidase and a family of leucine-rich repeat (LRR) proteins. Olive is extremely rich in glycoside compounds that are hydrolyzed by beta-glucosidases into defensive toxic products in response to phytophagous insect attacks. Assuming that Psyttalia host larvae sequester ingested glycosides, the injected venom GH1 beta-glucosidase could induce the release of toxic compounds, thus participating in parasitism success by weakening the host. Venom LRR proteins are similar to truncated Toll-like receptors and may possibly scavenge the host immunity. The abundance of one of these LRR proteins in the venom of only one of the two P. lounsburyi strains evidences intraspecific variation in venom composition. Altogether, venom intra- and inter-specific variation in Psyttalia spp. were much lower than previously reported in the Leptopilina genus (Figitidae), suggesting it might depend upon the parasitoid taxa. PMID- 27779242 TI - MiR1918 enhances tomato sensitivity to Phytophthora infestans infection. AB - Late blight of tomato is caused by the oomycete pathogen Phytophthora infestans. In our previous work, we identified and characterized a miR1918 in P. infestans (pi-miR1918), and showed that its sequence is similar to the sequence of tomato miR1918 (sly-miR1918). In this study, we used Arabidopsis thaliana pre-miR159a as a backbone to synthesize pi-miR1918 via PCR and mutagenesis. The artificial pi miR1918 was used to investigate the role of miR1918 in tomato-P. infestans interaction. Trangenic tomato plants that overexpressed the artificial pi-miR1918 displayed more serious disease symptoms than wild-type tomato plants after infection with P. infestans, as shown by increased number of necrotic cells, lesion sizes and number of sporangia per leaf. The target genes of pi-miR1918 and sly-miR1918 were also predicted for tomato and P. infestans, respectively. qPCR analysis of these targets also performed during tomato-P. infestans interaction. The expression of target gene, RING finger were negatively correlated with miR1918 in the all Lines of transgenic tomato plants. In addition, we used the 5' RACE to determine the cleavage site of miR1918 to RING finger. These results suggested that miR1918 might be involved in the silencing of target genes, thereby enhancing the susceptibility of tomato to P. infestans infection. PMID- 27779245 TI - Association between DRD2 and DRD3 gene polymorphisms and gastrointestinal symptoms induced by levodopa therapy in Parkinson's disease. AB - Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077 2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects. PMID- 27779244 TI - Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy. AB - To evaluate the predictive value of genes involved in resistance to platinum taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR. Most of the patients (172 out of 187) received front-line carboplatin-paclitaxel regimen. Expression levels were correlated with overall (OS) and progression-free (PFS) survival by multivariate analysis. Patients with high TXN and THBS1 expression presented longer PFS (P=0.001 and P<0.001, respectively) and OS (P=0.024 and P<0.001, respectively). High TXR1 expression was associated with decreased PFS (P<0.001) and OS (P<0.001). Multivariate analysis demonstrated that high PRR13/low THBS1 expression was an independent factor for decreased PFS (hazards ratio: 1.94; 95% confidence interval (CI): 1.48-2.92; P=0.008) and OS (hazard ratio: 3.89; 95% CI: 2.16-6.87; P<0.001), whereas low TXN expression was correlated with decreased PFS (hazard ratio: 1.44; 95% CI: 1.05-2.84; P=0.043) and OS (hazard ratio: 2.38; 95% CI: 1.78-2.77; P=0.009). These findings indicate that PRR13/THBS1 and TXN expression could be used for the prediction of resistance to treatment of EOC patients and, therefore, merit to be further evaluated. PMID- 27779246 TI - Are patients willing to incur out-of-pocket costs for pharmacogenomic testing? PMID- 27779243 TI - Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa. AB - As the common birthplace of all human populations, modern humans have lived longer on the African continent than in any other geographical region of the world. This long history, along with the evolutionary need to adapt to environmental challenges such as exposure to infectious agents, has led to greater genetic variation in Africans. The vast genetic variation in Africans also extends to genes involved in the absorption, distribution, metabolism and excretion of pharmaceuticals. Ongoing cataloging of these clinically relevant variants reveals huge allele-frequency differences within and between African populations. Here, we examine Africa's large burden of infectious disease, discuss key examples of known genetic variation modulating disease risk, and provide examples of clinically relevant variants critical for establishing dosing guidelines. We propose that a more systematic characterization of the genetic diversity of African ancestry populations is required if the current benefits of precision medicine are to be extended to these populations. PMID- 27779247 TI - HLA-B18 as risk factor of liver fibrosis progression in HIV/HCV treatment experienced patients. PMID- 27779248 TI - Association of CTH variant with sinusoidal obstruction syndrome in children receiving intravenous busulfan and cyclophosphamide before hematopoietic stem cell transplantation. AB - Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (ORTT=10.6, 95% confidence interval (CI)=2.16, 51.54) and SOS risk, which was sex dependent (female patients, ORTT=21.82, 95% CI=3.590-132.649). The interaction between CTHc.1364 G>T and another risk variant (GSTA1*B) was explored. A recessive model with the use of GSTA1*B*B and CTH c.1364 TT genotypes proved to be useful at predicting SOS occurrence, indicating the possibility of using these gene variants as markers of SOS occurrence and to further individualize preemptive treatment aimed at reducing SOS incidence. PMID- 27779249 TI - The global spectrum of protein-coding pharmacogenomic diversity. AB - Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (FST>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response. PMID- 27779250 TI - The preparation of rat's acellular spinal cord scaffold and co-culture with rat's spinal cord neuron in vitro. AB - STUDY DESIGN: The rat's acellular spinal cord scaffold (ASCS) and spinal cord neurons were prepared in vitro to explore their biocompatibility. OBJECTIVES: The preparation of ASCS and co-culture with neuron may lay a foundation for clinical treatment of spinal cord injury (SCI). SETTING: Tianjin Medical University General Hospital, ChinaMethods:ASCS was prepared by chemical extraction method. Hematoxylin and eosin (H&E), myelin staining and scanning electron microscope were used to observe the surface structure of ASCS. Spinal cord neurons of rat were separated in vitro, and then co-cultured with prepared ASCS in virto. RESULTS: The prepared ASCS showed mesh structure with small holes of different sizes. H&E staining showed that cell components were all removed. The ASCS possessed fine three-dimensional network porous structure. DNA components were not found in the ASCS by DNA agarose gel electrophoresis. The cultured cells express neuron-specific enolase (NSE) antigen with long axons. H&E staining showed that the neurons adhered to the pore structures of ASCS, and the cell growth was fine. The survival rate of co-cultured cells was (97.53+/-1.52%) by MTT detection. Immunohistochemical staining showed that neurons on the scaffold expressed NSE and NeuN antigen. Cells were arranged closely, and the channel structures of ASCS were fully filled with neurons. The cells accumulated in the channel and grew well in good state. CONCLUSION: The structure of ASCS remained intact, and the neurons were closely arranged in the scaffolds. These results may lay a solid foundation for clinical treatment of SCI when considering glial scar replacement by biomaterials. PMID- 27779251 TI - Non-targeted transcriptomic effects upon thyroid irradiation: similarity between in-field and out-of-field responses varies with tissue type. AB - Non-targeted effects can induce responses in tissues that have not been exposed to ionizing radiation. Despite their relevance for risk assessment, few studies have investigated these effects in vivo. In particular, these effects have not been studied in context with thyroid exposure, which can occur e.g. during irradiation of head and neck tumors. To determine the similarity between in-field and out-of-field responses in normal tissue, we used a partial body irradiation setup with female mice where the thyroid region, the thorax and abdomen, or all three regions were irradiated. After 24 h, transcriptional regulation in the kidney cortex, kidney medulla, liver, lungs, spleen, and thyroid was analyzed using microarray technology. Thyroid irradiation resulted in transcriptional regulation in the kidney medulla and liver that resembled regulation upon direct exposure of these tissues regarding both strength of response and associated biological function. The kidney cortex showed fewer similarities between the setups, while the lungs and spleen showed little similarity between in-field and out-of-field responses. Interestingly, effects were generally not found to be additive. Future studies are needed to identify the molecular mechanisms that mediate these systemic effects, so that they may be used as targets to minimize detrimental side effects in radiotherapy. PMID- 27779253 TI - Synchronization in slowly switching networks of coupled oscillators. AB - Networks whose structure of connections evolves in time constitute a big challenge in the study of synchronization, in particular when the time scales for the evolution of the graph topology are comparable with (or even longer than) those pertinent to the units' dynamics. We here focus on networks with a slow switching structure, and show that the necessary conditions for synchronization, i.e. the conditions for which synchronization is locally stable, are determined by the time average of the largest Lyapunov exponents of transverse modes of the switching topologies. Comparison between fast- and slow-switching networks allows elucidating that slow-switching processes prompt synchronization in the cases where the Master Stability Function is concave, whereas fast-switching schemes facilitate synchronization for convex curves. Moreover, the condition of slow switching enables the introduction of a control strategy for inducing synchronization in networks with arbitrary structure and coupling strength, which is of evident relevance for broad applications in real world systems. PMID- 27779252 TI - NtKRP, a kinesin-12 protein, regulates embryo/seed size and seed germination via involving in cell cycle progression at the G2/M transition. AB - Kinesins comprise a superfamily of microtubule-based motor proteins involved in essential processes in plant development, but few kinesins have been functionally identified during seed development. Especially, few kinesins that regulate cell division during embryogenesis have been identified. Here we report the functional characterization of NtKRP, a motor protein of the kinesin-12 family. NtKRP is predominantly expressed in embryos and embryonic roots. NtKRP RNAi lines displayed reductions in cell numbers in the meristematic zone, in embryonic root length, and in mature embryo and seed sizes. Furthermore, we also show that CDKA;1 binds to NtKRP at the consensus phosphorylation sites and that the decreased cell numbers in NtKRP-silenced embryos are due to a delay in cell division cycle at the G2/M transition. In addition, binding between the cargo binding tail domain of NtKRP and CDKA; 1 was also determined. Our results reveal a novel molecular pathway that regulates embryo/seed development and critical role of kinesin in temporal and spatial regulation of a specific issue of embryo developmental. PMID- 27779254 TI - Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia. AB - Peripheral nerve damage does not fully explain the pathogenesis of trigeminal neuralgia (TN). Central nervous system changes can follow trigeminal nerve dysfunction. We hypothesized that brain white matter and functional connectivity changes in TN patients were involved in pain perception, modulation, the cognitive-affective system, and motor function; moreover, changes in functional reorganization were correlated with white matter alterations. Twenty left TN patients and twenty-two healthy controls were studied. Diffusion kurtosis imaging was analyzed to extract diffusion and kurtosis parameters, and functional connectivity density (FCD) mapping was used to explore the functional reorganization in the brain. In the patient group, we found lower axial kurtosis and higher axial diffusivity in tracts participated in sensory, cognitive affective, and modulatory aspects of pain, such as the corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, cingulated gyrus, forceps major and uncinate fasciculus. Patients exhibited complex FCD reorganization of hippocampus, striatum, thalamus, precentral gyrus, precuneus, prefrontal cortex and inferior parietal lobule in multiple modulatory networks that played crucial roles in pain perception, modulation, cognitive-affective system, and motor function. Further, the correlated structural-functional changes may be responsible for the persistence of long-term recurrent pain and sensory related dysfunction in TN. PMID- 27779256 TI - Erratum: The Etiology and Pathogenesis of Kienbock Disease. AB - [This corrects the article DOI: 10.1055/s-0036-1583755.]. PMID- 27779255 TI - LMO2 attenuates tumor growth by targeting the Wnt signaling pathway in breast and colorectal cancer. AB - The proto-oncogene LIM-domain only 2 (lmo2) was traditionally considered to be a pivotal transcriptional regulator in hematopoiesis and leukemia. Recently, the cytosolic localization of LMO2 was revealed in multiple epithelial tissues and a variety of solid tumors. However, the function of LMO2 in these epithelia and solid tumors remains largely unclear. The Wnt signaling pathway is a crucial determinant of development, and abnormalities in several key segments of this pathway contribute to oncogenesis. The current study demonstrated that LMO2 participates in the regulation of canonical Wnt signaling in the cytoplasm by binding to Dishevelled-1/2 (DVL-1/2) proteins. These interactions occurred at the PDZ domain of Dishevelled, and LMO2 subsequently attenuated the activation of the key factor beta-catenin in the canonical Wnt signaling pathway. Meanwhile, significantly decreased expression of LMO2 was detected in breast and colorectal cancers, and the downregulation of LMO2 in these cells increased cell proliferation and reduced apoptosis. Taken together, the data in this study revealed a novel crosstalk between LMO2 and the Wnt signaling pathway during tumorigenesis and suggested that LMO2 might be a tumor suppressor in certain solid tumors, in contrast to its traditional oncogenic role in the hematopoietic system. PMID- 27779258 TI - Colored spectrum characteristics of thermal noise on the molecular scale. AB - Thermal noise is of fundamental importance to many processes. Traditionally, thermal noise has been treated as white noise on the macroscopic scale. Using molecular dynamics simulations and power spectrum analysis, we show that the thermal noise of solute molecules in water is non-white on the molecular scale, which is in contrast to the conventional theory. In the frequency domain from 2 * 1011 Hz to 1013 Hz, the power spectrum of thermal noise for polar solute molecules resembles the spectrum of 1/f noise. The power spectrum of thermal noise for non-polar solute molecules deviates only slightly from the spectrum of white noise. The key to this phenomenon is the existence of hydrogen bonds between polar solute molecules and solvent water molecules. Furthermore, for polar solute molecules, the degree of power spectrum deviation from that of white noise is associated with the average lifetime of the hydrogen bonds between the solute and the solvent molecules. PMID- 27779257 TI - Erratum: Experimental evolution of an RNA virus in cells with innate immunity defects. AB - [This corrects the article DOI: 10.1093/ve/vev008.]. PMID- 27779259 TI - The segregation resistance of the Pt2ML/Os/Pd3Al sandwich catalyst for oxygen reduction reaction: a density functional theory study. AB - Pt1ML/Pd3Al, which comprises a Pd3Al core protected by a Pt monolayer, may experience Al dealloying because of the strong affinity of Al toward O. To circumvent this issue, the Pt2ML/Os/Pd3Al catalyst has been designed to suppress the migration of Al by inserting an Os monolayer at the interface between the Pd3Al core and two Pt monolayers. On the basis of segregation energies, Al leaching from the core to the 1st layer is determined to be endothermic even under O coverage, indicating an energetic preference for Al to reside in the core structure. The Pt2ML/Os/Pd3Al catalyst benefits from the energetic disadvantage of the inward movement of Os and the presence of the 2 ML Pt layer. As an ORR electrocatalyst, the relatively weak adsorption ability of Pt2ML/Os/Pd3Al suggests improved ORR activity. Finally, a representative OOH association mechanism with low reaction barriers of 0.46, 0.31, 0.38 and 0.41 eV for the OOH formation, OOH dissociation, OH formation and H2O formation steps suggests that the catalyst can effectively activate the O-O bond and eliminate OH, which can act as a catalytic poison. These findings suggest the design of stable sandwich catalysts as potential candidates for ORR electrocatalysis. PMID- 27779260 TI - Characterisation of isothiocyanic acid, HNCS, in the solid state: trapped by hydrogen bonding. AB - The crystal structure of [Ph4P][NCS].HNCS is reported. This is the first structural determination of isothiocyanic acid and hydrogen bonding between the NCS anion and HNCS fragment explored using computational chemistry. PMID- 27779261 TI - Experimental and theoretical studies on methylene blue and methyl orange sorption by wheat straw-derived biochar with a large surface area. AB - Wheat straw-derived biochar (BC-4-700) with a large surface area (2263.10 m2 g-1) has been synthesized using potassium hydroxide as an activating agent, and its sorption performance is evaluated by sorbing methylene blue (MB) and methyl orange (MO). The sorption behaviours of both MO and MB by BC-4-700 all follow pseudo-second-order and Langmuir models, and the driving forces for the two sorptions are attributed to the pi-pi interaction. The largest sorption quantity for MO by BC-4-700 is 3.24 mmol g-1, being 1.37 times larger than that for MB (2.36 mmol g-1). There is an inflection point in the isotherm sorption curve of MB. It is widely accepted that MB is a cationic dye and MO is an anionic dye. However, the two experimental phenomena cannot be explained well by the widely accepted MB+ form. The pH detection experiments on MB and MO solutions suggest that MO does not hydrolyze in water and the existing form in water is the well accepted MO-, whereas MB hydrolyzes in water and the existing forms in water most likely include both the well-accepted MB+ and the hydrolyzed form of MB+. This finding can account well for the two experimental phenomena mentioned above, which is helpful to understand deeply the behaviour of organic cations in water and the sorption mechanism of organic cations by sorption materials. PMID- 27779262 TI - A multi-responsive hydrogel with a triple shape memory effect based on reversible switches. AB - A novel multi-responsive shape memory hydrogel is described. The hydrogel shows multi-responsive shape memory performance and a programmable triple shape memory effect based on dual multi-responsive reversible switches, which will inspire the design and fabrication of novel shape memory systems. PMID- 27779263 TI - A bifunctional cationic porous organic polymer based on a Salen-(Al) metalloligand for the cycloaddition of carbon dioxide to produce cyclic carbonates. AB - A bifunctional cationic porous organic polymer based on a Salen-(Al) metalloligand (Al-CPOP) containing imidazolium functionality exhibited enhanced activity and good recyclability in the cycloaddition of carbon dioxide to produce cyclic carbonates without the addition of co-catalysts at atmospheric pressure. PMID- 27779264 TI - The death of the Job plot, transparency, open science and online tools, uncertainty estimation methods and other developments in supramolecular chemistry data analysis. AB - Data analysis is central to understanding phenomena in host-guest chemistry. We describe here recent developments in this field starting with the revelation that the popular Job plot method is inappropriate for most problems in host-guest chemistry and that the focus should instead be on systematically fitting data and testing all reasonable binding models. We then discuss approaches for estimating uncertainties in binding studies using case studies and simulations to highlight key issues. Related to this is the need for ready access to data and transparency in the methodology or software used, and we demonstrate an example a webportal () that aims to address this issue. We conclude with a list of best-practice protocols for data analysis in supramolecular chemistry that could easily be translated to other related problems in chemistry including measuring rate constants or drug IC50 values. PMID- 27779265 TI - Chirped-pulse Fourier transform millimeter-wave spectroscopy of ten vibrationally excited states of i-propyl cyanide: exploring the far-infrared region. AB - We report here further spectroscopic investigation of the astrochemically relevant molecule i-propyl cyanide. We observed and analysed the rotational spectra of the ground state of the molecule and ten vibrationally excited states with energies between 180-500 cm-1. For this, we used a segmented W-band spectrometer (75-110 GHz) and performed the experiments under room temperature conditions. This approach thus provides access to high-resolution, pure rotational data of vibrational modes that occur in the far-infrared fingerprint region, and that can be difficult to access with other techniques. The obtained, extensive data set will support further astronomical searches and identifications, such as in warmer regions of the interstellar space where contributions from vibrationally excited states become increasingly relevant. PMID- 27779266 TI - Stacking disorder in silicon carbide supported cobalt crystallites: an X-ray diffraction, electron diffraction and high resolution electron microscopy study. AB - Supported cobalt Fischer-Tropsch catalysts are characteristically nanoparticulate and the reduced SiC supported catalyst was found to contain both HCP and FCC polymorphs. This is reflected in the powder XRD patterns and generally there is a poor fit between the experimental and calculated diffractograms. This was ascribed to small crystallite sizes and the occurrence of disorder, manifested as peak broadening and peak shifts. Selected area electron diffraction data of suitably oriented cobalt catalyst grains on silicon carbide supports show non periodic disorder in the zone axis orientations that contain the common (001) (HCP) and (111) (FCC) reciprocal lattice planes. Both FCC and HCP polymorphs are present in the same grains and these show disorder mainly in the HCP component. The disorder is further examined using high angle annular dark field (HAADF) scanning transmission electron microscopy at atomic resolution and the stacking sequences elucidated. Random sequences of mainly FCC are interrupted by HCP sequences and twin surfaces with reverse stacking sequences are also present. This study highlights the presence of significant disorder in cobalt catalyst grains confirmed by HAADF microscopy. PMID- 27779267 TI - Analyte-responsive gated hollow mesoporous silica nanoparticles exhibiting inverse functionality and an AND logic response. AB - A multifunctional nanoparticle with designed selectivity was made using hollow mesoporous silica, ship-in-a-bottle synthesis of a crystalline solid-state detector, and protection of the crystal by acid-responsive nanogates. The system demonstrates the inverse application of the usual trapping of contents by the gate followed by their release. Instead, the gate protects the contents followed by selective exposure. Crystallization of [Pt(tpy)Cl](PF6) (tpy = 2,2':6',2'' terpyridine) inside the cavity of hollow mesoporous silica created the unique core/shell nanoparticle. The crystalline core becomes fluorescent in the presence of perchlorate. By condensing an acid-sensitive gate onto the particle, access to the pores is blocked and the crystal is protected. The new nanomaterial obeys Boolean AND logic; only the presence of both the analyte (ClO4-) and acid results in the optical response. PMID- 27779268 TI - N-HO and N-HCl supported 1D chains of heterobimetallic CuII/NiII-SnIV cocrystals. AB - The Schiff base H2L1 [N,N'-ethylenebis(3-methoxysalicylaldimine)] or H2L2 [N,N' ethylenebis(3-ethoxysalicylaldimine)] was reacted with MCl2.xH2O and SnCl4.5H2O to afford the supramolecular heterobimetallic systems (H2ED)2+.2[ML].[SnCl6]2- [M = Cu, L = L1 (1), L = L2 (2); M = Ni, L = L1 (3), L = L2 (4); ED = 1,2 ethylenediamine], whose structures were established by single crystal X-ray analyses. Each structure includes different entities, viz. a mononuclear [CuL]/[NiL] neutral complex (coformer), a hexachlorostannate dianion [SnCl6]2-, a 1,2-ethylenediammonium dication (H2ED2+) and, only in 2 and 4, a methanol molecule. Based on the work of Grothe et al. (Cryst. Growth Des., 2016, 16, 3237 3243), compounds 1 and 3 are cocrystal salts, 2 and 4 are cocrystal salt solvates. The ionic pairs (H2ED)2+.[SnCl6]2- in 1-4 are encapsulated by the Cu- or Ni-complexes, and stabilized by N-HO and one N-HCl bond interactions leading to infinite 1D chains. The antimicrobial studies of 1-4 against yeasts (C. albicans and S. cerevisiae) and Gram-positive (S. aureus and E. faecalis) and negative bacteria (P. aeruginosa and E. coli) indicate that the Ni2Sn systems (3 and 4) are more active than the analogous Cu2Sn ones (1 and 2). PMID- 27779269 TI - Total synthesis of (+/-)-ganocins B and C. AB - The first total synthesis of structurally unique polycyclic phenolic meroterpenoids, ganocins B and C is reported. The synthesis features gold catalyzed intramolecular cascade cyclization to construct the C/D ring bearing an angular methyl group, diastereoselective Michael addition, and acid-mediated one pot Robinson cyclization/deprotection/isomerization. PMID- 27779270 TI - A radical addition/cyclization of diverse ethers to 2-isocyanobiaryls under mildly basic aqueous conditions. AB - Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogenative addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution (BHAS). PMID- 27779272 TI - Effect of monocortical and bicortical screw numbers on the properties of a locking plate-intramedullary rod configuration. An in vitro study on a canine femoral fracture gap model. AB - OBJECTIVES: To evaluate the effect of varying the number and configuration of locking bicortical and monocortical screws on a plate-rod construct using a mid diaphyseal femoral ostectomy model. METHODS: Thirty Greyhound femurs were assigned to six groups (A-F). An intramedullary pin was placed in each bone following which a 3.5 mm locking plate was applied with six differing locking screw configurations. Groups A to C had one bicortical screw in the most proximal and distal plate holes and one to three monocortical locking screws in the proximal and distal fragments. Groups D to F had no bicortical screws placed and two to four monocortical locking screws in proximal and distal fragments. Each construct was axially loaded at 4 Hz from a preload of 10 Newtons (N) to 72 N, increasing to 144 N and 216 N, each of 6000 cycles with a further 45,000 cycles at 216 N to simulate a three to six week postoperative convalescence period. Constructs were then loaded to failure. RESULTS: No construct suffered screw loosening or a significant change in construct stiffness during cyclic loading. There was no significant difference in load to failure of any construct (p = 0.34), however, less variation was seen with monocortical constructs. All constructs failed at greater than 2.5 times physiological load, and failure was by bending of the intramedullary pin and plate rather than screw loosening or pull-out. CLINICAL SIGNIFICANCE: Axially loaded locking monocortical plate-rod constructs applied to the canine femur may confer no difference biomechanically to those employing locking bicortical screws. PMID- 27779271 TI - Inter- and intra-observer variability of radiography and computed tomography for evaluation of Zurich cementless acetabular cup placement ex vivo. AB - OBJECTIVE: To evaluate the inter- and intra-observer variability in measurement of the angle of lateral opening (ALO) and version angle measurement using digital radiography and computed tomography (CT). METHODS: Each hemipelvis was implanted with a cementless acetabular cup. Ventrodorsal and mediolateral radiographs were made of each pelvis, followed by CT imaging. After removal of the first cup, the pelves were implanted with an acetabular cup in the contralateral acetabulum and imaging was repeated. Three surgeons measured the ALO and version angles three times for each cup from the mediolateral radiographic projection. The same measurements were made using three-dimensional multiplanar reconstructions from CT images. Two anatomical axes were used to measure pelvic inclination in the sagittal plane, resulting in six measurements per cup. Two-way repeated measures analysis of variance evaluated inter- and intra-observer repeatability for radiographic and CT-based measurements. RESULTS: Version angle based on radiographic measurement did not differ within surgeons (p = 0.433), but differed between surgeons (p <0.001). Radiographic measurement of ALO differed within surgeons (p = 0.006) but not between surgeons (p = 0.989). The ALO and version angle measured on CT images did not differ with or between surgeons. CLINICAL SIGNIFICANCE: Assessment of inter- and intra-observer measurement of ALO and version angle was more reproducible using CT images than conventional mediolateral radiography for a Zurich cementless acetabular cup. PMID- 27779273 TI - Light-sheet microscopy by confocal line scanning of dual-Bessel beams. AB - We have developed a light-sheet microscope that uses confocal scanning of dual Bessel beams for illumination. A digital micromirror device (DMD) is placed in the intermediate image plane of the objective used to collect fluorescence and is programmed with two lines of pixels in the "on" state such that the DMD functions as a spatial filter to reject the out-of-focus background generated by the side lobes of the Bessel beams. The optical sectioning and out-of-focus background rejection capabilities of this microscope were demonstrated by imaging of fluorescently stained actin in human A431 cells. The dual-Bessel beam system enables twice as many photons to be detected per imaging scan, which is useful for low light applications (e.g., single-molecule localization) or imaging at high speed with a superior signal to noise. While demonstrated for two Bessel beams, this approach is scalable to a larger number of beams. PMID- 27779274 TI - Henry Norman Bethune (1890-1939): Surgeon, communist, humanitarian. PMID- 27779275 TI - Innovating for future health. PMID- 27779277 TI - Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy. AB - About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux related events that is proven on functional oesophageal tests. PMID- 27779278 TI - Magnetic resonance imaging of traumatic and non-traumatic brachial plexopathies. AB - Adult-onset brachial plexopathy can be classified into traumatic and non traumatic aetiologies. Traumatic brachial plexopathies can affect the pre- or postganglionic segments of the plexus. Non-traumatic brachial plexopathies may be due to neoplasia, radiotherapy, thoracic outlet syndrome and idiopathic neuralgic amyotrophy. Conventional magnetic resonance imaging (MRI) is useful to localise the area of injury or disease, and identify the likely cause. This review discusses some of the common causes of adult-onset brachial plexopathy and their imaging features on MRI. We also present a series of cases to illustrate some of these causes and their MRI findings. PMID- 27779279 TI - Iliac artery injury without bony lesions or neurological symptoms after blunt trauma. PMID- 27779276 TI - The debate on treating subclinical hypothyroidism. AB - Subclinical hypothyroidism (SCH) represents a mild or compensated form of primary hypothyroidism. The diagnosis of SCH is controversial, as its symptoms are non specific and its biochemical diagnosis is arbitrary. The treatment of SCH was examined among non-pregnant adults, pregnant adults and children. In non-pregnant adults, treatment of SCH may prevent its progression to overt hypothyroidism, reduce the occurrence of coronary heart disease, and improve neuropsychiatric and musculoskeletal symptoms associated with hypothyroidism. These benefits are counteracted by cardiovascular, neuropsychiatric and musculoskeletal side effects. SCH is associated with adverse maternal and fetal outcomes that may improve with treatment. Treating SCH in children is safe and may improve growth. Importantly, the evidence in this field is largely from retrospective and prospective studies with design limitations, which precludes a conclusive recommendation for the treatment of SCH. PMID- 27779280 TI - Hospitalised children with pandemic (H1N1) 2009 influenza. PMID- 27779281 TI - Policy options for increasing the supply of transplantable kidneys in Singapore. AB - Kidney transplantation is the preferred treatment for eligible end-stage renal disease patients. However, the supply of donated kidneys has been consistently insufficient to meet the transplantation requirements of the population. In this paper, I discuss the feasibility of several policy options that engage potential donors or key individuals in a Singapore context, including financial and non financial incentives for deceased/living organ donors and their families, improving actualisation rates of both donation after brain death, donation after cardiac death through quality improvement programmes and remuneration schemes, and a media platform for directed organ donation. I conclude by highlighting the most feasible policies to be considered. PMID- 27779282 TI - [Costs and benefits of psychiatry]. PMID- 27779284 TI - [Inter-sectoral costs and benefits arising from mental health (disorders)]. AB - BACKGROUND: Mental health disorders may bring costs and benefits to areas and sectors lying outside the health care system. However, little is known about these inter-sectoral costs and benefits (ICBs) in spite of the increasing interest in societal cost-benefit analyses (SCBA) that attempt to quantify all costs and benefits involved.
AIM: To present a first inventory of ICBs relating to mental health care and to describe the relation between ICBs and SCBA.
METHOD: We reviewed the literature and conducted a secondary analysis of the results of a previous study.
RESULTS: We found that at least eight mental health disorders were reported to have a (financial) impact on at least three sectors outside the health care system.
CONCLUSION: Further research into ICBs is needed so that future inter-sectoral policy can be better directed and targeted more efficiently. PMID- 27779283 TI - [Towards a sustainable, cost-effective mental health care; a policy perspective]. AB - BACKGROUND: After a decade of robust growth in spending, Dutch mental healthcare is on a more stricter budgetary path since 2012. High prevalence of illness and limited spending, imply the need for efficient mental healthcare delivery.
AIM: To advise how mental health care can be managed more efficiently. There will also have to be more differentiation between mild and serious psychiatric illnesses.
METHOD: Review of academic articles and policy studies.
RESULTS: With regard to the treatment of fairly common disorders, more attention needs to be given to integrated basic care and e-health. Employers and stakeholders can perhaps play a role in financing some of these services. Severe mental disorders can be handled more often on an integrated ambulatory basis setting than only in a hospital setting, while scaling down inpatient capacity. These steps would represent a major transition and would require spending cuts and a change in the provider 'landscape'.
CONCLUSION: Sustainable mental healthcare is inseparably linked to an agenda that provides value for money and it implies a major transition. However, in principle, it should be possible to fit these changes into the current system of governance. More attention needs to be given to coordination between the various domains, and to a reduction in administrative costs. Reimbursement methods should align e-health, collaborative care, case-management and best-practice pathways. PMID- 27779285 TI - [Prognostic modelling and proactive intervention in psychosis: efficacy and cost effectiveness]. AB - BACKGROUND: Diagnoses have heterogeneous outcomes, varying from good to extremely poor. There is a need to single out an ultra-high-risk group of individuals who have illnesses that might well end unfavourably or who might later develop serious psychopathology.
AIM: To devise a screening instrument that can identify a group of individuals who run a very high risk of developing a first episode psychosis, and to create a type of intervention that can modify the course of the illness.
METHOD: We developed a short screening instrument (PQ 16) and were able to ascertain its predictive value. We also tested an intervention that could influence risk factors and deal with emerging symptoms thereby achieving a better outcome for the patient.
RESULTS: We developed a two-step detection instrument with a positive predictive value of 44%. The intervention, involving cognitive behavioural therapy for ultra-high-risk patients, was effective and led to a risk reduction of about 50%. Using the ultra high-risk group of patients, we were able to model three prognostic profiles, each carrying a 4%, 13%, and 70% risk of subsequently developing psychosis. The intervention was cost-effective, reducing the financial burden on the health care services and on society as a whole.
CONCLUSION: Prognostic modelling and proactive intervention can achieve improvements in health at lower costs. PMID- 27779286 TI - [A study of cost-effectiveness of treating serious mental illness: challenges and solutions]. AB - BACKGROUND People with serious mental illness (SMI) often suffer high healthcare costs and enduring loss of quality of life. Increasing our understanding of the cost-effectiveness of people with SMI is important when striving for optimal health at affordable costs. AIM To describe aspects that can be important for cost-effectiveness research targeting people with SMI. METHOD These aspects are demonstrated by considering pro-active care, rehabilitation and involuntary treatment RESULTS The possible involvement of a large number of stakeholders outside of healthcare requires cost-effectiveness research to also map the costs and benefits outside of healthcare, preferably for each stakeholder specifically. Availability of data, the possibility to combine datasets, and ways to deal with dropouts require extra attention. CONCLUSION Cost-effectiveness research targeting people with SMI could be enhanced when solutions are found for the availability of data inside and outside of healthcare and when dropout can be compensated for by other sources of data, such that costs and benefits for each stakeholder can be estimated more reliably. PMID- 27779288 TI - [Social return on internet interventions for alcohol use disorders]. AB - BACKGROUND: One of the main reasons for treating patients using internet interventions is that this modality is considered highly efficient. However, little is known about the actual cost-effectiveness of internet interventions for alcohol use disorders (aud).
AIM: To provide insight in the cost effectiveness of internet interventions for the treatment of aud.
METHOD: Review of the relevant literature in this area.
RESULTS: A considerable amount of research has been performed on the effectiveness of internet interventions for aud, with mostly positive findings. However, research on the cost-effectiveness of these interventions has been relatively sparse. Based on the available evidence there are indications that internet interventions for aud can be cost-effective - although findings in the literature are mixed.
CONCLUSION: More research is needed to make valid estimates of the cost effectiveness of internet interventions for aud. Potential savings can only be estimated after the system has been used over a longer period. However, the evidence obtained thus far is promising. PMID- 27779287 TI - [Child maltreatment: long-term economic consequences and implications]. AB - BACKGROUND: Child maltreatment occurs frequently. This has detrimental effects later in life on mental health and is linked to considerable costs due to health care use and sick leave. Self-mastery, however, is a factor that may well mitigated the effects of child maltreatment .
AIM: To quantify the long term costs of child abuse and to test the hypothesis that self-mastery can modify the after-effects of maltreatment .
METHOD: Data were obtained from a psychiatric cohort study (n=5618). The risk factors were emotional neglect and mental, physical and sexual abuse before the age of 16.
RESULTS: When individuals are about 39 years old, the various forms of maltreatment to which they were subjected as children are associated with substantially higher health care costs and frequent absenteeism. Higher levels of self-mastery achieved in childhood were indeed associated with lower costs in adulthood.
CONCLUSION: Child maltreatment costs the Netherlands millions of euros annually because it leads to higher health care costs and more frequent sick leave. Active steps to curb child abuse are of both financial and economic significance. More training in self-mastery could perhaps be helpful, but further research is needed in this area. PMID- 27779289 TI - [Cost-effectiveness of psychotherapy for personality disorders. A systematic review on economic evaluation studies]. AB - BACKGROUND: So far, there has not been a complete overview of the cost effectiveness of psychotherapy for patients with a personality disorder.
AIM: To provide an overview of scientific literature on the cost-effectiveness of psychotherapy for patients with a personality disorder.
METHOD: We reviewed the literature systematically, searching the NHS EED, PubMed and PsycINFO databases. We concentrated solely on full economic evaluations of treatments in which all patients had a personality disorder.
RESULTS: Most studies concluded that at least one of the psychotherapeutic treatments investigated was cost-effective. Dialectical behavior therapy was studied the most; schema therapy came next, followed by cognitive behavioural therapy.
CONCLUSION: In general, scientific evidence indicates that psychotherapeutic treatments for patients with personality disorders are cost-effective relative to the comparator treatments. This is important information because it can influence decisions on whether the costs of psychotherapy should be reimbursed. PMID- 27779290 TI - [Child psychiatry: limited research, evidence for cost-effectiveness of treatment]. AB - BACKGROUND: Research into cost-effectiveness of treatment of child psychiatric disorders is extremely limited. There are two main reasons for this: it's a new field and the type of research required is intrinsically complicated.
AIM: To review selected articles that reveal the prevalence of child psychiatric disorders, demonstrate the complexity of cost-efficiency research in child psychiatry and point to the possible benefits of appropriate treatment.
METHOD: We provide an overview of a selected number of articles dealing with the prevalence of child psychiatric disorders and the costs involved, we stress the diffulty of assessing whether current treatment is cost-effective and we describe the possible benefits of treatment.
RESULTS: However, the limited number of articles that we located do indicate that the treatment of children with psychiatric disorders is cost-effective. Not only does it benefit the child, it also eases the burden on the parents and on society as a whole. Findings need to be interpreted in the light of the limited scope and shortcomings of the research done so far.
CONCLUSION: Although current research seems to be cost effective, we stress the need for further investigations, particularly in the form of longer-term studies. PMID- 27779291 TI - [The tasks and aims of hospital psychiatry today and in the future]. AB - BACKGROUND: Care provided by consultation-liaison (CL) psychiatry and general hospital (GH) psychiatry varies widely. This means that certain services are almost unrecognisable and therefore less readily available to patients.
AIM: To describe the core tasks of current CL- and GH-psychiatry care and to suggest how these tasks can best be performed and developed in the future.
METHOD: We conducted a selective review of relevant CL- and GH-related literature and combined the information we obtained with the results of a consultation with CL-psychiatrists about how CL- and GL psychiatry should function in the future.
RESULTS: Core tasks of CL- and GH-psychiatry are: 1. inpatient and outpatient care for complex patients with combined somatic and psychiatric problems (including addiction) and 2. acute care, diagnosis and treatment of patients referred to the Emergency Department. We gave an outline of how the quality of training can be maintained and/or improved and we suggest ways in which the funding of CL- and GH-psychiatry can be safeguarded and, if possible, increased in the future.
CONCLUSION: We strongly recommend that large teaching hospitals and all university hospitals should have at their disposal a psychiatric consultation service that includes psychiatric Emergency Department facilities and specialised CL and GH inpatient and outpatient facility such as a medical-psychiatric unit. The CL- and GH-service should have a psychiatrist as gatekeeper and should be integrated into the hospital's chain of care. Partners in this chain of care are interns who have other medical specialisms, mental health specialists employed at other (mainly psychiatric) hospitals and general practitioners (GPs). PMID- 27779292 TI - [Mandatory treatment of forensic psychiatric patients in the Netherlands: costs and benefits in perspective]. AB - BACKGROUND: So far, it is not known what costs and benefits are connected with the tbs-measure, a measure that involves a mandatory treatment programme for forensic psychiatric patients.
AIM: To explore the costs and benefits that the tbs-measure has on society, on other important stakeholders such as victims and/or next-of-kin and the forensic psychiatric patients themselves.
METHOD: We studied the relevant literature.
RESULTS: The average costs of the tbs-treatment programme are 1.5 million euros. Additional costs result from recidivism among patients after tbs-treatment. Of these, 21.2% commit another serious offence after 9 years; this recidivism rate is much lower than rates for former offenders who have not received tbs-treatment (63.8%). Other costs arise through the impact that crimes have on stake-holders. Among the benefits of the tbs-programme are a reduction in psychopathological symptoms and in risk factors and lower recommitment rates (including judicial, non-judicial, voluntary and mandatory recommitment rates). Yet another benefit is the resultant increase of protective factors.
CONCLUSION: Forensic psychiatric patients form a unique group within the mental health system in the Netherlands; these patients have multiple complex psychiatric problems and display serious criminal behavior. This group cannot easily be treated elsewhere in the existing judicial or mental health care system because these systems differ in (judicial) frameworks and have different treatment goals, and the forensic psychiatric patients have different psychiatric disorders and display more serious criminal behaviour than patients in the alternative systems. The daily costs of treatment in the tbs-system are higher that in other systems - but they are not exorbitant, given the complexity of the group. The tbs-measure therefore contributes to the safety of society. PMID- 27779293 TI - [Online self-help for persons with suicidal intentions: budget impact analysis]. AB -

. PMID- 27779295 TI - [The willingness of the Dutch to pay for mental health care]. AB - BACKGROUND: How much are the Dutch prepared to pay for mental health care? Nearly every year the content of the basic health insurance package alters as a results of new insights and scientific and medical progress. Up till now, the government of the Netherlands has largely ignored the wishes of its people regarding which services should be included in or dropped from the basis health care package.
AIM: To describe a method for measuring the Dutch population's willingness to pay (wtp) for the inclusion of mental health care in the basic health insurance package and, at the same time, to present the first empirical findings obtained by this method.
METHOD: Data were collected in 2013 via a printed questionnaire on which the respondent was asked to declare how much he or she would be prepared to pay for the inclusion of mental health care in the basic health care package.
RESULTS: The average per capita amount that the Dutch were prepared to pay for the inclusion of mental health care was found be ? 25.90 per month.
CONCLUSION: The average amount that a Dutch national was prepared to pay for having mental health care included in the basic package was higher that the actual per capita amount paid for mental health care. In 2013 these costs were ? 15.80 per capita per month. PMID- 27779294 TI - [Comparison of efficacy of psychiatric treatment versus treatment in general medicine]. AB - BACKGROUND: There is increasing attention to the costs and efficacy of health care and in particular to psychiatry. To weigh the costs and benefits appropriately, it is important to be able to compare effects.
AIM: To describe the efficacy of psychiatric treatment compared to treatment in general medicine.
METHOD: Narrative review.
RESULTS: The average effect size of psychiatric treatment was 0.49 and that of general medicine treatment 0.45. The effect size of psychotherapy varied from 0.3 - 0.84, but in a meta-analysis, corrected for publication bias, the effect size average amounted to only 0.39.
CONCLUSION: The average efficacy of psychiatric treatments is similar to the efficacy of treatments in general medicine. However, there is a large variation in efficacy within the two treatment areas. The variation is even larger in the treatment results for individual patients. The main objective of 'personalised medicine' is to tailor the type of treatment to the particular symptoms of the individual patient so that he or she will not be exposed to types of treatment that are not strictly relevant to the patient's symptoms or illness. In view of the limited and less-than-perfect results of treatment and medication in the entire medical field, 'personalised medicine' seems to be a goal worth striving for in order to improve treatment outcomes. PMID- 27779296 TI - [Cooperation and client perspective are the terms for success; reflection on the cost-effectiveness of psychiatry]. AB - BACKGROUND: There is a growing interest in the cost-effectiveness of psychiatry in general. How do client organisations regard this growing interest?
AIM: To discuss the cost-effectiveness of psychiatry in general seen from the perspective of the patient/civilian and his or her environment.
METHOD: A critical appraisal of cost-effectiveness in psychiatry on the basis of a case study and relevant developments in society.
RESULTS: The increasing interest in the cost-effectiveness of psychiatry should be seen as a positive development, but we must be aware of the complexity of the factors involved and of the complications that are linked to this increased interest. One complication is that the societal benefits of psychiatry are being reduced to mere economic efficacy and another complication is that there is less concern about the benefits to the patient in terms of reduced psychiatric suffering and speedier recovery. Yet another problem is the increasing involvement of ethical issues.
CONCLUSION: The cost-efficiency of psychiatry can never be assessed in isolation, i.e. as a separate issue; it depends totally on effective cooperation with the patient, his or her immediate environment and partners and fellow-citizens. The importance of the client needs to be recognised as the binding element and all efforts should be directed towards strengthening the bond between the patient/citizen and the persons in his or her immediate environment. PMID- 27779297 TI - Expression of aurora kinases: Predictor of tumor dissemination in uterine carcinosarcoma. AB - Uterine carcinosarcoma is a rare, aggressive, and biphasic tumor. It comprises carcinomatous and sarcomatous components, and mitosis-associated factors are thought to discriminate these two lesions. Aurora kinases are mitotic enzymes that are highly expressed in uterine malignancies. To identify the clinical significance of aurora kinase expression, we performed immunohistochemistry on tissue microarrays using cores selected from areas with typical carcinomatous and sarcomatous characteristics. A total of 24 samples were included, from patients at Seoul National University Hospital diagnosed with uterine carcinosarcoma, and who undergone a staging operation between 1997 and 2012. Patients' clinical and pathological data were analyzed, and expression patterns of aurora kinases were investigated. Aurora kinases A and B were dominantly expressed in the cytoplasm, and phospho-aurora kinases A and B were expressed in the nuclei. Phospho-aurora kinase A and aurora kinase B showed significantly higher expression in the carcinomatous component (P=0.012 and 0.008). High expression of phospho-aurora kinase A was associated with lymphatic metastasis such as positive pelvic lymph node and omental involvement (P=0.012 and 0.037). Overexpression of aurora kinase B was related to vascular invasion (P=0.011). High expression of both phospho aurora kinase A and aurora kinase B was a prognostic factor for progression-free survival in uterine carcinosarcoma (P=0.049). In conclusion, expression of aurora kinases is associated with bidirectional tumor dissemination into the lymphatic and hematogenous pathways. In addition, high expression of phospho-aurora kinase A and aurora kinase B is a predictor of progression-free survival. Therefore, inhibitors of aurora kinases might be a prospective therapeutic options for uterine carcinosarcoma. PMID- 27779298 TI - [The Prefrontal Symptoms Inventory (PSI) in acquired brain injury: agreement between the scores of patients, relatives and professionals]. AB - INTRODUCTION: The use of self-reports about symptoms of malfunctioning in daily life derived from functional deficits of a prefrontal origin has become widespread in clinical practice, since they allow incremental ecological validity to be added to other specific tests. Yet it remains to be determined whether self assessment is sufficient on its own or if the participation of an external evaluator would be preferable. SUBJECTS AND METHODS: The Prefrontal Symptoms Inventory (PSI) was administered to 115 subjects being treated for a range of brain pathologies. The same test, referring to the patient, was administered to one of the professionals closely following the development of the case and, whenever possible (n = 88), a relative or caregiver. The psychometric goodness of the PSI was explored in the three samples, and the degree of correlation and agreement among the three assessments was estimated. RESULTS: The three assessments showed significant correlation, although the patients reported fewer symptoms than their relatives and caregivers in terms of executive functioning. The assessments of relatives and patients were superposed and showed a high degree of agreement as regards both profile and magnitude. CONCLUSIONS: In addition to the mandatory neuropsychological assessment, we recommend the administration of questionnaires or inventories about symptoms such as the PSI, with proven psychometric robustness, that make it possible to explore the impact of brain dysfunctions in daily functioning. Since many of these dysfunctions are accompanied by different degrees of anosognosia, they should be administered to external observers, relatives or professionals, with the intention of obtaining a more adequate assessment of the magnitude of the functional difficulties. PMID- 27779299 TI - [Neurosyphilis in the 21st century: a descriptive study in a tertiary hospital in Madrid]. AB - INTRODUCTION: Neurosyphilis can occur at any time following infection by Treponema pallidum and its incidence has increased over recent years. The epidemiological and clinical pattern has undergone a substantial change in the post-antibiotic era. AIMS: To describe and analyse the population of patients diagnosed with neurosyphilis at a tertiary hospital in Madrid from January to May 2015. PATIENTS AND METHODS: A retrospective analysis of the following data was performed: demographic, clinical, complementary tests -serology, cerebrospinal fluid (CSF), neuroimaging- and progression of 28 patients diagnosed between 2008 and 2015. RESULTS: Most of the patients were males (89.3%), Spanish (60.7%), with a mean age of 53 +/- 16.4 years. The most frequent forms were asymptomatic (39.3%), followed by ocular syphilis (21%), non-classical forms (14.3%), cognitive deterioration and neuropsychiatric alterations (11%). Fifty per cent presented a concomitant infection by human immunodeficiency virus, most of them asymptomatic, with a significant correlation between CD4+ T-cells and asymptomatic neurosyphilis. Only 50% presented VDRL+ in CSF, the diagnosis being based on the clinical features, serology and alterations in CSF (cytobiochemical or serological). Neuroimages were unspecific in most cases. The early and ocular forms were associated to a better clinical course. CONCLUSIONS: With respect to the pre-antibiotic era, an important decrease can be observed in the late-onset forms, as well as the appearance of non-classical forms that can mimic other conditions such as viral encephalitis. Diagnosis is complex and based on the clinical features, the serology and study of CSF, often with a complex interpretation, and thus clinical suspicion plays a fundamental role in the diagnosis. PMID- 27779300 TI - [Results of vagal nerve stimulation in patients with pharmacoresistant epilepsy in a national epilepsy referral centre]. AB - AIM: To describe clinical results and complications derived from vagal nerve stimulation therapy in drug resistant epileptic patients unsuitable for other surgical treatments, since the first implant in an epilepsy national referral centre. PATIENTS AND METHODS: A retrospective analysis of the patients implanted in our centre was held. Data related to baseline characteristics of their epilepsy and therapy complications was collected. RESULTS: 32 new implants in 31 patients are included, mean age of 34 years, 29.3 years of disease evolution, three anti-epileptic drugs at surgery and a postoperative follow-up of 4.03 years. Complex partial seizures types (71.9%) and cryptogenic aetiology (59.4%) were the most frequent. 75% of patients hadn't history of previous epilepsy surgery. 43.8% of patients had a seizure frequency improvement above 50%, with a better response in patients with complex partial seizures (p = 0.22) and cryptogenic aetiology. None statistical significance was found between antiepileptic drugs and seizure frequency. Dysphonia, hoarseness and dysphagia, mostly transient, were the side effects registered. There was an asystole during surgery, completely recovered. One device was replaced due to hardware rupture after a seizure related trauma, one had to be adjusted due to a previous vocal cord paresis, and one dysfunctioning device was removed. In 84.4% the tolerance was excellent. CONCLUSIONS: Vagal nerve stimulation is an effective treatment for significant seizure frequency improvement of resistant patients untreatable with other medical or surgical treatments. Further studies are needed to predict the individual response of each patient to therapy and optimizing indications, therefore contributing to cost/benefit optimization. PMID- 27779301 TI - Infratentorial congenital glioblastoma multiforme. A rare tumour with a still unknown biology. AB - INTRODUCTION: Congenital glioblastoma multiforme represents only 3% of congenital central nervous system tumours and an infratentorial location is unusual. CASE REPORT: A newborn with congenital glioblastoma multiforme with no mutation in the TP53 gene or p53 nuclear immunoreactivity that infiltrated practically the whole brainstem and also invaded supratentorial structures. CONCLUSIONS: As far as we know, only four cases with an infratentorial location have been reported previously, three in the cerebellum and one in the brainstem. The biology of congenital glioblastoma multiforme is not well known and, unlike glioblastoma multiforme in adults and children, mutations in the TP53 gene are uncommon. However, this is not associated with a more favourable prognosis. These observations suggest that specific biological processes underlie fetal glioblastoma multiforme development. PMID- 27779302 TI - [Brain asymmetry and dopamine: beyond motor implications in Parkinson's disease and experimental hemiparkinsonism]. AB - INTRODUCTION: Brain asymmetry could be defined as the existence of functional, anatomic or neurochemical differences between both hemispheres. It is a dynamic phenomenon, regulated by endogenous and exogenous factors. Its functional significance is poorly clarified and is only partially understood in very specific cases such as the relationship between the lateralized brain content of dopamine and its motor effects which is specially patent in Parkinson's disease. DEVELOPMENT: The asymmetric brain content of dopamine not only displays lateralized motor effects but also behavioral and autonomic asymmetric consequences. In fact, Parkinson's disease is characterized not only by unilateral motor symptoms that arise at the early stages, but has other non-motor symptoms such as autonomic or cognitive alterations that are also revealed asymmetrically. CONCLUSIONS: Brain asymmetry has been underestimated when analyzing the pathogeny of brain diseases and it has been partially studied only in some specific cases, such as Parkinson's disease. However, in order to appropriately understand some brain diseases such as Parkinson's disease, the need to consider this phenomenon has been highlighted. PMID- 27779303 TI - [Evaluation of the vagal nerve in a patient with hereditary motor sensory neuropathy type 1A]. PMID- 27779304 TI - [XX Reunion Anual de la Sociedad Canaria de Neurologia. Communications]. PMID- 27779305 TI - [Herpes zoster and risk of stroke]. PMID- 27779306 TI - [Myasthenia gravis and treatment with intravenous immunoglobulins]. PMID- 27779307 TI - [Myasthenia gravis and treatment with intravenous immunoglobulins. Reply]. PMID- 27779308 TI - Pulmonary function among Latino thoroughbred horse farmworkers. AB - BACKGROUND: Latino thoroughbred workers may be at risk for developing abnormal pulmonary function related to occupational exposures. METHODS: Eighty worker participants were recruited via community-based purposive sampling. Questionnaires and spirometry tests were administered by trained lay health promoters. Demographic and occupational factors were assessed for associations with respiratory outcomes via multivariable logistic regression. RESULTS: Twenty seven percent of participants exhibited abnormal pulmonary function (primarily restrictive), 79% reported any respiratory symptoms, and 94% infrequently used dust masks. Shorter duration of both current horse farm employment (<=5 years) and time living in the United States (<=10 years) increased the odds of abnormal pulmonary function. Shorter time living in the United States increased the odds of upper respiratory symptoms and shorter duration of current horse farm employment increased the odds of lower respiratory symptoms. CONCLUSIONS: Abnormal pulmonary function was high among this vulnerable worker group, suggesting the need for increased dust mask usage and further exposure assessment. Am. J. Ind. Med. 60:35-44, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779309 TI - Effectiveness of OSHA Outreach Training on carpenters' work-related injury rates, Washington State 2000-2008. AB - INTRODUCTION: Despite the size and breadth of OSHA's Outreach Training program for construction, information on its impact on work-related injury rates is limited. METHODS: In a 9-year dynamic cohort of 17,106 union carpenters in Washington State, the effectiveness of OSHA Outreach Training on workers' compensation claims rate was explored. Injury rates were calculated by training status overall and by carpenters' demographic and work characteristics using Poisson regression. RESULTS: OSHA Outreach Training resulted in a 13% non significant reduction in injury claims rates overall. The protective effect was more pronounced for carpenters in their apprenticeship years, drywall installers, and with increasing time since training. CONCLUSIONS: In line with these observed effects and prior research, it is unrealistic to expect OSHA Outreach Training alone to have large effects on union construction workers' injury rates. Standard construction industry practice should include hazard awareness and protection training, coupled with more efficient approaches to injury control. Am. J. Ind. Med. 60:45-57, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779310 TI - Exertional heat illness and acute injury related to ambient wet bulb globe temperature. AB - BACKGROUND: The Deepwater Horizon disaster cleanup effort provided an opportunity to examine the effects of ambient thermal conditions on exertional heat illness (EHI) and acute injury (AI). METHODS: The outcomes were daily person-based frequencies of EHI and AI. Exposures were maximum estimated WBGT (WBGTmax) and severity. Previous day's cumulative effect was assessed by introducing previous day's WBGTmax into the model. RESULTS: EHI and AI were higher in workers exposed above a WBGTmax of 20 degrees C (RR 1.40 and RR 1.06/ degrees C, respectively). Exposures above 28 degrees C-WBGTmax on the day of the EHI and/or the day before were associated with higher risk of EHI due to an interaction between previous day's environmental conditions and the current day (RRs from 1.0-10.4). CONCLUSIONS: The risk for EHI and AI were higher with increasing WBGTmax. There was evidence of a cumulative effect from the prior day's WBGTmax for EHI. Am. J. Ind. Med. 59:1169-1176, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27779311 TI - Detrimental effect of systemic antimicrobial CD4+ T-cell reactivity on gut epithelial integrity. AB - Healthy host-microbe mutualism relies on compartmentalization and proper regulation of systemic and mucosal immune responses. Nevertheless, the systemic immune system is frequently exposed to bouts of bacteraemia, which can trigger systemic antimicrobial immune reactivity including CD4+ T cells. Low-level bacteraemia can occur when immune compartmentalization is compromised, for example in the presence of innate immune deficiency or following use of non steroidal anti-inflammatory drugs. We generated an Escherichia coli strain expressing a defined T helper neo-epitope to study systemic antigen-specific antimicrobial CD4+ T cells and their potential involvement in the pathogenisis of inflammatory bowel diseases. We found that the dose of bacteria required for the induction of systemic antimicrobial CD4+ T-cell proliferation was high and not easily reached under physiological conditions. Importantly, however, when intestinal barrier function was compromised by induced damage to the intestinal epithelium, the presence of systemic antimicrobial CD4+ T cells specific for a single neo-antigen resulted in dramatically increased levels of bacterial translocation. This study therefore demonstrates that systemic antimicrobial CD4+ T-cell reactivity might impact adversely on the mucosa under conditions of reduced barrier function and that despite strong mucosal immune regulation, antigen-specific recognition is still sensitive. PMID- 27779313 TI - Do distracting activities increase tolerance for an infant cry? AB - Professionals recommend parents engage in distracting activities to mitigate negative effects of inconsolable infant crying (e.g., Deyo, Skybo, & Carroll, 2008; Goulet et al., 2009). We evaluated the availability of alternative activities on six undergraduates' tolerance for a recorded infant cry; three students tolerated the cry longer when distracting activities were available. Our results show that distracting activities could decrease the aversiveness of inconsolable infant crying for some individuals; additional research in natural caregiving situations will help determine the generality and social validity of this finding. PMID- 27779312 TI - Randomized clinical trial of sacral nerve stimulation for refractory constipation. AB - BACKGROUND: Open studies have reported favourable results for sacral nerve stimulation in the treatment of refractory constipation. Here, its efficacy was assessed in a double-blind crossover RCT. METHODS: Patients with at least two of the following criteria were included: fewer than three bowel movements per week; straining to evacuate on more than 25 per cent of attempts; or sensation of incomplete evacuation on more than 25 per cent of occasions. Response to therapy was defined as at least three bowel movements per week and/or more than 50 per cent improvement in symptoms. Responders to an initial 3-week peripheral nerve evaluation were offered permanent implantation of a pulse generator and were assigned randomly in a crossover design to two 8-week intervals of active or sham stimulation. At the end of the two trial periods, the patients received active stimulation until the final evaluation at 1 year. RESULTS: Thirty-six patients (34 women; mean(s.d.) age 45(14) years) underwent peripheral nerve evaluation. Twenty responded and received a permanent stimulator. A positive response was observed in 12 of 20 and 11 of 20 patients after active and sham stimulation periods respectively (P = 0.746). Pain related to the device occurred in five patients and wound infection or haematoma in three, leading to definitive removal of the pulse generator in two patients. At 1 year, 11 of the 20 patients with an implanted device continued to respond. Stimulation had no significant effect on colonic transit time. CONCLUSION: These results do not support the recommendation of permanent implantation of a pulse generator in patients with refractory constipation who initially responded to temporary nerve stimulation. Registration number: NCT01629303 (http://www.clinicaltrials.gov). PMID- 27779314 TI - Co-sleeping in school-aged children with a motor disability: a comparative population-based study. AB - AIM: To determine the prevalence and determinants of co-sleeping in school-aged children with a motor disability compared with the school-aged general population. METHOD: A questionnaire on demographic characteristics and co sleeping habits, along with the Sleep Disturbance Scale for Children (SDSC), was sent to parents of children aged between 4 years and 18 years followed in our tertiary paediatric neurorehabilitation clinic, and to school-aged children in a representative sample of state schools. RESULT: We analysed responses for 245 children with motor disability (142 males, 103 females; mean age 10y 6mo, standard deviation [SD] 3y 10mo, range 4-18y) and 2891 of the general population (1484 males, 1497 females; mean age [SD] 9y 6mo [3y 5mo], range 4-18y) (response rates 37% and 26% respectively). Cerebral palsy was the most common diagnosis among children with motor disability. Weekly co-sleeping was significantly more common in children with motor disability than in the general population (11.8% vs 7.9% respectively, p=0.032). Special care of the child with motor disability at night, mainly addressing epilepsy, was reported as a cause of co-sleeping by two thirds of parents. Factors associated with co-sleeping in the motor disability group were age, housing crowding, severe visual impairment, and pathological sleep according to the SDSC. INTERPRETATION: Co-sleeping is common among children with motor disability. It is influenced by personal and medical factors, as well as the requirements for special care at night. Therefore, health professionals should explore sleeping arrangements in families of children with motor disability. PMID- 27779315 TI - Teacher attunement to peer-nominated aggressors. AB - This study examined the associations between teacher attunement to aggressive students and students' characteristics in a sample (n = 278) of youth in 5th grade classrooms with the assumption that certain student characteristics may either prime or hinder teachers' attunement to aggressive students. Teacher attunement was measured as the agreement between teacher- and peer-nominations for students who start fights. Teachers rated their students on the following characteristics: academic competence, affiliation, popularity, internalizing behavior, and Olympian qualities. Higher affiliation, popularity, and internalizing behavior were associated with decreased odds for teacher attunement to aggressive youth. Higher Olympian qualities were associated with increased odds for teacher attunement to aggressive youth. Implications for interventions are discussed. Aggr. Behav. 43:263-272, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779316 TI - Work-related illness and injury claims among nationally certified athletic trainers reported to Washington and California from 2001 to 2011. AB - BACKGROUND: Little is known about the work-related injury and illnesses experienced by certified athletic trainers (AT). METHODS: The incidence and characteristics of injury/illness claims filed in two workers' compensation systems were described from 2001 to 2011. Yearly populations at risk were estimated from National Athletic Trainers' Association membership statistics. Incidence rate ratios (IRR) were reported by job setting. RESULTS: Claims were predominantly for traumatic injuries and disorders (82.7%: 45.7% sprains/strains, 12.0% open wounds, 6.5% bruises) and at these body sites (back 17.2%, fingers 12.3%, and knee 9.6%) and over half were caused by body motion and overexertion (51.5%). Compared with school settings, clinic/hospital settings had modestly higher claim rates (IRR = 1.29, 95% CI: 1.06-1.52) while other settings (e.g., professional or youth sport, nursing home) had lower claim rates (IRR = 0.63, 95% CI: 0.44-0.70). CONCLUSIONS: These first known estimates of work-related injuries/illnesses among a growing healthcare profession help identify occupational tasks and settings imposing injury risk for ATs. Am. J. Ind. Med. 59:1156-1168, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27779317 TI - Adhesives for fixed orthodontic bands. AB - BACKGROUND: Orthodontic treatment involves using fixed or removable appliances (dental braces) to correct the positions of teeth. It has been shown that the quality of treatment result obtained with fixed appliances is much better than with removable appliances. Fixed appliances are, therefore, favoured by most orthodontists for treatment. The success of a fixed orthodontic appliance depends on the metal attachments (brackets and bands) being attached securely to the teeth so that they do not become loose during treatment. Brackets are usually attached to the front and side teeth, whereas bands (metal rings that go round the teeth) are more commonly used on the back teeth (molars). A number of adhesives are available to attach bands to teeth and it is important to understand which group of adhesives bond most reliably, as well as reducing or preventing dental decay during the treatment period. OBJECTIVES: To evaluate the effectiveness of the adhesives used to attach bands to teeth during fixed appliance treatment, in terms of:(1) how often the bands come off during treatment; and(2) whether they protect the banded teeth against decay during fixed appliance treatment. SEARCH METHODS: The following electronic databases were searched: Cochrane Oral Health's Trials Register (searched 2 June 2016), Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 5) in the Cochrane Library (searched 2 June 2016), MEDLINE Ovid (1946 to 2 June 2016) and EMBASE Ovid (1980 to 2 June 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised and controlled clinical trials (RCTs and CCTs) (including split-mouth studies) of adhesives used to attach orthodontic bands to molar teeth were selected. Patients with full arch fixed orthodontic appliance(s) who had bands attached to molars were included. DATA COLLECTION AND ANALYSIS: All review authors were involved in study selection, validity assessment and data extraction without blinding to the authors, adhesives used or results obtained. All disagreements were resolved by discussion. MAIN RESULTS: Five RCTs and three CCTs were identified as meeting the review's inclusion criteria. All the included trials were of split-mouth design. Four trials compared chemically cured zinc phosphate and chemically cured glass ionomer; three trials compared chemically cured glass ionomer cement with light cured compomer; one trial compared chemically cured glass ionomer with a chemically cured glass phosphonate. Data analysis was often inappropriate within the studies meeting the inclusion criteria. AUTHORS' CONCLUSIONS: There is insufficient high quality evidence with regard to the most effective adhesive for attaching orthodontic bands to molar teeth. Further RCTs are required. PMID- 27779318 TI - Nativity, Country of Education, and Mexican-Origin Women's Breastfeeding Behaviors in the First 10 Months Postpartum. AB - BACKGROUND: Breastfeeding is associated with numerous health benefits for the infant and mother. Latina women in the United States have historically had high overall rates of initiation and duration of breastfeeding. However, these rates vary by nativity and time lived in the United States. Exclusive breastfeeding patterns among Latina women are unclear. In this study, we investigate the current and exclusive breastfeeding patterns of Mexican-origin women at four time points from delivery to 10 months postpartum to determine the combined association of nativity and country of education with breastfeeding duration and supplementation. METHODS: Data are from the Postpartum Contraception Study, a prospective cohort study of postpartum women ages 18-44 recruited from three hospitals in Austin and El Paso, Texas. We included Mexican-origin women who were born in either the United States or Mexico in the analytic sample (n = 593). RESULTS: Women completing schooling in Mexico had higher rates of overall breastfeeding throughout the study period than women educated in the United States, regardless of country of birth. This trend held in multivariate models while diminishing over time. Women born in Mexico who completed their schooling in the United States were least likely to exclusively breastfeed. DISCUSSION: Country of education should also be considered when assessing Latina women's risk for breastfeeding discontinuation. Efforts should be made to identify the barriers and facilitators to breastfeeding among US-educated Mexican-origin women to enhance existing breastfeeding promotion efforts in the United States. PMID- 27779320 TI - Physician, beware! The deckchair sign can be seen in dermatomyositis. PMID- 27779319 TI - Synthesis of New Tricyclic and Tetracyclic Fused Coumarin Sulfonate Derivatives and Their Inhibitory Effects on LPS-Induced Nitric Oxide and PGE2 Productions in RAW 264.7 Macrophages: Part 2. AB - The synthesis of a new series of 21 fused coumarin derivatives is described, and the biological evaluation of their in vitro antiinflammatory effects as inhibitors of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2 ) production in RAW 264.7 macrophages. The target compounds 1a-u were first tested for cytotoxicity to determine a non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production would not be caused by cytotoxicity. Compounds 1f and 1p were the most active PGE2 inhibitors with IC50 values of 0.89 and 0.95 uM, respectively. Western blot and cell-free COX-2 screening showed that their effects were due to inhibition of both COX-2 protein expression and COX-2 enzyme activity. Their IC50 values against the COX-2 enzyme were 0.67 and 0.85 uM, respectively, which is more potent than etoricoxib. The selectivity indexes of compounds 1f and 1p against COX-2 compared to COX-1 were 41.1 and 42.5, respectively. Compound 1f showed strong inhibitory effects at 5 uM concentration on COX-2 mRNA expression in LPS-induced RAW 264.7 macrophages. Moreover, the tricyclic compounds 1l and 1n as well as the tetracyclic analog 1u were the most potent NO inhibitors, with one-digit micromolar IC50 values. They showed dose dependent inhibition of inducible nitric oxide synthase (iNOS) protein expression. The tetracyclic derivative 1u was the most potent inhibitor of NO production. It also exhibited a strong inhibitory effect on iNOS mRNA expression in LPS-induced RAW 264.7 macrophages. PMID- 27779321 TI - Benthic injury dose-response models for polychlorinated biphenyl-contaminated sediment using equilibrium partitioning. AB - The study goal was to develop a sediment polychlorinated biphenyl (PCB) dose response model based on benthic invertebrate effects to PCBs. The authors used an equilibrium partitioning (EqP) approach to generate predicted PCB sediment effect concentrations (largely Aroclor 1254) associated with a gradient of toxic effects in benthic organisms from effects observed in aquatic toxicity studies. The present study differs from all other EqP collective sediment investigations in that the authors examined a common dose-response gradient of effects for PCBs rather than a single, protective value. The authors reviewed the chronic aquatic toxicity literature to identify measured aqueous PCB concentrations and associated benthic invertebrate effects. The authors control-normalized the aquatic toxic effect data and expressed results from various studies as a common metric, percent injury. Then, they calculated organic carbon-normalized sediment PCB concentrations (mg/kg organic carbon) from the aqueous PCB toxicity data set using EqP theory based on the US Environmental Protection Agency's (EPIWEB 4.1) derivation of the water-organic carbon partition coefficient (KOC ). Lastly, the authors constructed a nonlinear dose-response numerical model for these synoptic sediment PCB concentrations and biological effects: Y = 100/1 + 10([logEC50-logX] * [Hill slope]) (EC50 = median effective concentration). These models were used to generate "look-up" tables reporting percent injury in benthic biota for a range of Aroclor-specific sediment concentrations. For example, the model using the EPIWEB KOC estimate predicts mean benthic injury of 23.3%, 46.0%, 70.6%, 87.1%, and 95% for hypothetical sediment concentrations of 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, and 16 mg/kg dry weight of Aroclor 1254, respectively (at 1% organic carbon). The authors recommend the model presented for screening but suggest, when possible, determining a site-specific KOC that, along with the tables and equations, allows users to create their own protective dose-response sediment concentration. Environ Toxicol Chem 2017;36:1311-1329. (c) 2016 SETAC. PMID- 27779322 TI - Imiquimod-induced vitiligo-like hypopigmentation after treatment for radiation keratosis. PMID- 27779323 TI - An in silico approach to cytotoxicity of pharmaceuticals and personal care products on the rainbow trout liver cell line RTL-W1. AB - The authors constructed novel, robust, and validated linear Quantitative Structure-Toxicity Relationship (QSTR) models in line with Organisation of Co operation and Development (OECD) criteria using 2 cytotoxicity data sets which were obtained from the Alamar Blue and 5-carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM) assays. The data sets comprise the cytotoxic effect of structurally diverse and widely used pharmaceuticals, synthetic musks, and industrial chemicals on the rainbow trout (Oncorhynchus mykiss) liver cell line RTL-W1. Common descriptors defined the relationship between structure and cytotoxicity for both the Alamar Blue and the CFDA-AM assays which measure the metabolic activity and membrane integrity, respectively. Only the statistical parameters of the best Alamar Blue-based model were given (nTR = 13; R2 = 0.839; the root-mean-square error of the training set [RMSETR ] = 0.261; nTEST = 5; R2TEST = 0.903; RMSETEST = 0.181; CCCTEST = 0.939). The proposed QSTR model was able to predict the cytotoxicity of 101 diverse chemicals on the RTL-W1 cell line with 91% structural coverage. The authors found that in vitro-derived cytotoxicity data are promising predictors of in vivo fish toxicity and may provide an initial, rapid screening tool for acute fish toxicity assessment and reduce the need for extensive in vivo toxicity testing. Environ Toxicol Chem 2017;36:1162-1169. (c) 2016 SETAC. PMID- 27779324 TI - Fate and risk of atrazine and sulfentrazone to nontarget species at an agriculture site. AB - The present study evaluated the risk associated with the application and co occurrence of 2 herbicides, atrazine and sulfentrazone, applied to a 32-ha corn and soybean rotational field. Field concentrations of the compounds were measured in soil, runoff water, and groundwater, with peak mean atrazine and sulfentrazone concentrations found in the soil (144 ng/g dry wt, and 318 ng/g dry wt, respectively). Individual and mixture laboratory bioassays were conducted to determine the effects of atrazine and sulfentrazone on the survival of Daphnia magna and Pimephales promelas, the germination of Lactuca sativa, and the growth of Pseudokirchneriella subcapita and Lemna minor. Pseudokirchneriella subcapita and L. minor were the most susceptible species tested, and the effects on growth of the herbicides in mixtures best fit an independent action model. Risk quotients and margin of safety of 10% (MOS10) values were used to estimate risk and were calculated using runoff water concentrations. The MOS10 values were more sensitive than risk quotients in estimating risk. The MOS10 value for sulfentrazone runoff water concentration effects on P. subcapita was 7.8, and for L. minor was 1.1, with MOS10 values < 1 indicating potential risk. Overall, the environmentally relevant concentrations fell below the effect concentrations; therefore, atrazine and sulfentrazone posed little to no risk to the nontarget species tested. Environ Toxicol Chem 2017;36:1301-1310. (c) 2016 SETAC. PMID- 27779325 TI - Isotretinoin in acne: a single-centre experience. PMID- 27779326 TI - Olfactory symptoms reported by migraineurs with and without auras. AB - OBJECTIVE: Olfaction-related symptoms accompany migraine attacks and some, such as osmophobia, may be useful in differentiating migraine from other types of headaches. However, the types and frequencies of olfactory symptoms associated with migraine have not been well characterized. The goal of this study was to better characterize the olfactory symptoms of migraine. METHODS: A cross sectional study was devised. One hundred and thirteen patients who met the International Classification of Headache Disorders II criteria for migraine were administered a new 65-item questionnaire specifically focused on olfaction related experiences (eg, odor-related triggers, osmophobia, cacosmia, phantosmia, olfactory hallucinations, olfactory hypersensitivity, and self-perceived olfactory function). Visual analog scale ratings and frequencies were computed and compared between migraineurs with and without auras using t-tests and chi square analyses. RESULTS: While osmophobia was present in 95.5% of the patients, the prevalence of other olfaction-related symptoms was much lower (interictal olfactory hypersensitivity [IOH], 14.1%; olfactory hallucinations, 6.2%; phantosmia, 4.4%; cacosmia/euosmia, 2.6%). Migraine was commonly triggered by odors (90.2%), with perfume being the most common trigger (95.1%), followed by cleaning products (81.3%), cigarette smoke (71.5%), and motor vehicle exhaust (70.5%). No significant differences in symptom frequencies were apparent between migraineurs with or without auras (P > .40). Interestingly, patients with IOH reported being less likely to experience osmophobia and odor-triggered crisis than did those without this symptom (respective percentages: 75% vs. 99% and 69% vs. 94%, P <= .002). Osmophobia and odor triggered headache were associated with a mild decrease in self-reported olfactory acuity. CONCLUSION: Odor-related disturbances were common symptoms of the 113 migraineurs, with nearly all reporting osmophobia. Perfume odor was the most common trigger for the migraine. The reported symptoms did not differ between patients with and without auras. Patients who experienced IOH appeared to fundamentally differ from those who did not experience IOH in terms of the incidence of osmophobia and odor-triggered crisis. Subjects who reported experiencing osmophobia and odor-triggered headache reported having worse olfactory acuity. PMID- 27779327 TI - Effects of psychosocial work factors and psychological distress on self-assessed work ability: A 7-year follow-up in a general working population. AB - BACKGROUND: Toinvestigate the effects of psychosocial work factors (PWF) and psychological distress (PD) on self-assessed work ability. METHODS: This follow up study included 7,810 individuals (55%women) with good work ability at baseline. PWFandPD (measured by GHQ-12) were assessed at baseline and work ability at 7-year follow-up. Effects of PWF and PD on work ability were analyzed by logistic regression, odds ratios (OR) with 95% CI, and by mediation analysisusing 4-way decomposition. RESULTS: Low support was associated with poor work ability for both women and men (OR 1.78 and 1.89). For men, also low skill discretion was associated with poor work ability (OR 2.07). For both women and men, PD was associated with poor work ability (OR 3.41 and 1.84). PD did not act as an intermediate variablein the association between PWF and work ability. CONCLUSION: Strategies for sustainable work ability should focus on both working conditions and health factors. Am. J. Ind. Med. 60:121-130, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779328 TI - Does Australia's Health Policy Environment Create Unintended Outcomes for Birthing Women? PMID- 27779329 TI - Indications for Cesarean Delivery in Mexico: Evaluation of Appropriate Use and Justification. AB - BACKGROUND: Cesarean delivery is one of the most widely used surgical interventions in Latin America and in many cases it is performed with no clear medical indication. Our objective was to analyze the relationship between reported indications for a cesarean and support for that indication in the clinical record in four Mexican hospitals, during the 2006-2007 period. METHODS: The data are from 604 (37.1%) women from a total of 1,625 who were admitted to the hospital in labor, and who gave birth through cesarean. Multivariate logistical regression analysis was used to explore the association between indications for clinically justified or unjustified surgery and other clinical and sociodemographic variables. RESULTS: Supporting clinical information for indications of cesarean delivery were found in only 45 percent of the cases considered. The adjusted statistical analysis showed that the variables associated with an unjustified indication for cesarean were: not having had a prior birth (OR 1.84 [95% CI 1.16-2.89]), having a maximum cervical dilation of 4 centimeters or less at time of cesarean (OR 2.44 [95% CI 1.53-3.87]), and having received care in a private hospital (OR 6.11 [95% CI 1.90-19.57]). DISCUSSION: The indications for cesarean related to labor dynamics were those least supported. Not having had a prior birth poses the greatest risk of having a poorly supported indication for a cesarean delivery. It would be prudent to institute audits, and greater requirements for and surveillance of documentation for cesarean delivery indications. PMID- 27779331 TI - Comparisons of physical activity, adipokines, vitamin D status and dietary vitamin D intake among adolescents. AB - BACKGROUND: Considering that lifestyle and diet are key factors responsible for the increases in adiposity in youth, it is important to understand how vitamin D, adipokines and markers of glucose metabolism are related to physical activity level (PAL) during growth. The present study aimed to investigate associations between physical activity level, adiponectin/leptin ratio, vitamin D status and dietary vitamin D intake among adolescents. METHODS: A cross-sectional study was conducted with adolescents aged 14-18 years old who were living in Sao Paulo, Brazil. Serum 25 hydroxyvitamin D [25(OH)D], adiponectin (A), leptin (L), glucose and insulin were obtained after 12 h of fasting. Dietary calcium and vitamin D intake were measured by 24-h food record, as repeated in 62.6% of the sample. PAL was measured by the International Physical Activity Questionnaire (IPAQ). Pearson's chi-square test, Pearson correlation and linear regression analysis were performed. RESULTS: A total of 198 subjects, mean (SD) age 16.3 (1.4) years, 51% male, were enrolled in the study. Some 9% of participants were sedentary, 22% were insufficiently active (IA), 51% were active and 18% were very active (VA). The A/L ratio was lower among sedentary/IA subjects [2.2 (4.0) versus 5.6 (12.3); P = 0.01] compared to active/VA subjects. PAL was not associated with vitamin D status or markers of glucose metabolism. Serum 25(OH)D positively associated with vitamin D intake, after adjusting for sex, sun exposure and season of the year in regression analysis (partial r2 =0.026, P = 0.02). CONCLUSIONS: Low PAL was associated with a lower A/L ratio. Vitamin D status was not associated with sun exposure habits, although it was positively correlated with vitamin D intake. PMID- 27779332 TI - Novel seminal fluid proteins in the seed beetle Callosobruchus maculatus identified by a proteomic and transcriptomic approach. AB - The seed beetle Callosobruchus maculatus is a significant agricultural pest and increasingly studied model of sexual conflict. Males possess genital spines that increase the transfer of seminal fluid proteins (SFPs) into the female body. As SFPs alter female behaviour and physiology, they are likely to modulate reproduction and sexual conflict in this species. Here, we identified SFPs using proteomics combined with a de novo transcriptome. A prior 2D-sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis identified male accessory gland protein spots that were probably transferred to the female at mating. Proteomic analysis of these spots identified 98 proteins, a majority of which were also present within ejaculates collected from females. Standard annotation workflows revealed common functional groups for SFPs, including proteases and metabolic proteins. Transcriptomic analysis found 84 transcripts differentially expressed between the sexes. Notably, genes encoding 15 proteins were highly expressed in male abdomens and only negligibly expressed within females. Most of these sequences corresponded to 'unknown' proteins (nine of 15) and may represent rapidly evolving SFPs novel to seed beetles. Our combined analyses highlight 44 proteins for which there is strong evidence that they are SFPs. These results can inform further investigation, to better understand the molecular mechanisms of sexual conflict in seed beetles. PMID- 27779333 TI - Predictors of suicidal ideation in Korean American older adults: analysis of the Memory and Aging Study of Koreans (MASK). AB - OBJECTIVE: Our aim is to investigate the prevalence and predictors of suicidal ideation among Korean American older adults and assess the self-rated mental health of Korean American older adults with suicidal ideation with or without depressive syndrome. METHODS: The Memory and Aging Study of Koreans is a cross sectional, epidemiologic study of a community-representative sample of Korean American older adults (N = 1116) residing in the Baltimore-Washington area. Participants were interviewed using the Korean version of the Patient Health Questionnaire (PHQ-9K). In addition, demographic information, self-rated mental health, and self-rated physical health status were obtained. RESULTS: In this study, 14.7% of Korean American older adults reported suicidal ideation. Predictors of suicidal ideation included living alone, major or minor depressive syndrome (diagnosed by the PHQ-9K), shorter duration of residency in the USA, and poorer self-rated mental health status. Of those who reported suicidal ideation, 64% did not have minor or major depressive syndrome. However, their self-rated mental health was as poor as that of those with major or minor depressive syndrome but without suicidal ideation. CONCLUSION: Suicidal ideation without depressive syndromes was common among Korean American older adults. For this group of elders with poor self-rated mental health, future studies should look to improving early detection of suicide risks and developing feasible suicide prevention interventions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27779334 TI - Simultaneous in vivo assessment of cardiac and hepatic metabolism in the diabetic rat using hyperpolarized MRS. AB - Understanding and assessing diabetic metabolism is vital for monitoring disease progression and improving treatment of patients. In vivo assessments, using MRI and MRS, provide non-invasive and accurate measurements, and the development of hyperpolarized 13 C spectroscopy in particular has been demonstrated to provide valuable metabolic data in real time. Until now, studies have focussed on individual organs. However, diabetes is a systemic disease affecting multiple tissues in the body. Therefore, we have developed a technique to simultaneously measure metabolism in both the heart and liver during a single acquisition. A hyperpolarized 13 C MRS protocol was developed to allow acquisition of metabolic data from the heart and liver during a single scan. This protocol was subsequently used to assess metabolism in the heart and liver of seven control male Wistar rats and seven diabetic rats (diabetes was induced by three weeks of high-fat feeding and a 30 mg/kg injection of streptozotocin). Using our new acquisition, we observed decreased cardiac and hepatic pyruvate dehydrogenase flux in our diabetic rat model. These diabetic rats also had increased blood glucose levels, decreased insulin, and increased hepatic triglycerides. Decreased production of hepatic [1-13 C]alanine was observed in the diabetic group, but this change was not present in the hearts of the same diabetic animals. We have demonstrated the ability to measure cardiac and hepatic metabolism simultaneously, with sufficient sensitivity to detect metabolic alterations in both organs. Further, we have non-invasively observed the different reactions of the heart and liver to the metabolic challenge of diabetes. PMID- 27779335 TI - Left ventricular stiffness predicts outcome in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. AB - OBJECTIVES: Assessment of the prognostic role of left ventricular stiffness (LVS) in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). METHODS: We performed a complete two-dimensional transthoracic echocardiographic study before and after TAVI in patients with severe AS at high surgical risk. In order to assess LVS, we measured LV end diastolic pressure (EDP) invasively during TAVI and LV end-diastolic volume (EDV) by means of echocardiography. We defined LVS as the EDV indexed by body surface area at an EDP of 20 mm Hg (EDVI20 ). Our aim was to assess the impact of LVS on one-year all-cause mortality after TAVI. RESULTS: One hundred sixty-six patients undergoing TAVI (64% female; mean age 82.7 +/- 5.1 years) were enrolled. Seven patients died within the first 30 days after TAVI and 21 within 1 year. Overall follow-up duration was 580 +/- 478 days. At multivariate analysis, independent predictors of 1-year all-cause mortality were moderate-to-severe paravalvular leak (PVL; HR 4.7, 95% confidence interval [CI] 1.9-11, P=.0003), female gender (HR 3.5, 95% CI 1.0-12, P=.045), and EDVI20 (HR 0.94, 95% CI 0.90-0.98, P=.015). In particular, patients with higher LVS (EDVI20 <=48 mL/m2 ) had a 1-year mortality of 26.9% vs 7.4% in patients with lower LVS (EDVI20 >48 mL/m2 ; HR 4.2, 95% CI 1.6-10.6, P=.0007). Patients with higher LVS who developed moderate-to severe PVL had the worst outcome (incremental chi-square test, P=.014). CONCLUSION: In patients with AS, an increased LVS has a negative prognostic impact. Development of significant PVL in patients with higher LVS had an incremental adverse effect. PMID- 27779336 TI - Improvement in the prediction of exercise-induced elevation of left ventricular filling pressure in patients with normal left ventricular ejection fraction. AB - BACKGROUND: Noninvasive diagnosis of exercise-induced elevation of left ventricular filling pressure is difficult and remains unsatisfactory. The aim of this study was to assess the accuracy of the ratio of early diastolic transmitral (E) to mitral annular (e') velocity and to determine new parameters or parameter combinations with the ability to predict exercise-induced left atrial pressure (LAP) elevation. METHODS AND RESULTS: Eighty patients with paroxysmal atrial fibrillation (AF) referred for catheter AF ablation underwent simultaneous exercise echocardiography and direct invasive LAP measurements, as well as a resting and postexercise biomarker analysis. Exercise E/e' >=8.85 predicted exercise LAP >=20 mm Hg with 61.5% sensitivity and 88.9% specificity (area under the curve [AUC], 0.76). Of all of the individual parameters tested, the best prediction was achieved with exercise E/s' (s'=peak systolic mitral annular velocity) >=8.75 (sensitivity, 88.5%; specificity, 64.8%; positive predictive value, 54.8%; negative predictive value, 92.1%; AUC, 0.84). However, the combination of exercise E/A (A = late diastolic transmitral flow velocity) >=1.22 + exercise E/e' >=8.85 + exercise s'<=11.05 cm/s provided the most precise prediction of exercise LAP elevation (sensitivity, 84.6%; specificity, 79.6%; positive predictive value, 66.7%; negative predictive value, 91.5%; AUC, 0.90). CONCLUSIONS: Exercise E/e', when used as a sole parameter, was not sufficiently reliable to predict exercise-induced elevation of LAP. The application of a multivariate-adjusted combination of parameters appeared to be the preferable approach for the noninvasive prediction of exercise LAP elevation. PMID- 27779337 TI - Organocatalytic Asymmetric Benzylation and Aldol-Hemiacetalization of alpha,beta Unsaturated Trifluoromethyl Ketones: Efficient Enantioselective Construction of 3,4-Dihydroisocoumarins. AB - A new method has been developed for the organocatalytic enantioselective benzylation and aldol-hemiacetalization of alpha,beta-unsaturated trifluoromethyl ketones with toluene derivatives in the presence of a tertiary amine-thiourea catalyst. This method represents a facile and efficient strategy for the asymmetric synthesis of optically active 3,4-dihydroisocoumarins bearing a trifluoromethylated tetrasubstituted carbon stereocenter with high enantioselectivity. Notably, this strategy was used to synthesize several chiral trifluoromethylated analogues of typharin with high efficiency. PMID- 27779338 TI - Heterolytic (2 e) vs Homolytic (1 e) Oxidation Reactivity: N-H versus C-H Switch in the Oxidation of Lactams by Dioxirans. AB - Dioxiranes are powerful oxidants that can act via two different mechanisms: 1) homolytic (H abstraction and oxygen rebound) and 2) heterolytic (electrophilic oxidation). So far, it has been reported that the nature of the substrate dictates the reaction mode independently from the dioxirane employed. Herein, we report an unprecedented case in which the nature of the dioxirane rules the oxidation chemoselectivity. In particular, a switch from C-H to N-H oxidation is observed in the oxidation of lactams moving from dimethyl dioxirane (DDO) to methyl(trifluoromethyl)dioxirane (TFDO). A physical organic chemistry study, which combines the oxidation with two other dioxiranes methyl(fluoromethyl)dioxirane, MFDO, and methyl(difluoromethyl)dioxirane, DFDO, with computational studies, points to a diverse ability of the dioxiranes to either stabilize the homo or the heterolytic pathway. PMID- 27779339 TI - Ruthenium(II) Biscarboxylate-Catalyzed Borylations of C(sp2 )-H and C(sp3 )-H Bonds. AB - Versatile borylations of C(sp2 )-H and C(sp3 )-H were achieved with ruthenium(II) biscarboxylate complexes. The robust nature of the ruthenium(II) catalyst enabled C(sp3 )-H borylation on pyrrolidines, piperidines, and azepanes with ample scope and excellent positional selectivity control. PMID- 27779340 TI - Tris(imidazolin-2-ylidenamino)phosphine: A Crystalline Phosphorus(III) Superbase That Splits Carbon Dioxide. AB - We report the synthesis and remarkable properties of the phosphine P(NIiPr)3 (NIiPr=1,3-diisopropyl-4,5-dimethylimidazolin-2-ylidenamino), a crystalline solid accessible through a short and scalable route. Evaluation of the electron-donor properties reveals a Tolman electronic parameter (TEP) value of 2029.7 cm-1 for the new phosphine that is significantly lower than those of all known phosphines or even N-heterocyclic carbenes. Moreover, P(NIiPr)3 is more basic [pKBH+ (MeCN)=38.8] than Verkade's proazaphosphatranes, thus being the strongest reported nonionic phosphorus(III) superbase. The coordination chemistry of the new phosphine towards different metal centers has been explored, and due to its unique electron-releasing character, the phosphine is capable of capturing and cleaving the CO2 molecule. PMID- 27779341 TI - Study of neurometabolic and behavioral alterations in rodent model of mild traumatic brain injury: a pilot study. AB - Mild traumatic brain injury (mTBI) is the most common form of TBI (70-90%) with consequences of anxiety-like behavioral alterations in approximately 23% of mTBI cases. This study aimed to assess whether mTBI-induced anxiety-like behavior is a consequence of neurometabolic alterations. mTBI was induced using a weight drop model to simulate mild human brain injury in rodents. Based on injury induction and dosage of anesthesia, four animal groups were included in this study: (i) injury with anesthesia (IA); (ii) sham1 (injury only, IO); (iii) sham2 (only anesthesia, OA); and (iv) control rats. After mTBI, proton magnetic resonance spectroscopy (1 H-MRS) and neurobehavioral analysis were performed in these groups. At day 5, reduced taurine (Tau)/total creatine (tCr, creatine and phosphocreatine) levels in cortex were observed in the IA and IO groups relative to the control. These groups showed mTBI-induced anxiety-like behavior with normal cognition at day 5 post-injury. An anxiogenic effect of repeated dosage of anesthesia in OA rats was observed with normal Tau/tCr levels in rat cortex, which requires further examination. In conclusion, this mTBI model closely mimics human concussion injury with anxiety-like behavior and normal cognition. Reduced cortical Tau levels may provide a putative neurometabolic basis of anxiety-like behavior following mTBI. PMID- 27779342 TI - Prenatal diagnosis of Berry syndrome by fetal echocardiography: a case report. AB - We report a case in which Berry syndrome is diagnosed by fetal echocardiography. Fetal echocardiography showed that the ascending aorta, main pulmonary artery, left pulmonary artery, and right pulmonary artery were presented as a vascular complexity in the three vessels and pulmonary arterial branches view. PMID- 27779343 TI - Enhanced pi-Back-Donation as a Way to Higher Coordination Numbers in d10 [M(NHC)n ] Complexes: A DFT Study. AB - We aim to understand the electronic factors determining the stability and coordination number of d10 transition-metal complexes bearing N-heterocyclic carbene (NHC) ligands, with a particular emphasis on higher coordinated species. In this DFT study on the formation and bonding of Group 9-12 d10 [M(NHC)n ] (n=1 4) complexes, we found that all metals form very stable [M(NHC)2 ] complexes, but further coordination depends on the specific interplay of 1) the interaction energy (DeltaEint ) between the [M(NHC)n-1 ] (n=2-4) fragment and the incoming NHC ligand, and 2) the strain energy (DeltaEstrain ) associated with bending of the linear NHC-M-NHC arrangement. The key observation is that DeltaEstrain , which is an antagonist for higher coordination numbers, can significantly be lowered by M->NHC pi*-back-donation. This leads to favorable thermodynamics for n=3-4 for highly electrophilic metals in our study, and thus presents a general design motif to achieve coordination numbers beyond two. The scope of our findings extends beyond the NHC model systems and has wider implications for the synthesis of d10 [MLn ] complexes and their catalytic activity. PMID- 27779344 TI - Dexmedetomidine use in patients undergoing electrophysiological study for supraventricular tachyarrhythmias. AB - BACKGROUND: Dexmedetomidine is a selective alpha-2 adrenergic agonist with sedative, analgesic, and anxiolytic properties. Dexmedetomidine has not been approved for use in pediatrics. Dexmedetomidine has been reported to depress sinus node and atrioventricular nodal function in pediatric patients; it has been suggested that the use of dexmedetomidine may not be desirable during electrophysiological studies. AIM: We hypothesize that the use of dexmedetomidine does not inhibit the induction of supraventricular tachyarrhythmias (SVT) during electrophysiological studies and does not inhibit the ablation of such arrhythmias. METHODS: In this retrospective, observational cohort study, we reviewed all cases presenting to the cardiac catheterization laboratory for diagnosis or treatment of SVT since 2007. All cases were performed by the same electrophysiologist. The anesthesia was provided by one of the three cardiac anesthesiologists. One cardiac anesthesiologist did not use dexmedetomidine during electrophysiological studies. A second used dexmedetomidine, but only with an infusion. The third used dexmedetomidine with a primary bolus and an infusion. Thus, the patients were stratified into three different groups: Group 1 patients did not receive any dexmedetomidine. Group 2 patients received a dexmedetomidine infusion of 0.5-1 MUg.kg-1 .h-1 . Group 3 patients received a dexmedetomidine infusion of 0.5-1 MUg.kg-1 .h-1 and a dexmedetomidine bolus prior to the infusion of 0.5-1 MUg.kg-1 . We then compared those patients for the following variables: demographic data including age, sex, height, weight; anesthetic data such as, mask vs intravenous induction, identity of induction agent, amount of sevoflurane and propofol used; amount of dexmedetomidine used; presence of congenital heart disease and other comorbidities; the need for isoproterenol and dose, the need for adenosine and dose, and the need for any other medications to affect rhythm both before and after radiofrequency ablation; the ability to induce the arrhythmia, the type of arrhythmia, the presence of Wolff-Parkinson-White syndrome, the presence of an accessory pathway, the ablation rate, and the recurrence rate. RESULTS: There was no difference in the anesthetic agents, except there was a lesser amount of propofol used in the dexmedetomidine groups (chi2(2) = 48.2, P < 0.001). There was no difference in the electrophysiological parameters among groups, except the Group 1 patients did require the use of isoproterenol in the preablation period less often compared to the dexmedetomidine groups (chi2(2) = 15.2, P < 0.01). However, with the greater use of isoproterenol, there was no difference in the ability to induce the arrhythmia. Moreover, the percentage of patients ablated, and the recurrence rate among groups was the same. CONCLUSIONS: We conclude that dexmedetomidine does not interfere with the conduct of electrophysiological studies for SVT and the successful ablation of such arrhythmias. However, dexmedetomidine use did result in a greater need for isoproterenol. PMID- 27779345 TI - Quality of Life after Invasive or Breast-Conserving Surgery for Breast Cancer. PMID- 27779346 TI - Cardiovascular Health among Black and White Breast Cancer Patients Initiating Aromatase Inhibitor Therapy. AB - The purpose of this study was to compare the cardiovascular health of Black and White breast cancer patients undergoing adjuvant treatment. Baseline data from a cohort study of Black (n = 45) and White (n = 101) breast cancer patients initiating aromatase inhibitor treatment were analyzed. Participants had a cardiovascular health assessment, including carotid intimal medial thickness measurement, donated a blood sample, and completed a questionnaire. Atherosclerotic cardiovascular disease (ASCVD) event risk scores were calculated. Compared to their White counterparts, the Black patients had a significantly higher median ASCVD risk score (p = 0.009) and had a higher number of CVD risk factors (p < 0.05). Black patients were also more likely to have hypertension, diabetes, or to be obese than the White participants. The prevalence of cardiovascular disease and cardiovascular disease risk factors among Black and White breast cancer patients is high, and racial disparities exist which may have treatment implications. PMID- 27779347 TI - The effect of general anesthesia for ambulatory dental treatment on children in Chongqing, Southwest China. AB - BACKGROUND: The incidence of early childhood caries shows a significant increasing trend. Often, children younger than 6 years need additional help to finish the dental treatment. Therefore, general anesthesia (GA) could help to provide a successful environment for pediatric dental treatment. OBJECTIVES: The aim of this study was to assess the effect of dental treatment under general anesthesia (DGA) on the patients' oral health in Chongqing, Southwest China using the P-CPQ and the FIS questionnaires. METHODS: We collected the hospital's records of the children who received DGA from 2013 to 2014 and the questionnaires answered by their parents or caregivers before and after the treatment. Then the data were integrated and analyzed to assess the effect of DGA on the children and their family, the incidence of the complications during or after DGA, and the satisfaction of their parents. RESULTS: We collected 659 patients' records including 55.4% boys and 44.6% girls. There were 443 children younger than 4 years, and 216 children older than 4 years. The main reason why they chose DGA was the patients' fear for the treatment (95.1%). The mean cost of DGA almost reached a half (61.5%) or a third (15.3%) of the family's monthly earning. The mean P-CPQ score and FIS score significantly decreased after DGA. The highest incidence of complications was emergence agitation, headache, and nausea/vomiting. The incidence of emergence agitation and headache was related to the operation time. The majority of families reported a high degree of satisfaction. CONCLUSIONS: Children's oral health-related quality of life after DGA improved significantly. Meanwhile DGA showed a positive effect on the whole family and majority of families reported a high degree of satisfaction to it. PMID- 27779348 TI - Simultaneous detection of valine and lactate using MEGA-PRESS editing in pyogenic brain abscess. AB - Valine and lactate have been recognized as important metabolic markers to diagnose brain abscess by means of MRS. However, in vivo unambiguous detection and quantification is hampered by macromolecular contamination. In this work, MEGA-PRESS difference editing of valine and lactate is proposed. The method is validated in vitro and applied for quantitative in vivo experiments in one healthy subject and two brain abscess patients. It is demonstrated that with this technique the overlapping lipid signal can be reduced by more than an order of magnitude and thus the robustness of valine and lactate detection in vivo can be enhanced. Quantification of the two abscess MEGA-PRESS spectra yielded valine/lactate concentration ratios of 0.10 and 0.27. These ratios agreed with the concentration ratios determined from concomitantly acquired short-TE PRESS data and were in line with literature values. The quantification accuracy of lactate (as measured with Cramer-Rao lower bounds in LCModel processing) was better for MEGA-PRESS than for short-TE PRESS in all acquired in vivo datasets. The Cramer-Rao lower bounds of valine were only better for MEGA-PRESS in one of the two abscess cases, while in the other case coediting of isoleucine confounded the quantification in the MEGA-PRESS analysis. MEGA-PRESS and short-TE PRESS should be combined for unambiguous quantification of amino acids in abscess measurements. Simultaneous valine/lactate MEGA-PRESS editing might benefit the distinction of brain abscesses from tumors, and further categorization of bacteria with reasonable sensitivity and specificity. PMID- 27779349 TI - Evaluation of I-GelTM size 2 airway in different degrees of neck flexion in anesthetized children - a prospective, self-controlled trial. AB - BACKGROUND: A previous study by our group demonstrated an increase in oropharyngeal leak pressures and a deterioration of ventilation in maximum neck flexion with the I-GelTM . To ascertain the optimal degree of neck flexion which increases OPLP without compromising ventilation we conducted a prospective self controlled trial with the I-GelTM in different degrees of neck flexion in anesthetized paralyzed children. METHODOLOGY: The I-gelTM was inserted in 60 children undergoing inhalation induction with muscle paralysis for routine general anesthesia. Recordings of peak inspiratory pressures (PIP) at flexion of 15 degrees , 30 degrees , and 45 degrees were taken as the primary outcome. Expired tidal volume, ventilation scoring, fiberoptic gradings, and OPLP in different degrees of flexion were recorded as secondary outcomes. RESULTS: There was a significant increase in mean PIP in cm H2 O at flexion 30 degrees [13.3 (95% CI 12.8-13.8) cm H2 O, P < 0.001] and 45 degrees flexion (16.5 [15.9-17.1] cm H2 O, P < 0.001) compared to neutral. A decrease in the expired tidal volume was seen at flexion of 30 degrees (7.6 [7.3-7.8] cm H2 O, P = 0.00) and 45 degrees (7.6 [7.3-7.8] cm H2 O, P = 0.00). There was deterioration of ventilation score, mean [range] at 30 degrees flexion 2[0-3], and 45 degrees flexion 1[0-3] compared to the neutral 3[2-3]. There was a significant increase in OPLP with an increase in degree of flexion. CONCLUSION: We conclude that 15 degrees neck flexion can safely be applied without compromising ventilation with the I-GelTM in anesthetized paralyzed children. However, Flexion of 30 degrees or more warrants caution or the use of alternative devices like an endotracheal tube due to increase in PIP and worsening of ventilation score. PMID- 27779350 TI - Adrenal insufficiency in neonates after cardiac surgery with cardiopulmonary bypass. AB - BACKGROUND: Cardiopulmonary bypass (CPB) may lead to adrenal insufficiency (AI). Emerging evidence supports association of AI with morbidity after cardiac surgery. AIMS: The aim of this study was to define AI incidence in neonates undergoing complex cardiac surgery with CPB and its association with intraoperative post-CPB outcomes. METHODS: Forty subjects enrolled in a prior randomized control trial who received preoperative methylprednisolone as part of our institutional neonatal bypass protocol were included. No intraoperative steroids were given. ACTH stimulation tests were performed: preoperatively and 1 h after separation from CPB. AI was defined as <9 MUg.ml-1 increase in cortisol at 30 min post cosyntropin 1 mcg. Clinical outcomes were collected up to 90 min after CPB. RESULTS: 2/40 (5%) subjects had preoperative AI vs 13/40 (32.5%) post CPB AI, P <= 0.001. No significant difference was observed in age, gestational age, weight, CPB time, circulatory arrest, or STAT category between subjects with or without post-CPB AI. ACTH decreased from preoperative values 127.3 vs 35 pcg.ml-1 [median difference = 81.8, 95% CI = 22.7-127.3], while cortisol increased from 18.9 vs 75 MUg.dl-1 [median difference = 52.2, 95% CI = 36.3 70.9]. Post-CPB AI was associated with increased median colloid resuscitation, 275 vs 119 ml.kg-1 [median difference = 97.8, 95% CI = 7.1-202.2]; higher median peak lactate, 9.4 vs 6.9 mg.dl-1 [median difference = 3.2, 95% CI = 0.04-6.7]; median post-CPB lactate, 7.9 vs 4.3 mg.dl-1 , [median difference 3.6, 95% CI = 2.1-4.7], and median lactate on admission to CICU, 9.4 vs 6.0 mg.dl-1 [median difference = 3, 95% CI = 1.1-4.9]. No difference was observed in blood pressure or vasoactive inotrope score at any time point measured in operating room (OR). Higher initial post-CPB cortisol correlated with decreased cosyntropin response. CONCLUSIONS: Neonatal cardiac surgery with CPB and preoperative methylprednisolone leads to AI as determined by low-dose ACTH stimulation test in one-third of patients. AI is associated with increased serum lactate and colloid resuscitation in OR. Impact of preoperative methylprednisolone on results is not defined. Benefit of postoperative steroid administration in neonates with post CPB AI warrants further investigation. PMID- 27779352 TI - Prioritizing Patient-Reported Outcomes in Breast Cancer Surgery Quality Improvement. AB - Breast-cancer-specific tools that measure health-related quality of life (HRQOL) were developed for use in research or clinical practice, and little is known about these tools' performance ability for quality improvement. Furthermore, existing tools may not fully reflect all issues that contribute to quality care as seen by patients. Work is needed to identify and validate patient-reported outcome measures for use in quality improvement in breast cancer surgical care. We conducted an exploratory qualitative study in order to better understand what HRQOL domains and processes of care define high quality surgical care for women undergoing mastectomy for breast cancer from both the patient and clinician perspective. We conducted focus groups and one-on-one interviews with 15 women and administered a prioritization questionnaire to participants. We also conducted a prioritization questionnaire among surgical oncologists, general surgeons, and reconstructive surgeons who are members of the Washington State Medical Association. Both the patient and surgeon prioritization questionnaire asked participants to prioritize HRQOL and treatment satisfaction-related aspects of their breast cancer surgical care at key time points before and after mastectomy. A Stakeholder Advisory Panel was convened to review focus group, interview, and prioritization questionnaire results and make recommendations as to patient-reported outcome domains to focus on and existing instruments to use for quality improvement. Patients and clinicians largely agreed on important HRQOL domains, including emotional well-being, education, communication, and process of care. The Stakeholder Advisory Panel, composed of 12 clinicians and five patients, reviewed study findings and existing patient-reported outcomes measurement tools. The panel recommended that the BREAST-Q, a flexible tool with independently validated modules designed for research and clinical care, is an ideal tool to begin developing novel quality improvement benchmarks focused on patient-reported outcomes. PMID- 27779351 TI - Left Atrial Size and Left Ventricular End-Systolic Dimension Predict the Progression of Paroxysmal Atrial Fibrillation After Catheter Ablation. AB - INTRODUCTION: Although rare, some paroxysmal atrial fibrillations (AF) still progress despite radiofrequency (RF) ablation. In the study, we evaluated the long-term efficacy of RF ablation and the predictors of AF progression. METHODS: A total of 589 paroxysmal AF patients (404 men and 185 women; aged 54 +/- 12 years) who received 3-dimensional mapping and ablation were enrolled. Their clinical parameters and electrophysiological characteristics were collected. They were divided into Group 1 (N = 13, with AF progression) and Group 2 (N = 576, no AF progression). AF progression was defined as recurrence of persistent AF. RESULTS: Group 1 patients had larger left atrial (LA) diameter, larger left ventricle (LV) end-systolic and end-diastolic diameters, poorer LV systolic function, and more amiodarone use at baseline. After 1.2 +/- 0.5 procedures, 123 (21%) patients experienced recurrence during 56 +/- 29 months' follow-up. In the multivariate analysis, LA diameter (P = 0.018, HR = 1.12, 95% CI = 1.02-1.24) and LV end-systolic diameter (P = 0.005, HR = 1.10, 95% CI = 1.03-1.17) independently predicted AF progression. LA diameter >43 mm and LV end-systolic diameter >31 mm were the best cut-off values for predicting AF progression by ROC analysis. AF progression rate achieved 19% if they had both larger LA diameter (>43 mm) and LV end-systolic diameter (>31 mm). CONCLUSION: RF ablation prevents the progression of paroxysmal AF effectively, except in patients with increased LA diameter and LV end-systolic diameter on echocardiogram, suggesting more aggressive rhythm control therapies should be considered in these patients. PMID- 27779353 TI - Mortality following congenital diaphragmatic hernia repair: the role of anesthesia. AB - BACKGROUND: Mortality following surgical repair of congenital diaphragmatic hernia (CDH) remains high. The volume and type of perioperative intravenous fluid administered, baro-trauma, oxygen toxicity, and the duration of anesthesia are thought to affect outcome in surgical populations. AIMS: The aim of this retrospective observational study was to determine whether the perioperative volume or type of fluids and/or the duration of anesthesia were associated with postoperative mortality and if mortality was predicted by the oxygenation index (OI) prior to or following CDH surgical repair. METHODS: The records of infants with a left-sided CDH and without other congenital anomalies, who underwent surgical repair between April 2009 and March 2015, were examined. The oxygenation index was used to "quantify" the severity of lung function abnormality and reported as the best OI on day 1 after birth (OIBEST ), the OI immediately prior to surgery (OIPRE ) and at 1, 6, 12, and 24 h postsurgery (OI1h , OI6h , OI12h , OI24h ), respectively. The change in the OI index (delta OI) was calculated by subtracting OIPRE from postoperative OIs. RESULTS: The records of 37 CDH infants (median gestational age 35.8, range 31.5-41.4 weeks) were assessed; six died postoperatively. Neither the duration of anesthesia, the volume of crystalloids or colloids administered, nor the peak inflation pressures used during surgical repair were significantly correlated with postoperative mortality. Neither fetal tracheal occlusion nor use of a parietal patch significantly influenced mortality. The postoperative OI1h , OI6h , OI12h showed weak evidence for a difference between survivors and nonsurvivors. An OI24h of >=5.5 predicted mortality with 100% sensitivity (95% CI, confidence intervals (CI) 40-100) and 93.1% specificity (95% CI, 77-99). CONCLUSION: Neither the volume of intraoperative fluids administered nor the duration of anesthesia was associated with postoperative death. The OI 24 h postsurgery was the best predictor of an increased risk of mortality. PMID- 27779354 TI - Pharmacokinetics and analgesic effectiveness of intravenous parecoxib for tonsillectomy +/- adenoidectomy. AB - BACKGROUND: Few pharmacokinetic (PK) and pharmacodynamic (PD) data exist for COX 2 selective inhibitors in children. We wished to characterize the PKPD of parecoxib and its active metabolite, valdecoxib, in this population. METHODS: Children (n = 59) were randomized to parecoxib 0.25 mg.kg-1 , 1 mg.kg-1 , and 2 mg.kg-1 during tonsillectomy +/- adenoidectomy. Samples (4-6 per child) were obtained from indwelling cannula over 6 h. A second group of inpatient children (n = 15) given 1 mg.kg-1 contributed PK data from 6 to 24 h. Pain scores and rescue medication for the first group were recorded postoperatively for up to 24 h. PK data were pooled with those (10 samples/24 h) from a published study of children (n = 38) who underwent surgery. A three-compartment parent and one compartment metabolite model with first-order elimination was used to describe data using nonlinear mixed effects models. An EMAX model described the relationship between dose and rescue morphine equivalents during recovery. RESULTS: Parecoxib PK parameter estimates were CLPARECOXIB 19.1 L.h-1 .70 kg-1 , V1PARECOXIB 4.2 L.70 kg-1 , Q2PARECOXIB 6.29 L.h-1 .70 kg-1 , V2PARECOXIB 130 L.70 kg-1 , Q3PARECOXIB 6.02 L.h-1 .70 kg-1 , and V3PARECOXIB 2.03 L.70 kg-1 . We assumed all parecoxib was metabolized to valdecoxib with CLVALDECOXIB 9.53 L.h-1 .70 kg-1 and VVALDECOXIB 51 L.70 kg-1 . There was no maturation of clearance over the age span studied. There were no differences in pain scores between groups on waking, discharge, 12 h, or 24 h. There were no differences in analgesia consumption over 24 h between groups for tramadol, fentanyl, and morphine rescue use. Fentanyl and morphine consumption, expressed as morphine equivalents (0.13 mg.kg-1 ) in the 0.25 mg.kg-1 group, was greater than that observed in the 1 or 2 mg.kg-1 groups (0.095 mg.kg-1 ) in PACU. CONCLUSIONS: Parecoxib 0.9 mg.kg-1 in a 2-year-old, 0.75 mg.kg-1 in a 7-year-old, and 0.65 mg.kg-1 in a 12-year-old child achieves dose equivalence of 40 mg in a standard 70 kg person. Clearance maturation may occur in infants younger than the current cohort. Parecoxib doses above 1 mg.kg-1 add no additional analgesia. PMID- 27779355 TI - Leukemic infiltration presenting as myocardial hypertrophy after complete remission of acute myeloid leukemia. AB - Here, we report a rare case of isolated leukemic infiltrate of the myocardium (extramedullary involvement) presenting as restrictive cardiomyopathy in a patient in complete remission of acute myeloid leukemia. It was evaluated with multimodality imaging studies (echocardiography and cardiac MRI) and further confirmed by pathology. The present case highlights the importance of maintaining a high degree of clinical suspicion when evaluating patients with progressive ventricular hypertrophy of unknown cause, including recognition of the potential involvement by recurrent hematologic malignancy. PMID- 27779356 TI - Oral morphine dosing predictions based on single dose in healthy children undergoing surgery. AB - BACKGROUND: Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose. AIMS: The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens. METHODS: Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg.kg-1 , 200 mcg.kg-1 , 300 mcg.kg-1 ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG ), and absorption half-time (TABS ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg.kg-1 ) at different dosing intervals (3, 4, 5, 6, 8, 12 h). RESULTS: The oral morphine formulation had F 0.298 (CV 36.5%), TLAG 0.45 (CV 63.6%) h and TABS 0.71 (CV 55%) h. A single dose morphine 100 mcg.kg-1 achieved a mean CMAX 10 mcg.l-1 . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg.l-1 ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg.l-1 at steady state. CONCLUSIONS: Oral morphine 200 mcg.kg-1 then 100 mcg.kg-1 4 h or 150 mcg.kg-1 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses. PMID- 27779357 TI - Understanding Polymer-Cell Attachment. AB - The development of polymeric materials with cell adhesion abilities requires an understanding of cell-surface interactions which vary with cell type. To investigate the correlation between cell attachment and the nature of the polymer, a series of random and block copolymers composed of 2 (dimethylamino)ethyl acrylate and ethyl acrylate are synthesized through single electron transfer living radical polymerization. The polymers are synthesized with highly defined and controlled monomer compositions and exhibited narrow polydispersity indices. These polymers are examined for their performance in the attachment and growth of HeLa and HEK cells, with attachment successfully modeled on monomer composition and polymer chain length, with both cell lines found to preferentially attach to moderately hydrophobic functional materials. The understanding of the biological-material interactions assessed in this study will underpin further investigations of engineered polymer scaffolds with predictable cell binding performance. PMID- 27779359 TI - Ferrocene-Promoted Long-Cycle Lithium-Sulfur Batteries. AB - Confining lithium polysulfide intermediates is one of the most effective ways to alleviate the capacity fade of sulfur-cathode materials in lithium-sulfur (Li-S) batteries. To develop long-cycle Li-S batteries, there is an urgent need for material structures with effective polysulfide binding capability and well defined surface sites; thereby improving cycling stability and allowing study of molecular-level interactions. This challenge was addressed by introducing an organometallic molecular compound, ferrocene, as a new polysulfide-confining agent. With ferrocene molecules covalently anchored on graphene oxide, sulfur electrode materials with capacity decay as low as 0.014 % per cycle were realized, among the best of cycling stabilities reported to date. With combined spectroscopic studies and theoretical calculations, it was determined that effective polysulfide binding originates from favorable cation-pi interactions between Li+ of lithium polysulfides and the negatively charged cyclopentadienyl ligands of ferrocene. PMID- 27779358 TI - Comparative Endocytosis Mechanisms and Anticancer Effect of HPMA Copolymer- and PAMAM Dendrimer-MTCP Conjugates for Photodynamic Therapy. AB - Polymer architecture can influence biodistribution and the mode of presentation of bioactive agents to cells. Herein delivery, loading efficiency, and mode of cellular entry of polymer conjugates of the photosensitizer Meso-Tetra (4 Carboxyphenyl) Porphyrine (MTCP) are examined when attached to hyperbranched amine terminated poly(amido amine) (PAMAM) dendrimer or random coil linear N-(2 hydroxypropyl)methacrylamide (HPMA) copolymer containing free amines in the side chains. The in vitro dark cytotoxicity and phototoxicity of MTCP and related conjugates are assessed on mouth epidermal carcinoma (KB) and human adenocarcinoma alveolar basal epithelial (A549) cells. Phototoxicity of polymeric conjugates increases by ~100 and 4000 fold in KB and A549 cells compared with nonconjugated MTCP. The increase in phototoxicity activity is shown to result from increased rate of cellular uptake, whereas, cellular internalization of MTCP is negligible in comparison with the conjugated forms. The results of this study suggest the superiority of amine-terminated HPMA copolymer versus PAMAM dendrimer under study for delivery of MTCP. Treatment with various pharmacological inhibitors of endocytosis shows that polymer architecture influences the mechanism of cellular uptake of the conjugated photosensitizer. Results show that polymeric conjugates of MTCP improve solubility, influence the route and the rate of cellular internalization, and drastically enhance the uptake of the photosensitizer. PMID- 27779361 TI - Response to 'Challenging the concept of diffuse neurofibrillary tangles with calcification (Kosaka-Shibayama disease)'. PMID- 27779360 TI - A retrospective comparison of propofol alone to propofol in combination with dexmedetomidine for pediatric 3T MRI sedation. AB - BACKGROUND AND AIM: Both propofol and dexmedetomidine have been found to be safe and effective sedation for magnetic resonance imaging (MRI). Our program experienced an increase in patients arousing and experiencing an adverse airway event during propofol sedation for MRI in the first months of using a new 3T (Tesla) MRI scanner that was found to have a longer reverberation time compared to the previous 1.5 T MRI. In an effort to decrease patient arousal and adverse airway events during MRI, we administered a dexmedetomidine load prior to our standard propofol protocol. The objective was to compare adverse events and other outcome measures of patients sedated with propofol alone (Pro) and propofol preceded by a dexmedetomidine load (D+P). METHODS: We reviewed a sedation database and medical records for all children undergoing 3T MRI studies while sedated with propofol alone or propofol preceded by a dexmedetomidine load in 2014. RESULTS: Two hundred and fifty-six sedations were performed for MRI (87 Pro and 169 D+P). The two groups were comparable with regard to age, weight, gender, and American Society of Anesthesiologists status. Subjects in the D+P cohort had significantly fewer adverse events (10/169 patients (5.9%) vs 23/87 patients (26.4%) [OR 0.18, 95% CI: 0.08-0.39, P < 0.001]), particularly upper airway obstruction. Mean discharge time was longer in the D+P cohort compared to the Pro cohort (87.1, SD 26.3 min vs 69.7, SD 23.6; [mean difference 17.7 min, 95% CI: 10.6-24.8, P < 0.001]). CONCLUSIONS: The addition of a dexmedetomidine infusion prior to our propofol MRI sedation protocol resulted in fewer sedation-related adverse events, particularly upper airway obstruction. Further studies are needed to evaluate the potential for a reduction on adverse events with this drug combination. PMID- 27779362 TI - Role of monocyte recruitment in hemangiosarcoma metastasis in dogs. AB - Canine hemangiosarcoma (HSA) is a highly malignant tumour associated with short survival times because of early and widespread metastasis. In humans and rodents, monocytes play key roles in promoting tumour metastasis through stimulating tumour cell extravasation, seeding, growth and angiogenesis. Therefore, we investigated the potential association between monocyte infiltration and tumour metastasis in HSA and other common canine tumours. Immunohistochemistry was used to quantify CD18+ monocytes within metastases. We found that HSA metastases had significantly greater numbers of CD18+ monocytes compared with metastases from other tumour types. HSA cells were the highest producers of the monocyte chemokine CCL2, and stimulated canine monocyte migration in a CCL2 dependent manner. These results are consistent with the hypothesis that overexpression of CCL2 and recruitment of large numbers of monocytes may explain in part the aggressive metastatic nature of canine HSA. Thus, therapies designed to block monocyte recruitment may be an effective adjuvant strategy for suppressing HSA metastasis in dogs. PMID- 27779363 TI - Predictors for clinical deterioration of mental state in patients assessed by telephone-based mental health triage. AB - Patient safety research focussing on recognizing and responding to clinical deterioration is gaining momentum in generalist health, but has received little attention in mental health settings. The focus on early identification and prompt intervention for clinical deterioration enshrined in patient safety research is equally relevant to mental health, especially in triage and crisis care contexts, yet the knowledge gap in this area is substantial. The present study was a controlled cohort study (n = 817) that aimed to identify patient and service characteristics associated with clinical deterioration of mental state indicated by unplanned admission to an inpatient psychiatric unit following assessment by telephone-based mental health triage. The main objective of the research was to produce knowledge to improve understandings of mental deterioration that can be used to inform early detection, intervention, and prevention strategies at the point of triage. The results of the study found that the clinical profile of admitted patients was one of complexity and severity. Admitted patients were more likely to have had complex psychiatric histories with multiple psychiatric admissions, severe psychotic symptoms, a history of treatment non-adherence, and poorer social functioning than non-admitted patients. PMID- 27779364 TI - Insulin-like growth factor axis targeting in cancer and tumour angiogenesis - the missing link. AB - Numerous molecular players in the process of tumour angiogenesis have been shown to offer potential for therapeutic targeting. Initially denoted to be involved in malignant transformation and tumour progression, the insulin-like growth factor (IGF) signalling axis has been subject to therapeutic interference, albeit with limited clinical success. More recently, IGFs and their receptors have received attention for their contribution to tumour angiogenesis, which offers novel therapeutic opportunities. Here we review the contribution of this signalling axis to tumour angiogenesis, the mechanisms of resistance to therapy and the interplay with other pro-angiogenic pathways, to offer insight in the renewed interest in the application of IGF axis targeting agents in anti-cancer combination therapies. PMID- 27779365 TI - Transcriptome analysis of equine sarcoids. AB - Equine sarcoids are the most commonly detected skin tumours in Equidae. In the present research, a comparative transcriptomic analysis was performed which aimed at looking inside a tumour biology and identification of the expression profile as a potential source of cancer specific genes useful as biomarkers. We have used Horse Gene Expression Microarray data from matched equine sarcoids and tumour distant skin samples. In total, 901 significantly differentially expressed genes (DEGs) between lesional and healthy skin samples have been identified (fold change >= 2; P < 0.05). The large subset of DEGs, with decreased expression, was associated with a suppression of malignant transformation, whereas several overexpressed genes were involved in the processes associated with growth and progression of a tumour or immune system activity. Our results, as a first to date, showed comprehensive transcriptome analysis of skin tumour in horses and pinpointed significant pathways and genes related with oncogenesis processes. PMID- 27779367 TI - Codeine use among children in the United States: a nationally representative study from 1996 to 2013. AB - BACKGROUND: Concerns regarding the safety of codeine have been raised. Cases of life-threatening respiratory depression and death in children have been attributed to codeine's polymorphic metabolic pathway. International health agencies recommend restricted use of codeine in children. Despite these recommendations, the epidemiology of codeine use among children remains unknown. AIMS: Our objective was to examine patterns of codeine use in the US among children. METHODS: A cross-sectional analysis of children of age 0-17 years from 1996 to 2013 in the US was performed. Data were extracted from MEPS, a nationally representative set of health care surveys. Prevalence rates of codeine use between 1996 and 2013 were examined. Multivariable logistic regression examined relationships between codeine use and patient demographics. RESULTS: Codeine use remained largely unchanged from 1996 to 2013 (1.08 vs 1.03 million children, respectively). Odds of codeine use was higher in ages 12-17 (OR, 1.40; [1.21 1.61]), outside of the Northeastern US, and among those with poor physical health status (OR, 3.29 [1.79-6.03]). Codeine use was lower in children whose ethnicity was not white and those uninsured (OR, 0.47 [0.34-0.63]). Codeine was most frequently prescribed by emergency physicians (18%) and dentists (14%). The most common condition associated with codeine use was trauma-related pain. CONCLUSIONS: Pediatric codeine use has declined since 1996; however, more than 1 million children still used codeine in 2013. Health care providers must be made aware of guidelines advising against the use of codeine in children. Codeine is potentially hazardous and safer alternatives to treat children's pain are available. PMID- 27779366 TI - Immunohistochemical expression of MDR1-Pgp 170 in canine cutaneous and oral melanomas: pattern of expression and association with tumour location and phenotype. AB - Canine melanoma (CMM) more commonly affects the oral mucosa and the cutis. CMM shares several features with human melanomas (HMM), included resistance to a broad variety of antineoplastic chemotherapy agents. P-glycoprotein 1 (Pgp) expression is a well-recognized feature of multi-drug resistance and the purpose of this study was to investigate its expression in treatment naive CMM. We also investigated Pgp association with tumour location and histological features. Histology records of CMM were retrieved, including patients from 2012-2014. Twenty-five cases of CMM were included in this study. Results revealed that Pgp is expressed in CMM and oral tumours were more likely to have a membranous Pgp expression (100%) than cutaneous tumours (66.6%) (P = 0.010). Cytoplasmic and nuclear Pgp expression could also be identified. Results of this study bring useful data that help in understanding one of the possible mechanisms responsible of intrinsic chemotherapy resistance in canine CMM. PMID- 27779368 TI - Safety and Efficacy of Occipital Nerves Stimulation for the Treatment of Chronic Migraines: Randomized, Double-blind, Controlled Single-center Experience. AB - BACKGROUND: A recent multicenter study presented 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial for patients with chronic migraine (CM) undergoing peripheral nerve stimulation of the occipital nerves. We present the data from a single center of 20 patients enrolled at the Cleveland Clinic's Pain Management Department. METHODS: In this single center, 20 patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, Migraine Disability Assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life, satisfaction, and adverse events (AEs). RESULTS: Headache days per month were reduced by 8.51 (+/-9.81) days (P < 0.0001). The proportion of patients who achieved a 30% and 50% reduction in headache days and/or pain intensity was 60% and 35%, respectively. MIDAS and Zung PAD were reduced for all patients. Fifteen (75%) of the 20 patients at the site reported at least one AE. A total of 20 AEs were reported from the site. CONCLUSION: Our results support the 12-month efficacy of 20 CM patients receiving peripheral nerve stimulation of the occipital nerves in this single-center trial. PMID- 27779369 TI - Analysis of clinical characteristics and prognosis of patients with anaplastic lymphoma kinase-positive and surgically resected lung adenocarcinoma. AB - BACKGROUND: Recent research into lung cancer-related driver genes has identified a distinctive molecular subtype of non-small cell lung cancer (NSCLC) - anaplastic lymphoma kinase (ALK)-positive NSCLC. We evaluated the clinical features and survival rates of ALK-positive lung adenocarcinoma patients who had undergone surgery but had not received ALK inhibitor therapy, along with the characteristics of patients with distant metastases. METHODS: Clinical data of 40 patients with ALK-positive, postsurgical lung adenocarcinoma were retrospectively analyzed. Relationships between the patients' clinical characteristics, distant metastases, and their disease-free survival (DFS) and overall survival (OS) rates were assessed. RESULTS: Most patients were relatively young, never-smokers, had peripheral tumors, and the tumors were either moderately or poorly differentiated. The most common organ of distant metastases was the brain. The median time from surgery to brain metastasis was 17.2 months. The median OS following brain metastasis was 9.4 months. DFS in patients with early stage disease, peripheral tumors, no lymph node metastases, and treated with adjuvant therapy was significantly longer than for those with late stage disease (P = 0.015), central tumors (P = 0.000), lymph node metastases (P = 0.026), and not treated with adjuvant therapy (P = 0.000). Patients with early stage disease, peripheral tumors, and treated with adjuvant therapy obtained markedly longer OS than those with late stage disease (P = 0.021), central tumors (P = 0.003), and not treated with adjuvant therapy (P = 0.006). CONCLUSION: Patients with ALK positive surgically resected lung adenocarcinoma have distinctive clinical characteristics. The brain is the most common site of extrapulmonary metastasis. Survival is associated with stage, tumor location, and the administration of adjuvant therapy. PMID- 27779370 TI - A Randomised Controlled Trial to Test the Effectiveness of Planning Strategies to Improve Medication Adherence in Patients with Cardiovascular Disease. AB - BACKGROUND: Low levels of adherence to medication prescribed to treat and manage chronic disease may lead to maladaptive health outcomes. Theory-based, easy-to administer interventions that promote patients' effective self-regulation of their medication-taking behaviour are needed if adherence is to be maximised. We tested the effectiveness of an intervention adopting planning techniques to promote medication adherence. METHODS: Outpatients with cardiovascular disease (N = 71) were allocated to either an experimental condition, in which participants were asked to form implementation intentions and coping plans related to their treatment, or to a no-planning control condition, in which participants received no treatment. Patients also completed self-report measures of medication adherence, self-efficacy, and beliefs in medication necessity and concerns. Measures were administered at baseline and at 6-week follow-up. RESULTS: Results revealed no overall main effect for the intervention on medication adherence. Post-hoc moderator analyses revealed that the intervention was effective in patients with lower necessity beliefs compared to those with higher necessity beliefs. CONCLUSION: While current findings have promise in demonstrating the conditional effects of planning interventions, there is a need to replicate these findings by manipulating planning and beliefs independently and testing their direct and interactive effects on medication adherence. PMID- 27779371 TI - Ability of noninvasive criteria to predict hemodynamically significant aortic obstruction in adults with coarctation of the aorta. AB - OBJECTIVE: Coarctation of the aorta (CoA) is a common condition. Adult patients with newly diagnosed CoA and patients with recurring or residual CoA require evaluation of the severity of aortic obstruction. Cardiac catheterization is considered the gold standard for the evaluation of hemodynamically significant CoA. The European Society of Cardiology (ESC) Guidelines for the management of grown-up congenital heart disease (GUCH) include noninvasive criteria for identifying significant CoA. Our aim was to investigate the ability of the Class I and Class IIa ESC recommendations to identify significant CoA at cardiac catheterization. DESIGN: Sixty-six adult patients with native or recurrent CoA underwent diagnostic cardiac catheterization at the GUCH unit at the Sahlgrenska University Hospital in Gothenburg from October 1998 to November 2013. Clinical and imaging data, as well as data about cardiac catheterization were retrospectively collected from patient records. RESULTS: The Class I ESC recommendations predicted significant CoA with a sensitivity of 0.57, a specificity of 0.63, a positive predictive value of 0.67, and a negative predictive value of 0.53. The combination of Class I and Class IIa recommendations predicted significant CoA with a sensitivity of 0.75, a specificity of 0.42, a positive predictive value of 0.66 and a negative predictive value of 0.52. CONCLUSIONS: the noninvasive criteria proposed by the ESC guidelines to identify subjects with significant CoA performed poorly in our dataset. Further research is needed to develop more accurate, noninvasive criteria to evaluate CoA severity and thereby reduce the number of unnecessary cardiac catheterizations. PMID- 27779373 TI - The Blind Men and the Elephant: The Risk of Misdiagnosis in Children with Developmental Disabilities. PMID- 27779374 TI - Corrigendum: Carbon Nanotubes as Support in the Platinum-Catalyzed Hydrolytic Dehydrogenation of Ammonia Borane. PMID- 27779372 TI - SORL1 rs1699102 polymorphism modulates age-related cognitive decline and gray matter volume reduction in non-demented individuals. AB - BACKGROUND AND PURPOSE: SORL1 rs1699102 is associated with the risk of late-onset Alzheimer's disease. However, the effects of this single nucleotide polymorphism on cognition and brain structure during normal aging are unclear. This study aimed to examine the effects of the rs1699102 polymorphism on age-related cognitive decline and cortical gray matter reduction in the Chinese Han population. METHODS: A total of 780 non-demented adults completed a battery of neuropsychological tests. High-resolution T1-weighted structural magnetic resonance imaging data from 89 of these subjects were also collected using a Siemens Trio 3.0 Tesla scanner. RESULTS: The T allele carriers displayed an accelerated age-related change in episodic memory and processing speed tests relative to the CC genotype. A similar pattern was observed in the age-related gray matter volume (GMV) reduction of the right middle temporal pole. The GMV in this region was significantly positively correlated with the episodic memory scores. CONCLUSIONS: The SORL1 gene rs1699102 polymorphism has been found to be associated with age-related cognitive decline and GMV reduction of the right middle temporal pole in older adults. These findings elucidate how the SORL1 variants shape the neural system to modulate age-related cognitive decline and support the hypothesis that SORL1 may represent a candidate gene for late-onset Alzheimer's disease. PMID- 27779376 TI - Bioinspired Single-Walled Carbon Nanotubes as a Spider Silk Structure for Ultrahigh Mechanical Property. AB - Due to its unique hierarchical structure, natural spider silk features exceptional mechanical properties such as high tensile strength and great extensibility, making it one of the toughest materials. Herein, we design bioinspired spider silk single-walled carbon nanotubes (BISS-SWCNTs) that combine the hierarchical structure of spider silk and the high strength and conductivity of SWCNTs. To imitate the hierarchical structure, Fe nanoparticles are embedded on the surface of directly synthesized SWCNTs skeleton followed by coating an amorphous carbon layer. The carbon layer forms the spider silk-featured skin-core structure with SWCNTs, thus making the tube junction tougher. The embedded Fe nanoparticles act as glue spots for preventing interfacial slippages between the BISS-SWCNTs and the reinforced matrix. With only 2.1 wt % BISS-SWCNTs added, the tensile strength and Young's modulus of the BISS-SWCNTs/PMMA composites can be improved by 300%. More importantly, the BISS-SWCNTs also retain the high conductivity and transmittance of the pristine SWCNTs film. This unique bioinspired material will be of great importance in applications of multifunctional composite materials and has important implications for the future of biomimetic materials. PMID- 27779377 TI - Comprehensive Analysis of a Novel Ketoreductase for Pentangular Polyphenol Biosynthesis. AB - Arixanthomycins are pentangular polyphenols (PP) with potent antiproliferative activities that were discovered through the heterologous expression of environmental DNA-derived gene clusters. The biosynthesis of arixanthomycin and other PPs is unusual because it requires several novel type II polyketide synthase (PKS) enzymes for its complete maturation. Most type II PKSs contain a ketoreductase (KR) that mediates the C7-C12 first ring cyclization and C-9 reduction. In contrast, based on previous studies of product analysis and genome mining, the arixanthomycin (ARX) gene cluster harbors a C-11 reducing KR (ARX 27), a C9-C14 first-ring aromatase/cyclase (ARX 19), and an unprecedented C-17 and C-19 reducing KR (ARX 21). While bioinformatics is useful for predicting novel enzymes, the functions of ARX 19, ARX 21, and ARX 27 have yet to be confirmed. Further, the structural features that predispose the ARX biosynthetic enzymes to process atypical poly-beta-ketone scaffolds remain unknown. We report the crystal structure of ARX 21, the first structure of an enzyme involved in PP biosynthesis and likely a C-17 and C-19 reducing-KR, which is structurally similar to C-15 reducing KRs. Structural comparison of ARX 21 and other C-9 reducing KRs revealed a difference in the enzyme active site that may enlighten the molecular basis of KR substrate specificity. In addition, we report the successful in vitro reconstitution of ARX 19. The structural characterization of ARX 21 in conjunction with the in vitro results of ARX 19 lays the groundwork toward a complete in vitro and structural characterization of type II PKS enzymes involved in PP biogenesis. PMID- 27779378 TI - What Can We Learn from Bioactivity Data? Chemoinformatics Tools and Applications in Chemical Biology Research. AB - The ever increasing bioactivity data that are produced nowadays allow exhaustive data mining and knowledge discovery approaches that change chemical biology research. A wealth of chemoinformatics tools, web services, and applications therefore exists that supports a careful evaluation and analysis of experimental data to draw conclusions that can influence the further development of chemical probes and potential lead structures. This review focuses on open-source approaches that can be handled by scientists who are not familiar with computational methods having no expert knowledge in chemoinformatics and modeling. Our aim is to present an easily manageable toolbox for support of every day laboratory work. This includes, among other things, the available bioactivity and related molecule databases as well as tools to handle and analyze in-house data. PMID- 27779379 TI - 3D Printing of Ultratough Polyion Complex Hydrogels. AB - Polyion complex (PIC) hydrogels have been proposed as promising engineered soft materials due to their high toughness and good processability. In this work, we reported manufacturing of complex structures with tough PIC hydrogels based on three-dimensional (3D) printing technology. The strategy relies on the distinct strength of ionic bonding in PIC hydrogels at different stages of printing. In concentrated saline solution, PIC forms viscous solution, which can be directly extruded out of a nozzle into water, where dialyzing out of salt and counterions results in sol-gel transition to form tough physical PIC gel with intricate structures. The printability of PIC solutions was systematically investigated by adjusting the PIC material formula and printing parameters in which proper viscosity and gelation rate were found to be key factors for successful 3D printing. Uniaxial tensile tests were performed to printed single fibers and multilayer grids, both exhibiting distinct yet controllable strength and toughness. More complex 3D structures with negative Poisson's ratio, gradient grid, and material anisotropy were constructed as well, demonstrating the flexible printability of PIC hydrogels. The methodology and capability here provide a versatile platform to fabricate complex structures with tough PIC hydrogels, which should broaden the use of such materials in applications such as biomedical devices and artificial tissues. PMID- 27779380 TI - Quantitative Chemical Proteomic Profiling of Ubiquitin Specific Proteases in Intact Cancer Cells. AB - Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes and are emerging as pioneering drug targets. Herein, we present a novel probe, Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling identified 12 USPs, including USP4, USP16, and USP33, as inhibitor targets using submicromolar probe concentrations. This represents the first intact cell activity-based profiling of deubiquitinating enzymes. Further analysis demonstrated functional inhibition of USP33 and identified a synergistic relationship in combination with ATR inhibition, consistent with USP4 inhibition. PMID- 27779381 TI - Electrochemical Glucose Sensing: Is There Still Room for Improvement? AB - As diabetes is considered one of the biggest health care challenges of the coming decades substantial effort is being made to develop novel glucose monitoring systems, this includes thousands of articles which are being published every year. To the question in the title, we answer an unequivocal "yes" but maybe not necessarily in the areas where most of the published research is focused. PMID- 27779382 TI - Strontium-Substituted Submicrometer Bioactive Glasses Modulate Macrophage Responses for Improved Bone Regeneration. AB - Host immune response induced by foreign bone biomaterials plays an important role in determining their fate after implantation. Hence, it is well worth designing advanced bone substitute materials with beneficial immunomodulatory properties to modulate the host-material interactions. Bioactive glasses (BG), with excellent osteoconductivity and osteoinductivity, are regarded as important biomaterials in the field of bone regeneration. In order to explore a novel BG-based osteoimmunomodulatory implant with the capacity of potentially enhancing bone regeneration, it is a possible way to regulate the local immune microenvironment through manipulating macrophage polarization. In this study, strontium substituted submicrometer bioactive glass (Sr-SBG) was prepared as an osteoimmunomodulatory bone repair material. To investigate whether the incorporation of Sr into SBG could synergistically improve osteogenesis by altering macrophage response, we systematically evaluated the interaction between Sr-SBG and macrophage during the process of bone regeneration by in vitro biological evaluation and in vivo histological assessment. It was found that the Sr-SBG modulates proper inflammatory status, leading to enhanced osteogenesis of mouse mesenchymal stem cells (mMSCs) and suppressed osteoclastogenesis of RAW 264.7 cells compared to SBG without strontium substitution. In vivo study confirmed that Sr-SBG initiated a less severe immune response and had an improved effect on bone regeneration than SBG, which corresponded with the in vitro evaluation. In conclusion, these findings suggested that Sr-SBG could be a promising immunomodulatory bone repair material designed for improved bone regeneration. PMID- 27779383 TI - Production of 7,8-Dihydroxy Unsaturated Fatty Acids from Plant Oils by Whole Recombinant Cells Expressing 7,8-Linoleate Diol Synthase from Glomerella cingulata. AB - The reaction conditions for the production of 7S,8S-dihydroxy-9,12(Z,Z) octadecadienoic acid from linoleic acid by recombinant Escherichia coli expressing 7,8-linoleate diol synthase from Glomerella cingulata were optimized using response surface methodology. The optimal reaction conditions were pH 7.0, 18.6 degrees C, 10.8% (v/v) dimethyl sulfoxide, 44.9 g/L cells, and 14.3 g/L linoleic acid, with agitation at 256 rpm. Under these conditions, recombinant cells produced 7,8-dihydroxy unsaturated fatty acids in the range of 7.0-9.8 g/L from 14.3 g/L linoleic acid, 14.3 g/L oleic acid, and plant oil hydrolysates such as waste oil and olive oil containing 14.3 g/L linoleic acid or oleic acid. To the best of the authors' knowledge, this is the first report on the biotechnological production of 7,8-dihydroxy unsaturated fatty acids. PMID- 27779385 TI - Deep-Eutectic Solvents as MWCNT Delivery Vehicles in the Synthesis of Functional Poly(HIPE) Nanocomposites for Applications as Selective Sorbents. AB - We report an alternative green strategy based on deep-eutectic solvents (DES) to deliver multiwalled carbon nanotubes (MWCNTs) for a bottom-up approach that allows for the selective interfacial functionalization of nonaqueous poly(high internal phase emulsions), poly(HIPEs). The formation and polymerization of methacrylic and styrenic HIPEs were possible through stabilization with nitrogen doped carbon nanotube (CNX) and surfactant mixtures using a urea-choline chloride DES as a delivering phase. Subtle changes in CNX concentration (less than 0.2 wt % to the internal phase) produced important changes in the macroporous monolith functionalization, which in turn led to increased monolith hydrophobicity and pore openness. These materials displayed great oleophilicity with water contact angles as high as 140 degrees making them apt for biodiesel, diesel, and gasoline fuel sorption applications. Overall, styrene divinylbenzene (StDvB) based poly(HIPEs) showed hydrophobicity and fuel sorption capacities as high as 4.8 (g/g). Pore hierarchy, namely pore openness, regulated sorption capacity, and sorption times where greater openness resulted in faster sorption and increased sorption capacity. Monoliths were subject to 20 sorption-desorption cycles demonstrating recyclability and stable sorption capacity. Finally, CNX/surfactant hybrids made it possible to reduce surfactant requirements for successful HIPE formation and stabilization during polymerization. All poly(HIPEs) retained acceptable conversion as a function of CNX loading nearing 90% or better with thermal stability as high as 283 degrees C. PMID- 27779386 TI - Self-Activated Yellow Light Emitting Phosphors of alpha, beta-Ca3B2N4 with Long Afterglow Properties. AB - Defect luminescence has been considered to be one of the most efficient ways to resolve the problem of the recent limited supply and increased demand for rare earth elements. So, in this work, a novel self-activated long-persistent green yellow and yellow emitting phosphors of alpha-Ca3B2N4 and beta-Ca3B2N4 has been successfully synthesized by sample-pressuring sintering. The alpha-Ca3B2N4 and beta-Ca3B2N4 all have a broad excitation band peaked at 300 and 350 nm and emit yellow-green light peaked at 550 nm and yellow light peaked at 575 nm respectively with the long afterglow properties. The crystal structures and electron structures of alpha-Ca3B2N4 and beta-Ca3B2N4 have been investigated to show that orthorhombic beta-Ca3B2N4 corresponds to an ordered superstructure of cubic alpha-Ca3B2N4 and the phase transformation between alpha-Ca3B2N4 and beta Ca3B2N4 would happen during the preparation process, which produces many intrinsic defects forming the luminescent center. The thermoluminescence (TL) curve shows that there are traps in the host lattice with the TL peak located at 310 K. The results indicate that alpha-Ca3B2N4 and beta-Ca3B2N4 with the defect related PL and LPL properties have potential applications in the LED and LPL used phosphors. PMID- 27779384 TI - NMR Crystallography of a Carbanionic Intermediate in Tryptophan Synthase: Chemical Structure, Tautomerization, and Reaction Specificity. AB - Carbanionic intermediates play a central role in the catalytic transformations of amino acids performed by pyridoxal-5'-phosphate (PLP)-dependent enzymes. Here, we make use of NMR crystallography-the synergistic combination of solid-state nuclear magnetic resonance, X-ray crystallography, and computational chemistry-to interrogate a carbanionic/quinonoid intermediate analogue in the beta-subunit active site of the PLP-requiring enzyme tryptophan synthase. The solid-state NMR chemical shifts of the PLP pyridine ring nitrogen and additional sites, coupled with first-principles computational models, allow a detailed model of protonation states for ionizable groups on the cofactor, substrates, and nearby catalytic residues to be established. Most significantly, we find that a deprotonated pyridine nitrogen on PLP precludes formation of a true quinonoid species and that there is an equilibrium between the phenolic and protonated Schiff base tautomeric forms of this intermediate. Natural bond orbital analysis indicates that the latter builds up negative charge at the substrate Calpha and positive charge at C4' of the cofactor, consistent with its role as the catalytic tautomer. These findings support the hypothesis that the specificity for beta elimination/replacement versus transamination is dictated in part by the protonation states of ionizable groups on PLP and the reacting substrates and underscore the essential role that NMR crystallography can play in characterizing both chemical structure and dynamics within functioning enzyme active sites. PMID- 27779388 TI - Health Risks and Benefits of Chickpea (Cicer arietinum) Consumption. AB - Chickpeas (CPs) are one of the most commonly consumed legumes, especially in the Mediterranean area as well as in the Western world. Being one of the most nutritional elements of the human diet, CP toxicity and allergy have raised health concerns. CPs may contain various antinutritional compounds, including protease inhibitors, phytic acid, lectins, oligosaccharides, and some phenolic compounds that may impair the utilization of the nutrients by people. Also, high consumption rates of CPs have enhanced the allergic problems in sensitive individuals as they contain many allergens. On the other hand, beneficial health aspects of CP consumption have received attention from researchers recently. Phytic acid, lectins, sterols, saponins, dietary fibers, resistant starch, oligosaccharides, unsaturated fatty acids, amylase inhibitors, and certain bioactive compounds such as carotenoids and isoflavones have shown the capability of lowering the clinical complications associated with various human diseases. The aim of this paper is to unravel the health risks as well as health-promoting aspects of CP consumption and to try to fill the gaps that currently exist. The present review also focuses on various prevention strategies to avoid health risks of CP consumption using simple but promising ways. PMID- 27779387 TI - Engineering an Affinity-Enhanced Peptide through Optimization of Cyclization Chemistry. AB - Peptide cyclization is a strategy used to improve stability and activity of peptides. The most commonly used cyclization method is disulfide bridge formation of cysteine-containing peptides, as is typically found in nature. Over the years, an increasing number of alternative chemistries for peptide cyclization with improved efficiency, kinetics, orthogonality, and stability have been reported. However, there has been less appreciation for the opportunity to fine-tune peptide activity via the diverse chemical entities introduced at the site of linkage by different cyclization strategies. Here, we demonstrate how cyclization optimization of an M2 "anti-inflammatory" macrophage-binding peptide (M2pep) resulted in a significant increase in binding affinity of the optimized analog to M2 macrophages while maintaining binding selectivity compared to M1 "pro inflammatory" macrophages. In this study, we report synthesis and evaluation of four cyclic M2pep(RY) analogs with diverse cyclization strategies: (1) Asp [amide]-Lys, (2) azido-Lys-[triazole(copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC))]-propargyl-Gly, (3) Cys-[decafluorobiphenyl (DFBP)]-Cys, and (4) Cys-[decafluorobiphenyl sulfone (DFS)]-Cys, whereby the chemical entity or linker at the linkage site is shown in the square bracket and is between the residues involved in cyclization. These peptides are compared to a disulfide cyclized M2pep(RY) that we previously reported as a serum-stable, affinity enhanced analog to the original linear M2pep. DFBP-cyclized M2pep(RY) exhibits the highest binding activity to M2 macrophages with apparent dissociation constant (KD) about 2.03 MUM compared to 36.3 MUM for the original disulfide cyclized M2pep(RY) and 220 MUM for the original linear peptide. DFS-cyclized M2pep(RY) also binds more strongly than the original cyclized analog, whereas amide- and triazole-cyclized M2pep(RY) analogs bind less strongly. We verified that DFBP alone has negligible binding to M2 macrophages and the incorporation of diphenylalanine to the original sequence improves binding activity at the expense of solubility and increased toxicity. In conclusion, we report development of cyclic M2pep(RY) analogs with diverse cyclization strategies leading to the discovery of DFBP-cyclized M2pep(RY) with enhanced M2 macrophage-binding activity. PMID- 27779389 TI - Visual Monitoring of Food Spoilage Based on Hydrolysis-Induced Silver Metallization of Au Nanorods. AB - Colorimetric detection of biogenic amines, well-known indicators of food spoilage, plays an important role for monitoring of food safety. However, common colorimetric sensors for biogenic amines suffer from low color resolution or complicated design and intricate output for the end-users. Herein, we explored a simple but effective strategy for visual monitoring of biogenic amines with multiple color change based on hydrolysis-induced silver metallization reaction to tune the localized surface plasmon resonance (LSPR) adsorption of Au nanorods (NRs). The color change and blue shift of longitudinal LSPR peak of Au NRs were closely related to the concentration of biogenic amines. This strategy provided a simple, sensitive, robust, nondestructive, cost-effective, and user-friendly platform for in situ evaluating the freshness of foodstuffs. PMID- 27779390 TI - Quantification of the Void Volume in Single-Crystal Silicon. AB - This paper investigates the use of a method based on Cu decoration and neutron activation to determine the total volume of voids in a silicon single crystal. A measurement protocol was developed and tested in an experiment carried out with a 5 cm3 volume and 10 g mass high-purity natural silicon sample. The few percent uncertainty reached in the determination of the Cu concentration, at a 1014 cm-3 level, makes this method a candidate to set an upper limit to the concentration of the vacancies contributing to the void volume in the enriched silicon material used to determine the Avogadro constant. PMID- 27779391 TI - Mechanism of Translation Termination: RF1 Dissociation Follows Dissociation of RF3 from the Ribosome. AB - Release factors 1 and 2 (RF1 and RF2, respectively) bind to ribosomes that have a stop codon in the A site and catalyze the release of the newly synthesized protein. Following peptide release, the dissociation of RF1 and RF2 from the ribosome is accelerated by release factor 3 (RF3). The mechanism for RF3-promoted dissociation of RF1 and RF2 is unclear. It was previously proposed that RF3 hydrolyzes GTP and dissociates from the ribosome after RF1 dissociation. Here we monitored directly the dissociation kinetics of RF1 and RF3 using Forster resonance energy transfer-based assays. In contrast to the previous model, our data show that RF3 hydrolyzes GTP and dissociates from the ribosome before RF1 dissociation. We propose that RF3 stabilizes the ratcheted state of the ribosome, which consequently accelerates the dissociation of RF1 and RF2. PMID- 27779392 TI - Synthesis and Straightforward Quantification Methods of Imino Nitroxide-Based Hexaradical Architecture on a Cyclotriphosphazene Scaffold. AB - The synthesis of a homogeneous neutral hexaradical architecture consisting of six imino nitroxide radical moieties covalently bonded on a cyclotriphosphazene scaffold was reported. The synthesis of hexaradical imino nitroxide compounds follows the Ullman procedure involving the condensation of 2,3-bis(hydroxylamino) 2,3-dimethylbutane with hexa-(4-formylphenoxy)cyclotriphosphazene (3) followed by oxidation of the condensation product hexa-[4-(1-hydroxy-4,4,5,5-tetramethyl-2 imidazoline-2-yl)phenoxy]cyclotriphosphazene (2) by NaIO4. Characterization of hexaradical was performed by X-ray and SQUID in solid state and by EPR, absorption spectroscopy, and electrochemistry in solution. CV of 1 shows an oxidation peak at 1.184 V (vs SCE) and a reduction peak at -0.883 V, both characteristics of the presence of phenyl imino nitroxide (7) moieties, suggesting that the contribution of the cyclotriphosphazene core is negligible. Attention was particularly focused on developing methods, UV-vis spectroscopy and square-wave voltammetry, to quantify the number of radicals in a way to confirm easily and rapidly the polyradicals' structure. PMID- 27779394 TI - Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations. AB - The benzylation of alcohols with the commonly used combination of benzyl bromide and sodium hydride in DMF can lead to the formation of an amine side product, N,N'-dimethyl-1-phenyl-1-(o-tolyl)methanamine. This amine coeluted with benzylated galactal during column chromatography and was found to be a catalyst poison in thiourea-catalyzed glycosylations of galactals. It may also be problematic for other base-sensitive reactions involving benzylated substrates. Solutions to this problem are described. PMID- 27779393 TI - Total Synthesis of Swinholide A: An Exposition in Hydrogen-Mediated C-C Bond Formation. AB - Diverse hydrogen-mediated C-C couplings enable construction of the actin-binding marine polyketide swinholide A in only 15 steps (longest linear sequence), roughly half the steps required in two prior total syntheses. The redox-economy, chemo- and stereoselectivity embodied by this new class of C-C couplings are shown to evoke a step-change in efficiency. PMID- 27779395 TI - Dragmacidins G and H, Bisindole Alkaloids Tethered by a Guanidino Ethylthiopyrazine Moiety, from a Lipastrotethya sp. Marine Sponge. AB - LCMS analysis of the extract and a cytotoxicity assay of the HPLC fractions generated from a small-scale extract of a Lipastrotethya sp. marine sponge demonstrated the presence of bisindole alkaloids that were associated with the cytotoxic activity. Two bisindole alkaloids tethered by a guanidino ethylthiopyrazine moiety, dragmacidins G (1) and H (2), were isolated, and their structures were assigned by analysis of the MS and NMR data. They showed moderate cytotoxic activity against HeLa cells. PMID- 27779396 TI - Near-Infrared Photoacoustic Imaging Probe Responsive to Calcium. AB - Photoacoustic imaging (PAI) is an attractive imaging modality that can volumetrically map the distribution of photoabsorbing molecules with deeper tissue penetration than multiphoton microscopy. To enable dynamic sensing of divalent cations via PAI, we have engineered a new reversible near-infrared probe that is more sensitive to calcium as compared to other biologically relevant cations. The metallochromic compound showed a strong reduction of its peak absorbance at 765 nm upon addition of calcium ions that was translated into robust signal changes in photoacoustic images. Therefore, the heptamethine cyanine dye will be an attractive scaffold to create a series of metallochromic sensors for molecular PAI. PMID- 27779397 TI - Photochemical Chiral Symmetry Breaking in Alanine. AB - We introduce a general theoretical approach for the simulation of photochemical dynamics under the influence of circularly polarized light to explore the possibility of generating enantiomeric enrichment through polarized-light selective photochemistry. The method is applied to the simulation of the photolysis of alanine, a prototype chiral amino acid. We show that a systematic enantiomeric enrichment can be obtained depending on the helicity of the circularly polarized light that induces the excited-state photochemistry of alanine. By analyzing the patterns of the photoinduced fragmentation of alanine we find an inducible enantiomeric enrichment up to 1.7%, which is also in good correspondence to the experimental findings. Our method is generally applicable to complex systems and might serve to systematically explore the photochemical origin of homochirality. PMID- 27779398 TI - Mechanically Induced Fe(III) Catalysis at Room Temperature: Solvent-Free Cross Dehydrogenative Coupling of 3-Benzylic Indoles with Methylenes/Indoles. AB - An Fe(III)-catalyzed solvent-free cross-dehydrogenative coupling of 3-benzylic indoles and compounds with acidic methylene groups has been achieved under high speed ball-milling (HSBM) conditions at room temperature. The reactions afford desired 3-arylmethylindole derivatives in moderate to high yields within 21 min of grinding. Besides, both N-substituted and N-free indoles can take part in this mechanochemical reaction as efficient nucleophiles to give bisindoles with satisfactory results. Remarkably, this protocol displays the possibility to induce high activity when using iron catalysts under HSBM conditions. PMID- 27779399 TI - Targeting the Nerve Growth Factor (NGF) Pathway in Drug Discovery. Potential Applications to New Therapies for Chronic Pain. AB - The neurotrophin nerve growth factor (NGF) has been implicated as a key mediator of chronic pain. NGF binds the tropomysin receptor kinase A (TrkA) and p75, resulting in the activation of downstream signaling pathways that have been linked to pro-nociception. While anti-NGF antibodies have demonstrated analgesia both preclinically and in patients, the mechanism of action of these agents remains unclear. We describe ligands targeting NGF, its receptors, and downstream/related targets. This Perspective highlights large and small molecule approaches to targeting the NGF-TrkA pathway both extra- and intracellularly. In addition, we present a strategic framework for future drug discovery efforts in this pathway beyond the targeting of NGF or its receptors. While existing tools have greatly informed NGF-mediated signaling, ongoing and future pathway research may help focus new drug discovery efforts on key novel targets and mechanisms. This may result in highly differentiated therapeutics with greater efficacy and/or improved safety profiles. PMID- 27779400 TI - Effect of Anion and Alkyl Side Chain on Structural and Dynamic Features of Ester Functionalized Ionic Liquids: Confirming Nanoscale Organization. AB - The effects of ester addition on structural and dynamic properties of biodegradable ILs composed of the 1-(alkoxycarbonyl)-3-alkylimidazolium cation ([C1COOCnC1im]+, n = 1, 2, 4) coupled with [Br]-, [NO3]-, [BF4]-, [PF6]-, [TfO]-, and [Tf2N]- are explored using the molecular dynamics (MD) simulations and quantum theory of atoms in molecules (QTAIM) at 400 K. Formation of the intramolecular H bonds between O atoms of the ester group and H atoms of the imidazolium ring as well as the nearest H atom of the alkyl chain to the ester group are disclosed from reduced density gradient (RDG) results. Nanoscale organization that leads to aggregation of the alkyl chain into the uncharged domains and formation of different morphologies can be clearly found by the results of site-site static partial structure factors of cations. Despite the fact that H atoms of the imidazolium ring are more acidic than the nearest H atoms of the alkyl side chain to the ester group, the cation-cation spatial distribution functions (SDFs) and the velocity SDFs demonstrate a reverse trend. This corresponds to the long-range organization of cations and nanoscale arrangement. Transport properties were calculated using the Green-Kubo and Einstein relations. Cations totally diffuse faster than anions and their discrepancies gradually vanish with elongation of the alkyl side chain. The translational motion of the terminal carbon atoms of the ester-functionalized cations decrease when the alkyl group is elongated, whereas the reverse trend is reported for common imidazolium-based ILs. The dynamic heterogeneity of selected ILs is comprehensively investigated by the computing vibrational density of states, van Hove function, and non-Gaussian parameter. Non-Gaussian parameters are finite over the entire time scale for ILs composed of bulkier cations and diverge from zero, verifying the long-lived cage effect. Nanoscale ordering is believed to be responsible for these observations. Finally, the simulated viscosity and ionic conductivity are in good agreement with the experimental data. PMID- 27779402 TI - Detection and Activity Profiling of Synthetic Cannabinoids and Their Metabolites with a Newly Developed Bioassay. AB - Synthetic cannabinoids (SCs) are the largest group of compounds currently monitored in Europe by the EU Early Warning System on new psychoactive substances. Emerging recreational use of these products has led to multiple cases of adverse health effects and even death. In contrast to marijuana, where Delta9 tetrahydrocannabinol (Delta9THC) is metabolized to only one major active metabolite, it has been reported that several major phase I metabolites of SCs remain biologically active, exerting cannabinoid (CB) receptor affinity, potency, and efficacy greater than those of Delta9THC. It is therefore reasonable that more SCs can also be biotransformed into molecules with various levels of CB activity. Here, we developed and applied a new G-protein coupled receptor (GPCR) activation assay based on NanoLuc binary technology (Promega). More specifically, by demonstrating CB1 and CB2 receptor activation by JWH-018 and a selection of its metabolites, we are the first to show the suitability of the newly developed bioassay for monitoring GPCR-mediated activity. We also successfully applied this reporter system to evaluate the in vitro activity of JWH-122, JWH-210, and PB-22, their 5-fluoro analogues (MAM-2201, EAM-2201, and 5F-PB-22, respectively), and their main phase I metabolites. By doing so, we demonstrate that several major metabolites of these SCs retain their activity at cannabinoid receptors. All of these active metabolites may prolong the parent compound's psychotropic and physiological effects and may contribute to its toxicity profile. We also demonstrate a proof of concept of the applicability of the newly developed bioassay for screening urine for CB receptor activity exerted by SCs. PMID- 27779401 TI - Highly Efficient Fenton and Enzyme-Mimetic Activities of Mixed-Phase VOx Nanoflakes. AB - Artificial enzyme mimetics is a current research area with much interest from scientific community. Some nanomaterials have been found to possess intrinsic enzyme-mimetic activity. In this study, VOx nanoflakes with mixed-phases are synthesized via a quick and facile one-pot synthetic process and their Fenton reaction and enzyme-mimetic activities have been studied. The results show that obtained VOx is not only highly effective Fenton reagent, completely decomposing Rhodamine B (RhB) within less than 1 min, but also exhibits excellent intrinsic peroxidase-like activity as well as H2O2 catalase-like activity. Our results suggest that this VOx nanomaterial can effectively mimic the enzyme cascade reaction of horseradish peroxidase (HRP). VOx nanoflakes have excellent affinity toward 3,3',5,5'-tetramethylbenzidine (TMB) for oxidation and henceforth, it can be used for the colorimetric assay of glucose and H2O2. Moreover, this study indicates that VOx nanoflakes can also be used for the efficient degradation of environmental pollutants. PMID- 27779403 TI - Predicting the Strength of Anion-pi Interactions of Substituted Benzenes: the Development of Anion-pi Binding Substituent Constants. AB - A computational study aimed at accurately predicting the strength of the anion-pi binding of substituted benzenes is presented. The anion-pi binding energies (Ebind) of 37 substituted benzenes and the parent benzene, with chloride or bromide were investigated at the MP2(full)/6-311++G** level of theory. In addition, energy decomposition analysis was performed on 27 selected chloride arene complexes via symmetry adapted perturbation theory (SAPT), using the SAPT2+ approach. Initial efforts aimed to correlate the anion-pi Ebind values with the sum of the Hammett constants sigmap (Sigmasigmap) or sigmam (Sigmasigmam), as done by others. This proved a decent approach for predicting the binding strength of aromatics with electron-withdrawing substituents. For the Cl--substituted benzene Ebind values, the correlation with the Sigmasigmap and Sigmasigmam values of aromatics with electron-withdrawing groups had r2 values of 0.89 and 0.87 respectively. For the Br--substituted benzene Ebind values, the correlation with the Sigmasigmap and Sigmasigmam values of aromatics with electron-withdrawing groups had r2 values of 0.90 and 0.87. However, adding aromatics with electron donating substituents to the investigation caused the correlation to deteriorate. For the Cl--substituted benzene complexes the correlation between Ebind values and the Hammett constants had r2 = 0.81 for Sigmasigmap and r2 = 0.84 for Sigmasigmam. For the Br--substituted benzene complexes, the respective r2 values were 0.71 for Sigmasigmap and 0.79 for Sigmasigmam. The deterioration in correlation upon consideration of substituted benzenes with electron-donating substituents is due to the anion-pi binding energies becoming more attractive regardless of what type of substituent is added to the aromatic. A similar trend has been reported for parallel face-to-face substituted benzene-benzene binding. This is certainly counter to what electrostatic arguments would predict for trends in anion-pi binding energies, and this discrepancy is further highlighted by the SAPT2+ calculated electrostatic component energies (Eele). The Eele values for the Cl--substituted benzene anion-pi complexes are all more binding than the Eele value for the Cl--benzene complex, with the exception of chloride-1,3,5 trimethylbenzene. Again, this is a similar trend to what has been reported for parallel face-to-face substituted benzene-benzene binding. A discussion on this surprising result is presented. In addition, an improved approach to predicting the relative anion-pi binding strength of substituted benzene is developed using the results of the SAPT2+ calculations. PMID- 27779404 TI - Rotation-Driven Microfluidic Disc for White Blood Cell Enumeration Using Magnetic Bead Aggregation. AB - We recently defined a magnetic bead-based assay that exploited an agglutination like response for DNA and applied it to DNA-containing cell enumeration using inexpensive benchtop hardware [ J. Am. Chem. Soc. 2012 , 134 ( 12 ), 5689 - 96 ]. Although cost-efficient, the open-well format assay required numerous manual steps, and the magnetic field actuation scheme was not readily adaptable for integration. Here, we demonstrate a low-cost (<$2 in-lab), higher-throughput "pinwheel assay" platform that relies on a combination of a disposable rotation driven microdisc (RDM), and a simple bidirectional rotating magnetic field (bi RMF). The assay was transformed into an integrated microfluidic system using a multilayered polyester microfluidic disc created through laser print, cut and laminate fabrication, with fluid flow controlled by rotation speed without any mechanical valves. The RDM accepts four samples that undergo on-chip dilution to five different concentrations that cover the effective concentration range needed for downstream cell counting by pinwheel assay. We show that a bi-RMF is effective for the simultaneous actuation of pinwheel assays in 20 detection chambers. The optimization of the bi-RMF frequencies allows the RDM-based pinwheel assay detect human genomic DNA down to a mass of human genomic DNA (5.5 picograms) that is roughly equal to the mass in a single cell. For proof of principle, enumeration of the white blood cells in human blood samples on the RDM provided data correlating well (C.V. of 10%) with those obtained in a clinical lab. Fusing the cost-effective RDM with a simple bi-RMF provides a promising strategy for automation and multiplexing of magnetic particle-based agglutination assays. PMID- 27779405 TI - Regular Nanoscale Protein Patterns via Directed Adsorption through Self-Assembled DNA Origami Masks. AB - DNA origami has become a widely used method for synthesizing well-defined nanostructures with promising applications in various areas of nanotechnology, biophysics, and medicine. Recently, the possibility to transfer the shape of single DNA origami nanostructures into different materials via molecular lithography approaches has received growing interest due to the great structural control provided by the DNA origami technique. Here, we use ordered monolayers of DNA origami nanostructures with internal cavities on mica surfaces as molecular lithography masks for the fabrication of regular protein patterns over large surface areas. Exposure of the masked sample surface to negatively charged proteins results in the directed adsorption of the proteins onto the exposed surface areas in the holes of the mask. By controlling the buffer and adsorption conditions, the protein coverage of the exposed areas can be varied from single proteins to densely packed monolayers. To demonstrate the versatility of this approach, regular nanopatterns of four different proteins are fabricated: the single-strand annealing proteins Redbeta and Sak, the iron-storage protein ferritin, and the blood protein bovine serum albumin (BSA). We furthermore demonstrate the desorption of the DNA origami mask after directed protein adsorption, which may enable the fabrication of hierarchical patterns composed of different protein species. Because selectivity in adsorption is achieved by electrostatic interactions between the proteins and the exposed surface areas, this approach may enable also the large-scale patterning of other charged molecular species or even nanoparticles. PMID- 27779406 TI - Multilevel Investigation of Charge Transport in Conjugated Polymers. AB - Conjugated polymers have attracted the world's attentions since their discovery due to their great promise for optoelectronic devices. However, the fundamental understanding of charge transport in conjugated polymers remains far from clear. The origin of this challenge is the natural disorder of polymers with complex molecular structures in the solid state. Moreover, an effective way to examine the intrinsic properties of conjugated polymers is absent. Optoelectronic devices are always based on spin-coated films. In films, polymers tend to form highly disordered structures at nanometer to micrometer length scales due to the high degree of conformational freedom of macromolecular chains and the irregular interchain entanglement, thus typically resulting in much lower charge transport properties than their intrinsic performance. Furthermore, a subtle change of processing conditions may dramatically affect the film formation-inducing large variations in the morphology, crystallinity, microstructure, molecular packing, and alignment, and finally varying the effective charge transport significantly and leading to great inconsistency over an order of magnitude even for devices based on the same polymer semiconductor. Meanwhile, the charge transport mechanism in conjugated polymers is still unclear and its investigation is challenging based on such complex microstructures of polymers in films. Therefore, how to objectively evaluate the charge transport and probe the charge transport mechanism of conjugated polymers has confronted the world for decades. In this Account, we present our recent progress on multilevel charge transport in conjugated polymers, from disordered films, uniaxially aligned thin films, and single crystalline micro- or nanowires to molecular scale, where a derivative of poly(para-phenylene ethynylene) with thioacetyl end groups (TA-PPE) is selected as the candidate for investigation, which could also be extended to other conjugated polymer systems. Our systematic investigations demonstrated that 3-4 orders higher charge transport properties could be achieved with the improvement of polymer chain order and confirmed efficient charge transport along the conjugated polymer backbones. Moreover, with downscaling to molecular scale, many novel phenomena were observed such as the largely quantized electronic structure for an 18 nm-long TA-PPE and the modulation of the redox center of tetrathiafulvalene (TTF) units on tunneling charge transport, which opens the door for conjugated polymers used in nanometer quantum devices. We hope the understanding of charge transport in PPE and its related conjugated polymer at multilevel scale in this Account will provide a new method to sketch the charge transport properties of conjugated polymers, and new insights into the combination of more conjugated polymer materials in the multilevel optoelectronic and other related functional devices, which will offer great promise for the next generation of electronic devices. PMID- 27779407 TI - Ultrasensitive Detection of alpha-Fetoprotein by Total Internal Reflection Scattering-Based Super-Resolution Microscopy for Superlocalization of Nano Immunoplasmonics. AB - Superlocalization of immunoplasmonic nanotags on antibody-bound gold-nanoislands (GNIs) along the x and y coordinates was determined using total internal reflection scattering-based super-resolution microscopy (TIRS-SRM) at subdiffraction limit resolution. Individual immunoplasmonic nanotags (20 nm silver nanoparticles) and 100 nm GNIs were selectively acquired in the evanescent field layer by wavelength-dependent plasmonic scattering using two illumination lasers (405 and 635 nm, respectively). alpha-Fetoprotein (AFP), a liver cancer related model protein, was immobilized as a target molecule on the GNI arrays. The centroid position of a localized immunoplasmonic nanotag on the GNI was resolved at less than 10 nm of spatial resolution by applying 2D Gaussian fitting to its point spread function. This method showed enhanced sensitive quantification with a limit of detection (LOD) of 7.04 zM (1-2 molecules of AFP/GNI), which was 100-5000000000 times lower than detection limits obtained with previous AFP detection methods. Furthermore, the method was also successfully applied to quantify AFP molecules at the single-molecule level in human serum samples. The wavelength-dependent TIRS-SRM method was demonstrated to be an effective tool for superlocalizing individual protein molecules and interactions in nanoscale regions and was a reliable method for the ultrasensitive quantitative detection of disease-related protein molecules as a nanosensor and for diagnosis at the single-molecule level. PMID- 27779408 TI - Molecular Mechanism behind Solvent Concentration-Dependent Optimal Activity of Thermomyces lanuginosus Lipase in a Biocompatible Ionic Liquid: Interfacial Activation through Arginine Switch. AB - Thermomyces lanuginosus lipase (TLL) is an industrially significant catalyst for the production of biodiesel due to its operability over a wide range of pH's and temperatures. Molecular dynamics simulations of TLL in aqueous solutions of a biocompatible ionic liquid (IL), cholinium glycinate (ChGly), have been carried out to investigate the microscopic reasons for the experimentally observed enhancement in the activity of TLL upon addition of a room temperature IL (RTIL), especially at an optimal concentration. Eight different TLL systems, in both their open and closed forms, at various concentrations of the RTIL in water have been studied. A special orientation of the lid residue, W89, in the closed form, which enables an optimal substrate-binding rate, has been identified, which can be probed via fluorescence spectroscopy. The flipping and consequent exposure of W89 in the open form of TLL induce a change in the lid helicity and orientation in such a way that residue R84 from the front lid hinge gets trapped around a particular region in all systems except at a 0.5 M IL concentration. At that concentration, R84 exhibits considerable fluxionality and moves back and forth via a water channel that is formed because of the chaotropic nature of the cholinium cation. Arginine switch is well established to be the primary signature of interfacial activation of TLL, which is observed here at an optimal IL concentration (0.5 M) without the use of a substrate or surfactant. The present work can pave the way for development of a broader platform for understanding lipases and their application in environment-friendly catalysis. PMID- 27779409 TI - Stereoselective Synthesis of Oxabicyclo[2.2.1]heptenes via a Tandem Dirhodium(II) Catalyzed Triazole Denitrogenation and [3 + 2] Cycloaddition. AB - A novel synthetic strategy for the diastereoselective synthesis of structurally diverse oxabicyclo[2.2.1]heptenes has been developed, featuring a tandem reaction combining a Rh-catalyzed triazole denitrogenation and a novel type of [3 + 2] cycloaddition reaction. This tandem reaction was thought to proceed via a five membered oxonium ylide intermediate, which was formed by the intramolecular nucleophilic attack of the carbonyl group on the alpha-imino metallocarbene followed by an inter- or intramolecular [3 + 2] dipolar cycloaddition with a range of alkynes and alkenes. PMID- 27779410 TI - Synthesis of 1,4-Dicarbonyl Compounds from Silyl Enol Ethers and Bromocarbonyls, Catalyzed by an Organic Dye under Visible-Light Irradiation with Perfect Selectivity for the Halide Moiety over the Carbonyl Group. AB - We report the visible-light-induced radical coupling reaction of silyl enol ethers with alpha-bromocarbonyl compounds to give 1,4-dicarbonyls. The reaction was effectively accelerated using an inexpensive organic dye (eosin Y) as a photoredox catalyst. 1,4-Dicarbonyl compounds alone were afforded, without the generation of carbonyl adducts of the alpha-halocarbonyls, which are usually generated in the presence of fluoride anions or Lewis acids. A variety of silyl enol ethers, alpha-bromoketones, alpha-bromoesters, and alpha-bromoamides were applied to this system to produce the coupling compounds. PMID- 27779411 TI - Synthesis of Tryptanthrins by Organocatalytic and Substrate Co-catalyzed Photochemical Condensation of Indoles and Anthranilic Acids with Visible Light and O2. AB - A metal-free catalytic approach to tryptanthrins has been achieved for the first time. The unique process is realized by an organocatalytic and indole and anthranilic acid substrate co-catalyzed photochemical oxidative condensation with visible light and O2. The truly environmentally friendly reaction conditions enable various reactants to participate in the process to deliver structurally diverse tryptanthrins. PMID- 27779412 TI - Organocatalytic Enantioselective Synthesis of alpha-Hydroxyketones through a Friedel-Crafts Reaction of Naphthols and Activated Phenols with Aryl- and Alkylglyoxal Hydrates. AB - An efficient organocatalytic asymmetric synthesis of alpha-hydroxyketones has been developed. Quinine-derived thiourea catalyzed the enantioselective Friedel Crafts alkylation of naphthols and activated phenols with aryl- and alkylglyoxal hydrates, providing the corresponding chiral alpha-hydroxyketones with high yields (up to 97%) and excellent enantioselectivities (up to 99% ee). PMID- 27779413 TI - Palladium-Catalyzed Highly Regio- and Enantioselective Hydroesterification of Aryl Olefins with Phenyl Formate. AB - An effective Pd-catalyzed regio- and enantioselective hydroesterification of aryl olefins with phenyl formate is described. A variety of phenyl 2-arylpropanoates can be obtained in good yields with high b/l ratios and ee's without using toxic CO gas. PMID- 27779414 TI - Nickel(II)-Catalyzed Enantioselective alpha-Vinylation of beta-Keto Amides/Esters with Hypervalent Iodine Salts. AB - The enantioselective alpha-vinylation of beta-keto amides/esters using hypervalent iodine salts has been accomplished via a chiral N,N'-dioxide nickel(II) complex promoted electrophilic addition and reductive elimination process. A wide range of vinyl-substituted all-carbon quaternary beta-keto amides/esters were obtained in high yields and ee values (up to 99% yield and 99% ee). Moreover, the catalytic system has been applied to the enantioselective alkynylation/arylation of beta-ketoamides with good results. PMID- 27779416 TI - Iridium-Catalyzed Cyclization of Isoxazolines and Alkenes: Divergent Access to Pyrrolidines, Pyrroles, and Carbazoles. AB - A heterogeneous iridium-complex-catalyzed N-O-cleaving rearrangement/cyclization of 2,3-dihydroisoxazoles with alkenes has been developed. It provides divergent access to multiple substituted pyrrolidines, pyrroles, and carbazoles. The iridium catalyst remains highly catalytic active after seven cycles. The gram scale synthesis afforded a carbazole with strong bluish-violet fluorescence. PMID- 27779415 TI - Cascade Phosphinoylation/Cyclization/Isomerization Process for the Synthesis of 2 Phosphinoyl-9H-pyrrolo[1,2-a]indoles. AB - Pyrrolo[1,2-a]indole is a common structural motif found in many natural products and pharmaceuticals. A silver-mediated oxidative phosphinoylation of N-propargyl substituted indoles was used to construct a variety of 2-phosphinoyl-9H pyrrolo[1,2-a]indoles under mild conditions. This transformation offers a straightforward route to the formation of the C-P bond, cyclization, and isomerization in one step. PMID- 27779417 TI - Incorporation of Hard and Soft Protein-Protein Interactions into Models for Crowding Effects in Binary and Ternary Protein Mixtures. Comparison of Approximate Analytical Solutions with Numerical Simulation. AB - In order to better understand how nonspecific interactions between solutes can modulate specific biochemical reactions taking place in complex media, we introduce a simplified model aimed at elucidating general principles. In this model, solutions containing two or three species of interacting globular proteins are modeled as a fluid of spherical particles interacting through square well potentials that qualitatively capture both steric hard core repulsion and longer ranged attraction or repulsion. The excess chemical potential, or free energy of solvation, of each particle species is calculated as a function of species concentrations, particle radii, and square well interaction range and depth. The results of analytical models incorporating two-body and three-body interactions are compared with the estimates of free energy obtained via Widom insertion into simulated equilibrium square-well fluids. The analytical models agree well with results of numeric simulations carried out for a variety of model parameters and fluid compositions up to a total particle volume fraction of ca. 0.2. PMID- 27779418 TI - Synthesis of Perylene-3,4,9,10-tetracarboxylic Acid Derivatives Bearing Four Different Substituents at the Perylene Core. AB - Nucleophilic aromatic substitution reactions on 1,7-dibromoperylene-3,4,9,10 tetracarboxylic monoimide dibutylester, using phenol and pyrrolidine reagents, have been exploited to synthesize perylenes with four different substituents at the perylene core. The first substitution is always regiospecific at the imide activated 7-position. A second substitution reaction does not always replace the bromine at C-1, but may replace a phenol substituent at the highly activated 7 position. Exploiting this reactivity pattern, a "mixed" 1,7-diphenoxy, 1,7 dipyrrolidinyl, and two 1-phenoxy-7-pyrrolidinyl derivatives have been synthesized. PMID- 27779419 TI - Solvent-Free Benzoin and Stetter Reactions with a Small Amount of NHC Catalyst in the Liquid or Semisolid State. AB - The intermolecular or intramolecular asymmetric benzoin reaction was catalyzed by a small amount of N-heterocyclic carbene (NHC) (0.2-1 mol %) under solvent-free conditions. The solvent-free intramolecular asymmetric Stetter reaction also proceeded efficiently with NHC (0.2-1 mol %). In some cases, even solid-to-solid or solid-to-liquid conversions took place with low catalyst loading (0.2-1 mol %). PMID- 27779420 TI - KOtBu-Promoted Oxidation of (Hetero)benzylic Csp3-H to Ketones with Molecular Oxygen. AB - An efficient and practical (hetero)benzylic sp3 C-H oxidation method has been developed. Notably, this user-friendly protocol employs inexpensive potassium tert-butoxide (KOtBu) as a promoter and proceeds under mild conditions using oxygen as the oxidant. A large variety of oxidation products were prepared in good to excellent yields. The utility of this "green" methodology was further demonstrated by the scale-up preparation of a biologically valued molecule. PMID- 27779421 TI - Parametric Response Mapping as an Imaging Biomarker in Lung Transplant Recipients. AB - RATIONALE: The predominant cause of chronic lung allograft failure is small airway obstruction arising from bronchiolitis obliterans. However, clinical methodologies for evaluating presence and degree of small airway disease are lacking. OBJECTIVES: To determine if parametric response mapping (PRM), a novel computed tomography voxel-wise methodology, can offer insight into chronic allograft failure phenotypes and provide prognostic information following spirometric decline. METHODS: PRM-based computed tomography metrics quantifying functional small airways disease (PRMfSAD) and parenchymal disease (PRMPD) were compared between bilateral lung transplant recipients with irreversible spirometric decline and control subjects matched by time post-transplant (n = 22). PRMfSAD at spirometric decline was evaluated as a prognostic marker for mortality in a cohort study via multivariable restricted mean models (n = 52). MEASUREMENTS AND MAIN RESULTS: Patients presenting with an isolated decline in FEV1 (FEV1 First) had significantly higher PRMfSAD than control subjects (28% vs. 15%; P = 0.005), whereas patients with concurrent decline in FEV1 and FVC had significantly higher PRMPD than control subjects (39% vs. 20%; P = 0.02). Over 8.3 years of follow-up, FEV1 First patients with PRMfSAD greater than or equal to 30% at spirometric decline lived on average 2.6 years less than those with PRMfSAD less than 30% (P = 0.004). In this group, PRMfSAD greater than or equal to 30% was the strongest predictor of survival in a multivariable model including bronchiolitis obliterans syndrome grade and baseline FEV1% predicted (P = 0.04). CONCLUSIONS: PRM is a novel imaging tool for lung transplant recipients presenting with spirometric decline. Quantifying underlying small airway obstruction via PRMfSAD helps further stratify the risk of death in patients with diverse spirometric decline patterns. PMID- 27779423 TI - Changing Attitudes and Animal Welfare in Small Island Developing States: Dogs on New Providence, The Bahamas. AB - This article compares results from a study in 2014 with a similar study from 1998 (Fielding, 1999 ) to examine changes in the care of dogs in New Providence, The Bahamas. The results from a survey of 379 residents indicated a general lack of improvement in matters associated with the care of dogs during the past 16 years. For example, in 1998, it was estimated that 35% of caregivers had at least 1 dog sterilized, and in 2014, the corresponding figure was 37%. In 1998, 14% of households with dogs allowed their dogs to roam compared with 41.7% in 2014. These observations do not indicate inactivity on behalf of nonhuman animal welfare groups or archaic animal welfare legislation, as free spay/neuter campaigns have occurred and stricter laws have been passed since 1998. Rather, it is conjectured that these findings may reflect not only insufficiently sustained and coordinated initiatives in education, access to welfare interventions, and law enforcement, but also as-yet-unknown inadequacies in the approaches used in this cultural setting. PMID- 27779424 TI - Putting a brake on stress signaling: miR-625-3p as a biomarker for choice of therapy in colorectal cancer. PMID- 27779422 TI - Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis. AB - RATIONALE: Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function. OBJECTIVES: To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS). METHODS: We examined the expression of cystatin A and SPINK5 in the nasal epithelial cells of patients with CRS. Additionally, the in vitro effects of recombinant EPIs on the secretion of the epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin in airway epithelial cells, and the in vivo effects of recombinant EPIs in the nasal epithelium of mice exposed to multiple airborne allergens (MAA) were examined. MEASUREMENTS AND MAIN RESULTS: Compared with control subjects and patients with noneosinophilic CRS, patients with eosinophilic CRS showed significantly lower protein and mRNA expression of cystatin A and SPINK5 in the nasal epithelium. Allergen-induced production of IL-25, IL-33, and thymic stromal lymphopoietin in normal human bronchial epithelial cells was inhibited by treatment with recombinant cystatin A or SPINK5. Conversely, the production of these cytokines was increased when cystatin A or SPINK5 were knocked down with small interfering RNA. Chronic MAA exposure induced goblet cell metaplasia and epithelial disruption in mouse nasal epithelium and decreased the tissue expression and nasal lavage levels of cystatin A and SPINK5. Intranasal instillations of recombinant EPIs attenuated this MAA-induced pathology. CONCLUSIONS: Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS. PMID- 27779425 TI - Serum Concentration of Risperidone and Adverse Effects in Children and Adolescents. PMID- 27779426 TI - WAIS-IV GAI and CPI discrepancies in multiple sclerosis and traumatic brain injury. AB - We examined relationships between the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) General Ability Index (GAI) and Cognitive Proficiency Index (CPI) in two clinical samples. The mean pattern produced by 42 individuals with multiple sclerosis (MS) and 47 with traumatic brain injury (TBI) was the same, GAI > CPI. This pattern occurred in 61.9% and 78.7% of the protocols of patients with MS or TBI, respectively. The MS sample earned a significantly larger CPI mean than did patients with TBI. The group means did not differ on the GAI. Patients with TBI had significantly larger GAI-CPI discrepancy score means than those with MS. Receiver operating characteristics (ROC) analysis assessed the ability of GAI-CPI discrepancies to differentiate the samples. The area under curve (AUC) was 0.67, 95% [0.55, 0.78], which indicated low accuracy in terms of group classification. PMID- 27779427 TI - Cognitive and behavioral outcomes among seizure-controlled children with partial epilepsy on antiepileptic drug monotherapy. AB - The objective of this study was to assess cognitive performance and behavioral symptoms in a sample of children diagnosed with partial epilepsy who were seizure controlled on AED monotherapy for one year. Ninety-eight seizure-controlled children on AED monotherapy were included in this study. Specific AEDs examined included topiramate, divalproex sodium, lamotrigine, levetiracetam, and oxcarbazepine. Groups did not differ on age, region of focal epilepsy, or Full Scale IQ. Direct measures included the WISC-IV and selected tests from the DKEFS (Verbal Fluency and Trail Making Test). Parent report measures included the BRIEF and the BASC-PRS. A series of ANOVAs revealed significant differences across the AED cohorts within many domains of cognitive functioning and behavioral presentation. Children prescribed divalproex sodium or topiramate demonstrated weaker working memory and verbal fluency, when compared with children prescribed other AEDs. Additionally, parents of children prescribed topiramate reported greater executive functioning and adaptive skills deficits. The pattern of findings suggests that children prescribed divalproex sodium or topiramate generally demonstrated a higher risk of cognitive and behavioral impairments compared to the other AEDs. Future prospective studies are required in order to better understand the relationship between AED type and these outcomes to inform clinical practice. PMID- 27779428 TI - Neuropsychological stimulation of executive functions in children with typical development: A systematic review. AB - This systematic review aimed to characterize empirical studies on neuropsychological interventions to stimulate executive functions in children with typical development. Searches were conducted according to the PRISMA method. Nineteen (19) studies on the analysis to evaluate the effectiveness of intervention programs in pre-school and school children were obtained. There was a predominance of studies that used computerized cognitive training, most of them involving the stimulation of working memory. Others used pen and paper forms, or hybrid tasks, and some programs used a school curriculum approach aiming to improve self-regulation. Results provide preliminary evidence on the effectiveness of such on the executive performance in children with typical development. Each executive component, as well as each type of intervention has its peculiarities. Computerized trainings and pen and paper tasks tend to improve the targeted executive functions, but transfer effects are still inconsistent. Regarding the effects of programs using school curriculum approach, they seem to be more generalizable, with functionality gains accomplishing mainly socio emotional regulation. Multimodal approaches may be even more effective. Follow-up studies should be targeted in order to track the maintenance of direct and transfer effects regarding mainly cognitive and social development associated to school achievement. PMID- 27779429 TI - Heterogeneous effects of old age on human muscle oxidative capacity in vivo: a systematic review and meta-analysis. AB - Despite intensive efforts to understand the extent to which skeletal muscle mitochondrial capacity changes in older humans, the answer to this important question remains unclear. To determine what the preponderance of evidence from in vivo studies suggests, we conducted a systematic review and meta-analysis of the effects of age on muscle oxidative capacity as measured noninvasively by magnetic resonance spectroscopy. A secondary aim was to examine potential moderators contributing to differences in results across studies, including muscle group, physical activity status, and sex. Candidate papers were identified from PubMed searches (n = 3561 papers) and the reference lists of relevant papers. Standardized effects (Hedges' g) were calculated for age and each moderator using data from the 22 studies that met the inclusion criteria (n = 28 effects). Effects were coded as positive when older (age, >=55 years) adults had higher muscle oxidative capacity than younger (age, 20-45 years) adults. The overall effect of age on oxidative capacity was positive (g = 0.171, p < 0.001), indicating modestly greater oxidative capacity in old. Notably, there was significant heterogeneity in this result (Q = 245.8, p < 0.001; I2 = ~70%-90%). Muscle group, physical activity, and sex were all significant moderators of oxidative capacity (p <= 0.029). This analysis indicates that the current body of literature does not support a de facto decrease of in vivo muscle oxidative capacity in old age. The heterogeneity of study results and identification of significant moderators provide clarity regarding apparent discrepancies in the literature, and indicate the importance of accounting for these variables when examining purported age-related differences in muscle oxidative capacity. PMID- 27779430 TI - Words matter: Reframing exercise is medicine for the general population to optimize motivation and create sustainable behaviour change. AB - Exercise is medicine (EIM) is grounded in strong evidence regarding the benefits of physical activity. Despite the contributions of EIM initiatives worldwide, rates of physical inactivity remain alarmingly high. We propose a reframe of EIM for the general population to improve motivation and foster sustainable behaviour change. We draw on a solid knowledge-base to explain the value of broadening the nomenclature to physical activity and of promoting a message of well-being via enjoyable physical activity. PMID- 27779431 TI - Acellular dermal matrix: New applications for free flap pedicle coverage - A prospective study in 10 patients. AB - INTRODUCTION: The goal of lower extremity reconstruction after trauma is the coverage of defects to give patients a healed wound and to let them resume their life, ambulate and return to work, while preventing amputation. In this article, we describe an innovative use of Integra(r) for free flap pedicle coverage in lower extremity reconstruction. MATERIALS AND METHODS: Between January 2011 and December 2015, ten patients, four women and six men, underwent a lower limb reconstruction with an association of free flap and Integra(r) to cover the flap pedicle. The mean age of the patients was 38.8+/-15.6 years at the time of surgery (range of 14-59 years). The mean defect size was 102+/-54 cm2 (range of 40-160 cm2). The bone and/or tendons were exposed at the level of the middle third of the leg in 2 cases, at the level of the distal leg in 5 cases and at the level of the foot in 3 cases. RESULTS: There were no intra-operative complications. Mean size of Integra(r) needed for flap pedicle coverage was 12.8+/-2.3 cm2 (range 10-15 cm2). The mean follow-up was 41+/-19 months (range 21 70 months). Revision surgery was necessary in three cases due to haematoma of the pedicle. In these cases, the dermal substitute was easily removed while awaiting revision. This allowed flap survival in all cases. A skin graft was performed after a mean time of 3.4+/-0.8 weeks post-operatively. Complications at the donor site level included one seroma and a case of hypertrophic scar. Complete healing of both the donor and recipient sites was achieved in all cases. CONCLUSIONS: The combination of free flap and Integra(r) appears to be a useful option in covering complex defects in the lower limb. The dermal substitute avoids skin tension and compression of the pedicle. Haematomas of the pedicle, if they occur, are highly visible and thus easy to manage. We hypothesize that the use of dermal substitute for this specific indication of pedicle coverage will expand in the near future. PMID- 27779433 TI - Patient preferences for diabetes treatment attributes and drug classes. AB - OBJECTIVE: To identify which treatment attributes are most influential in determining patient preferences for diabetes treatments and explore patient preferences for diabetes drug classes. RESEARCH DESIGN AND METHODS: US adults with type 1 or type 2 diabetes completed an online adaptive conjoint analysis survey. The survey examined 14 attributes, including efficacy, regimen, and risk of common side effects and rare but serious adverse events. Respondents selected between hypothetical treatments with different attributes. Sawtooth Software, ordinary least-squares regression, and hierarchical Bayes regression were used to calculate utilities (i.e. preference weights), importance ratings, and shares of preference across 13 diabetes drug classes or combination products. RESULTS: A total of 167 adults (mean age 58 years; 55% female) with type 1 or type 2 diabetes completed the survey. Based on importance ratings, the most influential attributes driving preferences were regimen, risk of diarrhea, weight change, risk of hypoglycemia, and efficacy. Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) were highly preferred in direct comparison to each of the other classes (range: 84.2-99.9%), with the exception of dipeptidyl peptidase-4 inhibitors (DPP-4is); DPP-4is (52.9%) were preferred over SGLT-2is (47.1%). CONCLUSIONS: Although preferences varied across participants, attributes with the greatest likelihood of affecting daily life and routine were generally more influential in determining patient preferences. DPP-4is and SGLT-2is were overwhelmingly preferred over other drug classes, primarily due to favorable regimen and side effect profiles. Understanding patient preferences can help optimize patient-centered treatment and may lead to improved patient satisfaction, adherence, and outcomes. LIMITATIONS: The primary limitations of this study are that a small sample size of type 1 diabetes patients were included, which may reduce the reliability of the preference estimates, and patients were recruited from a patient panel and may not be representative of patients with diabetes in the US. PMID- 27779432 TI - An open-label prospective clinical study to assess the efficacy of increasing levocetirizine dose up to four times in chronic spontaneous urticaria not controlled with standard dose. AB - OBJECTIVE: The EAACI/GA2LEN/EDF/WAO recommendation of increasing antihistamines' dose up to four times in urticaria not adequately controlled with the standard dose is largely based on expert opinion. The objective of this study is to test the current urticaria guidelines of up-dosing antihistamines as second-line treatment. METHODS: This was an open-label study conducted prospectively on 113 patients with chronic spontaneous urticaria. All patients were treated with sequentially increasing doses of levocetrizine (5 mg, 10 mg, 15 mg and 20 mg/day) every week till the patients became completely asymptomatic or dose of 20 mg/day reached. Urticaria Activity Score (UAS)-7, urticaria-related quality-of-life (CU Q2oL) and patients' global assessment were used to assess treatment response. RESULTS: Twenty-one (18.58%) patients became asymptomatic with levocetirizine 5 mg/day, while 50 required higher doses of levocetirizine for complete control: 29/92 (31.52%), 6/63 (9.52%) and 15/57 (26.31%) with 10 mg, 15 mg and 20 mg/day, respectively. The percentage of patients experiencing >75% improvement increased with increasing doses of levocetirizine: 26.54%, 53.98%, 60.17% and 69.91% with 5 mg, 10 mg, 15 mg and 20 mg/day, respectively. Sequential up-dosing of levocetirizine produced a progressive improvement in both urticaria control (UAS 7) and quality-of-life (CU-Q2oL) without significantly increasing somnolence. CONCLUSIONS: Our results support the current recommendations of increasing antihistamines up to four times the standard dose in patients who fail the first line treatment. PMID- 27779434 TI - The Effects of Discrimination Are Associated With Cigarette Smoking Among Black Males. AB - : Previous research has demonstrated that experiencing interpersonal discrimination is associated with cigarette smoking. Few studies have examined the relationship between the effects of physical and emotional discrimination and cigarette usage, and none have examined this relationship among Black men. The aim of this study was to examine the association between the effects of physical and emotional discrimination and cigarette smoking. METHODS: Data from the Indiana Black Men's Health Study, a community-based sample of adult Black men, was used to conduct multivariate logistic regression to examine the relationship between the physical and emotional effects of discrimination and smoking, net of healthcare and workplace discrimination, age, education, household income, and being married. RESULTS: After adjusting for having an emotional response to discrimination, health care and workplace discrimination, age, education, household income, and being married, males who had a physical response to discrimination (e.g., upset stomach or headache) had higher odds of cigarette use (odds ratio (OR): 1.95, 95% confidence interval (CI): 1.15-3.30) than men who did not have a physical response to discrimination. CONCLUSION: Findings from the study suggest that Black males may use cigarette smoking as a means to mitigate the stress associated with experiences of discrimination. Future research is needed further to explore if and how Black males use cigarette smoking to cope with unfair treatment. PMID- 27779435 TI - Chronic Pain Patients Are Not Immune to Opioid Harms. PMID- 27779436 TI - Observational Prospective study to esTIMAte the rates of outcomes in patients undergoing PCI with drug-eluting stent implantation who take statins -follow-up (OPTIMA II). AB - OBJECTIVE: The OPTIMA II study sought to evaluate rates of major adverse cardiac and cerebrovascular events (MACCEs) during the long-term follow-up of chronic statin users who underwent percutaneous coronary intervention (PCI) with implantation of a drug-eluting stent (DES). RESEARCH DESIGN AND METHODS: OPTIMA II was a non-interventional, observational study conducted at a single center in the Russian Federation. Included patients were aged >=18 years with stable angina who had received long-term (>=1 month) statin therapy prior to elective PCI with DES implantation and who had participated in the original OPTIMA study. Patients received treatment for stable angina after PCI as per routine study site clinical practice. Study data were collected from patient medical records and a routine visit 4 years after PCI. CLINICAL TRIAL REGISTRATION: NCT02099565. MAIN OUTCOME MEASURES: Rate of MACCEs 4 years after PCI. RESULTS: Overall, 543 patients agreed to participate in the study (90.2% of patients in the original OPTIMA study). The mean (+/- standard deviation [SD]) duration of follow-up from the date of PCI to data collection was 4.42 +/- 0.58 (range: 0.28-5.56) years. The frequency of MACCEs (including data in patients who died) was 30.8% (95% confidence interval: 27.0-34.7); half of MACCEs occurred in the first year of follow-up. After PCI, the majority of patients had no clinical signs of angina. Overall, 24.3% of patients discontinued statin intake in the 4 years after PCI. Only 7.7% of patients achieved a low-density lipoprotein (LDL) cholesterol goal of <1.8 mmol/L. Key limitations of this study related to its observational nature; for example, the sample size was small, the clinical results were derived from outpatients and hospitalized medical records, only one follow-up visit was performed at the end of the study (after 4 years' follow-up), only depersonalized medical information was made available for statistical analysis, and adherence to statin treatment was evaluated on the basis of patient questionnaire. CONCLUSIONS: Long-term follow-up of patients who underwent PCI with DES implantation demonstrated MACCEs in nearly one-third of patients, which is comparable to data from other studies. PCI was associated with relief from angina or minimal angina frequency, but compliance with statin therapy and the achievement of LDL cholesterol targets 4 years after PCI were suboptimal. PMID- 27779437 TI - When Pain Is Medicine. AB - Stripped of any sense of comfort or dignity on that hospital bed, my 84-year-old father, my best friend, was enduring raw, intrusive medical procedures against his own wish; defenseless, vulnerable, agonized. A feeding tube went in through his nose; catheter tubes drained urine out of his bladder; a suction pump drew out fluid from his airway. A needle jammed into the central line, making it impossible for him to turn his head. Dialysis took over the job of his kidneys. But no painkillers were given for fear his weak heart could not take more chemicals. Three nights later, the blood report arrived, which stated my father had no blood infection, for which he was undergoing treatment for a week. Could they not have waited till the report came before breaking him up? PMID- 27779438 TI - Effects of consecutive days of match play on technical performance in tennis. AB - Elite tennis is characterised by repeated bouts of up to 5-set match play, yet little is known about the technical requirements of shots played. This study therefore investigated technical performance changes over consecutive days of prolonged, simulated tennis match play. A total of 7 well-trained men tennis players performed 4 consecutive days of competitive 4-h match play. Matches were notated to determine between-day changes in groundstroke and serve performance, as well as point and match durations. Changes >=75% likely to exceed the smallest important effect size (0.2) were considered meaningful and represented as effect size +/- 90% confidence interval. Effective playing time reduced on days 3 and 4, alongside likely increases in "stretch" groundstrokes over the 4 days (mean effect size +/- 90% confidence interval; 0.57 +/- 0.38) and "stretch" backhand returns on days 2 and 3 (0.39 +/- 0.54 and 0.67 +/- 0.55). Relative unforced errors increased on day 4 (vs. day 2; 0.36 +/- 0.22) and second-serve winning percentage reduced after day 1 (-0.47 +/- 0.50). Further, a likely increase in emotional outbursts characterised day 3 (vs. day 2; 0.73 +/- 0.57). Consecutive day match play impairs hitting accuracy, stroke positioning and emotional responses; an understanding of which prepares players for elite-standard tennis tournament play. PMID- 27779439 TI - Comparison of ergometer- and track-based testing in junior track-sprint cyclists. Implications for talent identification and development. AB - Talent identification (TID) and talent development (TDE) programmes in track sprint cycling use ergometer- and track-based tests to select junior athletes and assess their development. The purpose of this study was to assess which tests are best at monitoring TID and TDE. Ten male participants (16.2 +/- 1.1 year; 178.5 +/- 6.0 cm and 73.6 +/- 7.6 kg) were selected into the national TID squad based on initial testing. These tests consisted of two 6-s maximal sprints on a custom built ergometer and 4 maximal track-based tests (2 rolling and 2 standing starts) using 2 gear ratios. Magnitude-based inferences and correlation coefficients assessed changes following a 3-month TDE programme. Training elicited meaningful improvements (80-100% likely) in all ergometer parameters. The standing and rolling small gear, track-based effort times were likely and very likely (3.2 +/- 2.4% and 3.3 +/- 1.9%, respectively) improved by training. Stronger correlations between ergometer- and track-based measures were very likely following training. Ergometer-based testing provides a more sensitive tool than track-based testing to monitor changes in neuromuscular function during the early stages of TDE. However, track-based testing can indicate skill-based improvements in performance when interpreted with ergometer testing. In combination, these tests provide information on overall talent development. PMID- 27779440 TI - Internet-Based Resources for Disease Self-Care Among Middle-Aged and Older Women with Chronic Conditions. AB - OBJECTIVE: This two-part study analyzed data collected from middle-aged (age 44 64) and older women (age 65+) with one or more chronic conditions who completed the National Council on Aging Chronic Care Survey. MATERIALS AND METHODS: Part One analyzed data from 418 women to describe sociodemographics, disease types, and healthcare utilization associated with Internet use among middle-aged and older women with 1 or more chronic diseases. Part Two analyzed data from the 251 Internet-using women to identify the online self-care resources they are using (format, host organization) and for what purposes. RESULTS: Approximately 31% of participants were age 65 years or older, 30% reported having three or more chronic condition types, and 65% reported using the Internet. A significantly larger proportion of older women reported multiple chronic conditions, and a significantly fewer number of older women reported using the Internet. A significantly smaller proportion of Internet users were non-Hispanic white, more educated, and employed. A significantly larger proportion of non-Internet users reported needing help learning what to do to manage their health conditions and needing help learning how to care for their health conditions. Among only Internet-using women, 18.7% participated in online discussions/chatrooms/listserv and 45.2% read about the experiences of others with chronic diseases. Interest in websites and online courses varied. CONCLUSION: Understanding Internet use among women with chronic conditions can inform targeted efforts to increase Internet availability, educate potential users about the benefits of online resources, and effectively tailor Internet-based materials to self-care needs. PMID- 27779443 TI - Prevalence of Klebsiella oxytoca in Anolis carolensis of Louisiana. AB - Klebsiella oxytoca is a gram-negative bacterium that can be found throughout the environment as well as on mucosal membranes of mammals including humans. This bacterium is responsible for a variety of infections in humans including nosocomial infections resulting in hospital outbreaks. Reptiles including snakes, tuataras, and turtles have been shown to harbor this bacterium, and previous studies have shown that pet reptiles are a potential source for dissemination of pathogenic bacteria. Green anoles (Anolis carolensis) are a common lizard found in the southeastern part of the United States. For this study, the prevalence of K. oxytoca in free-living green anoles from Louisiana was tested to determine whether anoles are a possible source of pathogenic bacteria. Of the 42 green anoles tested, 7 (17%) were positive for K. oxytoca, demonstrating that anoles are a potential source for human infection from this bacterium. PMID- 27779442 TI - Risk-Benefit Analysis of Pediatric-Inspired Versus Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Protocols for Acute Lymphoblastic Leukemia in Adolescents and Young Adults. AB - PURPOSE: To estimate the risk-benefit trade-off of a pediatric-inspired regimen versus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) for first-line treatment of adolescents/young adult (AYA; ages 16-39 years) patients with Philadelphia-negative acute lymphoblastic leukemia. METHODS: Patient outcomes were simulated using a 6-state Markov model, including complete response (CR), no CR, first relapse, second CR, second relapse, and death. A Weibull distribution was fit to the progression-free survival curve of hyper-CVAD-treated AYA patients from a single-center study, and comparable patient data from a retrospective study of pediatric regimen-treated AYA patients were utilized to estimate a relative progression difference (hazard ratio = 0.51) and model survival differences. Health-state utilities were estimated based on treatment stage, with an assumption that the pediatric protocol had 0.10 disutility compared with hyper-CVAD before the maintenance phase of treatment. Total life-years and quality-adjusted life-years (QALYs) were compared between treatment protocols at 1, 5, and 10 years, with additional probabilistic sensitivity analyses. RESULTS: Treatment with the pediatric inspired protocol was associated with a 0.04 increase in life-years, but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increase in life-years and 0.25 and 0.32 increase in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was offset by more favorable progression-free survival and overall survival relative to hyper-CVAD. CONCLUSIONS: Our exploratory analysis suggests that, compared with hyper-CVAD, pediatric-inspired protocols may increase life-years throughout treatment stages and QALYs in the long term. PMID- 27779444 TI - Selective Anticancer Activity of Acacetin Against Chronic Lymphocytic Leukemia Using Both In Vivo and In Vitro Methods: Key Role of Oxidative Stress and Cancerous Mitochondria. AB - The present study investigates the in vitro and in vivo effect of acacetin (4' methoxy-5,7-dihydroxyflavone) on chronic lymphocytic leukemia (CLL) B-lymphocytes and mitochondria. CLL B-lymphocytes and healthy B-lymphocytes were obtained from CLL patients and healthy donors, respectively. Mitochondria were isolated from B lymphocytes of both groups. Xenografts in severe combined immune deficient mice were used to examine the toxicity and anti CLL activity of acacetin. We evaluated and compared the mechanism of action of acacetin on CLL and healthy B-lymphocytes and their mitochondria. We have found that acacetin (10 MUM) can selectively induce apoptosis on CLL B-lymphocyte (25% at 24 h) by directly targeting mitochondria, through increased reactive oxygen species (ROS) formation, MMP collapse, MPT, release of cytochrome c, caspase 3 activation, and finally apoptosis, while sparing normal healthy B-lymphocytes unaffected at similar concentrations. Besides, oral administration of acacetin showed a potent in vivo anticancer activity in CLL xenograft mouse models. Our in vivo findings indicate that acacetin accumulates and kills CLL B-lymphocyte in a rather selective way through targeting cancerous mitochondria and ROS formation, which ends in CLL therapy. Finally, we can recommend acacetin as a promising compound for further drug development assays for the CLL treatment. PMID- 27779445 TI - Determining Cannabis Use Status From a Photograph: An Assessment of the "Jay-dar" in Neuropsychologists. AB - BACKGROUND: Few studies examining the cognitive effects of chronic cannabis use utilize research designs where examiners are blind to user status. Even in those that do, researchers may be able to guess the user status of participants, leaving these studies vulnerable to the expectancy effect confound. OBJECTIVES: The present study examined the ability of neuropsychologists (those who would conduct research on the cognitive effects of cannabis) to differentiate cannabis users and nonusers based on physical appearance from photographs. METHOD: We recruited 84 participants from an international neuropsychology listserv. The sample was 59.5% female and 95.2% Caucasian, with a mean age of 41.39 years (range 26-65). Each neuropsychologist rated 25 target faces (12 cannabis users, 13 nonusers) on a Marijuana Use Likelihood Index based upon individuals' photographs. RESULTS: Results indicate a main effect of user group, as neuropsychologists ascribed higher ratings to cannabis users on the Marijuana Use Likelihood Index, suggesting they perceive them as more likely to be users, relative to nonusers. Results also demonstrated a main effect of gender, as males received higher user ratings than females, and a significant main effect of rater gender, as female raters were more likely to rate individuals as cannabis users relative to male raters. Conclusions/Importance: The results demonstrate the importance of assessing researchers' expectations when studying the effects of chronic cannabis use, as even those designs that keep examiners blind to participant user status may be vulnerable to expectancy effects if examiners are able to guess user status based upon appearance alone. PMID- 27779446 TI - A Comparison of Extremity Thrombosis Rates in Adolescent and Young Adult Versus Younger Pediatric Oncology Patients at a Children's Hospital. AB - PURPOSE: To examine whether the rates of thrombosis in children (<=14 years of age) and adolescent/young adult (AYA) patients (15-22 years of age) with cancer is different. METHODS: We retrospectively studied the rates of thrombosis in children and AYA patients at the Children's Hospital of Pittsburgh during the years 2002-2010, using the tumor registry database. This list was then divided into two groups based on age at diagnosis. A review of ICD-9 codes from hospital billing records was then performed to identify patients who carried diagnoses of cancer (140.x-239.x) and venous thrombosis of the extremities/vena cavae (453.x) simultaneously. This list was confirmed by electronic medical record review. Proportions, comparisons, and descriptive statistics were then performed. RESULTS: One thousand three hundred nine total patients were identified; 274 patients fit into the AYA age category (mean age 17.3 years) and 1036 patients were in the child group (mean age 6.5 years). Overall, 30 patients (2.29%) had thrombosis: 4.76% of the AYA patients (13/273) and 1.64% of the child group (17/1036). The difference in these proportions had a p-value = 0.004. CONCLUSIONS: This study suggests that the risk of extremity deep vein thrombosis is higher in the AYA subset of oncology patients than in the patients who are 14 years or younger. Prospective studies to elucidate the true rate of thrombosis, as well as to study the benefit of prophylactic anticoagulation in the AYA population, should be undertaken. PMID- 27779447 TI - Routine Drug Screening for Patients in the Emergency Department of a State Psychiatric Hospital: A Naturalistic Cohort Study. AB - OBJECTIVE: This study investigates the proportion of drug users among patients with mental disorders who attended the emergency department of one major psychiatric hospital in Northern Israel, the most frequent psychiatric diagnoses associated with drug use, and the impact of confirmed drug use on hospital admission. We hypothesized that the proportion of individuals with positive urine drug test results presenting at the psychiatric emergency department during the study period would be 20% to 30%. METHODS: An unselected cohort of 2,019 adult patients who visited the emergency department of Sha'ar Menashe Mental Health Center, a university-affiliated government facility, was evaluated and underwent routine urine drug testing between April 2012 and February 2014. Clinical, demographic, and urine drug test data were collected from medical records and statistically analyzed, comparing diagnostic evaluation at admission and after discharge from either the emergency department or the hospital. Univariate and logistic regression analyses were used to identify the possible variables associated with drug use in this sample. RESULTS: Urine drug test results showed that 194 of the 2,019 subjects (9.6%) had used a psychoactive substance before attending the emergency department. Among patients with positive urine drug test results, the majority (77.8%) used cannabis, 25.8% used opiates, 24.7% used ecstasy, and 5.2% used cocaine. Differences in the prevalence of positive urine drug test results between admitted and nonadmitted patients did not reach a statistically significant level. The frequency of positive urine drug test results across lifetime International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) diagnoses was 27.2% for substance related disorders, 4.8% for psychotic disorders, 4.2% for mood disorders, 11.0% for personality disorders, and 11.5% for nonpsychotic disorders. Both univariate and logistic regression analyses revealed that younger age (18-40), male sex, fewer years of education, single marital status, and ICD-10 diagnosis of substance-related, personality, and nonpsychotic disorders were indicators of higher likelihood of positive urine drug test findings. CONCLUSIONS: Results suggest that routine urine toxicology screening is not necessary in the psychiatric emergency department as an adjunct to a thorough psychiatric clinical examination. However, urine drug tests should be performed when the clinical evaluation cannot determine whether the mental disorder is the result of illicit drug use or clearly non-drug-related. PMID- 27779448 TI - The conceptualization of mistreatment by older American Indians. AB - The problem of how to conceptualize elder mistreatment goes back several decades, and is especially important for ethnic minority populations, who may have perspectives that differ from the dominant society. This community-based participatory research study, which examined perceptions of mistreatment by family among 100 urban and rural older American Indians, permits a rare glimpse into how Native elders themselves understand this issue. Here, good treatment was conceptualized in terms of being taken care of, having one's needs met, and being respected. We found relatively high standards for how elders should be treated such as the belief that an elder's needs should be anticipated and met without the elder needing to ask-in the face of widespread accounts of the mistreatment of elders within the community, largely through various acts of financial exploitation and neglect. Substance abuse and culture loss were blamed formuch of the elder mistreatment occurring in contemporary Native communities. PMID- 27779449 TI - Anatomic Insights into Disrupted Small-World Networks in Pediatric Posttraumatic Stress Disorder. AB - Purpose To use diffusion-tensor (DT) imaging and graph theory approaches to explore the brain structural connectome in pediatric posttraumatic stress disorder (PTSD). Materials and Methods This study was approved by the relevant research ethics committee, and all participants' parents or guardians provided informed consent. Twenty-four pediatric patients with PTSD and 23 control subjects exposed to trauma but without PTSD were recruited after the 2008 Sichuan earthquake. The structural connectome was constructed by using DT imaging tractography and thresholding the mean fractional anisotropy of 90 brain regions to yield 90 * 90 partial correlation matrixes. Graph theory analysis was used to examine the group-specific topologic properties, and nonparametric permutation tests were used for group comparisons of topologic metrics. Results Both groups exhibited small-world topology. However, patients with PTSD showed an increase in the characteristic path length (P = .0248) and decreases in local efficiency (P = .0498) and global efficiency (P = .0274). Furthermore, patients with PTSD showed reduced nodal centralities, mainly in the default mode, salience, central executive, and visual regions (P < .05, corrected for false-discovery rate). The Clinician-Administered PTSD Scale score was negatively correlated with the nodal efficiency of the left superior parietal gyrus (r = -0.446, P = .043). Conclusion The structural connectome showed a shift toward "regularization," providing a structural basis for functional alterations of pediatric PTSD. These abnormalities suggest that PTSD can be understood by examining the dysfunction of large-scale spatially distributed neural networks. (c) RSNA, 2016. PMID- 27779450 TI - Exploitation of functional nanomaterials in therapy and diagnostics. PMID- 27779451 TI - Longitudinal Conjoint Patterns of Alcohol and Tobacco Use Throughout Emerging Adulthood. AB - BACKGROUND: The concurrent use of alcohol and tobacco has a multiplicative effect on both social and physical consequences. While it is known that alcohol and tobacco use are strongly correlated in emerging adulthood, there is significant individual variability in use. However, little research has examined how patterns of concurrent use are related over time. OBJECTIVES: The current study explores these longitudinal conjoint trajectories, as well as the associated sociodemographic factors. METHODS: We used sequential latent class growth analysis to explore the co-occurring longitudinal patterns of recent alcohol and tobacco use across emerging adulthood (10 data collection periods, 2004-2009) with a diverse sample of 2,244 college students (60% female; 54% White). RESULTS: Twenty distinct patterns of conjoint alcohol and tobacco use were found. There was more variation in tobacco use trajectories among alcohol users than variation in alcohol trajectories among tobacco users. Using multinomial logistic regression models we determined the impact of sociodemographic characteristics on classification into each conjoint pattern versus the normative trajectory (Abstaining tobacco/Low alcohol). Male gender, White race, fraternity/sorority affiliation, and higher family income were significantly associated with riskier conjoint trajectory patterns. Conclusions/Importance: Findings highlight the diversity of alcohol and tobacco use behaviors across emerging adulthood. The low variation in alcohol use among tobacco users indicates that tobacco use is a significant risk factor for heavier drinking. A better understanding of the covarying use of these two ubiquitous substances may provide new avenues for preventing and reducing the use of both. PMID- 27779453 TI - The fixed-dose combination of lercanidipine and enalapril: more than mere blood pressure reduction. PMID- 27779452 TI - Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity. AB - RATIONALE: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies. OBJECTIVES: Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies. METHODS: Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed. MEASUREMENTS AND MAIN RESULTS: Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS1) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor. CONCLUSIONS: Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies. PMID- 27779454 TI - Effects of lercanidipine hydrochloride versus felodipine sustained-release on day to-day home blood pressure variability. AB - OBJECTIVE: The objective of this study was to compare the effectiveness of lercanidipine with felodipine in patients with mild-to-moderate hypertension on day-to-day home blood pressure variability. METHODS: This is a sub-study of a multicenter, randomized, open-label, parallel group and active controlled clinical trial. Hypertensive patients aged 18-75 (i.e. diastolic blood pressure >=90 mmHg and <110 mmHg; systolic blood pressure >=140 mmHg and <180 mmHg) and 24 h mean BP >130/80 mmHg) were eligible for this study. During the study, blood pressure (BP) and heart rate (HR) were recorded. The day-to-day BP variability (BPV) and HR variability (HRV) were obtained by the standard deviation (SD) of daily BP/HR average (of six readings) in 7 days. RESULTS: There were 186 patients (89 and 97 patients in the lercanidipine and felodipine groups, respectively) included in this study. Lercanidipine hydrochloride 10 mg/d and felodipine sustained-release tablets 5 mg/d were given to their respective groups. After 6 weeks of treatment, SD of home BP significantly reduced compared with baseline in both groups (P < .05) while SD of home HR also changed significantly after treatment (P < .05). There was no significant difference in SD of home BPV between the lercanidipine and felodipine groups after treatment. CONCLUSION: Treatment with lercanidipine and felodipine both resulted in reduction of BPV and HRV. There was no significant inter-group difference in reduction of BPV between the groups. Lercanidipine is an effective antihypertensive drug in improving BPV. National clinical trial: NCT01520285. PMID- 27779456 TI - Lercanidipine effect on circulating CD34+ progenitor cells in elderly patients: a randomized study. AB - OBJECTIVE: This randomized study evaluates the effects of lercanidipine - as well as its antihypertensive efficacy - on the number of circulating endothelial progenitor cells (EPCs) in elderly patients with hypertension. RESEARCH DESIGN AND METHODS: In total, 61 patients with hypertension were randomly assigned to lercanidipine 10 mg/day or to other antihypertensive treatments (control group). MAIN OUTCOME MEASURES: Cytometry analysis was conducted at baseline, at 12 weeks and at 24 weeks. Routine clinical examination was also performed. RESULTS: Overall, the number of circulating EPCs had already significantly increased with lercanidipine, compared with baseline values, after 12 weeks; this increase was sustained until the end of the study. On the other hand, the number of circulating EPCs remained stable in the control group throughout the study period. At 12 weeks, a significant reduction in blood pressure, compared with baseline values, was observed in both groups. Regression analysis showed a significant negative correlation between systolic blood pressure and the number of circulating EPCs. CONCLUSIONS: Although the limited number of patients and the short follow-up hamper the analysis, this study suggests that lercanidipine may increase EPC concentration independently from its anti-hypertensive effect. PMID- 27779455 TI - The efficacy of renal artery stent combined with optimal medical therapy in patients with severe atherosclerotic renal artery stenosis. AB - OBJECTIVE: To evaluate the efficacy of renal artery stent combined with optimal medical therapy as treatment for renal artery stenosis. RESEARCH DESIGN AND METHODS: A prospective cohort study was conducted. Patients with severe atherosclerotic renal artery stenosis received percutaneous renal artery stent because of poorly controlled hypertension or preservation of renal function. The patients also received optimal medical therapy to achieve the blood pressure, lipid and blood glucose targets. MAIN OUTCOME MEASURES: All patients underwent a 12 month follow-up to observe the effect of the procedure on blood pressure control, number of antihypertensive medications and creatinine level. RESULTS: Stents were placed in 185 renal arteries of 149 patients. Mean stenosis was 83.1 +/- 7.0%. The success rate of renal artery stent was 99.3%. At 12 months, estimated glomerular filtration rate increased significantly compared with baseline (84.1 +/- 28.8 vs. 76.5 +/- 22.50 ml/min *1.73 m2, p < 0.05). Both office blood pressure and 24 hour blood pressure significantly decreased compared with baseline (from 153/83 mmHg to 134/73 mmHg and from 143/80 mmHg to 124/69 mmHg, respectively; p < 0.05), and less antihypertensive medication was taken compared with baseline (1.5 +/- 0.8 vs. 2.2 +/- 0.9; p < 0.05). CONCLUSIONS: Renal artery stent combined with optimal medical therapy as a treatment has a beneficial effect on blood pressure control and estimated glomerular filtration rate in selected patients with atherosclerotic renal artery stenosis. Larger studies with a longer follow-up appear necessary to further confirm these intriguing findings. PMID- 27779457 TI - Fixed-dose lercanidipine and enalapril in field practice: a meta-analysis. AB - OBJECTIVE: This meta-analysis evaluates the efficacy and safety of lercanidipine/enalapril fixed-dose combination in patients with mild to moderate essential hypertension. METHODS: Four observational studies on patients with sitting diastolic blood pressure (SDBP) between 95 and 109 mmHg, treated with lercanidipine/enalapril fixed-dose combination, were analyzed. The Random-Effect Model was used to limit heterogeneity across the studies. Weights were applied to determine the influence of each study on the combined results. The efficacy outcome measure was the reduction from baseline to endpoint in systolic and diastolic blood pressure (SBP and DBP, respectively). The incidence of treatment emergent adverse events (TEAEs) was also investigated. RESULTS: The total number of patients analyzed for efficacy and safety was 9565. No differences between study groups in demographics characteristics were observed. Mean blood pressure in the pooled population of the four studies was 162/94 mmHg at baseline. Overall, the lercanidipine/enalapril fixed-dose combination reduced SBP by 26 mmHg (95% CI, 23-29), and DBP by 13 mmHg (12-15), p < 0.05 for both. No safety concerns were reported. CONCLUSION: This meta-analysis supports the use of the lercanidipine/enalapril fixed-dose combination for the treatment of mild-to moderate hypertension. PMID- 27779458 TI - Dose-response effect of the lercanidipine/enalapril combination: a pooled analysis. AB - OBJECTIVE: The dose-effect relationship of fixed-dose combinations of anti hypertensive drugs has been only poorly explored. This pooled analysis investigates the dose-response relationship of fixed-dose lercanidipine + enalapril in patients with mild-to-moderate hypertension. RESEARCH DESIGN AND METHODS: This was an individual patient data analysis of four randomized studies (n = 2340). MAIN OUTCOME MEASURES: The primary efficacy variable was the change from baseline in sitting diastolic blood pressure (SDBP). Secondary variables were change from baseline in sitting systolic BP (SSBP), proportion of responder patients, and safety. RESULTS: All fixed-dose combinations were superior to placebo in the reduction of SDBP. The greatest effect was observed with the market-available combination lercanidipine 20 mg/enalapril 20 mg (-15.3 mmHg vs. baseline; p < 0.05). The reduction in SDBP associated with the other two marketed fixed combinations of lercanidipine/enalapril were -10.7 mmHg for the 10 mg/20 mg combination and -9.8 mmHg for the 10 mg/10 mg combination (p < .05 for both comparisons). Similar findings were reported for SSBP reduction: the greatest effect was observed with lercanidipine 20 mg/enalapril 20 mg (-19.2 mmHg). The reduction in SSBP was -12.5 mmHg for the 10 mg/20 mg combination and -11.1 mmHg for the 10 mg/10 mg combination (p < .05 for all comparisons). The highest responder rate was reported with lercanidipine 20 mg/enalapril 20 mg (75.0%); this figure was 56.1% with the 10 mg/20 mg and 53.0% with the 10/10 mg combination. No safety concerns were reported. CONCLUSION: This pooled analysis of four randomized studies shows evidence of a dose-response effect in BP reduction with different fixed combinations of lercanidipine + enalapril. To our knowledge, this is the first analysis investigating the dose-response effect of a specific fixed-dose combination of anti-hypertensive agents. Further studies on this intriguing topic are however necessary. PMID- 27779459 TI - Vascular effects of the lercanidipine/enalapril combination: clinical relevance. AB - Hypertension is associated with alterations in the vascular structure, which in turn enhance the risk of cardiovascular events. Notably, anti-hypertensive treatment may prevent or regress the changes of arterial wall structures. Lercanidipine is a third-generation CCB with peculiar pharmaceutical properties. Enalapril is an effective drug acting on the renin-angiotensin-aldosterone axis. This commentary discusses the vascular effects of the lercanidipine/enalapril combination, and comments on their potential clinical relevance. PMID- 27779460 TI - Lercanidipine valuable effect on urine protein losses: the RED LEVEL study. AB - OBJECTIVE: The RED LEVEL study (REnal Disease: LErcanidipine Valuable Effect on urine protein Losses) directly compares, in an explorative fashion, the effects of lercanidipine + enalapril and amlodipine + enalapril combinations on renal parameters in hypertensive subjects. RESEARCH DESIGN AND METHODS: This was a 1 year, prospective, multi-center, randomized, open-label, blinded-endpoint (PROBE) study in hypertensive patients with albuminuria. MAIN OUTCOME MEASURES: Renal function (albuminuria, serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria); blood pressure. RESULTS: Albuminuria was significantly reduced, compared with baseline values, with the lercanidipine + enalapril combination over the entire study period; at month 3, month 6 and month 12, changes from baseline were: -162.5 (p-value = 0.0439), -425.8 (p-value = 0.0010), -329.0 (p-value = 0.0011) mg/24 h), respectively. On the other hand, this improvement was not observed with enalapril + amlodipine. Other parameters of renal function such as serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria did not change over the study. Both lercanidipine + enalapril and amlodipine + enalapril significantly reduced systolic and diastolic blood pressure values from baseline all over the study period with no significant differences between groups. Safety outcomes were comparable between the two groups. CONCLUSIONS: Overall, the results of this explorative study lend support to the anti-albuminuric effect of the lercanidipine + enalapril combination and to the long term renal-protective effects of this combination in patients with hypertension. PMID- 27779461 TI - Differential effects of lercanidipine/enalapril versus amlodipine/enalapril and hydrochlorothiazide/enalapril on target organ damage and sympathetic activation in non-obese essential hypertensive subjects. AB - OBJECTIVE: The aim of the present study was to compare the effects of the combination of lercanidipine/enalapril versus amlodipine/enalapril and hydrochlorothiazide/enalapril on blood pressure, target organ damage and sympathetic activation in patients with grade 2 essential hypertension. RESEARCH DESIGN AND METHODS: This was a 3 month, randomized, blinded-endpoint study in essential hypertensive patients. MAIN OUTCOME MEASURES: Office and ambulatory blood pressure, arterial stiffness, urinary albumin to creatinine ratio, renal arterial resistive index, and muscle sympathetic nerve activity were evaluated at baseline, after a 2 week run-in placebo period, at 1 month and at 3 months. RESULTS: In total, 56 patients were assigned to lercanidipine/enalapril (n = 19), enalapril/amlodipine (n = 18) and hydrochlorothiazide/enalapril (n = 19). Each pharmacological combination tested was effective in reducing office blood pressure at 1 month and 3 months, and 24 h ambulatory blood pressure at 3 months. Renal arterial resistive index (RI) significantly improved at 1 month and 3 months compared with baseline in all groups. However in the lercanidipine/enalapril and hydrochlorothiazide/enalapril groups, RI was favorably reduced (0.53 +/- 0.03 and 0.54 +/- 0.04 respectively, p < 0.05) in comparison with the enalapril/amlodipine RI value (0.57 +/- 0.03) at 3 months. Moreover, after 3 months of treatment, a significant decrease (by -5.47 bursts/min) (p < 0.05) in muscle sympathetic nerve activity was observed in the lercanidipine/enalapril group (50.79 +/- 6.49) compared with baseline (56.26 +/- 6.05), while no differences were detected in the amlodipine/enalapril and hydrochlorothiazide/enalapril groups. CONCLUSIONS: Our study provides evidence of the efficacy of the lercanidipine/enalapril combination in ameliorating hypertension-related target organ damage and in reducing sympathetic overdrive. PMID- 27779462 TI - Understanding breast cancer screening behaviors of Korean American women in sociocultural contexts. AB - This study examines the breast cancer screening behaviors of Korean American women focusing on their cultural beliefs and access to health care. A total of 111 Korean American women participated in the cross-sectional survey research. Korean American women who felt embarrassed about breast cancer screenings were less likely to have received clinical breast exams or mammograms. Implications to culturally competent social work practice in promoting their breast cancer screening behaviors are discussed. PMID- 27779464 TI - Transvection Arising from Transgene Interactions in Zebrafish. AB - There has been a rapid expansion in use of transgenic technologies in zebrafish. We report a novel example of transinteractions of genetic elements, or transvection. This interaction led to a novel expression pattern and illustrates a precautionary example regarding use of transgenes in zebrafish. PMID- 27779463 TI - A Zebrafish Live Imaging Model Reveals Differential Responses of Microglia Toward Glioblastoma Cells In Vivo. AB - Glioblastoma multiforme is the most common and deadliest form of brain cancer. Glioblastomas are infiltrated by a high number of microglia, which promote tumor growth and surrounding tissue invasion. However, it is unclear how microglia and glioma cells physically interact and if there are differences, depending on glioma cell type. Hence, we have developed a novel live imaging assay to study microglia-glioma interactions in vivo in the zebrafish brain. We transplanted well-established human glioblastoma cell lines, U87 and U251, into transgenic zebrafish lines with labelled macrophages/microglia. Our confocal live imaging results show distinct interactions between microglia and U87, as well as U251 glioblastoma cells that differ in number and nature. Importantly these interactions do not appear to be antitumoral as zebrafish microglia do not engulf and phagocytose the human glioblastoma cells. Finally, xenotransplants into the irf8-/- zebrafish mutant that lacks microglia, as well as pharmacological inhibition of the CSF-1 receptor (CSF-1R) on microglia, confirm a prominent role for zebrafish microglia in promoting human glioblastoma cell growth. This new model will be an important tool for drug screening and the development of future immunotherapeutics targeting microglia within glioma. PMID- 27779465 TI - Office of Laboratory Animal Welfare Comments. AB - In support of the new column in Zebrafish dedicated to initiating conversations about animal care policies and compliance for the zebrafish, the Office of Laboratory Animal Welfare (OLAW) has offered the following clarification and guidance. PMID- 27779466 TI - Guillain-Barre Syndrome and Healthcare Needs during Zika Virus Transmission, Puerto Rico, 2016. AB - To assist with public health preparedness activities, we estimated the number of expected cases of Zika virus in Puerto Rico and associated healthcare needs. Estimated annual incidence is 3.2-5.1 times the baseline, and long-term care needs are predicted to be 3-5 times greater than in years with no Zika virus. PMID- 27779467 TI - Travel-Related Tick-Borne Encephalitis, Israel, 2006-2014. AB - During 2006-2014, four tick-borne encephalitis (TBE) cases occurred among Israeli travelers. We calculated TBE incidence at 321.0, 45.0, 13.2, and 7.5 cases/100,000 travelers/year of travel to Sweden, Switzerland, Austria, and Germany, respectively. TBE incidence among travelers to these destinations appears to justify TBE vaccination in accordance with World Health Organization recommendations. PMID- 27779469 TI - Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes. AB - Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques. OM displayed a concentration-dependent action on action potential configuration: 1 MUM OM had no effect, while action potential duration and phase-1 repolarization were reduced and the plateau potential was depressed progressively at higher concentrations (10 - 100 MUM; P < 0.05 compared to control). Accordingly, OM (10 MUM) decreased the density of the transient outward K+ current (Ito), the L-type Ca2+ current (ICa) and the rapid delayed rectifier K+ current (IKr), but failed to modify the inward rectifier K+ current (IK1). It is concluded, that although the therapeutic concentrations of OM are not likely to influence cardiac ion currents significantly, alterations of the major cardiac ion currents can be anticipated at concentrations above those clinically tolerated. PMID- 27779470 TI - Tumour-associated macrophages influence canine mammary cancer stem-like cells enhancing their pro-angiogenic properties. AB - Cancer stem-like cells as cells with ability to self-renewal and potential to differentiate into various types of cells are known to be responsible for tumour initiation, recurrence and drug resistance. Hence a comprehensive research is concentrated on discovering cancer stem-like cells biology and interdependence between them and other cells. The aim of our study was to evaluate the impact of macrophages on cancer stem-like cells in canine mammary carcinomas. As recent studies indicated presence of macrophages in cancer environment stimulates cancer cells into more motile and invasive cells by acquisition of macrophage phenotypes. From two canine mammary tumour cell lines, CMT-U27 and P114 cancer stem-like cells were stained with Sca1, CD44 and EpCAM monoclonal antibodies and isolated. Those cells were next co-cultured with macrophages for 5 days and used for further experiments. Canine Gene Expression Microarray revealed 29 different expressed transcripts in cancer stem-like cells co-cultured with macrophages compared to those in mono-culture. Up-regulation of C-C motif chemokine 2 was considered as the most interesting for further investigation. Additionally, those cells showed overexpression of genes involved in non-canonical Wnt pathway. The results of 3D tubule formation in endothelial cells induced by cancer stem-like cells co-cultured with macrophages compared to cancer stem-like cells from mono cultures and with addition of Recombinant Canine CCL2/MCP-1 revealed the same stimulating effect. Based on those results we can conclude that macrophages have an impact on cancer stem-like cells increasing secretion of pro-angiogenic factors. PMID- 27779468 TI - TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. AB - Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (alpha Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that alpha-Syn and tau overlap pathologically. The connections between alpha-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of alpha-Syn and tau. We found that TRIM28 regulates alpha-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and alpha-Syn mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points. PMID- 27779471 TI - The adaptive role of nitric oxide and hydrogen sulphide in vasoactive responses of thoracic aorta is triggered already in young spontaneously hypertensive rats. AB - The aorta plays an important role in blood pressure control so the early determination of its vasoactive properties could predict pathological changes in hypertension. The aim of study was to compare vasoactive properties and geometry of thoracic aorta (TA) and the participation of two vasoactive transmitters, nitric oxide (NO) and hydrogen sulphide (H2S), in TA tone regulation in young Wistar rats (WR) and spontaneously hypertensive rats (SHR). Four-weeks-old WR and SHR were used. Systolic blood pressure (sBP) was measured by plethysmography. The vasoactivity of TA was evaluated by changes in isometric tension. For morphological study the geometry of TA was measured using light microscopy. Decomposition of NO donor (nitrosoglutathione, GSNO) induced by H2S donor (Na2S) was studied by UV-VIS spectroscopy. In SHR the sBP was not increased in spite of cardiac hypertrophy compared to WR. Vasoconstriction to noradrenaline (NA) was decreased in SHR compared to WR which correlated with arterial wall hypotrophy. Acetylcholine (Ach)-induced vasorelaxation was increased and NO component participated in vasorelaxation and basal tone regulation significantly more in SHR. Na2S induced biphasic effect in both experimental groups, however, the shift towards vasorelaxation was demonstrated in SHR. Pretreatment with NO-synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME), diminished the contractile part of vasoactive Na2S effects in both strains, moreover, an increased sensitivity in behalf of vasorelaxation was observed in SHR. Pretreatment with Na2S did not affect Ach-induced vasorelaxation in WR, but an inhibition was demonstrated in SHR. On the other hand, pretreatment with Na2S increased the release of NO from GSNO which corresponded with increased GSNO-induced vasorelaxation in both groups. However, this effect was stronger in SHR. The study showed that TA of prehypertensive SHR disposed by decreased contractility and strengthened endothelium-regulated vasorelaxant mechanisms involving of NO and H2S interaction which could serve as adaptive mechanisms in the adulthood. PMID- 27779472 TI - Embelin supplementation of in vitro maturation medium does not influence nuclear and cytoplasmic maturation of pig oocytes. AB - Oxidative stress caused from in vitro culture contributes to inadequate oocyte maturation which leads to a poor embryo development. Therefore, it is important to protect oocytes and embryos against oxidative stress. This study was aimed at evaluating the effect of Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antioxidant with various pharmacologic activities, on nuclear and cytoplasmic maturation of pig oocytes as well as on steroidogenesis of cumulus cells (CCs). Another objective was to determine the influence of Embelin on developmental competence of pig oocytes as well as the expression levels of three key genes (Nanog, Sox2 and Oct4) involved in the control of pluripotency in parthenogenetically activated embryos. Embelin (0, 10, 20 and 40 MUM) was added during in vitro maturation of cumulus oocyte complexes; media of both the first and the second day of culture were collected and assayed for progesterone and estradiol-17beta. At the end of the maturation period, the oocytes were fixed (to determine nuclear maturation) or partenogenically activated to evaluate cytoplasmic maturation and genes expression. Embelin did not exert any effect on the proportion of MII oocytes, steroidogenesis of CCs, percentage of embryos that developed to blastocyst stage and the number of blastomeres/blastocyst. Moreover, no significant differences of Oct4, Nanog and Sox2 transcripts were detected in blastocyst stage embryos. In conclusion, Embelin did not influence the reproductive parameters assessed, confirming that it is not possible to predict whether the beneficial effect exerted by an antioxidant in a particular tissue could be present also in another one. PMID- 27779473 TI - All genes encoding enzymes participating in melatonin biosynthesis in the chicken pineal gland are transcribed rhythmically. AB - Our recent research on the pineal gland of young chickens confirmed that three genes encoding enzymes involved in pineal melatonin biosynthesis, tryptophan hydroxylase 1 (Tph1), arylalkylamine-N-acetyltransferase (Aanat) and acetylserotonin O-methyltransferase (Asmt), are transcribed rhythmically under light:dark (L:D) 12:12 conditions in vivo. Additionally, in the pineal gland of maturing chickens, the dopa decarboxylase (Ddc) gene is transcribed rhythmically at a specific stage of the developmental process. Therefore, the aim of the present study was to verify whether all of these genes are transcribed rhythmically in vivo under constant darkness (D:D) and in pinealocyte cultures under both L:D and D:D. Experiments were performed on chickens maintained under L:D 12:12 conditions. Chickens at 15 days of age were divided into two groups; chickens from the first group remained under the same conditions, whereas those from the second group were kept in darkness. Subsequently, 16-day-old animals were sacrificed every 2 hours over a 24-h period. For the in vitro experiments, 16-day-old chickens were sacrificed at ZT 6, and their pineal glands were isolated. Pineal cultures were maintained for up to two days in L:D conditions. Then, the pinealocyte cultures were divided into two groups: the first remained under L:D conditions, whereas the second was transferred to D:D conditions. Pinealocytes were subsequently collected every 2 hours over a 24-h period. Transcription was evaluated using the RT-qPCR method, and the rhythm percentage was calculated through Cosinor analysis. The mRNA levels of all genes examined were rhythmic under all conditions. Moreover, in silico analysis of the promoters of all of the genes examined revealed the presence of enhancer box sequences in all of the promoters as well as DBP/E4BP4 binding elements in the promoters of Tph1 and Asmt. This suggests that these genes may all be regulated transcriptionally by the molecular clock mechanism and may be considered clock as controlled genes. PMID- 27779474 TI - Metabolic effects of subchronic peripheral oxytocin administration in lean and obese zucker rats. AB - Increasing evidence indicates a role of oxytocin in controlling energy metabolism. The aim of his study was to investigate oxytocin effects on obese phenotype in leptin-resistant Zucker fatty rats, focusing on glucose and lipid metabolism. Zucker fatty rats and their lean controls were treated with oxytocin (3.6 MUg/100g body weight/day) by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hours intraperitoneal glucose tolerance test was performed in fasting rats. Oxytocin decreased food intake in both phenotypes while body weight gain reduced only in obese animals. In obese rats oxytocin impaired hepatic insulin extraction and enhanced liver triglyceride accumulation. Moreover, in the skeletal muscle of lean rats oxytocin treatment downregulated insulin signal transduction by decreasing of insulin receptor substrate 1 protein level and stimulating of its serine phosphorylation. Concurrently, the gene expression of insulin receptor substrate 1 in the skeletal muscle and adipose tissue was downregulated by oxytocin. In obese rats, oxytocin reduced adipocyte size and normalised mRNA levels of both fatty acid binding protein 4 and fatty acid synthase but attenuated gene expression of glucose transporter 4. The present study in Zucker fatty rats demonstrated ambivalent effects of oxytocin treatment with predominantly negative impact on skeletal muscle insulin pathway in lean animals. PMID- 27779475 TI - Maternal high-fat diet during pregnancy and lactation had gender difference effect on adiponectin in rat offspring. AB - This study investigated the effect of a high-fat (HF) diet on plasma adiponectin and steroid hormones levels, and the protein expression of adiponectin and its receptors, in the gonads and gonadal (periovarian and epididymal) white adipose tissue (WAT) of dams and their offspring. Female Wistar rats were fed a HF diet (30% fat) or a standard breeding (BD) diet (5% fat) during pregnancy and lactation. At 21 days of lactation, mothers and both sexes of prepubertal offspring were killed by decapitation. Plasma adiponectin, testosterone (T) and oestradiol (E2) levels were analyzed by ELISA. The protein expression of adiponectin and its receptors 1 (AdipoR1) and 2 (AdipoR2) was assayed by Western blot and immunohistochemistry. Plasma adiponectin levels in HF dams were lower compared to BD dams, and correlated with protein expression of adiponectin and its receptors, but not with steroid hormone levels. Female HF offspring had lower plasma adiponectin levels, reduced intensity of adiponectin and AdipoR1 in the ovary, and decreased E2 in parallel with increased T. In contrast, male HF offspring had higher plasma adiponectin levels, increased intensity of adiponectin and AdipoR1 in the testis, and decreased T in parallel with increased E2. In conclusion, feeding a HF diet to dams during pregnancy and lactation disturbs plasma adiponectin levels and protein expression, both in female and male offspring; it lowers adiponectin secretion and protein expression in the female whereas in male it is increased. As a consequence, there is disruption of steroid secretion in offspring, towards T in females, and E2 in males. PMID- 27779476 TI - Association of adiponectin and leptin-to-adiponectin ratio with the function of platelets in morbidly obese patients. AB - Adipokines regulate glucose homeostasis, insulin sensitivity, lipids metabolism, reproduction, as well as endothelial and platelets function. The study compares the plasma and adipose tissue concentrations of total adiponectin, leptin, leptin receptor and leptin-to-adiponectin ratio (LAR) in morbidly obese patients. Additionally it evaluates selected adipokines (leptin, adiponectin), endothelial markers and LAR depending on the gender in morbidly obese and non-obese subjects. The study involved 51 patients (31 women aged 21 - 60 (mean age of 39) and 20 men aged 24 to 60 (mean age of 41)). The eligibility criterion included the BMI >= 40 kg/m2. The non-obese group consisted of 30 healthy volunteers with the BMI < 24.9 kg/m2; nineteen women, aged 24 - 53 (mean age of 41), and 11 men aged 21 - 52 (mean age of 38). In the plasma and adipose tissue, the concentrations of total adiponectin, leptin, leptin receptor and plasma soluble forms of E-selectin, P selectin, thrombomodulin were measured applying immunoassay techniques. There were noted significantly higher plasma leptin and sE-selectin concentrations, leptin-to-adiponectin ratio, additionally lower concentrations of plasma leptin receptor and sP-selectin in obese subjects regardless of the gender. Significantly higher concentrations of total adiponectin, leptin, leptin receptor expressed per 1 mg of total protein in adipose tissue, as compared to plasma in morbidly obese patients, were observed. Significant positive correlations between the BMI and the concentration of leptin and between total adiponectin and sP selectin were reported in the subject group. Similarly there were noted significant negative correlations between leptin receptor and the BMI and between leptin-to-adiponectin ratio and sP-selectin in obese patients. The study has shown that adiponectin has a positive impact on platelets through a possible reduction in sP-selectin, and thus on platelets activation. On the other hand an elevated sE-selectin reveals perspective about the endothelium stimulation and a higher risk of endothelial damage in morbidly obese patients. Also in morbidly obese the higher leptin level and leptin-to-adiponectin ratio and simultaneously lower concentration of leptin receptor are associated with leptin resistance, additionally in possible future risk of insulin resistance and diabetes type 2. PMID- 27779477 TI - Diets with no or low amounts of dietary fiber can reduce small intestinal ulcers induced by non-steroidal anti-inflammatory drugs in dogs. AB - Recent progress in endoscopic techniques has revealed that non-steroidal anti inflammatory drugs (NSAIDs) often cause ulcers in the small intestine in humans, but effective therapy is not available at present. In the present study, we investigated the effects of feeding condition and the amount of dietary fiber (DF) in the diet on the formation of gastrointestinal ulcers induced by NSAIDs in dogs. Several types of diets containing various percentages of DF were given to dogs. Indomethacin (1 or 3 mg/kg, p.o.), ketoprofen (2 mg/kg, s.c.), or fulnixin (1 mg/kg, s.c.) was administered once daily at 10 a.m. after a morning meal or without a morning meal (fasted condition) for 3 - 7 days. Gastrointestinal lesions were examined 24 h after the final dose of the drugs. When indomethacin (3 mg/kg) was administered after a morning meal (fed condition) for 7 days, it produced many lesions in the small intestine. However, when it was given in the fasted condition without the morning meal, the lesions were markedly decreased. All the NSAIDs given after feeding of regular dry food containing 6% DF once a day for 3 days produced many lesions in the small intestine. The lesions were decreased or increased in dogs given prescription diets containing low DF (1.1%) and high DF (15.4%), respectively. Furthermore, lesions were not observed in dogs given canned diet containing very low DF (< 0.1%), whereas lesions appeared again in dogs given canned diet supplemented with cellulose (3 or 10%) but not with pectin (10%). These results suggested that both feeding condition and insoluble DF, such as cellulose in the diet, play an important role in the formation of NSAID-induced small intestinal lesions, and that a diet with no or low amounts of DF may decrease gastrointestinal side-effects associated with the use of NSAIDs. PMID- 27779478 TI - The effect of the angiotensin II receptor, type 1 receptor antagonists, losartan and telmisartan, on thioacetamide-induced liver fibrosis in rats. AB - It has been reported previously that the density of angiotensin II receptors is increased in the rat liver in experimentally-induced fibrosis. We hypothesized that pharmacological blockade of angiotensin receptors may produce beneficial effects in models of liver fibrosis. In this study, we used the widely used thioacetamide (TAA)-induced model of liver fibrosis (300 mg/L TAA ad libitum for 12 weeks). Rats received daily injections (i.p), lasting 4 weeks of the angiotensin II type 1 receptor antagonists, losartan 30 mg/kg (TAA + L) or telmisartan 10 mg/kg (TAA + T) and were compared to rat that received TAA alone. Chronic treatment with losartan and telmisartan was associated with a significant reduction in the activity of alkaline phosphatase, and decreased concentrations of tumor necrosis factor-alpha and transforming growth factor beta-1 compared to controls. We also found a significant reduction interleukin-6 in rats receiving telmisartan (P < 0.05) but not losartan. Both treatments increased the concentration of liver glutathione along with a concomitant decrease of GSSG compared to controls. In addition, increased paraoxonase 1 activity was observed in the serum of rats receiving telmisartan group compared to the TAA alone controls. Finally, histological evaluation of liver sections revealed losartan and telmisartan treatment was associated with reduced inflammation and liver fibrosis. Taken together, these results indicate that both telmisartan and losartan have anti-inflammatory and anti-oxidative properties in the TAA model of liver fibrosis. These finding add support to a growing body of literature indicating a potentially important role for the angiotensin system in liver fibrosis and indicate angiotensin antagonists may be useful agents for fibrosis treatment. PMID- 27779479 TI - Pronociceptive effects induced by cutaneous application of a transient receptor potential ankyrin 1 (TRPA1) channel agonist methylglyoxal in diabetic animals: comparison with tunicamycin-induced endoplastic reticulum stress. AB - Methylglyoxal (MG) is a reactive carbonyl compound generated in diabetes mellitus. MG is an established transient receptor potential ankyrin 1 (TRPA1) channel agonist that contributes to TRPA1-mediated diabetic pain hypersensitivity. Here we studied whether exposure to diabetes and thereby to elevated endogenous MG modulates hypersensitivity induced by intradermal MG. Moreover, since diabetes induces endoplasmic reticulum (ER) stress, we compared the role of TRPA1 in diabetes and ER stress by assessing whether tunicamycin induced ER stress, without diabetes, produces TRPA1-mediated pain hypersensitivity and by assessing whether ER stress and diabetes have similar modulatory effects on MG-induced hypersensitivity. In vitro patch clamp recording was performed to assess whether tunicamycin is a TRPA1 agonist. Behavioral tests showed that mechanical hypersensitivity induced by MG is reduced in diabetes and ER stress. In healthy controls, hypersensitivity induced by MG was reduced when MG was administered for the second time in the same but not adjacent plantar sites. Hypersensitivity induced by ER stress was reversed by pharmacological blocking of TRPA1. In vitro patch clamp recording indicated that tunicamycin itself (30 MUM) is not a TRPA1 agonist. The results indicate that pain hypersensitivity induced by non-diabetic ER stress as well as that induced by diabetes is mediated TRPA1. Reduction of MG-induced hypersensitivity in diabetes or ER stress may, at least partly, be explained by peripheral mechanisms. PMID- 27779480 TI - Involvement of corticotropin-releasing factor receptors type 2, located in periaquaductal gray matter, in central and peripheral CRF-induced analgesic effect on somatic pain sensitivity in rats. AB - Corticotropin-releasing factor (CRF) is involved in the regulation of pain sensitivity and can induce an analgesic effect in animals and humans. The periaqueductal gray matter (PAGM) of the midbrain is one of the key structures of the antinociceptive system. The aim of the study was to investigate the involvement of CRF receptor type 2 (CRF-R2 receptors), localized in the PAGM, in the analgesic effect caused by central or systemic CRF on somatic pain sensitivity in conscious rats. Somatic pain sensitivity was tested by a tail flick test (measuring tail flick latency induced by tail's thermal stimulation). The involvement of CRF-R2 receptors was studied by administering the selective antagonist astressin2-B into the PAGM. Both peripheral and central CRF administration caused an increase in tail flick latencies (analgesic effect). Administration of astressin2-B into the PAGM attenuated the analgesic effect induced by the central as well as systemic CRF administration. The results suggest that one of the mechanisms of the CRF-induced analgesic effect may be mediated by CRF-R2 receptors located in PAGM. PMID- 27779481 TI - A novel non-opioid binding site for endomorphin-1. AB - Endomorphins are natural amidated opioid tetrapeptides with the following structure: Tyr-Pro-Trp-Phe-NH2 (endomorphin-1), and Tyr-Pro-Phe-Phe-NH2 (endomorphin-2). Endomorphins interact selectively with the MU-opioid or MOP receptors and exhibit nanomolar or sub-nanomolar receptor binding affinities, therefore they suggested to be endogenous agonists for the MU-opioid receptors. Endomorphins mediate a number of characteristic opioid effects, such as antinociception, however there are several physiological functions in which endomorphins appear to act in a fashion that does not involve binding to and activation of the MU-opioid receptor. Our recent data indicate that a radiolabelled [3H]endomorphin-1 with a specific radioactivity of 2.35 TBq/mmol - prepared by catalytic dehalogenation of the diiodinated peptide precursor in the presence of tritium gas - is able to bind to a second, naloxone insensitive recognition site in rat brain membranes. Binding heterogeneity, i.e., the presence of higher (Kd = 0.4 nM / Bmax = 120 fmol/mg protein) and lower (Kd = 8.2 nM / Bmax = 432 fmol/mg protein) affinity binding components is observed both in saturation binding experiments followed by Schatchard analysis, and in equilibrium competition binding studies. The signs of receptor multiplicity, e.g., curvilinear Schatchard plots or biphasic displacement curves are seen only if the non-specific binding is measured in the presence of excess unlabeled endomorphin-1 and not in the presence of excess unlabeled naloxone. The second, lower affinity non-opioid binding site is not recognized by heterocyclic opioid alkaloid ligands, neither agonists such as morphine, nor antagonists such as naloxone. On the contrary, endomorphin-1 is displaced from its lower affinity, higher capacity binding site by several natural neuropeptides, including methionine-enkephalin-Arg-Phe, nociceptin-orphanin FQ, angiotensin and FMRF amide. This naloxone-insensitive, consequently non-opioid binding site seems to be present in nervous tissues carrying low density or no MU-opioid receptors, such as rodent cerebellum, or brain of MU-opioid receptor deficient (MOPr-/-) transgenic or 'knock-out' (K.O.) mice. The newly described non-opioid binding component is not coupled to regulatory G-proteins, nor does it affect adenylyl cyclase enzyme activity. Taken together endomorphin-1 carries opioid and, in addition to non-opioid functions that needs to be taken into account when various effects of endomorphin-1 are evaluated in physiological or pathologic conditions. PMID- 27779482 TI - Influence of premedication with alprazolam on the occurence of obstructive apneas. A prospective randomized double-blind study. AB - Postoperative development or worsening of obstructive sleep apnea is a potential complication of anesthesia. The objective of this study was to study the effects of a premedication with alprazolam on the occurrence of apneas during the immediate postoperative period. Fifty ASA 1 - 2 patients undergoing a colonoscopy were recruited. Patients with a history of obstructive sleep apnea (OSA) were excluded. Recruited patients were randomly assigned to one of two groups: in Group A, they received 0.5 mg of alprazolam orally one hour before the procedure; and in Group C, they received placebo. Anesthesia technique was identical in both groups. Patients were monitored during the first two postoperative hours to establish their AHI (apnea hypopnea index, the number of apneas and hypopneas per hour). Nine patients were excluded (4 in group A and 5 in group C) due to technical problems or refusal. Interestingly, premedication by alprazolam did not change intra-operative propofol requirements. During the first two postoperative hours, the AHI was significantly higher in group A than in group C (Group A: 20.33 +/- 10.97 h-1, C: 9.63 +/- 4.67 h-1). These apneas did not induce significant arterial oxygen desaturation, or mandibular instability. Our study demonstrates that a premedication with 0.5 mg of alprazolam doesn't modify intra operative anesthetic requirements during colonoscopy, but is associated with a higher rate of obstructive apneas during at least three and a half hours after ingestion. No severe side effects were observed in our non-obese population. Our results must be confirmed on a larger scale. PMID- 27779483 TI - The influence of resiniferatoxin on the chemical coding of caudal mesenteric ganglion neurons supplying the urinary bladder in the pig. AB - Resiniferatoxin (RTX) is used as experimental drug therapy for a range of neurogenic urinary bladder disorders. The present study investigated the chemical coding of caudal mesenteric ganglion (CaMG) neurons supplying the porcine urinary bladder after intravesical RTX instillation. The CaMG neurons were visualized with retrograde tracer Fast Blue (FB) and their chemical profile was disclosed with double-labelling immunohistochemistry using antibodies against tyrosine hydroxylase (TH), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), calbindin (CB), galanin (GAL) and neuronal nitric oxide synthase (nNOS). It was found that in both the control (n = 6) and RTX-treated pigs (n = 6), the vast majority (92.3 +/- 2.7% and 93.1 +/- 1.3%, respectively) of FB-positive (FB+) nerve cells were TH+. Intravesical instillation of RTX caused a decrease in the number of FB+ / TH + neurons immunopositive to NPY (91.0 +/- 2.2% in control animals vs. 58.8 +/- 5.0% in RTX-treated pigs) or VIP (1.7 +/ 0.5% vs. 0%) and an increase in the number of FB+ / TH+ neurons immunoreactive to SOM (3.4 +/- 1.5% vs. 20.6 +/- 4.3%), CB (1.8 +/-0.7% vs. 13.4 +/- 2.3%), GAL (1.5 +/- 0.6% vs. 7.5 +/- 1.0%) or nNOS (0% vs. 10.9 +/- 3.4%). The present results suggest that therapeutic effects of RTX on the mammalian urinary bladder can be partly mediated by CaMG neurons. PMID- 27779484 TI - Intravenous Acetaminophen for Renal Colic in the Emergency Department: Where Do We Stand? AB - BACKGROUND: The efficacy, safety, opioid-sparing effects, and cost-benefit analyses of intravenous (IV) acetaminophen (APAP) in treating renal colic remain controversial. STUDY QUESTION: To evaluate the safety, efficacy, opioid-sparing effects, and cost-benefits of IV APAP in patients who present with renal colic in the emergency department (ED). DATA SOURCES: We systematically searched PubMed (January 1970 to April 2016). STUDY DESIGN: Randomized controlled trials which evaluated IV APAP for renal colic in the ED were eligible. The clinical outcomes measured were change in pain scores from baseline, incidence of adverse events, use of rescue analgesia, and cost-benefits. Forest plots were constructed using the Mantel-Haenszel method in a random effect model to changes in pain scores from the baseline to designated intervals. RESULTS: The analysis suggested a difference in pain reduction favoring IV APAP over morphine. IV APAP had a significant effect in pain reduction than IV morphine (difference in mean pain score reduction = 7.5 in a 100-point visual analog scale (VAS); 95% confidence interval [CI], 1.99-13.00; P = 0.008). There was mild-to-moderate study heterogeneity (I = 42%). No difference was observed when IV APAP was compared with intramuscular piroxicam for pain reduction (difference in mean pain score reduction = 0.17 in a VAS reduction >=50% VAS; 95% CI, -0.22 to 0.57) and to intramuscular diclofenac (difference in mean pain score reduction = 0.00 in a numeric rating scale reduction >=50%; 95% CI, -0.12 to 0.12). The analysis for nonsteroidal anti-inflammatory drugs versus IV APAP revealed no difference (difference in mean pain score reduction = 0.01 in a 100-point VAS; 95% CI, -0.10 to 0.13; P = 0.80). CONCLUSIONS: In this meta-analysis, we found that data on the efficacy, safety, opioid-sparing effects, and cost-benefit analyses of IV APAP for renal colic were weak. Based on the available data, IV APAP should not be considered as an alternative to opioids or nonsteroidal anti-inflammatory drugs for the primary management of renal colic in the ED. PMID- 27779485 TI - Multiple Scattered Purpuric Vesicles: Answer. PMID- 27779487 TI - If Cellular Blue Melanocytic Lesions Do Not Form a Spectrum.... PMID- 27779486 TI - Necrotizing Infundibular Crystalline Folliculitis (NICF) Induced by Anti-Tumoral Therapies: Report of 2 Cases. AB - Necrotizing Infundibular Crystalline Folliculitis (NICF) is rare entity of unknown pathogenesis presenting as follicular crystalline papules arising in seborrheic areas. We report 2 cases of NICF in patients under targeted therapy for metastatic adenocarcinoma. In one case, the lesions reappeared cyclically every 3 weeks after each injection and in the other case, lesions persisted until disruption of the continuous oral therapy. Punch-biopsies demonstrated folliculitis with a plugging crystalline material associated with either bacteria or yeast. These are the first descriptions of drug-induced NICF. PMID- 27779489 TI - An Unusual Cause of Talipes Equinovarus: Agenesis of Leg Muscles. PMID- 27779488 TI - Venous Thromboembolism as Predictor of Acute Care Hospital Transfer and Inpatient Rehabilitation Length of Stay. AB - OBJECTIVE: The aim of this study was to investigate the impact of venous thromboembolism (VTE) on rate of acute care hospital transfer, inpatient rehabilitation (IPR) length of stay (LOS), and functional outcomes. DESIGN: This was a retrospective cohort study of 2312 consecutive patient discharges from a single IPR facility over an 18-month period. RESULTS: When age, sex, reason for admission, and admission Functional Independence Measure (FIM) scores were controlled for, those with VTE had nearly 2 times greater odds for transfer to acute care hospital than did those without a diagnosis of VTE. Inpatient rehabilitation LOS was 4.700 days (95% confidence interval [CI], 2.956-6.445 days) longer for those with a diagnosis of VTE prior to IPR admission and 2.287 days (95% CI, 1.026-3.547 days) longer for those with a diagnosis of VTE during IPR admission compared with those without a diagnosis of VTE. There was no difference in FIM change based on VTE diagnosis. Venous thromboembolism diagnosis during IPR was associated with a significant decrease in FIM efficiency (-0.358; 95% CI, -0.654 to -0.062) if diagnosed during IPR admission, but there was no difference in FIM efficiency if VTE was diagnosed prior to IPR. CONCLUSIONS: Patients with a diagnosis of VTE were more likely to be transferred to the acute care hospital and have longer IPR LOS independent of admission FIM scores. It is important to prevent development of VTE. TO CLAIM CME CREDITS: Complete the self assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) understand the association of venous thromboembolism (VTE) diagnosis with acute hospital transfer and inpatient rehabilitation length of stay; (2) identify reasons for acute hospital transfer in patients diagnosed with VTE; and (3) understand the relationship between VTE diagnosis and functional outcomes during inpatient rehabilitation. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 27779490 TI - Paraplegia Following Lumbar Epidural Steroid Injection in a Patient With a Spinal Dural Arteriovenous Fistula. AB - We report a patient with a previously undiagnosed spinal dural arteriovenous fistula (SDAVF) who became acutely paraplegic following a lumbar epidural steroid injection for lumbar spinal stenosis. Magnetic resonance imaging showed multiple flow voids and serpentine vessels on the cord surface with cord edema extending from T3 through the conus. Spinal angiography confirmed an SDAVF fed by the left lateral sacral artery, which was subsequently endovascularly embolized, and the patient had a partial return of function. Presence of an undiagnosed SDAVF should be considered in patients presenting with lower-extremity weakness without pain and considered a contraindication to lumbar epidural steroid injection. PMID- 27779491 TI - The Effect of Omeprazole Usage on the Viability of Random Pattern Skin Flaps in Rats. AB - BACKGROUND: Necrosis of random pattern flaps caused by inadequate blood flow, especially in the distal part of the flap is one of the biggest challenges in reconstructive surgery. Various agents have been used to prevent flap ischemia. In this study, we used omeprazole, which is a potent inhibitor of gastric acidity to increase flap viability. METHODS: In this study, 35 Wistar-Albino type rats which were divided into 5 equal groups were used. Random-pattern dorsal skin flaps were raised in all groups at seventh day of the study. Group 1 was accepted as control group, and the rats in this group was only given distilled water intraperitoneally for 14 days. Group 2 and group 3 received 10 and 40 mg/kg omeprazole daily for 14 days, respectively. Group 4 and group 5 were given distilled water for the first 7 days and then after the operations they received 10 and 40 mg/kg omeprazole daily for 7 days, respectively. Survival rates of the flaps were examined seventh day after elevation of the flaps by digital imaging and scintigraphy. After assessment of the amount of necrosis, number of vascular structures were counted histopathologically. RESULTS: Percentage of flap necrosis was found to be less in all omeprazole received groups. On digital imaging, percentages of flap necrosis in the study groups were statistically significantly lower than that of the control group (P < 0.001), but there was no significant difference between the study groups (P > 0.05).In the histopathologic specimens, it was detected that the mean number of vessels in proximal (a) and distal (c) portions of the flap in the study groups showed a significant increase when compared with the control group (P < 0.01 for groups 2, 4 and 5, and P < 0.05 for group 3). CONCLUSIONS: In conclusion, possible clinical usage of medications increasing gastrin during flap surgeries can be thought as a positive contributor. In this sense, this study showed that parenteral administration of omeprazole in skin flap surgery increases flap viability possibly by increasing gastrin levels. PMID- 27779492 TI - Willingness to Be a Brain Donor: A Survey of Research Volunteers From 4 Racial/Ethnic Groups. AB - INTRODUCTION: Racial and ethnic groups are under-represented among research subjects who assent to brain donation in Alzheimer disease research studies. There has been little research on this important topic. Although there are some studies that have investigated the barriers to brain donation among African American study volunteers, there is no known research on the factors that influence whether or not Asians or Latinos are willing to donate their brains for research. METHODS: African American, Caucasian, Asian, and Latino research volunteers were surveyed at 15 Alzheimer Disease Centers to identify predictors of willingness to assent to brain donation. RESULTS: Positive predictors included older age, Latino ethnicity, understanding of how the brain is used by researchers, and understanding of what participants need to do to ensure that their brain will be donated. Negative predictors included African/African American race, belief that the body should remain whole at burial, and concern that researchers might not be respectful of the body during autopsy. DISCUSSION: The predictive factors identified in this study may be useful for researchers seeking to increase participation of diverse ethnic groups in brain donation. PMID- 27779493 TI - Participation of hippocampal nitric oxide synthase and soluble guanylate cyclase in the modulation of behavioral responses elicited by the rat forced swimming test. AB - Systemic or hippocampal administration of nitric oxide (NO) synthase inhibitors induces antidepressant-like effects in animals, implicating increased hippocampal levels of NO in the neurobiology of depression. However, the role played by different NO synthase in this process has not been clearly defined. As stress is able to induce neuroinflammatory mechanisms and trigger the expression of inducible nitric oxide synthase (iNOS) in the brain, as well as upregulate neuronal nitric oxide synthase (nNOS) activity, the aim of the present study was to investigate the possible differential contribution of hippocampal iNOS and nNOS in the modulation of the consequences of stress elicited by the forced swimming test. Male Wistar rats received intrahippocampal injections, immediately after the pretest or 1 h before the forced swimming test, of selective inhibitors of nNOS (N-propyl-L-arginine), iNOS (1400W), or sGC (ODQ), the main pharmacological target for NO. Stress exposure increased nNOS and phospho-nNOS levels at all time points, whereas iNOS expression was increased only 24 h after the pretest. All drugs induced an antidepressant-like effect. However, whereas the nNOS inhibitor was equally effective when injected at different times, the iNOS inhibitor was more effective 24 h after the pretest. These results suggest that hippocampal nNOS and iNOS contribute to increase in NO levels in response to stress, although with a differential time course after stress exposure. PMID- 27779494 TI - Lymphocyte-monocyte ratio at admission predicts possible outcomes in patients with acute-on-chronic liver failure. AB - BACKGROUND: The lymphocyte-monocyte ratio (LMR) in the peripheral blood is suggested to be a potential biomarker for predicting the clinical outcomes of several diseases. We aimed to evaluate the relative efficiency of LMR for predicting 3-month mortality in patients with acute-on-chronic liver failure (AoCLF). PATIENTS AND METHODS: In this study, 74 chronic hepatitis B patients, 90 AoCLF patients, and 70 healthy controls were followed up for 4 months. The primary endpoint was 3-month in-hospital mortality. Hematological and virological parameters as well as liver biochemistry were determined using blood samples ordered upon admission. A panel of clinical and biochemical variables were analyzed for potential associations with outcomes using Cox proportional hazards and multiple regression models. RESULTS: A significantly lower LMR was detected in AoCLF patients than in healthy controls and chronic hepatitis B groups (both P=0.001). The LMR inversely correlated with model for end-stage liver disease scores, and a lower LMR was associated with increased 3-month mortality. Multivariate analysis suggested that both LMR and model for end-stage liver disease scores were independent predictors of 3-month mortality (P<0.01). CONCLUSION: A low LMR measured at admission is predictive of a poor prognosis in AoCLF patients. PMID- 27779495 TI - Exploring NICU Nurses' Affective Responses to End-of-Life Care. AB - BACKGROUND: The survival rate for infants born with life-threatening problems has improved greatly over the last few decades. Nevertheless, infants still die in neonatal intensive care units (NICUs) every day. Despite existing standards of care, some aspects of end-of-life care (EOLC) are still not delivered consistently. Little is known about how NICU nurses' individual experiences affect EOLC. PURPOSE: The purpose of this study was to explore, through lived and told stories, the affective, interactional, and meaning-related responses that NICU nurses have while caring for dying infants and their families. Coping strategies and changes in practice were also explored. METHODS: Thirty-six members of the National Association of Neonatal Nurses submitted written narratives about an EOLC experience during which the nurse experienced strong emotions. FINDINGS: Narrative analysis revealed many affective responses, but 3 were the most frequent: responsibility, moral distress, and identification. Coping methods included healthy and less healthy strategies, such as colleague support, informal and formal debriefing, practicing intentional gratefulness, avoidance, and compartmentalization. Changes in practice identified were universally described as professional growth through the use of reflective practice. IMPLICATIONS FOR PRACTICE & RESEARCH: Educators should discuss the range of emotions experienced by caregivers related to EOLC and healthy coping strategies and encourage the use of reflective practice as a facilitator of professional growth. Nurse leaders should promote supportive environments in NICUs and ensure debriefing opportunities for nurses who have recently cared for a dying infant. Future research should focus on formulating interventions to utilize debriefing with NICU nurses and perhaps the development of EOLC mentors. PMID- 27779496 TI - Reducing HIV Racial/Ethnic Disparities: What's Good Data Got to Do with It? PMID- 27779498 TI - Bayesian Approaches to Racial Disparities in HIV Risk Estimation Among Men Who Have Sex with Men. AB - BACKGROUND: Men who have sex with men (MSM) continue to be overrepresented for new HIV infections compared with non-MSM. This disparity becomes even more alarming when considering racial groups. We describe the race-specific effects in HIV prevalence among MSM relative to non-MSM and explore the causes of disagreement among estimates. METHODS: We used data from the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative longitudinal survey conducted in the US Bayesian learning corrected for potential misclassification of MSM status and adjusted for residual confounding, hypothesized to explain the MSM racial disparity in HIV. We articulated the structure and strength of the latent confounders that would make race-specific risk gradients equivalent. RESULTS: Compared with non-MSM, the adjusted prevalence odds ratio (POR) and 95% credible interval for black MSM having self-reported HIV infection was 5.8 (2.0, 16), while the POR for white MSM was 12 (4.2, 31). For all MSM, the POR for HIV infection was 9.3 (3.6, 23) with black men having 2.6 times the odds of prevalent infection compared with white men. CONCLUSIONS: The observed race-specific associations in MSM are likely not due to misclassification alone, but represent a constellation of factors that differ between racial groups. We recommend specific risk factors in surveys needed to further identify the behavioral characteristics that lead to the observed differences when the estimates are stratified by race. PMID- 27779497 TI - Variable Selection for Confounding Adjustment in High-dimensional Covariate Spaces When Analyzing Healthcare Databases. AB - BACKGROUND: Data-adaptive approaches to confounding adjustment may improve performance beyond expert knowledge when analyzing electronic healthcare databases and have additional practical advantages for analyzing multiple databases in rapid cycles. Improvements seemed possible if outcome predictors were reliably identified empirically and adjusted. METHODS: In five cohort studies from diverse healthcare databases, we implemented a base-case high dimensional propensity score algorithm with propensity score decile-adjusted outcome models to estimate treatment effects among prescription drug initiators. The original variable selection procedure based on the estimated bias of each variable using unadjusted associations between confounders and exposure (RRCE) and disease outcome (RRCD) was augmented by alternative strategies. These included using increasingly adjusted RRCD estimates, including models considering >1,500 variables jointly (Lasso, Bayesian logistic regression); using prediction statistics or likelihood-ratio statistics for covariate prioritization; directly estimating the propensity score with >1,500 variables (Lasso, Bayesian regression); or directly fitting an outcome model using all covariates jointly (Lasso, Ridge). RESULTS: In five example studies, most tested augmentations of the base-case hdPS did not meaningfully change estimates in light of wide confidence intervals except for Bayesian regression and Lasso to estimate RRCD, which moved estimates minimally closer to the expectation in three of five examples. The direct outcome estimation with Lasso performed worst. CONCLUSION: Overall, the basic heuristic of variable reduction in high-dimensional propensity score adjustment performed, as well as alternative approaches in diverse settings. Minor improvements in variable selection may be possible using Bayesian outcome regression to prioritize variables for propensity score estimation when outcomes are rare. See video abstract at, http://links.lww.com/EDE/B162. PMID- 27779499 TI - An Overview of the Innate and Adaptive Immune System in Inflammatory Bowel Disease. AB - Inflammatory bowel diseases (IBDs) are thought to develop as a result of complex interactions between host genetics, the immune system and the environment including the gut microbiome. Although an improved knowledge of the immunopathogenesis of IBDs has led to great advances in therapy such as the highly effective anti-tumor necrosis factor class of medications, a significant proportion of patients with Crohn's disease and ulcerative colitis do not respond to anti-tumor necrosis factor antibodies. Further understanding of the different immune pathways involved in the genesis of chronic intestinal inflammation is required to help find effective treatments for IBDs. In this review, the role of the mucosal innate and adaptive immune system in IBD is summarized, highlighting new areas of discovery which may hold the key to identifying novel predictive or prognostic biomarkers and new avenues of therapeutic discovery. PMID- 27779500 TI - Overground gait training using a motorized assistive device in patients with severe disabilities after stroke. AB - Regaining of the patient's ability to walk after stroke is an important goal of rehabilitation programmes. The ultimate goal of gait rehabilitation is to empower patients for overground walking. We have previously developed a prototype of a therapist-controlled mobile platform with compliant pelvis support mechanism that enables balance training during overground walking (device E-go). The aim of this pilot randomized controlled study was to explore the usefulness of the E-go in reducing the number of therapists needed during walking training, and to explore the effectiveness of the E-go on walking abilities in severely affected stroke patients. The study included 19 subacute poststroke patients divided into two groups. The experimental group (nine patients) trained to walk with the E-go and the control group trained within conventional physiotherapy programs for 3 weeks. Outcome measures were walking distance and speed, Fugl-Meyer Assessment, Berg Balance Scale, Functional Ambulation Category and the number of therapists needed during training. At the end of the training both groups significantly improved in walking speed, walking distance, Berg Balance Scale and Fugl-Meyer Assessment (P<=0.001), but there were no between-group differences. The experimental group on average needed a lower number of therapists (P=0.040). These findings highlight the potential of the E-go for overground walking training in severely disabled subacute stroke patients. PMID- 27779501 TI - Foreword: Characteristics of RIME Papers That Make the Cut. PMID- 27779504 TI - Scholarly Conversations in Medical Education. AB - This supplement includes the eight research papers accepted by the 2016 Research in Medical Education Program Planning Committee. In this Commentary, the authors use "conversations in medical education" as a guiding metaphor to explore what these papers contribute to the current scholarly discourse in medical education. They organize their discussion around two domains: the topic of study and the methodological approach. The authors map the eight research papers to six "hot topics" in medical education: (1) curriculum reform, (2) duty hours restriction, (3) learner well-being, (4) innovations in teaching and assessment, (5) self regulated learning, and (6) learning environment, and to three purposes commonly served by medical education research: (1) description, (2) justification, and (3) clarification. They discuss the range of methods employed in the papers. The authors end by encouraging educators to engage in these ongoing scholarly conversations. PMID- 27779505 TI - Scholarly Concentration Program Development: A Generalizable, Data-Driven Approach. AB - PURPOSE: Scholarly concentration programs-also known as scholarly projects, pathways, tracks, or pursuits-are increasingly common in U.S. medical schools. However, systematic, data-driven program development methods have not been described. METHOD: The authors examined scholarly concentration programs at U.S. medical schools that U.S. News & World Report ranked as top 25 for research or primary care (n = 43 institutions), coding concentrations and mission statements. Subsequently, the authors conducted a targeted needs assessment via a student led, institution-wide survey, eliciting learners' preferences for 10 "Pathways" (i.e., concentrations) and 30 "Topics" (i.e., potential content) augmenting core curricula at their institution. Exploratory factor analysis (EFA) and a capacity optimization algorithm characterized best institutional options for learner focused Pathway development. RESULTS: The authors identified scholarly concentration programs at 32 of 43 medical schools (74%), comprising 199 distinct concentrations (mean concentrations per program: 6.2, mode: 5, range: 1-16). Thematic analysis identified 10 content domains; most common were "Global/Public Health" (30 institutions; 94%) and "Clinical/Translational Research" (26 institutions; 81%). The institutional needs assessment (n = 468 medical students; response rate 60% overall, 97% among first-year students) demonstrated myriad student preferences for Pathways and Topics. EFA of Topic preferences identified eight factors, systematically related to Pathway preferences, informing content development. Capacity modeling indicated that offering six Pathways could guarantee 95% of first-year students (162/171) their first- or second-choice Pathway. CONCLUSIONS: This study demonstrates a generalizable, data-driven approach to scholarly concentration program development that reflects student preferences and institutional strengths, while optimizing program diversity within capacity constraints. PMID- 27779506 TI - Differential Weighting for Subcomponent Measures of Integrated Clinical Encounter Scores Based on the USMLE Step 2 CS Examination: Effects on Composite Score Reliability and Pass-Fail Decisions. AB - PURPOSE: Medical schools administer locally developed graduation competency examinations (GCEs) following the structure of the United States Medical Licensing Examination Step 2 Clinical Skills that combine standardized patient (SP)-based physical examination and the patient note (PN) to create integrated clinical encounter (ICE) scores. This study examines how different subcomponent scoring weights in a locally developed GCE affect composite score reliability and pass-fail decisions for ICE scores, contributing to internal structure and consequential validity evidence. METHOD: Data from two M4 cohorts (2014: n = 177; 2015: n = 182) were used. The reliability of SP encounter (history taking and physical examination), PN, and communication and interpersonal skills scores were estimated with generalizability studies. Composite score reliability was estimated for varying weight combinations. Faculty were surveyed for preferred weights on the SP encounter and PN scores. Composite scores based on Kane's method were compared with weighted mean scores. RESULTS: Faculty suggested weighting PNs higher (60%-70%) than the SP encounter scores (30%-40%). Statistically, composite score reliability was maximized when PN scores were weighted at 40% to 50%. Composite score reliability of ICE scores increased by up to 0.20 points when SP-history taking (SP-Hx) scores were included; excluding SP Hx only increased composite score reliability by 0.09 points. Classification accuracy for pass-fail decisions between composite and weighted mean scores was 0.77; misclassification was < 5%. CONCLUSIONS: Medical schools and certification agencies should consider implications of assigning weights with respect to composite score reliability and consequences on pass-fail decisions. PMID- 27779507 TI - Professionalism in the Twilight Zone: A Multicenter, Mixed-Methods Study of Shift Transition Dynamics in Surgical Residencies. AB - PURPOSE: Duty hours rules sparked debates about professionalism. This study explores whether and why general surgery residents delay departures at the end of a day shift in ways consistent with shift work, traditional professionalism, or a new professionalism. METHOD: Questionnaires were administered to categorical residents in 13 general surgery programs in 2014 and 2015. The response rate was 76% (N = 291). The 18 items focused on end-of-shift behaviors and the frequency and source of delayed departures. Follow-up interviews (N = 39) examined motives for delayed departures. The results include means, percentages, and representative quotations from the interviews. RESULTS: A minority (33%) agreed that it is routine and acceptable to pass work to night teams, whereas a strong majority (81%) believed that residents exceed work hours in the name of professionalism. Delayed departures were ubiquitous: Only 2 of 291 residents were not delayed for any of 13 reasons during a typical week. The single most common source of delay involved a desire to avoid the appearance of dumping work on fellow residents. In the interviews, residents expressed a strong reluctance to pass work to an on-call resident or night team because of sparse night staffing, patient ownership, an aversion to dumping, and the fear of being seen as inefficient. CONCLUSIONS: Resident behavior is shaped by organizational and cultural contexts that require attention and reform. The evidence points to the stunted development of a new professionalism, little role for shift-work mentalities, and uneven expression of traditional professionalism in resident behavior. PMID- 27779509 TI - The Learning Environment Counts: Longitudinal Qualitative Analysis of Study Strategies Adopted by First-Year Medical Students in a Competency-Based Educational Program. AB - PURPOSE: The move toward competency-based education will require medical schools and postgraduate training programs to restructure learning environments to motivate trainees to take personal ownership for learning. This qualitative study explores how medical students select and implement study strategies while enrolled in a unique, nontraditional program that emphasizes reflection on performance and competence rather than relying on high-stakes examinations or grades to motivate students to learn and excel. METHOD: Fourteen first-year medical students volunteered to participate in three, 45-minute interviews (42 overall) scheduled three months apart during 2013-2014. Two medical educators used structured interview guides to solicit students' previous assessment experiences, preferred learning strategies, and performance monitoring processes. Interviews were digitally recorded and transcribed verbatim. Participants confirmed accuracy of transcripts. Researchers independently read transcripts and met regularly to discuss transcripts and judge when themes achieved saturation. RESULTS: Medical students can adopt an assessment for learning mind-set with faculty guidance and implement appropriate study strategies for mastery-learning demands. Though students developed new strategies at different rates during the year, they all eventually identified study and performance monitoring strategies to meet learning needs. Students who had diverse learning experiences in college embraced mastery-based study strategies sooner than peers after recognizing that the learning environment did not reward performance-based strategies. CONCLUSIONS: Medical students can take ownership for their learning and implement specific strategies to regulate behavior when learning environments contain building blocks emphasized in self-determination theory. Findings should generalize to educational programs seeking strategies to design learning environments that promote self-regulated learning. PMID- 27779508 TI - "Staying in the Game": How Procedural Variation Shapes Competence Judgments in Surgical Education. AB - PURPOSE: Emerging research explores the educational implications of practice and procedural variation between faculty members. The potential effect of these variations on how surgeons make competence judgments about residents has not yet been thoroughly theorized. The authors explored how thresholds of principle and preference shaped surgeons' intraoperative judgments of resident competence. METHOD: This grounded theory study included reanalysis of data on the educational role of procedural variations and additional sampling to attend to their impact on assessment. Reanalyzed data included 245 hours of observation across 101 surgical cases performed by 29 participants (17 surgeons, 12 residents), 39 semistructured interviews (33 with surgeons, 6 with residents), and 33 field interviews with residents. The new data collected to explore emerging findings related to assessment included two semistructured interviews and nine focused field interviews with residents. Data analysis used constant comparison to refine the framework and data collection process until theoretical saturation was reached. RESULTS: The core category of the study, called staying in the game, describes how surgeons make moment-to-moment judgments to allow residents to retain their role as operators. Surgeons emphasized the role of principles in making these decisions, while residents suggested that working with surgeons' preferences also played an important role in such intraoperative assessment. CONCLUSIONS: These findings suggest that surgeons' and residents' work with thresholds of principle and preference have significant implications for competence judgments. Making use of these judgments by turning to situated assessment may help account for the subjectivity in assessment fostered by faculty variations. PMID- 27779510 TI - Individual and Institutional Components of the Medical School Educational Environment. AB - PURPOSE: To examine, using a systems framework, the relative influence of individual-level and institution-level factors on student perceptions of the medical school educational environment. METHOD: A series of hierarchical linear models were fit to a large, 18-school longitudinal dataset of student perceptions of the educational environment, various demographics, and student empathy, tolerance of ambiguity, coping, and patient-provider orientation. Separate models were evaluated for individual-level factors alone, institution-level factors alone, and the combination of individual- and institution-level factors. RESULTS: The individual-level model accounted for 56.7% of the variance in student perceptions of the educational environment. However, few specific variables at the individual level had noteworthy direct effects on these perceptions. Similarly, the institution-level model accounted for 10.3% of the variance in student perceptions, but the specific characteristics of the institution explained little of this impact. The combined individual- and institution-level model attributed 45.5% of the variance in student perceptions to individual-level factors and 10.8% to institution-level factors. Again, specific variables explained little of this impact. CONCLUSIONS: These findings indicate that the impact of individual-level factors on perceptions of the educational environment is about four times greater than institution-level factors. This contrast reflects the fact that the educational environment is defined through a learner, not institutional lens. Nonetheless, institutions vary in learner perceptions of their environments, and these differences may provide some support for institutional initiatives to improve the educational environment. More broadly, these results evidence the complexity of the educational environment, both in defining it and in understanding its dynamics. PMID- 27779511 TI - The Impact of Emotion on Learners' Application of Basic Science Principles to Novel Problems. AB - PURPOSE: Training to become a physician is an emotionally laden experience. Research in cognitive psychology indicates that emotions can influence learning and performance, but the materials used in such research (e.g., word lists) rarely reflect the complexity of material presented in medical school. The present study examined whether emotions influence learning of basic science principles. METHOD: Fifty-five undergraduate psychology students were randomly assigned to write about positive, negative, or neutral life events for nine minutes. Participants were then taught three physiological concepts, each in the context of a single organ system. Testing consisted of 13 clinical cases, 7 presented with the same concept/organ system pairing used during training ("near transfer") and 6 with novel pairings ("far transfer"). Testing was repeated after one week with 13 additional cases. RESULTS: Forty-nine students provided complete data. Higher test scores were found when the concept/organ system pairing was held constant (near transfer = 51% correct vs. far = 33%; P < .001). Emotion condition influenced participants' overall performance, with individuals in the neutral condition (50.1%) performing better than those in the positive (38.2%, P < .05) and negative (37.7%, P < .001) emotion conditions. CONCLUSIONS: These data suggest that regardless of whether the emotion is positive or negative, mild affective states can impair learning of basic science concepts by novices. Demands on working memory and subsequent cognitive load provide a potential explanation. Future work will examine the extent to which these findings generalize to medical trainees. PMID- 27779512 TI - The Discriminatory Patient and Family: Strategies to Address Discrimination Towards Trainees. AB - PURPOSE: Trainee mistreatment remains an important and serious medical education issue. Mistreatment toward trainees by the medical team has been described; mistreatment by patients and families has not. Motivated by discrimination towards a resident by a family in their emergency department, the authors sought to identify strategies for trainees and physicians to respond effectively to mistreatment by patients and families. METHOD: A purposeful sample of pediatric faculty educational leaders was recruited from April-June 2014 at Stanford University. Using a constructivist grounded theory approach, semistructured one on-one interviews were conducted. Participants were asked to describe how they would respond to clinical scenarios of families discriminating against trainees (involving race, gender, and religion). Interviews were audio-recorded, transcribed, and anonymized. The authors analyzed interview transcripts using constant comparative analysis and performed post hoc member checking. This project was IRB approved. RESULTS: Four themes emerged from interviews with 13 faculty: assess illness acuity, cultivate a therapeutic alliance, depersonalize the event, and ensure a safe learning environment. Participants wanted trainees to feel empowered to remove themselves from care when necessary but acknowledged that removal was not always possible or easy. Nearly all participants agreed that trainee and faculty development was needed. Suggested educational strategies included team debriefing and critical reflection. CONCLUSIONS: Discrimination towards trainees by patients and families is an important issue. As this type of mistreatment cannot be fully prevented, effective preparation is essential. Effective response strategies exist and can be taught to trainees to empower responses that protect learners and preserve patient care. PMID- 27779514 TI - Patient Eligibility for Randomized Controlled Trials in Critical Care Medicine: An International Two-Center Observational Study. AB - OBJECTIVE: We conducted this study to determine the generalizability of information gained from randomized controlled trials in critically ill patients by assessing the incidence of eligibility for each trial. DESIGN: Prospective, observational cohort study. We identified the 15 most highly cited randomized controlled trials in critical care medicine published between 1998 and 2008. We examined the inclusion and exclusion criteria for each randomized controlled trial and then assessed the eligibility of each patient admitted to a study ICU for each randomized controlled trial and calculated rates of potential trial eligibility in the cohort. SETTING: Three ICUs in two academic medical centers in Canada and the United States. PATIENTS: Adults admitted to participating medical or surgical ICU in November 2010 or July 2011. MEASUREMENTS AND MAIN RESULTS: Among the 15 trials, the most common trial inclusion criteria were clinical criteria for sepsis (six trials) or acute respiratory distress syndrome (four trials), use of invasive mechanical ventilation (five trials) or related to ICU type or duration of ICU stay (five trials). Of the 93 patients admitted to a study ICU, 52% of patients (n = 48) did not meet enrollment criteria for any studied randomized controlled trial and 30% (n = 28) were eligible for only one of the 15. Trial ineligibility was mostly due to failure to meet inclusion criteria (87% of screening assessments) rather than meeting specific exclusion criteria (52% of screening assessments). Of the positive screening assessments, 85% occurred on the first day of ICU admission. CONCLUSIONS: Slightly more than half of the patients assessed were not eligible for enrollment in any of 15 major randomized controlled trials in critical care, most often due to the absence of the specific clinical condition of study. The majority of patients who met criteria for a randomized controlled trial did so on the first day of ICU admission. PMID- 27779515 TI - Frequent Coamplification of Receptor Tyrosine Kinase and Downstream Signaling Genes in Japanese Primary Gastric Cancer and Conversion in Matched Lymph Node Metastasis. AB - OBJECTIVE: To establish the gene copy number status of receptor tyrosine kinase (RTK) and downstream signaling (DSS) genes genes in primary gastric cancer (primGC) and matched lymph node metastases (LNmet). BACKGROUND: Evidence suggests that coamplification between RTKs and DSSs and conversion between primGC and LNmet are associated with resistance to targeted therapy. METHODS: DNA from 237 Japanese primGC and 103 matched LNmet was analyzed using a newly developed multiplex ligation-dependent probe amplification (MLPA) probemix to investigate RTK (EGFR, HER2, FGFR2, and MET) and DSS (PIK3CA, KRAS, MYC, and CCNE1) gene copy number status. Results were compared between primGC and LNmet and related to clinicopathological data including survival. RESULTS: A total of 150 (63%) primGC had either RTK or DSS amplification. DSS coamplification was more frequent than RTK coamplification in primGC and LNmets. Moreover, 70 (30%) GC showed a disconcordant RTK and/or DSS gene copy number status between primGC and LNmet, most common was negative conversion for DSS genes (n=40 GC). The presence of RTK amplification in primGC was related to poorer survival in univariate analysis (P=0.04). CONCLUSIONS: This is the first and most comprehensive study in gastric cancer investigating the concordance between gene copy number status of targetable RTKs and downstream signaling oncogenes in primGC and LNmets. Future studies need to establish whether the relative high frequency of RTK and DSS coamplification and/or the relative high rate of negative conversion in LNmet can potentially explain recent failures of RTK targeted therapy in gastric cancer patients. PMID- 27779517 TI - Factors Affecting Speech Perception Improvement Post Implantation in Congenitally Deaf Adults. AB - OBJECTIVES: To identify factors preimplantation associated with postimplantation speech perception improvement in the adult congenitally deaf population. DESIGN: Forty-four adult cochlear implant (CI) patients who had a severe to profound hearing loss from birth were identified from this centre's database. Eight preimplantation factors, speech intelligibility, preimplantation hearing levels, communication mode, preimplantation speech perception scores, progression of hearing loss, age at implantation, hearing aid use preimplantation, and gender, were recorded during the CI assessment process. These factors were investigated to determine their effect on speech perception improvement postimplantation. The outcome measures were the improvement in scores for the BKB Sentence test and CUNY Sentence test with lipreading after implantation. In the final analysis, 26 patients were included in the CUNY analysis, and 30 patients were included in the BKB analysis. RESULTS: Speech intelligibility rating, preimplantation hearing levels, and communication mode were shown to be significantly associated with improvements in speech perception postimplantation. CONCLUSION: Three factors were identified that affected speech perception improvement postimplantation: speech intelligibility, preimplantation hearing levels, and communication mode. These factors can be used to counsel CI patients regarding potential speech perception improvements from cochlear implantation, although these are based on average data and may not reflect individual performance. PMID- 27779518 TI - Change in Psychosocial Health Status Over 5 Years in Relation to Adults' Hearing Ability in Noise. AB - OBJECTIVES: The aim of this study was to establish the longitudinal relationship between hearing ability in noise and psychosocial health outcomes (i.e., loneliness, anxiety, depression, distress, and somatization) in adults aged 18 to 70 years. An additional objective was to determine whether a change in hearing ability in noise over a period of 5 years was associated with a change in psychosocial functioning. Subgroup effects for a range of factors were investigated. DESIGN: Longitudinal data of the web-based Netherlands Longitudinal Study on Hearing (NL-SH) (N = 508) were analyzed. The ability to recognize speech in noise (i.e., the speech-reception-threshold [SRTn]) was measured with an online digit triplet test at baseline and at 5-year follow-up. Psychosocial health status was assessed by online questionnaires. Multiple linear regression analyses and longitudinal statistical analyses (i.e., generalized estimating equations) were performed. RESULTS: Poorer SRTn was associated longitudinally with more feelings of emotional and social loneliness. For participants with a high educational level, the longitudinal association between SRTn and social loneliness was significant. Changes in hearing ability and loneliness appeared significantly associated only for specific subgroups: those with stable pattern of hearing aid nonuse (increased emotional and social loneliness), who entered matrimony (increased social loneliness), and low educational level (less emotional loneliness). No significant longitudinal associations were found between hearing ability and anxiety, depression, distress, or somatization. CONCLUSIONS: Hearing ability in noise was longitudinally associated with loneliness. Decline in hearing ability in noise was related to increase in loneliness for specific subgroups of participants. One of these subgroups included participants whose hearing deteriorated over 5 years, but who continued to report nonuse of hearing aids. This is an important and alarming finding that needs further investigation. PMID- 27779519 TI - Who's the Fairest of Them All? Meeting the Challenges of Medical Student and Resident Selection. PMID- 27779520 TI - Suggestions for Improving the Medical Student Performance Evaluation. PMID- 27779521 TI - More About the Role of USMLE Step 1 Scores in Resident Selection. PMID- 27779522 TI - More About the Role of USMLE Step 1 Scores in Resident Selection. PMID- 27779523 TI - More About the Role of USMLE Step 1 Scores in Resident Selection. PMID- 27779524 TI - In Reply to Ruddy et al, to Gumbert et al, and to Stoddard. PMID- 27779525 TI - Numerical USMLE Step 1 Scores Are Still Important in Selection of Residency Applicants. PMID- 27779526 TI - In Reply to Jayakumar. PMID- 27779527 TI - Artist's Statement: The Caregiver. PMID- 27779528 TI - Wit: [Excerpt from the play]. PMID- 27779529 TI - Commentary on Wit. PMID- 27779530 TI - The Gold-Hope Tang, MD 2016 Humanism in Medicine Essay Contest: Second Place: The Power of Walking. PMID- 27779531 TI - The Night Your Child Died: An Open Letter From Your Doctor. PMID- 27779532 TI - Behind the Veil. PMID- 27779533 TI - Partnering With Patients to Improve Care: The Value of Patient and Family Advisory Councils. AB - Increasingly, healthcare organizations are adopting patient and family advisory councils as a key strategy to create a culture grounded in patient- and family centered principles and improve the patient experience. In the 1st of a 3-part series, the chief nurse executive and the director of patient- and family centered care at a Magnet(r)-designated academic medical center discuss how a stronger patient voice can lead to better care and improved clinical outcomes. The authors examine ways in which the Magnet culture helped drive change and offer tips to establish a successful patient and family advisory council. PMID- 27779534 TI - Translating Market Forces Into Frontline Terms. AB - To transform healthcare delivery, frontline nursing staff must be committed to their work and to driving their organization's mission forward. However, Advisory Board Survey Solutions data show that nurses are the least engaged as compared with other frontline staff. In this article, the authors identify a top opportunity for improving nurse engagement: ensuring that nurses understand how executives' actions reflect their organization's missions and values. PMID- 27779535 TI - The Influence of Emerging Leadership in Nursing: An Interview With Dr Casey Shillam. AB - This department highlights emerging nursing leaders who have demonstrated leadership in advancing innovation and patient care in practice, policy, research, education, and theory. This interview profiles Casey Shillam, PhD, RN, associate dean for baccalaureate education, University of Portland School of Nursing, Oregon. PMID- 27779536 TI - Theory of Constraints: What Can We Learn to Support the Nursing Workforce? AB - Demand for nurses is influenced by many factors. Labor statistics and health services literature reveal current and predicted supply gaps in meeting this demand. One strategy in response can be drawn from manufacturing industries. This column suggests the application of the Theory of Constraints in efforts to relieve bottlenecks in producing and retaining nurse labor. PMID- 27779537 TI - The Effect of Authentic Leadership, Person-Job Fit, and Civility Norms on New Graduate Nurses' Experiences of Coworker Incivility and Burnout. AB - OBJECTIVE: This study examined the influence of authentic leadership, person-job fit with 6 areas of worklife, and civility norms on coworker incivility and burnout among new graduate nurses. BACKGROUND: New graduate nurses report experiencing high levels of workplace incivility from coworkers, which has been found to negatively impact their job and career satisfaction and increase their intention to leave. The role of civility norms in preventing burnout and subsequent exposure to incivility from coworkers has yet to be examined among new graduate nurses. METHODS: A cross-sectional mail survey of 993 new graduate nurses across Canada was conducted. RESULTS: The results supported the hypothesized relationships between study variables. CONCLUSIONS: Civility norms play a key role in preventing early career burnout and coworker incivility experienced by new graduate nurses. Leaders can influence civility norms by engaging in authentic leadership behaviors and optimizing person-job fit. PMID- 27779538 TI - Developing Competency to Sustain Evidence-Based Practice. AB - Organizations must ensure that nursing care delivery is based on best evidence. This article describes how a clinical research hospital used a competency-based approach to structure the development and execution of a strategic plan and integrated evidence-based practice concepts into the activities of nurses at all levels. The article will also describe the process for developing and implementing the competency across our department including outcomes achieved. PMID- 27779539 TI - A Pilot Study: Testing of the Psychological Conditions Scale Among Hospital Nurses. AB - OBJECTIVE: The aim of this study was to test the reliability and validity of the Psychological Conditions Scale (PCS), a measure of drivers of engagement in hospital-based nurses. BACKGROUND: Research suggests drivers of engagement are positive links to patient, employee, and hospital outcomes. Although this scale has been used in other occupations, it has not been tested in nursing. METHODS: A cross-sectional, methodological study using a convenience sample of 200 nurses in a large Magnet(r) hospital in New Jersey. RESULTS: Cronbach's alpha's ranged from .64 to .95. Principal components exploratory factor analysis with oblique rotation revealed that 13 items loaded unambiguously in 3 domains and explained 76% of the variance. Mean PCS scores ranged from 3.62 to 4.68 on a 5-point Likert scale. CONCLUSIONS: The scale is an adequate measure of drivers of engagement in hospital-based nurses. Leadership efforts to promote the facilitators of engagement are recommended. PMID- 27779540 TI - Satisfaction Data Collected by E-mail and Smartphone for Emergency Department Patients: How Do Responders Compare With Nonresponders? AB - OBJECTIVE: This study profiles an innovative approach to capture patient satisfaction data from emergency department (ED) patients by implementing an electronic survey method. This study compares responders to nonresponders. BACKGROUND: Our hypothesis is that the cohort of survey respondents will be similar to nonresponders in terms of the key characteristics of age, gender, race, ethnicity, ED disposition, and payor status. METHODS: This study is a cross sectional design using secondary data from the database and provides an opportunity for univariate analysis of the key characteristics for each group. The data elements will be abstracted from the database and compared with the same key characteristics from a similar sample from the database on nonresponders to the ED satisfaction survey. FINDINGS: Age showed a statistically significant difference between responders and nonresponders. Comparison by disposition status showed no substantial difference between responders and nonresponders. Gender distribution showed a greater number of female than male responders. Race distribution showed a greater number and response by white and Asian patients as compared with African Americans. A review of ethnicity showed fewer Hispanics responded. An evaluation by payor classification showed greater number and response rate by those with a commercial or Workers Comp payor source. The response rate by Medicare recipients was stronger than expected; however, the response rate by Medicaid recipients and self-pay could be a concern for underrepresentation by lower socioeconomic groups. Finally, the evaluation of the method of notification showed that notification by both e-mail and text substantially improved response rates. CONCLUSION: The evaluation of key characteristics showed no difference related to disposition, but differences related to age, gender, race, ethnicity, and payor classification. These results point to a potential concern for underrepresentation by lower socioeconomic groups. The results showed that notification by both e-mail and text substantially improved response rates. PMID- 27779541 TI - Philanthropic Donor Perspectives on Supporting Nursing Excellence in a Community Hospital. AB - OBJECTIVE: The purpose of this research is to explore donors' perspectives on support of nursing excellence in a community hospital. BACKGROUND: Philanthropic support is rapidly becoming critical to support nursing excellence in hospitals, including continuing education, nursing research, and professional development. However, no research has examined the experience of private donors who support nursing programs in community hospitals. METHODS: Structured interviews were conducted with individuals with a history of providing significant financial support (gifts >$50 000) targeted specifically for nursing in a 176- bed community hospital in the southeastern United States. Analysis was performed using descriptive content analysis. RESULTS: Four themes emerged that centered around making a difference, helping nurses meet new challenges, an existing foundation of service, and valuing excellent nursing care received. CONCLUSIONS: This research provides specific information that nursing administrators can use when seeking philanthropic gifts to support nursing excellence programs in US community hospitals. PMID- 27779543 TI - Letter From Editor-November 2016. PMID- 27779542 TI - The Center for Nursing Excellence: A Health System Model for Intentional Improvement and Innovation. AB - An innovative Center for Nursing Excellence model that supports structural empowerment and the achievement of exemplary nursing, patient, and organizational outcomes was implemented in 2 separate health systems in the western United States. Formal leadership roles for nursing practice, research, professional education, and Magnet(r) continual readiness are aligned to ensure that Magnet designation is attained and maintained in system hospitals. PMID- 27779544 TI - Hyperthermic Intraperitoneal Perfusion Chemotherapy and Cytoreductive Surgery for Controlling Malignant Ascites From Ovarian Cancer. AB - BACKGROUND: Malignant ascites, a complication often seen in patients with ovarian cancer (OC), is difficult to treat, but hyperthermic intraperitoneal chemotherapy (HIPEC) has a good efficacy. OBJECTIVE: The aim of this study was to assess the efficacy of cytoreductive surgery (CRS) combined with HIPEC for controlling malignant ascites from OC. MATERIALS AND METHODS: From December 2009 until December 2014, 53 patients with OC and malignant ascites were treated with CRS and HIPEC. Patients in good health condition were treated with CRS followed by HIPEC (CRS + HIPEC), and patients in poor health condition were treated initially with B-mode ultrasound-guided HIPEC followed by delayed CRS upon improvement of their health condition (HIPEC + delayed CRS). Resolution of ascites, complete CRS, overall survival, and disease-free survival were analyzed. RESULTS: All patients showed ascites regression. The total objective remission rate was 100%, even for patients in the poor condition group before CRS. Complete CRS was successful in 30 (88.23%) of 34 patients in the good condition group, and 17 (89.47%) of 19 patients in the poor condition group (P > 0.05). Median disease free survival and median overall survival were 21 and 39 months in the good condition group, and 22 and 38 months in the poor condition group, respectively (P > 0.05). CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy is effective at controlling ascites in patients with OC, even for patients in poor condition before CRS, or when complete CRS is not feasible. Furthermore, the regression of ascites appears not to be dependent on complete resection. PMID- 27779545 TI - The Associations of Genetic Variants in E-cadherin Gene With Clinical Outcome of Epithelial Ovarian Cancer. AB - OBJECTIVE: The E-cadherin protein plays major roles in tumor progression, invasion, and metastasis. Polymorphisms located in the E-cadherin gene (CDH1) may contribute to increased risks of specific cancers. In this study, we evaluated the associations between genetic variants in CDH1 and the clinical outcomes of patients with epithelial ovarian cancer (EOC). MATERIALS AND METHODS: We assessed the -160C/A and -347G/GA polymorphisms in the promoter region, as well as the 3' UTR +54C/T polymorphism of E-cadherin, in 257 patients with EOC by ligase detection reaction-polymerase chain reaction. RESULTS: Multivariate analysis showed that patients with EOC with the CDH1 -347GA/GA genotype had shorter progression-free survival and overall survival (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.06-4.40 and HR, 2.06; 95% CI, 1.01-4.19, respectively) compared to those carrying the G/G genotype. Likewise, the patients with the CDH1 -160A/A genotype had a shorter progression-free survival than those with the C/C genotype (HR, 4.12; 95% CI, 1.43-111.88). No significant association was detected between the CDH1 3'-UTR +54C/T polymorphism and survival of the patients with EOC. CONCLUSIONS: The CDH1 -347GA/GA and -160A/A genotypes may be prognostic markers that can help to identify patients at increased risk of invasive/metastatic cancer in northern China. PMID- 27779546 TI - Is Ovarian Cancer Being Managed According to Clinical Guidelines? Evidence From a Population-Based Clinical Audit. AB - BACKGROUND: In the northwestern Italian region of Piedmont, current statistics on hospitalizations show that surgical treatment for ovarian cancer (OC) is taking place in many small hospitals, as opposed to a more centralized approach. A population-based clinical audit was promoted to investigate whether OC is being managed according to clinical guidelines, identify determinants of lack of adherence to guidelines, and evaluate the association between adherence to guidelines and survival. PATIENTS AND METHODS: Residents diagnosed with OC in 2009 were identified in the regional hospital discharge records database. All hospitalizations within 2 years from diagnosis were reviewed. Patients were classified according to their initial pattern of care, defined as "with curative intent" (CIPC) if including debulking surgery aimed at maximal cytoreduction. Adherence to guidelines for surgery and chemotherapy and the effects of this adherence on OC survival were investigated with logistic regression and Cox models. RESULTS: The final study sample consisted of 344 patients with OC, 215 (62.5%) of whom received CIPC. Increasing age, comorbidities, and metastases were negatively associated with receiving CIPC. In the CIPC group, surgical treatment was adherent to guidelines in 35.2%, whereas chemotherapy was adherent in 87.8%. Surgical treatment that was adherent to guidelines [hazard ratio (HR), 0.72; 95% confidence interval (CI), 0.45-1.15] and absence of residual tumor (HR, 0.55; 95% CI, 0.32-0.94) were associated with better survival in the CIPC group, and chemotherapy that was adherent to guidelines was associated with a significant reduction in the risk of death (HR, 0.49; 95% CI, 0.28-0.87). CONCLUSIONS: Results support the need to reorganize the clinical pathway of patients with OC in the Piedmont Region and the need for better adherence to current guidelines. PMID- 27779547 TI - Molecular Analysis of Single Tumor Glands Using the Crypt Isolation Method in Endometrial Carcinomas. AB - OBJECTIVE: Endometrial adenocarcinomas are characterized by the presence of many single tumor glands in which multiple genetic changes have accumulated. To elucidate the differences in molecular abnormalities among single tumor glands, individual tumor glands were analyzed and microsatellite alterations (loss of heterozygosity (LOH) and microsatellite instability [MSI]) were examined using the crypt isolation method in glands from each tumor from patients with endometrial carcinoma. METHODS: Twenty-five patients with endometrial adenocarcinoma who underwent surgery were included in this study. We obtained cancerous individual isolated tumor glands from each patient using the crypt isolation method. For LOH and MSI analyses, we used 15 microsatellite markers (3p, 5q, 10q, 13q, 17p, 18q, BAT25, and BAT26) and the promoter regions of 6 genes (transforming growth factor beta receptor II, BAX, insulin-like growth factor II receptor, E2F4, MutS homolog 3, and MSH6). RESULTS: Loss of heterozygosity was detected in 8 (32%) of 25 patients, and MSI was detected in 9 (36%) of 25 patients. Some MSI-positive carcinomas had LOH in single tumor gland samples, and the coexistence of LOH and MSI was confirmed. In 16 (64%) of 25 cases, intratumoral genetic heterogeneity among single tumor gland samples was detected. CONCLUSIONS: By analyzing multiple single tumor glands within the same tumor, we found that endometrial adenocarcinoma was composed of various tumor glands with different molecular abnormalities, even in a limited region within the same tumor. PMID- 27779548 TI - Cervix Cancer Research Network (CCRN): Improving Access to Cervix Cancer Trials on a Global Scale. AB - Eighty-seven percent of cervix cancer occurs in less-developed regions of the world, and there is up to an 18-fold difference in mortality rate for cervix cancer depending on the region of the world. The Cervix Cancer Research Network (CCRN) was founded through the Gynecologic Cancer InterGroup with the aim of improving access to clinical trials in cervix cancer worldwide, and in so doing improving standards of care. The CCRN recently held its first international educational symposium in Bangkok. Sixty-two participants attended from 16 different countries including Pakistan, India, Bangladesh, Thailand, Malaysia, Singapore, Philippines, Taiwan, China, Vietnam, Korea, Japan, Columbia, Brazil, Canada, and the United States. The focus of this symposium was to evaluate progress, to promote new clinical trials for the CCRN, and to provide education regarding the role of brachytherapy in the treatment of cervical cancer. PMID- 27779549 TI - Measures of Patient Activation and Social Support in a Peer-Led Support Network for Women With Cardiovascular Disease. AB - PURPOSE: Social support has been associated with beneficial effects on many disease states and overall health and well-being. However, there is limited research exploring the impact of peer-led support models among women living with coronary heart disease. This study describes the structure of peer-led support groups offered by WomenHeart (WH): The National Coalition for Women Living with Heart Disease, and assesses WH participants' quality of life and social, emotional, and physical health. METHODS: Participants were recruited from 50 WH groups. A 70-item online survey was administered, and the main analytic sample included 157 women. Multivariate logistic regression was used to examine the association between patient activation levels (lower activation levels: 1, 2 vs higher activation levels: 3, 4) and social support scores (range: lowest 8 to highest 34), adjusting for age. RESULTS: High levels of social support, patient activation, physical activity, and low levels of stress, anxiety, and depression were reported. Those who were at or above the median for the social support measures (indicating high levels of social support) had greater odds of high levels of patient activation (level 3 or 4) than individuals reporting low levels of social support (OR = 2.23; 95% CI, 1.04-4.76; P = .012). CONCLUSIONS: Women who regularly attended a support group by a trained peer leader were highly engaged in their health care and had low levels of stress, anxiety, and depression. These findings lend credibility to the value of the peer support model and could potentially be replicated in other disease states to enhance patient care. PMID- 27779550 TI - Short- and Long-term Effects of Pulmonary Rehabilitation in Patients With Mild COPD: A COMPARISON WITH PATIENTS WITH MODERATE TO SEVERE COPD. AB - PURPOSE: Pulmonary rehabilitation (PR) is effective in patients with moderate to severe chronic obstructive pulmonary disease (COPD). However, the effects of PR in patients with mild COPD have not yet been established. Thus, this study investigated the short- and long-term effects of PR in patients with mild COPD in comparison with patients with moderate to severe disease. METHODS: A total of 32 patients with mild (group 1) and 29 with moderate to severe (group 2) COPD completed the study. Both groups participated in a 12-week PR program with exercise training and psychosocial support and education. Outcome measures at baseline, 3 (post-PR), 6, and 9 months later included 6-minute walk test (6MWT); Modified Medical Research Council Dyspnea Scale; 1-repetition maximum chest press and knee extension; a brief physical activity assessment; the number of exacerbations in the past 3 months and the St. George Respiratory Questionnaire (SGRQ). RESULTS: Improvements in the 6MWT, chest press, knee extension, and physical activity were observed post-PR (P < .001), with no differences between the 2 groups. Reduction in the number of exacerbations (P < .001) and improvements in the SGRQ total (P < .001) were also observed, however, with greater magnitude in group 2 (P = .029 and P < .001, respectively). Except for peripheral muscle strength (P < .002), all the achieved benefits were sustained at 6 and 9 months (P > .05). CONCLUSIONS: Pulmonary rehabilitation improves exercise tolerance, muscle strength, physical activity, and health-related quality of life and reduces exacerbations in patients with mild COPD as it does in patients with moderate to severe COPD. Moreover, most of these benefits were maintained at 9-month follow-up, suggesting that PR could be part of the management of mild COPD. PMID- 27779551 TI - Does Exercise Ventilatory Inefficiency Predict Poor Outcome in Heart Failure Patients With COPD? AB - PURPOSE: To investigate whether the opposite effects of heart failure (HF) and chronic obstructive pulmonary disease (COPD) on exercise ventilatory inefficiency (minute ventilation [(Equation is included in full-text article.)E]-carbon dioxide output [(Equation is included in full-text article.)CO2] relationship) would negatively impact its prognostic relevance. METHODS: After treatment optimization and an incremental cardiopulmonary exercise test, 30 male patients with HF-COPD (forced expiratory volume in 1 second [FEV1] = 57% +/- 17% predicted, ejection fraction = 35% +/- 6%) were prospectively followed up during 412 +/- 261 days for major cardiac events. RESULTS: Fourteen patients (46%) had a negative outcome. Patients who had an event had lower echocardiographically determined right ventricular fractional area change (RVFAC), greater ventilatory inefficiency (higher (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir), and lower end-tidal CO2 (PETCO2) (all P < .05). Multivariate Cox models revealed that (Equation is included in full text article.)E/(Equation is included in full-text article.)CO2 nadir >36, DeltaPETCO2(PEAK-REST)>=2 mm Hg, and PETCO2PEAK<=33 mm Hg added prognostic value to RVFAC<=45%. Kaplan-Meyer analyses showed that although 18% of patients with RVFAC>45% had a major cardiac event after 1 year, no patient with RVFAC>45% and (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 nadir <=36 (or PETCO2PEAK>33 mm Hg) had a negative event. Conversely, although 69% of patients with RVFAC<=45% had a major cardiac event after 1 year, all patients with RVFAC<=45% and DeltaPETCO2(PEAK-REST)>=2 mm Hg had a negative event. CONCLUSION: Ventilatory inefficiency remains a powerful prognostic marker in HF despite the presence of mechanical ventilatory constraints induced by COPD. If these preliminary findings are confirmed in larger studies, optimal thresholds for outcome prediction are likely greater than those traditionally recommended for HF patients without COPD. PMID- 27779553 TI - Histopathological determination of thin melanomas at risk for metastasis. PMID- 27779554 TI - Thin melanoma subtyping fits well with the American Joint Committee on Cancer staging system. PMID- 27779555 TI - A meta-analysis of the pedunculopontine nucleus deep-brain stimulation effects on Parkinson's disease. AB - Postural instability and gait disturbance (PIGD) are common symptoms in patients with advanced Parkinson's disease (PD). The deep-brain stimulation (DBS) of the pedunculopontine nucleus (PPN) shows a promising effect on PIGD. However, the quantitative effects of PPN DBS for PD, especially for PIGD, and the efficacy of PPN DBS combined with levodopa are controversial and ambiguous to clinical practice. We carried out a meta-analysis of original researches on PPN to PIGD/PD from the electronic databases MEDLINE and EMBASE. The scores of united Parkinson's disease rating scores (UPDRS) III were used to evaluate the improvement in motor function and the scores of UPDRS III subitems 27-30 were used to evaluate the improvement in PIGD. The outcome was expressed as the mean difference and the percentage change between the scores of baseline and end point. The quality of studies was assessed using the 'assessing risk of bias' table. Overall, 909 articles were screened and seven studies were included with a total of 45 patients. The improvement in PIGD was significant, but there were no such effects on motor function. All the differences in PIGD scores were greater in the OFF medicine state rather than the ON medicine state, especially in the comparison between postsurgery ON stimulation and presurgery. PPN DBS indeed improved PIGD in advanced PD patients. This result could inspire more researchers to focus on its clinical application. PMID- 27779556 TI - Multimodal Imaging of Serpiginous Choroiditis. AB - PURPOSE: To report a case of atypical serpiginous choroiditis with previously unreported findings on optical coherence tomographic angiography. CASE REPORT: A 35-year-old otherwise healthy man had a 1-week history of vision loss in his right eye. The visual acuity in right eye was counting fingers at 1 meter. Fundoscopy showed a classic peripapillary serpiginous lesion and a solitary macular lesion. Fundus fluorescein angiography revealed early hypofluorescence of active lesions with gradual increase in fluorescence across the phase of angiogram. Optical coherence tomography showed hyperreflectivity in outer retinal layers and loss of ellipsoid zone band. The patient was treated with oral prednisone and visual acuity returned to near normal. The inflammation recurred once the patient discontinued corticosteroid therapy. The flare-up was treated with intravenous methylprednisolone followed by oral steroids. Oral azathioprine was added as a steroid-sparing agent and oral prednisone was tapered slowly and discontinued. The visual acuity returned to normal with settlement of all lesions after initiating azathioprine. Optical coherence tomography showed reintegration of retinal anatomy. No recurrence was seen after discontinuation of corticosteroids. Optical coherence tomographic angiography in resolved serpiginous choroiditis was consistent with loss of choriocapillaris homogeneity. CONCLUSIONS: Serpiginous choroiditis may manifest with multifocal lesions and may be confused with relentless placoid chorioretinitis. However, it ends up in a typical geographic scar. Optical coherence tomography can be used to monitor the changes in retinal structure. Choriocapillaris changes as seen on optical coherence tomographic angiography may be a possible mechanism behind the development of choroidal neovascularization in later stages of the disease. PMID- 27779558 TI - MICROBIOLOGIC SPECTRUM AND VISUAL OUTCOMES OF ACUTE-ONSET ENDOPHTHALMITIS UNDERGOING THERAPEUTIC PARS PLANA VITRECTOMY. AB - PURPOSE: To report the clinical presentation, microbiologic spectrum, and visual outcomes associated with acute-onset infectious endophthalmitis undergoing therapeutic pars plana vitrectomy. METHODS: Multicenter interventional retrospective noncomparative consecutive case series. Billing records were reviewed to identify all charts for patients undergoing pars plana vitrectomy within 14 days of diagnosis of acute-onset infectious endophthalmitis over a 4 year period at 5 large tertiary referral retina practices. Statistical analysis was performed to assess for factors associated with visual outcomes. RESULTS: Seventy patients were identified. The most common clinical setting was postcataract surgery (n = 20). Only 3 patients (4.3%) presented with 20/400 or better visual acuity (VA). Although most of the patients initially underwent vitreous tap and intravitreal antibiotic injection (n = 47, 67.1%), all patients eventually underwent pars plana vitrectomy within 14 days of presentation with 68.5% (48/70) of patients undergoing pars plana vitrectomy within 48 hours of presentation. Positive intraocular cultures were obtained in 56 patients (80%). The most common identified organism was Streptococcus sp (n = 19). Visual acuity at last follow-up was 20/400 or better in 19 patients (27.1%). Three patients underwent evisceration or enucleation (4.3%). Last recorded postoperative VA (mean LogMAR 1.99 +/- 0.94, Snellen VA equivalent finger count) improved from presenting VA (mean LogMAR 2.37 +/- 0.38, Snellen VA hand motions) (P <= 0.001). There was no statistically significant correlation between the underlying etiology or the timing of surgery with this VA outcome. CONCLUSION: Although less than one-third of patients achieved 20/400 or better VA, this VA often improved significantly from presenting VA. PMID- 27779559 TI - TRAUMATIC PROLIFERATIVE VITREORETINOPATHY: Clinical and Histopathological Observations. AB - PURPOSE: To determine the phases of traumatic proliferative vitreoretinopathy after open globe injury by assessing cellular components, extracellular matrix constituents of proliferative vitreoretinopathy membranes, and intraretinal changes over time. METHODS: Twenty-one epiretinal and/or subretinal membrane specimens were obtained from 21 patients with open globe injuries. The patients were divided into Groups A (<=28 days), B (29-120 days), and C (>120 days) according to the interval between injury and vitrectomy. The staining intensity and percentage of positive cells in membranes were compared among the groups, and proliferative indices for Ki-67 and proliferating cell nuclear antigen were assessed. Intraretinal changes were evaluated through histology and immunohistochemistry. Fundus photography was performed during vitrectomy. RESULTS: The proliferating cell nuclear antigen proliferative index was significantly higher in Group B (P = 0.002) than in Group A, and lower in Group C (P < 0.001) than in Group B. alpha-smooth muscle actin expression increased from day 29 to 120 after injury. Meanwhile, intraretinal gliosis and fibrosis developed. CONCLUSION: Active proliferation and contraction in proliferative vitreoretinopathy membranes continue until 120 days after injury, and are accompanied by the initiation of intraretinal gliosis and fibrosis. These findings provide further insight into the optimal timing of vitrectomy after trauma. PMID- 27779560 TI - Cost Analysis of Cerebrospinal Fluid Leaks and Cerebrospinal Fluid Leak Prevention in Patients Undergoing Cerebellopontine Angle Surgery. AB - OBJECTIVE: To determine if cranioplasty techniques following translabyrinthine approaches to the cerebellopontine angle are cost-effective. STUDY DESIGN: Retrospective case series. PATIENTS: One hundred eighty patients with available financial data who underwent translabyrinthine approaches at a single academic referral center between 2005 and 2015. INTERVENTION: Cranioplasty with a dural substitute, layered fat graft, and a resorbable mesh plate secured with screws Main Outcome Measures: billing data was obtained for each patient's hospital course for translabyrinthine approaches and postoperative cerebrospinal fluid (CSF) leaks. RESULTS: One hundred nineteen patients underwent translabyrinthine approaches with an abdominal fat graft closure, with a median cost of $25759.89 (range, $15885.65-$136433.07). Sixty-one patients underwent translabyrinthine approaches with a dural substitute, abdominal fat graft, and a resorbable mesh for closure, with a median cost of $29314.97 (range, $17674.28-$111404.55). The median cost of a CSF leak was $50401.25 (range, $0-$384761.71). The additional cost of a CSF leak when shared by all patients who underwent translabyrinthine approaches is $6048.15. The addition of a dural substitute and a resorbable mesh plate after translabyrinthine approaches reduced the CSF leak from 12 to 1.9%, an 84.2% reduction, and a median savings per patient of $2932.23. Applying our cohort's billing data to previously published cranioplasty techniques, costs, and leak rate improvements after translabyrinthine approaches, all techniques were found to be cost-effective. CONCLUSION: Resorbable mesh cranioplasty is cost effective at reducing CSF leaks after translabyrinthine approaches. Per our billing data and achieving the same CSF leak rate, cranioplasty costs exceeding $5090.53 are not cost-effective. PMID- 27779561 TI - Nystagmus at the Onset of Vertiginous Attack in Meniere's Disease. AB - OBJECTIVE: To clarify the direction and characteristics of nystagmus at the onset of a vertiginous attack in Meniere's disease. PATIENTS: Two patients with Meniere's disease, whose nystagmus at the onset of a vertiginous attack was recorded using electronystagmography. INTERVENTIONS: Diagnostic. MAIN OUTCOME MEASURES: Electronystagmographic recordings of nystagmus. RESULTS: In both patients, nystagmus was directed toward the affected side over the entire course of the vertiginous attack. One patient experienced a severe sensation of vertigo and exhibited strong nystagmus from the onset of the attack. The other patient reported a mild sensation of vertigo, which was accompanied by intermittent nystagmus. CONCLUSIONS: Vertiginous attacks in Meniere's disease are accompanied by irritative nystagmus. The intensity and characteristics (e.g., continuous or intermittent expression) of the nystagmus may be associated with pathophysiological severity. PMID- 27779562 TI - Implantation of Bone-Anchored Hearing Devices Through a Minimal Skin Punch Incision Versus the Epidermal Flap Technique. AB - OBJECTIVE: To compare the minimal skin punch incision without additional skin incision or soft tissue reduction with the epidermal flap technique and soft tissue reduction, for the implantation of percutaneous bone-anchored hearing devices. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary care referral center. SUBJECTS AND METHODS: Two hundred seventeen patients underwent 220 implantations. Sixty five cases underwent implantation by means of a skin punch resection without soft tissue reduction (punch group) and 155 cases underwent epidermal flap and soft tissue reduction (dermatome group). Main outcome measures were duration of surgery, perioperative adverse events, skin tolerance, and revision surgery. RESULTS: The duration of surgery was shorter in the punch group (p < 0.001). The percentage of normal to moderate skin reactions, by Holgers classification, was higher in the punch group (90%) than in the dermatome group (84%). No severe reactions occurred in the punch group, but did occur in 7% in the dermatome group. These differences, although clinically important, did not reach statistical significance (p = 0.071). The rate of revision surgeries was not significantly different between the two groups. The indication for revision was different: mainly for skin issues in the dermatome group, against implant dislocation in the punch group. CONCLUSION: The implantation of the currently available percutaneous bone-anchored hearing implants with a minimal skin punch resection shortened duration of surgery and improved postoperative appearance, while preserving a good skin tolerance. In the punch group, there were less skin issues leading to revision surgery, however we did observe more implant dislocations needing revision surgery. PMID- 27779564 TI - X-linked Malformation and Cochlear Implantation. AB - OBJECTIVE: To evaluate if cochlear implantation is safe and constitutes an option for hearing rehabilitation of children with x-linked inner ear malformation. STUDY DESIGN: Retrospective patient review in combination with a multidisciplinary follow-up. SETTING: Tertiary referral hospital and cochlear implant program. PATIENTS: Ten children with severe-profound mixed hearing loss and radiological findings consistent with Incomplete Partition type 3 cochlear malformation received cochlear implants during the years 2007 to 2015. Nine of the children had a mutation affecting the gene POU3F4 on Xq21. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: Surgical events, intraoperative measures and electrical stimulation levels, hearing and spoken language abilities. RESULTS: In all, 15 cochlear implantations were performed. In three cases the electrode was found to be in the internal auditory canal on intraoperative x-ray and repositioned successfully. One child had a postoperative rhinorrhea confirmed to be cerebrospinal fluid but this resolved on conservative treatment. No severe complications occurred. Postoperative electrical stimulation levels were higher in 9 of 10 children, as compared with typically reported average levels in patients with a normal cochlea. Eight patients developed spoken language to various degrees while two were still at precommunication level. However, speech recognition scores were lower than average pediatric cases. CONCLUSION: Cochlear implantation is a safe procedure for children with severe profound mixed hearing loss related to POU3F4 mutation inner ear malformation. The children develop hearing and spoken language but outcome is below average for pediatric CI recipients. PMID- 27779563 TI - Hearing Changes After Intratympanically Applied Steroids for Primary Therapy of Sudden Hearing Loss: A Meta-analysis Using Mathematical Simulations of Drug Delivery Protocols. AB - OBJECTIVE: Controlled and uncontrolled studies with primary intratympanic or combined intratympanic and systemic application of glucocorticosteroids for idiopathic sudden hearing loss were analyzed by means of a meta-analysis in an attempt to establish optimal local drug delivery protocols. STUDY DESIGN: A total of 25 studies with 28 treatment groups between January 2000 and June 2014 were selected that adequately described drug delivery protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time the drug remained in the middle ear, and the specific timing of injections. Various factors were compared with hearing outcome, including baseline data, individual parameters of the application protocols, calculated peak concentration (Cmax), and total dose (area under the curve). RESULTS: There was no dependence of hearing outcome on individual parameters of the application protocol, Cmax, or area under the curve. Final hearing threshold was notably independent of delay of treatment. CONCLUSION: During primary intratympanic or combined steroid therapy of idiopathic sudden hearing loss, the tendency toward early treatment having a positive effect on hearing improvement is thought to be a "sham effect," likely related to spontaneous recovery. Change in pure-tone average may not be an adequate outcome parameter to assess effectiveness of the intervention, as it depends on the degree of initial hearing loss. Final pure-tone average provides a better alternative. PMID- 27779565 TI - Combined exercise reduces arterial stiffness, blood pressure, and blood markers for cardiovascular risk in postmenopausal women with hypertension. AB - OBJECTIVE: Postmenopausal women exhibit elevated brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness, which is associated with an increased risk of cardiovascular events and mortality. The purpose of this study is to examine the impact of combined resistance and aerobic exercise training on baPWV, blood pressure (BP), and cardiovascular fitness in postmenopausal women with stage 1 hypertension. METHODS: Twenty postmenopausal women (age, 75 +/- 2 y; systolic BP, 152 +/- 2 mm Hg, diastolic BP, 95 +/- 3 mm Hg) were randomly assigned to a "no-exercise" (CON, n = 10) or combined exercise (EX, n = 10) group. The EX group performed resistance and aerobic exercise for 12 weeks, 3 times per week. Exercise intensity was increased gradually, from 40% to 70% of heart rate reserve, every 4 weeks. BaPWV, BP, blood nitrite/nitrate, endothelin-1 (ET-1), cardiovascular fitness, and body composition were measured before and after the 12-week intervention. RESULTS: BP, baPWV (-1.2 +/- 0.4 m/s), ET-1 (-2.7 +/- 0.3 MUmol/mL), nitrite/nitrate (+4.5 +/- 0.5 MUM), functional capacity, and body composition were significantly improved (P < 0.05) in the EX group after 12 weeks of training, but no changes were observed in the CON group. CONCLUSIONS: These findings indicate that 12 weeks of combined exercise training improves arterial stiffness, BP, ET-1, blood nitrite/nitrate, functional capacity, and body composition in postmenopausal women with stage 1 hypertension. Thus, this study provides evidence that combined exercise training is a useful therapeutic method to improve cardiovascular health which can reduce cardiovascular disease risk in postmenopausal women with hypertension. PMID- 27779566 TI - In-hospital complications of bilateral salpingo-oophorectomy at benign hysterectomy: a population-based cohort study. AB - OBJECTIVE: The study compared the in-hospital complications and related outcomes between women who underwent bilateral salpingo-oophorectomy at hysterectomy for benign diseases and those who had hysterectomy only. METHODS: We conducted a population-based, retrospective cohort study using data from Taiwan's National Health Insurance program. Women who underwent concurrent bilateral salpingo oophorectomy at hysterectomy for benign indications (n = 34,509) were compared with those who had hysterectomy only (n = 176,305). Separate models were estimated to account for the effect of baseline comorbid condition, age, and hysterectomy approach on the relationship between bilateral salpingo-oophorectomy and study outcomes. A secondary analysis was also performed to evaluate the association of inpatient readmission within 30 days and complications among women who underwent bilateral salpingo-oophorectomy. RESULTS: The addition of a bilateral salpingo-oophorectomy to hysterectomy was associated with a lower risk of surgical complications, a longer length of hospital stay, and an increased risk of inpatient readmission within 30 days. Among women who underwent bilateral salpingo-oophorectomy, women with complications were also more likely to require inpatient readmission within 30 days than those without complications. Our data also suggested that bilateral salpingo-oophorectomy was not associated with an overall risk of medical complications, with the exception of urethral obstruction. The relationships remained even after adjustments by age, surgical indications, hysterectomy approach, and health-related risk factors, such as baseline comorbid condition and status of any prior catastrophic illness. CONCLUSIONS: Bilateral salpingo-oophorectomy at hysterectomy for benign conditions is not associated with an increased risk of in-hospital complications. PMID- 27779567 TI - Moderate-vigorous recreational physical activity and breast cancer risk, stratified by menopause status: a systematic review and meta-analysis. AB - OBJECTIVE: Physical inactivity increases postmenopausal and possibly premenopausal breast cancer risk, although different biologic mechanisms are proposed. Our primary objective was to estimate breast cancer risk associated with high versus low levels of moderate-vigorous recreational activity, separately for premenopausal and postmenopausal women. METHODS: We conducted a systematic review of literature published to July 2015. Included reports were cohort or case-control studies relating moderate-vigorous recreational physical activity (metabolic equivalent >=3.0) to breast cancer incidence, exclusively (>=90%) in premenopausal or postmenopausal women. We appraised study quality and performed meta-analyses using random effects modeling. Subgroup meta-analyses were based on tumor subtype, race, body mass index, parity, hormone therapy use, family history of cancer, and statistical adjustment for body fatness. Dose response relations were examined. RESULTS: Pooled relative risks (RRs, 95% CI) for women with higher versus lower levels of moderate-vigorous recreational activity were RR = 0.80 (0.74-0.87) and RR = 0.79 (0.74-0.84) for premenopausal (43 studies) and postmenopausal (58 studies) breast cancer, respectively, with high heterogeneity. Inverse associations were weaker among postmenopausal cohort studies (RR = 0.90 [0.85-0.95]) and studies that statistically adjusted for nonrecreational (eg, occupational, household) activity (RR = 0.91 [0.77-1.06] premenopausal, RR = 0.96 [0.86-1.08] postmenopausal). Risk estimates with versus without body fatness adjustment did not vary by menopause status, although other subgroup effects were menopause-dependent. Among studies of overweight/obese women, there was an inverse association with postmenopausal but not premenopausal breast cancer (RR = 0.88 [0.82-0.95] and RR = 0.99 [0.98-1.00], respectively). Dose-response curves were generally nonlinear. CONCLUSIONS: Although risk estimates may be similar for premenopausal and postmenopausal breast cancer, subgroup effects may be menopause-dependent. PMID- 27779569 TI - Marla Shapiro, CM, MDCM, CCFP, MHSc, FRCPC, FCFP, NCMP 2016-2017 NAMS President. PMID- 27779568 TI - Longitudinal changes in menopausal symptoms comparing women randomized to low dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. AB - OBJECTIVE: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 MUg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow up time point were compared by treatment arm using exact chi tests in an intent to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens. PMID- 27779570 TI - The influence of living donor SHROOM3 and ABCB1 genetic variants on renal function after kidney transplantation. AB - OBJECTIVE: A genome-wide association study has identified several gene polymorphisms associated with loss of renal function. The effect of these variants on renal function in kidney transplant recipients receiving immunosuppressive treatment is unknown. MATERIALS AND METHODS: A cohort of 189 kidney transplant recipients and their living donors were recruited from West China Hospital of Sichuan University, on whom we assessed the association of five single nucleotide polymorphisms with renal function after kidney transplantation. RESULTS: Glomerular filtration rate estimated by serum creatinine was significantly higher in recipients carrying allograft with the A allele at rs17319721 in SHROOM3 (shroom family member 3) than those in the group with the GG genotype from month 1 to month 6 after transplantation (P=0.020). Covariate adjustment analysis showed that the variant at rs17319721 in SHROOM3 was an independent risk factor for renal dysfunction after the first month after transplantation (P=0.022). The estimated glomerular filtration rate was the lowest in recipients with allograft carrying both the A allele at rs17319721 in SHROOM3 and the CC genotype at rs1045642 in ABCB1 (P<0.05). CONCLUSION: The genetic variants in SHROOM3 and ABCB1 in donors were associated closely with renal function after kidney transplantation. PMID- 27779571 TI - Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study. AB - BACKGROUND: Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. OBJECTIVE: To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. MATERIALS AND METHODS: A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. RESULTS: Among remitters (n=95), there was a strong concordance (Kendall's tau-b=0.84, P=0.0001; Cohen's kappa=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (>=85%), specificity (>=86%), and accuracy (>=89%) of the tool. CONCLUSION: Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. PMID- 27779572 TI - Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression. AB - BACKGROUND: Induction therapy with a T cell-depleting agent followed by mycophenolate mofetil and tacrolimus is presently the most frequently used immune suppression (IS) regimen in islet transplantation. This study assesses its safety and tolerability in nonuremic type 1 diabetic recipients. METHODS: Fifty-one patients (age, between 29 and 63 years) with high glycemic variability and problematic hypoglycemia received intraportal islet grafts under anti-thymocyte globulin-mycophenolate mofetil-tacrolimus protocol. They were followed up for over 48 months for function of the implant and adverse events. RESULTS: Severe hypoglycemia and diabetic ketoacidosis were absent in patients with functioning graft. Immune suppressive therapy was maintained for 48 months in 29 recipients with sustained function (group A), whereas 16 patients stopped earlier due to graft failure (group B) and in 6 for other reasons. Group A was significantly older at the time of implantation and achieved higher graft function at posttransplantation month 6 under similar dose of IS. Prevalence of IS-related side effects was similar in groups A and B, occurring predominantly during the first year posttransplantation. IS-related serious adverse events (SAE) were reported in 47% of patients, with 4 presenting with cytomegalovirus infection and 4 (age, 42-59 years) diagnosed with cancer. Except in 1 patient with cancer, all SAEs resolved after appropriate treatment. CONCLUSIONS: These risk/benefit data serve as a basis for clinical decision-making before entering an intraportal islet transplantation protocol. A longer benefit is observed in recipients of higher age (>=40 years), but it is not associated with more side effects and SAE. PMID- 27779574 TI - A Re-evaluation of Discarded Deceased Donor Kidneys in the UK: Are Usable Organs Still Being Discarded? AB - BACKGROUND: A significant proportion of procured deceased donor kidneys are subsequently discarded. The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012, enabling kidneys at risk of discard to be simultaneously offered to participating centers. We undertook an analysis of discarded kidneys to determine if unnecessary organ discard was still occurring since the KFTS was introduced. METHODS: Between April and June 2015, senior surgeons independently inspected 31 consecutive discarded kidneys from throughout the United Kingdom. All kidneys were biopsied. Organs were categorized as usable, possibly usable pending histology, or not usable for implantation. After histology reports were available, final assessments of usability were made. RESULTS: There were 19 donors (6 donations after brain death, 13 donations after circulatory death), with a median (range) donor age of 67 (29-83) years and Kidney Donor Profile Index of 93 (19-100). Reasons for discard were variable. Only 3 discarded kidneys had not entered the KFTS. After initial assessment postdiscard, 11 kidneys were assessed as usable, with 9 kidneys thought to be possibly usable. Consideration of histological data reduced the number of kidneys thought usable to 10 (10/31; 32%). CONCLUSIONS: The KFTS scheme is successfully identifying organs at high risk of discard, though potentially transplantable organs are still being discarded. Analyses of discarded organs are essential to identify barriers to organ utilization and develop strategies to reduce unnecessary discard. PMID- 27779573 TI - Individual Frailty Components and Mortality in Kidney Transplant Recipients. AB - BACKGROUND: Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. METHODS: Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. RESULTS: Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poor: PR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk. CONCLUSIONS: Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients. PMID- 27779575 TI - A Snapshot of Antibody-Mediated Rejection Goes Viral. PMID- 27779576 TI - Is There a Role for mTOR Inhibitors in Renal Transplantation? PMID- 27779578 TI - Does small-volume resuscitation with crystalloids or colloids influence hemostasis and survival of rabbits subjected to lethal uncontrolled hemorrhage? AB - BACKGROUND: Prehospital, small-volume resuscitation of combat casualties with a synthetic colloid (6% hydroxyethyl starch [HES] 670/0.75) has been recommended when blood or blood components are unavailable. We studied hemostatic effects of a newer synthetic colloid (6% HES, 130/0.4) compared with either a natural colloid (albumin) or to crystalloids in an uncontrolled hemorrhage model. METHODS: Spontaneously breathing New Zealand white rabbits (3.4 +/- 0.1 kg) were anesthetized, instrumented, and subjected to a splenic injury with uncontrolled bleeding. Fifteen minutes after injury, rabbits were in shock (mean arterial pressure [MAP] = 26 +/- 1.3 mm Hg, and received colloids (6% HES, 130/0.4 or 5% albumin at 15 mL/kg), or crystalloids (normal saline at 30 mL/kg or 5% hypertonic saline at 7.5 mL/kg) for resuscitation in two intravenous bolus injections (15 minutes apart) to raise their MAP to 65 mm Hg, n = 9/group. Animals were monitored for 2.5 hours or until death, and blood losses were measured. Blood samples were analyzed for arterial blood gas, complete blood count, and coagulation measures. RESULTS: There were no differences among groups in baseline measures and initial hemorrhage volume (11.9 +/- 0.6 mL/kg) at 15 minutes postinjury. Twenty minutes after fluid resuscitation (1 hour postinjury), MAP was higher, shock indices were lower, and blood pH was higher in colloids versus. crystalloids groups (p < 0.05). Administration of 6% HES 130/0.4 colloid produced the largest hemodilution (54% decrease in hematocrit, p < 0.05 vs. hypertonic saline). Activated partial thromboplastin time increased approximately 35% above baseline in all groups except in 6% HES 130/0.4 group in which it doubled. Clot strength was reduced (15%) only in the 6% HES 130/0.4 group. 6% HES 130/0.4 resuscitation produced the largest blood loss and 33% survival rate that was not different than the crystalloid groups. Albumin produced the best hemostatic and survival outcomes (78%). CONCLUSION: Small-volume resuscitation with crystalloids appeared inadequate to treat hypovolemic shock and prevent death. 6% HES 130/0.4 was effective hemodynamically but detrimental to hemostasis. Albumin produced the best outcomes consistent with our previous observations. Further studies are needed to prove benefit of albumin solution as a possible resuscitation fluid for treating combat casualties at the point of injury. PMID- 27779577 TI - Extracorporeal membrane oxygenation for adult respiratory distress syndrome in trauma patients: A case series and systematic literature review. AB - BACKGROUND: Venovenous extracorporeal membrane oxygenation (vv-ECMO) is an established salvage therapy for severe respiratory failure, and may provide an alternative form of treatment for trauma-induced adult respiratory distress syndrome (ARDS) when conventional treatments have failed. The need for systemic anticoagulation is a relative contraindication for patients with bleeding risks, especially in multitraumatic injury. METHODS: We describe a case series of four trauma patients with ARDS who were managed with ECMO admitted to the neuro critical care unit at Addenbrooke's Hospital, Cambridge (UK), from January 2000 to January 2016. We performed a systematic review of the available literature to investigate the safety and efficacy of vv-ECMO in posttraumatic ARDS, focusing on the use of different anticoagulation strategies and risk of bleeding on patients with multiple injuries. RESULTS: Thirty-one patients were included. A heparin bolus was given in 16 cases. Eleven patients developed complications during treatment with ECMO with three cases of major bleeding. In all documented cases of bleeding a bolus and infusion of heparin was administered, aiming for an activated clotting time (ACT) target longer than 150 seconds. Two patients treated with heparin-free ECMO developed thromboembolic complications. Four patients died, and death was never directly or indirectly related to use of ECMO. CONCLUSION: vv-ECMO can be lifesaving in respiratory failure. Our experience and our literature review suggest that vv-ECMO should be considered as a rescue treatment for the management of severe hypoxemic respiratory failure secondary to ARDS in trauma patients.For patients with a high risk of bleeding, the use of ECMO with no initial anticoagulation could be considered a valid option. For patients with a moderate risk of bleeding, use of a heparin infusion keeping an ACT target shorter than 150 seconds can be appropriate. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 27779579 TI - Epidemiology and outcomes of children with accidental hypothermia: A propensity matched study. AB - BACKGROUND: The purpose of this study was to explore the epidemiology and outcomes of hospitalized children with a diagnosis of accidental hypothermia. METHODS: The 2012 Kids' Inpatient Database, detailing discharge diagnoses in children admitted to US hospitals, was analyzed using International Classification of Diseases, Ninth Revision, Clinical Modification codes to filter out relevant patients. Children ages 1 month to 17 years were included in the analysis. Demographic and outcome variables in the hypothermia group were compared with the rest of the patients. In a separate analysis, children with hypothermia were matched 1:1 using a correlative propensity score using sex, age, hospital region, income quartiles, race, ventilation status, coagulopathy, drowning, and All Patient Refined Diagnosis Related Groups severity score and their outcomes were compared with controls. The sample data were weighted to get a national estimate. RESULTS: Accidental hypothermia was present in 1,028 cases out of 1,915,435 discharges. Children with hypothermia were more likely to be males (54.7% vs. 50.9%; p < 0.05) and infants (32.6% vs. 17.5%); they were less likely to be teens (30% vs. 37.8%). Children with hypothermia were more likely to be admitted in the Southern region (48.3% vs. 38.4%; p < 0.05) and have a higher mortality rate compared to all other discharges (8.5% vs. 0.3%; p < 0.05) or when compared with the matched controls (8.9% vs. 4.4%). CONCLUSIONS: The diagnosis of accidental hypothermia significantly increased mortality in hospitalized children. Interestingly, accidental hypothermia was more common in Southern states compared to the other areas of the United States. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level III. PMID- 27779580 TI - What is the detailed protocol and transfusion content for trauma patients who receive packed red blood cells? PMID- 27779581 TI - Gun violence is structural violence: Our role as trauma surgeons. PMID- 27779583 TI - Model of trauma-induced coagulopathy including hemodilution, fibrinolysis, acidosis, and hypothermia: Impact on blood coagulation and platelet function. AB - BACKGROUND: Trauma-induced coagulopathy (TIC) is commonly seen among patients with severe injury. The dynamic process of TIC is characterized by variability of the features of the disease. METHODS: A model of TIC was created. Hemodilution was produced by mixing the blood with 40% Tris/saline solution, fibrinolysis by treating the blood with 160 ng/mL tPA, acidosis by adding 1.2 mg/mL lactic acid achieving pH 7.0 to 7.1, and hypothermia by running the assay at 31 degrees C. Intact blood tested at 37 degrees C served as control. Clot formation was evaluated using rotation thromboelastometry. Platelet adhesion and aggregation were assayed at a shear rate of 1800 s(-) using Impact-R device. RESULTS: Clotting time was not affected by any of the TIC constituents used. Clotting initiation was reduced by hemodilution and further reduced by additive hypothermia. The propagation phase of blood clotting was reduced by hemodilution, further reduced by additive hypothermia, and maximally reduced if additionally combined with fibrinolysis. No effect of fibrinolysis on clot propagation was observed at 37 degrees C. Maximum clot firmness was reduced by hemodilution, further reduced by additive fibrinolysis, and maximally reduced if additionally combined with hypothermia. No effect of hypothermia on clot strength was observed in the absence of fibrinolysis. Platelet adhesion (percentage of surface coverage) and aggregation (aggregate size) under flow condition were reduced by hemodilution and further reduced by additive acidosis. Introduction of tPA to diluted blood had no effect on platelet function. CONCLUSION: The study revealed a differential effect of TIC constituents-hemodilution, hypothermia, fibrinolysis, and acidosis-on clot formation and platelet function. The effect of one factor may influence that of another factor. These data may be helpful to better understand the pathogenesis of TIC and to elaborate an individually tailored treatment strategy. LEVEL OF EVIDENCE: A new model of TIC is created. Contribution of various constituents to pathogenesis of TIC and their interactions are evaluated. PMID- 27779585 TI - Exosomes, not protein or lipids, in mesenteric lymph activate inflammation: Unlocking the mystery of post-shock multiple organ failure. AB - BACKGROUND: Previous studies have shown that mesenteric lymph (ML) has a crucial role in driving the systemic inflammatory response after trauma/hemorrhagic shock (T/HS). The specific mediators in the ML that contribute to its biological activity remain unclear despite decades of study. Exosomes are extracellular vesicles that are shed into body fluids such as serum and urine that can mediate intercellular communication. We hypothesized that exosomes are present in the ML after trauma/shock and are responsible for the biological activity of ML. METHODS: Male rats underwent cannulation of the vessels and mesenteric lymph duct. T/HS was induced by laparotomy and 60 minutes of HS (mean arterial pressure, 35 mmHg), followed by resuscitation. The ML was collected during three distinct time periods (pre-shock, shock, and resuscitation phase) and subsequently separated into exosome and supernatant fractions. Exosomes were characterized by electron microscope, nanoparticle tracking analysis, and immunoblotting. The biological activity of exosomes and supernatant of ML were characterized using a monocyte NF-kappaB reporter assay and by measuring macrophage intracellular TNF-alpha production. RESULTS: Exosomes were identified in ML by size and expression of the exosome markers CD63 and HSP70. The number of exosomes present in the ML was 2-fold increased during shock and 4-fold decreased in resuscitation phase compared to pre-shock. However, biological activity of exosomes isolated during the resuscitation phase was markedly increased and caused an 8-fold increase in monocyte NF-kappaB activation compared to supernatant. Macrophage TNF-alpha production was also increased after exposure to exosomes harvested in the resuscitation phase. The ML supernatant fraction had no effect on TNF-alpha production during any phase. CONCLUSIONS: Our findings show that exosomes, and not the liquid fraction of ML, are the major component triggering inflammatory responses in monocytes and macrophages after experimental T/HS. PMID- 27779586 TI - Massive transfusion in pediatric trauma: We need to focus more on "how". PMID- 27779588 TI - Re: Screening for pediatric blunt cerebrovascular injury. PMID- 27779589 TI - Extracorporeal life support in trauma: Worth the risks? A systematic review of published series. AB - BACKGROUND: Extracorporeal life support (ECLS) is a potentially life-saving procedure for trauma patients with severe respiratory failure. Despite this, only a limited number of publications report series of trauma patients who underwent ECLS. The performance and safety of this technology in trauma patients is not fully understood. We described the efficacy and complications of ECLS in trauma patients with respiratory failure. METHODS: A systematic review of published reports was performed utilizing the Medical Literature Analysis and Retrieval System Online (MEDLINE). Studies reporting ECLS in five trauma patients or more were examined for eligibility. Eligible trials were examined for patient characteristics, trauma characteristics, and anticoagulation management. Outcomes were examined for survival, causes of overall mortality, and the incidence of bleeding-related mortality. RESULTS: Six hundred five studies were identified in the initial literature search. Of these, 12 studies met the inclusion and exclusion criteria with a total of 215 patients. The overall survival to discharge ranged from 50% to 79%. Survival to discharge after venovenous-ECLS and venoarterial-ECLS were different, ranging from 56% to 89% and 42% to 63%, respectively. The leading cause of mortality was sepsis, which was the cause in 48% of all deaths. Bleeding-related mortality ranged between 0% and 38%, and was consistently lower than 15% in studies after 1995. Reported patients with traumatic intracranial hemorrhage (ICH) had survival ranging from 60% to 93%, with no mortalities related to their ICH. There was a recent trend towards initially heparin-free circuitry followed by a lower-than-standard activated clotting time target range. CONCLUSION: The use of ECLS in trauma patients when needed may provide survival benefits that significantly overweigh the feared risk of bleeding associated. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 27779590 TI - Western Trauma Association Critical Decisions in Trauma: Management of rib fractures. AB - This is a recommended management algorithm from the Western Trauma Association addressing the management of adult patients with rib fractures. Because there is a paucity of published prospective randomized clinical trials that have generated Class I data, these recommendations are based primarily on published observational studies and expert opinion of Western Trauma Association members. The algorithm and accompanying comments represent a safe and sensible approach that can be followed at most trauma centers. We recognize that there will be patient, personnel, institutional, and situational factors that may warrant or require deviation from the recommended algorithm. We encourage institutions to use this as a guideline to develop their own local protocols. PMID- 27779591 TI - Considerations of a test-retest reliability study in injury prevention. PMID- 27779593 TI - A safe and effective management strategy for BCVI. PMID- 27779592 TI - Improved outcomes following implementation of an acute gastrointestinal bleeding multidisciplinary protocol. AB - BACKGROUND: Effective multidisciplinary management of gastrointestinal bleeding (GIB) requires effective communication. We instituted a protocol to standardize communication practices with the hypothesis that outcomes would improve following protocol initiation. METHODS: We performed a retrospective cohort analysis of 442 patients who required procedural management of acute GIB at our institution during a 50-month period spanning 25 months before and 25 months after implementation of a multidisciplinary communication protocol. The protocol stipulates that when a patient with severe GIB is identified, a conference call is coordinated among the gastroenterology, interventional radiology, and acute care surgery teams. A consensus plan is generated and then reassessed following procedural interventions and changes in patients' status. Patients' characteristics, management strategies, and outcomes were compared before and after protocol initiation. RESULTS: Patient populations before and after protocol initiation were similar in age, comorbidities, outpatient use of antiplatelet/anticoagulant medications, admission vital signs, and admission laboratory values. The median interval between admission and the first procedure was significantly shorter in the protocol group (40 vs 47 hours, p = 0.046). The proportion of patients who received packed red blood cell transfusions decreased following protocol initiation (41% vs 50%, p = 0.018). Median hospital length of stay was significantly shorter in the protocol group (5.0 vs 6.0 days, p = 0.014). Readmissions with GIB were decreased after protocol implementation (8% vs. 15%, p = 0.023). CONCLUSION: Implementation of a multidisciplinary protocol for management of acute GIB was associated with earlier intervention, fewer packed red blood cell transfusions, shorter hospital length of stay, and fewer readmissions with GIB. Future research should seek to establish causal relationships between communication practices and outcomes. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 27779594 TI - International rotations: A valuable source to supplement operative experience for acute-care surgery, trauma, and surgical critical care fellows. AB - BACKGROUND: Acute-care surgery (ACS), trauma, and surgical critical care (SCC) fellowships graduate fellows deemed qualified to perform complex cases immediately upon graduation. We hypothesize international fellow rotations can be a resource to supplement operative case exposure. METHODS: A survey was sent to all program directors (PDs) of ACS and SCC fellowships via e-mail. Data were captured and analyzed using the REDCap (Research Electronic Data Capture) tool. RESULTS: The survey was sent to 113 PDs, with a response rate of 42%. Most fellows performed less than 150 operative cases (59.5%). The majority of PDs thought the operative exposure either could be improved or was not enough to ensure expertise in trauma and emergent general surgery. Only a minority of the PDs found their case load exceptional (can be improved: 43%, not enough: 30% exceptional: 27%). Most PDs thought an international experience could supplement the breadth of cases, provide research opportunities, and improve understanding of trauma systems (70%). Ten sites offered international rotations (70%). Most fellowships would be willing to provide reciprocity to the host institution (90%). CONCLUSIONS: The majority of PDs for ACS, trauma, and SCC programs perceive a need for increased quality and quantity of operative cases. The majority recognize international fellow rotations as a valuable tool to supplement fellows' education. PMID- 27779595 TI - Sympathoadrenal activation and endotheliopathy are drivers of hypocoagulability and hyperfibrinolysis in trauma: A prospective observational study of 404 severely injured patients. AB - BACKGROUND: One third of severely injured patients present with a laboratory based diagnosis of coagulopathy. This study investigated clinical and biomarker profile of patients with rapid thrombelastography (rTEG) coagulopathy, hypothesizing that sympathoadrenal activation and endothelial damage were drivers of this condition. METHODS: Prospective observational study of 404 trauma patients admitted to a Level 1 US Trauma Center. Patients with admission rTEG and plasma measurements of catecholamines (adrenaline, noradrenaline) and biomarkers reflecting endothelial activation/damage (syndecan-1, thrombomodulin, sE selectin, sVE-cadherin, nucleosomes) were included. Demography, injury type/severity, physiology, treatment, and inhospital mortality were recorded. RESULTS: Patients had a median Injury Severity Score (ISS) of 17, 73% from blunt injury. One third (35%) of the patients had rTEG coagulopathy, which was associated with higher plasma adrenaline, syndecan-1, and nucleosomes (all <0.05), higher transfusion requirements and higher early (<24 hours, 9.3% vs. 2.5%) and late (28 days, 23.8% vs. 13.4%) mortality. By adjusted linear regression analyses, high plasma adrenaline, sVE-cadherin, and syndecan-1 (reflecting sympathoadrenal activation and endothelial cell junction and glycocalyx damage) along with male sex, high ISS, low platelet count and prehospital red blood cell transfusion were independently associated with hypocoagulable rTEG, whereas prehospital plasma and sE-selectin (reflecting endothelial activation) were independently associated with more hypercoagulable rTEG. CONCLUSION: In this cohort of severely injured trauma patients, rTEG coagulopathy was associated with sympathoadrenal activation, endotheliopathy, and excess mortality. High adrenaline and biomarkers reflecting endothelial cell junction and glycocalyx damage were independently associated with hypocoagulability and hyperfibrinolysis. These findings support that sympathoadrenal activation and endotheliopathy contribute to trauma-induced coagulopathy and warrants further studies of endothelial repair management. LEVEL OF EVIDENCE: Prognostic, Level III. PMID- 27779596 TI - Acute care surgery fellowship graduates' practice patterns: The additional training is an asset. AB - BACKGROUND: Over the past decade, the American Association for the Surgery of Trauma Acute Care Surgery (ACS) fellowship program has matured to 20 verified programs. As part of an ongoing curricular evaluation, we queried the current practice patterns of the graduates of ACS fellowship programs regarding their view on their ACS training. We hypothesized that the majority of ACS fellowship graduates would be practicing ACS in academic Level I trauma centers and that fellowship training was pivotal in their career. METHODS: Graduates of American Association for the Surgery of Trauma-certified ACS fellowships completed an online survey that included practice demographics, specific categories of cases delineated by the current ACS curriculum, and perceived impact of training. RESULTS: Surveys were submitted by 56 of 77 graduates for a completion rate of 73%. The majority of respondents were male (68%) aged 40 years or younger (80%). All but four completed ACS fellowship training in last 5 years (93%), and 83% completed fellowship in the last 3 years. Regarding their current practice, broadly defined ACS predominated (96%) with 2% practicing only trauma surgery and 2% only general surgery. Practice settings were 64% urban, 29% suburban, and 7% rural locations, with 84% of graduates practicing in a hospital-based group. The practitioner's hospital was identified as university/university-affiliated in 53%, community in 38%, and military in 9%, with 91% identified as a teaching hospital; trauma designation was identified as Level I (55%), Level II (39%), and other (6%). The graduates' average current practice mix is 10% elective general surgery, 29% emergency general surgery, 32% trauma, 25% surgical critical care, and 4% other (burn, bariatric, vascular, and thoracic). Only 16% of graduates do not perform elective cases. Case specifics demonstrated 92% of graduates perform vascular cases, 88% perform thoracic cases, and 70% perform complex hepatobiliary. Practice elements that were satisfiers included (1) scope of practice, (2) case mix, (3) percentage emergency general surgery, (4) lifestyle, (5) case complexity (with 3 and 4 tied). Graduates agreed the ACS fellowship training prepared them well for practice and was worth the time invested (both 82%), increased their marketability and self-confidence (80%), and prepared them well for academics (71%) and administration (63%). Of those surveyed, 93% would encourage others to do an ACS fellowship. CONCLUSION: Although 93% of graduates practice in urban/suburban areas, there was a mixture of university, university affiliated, and community institutions and an almost even division of Levels I and II designation. Graduates demonstrate ongoing use of their acquired advanced operative training, particularly in vascular and thoracic surgery. The majority of ACS fellowship graduates were practicing ACS and felt fellowship training was valuable in their career path and that they would recommend it to others. PMID- 27779597 TI - Abnormalities in fibrinolysis at the time of admission are associated with deep vein thrombosis, mortality, and disability in a pediatric trauma population. AB - BACKGROUND: Abnormalities in fibrinolysis are common and associated with increased mortality in injured adults. While hyperfibrinolysis (HF) and fibrinolysis shutdown (SD) are potential prognostic indicators and treatment targets in adults, these derangements are not well described in a pediatric trauma cohort. METHODS: This was a prospective analysis of highest level trauma activations in subjects aged 0 to 18 years presenting to our academic center between June 1, 2015, and July 31, 2016, with admission rapid thrombelastograph. Shutdown was defined as LY30 (lysis 30 minutes after the maximum amplitude has been reached) of 0.8% or less and HF defined as LY30 of 3.0% or greater. Variables of interest included demographics, admission vital signs and laboratory values, injuries, incidence of venous thromboembolism under our screening protocol, death, and functional disability (discharge to facility or dependence in functional independence measure category). Youden index determined optimal definition of SD, then Wilcoxon rank-sum, Kruskal-Wallis, and Fisher exact tests were performed. RESULTS: One hundred thirty-three patients are included with median age of 10 years (interquartile range [IQR], 5-13 years); male sex, 5.4%; median Injury Severity Score, 17 (IQR, 10-26); blunt mechanism, 68.4%. Youden analysis defined SD as LY30 of 0.8 or less. In total, 38.3% (n = 51) had SD on admission; 19.6% (n = 26) had HF, and 42.1% (n = 56) were normal. Mortality rate was 9.0% (n = 12), and deep vein thrombosis incidence was 10.7% (n = 13/121 surviving). Shutdown and HF were both associated with mortality (p = 0.014 and p = 0.021) and blood transfusion (p = 0.001 and p < 0.001); SD was also associated with disability (p < 0.001) and deep vein thrombosis (p = 0.002). Blunt mechanism was associated with SD, and penetrating mechanism was associated with HF (p = 0.011). Both SD (p = 0.001) and HF (p = 0.036) were associated with elevated international normalized ratio. LY30 did not differ significantly across age groups. CONCLUSIONS: Children demonstrate high rates of inhibition (SD) and overactivation (HF) of fibrinolysis after injury. Shutdown and HF are both associated with poor outcomes. Shutdown is a particularly poor prognostic indicator, accounting for the greatest percentage of death, disability, and patients requiring transfusion, as well as later development of hypercoagulable state. The addition of thrombelastograph to pediatric trauma care protocols should be considered as it contributes important prognostic and clinical information. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 27779598 TI - Clinical significance of computed tomography contrast extravasation in blunt trauma patients with a pelvic fracture. AB - INTRODUCTION: Blunt pelvic fractures can be associated with major pelvic bleeding. The significance of contrast extravasation (CE) on computed tomography (CT) is debated. We sought to update our experience with CE on CT scan for the years 2009-2014 to determine the accuracy of CE in predicting the need for angioembolization. METHODS: This is a retrospective review of the trauma registry and our electronic medical record from a Level I trauma center. Patients seen from July 1, 2009, to September 7, 2014, with blunt pelvic fractures and contrast enhanced CT were included. Standard demographic, clinical, and injury data were obtained. Patient records were queried for CE, performance of angiography, and angioembolization. Positive patients were those where CE was associated with active bleeding requiring angioembolization. All other patients were considered negative. RESULTS: There were 497 patients during the study time period with blunt pelvic fracture meeting inclusion criteria, and 75 patients (15%) had CE. Of those patients with CE, 30 patients (40%) underwent angiography, and 17 patients (23%) required angioembolization. The sensitivity, specificity, positive predictive value, and negative predictive value of CE on CT were 100%, 87.9%, 22.7%, and 100%, respectively. Two patients without CE underwent angiography but did not undergo embolization. Patients with CE had higher mortality (13 vs. 6%, p < 0.05) despite not having higher ISS scores. CONCLUSIONS: This study reinforces that CE on CT pelvis with blunt trauma is common, but many patients will not require angioembolization. The negative predictive value of 100% should be reassuring to trauma surgeons such that if a modern CT scanner is used, and there is no CE seen on CT, then the pelvis will not be a source of hemorrhagic shock. All of these findings are likely due to both increased comfort with observing CEs and the increased sensitivity of modern CT scanners. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 27779601 TI - A Normative Baseline for the Srs-22 From Over 1000 Healthy Adolescents in India: Which Demographic Factors Affect Outcome? AB - STUDY DESIGN: A prospective analysis. OBJECTIVE: This study aims to 1) establish a baseline for the SRS-22 in South East Asia and 2) evaluate the influence of patient demographics on the SRS-22. SUMMARY OF BACKGROUND DATA: Previous studies have established a baseline for the SRS-22 in the US and described the impact of patient demographics. While the SRS-22 is used internationally, limited normative data are available. METHODS: After approval from the local hospital and school board, 1200 adolescents (age 10-18 years) were asked to anonymously complete the SRS-22 in English. The following demographic factors were assessed: height, weight, age, gender, household income (range <$30K to >$200K), and household status (single/dual parent income). Participants with a prior spine history or active medical problems were excluded. Statistical analysis was done with a Pearson correlation followed by an analysis of variance (ANOVA). RESULTS: One thousand nineteen unaffected adolescents completed the SRS-22 (mean age 14.4 +/- 1.6 years). Demographics were as follows: gender (42%F, 58%M), household status (640 single/379 dual), height (157 +/- 12 cm), weight (46 +/- 11.2 kg), body mass index (BMI; 18.5 +/- 3.6). SRS-22 score for all patients and by gender: Mean [4.0 +/- 0.4, (F)4.0 +/- 0.4, (M)3.9 +/- 0.4, P < 0.0001], Activity [3.9 +/- 0.4, (F)4.0 +/- 0.5, (M)3.9 +/- 0.6], Pain [4.3 +/- 0.6; (F)4.4 +/- 0.6, (M)4.2 +/- 0.7, P < 0.001], Image [3.9 +/- 0.6, (F)3.9 +/- 0.6, (M)3.9 +/- 0.6], and Mental [3.7 +/- 0.6, (F)3.8 +/- 0.6, (M)3.7 +/- 0.6, P < 0.001]. Male gender was associated with worse pain (-0.15), mental health (-0.11), and overall SRS-22 score (-0.11). Age was correlated with a worse image (r = -0.17, P = < 0.000), while higher BMI was associated with less pain (0.07/0.02). CONCLUSION: Younger age, female gender, and higher BMI correlated with a better SRS-22 score. Income and household status did not affect SRS-22. These findings contrast data gathered in the US but should be considered in conjunction with the minimal clinically important difference (MCID). This study establishes the first normative baseline for the SRS-22 in SE Asia and analyzed the effect of demographics on the outcome score. LEVEL OF EVIDENCE: 2. PMID- 27779600 TI - Lumbar Spine Paraspinal Muscle and Intervertebral Disc Height Changes in Astronauts After Long-Duration Spaceflight on the International Space Station. AB - STUDY DESIGN: Prospective case series. OBJECTIVE: Evaluate lumbar paraspinal muscle (PSM) cross-sectional area and intervertebral disc (IVD) height changes induced by a 6-month space mission on the International Space Station. The long term objective of this project is to promote spine health and prevent spinal injury during space missions and here on Earth. SUMMARY OF BACKGROUND DATA: National Aeronautics and Space Administration (NASA) crewmembers have a 4.3 times higher risk of herniated IVDs, compared with the general and military aviator populations. The highest risk occurs during the first year after a mission. Microgravity exposure during long-duration spaceflights results in approximately 5 cm lengthening of body height, spinal pain, and skeletal deconditioning. How the PSMs and IVDs respond during spaceflight is not well described. METHODS: Six NASA crewmembers were imaged supine with a 3 Tesla magnetic resonance imaging. Imaging was conducted preflight, immediately postflight, and then 33 to 67 days after landing. Functional cross-sectional area (FCSA) measurements of the PSMs were performed at the L3-4 level. FCSA was measured by grayscale thresholding within the posterior lumbar extensors to isolate lean muscle on T2-weighted scans. IVD heights were measured at the anterior, middle, and posterior sections of all lumbar levels. Repeated measures analysis of variance was used to determine significance at P < 0.05, followed by post-hoc testing. RESULTS: Paraspinal lean muscle mass, as indicated by the FCSA, decreased from 86% of the total PSM cross-sectional area down to 72%, immediately after the mission. Recovery of 68% of the postflight loss occurred during the next 6 weeks, still leaving a significantly lower lean muscle fractional content compared with preflight values. In contrast, lumbar IVD heights were not appreciably different at any time point. CONCLUSION: The data reveal lumbar spine PSM atrophy after long-duration spaceflight. Some FCSA recovery was seen with 46 days postflight in a terrestrial environment, but it remained incomplete compared with preflight levels. LEVEL OF EVIDENCE: 4. PMID- 27779602 TI - Spinal Surgeon Variation in Single-Level Cervical Fusion Procedures: A Cost and Hospital Resource Utilization Analysis. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To compare perioperative costs and outcomes of patients undergoing single-level anterior cervical discectomy and fusions (ACDF) at both a service (orthopedic vs. neurosurgical) and individual surgeon level. SUMMARY OF BACKGROUND DATA: Hospital systems are experiencing significant pressure to increase value of care by reducing costs while maintaining or improving patient-centered outcomes. Few studies have examined the cost-effectiveness cervical arthrodesis at a service level. METHODS: A retrospective review of patients who underwent a primary 1-level ACDF by eight surgeons (four orthopedic and four neurosurgical) at a single academic institution between 2013 and 2015 was performed. Patients were identified by Diagnosis-Related Group and procedural codes. Patients with the ninth revision of the International Classification of Diseases coding for degenerative cervical pathology were included. Patients were excluded if they exhibited preoperative diagnoses or postoperative social work issues affecting their length of stay. Comparisons of preoperative demographics were performed using Student t tests and chi-squared analysis. Perioperative outcomes and costs for hospital services were compared using multivariate regression adjusted for preoperative characteristics. RESULTS: A total of 137 patients diagnosed with cervical degeneration underwent single-level ACDF; 44 and 93 were performed by orthopedic surgeons and neurosurgeons, respectively. There was no difference in patient demographics. ACDF procedures performed by orthopedic surgeons demonstrated shorter operative times (89.1 +/- 25.5 vs. 96.0 +/- 25.5 min; P = 0.002) and higher laboratory costs (Delta+$6.53 +/- $5.52 USD; P = 0.041). There were significant differences in operative time (P = 0.014) and labor costs (P = 0.034) between individual surgeons. There was no difference in total costs between specialties or individual surgeons. CONCLUSION: Surgical subspecialty training does not significantly affect total costs of ACDF procedures. Costs can, however, vary between individual surgeons based on operative times. Variation between individual surgeons highlights potential areas for improvement of the cost effectiveness of spinal procedures. LEVEL OF EVIDENCE: 4. PMID- 27779603 TI - Lumbar Fusion in Utah Workers' Compensation Patients: Changing Outcomes Across a Decade. AB - STUDY DESIGN: This study was a retrospective-cohort design involving a review of patient medical and cost records and a 2-year postsurgery follow-up outcome survey. OBJECTIVE: To evaluate the functional and cost outcomes associated with recent lumbar fusion surgeries in Utah workers and compare these outcomes with a comparable prior study cohort. SUMMARY OF BACKGROUND DATA: Lumbar fusion performed on injured workers has dramatically increased over the past 2 decades and this likely coincided with the increased use of more advanced surgical instrumentation. Considering the recent changes in lumbar fusion surgery, there is a need to identify how patient outcomes have changed among injured workers. MATERIALS AND METHODS: Retrospective chart review and 2-year postsurgery follow up survey of patient outcomes were performed. Postsurgical outcomes for this sample were compared with established norms for back pain patients and a previous cohort of compensated lumbar fusion patients obtained from Workers' Compensation Fund of Utah. RESULTS: The current cohort evidenced a solid fusion rate of 89% and significant increase in the use of surgical instrumentation, particularly titanium fusion cages. Despite increased solid fusion rates, injured workers who have undergone lumbar fusion in Utah demonstrated equivalent and in some cases worse outcomes than those documented a decade ago. Specifically, there were significant increases in back pain dysfunction and narcotic medication usage in the current versus the past cohort. Medical and compensation costs for compensated lumbar fusion patients in Utah also significantly increased since the mid-1990s. CONCLUSION: Over the past decade, injured workers who have undergone lumbar fusion in Utah showed an increase in solid fusion rates and costs without a corresponding improvement in patient outcomes. LEVEL OF EVIDENCE: 3. PMID- 27779604 TI - The Prediction and Prevention of Dysphagia After Occipitospinal Fusion by Use of the S-line (Swallowing Line). AB - STUDY DESIGN: Clinical case series and risk factor analysis of dysphagia after occipitospinal fusion (OSF). OBJECTIVE: The aim of this study was to develop new criteria to avoid postoperative dysphagia by analyzing the relationship among the craniocervical alignment, the oropharyngeal space, and the incidence of dysphagia after OSF. SUMMARY OF BACKGROUND DATA: Craniocervical malalignment after OSF is considered to be one of the primary triggers of postoperative dysphagia. However, ideal craniocervical alignment has not been confirmed. METHODS: Thirty-eight patients were included. We measured the O-C2 angle (O-C2A) and the pharyngeal inlet angle (PIA) on the lateral cervical radiogram at follow-up. PIA is defined as the angle between McGregor's line and the line that links the center of the C1 anterior arch and the apex of cervical sagittal curvature. The impact of these two parameters on the diameter of pharyngeal airway space (PAS) and the incidence of the dysphagia were analyzed. RESULTS: Six of 38 cases (15.8%) exhibited the dysphagia. A multiple regression analysis showed that PIA was significantly correlated with PAS (beta = 0.714, P = 0.005). Receiver-operating characteristic curves showed that PIA had a high accuracy as a predictor of the dysphagia with an AUC (area under the curve) of 0.90. Cases with a PIA less than 90 degrees showed significantly higher incidence of dysphagia (31.6%) than those with a 90 or more degrees of PIA (0.0%) (P = 0.008). CONCLUSION: Our results indicated that PIA had the high possibility to predict postoperative dysphagia by OSF with the condition of PIA <90 degrees . Based on these results, we defined "Swallowing line (S-line)" for the reference of 90 degrees of PIA. S-line (-) is defined as PIA <90 degrees , where the apex of cervical lordosis protruded anterior to the "S-line," which should indicate the patient is at a risk of postoperative dysphagia. LEVEL OF EVIDENCE: 4. PMID- 27779605 TI - Does Lordotic Angle of Cage Determine Lumbar Lordosis in Lumbar Interbody Fusion? AB - STUDY DESIGN: Retrospective, radiological analysis. OBJECTIVE: To determine that 15 degrees lordotic angle cages create higher lumbar lordosis in open transforaminal lumbar interbody fusion (TLIF) than 4 degrees and 8 degrees cages. SUMMARY OF BACKGROUND DATA: Restoration of lumbar lordosis is important to obtain good outcome after lumbar fusion surgery. Various shapes and angles of cages in interbody fusion have been used; however, it is not proved that lordotic angle of cages determine lumbar lordosis. METHODS: Sixty-seven patients were evaluated after TLIF using 15 degrees cages and screw instrumentation. For comparison, TLIF using 4 degrees lordotic angle cages in 65 patients and 8 degrees cages in 49 patients were analyzed. Lumbar lordosis angles, segmental lordosis angles, disc height, and bony union rate were measured on the radiographs. RESULTS: The lumbar lordosis was 31.1 degrees preoperatively, improved to 42.9 degrees postoperatively, and decreased to 36.4 degrees at the last follow-up in the 15 degrees group. It was 35.8 degrees before surgery, corrected to 41.5 degrees after surgery, and changed to 33.6 degrees at the last follow-up in the 4 degrees group. In the 8 degrees group, it was 32.7 degrees preoperatively, improved to 39.1 degrees postoperatively, and decreased to 34.5 degrees at the last follow-up. These changes showed statistical significances (P < 0.001). The segmental lordosis at L4-5 was 6.6 degrees before surgery, 13.1 degrees after surgery, and 9.8 degrees at the last follow-up in the 15 degrees group. It was 6.9 degrees , 9.5 degrees , and 6.2 degrees in the 4 degrees group and 6.7 degrees , 9.8 degrees , and 8.1 degrees in the 8 degrees group, respectively (P < 0.001). The disc height restoration was better in the 15 degrees group than in the 4 degrees and 8 degrees groups (P < 0.001). Bony union rate was not significant among the three groups (P = 0.087). CONCLUSION: The lordotic angle of the cages determined restoration of lumbar lordosis after TLIF. Cages with sufficient lordotic angle showed better restoration of lumbar lordosis and prevention of loss of correction. LEVEL OF EVIDENCE: 4. PMID- 27779606 TI - Surgical and Radiographic Outcomes After Pedicle Subtraction Osteotomy According to Surgeon's Experience. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: The aim of this study was to evaluate and compare the surgical, radiographic, and clinical outcomes of pedicle subtraction osteotomy (PSO) according to surgeon's experience. SUMMARY OF BACKGROUND DATA: Although PSO has been widely used to correct spinal deformities, it still remains technically demanding procedure with high complications. METHODS: Comparative analysis of 40 consecutive patients treated with lumbar PSOs was performed. According to time period, the former and latter 20 patients were divided into group 1 and group 2, respectively. Patients' demographic data, operative, radiographic/clinical outcomes, and complications were compared between the groups. RESULTS: Baseline characteristics and preoperative radiographic parameters were not different between the groups. Significant reductions of operative time (569.6 vs. 392.0 minutes, P = 0.000), surgical bleeding (1777.5 vs. 949.5 mL, P = 0.002), and transfused volume of red blood cell (1232.6 vs. 864.1 mL, P = 0.041) in group 2 were observed. Postoperative sagittal vertical axis was significantly different between the groups (40.1 and 3.6 mm, groups 1 and 2, respectively, P = 0.008), and the difference was sustained to the ultimate follow-up (59.4 vs. 13.2 mm, P = 0.003). There was a difference regarding the amount of curve correction by PSO, which was significantly greater in group 2 (25.7 degrees vs. 35.8 degrees , P = 0.023). Intraoperative complications (7 vs. 1, P = 0.019) were significantly lower in group 2. Total complications (20 vs. 10, P = 0.070), postoperative transient neurologic deficit (2 vs. 1), and revision surgery (4 vs. 3) were also lower in group 2, without statistical significance. The amount of the improvement of SRS 22 score was not different between the groups (P = 0.395). CONCLUSION: PSO may be performed in patients with fixed sagittal imbalance with an acceptable rate of complications after about 20 cases. With acquisition of surgical experiences, surgeons could perform PSO more effectively and safely. PMID- 27779607 TI - Association of Lumbar Spondylolisthesis With Low Back Pain and Symptomatic Lumbar Spinal Stenosis in a Population-based Cohort: The Wakayama Spine Study. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine the association between lumbar spondylolisthesis and low back pain and symptomatic lumbar spinal stenosis (LSS) in a population-based cohort. SUMMARY OF BACKGROUND DATA: The basic epidemiology of lumbar spondylolisthesis is not well known. There is little information regarding the association between lumbar spondylolisthesis and clinical symptoms such as low back pain and LSS symptoms. METHODS: This cross sectional study included data from 938 participants (308 males, 630 females; mean age, 67.3 years; range, 40-93 years). Lumbar spondylolisthesis was defined as a slip of >=5%. Diagnostic criteria for symptomatic LSS required the presence of both leg symptoms and radiographic LSS findings on magnetic resonance imaging. The prevalence of low back pain and symptomatic LSS was compared between those with or without spondylolisthesis. Furthermore, we determined the association between the amount of slippage and presence of symptomatic LSS. RESULTS: The prevalence of spondylolisthesis at any level was 15.8% in the total sample, 13.0% in males, and 17.1% in females; the prevalence was not significantly different between males and females (P = 0.09). In both, males and females, symptomatic LSS was related to spondylolisthesis [odds ratio (OR): 2.07; 95% CI: 1.20-3.44]; however, no such association was found for spondylolisthesis and presence of low back pain. The amount of slippage was not related to the presence of symptomatic LSS (P = 0.93). CONCLUSION: This population-based cohort study revealed that lumbar spondylolisthesis had a closer association with leg symptoms than with low back pain. There was a significant difference in the presence of symptomatic LSS between participants with and without spondylolisthesis. However, the amount of slippage was not related to the presence of symptomatic LSS. LEVEL OF EVIDENCE: 3. PMID- 27779608 TI - Early Detection of Progressive Adolescent Idiopathic Scoliosis: A Severity Index. AB - STUDY DESIGN: Early detection of progressive adolescent idiopathic scoliosis (AIS) was assessed based on 3D quantification of the deformity. OBJECTIVE: Based on 3D quantitative description of scoliosis curves, the aim is to assess a specific phenotype that could be an early detectable severity index for progressive AIS. SUMMARY OF BACKGROUND DATA: Early detection of progressive scoliosis is important for adapted treatment to limit progression. However, progression risk assessment is mainly based on the follow up, waiting for signs of rapid progression that generally occur during the growth peak. METHODS: Sixty five mild scoliosis (16 boys, 49 girls, Cobb Angle between 10 and 20 degrees ) with a Risser between 0 and 2 were followed from their first examination until a decision was made by the clinician, either considering the spine as stable at the end of growth (26 patients) or planning to brace because of progression (39 patients). Calibrated biplanar x-rays were performed and 3D reconstructions of the spine allowed calculating six local parameters related to main curve deformity. For progressive curve 3D phenotype assessment, data were compared with those previously assessed for 30 severe scoliosis (Cobb Angle > 35 degrees ), 17 scoliosis before brace (Cobb Angle > 29 degrees ) and 53 spines of nonscoliosis subjects. A predictive discriminant analysis was performed to assess similarity of mild scoliosis curves either to those of scoliosis or nonscoliosis spines, yielding a severity index (S-index). S-index value at first examination was compared with clinical outcome. RESULTS: At the first exam, 53 out of 65 predictions (82%) were in agreement with actual clinical outcome. Approximately, 89% of the curves that were predicted as progressive proved accurate. CONCLUSION: Although still requiring large scale validation, results are promising for early detection of progressive curves. LEVEL OF EVIDENCE: 2. PMID- 27779610 TI - Factors Influencing the Soft Tissue Changes Around Single Laser Microtextured Implants-Abutments in the Anterior Maxilla: A 5-Year Retrospective Study. AB - PURPOSE: The aim of this study was to evaluate the possible factors that influenced the periimplant soft tissue changes around single implants-abutments with laser-microtextured surface (LMS) in the esthetic zone. MATERIALS AND METHODS: Thirty-nine units, formed by implant-abutment with LMS were studied. Variables possibly associated with the periimplant soft tissue changes were obtained from clinical measurements (plaque [present/absent], periimplant biotype [thin/thick], and probing depth); intrasurgical measurements (vertical height in millimeters of the keratinized gingiva in the vestibular part of the implant site vestibular keratinized gingiva [VKG], implant vestibular crestal exposition, vestibular crestal level, and vestibular bone width); cast models (implant position [buccal/palatal], implant abutments angle); periapical radiographs (distance from the contact point to the interproximal bone crest of the adjacent tooth [CP-BC], distance from the contact point to the implant platform [CP-P], distance from the contact point to the first bone to implant contact [CP-IB]); and digital clinical photographs. Fisher exact test was used to determine the influence of each factor on the papilla level and on the facial marginal mucosal level. RESULTS: The papillae level at the implant sites was significantly associated with the distance from the contact point to the alveolar bone crest, whereas no association was found with other variables. Periimplant biotype, differences in the VKG, CP-BC, and CP-IB were found associated with the different facial marginal mucosal level groups. CONCLUSIONS: This study showed that the papilla level at single-tooth implants-abutments with LMS in the anterior maxilla was mainly influenced by the interproximal bone crest level of the adjacent tooth, whereas the marginal mucosal level was affected by periimplant biotype, facial bone crest level, and crestal implant exposition. PMID- 27779611 TI - Effects of Alendronate on Bone Remodeling Around Osseointegrated Implants in Rats. AB - OBJECTIVE: To determine the effects of alendronate on bone remodeling around osseointegrated implants in rats. MATERIALS AND METHODS: The maxillary first molars were extracted from 36 male Sprague-Dawley rats, and replaced with customized implants. They were then administered twice-weekly subcutaneous injections of either alendronate (alendronate group) or saline (control group) after allowing a 4-week period for osseointegration. They were killed at 4, 8, or 12 weeks after the commencement of the injection protocol, and the implant sites were evaluated comprehensively by microcomputed tomographic, histologic, and biochemical assessments. RESULTS: It was hard to find statistically significant differences from microcomputed tomographic analyses. In addition, inconsistent variations were derived from histologic data. However, biochemical data showed statistically significant differences; serum osteocalcin level was statistically significantly lower in the alendronate group than in the control group at 8 weeks after the commencement of injections. In addition, serum osteocalcin level in the alendronate group was statistically significantly lower at 8 and 12 weeks after the initial injection point than at preinjection. CONCLUSIONS: The results suggest alendronate might affect bone remodeling activity around osseointegrated implants negatively, and serum osteocalcin could serve as an accessory tool to evaluate this effect. PMID- 27779612 TI - Autoimmune Pancreatitis and Inflammatory Bowel Disease: An Updated Review. AB - Autoimmune pancreatitis (AIP) occurring in association with inflammatory bowel disease (IBD) is rather rare and carries a worse prognosis and greater disease severity compared with IBD alone. Although it is an infrequently documented association, progress over the last 20 years has led to better understanding of the association between AIP and IBD. IBD has a stronger association with type 2 than with type 1 AIP. Clinical and histologic features of AIP-IBD more often reveal features of type 2 AIP. Imaging is not helpful in facilitating the diagnosis of AIP and IBD. Similarly, attempts to identify a serological marker have not yielded better result. A proposed lymphocyte homing mechanism provides some insight into the mechanism of pathogenesis. This review represents an update of our current knowledge of the association between AIP and IBD. PMID- 27779613 TI - Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study. AB - GOALS/BACKGROUND: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. STUDY: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. RESULTS: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. CONCLUSIONS: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk. PMID- 27779614 TI - The "Air in the CT X-ray Tube Oil" Artifact-Examples of the Quality Control Images and the Evaluation of Four Potential Clinical Patients' Head Computed Tomography Cases. AB - We present a newly reposted scanner-based artifact-with 4 potential patients' head computed tomography (CT) cases-the "Air in the CT X-ray Tube Oil" artifact with a 64-slice multidetector CT. This artifact mimics diseases, which cause hypodense findings in CT images. It can be difficult to notice in the clinical patient imaging but can be also very difficult to verify in quality control tests. PMID- 27779615 TI - A German-language replication study analysing the role of figurative speech in reasoning. AB - According to the metaphorical framing model, the use of metaphors in discussing an issue influences recipients' understanding and assessment of that issue. In a recent study, participants read a text referring to a city's crime problem either as a beast or a virus and then proposed counter-measures for that problem. Participants' suggestions differed depending on the metaphor they had read. This replication matched the original procedure regarding the content of the rhetorical figures (beast vs virus), the topic under focus (crime) and the measurement of the dependent variable (open-end format to collect participants' proposals). The procedure differed from the original with respect to language (German instead of English) and by including the formal type of rhetorical figure (metaphor or simile) as a factor. A systematic influence of the content of the figure on subjects' proposals was observed. Presenting the rhetorical figure as a metaphor or a simile had no effect. Taken together, we were able to replicate the main effect of the original study. Metaphors do indeed frame reasoning. PMID- 27779616 TI - Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy. AB - The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity. Consistent with this, priming with intra-tumoral Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous B16 melanoma tumours. We also show that combination of either therapy alone with anti-PD-1 immune checkpoint blockade augmented both the Th1 response induced by systemically delivered Reovirus in combination with GM-CSF, and also the Th17 response induced by VSV-ASMEL. Significantly, anti-PD-1 also uncovered an anti-tumour Th1 response following VSV-ASMEL treatment that was not seen in the absence of checkpoint blockade. Finally, the combination of all three treatments (priming with systemically delivered Reovirus, followed by double boosting with systemic VSV ASMEL and anti-PD-1) significantly enhanced survival, with long-term cures, compared to any individual, or double, combination therapies, associated with strong Th1 and Th17 responses to tumour antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumour immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumour immune responses. PMID- 27779617 TI - Diversity and oceanic distribution of prasinophytes clade VII, the dominant group of green algae in oceanic waters. AB - Prasinophytes clade VII is a group of pico/nano-planktonic green algae (division Chlorophyta) for which numerous ribosomal RNA (rRNA) sequences have been retrieved from the marine environment in the last 15 years. A large number of strains have also been isolated but have not yet received a formal taxonomic description. A phylogenetic analysis of available strains using both the nuclear 18S and plastidial 16S rRNA genes demonstrates that this group composes at least 10 different clades: A1-A7 and B1-B3. Analysis of sequences from the variable V9 region of the 18S rRNA gene collected during the Tara Oceans expedition and in the frame of the Ocean Sampling Day consortium reveal that clade VII is the dominant Chlorophyta group in oceanic waters, replacing Mamiellophyceae, which have this role in coastal waters. At some location, prasinophytes clade VII can even be the dominant photosynthetic eukaryote representing up to 80% of photosynthetic metabarcodes overall. B1 and A4 are the overall dominant clades and different clades seem to occupy distinct niches, for example, A6 is dominant in surface Mediterranean Sea waters, whereas A4 extend to high temperate latitudes. Our work demonstrates that prasinophytes clade VII constitute a highly diversified group, which is a key component of phytoplankton in open oceanic waters but has been neglected in the conceptualization of marine microbial diversity and carbon cycle. PMID- 27779618 TI - A studyforrest extension, retinotopic mapping and localization of higher visual areas. AB - The studyforrest (http://studyforrest.org) dataset is likely the largest neuroimaging dataset on natural language and story processing publicly available today. In this article, along with a companion publication, we present an update of this dataset that extends its scope to vision and multi-sensory research. 15 participants of the original cohort volunteered for a series of additional studies: a clinical examination of visual function, a standard retinotopic mapping procedure, and a localization of higher visual areas-such as the fusiform face area. The combination of this update, the previous data releases for the dataset, and the companion publication, which includes neuroimaging and eye tracking data from natural stimulation with a motion picture, form an extremely versatile and comprehensive resource for brain imaging research-with almost six hours of functional neuroimaging data across five different stimulation paradigms for each participant. Furthermore, we describe employed paradigms and present results that document the quality of the data for the purpose of characterising major properties of participants' visual processing stream. PMID- 27779619 TI - A database of human exposomes and phenomes from the US National Health and Nutrition Examination Survey. AB - The National Health and Nutrition Examination Survey (NHANES) is a population survey implemented by the Centers for Disease Control and Prevention (CDC) to monitor the health of the United States whose data is publicly available in hundreds of files. This Data Descriptor describes a single unified and universally accessible data file, merging across 255 separate files and stitching data across 4 surveys, encompassing 41,474 individuals and 1,191 variables. The variables consist of phenotype and environmental exposure information on each individual, specifically (1) demographic information, physical exam results (e.g., height, body mass index), laboratory results (e.g., cholesterol, glucose, and environmental exposures), and (4) questionnaire items. Second, the data descriptor describes a dictionary to enable analysts find variables by category and human-readable description. The datasets are available on DataDryad and a hands-on analytics tutorial is available on GitHub. Through a new big data platform, BD2K Patient Centered Information Commons (http://pic-sure.org), we provide a new way to browse the dataset via a web browser (https://nhanes.hms.harvard.edu) and provide application programming interface for programmatic access. PMID- 27779620 TI - Double-target Antisense U1snRNAs Correct Mis-splicing Due to c.639+861C>T and c.639+919G>A GLA Deep Intronic Mutations. AB - Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of the alpha-galactosidase A (alpha-Gal A) enzyme, which is encoded by the GLA gene. GLA transcription in humans produces a major mRNA encoding alpha-Gal A and a minor mRNA of unknown function, which retains a 57-nucleotide-long cryptic exon between exons 4 and 5, bearing a premature termination codon. NM_000169.2:c.639+861C>T and NM_000169.2:c.639+919G>A GLA deep intronic mutations have been described to cause Fabry disease by inducing overexpression of the alternatively spliced mRNA, along with a dramatic decrease in the major one. Here, we built a wild-type GLA minigene and two minigenes that carry mutations c.639+861C>T and c.639+919G>A. Once transfected into cells, the minigenes recapitulate the molecular patterns observed in patients, at the mRNA, protein, and enzymatic level. We constructed a set of specific double-target U1asRNAs to correct c.639+861C>T and c.639+919G>A GLA mutations. Efficacy of U1asRNAs in inducing the skipping of the cryptic exon was evaluated upon their transient co transfection with the minigenes in COS-1 cells, by real-time polymerase chain reaction (PCR), western blot analysis, and alpha-Gal A enzyme assay. We identified a set of U1asRNAs that efficiently restored alpha-Gal A enzyme activity and the correct splicing pathways in reporter minigenes. We also identified a unique U1asRNA correcting both mutations as efficently as the mutation-specific U1asRNAs. Our study proves that an exon skipping-based approach recovering alpha-Gal A activity in the c.639+861C>T and c.639+919G>A GLA mutations is active. PMID- 27779621 TI - A studyforrest extension, simultaneous fMRI and eye gaze recordings during prolonged natural stimulation. AB - Here we present an update of the studyforrest (http://studyforrest.org) dataset that complements the previously released functional magnetic resonance imaging (fMRI) data for natural language processing with a new two-hour 3 Tesla fMRI acquisition while 15 of the original participants were shown an audio-visual version of the stimulus motion picture. We demonstrate with two validation analyses that these new data support modeling specific properties of the complex natural stimulus, as well as a substantial within-subject BOLD response congruency in brain areas related to the processing of auditory inputs, speech, and narrative when compared to the existing fMRI data for audio-only stimulation. In addition, we provide participants' eye gaze location as recorded simultaneously with fMRI, and an additional sample of 15 control participants whose eye gaze trajectories for the entire movie were recorded in a lab setting to enable studies on attentional processes and comparative investigations on the potential impact of the stimulation setting on these processes. PMID- 27779622 TI - Mothers do it differently: reproductive experience alters fear extinction in female rats and women. AB - Fear extinction is the laboratory basis of exposure therapy for anxiety disorders. Recent findings have revealed that estradiol is necessary to the consolidation of extinction memories in females. These findings are based on studies conducted using virgin rats and young women whose reproductive history is unknown. We hypothesized that motherhood, which results in extensive endocrinological, neurobiological and behavioral changes, may lead to alterations in fear extinction in females. We used a cross-species translational approach to investigate the impact of reproductive experience on fear extinction and fear relapse in female rats (n=116) and women (n=64). Although freezing during extinction recall was associated with estrous cycle phase during extinction training in virgin rats, this association was mitigated in age-matched reproductively experienced rats, even when fear extinction occurred 3 months after pups had been weaned, and even though reproductively experienced rats exhibited attenuated serum estradiol levels. In addition, although serum estradiol levels predicted extinction recall in human women with no prior reproductive experience, no such association was found in women with children. Finally, although virgin rats displayed both renewal and reinstatement after fear extinction, these common relapse phenomena were absent in rats with reproductive experience. Together, these findings suggest that reproductive experience alters the endocrine and behavioral features of fear extinction in females long after the hormonal surges of pregnancy and lactation have diminished. These results highlight the need to incorporate both hormonal and reproductive status as important factors in current models of fear extinction in females. PMID- 27779623 TI - Emergence of social behavior deficit, blunted corticolimbic activity and adult depression-like behavior in a rodent model of maternal maltreatment. AB - Disrupted social behavior is a core symptom of multiple psychiatric and neurodevelopmental disorders. Many of these disorders are exacerbated by adverse infant experiences, including maltreatment and abuse, which negatively affect amygdala development. Although a link between impaired social behavior, abnormal amygdala function and depressive-like behavior following early adversity has been demonstrated in humans and animal models, the developmental emergence of maltreatment-related social deficits and associated amygdala neural activity are unknown. We used a naturalistic rodent model of maternal maltreatment during a sensitive period, postnatal days 8-12 (PN8-12), which produces social behavior deficits that precede adolescent depressive-like behavior and amygdala dysfunction, to examine social behavior in infancy, periweaning and adolescence. Neural activity in response to the social behavior test was assessed via c-Fos immunohistochemistry at these ages. A separate group of animals was tested for adult depressive-like behavior in the forced swim test. Maltreatment spared infant (PN16-18) social behavior but disrupted periweaning (PN20-22) and adolescent (PN42-48) social behavior. Maltreated rats exhibited blunted neural activation in the amygdala and other areas implicated in social functioning, including the medial prefrontal cortex and nucleus accumbens, at these ages and increased adult depressive-like behavior. These findings may suggest corticolimbic involvement in the emergence of maltreatment-induced social deficits that are linked to adult depressive-like behavior, thereby highlighting potential targets for therapeutic intervention. Understanding how infant experiences influence social behavior and age-specific expression across development may provide insights into basic neural mechanisms of social behaviors and disease-relevant social dysfunction exacerbated by early-life stress. PMID- 27779624 TI - Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. AB - Propionic acid (PPA) is a ubiquitous short-chain fatty acid, which is a major fermentation product of the enteric microbiome. PPA is a normal intermediate of metabolism and is found in foods, either naturally or as a preservative. PPA and its derivatives have been implicated in both health and disease. Whereas PPA is an energy substrate and has many proposed beneficial effects, it is also associated with human disorders involving mitochondrial dysfunction, including propionic acidemia and autism spectrum disorders (ASDs). We aimed to investigate the dichotomy between the health and disease effects of PPA by measuring mitochondrial function in ASD and age- and gender-matched control lymphoblastoid cell lines (LCLs) following incubation with PPA at several concentrations and durations both with and without an in vitro increase in reactive oxygen species (ROS). Mitochondrial function was optimally increased at particular exposure durations and concentrations of PPA with ASD LCLs, demonstrating a greater enhancement. In contrast, increasing ROS negated the positive PPA effect with the ASD LCLs, showing a greater detriment. These data demonstrate that enteric microbiome metabolites such as PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration and microenvironment redox state with these effects amplified in LCLs derived from individuals with ASD. As PPA, as well as enteric bacteria, which produce PPA, have been implicated in a wide variety of diseases, including ASD, diabetes, obesity and inflammatory diseases, insight into this metabolic modulator from the host microbiome may have wide applications for both health and disease. PMID- 27779625 TI - Childhood adverse life events and parental psychopathology as risk factors for bipolar disorder. AB - Childhood adverse events are risk factors for later bipolar disorder. We quantified the risks for a later diagnosis of bipolar disorder after exposure to adverse life events in children with and without parental psychopathology. This register-based population cohort study included all persons born in Denmark from 1980 to 1998 (980 554 persons). Adversities before age 15 years were: familial disruption; parental somatic illness; any parental psychopathology; parental labour market exclusion; parental imprisonment; placement in out-of-home care; and parental natural and unnatural death. We calculated risk estimates of each of these eight life events as single exposure and risk estimates for exposure to multiple life events. Main outcome variable was a diagnosis of bipolar disorder after the age of 15 years, analysed with Cox proportional hazard regression. Single exposure to most of the investigated adversities were associated with increased risk for bipolar disorder, exceptions were parental somatic illness and parental natural death. By far the strongest risk factor for bipolar disorder in our study was any mental disorder in the parent (hazard ratio 3.53; 95% confidence interval 2.73-4.53) and the additional effects of life events on bipolar risk were limited. An effect of early adverse life events on bipolar risk later in life was mainly observed in children without parental psychopathology. Our findings do not exclude early-life events as possible risk factors, but challenge the concept of adversities as important independent determinants of bipolar disorder in genetically vulnerable individuals. PMID- 27779627 TI - A support vector machine model provides an accurate transcript-level-based diagnostic for major depressive disorder. AB - Major depressive disorder (MDD) is a critical cause of morbidity and disability with an economic cost of hundreds of billions of dollars each year, necessitating more effective treatment strategies and novel approaches to translational research. A notable barrier in addressing this public health threat involves reliable identification of the disorder, as many affected individuals remain undiagnosed or misdiagnosed. An objective blood-based diagnostic test using transcript levels of a panel of markers would provide an invaluable tool for MDD as the infrastructure-including equipment, trained personnel, billing, and governmental approval-for similar tests is well established in clinics worldwide. Here we present a supervised classification model utilizing support vector machines (SVMs) for the analysis of transcriptomic data readily obtained from a peripheral blood specimen. The model was trained on data from subjects with MDD (n=32) and age- and gender-matched controls (n=32). This SVM model provides a cross-validated sensitivity and specificity of 90.6% for the diagnosis of MDD using a panel of 10 transcripts. We applied a logistic equation on the SVM model and quantified a likelihood of depression score. This score gives the probability of a MDD diagnosis and allows the tuning of specificity and sensitivity for individual patients to bring personalized medicine closer in psychiatry. PMID- 27779629 TI - Organelle-specific bioprobes based on fluorogens with aggregation-induced emission (AIE) characteristics. AB - Bioprobes based on fluorogens with aggregation-induced emission (AIE) characteristics have been increasingly used in chemosensing and bioimaging due to their high sensitivity, photostability and biocompatibility. In this review, we summarize the design of cellular organelle specific (cytoplasm membrane, mitochondria, lysosomes, lipid droplets and nucleus) AIE bioprobes and their applications in organelle imaging, organelle bioactivity monitoring, and image guided cancer cell ablation. PMID- 27779626 TI - SNP-based heritability estimates of the personality dimensions and polygenic prediction of both neuroticism and major depression: findings from CONVERGE. AB - Biometrical genetic studies suggest that the personality dimensions, including neuroticism, are moderately heritable (~0.4 to 0.6). Quantitative analyses that aggregate the effects of many common variants have recently further informed genetic research on European samples. However, there has been limited research to date on non-European populations. This study examined the personality dimensions in a large sample of Han Chinese descent (N=10 064) from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology study, aimed at identifying genetic risk factors for recurrent major depression among a rigorously ascertained cohort. Heritability of neuroticism as measured by the Eysenck Personality Questionnaire (EPQ) was estimated to be low but statistically significant at 10% (s.e.=0.03, P=0.0001). In addition to EPQ, neuroticism based on a three-factor model, data for the Big Five (BF) personality dimensions (neuroticism, openness, conscientiousness, extraversion and agreeableness) measured by the Big Five Inventory were available for controls (n=5596). Heritability estimates of the BF were not statistically significant despite high power (>0.85) to detect heritabilities of 0.10. Polygenic risk scores constructed by best linear unbiased prediction weights applied to split-half samples failed to significantly predict any of the personality traits, but polygenic risk for neuroticism, calculated with LDpred and based on predictive variants previously identified from European populations (N=171 911), significantly predicted major depressive disorder case-control status (P=0.0004) after false discovery rate correction. The scores also significantly predicted EPQ neuroticism (P=6.3 * 10 6). Factor analytic results of the measures indicated that any differences in heritabilities across samples may be due to genetic variation or variation in haplotype structure between samples, rather than measurement non-invariance. Findings demonstrate that neuroticism can be significantly predicted across ancestry, and highlight the importance of studying polygenic contributions to personality in non-European populations. PMID- 27779638 TI - Sickness absence and permanent work disability in relation to upper- and lower body pain and occupational mechanical and psychosocial exposures. AB - OBJECTIVE: The aim of this study was to examine if combined pain (pain in the upper and lower body), high occupational mechanical exposures, and job strain predict sickness absence and permanent work disability, particularly if co occurring. METHODS: This longitudinal study was based on the musculoskeletal research database at the Danish Ramazzini Centre. We linked baseline information from 2001-2004 on musculoskeletal pain, job titles, and covariates with register information on sickness absence and permanent work disability. Mechanical and psychosocial exposure estimates were obtained from job exposure matrices. We used multivariable Cox regression. RESULTS: The study included 25 292 persons. Compared to low occupational mechanical exposures and no pain, low mechanical exposures and combined pain showed an adjusted hazard ratio (HR adj) of 1.81 [95% confidence interval (95% CI) 1.58-2.08], while high mechanical exposures and combined pain showed HR adj3.71 (95% CI 3.24-4.25) for sickness absence. The corresponding values for permanent work disability were 3.35 (95% CI 1.74-6.45) and 4.59 (95% CI 2.36-8.94). Job strain showed an association with sickness absence [HR adj1.24 (95% CI 1.10-1.39)], while low social support was associated with both sickness absence and permanent work disability [HR adj1.30 (95% CI 1.19 1.41) and 2.19 (95% CI 1.41-3.41), respectively]. CONCLUSIONS: Combined pain in the upper and lower body was associated with sickness absence and permanent work disability, and high occupational mechanical exposures further increased the risk. Job strain showed a modest association with sickness absence, while low social support at work was associated with both outcomes, especially permanent work disability. PMID- 27779639 TI - Long-term effectiveness of an educational and physical intervention for preventing low-back pain recurrence: a randomized controlled trial. AB - OBJECTIVE: Low-back pain (LBP) is a common and recurrent condition, but the evidence is scarce about effective strategies to prevent recurrence and disability in the longer term. This study investigated the effect of a light exercise program, initiated in the workplace and continued at home, in reducing recurrence of LBP episodes among healthcare workers. METHODS: A total of 353 healthcare workers from ten hospitals were enrolled in a randomized controlled trial (RCT) and were randomized to the intervention or control groups, the latter of which received usual care. The intervention comprised three steps: (i) a 2 hour education session, (ii) five weekly 90-minutes exercise training sessions in the workplace, and (iii) a home-based self-managed exercise program. The main outcome was recurrence of LBP with sick-leave at 24-months follow-up. RESULTS: At two-year follow-up, 35 workers (24%) in the intervention group and 31 workers (21%) in the control group had at least one LBP recurrence with sick leave. No effect was observed between groups [odds ratio (OR) 1.22, 95% confidence interval (95% CI) 0.67-2.23, P=0.516]. The intervention was effective in reducing fear avoidance with a mean reduction of -3.6 (95% CI -4.8- -2.4) points on the fear avoidance beliefs questionnaire score for physical activity (FABQ-P) in the intervention group compared with -1.3 (95% CI -2.2- -0.3) points in the control group (P<0.05). It was also effective in improving muscle endurance with a mean increase of 13.9 (95% CI 3.3-24.5) minutes on the Sorensen test in the intervention group compared with -8.3 (95% CI-17.5-0.9) minutes in the control group (P<0.05). Healthcare utilization was reduced in the intervention group for painkillers, medical visits, imaging and outpatient physiotherapy. CONCLUSION: It was not possible to conclude about the effectiveness of a light exercise program to reduce LBP recurrence episodes in the long-term in healthcare workers. However, it was effective to improve muscle endurance, and to reduce fear avoidance beliefs and healthcare utilization. Further studies are necessary in order to identify effective interventions to reduce LBP recurrence and related sick-leaves. PMID- 27779640 TI - Aquaporin 1 contributes to chondrocyte apoptosis in a rat model of osteoarthritis. AB - Aquaporins (AQPs) have been found to be associated with a number of diseases. However, the role of AQP-1 in the pathogenesis of osteoarthritis remains unclear. We previously found that AQP-1 expression was upregulated in osteoarthritic cartilage and strongly correlated with caspase-3 expression and activity. The aim of this study was to further investigate the association of AQP-1 expression with chondrocyte apoptosis in a rat model of osteoarthritis, using RNA interference to knock down AQP-1. For this purspose, 72 male Sprague-Dawley rats were randomly assigned to 3 groups as follows: the control group not treated surgically (n=24), the sham-operated group (n=24), and the osteoarthritis group (n=24). Osteoarthritis was induced by amputating the anterior cruciate ligament and medial collateral ligament and partially excising the medial meniscus. Chondrocytes from the rats with osteoarthritis were isolated and cultured. shRNAs were used to knock down AQP-1 expression in the cultured chondrocytes. The expression of AQP-1 and caspase-3 was determined by reverse transcription quantitative polymerase chain reaction. Caspase-3 activity was measured using a caspase-3 colorimetric assay. The rats in our model of osteoarthritis exhibited severe cartilage damage. The knockdown of AQP-1 decreased caspase-3 expression and activity in the cultured chondrocytes. In addition, the expression of AQP-1 positively correlated with caspase-3 expression and activity. Thus, the findings of our study, suggest that AQP-1 promotes caspase-3 activation and thereby contributes to chondrocyte apoptosis and to the development of osteoarthritis. PMID- 27779641 TI - AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells. AB - Chinese medicines are emerging as an attractive new generation of anticancer drugs. Here, we explored the impact of salvianolic acid B (Sal B), the major water-soluble compounds of Danshen, on apoptosis and autophagy of human hepatocellular carcinoma cells (HCC). We also investigated the related molecular mechanisms. We found that Sal B exhibits potent ability to inhibit HCC cells viability in a concentration-dependent manner, and to induce apoptosis via the mitochondrial apoptosis pathway. Additionally, Sal B could also induce autophagy. Furthermore, pretreatment with the autophagy inhibitor chloroquine or 3 methyladenine showed the potential in attenuating the apoptosis rate induced by Sal B. Mechanistically, Sal B treatment inhibited the AKT/mTOR signaling cascade in vitro. Overexpression of AKT abolished the effects of Sal B on HCC cells, suggesting a critical role of the AKT/mTOR signaling pathway in Sal B-induced biological effects. Our results indicated that the mitochondrial pathway was involved in Sal B-induced apoptosis of HCC cells. Moreover, the AKT/mTOR signaling pathway was involved in Sal B-induced autophagy, which promoted apoptosis. This study may provide a promising strategy for using Sal B as a chemotherapeutic agent for patients with HCC. PMID- 27779643 TI - Screening for genes, transcription factors and miRNAs associated with the myogenic and osteogenic differentiation of human adipose tissue-derived stem cells. AB - In the present study, we aimed to reveal the molecular mechanisms responsible for the differentiation of human adipose tissue-derived stem cells (hASCs) into myocytes and osteoblasts. Microarray data GSE37329 were obtained from the Gene Expression Omnibus database, including three hASC cell lines from healthy donors, two osteogenic lineages and two myogenic lineages from the in vitro-induction of hASCs. Differentially expressed genes (DEGs) in the two lineages were firstly screened. Subsequently, the underlying functions of the two sets of DEGs were investigated by Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, followed by protein-protein interaction (PPI) network construction. Regulatory relationships between transcription factors (TFs) and microRNAs (miRNAs or miRs) with target genes were finally explored using different algorithms. A total of 665 and 485 DEGs were identified from the hASC-derived myogenic and osteogenic lineages, respectively. The shared upregulated genes (n=205) in the two sets of DEGs were mainly involved in metabolism-related pathways, whereas the shared downregulated genes (n=128) were significantly enriched in the transforming growth factor-beta (TGF-beta) signaling pathway. Four genes, vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), nerve growth factor (NGF) and interleukin 1B (IL1B), presented with relatively higher degrees in both PPI networks. The transcription factor RAD21 was predicted to target shared upregulated and downregulated genes as well as specific downregulated genes in the myogenic and the osteogenic lineages. In addition, miRNA-DEG interaction analysis revealed that hsa-miR-1 regulated the most shared DEGs in the two lineages. There may be a correlation between the four genes, VEGFA, FGF2, IL1B and NGF, and the differentiation of hASCs into myocytes and osteoblasts. The TF RAD21 and hsa-miR 1 may play important roles in regulating the expression of differentiation associated genes. PMID- 27779642 TI - Impact of vitamin E-blended UHMWPE wear particles on the osseous microenvironment in polyethylene particle-induced osteolysis. AB - Aseptic loosening mediated by wear particle-induced osteolysis (PIO) remains the major cause of implant loosening in endoprosthetic surgery. The development of new vitamin E (alpha-tocopherol)-blended ultra-high molecular weight polyethylene (VE-UHMWPE) with increased oxidation resistance and improved mechanical properties has raised hopes. Furthermore, regenerative approaches may be opened, as vitamin E supplementation has shown neuroprotective characteristics mediated via calcitonin gene-related peptide (CGRP), which is known to affect bone remodeling in PIO. Therefore, the present study aimed to further clarify the impact of VE-UHMWPE wear particles on the osseous microenvironment and to identify the potential modulatory pathways involved. Using an established murine calvaria model, mice were subjected to sham operation (SHAM group), or treated with UHMWPE or VE-UHMWPE particles for different experimental durations (7, 14 and 28 days; n=6/group). Morphometric analysis by micro-computed tomography detected significant (p<0.01) and comparable signs of PIO in all particle-treated groups, whereas markers of inflammation [tumor necrosis factor (TNF) alpha/tartrate resistant acid phosphatase (TRAP) staining] and bone remodeling [Dickkopf-related protein 1 (DKK-1)/osteoprotegerin (OPG)] were most affected in the early stages following surgery. Taking the present data into account, VE UHMWPE appears to have a promising biocompatibility and increased ageing resistance. According to the alpha-CGRP serum levels and immunohistochemistry, the impact of vitamin E on neuropeptidergic signaling and its chance for regenerative approaches requires further investigation. PMID- 27779644 TI - All-trans retinoic acid shifts rosiglitazone-induced adipogenic differentiation to osteogenic differentiation in mouse embryonic fibroblasts. AB - Rosiglitazone (RSG) is a potent drug used in the treatment of insulin resistance; however, it is associated with marked skeletal toxicity. RSG-induced osteoporosis may contribute to the promotion of adipogenic differentiation at the expense of osteogenic differentiation in bone marrow stromal cells. The aim of this study was to investigate whether RSG-induced bone toxicity can be reversed by combined treatment with all-trans retinoic acid (ATRA). We examined different osteogenic markers in mouse embryonic fibroblasts (MEFs) following treatment with RSG, ATRA, or RSG and ATRA in combination. We examined the effects of RSG and/or ATRA on ectopic bone formation, and dissected the possible molecular mechanisms underlying this process. We found that ATRA or RSG both induced alkaline phosphatase (ALP) activity in the MEFs, and that the ATRA-induced ALP activity was enhanced by RSG and vice versa. However, only the combination of RSG and ATRA increased the expression of osteopontin and osteocalcin, promoted matrix mineralization, and induced ectopic ossification in MEFs. Mechanistically, we found that the osteogenic differentiation induced by the combination of RSG and ATRA may be mediated partly by suppressing RSG-induced adipogenic differentiation and activating bone morphogenetic protein (BMP)/Smad signaling. On the whole, our findings demonstrate that RSG in combination with ATRA promotes the commitment of MEFs to the osteoblast lineage. Thus, the combination of these two agents may prove to be a promising and novel therapeutic regimen for insulin resistance without skeletal toxicity. It may also be a better strategy with which to prevent RSG-induced osteoporosis. PMID- 27779645 TI - Depletion of the triggering receptor expressed on myeloid cells 2 inhibits progression of renal cell carcinoma via regulating related protein expression and PTEN-PI3K/Akt pathway. AB - The triggering receptor expressed on myeloid cells 2 (TREM-2) is suggested to be involved in the development of certain human malignancies. However, the functions of TREM-2 in renal cell carcinoma (RCC) are still less known. To reveal the effects of TREM-2 on the RCC progression, we examined the TREM-2 expression in RCC tumor tissues. Then, we analyzed the cell proliferation, cell apoptosis, cell cycle and expression of the relative factors in two selected RCC cell lines post RNA interference. We also analyzed the functions of TREM-2 in an in vivo nude mouse model. We found that, the expression of TREM-2 was abnormally elevated in RCC tumor tissues. Silencing TREM-2 inhibited cell growth, induced G1 phase arrest of cell cycle and cell apoptosis in RCC cells. In vivo, the results showed that depletion of TREM-2 significantly inhibited the ACHN tumor growth in the nude mouse model. The analysis of relative protein factors suggested that silencing TREM-2 downregulated the expression levels of Bcl2 and PCNA, and upregulated the expression levels of Bax and caspase-3 in RCC cell lines. Depletion of TREM-2 inactivated PI3K/Akt pathway through increasing the expression of PTEN. Taken together, TREM-2 acts as an oncogene in the development of RCC and can be considered as a novel therapeutic factor in the treatment of RCC. PMID- 27779647 TI - Asiatic acid inhibits lactate-induced cardiomyocyte apoptosis through the regulation of the lactate signaling cascade. AB - The lactate signaling cascade has recently been linked to mitochondrial energy metabolism and cardiomyocyte apoptosis in several cardiovascular diseases. Asiatic acid (AA) exhibits a variety of pharmacological effects, including antioxidant and anti-apoptotic effects. In this study, we investigated the protective effects of AA against the lactate-induced apoptosis of cardiomyocytes, as well as its mechanisms of action. Neonatal rat cardiomyocytes were pre-treated with 20 uM AA for 24 h, followed by exposure to 20 mM lactate for a further 24 h. Cell viability was determined by a cell counting kit-8 (CCK-8) assay. Cell apoptosis, reactive oxygen species (ROS) levels and mitochondrial membrane potential (Deltapsim) were evaluated by flow cytometry or fluorescence microscopy. The expression levels of mitochondrial monocarboxylate transporter 1 (MCT1) and cytoplasmic cytochrome c, cleaved caspase-9 and caspase-3 were assayed by western blot analysis. Our results revealed that AA significantly inhibited lactate-induced apoptosis, intracellular ROS generation and the loss of Deltapsim. AA also increased the expression of mitochondrial MCT1 and reduced the expression of cytoplasmic cytochrome c, cleaved caspase-9 and caspase-3 in the lactate-stimulated cardiomyocytes. To the best of our knowledge, our data demonstrate for the first time that AA plays a cytoprotective role in lactate induced apoptosis by regulating the lactate signaling cascade, involving the inhibition of oxidative stress and mitochondria-dependent caspase activation, as well as the upregulation of mitochondrial MCT1 expression. PMID- 27779646 TI - Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms. AB - In contrast to hepatocyte growth factor (HGF), the therapeutic potential and pathophysiologic roles of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver diseases remain relatively unknown. To address the lack of effective pharmacologic treatments for cholestatic liver injuries, as well as to clarify the biologic features of these growth factors, we explored the effects of HB-EGF and HGF in mice with cholestatic liver injury induced by bile duct ligation (BDL). The mice were assessed 3, 5 and/or 14 days after BDL (acute, subacute and/or chronic phases, respectively) and intravenous injection of adenoviral vector expressing LacZ (control), HB-EGF, HGF, or HB-EGF and HGF. HB EGF, HGF, or a combination of the growth factors exerted potent antioncotic (antinecrotic), antiapoptotic, anticholestatic, and regenerative effects on hepatocytes in vivo, whereas no robust antiapoptotic or regenerative effects were detected in interlobular bile ducts. Based on serum transaminase levels, the acute protective effects of HB-EGF on hepatocytes were greater than those of HGF. On the other hand, liver fibrosis and cholestasis during the chronic phase were more potently inhibited by HGF compared with HB-EGF. Compared with either growth factor alone, combining HB-EGF and HGF produced greater anticholestatic and regenerative effects during the chronic phase. Taken together, these findings suggest that HB-EGF and HGF inhibited BDL-induced cholestatic liver injury, predominantly by exerting acute cytoprotective and chronic antifibrotic effects, respectively; combining the growth factors enhanced the anticholestatic effects and liver regeneration during the chronic phase. Our results contribute to a better understanding of the pathophysiologic roles of HB-EGF and HGF, as well as to the development of novel effective therapies for cholestatic liver injuries. PMID- 27779649 TI - Effect of curcumin and paclitaxel on breast carcinogenesis. AB - Global cancer burden increased to 14.1 million new cases in 2012; and breast cancer is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012. Curcumin is the major bioactive ingredient extracted from the rhizome of the plant Curcuma longa (turmeric). Paclitaxel is a microtubule-stabilizing agent originally isolated from the bark of Taxus brevifolia. Curcumin and paclitaxel were evaluated with two human breast cancer cell lines as the luminal MCF-7 and the basal-like MDA-MB-231 that are either positive or negative for hormonal receptors estrogen receptor, progesterone receptor and HER2, respectively. Results indicated that curcumin combined with paclitaxel decreased c-Ha-Ras, Rho-A, p53 and Bcl-xL gene expression in comparison to control and substances alone in MCF-7 cell line. These two substances alone and combined decreased gene expression of Bcl-2 and NF-kappaB. However, CCND1 increased when both substances were combined in MCF-7 cells. Such substances decreased Bcl-2 and increased Bax protein expression. However, curcumin alone decreased IkappaBalpha and Stat-3 gene expression. Paclitaxel alone and combined increased IkappaBalpha and Stat-3. Curcumin alone and combined with paclitaxel increased p53, Bid, caspase-3, caspase-8 and Bax gene expression in MDA-MB-231, whereas Bcl-xL decreased such expression in MDA-MB-231 cells. When paclitaxel and curcumin were combined the expression of Bcl-2 protein was decreased. However, either substance alone and combined increased Bax protein expression corroborating the apoptotic effect of these substances. It can be concluded that curcumin may be of considerable value in synergistic therapy of breast cancer reducing the associated toxicity with use of drugs. PMID- 27779648 TI - Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Recently developed molecular targeted therapies are not available for patients with ESCC. After curative surgical resection, patients frequently suffer distant metastasis and recurrence. Exploration of novel ESCC metastatic pathways may lead to the development of new treatment protocols for this disease. Accordingly, we have sequentially identified microRNA (miRNA)-mediated metastatic pathways in several cancers. Our past studies of miRNA expression signatures have shown that microRNA-375 (miR-375) is frequently reduced in several types of cancers, including ESCC. In the present study, we aimed to investigate novel miR 375-mediated metastatic pathways in ESCC cells. The expression of miR-375 was downregulated in ESCC tissues, and ectopic expression of this miRNA markedly inhibited cancer cell migration and invasion, suggesting that miR-375 acted as an antimetastatic miRNA in ESCC cells. Our strategies for miRNA target searching demonstrated that matrix metalloproteinase 13 (MMP13) was directly regulated by miR-375 in ESCC cells. Overexpression of MMP13 was observed in ESCC clinical tissues, and the expression of MMP13 promoted cancer cell aggressiveness. Moreover, oncogenic genes, including CENPF, KIF14 and TOP2A, were shown to be regulated downstream of MMP13. Taken together, these findings demonstrated that the antitumor miR-375/oncogenic MMP13 axis had a pivotal role in ESCC aggressiveness. These results provide novel insights into the potential mechanisms of ESCC pathogenesis. PMID- 27779650 TI - HOXB4 knockdown reverses multidrug resistance of human myelogenous leukemia K562/ADM cells by downregulating P-gp, MRP1 and BCRP expression via PI3K/Akt signaling pathway. AB - Multidrug resistance (MDR) plays a pivotal role in human chronic myelogenous leukemia (CML) chemotherapy failure. MDR is mainly associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) proteins. Phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with multidrug resistance 1 (MDR1)/P glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) expression in many human malignancies. Homeobox (HOX) B4, a member of the HOX gene family, has been reported to be correlated with occurrence, development, poor prognosis and drug resistance of human leukemia. In the present study, HOXB4 expression was analyzed in K562 cell line and its MDR subline K562/ADM. Compared with K562 cells, drug-resistant K562/ADM cells demonstrated evidently higher HOXB4 expression. In addition, we firstly investigated the reversal effect of HOXB4 deletion on K562/ADM cells and the underlying mechanism. The Cell Counting kit-8 (CCK-8) and flow cytometry assays showed that knockdown of HOXB4 enhanced chemosensitivity and decreased drug efflux in K562/ADM cells. Moreover, HOXB4 knockout led to downregulation of P-gp, MRP1 and BCRP expression and PI3K/Akt signaling activity, suggesting that repression of HOXB4 might be a key point to reverse MDR of K562/ADM cells. PMID- 27779651 TI - Expression of beta1- and beta2-adrenergic receptors in the lungs and changes in the levels of corresponding autoantibodies in an aged rat model of heart failure. AB - beta-adrenergic receptors (beta-ARs) and anti-beta1-AR autoantibodies play important roles in heart failure. This study was designed to investigate the expression of beta1- and beta2-ARs in the lungs, and their relevance to the corresponding autoantibodies in an aged rat model of heart failure. In addition, we investigated the association between anti-beta-AR autoantibody and soluble Fas (sFas) and soluble Fas ligand (sFasL). Aged male Wistar rats were divided into the sham-operated control group and the heart failure group. At 0 and 9 weeks post-surgery, the protein levels of beta1- and beta2-ARs in the heart and lungs were measured by western blot analysis. The plasma concentrations of autoantibodies, sFas and sFasL were determined by enzyme-linked immunosorbent assay (ELISA). The protein levels of pulmonary beta1- and beta2-ARs were decreased in the heart failure group when compared with the control group (P<0.01). Both the frequencies of the occurrence and the titers of autoantibodies against beta2-AR increased at 9 weeks post-surgery (P<0.01). The levels of sFas and sFasL were also elevated, although there was no difference in the levels of sFas and sFasL between the groups, with positive and negative anti-beta-AR autoantibody. These findings suggested that during the development of heart failure, the densities of pulmonary beta1- and beta2-ARs decreased. The levels of anti-beta2-AR autoantibody exhibited similar changes as those of anti-beta1-AR autoantibody, and there was no definite association between anti-beta-AR autoantibody and the levels of sFas/sFasL. PMID- 27779652 TI - [Retracted] Epidermal growth factor-stimulated human cervical cancer cell growth is associated with EGFR and cyclin D1 activation, independent of COX-2 expression levels. AB - Following the publication of this article, which was concerned with the expression of phosphorylated epidermal growth factor receptor (pEGFR) and cyclin D1 activation independently of the expression levels of cyclo-oxygenase-2, an interested reader drew to our attention apparent anomalies associated with the western blot data shown in Fig. 2C. Following an internal investigation at the New York University School of Medicine, we were requested to produce the original film, or the scan of the image of the film, for verification. Unfortunately, we were unable to provide the original film or scanned image to disprove the allegation, since the original pEGFR image could not be found. Therefore, the Investigation Committee recommended that this article be retracted, and we are withdrawing the article in line with the request. All the authors agree to the retraction of this paper. We sincerely regret any inconvenience this has caused. [the original article was published in the International Journal of Oncology 40: 13-20, 2012; DOI: 10.3892/ijo.2011.1211]. PMID- 27779653 TI - Anti-inflammatory effect of salidroside on phorbol-12-myristate-13-acetate plus A23187-mediated inflammation in HMC-1 cells. AB - Salidroside [2-(4-hydroxyphenyl)ethyl beta-D-gluco-pyranoside (SAS)] has been identified as the most potent ingredient of the plant Rhodiola rosea L. Previous studies have demonstrated that it possesses a number of pharmacological properties, including anti-aging, anti-fatigue, antioxidant, anticancer and anti inflammatory properties. In this study, to ascertain the molecular mechanisms responsible for the anti-inflammatory activity of SAS, we used phorbol-12 myristate-13-acetate (PMA) plus A23187 to induce inflammation in human mast cell line-1 (HMC-1). The HMC-1 cells were treated with SAS prior to being stimulated with PMA plus A23187. Pro-inflammatory cytokine production was measured by enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Western blot analysis was used to examine the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB). SAS inhibited the mRNA expression and production of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF). In cells stimulated with PMA plus A23187, SAS suppressed the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and c-jun N-terminal kinase 1/2 (JNK1/2), but not that of p38 MAPK. SAS suppressed the expression of NF-kappaB in the nucleus. On the whole, our results suggest that SAS exerts an anti inflammatory effect by inhibiting the production of pro-inflammatory cytokines through the blocking of the NF-kappaB and MAPK signaling pathways. PMID- 27779654 TI - Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review). AB - The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments. On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target. The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately. Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2. Most of these influence cell proliferative activity. Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis. The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted. PMID- 27779655 TI - Human telomerase reverse transcriptase regulation by DNA methylation, transcription factor binding and alternative splicing (Review). AB - The catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), plays an essential role in telomere maintenance to oppose cellular senescence and, is highly regulated in normal and cancerous cells. Regulation of hTERT occurs through multiple avenues, including a unique pattern of CpG promoter methylation and alternative splicing. Promoter methylation affects the binding of transcription factors, resulting in changes in expression of the gene. In addition to expression level changes, changes in promoter binding can affect alternative splicing in a cotranscriptional manner. The alternative splicing of hTERT results in either the full length transcript which can form the active telomerase complex with hTR, or numerous inactive isoforms. Both regulation strategies are exploited in cancer to activate telomerase, however, the exact mechanism is unknown. Therefore, unraveling the link between promoter methylation status and alternative splicing for hTERT could expose yet another level of hTERT regulation. In an attempt to provide insight into the cellular control of active telomerase in cancer, this review will discuss our current perspective on CpG methylation of the hTERT promoter region, summarize the different forms of alternatively spliced variants, and examine examples of transcription factor binding that affects splicing. PMID- 27779657 TI - ADAM17 promotes epithelial-mesenchymal transition via TGF-beta/Smad pathway in gastric carcinoma cells. AB - Although a disintegrin and metalloproteinase-17 (ADAM17) overexpression has been demonstrated in numerous human tumors including gastric cancer, its role in gastric cancer development remains to be clarified. In the present study, we identify that ADAM17 activates TGF-beta/Smad signaling to promote epithelial mesenchymal transition (EMT) in gastric cancer cells. We found that ADAM17 promotes proliferation, migration and invasion in gastric carcinoma cells. Subsequently, we revealed that silencing ADAM17 induces the expression of epithelial marker of E-cadherin and downregulates expression of mesenchymal markers including N-cadherin, vimentin and Snail in MGC803 and MKN45 cells, whereas ADAM17 overexpression reverses these changes in BGC823 and HGC27 cells. Furthermore, ADAM17 knockdown significantly inhibits the expression of TGF-beta and its downstream signaling molecules p-Smad2 and p-Smad3 in MGC803 and MKN45 cells. Consistently, ADAM17 overexpression reversed these changes in BGC823 and HGC27 cells. These results suggest that ADAM17 promotes epithelial-mesenchymal transition via the TGF-beta/Smad pathway. Collectively, the present study demonstrates that ADAM17 plays a critical role in the development of gastric cancer and provides a potential therapeutic target for gastric cancer. PMID- 27779656 TI - Circulating tumor cell clusters: What we know and what we expect (Review). AB - The major cause of cancer-associated mortality is tumor metastasis, a disease that is far from understood. Many studies have observed circulating tumor cells (CTCs) in patients' circulation systems, and a few latest investigations showed that CTC clusters have a potentially high capacity of metastasis. The capture and analysis of CTC clusters offer new insights into tumor metastasis and can facilitate the development of cancer treatments. We reviewed the research history of the CTC clusters, as well as the technologies used for detecting and isolating CTC clusters. In addition, we discuss the characteristics of CTC clusters and their roles in tumor dissemination. Clinical relevance of CTC clusters was also implicated in currently limited data. Moving forward, the next frontier in this field is to develop more efficient capture methods and decipher conundrums of characterization of CTC clusters. This will ultimately identify the clinical value of CTC clusters as a biomarker and therapeutic target. PMID- 27779658 TI - Ethanol extract of baked Gardeniae Fructus exhibits in vitro and in vivo anti metastatic and anti-angiogenic activities in malignant cancer cells: Role of suppression of the NF-kappaB and HIF-1alpha pathways. AB - Gardeniae Fructus (GF, Zhi Zi in China), a fruit of Gardenia jasminoides Ellis, has been used in traditional medicine to reduce inflammation and headache and to treat hepatic disorders, hypertension, and icterus. In recent studies, extract of raw or stir-baked GF was shown to have pharmacological activities for viral infection, thrombosis, hyperlipidemia, convulsion, inflammation, oxidative stress, and others. In addition, baked GF extract suppressed the proteolytic activities and altered the cellular morphology of tumor cells. However, the effects of ethanol extract of baked GF (EBGF) on the metastatic and angiogenic capacities of malignant tumor cells and its detailed mechanism of action have not been reported. In this study, we found that EBGF significantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 and -13 and uPA expression via suppression of PMA-induced nuclear translocation of NF-kappaBp65. Metastatic potential, including migration, invasion, and colonization, was substantially reduced by EBGF with no cytotoxicity. In addition, EBGF attenuated tumor-induced angiogenesis, including microvessel sprouting, migration of endothelial cells (ECs), and tube formation of ECs, by inhibiting the release of pro-angiogenic factors from tumor cells. In C57BL/6 mice, we observed that daily administration of EBGF at 50 and 100 mg/kg suppressed metastatic colonization of B16F10 melanoma cells in the lungs. Furthermore, EBGF administration did not cause adverse effects, suggesting that EBGF is safe and may be a potential herbal medicine capable of controlling metastatic malignant cancers. PMID- 27779659 TI - microRNA-361 targets Wilms' tumor 1 to inhibit the growth, migration and invasion of non-small-cell lung cancer cells. AB - The expression and functions of microRNA-361 (miR-361) have been studied in various human cancers. However, its expression and role in non-small-cell lung cancer (NSCLC) remains unclear. In the present study, the expression levels of miR-361 in NSCLC tissues and cell lines were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, the effect of miR-361 on the proliferation, migration and invasion of NSCLC cells was assessed. Furthermore, a dual-Luciferase reporter assay, RT-qPCR and western blotting were performed to investigate whether miR-361 directly targeted the 3' untranslated region of Wilms' tumor 1 (WT1). The results of the present study revealed that miR-361 was downregulated in NSCLC tissues and cell lines. Enforced expression of miR-361 suppressed the proliferation, migration and invasion of NSCLC cells. WT1 was identified as a direct target gene of miR-361 in NSCLC. Furthermore, knockdown of WT1 had similar effects to miR-361 overexpression in NSCLC cells. The present study provided novel insights into the molecular mechanism underlying the rapid growth and metastasis of NSCLC, and identified the association between miR-361 and WT1 as a potential therapeutic target for the treatment of NSCLC. PMID- 27779660 TI - miR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. AB - MicroRNAs (miRNAs) were reported to be involved in the development of clear cell renal cell carcinoma (ccRCC). However, the study on miRNAs in ccRCC is far from complete. The present study identified miRNAs which could act as potential novel prognostic markers for ccRCC, and analyzed its possible mechanism. We found that miR-19a correlated with poor prognosis of ccRCC patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Both the microarray screening result and TCGA KIRC dataset analysis showed that miR-19a was significantly upregulated in ccRCC tissues, and further analysis of TCGA data revealed that the upregulated level of miR-19a was strongly associated with advanced T stage and poor prognosis of ccRCC patients. Consistent with clinical observations, miR-19a overexpression significantly promoted ccRCC cell proliferation in vitro. To further explore the mechanism by which miR-19a correlated with cell proliferation and poor prognosis of ccRCC, we performed gene set enrichment analysis (GSEA) for target genes of miR-19a in ccRCC patients. Result indicated that the key target genes of miR-19a included SMAD4 and PTEN. In ccRCC tissues, expression levels of SMAD4 and PTEN were negatively correlated with expression level of miR-19a, revealing that miR-19a suppressed the expression of SMAD4 and PTEN in ccRCC patients. miR-19a overexpression significantly suppressed the expression of SMAD4 and PTEN in vitro, further verifying that SMAD4 and PTEN were the target genes of miR-19a in ccRCC cells. Our results elucidated the tumor promoting role of miR-19a and established miR 19a as a potential novel prognostic marker for ccRCC. PMID- 27779661 TI - Notch1 is associated with the differentiation of human bone marrow-derived mesenchymal stem cells to cardiomyocytes. AB - Notch signaling is involved in the early process of differentiation to determine the fate of stem cells. However, the precise role of Notch in human bone marrow derived mesenchymal stem cells (hBMSCs) remains unclear. The present study aimed to investigate the involvement of Notch signalling during the course of hBMSC differentiation into cardiomyocytes using hBMSCs, with multilineage differentiation ability, isolated and purified from human bone marrow. Flow cytometric analysis revealed that CD29, CD44 and CD90 were highly expressed on the surface of cells in their fifth passage, whereas detection of CD34, CD45, CD54 and HLA-DR was negative. Visualization of morphological changes, western blotting, immunocytochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that hBMSCs differentiate into cardiomyocytes through treatment with 5-azacytidine (5-aza). Transmission electron microscopy revealed ultramicroscopic details of differentiated hBMSCs. Western blotting and immunocytochemistry demonstrated increased protein expression levels of alpha-actin and cardiac troponin T expression, and RT-qPCR revealed increased mRNA expression of Notch1 early in the process of differentiation (days 1, 4 and 7), and increased mRNA expression levels of the transcription factors GATA binding protein-4 and NK2 homeobox 5 at day 28 day. In conclusion, differentiation of hBMSCs into cardiomyocytes was induced in vitro by 5-aza, and was associated with upregulation of Notch1, GATA binding protein-4 and Nkx2.5 expression. Overexpression of the Notch1 signaling pathway may represent a potential mechanism underlying the differentiation of hBMSCs. PMID- 27779662 TI - Chromosome 10q26 deletion syndrome: Two new cases and a review of the literature. AB - The current study presents the cases of two unrelated patients with similar clinical features, including craniofacial anomalies, developmental delay/intellectual disability and cardiac malformations, that are consistent with chromosome 10q26 deletion syndrome. High-resolution single-nucleotide polymorphism analysis revealed that 10q26 terminal deletions were present in these two patients. The locations and sizes of the 10q26 deletions in these two patients were compared with the locations and sizes of 10q26 deletions in 30 patients recorded in the DECIPHER database and 18 patients characterized in previous studies through chromosomal microarray analysis. The clinical features and locations of the 10q26 deletions of these patients were reviewed in an attempt to map or refine a critical region (CR) for phenotypes. Additionally, the association between previously suggested CRs and phenotypic variability was discussed. The current study emphasize that a distal 10q26 terminal deletion with a breakpoint at ~130 Mb may contribute to the common clinical features of 10q26 deletion syndrome. PMID- 27779663 TI - Post-translational modifications of FOXO family proteins (Review). AB - The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs. PMID- 27779664 TI - Inhalation of inactivated-Mycobacterium phlei prevents asthma-mediated airway hyperresponsiveness and airway eosinophilia in mice by reducing IL-5 and IL-13 levels. AB - The present study aimed to investigate whether inhalation of inactivated Mycobacterium phlei could prevent airway hyperresponsiveness and airway eosinophilia. A total of 24 male Balb/c mice were randomly divided into three groups: Normal control group (group A), asthma model group (group B) and the intervention group (group C), (8 mice/group). Group A mice were sensitized and with challenged saline and group B with ovalbumin (OVA). Group C mice were administered with aerosol Mycobacterium phlei once daily prior to the allergen challenge. Airway responsiveness in each group was assessed. All the animals were sacrificed and lung tissues, blood samples and bronchoalveolar lavage fluid (BALF) were harvested. Cell fractionation and differential cells were counted in serum and BALF. HE staining and alcian blue/periodic acid Schiff staining were used to measure airway eosinophilic inflammation and mucus production. The levels of the cytokines IL-5, IL-13 and IgE were measured in lung and BALF as determined by ELISA and reverse transcription-quantitative polymerase chain reaction assays. The results indicated that inactivated-Mycobacterium phlei suppressed the airway hyperresponsiveness and mitigated airway eosinophilia induced by a methacholine challenge, and significantly reduced the levels of cytokines IL-5 and IL-13 in lung tissue and IgE level in BALF when compared with the OVA-sensitized mice. In conclusion, inhalation of inactivated-Mycobacterium phlei could reduce OVA induced airway hyperresponsiveness and may be a potential alternative therapy for allergic airway diseases. PMID- 27779665 TI - Effect of zinc deficiency on mouse renal interstitial fibrosis in diabetic nephropathy. AB - There is emerging evidence that tubulointerstitial fibrosis is the final common pathway of the majority of chronic progressive renal diseases, including diabetic nephropathy (DN). Zinc, an essential dietary element, has been suggested to be important for a number of protein functions during fibrosis in vivo and in vitro. However, the effect of zinc deficiency (ZnD) on renal interstitial fibrosis in DN remains unclear. The present study investigated the effect and the underlying mechanisms of ZnD on renal interstitial fibrosis during DN using an streptozotocin-induced model of diabetes with immunofluorescence staining and western blot analysis. The present study identified that dietary zinc restriction significantly decreased zinc concentrations in the plasma and mouse kidney. ZnD enhanced albuminuria and extracellular matrix protein expression, associated with diabetic renal interstitial fibrosis by activation of renal interstitial fibroblasts and regulation of the expression of fibrosis-associated factors, which may be mediated by the activation of fibroblasts via the TGF-beta/Smad signaling pathway. The data indicates that ZnD serves an important role in the pathogenic mechanisms of renal interstitial fibrosis during the development of DN. PMID- 27779667 TI - Lipopolysaccharide-induced cytokine expression pattern in peripheral blood mononuclear cells in childhood obesity. AB - Obesity is characterized by the abnormal or excessive fat accumulation that may impair health and extensive increase in body mass index (BMI). Childhood obesity may occur due to disturbances in metabolic regulation, which lead to metabolic syndrome and other diseases. Peripheral blood suspended immune cells are responsible for immune surveillance. The aim of the present study was to map the inflammatory cytokine expression pattern of isolated peripheral blood mononuclear cells (PBMCs) following lipopolysaccharide (LPS) stress in vitro and clinical chemistry parameters in the plasma of subjects. PBMCs were isolated through density gradient ultracentrifugation of the blood from obese infants that would reflect the cytokine response. Isolated PBMCs were cultured in vitro in RPMI-1640 medium and stressed with 1 ug LPS in order to investigate the expression pattern of cytokines, such as interleukin (IL)-2, interferon (IFN)-gamma, IFN-alpha, tumor necrosis factor-alpha and IL-6 using enzyme-linked immunosorbent assays and reverse transcription-quantitative polymerase chain reaction. Levels of NO, lipid levels, total protein, albumin, marker enzymes aspartate transaminase and alanine transaminase, malondialdehyde (MDA), and reduced glutathione in the plasma were detected. Reduction in the expression of the inflammatory cytokines in PBMCs, reduced protein and globulins, and altered MDA and GSH levels in the plasma were observed. Altered or compromised pro-inflammatory signals from PBMCs in vitro and the clinical chemistry parameters of the plasma suggested that there were compromised immunological responses in obese children compared with matched controls. PMID- 27779666 TI - Effects of the IGF-1/PTEN/Akt/FoxO signaling pathway on male reproduction in rats subjected to water immersion and restraint stress. AB - The aim of the present study was to determine the effects of the insulin-like growth factor 1 (IGF-1)/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt/forkhead box (FoxO) signaling pathway on male reproduction in rats subjected to water immersion and restraint stress (WRS). Sperm morphology, sperm malformation rate, and serum testosterone concentration were analyzed following WRS. In addition, the expression levels and immunolocalization of IGF-1, PTEN, Akt and FoxO proteins, as well as the rate of cell apoptosis in rat testes, were investigated. The results indicated that sperm malformation rate, serum testosterone concentration, and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were increased in the testes after WRS. Furthermore, IGF-1 and FoxO1 proteins were predominantly localized in the sperm cytoplasm during the late stages of spermatogenesis. FoxO1 protein was also localized in Leydig cell cytoplasm. PTEN and total Akt proteins were predominantly expressed in the cytoplasm of Leydig cells and spermatogonia. PTEN protein was also detected in vascular endothelial cells. In addition, IGF-1, PTEN, Akt1, Akt2, FoxO3 and FoxO4 gene expression levels were upregulated following WRS, and peaked after 7 h of WRS. During the recovery period, the expression levels of these genes gradually returned to normal levels. The present study demonstrated that WRS induced sperm damage in the testes. In addition, the results indicated that the IGF-1/PTEN/Akt/FoxO signaling pathway may serve an anti-stress role in the testes of rats subjected to WRS. PMID- 27779668 TI - Peptide mimics of a carbohydrate-associated epitope expressed by cancer cells: Identification of vaccine candidates. AB - Cancer-associated antigen 215 (CA215) is an immunoglobulin molecule expressed by numerous tumor types. Membrane-bound and soluble CA215 have been detected in the majority of cancer cells and rarely identified in normal tissues. In addition, CA215C is a carbohydrate-associated epitope in the variable region of CA215, which is specifically recognized by the monoclonal antibody, RP215. However, CA215C is not a suitable vaccine candidate as it is a thymus-independent antigen. In the present study, RP215 was used as a target to screen short peptide mimics of CA215C from a phage display peptide library. Following three rounds of screening, 30 positive phage clones that specifically bound to RP215 were identified and sequenced. The result of amino-acid sequence analysis revealed five conserved sequence groups for seventeen of the positive phage clones. The sequences of phage clones 2, 13 and 42 were selected for peptide synthesis and binding analysis. The synthetic peptides R2 and R42 specifically bound RP215. Antisera from mice immunized with R2-BSA or R42-BSA bound purified CA215C and innate CA215C expressed on human hepatic and rectal carcinoma tissues, as demonstrated by immunohistochemistry. Furthermore, R2-BSA and R42-BSA antisera inhibited RP215 binding to cancer tissues. These results revealed that R2-BSA and R42-BSA antisera had similar characteristics to RP215 and that the synthetic peptides R2 and R42 may mimic the CA215C epitope. R2 and R42 peptides may therefore have potential for development into a tumor vaccine. PMID- 27779669 TI - NFAT5 participates in seawater inhalation-induced acute lung injury via modulation of NF-kappaB activity. AB - Nuclear factor of activated T cells 5 (NFAT5) is a transcription factor that can be activated by extracellular tonicity. It has been reported that NFAT5 may increase the transcription of certain osmoprotective genes in the renal system, and the aim of the current study was to explore the role of NFAT5 in seawater inhalation-induced acute lung injury. Though establishing the model of seawater inhalation-induced acute lung injury, it was demonstrated that seawater inhalation enhanced the transcription and protein expression of NFAT5 (evaluated by reverse transcription-polymerase chain reaction, immunohistochemistry stain and western blotting) and activation of nuclear factor (NF)-kappaB (evaluated by western blotting and mRNA expression levels of three NF-kappaB-dependent genes) both in lung tissue and rat alveolar macrophage cells (NR8383 cells). When expression of NFAT5 was reduced in NR8383 cells using an siRNA targeted to NFAT5, the phosphorylation of NF-kappaB and transcription of NF-kappaB-dependent genes were significantly reduced. In addition, the elevated content of certain inflammatory cytokines [tumor necrosis factor alpha, interleukin (IL)-1 and IL-8] were markedly reduced. In conclusion, NFAT5 serves an important pathophysiological role in seawater inhalation-induced acute lung injury by modulating NF-kappaB activity, and these data suggest that NFAT5 may be a promising therapeutic target. PMID- 27779670 TI - Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells. AB - Early reports suggest that nuclear factor IA (NFIA) is important in the pathogenesis of glioma. Our previous study demonstrated that the long non-coding RNA (lncRNA), RP5-833A20.1, suppressed the expression of NFIA in THP-1 macrophage derived foam cells. However, the effect and possible mechanism of RP5-833A20.1 on glioma remains to be fully elucidated, and whether the NFIA-dependent pathway is involved in its progression has not been investigated. In the present study, the mechanisms by which RP5-833A20.1 regulates the expression of NFIA in glioma were investigated. The expression levels of RP5-833A20.1 and NFIA were determined in U251 cells and clinical samples using reverse transcription-quantitative polymerase chain reaction (PCR) analysis. The effects of RP5-833A20.1 on cell proliferation, invasion, cell cycle and apoptosis were evaluated using in vitro assays. The potential changes in protein expression were investigated using western blot analysis. The methylation status of the CpG island in the NFIA promoter was determined using bisulfite PCR (BSP) sequencing. It was found that the expression of RP5-833A20.1 was downregulated, whereas the expression of NFIA was upregulated in glioma tissues, compared with corresponding adjacent nontumor tissues from 20 patients with glioma. The overexpression of RP5-833A20.1 inhibited proliferation and cell cycle progression, and induced apoptosis in the U251 cells. The mRNA and protein levels of NFIA were markedly inhibited by overexpression of RP5-833A20.1 in the U251 cells. The overexpression of RP5 833A20.1 increased the expression of microRNA-382-5p in the U251 cells. The BSP assay revealed that the overexpression of RP5-833A20.1 enhanced the methylation level of the NFIA promoter. These results demonstrated that RP5-833A20.1 inhibited tumor cell proliferation, induced apoptosis and inhibited cell-cycle progression by suppressing the expression of NFIA in U251 cells. Collectively, these results indicated RP5-833A20.1 as a novel therapeutic target for glioma. PMID- 27779671 TI - Simvastatin exerts anti-hepatitis B virus activity by inhibiting expression of minichromosome maintenance protein 7 in HepG2.2.15 cells. AB - Simvastatin (SIM), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to inhibit the activity of hepatitis B virus (HBV), however, the mechanism underlying its antiviral function remains unknown. Minichromosome maintenance (MCM) 7, a component of the MCM complex, has been reported to act as an important host factor aiding virus genome replication in host cells. The present study demonstrated that downregulation of MCM7 inhibited the expression of proteins transferred by adenoviral vectors. This suggests an association between MCM7 and viral DNA expression. Thus, the current study aimed to investigate whether SIM affected MCM7 expression. Notably, the results of the present study indicated that following exposure to SIM the protein expression levels of MCM7 in HepG2.2.15, a human HBV-transfected liver cell line, was decreased. In addition, the HBV DNA replication in the cell line was suppressed. As quantitative polymerase chain reaction experiments demonstrated that SIM did not downregulate the mRNA expression level of MCM7, the current study further investigated whether SIM affects the translation of MCM7. Western blot experiments indicated that SIM improved the activation of eukaryotic initiation factor-2alpha (eIF2alpha), a protein synthesis initiation factor, and upregulated the upstream factors of eIF2alpha, protein kinase RNA-like endoplasmic reticulum kinase, which is regulated by the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) signaling pathway. These results indicated that SIM induced HBV downregulation via an MCM-dependent mechanism, and SIM may inhibit MCM7 expression by increasing the phosphorylation of eIF2alpha, which is mediated by the LKB1-AMPK signaling pathway. PMID- 27779672 TI - Knockdown of macrophage inhibitory cytokine-1 in RPMI-8226 human multiple myeloma cells inhibits osteoclastic differentiation through inhibiting the RANKL-Erk1/2 signaling pathway. AB - Patients with multiple myeloma (MM) often develop myeloma bone disease (MBD). The development of MBD from MM is considered to be caused by an abnormal bone marrow microenvironment. Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-beta superfamily. In patients with MM, MIC-1 is expressed at high levels, however, whether this increased expression of MIC-1 is associated with the development of MBD from MM remains to be elucidated. The present study investigated whether MIC-1 is essential for the osteoclastic differentiation of peripheral blood mononuclear cells (PBMNCs) by using a co culture system, in which the PBMNCs were co-cultured with RPMI-8226 cells. The expression of MIC-1 in the RPMI-8226 cells was knocked down using RNA interference. Osteoclastic differentiation was evaluated using tartrate-resistant acid phosphatase staining and lacunar resorption on dentine slices. The expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and phosphorylation of extracellular signal-regulated kinase (Erk)1/2 were measured using Western blotting. It was found that the reduced expression of MIC-1 in the RPMI-8226 cells inhibited the osteoclastic differentiation of PBMNCs and decreased the expression levels of RANKL and phosphorylated Erk1/2. It was concluded that MIC-1 promoted the osteoclastic differentiation of PBMNCs via the RANKL-Erk1/2 signaling pathway and, therefore, MIC-1 may offer potential as a target in the design of strategies to treat MBD. PMID- 27779673 TI - Suppressive effects of Gua Lou Gui Zhi decoction on MCAO-induced NO and PGE2 production are dependent on the MAPK and NF-kappaB signaling pathways. AB - The present study aimed to investigate the inhibitory effects, and underlying mechanisms, of Gua Lou Gui Zhi decoction (GLGZD) in a rat model of neuroinflammation. Sprague-Dawley rats were treated with GLGZD following middle cerebral artery occlusion (MCAO). Neurological function and infarct volume were evaluated to confirm successful generation of the rat model. Subsequently, brain tissues and blood samples were collected for further analysis. Nitric oxide (NO) and prostaglandin E2 (PGE2) were evaluated in peripheral blood samples using the Griess reagent assay and an ELISA, respectively. The relative expression levels of inducible nitric oxide synthase (iNOS) and cylooxygenase-2 (COX-2) were detected by quantitative polymerase chain reaction and immunohistochemistry. The associated pathways, including nuclear factor-kappaB (NF-kappaB) and mitogen activated protein kinases (MAPK) signaling pathways, were detected by electrophoretic mobility shift assay and western blotting. The results demonstrated that treatment with GLGZD significantly inhibited MCAO-induced inflammation; GLGZD suppressed the production of NO and PGE2, and the expression of iNOS and COX-2, by inhibiting NF-kappaB activation and MAPK phosphorylation. These findings suggest that GLGZD, a potential agent for post-stroke treatment, may exert anti-inflammatory effects, thus providing neuroprotection. PMID- 27779674 TI - Systemic symptoms in irritable bowel syndrome: An investigative study on the role of enterocyte disintegrity, endotoxemia and inflammation. AB - Irritable bowel syndrome (IBS) is often accompanied by extra-intestinal symptoms, including fatigue and musculoskeletal pain. The present study aimed to investigate whether these symptoms were associated with markers of enterocyte disintegrity, endotoxemia and inflammation. Patients with IBS were recruited consecutively from our outpatient clinic (n=94) and compared with a group of healthy controls (n=20). Habitual symptoms were assessed using the IBS Severity Scoring System, the Fatigue Impact Scale and Visual Analogue Scales for measuring musculoskeletal pain. A lactulose challenge test was performed to induce post prandial symptoms, and blood samples were obtained prior to and 90 min following lactulose ingestion to determine levels of intestinal fatty acid binding protein (iFABP), lipopolysaccharide (LPS), the LPS co-receptor soluble cluster of differentiation (sCD) 14, monocyte chemoattractant protein-1 (MCP-1) and calprotectin. Habitual symptom scores were high among the included patients, and lactulose ingestion induced significantly more symptoms in the patient group compared with the healthy control group (P=0.0001). Serum levels of iFABP were reduced in IBS patients compared with healthy controls, prior to and following lactulose ingestion (P=0.0002 and P=0.0001, respectively). Following lactulose ingestion, iFABP levels decreased in IBS patients (P=0.0001) and in healthy controls (P=0.02). Fasting levels of LPS, sCD14, MCP-1 and calprotectin were not significantly different between IBS patients and healthy controls. However, following lactulose ingestion, LPS levels increased in healthy controls (P=0.03), whereas MCP-1 levels decreased in IBS patients (P=0.008). Intestinal and extra intestinal symptom severities were not correlated with levels of circulating biomarkers. No assessed biomarker in the present study appeared to be associated with symptom development in IBS patients. However, the implications of the low levels of iFABP observed require further investigation. PMID- 27779675 TI - Resveratrol alleviates sepsis-induced myocardial injury in rats by suppressing neutrophil accumulation, the induction of TNF-alpha and myocardial apoptosis via activation of Sirt1. AB - Sepsis is a severe inflammatory response to systemic infection that frequently affects the myocardium. Previous studies have suggested that resveratrol (RESV) is protective in sepsis. The present study aimed to investigate the role of sirtuin 1 (Sirt1) signaling in the protective effect of intraperitoneally administered RESV against sepsis-induced myocardial injury. Cecal ligation and puncture, or a sham operation, were performed in male Sprague-Dawley rats, and the levels of tumor necrosis factor (TNF)-alpha and myeloperoxidase (MPO) were assessed by ELISA and an MPO activity kit, respectively. The extent of myocardial apoptosis was assessed by TUNEL staining. The protein expression levels of Sirt1, acetylated (Ac)-Forkhead box O1 (FoxO1), B cell lymphoma 2 apoptosis regulator (Bcl-2) and Bcl-2 associated protein X apoptosis regulator (Bax) were detected by western blot analysis. RESV was demonstrated to attenuate myocardial apoptosis and decrease the production of TNF-alpha and MPO. Additionally, RESV upregulated the expression of Sirt1 and Bcl-2, and downregulated the expression of Ac-FoxO1 and Bax. The protective effects of RESV were abolished by EX527, a Sirt1 inhibitor. RESV has therefore been demonstrated to attenuate myocardial injury in sepsis by decreasing neutrophil accumulation, TNF-alpha expression, and myocardial apoptosis via activation of Sirt1 signaling. These results suggest a novel therapeutic strategy for the clinical treatment of sepsis. PMID- 27779676 TI - Inhibitory effects of dieckol on hypoxia-induced epithelial-mesenchymal transition of HT29 human colorectal cancer cells. AB - Hypoxia-induced epithelial-mesenchymal transition (EMT) has been identified as essential for tumor progression and metastasis. The present study examined the effects of an antioxidant, dieckol, on hypoxia-induced EMT in HT29 human colorectal cancer cells. HT29 cells were treated with a hypoxia-inducing agent, CoCl2, and an increase in the levels of intracellular reactive oxygen species (ROS) and various morphological changes, such as loss of cell-cell contact and aggressive cell migration were observed. CoCl2 also induced an increase in the expression of hypoxia-inducible factor 1alpha (HIF1alpha) and various mesenchymal specific markers, including vimentin and snail family transcriptional repressor 1 (Snail1), and a decrease in the expression of E-cadherin, thus suggesting that CoCl2 induced EMT in HT29 cells. Conversely, the CoCl2-induced EMT of HT29 cells was suppressed following treatment with dieckol. In addition, ROS generation, EMT marker protein expression and intracellular localization, cell migration and cell invasion were attenuated following dieckol treatment. The findings of the present study suggested that dieckol may inhibit hypoxia-induced EMT in HT29 cells by regulating the levels of cellular ROS and protein expression levels downstream of the HIF1alpha signaling pathway. Therefore, dieckol has the potential to become an attractive therapeutic agent for the treatment of colorectal cancer. PMID- 27779677 TI - [Corrigendum] Genetic and epigenetic alterations are involved in the regulation of TPM1 in cholangiocarcinoma. AB - Following the publication of this article, an interested reader drew to our attention anomalies associated with the data shown in Fig. 2, which presented the mRNA and protein expression levels of tropomyosin 1 (TPM1) in HuCCT1 cells. Essentially, the control bands for alpha-tubulin had been duplicated across from Fig. 2A to Fig. 2B, and from Fig. 2D to Fig. 2E [the experiments showing treatment of the cells with (A) manumycin A, (B) U0126, (D) 5-aza-2-deoxycytidine (DAC) and (E) trichostatin A (TSA)], respectively. After having re-examined our original data, we realize that the figure was compiled incorrectly, and have returned to our source data. A corrected version of Fig. 2 is presented here, showing the correct control alpha-tubulin data for Fig. 2A and E, as they ought to have appeared. This error did not overall affect the conclusions reported in the study. We sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience this mistake has caused. [the original article was published in the International Journal of Oncology 42: 690-698, 2013; DOI: 10.3892/ijo.2012.1741]. PMID- 27779678 TI - HEB silencing induces anti-proliferative effects on U87MG cells cultured as neurospheres and monolayers. AB - Glioblastoma multiforme (GBM) is a lethal tumor and novel strategies are required to overcome resistance. Transcription factor 12 (HEB) has been associated with neural and stem cell proliferation, is overexpressed in certain tumor types and is induced in irradiated U87MG cells. The present study aimed to determine whether HEB knockdown, with or without irradiation, may sensitize GBM cells. U87MG GBM and ACBRI-371 primary human astrocytes were cultured in monolayers or neurospheres. Cell proliferation and death, cell cycle and sub-G1 detection, and cluster of differentiation (CD) 133 immunofluorescence were analyzed by flow cytometry, whereas HEB protein expression was analyzed by immunocytochemistry and western blotting. Greater HEB protein expression was observed in U87MG neurospheres compared with ACBRI-371, and the two cell lines exhibited nuclear HEB expression. HEB silencing in cells grown in monolayers induced a significant reduction in proliferation and decreased the proportion of cells in G0/G1 phase. In addition, HEB silencing reduced (two-fold) the number of neurospheres compared with control scrambled (SCR) cells. HEB silencing combined with irradiation reduced U87MG cell proliferation when cultured in monolayers and reduced neurosphere cell number compared with the SCR irradiated group; however, not significantly. Differentiation of U87MG cells from neurospheres was reduced in HEB-silenced cells, whereas in irradiated cells the proportion of CD133+ cells was similar in HEB-silenced cells compared with the SCR control. These results suggest that HEB may contribute to the proliferation and maintenance of GBM cells. However, only limited effects were exerted by irradiation in HEB-silenced cells. HEB may be a potential target to decrease proliferation in U87MG GBM cells, grown as monolayers or neurospheres, and may provide important information for the development of novel strategies for cancer therapy. PMID- 27779680 TI - [Corrigendum] Analysis of different components in the peritumoral tissue microenvironment of colorectal cancer: A potential prospect in tumorigenesis. AB - Owing to an oversight during the proof checking stage, the above article has been published with the incorrect author listed for correspondence. The first author, Chao Huang, is listed as the corresponding author, although he was only intended to have been temporarily assigned to handle queries during the pre-press stages of the publication. The correct corresponding author should have been listed as Professor Bin Wen (also at the Spleen-Stomach Institute, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510000, P.R. China). The email address for Professor Wen is: wenbin@gzucm.edu.cn. We sincerely apologize for this mistake, and regret any inconvenience this mistake has caused [the original article was published in the Molecular Medicine Reports 14: 2555-2565, 2016; DOI: 10.3892/mmr.2016.5584]. PMID- 27779679 TI - miR-129 predicts prognosis and inhibits cell growth in human prostate carcinoma. AB - MicroRNAs (miRNAs) are a class of small, well-conserved, non-coding RNAs that are increasingly identified as diagnostic and prognostic biomarkers in a number of cancers. Deregulated miR-129 is closely associated with tumorigenesis and cancer progression. However, the potential role of miR-129 in prostate cancer remains largely elusive. The present study investigated the role of miR-129 as a prognostic biomarker for tumor progression and clinical prognosis in prostate cancer patients. The examined prostate cancer tissues exhibited a significant reduction in miR-129 expression compared with the normal tissues (P=0.013). The expression levels of miR-129 were negatively correlated with histological grade (P<0.001), high preoperative prostate-specific antigen serum levels (P<0.001), pathological stage (P<0.001), high Gleason score (P<0.001), lymph node metastasis (P=0.002), angiolymphatic invasion (P=0.018), and biochemical recurrence (BCR; P=0.001). Use of the Kaplan-Meier analysis demonstrated that low miR-129 expression was closely associated with poorer BCR-free survival. Multivariate survival analysis indicated that miR-129 expression may be an independent prognostic marker for BCR-free survival in prostate cancer patients (P<0.001). Overexpression of miR-129 markedly attenuated prostate cancer cell growth by rescuing cell cycle-regulated protein expression. The present study suggests that miR-129 is downregulated in the cancerous tissues of prostate cancer patients, which was associated with poor BCR-free survival. Thus, it may be considered as a novel independent prognostic biomarker for prostate cancer. In addition, downregulation of miR-129 may serve a critical role in the proliferation of prostate cancer cells. PMID- 27779681 TI - SLC25A13 cDNA cloning analysis using peripheral blood lymphocytes facilitates the identification of a large deletion mutation: Molecular diagnosis of an infant with neonatal intrahepatic cholestasis caused by citrin deficiency. AB - Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder resulting from biallelic mutations of the SLC25A13 gene. Due to the lack of well-recognized clinical or biochemical diagnostic criteria, the definitive diagnosis of this disease relies on the genetic analysis of SLC25A13 at present. As novel large deletion/insertion mutations of the SLC25A13 gene are difficult to detect using routine DNA analytic approaches, the timely diagnosis of patients with these types of mutations remains a challenge. The present study aimed to examine SLC25A13 mutations in an infant with a suspected diagnosis of NICCD. DNA was extracted from blood samples, and SLC25A13 mutations were examined by screening for high-frequency mutations and Sanger sequencing. Reverse transcription-polymerase chain reaction and cDNA cloning analyses were then performed using peripheral blood lymphocytes (PBLs) to identify the obscure mutation. The results demonstrated that the infant was heterozygous for a paternally-inherited mutation, c.851_854del4, and a maternally inherited large deletion, c.1019_1177+893del, which has not been reported previously. A positive diagnosis of NICCD was made, and the infant responded favorably to a galactose-free and medium-chain triglyceride-enriched formula. The present study confirmed the effectiveness of this formula in NICCD therapy, enriched the SLC25A13 mutational spectrum and supported the feasibility of cDNA cloning analysis using PBLs as a molecular tool for facilitating the identification of large SLC25A13 deletions. PMID- 27779682 TI - The Hedgehog signaling pathway is associated with poor prognosis in breast cancer patients with the CD44+/CD24- phenotype. AB - Cancer stem cells (CSCs) have been suggested to serve an important role in tumor recurrence and metastasis in breast cancer. The hedgehog (Hh) signaling pathway is essential for the maintenance of breast CSCs. The present study used immunohistochemistry to investigate the expression of Patched (PTCH) and Gli1, which are the main components of the Hh signaling pathway, as well as the expression of cluster of differentiation (CD)44/CD24, which are markers for breast CSCs, in 266 patients with breast cancer. The combined expression of PTCH and Gli1 was significantly associated with larger tumors (>2.0 cm; P=0.001), lymph node metastasis (P=0.003), invasive lobular carcinoma (P=0.016) and Grade II-III tumors (P<0.001). In addition, PTCH and Gli1 expression was associated with lymph node metastasis (P=0.005 and P=0.001) and Grade II-II tumors (P=0.020 and P=0.033) in breast cancer patients with the CD44+/CD24- phenotype. The expression of PTCH and Gli1 was also associated with significantly shorter overall survival and disease-free survival (DFS) in breast cancer patients with the CD44+/CD24- phenotype. Multivariate Cox regression analysis demonstrated that PTCH expression and the CD44+/CD24- phenotype were independent prognostic factors for decreased DFS in patients with breast cancer. These findings suggest that the Hh signaling pathway in breast CSCs may contribute to the poor outcome of patients with breast cancer. PMID- 27779683 TI - Pien Tze Huang suppresses VEGF-C-mediated lymphangiogenesis in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common malignancies worldwide. The majority of patients are not suitable for surgery due to the presence of metastatic disease at the time of diagnosis, which has led to a high mortality rate for patients with CRC. Lymphangiogenesis, formation of new lymphatic vessels, plays an critical role in cancer progression particularly in cancer metastasis. Vascular endothelial growth factor-C (VEGF-C) has been previously demonstrated to play a pivotal role in cancer metastasis and therefore has become an attractive target for anticancer treatments. Pien Tze Huang (PZH) is a well known traditional Chinese formula, which has exhibited significant therapeutic effects against CRC. However, the molecular mechanisms underlying its anticancer effects, particularly in regards to antimetastasis activity, still require further elucidation. In the present study, we evaluated the effects of PZH on cell migration and VEGF-C expression using various human CRC cell lines. Moreover, using a VEGF-C-stimulated human lymphatic endothelial cell (HLEC) model, we demonstrated that PZH suppresses lymphangiogenesis by attenuating cell migration and tube formation. This indicates that PZH possesses significant antimetastatic activity. Moreover, suppression of lymphangiogenesis by PZH via the downregulation of VEGF-C may be a potential molecular mechanism by which PZH inhibits metastasis in CRC. PMID- 27779684 TI - Microfluidic profiling of apoptosis-related genes after treatment with BH3 mimetic agents in astrocyte and glioblastoma cell lines. AB - Glioblastoma (GB) is the most frequent and biologically the most aggressive primary brain tumor in adults. Standard treatment for newly diagnosed GB consists of surgical resection, radiotherapy and chemotherapy. Resistance to therapy is a major obstacle, even with optimal treatment with a survival median of only 12-15 months. The heterogeneity and treatment response of GB makes this tumor type a challenging area of research. The aim of our study was to study the response of normal human astrocyte (HA) and human GB (T98G) cell lines to apoptosis inhibitors in vitro. ABT-737 is an inhibitor of anti-apoptotic proteins Bcl-2, Bcl-xL, Bcl-w, while MIM-1 is an Mcl-1 protein inhibitor. The viability of the cells was assayed biochemically using the cytotoxic methyl thiazolyl tetrazolium (MTT) assay. Changes in the expression of apoptosis-associated genes (n=93) in two human brain cell lines after treatment with the apoptosis inhibitors ABT-737 and MIM-1 (individually), between the apoptosis inhibitor treated group and the control group, were determined using a commercially pre-designed microfluidic array. Significant changes in apoptotic gene expression with more than a 2.0-fold difference in their expression levels were obtained in both cell lines; the most altered genes were in the HA cell line after MIM-1 treatment (n=42). These results contribute to the importance of apoptosis in normal and cancerous brain tissues and provide information on the effect of apoptosis inhibitors on cell viability and gene expression. Despite extensive investigations, a cure for GB is currently not available. The identification of an apoptotic gene panel and determining the sensitivity of normal and GB brain cells to individual apoptosis inhibitors could help to improve clinical practice and increase our understanding of brain tumor cell metabolism and apoptosis inhibitors in GB cells and astrocytes. Recognizing expression changes in pro-apoptotic and anti-apoptotic genes could contribute to the development of new treatments. PMID- 27779686 TI - Alterations in ACE and ABCG2 expression levels in the testes of rats subjected to atropine-induced toxicity. AB - Atropine-induced damage is associated with enzyme and protein alterations. The aim of the present study was to investigate atropine-induced alterations in testicular expression levels of angiotensin-converting enzyme (ACE) and adenosine 5'-triphosphate binding cassette sub-family G member 2 (ABCG2) following atropine treatment. Male Wistar rats received 15 mg/kg/day atropine for 7 days; control rats received an identical volume of saline, Following treatment, the testes were harvested for immunohistochemistry and in situ hybridization to examine the protein and gene expression levels of ACE and ABCG2 by digital image analysis. ACE gene and protein expression levels were significantly reduced in the testes of atropine-treated rats, compared with control rats (P=0.0001 and P<0.001, respectively). In addition, ABCG2 gene and protein expression levels were significantly increased in the testes of atropine-treated rats, compared with control rats (P=0.0017 and P<0.001, respectively). Thus, the results of the present study demonstrate that testicular protein and gene expression levels of ACE and ABCG2 were altered as a result of atropine-induced toxicity in the rats. These alterations may result in abnormal testicular function, and the proteins and genes identified in the present study may be useful to elucidate the mechanisms underlying atropine-induced toxicity and provide a direction for further studies. PMID- 27779685 TI - Identification of potential biomarkers and drugs for papillary thyroid cancer based on gene expression profile analysis. AB - The present study aimed to systematically examine the molecular mechanisms of papillary thyroid cancer (PTC), and identify potential biomarkers and drugs for the treatment of PTC. Two microarray data sets (GSE3467 and GSE3678), containing 16 PTC samples and 16 paired normal samples, were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Analysis package. Subsequently, the common DEGs were screened for functional and pathway enrichment analysis using the Database for Annotation Visualization and Integrated Discovery. The representative interaction subnetwork was further derived using Molecular Complex Detection software. In addition, the potential drugs for the hub DEGs in the subnetwork were screened from DrugBank and the potential drug-like ligands, which interacted with genes, were selected using MTiOpenScreen. A total of 167 common DEGs, including 77 upregulated and 90 downregulated DEGs, were screened. The common DEGs were associated with the functions of plasma membrane, extracellular matrix, response to steroid hormone stimulus and cell adhesion, and the pathways of tyrosine metabolism and cell adhesion molecules were significantly enriched. A total of eight common DEGs (MET, SERPINA1, LGALS3, FN1, TNFRSF11B, LAMB3 and COL13A1) were involved in the subnetwork. The two drugs, lanoteplase and ocriplasmin, and four drugs, beta-mercaptoethanol, recombinant alpha 1 antitrypsin, PPL-100 and API, were found for FN1 and SERPINA1, respectively. The common DEGs identified may be potential biomarkers for PCT. FN1 and SERPINA1 may be involved in PTC by regulating epithelial-to-mesenchymal transition and responding to steroid hormone stimuli, respectively. Ocriplasmin, beta mercaptoethanol and recombinant alpha 1-antitrypsin may be potential drugs for the treatment of PTC. PMID- 27779687 TI - Gambogenic acid induces proteasomal degradation of CIP2A and sensitizes hepatocellular carcinoma to anticancer agents. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is overexpressed in many human malignancies. It regulates phosphorylated AKT and stabilizes c-Myc in cell proliferation and tumor formation, suggesting that CIP2A plays an essential role in the development of cancer. In the present study, we report that a natural compound, gambogenic acid (GEA), induced the degradation of CIP2A via the ubiquitin-proteasome pathway. Interestingly, the combination of GEA and proteasome inhibitors potentiated the accumulation of ubiquitinated CIP2A and aggresome formation. In addition, GEA exhibited an inhibitory effect on cell proliferation and CIP2A-downstream signaling molecules (c-Myc and pAKT). Furthermore, GEA and CIP2A silencing enhanced the chemosensitivity of hepatocellular carcinoma cells to anticancer agents, suggesting that a combination of a CIP2A inhibitor and anticancer agents could be a valuable clinical therapeutic strategy. These results indicate that GEA is a CIP2A inhibitor that interferes with the ubiquitination and destabilization of CIP2A, providing a promising strategy to enhance the combinational therapy for hepatocellular carcinoma. PMID- 27779688 TI - [Retracted] Inhibitory effects of ethyl pyruvate administration on human gastric cancer growth via regulation of the HMGB1-RAGE and Akt pathways in vitro and in vivo. AB - Following the publication of this article, an interested reader drew to the attention of the Editorial Board that the above article appeared to contain a series of Figures that featured duplicated data. Following an internal investigation, the Editorial Board reached the conclusion that the allegations of the reader were well-founded. Specifically, the GAPDH bands shown in Figs. 2 and 3 are identical with those in Figs. 4C and 5D, with the exception that the images have been reversed. Furthermore, certain data in Fig. 4C of this paper appeared to have been shared with Fig. 3 in the following article (albeit for purportedly different experiments): Zhang J, Zhu J, Zhou Z, Chen W and Chen N: Inhibitory effects of ethyl pyruvate on invasion and metastasis of human gastric cancer SGC 7901 cells via downregulation of Akt pathway. China J Cancer Prev Treat (Chin) 39: 776-779, 2012. Despite numerous attempts at doing so, we were unable to receive any response to our request for further information from the authors of this article. Given the extent of the anomalies with the data between the aforementioned papers, the Editorial Board has therefore decided to retract the article from Oncology Reports. We regret any inconvenience in this regard. [the original article was published in the Oncology Reports 27: 1511-1519, 2012; DOI: 10.3892/or.2012.1623]. PMID- 27779689 TI - Mitochondrial transcription factor A contributes to cisplatin resistance in patients with estrogen receptor-positive breast cancer. AB - Previous studies have reported that triple-negative breast cancer is more sensitive to cytotoxic treatment, compared with estrogen receptor (ER)-positive cancer. However, the underlying molecular mechanisms remain to be fully elucidated. In the present study, we employed reverse transcription-quantitative polymerase chain reaction, western blot and in vivo assays to investigate the underlying mechanisms. The sensitivities of cells to cisplatin were examined in ER-positive and ER-negative breast cancer cells, and it was found that the ER negative cells were more sensitive to cisplatin, compared with the ER-positive cells. In addition, it was found that mitochondrial transcription factor A (TFAM), which functions in mitochondrial DNA replication and repair, was expressed at a high level in ER-positive cell lines and patient tissues, compared with ER-negative cell lines and tissues. It was also found that the sensitivity to cisplatin was decreased when TFAM was knocked down in the breast cancer cells, and these effects were reversed when TFAM was reintroduced to the cells. Similar results were observed in xenograft tumors. The results of the present study provided evidence that resistance to cisplatin chemotherapy in ER-positive breast cancer may be through TFAM and indicated that TFAM may be a target for chemoresistance in patients with breast cancer. These findings offer potential guidance for chemotherapy in patients with breast cancer. PMID- 27779690 TI - Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition. AB - Inhibition of epidermal growth factor receptor (EGFR) signalling has emerged as a new treatment strategy for oral squamous cell carcinoma (OSCC). Previously, we found that loss of EGFR expression in OSCC was associated with epithelial mesenchymal transition (EMT), and may have functional implications with regard to resistance to cetuximab, a monoclonal anti-EGFR antibody. Eribulin (a microtubule inhibitor) reportedly renders breast cancer less aggressive, and less likely to metastasise, by triggering mesenchymal-to-epithelial (MET) transition. In the present study we evaluated whether eribulin-induced MET was associated with re sensitization of resistant OSCC cell lines to cetuximab. In vitro antiproliferative activities were determined in three human OSCC lines (OSC-20, OSC-19 and HOC313) treated with eribulin. These three human OSCC represented different EMT/MET states. Interestingly, HOC313 cells (mesenchymal phenotype) were highly sensitive to eribulin in comparison with other cell lines, and significantly enhanced the anti-proliferative effect of cetuximab in response to the drug. Eribulin also underwent a MET-associated gene switch that resulted in morphological changes and high EGFR expression in HOC313 cells, and abrogated a TGF-beta-induced EMT gene expression signature. Eribulin-dependent sensitization of OSCC to cetuximab is likely due to induction of MET. Combination therapies based on eribulin and cetuximab have potential as a novel treatment regimen in OSCC. PMID- 27779691 TI - miR-4262 promotes the proliferation of human cutaneous malignant melanoma cells through KLF6-mediated EGFR inactivation and p21 upregulation. AB - Alterations in the levels and functions of microRNAs (miRs) have been associated with carcinogenesis. In this study, we investigated the role and underlying mechanism of miR-4262 in the proliferation of human cutaneous malignant melanoma (CMM) cells. The expression levels of miR-4262 were significantly upregulated in cancerous tissues compared with those in matched adjacent normal tissues from 110 CMM patients. miR-4262 was also regulated in five types of CMM cell lines, displaying an opposite expression pattern to that of Kruppel-like 6 (KLF6), a proven tumor suppressor in several cancers other than CMM. KLF6 overexpression sharply reduced A375 cell proliferation, suppressed the activation of epidermal growth factor receptor (EGFR) and increased p21 expression levels, while knockdown of KLF6 by siRNA transfection had an opposite effect. Furthermore, KLF6 was proven to be a direct target gene of miR-4262 by bioinformatic analysis and KLF6-3'UTR luciferase reporter assay. Finally, our data on miR-4262 mimic and inhibitor transfection indicated that miR-4262 could markedly reduce the expression of KLF6 protein and had a stimulatory effect on A375 cell proliferation. Our findings indicate that KLF6 acts as a tumor suppressor in CMM cells and miR-4262 promotes the proliferation of CMM cells through KLF6-mediated EGFR inactivation and p21 upregulation. PMID- 27779692 TI - Angiomotin promotes the malignant potential of colon cancer cells by activating the YAP-ERK/PI3K-AKT signaling pathway. AB - Colorectal cancer (CRC) is a leading cause of cancer-related deaths with an increasing incidence in China. The aberrant expression of angiomotin (AMOT) has been confirmed in a variety of tumors and can interact with Yes-associated protein (YAP) to either promote or suppress the progression of cancer. Unfortunately, its role in CRC remains poorly elucidated. Herein, higher levels of AMOT were observed in CRC cell lines. Upregulation of AMOT in LoVo cells markedly increased cell proliferation and apoptotic resistance to 5-fluorouracil. Moreover, its increase also promoted cell invasion and migration. Simultaneously, AMOT silencing markedly attenuated the growth and metastatic potential of HCT116 cells. Notably, AMOT upregulation promoted the activity of YAP by decreasing the expression of phosphorylated YAP and YAP in the cytoplasm and increasing YAP levels in the nucleus. Further mechanistic analysis corroborated that transfection with YAP siRNA notably diminished cell growth, invasion and migration in the AMOT-overexpressing LoVo cells. Additionally, upregulation of AMOT induced the activation of the ERK and AKT pathways by YAP expression, both associated with the development of CRC. Collectively, these results suggest that AMOT may function as an oncogene in the progression of CRC by activating the YAP ERK/PI3K-AKT signaling pathway. Therefore, this study presents a promising therapeutic target for CRC. PMID- 27779693 TI - Metformin potentiates the anticancer activities of gemcitabine and cisplatin against cholangiocarcinoma cells in vitro and in vivo. AB - Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways. Metformin upregulated the expression of p21Waf1 and p27kip1, and downregulated the expression of cyclin D1, a key protein required for cell cycle progression. The combination of gemcitabine and cisplatin inhibited the proliferation and induced the apoptosis of human cholangiocarcinoma cells by inducing the phosphorylation of AMPK, downregulating cyclin D1, and activating caspase-3. Administration of metformin enhanced the efficacy of gemcitabine and cisplatin to suppress the growth of cholangiocarcinoma tumors established in experimental models by inhibiting cell proliferation and inducing cell apoptosis through their effects on AMPK, cyclin D1 and caspase-3. Given that metformin has been used to treat type 2 diabetes patients for over half a century due to its superior safety profile, the results presented here indicate that metformin may be a potent agent for enhancing the efficacy of gemcitabine and cisplatin in the treatment of cholangiocarcinoma. PMID- 27779694 TI - Fentanyl induces autophagy via activation of the ROS/MAPK pathway and reduces the sensitivity of cisplatin in lung cancer cells. AB - Cancer pain is the most common complication of lung carcinoma. Opioid agonist fentanyl is widely used for relieving pain in cancer patients, and cisplatin (DDP)-based chemotherapy is commonly used for the treatment of advanced lung cancer; these two drugs are always used together in lung carcinoma patients. However, the mechanisms and related biological pathways by which fentanyl influences cisplatin sensitivity are relatively poorly reported. Here, we found that fentanyl reduces the sensitivity of cisplatin in human lung cancer cells and induces autophagy. Fentanyl induced reactive oxygen species (ROS) generation and JNK activation. N-acetyl-L-cysteine is a ROS scavenger and antioxidant, and the inhibition of JNK with SP600125 prevented fentanyl-induced autophagy. We also found that 3-methyladenine (3-MA; an autophagy inhibitor) increased the sensitivity of DDP and weakened the inhibition of fentanyl. In conclusion, fentanyl reduces the sensitivity of cisplatin in lung cancer cells through the ROS-JNK-autophagy pathway, whereas the autophagy inhibitor 3-MA may weaken this effect. PMID- 27779695 TI - Enhancement of radiosensitivity by inhibition of c-Jun N-terminal kinase activity in a Lewis lung carcinoma-bearing subcutaneous tumor mouse model. AB - Stereotactic radiosurgery has been recognized as an effective treatment approach for metastatic brain tumors. By increasing the sensitivity of the tumor to radiation and decreasing the marginal dose, it is possible to improve therapeutic efficacy and decrease side-effects. In radiation-induced cells, c-Jun N-terminal kinase (JNK) signaling mediates the phosphorylation of H2AX, which indicates DNA damage sensitivity and modulates the effect of radiation. Lewis lung cancer (LLC) and breast cancer (4T1) cells were irradiated with a Gamma Knife in cell culture tubes. To evaluate the relationship between radiosensitivity and JNK activity, clonogenic assay was performed. DNA damage response was estimated by gammaH2AX focus formation assay and apoptosis-related protein levels were assessed by western blotting. The mice were subcutaneously inoculated with LLC cells, and irradiated concomitantly with JNK inhibitor treatment. The effect of the JNK inhibitor was investigated by tumor volumetry and immunohistochemistry. gammaH2AX expression, which mediates repair of radiation-induced DNA damage, was reduced in the cancer cell group pretreated with the JNK inhibitor. This finding shows that JNK inhibition may increase the radiosensitivity in radiated lung and breast cancer cells. For the in vivo study, irradiated tumor growth was significantly delayed in the JNK inhibitor-treated mouse group. Blockade of JNK signaling decreased gammaH2AX expression and increased apoptosis in the radiation-induced cancer cells. JNK inhibitor may be useful for enhancing the radiosensitivity of lung and breast cancer cells and improving the treatment efficacy of radiosurgical approaches for metastatic brain tumors. PMID- 27779696 TI - Microfloral diversity in the lower respiratory tracts of neonates with bacterial infectious pneumonia combined with ventilator-associated pneumonia. AB - Bacterial infectious pneumonia is one of the major causes of mortality in neonates, particularly when the neonates suffer from ventilator-associated pneumonia (VAP). However, the causes of pneumonia are difficult to define. Thus, the present study focused on understanding the diversity of microflora in the lower respiratory tract to elucidate the causes. The experimental groups comprised newborns who suffered from infectious pneumonia with or without VAP (IVAP and IP groups, respectively), whereas the control group comprised newborns who suffered from respiratory distress syndrome (RDS) without VAP (RDS group). Following 1, 3 and 5 days of ventilation, sputum samples were collected and the DNA was extracted. The DNA was amplified and separated, and the 16S rDNA was then sequenced and analyzed for diversity. The results of the diversity and Shannon Wiener indices were ordered as follows: IVAP group < IP group < RDS group. The percentages of Streptococcus sp., Serratia sp. and Achromobacter sp. in the IP and IVAP groups were higher, compared with those in the RDS group, whereas the percentages of Klebsiella sp. and Acinetobacter sp. were lower on day 1. The percentages of Klebsiella sp. and Streptococcus sp. on days 1 and 3 were ordered as follows: IVAP group > IP group > RDS group, and the percentages of Serratia sp., Acinetobacter sp. and Achromobacter sp. were ordered as follows: IVAP group < IP group < RDS group. After 3-5 days, the percentages of Klebsiella sp., Acinetobacter sp., Streptococcus sp., Serratia sp. and Achromobacter sp. in the IVAP group were lower, compared with those in the RDS and IP groups. It was concluded that the decreased microfloral diversity, increased constituent ratios of Klebsiella sp. and Streptococcus sp., and decreased ratios of Serratia sp. and Acinetobacter sp. in the lower respiratory tract of neonates suffering from pneumonia may be indicators of VAP. PMID- 27779697 TI - Myofibroblast distribution is associated with invasive growth types of colorectal cancer. AB - Both the invasive growth types of colorectal cancer (CRC) and the number of myofibroblasts have been associated with histopathological factors such as lymph node and liver metastasis, and local recurrence. However, there are few studies, that have assessed the association between invasive growth type and myofibroblast distribution in CRC. We aimed to evaluate the relationship between the clinicopathological factors of CRC and two invasive growth types, the expanding and infiltrating types. We categorized 150 cases of pT3 CRC into the expanding and infiltrating types and measured the myofibroblast density of three histological layers: the submucosa (SM), the muscularis propria (MP) and the subserosa (SS). We compared these two invasive growth types and analyzed the relationship between clinicopathological factors and myofibroblast density. Myofibroblast density was significantly higher in the infiltrating type than that in the expanding type (P<0.05). In the lymph node metastasis-positive group of the infiltrating type, myofibroblast density in MP was significantly higher than that in the lymph node metastasis-negative group (P<0.001). In the infiltrating type, the group with the higher level of lymphatic invasion had a significantly higher density of myofibroblasts in the MP than the group with the lower level of lymphatic invasion (P<0.01). These results suggest that myofibroblasts participate more in the infiltrating type compared with the expanding type of CRC. It would appear that myofibroblasts present in the MP play an important role in the malignant potential of the infiltrating type compared to the expanding type. PMID- 27779698 TI - TIPE2 suppresses the tumorigenesis, growth and metastasis of breast cancer via inhibition of the AKT and p38 signaling pathways. AB - Breast cancer is the second leading cause of cancer-related deaths in female patients, and the main reasons are late diagnosis, limited therapeutic options and metastasis. Therefore, development of molecular therapeutic targets for breast cancer to suppress tumorigenesis, growth and metastasis may improve the therapeutic options and be of great benefit to patients. Tumor necrosis factor alpha-induced protein 8-like 2 (TIPE2) is a novel molecule for maintaining immune homeostasis and is involved in cancer development. Previous studies have shown that TIPE2 plays a suppressive role in the development of several types of human cancers. However, its role in breast cancer is still not clear. In the present study, we detected TIPE2 expression in human breast cancer and adjacent normal tissues. The expression of TIPE2 was reduced in breast cancer tissues compared to the level in adjacent normal tissues. We then established a breast cancer cell line stably expressing TIPE2 to investigate the role of TIPE2 in breast cancer carcinogenesis. Our results showed that overexpression of TIPE2 significantly inhibited the proliferation of MDA-MB-231 cells as detected by Cell Counting Kit 8 assay and suppressed the migration and invasion of breast cancer cells as detected by Transwell migration and invasion assays in vitro. TIPE2 also promoted cell apoptosis as detected by flow cytometry analysis. Moreover, TIPE2 inhibited the tumorigenesis of breast cancer in vivo. Mechanistically, TIPE2 inhibited the phosphorylation of AKT and p38 as detected by western blot analysis. Taken together, TIPE2 suppressed breast cancer tumorigenesis, growth and metastasis possibly via regulation of the AKT and p38 signaling pathways. The results indicate that TIPE2 may be a potential therapeutic target for breast cancer therapy. PMID- 27779699 TI - Differential expression of filamin B splice variants in giant cell tumor cells. AB - Giant cell tumor of bone (GCT) is the most commonly reported non-malignant bone tumor in Hong Kong. This kind of tumor usually affects people aged 20-40 years. Also, it is well known for recurrence locally, especially when the tumor cannot be removed completely. Filamins are actin-binding proteins which contain three family members, filamin A, B and C. They are the products of three different genes, FLNA, FLNB and FLNC, which can generate various transcript variants in different cell types. In this study, we focused on the effects of FLNBv2 and FLNBv4 toward GCT cells. The only difference between FLNBv2 and FLNBv4 is that FLNBv4 does not contain hinge 1 region. We found that the relative abundance of FLNBv4 varies among different GCT cell lines while the expression level of FLNBv4 in normal osteoblasts was only marginally detectable. In the functional aspect, overexpression of FLNBv4 led to upregulation of RANKL, OCN, OPG and RUNX2, which are closely related to GCT cell survival and differentiation. Moreover, FLNBv4 can have a negative effect on cell viability of GCT cells when compare with FLNBv2. In conclusion, splicing variants of FLNB are differentially expressed in GCT cells and may play a role in the proliferation and differentiation of tumor cells. PMID- 27779700 TI - Decreased expression of long non-coding RNA GAS5 promotes cell proliferation, migration and invasion, and indicates a poor prognosis in ovarian cancer. AB - Long non-coding RNA growth arrest-specific 5 (GAS5) was reported to be aberrantly expressed in various types of cancers. However, the role of GAS5 in the evolution and progression of ovarian cancer remains elusive. In the present study, we aimed to investigate the cellular function and clinical significance of GAS5 in ovarian cancer. GAS5 expression levels in 63 ovarian cancer tissues were detected by quantitative real-time PCR. Cell Counting Kit-8 (CCK-8) assay was performed to analyze the effect of GAS5 on cell proliferation. The effect of GAS5 on cell migration and invasion was detected using Transwell assay. Cell apoptosis was evaluated by flow cytometry and Hoechst staining. SKOV3 cells with stable expression of GAS5 were injected into nude mice to study the effect of GAS5 on tumorigenesis in vivo. Western blotting was used to determine the protein levels of GAS5 potential targets. The results showed that GAS5 was markedly decreased in tumor tissues and a lower expression of GAS5 was detected in tumors with larger size, deeper invasive depth and higher tumor stage. Patients with low GAS5 expression level had poorer disease-free (P<0.0001) and overall survival (P=0.0016) than those with high GAS5 expression. Moreover, overexpression of GAS5 was demonstrated to suppress ovarian cancer cell proliferation in vitro and in vivo. Finally, we found that GAS5 influenced ovarian cancer cell proliferation, partly via regulating cyclin D1, p21 and apoptosis protease activating factor 1 (APAF1) expression. Our findings suggest that lncRNA GAS5 may represent a novel indicator of poor prognosis in ovarian cancer and may be a potential therapeutic target for diagnosis and therapy. PMID- 27779701 TI - Downregulation of microRNA-574 in cancer stem cells causes recurrence of prostate cancer via targeting REL. AB - miR-574-5p has been reported involved in the pathogenesis of numerous human malignancies such as colorectal and lung cancer. In this study, we aimed to explore the roles of REL and miR-574 in the recurrence of prostate cancer (PCa) and to identify the underlying molecular mechanisms. Our literature search found that miR-574 is regulated in cancer stem cells (CSCs), and next we used the microRNA (miRNA) database (www.mirdb.org) to find REL as a target of miR-574. Luciferase assay was performed to verify the miRNA/target relationship. Oligo transfection, real-time PCR and western blot analysis were used to support the conclusions. We validated REL to be the direct gene via luciferase reporter assay system, and real-time PCR and western blot analysis were also conducted to study the mRNA and protein expression level of REL between different groups (recurrence and non-recurrence) or cells treated with scramble control, miR-574 mimics, REL siRNA and miR-574 inhibitors, indicating the negative regulatory relationship between miR-574 and REL. We also investigated the relative viability of prostate CSCs when transfected with scramble control, miR-574 mimics, REL siRNA and miR 574 inhibitors to validate miR-574 to be positively interfering with the viability of prostate CSCs. We then investigated the relative apoptosis of prostate CSCs when transfected with scramble control, miR-574 mimics, REL siRNA and miR-574 inhibitors. The results showed miR-574 inhibited apoptosis. In conclusion, miR-574 might be a novel prognostic and therapeutic target in the management of PCa recurrence. PMID- 27779702 TI - Extract of Caulis Spatholobi, a novel blocker targeting tumor cell-induced platelet aggregation, inhibits breast cancer metastasis. AB - Metastasis of breast cancer is the vital step for malignant progression. During such a process, hematogenous metastasis is an indispensable approach for the dissemination of cancer cells. A platelet, contributes to hypercoagulable state, and is also identified the crucial factor in the coagulation system for supporting metastasis. Therefore, the relationship of a platelet and a tumor cell plays a critical role in tumor cell metastasis. Consequently, inhibiting tumor cell-induced platelet aggregation (TCIPA) is recongnized as a crucial target on suppression of tumor metastasis such as aspirin (ASA). Under such circumstance, here we report that, through dissociating the tumor-platelet (T-P) complex, 80% ethanol extracts of Caulis Spatholobi (SET) successfully alleviated the hypercoagulation state, thereby reducing tumor metastasis and improving the prospects of survival in breast cancer cell model. Through MTT and anti aggregation assay stimulated by ADP, we detected the optimum treatment time and the optimum dose of SET. By using confocal microscopy, we observed that SET can strongly block the formation of T-P complex in vitro. The result was further quantified and confirmed by the FACS analysis. The fluorescent value of T-P complex was obviously decreased in the drug-treated groups. In vivo, 4T1 cells were injected through the mouse tail vein for dynamic visualization by small animal imaging system. The metastatic intensity was quantified and the survival curve was analyzed. Additionally, general observation and hematoxylin and eosin (H&E) staining of lung tissue was performed. SET exerted an obvious effect on the inhibition of metastasis and increasing the survival rate of mice. For the molecular mechanism study of anti-TCIPA, zymography and RT-PCR assay preliminarily revealed the molecular mechanism of SET in the regulation of P-T interaction. Collectively, through drug efficacy identification and pharmacological revealing, we have obtained a promising candidate for the interference of breast metastasis by suppressing TCIPA, which will be beneficial for clinical cancer treatment. PMID- 27779703 TI - Resveratrol induces cell cycle arrest and apoptosis in human eosinophils from asthmatic individuals. AB - Eosinophils exert a number of inflammatory effects through the degranulation and release of intracellular mediators, and are considered to be key effector cells in allergic disorders, including asthma. In order to investigate the regulatory effects of the natural polyphenol, resveratrol, on eosinophils derived from asthmatic individuals, the cell counting Kit-8 assay and flow cytometry analysis were used to determine cell proliferation and cell cycle progression in these cells, respectively. Cellular apoptosis was detected using annexin V-fluorescein isothiocyanate/propidium iodide double-staining. The protein expression levels of p53, p21, cyclin-dependent kinase 2 (CDK2), cyclin A, cyclin E, Bim, B-cell lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax) were measured by western blot analysis following resveratrol treatment. The results indicated that resveratrol effectively suppressed the proliferation of eosinophils from asthmatic patients in a concentration- and time-dependent manner. In addition, resveratrol was observed to arrest cell cycle progression in G1/S phase by increasing the protein expression levels of p53 and p21, and concurrently reducing the protein expression levels of CDK2, cyclin A and cyclin E. Furthermore, resveratrol treatment significantly induced apoptosis in eosinophils, likely through the upregulation of Bim and Bax protein expression levels and the downregulation of Bcl-2 protein expression. These findings suggested that resveratrol may be a potential agent for the treatment of asthma by decreasing the number of eosinophils. PMID- 27779704 TI - Overexpression of miR-422a inhibits cell proliferation and invasion, and enhances chemosensitivity in osteosarcoma cells. AB - Osteosarcoma (OS) is an aggressive malignant tumor that is mesenchymal in origin with a very low 5-year survival rate, particularly in the patients with locally advanced or metastatic tumors and recurrent disease. MicroRNAs (miRNAs) play a critical role in essential biological processes as cellular proliferation, differentiation and apoptosis in normal or cancer cells, including OS cells. In the present study, we aimed to investigate the role of miR-422a in OS. We demonstrated that miR-422a expression was significantly downregulated in OS tissues and cell lines compared with the normal controls. In addition, overexpression of miR-422a was able to inhibit cell proliferation and the ability of invasion, and enhance paclitaxel and cisplatin-mediated apoptosis in OS cells. Inversely, downregulation of miR-422a exhibited an opposite role. We further demonstrated that miR-422a directly targeted TGFbeta2 and regulated its expression and the activation of downstream molecules, smad2 and smad3 in OS cells. Thus, miR-422a/TGFbeta2/smad axis may be a potential target for OS treatment. PMID- 27779705 TI - Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. AB - Melanoma is the most aggressive skin malignancy with a high rate of mortality and is frequently refractory to many therapeutics, thus demanding the discovery of novel effective anti-melanoma agents. Diphenhydramine (DPH) is an H1 histamine receptor antagonist and a relatively safe drug. Previous studies have revealed the in vitro cytotoxicity of DPH against melanoma cells, but the mechanisms involved concerning its cytotoxicity and the in vivo anti-melanoma effect remain unknown. We herein present the first evidence supporting that DPH is selectively proapoptotic for a panel of melanoma cell lines irrespective of BRAFV600E status while sparing normal melanocytes. Of note, DPH effectively suppressed tumor growth and prolonged the length of survival of mice bearing B16-F10 melanoma. Mechanistic investigation further revealed that DPH downregulated antiapoptotic MCL-1, whereas MCL-1 overexpression impeded the proapoptotic action of DPH. Moreover, DPH attenuated STAT3 activation, as evidenced by the reduced levels of tyrosine 705-phosphorylated STAT3. Notably, ectopic expression of constitutively active STAT3 mutant reduced DPH-induced apoptosis but also protected MCL-1 from downregulation by DPH, illustrating that DPH impairs STAT3 activation to block STAT3-mediated induction of MCL-1 in eliciting apoptosis. Collectively, we for the first time validate the in vivo anti-melanoma effect of DPH and also establish DPH as a drug targeting STAT3/MCL-1 survival signaling pathway to induce apoptosis. Our discovery therefore suggests the potential to repurpose DPH as an anti-melanoma therapeutic agent. PMID- 27779706 TI - Effect of colorectal cancer on the number of normal stem cells circulating in peripheral blood. AB - Bone marrow (BM) residing stem cells are mobilized from their BM niches into peripheral blood (PB) in several pathological situations including tissue organ injury and systemic inflammation. We recently reported that the number of BM derived stem cells (SCs) increases in patients with pancreatic and stomach cancer. Accordingly, we observed higher numbers of circulating very small embryonic/epiblast-like stem cells (VSELs) and mesenchymal stem cells (MSCs) that were associated with the activation of pro-mobilizing complement cascade and an elevated level of sphingosine-1 phosphate (S1P) in PB plasma. We wondered if a similar correlation occurs in patients with colorectal cancer (CRC). A total of 46 patients were enrolled in this study: 17 with CRC, 18 with benign colonic adenomas (BCA) and 11 healthy individuals. By employing fluorescence-activated cell sorting (FACS) we evaluated the number of BM-derived SCs circulating in PB: i) CD34+/Lin-/CD45- and CD133-/Lin-/CD45- VSELs; ii) CD45-/CD105+/CD90+/CD29+ MSCs; iii) CD45-/CD34+/CD133+/KDR+ endothelial progenitor cells (EPCs); and iv) CD133+/Lin-/CD45+ or CD34+/Lin-/CD45+ cells enriched for hematopoietic stem/progenitor cells (HSPCs). In parallel, we measured in the PB parameters regulating the egress of SCs from BM into PB. In contrast to pancreatic and gastric cancer patients, CRC subjects presented neither an increase in the number of circulating SCs nor the activation of pro-mobilizing factors such as complement, coagulation and fibrinolytic cascade, circulating stromal derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF) and intestinal permeability marker (zonulin). In conclusion, mobilization of SCs in cancer patients depends on the type of malignancy and its ability to activate pro mobilization cascades. PMID- 27779707 TI - ST3Gal III modulates breast cancer cell adhesion and invasion by altering the expression of invasion-related molecules. AB - Changes in the carbohydrate structure on the surface of tumor cells is an important feature of cancer metastasis. The specific role of sialic acids in the glycoconjugate terminal has not yet been clearly elucidated in these processes. Previously, we reported that alpha2,3-sialic acid residues in breast cancer are associated with metastatic potential. The alpha2,3-sialyltransferase ST3Gal III, which adds alpha2,3-sialic acids to glycoproteins, is overexpressed in various tumors, and enzyme activity is correlated with tumor metastasis, yet its mechanistic role has not been fully evaluated. In the present study, we aimed to investigate the influence of ST3Gal III on key steps in the process of breast cancer metastasis. ST3Gal III-overexpressing and ST3Gal III-silenced breast cancer MDA-MB-231 cell lines were generated. They showed an increase or decrease in the tumor-associated antigen sialyl-Lewis X (SLeX). The E-selectin binding capacity of the transfectants was proportional to cell surface SLeX levels. Cell migration and invasion were positively correlated with ST3Gal III levels. Moreover, ST3Gal III expression modulated the protein expression of invasion related molecules, including beta1 integrin, matrix metalloproteinase (MMP)-2, MMP-9 and cyclooxygenase-2, which may account for the mechanism involved in the effects of ST3Gal III on breast cancer invasiveness. In conclusion, our findings in these novel models of ST3Gal III expression revealed a critical requirement for ST3Gal III in several steps of breast cancer metastasis. ST3Gal III modulates breast cancer cell adhesion and invasion by altering the expression of invasion related molecules. This study provides novel insights into the mechanisms underlying metastasis and suggests a new target for the effective drug treatment of breast cancer metastasis. PMID- 27779709 TI - Comparative gene expression profiling of ADAMs, MMPs, TIMPs, EMMPRIN, EGF-R and VEGFA in low grade meningioma. AB - MMPs (matrix metalloproteinases), ADAMs (a disintegrin and metalloproteinase) and TIMPs (tissue inhibitors of metalloproteinases) are implicated in invasion and angiogenesis: both are tissue remodeling processes involving regulated proteolysis of the extracellular matrix, growth factors and their receptors. The expression of these three groups and their correlations with clinical behaviour has been reported in gliomas but a similar comprehensive study in meningiomas is lacking. In this study, we aimed to evaluate the patterns of expression of 23 MMPs, 4 TIMPs, 8 ADAMs, selective growth factors and their receptors in 17 benign meningiomas using a quantitative real-time polymerase chain reaction (qPCR). Results indicated very high gene expression of 13 proteases, inhibitors and growth factors studied: MMP2 and MMP14, TIMP-1, -2 and -3, ADAM9, 10, 12, 15 and 17, EGF-R, EMMPRIN and VEGF-A, in almost every meningioma. Expression pattern analysis showed several positive correlations between MMPs, ADAMs, TIMPs and growth factors. Furthermore, our findings suggest that expression of MMP14, ADAM9, 10, 12, 15 and 17, TIMP-2, EGF-R and EMMPRIN reflects histological subtype of meningioma such that fibroblastic subtype had the highest mRNA expression, transitional subtype was intermediate and meningothelial type had the lowest expression. In conclusion, this is the first comprehensive study characterizing gene expression of 8 ADAMs in meningiomas. These neoplasms, although by histological definition benign, have invasive potential. Taken together, the selected elevated gene expression pattern may serve to identify targets for therapeutic intervention or indicators of biological progression and recurrence. PMID- 27779708 TI - Enteroendocrine cells, stem cells and differentiation progenitors in rats with TNBS-induced colitis. AB - Patients with inflammatory bowel disease (IBD), as well as animal models of human IBD have abnormal enteroendocrine cells. The present study aimed to identify the possible mechanisms underlying these abnormalities. For this purpose, 40 male Wistar rats were divided into 4 groups as follows: the control group, the group with trinitrobenzene sulfonic acid (TNBS)-induced colitis with no treatment (TNBS group), the group with TNBS-induced colitis treated with 3-[(dodecylthiocarbonyl) methyl]-glutarimide (DTCM-G; an activator protein-1 inhibitor) (DTCM-G group), and the group with TNBS-induced colitis treated with dehydroxymethylepoxyquinomicin (DHMEQ; a nuclear factor-kappaB inhibitor) treatment (DHMEQ group). Three days following the administration of TNBS, the rats were treated as follows: those in the control and TNBS groups received 0.5 ml of the vehicle [0.5% carboxymethyl cellulose (CMC)], those in the DTCM-G group received DTCM-G at 20 mg/kg body weight in 0.5% CMC, and those in the DHMEQ group received DHMEQ at 15 mg/kg body weight in 0.5% CMC. All injections were administered intraperitoneally twice daily for 5 days. The rats were then sacrificed, and tissue samples were taken from the colon. The tissue sections were stained with hemotoxylin-eosin and immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP), somatostatin, Musashi1 (Msi1), Math1, Neurogenin3 (Neurog3) and NeuroD1. The staining was quantified using image analysis software. The densities of CgA-, PYY , PP-, Msi1-, Neurog3- and NeuroD1-positive cells were significantly lower in the TNBS group than those in the control group, while those of serotonin-, oxyntomodulin- and somatostatin-positive cells were significantly higher in the TNBS group than those in the control group. Treatment with either DTCM-G or DHMEQ restored the densities of enteroendocrine cells, stem cells and their progenitors to normal levels. It was thus concluded that the abnormalities in enteroendocrine cells and stem cells and their differentiation progenitors may be caused by certain signaling substances produced under inflammatory processes, resulting in changes in hormone expression in enteroendocrine cells. These substances may also interfere with the colonogenic activity and the differentiation of the stem-cell secretory lineage into mature enteroendocrine cells. PMID- 27779710 TI - Antihypertensive therapy improves insulin resistance and serum levels of interleukin-6 and -10 in spontaneously hypertensive rats with steatohepatitis. AB - Metabolic syndrome based on insulin resistance (IR) and hypertension is a risk factor for advanced liver disease and cardiovascular disease in patients with nonalcoholic steatohepatitis (NASH). The present study investigated the effects of severe hypertension induced by a high-salt (HS) diet and antihypertensive therapy on the pathophysiological condition of spontaneously hypertensive rats (SHRs) with steatohepatitis. Steatohepatitis was induced using a choline deficient, L-amino acid-defined diet (CDAA). Male SHRs (7-week-old) were randomly divided into five groups: Those receiving 6 weeks of standard chow with a normal salt concentration, followed by an additional 8 weeks of standard chow or CDAA with a normal salt concentration (control and CDAA groups, respectively); and those receiving 6 weeks of standard chow with HS, followed by CDAA with HS for an additional 8 weeks, with or without the antihypertensive agents, amlodipine (Aml) or hydralazine. In the CDAA and CDAA+HS groups, blood pressure was significantly correlated with serum levels of insulin, fasting blood glucose and homeostasis model assessment (HOMA)-IR. Antihypertensive therapy ameliorated the elevated glucose, insulin and HOMA-IR. Furthermore, the increased levels of serum interleukin (IL)-6 following the CDAA+HS diet were attenuated by antihypertensive therapy. The serum levels of IL-10 were increased by antihypertensive therapy, and the decrease in the proportion of splenic CD4+CD25+forkhead box P3+ T cells observed following the CDAA+HS diet tended to be restored by Aml. In conclusion, antihypertensive therapy improved glucose metabolism and imbalances in cytokine expression in the rat model of hypertension with steatohepatitis, suggesting that antihypertensive therapy acting through immunological factors may be beneficial for patients with metabolic syndrome-associated NASH. PMID- 27779712 TI - PA-MSHA inhibits proliferation and induces apoptosis in human non-small cell lung cancer cell lines with different genotypes. AB - The present study examined the potential of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) to inhibit proliferation and induce apoptosis in non-small-cell lung cancer (NSCLC) cell lines. It also investigated its mechanisms of action in different genotypes of human NSCLC. A total of three NSCLC cell lines, PC-9, A549, and NCI-H1975, were treated with PA-MSHA at different concentrations. The anti-proliferative effect of PA-MSHA was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle distribution and apoptosis induced by the treatment were measured by flow cytometry (FCM) with Annexin V/propidium iodide staining. Western blotting was conducted to determine the expression level of apoptosis-associated proteins. PA MSHA was demonstrated to exert a time- and concentration-dependent cytotoxic effect in PC-9, A549, and NCI-H1975 cells. The FCM indicated that all the different concentrations of PA-MSHA used in the present study induce apoptosis and cell cycle arrest of NSCLC cells. Treatment with PA-MSHA may exert anti proliferative effects on NSCLC cells by affecting regulation of the cell cycle and inducing apoptosis that is mediated in part by an intrinsic apoptosis signaling pathway. These data suggest that PA-MSHA has the potential to inhibit proliferation and induce apoptosis in NSCLC cells. Furthermore, these data provide mechanistic details for the potential application of PA-MSHA-based therapeutic strategies for the treatment of different NSCLC genotypes. This present study suggests potential novel strategies to maximize effective therapeutic strategies targeting anti-epidermal growth factor receptor for future clinical trials. PMID- 27779713 TI - A novel blood-pooling MR contrast agent: Carboxymethyl-diethylaminoethyl dextran magnetite. AB - Gadofosveset trisodium is available as a prolonged pooling vascular contrast agent for magnetic resonance imaging. As gadolinium (Gd)-based agents may increase the risk for nephrogenic systemic fibrosis in patients with severe renal insufficiency, the present study synthesized carboxymethyl-diethylaminoethyl dextran magnetite (CMEADM) particles as a blood-pooling, non-Gd-based contrast agent. CMEADM particles carry a negative or positive charge due to the binding of amino and carboxyl groups to the hydroxyl group of dextran. The present study evaluated whether the degree of charge alters the blood-pooling time. The evaluation was performed by injecting four groups of three Japanese white rabbits each with CMEADM-, CMEADM2-, CMEADM+ (surface charges: -10.4, -41.0 and +9.6 mV, respectively) or with ultrasmall superparamagnetic iron oxide (USPIO; -11.5 mV). The relative signal intensity (SIrel) of each was calculated using the following formula: SIrel = (SI post-contrast - SI pre-contrast / SI pre-contrast) x 100. Following injection with the CMEADMs, but not with USPIO, the in vivo pooling time was prolonged to >300 min. No significant differences were attributable to the electric charge among the CMEADM-, CMEADM2- or and CMEADM+ particles when analyzed with analysis of variance and Tukey's HSD test. Taken together, all three differently-charged CMEADM2 particles exhibited prolonged vascular enhancing effects, compared with the USPIO. The degree of charge of the contrast agents used in the present study did not result in alteration of the prolonged blood pooling time. PMID- 27779711 TI - Rapamycin inhibits lipopolysaccharide-induced neuroinflammation in vitro and in vivo. AB - Alzheimer's disease (AD) is the most common type of progressive neurodegenerative disorder, and is responsible for the most common form of dementia in the elderly. Inflammation occurs in the brains of patients with AD, and is critical for disease progression. In the present study, the effects of rapamycin (RAPA) on neuroinflammation lipopolysaccharide (LPS)-induced were investigated. SH-SY5Y human neuroblastoma cells were treated with 20 ug/ml LPS and 0.1, 1 or 10 nmol/l RAPA, and were analyzed at various time points (6, 12 and 24 h). The mRNA expression levels of interleukin (IL) 1beta, IL6 and hypoxia-inducible factor 1alpha (HIF1alpha) were determined using reverse transcription-quantitative polymerase chain reaction. The protein expression levels of phosphorylated (p )S6, p-nuclear factor kappaB (NFkappaB), p-inhibitor of NFkappaB kinase subunit beta (IKKbeta) and p-tau protein were measured by western blot analysis. p IKKbeta, p-NFkappaB, p-S6 and p-tau were significantly decreased at 6, 12 and 24 h when cells were treated with >=0.1 nmol/ml RAPA. In addition, female Sprague Dawley rats were intracranially injected with a single dose of 100 ug/kg LPS in the absence or presence of 1 mg/kg RAPA pretreatment. Brain tissues were subjected to immunohistochemical analysis 6-24 h later, which revealed that the expression levels of HIF1alpha and p-S6 in rat cerebral cortex were increased following LPS injection; however, this increase was abrogated by RAPA treatment. RAPA may therefore be considered a potential therapeutic agent for the early or emergency treatment of neuroinflammation. PMID- 27779714 TI - Whole-exome sequencing identification of novel DNAH5 mutations in a young patient with primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by structural and/or functional impairment of cilia throughout the whole body. Early diagnosis of PCD is important for the prevention of long-term sequelae, however early diagnosis is a challenge due to the phenotypic heterogeneity of PCD. In the current study, the patient with PCD was diagnosed at nine years old following several efforts to control intractable airway symptoms. The patient experienced a chronic productive cough beginning in early childhood and had multiple episodes of pneumonia and otitis media with effusion and sinusitis. No situs inversus or other heterotaxias were reported. Serial chest X-rays exhibited persistent atelectasis and bronchiectasis in the right middle lobe. When the patient was nine years old, electron microscopy of his cilia and genetic analysis were conducted. Electron microscopy of a biopsy specimen from the nasal mucosa indicated loss of the outer dynein arms. Whole-exome analysis of the genome demonstrated the presence of compound heterozygous mutations in DNAH5: NM_001369.2:c.5983C>T, p.Arg1995X in exon 36 and NM_001369.2:c.9101delG, p.Gly3034ValfsX22 in exon 54; neither of which have been previously reported in the literature in a Japanese patient. Notably, this case is, to the best of our knowledge, the first reported case of PCD caused by the DNAH5 mutation in a Japanese patient. PMID- 27779715 TI - miR-27a-mediated antiproliferative effects of metformin on the breast cancer cell line MCF-7. AB - Metformin was demonstrated to have effects on breast cancer, and microRNA-27a (miR-27a) is a prognostic marker for breast cancer progression and patient survival. AMPKalpha2 was found to be a suppressor in breast cancer MCF-7 cells. Therefore, the present study aimed to explain this phenomenon in regards to the relationship between microRNAs (miRNAs) and their target genes and to predict how AMPKalpha2 may be a downstream target gene of miR-27a, thus exploring the new mechanism of metformin in the treatment of breast cancer regarding miRNAs. The MTT assay was used to assess whether metformin can inhibit the growth of breast cancer MCF-7 cells. The levels of miR-27a and AMPKalpha2 mRNA were examined using RT-PCR, and the expression levels of AMPKalpha2 and caspase-3 were determined by western blot analyses after MCF-7 cells were treated with metformin. The association of miR-27a and AMPKalpha2 was confirmed by transfecting cells with miR-27a mimics, miR-27a inhibitors and its negative control (NC), respectively. A luciferase assay was conducted to detect the miR-27a binding to the AMPKalpha2 3' untranslated region (3'-UTR). The results of the MTT assay showed that metformin suppressed the growth of MCF-7 cells in a dose- and time-dependent manner. miR 27a was downregulated, and AMPKa2 was upregulated after intervention with metformin, and caspase-3 was activated. Transfection tests showed that the expression of AMPKalpha2 was downregulated in the MCF-7 cells after transfection of the miR-27a mimics. The luciferase assay verified the binding of miR-27a to the AMPKalpha2 3'-UTR. In conclusion, metformin inhibited MCF-7 cell growth, and miR-27a plays a vital role in this process by targeting AMPKalpha2. PMID- 27779716 TI - miR-300 promotes proliferation and EMT-mediated colorectal cancer migration and invasion by targeting p53. AB - p53 mutations in tumors can induce the loss of wild-type tumor-suppressing p53 function, which results in the increase in proliferation, migration and invasion ability in cancer cells. Studies have shown that the expression of p53 is regulated by several microRNAs (miRNAs). In the present study, we found that miR 300 and p53 were significantly increased in colorectal cancer (CRC) tissues when compared with levels noted in adjacent colorectal tissues. Both miR-300 and p53 were significantly correlated with lymphatic metastasis and TNM stage. Both miR 300 and p53 promoted CRC cell (SW480 and HT29) proliferation, migration, and invasion, respectively, in vitro. In addition, we found that miR-300 is a direct positive regulator of p53 through binding to the binding site in the 3'UTR of the p53 gene in human CRC cells. Moreover, both miR-300 and p53 induced CRC cell epithelial-mesenchymal transition (EMT) respectively. Taken together, we demonstrated that miR-300 promoted proliferation and EMT-mediated CRC migration and invasion by targeting p53. These findings provide a new theoretical basis and potential therapeutic targets, and thus lays the foundation for exploring the pathogenesis of CRC. PMID- 27779717 TI - miR-148a inhibits self-renewal of thyroid cancer stem cells via repressing INO80 expression. AB - Anaplastic thyroid carcinoma (ATC) is aggressive and lethal with extrathyroidal invasion, distant metastasis, and resistance to conventional therapies. Cancer stem cells (CSCs) are proposed to be responsible for high recurrence rate in ATC. MicroRNAs (miRNAs) have recently been found as an important class of cellular regulators of ATC carcinogenesis. Identification of CSC-related miRNAs and targets is therefore a priority for the development of new therapeutic paradigms. Patient-derived ATC cells were cultured in conditional media on poly-hema-treated dish. ATC CSCs were isolated and enriched through as a series of steps including initial isolation of sphere-forming CSC population, subsequent amplification of this CSC population in a xenograft model treated with cisplatin, and purification of CSCs from xenograft tumors followed by final enrichment using sphere-forming assays. Expression of CSC markers was measured by flow cytometry, immunofluorescence staining, qPCR and western blot analyses. Expression of miRNAs in ATC-CSCs was profiled by microarray analysis. Proliferation and differentiation rates were determined based on the size of spheres formed in vitro and tumors formed in vivo. We successfully isolated and enriched an ATC-CSC population. We identified 17 miRNAs differentially expressed in primary ATC cells vs. ATC-CSCs, among which miRNA-148a was significantly downregulated in ATC-CSCs. Overexpression of miRNA148a in ATC-CSCs induced cell cycle arrest and loss of stem cell characteristics. In addition, we identified INO80 as a target gene of miR-148a. The expression of INO80 was upregulated in ATC-CSCs and downregulated upon miRNA-148 overexpression. Overexpression of miRNA-148a and knockdown of INO80 acted synergistically to decrease the expression of stem cell marker genes as well as to attenuate stem cell-specific properties including the ability to form tumors. This study identified novel contrasting roles for miR-148a and INO80 in the regulation of the stemness of ATC-CSCs and their capacity to initiate tumor formation. Our findings may open a new avenue for therapeutic development against ATC that targets INO80 in the CSCs through enhancing miRNA-148a levels. PMID- 27779718 TI - Upregulated CTHRC1 promotes human epithelial ovarian cancer invasion through activating EGFR signaling. AB - Epithelial ovarian cancer (EOC) is the major cause of deaths from gynecologic malignancies, and metastasis is the main cause of cancer related death. Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that has the ability to inhibit collagen matrix synthesis. In this study, we found that high CTHRC1 expression was associated with poor prognosis of EOC. In vitro experiments showed that CTHRC1 promoted migration and invasion of ovarian cancer cells. CTHRC1 had no effect on ovarian cancer cells viability. Additionally, EGFR inhibitors reduced the promotion effects of CTHRC1 on EOC cell invasion. After silencing of CTHRC1, downregulated expression of phosphorylation of EGFR/ERK1/2/AKT was observed in ovarian cancer cells. Taken together, our results suggest a role for CTHRC1 in the progression of ovarian cancer and identified CTHRC1 as a potentially important predictor for human ovarian cancer prognosis. PMID- 27779719 TI - Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP induced cell apoptosis by inhibiting cytoprotective autophagy. AB - Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Deregulation of microRNAs (miRNAs) has been reported to participate in CRC progression. In the present study, we observed downregulation of miR-218 and upregulation of YEATS domain containing 4 (YEATS4) in CRC tissues and in multidrug-resistant HCT-116/L-OHP cells compared with these levels in normal tissues and parental HCT-116 cells, respectively. The results indicated that miR 218 overexpression significantly decreased the IC50 value of oxaliplatin (L-OHP) in the HCT-116/L-OHP cells, and suppression of miR-218 significantly enhanced the IC50 of L-OHP in the HCT-116 cells. Flow cytometric analysis showed that miR-218 overexpression alone promoted cell apoptosis in the HCT-116/L-OHP cells, which was further enhanced in response to L-OHP, and miR-218 inhibition decreased cell apoptosis in the HCT-116 cells following treatment with L-OHP. Western blot analysis indicated that, compared with the small increase observed in HCT-116 cells, the relative LC3 II level in HCT-116/L-OHP cells after lysosome inhibition via chloroquine (CQ) was markedly upregulated following L-OHP treatment, suggesting induction of autophagy. Exposure of HCT-116/L-OHP cells to L-OHP after control mimic transfection increased autophagic flux, as reflected by increased LC3 II levels, while miR-218 overexpression partly reversed L-OHP-mediated LC3 II accumulation. Additionally, both miR-218 overexpression and CQ treatment promoted L-OHP-induced HCT-116/L-OHP cell apoptosis. Molecularly, our results confirmed that miR-218 directly targets the YEATS4 gene and inhibits YEATS4 expression. Furthermore, YEATS4 overexpression without the 3'-untranslated region (3'-UTR) restored miR-218-inhibited YEATS4 and LC3 II expression, and abolished miR-218 stimulated cell viability loss and cell apoptosis increase in response to L-OHP. In conclusion, miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression. PMID- 27779721 TI - [The question to refrain from or discontinue life-sustaining treatment]. PMID- 27779720 TI - PACE4 regulates apoptosis in human pancreatic cancer Panc-1 cells via the mitochondrial signaling pathway. AB - Previous studies have demonstrated the overexpression of paired basic amino acid cleaving enzyme 4 (PACE4) mRNA in prostate cancer tissues. This overexpression is correlated with higher circulating protein levels in certain patients, however, the role of PACE4 in apoptosis and the potential molecular mechanisms of pancreatic cancer remain to be elucidated. The aim of the present study was to investigate the effect and potential molecular mechanisms of PACE4 on apoptosis in the Panc-1 pancreatic cancer cell line. Cell proliferation was assessed using a Cell Counting Kit-8 assay. Apoptotic nuclear shrinkage was monitored using Hoechst 33258 staining. Caspase-3/7 activities were measured using a colorimetric caspase-glo 3/7 assay. Alterations in protein expression were monitored using Western blot analysis. The results indicated that PACE4 small interfering (si)RNA inhibited cell proliferation and activated caspase-3/7 activities. In addition, PACE4 siRNA significantly increased apoptosis via the activation of caspase-3 and the downregulation of anti-apoptotic proteins, X-linked inhibitor of apoptosis protein and phosphorylated-Akt. In addition, the results showed deregulation of the B cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 ratio which led to the release of cytochrome c following PACE4 siRNA transfection. In conclusion, PACE4 siRNA may exert antitumor activity through the mitochondrial pathway and is expected to be a promising therapeutic strategy for the treatment of pancreatic cancer. PMID- 27779722 TI - [Experiences from PLUS - program for learning and development in Swedish health care]. AB - Experiences from PLUS - program for learning and development in Swedish health care In Sweden, more than half of newly registered physicians have been trained outside of the country. Thus, they are not familiar with Swedish culture and the Swedish healthcare system. To support their introduction to a professional carrier in Sweden, in line with the WHO ethical code for recruitment of health personnel, the health care region of Western Sweden established PLUS - program for learning and development in Swedish Health care. A pilot program has now been completed. The physicians had a good biomedical background, but deficiencies in practical skills, cultural insights and knowledge about Swedish health care. PLUS was based on principles for adult learning with considerable time for reflection and supervision in a group with experienced colleagues. The program was evaluated by an external evaluator, who concluded that the participants felt more secure in their professional role, more familiar with Swedish Health care and better integrated into their health care team. It was concluded that this should lead to improved patient security and better working environment for the physician as well as his/her coworkers. PMID- 27779723 TI - [The willingness to pay for new drugs is based on ethical principles]. AB - The County Council's board for new therapies (the NT Council) provides recommendations on the use of new drugs based on the ethical platform of priorities, founded by the Swedish parliament. The Council has formulated a policy that interprets the parliamentary ethical platform and operationalize its need and solidarity principle and cost effectiveness principle in four dimensions. The NT Council weighs the health economic evaluation of the drug and the four dimensions: the severity of the condition, the rarity of the condition, the effect size and the data reliability to determine the willingness to pay level and whether the platform allows a recommendation for using of the drug. The severity of the condition has a greater impact than the other dimensions. In the assessment of severity there is also a trade-off between prevention and treatment of manifest diseases and in prevention, the size of the risk of falling ill is of importance. A slightly higher willingness to pay level is reasonable for treatment of very rare conditions, but it is important that identified patients are not given priority over anonymous patient groups with equally strong needs. PMID- 27779724 TI - [Central sensitisation and chronic organ-related pain]. AB - Central sensitisation and chronic organ-related pain Central sensitisation is an essential mechanism in chronic musculoskeletal pain. In recent years, increasing evidence has come to light suggesting that central sensitisation is also a cause of chronic organ-related pain. This has several important implications. One is the need for broader professional education in mechanism-based pain classification. Today, simple clinical diagnostic procedures are used for the identification of central sensitisation in chronic musculoskeletal disorders, and these may also prove useful in the classification of organ-related pain. The diagnosis of central sensitisation may also lead to a reduction in extensive investigations and recurrent surgical procedures. Information on central sensitisation (pain neurophysiology education) for patients with chronic musculoskeletal pain reduces their fear of pain and increases their self-reliance and coping. A similar therapeutic approach may also be useful in patients diagnosed with organ-related chronic pain. PMID- 27779725 TI - [Medical and scientific assessments as the basis for prioritization and resource allocation for new drug treatment - experiences from five years of systematic work]. AB - Medical and scientific assessments as the basis for prioritization and resource allocation for new drug treatment - experiences from five years of systematic workIn this study, the process for introduction of new drug treatment in Region Vastra Gotaland (second largest region in Sweden encompassing 1.6 million inhabitants, 17% of all inhabitants in Sweden) is described. A working group, consisting of persons with relevant expertise and declared conflicts of interest, contributes with medical and scientific assessments as the basis for prioritization and resource allocation. In 2011-2015, 111 new drug treatments were nominated by healthcare representatives, 84 fulfilled the criteria for assessments by the working group, and 57 (68%) were deemed to have high/medium high priority to receive introduction financing according to the severity of disease, the benefit/risk balance, and the level of evidence. When analyzing subsequent costs for new drug treatments for which data could be obtained and specifically evaluated, the results indicate that the process can contribute to rational use of medicines. PMID- 27779726 TI - [A healthy lifestyle in focus of new guidelines]. PMID- 27779727 TI - ? PMID- 27779728 TI - ? PMID- 27779729 TI - ? PMID- 27779730 TI - [Steps towards rational introduction of new pharmaceuticals in Sweden]. PMID- 27779732 TI - ? PMID- 27779731 TI - [Strong measures are required to prevent intellectual bias]. PMID- 27779733 TI - [The importance of good leaders and managers]. PMID- 27779734 TI - [Vaginal subtotal hysterectomy = true]. PMID- 27779735 TI - ? PMID- 27779736 TI - ? PMID- 27779737 TI - ? PMID- 27779738 TI - ? PMID- 27779739 TI - Cardioprotective potential of curcumin against norepinephrine-induced cell death: a microscopic study. AB - Cardiomyopathy and associated heart failure continues to be one of the most severe complications that threaten a large population. Curcumin, one of the three curcuminoids of the spice turmeric, is very well known for a multitude of health benefits and functions. Norepinephrine (NE), a catecholamine and also a stress hormone may cause the cardiomyocytes to develop increased sensitivity to death with its increasing concentrations. In this study, we investigated the cardioprotective effect of curcumin in NE-induced cardiac apoptosis using several fluorescent and nonfluorescent microscopic techniques like DAPI, PI, Giemsa, PicroSirius and TUNEL. The aim of the study was to assess the effect of curcumin in preventing the occurrence of features underlying apoptosis such as nuclear disruption, chromatin condensation, DNA fragmentation and alterations in mitochondrial membrane permeability. Our results show that curcumin protects the cardiomyocytes against apoptosis significantly and also helps them to revert to their normal physiological state. Hence, we propose that curcumin has the potential to act as a therapeutic agent for the attenuation of NE-induced cardiac cell death and modulation of apoptosis in H9c2 cardiomyocytes. PMID- 27779740 TI - Intraspecific priority effects modify compensatory responses to changes in hatching phenology in an amphibian. AB - In seasonal environments, modifications in the phenology of life-history events can alter the strength of time constraints experienced by organisms. Offspring can compensate for a change in timing of hatching by modifying their growth and development trajectories. However, intra- and interspecific interactions may affect these compensatory responses, in particular if differences in phenology between cohorts lead to significant priority effects (i.e. the competitive advantage that early-hatching individuals have over late-hatching ones). Here, we conducted a factorial experiment to determine whether intraspecific priority effects can alter compensatory phenotypic responses to hatching delay in a synchronic breeder by rearing moor frog (Rana arvalis) tadpoles in different combinations of phenological delay and food abundance. Tadpoles compensated for the hatching delay by speeding up their development, but only when reared in groups of individuals with identical hatching phenology. In mixed phenology groups, strong competitive effects by non-delayed tadpoles prevented the compensatory responses and delayed larvae metamorphosed later than in single phenology treatments. Non-delayed individuals gained advantage from developing with delayed larvae by increasing their developmental and growth rates as compared to single phenology groups. Food shortage prolonged larval period and reduced mass at metamorphosis in all treatments, but it did not prevent compensatory developmental responses in larvae reared in single phenology groups. This study demonstrates that strong intraspecific priority effects can constrain the compensatory growth and developmental responses to phenological change, and that priority effects can be an important factor explaining the maintenance of synchronic life histories (i.e. explosive breeding) in seasonal environments. PMID- 27779742 TI - Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy. AB - The aim of the study is to investigate the genetic characteristics and clinical features of a cohort of Chinese patients with early-onset epileptic encephalopathies (EOEEs). Targeted next-generation sequencing (NGS), focusing on 17 genes, was performed on 175 Chinese patients with EOEEs to screen gene mutations. The mutation rate was 32% (56/175). All mutations were de novo and heterozygous, including 41 novel and 15 reported mutations. Patients with cyclin dependent kinase-like 5 (CDKL5) gene mutation accounted for the largest proportion, 13.1% (23/175). All patients with CDKL5 mutation presented severe psychomotor developmental delay and refractory seizures. The female patients presented obvious Rett-like features, which were not observed in male patients. Potassium channel, voltage-gated KQT-like subfamily Q, member 2(KCNQ2) gene mutations were detected in 13 patients. Patients with this mutation presented with early seizure onset within the first week after birth. Valproate (VPA), levetiracetam (LEV) and topiramate (TPM) were effective in most patients. Patients with specific gene mutations presented some unique clinical features, but not always. Many genes are involved in EOEEs. Targeted NGS showed a high diagnostic yield in patients with EOEEs. These findings provide useful insights for recommending treatment of gene-associated EOEEs using antiepileptic drugs. PMID- 27779743 TI - Change-over in the editor position. PMID- 27779744 TI - Three-dimensional imaging of porous media using confocal laser scanning microscopy. AB - In the last decade, imaging techniques capable of reconstructing three dimensional (3-D) pore-scale model have played a pivotal role in the study of fluid flow through complex porous media. In this study, we present advances in the application of confocal laser scanning microscopy (CLSM) to image, reconstruct and characterize complex porous geological materials with hydrocarbon reservoir and CO2 storage potential. CLSM has a unique capability of producing 3 D thin optical sections of a material, with a wide field of view and submicron resolution in the lateral and axial planes. However, CLSM is limited in the depth (z-dimension) that can be imaged in porous materials. In this study, we introduce a 'grind and slice' technique to overcome this limitation. We discuss the practical and technical aspects of the confocal imaging technique with application to complex rock samples including Mt. Gambier and Ketton carbonates. We then describe the complete workflow of image processing to filtering and segmenting the raw 3-D confocal volumetric data into pores and grains. Finally, we use the resulting 3-D pore-scale binarized confocal data obtained to quantitatively determine petrophysical pore-scale properties such as total porosity, macro- and microporosity and single-phase permeability using lattice Boltzmann (LB) simulations, validated by experiments. PMID- 27779745 TI - The Safe Yield and Climatic Variability: Implications for Groundwater Management. AB - Methods for calculating the safe yield are evaluated in this paper using a high quality and long historical data set of groundwater recharge, discharge, extraction, and precipitation in a karst aquifer. Consideration is given to the role that climatic variability has on the determination of a climatically representative period with which to evaluate the safe yield. The methods employed to estimate the safe yield are consistent with its definition as a long-term average extraction rate that avoids adverse impacts on groundwater. The safe yield is a useful baseline for groundwater planning; yet, it is herein shown that it is not an operational rule that works well under all climatic conditions. This paper shows that due to the nature of dynamic groundwater processes it may be most appropriate to use an adaptive groundwater management strategy that links groundwater extraction rates to groundwater discharge rates, thus achieving a safe yield that represents an estimated long-term sustainable yield. An example of the calculation of the safe yield of the Edwards Aquifer (Texas) demonstrates that it is about one-half of the average annual recharge. PMID- 27779746 TI - Yihiella yeosuensis gen. et sp. nov. (suessiaceae, dinophyceae), a novel dinoflagellate isolated from the coastal waters of Korea. AB - A small (7-11 MUm long) dinoflagellate with thin amphiesmal plates was isolated into culture from a water sample collected in coastal waters of Yeosu, southern Korea, and examined by LM, SEM, and TEM, and molecular analyses. The hemispheric episome was smaller than the hyposome. The nucleus was oval and situated from the central to the episomal region of the cell. A large yellowish-brown chloroplast was located at the end of the hyposome, and some small chloroplasts extended into the periphery of the episome. The dinoflagellate had a single elongated apical vesicle (EAV) and a type E eyespot, which are key characteristics of the family Suessiaceae. Unlike other genera in this family, it had two long furrow lines, one on the episome and the other on the hyposome, and encircling the dorsal, and lateral sides of the cell body. The pyrenoid lacked starch sheaths, but tubular invaginations into the pyrenoid matrix from the cytoplasm were observed. In the TEM, the dinoflagellate was observed to have cable-like structures (CLSs) near the eyespot but so far not observed in other dinoflagellates. The SSU rDNA sequences examined were 1.2%-5.1% different from those of other genera in the family Suessiaceae, whereas the LSU (D1-D3) rDNA sequences of this dinoflagellate were 15.1%-31.5% different. The dinoflagellate lacked a 51-bp fragment in domain D2 of the LSU rDNA, but it had an ~100-bp fragment in domain D2. This feature has been found previously only in the genera Leiocephalium and Polarella, two other genera of the Suessiaceae. The molecular phylogeny and sequence divergence based on SSU, and LSU rDNA indicate that the Korean dinoflagellate holds a taxonomically distinctive position and we consider it to be a new species in a new genus in the family Suessiaceae, named Yihiella yeosuensis gen. et sp. nov. PMID- 27779741 TI - Deciphering the killer-cell immunoglobulin-like receptor system at super resolution for natural killer and T-cell biology. AB - Killer-cell immunoglobulin-like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease. PMID- 27779747 TI - Oscillatory dynamics and functional connectivity during gating of primary somatosensory responses. AB - KEY POINTS: Sensory gating is important for preventing excessive environmental stimulation from overloading neural resources. Gating in the human somatosensory cortices is a critically understudied topic, particularly in the lower extremities. We utilize the unique capabilities of magnetoencephalographic neuroimaging to quantify the normative neural population responses and dynamic functional connectivity of somatosensory gating in the lower extremities of healthy human participants. We show that somatosensory processing is subserved by a robust gating effect in the oscillatory domain, as well as a dynamic effect on interhemispheric functional connectivity between primary sensory cortices. These results provide novel insight into the dynamic neural mechanisms that underlie the processing of somatosensory information in the human brain, and will be vital in better understanding the neural responses that are aberrant in gait-related neurological disorders (e.g. cerebral palsy). ABSTRACT: Sensory gating (SG) is a phenomenon in which neuronal responses to subsequent similar stimuli are weaker, and is considered to be an important mechanism for preventing excessive environmental stimulation from overloading shared neural resources. Although gating has been demonstrated in multiple sensory systems, the neural dynamics and developmental trajectory underlying SG remain poorly understood. In the present study, we adopt a data-driven approach to map the spectrotemporal amplitude and functional connectivity (FC) dynamics that support gating in the somatosensory system (somato-SG) in healthy children and adolescents using magnetoencephalography (MEG). These data underwent time-frequency decomposition and the significant signal changes were imaged using a beamformer. Voxel time series were then extracted from the peak voxels and these signals were examined in the time and time-frequency domains, and then subjected to dynamic FC analysis. The results obtained indicate a significant decrease in the amplitude of the neural response following the second stimulation relative to the first in the primary somatosensory cortex (SI). A significant decrease in response latency was also found between stimulations, and each stimulation induced a sharp decrease in FC between somatosensory cortical areas. Furthermore, there were no significant correlations between somato-SG metrics and age. We conclude that somato-SG can be observed in SI in both the time and oscillatory domains, with rich dynamics and alterations in inter-hemispheric FC, and that this phenomenon has already matured by early childhood. A better understanding of these dynamics may provide insight to the numerous psychiatric and neurologic conditions that have been associated with aberrant SG across multiple modalities. PMID- 27779748 TI - Genetic abnormalities leading to qualitative defects of sperm morphology or function. AB - Infertility, defined by the inability of conceiving a child after 1 year is estimated to concern approximately 50 million couples worldwide. As the male gamete is readily accessible and can be studied by a simple spermogram it is easier to subcategorize male than female infertility. Subjects with a specific sperm phenotype are more likely to have a common origin thus facilitating the search for causal factors. Male infertility is believed to be often multifactorial and caused by both genetic and extrinsic factors, but severe cases of male infertility are likely to have a predominant genetic etiology. Patients presenting with a monomorphic teratozoospermia such as globozoospermia or macrospermia with more than 85% of the spermatozoa presenting this specific abnormality have been analyzed permitting to identify several key genes for spermatogenesis such as AURKC and DPY19L2. The study of patients with other specific sperm anomalies such as severe alteration of sperm motility, in particular multiple morphological anomalies of the sperm flagella (MMAF) or sperm unability to fertilize the oocyte (oocyte activation failure syndrome) has also enable the identification of new infertility genes. Here we review the recent works describing the identification and characterization of gene defects having a direct qualitative effect on sperm morphology or function. PMID- 27779749 TI - Sustained myrmecophagy in Nigerian chimpanzees: Preferred or fallback food? AB - OBJECTIVE: At some sites across Africa, chimpanzees consume army ants, often aided by plant tools, although consumption frequencies vary greatly. Other populations do not eat these insects at all, despite apparent abundance. The relative importance of this type of myrmecophagy for chimpanzee diet therefore remains unclear. We investigate if army ants constitute a preferred food or a fallback resource for chimpanzees at Gashaka, Nigeria, where army ants are consumed much more frequently than elsewhere. METHODS: Long-term records on temporal variation of climate and availability of fruit as the chimpanzees' preferred food are compared with rates of recovered army ant dipping wands and army ant remains in feces. RESULTS: Despite strict seasonality of rainfall and fruit abundance, myrmecophagy does not negatively correlate with fruit availability. Instead, army ant eating is sustained year round at high levels, with 44% of feces containing remains. CONCLUSIONS: Results contradict the fallback hypothesis and support the hypothesis that ants are a preferred food. Nevertheless, compared with fruit, ant-meals can normally provide only negligible amounts of nutrients. At Gashaka, however, nutritional yield may be significant, given that ant-dipping sessions provide on average 13 mg of dry weight to a chimpanzee. The species exclusively eaten here, Dorylus rubellus, might be particularly aggressive, thus resulting in greater harvesting success than elsewhere. Army ants may hence serve as a diet supplement or complement in terms of macro- or micronutrients. PMID- 27779750 TI - New perspectives on the development of muscle contractures following central motor lesions. AB - Muscle contractures are common in patients with central motor lesions, but the mechanisms responsible for the development of contractures are still unclear. Increased or decreased neural activation, protracted placement of a joint with the muscle in a short position and muscle atrophy have been suggested to be involved, but none of these mechanisms are sufficient to explain the development of muscle contractures alone. Here we propose that changes in tissue homeostasis in the neuromuscular-tendon-connective tissue complex is at the heart of the development of contractures, and that an integrated physiological understanding of the interaction between neural, mechanical and metabolic factors, as well as genetic and epigenetic factors, is necessary in order to unravel the mechanisms that result in muscle contractures. We hope thereby to contribute to a reconsideration of how and why muscle contractures develop in a way which will open a window towards new insight in this area in the future. PMID- 27779752 TI - The inheritance of juvenile onset primary open angle glaucoma. AB - Juvenile onset open angle glaucoma (JOAG) affects patients before 40 years of age, who present with high intraocular pressure and deep steep cupping of the optic nerve head. While it was considered to be inherited in an autosomal dominant fashion, recent studies have shown an autosomal recessive pattern as well as sporadic occurrence of the disease in several families. In this review, we analyze the genetic basis of the disease along with common mutations and their association with JOAG. We also analyzed the inheritance patterns in a large group of unrelated JOAG patients (n = 336) from Northern India wherein the prevalence of familial occurrence was assessed and segregation analysis performed, to determine the mode of inheritance. PMID- 27779751 TI - Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, alpha-actinin2 and filamin A. AB - KEY POINTS: Ion channels are transmembrane proteins that are synthesized within the cells but need to be trafficked to the cell membrane for the channels to function. Small-conductance, Ca2+ -activated K+ channels (SK, KCa 2) are unique subclasses of K+ channels that are regulated by Ca2+ inside the cells; they are expressed in human atrial myocytes and responsible for shaping atrial action potentials. We have previously shown that interacting proteins of SK2 channels are important for channel trafficking to the membrane. Using total internal reflection fluorescence (TIRF) and confocal microscopy, we studied the mechanisms by which the surface membrane localization of SK2 (KCa 2.2) channels is regulated by their interacting proteins. Understanding the mechanisms of SK channel trafficking may provide new insights into the regulation controlling the repolarization of atrial myocytes. ABSTRACT: The normal function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane. Small-conductance, Ca2+ -activated K+ channels (SK, KCa 2) are expressed in human atrial myocytes and are responsible for shaping atrial action potentials. Understanding the mechanisms of SK channel trafficking may provide new insights into the regulation controlling the repolarization of atrial myocytes. We have previously demonstrated that the C and N-termini of SK2 channels interact with the actin-binding proteins alpha actinin2 and filamin A, respectively. However, the roles of the interacting proteins on SK2 channel trafficking remain incompletely understood. Using total internal reflection fluorescence (TIRF) microscopy, we studied the mechanisms of surface membrane localization of SK2 (KCa 2.2) channels. When SK2 channels were co-expressed with filamin A or alpha-actinin2, the membrane fluorescence intensity of SK2 channels increased significantly. We next tested the effects of primaquine and dynasore on SK2 channels expression. Treatment with primaquine significantly reduced the membrane expression of SK2 channels. In contrast, treatment with dynasore failed to alter the surface membrane expression of SK2 channels. Further investigations using constitutively active or dominant-negative forms of Rab GTPases provided additional insights into the distinct roles of the two cytoskeletal proteins on the recycling processes of SK2 channels from endosomes. alpha-Actinin2 facilitated recycling of SK2 channels from both early and recycling endosomes while filamin A probably aids the recycling of SK2 channels from recycling endosomes. PMID- 27779754 TI - Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. AB - Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple cafe au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals. PMID- 27779755 TI - Single gene defects leading to sperm quantitative anomalies. AB - Azoospermia, defined by the absence of sperm in the ejaculate, is estimated to affect up to 1% of men in the general population. Assisted reproductive technologies have revolutionized the treatment of infertility, and some azoospermic men, those with a post-meiotic defect, can conceive following the use of viable spermatoza recovered from testicular or epididymal biopsies. Although male infertility is a multifactorial disease, it is believed that genetic factors are predominant in the etiology of azoospermia and severe oligozoospermia. Despite that assumption, substantiated by the high number of infertile knockout (KO) mice and the even higher number of genes expressed essentially in the testis, little is known about the pathophysiology of reduced sperm production, its primary causes or the genetic and epigenetic consequences for the gamete and the future conceptus. The identification of genetic abnormalities is therefore paramount to understand spermatogenesis, to adopt the best course of action for the patient and to provide adequate genetic counseling. We provide here a review of the recent literature on the genetics of azoospermia and oligozoospermia, focusing on defects directly altering sperm production. New sequencing technologies are contributing to the rapid evolution of the recent field of infertility genetics. PMID- 27779756 TI - The Norms of Popular Peers Moderate Friendship Dynamics of Adolescent Aggression. AB - This study examined whether peer norms for aggression within the classroom impact friendship selection, maintenance, and socialization processes related to aggression across the 1st year of secondary school (N = 1,134 students from 51 classes, Mage = 12.66). As hypothesized, longitudinal social network analyses indicated that friendship selection and influence processes related to aggression depended on the popularity norm within the classroom (i.e., the class-level association between popularity and aggression) rather than the descriptive norm (aggregated average of aggressive behavior). Hence, only in classes where the valence of aggression is high (because it is positively associated with popularity), adolescents tend to select their friends based on similarity in aggression and adopt the aggressive behavior of their friends. PMID- 27779753 TI - Nitric oxide synthase and cyclooxygenase modulate beta-adrenergic cutaneous vasodilatation and sweating in young men. AB - KEY POINTS: beta-Adrenergic receptor agonists such as isoproterenol induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. Using intradermal microdialysis, we evaluated the roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in beta adrenergic cutaneous vasodilatation and sweating elicited by administration of isoproterenol. We show that while NOS contributes to beta-adrenergic cutaneous vasodilatation, COX restricts cutaneous vasodilatation. We also show that combined inhibition of NOS and COX augments beta-adrenergic sweating These new findings advance our basic knowledge regarding the physiological control of cutaneous blood flow and sweating, and provide important and new information to better understand the physiological significance of beta-adrenergic receptors in the skin. ABSTRACT: beta-Adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. We evaluated the hypotheses that (1) nitric oxide synthase (NOS) contributes to beta-adrenergic cutaneous vasodilatation, whereas cyclooxygenase (COX) limits the vasodilatation, and (2) COX contributes to beta-adrenergic sweating. In 10 young males (25 +/- 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites infused with (1) lactated Ringer solution (control), (2) 10 mm Nomega -nitro-l-arginine (l-NNA), a non-specific NOS inhibitor, (3) 10 mm ketorolac, a non-specific COX inhibitor, or (4) a combination of l-NNA and ketorolac. All sites were co-administered with a high dose of isoproterenol (100 MUm) for 3 min to maximally induce beta-adrenergic sweating (beta-adrenergic sweating is significantly blunted by subsequent activations). Approximately 60 min after the washout period, three incremental doses of isoproterenol were co-administered (1, 10 and 100 MUm each for 25 min). Increases in CVC induced by the first and second 100 MUm isoproterenol were attenuated by l-NNA alone, and those in response to all doses of isoproterenol were reduced by l-NNA with co-infusion of ketorolac (all P <= 0.05). Ketorolac alone augmented increases in CVC induced by 10 MUm and by the second 100 MUm isoproterenol (both P <= 0.05). While isoproterenol-induced sweating was not affected by the separate administration of l-NNA or ketorolac (all P > 0.05), their combined administration augmented sweating elicited by the first 3 min of 100 MUm isoproterenol (P = 0.05). We show that while NOS contributes to beta adrenergic cutaneous vasodilatation, COX restrains the vasodilatation. Finally, combined inhibition of NOS and COX augments beta-adrenergic sweating. PMID- 27779757 TI - Analysis of cell-free fetal DNA in maternal blood for detection of trisomy 21, 18 and 13 in a general pregnant population and in a high risk population - a systematic review and meta-analysis. AB - INTRODUCTION: The aim of this study was to review the performance of non-invasive prenatal testing (NIPT) for detection of trisomy 21, 18 and 13 (T21, T18 and T13) in a general pregnant population as well as to update the data on high-risk pregnancies. MATERIAL AND METHODS: Systematic review and meta-analysis. PubMed, Embase and the Cochrane Library were searched. Methodological quality was rated using QUADAS and scientific evidence using GRADE. Summary measures of diagnostic accuracy were calculated using a bivariate random-effects model. RESULTS: In a general pregnant population, there is moderate evidence that the pooled sensitivity is 0.993 (95% CI 0.955-0.999) and specificity was 0.999 (95% CI 0.998 0.999) for the analysis of T21. Pooled sensitivity and specificity for T13 and T18 was not calculated in this population due to the low number of studies. In a high-risk pregnant population, there is moderate evidence that the pooled sensitivities for T21 and T18 are 0.998 (95% CI 0.981-0.999) and 0.977 (95% CI 0.958-0.987) respectively, and low evidence that the pooled sensitivity for T13 is 0.975 (95% CI 0.819-0.997). The pooled specificity for all three trisomies is 0.999 (95% CI 0.998-0.999). CONCLUSIONS: This is the first meta-analysis using GRADE that shows that NIPT performs well as a screen for trisomy 21 in a general pregnant population. Although the false positive rate is low compared with first trimester combined screening, women should still be advised to confirm a positive result by invasive testing if termination of pregnancy is under consideration. PMID- 27779759 TI - Discovery of a resting stage in the harmful, brown-tide-causing pelagophyte, Aureoumbra lagunensis: a mechanism potentially facilitating recurrent blooms and geographic expansion. AB - To date, the life stages of pelagophytes have been poorly described. This study describes the ability of Aureoumbra lagunensis to enter a resting stage in response to environmental stressors including high temperature, nutrient depletion, and darkness as well as their ability to revert from resting cells back to vegetative cells after exposure to optimal light, temperature, and nutrient conditions. Resting cells became round in shape and larger in size, filled with red accumulation bodies, had smaller and fewer plastids, more vacuolar space, contained lower concentrations of chl a and RNA, displayed reduced photosynthetic efficiency, and lower respiration rates relative to vegetative cells. Analysis of vegetative and resting cells using Raman microspectrometry indicated resting cells were enriched in sterols within red accumulation bodies and were depleted in pigments relative to vegetative cells. Upon reverting to vegetative cells, cells increased their chl a content, photosynthetic efficiency, respiration rate, and growth rate and lost accumulation bodies as they became smaller. The time required for resting cells to resume vegetative growth was proportional to both the duration and temperature of dark storage, possibly due to higher metabolic demands on stored energy (sterols) reserves during longer period of storage and/or storage at higher temperature (20 degrees C vs. 10 degrees C). Resting cells kept in the dark at 10 degrees C for 7 months readily reverted back to vegetative cells when transferred to optimal conditions. Thus, the ability of Aureoumbra to form a resting stage likely enables them to form annual blooms within subtropic ecosystems, resist temperature extremes, and may facilitate geographic expansion via anthropogenic transport. PMID- 27779760 TI - A novel root-to-shoot stomatal response to very high CO2 levels in the soil: electrical, hydraulic and biochemical signalling. AB - Investigations were undertaken in the context of the potential environmental impact of carbon capture and storage (CCS) transportation in the form of a hypothetical leak of extreme levels of CO2 into the soil environment and subsequent effects on plant physiology. Laboratory studies using purpose built soil chambers, separating and isolating the soil and aerial environments, were used to introduce high levels of CO2 gas exclusively into the rhizosphere. CO2 concentrations greater than 32% in the isolated soil environment revealed a previously unknown whole plant stomatal response. Time course measurements of stomatal conductance (gs ), leaf temperature and leaf abscisic acid (ABA) show strong coupling between all three variables over a specific period (3 h following CO2 gassing) occurring as a result of CO2 -specific detection by roots. The coupling of gs and ABA subsequently breaks down resulting in a rapid and complete loss of turgor in the shoot. Root access to water is severely restricted as evidenced by the inability to counter turgor loss, however, the plant regains some turgor over time. Recovery of full turgor is not achieved over the longer term. Results suggest an immediate perception and whole plant response as changes in measured parameters (leaf temperature, gs and ABA) occur in the shoot, but the response is solely due to detection of very high CO2 concentration at the root/soil interface which results in loss of stomatal regulation and disruption to control over water uptake. PMID- 27779758 TI - TRPV4 participates in pressure-induced inhibition of renin secretion by juxtaglomerular cells. AB - KEY POINTS: Increase in blood pressure in the renal afferent arteriole is known to induce an increase in cytosolic calcium concentration ([Ca2+ ]i ) of juxtaglomerular (JG) cells and to result in a decreased secretion of renin. Mechanical stimulation of As4.1 JG cells induces an increase in [Ca2+ ]i that is inhibited by HC067047 and RN1734, two inhibitors of TRPV4, or by siRNA-mediated repression of TRPV4. Inhibition of TRPV4 impairs pressure-induced decrease in renin secretion. Compared to wild-type mice, Trpv4-/- mice present increased resting plasma levels of renin and aldosterone and present a significantly altered pressure-renin relationship. We suggest that TRPV4 channel participates in mechanosensation at the juxtaglomerular apparatus. ABSTRACT: The renin angiotensin system is a crucial blood pressure regulation system. It consists of a hormonal cascade where the rate-limiting enzyme is renin, which is secreted into the blood flow by renal juxtaglomerular (JG) cells in response to low pressure in the renal afferent arteriole. In contrast, an increase in blood pressure results in a decreased renin secretion. This is accompanied by a transitory increase in [Ca2+ ]i of JG cells. The inverse relationship between [Ca2+ ]i and renin secretion has been called the 'calcium paradox' of renin release. How increased pressure induces a [Ca2+ ]i transient in JG cells, is however, unknown. We observed that [Ca2+ ]i transients induced by mechanical stimuli in JG As4.1 cells were completely abolished by HC067047 and RN1734, two inhibitors of TRPV4. They were also reduced by half by siRNA-mediated repression of TRPV4 but not after repression or inhibition of TRPV2 or Piezo1 ion channels. Interestingly, the stimulation of renin secretion by the adenylate cyclase activator forskolin was totally inhibited by cyclic stretching of the cells. This effect was mimicked by stimulation with GSK1016790A and 4alphaPDD, two activators of TRPV4 and inhibited in the presence of HC067047. Moreover, in isolated perfused kidneys from Trpv4-/- mice, the pressure-renin relationship was significantly altered. In vivo, Trpv4-/- mice presented increased plasma levels of renin and aldosterone compared to wild-type mice. Altogether, our results suggest that TRPV4 is involved in the pressure-induced entry of Ca2+ in JG cells, which inhibits renin release and allows the negative feedback regulation on blood pressure. PMID- 27779761 TI - Molecular recognition at cholinergic synapses: acetylcholine versus choline. AB - KEY POINTS: Neuromuscular acetylcholine (ACh) receptors have a high affinity for the neurotransmitter ACh and a low affinity for its metabolic product choline. At each transmitter binding site three aromatic groups determine affinity, and together provide ~50% more binding energy for ACh than for choline. Deprotonation of alphaY190 by a nearby lysine strengthens the interaction between this aromatic ring and both ACh and choline. H-bonds position ACh and choline differently in the aromatic cage to generate the different affinities. ABSTRACT: Acetylcholine (ACh) released at the vertebrate nerve-muscle synapse is hydrolysed rapidly to choline (Cho), so endplate receptors (AChRs) are exposed to high concentrations of both of these structurally related ligands. To understand how these receptors distinguish ACh and Cho, we used single-channel electrophysiology to measure resting affinities (binding free energies) of these and other agonists in adult type mouse AChRs having a mutation(s) at the transmitter-binding sites. The aromatic rings of alphaY190, alphaW149 and alphaY198 each provide ~50% less binding energy for Cho compared to ACh. At alphaY198 a phenylalanine substitution had no effect, but at alphaY190 this substitution caused a large, agonist independent loss in binding energy that depended on the presence of alphaK145. The results suggest that (1) alphaY190 is deprotonated by alphaK145 to strengthen the interaction between this benzene ring and the agonist's quaternary ammonium (QA) and (2) AChRs respond strongly to ACh because an H-bond positions the QA to interact optimally with the rings, and weakly to Cho because a different H-bond tethers the ligand to misalign the QA and form weaker interactions with the aromatic groups. The results suggest that the difference in ACh versus Cho binding energies is determined by different ligand positions within a fixed protein structure. PMID- 27779764 TI - Quality of life, anxiety and depression symptoms in early and late pregnancy in women with pregestational diabetes. AB - INTRODUCTION: The aim of this study was to explore changes in health-related quality of life, anxiety and depression symptoms during pregnancy in women with pregestational diabetes. MATERIAL AND METHODS: An observational cohort study including 137 pregnant women with pregestational diabetes (110 with type 1 and 27 with type 2). To evaluate changes from early to late pregnancy, the internationally validated questionnaires 36-Item Short-Form Health Survey (SF-36) and Hospital Anxiety and Depression Scale (HADS) were completed at 8 and 33 gestational weeks. RESULTS: From early to late pregnancy, the SF-36 scales Physical Function, Role Physical, Bodily Pain and Physical Component Summary worsened (p < 0.0001 for all scales). Physical Component Summary score deteriorated from mean 52.3 (SD 6.5) to 40.0 (9.7) (p < 0.0001) and the deterioration was negatively associated with gestational weight gain in multiple linear regression (beta = -0.34/kg, p = 0.03). The SF-36 scale Mental Health improved (p = 0.0009) and the Mental Component Summary score increased moderately from 47.6 (10.6) to 53.5 (8.6) (p < 0.0001). Greater improvement in Mental Component Summary score was seen with lower HbA1c in late pregnancy. The HADS anxiety score improved slightly from 5.0 (3.3) to 4.5 (3.4) (p = 0.04) whereas the HADS depression score remained unchanged. The prevalence of women with HADS anxiety or depression score >=8 did not change. CONCLUSIONS: Physical quality of life deteriorated whereas mental quality of life improved slightly during pregnancy in women with pregestational diabetes. A minor reduction in anxiety and stable depression symptoms was observed. The results on mental health are reassuring, considering the great demands that pregnancy places on women with pregestational diabetes. PMID- 27779762 TI - Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility. AB - KEY POINTS: Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. ABSTRACT: Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K+ current and a drastic decrease in the slow delayed rectifier K+ current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K+ currents influences ventricular arrhythmia susceptibility. PMID- 27779765 TI - The complex biology and contribution of Staphylococcus aureus in atopic dermatitis, current and future therapies. AB - Atopic dermatitis (AD) is a complex, chronic inflammatory skin disorder affecting more than 10% of U.K. children and is a major cause of occupation-related disability. A subset of patients, particularly those with severe AD, are persistently colonized with Staphylococcus aureus and exacerbation of disease is commonly associated with this bacterium by virtue of increased inflammation and allergic sensitization, aggravated by skin barrier defects. Understanding the complex biology of S. aureus is an important factor when developing new drugs to combat infection. Staphylococcus aureus generates exoproteins that enable invasion and dissemination within the host skin but can also damage the skin and activate the host immune system. Antibiotics are often used by dermatologists to aid clearance of S. aureus; however, these are becoming less effective and chronic usage is discouraged with the emergence of multiple antibiotic-resistant strains. New ways to target S. aureus using monoclonal antibodies and vaccines are now being developed. This review will attempt to evaluate the key biology of S. aureus, current treatment of S. aureus infections in AD and recent advances in developing new anti-S. aureus therapies that have potential in severe AD. PMID- 27779763 TI - Altering intracellular pH reveals the kinetic basis of intraburst gating in the CFTR Cl- channel. AB - KEY POINTS: The cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in the genetic disease cystic fibrosis (CF), forms a gated pathway for chloride movement regulated by intracellular ATP. To understand better CFTR function, we investigated the regulation of channel openings by intracellular pH. We found that short-lived channel closures during channel openings represent subtle changes in the structure of CFTR that are regulated by intracellular pH, in part, at ATP-binding site 1 formed by the nucleotide-binding domains. Our results provide a framework for future studies to understand better the regulation of channel openings, the dysfunction of CFTR in CF and the action of drugs that repair CFTR gating defects. ABSTRACT: Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated Cl- channel defective in the genetic disease cystic fibrosis (CF). The gating behaviour of CFTR is characterized by bursts of channel openings interrupted by brief, flickery closures, separated by long closures between bursts. Entry to and exit from an open burst is controlled by the interaction of ATP with two ATP-binding sites, sites 1 and 2, in CFTR. To understand better the kinetic basis of CFTR intraburst gating, we investigated the single-channel activity of human CFTR at different intracellular pH (pHi ) values. When compared with the control (pHi 7.3), acidifying pHi to 6.3 or alkalinizing pHi to 8.3 and 8.8 caused small reductions in the open-time constant (tauo ) of wild-type CFTR. By contrast, the fast closed-time constant (taucf ), which describes the short-lived closures that interrupt open bursts, was greatly increased at pHi 5.8 and 6.3. To analyse intraburst kinetics, we used linear three-state gating schemes. All data were satisfactorily modelled by the C1 <-> O <-> C2 kinetic scheme. Changing the intracellular ATP concentration was without effect on tauo , taucf and their responses to pHi changes. However, mutations that disrupt the interaction of ATP with ATP-binding site 1, including K464A, D572N and the CF-associated mutation G1349D all abolished the prolongation of taucf at pHi 6.3. Taken together, our data suggest that the regulation of CFTR intraburst gating is distinct from the ATP-dependent mechanism that controls channel opening and closing. However, our data also suggest that ATP-binding site 1 modulates intraburst gating. PMID- 27779766 TI - Investigating economic specialization on the central Peruvian coast: A reconstruction of Late Intermediate Period Ychsma diet using stable isotopes. AB - OBJECTIVES: Hypothetical models of socioeconomic organization in pre-Columbian societies generated from the rich ethnohistoric record in the New World require testing against the archaeological and bioarchaeological record. Here, we test ethnohistorian Maria Rostworowski's horizontality model of socioeconomic specialization for the Central Andean coast by reconstructing dietary practices in the Late Intermediate Period (c. AD 900-1470) Ychsma polity to evaluate complexities in social behaviors prior to Inka imperial influence. MATERIALS AND METHODS: Stable carbon and nitrogen isotope analysis of archaeological human bone collagen and apatite (delta13 Ccol[VPDB], delta15 Ncol[AIR] , delta13 Cap[VPDB] ) and locally available foods is used to reconstruct the diets of individuals from Armatambo (n = 67), associated ethnohistorically with fishing, and Rinconada Alta (n = 46), associated ethnohistorically with agriculture. RESULTS: Overall, mean delta15 Ncol[AIR] is significantly greater at Armatambo, while mean delta13 Ccol[VPDB] and mean delta13 Cap[VPDB] are not significantly different between the two sites. Within large-scale trends, adult mean delta13 Cap[VPDB] is significantly greater at Armatambo. In addition, nearly one-third of Armatambo adults and adolescents show divergent delta15 Ncol[AIR] values. DISCUSSION: These results indicate greater reliance on marine resources at Armatambo versus Rinconada Alta, supporting the ethnohistoric model of socioeconomic specialization for the Central Andean coast. Deviations from large-scale dietary trends suggest complexities not accounted for by the ethnohistoric model, including intra-community subsistence specialization and/or variation in resource access. PMID- 27779767 TI - Thrombotic issues in transgender medicine: A review. AB - Clinicians, including hematologists, are more frequently encountering transgender individuals in practice; however, most lack training on the management and complications of transgender medicine. Hormonal therapy forms the backbone of medical interventions for patients undergoing gender transition. While supplementing an individual's intrinsic sex hormone is associated with a variety of hematologic complications including increased rates of venous thrombosis, cardiovascular events, erthyrocytosis, and malignancy, the risks of supplementing with opposing sex hormones are not well understood. Data on the hematologic complications of these therapies are accumulating but remain limited, and clinicians have little experience with their management. This review highlights the current interventions available in transgender medicine and related potential hematologic complications, and it suggests simple, evidence-based management going forward. Am. J. Hematol. 92:204-208, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779769 TI - Management of anemia in patients with congestive heart failure. AB - Anemia is an independent risk factor for adverse patient outcomes. There are no guidelines for management of anemia in patients with congestive heart failure (CHF), despite its high incidence. Four objectives were defined by the International Anemia Management and Clinical Outcomes Expert Panel (AMCO), a multinational group of interdisciplinary experts identified by the Society for the Advancement of Blood Management (SABM) to: determine the prevalence of anemia in outpatients; to determine the prevalence of hospital-acquired anemia; to assess the impact of anemia management on clinical outcomes such as quality of life and functional status; and to provide recommendations for primary care physicians and specialists for the diagnosis, evaluation, and management of anemia in patients with CHF. Anemia and iron deficiency were confirmed to be highly prevalent in patients with CHF. Intravenous iron therapy improves anemia, cardiac function and exercise tolerance, leading to improvement in quality of life. Anemia management has been demonstrated to be cost-effective. Clinical care pathways to manage anemia in patients with CHF are recommended as best practices in order to improve patient outcomes. Am. J. Hematol. 92:88-93, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779768 TI - Randomized controlled trial of family-based education for patients with heart failure and their carers. AB - AIM: The aim of this study was to evaluate a heart failure education programme developed for patients and carers in Thailand. BACKGROUND: Heart failure is major health problem. This is the first trial of a family-based education programme for heart failure patients and carers residing in rural Thailand. DESIGN: Randomized controlled trial. METHODS: One hundred patient-carer dyads attending cardiac clinics in southern Thailand from April 2014 - March 2015 were randomized to usual care (n = 50) or a family-based education programme (n = 50) comprising face-to-face counselling, a heart failure manual and DVD and telephone support. Assessments of heart failure knowledge, health-related quality of life, self-care behaviours and perceived control were conducted at baseline, three and six months. RESULTS: Linear mixed-effects model revealed that patients and carers who received the education programme had higher knowledge scores at three and six months than those who received usual care. Among those who received the education programme, when compared with those who received usual care, patients had better self-care maintenance and confidence, and health-related quality of life scores at three and six months, and better self-care management scores at six months, whereas carers had higher perceived control scores at three months. CONCLUSION: Addressing a significant service gap in rural Thailand, this family-based heart failure programme improved patient knowledge, self-care behaviours and health related quality of life and carer knowledge and perceived control. PMID- 27779770 TI - Elective surgery to save my life: rethinking the "choice" in bariatric surgery. AB - AIMS: The aim of this study was to explicate the processes by which a patient's choice to undergo bariatric surgery is made to feel like a medical necessity, to explore the ways widespread societal stigmatization of weight and bariatric surgery shapes patient and provider discourse about surgery and to discuss patient rationalizations of the choice to have surgery. BACKGROUND: Severe obesity is currently highly stigmatized. Bariatric surgery has become an increasingly used option for individuals seeking to lose drastic amounts of weight. The surgery itself, however, remains stigmatized across many diverse settings. DESIGN: This research design is centred on an ethnographic study of bariatric surgery patients who undergo surgery at a particular bariatric clinic in the American Southwest. METHODS: Data collection included repeated ethnographic interviews with 35 individuals enrolled in the bariatric programme over the past 5 years. The interviews were supplemented by extensive participant observation, starting in 2014 to date. Thematic analysis of fieldnotes and transcribed interviews followed. RESULTS: People who have bariatric surgery for weight-loss may trade one type of stigma for another. Thus, individuals who qualify for bariatric surgery based on weight alone may be reluctant to explore the surgery as a viable option. This research also shows that younger women are more likely to face the effects of weight-related stigma, which has an impact on their motivations for undergoing bariatric surgery. CONCLUSION: Stigma - both weight-related and surgery-related - needs to be addressed at a larger level, in terms of policy and in clinical bariatric programmes. PMID- 27779771 TI - Efficacy and Tolerability of Antiepileptic Drugs in Patients with Focal Epilepsy: Systematic Review and Network Meta-analyses. AB - Several newer antiepileptic drugs (AEDs) have been introduced into clinical practice, offering choices for individualizing the treatment of epilepsy since AEDs have different efficacy and tolerability profiles. In particular, questions exist regarding which AEDs are the best options for the monotherapy of focal epilepsy. Is carbamazepine (CBZ), which is considered the standard treatment for focal epilepsy, still the best option for monotherapy of focal epilepsy, despite the emergence of new AEDs? In this systematic review, we compared the relative tolerability of all available AEDs for monotherapy of all types of epilepsy as well as their efficacy in the monotherapy of focal epilepsy. In addition, we compared CBZ with other AEDs for the monotherapy of focal epilepsy. We performed a search of the MEDLINE/PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for randomized controlled clinical trials. To compare the relative efficacy and tolerability of the AEDs, we performed network meta-analyses using a Bayesian random-effects model. Sensitivity analyses were conducted to determine the robustness of the results. A total of 65 studies were included in this review, composing 16,025 patients. Clobazam, levetiracetam, lamotrigine, oxcarbazepine, sulthiame, topiramate, and valproate had the best efficacy profiles and demonstrated no evidence of superiority or inferiority compared with CBZ. However, CBZ showed the greatest risk of patient discontinuation due to intolerable adverse reactions, whereas lamotrigine had the best safety profile and an 81% probability of being the best for the tolerability outcome of patient withdrawals from the study due to intolerable adverse reactions, followed by sulthiame (60%) and clobazam (51%). The newer AEDs-levetiracetam, lamotrigine, oxcarbazepine, sulthiame, and topiramate-should be considered for monotherapy of focal epilepsy because they were demonstrated to be as effective as the older ones (CBZ, clobazam, and valproate) for the treatment of focal epilepsy and were more tolerable. Lamotrigine was the AED with the best tolerability profile, suggesting that it may be the best option for the treatment of focal epilepsy in children and adults. PMID- 27779772 TI - The effectiveness of multimedia education for patients with type 2 diabetes mellitus. AB - AIMS: The aim of this study was to explore the effectiveness of two types of health education on improving knowledge concerning diabetes and insulin injection, insulin injection skills and self-efficacy, satisfaction with health education and glycated haemoglobin (HbA1c) and creatinine levels among patients with type 2 diabetes who began insulin therapy using a pen injector. BACKGROUND: Insulin therapy is recommended to facilitate the regulation of plasma glucose; however, patient's acceptance of insulin therapy is generally low. Healthcare providers should help them improve their knowledge of diabetes and insulin injection, as well as their insulin injection skills. DESIGN: A randomized repeated measures experimental study design. METHODS: The experimental (n = 21) and control (n = 21) groups received multimedia and regular health education programmes, respectively from October 2013-August 2014. Four structured questionnaires were used and videotapes were applied to demonstrate injection skills. RESULTS: Generalized estimating equations showed that the experimental group's scores were significantly higher than those of the control group for diabetes and insulin injection knowledge, insulin injection skills, self-efficacy in insulin injection and satisfaction with health education. On the other hand, an analysis of covariance revealed glycated hemoglobin (HbA1c) and creatinine levels did not differ significantly between the two groups. CONCLUSIONS: Implementation of a multimedia diabetes education programme could improve patients' diabetes and insulin injection knowledge, insulin injection skills, self-efficacy in insulin injection and satisfaction with health education. Healthcare providers should improve quality of patient care by providing multimedia diabetes health education. PMID- 27779773 TI - Glucocerebrosidase, Parkinson disease, and the "senses and intellect". PMID- 27779775 TI - Clonidine for Sedation and Analgesia and Withdrawal in Critically Ill Infants and Children. AB - The need for sedation and analgesia and treatment of iatrogenic drug withdrawal is common in critically ill children. First-line therapy typically includes opioid agonists. However, clonidine, a central alpha2 agonist, has been suggested as a treatment option for sedation and analgesia and iatrogenic drug withdrawal. Therefore, we conducted a literature search to identify articles evaluating the use of enteral (PO) and transdermal clonidine in critically ill infants and children for sedation and analgesia and treatment of iatrogenic drug withdrawal. The literature search was limited to English-language articles in Medline (1946 May 2016), Embase (1988-May 2016), and International Pharmaceutical Abstracts (1970-May 2016). Reference citations from relevant articles were also reviewed. Ten case reports and studies, representing a total of 114 children receiving clonidine, were included. Fifty patients (43.9%) received clonidine for sedation and analgesia while mechanically ventilated, and 33 (29.0%) received clonidine for treatment or prevention of drug withdrawal. The remaining 31 patients (27.1%) were included in a pharmacokinetic study that did not evaluate clinical outcomes. Seventy-nine patients (69.3%) received PO clonidine, with a dosage range of 2-15 ug/kg/day divided every 6-8 hours. Thirty-five patients (30.7%) received transdermal clonidine, with a dosage range of 2.3-20 ug/kg/day. Whole, cut, and occluded transdermal patches were used in the reports. Patients receiving cut patches had more variable and significantly higher serum clonidine concentrations than those receiving whole patches. Only three studies reported that the PO clonidine dose was tapered at the end of therapy; however, no report specifically described the process. The two most common adverse events reported with PO and transdermal clonidine were bradycardia and hypotension. PO and transdermal clonidine have a potential role for sedation and analgesia and drug withdrawal in critically ill infants and children. The use of cut transdermal patches should be avoided. Future prospective studies are needed to further define clonidine's role as adjunct therapy or monotherapy. PMID- 27779774 TI - Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma. PMID- 27779777 TI - Reducing patient delay in Acute Coronary Syndrome (RAPiD): research protocol for a web-based randomized controlled trial examining the effect of a behaviour change intervention. AB - AIMS: To evaluate the efficacy of a behaviour change technique-based intervention and compare two possible modes of delivery (text + visual and text-only) with usual care. BACKGROUND: Patient delay prevents many people from achieving optimal benefit of time-dependent treatments for acute coronary syndrome. Reducing delay would reduce mortality and morbidity, but interventions to change behaviour have had mixed results. Systematic inclusion of behaviour change techniques or a visual mode of delivery might improve the efficacy of interventions. DESIGN: A three-arm web-based, parallel randomized controlled trial of a theory-based intervention. METHODS: The intervention comprises 12 behaviour change techniques systematically identified following systematic review and a consensus exercise undertaken with behaviour change experts. We aim to recruit n = 177 participants who have experienced acute coronary syndrome in the previous 6 months from a National Health Service Hospital. Consenting participants will be randomly allocated in equal numbers to one of three study groups: i) usual care, ii) usual care plus text-only behaviour change technique-based intervention or iii) usual care plus text + visual behaviour change technique-based intervention. The primary outcome will be the change in intention to phone an ambulance immediately with symptoms of acute coronary syndrome >=15-minute duration, assessed using two randomized series of eight scenarios representing varied symptoms before and after delivery of the interventions or control condition (usual care). Funding granted January 2014. DISCUSSION: Positive results changing intentions would lead to a randomized controlled trial of the behaviour change intervention in clinical practice, assessing patient delay in the event of actual symptoms. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT02820103. PMID- 27779778 TI - Cold pressor gel test: A safe alternative to the cold pressor test in fMRI. AB - PURPOSE: This study describes a new methodology-the cold pressor gel test (CPGT) for delivering an accessible experimental pain stimulus, which is reproducible and safe for functional MRI (fMRI). METHODS: The cold pressor test was modified to put safety precautions into the CPGT. The material used is cool gelled water with a thickening product, which provides a stable temperature at 0.2 degrees C. Thirteen women with chronic pelvic pain were scanned using a 3 Tesla (T) MR scanner equipped with a 12-channel head coil. Changes in BOLD activation during cold-induced pain were estimated. RESULTS: The results have demonstrated that gel substances maintain a stable temperature during the experiment, resulting in an insignificant variation. Before the experiment, the mean temperature was 0.2 +/- 0.11 degrees C, and at the end it was 0.7 +/- 0.15 degrees C. The time taken by participants to reach the maximum level of pain during the CPGT was 56.92 +/- 11.09 s. The pain intensity during the experiments was 6.92 +/- 1.66 on the visual analog scale (VAS). The fMRI analysis showed significant BOLD activation in the main brain regions involved in chronic pain processing. CONCLUSION: The CPGT is an experimental tool to deliver pain that is easily reproducible, particularly in brain functional imaging studies. Moreover, it is cost-effective, safe, and compatible with fMRI. Magn Reson Med 78:1464-1468, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27779776 TI - A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio(r) ) in cardiac surgery: the REVAKI-1 study. AB - AIMS: Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio(r) , Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre-clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. METHODS: We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. RESULTS: Thirty-six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUCinfinity 537 ng h ml-1 , Cmax 189.4 ng ml-1 and t1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post-surgery nitric oxide bioavailability. CONCLUSIONS: Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery. PMID- 27779779 TI - Direct SAR mapping by thermoacoustic imaging: A feasibility study. AB - PURPOSE: To develop a new method capable of directly measuring specific absorption rate (SAR) deposited in tissue using the thermoacoustic signal induced by short radiofrequency (RF) pulse excitation. THEORY: A detailed model based on the thermoacoustic wave generation and propagation is presented. METHODS: We propose a new concept for direct measurement of SAR, to be used as a safety assessment/monitoring tool for MRI. The concept involves the use of short bursts of RF energy and the measurement of the resulting thermoacoustic excitation pattern by an array of ultrasound transducers, followed by image reconstruction to yield the 3D SAR distribution. We developed a simulation framework to model this thermoacoustic SAR mapping concept and verified the concept in vitro. RESULTS: Simulations show good agreement between reconstructed and original SAR distributions with an error of 4.2, 7.2, and 8.4% of the mean SAR values in axial, sagittal, and coronal planes and support the feasibility of direct experimental mapping of SAR distributions in vivo. The in vitro experiments show good agreement with theory (r2 = 0.52). CONCLUSIONS: A novel thermoacoustic method for in vivo mapping of local SAR patterns in MRI has been proposed and verified in simulation and in a phantom experiment. Magn Reson Med 78:1599-1606, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27779781 TI - EPA-Registered Repellents for Mosquitoes Transmitting Emerging Viral Disease. AB - In many parts of the United States, mosquitoes were previously nuisance pests. However, they now represent a potential threat in the spread of viral diseases. The Aedes aegypti, Aedes albopictus, and Culex species mosquitoes are endemic to the United States and together may transmit a variety of viral diseases of growing concern, including West Nile virus, chikungunya, dengue fever, and Zika virus. The Centers for Disease Control and Prevention and the Environmental Protection Agency (EPA) recommend N,N-diethyl-meta-toluamide (DEET) as a first line mosquito repellent, but for patients refusing to use DEET or other conventional repellents, guidance is limited to any EPA-registered product. Therefore, we conducted a systematic review of the literature to identify which EPA-registered personal mosquito repellent provides the best protection from A. aegypti, A. albopictus, and Culex spp. mosquitoes. We abstracted data from 62 published reports of EPA-registered mosquito repellents. The conventional repellent picaridin has the strongest data to support its use as a second-line agent, while IR3535 and oil of lemon eucalyptus are reasonably effective natural products. Citronella, catnip, and 2-undecanone offer limited protection or have limited data. These results can be used by pharmacists and other health care professionals to advise patients on the selection of an EPA-registered mosquito repellent. Regardless of the repellent chosen, it is vital for patients to follow all instructions/precautions in the product labeling to ensure safe and effective use. PMID- 27779780 TI - Incidence and time trends of drug-induced parkinsonism: A 30-year population based study. AB - BACKGROUND: Epidemiological studies of drug-induced parkinsonism remain limited. OBJECTIVES: To investigate the incidence and time trends of drug-induced parkinsonism over 30 years in a geographically defined American population. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug-induced parkinsonism associated with dopamine blocking or dopamine-depleting medications. RESULTS: Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug-induced parkinsonism (11.9%). The average annual incidence rate of drug-induced parkinsonism was 3.3 per 100,000 person-years, was higher in women, and increased with older age. Drug induced parkinsonism was the fifth-most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug-induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49-0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women. CONCLUSIONS: The incidence of drug induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug-induced parkinsonism decreased over the 30 years of the study because of changes in drug use. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 27779782 TI - Use of Tumor Necrosis Factor-Alpha Inhibitors in Children and Young Adults With Juvenile Idiopathic Arthritis or Rheumatoid Arthritis. AB - OBJECTIVE: To characterize the use of tumor necrosis factor-alpha inhibitors (TNFIs) in children with juvenile idiopathic arthritis (JIA) and young adults with rheumatoid arthritis (RA). METHODS: Patients with incident JIA or RA were identified by using the Truven Health MarketScan Commercial Claims and Encounters database from 2009 to 2013. The incident diagnosis was defined as no prior claims with a JIA/RA code and no JIA/RA medications recorded during the previous 6 months. TNFI use patterns were examined, including switching among TNFIs, adherence, persistence, and time from diagnosis to TNFI use. Earlier TNFI treatment without prior use of traditional disease-modifying antirheumatic drugs (DMARDs) and use of specific TNFIs were analyzed by age group. RESULTS: Of 6929 children and young adults with new diagnoses of JIA/RA, 18.6% were treated with TNFIs. In these TNFI users, 39.1% received earlier TNFI therapy without prior use of DMARDs. The use of TNFIs was higher in patients diagnosed between 2012 and 2013 than that in patients diagnosed between 2009 and 2011 (hazard ratio 1.13, 95% confidence interval 1.00-1.28). Etanercept was the most commonly used, especially by children aged < 12 (75.5%) and adolescents aged 12 to 17 (62.5%) years. Adherence measured as mean proportion of days covered ranged from 70.4% to 93.2% for individual TNFI agents. Only about 60% of patients continuously took TNFIs for 12 months. When switching occurred, switching from etanercept to adalimumab was the most common pattern. CONCLUSION: Earlier TNFI therapy was observed in 39.1% of children and young adults taking TNFIs. In addition, the time to the first TNFI prescription became shorter over the study period. Future research should evaluate the long-term effectiveness and safety of this more aggressive TNFI therapy. PMID- 27779783 TI - 1.5 Versus 3 tesla magnetic resonance planimetry in neurodegenerative parkinsonism. PMID- 27779784 TI - Pisa syndrome in Parkinson's disease: An integrated approach from pathophysiology to management. AB - Pisa syndrome was first described in 1972 in patients treated with neuroleptics. Since 2003, when it was first reported in patients with Parkinson's disease (PD), Pisa syndrome has progressively drawn the attention of clinicians and researchers. Although emerging evidence has partially clarified its prevalence and pathophysiology, the current debate revolves around diagnostic criteria and assessment and the effectiveness of pharmacological, surgical, and rehabilitative approaches. Contrary to initial thought, Pisa syndrome is common among PD patients, with an estimated prevalence of 8.8% according to a large survey. Furthermore, it is associated with the following specific patient features: more severe motor phenotype, ongoing combined pharmacological treatment with levodopa and dopamine agonists, gait disorders, and such comorbidities as osteoporosis and arthrosis. The present literature on treatment outcomes is scant, and the uneven effectiveness of specific treatments has produced conflicting results. This might be because of the limited knowledge of Pisa syndrome pathophysiology and its variable clinical presentation, which further complicates designing randomized clinical trials on this condition. However, because some forms of Pisa syndrome are potentially reversible, there is growing consensus on the importance of its early recognition and the importance of pharmacological adjustment and rehabilitation. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27779786 TI - Positive Impact of Continuous-Flow Left Ventricular Assist Device Implantation on Glycemic Control in Patients with Type 2 Diabetes Mellitus and Advanced Chronic Systolic Heart Failure. AB - STUDY OBJECTIVE: To evaluate the impact of continuous-flow left ventricular assist device (LVAD) implantation on glycemic control in patients with type 2 diabetes mellitus and advanced chronic systolic heart failure. DESIGN: Retrospective medical record review. SETTING: Large academic tertiary and quaternary care hospital. PATIENTS: Eighty-three adults with type 2 diabetes mellitus and advanced chronic systolic heart failure who underwent implantation of a continuous-flow LVAD between July 1, 2008, and June 30, 2013. MEASUREMENTS AND MAIN RESULTS: Baseline demographic data and laboratory values pertinent to glycemic control (hemoglobin A1c [A1C], total daily insulin requirements, noninsulin antidiabetic medication use, and body mass index [BMI]) were collected for each patient. Pre-LVAD data were compared with data obtained during the 24 months after LVAD implantation. The mean age of the study population was 61.3 years, 70% were men, and 63% had ischemic cardiomyopathy. The first available mean +/- SD A1C after LVAD implantation was 6.21 +/- 1.5% at a median of 4.8 months (interquartile range 3.3-8.9), which represented a significant decrease from the pre-LVAD A1C of 7.46 +/- 1.5% (p<0.001). Average daily insulin requirements decreased by 22.9 units at the end of 24 months (p<0.001). Over half of patients with prescriptions for noninsulin antidiabetic medications were able to discontinue therapy by the end of the study. Of note, BMI increased in the second year after LVAD implantation from a baseline of 32.3 kg/m2 to 34.9 kg/m2 (p=0.004). Regression analysis revealed that baseline A1C was the only independent predictor of change in A1C. CONCLUSION: LVAD implantation was associated with a significant improvement in glycemic control. Further prospective studies are needed to evaluate the long-term impact of LVAD implantation on the clinical course of diabetes. PMID- 27779785 TI - Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate. AB - : Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between "true" and calculated glomerular filtration rate (GFR). We compared the performance of the four-variable and six-variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with "true," or measured, GFR (mGFR) and the impact of this difference on Model for End-Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was >=3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 * (creatinine-0.836 ) * (urea-0.229 ) * (international normalized ratio-0.113 ) * (age-0.129 [Corrected November 29, 2016: originally written as "age-129."]) * (sodium0.972 ) * 0.809 (if female) * 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. CONCLUSION: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582-591). PMID- 27779787 TI - Nonstandard work arrangements and worker health and safety. AB - Arrangements between those who perform work and those who provide jobs come in many different forms. Standard work arrangements now exist alongside several nonstandard arrangements: agency work, contract work, and gig work. While standard work arrangements are still the most prevalent types, the rise of nonstandard work arrangements, especially temporary agency, contract, and "gig" arrangements, and the potential effects of these new arrangements on worker health and safety have captured the attention of government, business, labor, and academia. This article describes the major work arrangements in use today, profiles the nonstandard workforce, discusses several legal questions about how established principles of labor and employment law apply to nonstandard work arrangements, summarizes findings published in the past 20 years about the health and safety risks for workers in nonstandard work arrangements, and outlines current research efforts in the area of healthy work design and worker well being. Am. J. Ind. Med. 60:1-10, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779788 TI - 'Clinical Chatter': every nurse informed. AB - AIMS AND OBJECTIVES: To assess the acceptability and usability of a standardised communication tool for nurses. BACKGROUND AND SIGNIFICANCE: Communication is key in health care. On a daily, if not hourly, basis, nursing staff is inundated with new information regarding tools and resources, practice changes and the work environment. However, there is currently no standardised messaging or delivery method to effectively communicate new information. Even with a plethora of communication tools such as flyers, posters, emails, unit huddles and unit meetings, there is no means to guarantee attendance to crucial information. DESIGN: Descriptive, cross-sectional online survey, implemented at a nonacademic, suburban hospital with 280 nurses. METHODS: The Clinical Chatter, an online tool developed by nursing leadership to standardise messages regarding the organisation, new tools and resources, professional development, recognition and unit updates, was delivered to each nurse on a weekly basis followed by administration of Acceptability and Usability scales. RESULTS: The Clinical Chatter tool has adequate acceptability and usability as a method of communication among nurses in a hospital organisation. Sociodemographic variables of age and years of experience had no statistically significant association with perceived acceptance and usefulness of the tool. CONCLUSION: The findings indicate that the Clinical Chatter tool can be used as a standardised communication tool to deliver key information among nurses working in a hospital organisation. Nursing leadership must establish and support a clear communication system to enhance patient care and outcomes and improve nursing job satisfaction. RELEVANCE TO CLINICAL PRACTICE: Communication is vital to advancing health care. Lack of communication among nursing has been linked to unsafe patient care: medication errors, unhealthy work environments and decreased nurse retention rates. Clinical Chatter is an effective communication tool for presentation of institutional information to nursing personnel. PMID- 27779789 TI - Role of Cytochrome P450 2B6 Pharmacogenomics in Determining Efavirenz-Mediated Central Nervous System Toxicity, Treatment Outcomes, and Dosage Adjustments in Patients with Human Immunodeficiency Virus Infection. AB - For treatment-naive patients with human immunodeficiency virus infection, efavirenz (EFV), together with tenofovir and emtricitabine, was once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system (CNS) toxicities from EFV prompted the U.S. Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and often the mainstay of treatment outside the United States because newer antiretroviral treatments are more expensive. CNS toxicity occurring with the recommended standard dose of EFV remains a challenge and may in part be attributable to polymorphisms in cytochrome P450 (CYP) 2B6, the enzyme involved in the major metabolic pathway for converting EFV to inactive metabolites. Functionally deficient alleles of CYP2B6 such as CYP2B6*6, *18, and *22 may be responsible for significantly higher therapeutic concentrations of EFV at a standard dose of 600 mg/day. We conducted a thorough review of the reported studies to elucidate the relationship between polymorphisms in CYP2B6 with adverse events and treatment response, including virologic suppression, immunologic response, resistance, and discontinuation of treatment. Compelling evidence exists to support the case for CYP2B6 genotype-guided EFV therapy while acknowledging the need for prospective controlled clinical trials to evaluate its clinical utility. PMID- 27779791 TI - Improving Hurricane Power Outage Prediction Models Through the Inclusion of Local Environmental Factors. AB - Tropical cyclones can significantly damage the electrical power system, so an accurate spatiotemporal forecast of outages prior to landfall can help utilities to optimize the power restoration process. The purpose of this article is to enhance the predictive accuracy of the Spatially Generalized Hurricane Outage Prediction Model (SGHOPM) developed by Guikema et al. (2014). In this version of the SGHOPM, we introduce a new two-step prediction procedure and increase the number of predictor variables. The first model step predicts whether or not outages will occur in each location and the second step predicts the number of outages. The SGHOPM environmental variables of Guikema et al. (2014) were limited to the wind characteristics (speed and duration of strong winds) of the tropical cyclones. This version of the model adds elevation, land cover, soil, precipitation, and vegetation characteristics in each location. Our results demonstrate that the use of a new two-step outage prediction model and the inclusion of these additional environmental variables increase the overall accuracy of the SGHOPM by approximately 17%. PMID- 27779792 TI - Editorial: Crossing the caring chasm. PMID- 27779790 TI - Voxelwise analysis of simultaneously acquired and spatially correlated 18 F fluorodeoxyglucose (FDG)-PET and intravoxel incoherent motion metrics in breast cancer. AB - PURPOSE: Diffusion-weighted imaging (DWI) and 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET) independently correlate with malignancy in breast cancer, but the relationship between their structural and metabolic metrics is not completely understood. This study spatially correlates diffusion, perfusion, and glucose avidity in breast cancer with simultaneous PET/MR imaging and compares correlations with clinical prognostics. METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, with written informed consent and approval of the institutional review board and using simultaneously acquired FDG-PET and DWI, tissue diffusion (Dt ), and perfusion fraction (fp ) from intravoxel incoherent motion (IVIM) analysis were registered to FDG-PET within 14 locally advanced breast cancers. Lesions were analyzed using 2D histograms and correlation coefficients between Dt , fp , and standardized uptake value (SUV). Correlations were compared with prognostics from biopsy, metastatic burden from whole-body PET, and treatment history. RESULTS: SUV||Dt correlation coefficient significantly distinguished treated (0.11 +/- 0.24) from nontreated (-0.33 +/- 0.26) patients (P = 0.005). SUV||fp correlations were on average negative for the whole cohort (-0.17 +/- 0.13). CONCLUSION: Simultaneously acquired and registered FDG-PET/DWI allowed quantifiable descriptions of breast cancer microenvironments that may provide a framework for monitoring and predicting response to treatment. Magn Reson Med 78:1147-1156, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27779793 TI - Two Independent Orthogonal Stereomutations at a Single Asymmetric Center: A Narcissistic Couple. AB - The energy barriers in our recently discovered Walden-type inversion of chlorophosphonium salts are similar to those for Cope rearrangements of caged cyclic hydrocarbons. Therefore, we have designed a molecular system that integrates the two processes, thereby producing the first embodiment of a chemical species that can undergo two entirely different and independent stereomutation mechanisms at the same nominal asymmetric center. Thus, the energy barrier to the rearrangement of 9-phenyl-9-phosphabarbaralane oxide, which is easily prepared by a new high-yielding synthesis, was found to be roughly 11 kcal mol-1 . This value is in contrast to the parent barbaralane (7.3 kcal mol-1 ) but in good agreement with our computational results for the rearrangement barriers. Crucially, in the corresponding chlorophosphonium derivative, two stereomutations occur simultaneously: a fast Cope rearrangement (barrier ~12 kcal mol-1 ) and a slow Walden-type inversion of the phosphorus center (barrier ~21 kcal mol-1 ). The computational model also revealed a relationship between the Cope rearrangement barrier and the bridgehead distance. The phenomenon of two independent and geometrically orthogonal stereomutations at a single asymmetric center provided important general insights into reaction pathway bifurcation, microscopic reversibility, and dynamic stereochemistry. This first example of coexisting alternative mechanisms that involve covalent bonds may encourage the design of new types of dynamic molecular structures. PMID- 27779794 TI - An invasive wetland grass primes deep soil carbon pools. AB - Understanding the processes that control deep soil carbon (C) dynamics and accumulation is of key importance, given the relevance of soil organic matter (SOM) as a vast C pool and climate change buffer. Methodological constraints of measuring SOM decomposition in the field prevent the addressing of real-time rhizosphere effects that regulate nutrient cycling and SOM decomposition. An invasive lineage of Phragmites australis roots deeper than native vegetation (Schoenoplectus americanus and Spartina patens) in coastal marshes of North America and has potential to dramatically alter C cycling and accumulation in these ecosystems. To evaluate the effect of deep rooting on SOM decomposition we designed a mesocosm experiment that differentiates between plant-derived, surface SOM-derived (0-40 cm, active root zone of native marsh vegetation), and deep SOM derived mineralization (40-80 cm, below active root zone of native vegetation). We found invasive P. australis allocated the highest proportion of roots in deeper soils, differing significantly from the native vegetation in root : shoot ratio and belowground biomass allocation. About half of the CO2 produced came from plant tissue mineralization in invasive and native communities; the rest of the CO2 was produced from SOM mineralization (priming). Under P. australis, 35% of the CO2 was produced from deep SOM priming and 9% from surface SOM. In the native community, 9% was produced from deep SOM priming and 44% from surface SOM. SOM priming in the native community was proportional to belowground biomass, while P. australis showed much higher priming with less belowground biomass. If P. australis deep rooting favors the decomposition of deep-buried SOM accumulated under native vegetation, P. australis invasion into a wetland could fundamentally change SOM dynamics and lead to the loss of the C pool that was previously sequestered at depth under the native vegetation, thereby altering the function of a wetland as a long-term C sink. PMID- 27779795 TI - DNA extraction from benthic Cyanobacteria: comparative assessment and optimization. AB - AIMS: Benthic Cyanobacteria produce toxic and odorous compounds similar to their planktonic counterparts, challenging the quality of drinking water supplies. The biofilm that benthic algae and other micro-organisms produce is a complex and protective matrix. Monitoring to determine the abundance and identification of Cyanobacteria, therefore, relies on molecular techniques, with the choice of DNA isolation technique critical. This study investigated which DNA extraction method is optimal for DNA recovery in order to guarantee the best DNA yield for PCR based analysis of benthic Cyanobacteria. METHODS AND RESULTS: The conventional phenol-chloroform extraction method was compared with five commercial kits, with the addition of chemical and physical cell-lysis steps also trialled. The efficacy of the various methods was evaluated by measuring the quantity and quality of DNA by UV spectrophotometry and by quantitative PCR (qPCR) using Cyanobacteria-specific primers. The yield and quality of DNA retrieved with the commercial kits was significantly higher than that of DNA obtained with the phenol-chloroform protocol. CONCLUSIONS: Kits including a physical cell-lysis step, such as the MO BIO Power Soil and Biofilm kits, were the most efficient for DNA isolation from benthic Cyanobacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: These commercial kits allow greater recovery and the elimination of dangerous chemicals for DNA extraction, making them the method of choice for the isolation of DNA from benthic mats. They also facilitate the extraction of DNA from benthic Cyanobacteria, which can help to improve the characterization of Cyanobacteria in environmental studies using qPCRs or population composition analysis using next generation sequencing. PMID- 27779796 TI - Changes in the relationship between asthma and associated risk factors over fifty years. AB - BACKGROUND: Childhood asthma is a common condition whose prevalence is changing. We hypothesized that the relationship between asthma and associated risk factors has changed over a 50-year period. METHODS: An ecological study design was used. Children aged 8-13 attending schools in Aberdeen city were surveyed on seven occasions between 1964 and 2014. The following were determined: history of asthma, history of eczema, parental smoking, parental asthma, sex and socio economic status. Analysis was by a structural change model with two knots. The outcome reported was the change in odds ratio between asthma and a given risk factor during a given period. RESULTS: There were 23,241 questionnaires distributed and 17,439 returned (75%). The odds ratio (OR) for a child with asthma to have eczema increased between 1989 and 1999 by 1.031 [95% CI 1.028, 1.035] and by 1.042 between 2004 and 2014 [1.038, 1.047]. The OR for a child with asthma to have a parent who smoked rose by 1.032 [1.028, 1.036] between 1989 and 1999 and by 1.043 [1.038, 1.047] between 2004 and 2014), and to have a parent with asthma (1.027 [1.022, 1.031] for 1994-99 and 1.042 [1.037, 1.048] for 2004 2014). The OR for a child with asthma being male, but not and being from the most deprived communities, rose between 1989-1999 and 2004-2014. CONCLUSIONS: The relationship between asthma prevalence and particular risk factors changed over the 50-year period of study, and this might reflect changes in children's environment and/or susceptibility. PMID- 27779797 TI - N-Methylanilines as Simple and Efficient Promoters for Radical-Type Cross Coupling Reactions of Aryl Iodides. AB - Activation of the carbon-halogen bonds in aryl halides is a key step in transition-metal-free cross-coupling reactions. In this paper, a new and efficient radical initiation system for the activation of iodoarenes to produce aryl radicals was discovered, which employs the combination of N-methylanilines and tBuOK. This radical initiation system is robust and versatile, enabling various types of aryl-radical-related reactions. PMID- 27779798 TI - Catalytic Activity of Thiolate-Bridged Diruthenium Complexes Bearing Pendent Ether Moieties in the Oxidation of Molecular Dihydrogen. AB - Thiolate-bridged diruthenium complexes bearing pendent ethers have been found to work as effective catalysts toward the oxidation of molecular dihydrogen into protons and electrons in water. The pendent ether moiety in the complex plays an important role to facilitate the proton transfer between the metal center and the external proton acceptor. PMID- 27779799 TI - Diagnosis and long-term outcome of renal cysts after laparoscopic partial nephrectomy in children. AB - OBJECTIVE: To document the imaging follow-up of laparoscopic partial nephrectomy (LPN) in children and to investigate the natural history of cystic lesions following LPN. PATIENTS AND METHODS: We reviewed the ultrasonography (US) imaging reports performed during the follow-up of 125 children (77 girls, 48 boys; mean age 3.2 years) who underwent LPN in two centres of paediatric surgery in the period 2005-2015. RESULTS: A transperitoneal approach was adopted in 83 children and a retroperitoneal approach in 42. The mean follow-up was 4.2 years. At US, an avascular cyst related to the operative site was found after 61/125 procedures (48.8%). As for their appearance, 53/61 cysts were simple and anechoic, and eight of the 61 cysts appeared septated. The mean diameter of the cysts was 3.3 * 2.8 cm. As for their course, 13/61 cysts (21.3%) disappeared after a mean of 4 years, 26/61 (42.6%) did not significantly change in dimension, 17/61 (27.8%) decreased in size, and only five of the 61 cysts (8.3%) enlarged. The cysts were asymptomatic in 51 children (83.6%), while they were associated with urinary tract infections (UTIs) and abdominal pain in the remaining 10; none required a re-intervention. CONCLUSIONS: The US finding of a simple cyst at the operative site after LPN is common during follow-up, with an incidence of ~50% in our series. In regard to aetiology, probably a seroma takes the place of the removed hemi-kidney. There was no correlation between cyst formation and type of surgical technique adopted. As there was no correlation between cysts and clinical outcomes, renal cysts after LPN can be managed conservatively, with periodic US evaluations. PMID- 27779800 TI - The expanded criteria donor for kidney transplant: not a nearly new car. PMID- 27779801 TI - Asymmetric Catalytic Aza-Diels-Alder/Ring-Closing Cascade Reaction Forming Bicyclic Azaheterocycles by Trienamine Catalysis. AB - An asymmetric catalytic aza-Diels-Alder/ring-closing cascade reaction between acylhydrazones and in situ formed trienamines is presented. The reaction proceeds through a formal aza-Diels-Alder cycloaddition, followed by a ring-closing reaction forming the hemiaminal ring leading to chiral bicyclic azaheterocycles in moderate to good yield (up to 71 %), good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). Furthermore, transformations are presented to show the potential application of the formed product. PMID- 27779802 TI - Quantification of breast stiffness using MR elastography at 3 Tesla with a soft sternal driver: A reproducibility study. AB - PURPOSE: Previous studies of breast MR elastography (MRE) evaluated the technique at magnetic field strengths of 1.5 Tesla (T) with the breast in contact with the driver. The aim of this study is to evaluate breast stiffness measurements and their reproducibility using a soft sternal driver at 3T and compare the results with qualitative measures of breast density. MATERIALS AND METHODS: Twenty-two healthy volunteers each underwent two separate breast MRE scans in a 3T MRI. MRE vibrations were introduced into the breasts at 60 Hz using a soft sternal driver and axial slices were collected using a gradient echo MRE sequence. Mean stiffness measurements were calculated for each volunteer as well as a measure of reproducibility using concordance correlation between scans. Mean stiffness values for each volunteer were assessed and related to amounts of fibroglandular tissue (i.e., breast lobules, ducts, and fibrous connective tissue). RESULTS: The stiffness values were reproducible with a significant P-value < 0.0001 between two scans with concordance correlation of 0.87 and 0.91 for center slice and grouping all slices, respectively. Volunteers with dense breasts (i.e., higher grades of fibroglandular tissue) had mean stiffness values of 0.96 kPa (center slice) and 0.92 kPa (all slices) while those without dense breasts had mean stiffness values of 0.85 kPa (center slice) and 0.83 kPa (all slices) (P <= 0.05). CONCLUSION: Breast MRE is a reproducible technique at 3T using a soft sternal driver. Dense breasts had significantly higher stiffness measurements compared with nondense breasts. LEVEL OF EVIDENCE: 2 J. MAGN. RESON. IMAGING 2017;45:1379-1384. PMID- 27779803 TI - Developing a research agenda for understanding the stigma of addictions Part I: Lessons from the Mental Health Stigma Literature. AB - BACKGROUND AND OBJECTIVES: Although advocates and providers identify stigma as a major factor in confounding the recovery of people with SUDs, research on addiction stigma is lacking, especially when compared to the substantive literature examining the stigma of mental illness. METHODS: A review of key studies from the stigma literature that yielded empirically supported concepts and methods from the mental health arena was contrasted with the much smaller and mostly descriptive findings from the addiction field. RESULTS: Integration of this information led to Part I of this two part paper, development of a research paradigm seeking to understand phenomena of addiction stigma (eg, stereotypes, prejudice, and discrimination) and its different types (public, self, and label avoidance). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In Part II paper (American Journal of Addictions, Vol 26, pages 67-74, this issue), we address how this literature informs a research program meant to develop and evaluate and stigma strategies (eg, education, contact, and protest). Both papers end with recommendations for next steps to jumpstart the addiction stigma portfolio. Here in Part I, we offer one possible list of key research issues for studies attempting to describe or explain addiction stigma. (Am J Addict 2017;26:59-66). PMID- 27779804 TI - Severe anaphylaxis requiring intensive care during oral food challenge-It is not always peanuts. PMID- 27779805 TI - The competitive status of trees determines their responsiveness to increasing atmospheric humidity - a climate trend predicted for northern latitudes. AB - The interactive effects of climate variables and tree-tree competition are still insufficiently understood drivers of forest response to global climate change. Precipitation and air humidity are predicted to rise concurrently at high latitudes of the Northern Hemisphere. We investigated whether the growth response of deciduous trees to elevated air humidity varies with their competitive status. The study was conducted in seed-originated silver birch and monoclonal hybrid aspen stands grown at the free air humidity manipulation (FAHM) experimental site in Estonia, in which manipulated stands (n = 3 for both species) are exposed to artificially elevated relative air humidity (6-7% over the ambient level). The study period included three growing seasons during which the stands had reached the competitive stage (trees were 7 years old in the final year). A significant 'treatment*competitive status' interactive effect on growth was detected in all years in birch (P < 0.01) and in one year in aspen stands (P = 0.015). Competitively advantaged trees were always more strongly affected by elevated humidity. Initially the growth of advantaged and neutral trees of both species remained significantly suppressed in humidified stands. In the following years, dominance and elevated humidity had a synergistic positive effect on the growth of birches. Aspens with different competitive status recovered more uniformly, attaining similar relative growth rates in manipulated and control stands, but preserved a significantly lower total growth yield due to severe initial growth stress. Disadvantaged trees of both species were never significantly affected by elevated humidity. Our results suggest that air humidity affects trees indirectly depending on their social status. Therefore, the response of northern temperate and boreal forests to a more humid climate in future will likely be modified by competitive relationships among trees, which may potentially affect species composition and cause a need to change forestry practices. PMID- 27779806 TI - Role of parathyroid hormone in regeneration of irradiated bone in a murine model of mandibular distraction osteogenesis. AB - BACKGROUND: The purpose of this study was to measure the histologic and histomorphometric effects of parathyroid hormone (PTH) treatment on irradiated bone undergoing distraction osteogenesis (DO). METHODS: Thirty-four rats were divided into 3 groups. The control group underwent DO and the radiation control group underwent radiotherapy (RT) before DO. The PTH group underwent RT and received PTH during DO. Quantitative histology and histomorphometry were performed. RESULTS: RT resulted in a depletion of osteocytes and increase in empty lacunae. Treatment with PTH resulted in an increase in osteocyte counts and decrease in empty lacunae (p < .05), restoring osteocytes to levels seen in nonradiated bone (p = .121). RT decreased bone volume to tissue volume (BV-TV) ratio and increased osteoid volume to tissue volume (OV-TV) ratio, signifying increased immature bone formation. PTH treatment restored OV-TV ratio to that observed in nonradiated bone. CONCLUSION: PTH treatment of irradiated bone enhanced bone regeneration and restored osteocyte counts and OV-TV ratio to levels comparable to nonradiated bone. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 464-470, 2017. PMID- 27779807 TI - Synthesis and characterization of photo-responsive magnetic molecularly imprinted microspheres for the detection of sulfonamides in aqueous solution. AB - A dual responsive molecularly imprinted polymer sensitive to both photonic and magnetic stimuli was successfully prepared for the detection of four sulfonamides in aqueous media. The photoresponsive magnetic molecularly imprinted polymer was prepared by surface imprinting polymerization using superparamagnetic Fe3 O4 nanoparticles functionalized with a silica layer as a support, water-soluble 4 [(4-methacryloyloxy)phenylazo]benzenesulfonic acid as the functional monomer, and sulfadiazine as the template. The magnetic molecularly imprinted polymers showed specific affinity to sulfadiazine and its structural analogs in aqueous media. Upon alternate irradiation at 365 and 440 nm, the quantitative bind and release of the four sulfonamides by magnetic molecularly imprinted polymers occurred. Furthermore, the prepared magnetic molecularly imprinted polymers were used as solid-phase extraction material selectively extracted the four sulfonamides from water samples with good recoveries. Thus, a simple, convenient, and reliable detection method for sulfonamides in the environment based on responsive magnetic molecularly imprinted polymers was successfully established. PMID- 27779808 TI - Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma. AB - Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c-MET signaling in SS. Both HGF and c-MET were highly expressed in Yamato-SS cells, resulting in activation of c-MET and its downstream AKT and extracellular signal-regulated kinase signaling pathways, whereas c-MET was expressed but not activated in SYO-1 or HS-SY-II cells. c-MET activated Yamato-SS cells showed higher anchorage-independent growth ability and less sensitivity to chemotherapeutic agents than did c-MET-inactivated SYO-1 or HS-SY-II cells. INC280, a selective c-MET inhibitor, inhibited growth of Yamato SS cells both in vitro and in vivo but not that of SYO-1 or HS-SY-II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c MET and its downstream effectors in Yamato-SS cells. Co-expression of HGF and c MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c-MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c-MET-activated SS. HGF/c-MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c-MET inhibitors. PMID- 27779809 TI - Long-term safety and efficacy of perinatal probiotic intervention: Evidence from a follow-up study of four randomized, double-blind, placebo-controlled trials. AB - BACKGROUND: Societies worldwide are faced with a progressive increase in immune mediated health problems such as allergic, autoimmune, and inflammatory diseases, as well as obesity. Perinatal administration of specific probiotic bacteria is an attractive approach in reducing the risk of these conditions, but long-term efficacy and safety data are lacking. The aim here was to evaluate the clinical benefit and long-term safety of specific probiotics administered during the perinatal period. METHODS: The probiotic strains used were Lactobacillus rhamnosus GG, Bifidobacterium lactis Bb-12, Lactobacillus paracasei ST11, and Bifidobacterium longum BL999. The children involved have subsequently undergone prospective long-term follow-up. In addition to physical examination, data were collected by structured questionnaires on non-communicable diseases and continued probiotic use, and growth data from welfare clinics and school nurses. RESULTS: Altogether 303 mother-infant pairs were included in the analysis. Seventy-six of 163 (47%) children receiving perinatal probiotics had developed allergic disease compared with 79 of 140 (56%) receiving placebo (OR 0.67, 95% confidence intervals [CI] 0.43-1.06, p = 0.09). Fifty-nine of 133 (44%) children receiving L. rhamnosus GG perinatally had developed allergic disease, OR 0.62, 95% CI 0.38 0.99, p = 0.047, as compared to placebo. We found no differences in growth or non communicable disease prevalence between children receiving perinatally probiotics or placebo. CONCLUSIONS: Perinatal probiotic administration is safe in long-term follow-up. Children receiving L. rhamnosus GG perinatally tended to have decreased allergy prevalence. PMID- 27779811 TI - Biofilm formation and antimicrobial susceptibility of staphylococci and enterococci from osteomyelitis associated with percutaneous orthopaedic implants. AB - Staphylococci and enterococci account for most deep infections associated with bone-anchored percutaneous implants for amputation treatment. Implant-associated infections are difficult to treat; therefore, it is important to investigate if these infections have a biofilm origin and to determine the biofilm antimicrobial susceptibility to improve treatment strategies. The aims were: (i) to test a novel combination of the Calgary biofilm device and a custom-made susceptibility MIC plate (Sensititre(r) ), (ii) to determine the biofilm formation and antimicrobial resistance in clinical isolates causing implant-associated osteomyelitis, and (iii) to describe the associated clinical outcome. Enterococci and staphylococci were characterized by microtitre plate assay, Congo Red Agar plate test, and PCR. Biofilm susceptibility to 10 antimicrobials and its relationship to treatment outcomes were determined. The majority of the strains produced biofilm in vitro showing inter- and intraspecies differences. Biofilms showed a significantly increased antimicrobial resistance compared with their planktonic counterparts. Slime-producing strains tolerated significantly higher antimicrobial concentrations compared with non-producers. All seven staphylococcal strains carried ica genes, but two did not produce slime. The degree of biofilm formation and up-regulated antibiotic resistance may translate into a variable risk of treatment failure. This new method set-up allows for the reproducible determination of minimum biofilm eradication concentration of antimicrobial agents, which may guide future antimicrobial treatment decisions in orthopaedic implant-associated infection. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2630-2640, 2017. PMID- 27779810 TI - TRPA1 gene polymorphisms and childhood asthma. AB - BACKGROUND: Animal data have suggested that the transient receptor potential ankyrin-1 (TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes. METHODS: We analysed associations between 31 TRPA1 single nucleotide polymorphisms (SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure. RESULTS: In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 (OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 (OR 1.30 (1.09-1.55), p = 0.003), rs920829 (OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 (OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were. CONCLUSION: This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words). PMID- 27779813 TI - Polyurethane/polystyrene-silica electrospun nanofibrous composite for the headspace solid-phase microextraction of chlorophenols coupled with gas chromatography. AB - A novel electrospun composite nanofiber-based adsorbent (polyurethane/polystyrene silica) was fabricated, characterized, and used in the headspace solid-phase microextraction of the acetylated derivatives of chlorophenols in water samples before gas chromatography with micro electron capture detection. The surface morphology, chemical composition, thermal stability, and structure of the fibers were investigated by scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and Brunauer-Emmett-Teller and Barrett Joyner-Halenda techniques. The effect of the main parameters influencing the efficiency of the method including extraction temperature, salt concentration, and extraction time was investigated and the optimized conditions were obtained. The linear dynamic ranges were 0.1-800 ng/mL. The relative standard deviations (n = 3) and the limits of detection were 2.64-9.57% and 0.0234-0.830 ng/mL, respectively. The relative recoveries for real samples (river water and sewage of our university campus) were between 90.8 and 111%. PMID- 27779814 TI - Use and Evaluation of Postpartum Care Services in Rural Malawi. AB - PURPOSE: The purpose of this study was to examine women's evaluation of postpartum care services (postpartum clinical assessments, health education, and midwife kindness) received from midwives prior to discharge in rural health facilities, and to examine husband-and-wife-farmer dyads' reasons for their decisions to return or not return for 1-week postpartum care visits in rural central Malawi. DESIGN: Cross-sectional matched-pairs survey design. METHODS: Participants included a convenience sample of 70 husband-and-wife-farmer dyads living in rural communities who had a live birth in the past year at one of four health facilities in Ntcheu district, central Malawi. Data were collected using an interviewer-administered postpartum care questionnaire from the World Health Organization (WHO) Safe Motherhood Needs Assessment Questionnaires. Data analysis included univariate and multivariate statistics. FINDINGS: Women's evaluation of postpartum care assessments received from midwives in rural health facilities prior to discharge included partial assessments of blood pressure (44%), temperature (41%), abdominal examination (50%), vaginal examination/bleeding (46%), breast examination/soreness (34%), and baby examination (77%). Only 16% of the women received all six of these postpartum clinical assessments prior to discharge, while 11% received none. Women also reported that midwives did not: introduce themselves (50%); ask if patients had questions (44%); explain what they were doing (43%); or explain what to expect after delivery (50%). Despite this, 77% of women felt midwives paid close attention to them and 83% gave an overall positive evaluation (3.5-5 on a scale of 1-5). Numbers of postpartum clinical assessments (p = .09) and overall evaluation (p = .71) did not differ between the four health facilities. The top three reasons for husbands' and wives' decisions to return for 1-week postpartum care visits were: being advised to return for care, wanted the mother to be examined, and wanted the baby to be examined. Participants stated prior negative experiences, or not perceiving a need for care (feels fine), may potentially prevent them from returning for postpartum care visits in a health facility. CONCLUSIONS: Most women reported they received only partial postpartum clinical assessments; thus, it is important for health facilities to address the adequacy of postpartum clinical assessments provided to women by midwives before discharge. Women returned for 1-week postpartum care visits because they were advised to return for care, and also to make sure their babies were examined. However, the principal reason why husbands permitted their wives to return for postpartum care was because they wanted their wives to be examined. CLINICAL RELEVANCE: Midwives need to advise all patients to return for postpartum care visits consistent with WHO or country guidelines, and continue to educate husbands and wives regarding the importance of postpartum care even when the wife feels fine. Refresher in-service trainings on postpartum care are recommended for midwives to encourage them to perform the recommended postpartum clinical assessments. PMID- 27779812 TI - A Mussel-Inspired Conductive, Self-Adhesive, and Self-Healable Tough Hydrogel as Cell Stimulators and Implantable Bioelectronics. AB - A graphene oxide conductive hydrogel is reported that simultaneously possesses high toughness, self-healability, and self-adhesiveness. Inspired by the adhesion behaviors of mussels, our conductive hydrogel shows self-adhesiveness on various surfaces and soft tissues. The hydrogel can be used as self-adhesive bioelectronics, such as electrical stimulators to regulate cell activity and implantable electrodes for recording in vivo signals. PMID- 27779816 TI - Key Concepts in Pregnancy of Unknown Location: Identifying Ectopic Pregnancy and Providing Patient-Centered Care. AB - Pregnancy of unknown location (PUL) is a descriptive term for when a woman with a positive pregnancy test has a transvaginal ultrasound that cannot determine the site of the pregnancy. While the majority of women with PUL are subsequently diagnosed with a spontaneous abortion or viable intrauterine pregnancy, 7% to 20% of these women have an ectopic pregnancy. The potential for morbidity and mortality related to an ectopic pregnancy means that considerable care is necessary in the evaluation and management of women with PUL. In some cases, the location of the pregnancy is never determined and the PUL is categorized as resolving or persisting. Evidence suggests expectant management is a safe and effective approach for most women with PUL and should be the mainstay of care. However, in the case of persisting PUL, continued concern for ectopic pregnancy remains. Strategies for deciding when to intervene when a woman has a PUL are reviewed. A variety of clinical tools, including serum beta human chorionic gonadotropin (beta-hCG), repeat ultrasonography, dilation and curettage (D&C), and empiric methotrexate therapy are discussed. Finally, a proposal is made that women with persisting PUL can be presented with the option of choosing expectant management, diagnostic D&C, or empiric methotrexate treatment. PMID- 27779815 TI - Synthesis and biological evaluation of 1, 2, 4-oxadiazole derivatives as novel GPR119 agonists. AB - A series of 1, 2, 4-oxadiazole derivatives have been designed and synthesized, and 25 compounds were evaluated their abilities by the assay of cAMP concentration in GPR119-transfected HEK293T cells. All compounds showed acceptable agonistic effects on GPR119. Among these compounds, 4p exhibited the best agonistic effects with the EC50 of 20.6 nm, which was comparable to that of positive control GPR119 agonist GSK1292263. The agonistic activity of these 1,2,4 oxadiazole derivatives led to the establishment of a structure-activity relationship. PMID- 27779817 TI - How Effective is Cultural Competence Training of Healthcare Providers on Improving Patient Satisfaction of Minority Groups? A Systematic Review of Literature. AB - BACKGROUND: With the rapid growth of minority populations in the United States, the need to train healthcare providers to give culturally competent care has never been greater. Extensive research on cultural competence of healthcare providers has been conducted, but no systematic review specifically focused on the effect of cultural competence training on patient satisfaction of clients from minority groups. AIMS: To search and critically appraise published research articles that evaluated the effectiveness of cultural competence training of healthcare providers on improving patient satisfaction of clients from minority groups. METHODS: Using MeSH entry terms: Competency, Cultural; Cultural Competencies; Cultural Competence; Competence, Cultural; Satisfaction, Patient; and non-MeSh text words: Cultural Awareness, Cultural Sensitivity, Cultural Competence Training, Cultural Sensitivity Training, and Cultural Awareness Training, a comprehensive literature search of peer-reviewed articles from 2002 to 2014 in CINAHL, Cochrane, PsycINFO, PubMed, and Web of Science databases was conducted. Original studies that reported cultural competence training and measured its impact on patient satisfaction were included. Quality of the reviewed studies was assessed on the basis of methodological limitations related to experimental design, sample size and sampling approaches, and ethnic spread of the participants. RESULTS: Seven studies met the inclusion criteria. Six studies revealed that cultural competence training intervention significantly increased the cultural competence level of healthcare providers. Five studies demonstrated that cultural competence training of healthcare providers was significantly associated with increased patient satisfaction. LINKING EVIDENCE TO ACTION: Cultural competence training is an effective intervention that enables healthcare providers to give culturally competent care that increases satisfaction of patients from minority groups. However, more research with better research designs, large sample sizes, and validated standardized cultural competence and patient satisfaction assessment tools is needed to unequivocally attribute cultural competence training to patient satisfaction. PMID- 27779818 TI - Positive cooperative regulation of double binding sites for human acetylcholinesterase. AB - Acetylcholinesterase is a potent enzyme that regulates neurotransmission by rapidly hydrolyzing the neurotransmitter acetylcholine in synapses of the nervous system. As drug target of anti-AD, it has catalytic and peripheral anionic sites. However, the regulation relation between these two sites is unclear. Therefore, we constructed dynamics fluctuation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in double-site system (hAChE/TZ5) is distinctly different from that in the free state and single-site systems (hAChE/huprine and hAChE/1YL). The community network analysis indicates that the information freely transfers from the peripheral anionic site to the catalytic active site in hAChE/TZ5. Furthermore, the binding free energy between the inhibitor and hAChE for hAChE/TZ5 is significantly lower than of either hAChE/huprine or hAChE/1YL. Thus, a hypothesis of 'positive cooperative regulation' is proposed for the regulation of double binding sites and further confirmed by the weakening and mutation community analyses. Finally, one possible cooperative regulation pathway of W86-TZ5-W286 was identified based on the shortest path algorithm and was confirmed by the network perturbation analysis. Interestingly, the regulation pathway for single-site systems is significantly different from that of dual-site system. The process targeting on the shortest pathway can better regulate the hydrolyzing the neurotransmitter acetylcholine and significantly inhibit the aggregation of Abeta amyloid. PMID- 27779819 TI - The role and value of ultrasound elastography in the evaluation of thyroid nodules. PMID- 27779820 TI - Provider Perspectives on Safety in Primary Care in Albania. AB - PURPOSE: The purpose of this study was to determine the safety attitudes of specialist physicians (SPs), general physicians (GPs), and nurses in primary care in Albania. DESIGN: The study was cross-sectional. It involved the SPs, GPs, and nurses from five districts in Albania. A demographic questionnaire and the adapted Safety Attitudes Questionnaire (SAQ)-Long Ambulatory Version A was used to gather critical information regarding the participant's profile, perception of management, working conditions, job satisfaction, stress recognition, safety climate, and perceived teamwork. METHODS: The onsite data collectors distributed questionnaires at the primary care clinics and then collected them. Descriptive statistics were used to summarize the responses. The significance of mean difference among SPs, GPs, and nurses was tested using analysis of variance. FINDINGS: Five hundred twenty-three questionnaires were completed. The concept of patient safety in relation to job satisfaction received the highest ratings. Stress recognition had low ratings. There was a high level of teamwork in SPs, GPs, and nurses. Healthcare staff agreed that it was difficult to discuss errors in their primary healthcare center. Physicians in contrast to nurses were most likely to affirm that they do not make errors in hostile situations. CONCLUSIONS: Errors are difficult to discuss. It was clear that primary care staff, such as physicians, never considered the likelihood of errors occurring during tense situations. CLINICAL RELEVANCE: Staff at primary healthcare centers are used to adverse events and errors. Despite the demand for safety improvement and the existing evidence on the epidemiology of outpatient medical errors, most research has only been conducted in hospital settings. Many patients are put at risk and some are harmed as a result of adverse events in primary care. Adequate communication and technical skills should be utilized by primary care providers (PCPs) for improvement of patient safety. The patient safety measures should include assessment of the safety attitudes of PCPs. PMID- 27779821 TI - Aortic thrombosis in dogs. AB - OBJECTIVE: To review information regarding etiology, pathophysiology, and treatment options for aortic thrombotic disease in dogs. ETIOLOGY: Diseases resulting in hypercoagulable states can cause thrombus formation in the distal aorta, and account for the majority of cases of aortic thrombosis (ATh) in dogs, although a substantial number of cases have no identifiable underlying cause. Aortic thromboembolism (ATE) also occurs but appears to be much less frequently documented. DIAGNOSIS: The presentation of ATh and ATE in dogs is more varied compared to cats. Diagnosis can be challenging due to nonspecific clinical signs. Definitive diagnosis involves direct visualization of the thrombus, which is often obtained via ultrasound; however, other imaging modalities such as computed tomography scans can be utilized. THERAPY: The optimal treatment for aortic thrombotic disease in dogs has yet to be determined. Although not always possible, treatment of concurrent diseases that may promote thrombosis is an important aspect of thrombus resolution. A recent retrospective study reported positive results with long-term warfarin therapy; however, other studies have not reported similar results. Unfractionated or low-molecular weight heparins are additional anticoagulants that have been utilized. Platelet inhibitor therapy should also be considered in combination with anticoagulant therapy. PROGNOSIS: Survival for dogs with ATh or ATE is reported to be between 50% and 60%. Dogs that present with chronic clinical signs appear to have a better prognosis than those who are acutely affected or those who are severely affected. PMID- 27779822 TI - Frailty Is a Major Related Factor for at Risk of Malnutrition in Community Dwelling Older Adults. AB - PURPOSE: We investigated the relationships among geriatric syndrome, physiological functions, and body composition in community-dwelling older people with varying nutritional statuses. Other factors correlated with nutritional status in community-dwelling older people were also explored. BACKGROUND: The World Health Organization has initiated preventive programs for addressing malnutrition. However, few studies have focused on the correlations among geriatric syndrome, physiological functions, and body composition in older people at risk of malnutrition. DESIGN: We conducted a cross-sectional study. METHODS: Older people who lived in an urban Taiwanese community were recruited for this research study. The inclusion criteria were age 65 years or older, ability to communicate in Taiwanese, clear consciousness, and ability to communicate independently. The nutritional status of participants was evaluated with the Mini Nutritional Assessment-Short Form. The frailty status was assessed with the Study of Osteoporotic Fractures (SOF) index. The SOF index included the following three items: body weight loss of >5% within 1 year, difficulty in standing from a sitting position in a chair without an armrest five times, and feeling deprived of energy. Participants over 65 years of age, living in a community and without mental illness or acute disease were included in the study. FINDINGS: Compared with well-nourished older adults, those at risk of malnutrition were predominantly male; presented with lower body weight, lower body mass index values, lower skeletal mass indices, and poorer muscle strength; and were unable to rise from a seated position in a chair without using the armrest five times. Subjects at risk of malnutrition were less energetic, were more commonly characterized as being sarcopenia, and demonstrated frailty. Body composition analysis demonstrated that a skeletal muscle index of approximately 9.93 and a body fat mass of less than 12.25 kg were related to an increased risk of malnutrition. Older people who were frail exhibited a particularly high risk of malnutrition. CONCLUSIONS: The results revealed that the evaluation of malnutrition risk should be conducted in older persons living in the community. Frailty in particular was identified as a major risk factor for malnutrition in community-dwelling elderly persons. CLINICAL RELEVANCE: Community nurses should pay attention to the nutritional conditions of community-dwelling elderly persons. Community nurses should assess the at-risk population and provide effective preventive strategies and programs to reduce the prevalence of malnutrition and frailty. PMID- 27779823 TI - Portopulmonary hypertension and liver transplantation: A duo in question. PMID- 27779824 TI - 5-Amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives with in vitro immunomodulatory activities. AB - Isoxazoles are an important class of compounds of potential therapeutic value. The aim of this study was to determine immunotropic effects of 5-amino-3-methyl-4 isoxazolecarboxylic acid hydrazide derivatives on spontaneous and mitogen-induced lymphocyte proliferation in young and old mice, cytokine production by peritoneal cells as well as possible mechanism of action in a model of Jurkat cells. Three month-old and 13-month-old BALB/c mice were used as donors of the cells from a thymus, a spleen, mesenteric lymph nodes, and a peritoneal cavity. Spontaneous and concanavalin A or lipopolysaccharide (LPS)-induced cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric method. IL-1beta and TNF-alpha production induced by LPS in macrophage-enriched peritoneal cell cultures was measured by enzyme-linked immunoassay. 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide, 01K (4-phenyl 1-(5-amino-3-methylisoxazole-4-carbonyl)-thiosemicarbazide), and 06K (4-(4 chlorophenyl)-1-(5-amino-3-methylisoxazole-4-carbonyl)-thiosemicarbazide) exhibited regulatory activity in the proliferation tests. Prevailing stimulatory activity of the hydrazide and inhibitory activity of 01K and 06K was observed. Those effects were connected with different influence of the compounds on signaling proteins expression in Jurkat cells. The regulatory effects of the compounds on IL-1beta production were more profound than those on TNF-alpha. Differences in the compound activity in young versus old mice were mainly restricted to 01K. Immunosuppressive isoxazole leflunomide and a stimulatory RM 11 (1,7-dimethyl-8-oxo-1,2H-isoxazole [5,4-e]triazepine) were applied as reference drugs. PMID- 27779825 TI - A Racial Equity Toolkit for Midwifery Organizations. AB - Midwifery associations are increasing awareness and commitment to racial equity in the profession and in the communities we serve. Moving these commitments from words into action may be facilitated by a racial equity toolkit to help guide midwifery organizations to consider all policies, initiatives, and actions with a racial equity lens. Racial equity impact analyses have been used in recent years by various governmental agencies in the United States and abroad with positive results, and emerging literature indicates that nonprofit organizations are having similarly positive results. This article proposes a framework for midwifery organizations to incorporate a racial equity toolkit, starting with explicit intentions of the organization with regard to racial equity in the profession. Indicators of success are elucidated as the next step, followed by the use of a racial equity impact analysis worksheet. This worksheet is applied by teams or committees when considering new policies or initiatives to examine those actions through a racial equity lens. An organizational change team and equity advisory groups are essential in assisting organizational leadership to forecast potential negative and positive impacts. Examples of the components of a midwifery-specific racial equity toolkit are included. PMID- 27779826 TI - Mystacial Whisker Layout and Musculature in the Guinea Pig (Cavia porcellus): A Social, Diurnal Mammal. AB - All mammals (apart from apes and humans) have whiskers that make use of a similar muscle arrangement. Whisker specialists, such as rats and mice, tend to be nocturnal and arboreal, relying on their whisker sense of touch to guide exploration around tree canopies at night. As such, nocturnal arboreal rodents have many whiskers that are organised into a grid-like pattern, and moved using a complex array of muscles. Indeed, most arboreal, nocturnal mammals tend to have specialised whiskers that are longer and arranged in a dense, regular grid, compared with terrestrial, diurnal mammals. The guinea pig diverged early from murid rodents (around 75 million years ago), and are ground-dwelling, diurnal animals. It would be predicted that, as a terrestrial mammal, they may have less whiskers and a reduced muscle architecture compared to arboreal, nocturnal rodents. We examined the mystacial whisker layout, musculature and movement capacity of Guinea pig (Cavia porcellus) whiskers and found that they did indeed have a disorganized whisker layout, with a fortification around the eye area. In addition, there was a reduction in musculature, especially in the intrinsic muscles. Despite guinea pigs not cyclically moving their whiskers, the mystacial musculature was still very similar to that of murid rodents. We suggest that the conserved presence of whisker layout and musculature, even in visual mammals such as primates and guinea pigs, may indicate that whiskers still play an important role in these animals, including protecting the eyes and being involved in tactile social behaviors. Anat Rec, 300:527-536, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27779827 TI - A Mixed-Methods Study of Vicarious Posttraumatic Growth In Certified Nurse Midwives. AB - INTRODUCTION: The purpose of this mixed-methods study was to investigate vicarious posttraumatic growth in certified nurse-midwives (CNMs) who have struggled after attending traumatic births. Vicarious posttraumatic growth involves positive changes in a clinician's life due to caring for patients who are traumatized. METHODS: A convergent parallel mixed-methods design was used. The American College of Nurse-Midwives (ACNM) sent out e-mails to all CNM members with a link to the electronic survey. CNMs completed the Posttraumatic Growth Inventory and the Core Beliefs Inventory in the quantitative portion. For the qualitative portion CNMs responded to a statement asking them to describe their experiences of any positive changes in their beliefs or life after attending traumatic births. IBM SPSS 23.0 and Krippendorff's content analysis were used to analyze the quantitative and qualitative data, respectively. RESULTS: The sample consisted of 425 CNMs who completed the quantitative portion and 315 (74%) who completed the qualitative portion. CNMs reported a small degree of both disruption of their core beliefs and vicarious posttraumatic growth. Personal Strength was the dimension of the Posttraumatic Growth Inventory that reflected the highest growth, followed by Appreciation of Life, Relating to Others, Spiritual Change, and New Possibilities. In the qualitative findings, Personal Strength was also the category of vicarious posttraumatic growth most frequently described. DISCUSSION: This study confirmed a positive relationship between the degree that a CNM's core beliefs are challenged and the amount of vicarious posttraumatic growth that is experienced. The qualitative comments of the CNMs matched the quantitative scores of the Posttraumatic Growth Inventory. PMID- 27779828 TI - Alternative approaches to vertebrate ecotoxicity tests in the 21st century: A review of developments over the last 2 decades and current status. AB - The need for alternative approaches to the use of vertebrate animals for hazard assessment of chemicals and pollutants has become of increasing importance. It is now the first consideration when initiating a vertebrate ecotoxicity test, to ensure that unnecessary use of vertebrate organisms is minimized wherever possible. For some regulatory purposes, the use of vertebrate organisms for environmental risk assessments has been banned; in other situations, the number of organisms tested has been dramatically reduced or the severity of the procedure refined. However, there is still a long way to go to achieve a complete replacement of vertebrate organisms to generate environmental hazard data. The development of animal alternatives is based not just on ethical considerations but also on reducing the cost of performing vertebrate ecotoxicity tests and in some cases on providing better information aimed at improving environmental risk assessments. The present Focus article provides an overview of the considerable advances that have been made toward alternative approaches for ecotoxicity assessments over the last few decades. Environ Toxicol Chem 2016;35:2637-2646. (c) 2016 SETAC. PMID- 27779830 TI - Construction and histological analysis of a 3D human arterial wall model containing vasa vasorum using a layer-by-layer technique. AB - There is considerable global demand for three-dimensional (3D) functional tissues which mimic our native organs and tissues for use as in vitro drug screening systems and in regenerative medicine. In particular, there has been an increasing number of patients who suffer from arterial diseases such as arteriosclerosis. As such, in vitro 3D arterial wall models that can evaluate the effects of novel medicines and a novel artificial graft for the treatment are required. In our previous study, we reported the rapid construction of 3D tissues by employing a layer-by-layer (LbL) technique and revealed their potential applications in the pharmaceutical fields and tissue engineering. In this study, we successfully constructed a 3D arterial wall model containing vasa vasorum by employing a LbL technique for the first time. The cells were coated with extracellular matrix nanofilms and seeded into a culture insert using a cell accumulation method. This model had a three-layered hierarchical structure: a fibroblast layer, a smooth muscle layer, and an endothelial layer, which resembled the native arterial wall. Our method could introduce vasa vasorum into a fibroblast layer in vitro and the 3D arterial wall model showed barrier function which was evaluated by immunostaining and transendothelial electrical resistance measurement. Furthermore, electron microscopy observations revealed that the vasa vasorum was composed of single-layered endothelial cells, and the endothelial tubes were surrounded by the basal lamina, which are known to promote maturation and stabilization in native blood capillaries. These models should be useful for tissue engineering, regenerative medicine, and pharmaceutical applications. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 814-823, 2017. PMID- 27779831 TI - Infectious diseases in Poland in 2014 AB - PURPOSE of the STUDY: The aim of the study is to assess epidemiological situation of infectious and parasitic diseases in Poland in 2014, and an indication of the potential health risks from communicable diseases occurring in other areas of the globe. MATERIAL AND METHODS: This paper is a summary of the analysis and evaluation of the results of epidemiological surveillance of infectious diseases in Poland in 2014, and those elements of European and global epidemiological background, which in this period had an impact on the epidemiological situation in Poland or constituted a threat. The main source of data for this study are statistical reports included in annual bulletins "Infectious diseases and poisoning in Poland in 2014" and "Immunizations in Poland in 2014" (NIPH-PZH, GIS, Warsaw 2015) and the data contained in the articles of "Epidemiological chronicle" presented in the Data on deaths are based on the statement of the Department for Demographic Research and Labour Market CSO presenting numbers of deaths from infectious and parasitic diseases registered in Poland in 2014, and in the previous years. RESULTS: Upper respiratory tract infection classified as "suspected flu and the flu season" in the since many years are the largest position among the diseases subject to disease surveillance. In the last decade, particularly large increase in the incidence of upper respiratory tract infection was reported in the flu season 2013., when the increase in comparison to the median of years 2008-2012 amounted to 189.8%. In 2014. Number of reported cases was 3 137 056 which represented a nonsignificant decrease of 0.8% compared with the previous year. However, compared to the median of the years 2008-2012 it was an increase of 187.4%. Better then based on calendar year is a picture obtained by examining the incidence of seasonal periods in the annual, but counted from 1 September to 31 August of the following year. In such a setup, in the 2012/2013 season were recorded 3 025 258 of cases, and in the season 2013/2014 recorded number was 2 780 945. In such a way in the 2013/2014 season decrease in the number of cases as compared to the season 2012/2013 was 8%. Another group of infections with a high incidence are intestinal ones. In 2014. Incidence of intestinal infections with Salmonella etiology increased in comparison with the previous year by 10.8%, but in relation to the median of 2008-2012 was lower by 7.3%. Incidence of an important group of intestinal infections, which are diarrhea cases in children under 2 years, increased in 2014. in the category of infections of viral etiology and a decreased among bacterial ones. In 2014. upward trend of intestinal infections caused by viruses persited. Among these infections dominated rotavirus infections in children. Number of reported foodborne infections of viral etiology was 51 561 (134.0/100 000). Most of them were caused by rotavirus: 33 789 (87.8/100 000). Number of cases of whooping cough reported in 2014 was 2 101 (5.5/100 000), it was a decrease of incidence as compared with the previous year by 3.7%. After the epidemic increase in cases of rubella in 2013. there has been a decline in the incidence of the disease by 84.7%. No single case of congenital rubella was reported. In 2014. it were reported 110 cases of measles (0.29 / 100 000). In 2014. Number of cases of invasive diseases caused by H. influenzae was 41, incidence: (0.11 / 100 000). This was an increase of 64.1%, as compared with the previous year. Among them, the number of sepsis cases increased by 150% from 10 to 25. None of these cases was fatal. The number of invasive diseases caused by Streptococcus pneumoniae in 2014. amounted to 704. In comparison with 2013. This was an increase of 30.4%, but as compared with the median of the 2008-2012 period it was 91.9%. Among the cases of invasive S. pneumoniae infections 59 were fatal. The downward trend in the incidence of tuberculosis in total (all forms of TB) is clearly sustainable. In 2014. Incidence of this disease has decreased in comparison with the previous year from 18.8 / 100 000 to 17.4 and pulmonary tuberculosis from 17.8 to 16.4 / 100 000. In 2014. There were reported 1 157 cases of newly diagnosed HIV infections (3.01 / 100 000). And it was not a significant increase in the incidence of 4.5%, as compared with the previous year. The number of reported new AIDS cases decreased by 8.6%. In recent decades, there were no indiginus cases of malaria in Poland. Registered cases of malaria apply to persons who acquired it abroad in endemic areas. 19 such cases were reported in 2014. In 2014. there were no cases of diphtheria, poliomyelitis, rabies and viral haemorrhagic fevers with exception of dengue, of which 15 cases acquired in endemic areas were reported. Total number of deaths due to infectious and parasitic diseases in 2014 in Poland. was 2 169. The share of deaths from these causes in reference to the total number of deaths was 0.58%, and mortality due to infectious diseases was 5.6 per 100 000. Most deaths (24.6%) were caused by tuberculosis and its consequences. PMID- 27779833 TI - Chickenpox in Poland in 2014 AB - BACKGROUND: A large number of chickenpox cases, occurring especially in children between 0-14 years old and among those who are not vaccinated, indicates the rationale for the use of chickenpox vaccinations. In Poland since 2002, chickenpox vaccination is included in the National Immunisation Programme as recommended. AIM. To assess epidemiological situation of chickenpox in Poland in 2014 in comparison to previous years. AIM: To assess epidemiological situation of chickenpox in Poland in 2014 in comparison to previous years. METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletins "Infectious diseases and poisonings in Poland in 2014" and "Vaccinations in Poland in 2014" (1;2). National Immunisation Programme for year 2014 was also used (3). RESULTS: In 2014, 221 628 cases of chickenpox were registered in Poland. The incidence was 575.9 and was lower than in 2013 (463.6). The highest number of cases was reported in mazowieckie voivodeship (35 321), the lowest in podlaskie voivodeship (5 346). The highest incidence was recorded in children aged 4 years. The chickenpox incidence among men was higher by 12.4% comparing to women (543.4). The incidence among rural residents (595.0) was higher by 9.8 % than among urban residents. Number of cases hospitalized due to mumps was 1 467. Number of people vaccinated against chickenpox was 63 608. SUMMARY: In 2014, there was increase in the incidence of chickenpox in Poland. Since 2002 the number of people vaccinated against chickenpox increased. The increase in the number of people vaccinated against chickenpox would help maintain the downward trend in subsequent years. PMID- 27779832 TI - Mumps in Poland in 2014 AB - BACKGROUND: Vaccination against mumps from 2003 is mandatory in Poland and given as two dose scheme with MMR vaccine (mumps, measles, and rubella). Earlier this vaccination was only recommended. Despite observed decline in mumps incidence for over a decade which is a result of conducted vaccinations, mumps is still a common disease among the children. AIM: To assess epidemiological situation of mumps in Poland in 2014, including vaccination coverage in Polish population, in comparison to previous years. METHODS: The descriptive analysis was based on data retrieved from routine mandatory surveillance system and published in the annual bulletins "Infectious diseases and poisonings in Poland in 2014" and "Vaccinations in Poland in 2014" (1). Mumps cases were classified according to the criteria of surveillance case definition implemented in the European Union (Commission Decision of 28 April 2008 amending Decision 2002/253/EC). National Immunisation Programme for year 2014 was also used. RESULTS: In total, there were 2 508 mumps cases registered in Poland in 2014. Incidence of mumps was 6.5 per 100,000 and it was higher by 3.1 % in comparison with 2013 and lower by 9.7 % in comparison with median for the years 2008-2012. The highest incidence rate was observed among children aged 4 years (61.3 per 100,000). Incidence in men (7.8 per 100,000) was higher than in women (5.3). In 2014, 31 people were hospitalized due to mumps. Vaccination coverage of children aged 3 years in Poland in 2013 was 97.0% and it was lower by 0.5 % in comparison with year 2013 (97.5 %). CONCLUSIONS: Systematic execution of mumps vaccination in accordance with the National Immunisation Programme resulted in a significant decrease in the number of registered cases. Due to the high vaccination coverage further decline in the number of cases is expected. PMID- 27779834 TI - Scarlet fever in Poland in 2014 AB - OBJECTIVE: Assessment of the epidemiological situation of scarlet fever in Poland in 2014. MATERIALS AND METHODS: The evaluation was performed by reviewing surveillance data published in the bulletin "Infectious diseases and poisonings in Poland in 2014" as well as in previous bulletins, and unpublished data collected under Statistical survey program of official statistics. These data relate to cases of scarlet fever registered by health sanitary inspection on the basis of statutory notification of scarlet fever reported by physicians. RESULTS: In 2014, annual, incidence rate of scarlet fever in Poland was about 9% lower in comparison to previous year. There were 22 855 cases all over the country and the incidence was 59.5 per 100,000 population; depending on the voivodeship ranged from 19.5 in podkarpackie to 93.2 in pomorskie. The highest incidence was noted among 4-year-old children (981.4) and 5-year-old children (971.0). However the incidence among children and young people up to 15 years accounted for 95.7% of all cases. The incidence among men (67.2) was higher by 28.5% than incidence among women (52.3). Incidence rate in urban areas, in any size town, was higher than in rural areas. Overall incidence in urban areas was 66.4; in rural areas - 49.0. 1,11% of patients were hospitalized. There were no reported deaths related to scarlet fever. SUMMARY: In the surveillance of scarlet fever it is necessary to ensure that the collected data will be valid and reliable. Very low specificity of this surveillance may not only impinge on the assessment of epidemiological situation of this disease in Poland but also overshadow the situation of other diseases, including diseases under elimination program (rubella, measles). This is one of the greatest challenges facing sanitary inspection in the coming years. PMID- 27779835 TI - Legionellosis in Poland in 2014 AB - OBJECTIVE: The aim of the study was to assess the epidemiological situation of legionellosis in Poland in 2014. MATERIAL AND METHODS: We reviewed data published in the annual bulletin: "Infectious diseases and poisonings in Poland in 2014" and its prior versions along with the legionellosis case reports sent to the Department of Epidemiology of NIPH - NIH. RESULTS: In Poland, both two forms of legionellosis - Legionnaires' disease (a severe form of disease accompanied by pneumonia) and Pontiac fever (mild, influenza-like form of infection) - are routinely reported to the surveillance. In 2014, a total of 14 cases were reported (12 cases of Legionnaires' disease and 2 cases of Pontiac fever); the incidence (0.036 per 100,000 population) was comparable to previous year as well as the median (incidence) for 2008-2012. The infections were reported in eight provinces, including five, which in previous years usually did not register any cases. The incidence in males (0.04 per 100,000) was slightly higher compared to females (0.03). Death rate of females was unusually high = 75%. No outbreaks or clusters were reported - only sporadic cases. All patients required hospitalization, including cases of Pontiac fever. The Sanitary Inspection reported three fatal cases - all women 49- 60 years/old. Twelve cases were likely acquired in the country, including two probably in hospital and three linked with inhalation of aerosols during professional activity. Two cases were associated with travels abroad (one to Italy and one to Germany). SUMMARY AND CONCLUSIONS: In 2014 diagnosis of legionellosis cases was confirmed by rapid chromatographic test detecting legionella antigen in urine. The examinations were performed even in small town hospitals, so infections were detected and reported in provinces which usually did not register any cases. This study suggests, that legionellosis is likely under recognized and under diagnosed in all provinces of the country. Presumably physicians often do not suspect or not confirm the clinical diagnosis of Legionnaires' disease in cases with atypical pneumonia. PMID- 27779836 TI - Campylobacteriosis in Poland in 2013 and 2014 AB - THE PURPOSE OF THE STUDY: Evaluation of the epidemiological situation of campylobacteriosis in Poland in 2013 and 2014 in comparison with the situation in the previous years. MATERIAL AND METHODS: The evaluation of the epidemiological situation was carried out on the basis of the analysis of the data contained in the annual bulletins "Infectious diseases and poisonings in Poland" for the years 2012- 2014, extended by the information from the individual questionnaires of diseases and forms of the epidemiological investigations of outbreaks of campylobacteriosis, sent by the sanitary-epidemiological stations to the Department of Epidemiology and also on data from the Department of Demographic Studies of the Central Statistical Office. RESULTS: In 2013 in Poland it was registered 552 cases of campylobacteriosis, while in 2014 the number of registered cases was 652. It is respectively by almost 30% and 50% more than in 2012. The overall incidence for 2013 was 1.43 and for 2014 it was 1.69 per 100 000. In 2013 all reported cases were classified as confirmed, whereas in 2014 - number of confirmed cases was 650, and two as probable. Both in 2013 and in 2014 incidence much higher than the total for the in three provinces: Slaskie (respectively 3.89 and 4.7/ 100 000), Warminsko- Mazurskie (4.42 and 3.53/ 100 000) and Lubuskie (3.03 and 4.51/100000) incidence was both in 2013 and 2014 Markedly higher then for the country as a whole. The percentage of hospitalization was higher than in previous years and amounted in 2013 to 71.4% and in 2014 to 74.4%. In 2013 Campylobacter species was identified in more than 83% of patients and in almost 87% in 2014. In 2013 over 77% and in 2014 as much as 82% of cases were caused by C. jejuni, and correspondingly more than 6% and almos 5% by C.coli. As in previous years, the majority of cases, in 2013 - 435 (79%) and in 2014 - 491 (75%) occurred in the age group 0-4. In 2013 therte were recorded two, and 2014 - 7 outbreaks caused by Campylobacter jejuni. CONCLUSIONS: In Poland, despite the gradual improvement in sencitivity of surveillance, campylobacteriosis it is still a disease very rarely diagnosed and reported. Diagnosis of infection with Campylobacter sp. perform laboratories in limited number of counties, which is not sufficient for proper evaluation of the epidemiological situation of the disease in Poland as a whole. PMID- 27779837 TI - Foodborne botulism in Poland in 2014 AB - OBJECTIVES: The aim of the study is to assess the epidemiology of foodborne botulism in Poland in 2014 compared to previous years. MATERIALS AND METHODS: We reviewed (1) surveillance data published in the annual bulletin "Infectious diseases and poisonings in Poland in 2014" and in previous publications, and (2) unpublished data retrieved from botulism case reports for 2014 sent to the Department of Epidemiology NIPH-NIH by Sanitary-Epidemiological Stations. RESULTS: In 2014, a total of 29 foodborne botulism cases (including 17 laboratory confirmed) was reported; the annual incidence rate (0.08 per 100,000 population) increased slightly in comparison to previous year, but was similar to the median incidence for years 2008 to 2012. The highest incidence in the country was reported in Lubelskie province (0.33). Incidence in rural areas (0.09) was only slightly higher than the incidence in urban areas (0.06). Men, had more than 4 times higher incidence than women; the highest incidence rate (0.31) was observed among men in the age group of 20-24 years. Most cases were associated with consumption of different types of commercially canned meat. Home-made vegetable meat preserves were also a common vehicle. All cases were hospitalized. Two deaths related to the disease were reported. CONCLUSIONS: Since 2008, the epidemiological situation of foodborne botulism in the country remains stable with an average 30 cases per year and corresponding incidence rate of 0.08 per 100,000 population. However, in 2014 draws attention a significant number of cases with undetermined food vehicle and relatively high percentage of cases with no laboratory confirmation. Therefore, it is important to enhance epidemiological investigation as well as laboratory capacity for surveillance. PMID- 27779838 TI - Hepatitis A in Poland in 2014 AB - AIM: The aim of this article is to assess the epidemiological situation of hepatitis A in Poland in 2014 with the regard to the recent years. MATERIALS AND METHODS: The assessment was conducted based on the results of the analysis of data from the bulletins "Infectious diseases and poisonings in Poland in 2014" and "Vaccinations in Poland in 2014", as well as information from the individual cases questionnaires and reports of epidemiological investigations in outbreaks of hepatitis A, submitted by the sanitary-epidemiological stations to the Department of Epidemiology in NIPH-NIH. RESULTS: In 2014 in Poland there were 76 cases of hepatitis A registered. Incidence per 100 000 inhabitants was 0.20, and in different voivodeships varied from 0.07 (in Dolnoslaskie voivodeship) to 0.30 (in Malopolskie voivodeship). The incidence among male and female did not differ (and was 0.20/ 100 000). CONCLUSIONS: In 2014 despite the increase in the number of cases (comparing it to the previous year) no significant change in epidemiological situation of hepatitis A was observed. Poland is still regarded as a country of low endemicity of hepatitis A. In routine surveillance system there is no information concerning the professional affiliation of persons being vaccinated, whereas the vaccinations themselves are recommended in the Polish vaccination schedule. Particular attention should be directed towards the vaccinations of persons who take part in berries primal production, product of which Poland is a major exporter of in the EU. In the light of increasing number of international hepatitis A outbreaks (which could be characterized by the prolonged duration, as well as the high possibility of secondary cases appearing- especially in countries of low endemicity) the maintenance of high level routine surveillance in Poland gains importance. The latter could also contribute to the efficiency of epidemiological investigations in multistate outbreaks. PMID- 27779839 TI - Hepatitis B in Poland in 2014 AB - OBJECTIVE: The aim of the study was to assess the epidemiological situation of hepatitis B in Poland in 2014 in comparison with the previous years. MATERIAL AND METHODS: The evaluation of the epidemiological situation was carried out on a basis of analysis of data from case-based reports on acute hepatitis B registered by sanitary and epidemiological stations, aggregate data derived from annual bulletins "Infectious diseases and poisonings in Poland", data from annual bulletin "Vaccinations in Poland" and data on locally registered HBsAg carriers. RESULTS: In 2014, a total of 2,763 cases of hepatitis B were registered, including 36 cases of HBV and HCV co-infections. Acute cases accounted for 2.5% of all HBV cases, the incidence was 0.18 per 100,000 and was slightly lower than in 2013. In the age group of children up to 14 years which were subject to universal vaccination as neonates, acute infections were not identified, in the age group 15-19 years vaccinated at the age of 14 one acute hepatitis B case was reported . Probably, 75% of acute hepatitis B cases occurred in connection with medical procedures carried out in health care facilities.The incidence of chronic and unknown stage of hepatitis B was 7.0 per 100,000 population and was higher by 85% compared to the previous year. The change in the incidence of chronic and UNK hepatitis B observed is related to the modification of case definition for hep B used in the surveillance in 2014 and changes in the regulations on reporting entities. Chronic and UNK cases were noted 1.4-fold more frequently in men than in women and were 1.5-fold more common among urban than rural dwellers. Great differences in incidence maintain between voivodeships, the highest incidence of chronic hepatitis B was recorded in slaskie voivodeship - 14.5 per 100,000 population.In 2014, 7 people died due to acute hepatitis B, and 44 due to chronic hepatitis B. CONCLUSIONS: Legislation changes in the epidemiological surveillance implemented in 2014 allowed for a more complete assessment of the epidemiological situation of chronic hepatitis B and revealed underestimation of assessments for the previous years. The continuing downward trend in the incidence of acute hepatitis B indicates the effectiveness of universal vaccination of newborns which is effective for 18 years and the sustainability of improvement in sanitary condition and compliance with safety precautions by medical personnel. In a situation when the majority of new infections still occur probably during medical procedures, it is recommended to execute vaccinations in all persons previously unvaccinated, especially those chronically ill and prior to planned surgeries. PMID- 27779840 TI - Tetanus in Poland in 2014 AB - : For many years the number of tetanus cases reported in Poland remaing below fifty with marked randomvariations. Almost all disease occur in people unvaccinated. Some of them, especially in people over age 60, arefatal. THE AIM OF THE STUDY: The aim of the study is to present the data of epidemiological surveillance of tetanus in Poland in 2014. MATERIAL AND METHODS: Analyzed material are the individual reports of cases of tetanus sent to the Department of Epidemiology at NIPH-PZH and bulletin data "Infectious diseases and poisoning in Poland in 2014". RESULTS: In 201 number of tetanus cases recorded in Poland was 13. It amounted to six men and seven women. Among those 9 was over 59 years of age. Out of them 4 people died. All were women over 69 years of age. SUMMARY AND CONCLUSIONS: Tetanus is an infectious disease acquired in the environment and associated with the contamination of wounds. Infections and deaths could be prevented by vaccination. Particular risk life and health carries illness after 60 years of age. PMID- 27779841 TI - Reinvestigation of the Absolute Configurations of Chiral beta-Mercaptoalkanones Using Vibrational Circular Dichroism and 1H NMR Analysis. AB - The absolute configurations of chiral beta-mercaptoalkanones were previously assigned on the basis of the 1H NMR anisotropy method using (S)-2-methoxy-2-(1 naphthyl)propionic acid ((S)-MalphaNP) as the chiral auxiliary. This study presents a reinvestigation of the configurations of 4-mercapto-2-pentanone 1, 4 mercapto-2-heptanone 2, and 2-mercapto-4-heptanone 3. Enantiomers of 1, 2, and 3 were obtained by lipase-catalyzed hydrolyses of the respective acetylthioalkanones. Upon derivatization with (S)-MalphaNP, the configurations of the reaction products were deduced based on the order of the HPLC elution of the diastereoisomeric thioesters, assuming that the sector rule previously developed for secondary alcohols is also valid for thiols. In addition, the configurations were experimentally determined by vibrational circular dichroism (VCD) and 1H NMR analyses after esterification with (R)-hydratropic acid (HTA) and 2-methoxy-2 phenylacetic acid (MPA). The assignments of the configurations using VCD and NMR analyses of HTA- and MPA-thioesters were in agreement. However, they were opposite to those deduced for (S)-MalphaNP thioesters via the sector rule. Consequently, the formerly assigned configurations of beta-mercaptoalkanones deduced via investigation of (S)-MalphaNP-derivatives have to be revised. PMID- 27779842 TI - Toward Automatic Rhodopsin Modeling as a Tool for High-Throughput Computational Photobiology. AB - We report on a prototype protocol for the automatic and fast construction of congruous sets of QM/MM models of rhodopsin-like photoreceptors and of their mutants. In the present implementation the information required for the construction of each model is essentially a crystallographic structure or a comparative model complemented with information on the protonation state of ionizable side chains and distributions of external counterions. Starting with such information, a model formed by a fixed environment system, a flexible cavity system, and a chromophore system is automatically generated. The results of the predicted vertical excitation energy for 27 different rhodopsins including vertebrate, invertebrate, and microbial pigments indicate that such basic models could be employed for predicting trends in spectral changes and/or correlate the spectral changes with structural variations in large sets of proteins. PMID- 27779843 TI - Steric Switching from Photochemical to Thermal Reaction Pathways for Enhanced Efficiency in Metal-Mediated Nitrogen Fixation. AB - Programmed manipulation of the subtle interplay of nonbonded steric interactions within a supporting ligand environment has been used for the conversion of a photochemically driven chemical cycle for group 6 metal-mediated nitrogen fixation into a thermally promoted process with increased energy efficiency and atom economy for key transformations involving N=N bond cleavage and N-atom functionalization of coordinated N2. PMID- 27779844 TI - Material and Ingenious Synthesis Strategy for Short-Wavelength Infrared Light Emitting Device. AB - Infrared (IR) light-emitting materials have wide applications. However, variety and economical accesses to obtain IR materials and devices are still limited, because the IR-emitting materials are always suffering from two obstacles, namely, lower absorption and lower emission efficiency. In this work, using a modified high-temperature solid-state reaction an efficient short-wavelength IR luminescent material is successfully synthesized. On the basis of the excellent luminescent properties, a convenient IR light-emitting diode (LED) device is fabricated by combining the novel IR material with a commercial UV LED chip. Besides the anticipation that it may lead to a boost of the application of IR device in different fields, importantly, we also consider that the ingenious synthesis strategy may open a door for obtaining novel ions doped functional materials. PMID- 27779845 TI - When are Many-Body Effects Significant? AB - Many-body effects are required for an accurate description of both structure and dynamics of large chemical systems. However, there are numerous such interactions to consider, and it is not obvious which ones are significant. We provide a general and fast method for establishing which small set of three- and four-body interactions are important. This is achieved by estimating the maximum many-body effects, epsilonmax, that can arise in a given arrangement of bodies. Through careful analysis of epsilonmax, we find two overall causes for significant many body interactions. First, many-body induction propagates in nonbranching paths, that is, in a chain-like manner. Second, linear arrangements of bodies promote the alignment of the dipoles to reinforce the many-body interaction. Consequently, compact and extended linear arrangements are favored. The latter result is not intuitive as these linear arrangements can lead to significant many body effects extending over large distances. For the first time, this study provides a rigorous explanation as to how cooperative effects provide enhanced stability in helices making them one of the most common structures in biomolecules. Not only do these helices promote linear dipole alignment, but their chain-like structure is consistent with the way many-body induction propagates. Finally, using epsilonmax to screen for significant many-body interactions, we are able to reproduce the total three- and four-body interaction energies using a small number of individual many-body interactions. PMID- 27779846 TI - Hybrid Light-Matter States in a Molecular and Material Science Perspective. AB - The notion that light and matter states can be hybridized the way s and p orbitals are mixed is a concept that is not familiar to most chemists and material scientists. Yet it has much potential for molecular and material sciences that is just beginning to be explored. For instance, it has already been demonstrated that the rate and yield of chemical reactions can be modified and that the conductivity of organic semiconductors and nonradiative energy transfer can be enhanced through the hybridization of electronic transitions. The hybridization is not limited to electronic transitions; it can be applied for instance to vibrational transitions to selectively perturb a given bond, opening new possibilities to change the chemical reactivity landscape and to use it as a tool in (bio)molecular science and spectroscopy. Such results are not only the consequence of the new eigenstates and energies generated by the hybridization. The hybrid light-matter states also have unusual properties: they can be delocalized over a very large number of molecules (up to ca. 105), and they become dispersive or momentum-sensitive. Importantly, the hybridization occurs even in the absence of light because it is the zero-point energies of the molecular and optical transitions that generate the new light-matter states. The present work is not a review but rather an Account from the author's point of view that first introduces the reader to the underlying concepts and details of the features of hybrid light-matter states. It is shown that light-matter hybridization is quite easy to achieve: all that is needed is to place molecules or a material in a resonant optical cavity (e.g., between two parallel mirrors) under the right conditions. For vibrational strong coupling, microfluidic IR cells can be used to study the consequences for chemistry in the liquid phase. Examples of modified properties are given to demonstrate the full potential for the molecular and material sciences. Finally an outlook of future directions for this emerging subject is given. PMID- 27779849 TI - Sample Preparation for Bioanalytical and Pharmaceutical Analysis. AB - Biological and pharmaceutical samples represent formidable challenges in sample preparation that hold important consequences for bioanalysis and genotoxic impurity quantification. This Feature will emphasize significant advances toward the development of rapid, sensitive, and selective sample preparation methods. PMID- 27779848 TI - Single Molecule Force Measurements in Living Cells Reveal a Minimally Tensioned Integrin State. AB - Integrins mediate cell adhesion to the extracellular matrix and enable the construction of complex, multicellular organisms, yet fundamental aspects of integrin-based adhesion remain poorly understood. Notably, the magnitude of the mechanical load experienced by individual integrins within living cells is unclear, due principally to limitations inherent to existing techniques. Here we use Forster resonance energy transfer-based molecular tension sensors to directly measure the distribution of loads experienced by individual integrins in living cells. We find that a large fraction of integrins bear modest loads of 1-3 pN, while subpopulations bearing higher loads are enriched within adhesions. Further, our data indicate that integrin engagement with the fibronectin synergy site, a secondary binding site specifically for alpha5beta1 integrin, leads to increased levels of alpha5beta1 integrin recruitment to adhesions but not to an increase in overall cellular traction generation. The presence of the synergy site does, however, increase cells' resistance to detachment by externally applied loads. We suggest that a substantial population of integrins experiencing loads well below their peak capacities can provide cells and tissues with mechanical integrity in the presence of widely varying mechanical loads. PMID- 27779850 TI - Using Antigen-antibody Binding Kinetic Parameters to Understand Single-Molecule Array Immunoassay Performance. AB - This paper provides insights into the performance of single-molecule array (Simoa) immunoassays by examining the effects of various capture and detector antibody-antigen binding kinetic parameters. Simoa is similar to other immunoassays in that the overall Simoa performance is heavily dependent on the choice of antibodies; however, little is known about how the different properties of the antibodies result in the wide variations in assay performance. Here, we focus on antibody-antigen binding kinetics and demonstrate how the association (kon) and dissociation (koff) rate constants of the capture and detection antibodies affect Simoa performance. We compared six different antibodies with over a four-log range of equilibrium dissociation constants (KD) and found that Simoa assay performance had an inverse relationship to the koff value of the detection antibody. The Simoa fluorescent signals were highest when the koff of the detection antibody was less than 10-5 s-1. The capture antibody koff did not have as significant an effect, but a koff of less than 10-3 s-1 was preferred. We also found that the kon values of the capture and detection antibodies were not important factors for Simoa performance. Therefore, the assay optimization process could be accelerated by choosing detection antibodies with the slowest koff values. PMID- 27779851 TI - Recent Advances in Subporphyrins and Triphyrin Analogues: Contracted Porphyrins Comprising Three Pyrrole Rings. AB - Subporphyrinato boron (subporphyrin) was elusive until the syntheses of tribenzosubporphine in 2006 and meso-aryl-substituted subporphyrin in 2007. These novel contracted analogues possess a 14pi-electron conjugated system embedded in a bowl-shaped structure. They exhibit absorption and fluorescence in the UV/vis region and nonlinear optical properties due to their octupolar structures. The unique coordination geometry around the central boron atom in the structure of subporphyrin enabled investigation of rare boron species, such as borenium cations, boron hydrides, and boron peroxides. Along with the burgeoning development of the chemistry of subporphyrins, analogous triphyrin systems have also emerged. Their rich coordination chemistry as a result of their free-base structures, which are different from the boron-coordinating structure of subporphyrins, has been intensively investigated. On the basis of the unique structures and reactivities of subporphyrins and their related triphyrin analogues, supramolecular architectures and covalently linked multicomponent systems have also been actively pursued. This Review provides an overview of the development of subporphyrin and triphyrin chemistry in the past decade and future prospects in this field, which may inspire molecular design toward applications based on their unique properties. PMID- 27779852 TI - Aggregation Control of alpha-Sexithiophene via Isothermal Encapsulation Inside Single-Walled Carbon Nanotubes. AB - Liquid-phase encapsulation of alpha-sexithiophene (6T) molecules inside individualized single-walled carbon nanotubes (SWCNTs) is investigated using Raman imaging and spectroscopy. By taking advantage of the strong Raman response of this system, we probe the encapsulation isotherms at 30 and 115 degrees C using a statistical ensemble of SWCNTs deposited on a oxidized silicon substrate. Two distinct and sequential stages of encapsulation are observed: Stage 1 is a one-dimensional (1D) aggregation of 6T aligned head-to-tail inside the nanotube, and stage 2 proceeds with the assembly of a second row, giving pairs of aligned 6Ts stacked together side-by-side. The experimental data are fitted using both Langmuir (type VI) and Ising models, in which the single-aggregate (stage 1) forms spontaneously, whereas the pair-aggregate (stage 2) is endothermic in toluene with formation enthalpy of DeltaHpair = (260 +/- 20) meV. Tunable Raman spectroscopy for each stage reveals a bathochromic shift of the molecular resonance of the pair-aggregate, which is consistent with strong intermolecular coupling and suggestive of J-type aggregation. This quantitative Raman approach is sensitive to roughly 10 molecules per nanotube and provides direct evidence of molecular entry from the nanotube ends. These insights into the encapsulation process guide the preparation of well-defined 1D molecular crystals having tailored optical properties. PMID- 27779853 TI - Real-Time Monitoring of Nitric Oxide at Single-Cell Level with Porphyrin Functionalized Graphene Field-Effect Transistor Biosensor. AB - An ultrasensitive and highly efficient assay for real-time monitoring of nitric oxide (NO) at single-cell level based on a reduced graphene oxide (RGO) and iron porphyrin-functionalized graphene (FGPCs) field-effect transistor (FET) biosensor is reported. A layer-to-layer assembly of RGO and FGPCs on a prefabricated FET sensor surface through pi-pi stacking interaction allowed superior electrical conductivity caused by RGO, and highly catalytic specificity induced by metalloporphyrin, ensuring the ultrasensitive and highly specific detection of NO. The results demonstrated that the RGO/FGPCs FET biosensor was capable of real time monitoring of NO in the range from 1 pM to 100 nM with the limit of detection as low as 1 pM in phosphate-buffered saline (PBS) and 10 pM in the cell medium, respectively. Moreover, the developed biosensor could be used for real time monitoring of NO released from human umbilical vein endothelial cells (HUVECs) at single-cell level. Along with its miniaturized sizes, ultrasensitive characteristics, and fast response, the FET biosensor is promising as a new platform for potential biological and diagnostic applications. PMID- 27779854 TI - Determining the Fate of a Non-Heme Iron Oxidation Catalyst Under Illumination, Oxygen, and Acid. AB - We analyze the stability of the non-heme water oxidation catalyst (WOC), Fe(bpmcn)Cl2 toward oxygen and illumination under nonaqueous and acidic conditions. Fe(bpmcn)Cl2 has been previously used as a C-H activation catalyst, a homogeneous WOC, and as a cocatalyst anchored to WO3 for photoelectrochemical water oxidation. This paper reports that the ligand dissociates at pH 1 with a rate constant k = 19.8(2) * 10-3 min-1, resulting in loss of catalytic activity. The combination of UV-vis experiments, 1H NMR spectroscopy, and cyclic voltammetry confirm free bpmcn and Fe2+ present in solution under acidic conditions. Even under nonaqueous conditions, both oxygen and illumination together show slow oxidation of iron over the course of a few hours, consistent with forming an Fe3+-O2- intermediate as corroborated by resonance-enhanced Raman spectroscopy, with a rate constant of k = 3.03(8) * 10-3 min-1. This finding has implications in both the merits of non-heme iron complexes as WOCs as well as cocatalysts in photoelectrochemical schemes: the decomposition mechanisms may include both anchoring group hydrolysis and instability under illumination. PMID- 27779855 TI - Eu2+-Doped Sr2B2-2xSi2+3xAl2-xN8+x: A Boron-Containing Orange-Emitting Nitridosilicate with Interesting Composition-Dependent Photoluminescence Properties. AB - Novel Sr2-yEuyB2-2xSi2+3xAl2-xN8+x phosphors were investigated as a function of the boron and aluminum over silicon ratio and as a function of the Eu2+ concentration. Samples were prepared via solid-state reaction synthesis by carefully controlling the synthesis conditions and composition. At high boron and aluminum content, that is, x = 0, a Eu2+ 5d-4f emission is observed of which the maximum shifts from 595 nm for low Eu concentrations (y = 0.005) toward 623 nm for high Eu concentrations (y = 0.5). The samples can be excited by UV or blue light up to ~475 nm. Substitution of [B2Al]9+ units by [Si3N]9+ units, increasing x up to 0.15, greatly improves the luminescence efficiency up to 46% and shows a very large redshift of the excitation bands with ~100 nm, while the emission band shifts with ~10 nm. The shifts are attributed to the lowering of the 5d level as a result of the decreased Eu-N distance upon substitution. Temperature-dependent measurements show that the Eu2+ 5d-4f emission is largely thermally quenched at room temperature for x = 0 due to thermal ionization toward the conduction band, explaining the low luminescence efficiency. The lowering of the 5d level at larger values of x reduces the thermal ionization and consequently increases the thermal stability and quantum efficiency, resulting in strongly luminescent blue to-orange conversion phosphors that are interesting for light-emitting diode applications. PMID- 27779856 TI - Nonclassical Crystal Growth as Explanation for the Riddle of Polarity in Centrosymmetric Glycine Crystals. AB - The riddle of anomalous polar behavior of the centrosymmetric crystal of alpha glycine is resolved by the discovery of a polar, several hundred nanometer thick hydrated layer, created at the {010} faces during crystal growth. This layer was detected by two independent pyroelectric analytical methods: (i) periodic temperature change technique (Chynoweth) at ambient conditions and (ii) contactless X-ray photoelectron spectroscopy under ultrahigh vacuum. The total polarization of the surface layer is extremely large, yielding ~1 MUC.cm-2, and is preserved in ultrahigh vacuum, but disappears upon heating to 100 degrees C. Molecular dynamics simulations corroborate the formation of polar hydrated layers at the sub-microsecond time scale, however with a thickness of only several nanometers, not several hundred. This inconsistency might be reconciled by invoking a three-step nonclassical crystal growth mechanism comprising (i) docking of clusters from the supersaturated solution onto the evolving crystal, (ii) surface recognition and polar induction, and (iii) annealing and dehydration, followed by site-selective recrystallization. PMID- 27779857 TI - Controlled Detachment of Chemically Glued Cells. AB - We demonstrate a chemically detachable cell-glue system based on linkers containing disulfide bonds as well as functional groups for metabolic glycoengineering and bioorthogonal click chemistry. Azide groups are generated on the cell surface by metabolic glycoengineering, and they are further modified into tetrazine (Tz) or trans-cyclooctene (TCO) using rationally designed cross linkers. When the Tz-modified and TCO-modified cells are mixed together, cell gluing between these two cell groups is established by Tz-TCO click chemistry. This artificial cell-cell adhesion can be broken by the administration of glutathione (5 mM), which triggers the degradation of disulfide bonds. Both the gluing and detachment processes are rapid (<10 min) and minimally cytotoxic. PMID- 27779858 TI - Highly Increased Flow-Induced Power Generation on Plasmonically Carbonized Single Walled Carbon Nanotube . AB - We generate networks and carbonization between individualized single-walled carbon nanotubes (SWCNTs) by an optimized plasmonic heating process using a halogen lamp to improve electrical properties for flow-induced energy harvesting. These properties were characterized by Raman spectra, a field-emission-scanning probe, transmission electron microscopy, atomic force microscopy and thermographic camera. The electrical sheet resistance of carbonized SWCNTs was decreased to 2.71 kOmega/?, 2.5 times smaller than normal-SWCNTs. We demonstrated flow-induced voltage generation on SWCNTs at various ion concentrations of NaCl. The generated voltage and current for the carbonized-SWCNTs were 9.5 and 23.5 times larger than for the normal-SWCNTs, respectively, based on the electron dragging mechanism. PMID- 27779860 TI - Modulation of Zn-C Bond Lengths Induced by Ligand Architecture in Zinc Carbatrane Compounds. AB - Bond lengths between pairs of atoms in covalent molecules are generally predicted well by the sum of their respective covalent radii, such that there are usually only small variations in related compounds. It is, therefore, significant that we have demonstrated that the incorporation of appropriately sized linkers between carbon and a metal center provides a means to modulate the length and nature of a metal-carbon interaction. Specifically, X-ray diffraction studies on a series of tris(1-methylimidazol-2-ylthio)methyl zinc complexes, [TitmMe]ZnX, demonstrate how the Zn-C bond lengths are highly variable (2.17-2.68 A) and are up to 0.67 A longer than the average value listed in the Cambridge Structural Database (2.01 A). Furthermore, density functional theory calculations on [TitmMe]ZnCl demonstrate that the interaction is very flexible, such that either increasing or decreasing the Zn-C length from that in the equilibrium structure is associated with little energy change in comparison to that for other compounds with Zn-C bonds. PMID- 27779861 TI - beta,gamma-Vicinal Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Directed Nucleopalladation. AB - A palladium(II)-catalyzed 1,2-dicarbofunctionalization reaction of unactivated alkenes has been developed, wherein a cleavable bidentate directing group is used to control the regioselectivity and stabilize the putative alkylpalladium(II) intermediate. Under the optimized reaction conditions, a broad range of nucleophiles and electrophiles were found to participate in this transformation, providing moderate to high yields. 3-Butenoic acid derivatives containing internal alkenes and alpha-substituents were reactive substrates, offering a powerful platform for preparing beta,gamma-substituted carbonyl compounds with multiple stereocenters. PMID- 27779862 TI - Linear Absorption Spectra from Explicitly Time-Dependent Equation-of-Motion Coupled-Cluster Theory. AB - We report an explicitly time-dependent approach to the generation of linear absorption spectra for molecular systems within the framework of equation-of motion (EOM) coupled-cluster (CC) theory. While most time-dependent CC approaches consider the perturbation and time-evolution of a CC wave function, the present work considers the time-evolution of a CC dipole function. The dipole function formalism introduces no approximations and requires the evolution of only one time-dependent quantity, either the left or right dipole function. This time dependent framework can be used to compute linear absorption spectra for molecules with a high density of states over a broad spectral range, a case for which conventional frequency-domain computations may become impractical. We validate the approach by comparing absorption spectra for small molecules computed at EOM second-order approximate CC (CC2) and time-dependent EOM-CC2 (TD EOM-CC2) levels of theory. TD-EOM-CC2 computations are also used to predict extreme ultraviolet absorption spectra for third-row ions that are in reasonable agreement with experiment. PMID- 27779863 TI - Large-Scale Cubic-Scaling Random Phase Approximation Correlation Energy Calculations Using a Gaussian Basis. AB - We present an algorithm for computing the correlation energy in the random phase approximation (RPA) in a Gaussian basis requiring [Formula: see text] operations and [Formula: see text] memory. The method is based on the resolution of the identity (RI) with the overlap metric, a reformulation of RI-RPA in the Gaussian basis, imaginary time, and imaginary frequency integration techniques, and the use of sparse linear algebra. Additional memory reduction without extra computations can be achieved by an iterative scheme that overcomes the memory bottleneck of canonical RPA implementations. We report a massively parallel implementation that is the key for the application to large systems. Finally, cubic-scaling RPA is applied to a thousand water molecules using a correlation consistent triple-zeta quality basis. PMID- 27779859 TI - Continuous Fluorescence Assays for Reactions Involving Adenine. AB - 5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5' methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic assays for these enzymes are challenging, as the ultraviolet absorbance spectra for reactant MTA and product adenine are similar. We report a new assay using 2-amino-5'-methylthioadenosine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes. Hydrolysis or phosphorolysis of 2AMTA forms 2,6-diaminopurine, a fluorescent and easily quantitated product. We kinetically characterize 2AMTA with human MTAP, bacterial MTANs and use 2,6 diaminopurine as a fluorescent substrate for yeast adenine phosphoribosyltransferase. 2AMTA was used as the substrate to kinetically characterize the dissociation constants for three-transition-state analogue inhibitors of MTAP and MTAN. Kinetic values obtained from continuous fluorescent assays with MTA were in good agreement with previously measured literature values, but gave smaller experimental errors. Chemical synthesis from ribose and 2,6-dichloropurine provided crystalline 2AMTA as the oxalate salt. Chemo enzymatic synthesis from ribose and 2,6-diaminopurine produced 2-amino-S adenosylmethionine for hydrolytic conversion to 2AMTA. Interaction of 2AMTA with human MTAP was also characterized by pre-steady-state kinetics and by analysis of the crystal structure in a complex with sulfate as a catalytically inert analogue of phosphate. This assay is suitable for inhibitor screening by detection of fluorescent product, for quantitative analysis of hits by rapid and accurate measurement of inhibition constants in continuous assays, and pre-steady-state kinetic analysis of the target enzymes. PMID- 27779864 TI - One-Pot Access to Benzo[a]carbazoles via Palladium(II)-Catalyzed Hetero- and Carboannulations. AB - A Pd(II)-catalyzed direct synthesis of benzo[a]carbazoles has been achieved through aminopalladation of alkynes, followed by intramolecular nucleophilic addition of the generated carbon-palladium bond to a tethered cyano/aldehyde group. Compared to literature procedures, this synthetic approach is operationally simple, uses simple substrates, and offers a fast intramolecular assembly resulting in the direct synthesis of benzo[a]carbazoles in which a wide variation of substituents at different sites is well-tolerated, leaving enough opportunity for diversification. PMID- 27779866 TI - Custom-Designed Affinity Capture LC-MS F(ab')2 Assay for Biotransformation Assessment of Site-Specific Antibody Drug Conjugates. AB - Affinity capture liquid chromatography-mass spectrometry (LC-MS) intact antibody assay has been widely used for direct drug-to-antibody ratio (DAR) and catabolite characterization of antibody-drug conjugates (ADCs). However, the intact mass spectra of new ADCs, which incorporate new types of linkers and payloads other than maytansines and auristatins, are more complex than those examined previously. The current method has showed some limitations in elucidating certain structural modifications. Herein, we report an alternative analytical approach for ADCs, such as THIOMAB antibody-drug conjugates (TDCs), where the linker drugs are site-specifically conjugated in the Fab region. The newly developed affinity capture LC-MS F(ab')2 assay incorporates affinity capture of human IgGs via binding to the Fab region, followed by on-bead IdeS digestion to remove the Fc domain specifically and uniformly. The resulting F(ab')2 (~100 kDa) fragments contain the key ADC biotransformation information, such as drug-to-antibody ratio and drug metabolism and are more readily analyzed by electrospray ionization LC MS than the intact ADC (~150 kDa). The reduced size of analytes results in improved mass spectral sensitivity and resolution. In addition, the reduced and optimized sample preparation time, for example, rapid removal of the Fc fragment by IdeS digestion, minimizes assay artifacts of drug metabolism and skewed DAR profiles that may result from the prolonged incubation times (e.g., overnight enzymatic treatment for Fc deglycosylation). The affinity capture LC-MS F(ab')2 assay provides more detailed and accurate information on ADC biotransformations in vivo, enabling analysis of low-dose, labile, and complex site-specific ADCs with linker-drug conjugated in the Fab region. PMID- 27779865 TI - Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells. AB - The Sonic Hedgehog (Shh) signaling pathway plays a critical role during embryonic development and cancer progression. N-terminal palmitoylation of Shh by Hedgehog acyltransferase (Hhat) is essential for efficient signaling, raising interest in Hhat as a novel drug target. A recently identified series of dihydrothienopyridines has been proposed to function via this mode of action; however, the lead compound in this series (RUSKI-43) was subsequently shown to possess cytotoxic activity unrelated to canonical Shh signaling. To identify a selective chemical probe for cellular studies, we profiled three RUSKI compounds in orthogonal cell-based assays. We found that RUSKI-43 exhibits off-target cytotoxicity, masking its effect on Hhat-dependent signaling, hence results obtained with this compound in cells should be treated with caution. In contrast, RUSKI-201 showed no off-target cytotoxicity, and quantitative whole-proteome palmitoylation profiling with a bioorthogonal alkyne-palmitate reporter demonstrated specific inhibition of Hhat in cells. RUSKI-201 is the first selective Hhat chemical probe in cells and should be used in future studies of Hhat catalytic function. PMID- 27779867 TI - An Exceptionally Stable Metal-Organic Framework Supported Molybdenum(VI) Oxide Catalyst for Cyclohexene Epoxidation. AB - Molybdenum(VI) oxide was deposited on the Zr6 node of the mesoporous metal organic framework NU-1000 via condensed-phase deposition where the MOF is simply submerged in the precursor solution, a process named solvothermal deposition in MOFs (SIM). Exposure to oxygen leads to a monodisperse, porous heterogeneous catalyst, named Mo-SIM, and its structure on the node was elucidated both computationally and spectroscopically. The catalytic activity of Mo-SIM was tested for the epoxidation of cyclohexene. Near-quantitative yields of cyclohexene oxide and the ring-opened 1,2-cyclohexanediol were observed, indicating activity significantly higher than that of molybdenum(VI) oxide powder and comparable to that of a zirconia-supported analogue (Mo-ZrO2) prepared in a similar fashion. Despite the well-known leaching problem of supported molybdenum catalysts (i.e., loss of Mo species thus causes deactivation), Mo-SIM demonstrated no loss in the metal loading before and after catalysis, and no molybdenum was detected in the reaction mixture. In contrast, Mo-ZrO2 led to significant leaching and close to 80 wt % loss of the active species. The stability of Mo-SIM was further confirmed computationally, with density functional theory calculations indicating that the dissociation of the molybdenum(VI) species from the node of NU-1000 is endergonic, corroborating the experimental data for the Mo-SIM material. PMID- 27779868 TI - Ultratrace Determination of Tin, Germanium, and Selenium by Hydride Generation Coupled with a Novel Solution-Cathode Glow Discharge-Atomic Emission Spectrometry Method. AB - We herein describe a novel method of hydride generation (HG) coupled to a newly designed atmospheric pressure solution-cathode glow discharge (SCGD) spectrometric technique for the ultratrace determination of tin, germanium, and selenium. In this novel SCGD process, gas introduction was permitted using a hollow titanium tube as both the anode and sampling port. In these experiments, the analytes were converted into volatile hydrides upon passing through the hydride generator, and were introduced into the near-anode region of the SCGD system, where they were detected directly by atomic emission spectrometry (AES). A significant improvement in both selectivity and sensitivity was achieved, which was reflected in an improvement in the detection limits (DLs) by 3 orders of magnitude, in addition to successful valence analysis of Se without the requirement for chromatographic separation. In the absence of a strict sample pretreatment process and with a reduction in electrolyte consumption, the detection limits of Sn, Ge, and Se were determined to be 0.8, 0.5, and 0.2 MUg.L 1. Moreover, our HG-SCGD-AES system demonstrated excellent repeatability (<3% peak height relative standard deviation) and more than 2 orders of linear dynamic range. The optimal operating conditions are outlined herein, and the analytical performance of the system is evaluated as described. Furthermore, our method was applied for the analysis of Sn, Ge, and Se in both environmental and biological samples, and the obtained results were in good agreement with reference values. PMID- 27779869 TI - Ion-Mobility-Derived Collision Cross Section as an Additional Identification Point for Multiresidue Screening of Pesticides in Fish Feed. AB - Ion mobility spectrometry allows for the measurement of the collision cross section (CCS), which provides information about the shape of an ionic molecule in the gas phase. Although the hyphenation of traveling-wave ion mobility spectrometry (TWIMS) with high-resolution quadrupole time-of-flight mass spectrometry (QTOFMS) has been mainly used for structural elucidation purposes, its potential for fast screening of small molecules in complex samples has not yet been thoroughly evaluated. The current work explores the capabilities of ultrahigh-performance liquid chromatography (UHPLC) coupled to a new design TWIMS QTOFMS for the screening and identification of a large set of pesticides in complex salmon feed matrices. A database containing TWIMS-derived CCS values for more than 200 pesticides is hereby presented. CCS measurements showed high intra- and interday repeatability (RSD < 1%), and they were not affected by the complexity of the investigated matrices (DeltaCCS <= 1.8%). The use of TWIMS in combination with QTOFMS was demonstrated to provide an extra-dimension, which resulted in increased peak capacity and selectivity in real samples. Thus, many false-positive detections could be straightforwardly discarded just by applying a maximum DeltaCCS tolerance of +/-2%. CCS was proposed as a valuable additional identification point in the pesticides screening workflow. Several commercial fish feed samples were finally analyzed to demonstrate the applicability of the proposed approach. Ethoxyquin and pirimiphos-methyl were identified in most of the analyzed samples, whereas tebuconazole and piperonil butoxide were identified for the first time in fish feed samples. PMID- 27779870 TI - Hybrid Modeling Approach to Estimate Exposures of Hazardous Air Pollutants (HAPs) for the National Air Toxics Assessment (NATA). AB - A hybrid air quality model has been developed and applied to estimate annual concentrations of 40 hazardous air pollutants (HAPs) across the continental United States (CONUS) to support the 2011 calendar year National Air Toxics Assessment (NATA). By combining a chemical transport model (CTM) with a Gaussian dispersion model, both reactive and nonreactive HAPs are accommodated across local to regional spatial scales, through a multiplicative technique designed to improve mass conservation relative to previous additive methods. The broad scope of multiple pollutants capturing regional to local spatial scale patterns across a vast spatial domain is precedent setting within the air toxics community. The hybrid design exhibits improved performance relative to the stand alone CTM and dispersion model. However, model performance varies widely across pollutant categories and quantifiably definitive performance assessments are hampered by a limited observation base and challenged by the multiple physical and chemical attributes of HAPs. Formaldehyde and acetaldehyde are the dominant HAP concentration and cancer risk drivers, characterized by strong regional signals associated with naturally emitted carbonyl precursors enhanced in urban transport corridors with strong mobile source sector emissions. The multiple pollutant emission characteristics of combustion dominated source sectors creates largely similar concentration patterns across the majority of HAPs. However, reactive carbonyls exhibit significantly less spatial variability relative to nonreactive HAPs across the CONUS. PMID- 27779871 TI - Elemental Quantification and Residues Characterization of Wet Digested Certified and Commercial Carbon Materials. AB - Inductively coupled plasma optical emission spectroscopy (ICP-OES) is a common, relatively low cost, and straightforward analytical technique for the study of trace quantities of metals in solid materials, but its applicability to nanocarbons (e.g., graphene and nanotubes) has suffered from the lack of efficient digestion steps and certified reference materials (CRM). Here, various commercial and certified graphitic carbon materials were subjected to a "two step" microwave-assisted acid digestion procedure, and the concentrations of up to 18 elements were analyzed by ICP-OES. With one exception (Sm), successful quantification of all certified elements in the two reference nanocarbons studied was achieved, hence validating the sample preparation approach used. The applicability of our "two-step" protocol was further confirmed for a commercial single-walled carbon nanotube sample. However, the digestion was markedly incomplete for all other commercial materials tested. Where possible, the digestion residues of the carbon materials analyzed (CRM included) were characterized to understand the structural changes that take place and how this may explain the challenge of disintegrating graphitic carbon. In this respect, it was found that solid state nuclear magnetic resonance holds considerable promise as a nonlocalized, easily interpretable, and reliable tool to access the efficient disintegration of these materials. PMID- 27779872 TI - The Activation of Carboxylic Acids via Self-Assembly Asymmetric Organocatalysis: A Combined Experimental and Computational Investigation. AB - The heterodimerizing self-assembly between a phosphoric acid catalyst and a carboxylic acid has recently been established as a new activation mode in Bronsted acid catalysis. In this article, we present a comprehensive mechanistic investigation on this activation principle, which eventually led to its elucidation. Detailed studies are reported, including computational investigations on the supramolecular heterodimer, kinetic studies on the catalytic cycle, and a thorough analysis of transition states by DFT calculations for the rationalization of the catalyst structure-selectivity relationship. On the basis of these investigations, we developed a kinetic resolution of racemic epoxides, which proceeds with high selectivity (up to s = 93), giving the unreacted epoxides and the corresponding protected 1,2-diols in high enantiopurity. Moreover, this approach could be advanced to an unprecedented stereodivergent resolution of racemic alpha-chiral carboxylic acids, thus providing access to a variety of enantiopure nonsteroidal anti-inflammatory drugs and to alpha-amino acid derivatives. PMID- 27779873 TI - An Analysis of Bubble Deformation by a Sphere Relevant to the Measurements of Bubble-Particle Contact Interaction and Detachment Forces. AB - Atomic force microscopy makes it possible to measure the interacting forces between individual colloidal particles and air bubbles, which can provide a measure of the particle hydrophobicity. To indicate the level of hydrophobicity of the particle, the contact angle can be calculated, assuming that no interfacial deformation occurs with the bubble retaining a spherical profile. Our experimental results obtained using a modified sphere tensiometry apparatus to detach submillimeter spherical particles show that deformation of the bubble interface does occur during particle detachment. We also develop a theoretical model to describe the equilibrium shape of the bubble meniscus at any given particle position, based on the minimization of the free energy of the system. The developed model allows us to analyze high-speed video captured during detachment. In the system model deformation of the bubble profile is accounted for by the incorporation of a Lagrange multiplier into both the Young-Laplace equation and the force balance. The solution of the bubble profile matched to the high-speed video allows us to accurately calculate the contact angle and determine the total force balance as a function of the contact point of the bubble on the particle surface. PMID- 27779874 TI - Direct Enrichment of Metallic Single-Walled Carbon Nanotubes by Using NO2 as Oxidant to Selectively Etch Semiconducting Counterparts. AB - We report an efficient method for enriching high-purity metallic single-walled carbon nanotubes (m-SWCNTs) by using NO2 as oxidant to remove semiconducting components at 220 degrees C. After etching, m-SWCNTs with purity higher than 90% were obtained. The surviving m-SWCNTs retain an intact structure without any extra defects on their surface. PMID- 27779875 TI - Reactivity Indexes of Fullerene and Bismullene Mixed Clusters: How the Intruders Modify the Properties. AB - In this investigation, the feasibility of functionalizing fullerene and bismullene with Bi and C as intruders is theoretically explored. The systems analyzed are C60-xBix (with x = 0-10, fullerene-like) and Bi60-yCy (with y = 0 10, bismullene-like). Optimized geometries, reactivity indexes, and highest occupied molecular orbital to lowest unoccupied molecular orbital (HOMO-LUMO) gaps (for analyzing the potential application of these molecules as materials for solar cells) are reported. The most stable structures of bismullene-like systems have cage geometries. The most stable fullerene-like geometries resemble a cup with bismuth atoms at the edge of the bowl. The presence of intruders increases the electron acceptor power and decreases the electron donor power in most cases. HOMO-LUMO gaps indicate that bismullene-like clusters represent better candidates for building solar cells than fullerene-like clusters. This information could be useful for future experiments. PMID- 27779876 TI - Size-Dependent Ligand Quenching of Ferromagnetism in Co3(benzene)n+ Clusters Studied with X-ray Magnetic Circular Dichroism Spectroscopy. AB - Cobalt-benzene cluster ions of the form Co3(bz)n+ (n = 0-3) were produced in the gas phase, mass-selected, and cooled in a cryogenic ion trap held at 3-4 K. To explore ligand effects on cluster magnetic moments, these species were investigated with X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (XMCD) spectroscopy. XMCD spectra yield both the spin and orbital angular momenta of these clusters. Co3+ has a spin magnetic moment of MUS = 6 MUB and an orbital magnetic moment of MUL = 3 MUB. Co3(bz)+ and Co3(bz)2+ complexes were found to have spin and orbital magnetic moments identical to the values for ligand-free Co3+. However, coordination of the third benzene to form Co3(bz)3+ completely quenches the high spin state of the system. Density functional theory calculations elucidate the spin states of the Co3(bz)n+ species as a function of the number of attached benzene ligands, explaining the transition from septet to singlet for n = 0 -> 3. PMID- 27779877 TI - Synthesis of scpBNA-mC, -A, and -G Monomers and Evaluation of the Binding Affinities of scpBNA-Modified Oligonucleotides toward Complementary ssRNA and ssDNA. AB - We previously reported the synthesis and evaluation of 2'-O,4'-C spirocyclopropylene-bridged nucleic acid (scpBNA) bearing a thymine (T) nucleobase. Oligonucleotides (ONs) modified with scpBNA-T exhibited strong binding affinity to complementary single-stranded RNA (ssRNA) and high enzymatic stability. These biophysical properties suggest that scpBNAs are well suited for use in antisense strategies. Herein, we describe the synthesis of scpBNA monomers bearing 5-methylcytosine (mC), adenine (A), and guanine (G) nucleobases for use in a variety of sequences. The prepared scpBNA monomers were incorporated into ONs at various positions. The scpBNA-modified ONs exhibited excellent duplex forming ability with the complementary ssRNA comparable to ONs modified with 2' O,4'-C-methylene-bridged nucleic acid (2',4'-BNA/LNA). Moreover, ON modified with scpBNA-mC, -A, and -G showed higher enzymatic stability than the corresponding 2',4'-BNA/LNA-modified ON. These results demonstrated a promising role for the incorporation of scpBNA monomers into therapeutic antisense ONs. PMID- 27779878 TI - Lateral Diffusion of a Submicrometer Particle on a Lipid Bilayer Membrane. AB - In past decades, nanoparticles and nanomaterials have been actively used for applications such as visualizing nano/submicrometer cell structure, killing cancer cells, and using drug delivery systems. It is important to understand the physicochemical mechanisms that govern the motion of nanoparticles on a plasma membrane surface. However, the motion of small particles of <1000 nm on lipid membranes is poorly understood. In this study, we investigated the diffusion of particles with a diameter of 200-800 nm on a lipid membrane using cell-sized liposomes. Particle-associated liposomes were obtained by applying centrifugal force to a mixture of liposomes and particle solutions. We measured the thermal motion of the particles by phase-contrast microscopy. We found that (i) the particle-size dependence of the diffusion of particles adhering to membranes was better described by the DADL model rather than the Einstein-Stokes model, (ii) the diffusion coefficient of a particle strongly depends on the adsorption state of the particle, such as fully or partially wrapped by the membrane, and (iii) anomalous diffusion was induced by the localization of particles on the neck of budded vesicles. PMID- 27779879 TI - Multi-Scale Modeling of the Gamma Radiolysis of Nitrate Solutions. AB - A multiscale modeling approach has been developed for the extended time scale long-term radiolysis of aqueous systems. The approach uses a combination of stochastic track structure and track chemistry as well as deterministic homogeneous chemistry techniques and involves four key stages: radiation track structure simulation, the subsequent physicochemical processes, nonhomogeneous diffusion-reaction kinetic evolution, and homogeneous bulk chemistry modeling. The first three components model the physical and chemical evolution of an isolated radiation chemical track and provide radiolysis yields, within the extremely low dose isolated track paradigm, as the input parameters for a bulk deterministic chemistry model. This approach to radiation chemical modeling has been tested by comparison with the experimentally observed yield of nitrite from the gamma radiolysis of sodium nitrate solutions. This is a complex radiation chemical system which is strongly dependent on secondary reaction processes. The concentration of nitrite is not just dependent upon the evolution of radiation track chemistry and the scavenging of the hydrated electron and its precursors but also on the subsequent reactions of the products of these scavenging reactions with other water radiolysis products. Without the inclusion of intratrack chemistry, the deterministic component of the multiscale model is unable to correctly predict experimental data, highlighting the importance of intratrack radiation chemistry in the chemical evolution of the irradiated system. PMID- 27779880 TI - Nanoconfinement's Dramatic Impact on Proton Exchange between Glucose and Water. AB - Glucose nanoconfined by solubilization in water-containing AOT (sodium bis(2 ethylhexyl) sulfosuccinate) reverse micelles has been investigated using 1H NMR. NMR spectra reveal well-defined signals for the glucose hydroxyl groups that suggest slow chemical exchange between them and the water hydroxyl groups. Using the EXSY (ZZ-exchange) method, the chemical exchange rate from water to glucose hydroxyl groups was measured for glucose in reverse micelles as a function of size (water pool diameter of ~1-5 nm) at 25 degrees C. The chemical exchange rates observed in the nanoconfined interior are dramatically slower (5-20 times) than those observed for glucose in bulk aqueous solution at the same concentration as the micelle interior. Exchange rate constants are calculated via a mechanism that accounts for these observations, and implications of these results are presented and discussed. PMID- 27779881 TI - Specific Ion Effects and pH Dependence on the Interaction Forces between Polystyrene Particles. AB - Colloidal interactions have been extensively studied due to the wide number of applications where colloids are present. In general, the electric double layer force and the van der Waals interaction dominate the net force acting between two colloids at large separation distances. However, it is well accepted that some other phenomena, especially those acting at short separation distances, might be relevant and induce substantial changes in the force profiles. Within these phenomena, those related to the surface contact angle, the hydration degree of the ions, or the pH, may dominate the force profiles features, not only at short distances. In this paper, we analyzed the effect of the pH and counterion type on the long-range as well as short-range forces between polystyrene colloidal particles by using the colloidal probe technique based on AFM. Our results confirm that the features of the force profiles between polystyrene surfaces are strongly affected by the pH and hydration degree of the counterions in solution. Additionally, we performed a study of the role of the pH on the wettability properties of hydrated and nonhydrated polystyrene sheets to scan the wettability properties of this material with pH. Contact angle measurements confirmed that the polystyrene surface is hydrophobic in aqueous solutions over the entire range of pHs investigated. These results are in good agreement with the features observed in the force profiles at low pH. At high pH, a short-range repulsion similar to the one observed for hydrophilic materials is observed. This repulsion scales with the pH, and it also depends on the hydration degree of the ions in solution. This way, the short-range forces between polystyrene surfaces may be tunable with the pH, and its origin does not seem to be related to the hydrophobicity of the material. PMID- 27779882 TI - Probing the H2-Induced Restructuring of Pt Nanoclusters by H2-TPD. AB - Metal clusters with sizes below 1 nm attract great scientific interest, but the main information on their properties still comes from quantum mechanics modeling and costly physical methods of limited availability. We have studied ultradispersed Pt/gamma-Al2O3 samples with temperature-programmed desorption (TPD) and complementary adsorption/desorption techniques and observed that the H2 TPD profile of Pt/gamma-Al2O3 is strongly dependent on the pretreatment conditions (0 < PH2 <= 1 bar; 200 K <= T <= 470 K). The results corroborate recent theoretical and spectroscopic studies predicting alterations in the structure of Pt nanoclusters under H2-treatment conditions but reveal that the restructuring needs to overcome continuous activation barriers and leads both to an increase in surface coverage and strengthening of the Pt-H bonds. This was interpreted as being a consequence of the strong interaction of Pt clusters with the support. The results extend insights into the behavior of supported metal particles and expand the potential of existing experimental techniques. PMID- 27779883 TI - Selective Pinacol-Coupling Reaction using a Continuous Flow System. AB - The first continuous flow pinacol coupling reaction of carbonyl compounds was successfully achieved within only 2 min during a single pass through a cartridge filled with zinc(0). The optimized method allowed the efficient production of gram-scale value-added compounds with high productivity. The developed methodology is efficient for aromatic or alpha,beta-unsaturated aldehydes but gives moderate results for more stable acetophenone derivatives. Moreover, the flow method displayed better results in terms of yield and selectivity in comparison to the corresponding batch methodology. PMID- 27779885 TI - Following in Real Time the Two-Step Assembly of Nanoparticles into Mesocrystals in Levitating Drops. AB - Mesocrystals composed of crystallographically aligned nanocrystals are present in biominerals and assembled materials which show strongly directional properties of importance for mechanical protection and functional devices. Mesocrystals are commonly formed by complex biomineralization processes and can also be generated by assembly of anisotropic nanocrystals. Here, we follow the evaporation-induced assembly of maghemite nanocubes into mesocrystals in real time in levitating drops. Analysis of time-resolved small-angle X-ray scattering data and ex situ scanning electron microscopy together with interparticle potential calculations show that the substrate-free, particle-mediated crystallization process proceeds in two stages involving the formation and rapid transformation of a dense, structurally disordered phase into ordered mesocrystals. Controlling and tailoring the particle-mediated formation of mesocrystals could be utilized to assemble designed nanoparticles into new materials with unique functions. PMID- 27779886 TI - Direct Identification and Determination of Conformational Response in Adsorbed Individual Nonplanar Molecular Species Using Noncontact Atomic Force Microscopy. AB - In recent years atomic force microscopy (AFM) at highest resolution was widely applied to mostly planar molecules, while its application toward exploring species with structural flexibility and a distinct 3D character remains a challenge. Herein, the scope of noncontact AFM is widened by investigating subtle conformational differences occurring in the well-studied reference systems 2H-TPP and Cu-TPP on Cu(111). Different saddle-shape conformations of both species can be recognized in conventional constant-height AFM images. To unambiguously identify the behavior of specific molecular moieties, we extend data acquisition to distances that are inaccessible with constant-height measurements by introducing vertical imaging, that is, AFM mapping in a plane perpendicular to the sample surface. Making use of this novel technique the vertical displacement of the central Cu atom upon tip-induced conformational switching of Cu-TPP is quantified. Further, for 2H-TPP two drastically different geometries are observed, which are systematically characterized. Our results underscore the importance of structural flexibility in adsorbed molecules with large conformational variability and, consequently, the objective to characterize their geometry at the single-molecule level in real space. PMID- 27779884 TI - De Novo MS/MS Sequencing of Native Human Antibodies. AB - One direct route for the discovery of therapeutic human monoclonal antibodies (mAbs) involves the isolation of peripheral B cells from survivors/sero-positive individuals after exposure to an infectious reagent or disease etiology, followed by single-cell sequencing or hybridoma generation. Peripheral B cells, however, are not always easy to obtain and represent only a small percentage of the total B-cell population across all bodily tissues. Although it has been demonstrated that tandem mass spectrometry (MS/MS) techniques can interrogate the full polyclonal antibody (pAb) response to an antigen in vivo, all current approaches identify MS/MS spectra against databases derived from genetic sequencing of B cells from the same patient. In this proof-of-concept study, we demonstrate the feasibility of a novel MS/MS antibody discovery approach in which only serum antibodies are required without the need for sequencing of genetic material. Peripheral pAbs from a cytomegalovirus-exposed individual were purified by glycoprotein B antigen affinity and de novo sequenced from MS/MS data. Purely MS derived mAbs were then manufactured in mammalian cells to validate potency via antigen-binding ELISA. Interestingly, we found that these mAbs accounted for 1 to 2% of total donor IgG but were not detected in parallel sequencing of memory B cells from the same patient. PMID- 27779887 TI - Two-Component Assembly of Thiochroman-4-ones and Tetrahydrothiopyran-4-ones Using a Rhodium-Catalyzed Alkyne Hydroacylation/Thio-Conjugate-Addition Sequence. AB - beta'-Thio-substituted-enones, assembled from the combination of beta-tert butylthio-substituted aldehydes and alkynes, using rhodium catalysis, are shown to smoothly undergo in situ intramolecular S-conjugate addition to deliver a range of S-heterocycles in a one-pot process. Aryl, alkenyl, and alkyl aldehydes can all be employed, to provide thiochroman-4-ones, hexahydro-4H-thiochromen-4 ones, and tetrahydrothiopyran-4-ones, respectively. A variety of in situ oxidations are also performed, allowing access to S,S-dioxide derivatives, as well as unsaturated variants. PMID- 27779888 TI - Photon-Induced Quantum Oscillations of the Terahertz Conductivity in Graphene. AB - In this work, we present a theory that is able to explain the nonmonotonic decreasing behavior (observed in experimental data1-12) of the graphene terahertz conductivity with the increase of the field frequency. In this connection, the displacement of the structure of topological states inside the energy band gap, which appears in graphene due to the strong photon-electron coupling, and the narrowing of this gap, as result of electron transitions from bound photon dressed electron states to extended states outside the energy gap driven by the field frequency, lead to a periodic change of singularities near the edge of the band gap, resulting in subtle quantum oscillations of the dynamical terahertz conductivity. This quantum contribution complements the Drude response, which fits the spectral range. On the other hand, the scattering processes by impurities favor interband transitions, suppressing this way intraband terahertz absorptions, which are related to optical transitions from inside to outside the gap. PMID- 27779889 TI - Tuning the Photoelectrocatalytic Hydrogen Evolution of Pt-Decorated Silicon Photocathodes by the Temperature and Time of Electroless Pt Deposition. AB - The electroless deposition of Pt nanoparticles (NPs) on hydrogen-terminated silicon (H-Si) surfaces is studied as a function of the temperature and the immersion time. It is demonstrated that isolated Pt structures can be produced at all investigated temperatures (between 22 and 75 degrees C) for short deposition times, typically within 1-10 min if the temperature is 45 degrees C or less than 5 min at 75 degrees C. For longer times, dendritic metal structures start to grow, ultimately leading to highly rough interconnected Pt networks. Upon increasing the temperature from 22 to 75 degrees C and for an immersion time of 5 min, the average size of the observed Pt NPs monotonously increases from 120 to 250 nm, and their number density calculated using scanning electron microscopy decreases from (4.5 +/- 1.0) * 108 to (2.0 +/- 0.5) * 108 Pt NPs cm-2. The impact of both the morphology and the distribution of the Pt NPs on the photoelectrocatalytic activity of the resulting metallized photocathodes is then analyzed. Pt deposited at 45 degrees C for 5 min yields photocathodes with the best electrocatalytic activity for the hydrogen evolution reaction. Under illumination at 33 mW cm-2, this optimized photoelectrode shows a fill factor of 45%, an efficiency (eta) of 9.7%, and a short-circuit current density (|Jsc|) at 0 V versus a reversible hydrogen electrode of 15.5 mA cm-2. PMID- 27779890 TI - Positive-Negative Birefringence in Multiferroic Layered Metasurfaces. AB - We uncover and identify the regime for a magnetically and ferroelectrically controllable negative refraction of a light-traversing multiferroic, oxide-based metastructure consisting of alternating nanoscopic ferroelectric (SrTiO3) and ferromagnetic (Y3Fe2(FeO4)3, YIG) layers. We perform analytical and numerical simulations based on discretized, coupled equations for the self-consistent Maxwell/ferroelectric/ferromagnetic dynamics and obtain a biquadratic relation for the refractive index. Various scenarios of ordinary and negative refraction in different frequency ranges are analyzed and quantified by simple analytical formula that are confirmed by full-fledge numerical simulations. Electromagnetic waves injected at the edges of the sample are propagated exactly numerically. We discovered that, for particular GHz frequencies, waves with different polarizations are characterized by different signs of the refractive index, giving rise to novel types of phenomena such as a positive-negative birefringence effect and magnetically controlled light trapping and accelerations. PMID- 27779891 TI - Superlattice of Single Atom Magnets on Graphene. AB - Regular arrays of single atoms with stable magnetization represent the ultimate limit of ultrahigh density storage media. Here we report a self-assembled superlattice of individual and noninteracting Dy atoms on graphene grown on Ir(111), with magnetic hysteresis up to 5.6 T and spin lifetime of 1000 s at 2.5 K. The observed magnetic stability is a consequence of the intrinsic low electron and phonon densities of graphene and the 6-fold symmetry of the adsorption site. Our array of single atom magnets has a density of 115 Tbit/inch2, defined by the periodicity of the graphene moire pattern. PMID- 27779893 TI - Students' Food Intake from Home-Packed Lunches in the Traditional versus Balanced School Day. AB - PURPOSE: To assess the type and quantity of foods children brought and consumed at school in the balanced school day (BSD), with two 20-minute eating periods, versus the traditional schedule (TS), with one 20-minute lunch. METHODS: Direct observation identified food items and amounts in BSD and TS lunches of grade 3 and 4 students (n = 321). RESULTS: The mean (SD) servings of foods packed in BSD lunches were significantly higher than the TS lunches for milk and alternatives (0.69 (0.70) vs 0.47 (0.49), P = 0.02), sugar-sweetened beverages (SSBs; 0.91 (1.24) vs 0.57 (0.99), P = 0.01), and snacks (2.74 (1.55) vs 2.24 (1.48), P < 0.01). Regardless of schedule, only 40.8% of students had vegetables packed in their lunch, whereas 92.8% had snacks. When comparing foods eaten, SSBs and snacks remained significantly higher in the BSD (0.75 (1.02) vs 0.48 (0.83), P = 0.03; 2.37 (1.44) vs 1.93 (1.36), P = 0.01, respectively). The proportion of children (%) whose consumption met one-third of Canada's Food Guide recommendations for vegetables and fruit was low (27.5% BSD, 31.0% TS). CONCLUSIONS: The BSD may have unintended negative consequences on the type and amount of foods packed in school lunches. Support for families should focus on encouraging more vegetables and fruit and fewer SSBs and snacks in packed lunches. PMID- 27779894 TI - Influence of Sulforaphane Metabolites on Activities of Human Drug-Metabolizing Cytochrome P450 and Determination of Sulforaphane in Human Liver Cells. AB - The influence of metabolites of sulforaphane, natural compounds present in broccoli (Brassica oleracea var. botrytis italica) and in other cruciferous vegetables, on drug-metabolizing cytochrome P450 (CYP) enzymes in human liver microsomes and possible entry of sulforaphane into human hepatic cells were investigated. Metabolites studied are compounds derived from sulforaphane by the mercapturic acid pathway (conjugation with glutathione and by following reactions), namely sulforaphane glutathione and sulforaphane cysteine conjugates and sulforaphane-N-acetylcysteine. Their possible effect on four drug metabolizing CYP enzymes, CYP3A4 (midazolam 1'-hydroxylation), CYP2D6 (bufuralol 1'-hydroxylation), CYP1A2 (7-ethoxyresorufin O-deethylation), and CYP2B6 (7 ethoxy-4-(trifluoromethyl)coumarin O-deethylation), was tested. Inhibition of four prototypical CYP activities by sulforaphane metabolites was studied in pooled human liver microsomes. Sulforaphane metabolites did not considerably affect biological function of drug-metabolizing CYPs in human liver microsomes except for CYP2D6, which was found to be inhibited down to 73-78% of the original activity. Analysis of the entry of sulforaphane into human hepatocytes was done by cell disruption by sonication, methylene chloride extraction, and modified high-performance liquid chromatography method. The results have shown penetration of sulforaphane into the human hepatic cells. PMID- 27779892 TI - Examining Diet-Related Care Practices Among Adults with Type 2 Diabetes: A Focus on Glycemic Index Choices. AB - We examined self-care dietary practices and usual intakes among adults with Type 2 diabetes in Alberta, Canada, using data from the Healthy Eating and Active Living for Diabetes study. Participants completed a modified Fat/Sugar/Fruit/Vegetable Screener and answered questions about the number of days per week they followed specific diabetes self-care dietary recommendations. Capillary blood samples were collected to assess glycemic control measured by hemoglobin A1c (HbA1c). ANOVA was used to examine differences in dietary self care, intakes, and glycemic control across categories of days/week of practicing recommended dietary behaviour. Participants (n = 196) were 51% women, mean +/- SD age 59.6 +/- 8.5 years, with BMI 33.6 +/- 6.5 kg/m2, and diabetes duration of 5.1 +/- 6.3 years. Sixteen percent of participants were unfamiliar with low-GI eating and 28% did not include low-GI foods in their diet. Overall, lower mean intake of saturated fat, trans fat, added sugars, higher fibre, and greater GI were each associated with meeting diabetes-related dietary behaviours including: eating >=5 servings of vegetables and fruit; avoiding processed high fat foods; and replacing high with low-GI foods (P < 0.05). No clear pattern was observed for low-GI eating and HbA1c. PMID- 27779895 TI - Immediate Prosthetic Loading of Implants Placed in Reconstructed Jaws After Hyperbaric Oxygen Therapy. PMID- 27779897 TI - Decreased In-Hospital Mortality after Lobectomy Using Video-assisted Thoracoscopic Surgery Compared with Open Thoracotomy. AB - RATIONALE: There is a paucity of data regarding the optimal surgical approach for lung lobectomy. Lobectomy performed by video-assisted thoracoscopic surgery (VATS) has been associated with lower morbidity as compared with lobectomy performed by thoracotomy. However, no multicenter studies have shown improved mortality with VATS lobectomy compared with open surgical lobectomy. OBJECTIVES: We used data from the United States Healthcare Cost and Utilization Project Nationwide Inpatient Sample database from 2009 to 2012 to compare VATS with open lobectomy for in-hospital mortality and other short-term outcomes. METHODS: We used International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes to identify the patients undergoing lobectomy. We used 1:1 ratio propensity matching with the nearest neighbor method without replacement to generate matched pairs. MEASUREMENTS AND MAIN RESULTS: Over the 4 year period, 27,451 patients underwent lobectomy. The majority of these procedures were performed by thoracotomy (65%) as compared with VATS (35%). A total of 9,393 matched pairs were created. VATS lobectomy was associated with significantly lower in-hospital mortality when compared with thoracotomy (1.3% vs. 2.5%, P < 0.001). A shorter length of hospital stay was observed for those undergoing VATS lobectomy (6.21 vs. 8.75 d, P < 0.001). The overall rate of perioperative complications was low, with those undergoing VATS being less likely to have any perioperative morbidity. CONCLUSIONS: In recent years, the use of VATS for lobectomy has increased relative to thoracotomy. This trend has coincided with increased survival and shorter length of stay for VATS lobectomy compared with thoracotomy. Further studies are needed to identify comorbidities that identify ideal candidates for VATS lobectomy. PMID- 27779896 TI - Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome. AB - The Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial is a multicenter, randomized trial designed to assess the efficacy and safety of early neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome. This document provides background for interpretation of the trial results, and highlights unique design approaches that may inform future trials of acute illness. We describe the process by which ROSE was chosen as the inaugural trial of the multidisciplinary Prevention and Early Treatment of Acute Lung Injury Network, provide the trial methodology using the Consolidated Standards of Reporting Trials framework, and discuss key design challenges and their resolution. Four key design issues proved challenging-feasibility, choice of sedation depth in the control group, impact of emphasizing early treatment on enrollment criteria and protocol execution, and choice of positive end-expiratory pressure strategy. We used literature, an iterative consensus model, and internal surveys of current practice to inform design choice. ROSE will provide definitive, Consolidated Standards of Reporting Trials adherent data on early neuromuscular blockade for future patients with acute respiratory distress syndrome. Our multidisciplinary approach to trial design may be of use to other trials of acute illness. Clinical trial registered with www.clinicaltrials.gov (NCT02509078). PMID- 27779898 TI - Reflections About Inflammatory Bowel Disease and Vitamins A and D. AB - Ulcerative colitis and Crohn's disease are two major forms of the inflammatory bowel diseases (IBDs). Vitamin A (VA) and vitamin D (VD) may be associated with reduction in inflammation in these disorders. The aim of this review was to show the current evidence that may associate VA and VD with IBDs. Data linking VA, VD, and IBDs were studied. Both VA and VD may be related to the immune system in different manners. The active form of VA, retinoic acid, may be related to the growth factor-beta and release of interleukin-10 (IL-10), thus involved with the resolution of the inflammation. Its deficiency is associated with the increase of disease activity. The active form of VD is 1,25(OH)2D3 that produces biological effects via the nuclear hormone receptor named VD receptor (VDR), which may interfere with the immune cells and macrophages leading to the suppression of the inflammatory process by decreasing the release of TNF-alpha, IL-1, IL-6, and IL 8, IL-12, and IL-23. VDR may also activate nucleotide-binding oligomerization domain 2 expression and stimulate the production of the defensin and cathelicidin that are important to the homeostasis of the mucosal immune barrier. The use of VA and VD could be helpful in the treatment and prevention of IBDs but more studies are necessary to establish the precise role of these compounds in the prevention or remission of these inflammatory processes. PMID- 27779899 TI - Energy Density is Not a Consistent Correlate of Adiposity in Women During the Menopausal Transition. AB - PURPOSE: The association between the energy density (ED) of foods and adiposity has been reported previously. However, whether the contribution of ED to adiposity remains significant when controlled for energy intake (EI) and physical activity energy expenditure (PAEE) remains to be clearly established. We aimed to investigate the independent contribution of ED to variations in body composition in women during the menopausal transition. METHODS: Sixty-seven women from the MONET cohort study were analyzed. Seven-day food records were used to assess EI and ED. Body composition (body fat mass (FM) and trunk-fat mass (TFM)) was measured with dual-energy X-ray absorptiometry; PAEE was assessed with accelerometers. This secondary analysis of data included measurements obtained at years 1 and 5 of the study. RESULTS: Mean ED was correlated with FM (r = 0.22; P = 0.04) and TFM (r = 0.22; P = 0.04) at year 1, but not at year 5. The multiple regression analysis showed that EI and ED contributed to 14% of the variance in FM and TFM at year 1. CONCLUSION: These results suggest that ED is a modest but inconsistent determinant of adiposity in healthy women at the time of the menopause transition. PMID- 27779901 TI - Identification and Characterization of a Dendritic Cell Precursor in Parenchymal Lung Tissue. AB - The pulmonary parenchymal and mucosal microenvironments are constantly exposed to the external environment and thus require continuous surveillance to maintain steady-state immunological homeostasis. This is achieved by a mobile network of pulmonary dendritic cells (DC) and macrophages (mo) that constantly sample and process microenvironmental antigens into signals that can initiate or dampen inflammation, either locally or after onward migration to draining lymph nodes. The constant steady-state turnover of pulmonary DC and mo requires replenishment from bone marrow precursors; however, the nature of the pulmonary precursor cell (PC) remains unclear, although recent studies suggest that subsets of pulmonary DC may derive from circulating monocytic precursors. In the current study, we describe a population of cells in steady-state mouse lung tissue that has the surface phenotypic and ultrastructural characteristics of a common DC progenitor. Irradiation and reconstitution studies confirmed the bone marrow origins of this PC and showed that it had rapid depletion and reconstitution kinetics that were similar to those of DC, with a 50% repopulation by donor-derived cells by Days 7 9 after reconstitution. This was significantly faster than the rates observed for mo, which showed 50% repopulation by donor-derived cells beyond Days 16-21 after reconstitution. Purified PC gained antigen-presenting function and a cell surface phenotype similar to that of pulmonary DC after maturation in vitro, with light and electron microscopy confirming a myeloid DC morphology. To the best of our knowledge, this is the first study to describe a PC for DC in lung tissue; the findings have implications for the restoration of pulmonary immunological homeostasis after bone marrow transplant. PMID- 27779902 TI - Vitamin D Status and Bone Mineral Density is Influenced by Vitamin D Supplementation and Vitamin K1 Intake in Adults with Diabetes and Chronic Kidney Disease. AB - PURPOSE: Patients with diabetes (DM) and chronic kidney disease (CKD) are at increased risk for suboptimal bone health. The study objective was to investigate the relationships between vitamin D (vitD), vitamin K1 (vitK1), and calcium intake with bone mineral density (BMD) and vitamin D status in an ambulatory population with DM and CKD. METHODS: Adults (age 18-80 years; n = 62) with DM and CKD (stages 1-4) were recruited from the Northern Alberta Renal Program. Primary outcome variables included vitD, vitK1, and calcium intake; serum 25(OH)D, 1,25(OH)2D; and BMD as measured by dual X-ray absorptiometry. Statistical significance was determined at P < 0.05. RESULTS: Participants met the estimated average requirement or adequate intake for vitD, vitK1, and calcium intake in 73% (n = 45), 66% (n = 39), and 52% (n = 31), respectively, with a combined intake of micronutrient supplementation and diet. Participants had serum 25(OH)D concentrations >=75 nmol/L (n = 41), normal BMDs (n = 48), and 66% (n = 41/62) were taking vitD supplements (>1000 IU/D). BMD was positively influenced by serum 25(OH)D. However, serum 25(OH) >=100 nmol/L was associated with lower BMD (absolute and T-scores) for whole-body and spine (P <= 0.05). VitK1 intake (>=200 MUg/day) was associated with higher whole-body and femoral-neck BMDs (absoluteand T-scores; P <= 0.05). CONCLUSION: VitD status and BMD in adults with DM and CKD was influenced by vitD supplementation and vitK1 intake. PMID- 27779900 TI - Ablation of Pericyte-Like Cells in Lungs by Oropharyngeal Aspiration of Diphtheria Toxin. AB - We demonstrated previously that FoxD1-derived cells in the lung are enriched in pericyte-like cells in mouse lung. These cells express the common pericyte markers and are located adjacent to endothelial cells. In this study, we demonstrate the feasibility of administering diphtheria toxin (DT) by oropharyngeal aspiration as an approach to ablating FoxD1-derived cells. We crossed mice expressing Cre-recombinase under the FoxD1 promoter to Rosa26-loxP STOP-loxP-iDTR mice and generated a bitransgenic line (FoxD1-Cre;Rs26-iDTR) in which FoxD1-derived cells heritably express simian or human diphtheria toxin receptor and are sensitive to DT. We delivered low-dose (0.5 ng/g) and high-dose (1ng/g * 2) to FoxD1-Cre;Rs26-iDTR mice and littermate control mice by oropharyngeal aspiration and evaluated ablation by flow cytometry and immunohistochemistry. FoxD1-Cre mice showed a 40-50% reduction in PDGFRbeta+ cells by flow cytometry at Days 2 and 7 after DT administration, with a return of PDGFRbeta+ cells at Day 28. Confocal microscopy revealed an observable reduction in pericyte markers. Bronchoalveolar lavage fluid analysis revealed no significant differences in total protein, bronchoalveolar lavage fluid red blood cell, or white blood cell counts at low dose. However, at high-dose DT, there was a proinflammatory effect in the control mice and increased mortality associated with systemic toxicity in Cre+ mice. Low-dose DT reduced lung PDGFRbeta+ stromal cells in the FoxD1-Cre;iDTR transgenic model without a differential effect on lung inflammation in DT-sensitive and DT-insensitive animals. Low-dose DT is a viable method for transient lineage-specific stromal cell ablation in the lung that minimizes systemic toxicity. PMID- 27779903 TI - Monitoring Seven Potentially Pathogenic Escherichia coli Serogroups in a Closed Herd of Beef Cattle from Weaning to Finishing Phases. AB - The goal of this study was to monitor Shiga toxin-producing Escherichia coli (STEC) serogroups and virulence genes in cattle (n = 30) originating from a closed herd. Fecal samples were collected (1) at weaning, (2) upon arrival to a feedlot, (3) after 30 days on feed (DOF), and (4) after 135 DOF. DNA was extracted from feces for detection of virulence and serogroup genes by polymerase chain reaction (PCR) and immunomagnetic separation and pulsed-field gel electrophoresis (PFGE) were performed to collect and subtype STEC isolates. The prevalence of each serogroup measured by PCR from weaning to 135 DOF was 23.3 80.0% for O26, 33.3-46.7% for O45, 70.0-73.3% for O103, 36.7-86.7% for O111, 56.7 6.7% for O121, 26.7-66.7% for O145, and 66.7-90.0% for O157. Total fecal samples positive for virulence genes were 87.5% for ehxA, 85.8% for stx1, 60.0% for stx2, 52.5% for eae, and 44.2% for the autoagglutinating adhesion gene, saa. The prevalence of each serogroup and virulence gene tended to increase by 135 DOF, with the exception of O121, stx2, and saa. The frequency of detection of some virulence genes was largely affected over time, most notably with saa and stx2 decreasing, and eae increasing when cattle were transitioned to concentrate-based diets. PFGE analysis of O157 and O103 fecal isolates revealed dominant pulsotypes, but the presence of identical O103 isolates, which differed in virulence profiles. Overall, this study showed that fecal shedding of E. coli serogroups and virulence-associated genes are highly variable over time as cattle move from ranch to feedlot. To mitigate STEC, it is important to understand the factors affecting both prevalence of individual serogroups and the presence of virulence factors. PMID- 27779904 TI - Food and Culinary Knowledge and Skills: Perceptions of Undergraduate Dietetic Students. AB - PURPOSE: The objective of the current study was to examine food and culinary skills and knowledge of dietetic students. METHODS: An online bilingual survey was created using Survey MonkeyTM to explore the skills, knowledge, and perceptions of undergraduate dietetic students regarding food and cooking. Chi square and logistic regression analyses were used to compare skills and knowledge of food and culinary concepts. RESULTS: The final sample included second- (n = 22) and third-year (n = 22) students within the Baccalaureat specialise en sciences de la nutrition program at the University of Ottawa. There were no significant differences (P > 0.05) on 3 of 4 skills (preparing a cake, whipping egg whites, or baking a yeast bread) or knowledge concepts (fold, baste, braise, grill, and poach) amongst second- and third-year students. Third-year students perceived more skill in preparing a bechamel sauce. There was a trend for third year students (59%) to have higher food and cooking skills and knowledge compared with second-year students (32%). CONCLUSIONS: Perceived knowledge and confidence was proportional with the academic year, whereas overall knowledge and skills of food and culinary concepts were moderate among both groups of students. This research suggests that more dedicated time may need to be spent on food and cooking competencies in undergraduate dietetic education. PMID- 27779907 TI - The Neurocognitive Cost of Enhancing Cognition with Methylphenidate: Improved Distractor Resistance but Impaired Updating. AB - A balance has to be struck between supporting distractor-resistant representations in working memory and allowing those representations to be updated. Catecholamine, particularly dopamine, transmission has been proposed to modulate the balance between the stability and flexibility of working memory representations. However, it is unclear whether drugs that increase catecholamine transmission, such as methylphenidate, optimize this balance in a task-dependent manner or bias the system toward stability at the expense of flexibility (or vice versa). Here we demonstrate, using pharmacological fMRI, that methylphenidate improves the ability to resist distraction (cognitive stability) but impairs the ability to flexibly update items currently held in working memory (cognitive flexibility). These behavioral effects were accompanied by task-general effects in the striatum and opposite and task-specific effects on neural signal in the pFC. This suggests that methylphenidate exerts its cognitive enhancing and impairing effects through acting on the pFC, an effect likely associated with methylphenidate's action on the striatum. These findings highlight that methylphenidate acts as a double-edged sword, improving one cognitive function at the expense of another, while also elucidating the neurocognitive mechanisms underlying these paradoxical effects. PMID- 27779905 TI - Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation. AB - RATIONALE: Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. OBJECTIVES: To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. METHODS: Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. MEASUREMENTS AND MAIN RESULTS: Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2-year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40. CONCLUSIONS: A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy. PMID- 27779908 TI - States of Mind: Characterizing the Neural Bases of Focus and Mind-wandering through Dynamic Functional Connectivity. AB - During tasks that require continuous engagement, the mind alternates between mental states of focused attention and mind-wandering. Existing research has assessed the functional connectivity of intrinsic brain networks underlying the experience and training of these mental states using "static" approaches that assess connectivity across an entire task. To disentangle the different functional connectivity between brain regions that occur as the mind fluctuates between discrete brain states, we employed a dynamic functional connectivity approach that characterized brain activity using a sliding window. This approach identified distinct states of functional connectivity between regions of the executive control, salience, and default networks during a task requiring sustained attention to the sensations of breathing. The frequency of these distinct brain states demonstrated opposing correlations with dispositional mindfulness, suggesting a correspondence to the mental states of focused attention and mind-wandering. We then determined that an intervention emphasizing the cultivation of mindfulness increased the frequency of the state that had been associated with a greater propensity for focused attention, especially for those who improved most in dispositional mindfulness. These findings provide supporting evidence that mind-wandering involves the corecruitment of brain regions within the executive and default networks. More generally, this work illustrates how emerging neuroimaging methods may allow for the characterization of discrete brain states based on patterns of functional connectivity even when external indications of these states are difficult or impossible to measure. PMID- 27779906 TI - Medial Prefrontal-Medial Temporal Theta Phase Coupling in Dynamic Spatial Imagery. AB - Hippocampal-medial prefrontal interactions are thought to play a crucial role in mental simulation. Notably, the frontal midline/medial pFC (mPFC) theta rhythm in humans has been linked to introspective thought and working memory. In parallel, theta rhythms have been proposed to coordinate processing in the medial temporal cortex, retrosplenial cortex (RSc), and parietal cortex during the movement of viewpoint in imagery, extending their association with physical movement in rodent models. Here, we used noninvasive whole-head MEG to investigate theta oscillatory power and phase-locking during the 18-sec postencoding delay period of a spatial working memory task, in which participants imagined previously learned object sequences either on a blank background (object maintenance), from a first-person viewpoint in a scene (static imagery), or moving along a path past the objects (dynamic imagery). We found increases in 4- to 7-Hz theta power in mPFC when comparing the delay period with a preencoding baseline. We then examined whether the mPFC theta rhythm was phase-coupled with ongoing theta oscillations elsewhere in the brain. The same mPFC region showed significantly higher theta phase coupling with the posterior medial temporal lobe/RSc for dynamic imagery versus either object maintenance or static imagery. mPFC theta phase coupling was not observed with any other brain region. These results implicate oscillatory coupling between mPFC and medial temporal lobe/RSc theta rhythms in the dynamic mental exploration of imagined scenes. PMID- 27779909 TI - Early Cross-modal Plasticity in Adults. AB - It is known that, after a prolonged period of visual deprivation, the adult visual cortex can be recruited for nonvisual processing, reflecting cross-modal plasticity. Here, we investigated whether cross-modal plasticity can occur at short timescales in the typical adult brain by comparing the interaction between vision and touch during binocular rivalry before and after a brief period of monocular deprivation, which strongly alters ocular balance favoring the deprived eye. While viewing dichoptically two gratings of orthogonal orientation, participants were asked to actively explore a haptic grating congruent in orientation to one of the two rivalrous stimuli. We repeated this procedure before and after 150 min of monocular deprivation. We first confirmed that haptic stimulation interacted with vision during rivalry promoting dominance of the congruent visuo-haptic stimulus and that monocular deprivation increased the deprived eye and decreased the nondeprived eye dominance. Interestingly, after deprivation, we found that the effect of touch did not change for the nondeprived eye, whereas it disappeared for the deprived eye, which was potentiated after deprivation. The absence of visuo-haptic interaction for the deprived eye lasted for over 1 hr and was not attributable to a masking induced by the stronger response of the deprived eye as confirmed by a control experiment. Taken together, our results demonstrate that the adult human visual cortex retains a high degree of cross-modal plasticity, which can occur even at very short timescales. PMID- 27779910 TI - Decoding Dynamic Brain Patterns from Evoked Responses: A Tutorial on Multivariate Pattern Analysis Applied to Time Series Neuroimaging Data. AB - Multivariate pattern analysis (MVPA) or brain decoding methods have become standard practice in analyzing fMRI data. Although decoding methods have been extensively applied in brain-computer interfaces, these methods have only recently been applied to time series neuroimaging data such as MEG and EEG to address experimental questions in cognitive neuroscience. In a tutorial style review, we describe a broad set of options to inform future time series decoding studies from a cognitive neuroscience perspective. Using example MEG data, we illustrate the effects that different options in the decoding analysis pipeline can have on experimental results where the aim is to "decode" different perceptual stimuli or cognitive states over time from dynamic brain activation patterns. We show that decisions made at both preprocessing (e.g., dimensionality reduction, subsampling, trial averaging) and decoding (e.g., classifier selection, cross-validation design) stages of the analysis can significantly affect the results. In addition to standard decoding, we describe extensions to MVPA for time-varying neuroimaging data including representational similarity analysis, temporal generalization, and the interpretation of classifier weight maps. Finally, we outline important caveats in the design and interpretation of time series decoding experiments. PMID- 27779912 TI - Stronger Together: Use of Storytelling at a Dietetics Conference to Promote Professional Collaboration. AB - During a Dietitians of Canada conference session (2015), 4 facilitators drew upon "Alice's Adventures in Wonderland" (Alice) to engage participants in discussing the future of dietetic education. The aim was to feature Nova Scotia (NS) collaborative experiences as an example of dietetic education planning that could be implemented elsewhere. Three vignettes from the Alice story were chosen as metaphoric representations of dilemmas and assumptions commonly faced by dietetic educators. Story quotations and facilitator questions related to each vignette guided discussion. The 3-part story-based arts approach of hearing stories, recognizing stories, and telling stories enabled participants to reflect on their own practice, relate to the challenges of others, and question conventional wisdom. Participants heard the Alice stories, recognized their experiences through the NS examples and had an opportunity to tell their own stories during discussions. Participants identified barriers to and strategies for collaborative planning in their own regions. Evaluation suggests most participants were positively engaged by the storytelling approach. Participants recommended that future offerings allow more time for orientation and for completion of planned activities. Bilingual programming should also be considered. Participants valued the unconventional approach to workshop engagement and planned to implement it in their own workplaces. PMID- 27779911 TI - Neural Systems Underlying Individual Differences in Intertemporal Decision making. AB - Excessively choosing immediate over larger future rewards, or delay discounting (DD), associates with multiple clinical conditions. Individual differences in DD likely depend on variations in the activation of and functional interactions between networks, representing possible endophenotypes for associated disorders, including alcohol use disorders (AUDs). Numerous fMRI studies have probed the neural bases of DD, but investigations of large-scale networks remain scant. We addressed this gap by testing whether activation within large-scale networks during Now/Later decision-making predicts individual differences in DD. To do so, we scanned 95 social drinkers (18-40 years old; 50 women) using fMRI during hypothetical choices between small monetary amounts available "today" or larger amounts available later. We identified neural networks engaged during Now/Later choice using independent component analysis and tested the relationship between component activation and degree of DD. The activity of two components during Now/Later choice correlated with individual DD rates: A temporal lobe network positively correlated with DD, whereas a frontoparietal-striatal network negatively correlated with DD. Activation differences between these networks predicted individual differences in DD, and their negative correlation during Now/Later choice suggests functional competition. A generalized psychophysiological interactions analysis confirmed a decrease in their functional connectivity during decision-making. The functional connectivity of these two networks negatively correlates with alcohol-related harm, potentially implicating these networks in AUDs. These findings provide novel insight into the neural underpinnings of individual differences in impulsive decision-making with potential implications for addiction and related disorders in which impulsivity is a defining feature. PMID- 27779913 TI - Estrogen Suppresses Interaction of Melanocortin 2 Receptor and Its Accessory Protein in the Primate Fetal Adrenal Cortex. AB - We have shown that fetal adrenal fetal zone (FZ) volume and serum dehydroepiandrosterone sulfate (DHAS) levels were increased, whereas definitive and transitional zone (DZ/TZ) volume was unaltered, in baboons in which estrogen levels were suppressed by the administration of the aromatase inhibitor letrozole. The interaction of the melanocortin 2 receptor (MC2R) with its accessory protein (MRAP) is essential for trafficking MC2R to the adrenal cell surface for binding to ACTH. The present study determined whether the estrogen dependent regulation of fetal adrenocortical development is mediated by ACTH and/or expression/interaction of MC2R and MRAP. Fetal pituitary proopiomelanocortin mRNA and plasma ACTH levels and fetal adrenal MC2R-MRAP interaction were assessed in baboons in which estrogen was suppressed/restored by letrozole/letrozole plus estradiol administration during the second half of gestation. Although fetal pituitary proopiomelanocortin and plasma ACTH levels and fetal adrenal MC2R and MRAP protein levels were unaltered, MC2R-MRAP interaction was 2-fold greater (P < .05) in the DZ/TZ in letrozole-treated baboons than in untreated animals and restored by letrozole plus estradiol treatment. We propose that the increasing levels of estradiol with advancing pregnancy suppress interaction of MC2R with MRAP, thereby diminishing MC2R movement to the cell membrane in the DZ/TZ. This would be expected to reduce progenitor cell proliferation in the DZ and migration to the FZ, thereby restraining FZ growth and DHAS production to maintain fetal adrenal DHAS and placental estradiol levels in a physiological range late in gestation. PMID- 27779914 TI - Estradiol Synthesis in Gut-Associated Lymphoid Tissue: Leukocyte Regulation by a Sexually Monomorphic System. AB - 17beta-estradiol is a potent sex hormone synthesized primarily by gonads in females and males that regulates development and function of the reproductive system. Recent studies show that 17beta-estradiol is locally synthesized in nonreproductive tissues and regulates a myriad of events, including local inflammatory responses. In this study, we report that mesenteric lymph nodes (mLNs) and Peyer's patches (Pps) are novel sites of de novo synthesis of 17beta estradiol. These secondary lymphoid organs are located within or close to the gastrointestinal tract, contain leukocytes, and function at the forefront of immune surveillance. 17beta-estradiol synthesis was initially identified using a transgenic mouse with red fluorescent protein coexpressed in cells that express aromatase, the enzyme responsible for 17beta-estradiol synthesis. Subsequent immunohistochemistry and tissue culture experiments revealed that aromatase expression was localized to high endothelial venules of these lymphoid organs, and these high endothelial venule cells synthesized 17beta-estradiol when isolated and cultured in vitro. Both mLNs and Pps contained 17beta-estradiol with concentrations that were significantly higher than those of peripheral blood. Furthermore, the total amount of 17beta-estradiol in these organs exceeded that of the gonads. Mice lacking either aromatase or estrogen receptor-beta had hypertrophic Pps and mLNs with more leukocytes than their wild-type littermates, demonstrating a role for 17beta-estradiol in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase expression, 17beta estradiol content, or steroidogenic capacity in these lymphoid organs. PMID- 27779915 TI - GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40). AB - Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence-activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice. The TG-induced increase in plasma GLP-1 was only significantly reduced in the GPR119-deficient and the FFA1/FFA4 double deficient mice, but not in the FFA1, and FFA4-deficient mice. In mouse colonic crypt cultures the synthetic FFA1 agonists, TAK-875 stimulated GLP 1 secretion to a similar extent as the prototype GLP-1 secretagogue neuromedin C; this, however, only corresponded to approximately half the maximal efficiency of the GPR119 agonist AR231453, whereas the GPR120 agonist Metabolex-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist, a clear synergistic, ie, more than additive, effect was observed. It is concluded that the 2-monoacylglycerol receptor GPR119 is at least as important as the long-chain fatty acid receptor FFA1 in mediating the TG-induced secretion of incretins and that the 2 receptors act in synergy, whereas FFA4 plays a minor if any role. PMID- 27779917 TI - Impact of Checklist Use on Wellness and Post-Elective Surgery Appointments in a Veterinary Teaching Hospital. AB - Cognitive functioning is often compromised with increasing levels of stress and fatigue, both of which are often experienced by veterinarians. Many high-stress fields have implemented checklists to reduce human error. The use of these checklists has been shown to improve the quality of medical care, including adherence to evidence-based best practices and improvement of patient safety. Although it has been recognized that veterinary medicine would likely demonstrate similar benefits, there have been no published studies to date evaluating the use of checklists for improving quality of care in veterinary medicine. The purpose of the current study was to evaluate the impact of checklists during wellness and post-elective surgery appointments conducted by fourth-year veterinary students within their Community Practice rotation at a US veterinary teaching hospital. Students were randomly assigned to one of two groups: those who were specifically asked to use the provided checklists during appointments, and those who were not asked to use the checklists but had them available. Two individuals blinded to the study reviewed the tapes of all appointments in each study group to determine the amount and type of medical information offered by veterinary students. Students who were specifically asked to use the checklists provided significantly more information to owners, with the exception of keeping the incision clean. Results indicate the use of checklists helps students provide more complete information to their clients, thereby potentially enhancing animal care. PMID- 27779918 TI - Producing Interdisciplinary Competent Professionals: Integrating One Health Core Competencies into the Veterinary Curriculum at the University of Rwanda. AB - Infectious diseases of grave concern to human health are emerging from wildlife and livestock populations in multiple regions of the world. Responding effectively to these emerging pandemics requires engagement of multidisciplinary groups of professionals. Using a One Health approach, One Health Central and Eastern Africa (OHCEA), a network of seven schools of public health and seven veterinary schools, with the support of the United States Agency for International Development (USAID), has engaged in curriculum review with the aim of building the skills of multidisciplinary groups of professionals to improve their capacity to respond to emerging infectious diseases. Through stakeholder analysis and curriculum development workshops, the University of Rwanda's School of Veterinary Medicine, in association with Tufts University, revised its curriculum to incorporate One Health competencies to be better prepared to respond to any infectious disease outbreak in Africa. The revised curriculum aimed to build cross-sectoral skills and knowledge; transform students' ways of thinking about infectious disease outbreak response; link human, veterinary, and wildlife health training opportunities; and strengthen community frontline responder training. Eight different disciplines engaged in the curriculum review process: Veterinary Medicine, Livestock Production, Wildlife and Aquatic Resources, Environmental Health and Epidemiology, Communication Technology, Engineering, Agriculture, and Public Health. One Health competencies such as communication, collaboration, leadership, and advocacy were added to the new curriculum, helping ensure that each professional be appropriately equipped with skills to recognize and respond effectively to any emerging infections. PMID- 27779916 TI - Developmental and Thyroid Hormone Regulation of the DNA Methyltransferase 3a Gene in Xenopus Tadpoles. AB - Thyroid hormone is essential for normal development in vertebrates. In amphibians, T3 controls metamorphosis by inducing tissue-specific gene regulation programs. A hallmark of T3 action is the modification of chromatin structure, which underlies changes in gene transcription. We found that mRNA for the de novo DNA methyltransferase (DNMT) dnmt3a, but not dnmt1, increased in the brain of Xenopus tadpoles during metamorphosis in parallel with plasma [T3]. Addition of T3 to the rearing water caused a time-dependent increase in dnmt3a mRNA in tadpole brain, tail, and hind limb. By analyzing data from a genome-wide analysis of T3 receptor (TR) binding in tadpole tail, we identified several putative T3 response elements (TREs) within the dnmt3a locus. Using in vitro DNA binding, transient transfection-reporter, and chromatin immunoprecipitation assays for TRs, we identified two functional TREs at -7.1 kb and +5.1 kb relative to the dnmt3a transcription start site. Sequence alignment showed that these TREs are conserved between two related frog species, X. laevis and X. tropicalis, but not with amniotes. Our previous findings showed that this gene is directly regulated by liganded TRs in mouse brain, and whereas the two mouse TREs are conserved among Eutherian mammals, they are not conserved in Xenopus species. Thus, although T3 regulation of dnmt3a may be an ancient pathway in vertebrates, the genomic sites responsible for hormone regulation may have diverged or arisen by convergent evolution. We hypothesize that direct T3 regulation of dnmt3a may be an important mechanism for modulating global changes in DNA methylation. PMID- 27779919 TI - Teaching Tip-Studying to Become a Veterinarian: A Course for Student Support. AB - During the last decade, concerns over veterinary students' stress have been expressed in several studies, and the need for student support has become evident. In addition, the importance of professional and personal identity development in veterinary curricula has been widely recognized. There is a need to integrate academic and professional skills instruction with training in personal-life balance. Even though tools for student support and stress management exist within universities, reports on active and creative practices in veterinary education are scarce. We report here a course that has been organized twice as an optional part of veterinary studies to provide students with tools for everyday life and personal development toward a future veterinary career. Students defined their own learning objectives in this course, and they reported having received tools and knowledge especially for time management and stress control. The course gave the students an opportunity to step back from their busy schedules, think over their lives and actions, and even take concrete actions that have a positive effect on their well-being. The rich qualitative material collected during the pilot course has been used not only for developing the course further but also for development of the mandatory curriculum. PMID- 27779920 TI - Formative and Summative Assessment in Veterinary Pathology and Other Courses at a Mexican Veterinary College. AB - The Faculty of Veterinary Medicine and Animal Science of the National Autonomous University of Mexico (UNAM) uses the Moodle learning management system for formative and summative computer assessment. The authors of this article-the teacher primarily responsible for Moodle implementation and a researcher who is a recent Moodle adopter-describe and discuss the students' and teachers' attitudes to summative and formative computer assessment in Moodle. Item analysis of quiz results helped us to identify and fix poorly performing questions, which greatly reduced student complaints and improved objective assessment. The use of certainty-based marking (CBM) in formative assessment in veterinary pathology was well received by the students and should be extended to more courses. The importance of having proficient computer support personnel should not be underestimated. A properly translated language pack is essential for the use of Moodle in a language other than English. PMID- 27779921 TI - An Interactive Teddy Bear Clinic Tour: Teaching Veterinary Students How to Interact with Young Children. AB - Although there are existing guidelines for teaching and learning skillful client communication, there remains a need to integrate a developmental focus into veterinary medical curricula to prepare students for interactions with children who accompany their companion animals. The objectives of this teaching tip are (1) to describe the use of a Teddy Bear Clinic Tour as an innovative, applied practice method for teaching veterinary students about clinical communication with children, and (2) to provide accompanying resources to enable use of this method to teach clinical communication at other facilities. This paper includes practical guidelines for organizing a Teddy Bear Clinic Tour at training clinics or colleges of veterinary medicine; an anecdotal description of a pilot study at the Ontario Veterinary College Smith Lane Animal Hospital; and printable resources, including a list of specific clinical communication skills, a sample evaluation sheet for supervisors and students, recommendations for creating a child-friendly environment, examples of child-friendly veterinary vocabulary, and a sample script for a Teddy Bear Clinic Tour. Informed by the resources provided in this teaching tip paper, the Teddy Bear Clinic Tour can be used at your facility as a unique teaching method for clinical communication with children and as a community outreach program to advertise the services at the facility. PMID- 27779922 TI - Intervention Mapping to Develop a Print Resource for Dog-Walking Promotion in Canada. AB - Promoting dog walking among dog owners is consistent with One Health, which focuses on the mutual health benefits of the human-animal relationship for people and animals. In this study, we used intervention mapping (a framework to develop programs and resources for health promotion) to develop a clearer understanding of the determinants of dog walking to develop curricular and educational resources for promoting regular dog walking among dog owners. Twenty-six adult dog owners in Ontario participated in a semi-structured interview about dog walking in 2014. Thematic analysis entailing open, axial, and selective coding was conducted. Among the reasons why the participating dog owners walk their dog were the obligation to the dog, the motivation from the dog, self-efficacy, the dog's health, the owner's health, socialization, a well-behaved dog, and having a routine. The main barriers to dog walking were weather, lack of time, the dog's behavior while walking, and feeling unsafe. We compared interview results to findings in previous studies of dog walking to create a list of determinants of dog walking that we used to create a matrix of change objectives. Based on these results, we developed a print resource to promote regular dog walking among dog owners. The findings can be used by veterinary educators to inform course content that specifically educates veterinary students on the promotion of dog walking among dog owners and the benefits to both humans and animals. The study also offers veterinarians a further understanding upon which to initiate a conversation and develop educational resources for promoting regular dog walking among dog-owning clients. PMID- 27779924 TI - Malaria Vector Control. PMID- 27779923 TI - Photochemical Elimination of Endocrine Disrupting Chemical (EDC) by ZnO Nanoparticles, Synthesized by Gel Combustion. AB - Zinc Oxide (ZnO) nanoparticles prepared by gel combustion synthesis using cassava pearl starch have been characterized by various microscopy and spectroscopy techniques. The particle size averaged around 45 nm, revealed zincite structure, hexagonal, agglomerated morphology and possessed an excellent photocatalytic activity in sunlight. Contrary to the existing literature survey, this photocatalyst possessed a band gap of 2.7 eV, causing an extended absorption towards broader range of the solar spectrum, thus making it an excellent visible light-activated photocatalyst. Photocatalytic activity was investigated on one of the highly resistant, most-focused endocrine disrupting chemical (EDC) benzophenone-3 (BP-3), which is used in personnel care products. The observations reveal a near complete photooxidative degradation of BP-3. A reaction mechanism for the photooxidative pathway was proposed based on the isolated intermediates. PMID- 27779925 TI - Discovery to Development: Insecticides for Malaria Vector Control. AB - This report provides an outline of a program for the discovery of new public health insecticides for malaria vector control. The status of malaria vector control is first reviewed in terms of the chemical, physical chemical, and biochemical properties of the current WHOPES-recommended and approved vector control agents. This review provides a basis for a discussion on the critical need for discovery and development of multiple new chemical malaria vector control agents with novel and diverse modes of action. The Innovative Vector Control Consortium (IVCC) New Active Ingredient Target Product Profile (TPP) describes the essential attributes for a successful new malaria vector control agent and then serves as the basis for development of a discovery cascade. The cascade addresses these attributes experimentally at each stage of the discovery process - from design and assembly of an appropriate collection of chemicals for screening, through development of testing protocols to sort candidates, and into the detailed profiling of advanced pre-development candidates against TPP requirements. In addition, this program defines a staged development system to provide intermediate guidance to the insecticide explorer regarding the progress of their discovery program against the ultimate product goal. PMID- 27779926 TI - Discovery of Rigidified alpha,beta-Unsaturated Imines as New Resistance-breaking Insecticides for Malaria Vector Control. AB - During our continuous search for new resistance-breaking insecticides applicable to malaria vector control, a new class of alpha,beta-unsaturated imines was identified by applying the principle of conformational rigidification as a powerful tool for compound optimisation. Herein we describe the successful synthesis of these compounds and their biological test results. Our lead compound 16 from this insecticidal class outperforms market standards, notably for the control of mosquito strains that exhibit either metabolic or target-site resistance to these established insecticides. In our model system for insecticide treated mosquito nets the compound reveals long-lasting efficacy for up to several months. PMID- 27779927 TI - Identification and Optimization of New Leads for Malaria Vector Control. AB - A significant proportion of the world's population remains at risk from malaria, and whilst great progress has been made in reducing the number of malaria cases globally through the use of vector control insecticides, these gains are under threat from the emergence of insecticide resistance. The spread of resistance in the vector populations, principally to pyrethroids, is driving the need for the development of new tools for malaria vector control. In order to identify new leads 30,000 compounds from the Syngenta corporate chemical collection were tested in a newly developed screening platform. More than 3000 compounds (10%) showed activity at <=200 mg active ingredient (AI) litre-1 against Anopheles stephensi. Further evaluation resulted in the identification of 12 viable leads for the control of adult mosquitoes, most originating from current or former insecticide projects. Surprisingly, one of these leads emerged from a former PPO herbicide project and one from a former complex III fungicide project. This indicates that representatives of certain herbicide and fungicide projects and modes of action can also represent a valuable source of leads for malaria vector control. Optimization of the diphenyl ether lead 1 resulted in the identification of the cyano-pyridyl compound 31. This compound 31 exhibits good activity against mosquito species including rdl resistant Anopheles. It is only slightly weaker than permethrin and does not show relevant levels of cross-resistance to the organochlorine insecticide dieldrin. PMID- 27779928 TI - Bivalent Carbamates as Novel Control Agents of the Malaria Mosquito, Anopheles gambiae. AB - Widespread pyrethroid resistance has caused an urgent need to develop new insecticides for control of the malaria mosquito, Anopheles gambiae. Insecticide discovery efforts were directed towards the construction of bivalent inhibitors that occupy both the peripheral and catalytic sites of the mosquito acetylcholinesterase (AChE). It was hypothesized that this approach would yield a selective, high potency inhibitor that would also circumvent known catalytic site mutations (e.g. G119S) causing target site resistance. Accordingly, a series of bivalent phthalimide-pyrazole carbamates were prepared having an alkyl chain linker of varying length, along with other modifications. The most active compound was (1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-4-yl methylcarbamate, 8a), which has a chain length of three carbons, good mosquito anticholinesterase activity, and ca. 5-fold selectivity compared to human AChE. Moreover, this compound was toxic to mosquitoes by topical application (LD50 = 63 ng/female) with only 6-fold cross resistance in the Akron strain of Anopheles gambiae that showed 50- to 60-fold resistance to conventional carbamate insecticides. However, contact lethality in the WHO paper assay was disappointing. The implications of these results for design of new mosquitocides are discussed. PMID- 27779929 TI - Vector Control in Developing Countries: Challenges and Solutions. AB - Undoubtedly, reducing vector populations or their interactions with hosts below a critical level is a practical and proven method of disease control. Introduction of insecticide-treated bed nets has significantly reduced malaria in some parts of the world. However, for many reasons, implementation of such strategies is challenging and the protection offered by particular products limited: bed nets are only effective during sleep. Other methods have been launched, but low customer appeal, high cost, low specificity, and lack of sustainability and effectiveness are often reasons for failure. The proposed solution to these problems should also consider safety and environmental impact and be forward thinking for continued functioning in a rapidly changing local environment. To this end, a chemical system has been identified that could be used to make an autonomous trap with chemo-attractant system. PMID- 27779931 TI - Evaluation of Commercial Agrochemicals as New Tools for Malaria Vector Control. AB - Malaria is a vector-borne and life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. The vector control insecticide market represents a small fraction of the crop protection market and is estimated to be valued at up to $500 million at the active ingredient level. Insecticide resistance towards the current WHOPES approved products urgently requires the development of new tools to protect communities against the transmission of malaria. The evaluation of commercial products for malaria vector control is a viable and cost effective strategy to identify new malaria vector control products. Several examples of such spin-offs from crop protection insecticides are already evidencing the success of this strategy, namely pirimiphos-methyl for indoor residual sprays and spinosad, diflubenzuron, novaluron, and pyriproxifen for mosquito larvae control, a supplementary technology for control of malaria vectors. In our study the adulticidal activities of 81 insecticides representing 23 insecticidal modes of action classes, 34 fungicides from 6 fungicidal mode of action classes and 15 herbicides from 2 herbicidal modes of action classes were tested in a newly developed screening system. WHOPES approved insecticides for malaria vector control consistently caused 80-100% mortality of adult Anopheles stephensi at application rates between 0.2 and 20 mg active ingradient (AI) litre-1. Chlorfenapyr, fipronil, carbosulfan and endosulfan showed the expected good activity. Four new insecticides and three fungicides with promising activity against adult mosquitoes were identified, namely the insecticides acetamiprid, thiamethoxam, thiocyclam and metaflumizone and the fungicides diflumetorin, picoxystrobin, and fluazinam. Some of these compounds certainly deserve to be further evaluated for malaria vector control. This is the first report describing good activity of commercial fungicides against malaria vectors. PMID- 27779933 TI - Rapid and Straightforward Quantification of Recombinant Proteins Using Fluorescence Polarization. PMID- 27779930 TI - Chemosterilants for Control of Insects and Insect Vectors of Disease. AB - Both historically and at present, vector control is the most generally effective means of controlling malaria transmission. Insecticides are the predominant method of vector control, but the sterile insect technique (SIT) is a complementary strategy with a successful track record in both agricultural and public health sectors. Strategies of genetic and radiation-induced sterilization of Anopheles have to date been limited by logistical and/or regulatory hurdles. A safe and effective mosquito chemosterilant would therefore be of major utility to future deployment of SIT for malaria control. Here we review the prior and current use of chemosterilants in SIT, and assess the potential for future research. Recent genomic and proteomic studies reveal opportunities for specific targeting of seminal fluid proteins, and the capacity to interfere with sperm motility and storage in the female. PMID- 27779934 TI - Nucleotide and Nucleotide Sugar Analysis in Cell Extracts by Capillary Electrophoresis. AB - In biotechnological processes the intracellular level of nucleotides and nucleotide sugars have a direct impact on the post-translational modification (glycosylation) of the therapeutic protein products and on the exopolysaccharide pattern of the cells. Thus, they are precursors and also key components in the production of glycoproteins and glycolipids. All four nucleotides (at different phosphorylation stages) and their natural sugar derivatives coexist in biological samples. Their relative ratios depend on the actual conditions under which the cells are grown. Therefore, their simultaneous determination at different time points and different cell culture conditions in biotechnological samples is of interest in order to develop the optimal cell culture process. In our study capillary electrophoresis (CE) combined with UV detection @ 260 nm was selected for the separation and quantification of the complex nucleotide mixture of the structurally very similar nucleotides and nucleotide sugars in cell extracts. The high separation efficiency of CE as well as its insensitivity to the complex cell matrix makes this method superior to commonly used HPLC methods. In our study eleven nucleotides and six nucleotide sugars were analyzed. A robust and reproducible analysis system was developed. As background electrolyte borate (40 mM, pH 9.5) was used containing 1% PEG (MW 35'000 Da) which enhanced resolution. In order to obtain high reproducibility in terms of migration time, mandatory for the unambiguous identification of the single compounds in the complex cell extract mixtures, dynamic coating was also employed. The method was tested for CHO cell extracts where three sugar nucleotides and seven nucleotides were identified and quantified using GDP-Glc as internal standard. PMID- 27779935 TI - Thanks to the Clever 'String Pullers' at biotechnet. AB - For years biotechnet Switzerland has provided access to biotechnology capacity at Swiss universities of applied sciences, universities and research centres. Innovative companies put their trust in its support and services in research, development and training. Now two of the individuals who have made biotechnet what it is while keeping it on course for the future are departing. PMID- 27779936 TI - Off they go: Single-use Technology in Future Production BioTech 2016 Conference at ZHAW Waedenswil. AB - "Keep up with today's single-use technology standard but also remain one step ahead" - that could have been the motto of the BioTech 2016 conference at ZHAW Waedenswil on September 5 and 6, which brought together manufacturers, suppliers, users, regulatory specialists and representatives of organizations in this field to implement single-use devices all over the world. It was an effectiveness analysis of the trend to replace reusable equipment in production facilities with single-use components. PMID- 27779937 TI - Physical Activity Changes during Pregnancy in a Comparative Impact Trial. AB - OBJECTIVES: Delta Healthy Sprouts was designed to test the comparative impact of 2 home visiting curricula on weight status, dietary intake, physical activity, and other health behaviors of rural, southern African-American women and their infants. Results pertaining to physical activity outcomes in the gestational period are reported. METHODS: Eighty-two women, early in their second trimester of pregnancy, were enrolled and randomly assigned to one of 2 treatment arms. Self-reported physical activity was measured 3 times in the gestational period (gestational months 4, 6 and 8). Generalized linear mixed models were used to test for significant treatment, time, and treatment by time effects on weekly minutes of moderate-to-vigorous physical activity (MVPA). RESULTS: Significantly less MVPA was performed at gestational month 8 when compared with gestational month 4 (enrollment) for both treatment arms. Statistically significant effects were not found for treatment or treatment by time interaction. CONCLUSIONS: Neither the Parents as Teachers (control) curriculum nor the Parents as Teachers Enhanced intervention proved effective at increasing or maintaining MVPA in this cohort of pregnant women. Lack of adequate physical activity in pregnancy remains an important public health concern, especially given its known health benefits. PMID- 27779938 TI - Anxiety Mediates Perceived Discrimination and Health in African-American Women. AB - OBJECTIVE: We examined the mediational role of symptoms of anxiety in accounting for the association of discrimination and chronic health conditions among African American women. METHODS: Participants were 646 African-American women who completed self-report measures of perceived racial discrimination, symptoms of anxiety, and diagnosed chronic health problems. RESULTS: We examined the mediation hypothesis using a path analytic procedure. Mediational analyses indicated that, above and beyond symptoms of depression, age, and education status, anxiety symptoms were associated with both racial discrimination (beta = .03, SE = .01, p < .001) and chronic health problems (beta = .33, SE = .09, p < .001) and significantly mediated the discrimination-health association (beta = .01, SE = .01, p = .16). CONCLUSIONS: These findings highlight the potentially vital role of symptoms of anxiety in the process that occurs from an individual's perception of discrimination to reported chronic health outcomes. Future research expanding our understanding of the interconnection of psychosocial stressors, discrimination, and their biological sequelae is needed. PMID- 27779939 TI - Prevalence of Internet Gaming Disorder among Korean Adolescents and Associations with Non-psychotic Psychological Symptoms, and Physical Aggression. AB - OBJECTIVE: We examined the prevalence rates of Internet gaming disorder among South Korean middle school students, the dominant symptoms of Internet gaming disorder, and the interrelationships between such disorder and non-psychotic psychological symptoms (ie, anxiety, depression, and impulsiveness) and with physical aggression. METHODS: Data were collected from a national sample of 2024 students (70.3% gamers; 50.6% boys). Gaming disorder and prevalent symptoms were measured by the 9 diagnostic criteria proposed in DSM-5. RESULTS: Our results showed 5.9% of the sample (boys 10.4%, girls 1.2%) was classified as adolescents with gaming disorder. Meanwhile, 8% (boys 14.2%, girls 5.9%) of the sample was found to be at high risk of gaming disorder. The prevalent symptoms were mood modification, behavioral salience, conflict, withdrawal, and relapse, in that order. A total of 9.2%, 15.1%, and 10.9% of the adolescents with gaming disorder had non-psychotic psychological anxiety, depression, and impulsiveness symptoms, respectively. Nearly 11% of students with Internet gaming disorder had 2 non psychotic psychological symptoms or more. CONCLUSION: These results provide supportive empirical evidence that Internet gaming disorder can lead to severe distress and that it can be associated with comorbid symptoms that are relevant to development or continuance of the gaming disorder. PMID- 27779940 TI - Early Adverse Experiences and Health: The Transition to College. AB - OBJECTIVE: This study cross-sectionally and prospectively examined the impact of adversity experienced prior to college on the health and well-being of students adjusting to their first college semester. METHODS: Two-hundred sixteen (216) first-year students completed measures of adverse life experiences, perceived stress, physical symptoms, and health-related behaviors during the first 2 weeks of college entry and again at the end of the first semester. RESULTS: Reported adversity prior to college predicted greater perceived stress and physical symptoms at college entry and an increase in physical symptoms over the semester; perceived stress mediated the prospective changes. Early adversity predicted smoking, alcohol use problems, and risky sexual behavior at college entry, but was unrelated to the change in smoking, alcohol use problems, or risky sexual behavior. Adversity was not related to drug use at college entry but did predict change in drug use over the semester. CONCLUSION: Some risk factors associated with early adversity are present when students matriculate, but adversity also may impact mental and physical health prospectively during the transition to college. Interventions directed at reducing distress may prevent negative developmental consequences. PMID- 27779941 TI - Interaction Effects of Happiness and Physical Activity on Smoking Initiation. AB - OBJECTIVE: Our aim was to assess the potential relationships among happiness, physical activity, and smoking initiation among undergraduate medical students in Saudi Arabia. METHODS: We performed a cross-sectional study of randomly selected first- to fifth-year undergraduate medical students. Smoking initiation was defined as "ever trying smoking a cigarette, waterpipe, cigar/cigarillo, or other type of tobacco, even one or 2 puffs." The short scale Oxford Happiness Questionnaire was used to assess each student's happiness. Multivariate logistic regression analysis was performed. RESULTS: Of the 406 students surveyed (208 boys, 198 girls), 86 (21.1%) had initiated smoking. We found an interaction between physical activity (PA) and happiness on smoking initiation (p-interaction = .012). Among boys with low levels of PA, lower levels of happiness were associated with a greater likelihood of smoking initiation (OR = 5.8, 95%CI = 1.9 - 17.5). Also, high levels of PA increased the chance of smoking initiation among male students with high levels of happiness (OR = 5.6, 95%CI = 2.1 - 14.5). CONCLUSION: Our results suggest that young men with low levels of happiness and low levels of PA, as well as high levels of PA and high levels of happiness, may be targeted as a priority population in tobacco control intervention programs. PMID- 27779942 TI - Head Start Staff Reactions to a Novel Tobacco Intervention: A Qualitative Analysis. AB - OBJECTIVES: As tobacco use becomes increasingly concentrated in communities of low socio-economic position (SEP), scalable cessation interventions are needed. Head Start programs offer one setting in which a family-focused intervention can be implemented in low SEP communities. We assessed the experiences of Head Start (HS) staff who received training in a pilot motivational interviewing (MI) tobacco intervention, to improve future feasibility. METHODS: Focus group interviews were conducted with HS staff to assess their reactions to MI training and their use of MI in their work with families. Transcripts were analyzed using thematic analysis and a 4-step approach informed by grounded theory. RESULTS: HS staff reported advantages of MI beyond its use as a tobacco intervention, despite systematic barriers to broad implementation. Facilitators of MI use included enhanced engagement with families, and opportunities for professional development. Barriers to MI use included limited institutional support and low priority for a tobacco intervention among families with pressing social and financial concerns. CONCLUSIONS: HS Staff voiced support for broader training in MI interventions in HS programs. System-wide standards to ensure adequate training and support for an MI tobacco intervention were identified as priorities. PMID- 27779943 TI - The Future of the Small Rural Grocery Store: A Qualitative Exploration. AB - OBJECTIVES: Rural communities face unique challenges to and opportunities for offering more healthful foods and are often understudied in comparison to their urban counterparts. The purpose of this study was to conduct a qualitative assessment of rural storeowners' perceptions of their communities, their business practices, and factors that influences their viability, sustainability, and ability to support healthy food choices. METHODS: We conducted interviews with storeowners (N = 15) in small stores in rural Nebraska and explored perceptions of business practices, role in the community, and consumer demand for more healthful foods. RESULTS: The storeowners reported strategies they employ to remain competitive, such as selling alcohol and tobacco, focusing on customer service, and ensuring quality of products. Manufacturer and distributor agreements often put constraints on their business models. Key challenges reported included a dwindling population and competition with larger chains in neighboring towns set in a sparsely populated landscape. Goals for the future included expanding equipment, largely to offer more prepared foods. CONCLUSIONS: This study adds to the literature around food access in rural communities, and can inform future implementation strategies to work with storeowners to improve healthy food access. PMID- 27779944 TI - Social Norms, Perceptions and Dual/Poly Tobacco Use among Texas Youth. AB - OBJECTIVES: We assessed risk perceptions and social norms about tobacco use across adolescent non-users of tobacco, single- product users, and dual/poly product users. METHODS: Use behaviors specific to e-cigarettes, cigarettes, hookah, cigars, and smokeless tobacco were assessed among 6th, 8th and 10th grade students (sample [n] = 3907 from a population of [N] = 461,069 students). Multivariate regression was used to examine differences in these factors across use categories, adjusted for demographic factors. RESULTS: Results highlight differences between non-users and single- or dual/poly-product users for most tobacco products. Dual/poly-product users differed from single-product users most notably in their higher perceived use of tobacco products by close friends and dating partners, and a higher proportion of single-product users reported most products were not harmful and not addictive compared to non-users. Few differences were seen between dual/poly-product users and single-product users in their perceptions of harm and addictiveness. CONCLUSIONS: Findings demonstrate the importance of proximal social influences (ie, close friends and dating partners) for adolescent dual/poly-tobacco product users. Understanding similarities and differences in risk factors between these adolescent groups can guide effective public health prevention and treatment programs. PMID- 27779946 TI - Which Design Components of Nutrition Infographics Make Them Memorable and Compelling? AB - OBJECTIVES: Which design features of nutrition infographics make them memorable and compelling? METHODS: First, we conducted 3 focus groups with a total of 28 participants to understand preferred infographic characteristics of adults who were mostly in their early 20s. Second, using between subject design, a slide show of single-image infographics was displayed to an independent sample of college students and young career university employees (N = 50). We assigned participants randomly to either active or passive processing conditions. We conducted correlation and regression analyses to examine differences in recall and intention by infographic characteristics and processing conditions. RESULTS: Regardless of whether a person was actively or passively viewing the infographics, the most robust predictor of recall was an action-oriented title (p = .003). Surprisingly, infographics in color (vs black-and-white), humorous, or simply worded were no more memorable or effective than if they simply had actionable titles. CONCLUSIONS: Action-oriented titles make infographics memorable and compelling. Regardless of how involved a person is in processing an infographic, cartoon, or illustration, time spent on perfecting an action oriented title will be time better spent than on making the infographic colorful, humorous, or detailed. Whereas content and detail of the infographic are important, effectiveness might be improved by the command given in its title or subtitle. PMID- 27779945 TI - HPV Awareness, Knowledge and Vaccination Attitudes among Church-going African American Women. AB - OBJECTIVES: The purpose of this exploratory study was to improve understanding of the sociodemographic correlates of human papillomavirus (HPV) awareness, knowledge, and vaccination attitudes in a convenience sample of church-going, African-American women and how knowledge about HPV-related cancers relates to vaccination attitudes for girls and boys. METHODS: Participants (N = 308) answered survey questions about HPV awareness, knowledge, and vaccination attitudes. Associations between variables were assessed using Bonferroni-adjusted chi-square tests and regression analyses. RESULTS: Younger age was associated with having heard of HPV and willingness to vaccinate a daughter or son in covariate-adjusted analyses. Younger age and greater education were associated with knowledge that HPV causes cervical cancer. A positive association existed between willingness to vaccinate a daughter or son based on knowledge of the number of cancers associated with HPV. Knowledge that HPV was related to non cervical cancers was significantly associated with greater willingness to vaccinate sons. CONCLUSIONS: Knowledge that HPV causes multiple cancers is important to willingness to vaccinate a child. Education campaigns should emphasize that HPV is also related to non-cervical cancers. African-American women of older age and less education might benefit from church-based HPV educational campaigns. PMID- 27779948 TI - Denver, First Look. PMID- 27779949 TI - Autonomous, Computer-Based Behavioral Health Countermeasure Evaluation at HI-SEAS Mars Analog. AB - INTRODUCTION: Living in an isolated, confined environment (ICE) can induce conflict, stress, and depression. Computer-based behavioral health countermeasures are appealing for training and treatment in ICEs because they provide confidentiality and do not require communication with the outside environment. We evaluated the Virtual Space Station (VSS), a suite of interactive computer-delivered psychological training and treatment programs, at the Hawaii Space Exploration Analog and Simulation (HI-SEAS) III expedition. METHODS: Six subjects (3 male, 3 female) spent 8 mo in group-isolation and used the Conflict, Stress, and Depression modules in the VSS. Survey evaluations, data collected within the program, and postdeployment interviews were collected. RESULTS: This crew dealt with behavioral health issues common to ICEs. The VSS proved to be a valuable resource and was used both as intended, and in unanticipated ways, to help maintain behavioral health. The Conflict and Stress Modules were rated as highly acceptable (1.8 on a 7-point Likert scale). The crew identified a total of 13 stressors and worked on 9 problems through the VSS. Opinions about the modules were highly individualized. Crewmembers identified exercises in the VSS that were applicable and not applicable to their needs. Additional content to improve the program was identified. DISCUSSION: Autonomous, confidential training and treatment for behavioral health issues will need to be a critical component of long duration spaceflight travel. This work provides an evaluation of such a tool in a relevant ICE. Anderson AP, Fellows AM, Binsted KA, Hegel MT, Buckey JC. Autonomous, computer-based behavioral health countermeasure evaluation at HI-SEAS Mars analog. Aerosp Med Hum Perform. 2016; 87(11):912-920. PMID- 27779950 TI - Color Vision and Performance on Color-Coded Cockpit Displays. AB - INTRODUCTION: Although there are numerous studies that demonstrate that color vision deficient (CVD) individuals perform less well than color vision normal (CVN) individuals in tasks that require discrimination or identification of colored stimuli, there remains a need to quantify the relationship between the type and severity of CVD and performance on operationally relevant tasks. METHODS: Participants were classified as CVN (N = 45) or CVD (N = 49) using the Rabin cone contrast test, which is the standard color vision screening test used by the United States Air Force. In the color condition, test images that were representative of the size, shape, and color of symbols and lines used on fifth generation fighter aircraft displays were used to measure operational performance. In the achromatic condition, all symbols and lines had the same chromaticity but differed in luminance. Subjects were asked to locate and discriminate between friend vs. foe symbols (red vs. green, or brighter vs. dimmer) while speed and accuracy were recorded. RESULTS: Increasing color deficiency was associated with decreasing speed and accuracy for the color condition (R2 > 0.2), but not for the achromatic condition. Mean differences between CVN and CVD individuals showed the same pattern. DISCUSSION: Although lower CCT scores are clearly associated with lower performance in color related tasks, the magnitude of the performance loss was relatively small and there were multiple examples of high-performing CVD individuals who had higher operational scores than low-performing CVN individuals. Gaska JP, Wright ST, Winterbottom MD, Hadley SC. Color vision and performance on color-coded cockpit displays. Aerosp Med Hum Perform. 2016; 87(11):921-927. PMID- 27779951 TI - Neck Muscle Strain in Air Force Pilots Wearing Night Vision Goggles. AB - INTRODUCTION: Flight-induced neck pain is common in high performance jet pilots, with incidents frequently attributed to high Gz flight maneuvers. The additional load of helmet-mounted night vision goggles (NVG) is believed to increase the risk, possibly from neck muscle strain in counteracting muscles. Hence, the aim was to investigate the effect of NVG on neck muscle strain as well as on the activity level distribution through a simulated flight session in air force pilots. METHODS: In this post hoc randomized crossover trial, four senior air force pilots each completed two identical 1.5-h dynamic flight simulations in a human centrifuge: one with a standard helmet and NVG, and one with a standard helmet only. Simulations included repeated exposure to 3-7 Gz, during which neck muscle activity was recorded bilaterally from the anterior neck, the upper and lower posterior neck, and the upper shoulders. The number of muscle activities surpassing 50% of maximum voluntary electrical activity (MVE) and total time of activity at each MVE percentile were compared between NVG and control flights. RESULTS: There was no overall effect in number of neck strain activities between NVG and control flights; however, significantly more activities emerged in the anterior neck. In addition, MVE percentile data showed a tendency of higher activity in the lower posterior neck during NVG flights. CONCLUSIONS: The results showed that the additional load of helmet-mounted NVG increases neck muscle strain in anterior stabilizing muscles, indicating that the inertia of head-worn NVG elevates the risk of flight-related neck pain. Pousette MW, Lo Martire R, Linder J, Kristoffersson M, Ang BO. Neck muscle strain in air force pilots wearing night vision goggles. Aerosp Med Hum Perform. 2016; 87(11):928-932. PMID- 27779953 TI - Communication Delays Impact Behavior and Performance Aboard the International Space Station. AB - INTRODUCTION: Long-duration space explorations will involve significant communication delays that will likely impact individual and team outcomes. However, the extent of these impacts and the appropriate countermeasures for their mitigation remain largely unknown. This study examined the feasibility and acceptability of utilizing the International Space Station (ISS) as a research platform to assess the impacts of communication delays on individual and team behavior and performance. METHODS: For this study, 3 ISS crewmembers and 18 mission support personnel performed 10 tasks identified by subject matter experts as meeting study criteria, 6 tasks without a delay in communication and 4 tasks with a 50-s one-way delay. Assessments of individual and team performance and behavior were obtained after each task. The completion rate of posttask assessments and postmission interviews with astronauts were used to assess feasibility and acceptability. RESULTS: Posttask assessments were completed in 100% of the instances where a crewmember was assigned to a task and in 83% where mission support personnel were involved. Qualitative analysis of postmission interviews found the study to be important and acceptable to the three astronauts. However, they also reported the study was limited in the number and type of tasks included, limitations in survey questions, and preference for open ended to scaled items. DISCUSSION: Although the ISS is considered a high fidelity analog for long-duration space missions, future studies of communication delays on the ISS must take into considerations the constraints imposed by mission operations and subject preferences and priorities. Kintz KM, Palinkas LA. Communication delays impact behavior and performance aboard the International Space Station. Aerosp Med Hum Perform. 2017; 87(11):940-946. PMID- 27779952 TI - Psychometric Personality Differences Between Candidates in Astronaut Selection. AB - INTRODUCTION: This paper investigates personality traits as potential factors for success in an astronaut selection by comparing personality profiles of unsuccessful and successful astronaut candidates in different phases of the ESA selection procedure. It is further addressed whether personality traits could predict an overall assessment rating at the end of the selection. METHODS: In 2008/2009, ESA performed an astronaut selection with 902 candidates who were either psychologically recommended for mission training (N = 46) or failed in basic aptitude (N = 710) or Assessment Center and interview testing (N = 146). Candidates completed the Temperament Structure Scales (TSS) and the NEO Personality Inventory Revised (NEO-PI-R). RESULTS: Those candidates who failed in basic aptitude testing showed higher levels of Neuroticism (M = 49.8) than the candidates who passed that phase (M = 45.4 and M = 41.6). Additionally, candidates who failed in basic testing had lower levels of Agreeableness (M = 132.9) than recommended candidates (M = 138.1). TSS scales for Achievement (r = 0.19) and Vitality (r = 0.18) showed a significant correlation with the overall assessment rating given by a panel board after a final interview. DISCUSSION: Results indicate that a personality profile similar to Helmreich's "Right Stuff" is beneficial in astronaut selection. Influences of test anxiety on performance are discussed. Mittelstadt JM, Pecena Y, Oubaid V, Maschke P. Psychometric personality differences between candidates in astronaut selection. Aerosp Med Hum Perform. 2016; 87(11):933-939. PMID- 27779955 TI - Psychometric Properties of the Greek Version of the Gianaros Motion Sickness Assessment Questionnaire. AB - INTRODUCTION: The Motion Sickness Assessment Questionnaire (MSAQ) was developed in order to assess the multiple dimensions of the motion sickness syndrome (gastrointestinal, central nervous system, peripheral, and sopite-related symptoms). The aim of this study was to evaluate the psychometric properties of the Greek version of the MSAQ. METHODS: The MSAQ was translated into Greek and then translated back into English. Minor differences between the two texts were corrected. The Greek version was then administered to male subjects before and after nauseogenic motion stimulation. With the use of a motor driven rotating chair, the subjects were exposed to Coriolis cross-coupling stimulation. A battery of statistical tests was used to evaluate the psychometric properties of the MSAQ. RESULTS: There were 112 subjects who participated. Internal consistency, measured with Cronbach's alpha coefficient, was excellent for the total scale and subscales. The test-retest evaluation was done with Pearson's coefficient and Bland-Altman's plot for the total score and subscales and showed statistically significant results. Mean total MSAQ score was 19.04 before the exposure and 33.46 after the exposure, which was statistically significant. CONCLUSION: Results suggest the Greek-MSAQ is a valid instrument with satisfactory internal consistency, reliability, reproducibility, validity, and responsiveness and can be used in future studies of motion sickness in Greek speaking populations. Kousoulis P, Pantes A, Alevetsovitis G, Fydanaki O. Psychometric properties of the Greek version of the Gianaros Motion Sickness Assessment Questionaire. Aerosp Med Hum Perform. 2016; 87(11):954-957. PMID- 27779954 TI - Pilot and Passenger Injuries Associated with Powered Parachutes. AB - BACKGROUND: Powered parachutes are becoming a popular form of sport flying. No previous study has reviewed injuries in this sport. The purpose of this study was to describe the injuries associated with powered parachute flying, the flight factors involved in an incident, and the impact an incident has on current sport involvement. METHODS: National Transportation Safety Board incident reports involving powered parachutes between 2004 and 2015 were reviewed. Internet searches were performed to contact involved pilots to find further information. RESULTS: There were 71 incidents reported involving 117 people. Of these, 10 incidents involved 14 fatalities (12.0%). Of the 14 fatalities, 11 (78.5%) occurred in midflight. Pilot error was the most common finding for an incident and accounted for 53/71 incidents (74.6%). The main error was misjudging the distance required for takeoff and landing. This accounted for 37/71 incidents (52.1%). Orthopedic extremity injuries were the most common severe injuries reported. Surgical intervention was needed in 43.8% of injuries and 48.0% of those involved fractures. The median return to work was 14 d (range 0-180 d). Only 4/53 (7.5%) of the pilots contacted continued to fly powered parachutes. DISCUSSION: Powered parachute participants are at risk for unique injuries compared to other forms of flight. A powered parachute injury can have a significant impact on future pilot involvement in the sport. This study provides evidence for design changes in the aircraft and helps direct pilot training. This information can improve the safety and well-being of participants so they can continue to fly powered parachutes. Skelley NW, Yarholar LM, Richardson LC. Pilot and passenger injuries associated with powered parachutes. Aerosp Med Hum Perform. 2016; 87(11):947-953. PMID- 27779956 TI - Emergency Medical Considerations in a Space-Suited Patient. AB - INTRODUCTION: The Stratex Project is a high altitude balloon flight that culminated in a freefall from 41,422 m (135,890 ft), breaking the record for the highest freefall to date. Crew recovery operations required an innovative approach due to the unique nature of the event as well as the equipment involved. The parachutist donned a custom space suit similar to a NASA Extravehicular Mobility Unit (EMU), with life support system mounted to the front and a parachute on the back. This space suit had a metal structure around the torso, which, in conjunction with the parachute and life support assembly, created a significant barrier to extraction from the suit in the event of a medical emergency. For this reason the Medical Support Team coordinated with the pressure suit assembly engineer team for integration, training in suit removal, definition of a priori contingency leadership on site, creation of color-coded extraction scenarios, and extraction drills with a suit mock-up that provided insight into limitations to immediate access. This paper discusses novel extraction processes and contrasts the required medical preparation for this type of equipment with the needs of the prior record-holding jump that used a different space suit with easier immediate access. Garbino A, Nusbaum DM, Buckland DM, Menon AS, Clark JB, Antonsen EL. Emergency medical considerations in a space-suited patient. Aerosp Med Hum Perform. 2016; 87(11):958-962. PMID- 27779957 TI - Explosive Decompression with Resultant Air Gas Embolism in a Fourth Generation Fighter at Ground Level. AB - BACKGROUND: Arterial gas embolism (AGE) is a rare condition in the flying community most often only ever seen in flight while operating at high altitude or incidents involving hypobaric chambers. This article describes a severe case of AGE that occurred in a pilot of a fourth generation fighter aircraft at ground level. The environmental control system (ECS) malfunctioned, causing an overpressurized cockpit and a subsequent explosive decompression when the pilot opened the canopy to egress. CASE REPORT: The ECS onboard fourth generation fighter aircraft is composed of many computer-controlled subsystems. When these components fail, the system can potentially overpressurize the cockpit. Combined with opening the canopy without prior venting, this overpressurization can lead to a situation akin to a diver surfacing too quickly. A pilot experienced this scenario and subsequently developed symptoms of arterial gas embolization-one form of decompression illness (DCI). We reviewed the design of the environmental control system and recommend that the cockpit must be slowly depressurized to decrease risk of injury from rapid decompression. DISCUSSION: Literature review showed three similar cases of ground-based overpressurization causing AGE symptoms, although these cases were maintenance personnel intentionally testing aircraft cabin integrity and not associated with aircraft intending flight.7 The lessons learned from this case can be used to identify and hopefully prevent severe DCI from ground level cockpit overpressurization and to further general understanding of aircraft ECS. Zhang JX, Berry JR, Beckstrand DP. Explosive decompression with resultant air gas embolism in a fourth generation fighter at ground level. Aerosp Med Hum Perform. 2016; 87(11):963-967. PMID- 27779958 TI - Aeromedical Evaluation for an F-16 Candidate with Incomplete Paraplegia. AB - BACKGROUND: A candidate with paraplegia contacted the Institute of Aviation Medicine, Oslo, requesting a medical examination and medical certification for flying back seat on an F-16 Fighting Falcon. Thorough aeromedical examinations, including specialist evaluations, were initiated for the final decision to be made. CASE REPORT: Almost 13 yr earlier the candidate had acquired spinal cord damage at neurological level L1 after falling 4 m (13 ft) from out of a window. The CT scans showed luxation of the 12th thoracic vertebra with fracture and dislocation of the 1st lumbar vertebra. He went for surgery, where fixation of the 12th thoracic vertebra to the 1st lumbar vertebra was performed. He developed syringomyelia 1 yr postoperatively and was re-operated on twice in the following years. He was now in a wheelchair, but engaged himself in several sport activities such as sledge-hockey and sit-skiing, participating in several Paralympics. DISCUSSION: With respect to the general principles of aviation medicine, several considerations had to be taken into account before a medical certification could be given. The risks associated with an F-16 flight in relationship to the candidate's general health and the fixation of his spinal cord had to be evaluated. Also, his ability to perform required tasks during the flight and in case of an emergency was an important issue discussed. Finally, the candidate's medical and physical condition should not present a considerable risk to flight safety. After extensive specialist consultations and in-depth discussions, the candidate was given medical certification to fly back seat in a F-16. Chahal-Kummen M, Strand T-E, Owe JO, Gulliksen E, Wagstaff AS. Aeromedical evaluation for an F-16 candidate with incomplete paraplegia. Aerosp Med Hum Perform. 2016; 87(11):968-971. PMID- 27779959 TI - Development of a Geographic Information System for Risk-Informed Decision Making in Aerospace Medicine. PMID- 27779960 TI - You're the Flight Surgeon. AB - Martin BR. You're the flight surgeon: West Nile virus neuroinvasive disease. Aerosp Med Hum Perform. 2016; 87(11):976-979. PMID- 27779962 TI - Pain Assessment and Control in the Injured Elderly. AB - Elderly trauma patients may be at increased risk for underassessment and inadequate pain control in the emergency department (ED). We sought to characterize risk factors for oligoanalgesia in the ED in elderly trauma patients and determine whether it impacts outcomes in elderly trauma patients. We included elderly patients (age >=55 years) with Glasgow Coma Scale scores 13 to 15 and Injury Severity Score (ISS) >=9 admitted through the ED at a Level I trauma center. Patient characteristics and outcomes were compared between those who reported pain and received analgesics medication in the ED (MED) and those who did not (NO MED). A total of 183 elderly trauma patients were identified over a three-year study period, of whom 63 per cent had pain assessed via verbal pain score; of those who reported pain, 73 per cent received analgesics in the ED. The MED and NO MED groups were similar in gender, race, ED vitals, ISS, and hospital length of stay. However, NO MED was older, with higher head Abbreviated Injury Scale score and longer intensive care unit length of stay. Importantly, as patients aged they reported lower pain and were less likely to receive analgesics at similar ISS. Risk factors for oligoanalgesia may include advanced age and head injury. PMID- 27779963 TI - Surgical Hand Tracking in Open Surgery Using a Versatile Motion Sensing System: Are We There Yet? AB - With changes in work hour limitations, there is an increasing need for objective determination of technical proficiency. Electromagnetic hand-motion analysis has previously shown only time to completion and number of movements to correlation with expertise. The present study was undertaken to evaluate the efficacy of hand motion-tracking analysis in determining surgical skill proficiency. A nine-degree of-freedom sensor was used and mounted on the superior aspect of a needle driver. A one-way analysis of variance and Welch's t test were performed to evaluate significance between subjects. Four Novices, four Trainees, and three Experts performed a large vessel patch anastomosis on a phantom tissue. Path length, total number of movements, absolute velocity, and total time were analyzed between groups. Compared to the Novices, Expert subjects exhibited significantly decreased total number of movements, decreased instrument path length, and decreased total time to complete tasks. There were no significant differences found in absolute velocity between groups. In this pilot study, we have identified significant differences in patterns of motion between Novice and Expert subjects. These data warrant further analysis for its predictive value in larger cohorts at different levels of training and may be a useful tool in competence-based training paradigms in the future. PMID- 27779964 TI - Intraosseous Infusion as a Bridge to Definitive Access. AB - Intraosseous (IO) needle placement is an alternative for patients with difficult venous access. The purpose of this retrospective study was to examine indications and outcomes associated with IO use at a Level 1 trauma center (January 2008-May 2015). Data points included demographics, time to insertion, intravenous (IV) access points, indications, infusions, hospital and intensive care unit length of stay, and mortality. Of 68 patients with IO insertion analyzed (63.2% blunt trauma, 29.4% penetrating trauma, and 7.4% medical), 56 per cent were hypotensive on arrival and 38.2 per cent asystolic. The most common indications for IO infusion were difficult IV access (69%) and rapid sequence intubation (20.6%). The median time to IO access was three minutes. IV access was gained after IO in 72.1 per cent of patients. Through IO access, 30.9 per cent patients received crystalloid, 29.4 per cent received Advanced Care Life Support (ACLS) medications, 25 per cent rapid sequence intubation medications, 20.6 per cent blood products, and 2.9 per cent seizure medications. Overall, 80.9 per cent were intubated in the Emergency Department (ED), 26.5 per cent had ED thoracotomy, and 20.6 per cent had a laparotomy. Median crystalloid infused through IO was 180 cc in pediatric patients and 1 L in adults, respectively. Extravasation, the most common complication, was experienced by 7.4 per cent of patients. Inhospital mortality was 72.9 per cent. IO access should be considered when there is a need for rapid intervention requiring vascular access. PMID- 27779965 TI - Management of Completion and Total Thyroidectomy Patients Based on 1-Hour Postoperative Parathyroid Hormone. AB - After thyroid surgery, protocols based on postoperative parathyroid hormone (PTH) levels may prevent symptoms of hypocalcemia, while avoiding unnecessary prophylactic calcium and/or vitamin D supplementation. We examined the value of an initial management protocol based solely on a single PTH level measured one hour after completion or total thyroidectomy to prevent symptomatic hypocalcemia by conducting a retrospective review of 697 consecutive patients treated from July 2003 to April 2015. The proportion of patients who developed symptomatic hypocalcemia was similar between those treated before (n = 155) and after (n = 542) implementation of this 1-hour PTH protocol (16.8% vs 15.9%; P = 0.786). Those in the 1-hour PTH groups had lower overnight observation rates (97.4% vs 53.7%; P < 0.001) and length of stay (1.98 +/- 2.61 vs 0.89 +/- 1.87 days; P < 0.001), and required less calcium (3.9% vs 0.8%; P = 0.015) and vitamin D (2.6% vs 0%; P = 0.002) supplementation one year after surgery. Less than 1 per cent of patients discharged on the day of surgery in accordance with the 1-hour PTH guidelines returned to the emergency room for symptomatic hypocalcemia; none experienced significant morbidity. This protocol facilitates early discharge of low-risk patients and results in a similar or improved postoperative course compared with traditional overnight observation. PMID- 27779967 TI - Dysphagia after Cardiac Operations Is Associated with Increased Length of Stay and Costs. AB - Although the true incidence of postoperative dysphagia after cardiac surgery is unknown, it has been reported to occur in 3 to 21.6 per cent of patients. Historically, dysphagia has been associated with increased surgical complications and prolonged hospital stay. This study aimed to evaluate the costs and outcomes associated with dysphagia after cardiac surgery. Patients undergoing nonemergent, nontransplant cardiac operations between June 2013 and June 2014 were eligible for inclusion. Independent predictors of cost were identified through a multivariate linear regression model. Of the 354 patients (35% female) included for analysis, 56 (16%) were diagnosed with postoperative dysphagia. On univariate analysis, patients with dysphagia had increased intensive care unit and total hospital lengths of stay (11.8 vs 5.2 days, P < 0.001 and 18.2 vs 9.7 days, P < 0.001, respectively), and a 57 +/- 15 per cent increase in cost of care (P < 0.001). Dysphagia was not associated with higher rates of in-hospital mortality (3.6% vs 3.0%, P = 0.83). On multivariate linear regression, the development of dysphagia was independently associated with a 45.1 per cent increase in total hospital costs [95% confidence interval (31% and 59%), P < 0.001]. Dysphagia is an independent and major contributor to health care costs after cardiac operations, suggesting that postoperative dysphagia represents a highly suitable target for quality improvement and cost containment efforts. PMID- 27779966 TI - Does Incidental Appendectomy Increase the Risk of Complications after Abdominal Procedures? AB - Incidental appendectomy (IA) could potentially increase the risk of morbidity after abdominal procedures; however, such effect is not clearly established. The aim of our study is to test the association of IA with morbidity after abdominal procedures. We identified 743 (0.37%) IA among 199,233 abdominal procedures in the National Surgical Quality Improvement Program database (2005-2009). Cases with and without IA were matched on the index current procedural terminology code. Patient characteristics were compared using chi-squared test for categorical variables and Student t test for continuous variables. Multivariate logistic regression analysis was performed. Emergency and open surgeries were associated with performing IA. Multivariate analysis showed no association of IA with mortality [odds ratio (OR) = 0.51, 95% confidence interval (CI) = 0.26 1.02], overall morbidity (OR = 1.16, 95% CI = 0.92-1.47), or major morbidity (OR = 1.20, 95% CI = 0.99-1.48). However, IA increased overall morbidity among patients undergoing elective surgery (OR = 1.31, 95% CI = 1.03-1.68) or those >=30 years old (OR = 1.23, 95% CI = 1.00-1.51). IA was also associated with higher wound complications (OR = 1.46, 95% CI = 1.05-2.03). In conclusion, IA is an uncommonly performed procedure that is associated with increased risk of postoperative wound complications and increased risk of overall morbidity in a selected patient population. PMID- 27779968 TI - Role of Surgical Services in Profitability of Hospitals in California: An Analysis of Office of Statewide Health Planning and Development Annual Financial Data. AB - With constant changes in health-care laws and payment methods, profitability, and financial sustainability of hospitals are of utmost importance. The purpose of this study is to determine the relationship between surgical services and hospital profitability. The Office of Statewide Health Planning and Development annual financial databases for the years 2009 to 2011 were used for this study. The hospitals' characteristics and income statement elements were extracted for statistical analysis using bivariate and multivariate linear regression. A total of 989 financial records of 339 hospitals were included. On bivariate analysis, the number of inpatient and ambulatory operating rooms (ORs), the number of cases done both as inpatient and outpatient in each OR, and the average minutes used in inpatient ORs were significantly related with the net income of the hospital. On multivariate regression analysis, when controlling for hospitals' payer mix and the study year, only the number of inpatient cases done in the inpatient ORs (beta = 832, P = 0.037), and the number of ambulatory ORs (beta = 1,485, 466, P = 0.001) were significantly related with the net income of the hospital. These findings suggest that hospitals can maximize their profitability by diverting and allocating outpatient surgeries to ambulatory ORs, to allow for more inpatient surgeries. PMID- 27779969 TI - Admission Variables Associated with a Favorable Outcome after Mild Traumatic Brain Injury. AB - Consensus is lacking for ideal management of mild traumatic brain injury (mTBI) with intracranial hemorrhage (ICH). Patients are often monitored in the intensive care unit (ICU) without additional interventions. We sought to identify admission variables associated with a favorable outcome (ICU admission for 24 hours, no neurosurgical interventions, no complications or mortality) to divert these patients to a non-ICU setting in the future. We reviewed all patients with mTBI [Glasgow Coma Scale (GCS) = 13-15] and concomitant ICH between July 1, 2012, and June 30, 2015. Variables collected included demographics, vital signs, neurologic examination, imaging results, ICU course, mortality, and disposition. Of 201 patients, 78 (39%) had a favorable outcome. On univariate analysis, these patients were younger, more often had an isolated subarachnoid hemorrhage, and were more likely to have a GCS of 15 at admission. On multivariate regression analysis, after controlling for admission blood pressure, time to CT scan, and Marshall Score, age <55, GCS of 15 on arrival to the ICU, and isolated subarachnoid hemorrhage remained independent predictors of a favorable outcome. Patients meeting these criteria after mTBI with ICH likely do not require ICU level care. PMID- 27779970 TI - National Outcomes after Pressure Ulcer Closure: Inspiring Surgery. AB - Over two million Americans receive treatment for pressure ulcers (PUs) annually, but national surgical outcomes are not well described. This study investigated rates and risk factors of postoperative complications in patients with PU. The 2011 and 2012 American College of Surgeons-National Surgical Quality Improvement Project database was queried and PU patients undergoing flap closure were identified. Descriptive statistics and multivariate regression analysis was used and reported as odds ratios (ORs) if (P < 0.05). Of 1196 patients identified with a primary diagnosis of PU, 327 (27%) underwent flap closure. Emergency interventions were performed in seven patients who were excluded from analysis. Characteristics were average age 53.3 (+/-17); 65 per cent male; 41 per cent with grossly contaminated or infected wounds; 29 per cent frail; and 16 per cent with an American Society of Anesthesiologists score of four or five. Myocutaneous or fasciocutaneous flaps were performed in 82 per cent of patients, local skin rearrangements in 17 per cent, and free flap in one patient. Complications were low with 1.9 per cent recurrence and 4.7 per cent reoperation rates. Higher American Society of Anesthesiologists was independently associated with mortality (odds ratio = 6.6) and steroid use correlated with flap failure (odds ratio = 15). No differences in complication profiles were identified based on technique, frailty, or contamination. Surgical closure can be considered reasonable in all patients fit for anesthesia. PMID- 27779971 TI - Robotic Colorectal Surgery: Our Initial Experience. AB - Robotic colorectal surgery was first performed at our institution in January 2014. The objective of this study is to present our initial experience with robotic colorectal surgery. This is a retrospective review of the prospectively collected data of all patients who underwent robotic colorectal surgery from January 2014 to April 2015. Baseline, perioperative, and postoperative data were obtained for analysis. A total of 101 patients with a mean age of 56 and a body mass index of 31 underwent robotic colorectal surgery between January 2014 and April 2015. The indication for surgery was malignancy in approximately 40 per cent, diverticulitis in 40 per cent, and benign diseases in 20 per cent of the patients. The most common operation was sigmoidectomy (40%) followed by low anterior resection (36%), abdominoperineal resection (7%), right hemicolectomy (6%), rectopexy (6%), total colectomy (4%), and left hemicolectomy (1%). The mean operative and docking time was 226 (range, 104-496) minutes and 3 (range, 1-18) minutes, respectively. The median number of lymph nodes harvested was 19 (range, 0-34). The median length of stay was 3 (range, 1-18) days. Anastomotic leak occurred in one patient and surgical site infection in two patients. Robotic colorectal surgery is safe and technically feasible. PMID- 27779972 TI - A Durable Laparoscopic Technique for the Repair of Large Paraesophageal Hernias. AB - Laparoscopic repair of large paraesophageal hernias has been challenging due to high recurrence rates with primary repair and complications associated with the use of nonabsorbable mesh to reinforce the hiatus. The aim of our study was to evaluate the recurrence rate over time and mesh-related complications using an absorbable polyglactin mesh secured with Bioglue to reinforce the hiatus after laparoscopic repair of large paraesophageal hernias. There were 190 patients who met inclusion criteria from June 2006 to June 2014. Follow-up was routinely performed at 1-year intervals, including endoscopy and/or video esophagram, and the gastroesophageal reflux disease health-related quality of life questionnaire. Mean follow-up was 21 months (3-88). There were no incidences of mesh erosion. Recurrence was detected in 17 patients (15.3%), with a median time to recurrence of 23 months (8-67). Recurrence rate was estimated with the Kaplan-Meier method to be 2.9 +/- 1.6 per cent, 11.6 +/- 3.7 per cent, 22.4 +/- 5.6 per cent, 25.1 +/ 6.0 per cent, and 29.5 +/- 7.9 per cent at 12, 24, 36, 48, and 60 months, respectively. The mean gastroesophageal reflux disease health-related quality of life was 2 in patients both with and without recurrence. Laparoscopic intrathoracic stomach repair using absorbable polyglactin mesh and Bioglue for crural reinforcement is effective, safe, and durable. The rate of recurrence plateaus over time with the majority of recurrences being small to moderate asymptomatic hernias. PMID- 27779973 TI - Influence of Weight Loss Attempts on Bariatric Surgery Outcomes. AB - Many payors require an additional attempt at nonsurgical weight loss before approval of bariatric procedures. This study evaluates this requirement by characterizing the prior weight loss attempts (WLAs) undergone by bariatric surgery patients and correlating those attempts to postoperative weight loss outcomes. Number and duration of WLAs were obtained from a preoperative clinic assessment. Body mass index (BMI) and percentage of excess weight loss (%EWL) were used to assess weight loss. Kruskal-Wallis and Spearman Correlation tests were performed to analyze data using GraphPad Prism 6. Mean number of WLAs before surgery was 3.5 +/- 0.2 attempts, with an average duration of 15.2 +/- 1.1 years. There was a significant negative correlation between duration of WLAs and preoperative BMI (r = -0.2637, P = 0.0025). No significant difference was found for preoperative BMI or mean 12-month %EWL among any WLA groups. The number and duration of dietary attempts before surgery do not significantly affect long-term weight loss outcomes after bariatric surgery. Given these data, an additional preoperative WLA may not be efficacious in improving patients' chances at weight loss. PMID- 27779974 TI - Racial Disparities in Access and Outcomes of Cholecystectomy in the United States. AB - Disparities in access to health care between white and minority patients are well described. We aimed to analyze the trends and outcomes of cholecystectomy based on racial classification. The Nationwide Inpatient Sample database was reviewed for all patients undergoing cholecystectomy from 2009 to 2012. Patients were stratified as white or non-white. A total of 243,536 patients were analyzed: 159,901 white and 83,635 non-white. Non-white patients had significantly higher proportions of Medicaid (25% vs 9.3%), self-pay (14% vs 7.1%), and no-charge (1.8% vs 0.64%). Non-white patients had significantly higher rates of emergent admission (84% vs 78%) compared with the white patients. Multivariate analysis revealed that non-whites had a significantly longer length of stay [mean difference of 0.14 days, 95% confidence interval (CI) 0.08-0.20] and higher total hospital charges (mean difference of $6748.00, 95% CI 5994.19-7501.81) than whites, despite a lower morbidity (odds ratio 0.94, 95% CI 0.90-0.98). Use of laparoscopy and mortality were not different. These differences persisted on subgroup analysis by insurance type. These findings suggest a gap in access to and outcomes of cholecystectomy in the minority population nationwide. PMID- 27779975 TI - Predictors of Mortality in Trauma Patients Aged 80 years or Older. AB - The population of the United States is predicted to age dramatically over the next few decades; as such older patients will comprise an increasing proportion of the injured populations. Due to multiple comorbidities and frailty, the old and very old are at greater risk for mortality than younger patients. To identify predictors of inhospital mortality in these patients, we performed a retrospective cohort study at our Level 1 trauma center. Between April 2009 and October 2014, we identified 193 trauma patients aged 80 years and older admitted to the intensive care unit. The mean age was 86 years old (4.9) and a majority of patients were white (57%) and male (54%). Univariate analysis found Injury Severity Score (P < 0.01), initial Glasgow Coma Scale (P < 0.01), admission pH (P = <0.01), admission lactate (P < 0.01), the need for mechanical ventilation (P < 0.01), and Geriatric Trauma Outcome Score (P < 0.01) to be predictors of mortality. Multivariate analysis identified length of mechanical ventilation [odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.60-0.90, P < 0.01], admission lactate (OR = 1.74, 95% CI = 1.21-2.51, P < 0.01), and the need for mechanical ventilation (OR = 18.2, 95% CI = 3.33-99.8, P < 0.01) as independent predictors of mortality. These predictors can help guide clinical decisions and should prompt early discussion of goals of care. The association between mechanical ventilation and mortality is confounded by withdrawal of care. PMID- 27779976 TI - Body Mass Index Significantly Impacts Outcomes of Colorectal Surgery. AB - There are limited data regarding the association between body mass index (BMI) and colorectal surgery outcomes. We sought to evaluate the effect of BMI on short term surgical outcomes in colon and rectal surgery patients in the United States. The American College of Surgeons National Surgery Quality Improvement Project database was used to identify all patients who underwent colon or rectal resection from 2005 to 2013. Multivariate regression analysis was used to assess the independent effect of BMI on outcomes. A total of 206,360 patients underwent colorectal resection during the study period. Of these, 3.2 per cent of patients were underweight (BMI < 18.5), 23.8 per cent patients were normal weight (18.5 <= BMI < 25), 26.5 per cent were overweight (25 <= BMI < 30), 25.2 per cent were obese (30 <= BMI < 40), and 5.3 per cent were morbidly obese (BMI >= 40). Underweight patients had longer length of stay (confidence interval: 2.70-3.49, P < 0.001) and higher mortality (adjusted odds ratio: 1.45, P < 0.01) compared with patients with a normal BMI. Morbidly obese patients had the highest overall morbidity rate compared with normal BMI patients (adjusted odds ratio: 1.53, confidence interval: 1.42-1.64, P < 0.01). BMI is associated with outcomes in colon and rectal surgery patients. Underweight and morbidly obese patients have a significantly increased risk of postsurgical complications compared with those with normal BMI. PMID- 27779977 TI - Anticipated Transfusion Requirements and Mortality in Patients with Orthopedic and Solid Organ Injuries. AB - Long bone fractures are cited as an etiology for significant blood loss; however, there is scant supporting literature. We examined the relationship between long bone fractures, blood transfusions, and solid organ injuries. We hypothesize that transfusions are rare with long bone fractures in the absence of a liver or splenic injury. We performed a retrospective analysis of patients admitted with femur, tibia, and humerus fractures. Outcomes included transfusion requirements and mortality. A total of 1837 patients were included. There were 182 patients with at least one solid organ injury. A greater portion of patients with femur fractures and a lower proportion of patients with tibia fractures required transfusion. Adjusting for solid organ injuries, there was no difference in transfusions for any patient with these fractures compared with the group, or when grouped by organ injury severity. A solid organ injury significantly increases the risk of death among patients with long bone fractures. Blood loss requiring transfusion in patients with orthopedic and solid organ injuries should not be attributed to the presence of fractures alone. The need for transfusions in these patients should lower the threshold for reimaging or intervention for the solid organ injury. Further study is warranted to quantify blood loss by fracture type with or without solid organ. PMID- 27779978 TI - Patient and Surgical Factors Contributing to Perioperative Infection in Complex Lower Extremity Trauma. AB - Infections in the traumatized lower extremity are a significant source of morbidity and expense. Outcomes after vascularized soft tissue reconstruction were analyzed to determine impact on infection rates. A retrospective review of a prospectively maintained database was performed, including 114 trauma patients requiring soft tissue reconstruction of lower extremity injuries at an urban Level I tertiary referral center from 2008 to 2015. Patient characteristics and perioperative outcomes were analyzed. After trauma, 39 (34.2%) patients developed wound infections, of which 74.4 per cent of infections occurred before soft tissue coverage. Isolated lower extremity injury yielded a 4-fold increase in the incidence of infection. Infection rates doubled in patients who smoked, sustained a fall, had a proximal third of the lower leg wound, or underwent external fixation. Comorbid diabetes, underlying fracture, and wound size were not predictive of infection. Overall, there was a 97.4 per cent rate of limb salvage after soft tissue reconstruction. In patients with infection before soft tissue reconstruction, a salvage rate of 96.6 per cent was achieved. Soft tissue reconstruction in the traumatized and infected lower extremity resulted in high limb salvage success rates, demonstrating vascularized tissue transfer in lower extremity injuries is effective in treating lower extremity infection. PMID- 27779979 TI - Outcomes of Nipple-Sparing Mastectomy: Role of Anatomic Measurements. AB - Nipple-sparing mastectomy (NSM) offers improved cosmesis for women undergoing mastectomy; however, there is increased risk for complications with this technique. We sought to determine if standard anatomic measurements could be used to predict complications of NSM. We performed a retrospective review of NSM for which anthropometric measurements of sternal notch to nipple distance, base width, and inframammary fold to nipple distance were available, and compared outcomes by anatomic measurements. We identified 102 cases of NSM with measurements available for study performed in 55 patients. Areola necrosis was associated with base width of greater than 15 cm (42.9% vs 10.9%, P = 0.02), infections were more likely with inframammary fold to nipple distance of more than 10 cm (29.2% vs 10.3%, P = 0.02), hematomas were more likely with sternal notch to nipple distance more than 30 cm (22.2% vs 4.3%, P = 0.03), and delayed wound healing was more likely with sternal notch to nipple distance of more than 25 cm (10.3% vs 1.6%, P = 0.03). There were no significant differences in nipple necrosis, skin flap necrosis, wound care requirements, or operative intervention based on anatomic measurement. Standard anatomic measurements are inconsistent predictors of outcome from NSM and should not be used alone to exclude attempts at NSM. PMID- 27779981 TI - Long-Term Nononcologic Outcomes for Laparoscopic Liver Resection: Improvement over Open Hepatectomy? AB - Prior studies of laparoscopic liver resection (LLR) have evaluated long-term outcomes in terms of cancer survival, but few have evaluated nononcologic outcomes. This study analyzes long-term nondisease-specific complications associated with LLR and open liver resection (OLR). We performed a retrospective single-institution review of patients undergoing liver resection for any reason from January 2005 to December 2014. Long-term complication was defined as any complication not related to the primary disease process, and occurring more than 90 days after surgery, emphasizing incisional hernia (IH) and small bowel obstruction (SBO). A total of 208 patients were included in the OLR group and 79 patients in the LLR group. Forty-one patients (19.6%) developed IH after OLR, whereas only six patients (7.5%) developed IH after LLR (P = 0.01). About 3.8 per cent of patients developed IH requiring surgical repair in both groups. Seven patients developed SBO (3.4%) after OLR; no patient developed SBO after LLR. Median time to development of complications was 13.8 months (range 3-54 months) after OLR compared with 8.5 months after LLR (range 6-36 months). Male gender, body mass index, prior abdominal surgery, and OLR were independent risk factors for development of long-term complications. There is a higher incidence of nondisease-specific complications after OLR than LLR. PMID- 27779980 TI - Minimally Invasive Video-Assisted Thyroidectomy: Almost a Decade of Experience at an Academic Center. AB - Minimally invasive video-assisted thyroidectomy (MIVAT) has gained acceptance as an alternative to conventional thyroidectomy. This technique results in less bleeding, postoperative pain, shorter recovery time, and better cosmetic results without increasing morbidity. We retrospectively assessed outcomes in 583 patients having MIVAT from May 2005 to September 2014. The study population was divided into groups according to periods: 2005 to 2009 and 2010 to 2014. Operative data, complications, and length of stay were collected and compared. Total thyroidectomy was undertaken in 185, completion thyroidectomy in 49, and hemithyroidectomy in 349. Malignancy was present in 127 (21.8%). Mean incision was 3.4 +/- 0.7 cm and estimated blood loss was 23.7 +/- 21.7 mL. Mean operative time was 86.5 +/- 39.3 minutes for all operations, 78.5 +/- 37.0 minutes for hemithyroidectomy, 70.9 +/- 30.1 minutes for completion thyroidectomy, and 106.8 +/- 41.3 minutes for total thyroidectomy. Postoperatively, 56 (9.6%) had unilateral vocal cord dysfunction, which resolved except for one case (0.17%). Fifty-nine patients (10.1%) developed hypocalcemia, but only three cases (0.51%) became permanent. Only one patient required readmission. In conclusion, MIVAT results in short operative times, minimal blood loss, and few complications and is safely performed in an academic institution. PMID- 27779982 TI - Impact of Massive Transfusion and Aging Blood in Acute Trauma. AB - Blood transfusions cause altered immunity and the duration of storage is contributory. In the era of massive transfusion protocols (MTPs) this impact is unclear, particularly as it relates to balanced transfusions. Trauma patients requiring our MTP after admission to our Level II trauma center were studied. The average age of blood transfused was calculated; old blood was a storage time of >=14 days versus new blood <14 days. Blood to plasma ratios of 1:1 were compared with ratios >1:1. Infections, organ dysfunction multiorgan injury (MOI), and death were compared based on ratios and blood storage times. Of 2200 trauma admissions, 89 patients required MTP. Penetrating injuries were the majority, n = 53; and Injury Severity Score was 33 +/- 14. Overall mortality was 31 per cent and sepsis was 28 per cent. Outcomes (storage time): Patients receiving old versus new blood had comparable age and Injury Severity Score. Sepsis rates, multiorgan injury and mortality were similar. Outcomes (packed red blood cells:fresh frozen plasma): Balanced transfusions (ratios of 1:1) demonstrated significant survival benefit and less infections compared with ratios >1:1. These data underscore the complexity of transfusion-related morbidity. In the modern era of MTP and balanced transfusions, the age of stored blood may not impact outcomes as demonstrated historically. PMID- 27779983 TI - Factors Associated with a Short (<2 Days) or Long (>10 Days) Length of Stay after Colectomy: A Multivariate Analysis of over 400 Patients. AB - A prospectively maintained database of 415 patients undergoing colectomy was evaluated. We performed a logistic regression analysis to identify factors associated with 1) length of stay (LOS) of 2 days or less and 2) LOS of 10 days or more. Investigated variables included demographics, American Society of Anesthesiology (ASA) score, diagnosis, operative procedure, approach and time, transfusion requirements, and occurrence of any complications. Factors associated with a LOS of two days or less included ASA [odds ratio (OR): 0.34, 95% confidence interval (CI): 0.208-0.576], use of transversus abdominis plane block (OR: 5.259, 95% CI: 2.825-9.791), and operative time (OR: 0.98, 95% CI: 0.974 0.986). Age >65 had an OR of 1.73, though this did not reach statistical significance. Factors associated with LOS >10 days included ASA (OR: 2.152, 95% CI: 1.245-3.721), anastomotic leak (OR: 2.163, 95% CI: 1.486-3.148), ileus (OR: 8.790, 95% CI: 4.501-17.165), and surgical site infection (OR: 5.846, 95% CI: 2.764-12.362). Cancer and transfusion status were associated but did not reach statistical significance. Although operative time was longer in left-sided resections, no differences in LOS were observed. In conclusion, numerous factors are associated with short or long LOS and may help stratify resource utilization after colectomy. Further study is needed to confirm our findings. PMID- 27779984 TI - Excision and Primary Closure May Be the Better Option in the Surgical Management of Pilonidal Disease in the Pediatric Population. AB - The optimal management of pilonidal disease in the pediatric population is still debated. We conducted a retrospective review of patients 21 years old and younger who underwent surgical management for pilonidal disease between 2009 and 2013 at a single pediatric institution. Sixty patients (41.7% male) were included in the analysis, with a mean age of 15.0 years (range, 13-20). Twelve (20%) had a prior drainage procedure for pilonidal abscess before the definitive operative treatment. After excision to the presacral fascia, 36 (60%) had primary closure, 17 (28.3%) were left to heal by secondary intention, and 7 (11.7%) had flap closure. Overall recurrence rate was 41.7 per cent with 33.3 per cent in the primary, 58.8 per cent in the secondary, and 42.9 per cent in the flap group, respectively. Ten (16.7%) patients developed postoperative complications, which were similar among surgical groups, gender, and body mass index. The average length of stay was 0.67 (median 0, range, 0-5) days. Primary closure had the shortest length of stay (analysis of variance P = 0.04), and flap closure had no reoperations (analysis of variance P < 0.01). Pilonidal disease remains surgically challenging. Our data suggest that excision and primary closure is a better option in the pediatric population. PMID- 27779985 TI - Do Antiplatelet and Anticoagulation Agents Matter after Repair of Traumatic Arterial Injuries? AB - Thrombosis is a devastating complication after repair of traumatic vascular injury. Although thrombosis rates have been described, the value of anticoagulation in preventing postrepair thrombosis is unknown. We hypothesize that postoperative anticoagulation reduces thrombosis rates. A total of 1524 consecutive patients with traumatic arterial injuries from January 2005 to June 2015 were identified, and 381 patients underwent the following repair types: direct suture of vessel wall, primary anastomosis, extra-anatomic reconstruction, tissue and synthetic interposition reconstruction. Twenty six patients received postoperative heparin at therapeutic levels, and 29 patients received postoperative aspirin for five consecutive days. The heparin and aspirin groups were matched with patients without postoperative anticoagulation by the following variables: anatomic arterial injury, type of vascular repair, and age. These groups were then compared using the following outcome measures: mortality, thrombosis of repaired vessel, amputation, hemorrhage, cerebral vascular accident, and extremity compartment syndrome. The demographics between the heparin, aspirin, and respectively matched groups were not statistically different. There was no statistically significant difference in the rate of thrombosis, bleeding, compartment syndrome, cerebral vascular accident, limb amputation, or mortality. Although there was no increase in bleeding complications with the use of heparin or aspirin, there was also no impact on the rate of thrombosis. PMID- 27779986 TI - Racial and Gender Differences in Arterial Anatomy of the Arm. AB - Prior studies have shown racial and gender differences with respect to maturation of arteriovenous fistulas. Women and minorities have lower maturation rates for unclear reasons. Small arterial diameter and high brachial artery bifurcation (HBB) are also implicated in reduced maturation rates. We sought to correlate differences in upper extremity arterial anatomy to race and gender. All upper extremity vascular mapping ultrasounds from 2013 to 2014 were retrospectively reviewed. A total of 509 arms in 284 patients were evaluated. Men had significantly higher mean arterial diameters than women at the elbow brachial (4.7 vs 3.9 mm, P < 0.01) and wrist radial arteries (2.1 vs 1.9 mm, P = 0.03). There were 20 (7%) patients with HBB of at least one arm, and 7 (2.5%) patients with bilateral HBB. African-American patients had significantly higher rates of both unilateral HBB (15.9% vs 5.4%, P = 0.02) and bilateral HBBs (9.1% vs 1.3%, P = 0.01). In conclusion, men had significantly larger arteries than women, and African-Americans had a higher rate of HBB than non-African-Americans. Consideration should be given for routine preoperative ultrasound to assess arterial anatomy before arteriovenous fistulas creation, particularly in women and in African-Americans. PMID- 27779987 TI - De novo Crohn's Disease after Ileal Pouch-Anal Anastomosis for Ulcerative Colitis and Inflammatory Bowel Disease Unclassified: Long-Term Follow-Up of a Prospective Inflammatory Bowel Disease Registry. AB - The risk of de novo Crohn's disease (CD) after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) versus inflammatory bowel disease unclassified (IBDU) or indeterminate colitis (IC) remains debatable. Here, we present updated results after long-term follow-up of a previously studied cohort of 334 patients with UC, IBDU, or IC who underwent IPAA during a 10-year period ending 2007. Of 334 study patients, 56 per cent were male and median age was 38 years (range: 8 81). Patients were classified as UC (n = 237) or IBDU (n = 97) preoperatively and UC (n = 236) or IC (n = 98) postoperatively. After a median follow-up of 76 months (range: 3-236), 63 patients (19%) developed CD within a median of 22 months (range: 1-213) from ileostomy closure compared with the previously published 40 patients (12%) with 26-month follow-up (P = 0.01). The development of de novo CD was similar for patients undergoing IPAA for UC (n = 40; 17%), IBDU (n = 21; 22%) or those classified as having UC (n = 42; 18%) or IC (n = 19; 19%) postoperatively; P > 0.05. Thus, patients with IBDU and IC can expect equivalent long-term outcome to patients with UC after IPAA. Pouch failure occurred in 13 (4%) study patients and was equal among all four groups. PMID- 27779989 TI - Analysis of Endoscopic Retrograde Cholangiopancreatography after Positive Intraoperative Cholangiogram: Is It Necessary? AB - The necessity of routine endoscopic retrograde cholangiopancreatography (ERCP) after positive intraoperative cholangiogram (IOC) during laparoscopic cholecystectomy is not well defined. We aimed to examine the incidence of positive IOC among patients who undergo IOC during cholecystectomy and the rate of subsequent ERCP stone extraction. The Nationwide Inpatient Sample database was reviewed for all patients undergoing cholecystectomy with IOC from 2002 to 2012. Patients were then analyzed for ERCP and stone extraction. A total of 73,508 patients who underwent cholecystectomy with IOC for a diagnosis of acute cholecystitis and found to have a bile duct stone were identified. Of these patients, 5915 underwent subsequent ERCP. In the patients that underwent subsequent ERCP, 1478 had a documented stone extraction during ERCP. The rate of stone extraction in the ERCP subset is 25 per cent, which is 2 per cent of all patients who had a positive IOC. The rate of stone extraction after positive IOC is low. Positive IOC may not warrant a routine postoperative ERCP. Our results suggest that clinical monitoring of patients with positive IOC is reasonable, as the majority of patients with a positive IOC ultimately have no stone extraction. PMID- 27779988 TI - Is Sentinel Lymph Node Dissection Necessary in All Patients with Ductal Carcinoma In Situ Undergoing Total Mastectomy? AB - When ductal carcinoma in situ (DCIS) is found on core needle biopsy, rates of upgrade to invasive cancer of 25 per cent and nodal positivity of 10 per cent have been reported. Sentinel lymph node dissection (SLND) is recommended when mastectomy is performed for DCIS. We investigated the role of SLND in DCIS patients undergoing partial and total mastectomy (TM). During the study period 2004 to 2013, 170 patients with DCIS were identified with a median age of 60 years (range 26-84 years). Of these, 58.2 per cent had partial mastectomy (PM) alone, 10.6 per cent had PM with SLND, and 31.1 per cent had TM with or without contralateral prophylactic mastectomy with SLND. Overall, SLND identified positive nodes in 4.2 per cent of patients. Upgrade to invasive carcinoma on final breast pathology was found in 8.2 per cent of patients overall, including 4.0 per cent of patients undergoing PM alone, 22.2 per cent undergoing PM with SLND, and 11.3 per cent for TM with SLND (P = 0.8). In this study, patients diagnosed with DCIS on core needle biopsy had lower than expected rates of positive sentinel nodes and upgrade to invasive carcinoma. Surgeons and patients should revisit the necessity of SLND in DCIS patients undergoing mastectomy, which could lead to decreased health expenditure, resources, time, morbidity, and emotional impact on patients. PMID- 27779990 TI - Type and Quantity of Pharmacologic Therapy for Crohn's Disease before Eventual Surgical Treatment. AB - Treatment of Crohn's disease (CD) relies on medical therapy with surgery reserved for medically refractory cases. This study measured pharmaceutical therapies that CD patients receive before surgery. Prospective data were collected on 558 patients undergoing surgery for medically refractory CD from November 1999 through June 2014. Patient demographics and preoperative medical therapies were tabulated, including types and number of doses of aminosalicylic acid, corticosteroids, immunomodulators, and biologic therapies. Most patients had been treated with preoperative aminosalicylic acid (72%), steroids (77%), or immunomodulators (69%). Forty-two per cent of patients were treated with a biologic before surgery with a mean number of 20 doses (range, 1-130). In 29 per cent of patients, all therapeutic modalities were used before surgery. Biologic therapy was more common in the last seven years of the study compared with the first eight years (64% vs 35%; P < 0.01). More patients had been treated with all therapeutic modalities before surgery in the second half of the study period (37% vs 19%; P < 0.01). CD patients undergoing surgery have had extensive pharmaceutical treatment. In the current era, more patients have been placed on biologic therapies and more than one third of them failed all available classes of medications before surgical intervention. PMID- 27779991 TI - Predictors of Ischemic Bowel in Patients with Small Bowel Obstruction. AB - Preoperative diagnosis of ischemic bowel in patients with small bowel obstruction (SBO) is a clinical challenge. The aim of this study was to identify preoperative variables associated with ischemic bowel found at operative exploration. We performed a 5-year retrospective review of patients admitted to a university affiliated, county funded hospital who underwent exploratory laparoscopy or laparotomy for SBO. Patients were excluded if they had a known preoperative malignancy or hernia on physical examination. Multivariate logistic regression was used to determine factors independently associated with bowel ischemia or ischemic perforation. One hundred and sixteen patients underwent exploratory surgery for SBO. Mean age was 52 +/- 14 years and most were male [64 (55.2%)]. Adhesions [92 (79.3%)] were the most common etiology of obstruction. Leukocytosis (P = 0.304) and acidosis (P = 0.151) were not significantly associated with ischemia or ischemic perforation. In addition, history of prior SBO (P = 0.618), tachycardia (P = 0.111), fever (P = 0.859), and time from admission to operation (P = 0.383) were not predictive of ischemic bowel. However, hyponatremia (<=134 mmol/L) and CT scan findings of wall thickening or a suspected closed loop were independently associated with bowel ischemia. Awareness of these predictors should heighten the concern for ischemic bowel in patients presenting with SBO. PMID- 27779992 TI - Survival Difference in Patients with Malignant Pleural Effusions Treated with Pleural Catheter or Talc Pleurodesis. AB - Malignant pleural effusions (MPE) are commonly managed with either pleural catheter (PC) or talc pleurodesis (TP). The aim of this study was to compare survival in MPE patients treated with either PC or TP. A retrospective review of our cancer center database was performed. Patients with metastatic cancer and MPE were analyzed. Demographic and clinical data were tabulated and compared. A total of 238 patients with MPE treated by either PC or TP were included. Of these, 79 patients comprised the PC group and 159 the TP group. PC had a higher incidence of advanced disease (stage III or IV) at initial diagnosis compared with TP (70.9% vs 57.2%, P = 0.05). TP had a longer postprocedure length of stay compared with PC (7.1 vs 5.0 days, P = 0.02); however, overall length of stay was similar (9.7 vs 11.1 days, P = 0.34). Readmissions were significantly lower in TP (11.9% vs 22.8%, P = 0.04). Mean survival was higher in TP compared with PC (18.7 vs 4.1 months, P < 0.001). Patients with metastatic cancer and MPE treated with TP had significantly higher survival compared with PC. This is likely related to a greater disease burden in PC, as 70 per cent of patients in this group had stage III or IV disease on initial presentation. PMID- 27779993 TI - Initiating a Standard Venous Thromboembolism Prophylaxis Order Set Designed to Improve Patient Outcomes at Los Angeles County+University of Southern California. AB - Improving patient safety is vital for all hospitals due to increasing public reporting and pay-for-performance reimbursement. Venous thromboembolism (VTE) remains a leading cause of preventable mortality accounting for 5 per cent of inpatient deaths. The purpose of this study was to outline the process of implementing standard VTE prophylactic order sets in a 600-bed academic safety net hospital and assess the resulting change in patient outcomes. Outcomes were assessed by comparing the rate that eligible inpatients receive VTE prophylaxis and the rate of preventable VTE's compared with total VTE's. From 2011 to 2015, random samples of 60 Los Angeles County+University of Southern California inpatients were generated monthly to examine compliance rates by comparing ICD-9 diagnostic codes to ordered VTE prophylaxis. All inpatient VTE's are retrospectively analyzed. Baseline-ordered VTE prophylaxis was 37 per cent in 2010. The target of 85 per cent was exceeded by the second quarter of 2012 to 2013 when compliance reached 88 per cent, a 51 per cent increase from baseline (P < 0.01). These results suggest VTE protocols are effective though standardization across service lines is often difficult. Despite these challenges, after implementing standard order sets, we saw compliance increase significantly. Ongoing analysis to determine whether VTE rates have significantly decreased is presently underway. PMID- 27779994 TI - Staging Rectal Cancer: The Utility of Chest Radiograph and Chest Computed Tomography. AB - The National Comprehensive Cancer Network recommends that patients who are newly diagnosed with rectal cancer undergo staging CT scan of the chest. It is unclear whether posteroanterior and lateral chest radiography (X-ray) alone would provide adequate staging for most of these patients. A retrospective review was performed on all patients who had a two-view chest X-ray along with a chest CT for rectal cancer staging from 2007 to 2015. A total of 74 patients had both modalities. Sixty-three (85%) had a normal chest X-ray and 11 (15%) had an abnormal chest X ray. Of the 63 patients with a normal chest X-ray, 40 (63%) had a corresponding normal chest CT and 23 (37%) had a lesion only noted on chest CT. Four patients (17%) in the latter group had metastatic cancer to the lung at the time of workup and four out of five of the tumors found to metastasize were within 5 cm from the anal verge. Our data suggest that a staging chest X-ray is unlikely to diagnose metastatic lungs lesions from a primary rectal cancer. Conversely, staging chest CT will accurately stage metastatic disease but will also reveal benign lung lesions in this patient population. PMID- 27779996 TI - Robotic Inguinal Hernia Repair: Technique and Early Experience. AB - Laparoscopic inguinal hernia repair has been shown to have multiple advantages compared with open repair such as less postoperative pain and earlier resume of daily activities with a comparable recurrence rate. We speculate robotic inguinal hernia repair may yield equivalent benefits, while providing the surgeon added dexterity. One hundred consecutive robotic inguinal hernia repairs with mesh were performed with a mean age of 56 years (25-96). Fifty-six unilateral hernias and 22 bilateral hernias were repaired amongst 62 males and 16 females. Polypropylene mesh was used for reconstruction. All but, two patients were completed robotically. Mean operative time was 52 minutes per hernia repair (45-67). Five patients were admitted overnight based on their advanced age. Regular diet was resumed immediately. Postoperative pain was minimal and regular activity was achieved after an average of four days. One patient recurred after three months in our earlier experience and he was repaired robotically. Mean follow-up time was 12 months. These data, compared with laparoscopic approach, suggest similar recurrence rates and postoperative pain. We believe comparative studies with laparoscopic approach need to be performed to assess the role robotic surgery has in the treatment of inguinal hernia repair. PMID- 27779997 TI - Negative Appendectomy: Clinical and Economic Implications. AB - Historically, performing a negative appendectomy (NA) was justified to reduce the incidence of perforation. Furthermore, it is also believed that NA is associated with minimal morbidity and cost. The purpose of this study was to evaluate the frequency, clinical characteristics, and economic implications of NA. We reviewed the inpatient admissions on 274,405 patients who underwent nonincidental appendectomy as their primary procedure from the California State Inpatient Databases (2005-2011). Overall, 96.9 per cent had appendicitis (nonperforated = 73.1%, perforated = 23.8% and 3.1%) had NA. NA rates decreased steadily from 4.2 per cent in 2005 to 2.5 per cent in 2011 (P < 0.01). The rates of appendectomy for perforated appendicitis rates also decreased slightly from 25.3 to 23.3 per cent during this time (P = <0.01). Multivariate regression showed that female gender, African American race, and public insurance were all associated with increased NA rates. Compared with patients with appendectomy for nonperforated appendicitis, NA was associated with longer length of stay (NA = 3.2 days vs nonperforated = 1.7 days), higher median cost per admission (NA = $8626 vs nonperforated = $7605), and higher morbidity (4.7 vs 1.9%), all P < 0.01. Contrary to classic justification for NA, we did not find an inverse association of appendectomy for perforated appendicitis and NA at the hospital level. In conclusion, NA is associated with substantial clinical and financial burden, while having no apparent impact on lowering the rate of appendectomy for perforated appendicitis. PMID- 27779995 TI - Second Primary Melanoma: Risk Factors, Histopathologic Features, Survival, and Implications for Follow-Up. AB - The impact on survival of a second primary melanoma (SPM) is unclear. We used our melanoma center's database to examine clinicopathologic risk factors and outcomes of stage 0 to IV cutaneous melanoma in patients with one versus two primaries. Among 12,325 patients with primary melanoma, 969 (7.86%) developed SPM. SPMs were significantly thinner than autologous primary melanomas (P = 0.01), and 451 SPM patients had better overall and melanoma-specific survival than 451 prognostically matched non-SPM patients (P < 0.0001 and 0.0001, respectively) at a median follow-up of 142.37 months. Patients with cutaneous melanoma are at high risk for development of SPM, but the development of SPM does not seem to impair survival. PMID- 27779998 TI - Examining the Quality of Rectal Cancer Operative Reports in Teaching Institutions: Is There an Opportunity for Resident Education? AB - The American Society of Colon and Rectal Surgeons rectal cancer checklist describes a set of best practices for rectal cancer surgery. The objective of this study was to assess the quality of operative reports for rectal cancer surgery based on the intraoperative American Society of Colon and Rectal Surgeons checklist items. Patients undergoing rectal cancer surgery at two public teaching hospitals from 2009 to 2015 were included. A total of 12 intraoperative checklist items were assessed. One hundred and fifty-eight operative reports were reviewed. Overall adherence to checklist items was 55 per cent, and was significantly higher in attending versus resident dictated reports (67% vs 51%, P < 0.01). Senior residents had significantly higher adherence to checklist items than junior residents (55% vs 44%, P < 0.01). However, overall adherence to rectal cancer checklist items was low. This represents an opportunity to improve the quality of operative documentation in rectal cancer surgery, which could also impact the technical quality of the operation itself. PMID- 27779999 TI - Appendicitis in Cancer Patients Is Often Observed and Can Represent Appendiceal Malignancy. AB - Appendectomy is standard of care for uncomplicated appendicitis, but cancer patients may not be optimal surgical candidates. Interval appendectomy is controversial, and appendiceal malignancy is rare. Study objectives were to review the role of surgery, observation, and interventional radiology (IR)-guided drainage in patients with appendicitis and advanced malignancy. Retrospective review was performed on cancer patients presenting to a tertiary academic cancer center from January 1, 2001 to December 31, 2014. Patients diagnosed with appendicitis were assigned to observation, surgery, and IR drainage after surgical evaluation. Success rates of initial treatment strategies were calculated. Rates of interval appendectomies and pathology were reviewed. Of 72 consults, 32 patients were included. Median age was 53 years, 50 per cent (16/32) were male, 50 per cent (16/32) had chemotherapy less than six weeks to presentation, and 63 per cent (20/32) had advanced stage malignancy. Of the 62.5 per cent (20/32) observed, 25 per cent (8/32) received immediate surgery, 12.5 per cent (4/32) required IR drainage, and 69 per cent (22/32) of patients were initially managed without surgery. Interval appendectomy rate was 19 per cent (6/32). Pathology confirmed appendiceal malignancies in 9.3 per cent (3/32). Cancer patients with acute appendicitis are frequently observed. High incidence of appendiceal malignancy may be due to the older median age. Interval appendectomy should be considered in this population. PMID- 27780000 TI - Complications of Diverting Ileostomy after Low Anterior Resection for Rectal Carcinoma. AB - There have been few studies directly comparing the postoperative complications in patients with a diverting ileostomy to patients who were not diverted after low anterior resection (LAR) for rectal carcinoma. This study is a retrospective chart review of all rectal carcinoma patients (99) who underwent a LAR from January 2009 to December 2014 at Loma Linda University Medical Center and Veterans Affairs Loma Linda Healthcare System. A majority of patients were diverted (58% vs 42%). The diverted patients were more likely to have a low tumor location (P < 0.01), preoperative chemoradiation (P < 0.01), and more intraoperative blood loss (P < 0.01). Our study shows a statistically significant higher overall complication rate among patients receiving a diverting ileostomy in the six months after LAR (61% vs 38%, P = 0.02). The difference is due to a higher rate of readmission (27% vs 14%) and acute kidney injury (14% vs 5%) in patients with a diverting ileostomy. It also shows that there is a higher rate of unplanned reoperation (11% vs 6%) due to anastomotic leak (17% vs 5%) in nondiverted patients. Further studies are needed to refine the specific indications to maximize the benefit of diverting ileostomy after LAR for rectal carcinoma. PMID- 27780001 TI - Small Bowel Obstructions in a Virgin Abdomen: Is an Operation Mandatory? AB - Though conventionally not considered standard of care, nonoperative management of patients with small bowel obstruction (SBO) without previous abdominal operations, so called "virgin abdomens," (VA) is presently being practiced. We aimed to determine outcomes of patients with VA undergoing operative and nonoperative management of SBO. A retrospective review of patients with SBO was performed; outcomes of patients with VA were analyzed. SBO with a VA was found in 103 patients over a 5-year period. With a mean follow-up of 4.5 years, nonoperative management was associated with successful resolution of obstruction in 61 per cent (63/103) of patients. Of those managed nonoperatively, 58/63 (92.1%) did not experience a recurrence. Of the 21 patients with a complete/high grade SBO on imaging, 16 (76.2%) were managed operatively. Of the 64 patients with a partial/low-grade obstruction or partial obstruction/ileus on imaging, 53 (82.8%) were managed nonoperatively. These data suggest that selected patients with SBO and a VA may safely undergo nonoperative management under close surgical monitoring. PMID- 27780003 TI - Tear Production Rate in a Mouse Model of Dry Eye According to the Phenol Red Thread and Endodontic Absorbent Paper Point Tear Tests. AB - This study compared the endodontic absorbent paper point test (EAPTT) and the phenol red thread test (PRTT) for the assessment of tear production rate in a mouse model of dry eye. Fourteen BALB/c breed female mice were allocated into experimental and control groups of equal number. For 6 wk, the experimental group was kept in dry-eye cabinets, whereas the control group was kept in normal cages under ambient conditions. In both groups, the tear production rate was measured by using EAPTT and PRTT before the study, at study baseline, and at weeks 2, 4, and 6. Tear production at weeks 2, 4, and 6 differed significantly between groups and tests. Evaluating the groups independently in terms of the test technique revealed significant differences in tear production rate between the 2 groups at the same measurement times. Due to their persistent exposure to evaporative stress factors, the tear production rate of the mice in the dry-eye cabinet was consistently lower than that of controls. Unlike PRTT, EAPTT can be readily applied to the small globes of laboratory animals without the need for forceps, thus saving time and effort. In addition, EAPTT was practical and imposed no undue stress on the mice, due to the test material's firmer structure. Therefore, compared with PRTT, EAPTT is safer and more reliable for the diagnosis of dry-eye syndrome in mice. PMID- 27780002 TI - Bordetella pseudohinzii as a Confounding Organism in Murine Models of Pulmonary Disease. AB - A group studying acute lung injury observed an increased percentage of neutrophils in the bronchoalveolar lavage (BAL) fluid of mice. BAL was performed, and lung samples were collected sterilely from 5 C57BL/6 mice that had been bred inhouse. Pure colonies of bacteria, initially identified as Bordetella hinzii were cultured from 2 of the 5 mice which had the highest percentages of neutrophils (21% and 26%) in the BAL fluid. Subsequent sequencing of a portion of the ompA gene from this isolate demonstrated 100% homology with the published B. pseudohinzii sequence. We then selected 10 mice from the investigator's colony to determine the best test to screen for B. pseudohinzii in the facility. BAL was performed, the left lung lobe was collected for culture and PCR analysis, the right lung lobe and nasal passages were collected for histopathology, an oral swab was collected for culture, and an oral swab and fecal pellets were collected for PCR analysis. B. pseudohinzii was cultured from the oral cavity, lung, or both in 8 of the 10 mice analyzed. All 8 of these mice were fecal PCR positive for B. pseudohinzii; 7 had increased neutrophils (5% to 20%) in the BAL fluid, whereas the 8th mouse had a normal neutrophil percentage (2%). Active bronchopneumonia was not observed, but some infected mice had mild to moderate rhinitis. B. pseudohinzii appears to be a microbial agent of importance in mouse colonies that can confound pulmonary research. Commercial vendors and institutions should consider colony screening, routine reporting, and exclusion of B. pseudohinzii. PMID- 27780004 TI - Effects of Daytime Exposure to Light from Blue-Enriched Light-Emitting Diodes on the Nighttime Melatonin Amplitude and Circadian Regulation of Rodent Metabolism and Physiology. AB - Regular cycles of exposure to light and dark control pineal melatonin production and temporally coordinate circadian rhythms of metabolism and physiology in mammals. Previously we demonstrated that the peak circadian amplitude of nocturnal blood melatonin levels of rats were more than 6-fold higher after exposure to cool white fluorescent (CWF) light through blue-tinted (compared with clear) rodent cages. Here, we evaluated the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit light rich in the blue appearing portion of the visible spectrum (465-485 nm), compared with standard broadspectrum CWF light, on melatonin levels during the subsequent dark phase and on plasma measures of metabolism and physiology. Compared with those in male rats under a 12:12-h light:dark cycle in CWF light, peak plasma melatonin levels at the middark phase (time, 2400) in rats under daytime LED light were over 7-fold higher, whereas midlight phase levels (1200) were low in both groups. Food and water intakes, body growth rate, and total fatty acid content of major metabolic tissues were markedly lower, whereas protein content was higher, in the LED group compared with CWF group. Circadian rhythms of arterial plasma levels of total fatty acids, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were generally lower in LED-exposed rats. Therefore, daytime exposure of rats to LED light with high blue emissions has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing and thus may influence scientific outcomes. PMID- 27780005 TI - Effects of Colored Enrichment Devices on Circadian Metabolism and Physiology in Male Sprague-Dawley Rats. AB - Environmental enrichment (EE) gives laboratory animals opportunities to engage in species-specific behaviors. However, the effects of EE devices on normal physiology and scientific outcomes must be evaluated. We hypothesized that the spectral transmittance (color) of light to which rats are exposed when inside colored enrichment devices (CED) affects the circadian rhythms of various plasma markers. Pair-housed male Crl:SD rats were maintained in ventilated racks under a 12:12-h light:dark environment (265.0 lx; lights on, 0600); room lighting intensity and schedule remained constant throughout the study. Treatment groups of 6 subjects were exposed for 25 d to a colored enrichment tunnel: amber, red, clear, or opaque. We measured the proportion of time rats spent inside their CED. Blood was collected at 0400, 0800, 1200, 1600, 2000, and 2400 and analyzed for plasma melatonin, total fatty acids, and corticosterone. Rats spent more time in amber, red, and opaque CED than in clear tunnels. All tubes were used significantly less after blood draws had started, except for the clear tunnel, which showed no change in use from before blood sampling began. Normal peak nighttime melatonin concentrations showed significant disruption in the opaque CED group. Food and water intakes and body weight change in rats with red-tinted CED and total fatty acid concentrations in the opaque CED group differed from those in other groups. These results demonstrate that the color of CED altered normal circadian rhythms of plasma measures of metabolism and physiology in rats and therefore might influence the outcomes of scientific investigations. PMID- 27780006 TI - Mortality Due to Porcine Reproductive and Respiratory Syndrome Virus in Immunocompromised Gottingen Minipigs (Sus scrofa domestica). AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection was diagnosed in 6 Gottingen minipigs (Sus scrofa domestica) with severe interstitial pneumonia. The virus was defined as a North American (NA) subtype virus, which is common in the commercial pig population and might be derived from a widely used attenuated live-virus vaccine in Europe. The ORF5 sequence of the isolated PRRSV was 98% identical to the vaccine virus. The affected pigs were part of a lung transplantation model and received tacrolimus and steroids as well as irradiation or CD8 antibody for immunosuppression. The likely source of the infection was pigs that were shedding the identified PRRSV, which were housed in a separate room of the same building. This case report provides evidence that a virus closely related to an attenuated live vaccine might cause severe pneumonia and death in PRRSVseronegative pigs receiving immunosuppressive treatment. We recommend strict barrier housing for immunocompromised pigs. PMID- 27780007 TI - Diaphragmatic Hernia of the Stomach with Gastric Rupture in a Domestic Pig. AB - A 5.5-mo-old castrated, male Red Duroc pig presented acutely with depression and abdominal pain 9 d after an altercation with another pig. A CT examination indicated right pneumothorax and herniation of the stomach into the thoracic cavity. Due to a poor prognosis, the pig was euthanized. A necropsy and gross examination revealed a tear of the diaphragmatic muscle in the region of the esophageal hiatus through which the stomach was displaced into the right side of the thoracic cavity. In addition, the herniated stomach had a rupture of the stomach wall through which the gastric mucosa was everted and exposed into the right thoracic cavity. The right thoracic cavity had acute fibrinous pleuritis, and the right lung was collapsed. CT scans performed every 1 to 2 wk for 2 mo prior to the pig's death did not reveal any abnormalities in the diaphragm. Trauma was considered the most likely cause of the diaphragmatic tear and subsequent herniation and rupture of the stomach. PMID- 27780010 TI - Juxtaarticular Myxoma in a Pigtail Macaque (Macaca nemestrina). AB - A 10-y-old pigtail macaque presented with a subcutaneous, soft-tissue mass overlying the right stifle joint. Here we describe the clinical case and histopathologic and immunohistochemical analysis of this lesion. This case represents the first published report of juxtaarticular myxoma in a pigtail macaque. PMID- 27780009 TI - Very Low Doses of Mycobacterium tuberculosis Yield Diverse Host Outcomes in Common Marmosets (Callithrix jacchus). AB - Identifying and refining small-animal models of tuberculosis that recapitulate aspects of human Mycobacterium tuberculosis infection can contribute to advancing our understanding of critical facets of the disease. To study the effects of very low-dose infections with 2 strains of M. tuberculosis on disease progression and survival in common marmosets, animals were challenged with strains Erdman and CDC1551 at doses ranging from 1 to 12 cfu. These data revealed that the susceptibility of marmosets to M. tuberculosis infection is influenced by strain virulence and initial dose. Marmoset infection with the Erdman strain, even at very low doses, resulted in rapid disease progression associated with severe weight loss, extensive pathology, and poor survival. By contrast, challenge with the less virulent CDC1551 strain resulted in slower disease progression, delayed weight loss, and prolonged survival. One marmoset infected with CDC1551 at a very low dose (approximately 1 cfu) was able to contain and control M. tuberculosis infection in a subclinical state that persisted as long as 300 d. These findings underscore the critical importance of understanding the heterogeneity in host outcome that can arise in association with different infectious doses and strains in the marmoset model of tuberculosis. PMID- 27780008 TI - Severe Hemophilia A in a Male Old English Sheep Dog with a C->T Transition that Created a Premature Stop Codon in Factor VIII. AB - Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C->T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies ('inhibitors') to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia. PMID- 27780011 TI - A Phyllodes-like Mammary Tumor in a Breeding Galago (Otolemur garnettii). AB - In humans, phyllodes tumors of the breast are rare fibroepithelial tumors that are further characterized as benign, borderline, or malignant according to their histomorphologic features. Phyllodes tumors are poorly responsive to treatment other than excision. NHP have a much lower frequency of mammary neoplasia than do humans, and none of the lesions reported previously in NHP are consistent with phyllodes tumors. Here we present the case of a mammary tumor in a northern greater galago (Otolemur garnettii) that was histologically characteristic of a malignant phyllodes tumor. An 11-y-old, multiparous, pregnant galago presented with a mass in the right middle mammary gland. A fine-needle aspirate yielded neoplastic epithelial cells. Because the animal was pregnant and showed no signs of skin ulceration, pain, or distress, she was allowed to deliver and nurse the infant. At 20 wk after initial presentation, the infant was weaned and the mother was euthanized. At necropsy, the mammary mass measured 3.5 * 2.5 * 1.5 cm, a 13 fold increase in volume since initial presentation. There was no evidence of metastasis in draining lymph nodes, lungs, or any other tissue examined. The tumor was composed of neoplastic stromal, glandular, and adipose tissues and was diagnosed as a malignant phyllodes tumor in light of its high stromal cellularity, high mitotic rate, and marked atypia. This tumor also exhibited liposarcomatous differentiation, which occurs frequently in malignant phyllodes tumors. To our knowledge, this report represents the first described case involving an NHP of a mammary tumor with characteristics consistent with human phyllodes tumors. PMID- 27780012 TI - Lectin Receptors Expressed on Myeloid Cells. AB - Lectins recognize a diverse array of carbohydrate structures and perform numerous essential biological functions. Here we focus on only two families of lectins, the Siglecs and C-type lectins. Triggering of intracellular signaling cascades following ligand recognition by these receptors can have profound effects on the induction and modulation of immunity. In this chapter, we provide a brief overview of each family and then focus on selected examples that highlight how these lectins can influence myeloid cell functioning in health and disease. Receptors that are discussed include Sn (Siglec-1), CD33 (Siglec-3), and Siglec 5, -7, -8, -9, -10, -11, -14, -15, -E, -F, and -G as well as Dectin-1, MICL, Dectin-2, Mincle/MCL, and the macrophage mannose receptor. PMID- 27780013 TI - Coordinated Regulation of Signaling Pathways during Macrophage Activation. AB - The functional and phenotypic diversity of macrophages has long been appreciated, and it is now clear that it reflects a complex interplay between hard-wired differentiation pathways and instructive signals in specific tissues (Lawrence T, Natoli G. 2011, Nat Rev Immunol11:750-761). Recent studies have begun to unravel the molecular basis for the integration of these intrinsic developmental pathways with extracellular signals from the tissue microenvironment that confer the distinct phenotypes of tissue-resident macrophages (Lavin Y et al. 2014. Cell159:1312-1326; Gosselin D et al. 2014. Cell159:1327-1340). Macrophage phenotype and function is particularly dynamic during inflammation or infection, as blood monocytes are recruited into tissues and differentiate into macrophages, and depending on the nature of the inflammatory stimulus, they may acquire distinct functional phenotypes (Xue J et al. 2014. Immunity40:274-288; Murray PJ et al. 2014. Immunity41:14-20). Furthermore, these functional activation states can be rapidly modified in response to a changing microenvironment. Here we will discuss several key signaling pathways that drive macrophage activation during the inflammatory response and discuss how these pathways are integrated to "fine tune" macrophage phenotype and function. PMID- 27780014 TI - Clinical Presentations and Epidemiology of Urinary Tract Infections. AB - Urinary tract infection (UTI) is one of the most common bacterial infections, and the incidence in women is much higher than in men. The diagnosis of a UTI can be made based on a combination of symptoms and a positive urine analysis or culture. Most UTIs are uncomplicated UTIs, defined as cystitis in a woman who is not pregnant, is not immunocompromised, has no anatomical and functional abnormalities of the urogenital tract, and does not exhibit signs of tissue invasion and systemic infection. All UTIs that are not uncomplicated are considered to be complicated UTIs. Differentiation between uncomplicated and complicated UTIs has implications for therapy because the risks of complications or treatment failure are increased for patients with a complicated UTI. Asymptomatic bacteriuria (ASB) is defined as the presence of a positive urine culture collected from a patient without symptoms of a UTI. Concerning the complicated UTI, it is possible to make a differentiation between UTI with systemic symptoms (febrile UTI) and UTI in a host, which carries an increased risk to develop complications of this UTI. Febrile UTIs are urosepsis, pyelonephritis, and prostatitis. A complicated host is defined as one that has an increased risk for complications, to which the following groups belong: men, pregnant women, immunocompromised patients, or those who have an anatomical or functional abnormality of the urogenital tract (e.g., spinal cord-injury patients, renal stones, urinary catheter). PMID- 27780015 TI - Potential for Meta-Analysis in the Realm of Preharvest Food Safety. AB - Meta-analysis, the statistical combination of results from multiple studies, can be used to summarize all of the available research on an intervention, etiology, descriptive, or diagnostic test accuracy question. Meta-analysis should be conducted as a component of a systematic review, to increase transparency in the selection of studies and to incorporate an evaluation of the risk of bias in the individual studies included in the meta-analysis. The process of meta-analysis may include a forest plot to graphically display the study results and the calculation of a weighted average summary effect size. Heterogeneity (differences in the effect size between studies) can be evaluated using formal statistics and the reasons for heterogeneity can be explored using sub-group analysis or meta regression. Thus, meta-analysis may be a useful methodology for preharvest food safety research to aid in policy or clinical decision-making or to provide input to quantitative risk assessment or other models. PMID- 27780016 TI - Monocyte, Macrophage, and Dendritic Cell Development: the Human Perspective. AB - The maintenance of monocytes, macrophages, and dendritic cells (DCs) involves manifold pathways of ontogeny and homeostasis that have been the subject of intense study in recent years. The concept of a peripheral mononuclear phagocyte system continually renewed by blood-borne monocytes has been modified to include specialized DC pathways of development that do not involve monocytes, and longevity through self-renewal of tissue macrophages. The study of development remains difficult owing to the plasticity of phenotypes and misconceptions about the fundamental structure of hematopoiesis. However, greater clarity has been achieved in distinguishing inflammatory monocyte-derived DCs from DCs arising in the steady state, and new concepts of conjoined lymphomyeloid hematopoiesis more easily accommodate the shared lymphoid and myeloid phenotypes of some DCs. Cross species comparisons have also yielded coherent systems of nomenclature for all mammalian monocytes, macrophages, and DCs. Finally, the clear relationships between ontogeny and functional specialization offer information about the regulation of immune responses and provide new tools for the therapeutic manipulation of myeloid mononuclear cells in medicine. PMID- 27780019 TI - Regulatory Issues Associated with Preharvest Food Safety: European Union Perspective. AB - Free movement of safe and wholesome food is an essential aspect of any society. This article contains an updated description of the regulatory issues associated with preharvest food safety within the European Union. Salmonella, Campylobacter, Trichinella, antimicrobial resistance, and bovine spongiform encephalopathy are dealt with in detail. Moreover, Cysticercus bovis/Taenia saginata, Toxoplasma, Yersinia, verotoxigenic/shigatoxigenic Escherichia coli, Listeria, and foodborne viruses are briefly covered. The article describes how the focus in the European Union is changing to involve a supply chain view with a focus on cost effectiveness. The precautionary principle-as well as the use of private standards as an instrument to ensure compliance-is dealt with. In addition, actions in the pipeline are presented and discussed. PMID- 27780017 TI - The Regulatory Function of Eosinophils. AB - Eosinophils are a minority circulating granulocyte classically viewed as being involved in host defense against parasites and promoting allergic reactions. However, a series of new regulatory functions for these cells have been identified in the past decade. During homeostasis, eosinophils develop in the bone marrow and migrate from the blood into target tissues following an eotaxin gradient, with interleukin-5 being a key cytokine for eosinophil proliferation, survival, and priming. In multiple target tissues, eosinophils actively regulate a variety of immune functions through their vast arsenal of granule products and cytokines, as well as direct cellular interaction with cells in proximity. The immunologic regulation of eosinophils extends from innate immunity to adaptive immunity and also involves non-immune cells. Herein, we summarize recent findings regarding novel roles of murine and human eosinophils, focusing on interactions with other hematopoietic cells. We also review new experimental tools available and remaining questions to uncover a greater understanding of this enigmatic cell. PMID- 27780020 TI - Murine Monocytes: Origins, Subsets, Fates, and Functions. AB - Monocytes are short-lived mononuclear phagocytes that circulate in the bloodstream and comprise two main subpopulations that in the mouse are best defined by the Ly6C marker. Intravascular functions of "classical" Ly6C+ monocytes and their interactions with other lymphoid and myeloid leukocytes in the circulation remain poorly understood. Rather, these cells are known to efficiently extravasate into tissues. Indeed, Ly6C+ monocytes and their descendants have emerged as a third, highly plastic and dynamic cellular system that complements the two classical, tissue-resident mononuclear phagocyte compartments, i.e., macrophages and dendritic cells, on demand. Following recruitment to injured tissue, Ly6C+ monocytes respond to local cues and can critically contribute to the initiation and resolution of inflammatory reactions. The second main murine monocyte subset, Ly6C- cells, derive in steady state from Ly6C+ monocytes and remain in the vasculature, where the cells act as scavengers. Moreover, a major fraction of Ly6C- monocytes adheres to the capillary endothelium and patrols the vessel wall for surveillance. Given the central role of monocytes in homeostasis and pathology, in-depth study of this cellular compartment can be highly informative on the health state of the organism and provides an attractive target for therapeutic intervention. PMID- 27780018 TI - Inflammation-a Critical Appreciation of the Role of Myeloid Cells. AB - What is inflammation's big idea? In this brief overview of the role of myeloid cells in inflammation, we will critically discuss what drives the initiation, amplification, and resolution of inflammation in different anatomical sites in response to different pathological stimuli. It can be argued that we have a good understanding of the basic principles that underlie myeloid cell activation and the mobilization of innate immune cells to sites of injury and infection in acute inflammation. The challenge now for inflammation biologists is to understand how resolution of this normal physiological response goes wrong in hyperacute and chronic inflammation. A better understanding of how inflammation is regulated will allow us to develop new anti-inflammatory drugs that will reduce the burden of inflammatory disease without compromising the patient's immune defenses against infectious disease. Ideally such drugs should encourage a return to homeostasis and enhance tissue repair processes. PMID- 27780021 TI - How Should Medical Schools Respond to Students with Dyslexia? AB - We examine the dilemmas faced by a medical student with dyslexia who wonders whether he should "out" himself to faculty to receive the accommodations entitled by federal law. We first discuss scientific evidence on dyslexia's prevalence, unexpected nature, and neurobiology. We then examine the experiences of medical students who have revealed their dyslexia to illustrate the point that, far too often, attending physicians who know little about dyslexia can misperceive the motives or behavior of students with dyslexia. Because ignorance and misperception of dyslexia can result in bias against students with dyslexia, we strongly recommend a mandatory course for faculty that provides a basic scientific and clinical overview of dyslexia to facilitate greater understanding of dyslexia and support for students with dyslexia. PMID- 27780022 TI - How Should Colleagues Respond to Diminishing Capacities of an Aging Surgeon? AB - When an esteemed elderly colleague needs assistance completing procedures safely, fellow health professionals have the responsibility to respond in order to mitigate risk to patients. There is a strong ethical basis for bringing the surgeon's declining capacity to his or her attention as well as to the attention of others. Ongoing capacity assessments could be one method for tracking diminished capacities among surgeons so that they can stop practicing surgery before putting patients at risk. PMID- 27780023 TI - Medical Schools' Willingness to Accommodate Medical Students with Sensory and Physical Disabilities: Ethical Foundations of a Functional Challenge to "Organic" Technical Standards. AB - Students with sensory and physical disabilities are underrepresented in medical schools despite the availability of assistive technologies and accommodations. Unfortunately, many medical schools have adopted restrictive "organic" technical standards based on deficits rather than on the ability to do the work. Compelling ethical considerations of justice and beneficence should prompt change in this arena. Medical schools should instead embrace "functional" technical standards that permit accommodations for disabilities and update their admissions policies to promote applications from qualified students with disabilities. Medical schools thus should focus on what students with disabilities can do, rather than what they cannot do, because these students further diversify the health care profession and improve our ability to care for an expanding population of patients with disabilities. PMID- 27780024 TI - Learning from Physicians with Disabilities and Their Patients. AB - Although progress has been made in diversifying medical school admissions and faculty, this has not extended to physicians with physical disabilities. To improve our understanding of medical students and physicians with physical and sensory disabilities, the authors propose systematically gathering information on the needs and experiences of four groups: physicians who had disabilities before beginning practice, physicians whose disabilities were incurred during their medical careers, physicians drawn from those two groups, and patients of physicians with disabilities. It is hoped these data would be used by counselors, administrators, and admissions committees in advising medical school applicants with disabilities and in revising institutional policies with a view to increasing matriculation and graduation rates of medical students with disabilities. PMID- 27780025 TI - Technical Standards and Lawsuits Involving Accommodations for Health Professions Students. AB - This article will discuss the legal obligations of medical schools to accommodate applicants and students with disabilities. The article begins by describing the problem of denial of medical education to such students, a problem that results from both discrimination in admissions and denial of accommodations to incumbent students with disabilities. The article then discusses the disability rights legislation that prohibits discrimination against-and requires reasonable accommodation of-qualified medical students with disabilities. It concludes by reviewing a number of lawsuits involving requests for accommodation and how disability rights law was applied in those cases. PMID- 27780026 TI - Competence not Age Determines Ability to Practice: Ethical Considerations about Sensorimotor Agility, Dexterity, and Cognitive Capacity. AB - Consideration of the effects of aging on physicians' practice is crucial to addressing aging clinicians' competence, that is, their ability to practice with reasonable skill and safety. Given physician workforce shortages even in resource abundant countries, the establishment of a compulsory retirement age in the US is impractical and unlikely. Several US hospitals and institutions have sought to address concerns about competence by establishing mandatory age-linked testing and evaluation for physicians. However, these procedures have raised questions regarding age discrimination and test validity. PMID- 27780027 TI - Perspectives on the Meaning of "Disability". AB - The meaning of "disability" has shifted with changes in public policy. Half a century ago, Congress was convinced that narrow determinations of disability are easy for physicians to make. But with the advent of universal civil rights protection against disability discrimination in the US, deciding whether particular individuals are disabled became increasingly contentious, until Congress intervened. What should now be addressed in each case is not whether the functionally compromised person is severely disabled enough to exercise a right, but whether mitigating interventions and reasonable accommodations can together achieve equitable access for that person. PMID- 27780028 TI - Just and Realistic Expectations for Persons with Disabilities Practicing Nursing. AB - The Americans with Disabilities Act prohibits discrimination on the basis of disability and requires schools to provide reasonable accommodations for persons with disabilities. The profession of nursing is striving for diversity and inclusion, but barriers still exist to realizing accommodations for people with disabilities. Promoting disclosure, a supportive and enabling environment, resilience, and realistic expectations are important considerations if we are to include among our ranks health professionals who can understand, based on similar life experiences of disability, a fuller range of perspectives of the patients we care for. PMID- 27780029 TI - Why Increasing Numbers of Physicians with Disability Could Improve Care for Patients with Disability. AB - Erroneous assumptions among health care professionals about the daily lives, preferences, values, and expectations of persons with disability can contribute to documented health care disparities, faulty communication, and substandard quality of care affecting this heterogeneous population. Efforts to reduce racial and ethnic disparities have focused on expanding diversity in the physician workforce. Would expanding the numbers of physicians with disability benefit patients with disability? Increasing the number of physicians who identify as "disabled" is one strategy for proactively confronting disability-related barriers affecting patients, but such efforts will likely face substantial challenges. Nonetheless, physicians who require accommodations to practice (e.g., a height-adjustable examination table) could plausibly benefit patients needing similar accommodations and perhaps be well-positioned to provide patient-centered care to persons with comparable disability. PMID- 27780030 TI - Technical Standards and Deaf and Hard of Hearing Medical School Applicants and Students: Interrogating Sensory Capacity and Practice Capacity. AB - Applicants to medical schools who are deaf and hard of hearing (DHoH) or who have other disabilities face significant barriers to medical school admission. One commonly cited barrier to admission is medical schools' technical standards (TS) for admission, advancement, and graduation. Ethical values of diversity and equity support altering the technical standards to be more inclusive of people with disabilities. Incorporating these values into admissions, advancement, and graduation considerations for DHoH and other students with disabilities can contribute to the physician workforce being more representative of the diverse patients it serves and better able to care for them. PMID- 27780033 TI - Chlorination of bisphenol F and the estrogenic and peroxisome proliferator activated receptor gamma effects of its disinfection byproducts. AB - The reaction kinetics and transformation pathways between bisphenol F (BPF) and sodium hypochlorite were investigated at pH values ranging from 6.5 to 8.5 and with different initial concentration ratios. The reaction rate was pH- and free available chlorine (FAC)-dependent: the reaction rate at pH 8.5 was almost 10 times than that at pH 6.5. A total of 40 compounds were tentatively identified as chloro-substituted BPF and polyphenolic compounds by liquid chromatography quadrupole time-of-flight mass spectrometry operating in electrospray ionization mode (LC-ESI-Q-ToF), and 4 main byproducts were confirmed by 1H and 13C nuclear magnetic resonance (NMR). Toxicity tests indicated that the estrogenic effects of chloro-substituted BPF decrease as the chlorine substitution increase. On the contrary, increasing numbers of chlorines on the phenolic rings of BPF enhanced the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) activity. Tetra-chlorinated BPF had an approximately 6.9-fold higher activity than BPF. PMID- 27780031 TI - Microstructural brain abnormalities in medication-free patients with major depressive disorder: a systematic review and meta-analysis of diffusion tensor imaging. AB - BACKGROUND: Multiple meta-analyses of diffusion tensor imaging (DTI) studies have reported impaired white matter integrity in patients with major depressive disorder (MDD). However, owing to inclusion of medicated patients in these studies, it is difficult to conclude whether these reported alterations are associated with MDD or confounded by medication effects. A meta-analysis of DTI studies on medication-free (medication-naive and medication washout) patients with MDD would therefore be necessary to disentangle MDD-specific effects. METHODS: We analyzed white matter alterations between medication-free patients with MDD and healthy controls using anisotropic effect size-signed differential mapping (AES-SDM). We used DTI query software for fibre tracking. RESULTS: Both pooled and subgroup meta-analyses in medication washout patients showed robust fractional anisotropy (FA) reductions in white matter of the right cerebellum hemispheric lobule, body of the corpus callosum (CC) and bilateral superior longitudinal fasciculus III (SLF III), whereas FA reductions in the genu of the CC and right anterior thalamic projections were seen in only medication-naive patients. Fibre tracking showed that the main tracts with observed FA reductions included the right cerebellar tracts, body of the CC, bilateral SLF III and arcuate fascicle. LIMITATIONS: The analytic techniques, patient characteristics and clinical variables of the included studies were heterogeneous; we could not exclude the effects of nondrug therapies owing to a lack of data. CONCLUSION: By excluding the confounding influences of current medication status, findings from the present study may provide a better understanding of the underlying neuropathology of MDD. PMID- 27780032 TI - Plasticity-dependent, full detonation at hippocampal mossy fiber-CA3 pyramidal neuron synapses. AB - Mossy fiber synapses on CA3 pyramidal cells are 'conditional detonators' that reliably discharge postsynaptic targets. The 'conditional' nature implies that burst activity in dentate gyrus granule cells is required for detonation. Whether single unitary excitatory postsynaptic potentials (EPSPs) trigger spikes in CA3 neurons remains unknown. Mossy fiber synapses exhibit both pronounced short-term facilitation and uniquely large post-tetanic potentiation (PTP). We tested whether PTP could convert mossy fiber synapses from subdetonator into detonator mode, using a recently developed method to selectively and noninvasively stimulate individual presynaptic terminals in rat brain slices. Unitary EPSPs failed to initiate a spike in CA3 neurons under control conditions, but reliably discharged them after induction of presynaptic short-term plasticity. Remarkably, PTP switched mossy fiber synapses into full detonators for tens of seconds. Plasticity-dependent detonation may be critical for efficient coding, storage, and recall of information in the granule cell-CA3 cell network. PMID- 27780034 TI - Frequency Tuning of Collapse-Mode Capacitive Micromachined Ultrasonic Transducer. AB - The information in an ultrasound image depends on the frequency that is used. In a clinical examination it may therefore be beneficial to generate ultrasound images acquired at multiple frequencies, which is difficult to achieve with conventional transducers. Capacitive micromachined ultrasonic transducers (CMUTs) offer a frequency response that is tunable by the bias voltage. In this study we investigate this frequency tunability for ultrasonic imaging. We characterized a CMUT array operated at bias voltages up to three times higher than the collapse voltage. All elements of the array were connected to a single transmit and receive channel through a bias circuit. We quantified the transmit-receive and transmit sensitivity as a function of frequency for a range of bias voltages. Impulse response measurements show that the center frequency is modifiable between 8.7MHz and 15.3MHz with an applied bias voltage of -50V to -170V. The maximum transmit sensitivity is 52kPa/V at a center frequency of 9.0MHz with an applied bias voltage of -105V. The -3dB transmit range in center frequency accessible with the variable bias voltage is 6.7-15.5MHz. This study shows that a collapse-mode CMUT can operate efficiently at multiple center frequencies when the driving pulse and the bias voltage are optimized. We demonstrate the usefulness of frequency tuning by comparing images at different optimal combinations of driving frequency and bias voltage, acquired by linearly moving the transducer across a tissue mimicking phantom. PMID- 27780035 TI - RNA-Seeded Functional Amyloids Balance Growth and Survival. AB - In this issue of Developmental Cell, Audas et al. (2016) report non-membrane enclosed amyloid bodies (ABs) assembled in the nuclei of cells exposed to heat and low pH. Remarkably, ABs form not by liquid-to-liquid phase separation, implicated in RNA-seeded granule assembly, but by an amyloidogenic process that promotes a liquid-to-solid transition. PMID- 27780036 TI - Heat FLiPs a Hormonal Switch for Longevity. AB - Temperature-sensing neurons in C. elegans reduce the life-shortening effects of high temperatures via steroid signaling. In this issue of Developmental Cell, Chen et al. (2016) elucidate the underlying mechanisms by which the transcription factor CREB induces the neuropeptide FLP-6 in the temperature-sensing neurons to counteract the life-shortening effects of high temperature. PMID- 27780038 TI - RhoGTPases Spread the Word for Synaptic Crosstalk. AB - Excitatory synaptic strengthening and the corresponding enlargement of dendritic spines are thought to be essential for learning and memory. In two recent Nature papers, Harward et al. (2016) and Hedrick et al. (2016) provide insight into the mechanisms that regulate these processes and illuminate the molecular basis of crosstalk between synapses. PMID- 27780037 TI - WASP and WAVE Team Up at the Leading Edge. AB - Arp2/3-dependent branched actin networks drive membrane protrusions, with WAVE being recognized as the critical Arp2/3 activator in this process. In this issue of Developmental Cell, Zhu et al. (2016) demonstrate that WASP, an Arp2/3 activator mostly involved in endocytosis, collaborates with WAVE to promote migration of neuroblasts in Caenorhabditis elegans. PMID- 27780039 TI - Lipids and Their Trafficking: An Integral Part of Cellular Organization. AB - An evolutionarily conserved feature of cellular organelles is the distinct phospholipid composition of their bounding membranes, which is essential to their identity and function. Within eukaryotic cells, two major lipid territories can be discerned, one centered on the endoplasmic reticulum and characterized by membranes with lipid packing defects, the other comprising plasma-membrane derived organelles and characterized by membrane charge. We discuss how this cellular lipid organization is maintained, how lipid flux is regulated, and how perturbations in cellular lipid homeostasis can lead to disease. PMID- 27780040 TI - Functional Coordination of WAVE and WASP in C. elegans Neuroblast Migration. AB - Directional cell migration is critical for metazoan development. We define two molecular pathways that activate the Arp2/3 complex during neuroblast migration in Caenorhabditis elegans. The transmembrane protein MIG-13/Lrp12 is linked to the Arp2/3 nucleation-promoting factors WAVE or WASP through direct interactions with ABL-1 or SEM-5/Grb2, respectively. WAVE mutations partially impaired F-actin organization and decelerated cell migration, and WASP mutations did not inhibit cell migration but enhanced migration defects in WAVE-deficient cells. Purified SEM-5 and MIG-2 synergistically stimulated the F-actin branching activity of WASP Arp2/3 in vitro. In GFP knockin animals, WAVE and WASP were largely organized into separate clusters at the leading edge, and the amount of WASP was less than WAVE but could be elevated by WAVE mutations. Our results indicate that the MIG 13-WAVE pathway provides the major force for directional cell motility, whereas MIG-13-WASP partially compensates for its loss, underscoring their coordinated activities in facilitating robust cell migration. PMID- 27780041 TI - Regulation of Drosophila Brain Wiring by Neuropil Interactions via a Slit-Robo RPTP Signaling Complex. AB - The axonal wiring molecule Slit and its Round-About (Robo) receptors are conserved regulators of nerve cord patterning. Robo receptors also contribute to wiring brain circuits. Whether molecular mechanisms regulating these signals are modified to fit more complex brain wiring processes is unclear. We investigated the role of Slit and Robo receptors in wiring Drosophila higher-order brain circuits and identified differences in the cellular and molecular mechanisms of Robo/Slit function. First, we find that signaling by Robo receptors in the brain is regulated by the Receptor Protein Tyrosine Phosphatase RPTP69d. RPTP69d increases membrane availability of Robo3 without affecting its phosphorylation state. Second, we detect no midline localization of Slit during brain development. Instead, Slit is enriched in the mushroom body, a neuronal structure covering large areas of the brain. Thus, a divergent molecular mechanism regulates neuronal circuit wiring in the Drosophila brain, partly in response to signals from the mushroom body. PMID- 27780044 TI - Evolution of Biological Image Stabilization. AB - The use of vision to coordinate behavior requires an efficient control design that stabilizes the world on the retina or directs the gaze towards salient features in the surroundings. With a level gaze, visual processing tasks are simplified and behaviorally relevant features from the visual environment can be extracted. No matter how simple or sophisticated the eye design, mechanisms have evolved across phyla to stabilize gaze. In this review, we describe functional similarities in eyes and gaze stabilization reflexes, emphasizing their fundamental role in transforming sensory information into motor commands that support postural and locomotor control. We then focus on gaze stabilization design in flying insects and detail some of the underlying principles. Systems analysis reveals that gaze stabilization often involves several sensory modalities, including vision itself, and makes use of feedback as well as feedforward signals. Independent of phylogenetic distance, the physical interaction between an animal and its natural environment - its available senses and how it moves - appears to shape the adaptation of all aspects of gaze stabilization. PMID- 27780042 TI - Immunoexpression of BMP-2 and BMP-4 and their receptors, BMPR-IA and BMPR-II, in ameloblastomas and adenomatoid odontogenic tumors. AB - OBJECTIVES: The present study evaluated the immunohistochemical expression of BMP 2 and BMP-4 and of their receptors (BMPR-IA and BMPR-II) in solid ameloblastoma (SA), unicystic ameloblastoma (UA) and adenomatoid odontogenic tumor (AOT) in order to obtain a better understanding of their role in the development and biological behavior of these tumors. DESIGN: This study analyzed these proteins in 30 cases of SA, 10 cases of UA, and 30 cases of AOT. Immunoexpression was evaluated in the parenchyma and stroma by attributing the following scores: 0, no stained cells; 1, <=10%; 2, >10% and <=25%; 3, >25% and <=50%; 4, >50% and <=75%.; 5, >75% stained cells. RESULTS: In SAs, positive correlations were observed between the stromal and parenchymal expression of BMP-2 (p<0.001) and between the stromal expression of BMP-2 and BMP-4 (p=0.020), as well as between the stromal expression of BMPR-II and BMP-4 (p=0.001) and the stromal and parenchymal expression of BMPR-II (p<0.001). In UAs, correlations were detected between the stromal and parenchymal expression of BMP-4 (p=0.035) and between the stromal expression of BMP-4 and BMPR-IA (p=0.022). In AOTs, analysis of immunoexpression in the parenchyma revealed positive correlations between all proteins. CONCLUSION: BMPs and their receptors play an important role in the differentiation and development of ameloblastomas and AOTs, but may not explain the different biological behaviors of these lesions. The positive correlation observed in AOTs might be related to the formation of mineralized material in this tumor. PMID- 27780043 TI - A Conserved Developmental Mechanism Builds Complex Visual Systems in Insects and Vertebrates. AB - The visual systems of vertebrates and many other bilaterian clades consist of complex neural structures guiding a wide spectrum of behaviors. Homologies at the level of cell types and even discrete neural circuits have been proposed, but many questions of how the architecture of visual neuropils evolved among different phyla remain open. In this review we argue that the profound conservation of genetic and developmental steps generating the eye and its target neuropils in fish and fruit flies supports a homology between some core elements of bilaterian visual circuitries. Fish retina and tectum, and fly optic lobe, develop from a partitioned, unidirectionally proliferating neurectodermal domain that combines slowly dividing neuroepithelial stem cells and rapidly amplifying progenitors with shared genetic signatures to generate large numbers and different types of neurons in a temporally ordered way. This peculiar 'conveyor belt neurogenesis' could play an essential role in generating the topographically ordered circuitry of the visual system. PMID- 27780047 TI - Comparative Aspects of Hearing in Vertebrates and Insects with Antennal Ears. AB - The evolution of hearing in terrestrial animals has resulted in remarkable adaptations enabling exquisitely sensitive sound detection by the ear and sophisticated sound analysis by the brain. In this review, we examine several such characteristics, using examples from insects and vertebrates. We focus on two strong and interdependent forces that have been shaping the auditory systems across taxa: the physical environment of auditory transducers on the small, subcellular scale, and the sensory-ecological environment within which hearing happens, on a larger, evolutionary scale. We briefly discuss acoustical feature selectivity and invariance in the central auditory system, highlighting a major difference between insects and vertebrates as well as a major similarity. Through such comparisons within a sensory ecological framework, we aim to emphasize general principles underlying acute sensitivity to airborne sounds. PMID- 27780046 TI - The Evolving Neural and Genetic Architecture of Vertebrate Olfaction. AB - Evolution sculpts the olfactory nervous system in response to the unique sensory challenges facing each species. In vertebrates, dramatic and diverse adaptations to the chemical environment are possible because of the hierarchical structure of the olfactory receptor (OR) gene superfamily: expansion or contraction of OR subfamilies accompanies major changes in habitat and lifestyle; independent selection on OR subfamilies can permit local adaptation or conserved chemical communication; and genetic variation in single OR genes can alter odor percepts and behaviors driven by precise chemical cues. However, this genetic flexibility contrasts with the relatively fixed neural architecture of the vertebrate olfactory system, which requires that new olfactory receptors integrate into segregated and functionally distinct neural pathways. This organization allows evolution to couple critical chemical signals with selectively advantageous responses, but also constrains relationships between olfactory receptors and behavior. The coevolution of the OR repertoire and the olfactory system therefore reveals general principles of how the brain solves specific sensory problems and how it adapts to new ones. PMID- 27780045 TI - Mechanosensation and Adaptive Motor Control in Insects. AB - The ability of animals to flexibly navigate through complex environments depends on the integration of sensory information with motor commands. The sensory modality most tightly linked to motor control is mechanosensation. Adaptive motor control depends critically on an animal's ability to respond to mechanical forces generated both within and outside the body. The compact neural circuits of insects provide appealing systems to investigate how mechanical cues guide locomotion in rugged environments. Here, we review our current understanding of mechanosensation in insects and its role in adaptive motor control. We first examine the detection and encoding of mechanical forces by primary mechanoreceptor neurons. We then discuss how central circuits integrate and transform mechanosensory information to guide locomotion. Because most studies in this field have been performed in locusts, cockroaches, crickets, and stick insects, the examples we cite here are drawn mainly from these 'big insects'. However, we also pay particular attention to the tiny fruit fly, Drosophila, where new tools are creating new opportunities, particularly for understanding central circuits. Our aim is to show how studies of big insects have yielded fundamental insights relevant to mechanosensation in all animals, and also to point out how the Drosophila toolkit can contribute to future progress in understanding mechanosensory processing. PMID- 27780050 TI - The Basal Ganglia Over 500 Million Years. AB - The lamprey belongs to the phylogenetically oldest group of vertebrates that diverged from the mammalian evolutionary line 560 million years ago. A comparison between the lamprey and mammalian basal ganglia establishes a detailed similarity regarding its input from cortex/pallium and thalamus, as well as its intrinsic organisation and projections of the output nuclei. This means that the basal ganglia circuits now present in rodents and primates most likely had evolved already at the dawn of vertebrate evolution. This includes the 'direct pathway' with striatal projection neurons (SPNs) expressing dopamine D1 receptors, which act to inhibit the tonically active GABAergic output neurons in globus pallidus interna and substantia nigra pars reticulata that at rest keep the brainstem motor centres under tonic inhibition. The 'indirect pathway' with dopamine D2 receptor-expressing SPNs and intrinsic basal ganglia nuclei is also conserved. The net effect of the direct pathway is to disinhibit brainstem motor centres and release motor programs, while the indirect pathway instead will suppress motor activity. Transmitters, connectivity and membrane properties are virtually identical in lamprey and rodent basal ganglia. We predict that the basal ganglia contains a series of modules each controlling a given pattern of behaviour including locomotion, eye-movements, posture, and chewing that contain both the direct pathway to release a motor program and the indirect pathway to inhibit competing behaviours. The phasic dopamine input serves value-based decisions and motor learning. During vertebrate evolution with a progressively more diverse motor behaviour, the number of modules will have increased progressively. These new modules with a similar design will be used to control newly developed patterns of behaviour - a process referred to as exaptation. PMID- 27780048 TI - Parallel Computations in Insect and Mammalian Visual Motion Processing. AB - Sensory systems use receptors to extract information from the environment and neural circuits to perform subsequent computations. These computations may be described as algorithms composed of sequential mathematical operations. Comparing these operations across taxa reveals how different neural circuits have evolved to solve the same problem, even when using different mechanisms to implement the underlying math. In this review, we compare how insect and mammalian neural circuits have solved the problem of motion estimation, focusing on the fruit fly Drosophila and the mouse retina. Although the two systems implement computations with grossly different anatomy and molecular mechanisms, the underlying circuits transform light into motion signals with strikingly similar processing steps. These similarities run from photoreceptor gain control and spatiotemporal tuning to ON and OFF pathway structures, motion detection, and computed motion signals. The parallels between the two systems suggest that a limited set of algorithms for estimating motion satisfies both the needs of sighted creatures and the constraints imposed on them by metabolism, anatomy, and the structure and regularities of the visual world. PMID- 27780051 TI - The Influence of Wiring Economy on Nervous System Evolution. AB - The activity and maintenance of neurons requires substantial metabolic energy, resulting in selective pressure to decrease resource consumption by the nervous system. The wiring economy principle proposes that animals have evolved mechanisms that wire circuits efficiently by minimizing neurite length. Computational modeling of neuronal morphology, microcircuit organization, and neural networks reveals that wiring economy is a significant determinant of nervous system layout. The strategies for reducing wiring costs are shared across phyla and point to the possibility of generalizable rules that specify the development of efficient nervous systems. As the developmental mechanisms underpinning wiring economy are only now being elucidated, whether the molecular basis of this phenomenon is the result of conserved genetic programs or convergent evolution remains to be determined. PMID- 27780052 TI - The Molecular Basis of Human Brain Evolution. AB - Humans are a remarkable species, especially because of the remarkable properties of their brain. Since the split from the chimpanzee lineage, the human brain has increased three-fold in size and has acquired abilities for vocal learning, language and intense cooperation. To better understand the molecular basis of these changes is of great biological and biomedical interest. However, all the about 16 million fixed genetic changes that occurred during human evolution are fully correlated with all molecular, cellular, anatomical and behavioral changes that occurred during this time. Hence, as humans and chimpanzees cannot be crossed or genetically manipulated, no direct evidence for linking particular genetic and molecular changes to human brain evolution can be obtained. Here, I sketch a framework how indirect evidence can be obtained and review findings related to the molecular basis of human cognition, vocal learning and brain size. In particular, I discuss how a comprehensive comparative approach, leveraging cellular systems and genomic technologies, could inform the evolution of our brain in the future. PMID- 27780053 TI - Fan worm eyes. AB - A quick guide to the diverse and unusual eyes of polychaete fan worms, by Michael Bok and Dan-Eric Nilsson. PMID- 27780054 TI - Revealing the world of autism through the lens of a camera. AB - People with autism spectrum disorder (ASD) show atypical attention to social stimuli [1] and gaze at faces [2] and complex images [3] in unusual ways. But all studies to date are limited by the experimenter's selected stimuli, which are generally photographs taken by people without autism. What might participants with ASD show us if they were the ones taking the photos? We gave participants a digital camera and analysed the photos they took: images taken by participants with ASD had unusual features and showed strikingly different ways of photographing other people. PMID- 27780055 TI - Cross-modal impacts of anthropogenic noise on information use. AB - Anthropogenic noise is a global pollutant, and there is rapidly accumulating evidence of impacts on a range of animal taxa [1,2]. While many studies have considered how additional noise may affect information provision and use, they have focused on the masking and consequent alteration of acoustic signals and cues; so-called unimodal effects [3]. Using field-based experimental trials on habituated wild dwarf mongooses (Helogale parvula) [4], we combine sound playbacks and faecal presentations to demonstrate that anthropogenic noise can disrupt responses to information from different sensory modalities. The adaptive, stronger response exhibited towards predator faeces compared with control faeces in ambient-noise conditions was detrimentally affected by road-noise playback. Specifically, having taken longer to detect the faeces, the mongooses interacted less with the predator cue, did not show increased vigilance following its detection, and spent less time in the safe vicinity of a burrow refuge, thus suffering a potentially increased predation risk. Our results are the first to show that anthropogenic noise could alter responses to olfactory cues, strongly indicating the possibility of cross-modal impacts of noise pollution on information use [3]. PMID- 27780056 TI - Evolution: Organelles Caught in the Act. AB - Mitochondria in the protist Brevimastigomonas motovehiculus are in the process of dismantling their mitochondrial electron transport chain complexes as they adapt to anaerobic environments. Novel protein interactions suggest a highly complicated process rather than the simple removal of unnecessary genes. PMID- 27780057 TI - Motor Control: No Constant but Change. AB - We rely on predictions to rapidly select our walking gaits. New research suggests that the formation of these predictions is driven by the difference between the walk we expect and the walk we get. PMID- 27780058 TI - Zoology: At Last an Exit for Ctenophores. AB - Ctenophores, one of the most basal branches in the tree of life, have been found to have a through-gut, complete with mouth and anus. Basal animals are surprisingly complex and simplification has been rampant in animal evolution. PMID- 27780049 TI - Unraveling the Evolutionary Determinants of Sleep. AB - Despite decades of intense study, the functions of sleep are still shrouded in mystery. The difficulty in understanding these functions can be at least partly attributed to the varied manifestations of sleep in different animals. Daily sleep duration can range from 4-20 hrs among mammals, and sleep can manifest throughout the brain, or it can alternate over time between cerebral hemispheres, depending on the species. Ecological factors are likely to have shaped these and other sleep behaviors during evolution by altering the properties of conserved arousal circuits in the brain. Nonetheless, core functions of sleep are likely to have arisen early and to have persisted to the present day in diverse organisms. This review will discuss the evolutionary forces that may be responsible for phylogenetic differences in sleep and the potential core functions that sleep fulfills. PMID- 27780059 TI - Episodic Memory: Rats Master Multiple Memories. AB - A new study in which rats had to discriminate odors according to whether they were novel for a particular environmental context has found that they can accurately discriminate a large number of odors and multiple context transitions, suggesting that they are able to form and remember multiple episodic memories. PMID- 27780061 TI - Systems Neuroscience: The Balancing Act of Behavioral Regulation. AB - In the brain, the striatum and prefrontal cortex interact to gauge the value of actions and the self-regulatory demands in a given environment. New research, involving manipulation of the neural circuitry, has revealed multiple routes by which 'imbalances' in circuit function cause regulation deficits. PMID- 27780060 TI - Palaeontology: A Hook to the Past. AB - The poorly understood Triassic reptile Drepanosaurus is known for its excessively large claws. New discoveries demonstrate a remarkable modification of the bones in the wrist and forearm, a significant departure from the typical five-digit tetrapod limb. PMID- 27780062 TI - Membrane Trafficking: An Endosome Tether Meets a Rab and Collapses. AB - Long-range tethering is a ubiquitous recognition event preceding membrane fusion. A new study shows that Rab GTPase binding causes 'entropic collapse' of the coiled-coil endosome tether EEA1, driving membrane apposition and facilitating short-range interactions required for fusion. PMID- 27780063 TI - Ageing: Why Males Curtail the Longevity of Their Mates. AB - Male nematodes secrete pheromones that accelerate the somatic senescence of potential mates. A new study shows that this harm most likely is an unintended by product of the males' aim to speed up sexual maturation and delay reproductive senescence of future partners. PMID- 27780064 TI - Axonal Degeneration: RIPK1 Multitasking in ALS. AB - A recent study reports that microglia and oligodendrocytes promote motor neuron degeneration by inducing inflammation and necroptosis in a manner dependent on receptor-interacting kinase 1 (RIPK1). These findings could be significant for our understanding of the neurobiology and treatment of neurodegenerative diseases like amyotrophic lateral sclerosis. PMID- 27780065 TI - Sexual Selection: Roles Evolving. AB - In a role-reversed beetle, in which sexual selection acts primarily on females, females evolved to more rapidly court and copulate after many generations of experimentally increased female sexual competition. PMID- 27780066 TI - Evolving understanding of nervous system evolution. AB - In this Guest Editorial, Jeremy Niven and Lars Chittka introduce our special issue on the evolution of nervous systems. PMID- 27780067 TI - Early evolution of neurons. AB - How did a structure as complex as our own brain ever evolve? Although biologists have pondered this question since Charles Darwin, the explosion of molecular information in recent years has provided new insights into this question, particularly its first step: the evolution of neurons. Meshing information about genomes with insights from more classical anatomical, physiological, and developmental approaches has led to some remarkable insights and surprises. Because 'phylogenomics' is still a young field, however, there are arguments about which genes to include in comparisons, how much to weigh genetic versus 'classical' features, and which algorithms to use in making such comparisons. One source of serious discussion is the explanation for a feature being present in one clade (a group of animals with a common ancestor) but absent in a second clade. Does the feature's absence in clade 2 mean that the feature was never present in the ancestors of clade 2, or was it present in clade 2's ancestors but subsequently lost? A second phylogenomic problem is posed by convergent evolution (or 'homoplasy' in genetic terminology): a feature or a molecule that is present in two clades might have evolved independently in each clade. Both of these problems, secondary loss and homoplasy, confound the interpretation of evolutionary relationships. For the moment, the only solution to these problems is to compare more genes in more animals to see whether the features that are missing from one species, for instance, can be found in other closely-related species. The purpose of this primer is not to consider the evolution of brains, however, but the more modest goal of determining the evolution of neurons, the information processing cells that compose brains. Even this more limited goal is, at this juncture, beyond our reach, but the journey to this goal has already uncovered some remarkable relationships and has made clearer what are the key questions and how they can be approached. PMID- 27780068 TI - Nematode nervous systems. AB - Nematodes comprise one of the largest phyla in the animal kingdom, both in terms of individual numbers and species diversity. Although only 20,000-30,000 species have been described, it is estimated that the true number ranges between 100,000 and 10 million. Marine, freshwater, and terrestrial species are all widespread, and some nematodes have even been isolated from such inhospitable environments as deserts, hot springs, and polar seas. Some nematode species are parasitic, with either plant or animal hosts; other species are free-living microbivores, scavengers, or predators of insects or other nematodes. Nematodes vary widely in size, from small microbivores that grow no larger than 100 MUm to large animal parasites growing to several meters in length. They adopt a variety of reproductive strategies: most species are gonochoristic (i.e., have male and female sexes), but self-fertile hermaphroditic species are not uncommon, and parthenogenetic species are also known. Nematodes belong to the superphylum Ecdysozoa, a clade of moulting animals that also includes arthropods, tardigrades and priapulids. Although nematode fossils are rare, the origin of the nematode phylum is believed to be very ancient, with the divergence from arthropods estimated based on molecular data to have been between 900 and 1,300 Ma. PMID- 27780069 TI - Arthropod neurons and nervous system. AB - Arthropods are very diverse, come in many different forms with diverse adaptations, and through such diversity have populated all environmental niches on the planet. Almost 80% of the animals on planet Earth belong to this phylum. Despite their very diverse phenotypes they share fundamental similarities which were previously used to generate a phylogenetic tree. All arthropods have segmented bodies and possess jointed limbs at all or many of their body segments. An additional common feature of arthropods is their exoskeleton, made mainly of chitin and/or sclerotin. PMID- 27780070 TI - Evolution of highly diverse forms of behavior in molluscs. AB - Members of the phylum Mollusca demonstrate the animal kingdom's tremendous diversity of body morphology, size and complexity of the nervous system, as well as diversity of behavioral repertoires, ranging from very simple to highly flexible. Molluscs include Solenogastres, with their worm-like bodies and behavior (see phylogenetic tree; Figure 1); Bivalvia (mussels and clams), protected by shells and practically immobile; and the cephalopods, such as the octopus, cuttlefish and squid. The latter are strange-looking animals with nervous systems comprising up to half a billion neurons, which mediate the complex behaviors that characterize these freely moving, highly visual predators. Molluscs are undoubtedly special - their extraordinary evolutionary advance somehow managed to sidestep the acquisition of the rigid skeleton that appears essential to the evolution of other 'successful' phyla: the exoskeleton in ecdysozoan invertebrates and the internal skeleton in Deuterostomia, including vertebrates. PMID- 27780071 TI - Myelination. AB - Myelin is a key evolutionary acquisition that underlay the development of the large, complex nervous systems of all hinged-jaw vertebrates. By promoting rapid, efficient nerve conduction, myelination also made possible the development of the large body size of these vertebrates. In addition to increasing the speed of nerve conduction, myelination has emerged as a source of plasticity in neural circuits that is crucial for proper timing and function. Here, we briefly describe the organization of myelin and of myelinated axons, as well as the functions of myelin in nerve conduction and neural circuits, and consider its potential evolutionary origins. PMID- 27780072 TI - Sensory matched filters. AB - As animals move through their environments they are subjected to an endless barrage of sensory signals. Of these, some will be of utmost importance, such as the tell-tale aroma of a potential mate, the distinctive appearance of a vital food source or the unmistakable sound of an approaching predator. Others will be less important. Indeed some will not be important at all. There are, for instance, wide realms of the sensory world that remain entirely undetected, simply because an animal lacks the physiological capacity to detect and analyse the signals that characterise this realm. Take ourselves for example: we are completely insensitive to the Earth's magnetic field, a sensory cue of vital importance as a compass for steering the long distance migration of animals as varied as birds, lobsters and sea turtles. We are also totally oblivious to the rich palette of ultraviolet colours that exist all around us, colours seen by insects, crustaceans, birds, fish and lizards (in fact perhaps by most animals). Nor can we hear the ultrasonic sonar pulses emitted by bats in hot pursuit of flying insect prey. The simple reason for these apparent deficiencies is that we either lack the sensory capacity entirely (as in the case of magnetoreception) or that our existing senses are incapable of detecting specific ranges of the stimulus (such as the ultraviolet wavelength range of light). PMID- 27780073 TI - Central Brain Circuitry for Color-Vision-Modulated Behaviors. AB - Color is famous for not existing in the external world: our brains create the perception of color from the spatial and temporal patterns of the wavelength and intensity of light. For an intangible quality, we have detailed knowledge of its origins and consequences. Much is known about the organization and evolution of the first phases of color processing, the filtering of light in the eye and processing in the retina, and about the final phases, the roles of color in behavior and natural selection. To understand how color processing in the central brain has evolved, we need well-defined pathways or circuitry where we can gauge how color contributes to the computations involved in specific behaviors. Examples of such pathways or circuitry that are dedicated to processing color cues are rare, despite the separation of color and luminance pathways early in the visual system of many species, and despite the traditional definition of color as being independent of luminance. This minireview presents examples in which color vision contributes to behaviors dominated by other visual modalities, examples that are not part of the canon of color vision circuitry. The pathways and circuitry process a range of chromatic properties of objects and their illumination, and are taken from a variety of species. By considering how color processing complements luminance processing, rather than being independent of it, we gain an additional way to account for the diversity of color coding in the central brain, its consequences for specific behaviors and ultimately the evolution of color vision. PMID- 27780074 TI - Fossils and the Evolution of the Arthropod Brain. AB - The discovery of fossilized brains and ventral nerve cords in lower and mid Cambrian arthropods has led to crucial insights about the evolution of their central nervous system, the segmental identity of head appendages and the early evolution of eyes and their underlying visual systems. Fundamental ground patterns of lower Cambrian arthropod brains and nervous systems correspond to the ground patterns of brains and nervous systems belonging to three of four major extant panarthropod lineages. These findings demonstrate the evolutionary stability of early neural arrangements over an immense time span. Here, we put these fossil discoveries in the context of evidence from cladistics, as well as developmental and comparative neuroanatomy, which together suggest that despite many evolved modifications of neuropil centers within arthropod brains and ganglia, highly conserved arrangements have been retained. Recent phylogenies of the arthropods, based on fossil and molecular evidence, and estimates of divergence dates, suggest that neural ground patterns characterizing onychophorans, chelicerates and mandibulates are likely to have diverged between the terminal Ediacaran and earliest Cambrian, heralding the exuberant diversification of body forms that account for the Cambrian Explosion. PMID- 27780075 TI - Thermal intensification of microbial Fe(II)/Fe(III) redox cycling in a pristine shallow sand aquifer on the Canadian Shield. AB - This investigation evaluates spatial relationships between summer (July) groundwater temperatures and Fe(II)/Fe(III) biogeochemical cycling over a five year period in a shallow pristine sand aquifer at Meilleurs Bay near Deep River, Ontario, Canada. A warm subsurface thermal island of 12.5-16.1 degrees C, compared to background conditions of 10-11 degrees C, was manifest in contour maps of average groundwater temperature over the study period. The warm zone coincided with an area of convergent groundwater flow, implicating horizontal heat transfer by advective convection as the reason for elevated temperatures. Additionally, high concentrations of dissolved Fe(II) and Fe(III) overlapped the warm thermal island, indicative of increased rates of bacterial Fe(II)-oxidation and Fe(III)-reduction. A depletion in the modal abundance of Fe(II)-bearing minerals, notably amphibole and biotite, inside the area of the warm thermal island was also observed, suggesting enhanced mineral dissolution owing to chemoautotrophic Fe(II)-oxidation coupled to the reduction and fixation of dissolved inorganic carbon as biomass. Throughout the aquifer, redox conditions were poised in terms of Eh and pH close to equilibrium with respect to the Fe(II)/Fe(OH)3 couple, feasibly enabling simultaneous bacterial Fe(II)-oxidation and Fe(III)-reduction with an adequate supply of electron acceptors and donors, respectively. The significance of higher groundwater temperature as a determinant of elevated dissolved Fe(II) and Fe(III) concentrations induced by thermal intensification of microbial biogeochemical activities yielded Pearson product moment correlations in which temperature alone, as a single independent variable, explains almost 30 to nearly 60 percent of the variation in the measured dissolved Fe(II) and Fe(III) concentrations in the groundwater. These results emphasize the important influence of thermal conditions on biogeochemical processes in aquifers coupled to the development of steep gradients in groundwater quality over short distances in shallow unconfined groundwater systems. PMID- 27780076 TI - The burden of HPV associated cancers in two regions in Nigeria 2012-2014. AB - INTRODUCTION: HPV attributable cancers are the second most common infection related cancers worldwide, with much higher burden in less developed regions. There are currently no country-specific estimates of the burden of these cancers in Nigeria just like many other low and middle income countries. METHODS: In this study, we quantified the proportion of the cancer burden in Nigeria that is attributable to HPV infection from 2012 to 2014 using HPV prevalence estimated from previous studies and data from two population based cancer registries (PBCR) in Nigeria. We considered cancer sites for which there is strong evidence of an association with HPV infection based on the International Agency for Research on Cancer (IARC) classification. We obtained age and sex-specific estimates of incident cancers and using the World Standard Population, we derived age standardized incidence (ASR) rates for each cancer type by categories of sex, and estimated the population attributable fractions (PAF). RESULTS: The two PBCR reported 4336 new cancer cases from 2012 to 2014. Of these, 1627 (37.5%) were in males and 2709 (62.5%) in females. Some 11% (488/4336) of these cancers were HPV associated; 2% (38/1627) in men and 17% (450/2709) in women. Of the HPV associated cancers, 7.8% occurred in men and 92.2% in women. The ASRs for HPV associated cancers was 33.5 per 100,000; 2.3 and 31.2 per 100,000 in men and women respectively. The proportion of all cancers attributable to HPV infection ranged from 10.2 to 10.4% (442-453 of 4336) while the proportion of HPV associated cancers attributable to HPV infection ranged from 90.6% to 92.8% (442 453 of the 488 cases). In men, 55.3% to 68.4% of HPV associated cancers were attributable to HPV infection compared to 93.6% to 94.8% in women. The combined ASR for HPV attributable cancers ranged from 31.0 to 31.7 per 100,000. This was 1.4 to 1.7 per 100,000 in men and 29.6 to 30.0 per 100,000 in women. In women, cervical cancer (n=392, ASR 28.3 per 100,000) was the commonest HPV attributable cancer, while anal cancer (n=21, ASR 1.2 per 100,000) was the commonest in men. CONCLUSIONS: HPV attributable cancers constitute a substantial cancer burden in Nigerian women, much less so in men. A significant proportion of cancers in Nigerian women would be prevented if strategies such as HPV DNA based screening and HPV vaccination are implemented. PMID- 27780077 TI - Association of cigarette smoking and microRNA expression in rectal cancer: Insight into tumor phenotype. AB - Smoking is known to influence messenger RNA (mRNA) expression in colorectal cancer (CRC) cases. As microRNAs (miRNAs) are known repressors of mRNAs, we hypothesize that smoking may influence miRNA expression, thus altering mRNA expression. Our sample consisted of 1447 CRC cases that had normal colorectal mucosa and carcinoma miRNA data and lifestyle data. We examined current smoking, current versus never and former versus never (C/F/N) smoking1, and pack-years smoked with miRNA expression in normal mucosa as well as differential miRNA expression between paired normal and carcinoma tissue for colon and rectal tissue to determine associations between smoking and miRNA expression. We adjusted for multiple comparisons using the Benjamini Hochberg false discovery rate (FDR). Significant associations were seen for rectal differential miRNA expression only. We analyzed miRNAs significantly associated with smoking with CIMP and MSI status, using a polytomous logistic regression. Two hundred and thirty-one miRNAs were differentially expressed with current smoking, 172 with C/F/N, and 206 with pack-years smoked; 111 were associated with all three. Forty-three miRNAs were unique to current smoking, 14 were unique to C/F/N and 57 were unique to pack years smoked. Of the 306 unique miRNAs associated with cigarette smoking, 41 were inversely associated and 200 were directly associated with CIMP high or MSI tumor molecular phenotype for either colon or rectal cancer. Our results suggest that cigarette smoking can alter miRNA expression and, given associations with CIMP high and MSI tumor molecular phenotype, it is possible that smoking influences tumor phenotype through altered miRNA expression. PMID- 27780078 TI - Loeys-Dietz syndrome and pregnancy: The first ten years. AB - The physiological and haemodynamic changes that occur in pregnancy and the postpartum period increase the risk of aortic dissection. Loeys-Dietz syndrome results from mutations in the genes encoding components of the TGF-beta signalling pathway; aortic pathology is of particular concern in this condition but other vascular abnormalities can also be present. Significant maternal morbidity and mortality has been described in patients with Loeys-Dietz syndrome, but successful and uncomplicated pregnancies are still possible. Nevertheless, all patients with this condition should, at present, be treated as very high risk in pregnancy and the postpartum period, until reliable risk prediction tools become available. This review summarises the recent advances in the understanding of the pathophysiology of this condition, and the management strategies currently advocated. PMID- 27780079 TI - Relationship of serum uric acid and Killip class on mortality after acute ST segment elevation myocardial infarction and primary percutaneous coronary intervention. AB - BACKGROUND: There is conflicting information regarding the association between hyperuricemia and survival in STEMI patients. Our study examined the interaction between hyperuricemia and Killip class on mortality of STEMI patients. METHODS: We analyzed 951 consecutive STEMI patients between February 2006 and September 2012. Hyperuricemia was defined as SUA of at least 7mg/dL in males and 6mg/dL in females. Killip class I patients were divided into hyperuricemia and normouricemia groups. RESULTS: The Killip class I hyperuricemia and normouricemia groups had similar baseline and procedural characteristics, but the hyperuricemia group had significantly greater BMI, serum creatinine, and SUA, and a lower TIMI risk score (2, IQR: 1-4 vs. 3, IQR: 2-4, p=0.019). The hyperuricemia group also had greater 30-day and 1-year mortality rates (2.9% vs. 0.3%, p=0.022; 6.5% vs. 1.1%, p=0.002, respectively). However, hyperuricemia was not associated with mortality of patients in Killip classes II-IV or in the overall study population. Hyperuricemia was associated with increased mortality in subgroups of patients who were at least 65years-old, male, had BMI of 25kg/m2 or less, were in Killip class I, without diabetes, and who did not receive intra-aortic balloon pump support. Hyperuricemia interacted with Killip class I in increasing the risk for 1-year mortality (p for interaction=0.038). CONCLUSIONS: Hyperuricemia increased the 1-year mortality of STEMI patients in Killip class I, but not of patients in Killip classes II-IV. An interaction of hyperuricemia and Killip class significantly affects the mortality of STEMI patients. PMID- 27780080 TI - Iron biofortification in the 21st century: setting realistic targets, overcoming obstacles, and new strategies for healthy nutrition. AB - Plant-based foods offer a wide range of nutrients that are essential for human and animal health. Among these nutrients, iron stands out as one of the most important micronutrients. Increasing the iron content in many staple and non staple plant foods continues to be a goal of many scientists around the world. However, the success of such initiatives has sometimes fallen short of their expected targets. In this review we highlight the most recent and promising results that have contributed to increasing the iron content in different crops. We also discuss methods that to date have been used to reach iron biofortification goals and new strategies that we believe are most promising for crop biofortification in the future. Plant anatomical, physiological and metabolic hurdles still need to be tackled for making progress on further increasing currently reached levels of micronutrient improvements. New strategies need to take into account growing environmental challenges that may constrain biofortification efforts. PMID- 27780082 TI - Theoretical ecology as etiological from the start. AB - The world's leading environmental advisory institutions look to ecological theory and research as an objective guide for policy and resource management decision making. In addition to the theoretical and broadly philosophical merits of doing so, it is therefore practically significant to clear up confusions about ecology's conceptual foundations and to clarify the basic workings of inferential methods used in the science. Through discussion of key moments in the genesis of the theoretical branch of ecology, this essay elucidates a general heuristic role of teleological metaphors in ecological research and defuses certain enduring confusions about work in ecology. PMID- 27780081 TI - Human enterovirus and rhinovirus infections are associated with otitis media in a prospective birth cohort study. AB - BACKGROUND: Human enteroviruses (HEVs) and rhinoviruses (HRVs) have been linked to acute otitis media (AOM). OBJECTIVES: The present study evaluates the aforementioned association in a birth cohort setting. STUDY DESIGN: The cohort included 286 healthy infants (191 boys) followed from birth up to the age of 2 years in the Type 1 Diabetes Prediction and Prevention study in Finland. Stool samples were collected monthly and analyzed for the presence of HRV and HEV RNA using RT-PCR. Clinical symptoms were recorded by a questionnaire every 3-6 months. RESULTS: Altogether 610 AOM episodes were reported during the follow-up. 9.8% of the stool samples were positive for HRV and 6.8% for HEV. HRV positivity peaked at the age of 3-6 months declining gradually after this age, whereas HEV positivity peaked later, at the age of 12-24 months. The risk of AOM was increased in children who were HEV positive at least once at the age of 6-12 months (OR 2.2 [95%CI 1.1-4.2], P=0.023) or who were HRV positive at least once at the age of 18-24 months (OR 2.3 [95%CI 1.0-5.2], P=0.042). Having an older sibling, short breast-feeding and maternal smoking during pregnancy were also significantly associated with AOM. CONCLUSIONS: HRV and HEV infections are frequent during the first months of life. The observed trend for increased risk of AOM in HRV and HEV positive children is in line with the results from hospital series suggesting that these viruses may play an independent role in the pathogenesis of AOM. PMID- 27780083 TI - Temperature, water activity and pH during conidia production affect the physiological state and germination time of Penicillium species. AB - Conidial germination and mycelial growth are generally studied with conidia produced under optimal conditions to increase conidial yield. Nonetheless, the physiological state of such conidia most likely differs from those involved in spoilage of naturally contaminated food. The present study aimed at investigating the impact of temperature, pH and water activity (aw) during production of conidia on the germination parameters and compatible solutes of conidia of Penicillium roqueforti and Penicillium expansum. Low temperature (5 degrees C) and reduced aw (0.900 aw) during sporulation significantly reduced conidial germination times whereas the pH of the sporulation medium only had a slight effect at the tested values (2.5, 8.0). Conidia of P. roqueforti produced at 5 degrees C germinated up to 45h earlier than those produced at 20 degrees C. Conidia of P. roqueforti and P. expansum produced at 0.900 aw germinated respectively up to 8h and 3h earlier than conidia produced at 0.980 aw. Furthermore, trehalose and mannitol assessments suggested that earlier germination might be related to delayed conidial maturation even though no ultra structural modifications were observed by transmission electron microscopy. Taken together, these results highlight the importance of considering environmental conditions during sporulation in mycological studies. The physiological state of fungal conidia should be taken into account to design challenge tests or predictive mycology studies. This knowledge may also be of interest to improve the germination capacity of fungal cultures commonly used in fermented foods. PMID- 27780084 TI - Accuracy of inclinometer functions of the activPAL and ActiGraph GT3X+: A focus on physical activity. AB - PURPOSE: The purpose of the study was to examine the accuracy of inclinometer functions of the ActiGraph GT3X+ (AG) (worn on the waist and wrist) and the activPAL (AP) in assessing time spent sitting, standing, and stepping. METHODS: A total of 62 adults (age: 18-40 yrs; male:37; female:25) wore three activity monitors (AG waist, and AG wrist, and AP) while completing 15 different types of activities. The 15 activities were classified into 3 different postures (sitting, standing, and stepping) based on the directly observed behaviors. Minutes estimated from the inclinometers of the three monitors were directly compared to those from direct observation (criterion method) using mean absolute percent error (MAPE) values, effect sizes (Cohen's D), and equivalence testing. RESULTS: The AP was more accurate than the both waist- and wrist-worn AG in both sitting and standing activities, but the AG was more accurate than the AP in stepping activity when the stepping activity was determined with 0.7 step/s threshold. Equivalence testing indicated that the time measured by the waist-, wrist-worn AG, and AP showed significant equivalence to the time in the equivalence zone (90% confidence interval: 2.7 to 3.3min) for 6, 5, and 7 activities, respectively. CONCLUSIONS: The AP was reasonably accurate for detecting sitting, standing, and stepping, and the AG was very accurate for classifying stepping when the stepping activity was determined by the formula created by 0.7 step/s threshold. It is expected that the result of the study would contribute to performing movement pattern analyses and health promotion research for classifying activities. PMID- 27780085 TI - Proceedings of the Eighth International Workshop on Advances in Electrocorticography. AB - Excerpted proceedings of the Eighth International Workshop on Advances in Electrocorticography (ECoG), which convened October 15-16, 2015 in Chicago, IL, are presented. The workshop series has become the foremost gathering to present current basic and clinical research in subdural brain signal recording and analysis. PMID- 27780086 TI - Are people with epilepsy using eHealth-tools? AB - INTRODUCTION: Self-management for people with epilepsy (PWE) should lead to shared decision-making and thus to adherence to the treatment plan. eHealth is an important way of supporting PWE in their self-management. METHOD: In this survey, we used a mixed method to explore the following: 1) which factors were monitored by PWE and how (using pen and paper or eHealth-tools), 2) how many PWE own a computer or smartphone, and 3) how do they perceive the use of eHealth. A consecutive series of 1000 PWE attending the outpatient clinic of a tertiary epilepsy center were asked to fill in a questionnaire. RESULTS: In comparison with the general population, fewer PWE owned a computer or smartphone. They were, however, more likely to self-monitor their health than other patients suffering from a chronic condition. Although PWE did not use eHealth-tools often, they perceived it as a user-friendly tool, promoting health behavior as well as adherence. On the other hand, problems with privacy and the perception that not everyone is able to use eHealth were considered as disadvantages by PWE. Promoting self-care was perceived as both an advantage and a disadvantage. It was seen as an advantage when PWE mentioned the option of eHealth-tools in order to gain insight into one's epilepsy. At the same time, it was seen as a disadvantage because it confronts PWE with their disease, which causes emotional stress. CONCLUSION: The high level of self-monitoring combined with a low usage of eHealth-tools seems to indicate that there is a need for a more tailored approach to stimulate the use of eHealth-tools by PWE. Further research should focus on this aspect, e.g., what PWE need in order to make more use of eHealth-tools in their self-care. PMID- 27780087 TI - Surface modification of nanostructure lipid carrier (NLC) by oleoyl-quaternized chitosan as a mucoadhesive nanocarrier. AB - A nanostructure lipid carrier (NLC) composed of solid, and liquid lipid as a core has been developed as a delivery system for hydrophobic drug molecules. The aim of this research was to fabricate an oleoyl-quaternized-chitosan (CS)-coated NLC, where the mucoadhesive property of nanoparticles is enhanced for more efficient drug delivery. NLC loaded with alpha-mangostin (AP), a model hydrophobic drug, were fabricated using a high pressure homogenization process and subsequently coated with CS. The fabricated nanoparticles showed particle sizes in the range of 200-400nm, with low polydispersity, high physical stability and excellent encapsulation efficiency (EE>90%). Additionally, in vitro viability, cytotoxicity and ability of NLC and CS-NLC to affect apoptosis in carcinoma Caco-2 cells were determined using the Triplex assay. Gene expressiom analysis were performed using quantitative reverse transcription Polymerase Chain Reaction (RT-qPCR). Moreover, in vivo toxicological testing of NLCs was conducted in zebrafish embryos. Results indicated that CS-NLC provieded high cytotoxicity than NLC itself. In the case of AP loaded nanoparticles, NLC loaded with AP (AP-NLC), and CS-NLC loaded with AP (CS-AP-NLC) exhibited higher cytotoxicity to Caco-2 over Hela cells. These results indicate that CS-NLC shows enhanced cellular uptake but increased cytotoxicity characteristics over NLC and therefore careful optimization of dosage and loading levels in CS-NLC is needed to allow cancer cell targeting, and for exploiting the potential of these systems in cancer therapy. PMID- 27780088 TI - Real-time label-free detection and kinetic analysis of Etanercept-Protein A interactions using quartz crystal microbalance. AB - A quartz crystal microbalance (QCM) was constructed to assess if such a biosensor has value as a complementary real-time label-free analysis platform for the biopharmaceutical industry. This was achieved through modifying QCM crystals with a low-fouling carboxymethyl-dextran layer bearing Protein A, and then injecting solutions containing Etanercept (i.e., Enbrel(r)) into the QCM chambers. The kinetics of Enbrel(r) - Protein A interactions was modeled using the Langmuir binding model and Enbrel(r) concentrations between 0.75-300ngmL-1. The resulting equilibrium dissociation and association constants (KD and KA) were 5.06*10-8M and 1.98*107M-1, respectively. The association and dissociation rate constants (kon and koff) decreased substantially as Enbrel(r) concentration, [C], increased, despite that the net binding rate, (kon[C]+koff), increased. The decrease in kon and koff was hypothesized to be a consequence of mass transport limitations. To verify this, QCM dissipation measurements were analyzed to provide insight on solution viscosity. As Enbrel(r) concentration increased, the net change in dissipation, DeltaD, became larger. An augmentation of DeltaD is associated with a higher solution viscosity, which would result in an increase in mass transport limitations. Therefore, the decrease in kon and koff for increasing Enbrel(r) concentration can be attributed to mass transport limitations. In conclusion, QCM is a valuable complementary real-time label-free biosensor analysis platform for the biopharmaceutical industry. Unlike the surface plasmon resonance (SPR) platform, QCM allows measuring dissipation, which can provide insight on how mass transport limitations impact interaction kinetics. PMID- 27780089 TI - The relationship between MTHFR C677T gene polymorphism and essential hypertension in a sample of an Algerian population of Oran city. AB - BACKGROUND: Many studies have investigated the role of 5,10 methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in essential hypertension (EH), but with conflicting results. AIM: To determine the eventual association between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and hypertension in a sample of Algerian population from the Oran city. METHODS: A case-control study has been performed in 154 subjects including 82 hypertensives defined as subjects with elevated systolic blood pressure SBD>=140mmHg and or sustained diastolic blood pressure DBP>=90mmHg, and 72 normotensive subjects. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to detect the MTHFR C677T variant. RESULTS: We observe no significant differences between allelic and genotypic frequencies between cases and controls for C677T polymorphism (OR=1.51, 95% CI=0.89-2.56, P=0.13). Analyses adjusted for age, sex and body mass index improved the association level, though the association was still not significant (30% vs. 22%, OR=1.75, 95% CI=0.95-3.24, P=0.07). CONCLUSION: This work showed that genetic polymorphism related to the MTHFR gene (C677T) is not associated with the risk of hypertension in this sample of Algerian population. Larger case control samples are required to clearly assess the role of this genetic variant in EH. PMID- 27780090 TI - A case of obturator hernia leading to right thigh abscess in China. AB - The purpose of this case is to investigate a case of obturator hernia leading to right thigh abscess on 68-year-old woman of China. A 68-year-old Chinese woman was referred to China-Japan Friendship Hospital of Jilin University with abdominal pain, bloating, exhaust, stop defecation in 2011. She had chronic bronchitis, emphysema with a history of 20 years. This patient did not have any bad habits, such as smoking, alcohol consumption, etc. In this surgery, CT was used to diagnose the basic condition of the patient. Surgery was used for treatment of patients with diseases. In addition, this operation was performed by the china-Japan Friendship Hospital of Jilin University. The results of this case showed that the cervix of rectal right anterior wall can hit a funicular neoplasm, toughening, smooth, with tenderness, considering for the external pressure bowel loops. The inside of the right thigh showed obvious swelling, skin slightly bruising, and tenderness. Chest radiographs showed that patients had emphysema, multiple planes of fluid and air in the abdomen. Patients had been successfully operated, but she died because of severe infection. PMID- 27780091 TI - Gender-differentiated effects of theory of mind, emotion understanding, and social preference on prosocial behavior development: A longitudinal study. AB - Although key differences have been found in boys' and girls' prosocial behavior toward peers, few studies have systematically examined gender differences in how intrinsic perspective-taking abilities-theory of mind (ToM) and emotion understanding (EU)-and the extrinsic peer environment relate to prosocial behavior. In this prospective longitudinal study, we studied gender differences in the relations between children's observed prosocial behavior and their ToM, EU, and social preference ratings in 114 children (58 boys and 56 girls). We used conventional ToM and EU tasks at 5 and 7years of age. Observed prosocial behavior in triadic peer interactions was assessed at both time points. Controlling for gender, age, verbal ability, and earlier prosocial behavior, ToM at 5years was found to predict prosocial behavior at 7years. Results also revealed gender differentiated associations at 7years, whereby only girls' prosocial behavior was positively associated with EU. Results are discussed in terms of gender differentiated patterns of socialization. PMID- 27780092 TI - Influence of temperature and hydraulic retention on the production of volatile fatty acids during anaerobic fermentation of cow manure and maize silage. AB - The aim of this study was to verify the efficiency of a separate hydrolysis step by testing different working temperatures (37-55 degrees C) and hydraulic retention times (two, four and six days) and by evaluating readily biodegradable carbon production. The fermentation products included primarily acetic, propionic and butyric acids. These acids can be easily converted into biogas or can be recovered in a biorefinery approach, for example, to produce polyhydroxyalkanoates. The optimal condition was found by applying an organic loading rate of 17.9gTVSm-3 with a four-day retention time at 37 degrees C for an acidification yield of 183.2gCODVFAkgVSfed-1. PMID- 27780094 TI - Transport and retention of TiO2 and polystyrene nanoparticles during drainage from tall heterogeneous layered columns. AB - Recent developments in nanotechnology have seen an increase in the use of manufactured nanomaterials. Although their unique physicochemical properties are desirable for many products and applications, concern continues to exist about their environmental fate and potential to cause risk to human and ecological health. The purpose of this work was to examine one aspect of nanomaterial environmental fate: transport and retention in the unsaturated zone during drainage. The work made use of tall segmented columns packed with layers of two different porous media, one medium sand and one fine sand. The use of tall columns allowed drainage experiments to be conducted where the water table remained within the height of the column, permitting control of final saturation profiles without the need for capillary barrier membranes which can potentially complicate analyses. Experiments were conducted with titanium dioxide (TiO2) and polystyrene nanomaterials. For the strongly negatively-charged polystyrene nanomaterials, little retention was observed under the conditions studied. For the TiO2 nanomaterials, results of the work suggest that while saturated fine sand layers may retain more nanomaterials than saturated coarse sand layers, significantly greater retention is possible in unsaturated media. Furthermore, unsaturated medium sand layers exhibited significantly greater retention than adjacent saturated fine sand layers when present at low saturations high above the water table. Retention by unsaturated media were found to correlate strongly with elevation. Free drainage experiments including both primary and secondary drainages in homogeneous columns showed evidence of redistribution during imbibition and secondary drainage, but still showed substantial unsaturated retention of TiO2 nanoparticles high in the column, despite re-saturation with- and drainage of nanoparticle-free water. PMID- 27780095 TI - Coastal urban lighting has ecological consequences for multiple trophic levels under the sea. AB - Urban land and seascapes are increasingly exposed to artificial lighting at night (ALAN), which is a significant source of light pollution. A broad range of ecological effects are associated with ALAN, but the changes to ecological processes remain largely unstudied. Predation is a key ecological process that structures assemblages and responds to natural cycles of light and dark. We investigated the effect of ALAN on fish predatory behaviour, and sessile invertebrate prey assemblages. Over 21days fish and sessile assemblages were exposed to 3 light treatments (Day, Night and ALAN). An array of LED spotlights was installed under a wharf to create the ALAN treatments. We used GoPro cameras to film during the day and ALAN treatments, and a Dual frequency IDentification SONar (DIDSON) to film during the night treatments. Fish were most abundant during unlit nights, but were also relatively sedentary. Predatory behaviour was greatest during the day and under ALAN than at night, suggesting that fish are using structures for non-feeding purposes (e.g. shelter) at night, but artificial light dramatically increases their predatory behaviour. Altered predator behaviour corresponded with structural changes to sessile prey assemblages among the experimental lighting treatments. We demonstrate the direct effects of artificial lighting on fish behaviour and the concomitant indirect effects on sessile assemblage structure. Current and future projected use of artificial lights has the potential to significantly affect predator-prey interactions in marine systems by altering habitat use for both predators and prey. However, developments in lighting technology are a promising avenue for mitigation. This is among the first empirical evidence from the marine system on how ALAN can directly alter predation, a fundamental ecosystem process, and have indirect trophic consequences. PMID- 27780093 TI - Characterization of a hybrid powdered activated carbon-dynamic membrane bioreactor (PAC-DMBR) process with high flux by gravity flow: Operational performance and sludge properties. AB - Three PAC-DMBRs were developed for wastewater treatment under different PAC dosages with biomass concentrations averaged at 2.5, 3.5 and 5.0g/L. The DMBRs could be continuously operated at 40-100L/m2h, while higher fluxes were obtained within the PAC-DMBRs with hydraulic retention times varying in 4-10h. A dose of 1g/L PAC brought about obvious improvement in the sludge particle size distribution, settling, flocculating and dewatering properties due to the formation of biological PAC, and the sludge properties were further improved at a higher PAC dose (3g/L). The addition of PAC notably shortened the DM formation time after air backwashing and enhanced pollutant removal. Moreover, under a long solid retention time (approximately 150d), the concentrations of both soluble and bound extracellular polymeric substances (EPS) decreased substantially because of the adsorption and biodegradation effects of the biological PAC. No obvious impact on biomass activity was observed with PAC addition. PMID- 27780096 TI - Potential applications of olive mill wastewater as biopesticide for crops protection. PMID- 27780097 TI - Past, present and future concentrations of ground-level ozone and potential impacts on ecosystems and human health in northern Europe. AB - This review summarizes new information on the current status of ground-level ozone in Europe north of the Alps. There has been a re-distribution in the hourly ozone concentrations in northern Europe during 1990-2015. The highest concentrations during summer daytime hours have decreased while the summer night time and winter day- and night-time concentrations have increased. The yearly maximum 8-h mean concentrations ([O3]8h,max), a metric used to assess ozone impacts on human health, have decreased significantly during 1990-2015 at four out of eight studied sites in Fennoscandia and northern UK. Also the annual number of days when the yearly [O3]8h,max exceeded the EU Environmental Quality Standard (EQS) target value of 60ppb has decreased. In contrast, the number of days per year when the yearly [O3]8h,max exceeded 35ppb has increased significantly at two sites, while it decreased at one far northern site. [O3]8h,max is predicted not to exceed 60ppb in northern UK and Fennoscandia after 2020. However, the WHO EQS target value of 50ppb will still be exceeded. The AOT40 May-July and AOT40 April-September metrics, used for the protection of vegetation, have decreased significantly at three and four sites, respectively. The EQS for the protection of forests, AOT40 April-September 5000ppbh, is projected to no longer be exceeded for most of northern Europe sometime before the time period 2040-2059. However, if the EQS is based on Phytotoxic Ozone Dose (POD), POD1, it may still be exceeded by 2050. The increasing trend for low and medium range ozone concentrations in combination with a decrease in high concentrations indicate that a new control strategy, with a larger geographical scale than Europe and including methane, is needed for ozone abatement in northern Europe. PMID- 27780098 TI - Correlations between aromaticity of dissolved organic matter and trace metal concentrations in natural and effluent waters: A case study in the Sagami River Basin, Japan. AB - Chemical speciation, reactivity, and bioavailability of trace metals in aqueous systems arestrongly influenced by dissolved organic matter (DOM). DOM is a mixture of diverse components, so a range of organic molecules potentially participates in the occurrence of dissolved trace metals. In this study, we investigated water quality variables that influence dissolved trace metal concentrations in natural and effluent water systems with a particular attention given to the relationship between DOM optical properties and dissolved copper and iron concentrations. We found that specific UV absorbance (SUVA254: an indicator of DOM aromaticity) has a significant correlation with dissolved trace metal to dissolved organic carbon concentration ratios ([Me]T/[DOC]) for copper and iron in natural freshwaters and treated municipal wastewater in the Sagami River basin, Japan. This trend was also prevalent for other freshwaters in temperate climates except for Fe-rich waters. Our findings indicate that the concentrations of dissolved copper and iron in natural and effluent waters are significantly influenced not only by DOM concentration, but also by aromaticity of DOM, and that this DOM property can be inferred from spectrophotometric measurements. PMID- 27780099 TI - Evaluation of a CFD-based approach to estimate pollutant distribution within a real urban canopy by means of passive samplers. AB - The distribution of pollutants is spatially heterogeneous within urban streets making difficult to build a realistic concentration map. In this paper, a methodology based on computational fluid dynamic modeling with Reynolds-averaged Navier-Stokes approach is used to compute maps of concentration for a period of several weeks. The methodology is evaluated by comparing simulation results against experimental data from two different campaigns where a large number of passive samplers deployed in an area with heavy vehicular traffic in Madrid (Spain). The evaluation shows that the methodology is able to reproduce the general pattern of several-week averaged pollutant distribution in an urban area with heavy vehicular traffic, resolving the spatial variability up to a resolution of 1-2m. In addition, the model results fit satisfactorily the time evolution of the pollutant concentration measured at an air quality station deployed in the studied area. However, problems were detected close to zones with complex emissions patterns (tunnels, street forks, etc.), where the model compared poorly against passive sampler measurements. A preliminary assessment of the uncertainties induced in the numerical methodology due to consider NO2 as non reactive pollutant under winter conditions indicates that it would be an acceptable approach for this particular case study. Overall, our analysis contributes to raise the confidence in that approached similar to the one presented in this study can be adopted for dealing with several aspects of the air quality management such as air quality assessment, optimization of the location of measurement stations, and the evaluation of air pollution reduction strategies. PMID- 27780100 TI - Hydrochemical characterization of a mine water geothermal energy resource in NW Spain. AB - Abandoned and flooded mine networks provide underground reservoirs of mine water that can be used as a renewable geothermal energy source. A complete hydrochemical characterization of mine water is required to optimally design the geothermal installation, understand the hydraulic behavior of the water in the reservoir and prevent undesired effects such as pipe clogging via mineral precipitation. Water pumped from the Barredo-Figaredo mining reservoir (Asturias, NW Spain), which is currently exploited for geothermal use, has been studied and compared to water from a separate, nearby mountain mine and a river that receives mine water discharge and partially infiltrates into the mine workings. Although the hydrochemistry was altered during the flooding process, the deep mine waters are currently near neutral, net alkaline, high metal waters of Na-HCO3 type. Isotopic values suggest that mine waters are closely related to modern meteoric water, and likely correspond to rapid infiltration. Suspended and dissolved solids, and particularly iron content, of mine water results in some scaling and partial clogging of heat exchangers, but water temperature is stable (22 degrees C) and increases with depth, so, considering the available flow (>100Ls-1), the Barredo-Figaredo mining reservoir represents a sustainable, long-term resource for geothermal use. PMID- 27780101 TI - Characteristics of on-road NOx emissions from Euro 6 light-duty diesel vehicles using a portable emissions measurement system. AB - This paper presents the on-road nitrogen oxides (NOx) emissions measurements from Euro 6 light-duty diesel vehicles using a portable emissions measurement system on the predesigned test routes in the metropolitan area of Seoul, Korea. Six diesel vehicles were tested and the NOx emissions results were analyzed according to the driving routes, driving conditions, data analysis methods, and ambient temperatures. Total NOx emissions for route 1, which has higher driving severity than route 2, differed by -4-60% from those for route 2. The NOx emissions when the air conditioner (AC) was used were higher by 68% and 85%, on average, for routes 1 and 2, respectively, compared to when the AC was not used. The analytical results for NOx emissions by the moving averaging window method were higher by 2-31% compared to the power binning method. NOx emissions at lower ambient temperatures (0-5 degrees C) were higher by 82-192% compared to those at higher ambient temperatures (15-20 degrees C). This result shows that performance improvements of exhaust gas recirculation and the NOx after-treatment system will be needed at lower ambient temperatures. PMID- 27780102 TI - Persistent Organic Pollutants in sediment and fish in the River Thames Catchment (UK). AB - Some organic pollutants including polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and hexachlorobenzene (HCB) have been banned from production and use in the UK for >30years but due to their toxicity and persistence are still of concern. However, due to their hydrophobicity they are present at very low concentrations and are difficult to measure in water, and so other matrices need to be sampled in order to best assess contamination. This study measured concentrations of SigmaICES 7 PCBs (PCB congeners 28, 52, 101, 118, 138, 153 and 180) and Sigma6 PBDEs (PBDE congeners 28, 47, 99, 100, 153, 154) and HCB in both bed-sediments and wild roach (a common pelagic fish) in the Thames Basin. The highest sediment concentrations were detected in an urbanised tributary of the Thames, The Cut at Bracknell (HCB: 0.03-0.40MUg/kg dw; ICES 7 PCBs: 4.83-7.42MUg/kg dw; 6 BDEs: 5.82-23.10MUg/kg dw). When concentrations were expressed on a dry weight basis, the fish were much more contaminated than the sediments, but when sediment concentrations were normalised to organic carbon concentration they were comparable to the fish lipid normalised concentrations. Thus, despite the variability in the system, both sediments and wild fish can be considered suitable for representing the level of POPs contamination of the river system given sufficient sample numbers. PMID- 27780103 TI - Cliff-nesting seabirds influence production and sediment chemistry of lakes situated above their colony. AB - Seabirds that congregate in large numbers during the breeding season concentrate marine-derived nutrients to their terrestrial nesting sites, and these nutrients disperse and enhance production in nearby terrestrial, freshwater and marine ecosystems. In the Canadian Arctic, large seabird colonies (>100,000 breeding pairs) nest on cliff faces that drain directly in the ocean, ultimately returning the nutrients back to the marine environment from which they were derived. However, strong winds blowing up cliff faces could transport nutrients up in elevation and onto surrounding terrestrial and aquatic environments. Here, we assess the degree to which seabird nutrients and metals have been delivered to coastal lakes near Hudson Strait (Nunavut, Canada) over the past century. Three lakes located at a higher elevation and increasing distance from a thick-billed murre (Uria lomvia) colony (~400,000 breeding pairs) were sampled for surface water chemistry. In addition, algal assemblages, nitrogen isotopes, and metal/metalloids were analyzed in four dated sediment cores. Elevated nutrients and major ions, as well as an enriched delta15N signature in the sediment cores, were measured in the lake <100m from the cliff, whilst no comparable changes were recorded in lakes >1km from the seabird colony. In contrast, similar oligotrophic and benthic diatom assemblages were identified in all three lakes, suggesting that diatoms were not influenced by enhanced nutrient inputs in this Arctic environment. Chemical tracers (e.g., total mercury) and algal assemblages in the lake near the colony suggest climate warming since ~1950 was the most likely driver of limnological changes, but this effect was muted in the more distant lakes. These pronounced changes in the seabird-impacted lake suggest that, with warming air temperatures and diminished lake ice cover, longer growing seasons may allow for aquatic organisms to more fully exploit the seabird nutrient subsidies. PMID- 27780104 TI - An innovative multistage treatment system for sanitary landfill leachate depuration: Studies at pilot-scale. AB - In this work, an innovative methodology for the treatment of landfill leachates, after aerobic lagooning, is proposed and adjusted at pilot-scale. This methodology involves an aerobic activated sludge biological pre-oxidation (ASBO), a coagulation/sedimentation step (240mgFe3+/L, at pH4.2) and a photo-oxidation through a photo-Fenton (PF) reaction (60mg Fe2+, at pH2.8) combining solar and artificial light. The ASBO process applied to a leachate after aerobic lagooning, with high organic and nitrogen content (1.1-1.5gC/L; 0.8-3.0gN/L) and low biodegradability (BOD5/COD =0.07-0.13), is capable to oxidise 62-99% of the ammonium nitrogen, consuming only the affluent alkalinity (70-100%). The coagulation/sedimentation stage led to the humic acids precipitation, promoting a marked change in leachate colour, from dark-brown to yellowish-brown (related to fulvic acids), accompanied by a reduction of 60%, 58% and 88% on DOC, COD and TSS, respectively. The PF system promoted the degradation of the recalcitrant organic molecules into more easily biodegradable ones. According to Zahn-Wellens biodegradability test, a leachate with 419mg DOC/L after coagulation, would have to be photo-oxidized until DOC <256mg/L, consuming 117mM of H2O2 and 10.4kJ/L of accumulated UV energy, to achieve an effluent that can be biologically treated in compliance with the COD discharge limit (150mg O2/L) into water bodies. The biological process downstream from the photocatalytic system would promote a mineralization >60%. The PF step cost to treat 100m3/day of leachate was 6.41?/m3, combining 1339m2 of CPCs with 31 lamps. PMID- 27780106 TI - How many ways are there to make a root? AB - Plants often make the same organ in different development contexts. Roots are a quintessential example, with embryonic, primary, lateral, adventitious, and regenerative roots common to many plants. The cellular origins and early morphologies of different roots can vary greatly, but the adult structures can be remarkably similar. Recent studies have highlighted the diversity of mechanisms that can initiate roots while late patterning mechanisms are frequently shared. In the middle stages when patterning emerges, evidence shows that antagonistic auxin-cytokinin interactions regulate tissue patterns in root embryogenesis, vascular organization, and regeneration but it is not yet clear if a common ontogeny for the root body plan exists. PMID- 27780105 TI - Initiation into prescription opioid injection and associated trends in heroin use among people who use illicit drugs. AB - OBJECTIVES: Prescription opioid (PO) injection among people who use illicit drugs (PWUD) is an ongoing concern, yet little is known about drug use trajectories associated with initiating PO injection, including potential associations with heroin use. This study aimed to identify predictors of PO injection initiation among PWUD, and examine trends in heroin use before and after initiating PO injection. METHODS: Data were merged from three cohorts of PWUD recruited between September 2005 and November 2015. Predictors of PO injection initiation were identified using extended Cox regression models. Trends in heroin use pre- and post-initiation were examined with McNemar's test and compared to matched controls with linear growth curve models. RESULTS: Among 1580 participants, 247 initiated PO injection yielding an incidence density of 3.9 (95% Confidence Interval [CI]: 3.4-4.4) per 100 person-years. In a multivariable analysis, independent predictors of PO injection initiation included heroin injection (Adjusted Hazard Ratio [AHR]=4.39, 95% CI: 3.24-5.95) and non-injection PO use (AHR=1.99, 95% CI: 1.25-3.17). In a sub-analysis, compared to matched controls, PO injection corresponded with elevated heroin use post-initiation (p<=0.05). DISCUSSION: In this study, heroin use and non-injection PO use strongly predicted PO injection initiation. Those who initiated PO injecting had elevated heroin use patterns post-initiation compared to controls. These findings suggest that transitioning to PO injection does not appear to be a substitute for heroin use among PWUD. These findings highlight the importance of addressing PO injection in harm reduction and treatment settings. PMID- 27780107 TI - Identifying common donors in DNA mixtures, with applications to database searches. AB - Several methods exist to compute the likelihood ratio LR(M, g) evaluating the possible contribution of a person of interest with genotype g to a mixed trace M. In this paper we generalize this LR to a likelihood ratio LR(M1, M2) involving two possibly mixed traces M1 and M2, where the question is whether there is a donor in common to both traces. In case one of the traces is in fact a single genotype, then this likelihood ratio reduces to the usual LR(M, g). We explain how our method conceptually is a logical consequence of the fact that LR calculations of the form LR(M, g) can be equivalently regarded as a probabilistic deconvolution of the mixture. Based on simulated data, and using a semi continuous mixture evaluation model, we derive ROC curves of our method applied to various types of mixtures. From these data we conclude that searches for a common donor are often feasible in the sense that a very small false positive rate can be combined with a high probability to detect a common donor if there is one. We also show how database searches comparing all traces to each other can be carried out efficiently, as illustrated by the application of the method to the mixed traces in the Dutch DNA database. PMID- 27780108 TI - Bringing colour back after 70 years: Predicting eye and hair colour from skeletal remains of World War II victims using the HIrisPlex system. AB - Retrieving information about externally visible characteristics from DNA can provide investigative leads to find unknown perpetrators, and can also help in disaster victim and other missing person identification cases. Aiming for the application to both types of forensic casework, we previously developed and forensically validated the HIrisPlex test system enabling parallel DNA prediction of eye and hair colour. Although a recent proof-of-principle study demonstrated the general suitability of the HIrisPlex system for successfully analysing DNA from bones and teeth of various storage times and conditions, practical case applications to human remains are scarce. In this study, we applied the HIrisPlex system to 49 DNA samples obtained from bones or teeth of World War II victims excavated at six sites, mostly mass graves, in Slovenia. PCR-based DNA quantification ranged from 4pg/MUl to 313pg/MUl and on an average was 41pg/MUl across all samples. All 49 samples generated complete HIrisPlex profiles with the exception of one MC1R DNA marker (N29insA) missing in 83.7% of the samples. In 44 of the 49 samples (89.8%) complete 15-loci autosomal STR (plus amelogenin) profiles were obtained. Of 5 pairs of skeletal remains for which STR profiling suggested an origin in the same individuals, respectively, 4 showed the same HIrisPlex profiles and predicted eye and hair colours, respectively, while discrepancies in one pair (sample 26 and 43) are likely to be explained by DNA quantity and quality issues observed in sample 43. Sample 43 had the lowest DNA concentration of only 4pg/MUl, producing least reliable STR results and could be misleading in concluding that samples 43 and 26 originate from the same individual. The HIrisPlex-predicted eye and hair colours from two skeletal samples, suggested to derive from two brothers via STR profiling together with a living sister, were confirmed by the living sister's report. Overall, we demonstrate that after more than 70 years, HIrisPlex-based eye and hair colour prediction from skeletal remains is feasible with high success rate. Our results further encourage the use of the HIrisPlex system in missing person/disaster victim identification to aid the identification process in cases where ante mortem samples or putative relatives are not directly available, and DNA predicted eye and hair colour information provides leads for locating them, allowing STRbased individual identification. PMID- 27780109 TI - Efficacy of a progressive resistance exercise program to increase toe flexor strength in older people. AB - BACKGROUND: Reduced toe flexor strength is an independent predictor of falls in older people. However it is unknown whether strengthening programs can restore toe flexor strength in older individuals. The aim of this study was to investigate whether a progressive resistance training program, focused specifically on the foot muscles, could improve toe flexor strength in community dwelling older people. METHODS: After baseline testing, 85 men and women (age range 60-90years) were randomized to either a supervised, progressive resistance training (n=43) or a home-based exercise (n=42) group for 12weeks. A further 32 participants were recruited for a control group. The primary outcome measures were hallux and lesser toe flexor strength pre- and post-intervention. Secondary outcome measures were exercise compliance, components of the Foot Health Status Questionnaire and single-leg balance time. FINDINGS: Average class attendance was 89% with 68 participants from the two intervention groups (80%) completing the follow-up assessments. Participants in the supervised, progressive resistance training group significantly increased their toe strength (up to 36%; P<0.02), whereas there was no change in toe strength in either the home-based or control groups. This increased toe strength was accompanied by a significant improvement in perceived general foot health and single-leg balance time compared to the other groups (P<0.05). INTERPRETATION: Progressive resistance exercises are a viable intervention to increase toe flexor strength in older adults. A clinical trial is now required to determine whether this intervention can reduce the number of falls suffered by older adults. PMID- 27780110 TI - Latent classes of childhood poly-victimization and associations with suicidal behavior among adult trauma victims: Moderating role of anger. AB - The aims of the present study were first to identify discrete patterns of childhood victimization experiences including crime, child maltreatment, peer/sibling victimization, sexual violence, and witnessing violence among adult trauma victims using latent class analysis; second, to examine the association between class-membership and suicidal behavior, and third to investigate the differential role of dispositional anger on the association between class membership and suicidal behavior. We hypothesized that those classes with accumulating exposure to different types of childhood victimization (e.g., poly victimization) would endorse higher suicidal behavior, than the other less severe classes, and those in the most severe class with higher anger trait would have stronger association with suicidal behavior. Respondents were 346 adults (N=346; Mage=35.0years; 55.9% female) who had experienced a lifetime traumatic event. Sixty four percent had experienced poly-victimization (four or more victimization experiences) and 38.8% met the cut-off score for suicidal behavior. Three distinct classes emerged namely, the Least victimization (Class 1), the Predominantly crime and sibling/peer victimization (Class 2), and the Poly victimization (Class 3) classes. Regression analysis controlling for age and gender indicated that only the main effect of anger was significantly associated with suicidal behavior. The interaction term suggested that those in the Poly victimization class were higher on suicidal behavior as a result of a stronger association between anger and suicidal behavior in contrast to the association found in Class 2. Clinical implications of findings entail imparting anger management skills to facilitate wellbeing among adult with childhood poly victimization experiences. PMID- 27780111 TI - Risk terrain modeling predicts child maltreatment. AB - As indicated by research on the long-term effects of adverse childhood experiences (ACEs), maltreatment has far-reaching consequences for affected children. Effective prevention measures have been elusive, partly due to difficulty in identifying vulnerable children before they are harmed. This study employs Risk Terrain Modeling (RTM), an analysis of the cumulative effect of environmental factors thought to be conducive for child maltreatment, to create a highly accurate prediction model for future substantiated child maltreatment cases in the City of Fort Worth, Texas. The model is superior to commonly used hotspot predictions and more beneficial in aiding prevention efforts in a number of ways: 1) it identifies the highest risk areas for future instances of child maltreatment with improved precision and accuracy; 2) it aids the prioritization of risk-mitigating efforts by informing about the relative importance of the most significant contributing risk factors; 3) since predictions are modeled as a function of easily obtainable data, practitioners do not have to undergo the difficult process of obtaining official child maltreatment data to apply it; 4) the inclusion of a multitude of environmental risk factors creates a more robust model with higher predictive validity; and, 5) the model does not rely on a retrospective examination of past instances of child maltreatment, but adapts predictions to changing environmental conditions. The present study introduces and examines the predictive power of this new tool to aid prevention efforts seeking to improve the safety, health, and wellbeing of vulnerable children. PMID- 27780112 TI - Tracing metabolism from lignocellulosic biomass and gaseous substrates to products with stable-isotopes. AB - Engineered microbes offer a practical and sustainable alternative to traditional industrial approaches. To increase the economic feasibility of biological processes, microbial isolates are engineered to take up inexpensive feedstocks (including lignocellulosic biomass, syngas, methane, and carbon dioxide), and convert them into substrates of central metabolism and further into value-added products. To trace the metabolism of these feedstocks into products, isotopic tracers are applied together with isotopomer analysis techniques such as 13C metabolic flux analysis to provide a detailed picture of pathway utilization. Flux data is then integrated with kinetic models and constraint-based approaches to identify metabolic bottlenecks, propose novel metabolic engineering strategies, and improve process performance. PMID- 27780113 TI - The dysfunction of platelets in paroxysmal nocturnal hemoglobinuria. AB - INTRODUCTION: Thrombosis is a dangerous complication of paroxysmal nocturnal hemoglobinuria (PNH) and has a high mortality rate. However, the mechanism underlying the development of thrombosis in PNH remains unclear. To explore this, platelet function and serum complement activity were investigated in 14 patients with classical PNH, 11 with PNH aplastic anemia (AA) and 30 healthy controls. MATERIAL AND METHODS: Serum concentrations of the terminal complement complex (sC5b-9) were determined by enzyme-linked immunofluorescence assay (ELISA), and the levels of C5b-9, CD61 and CD62p on platelet membranes were determined by flow cytometry. Clinical parameters were assessed, including D-dimer and platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (ARA). RESULTS: Serum sC5b-9 concentrations were significantly lower in the PNH/PNH-AA than in the control group (P<0.01). C5b-9 deposition was significantly higher on CD59- platelets than on CD59+ platelets in PNH/PNH-AA patients and healthy controls (P<0.01 for each). D-dimer concentration was significantly higher in PNH/PNH-AA patients - especially those with lactate dehydrogenase (LDH) concentrations>1000U/L - than in controls (P<0.05). CD61 (P<0.05) expression was lower on CD59+ platelets in PNH than in controls and CD5- platelets in PNH. Expression of CD62p (P<0.01) was lower on CD59- and CD59+ platelets (P<0.01) in PNH cases than in controls. Platelet aggregation stimulated by the agonists ADP and ARA in the PNH/PNH-AA patients was significantly lower than that in controls (P<0.05). CONCLUSIONS: The adhesion and aggregation of platelets, especially of CD59+ platelets, were compensatively decreased in PNH/PNH-AA patients without active thrombosis. PMID- 27780114 TI - Can mean platelet volume be used as a biomarker of pathological fibrin clot strength related to obesity? PMID- 27780115 TI - Formative evaluation on a physical activity health promotion program for the group home setting. AB - Physical inactivity and high rates of chronic conditions is a public health concern for adults with intellectual disability. Few health promotion programs target the group home setting which is the pre-dominant form of residential accommodation for persons with intellectual disability. A process evaluation of a physical activity health promotion program, Menu-Choice, was conducted with five group home sites for adults with intellectual and developmental disabilities. Menu-Choice assists group home staff in including physical activity goals within resident schedules. The physical activity program was designed based on theoretical frameworks, community-based participatory approaches, and established health promotion guidelines for adults with disabilities. Fourteen program coordinators (age M 39; 77% females), 22 staff (age M 39; 82% females), and 18 residents (age M 59; 72% females; 56% ambulatory) participated. Results from the fidelity survey and program completion highlight potential challenges with implementation. Findings will assist with the refinement of the program for continued implementation trials in the group home community. PMID- 27780117 TI - Light induced structural changes of the photoprotein mnemiopsin: Characterization and contribution in photoinactivation. AB - Mnemiopsin, an EF-hand Ca2+ binding photoprotein isolated from luminous ctenophore Mnemiopsis leidyi, emits blue light from its chromophore, coelenterazine, which is non-covalently bond in its central hydrophobic core. Previous studies have revealed unique biochemical properties for ctenophore photoproteins such as inactivation by light, but only few have focused on photoinactivation process. To understand the nature of photoinactivation process we have investigated the impact of light alone and in the presence of Ca2+ ion on the structure of this photoprotein. We used UV-Vis, circular dichroism (CD) and fluorescence spectroscopy following Ca2+ binding assay to analyze the light effects on mnemiopsin conformation in comparison with aequorin at both apo and holo form. Our results showed light induced structural changes which resulted into photoinactivation. These changes include significant modification on secondary structure of mnemiopsin in comparison with aequorin. Our data also revealed that light could influence structure of apo protein regardless of presence of coelenterazine. The comparative studies of Ca2+ ion binding affinity following light exposure, also showed that light induced structural changes could presumably affect coelenterazine binding or its conformation in binding site in such a way that causes photoinactivation. In conclusion, we have proposed that structural rearrangement of helix 5 and C-terminal motif could be responsible for light induced structural changes. PMID- 27780116 TI - "We're giving you something so we get something in return": Perspectives on research participation and compensation among people living with HIV who use drugs. AB - BACKGROUND: Compensation for participating in research has been a fundamental element of the research apparatus despite concerns about its impact on incentivising participation. Researchers and research ethics boards acknowledge that compensation may prompt structurally vulnerable populations, such as people who use drugs (PWUD), to engage in research primarily out of financial need. Thus, institutional restrictions around compensation have been implemented. This study explores the ethical implications of compensation practices aimed at 'protecting' structurally vulnerable people living with HIV (PLHIV) who use drugs within the context of individuals' lived realities. METHODS: We draw on five focus groups conducted in 2011 with 25 PLHIV who use drugs and access a community based HIV care facility in Vancouver, Canada. This analysis focused on participants' perceptions of research compensation, which became the central point of discussion in each group. RESULTS: Participants viewed research as a transactional process through which they could challenge the underpinnings of bioethics and bargain for compensation. Research compensation was thus critical to attracting participants and positioned as a 'legitimate' form of income. Participants' medicalised identities, specifically living with HIV, were fundamental to justifying compensation. The type of compensation (e.g. gift card, cash) also significantly impacted whether participants were fully compensated and, at times, served to exacerbate their structural vulnerability. CONCLUSION: Research compensation is critical in shaping structurally vulnerable populations' participation and experiences with research and can further marginalize individuals. Practices surrounding research compensation, particularly for drug using and HIV-positive populations, need to be evaluated to ensure participants are equitably compensated for the expertise they provide. PMID- 27780118 TI - Molecular hybridization approach of bio-potent CuII/ZnII complexes derived from N, O donor bidentate imine scaffolds: Synthesis, spectral, human serum albumin binding, antioxidant and antibacterial studies. AB - Novel bio-relevant monometallic Schiff base complexes of the type, [Cu(L1)2] (1), [Zn(L1)2].2H2O (2), [Cu(L2)2].2H2O (3) and [Zn(L2)2].H2O (4) [L1(E)-3-(((3-chloro 4-hydroxyphenyl)imino)methyl)naphthalen-2-ol and L2(E)-2-chloro-4-((1-(5-chloro-2 hydroxyphenyl)ethylidene)amino)phenol] were synthesized and characterized. A comparative account of analytical, spectroscopic (FT-IR, 1H and 13C NMR, Mass, UV vis and EPR), thermal (TGA/DTA), XRD and SEM studies revealed a correlation between the structure and function of these biologically active molecular entities. HSA (Human serum albumin) binding profiles of the metal complexes (1-4) were monitored using biophysical techniques viz., absorbance, fluorescence, circular dichromism (CD) and foster resonance energy transfer (FRET). The intrinsic binding constant (Kb) demonstrated substantial binding propensity of L1 linked complexes (1 and 2) in comparison to L2 complexes (3 and 4) suggesting L1 to be more bio-active pharmacophore due to higher planarity and conjugation as compared to L2 ligand. The outcome of fluorescence study revealed static quenching mechanism on the basis of the quenching of HSA by the complexes (1-4). However, modifications in the secondary structure of HSA by complexes (1-4) inferred via CD measurements which revealed the enhancement of alpha-helicity (67.47% to 69.20%) with the preference order of 1>2>3>4. Furthermore, in-vitro antibacterial study against different bacteria and antioxidant activities against DPPH and superoxide radical (O2-) at variable concentrations outspread discernible bio-potencies of the metal complexes as compared to free ligand scaffolds due to the chelation effect. PMID- 27780119 TI - Comparison of sand-based water filters for point-of-use arsenic removal in China. AB - Contamination of groundwater wells by arsenic is a major problem in China. This study compared arsenic removal efficiency of five sand-based point-of-use filters with the aim of selecting the most effective filter for use in a village in Shanxi province, where the main groundwater source had arsenic concentration >200 MUg/L. A biosand filter, two arsenic biosand filters, a SONO-style filter and a version of the biosand filter with nails embedded in the sand were tested. The biosand filter with embedded nails was the most consistent and effective under the study conditions, likely due to increased contact time between water and nails and sustained corrosion. Effluent arsenic was below China's standard of 50 MUg/L for more than six months after construction. The removal rate averaged 92% and was never below 86%. In comparison, arsenic removal for the nail-free biosand filter was never higher than 53% and declined with time. The arsenic biosand filter, in which nails sit in a diffuser basin above the sand, performed better but effluent arsenic almost always exceeded the standard. This highlights the positive impact on arsenic removal of embedding nails within the top layer of biosand filter sand and the promise of this low-cost filtration method for rural areas affected by arsenic contamination. PMID- 27780120 TI - Mixtures of herbicides and metals affect the redox system of honey bees. AB - The increasing loss of bee colonies in many countries has prompted a surge of studies on the factors affecting bee health. In North America, main crops such as maize and soybean are cultivated with extensive use of pesticides that may affect non-target organisms such as bees. Also, biosolids, used as a soil amendment, represent additional sources of metals in agroecosystems; however, there is no information about how these metals could affect the bees. In previous studies we investigated the effects of environmentally relevant doses of herbicides and metals, each individually, on caged honey bees. The present study aimed at investigating the effects of mixtures of herbicides (glyphosate and atrazine) and metals (cadmium and iron), as these mixtures represent more realistic exposure conditions. Levels of metal, vitamin E, carotenoids, retinaldehyde, at-retinol, retinoic acid isomers (9-cis RA, 13-cis RA, at-RA) and the metabolites 13-cis-4 oxo-RA and at-4-oxo-RA were measured in bees fed for 10 days with contaminated syrup. Mixtures of herbicides and cadmium that did not affect bee viability, lowered bee alpha- and beta-carotenoid contents and increased 9-cis-RA as well as 13-cis-4-oxo-RA without modifying the levels of at-retinol. Bee treatment with either glyphosate, a combination of atrazine and cadmium, or mixtures of herbicides promoted lipid peroxidation. Iron was bioconcentrated in bees and led to high levels of lipid peroxidation. Metals also decreased zeaxanthin bee contents. These results show that mixtures of atrazine, glyphosate, cadmium and iron may affect different reactions occurring in the metabolic pathway of vitamin A in the honey bee. PMID- 27780121 TI - Psidium guajava L. leaves as source of proanthocyanidins: Optimization of the extraction method by RSM and study of the degree of polymerization by NP-HPLC-FLD ESI-MS. AB - Due to the importance of the proanthocyanidins (PAs) bioactivity and its relationship with the PAs degree of polymerization (DP), an experimental design was carried out to establish the best extraction conditions in order to evaluate the proanthocyanidins content and their degree of polymerization in Psidium guajava leaves at different oxidation state. Optimal conditions achieved by response surface methodology were 50% acetone/water (v/v), 48 degrees C, 30min, and 0% acetic acid (v/v). The highest DP has been found in the low oxidized state (DP 13 plus the polymers). Medium and high oxidized state leaves reported a DP 11 plus the polymers. The total amounts of proanthocyanidins (sum of PAs by HPLC-FLD ESI-MS) decreased when oxidation state of leaves increased (15.8+/-0.4, 12.6+/ 0.4, and 10.5+/-0.3mg/g leaf dry weight (d.w.) in low, medium and high oxidized state leaves, respectively). Guava leaves present an interesting source of low DP PAs. PMID- 27780122 TI - Analysis of injury severity of large truck crashes in work zones. AB - Work zones are critical parts of the transportation infrastructure renewal process consisting of rehabilitation of roadways, maintenance, and utility work. Given the specific nature of a work zone (complex arrangements of traffic control devices and signs, narrow lanes, duration) a number of crashes occur with varying severities involving different vehicle sizes. In this paper we attempt to investigate the causal factors contributing to injury severity of large truck crashes in work zones. Considering the discrete nature of injury severity categories, a number of comparable econometric models were developed including multinomial logit (MNL), nested logit (NL), ordered logit (ORL), and generalized ordered logit (GORL) models. The MNL and NL models belong to the class of unordered discrete choice models and do not recognize the intrinsic ordinal nature of the injury severity data. The ORL and GORL models, on the other hand, belong to the ordered response framework that was specifically developed for handling ordinal dependent variables. Past literature did not find conclusive evidence in support of either framework. This study compared these alternate modeling frameworks for analyzing injury severity of crashes involving large trucks in work zones. The model estimation was undertaken by compiling a database of crashes that (1) involved large trucks and (2) occurred in work zones in the past 10 years in Minnesota. Empirical findings indicate that the GORL model provided superior data fit as compared to all the other models. Also, elasticity analysis was undertaken to quantify the magnitude of impact of different factors on work zone safety and the results of this analysis suggest the factors that increase the risk propensity of sustaining severe crashes in a work zone include crashes in the daytime, no control of access, higher speed limits, and crashes occurring on rural principal arterials. PMID- 27780123 TI - Life-cycle exposure to BDE-47 results in thyroid endocrine disruption to adults and offsprings of zebrafish (Danio rerio). AB - 2,2,4',4'-Tetrabromodi-phenyl ether (BDE-47) is predominantly concentrated in humans and wildlife and disturbs thyroid hormone homeostasis. The purpose of this study was to characterize the thyroid endocrine disruption induced by life-cycle exposure to BDE-47 in adults and offspring of zebrafish (Danio rerio). We exposed zebrafish embryos at the blastula stage to different concentrations of BDE-47 (1, 5, and 10MUg/L). Exposure duration was 180days until fish reached adulthood. In F0 larvae, exposure decreased survival and increased malformations at 4 dpf. Thyroid hormone concentrations did not differ significantly between the F0 larvae and controls. All exposures significantly up-regulated expression of tshbeta, pa8, ugt1 and tg and down-regulated ttr. Significant up-regulation of dio2 and crh was observed in the 10MUg/L BDE-47 group. There was no significant difference in the growth and somatic index between F0 adults and controls. BDE-47 (10MUg/L) significantly decreased whole-body content of thyroxine (T4) but significantly increased triiodothyronine (T3) in both sexes. All exposures up-regulated expression of crh, tshbeta, pa8, ugt1 and tg and down-regulated ttr. Exposure to 10MUg/L BDE-47 significantly up-regulated dio2 and ugt1 in both sexes. BDE-47 exposure (5 and 10MUg/L) significantly increased the activity of pethoxy resorufin-O-deethylase and UDP-glucuronosyl transferase. BDE-47 (10MUg/L) significantly increased activity of ethoxy- and methoxy-resorufin-O-deethylase. In F1 offspring without continued BDE-47 (10MUg/L) treatment, T4 significantly decreased and T3 increased. T4 was further decreased and T3 was further increased with continued BDE-47 treatment. Continued BDE-47 exposure decreased hatching and increased malformation compared with those without BDE-47 exposure. Expression of crh, tshbeta, dio2, pa8, ugt1 and tg was significantly up-regulated without BDE 47 exposure and with continued exposure. With continued BDE-47 exposure, dio1 was significantly up-regulated and ttr was significantly down-regulated. All the genes showed clear differences between continued exposure to 10MUg/L BDE-47 and without BDE-47 exposure. These results suggest that parental exposure to BDE-47 results in thyroid endocrine disruption in adults and offspring. PMID- 27780125 TI - Thermohalochromism of phenolate dyes conjugated with nitro-substituted aryl groups. AB - The cationic halochromism and thermohalochromism of four phenolate dyes conjugated with aryl moieties substituted with one or two nitro groups were investigated in the presence of organic (tetra-n-butylammonium bromide and benzyltriethylammonium chloride) and inorganic (sodium perchlorate) salts, in hydrogen-bond donating (water, 1-propanol, 1-butanol and 2-propanol) and hydrogen bond accepting (acetonitrile and dimethylsulfoxide) solvents. Although a positive halochromic response was observed in water for tetraalkylammonium salts, their thermohalochromic behavior was negligible. A negative halochromic behavior was observed for the dyes in all solvents, when the added cation was Na+. Plots of Deltalambdamaxvs. c (Na+) allowed the apparent association constants for the solvated phenolate-cation pair to be estimated. In most cases, a positive thermohalochromism was observed in the range of 25-50 degrees C, exceptions being the more sterically hindered phenolate dyes in the less polar solvents 2-propanol and acetonitrile. The observed variations were rationalized by invoking the effect of temperature on the phenolate-cation, phenolate-solvent and cation solvent interactions. PMID- 27780124 TI - Unveiling the neurotoxicity of methylmercury in fish (Diplodus sargus) through a regional morphometric analysis of brain and swimming behavior assessment. AB - The current study aims to shed light on the neurotoxicity of MeHg in fish (white seabream - Diplodus sargus) by the combined assessment of: (i) MeHg toxicokinetics in the brain, (ii) brain morphometry (volume and number of neurons plus glial cells in specific brain regions) and (iii) fish swimming behavior (endpoints associated with the motor performance and the fear/anxiety-like status). Fish were surveyed for all the components after 7 (E7) and 14 (E14) days of dietary exposure to MeHg (8.7MUgg-1), as well as after a post-exposure period of 28days (PE28). MeHg was accumulated in the brain of D. sargus after a short time (E7) and reached a maximum at the end of the exposure period (E14), suggesting an efficient transport of this toxicant into fish brain. Divalent inorganic Hg was also detected in fish brain along the experiment (indicating demethylation reactions), although levels were 100-200 times lower than MeHg, which pinpoints the organic counterpart as the great liable for the recorded effects. In this regard, a decreased number of cells in medial pallium and optic tectum, as well as an increased hypothalamic volume, occurred at E7. Such morphometric alterations were followed by an impairment of fish motor condition as evidenced by a decrease in the total swimming time, while the fear/anxiety like status was not altered. Moreover, at E14 fish swam a greater distance, although no morphometric alterations were found in any of the brain areas, probably due to compensatory mechanisms. Additionally, although MeHg decreased almost two-fold in the brain during post-exposure, the levels were still high and led to a loss of cells in the optic tectum at PE28. This is an interesting result that highlights the optic tectum as particularly vulnerable to MeHg exposure in fish. Despite the morphometric alterations reported in the optic tectum at PE28, no significant changes were found in fish behavior. Globally, the effects of MeHg followed a multiphasic profile, where homeostatic mechanisms prevented circumstantially morphometric alterations in the brain and behavioral shifts. Although it has become clear the complexity of matching brain morphometric changes and behavioral shifts, motor-related alterations induced by MeHg seem to depend on a combination of disruptions in different brain regions. PMID- 27780126 TI - Analyzing Raman - Infrared spectral correlation in the recently found meteorite Csatalja. AB - Correlating the Raman and infrared spectra of shocked minerals in Csatalja ordinary chondrite (H4, S2, W2) with controlling the composition by EPMA measurements, we identified and improved various shock indicators, as infrared spectro-microscopic analysis has been poorly used for shock impact alteration studies of meteorites to date. We also provide reference spectra as SOM for the community with local mineralogical and shock alteration related context to support further standardization of the IR ATR based measurements. Raman band positions shifted in conjunction with the increase in full width half maximum (FWHM) with shock stage in olivine minerals while in the infrared spectra when comparing the IR band positions and IR maximal absorbance, increasing correlation was found as a function of increasing shock effects. This is the first observational confirmation with the ATR method of the already expected shock related disordering. In the case of shocked pyroxenes the well-known peak broadening and peak shift was confirmed by Raman method, beyond the level that could have been produced by only chemical changes. With increasing shock level the 852-864cm-1 and 1055-1071cm-1 FTIR bands finally disappeared. From the shock effect occasionally mixed mineral structures formed, especially feldspars together with pyroxene. Feldspars were only present in the shock melted volumes, thus produced by the shock effect itself. Based on the above mentioned observations in Csatalja meteorite the less shocked (only fractured) part witnessed 2-6GPa shock pressure with temperature below 100 degrees C. The moderately shocked parts (minerals with mosaicism and mechanical twins) witnessed 5-10GPa pressure and 900 degrees C temperature. The strongly shocked area (many olivine and pyroxene grains) was subject to 10-15GPa and 1000 degrees C. The existence of broad peak near 510cm-1 and disappearance of other peaks of feldspar at 480 and 570cm-1 indicate the presence of maskelynite, which proposes that the peak shock pressure could reach 20GPa at certain locations. We identified higher shock levels than earlier works in this meteorite and provided examples how heterogeneous the shock effect and level could be at small spatial scale. The provided reference spectra support the future improvement for the standardization of infrared ATR based methods and the understanding of shock-related mineral alterations beyond the optical appearance. PMID- 27780127 TI - Highly sensitive turn-on fluorescence detection of thrombomodulin based on fluorescence resonance energy transfer. AB - As an integral glycoprotein on the surface of endothelial cells, thrombomodulin (TM) has very high affinity for thrombin. TM has been regarded to be a marker of endothelial damage since it can be released during endothelial cell injury. In this work, a highly sensitive fluorescence method for the quantitative detection of TM was developed. TM antibody (Ab) and bovine serum albumin (BSA) were bound on gold nanoparticles (AuNPs) to construct BSA-AuNPs-Ab nanocomposites and they were characterized by transmission electron microscope and UV-vis spectrophotometry. The fluorescence of acridine orange (AO) was quenched by the prepared gold nanocomposites based on fluorescence resonance energy transfer (FRET). In the presence of TM, the fluorescence was turned on due to the effective separation of AO from the surface of gold nanocomposites. Under optimum conditions, the enhanced fluorescence intensity displayed a linear relationship with the logarithm of the TM concentration from 0.1pgmL-1 to 5ngmL-1 with a low detection limit of 12fgmL-1. The release of soluble thrombomodulin (sTM) by the injured HUVEC-C cells in the presence of H2O2 was investigated using the proposed method. The released sTM content in the growth medium was found to be increased with the enhancement of contact time of the cells with H2O2. PMID- 27780129 TI - Optical, phonon and efficient visible and infrared photocatalytic activity of Cu doped ZnS micro crystals. AB - We report, the enhanced photocatalytic behaviour of Cu doped ZnS micro crystals. ZnS and different concentrations of Cu doped ZnS microcrystals were prepared. X ray diffraction confirms the crystalline and phase of the particles. Morphology and sizes were studied using Scanning Electron Microscopy (SEM). Recorded optical absorption spectra show a band for around 365nm for pure ZnS, but there is a broad band in the near infrared regime for the Cu-doped ZnS microcrystals which are attributed to the d-d transitions of Cu2+ ions. Phonon properties of as prepared samples were investigated using Raman spectroscopy. Present work we investigate the potential of ZnS and Cu doped ZnS as a photocatalyst. For this from the degradation of methylene blue dye in aqueous media the photocatalytic activity of pure and highest doped ZnS samples with the irradiation of white light and infrared, enhanced photocatalytic activity were observed. Mechanism of white light an IR light based photocatalytic activity is explained based on the electron-hole pair production. PMID- 27780128 TI - The role of hydrogen bonding in the fluorescence quenching of 2,6-bis((E)-2 (benzoxazol-2-yl)vinyl)naphthalene (BBVN) in methanol. AB - The excited state hydrogen bonding dynamics of BBVN in hydrogen donating methanol solvent was explored at the TD-BMK/cc-pVDZ level of theory with accounting for the bulk environment effects at the polarizable continuum model (PCM). The heteroatoms of the BBVN laser dye form hydrogen bonds with four methanol molecules. In the formed BBVN-(MeOH)4 complex, the A-type hydrogen bond (N...HO), of an average strength of 25kJmol-1, is twofold stronger than the B-type (O...HO) one. Upon photon absorption, the total HB binding energy increases from 78.5kJmol 1 in the ground state to 82.6kJmol-1 in the first singlet (S1) excited state. In consequence of the hydrogen bonding interaction, the absorption band maximum of the BBVN-(MeOH)4 complex, which was anticipated at 398nm (exp. 397), is redshifted by 5nm relative to that of the free dye in methanol. The spectral shift of the stretching vibrational mode for the hydrogen bonded hydroxyl groups (with a maximum shift of 285cm-1) from that of the free methanol indicated the elevated strengthening of hydrogen bonds in the excited state. The vibrational modes associated with hydrogen bonding provide effective accepting modes for the dissipation of the excitation energy, thus, decreasing the fluorescence quantum yield of BBVN in alcohols as compared to that in the polar aprotic solvents. Since there is no sign of photochemistry or phosphorescence, it seems reasonable in view of the outcomes of this study to assign the major decay process of the excited singlet (S1) of BBVN in alcohols to vibronically induced internal conversion (IC) facilitated by hydrogen bonding. PMID- 27780130 TI - Investigation of gene expressions in differentiated cell derived bone marrow stem cells during bone morphogenetic protein-4 treatments with Fourier transform infrared spectroscopy. AB - A model was set up to predict the differentiation patterns based on the data extracted from FTIR spectroscopy. For this reason, bone marrow stem cells (BMSCs) were differentiated to primordial germ cells (PGCs). Changes in cellular macromolecules in the time of 0, 24, 48, 72, and 96h of differentiation, as different steps of the differentiation procedure were investigated by using FTIR spectroscopy. Also, the expression of pluripotency (Oct-4, Nanog and c-Myc) and specific genes (Mvh, Stella and Fragilis) were investigated by real-time PCR. However, the expression of genes in five steps of differentiation was predicted by FTIR spectroscopy. FTIR spectra showed changes in the template of band intensities at different differentiation steps. There are increasing changes in the stepwise differentiation procedure for the ratio area of CH2, which is symmetric to CH2 asymmetric stretching. An ensemble of expert methods, including regression tree (RT), boosting algorithm (BA), and generalized regression neural network (GRNN), was the best method to predict the gene expression by FTIR spectroscopy. In conclusion, the model was able to distinguish the pattern of different steps from cell differentiation by using some useful features extracted from FTIR spectra. PMID- 27780132 TI - The scorpion venom peptide BmKn2 induces apoptosis in cancerous but not in normal human oral cells. AB - AIM: This study aimed to investigate the mechanism of the induction of apoptosis of human oral cancer cells by the scorpion venom peptide BmKn2. METHODS: Human oral squamous carcinoma cells (HSC4), mouth epidermoid carcinoma cells (KB), human normal gingival cells (HGC) and dental pulp cells (DPC) were treated with BmKn-2 peptide for 24h. Cell viability was determined by the MTT assay. Apoptosis was assessed using phase contrast microscopy, by propidium iodide (PI) staining to assess nuclear morphology and by Annexin V staining. Apoptotic signaling pathways were investigated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. RESULTS: BmKn-2 showed potent cytotoxic effects towards both HSC4 and KB cells with the associated induction of apoptosis. The cells showed distinct morphological changes, nuclear disintegration and an increase in the number of Annexin V-positive cells. Interestingly, at concentrations which kill cancerous cells, BmKn-2 did not affect cell viability or mediate the induction of apoptosis in normal HGC or DPC. Induction of apoptosis by BmKn-2 in HSC4 and KB cells was associated with the activation of tumor suppress p53. Pro-apoptotic BAX expression was increased, whereas antiapoptotic BCL-2 expression was decreased in BmKn-2 exposed HSC4 and KB cells. BmKn-2 treated-oral cancer cells showed distinct upregulation of initiator caspase-9, with no effect on caspase-8 expression. Increased expression levels of executor caspases-3 and -7 were also found in treated cells for both oral cancers. CONCLUSION: This study has suggested for the first time that BmKn-2 exerts selective cytotoxic effects on human oral cancer cells by inducting apoptosis via a p53-dependent intrinsic apoptotic pathway. BmKn-2 peptide originally derived from a natural source shows great promise as a candidate treatment for oral cancer, with minimal effects on healthy tissue. PMID- 27780131 TI - Plant-derived cardiac glycosides: Role in heart ailments and cancer management. AB - Cardiac glycosides, the cardiotonic steroids such as digitalis have been in use as heart ailment remedy since ages. They manipulate the renin-angiotensin axis to improve cardiac output. However; their safety and efficacy have come under scrutiny in recent times, as poisoning and accidental mortalities have been observed. In order to better understand and exploit them as cardiac ionotropes, studies are being pursued using different cardiac glycosides such as digitoxin, digoxin, ouabain, oleandrin etc. Several cardiac glycosides as peruvoside have shown promise in cancer control, especially ovary cancer and leukemia. Functional variability of these glycosides has revealed that not all cardiac glycosides are alike. Apart from their specific affinity to sodium-potassium ATPase, their therapeutic dosage and behavior in poly-morbidity conditions needs to be considered. This review presents a concise account of the key findings in recent years with adequate elaboration of the mechanisms. This compilation is expected to contribute towards management of cardiac, cancer, even viral ailments. PMID- 27780133 TI - A systematic review of the protective role of swertiamarin in cardiac and metabolic diseases. AB - BACKGROUND: Swertiamarin, is a secoiridoid glycoside found in genera of Enicostemma Species (Enicostemma littorale and Enicostemma axillare) belonging to the family of gentianaceae, which has been reported to cure many diseases such as diabetes, hypertension, atherosclerosis, arthritis, malaria and abdominal ulcers. However, to the best of our knowledge, till date systematic studies to understand the molecular basis of cardiac and metabolic disease preventing properties of swertiamarin has not been reported. AIM OF THE REVIEW: The present review aims to compile an up-to-date information on the progress made in the protective role of swertiamarin in cardiac and metabolic diseases with the objective of providing a guide for future research on this bioactive molecule. MATERIALS AND METHODS: Information on the swertiamarin was collected from major scientific databases (Pubmed, Springer, google scholar, and Web of Science) for publication between1974-2016. In this review, the protective role of swertiamarin on cardiac and metabolic diseases was discussed. RESULTS: Swertiamarin reported to exhibit a wide range of biological activities such as anti-atherosclerotic, antidiabetic, anti-inflammatory and antioxidant effects. These activities were mainly due to its effect on various signaling pathways associated with cardiac remodeling events such as inhibition of NF-kB expression, LDL oxidation, apoptosis, inflammatory and lipid peroxidation markers and stimulation of antioxidant enzymes. CONCLUSION: Sweriamarin exhibit a wide range of biological activities. This review presents evidence supporting the point of view that swertiamarin should be considered a potential therapeutic agent against cardiac and metabolic diseases, giving rise to novel applications in their prevention and treatment. PMID- 27780134 TI - Inhibitory effects of norlignans isolated from Anemarrhena asphodeloides on degranulation of rat basophilic leukemia- 2H3Cells. AB - Anemarrhena asphodeloides is known to suppress inflammation and lower various fevers. To determine the active component of A. asphodeloides, ethanol (EtOH) extract of A. asphodeloides rhizomes was fractionized. The compounds isolated from the dichloromethane (CH2Cl2) soluble fraction were identified as 4'-O methylnyasol (1), nyasol (2), 3"-methoxynyasol (3), 3"-hydroxy-4"-methoxy-4" dehydroxynyasol (4), 4-hydroxybenzaldehyde (5), and 4-hydroxyacetophenone (6). The four norlignans (1-4) potently inhibited the release of beta-hexosaminidase from immunoglobulin E (IgE)/dinitrophenol-conjugated bovine serum albumin (DNP BSA)-treated rat basophilic leukemia (RBL)-2H3 and A23187 plus phorbol 12 myristate 13-acetate co-treated isolated rat primary mast cells, as markers of degranulation and histamine release. The intraperitoneal treatment with the EtOH extract significantly suppressed the fetal reaction, and serum histamine release induced by compound 48/80 in mice. These results suggest that the four active norlignan compounds and the EtOH extract of A. asphodeloides may have potential to be developed as medicines for the treatment of allergies by inhibiting the activation of mast cells. PMID- 27780135 TI - Structural characterization of a novel derivative of myricetin from Mimosa pudica as an anti-proliferative agent for the treatment of cancer. AB - The study was initiated to determine the anticancer activity of a novel compound isolated from the plant Mimosa pudica. The structure of the compound was identified as a derivative of myricetin having alkyl, hydroxy alkyl and methyl substitutions on the basis of spectral evidences (UV-vis, FT-IR, 1H NMR and Mass spectra). The isolated compound was interpreted as 2-(2',6'-dimethyl-3',4',5' alkyl or hydroxy alkyl substituted phenyl)-3-oxy-(alkyl or hydoxy alkyl)- 5,7 dihydroxy-chromen-4-one. In vitro evaluation of anticancer activity against human lung adenocarcinoma cell line (A549) and human erythroleukemic cell line (K562) were conducted using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In vivo anticancer activity was determined against Dalton's Ascites Lymphoma (DAL) in Swiss albino mice. The mice were treated with intraperitoneal administration of the compound at 25mg/kg and 100mg/kg body weight and were compared with the normal, DAL control and standard drug cyclophosphamide treated groups. The histology revealed that the compound could protect the cellular architecture of liver and kidney. The results from the in vitro, in vivo and histological examinations confirmed the ethnopharmacological significance of the isolated compound and could be considered further for the development of an effective drug against cancer. PMID- 27780136 TI - Pro-survival effects by NF-kappaB, Akt and ERK(1/2) and anti-apoptosis actions by Six1 disrupt apoptotic functions of TRAIL-Dr4/5 pathway in ovarian cancer. AB - Apoptotic signaling provoked by death receptors, DR4 and DR5, are generally considered to promote cell death and chemosensitivity in multiple cancers, but this view is being thrown into doubt with recent findings that up-regulated DR4 and DR5 in advanced stages of ovarian cancer are associated with the poor prognosis. For this conflict, two reasonable explanations have been proposed: one is that DR4 and DR5 not exclusively mediate apoptotic pathway, but also favor survival signal; another is that apoptotic signals by DR4 and DR5 are disrupted by some regulators. This study identified these two speculations in TRAIL resistant (SKOV-3ip1 and A2780) or sensitive (OVCAR-3) ovarian cancer cells. Activation of DR4 and DR5 using their specific ligand, TRAIL, activated pro survival factors including NF-kappaB, Akt and ERK(1/2) in ovarian cancer SKOV 3ip1 and A2780 cells. Pharmacological inhibition of their activities potentiated TRAIL cytotoxicity, reducing cell viability and increasing apoptosis. Six1, a homeobox transcription factor, had higher expression in SKOV-3ip1 and A2780 cells than in OVCAR-3 cells. Silencing Six1 raised levels of apoptotic factors including cleaved Bid, caspase-8 and caspase-3, and overrode the TRAIL resistance. Co-treatment with Six1 knockdown and peptidyl O-glycosyltransferase 14 overexpression showed additive effects on apoptosis signal, leading to increased apoptosis in SKOV-3ip1 and A2780 cells. This study demonstrated that pro-survival effects by NF-kappaB, Akt and ERK(1/2) and anti-apoptosis actions by Six1 disrupt apoptotic functions of TRAIL-Dr4/5 pathway in ovarian cancer, which may explain why up-regulated DR4 and DR5 in ovarian cancer are associated with poor prognosis and low survival ratio of the patients. PMID- 27780137 TI - Anti-oxidant, anti-inflammatory, analgesic and antipyretic activities of grapevine leaf extract (Vitis vinifera) in mice and identification of its active constituents by LC-MS/MS analyses. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Vitis vinifera is used in traditional medicine for diarrhea, hepatitis and stomachaches. The objective of this study was to investigate the anti-oxidant, anti-inflammatory, analgesic and antipyretic properties of the hydroalcoholic leaf extract of Vitis vinifera (EVV) on experimental models to provide scientific basis for its use. MATERIALS AND METHODS: The EVV was chemically characterized by LC-MS/MS analyses. The in vitro antioxidant activities of the EVV extract were measured using 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging assay and Ferric reducing antioxidant power assay (FRAP). Analgesic activity using acetic acid induced writhing and formalin test in mice, anti-inflammatory activity using carrageenan induced paw oedema and acetic acid-induced vascular permeability in mice, and antipyretic activity using Brewer's yeast induced pyrexia in rats were evaluated at 100mg/kg, 200mg/kg, and 400mg/kg doses of the extract. RESULTS: The extract (EVV) was found to contain resveratrol, quercetin, catechin, flavone, flavonols, anthocyanin, gallic acid and epicatechin. EVV produced significant dose-response anti inflammatory activity against carrageenan-induced paw edema. EVV at dosages of 100, 200 and 400mg/kgbw significantly reduced carrageenan-induced paw edema by 34.48% (P<0.05), 36.20% (P<0.05), and 41.37% (P<0.05) at 5h after carrageenan injection, respectively. Also EVV extract reduces significantly acetic acid induced vascular permeability in mice dose dependently. EVV (100, 200 and 400mg/kgbw) produced significant dose-response analgesic activity in the formalin test. However, the low percentage inhibition (50%) suggests that it is not a centrally acting analgesic. Extract at dosages of 100, 200 and 400mg/kg bw, p.o. significantly reduced acetic acid-induced writhing by 48.15% (p<0.05), 57.97% (p<0.05), and 68.09% (p<0.05), respectively. The extract also caused marked dose dependent inhibition of formalin-induced pain in the second phase (p<0.05). Statistical significant reduction in rectal temperatures was observed in standard group at 21 and 23h, and in 200mg/kg and 400mg/kg doses of the extract at 23h (p<0.05) compared with the 19h. CONCLUSIONS: The results obtained indicated potential analgesic, anti-inflammatory and antipyretic effects of them hydroalcoholic leaf extract of V. vinifera observed at doses tested which support the claim for the traditional use of the plant in the treatment of various inflammatory and pain diseases. PMID- 27780138 TI - Malva sylvestris extract protects upon lithium carbonate-induced kidney damages in male rat. AB - Malva sylvestris has recently attracted special attention due to its potential activities in many chronic disorders. We aimed to assess the beneficial effects of Malva sylvestris extract against lithium carbonate induced renal damage in male Wistar rats. For this purpose, Malva sylvestris extract at a dose of 0.2g/kg was orally administrated, followed by 25mg/kg of lithium carbonate (intraperitoneal injection) for 30 days. Malva sylvestris extract was proved to contain large amounts of K+, Na+, Ca++ and the existence of phenolic acids and flavonoids shown by the obtained HPLC-based analysis. The antioxidant capacities in vitro showed high level of radical scavenging activity and reducing power. The in vivo results showed that intraperitoneal injection of lithium carbonate exhibited a significant increase (p<0.01) of serum creatinine and urea and reduced serum sodium and potassium concentrations. Lithium carbonate also induced oxidative damage as indicated by a significant raise in LPO level associated with a decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in the kidney. However, pretreatment with Malva sylvestris extract restored the status of all parameters studied. It can be concluded that lithium carbonate has induced oxidative stress, biochemical changes and histopathological damage but the supplementation with Malva sylvestris extract has prevented such toxicity. PMID- 27780139 TI - Platycodin D inhibits interleukin-13-induced the expression of inflammatory cytokines and mucus in nasal epithelial cells. AB - Allergic rhinitis (AR) is a common chronic inflammatory condition of the nasal mucosal tissue. Platycodin D (PLD), a triterpenoid saponin isolated from the root of Platycodon grandiflorum, has anti-inflammatory effects in a mouse model of allergic asthma. However, the anti-inflammatory effects of PLD in the nasal mucosa have not been deeply investigated. The objective was to investigate the effect of PLD on inflammatory cytokines and mucus production from nasal epithelial cells. Our study showed that PLD inhibited the levels of granulocyte macrophage colony-stimulating factor (GM-CSF) and eotaxin in interleukin (IL)-13 stimulated RPMI2650 cells. PLD also suppressed IL-13-induced mucin 5AC (MUC5AC) expression in RPMI2650 cells. Moreover, PLD treatment prevented IL-13-induced p NF-kappaB p65 expression in RPMI2650 cells, as well as MAPK signaling pathway activation. Taken together, our results provided evidence that PLD inhibits IL-13 induced the expression of inflammatory cytokines and mucus in nasal epithelial cells by inhibiting the activation of NF-kappaB and MAPK signaling pathways. PMID- 27780140 TI - MicroRNA-24 increases hepatocellular carcinoma cell metastasis and invasion by targeting p53: miR-24 targeted p53. AB - MicroRNA-24 (miR-24), a member of the miRNA family, functions as an oncogene in various types of human cancer. However, the underlying mechanisms of miR-24 involvement in the development and progression of hepatocellular carcinoma (HCC) remain poorly understood. The present study revealed that miRNA-24 down-regulates p53 through binding to the 3'-UTR of p53 mRNA based on a luciferase reporter assay, and that the expression level of miR-24 could affect the invasion of HCC lines via p53. Down-regulation of p53 significantly attenuated the inhibitory effects of miR-24 knockdown on the invasion of HCC cells, suggesting that miR-24 could be a potential target for HCC treatment. Moreover, our results revealed that miR-24 expression was significantly increased in HCC metastatic tumor tissues compared with matched non-metastatic tumor tissues, and that the up regulation of miR-24 was significantly associated with down-regulation of p53 in the HCC tissues. In conclusion, this study demonstrates that miR-24 functions as an oncogene in HCC, at least partly by promoting cell invasion through down regulation of p53. Therefore, miR-24 may be a potential therapeutic target for treatment of HCC. PMID- 27780141 TI - Rapid permissive action of dexamethasone on the regulation of blood pressure in a rat model of septic shock. AB - Glucocorticoids (GCs) play a vital role in the regulation of blood pressure by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. GCs achieve this function by controlling vascular smooth muscle tone. Clinically, low to moderate doses of GCs are generally used in the treatment of septic shock in recent years. GCs are now known to have both genomic and non-genomic effects. While genomic effects of GCs were well studied, few non-genomic effects were reported, much less the non genomic mechanisms. One of the most important characters of their non-genomic effects is short latency. The aim of this study was to determine whether GCs can rapidly regulate blood pressure by their permissive action on norepinephrine (NE). Adrenalectomized rats were subjected to cecal ligation and puncture to induce septic shock. The septic rats displayed a significant decrease in the blood pressure response to NE. Dexamethasone (DEX) rapidly restores this hyporeactivity to NE in adrenalectomized septic rats. Further studies showed that DEX potentiates the NE-induced shrinkage and actin cytoskeleton rearrangement of single cell from mesenteric arteries in a short time. These findings suggest that GCs probably exert their permissive actions on the pressure response to NE through rapid non-genomic mechanisms. In this article, we found that as an adjunctive therapy for septic shock, the use of GCs may involve a rapid permissive action, and non-genomic effects of GCs may be involved in these processes. PMID- 27780142 TI - Sevoflurane protects against hepatic ischemia/reperfusion injury by modulating microRNA-200c regulation in mice. AB - This present study was aimed to investigate the molecular mechanisms involved in sevoflurane protection of hepatic ischemia-reperfusion (I/R) injury. Firstly, we investigated the protective effects of sevoflurane against hepatic I/R injury. Biochemical analysis results showed that sevoflurane preconditioning significantly protected against hepatic I/R injury by reducing liver enzymes and improving antioxidant defense markers. We also found that sevoflurane attenuates I/R-induced hepatic cell death, by TUNEL staining, DNA fragmentation ELISA and PARP activity determination. Next, In order to find the molecular mechanism of sevoflurane preconditioning in hepatic I/R injury, we poured our attention to microRNAs regulation. We focused on miR-200c, one of microRNAs which screened from the gene expression omnibus (GEO). Furthermore, a hydrogen peroxide (H2O2) induced oxidative stress apoptosis model was also established to mimic hepatic I/R injury, the effects of MiR-200c was investigated. We observed that MiR-200c inhibition decreased the H2O2-induced apoptosis of hepatic AML-12 cells. And also, ZEB1 is found as a target gene of miR-200c and is involved in H2O2-induced apoptosis. On the other hand, the in vivo model was established to examine whether sevoflurane protect against hepatic IR injury by downregulating MiR-200c. Together with the biochemical tests and apoptosis detection, results showed that over-expression of miR-200c significantly inhibited the protect effect of sevoflurane in Hepatic IR injury. Summarizing, sevoflurane preconditioning seems to ameliorate hepatic I/R injury in mice, mediated by mechanisms that include microRNA 200c down regulation. However, further more studies need to be carried out to verify this point. PMID- 27780143 TI - Antibiotic drug levofloxacin inhibits proliferation and induces apoptosis of lung cancer cells through inducing mitochondrial dysfunction and oxidative damage. AB - Lung cancer is the leading cause of cancer death worldwide and its clinical management remains challenge. Here, we repurposed antibiotic levofloxacin for lung cancer treatment. We show that levofloxacin is effectively against a panel of lung cancer cell lines via inhibiting proliferation and inducing apoptosis, regardless of cellular origin and genetic pattern, in in vitro cell culture system and in vivo xenograft lung tumor model. Mechanistically, levofloxacin inhibits activities of mitochondrial electron transport chain complex I and III, leading to inhibition of mitochondrial respiration and reduction of ATP production. In addition, levofloxacin significantly increases levels of ROS, mitochondrial superoxide and hydrogen peroxide in vitro and oxidative stress markers (HEL and 4-HNE) in vivo. Antioxidants, such as NAC and vitamin C, prevent the inhibitory effects of levofloxacin, confirming the induction of oxidative damage as the mechanism of its action in lung cancer cells. Our work demonstrates that levofloxacin is a useful addition to the treatment of lung cancer. Our work also suggests that targeting mitochondria may be an alternative therapeutic strategy for lung cancer treatment. PMID- 27780144 TI - Fructose-1,6-bisphosphatase is a novel regulator of Wnt/beta-Catenin pathway in breast cancer. AB - Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is a tumor suppressor that frequently down-regulated in cancers, especially breast cancer. Here, we provide both supporting and contradicting evidences about the expression pattern and function of FBP1 in breast cancer. Data mining of Oncomine database showed that FBP1 is commonly up-regulated in tumor tissues compared with non-tumor tissues regardless of histological type. Analysis of a large-scale cohort derived from Kaplan-Meier Plotter showed that lower FBP1 expression associated with poor clinical outcome. Genetic silencing of FBP1 reduced aerobic glycolysis and the malignant potential of breast cancer cells. Gene set enrichment analysis (GSEA) of the expression profiles of breast cancer cells (n=59) revealed that cells exhibiting high expression of FBP1 had a lower activity of Wnt/beta-Catenin pathway. FBP1 down-regulation enhanced the activity of Wnt/beta-Catenin pathway and increased the level of its downstream targets, including c-Myc and MMP7. Collectively, our findings indicate that elevated FBP1 is a critical modulator in breast cancer progression by altering glucose metabolism and the activity of Wnt/beta-Catenin pathway. PMID- 27780145 TI - Circadian variation of isoniazid pharmacokinetics in mice. AB - INTRODUCTION: This study is designed to investigate whether the pharmacokinetics of the antituberculous agent isoniazid (INH) varied according to the circadian dosing-time. METHODS: A total of 168 male mice aged 10 weeks and synchronized for 3 weeks to 12h light and 12h dark were used. A single INH (100mg/kg) dose was administered by intraperitonal (i.p.) route at either of the four different circadian stages (1, 7, 13 and 19h after light onset, HALO). At each circadian stage, blood samples were withdrawn at 0, 0.1, 0.2, 0.4, 1, 1.3, 2, 2.5, 4, 5, 6.3, 8, 24 and 48h following drug injection. The pharmacokinetics parameters (AUC0-infinity, Ke, Cmax, T 1/2, ClT and Vd) were calculated for each circadian time. RESULTS: There were relevant differences in Cmax between the four circadian groups (p<0.005), maximum and minimum Cmax were obtained when INH was injected at 1 HALO (490mgL-1) and at 7 HALO (270mgL-1) respectively. AUC0-infinity also varied significantly according to the circadian-time of injection (2093mgL-1h-1 at 1 HALO vs 759mgL-1h-1 at 7 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (Cl) were observed at 7 HALO (0.22Lh-1kg-1) and 1 HALO (0.13Lh-1kg-1) respectively (p<0.05). The Cosinor analysis showed a circadian rhythm in different pharmacokinetic parameters. Cmax and AUC0-infinity have a significant circadian rhythm with an acrophase located at 2.64 HALO+/-0.21h (the beginning of the rest span) (p<0.001), whereas ClT and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.4 HALO and at 8.66 HALO (the second half of the rest span) (p<0.001). CONCLUSION: Plasma INH chronopharmacokinetics might be involved in the mechanism of circadian variation of toxicity since the time of optimal tolerance to INH corresponds to that of the lowest Cmax and AUC0-infinity and the highest ClT occured when this drug injected in the second half of light-rest phase (7 HALO). PMID- 27780146 TI - Evaluation of potent phytomedicine for treatment of psoriasis using UV radiation induced psoriasis in rats. AB - The aim of present study was to determine the effect of newly formulated gels and suspensions of extractive Phytoconstituents of Woodfordia fructicosa flowers and Gardenia gummifera leaves by using UV Radiation induced psoriasis in rats. Both plants are traditionally claimed to be useful in treatment of number of skin diseases. However, there are no established scientific reports for their potential in psoriasis. Formulated Gels and Suspensions of ethanolic extract of both plants were tested for acute dermal and oral toxicity study respectively. The results of acute dermal toxicity at concentration 1% w/w and oral toxicity at dose 1000mg/kg showed that the gels and suspensions were safe. Psoriasis was induced in Wistar rats by espousing 10% area of total body by UV radiations. Anti psoriatic activity was performed by applying 0.1% gel and orally at a dose 100mg/kg body weight in rats. Severity Index, histological study and biochemical estimation were analyzed. The results of our studies showed that the test formulations (Gels and Suspensions) of both plant extracts exhibited potential effect in anti-psoriatic activity. PMID- 27780147 TI - Stem cell therapies for congenital heart disease. AB - Congenital heart disease (CHD) is the most prevalent congenital anomaly in newborn babies. Cardiac malformations have been induced in different animal model experiments, by perturbing some molecules that take part in the developmental pathways associated with myocyte differentiation, specification, or cardiac morphogenesis. The exact epigenetic, environmental, or genetic, basis for these molecules perturbations is yet to be understood. But, scientist have bridged this gap by introducing autologous stem cell into the defective hearts to treat CHD. The choice of stem cells to use has also raised an issue. In this review, we explore different stem cells that have been recently used, as an update into the pool of this knowledge and we suggested the future perspective into the choice of stem cells to control this disease. We propose that isolating mesenchymal stem cells from neonate will give a robust heart regeneration as compared to adults. This source are easily isolated. To unveil stem cell therapy beyond its possibility and safety, further study is required, including largescale randomized, and clinical trials to certify the efficacy of stem cell therapy. PMID- 27780148 TI - Melatonin can attenuate ciprofloxacin induced nephrotoxicity: Involvement of nitric oxide and TNF-alpha. AB - BACKGROUND: Ciprofloxacin is a synthetic broad-spectrum antimicrobial agent of fluoroquinolone family. The aim of our investigation was to evaluate the role of oxidative damage and inflammation in nephrotoxic potential of Ciprofloxacin and protective effects of melatonin against its nephrotoxicity in male Wistar rats. METHODS: The animals were divided into six groups: Control, ciprofloxacin (100mg/kg/day, i.p), ciprofloxacin with three doses (2.5, 5 and 10mg/kg/day) of melatonin and a group which received ciprofloxacin (100mg/kg/day) plus vitamin E (100mg/kg/day) for 8 consecutive days. 24h after last injection, the animals were euthanized and kidney tissues were separated. Finally reactive oxygen species, glutathione content, lipid peroxidation, protein carbonyl, nitric oxide and TNF alpha were evaluated. Also, pathological examination and measuring of kidney biochemical markers (BUN and Cr) were done. RESULTS: The administration of ciprofloxacin for 8days resulted in significant increase (P<0.01) in kidney biomarkers (BUN and Cr) and pathological changes. Also, Oxidative stress was evident in ciprofloxacin group by significantly (p<0.001) increased reactive oxygen species, lipid peroxidation and protein carbonyl level and decreased glutathione content (p<0.001). Increased in inflammation process was shown by increase in NO and TNF-alpha (P<0.001). Administration of melatonin was able to protect against deterioration in nephrotoxic markers and suppressed the increase in oxidative stress and inflammatory markers. CONCLUSION: Our study showed the critical role of oxidative damage and inflammation in ciprofloxacin-induced nephrotoxicity that markedly inhibited by administration of melatonin. So, melatonin can be suggested for prevention of ciprofloxacin-induced nephrotoxicity. PMID- 27780149 TI - Nanofibrous bioengineered heart valve-Application in paediatric medicine. AB - Heart valves are currently under thorough investigation in tissue engineering (TE) research. Mechanical and biological heart valve prostheses which are recently used have several shortcomings. While allogenic and xenogenic biological prostheses are related to graft rejection, degeneration and thrombosis, resulting in a high rate of reoperation. Mechanical prostheses on the other hand are based on metallic, carbon, and polymeric components, and require continuous treatment with anticoagulant, which result in adverse reactions, e.g. endocarditis and thromboembolic complications. Therefore, there has been efforts to synthesize bioartificial heart valve using bioengineering. The resulting product must be durable with appropriate mechanical properties, biocompatible, and have the ability to grow. Diseased heart valves replacement by surgery is now common, this enhances quality of life and survival for many patients. The center of attraction of recent methods in regenerative medicine are based on the restoration of pathologically altered tissue architectures by cells transplantation in combination with supportive scaffolds, and growth factors. We propose that nanofiber scaffold for paediatric Tissue Engineered Heart Valve (TEHV) will meet most of these requirements, particularly those related to somatic growth, in addition, as the nanofiber scaffold is eroded and new valve is formed, the valve develops in the child until adulthood. PMID- 27780150 TI - Design of a Fingertip-Mounted Tactile Display with Tangential Skin Displacement Feedback. AB - Application of tangential skin displacement at the fingertip has been shown to be effective in communicating direction and has potential for several applications. We have developed a portable, fingertip-mounted tactile display capable of displacing and stretching the skin of the fingerpad, using a 7 mm hemispherical tactor. In vivo tests of fingerpad skin stiffness were performed to determine the forces required to effectively render stimuli. Other design parameters such as stimulus speed and displacement were derived from our earlier work. The tactile display is capable of rendering ?pm 1 mm of displacement at arbitrary orientations within a plane and with rates of approximately 5 mm/s. Compliance and backlash in the device's drive train were characterized using external measurements, and were compensated for in software to reduce the impact on device hysteresis. PMID- 27780151 TI - A Regression and Boundary-Crossing-Based Model for the Perception of Delayed Stiffness. AB - The stiffness of the environment with which we come in contact is the local derivative of a force field. The boundary of an elastic field is a singular region where local stiffness is ill-defined. We found that subjects interacting with delayed force fields tend to underestimate stiffness if they do not move across the boundary. In contrast, they tend to overestimate stiffness when they move across the elastic field boundary. We propose a unifying computational model of stiffness perception based on an active process that combines the concurrent operations of a force and of a position-control system. PMID- 27780152 TI - Six-DoF Haptic Rendering of Contact Between Geometrically Complex Reduced Deformable Models. AB - Real-time evaluation of distributed contact forces between rigid or deformable 3D objects is a key ingredient of 6-DoF force-feedback rendering. Unfortunately, at very high temporal rates, there is often insufficient time to resolve contact between geometrically complex objects. We propose a spatially and temporally adaptive approach to approximate distributed contact forces under hard real-time constraints. Our method is CPU based, and supports contact between rigid or reduced deformable models with complex geometry. We propose a contact model that uses a point-based representation for one object, and a signed-distance field for the other. This model is related to the voxmap pointshell method (VPS), but gives continuous contact forces and torques, enabling stable rendering of stiff penalty based distributed contacts. We demonstrate that stable haptic interactions can be achieved by point-sampling offset surfaces to input "polygon soup'' geometry using particle repulsion. We introduce a multi-resolution nested pointshell construction which permits level-of-detail contact force computation, and enables contact graceful degradation in close-proximity scenarios. Parametrically deformed distance fields are proposed to support contact between reduced deformable objects. We present several examples of 6-DoF haptic rendering of geometrically complex rigid and deformable objects in distributed contact at real time kilohertz rates. PMID- 27780153 TI - Corrections to the "2009 Reviewers List'. AB - Several names in the "2009 Reviewers List" published in the January-March 2010 issue of Transactions on Haptics were incomplete or incorrect. A list of corrected names is presented here. PMID- 27780154 TI - Maternal and neonatal outcomes following expectant management of preterm prelabour rupture of membranes before viability. AB - AIM: To assess the contemporary maternal and neonatal outcomes following expectant management of preterm premature rupture of membranes (PPROM) prior to 24 weeks' gestation and to identify prognostic indicators of this morbid presentation. METHODS: We performed a systematic review in the Pubmed and EMBASE databases to identify the primary (perinatal mortality, severe neonatal morbidity and serious maternal morbidity) and secondary (neonatal survival and morbidity) outcomes following expectant management of previable PPROM. RESULTS: Mean latency between PPROM and delivery ranged between 20 and 43 days. Women with PPROM <24 weeks had an overall live birth rate of 63.6% and a survival-to-discharge rate of 44.9%. The common neonatal morbidities were respiratory distress syndrome, bronchopulmonary dysplasia and sepsis. The majority of neonatal deaths within 24 h post birth were associated with pulmonary hypoplasia, severe intraventricular haemorrhage and neonatal sepsis. The common maternal outcomes were chorioamnionitis and caesarean sections. The major predictors of neonatal survival were later gestational age at PPROM, adequate residual amniotic fluid levels, C-reactive protein <1 mg/dL within 24 h of admission and PPROM after invasive procedures. CONCLUSION: Pregnancy latency and neonatal survival following previable PPROM has improved in recent years, although neonatal morbidity remains unchanged despite recent advances in obstetric and neonatal care. There is heterogeneity in management practices across centres worldwide. PMID- 27780155 TI - The importance of clinically and ethically fine-tuning decision-making about cesarean delivery. AB - In obstetric practice, each pregnant woman presents with a composite of maternal and fetal characteristics that can alter the risk of significant harm without cesarean intervention. The hospital's availability of resources and the obstetrician's training, experience, and skill level can also alter the risk of significant harm without cesarean intervention. This paper proposes a clinical ethical framework that takes these clinical and organizational factors into account, to promote a deliberative rather than simplistic approach to decision making and counseling about cesarean delivery. The result is a clinical ethical framework that should guide the obstetrician in fine-tuning his or her evidence based, beneficence-based analysis of specific clinical and organizational factors that can affect the strength of the beneficence-based clinical judgment about cesarean delivery. We illustrate the clinical application of this framework for three common obstetric conditions: Category II fetal heart rate tracing, prior non-classical cesarean delivery, and breech presentation. PMID- 27780156 TI - Ground effect on the aerodynamics of three-dimensional hovering wings. AB - This paper reports the results of combined experimental and numerical studies on the ground effect on a pair of three-dimensional (3D) hovering wings. Parameters investigated include hovering kinematics, wing shapes, and Reynolds numbers (Re). The results are consistent with the observation by another study (Gao and Lu, 2008 Phys. Fluids, 20 087101) which shows that the cycle-averaged aerodynamic forces generated by two-dimensional (2D) wings in close proximity to the ground can be broadly categorized into three regimes with respect to the ground clearance; force enhancement, force reduction, and force recovery. However, the ground effect on a 3D wing is not as significant as that on a 2D flapping wing reported in (Lu et al 2014 Exp. Fluids, 55 1787); this could be attributed to a weaker wake capture effect on 3D wings. Also, unlike a 2D wing, the leading edge vortex (LEV) remains attached on a 3D wing regardless of ground clearance. For all the wing kinematics considered, the three above-mentioned regimes are closely correlated to a non-monotonic trend in the strength of downwash due to the restriction of root and tip vortex formation, and a positional shift of wake vortices. The root vortices in interaction with the ground induce an up-wash in between the two wings, causing a strong 'fountain effect' (Maeda and Liu, 2013 J. Biomech. Sci. Eng., 8 344) that may increase the body lift of insects. The present study further shows that changes in wing planform have insignificant influence on the overall trend of ground effect except for a parallel shift in force magnitude, which is caused mainly by the difference in aspect ratio and leading edge pivot point. On the two Reynolds numbers investigated, the results for the low Re case of 100 do not deviate significantly from those of a higher Re = 5000 except for the difference in force magnitudes, since low Reynolds number generates lower downwash, weaker LEV, and lower rotational circulation. Additionally, lower Re leads to a weaker fountain effect. PMID- 27780157 TI - The geometric effects of a woodpecker's hyoid apparatus for stress wave mitigation. AB - In this study a woodpecker's hyoid apparatus was characterized to determine its impact mitigation mechanism using finite element (FE) analysis. The woodpecker's hyoid apparatus, comprising bone and muscle, has a unique geometry compared to those of other birds. The hyoid starts at the beak tip, surrounds the woodpecker's skull, and ends at the upper beak/front head intersection while being surrounded by muscle along the whole length. A FE model of the hyoid apparatus was created based on the geometry, microstructure, and mechanical properties garnered from our experimental measurements. We compared the impact mitigation capabilities of the hyoid apparatus with an idealized straight cylinder and a tapered cylinder. The results showed that the hyoid geometry mitigated a greater amount of pressure and impulse compared to the straight or tapered cylinders. The initially applied longitudinal wave lost its strength from attenuation and conversion to transverse shear waves. This is due to the spiral curvature and tapered geometry, which induced lateral displacement in the hyoid bone. The lateral displacement of the bony hyoid induced strains on the adjacent muscle, where the energy dissipated due to the muscle's viscoelasticity. Quantitatively, as the stress wave traveled from the anterior to the posterior end of the hyoid apparatus, its pressure decreased 75% and the associated impulse decreased 84%. The analysis of the woodpecker's hyoid apparatus provides a novel perspective on impact mitigation mediated by a spiral-shaped structure and viscoelastic biocomposite. PMID- 27780158 TI - Photonics and optoelectronics of two-dimensional materials beyond graphene. AB - Apart from conventional materials, the study of two-dimensional (2D) materials has emerged as a significant field of study for a variety of applications. Graphene-like 2D materials are important elements of potential optoelectronics applications due to their exceptional electronic and optical properties. The processing of these materials towards the realization of devices has been one of the main motivations for the recent development of photonics and optoelectronics. The recent progress in photonic devices based on graphene-like 2D materials, especially topological insulators (TIs) and transition metal dichalcogenides (TMDs) with the methodology level discussions from the viewpoint of state-of-the art designs in device geometry and materials are detailed in this review. We have started the article with an overview of the electronic properties and continued by highlighting their linear and nonlinear optical properties. The production of TIs and TMDs by different methods is detailed. The following main applications focused towards device fabrication are elaborated: (1) photodetectors, (2) photovoltaic devices, (3) light-emitting devices, (4) flexible devices and (5) laser applications. The possibility of employing these 2D materials in different fields is also suggested based on their properties in the prospective part. This review will not only greatly complement the detailed knowledge of the device physics of these materials, but also provide contemporary perception for the researchers who wish to consider these materials for various applications by following the path of graphene. PMID- 27780159 TI - Deep data mining in a real space: separation of intertwined electronic responses in a lightly doped BaFe2As2. AB - Electronic interactions present in material compositions close to the superconducting dome play a key role in the manifestation of high-T c superconductivity. In many correlated electron systems, however, the parent or underdoped states exhibit strongly inhomogeneous electronic landscape at the nanoscale that may be associated with competing, coexisting, or intertwined chemical disorder, strain, magnetic, and structural order parameters. Here we demonstrate an approach based on a combination of scanning tunneling microscopy/spectroscopy and advanced statistical learning for an automatic separation and extraction of statistically significant electronic behaviors in the spin density wave regime of a lightly (~1%) gold-doped BaFe2As2. We show that the decomposed STS spectral features have a direct relevance to fundamental physical properties of the system, such as SDW-induced gap, pseudogap-like state, and impurity resonance states. PMID- 27780160 TI - Semicircular Canal Size and Locomotion in Colobine Monkeys: A Cautionary Tale. AB - The semicircular canals of the inner ear constitute the organ of balance, tracking head rotation during movement and facilitating stabilisation of vision. Morphological characteristics of the canals are correlated with agility scores related to locomotion. To date, however, the relationship between canal morphology and specific locomotor behaviours, such as leaping, is unclear. Knowledge of such a relationship could strengthen the inferences of locomotion of extinct taxa. To test this, crania of two sets of closely related primate species (Presbytis melalophos and P. potenziani; Colobus guereza and C. polykomos) that differ in the percentage of leaping in their locomotor repertoire were examined using microscopic computed tomography. Three-dimensional virtual models of the bony labyrinth were derived, and the radius of curvature of each of the three canals was evaluated relative to cranial size. The findings are contradictory; one leaping form (P. melalophos) differs from its congener in possessing significantly larger lateral canals, a pattern seen in previous studies of primates, while the other leaper (C. guereza) has significantly smaller posterior canals than its close relative. These results undermine efforts to determine specific locomotor behaviours from the bony labyrinth of extinct primates. PMID- 27780162 TI - [Entscheidungsfindung fur die klinische Praxis: Aktuelle Konzepte und Behandlungsalgorithmen mit Immun-Checkpoint-Inhibitoren beim Melanom]. PMID- 27780161 TI - [Immunonkologie beim malignen Melanom: Von der Monotherapie zur Kombinationstherapie - aktuelle Studiendaten und Fragestellungen]. PMID- 27780163 TI - Giant Hypothalamic Hamartoma in an Infant: A Case Report and Review of the Literature. AB - Giant hypothalamic hamartomas (GHH) are extremely rare lesions in infants and usually intrinsically epileptogenic. We present the case of a 10-month-old girl child presenting with drug-resistant seizures and a giant hypothalamic lesion that was confirmed as hamartoma on histopathology. Surgical decompression and disconnection from the hypothalamus was performed with the intent of controlling her seizures. Unfortunately, the patient developed right middle cerebral artery and posterior cerebral artery territory infarction, possibly due to vasospasm or thrombosis of the vessels. The patient had a stormy postoperative course but has recovered well neurologically at the 18-month follow-up. Histopathological examination revealed abnormal clusters of NeuN-positive neurons, which was confirmatory of hypothalamic hamartoma. A review of the published literature on infantile GHH, its management and the postoperative complications is undertaken in this short report. PMID- 27780164 TI - Assessment of Palliative Care in Lung Cancer in Turkey. AB - OBJECTIVE: To investigate the symptoms of lung cancer in Turkey and to evaluate approaches to alleviate these symptoms. SUBJECTS AND METHODS: This study included 1,245 lung cancer patients from 26 centers in Turkey. Demographic characteristics as well as information regarding the disease and treatments were obtained from medical records and patient interviews. Symptoms were evaluated using the Edmonton Symptom Assessment Scale (ESAS) and were graded on a scale between 0 and 10 points. Data were compared using the chi2, Student t, and Mann-Whitney U tests. Potential predictors of symptoms were analyzed using logistic regression analysis. RESULTS: The most common symptom was tiredness (n = 1,002; 82.1%), followed by dyspnea (n = 845; 69.3%), appetite loss (n = 801; 65.7%), pain (n = 798; 65.4%), drowsiness (n = 742; 60.8%), anxiety (n = 704; 57.7%), depression (n = 623; 51.1%), and nausea (n = 557; 45.5%). Of the 1,245 patients, 590 (48.4%) had difficulty in initiating or maintaining sleep. The symptoms were more severe in stages III and IV. Logistic regression analysis indicated a clear association between demographic characteristics and symptom distress, as well as between symptom distress (except nausea) and well-being. Overall, 804 (65.4%) patients used analgesics, 630 (51.5%) received treatment for dyspnea, 242 (19.8%) used enteral/parenteral nutrition, 132 (10.8%) used appetite stimulants, and 129 (10.6%) used anxiolytics/antidepressants. Of the 799 patients who received analgesics, 173 (21.7%) reported that their symptoms were under control, and also those on other various treatment modalities (dyspnea: 78/627 [12.4%], appetite stimulant: 25/132 [18.9%], and anxiolytics/antidepressants: 25/129 [19.4%]) reported that their symptoms were controlled. CONCLUSION: In this study, the symptoms progressed and became more severe in the advanced stages of lung cancer, and palliative treatment was insufficient in most of the patients in Turkey. PMID- 27780166 TI - A Case of Metachronous Single Metastasis of Medulloblastoma to the Lateral Ventricle: De novo Lesion or Metastasis due to Reversed Cerebrospinal Fluid Flow following Ventriculoperitoneal Shunt? PMID- 27780167 TI - Do JJ Stents Increase the Effectiveness of Extracorporeal Shock Wave Lithotripsy for Pediatric Renal Stones? AB - PURPOSE: We aimed to evaluate the effects of preoperative urinary catheterization in nephrolithiasis treatment with extracorporeal shock wave lithotripsy (SWL). METHODS: Patients admitted to the Department of Pediatric Surgery for renal stones between June 2012 and June 2014 were evaluated retrospectively. Patients were divided into 2 groups based on JJ stent placements. Group 1 did not receive JJ stents, while group 2 did. The recorded demographic data for each group included age, gender, stone size, location, sessions, and complications. The Elmed Complit ESWL system was used with 11-13 kV, and 1,000-1,200 shots in patients 2-4 years of age, and 11-14 kV, and 1,000-1,500 shots for patients over 4 years. RESULTS: In group 1, 18 sessions of SWL were performed on 8 female and 2 male children with a mean age of 4.5 (range 2-12) years and stone diameter of 9 (range 7-15) mm. The locations of the renal stones were in the upper pole in 1 patient, 7 in the lower pole, and 2 in the pelvis renalis. Postoperatively, 1 patient had hematuria, 2 had dysuria, and one had a stone in the external urethral meatus. Eighty percent of patients were stone free; there were no fragmentations in 2 patients, and 1 patient discontinued treatment. In group 2, 15 SWL sessions were performed on 5 female and 5 male children aged 4 (range 3-5) and the stone diameter was 9 (range 7-16) mm. The locations of the renal stones were in the upper pole in 6 patients, in the lower pole in 3 patients, and in the ureteropelvic junction in one patient. JJ stents were placed in all patients preoperatively. Postoperatively, 3 patients had hematuria and one had dysuria. At the end of the study, all of the patients were stone free. Statistically, there were no differences in age, gender, stone size, location, and the number of sessions. CONCLUSIONS: Our results indicate that SWL without preoperative ureteral stenting is an effective and safe procedure that can be carried out in the pediatric population. Preoperative JJ stenting is unnecessary in patients, especially in those with smaller stone diameters. PMID- 27780168 TI - Specific Antibodies for the Detection of Alternaria Allergens and the Identification of Cross-Reactive Antigens in Other Fungi. AB - BACKGROUND: The mould Alternaria alternata is an important source of respiratory allergens. A. alternata extracts show great variations regarding allergenic potency. The aim of this study was to generate antibody probes specific for important Alternaria allergens and to use them to study allergen expression, depending on different culture conditions, as well as to search for cross reactive allergens in other mould species. METHODS: Synthetic peptides from antigenic regions of A. alternata allergens (Alt a 1, Alt a 2, Alt a 3, Alt a 6 and Alt a 8) were used to raise highly specific rabbit antibodies. These antibodies and IgE from allergic patients were used to detect allergens by immunoblotting in extracts of 4 A. alternata strains grown under varying culturing conditions, in commercial skin-prick extracts and in closely (Cladosporium herbarum and Aureobasidium pullulans) or distantly related (Aspergillus niger and Penicillium chrysogenum) mould species. RESULTS: There was a wide variation of expression of the individual A. Alternata allergens, depending on the strain and culture conditions, but the antibody probes allowed us to distinguish strains and culture conditions with low and high allergen expression. In the commercial skin-prick solutions, varying levels of Alt a 1 were found, but no other allergens were detectable. Alt a 1 was identified as species-specific A. Alternata allergen, whereas Alt a 3, 6- and Alt a 8-cross reactive antigens were found in C.herbarum and/or A. pullulans. CONCLUSIONS AND CLINICAL RELEVANCE: Peptide-specific antibodies are useful to analyze diagnostic and therapeutic mould extracts, to study the presence of A. Alternata allergens in biological samples and to search for cross-reactive allergens in other mould species. PMID- 27780170 TI - Curcumin (Diferulolylmethane) Reduces Transglutaminase 2 Overexpression Induced by Retinoic Acid in Human Nervous Cell Lines. AB - OBJECTIVES: Curcumin, a naturally occurring compound derived from turmeric (Curcuma longa) has long been suggested to have strong therapeutic or preventive potential against human diseases because of its antioxidative, anticancerous, and anti-inflammatory effects. Curcumin is known to exert anti-inflammatory effects by interrupting NF-kappaB signaling at multiple levels. Many observations indicate that curcumin shows its valuable potential by inhibiting the activity of I-kappaB kinase. Transglutaminase 2 (TG2) expression is increased in inflammatory diseases. Data in the literature suggest that this enzyme activates the proinflammatory transcriptional factor NF-kappaB by inducing the polymerization of its inhibitory subunit I-kappaBalpha, which in turn results in the dissociation of NF-kappaB and its translocation to the nucleus, where it is capable of upregulating host inflammatory genes. Interestingly, NF-kappaB regulatory response elements are also present in the TG2 promoter, suggesting a possible role for this pathway in the mechanism responsible for chronic inflammation. On the basis of these literature data, our objective was to analyze the effects of curcumin on TG2 expression in human nervous cell lines. METHODS: Human nervous cell lines were treated with curcumin alone or in association with retinoic acid in order to induce TG2 overexpression. TG2 levels were analyzed by Western blot and real-time PCR analyses. RESULTS: Curcumin was able to downregulate the expression of TG2 in human nervous cell lines, which was also the case after treatment with retinoic acid. CONCLUSIONS: These results suggest a possible use of curcumin in reducing TG2 overexpression in human nervous cells. PMID- 27780169 TI - The Effects of Carvedilol on Cardiac Function and the AKT/XIAP Signaling Pathway in Diabetic Cardiomyopathy Rats. AB - OBJECTIVES: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction, myocardial inflammation, interstitial fibrosis and cardiomyocytes apoptosis. The present study aimed to investigate the effects of carvedilol on cardiac function and the AKT/XIAP signaling pathway in DCM rats. METHODS: Male Wistar rats were randomly divided into 3 groups: the control group, diabetic mellitus (DM) group and DM with carvedilol treatment group. DM rats were induced by streptozotocin accompanied by high energy intake. Carvedilol was orally administered at a dose of 10 mg/kg/day. After 16 weeks, the interrelated blood data were detected by biochemical analysis. Cardiac function was evaluated by echocardiography and the serum NT-proBNP level. The changes of myocardium ultrastructural and fibrosis were determined by electron microscopy and Masson's staining. Apoptotic cells were examined by TUNEL staining and interrelated proteins were measured by immunohistochemical and Western blots. RESULTS: Rats in the DM group showed significant serum elevation of glucose, cholesterol, triglyceride, NT-proBNP, IL-1beta and TNF-alpha, along with decreased cardiac function. Moreover, in the DM group, the levels of myocardial apoptosis and fibrosis were all increased accompanied by upregulation of caspase-3 and downregulation of phos-AKT and phos-XIAP, whereas carvedilol treatment prevented or reversed all the changes without influencing plasma levels of glucose, cholesterol and triglyceride. CONCLUSIONS: The AKT/XIAP signaling pathway may be involved in DCM. Carvedilol can improve cardiac function, possibly not only by upregulating the AKT/XIAP antiapoptotic signaling pathway and subsequently attenuating myocardial fibrosis, but also through suppressing the myocardial inflammation response. PMID- 27780173 TI - 16th Biennial Meeting of the International Gynecologic Cancer Society. PMID- 27780171 TI - [Vorwort]. PMID- 27780174 TI - CLINICAL SPECTRUM OF MACULAR-FOVEAL CAPILLARIES EVALUATED WITH OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To describe macular-foveal capillaries (MFC) by means of optical coherence tomography angiography and to identify the clinical spectrum of this angiographic feature. METHODS: Patients with MFC presenting at the Medical Retina & Imaging Unit of the Department of Ophthalmology, University Vita-Salute San Raffaele in Milan were recruited. Patients underwent a complete ophthalmologic examination that included slit-lamp examination, fundus examination, measurement of best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography was performed in selected cases. Optical coherence tomography angiography was performed through Zeiss prototype (AngioPlex, CIRRUS HD-OCT models 5000; Carl Zeiss Meditec, Inc, Dublin, OH). RESULTS: Twelve eyes of 10 consecutive white patients (5 men and 5 women; 50%) presenting MFC were included. Mean age was 66.2 +/- 10.2 years (range, 53-79 years); mean best-corrected visual acuity was 0.1 +/- 0.13 logarithm of the minimum angle of resolution (range, 0-0.4 logarithm of the minimum angle of resolution, corresponding to 20/20 to 20/50). Mean central macular thickness was 348 +/- 57.6 MUm. Two patients were affected by macular pucker, two by postsurgical macular edema, two by age-related macular degeneration, one by diabetic retinopathy, one by dome-shaped macula, one presented with chronic serous chorioretinopathy, and one with branch artery occlusion. Six eyes disclosed a complete absence of the foveal avascular zone, whereas the six other cases showed a partial foveal avascularity. No significant difference was found between complete and incomplete MFC with regards to best-corrected visual acuity (P = 0.272) and central macular thickness (P = 0.870). CONCLUSION: Cases of persistent MFC are heterogeneous in demographic characteristics, fundus appearance, and visual function. However, MFC, presenting either as complete absence of the foveal avascular zone or only partial foveal avascularity, may complicate different retinal abnormalities or represents a coincident finding. PMID- 27780175 TI - Player Selection Bias in National Football League Draftees. AB - Beyer, KS, Fukuda, DH, Redd, MJ, Stout, JR, and Hoffman, JR. Player selection bias in National Football League draftees. J Strength Cond Res 30(11): 2965-2971, 2016-Relative age effects (RAEs) have been studied as a potential factor associated with player selection bias in numerous sports. However, little research has examined the role of RAEs among National Football League (NFL) draftees. The purpose of the current study was to determine the existence of RAEs in NFL draftees from the last 10 NFL drafts. Draftee birth dates were collected and divided into calendar and scholastic quarters (SQ1-SQ4). To determine the presence of RAEs in specific subsets, NFL draftees were grouped according to round drafted, position, level of conference play, and age at the time of the draft. Significant chi tests (p <= 0.05) comparing observed birth-date distributions vs. the expected birth-date distribution from the general population were followed up by calculating the standardized residual for each quarter (z > +/-2.0 indicating significance). Overall, no RAEs were seen when birth-date distribution was assessed using calendar quarters (p = 0.47), but more draftees were born in SQ2 (December-February) than expected (p < 0.01; z = +2.2). Significantly more draftees were born in SQ2 than expected for middle-round draftees (p = 0.01; z = +2.4), skill positions (p = 0.03; z = +2.3), Power Five college draftees (p < 0.01; z = +2.6), and early draftees (p < 0.01; z = +3.1). However, reverse RAEs were seen among late draftees, with fewer draftees being born in SQ2 (z = -3.6) and more being born in SQ4 (June-August; z = +2.6) than expected. In contrast to previous research, the current study observed significant RAEs in NFL draftees from the last 10 years. This player selection bias should be considered when evaluating long-term athlete development models in American football. PMID- 27780176 TI - A population-based study of quantitative sensory testing in adolescents with and without chronic pain. AB - Quantitative sensory testing (QST) has been used to characterize pain sensitivity in individuals with and without pain conditions. Research remains limited in pediatric populations, hindering the ability to expand the utility of QST toward its potential application in clinical settings and clinical predictive value. The aims of this study were to examine pain sensitivity using QST in adolescents with chronic pain compared to adolescents without chronic pain and identify predictors of pain sensitivity. A population-based study conducted from 2010 to 2011 provided data on 941 adolescents, 197 were classified as having chronic pain and 744 were classified without chronic pain. Self-reported data on pain characteristics, psychological functioning, and QST responses were examined. The findings revealed lower pressure pain threshold and tolerance on the trapezius (P's = 0.03) in adolescents with chronic pain compared to adolescents without chronic pain, but no differences on heat or cold-pressor pain tasks. Female sex (P's = 0.02) and poorer psychological functioning (P's = 0.02) emerged as significant predictors of greater pain sensitivity across all pain modalities. Exploratory analyses revealed several associations between clinical pain characteristics and QST responses within the chronic pain cohort. Findings from this large pediatric sample provide comprehensive data that could serve as normative data on QST responses in adolescents with and without chronic pain. These findings lay the groundwork toward developing future QST research and study protocols in pediatric populations, taking into consideration sex and psychological distress. PMID- 27780177 TI - The Vulvar Pain Assessment Questionnaire inventory. AB - Millions suffer from chronic vulvar pain (ie, vulvodynia). Vulvodynia represents the intersection of 2 difficult subjects for health care professionals to tackle: sexuality and chronic pain. Those with chronic vulvar pain are often uncomfortable seeking help, and many who do so fail to receive proper diagnoses. The current research developed a multidimensional assessment questionnaire, the Vulvar Pain Assessment Questionnaire (VPAQ) inventory, to assist in the assessment and diagnosis of those with vulvar pain. A large pool of items was created to capture pain characteristics, emotional/cognitive functioning, physical functioning, coping skills, and partner factors. The item pool was subsequently administered online to 288 participants with chronic vulvar pain. Of those, 248 participants also completed previously established questionnaires that were used to evaluate the convergent and discriminant validity of the VPAQ. Exploratory factor analyses of the item pool established 6 primary scales: Pain Severity, Emotional Response, Cognitive Response, and Interference with Life, Sexual Function, and Self-Stimulation/Penetration. A brief screening version accompanies a more detailed version. In addition, 3 supplementary scales address pain quality characteristics, coping skills, and the impact on one's romantic relationship. When relationships among VPAQ scales and previously researched scales were examined, evidence of convergent and discriminant validity was observed. These patterns of findings are consistent with the literature on the multidimensional nature of vulvodynia. The VPAQ can be used for assessment, diagnosis, treatment formulation, and treatment monitoring. In addition, the VPAQ could potentially be used to promote communication between patients and providers, and point toward helpful treatment options and/or referrals. PMID- 27780178 TI - Reduced excitability and impaired nociception in peripheral unmyelinated fibers from Nav1.9-null mice. AB - The upregulation of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 has previously been associated with inflammatory hyperalgesia. Na1.9 knockout (KO) mice, however, did not seem insensitive in conventional tests of acute nociception. Using electrophysiological, neurochemical, and behavioral techniques, we now show NaV1.9-null mice exhibit impaired mechanical and thermal sensory capacities and reduced electrical excitability of nociceptors. In single fiber recordings from isolated skin, the electrical threshold of NaV1.9 KO C fibers was elevated by 55% and the median von Frey threshold was 32 mN in contrast to 8 mN in wild types (WTs). The prevalence of C mechano-heat-sensitive (CMH) fibers was only 25.6% in NaV1.9 KO animals compared to 75.8% in the WT group, and the heat threshold of these CMH fibers was 40.4 degrees C in the control vs 44 degrees C in the KO group. Compound action potential recordings from isolated sciatic nerve segments of NaV1.9 KO mice revealed lower activity induced slowing of conduction velocity upon noxious heat stimulation: 8% vs 30% in WTs. Heat-induced calcitonin gene-related peptide release from the skin was less in the KO than in the WT group. The reduced noxious heat sensitivity was finally confirmed with the Hargreaves test using 2 rates of radiant heating of the plantar hind paws. In conclusion, NaV1.9 presumably contributes to acute thermal and mechanical nociception in mice, most likely through increasing the excitability but probably also by amplifying receptor potentials irrespective of the stimulus modality. PMID- 27780179 TI - Musculoskeletal complaints while growing up from age 11 to age 14: the PIAMA birth cohort study. AB - For musculoskeletal complaints (MSCs) among adults, several risk factors are known, but the most important determinant is an earlier episode of MSCs. Research has shifted to younger ages, showing a high prevalence of MSCs among children and adolescents. Our purpose was to evaluate the prevalence of MSCs among those growing up from age 11 to 14 and to explore the role of several sociodemographic, growth and development, psychosocial, and lifestyle factors. Data collected at age 11 (n = 2651) and age 14 (n = 2522) in the ongoing Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study were used. Analyses included multiple logistic regression analyses using stepwise backward selection. The 1-year prevalence of any MSCs for at least 1 month increased from 15.8% at age 11 to 24.4% at age 14, and this was also found for upper extremity complaints (from 4.7% to 7.6%), back complaints (from 2.7% to 9.3%), and lower extremity complaints (from 11.9% to 14.7%). More MSCs were found among girls, those with sports injuries, those with sleeping problems, and those with daytime tiredness, although complaints at age 11 were by far the most important factor associated with MSCs at age 14 for all pain sites. This study showed that MSC is already common at an early age and that already at age 14 the factor with the strongest association is an earlier episode of MSCs. Sleeping problems and tiredness may also play a role in the early development of MSCs, either as determinant or as a consequence. PMID- 27780180 TI - Endocrinopathies in women during opioid therapy cause loss of androgens, fatigue, listlessness, loss of libido and quality of life: stop prescribing opioids or follow the 2016 Centers for Disease Control and Prevention guidelines? PMID- 27780181 TI - Benefit and harm of adding ketamine to an opioid in a patient-controlled analgesia device for the control of postoperative pain: systematic review and meta-analyses of randomized controlled trials with trial sequential analyses. AB - Ketamine is often added to opioids in patient-controlled analgesia devices. We tested whether in surgical patients, ketamine added to an opioid patient controlled analgesia decreased pain intensity by >=25%, cumulative opioid consumption by >=30%, the risk of postoperative nausea and vomiting by >=30%, the risk of respiratory adverse effects by >=50%, and increased the risk of hallucination not more than 2-fold. In addition, we searched for evidence of dose responsiveness. Nineteen randomized trials (1349 adults, 104 children) testing different ketamine regimens added to various opioids were identified through searches in databases and bibliographies (to 04.2016). In 9 trials (595 patients), pain intensity at rest at 24 hours was decreased by 32% with ketamine (weighted mean difference -1.1 cm on the 0-10 cm visual analog scale [98% CI, 1.8 to -0.39], P < 0.001). In 7 trials (495 patients), cumulative 24 hours morphine consumption was decreased by 28% with ketamine (weighted mean difference -12.9 mg [-22.4 to -3.35], P = 0.002). In 7 trials (435 patients), the incidence of postoperative nausea and vomiting was decreased by 44% with ketamine (risk ratio 0.56 [0.40 to 0.78], P < 0.001). There was no evidence of a difference in the incidence of respiratory adverse events (9 trials, 871 patients; risk ratio 0.31 [0.06 to 1.51], P = 0.08) or hallucination (7 trials, 690 patients; odds ratio 1.16 [0.47 to 2.79], P = 0.70). Trial sequential analyses confirmed the significant benefit of ketamine on pain intensity, cumulative morphine consumption, and postoperative nausea and vomiting and its inability to double the risk of hallucination. The available data did not allow us to make a conclusion on respiratory adverse events or to establish dose-responsiveness. PMID- 27780182 TI - THE SPECTRUM OF AMALRIC TRIANGULAR CHOROIDAL INFARCTION. AB - PURPOSE: To describe the multimodal imaging findings, including optical coherence tomography angiography analysis, and spectrum of etiologies associated with Amalric triangular choroidal infarction. METHODS: This study is a multicenter, retrospective, observational case series review of the clinical and multimodal imaging findings for six patients with Amalric triangular choroidal infarction. RESULTS: Six patients (10 eyes) with Amalric triangular choroidal infarction were enrolled. Patients' ages ranged from 7 years to 90 years (mean 54 years, median 60 years). Wedge-shaped or triangular areas of choroidal ischemia were evident with fluorescein angiography in all patients and with indocyanine green angiography in one patient. Optical coherence tomography angiography demonstrated choriocapillaris flow reduction that colocalized with outer retinal structural abnormalities with en face optical coherence tomography and corresponded with the triangular zones of choroidal infarction identified with fluorescein angiography in one patient. Etiologies included giant cell arteritis in three cases: traumatic carotid dissection, traumatic retrobulbar hemorrhage, and malignant hypertension secondary to lupus-associated nephropathy. CONCLUSION: The Amalric triangular syndrome of choroidal infarction can occur as a result of a spectrum of etiologies, especially giant cell arteritis. Infarction is evident on traditional angiography in all cases. Optical coherence tomography angiography may provide a simple noninvasive tool to evaluate choroidal ischemia. PMID- 27780183 TI - DOME-SHAPED MACULOPATHY: ENHANCED VISUALIZATION WITH RADIAL OPTICAL COHERENCE TOMOGRAPHY SCANS. AB - PURPOSE: To describe two cases of dome-shaped macula (DSM) and serous macular detachment, the diagnosis of which was enhanced with a radial optical coherence tomography (OCT) scanning protocol. METHODS: Retrospective case series of DSM associated with serous macular detachment. Multimodal retinal imaging was performed including spectral domain OCT with a radial scan protocol and en face OCT angiography. Anatomical outcomes before and after therapy are presented. RESULTS: Two cases of DSM associated with serous macular detachment are described. The dome-shaped macular bulge was more clearly elicited as the cause of serous macular detachment with the employment of a radial OCT scanning protocol. Subretinal fluid resolved in both cases using either intravitreal aflibercept injection or half-fluence photodynamic therapy. En face OCT angiography of the choroid demonstrated reduction in the caliber of choroidal vessels after treatment. CONCLUSION: A radial OCT scanning protocol should be considered in eyes with suspicion of DSM, especially in myopic eyes with subretinal fluid. Intravitreal aflibercept therapy or photodynamic therapy may be considered as a treatment for serous macular detachment because of DSM. PMID- 27780184 TI - Physiological Responses to Arm Activity in Individuals With Chronic Obstructive Pulmonary Disease Compared With Healthy Controls: A SYSTEMATIC REVIEW. AB - PURPOSE: The mechanisms underlying physiological limitations during arm activity in individuals with chronic obstructive pulmonary disease (COPD) are unknown. The objective of this systematic review was to describe cardiorespiratory responses, symptoms, chest wall kinematics, muscle activity, and lung volumes during arm activity in individuals with COPD relative to the responses of healthy controls. METHODS: Original research articles that compared cardiorespiratory responses, symptoms, muscle activity, chest wall kinematics, and lung function during arm activity between individuals with COPD and healthy controls were identified after searches of 5 electronic databases and reference lists of pertinent articles. Two reviewers performed the electronic and manual searches with 1 screening title and abstracts. Two investigators screened the full texts to determine eligibility for inclusion. One reviewer performed the data extraction and tabulation using a standardized form with a second reviewer double-checking the data extracted. RESULTS: Of the 54 full-text articles assessed for eligibility, 6 met the inclusion criteria. Reduced cardiorespiratory responses during peak arm exercise in individuals with COPD compared with healthy controls were evident. Compared with healthy controls, individuals with COPD had increased dyspnea and hyperinflation during peak arm exercise. Increased effort of the trapezius muscle during arm activities was also found in persons with COPD compared with healthy controls. CONCLUSIONS: There is limited evidence describing physiological responses during arm activity in individuals with COPD. Findings of this systematic review suggest that individuals with COPD have decreased cardiorespiratory responses during peak arm exercise compared with controls but increased dyspnea, hyperinflation, and arm muscle effort. PMID- 27780186 TI - Preoperative Thromboelastography as a Sensitive Tool Predicting Those at Risk of Developing Early Hepatic Artery Thrombosis After Adult Liver Transplantation. AB - BACKGROUND: Whilst causes of hepatic artery thrombosis (HAT) after liver transplantation (LT) are multifactorial, early HAT (E-HAT) remains pertinent complication impacting on graft and patient survival. Currently there is no screening tool that would identify patients with increased risk of developing E HAT. METHODS: We analyzed the native procoagulant state of LT recipients, identified through pretransplant thromboelastographic (TEG) data among other known risk factors, to identify risk factors for E-HAT. RESULTS: The outcomes of 828 adult patients undergoing LT between 2008 and 2013 were analyzed. Overall, 79 (9.5%) patients experienced HAT, E-HAT was diagnosed in 23, and in the remainder this was "late" HAT. The maximum amplitude (MA) on preoperative TEG was significantly higher in patients diagnosed with E-HAT compared with those who did not (71.2 mm vs 57.9 mm; P < 0.0001). Receiver operating characteristic analysis with the cutoff value for MA of 65 mm or greater returned area under the curve of 0.750 (P < 0.001) predicting E-HAT with a sensitivity of 70%. A total of 7% of patients with an MA of 65 mm or greater went on to develop E-HAT (hazard ratio, 5.28; 95% confidence interval, 2.10-12.29; P < 0.001), whereas only 1.2% patients with an MA less than 65 mm experienced E-HAT. CONCLUSIONS: Preoperative TEG may reliably identify group of recipients at greater risk of developing E-HAT, and intense surveillance and anticoagulation prophylaxis may avoid this serious complication after LT. PMID- 27780185 TI - Liver Transplantation for Hepatic Trauma: A Study From the European Liver Transplant Registry. AB - BACKGROUND: Liver transplantation is the most extreme form of surgical management of patients with hepatic trauma, with very limited literature data supporting its use. The aim of this study was to assess the results of liver transplantation for hepatic trauma. METHODS: This retrospective analysis based on European Liver Transplant Registry comprised data of 73 recipients of liver transplantation for hepatic trauma performed in 37 centers in the period between 1987 and 2013. Mortality and graft loss rates at 90 days were set as primary and secondary outcome measures, respectively. RESULTS: Mortality and graft loss rates at 90 days were 42.5% and 46.6%, respectively. Regarding general variables, cross clamping without extracorporeal veno-venous bypass was the only independent risk factor for both mortality (P = 0.031) and graft loss (P = 0.034). Regarding more detailed factors, grade of liver trauma exceeding IV increased the risk of mortality (P = 0.005) and graft loss (P = 0.018). Moreover, a tendency above the level of significance was observed for the negative impact of injury severity score (ISS) on mortality (P = 0.071). The optimal cut-off for ISS was 33, with sensitivity of 60.0%, specificity of 80.0%, positive predictive value of 75.0%, and negative predictive value of 66.7%. CONCLUSIONS: Liver transplantation seems to be justified in selected patients with otherwise fatal severe liver injuries, particularly in whom cross-clamping without extracorporeal bypass can be omitted. The ISS cutoff less than 33 may be useful in the selection process. PMID- 27780187 TI - Predictors of Successful Downstaging of Hepatocellular Carcinoma Outside Milan Criteria. AB - BACKGROUND: Patients with hepatocellular carcinoma (HCC) outside Milan criteria (MC) may be candidates for liver transplantation (LT) after successful downstaging. Factors that predict successful downstaging are unclear. We aimed to identify the predictors of successful downstaging of HCC in patients outside MC. METHODS: We performed a retrospective cohort study on consecutive patients with HCC outside MC who received downstaging with locoregional therapy. Clinical and laboratory variables, tumor characteristics including total tumor volume (TTV) and up-to-7 criteria were recorded. We performed univariate and multivariate logistic regression analyses to identify variables associated with successful downstaging. RESULTS: Of 675 patients with HCC, 90 patients outside MC received downstaging. Fifty-three (59%) patients were successfully downstaged, 37 (41%) failed downstaging. University of California at San Francisco criteria, alpha fetoprotein, up-to-7 criteria, TTV, and platelet count were predictors of successful downstaging on univariate analysis. Total tumor volume was an independent predictor of successful downstaging on multivariate logistic regression (P = 0.04, area under receiver operating characteristic curve 0.89 (95% confidence interval, 0.82-0.96). Fifty-two (76%) of 68 patients with TTV less than 200 cm were successfully downstaged, whereas only 1 (4.5%) of 22 patients with TTV greater than 200 cm were successfully downstaged. Forty-five (50%) patients underwent LT. Kaplan-Meier survival rates at 1 and 5 years post-LT were 95.3% and 79.4%, respectively. Patients who were successfully downstaged had better survival than patients who failed downstaging (P < 0.01). CONCLUSIONS: Total tumor volume is a good predictor of successful downstaging of HCC. Patients with TTV less than 200 cm may be considered good candidates for downstaging. Further studies with larger cohort of patients are needed to validate this approach in patients with HCC outside Milan. PMID- 27780188 TI - Liver Transplantation With Older Donors: A Comparison With Younger Donors in a Context of Organ Shortage. AB - BACKGROUND: Older liver grafts have been considered in the past decade due to organ shortage. The aim was to compare outcomes after liver transplantation with either younger or older donors. METHODS: Patients transplanted in our center between 2004 and 2014 with younger donors (younger than 60 years; n = 253) were compared with older donors (older than 75 years; n = 157). Multiorgan transplantations, split grafts, or non-heart-beating donors were not included. RESULTS: Donors in the older group were mostly women deceased from stroke, and only 3 patients had experienced cardiac arrest. Liver tests were significantly better in the older group than in the younger group. There was no difference regarding cold ischemia time, model for end-stage liver disease score, and steatosis. There was no significant difference regarding primary nonfunction and dysfunction, hepatic artery and biliary complications, and retransplantation rates. Graft survival was not different (65% and 64% in the older and younger groups, P = 0.692). Within the older group, hepatitis C infection, retransplantation, and emergency transplantation were associated with poor graft survival. CONCLUSIONS: Provided normal liver tests and the absence of cardiac arrest in donors, older liver grafts (>75 years) may be safely attributed to non hepatitis C-infected recipients in the setting of a first and nonurgent transplantation. PMID- 27780189 TI - Changes in the Expression of miR-34a and its Target Genes Following Spinal Cord Injury In Rats. AB - BACKGROUND Results from DNA microarray experiments have shown that the expression of miR-34s undergoes significant changes following spinal cord injury (SCI). The present study was designed to detect changes in the expression of miR-34s and its target genes during the acute and sub-acute stages of SCI. MATERIAL AND METHODS Luxol fast blue (LFB) staining for myelin was used to observe the differences in the general morphology of the spinal cord after SCI in a contusion model in rats. qPCR was carried out to determine the expression variation of miR-34s and its target genes during the acute and sub-acute stages of SCI. The mimic technique was used to further confirm the regulatory effect of miR-34a on the potential target genes. RESULTS The expression level of miR-34a decreased immediately after SCI and persisted for 21 days after SCI. The expression level of miR-34c began decreasing at day 1 after SCI and persisted until day 14. The expression level of miR-34b did not undergo significant change after SCI. The results of double immunofluorescence and in-situ hybridization suggested that miR-34a was highly expressed in spinal cord neurons. Based on our bioinformatics analysis, we postulated that miR-34a might participate in post-SCI cell apoptosis by regulating the target gene Notch1, and likely participated in the inflammatory response and glial scar formation by regulating the candidate genes Csf1r and PDGFRa, respectively. The expression levels of the candidate genes Csf1r and PDGFRa were consistent with Notch1 after SCI. The mimic technique further confirmed the regulatory effect of miR-34a on the aforementioned target genes. CONCLUSIONS We postulate that miR-34a and miR-34c might participate in multiple aspects of cytobiological activities following SCI. MiR-34a in particular may participate in cell apoptosis, inflammatory response, and glial scar formation by regulating the target gene Notch1 and candidate target genes Csf1r and PDGFRa respectively. PMID- 27780190 TI - Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis. AB - In most Gram-negative pathogens, the hydrolysis of UDP-2,3-diacylglucosamine to generate lipid X in lipid A biosynthesis is catalysed by the membrane-associated enzyme LpxH. We report the crystal structure of LpxH in complex with its product, lipid X, unveiling a unique insertion lid above the conserved architecture of calcineurin-like phosphoesterases. This structure reveals elaborate interactions surrounding lipid X and provides molecular insights into the substrate selectivity, catalysis and inhibition of LpxH. PMID- 27780191 TI - Rapid submarine ice melting in the grounding zones of ice shelves in West Antarctica. AB - Enhanced submarine ice-shelf melting strongly controls ice loss in the Amundsen Sea embayment (ASE) of West Antarctica, but its magnitude is not well known in the critical grounding zones of the ASE's major glaciers. Here we directly quantify bottom ice losses along tens of kilometres with airborne radar sounding of the Dotson and Crosson ice shelves, which buttress the rapidly changing Smith, Pope and Kohler glaciers. Melting in the grounding zones is found to be much higher than steady-state levels, removing 300-490 m of solid ice between 2002 and 2009 beneath the retreating Smith Glacier. The vigorous, unbalanced melting supports the hypothesis that a significant increase in ocean heat influx into ASE sub-ice-shelf cavities took place in the mid-2000s. The synchronous but diverse evolutions of these glaciers illustrate how combinations of oceanography and topography modulate rapid submarine melting to hasten mass loss and glacier retreat from West Antarctica. PMID- 27780192 TI - Pathogenesis and progression of oesophageal adenocarcinoma varies by prior diagnosis of Barrett's oesophagus. AB - BACKGROUND: The absolute risk of oesophageal adenocarcinoma (EA) among individuals with Barrett's oesophagus (BE) is low and a majority of EA cases are diagnosed among individuals with no prior BE diagnosis. To ensure that insights from EA case-control studies are transferable to clinical management of BE populations, we conducted a case-case study to compare the clinical presentation, medical history and survival of EA cases with and without a prior BE diagnosis in the Surveillance, Epidemiology and End Results Medicare database. METHODS: Eligible EA cases were diagnosed at age ?68 years during 1994-2009. There were 5271 EA cases in this study, 87% of which did not have a prior diagnosis of BE (EA-no prior BE). RESULTS: Multivariable case-case comparisons evidenced adverse associations of GERD, ever cigarette smoking, hypertension, dyslipidemia, weight loss, peptic ulcer and irritable bowel disease each in EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose and diabetes did not differ between groups. EA-prior BE cases were diagnosed with less advanced disease, were more likely to undergo surgery and less likely to receive chemotherapy and radiotherapy, and had better overall mean survival (2.5 vs 1.4 years). This survival advantage persisted in the multivariable Cox model (HR=0.69, 95%CI: 0.60, 0.78), despite adjustment for many factors including stage, grade and clinical interventions. CONCLUSIONS: This study provides evidence that EA cases occurring among individuals previously diagnosed with BE are different from the large majority of EA cases that occur without a prior BE diagnosis. Regardless of whether these differences emanate from aetiology, biology and/or selection biases, they underscore the importance of a prudent approach in using knowledge from EAC case-control studies in the management of BE populations. PMID- 27780194 TI - Reply to 'Comment on "Validation of a contemporary prostate cancer grading system using prostate cancer death as outcome"'. PMID- 27780193 TI - Short-term breast cancer survival in relation to ethnicity, stage, grade and receptor status: national cohort study in England. AB - BACKGROUND: In the re-organisation of cancer registration in England in 2012, a high priority was given to the recording of cancer stage and other prognostic clinical data items. METHODS: We extracted 86 852 breast cancer records for women resident in England and diagnosed during 2012-2013. Information on age, ethnicity, socio-economic status, comorbidity, tumour stage, grade, morphology and oestrogen, progesterone and HER2 receptor status was included. The two-year cumulative risk of death from any cause was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regressions were used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI). The follow-up ended on 31 December 2014. RESULTS: The completeness of registration for prognostic variables was generally high (around 80% or higher), but it was low for progesterone receptor status (41%). Women with negative receptor status for each of the oestrogen, progesterone and HER2 receptors (triple-negative cancers) had an adjusted HR for death of 2.00 (95%CI 1.84-2.17). Black women had an age-adjusted HR of 1.77 (1.48-2.13) compared with White women. CONCLUSIONS: The excess mortality of Black women with breast cancer has contributions from socio-economic factors, stage distribution and tumour biology. The study illustrates the richness of detail in the national cancer registration data. This allows for analysis of cancer outcomes at a high level of resolution, and may form the basis for risk stratification. PMID- 27780195 TI - Comment on 'Validation of a contemporary prostate cancer grading system using prostate cancer death as outcome'. PMID- 27780196 TI - How Relevant Is Sexual Transmission of Zika Virus? AB - Christian Althaus and Nicola Low reflect on the contribution of sexual transmission to the spread of Zika virus. PMID- 27780197 TI - Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study). AB - BACKGROUND: Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk. METHODS AND FINDINGS: We conducted a randomised, double-blind, placebo controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47-0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64 0.98, p = 0.03; number needed to treat = 10, 95% CI 5-115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33-1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21-1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups. CONCLUSIONS: The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000322730. PMID- 27780198 TI - Impacts on Breastfeeding Practices of At-Scale Strategies That Combine Intensive Interpersonal Counseling, Mass Media, and Community Mobilization: Results of Cluster-Randomized Program Evaluations in Bangladesh and Viet Nam. AB - BACKGROUND: Despite recommendations supporting optimal breastfeeding, the number of women practicing exclusive breastfeeding (EBF) remains low, and few interventions have demonstrated implementation and impact at scale. Alive & Thrive was implemented over a period of 6 y (2009-2014) and aimed to improve breastfeeding practices through intensified interpersonal counseling (IPC), mass media (MM), and community mobilization (CM) intervention components delivered at scale in the context of policy advocacy (PA) in Bangladesh and Viet Nam. In Bangladesh, IPC was delivered through a large non-governmental health program; in Viet Nam, it was integrated into government health facilities. This study evaluated the population-level impact of intensified IPC, MM, CM, and PA (intensive) compared to standard nutrition counseling and less intensive MM, CM, and PA (non-intensive) on breastfeeding practices in these two countries. METHODS AND FINDINGS: A cluster-randomized evaluation design was employed in each country. For the evaluation sample, 20 sub-districts in Bangladesh and 40 communes in Viet Nam were randomized to either the intensive or the non-intensive group. Cross-sectional surveys (n ~ 500 children 0-5.9 mo old per group per country) were implemented at baseline (June 7-August 29, 2010, in Viet Nam; April 28-June 26, 2010, in Bangladesh) and endline (June 16-August 30, 2014, in Viet Nam; April 20-June 23, 2014, in Bangladesh). Difference-in-differences estimates (DDEs) of impact were calculated, adjusting for clustering. In Bangladesh, improvements were significantly greater in the intensive compared to the non intensive group for the proportion of women who reported practicing EBF in the previous 24 h (DDE 36.2 percentage points [pp], 95% CI 21.0-51.5, p < 0.001; prevalence in intensive group rose from 48.5% to 87.6%) and engaging in early initiation of breastfeeding (EIBF) (16.7 pp, 95% CI 2.8-30.6, p = 0.021; 63.7% to 94.2%). In Viet Nam, EBF increases were greater in the intensive group (27.9 pp, 95% CI 17.7-38.1, p < 0.001; 18.9% to 57.8%); EIBF declined (60.0% to 53.2%) in the intensive group, but less than in the non-intensive group (57.4% to 40.6%; DDE 10.0 pp, 95% CI -1.3 to 21.4, p = 0.072). Our impact estimates may underestimate the full potential of such a multipronged intervention because the evaluation lacked a "pure control" area with no MM or national/provincial PA. CONCLUSIONS: At-scale interventions combining intensive IPC with MM, CM, and PA had greater positive impacts on breastfeeding practices in Bangladesh and Viet Nam than standard counseling with less intensive MM, CM, and PA. To our knowledge, this study is the first to document implementation and impacts of breastfeeding promotion at scale using rigorous evaluation designs. Strategies to design and deliver similar programs could improve breastfeeding practices in other contexts. TRIAL REGISTRATION: ClinicalTrials.gov NCT01678716 (Bangladesh) and NCT01676623 (Viet Nam). PMID- 27780199 TI - Factors Associated with the Time of Admission among Notified Dengue Fever Cases in Region VIII Philippines from 2008 to 2014. AB - In cases of Dengue fever, late hospital admission can lead to treatment delay and even death. In order to improve early disease notification and management, it is essential to investigate the factors affecting the time of admission of Dengue cases. This study determined the factors associated with the time of admission among notified Dengue cases. The study covered the period between 2008 and 2014 in Region VIII, Philippines. The factors assessed were age, sex, hospital sector, hospital level, disease severity based on the 1997 WHO Dengue classification, and period of admission (distinguishing between the 2010 Dengue epidemic and non epidemic time). We analysed secondary data from the surveillance of notified Dengue cases. We calculated the association through chi-square test, ordinal logistic regression and linear regression at p value < 0.05. The study included 16,357 admitted Dengue cases. The reported cases included a majority of children (70.09%), mild cases of the disease (64.00%), patients from the public sector (69.82%), and non-tertiary hospitals (62.76%). Only 1.40% of cases had a laboratory confirmation. The epidemic period in 2010 comprised 48.68% of all the admitted cases during this period. Late admission was more likely among adults than children (p<0.05). The severe type of the disease was more likely to be admitted late than the mild type (p<0.05). Late admission was also more likely in public hospitals than in private hospitals (p<0.05); and within tertiary level hospitals than non-tertiary hospitals (p<0.05). Late admission was more likely during the non-epidemic period than the 2010 epidemic period (p<0.05). A case fatality rate of 1 or greater was significantly associated with children, severe diseases, tertiary hospitals and public hospitals when admitted late (p<0.05). Data suggests that early admission among child cases was common in Region VIII. This behavior is encouraging, and should be continued. However, further study is needed on the late admission among tertiary, public hospitals and non-epidemic period with reference to the quality of care, patient volume, out of pocket expense, and accessibility We recommend the consistent use of the 2009 WHO Dengue guidelines in order to standardize the admission criteria and time across hospitals. PMID- 27780200 TI - Neisserial Heparin Binding Antigen (NHBA) Contributes to the Adhesion of Neisseria meningitidis to Human Epithelial Cells. AB - Neisserial Heparin Binding Antigen (NHBA) is a surface-exposed lipoprotein ubiquitously expressed by Neisseria meningitidis strains and an antigen of the Bexsero(r) vaccine. NHBA binds heparin through a conserved Arg-rich region that is the target of two proteases, the meningococcal NalP and human lactoferrin (hLf). In this work, in vitro studies showed that recombinant NHBA protein was able to bind epithelial cells and mutations of the Arg-rich tract abrogated this binding. All N-terminal and C-terminal fragments generated by NalP or hLf cleavage, regardless of the presence or absence of the Arg-rich region, did not bind to cells, indicating that a correct positioning of the Arg-rich region within the full length protein is crucial. Moreover, binding was abolished when cells were treated with heparinase III, suggesting that this interaction is mediated by heparan sulfate proteoglycans (HSPGs). N. meningitidis nhba knockout strains showed a significant reduction in adhesion to epithelial cells with respect to isogenic wild-type strains and adhesion of the wild-type strain was inhibited by anti-NHBA antibodies in a dose-dependent manner. Overall, the results demonstrate that NHBA contributes to meningococcal adhesion to epithelial cells through binding to HSPGs and suggest a possible role of anti-Bexsero(r) antibodies in the prevention of colonization. PMID- 27780201 TI - Environmental Nontuberculous Mycobacteria in the Hawaiian Islands. AB - Lung disease caused by nontuberculous mycobacteria (NTM) is an emerging infectious disease of global significance. Epidemiologic studies have shown the Hawaiian Islands have the highest prevalence of NTM lung infections in the United States. However, potential environmental reservoirs and species diversity have not been characterized. In this cross-sectional study, we describe molecular and phylogenetic comparisons of NTM isolated from 172 household plumbing biofilms and soil samples from 62 non-patient households and 15 respiratory specimens. Although non-uniform geographic sampling and availability of patient information were limitations, Mycobacterium chimaera was found to be the dominant species in both environmental and respiratory specimens. In contrast to previous studies from the continental U.S., no Mycobacterium avium was identified. Mycobacterium intracellulare was found only in respiratory specimens and a soil sample. We conclude that Hawai'i's household water sources contain a unique composition of Mycobacterium avium complex (MAC), increasing our appreciation of NTM organisms of pulmonary importance in tropical environments. PMID- 27780202 TI - Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor. AB - Genome-wide association studies and candidate gene studies have identified several genetic variants that increase glioma risk. The majority of these variants are non-coding and the mechanisms behind the increased risk in carriers are not known. In this study, we hypothesize that some of the established glioma risk variants induce aberrant DNA methylation in the developing tumor, either locally (gene-specific) or globally (genome-wide). In a pilot data set including 77 glioma patients, we used Illumina beadchip technology to analyze genetic variants in blood and DNA methylation in matched tumor samples. To validate our findings, we used data from the Cancer Genome Atlas, including 401 glioblastoma patients. Consensus clustering identified the glioma CpG island methylator phenotype (gCIMP) and two additional subgroups with distinct patterns of global DNA methylation. In the pilot dataset, gCIMP was associated with two genetic variants in CDKN2B-AS1, rs1412829 and rs4977756 (9p21.3, p = 8.1 x 10-7 and 4.8 x 10-5, respectively). The association was in the same direction in the TCGA dataset, although statistically significant only when combining individuals with AG and GG genotypes. We also investigated the relation between glioma risk variants and DNA methylation in the promoter region of genes located within 30 kb of each variant. One association in the pilot dataset, between the TERT risk variant rs2736100 and lower methylation of cg23827991 (in TERT; p = 0.001), was confirmed in the TCGA dataset (p = 0.001). In conclusion, we found an association between rs1412829 and rs4977756 (9p21.3, CDKN2B-AS1) and global DNA methylation pattern in glioma, for which a trend was seen also in the TCGA glioblastoma dataset. We also found an association between rs2736100 (in TERT) and levels of methylation at cg23827991 (localized in the same gene, 3.3 kbp downstream of the risk variant), which was validated in the TCGA dataset. Except for this one association, we did not find strong evidence for gene-specific DNA methylation mediated by glioma risk variants. PMID- 27780203 TI - snRNA 3' End Processing by a CPSF73-Containing Complex Essential for Development in Arabidopsis. AB - Uridine-rich small nuclear RNAs (snRNAs) are the basal components of the spliceosome and play essential roles in splicing. The biogenesis of the majority of snRNAs involves 3' end endonucleolytic cleavage of the nascent transcript from the elongating DNA-dependent RNA ploymerase II. However, the protein factors responsible for this process remain elusive in plants. Here, we show that DEFECTIVE in snRNA PROCESSING 1 (DSP1) is an essential protein for snRNA 3' end maturation in Arabidopsis. A hypomorphic dsp1-1 mutation causes pleiotropic developmental defects, impairs the 3' end processing of snRNAs, increases the levels of snRNA primary transcripts (pre-snRNAs), and alters the occupancy of Pol II at snRNA loci. In addition, DSP1 binds snRNA loci and interacts with Pol-II in a DNA/RNA-dependent manner. We further show that DSP1 forms a conserved complex, which contains at least four additional proteins, to catalyze snRNA 3' end maturation in Arabidopsis. The catalytic component of this complex is likely the cleavage and polyadenylation specificity factor 73 kDa-I (CSPF73-I), which is the nuclease cleaving the pre-mRNA 3' end. However, the DSP1 complex does not affect pre-mRNA 3' end cleavage, suggesting that plants may use different CPSF73-I containing complexes to process snRNAs and pre-mRNAs. This study identifies a complex responsible for the snRNA 3' end maturation in plants and uncovers a previously unknown function of CPSF73 in snRNA maturation. PMID- 27780204 TI - The Sweet Potato NAC-Domain Transcription Factor IbNAC1 Is Dynamically Coordinated by the Activator IbbHLH3 and the Repressor IbbHLH4 to Reprogram the Defense Mechanism against Wounding. AB - IbNAC1 is known to activate the defense system by reprogramming a genetic network against herbivory in sweet potato. This regulatory activity elevates plant defense potential but relatively weakens plants by IbNAC1-mediated JA response. The mechanism controlling IbNAC1 expression to balance plant vitality and survival remains unclear. In this study, a wound-responsive G-box cis-element in the IbNAC1 promoter from -1484 to -1479 bp was identified. From a screen of wound activated transcriptomic data, one transcriptional activator, IbbHLH3, and one repressor, IbbHLH4, were selected that bind to and activate or repress, respectively, the G-box motif in the IbNAC1 promoter to modulate the IbNAC1 mediated response. In the early wound response, the IbbHLH3-IbbHLH3 protein complex binds to the G-box motif to activate IbNAC1 expression. Thus, an elegant defense network is activated against wounding stress. Until the late stages of wounding, IbbHLH4 interacts with IbbHLH3, and the IbbHLH3-IbbHLH4 heterodimer competes with the IbbHLH3-IbbHLH3 complex to bind the G-box and suppress IbNAC1 expression and timely terminates the defense network. Moreover, the JAZs and IbEIL1 proteins interact with IbbHLH3 to repress the transactivation function of IbbHLH3 in non-wounded condition, but their transcription is immediately inhibited upon early wounding. Our work provides a genetic model that accurately switches the regulatory mechanism of IbNAC1 expression to adjust wounding physiology and represents a delicate defense regulatory network in plants. PMID- 27780206 TI - Texas and Its Measles Epidemics. AB - Peter Hotez reflects on declining vaccination rates in Texas and the potential for future measles epidemics. PMID- 27780205 TI - STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways. AB - STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-gamma, interleukin-6 (IL-6), and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-alpha binding. This, in turn, substantially attenuated cardinal IFN-gamma responses, including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon independent activities of this protein. PMID- 27780208 TI - Prognostic Importance of Dyspnea for Cardiovascular Outcomes and Mortality in Persons without Prevalent Cardiopulmonary Disease: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND: The relationship between dyspnea and incident heart failure (HF) and myocardial infarction (MI) among patients without previously diagnosed cardiopulmonary disease is unclear. We studied the prognostic relevance of self reported dyspnea for cardiovascular outcomes and all-cause mortality in persons without previously diagnosed cardiopulmonary disease. METHODS AND RESULTS: We studied 10 881 community-dwelling participants (mean age 57+/-6, 56% women, 25% black) who were free of prevalent cardiopulmonary disease from Atherosclerosis Risk in Communities Study. Dyspnea status at study entry using the modified Medical Research Council (mMRC) scale. The primary outcomes were time to HF, MI or all-cause death. Dyspnea prevalence was 22%, and was mild (mMRC grade 1 or 2) in 21% and moderate-to-severe (mMRC 3 or 4) in 1%. The main correlates of dyspnea were older age, female sex, higher BMI and active smoking. Over a follow-up of 19+/-5 years, greater self-reported dyspnea severity was associated with worse prognosis. Mild dyspnea was associated with significantly heightened risk of HF (adjusted Hazard Ratio, HR,1.30; 95% CI: 1.16-1.46), MI (adjusted HR 1.34; 95%CI: 1.20-1.50), and death (adjusted HR 1.16; 95%CI: 1.06-1.26), with moderate/severe dyspnea associated with an even greater risk (adjusted HR 2.14, 95%CI: 1.59-2.89; 1.93, 95%CI: 1.41-2.56; 1.96, 95%CI: 1.55-2.48, respectively). CONCLUSION: In community-dwelling persons free of previously diagnosed cardiopulmonary disease, self-reported dyspnea is common and, even when of mild intensity, it is independently associated with a greater risk of incident HF, MI, and death. Our data emphasize the prognostic importance of even mild self-reported dyspnea for cardiovascular outcomes. PMID- 27780207 TI - Visual BOLD Response in Late Blind Subjects with Argus II Retinal Prosthesis. AB - Retinal prosthesis technologies require that the visual system downstream of the retinal circuitry be capable of transmitting and elaborating visual signals. We studied the capability of plastic remodeling in late blind subjects implanted with the Argus II Retinal Prosthesis with psychophysics and functional MRI (fMRI). After surgery, six out of seven retinitis pigmentosa (RP) blind subjects were able to detect high-contrast stimuli using the prosthetic implant. However, direction discrimination to contrast modulated stimuli remained at chance level in all of them. No subject showed any improvement of contrast sensitivity in either eye when not using the Argus II. Before the implant, the Blood Oxygenation Level Dependent (BOLD) activity in V1 and the lateral geniculate nucleus (LGN) was very weak or absent. Surprisingly, after prolonged use of Argus II, BOLD responses to visual input were enhanced. This is, to our knowledge, the first study tracking the neural changes of visual areas in patients after retinal implant, revealing a capacity to respond to restored visual input even after years of deprivation. PMID- 27780209 TI - Viral RNA Degradation and Diffusion Act as a Bottleneck for the Influenza A Virus Infection Efficiency. AB - After endocytic uptake, influenza viruses transit early endosomal compartments and eventually reach late endosomes. There, the viral glycoprotein hemagglutinin (HA) triggers fusion between endosomal and viral membrane, a critical step that leads to release of the viral segmented genome destined to reach the cell nucleus. Endosomal maturation is a complex process involving acidification of the endosomal lumen as well as endosome motility along microtubules. While the pH drop is clearly critical for the conformational change and membrane fusion activity of HA, the effect of intracellular transport dynamics on the progress of infection remains largely unclear. In this study, we developed a comprehensive mathematical model accounting for the first steps of influenza virus infection. We calibrated our model with experimental data and challenged its predictions using recombinant viruses with altered pH sensitivity of HA. We identified the time point of virus-endosome fusion and thereby the diffusion distance of the released viral genome to the nucleus as a critical bottleneck for efficient virus infection. Further, we concluded and supported experimentally that the viral RNA is subjected to cytosolic degradation strongly limiting the probability of a successful genome import into the nucleus. PMID- 27780210 TI - Towards Equity in Service Provision for Gay Men and Other Men Who Have Sex with Men in Repressive Contexts. AB - Chris Beyrer and colleagues reflect on an underappreciated trend in multiple African, Asian, and Caribbean settings, in which the provision of HIV and other essential health services for sexual and gender minorities is expanding despite challenging legal and social environments. PMID- 27780211 TI - The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. AB - BACKGROUND: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. METHODS AND FINDINGS: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. CONCLUSIONS: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached. PMID- 27780212 TI - Effects of an Offshore Wind Farm (OWF) on the Common Shore Crab Carcinus maenas: Tagging Pilot Experiments in the Lillgrund Offshore Wind Farm (Sweden). AB - Worldwide growth of offshore renewable energy production will provide marine organisms with new hard substrate for colonization in terms of artificial reefs. The artificial reef effect is important when planning offshore installations since it can create habitat enhancement. Wind power is the most advanced technology within offshore renewable energy sources and there is an urgent need to study its impacts on the marine environment. To test the hypothesis that offshore wind power increases the abundance of reef species relative to a reference area, we conduct an experiment on the model species common shore crab (Carcinus maenas).Overall, 3962 crabs were captured, observed, marked and released in 2011 and 1995 crabs in 2012. Additionally, carapace size, sex distribution, color morphs and body condition was recorded from captured crabs. We observed very low recapture rates at all sites during both years which made evaluating differences in population sizes very difficult. However, we were able to estimate population densities from the capture record for all three sites. There was no obvious artificial reef effect in the Lillgrund wind farm, but a spill-over effect to nearby habitats cannot be excluded. We could not find any effect of the wind farm on either, morphs, sex distribution or condition of the common shore crab. Our study found no evidence that Lillgrund wind farm has a negative effect on populations of the common shore crab. This study provides the first quantitative and experimental data on the common shore crab in relation to offshore wind farms. PMID- 27780213 TI - So Long and Thanks for All the Fish: Overexploitation of the Regionally Endemic Galapagos Grouper Mycteroperca olfax (Jenyns, 1840). AB - The regionally endemic Galapagos Grouper, locally known as bacalao, is one of the most highly prized finfish species within the Galapagos Marine Reserve (GMR). Concerns of overfishing, coupled with a lack of fishing regulations aimed at this species raises concerns about the current population health. We assessed changes in population health over a 30-year period using three simple indicators: (1) percentage of fish below reproductive size (Lm); (2) percentage of fish within the optimum length interval (Lopt); and (3) percentage of mega-spawners in the catch. Over the assessed period, none of the indicators reached values associated with healthy populations, with all indicators declining over time. Furthermore, the most recent landings data show that the vast majority of the bacalao caught (95.7%,) were below Lm, the number of fish within the Lopt interval was extremely low (4.7%), and there were virtually no mega-spawners (0.2%). Bacalao fully recruit to the fishery 15 cm below the size at which 50% of the population matures. The Spawning Potential Ratio is currently 5% of potential unfished fecundity, strongly suggesting severe overfishing. Our results suggest the need for bacalao-specific management regulations that should include minimum (65 cm TL) and maximum (78 cm TL) landing sizes, slot limits (64-78 cm TL), as well as a closed season during spawning from October to January. It is recognized that these regulations are harsh and will certainly have negative impacts on the livelihoods of fishers in the short term, however, continued inaction will likely result in a collapse of this economically and culturally valuable species. Alternative sources of income should be developed in parallel with the establishment of fishing regulations to limit the socio-economic disruption to the fishing community during the transition to a more sustainable management regime. PMID- 27780214 TI - A Simpler Creatinine Index Can Predict Long-Term Survival in Chinese Hemodialysis Patients. AB - BACKGROUND: Low lean body mass (LBM) is an indicator of malnutrition inflammation syndrome, which is common in hemodialysis (HD) patients. The creatinine index (CI) has been validated as a reliable method to estimate LBM and evaluate the protein-energy status of HD patients. However, the traditional creatinine index formula was complex. We sought to investigate the impact of CI derived from a new simple formula on Chinese HD patient outcomes. METHODS: In this retrospective cohort study, we enrolled 1269 patients who initiated HD between February 1981 and February 2012 and followed them until the end of February 2013. CI was calculated using the simple creatinine kinetic model (CKM) formula. Multiple linear regression analysis and Cox regression proportional hazard analysis were used to define independent variables and compare survival between groups. RESULTS: The 1269 HD patients were categorized into 3 groups according to the tertiles of calculated CI between men and women. Each group consisted of 423 patients (50.6% men, 49.4% women). Patients in the highest sex-specific tertile of CI had longer overall survival (HR, 0.46; P 0.002). BMI did not significantly associate with survival after adjustment (HR,0.99; P 0.613). CONCLUSIONS: CI derived from the simple CKM formula serves as a good parameter than BMI to predict the survival of HD patients. The formula could extend its convenient use in clinical practice for HD patients. PMID- 27780215 TI - Return to Work: A Cut-Off of FIM Gain with Montebello Rehabilitation Factor Score in Order to Identify Predictive Factors in Subjects with Acquired Brain Injury. AB - Return to work (RTW) for people with acquired brain injury (ABI) represents a main objective of rehabilitation: this work presents a strong correlation between personal well-being and quality of life. The aim of this study is to investigate the prognostic factors that can predict RTW after ABI (traumatic or non- traumatic aetiology) in patients without disorders of consciousness (e.g. coma, vegetative or minimally conscious state) at the beginning of their admission to rehabilitation. At the end of a 6-month follow-up after discharge, data were successfully collected in 69 patients. The rehabilitation effectiveness (functional Recovery) between admission and discharge was assessed by Functional Independent Measure (FIM) gain, through the Montebello Rehabilitation Factor Score (MRFS), which was obtained as follows: (discharge FIM-admission FIM)/(Maximum possible FIM-Admission FIM) x 100. The cut-off value (criterion) deriving from MRFS, which helped identify RTW patients, resulted in .659 (sn 88.9%; sp 52.4%). Considering the Mini Mental State Examination (MMSE) and the MRFS data, the multivariable binary logistic regression analysis presented 62.96% of correct RTW classification cases, 80.95% of non-RTW leading to an overall satisfactory predictability of 73.91%. The results of the present study suggest that occupational therapy intervention could modify cut-off in patients with an MFRS close to target at the end of an in-hospital rehabilitative program thus developing their capabilities and consequently surpassing cut-off itself. PMID- 27780216 TI - Performance Evaluation of the MyT4 Technology for Determining ART Eligibility. AB - BACKGROUND: In resource-limited countries, CD4 T-cell (CD4) testing continues to be used for determining antiretroviral therapy (ART) initiation eligibility and opportunistic infection monitoring. To support expanded access to CD4 testing, simple and robust technologies are necessary. We conducted this study to evaluate the performance of a new Point-of-Care (POC) CD4 technology, the MyT4, compared to conventional laboratory CD4 testing. METHODS: EDTA venous blood from 200 HIV positive patients was tested in the laboratory using the MyT4 and BD FACSCaliburTM. RESULTS: The MyT4 had an r2 of 0.82 and a mean bias of 12.3 cells/MUl. The MyT4 had total misclassifications of 14.7% and 8.8% when analyzed using ART eligibility thresholds of 350 and 500 cells/MUl, respectively. CONCLUSIONS: We conclude that the MyT4 performed well in classifying patients using the current ART initiation eligibility thresholds in Mozambique when compared to the conventional CD4 technology. PMID- 27780218 TI - Current Situation, Determinants, and Solutions to Drug Shortages in Shaanxi Province, China: A Qualitative Study. AB - OBJECTIVE: Drug shortages were a complex global problem. The aim of this study was to analyze, characterize, and assess the drug shortages, and identify possible solutions in Shaanxi Province, western China. METHODS: A qualitative methodological approach was conducted during May-June 2015 and December 2015 January 2016. Semi-structured interviews were performed to gather information from representatives of hospital pharmacists, wholesalers, pharmaceutical producers, and local health authorities. RESULTS: Thirty participants took part in the study. Eight traditional Chinese medicines and 87 types of biologicals and chemicals were reported to be in short supply. Most were essential medicines. Five main determinants of drug shortages were detected: too low prices, too low market demands, Good Manufacturing Practice (GMP) issues, materials issues, and approval issues for imported drugs. Five different solutions were proposed by the participants: 1) let the market decide the drug price; 2) establish an information platform; 3) establish a reserve system; 4) enhance the communication among the three parties in the supply chain; and 5) improve hospital inventory management. CONCLUSIONS: Western China was currently experiencing a serious drug shortage. Numerous reasons for the shortage were identified. Most drug shortages in China were currently because of "too low prices." To solve this problem, all of the stakeholders, especially the government, needed to participate in managing the drug shortages. PMID- 27780217 TI - The Tuberculosis Cascade of Care in India's Public Sector: A Systematic Review and Meta-analysis. AB - BACKGROUND: India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world's "missing" patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The "cascade of care" is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions. METHODS AND FINDINGS: The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India's TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014-2015), one WHO dataset (2015), and three RNTCP reports (2014 2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000-2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000-3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775 1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India. CONCLUSIONS: Increasing case detection is critical to improving outcomes in India's TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India. PMID- 27780220 TI - Constraining Forest Certificate's Market to Improve Cost-Effectiveness of Biodiversity Conservation in Sao Paulo State, Brazil. AB - The recently launched Brazilian "forest certificates" market is expected to reduce environmental compliance costs for landowners through an offset mechanism, after a long history of conservation laws based in command-and-control and strict rules. In this paper we assessed potential costs and evaluated the cost effectiveness of the instrument when introducing to this market constraints that aim to address conservation objectives more specifically. Using the conservation planning software Marxan with Zones we simulated different scopes for the "forest certificates" market, and compared their cost-effectiveness with that of existing command-and-control (C&C), i.e. compliance to the Legal Reserve on own property, in the state of Sao Paulo. The simulations showed a clear potential of the constrained "forest certificates" market to improve conservation effectiveness and increase cost-effectiveness on allocation of Legal Reserves. Although the inclusion of an additional constraint of targeting the BIOTA Conservation Priority Areas doubled the cost (+95%) compared with a "free trade" scenario constrained only by biome, this option was still 50% less costly than the baseline scenario of compliance with Legal Reserve at the property. PMID- 27780219 TI - Engineering Permissive Insertion Sites in the Bacteriophage Phi29 DNA-Linked Terminal Protein. AB - Many different DNA delivery vehicles have been developed and tested, all with their advantages and disadvantages. The bacteriophage phi29 terminal protein (TP) is covalently linked to the 5' ends of the phage genome during the DNA replication process. Our approach is to utilize this TP as a platform to incorporate different protein or peptide modules that can target the DNA to the interior of the cell, to the nucleus, or even to subcellular compartments. In order to be able to insert different peptide modules on the TP sequence to endow it with desired functions and/or eliminate unwanted regions of the protein, we have carried out a transposition screening to detect insertion-permissive points on the sequence of the TP. We report the functional characterization of 12 insertion mutants of the TP, and the identification of one site at position 38 that allows the insertion of peptides up to 17 amino acids in length while maintaining the ability of the TP to support DNA amplification in vitro. A protein with one insertion at that position containing a cysteine residue, a linker, and a thrombin recognition site was purified and its amplification activity was optimized. PMID- 27780221 TI - Breeding, Early-Successional Bird Response to Forest Harvests for Bioenergy. AB - Forest regeneration following timber harvest is a principal source of habitat for early-successional birds and characterized by influxes of early-successional vegetation and residual downed woody material. Early-successional birds may use harvest residues for communication, cover, foraging, and nesting. Yet, increased market viability of woody biomass as bioenergy feedstock may intensify harvest residue removal. Our objectives were to: 1) evaluate effects of varying intensities of woody biomass harvest on the early-successional bird community; and (2) document early-successional bird use of harvest residues in regenerating stands. We spot-mapped birds from 15 April- 15 July, 2012-2014, in six woody biomass removal treatments within regenerating stands in North Carolina (n = 4) and Georgia (n = 4), USA. Treatments included clearcut harvest followed by: (1) traditional woody biomass harvest with no specific retention target; (2) 15% retention with harvest residues dispersed; (3) 15% retention with harvest residues clustered; (4) 30% retention with harvest residues dispersed; (5) 30% retention with harvest residues clustered; and (6) no woody biomass harvest (i.e., reference site). We tested for treatment-level effects on breeding bird species diversity and richness, early-successional focal species territory density (combined and individual species), counts of breeding birds detected near, in, or on branches of harvest piles/windrows, counts of breeding bird behaviors, and vegetation composition and structure. Pooled across three breeding seasons, we delineated 536 and 654 territories and detected 2,489 and 4,204 birds in the North Carolina and Georgia treatments, respectively. Woody biomass harvest had limited or short-lived effects on the early-successional, breeding bird community. The successional trajectory of vegetation structure, rather than availability of harvest residues, primarily drove avian use of regenerating stands. However, many breeding bird species used downed wood in addition to vegetation, indicating that harvest residues initially may provide food and cover resources for early-successional birds in regenerating stands prior to vegetation regrowth. PMID- 27780222 TI - Population Screening Using Sewage Reveals Pan-Resistant Bacteria in Hospital and Community Samples. AB - The presence of pan-resistant bacteria worldwide possesses a threat to global health. It is difficult to evaluate the extent of carriage of resistant bacteria in the population. Sewage sampling is a possible way to monitor populations. We evaluated the presence of pan-resistant bacteria in Israeli sewage collected from all over Israel, by modifying the pour plate method for heterotrophic plate count technique using commercial selective agar plates. This method enables convenient and fast sewage sampling and detection. We found that sewage in Israel contains multiple pan-resistant bacteria including carbapenemase resistant Enterobacteriacae carrying blaKPC and blaNDM-1, MRSA and VRE. blaKPC carrying Klebsiella pneumonia and Enterobacter cloacae were the most common Enterobacteriacae drug resistant bacteria found in the sewage locations we sampled. Klebsiella pneumonia, Enterobacter spp., Escherichia coli and Citrobacter spp. were the 4 main CRE isolated from Israeli sewage and also from clinical samples in our clinical microbiology laboratory. Hospitals and Community sewage had similar percentage of positive samplings for blaKPC and blaNDM-1. VRE was found to be more abundant in sewage in Israel than MRSA but there were more locations positive for MRSA and VRE bacteria in Hospital sewage than in the Community. Therefore, our upgrade of the pour plate method for heterotrophic plate count technique using commercial selective agar plates can be a useful tool for routine screening and monitoring of the population for pan-resistant bacteria using sewage. PMID- 27780223 TI - LIM-Only Protein 4 (LMO4) and LIM Domain Binding Protein 1 (LDB1) Promote Growth and Metastasis of Human Head and Neck Cancer (LMO4 and LDB1 in Head and Neck Cancer). AB - Squamous cell carcinoma of the head and neck (HNSCC) accounts for more than 300,000 deaths worldwide per year as a consequence of tumor cell invasion of adjacent structures or metastasis. LIM-only protein 4 (LMO4) and LIM-domain binding protein 1 (LDB1), two directly interacting transcriptional adaptors that have important roles in normal epithelial cell differentiation, have been associated with increased metastasis, decreased differentiation, and shortened survival in carcinoma of the breast. Here, we implicate two LDB1-binding proteins, single-stranded binding protein 2 (SSBP2) and 3 (SSBP3), in controlling LMO4 and LDB1 protein abundance in HNSCC and in regulating specific tumor cell functions in this disease. First, we found that the relative abundance of LMO4, LDB1, and the two SSBPs correlated very significantly in a panel of human HNSCC cell lines. Second, expression of these proteins in tumor primaries and lymph nodes involved by metastasis were concordant in 3 of 3 sets of tissue. Third, using a Matrigel invasion and organotypic reconstruct assay, CRISPR/Cas9-mediated deletion of LDB1 in the VU-SCC-1729 cell line, which is highly invasive of basement membrane and cellular monolayers, reduced tumor cell invasiveness and migration, as well as proliferation on tissue culture plastic. Finally, inactivation of the LDB1 gene in these cells decreased growth and vascularization of xenografted human tumor cells in vivo. These data show that LMO4, LDB1, and SSBP2 and/or SSBP3 regulate metastasis, proliferation, and angiogenesis in HNSCC and provide the first evidence that SSBPs control LMO4 and LDB1 protein abundance in a cancer context. PMID- 27780224 TI - Glioblastoma Segmentation: Comparison of Three Different Software Packages. AB - To facilitate a more widespread use of volumetric tumor segmentation in clinical studies, there is an urgent need for reliable, user-friendly segmentation software. The aim of this study was therefore to compare three different software packages for semi-automatic brain tumor segmentation of glioblastoma; namely BrainVoyagerTM QX, ITK-Snap and 3D Slicer, and to make data available for future reference. Pre-operative, contrast enhanced T1-weighted 1.5 or 3 Tesla Magnetic Resonance Imaging (MRI) scans were obtained in 20 consecutive patients who underwent surgery for glioblastoma. MRI scans were segmented twice in each software package by two investigators. Intra-rater, inter-rater and between software agreement was compared by using differences of means with 95% limits of agreement (LoA), Dice's similarity coefficients (DSC) and Hausdorff distance (HD). Time expenditure of segmentations was measured using a stopwatch. Eighteen tumors were included in the analyses. Inter-rater agreement was highest for BrainVoyager with difference of means of 0.19 mL and 95% LoA from -2.42 mL to 2.81 mL. Between-software agreement and 95% LoA were very similar for the different software packages. Intra-rater, inter-rater and between-software DSC were >= 0.93 in all analyses. Time expenditure was approximately 41 min per segmentation in BrainVoyager, and 18 min per segmentation in both 3D Slicer and ITK-Snap. Our main findings were that there is a high agreement within and between the software packages in terms of small intra-rater, inter-rater and between-software differences of means and high Dice's similarity coefficients. Time expenditure was highest for BrainVoyager, but all software packages were relatively time-consuming, which may limit usability in an everyday clinical setting. PMID- 27780225 TI - Additive Promotion of Viral Internal Ribosome Entry Site-Mediated Translation by Far Upstream Element-Binding Protein 1 and an Enterovirus 71-Induced Cleavage Product. AB - The 5' untranslated region (5' UTR) of the enterovirus 71 (EV71) RNA genome contains an internal ribosome entry site (IRES) that is indispensable for viral protein translation. Due to the limited coding capacity of their RNA genomes, EV71 and other picornaviruses typically recruit host factors, known as IRES trans acting factors (ITAFs), to mediate IRES-dependent translation. Here, we show that EV71 viral proteinase 2A is capable of cleaving far upstream element-binding protein 1 (FBP1), a positive ITAF that directly binds to the EV71 5' UTR linker region to promote viral IRES-driven translation. The cleavage occurs at the Gly 371 residue of FBP1 during the EV71 infection process, and this generates a functional cleavage product, FBP11-371. Interestingly, the cleavage product acts to promote viral IRES activity. Footprinting analysis and gel mobility shift assay results showed that FBP11-371 similarly binds to the EV71 5' UTR linker region, but at a different site from full-length FBP1; moreover, FBP1 and FBP11 371 were found to act additively to promote IRES-mediated translation and virus yield. Our findings expand the current understanding of virus-host interactions with regard to viral recruitment and modulation of ITAFs, and provide new insights into translational control during viral infection. PMID- 27780227 TI - Climate Risk Modelling of Balsam Woolly Adelgid Damage Severity in Subalpine Fir Stands of Western North America. AB - The balsam woolly adelgid (Adelges piceae (Ratzeburg) (Homoptera: Adelgidae)) (BWA) is a nonnative, invasive insect that threatens Abies species throughout North America. It is well established in the Pacific Northwest, but continues to move eastward through Idaho and into Montana and potentially threatens subalpine fir to the south in the central and southern Rocky Mountains. We developed a climatic risk model and map that predicts BWA impacts to subalpine fir using a two-step process. Using 30-year monthly climate normals from sites with quantitatively derived BWA damage severity index values, we built a regression model that significantly explained insect damage. The sites were grouped into two distinct damage categories (high damage and mortality versus little or no mortality and low damage) and the model estimates for each group were used to designate distinct value ranges for four climatic risk categories: minimal, low, moderate, and high. We then calculated model estimates for each cell of a 4 kilometer resolution climate raster and mapped the risk categories over the entire range of subalpine fir in the western United States. The spatial variation of risk classes indicates a gradient of climatic susceptibility generally decreasing from the Olympic Peninsula in Washington and the Cascade Range in Oregon and Washington moving eastward, with the exception of some high risk areas in northern Idaho and western Montana. There is also a pattern of decreasing climatic susceptibility from north to south in the Rocky Mountains. Our study provides an initial step for modeling the relationship between climate and BWA damage severity across the range of subalpine fir. We showed that September minimum temperature and a metric calculated as the maximum May temperature divided by total May precipitation were the best climatic predictors of BWA severity. Although winter cold temperatures and summer heat have been shown to influence BWA impacts in other locations, these variables were not as predictive as spring and fall conditions in the Pacific Northwest. PMID- 27780228 TI - Correction: Decreased Sperm Motility Retarded ICSI Fertilization Rate in Severe Oligozoospermia but Good-Quality Embryo Transfer Had Achieved the Prospective Clinical Outcomes. AB - [This corrects the article DOI: 10.1371/journal.pone.0163524.]. PMID- 27780226 TI - The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life. AB - A drug's biological half-life is defined as the time required for the human body to metabolize or eliminate 50% of the initial drug dosage. Correctly measuring the half-life of a given drug is helpful for the safe and accurate usage of the drug. In this study, we investigated which gene ontology (GO) terms and biological pathways were highly related to the determination of drug half-life. The investigated drugs, with known half-lives, were analyzed based on their enrichment scores for associated GO terms and KEGG pathways. These scores indicate which GO terms or KEGG pathways the drug targets. The feature selection method, minimum redundancy maximum relevance, was used to analyze these GO terms and KEGG pathways and to identify important GO terms and pathways, such as sodium independent organic anion transmembrane transporter activity (GO:0015347), monoamine transmembrane transporter activity (GO:0008504), negative regulation of synaptic transmission (GO:0050805), neuroactive ligand-receptor interaction (hsa04080), serotonergic synapse (hsa04726), and linoleic acid metabolism (hsa00591), among others. This analysis confirmed our results and may show evidence for a new method in studying drug half-lives and building effective computational methods for the prediction of drug half-lives. PMID- 27780229 TI - A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation. AB - Defects in neutrophil function have been implicated in a wide spectrum of clinical conditions. Several models are employed to study activated human neutrophils akin to those found at a site of inflammation. These include whole blood (WB) ex vivo stimulation with lipopolysaccharide (LPS) and in vivo techniques: cantharidin blister, skin windows and intra-dermal injection of UV killed E.coli (UVKEc). Neutrophils obtained from these have never been compared. We compared the activation status of neutrophils from each technique in order to inform the optimal model for use in human studies. Healthy male volunteers were randomised to undergo one of the four techniques (n = 5/group). LPS: WB stimulated with 1ng/ml of LPS for 4 hours. Cantharidin: 12.5MUl of 0.1% cantharidin elicited a single blister, aspirated at 24 hours. Skin windows: four 6mm mechanical-suction blisters created, de-roofed and an exudate-collection chamber placed over the windows for 4 hours before aspiration. UVKEc: 1.5 x 107 UVKEc injected intra-dermally. A single 10mm mechanical-suction blister formed and aspirated at 4 hours. Unstimulated WB used as the control. Flow cytometry was used to determine activation status using CD16, CD11b, CD54, CD62L and CD88. Functional status was assessed with a phagocytosis assay. The pattern of neutrophil activation was similar in all models. Neutrophil CD11b was elevated in all models, most markedly in UVKEc (p<0.0001), and CD54 was also elevated but only significant in the LPS model (p = 0.001). CD62L was significantly reduced in all 4 models (p<0.0001) and CD88 was also suppressed in all. There were no changes in CD16 in any model, neither was there any significant difference in the phagocytic capacity of the neutrophils. In summary, there are no significant differences in activation marker expression or phagocytic capacity in the neutrophils obtained from each technique. Therefore we believe whole blood stimulation is the best model in experimentally challenging inpatient populations. PMID- 27780231 TI - A Single Amino Acid Dictates Protein Kinase R Susceptibility to Unrelated Viral Antagonists. AB - During millions of years of coevolution with their hosts, cytomegaloviruses (CMVs) have succeeded in adapting to overcome host-specific immune defenses, including the protein kinase R (PKR) pathway. Consequently, these adaptations may also contribute to the inability of CMVs to cross species barriers. Here, we provide evidence that the evolutionary arms race between the antiviral factor PKR and its CMV antagonist TRS1 has led to extensive differences in the species specificity of primate CMV TRS1 proteins. Moreover, we identify a single residue in human PKR that when mutated to the amino acid present in African green monkey (Agm) PKR (F489S) is sufficient to confer resistance to HCMVTRS1. Notably, this precise molecular determinant of PKR resistance has evolved under strong positive selection among primate PKR alleles and is positioned within the alphaG helix, which mediates the direct interaction of PKR with its substrate eIF2alpha. Remarkably, this same residue also impacts sensitivity to K3L, a poxvirus-encoded pseudosubstrate that structurally mimics eIF2alpha. Unlike K3L, TRS1 has no homology to eIF2alpha, suggesting that unrelated viral genes have convergently evolved to target this critical region of PKR. Despite its functional importance, the alphaG helix exhibits extraordinary plasticity, enabling adaptations that allow PKR to evade diverse viral antagonists while still maintaining its critical interaction with eIF2alpha. PMID- 27780230 TI - The Drosophila CD36 Homologue croquemort Is Required to Maintain Immune and Gut Homeostasis during Development and Aging. AB - Phagocytosis is an ancient mechanism central to both tissue homeostasis and immune defense. Both the identity of the receptors that mediate bacterial phagocytosis and the nature of the interactions between phagocytosis and other defense mechanisms remain elusive. Here, we report that Croquemort (Crq), a Drosophila member of the CD36 family of scavenger receptors, is required for microbial phagocytosis and efficient bacterial clearance. Flies mutant for crq are susceptible to environmental microbes during development and succumb to a variety of microbial infections as adults. Crq acts parallel to the Toll and Imd pathways to eliminate bacteria via phagocytosis. crq mutant flies exhibit enhanced and prolonged immune and cytokine induction accompanied by premature gut dysplasia and decreased lifespan. The chronic state of immune activation in crq mutant flies is further regulated by negative regulators of the Imd pathway. Altogether, our data demonstrate that Crq plays a key role in maintaining immune and organismal homeostasis. PMID- 27780232 TI - Typhoid Fever in South Africa in an Endemic HIV Setting. AB - BACKGROUND: Typhoid fever remains an important disease in Africa, associated with outbreaks and the emerging multidrug resistant Salmonella enterica serotype Typhi (Salmonella Typhi) haplotype, H58. This study describes the incidence of, and factors associated with mortality due to, typhoid fever in South Africa, where HIV prevalence is high. METHODS AND FINDINGS: Nationwide active laboratory-based surveillance for culture-confirmed typhoid fever was undertaken from 2003-2013. At selected institutions, additional clinical data from patients were collected including age, sex, HIV status, disease severity and outcome. HIV prevalence among typhoid fever patients was compared to national HIV seroprevalence estimates. The national reference laboratory tested Salmonella Typhi isolates for antimicrobial susceptibility and haplotype. Unadjusted and adjusted logistic regression analyses were conducted determining factors associated with typhoid fever mortality. We identified 855 typhoid fever cases: annual incidence ranged from 0.11 to 0.39 per 100,000 population. Additional clinical data were available for 369 (46.8%) cases presenting to the selected sites. Among typhoid fever patients with known HIV status, 19.3% (29/150) were HIV-infected. In adult females, HIV prevalence in typhoid fever patients was 43.2% (19/44) versus 15.7% national HIV seroprevalence (P < .001); in adult males, 16.3% (7/43) versus 12.3% national HIV seroprevalence (P = .2). H58 represented 11.9% (22/185) of Salmonella Typhi isolates tested. Increased mortality was associated with HIV infection (AOR 10.7; 95% CI 2.3-50.3) and disease severity (AOR 9.8; 95% CI 1.6 60.0) on multivariate analysis. CONCLUSIONS: Typhoid fever incidence in South Africa was largely unchanged from 2003-2013. Typhoid fever mortality was associated disease severity. HIV infection may be a contributing factor. Interventions mandate improved health care access, including to HIV management programmes as well as patient education. Further studies are necessary to clarify relationships between HIV infection and typhoid fever in adults. PMID- 27780233 TI - A Comprehensive Analysis on the Association between Tobacco-Free Betel Quid and Risk of Head and Neck Cancer in Taiwanese Men. AB - OBJECTIVES: Although betel quid (BQ) is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature regarding the dose response, BQ types, HNC sites, and BQ cessation. The current study was conducted to fill these insufficiencies. MATERIALS AND METHODS: A hospital-based case control study was conducted to evaluate the association between BQ and HNC. In person interview was conducted to collect data on BQ chewing. The current analysis included 487 men newly diagnosed with HNC and 617 male controls who were frequency-matched to the cases by age. The association between BQ and HNC was assessed using multivariable unconditional logistic regression. RESULTS: Ever BQ chewing was associated with an increased HNC risk regardless of the BQ types. A non-linear positive association between BQ and HNC was observed, with a steep rise in HNC risk for the first 5 pack-years or 200,000 minutes of BQ consumption. Every year of BQ cessation was associated with a 2.9% reduction in HNC risk; however, the risk did not reduce to the level of non-BQ chewers even after 20 years of BQ cessation. Eliminating BQ chewing may prevent 51.6% of HNCs, 62.6% of oral cancers, and 41.3% of pharyngeal cancers in Taiwan. CONCLUSION: Our results supported the positive association between BQ and HNC. BQ cessation is effective in reducing HNC risk and should be encouraged. Because BQ cessation may not reduce the HNC risk to the level of non-BQ chewers, it is important to prevent the initiation of BQ chewing. PMID- 27780234 TI - Early Fluid Resuscitation by Lactated Ringer's Solution Alleviate the Cardiac Apoptosis in Rats with Trauma-Hemorrhagic Shock. AB - Cardiac trauma has been recognized as a complication associated with blunt chest trauma involving coronary artery injury, myocardium contusion and myocardial rupture. Secondary cardiac injuries after trauma supposed to be a critical factor in trauma patients, but the mechanism is not fully explored. Overproduction of TNF-alpha had been reported in multiple trauma animals, this induces oxidative stress resulting in cardiac apoptosis. Apoptosis gradually increases after trauma and reaches to a maximum level in 12 h time. TNF-alpha increases the expression of NFkB, and induces the expression of caspase-3 and resulted in cell apoptosis. The effect can be attenuated by non-selective caspase inhibitor and IL10. Fas induced cardiac apoptosis and hypertrophy in ischemic heart disease. In this study, we demonstrated a trauma-hemorrhagic shock (THS) model in rats and resuscitated rats by lactated Ringer's (L/R) solution after shock in different hours (0 hour, 4 hours, 8 hours). NFkB gradually increased after the first 8 hours of shock, and can be reduced by fluid resuscitation. NFkB is known as a downstream pathway of Fas related apoptosis, we found Fas ligand, caspase-8 levels elevate after shock, and can be reduced by resuscitation. In addition, resuscitation can activate insulin-like growth factor (IGF-1)/Akt pathway, at the same time. It can block mitochondrial damage by decrease the effect of tBid. In conclusion, THS can induce secondary cardiac injury. Fas showed to be an important element in caspase cascade induced myocardium apoptosis. By L/R fluid resuscitation, the suppression of caspase cascade and activation of IGF-I/Akt pathway showed antiapoptotic effects in traumatic heart of rats. PMID- 27780235 TI - Comparison of HLA-A, -B and -DRB1 Loci Polymorphism between Kidney Transplants of Uremia Patients and Healthy Individuals in Central China. AB - Chronic kidney disease is becoming a global public health problem, which will usually cause uremia at the end stage of chronic kidney failure. So far, kidney transplant is the most effective and proper therapy for uremia, however, the short supply of matched donor kidney has been a persistent bottleneck for transplantation. HLA matching of HLA-A, -B and -DRB1 loci is very important for the allocation of kidney transplants. In this study, we investigated genotypes of HLA-A, -B and -DRB1 loci based on 1,464 uremia patients and 10,000 unrelated healthy individuals in Henan province of China, and compared the frequency distribution of these HLA alleles and corresponding haplotypes between patient and healthy groups. We detected 23 HLA-A, 49 HLA-B and 17 HLA-DRB1 alleles in total. The predominant alleles of HLA-A, -B and -DRB1 loci in patients are the same as those in healthy group. The seven most frequent alleles account for about 87%, 50%, and 77% at HLA-A, -B and -DRB1 loci, respectively. The haplotypes (combinations of HLA-A, -B, and -DRB1) with significantly different frequency between patients and controls mostly account for less than 1%. Overall, this suggests that HLA matching is not a potential difficulty for kidney transplant of uremia patients. However, three of the top seven frequent HLA-DRB1 alleles have a significantly different distribution in patients and controls, while only one alleles for HLA-B and zero for HLA-A loci. These HLA-DRB1 alleles may be closely associated with uremia. This study sheds new lights on the composition and difference of HLA genotypes in uremia patients and healthy populations in Central China that can serve as a guide to HLA matching for kidney transplants and a resource for HLA typing-related studies. PMID- 27780236 TI - Conditioned Medium from Placental Mesenchymal Stem Cells Reduces Oxidative Stress during the Cryopreservation of Ex Vivo Expanded Umbilical Cord Blood Cells. AB - BACKGROUND: The limited cell dose in umbilical cord blood (UCB) necessitates ex vivo expansion of UCB. Further, the effective cryopreservation of these expanded cells is important in widening their use in the clinics. During cryopreservation, cells experience oxidative stress due to the generation of reactive oxygen species (ROS). Conditioned medium from mesenchymal stem cells (MSCs-CM) has been shown to alleviate the oxidative stress during wound healing, Alzheimer's disease and ischemic disease. This premise prompted us to investigate the influence of MSCs-CM during cryopreservation of expanded UCB cells. METHODOLOGY/PRINCIPLE FINDINGS: CM-was collected from cord/placental MSCs(C-MSCs-CM, P-MSC-CM). UCB CD34+cells were expanded as suspension cultures in serum free medium containing cytokines for 10 days. Cells were frozen with/without C-MSCs-CM and or P-MSCs-CM in the conventional freezing medium containing 20%FCS +10%DMSO using a programmable freezer and stored in liquid nitrogen. Upon revival, cells frozen with MSCs-CM were found to be superior to cells frozen in conventional medium in terms of viability, CD34+content and clonogenecity. Priming of revived cells for 48 hrs with MSCs-CM further improved their transplantation ability, as compared to those cultured without MSCs-CM. P-MSCs-CM radically reduced the oxidative stress in cryopreserved cells, resulting in better post thaw functionality of CD34+ cells than with C-MSCs-CM. The observed cryoprotective effect of MSCs-CM was primarily due to anti-oxidative and anti-apoptotic properties of the MSCs-CM and not because of the exosomes secreted by them. CONCLUSIONS/SIGNIFICANCE: Our data suggest that MSCs-CM can serve as a valuable additive to the freezing or the priming medium for expanded UCB cells, which would increase their clinical applicability. PMID- 27780237 TI - Psychometric Properties of a Generic, Patient-Centred Palliative Care Outcome Measure of Symptom Burden for People with Progressive Long Term Neurological Conditions. AB - BACKGROUND: There is no standard palliative care outcome measure for people with progressive long term neurological conditions (LTNC). This study aims to determine the psychometric properties of a new 8-item palliative care outcome scale of symptom burden (IPOS Neuro-S8) in this population. DATA AND METHODS: Data were merged from a Phase II palliative care intervention study in multiple sclerosis (MS) and a longitudinal observational study in idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). The IPOS Neuro-S8 was assessed for its data quality, score distribution, ceiling and floor effects, reliability, factor structure, convergent and discriminant validity, concurrent validity with generic (Palliative care Outcome Scale) and condition specific measures (Multiple Sclerosis Impact Scale; Non motor Symptoms Questionnaire; Parkinson's Disease Questionnaire), responsiveness and minimally clinically important difference. RESULTS: Of the 134 participants, MS patients had a mean Extended Disability Status Scale score 7.8 (SD = 1.0), patients with an IPD, MSA or PSP were in Hoehn & Yahr stage 3-5. The IPOS Neuro S8 had high data quality (2% missing), mean score 8 (SD = 5; range 0-32), no ceiling effects, borderline floor effects, good internal consistency (Cronbach's alpha = 0.7) and moderate test-retest reliability (intraclass coefficient = 0.6). The results supported a moderately correlated two-factor structure (Pearson's r = 0.5). It was moderately correlated with generic and condition specific measures (Pearson's r: 0.5-0.6). There was some evidence for discriminant validity in IPD, MSA and PSP (p = 0.020), and for good responsiveness and longitudinal construct validity. CONCLUSIONS: IPOS Neuro-S8 shows acceptable to promising psychometric properties in common forms of progressive LTNCs. Future work needs to confirm these findings with larger samples and its usefulness in wider disease groups. PMID- 27780239 TI - Hybrid Origins of Carex rostrata var. borealis and C. stenolepis, Two Problematic Taxa in Carex Section Vesicariae (Cyperaceae). AB - Hybridization is frequent in the large and ecologically significant genus Carex (Cyperaceae). In four important sections of the northern regions (Ceratocystis, Glareosae, Phacocystis and Vesicariae), the frequent occurrence of hybrids often renders the identification of "pure" species and hybrids difficult. In this study we address the origins and taxonomic rank of two taxa of section Vesicariae: Carex rostrata var. borealis and C. stenolepis. The origin and taxonomic status of C. stenolepis has been the subject of substantial debate over the years, whereas C. rostrata var. borealis has received very little attention in the years since its first description in the 19th century. By performing an extensive sampling of relevant taxa from a broad distribution range, and analyzing data from fifteen microsatellite loci developed specifically for our study together with pollen stainability measures, we resolve the hybrid origins of C. rostrata var. borealis and C. stenolepis and provide new insights into this taxonomically challenging group of sedges. Our results are in accordance with previous findings suggesting that C. stenolepis is a hybrid between C. vesicaria and C. saxatilis. They are also in accordance with a previous proposition that C. rostrata var. borealis is a hybrid between C. rostrata and C. rotundata, and furthermore suggest that both hybrids are the result of multiple, recent (i.e., postglacial) hybridization events. We found little evidence for successful sexual reproduction within C. rostrata var. borealis and C. stenolepis, but conclude that the common and recurrent, largely predictable occurrence of these taxa justifies accepting both hybrids as hybrid species with binomial names. There are, however, complications as to types and priority names, and we therefore choose to address these problems in a separate paper. PMID- 27780238 TI - Bacterial Etiology and Risk Factors Associated with Cellulitis and Purulent Skin Abscesses in Military Trainees. AB - : Military trainees are at high risk for skin and soft-tissue infections (SSTIs). Although Staphylococcus aureus is associated with purulent SSTI, it is unclear to what degree this pathogen causes nonpurulent cellulitis. To inform effective prevention strategies and to provide novel insights into SSTI pathogenesis, we aimed to determine the etiology of SSTI in this population. We conducted a prospective observational study in US Army Infantry trainees with SSTI (cutaneous abscesses and cellulitis) from July 2012 through December 2014. We used standard microbiology, serology, and high-throughput sequencing to determine the etiology of SSTI. Furthermore, we compared purported risk factors as well as anatomic site colonization for S. aureus. Among 201 SSTI cases evaluated for SSTI risk factors, cellulitis was associated with lower extremity blisters (P = 0.01) and abscess was associated with methicillin-resistant S. aureus (MRSA) colonization (P<0.001). Among the 22 tested cellulitis cases that were part of the microbiome analysis, only 1 leading edge aspirate was culturable (Coagulase-negative Staphylococcus). Microbiome evaluation of aspirate specimens demonstrated that Rhodanobacter terrae was the most abundant species (66.8% average abundance), while abscesses were dominated by S. aureus (92.9% average abundance). Although abscesses and cellulitis share the spectrum of clinical SSTI, the bacterial etiologies as determined by current technology appear distinct. Furthermore, the presence of atypical bacteria within cellulitis aspirates may indicate novel mechanisms of cellulitis pathogenesis. CLINICAL TRIALS REGISTRATION: NCT01105767. PMID- 27780240 TI - Expression of Soluble Forms of Yeast Diacylglycerol Acyltransferase 2 That Integrate a Broad Range of Saturated Fatty Acids in Triacylglycerols. AB - The membrane proteins acyl-CoA:diacylglycerol acyltransferases (DGAT) are essential actors for triglycerides (TG) biosynthesis in eukaryotic organisms. Microbial production of TG is of interest for producing biofuel and value-added novel oils. In the oleaginous yeast Yarrowia lipolytica, Dga1p enzyme from the DGAT2 family plays a major role in TG biosynthesis. Producing recombinant DGAT enzymes pure and catalytically active is difficult, hampering their detailed functional characterization. In this report, we expressed in Escherichia coli and purified two soluble and active forms of Y. lipolytica Dga1p as fusion proteins: the first one lacking the N-terminal hydrophilic segment (Dga1pDelta19), the second one also devoid of the N-terminal putative transmembrane domain (Dga1pDelta85). Most DGAT assays are performed on membrane fractions or microsomes, using radiolabeled substrates. We implemented a fluorescent assay in order to decipher the substrate specificity of purified Dga1p enzymes. Both enzyme versions prefer acyl-CoA saturated substrates to unsaturated ones. Dga1pDelta85 preferentially uses long-chain saturated substrates. Dga1p activities are inhibited by niacin, a specific DGAT2 inhibitor. The N-terminal transmembrane domain appears important, but not essential, for TG biosynthesis. The soluble and active proteins described here could be useful tools for future functional and structural studies in order to better understand and optimize DGAT enzymes for biotechnological applications. PMID- 27780241 TI - Comparison of Anesthesia-Controlled Operating Room Time between Propofol-Based Total Intravenous Anesthesia and Desflurane Anesthesia in Open Colorectal Surgery: A Retrospective Study. AB - We conducted a retrospective study to investigate the anesthesia-controlled time and factors that contribute to prolonged extubation in open colorectal surgery. Using our hospital database, demographic data, various time intervals (waiting for anesthesia time, anesthesia time, surgical time, emergence time, exit from operating room after extubation, total operating room time, and post-anesthesia care unit stay time), and incidence of prolonged extubation (>= 15 mins), were compared between patients who received desflurane/fentanyl-based anesthesia and total intravenous anesthesia via target-controlled infusion with fentanyl/propofol. Logistic regression analyses were performed to assess the association between variables that contributed to prolonged extubation. In conclusion, the anesthesia-controlled time was similar in desflurane anesthesia and propofol-based total intravenous anesthesia for open colorectal surgery in our hospital. Surgical time greater than 210 minutes, as well as age, contributed to prolonged extubation. PMID- 27780242 TI - Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts. AB - Cytochrome-c-oxidase (COX) deficiency is a frequent cause of mitochondrial disease and is associated with a wide spectrum of clinical phenotypes. We studied mitochondrial function and biogenesis in fibroblasts derived from the Cohen (CDs) rat, an animal model of COX deficiency. COX activity in CDs-fibroblasts was 50% reduced compared to control rat fibroblasts (P<0.01). ROS-production in CDs fibroblasts increased, along with marked mitochondrial fragmentation and decreased mitochondrial membrane-potential, indicating mitochondrial dysfunction. Surprisingly, cellular ATP content, oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) were unchanged. To clarify the discrepancy between mitochondrial dysfunction and ATP production, we studied mitochondrial biogenesis and turnover. The content of mitochondria was higher in CDs-fibroblasts. Consistently, AMPK activity and the expression of NRF1-target genes, NRF2 and PGC1-alpha that mediate mitochondrial biogenesis were increased (P<0.01 vs control fibroblast). In CDs-fibrobalsts, the number of autophagosomes (LC3+ puncta) containing mitochondria in CDs fibroblasts was similar to that in control fibroblasts, suggesting that mitophagy was intact. Altogether, our findings demonstrate that mitochondrial dysfunction and oxidative stress are associated with an increase in mitochondrial biogenesis, resulting in preservation of ATP generation. PMID- 27780243 TI - Local Electrical Dyssynchrony during Atrial Fibrillation: Theoretical Considerations and Initial Catheter Ablation Results. AB - BACKGROUND: Electrogram-based identification of the regions maintaining persistent Atrial Fibrillation (AF) is a subject of ongoing debate. Here, we explore the concept of local electrical dyssynchrony to identify AF drivers. METHODS AND RESULTS: Local electrical dyssynchrony was calculated using mean phase coherence. High-density epicardial mapping along with mathematical model were used to explore the link between local dyssynchrony and properties of wave conduction. High-density mapping showed a positive correlation between the dyssynchrony and number of fibrillatory waves (R2 = 0.68, p<0.001). In the mathematical model, virtual ablation at high dyssynchrony regions resulted in conduction regularization. The clinical study consisted of eighteen patients undergoing catheter ablation of persistent AF. High-density maps of left atrial (LA) were constructed using a circular mapping catheter. After pulmonary vein isolation, regions with the top 10% of the highest dyssynchrony in LA were targeted during ablation and followed with ablation of complex atrial electrograms. Catheter ablation resulted in termination during ablation at high dyssynchrony regions in 7 (41%) patients. In another 4 (24%) patients, transient organization was observed. In 6 (35%) there was no clear effect. Long-term follow up showed 65% AF freedom at 1 year and 22% at 2 years. CONCLUSIONS: Local electrical dyssynchrony provides a reasonable estimator of regional AF complexity defined as the number of fibrillatory waves. Additionally, it points to regions of dynamical instability related with action potential alternans. However, despite those characteristics, its utility in guiding catheter ablation of AF is limited suggesting other factors are responsible for AF persistence. PMID- 27780244 TI - Protective Effects of Quercetin on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2 Signaling Pathway. AB - The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in mitochondrial biogenesis. Recently, quercetin has been proved to have a protective effect against mitochondria damage after traumatic brain injury (TBI). However, its precise role and underlying mechanisms in traumatic brain injury are not yet fully understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism of these effects in a weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administrated 30 min after TBI. In this experiment, ICR mice were divided into four groups: A sham group, TBI group, TBI + vehicle group, and TBI + quercetin group. Brain samples were collected 24 h later for analysis. Quercetin treatment resulted in an upregulation of Nrf2 expression and cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were restored by quercetin treatment. Quercetin markedly promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus. These observations suggest that quercetin improves mitochondrial function in TBI models, possibly by activating the Nrf2 pathway. PMID- 27780245 TI - The Modified HZ Conjugate Gradient Algorithm for Large-Scale Nonsmooth Optimization. AB - In this paper, the Hager and Zhang (HZ) conjugate gradient (CG) method and the modified HZ (MHZ) CG method are presented for large-scale nonsmooth convex minimization. Under some mild conditions, convergent results of the proposed methods are established. Numerical results show that the presented methods can be better efficiency for large-scale nonsmooth problems, and several problems are tested (with the maximum dimensions to 100,000 variables). PMID- 27780246 TI - Supramolecular Organization of Collagen Fibrils in Healthy and Osteoarthritic Human Knee and Hip Joint Cartilage. AB - Cartilage matrix is a composite of discrete, but interacting suprastructures, i.e. cartilage fibers with microfibrillar or network-like aggregates and penetrating extrafibrillar proteoglycan matrix. The biomechanical function of the proteoglycan matrix and the collagen fibers are to absorb compressive and tensional loads, respectively. Here, we are focusing on the suprastructural organization of collagen fibrils and the degradation process of their hierarchical organized fiber architecture studied at high resolution at the authentic location within cartilage. We present electron micrographs of the collagenous cores of such fibers obtained by an improved protocol for scanning electron microscopy (SEM). Articular cartilages are permeated by small prototypic fibrils with a homogeneous diameter of 18 +/- 5 nm that can align in their D periodic pattern and merge into larger fibers by lateral association. Interestingly, these fibers have tissue-specific organizations in cartilage. They are twisted ropes in superficial regions of knee joints or assemble into parallel aligned cable-like structures in deeper regions of knee joint- or throughout hip joints articular cartilage. These novel observations contribute to an improved understanding of collagen fiber biogenesis, function, and homeostasis in hyaline cartilage. PMID- 27780247 TI - Genetic Vulnerability and the Relationship of Commercial Germplasms of Maize in Brazil with the Nested Association Mapping Parents. AB - A few breeding companies dominate the maize (Zea mays L.) hybrid market in Brazil: Monsanto(r) (35%), DuPont Pioneer(r) (30%), Dow Agrosciences(r) (15%), Syngenta(r) (10%) and Helix Sementes (4%). Therefore, it is important to monitor the genetic diversity in commercial germplasms as breeding practices, registration and marketing of new cultivars can lead to a significant reduction of the genetic diversity. Reduced genetic variation may lead to crop vulnerabilities, food insecurity and limited genetic gains following selection. The aim of this study was to evaluate the genetic vulnerability risk by examining the relationship between the commercial Brazilian maize germplasms and the Nested Association Mapping (NAM) Parents. For this purpose, we used the commercial hybrids with the largest market share in Brazil and the NAM parents. The hybrids were genotyped for 768 single nucleotide polymorphisms (SNPs), using the Illumina Goldengate(r) platform. The NAM parent genomic data, comprising 1,536 SNPs for each line, were obtained from the Panzea data bank. The population structure, genetic diversity and the correlation between allele frequencies were analyzed. Based on the estimated effective population size and genetic variability, it was found that there is a low risk of genetic vulnerability in the commercial Brazilian maize germplasms. However, the genetic diversity is lower than those found in the NAM parents. Furthermore, the Brazilian germplasms presented no close relations with most NAM parents, except B73. This indicates that B73, or its heterotic group (Iowa Stiff Stalk Synthetic), contributed to the development of the commercial Brazilian germplasms. PMID- 27780249 TI - A Complex Network Theory Approach for the Spatial Distribution of Fire Breaks in Heterogeneous Forest Landscapes for the Control of Wildland Fires. AB - Based on complex network theory, we propose a computational methodology which addresses the spatial distribution of fuel breaks for the inhibition of the spread of wildland fires on heterogeneous landscapes. This is a two-level approach where the dynamics of fire spread are modeled as a random Markov field process on a directed network whose edge weights are determined by a Cellular Automata model that integrates detailed GIS, landscape and meteorological data. Within this framework, the spatial distribution of fuel breaks is reduced to the problem of finding network nodes (small land patches) which favour fire propagation. Here, this is accomplished by exploiting network centrality statistics. We illustrate the proposed approach through (a) an artificial forest of randomly distributed density of vegetation, and (b) a real-world case concerning the island of Rhodes in Greece whose major part of its forest was burned in 2008. Simulation results show that the proposed methodology outperforms the benchmark/conventional policy of fuel reduction as this can be realized by selective harvesting and/or prescribed burning based on the density and flammability of vegetation. Interestingly, our approach reveals that patches with sparse density of vegetation may act as hubs for the spread of the fire. PMID- 27780248 TI - TheSNPpit-A High Performance Database System for Managing Large Scale SNP Data. AB - The fast development of high throughput genotyping has opened up new possibilities in genetics while at the same time producing considerable data handling issues. TheSNPpit is a database system for managing large amounts of multi panel SNP genotype data from any genotyping platform. With an increasing rate of genotyping in areas like animal and plant breeding as well as human genetics, already now hundreds of thousand of individuals need to be managed. While the common database design with one row per SNP can manage hundreds of samples this approach becomes progressively slower as the size of the data sets increase until it finally fails completely once tens or even hundreds of thousands of individuals need to be managed. TheSNPpit has implemented three ideas to also accomodate such large scale experiments: highly compressed vector storage in a relational database, set based data manipulation, and a very fast export written in C with Perl as the base for the framework and PostgreSQL as the database backend. Its novel subset system allows the creation of named subsets based on the filtering of SNP (based on major allele frequency, no-calls, and chromosomes) and manually applied sample and SNP lists at negligible storage costs, thus avoiding the issue of proliferating file copies. The named subsets are exported for down stream analysis. PLINK ped and map files are processed as in- and outputs. TheSNPpit allows management of different panel sizes in the same population of individuals when higher density panels replace previous lower density versions as it occurs in animal and plant breeding programs. A completely generalized procedure allows storage of phenotypes. TheSNPpit only occupies 2 bits for storing a single SNP implying a capacity of 4 mio SNPs per 1MB of disk storage. To investigate performance scaling, a database with more than 18.5 mio samples has been created with 3.4 trillion SNPs from 12 panels ranging from 1000 through 20 mio SNPs resulting in a database of 850GB. The import and export performance scales linearly with the number of SNPs and is largely independent of panel and database size. Import speed is around 6 mio SNPs/sec, export between 60 and 120 mio SNPs/sec. Being command line based, imports and exports can easily be integrated into pipelines. TheSNPpit is available under the Open Source GNU General Public License (GPL) Version 2. PMID- 27780250 TI - Landscape, Environmental and Social Predictors of Hantavirus Risk in Sao Paulo, Brazil. AB - Hantavirus Pulmonary Syndrome (HPS) is a disease caused by Hantavirus, which are negative-sense RNA viruses in the family Bunyaviridae that are highly virulent to humans. Numerous factors modify risk of Hantavirus transmission and consequent HPS risk. Human-driven landscape change can foster transmission risk by increasing numbers of habitat generalist rodent species that serve as the principal reservoir host. Climate can also affect rodent population dynamics and Hantavirus survival, and a number of social factors can influence probability of HPS transmission to humans. Evaluating contributions of these factors to HPS risk may enable predictions of future outbreaks, and is critical to development of effective public health strategies. Here we rely on a Bayesian model to quantify associations between annual HPS incidence across the state of Sao Paulo, Brazil (1993-2012) and climate variables (annual precipitation, annual mean temperature), landscape structure metrics (proportion of native habitat cover, number of forest fragments, proportion of area planted with sugarcane), and social factors (number of men older than 14 years and Human Development Index). We built separate models for the main two biomes of the state (cerrado and Atlantic forest). In both biomes Hantavirus risk increased with proportion of land cultivated for sugarcane and HDI, but proportion of forest cover, annual mean temperature, and population at risk also showed positive relationships in the Atlantic forest. Our analysis provides the first evidence that social, landscape, and climate factors are associated with HPS incidence in the Neotropics. Our risk map can be used to support the adoption of preventive measures and optimize the allocation of resources to avoid disease propagation, especially in municipalities that show medium to high HPS risk (> 5% of risk), and aimed at sugarcane workers, minimizing the risk of future HPS outbreaks. PMID- 27780251 TI - Effect of School-Based Home-Collaborative Lifestyle Education on Reducing Subjective Psychosomatic Symptoms in Adolescents: A Cluster Randomised Controlled Trial. AB - In this study, we aimed to assess the effectiveness of a school-based home collaborative lifestyle education program for adolescents (PADOK) in reducing poor subjective psychosomatic symptoms (SPS). The study was designed as a two armed parallel cluster randomised controlled trial and the study population comprised adolescent students (aged 12-14 years, n = 1,565) who were recruited from 19 middle schools in Japan. The PADOK intervention or usual school programme was provided in schools to all eligible participants. The primary outcome was the SPS score at 6 months, while secondary outcomes included lifestyle factors, BMI, and dietary intakes. Analyses were undertaken on an intention to treat (ITT) basis accounting for the clustered design. Nineteen schools were randomised to the PADOK group (10 schools) and control group (9 schools). The numbers of students used for analysis were 1,509 for ITT and 1,420 (94.1%) for PPS. At 6 months, the crude mean change from baseline of the SPS scores by ITT analysis showed a significantly greater reduction in the PADOK group compared to that in the control group (-0.95, 95% CI -1.70 to -0.20, P = 0.016), while those for baseline-adjusted and multivariate-adjusted values showed similar directionality but were not significant (P = 0.063 and P = 0.130). The results indicated that the PADOK program may improve poor SPS scores among adolescents. PMID- 27780252 TI - The Trophic Significance of the Indo-Pacific Humpback Dolphin, Sousa chinensis, in Western Taiwan. AB - Indo-Pacific humpback dolphins (Sousa chinensis) have attracted considerable attention due to their critically endangered status and related conservation issues, but their trophic relationships and ecological significance in coastal ecosystems are poorly understood. For instance, this species is noticeably more abundant in the Xin-Huwei River Estuary (Ex) of Western Taiwan than in the nearby Zhuoshui River Estuary (Ez), though it is unclear why the distribution shows such partitioning. To explore this topic, we conducted field surveys seasonally for two years from 2012 to 2013 and constructed Ecopath models of Ex, Ez, and an offshore site (Dm) to compare energy flow within the food webs. Model comparisons showed that the availability of food resources was the main factor influencing the biomass of Indo-Pacific humpback dolphins. Specifically, its more frequent occurrence in Ex can be attributed to greater phytoplankton production and greater biomasses of macroinvertebrates and prey fish than in the other two areas. An increase in fishing activity might decrease the food availability and, consequently, the biomass of the dolphins. Although the decline in the dolphin population would increase the biomass of some prey fish species, local fishermen might not necessarily benefit from the decline due to the concurrent decrease of highly valued crabs and shrimp. Collectively, our work suggests that the Indo Pacific humpback dolphin is a keystone species in tropical coastal waters of Taiwan, and thereby exhibit a disproportional large ecological impact given their relatively low abundance. PMID- 27780253 TI - IL-12/IL-23p40 Is Highly Expressed in Secondary Lymphoid Organs and the CNS during All Stages of EAE, but Its Deletion Does Not Affect Disease Perpetuation. AB - BACKGROUND: Interleukin (IL)-12 and IL-23 are heterodimers that share the p40 subunit, and both cytokines are critical in the differentiation of T helper (Th)1 and Th17 cells, respectively. Th1 and Th17 effector cells have been implicated in the pathogenesis of experimental autoimmune encephalitis (EAE), an animal model of the human central nervous system (CNS) autoimmune demyelinating disorder multiple sclerosis (MS). However, ustekinumab, a monoclonal antibody (mAb) against p40 failed to show efficacy over placebo in a phase II clinical trial in patients with MS. The role of p40 in initial T cell priming and maintenance in secondary lymphoid tissues is not yet well understood. METHODS: Active EAE was induced in the B6.129-IL12b strain of p40eYFP reporter mice (yet40 mice), and Th1 and Th17 polarized cells were adoptively transferred into p40-deficient mice. Cellular subsets were phenotyped by multi-parameter flow cytometry, and p40 tissue expression was identified by confocal microscopy. RESULTS: We show that yet40 mice are susceptible to EAE, and that p40 is highly expressed in secondary lymphoid organs and the CNS during all stages of the disease. Interestingly, p40 expression in the recipient is not required for EAE induction after adoptive transfer of activated and differentiated encephalitogenic Th1 and Th17 cells into p40-deficient mice. Peripheral antagonism of T helper cell trophic factors critical for the differentiation and maintenance of Th1 and Th17 cells ameliorates EAE, indicating that p40 may play a critical role in the induction of CNS autoimmunity but not in its perpetuation. CONCLUSION: Our data may explain why ustekinumab did not ameliorate paraclinical and clinical disease in patients with MS. In patients with already established disease, activated antigen-specific encephalitogenic CD4+ T cells are likely already differentiated, and are not dependent on p40 for maintenance. A clinical trial of longer duration with anti p40 mAbs or other forms of pharmacological p40 antagonism, or sequential anti-p40 therapy following T cell depletion may show a benefit by affecting de novo generation of autoimmune T cells. PMID- 27780254 TI - The Role of Myeloid-Derived Suppressor Cells in Patients with Solid Tumors: A Meta-Analysis. AB - Targeting immune cells or factors are effective for patients with solid tumors. Myeloid-derived suppressor cells (MDSCs) are known to have immunosuppressive functions, and the levels of MDSCs in patients with solid tumor are assumed to have prognostic values. This meta-analysis aimed at evaluating the relationship between MDSCs and the prognosis of patients with solid tumors. We searched articles in PUBMED and EMBASE comprehensively, updated to March 2016. Eight studies with 442 patients were included in the meta-analysis. We analyzed pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). The results showed that MDSCs were associated with poor OS (HR, 1.94; 95% confidence interval [CI], 1.42-2.66; P < 0.0001) in patients with solid tumors. PFS/RFS (HR, 1.85; 95% CI, 1.16-2.97; P = 0.01) also indicated the association between MDSCs and prognosis. The HRs and 95% CIs for OS in Asian and non-Asian patients were 2.53 (95% CI 1.61-3.42, p < 0.00001) and 1.67 (95% CI 1.14-2.46, p < 0.0001), respectively. We further analyzed the data according to tumor types. The combined HRs and 95% CIs for OS were 1.26 (95% CI 1.10-1.44, p = 0.0003) for gastrointestinal (GI) cancer, 2.59 (95% CI 1.69-3.98, p < 0.0001) for hepatocellular carcinoma (HCC) and 1.86 (95% CI 1.26-2.75, p = 0.002) for other tumor types. In conclusion, MDSCs had a fine prognostic value for OS and PFS/RFS in patients with solid tumors. MDSCs could be used as biomarkers to evaluate prognosis in clinical practice. PMID- 27780255 TI - An Optimised Human Cell Culture Model for Alveolar Epithelial Transport. AB - Robust and reproducible in vitro models are required for investigating the pathways involved in fluid homeostasis in the human alveolar epithelium. We performed functional and phenotypic characterisation of ion transport in the human pulmonary epithelial cell lines NCI-H441 and A549 to determine their similarity to primary human alveolar type II cells. NCI-H441 cells exhibited high expression of junctional proteins ZO-1, and E-cadherin, seal-forming claudin-3, 4, -5 and Na+-K+-ATPase while A549 cells exhibited high expression of pore forming claudin-2. Consistent with this phenotype NCI-H441, but not A549, cells formed a functional barrier with active ion transport characterised by higher electrical resistance (529 +/- 178 Omega cm2 vs 28 +/- 4 Omega cm2), lower paracellular permeability ((176 +/- 42) *10-8 cm/s vs (738 +/- 190) *10-8 cm/s) and higher transepithelial potential difference (11.9 +/- 4 mV vs 0 mV). Phenotypic and functional properties of NCI-H441 cells were tuned by varying cell seeding density and supplement concentrations. The cells formed a polarised monolayer typical of in vivo epithelium at seeding densities of 100,000 cells per 12-well insert while higher densities resulted in multiple cell layers. Dexamethasone and insulin-transferrin-selenium supplements were required for the development of high levels of electrical resistance, potential difference and expression of claudin-3 and Na+-K+-ATPase. Treatment of NCI-H441 cells with inhibitors and agonists of sodium and chloride channels indicated sodium absorption through ENaC under baseline and forskolin-stimulated conditions. Chloride transport was not sensitive to inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) under either condition. Channels inhibited by 5-nitro-1-(3-phenylpropylamino) benzoic acid (NPPB) contributed to chloride secretion following forskolin stimulation, but not at baseline. These data precisely define experimental conditions for the application of NCI-H441 cells as a model for investigating ion and water transport in the human alveolar epithelium and also identify the pathways of sodium and chloride transport. PMID- 27780256 TI - Quality Traceability System of Traditional Chinese Medicine Based on Two Dimensional Barcode Using Mobile Intelligent Technology. AB - Currently, the chemical fingerprint comparison and analysis is mainly based on professional equipment and software, it's expensive and inconvenient. This study aims to integrate QR (Quick Response) code with quality data and mobile intelligent technology to develop a convenient query terminal for tracing quality in the whole industrial chain of TCM (traditional Chinese medicine). Three herbal medicines were randomly selected and their chemical two-dimensional barcode (2D) barcodes fingerprints were constructed. Smartphone application (APP) based on Android system was developed to read initial data of 2D chemical barcodes, and compared multiple fingerprints from different batches of same species or different species. It was demonstrated that there were no significant differences between original and scanned TCM chemical fingerprints. Meanwhile, different TCM chemical fingerprint QR codes could be rendered in the same coordinate and showed the differences very intuitively. To be able to distinguish the variations of chemical fingerprint more directly, linear interpolation angle cosine similarity algorithm (LIACSA) was proposed to get similarity ratio. This study showed that QR codes can be used as an effective information carrier to transfer quality data. Smartphone application can rapidly read quality information in QR codes and convert data into TCM chemical fingerprints. PMID- 27780257 TI - Looking for Rhizobacterial Ecological Indicators in Agricultural Soils Using 16S rRNA metagenomic Amplicon Data. AB - INTRODUCTION: Biological communities present in soil are essential to sustainable and productive agricultural practices; however, an accurate determination of the ecological status of agricultural soils remains to date an elusive task. An ideal indicator should be pervasive, play a relevant role in the ecosystem, show a rapid and proportional answer to external perturbations and be easily and economically measurable. Rhizobacteria play a major role in determining soil properties, becoming an attractive candidate for the detection of ecological indicators. The application of massive sequencing technologies to metagenomic analysis is providing an increasingly more precise view of the structure and composition of soil communities. In this work, we analyse soil rhizobacterial composition under various stress levels to search for potential ecological indicators. GENERAL BIODIVERSITY INDICATORS: Our results suggest that the Shannon index requires observation of a relatively large number of individuals to be representative of the true population diversity, and that the Simpson index may underestimate rare taxa in rhizobacterial environments. TAXONOMICAL CLASSIFICATION METHODS: Detection of indicator taxa requires comparison of taxonomical classification of sequences. We have compared RDP classifier, RTAX and similarity-based taxonomical classification and selected the latter for taxonomical assignment because it provides larger detail. TAXONOMY-BASED ECOLOGICAL INDICATORS: The study of significant variations in common, clearly identified, taxa, using paired datasets allows minimization of non-treatment effects and avoidance of false positives. We have identified taxa associated to specific perturbations as well as taxa generally affected in treated soils. Changes in these taxa, or combinations of them, may be used as ecological indicators of soil health. The overall number and magnitude of changes detected in taxonomic groups does also increase with stress. These changes constitute an alternative indicator to measuring specific taxa, although their determination requires large sample sizes, better obtained by massive sequencing. SUMMARY: The main ecological indicators available are the Shannon index, OTU counts and estimators, overall detection of the number and proportion of changes, and changes of specific indicator taxa. Massive sequencing remains the most accurate tool to measure rhizobacterial ecological indicators. When massive sequencing is not an option, various cultivable taxonomic groups, such as specific groups in the Actinobacteria tree, are attractive as potential indicators of large disruptions to the rhizobiome. PMID- 27780258 TI - Local Application of Probiotic Bacteria Prophylaxes against Sepsis and Death Resulting from Burn Wound Infection. AB - OBJECTIVE: To determine if local prophylactic application of probiotic bacteria to burn wounds will prevent death in a mouse model of burn wound sepsis. BACKGROUND: Infection remains the most common complication after burn injury and can result in sepsis and death, despite the use of topical and systemic antibiotics. Pseudomonas aeruginosa is a frequently implicated pathogen. Local application of probiotics directly to burn wounds is an attractive novel intervention that avoids the pitfalls of standard antibiotic therapies. METHODS: A burn-sepsis model was established using a sub-eschar injection of bioluminescent P. aeruginosa; infection was tracked using a charge-coupled camera. Full-thickness burn injuries were placed on the dorsums of adult mice; the injured sites were then treated with vehicle (burn wound control), probiotics (Lactobacillus plantarum only), pathogenic bacteria (Pseudomonas aeruginosa only), or probiotics plus pathogen (Lactobacillus plus Pseudomonas). Animals were monitored until death/moribundity or for one week, then sacrificed. Harvested tissues were subjected to imaging and molecular assays. RESULTS: Control and probiotic-only animals showed no mortality (100% survival) at one week. Pseudomonas-only animals showed > 90% mortality within 40 hours of infection. In contrast, animals treated with probiotics plus Pseudomonas showed less than 10% mortality. Use of bioluminescent Pseudomonas bacteria demonstrated that probiotic therapy inhibited septicemic accumulation of the pathogen in remote organs. In addition, probiotic therapy successfully suppressed the infection-dependent induction of TNF-alpha and interleukins 6 and 10 in the liver. CONCLUSIONS: Local probiotic therapy shows great potential as a valuable adjunct in the management of complicated burn injury. PMID- 27780261 TI - Inverting Monotonic Nonlinearities by Entropy Maximization. AB - This paper proposes a new method for blind inversion of a monotonic nonlinear map applied to a sum of random variables. Such kinds of mixtures of random variables are found in source separation and Wiener system inversion problems, for example. The importance of our proposed method is based on the fact that it permits to decouple the estimation of the nonlinear part (nonlinear compensation) from the estimation of the linear one (source separation matrix or deconvolution filter), which can be solved by applying any convenient linear algorithm. Our new nonlinear compensation algorithm, the MaxEnt algorithm, generalizes the idea of Gaussianization of the observation by maximizing its entropy instead. We developed two versions of our algorithm based either in a polynomial or a neural network parameterization of the nonlinear function. We provide a sufficient condition on the nonlinear function and the probability distribution that gives a guarantee for the MaxEnt method to succeed compensating the distortion. Through an extensive set of simulations, MaxEnt is compared with existing algorithms for blind approximation of nonlinear maps. Experiments show that MaxEnt is able to successfully compensate monotonic distortions outperforming other methods in terms of the obtained Signal to Noise Ratio in many important cases, for example when the number of variables in a mixture is small. Besides its ability for compensating nonlinearities, MaxEnt is very robust, i.e. showing small variability in the results. PMID- 27780259 TI - Doing It Your Way: How Individual Movement Styles Affect Action Prediction. AB - Individuals show significant variations in performing a motor act. Previous studies in the action observation literature have largely ignored this ubiquitous, if often unwanted, characteristic of motor performance, assuming movement patterns to be highly similar across repetitions and individuals. In the present study, we examined the possibility that individual variations in motor style directly influence the ability to understand and predict others' actions. To this end, we first recorded grasping movements performed with different intents and used a two-step cluster analysis to identify quantitatively 'clusters' of movements performed with similar movement styles (Experiment 1). Next, using videos of the same movements, we proceeded to examine the influence of these styles on the ability to judge intention from action observation (Experiments 2 and 3). We found that motor styles directly influenced observers' ability to 'read' others' intention, with some styles always being less 'readable' than others. These results provide experimental support for the significance of motor variability for action prediction, suggesting that the ability to predict what another person is likely to do next directly depends on her individual movement style. PMID- 27780260 TI - Two New FRET Imaging Measures: Linearly Proportional to and Highly Contrasting the Fraction of Active Molecules. AB - We developed two new FRET imaging measures for intramolecular FRET biosensors, called linearly proportional (LP) and highly contrasting (HC) measures, which can be easily calculated by the fluorescence intensities of donor and acceptor as a ratio between their weighted sums. As an alternative to the conventional ratiometric measure, which non-linearly depends on the fraction of active molecule, we first developed the LP measure, which is linearly proportional to the fraction of active molecules. The LP measure inherently unmixes bleed-through signals and is robust against fluorescence noise. By extending the LP measure, we furthermore designed the HC measure, which provides highly contrasting images of the molecular activity, more than the ratiometric measure. In addition to their advantages, these measures are insensitive to the biosensor expression level, which is a fundamental property of the ratiometric measure. Using artificial data and FRET imaging data, we showed that the LP measure effectively represents the fraction of active molecules and that the HC measure improves visual interpretability by providing high contrast images of molecular activity. Therefore, the LP and HC measures allow us to gain more quantitative and qualitative insights from FRET imaging than the ratiometric measure. PMID- 27780262 TI - The Specific alpha1-Adrenergic Receptor Antagonist Prazosin Influences the Urine Proteome. AB - Urine, reflecting many changes in the body, is a better source than blood for biomarker discovery. However, even under physiological conditions, the urine proteome often varies. Understanding how various regulating factors affect urine proteome helps link changes to urine proteome with urinary biomarkers of physiological conditions as well as corresponding diseases. To evaluate the possible impact of alpha1-adrenergic receptor on urine proteome, this study investigated effects of the specific inhibitor prazosin on the urine proteome in a rat model by using tandem mass tagging and two-dimensional liquid chromatography-tandem mass spectrometry. A total of 775 proteins were identified, approximately half of which were influenced by prazosin treatment, indicating that the sympathetic nervous system exerts a significant impact on urine proteome. Eight significantly changed proteins were previously annotated as urinary candidate biomarkers. Angiotensinogen, haptoglobin, and beta-2 microglobulin, which were reported to be associated with blood pressure, were validated via Western blot. Prazosin is widely used in clinical practice; thus, these protein changes should be considered when studying corresponding diseases such as hypertension, post-traumatic stress disorder and benign prostatic hyperplasia. The related physiological activities of alpha1-receptors, controlling blood pressure and fear response might significantly affect the urine proteome and warrant further biomarker studies. PMID- 27780263 TI - Endocytic Pathways Used by Andes Virus to Enter Primary Human Lung Endothelial Cells. AB - Andes virus (ANDV) is the major cause of hantavirus pulmonary syndrome (HPS) in South America. Despite a high fatality rate (up to 40%), no vaccines or antiviral therapies are approved to treat ANDV infection. To understand the role of endocytic pathways in ANDV infection, we used 3 complementary approaches to identify cellular factors required for ANDV entry into human lung microvascular endothelial cells. We screened an siRNA library targeting 140 genes involved in membrane trafficking, and identified 55 genes required for ANDV infection. These genes control the major endocytic pathways, endosomal transport, cell signaling, and cytoskeleton rearrangement. We then used infectious ANDV and retroviral pseudovirions to further characterize the possible involvement of 9 of these genes in the early steps of ANDV entry. In addition, we used markers of cellular endocytosis along with chemical inhibitors of known endocytic pathways to show that ANDV uses multiple routes of entry to infect target cells. These entry mechanisms are mainly clathrin-, dynamin-, and cholesterol-dependent, but can also occur via a clathrin-independent manner. PMID- 27780264 TI - Ubiquitin Carboxy-Terminal HydrolaseL3 Correlates with Human Sperm Count, Motility and Fertilization. AB - Ubiquitin C-terminal hydrolase L3 (UCHL3) belongs to the group of deubiquitinating enzymes and plays a part in apoptosis of germ cells and the differentiation of spermatocytes into spermatids. However, the exact role of UCHL3 in human spermatogenesis and sperm function remains unknown. Here we examined the level and activity of UCHL3 in spermatozoa from men with asthenozoospermia (A), oligoasthenozoospermia (OA) or normozoospermia (N). Immunofluorescence indicated that UCHL3 was mainly localized in the acrosome and throughout the flagella, and western blotting revealed a lower level in A or OA compared with N (p < 0.05). The catalytic activity of UCHL3 was decreased in spermatozoa from A or OA (p < 0.05, p < 0.001, respectively). The level and activity of UCHL3 were positively correlated with sperm count, concentration and motility. The UCHL3 level was positively correlated with the normal fertilization rate (FR) and percentage of embryos suitable for transfer/cryopreservation of in vitro fertilization (IVF). The UCHL3 activity was also positively correlated with FR, the percentage of embryos suitable for transfer/cryopreservation and high quality embryos rate of IVF. Aforementioned correlations were not manifested in intra-cytoplasmic sperm injection (ICSI). These findings suggest that UCHL3 may play a role in male infertility. PMID- 27780266 TI - The Effect of Gender in the Publication Patterns in Mathematics. AB - Despite the increasing number of women graduating in mathematics, a systemic gender imbalance persists and is signified by a pronounced gender gap in the distribution of active researchers and professors. Especially at the level of university faculty, women mathematicians continue being drastically underrepresented, decades after the first affirmative action measures have been put into place. A solid publication record is of paramount importance for securing permanent positions. Thus, the question arises whether the publication patterns of men and women mathematicians differ in a significant way. Making use of the zbMATH database, one of the most comprehensive metadata sources on mathematical publications, we analyze the scholarly output of ~150,000 mathematicians from the past four decades whose gender we algorithmically inferred. We focus on development over time, collaboration through coautorships, presumed journal quality and distribution of research topics-factors known to have a strong impact on job perspectives. We report significant differences between genders which may put women at a disadvantage when pursuing an academic career in mathematics. PMID- 27780265 TI - Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis. AB - Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of anti-chromatin/chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4pac), H2B peptide acetylated at lysine 12 (H2Bpac), H3 peptide trimethylated at lysine 27 (H3pme), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4pac showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bpac exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3pme appeared not specific for SLE. Anti-H4pac and anti-H2Bpac reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bpac and a more pronounced reactivity with the modified equivalent of H3pme and H2Bpac. In conclusion, reactivity with H4pac and H2Bpac is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bpac is in particular associated with lupus nephritis. PMID- 27780267 TI - Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study. AB - INTRODUCTION: von Willebrand disease (VWD) is a hereditary bleeding disorder, caused by a deficiency in the levels and/or function of von Willebrand factor (VWF). Women with VWD appear to be at increased risk of experiencing postpartum hemorrhage (PPH), though the levels of VWF increase during pregnancy. There is limited knowledge of how PPH is associated with the subtype of VWD, plasma levels of other coagulations factors than VWF and given hemostatic treatment. AIMS: The aims were to investigate the incidence of PPH in women with VWD and to analyse the correlation between PPH and: (1) type of VWD, (2) laboratory monitoring of VWF and FVIII and (3) hemostatic drug treatment. METHODS: This was a retrospective observational study. The study participants (n = 34) were recruited from the Coagulation Unit, Karolinska University hospital. Fifty-nine deliveries, which occurred in 14 different obstetrics units (years 1995-2012) were included in the study. RESULTS: The incidence of primary PPH was 44%, severe primary PPH 20% and secondary PPH 12%. VWD type 3 was associated with a higher risk of experiencing severe primary PPH compared to other subtypes. FVIII:C in pregnancy was inversely correlated to blood loss during delivery. There was a significantly higher incidence of secondary PPH when the VWD diagnosis was unknown at time of delivery. CONCLUSIONS: The women with VWD are at higher risk of PPH, especially those with type 3 VWD or when diagnosis is unknown prior to delivery. Identification of pregnant women with undiagnosed VWD may be of importance in order to prevent PPH. PMID- 27780268 TI - Demography of Symbiotic Nitrogen-Fixing Trees Explains Their Rarity and Successional Decline in Temperate Forests in the United States. AB - Symbiotic nitrogen (N) fixation is the major N input to many ecosystems. Although temperate forests are commonly N limited, symbiotic N-fixing trees ("N fixers") are rare and decline in abundance as succession proceeds-a challenging paradox that remains unexplained. Understanding demographic processes that underlie N fixers' rarity and successional decline would provide a proximate answer to the paradox. Do N fixers grow slower, die more frequently, or recruit less in temperate forests? We quantified demographic rates of N-fixing and non-fixing trees across succession using U.S. forest inventory data. We used an individual based model to evaluate the relative contribution of each demographic process to community dynamics. Compared to non-fixers, N fixers had lower growth rates, higher mortality rates, and lower recruitment rates throughout succession. The mortality effect contributed more than the growth effect to N fixers' successional decline. Canopy and understory N fixers experienced these demographic disadvantages, indicating that factors in addition to light limitation likely contribute to N fixers' successional decline. We show that the rarity and successional decline of N-fixing trees in temperate forests is due more to their survival disadvantage than their growth disadvantage, and a recruitment disadvantage might also play a large role. PMID- 27780269 TI - Comparative Assessment of Vitamin-B12, Folic Acid and Homocysteine Levels in Relation to p53 Expression in Megaloblastic Anemia. AB - BACKGROUND: Megaloblastic anemia (MBA), also known as macrocytic anemia, is a type of anemia characterized by decreased number of RBCs as well as the presence of unusually large, abnormal and poorly developed erythrocytes (megaloblasts), which fail to enter blood circulation due to their larger size. Lack of vitamin B12 (VB12) and / or folate (Vitamin-B9, VB9) with elevated homocysteine is the key factor responsible for megaloblastic anemia. Prior studies have demonstrated the induction of apoptosis in these abnormal under-developed erythrocytes. However, it is not clear whether this apoptosis induction is due to elevated p53 level or due to any other mechanism. Furthermore, it is also not fully known whether decreased vitamin-B12 and / or folate are responsible for apoptosis induction mediated by p53 in pre-erythroblasts. METHODS: Levels of serum VB9, VB12 and homocysteine in 50 patients suffering from MBA were compared with 50 non megaloblastic anemia control subjects, who were referred by the clinicians for bone marrow examination for medical conditions other than MBA. Next, we have measured the p53 expression in the paraffin embedded blocks prepared from bone marrow biopsy, using immunohistochemistry, and the expression levels correlated with VB9 and VB12 levels. RESULTS: Out of 50 MBA patients 40 (80%) and 44 (88%) subjects had very low VB12 and VB9 levels respectively. In contrast, only 2 (4%) and 12 (24%) non-megaloblastic anemia controls, out of 50 subjects, had low VB12 and VB9 respectively. Correlating with low vitamin B9 and B12, the homocysteine levels were high in 80% cases. But, only 20% non-megaloblastic controls exhibited high homocysteine in plasma. Immunohistochemical analysis for p53 expression showed a significantly high level of expression in MBA cases and no-or very low expression in control subjects. Our correlation studies comparing the VB12 and VB9 levels with p53 expression concludes unusually high p53 levels in patients suffering from VB12 and VB9 deficiency induced MBA compared to control subjects not suffering from MBA. CONCLUSION: Tumor protein p53 is the key protein expressed heavily in the bone marrow biopsies of patients suffering from VB12 and VB9 deficiency induced MBA but not in control subjects. Hence, p53 expression could be used as a surrogate marker for confirming the VB9 and VB12 induced MBA. PMID- 27780271 TI - Quantification of Coupled Stiffness and Fiber Orientation Remodeling in Hypertensive Rat Right-Ventricular Myocardium Using 3D Ultrasound Speckle Tracking with Biaxial Testing. AB - Mechanical and structural changes of right ventricular (RV) in response to pulmonary hypertension (PH) are inadequately understood. While current standard biaxial testing provides information on the mechanical behavior of RV tissues using surface markers, it is unable to fully assess structural and mechanical properties across the full tissue thickness. In this study, the mechanical and structural properties of normotensive and pulmonary hypertension right ventricular (PHRV) myocardium through its full thickness were examined using mechanical testing combined with 3D ultrasound speckle tracking (3D-UST). RV pressure overload was induced in Sprague-Dawley rats by pulmonary artery (PA) banding. The second Piola-Kirchhoff stress tensors and Green-Lagrangian strain tensors were computed in the RV myocardium using the biaxial testing combined with 3D-UST. A previously established non-linear curve-fitting algorithm was applied to fit experimental data to a Strain Energy Function (SEF) for computation of myofiber orientation. The fiber orientations obtained by the biaxial testing with 3D-UST compared well with the fiber orientations computed from the histology. In addition, the re-orientation of myofiber in the right ventricular free wall (RVFW) along longitudinal direction (apex-to-outflow-tract direction) was noticeable in response to PH. For normotensive RVFW samples, the average fiber orientation angles obtained by 3D-UST with biaxial test spiraled from 20 degrees at the endo-cardium to -42 degrees at the epi-cardium (Delta = 62 degrees ). For PHRV samples, the average fiber orientation angles obtained by 3D-UST with biaxial test had much less spiral across tissue thickness: 3 degrees at endo-cardium to -7 degrees at epi-cardium (Delta = 10 degrees , P<0.005 compared to normotensive). PMID- 27780270 TI - Placental Chemokine Receptor D6 Is Functionally Impaired in Pre-Eclampsia. AB - BACKGROUND: Pre-eclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality worldwide. It is defined by new onset of hypertension and proteinuria after the 20th week of gestation and characterized by systemic exaggerated inflammatory response. D6 is a chemokines scavenger receptor that binds with high affinity CC chemokines, internalizes and targets the ligands for degradation. It is expressed in trophoblast-derived tissues and prevents excessive placenta leukocyte infiltration.The aim of this study was to investigate the expression and function of D6 in human placentae from pre eclamptic and healthy pregnant women. METHODS AND RESULTS: Plasma levels of D6 binding CC chemokines (CCL-2, CCL-3, CCL-4, CCL-7, CCL-11) and pro-inflammatory cytokines (IL-6, TNF-alpha, CRP) were analyzed in 37 healthy pregnant women and 38 patients with PE by multiplex bead assay. Higher circulating levels of CCL7, CCL11, IL-6, (p<0.0001) and CRP (p<0.05) were observed in PE women compared to controls. Levels of circulating CCL4 were decreased in PE (p<0.001), while no significant differences of CCL2, CCL3 or TNF-alpha levels were detected. Immunofluorescent staining of placental sections showed higher expression of D6 receptor in the PE syncytiotrophoblast. Confocal and Western blot (WB) analyses revealed a prevalent distribution of D6 in trophoblast cells membranes in PE. Increased activation of D6 intracellular pathway was observed by Western blot analyses of p-LIMK and p-cofilin in trophoblast cell lysates. D6 functional assays showed reduced scavenging of CCL2 in PE cells compared to controls. Since actin filaments spatial assembling is essential for D6 intracellular trafficking and scavenging activity, we investigated by confocal microscopy trophoblast cytoskeleton organization and we observed a dramatic disarrangement in PE compared to controls. CONCLUSIONS: our results suggest membrane distribution of D6 receptor on trophoblast cell membranes in PE, together with reduced functionality, probably due to cytoskeleton impairment. PMID- 27780272 TI - New Assays to Characterise Growth-Related Phenotypes of Plasmodium falciparum Reveal Variation in Density-Dependent Growth Inhibition between Parasite Lines. AB - The growth phenotype of asexual blood stage malaria parasites can influence their virulence and also their ability to survive and achieve transmission to the next host, but there are few methods available to characterise parasite growth parameters in detail. We developed a new assay to measure growth rates at different starting parasitaemias in a 96-well format and applied it to characterise the growth of Plasmodium falciparum lines 3D7-A and 3D7-B, previously shown to have different invasion rates and to use different invasion pathways. Using this simple and accurate assay we found that 3D7-B is more sensitive to high initial parasitaemia than 3D7-A. This result indicates that different parasite lines show variation in their levels of density-dependent growth inhibition. We also developed a new assay to compare the duration of the asexual blood cycle between different parasite lines. The assay is based on the tight synchronisation of cultures to a 1 h parasite age window and the subsequent monitoring of schizont bursting and formation of new rings by flow cytometry. Using this assay we observed differences in the duration of the asexual blood cycle between parasite lines 3D7 and HB3. These two new assays will be useful to characterise variation in growth-related parameters and to identify growth phenotypes associated with the targeted deletion of specific genes or with particular genomic, transcriptomic or proteomic patterns. Furthermore, the identification of density-dependent growth inhibition as an intrinsic parasite property that varies between parasite lines expands the repertoire of measurable growth-related phenotypic traits that have the potential to influence the outcome of a malarial blood infection. PMID- 27780273 TI - Grain Filling Characteristics and Their Relations with Endogenous Hormones in Large- and Small-Grain Mutants of Rice. AB - This study determined if the variation in grain filling parameters between two different spikelet types of rice (Oryza sativa L.) is regulated by the hormonal levels in the grains. Two rice mutants, namely, a large-grain mutant (AZU-M) and a small-grain mutant (ZF802-M), and their respective wild types (AZU-WT and ZF802 WT) were grown in the field. The endosperm cell division rate, filling rate, and hormonal levels: zeatin + zeatin riboside (Z+ZR), indo-3-acetic acid (IAA), polyamines (PAs), and abscisic acid (ABA) were determined. The results showed that there was no significant difference between the filling and endosperm cell division rates. These rates were synchronous between the superior and inferior spikelets for both mutants. However, the abovementioned parameters were significantly different between the two spikelet types for the two wild types. The superior spikelets filled faster and their filling rate was higher compared to the inferior ones. Changes in the concentrations of plant hormones were consistent with the observed endosperm cell division rate and the filling rate for both types of spikelets of mutant and wild type plants. Regression analysis showed a significant positive correlation between cell division and filling rates with the concentrations of the investigated hormones. Exogenous chemical application verified the role of ABA, IAA, and PAs in grain filling. The results indicate that poor filling of inferior spikelets in rice occurs primarily due to the reduced hormone concentrations therein, leading to lower division rate of endosperm cells, fewer endosperm cells, slower filling rate, and smaller grain weight. PMID- 27780274 TI - Increased Rates of Prolonged Length of Stay, Readmissions, and Discharge to Care Facilities among Postoperative Patients with Disseminated Malignancy: Implications for Clinical Practice. AB - BACKGROUND: The impact of surgery on end of life care for patients with disseminated malignancy (DMa) is incompletely characterized. The purpose of this study was to evaluate postoperative outcomes impacting quality of care among DMa patients, specifically prolonged length of hospital stay, readmission, and disposition. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for years 2011-2012. DMa patients were matched to non-DMa patients with comparable clinical characteristics and operation types. Primary hepatic operations were excluded, leaving a final cohort of 17,972 DMa patients. The primary outcomes were analyzed using multivariate Cox regression models. RESULTS: DMa patients represented 2.1% of all ACS-NSQIP procedures during the study period. The most frequent operations were bowel resections (25.3%). Compared to non-DMa matched controls, DMa patients had higher rates of postoperative overall morbidity (24.4% vs. 18.7%, p<0.001), serious morbidity (14.9% vs. 12.0%, p<0.001), mortality (7.6% vs. 2.5%, p<0.001), prolonged length of stay (32.2% vs. 19.8%, p<0.001), readmission (15.7% vs. 9.6%, p<0.001), and discharges to facilities (16.2% vs. 12.9%, p<0.001). Subgroup analyses of patients by procedure type showed similar results. Importantly, DMa patients who did not experience any postoperative complication experienced significantly higher rates of prolonged length of stay (23.0% vs. 11.8%, p<0.001), readmissions (10.0% vs. 5.2%, p<0.001), discharges to a facility (13.2% vs. 9.5%, p<0.001), and 30-day mortality (4.7% vs. 0.8%, p<0.001) compared to matched non-DMa patients. CONCLUSION: Surgical interventions among DMa patients are associated with poorer postoperative outcomes including greater postoperative complications, prolonged length of hospital stay, readmissions, disposition to facilities, and death compared to non-DMa patients. These data reinforce the importance of clarifying goals of care for DMa patients, especially when acute changes in health status potentially requiring surgery occur. PMID- 27780276 TI - SMFM 2016 Archive: Hypertension-Part 2 (Podcast). PMID- 27780275 TI - Diagnostic Accuracy of the FIGO and the 5-Tier Fetal Heart Rate Classification Systems in the Detection of Neonatal Acidemia. AB - Objective The objective of this study was to determine ability to detect neonatal acidemia and interobserver agreement with the FIGO 3-tier and 5-tier fetal heart rate (FHR) classification systems. Design This was a case-control study. Setting This study was set at the University Medical Center. Population A total of 202 FHR tracings of 102 women who delivered an acidemic fetus (umbilical arterial cord gas pH <= 7.10 and BE < - 8) and 100 who delivered a nonacidemic fetus (umbilical arterial cord gas pH > 7.10) were assessed. A subanalysis was performed for those fetuses who suffered severe metabolic acidemia (pH <= 7.0 and BE < - 12). Methods Two reviewers blind to clinical and outcome data classified tracings according to the new 3-tier system proposed by the FIGO and the 5-tier system proposed by Parer and Ikeda. Main Outcome Measures Sensitivity and specificity for detecting neonatal acidemia and interobserver agreement in classifying FHR tracings into categories of both systems were studied. Results The 3-tier system showed a greater sensitivity and lower specificity to detect neonatal acidemia (43.6% sensitivity, 82.5% specificity) and severe metabolic acidemia (71.4% sensitivity, 74.0% specificity) compared with the 5-tier system (36.3% sensitivity, 88% specificity and 61.9% sensitivity, 80.1% specificity, respectively). Both systems were compared by area under the receiver-operating characteristic curve, with comparable predictive ability for detecting neonatal acidemia (FIGO-area under the curve [AUC]: 0.63 [95% confidence interval [CI]: 0.57-0.68] and Parer-AUC: 0.62 [95% CI: 0.56-0.67]). Interobserver agreement was moderate for both systems, but performance at each specific category showed a better agreement for the 5-tier system identifying a pathological tracing (orange or red, kappa: 0.625 vs. pathological category, kappa: 0.538). Conclusion Both systems presented a comparable ability to predict neonatal acidemia, although the 5-tier system showed a better interobserver agreement identifying pathological tracings. PMID- 27780277 TI - Hernia Sac Presence Portends Better Survivability of Isolated Congenital Diaphragmatic Hernia with "Liver-Up". AB - Objective The objective of this study was to investigate the prognostic value of a hernia sac in isolated congenital diaphragmatic hernia (CDH) with intrathoracic liver herniation ("liver-up"). Study Design A retrospective study from the single tertiary center. Isolated "liver-up" CDH neonates referred to our institution between 2000 and 2015 were reviewed for the presence or absence of a hernia sac. Association between the presence of a hernia sac and survival was assessed. Results Over the study period, there were 29 isolated CDH patients with "liver up" who were treated, 7 (24%) had a sac, and 22 (76%) did not. Demographics were similar between groups. However, disease acuity, assessed from lower Apgar scores (p = 0.044), lower probability of survival (p = 0.037), and lower admission oxygenation (p = 0.027), was higher in neonates without a sac. Hospital survival was significantly higher for those with sac compared with those without (7/7, 100 vs. 7/22, 32%, p = 0.002). Conclusion The presence of a hernia sac may be associated with better survival for isolated "liver-up" CDH. As the presence of sac can be prenatally detected, it may be a useful marker to aid perinatal decision making. PMID- 27780278 TI - [Correction: Chronic Disease Self-management Support for People with a Migrant Background: towards a Peer-led Group Program to Improve Equity in Health]. PMID- 27780279 TI - [Professionalization of Legal Dental Experts in Germany: Results of Studies on Structured Focus Groups]. AB - BACKGROUND: Legal expert opinions are a crucial instrument of professional self control in medicine. To give impulses for further development, focus groups were initiated to reflect upon the perspective of legal dental experts. METHODS: 5 focus group discussions on the topic "Professionalization of legal dental experts" were conducted. A total of 32 experienced legal dental experts participated in the discussions. The results were evaluated by qualitative content analysis. RESULTS: A catalogue of 68 ideas was generated for improvement and divided into 15 categories. Among these were periodic quality circles, interprofessional exchange, supervision of novices and periodic feedback for legal dental experts and dentists. CONCLUSION: Self-reflection can be included as an instrument for quality improvement of legal dental expert opinions. PMID- 27780280 TI - [10 Years of Quality Management: Perception and Importance from GPs' Point of View]. AB - BACKGROUND: Quality management (QM) became mandatory for the ambulatory sector of the German health care system 10 years ago. OBJECTIVES: The aim of this study was to find out how general practitioners (GPs) perceived the introduction of this measure, how they see it today and what they expect of the future concerning QM. MATERIALS AND METHODS: In a qualitative study, interviews following a semi structured guideline with GPs were conducted. Following transcription, interviews were coded in triangulation, first inductively, then deductively until saturation was reached. Main topics and code families were agreed on after discussion. RESULTS: There was consensus on the necessity of standardization of basic processes like hygiene. However, the application of QM to an activity that emphasizes personal relationships and communication was seen as barely possible. GPs stated that they reduced QM to a tolerable and for them reasonable minimum. GPs mostly refused certification. The next 10 years were seen with pessimism in terms of more bureaucratic guidelines. CONCLUSION: The statutory introduction of QM was an attack on medical professionalism. Instead of passive resistance and reduction of QM to a minimum, engaged independent quality work might help to regain the trust of society we seem to have lost and restore the professional autonomy we need for our work. PMID- 27780282 TI - Clinical Images: A Cloudy Skull-Hypophosphatasia as Reason for Copper-Beaten Skull. PMID- 27780281 TI - Surgical Management of Functional Constipation: Preliminary Report of a New Approach Using a Laparoscopic Sigmoid Resection Combined with a Malone Appendicostomy. AB - Introduction Functional constipation is a common problem in children. It usually can be managed with laxatives but a small subset of patients develop intolerable cramps and need to be temporarily treated with enemas. The senior author has previously reported: 1) open sigmoid resection as a surgical option, but this did not sufficiently reduce the laxative need, then 2) a transanal approach (with resection of rectosigmoid), but this led to a high rate of soiling due to extensive stretching of the anal canal and loss of the rectal reservoir. The understanding of these procedures' results has led us to use a laparoscopic sigmoid +/- left colonic resection with a Malone appendicostomy for these patients, to decrease the laxative requirements, temporarily treat with antegrade flushes, and to reduce postoperative soiling. Methods A single-institution retrospective review (3/2014-9/2015) included patients who failed our laxative protocol, and therefore were considered surgical candidates. Patients with anorectal malformation (ARM), Hirschsprung disease, spina bifida, tethered cord, trisomy 21, cerebral palsy, mitochondrial disease, prior colon resection at other facilities, or those that did not participate in our laxative program were excluded. Demographics, duration of symptoms, prior treatments, postoperative complications, and postoperative bowel regimens were evaluated. Results A total of 6 patients (3 males; median age of 12.5 years) presented with soiling related to constipation and intolerance to laxatives. Four patients failed preoperative cecostomy (done prior to referral to us). An average of 4.7 medication treatments were previously tried. In all, 4 patients had required in-patient disimpactions. Duration of symptoms was 7.5 years (median). The median senna dose was 30 mg (range, 15-150 mg), and all patients had intolerable symptoms or failed to empty their colon, which we considered a failed laxative trial. All had contrast enemas that demonstrated a dilated and/or redundant sigmoid colon, and colonic manometry was abnormal in 4. All patients underwent laparoscopic sigmoid and left colon resection, or only sigmoid resection (a low anterior resection). Two patients had postoperative colitis treated with oral antibiotics. The median follow-up was 52 days (range, 8-304 days). Five patients are on antegrade enemas with plans to convert to laxatives at 6 months, 1 is taking laxatives alone at a 33% lower dosage. Five of six are completely clean, 1 soils occasionally and their daily flush is being adjusted. Conclusion Only a minority of patients with functional constipation are medically unmanageable. This preliminary report shows that laparoscopic colon resection combined with antegrade flushes is an effective surgical technique to treat that group. A laparoscopic approach, guided by contrast enema and colonic manometry, allows for a defined resection of the abnormal segment of colon with the advantages of minimally invasive surgery including allowing for an extensive rectal resection (an improvement over open sigmoid resection) and avoidance of overstretching of the anal canal and removal of the rectal reservoir (an improvement over the transanal approach). Having antegrade access is useful to manage soiling and avoiding cramping from laxatives in the early postoperative period. Although our series is small, we believe that long-term most patients can avoid antegrade flushes and be on no, or a dramatically reduced, laxative dose. PMID- 27780283 TI - Sleep Disturbances in Children with Rolandic Epilepsy. AB - Background The aim of this study is to investigate through polysomnography sleep quality in children with rolandic epilepsy and compare sleep variables between these children and healthy controls. Methods Our study population included 15 children with rolandic epilepsy and 27 healthy children who underwent overnight polysomnography. Parameters about sleep architecture and sleep respiratory events were recorded and analyzed. The level of statistical significance was set at 0.05. Results Patients and controls did not differ in basic epidemiological traits. The percentage of sleep stage rapid eye movement was significantly lower in the epilepsy group. Moreover, the mean value of the obstructive apnea index and the obstructive apnea-hypopnea index was significantly higher in children with rolandic epilepsy compared with healthy children. Longest apnea duration and basal Spo 2 during sleep had also the trend to be higher and lower, respectively, in children with epilepsy. Conclusions Children with rolandic epilepsy exhibit alterations in sleep architecture, as well as in sleep respiratory patterns. Therefore, sleep quality should be routinely considered in the long-term follow up of these children. PMID- 27780284 TI - Effect of Continuous and Intermittent Exercises on Oxidised HDL and LDL Lipids in Runners. AB - We studied the effects of different types of exercises on the concentrations of oxidised HDL (oxHDLlipids) and LDL lipids (oxLDLlipids), serum lipids, antioxidant potential, paraoxonase and malondialdehyde in endurance runners by performing both a 40-min continuous run (velocity corresponding to 80% VO2max) and a 40-min intermittent run (2-min run, velocity corresponding to 100% VO2max, and 2-min rest) using a treadmill. Blood samples were taken before exercise, after 20 and 40 min of exercise, and 15 and 90 min after the end of exercise. The concentrations of oxLDLlipids remained unchanged during the running tests, but after a 90-min recovery the concentrations decreased by 4% (P<0.05) for the intermittent run and by 16% (P<0.01) for the continuous run. The acute effect of the intermittent and continuous run increased the concentrations of oxHDLlipids by 26 and 25%, respectively (P<0.001 for both). Interestingly, oxHDLlipids did not increase after the first half of the run in middle-distance runners during the intermittent run, and a similar phenomenon was seen in marathon runners during the continuous run. These results may indicate that acute physical exercise increases the transport of lipid oxidation products by HDL, although a different training history or genetic background may alter these acute responses. PMID- 27780285 TI - Biomechanical Comparison of Five Posterior Cruciate Ligament Reconstruction Techniques. AB - No surgical technique recreates native posterior cruciate ligament (PCL) biomechanics. We compared the biomechanics of five different PCL reconstruction techniques versus the native PCL. Cadaveric knees (n = 20) were randomly assigned to one of five reconstruction techniques: Single bundle all-inside arthroscopic inlay, single bundle all-inside suspensory fixation, single bundle arthroscopic assisted open onlay (SB-ONL), double bundle arthroscopic-assisted open inlay (DB INL), and double bundle all-inside suspensory fixation (DB-SUSP). Each specimen was potted and connected to a servo-hydraulic load frame for testing in three conditions: PCL intact, PCL deficient, and PCL reconstructed. Testing consisted of a posterior force up to 100 N at a rate of 1 N/s at four knee flexion angles: 10, 30, 60, and 90 degrees. Three material properties were measured under each condition: load to 5 mm displacement, maximal displacement, and stiffness. Data were normalized to the native PCL, compared across techniques, compared with all PCL-intact knees and to all PCL-deficient knees using one-way analysis of variance. For load to 5 mm displacement, intact knees required significantly (p < 0.03) more load at 30 degrees of flexion than all reconstructions except the DB SUSP. At 60 degrees of flexion, intact required significantly (p < 0.01) more load than all others except the SB-ONL. At 90 degrees, intact, SB-ONL, DB-INL, and DB-SUSP required significantly more load (p < 0.05). Maximal displacement testing showed the intact to have significantly (p < 0.02) less laxity than all others except the DB-INL and DB-SUSP at 60 degrees. At 90 degrees the intact showed significantly (p < 0.01) less laxity than all others except the DB-SUSP. The intact was significantly stiffer than all others at 30 degrees (p < 0.03) and 60 degrees (p < 0.01). Finally, the intact was significantly (p < 0.05) stiffer than all others except the DB-SUSP at 90 degrees. No technique matched the exact properties of the native PCL, but the double bundle reconstructions more closely recreated the native biomechanics immediately after implantation, with the DB SUSP coming closest to the native ligament. This study contributes new data for consideration in PCL reconstruction technique choice. PMID- 27780286 TI - Preoperative Ultrasonographic Prediction of Hamstring Tendon Diameter for Anterior Cruciate Ligament Repair. AB - The incidence of anterior cruciate ligament (ACL) injuries is rising every year. The autologous hamstring tendon graft, using semitendinosus tendon (SMT) and gracilis tendon (GR), is a common repair technique in the management of ACL injuries due to its multiple advantages. Using a final graft with a minimum diameter of 8 mm is necessary to avoid graft failure. The aim of this study was to find a correlation between preoperative ultrasound (USG) measurement of the SMT and GR tendon diameters (SMTd and GRd) and their actual diameters measured during the grafting procedure. In the present study, 33 male patients aged between 16 and 43 years with ACL injury that required grafting were enrolled. Before the grafting procedure, we sonographically measured the SMTd, GRd, and calculated the hamstring tendon diameter (SMTd + GRd) as the sum of these two. During surgery, we obtained the SMTd, GRd, and SMTd + GRd; we also obtained the length of both tendons and the final graft diameter (FGd). We then compared the obtained values. Mean age was 25.6 +/- 7.9 years in our study population. The mean SMTd, GRd, and SMTd + GRd obtained by USG versus transoperatively were 4.9 versus 4.7 mm, 4.3 versus 3.8 mm, and 9.3 versus 8.6 mm, respectively. The mean of FGd was 8.4 mm and the mean length of both tendons was 14.2 cm. The GRd obtained by USG positively correlated with SMTd, SMT tendon length, GRd, and SMTd + GRd (r = 0.460, 0.404, 0.411, and 0.508, respectively). USG-obtained GRd predicts a final tendon diameter < 8 mm (high risk of failure) with a sensitivity, specificity, positive predictive value, and negative predictive value of 100, 54, 28 and 100%, respectively, using 4.5 mm as cutoff. Of all obtained grafts, 85% were deemed adequate (>= 8 mm) using transoperative measurement, while 91% were >= 8 mm using USG measurement. The USG measurement of hamstring tendons is a useful method to predict their transoperative diameter. GRd obtained by USG is the best predictor of transoperative GRd and SMTd + GRd. PMID- 27780287 TI - Infection following Anterior Cruciate Ligament Reconstruction: An Analysis of 6,389 Cases. AB - Infection following anterior cruciate ligament reconstruction (ACLR) is rare. Previous authors have concluded that diabetes, tobacco use, and previous knee surgery may influence infection rates following ACLR. The purpose of this study was to identify a cohort of patients undergoing ACLR and define (1) the incidence of infection after ACLR from a large multicenter database and (2) the risk factors for infection after ACLR. We identified patients undergoing elective ACLRs in the American College of Surgeons National Surgical Quality Improvement Program database between 2007 and 2013. The primary outcome was any surgical site infection within 30 days of surgery. We performed univariate and multivariate analyses comparing infected and noninfected cases to identify risk factors for infection. In total, 6,398 ACLRs were available for analysis of which 39 (0.61%) were diagnosed with a postoperative infection. Univariate analysis identified preoperative dyspnea, low hematocrit, operative time > 1 hour, and hospital admission following surgery as predictors of postoperative infection. Diabetes, tobacco use, age, and body mass index (BMI) were not associated with infection (p > 0.05). After multivariate analysis, the only independent predictor of postoperative infection was hospital admission following surgery (odds ratio, 2.67; 95% confidence interval, 1.02-6.96; p = 0.04). Hospital admission following surgery was associated with an increased incidence of infection in this large, multicenter cohort. Smoking, elevated BMI, and diabetes did not increase the risk infection in the present study. Surgeons should optimize outpatient operating systems and practices to aid in same-day discharges following ACLR. PMID- 27780288 TI - The use of incretins and fractures - a meta-analysis on population-based real life data. AB - The aim of the present study was to estimate the effect of incretins on fracture risk in the real-world situation by meta-analysis of the available population based cohort data. Pubmed and Embase were searched for original articles investigating use of incretin agents, and fracture risk up to December 2015. Adjusted results were extracted and pooled by use of generic inverse variance methods, assuming a random-effects model. Neither current dipeptidyl peptidase 4 inhibitor use nor current glucagon-like peptide 1 receptor agonist use was associated with a decreased risk of fracture: pooled relative risk (pooled RR [95% confidence interval]: 1.02 [0.91-1.13] and 1.03 [0.87-1.22]), respectively. This meta-analysis demonstrated that current use of incretin agents, was not associated with decreased fracture risk. Our findings show the value of representative real-world populations, and the risks associated with suggesting benefits for medications on the basis of safety reporting in randomized controlled trials. PMID- 27780289 TI - Lessons learned on the design and the conduct of Post-Authorization Safety Studies: review of 3 years of PRAC oversight. AB - AIMS: To describe and characterize the first cohort of Post-Authorization Safety Study (PASS) protocols reviewed under the recent European pharmacovigilance legislation. METHODS: A systematic approach was used to compile all publicly available information on PASS protocols and assessments submitted from July 2012 to July 2015 from Pharmacovigilance Risk Assessment Committee (PRAC) minutes, European Medicines Agency (EMA) and European Network of Pharmacovigilance and Pharmacoepidemiology (ENCePP) webpages. RESULTS: During the study period, 189 different PASS protocols were submitted to the PRAC, half of which were entered in the ENCePP electronic register of post-authorization studies (EU-PAS) by July 2015. Those protocols were assessed during 353 PRAC reviews. The EMA published only 31% of the PRAC feedback, of which the main concerns were study design (37%) and feasibility (30%). Among the 189 PASS, slightly more involved primary data capture (58%). PASS assessing drug utilization mainly leveraged secondary data sources (58%). The majority of the PASS did not include a comparator (65%) and 35% of PASS also evaluated clinical effectiveness endpoints. CONCLUSIONS: To the best of our knowledge this is the first comprehensive review of three years of PASS protocols submitted under the new pharmacovigilance legislation. Our results show that both EMA and PASS sponsors could respectively increase the availability of protocol assessments and documents in the EU-PAS. Protocol content review and the high number of PRAC comments related to methodological issues and feasibility concerns should raise awareness among PASS stakeholders to design more thoughtful studies according to pharmacoepidemiological principles and existing guidelines. PMID- 27780290 TI - Coinage Metal Complexes of Bis-Alkynyl-Functionalized N-Heterocyclic Carbenes: Reactivity, Photophysical Properties, and Quantum Chemical Investigations. AB - Bis-phenylpropynyl-functionalized imidazolium salts and their corresponding gold and copper N-heterocyclic carbene (NHC) complexes were prepared in order to investigate their potential application for the synthesis of heterometallic coinage metal compounds. By transmetalation reactions with different precious metal sources, including copper and silver phenylacetylides [MCCPh]n (M=Cu, Ag), polynuclear compounds were obtained, which were further investigated for their photoluminescence properties. Additionally, one gold NHC complex was post functionalized by autocatalytic hydration of the alkynyl side chains. Time dependent DFT investigations of singlet electronic excitations in representative complexes revealed excited states of diverse character, as determined by the specific complex structure and metallophilic interactions. PMID- 27780291 TI - Biology and evolution of arbuscular mycorrhizal symbiosis in the light of genomics. AB - 531 I. 531 II. 532 III. 532 IV. 534 V. 534 535 References 535 SUMMARY: Arbuscular mycorrhizal (AM) fungi associate with the vast majority of land plants, providing mutual nutritional benefits and protecting hosts against biotic and abiotic stresses. Significant progress was made recently in our understanding of the genomic organization, the obligate requirements, and the sexual nature of these fungi through the release and subsequent mining of genome sequences. Genomic and genetic approaches also improved our understanding of the signal repertoire used by AM fungi and their plant hosts to recognize each other for the initiation and maintenance of this association. Evolutionary and bioinformatic analyses of host and nonhost plant genomes represent novel ways with which to decipher host mechanisms controlling these associations and shed light on the stepwise acquisition of this genetic toolkit during plant evolution. Mining fungal and plant genomes along with evolutionary and genetic approaches will improve understanding of these symbiotic associations and, in the long term, their usefulness in agricultural settings. PMID- 27780292 TI - Diversity of Antibiotic Resistance Genes in Enterococcus Strains Isolated from Ready-to-Eat Meat Products. AB - The objective of the study was to answer the question of whether the ready-to-eat meat products can pose indirect hazard for consumer health serving as reservoir of Enterococcus strains harboring tetracyclines, aminoglycosides, and macrolides resistance genes. A total of 390 samples of ready-to-eat meat products were investigated. Enterococcus strains were found in 74.1% of the samples. A total of 302 strains were classified as: Enterococcus faecalis (48.7%), Enterococcus faecium (39.7%), Enterococcus casseliflavus (4.3%), Enterococcus durans (3.0%), Enterococcus hirae (2.6%), and other Enterococcus spp. (1.7%). A high percentage of isolates were resistant to streptomycin high level (45%) followed by erythromycin (42.7%), fosfomycin (27.2%), rifampicin (19.2%), tetracycline (36.4%), tigecycline (19.9%). The ant(6')-Ia gene was the most frequently found gene (79.6%). Among the other genes that encode aminoglycosides-modifying enzymes, the highest portion of the strains had the aac(6')-Ie-aph(2'')-Ia (18.5%) and aph(3'')-IIIa (16.6%), but resistance of isolates from food is also an effect of the presence of aph(2'')-Ib, aph(2'')-Ic, aph(2'')-Id genes. Resistance to tetracyclines was associated with the presence of tetM (43.7%), tetL (32.1%), tetK (14.6%), tetW (0.7%), and tetO (0.3%) genes. The ermB and ermA genes were found in 33.8% and 18.9% of isolates, respectively. Nearly half of the isolates contained a conjugative transposon of the Tn916/Tn1545 family. Enterococci are widely present in retail ready-to-eat meat products. Many isolated strains (including such species as E. casseliflavus, E. durans, E. hirae, and Enterococcus gallinarum) are antibiotic resistant and carry transferable resistance genes. PMID- 27780293 TI - Postsynthetic Incorporation of a Singlet Oxygen Photosensitizer in a Metal Organic Framework for Fast and Selective Oxidative Detoxification of Sulfur Mustard. AB - A fullerene-based photosensitizer is incorporated postsynthetically into a Zr6 based MOF, NU-1000, for enhanced singlet oxygen production. The structural organic linkers in the MOF platform also act as photosensitizers which contribute to the overall generation of singlet oxygen from the material under UV irradiation. The singlet oxygen generated by the MOF/fullerene material is shown to oxidize sulfur mustard selectively to the less toxic bis(2 chloroethyl)sulfoxide with a half-life of only 11 min. PMID- 27780294 TI - N-Methyl-Benzothiazolium Salts as Carbon Lewis Acids for Si-H sigma-Bond Activation and Catalytic (De)hydrosilylation. AB - N-Me-Benzothiazolium salts are introduced as a new family of Lewis acids able to activate Si-H sigma bonds. These carbon-centred Lewis acids were demonstrated to have comparable Lewis acidity towards hydride as found for the triarylboranes widely used in Si-H sigma-bond activation. However, they display low Lewis acidity towards hard Lewis bases such as Et3 PO and H2 O in contrast to triarylboranes. The N-Me-benzothiazolium salts are effective catalysts for a range of hydrosilylation and dehydrosilylation reactions. Judicious selection of the C2 aryl substituent in these cations enables tuning of the steric and electronic environment around the electrophilic centre to generate more active catalysts. Finally, related benzoxazolium and benzimidazolium salts were found also to be active for Si-H bond activation and as catalysts for the hydrosilylation of imines. PMID- 27780296 TI - Composition, Taste, Aroma, and Antioxidant Activity of Solidified Noncentrifugal Brown Sugars Prepared from Whole Stalk and Separated Pith of Sugarcane (Saccharum officinarum L.). AB - In this study, 2 types of solidified noncentrifugal brown sugars (W-NCS and P NCS) were prepared from the whole stalk and separated pith, respectively, of raw sugarcane (Saccharum officinarum L.). These products were discriminated in terms of their quality attributes, including color, sugars and minerals composition, taste, aroma, and antioxidant activity. The brown color of P-NCS was clearly different compared with that of W-NCS with a color difference value (DeltaE* ) of 9.36. There was no difference in the sugars and minerals composition between the 2 types of sugar, which led to very similar taste profiles. However, P-NCS had a weaker aroma intensity than W-NCS did. Moreover, P-NCS retained more than 60% of the antioxidant activity of W-NCS. The information gleaned from this study might be used to select appropriate end-uses for these 2 types of sugars. PMID- 27780295 TI - Influence of Different Kinds of Music on Walking in Children. AB - PURPOSE: The aim of this study was to evaluate the effect of different kinds of music on submaximal performance and exercise tolerance in healthy children by means of the 6-minute walking test (6MWT) and to explore the influence of gender. DESIGN: Cross-over study. METHOD: Ninety-seven children performed 6MWT in four conditions (without music, with their preferred music, with slow and with fast music). Distance, cardio-respiratory parameters, perceived exertion rate, and amount of dyspnea were measured. FINDINGS: Walked distance depended on the kind of music (p = .022). To listen to fast music promoted a longer distance when compared with slow music. Walked distance was not influenced by gender (p = .721) and there was no interaction between music and gender for walked distances (p = .069). The other parameters were not modified by music and gender. CONCLUSION: Music influences submaximal performances without modifying exercise tolerance in healthy children. CLINICAL RELEVANCE: Music does modify submaximal performance in children. PMID- 27780298 TI - Manufacture and Incorporation of Liposome-Entrapped Ethylenediaminetetraacetic Acid into Model Miniature Gouda-Type Cheese and Subsequent Effect on Starter Viability, pH, and Moisture Content. AB - Liposome-encapsulated ethylenediaminetetraacetic acid (EDTA) was incorporated into a model miniature Gouda-type cheese (20 g) in order to assess its effect on rennet gelation, starter viability, pH, and moisture content. EDTA was encapsulated within 2 different food-grade proliposome preparations, Pro-Lipo Duo and Pro-Lipo C (50% and 40% unsaturated soybean phospholipids and 50% and 60% aqueous medium, respectively), using the following high-shear technologies: Ultra Turrax (5000 rpm), 2-stage homogenization (345 bar), or microfluidization (690 bar). Liposome size distribution was affected by the high-shear technology employed with the proportion of large vesicles (>100 nm) decreasing in the order microfluidization < 2-stage homogenization < Ultra-Turrax. All EDTA-containing liposomes were stable during 28 d refrigerated storage, with no significant (P <= 0.05) change in size distribution or EDTA entrapment efficiency (%EE). Liposome composition affected the entrapment of EDTA, with Pro-Lipo C having a significantly greater %EE than Pro-Lipo Duo, 63% and 54%, respectively. For this reason, Pro-Lipo C EDTA liposomes, with and without EDTA, were incorporated into model miniature Gouda-type cheese. Addition of liposome-encapsulated EDTA to milk during cheese making did not impact pH or rennet gel formation. No differences in composition or pH were evident in liposome-treated cheeses. The results of this study show that the incorporation of liposome-encapsulated EDTA into milk during cheese manufacture did not affect milk fermentation, moisture content, or pH, suggesting that this approach may be suitable for studying the effects of calcium equilibrium on the texture of brine-salted cheeses. PMID- 27780297 TI - Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation. AB - AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1 (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1 (coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 +/- 0.7 min after administration of 2.5 mg intravenous midazolam, 7 +/- 4.4 min after 2.5 mg Nazolam, and 4 +/- 1.8 min after 5 mg Nazolam. Sedation duration was 118 +/- 95.6 min for 2.5 mg intravenous midazolam, 76 +/- 80.4 min for 2.5 mg Nazolam, and 145 +/- 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation. PMID- 27780299 TI - Biochar-stimulated plant performance is strongly linked to microbial diversity and metabolic potential in the rhizosphere. AB - The 'biochar effect' depicts a phenomenon in which biochar soil amendment enhances plant performance by promoting growth and suppressing disease. Although this phenomenon has been observed in numerous studies, the mode of action that explains it is currently unknown. In order to elucidate mechanisms responsible for the 'biochar effect', we comprehensively monitored tomato plant development and resistance to the foliar fungal pathogen Botrytis cinerea, in biochar-amended and nonamended soils using native biochar and washed biochar, striped of labile chemical constituents. We concomitantly assessed bacterial community succession in the rhizosphere by high-throughput 16S rRNA gene amplicon sequencing and carbon-source utilization profiling. Biochar had little impact on plant physiological parameters. However, both native and washed biochar treatments were characterized by higher rhizosphere bacterial diversity and enhanced carbohydrate and phenolic compound utilization rates coupled to stimulation of bacteria known to degrade phenolic compounds. This study indicates that the 'biochar effect' is at least partially dictated by increased diversity and changes in metabolic potential in the rhizosphere microbiome, which is primarily triggered by the recalcitrant carbon backbone of the biochar and tightly bound compounds. It corresponds to the growing consensus that soil amendments which enhance microbial diversity have important benefits to ecosystem functioning. PMID- 27780300 TI - The Memorable and Upbeat M.C. Chang. PMID- 27780301 TI - M.C. Chang as a Mentor: A Memoir. PMID- 27780302 TI - M.C. Chang: A Pioneer of Mammalian In Vitro Fertilization. PMID- 27780303 TI - Min Chueh Chang, In Context. PMID- 27780305 TI - Maturation of oxycodone pharmacokinetics in neonates and infants: Oxycodone and its metabolites in plasma and urine. AB - AIMS: This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year-old infants. METHODS: Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg kg-1 during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified. The unconjugated forms of these compounds were determined in urine collected after up to 24 or 48 h from 25 infants. Pharmacokinetics was determined using noncompartmental analysis and reported for six clinically relevant age groups based on postmenstrual age. RESULTS: Oxycodone pharmacokinetics changed markedly with patient age. Preterm neonates were found to have the highest pharmacokinetic variability out of the study population. In extremely preterm neonates (n = 6) median of elimination half-life was 8.8 h (range 6.8-12.5), in preterm (n = 11) 7.4 h (4.2-11.6), and in older neonates (n = 22) 4.1 h (2.4-5.8), all of which were significantly longer than that in infants aged 6-24 months (n = 12) 2.0 h (1.7-2.6). Median renal clearance was fairly constant in all age groups, whereas non-renal clearance markedly increased with age. Noroxycodone was the major metabolite in plasma and urine. CONCLUSIONS: Oxycodone elimination is slower and pharmacokinetic variability more pronounced in neonates when compared to older infants. These findings highlight the importance of careful dose titration for neonates. PMID- 27780306 TI - The multidrug resistance transporters CgTpo1_1 and CgTpo1_2 play a role in virulence and biofilm formation in the human pathogen Candida glabrata. AB - The mechanisms of persistence and virulence associated with Candida glabrata infections are poorly understood, limiting the ability to fight this fungal pathogen. In this study, the multidrug resistance transporters CgTpo1_1 and CgTpo1_2 are shown to play a role in C. glabrata virulence. The survival of the infection model Galleria mellonella, infected with C. glabrata, was found to increase upon the deletion of either CgTPO1_1 or CgTPO1_2. The underlying mechanisms were further explored. In the case of CgTpo1_1, this phenotype was found to be consistent with the observation that it confers resistance to antimicrobial peptides (AMP), such as the human AMP histatin-5. The deletion of CgTPO1_2, on the other hand, was found to limit the survival of C. glabrata cells when exposed to phagocytosis and impair biofilm formation. Interestingly, CgTPO1_2 expression was found to be up-regulated during biofilm formation, but and its deletion leads to a decreased expression of adhesin-encoding genes during biofilm formation, which is consistent with a role in biofilm formation. CgTPO1_2 expression was further seen to decrease plasma membrane potential and affect ergosterol and fatty acid content. Altogether, CgTpo1_1 and CgTpo1_2 appear to play an important role in the virulence of C. glabrata infections, being at the cross-road between multidrug resistance and pathogenesis. PMID- 27780307 TI - The contribution of recently identified adult BMI risk loci to paediatric obesity in a Singaporean Chinese childhood dataset. AB - INTRODUCTION: Recent genome-wide association studies have identified 103 adult obesity risk loci; however, it is unclear if these findings are relevant to East Asian childhood body mass index (BMI) levels. METHODS AND RESULTS: We evaluated for paediatric obesity associations at these risk loci utilizing genome-wide data from Chinese childhood subjects in the Singapore Cohort study Of the Risk factors for Myopia study (N = 1006). A weighted gene-risk score of all adult obesity risk loci in the Singapore Cohort study Of the Risk factors for Myopia study showed strong associations with BMI at age 9 (p-value = 3.40 * 10-12 ) and 4-year average BMI (age 9 to 12, p-value = 6.67 * 10-8 ). Directionally consistent nominal associations for 15 index single nucleotide polymorphisms (SNPs) (p-value < 0.05) were observed. Pathway analysis with genes from these 15 replicating loci revealed over-representation for the G-protein-coupled receptor (GPCR)-mediated integration of entero-endocrine signalling pathway exemplified by L-cell (adjusted p-value = 0.018). Evaluations of birth weight to modify the effects of BMI risk SNPs in paediatric obesity did not reveal significant interactions, and these SNPs were generally not associated with birth weight. CONCLUSIONS: At least some common adult BMI risk variants predispose to paediatric obesity risk in East Asians. PMID- 27780309 TI - Incidental inflammatory adenoma with beta-catenin activation in the setting of paediatric NASH. AB - : Hepatocellular adenomas (HCA) are benign tumours with potential for malignant transformation with no recommendations regarding management in the paediatric population. We report a case of an inflammatory adenoma with beta-catenin activated pathway in an obese, paediatric patient with nonalcoholic steatohepatitis (NASH). CASE REPORT: An 11-year-old female presented with a microlobulated liver lesion measuring >5 cm in magnetic resonance imaging (MRI) with inflammatory adenoma with beta-catenin activated pathology arising in a background of NASH, nonalcoholic fatty liver disease (NAFLD) activity score 5/8. Imaging follow-up demonstrated stable disease without progression for 3 years. DISCUSSION: Malignant transformation of Hepatocellular adenomas in a child is approximately 4.2%. It is unknown if hepatic steatosis increases this risk. Obese patients mainly develop inflammatory and beta-catenin activated (highest risk for malignant transformation) adenomas. Our patient had inflammatory and beta-catenin activation, which led to monitoring for malignant transformation. CONCLUSION: We report a beta-catenin activated inflammatory adenoma in a child with obesity and NASH with ongoing expectant management. PMID- 27780308 TI - Role of Fibulin 3 in Aging-Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage. AB - OBJECTIVE: The EFEMP1 gene encoding fibulin 3 is specifically expressed in the superficial zone (SZ) of articular cartilage. The aims of this study were to examine the expression patterns of fibulin 3 in the knee joints during aging and during osteoarthritis (OA) and to determine the role of fibulin 3 in the pathogenesis of OA. METHODS: Immunohistochemical analysis was performed on normal and OA knee cartilage samples from humans and mice. Experimental OA was induced in wild-type and fibulin 3-/- mice, and the severity of OA was evaluated by histologic scoring. To examine fibulin 3 function, human chondrocyte monolayer cultures were transfected with small interfering RNA (siRNA), followed by quantitative polymerase chain reaction and Western blot analyses. Human bone marrow-derived mesenchymal stem cells (BM-MSCs) were transduced with an EFEMP1 lentivirus and analyzed for markers of chondrogenesis. RESULTS: Fibulin 3 was specifically expressed in the SZ of normal knee joint cartilage from humans and mice, and the expression levels declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin 3-/- mice compared with wild-type mice. Fibulin 3 expression was high in undifferentiated human BM-MSCs and decreased during chondrogenesis. Suppression of fibulin 3 by siRNA significantly increased the expression of SOX9, type II collagen, and aggrecan in human articular chondrocytes, while overexpression of fibulin 3 inhibited chondrogenesis in BM-MSCs. CONCLUSION: Fibulin 3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin 3 regulates differentiation of adult progenitor cells, and its aging-related decline is an early event in the pathogenesis of OA. Preventing aging-associated loss of fibulin 3 or restoring it to normal levels in SZ chondrocytes has the potential to delay or prevent the onset of OA. PMID- 27780310 TI - Impacts of Scarification and Degermination on the Expansion Characteristics of Select Quinoa Varieties during Extrusion Processing. AB - Extrusion of 2 quinoa varieties, Cherry Vanilla and Black (scarified and unscarified) and a mixed quinoa variety, Bolivian Royal (scarified and degermed) were studied for their extrusion characteristics. A corotating twin-screw extruder with a 3 mm round die was used. Feed moisture contents of 15%, 20%, and 25% (wet basis) were studied. The extruder barrel temperature was kept constant at 140 degrees C and screw speeds were varied from 100, 150, and 200 revolutions per minutes. Process responses (specific mechanical energy, back pressure, and torque) and product responses (expansion ratio, unit density, and water absorption index/water solubility index) were evaluated. The degermed Bolivian Royal showed the highest expansion in comparison to all other varieties, attributed to its significantly low levels of fat, fiber, and protein. The scarified Cherry Vanilla resulted in the lowest expansion ratio. This was attributed to the increase in the protein content from the removal of the outer layer. The results indicate that all the varieties performed differently in the extrusion process due to their modification processes as well as the individual variety characteristics. PMID- 27780311 TI - Initiation of and adherence to tamoxifen and aromatase inhibitor therapy among elderly women with ductal carcinoma in situ. AB - BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project B35 and International Breast Cancer Intervention Studies II Ductal Carcinoma In Situ trials showed similar treatment effects of anastrozole and tamoxifen in reducing cancer recurrence risk among ductal carcinoma in situ (DCIS) patients. Studies have shown low levels of hormone therapy drug initiation for DCIS patients, but the current body of literature lacks information on the 5-year adherence rates for these drugs from population-based studies. METHODS: This study evaluated the initiation and 5-year adherence levels for women aged 66 to 85 years who had been diagnosed with estrogen receptor (ER)-positive DCIS between 2007 and 2011 according to the Surveillance, Epidemiology, and End Results and Texas Cancer Registry databases linked to Medicare claims. Chi-square tests, trend tests, and logistic regression were used to identify factors associated with treatment initiation. RESULTS: There were 2871 women with ER-positive DCIS, and approximately 45% began treatment with tamoxifen or aromatase inhibitors (AIs) within 1 year of their DCIS diagnosis. The median age was 73 years for the users and 75 years for the nonusers. Women aged 66 to 70 years who underwent lumpectomy and radiation therapy were significantly more likely to initiate hormone therapy. The initiation of therapy was also significantly associated with patients' geographic location, education, marital status, diagnosis year, and race/ethnicity. Among users, adherence decreased from 67% in the first year to 30% in the fifth year. CONCLUSIONS: Initiation and adherence levels for tamoxifen or AIs among older women with ER-positive DCIS are low. Future studies should develop methods to ensure that informed discussions take place between health care providers and patients regarding hormonal therapy for cancer prevention. Cancer 2017;123:940-47. (c) 2016 American Cancer Society. PMID- 27780313 TI - Synthesis, carbonic anhydrase I and II isoenzymes inhibition properties, and antibacterial activities of novel tetralone-based 1,4-benzothiazepine derivatives. AB - Benzothiazepine compounds have a wide range of applications such as antibacterial, antidepressants, anticonvulsants, antihypertensives, antibiotics, antifungal, hypnotic, enzyme inhibitors, antitumor, anticancer and anti-HIV agents. In this study, the synthesis of novel tetralone-based benzothiazepine derivatives (1-16) and their in vitro antibacterial activity and human carbonic anhydrase isoenzymes I and II (hCA I and II) inhibitory effects were investigated. Both isoenzymes were purified by sepharose-4B-l-tyrosine sulfanilamide affinity chromatography from fresh human red blood cells. All compounds demonstrated the low nanomolar inhibitory effects on both isoenzymes using esterase activity. Benzothiazepine derivative 2 demonstrated the best hCA I inhibitory effect with Ki value of 18.19 nM. Also, benzothiazepine derivative 7 showed the best hCA II inhibitory effect with Ki value of 11.31 nM. On the other hand, acetazolamide clinically used as CA inhibitor, showed Ki value of 19.92 nM against hCA I and 33.60 nM against hCA II, respectively. PMID- 27780314 TI - miR-192-5p mediates hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes via targeting of FABP3. AB - Myocardial ischemia/reperfusion (I/R) injury is a leading cause of morbidity and mortality. In this study, we investigated the role of miR-192-5p in hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis. H9c2 cardiomyocytes were subjected to H/R and tested for miR-192-5p expression. Overexpression and knockdown experiments were performed to determine the effects of manipulating miR 192-5p on apoptotic responses. H/R-treated H9c2 cells exhibited a 2.2-fold increase in miR-192-5p levels. Overexpression of miR-192-5p significantly augmented apoptosis in H9c2 cells after H/R, which was accompanied by a significant increase in the ratio of Bax/Bcl-2. In contrast, delivery of anti-miR 192-5p inhibitors significantly reduced apoptosis induced by H/R. FABP3 was identified to be a functional target of miR-192-5p. Restoration of FABP3 prevented apoptosis in miR-192-5p-transfected H9c2 cells, whereas downregulation of FABP3 enhanced apoptosis in H/R-exposed H9c2 cells. In conclusion, miR-192-5p mediates H/R-induced apoptosis in cardiomyocytes by targeting FABP3 and represents a potential target for prevention of myocardial I/R injury. PMID- 27780312 TI - Interrelationships of child appetite, weight and snacking among Hispanic preschoolers. AB - BACKGROUND: Snacking among US preschoolers has increased in recent decades, raising questions about whether snacking contributes to dietary excess. OBJECTIVES: This research aimed to characterize snacking contributions to dietary excess and to evaluate associations with appetite and weight among preschool-aged children. METHODS: This study is a cross-sectional, observational study of 187 Hispanic low-income preschoolers. Three 24-h dietary recalls were used to assess snacking frequency and parameters of dietary excess including energy, saturated fat, trans fats and added sugars. Parental reports of child satiety responsiveness, food responsiveness, and enjoyment of food were obtained. Child height and weight were measured. RESULTS: Children consumed 28% (395 kcal) of daily energy from snacks eaten at 2.3 +/- 1.0 occasions per day. Greater snacking frequency was associated with greater daily intakes of energy (p < 0.05) and added sugars (p < 0.001). Among overweight/obese children, higher enjoyment of food was associated with more frequent snacking and greater energy intake from snacks (p = 0.01). Inverse associations of enjoyment of food with snacking frequency and energy intake were seen among normal weight children (p < 0.05). CONCLUSIONS: More frequent snacking among low-income Hispanic preschoolers may contribute to excessive intakes of energy and added sugars, particularly among overweight/obese children with greater motivation to eat. PMID- 27780315 TI - Dental cavity liners for Class I and Class II resin-based composite restorations. AB - BACKGROUND: Resin-based composite (RBC) is currently accepted as a viable material for the restoration of caries for posterior permanent teeth requiring surgical treatment. Despite the fact that the thermal conductivity of the RBC restorative material closely approximates that of natural tooth structure, postoperative hypersensitivity is sometimes still an issue. Dental cavity liners have historically been used to protect the pulp from the toxic effects of some dental restorative materials and to prevent the pain of thermal conductivity by placing an insulating layer between restorative material and the remaining tooth structure. OBJECTIVES: The objective of this review was to assess the effects of using dental cavity liners in the placement of Class I and Class II resin-based composite posterior restorations in permanent teeth in children and adults. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 25 May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library (searched 25 May 2016), MEDLINE Ovid (1946 to 25 May 2016), Embase Ovid (1980 to 25 May 2016) and LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 25 May 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomized controlled trials assessing the effects of the use of liners under Class I and Class II posterior resin-based composite restorations in permanent teeth (in both adults and children). We included both parallel and split-mouth designs. DATA COLLECTION AND ANALYSIS: We utilized standard methodological procedures prescribed by Cochrane for data collection and analysis. Two review authors screened the search results and assessed the eligibility of studies for inclusion against the review inclusion criteria. We conducted risk of bias assessments and data extraction independently and in duplicate. Where information was unclear we contacted study authors for clarification. MAIN RESULTS: Eight studies, recruiting over 700 participants, compared the use of dental cavity liners to no liners for Class I and Class II resin-based composite restorations.Seven studies evaluated postoperative hypersensitivity measured by various methods. All studies were at unclear or high risk of bias. There was inconsistent evidence regarding postoperative hypersensitivity (either measured using cold response or patient-reported), with a benefit shown at some, but not all, time points (low-quality evidence).Four trials measured restoration longevity. Two of the studies were judged to be at high risk and two at unclear risk of bias. No difference in restoration failure rates were shown at one year follow-up, with no failures reported in either group for three of the four studies; the fourth study had a risk ratio (RR) 1.00 (95% confidence interval (CI) 0.07 to 15.00) (low-quality evidence). Three studies evaluated restoration longevity at two years follow-up and, again, no failures were shown in either group.No adverse events were reported in any of the included studies. AUTHORS' CONCLUSIONS: There is inconsistent, low-quality evidence regarding the difference in postoperative hypersensitivity subsequent to placing a dental cavity liner under Class I and Class II posterior resin-based composite restorations in permanent posterior teeth in adults or children 15 years or older. Furthermore, no evidence was found to demonstrate a difference in the longevity of restorations placed with or without dental cavity liners. PMID- 27780317 TI - The Perinatal Depression Treatment Cascade: Baby Steps Toward Improving Outcomes. AB - OBJECTIVE: Perinatal depression is a common and costly health concern with serious implications for the mother and child. We sought to quantify the "Perinatal Depression Treatment Cascade"-the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response for women with antenatal (AND) and postpartum depression (PPD). DATA SOURCES: A systematic search was conducted to identify articles about diagnostic rates, treatment rates, adequate treatment rates, and remission rates for AND and PPD. We searched PubMed and EMBASE through March 2015. STUDY SELECTION: Articles were included if they were in English and examined rates of detection, treatment, adequate treatment, or remission for AND or PPD. DATA EXTRACTION AND ANALYSIS: Mean rates of diagnosis, treatment, adequate treatment, and remission were calculated and weighted based on the number of subjects in each study. Search results were dually reviewed for confirmation of study eligibility and data abstraction. RESULTS: Decrements occur at each branch of the cascade. Data suggest that 49.9% of women with AND and 30.8% of women with PPD are identified in clinical settings; 13.6% of women with AND and 15.8% of women with PPD receive treatment; 8.6% of women with AND and 6.3% of women with PPD receive adequate treatment; and 4.8% of women with AND and 3.2% of women with PPD achieve remission. CONCLUSIONS: Application of the treatment cascade model suggests multiple opportunities for improving perinatal depression management, informing optimal allocation of resources, and providing adequate treatment to this underrecognized and undertreated population.. PMID- 27780316 TI - Can we eliminate neoadjuvant chemoradiotherapy in favor of neoadjuvant multiagent chemotherapy for select stage II/III rectal adenocarcinomas: Analysis of the National Cancer Data base. AB - BACKGROUND: Stage II and III rectal cancers have been effectively treated with neoadjuvant chemoradiotherapy (NCRT) followed by definitive resection. Advancements in surgical technique and systemic therapy have prompted investigation of neoadjuvant multiagent chemotherapy (NMAC) regimens with the elimination of radiation (RT). The objective of the current study was to investigate factors that predict for the use of NCRT versus NMAC and compare outcomes using the National Cancer Data Base (NCDB) for select stage II and III rectal cancers. METHODS: In the NCDB, 21,707 patients from 2004 through 2012 with clinical T2N1 (cT2N1), cT3N0, or cT3N1 rectal cancers were identified who had received NCRT or NMAC followed by low anterior resection. Kaplan-Meier analyses, log-rank tests, and Cox-proportional hazards regression analyses were conducted along with propensity score matching analysis to reduce treatment selection bias. RESULTS: The 5-year actuarial overall survival (OS) rate was 75% for patients who received NCRT versus 67.2% for those who received NMAC (P < .01). On MVA, those who received NCRT had improved OS (hazard ratio, 0.77. P < .01), and this effect was confirmed on propensity score matching analysis (hazard ratio, 0.72; P = .01). In the same model, the following variables improved OS: age < 65 years, having private insurance, treatment at an academic center, living in an affluent zip code, a low comorbidity score, receipt of adjuvant chemotherapy, and a shorter interval before surgery (all P < .05). African Americans, men, patients with high-grade tumors, those with cT3N1 tumors, and those who underwent incomplete (R1) resection had worse OS (all P < .05). CONCLUSIONS: In this series, the elimination of neoadjuvant RT for select patients with stage II and III rectal adenocarcinoma was associated with worse OS and should not be recommended outside of a clinical trial. Cancer 2017;123:783-93. (c) 2016 American Cancer Society. PMID- 27780319 TI - Why Do Some Nonnative People Who Migrate to Another Country Have Better Health Status Than Their Native-Born Counterparts? PMID- 27780318 TI - Determination of Adherence Profiles in Schizophrenia Using Self-Reported Adherence: Results From the FACE-SZ Dataset. AB - OBJECTIVE: Medication nonadherence is one of the most important, and potentially modifiable, prognostic factors in the outcome of patients with schizophrenia. The aim of this article is to propose a new classification of adherence profiles according to the Medication Adherence Rating Scale (MARS) in a large community dwelling sample of French patients with schizophrenia to provide a new tool to help clinicians in daily practice. METHODS: 319 community-dwelling patients from a national network of 10 Schizophrenia Expert Centers were interviewed between January 2009 and January 2014. Assessments were conducted with a dedicated electronic medical record including the Structured Clinical Interview for DSM-IV Disorders. A cluster analysis was performed to explore clinical variables associated with poor adherence. RESULTS: Two distinct groups of patients were identified relative to their main adherence style. Items about medications' subjective negative effects constituted the greatest discriminating factor between the 2 clusters. Patients with poor adherence (n = 117) were significantly younger (adjusted OR [aOR] = 1.036; 95% CI, 1.004-1.069) and had higher levels of current depression (aOR = 0.894; 95% CI, 0.829-0.964) and lower insight (aOR = 0.820; 95% CI, 0.693-0.970). CONCLUSIONS: The MARS provides a useful tool for clinicians and can also aid in the evaluation of adherence styles and their determinants in patients with schizophrenia. The element providing the greatest discriminative power between the 2 clusters was a subjective negative attitude toward medication. The findings also suggest that depression is more frequent in schizophrenia patients with poor adherence and that improving insight into illness might be suggested as a first-line intervention to improve adherence in this population. PMID- 27780320 TI - Early Nonresponse in the Antipsychotic Treatment of Acute Mania: A Criterion for Reconsidering Treatment? Results From an Individual Patient Data Meta-Analysis. AB - OBJECTIVE: To investigate whether early nonresponse to antipsychotic treatment of acute mania predicts treatment failure and, if so, to establish the best definition or criterion of an early nonresponse. DATA SOURCES: Short-term efficacy studies assessing antipsychotics that were submitted to the Dutch Medicines Evaluation Board during an 11-year period as part of the marketing authorization application for the indication of acute manic episode of bipolar disorder. Pharmaceutical companies provided their raw patient data, which enabled us to perform an individual patient data meta-analysis. STUDY SELECTION: All double-blind, randomized, placebo-controlled trials assessing the efficacy of antipsychotics for acute manic episode of bipolar disorder were included (10 trials). DATA EXTRACTION: All patients with data available for completer analysis (N = 1,243), symptom severity scores on the Young Mania Rating Scale (YMRS) at weeks 0, 1, and 2 and at study end point (week 3 or 4). RESULTS: The a priori chances of nonresponse and nonremission at study end point were 40.9% (95% CI, 38.2%-43.6%) and 65.3% (95% CI, 62.0%-68.6%), respectively. Early nonresponse in weeks 1 and 2, defined by cutoff scores ranging from a <= 10% to a <= 50% reduction in symptoms compared to baseline on the YMRS, significantly predicted nonresponse (<= 0% symptom reduction) and nonremission (YMRS score higher than 8) in week 3. The predictive value of early nonresponse (PVnr_se) at week 1 for both nonresponse and nonremission at study end point declined linearly with increasing cutoff scores of early nonresponse; nonresponse: 76.0% (95% CI, 69.7%-82.3%) for a <= 10% response to 48.7% (95% CI, 45.5%-51.9%) for a <= 50% response; nonremission: 92.2% (95% CI, 88.3%-96.1%) for a <= 10% response to 76.8% (95% CI, 74.4%-79.5%) for a <= 50% response. A similar linear decline was observed for increasing cutoff scores of early nonresponse at week 2 for nonresponse, but not for nonremission at end point: nonresponse 90.3% (95% CI, 84.6%-96.0%) for a <= 10% response to 65.0% (95% CI, 61.4%-68.6%) for a <= 50% response; nonremission: 94.2% (95% CI, 89.7%-98.7%) for a <= 10% response and 93.2% (95% CI, 93.1%-95.1%) for a <= 50% response. Specific antipsychotic characteristics did not modify these findings at either time point (week 1: P = .127; week 2: P = .213). CONCLUSIONS: When patients fail to respond early (1-2 weeks) after the initiation of antipsychotic treatment for acute mania, clinicians should reconsider their treatment choice using a 2-stage strategy. PMID- 27780321 TI - Parental Antecedents of Psychosis Are Associated With Severity of Positive and Negative Symptoms in Schizophrenia Patients. PMID- 27780322 TI - Pregabalin Use Among Opioid-Addicted Patients in Switzerland. PMID- 27780323 TI - The Association Between PTSD and ADHD: Does the Association Reveal a PTSD Somatoform Subtype? PMID- 27780324 TI - Drs Spencer and Biederman Reply. PMID- 27780325 TI - Antidepressants and Risk of Dementia: Methodology Is Essential. PMID- 27780326 TI - Dr Kao Replies. PMID- 27780327 TI - Correction: A Randomized Clinical Trial of High Eicosapentaenoic Acid Omega-3 Fatty Acids and Inositol as Monotherapy and in Combination in the Treatment of Pediatric Bipolar Spectrum Disorders: A Pilot Study. AB - This corrects the article DOI: 10.4088/JCP.14m09267. PMID- 27780328 TI - Cardiometabolic Risks in Schizophrenia and Directions for Intervention, 3: Psychopharmacological Interventions. AB - Patients with schizophrenia have increased prevalence rates for many cardiometabolic risk factors; the prevalence and severity of these risks increase after the institution of antipsychotic medication. Nearly 2 dozen different pharmacologic interventions have been trialed to prevent or attenuate antipsychotic-related cardiometabolic changes. Metformin (usually 1,000-1,500 mg/d) has emerged as the best-studied intervention; in short- and intermediate duration randomized controlled trials, it has been shown to bring about improvements in weight and other anthropometric indices, in fasting sugar and other glycemic control indices, and in total cholesterol and other lipid metabolism indices. Topiramate and aripiprazole are other possible interventions with support in literature; besides improving metabolic outcomes, these drugs may improve indices of psychopathology, as well. Encouraging though the findings are, there are many unanswered questions that require attention in future research. PMID- 27780329 TI - Recognizing and Assessing Risk Factors for Difficult-to-Treat Depression and Treatment-Resistant Depression. AB - Many patients will not respond adequately to their initial trial of antidepressant medication or subsequent trials. By identifying features that can signal potential treatment-resistant or difficult-to-treat depression early in the course of illness, clinicians may be able to find the right balance of treatment strategies to help patients achieve remission. Here, follow the case of Alice, a 32-year-old lawyer with a treatment-resistant depressive episode. PMID- 27780330 TI - Enhancing Approaches to the Identification and Management of Pseudobulbar Affect. AB - Pseudobulbar affect (PBA) is a socially debilitating condition that primarily affects people with neurologic diseases, such as Alzheimer's disease or multiple sclerosis. This condition is characterized by uncontrolled, exaggerated expressions of laughing or crying-often when the situation does not warrant this behavior. Although the true prevalence of PBA is surprisingly high, this condition remains widely misdiagnosed and underdiagnosed. While its exact etiology is unknown, PBA likely results from disruptions in the brain structures and/or neurotransmitters that regulate emotions. Differential diagnosis of PBA includes ruling out depression or other psychiatric conditions. Treatment of PBA has traditionally centered on antidepressant therapies, but newer therapeutic options include combination agents employing multiple modalities. Therapy should include patient counseling to reassure patients and families that PBA is not the fault of the individual. Counseling should also emphasize safety precautions to minimize adverse events and maximize appropriate adherence to the selected therapies. PMID- 27780332 TI - A Cohort Study of Mortality in Individuals With and Without Schizophrenia After Diagnosis of Lung Cancer. AB - OBJECTIVE: Individuals with serious mental illness have increased mortality relative to those without these illnesses. Although cancer is a leading cause of death, few studies have evaluated potential disparities relative to mortality for individuals with serious mental illness who are diagnosed with cancer. In this study, we evaluated mortality after diagnosis of a common malignancy (lung cancer) in a prototypical serious mental illness (schizophrenia). METHODS: Using administrative data in the Veterans Affairs system, we identified 34,664 individuals who were diagnosed with lung cancer between October 1, 2001, and September 30, 2005. We conducted a survival analysis comparing individuals with and without ICD-9-CM schizophrenia using data through September 30, 2010. Controlling variables were age, gender, smoking status, marital status, service connection, homelessness status, and presence of a substance use disorder. RESULTS: Our results demonstrated significantly poorer survival after lung cancer diagnosis for individuals with schizophrenia compared to those without schizophrenia. The hazard ratio for all-cause mortality associated with schizophrenia was 1.33 (95% CI, 1.22-1.44). CONCLUSIONS: Individuals with schizophrenia are at higher risk of death after diagnosis of lung cancer than those without schizophrenia. Future studies should further characterize cause of death, quality of cancer care received, and barriers to care. PMID- 27780331 TI - Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer's Disease. AB - OBJECTIVE: Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia. METHODS: Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness. RESULTS: The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome. CONCLUSIONS: Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00403520. PMID- 27780333 TI - Persistence in Therapy With Risperidone and Aripiprazole in Pediatric Outpatients: A 2-Year Naturalistic Comparison. AB - OBJECTIVE: The practical effectiveness of second-generation antipsychotics in children and adolescents is an understudied issue. It is a crucial area of study, though, because such patients are often treated for long-lasting disorders. METHODS: We carried out a 24-month (March 2012-March 2014) observational study on an unselected population of pediatric outpatients treated with risperidone, aripiprazole, olanzapine, or quetiapine aiming to (1) describe drug use, (2) compare post hoc the discontinuation rates due to specific causes and dose adjustments by Kaplan-Meier analyses between drugs, and (3) analyze predictors influencing these outcomes by Cox multivariate models. RESULTS: Among 184 pediatric patients, 77% patients were prescribed risperidone, and 18% were prescribed aripiprazole. Olanzapine or quetiapine were scantly used; therefore, they were excluded from analyses. Risperidone was prevalent in younger, male patients with disruptive behavioral disorders; aripiprazole, in patients with tic disorders. Overall, discontinuations occurred mostly in the first 6 months, and, at 24 months, the discontinuation numbers were similar between users of risperidone and aripiprazole (41.5% vs 39.4%). In univariate analyses, dose reduction was higher for aripiprazole (P = .033). Multivariate analyses yielded the following predictors: for all-cause discontinuation, baseline severity (hazard ratio [HR] = 1.48, P = .001) and dose increase (HR = 3.55, P = .001); for patient-decided discontinuation, dose change (increase: HR = 6.43, P = .004; reduction: HR = 7.89, P = .049) and the presence of concomitant drugs (HR = 4.03, P = .034), while autistic patients discontinued less (HR = 0.23, P = .050); for clinician-decided discontinuation due to adverse drug reactions, baseline severity (HR = 1.96, P = .005) and dose increase (HR = 5.09, P = .016); for clinician-decided discontinuation due to inefficacy, baseline severity (HR = 2.88, P = .014) and the use of aripiprazole (HR = 5.55, P = .013); for dose increase, none; for dose reduction, the occurrence of adverse drug reactions (HR = 4.74, P = .046), while dose reduction was less probable in autistic patients (HR = 0.22, P = .042). CONCLUSIONS: The findings of this study show a similarity between the overall effectiveness of risperidone and aripiprazole in a real-life pediatric outpatient setting. PMID- 27780334 TI - Efficacy of Vortioxetine on Cognitive Functioning in Working Patients With Major Depressive Disorder. AB - OBJECTIVE: This post hoc analysis investigates the effect of vortioxetine on cognitive functioning and depressive symptoms in working adults with major depressive disorder (MDD). METHODS: Population data from FOCUS, a double-blind, randomized, placebo-controlled study investigating the efficacy of vortioxetine versus placebo on cognitive functioning and depression in patients with MDD, were used to analyze mean change from baseline scores for the Digit Symbol Substitution Test (DSST), Trail Making Test A/B (TMT-A/B), Stroop, and Perceived Deficits Questionnaire (PDQ). FOCUS, conducted from December 2011 through May 2013, included adult patients with recurrent MDD according to DSM-IV-TR criteria. Change in depression severity (Montgomery-Asberg Depression Rating Scale [MADRS] total score) was analyzed using data from 3 additional short-term placebo controlled studies (2 of which included duloxetine) and 1 relapse prevention study. Analyses were done according to patients' working status at baseline and workplace position. All analyses were made versus placebo. RESULTS: In FOCUS, the effect versus placebo on the DSST was 5.6 for 10 mg and 5.0 for 20 mg (P < .001 for both doses) in working patients; the effect was 4.0 (P < .001 for both doses) in total study population. The effect remained significant when adjusting for change in MADRS. In patients with "professional" positions, the effect was 9.2 for 10 mg (P = .006) and 9.0 for 20 mg (P = .001). A similar pattern of results was also observed for TMT-A/B, Stroop, PDQ, and MADRS total score. The efficacy of duloxetine was not different in working patients (MADRS). CONCLUSIONS: The beneficial effects of vortioxetine on objective and subjective measures of cognitive functioning are greater in working patients with MDD; the observed benefits were independent of improvement in depressive symptoms. TRIAL REGISTRATION: This study is a secondary analysis of data from 5 registered trials: ClinicalTrials.gov identifiers: NCT01422213, NCT00635219, NCT00735709, NCT01140906, NCT00596817. PMID- 27780335 TI - A Randomized Trial of Dialectical Behavior Therapy in High-Risk Suicidal Veterans. AB - OBJECTIVE: Despite advances in suicide prevention implemented throughout the US Department of Veterans Affairs (VA) including the hiring of Suicide Prevention Coordinators (SPCs) at every VA hospital, enhanced monitoring, and the availability of 24-hour crisis hotline services, suicide by veterans remains a critical problem affecting 20 veterans daily. Few empirically based treatment strategies for suicide prevention for postdeployment military personnel exist. This study aimed to test whether dialectical behavior therapy (DBT), one of the few psychosocial treatments with proven efficacy in diminishing suicidal behavior in individuals with personality disorder, can be applied to veterans irrespective of personality diagnosis. METHODS: From January 2010 to December 2014, 91 nonpsychotic veterans at high risk for suicide (61 men, 30 women) were randomly assigned to a 6-month treatment trial at a veterans' medical center comparing standard DBT to treatment as usual (TAU) and followed for 6 months after trial completion. Primary outcome was suicide attempts, measured with the Columbia Suicide Severity Rating Scale, and secondary outcomes were suicide ideation, depression, hopelessness, and anxiety. There were no exclusions pertaining to substance abuse, homelessness, or medical comorbidity. RESULTS: Both DBT and TAU resulted in improvements in suicidal ideation, depression, and anxiety during the course of the 6-month treatment trial that did not differ between treatment arms. Survival analyses for suicide attempts and hospitalizations did not differ between treatment arms. However, DBT subjects utilized significantly more individual mental health services than TAU subjects (28.5 +/- 19.6 vs 14.7 +/- 10.9, F1,77 = 11.60, P = .001). CONCLUSIONS: This study is the first to examine 6 month DBT in a mostly male, veteran population. Increased mental health treatment service delivery, which included enhanced monitoring, outreach, and availability of a designated SPC, did not yield statistically significant differences in outcome for veterans at risk for suicide in TAU as compared to the DBT treatment arm. However, both treatments had difficulty with initial engagement post hospitalization. Future studies examining possible sex differences and strategies to boost retention in difficult-to-engage, homeless, and substance-abusing populations are indicated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02462694. PMID- 27780337 TI - Glutamatergic Agents as Add-On Medication for the Treatment of Obsessive Compulsive Disorder: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The aim of the present study was to review the existing literature on clinical trials with glutamatergic agents in adults with obsessive-compulsive disorder (OCD) and to perform a meta-analysis to estimate the overall effect size. DATA SOURCES: We searched in MEDLINE, Embase, and the Cochrane Library for eligible studies, using the following search terms: (glutamate OR glutaminergic OR glutamatergic OR NMDA OR AMPA OR kainate) AND (obsessive-compulsive disorder OR obsessive OR compulsive OR OCD). A separate search was performed for generally known glutamatergic agents. The databases were searched for articles published by May 31, 2015. STUDY SELECTION: Eligible studies were double-blind, randomized controlled trials that tested the efficacy of add-on treatment with a glutamatergic agent in patients with OCD. DATA EXTRACTION: Data were extracted independently by 2 reviewers. We extracted dichotomous data (number of patients with response and remission) to estimate relative risk ratios (RRs), as well as continuous data (scores in Yale-Brown Obsessive Compulsive Scale and Clinical Global Impressions-Severity of Illness and -Improvement scales), which were used to estimate standardized mean differences. Effect sizes were estimated using a random-effects model. RESULTS: Eight randomized controlled trials were identified. The overall ratio for response was RR = 3.71 (95% CI, 2.35-5.83; P < .001). When limited to the studies with treatment-resistant patients, the effect size remained significant (RR = 4.30; 95% CI, 2.19-8.43; P < .001). Secondary outcomes, such as the standardized mean differences for continuous data, showed the statistically significant superiority (P < .001) of glutamatergic agents over placebo. The risk of dropouts was RR = 1.18 (95% CI, 0.83-1.69; P = .361) and the risk of dropouts due to adverse effects was RR = 3.04 (95% CI, 1.57-5.89; P = .001). CONCLUSIONS: Glutamatergic agents are effective as add-on treatment for OCD in general and especially for treatment-refractory OCD. PMID- 27780336 TI - Improving Physical Health in Patients With Chronic Mental Disorders: Twelve-Month Results From a Randomized Controlled Collaborative Care Trial. AB - OBJECTIVE: Persons with chronic mental disorders are disproportionately burdened with physical health conditions. We determined whether Life Goals Collaborative Care compared to usual care improves physical health in patients with mental disorders within 12 months. METHODS: This single-blind randomized controlled effectiveness study of a collaborative care model was conducted at a midwestern Veterans Affairs urban outpatient mental health clinic. Patients (N = 293 out of 474 eligible approached) with an ICD-9-CM diagnosis of schizophrenia, bipolar disorder, or major depressive disorder and at least 1 cardiovascular disease risk factor provided informed consent and were randomized (February 24, 2010, to April 29, 2015) to Life Goals (n = 146) or usual care (n = 147). A total of 287 completed baseline assessments, and 245 completed 12-month follow-up assessments. Life Goals included 5 weekly sessions that provided semistructured guidance on managing physical and mental health symptoms through healthy behavior changes, augmented by ongoing care coordination. The primary outcome was change in physical health-related quality of life score (Veterans RAND 12-item Short Form Health Survey [VR-12] physical health component score). Secondary outcomes included control of cardiovascular risk factors from baseline to 12 months (blood pressure, lipids, weight), mental health-related quality of life, and mental health symptoms. RESULTS: Among patients completing baseline and 12-month outcomes assessments (N = 245), the mean age was 55.3 years (SD = 10.8; range, 25 78 years), and 15.4% were female. Intent-to-treat analysis revealed that compared to those in usual care, patients randomized to Life Goals had slightly increased VR-12 physical health scores (coefficient = 3.21; P = .01). CONCLUSIONS: Patients with chronic mental disorders and cardiovascular disease risk who received Life Goals had improved physical health-related quality of life. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01487668 and NCT01244854. PMID- 27780338 TI - A Longitudinal Study of the Relationships Between Mood Symptoms, Body Mass Index, and Serum Adipokines in Bipolar Disorder. AB - OBJECTIVE: There is a bidirectional relationship between obesity and mood disorders, with each increasing the risk of developing the other. This relationship suggests that they have overlapping pathophysiologic mechanisms. Adipose tissue-derived hormones, or adipokines, regulate appetite and metabolism and have activity in limbic brain regions, making them potential shared etiologic factors between elevated body mass index (BMI) and mood disorders. However, the precise relationships between BMI, mood, and adipokines are unknown. METHODS: We measured the serum levels of adiponectin, lipocalin-2, resistin, adipsin, and leptin in 53 people with early-stage DSM-IV-defined bipolar disorder, diagnosed with the Mini-International Neuropsychiatric Interview, and 22 healthy comparison subjects. Participants were followed at the University of British Columbia Mood Disorders Centre between June 2004 and June 2012. We were primarily interested in determining, in patients, (1) whether BMI and recent mood episodes predicted adipokine levels and (2) whether adipokine levels in turn predicted subsequent mood relapses and change in BMI. RESULTS: Using linear regression, we found that (1) past-6-month mood episodes predicted lower adiponectin (beta = -0.385, P = .04) and adipsin (beta = -0.376, P = .03) levels and higher lipocalin-2 levels (beta = 0.411, P = .03), (2) BMI did not predict adipokine levels, and (3) treatment with second-generation antipsychotics was associated with higher resistin levels (beta = 0.482, P < .01). Furthermore, lower adiponectin (beta = 0.353, P = .01) and leptin (beta = -0.332, P = .02) levels predicted depressive relapse over 12 months, while higher adipsin (beta = 0.496, P < .01) and leptin (beta = 0.421, P < .01) levels predicted BMI gain. CONCLUSIONS: Our results suggest that mood episodes and medication treatment contribute to adipokine abnormalities in bipolar disorder and that adipokines influence psychiatric illness course and BMI change. Adipokines may represent a novel pathophysiologic mechanism linking elevated BMI and mood disorders and deserve further study as potential mood-regulating molecules. PMID- 27780339 TI - Time Trends in Lifetime Incidence Rates of First-Time Diagnosed Bipolar and Depressive Disorders Across 16 Years in Danish Psychiatric Hospitals: A Nationwide Study. AB - OBJECTIVE: There is conflicting evidence as to whether or not the incidences of affective disorders are on the rise. The aim of the present study was to identify time trends across 16 years in the incidences of affective disorders in a nationwide sample. METHODS: Using the Danish Psychiatric Central Research Registry, age- and sex-adjusted incidence rates of diagnosed affective disorders in Danish psychiatric hospitals using ICD-10 classification were calculated per 100,000 person-years for the population aged 4-65 years during the period 1995 2010. RESULTS: Incidence rates of diagnosed bipolar disorder increased from 11.5 to 24.5, and there was an increase from 86.2 to 189.7 per 100,000 person-years for depression. Time trends were most pronounced for individuals up to 29 years of age. A sizeable part of the increase in incidence rates could be attributed to an increase in the total number of persons diagnosed in psychiatry. CONCLUSIONS: Time trends in incidence rates showed an increase for bipolar disorder and depressive disorders across 16 years, but found that some of the observed increase in incidence rates was related to a more widespread trend in Danish society of seeking and receiving psychiatric assistance. PMID- 27780340 TI - CD9 Expression in Colorectal Carcinomas and Its Prognostic Significance. AB - BACKGROUND: CD9, a member of the tetraspanin superfamily, is a tumor suppressor in many malignancies. The aim of this study was to evaluate the immunohistochemical expression of CD9 in colorectal carcinomas (CRCs) and determine clinicopathological and prognostic significance of its expression. METHODS: The CD9 expression status of 305 CRCs was evaluated using a semi quantitative scoring system in tumor cells (T-CD9) and immune cells (I-CD9) by classifying the results as high and low expression. RESULTS: High T-CD9 (T-CD9 [+]) expression was detected in 175 samples (57.6%) and high I-CD9 (I-CD9 [+]) expression was detected in 265 samples (86.9%). Using Kaplan- Meier survival analysis, the T-CD9 (+) group showed a tendency for better disease-free survival (DFS) (p = .057). In left-sided tumors, DFS was significantly longer in the T-CD9 (+) group (p = .021) but no statistical significance was observed with right sided tumors (p = .453). I-CD9 (+) CRCs significantly correlated with well/moderately differentiation (p = .014). In Kaplan-Meier analysis, the I-CD9 (+) group had a tendency towards worse DFS compared to the I-CD9 (-) group (p = .156). In combined survival analysis of T-CD9 and I-CD9, we found that the longest DFS was among patients in the T-CD9 (+)/I-CD9 (-) group, whereas the T CD9 (-)/I-CD9 (+) group showed the shortest DFS (p = .054). CONCLUSIONS: High expression of T-CD9 was associated with a favorable DFS, especially in left-sided CRCs. Combined evaluation of T-CD9 and I-CD9 is required to determine the comprehensive prognostic effect of CD9 in CRCs. PMID- 27780342 TI - Cp*CoIII-Catalyzed Synthesis of Pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-iums via Tandem C-H Activation and Subsequent Annulation from 1-(Pyridin-2-yl)-1H-indoles and Internal Alkynes. AB - A Cp*CoIII-catalyzed C2-selective C-H alkenylation/annulation cascade transformation of 1-(pyridin-2-yl)-1H-indoles with internal alkynes to afford pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-iums is presented. Moreover, 6,7-dihydro 4H-pyrido[2',1':2,3]pyrimido[1,6-a]indole, a new functionalized N-fused indole core heterocycle, could be constructed effectively via reduction of pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-ium by NaBH4. PMID- 27780341 TI - Chemical Mechanism of the Branched-Chain Aminotransferase IlvE from Mycobacterium tuberculosis. AB - The biosynthetic pathway of the branched-chain amino acids is essential for Mycobacterium tuberculosis growth and survival. We report here the kinetic and chemical mechanism of the pyridoxal 5'-phosphate (PLP)-dependent branched-chain aminotransferase, IlvE, from M. tuberculosis (MtIlvE). This enzyme is responsible for the final step of the synthesis of the branched-chain amino acids isoleucine, leucine, and valine. As seen in other aminotransferases, MtIlvE displays a ping pong kinetic mechanism. pK values were identified from the pH dependence on V as well as V/K, indicating that the phosphate ester of the PLP cofactor, and the alpha-amino group from l-glutamate and the active site Lys204, play roles in acid base catalysis and binding, respectively. An intrinsic primary kinetic isotope effect was identified for the alpha-C-H bond cleavage of l-glutamate. Large solvent kinetic isotope effect values for the ping and pong half-reactions were also identified. The absence of a quininoid intermediate in combination with the Dkobs in our multiple kinetic isotope effects under single-turnover conditions suggests a concerted type of mechanism. The deprotonation of C2 of l-glutamate and the protonation of C4' of the PLP cofactor happen synchronously in the ping half-reaction. A chemical mechanism is proposed on the basis of the results obtained here. PMID- 27780344 TI - 0.1% Polyhexanide-Betaine Solution as an Adjuvant in a Case-Series of Chronic Wounds. AB - INTRODUCTION: The application of 0.1% polyhexanide-betaine gel and irrigating solution was used in place of saline during standard of care wound treatment for 70 chronic wounds of various etiologies. Our goal in this study sample was to investigate the number of days to wound closure, change in absolute wound size, and antimicrobial initiation from baseline visit, following application of polyhexanide-betaine in standard of care wound treatment. Results suggested a benefit of Prontosan(r) (Polyhexanide-betaine, B. Braun Medical Inc., Allentown, Pennsylvania), with very few patients being administered supplemental antibiotic treatment. MATERIALS AND METHODS: A retrospective chart analysis evaluated 0.1% polyhexanide-betaine as an adjuvant in the management of chronic non-healing wounds. Over a two-year period at a single wound center, 0.1% polyhexanide betaine gel and irrigating solution were applied in place of saline during standard of care wound treatment for 70 chronic wounds of various etiologies. Standard weekly wound protocols and debridement were performed. All wounds were evaluated for days to closure, change in wound dimensions, and number of patients requiring antibiotic therapy after initial consultation at the study site. RESULTS: A case series of 49 patients presented 70 wounds for analysis. Antimicrobial therapy was initiated in five of 49 patients. Days to wound closure revealed that venous wounds showed the shortest number of days to closure (29 days) with diabetic ulcers the longest (92 days). Significant comorbid conditions and concomitant medications were present in all groups and did not appear associated with closure rates. CONCLUSIONS: The use of 0.1% polyhexanide-betaine gel and solution in treating chronic non-healing wounds provided a moist wound healing environment facilitating closure. Of particular note was the fact that with polyhexanide-betaine, antimicrobial therapy was not initiated in nearly 90% of patients. It is theorized that the antimicrobial effect of 0.1% polyhexanide betaine gel and solution inhibited bacterial colonization and reduced the need for antimicrobial usage. A prospective controlled and randomized study is warranted to further explore this theory. PMID- 27780343 TI - Gene Editing and Genetic Lung Disease. Basic Research Meets Therapeutic Application. AB - Although our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin deficiency is extensive, treatment options are lacking. Because the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intratracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene-editing technology is a promising approach to repairing or inactivating disease-causing mutations. Recent reports have provided proof of concept by using CRISPR/Cas9 to successfully repair or inactivate mutations in animal models of monogenic human diseases. Potential pulmonary applications of CRISPR/Cas9 gene editing include gene correction of monogenic diseases in pre- or postnatal lungs and ex vivo gene editing of patient-specific airway stem cells followed by autologous cell transplant. Strategies to enhance gene-editing efficiency and eliminate off-target effects by targeting pulmonary stem/progenitor cells and the assessment of short-term and long-term effects of gene editing are important considerations as the field advances. If methods continue to advance rapidly, CRISPR/Cas9-mediated gene editing may provide a novel opportunity to correct monogenic diseases of the respiratory system. PMID- 27780345 TI - Radiofrequency in the Management of Colorectal Liver Metastases: A 10-Year Experience at a Single Center. AB - BACKGROUND: Liver resection is the curative treatment for patients with colorectal liver metastases (CRLMs), with five-year survival rates of 30-50%. Radiofrequency ablation (RFA) is a local and useful alternative for patients with non-resectable CRLMs to obtain complete tumor clearance. The aim of this study was to analyze survival rates with this local treatment. MATERIALS AND METHODS: All patients who underwent RFA and resection or RFA alone for unresectable CRLMs between 2001 and 2012 were included in a retrospective study. Descriptive and survival statistics were calculated. Morbidity, mortality, and recurrence were also analyzed. RESULTS: The study involved 72 patients and 179 lesions. RFA was performed in 109 procedures. Mortality was 2.7% and morbidity was 25.7%. Local recurrence concerned 25.7% of lesions. Independent risk factors for recurrence were more than one CRLM (p= 0.0427) and size of largest CRLM greater than 3 cm (p= 0.0139). The five-year overall survival rate was 45.5% and the five-year disease-free survival (DFS) was 9.9%. CONCLUSION: This study shows RFA has good oncological outcomes. The combination of RFA and resection is considered as a curative treatment for patients with unresectable CRLMs. PMID- 27780346 TI - The Indication and Surgical Treatment of 286 Midurethral Synthetic Sling Complications: A Multicenter Study. AB - INTRODUCTION AND HYPOTHESIS: 1) Evaluate the most common indication for sling removal in patients with synthetic mesh slings; 2) identify the location of pain for each of the three types of synthetic sling procedures including retropubic (RP) sling, transobturator (TOT) sling, and single incision slings (SIS), and 3) describe the surgical approach to each of the above and its associated complications. MATERIALS AND METHODS: A retrospective chart review of all patients who underwent surgical removal of a sling due to a mesh-related complications from 2011 to 2013 at three referral centers. RESULTS: There were 337 sling complications followed by the IUGA/ICS mesh complication classification. RP slings were more likely to have urinary tract complications (category 4) and intra-abdominal site complications (S5). Of those, 286 slings were removed, 106 (37.1%) were RP, 131 (45.8%) TOT, and 44 (15.4%) SIS. Vaginal pain was the most common reason for sling removal. Twenty-one percent of the TOT had groin pain which was a five times higher risk than RP (OR 5.3, 95% CI 1.5 18.7), and the RP was three times more likely to have suprapubic pain than the TOT (OR 2.97, 95% CI 1.3-7.0). Fifteen percent of the TOT had either unilateral or bilateral groin mesh removal. CONCLUSION: The most common indication for sling removal was vaginal pain. RP sling had a higher risk of suprapubic pain and TOT sling had a higher risk of groin pain. Patients with a history of SIS had a higher incidence of urethral erosion. TOT removal had the highest intraoperative complication rate. PMID- 27780347 TI - Indications and Complications Associated with the Removal of 506 Pieces of Vaginal Mesh Used in Pelvic Floor Reconstruction: A Multicenter Study. AB - STUDY OBJECTIVE: Synthetic mesh utilized to treat stress urinary incontinence (SUI) and pelvic organ prolapse (POP) can often result in postoperative complications. The objectives of this study were to determine: 1) the most common indications for mesh removal; 2) the incidences of the removal of specific mesh procedures (such as suburethral sling [SUS], transvaginal mesh [TVM], or sacrocolpopexy); and 3) the idences and types of surgical complications associated with mesh removal. DESIGN: This was a retrospective study. Design Classification: Canadian Task Force II-3. SETTING: Three tertiary referral centers in the United States. PATIENTS: We examined data from all patients at the three centers who underwent surgical removal of synthetic materials from previous SUS, TVM, and sacrocolpopexy procedures for mesh-related complications from 2011 to 2013. INTERVENTION: Patients underwent vaginal, intra-abdominal, and inguinal mesh revisions by cutting, partial removal, or total removal of the mesh for mesh related complications. MEASUREMENTS AND RESULTS: Overall, 445 patients with complications underwent mesh removal laparoscopically, via groin dissection and/or transvaginally. There were a total of 506 mesh products removed. Of these, 56.5% were slings and 43.5% were for pelvic organ prolapse (POP). Synthetic mesh removed from patients included: transvaginal mesh (TVM) anterior for anterior vaginal prolapse, TVM posterior for posterior vaginal prolapse, sacrocolpopexy mesh, and suburethral slings (SUS) for stress urinary incontinence. Synthetic SUS removed included: retropubic (RPS), transobturator (TOT), and single-incision slings (SIS). TOT was the most common type of sling removed. Patients with a sling who only complained of vaginal pain with or without intercourse underwent a vaginal approach for surgical revision/removal of the sling (86.6%). Patients with an RPS with lower abdominal/suprapubic pain and vaginal pain underwent a vaginal and laparoscopic approach for sling removal (18.4%). Patients with a TOT sling who complained of vaginal and groin pain underwent a vaginal and inguinal approach for sling removal (4.3%). In patients who had POP mesh removal, 42.3% had an anterior TVM, 30.6% had a posterior TVM, 14% had both anterior and posterior TVMs, and 13.1% underwent sacrocolpopexy mesh removal. Complications encountered during mesh revision/removal surgery were: two blood transfusions from complete RPS removal (vaginal and laparoscopic approach), three urethral injuries during TOT sling removal (vaginal approach), two ureteral injuries during anterior vaginal wall mesh removal, and two rectal injuries during posterior vaginal wall mesh removal. All injuries were repaired at the time of mesh removal without recurrence. CONCLUSION: In our study, the most common indication for mesh removal was pain with or without intercourse. The most common mesh procedure resulting in removal was the TOT sling. Use of a vaginal approach only for sling removal had the lowest incidence of intraoperative complications. Laparoscopic RPS removal had the highest incidence of required blood transfusions, anterior TVM had the highest incidence of ureteral injury, and posterior TVM had the highest incidence of rectal injury. Overall, sling, TVM, and sacrocolpopexy mesh removal are safe procedures when performed by experienced surgeons. PMID- 27780348 TI - Increased Femoral Component Size Options Improves Manipulation Rate in Females and Knee Society Clinical Scores in Males. AB - INTRODUCTION: The gender-specific total knee arthroplasty (TKA) debate focuses on differences in distal femoral mediolateral to anteroposterior aspect ratio between males and females. However, randomized studies have been unable to demonstrate significant differences in outcomes utilizing gender-specific implants. No studies have examined the effect of intermediate femoral component sizes on outcome. We compared outcomes before and after intermediate sizing availability. MATERIALS AND METHODS: We identified 331 patients (413 knees) who underwent primary TKA between 2003 and 2004 with a single complete knee system. There were 121 males and 210 females. Three intermediate femoral sizes were added in March 2004 to the six initial options. Patients before March 2004 were assigned to group 1 (n=178), and after to group 2 (n=235). RESULTS: Follow-up averaged 8.5 years. Preoperative demographics and clinical scores were similar between groups. Knee Society (KS) clinical and functional scores improved in females in both groups, but there was no significant difference. Male patients in group 2 had a significant improvement in KS clinical scores compared to male patients in group 1 (group 1: 33.9, group 2: 41.1; p=0.01). Females in group 2 had significantly less need for manipulation, 1.9%, versus females in group 1, 8.7% (p=0.01). MUA rates were similar for men between groups. Overall, there were 19 revisions (4.6%) with no differences between groups or by genders. Once intermediate sizes were available, they were used in 48% of females and 13% of males. The average femoral component size for females in group 1 was 65 mm and decreased in group 2 to 62.5 mm. The average size of femoral components in males was 70 mm in both groups. CONCLUSIONS: Availability of intermediate size femoral component sizes was associated with a lower rate of manipulation in female patients. Greater KS clinical score improvement was observed in men after availability of additional femoral sizes. PMID- 27780349 TI - Early Experience with Vitamin E Antioxidant-Infused Highly Cross-Linked Polyethylene Inserts in Primary Total Knee Arthroplasty. AB - BACKGROUND: In past decades, polyethylene wear was a major cause of failure in total knee arthroplasty (TKA). Polyethylene for use in arthroplasty has been vastly improved in recent years, with improved materials as well as manufacturing and sterilization processes. Testing has shown that infusion of vitamin E prevents oxidative degradation of polyethylene without remelting, allowing the material to maintain mechanical properties and wear resistance over time. The purpose of this study is to review the early result of patients undergoing primary TKA with vitamin E antioxidant-infused polyethylene inserts. MATERIALS AND METHODS: A query of our practice registry revealed 148 patients (163 knees) who underwent primary cemented TKA using the Vanguard(r) Complete Knee System and E1(r) Antioxidant Infused polyethylene bearings (Zimmer Biomet, Warsaw, Indiana) between May 2009 and May 2013. Indications for E1(r) bearings were younger, more active patients. There were 65 males (44%) and 82 females (56%). Mean age was 50.6 years and mean BMI was 37.3 kg/m2. RESULTS: At mean follow-up of 3.2 years (range 6 weeks to 6.4 years), there have been seven revisions (4.3%): three two staged exchanges for infection, two for arthrofibrosis (one insert only, one femoral and tibial), and two (insert only) for late instability with imbalanced tight posteromedial and loose lateral structures. No aseptic loosening has occurred. Mean range of motion improved from 108 degrees preoperatively to 112 degrees , Knee Society clinical scores improved from 36 to 84 and function scores from 56 to 66. Postoperative radiographs, available for 160 TKA, revealed lateral patellar tilt in one knee, and satisfactory position, alignment, and fixation in all others. CONCLUSION: At up to 6.4 years' follow-up, two mechanical failures of the device have occurred and no aseptic loosening. Survival was 100% with aseptic loosening as the endpoint, and 95.7% with revision for any reason as the endpoint. PMID- 27780350 TI - Text messaging versus email for emergency medicine residents' knowledge retention: a pilot comparison in the United States. AB - We evaluated the effectiveness of text messaging versus email, as a delivery method to enhance knowledge retention of emergency medicine (EM) content in EM residents. We performed a multi-centered, prospective, randomized study consisting of postgraduate year (PGY) 1 to PGY 3 & 4 residents in three United States EM residency programs in 2014. Fifty eight residents were randomized into one delivery group: text message or email. Participants completed a 40 question pre- and post-intervention exam. Primary outcomes were the means of pre- and post intervention exam score differences. Data were analyzed using descriptive statistics, paired t-test, and multiple linear regressions. No significant difference was found between the primary outcomes of the two groups (P=0.51). PGY 2 status had a significant negative effect (P=0.01) on predicted exam score difference. Neither delivery method enhanced resident knowledge retention. Further research on implementation of mobile technology in residency education is required. PMID- 27780351 TI - Continuing education requirements among State Occupational Therapy Regulatory Boards in the United States of America. AB - PURPOSE: The purpose of this study is to compare and contrast the contents of each state's occupational therapy (OT) regulatory board requirements regarding licensees' acquisition of continuing education units in the United States of America. METHODS: Data related to continuing education requirements from each OT regulatory board of all 50 states and the District of Columbia in the United States were reviewed and categorized by two reviewers. Analysis was conducted based on the categorization of the continuing education requirements and activities required, allowed, and not allowed/not mentioned for continuing education units. RESULTS: Findings revealed non-uniformity and inconsistency of continuing education requirements for licensure renewal between OT regulatory boards and was coupled with lack of specific criteria for various continuing education activities. Continuing education requirements were not tailored to meet the needs of individual licensee's current and anticipated professional role and job responsibilities, with a negative bias towards presentation and publication allowed for continuing education units. Few boards mandated continuing education topics on ethics related to OT practice within each renewal cycle. CONCLUSION: OT regulatory boards should move towards unifying the reporting format of continuing education requirements across all states to reduce ambiguity and to ensure licensees are equipped to provide ethical and competent practice. Efforts could be made to enact continuing education requirements specific to the primary role of a particular licensee. Finally, assigning the amount of continuing education credits to be awarded for different activities should be based on research evidence rather than arbitrary determination. PMID- 27780352 TI - Seasonal Study of Mercury Species in the Antarctic Sea Ice Environment. AB - Limited studies have been conducted on mercury concentrations in the polar cryosphere and the factors affecting the distribution of mercury within sea ice and snow are poorly understood. Here we present the first comprehensive seasonal study of elemental and total mercury concentrations in the Antarctic sea ice environment covering data from measurements in air, sea ice, seawater, snow, frost flowers, and brine. The average concentration of total mercury in sea ice decreased from winter (9.7 ng L-1) to spring (4.7 ng L-1) while the average elemental mercury concentration increased from winter (0.07 ng L-1) to summer (0.105 ng L-1). The opposite trends suggest potential photo- or dark oxidation/reduction processes within the ice and an eventual loss of mercury via brine drainage or gas evasion of elemental mercury. Our results indicate a seasonal variation of mercury species in the polar sea ice environment probably due to varying factors such as solar radiation, temperature, brine volume, and atmospheric deposition. This study shows that the sea ice environment is a significant interphase between the polar ocean and the atmosphere and should be accounted for when studying how climate change may affect the mercury cycle in polar regions. PMID- 27780353 TI - Introduction: Genome Modifying Mechanisms. PMID- 27780354 TI - Line Tension Assists Membrane Permeation at the Transition Temperature in Mixed Phase Lipid Bilayers. AB - The umbrella sampling method has been used to evaluate the free energy profile for a large permeant moving through a lipid bilayer, represented using a coarse grained simulation model, at and below its gel-fluid transition temperature. At the lipid transition temperature, determined to be 302 K for the MARTINI 2.0 model of DPPC, the permeation barrier for passage through an enclosed fluid domain embedded in a patch of gel was significantly lower than that for passage through a fluid stripe domain. In contrast, permeation through a fluid domain in a stripe geometry produced a free energy profile nearly identical to that of a gel-free fluid bilayer. In both cases, insertion of the permeant into a fluid domain coexisting with the gel phase led to a shift in phase composition, as lipids transitioned from fluid to gel to accommodate the area occupied by the permeant. In the case of the enclosed fluid domain, this transition produced a decrease in the length of the fluid-gel interface as the approximately circular fluid domain shrank. The observed decrease in the apparent permeation barrier, combined with an approximation for the change in interfacial length, enabled estimation of the interfacial line tension to be between 10 and 13 pN for this model. The permeation barrier was shown to drop even further in simulations performed at temperatures below the transition temperature. The results suggest a mechanism to explain the experimentally observed anomalous peak in the temperature-dependent permeability of lipid bilayers near their transition temperatures. The contribution of this mechanism toward the permeability of a gel phase containing a thermal distribution of fluid-phase domains is estimated using a simple statistical thermodynamic model. PMID- 27780355 TI - Development of Visible-Wavelength MALDI Cell Mass Spectrometry for High Efficiency Single-Cell Analysis. AB - Mass is a fundamental physical property of an individual cell, from which is revealed the cell growth, cycle, and activity. Taking advantage of cell mass spectrometry (CMS), accurate mass measurement of a charged single cell has been achieved. However, with the increasing demand for high-efficiency single-cell analysis in biology, the limited throughput and inefficient cell desorption/ionization of the CMS inevitably become important issues. To address the challenge, a state of the art visible-wavelength matrix assisted laser desorption/ionization (MALDI) CMS was developed. The employed transmission mode laser ablation and fast evaporation sample preparation enabled the visible wavelength MALDI to be soft enough and to generate intact charged cells for mass measurement. By using resorufin as matrix, ten sorts of cells, viz., red blood cells (RBCs), Jurkat (JK), CCRF-CEM, SNU-5, BGC-803, MCF-7, L-O2, 293T, Hep G2, and A549 cells, have been successfully analyzed. It was found that the desorption/ionization efficiency of visible-wavelength MALDI was at least 3-fold higher than that of conventional laser-induced acoustic desorption (LIAD) and relevant to the suspension/adherent property of analyzed cells. Based on the measured mass, different cell types in either the individual or mixed state can be differentiated successfully. PMID- 27780357 TI - Preface to Forum on Electrochemical Applications of Carbon Nanomaterials and Interfaces. PMID- 27780356 TI - Novel Fluorescein-Based Fluorescent Probe for Detecting H2S and Its Real Applications in Blood Plasma and Biological Imaging. AB - A broad-spectrum fluorescent probe, which can be applied to monitoring H2S in various biological systems, has been rationally designed and synthesized. This specific probe was applied to localize the endogenous H2S in living Raw264.7 macrophage cells, HepG2 cells, and H9C2 cells. At the same time, the probe has successfully visualized CBS- and CSE-induced endogenous H2S production and monitored CBS and CSE activity in H9C2 cells. This probe could serve as a powerful molecular imaging tool to further explore the physiological function and the molecular mechanisms of endogenous H2S in living animal systems. PMID- 27780358 TI - Enantioselective Synthesis of alpha-Allyl-alpha-aryldihydrocoumarins and 3 Isochromanones via Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. AB - An enantioselective Pd-catalyzed DAAA of alpha-aryl-beta-oxo esters has been developed employing the (R,R)-ANDEN-phenyl Trost ligand to prepare a series of alpha-aryl-alpha-allyldihydrocoumarins and 3-isochromanones. A variety of aryl groups were successfully employed to afford the dihydrocoumarin and 3 isochromanone products in high yields up to 95% and ee's up to 96%. Under these conditions, substrates containing di- and mono-ortho-substituted aryl groups gave the highest levels of enantioselectivities. This work represents the first example of the enantioselective preparation of all-carbon quaternary alpha-allyl alpha-aryl dihydrocoumarins and 3-isochromanones. PMID- 27780360 TI - Counterintuitive Reconstruction of the Polar O-Terminated ZnO Surface with Zinc Vacancies and Hydrogen. AB - Understanding the structure of ZnO surface reconstructions and their resultant properties is crucial to the rational design of ZnO-containing devices ranging from optoelectronics to catalysts. Here, we are motivated by recent experimental work that showed a new surface reconstruction containing Zn vacancies ordered in a Zn(3 * 3) pattern in the subsurface of (0001)-O-terminated ZnO. Reconstruction with Zn vacancies on (0001)-O is surprising and counterintuitive because Zn vacancies enhance the surface dipole rather than reduce it. In this work, we show using density functional theory (DFT) that subsurface Zn vacancies can form on (0001)-O when coupled with adsorption of surface H and are in fact stable under a wide range of common conditions. We also show that these vacancies have a significant ordering tendency and that Sb-doping-created subsurface inversion domain boundaries (IDBs) enhance the driving force of Zn vacancy alignment into large domains of the Zn(3 * 3) reconstruction. PMID- 27780359 TI - Insights into the Response of Soybean Mitochondrial Proteins to Various Sizes of Aluminum Oxide Nanoparticles under Flooding Stress. AB - Rapid developments in nanotechnology have led to the increasing use of nanoparticles (NPs) in the agricultural sector. For possible interactions between NPs and crops under flooding stress to be investigated, the molecular mechanisms in soybeans affected by exposure to various sizes of Al2O3 NPs were analyzed using a proteomic technique. In plants exposed to 30-60 nm Al2O3 NPs, the length of the root including hypocotyl was increased, and proteins related to glycolysis were suppressed. Exposure to 30-60 nm Al2O3 NPs mediated the scavenging activity of cells by regulating the ascorbate/glutathione pathway. Hierarchical clustering analysis indicated that ribosomal proteins were also increased upon exposure to flooding-stressed plants with 30-60 nm Al2O3 NPs. Mitochondrion was the target organelle of Al2O3 NPs under flooding-stress conditions. Mitochondrial proteomic analysis revealed that the abundance of voltage-dependent anion channel protein was increased upon exposure to flooding-stressed soybeans with 135 nm Al2O3 NPs, indicating the permeability of the mitochondrial membrane was increased. Furthermore, isocitrate dehydrogenase was increased upon exposure of plants to 5 nm Al2O3 NPs under flooding conditions. These results suggest that Al2O3 NPs of various sizes affect mitochondrial proteins under flooding stress by regulating membrane permeability and tricarboxylic acid cycle activity. PMID- 27780361 TI - VEGF gene polymorphisms and outcome of epithelial ovarian cancer patients. AB - AIM: Since VEGF polymorphisms were associated with variable protein production, we analyzed herein their roles in outcome of epithelial ovarian cancer (EOC) patients. METHODS: Genotypes of 85 patients with primary EOC were identified in DNA by real-time PCR. Progression-free survival and overall survival were analyzed using Kaplan-Meier method, univariate Cox model and bootstrap resampling study. RESULTS: At 60 months of follow-up, progression-free survival was shorter in patients with VEGF c.-2578 CC genotype compared with others (52.7 vs 82.2%; p = 0.04). Those patients had 2.15 more chance of presenting disease progression than others (p = 0.04); bootstrap study validated the result (p = 0.03). CONCLUSION: Our data suggest that VEGF c.-2578C>A polymorphism acts as a prognostic factor in EOC. PMID- 27780362 TI - Waist circumference to height ratio predicts inflammatory risk in children. AB - BACKGROUND: The increase in obesity, especially the increase of visceral fat, has been directly associated with health risk. Additionally, a waist-to-height ratio (WHtR) (0.5) has been proposed as an indicator of early health risk. AIMS: To test the association between anthropometric measurements and inflammatory mRNA expression and to evaluate the effectiveness of WHtR to predict inflammatory risk in children. SUBJECTS AND METHODS: Anthropometric measurements and fasting blood samples were collected in 94 Brazilian children (46 boys) aged 9-11 years. Children were identified as being at inflammatory risk based on cytokine mRNA expression levels at and above the 75th percentile. Inflammatory cytokine mRNA expression levels were determined through buff-coat using real-time polymerase chain reaction. RESULTS: Body mass index (BMI), waist circumference (WC) and WHtR showed moderate-to-strong association with inflammatory cytokine mRNA gene expression. WHtR = 0.51 was the most accurate cut-off point in distinguishing children at inflammatory risk. Compared with children with WHtR <0.51, children with a WHtR >=0.51 presented an odds ratio of 2.643 (95% CI = 1.749-3.994) for both diagnosed IL-6 and MCP-1 above the 75th percentile and 2.796 (95% CI = 1.802 4.338) for TNF-alpha above the 75th percentile. WHtR = 0.50 presented the same values of sensitivity and odds ratio and ~7% lower specificity compared to WHtR = 0.51. CONCLUSION: Anthropometric measurements have shown a moderate-to-strong association with the mRNA expression of inflammatory genes and a WHtR of 0.5 could serve as a cut-off point, suggesting increased risk of inflammatory responses. PMID- 27780363 TI - The Role of Interleukin-33 as an Inflammatory Marker in Differential Diagnosis of Idiopathic Granulomatous Mastitis and Breast Cancer. AB - INTRODUCTION: Idiopathic granulomatous mastitis (IGM) is a rare benign inflammatory breast disease that can clinically and radiographically mimic breast carcinoma and bacterial mastitis. The aim of this study is to investigate the importance of levels of the inflammation markers, interleukin-33 (IL-33), soluble ST2 receptor of IL-33 (sST2), procalcitonin (PCT), and CRP on differential diagnosis of IGM and breast cancer (BC). METHODS: 25 patients with IGM and 32 patients with primary BC who applied to General Surgery Clinic, and 30 healthy volunteer women with similar demographic condition were enrolled in the study. While the IL-33, sST2, and PCT levels were measured with ELISA method, other biochemical parameters were studied with autoanalyzer. RESULTS: IL-33, sST2 levels were significantly higher in both BC and IGM groups than in control (p < 0.001). More importantly, the IL-33 levels of IGM group were found to be significantly higher when compared to the group with BC (p < 0.001). Accordingly the sST2 levels of the patients with IGM were significantly lower than the patients with BC (p < 0.001). There was no statistical significance between PCT levels BC and IGM groups (p > 0.05). CONCLUSION: The results of our study suggest that measurement of IL-33 and its receptor sST2 levels, alongside radiological studies can help distinguishing IGM from BC. Findings of our study need to be supported with additional studies. PMID- 27780364 TI - Bile acids and their oxo derivatives: environmentally safe materials for drug design and delivery. AB - PURPOSE: Animal tests have been often used in toxicology to determine parameters describing toxicity of a particular substance. However, in vivo tests must fulfill ethical requirements, and are both time and money consuming. Therefore, computational methods are considered to be very useful in toxicity prediction. METHODS: Retention parameters were acquired by normal-phase TLC. Lipophilicity was used as a key parameter for predicting toxic potential. The correlation coefficients between calculated log P values obtained by five different software and experimentally determined hydrophobicity parameters ([Formula: see text](tol/et), [Formula: see text](tol/but), b(tol/et) and b(tol/but)) were calculated. RESULTS: Correlation analysis provided reliable information (r2 > 0,8) for aquatic species - minnow, medaka, daphnia, and algae. In addition valuable data regarding rodents and AMES test were obtained. CONCLUSIONS: Tested bile acids show relatively good toxicological properties. Less toxic effects are noticed in compounds with higher polarity. Compounds 5, 6, 7, 12, and 13 would be the best candidates for further testing. These compounds show good biological potential which is coupled with low toxicity. PMID- 27780365 TI - Adherence and safety of regorafenib for patients with metastatic colorectal cancer: observational real-life study. AB - AIM: In this prospective multicenter real-life observational cohort study, we investigated the acceptance, adherence and safety of regorafenib, in the treatment of metastatic colorectal cancer patients. PATIENTS & METHODS: A total of 136 patients were recruited at six oncological hospital sites in southern Italy. The adherence to the treatment was measured with patient-completed medication diaries, physician interviews and pill counts. RESULTS: We found a statistically significant improvement of therapy adhesion by the acceptance questionnaire. The Eastern Cooperative Oncology Group performance status, the level of acceptance, the educational level and the concomitant usage of oral medications influenced the adherence to the treatment. CONCLUSION: Patients' level of education, concomitant other oral medications and patients' general clinical condition may influence the adherence to regorafenib. PMID- 27780366 TI - Coexisting COPD in elderly asthma with fixed airflow limitation: Assessment by DLco %predicted and HRCT. AB - BACKGROUND: Asthma patients with fixed airflow limitation (FL) are theoretically classified into two phenotypes, that is, coexisting chronic obstructive pulmonary disease (COPD) and asthmatic airway remodeling. However, the precise percentages of such patients are not known. OBJECTIVE: To assess the prevalence of patients with both FL and COPD components in elderly asthma. METHODS: We evaluated patients by lung diffusion impairment and emphysematous findings in high resolution computed tomography (HRCT) as candidates for COPD components, as a multicenter, cross-sectional survey. Asthma outpatients >= 50 years of age were enrolled from Tohoku University Hospital, Sendai, Japan, and four hospitals (Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Sendai, JAPAN; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to November 30, 2014. RESULTS: The prevalence of patients with FEV1/FVC <70% was 31.0% of those in their 50s, 40.2% of those in their 60s and 61.9% of those in their 70s or older. The prevalence of those patients with lung diffusion impairment (i.e. the percent predicted values of diffusing capacity of the lung for carbon monoxide (DLco %predicted) <80%) or emphysematous findings in HRCT (i.e. the appearance of low attenuation area (LAA)) was 18.3% of those in their 50s, 13.8% of those in their 60s and 35.7% of those in their 70s or older. CONCLUSIONS: Nearly half of the patients with FL in elderly asthma show coexisting COPD components when assessed by DLco %predicted and LAA in HRCT. PMID- 27780367 TI - The role of multi modality imaging in selecting patients and guiding lead placement for the delivery of cardiac resynchronization therapy. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) is an effective pacemaker delivered treatment for selected patients with heart failure with the target of restoring electro-mechanical synchrony. Imaging techniques using echocardiography have as yet failed to find a metric of dyssynchrony to predict CRT response. Current guidelines are thus unchanged in recommending prolonged QRS duration, severe systolic function and refractory heart failure symptoms as criteria for CRT implantation. Evolving strain imaging techniques in 3D echocardiography, cardiac MRI and CT may however, overcome limitations of older methods and yield more powerful CRT response predictors. Areas covered: In this review, we firstly discuss the use of multi modality cardiac imaging in the selection of patients for CRT implantation and predicting the response to CRT. Secondly we examine the clinical evidence on avoiding areas of myocardial scar, targeting areas of dyssynchrony and in doing so, achieving the optimal positioning of the left ventricular lead to deliver CRT. Finally, we present the latest clinical studies which are integrating both clinical and imaging data with X-rays during the implantation in order to improve the accuracy of LV lead placement. Expert commentary: Image integration and fusion of datasets with live X-Ray angiography to guide procedures in real time is now a reality for some implanting centers. Such hybrid facilities will enable users to interact with images, allowing measurement, annotation and manipulation with instantaneous visualization on the catheter laboratory monitor. Such advances will serve as an invaluable adjunct for implanting physicians to accurately deliver pacemaker leads into the optimal position to deliver CRT. PMID- 27780368 TI - Alectinib for treatment of ALK-positive non-small-cell lung cancer. AB - Alectinib is a highly selective second-generation ALK inhibitor that is active against most crizotinib ALK resistance mutations, with a good penetration in CNS and a good safety profile. Thanks to the positive results of Phase II trials, alectinib was approved in Japan and by the US FDA for ALK-positive non-small-cell lung cancer (NSCLC) patients pretreated with crizotinib. Recently, the Phase III J-ALEX study demonstrated superiority of alectinib over crizotinib in crizotinib naive ALK-positive NSCLC, with an impressive improvement of progression-free survival. From the results and those expected of Phase III ALEX study, alectinib might become the frontline treatment of ALK-positive NSCLC. This article summarizes the therapeutic options in ALK-positive advanced NSCLC, and the chemical, pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy of alectinib. PMID- 27780369 TI - Early lung surveillance of cystic fibrosis: what have we learnt? PMID- 27780370 TI - Ornidazole-induced fixed drug reaction on sole: case report and review of the literature. AB - BACKGROUND: Fixed drug eruption (FDE) is a special variant of drug reaction seen on skin or mucous membrane, and typically recurs at the same location. Ornidazole induced FDE cases have been reported extremely rare. CASE: The 48-year-old female patient was diagnosed for ornidazole-induced fixed drug reaction on the sole. The patient's history revealed that the lesion occurred for the third time in the last 6 months and she was administered ornidazole tablet 3 times by the gynecologist for genitourinary tract infection. CONCLUSION: This report presents a case of fixed drug reaction located at the sole induced by ornidazole use and a literature review. PMID- 27780372 TI - Sweep frequency impedance measures in young infants: developmental characteristics from birth to 6 months. AB - OBJECTIVE: International Journal of Audiology To study the developmental characteristics of sweep frequency impedance (SFI) measures in healthy infants from birth to 6 months. DESIGN: All infants were assessed using high-frequency tympanometry (HFT), distortion product otoacoustic emission (DPOAE) and SFI tests. SFI measures consisted of measurement of resonance frequency (RF) and mobility (DeltaSPL) of the outer and middle ear. A mixed model analysis of variance was applied to the SFI data to examine the effect of age on RF and DeltaSPL. STUDY SAMPLE: Study included 117 ears from 83 infants of different age groups from birth to 6 months. RESULTS: The mean RF of the outer ear increased from 279 Hz at birth to 545 Hz at 4 months, whereas mean DeltaSPL of the outer ear decreased from 7.9 dB at birth to 3.7 dB at 4 months of age. In contrast, the mean RF and DeltaSPL of the middle ear did not change significantly with age up to 6 months. CONCLUSIONS: Developmental characteristics should be considered when evaluating the function of the outer and middle ear of young infants (<=6 months) using the SFI. The preliminary normative SFI data established in this study may be used to assist with the evaluation. PMID- 27780371 TI - Neutrophil to Lymphocyte Ratio on Appendectomy of Geriatric and Nongeriatric Patients. AB - PURPOSE: Acute appendicitis is the most frequent emergency procedure that requires acute surgical intervention. The mortality risk is higher in geriatric patients. There is not a single parameter to diagnose it easily and negative appendectomy is traditionally accepted however the operation itself can cause morbidity and mortality especially in elderly patients. The neutrophil-to lymphocyte ratio is a predictor of acute inflammation and was recently studied for the diagnosis of AA. The aim of this study is to analyze the diagnostic value of NLR on positive appendectomy rates amongst geriatric and nongeriatric patients. MATERIALS AND METHODS: 755 patients admitted to the emergency department, with abdominal pain who underwent urgent laparotomy after diagnosed as acute appendicitis. Patients' ages, genders, laboratory results, and intraoperative findings were collected. Geriatric patients were analyzed in group one, and nongeriatric patients were in group 2. Groups then sorted into subgroups by means of positive and negative appendectomies. RESULTS: Although NLR was higher in positive appendectomy subgroup in group 1 it was not statistically significant. NLR could not independently predict positive appendectomy in geriatric patients. In group 2, male gender was significantly higher in the positive appendectomy group (p < 0.001). NLR was also significantly higher in the positive appendectomy group (p < 0.001). In group 2 NLR could independently predict positive appendectomy (p < 0.001). CONCLUSION: NLR could not predict positive appendectomy rates in the geriatric population but could in the nongeriatric patient group. To find the optimal NLR levels, prospective randomized studies are needed. PMID- 27780373 TI - p62/SQSTM1 is required for the protection against endoplasmic reticulum stress induced apoptotic cell death. AB - Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding or calcium homeostasis in the ER. To cope with these stresses, ER stress activates the unfolded protein response (UPR) pathway, but unresolved ER stress induces reactive oxygen species (ROS) accumulation leading to apoptotic cell death. However, the mechanisms that underlie protection from ER stress-induced cell death are not clearly defined. The nuclear factor erythroid 2 related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway plays a crucial role in the protection of cells against ROS-mediated oxidative damage. Keap1 acts as a negative regulator of Nrf2 activation. In this study, we investigated the role of the Nrf2-Keap1 pathway in protection from ER stress induced cell death using tunicamycin (TM) as an ER stress inducer. We found that Nrf2 is an essential protein for the prevention from TM-induced apoptotic cell death and its activation is driven by autophagic Keap1 degradation. Furthermore, ablation of p62, an adapter protein in the autophagy process, attenuates the Keap1 degradation and Nrf2 activation that was induced by TM treatment, and thereby increases susceptibility to apoptotic cell death. Conversely, reinforcement of p62 alleviated TM-induced cell death in p62-deficient cells. Taken together, these results demonstrate that p62 plays an important role in protecting cells from TM-induced cell death through Nrf2 activation. PMID- 27780374 TI - Superior Pedicle Mammaplasty without Parenchymal Incisions after Massive Weight Loss. AB - BACKGROUND: After considerable weight loss, the breast suffers significant deformation. The ptotic breast is characterized by a lack of superior pole, tissue excess in the inferior pole, down-migration of nipple-areola complex (NAC) with redundancy of skin tissue. The authors describe a mastopexy technique based on a modulated and progressive reshaping, back rotation, and suspension of mammary gland parenchyma without parenchymal incisions. METHODS: Forty-five patients with bilateral moderate or severe breast ptosis underwent mastopexy from January 2011 to January 2014 with complete detachment of breast from the pectoralis major muscle and the plication of parenchyma without any parenchymal incision. Patients were followed up for one year, reporting any complication, and measuring the jugulum-NAC distance. The outcomes were assessed by the patients as well as the surgical team. RESULTS: The aesthetic outcomes were good or excellent in all patients. The new mammary contour and the distance between the jugular fossa and the nipple were stable during this time with a good filling of upper pole. No major complications were reported. CONCLUSIONS: This technique gave good breast shape, long-term projection, and upper pole fullness, without parenchymal incisions. It restores breast shape and projection, especially in post-bariatric patients. A similar technique has not been described yet. PMID- 27780375 TI - Which Suture Material is Optimal for Pancreaticojejunostomy Anastomosis? An In Vitro Study. AB - BACKGROUND: Which suture material is optimal for pancreaticojejunostomy (PJ) anastomosis is a matter of debate with contradictory results. The aim of the present in vitro study was to determine the effects of pancreatic juice, bile, and their mixture on different suture materials in terms of breaking strength and disintegration. MATERIAL AND METHODS: Four suture materials, silk, polyglactin 910, polydioxanone, and polypropylene, were tested in pancreatic juice, bile, and their mixture. Determination of breaking strength and disintegration under electron microscope for each suture material was done on days 0, 3, 6, and 10. RESULTS: The breaking strength of polyglactin 910 and silk was significantly higher than polypropylene and polydioxanone (p < .05). Polyglactin 910 significantly lost its breaking strength with time in pancreatic juice, bile, and their mixture (p < .001). The breaking strength of each type of suture did not significantly alter in pancreatic juice, bile, and their mixture at the baseline measurement and at the end of the experiment (p > .05). No obvious disintegration has been observed under electron microscope in the architecture and appearance of suture materials after days of exposure to pancreatic juice, bile, and their mixture. CONCLUSIONS: None of the suture materials was disintegrated on exposure to pancreatic juice, bile, and their mixture. Polyglactin 910 has the highest breaking strength and significantly loses its strength throughout the experiment but still remains higher than other suture materials. Polypropylene, polydioxanone, and silk showed less variation across the incubation period. PMID- 27780376 TI - Evaluation of inflammatory markers interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) in asthma. AB - INTRODUCTION: Even though IL-6 and MMP-9 are associated with airway inflammation in asthma, there is paucity of data in Indian population. OBJECTIVE: To determine the levels of IL-6 and MMP-9 in the serum of patients suffering from asthma, and correlate with (a) disease severity, as per GINA guidelines; (b) clinical phenotypes; and (c) response to treatment. METHODOLOGY: The levels of IL-6 and MMP-9 were compared between moderate persistent asthma (n = 25), severe persistent asthma (n = 25) and normal controls (n = 30). IL-6 and MMP-9 were measured by ELISA (R&D Systems Inc., USA and Canada) and compared between controls and asthmatics and between groups of different asthma severity, clinical variables, spirometry, and allergen sensitization. Spirometry was repeated after 2 months of ICS+LABA to assess response to treatment in relation to baseline IL-6 and MMP-9 levels. RESULTS: We observed a significant difference in both IL-6 and MMP-9 levels among asthmatics versus controls (p < 0.001), moderate versus severe persistent asthma (p < 0.001). A significant negative correlation was observed between MMP-9 and pre-bronchodilator FEV1 and FVC, but not with IL-6. There was no association between IL-6 and MMP-9 with asthma duration, total IgE, AEC, number of allergens sensitized and degree of sensitization. No significant correlation (p > 0.5) was observed with IL-6 and MMP-9 levels and FEV1 improvement after 2 months of ICS+LABA. CONCLUSION: Higher levels of IL-6 and MMP 9 were observed in asthmatics as compared to controls and in severe persistent asthma as compared to moderate persistent asthma, higher levels of MMP-9 was associated with lower lung functions. PMID- 27780377 TI - Parent perceptions of their child's communication and academic experiences with cochlear implants. AB - OBJECTIVE: To explore parent perceptions of communication and academic experiences of cochlear implant (CI) recipients under the age of 18. DESIGN: Cross-sectional survey design. Two surveys (K-12, birth-5) queried parent perceptions of the impact of CI on communication, listening in various environments and academic achievement. Surveys contained 16-23 multiple choice and/or Likert ratings, plus four open-ended questions to assess reasons for obtaining a CI, satisfaction with CI and suggestions for professionals. STUDY SAMPLE: Surveys were sent to 156 parents of CI recipients; 81 surveys returned; response rate 52%. RESULTS: According to parent report, 95% of K-12 children and 100% of preschool children used spoken language as their primary mode of communication; majority of K-12 children performed same as or better than peers across academic subjects; 99% of respondents were pleased with their decision to obtain a CI. The most important reasons reported for choosing CIs were for their child to use the same language as their families and to effectively communicate in hearing society. Satisfaction with CI was better in quiet than in noise. Respondents stressed the importance of audiologists having excellent skills in CI management and programming. CONCLUSIONS: Respondents were positive about the benefits of obtaining CI for their child. PMID- 27780378 TI - Anthropometric measurements of newborns of women who smoke waterpipe during pregnancy: a comparative retrospective design. AB - Waterpipe tobacco smoking carries adverse health consequences due to high level of chemical toxicants. This study investigated the anthropometric measurements of singleton newborns of Jordanian women with no known chronic diseases who smoked waterpipe during pregnancy, and the difference in these measurements in newborns of pregnant women who smoked waterpipe, cigarettes, both types, and none during pregnancy. The study also investigated the pattern of different types of tobacco smoking as a function of pregnancy trimester. A descriptive, comparative, retrospective, cross-sectional design was used. Two hundred and eight-five women (74 waterpipe, 84 cigarettes, 26 dual, 101 none) and their newborns were recruited from three hospitals. A questionnaire was used while interviewing mothers to assess tobacco smoking pattern. The results showed that compared with non-smokers, mean birth weight was 0.47 kg (95%CI = -0.70 to -0.35) lower for waterpipe-only smokers, 0.23 kg (95%CI = -0.41 to -0.8) lower for cigarette-only users, and 0.59 kg (95%CI = -0.81 to -0.31) lower for dual users. Compared to non smokers, mean newborn length was 2.7 cm (95%CI = -3.80 to -1.42) lower for dual smokers, 2.2 cm (95%CI = -3.28 to -1.58) lower for waterpipe smokers, and 1.2 cm (95%CI = -2.01 to -0.45) lower for cigarette smokers. Compared with non-smokers, mean newborn head circumference was 1.9 cm (95%CI = -2.72 to -1.65) lower for waterpipe smokers, 1.7 cm (95%CI = -2.65 to -1.16) lower for dual smokers, and 0.8 cm (95%CI= -1.34 to -0.36) lower for cigarette smokers. From these results, we may conclude that waterpipe tobacco smoking during pregnancy can contribute to a reduction in newborn's anthropometric measurements. Increasing awareness of waterpipe tobacco smoking adverse effects and developing cessation interventions in pregnancy is needed. PMID- 27780379 TI - Pre-Hepatectomy Assessment of Bile Transporter Expression by Gadoxetic Acid Enhanced MRI in a Rat Model of Liver Cirrhosis. AB - BACKGROUND: Gadoxetic acid is a liver-specific intravenous T1 magnetic resonance (MR) contrast agent that is excreted via the hepatobiliary system. We hypothesize that hepatocyte expressions of bile transporters (OATP1 and MRP2) correlate with dynamic profile of Gadoxetic acid enhanced (GE)-MR imaging (MRI). METHODS: Two groups of rats, control (n = 6) and cirrhosis (n = 12), received gadoxetic acid enhanced MRI followed by 70% hepatectomy. The change in MR signal intensity from the baseline before the contrast injection (DeltaSI) was analyzed every minute for 30 min. Dynamic signal intensity retention ratio (DSR) was defined as the mean DeltaSI of the third 10-minmin period divided by the first 10-minmin period. Real-time PCR was utilized to quantify mRNA expressions. RESULTS: Compared to the control, cirrhosis group demonstrated lower mRNA levels of OATP1 (0.038 +/- 0.020 vs. 0.232 +/- 0.0979; p = 0.004), MRP2 (0.201 +/- 0.084 vs. 0.7567 +/- 0.254; p = 0.002), and OATP1/MRP2 mRNA ratio (0.193 +/- 0.065 vs. 0.342 +/- 0.206; p = 0.032). DSR was higher in the cirrhosis group (0.678 +/- 0.554 vs -0.125 +/- 0.839; p = 0.033). In the cirrhosis group, there was an inverse correlation between the ratios of OATP1/MRP2 mRNA and DSR (R = -0.709, p = 0.01). CONCLUSION: Bile transporters OATP1/MRP2 mRNA expression ratio in rat liver tissue decreased with DMN-induced liver injury. The expressions of bile transporters correlated with GE-MRI DSR. The GE-MRI DSR has potential utility in qualifying OATP1/MRP2 mRNA expression. PMID- 27780380 TI - A web-based educational video to improve asthma knowledge for limited English proficiency Latino caregivers. AB - OBJECTIVES: To evaluate limited English proficiency (LEP) Latino caregiver asthma knowledge after exposure to an educational video designed for this target group. METHODS: A cross-sectional, interventional study was performed. We aimed to evaluate the post-test impact on asthma knowledge from baseline after exposure to a patient-centered, evidence-based, and professionally produced Spanish asthma educational video. Participants included LEP Latino caregivers of children 2-12 years old with persistent asthma. Enrollment was performed during ED encounters or scheduled through a local community organization. Asthma knowledge was measured with a validated Spanish parental asthma knowledge questionnaire. Differences in mean scores were calculated with a paired t-test. RESULTS: Twenty caregivers were enrolled. Participants included mothers (100%) from Puerto Rico (75%), with a high-school diploma or higher (85%), with no written asthma action plan (65%), whose child's asthma diagnosis was present for at least 3 years (80%). Mean baseline asthma knowledge scores improved 8 points from 58.4 to 66.4 after watching the educational video (95% CI 5.3-10.7; t(19) = 6.21, p < 0.01). Knowledge improvements were similar across the ED and community groups. Knowledge gains were observed in the areas of ED utilization, medication usage, and activity limitations. CONCLUSIONS: The developed educational video improved caregiver asthma knowledge for a Latino population facing communication barriers to quality asthma care. Dissemination of this educational resource to LEP caregivers has the potential to improve pediatric asthma care in the United States. PMID- 27780381 TI - Factors associated with and impact of pain persistence in Asian patients with depression: a 3-month, prospective observational study. AB - OBJECTIVE: We investigated the depression outcomes and the factors associated with pain persistence in Asian patients treated for major depressive disorder (MDD). METHODS: This observational study enrolled 909 Asian adult inpatients and outpatients. The presence or absence of painful physical symptoms and severity of depression were assessed at baseline and after three months of treatment. Factors associated with pain persistence and outcome of depression were investigated using regression methods. RESULTS: Of the 909 patients enrolled, 684 were included in the analysis and evaluated at three months. Of them, 335 (49%) had no pain at baseline nor follow up, 198 (29%) at baseline but not at follow up and 151 (22%) in both assessments. Pain more frequently persisted in patients who were divorced/widowed/separated, with >1 comorbidity, aged <40 years, with previous MDD episodes, taking pain medications, and with greater depression severity. At three months, response/remission were 84%/73% in the no pain group, 83%/63% in the remitted pain group and 46%/25% in the persistent pain group (differences all p < .0001; all bivariate comparisons were statistically significant with p < .05 except response between no pain and remitted pain). Persistent pain was also associated with less improvement in quality of life and health state. CONCLUSIONS: Pain should be taken into account when diagnosing MDD and when tailoring therapy. PMID- 27780382 TI - Corrigendum. PMID- 27780383 TI - When how you say it matters - the value of simulated patient training. PMID- 27780384 TI - Predicting feeding tube and tracheotomy dependence in laryngeal cancer patients. AB - CONCLUSIONS: The two scales reliably measure laryngeal edema and dysfunction in laryngeal cancer patients. The eight categories from these scales, and abnormal pharyngeal squeeze, can be used to form a new rating scale intended to help clinicians identify and circumvent swallowing complications after chemo irradiation. OBJECTIVES: The objectives were to compare two laryngeal edema rating scales in laryngeal cancer patients and determine if post-radiation +/- chemotherapy edema predicts dependence on a feeding tube and/or tracheostomy. METHODS: A retrospective chart review between 2005-2008 revealed 28 laryngeal cancer patients status post-radiation +/- chemotherapy, with video laryngoscopies performed within 6 months after treatment. Four raters evaluated videos based on the Laryngopharyngeal Edema Scale (LES) and the Reflux Finding Score (RFS). Tracheostomy and feeding tube outcomes were then correlated with the two scales. RESULTS: Feeding tube and tracheostomy dependence were associated with pre treatment vocal cord paralysis, advanced T stage, and chemoradiation. Eight categories from the LES and RFS scales were significantly associated with the need for a feeding tube. PMID- 27780385 TI - Catheter and Laryngeal Mask Endotracheal Surfactant Therapy: the CALMEST approach as a novel MIST technique. AB - PURPOSE: Neonatal respiratory distress syndrome (RDS) is a major cause of mortality and morbidity among preterm infants. Although the INSURE (INtubation, SURfactant administration, Estubation) technique for surfactant replacement therapy is so far the gold standard method, over the last years new approaches have been studied, i.e. less invasive surfactant administration (LISA) or minimally invasive surfactant therapy (MIST). Here we propose an originally modified MIST, called CALMEST (Catheter And Laryngeal Mask Endotracheal Surfactant Therapy), using a particular laryngeal mask as a guide for a thin catheter to deliver surfactant directly in the trachea. MATERIALS AND METHODS: We performed a preliminary study on a mannequin and a subsequent in vivo pilot trial. RESULTS AND CONCLUSIONS: This novel procedure is quick, effective and well tolerated and might represent an improvement in reducing neonatal stress. Ultimately, CALMEST offers an alternative approach that could be extremely useful for medical staff with low expertise in laryngoscopy and intubation. PMID- 27780386 TI - Concurrent study of stability and cytotoxicity of a novel nanoemulsion system - an artificial neural networks approach. AB - Problems commonly associated with using nanoemulsions are their cytotoxic effects and low stability profiles. Here, for the first time, concentrations of ingredients of a nanoemulsion system were investigated to obtain the most stable nanoemulsion system with the least cytotoxic effect on MCF7 cell line. Artificial neural networks (ANNs) were used to model the experimentally obtained data. Surfactant concentration was found to be the dominant factor in determining the stability - surfactant concentration above a critical point made the preparation unstable, while it appeared not to be influencing the cytotoxicity. Concentration of oil showed a direct relationship to the cytotoxicity with a minimum value required to provide an acceptable safety profile for the preparation. Co surfactant appeared not to be considerably effective on neither stability nor cytotoxicity. To obtain the optimum preparation with maximum stability and minimum cytotoxicity, surfactant and oil values need to be kept at their maximum and minimum possible, respectively. PMID- 27780387 TI - Statement of retraction. PMID- 27780389 TI - The Antinomian Personality: The Hippie Character Type ?. PMID- 27780388 TI - Toxicological effects of three types of silver nanoparticles and their salt precursors acting on human U-937 and HL-60 cells. AB - The growing popularity of nanomaterials requires a systematic study of their effects on the human body. Silver nanoparticles (AgNPs), due to their antiseptic properties, are used in almost every area of life. The purpose of the study was to examine whether the precursor used for the synthesis of nanoparticles affects their bio-influence and modifies their impact on cells of the human immune system. To compare the effects of precursor silver salts (AgNO3, CH3COOAg and AgClO4) and corresponding nanoparticles (TAN TAA and TAC) cytotoxicity study was conducted on two cell lines U-937 and HL-60. For both cell lines, silver salts are more toxic than the corresponding nanoparticles. Cell viability after treatment with the two forms of silver (salt/particle) is dependent on silver dose and degree of cells differentiation. Addition of the silver salt of doses greater than 5 mg/L results in decreased cell viability by over 60%, whereas nanoparticles' addition reduces cell viability on average by 30%. On the basis of the determined LD50 values it can be stated that for the tested cells the most toxic are AgClO4 and TAC. Production of nitric oxide, which is a mediator of inflammation, is the greatest after treatment of the cells by TAC. Different interactions of studied nanoparticles with albumin has been found and it was shown that addition of albumin to the cells treated by nanoparticles reduces their toxic effects. Obtained by us highly purified, mono-disperse AgNPs exhibit diverse effects relative to the biological systems, depending on the precursor salt used. PMID- 27780391 TI - Contents Volume Thirty One 1968. PMID- 27780390 TI - Psychiatric Illness in a Small Ladino Community ?. PMID- 27780395 TI - Patient Changes during Classical Psychoanalysis as a Function of Initial Status and Duration of Treatment ?. PMID- 27780397 TI - Healthcare costs associated with rivaroxaban or warfarin use for the treatment of venous thromboembolism. AB - INTRODUCTION: Rivaroxaban has been shown to have similar efficacy but less major bleeding than warfarin in randomized trials of patients experiencing venous thromboembolism (VTE). This report sought to assess healthcare costs up to 12 months following an index VTE in patients prescribed either rivaroxaban or warfarin. MATERIALS AND METHODS: This study analyzed claims from the MarketScan Commercial Claims and Encounters Database from November 2011-July 2015. It selected adults newly-diagnosed with VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) if they had an outpatient prescription claim for rivaroxaban or warfarin within 7-days of the index event. Warfarin users were 2:1 propensity score matched to rivaroxaban users and followed until the end of insurance coverage, end of data availability or 12-months of follow-up. Total per patient healthcare costs, including inpatient, outpatient, and overall pharmacy costs, were compared using a multivariable generalized linear model. RESULTS: In total, 10,929 rivaroxaban patients were matched to 21,858 warfarin patients. Mean follow up for rivaroxaban and warfarin patients was 317- and 321-days for those experiencing an index DVT, and 313- and 318-days for those with PE. Mean overall treatment costs per patient were lower for rivaroxaban vs warfarin users ( $1,116, p = .0016). This cost difference was driven by lower inpatient (-$622) and outpatient (-$1,156) treatment costs, and the higher pharmacy costs ($661) were, therefore, fully offset. Results were similar when analysis was restricted to DVT patients. No significant difference in total costs was observed in patients experiencing an index PE. LIMITATIONS: Claims databases are subject to inaccuracies and missing data. Prescription claims may not fully reflect actual medication utilization. Despite propensity-score matching and regression, residual confounding cannot be excluded. CONCLUSIONS: Rivaroxaban was associated with significantly lower total per patient VTE treatment costs, despite higher pharmacy costs. These savings are the result of decreased inpatient and outpatient healthcare utilization costs associated with rivaroxaban. PMID- 27780399 TI - Management of Transient Monocular Vision Loss and Retinal Artery Occlusions. AB - Acute transient or permanent retinal occlusive disease requires prompt medical attention and can be an ophthalmological emergency. Central retinal artery occlusion leads to permanent and severe monocular visual loss in the majority of patients. Transient monocular vision loss leaves no permanent deficits, but requires the same level of clinical vigilance, as it portends possible future adverse events, including loss of vision and stroke. Acute treatment options remain limited, and secondary prevention of cerebral ischemic events is the mainstay of management. This article reviews the current evidence for managing patients with retinal ischemia. PMID- 27780398 TI - Microbial cooperation in the rhizosphere improves liquorice growth under salt stress. AB - Liquorice (Glycyrrhiza uralensis Fisch.) is one of the most widely used plants in food production, and it can also be used as an herbal medicine or for reclamation of salt-affected soils. Under salt stress, inhibition of plant growth, nutrient acquisition and symbiotic interactions between the medicinal legume liquorice and rhizobia have been observed. We recently evaluated the interactions between rhizobia and root-colonizing Pseudomonas in liquorice grown in potting soil and observed increased plant biomass, nodule numbers and nitrogen content after combined inoculation compared to plants inoculated with Mesorhizobium alone. Several beneficial effects of microbes on plants have been reported; studies examining the interactions between symbiotic bacteria and root-colonizing Pseudomonas strains under natural saline soil conditions are important, especially in areas where a hindrance of nutrients and niches in the rhizosphere are high. Here, we summarize our recent observations regarding the combined application of rhizobia and Pseudomonas on the growth and nutrient uptake of liquorice as well as the salt stress tolerance mechanisms of liquorice by a mutualistic interaction with microbes. Our observations indicate that microbes living in the rhizosphere of liquorice can form a mutualistic association and coordinate their involvement in plant adaptations to stress tolerance. These results support the development of combined inoculants for improving plant growth and the symbiotic performance of legumes under hostile conditions. PMID- 27780400 TI - The effects of nanotopography and coculture systems to promote angiogenesis for wound repair. AB - Insufficient angiogenesis in severe wounds delays wound repair because of a lack of blood supply to the wound site. Therefore, pro-angiogenic therapeutics may enhance wound repair. Many studies have investigated various physical and biochemical cues to improve angiogenesis, such as biocompatible materials, surface modifications, angiogenic factors and coculture systems using various cell types. However, the present capability to mimic the micro- and nanostructure of the natural microenvironment, particularly its porous, fibrous features, is limited. Nanotopography may represent a promising tool to overcome these limitations. Here, we discuss various approaches to the use of nanotopography to enhance angiogenesis and consider the combination of coculture systems with nanotopography to mimic the native environment for promotion of angiogenesis in wound healing and repair. PMID- 27780401 TI - Platelet rich plasma releasate promotes proliferation of skeletal muscle cells in association with upregulation of PCNA, cyclins and cyclin dependent kinases. AB - Platelet rich plasma (PRP) contains various cytokines and growth factors which may be beneficial to the healing process of injured muscle. The purpose of this study is to investigate the effect and molecular mechanism of PRP releasate on proliferation of skeletal muscle cells. Skeletal muscle cells intrinsic to Sprague-Dawley rats were treated with PRP releasate. Cell proliferation was evaluated by 3-[4,5-Dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and immunocytochemistry with Ki-67 stain. Flow cytometric analysis was used to evaluate the cell cycle progression. Western blot analysis was used to evaluate the protein expressions of PCNA, cyclin E1, cyclin A2, cyclin B1, cyclin dependent kinase (cdk)1 and cdk2. The results revealed that PRP releasate enhanced proliferation of skeletal muscle cells by shifting cells from G1 phase to S phase and G2/M phases. Ki-67 stain revealed the increase of proliferative capability after PRP releasate treatment. Protein expressions including cyclin A2, cyclin B1, cdk1, cdk2 and PCNA were up-regulated by PRP releasate in a dose dependent manner. It was concluded that PRP releasate promoted proliferation of skeletal muscle cells in association with the up-regulated protein expressions of PCNA, cyclin A2, cyclin B1, cdk1 and cdk2. PMID- 27780402 TI - A systematic review on the treatment of phantom limb pain with spinal cord stimulation. AB - : Phantom limb pain (PLP) is a challenging chronic pain syndrome to treat with pharmacologic agents being first line of management. However, when these agents fail to provide pain relief, other interventions must be considered in a clinical setting. Spinal cord stimulation (SCS) has been shown to provide analgesia in PLP, and should be considered by clinicians. METHODS: This PRISMA systematic review analyzes the efficacy of SCS for treatment of PLP. RESULTS: After review of 12 studies, there are mixed results to base a conclusion on. DISCUSSION: While there is some evidence of efficacy, due to the relatively small number of patients in each study, further research is needed to demonstrate the benefits of SCS for PLP. PMID- 27780403 TI - Pluronic-attached polyamidoamine dendrimer conjugates overcome drug resistance in breast cancer. AB - AIM: To design pluronic F68 (PF68)-conjugated polyamidoamine (PAMAM) dendrimer conjugates for doxorubicin (DOX) delivery for overcoming multidrug resistance, and clarify the reversal mechanism. MATERIALS & METHODS: A series of PAMAM-PF68 conjugates were designed. The antitumor activity of the DOX-loaded conjugates was evaluated against MCF-7/ADR cells, tumor spheroids and tumors. Several bioinformatics were detected to characterize the reversal mechanism. RESULTS: Increased antitumor activity of the DOX-loaded conjugates was achieved in vitro and in vivo. The complexes induced more DOX accumulation via caveolae-mediated endocytosis. After escaping from the endosome/lysosome, the nuclear trafficking of DOX was achieved. Apoptosis was significantly increased by regulating mitochondrial function and gene expression. CONCLUSION: With optimized PF68 modification, PAMAM-PF68 conjugates can significantly overcome multidrug resistance in vitro and in vivo. PMID- 27780405 TI - Optimization of physical and morphological regime for improved cellulase free xylanase production by fed batch fermentation using Aspergillus niger (KP874102.1) and its application in bio-bleaching. AB - The physiological and morphological changes were extensively studied during fed batch fermentation using newly isolated Aspergillus niger (KP874102.1). Significantly higher xylanase production was possible through optimization of environmental stresses by fed batch process. The fed batch fermentation was carried out for improved xylanase production (2524 U) where initial xylan was kept 1.5 g/L in the production medium. However, 3 g/L of xylan with 50 mM K2HPO4 having pH-7 was consecutively fed at 72 and 120 h of fermentation. K2HPO4 showed significant role both the morphology of the microorganism and produces enzymes in fed batch fermentation. During feeding phase, the pH was found in the range of 6.5 to 7 which was used as marker for the fed batch process. The crude enzyme was used for the bio-bleaching of banana pulp. PMID- 27780416 TI - A Group-Psyche Model for Teachers of Community Psychiatry. PMID- 27780415 TI - Differential uptake of nanoparticles by human M1 and M2 polarized macrophages: protein corona as a critical determinant. AB - AIM: To investigate the interaction behavior of M1- and M2-type macrophages with nanoparticles of different sizes with/without the presence of serum. MATERIALS & METHODS: THP-1 human monocytes were differentiated into M1 and M2 macrophages, and the uptake of silica nanoparticle (50-1000 nm) was studied using flow cytometry and different microscopies. RESULTS: Without serum, higher uptake of all-sized nanoparticles was observed by M1 compared with M2. With serum, uptake of nanoparticles (200-1000 nm) was dramatically increased by M2. Furthermore, serum proteins adsorbed (corona) by nanoparticles were found to be the ligands for receptors expressed by M2, as revealed by SDS-PAGE and gene profiling analyses. CONCLUSION: The observed differential uptake by M1 and M2 macrophages will help understand the fate of nanoparticles in vivo. PMID- 27780417 TI - The Mental Hospital from the Patient Perspective ?. PMID- 27780404 TI - Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. AB - Severe hepatic inflammation is a common cause of acute or chronic liver disease. Macrophages are one of the key mediators which regulate the progress of hepatic inflammation. Increasing evidence shows that the TAM (TYRO3, AXL and MERTK) family of RTKs (receptor tyrosine kinases), which is expressed in macrophages, alleviates inflammatory responses through a negative feedback loop. However, the functional contribution of each TAM family member to the progression of hepatic inflammation remains elusive. In this study, we explore the role of individual TAM family proteins during autophagy induction and evaluate their contribution to hepatic inflammation. Among the TAM family of RTKs, AXL (AXL receptor tyrosine kinase) only induces autophagy in macrophages after interaction with its ligand, GAS6 (growth arrest specific 6). Based on our results, autophosphorylation of 2 tyrosine residues (Tyr815 and Tyr860) in the cytoplasmic domain of AXL in mice is required for autophagy induction and AXL-mediated autophagy induction is dependent on MAPK (mitogen-activated protein kinase)14 activity. Furthermore, induction of AXL-mediated autophagy prevents CASP1 (caspase 1)-dependent IL1B (interleukin 1, beta) and IL18 (interleukin 18) maturation by inhibiting NLRP3 (NLR family, pyrin domain containing 3) inflammasome activation. In agreement with these observations, axl-/- mice show more severe symptoms than do wild-type (Axl+/+) mice following acute hepatic injury induced by administration of lipopolysaccharide (LPS) or carbon tetrachloride (CCl4). Hence, GAS6-AXL signaling-mediated autophagy induction in murine macrophages ameliorates hepatic inflammatory responses by inhibiting NLRP3 inflammasome activation. PMID- 27780420 TI - The Firesetter Syndrome ?. PMID- 27780421 TI - Notes and Comments. PMID- 27780422 TI - The Clergyman's Role in the Therapeutic Process: Disagreement between Clergymen and Psychiatrists ?. PMID- 27780423 TI - A Conversation Concerning Face-to-Face Interaction ?. PMID- 27780424 TI - Characterisation of the human-seat coupling in response to vibration. AB - Characterising the coupling between the occupant and vehicle seat is necessary to understand the transmission of vehicle seat vibration to the human body. In this study, the vibration characteristics of the human body coupled with a vehicle seat were identified in frequencies up to 100 Hz. Transmissibilities of three volunteers seated on two different vehicle seats were measured under multi-axial random vibration excitation. The results revealed that the human-seat system vibration was dominated by the human body and foam below 10 Hz. Major coupling between the human body and the vehicle seat-structure was observed in the frequency range of 10-60 Hz. There was local coupling of the system dominated by local resonances of seat frame and seat surface above 60 Hz. Moreover, the transmissibility measured on the seat surface between the human and seat foam is suggested to be a good method of capturing human-seat system resonances rather than that measured on the human body in high frequencies above 10 Hz.Practitioner Summary: The coupling characteristics of the combined human body and vehicle seat system has not yet been fully understood in frequencies of 0.5-100 Hz. This study shows the human-seat system has distinctive dynamic coupling characteristics in three different frequency regions: below 10 Hz, 10-60 Hz, and above 60 Hz. PMID- 27780431 TI - Suicide and Anonymity ?. PMID- 27780435 TI - The Taboo of Suicide. PMID- 27780425 TI - Cost-effectiveness of seasonal quadrivalent versus trivalent influenza vaccination in the United States: A dynamic transmission modeling approach. AB - Trivalent inactivated influenza vaccines (IIV3s) protect against 2 A strains and one B lineage; quadrivalent versions (IIV4s) protect against an additional B lineage. The objective was to assess projected health and economic outcomes associated with IIV4 versus IIV3 for preventing seasonal influenza in the US. A cost-effectiveness model was developed to interact with a dynamic transmission model. The transmission model tracked vaccination, influenza cases, infection spreading interactions, and recovery over 10 y (2012-2022). The cost effectiveness model estimated influenza-related complications, direct and indirect costs (2013-2014 US$), health outcomes, and cost-effectiveness. Inputs were taken from published/public sources or estimated using regression or calibration. Outcomes were discounted at 3% per year. Scenario analyses tested the reliability of the results. Seasonal vaccination with IIV4 versus IIV3 is predicted to reduce annual influenza cases by 1,973,849 (discounted; 2,325,644 undiscounted), resulting in 12-13% fewer cases and influenza-related complications and deaths. These reductions are predicted to translate into 18,485 more quality-adjusted life years (QALYs) accrued annually for IIV4 versus IIV3. Increased vaccine-related costs ($599 million; 5.7%) are predicted to be more than offset by reduced influenza treatment costs ($699 million; 12.2%), resulting in direct medical cost saving annually ($100 million; 0.6%). Including indirect costs, savings with IIV4 are predicted to be $7.1 billion (5.6%). Scenario analyses predict IIV4 to be cost-saving in all scenarios tested apart from low infectivity, where IIV4 is predicted to be cost-effective. In summary, seasonal influenza vaccination in the US with IIV4 versus IIV3 is predicted to improve health outcomes and reduce costs. PMID- 27780436 TI - Experience with Multifamily, Time Limited, Outpatient Groups at a Community Psychiatric Clinic ?. PMID- 27780438 TI - Myths, Metaphors, and Political Conformity ?. PMID- 27780437 TI - Whole body vibration exposure patterns in Canadian prairie farmers. AB - Whole body vibration is a significant physical risk factor associated with low back pain. This study assessed farmers' exposure to whole body vibration on the Canadian prairies according to ISO 2631-1. Eighty-seven vibration measurements were collected with a triaxial accelerometer embedded in a rubber seat pad at the operator-seat interface of agricultural machinery, including tractors, combines, pickup trucks, grain trucks, sprayers, swathers, all-terrain vehicles, and skid steers. Whole body vibration was highest in the vertical axis, with a mean (range) frequency-weighted root mean squared acceleration of 0.43 m/s2 (0.19-1.06 m/s2). Mean crest factors exceeded 9 in all 3 axes, indicating high mechanical shock content. The vertical axis vibration dose value was 7.55 m/s1.75 (2.18 37.59 m/s1.75), with 41.4% of measurements within or above the health guidance caution zone. These high exposures in addition to an ageing agricultural workforce may increase health risks even further, particularly for the low back. Practitioner Summary: Agricultural workers are frequently exposed to whole body vibration while operating farm equipment, presenting a substantial risk to musculoskeletal health including the low back. Assessing vibration exposure is critical in promoting a safe occupational environment, and may inform interventions to reduce farmer's exposure to vibration. PMID- 27780439 TI - Management Succession and Administrative Style. PMID- 27780442 TI - Notes and Comments. PMID- 27780440 TI - Helping Transactions: Classificatoryand Semantic Considerations. PMID- 27780443 TI - The Sense of Becoming Psychotic ?. PMID- 27780444 TI - "End-Setting" as a Therapeutic Event ?. PMID- 27780446 TI - Psychiatry for Everyman ?. PMID- 27780445 TI - A Comprehensive Review of Postoperative Management of Descemet's Membrane Endothelial Keratoplasty. AB - INTRODUCTION: As Descemet's Membrane Endothelial Keratoplasty (DMEK) continues to gain in popularity, the postoperative management of DMEK surgery is becoming increasingly important, as these management strategies may affect postoperative success rates. MATERIALS AND METHODS: This article reviews the current evidence for postoperative management in DMEK. RESULTS: There are variable strategies in the postoperative management of DMEK as it relates to postoperative positioning, need for and timing of rebubble, tamponade agent utilized (both primarily and at rebubble), steroid agent and tapering schedule, timing of secondary regraft when required, and postoperative monitoring. DISCUSSION: While a great deal of attention is rightly devoted to developing better surgical techniques for DMEK, we believe it is also crucial to develop a better understanding of and evidence based best practice in the postoperative management of DMEK, as this may have important implications for outcomes. PMID- 27780447 TI - A Psychotherapeutic Encounter with a Self-Mutilating Patient ?. PMID- 27780448 TI - Mary Ladd Gavell 1919-1967. PMID- 27780450 TI - The Clinician-ExecutiveSome Problematic Issues for the Psychiatrist in Mental Health Organizations ?. PMID- 27780451 TI - Comment: II. PMID- 27780452 TI - Comment: III. PMID- 27780454 TI - Comment: I. PMID- 27780453 TI - The Continuous Case Seminar ?. PMID- 27780456 TI - The Relationship of Types of Daydream Behavior to Selected MMPI Scales ?. PMID- 27780457 TI - Mental Health Professions and the Division of Labor in a Metropolitan Community ?. PMID- 27780458 TI - The First Lie ?. PMID- 27780459 TI - Suicide among Patients in Mental Hospitals. PMID- 27780460 TI - Northern Children under Desegregation ?. PMID- 27780461 TI - Personality Description from the Viewpoin of Adaptation ?. PMID- 27780462 TI - Communicative Unclarity: Some Comments on the Rhetoric of Confusion ?. PMID- 27780463 TI - The "Army" Incident: The Psychology of Uniforms and Their Abolition on an Adolescent Ward ?. PMID- 27780465 TI - Children Who Work and the Concept of Work Style ?. PMID- 27780466 TI - Metamorphosis in a Children's Residential Treatment Center ?. PMID- 27780464 TI - Denial of Presidential Disability: A Case Study of Woodrow Wilson ?. PMID- 27780469 TI - Contents for Volume Thirty 1967. PMID- 27780478 TI - The efficacy of psychotherapy, pharmacotherapy and their combination on functioning and quality of life in depression: a meta-analysis. AB - BACKGROUND: There is growing recognition of the importance of both functioning and quality of life (QoL) outcomes in the treatment of depressive disorders, but the meta-analytic evidence is scarce. The objective of this meta-analysis of randomized controlled trials (RCTs) was to determine the absolute and relative effects of psychotherapy, pharmacotherapy and their combination on functioning and QoL in patients with depression. METHOD: One hundred and fifty-three outcome trials involving 29 879 participants with depressive disorders were identified through database searches in Pubmed, PsycINFO and the Cochrane Central Register of Controlled Trials. RESULTS: Compared to control conditions, psychotherapy and pharmacotherapy yielded small to moderate effect sizes for functioning and QoL, ranging from g = 0.31 to g = 0.43. When compared directly, initial analysis yielded no evidence that one of them was superior. After adjusting for publication bias, psychotherapy was more efficacious than pharmacotherapy (g = 0.21) for QoL. The combination of psychotherapy and medication performed significantly better for both outcomes compared to each treatment alone yielding small effect sizes (g = 0.32 to g = 0.39). Both interventions improved depression symptom severity more than functioning and QoL. CONCLUSION: Despite the small number of comparative trials for some of the analyses, this study reveals that combined treatment is superior, but psychotherapy and pharmacotherapy alone are also efficacious for improving functioning and QoL. The overall relatively modest effects suggest that future tailoring of therapies could be warranted to better meet the needs of individuals with functioning and QoL problems. PMID- 27780479 TI - Association of Airborne Microorganisms in the Operating Room With Implant Infections: A Randomized Controlled Trial. AB - : OBJECTIVE To evaluate the association of airborne colony-forming units (CFU) at incision sites during implantation of prostheses with the incidence of either incisional or prosthesis-related surgical site infections. DESIGN Randomized, controlled trial. SETTING Primary, public institution. PATIENTS Three hundred patients undergoing total hip arthroplasty, instrumented spinal procedures, or vascular bypass graft implantation. METHODS Patients were randomly assigned in a 1:1 ratio to either the intervention group or the control group. A novel device (Air Barrier System), previously shown to reduce airborne CFU at incision sites, was utilized in the intervention group. Procedures assigned to the control group were performed without the device, under routine operating room atmospheric conditions. Patients were followed up for 12 months to determine whether airborne CFU levels at the incision sites predicted the incidence of incisional or prosthesis-related infection. RESULTS Data were available for 294 patients, 148 in the intervention group and 146 in the control group. CFU density at the incision site was significantly lower in the intervention group than in the control group (P<.001). The density of airborne CFU at the incision site during the procedures was significantly related to the incidence of implant infection (P=.021). Airborne CFU densities were 4 times greater in procedures with implant infection versus no implant infection. All 4 of the observed prosthesis infections occurred in the control group. CONCLUSION Reduction of airborne CFU specifically at the incision site during operations may be an effective strategy to reduce prosthesis-related infections. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01610271 Infect Control Hosp Epidemiol 2016;1-8. PMID- 27780480 TI - Measles, mumps, rubella and VZV: importance of serological testing of vaccine preventable diseases in young adults living with HIV in Germany. AB - Measles, mumps, rubella (MMR) and varicella zoster virus (VZV) infection can cause serious diseases and complications in the HIV-positive population. Due to successful vaccination programmes measles, mumps and congenital rubella syndrome has become neglected in Germany. However, recent outbreaks of measles have occurred from import-associated cases. In this cross-sectional study the serostatus for MMR and VZV in 2013 HIV-positive adults from three different university outpatient clinics in Bonn (n = 544), Cologne (n = 995) and Munich (n = 474) was analysed. Sera were tested for MMR- and VZV-specific immunglobulin G antibodies using commercial immunoassays. Seronegativity was found in 3% for measles, 26% for mumps, 11% for rubella and 2% for VZV. Regarding MMR, 35% of patients lacked seropositivity against at least one infectious agent. In multivariable analysis younger age was strongly associated with seronegativity against all four viruses, measles, mumps, rubella (P < 0.001, P < 0.001 and P = 0.001, respectively) and VZV (P = 0.001). In conclusion, there is high need for MMR and VZV vaccination in people living with HIV in Germany born in 1970 or later. Thus, systematic MMR and VZV antibody screening and vaccination should be implemented in the HIV-positive population to prevent serious disease and complications of vaccine-preventable diseases. PMID- 27780481 TI - Poultry: the most common food in outbreaks with known pathogens, United States, 1998-2012. AB - As poultry consumption continues to increase worldwide, and as the United States accounts for about one-third of all poultry exports globally, understanding factors leading to poultry-associated foodborne outbreaks in the United States has important implications for food safety. We analysed outbreaks reported to the United States' Foodborne Disease Outbreak Surveillance System from 1998 to 2012 in which the implicated food or ingredient could be assigned to one food category. Of 1114 outbreaks, poultry was associated with 279 (25%), accounting for the highest number of outbreaks, illnesses, and hospitalizations, and the second highest number of deaths. Of the 149 poultry-associated outbreaks caused by a confirmed pathogen, Salmonella enterica (43%) and Clostridium perfringens (26%) were the most common pathogens. Restaurants were the most commonly reported location of food preparation (37% of poultry-associated outbreaks), followed by private homes (25%), and catering facilities (13%). The most commonly reported factors contributing to poultry-associated outbreaks were food-handling errors (64%) and inadequate cooking (53%). Effective measures to reduce poultry contamination, promote safe food-handling practices, and ensure food handlers do not work while ill could reduce poultry-associated outbreaks and illnesses. PMID- 27780482 TI - Bitemporal v. high-dose right unilateral electroconvulsive therapy for depression: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Brief-pulse electroconvulsive therapy (ECT) is the most acutely effective treatment for severe depression though concerns persist about cognitive side-effects. While bitemporal electrode placement is the most commonly used form worldwide, right unilateral ECT causes less cognitive side-effects though historically it has been deemed less effective. Several randomized trials have now compared high-dose (>5* seizure threshold) unilateral ECT with moderate-dose (1.0-2.5* seizure threshold) bitemporal ECT to investigate if it is as effective as bitemporal ECT but still has less cognitive side-effects. We aimed to systematically review these trials and meta-analyse clinical and cognitive outcomes where appropriate. METHOD: We searched PubMed, PsycINFO, Web of Science, Cochrane Library and EMBASE for randomized trials comparing these forms of ECT using the terms 'electroconvulsive' OR 'electroshock' AND 'trial'. RESULTS: Seven trials (n = 792) met inclusion criteria. Bitemporal ECT did not differ from high dose unilateral ECT on depression rating change scores [Hedges's g = -0.03, 95% confidence interval (CI) -0.17 to 0.11], remission (RR 1.06, 95% CI 0.93-1.20), or relapse at 12 months (RR 1.42, 95% CI 0.90-2.23). There was an advantage for unilateral ECT on reorientation time after individual ECT sessions (mean difference in minutes = -8.28, 95% CI -12.86 to -3.70) and retrograde autobiographical memory (Hedges's g = -0.46, 95% CI -0.87 to -0.04) after completing an ECT course. There were no differences for general cognition, category fluency and delayed visual and verbal memory. CONCLUSIONS: High-dose unilateral ECT does not differ from moderate-dose bitemporal ECT in antidepressant efficacy but has some cognitive advantages. PMID- 27780483 TI - A population-based longitudinal study of Clostridium difficile infection-related hospitalization in mid-age and older Australians. AB - Clostridium difficile is the principal cause of infectious diarrhoea in hospitalized patients. We investigated the incidence and risk factors for hospitalization due to C. difficile infection (CDI) in older Australians. We linked data from a population-based prospective cohort study (the 45 and Up Study) of 266 922 adults aged ?45 years recruited in New South Wales, Australia to hospitalization and death records for 2006-2012. We estimated the incidence of CDI hospitalization and calculated days in hospital and costs per hospitalization. We also estimated hazard ratios (HR) for CDI hospitalization using Cox regression with age as the underlying time variable. Over a total follow-up of 1 126 708 person-years, 187 adults had an incident CDI hospitalization. The crude incidence of CDI hospitalization was 16.6/100 000 person-years, with a median hospital stay of 6 days, and a median cost of AUD 6102 per admission. Incidence increased with age and year of follow-up, with a threefold increase for 2009-2012. After adjustment, CDI hospitalization rates were significantly lower in males than females (adjusted HR 0.6, 95% confidence interval 0.4-0.7). CDI hospitalization rates increased significantly over 2009 2012. There is a need to better understand the increasing risk of CDI hospitalization in women. PMID- 27780484 TI - Prospective use of whole genome sequencing (WGS) detected a multi-country outbreak of Salmonella Enteritidis. AB - Since April 2015, whole genome sequencing (WGS) has been the routine test for Salmonella identification, surveillance and outbreak investigation at the national reference laboratory in England and Wales. In May 2015, an outbreak of Salmonella Enteritidis cases was detected using WGS data and investigated. UK cases were interviewed to obtain a food history and links between suppliers were mapped to produce a food chain network for chicken eggs. The association between the food chain network and the phylogeny was explored using a network comparison approach. Food and environmental samples were taken from premises linked to cases and tested for Salmonella. Within the outbreak single nucleotide polymorphism defined cluster, 136 cases were identified in the UK and 18 in Spain. One isolate from a food containing chicken eggs was within the outbreak cluster. There was a significant association between the chicken egg food chain of UK cases and phylogeny of outbreak isolates. This is the first published Salmonella outbreak to be prospectively detected using WGS. This outbreak in the UK was linked with contemporaneous cases in Spain by WGS. We conclude that UK and Spanish cases were exposed to a common source of Salmonella-contaminated chicken eggs. PMID- 27780485 TI - Meiotic arrest as an alternative to increase the production of bovine embryos by somatic cell nuclear transfer. AB - This study aimed to evaluate the effect of meiotic arrest using phosphodiesterase type 3A (PDE 3A) inhibitors, cilostamide and C-type natriuretic peptide (NPPC), on pre-maturation (PM) of oocytes to be used in the production of cloned embryos. Nuclear maturation, in vitro embryo production (IVP), somatic cell nuclear transfer (SCNT) and parthenogenetic activation (PA), and total cells number of cloned embryos were evaluated. The results were analysed by chi-squared and Kruskal-Wallis test with a P-value 0.05) between control and PM, both for cleavage (78.2% and 76.9%) and blastocyst (35.5% and 29.3%) rates. After SCNT, cleavage rate was also similar (P > 0.05) between control and PM (66% and 51.9%) however, blastocyst rate was lower (P < 0.05) in the PM group than in the control group (7.4% and 30.2%). After 6 h of PM with 100 nM of NPPC, approximately 84.9% of the oocytes remained at GV. No difference was found between control and PM in cleavage (69.2% and 76.1%) and blastocyst rates (37,4% and 35%) after IVP. Similarly, no differences between PM and control groups were observed for cleavage (69.2% and 68.4%) and blastocyst (24.4% and 21.5%) rates. SCNT and PA embryos from control or PM oocytes had similar total cell number. It can be concluded that PM for 6 h with 100 nM NPPC is feasible for cloned embryo production without affecting embryo outcome. PMID- 27780486 TI - Surface and Mechanical Characterization of Dental Yttria-Stabilized Tetragonal Zirconia Polycrystals (3Y-TZP) After Different Aging Processes. AB - Yttria-stabilized tetragonal zirconia polycrystals (3Y-TZP) is a ceramic material used in indirect dental restorations. However, phase transformation at body temperature may compromise the material's mechanical properties, affecting the clinical performance of the restoration. The effect of mastication on 3Y-TZP aging has not been investigated. 3Y-TZP specimens (IPS E-max ZirCAD and Z5) were aged in three different modes (n=13): no aging (control), hydrothermal aging (HA), or chewing simulation (CS). Mechanical properties and surface topography were analyzed. Analysis of variance showed that neither aging protocol (p=0.692) nor material (p=0.283) or the interaction between them (p=0.216) had a significant effect on flexural strength, values ranged from 928.8 MPa (IPSHA) to 1,080.6 MPa (Z5HA). Nanoindentation analysis showed that material, aging protocol, and the interaction between them had a significant effect (p<0.001) on surface hardness and reduced Young's modulus. The compositional analysis revealed similar yttrium content for all the experimental conditions (aging: p=0.997; material: p=0.248; interaction material*aging: p=0.720). Atomic force microscopy showed an effect of aging protocols on phase transformation, with samples submitted to CS exhibiting features compatible with maximized phase transformation, such as increased volume of the material microstructure at the surface leading to an increase in surface roughness. PMID- 27780487 TI - Vitamin E and the risk of pneumonia: using the I 2 statistic to quantify heterogeneity within a controlled trial. AB - Analyses in nutritional epidemiology usually assume a uniform effect of a nutrient. Previously, four subgroups of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish male smokers aged 50-69 years were identified in which vitamin E supplementation either significantly increased or decreased the risk of pneumonia. The purpose of this present study was to quantify the level of true heterogeneity in the effect of vitamin E on pneumonia incidence using the I 2 statistic. The I 2 value estimates the percentage of total variation across studies that is explained by true differences in the treatment effect rather than by chance, with a range from 0 to 100 %. The I 2 statistic for the effect of vitamin E supplementation on pneumonia risk for five subgroups of the ATBC population was 89 % (95 % CI 78, 95 %), indicating that essentially all heterogeneity was true variation in vitamin E effect instead of chance variation. The I 2 statistic for heterogeneity in vitamin E effects on pneumonia risk was 92 % (95 % CI 80, 97 %) for three other ATBC subgroups defined by smoking level and leisure-time exercise level. Vitamin E decreased pneumonia risk by 69 % among participants who had the least exposure to smoking and exercised during leisure time (7.6 % of the ATBC participants), and vitamin E increased pneumonia risk by 68 % among those who had the highest exposure to smoking and did not exercise (22 % of the ATBC participants). These findings refute there being a uniform effect of vitamin E supplementation on the risk of pneumonia. PMID- 27780488 TI - Electron Probe Microanalysis of Ni Silicides Using Ni-L X-Ray Lines. AB - We report electron probe microanalysis measurements on nickel silicides, Ni5Si2, Ni2Si, Ni3Si2, and NiSi, which were done in order to investigate anomalies that affect the analysis of such materials by using the Ni L3-M4,5 line (Lalpha). Possible sources of systematic discrepancies between experimental data and theoretical predictions of Ni L3-M4,5 k-ratios are examined, and special attention is paid to dependence of the Ni L3-M4,5 k-ratios on mass-attenuation coefficients and partial fluorescence yields. Self-absorption X-ray spectra and empirical mass-attenuation coefficients were obtained for the considered materials from X-ray emission spectra and relative X-ray intensity measurements, respectively. It is shown that calculated k-ratios with empirical mass attenuation coefficients and modified partial fluorescence yields give better agreement with experimental data, except at very low accelerating voltages. Alternatively, satisfactory agreement is also achieved by using the Ni L3-M1 line (Ll) instead of the Ni L3-M4,5 line. PMID- 27780489 TI - Risk assessment and laboratory investigation of respiratory illness in travellers returning to Singapore 2012-2015: experience from the MERS-CoV Surveillance Programme. AB - Since the emergence of Middle East respiratory syndrome coronavirus (MERS-CoV), Singapore has enhanced its national surveillance system to detect the potential importation of this novel pathogen. Using the guidelines from the Singapore Ministry of Health, a suspect case was defined as a person with clinical signs and symptoms suggestive of pneumonia or severe respiratory infection with breathlessness, and with an epidemiological link to countries where MERS-CoV cases had been reported within the preceding 14 days. This report describes a retrospective review of 851 suspected MERS-CoV cases assessed at the adult tertiary-care hospital in Singapore between September 2012 and December 2015. In total, 262 patients (31%) were hospitalized. All had MERS-CoV infection ruled out by RT-PCR or clinical assessment. Two hundred and thirty (88%) of the hospitalized patients were also investigated for influenza virus by RT-PCR. Of these, 62 (27%) tested positive for seasonal influenza. None of the patients with positive influenza results had been vaccinated in the year prior to hospital admission. Ninety-three (36%) out of the 262 hospitalized patients had clinical and/or radiological evidence of pneumonia. This study demonstrates the potential benefits of pre-travel vaccination against influenza and pneumococcal disease. PMID- 27780490 TI - Evaluation of the limiting antigen avidity EIA (LAg) in people who inject drugs in Greece. AB - This analysis assessed the utility of the limiting antigen avidity assay (LAg). Samples of people who inject drugs (PWID) in Greece with documented duration of HIV-1 infection were tested by LAg. A LAg-normalized optical density (ODn) ?1.5 corresponds to a recency window period of 130 days. The proportion true recent (PTR) and proportion false recent (PFR) were estimated in 28 seroconverters and in 366 samples collected >6 months after HIV diagnosis, respectively. The association between LAg ODn and HIV RNA level was evaluated in 232 persons. The PTR was 85.7%. The PFR was 20.8% but fell to 5.9% in samples from treatment-naive individuals with long-standing infection (>1 year), and to 0 in samples with the circulating recombinant form CRF35 AD. A LAg-based algorithm with a PFR of 3.3% estimated a similar incidence trend to that calculated by analyses based on HIV-1 seroconversions. In recently infected persons indicated by LAg, the median log10 HIV RNA level was high (5.30, interquartile range 4.56-5.90). LAg can help identify highly infectious HIV(+) individuals as it accurately identifies recent infections and is correlated with the HIV RNA level. It can also produce reliable estimates of HIV-1 incidence. PMID- 27780491 TI - Association of adverse childhood experiences with lifetime mental and substance use disorders among men and women aged 50+ years. AB - BACKGROUND: Given growing numbers of older adults with mental and substance use disorders (MSUDs), this study examined the association between ten types of adverse childhood experiences (ACEs) and lifetime MSUDs among those aged 50+. METHODS: Data (N = 14,738 for the 50+ age group) came from the 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions. Using multivariable binary logistic regression analyses, we examined relationships between ten ACEs and six lifetime MSUDs (major depressive disorder (MDD) and anxiety, post-traumatic stress, alcohol use, drug use, and nicotine use disorders). Gender differences were examined using tests of interaction effects and gender-separate logistic regression models. RESULTS: Of the sample, 53.2% of women and 50.0% of men reported at least one ACE. For both genders, parental/other adult's substance abuse was the most prevalent (22.6%), followed by physical abuse, and emotional neglect. Child abuse and neglect and parental/other adult's mental illness and substance abuse had small but consistently significant associations with MSUDs (e.g., odds ratio = 1.28, 95% CI = 1.12-1.46 for parental/other adult's substance misuse and MDD). Although the relationship between total number of ACEs and MSUDs was cumulative for both men and women, the associations of physical abuse, sexual abuse, emotional neglect, and parental separation/divorce with MSUDs were stronger among men. CONCLUSIONS: This study underscores the significant yet modest association between ACEs and lifetime MSUDs in late life. More research is needed to investigate why ACEs seem to have greater effects on older men and to discern the sources of gender differences in ACEs' effects. PMID- 27780492 TI - Mechanisms for floor surfaces or environmental ground contamination to cause human infection: a systematic review. AB - Shoe soles have been shown to transfer infectious microorganisms to floor and ground surfaces. However, the possible modes of transmission of infectious agents from floors or ground surfaces to human contact for infection have not been systematically reviewed. A systematic review was performed on articles indexed in medical databases (Medline, EMBASE, PubMed) using a pre-defined search strategy and MeSH terms (date of last search: 15 March 2016). Only primary research studies in English that investigated the transmission dynamics of infectious microorganisms from floor or ground surfaces to human infection were included. Extraction of articles was performed two independent reviewers using pre-defined data fields in an Excel sheet. Disagreements were resolved by consensus. Thirty studies met the inclusion criteria. Almost all hospital-associated microorganisms including methicillin-resistant Staphylococcus aureus, Clostridium difficile, and multidrug-resistant Gram-negative species were identified on floor or ground surfaces. Several modes of transmission dynamics, most commonly direct contact or aerosolization, were identified. In conclusion, interventions such as efficient cleaning of floor surfaces and vectors that transfer infectious organisms to floors such as shoe soles could be an effective infection control strategy to prevent human disease. PMID- 27780493 TI - Influence of personality on depression, burden, and health-related quality of life in family caregivers of persons with dementia. AB - BACKGROUND: Personality may predispose family caregivers to experience caregiving differently in similar situations and influence the outcomes of caregiving. A limited body of research has examined the role of some personality traits for health-related quality of life (HRQoL) among family caregivers of persons with dementia (PWD) in relation to burden and depression. METHODS: Data from a large clinic-based national study in South Korea, the Caregivers of Alzheimer's Disease Research (CARE), were analyzed (N = 476). Path analysis was performed to explore the association between family caregivers' personality traits and HRQoL. With depression and burden as mediating factors, direct and indirect associations between five personality traits and HRQoL of family caregivers were examined. RESULTS: Results demonstrated the mediating role of caregiver burden and depression in linking two personality traits (neuroticism and extraversion) and HRQoL. Neuroticism and extraversion directly and indirectly influenced the mental HRQoL of caregivers. Neuroticism and extraversion only indirectly influenced their physical HRQoL. Neuroticism increased the caregiver's depression, whereas extraversion decreased it. Neuroticism only was mediated by burden to influence depression and mental and physical HRQoL. CONCLUSIONS: Personality traits can influence caregiving outcomes and be viewed as an individual resource of the caregiver. A family caregiver's personality characteristics need to be assessed for tailoring support programs to get the optimal benefits from caregiver interventions. PMID- 27780494 TI - Group C rotavirus infection in patients with acute gastroenteritis in outbreaks in western India between 2006 and 2014. AB - Faecal specimens collected from outbreak (n = 253) and sporadic (n = 147) cases of acute gastroenteritis that occurred in western India between 2006 and 2014 were tested for group C rotavirus (GCR) using partial VP6 gene-based RT-PCR. All specimens were tested previously for the presence of other viral and bacterial aetiological agents by conventional methods. The rate of GCR detection was 8.6% and 0.7% in outbreak and sporadic cases, respectively. GCR infections prevailed in outbreaks reported from rural areas (10.9%) compared to urban areas (1.6%). Clinical severity score of the patients with GCR infection (n = 23) indicated severe disease in the majority (70%) of cases. The age distribution analysis indicated 52.1% of GCR infections in children aged <10 years. The male:female ratio in GCR-positive patients was 2.3:1. Of the 23 GCR-positive cases, 17 (73.9%) had a sole GCR infection and six had mixed infections with other viral and/or bacterial agents. Phylogenetic analysis of nucleotide sequences classified GCR strains of the study in to I2 genotype of the VP6 gene. This is the first study to show the occurrence of GCR in gastroenteritis outbreaks in India. PMID- 27780495 TI - Information for mental health systems: an instrument for policy-making and system service quality. AB - AIMS: Information is crucial in mental healthcare, yet it remains undervalued by stakeholders. Its absence undermines rationality in planning, makes it difficult to monitor service quality improvement, impedes accountability and human rights monitoring. For international organizations (e.g., WHO, OECD), information is indispensable for achieving better outcomes in mental health policies, services and programs. This article reviews the importance of developing system level information with reference to inputs, processes and outputs, analyzes available tools for collecting and summarizing information, highlights the various goals of information gathering, discusses implementation issues and charts the way forward. METHODS: Relevant publications and research were consulted, including WHO studies that purport to promote the use of information systems to upgrade mental health care in high- and low-middle income countries. RESULTS: Studies have shown that once information has been collected by relevant systems and analyzed through indicator schemes, it can be put to many uses. Monitoring mental health services, represents a first step in using information. In addition, studies have noted that information is a prime resource in many other areas such as evaluation of quality of care against evidence based standards of care. Services data may support health services research where it is possible to link mental health data with other health and non-health databases. Information systems are required to carefully monitor involuntary admissions, restrain and seclusion, to reduce human rights violations in care facilities. Information has been also found useful for policy makers, to monitor the implementation of policies, to evaluate their impact, to rationally allocate funding and to create new financing models. CONCLUSIONS: Despite its manifold applications, Information systems currently face many problems such as incomplete recording, poor data quality, lack of timely reporting and feedback, and limited application of information. Corrective action is needed to upgrade data collection in outpatient facilities, to improve data quality, to establish clear rules and norms, to access adequate information technology equipment and to train health care personnel in data collection. Moreover, it is necessary to shift from mere administrative data collection to analysis, dissemination and use by relevant stakeholders and to develop a "culture of information" to dismantle the culture of intuition and mere tradition. Clinical directors, mental health managers, patient and family representatives, as well as politicians should be educated to operate with information and not just intuition. PMID- 27780496 TI - Cognitive and anatomical correlates of anosognosia in amnestic mild cognitive impairment and early-stage Alzheimer's disease. AB - BACKGROUND: Anosognosia is a common feature in Alzheimer's disease (AD). The brain substrates of anosognosia are not fully understood, and less is known about the cognitive substrates of anosognosia in prodromal and early stages of AD. METHODS: Fourty-seven patients with amnestic-type mild cognitive impairment (aMCI) (n = 26) and early-stage AD (n = 21) were included, and Clinical Insight Rating Scale and Anosognosia Questionnaire for Dementia (AQ-D) were used to assess anosognosia. A detailed neuropsychological battery was administered; each patient underwent a structural magnetic resonance imaging (MRI). Correlation between anosognosia and performance in individual cognitive domains as well as correlation between anosognosia and cortical thickness values in regions of interest were assessed. RESULTS: Performance of the anosognosic patients in Digit Ordering Test (DOT), Digit Span Backwards, and Clock Drawing Test (CDT) was significantly worse compared to non-anosognosic patients in the total study population and in the aMCI subgroup but not in AD group. AQ-D scores negatively correlated with Mini-Mental State Examination (MMSE), California Verbal Learning Test (CVLT), Digit Span Backwards and CDT scores in total group and MMSE, CVLT, DOT, and Digit Span Backwards scores in the aMCI group. No significant correlations were found between cortical thickness measurements and AQ-D scores in any of the patient populations. CONCLUSIONS: Anosognosia was associated with episodic memory, working memory, and executive functions in the total population and aMCI group, but no association was found in early-stage AD patients. Anosognosia in the early stages of AD may be related with non-structural changes such as hypoconnectivity rather than structural changes. PMID- 27780497 TI - Prevalence and husbandry-related risk factors of myiasis in domestic cavies in the western highlands of Cameroon. AB - The presence of parasites on the farm can be a cause of losses in animal production, and often a threat to public health. A cross-sectional study was carried out in rural areas of the western highlands of Cameroon to determine the prevalence and husbandry-related risk factors associated with Cordylobia anthropophaga infestations in domestic cavies. The overall prevalence of myiasis in animals was 2.80% [95% confidence interval (CI) 1.50-5.10]; myiasis was found in 2% and 4.30% animals in Menoua and Bamboutos divisions, respectively. Eleven farms (8.95%) in total were infested with C. anthropophaga, with 6.41% and 13.34% of farms in the Menoua and Bamboutos divisions, respectively. The relative risk of infestation within each factor showed that the risk of myiasis in animals kept in kitchen compartments without litter was 6.16 times higher (95% CI 1.71-22.29, P = 0.04) than in animals kept in kitchens and house floors. Despite the low prevalence, the burden of cordylobiasis needs to be assessed. It is assumed that the risk of humans acquiring the disease is higher in farmers keeping cavies in kitchen compartments without litter. Farmers need to be educated on control measures to reduce the risk of infestation, which include both sanitation and medical (larvae extraction) measures. PMID- 27780499 TI - When the grass isn't greener: a case series of young children with accidental marijuana ingestion. AB - Marijuana is the most commonly used illicit drug in Canada, with 10% of the general population admitting to its use in the past year. This high prevalence increases risk of accidental ingestion in young children. We report four pediatric cases of accidental marijuana ingestion who presented to our local emergency department with altered mental status. Three patients had extensive testing, including one patient who underwent lumbar puncture and empirical treatment for meningitis. To our knowledge, this is the first Canadian case series since McNabb et al., published over 2 decades ago. The case series aims to highlight the importance of considering acute marijuana intoxication in the differential diagnosis when assessing young children with altered level of consciousness. PMID- 27780500 TI - Adverse Events Following Diagnostic Urethral Catheterization in the Pediatric Emergency Department. AB - OBJECTIVES: The purpose of this study was to assess adverse events associated with diagnostic urethral catheterization (UC) in young children and to determine their impact on the patient and their family. METHODS: This was a prospective cohort study conducted in the emergency department of a tertiary-care pediatric hospital. All 3- to 24-month-old children with fever who had a diagnostic UC were eligible. Parents who consented to participate were contacted by phone within 7 to 10 days after the UC to answer a standardized questionnaire inquiring about complications. The primary outcome was the occurrence of an unfavourable event in the seven days following UC, defined as painful urination, genital pain, urinary retention, hematuria or secondary urinary tract infection. Secondary outcomes included the need for further medical care and the need for parents to miss school or work. RESULTS: Of the 199 patients who completed the study, 41 (21%) reported a complication: painful urination in 19 (10%) children, genital pain in 16 (8%), urinary retention in 11 (6%), gross hematuria in 9 (5%), and secondary urinary tract infection in 1 (0.5%). Three (1%) parents reported the need for further medical care and three (1%) missed work. Two independent variables (male sex and age 12-23 months) were associated with a higher risk of adverse events. CONCLUSIONS: Urethral catheterization is associated with adverse events in 21% of young children in the week following the procedure. Accordingly, this procedure should be used judiciously in children, considering its potential to cause unfavourable events. PMID- 27780501 TI - Definition and application of precision medicine. AB - "No abstract". PMID- 27780498 TI - Factors affecting carriage and intensity of infection of Calodium hepaticum within Norway rats (Rattus norvegicus) from an urban slum environment in Salvador, Brazil. AB - Urban slum environments in the tropics are conducive to the proliferation and the spread of rodent-borne zoonotic pathogens to humans. Calodium hepaticum (Brancroft, 1893) is a zoonotic nematode known to infect a variety of mammalian hosts, including humans. Norway rats (Rattus norvegicus) are considered the most important mammalian host of C. hepaticum and are therefore a potentially useful species to inform estimates of the risk to humans living in urban slum environments. There is a lack of studies systematically evaluating the role of demographic and environmental factors that influence both carriage and intensity of infection of C. hepaticum in rodents from urban slum areas within tropical regions. Carriage and the intensity of infection of C. hepaticum were studied in 402 Norway rats over a 2-year period in an urban slum in Salvador, Brazil. Overall, prevalence in Norway rats was 83% (337/402). Independent risk factors for C. hepaticum carriage in R. norvegicus were age and valley of capture. Of those infected the proportion with gross liver involvement (i.e. >75% of the liver affected, a proxy for a high level intensity of infection), was low (8%, 26/337). Sixty soil samples were collected from ten locations to estimate levels of environmental contamination and provide information on the potential risk to humans of contracting C. hepaticum from the environment. Sixty percent (6/10) of the sites were contaminated with C. hepaticum. High carriage levels of C. hepaticum within Norway rats and sub-standard living conditions within slum areas may increase the risk to humans of exposure to the infective eggs of C. hepaticum. This study supports the need for further studies to assess whether humans are becoming infected within this community and whether C. hepaticum is posing a significant risk to human health. PMID- 27780502 TI - A new concept and classification of corona mortis and its clinical significance. AB - PURPOSE: The obturator artery and its accessory (aberrant) arising from different origins and crossing the pubic rami are vascular variations. The internal iliac artery usually provides the obturator artery which may communicates with the external iliac artery through either the accessory obturator or inferior epigastric artery. A collateral circulation between the external and internal iliac system is known as corona mortis. The aim of current study is to provide sufficient data of vascular variability crossing the pubic rami for clinical field. METHODS: Present study includes 208 hemipelvises dissected in the Institution of Anatomy, Medical University of Graz. During dissection, the obturator artery and its accessory crossing the superior rami of pubic bone were found to have different origins. RESULTS: The obturator artery arising from the external iliac artery and from the femoral artery accounts for 9.8% and 1.1% respectively. Therefore, it passes over the superior pubic rami in 10.9%. Further, the accessory (aberrant) artery arises only from the femoral artery in 1.1%. In present study, the vascular variation crossing the superior pubic rami with or without collateral circulation between external and internal iliac system referred as corona mortis is addressed. This study includes new classification of obturator and accessory obturator arteries as well as the corona mortis. It includes a comparison of corona mortis incidence in Austria population and other populations. The corona mortis found to be in 12% of Austrian population. CONCLUSION: A great attention of clinicians, radiologists, surgeons, orthopedic surgeons, obstetricians and gynecologists has to be considered before pubic surgical procedures such as internal fixation of pubic fracture, an inguinal hernia repair. Further, traumatic pubic rami fracture may lead to massive hemor- rhage due to laceration of the obturator artery. PMID- 27780503 TI - Biomechanical analysis of tension band wiring (TBW) of transverse fractures of patella. AB - PURPOSE: Tension band wiring is commonly used for fixation of simple transverse fractures. The popular configuration is parallel Kirschner wires (K-wires) and a stainless steel wire loop placed in a vertically oriented figure-of-8. METHODS: We used a wooden model of a patella with a midway transverse fracture and compared four different types of fixation. The first construct had a vertical figure-of-8 with one twist of wire. The second contained a vertical figure-of-8 with two twists of wire. The third was a vertical figure-of-8 with two twists of wire placed at adjacent corners while the last one had a horizontal figure-of-8 with two twists of wire placed at adjacent corners. Interfragmentary compression at the point of wire breakage was measured for each construct as well as permanent displacement on cyclic loading. RESULTS: Placement of the figure-of eight in a horizontal orientation with two wire twists at the corner improved interfragmentary compression by 63% (p < 0.05, Tukey post hoc test). On cyclic loading, all the constructs with vertical figure-of-eight but none with a horizontal construct failed (p=0.01; Fisher's exact test). Permanent fracture displacement after cyclic loading was 67% lower with horizontal figure- of-eight constructs (p < 0.05; t test). CONCLUSION: Placing wire twists at the corner and a horizontal placement of figure-of-8 improves stability of the construct. PMID- 27780505 TI - Social network analysis of Iranian researchers in the field of violence. AB - PURPOSE: The social network analysis (SNA) is a paradigm for analyzing structural patterns in social re- lations, testing knowledge sharing process and identifying bottlenecks of information flow. The purpose of this study was to determine the status of research in the fleld of violence in Iran using SNA. METHODS: Research population included all the papers with at least one Iranian affiliation published in violence fleld indexed in SCIE, PubMed and Scopus databases. The co word maps, co-authorship network and structural holes were drawn using related software. In the next step, the active authors and some measures of our network including degree centrality (DC), closeness, eigenvector, betweeness, density, diameter, compactness and size of the main component were assessed. Likewise, the trend of the published articles was evaluated based on the number of documents and their citations from 1972 to 2014. RESULTS: Five hundred and seventy one records were obtained. The five main clusters and hot spots were mental health, violence, war, psychiatric disorders and suicide. The co-authorship network was complex, tangled and scale free. The top nine authors with cut point role and top ten active authors were identified. The mean (standard deviation) of normalized DC, closeness, eigenvector and betweeness were 0.449 (0.805), 0.609 (0.214), 2.373 (7.353) and 0.338 (1.122), respectively. The density, diameter and mean compactness of our co-authorship network were 0.0494, 3.955 and 0.125, respectively. The main component consisted of 216 nodes that formed 17% of total size of the network. Both the number of the documents and their citations has increased in the field of violence in the recent years. CONCLUSION: Although the number of the documents has recently increased in the field of violence, the information flow is slow and there are not many relations among the authors in the network. However, the active authors have ability to influence the flow of knowledge within the network. PMID- 27780504 TI - Treatment of osteoporotic intertrochanteric fractures by zoledronic acid injection combined with proximal femoral nail anti-rotation. AB - OBJECTIVE: To observe the clinical results of proximal femoral nail anti-rotation (PFNA) combined with zoledronic acid injection in the treatment of osteoporotic intertrochanteric fractures in the elderly. METHODS: 60 elderly patients with osteoporotic intertrochanteric fractures were diagnosed using a dual energy X-ray bone density instrument. Patients were randomly divided into treatment or control groups (30 cases in each group). Patients in both groups were treated by closed/open reduction and internal fixation using PFNA. In the treatment group, patients received one zoledronic phosphonic acid injection of 5 mg/100 ml via intravenous drip, in addition to 600 mg of Caltrate D (qd) and 0.25 mg of alpha ossification alcohol (qd). The control group received 600 mg of Caltrate D (qd) and 0.25 mg of alpha ossification alcohol (qd). The oral drugs were administered for 12 months. Bone pain relief was observed, and changes in the bone mineral density (BMD) of the lumbar and health-side hip were recorded. Clinical results were evaluated using the Visual Analogue Scale (VAS), Harris joint function score, and Osteo- porosis Quality of Life Scale (OQOLS). RESULTS: Compared with the control group, bone pain symptoms were significantly alleviated (p < 0.05) in the treatment group. In the treatment and control groups, both between-group and within-group differences in BMD were significantly increased in L1e4, femoral neck and trochanter (p < 0.05). No significant differences were found between the two groups in regard to the involved hip or the total rate of improvement at the end of the follow-up period, although cases in the treatment group had higher OQOLS scores than those of the controls (p = 0.04). Cases in the treatment group healed more quickly than those in the control group [(13 +/- 3.2) weeks vs (15 +/ 4.6) weeks, p = 0.02]. During the follow-up period, cases in the treatment group had no new fractures, whereas 2 new cases of hip fracture and 2 cases of distal radial fractures were observed among the controls. CONCLUSION: Zoledronic acid injection combined with PFNA is a favorable treatment option for the elderly patients with osteoporotic intertrochanteric fracture. It can effectively relieve bone pain, increase bone density, improve quality of life, reduce the occurrence of new fractures and promote fracture healing. PMID- 27780506 TI - Differences in cognitive profiles between traumatic brain injury and stroke: A comparison of the Montreal Cognitive Assessment and Mini-Mental State Examination. AB - PURPOSE: To investigate the profiles of cognitive impairment through Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) in patients with chronic traumatic brain injury (TBI) or stroke and to evaluate the sensitivity of the two scales in patients with TBI. METHODS: In this cohort study, a total of 230 patients were evaluated, including TBI group (n = 103) and stroke group (n = 127). The cognitive functions of two groups were evaluated by designated specialists using MoCA (Beijing version) and MMSE (Chinese version). RESULTS: Comparedwith the patientswith stroke, the patientswith TBI received significantly lower score in orientation subtest and recall subtest in both tests.MoCA abnormal rates in the TBI group and stroke group were 94.17% and 86.61% respectively,whileMMSE abnormal rateswere 69.90% and 57.48%, respectively. In the TBI group, 87.10% patientswith normalMMSE score had abnormalMoCA score and in the stroke group, about 70.37% patients with normal MMSE score had abnormal MoCA score. The diagnostic consistency of two scales in the TBI group and the stroke group were 72% and 69%, respectively. CONCLUSION: In our rehabilitation center, patients with TBI may have more extensive and severe cognitive impairments than patients with stroke, prominently in orientation and recall domain. In screening post- TBI cognitive impairment, MoCA tends to be more sensitive than MMSE. PMID- 27780507 TI - Does serum calcium relate to different types of hip fracture? A retrospective study. AB - PURPOSE: To investigate the potential correlation between two different types of hip fractures and serum calcium levels. METHODS: We consecutively studied 101 cases of femoral neck fracture and 95 cases of femoral inter- trochanteric fracture between January 2011 and December 2013. Fasting blood samples were taken and serum calcium measurements were performed respectively in three periods: the time of admission, postoperation, and discharge. Creatinine, alkaline phosphatase and albumin were also analyzed. RESULTS: Considering the levels of serum calcium between two groups at the time of admission, post- operation and discharge, there was significant difference at admission and discharge (p <0.05), while there was no significant difference at the time of postoperation (p > 0.05). The magnitude of serum calcium fluctuation was larger in femoral neck group than femoral intertrochanteric group. Concerning alkaline phosphatase and albumin levels at admission, there was no significant difference between two groups (p > 0.05). CONCLUSION: The capability of reservation and restoration of serum calcium in patients with femoral neck fracture is better than that in patients with femoral intertrochanteric fracture. A low serum calcium level may be susceptible to femoral intertrochanteric fracture. PMID- 27780508 TI - External fixation versus open reduction and internal fixation for tibial pilon fractures: A meta-analysis based on observational studies. AB - PURPOSE: Tibial pilon fractures remain challenging for an orthopaedic surgeon to repair. External fixation (ExFix) and open reduction and internal fixation (ORIF) are two widely used methods for repairing tibial pilon fractures. However, conclusions of comparative studies regarding which method is superior are controversial. Our aim is to compare ORIF and ExFix and clarify which method is better in terms of reduction and union results and major complications. METHODS: A computerized research of MEDLINE, EMBASE, Springer, and Cochrane Library (before December 2014) for studies of any design comparing ORIF and ExFix was conducted. Weighted mean difference (WMD), risk ratio (RR) and corresponding 95% confidence intervals (CI) were used for esti- mating the effects of the two methods. Statistical analyses were done using Review Manager Version 5.2. RESULTS: Ten cohort studies and one randomized clinical trial were included in our ultimate analysis. And the analysis found no significant difference between the two methods in deep infection (p = 0.13), reduction (p = 0.11), clinical evaluation (p = 0.82), post-traumatic arthrosis (p = 0.87), and union time (p = 0.35). Besides, ExFix group was found to have a higher rate of superficial infection (p =0.001), malunion (p = 0.01) and nonunion (p = 0.02), but have a lower risk of unplanned hardware removal (p = 0.0002). CONCLUSIONS: We suggest that ORIF has a relatively lower incidence rate of superficial infection, malunion and nonunion, but a higher rate of unplanned hardware removal. No difference was found in deep infection, reduction, clinical evaluation, post traumatic arthrosis and union time. PMID- 27780509 TI - Subtrochanteric osteoid osteoma: A misdiagnosed case complicated by a hip fracture. AB - A 34-year-old man with a subtrochanteric osteoid osteoma localized to the lateral cortex of the left femur is reported. The patient presented with mild spontaneous pain of the lateral thigh and knee. He refused a radiographic examination and was treated as a greater trochanteric pain syndrome for 9 months. He was then admitted with a transcervical fracture of the neck of the left femur after a fall from standing height. The fracture was fixed with 3 cannulated screws and healed uneventfully. His symptoms worsened after the first postoperative year. Eighteen months postoperatively the pain was dull, worsening at night, and relieved only with anti-inflammatory drugs, and he had a limp. New radiographs and tomograms were indicative of a lateral subtrochanteric osteoid osteoma with a subperiosteal localization. The lesion was treated successfully with surgical excision of a piece of reactive bone including the nidus. PMID- 27780510 TI - Bilateral segmental pelvic and femoral fractures in a young female: A rare case report. AB - The management of multiple complicated injured patients remains a great challenge despite advance- ments in modern medical care. We present a rare case of bilateral unstable pelvic fractures associated with bilateral segmental femoral shaft fractures.We have proposed a mechanism of such complex injury pattern and discussed the plan of management. We believe that a timely and aggressive surgical intervention to fix all the major fractures soon after medically stabilizing the patient helped our patient to overcome these serious and lethal injuries. It is necessary to establish an optimal protocol for management of such complex fractures by conducting prospective and multicentric studies in the future. PMID- 27780511 TI - Computed tomography angiography and magnetic resonance imaging performance of acute segmental single compartment syndrome following an Achilles tendon repair: A case report and literature review. AB - Acute compartment syndrome of the lower extremity is a serious postinjury complication that requires emergency treatment. Early diagnosis is of paramount importance for a good outcome. Four muscle compartments in the calf (anterior, lateral, deep posterior, and superficial posterior) may be individually or collectively affected. Acute segmental single-compartment syndrome is an extremely rare condition characterized by high pressure in a single compartment space with threatening of the segmental tissue viability. In this case report, we describe a young man with Achilles tendon rupture who complained of postoperative pain in the anterior tibial region. Emergent computed tomography angiography and magnetic resonance imaging revealed local muscle edema. Segmental anterior compartment syndrome was diagnosed and fasciotomy was performed. PMID- 27780512 TI - A six months old neglected anterior shoulder dislocation managed by closed reduction and Latarjet procedure. AB - A neglected shoulder dislocation is a rarer entity and only few cases are reported in the literature. An anterior dislocation of the shoulder is rarely missed as patients present with limb in abduction and external rotation, an attitude very familiar to orthopaedic surgeon. Occasionally such cases are missed when they present with fracture of proximal humerus or when they receive treatment from unqualified practitioners who commonly practise in rural areas. Owing to very few reports there is paucity of literature and no standard treatment protocol exists for neglected anterior dislocation of the shoulder, though most such chronic cases are managed by open reduction. This case report describes a six months old neglected anterior dislocation with a significant Hill Sachs lesion, which was managed by closed reduction and Latarjet procedure. PMID- 27780513 TI - Management of humeral fracture nonunion in severe osteoporosis by a combination of locking plating and intramedullary fibular grafting. AB - Nonunion of the humerus in a severely osteoporotic bone is a likely event especially if the fracture is transverse. The management of such a combination is a challenge. Most of the conventional fixation methods are unlikely to succeed as the bone failure precedes implant failure in osteoporosis. The challenge is further compounded in severe osteoporosis when the cortical thickness is affected more severely. We used a combination of an intramedullary fibula with a locking plate in 5 cases. The results show that it may be a good combination in such situations as the bone strength is augmented and the plate pullout is less likely. PMID- 27780514 TI - A totally laparoscopic peritoneal free flap for reconstruction of hand. AB - Management of defects on the hand and foot with exposed tendons remains a major challenge for plastic surgeons. Here, we present a case of hand reconstruction with a totally laparoscopic peritoneal flap. The anterior rectus sheath was preserved in situ. The peritoneal free flap supplied by peritoneal branches of the deep inferior epigastric artery was retrieved by laparoscopy to cover the soft tissue defect of the hand. The defect of the dorsal hand was 17 cm *12 cm. The peritoneal flap measuring 22 cm * 15 cm survived completely without any complications. A following split-thickness skin graft offered the suc- cessful wound closure. Motor and sensory function improved gradually within the first year follow-up. The totally laparoscopic peritoneal free flap is a good choice for reconstruction of the soft tissue de- fects accompanied by exposed tendons on the hand and foot. PMID- 27780515 TI - Kirschner wire migration from subcapital humeral fracture site, causing hydropneumothorax. AB - Migration of wires or pins around the shoulder is a known complication, though their migration within the chest is uncommon. We report an unusual case of hydropneumothorax due to migration of a bent Kirschner wire from the right proximal humerus in a 63 year-old man. We reviewed his clinical history, physical examination, imaging findings, surgical method and outcome. We also reviewed the literature on orthopaedic wire migration and latest technique in removal of the wires. Chest radiographs and chest computerized tomography are useful in detection and diagnosis of this disorder. Regular radiographic follow-up is needed for patients with internal fixation devices; any fractured or migrated pins or wires must be removed immediately to prevent dangerous complications. It is always important to remove the wires at the end of the treatment. Early removal of fixation wires and regular follow-up if wires are retained are essential to prevent serious complications. PMID- 27780516 TI - Anterolateral thigh free flap for simultaneous reconstruction of digital extensor tendon and defect of the dorsal hand: A case report. AB - This paper describes a new technique in the repair of the hand defect with digital extensor tendon injury. The anterolateral thigh flap with the thick femoral fascia has been used in the reconstruction of the composite defect of the dorsal hand, especially the defect of tendon. This technique requires short period of treatment and hence causes less damage to the donor site but shows a better recovery of the hand function. A favorable curative effect has been obtained in this patient. PMID- 27780517 TI - Effect and possible mechanisms of melatonin treatment on the quality and developmental potential of aged bovine oocytes. AB - After reaching the metaphase II (MII) stage, unfertilised oocytes undergo a time dependent process of quality deterioration referred to as oocyte aging. The associated morphological and cellular changes lead to decreased oocyte developmental potential. This study investigated the effect of exogenous melatonin supplementation on in vitro aged bovine oocytes and explored its underlying mechanisms. The levels of cytoplasmic reactive oxygen species and DNA damage response in bovine oocytes increased during in vitro aging. Meanwhile, maturation promoting factor activity significantly decreased and the proportion of morphologically abnormal oocytes significantly increased. Melatonin supplementation significantly decreased quality deterioration in aged bovine MII oocytes (P<0.05). Additionally, it decreased the frequency of aberrant spindle organisation and cortical granule release during oocyte aging (P<0.05). In the melatonin-supplemented group, mitochondrial membrane potential and ATP production were significantly increased compared with control. Furthermore, melatonin treatment significantly increased the speed of development of bovine oocytes to the blastocyst stage after in vitro fertilisation and significantly decreased the apoptotic rate in the blastocysts (P<0.05). The expression of Bax and Casp3 in the blastocysts was significantly reduced after treatment with melatonin, whereas expression of Bcl2 significantly increased (P<0.05). In conclusion, these findings suggest that supplementation of aged bovine oocytes with exogenous melatonin improves oocyte quality, thereby enhancing the developmental capacity of early embryos. PMID- 27780518 TI - Sleep restriction in Wistar rats impairs epididymal postnatal development and sperm motility in association with oxidative stress. AB - Good sleep quality has a direct effect on the activity of the neuroendocrine reproductive control axis and oxidative stress. Thus, the aim of the present study was to evaluate whether sleep restriction (SR) during the peripubertal period impaired the postnatal development of the epididymis in Wistar rats. After 21 days SR (18h per day), epididymides were collected on Postnatal Day (PND) 62 for evaluation of oxidative stress markers, inflammatory profile, sperm count and histopathological and stereological analyses; in addition, the motility of spermatozoa from the vas deferens was examined. SR significantly increased lipid peroxidation and glutathione levels in the caput and cauda epididymidis, and increased levels of total radical-trapping antioxidant potential in the caput epididymidis only. Neutrophil migration to the caput or corpus epididymidis was decreased by SR, and the size of the luminal compartment in the 2A region and the epithelial compartment in the 5A/B region was also decreased. In these regions, there was an increase in the size of the interstitial compartment. The percentage of immotile spermatozoa was higher in the SR group. In conclusion, SR affects epididymal postnatal development, as well as sperm motility, in association with increased oxidative stress and a decrease in the size of the epithelial compartment in the cauda epididymidis. PMID- 27780520 TI - Stability analysis and compensation of network-induced delays in communication based power system control: A survey. AB - This survey is to summarize and compare existing and recently emerging approaches for the analysis and compensation of the effects of network-induced delays on the stability and performance of communication-based power control systems. Several important communication-based power control systems are briefly introduced. The deterministic and stochastic methodologies of analyzing the impacts of network induced delays on the stability of the communication-based power control systems are summarized and compared. A variety of control approaches are reviewed and compared for mitigating the effects of network-induced delays, depending on several design requirements, such as model dependence and design difficulty. The summary and comparison of these control approaches in this survey provide researchers and utilities valuable guidance for designing advanced communication based power control systems in the future. PMID- 27780521 TI - Comments on SOPICA study in Spain. PMID- 27780522 TI - Reply to "Comments on SOPICA study in Spain". PMID- 27780523 TI - Editorial: Accountability in maternal and neonatal health programs. PMID- 27780524 TI - Current Evidence Does Not Support Exercise Therapy for Perceived Fatigue in Multiple Sclerosis. PMID- 27780525 TI - The Authors Respond. PMID- 27780519 TI - International Congress of Drug Therapy in HIV Infection 23-26 October 2016, Glasgow, UK. PMID- 27780526 TI - Efficacy and Safety of Leg-Press Training With Moderate Vibration After Total Knee Arthroplasty Remains Unclear. PMID- 27780527 TI - The Authors Respond. PMID- 27780528 TI - Visual Impairment After a Stroke. PMID- 27780529 TI - Self-similarity and recursion as default modes in human cognition. AB - Humans generate recursive hierarchies in a variety of domains, including linguistic, social and visuo-spatial modalities. The ability to represent recursive structures has been hypothesized to increase the efficiency of hierarchical processing. Theoretical work together with recent empirical findings suggests that the ability to represent the self-similar structure of hierarchical recursive stimuli may be supported by internal neural representations that compress raw external information and increase efficiency. In order to explicitly test whether the representation of recursive hierarchies depends on internalized rules we compared the processing of visual hierarchies represented either as recursive or non-recursive, using task-free resting-state fMRI data. We aimed to evaluate the relationship between task-evoked functional networks induced by cognitive representations with the corresponding resting-state architecture. We observed increased connectivity within Default Mode Network (DMN) related brain areas during the representation of recursion, while non-recursive representations yielded increased connectivity within the Fronto-Parietal Control-Network. Our results suggest that human hierarchical information processing using recursion is supported by the DMN. In particular, the representation of recursion seems to constitute an internally-biased mode of information-processing that is mediated by both the core and dorsal-medial subsystems of the DMN. Compressed internal rule representations mediated by the DMN may help humans to represent and process hierarchical structures in complex environments by considerably reducing information processing load. PMID- 27780530 TI - Localization of transient immature hematopoietic cells to two distinct, potential niches in the developing mouse placenta. AB - Previous studies have shown that human and mouse placentas have hematopoietic potential during mid-gestation. In this investigation, we used histological and immunohistological approaches to visualize hematopoietic cells in mouse placenta between 9.5 and 12.5 days of gestation (gd), identifying their topography and niche. Putative hematopoietic foci were present on 10.5 and 11.5 gd but not 9.5 or 12.5 gd and was restricted to the placental labyrinth. Two major niches each with distinctive hematopoietic cell clusters were present. One type of hematopoietic cell cluster involved the chorioallantoic vasculature and fetal vessels near the chorionic plate. These clusters resembled the hematopoietic stem cells produced by large embryonic arteries such as aorta that persist in postnatal marrow. The other type of hematopoietic cell cluster identified was at the opposite side of labyrinth next to the junctional zone and was composed of erythropoietic foci. Our results suggest that mouse placenta not only produces hematopoietic stem/progenitor cells but also a second wave of primitive erythrocytes that may support a rapid, mid-pregnancy, fetal growth trajectory. Our data also point to a close relationships in the origins of hematopoietic and endothelial cells within placenta. PMID- 27780531 TI - CD9 suppresses human extravillous trophoblast invasion. AB - During human placentation, the extravillous trophoblast (EVT) invades the maternal decidua and reconstructs maternal spiral arteries. However, the precise mechanisms that control EVT behavior have not yet been elucidated in detail. CD9 has been reported to be a cell-motility-related molecule. Since we previously observed that CD9 was expressed on human EVT, we examined the possible involvement of CD9 in the invasion process of EVT. Placental and umbilical samples were obtained from patients who underwent legal abortions, normal delivery, or hysterectomy. The expression of CD9 at the implantation site and on isolated EVT from a villous explant culture, an EVT-derived immortalized cell line, Swan71, and HUVEC was examined by immunocytochemical staining, flow cytometry, and RT-PCR. The effects of anti-CD9 functional antibody (ALB6) on EVT and Swan71 cell invasion were further examined by matrigel invasion assay along with shRNAmir gene knockdown treatment. CD9 was highly expressed on EVT at the boundary region of EVT invasion and intravascular EVT. EVT and Swan71 cell invasions were promoted by ALB6 or shRNAmir treatment. CD9 expression on Swan71 cells was reduced under hypo-oxygenic conditions, while its expression was increased by the co-culture with HUVEC. These findings suggest that CD9 could attenuate EVT invasion under the influence of an oxygen environment and maternal endothelial cells, proposing that CD9 is a potential regulator of human placental formation. PMID- 27780532 TI - Intact feto-placental growth in microRNA-210 deficient mice. AB - MicroRNA-210 (miR-210) has been implicated in homeostatic adaptation during hypoxia. We hypothesized that miR-210 deficiency impacts feto-placental growth. As expected, mir-210 knockout (ko) mice exhibited markedly reduced placental miR 210 expression, compared to wild-type (wt) mice. Mating of mir-210 heterozygotes resulted in near Mendelian progeny distribution, with insignificant differences between wt and ko animals with regard to embryo or placental weight and gross morphology. Intriguingly, exposure of mice to non-severe hypoxia (O2 = 12%) between E11.5-E17.5 reduced placental miR-210 expression, with slight expression changes of some miR-210 target mRNAs. Thus, miR-210 is likely dispensable for feto-placental growth in normoxia or non-severe hypoxia. PMID- 27780533 TI - Activation of the IL-1beta/CXCL1/MMP-10 axis in chorioamnionitis induced by inactivated Group B Streptococcus. AB - Infection or inflammation during pregnancy is known to lead to maternal immune activation triggering a fetal inflammatory response syndrome associated with deleterious effects, such as brain injury and neurodevelopmental disabilities. Group B Streptococcus (GBS) - one of the most common bacterium colonizing pregnant women - can be responsible for chorioamnionitis. Given that interleukin (IL)-1beta has a major role in anti-GBS host defense, we hypothesized that IL 1beta-driven innate immune response is implicated in GBS-induced chorioamnionitis. Using a rat model of GBS-induced chorioamnionitis, this study showed that inflammatory response to this pathogen was associated with maternal and placental IL-1beta hyper expression. Following placental chemokine (C-X-C motif) ligand 1 (CXCL1) production, polymorphonuclear leukocytes (PMN) placental infiltration started at 24 h post-GBS exposure, and MMP-10 was released within these placentas. At 72 h, PMN infiltration extended to membranes and to membranes' arteries. This was associated with IL-1beta release within the fetus blood at 72 h. Such a GBS-associated inflammatory cascade might be deleterious for fetal organs. These results pave the way toward targeted placento-protective anti-inflammatory strategies against GBS-induced chorioamnionitis. PMID- 27780534 TI - Ex vivo culture of pre-placental tissues reveals that the allantois is required for maintained expression of Gcm1 and Tpbpalpha. AB - INTRODUCTION: Chorioallantoic fusion is essential for development of the labyrinth layer of the mouse placenta. However, events that occur after chorioallantoic attachment remain poorly described, partly due to difficulties of conducting ex vivo analysis of the placenta. Herein, we report conditions for ex vivo culture of the developing murine placenta. METHODS: Mesometrial halves of decidua containing pre-attachment chorions were cultured alone or with explants of allantoides from stage-matched controls and analyzed by confocal and immunofluorescence microscopy. Expression and levels of marker genes associated with specific placental cell types were measured by in situ hybridization and qRT PCR, respectively. RESULTS: After 24 h (hr) of co-culture, a mosaic pattern of eGFP+ and eGFP- cells were found when explants of pre-attachment chorions from eGFP+ embryos were co-cultured with stage-matched allantoides from eGFP- embryos or vice versa. In addition, proliferation increased in the allantoic region and folds formed on the chorionic plate. PECAM positive cells derived from the allantois were found in the chorionic region. Levels of the SynT-II marker, Gcm1, significantly increased at 24 h, although expression of Gcm1, was only found in explants co-cultured with an allantois at 12 h and 24 h. In addition, though levels of Tpbpalpha was not altered by co-culture with an allantois, Tpbpalpha was only detected in explants co-cultured with an allantois for 24 h. DISCUSSION: Our data show that chorioallantoic fusion and events associated with initiation of labyrinth layer formation can be modeled ex vivo, and reveal a previously unsuspected requirement of chorioallantoic fusion for Tpbpalpha expression. PMID- 27780535 TI - Etravirine inhibits ABCG2 drug transporter and affects transplacental passage of tenofovir disoproxil fumarate. AB - INTRODUCTION: All HIV positive pregnant women should receive combination antiretroviral therapy (cART) to prevent mother-to-child transmission (MTCT) of the virus. It has recently been shown that fetal exposure of nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and abacavir is decreased by placental ABC transporters p-glycoprotein (ABCB1) and BCRP (ABCG2). The aim of this study was to evaluate transporter-mediated drug-drug interactions (DDI) between etravirine (TMC125), a novel non-nucleoside reverse transcriptase inhibitor used in cART, and the NRTIs and to assess the relevance of such DDI for transplacental pharmacokinetics of TDF and abacavir. METHODS: In vitro accumulation assays and transport experiments on ABCB1 and ABCG2 overexpressing MDCKII monolayers were employed. Furthermore, the effect of etravirine on the transplacental passage of TDF and abacavir was assessed using in situ dually perfused rat placenta. RESULTS: We confirmed significant inhibition of ABCG2 but not ABCB1 by etravirine in hoechst accumulation assays. In transport studies on MDCKII-ABCG2 monolayers etravirine completely abolished the ABCG2-mediated transfer of [3H]-TDF. Similar effect was observed in [3H] abacavir albeit at markedly lower etravirine concentration. Using dually perfused rat placenta, etravirine co-administration resulted in reduced fetal-to-maternal passage of TDF but not abacavir. DISCUSSION: Etravirine is able to affect transplacental passage of TDF but not that of abacavir through interactions on ABCG2. These results should be considered when introducing etravirine into TDF containing cART in pregnancy. PMID- 27780536 TI - Placental disease and abnormal umbilical artery Doppler waveforms in trisomy 21 pregnancy: A case-control study. AB - INTRODUCTION: The objectives of this study were firstly to determine the proportion of placental pathology in fetuses affected by trisomy 21 (T21) using current pathological descriptive terminology and secondly to examine if a correlation existed between the finding of an abnormal umbilical artery Doppler (UAD) waveform, the presence of T21 and defined placental pathological categories. METHODS: This case-control study assessed singleton fetuses with karyotypically confirmed trisomy 21 where placental histopathology had been conducted from 2003 to 2015 inclusive, within a university tertiary obstetric centre. This was compared with unselected normal singleton control pregnancies matched within a week of gestation at delivery. Data included birthweight centiles and placental histopathology. Comparisons of Doppler findings across placental pathological categories were performed using statistical analysis. RESULTS: 104 cases were analysed; 52 cases of trisomy 21 and 52 controls. Fetal vascular malperfusion (48.1% vs. 5.8%, p = 0.001) and maturation defects (39.2% vs. 15.7%, p = 0.023) were more common in trisomy 21 placentas. Compared with controls, trisomy 21 fetuses were more likely to have shorter umbilical cords (p = 0.001) and had more UAD abnormalities. Amongst T21 pregnancies, umbilical artery Doppler abnormalities are associated with the presence of maternal vascular malperfusion. DISCUSSION: Fetal vascular malperfusion and maturation defects are more common in trisomy 21 placentas. Abnormal umbilical artery Doppler waveforms are more common in T21 and are associated with maternal vascular malperfusion. Placental disease may explain the increased rate of intrauterine death in T21. PMID- 27780537 TI - Bone mesenchymal stem cells improve pregnancy outcome by inducing maternal tolerance to the allogeneic fetus in abortion-prone matings in mouse. AB - INTRODUCTION: The successful pregnancy depends on maternal immune tolerance against the fetus. It has been reported that MSCs (mesenchymal stem cells) could play a regulatory role on immune cells such as CD4+T cells, macrophages and NK cells, but their effect on recurrent miscarriage is unknown. STUDY DESIGN: In a prospective study, the abortion-prone (CBA/J * DBA/2) H-2d * H-2k mice were utilized. Female CBA/J mice (8-10 weeks old) were injected with vehicle or MSCs via tail vein or uterine horns, and 14 days later, they were mated with DBA/2 males for the following experiments. RESULTS: Comparing with the control group, the embryo resorption rate in MSCs-horn injection group was dramatically decreased. MSCs were mainly located at the maternal-fetal interface, indicating that the reduction of resorption rate was due to MSCs' local effect. No matter which treatment was given, there was no significant difference in the levels of IL-4, IL-10, TNF-alpha and IFN-gamma in CD4+T cells and IL-10 and IL-12 in macrophages in spleens among each group. However, in contrast to other groups, the levels of IL-4 and IL-10 in CD4+T cells localized at the maternal-fetal interface in MSCs-horn injection group were dramatically increased, and TNF-alpha and IFN-gamma levels were notably decreased. While IL-10 expressed in macrophages was obviously higher than other groups and IL-12 in macrophages was significantly lower than other groups. CONCLUSIONS: The findings indicate that MSCs injection through uterine horns could decrease embryo resorption rate. PMID- 27780538 TI - Maternal plasma antioxidant status in the first trimester of pregnancy and development of obstetric complications. AB - INTRODUCTION: Oxidative stress is present in pregnancy complications. However, it is unknown if early maternal antioxidant status could influence later development of complications. The use of assisted reproduction techniques (ART) is rising due to the delay of first pregnancy and there is scarce information on its influence on oxidative balance. OBJECTIVE: To assess the possible relationship between maternal plasma antioxidant status in first trimester of gestation with later development of pregnancy complications, evaluating the influence of ART and nutrition. METHODS: Plasma from 98 healthy pregnant women was obtained at week 10, nutrition questionnaires filled and women were followed until delivery. We evaluated biomarkers of oxidative damage (carbonyls, malondialdehyde-MDA), antioxidants (thiols, reduced glutathione, phenolic compounds, catalase and superoxide dismutase activities) by spectrophotometry/fluorimetry and melatonin (ELISA). Antioxidant status score (Antiox-S) was calculated as the computation of antioxidants. Diet-antioxidants relationship was evaluated through multiple correspondence analysis. RESULTS: Melatonin and carbonyls exhibited a negative correlation. No difference in oxidative damage was found between groups, but Antiox-S was significantly lower in women who developed complications. No differences in oxidative damage or Antiox-S were found between ART and no-ART pregnancies. High consumption of foods of vegetable origin cluster with high plasma levels of phenolic compounds and with high Antiox-S. CONCLUSIONS: In early normal gestation, low plasma antioxidant status, assessed through a global score, associates with later development of pregnancy complications. Larger population studies could help to determine the value of Antiox-S as predictive tool and the relevance of nutrition on maternal antioxidant status. PMID- 27780540 TI - Endometrial androgen signaling and decidualization regulate trophoblast expansion and invasion in co-culture: A time-lapse study. AB - INTRODUCTION: To elucidate whether trophoblast expansion and invasion are modulated by androgen signaling in an in vitro co-culture model system with decidualizing endometrial stromal cells (ESCs). METHODS: We employed an in vitro co-culture model of early embryo implantation, consisting of human ESCs (EtsT499 cells) and spheroids generated by extravillous trophoblast (EVT) derived HTR8/Svneo. The ESCs were decidualized with 8-bromo-cAMP (8-br-cAMP) in the presence or absence of dihydrotestosterone (DHT) at various concentrations for 5 days before co-culture with EVT spheroids. Trophoblast expansion was monitored by fluorescent time-lapse imaging microscopy. ESCs motility was visualized by using CellTrackerTM Orange CMRA fluorescent probe. Apoptosis of ESCs was detected by CellEventTM Caspase-3/7(r) green detection reagent. Invasion assays were performed to quantify EVT invasion through a chemotaxis cell membrane. RESULTS: Expansion of EVT spheroids was significantly enhanced by decidualized compared to undifferentiated ESCs. This process was further stimulated if ESCs were first decidualized in the presence of DHT. In contrast to decidualized ESCs, undifferentiated cells actively migrated away from expanding EVT spheroids. Invasiveness of EVT toward decidualized ESCs was significantly attenuated in comparison to undifferentiated ESCs. DHT had no effect on EVT invasion. However, an inhibitor of intercellular gap junction communication significantly enhanced EVT invasion towards decidualized ESCs. CONCLUSIONS: These results indicate distinct roles for androgen signaling and gap junction formation in decidual cells in regulating trophoblast expansion and invasion. PMID- 27780539 TI - High levels of HtrA4 observed in preeclamptic circulation drastically alter endothelial gene expression and induce inflammation in human umbilical vein endothelial cells. AB - INTRODUCTION: Preeclampsia (PE) is a life-threatening pregnancy disorder characterized by wide-spread endothelial dysfunction. Placental factors circulating in the maternal blood are believed to cause endothelial dysfunction. Our previous study identified HtrA4 as a placenta-specific serine protease that is released into the maternal circulation and significantly increased in early onset PE. In this study, we examined the impact of HtrA4 on expression of endothelial genes related to vessel biology, using human umbilical vein endothelial cells (HUVECs) as a model. METHODS: HUVECs were treated with 0 or 3 MUg/ml HtrA4 (highest concentration seen in PE circulation) for 24 h and analysed by an endothelial cell biology PCR array containing 84 genes. HtrA4-induced changes were then validated by real-time RT-PCR and ELISA for time and dose dependency. RESULTS: High levels of HtrA4 significantly altered the expression of a range of genes related to inflammation, vaso-activity, angiogenesis, cell adhesion, platelet activation and coagulation. In particular, pro-inflammatory genes IL6, PTGS2 (COX2) and IL1B were significantly increased by HtrA4. IL6 protein in HUVEC media was also drastically increased. THBD, an anticoagulant factor reported to be increased in PE, was significantly up-regulated by HtrA4. In contrast, THBS1, which is involved in many regulatory processes of endothelial cell biology, was severely down-regulated by HtrA4. DISCUSSION: HtrA4 significantly increased the inflammatory responses of HUVECs, and altered their expression of a number of genes important for vessel biology. These data suggest that placenta-derived HtrA4 that is increased in PE circulation is a potential causal factor of endothelial dysfunction. PMID- 27780541 TI - ATF3 is a negative regulator of inflammation in human fetal membranes. AB - INTRODUCTION: Infection and inflammation stimulate pro-inflammatory cytokines, prostaglandins and matrix metalloproteinase (MMP)-9, which play a central role in myometrial contractions and rupture of fetal membranes. In human and mouse immune cells, activating transcription factor 3 (ATF3) is a negative regulator of inflammation. No studies have examined the role of ATF3 in human labour. METHODS: Primary amnion cells were used to determine the effect of interleukin (IL)-1beta and the bacterial product fibroblast-stimulating lipopeptide (fsl-1) on ATF3 expression, and the effect of ATF3 siRNA on pro-labour mediators. ATF3 expression was assessed in fetal membranes from non-labouring and labouring women at term and preterm, and after preterm pre-labour rupture of membranes (PPROM). RESULTS: IL-1beta and fsl-1 significantly increased ATF3 expression. Silencing ATF3 significantly increased IL-1beta- or fsl-1-induced expression of pro-inflammatory cytokines (TNF-alpha, IL-1alpha, IL-1beta, IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1 (MCP-1)); cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin PGF2alpha release; and MMP-9 expression. ATF3 expression was decreased in fetal membranes with term labour. There was no effect of preterm labour or PPROM on ATF3 expression. DISCUSSION: ATF3 is a negative regulator of inflammation in human fetal membranes; in primary amnion cells, ATF3 expression is induced by IL-1beta and fsl-1, and ATF3 silencing further exacerbates the inflammatory response when stimulated with these factors. Subsequently, ATF3 expression is decreased in fetal membranes after term labour and with preterm chorioamnionitis, conditions closely associated with inflammation and infection. Our data suggest that ATF3 may play a role in the terminal processes of human labour and delivery. PMID- 27780542 TI - Macrophage polarisation affects their regulation of trophoblast behaviour. AB - INTRODUCTION: During the first trimester of human pregnancy, fetally-derived extravillous trophoblast (EVT) invade into the uterine decidua and remodel the uterine spiral arteries to ensure that sufficient blood reaches the maternal fetal interface. Decidual macrophages have been implicated in the regulation of decidual remodelling, and aberrant activation of these immune cells is associated with pre-eclampsia. METHODS: The monocytic cell line THP-1 was activated to induce a classically- or alternatively-activated macrophage phenotype and the conditioned media was used to treat the EVT cell line SGHPL-4 in order to determine the effect of macrophage polarisation on trophoblast behaviour in vitro. SGHPL-4 cell functions were assessed using time-lapse microscopy, endothelial-like tube formation assays, and western blot. RESULTS: The polarisation state of the THP-1 cells was found to differentially alter the behaviour of trophoblast cells in-vitro with pro-inflammatory classically activated macrophage conditioned media significantly inhibiting trophoblast motility, impeding trophoblast tube formation, and inducing trophoblast expression of cleaved caspase 3, when compared to anti-inflammatory alternatively activated macrophage conditioned media. DISCUSSION: Macrophages can regulate trophoblast functions that are critical during decidual remodelling in early pregnancy. Importantly, there is differential regulation of trophoblast function in response to the polarisation state of these cells. Our studies indicate that the balance between a pro- and anti-inflammatory environment is important in regulating the cellular interactions at the maternal-fetal interface and that disturbances in this balance likely contribute to pregnancy disorders associated with poor trophoblast invasion and vessel remodelling. PMID- 27780543 TI - Discordance of cord insertions as a predictor of discordant fetal growth in monochorionic twins. AB - INTRODUCTION: The type of cord insertion within monochorionic twin pairs could be different. The purpose of study is to evaluate the association of different combinations of placental umbilical cord insertions with birth weight discordance in a large cohort of monochorionic twins. METHODS: All consecutive monochorionic placentas from either uncomplicated twin pregnancies or with fetal weight discordance examined and injected with color dye at our centers were included in this study (n = 374). Marginal or velamentous cord insertions were defined as abnormal. Placentas were categorized as concordant when the cord insertions of both fetuses were either normal-normal or abnormal-abnormal, and as discordant when they were normal-abnormal. Birth weight discordance was defined as a difference in birth weight of each twin >=25%. The association of different cord insertion combinations with birth weight discordance was analyzed. RESULTS: The rate of discordant cord insertions was 55% (204/374) in monochorionic twins. A highly significant association between discordant cord insertions and discordant birth weight was observed (p < 0.01). The odds ratios (OR) for birth weight discordance in the discordant cord insertion group compared with the concordant group were 2.3 (95% CI: 1.2-4.4) for the normal-marginal and 5.9 (95% CI: 3.8 10.4) for the normal-velamentous cord insertion subgroup. Discordant cord insertions are associated with the occurrence of unequal placental sharing (OR 4.3, 95%CI 2.7-6.9). DISCUSSION: Discordance of cord insertions is associated with discordance of birth weight and may therefore be an important indicator of adverse outcome in monochorionic twins. PMID- 27780545 TI - SMI for imaging of placental infarction. AB - Since superb Micro-vascular Imaging (SMI) is a new blood flow imaging technique that employs a unique algorithm to minimize motion artifacts, it can visualize low-velocity blood flow in small vessels. We demonstrate SMI imaging of the placental infarction in a case with fetal growth restriction, comparing a normal placenta on the same gestation. While SMI image in normal placenta clearly shows structures from the branching vessels to the peripheral villous trees in the cotyledons, they could not be seen in the case of fetal growth restriction. We think that the clinical value and future potential of SMI in placental evaluation have been clearly demonstrated. PMID- 27780546 TI - The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome. AB - OBJECTIVE: We aimed to compare obstetric outcome and placental-histopathology in pregnancies complicated by preeclampsia with severe features with and without HELLP syndrome. METHODS: Labor, maternal characteristics, neonatal outcome and placental histopathology of pregnancies complicated with severe preeclampsia during 2008-2015 were reviewed. Results were compared between those without signs of HELLP syndrome (severe preeclampsia group) and those with concomitant HELLP syndrome (HELLP group). Placental lesions were classified to maternal vascular lesions consistent with malperfusion, fetal vascular lesions consistent with fetal thrombo-occlusive disease, and inflammatory lesions. Small-for-gestational age (SGA) was defined as birth-weight <=10th% and <=5th%. Composite adverse neonatal outcome was defined as one or more early neonatal complications. RESULTS: Compared to the severe preeclampsia group (n = 223), the HELLP group (n = 64) was characterized by earlier gestational-age, 34.1 +/- 2.7 vs. 35.3 +/- 3.4 weeks, p = 0.010, higher rates of multiple pregnancies (p = 0.024), and thrombophilia (p = 0.028). Placentas in the HELLP group had higher rates of vascular and villous lesions consistent with maternal malperfusion (p = 0.023, p = 0.037 respectively). By multivariate logistic regression analysis models, vascular and villous lesions of maternal malperfusion were independently associated with HELLP syndrome (aOR 1.9, aOR 1.8, respectively). SGA was also more common in the HELLP group, both below the 10th percentile (p = 0.044) and the 5th percentile (p = 0.016). Composite adverse neonatal outcome did not differ between the groups. CONCLUSION: Severe preeclampsia and HELLP syndrome have similar placental histopathologic findings. However, HELLP syndrome is associated with higher rates of placental maternal vascular supply lesions and SGA suggesting that the two clinical presentations share a common etiopathogenesis, with higher placental dysfunction in HELLP syndrome. PMID- 27780547 TI - Pragmatism Over Politics. PMID- 27780544 TI - Isolation of human trophoblastic extracellular vesicles and characterization of their cargo and antiviral activity. AB - INTRODUCTION: Primary human trophoblasts release a repertoire of extracellular vesicles (EVs). Among them are nano-sized exosomes, which we found to suppress the replication of a wide range of diverse viruses. These exosomes contain trophoblastic microRNAs (miRNAs) that are expressed from the chromosome 19 miRNA cluster and exhibit antiviral properties. Here, we report our investigation of the cargo of placental EVs, focusing on the composition and the antiviral properties of exosomes, microvesicles, and apoptotic blebs. METHODS: We isolated EVs using ultracentrifugation and defined their purity using immunoblotting, electron microscopy, and nanoparticle tracking. We used liquid chromatography electrospray ionization-mass spectrometry, protein mass spectrometry, and miRNA TaqMan card PCR to examine the phospholipids, proteins, and miRNA cargo of trophoblastic EVs and an in vitro viral infection assay to assess the antiviral properties of EVs. RESULTS: We found that all three EV types contain a comparable repertoire of miRNA. Interestingly, trophoblastic exosomes harbor a protein and phospholipid profile that is distinct from that of microvesicles or apoptotic blebs. Functionally, trophoblastic exosomes exhibit the highest antiviral activity among the EVs. Consistently, plasma exosomes derived from pregnant women recapitulate the antiviral effect of trophoblastic exosomes derived from in vitro cultures of primary human trophoblasts. DISCUSSION: When compared to other trophoblastic EVs, exosomes exhibit a unique repertoire of proteins and phospholipids, but not miRNAs, and a potent viral activity. Our work suggests that human trophoblastic EVs may play a key role in maternal-placental-fetal communication. PMID- 27780548 TI - American Board of Vascular Surgery Directors. PMID- 27780549 TI - Commentaries. PMID- 27780550 TI - The American Board of Vascular Surgery and Independence of the Specialty. PMID- 27780551 TI - Assessment of nasal obstruction with rhinomanometry and subjective scales and outcomes of surgical and medical treatment. AB - INTRODUCTION: Prospective study of patients with nasal obstruction (NO) in order to measure therapeutic success by anterior active rhinomanometry (AAR), Nasal Obstruction Symptom Evaluation (NOSE) scale and Visual Analogue Scale (VAS) and to establish the correlation between these tests. METHODS: Patients with NO, on whom we performed an AAR, NOSE and VAS scales at baseline and after medical treatment (topical nasal steroid) or surgery (septoplasty, turbinoplasty or septoplasty and turbinoplasty). The nasal flow obtained by the AAR and the score of both subjective scales (NOSE and VAS) were compared and analyzed. RESULTS: A total of 102 patients were included in the study. Surgical treatment resulted in statistically significant differences with the AAR and the subjective scales. While in patients with medical treatment there was an increase in the AAR nasal flow but without statistical significance (P=.1363). The correlation between the AAR, the NOSE and VAS scales was measured finding a strong correlation between the NOSE and VAS scales only (r=.83327). CONCLUSIONS: The patients with NO treated surgically have better results when these are evaluated by AAR or with subjective scales. There is no significant correlation between AAR, NOSE and VAS scales, this is considered to be because the AAR and subjective scales are complementary and measure different aspects of NO. The AAR and subjective scales are useful tools to be used together for the follow up of patients with NO. PMID- 27780554 TI - Reply. PMID- 27780553 TI - Usefulness of Fragmented QRS Complexes in Patients With Congenital Heart Disease to Predict Ventricular Tachyarrhythmias. AB - Fragmented QRS complexes (fQRS) on 12-lead electrocardiogram are known predictors of ventricular tachyarrhythmia (VTA) in patients with coronary artery disease. There is limited knowledge of the clinical implications of fQRS in patients with congenital heart defects (CHD). Aims of this study were to examine (1) the occurrence of fQRS in patients with various types of CHD and (2) whether fQRS is associated with development of VTA. This study was designed as retrospective case control study. Patients with CHD with VTA were included and matched with control patients of the same age, gender, and CHD type. Clinical data and fQRS were analyzed and compared. The initial VTA episode developed in 139 patients with CHD at a mean age of 39 +/- 14 years. Compared with controls (n = 219, age 38 +/- 13 years), QRS duration was longer in patients with VTA (110 vs 100 ms; p <0.01). Furthermore, fQRS was more frequently observed in patients with VTA in the last electrocardiogram before VTA (n = 73 [53%] vs n = 67 [31%]; p <0.001), especially in patients with sustained VTA (64%). Multiple conditional logistic regression demonstrated more fQRS (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5 to 5.8; p = 0.002), nonsystemic ventricular dysfunction (OR 5.1, 95% CI 2.1 to 12.4; p <0.001), and more prolonged QRS complexes (OR 2.8, 95% CI 1.3 to 6.2; p = 0.011) in patients with VTA. Therefore, the presence of fQRS on electrocardiogram may be a useful tool in daily clinical practice to identify patients at risk for developing VTA in patients with CHD, in addition to known predictors of VTA. PMID- 27780552 TI - Relation of Erectile Dysfunction to Subclinical Myocardial Injury. AB - The circulating concentration of cardiac troponin I (cTnI) is an index of subclinical myocardial injury in several patient populations and in the general population. Erectile dysfunction is associated with greater risk for cardiovascular events, but the association with subclinical myocardial injury is not known. We aimed to test the hypothesis that the presence and severity of erectile dysfunction is associated with greater concentrations of cTnI in the general population. The presence and severity of erectile dysfunction was assessed by administering the International Index of Erectile Function 5 (IIEF-5) questionnaire to 260 men aged 30 to 65 years recruited from a population-based study. Concentrations of cTnI were determined by a high-sensitivity (hs) assay. Hs-cTnI levels were significantly higher in subjects with than in those without erectile dysfunction (median 2.9 vs 1.6 ng/l; p <0.001). Men with erectile dysfunction (i.e., IIEF-5 sum score <22) were also significantly older; had a higher systolic blood pressure, lower estimated glomerular filtration rate, higher augmentation index and N-terminal pro-B-type natriuretic peptide; and had a higher prevalence of hypertension, diabetes mellitus, and previous coronary artery disease than subjects without erectile dysfunction. These covariates were adjusted for in a multivariate linear regression model, yet the IIEF-5 sum score remained significantly negatively associated with the hs-cTnI concentration (standardized beta -0.206; p <0.001). In conclusion, the presence and severity of erectile dysfunction is associated with circulating concentrations of hs-cTnI, indicating subclinical myocardial injury independently of cardiovascular risk factors, endothelial dysfunction and heart failure biomarkers. PMID- 27780555 TI - Relation of Left Atrial Size to Atrial Fibrillation in Patients Aged <=22 Years. AB - Left atrial (LA) dilation has been shown to be associated with atrial fibrillation (AF) in the adult population, with some studies indicating that larger LAs are more prone to AF recurrence. The relation of LA size to AF in the pediatric and young adult population has not been investigated. In this study, all pediatric patients (aged <=22 years) who presented to Boston Children's Hospital from January 2002 to December 2012 with AF were reviewed. Patients with significant congenital heart disease, cardiomyopathies, proven channelopathies, previous cardiac surgery, end-stage renal disease, or severe lung disease/cystic fibrosis were excluded. LA measurements were taken using the echocardiogram performed at the initial presentation. In total, 48 patients with AF were identified. The median age at presentation was 17.1 years (range 3.7 to 22.9 years); 38 patients (79%) were men. Eleven patients (23%) had at least 1 recurrence of their AF. There was no difference in body mass index, prevalence of systemic hypertension, alcohol, stimulant, or illicit drug use between those who had an isolated episode of AF and those who had a recurrence. There was no significant difference in LA dimension Z-scores between groups, with only 2 patients (1 isolated AF, 1 recurrent AF) having Z-scores >2. In conclusion, AF in the young without underlying heart disease is not associated with LA dilation. PMID- 27780556 TI - Impact of Iron Deficiency on Response to and Remodeling After Cardiac Resynchronization Therapy. AB - Iron deficiency is prevalent in heart failure with reduced ejection fraction and relates to symptomatic status, readmission, and all-cause mortality. The relation between iron status and response to cardiac resynchronization therapy (CRT) remains insufficiently elucidated. This study assesses the impact of iron deficiency on clinical response and reverse cardiac remodeling and outcome after CRT. Baseline characteristics, change in New York Heart Association functional class, reverse cardiac remodeling on echocardiography, and clinical outcome (i.e., all-cause mortality and heart failure readmissions) were retrospectively evaluated in consecutive CRT patients who had full iron status and complete blood count available at implantation, implanted at a single tertiary care center with identical dedicated multidisciplinary CRT follow-up from October 2008 to August 2015. A total of 541 patients were included with mean follow-up of 38 +/- 22 months. Prevalence of iron deficiency was 56% at implantation. Patients with iron deficiency exhibited less symptomatic improvement 6 months after implantation (p value <0.001). In addition, both the decrease in left ventricular end-diastolic diameter (-3.1 vs -6.2 mm; p value = 0.011) and improvement in ejection fraction (+11% vs +15%, p value = 0.001) were significantly lower in patients with iron deficiency. Iron deficiency was significantly associated with an increased risk for heart failure admission or all-cause mortality (adjusted hazard ratio 1.718, 95% confidence interval 1.178 to 2.506), irrespectively of the presence of anemia (Hemoglobin <12 g/dl in women and <13 g/dl in men). In conclusion, iron deficiency is prevalent and affects both clinical response and reverse cardiac remodeling after CRT implantation. Moreover, it is a powerful predictor of adverse clinical outcomes in CRT. PMID- 27780557 TI - Benefits of Heart Rate Slowing With Ivabradine in Patients With Systolic Heart Failure and Coronary Artery Disease. AB - Heart rate (HR) is a risk factor in patients with chronic systolic heart failure (HF) that, when reduced, provides outcome benefits. It is also a target for angina pectoris prevention and a risk marker in chronic coronary artery disease without HF. HR can be reduced by drugs; however, among those used clinically, only ivabradine reduces HR directly in the sinoatrial nodal cells without other known effects on the cardiovascular system. This review provides current information regarding the safety and efficacy of HR reduction with ivabradine in clinical studies involving >36,000 patients with chronic stable coronary artery disease and >6,500 patients with systolic HF. The largest trials, Morbidity Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Disease and Left Ventricular Dysfunction and Study Assessing the Morbidity Mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease, showed no effect on outcomes. The Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial, a randomized controlled trial in >6,500 patients with HF, revealed marked and significant HR-mediated reduction in cardiovascular mortality or HF hospitalizations while improving quality of life and left ventricular mechanical function after treatment with ivabradine. The adverse effects of ivabradine predominantly included bradycardia and atrial fibrillation (both uncommon) and ocular flashing scotomata (phosphenes) but otherwise were similar to placebo. In conclusion, ivabradine improves outcomes in patients with systolic HF; rates of overall adverse events are similar to placebo. PMID- 27780558 TI - Clinical predictors of early acute respiratory distress syndrome in trauma patients. AB - BACKGROUND: The objectives of this study were to examine the incidence and severity of early acute respiratory distress syndrome (ARDS) according to the Berlin Definition and to identify risk factors associated with the development of early post-traumatic ARDS. METHODS: A 2.5-year retrospective database of adult trauma patients who required mechanical ventilation for greater than 48 hours at a level 1 trauma center was analyzed for variables predictive of early (<48 hours after injury), mild, moderate, and severe ARDS and in-hospital mortality. RESULTS: Of 305 patients, 59 (19.3%) developed early ARDS: mild, 27 (45.8%); moderate, 26 (44.1%); and severe, 6 (10.1%). Performance of an emergent thoracotomy, blunt mechanism, and fresh frozen plasma administration were independently associated with the development of early ARDS. ARDS was not predictive of mortality. CONCLUSIONS: Trauma patients with blunt mechanism, who receive fresh frozen plasma, or undergo thoracotomy, are at risk of developing early ARDS. PMID- 27780559 TI - Routine intraoperative cholangiography is unnecessary in patients with mild gallstone pancreatitis and normalizing bilirubin levels. AB - BACKGROUND: The benefit of intraoperative cholangiography (IOC) is controversial in patients with gallstone pancreatitis whose bilirubin levels are normalizing. IOC with subsequent endoscopic retrograde cholangiopancreatography may lengthen duration of surgery and length of stay, whereas failure to clear the common bile duct may result in recurrent pancreatitis. METHODS: We performed a 6-year retrospective cohort analysis of consecutive adult patients with mild gallstone pancreatitis undergoing same-admission cholecystectomy at 2 university-affiliated medical centers. Institution A routinely performed IOC, whereas institution B did not. The primary outcome was readmission within 30 days for recurrent pancreatitis. RESULTS: Of 520 patients evaluated, 246 (47%) were managed at institution A (routine IOC) and 274 (53%) were managed at institution B (restricted IOC). Patients at institution B had a shorter duration of surgery (1.0 vs 1.6 hours, P < .001), shorter length of stay (4 vs 5 days, P < .001), and fewer postoperative endoscopic retrograde cholangiopancreatographies performed (1.8% vs 21%, P < .001), without a difference in readmissions (1.5% vs 0%, P = .12). CONCLUSIONS: Routine IOC is not necessary in the setting of mild gallstone pancreatitis with normalizing bilirubin values. PMID- 27780560 TI - Silica nanoparticle based techniques for extraction, detection, and degradation of pesticides. AB - Silica nanoparticles (SiNPs) find applications in the fields of drug delivery, catalysis, immobilization and sensing. Their synthesis can be mediated in a facile manner and they display broad range compatibility and stability. Their existence in the form of spheres, wires and sheets renders them suitable for varied purposes. This review summarizes the use of silica nanostructures in developing techniques for extraction, detection and degradation of pesticides. Silica nanostructures on account of their sorbent properties, porous nature and increased surface area allow effective extraction of pesticides. They can be modified (with ionic liquids, silanes or amines), coated with molecularly imprinted polymers or magnetized to improve the extraction of pesticides. Moreover, they can be altered to increase their sensitivity and stability. In addition to the analysis of pesticides by sophisticated techniques such as High Performance Liquid Chromatography or Gas chromatography, silica nanoparticles related simple detection methods are also proving to be effective. Electrochemical and optical detection based on enzymes (acetylcholinesterase and organophosphate hydrolase) or antibodies have been developed. Pesticide sensors dependent on fluorescence, chemiluminescence or Surface Enhanced Raman Spectroscopic responses are also SiNP based. Moreover, degradative enzymes (organophosphate hydrolases, carboxyesterases and laccases) and bacterial cells that produce recombinant enzymes have been immobilized on SiNPs for mediating pesticide degradation. After immobilization, these systems show increased stability and improved degradation. SiNP are significant in developing systems for effective extraction, detection and degradation of pesticides. SiNPs on account of their chemically inert nature and amenability to surface modifications makes them popular tools for fabricating devices for 'on-site' applications. PMID- 27780561 TI - Minimally Invasive Extracorporeal Circulation Circuit Is Not Inferior to Off-Pump Coronary Artery Bypass Grafting: Meta-Analysis Using the Bayesian Method. AB - The pathophysiologic side effects of cardiopulmonary bypass have already been identified. Minimally invasive extracorporeal circulation technologies (MiECT) and off-pump coronary artery bypass graft surgery (OPCABG) aim to reduce these problems. This meta-analysis provides a comparison of MiECT and OPCABG in randomized and observational studies. A fully probabilistic, Bayesian approach of primary and secondary endpoints was conducted. MiECT does not give inferior results when compared with OPCABG. However, there is a trend to borderline significantly higher blood loss in this group in randomized controlled trials. The question whether MiECT is equivalent to OPCABG can be answered with the affirmative, but long-term follow-up data are needed to detect any advantage over time. PMID- 27780562 TI - Heart, Lung and Circulation Evolves: A Fond Farewell to Our 25th Anniversary Year and a Warm Welcome to New Initiatives. PMID- 27780563 TI - Unusual Cause of Persistent Chest Pain. PMID- 27780564 TI - Corrigendum to "GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease" [Mol. Genet. Metab. 111 (2014) 393-398]. PMID- 27780568 TI - Response to Letter of the Editor by Tomoyuki Kawada Regarding the Article "Contributory Factors to Caregiver Burden in Parkinson Disease" by Grun et al. PMID- 27780567 TI - Impacts of High-Protein Oral Nutritional Supplements Among Malnourished Men and Women with Sarcopenia: A Multicenter, Randomized, Double-Blinded, Controlled Trial. AB - BACKGROUND: Recent evidence suggests that nutritional interventions may improve muscle outcomes in malnutrition and sarcopenia. OBJECTIVES: We evaluated the effects of 2 high-quality oral nutritional supplements (ONS) differing in amount and type of key nutrients in older adult men and women. DESIGN: A multicenter, randomized, double-blinded, controlled clinical trial. PARTICIPANTS: Malnourished and sarcopenic men and women, 65 years and older (n = 330). INTERVENTION: A 24 week intervention period with 2 energy-rich (330 kcal) ONS treatment groups: Control ONS (CONS, 14 g protein; 147 IU vitamin D3) versus Experimental ONS (EONS, 20 g protein; 499 IU vitamin D3; 1.5 g CaHMB) taken twice daily. Both ONS also contained other vitamins, minerals, and nutrients in varying amounts. MEASUREMENTS: Isokinetic peak torque (PT, Nm) leg strength, grip strength (kg), and gait speed (m.s-1) were assessed at baseline and 12 and 24 weeks. Left and right leg muscle mass (LMM, kg) were assessed by dual-energy x-ray absorptiometry (DXA). Muscle quality (MQ) was leg strength expressed relative to the tested LMM (Nm.kg-1). Subgroup analyses were performed: severe sarcopenia (low skeletal mass index, low grip strength [<30 kg men; <20 kg women], low gait speed [<0.8 m.s-1]) and mild-moderate sarcopenia (low skeletal mass index, normal gait speed, or normal grip strength). RESULTS: Both ONS groups (EONS and CONS) improved PT, MQ, grip strength, and gait speed from baseline with no treatment differences. Those with severe sarcopenia (44%) exhibited lower baseline PT and MQ, with no differences in strength improvements between treatments. However, participants with mild-moderate sarcopenia exhibited higher baseline PT and MQ, with differences in strength improvements at 12 weeks (EONS > CONS, P = .032) in those with normal grip strength. There were no treatment differences based on sarcopenic severity for either grip strength or gait speed. CONCLUSION: ONS improved strength outcomes in malnourished older adults with sarcopenia. In those with mild-moderate sarcopenia, but not severe sarcopenia, consumption of the EONS improved leg muscle strength and quality compared with the standard CONS. PMID- 27780569 TI - Metformin Use and Cognitive Dysfunction Among Patients with Diabetes Mellitus. PMID- 27780570 TI - Polypharmacy and Medication Regimen Complexity as Risk Factors for Hospitalization Among Residents of Long-Term Care Facilities: A Prospective Cohort Study. AB - OBJECTIVES: To investigate the association between polypharmacy and medication regimen complexity with time to first hospitalization, number of hospitalizations, and number of hospital days over a 12-month period. DESIGN: A 12-month prospective cohort study. PARTICIPANTS AND SETTING: A total of 383 residents of 6 Australian long-term care facilities (LTCFs). MEASUREMENTS: The primary exposures were polypharmacy (>=9 regular medications) and the 65-item Medication Regimen Complexity Index (MRCI). Cox proportional hazards regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between polypharmacy and MRCI with time to first hospitalization. Poisson regression was used to compute incident rate ratios (IRR) and 95% CIs for the association between polypharmacy and MRCI with number of hospitalizations and number of hospital days. Models were adjusted for age, sex, length of stay in LTCF, comorbidities, activities of daily living, and dementia severity. RESULTS: There were 0.56 (95% CI 0.49-0.65) hospitalizations per person-year and 4.52 (95% CI 4.31-4.76) hospital days per person-year. In adjusted analyses, polypharmacy was associated with time to first hospitalization (HR 1.84; 95% CI 1.21-2.79), number of hospitalizations (IRR 1.51; 95% CI 1.09-2.10), and hospital days per person-year (IRR 1.39; 95% CI 1.24-1.56). Similarly, in adjusted analyses a 10 unit increase in MRCI was associated with time to first hospitalization (HR 1.17; 95% CI 1.06-1.29), number of hospitalizations (IRR 1.15; 95% CI 1.06-1.24), and hospital days per person-year (IRR 1.19; 95% CI 1.16-1.23). CONCLUSIONS: Polypharmacy and medication regimen complexity are associated with hospitalizations from LTCFs. This highlights the importance of regular medication review for residents of LTCFs and the need for further research into the risk-to benefit ratio of prescribing in this setting. PMID- 27780571 TI - The mTOR Conundrum: Essential for Muscle Function, but Dangerous for Survival. PMID- 27780572 TI - Determining Nurse Aide Staffing Requirements to Provide Care Based on Resident Workload: A Discrete Event Simulation Model. AB - BACKGROUND: Nursing aides provide most of the labor-intensive activities of daily living (ADL) care to nursing home (NH) residents. Currently, most NHs do not determine nurse aide staffing requirements based on the time to provide ADL care for their unique resident population. The lack of an objective method to determine nurse aide staffing requirements suggests that many NHs could be understaffed in their capacity to provide consistent ADL care to all residents in need. Discrete event simulation (DES) mathematically models key work parameters (eg, time to provide an episode of care and available staff) to predict the ability of the work setting to provide care over time and offers an objective method to determine nurse aide staffing needs in NHs. OBJECTIVES: This study had 2 primary objectives: (1) to describe the relationship between ADL workload and the level of nurse aide staffing reported by NHs; and, (2) to use a DES model to determine the relationship between ADL workload and nurse aide staffing necessary for consistent, timely ADL care. DESIGN: Minimum Data Set data related to the level of dependency on staff for ADL care for residents in over 13,500 NHs nationwide were converted into 7 workload categories that captured 98% of all residents. In addition, data related to the time to provide care for the ADLs within each workload category was used to calculate a workload score for each facility. The correlation between workload and reported nurse aide staffing levels was calculated to determine the association between staffing reported by NHs and workload. Simulations to project staffing requirements necessary to provide ADL care were then conducted for 65 different workload scenarios, which included 13 different nurse aide staffing levels (ranging from 1.6 to 4.0 total hours per resident day) and 5 different workload percentiles (ranging from the 5th to the 95th percentile). The purpose of the simulation model was to determine the staffing necessary to provide care within each workload percentile based on resident ADL care needs and compare the simulated staffing projections to the NH reported staffing levels. MEASURES: The percentage of scheduled care time that was omitted was estimated by the simulation model for each of the 65 workload scenarios using optimistic assumptions about staff productivity and efficiency. RESULTS: There was a low correlation between ADL workload and reported nurse aide staffing (Pearson = .11; P < .01), which suggests that most of the 13,500 NHs were not using ADL acuity to determine nurse aide staffing levels. Based on the DES model, the nurse aide staffing required for ADL care that would result in a rate of care omissions below 10% ranged from 2.8 hours/resident/day for NHs with a low workload (5th percentile) to 3.6 hours/resident/day for NHs with a high workload (95th percentile). In contrast, NHs reported staffing levels that ranged from an average of 2.3 to 2.5 hours/resident/day across all 5 workload percentiles. Higher workload NHs had the largest discrepancies between reported and predicted nurse aide staffing levels. CONCLUSIONS: The average nurse aide staffing levels reported by NHs falls below the level of staffing predicted as necessary to provide consistent ADL care to all residents in need. DES methodology can be used to determine nurse aide staffing requirements to provide ADL care and simulate management interventions to improve care efficiency and quality. PMID- 27780573 TI - Clinical Update on Nursing Home Medicine: 2016. AB - This is the tenth clinical update. It covers chronic kidney disease, dementia, hypotension, polypharmacy, rapid geriatric assessment, and transitional care. PMID- 27780575 TI - Expression Kinetics of RANTES and MCP-1 in the Brain of Deer Mice (Peromyscus maniculatus) Infected with Vesicular Stomatitis New Jersey Virus. AB - The vesicular stomatitis virus (VSV) causes encephalitis in mice when inoculated intranasally. The deer mouse (Peromyscus maniculatus), a native New World rodent, is also susceptible to VSV infection and develops similar central nervous system (CNS) lesions to those observed in other rodent species. Chemokines, such as regulated on activation, normal T-cell expressed and secreted (RANTES; CCL-5) and monocyte chemoattractant protein (MCP)-1 (CCL-2), which are important for chemotaxis and activation of inflammatory cells, are expressed during the course of VSV encephalitis. However, the role of CNS resident cells in chemokine expression is poorly characterized. Here, we show that during vesicular stomatitis New Jersey virus (VSNJV) encephalitis in deer mice, RANTES and MCP-1 are expressed only in the olfactory bulb (OB), where the virus was localized. This chemokine expression was followed by the influx of inflammatory cells to the OB later in the course of acute disease. Neurons, astrocytes and microglia expressed RANTES, while MCP-1 was expressed by neurons and astrocytes. Although astrocytes and microglia responded to VSNJV infection by expressing chemokines, neurons were the cell type that was predominantly infected. Therefore, infected neurons may have a critical role in initiating an immune response in the OB. The signalling between neurons and other CNS resident cells is most likely the mechanism by which astrocytes and microglia are activated during the course of VSV encephalitis. PMID- 27780574 TI - Study of 5 Volatile Organic Compounds in Exhaled Breath in Chronic Obstructive Pulmonary Disease. AB - INTRODUCTION: A major risk factor for chronic obstructive pulmonary disease (COPD) is tobacco smoke, which generates oxidative stress in airways, resulting in the production of volatile organic compounds (VOC). The purpose of this study was to identify VOCs in exhaled breath and to determine their possible use as disease biomarkers. METHOD: Exhaled breath from 100 healthy volunteers, divided into 3groups (never smokers, former smokers and active smokers) and exhaled breath from 57 COPD patients were analyzed. Samples were collected using BioVOC(r) devices and transferred to universal desorption tubes. Compounds were analyzed by thermal desorption, gas chromatography and mass spectrometry. VOCs analyzed were linear aldehydesand carboxylic acids. RESULTS: The COPD group and healthy controls (never smokers and former smokers) showed statistically significant differences in hexanal concentrations, and never smokers and the COPD group showed statistically significant differences in nonanal concentrations. CONCLUSIONS: Hexanal discriminates between COPD patients and healthy non-smoking controls. Nonanal discriminates between smokers and former smokers (with and without COPD) and never smokers. PMID- 27780577 TI - Bendamustine-Induced Nephrogenic Diabetes Insipidus in a Patient With AL Amyloidosis. AB - Nephrogenic diabetes insipidus is a condition characterized by polyuria with dilute urine due to the inability of the principal cells of the renal collecting ducts to respond to antidiuretic hormone and concentrate urine. Nephrogenic diabetes insipidus can be drug induced, and several chemotherapeutic agents have been reported to cause it. Bendamustine is a traditional chemotherapeutic agent being studied for treatment for relapsed systemic AL amyloidosis. We report a case of a 59-year-old man with AL amyloidosis who developed partial nephrogenic diabetes insipidus after receiving bendamustine for treatment of AL amyloidosis. The nephrogenic diabetes insipidus responded well to sodium restriction, hydrochlorothiazide, and desmopressin treatment, allowing the patient to receive subsequent bendamustine cycles without polyuria. Nephrogenic diabetes insipidus resolved shortly after completion of bendamustine therapy. PMID- 27780576 TI - Bile Cast Nephropathy Caused by Obstructive Cholestasis. AB - Acute kidney injury (AKI) is a major complication in patients with liver disease. Although hepatorenal syndrome is frequently involved, bile cast nephropathy, characterized by tubular bile cast formation, has been scarcely described in the setting of severe liver failure. Few renal histology studies are available in these patients. We describe a case of bile cast nephropathy in a patient with obstructive cholestasis caused by stones in the common bile duct. The kidney biopsy confirmed this diagnosis, with several green casts in tubular lumens, tubular injury, and bilirubin composition of the tubular casts with Hall stain. The patient had no confounding cause of kidney failure, and complete kidney recovery followed removal of the bile duct obstruction. This case shows that severe cholestasis is sufficient to cause AKI, and that AKI can be reversible after treatment of the biliary obstruction. PMID- 27780578 TI - Moderate hypothermia at warmer temperatures is safe in elective proximal and total arch surgery: Results in 665 patients. AB - OBJECTIVE: To evaluate adverse outcomes after elective aortic arch surgery performed at higher or lower temperatures (24.0 degrees C-28.0 degrees C vs 20.1 degrees C-23.9 degrees C) within the wide range of moderate hypothermia. METHODS: Over a 9-year period, a total of 665 patients underwent elective proximal (n = 479) or total (n = 186) arch replacement with moderate hypothermia and antegrade cerebral perfusion. Circulatory arrest was initiated at an actual temperature of 20.1 degrees C to 23.9 degrees C in the lower-temperature group (n = 334; 223 proximal, 111 total) and at 24.0 degrees C to 28.0 degrees C in the higher temperature group (n = 331; 256 proximal, 75 total). Composite adverse outcome was defined as operative mortality or persistent neurologic event or persistent hemodialysis at discharge. Multivariate logistic regression analysis was used to model adverse outcome. In addition to the actual temperature, a new, balanced variable, "predicted temperature," was analyzed to eliminate surgeon bias. We used this variable in a propensity score-matching analysis to validate the multivariate analysis results. RESULTS: A composite adverse outcome occurred in 7.2% of cases. Operative mortality was 5.1%. The rate of postoperative persistent neurologic deficits was 2.4%. No significant differences were found between the lower- and higher-predicted temperature groups within the moderate hypothermia range in the propensity score-matching analysis. The higher-actual temperature group had a lower rate of ventilator support at >48 hours (P = .036) and less need for tracheostomy (P = .023). Packed red blood cell transfusion and previous coronary artery bypass independently predicted composite adverse outcome (P = .0053 and .0002, respectively), operative mortality (P = .0051 and .0041), and postoperative stroke (P = .045 and .048). Cardiopulmonary bypass time independently predicted composite outcome (P = .0005), operative mortality (P < .0001), ventilatory support for >48 hours (P < .0001), and renal dysfunction (P = .0005). CONCLUSIONS: In elective proximal or total arch surgery, higher temperatures (>=24.0 degrees C-28.0 degrees C) within the wide range of moderate hypothermia (20.1 degrees C-28 degrees C) are safe and, compared with colder temperatures, not associated with significantly different rates of composite and adverse outcomes. PMID- 27780579 TI - Intra-aortic balloon pumps and continuous flow left ventricular assist devices: Don't let balloon pumps overstay their welcome. PMID- 27780580 TI - Antibacterial Efficacy of a New Sonic Irrigation Device for Root Canal Disinfection. AB - INTRODUCTION: Passive ultrasonic irrigation (PUI) is the most widespread method used to activate irrigation solutions. Concerns have been raised that PUI is less effective in curved root canals and is not passive at all. Our aim was to compare a novel passive sonic irrigation (PSI) device (6000 Hz) with PUI and manual irrigation (MI) with respect to their efficiency in removing different endodontic microorganisms from curved and straight root canals. METHODS: We performed 2 experiments as follows. In a 3-day infection model, we included 8 groups of single or dual microbial species that were rinsed with 0.9% sodium chloride using PSI, PUI, or MI. Colony-forming units (CFUs) were counted after incubation, and log10 transformations were performed for statistical comparisons. In a 21-d infection model, we tested the same irrigation protocols on 4 groups of microorganisms and used 1.5% sodium hypochlorite as an irrigant. Infection control samples were taken at day 0, 3, 5, and 7 after treatment and were subsequently reincubated. RESULTS: Using sodium chloride as an irrigant, the amount of reduction in CFUs compared with the negative control was approximately 3 log10 units for PSI at 6000 Hz, 2 log10 units for PUI, and 1 log10 unit for MI. PSI reduced the microorganism CFUs significantly better than PUI. Using sodium hypochlorite led to a significant reduction in microorganism CFUs even with MI. After 3 days, compared with MI, microorganism regrowth significantly reduced after PSI and PUI treatment, but in these groups, in at least half of the samples, microorganisms were detectable after 7 days. CONCLUSIONS: PSI at 6000 Hz might be at least equal to PUI with respect to reduction of the microbial load in curved and straight root canals. PMID- 27780581 TI - Preventable fine sediment export from the Burdekin River catchment reduces coastal seagrass abundance and increases dugong mortality within the Townsville region of the Great Barrier Reef, Australia. AB - The coastal seagrass meadows in the Townsville region of the Great Barrier Reef are crucial seagrass foraging habitat for endangered dugong populations. Deteriorating coastal water quality and in situ light levels reduce the extent of these meadows, particularly in years with significant terrestrial runoff from the nearby Burdekin River catchment. However, uncertainty surrounds the impact of variable seagrass abundance on dugong carrying capacity. Here, I demonstrate that a power-law relationship with exponent value of -1 (R2~0.87) links mortality data with predicted changes in annual above ground seagrass biomass. This relationship indicates that the dugong carrying capacity of the region is tightly coupled to the biomass of seagrass available for metabolism. Thus, mortality rates increase precipitously following large flood events with a response lag of <12-months. The management implications of this result are discussed in terms of climate scenarios that indicate an increased future likelihood of extreme flood events. PMID- 27780582 TI - External nutrient loading from land, sea and atmosphere to all 656 Swedish coastal water bodies. AB - Identifying the main sources of nutrient loading is a key factor for efficient mitigation of eutrophication. This study has investigated the pathways of external nutrient loading to 656 coastal water bodies along the entire Swedish coastline. The studied water bodies have been delineated to meet requirements in the European Union's Water Framework Directive, and recent status assessments have shown that 57% of them fail to attain good or high ecological status with respect to nutrients. The analysis in the study was performed on data from mass balance based nutrient budgets computed using the modelling framework Vattenwebb. The external nutrient contribution from the sea to the water bodies was highly variable, ranging from about 1% to nearly 100%, but the median contribution was >99% of the total external loading regarding both nitrogen and phosphorus. External loading from the atmosphere and local catchment area played a minor role in general. However, 45 coastal water bodies received >25% of the external nitrogen and phosphorus from their catchments. Loading from land typically peaked in April following ice-break and snow melting and was comparatively low during summer. The results indicate that for many eutrophicated Swedish coastal water bodies, nutrient abatement is likely to be optimally effective when potential measures in all of the catchment area of the concerned sea basin are considered. Local-scale mitigation in single water bodies will likely be locally effective only in the small proportion of areas where water and thereby also nutrient input from the catchment is high compared to the influx from the sea. Future studies should include nutrient reduction scenarios in order to refine these conclusions and to identify relevant spatial scales for coastal eutrophication mitigation measures from a water body perspective. PMID- 27780583 TI - Development of an evidence-based decision pathway for vestibular schwannoma treatment options. AB - OBJECTIVE: To integrate multiple sources of clinical information with patient feedback to build evidence-based decision support model to facilitate treatment selection for patients suffering from vestibular schwannomas (VS). METHODS: This was a mixed methods study utilizing focus group and survey methodology to solicit feedback on factors important for making treatment decisions among patients. Two 90-minute focus groups were conducted by an experienced facilitator. Previously diagnosed VS patients were recruited by clinical investigators at the University of Pittsburgh Medical Center (UPMC). Classical content analysis was used for focus group data analysis. Providers were recruited from practices within the UPMC system and were surveyed using Delphi methods. This information can provide a basis for multi-criteria decision analysis (MCDA) framework to develop a treatment decision support system for patients with VS. RESULTS: Eight themes were derived from these data (focus group + surveys): doctor/health care system, side effects, effectiveness of treatment, anxiety, mortality, family/other people, quality of life, and post-operative symptoms. These data, as well as feedback from physicians were utilized in building a multi-criteria decision model. DISCUSSION: The study illustrated steps involved in the development of a decision support model that integrates evidence-based data and patient values to select treatment alternatives. CONCLUSIONS: Studies focusing on the actual development of the decision support technology for this group of patients are needed, as decisions are highly multifactorial. Such tools have the potential to improve decision making for complex medical problems with alternate treatment pathways. PMID- 27780584 TI - FGF-2 for subacute tympanic membrane perforations. PMID- 27780585 TI - Purinergic signaling in kidney disease. AB - Nucleotides are key subunits for nucleic acids and provide energy for intracellular metabolism. They can also be released from cells to act physiologically as extracellular messengers or pathologically as danger signals. Extracellular nucleotides stimulate membrane receptors in the P2 and P1 family. P2X are ATP-activated cation channels; P2Y and P1 are G-protein coupled receptors activated by ATP, ADP, UTP, and UDP in the case of P2 or adenosine for P1. Renal P2 receptors influence both vascular contractility and tubular function. Renal cells also express ectonucleotidases that rapidly hydrolyze extracellular nucleotides. These enzymes integrate this multireceptor purinergic-signaling complex by determining the nucleotide milieu to titrate receptor activation. Purinergic signaling also regulates immune cell function by modulating the synthesis and release of various cytokines such as IL1-beta and IL-18 as part of inflammasome activation. Abnormal or excessive stimulation of this intricate paracrine system can be pro- or anti-inflammatory, and is also linked to necrosis and apoptosis. Kidney tissue injury causes a localized increase in ATP concentration, and sustained activation of P2 receptors can lead to renal glomerular, tubular, and vascular cell damage. Purinergic receptors also regulate the activity and proliferation of fibroblasts, promoting both inflammation and fibrosis in chronic disease. In this short review we summarize some of the recent findings related to purinergic signaling in the kidney. We focus predominantly on the P2X7 receptor, discussing why antagonists have so far disappointed in clinical trials and how advances in our understanding of purinergic signaling might help to reposition these compounds as potential treatments for renal disease. PMID- 27780586 TI - Hemodialysis patients receiving a greater Kt dose than recommended have reduced mortality and hospitalization risk. AB - Achieving an adequate dialysis dose is one of the key goals for dialysis treatments. Here we assessed whether patients receiving the current cleared plasma volume (Kt), individualized for body surface area per recommendations, had improved survival and reduced hospitalizations at 2 years of follow-up. Additionally, we assessed whether patients receiving a greater dose gained more benefit. This prospective, observational, multicenter study included 6129 patients in 65 Fresenius Medical Care Spanish facilities. Patients were classified monthly into 1 of 10 risk groups based on the difference between achieved and target Kt. Patient groups with a more negative relationship were significantly older with a higher percentage of diabetes mellitus and catheter access. Treatment dialysis time, effective blood flow, and percentage of on-line hemodiafiltration were significantly higher in groups with a higher dose. The mortality risk profile showed a progressive increase when achieved minus target Kt became more negative but was significantly lower in the group with 1 to 3 L clearance above target Kt and in groups with greater increases above target Kt. Additionally, hospitalization risk appeared significantly reduced in groups receiving 9 L or more above the minimum target. Thus, prescribing an additional 3 L or more above the minimum Kt dose could potentially reduce mortality risk, and 9 L or more reduce hospitalization risk. As such, future prospective studies are required to confirm these dose effect findings. PMID- 27780587 TI - Sociology, environment and health: a materialist approach. AB - OBJECTIVES: This paper reviews the sociology of environment and health and makes the case for a postanthropocentric approach based on new materialist theory. This perspective fully incorporates humans and their health into 'the environment', and in place of human-centred concerns considers the forces that constrain or enhance environmental capacities. STUDY DESIGN: This is not an empirical study. The paper uses a hypothetical vignette concerning child health and air pollution to explore the new materialist model advocated in the paper. METHODS: This paper used sociological analysis. RESULTS: A new materialist and postanthropocentric sociology of environment and health are possible. This radically reconfigures both sociological theory and its application to research and associated policies on health and the environment. Theoretically, human health is rethought as one among a number of capacities emerging from humans interactions with the social and natural world. Practically, the focus of intervention and policy shifts towards fostering social and natural interactions that enhance environmental (and in the process, human) potentiality. CONCLUSIONS: This approach to research and policy development has relevance for public health practice and policy. PMID- 27780590 TI - Special Issue Introduction: Science in the Public Eye. PMID- 27780589 TI - Risk factors for pressure ulcer development in Intensive Care Units: A systematic review. AB - INTRODUCTION: Pressure ulcers represent a significant problem for patients, professionals and health systems. Their reported incidence and prevalence are significant worldwide. Their character iatrogenic states that its appearance is preventable and its incidence is an indicator of scientific and technical quality both in primary care and specialized care. The aim of this review was to identify risk factors associated with the occurrence of pressure ulcers in critically ill patients. METHODOLOGY: The PRISMA Declaration recommendations have been followed and adapted to studies identifying risk factors. A qualitative systematic review of primary studies has been performed and a search was conducted of the PubMed, The Cochrane Library, Scopus and Web of Science databases. Methodological limitations in observational studies have been considered. RESULTS: From 200 references, 17 fulfilled the eligibility criteria. These studies included 19,363 patients admitted to intensive care units. Six studies were classified as high quality and 11 were classified as moderate quality. Risk factors that emerged as predictive of pressure ulcers development more frequently included age, length of ICU stay, diabetes, time of MAP <60-70mmHg, mechanical ventilation, length of mechanical ventilation, intermittent haemodialysis or continuous veno-venous haemofiltration therapy, vasopressor support, sedation and turning. CONCLUSIONS: There is no single factors which can explain the occurrence of pressure ulcers. Rather, it is an interplay of factors that increase the probability of its development. PMID- 27780591 TI - The effectiveness of a pay for performance program on diabetes care in Taiwan: A nationwide population-based longitudinal study. AB - Over the past two decades, studies have widely examined the effectiveness of pay for-performance (P4P) programs by conducting biochemical tests and assessing complications; however, the reported effectiveness of such programs among participants selected through purposeful sampling is controversial. Therefore, the objective of the current study was to analyze the effectiveness of a P4P program on patients' prognoses, including hospitalization for chronic diabetic complications, and all-cause mortality during specific follow-up years by using a nationwide population-based database in Taiwan. Based on 125,315 newly diagnosed type 2 diabetes patient cohort during 2002-2006, two control sets were designed by propensity-score-matching strategy according to participation of P4P program and followed up to 2012. The results indicated that full participants demonstrated the lowest risks of developing complications and all-cause mortality compared with nonparticipants. These findings confirm the long-term effect of P4P programs on full participants and reveal that this effect is not due to confounding variables. The results indicate the importance of performance management and adherence to interventions for patients with chronic diseases in a long-term observation. Comprehensive and continuous care is suggested to improve patient prognosis and quality of care. PMID- 27780588 TI - The non-mammalian MIF superfamily. AB - Macrophage migration inhibitory factor (MIF) was first described as a cytokine 50 years ago, and emerged in mammals as a pleiotropic protein with pro-inflammatory, chemotactic, and growth-promoting activities. In addition, MIF has gained substantial attention as a pivotal upstream mediator of innate and adaptive immune responses and with pathologic roles in several diseases. Of less importance in mammals is an intrinsic but non-physiologic enzymatic activity that points to MIF's evolution from an ancient defense molecule. Therefore, it is not surprising that mif-like genes also have been found across a range of different organisms including bacteria, plants, protozoa, helminths, molluscs, arthropods, fish, amphibians and birds. While Genebank analysis identifying mif-like genes across species is extensive, contained herein is an overview of the non-mammalian MIF-like proteins that have been most well studied experimentally. For many of these organisms, MIF contributes to an innate defense system or plays a role in development. For parasitic organisms however, MIF appears to function as a virulence factor aiding in the establishment or persistence of infection by modulating the host immune response. Consequently, a combined targeting of both parasitic and host MIF could lead to more effective treatment strategies for parasitic diseases of socioeconomic importance. PMID- 27780592 TI - Modification of the effects of air pollutants on mortality by temperature: A systematic review and meta-analysis. AB - Temperature extremes and air pollution both pose significant threats to human health, but it remains uncertain whether pollutants' effects on mortality are modified by temperature levels. In this review, we summarized epidemiologic evidence on the modification by temperature of the acute effects of air pollutants on non-accidental and cardiovascular mortality. The EMBASE, PubMed, ProQuest Dissertations and Theses, and Elsevier Science Direct databases were used to identify papers published up to 2nd December 2014. Studies with appropriate design, exposures and outcome indicators, quantitative estimates and high/intermediate quality were included. Twenty-one studies met the inclusion criteria, of which 12 reported the effects of PM10 on mortality modified by temperature, 10 studied O3, and the rest examined NO2, SO2, PM2.5, PM10-2.5, CO and black smoke. We divided temperature into low, medium, and high categories as defined in each study. In high temperature days, a 10MUg/m3 increment in PM10 concentration corresponded to pooled estimates of 0.78% (95% CI: 0.44%, 1.11%) and 1.28% (0.66%, 1.91%) increase in non-accidental and cardiovascular mortality, both statistically significantly higher than the estimates in medium temperature stratum. Pooled effects of O3 on non-accidental mortality on low and high temperature days were increases of 0.48% (0.28%, 0.69%) and 0.47% (0.32%, 0.63%) respectively, for 10MUg/m3 increase in exposure, both significantly higher than the increase of 0.20% (0.07%, 0.34%) on medium temperature days. The effect of O3 on cardiovascular mortality was strongest on high temperature days with pooled estimate of 1.63% (1.14%, 2.13%). No significant interactions between SO2/NO2 and temperature were detected by meta-analysis. Other pollutants were not analyzed due to the lack of suitable studies. In summary, we observed interactions between high temperature and PM10 and O3 in the effects on non-accidental and cardiovascular mortality. Low temperature modified the effects of air pollutants but not in a consistent fashion: the effect of PM10 oncardiovascular mortality was diminished but the association between O3 and non-accidental mortality was strengthened. PMID- 27780593 TI - Citizen science datasets reveal drivers of spatial and temporal variation for anthropogenic litter on Great Lakes beaches. AB - Accumulation of anthropogenic litter (AL) on marine beaches and its ecological effects have been a major focus of research. Recent studies suggest AL is also abundant in freshwater environments, but much less research has been conducted in freshwaters relative to oceans. The Adopt-a-BeachTM (AAB) program, administered by the Alliance for the Great Lakes, organizes volunteers to act as citizen scientists by collecting and maintaining data on AL abundance on Great Lakes beaches. Initial assessments of the AAB records quantified sources and abundance of AL on Lake Michigan beaches, and showed that plastic AL was >75% of AL on beaches across all five Great Lakes. However, AAB records have not yet been used to examine patterns of AL density and composition among beaches of all different substrate types (e.g., parks, rocky, sandy), across land-use categories (e.g., rural, suburban, urban), or among seasons (i.e., spring, summer, and fall). We found that most AL on beaches are consumer goods that most likely originate from beach visitors and nearby urban environments, rather than activities such as shipping, fishing, or illegal dumping. We also demonstrated that urban beaches and those with sand rather than rocks had higher AL density relative to other sites. Finally, we found that AL abundance is lowest during the summer, between the US holidays of Memorial Day (last Monday in May) and Labor Day (first Monday in September) at the urban beaches, while other beaches showed no seasonality. This research is a model for utilizing datasets collected by volunteers involved in citizen science programs, and will contribute to AL management by offering priorities for AL types and locations to maximize AL reduction. PMID- 27780594 TI - Tracking polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in sediments and soils from the southwest of Buenos Aires Province, Argentina (South eastern part of the GRULAC region). AB - PCBs and PBDEs (7 and 10 congeners, respectively) were analyzed in four coastal surface sediments collected from the northern shore of Bahia Blanca estuary and in nine soils from different locations of Bahia Blanca city and the surrounding region (Southwest of Buenos Aires Province, Argentina). Sediment samples showed PCBs(Sigma7) concentrations ranged from 0.61 to 17.6ngg-1 (dry weight=dw) and PBDEs(Sigma10) from 0.16 to 2.02ngg-1 dw, whereas in soil samples ranged from 0.04 to 1.67ngg-1 dw for PCBs(Sigma7) and 0.04 to 10.7ngg-1 dw for PBDEs(Sigma10). The highest concentrations of both chemicals were detected in the urban and industrial/port areas showing a dominance of the higher chlorinated PCB congeners: in sediments for PCB-180 (56+/-33%) and PCB-153 (11+/-6%); and in soils for PCB-138 (23+/-3%), PCB-153 (22+/-2%) and PCB-180 (18+/-7%). In contrast, lower chlorinated PCB congeners were predominant at more distant sites; in sediments for congeners PCB-28 (33+/-4%) and PCB-52 (14.5+/-0.2%); and in soils PCB-28 (56+/-14%) and PCB-52 (33+/-19%). PBDE-209 (high brominated PBDE) showed the highest relative abundance in both sample types i.e., sediment (94+/ 7%) and soil (80+/-12%). These findings can be considered lower or similar when compared with other sites of the world, and are likely associated with anthropogenic activities in their surrounding area, which has experienced a fast industrial growth in the last decade. This is the first investigation of PBDEs levels in the whole study area and of PCBs in soils from the Bahia Blanca city and surrounding region. This article provides new and useful information on POP levels in the South eastern part of the GRULAC region. PMID- 27780595 TI - High expression of NDRG3 associates with positive lymph node metastasis and unfavourable overall survival in laryngeal squamous cell carcinoma. AB - N-myc downstream-regulated gene 3 (NDRG3), which belongs to the NDRG family, is believed to play important roles in human cancer. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (qPCR) and western blotting tests with 10 fresh-frozen laryngeal squamous cell carcinoma (LSCC) samples and immunohistochemistry (IHC) analysis in 109 LSCC cases were performed to investigate the relationship between NDRG3 expression and the clinicopathological characteristics of LSCC. Results demonstrated that NDRG3 mRNA and protein expression levels were statistically higher in LSCC tissues than that in non-cancerous tissues (all p<0.05). IHC data showed that the NDRG3 protein expression was remarkably correlated with lymph node metastasis (p=0.043). Univariate and multivariate survival analysis implied that high NDRG3 expression (p=0.004), lymph node metastasis (p=0.044) and TNM stage (p=0.020) were independently associated with the unfavourable overall survival of patients with LSCC. The above findings suggested that NDRG3 may be identified as a novel biomarker predicting the prognosis of LSCC. PMID- 27780597 TI - MYC immunohistochemistry in angiosarcoma and atypical vascular lesions: practical considerations based on a single institutional experience. AB - Angiosarcoma (AS) is an uncommon vascular malignancy with an aggressive clinical course. Radiation-associated angiosarcoma (RAAS) and Stewart-Treves syndrome are associated with MYC gene amplification and protein overexpression, while other radiation-associated vascular lesions including atypical vascular lesions (AVL) are not associated with MYC overexpression. In contrast, de novo AS represent a group of molecularly heterogeneous tumours, for which MYC expression has not been extensively examined. In this study, MYC immunohistochemistry (IHC) was performed on representative whole tissue sections of a large retrospective cohort of de novo AS, RAAS, Stewart-Treves syndrome, and AVL and evaluated using a semi quantitative scoring method. MYC is strongly expressed in the majority of RAAS and Stewart-Treves syndrome. De novo AS demonstrate variable MYC expression, with high-grade tumours showing significantly higher MYC expression than low-grade tumours. In contrast, MYC expression in AVL is predominantly negative but may occasionally show focal staining. These results indicate that unequivocal strong MYC IHC staining supports the diagnosis of RAAS. In rare cases of RAAS without strong MYC expression, however, particularly relatively low-grade tumours for which the differential diagnosis includes AVL, the distinction between these lesions should be made on morphological grounds using previously established criteria (i.e., significant atypia, deep invasion, infiltrative growth, etc.). Increased MYC expression in high-grade de novo AS suggests that MYC overexpression may play a role in the pathogenesis of these tumours, and MYC IHC may be a prognostic and/or therapeutic biomarker in a subset of these tumours. PMID- 27780596 TI - Clinical application of a molecular assay for the detection of dermatophytosis and a novel non-invasive sampling technique. AB - The dermatophytoses are the most common superficial fungal infections worldwide. Clinical diagnosis is not reliable as there are many differentials, and laboratory diagnosis is required to gain access to treatment in more severe disease. Traditional diagnostic methods are limited by suboptimal sensitivity, specificity and prolonged turnaround times. Molecular methods are being used increasingly in the diagnostic algorithm in the clinical microbiology laboratory. The aim of this study was to evaluate a real-time polymerase chain reaction (RT PCR) targeting the chitin synthase 1 gene (CHS1) of dermatophytes for analytical specificity, and to assess its clinical application by comparing it to the current methods of microscopy and culture. We also assessed a novel non-invasive sample collection technique involving adhesive tape impressions of suspected lesions. The PCR was highly specific, being able to discern between cultures of dermatophytes and other microorganisms. It also proved to be more sensitive than traditional methods at detecting dermatophytes in clinical samples. Similar sensitivities were seen on the samples assessed by the adhesive tape technique. An internal control system allowed for the detection of inhibition in certain culture and clinical specimens. This rapid and cost-effective technique could be incorporated into the initial diagnostic algorithm for dermatophytosis in Australian laboratories. PMID- 27780598 TI - A rare case of rectal interdigitating dentritic cell sarcoma presenting with a polypoid appearance. PMID- 27780599 TI - Calretinin but not caveolin-1 correlates with tumour histology and survival in malignant mesothelioma. AB - Malignant mesothelioma (MM) continues to be a disease with poor prognosis and limited treatment options. Calretinin and caveolin-1 expression by tumour in MM have recently been described to be associated with tumour histology, differentiation and consequently survival. In a large, well annotated cohort, we studied both of these biomarkers and explored their association with clinicopathological parameters and survival. A retrospective search of patients with MM who underwent surgery at the Austin Hospital in Melbourne, Australia, was conducted. Clinical history and outcome data were retrieved from patient records. Tissue microarrays (TMAs) were constructed and stained for calretinin and caveolin-1. 'H scores' were derived, taking intensity and distribution of staining, and the cohort was dichotomised using median values for both markers. In the 329 patients evaluated, median age was 67 years. Males outnumbered females by 5:1. Epithelioid histology 202/319 (62.9%) was the most common, followed by biphasic 72/319 (21.8%) and sarcomatoid 45/319 (13.6%); histology could not be confirmed in 10 patients. Calretinin expression was detected in 246 of the 324 (76%) evaluable patients and high expression was associated with epithelioid histology (p < 0.0001). Caveolin-1 was expressed in 298 (94%) of 317 evaluable patients which was much higher compared to its expression in a cohort of lung adenocarcinomas (8/58, 13.7%). However, no association with histology was found (p = 0.409). When taken as a continuous variable, calretinin expression was found to be an independent predictor of survival, alongside histology, neutrophil lymphocyte ratio, weight loss and stage. No prognostic value was demonstrable for caveolin-1 expression and calretinin/caveolin-1 ratio. There was no relationship between calretinin and caveolin-1 expression. In MM, increased calretinin expression is associated with epithelioid histology and better survival. Caveolin 1 is a sensitive MM marker and is expressed in a high proportion of cases but lacks association with histology and survival. PMID- 27780600 TI - Usefulness of breast cytology after lipofilling. PMID- 27780602 TI - Angiomatoid Spitz naevus: novel observations and clues to diagnosis of a rare variant. PMID- 27780601 TI - Eltrombopag: liver toxicity, kidney injury or assay interference? PMID- 27780603 TI - Sensitivity of routine coagulation assays to direct oral anticoagulants: patient samples versus commercial drug-specific calibrators. AB - Most studies on the sensitivities of coagulation assays to direct oral anticoagulants (DOACs) are based on normal plasma spiked with anticoagulant in the laboratory. Recent studies have shown that reagent sensitivity varies significantly depending on whether spiked or patient samples are used. The aim of this study was to compare the sensitivities of routine coagulation assays in patient samples and commercial drug specific calibrators using commonly used activated partial thromboplastin time (APTT) and prothrombin time (PT) reagents (i.e., Actin FS and Neoplastine CI Plus for APTT and PT, respectively) in Australian laboratories. Samples collected at Pathology North Hunter (PN-H) for dabigatran (n=39), rivaroxaban, (n=56) or apixaban levels (n=22) between February 2013 and November 2015 were analysed and compared to two different commercial drug specific calibrators from different manufacturers for each DOAC. Our results show that dabigatran (Hyphen and Technoclone) and rivaroxaban (Stago) calibrators tend to overestimate the APTT but are similar to patient samples for PT. A cut off DOAC level of 50 ng/mL based on results from patient samples within the laboratory can be used as the lower limit which will result in prolongation of APTT for dabigatran (sensitivity 96%, n=25) and PT for rivaroxaban (sensitivity 97%, n=29), respectively. Individual laboratories should be familiar with the sensitivity of their coagulation reagents to different DOACs including differences between patient samples versus different commercial drug specific calibrators. PMID- 27780604 TI - The death of the hospital autopsy in Australia? The hospital autopsy rate is declining dramatically. PMID- 27780605 TI - IDH1/2 gene hotspot mutations in central nervous system tumours: analysis of 922 Chinese patients. AB - Mutations of isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes have been identified as early molecular events in the development of astrocytomas and oligodendrogliomas. Data regarding the status and prevalence of IDH1/2 mutations in Chinese patients are limited. Herein we report our data from West China Hospital, a major Chinese medical centre. IDH1(R132H) mutation was analysed by immunohistochemistry with the mutation-specific IDH1(R132H) antibody in 1011 patients, including 922 central nervous system (CNS) tumours and 89 non neoplastic CNS lesions, and PCR-based direct sequencing of IDH1/2 gene mutation in 570 of these samples. Correlation with clinicopathological features and immunohistochemical expression of p53, EGFR, PTEN and Ki-67 was examined. Our data showed that IDH1/2 mutation was present in oligodendrogliomas, anaplastic oligodendrogliomas, diffuse or anaplastic astrocytomas, and glioblastomas, with decreasing frequency, but not in other types of CNS tumours or non-neoplastic lesions examined. IDH1(R132) mutation was most frequent in oligodendrogliomas (57/62, 91.9%), with IDH1(R132H) mutation as the most frequent mutation form. Only one case for each of the rare mutations (R132C, R132G, R132L, and R132S) was identified in the 570 samples analysed by sequencing. Younger age, low expression of p53 and low Ki-67 index were significantly correlated with IDH1 mutation status (p=0.000). All tumours with IDH1(R132) mutations were supratentorial, with frontal lobe as the most frequent site for IDH-mutated gliomas. Only three IDH2(R172) mutation cases were detected in this series. Univariate survival analysis in 459 glioma patients with diffusely infiltrating gliomas showed that IDH1 mutations as well as the more classical prognosticators (age, WHO grade, p53 and Ki-67 index) were of prognostic significance. Multivariate analysis by Cox proportional hazard regression model demonstrated that lack of IDH1 mutation was an independent prognostic factor for both progression-free survival [relative risk (RR)=2.450, 95% confidence interval (CI)=1.351-4.444] and disease-specific survival (RR=2.489, 95%CI=1.155-5.363). PMID- 27780606 TI - Paranuclear dot-like pancytokeratin positivity and MLH1/PMS2 loss in large cell neuroendocrine carcinoma of the endometrium. PMID- 27780607 TI - Ultrasound-guided deep-arm veins insertion of long peripheral catheters in patients with difficult venous access after cardiac surgery. AB - OBJECTIVES: To analyze success rate, dwell-time, and complications of long peripheral venous catheters (L-PVCs) inserted under ultrasound guidance. BACKGROUND: In difficult venous access (DVA) patients, L-PVC can represent an alternative to central or midline catheters. METHODS: Prospective observational study. L-PVCs were positioned in DVA patients. The outcome of the cannulation procedure and the times and reasons for catheters removal were analyzed. RESULTS: A 100% placement success rate was documented. The catheter dwell-time was 14.7 +/ 11.1 days. Most catheters were removed at end-use in the absence of complications. The rate of catheters appropriately or inappropriately removed before completing the intravenous therapies was 27.7/1000 catheter-days. Two thrombophlebitis (1.91/1000 catheter-days) and 1 catheter-related bloodstream infection (0.96/1000 catheter-days) occurred. CONCLUSIONS: L-PVC could be a viable solution in DVA patients, as it may reduce the need for multiple vein punctures, patients' discomfort, and nursing workload. A better adherence to catheter management recommendations should further reduce complications. PMID- 27780608 TI - Leptin plasma concentrations, leptin gene expression, and protein localization in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes of the European beaver (Castor fiber). AB - The European beaver (Castor fiber) is the largest seasonal free-living rodent in Eurasia. Since the physiology and endocrine system of this species remains unknown, the present study aimed to determine plasma leptin concentrations and the expression of the leptin gene and protein in the hypothalamic-pituitary gonadal and hypothalamic-pituitary-adrenal (HPG and HPA) axes of beavers during breeding (April), postbreeding (July), and prebreeding (November) seasons. Leptin plasma concentrations did not change in females, whereas in males, leptin plasma concentrations were higher in July than those in April. The presence of leptin mRNA and protein was found in all examined tissues. In females, leptin mRNA expression in the hypothalamus, pituitary, ovaries, and myometrium was markedly higher in July than that in April. In males, leptin mRNA levels varied across the examined tissues of the HPG and HPA. Leptin synthesis increased in the hypothalamus during breeding and postbreeding seasons, but seasonal changes were not observed in the pituitary. In turn, testicular leptin levels were higher during breeding and prebreeding stages. Seasonal differences in the concentrations of leptin mRNA were also observed in the adrenal cortex. In males, leptin mRNA levels were higher in November than those in April or July. In females, leptin synthesis increased in the adrenal cortex during pregnancy relative to other seasons. This is the first ever study to demonstrate seasonal differences in leptin expression in beaver tissues, and our results could suggest that leptin is involved in the regulation of the HPG and HPA axes during various stages of the reproductive cycle in beavers. PMID- 27780609 TI - Introduction to a special issue on concept mapping. AB - Concept mapping was developed in the 1980s as a unique integration of qualitative (group process, brainstorming, unstructured sorting, interpretation) and quantitative (multidimensional scaling, hierarchical cluster analysis) methods designed to enable a group of people to articulate and depict graphically a coherent conceptual framework or model of any topic or issue of interest. This introduction provides the basic definition and description of the methodology for the newcomer and describes the steps typically followed in its most standard canonical form (preparation, generation, structuring, representation, interpretation and utilization). It also introduces this special issue which reviews the history of the methodology, describes its use in a variety of contexts, shows the latest ways it can be integrated with other methodologies, considers methodological advances and developments, and sketches a vision of the future of the method's evolution. PMID- 27780610 TI - Re: Novel approach in the treatment of a persistent oroantral fistula using an acellular dermal graft: technical note. PMID- 27780611 TI - Experimental model of osteonecrosis of the jaw in rats treated with zoledronic acid. AB - We have examined the development of medication-related osteonecrosis of the jaws (MRONJ) in rats with no previous accumulation of zoledronic acid in the mandible. Ten male Wistar rats (weight 350-400g) were anaesthetised with chloral hydrate 450mg/kg intraperitoneally and the first and second mandibular molars on the left side were extracted. The five experimental rats were given six injections of zoledronic acid 0.18mg/kg over the next four weeks (total dose 1.08mg/kg). Two injections were given at once as an intravenous bolus injection (0.36mg/kg). Then rats were given 4 injections (0.18mg/kg) with 1 week interval over the next four weeks, after which they observed for a further four weeks. The five control rats were injected with saline. At the end of the eighth week, the animals were killed by asphyxiation in a carbon dioxide chamber, and their bone structure was visualised using cone-beam computed tomography (CT) and Galaxis software. We then studied the mandibles histopathologically to investigate the incidence of necrosis and infiltration of inflammatory cells. The cone-beam CT images in the experimental group showed deficiencies in the bone structure in the extracted molar area of the lower alveolar ridge. The histological findings in the mandibles of the group given zoledronic acid showed necrosis and infiltration of inflammatory cells, which were not present in the control group. We conclude that the immediate effect of zoledronic acid on the bone tissue during regeneration is an important factor in the development of MRONJ, in addition to the previously reported effects of the duration of treatment with zoledronic acid. PMID- 27780612 TI - Use of a bolster to secure a skin regeneration system on the tongue. PMID- 27780613 TI - Multiple sclerosis and alcohol use disorders: In-hospital mortality, extended hospital stays, and overexpenditures. AB - INTRODUCTION: The objective of this study was to analyse the impact of alcohol use disorders (AUD) in patients with multiple sclerosis (MS) in terms of in hospital mortality, extended hospital stays, and overexpenditures. METHODS: We conducted a retrospective observational study in a sample of MS patients obtained from minimal basic data sets from 87 Spanish hospitals recorded between 2008 and 2010. Mortality, length of hospital stays, and overexpenditures attributable to AUD were calculated. We used a multivariate analysis of covariance to control for such variables as age and sex, type of hospital, type of admission, other addictions, and comorbidities. RESULTS: The 10,249 patients admitted for MS and aged 18-74 years included 215 patients with AUD. Patients with both MS and AUD were predominantly male, with more emergency admissions, a higher prevalence of tobacco or substance use disorders, and higher scores on the Charlson comorbidity index. Patients with MS and AUD had a very high in-hospital mortality rate (94.1%) and unusually lengthy stays (2.4 days), and they generated overexpenditures (1,116.9euros per patient). CONCLUSIONS: According to the results of this study, AUD in patients with MS results in significant increases in-hospital mortality and the length of the hospital stay and results in overexpenditures. PMID- 27780614 TI - Rapidly progressing dementia as a form of presentation of Cushing syndrome. PMID- 27780615 TI - Association between periodontal disease and dementia: A literature review. AB - INTRODUCTION: Periodontal disease and dementia are very prevalent, especially in elderly populations. Multiple studies have shown a link between these diseases; however, the conditions are highly heterogeneous and so is the diagnostic methodology, which may hinder interpretation and comparison of the results. The aim of this article is to provide a critical review of the literature linking these 2 processes. DEVELOPMENT: We retrieved 22 studies, most of which were retrospective, and analysed various methodological variables including study population, diagnosis of periodontitis, definition of dementia, adjusted variables, and results. The different aetiopathogenic mechanisms that may affect the progression and interaction of these 2 conditions were also analysed. CONCLUSIONS: Although available evidence indicates a positive association between periodontitis and dementia, both the strength of that association and the presence of a causal relationship have yet to be determined. PMID- 27780617 TI - The 2016 ESPEN Sir David Cuthbertson lecture: Interfering with neuroendocrine and metabolic responses to critical illness: From acute to long-term consequences. PMID- 27780616 TI - Perceived quality in a dementia unit: patients' caregivers as information providers. AB - INTRODUCTION: Dementia units (DU) provide comprehensive and specialised care to patients with dementia. However, assessment in these units normally focuses on patient management. The aim of this study was to determine satisfaction of the caregivers of patients managed in a DU and how they rated DU care. METHODS: We created a self-administered questionnaire which was completed by 236 caregivers visiting the DU in 2015. The questionnaire included 6 dimensions (accessibility, organisation, professionalism, relationship with staff, information, and facilities); data were analysed using problem rates. RESULTS: A total of 53.4% caregivers completed the questionnaire; most were women, patients' spouses, or first-degree relatives. The overall problem rates was 15.0% (95% CI, 13.9-16.1), with sizeable differences between dimensions: from 0.1% (95% CI, 0.0-0.4) for 'relationship with staff' and 'professionalism' to 49.3% (95% CI, 45.4-53.2) for 'information'. Waiting times over 30minutes were perceived as excessive. Information problems were not directly related to patient management. Satisfaction was scored 8.29/10 (median 8; SD 1.45); 77.3% (95% CI, 69.8-74.8) of respondents were highly satisfied. Ninety-nine percent of the caregivers stated that they would recommend the DU. CONCLUSIONS: This questionnaire provides interesting data on care quality as perceived by patients' caregivers. Our results have allowed us to identify problems and implement corrective actions. Our questionnaire has proved to be a useful tool for evaluating and improving care quality in DUs. PMID- 27780618 TI - Synthesis, structure-activity relationship and molecular docking of 3-oxoaurones and 3-thioaurones as acetylcholinesterase and butyrylcholinesterase inhibitors. AB - The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson's reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE. PMID- 27780619 TI - Elastofibroma dorsi: Clinical evaluation of 61 cases and review of the literature. AB - OBJECTIVE: Elastofibroma dorsi (ED) is a rare, benign, soft tissue tumor typically located between inferior corner of scapula and posterior chest wall causing mass, scapular snapping, and pain. When classic symptoms and localization are present, it is diagnosed without biopsy and treated with marginal resection. This study retrospectively analyzed patients operated on for ED to evaluate presenting symptoms, tumor size, complications, and clinical results, and to suggest optimal treatments. METHODS: This study included 51 patients who underwent surgery for ED in 2 different clinics between 2005 and 2015. Patient age, gender, profession, side affected, symptoms, average duration of symptoms, and tumor size were researched. Radiological examinations of patients were evaluated. Patients with lesions larger than 5 cm in size were operated on. Postoperative complications, recurrence, and functional results were evaluated using Constant score and compared to preoperative values. RESULTS: A total of 61 operated lesions of 51 patients clinically and radiologically diagnosed with ED were retrospectively evaluated. Average length of time patient experienced symptoms was 11.21 months. Lesions in 19 (37.2%) patients were bilateral, 10 of which were symptomatic and larger than 5 cm in size, meeting indication for surgery. Average lesion diameter was 8.7 cm. Average follow-up was 26.89 months. Average of preoperative Constant score of 67.28 subsequently increased to 92.88 (p < 0.05). Seroma and hematoma were observed in 11.5% of patients. CONCLUSION: Generally, good clinical results can be obtained with marginal resection without requiring a biopsy, considering classic complaints and radiological appearance of ED. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 27780620 TI - Variations of B cell subpopulations in peripheral blood of healthy Mexican population according to age: Relevance for diagnosis of primary immunodeficiencies. AB - BACKGROUND: Peripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population. METHODS: Peripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naive, memory with and without isotype switch, double-negative, transitional, and plasmablast cells. RESULTS: We observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age. CONCLUSIONS: In order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected. PMID- 27780621 TI - Analysis of utilization technologies for Eichhornia crassipes biomass harvested after restoration of wastewater. AB - Eichhornia crassipes (EC, water hyacinth) has gained attention due to its alarming reproductive capacity, which subsequently leads to serious ecological damage of water in many eutrophic lakes in the world. The traditional mechanical removal methods have disadvantages. They squander this valuable lignocellulosic resource. Meanwhile, there is a bottleneck for the subsequently reasonable and efficient utilization of EC biomass on a large scale after phytoremediation of polluted water using EC. As a result, the exploration of effective EC utilization technologies has become a popular research field. After years of exploration and amelioration, there have been significant breakthroughs in this research area, including the synthesis of excellent EC cellulose-derived materials, innovative bioenergy production, etc. This review organizes the research of the utilization of the EC biomass among several important fields and then analyses the advantages and disadvantages for each pathway. Finally, comprehensive EC utilization technologies are proposed as a reference. PMID- 27780622 TI - Effects of cooking method, cooking oil, and food type on aldehyde emissions in cooking oil fumes. AB - Cooking oil fumes (COFs) contain a mixture of chemicals. Of all chemicals, aldehydes draw a great attention since several of them are considered carcinogenic and formation of long-chain aldehydes is related to fatty acids in cooking oils. The objectives of this research were to compare aldehyde compositions and concentrations in COFs produced by different cooking oils, cooking methods, and food types and to suggest better cooking practices. This study compared aldehydes in COFs produced using four cooking oils (palm oil, rapeseed oil, sunflower oil, and soybean oil), three cooking methods (stir frying, pan frying, and deep frying), and two foods (potato and pork loin) in a typical kitchen. Results showed the highest total aldehyde emissions in cooking methods were produced by deep frying, followed by pan frying then by stir frying. Sunflower oil had the highest emissions of total aldehydes, regardless of cooking method and food type whereas rapeseed oil and palm oil had relatively lower emissions. This study suggests that using gentle cooking methods (e.g., stir frying) and using oils low in unsaturated fatty acids (e.g., palm oil or rapeseed oil) can reduce the production of aldehydes in COFs, especially long-chain aldehydes such as hexanal and t,t-2,4-DDE. PMID- 27780623 TI - Bioaccumulation and toxicity assessment of irrigation water contaminated with boron (B) using duckweed (Lemna gibba L.) in a batch reactor system. AB - The present study assesses ability of Lemna gibba L. using a batch reactor approach to bioaccumulation boron (B) from irrigation waters which were collected from a stream in largest borax reserve all over the world. The important note that bioaccumulation of B from irrigation water was first analyzed for first time in a risk assessment study using a Lemna species exposed to various B concentrations. Boron toxicity was evaluated through plant growth and biomass production during phytoremediation process. The result from the present experiment indicated that L. gibba was capable of removing 19-63% B from irrigation water depending upon contaminated level or initial concentration. We also found that B was removed from aqueous solution following pseudo second order kinetic model and Langmuir isotherm model better fitted equilibrium obtained for B phytoremediation. Maximum B accumulation in L. gibba was determined as 2088mgkg 1 at average inflow B concentration 17.39mgL-1 at the end of the experiment. Conversely, maximum bioconcentration factor obtained at lowest inflow B concentrations were 232 for L. gibba. The present study suggested that L. gibba was very useful B accumulator, and thus L. gibba-based techniques could be a reasonable phytoremediation option to remove B directly from water sources contaminated with B. PMID- 27780624 TI - Letter to the Editor on 'Hyaluronic Acid Injections in Medicare Knee Osteoarthritis Patients Are Associated With Longer Time to Knee Arthroplasty'. PMID- 27780625 TI - Letter to the Editor on "The Effects of a Hospitalist Comanagement Model for Joint Arthroplasty Patients in a Teaching Facility". PMID- 27780626 TI - Response to Letter to the Editor on 'Hyaluronic Acid Injections in Medicare Knee Osteoarthritis Patients Are Associated With Longer Time to Knee Arthroplasty'. PMID- 27780627 TI - First Japanese case of congenital generalized hypertrichosis with a copy number variation on chromosome 17q24. PMID- 27780628 TI - ICF components of outcome measures for mallet finger: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION/PURPOSE: The purpose of this study was to systematically review outcome measures used for the assessment of the conservative management of mallet finger to determine if they characterize the International Classification of Functioning, Disability, and Health components of activity, participation, environmental factors, or quality of life. METHODS/RESULTS: Five studies published within the last 10 years were included in the systematic review. A majority, 19 of the outcomes used by the authors, fell within the body functions and structures category. Six were related to activity, and 1 was related to participation. One was linked to environmental factors. Five were found to be not definable and related to quality of life. DISCUSSION/CONCLUSION: This systematic review suggests that many outcome measures focus on body structures and functions in the current research on the conservative treatment of mallet finger injuries. LEVEL OF EVIDENCE: 2a. PMID- 27780629 TI - Pertussis: Biology, epidemiology and prevention. AB - Despite long-standing vaccination programs, substantial increases in reported cases of pertussis have been described in several countries during the last 5years. Cases among very young infants who are at greatest risk of pertussis related hospitalizations and mortality are the most alarming. Multiple hypotheses including but not limited to the availability of more sensitive diagnostic tests, greater awareness, and waning vaccine-induced immunity over time have been posited for the current challenges with pertussis. The conference "Pertussis: biology, epidemiology and prevention" held in Annecy-France (November 11-13, 2015) brought together experts and interested individuals to examine these issues and to formulate recommendations for optimal use of current vaccines, with a particular focus on strategies to minimize severe morbidity and mortality among infants during the first months of life. The expert panel concluded that improving vaccination strategies with current vaccines and development of new highly immunogenic and efficacious pertussis vaccines that have acceptable adverse event profiles are currently the two main areas of investigation for the control of pertussis. Some possible pathways forward to address these main challenges are discussed in this report. PMID- 27780630 TI - Effect of Tdap when administered before, with or after the 13-valent pneumococcal conjugate vaccine (coadministered with the quadrivalent meningococcal conjugate vaccine) in adults: A randomised controlled trial. AB - Sequential or co-administration of vaccines has potential to alter the immune response to any of the antigens. Existing literature suggests that prior immunisation of tetanus/diphtheria-containing vaccines can either enhance or suppress immune response to conjugate pneumococcal or meningococcal vaccines. We examined this interaction among adult Australian travellers before attending the Hajj pilgrimage 2014. We also investigated tolerability of these vaccines separately and concomitantly. We randomly assigned each participant to one of three vaccination schedules. Group A received adult tetanus, diphtheria and acellular pertussis vaccine (Tdap) 3-4weeks before receiving CRM197-conjugated 13 valent pneumococcal vaccine (PCV13) and CRM197-conjugated quadrivalent meningococcal vaccine (MCV4). Group B received all three vaccines on one day. Group C received PCV13 and MCV4 3-4weeks before Tdap. Blood samples collected at baseline, each vaccination visit and 3-4weeks after vaccination were tested using the pneumococcal opsonophagocytic assay (OPA) and by ELISA for diphtheria and tetanus antibodies. Funding for meningococcal serology was not available. Participants completed symptom diaries after each vaccination. A total of 111 participants aged 18-64 (median 40) years were recruited. No statistically significant difference was detected across the three groups in achieving OPA titre ?1:8 post vaccination. However, compared to other groups, Group A had a statistically significant lower number of subjects achieving ?4-fold rise in serotype 3, and also significantly lower geometric mean titres (GMTs) to six (of 13) pneumococcal serotypes (3, 5, 18C, 4, 19A and 9V). Group C (given prior PCV13 and MVC4) had statistically significant higher pre-Tdap geometric mean concentration (GMC) of anti-diphtheria IgG; however, there was no difference across the three groups following Tdap. Anti-tetanus IgG GMCs were similar across the groups before and after Tdap. No serious adverse events were reported. In conclusion, Tdap vaccination 3-4weeks before concomitant administration of PCV13 and MCV4 significantly reduced the antibody response to six of the 13 pneumococcal serotypes in adults. The trial is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000536763. PMID- 27780631 TI - Meningococcal disease in the Asia-Pacific region: Findings and recommendations from the Global Meningococcal Initiative. AB - The Global Meningococcal Initiative (GMI) is a global expert group that includes scientists, clinicians, and public health officials with a wide range of specialties. The purpose of the Initiative is to promote the global prevention of meningococcal disease (MD) through education, research, and cooperation. The first Asia-Pacific regional meeting was held in November 2014. The GMI reviewed the epidemiology of MD, surveillance, and prevention strategies, and outbreak control practices from participating countries in the Asia-Pacific region.Although, in general, MD is underreported in this region, serogroup A disease is most prominent in low-income countries such as India and the Philippines, while Taiwan, Japan, and Korea reported disease from serogroups C, W, and Y. China has a mixed epidemiology of serogroups A, B, C, and W. Perspectives from countries outside of the region were also provided to provide insight into lessons learnt. Based on the available data and meeting discussions, a number of challenges and data gaps were identified and, as a consequence, several recommendations were formulated: strengthen surveillance; improve diagnosis, typing and case reporting; standardize case definitions; develop guidelines for outbreak management; and promote awareness of MD among healthcare professionals, public health officials, and the general public. PMID- 27780632 TI - "Symptomatic" infection-associated acute encephalopathy in children with underlying neurological disorders. AB - BACKGROUND: Development of infection-associated acute encephalopathy (AE) is precipitated by several factors, including viral agents, age, and genetic polymorphisms. In addition, children with prior underlying neurological disorders can also present with AE. METHOD: We reviewed 55 children with AE who were referred to hospitals participating in the Status Epilepticus Study Group from 1988 to 2013. AE was classified into eight subtypes: acute encephalopathy with biphasic seizures and late reduced diffusion (AESD); hemiconvulsion-hemiplegia syndrome (HH); acute necrotizing encephalopathy; hemorrhagic shock and encephalopathy syndrome (HSES); clinically mild encephalitis/encephalopathy with a reversible splenial lesion; acute encephalitis with refractory, repetitive partial seizures; Reye-like syndrome; and unclassified. RESULT: Of the 55 AE cases, 14 (25.4%) had underlying neurological disorders, including perinatal insults (n=6) and genetic syndrome and/or brain malformations (n=8). These preceding morbidities were relatively common in AESD (6/18, 33.3%), HH (3/9, 33.3%), and HSES (3/6, 50.0%). History of epilepsy or febrile seizures were frequent in HH cases (4/9, 44.4%), whereas they were rare in other AE subtypes. CONCLUSION: Among the AE subgroups, HH, HSES, and AESD frequently emerged in preceding etiologies with augmented neuronal excitability. These subgroups may have distinct pathomechanism from the "cytokine storm" mediated AEs during childhood. PMID- 27780633 TI - Estrogen variation during the menstrual cycle does not influence left ventricular diastolic function and untwisting rate in premenopausal women. AB - BACKGROUND: Although a cardioprotective effect of estrogen has been suggested by experimental studies, clinical data on the influence of estrogen on left ventricular (LV) diastolic function are sparse. The LV untwisting rate obtained by 2D speckle tracking echocardiography (2D-STE) is correlated with the time constant of LV pressure decay (tau), and this correlation is independent of left atrial pressure. Therefore, we used conventional Doppler echocardiography and 2D STE to investigate changes in LV diastolic function during a single menstrual cycle in premenopausal women. METHODS: Twenty healthy premenopausal woman (mean age, 28.1+/-2.7 years) were enrolled. Clinical and echocardiographic data were obtained during the follicular phase (F-phase) and luteal phase (L-phase) of a single menstrual cycle. We compared the clinical and echocardiographic data, and estrogen levels between the two phases. RESULTS: There were no significant differences in LV diastolic parameters derived from Doppler echocardiography (E/A, p=0.295; E/e', p=0.449, DcT, p=0.178) or 2D-STE (peak untwisting rate, p=0.892; time-to-peak untwisting, p=0.951) between the two phases of the menstrual cycle. However, there was a significant decrease in estrogen levels between the F- and L-phases (177+/-119pg/ml vs. 35+/-12pg/ml, p<0.0001). CONCLUSIONS: LV diastolic function in healthy premenopausal women did not significantly change during the menstrual cycle. Estrogen does not appear to have a significant acute effect on LV diastolic function in premenopausal woman. PMID- 27780634 TI - An oligodeoxyribonucleotide containing 5-formyl-2'-deoxycytidine (fC) at the CpG site forms a covalent complex with DNA cytosine-5 methyltransferases (DNMTs). AB - 5-Methylcytosine (mC) is known to induce epigenetic changes. Ten-eleven translocation (TET) enzymes produce the further oxidized 5-substituted cytosine derivatives, 5-formylcytosine (fC) and 5-carboxylcytosine (caC). However, their roles are unclear thus far. Here, we synthesized oligodeoxyribonucleotides (ODNs) containing 5-formyl-2'-deoxycytidine and examined their interactions with DNA cytosine-5 methyltransferase (DNMT). We found that the ODN sequence containing fCpG formed a covalent complex with both bacterial and mouse recombinant DNMTs in the absence of any cofactors. The covalent bonding with DNMT suggests that the fCpG sequence in DNA may play a role in epigenetic regulation. PMID- 27780635 TI - Discovery of fluorobenzimidazole HCV NS5A inhibitors. AB - Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series. PMID- 27780636 TI - Synthesis and bioactivities of amino acid ester conjugates of phenazine-1 carboxylic acid. AB - Phenazine-1-carboxylic acid (PCA) is a natural product that has been characterized by special chemical structures, interesting bioactivities and has been registered for fungicide against rice sheath blight in China. Phloem mobility is of great significance to long-distance transport of systemic pesticides in plants. In order to improve the phloem mobility and bioactivities of PCA, seventeen PCA-amino acid ester conjugates were designed and synthesized by conjugating PCA with different amino-acid esters. The conjugates were evaluated for their fungicidal activities against Rhizoctonia solani Kuhn and their phloem mobility was determined by HPLC. Results showed that conjugates a, b, c, d, e, l, m and p (EC50 values between 5.35 and 18.85MUg/mL) were more active than PCA (25.66MUg/mL). In particular, conjugates l and m exhibited the best fungicidal activities against Rhizoctonia solani Kuhn (EC50 values of them were 6.47MUg/mL and 5.35MUg/mL respectively). All these conjugates didn't have phloem mobility. PMID- 27780637 TI - MiR-106a: Promising biomarker for cancer. AB - MicroRNAs (miRNAs), which are characterized by highly conserved and small non coding RNAs, have been a hot spot regarding biological processes such as cellular proliferation, apoptosis and metabolism as well as cellular differentiation, signal transduction and carcinogenesis. MiRNA-106a (miR-106a), a member of the miR-17 family, has been validated to be aberrantly regulated in the diversity of tumors. The purpose of this review is supposed to deliver an intricate overview of miR-106a, including its role in cell proliferation, apoptosis, cell cycle, invasion and metastasis, involvement in drug resistance as well as its interactions with the target proteins and signaling pathways involved. PMID- 27780639 TI - Discovery of potent inhibitors of the lysophospholipase autotaxin. AB - The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel. PMID- 27780638 TI - 5-Aminopyrazole-4-carboxamide analogues are selective inhibitors of Plasmodium falciparum microgametocyte exflagellation and potential malaria transmission blocking agents. AB - Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) is essential for the exflagellation of male gametocytes. Inhibition of PfCDPK4 is an effective way of blocking the transmission of malaria by mosquitoes. A series of 5 aminopyrazole-4-carboxamide analogues are demonstrated to be potent inhibitors of PfCDPK4. The compounds are also able to block exflagellation of Plasmodium falciparum male gametocytes without observable toxicity to mammalian cells. PMID- 27780640 TI - Cu2+-labeled dansyl compounds as fluorescent and PET probes for imaging apoptosis. AB - Compound DNSTT-Cu2+, a novel chelate of Cu2+ with DOTA conjugated to a fluorescent dansyl fragment, is developed for imaging cell apoptosis. Apoptotic U 87MG cells could be selectively visualized by the fluorescence of DNSTT-Cu2+ from cytoplasm of cells, confirmed by the fluorescence of apoptosis cells co-labeled with Alexa Fluor 568-labeled annexin V, a conventional probe for selectively labeling membranes of apoptosis cells. A radioactive 64Cu2+ analog, DNSTT-64Cu2+, was easily synthesized, providing a potential PET probe for imaging apoptosis in vivo. PMID- 27780641 TI - Three-layer reconstruction of lower third nasal defects using forehead flap, reversed nasolabial flap, and auricular cartilage. AB - The reconstruction of a full-thickness defect of the distal third of the nose requires the restoration of all three anatomical layers. A practical method for three-layer reconstruction of the lower third of the nose and the long-term results of this technique are presented herein. A combined reconstruction technique was utilized, including a reverse subcutaneous pedicled nasolabial flap to restore the nasal mucosa, an auricular cartilage graft for structural support, and a forehead flap for cutaneous coverage of the defect. This technique was applied in 21 patients following the full-thickness excision of basal cell carcinoma of the lower part of the nose. All patients (12 male and nine female; mean age 59.8 years) were treated successfully and were satisfied with the aesthetic and functional outcomes. The wound had to be further revised in three cases for the correction of contour or residual deformities; however, no further complications were experienced. One patient had a wound infection and the cartilage had to be removed. The grafting procedure was repeated successfully after resolution of the infection. Donor site morbidity was unremarkable. Combined flaps from the forehead and nasolabial regions with an incorporated auricular cartilage graft can be used to reconstruct full-thickness defects of the lower third of the nose. PMID- 27780642 TI - Inferior subapical osteotomy for dentoalveolar decompensation of class III malocclusion in 'surgery-first' and 'surgery-early' orthognathic treatment. AB - Increasing experience with alternative timing protocols in orthognathic surgery has given way to new surgical and orthodontic techniques to shorten treatment times, reduce biological costs, and improve the final outcome. A prospective evaluation of class III patients who received an inferior segmental osteotomy (ISO) for decompensation of significantly retroclined lower incisors in the context of 'surgery-first' (SF) or 'surgery-early' (SE) timing protocols was performed. Treatment was planned virtually. A thorough periodontal assessment was performed at baseline and periodically until debonding. A minimally invasive surgical technique including selective interdental corticotomies and elective bone augmentation was used. Patient and orthodontist satisfaction with the treatment was evaluated. Eight patients (mean age 26.3 years) underwent surgery. One had isolated maxillary surgery and seven had bimaxillary surgery in combination or not with additional cosmetic procedures. The periodontal status of all patients remained stable throughout the observation period. The mean duration of orthodontic treatment was 8.7 months in the SF group and 10.5 months in the SE group. Satisfaction with treatment was extremely high. The ISO is a safe, reliable technique for dentoalveolar decompensation in timing protocols with a short or no orthodontic preparatory phase. This methodology may represent a reasonable approach in selected class III patients. PMID- 27780643 TI - Robotic Intracorporeal Padua Ileal Bladder: Surgical Technique, Perioperative, Oncologic and Functional Outcomes. AB - BACKGROUND: Robot-assisted radical cystectomy (RARC) with intracorporeal neobladder reconstruction is a challenging procedure. The need for surgical skills and the long operative times have led to concern about its reproducibility. OBJECTIVE: To illustrate our technique for RARC and totally intracorporeal orthotopic Padua ileal bladder. DESIGN, SETTING, AND PARTICIPANTS: From August 2012 to February 2014, 45 patients underwent this technique at a single tertiary referral centre. SURGICAL PROCEDURE: RARC, extended pelvic lymph node dissection, and intracorporeal partly stapled neobladder. Surgical steps are demonstrated in the accompanying video. MEASUREMENTS: Demographics, clinical, and pathological data were collected. Perioperative, 2-yr oncologic and 2-yr functional outcomes were reported. RESULTS AND LIMITATIONS: Intraoperative transfusion or conversion to open surgery was not necessary in any case and intracorporeal neobladder was successfully performed in all 45 patients. Median operative time was 305min (interquartile range [IQR]: 282-345). Median estimated blood loss was 210ml (IQR: 50-250). Median hospital stay was 9 d (IQR: 7-12). The overall incidence of perioperative, 30-d and 180-d complications were 44.4%, 57.8%, and 77.8%, respectively, while severe complications occurred in17.8%, 17.8%, and 35.5%, respectively. Two-yr daytime and night-time continence rates were 73.3% and 55.5%, respectively. Two-yr disease free survival, cancer specific survival, and overall survival rates were 72.5%, 82.3%, and 82.4%, respectively. The small sample size and high caseload of the centre might affect the reproducibility of these results. CONCLUSIONS: Our experience supports the feasibility of totally intracorporeal neobladder following RARC. Operative times and perioperative complication rates are likely to be reduced with increasing experience. PATIENT SUMMARY: We report the outcomes of our first 45 consecutive patients who underwent robot-assisted radical cystectomy with intracorporeal neobladders. Perioperative, oncologic, and functional outcomes support this technique as a feasible and safe surgical option in tertiary referral centres. PMID- 27780644 TI - Re: Atezolizumab in Patients with Locally Advanced and Metastatic Urothelial Carcinoma who have Progressed Following Treatment with Platinum-based Chemotherapy: A Single-arm, Multicenter, Phase 2 Trial. PMID- 27780645 TI - Getting Ready for Penile Transplantation. PMID- 27780646 TI - A patient in the clinic; a person in the world. Why shared decision making needs to center on the person rather than the medical encounter. AB - Interest in shared decision making (SDM) has increased and become widely promoted. However, from both practical and measurement perspectives, SDM's origin as an outgrowth of patient autonomy has resulted in narrowly conceptualizing and operationalizing decision making. The narrow focus on individual patient autonomy fails in four main ways: 1) excluding several facets of the roles, actions, and influences of decision partners in decision making; 2) focusing solely on the medical encounter; 3) ignoring the informational environment to which patients have access; and 4) treating each encounter as independent of all others. In addition to creating a research agenda that could answer important outstanding questions about how decisions are made and the consequences thereof, reconceiving SDM as centered on the person rather than the medical encounter has the potential to transform how illness is experienced by patients and families and how clinicians find meaning in their work. PMID- 27780647 TI - Does training general practitioners result in more shared decision making during consultations? AB - OBJECTIVE: We conducted a clustered randomised controlled trial to study the effects of shared decision making (SDM) on patient recovery. This study aims to determine whether GPs trained in SDM and reinforcing patients' treatment expectations showed more trained behaviour during their consultations than untrained GPs. METHODS: We compared 86 consultations conducted by 23 trained GPs with 89 consultations completed by 19 untrained GPs. The primary outcomes were SDM, as measured by the OPTION scale, and positive reinforcement, as measured by global observation. Secondary outcomes were the level of autonomy in decision making and the duration of the consultation. RESULTS: Intervention consultations scored significantly higher on most elements of the OPTION scale, and on the autonomy scale; however, they were three minutes longer in duration, and the mean OPTION score of the intervention group remained below average. CONCLUSION: Training GPs resulted in more SDM behaviour and more autonomy for the patient; however, this increase is not attributable to the adoption of a patient perspective. Furthermore, while we aimed to demonstrate that SDM facilitates the reinforcement of patients' positive expectations, the measurement of this behaviour was not reliable. PRACTICE IMPLICATIONS: In supporting SDM, professionals should give greater attention to patients' treatment expectations. PMID- 27780648 TI - Pain scores for venipuncture among ED patients. PMID- 27780649 TI - Pseudocoarctation of the aorta presented as chest discomfort with a pulsatile left supraclavicular mass and left arm coldness. PMID- 27780650 TI - Right atrial and ventricular function evaluated with speckle tracking in patients with acute pulmonary embolism. AB - AIMS: Assessment of right ventricular (RV) function in acute pulmonary embolism (PE) has prognostic significance. The aim of this study was to evaluate right atrium (RA) and RV myocardial damage with 2-dimensional speckle-tracking in patients with an acute central vs an acute peripheral PE. METHODS AND RESULTS: Twenty-six patients with acute PE and 10 controls were retrospectively enrolled. Right atrium and RV myocardial deformation was analyzed using speckle-tracking imaging echocardiography. Parameters were evaluated to illustrate myocardial damage in patients with a central or a peripherally located PE. Thirteen of the enrolled patients had a massive central PE, and thirteen subjects had a peripheral located PE. Baseline characteristics were not significantly different between the 3 groups besides a more elevated heart rate among patients with a central PE (P = .02) and a tendency of an increased D-dimer in this group. Right ventricular dimensions were more affected among patients with a PE. Compared with controls, segmental RV and RA strain/strain rate in the free wall was significantly reduced in patients with PE (P < .05). No difference was shown between the 2 groups of PE. CONCLUSION: This pilot study suggests that basal-/mid segments of RA and RV free wall are more affected in patients with a PE compared with controls. Interestingly, we found no significant difference in myocardial RA and RV damage between patients with a central and a peripheral PE. We advocate that PE no matter central or peripheral is a serious condition and that a peripheral PE has to be intensively treated similar to a central PE. PMID- 27780651 TI - Response to Letter to the Editor: "Why aren't our work results in burn care excellent?" PMID- 27780652 TI - Morphology of the Insertions of the Superficial Medial Collateral Ligament and Posterior Oblique Ligament Using 3-Dimensional Computed Tomography: A Cadaveric Study. AB - PURPOSE: To describe the insertions of the superficial medial collateral ligament (sMCL) and posterior oblique ligament (POL) and their related osseous landmarks. METHODS: Insertions of the sMCL and POL were identified and marked in 22 unpaired human cadaveric knees. The surface area, location, positional relations, and morphology of the sMCL and POL insertions and related osseous structures were analyzed on 3-dimensional images. RESULTS: The femoral insertion of the POL was located 18.3 mm distal to the apex of the adductor tubercle (AT). The femoral insertion of the sMCL was located 21.1 mm distal to the AT and 9.2 mm anterior to the POL. The angle between the femoral axis and femoral insertion of the sMCL was 18.6 degrees , and that between the femoral axis and the POL insertion was 5.1 degrees . The anterior portions of the distal fibers of the POL were attached to the fascia cruris and semimembranosus tendon, whereas the posterior fibers were attached to the posteromedial side of the tibia directly. The tibial insertion of the POL was located just proximal and medial to the superior edge of the semimembranosus groove. The tibial insertion of the sMCL was attached firmly and widely to the tibial crest. The mean linear distances between the tibial insertion of the POL or sMCL and joint line were 5.8 and 49.6 mm, respectively. CONCLUSIONS: This study used 3-dimensional images to assess the insertions of the sMCL and POL and their related osseous landmarks. The AT was identified clearly as an osseous landmark of the femoral insertions of the sMCL and POL. The tibial crest and semimembranosus groove served as osseous landmarks of the tibial insertions of the sMCL and POL. CLINICAL RELEVANCE: By showing further details of the anatomy of the knee, the described findings can assist surgeons in anatomic reconstruction of the sMCL and POL. PMID- 27780653 TI - Clinical Mimics: An Emergency Medicine-Focused Review of Stroke Mimics. AB - BACKGROUND: Stroke is a leading cause of death and disability and most commonly presents with focal neurologic deficit within a specific vascular distribution. Several other conditions may present in a similar manner. OBJECTIVES: This review provides emergency providers with an understanding of stroke mimics, use of thrombolytics in these mimics, and keys to differentiate true stroke from mimic. DISCUSSION: Stroke has significant morbidity and mortality, and the American Heart Association emphasizes rapid recognition and aggressive treatment for patients with possible stroke-like symptoms, including thrombolytics. However, many conditions mimic the presentation of stroke, with up to a 31% rate of misdiagnosis, leading to potentially harmful treatment. Stroke mimics are conditions that present with stroke-like symptoms, including seizures, headaches, metabolic, infection, space-occupying lesion, neurodegenerative disorder, peripheral neuropathy, syncope, vascular disorder, and functional disorder. Factors of history and physical examination supporting stroke vs. mimic are discussed, though any sudden-onset, objective, focal neurologic deficit in a patient should be assumed acute stroke until proven otherwise. Head computed tomography noncontrast is the first-line imaging modality. Magnetic resonance imaging is the most sensitive and specific imaging modality. Neurology consultation is recommended in the majority of patients. If stroke is suspected after evaluation, shared decision-making for further management and consideration of thrombolytics is recommended. CONCLUSIONS: Stroke mimics present a conundrum for emergency providers. A new focal neurologic deficit warrants rapid evaluation for stroke with neuroimaging and neurology consultation. Several mimics found on assessment may resolve with treatment. PMID- 27780655 TI - Lessons in ambivalence: The Shanghai Municipal Council's opium policies, 1906 1917. AB - BACKGROUND: Shanghai was considered to be a "capital of opium" in modern China, hence the history of opium in the city has received significant attention. In the Shanghai International Settlement, where Chinese and foreigners lived as neighbours, drugs were considered by the administration as both "trouble maker", and important financial resource. This paper explores how the Shanghai Municipal Council (SMC), the most senior governing body in the settlement, used its position to maximize political and economic profit from the trade and consumption of opium. METHODS: The paper is based on documentary analysis of records of the SMC board meetings and other related material stored at Shanghai Municipal Archives. Interpretive approaches were used to analyze the shifting SMC strategies on opium consumption, the competing power relations and the way they were negotiated between actors with a stake in the region, including semi colonialism and world systems analysis. RESULTS: With the dual purpose of preventing damage and enhancing municipal management, the SMC introduced a licensing system permitting the consumption and trade of drugs. However, the anti opium policies of the late Qing government and the Anglo-Chinese 10 Year Agreement meant SMC had to shut down opium "houses" (opium dens) and "shops" (for the sale of opium to be consumed off the premises). CONCLUSIONS: Over almost a decade, the SMC shifted emphasis from political regulation of a social, recreational practice to maximizing financial benefit. In the process, SMC made full use of the opportunities it gained from a period of ambivalent Chinese and British power relations and local community rule. PMID- 27780654 TI - Acculturative stress is associated with trajectory of anxiety symptoms during pregnancy in Mexican-American women. AB - Over half of pregnant women report anxiety symptoms and these symptoms may be precipitated by stressful experiences. Anxiety rates may be higher in Mexican American women who experience sociocultural stressors, such as acculturation, acculturative stress and discrimination. However, the role of such stressors on the trajectory of anxiety symptoms across pregnancy is not yet known. Mexican American women (n=151) completed surveys across pregnancy about acculturation, acculturative stress, perceived discrimination, and state anxiety. Multilevel modeling found that acculturation (Anglo orientation, b=0.050, SE=0.379, t (137.561)=0.134, p=0.894; Mexican orientation, b=0.775, SE=0.692, t (133.424)=1.121, p=0.264) and perceived discrimination (b=-1.259, SE=0.921, t (137.489)=-1.367, p=0.174) were not associated with the trajectory of anxiety symptoms. However, acculturative stress, even while controlling for perceived stress, was associated with high levels of anxiety symptoms that were elevated early in pregnancy (b=-0.045, SE=0.022, t (135.749)=-2, p=0.047). This work highlights the unique role of acculturative stress in risk for prenatal anxiety in early pregnancy. PMID- 27780656 TI - Uncovered issues in the association between uric acid and nonalcoholic fatty liver disease. PMID- 27780657 TI - Metabolic reprogramming & inflammation: Fuelling the host response to pathogens. AB - Successful immune responses to pathogens rely on efficient host innate processes to contain and limit bacterial growth, induce inflammatory response and promote antigen presentation for the development of adaptive immunity. This energy intensive process is regulated through multiple mechanisms including receptor mediated signaling, control of phago-lysomal fusion events and promotion of bactericidal activities. Inherent macrophage activities therefore are dynamic and are modulated by signals and changes in the environment during infection. So too does the way these cells obtain their energy to adapt to altered homeostasis. It has emerged recently that the pathways employed by immune cells to derive energy from available or preferred nutrients underline the dynamic changes associated with immune activation. In particular, key breakpoints have been identified in the metabolism of glucose and lipids which direct not just how cells derive energy in the form of ATP, but also cellular phenotype and activation status. Much of this comes about through altered flux and accumulation of intermediate metabolites. How these changes in metabolism directly impact on the key processes required for anti-microbial immunity however, is less obvious. Here, we examine the 2 key nutrient utilization pathways employed by innate cells to fuel central energy metabolism and examine how these are altered in response to activation during infection, emphasising how certain metabolic switches or 'reprogramming' impacts anti-microbial processes. By examining carbohydrate and lipid pathways and how the flux of key intermediates intersects with innate immune signaling and the induction of bactericidal activities, we hope to illustrate the importance of these metabolic switches for protective immunity and provide a potential mechanism for how altered metabolic conditions in humans such as diabetes and hyperlipidemia alter the host response to infection. PMID- 27780659 TI - Successful health communication in epileptology. AB - Advances in communication technologies have had an impact on virtually every aspect of daily life and have shaped the ways that persons with epilepsy learn about their disorder; communicate with their care providers, families and friends; and are viewed by society. This paper discusses drivers of changing communication patterns in epileptology and barriers that remain, available tools to enhance communication among and between all stakeholders, and potential future developments. PMID- 27780658 TI - An analysis of inter-professional collaboration in osteoporosis screening at a primary care level using the D'Amour model. AB - OBJECTIVES: This study describes the perspective of patients, nurses, pharmacists, doctors and policy makers to identify the level of collaboration and the areas for improvement to achieve inter-professional collaboration between doctors, nurses, pharmacists and policy makers in a primary care clinic. METHODS: Patients (n = 20), Nurses (n = 10), pharmacists (n = 11), doctors (n = 10) and policy makers (n = 5) from a primary care were individually interviewed using a semi-structured topic guide. Purposive sampling was used. Interviews were transcribed verbatim and analysed using thematic analysis informed by constant comparison. RESULTS: Patients, doctors, nurses, pharmacists and policy makers were eager for pharmacists to be more proactive in creating health awareness and conducting osteoporosis screening at the primary care clinic via inter professional collaboration. These findings were further examined using the D'Amour's structural model of collaboration which encompasses four main themes: shared goals and visions, internalization, formalization and governance. This model supports our data which highlights a lack of understanding of the pharmacists' role among the doctors, nurses, policy makers and pharmacists themselves. There is also a lack of governance and formalization, that fosters consensus, leadership, protocol and information exchange. Nonetheless, the stakeholders trust that pharmacists have sufficient knowledge to contribute to the screening of osteoporosis. Our primary care clinic can be described as developing towards an inter-professional collaboration in managing osteoporosis but is still in its early stages. CONCLUSIONS: Inter-professional collaboration in osteoporosis management at the primary care level is beginning to be practised. Efforts extending to awareness and acceptance towards the pharmacists' role will be crucial for a successful change. PMID- 27780660 TI - Clinical Utility of Real-Time MR-Navigated Ultrasound with Supine Breast MRI for Suspicious Enhancing Lesions Not Identified on Second-Look Ultrasound. AB - This study evaluated the usefulness of magnetic resonance (MR)-navigated ultrasound (US) for evaluation of magnetic resonance imaging (MRI)-detected lesions not visible on second-look US and analyzed differences in lesion-to nipple distance between supine and prone positions. Of the 831 consecutive patients who were diagnosed with breast cancer and examined with breast MRI from June 2013 to September 2015, 40 lesions in 37 patients who underwent MR-navigated US for MRI-detected lesions that were not visible on second-look US were included. First, MRI was performed in a prone position using a 1.5-T imager, and second, MRI was performed in a supine position for MR-navigated US. Of 40 lesions, 31 (78%) were identified with MR-navigated US, whereas 5 (13%) lesions disappeared on supine MRI and 4 (10%) exhibited no correlation on MR-navigated US. Of 31 lesions with pathologic confirmation, 7 (23%) were malignant, 2 (6%) were high-risk lesions and 22 (71%) were benign lesions. Comparison of the US findings of benign and malignant lesions revealed that orientation of the lesion differed significantly (p = 0.045), whereas lesion shape, margin and echo pattern did not significantly differ between the two groups (p = 0.088, p = 0.094 and p = 0.412, respectively). Median difference in lesion-to-nipple distance on supine and prone MRI was 8 mm (0-34 mm) in the horizontal direction and 5 mm (0-39.5 mm) in the vertical direction. Thirteen lesions exhibited a >1-cm difference in both horizontal and vertical directions. In conclusion, MR-navigated US was useful for the evaluation of MRI-detected lesions that were not visible on second-look US in breast cancer patients. PMID- 27780662 TI - Rapid subcutaneous desensitization for treatment of hypersensitivity reactions to etanercept in two patients with positive basophil activation test. PMID- 27780661 TI - High-Intensity Focused Ultrasound- and Radiation Therapy-Induced Immuno Modulation: Comparison and Potential Opportunities. AB - In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues. PMID- 27780663 TI - Characterization of Vibrio cholerae isolates from 1976 to 2013 in Shandong Province, China. AB - Cholera continues to be a serious public health issue in developing countries. We analyzed the epidemiological data of cholera from 1976 to 2013 in Shandong Province, an eastern coastal area of China. A total of 250 Vibrio cholerae isolates were selected for PCR analysis of virulence genes and pulsed-field gel electrophoresis (PFGE). The analysis of the virulence genes showed that the positive rates for tcpA and tcpI were the highest among strains from the southwest region, which had the highest incidence rate of cholera. Low positive rates for tcpA, tcpI and ctxAB among isolates from after 2000 may be an influencing factor contributing to the contemporary decline in cholera incidence rates. Spatiotemporal serotype shifts (Ogawa, Inaba, Ogawa, Inaba and O139) generally correlated with the variations in the PFGE patterns (PIV, PIIIc, PIa, PIIIb, PIIIa, PIb, and PII). O1 strains from different years or regions also had similar PFGE patterns, while O139 strains exclusively formed one cluster and differed from all other O1 strains. These data indicate that V. cholerae isolates in Shandong Province have continually undergone spatiotemporal changes. The serotype switching between Ogawa and Inaba originated from indigenous strains, while the emergence of serogroup O139 appeared to be unrelated to endemic V. cholerae O1 strains. PMID- 27780665 TI - Differences in men and women in acute coronary syndromes. PMID- 27780664 TI - Vascular enhancement pattern of mass in computed tomography may predict chemo responsiveness in advanced pancreatic cancer. AB - INTRODUCTION: Chemo-responsiveness in pancreatic cancer is known to be dependent on fibrosis and vascularity. The purpose of this study was to assess vascular enhancement in advanced pancreatic adenocarcinoma with or without liver metastasis in computed tomography (CT) and to analyze the correlation between enhancement patterns and chemo-responsiveness. METHODS: Patients were assigned to either a responder group (partial response or stable disease) or a non-responder group (progressive disease) according to chemo-responsiveness assessed by CT before and after gemcitabine-based chemotherapy. Hounsefield unit (HU) was measured in pancreatic mass and the largest metastatic liver mass using region of interest (ROI). HU differences (DeltaHU) between arterial and pre-contrast phase were calculated. RESULTS: Of the 101 study subjects, 78(77.2%) were assigned to the pancreas responder group {mean DeltaHU (+/-SD), 36.7(+/-21.6)} and 23(22.8%) to the pancreas non-responder group {mean DeltaHU (+/-SD), 20.6(+/-9.9)} (p = 0.001 for DeltaHUs). Of the 46 study subjects with liver metastasis, 25(54.3%) were assigned to the liver metastasis responder group {mean DeltaHU (+/-SD), 36.9(+/-21.0} and 21(45.7%) to the liver metastasis non-responder group {mean DeltaHU (+/-SD), 17.1 (+/-24.0)}, (p = 0.005 for DeltaHUs). CONCLUSION: CT determined mass vascular enhancement patterns may predict chemoresponse in advanced pancreatic cancer. PMID- 27780666 TI - Electrocardiographic Manifestations in three Psychiatric patients with Hypothermia - Case Report. AB - Hypothermia occurs when the core body temperature falls below 35 degrees C, which, in severe cases, can lead to electrocardiographic changes. Several conditions that occur in the psychiatric population increase the risk of hypothermia. This risk can be further increased by the use of several classes of medications such as antipsychotics, beta-adrenergic antagonists and benzodiazepines. We report on three psychiatric patients who were admitted for hypothermia and developed electrocardiographic manifestations (sinus bradycardia, QT prolongation and Osborn waves), which completely resolved after treatment. PMID- 27780667 TI - Co-administration of quercetin with pantoprazole sodium prevents NSAID-induced severe gastroenteropathic damage efficiently: Evidence from a preclinical study in rats. AB - Management of Nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy has emerged as a major medical and socioeconomic problem mainly because the highly efficacious gastroprotective drugs i.e. proton pump inhibitors (PPIs) like pantoprazole sodium (PTZ), worsen the NSAID-induced enteropathic damage and lack of approved therapeutic strategies/interventions to prevent this damage. Hence, the primary objective of the current study was to assess whether we can protect the GI mucosa against gastroenteropathic damage caused by diclofenac sodium (DIC) in rats by co-administration of PTZ and quercetin (QCT). Rats were treated twice daily with QCT (35, 50 and 100mgkg-1 peroral) and/or PTZ (4mgkg-1) or vehicle for a total of 10 days. In some experiments, DIC (9mgkg-1) was administered orally twice daily for the final 5days of PTZ/QCT+PTZ/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day, but, water was provided ad libitum. 12h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The experimental evidences suggested that co-administration of QCT with PTZ significantly attenuated the exacerbation of NSAID-induced enteropathic damage in a dose dependent manner. The combination of PTZ 4mgkg-1 and QCT at the doses of 50 or 100mgkg-1 was found to effective in preventing the DIC-induced gastroenteropathy. The present report focuses on the gastroenteroprotective ability of QCT and the mechanisms may be related to its ability to prevent GI blood loss, the lipid peroxidation, intestinal permeability alteration and alteration in GI luminal pH. PMID- 27780668 TI - The Role of Social Support and Self-efficacy for Planning Fruit and Vegetable Intake. AB - OBJECTIVE: The aim of the current study was to examine the joint effect of self efficacy, action planning, and received social support on fruit and vegetable intake. DESIGN: The study used a longitudinal design with 3 waves of data collection. SETTING: Major university campus in Beijing, China. PARTICIPANTS: Young adults (n = 286). VARIABLES MEASURED: Age, gender, body mass index, dietary self-efficacy, and baseline behavior were measured at time 1. Two weeks after time 1, received social support and action planning were assessed (time 2); 4 weeks after time 1, subsequent fruit and vegetable consumption was measured (time 3). ANALYSIS: In a path analysis, action planning at time 2 was specified as a mediator between self-efficacy at time 1 and fruit and vegetable intake at time 3, controlling for age, gender, body mass index, and baseline behavior. In addition, in a conditional process analysis, received social support at time 2 was specified as a moderator of the self-efficacy-planning relationship. RESULTS: Action planning mediated between self-efficacy and subsequent dietary behavior, and received social support moderated between self-efficacy and planning supporting a compensation effect. Action planning served as a proximal predictor of fruit and vegetable intake, and planning one's consumption was facilitated by dietary self-efficacy. CONCLUSIONS AND IMPLICATIONS: Through the identification of social cognitive factors influencing dietary planning, interventions can target self-efficacy and received social support to test the efficacy of these mechanisms in increasing individuals' ability to ensure they consume adequate amounts of fruits and vegetables. PMID- 27780669 TI - Facilitators and Barriers to the Achievement of Healthy Lifestyle Goals: Qualitative Findings From Australian Parents Enrolled in the PEACH Child Weight Management Program. AB - OBJECTIVES: To describe the qualitative research methods used in the Parenting Eating and Activity for Child Health (PEACH) randomized controlled trial and to examine parent-reported facilitators and barriers to the achievement of program goals. DESIGN: Qualitative study using semistructured interviews. SETTING: Parents enrolled in the Australian PEACH randomized controlled trial, a family focused child weight management program conducted blinded for review. PARTICIPANTS: A total of 95 parents of overweight children aged 5-10 years participated in face-to-face semistructured interviews. PHENOMENON OF INTEREST: Factors external to the PEACH intervention that facilitated or inhibited their success. ANALYSIS: Interviews were recorded, transcribed, and analyzed using thematic analysis techniques. RESULTS: Three facilitator themes were identified: (1) internal locus of parental control, (2) external locus of parental control, and (3) child factors. Six barrier themes were identified: (1) internal locus of parental control, (2) external locus of parental control, and (3) child factors; (4) maintenance and managing special occasions; (5) time management challenges; and (6) inconsistencies or lack of support. CONCLUSIONS AND IMPLICATIONS: The social and environmental barriers and time pressures identified by parents are a common feature of Western family life such that many parents are raising families in stressful situations. Insights provided by this qualitative research provide an important understanding of these experiences. Consideration of such issues in the design and implementation of future child weight management interventions may help to increase the acceptability and effectiveness of such programs. PMID- 27780670 TI - Type 2 diabetes and cardiovascular disease: A metabolic overview of recent clinical trials. PMID- 27780671 TI - Detailed analysis of targeted gene mutations caused by the Platinum-Fungal TALENs in Aspergillus oryzae RIB40 strain and a ligD disruptant. AB - Transcription activator-like effector nucleases (TALENs), which can generate DNA double-strand breaks at specific sites in the desired genome locus, have been used in many organisms as a tool for genome editing. In Aspergilli, including Aspergillus oryzae, however, the use of TALENs has not been validated. In this study, we performed genome editing of A. oryzae wild-type strain via error of nonhomologous end-joining (NHEJ) repair by transient expression of high efficiency Platinum-Fungal TALENs (PtFg TALENs). Targeted mutations were observed as various mutation patterns. In particular, approximately half of the PtFg TALEN mediated deletion mutants had deletions larger than 1 kb in the TALEN-targeting region. We also conducted PtFg TALEN-based genome editing in A. oryzae ligD disruptant (DeltaligD) lacking the ligD gene involved in the final step of the NHEJ repair and found that mutations were still obtained as well as wild-type. In this case, the ratio of the large deletions reduced compared to PtFg TALEN-based genome editing in the wild-type. In conclusion, we demonstrate that PtFg TALENs are sufficiently functional to cause genome editing via error of NHEJ in A. oryzae. In addition, we reveal that genome editing using TALENs in A. oryzae tends to cause large deletions at the target region, which were partly suppressed by deletion of ligD. PMID- 27780672 TI - [Quality in the anesthesia department of San Cecilio Hospital from the professionals' perspective]. AB - OBJECTIVE: To evaluate the quality of the services provided by the anaesthesia department of the San Cecilio Clinical University Hospital, from the health professionals' point of view. MATERIAL AND METHODS: Location: Andalusia. PARTICIPANTS: 134 health professionals in contact with the hospital anaesthesia department. Tool: self-administered questionnaire, measuring: accessibility, personal treatment, comfort, scientific and technical quality (scale 1 to 5), overall satisfaction (scale 0 to 10), and suggestions for improvement. A descriptive statistical and correlation analysis were performed, including mean differences (by sex, frequency of contact with the anaesthesia department, and unit), as well as a regression model. RESULTS: The quality of personal treatment received a mean of 4.2 points (SD 0.651), the scientific and technical quality 4.00 points (SD 0.532), accessibility 3.3 (SD 0.795), professional comfort 3.30 (SD 0.988), and patient comfort 2.62 points (SD 1.051). Overall satisfaction obtained a mean of 7.1 points (0 to 10 scale). Women and professionals working in units with less than 10 people had a better general evaluation of the anaesthesia department. The worse perspective was that of staff with daily contact with the anaesthesia department. Among the suggestions for improvement there were: Reducing waiting lists, creating special rooms to give information to families, improving working conditions, training and work satisfaction for staff, and achieving better communication and collaboration between health professionals. CONCLUSIONS: The internal evaluation shows the need for training strategies and organisational interventions in the anaesthesia department, in order to achieve a better quality and satisfaction for both professionals and patients. PMID- 27780673 TI - Transluminal attenuation-gradient coronary CT angiography on a 320-MDCT volume scanner: Effect of scan timing, coronary artery stenosis, and cardiac output using a contrast medium flow phantom. AB - PURPOSE: Transluminal-attenuation-gradient (TAG) may reflect patient characteristics and physiological parameters. Furthermore, TAG may be affected by factors such as the CT scanner speed, scanning method, scan timing after contrast medium (CM) injection, and the injection methods. The purpose of our study was to investigate quantitative TAG at different scan timing points after CM injection for coronary CT angiography. MATERIALS AND METHODS: Using a CM flow phantom and two types of connecting tube mimicking 0% and 70% coronary artery stenosis, we performed 320-detector volume scanning. The heart rate was set at 60bpm and cardiac-output (CO) at 2.0 and 4.0 l/min, respectively. The acquisition time repeated at 0.5-s intervals for 40 and 25s at a CO of 2.0- and 4.0 l/min. We measured the CT number on the same slice level, calculated the time-density-curve (TDC) and the TAG at each time point. RESULTS: At COs of 2.0 and 4.0 l/min at 0% stenosis, TAG exhibited smaller variations (-3.02 to +0.55HU/cm at 2.0 l/min, 2.63 to +0.43HU/cm at 4.0 l/min) than at 70% stenosis at each time point along the TDC. Compared with a CO at 2.0 l/min with 70% stenosis, the TAG curve for a CO at 4.0 l/min gradually changed with time (-6.64 to +1.18HU/cm at 2.0 l/min vs. -3.46 to +2.75HU/cm at 4.0 l/min). CONCLUSION: The TAG value was affected by scan timing after CM injection and by CO although the size of the connecting tube with and without stenosis was identical. PMID- 27780674 TI - Effects of shielding on pelvic and abdominal IORT dose distributions. AB - PURPOSE: To study the impact of shielding elements in the proximity of Intra Operative Radiation Therapy (IORT) irradiation fields, and to generate graphical and quantitative information to assist radiation oncologists in the design of optimal shielding during pelvic and abdominal IORT. METHOD: An IORT system was modeled with BEAMnrc and EGS++ Monte Carlo codes. The model was validated in reference conditions by gamma index analysis against an experimental data set of different beam energies, applicator diameters, and bevel angles. The reliability of the IORT model was further tested considering shielding layers inserted in the radiation beam. Further simulations were performed introducing a bone-like layer embedded in the water phantom. The dose distributions were calculated as 3D dose maps. RESULTS: The analysis of the resulting 2D dose maps parallel to the clinical axis shows that the bevel angle of the applicator and its position relative to the shielding have a major influence on the dose distribution. When insufficient shielding is used, a hotspot nearby the shield appears near the surface. At greater depths, lateral scatter limits the dose reduction attainable with shielding, although the presence of bone-like structures in the phantom reduces the impact of this effect. CONCLUSIONS: Dose distributions in shielded IORT procedures are affected by distinct contributions when considering the regions near the shielding and deeper in tissue: insufficient shielding may lead to residual dose and hotspots, and the scattering effects may enlarge the beam in depth. These effects must be carefully considered when planning an IORT treatment with shielding. PMID- 27780676 TI - Reply to: Comments on 'Intraoperative near-infrared fluorescence imaging using indocyanine green in colorectal carcinomatosis surgery: Proof of concept'. PMID- 27780675 TI - Oxaliplatin versus Mitomycin C for HIPEC in colorectal cancer peritoneal carcinomatosis. AB - OBJECTIVE: Compare long-term outcomes in colorectal cancer (CRC) patients with peritoneal carcinomatosis (PC) treated with peritonectomy/HIPEC using oxaliplatin versus MMC. BACKGROUND: Peritonectomy and heated intraperitoneal chemotherapy (HIPEC) greatly improves patient survival in CRC PC. This procedure is not uniform across centres and the optimal choice of HIPEC chemotherapeutic is unclear. Oxaliplatin and Mitomycin C (MMC) are the most commonly used agents and comparative studies have reported varying results. METHOD: 201 patients were retrospectively selected from the St George Hospital database, all of which had undergone peritonectomy/HIPEC for CRC PC. Oxaliplatin and MMC were used in 106 and 96 patients, respectively. Each patient's baseline characteristics, operative details, choice of chemotherapeutic agent and survival were noted. RESULTS: The two groups did not differ significantly at baseline. Patients receiving oxaliplatin had significantly greater unadjusted median survival compared to MMC (56.0 +/- 8.1 vs. 29.0 +/- 3.4 months) which translated into a hazards ratio of 0.59 (95% CI 0.37-0.91, p = 0.017). Subgroup analysis further confirmed an advantage with oxaliplatin in females, moderate-well differentiated tumours, tumours without signet ring pathology and PCI 10-15. CONCLUSION: Our study suggests oxaliplatin offers a survival advantage over MMC when used for HIPEC in CRC PC. Further studies to understand its efficacy, complications and ideal preparation are required. A Phase III randomised control trial comparing oxaliplatin and MMC would enhance decision-making. PMID- 27780677 TI - Total thyroidectomy alone versus ipsilateral versus bilateral prophylactic central neck dissection in clinically node-negative differentiated thyroid carcinoma. A retrospective multicenter study. AB - BACKGROUND: Central neck dissection (CND) remains controversial in clinically node-negative differentiated thyroid carcinoma (DTC) patients. The aim of this multicenter retrospective study was to determine the rate of central neck metastases, the morbidity and the rate of recurrence in patients treated with total thyroidectomy (TT) alone or in combination with bilateral or ipsilateral CND. METHODS: The clinical records of 163 clinically node-negative consecutive DTC patients treated between January 2008 and December 2010 in three endocrine surgery referral units were retrospectively evaluated. The patients were divided into three groups: patients who had undergone TT alone (group A), TT with ipsilateral CND (group B), and TT with bilateral CND (group C). RESULTS: The respective incidences of transient hypoparathyroidism and unilateral recurrent nerve injury were 12.6% and 1% in group A, 23.3% and 3.3% in B, and 36.7% and 0% in C. Node metastases were observed in 8.7% in group A, 23.3% in B, and 63.3% in C. Locoregional recurrence was observed in 3.9% of patients in group A and in 0% in B and C. CONCLUSIONS: We found no statistically significant differences in the rates of locoregional recurrence between the three groups. Therefore, TT appears to be an adequate treatment for these patients; CND is associated with higher rates of transient hypoparathyroidism and cannot be considered the treatment of choice even if it could help for more appropriate selection of patients for RAI. Ipsilateral CND could be an interesting option considering the lower rate of hypocalcemia to be validated by further studies. PMID- 27780678 TI - Exercising patient-centredness in prehabilitation programs. PMID- 27780679 TI - Iliac Artery Stent Fracture Associated with Atherosclerotic Iliac Aneurysm. PMID- 27780680 TI - Diseases affecting patients returning from abroad: Experience of a travel clinic in Japan from 2004 to 2014. AB - The number of patients returning from or staying abroad is likely to increase in the future. We performed a retrospective study of patients returning from abroad in our travel clinic in Japan. All patients presenting within 6 months of traveling abroad between 2004 and 2014 were included in the present study. A total of 2374 (mean age, 35 years) patients were seen by doctors specializing in treating infectious diseases. Of these, 918 were females and 87 of them lived abroad. Diagnoses and exposure regions were recorded for all patients. The most frequent region visited before attending our clinic was Southeast Asia (n = 1050, 44%), with a median duration for staying abroad of 8 days. The major purposes for overseas travel were tourism (n = 1302, 55%) and business (n = 684, 29%). Of the 2399 individual diagnoses made, the most frequent were diseases of the gastrointestinal system (n = 1083, 45%), skin and soft tissue (n = 440, 18%), systemic febrile disease without specific systems (419, 18%), and the respiratory system (353, 15%). The relative incidences of specific diseases changed drastically due to significant disease outbreaks, such as pandemic influenza in 2009. Exposure regions remained relatively constant throughout the study period, except for Japan. Vaccine-preventable diseases accounted for 5.3% of all the diseases, and 402 (26%) patients received pre-travel consultation and prophylaxis with vaccines and/or anti-malarial drug. We should make an effort to make more people notice the risk of travel and properly perform prophylaxis. PMID- 27780681 TI - [Opinions and nurse' satisfaction with INICIARE 2.0 scale: A qualitative study in a hospital setting]. AB - OBJECTIVE: To know the opinions and satisfaction of nurses with the use of INICIARE, an instrument developed for assessment of nursing care needs in hospitalized patients. INICIARE is based on Virginia Henderson's conceptual model, and built up with indicators of Nursing Outcomes Classification (NOC) taxonomy. METHOD: Exploratory qualitative study, using focus group technique for data collection. The sessions were recorded until saturation of information. A content analysis of syntactic, semantic and pragmatic levels of transcripts was performed. Participants' informed consent was obtained. RESULTS: Three focus groups were developed; 24 nurses from two Public Hospitals in Andalusia (Southern Spain) participated; and four thematic categories were created to measure satisfaction with the instrument. INICIARE helped the nursing process. Its closed format, and items in NOC taxonomy streamline evaluation, facilitates its inclusion in Electronic Information Systems, and strengthens effective communication at all levels. CONCLUSIONS: Nurses are satisfied with the use of INICIARE scale as a tool to enhance quality of care. It also has potential to be used as a tool for decision making in management of nursing care. PMID- 27780682 TI - Beyond the front end: Investigating a thigh worn accelerometer device for step count and bout detection in Parkinson's disease. AB - Free-living ambulation with accelerometer-based devices is an attractive methodology to assess habitual behaviour within Parkinson's disease (PD). However, slowness of movement can contribute to difficulty in quantifying ambulatory/walking outcomes within this group by these devices. This study investigates the use of a commercial accelerometer device (activPALTM) in those with moderate PD to understand its proprietary software (inbuilt algorithm) limitations. The values provided by the proprietary software are evaluated in comparison to novel algorithms on the same raw data to examine limitations for use within this cohort. The bespoke algorithms help to alter sensitivity in outcomes stemming from the same accelerometer data while also highlighting how slight changes in algorithms can drastically inflate/deflate values. In general, results show that the proprietary software generally quantifies lower values of outcomes (step and bout count), which is similar to previous findings. Variations in algorithm functionality highlight large heterogeneity in bout and step counts resulting from a lack of how they are defined within the literature. The novel alternative ambulatory algorithms presented here should be considered for use on raw data from the activPALTM in those with moderate/severe PD. PMID- 27780684 TI - Editorial commentary: Genetic testing in the absence of phenotype: When genetic testing may cause harm. PMID- 27780683 TI - Collective empowerment strategies for patients with Diabetes Mellitus: A systematic review and meta-analysis. AB - AIMS: To perform a systematic review and meta-analysis to identify and analyze collective empowerment strategies for patients with Diabetes Mellitus (DM). METHODS: The systematic review was performed using PubMed/MEDLINE, Science Direct and BVS. The term "Diabetes Mellitus" was used with each of the following describers, along with the connector "AND": "self-care", "health education", "motivation" and "empowerment". Inclusion criteria were: intervention study with control group published between 2004 and 2014. For meta-analysis, RevMan V 5.3 software was used. RESULTS: Among the nine analyzed articles, 66.7% (n=6) were developed in patients diagnosed with DM2. Concerning the indicators for intervention effectiveness evaluation, all articles (n=9) used glycated hemoglobin (HbA1c) and the most used instrument was Summary of Diabetes Self Care Activities Measure, representing 44.4% (n=4) of the studies. The types of strategies used were similar in the articles. There was evidence of a decrease in HbA1c levels in 66.7% (n=6). The meta-analysis found significant evidence indicating beneficial effects of empowerment. CONCLUSIONS: Programs based on collective empowerment in DM have shown the interventions lead to improvement in clinical parameters, behavior, increased knowledge about DM, and self-care. PMID- 27780685 TI - A new operative method for obtaining full-arch prostheses for immediate loading dental implants. AB - PURPOSE: Implant supported full-arch immediate prosthesis (also called the immediate Branemark protocol) revolutionized dental clinical practice due to the aesthetic/functional benefits it offers to the patient. This work presents a simplified and efficient technique for implant supported full-arch immediate prosthesis fabrication. METHODS: After diagnosing the necessity of the protocol, the implants were installed with a minimum torque of 35Ncm. For implant impression, the use of previously prepared castable cylinders (dispensing with impression posts), and a U-shaped acrylic (Mello technique) generated a cast without distortion. The Branemark protocol was fabricated on this cast without the metal test specimen. CONCLUSION: The simplified technique proposed in this article for Branemark protocol fabrication seemed to be effective. PMID- 27780687 TI - Interventions utilising contact with people with disabilities to improve children's attitudes towards disability: A systematic review and meta-analysis. AB - BACKGROUND: Children with disabilities are often the target of prejudice from their peers. The effects of prejudice include harmful health consequences. The Contact Hypothesis has previously shown to promote positive attitudes towards a range of social groups. OBJECTIVE: To conduct a systematic review and meta analysis on the effectiveness of school-based interventions for improving children's attitudes towards disability through contact with people with disabilities. METHODS: A comprehensive search was conducted across multiple databases. Studies were included if it evaluated an intervention that aimed to improve children's attitudes towards disability and involved either direct (in person) or indirect (e.g., extended) contact with people with disabilities. Data were synthesised in a meta-analysis. RESULTS: Twelve studies met the inclusion criteria. Of these, 11 found significant effects: six used direct contact, two used extended contact, two used parasocial (media-based) contact and one used guided imagined contact. One parasocial contact intervention found no significant effects. Three meta-analyses showed direct contact (d = 0.55, 95% CI 0.20 to 0.90) and extended contact (d = 0.61, 95% CI 0.15 to 1.07) improved children's attitudes; there was no evidence for parasocial contact (d = 0.20, 95% CI -0.01 to 1.40). CONCLUSIONS: Direct, extended, and guided imagined contact interventions are effective in improving children's attitudes towards disability; there was no evidence for parasocial contact. PMID- 27780688 TI - Patterns of care in women with high-intermediate risk endometrioid adenocarcinoma in the PORTEC-2 era: A SEER database analysis. AB - PURPOSE: We examined the radiotherapy patterns of care over an 8-year period during which the PORTEC-2 trial and other series were published. METHODS AND MATERIALS: Patients diagnosed with Stage I endometrioid adenocarcinoma (EA) between 2004 and 2011 were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Adjuvant radiation treatments were analyzed by year. Patterns of care from 2004 to 2008 were compared to those from 2009 to 2011 using the chi2 test. RESULTS: Analysis included 31,688 patients with Stage I EA. Among those diagnosed in 2004, 9.3% received adjuvant external beam radiotherapy (EBRT) and 5.0% received adjuvant brachytherapy. In 2011, 4.5% received EBRT and 9.3% received brachytherapy. In those diagnosed with high-intermediate risk (H-IR) EA in 2004, 58.8% received no adjuvant treatment, 28.3% received EBRT, and 12.9% received brachytherapy. In 2011, 57.8% of patients with H-IR disease received no adjuvant treatment, 14.3% received EBRT, and 27.9% received brachytherapy. There was a significant difference in the proportion of patients with H-IR EA treated with EBRT vs. brachytherapy alone before and after 2008 (p < 0.0001) with an increase in use of brachytherapy and a decrease in the use of EBRT. CONCLUSIONS: The use of brachytherapy alone after hysterectomy has increased over time in all women with Stage I EA and in those with H-IR disease. In almost all subsets, the proportion of women being treated with brachytherapy increased and the proportion treated with EBRT decreased. Less than 30% received adjuvant brachytherapy and over 50% of women were treated without adjuvant radiotherapy. PMID- 27780686 TI - MicroR-146 blocks the activation of M1 macrophage by targeting signal transducer and activator of transcription 1 in hepatic schistosomiasis. AB - Schistosomiasis is a chronic disease caused by the parasite of the Schistosoma genus and is characterized by egg-induced hepatic granulomas and fibrosis. Macrophages play a central role in schistosomiasis with several studies highlighting their differentiation into M2 cells involved in the survival of infected mice through limitation of immunopathology. However, little is known regarding the mechanisms of regulating macrophage differentiation. Here, we showed that the early stage of infection by Schistosoma japonicum induced expression of type 1T-helper-cell (Th1) cytokine, interferon-gamma (IFN-gamma), leading to increase in M1 cells. However, the presence of liver-trapped eggs induced the expression of Th2 cytokines including interleukin-4 (IL-4), IL-10, and IL-13 that upregulated the transcription of miR-146b by activating signal transducer and activator of transcription 3/6 (STAT3/6) that bind to the promoter of the pre-miR-146b gene. We found that the miR-146a/b was significantly upregulated in macrophages during the progression of hepatic schistosomiasis. The elevated miR-146a/b inhibited the IFN-gamma-induced differentiation of macrophages to M1 cells through targeting STAT1. Our data indicate the protective roles of miR-146a/b in hepatic schistosomiasis through regulating the differentiation of macrophages into M2 cells. PMID- 27780690 TI - Risk of Atrial Fibrillation and Bleeding Diathesis Associated With Ibrutinib Treatment: A Systematic Review and Pooled Analysis of Four Randomized Controlled Trials. AB - BACKGROUND: Clinical trials raised concern that ibrutinib may increase the risk of atrial fibrillation/flutter (Afib/Aflutter) and major bleeding. However, the association has not been statistically validated, and there is no consensus regarding optimal management of anticoagulation among patients receiving ibrutinib who develop Afib/Aflutter. We performed a systematic review and pooled analysis to precisely assess the risk of Afib/Aflutter and bleeding associated with ibrutinib treatment in patients with hematologic malignancies. PATIENTS AND METHODS: We searched PubMed, EMBASE, Cochrane Database, and meeting abstracts up to May 15, 2016, for randomized controlled trials comparing ibrutinib to chemotherapy, monoclonal antibody, or a combination. Primary outcomes were serious Afib/Aflutter and major bleeding. Secondary outcomes were all-grade Afib/Aflutter and bleeding. We calculated the Mantel-Haenszel risk ratio (RR) and estimated the effect of the treatments using a fixed-effects model. RESULTS: Ibrutinib treatment was associated with a significantly higher incidence of serious Afib/Aflutter (3.03% vs. 0.80%, RR = 3.80, 95% confidence interval [CI] = 1.56-9.29, P = .003), all-grade Afib/Aflutter (8.18% vs. 0.93%, RR = 8.81, 95% CI = 2.70-28.75, P = .0003), and all-grade bleeding (4.85% vs. 1.55%, RR = 2.93, 95% CI = 1.14-7.52, P = .03) compared to control treatments. The observed between treatment difference in major bleeding rates was not statistically significant (3.69% vs. 2.13%, RR = 1.72, 95% CI = 0.95-3.11, P = .07). The risk of these adverse events was not different between subgroups on the basis of pathology, treatment setting, dose, and duration of ibrutinib exposure. CONCLUSION: The risks of Afib/Aflutter and all-grade bleeding were significantly higher in the ibrutinib group. These results indicate the need for vigilant monitoring while the patient is receiving ibrutinib therapy, and careful assessment of the risks and benefits of anticoagulation is required. PMID- 27780689 TI - Bone Mineral Density According to Dual Energy X-ray Absorptiometry is Associated with Serial Serum Alkaline Phosphatase Level in Extremely Low Birth Weight Infants at Discharge. AB - BACKGROUND: To examine bone mineral density in extremely low birth weight infants at discharge and investigate whether serial measurements of serum alkaline phosphatase (ALP) and phosphate can predict bone mineralization. METHODS: The individuals were 70 preterm infants. Serum calcium, phosphate, and ALP were measured at weekly intervals during admission in extremely low birth weight infants (mean gestational age, 25.3+/-2.1 weeks; birth weight, 812.8+/-141.1 g). Bone mineral apparent density (BMAD) of the lumbar spine was prospectively evaluated by dual energy X-ray absorptiometry at discharge (n=70). RESULTS: BMAD was classified as poor (< 25th percentile) at < 0.014 g/cm3, fair (25th-75th percentile) at < 0.014-0.021 g/cm3, and good (> 75th percentile) at > 0.021 g/cm3, based on the distribution of BMAD values in infants with noncomplicated courses of prematurity (n=43). In a further multivariate analysis, the number of total parenteral nutrition days, phosphate at 2 postnatal weeks and 3 postnatal weeks, and ALP at 4 postnatal weeks and 5 postnatal weeks had an impact on bone mineral density at the lumbar spine, independent of gestational age and body weight. Peak ALP activities exceeding 650 IU/L revealed low bone mineral density with 80% sensitivity and 64% specificity (AUC, 0.70; p=0.005). CONCLUSION: Serial measurements of serum ALP and phosphate are associated with decreased bone mineralization by dual energy X-ray absorptiometry at discharge in extremely low birth weight infants. PMID- 27780691 TI - Regeneration of a Tooth in a Tissue-Engineered Mandible After Resection of a Central Giant Cell Tumor. Demonstrating Evidence of Functional Matrix Theory and Ectodermal Origin of Teeth in a Human Model-A Case Report. AB - Central giant cell tumors (CGCTs) are uncommon lesions occurring in the jaw. They are benign but locally destructive osteolytic lesions. They usually occur in pediatric patients 5 to 15 years of age. Multiple noninvasive modalities of treatment (intralesional steroids, interferon, calcitonin, and denosumab) have been described for those lesions, but for those that are refractory to treatment, enucleation and curettage or resection is a curative surgery. This case report describes a pediatric patient who was diagnosed with an aggressive CGCT of the left mandible encompassing the right angle to the condyle. The lesion became refractory to noninvasive treatments and immediate resection and reconstruction was performed using principles of tissue engineering. After 5 years of close observation, the patient showed normal morphology and growth of his mandible, but surprisingly developed a left mandibular third molar (tooth 17) in the site of the mandibular resection and reconstruction. This is the first case report in the literature to show the spontaneous development of teeth in a human reconstructed mandible, contributing evidence toward the functional matrix theory of mandibular growth and ectodermal origin of teeth. PMID- 27780692 TI - The Influence of Weight-Loss Expectations on Weight Loss and of Weight-Loss Satisfaction on Weight Maintenance in Severe Obesity. AB - BACKGROUND: Conflicting evidence exists as to whether cognitive mechanisms contribute to weight loss and maintenance. OBJECTIVE: To assess the influence of weight-loss expectations on weight loss, and of weight-loss satisfaction on weight maintenance, in individuals with severe obesity. DESIGN: A randomized controlled trial comparing two types of energy-restricted diets (high protein vs high carbohydrate) combined with weight-loss cognitive behavioral therapy, conducted over 51 weeks and divided into two phases: weight-loss phase (3 weeks of inpatient treatment and 24 weeks of outpatient treatment) and weight maintenance phase (24 weeks of outpatient treatment). PARTICIPANTS/SETTING: Eighty-eight participants with severe obesity (mean age=46.7 years and mean body mass index=45.6), referred to an eating and weight disorders clinical service, were studied. MAIN OUTCOME MEASURES: Body weight was assessed at baseline, and after 3, 27 (end of weight-loss phase), and 51 weeks (end of weight maintenance phase). Weight loss expectations were assessed at the time of enrollment, and weight-loss satisfaction was assessed after 27 weeks. STATISTICAL ANALYSES PERFORMED: The relationship between weight-loss expectations and weight loss was assessed using a linear mixed model. The association between weight-loss satisfaction and final outcomes was tested by linear regression. RESULTS: The two groups had similar weight-loss expectations and satisfaction, and their results were therefore pooled. In general, the total amount of expected weight loss (in kilograms), but not the percentage of expected weight loss, predicted weight loss, and both satisfaction with weight loss and the amount of weight lost (in kilograms) were independent predictors of weight maintenance. CONCLUSIONS: Higher expected weight loss improves weight loss, and both the total amount of weight lost and satisfaction with weight loss are associated with weight-loss maintenance at 1-year follow-up. PMID- 27780693 TI - Validation of a Magnetic Resonance Imaging-based Auto-contouring Software Tool for Gross Tumour Delineation in Head and Neck Cancer Radiotherapy Planning. AB - AIMS: To carry out statistical validation of a newly developed magnetic resonance imaging (MRI) auto-contouring software tool for gross tumour volume (GTV) delineation in head and neck tumours to assist in radiotherapy planning. MATERIALS AND METHODS: Axial MRI baseline scans were obtained for 10 oropharyngeal and laryngeal cancer patients. GTV was present on 102 axial slices and auto-contoured using the modified fuzzy c-means clustering integrated with the level set method (FCLSM). Peer-reviewed (C-gold) manual contours were used as the reference standard to validate auto-contoured GTVs (C-auto) and mean manual contours (C-manual) from two expert clinicians (C1 and C2). Multiple geometric metrics, including the Dice similarity coefficient (DSC), were used for quantitative validation. A DSC>=0.7 was deemed acceptable. Inter- and intra variabilities among the manual contours were also validated. The two-dimensional contours were then reconstructed in three dimensions for GTV volume calculation, comparison and three-dimensional visualisation. RESULTS: The mean DSC between C gold and C-auto was 0.79. The mean DSC between C-gold and C-manual was 0.79 and that between C1 and C2 was 0.80. The average time for GTV auto-contouring per patient was 8 min (range 6-13 min; mean 45 s per axial slice) compared with 15 min (range 6-23 min; mean 88 s per axial slice) for C1. The average volume concordance between C-gold and C-auto volumes was 86.51% compared with 74.16% between C-gold and C-manual. The average volume concordance between C1 and C2 volumes was 86.82%. CONCLUSIONS: This newly designed MRI-based auto-contouring software tool shows initial acceptable results in GTV delineation of oropharyngeal and laryngeal tumours using FCLSM. This auto-contouring software tool may help reduce inter- and intra-variability and can assist clinical oncologists with time-consuming, complex radiotherapy planning. PMID- 27780694 TI - Stereotactic Ablative Radiotherapy Versus Low Dose Rate Brachytherapy or External Beam Radiotherapy: Propensity Score Matched Analyses of Canadian Data. AB - AIMS: To compare biochemical failure-free survival (BFFS) and overall survival for prostate cancer treated with stereotactic ablative radiotherapy (SABR), low dose rate (LDR) brachytherapy or external beam radiotherapy (EBRT) using a large Canadian multi-institutional database. MATERIALS AND METHODS: Patients with low risk localised prostate cancer treated with SABR, LDR or EBRT and no androgen deprivation therapy were selected. Propensity score matching was used to create two sets of matched cohorts with LDR and EBRT serving as control groups. Kaplan Meier survival analysis and Cox proportional hazards regression were used to compare differences in BFFS and overall survival between treatment groups. RESULTS: The pre-matched cohort contained 602 patients; the median follow-up was >5.0 years. There were no significant differences in BFFS before or after matching for SABR versus LDR but the prostate-specific antigen (PSA) nadir was lower after LDR. For the SABR versus EBRT, SABR had a BFFS trend before matching (P = 0.08), which became significant after matching (P < 0.001). CONCLUSIONS: Using the Genitourinary Radiation Oncologists of Canada Prostate Cancer Risk Stratification database, low risk prostate cancer patients receiving SABR had similar BFFS compared with patients receiving LDR but better BFFS than EBRT patients. Further comparative studies of efficacy, quality of life and economic outcomes using a broader risk of patients are warranted. PMID- 27780695 TI - Real-time Image-guided Adaptive-predictive Prostate Radiotherapy using Rectal Diameter as a Predictor of Motion. AB - AIMS: To investigate a relationship between maximum rectal diameter (MRD) on pre treatment cone beam computed tomography (CBCT) and intra-fraction prostate motion, in the context of an adaptive image-guided radiotherapy (IGRT) method. MATERIALS AND METHODS: The MRD was measured on 2125 CBCTs from 55 retrospective patient datasets and related to prostate displacement from intra-fraction imaging. A linear regression model was developed to determine a threshold MRD associated with a high probability of small prostate displacement. Standard and reduced adaptive margin plans were created to compare rectum and bladder normal tissue complication probability (NTCP) with each method. RESULTS: A per-protocol analysis carried out on 1910 fractions from 51 patients showed with 90% confidence that for a MRD<=3 cm, prostate displacement will be <=5 mm and that for a MRD<=3.5 cm, prostate displacement will be <=5.5 mm. In the first scenario, if adaptive therapy was used instead of standard therapy, median reductions in NTCP for rectum and bladder were 0.5% (from 9.5% to 9%) and 1.3% (from 6.6% to 5.3%), respectively. In the second scenario, the NTCP for rectum and bladder would have median reductions of 1.1% and 2.6%, respectively. CONCLUSIONS: We have identified a potential method for adaptive prostate IGRT based upon predicting small prostate intra-fraction motion by measuring MRD on pre-treatment CBCT. PMID- 27780696 TI - Virtual mutation and directional evolution of anti-amoxicillin ScFv antibody for immunoassay of penicillins in milk. AB - In this study, an anti-amoxicillin single chain variable fragment (ScFv) antibody was evolved by directional mutagenesis of a contact amino acid residue based on the analysis of virtual mutation. Comparison with its parental ScFv, the mutant showed highly improved affinity for 11 penicillins with up to 6-folds increased sensitivity. Then, its recognition mechanisms for the 11 drugs were studied by using molecular docking. Results showed that the mutant-penicillins intermolecular forces increased and the total binding energies decreased dramatically, which were responsible for the improvement of antibody sensitivity. The ScFv mutant was used to develop an indirect competitive enzyme linked immunosorbent assay for determination of the 11 drugs in milk. The limits of detection were in the range of 0.2-3.0 ng/mL, the crossreactivities were in the range of 31%-132%, and the recoveries from standards fortified blank milk were in the range of 65.7%-92.4%. This is the first study reporting the directional evolution of a ScFv antibody based on virtual mutation and the use of ScFv antibody for determination of penicillins in foods of animal origin. PMID- 27780697 TI - Pulmonary artery dissection causing haemothorax in a cat: potential role of Dirofilaria immitis infection and literature review. AB - A 7-year-old male castrated domestic short-haired cat suddenly died. Gross examination revealed severe right-sided haemothorax with blood clots, four adult filarial nematodes in the blood clots and the caudal vena cava and haemorrhage dissecting into the tunica media of the right pulmonary artery. Histopathological investigation showed fibrosis of the tunica intima and disorganization/fragmentation of the elastic fibres accompanied by fibrous tissue deposition in the tunica media of both branches of pulmonary artery. Degenerative vasculopathy (intimal fibromuscular hyperplasia and medial hypertrophy/hyperplasia) involving pulmonary arteries was also observed. The polymerase chain reaction amplification and sequencing confirmed the identification of the parasite as Dirofilaria immitis. A diagnosis of pulmonary artery dissection with haemothorax and concomitant heartworm disease was formulated. Degenerative processes of the tunica media have been reported to cause pulmonary artery dissection in both humans and animals. Pulmonary artery remodelling induced by heartworms may be considered the underlying cause in the first case of feline pulmonary artery dissection, herein described. PMID- 27780698 TI - Management of borderline ovarian tumours. AB - Approximately 3000 American women are diagnosed with borderline ovarian tumours annually. Borderline tumours are similar to other types of adnexal masses. Prognostic factors include the International Federation of Gynecology and Obstetrics (FIGO) stage, presence of peritoneal implants, micropapillary pattern (for serous histology), microinvasion and intra-epithelial carcinoma (for mucinous histology). Approximately 65-70% of serous tumours and 90% of mucinous tumours are stage I, and 30% and 10%, respectively, are associated with extra ovarian spread. Fertility-preservation counselling is recommended for young patients. Fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group. Surgical staging generally includes resection of the primary borderline tumour, by either unilateral salpingo-oophorectomy or ovarian cystectomy, cytologic washings, omentectomy and peritoneal biopsies, and routine lymphadenectomy is not recommended. However, because the accuracy of frozen section examination is lower than optimal, caution is recommended. Postoperative therapy is recommended only for those women with serous borderline tumours and invasive implants. Fortunately, relapse is uncommon. PMID- 27780699 TI - Reply. PMID- 27780700 TI - Primary maternal cytomegalovirus infections: accuracy of fetal ultrasound to predict sequelae in offspring. PMID- 27780701 TI - Threatened preterm labor is a risk factor for impaired cognitive development in early childhood. AB - BACKGROUND: Threatened preterm labor is a leading cause of hospital admission during pregnancy. Patients with an episode of threatened preterm labor who deliver at term are considered to have false preterm labor. However, threatened preterm labor has been proposed as a pathologic insult that is not always sufficient to induce irreversible spontaneous preterm birth but that could alter the normal course of pregnancy. OBJECTIVE: The aim of this study was to evaluate threatened preterm labor during pregnancy as a risk factor of neurodevelopmental deficits of children at 2 years of age. STUDY DESIGN: Two-year-old children who were born late preterm (n=22) or at term after threatened preterm labor (n=23) were compared with at-term control children (n=42). Neurodevelopment was evaluated at a corrected age of 24-29 months with the use of the Merrill-Palmer Revised Scales of Development. RESULTS: Children who were born at term after threatened preterm labor had lower scores than control children on global cognitive index (95.4 vs 104.2; P=.011), cognition (95.1 vs 103.1; P=.021), fine motor (95.2 vs 103.4; P=.003), gross motor (84.7 vs 99.8; P=.001), memory (92.9 vs 100.4; P=.015), receptive language (93.9 vs 102.9; P=.03), speed of processing (105.7 vs 113.3; P=.011), and visual motor coordination (98.8 vs 106.7; P=.003) subtests. Children born at term after threatened preterm labor had an increased risk of mild neurodevelopmental delay compared with control children (odds ratio for global cognitive index, 2.06; 95% confidence interval, 1.09-3.88; P=.033). There were no significant differences in any cognitive domain between children who were born late preterm and children who were born at term after threatened preterm labor. CONCLUSIONS: Threatened preterm labor is a risk factor for impaired cognitive development at 2 years of age, even if birth occurred at term. PMID- 27780702 TI - Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia. AB - BACKGROUND: The underlying causes of vulvar pain in women with vulvodynia remain poorly understood. Catechol-O-methyltransferase, an enzyme that metabolizes catecholamines, is a neuromodulator that is involved with perception and sensitivity to pain. The catechol-O-methyltransferase gene is polymorphic, and a single nucleotide polymorphism is associated with low activity and heightened pain sensitivity. The variant allele that encodes this polymorphism commonly is called the "L allele" because of its low enzyme activity as opposed to the normal H (high activity) allele. OBJECTIVE: The methionine-containing catechol-O methyltransferase protein coded by the L allele results in elevated catecholamine levels, reduced inactivation of the dopaminergic and adrenergic systems, and increased sensitivity to pain. This polymorphism not only may decrease the pain threshold in response to acute pain but also may facilitate the development of chronic pain. Therefore, the objective of our study was to assess whether a variation in the catechol-O-methyltransferase genotype is involved in increased pain sensitivity in women with vulvodynia. STUDY DESIGN: We conducted a prospective cohort study. METHODS: Buccal swabs were collected from 167 white women with vulvodynia and 107 control subjects; the DNA was tested for a single nucleotide polymorphism at position 158 (rs4680) in the catechol-O methyltransferase gene. RESULTS: Women with vulvodynia had a marginally increased, yet not significant, prevalence of the catechol-O-methyltransferase genotype that is associated with high activity of the coded protein: 32.9% in the women with vulvodynia, as opposed to 21.5% in the control subjects (odds ratio, 1.80; 95% confidence interval, 1.02-3.15). Subgrouping the cases based on pain frequency revealed that the elevated occurrence of this catechol-O methyltransferase genotype was present in 40.6% of the subset of women who experienced pain only with sexual intercourse vs only 21.5% of control subjects (odds ratio, 2.50; 95% confidence interval, 1.27-4.93). Also, women with primary vulvodynia had a significantly higher prevalence of the H allele than did the control subjects (62.9% vs 48.1%; odds ratio, 1.82; 95% confidence interval, 1.05 3.17). CONCLUSION: Increased pain sensitivity in women with vulvodynia is not due to a genetically determined low catechol-O-methyltransferase enzyme activity. Other mechanisms may account for alterations in catechol-O-methyltransferase activity in women with pain that is limited to intercourse or primary vulvodynia that contributes to pain sensitivity. PMID- 27780703 TI - Every woman deserves a high-volume gynecologic surgeon. AB - Most women undergoing hysterectomy in the United States have their surgery performed by a low-volume gynecologic surgeon. Evidence supports that, when compared to patients operated on by high-volume surgeons, these women have worse outcomes including fewer minimally invasive procedures and increased rates of complications. The factors that promote low-volume surgeons and suggestions for how to change this are reviewed in this Viewpoint. PMID- 27780704 TI - Reply. PMID- 27780705 TI - Concerns about the safety of nicotine replacement therapy during pregnancy on lung development in children. PMID- 27780706 TI - Exercise in pregnancy: an association with placental weight? AB - BACKGROUND: Women with high levels of physical exercise have an increased demand for oxygen and nutrients. Thus, in pregnancies of women with high levels of exercise, it is conceivable that the supply of oxygen and nutrients to the placenta is suboptimal, and growth could be impaired. OBJECTIVE: The objective was to study the association of frequency of exercise during pregnancy with placental weight and placental to birthweight ratio. STUDY DESIGN: This was a prospective study of 80,515 singleton pregnancies in the Norwegian Mother and Child Cohort Study. Frequency of exercise was self-reported by a questionnaire at pregnancy weeks 17 and 30. Information on placental weight and birthweight was obtained by linkage to the Medical Birth Registry of Norway. RESULTS: Placental weight decreased with increasing frequency of exercise (tests for trend, P < .001). For nonexercisers in pregnancy week 17, the crude mean placental weight was 686.1 g compared with 667.3 g in women exercising >=6 times weekly (difference, 18.8 g; 95% confidence interval, 12.0-25.5). Likewise, in nonexercisers in pregnancy week 30, crude mean placental weight was 684.9 g compared with 661.6 g in women exercising >=6 times weekly (difference, 23.3 g; 95% confidence interval, 14.9-31.6). The largest difference in crude mean placental weight was seen between nonexercisers at both time points and women exercising >=6 times weekly at both time points (difference, 31.7 g; 95% confidence interval, 19.2-44.2). Frequency of exercise was not associated with placental to birthweight ratio. CONCLUSION: We found decreasing placental weight with increasing frequency of exercise in pregnancy. The difference in placental weight between nonexercisers and women with exercising >=6 times weekly was small and may have no clinical implications. PMID- 27780707 TI - Temporal relationship between posterior vaginal prolapse and defecatory symptoms. AB - BACKGROUND: Posterior vaginal prolapse is thought to cause difficult defecation and splinting for bowel movements. However, the temporal relationship between difficult defecation and prolapse is unknown. Does posterior vaginal prolapse lead to the development of defecation symptoms? Conversely, does difficult defecation lead to posterior prolapse? This prospective longitudinal study offered an opportunity to study these unanswered questions. OBJECTIVE: We sought to investigate the following questions: (1) Are symptoms of difficult defecation more likely to develop (and less likely to resolve) among women with posterior vaginal prolapse? (2) Is posterior vaginal prolapse more likely to develop among women who complain of difficult defecation? STUDY DESIGN: In this longitudinal study, parous women were assessed annually for defecatory symptoms (Epidemiology of Prolapse and Incontinence Questionnaire) and pelvic organ support (POP-Q examination). The unit of analysis for this study was a visit-pair (2 sequential visits from any participant). We created logistic regression models for symptom onset among those women who were symptom-free at the index visit and for symptom resolution among those women who had symptoms at the index visit. To investigate the change in posterior vaginal support (assessed at point Bp) as a function of symptom status, we created a standard regression model that controlled for Bp at the index visit for each visit-pair. RESULTS: We derived 3888 visit-pairs from 1223 women (each completed 2-7 annual visits). At the index visit, 1143 women (29%) reported difficulty with bowel movements, and 643 women (17%) reported splinting for bowel movements. Posterior vaginal prolapse (Bp>=0) was observed among 80 women (2%). Among those women without symptoms, posterior vaginal prolapse did not significantly increase the odds that defecatory symptoms would develop (difficult bowel movements, P=.378; splinting, P=.765). In contrast, among those with defecatory symptoms, posterior vaginal prolapse reduced the probability of symptom resolution (difficult bowel movements, P<.001; splinting, P=.162). The mean rate of change in posterior wall support was +0.13 cm. Among women without posterior vaginal prolapse, the presence of defecatory symptoms at the index visit did not have an effect on changes in Bp over time; however, among those with posterior vaginal prolapse (Bp>=0), defecatory symptoms were associated with more rapid worsening of posterior support (difficulty with bowel movements, P=.005; splinting, P=.057). CONCLUSION: Posterior vaginal prolapse did not increase the odds that new defecatory symptoms would develop among asymptomatic women but did increase the probability that defecatory symptoms would persist over time. Furthermore, among those women with established posterior vaginal prolapse, defecatory symptoms were associated with more rapid worsening of posterior vaginal wall descent. PMID- 27780708 TI - Risk factors for complete uterine rupture. AB - BACKGROUND: Complete uterine rupture is a rare peripartum complication associated with a catastrophic outcome. Because of its rarity, knowledge about its risk factors is not very accurate. Most previous studies were small and over a limited time interval. Moreover, international diagnostic coding was used in most studies. These codes are not able to differentiate between the catastrophic complete type and less catastrophic partial type. Complete uterine rupture is expected to increase as the rate of cesarean delivery increases. Thus, we need more accurate knowledge about the risk factors for this complication. OBJECTIVE: The objective of the study was to estimate the incidence and risk factors for complete uterine rupture during childbirth in Norway. STUDY DESIGN: This population-based study included women that gave birth after starting labor in 1967-2008. Data were from the Medical Birth Registry of Norway and Patient Administration System, complemented with information from medical records. We included 1,317,967 women without previous cesarean delivery and 57,859 with previous cesarean delivery. The outcome was complete uterine rupture (tearing of all uterine wall layers, including serosa and membranes). Risk factors were parameters related to demographics, pregnancy, and labor. Odds ratios for complete uterine rupture were computed with crude logistic regressions for each risk factor. Separate multivariable logistic regressions were performed to calculate the adjusted odds ratios and 95% confidence intervals. RESULTS: Complete uterine rupture occurred in 51 cases without previous cesarean delivery (0.38 per 10,000) and 122 with previous cesarean delivery (21.1 per 10,000). The strongest risk factor was sequential labor induction with prostaglandins and oxytocin, compared with spontaneous labor, in those without previous cesarean delivery (adjusted odds ratio, 48.0, 95% confidence interval, 20.5-112.3) and those with previous cesarean delivery (adjusted odds ratio, 16.1, 95% confidence interval, 8.6-29.9). Other significant risk factors for those without and with previous cesarean delivery, respectively, included labor augmentation with oxytocin (adjusted odds ratio, 22.5, 95% confidence interval, 10.9-41.2; adjusted odds ratio, 4.4, 95% confidence interval, 2.9-6.6), antepartum fetal death (adjusted odds ratio, 15.0, 95% confidence interval, 6.2-36.6; adjusted odds ratio, 4.0, 95% confidence interval, 1.1-14.2), and previous first-trimester miscarriages (adjusted odds ratio, 9.6, 95% confidence interval, 5.7-17.4; adjusted odds ratio, 5.00, 95% confidence interval, 3.4-7.3). After a previous cesarean delivery, the risk of rupture was increased by an interdelivery interval <16 months (adjusted odds ratio, 2.3; 95% confidence interval, 1.1-5.4) and a previous cesarean delivery with severe postpartum hemorrhage (adjusted odds ratio, 5.6; 95% confidence interval, 2.4-13.2). CONCLUSION: Sequential labor induction with prostaglandins and oxytocin and augmentation of labor with oxytocin are important risk factors for complete uterine rupture in intact and scarred uteri. PMID- 27780709 TI - Effects of coffee consumption on gut recovery after surgery of gynecological cancer patients: a randomized controlled trial. AB - BACKGROUND: Paralytic ileus that develops after elective surgery is a common and uncomfortable complication and is considered inevitable after an intraperitoneal operation. OBJECTIVE: The purpose of this study was to investigate whether coffee consumption accelerates the recovery of bowel function after complete staging surgery of gynecologic cancers. STUDY DESIGN: In this randomized controlled trial, 114 patients were allocated preoperatively to either postoperative coffee consumption with 3 times daily (n=58) or routine postoperative care without coffee consumption (n=56). Total abdominal hysterectomy and bilateral salpingo oophorectomy with systematic pelvic and paraaortic lymphadenectomy were performed on all patients as part of complete staging surgery for endometrial, ovarian, cervical, or tubal cancer. The primary outcome measure was the time to the first passage of flatus after surgery. Secondary outcomes were the time to first defecation, time to first bowel movement, and time to tolerance of a solid diet. RESULTS: The mean time to flatus (30.2+/-8.0 vs 40.2+/-12.1 hours; P<.001), mean time to defecation (43.1+/-9.4 vs 58.5+/-17.0 hours; P<.001), and mean time to the ability to tolerate food (3.4+/-1.2 vs 4.7+/-1.6 days; P<.001) were reduced significantly in patients who consumed coffee compared with control subjects. Mild ileus symptoms were observed in 17 patients (30.4%) in the control group compared with 6 patients (10.3%) in the coffee group (P=.01). Coffee consumption was well-tolerated and well-accepted by patients, and no intervention-related side-effects were observed. CONCLUSION: Coffee consumption after total abdominal hysterectomy and systematic paraaortic lymphadenectomy expedites the time to bowel motility and the ability to tolerate food. This simple, cheap, and well tolerated treatment should be added as an adjunct to the postoperative care of gynecologic oncology patients. PMID- 27780710 TI - The effects of baicalein on gastric mucosal ulcerations in mice: Protective pathways and anti-secretory mechanisms. AB - Many flavonoids have been shown to present good results for the treatment of gastric ulcers. Baicalein, a bioactive flavonoid derived from the Scutellaria baicalensis Georgi root, possesses several biological effects, such as anti inflammatory and antioxidant. This study was conducted to assess the gastroprotective properties of baicalein. Anti-ulcerogenic assay was performed using the protocol of ulcer induced by ethanol/HCl in mice; then, the role of presynaptic alpha2-receptors, sulfhydryl (SH) compounds, nitric oxide (NO), prostaglandin (PG) and ATP-sensitive K+ (KATP) channels in gastroprotection of baicalein was investigated. The levels of reduced glutathione (GSH) and the myeloperoxidase (MPO) activity were measured in the gastric mucosa. Parameters of gastric secretion (volume, [H+] and pH) were determined with or without the presence of the secretagogue agent histamine, as well as mucus in gastric contents, by the pylorus ligation model. In vitro H+,K+-ATPase activity was also determined. Baicalein (10, 30 and 100 mg/kg) exhibited a dose related gastroprotective effect (P < 0.001) against acidified ethanol-induced lesions. The intraperitoneal treatment of mice with a alpha2-adrenoreceptor antagonist (yohimbine; 2 mg/kg), a SH compounds blocker (N-ethylmaleimide, NEM; 10 mg/kg), a non-selective inhibitor of NO synthase (Nw-nitro-L-arginine methyl ester hydrochloride, L-NAME; 10 mg/kg), a non-selective inhibitor of cyclo-oxygenase (indomethacin; 10 mg/kg) or a KATP channel blocker (glibenclamide; 10 mg/kg) was able to reverse (P < 0.001) the gastroprotective response caused by baicalein (30 mg/kg). Baicalein (30 mg/kg; P < 0.05) was able to increase GSH levels and decreasing MPO activity. The intraduodenal treatment with baicalein (30 and 100 mg/kg) significantly increased (P < 0.05) the gastric mucus secretion. Additionally, the treatment with baicalein reduced (30 and 100 mg/kg; P < 0.05) the secretion volume and total acid secretion, and also increased (10, 30 and 100 mg/kg; P < 0.001) the pH value, after pylorus ligature. Baicalein (30 mg/kg) was also effective in inhibiting the effects of histamine on gastric secretion (volume, [H+] and pH; P < 0.001). Baicalein at 10 and 30 MUg/mL showed anti-H+,K+ ATPase activity. In conclusion, the present results provide convincing evidence that baicalein could be used as a cytoprotective (preventive effect) and anti ulcerogenic (anti-secretory effect) agent in the gastric ulcers. PMID- 27780711 TI - Mercury and protein thiols: Stimulation of mitochondrial F1FO-ATPase and inhibition of respiration. AB - In spite of the known widespread toxicity of mercury, its impact on mitochondrial bioenergetics is a still poorly explored topic. Even if many studies have dealt with mercury poisoning of mitochondrial respiration, as far as we are aware Hg2+ effects on individual complexes are not so clear. In the present study changes in swine heart mitochondrial respiration and F1FO-ATPase (F-ATPase) activity promoted by micromolar Hg2+ concentrations were investigated. Hg2+ was found to inhibit the respiration of NADH-energized mitochondria, whereas it was ineffective when the substrate was succinate. Interestingly, the same micromolar Hg2+ doses which inhibited the NADH-O2 activity stimulated the F-ATPase, most likely by interacting with adjacent thiol residues. Accordingly, Hg2+ dose dependently decreased protein thiols and all the elicited effects on mitochondrial complexes were reversed by the thiol reducing agent DTE. These findings clearly indicate that Hg2+ interacts with Cys residues of these complexes and differently modulate their functionality by modifying the redox state of thiol groups. The results, which cast light on some implications of metal-thiol interactions up to now not fully explored, may contribute to clarify the molecular mechanisms of mercury toxicity to mitochondria. PMID- 27780713 TI - Differential effects of angiotensin receptor blockers on pancreatic islet remodelling and glucose homeostasis in diet-induced obese mice. AB - Obesity leads to adverse endocrine pancreas remodelling, reduced islet lifespan and early type 2 diabetes onset. AT1R blockade shows beneficial pleiotropic effects. This study sought to compare the effects of losartan and telmisartan on pancreatic islets remodelling and glucose homeostasis in diet-induced obese mice. High-fat diet yielded overweight, insulin resistance, islet apoptosis and hypertrophy. Suitable insulin levels and preserved endocrine pancreas structure were correlated to adequate AKT-FOXO1 pathway functioning in losartan-treated animals. Conversely, telmisartan yielded enhanced PDX1 and GLP-1 islet expression along with greater GLP-1 levels, with the consequent better islet glucose sensing and uptake. Greater islet vascularisation coupled with reduced apoptosis and macrophage infiltration seems to underlie the beneficial findings in both treatments. In conclusion, these results provide compelling evidence that two antihypertensive drugs (telmisartan and losartan) ameliorate pancreatic islet structure, glucose handling, and vascularisation in obese mice. Although only telmisartan countered overweight, both drugs yielded reduced apoptosis and islet preservation, with translational potential. PMID- 27780715 TI - An efficient automatic workload estimation method based on electrodermal activity using pattern classifier combinations. AB - Automatic workload estimation has received much attention because of its application in error prevention, diagnosis, and treatment of neural system impairment. The development of a simple but reliable method using minimum number of psychophysiological signals is a challenge in automatic workload estimation. To address this challenge, this paper presented three different decomposition techniques (Fourier, cepstrum, and wavelet transforms) to analyze electrodermal activity (EDA). The efficiency of various statistical and entropic features was investigated and compared. To recognize different levels of an arithmetic task, the features were processed by principal component analysis and machine-learning techniques. These methods have been incorporated into a workload estimation system based on two types: feature-level and decision-level combinations. The results indicated the reliability of the method for automatic and real-time inference of psychological states. This method provided a quantitative estimation of the workload levels and a bias-free evaluation approach. The high-average accuracy of 90% and cost effective requirement were the two important attributes of the proposed workload estimation system. New entropic features were proved to be more sensitive measures for quantifying time and frequency changes in EDA. The effectiveness of these measures was also compared with conventional tonic EDA measures, demonstrating the superiority of the proposed method in achieving accurate estimation of workload levels. PMID- 27780714 TI - Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication. AB - BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer. PMID- 27780712 TI - Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. AB - Insights into the pathogenesis of inflammatory bowel diseases (IBDs) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are increased in inflamed intestinal tissues of patients with IBD. Loss-of-function variants of the IL23-receptor gene (IL23R) protect against IBD, and, in animals, blocking IL23 reduces the severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for the treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms also are emerging for the treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics. PMID- 27780716 TI - A novel compound heterozygous mutation in the SLC22A12 (URAT1) gene in a Japanese patient associated with renal hypouricemia. AB - A novel compound heterozygous mutation, including c.935_997delinsTGG, in exons 5/6 of SLC22A12 (URAT1) was identified in a patient with renal hypouricemia. This case expands the molecular mechanisms of renal hypouricemia, and suggests a potential relationship with exercise-induced renal failure. PMID- 27780717 TI - High-sensitive cardiac troponin T (hs-cTnT) assay as serum biomarker to predict cardiac risk in myotonic dystrophy: A case-control study. AB - BACKGROUND: Myotonic dystrophy (DM) is a genetic disorder caused by nucleotide repeats expansion. Sudden death represents the main cause of mortality in DM patients. Here, we investigated the relationship between serum cardiac biomarkers with clinical parameters in DM patients. METHODS: Case-control study included 59 DM patients and 22 healthy controls. An additional group of 62 controls with similar cardiac defects to DM were enrolled. RESULTS: NT-proBNP, hs-cTnT and CK levels were significantly increased in DM patients compared to healthy subjects (p=0.0008, p<0.0001, p<0.0001). Also, hs-cTnT levels were significantly higher in DM compared to control group with cardiac defects (p=0.0003). Positive correlation was found between hs-cTnT and hs-cTnI in both DM patients and controls (p=0.019, p=0.002). Independently from the age, the risk of DM disease was positively related to an increase in hs-cTnT (p=0.03). On the contrary, the risk of DM was not related to hs-cTnI, but was evidenced a role of PR interval (p=0.03) and CK (p=0.08). CONCLUSIONS: The levels of hs-cTnT were significantly higher in DM patients. Analysis, with anti-cTnT, shows that this increase might be linked to heart problems. This last finding suggests that hs-cTnT might represent a helpful serum biomarker to "predict" cardiac risk in DM disease. PMID- 27780718 TI - The long non-coding RNA 91H increases aggressive phenotype of breast cancer cells and up-regulates H19/IGF2 expression through epigenetic modifications. AB - Numerous genomic imprinting loci are regulated by long non-coding RNA (lncRNA). We have previously identified a new lncRNA at the H19/IGF2 locus transcribed in H19 antisense orientation and named 91H. This RNA is conserved among mammals. In mice, 91H regulates positively IGF2 expression from a novel promoter. However, in human the function of 91H at the H19/IGF2 locus remains largely undeciphered. Here, we observed that 91H, H19 and IGF2 are overexpressed in breast tumors. By using 91H-knockdown breast cancer cells, we demonstrated that 91H exerts oncogenic properties by promoting cell growth, migration and invasion as well as tumor growth in xenografted immunodeficient mouse model. Moreover, 91H-knockdown reduces the expression of H19 and IGF2 in breast cancer cells. By chromatin immunoprecipitation and methylation studies, we found that 91H expression prevents histone and DNA methylation on the maternal allele at the H19/IGF2 locus. These results indicate that 91H, through epigenetic modifications, is responsible of the maintenance of H19/IGF2 genomic imprinting allowing the allele specific expression of H19 and IGF2. Taken together, overexpression of 91H in breast cancer and 91H-induced epigenetic modifications on H19/IGF2 locus suggest that 91H may play essential role in breast cancer development. Further studies are needed to investigate their role in terms of diagnosis and therapeutic. PMID- 27780719 TI - Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation. AB - Recent studies revealed that mutations in SPOP (Speckle-type POZ protein) occur in up to 15% of patients with prostate cancer. However, the physiological role of SPOP in regulating prostate tumorigenesis remains elusive. Here, we identified the Cdc20 oncoprotein as a novel ubiquitin substrate of SPOP. As such, pharmacological inhibition of Cullin-based E3 ligases by MLN4924 could stabilize endogenous Cdc20 in cells. Furthermore, we found that Cullin 3, and, to a less extent, Cullin 1, specifically interacted with Cdc20. Depletion of Cullin 3, but not Cullin 1, could upregulate the abudance of Cdc20 largely via prolonging Cdc20 half-life. Moreover, SPOP, the adaptor protein of Cullin 3 family E3 ligase, specifically interacted with Cdc20, and promoted the poly-ubiquitination and subsequent degradation of Cdc20 in a degron-dependent manner. Importantly, prostate cancer-derived SPOP mutants failed to interact with Cdc20 to promote its degradation. As a result, SPOP-deficient prostate cancer cells with elevated Cdc20 expression became resistant to a pharmacological Cdc20 inhibitor. Therefore, our results revealed a novel role of SPOP in tumorigenesis in part by promoting the degradation of the Cdc20 oncoprotein. PMID- 27780720 TI - Unilateral olfactory sensitivity in multiple sclerosis. AB - It is not known whether lateralized olfactory sensitivity deficits are present in MS. Since projections from the olfactory bulb to the olfactory cortex are largely ipsilateral, and since both functional imaging and psychophysical studies suggest that the right side of the brain may be more involved in olfactory processing than the left, we addressed this issue by administering well-validated tests of odor detection, along with tests of odor identification, to each side of the nose of 73 MS patients and 73 age-, gender-, and race-matched normal controls. We also determined, in 63 of the MS patients, whether correlations were present between the olfactory test measures and MRI-determined lesions in brain regions ipsilateral and contralateral to the nose side that was tested. No significant left:right differences in either olfactory sensitivity or identification were present, although in both cases mean performance was lower in the MS than in the control subjects (ps<0.0001). Scores on the two sides of the nose were positively correlated with one another (threshold r=0.56, p<0.0001; Identification r=0.71, p<0.0001). The percent of MS patients whose bilateral test scores fell below the 10th percentile of controls did not differ between the odor identification and detection threshold tests. Both left and right odor identification and detection test scores were weakly correlated with lesion volumes in temporal and frontal lobe brain regions (r's<0.40). Our findings demonstrate that MS does not differentially influence odor perception on left and right sides of the nose, regardless of whether sensitivity or identification is being measured. They also indicate that tests of odor identification and detection are similarly influenced by MS and that such influences are associated with central brain lesions. PMID- 27780721 TI - Differential effect of chronic stress on mouse hippocampal memory and affective behavior: Role of major ovarian hormones. AB - Molecular mechanisms of depression-like pathophysiology in female rodent models are less reported compared to males, despite its higher prevalence in human females. Moreover, the stress-response in brain circuitries including reward and cognition circuitries varies with age or hormonal status of the females. So, to understand the stress-induced mood and cognitive disorders in intact females (with ovaries) and ovariectomized (OVX) females, we studied changes in mouse hippocampus, a functionally heterogeneous neural structure involved in both affective and cognitive behaviors. Here, we used a 6-day Chronic Unpredictable Stress (CUS) paradigm in mice to induce depression and related mood disorders. Interestingly, intact females and OVX females showed difference in mood disorder sub-phenotypes to CUS. Similar to an earlier report of CUS affecting the critical reward circuitry structure the nucleus accumbens differently in females with and without ovaries, cognitive behavior in intact females and OVX females also responded differentially to CUS, as evident from Morris Water Maze (MWM) test results. We report that the presence or absence of ovarian hormones, particularly the estrogen, has a significant impact in altering the hippocampus related spatial memory and affective behavior, in females. Our results also illustrate that estrogen administration improves both reward and cognitive behavior, and plays a significant role in alleviating stress-induced despair behavior and enhancing spatial reference memory following a brief 6-day stressful paradigm. Further, it also indicates that the NMDA receptor subunits, GRIN2A and GRIN2B, might mediate the effects of estrogen in the hippocampal functions, thus suggestive of a translational significance of the finding. PMID- 27780723 TI - Limb remote ischemic conditioning increases Notch signaling activity and promotes arteriogenesis in the ischemic rat brain. AB - BACKGROUND AND PURPOSE: We tested the hypothesis that limb remote ischemic conditioning (LRIC) treatment promotes arteriogenesis and increases Notch signaling activity during stroke recovery. METHODS: Adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO). LRIC was applied after the onset of focal ischemia (per-conditioning), followed by repeated short episodes of remote ischemia 24h after reperfusion (post-conditioning). Cerebral blood flow (CBF) was measured by Laser Doppler Flowmetry. Immunohistochemistry was used to reveal alpha-smooth muscle actin (alpha-SMA) immunopositive cells in the arteries of the brain. The cerebral angioarchitecture was visualized with a latex perfusion technique. RESULTS: LRIC treatment significantly elevated local cerebral blood flow and increased arteriogenesis as indicated by increased arterial diameter and vascular smooth muscle cell proliferation in the ischemic brain. The increased arteriogenesis significantly correlated with the functional outcome after stroke. Furthermore, LRIC treatment upregulated the expressions of Notch1 and Notch intracellular domain (NICD) in arteries surrounding the ischemic area. CONCLUSION: These results suggest that the therapeutic effects of LRIC may involve the promotion of arteriogenesis during the recovery phase after focal cerebral ischemia and that Notch1 signaling seems to be an important player in limb remote ischemia-mediated arteriogenesis. PMID- 27780724 TI - Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress. AB - Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABAA receptor competitive antagonist) but not by diazepam (a GABAA receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic-pituitary-adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABAA receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABAA receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABAA receptor. PMID- 27780722 TI - GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1alpha. AB - Traumatic brain injury (TBI) causes sustained disability due to compromised neurorepair mechanisms. Crucial to neurorepair and functional recovery following both TBI and stroke is hypoxia-inducible factor-1 alpha (HIF-1alpha). Based on reports that HIF-1alpha could be stabilized via S-nitrosylation, we tested the hypothesis that the S-nitrosylating agent S-nitrosoglutathione (GSNO) would stabilize HIF-1alpha, thereby stimulating neurorepair mechanisms and aiding in functional recovery. TBI was induced by controlled cortical impact (CCI) in adult rats. GSNO (0.05mg/kg) was administered at two hours after CCI. The treatment was repeated daily until the 14th day after CCI. Functional recovery was assessed by motor and cognitive functions, and the recovery was compared with the expression of HIF-1alpha. The mechanisms of GSNO-mediated S-nitrosylation of HIF-1alpha were determined using brain endothelial cells. While non-treated TBI animals showed sustained neurobehavioral deficits, GSNO treatment of TBI improved neurobehavioral functions. GSNO also increased the expression of HIF-1alpha and VEGF. The beneficial effects of GSNO on neurobehavioral functions in TBI animals were blocked by treatment with the HIF-1alpha inhibitor 2-methoxyestradiol (2 ME). The stimulatory effect of GSNO on VEGF was reversed not only by 2-ME but also by the denitrosylating agent dithiothreitol, confirming our hypothesis that GSNO's benefits are mediated by the stabilization of HIF-1alpha via S nitrosylation. GSNO's S-nitrosylation of HIF-1alpha was further confirmed using a biotin switch assay in endothelial cells. The data provide evidence that GSNO treatment of TBI aids functional recovery through stabilizing HIF-1alpha via S nitrosylation. GSNO is a natural component of the human brain/body, and its exogenous administration has not shown adverse effects in humans. Therefore, the translational potential of GSNO therapy in TBI is high. PMID- 27780726 TI - Insights into the neuroprotective mechanisms of 2-iminobiotin employing an in vitro model of hypoxic-ischemic cell injury. AB - Several animal models have been used to simulate cerebral hypoxia-ischemia and suggested neuroprotective effects of the biotin analogue 2-iminobiotin (2-IB). The aims of this study were to employ a human in-vitro hypoxia model to confirm protective effects of 2-IB on neuronal cells, determine the optimal neuroprotective concentrations of 2-IB and scrutinize underlying cellular effects of 2-IB. Neuronal IMR-32 cells were exposed to hypoxia employing an enzymatic hypoxia system and were thereafter incubated with various concentrations of 2-IB (10 to 300ng/ml). Cell damage, metabolic activity and generation of reactive oxygen species were quantified using colorimetric/fluorometric lactate dehydrogenase (LDH), tetrazolium-based (MTS) and reactive oxygen species assays. Proteome profiling arrays were performed to evaluate the regulation of cell stress protein expression by hypoxia and 2-IB. Seven hours of hypoxia led to morphological changes in IMR-32 cultures, increased neuronal cell damage (P<0.001), reduction of metabolic activity (P<0.01) and enhanced reactive oxygen species production (P<0.05). Post-hypoxic application of 2-IB (30ng/ml) attenuated hypoxia-induced LDH release (P<0.05) and increased metabolic activity of IMR-32 cells (P<0.05), while reactive oxygen species production was only by trend decreased. Array-based protein expression profiling revealed that 2-IB attenuated the expression of several hypoxia-induced cell stress-associated proteins by more than 25% (pp38alpha, HIF2alpha, ADAMTS1, pHSP27, PON2, PON3 and p27). Hypoxia-induced neuronal cell damage can be simulated using the described in-vitro model. 2-IB inhibits hypoxia-mediated neurotoxicity most efficiently at 30ng/ml and the underlying mechanisms involve a downregulation of stress associated protein expression. Our results suggest 2-IB as a potential drug for the treatment of perinatal hypoxia-ischemia. PMID- 27780725 TI - In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations. AB - Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [35S]GTPgammaS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays. The action of the AT compounds were compared with standard NOP agonists (N/OFQ and Ro 65-6570) and the NOP selective antagonist SB-612111. AT compounds displayed high NOP affinity and behaved as NOP agonists in all the functional assays consistently showing the following rank order of potency AT-127>=AT-090>=AT 035>AT-004= AT-001. AT compounds behaved as NOP full agonists in the calcium mobilization and mouse colon assays and as partial agonists in the [35S]GTPgammaS and BRET assays. Interestingly AT-090 and AT-127, contrary to standard nonpeptide agonists that display G protein biased agonism, behaved as an unbiased agonists. AT-090 and AT-127 displayed higher NOP selectivity than Ro 65-6570 at native mouse receptors. AT-090 and AT-127 might be useful pharmacological tools for investigating the therapeutic potential of NOP partial agonists. PMID- 27780727 TI - Methylation of Notch3 modulates chemoresistance via P-glycoprotein. AB - The global gene expression and DNA methylation of genes in adriamycin-resistant human breast cancer cells (MCF-7/ADM cells) are similar to those in paclitaxel resistant MCF-7 cells (MCF-7/PTX) and are significantly different from those in wild-type MCF-7 cells. DNA methylation is associated with chemoresistance in breast cancer and changes the characteristics of chemoresistant and chemosensitive cells. Here, we showed that the tumor-suppressor gene Notch3 was inactivated due to epigenetic silencing DNA hypermethylation in MCF-7/ADM cells. In addition, the drug efflux pump P-glycoprotein was negatively regulated by Notch3 and highly expressed in MCF-7/ADM cells. Taken together, our findings demonstrated that hypermethylation of Notch3 causes activation of P-glycoprotein in adriamycin-resistant cells. PMID- 27780728 TI - SERCA2a was serotonylated and may regulate sino-atrial node pacemaker activity. AB - The modulation of sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of protein serotonylation by intracellular 5-HT during varies physiological actions. Nevertheless, the functional role of protein serotonylation in controlling SAN automaticity is largely unexplored. In this study, we screened the cardiomyocytes proteins and found that sarco(endo)plasmic reticulum Ca ATPase type 2a (SERCA2a) can be serotonylated. Simulation studies using mathematical SAN cell model showed that variation of Ca2+ affinity of SERCA2a pump cause either tachycardia or bradycardia. PMID- 27780729 TI - Looped limulus anti-lipopolysaccharide derived peptide CLP-19 induces endotoxin tolerance involved inhibition of NF-kappaB activation. AB - Endotoxin tolerance (ET) is a complex protective mechanism against endotoxin shock. The looped CLP-19 peptide derived from Limulus anti-LPS peptide induced the ET phenomenon but the molecular mechanism has yet to be fully elucidated. Here, we confirmed that CLP-19 attenuated upon LPS stimulated pro-inflammatory factor secretion of TNF-alpha and IL-6 but increased anti-inflammatory factor production of IL-10 in dose- and time-dependent manners. CLP-19 also inhibited subsequent LPS stimulated expression of TLR4 on the cell membrane. Moreover, the CLP-19 inhibited degradation of the inhibitor of NF-kappaB (IkappaBalpha and IkappaBbeta) and reduced LPS induced NF-kappaB activity, but not of effects on expression of MyD88 and TRAF-6. Finally CLP-19 significantly increased survival of lethal LPS shock mouse models with significantly less pathological injury to lung. These findings collectively suggest that CLP-19 induces ET phenomenon involved inhibition of NF-kappaB activation. In conclusion, this study has revealed a novel function of CLP-19 that appears to represent a potential therapeutic agent for clinical treatment of septic shock. PMID- 27780730 TI - miR-203a is involved in HBx-induced inflammation by targeting Rap1a. AB - Hepatitis B virus (HBV) causes acute and chronic hepatitis, and is one of the major causes of cirrhosis and hepatocellular carcinoma. Accumulating evidence suggests that inflammation is the key factor for liver cirrhosis and hepatocellular carcinoma. MicroRNAs play important roles in many biological processes. Here, we aim to explore the function of microRNAs in the HBX-induced inflammation. First, microarray experiment showed that HBV+ liver samples expressed higher level of miR-203a compared to HBV- liver samples. To verify these alterations, HBx-coding plasmid was transfected into HepG2 cells to overexpress HBx protein. The real-time PCR results suggested that over-expression of HBx could induce up-regulation of miR-203a. To define how up-regulation of miR 203a can induce liver cells inflammation, we over-expressed miR-203a in HepG2 cells. Annexin V staining and BrdU staining suggested that overexpression of miR 203a significantly increased the cell apoptosis and proliferation, meanwhile, over-expression of miR-203a could lead to a decrease in G0/G1 phase cells and an increase in G2/M phase cells. Some cytokines production including IL-6 and IL-8 were significantly increased, but TGFbeta and IFNgamma were decreased in miR-203a over-expressed HepG2 cells. Luciferase reporter assay experiments, protein mass spectrum assay and real-time PCR all together demonstrated that Rap1a was the target gene of miR-203a. Further experiments showed that these alterations were modulated through PI3K/ERK/p38/NFkappaB pathways. These data suggested that HBV infection could up-regulate the expression of miR-203a, thus down regulated the expression of Rap1a and affected the PI3K/ERK/p38/NFkappaB pathways, finally induced the hepatitis inflammation. PMID- 27780731 TI - How to transform a recalcitrant Paenibacillus strain: From culture medium to restriction barrier. AB - Paenibacillus riograndensis SBR5T is a plant growth-promoting bacterium isolated from the wheat rhizosphere. Its recalcitrance to genetic manipulation is a major bottleneck for molecular studies, as has been reported for other Paenibacillus environmental isolates. An efficient electroporation protocol was established by evaluating diverse parameters and optimizing the culture medium, culture growth phase, electroporation solution, recovery medium, DNA input, and electric field strength. Efficiencies of approximately 2.8*104transformantsMUg-1 of plasmid DNA were obtained. The optimized protocol was tested with other Paenibacillus species, and the relevance of bypassing the restriction DNA defense system to transform Paenibacillus was highlighted. This protocol is the tool needed to deepen molecular studies with this strain and will aid in the manipulation of other new environmental isolates that also exhibit recalcitrant transformation difficulties. PMID- 27780732 TI - Altered postnatal maturation of striatal GABAergic interneurons in a phenotypic animal model of dystonia. AB - GABAergic disinhibition has been suggested to play a critical role in the pathophysiology of several basal ganglia disorders, including dystonia, a common movement disorder. Previous studies have shown a deficit of striatal GABAergic interneurons (IN) in the dtsz mutant hamster, one of the few phenotypic animal models of dystonia. However, mechanisms underlying this deficit are largely unknown. In the present study, we investigated the migration and maturation of striatal IN during postnatal development (18days of age) and at age of highest severity of dystonia (33days of age) in this hamster model. In line with previous findings, the density of GAD67-positive IN and the level of parvalbumin mRNA, a marker for fast spiking GABAergic IN, were lower in the dtsz mutant than in control hamsters. However, an unaltered density of Nkx2.1 labeled cells and Nkx2.1 mRNA level suggested that the migration of GABAergic IN into the striatum was not retarded. Therefore, different factors that indicate maturation of GABAergic IN were determined. While mRNA of the KCC2 cation/chloride transporters and the cytosolic carboanhydrase VII, used as markers for the so called GABA switch, as well as BDNF were unaltered, we found a reduced number of IN expressing the alpha1 subunit of the GABAA-receptor (37.5%) in dtsz hamsters at an age of 33days, but not after spontaneous remission of dystonia at an age of 90days. Since IN shift expression from alpha2 to alpha1 subunits during postnatal maturation, this result together with a decreased parvalbumin mRNA expression suggest a delayed maturation of striatal GABAergic IN in this animal model, which might underlie abnormal neuronal activity and striatal plasticity. PMID- 27780733 TI - Identification of the key pathway of oxazolinoanthracyclines mechanism of action in cells derived from human solid tumors. AB - Oxazolinodoxorubicin (O-DOX) and oxazolinodaunorubicin (O-DAU) are novel anthracycline derivatives with a modified daunosamine moiety. In the present study, we evaluated the cytotoxicities, genotoxicities and abilities of O-DOX and O-DAU to induce apoptosis in cancer cell lines (SKOV-3; A549; HepG2), and compared the results with their parent drugs. We assessed antiproliferative activity by MTT assay. We evaluated apoptosis-inducing ability by double-staining with fluorescent probes (Hoechst 33258/propidium iodide), and by determining expression levels of genes involved in programmed cell death by reverse transcription-polymerase chain reaction. Genotoxicities of the compounds were tested by comet assays. Oxazolinoanthracyclines demonstrated high anti-tumor activity. O-DOX had significantly higher cytotoxicity, apoptosis-inducing ability, and genotoxicity compared with parental doxorubicin (DOX) in all tested conditions, while O-DAU activity differed among cell lines. The mechanism of oxazoline analog action appeared to involve the mitochondrial pathway of programmed cell death. These results provide further information about oxazoline derivatives of commonly used anthracycline chemotherapy agents. O-DOX and O-DAU have the ability to induce apoptosis in tumor cells. PMID- 27780734 TI - Proteins brighten the brain. AB - Through selective activation/inhibition or dissection of neuronal circuits, optogenetic tools have raised hopes for a better understanding of neuropsychiatric mechanisms and therapeutic targets for various disorders. Although, overcoming serious limitations result in from conventional neuronal circuit study, this method has its own imperfections, such as optogenetic modulation of neural activity, using an internal, animal-generated, light source. In this review, limitations of external light delivery systems and possible approaches for using internal light sources in laboratory animals and perhaps, human being, are being addressed. PMID- 27780735 TI - Regional specificity of the gut-incretin response to small intestinal glucose infusion in healthy older subjects. AB - The importance of the region, as opposed to the length, of small intestine exposed to glucose in determining the secretion of the incretin hormones glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) remains unclear. We sought to compare the glycemic, insulinemic and incretin responses to glucose administered to the proximal (12-60cm beyond the pylorus), or more distal (>70cm beyond the pylorus) small intestine, or both. 10 healthy subjects (9M,1F; aged 70.3+/-1.4years) underwent infusion of glucose via a catheter into the proximal (glucose proximally; GP), or distal (glucose distally; GD) small intestine, or both (GPD), on three separate days in a randomised fashion. Blood glucose, serum insulin and plasma GLP-1, GIP and CCK responses were assessed. The iAUC for blood glucose was greater in response to GPD than GP (P<0.05), with no difference between GD and GP. GP was associated with minimal GLP-1 response (P=0.05), but substantial increases in GIP, CCK and insulin (P<0.001 for all). GPD and GD both stimulated GLP-1, GIP, CCK and insulin (P<0.001 for all). Compared to GP, GPD induced greater GLP-1, GIP and CCK responses (P<0.05 for all). Compared with GPD, GD was associated with greater GLP 1 (P<0.05), but reduced GIP and CCK (P<0.05 for both), responses. We conclude that exposure of glucose to the distal small intestine appears necessary for substantial GLP-1 secretion, while exposure of both the proximal and distal small intestine result in substantial secretion of GIP. PMID- 27780736 TI - Add-on therapy with anagliptin in Japanese patients with type-2 diabetes mellitus treated with metformin and miglitol can maintain higher concentrations of biologically active GLP-1/total GIP and a lower concentration of leptin. AB - Metformin, alpha-glucosidase inhibitors (alpha-GIs), and dipeptidyl peptidase 4 inhibitors (DPP-4Is) reduce hyperglycemia without excessive insulin secretion, and enhance postprandial plasma concentration of glucagon-like peptide-1 (GLP-1) in type-2 diabetes mellitus (T2DM) patients. We assessed add-on therapeutic effects of DPP-4I anagliptin in Japanese T2DM patients treated with metformin, an alpha-GI miglitol, or both drugs on postprandial responses of GLP-1 and glucose dependent insulinotropic polypeptide (GIP), and on plasma concentration of the appetite-suppressing hormone leptin. Forty-two Japanese T2DM patients with inadequately controlled disease (HbA1c: 6.5%-8.0%) treated with metformin (n=14), miglitol (n=14) or a combination of the two drugs (n=14) received additional treatment with anagliptin (100mg, p.o., b.i.d.) for 52 weeks. We assessed glycemic control, postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of leptin in those patients. Add-on therapy with anagliptin for 52 weeks improved glycemic control and increased the area under the curve of biologically active GLP-1 concentration without altering obesity indicators. Total GIP concentration at 52 weeks was reduced by add-on therapy in groups treated with miglitol compared with those treated with metformin. Add-on therapy reduced leptin concentrations. Add-on therapy with anagliptin in Japanese T2DM patients treated with metformin and miglitol for 52 weeks improved glycemic control and enhanced postprandial concentrations of active GLP-1/total GIP, and reduce the leptin concentration. PMID- 27780737 TI - Rat NEURL1 3'UTR is alternatively spliced and targets mRNA to dendrites. AB - Neuralized, an E3 ubiquitin ligase, interacts with and positively modulates the Notch pathway by promoting ubiquitination and subsequent endocytosis of its ligands. NEURL1 mRNA is dendritically localised in the dentate gyrus of an adult rat brain, implying that it may be locally translated, but its transport mechanisms remain unstudied. Here, we report the presence of a previously unknown, shorter splice-variant of rat NEURL1 3'UTR (1477bp in length), and identify it as a potential target of nonsense-mediated decay. We show that endogenous NEURL1 mRNAs with both longer and shorter 3'UTRs are enriched in the neurites of cultured rat primary hippocampal neurons. Both NEURL1 3'UTRs can mediate transport of reporter mRNAs into dendrites in primary hippocampal neurons. By analysing the dendritic trafficking capacity of reporter mRNAs linked to various regions of longer or shorter NEURL1 3'UTR, we localise the dendritic targeting element (DTE) of spliced version of NEURL1 3'UTR to its first half, corresponding to the nucleotides 1-148 and 416-914 of the full-length 3'UTR. In contrast, the dendritic targeting capacity of the full-length NEURL1 3'UTR is abolished by splitting its 3'UTR in two halves (nt 1-914 and nt 915-1744), suggesting that slightly different DTE might mediate dendritic transport of the two transcripts. PMID- 27780738 TI - Next-generation sequencing-based small RNA profiling of cerebrospinal fluid exosomes. AB - MicroRNAs (miRNAs), particularly those found in human body fluids, have been suggested as potential biomarkers. Among various body fluids, the cerebrospinal fluid (CSF) shows promise as a profiling target for diagnosis and monitoring of neurological diseases. However, relevant genome-scale studies are limited and no studies have profiled exosomal miRNAs in CSF. Therefore, we conducted a next generation sequencing-based genome-wide survey of small RNAs in the exosomal and non-exosomal (supernatant) fractions of healthy human CSF as well as serum in each donor. We observed miRNA enrichment in the exosomal fractions relative to the supernatant fractions of both CSF and serum. We also observed substantial differences in exosomal miRNA profiles between CSF and serum. Half of the reported brain miRNAs were found in CSF exosomal fractions. In particular, miR 1911-5p, specifically expressed in brain tissue, was detected in CSF but not in serum, as confirmed by digital PCR in three additional donors. Our data suggest that the brain is a major source of CSF exosomal miRNAs. Here we provide the important evidence that exosomal miRNAs in CSF may reflect brain pathophysiology. PMID- 27780739 TI - Oligomeric alpha-synuclein and glucocerebrosidase activity levels in GBA associated Parkinson's disease. AB - Alpha-synuclein oligomerization plays a key role in the development of Parkinson's disease (PD). Being the most common genetic contributor to PD, glucocerebrosidase 1 (GBA) mutations have been associated with decreased GBA enzymatic activity in PD patients with mutations in the GBA gene (GBA-PD). However, it is unknown whether the activities of other lysosomal hydrolases are being altered in GBA-PD patients and are accompanied by an increase in alpha synuclein oligomerization. The aim of our study was to estimate GBA enzymatic activity as well as the activities of five other lysosomal hydrolases (galactocerebrosidase, alpha-glucosidase, alpha-galactosidase, sphingomyelinase, alpha-iduronidase) in dried blood spots with assessing plasma oligomeric alpha synuclein levels in sporadic PD (sPD) patients, in GBA-PD patients and in controls. GBA enzymatic activity and plasma oligomeric alpha-synuclein levels were assessed in sPD patients (N=84), in GBA-PD patients (N=21) and controls (N=62) by LC-MS/MS and ELISA methods accordingly. GBA-PD patients showed lower GBA enzymatic activity compared to controls (p=0.001) and to sPD (p=0.0001). We also found the reduction of GLA enzymatic activity (but not of other lysosomal hydrolases) in GBA-PD (p=0.001). At the same time plasma oligomeric alpha synuclein levels were increased in GBA-PD group compared to sPD and controls (p=0.002 and p<0.0001, respectively). Our results suggest that the decrease in enzymatic activity of lysosomal hydrolases in GBA mutation carriers may contribute to PD pathogenesis by increasing the level of neurotoxic oligomeric alpha-synuclein species. PMID- 27780741 TI - Tertiary lymphoid organs in recalcitrant chronic rhinosinusitis. PMID- 27780740 TI - Comparative performance assessment of commercially available automatic external defibrillators: A simulation and real-life measurement study of hands-off time. AB - PURPOSE: Early and good quality cardiopulmonary resuscitation (CPR) and the use of automated external defibrillators (AEDs) improve cardiac arrest patients' survival. However, AED peri- and post-shock/analysis pauses may reduce CPR effectiveness. METHODS: The time performance of 12 different commercially available AEDs was tested in a manikin based scenario; then the AEDs recordings from the same tested models following the clinical use both in Pavia and Ticino were analyzed to evaluate the post-shock and post-analysis time. RESULTS: None of the AEDs was able to complete the analysis and to charge the capacitors in less than 10s and the mean post-shock pause was 6.7+/-2.4s. For non-shockable rhythms, the mean analysis time was 10.3+/-2s and the mean post-analysis time was 6.2+/ 2.2s. We analyzed 154 AED records [104 by Emergency Medical Service (EMS) rescuers; 50 by lay rescuers]. EMS rescuers were faster in resuming CPR than lay rescuers [5.3s (95%CI 5-5.7) vs 8.6s (95%CI 7.3-10). CONCLUSIONS: AEDs showed different performances that may reduce CPR quality mostly for those rescuers following AED instructions. Both technological improvements and better lay rescuers training might be needed. PMID- 27780742 TI - Association of a TNFSF13B (BAFF) regulatory region single nucleotide polymorphism with response to rituximab in antineutrophil cytoplasmic antibody-associated vasculitis. PMID- 27780744 TI - John Staniforth-An appreciation: The non-conformist nonconformist. PMID- 27780743 TI - Prevalence and Effect of Problematic Spasticity After Traumatic Spinal Cord Injury. AB - OBJECTIVE: To evaluate the prevalence and effect of spasticity after traumatic spinal cord injury (SCI). DESIGN: Prospective cohort study of the Rick Hansen Spinal Cord Injury Registry (RHSCIR) and retrospective review of inpatient medical charts. SETTING: Quaternary trauma center, rehabilitation center, and community settings. PARTICIPANTS: Individuals (N=860) with a traumatic SCI between March 1, 2005, and March 31, 2014, prospectively enrolled in the Vancouver site RHSCIR were eligible for inclusion. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Questionnaires (Penn Spasm Frequency Scale, Spinal Cord Injury Health Questionnaire) and antispasticity medication use. RESULTS: In 465 patients, the prevalence of spasticity at community discharge was 65%, and the prevalence of problematic spasticity (defined as discharged on antispasticity medication) was 35%. Problematic spasticity was associated with cervicothoracic neurologic level and injury severity (P<.001). In community follow-up, the prevalence of patients reporting any spasticity treatment (ie, problematic spasticity) was 35% at 1 year, 41% at 2 years, and 31% at 5 years postinjury. Interference with function caused by spasticity was reported by 27% of patients at 1 year, 25% at 2 years, and 20% at 5 years postinjury. Patients with American Spinal Injury Association Impairment Scale grade C injuries had the highest prevalence of ongoing spasticity treatment and functional limitation. CONCLUSIONS: Spasticity is a highly prevalent secondary consequence of SCI, particularly in patients with severe motor incomplete cervicothoracic injuries. It is problematic in one third of all patients with SCI up to 5 years postinjury. One in 5 patients will have ongoing functional limitations related to spasticity, highlighting the importance of close community follow-up and the need for further research into spasticity management strategies. PMID- 27780745 TI - Cross-sectional study of high-sensitivity cardiac troponins T and I in a hospital and community outpatient setting. AB - OBJECTIVES: Cardiac troponins are specific for the heart, but not for the acute coronary syndrome. We wanted to assess how common elevated cardiac troponin concentrations were, in a population with significant non-cardiac disease. DESIGN & METHODS: We measured both hs-cTnT and hs-cTnI on all samples submitted to the laboratory during one 24h period, and assessed the magnitude of the cTn concentration with the location and severity of disease of the patient. RESULTS: Community patients and patients from the maternity ward had the lowest cTn concentrations with results above the 99th percentile being only 0-2% of the total. As expected, the highest proportion of results >99th percentile came from Coronary Care and Intensive Care. However, substantial numbers of persons on Medical and Surgical wards, without a primary diagnosis of cardiac disease, also had cTn >99th percentile. Particularly for cTnT, there was a highly significant odds ratio predicting mortality when results above and below the 99th percentile were compared. CONCLUSIONS: Significant illnesses apart from the acute coronary syndrome are important causes of a rise in cTn to above the 99th percentile, and appear to reflect the total body burden of disease. Even when the high hs-cTn concentration is not due to the acute coronary syndrome, there is a significant association with all-cause mortality. PMID- 27780746 TI - Long-term noise exposures: A brief review. PMID- 27780747 TI - Intronless and intron-containing type I IFN genes coexist in amphibian Xenopus tropicalis: Insights into the origin and evolution of type I IFNs in vertebrates. AB - Type I IFNs are considered to be the core IFN species in vertebrates because of their predominant antiviral effects. But, a puzzling question remains to be answered, as to how intronless type I IFN genes in amniotes might have evolved from intron-containing type I IFN genes in fish and amphibians. In this study, intronless and intron-containing type I IFNs were found in the amphibian model, Xenopus tropicalis, with a total of sixteen and five genes, respectively. The intronless IFNs can be divided into three subgroups, and the intron-containing ones into two subgroups, implying that a retroposition event might have occurred in amphibians, resulting in the generation of intronless type I IFN genes. Two models were tentatively proposed to explain the evolution of type I IFNs in vertebrates: in model A, fish should possess the most primitive multi-exon containing type I IFNs, and intronless type I IFN genes in amphibians are the ancestor of modern intronless type I IFNs in amniotes; in model B, intronless type I IFN genes in X. tropicalis may just represent an independent bifurcation in this species or probably in amphibians, and intronless type I IFN genes in amniotes may have arisen from another retroposition event occurred in a transition period even when reptiles were diverged from amphibians. It is considered that the model B can reflect the current knowledge on the occurrence of intronless and intron-containing type I IFN genes in vertebrate lineages. This study thus contributes to a better understanding of the origin and evolution of type I IFNs in vertebrates, and of the occurrence of intronless I IFNs in higher vertebrates. PMID- 27780748 TI - Prophylactic Use of Oral Dexamethasone to Alleviate Fatigue During Regorafenib Treatment for Patients With Metastatic Colorectal Cancer. AB - BACKGROUND: Fatigue is the most common toxicity of all grade toxicities with regorafenib, was the second most common toxicity in the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) study, and is a major reason for early dose modification. The results from a recent randomized study suggested that dexamethasone (DEX) can improve cancer-related fatigue. PATIENTS AND METHODS: We retrospectively analyzed the effect of prophylactic use of an oral DEX on fatigue during regorafenib treatment in patients with metastatic colorectal cancer (mCRC). A total of 105 patients who had received regorafenib at our institution from May 2013 to August 2014 were divided into 2 groups according to oral DEX use (2 mg/day; at the physician's discretion). RESULTS: Of the 105 patients, 31 received prophylactic DEX and 74 received regorafenib alone. The time to dose modification was significantly longer in the DEX group than in the no DEX group (15 days vs. 9 days; P = .009). The incidence of fatigue (grade >= 1) was significantly lower with DEX than without DEX (25.8% vs. 50.0%; P = .022). Fewer patients experienced a decreased appetite (grade >= 1; 3.2% vs. 35.1%; P < .001) and hand-foot skin reaction (HFSR; grade >= 3; 3.2% vs. 25.7%, P = .002) with DEX than without DEX. CONCLUSION: DEX was effective in reducing fatigue during regorafenib treatment, resulting in prolonging the time to dose modification for regorafenib. The decreased incidence of appetite loss and HFSR also suggest that concurrent DEX administration with regorafenib warrants further investigation. PMID- 27780749 TI - Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study. AB - BACKGROUND: In patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC), outcomes with first-line chemotherapies are improved by adding weekly cetuximab. The APEC study investigated first-line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC; additional biomarker subgroups were also analyzed. PATIENTS AND METHODS: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2 weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated. RESULTS: In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations. CONCLUSION: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration. PMID- 27780751 TI - Medicinal plants used in Lesotho for treatment of reproductive and post reproductive problems. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Reproductive healthcare has been highlighted as a major challenge in Lesotho mainly due to the high prevalence of HIV/AIDS and sexually transmitted infections. As a result other reproductive ailments have not received much attention, particularly because healthcare facilities are already limited and many of them are inaccessible. For these reasons, medicinal plants play a major role in primary healthcare system in the country, in addition the plants are easily accessible, more affordable, and their use forms part of the cultural heritage. However, documentation of medicinal plants used for reproductive ailments is scattered, more importantly the biological and pharmacological properties, as well as toxicity of many of these plants are not yet known. AIM OF THE STUDY: To document the plants used by both male and female Basotho (residing in Lesotho) for the treatment of reproductive ailments, to explore their recorded biological and pharmacological effects as well as their toxicity, and to establish if these plants are used for similar purposes in other southern African cultures. MATERIALS AND METHODS: The results stem from published findings of recent interviews of traditional medicinal practitioners in the Maseru District of Lesotho, first author's own experiences and observations from the Qacha's Nek District as well as comprehensive literature survey including numerous books and unpublished data. Electronic databases such as Google, Google Scholar, PubMed, and ScienceDirect were also used to search for the chemical compounds, pharmacological activity, and toxicity of the plants. RESULTS: A total of 87 plant species are reported to be used for the treatment of several reproductive problems such as infertility, complications associated with pregnancy (twelve plants are used to treat conditions such as colic, heartburn, nausea, and constipation), cleansing and/ or toning of the uterus (with a purpose either to induce pregnancy or to get rid of the placenta, for example Withania somnifera and Zantedeschia albomaculata), difficult childbirth, as well treatment of breast and cervical cancer, cysts, fibroids, and testicular tumours (e.g. Hypoxis hemerocallidea). For the toning of the uterus, it is common to use a combination of plants, e.g. Gunnera perpensa, Scabiosa columbaria, and Eriospermum ornithogaloides. CONCLUSIONS: Of the 87 plants used for reproductive healthcare, the highest number (31) is used for the treatment of infertility (in both men and women). The pharmacological effects, active compounds, and toxicology of many of these plants are not yet known. PMID- 27780752 TI - Ethnobotanical survey of medicinal plants used to manage High Blood Pressure and Type 2 Diabetes Mellitus in Bitterfontein, Western Cape Province, South Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of this study was to identify and document medicinal plants used to manage High Blood Pressure and Type 2 Diabetes Mellitus in Bitterfontein, Western Cape Province, South Africa. METHODS: One hundred and twelve (112) respondents were interviewed between August 2014 and September 2015 through semi-structured surveys to gather data on the percentage of people who had been diagnosed with High Blood Pressure and/or Type 2 Diabetes Mellitus and to determine the frequency of medicinal plant and allopathic medicine use. Twelve (12) key respondents were subsequently selected, using a non probability snowball sampling method. They were interviewed in-depth concerning their plant practices and assisted with plant collection. RESULTS: Twenty-four plant (24) species belonging to 15 families were identified for the management of High Blood Pressure and Type 2 Diabetes Mellitus. The most frequently reported families were Asteraceae (20.8%), Lamiaceae (16.67%), Crassulaceae (8.33%) and Aizoaceae (8.33%). The remaining (45.54%) were evenly split over eleven families- Fabaceae, Amaryllidaceae, Anacardiaceae, Capparaceae, Geraniaceae, Apiaceae, Convolvulaceae, Apocynaceae, Rutaceae, Asphodelaceae and Thymelaeaceae. The most commonly used plant species overall was Lessertia frutescens (96.55%). The most frequently used plant parts included leaves (57.63%) roots/bulbs (15.25%) and stems (11.86%), mostly prepared as infusions or decoctions for oral administration. CONCLUSIONS: Medicinal plants are widely used by High Blood Pressure and Type 2 Diabetes Mellitus sufferers. They employ diverse plant species to manage both conditions. In addition, some sufferers often use prescribed allopathic medication, as well as medicinal plants, but at different intervals. Despite high usage the plants identified are not currently threatened (Red Data list status: least concern). PMID- 27780750 TI - Siderophore-mediated iron acquisition and modulation of host-bacterial interactions. AB - Iron is an essential micronutrient for most life forms including the majority of resident bacteria of the microbiota and their mammalian hosts. Bacteria have evolved numerous mechanisms to competitively acquire iron within host environments, such as the secretion of small molecules known as siderophores that can solubilize iron for bacterial use. However, siderophore biosynthesis and acquisition is not a capability equally harbored by all resident bacteria. Moreover, the structural diversity of siderophores creates variability in the susceptibility to host mechanisms that serve to counteract siderophore-mediated iron acquisition and limit bacterial growth. As a result, the differential capabilities to acquire iron among members of a complex microbial community carry important implications for the growth and function of resident bacteria. Siderophores can also directly influence host function by modulating cellular iron homeostasis, further providing a mechanism by which resident bacteria may influence their local environment at the host-microbial interface. This review will explore the putative mechanisms by which siderophore production by resident bacteria in the intestines may influence microbial community dynamics and host bacterial interactions with important implications for pathogen- and microbiota driven diseases including infection, inflammatory bowel diseases and colorectal cancer. PMID- 27780753 TI - The essential oil from the twigs of Cinnamomum cassia Presl alleviates pain and inflammation in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Presl (Lauraceae) can be found southern China and its bark is commonly used for centuries as ingredient in food and cosmetic industry. The twigs of Cinnamomum cassia Presl is popularly used in China to treat inflammatory processes, pain, menstrual disorders, hypertension, fever etc. The aim of this study is to evaluate the antinociceptive and anti inflammatory properties of the essential oil (EO) from the twigs of Cinnamomum cassia Presl. MATERIAL AND METHODS: The chemical characterization of the EO was performed by gas chromatography coupled with mass spectrometry (GC-MS). The EO doses of 15, 30, and 60mg/kg were employed in the biological assays. The antinociceptive effects of the EO were evaluated using the models of acetic acid induced writhing, oxytocin-induced writhing, and formalin and complete Freund's adjuvant (CFA) -induced overt pain tests. we also investigated the effect of the EO in pain intensity to a mechanical stimulus (mechanical hyperalgesia) after carrageenan by using an electronic version of von Frey filaments. Evaluation of anti-inflammatory activity was based on paw edema induced by carrageenan (300ug/25uL/paw) in mice. The levels of cytokines, NO, and PGE2 in paw skin tissue were determined according to instructions. COX-2 and iNOS proteins in paw skin tissue were assessed by Western Blot. RESULTS: The EO (15, 30, and 60mg/kg) reduced the number of abdominal writhings induced by acetic acid with inhibition of 38.0%, 55.4% and 58.7%, respectively. The EO (15, 30, and 60mg/kg) also reduced the number of abdominal writhings induced by oxytocin with inhibition of 27.3%, 51.7% and 69.0%, respectively. The EO significant inhibited the inflammatory (second phase: 10-30min) phase of the formalin-induced paw flinching and licking at the doses of 15, 30, and 60mg/kg. The EO at the tested doses of 15, 30, and 60mg/kg showed inhibited CFA-induced paw flinching and licking. The EO (15, 30, and 60mg/kg) also inhibited carrageenan-induced mechanical hyperalgesia and paw edema. It also decreased the levels of cytokines (TNF-alpha, and IL-1beta), NO, and PGE2 in carrageenan-induced mice paw skin tissue. Moreover, Western blot analysis showed that COX-2 and iNOS expressions in paw skin tissue of mice were significantly reduced. CONCLUSIONS: These results demonstrate that the antinociceptive and anti-inflammatory properties of the EO from the twigs of Cinnamomum cassia Presl, corroborating its use in folk medicine. PMID- 27780754 TI - PPARgamma agonists induce adipocyte differentiation by modulating the expression of Lipin-1, which acts as a PPARgamma phosphatase. AB - PPARgamma agonists induced obesity in animal models as a side effect. Microarray experiments reveal that PPARgamma agonist upregulates the expression of lipin-1 and this upregulation is correlated with the activity of the agonists. Lipin-1 induced by PPARgamma agonists decreased the levels of PPARgamma and ERK1/2 phosphorylation through direct interaction with these proteins in 3T3-L1 cells. In PPARgamma agonist-treated 3T3-L1 preadipocytes, the knockdown of lipin-1 expression by small interfering RNA inhibited the adipogenesis that was induced by PPARgamma agonists. In contrast, PPARgamma2 expression was increased, and lipid droplets were accumulated in lipin-1-overexpressing 3T3-L1 adipocytes. Rosiglitazone (RGZ), a strong PPARgamma agonist, synergistically promoted PPARgamma dephosphorylation and adipogenesis in lipin-1-overexpressing 3T3-L1 preadipocytes. Therefore, lipin-1 has dual functions as a transcriptional cofactor and phosphatidate phosphatase (PAP) in the differentiation of preadipocyte cells induced by strong PPARgamma agonists. In addition, the adipogenesis of 3T3-L1 cells was markedly upregulated by diacylglycerol (DAG), which was produced by lipin-1. Therefore, lipin-1 induction by PPARgamma agonists might be an important factor in understanding the biological mechanism of the agonists' adverse effects, and this information may be valuable in the development of type-2 diabetes mellitus (T2DM) therapeutics with reduced adverse effects and greater tolerability. PMID- 27780755 TI - St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic beta cells. AB - The extract of the herbaceous plant St. John's wort (SJW) and its phloroglucinol component hyperforin (HPF) were previously shown to inhibit cytokine-induced STAT 1 and NF-kappaB activation and prevent damage in pancreatic beta cells. To further clarify the mechanisms underlying their protective effects, we evaluated the phosphorylation state of various factors of cytokine signaling pathways and the expression of target genes involved in beta-cell function, inflammatory response and apoptosis induction. In the INS-1E beta-cell line, exposed to a cytokine mixture with/without SJW extract (2-5MUg/ml) or HPF (1-5MUM), protein phosphorylation was assessed by western blotting and expression of target genes by real-time quantitative PCR. SJW and HPF markedly inhibited, in a dose dependent manner (from 60 to 100%), cytokine-induced activating phosphorylations of STAT-1, NF-kappaB p65 subunit and IKK (NF-kappaB inhibitory subunit IkappaBalpha kinase). MAPK and Akt pathways were also modulated by the vegetal compounds through hindrance of p38 MAPK, ERK1/2, JNK and Akt phosphorylations, each reduced by at least 65% up to 100% at the higher dose. Consistently, SJW and HPF a) abolished cytokine-induced mRNA expression of pro-inflammatory genes; b) avoided down-regulation of relevant beta-cell functional/differentiation genes; c) corrected cytokine-driven imbalance between pro- and anti-apoptotic factors, by fully preventing up-regulation of pro-apoptotic genes and preserving expression or function of anti-apoptotic Bcl-2 family members; d) protected INS 1E cells against cytokine-induced apoptosis. In conclusion, SJW extract and HPF exert their protective effects through simultaneous inhibition of multiple phosphorylation steps along various cytokine signaling pathways and consequent restriction of inflammatory and apoptotic gene expression. Thus, they have a promising therapeutic potential for the prevention or limitation of immune mediated beta-cell dysfunction and damage leading to type 1 diabetes. PMID- 27780756 TI - Spectrophotometric assays for monitoring tRNA aminoacylation and aminoacyl-tRNA hydrolysis reactions. AB - Aminoacyl-tRNA synthetases play a central role in protein synthesis, catalyzing the attachment of amino acids to their cognate tRNAs. Here, we describe a spectrophotometric assay for tyrosyl-tRNA synthetase in which the Tyr-tRNA product is cleaved, regenerating the tRNA substrate. As tRNA is the limiting substrate in the assay, recycling it substantially increases the sensitivity of the assay while simultaneously reducing its cost. The tRNA aminoacylation reaction is monitored spectrophotometrically by coupling the production of AMP to the conversion of NAD+ to NADH. We have adapted the tyrosyl-tRNA synthetase assay to monitor: (1) aminoacylation of tRNA by l- or d-tyrosine, (2) cyclodipeptide formation by cyclodipeptide synthases, (3) hydrolysis of d-aminoacyl-tRNAs by d tyrosyl-tRNA deacylase, and (4) post-transfer editing by aminoacyl-tRNA synthetases. All of these assays are continuous and homogenous, making them amenable for use in high-throughput screens of chemical libraries. In the case of the cyclodipeptide synthase, d-tyrosyl-tRNA deacylase, and post-transfer editing assays, the aminoacyl-tRNAs are generated in situ, avoiding the need to synthesize and purify aminoacyl-tRNA substrates prior to performing the assays. Lastly, we describe how the tyrosyl-tRNA synthetase assay can be adapted to monitor the activity of other aminoacyl-tRNA synthetases and how the approach to regenerating the tRNA substrate can be used to increase the sensitivity and decrease the cost of commercially available aminoacyl-tRNA synthetase assays. PMID- 27780757 TI - Heterologous expression of the human Phosphoenol Pyruvate Carboxykinase (hPEPCK M) improves hydrogen and ethanol synthesis in the Escherichia coli dcuD mutant when grown in a glycerol-based medium. AB - The production of biodiesel has emerged as an alternative to fossil fuels. However, this industry generates glycerol as a by-product in such large quantities that it has become an environmental problem. The biotransformation of this excess glycerol into other renewable bio-energy sources, like H2 and ethanol, by microorganisms such as Escherichia coli is an interesting possibility that warrants investigation. In this work we hypothesized that the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) could be improved by a controlled expression of the human mitochondrial GTP-dependent PEP carboxykinase. This heterologous expression was tested in several E. coli mutant backgrounds with increased availability of C4 intermediates. It was found that this metabolic rewiring improved the synthesis of the target products in several mutants, with the dcuD mutant being the most suitable background for hydrogen and ethanol specific productions and glycerol consumption. These factors increased by 2.46, 1.73 and 1.95 times, respectively, when compared to those obtained for the wild type strain. PMID- 27780758 TI - SCCT guidelines for the performance and acquisition of coronary computed tomographic angiography: A report of the society of Cardiovascular Computed Tomography Guidelines Committee: Endorsed by the North American Society for Cardiovascular Imaging (NASCI). AB - In response to recent technological advancements in acquisition techniques as well as a growing body of evidence regarding the optimal performance of coronary computed tomography angiography (coronary CTA), the Society of Cardiovascular Computed Tomography Guidelines Committee has produced this update to its previously established 2009 "Guidelines for the Performance of Coronary CTA" (1). The purpose of this document is to provide standards meant to ensure reliable practice methods and quality outcomes based on the best available data in order to improve the diagnostic care of patients. Society of Cardiovascular Computed Tomography Guidelines for the Interpretation is published separately (2). The Society of Cardiovascular Computed Tomography Guidelines Committee ensures compliance with all existing standards for the declaration of conflict of interest by all authors and reviewers for the purpose ofclarity and transparency. PMID- 27780759 TI - Purification, preliminary X-ray crystallography and biophysical studies of triose phosphate isomerase-beta-globin subunit complex. AB - Triose phosphate isomerase (TIM) is a cytoplasmic enzyme of prime importance in the mammalian glycolytic pathway. It has a major role in the conversion of dihydroxyacetone phosphate into glyceraldehyde-3-phosphate. We have successfully purified a stable complex of TIM with beta-globin subunit from the sheep kidney using a simple two-step chromatography procedure. It is seen for the first time that TIM is forming a stable complex with beta-globin. The purified protein protein complex was crystallized and preliminary diffraction data were collected at 2.1A resolution. We further studied guanidinium chloride (GdmCl)-induced denaturation of TIM-beta-globin complex by monitoring changes in the mean residue ellipticity at 222nm ([theta]222) and difference absorption coefficient at 406nm (Deltaepsilon406) at pH 7.5 and 25 degrees C. We have observed that GdmCl-induced denaturation is reversible. Coincidence of normalized transition curves of both physical properties ([theta]222 and Deltaepsilon406) suggests that folding/unfolding of TIM and beta-subunit proteins is a two-state process. Denaturation curves of [theta]222 and Deltaepsilon406 were used to estimate the stability parameters of the protein-protein complex. This is the first report on the isolation, purification, crystallization and biophysical characterization of the naturally occurring complex of TIM with the beta-globin subunit. PMID- 27780761 TI - Quinazoline derivatives as cathepsins B, H and L inhibitors and cell proliferating agents. AB - Cysteine Cathepsins well known to be involved in cancer, inflammation and regulation of degenerative processes like apoptosis have become specific targets in drug designing. The potential of quinazolines and their derivatives in medicinal chemistry led us to synthesise a novel series of seven compounds of quinazolines to evaluate their effect on cathepsins and cellular aspects of HepG2 cells. In the present work we report the solvent free microwave assisted synthesis of (E)-8-benzylidene-5,6,7,8-tetrahydro-2,4-diarylquinazolines as inhibitors of mammalian hepatic cysteine proteases viz. Cathepsins B, H and L. In vitro inhibition of Cathepsins B, H and L is correlated well with in vitro studies when tested using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium Bromide) assay on HepG2 cells, hepatocellular carcinoma cell line. The studies have been extended to evaluate the type of inhibition exhibited by the individual enzyme. Out of the seven compounds 1g i.e. (E)-8-(4 fluorobenzylidene)-4-(4-fluorophenyl)-2-phenyl-5, 6, 7, 8-tetrahydroquinazoline has been found to be most inhibitory for Cathepsins B, H and L to a maximum extent with the Ki values of 10-10M, 10-10M and 10-9M order respectively. In silico studies of all compounds have also been done at the active sites of Cathepsin B, H and L. PMID- 27780762 TI - Differential Expression of miRNAs in Nontumor Liver Tissue of Patients With Hepatocellular Cancer Caused by Nonalcoholic Steatohepatitis Cirrhosis. PMID- 27780760 TI - Effective synthesis of theaflavin-3,3'-digallate with epigallocatechin-3-O gallate and epicatechin gallate as substrates by using immobilized pear polyphenol oxidase. AB - In the present study, pear polyphenol oxidase (PPO) was purified, immobilized and applied for the synthesis of theaflavin-3,3'-digallate (TF3). Firstly, PPO of pear (Pyrus bretschneideri Rehd cv. Huangguan) was purified 24.36-fold in specific activity with a recovery of 6.77% by sequential use of precipitation with 70% saturated ammonium sulfate and chromatography of DEAE-Sepharose Fast Flow column. The purified pear PPO, found to be a dimer of identical subunits of molecular mass 35kDa, was then successfully immobilized onto Fe3O4/chitosan nanoparticles via glutaraldehyde coupling reaction. Finally, TF3 was effectively synthesized by applying the immobilized PPO as biocatalyst with epicatechin gallate (ECG) and epigallocatechin-3-O-gallate (EGCG) as substrates, and the maximum yield of TF3 was 42.23% based on the amount of ECG added. In addition, the immobilized enzyme still remained 85% of its initial ability after successive usage of 8 cycles and could be stored for 30days with less loss of activity. All the results suggest that the developed procedure is quite useful and has great potential for synthesis of TF3 and other theaflavins. PMID- 27780763 TI - Classification schemes for carcinogenicity based on hazard-identification have become outmoded and serve neither science nor society. AB - Classification schemes for carcinogenicity based solely on hazard-identification such as the IARC monograph process and the UN system adopted in the EU have become outmoded. They are based on a concept developed in the 1970s that chemicals could be divided into two classes: carcinogens and non-carcinogens. Categorization in this way places into the same category chemicals and agents with widely differing potencies and modes of action. This is how eating processed meat can fall into the same category as sulfur mustard gas. Approaches based on hazard and risk characterization present an integrated and balanced picture of hazard, dose response and exposure and allow informed risk management decisions to be taken. Because a risk-based decision framework fully considers hazard in the context of dose, potency, and exposure the unintended downsides of a hazard only approach are avoided, e.g., health scares, unnecessary economic costs, loss of beneficial products, adoption of strategies with greater health costs, and the diversion of public funds into unnecessary research. An initiative to agree upon a standardized, internationally acceptable methodology for carcinogen assessment is needed now. The approach should incorporate principles and concepts of existing international consensus-based frameworks including the WHO IPCS mode of action framework. PMID- 27780764 TI - Biodegradable and biomimetic elastomeric scaffolds for tissue-engineered heart valves. AB - : Valvular heart diseases are the third leading cause of cardiovascular disease, resulting in more than 25,000 deaths annually in the United States. Heart valve tissue engineering (HVTE) has emerged as a putative treatment strategy such that the designed construct would ideally withstand native dynamic mechanical environment, guide regeneration of the diseased tissue and more importantly, have the ability to grow with the patient. These desired functions could be achieved by biomimetic design of tissue-engineered constructs that recapitulate in vivo heart valve microenvironment with biomimetic architecture, optimal mechanical properties and possess suitable biodegradability and biocompatibility. Synthetic biodegradable elastomers have gained interest in HVTE due to their excellent mechanical compliance, controllable chemical structure and tunable degradability. This review focuses on the state-of-art strategies to engineer biomimetic elastomeric scaffolds for HVTE. We first discuss the various types of biodegradable synthetic elastomers and their key properties. We then highlight tissue engineering approaches to recreate some of the features in the heart valve microenvironment such as anisotropic and hierarchical tri-layered architecture, mechanical anisotropy and biocompatibility. STATEMENT OF SIGNIFICANCE: Heart valve tissue engineering (HVTE) is of special significance to overcome the drawbacks of current valve replacements. Although biodegradable synthetic elastomers have emerged as promising materials for HVTE, a mature HVTE construct made from synthetic elastomers for clinical use remains to be developed. Hence, this review summarized various types of biodegradable synthetic elastomers and their key properties. The major focus that distinguishes this review from the current literature is the thorough discussion on the key features of native valve microenvironments and various up-and-coming approaches to engineer synthetic elastomers to recreate these features such as anisotropic tri-layered architecture, mechanical anisotropy, biodegradability and biocompatibility. This review is envisioned to inspire and instruct the design of functional HVTE constructs and facilitate their clinical translation. PMID- 27780765 TI - Influence of strain on the corrosion of magnesium alloys and zinc in physiological environments. AB - : During implantation load-bearing devices experience stress that may influence its mechanical and corrosion profile and potentially lead to premature rupture. The susceptibility to stress corrosion cracking (SCC) of the Mg-Al alloy AZ61 and Zn was studied in simulated body fluid (m-SBF) and whole blood by slow strain rate (SSR) testing in combination with electrochemical impedance spectroscopy (EIS) and further ex situ analysis including scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy. AZ61 was found to be highly susceptible to SCC. EIS analysis show that although the majority of cracking occurred during the apparent plastic straining, cracking initiation occurs already in the elastic region at ~50% of the ultimate tensile strength (UTS). Shifts in EIS phase angle and open circuit potential can be used to detect the onset of SCC. Zinc demonstrated a highly ductile behavior with limited susceptibility to SCC. No significant decrease in UTS was observed in m-SBF but a decrease in time to failure by ~25% compared to reference samples indicates some effect on the mechanical properties during the ductile straining. The formation of micro cracks, ~10MUm deep, was indicated by the EIS analysis and later confirmed by ex situ SEM. The results of SSR analysis of zinc in whole blood showed a reduced effect compared to m-SBF and no cracks were detected. It appears that formation of an organic surface layer protects the corroding surface from cracking. These results highlight the importance of considering the effect of biological species on the degradation of implants in the clinical situation. STATEMENT OF SIGNIFICANCE: Strain may deteriorate the corrosion properties of metallic implants drastically. We study the influence of load on the corrosion properties of a magnesium alloy and zinc by a combination of electrochemical impedance spectroscopy (EIS) and slow strain rate analysis. This combination of techniques has previously not been used for studying degradation in physiological relevant electrolytes. EIS provide valuable information on the initial formation of cracks, detecting crack nucleation before feasible in slow strain rate analysis. This sensitivity of EIS shows the potential for electrochemical methods to be used for in situ monitoring crack formation of implants in more applied studies. PMID- 27780766 TI - Effects of 5-HT-7 receptor ligands on memory and cognition. AB - The 5-HT7R is the most recently cloned serotonin receptor and thus one the least studied. Many drugs, experimental and in clinical use bind to 5-HT7 with high affinity, though their effects have yet to be clearly elucidated. Its physiological function, though not completely clear, is mostly associated with learning and memory, with both agonists and antagonists possessing subtle procognitive and promnesic properties. We consider it a promising area of research, though still in its infancy, which may one day lead to clinical benefits for patients with various afflictions characterised by cognitive dysfunction, particularily autism spectrum disorder, fragile X syndrome and Alzheimer's disease. PMID- 27780767 TI - Localization and distribution of superoxide dismutase-1 in the neural tube morphogenesis of chick embryo. AB - Superoxide dismutase 1 (SOD- 1) is an antioxidant enzyme that regulates the levels of Reactive oxygen species (ROS) by catalyzing the conversion of superoxide radical into hydrogen peroxide (H2O2) and oxygen. ROS are known to play a significant role in various cellular processes, via redox modification of a variety of molecules that participate in signaling pathways involved in this processes. As the levels of ROS in cells are controlled by the levels of antioxidant enzymes, thus SOD-1 may be indirectly involved in regulating different cellular processes by maintaining the required levels of H2O2. Therefore, in the present study we have investigated the possible involvement of SOD- 1 in the neurulation during the development of chick embryo. During gastrulation, SOD- 1 immunoreactivity was observed throughout the ectoderm and cauda mesoderm areas, however, its presence during neurulation was restricted to certain areas of neural tube particularly in the dorsal neural tube where neural tube closure takes place. Assaying enzyme activity revealed a significant increase in the SOD activity during neurulation. Further, inhibition of SOD- 1 by Diethyldithiocarbamate (DDC) induced abnormalities in the development of the neural tube. SOD- 1 inhibition specifically affected the closure of neural tube in the anterior region. Thus, here we report the presence of SOD- 1 mainly in the ectoderm and tissues of ectodermal origin during gastrulation to neurulation which suggests that it may be involved in the regulating the cellular processes during neural tube morphogenesis. PMID- 27780768 TI - Influence of Functional Capacity Evaluation on Physician's Assessment of Physical Capacity of Veterans With Chronic Pain: A Retrospective Analysis. AB - BACKGROUND: Physicians have difficulty predicting patients' occupational limitations, abilities, and success from clinical evaluation (CE) of pathology and impairments, especially in the presence of chronic pain. Additional information from a functional capacity evaluation (FCE) may improve the accuracy of their physical capacity assessments. It is not known whether FCE information will change these assessments. No such study has been published using Veterans or non-Veterans. OBJECTIVE: To determine the influence of FCE data on the physician's assessment of the US Department of Labor's Dictionary of Occupational Titles (DOT) work capacity levels of Veterans with chronic moderate-intensity pain. DESIGN: Retrospective analysis. SETTING: Tertiary care medical center. PARTICIPANTS: Veterans aged 18-60 years with moderate chronic musculoskeletal pain who were seeking employment. METHODS: Two kinesiotherapists performed FCEs on all participants, namely, the lumbar protocol of the EvalTech Functional Testing System (BTE, Inc, Hanover, MD). One physiatrist performed CEs in all participants. Two other physiatrists assessed DOT physical capacity levels using CE data alone and later using combined CE and FCE data. MAIN OUTCOME MEASUREMENTS: DOT physical capacity level (sedentary = 1, light = 2, medium = 3, heavy = 4, very heavy = 5). RESULTS: Of 55 charts reviewed, 27 met inclusion/exclusion criteria. The mean age was 38 years, and there were 25 male and 2 female participants. The predominant pain location was the lower back. DOT scores for 2 physicians were averaged. The mean +/- SD DOT scores for CE only and CE+FCE conditions were 2.04 +/- 0.33 and 2.40 +/- 0.90, respectively. In all, 65% of DOT scores changed (17% decreased and 48% increased at least 1 level) after FCE data were considered. A 1-sample t test revealed that the mean CE+FCE DOT score was significantly greater than the mean CE-only score (by 20%, P = .02). Interrater agreement (weighted kappa) for CE+FCE-based DOT scores was much higher than for CE alone (0.715 versus 0.182). CONCLUSION: The addition of FCE data to CE changed the majority of physician-assigned DOT levels. FCE significantly increased the mean DOT physical work capacity level provided by the physician to Veterans with chronic moderate-intensity pain, especially if the initial assessment was designated as "light." FCE may facilitate a more objective and accurate determination of Veterans' work capacity. LEVEL OF EVIDENCE: III. PMID- 27780769 TI - Effect of Backpack Strap Patterns on Gait Parameters in Young Adults at Self Selected Normal and Fast Walking Speeds. AB - BACKGROUND: The effects of backpack load on young adults' gait parameters have received little attention. We previously reported that with a backpack load within 15% body weight (BW), young adults maintain their gait parameters at the expense of increased exertion during a 6-minute walk at self-selected normal walking speed. However, the effect of backpack strap pattern on gait parameters during faster walking or longer stride length has not been evaluated. OBJECTIVE: To determine the effect of different backpack strap patterns on gait parameters during a 12-minute walk test in young adults at self-selected normal and fast walking speeds. DESIGN: A crossover, self-controlled experimental study with repeated measures. SETTING: Department of Medical Rehabilitation, University of Nigeria. PARTICIPANTS: A convenience sample of 24 healthy young adults (21.29 +/- 1.20 years) who voluntarily signed an informed consent form, were able to wear a backpack on 1 and on both shoulders, were able to walk independently, and passed the physical activity readiness screening participated in this study. METHODS: Using a validated method of an observational gait analysis, each participant carried out a 12-minute walk test at self-determined normal and fast walking speeds, respectively. The effect of the following test conditions on the selected gait parameters was evaluated: normal and fast walking without load, and normal and fast walking with 10% and 20% BW backpack carried each on 1 and both shoulders. MAIN OUTCOME MEASUREMENT: Stride length, stride time, velocity, cadence, and base of support were assessed by the equation definitions method of the velocity field diagram. RESULTS: At self-selected fast walking speed with 10% BW backpack load, stride time (P = .004) and cadence (P = .006) were significantly decreased when participants wore a double-strap backpack. At self selected normal walking speed with 20% BW backpack load, cadence was significantly decreased with double-strap backpack carriage (P = .008). Cadence (P < .001), velocity (P < .001), and stride time (P < .001)were also significantly decreased at both conditions of single and double-strap backpack carriage of 20% BW respectively at fast walking speed. CONCLUSION: Backpack strap patterns do not affect the gait parameters of young adults in a 12-minute bout of normal walking speed, provided that the load is less than 20% BW. However, a load up to 10% BW carried on a double strap causes a decrease in stride time and cadence when these individuals walk fast. LEVEL OF EVIDENCE: Not applicable. PMID- 27780770 TI - Residual Limb Hyperhidrosis Managed by Botulinum Toxin Injections, Enhanced by the Iodine-Starch Test: A Case Report. AB - : Hyperhidrosis of the residual limb is a common condition affecting patients with amputations. The iodine-starch test is used by dermatologists to identify focal areas of hyperhidrosis before treatment with botulinum toxin. Here, we describe a case of a patient with a transtibial amputation with moderate-to severe hyperhidrosis who received intradermal botulinum toxin injections to treat residual limb hyperhidrosis, with particular emphasis given to the utility of the iodine-starch test in managing this common condition. The iodine-starch test successfully identified hyperhidrotic areas before treatment as well as confirmed the physiologic anhidrotic effect of the botulinum toxin treatment. LEVEL OF EVIDENCE: V. PMID- 27780771 TI - Percutaneous Needle Tenotomy for the Treatment of Lateral Epicondylitis: A Systematic Review of the Literature. AB - OBJECTIVE: To analyze the literature to determine whether controlled studies on percutaneous tenotomy have been published, and if so, to systematically assess the efficacy of percutaneous tenotomy for the treatment of tendinosis at the lateral epicondyle of the elbow. DESIGN: Systematic review of the available literature. METHODS: Cochrane Controlled Trials Register (CENTRAL), MEDLINE, EMBASE, CINAHL, and Web of Science databases were searched in November 2015, unrestricted by date. After the initial search, we excluded conference proceedings, theses, reviews, expert opinions, and publications written in languages other than English. Next, 2 independent reviewers screened all of the remaining records with regard to their titles and abstracts, and subsequently, the full texts of identified publications potentially relevant to the present study. RESULTS: Six articles focused on percutaneous tenotomy, none of which were controlled against a placebo or conservative treatment group. The absence of true randomized controlled trials created a great deal of heterogeneity between the studies; thus we could not include any of our studies in the intended final quantitative analysis with meta-analysis tools. We describe all 6 studies identified by this systematic review with a detailed analysis of the procedural methods, outcome measures, and conclusions of each study. CONCLUSIONS: Percutaneous tenotomy presents an alternative to surgical release of the common extensor tendon for the treatment of chronic tendinosis at the lateral epicondyle of the elbow. Current research supporting the efficacy of this procedure, however, is of low quality (level II to level IV). LEVEL OF EVIDENCE: III. PMID- 27780772 TI - Pre- and postoperative stoma education and guidance within an enhanced recovery after surgery (ERAS) programme reduces length of hospital stay in colorectal surgery. AB - INTRODUCTION: Stoma formation delays discharge after colorectal surgery. Stoma education is widely recommended, but little data are available regarding whether educational interventions are effective. The aim of this prospective study was to investigate whether an enhanced recovery after surgery (ERAS) programme with dedicated ERAS and stoma nurse specialists focusing on counselling and stoma education can reduce the length of hospital stay, re-admission, and stoma-related complications and improve health-related quality of life (HRQoL) compared to current stoma education in a traditional standard care pathway. METHODS: In a single-center study 122 adult patients eligible for laparoscopic or open colorectal resection who received a planned stoma were treated in either the ERAS program with extended stoma education (n = 61) or standard care with current stoma education (n = 61). The primary endpoint was total postoperative hospital stay. Secondary endpoints were postoperative hospital stay, major or minor morbidity, early stoma-related complications, health-related quality of life, re admission rate, and mortality. HRQoL was measured by the generic 15D instrument. RESULTS: Total hospital stay was significantly shorter in the ERAS group with education than the standard care group (median [range], 6 days [2-21 days] vs. 9 days [5-45 days]; p < 0.001). Regarding overall major and minor morbidity, re admission rate, HRQoL, stoma-related complications and 30-day mortality, the two treatment groups exhibited similar outcomes. CONCLUSION: Patients receiving a planned stoma can be included in an ERAS program. Pre-operative and postoperative stoma education in an enhanced recovery programme is associated with a significantly shorter hospital stay without any difference in re-admission rate or early stoma-related complications. PMID- 27780775 TI - Simultaneous Uterine and Bladder Rupture Following Successful Vaginal Birth After Cesarean Delivery: Laparoscopic Repair of Defect. AB - When gross hematuria occurs after a successful vaginal birth after cesarean section, bladder injury should be suspected. We report a postpartum patient who experienced progressively worsening abdominal pain a few hours after delivery and was found to have a simultaneous bladder and uterine rupture, which were successfully repaired via a laparoscopic approach. This case highlights a laparoscopic approach to repairing both defects in the immediate postpartum period. PMID- 27780776 TI - Physician Education on Controllable Costs Significantly Reduces Cost of Laparoscopic Hysterectomy. AB - STUDY OBJECTIVE: To determine whether educating surgeons about their controllable instrumentation costs by providing cost data on total laparoscopic hysterectomy (LH) would reduce the cost of this procedure. DESIGN: Prospective cohort study (Canadian Task Force classification III). SETTING: Academic-affiliated community hospital. PATIENTS: Patients who underwent LH between April 2014 and March 2015 with surgeons who performed at least 10 LHs during that time period, along with a second group who underwent LH with the same cohort of surgeons between July 2015 and September 2015. INTERVENTION: The cost of LH was calculated for all surgeons who performed more than 10 LHs between April 2014 and March 2015. Itemized cost data were collected. The individual costs, as well as a summary of the data, were shared with all of the physicians to highlight areas of potential cost savings. The costs were then measured for 3 months after the educational intervention (July-September 2015) to gauge the impact of physician cost education. MEASUREMENTS AND MAIN RESULTS: Thirteen surgeons met the criteria for inclusion in this analysis. Together, they performed 271 hysterectomies, with an average instrumentation cost of $1539.47 +/- $294.16 and an average operating room time of 178 +/- 26 minutes. Bipolar instrument choice represented 37% of the baseline costs, followed by 10% for trocar, 9% for cuff closure, and 8% for uterine manipulator. This same group of surgeons performed a total of 69 hysterectomies in the 3-month follow-up period of July-September 2015, with an average instrumentation cost of $1282.62 +/- $235.03 and an average operating room time of 163 +/- 50 minutes. There was statistically significant cost reduction of $256.85 +/- $190.69 (p = .022), with no significant change in operating room time. Bipolar instrument cost decreased significantly, by $130.02 +/- $125.02 (p = .021), representing 51% of the total cost savings. Trocar, cuff closure, and uterine manipulator costs were not significant sources of cost savings on average, but did represent sources of cost savings for some surgeons individually. CONCLUSION: Given adequate education about the products available for use in their institution, surgeons make informed decisions regarding the choice of instrumentation, allowing them to directly impact the cost of total LH, resulting in cost savings. PMID- 27780773 TI - The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition. AB - Mycobacterium tuberculosis is a facultative anaerobe and its characteristic pathological hallmark, the granuloma, exhibits hypoxia in humans and in most experimental models. Thus the host and bacillary adaptation to hypoxia is of central importance in understanding pathogenesis and thereby to derive new drug treatments and vaccines. PMID- 27780777 TI - Surgical Competency for Robot-Assisted Hysterectomy: Development and Validation of a Robotic Hysterectomy Assessment Score (RHAS). AB - STUDY OBJECTIVE: To develop and validate a procedure-specific scoring algorithm to objectively measure robotic surgical skills during robot-assisted hysterectomy and to facilitate robotic surgery training and education. DESIGN: (Canadian Task Force classification III). SETTING: A National Comprehensive Cancer Network designated comprehensive cancer center. PATIENTS: Deidentified videos for robot assisted hysterectomies were evaluated. INTERVENTIONS: Videos from 26 robotic hysterectomies performed by surgeons with varying degrees of experience using the scoring system were evaluated. In phase I, critical elements of a robotic hysterectomy were deconstructed into 6 key domains to assess technical skills for procedure completion. Anchor descriptions were developed for each domain to match a 5-point Likert scale. Delphi methodology was used for content validation. A panel of 5 expert robotic surgeons refined this scoring system. In phase II, video recordings of procedures performed by surgeons with varying degrees of experience (expert, advanced beginner, and novice) were evaluated by blinded expert reviewers using the scoring system. Descriptive statistics were used to summarize the scores for each domain. Intraclass correlation was used to determine the interrater reliability. A p value <.05 was considered significant. MEASUREMENTS AND MAIN RESULTS: The average score for the 3 classes of surgeon was 75.6 for expert, 71.3 for advanced beginner, and 69.0 for novice (p = .006). There were significant differences in scores of most individual domains among the various classes of surgeons. Novice surgeons took significantly longer than expert surgeons to complete their half of a hysterectomy (22.2 vs 12.0 minutes; p = .001). CONCLUSION: This pilot study demonstrates the feasibility of using a standardized rubric for clinical skills assessment in robotic hysterectomy. Blinded expert reviewers were able to differentiate between varying levels of surgical experience using this assessment tool. PMID- 27780774 TI - The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis. AB - Systemic lupus erythematosus (SLE) is a chronic multi-factorial autoimmune disease initiated by genetic and environmental factors, which in combination trigger disease onset in susceptible individuals. Damage to the kidney as a consequence of lupus nephritis (LN) is one of the most prevalent and severe outcomes, as LN affects up to 60% of SLE patients and accounts for much of SLE associated morbidity and mortality. As remarkable strides have been made in unlocking new inflammatory mechanisms associated with signaling molecules of programmed cell death pathways, this review explores the available evidence implicating the action of these pathways specifically within dendritic cells and macrophages in the control of kidney disease. Although advancements into the underlying mechanisms responsible for inducing cell death inflammatory pathways have been made, there still exist areas of unmet need. By understanding the molecular mechanisms by which dendritic cells and macrophages contribute to LN pathogenesis, we can improve their viability as potential therapeutic targets to promote remission. PMID- 27780779 TI - Afatinib-Induced Severe Interstitial Lung Disease Successfully Treated with High Dose Corticosteroid Therapy: A Case Report. PMID- 27780778 TI - Resting state connectivity of the human habenula at ultra-high field. AB - The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network. PMID- 27780780 TI - Role of Local Ablative Therapy in Patients with Oligometastatic and Oligoprogressive Non-Small Cell Lung Cancer. AB - Because of an improved understanding of lung cancer biology and improvement in systemic treatment, an oligometastatic state in which metastatic disease is present at a limited number of anatomic sites is being increasingly recognized. An oligoprogressive state, which is a similar but distinct entity, refers to disease progression at a limited number of anatomic sites, with continued response or stable disease at other sites of disease. Such an oligoprogressive state is best described in patients with NSCLC treated with molecular targeted therapy. Possible explanations for development of the oligoprogressive state include the presence of underlying clonal heterogeneity and extrinsic selection pressure due to the use of targeted therapy. Traditionally, local ablative therapy (LAT) has been limited to symptom palliation in patients with advanced NSCLC, but the presence of oligometastatic or oligoprogressive disease provides a unique opportunity to evaluate the role of LAT such as surgery, radiation therapy, radiofrequency ablation, or cryoablation. There is increasing evidence to support the clinical benefit of LAT in patients with NSCLC with limited metastatic disease and in selected individuals in whom resistance to targeted therapies develops. In the latter instance, adequate treatment of drug-resistant clones by LAT could potentially help in avoiding switching systemic therapy prematurely. This review focuses on the biology of oligometastatic and oligoprogressive NSCLC and describes the role of LAT in the treatment of these conditions. PMID- 27780781 TI - Ycf1/Tic214 Is Not Essential for the Accumulation of Plastid Proteins. PMID- 27780782 TI - AtPRMT5 Regulates Shoot Regeneration through Mediating Histone H4R3 Dimethylation on KRPs and Pre-mRNA Splicing of RKP in Arabidopsis. AB - Protein arginine methylation plays important roles in diverse biological processes, but its role in regulating shoot regeneration remains elusive. In this study, we characterized the function of the protein arginine methyltransferase AtPRMT5 during de novo shoot regeneration in Arabidopsis. AtPRMT5 encodes a type II protein arginine methyltransferase that methylates proteins, including histones and RNA splicing factors. The frequency of shoot regeneration and the number of shoots per callus were decreased in the atprmt5 mutant compared with those in the wild type. Chromatin immunoprecipitation analysis revealed that AtPRMT5 targets KIP-RELATED PROTEINs (KRPs), which encode the cyclin-dependent kinase inhibitors that repress the cell cycle. During shoot regeneration, the KRP transcript level increased in the atprmt5 mutant, which resulted from reduced histone H4R3 methylation in the KRP promoter. Overexpression of KRP significantly reduced the frequency of shoot regeneration and shoot number per callus. Furthermore, abnormal pre-mRNA splicing in the gene RELATED TO KPC1 (RKP), which encodes an ubiquitin E3 ligase, was detected in the atprmt5 mutant. RKP functions in regulating KRP protein degradation, and mutation in RKP inhibited shoot regeneration. Thus, AtPRMT5 regulated shoot regeneration through histone modification-mediated KRP transcription and RKP pre-mRNA splicing. Our findings provide new insights into the function of protein arginine methylation in de novo shoot regeneration. PMID- 27780783 TI - Age-related changes in acute central leptin effects on energy balance are promoted by obesity. AB - Leptin is a key catabolic regulator of food intake (FI) and energy expenditure. Both aging and obesity have been shown to induce leptin-resistance. The present study aimed to analyze age-related changes in the anorexigenic and hypermetabolic responsiveness to acute intracerebroventricular leptin administration in different age-groups of normally fed male Wistar rats (adult and old rats from 3 to 24months of age, NF3 to NF24, respectively). The expressions of the long form of the leptin receptor (Ob-Rb) and inhibitory SOCS3 genes were also assessed by quantitative RT-PCR in the arcuate nucleus (ARC). The influence of high-fat diet induced obesity (HF) on the anorexigenic leptin effects were also tested in younger and older middle-aged groups (HF6 and HF12). Leptin-induced anorexia varied with age: leptin suppressed re-feeding FI (following 48-h fasting) strongly in young adult (NF3), but not in younger or older middle-aged (NF6 or NF12) or in aging (NF18) rats. However, anorexigenic leptin effects reached statistical significance again in old NF24 rats. Leptin-induced hypermetabolism, on the other hand, showed monotonous age-related decline and disappeared by old age. Ob-Rb expression declined until 12months of age followed by a partial recovery in NF18 and NF24 groups. On the other hand, SOCS3 expression was high in NF6 and NF18 and to some extent in NF24 rats. Age-related alterations of Ob-Rb and SOCS3 expression in the ARC may partly contribute to the explanation of age related variations in anorexigenic but not hypermetabolic leptin effects. High fat diet-induced obesity was associated with resistance to leptin-induced anorexia in HF6, similar to that seen in NF6. However, instead of the expected leptin-resistance in HF12, a strong leptin-induced suppression of re-feeding was detected in these obese middle-aged rats. Our results suggest that acute central effects of leptin on anorexia and hypermetabolism change in disparate ways during aging, implying separate mechanisms (e.g. signal transduction pathways) of different leptin actions. The age-related pattern shown by leptin-induced anorexia may contribute to the explanation of middle-aged obesity, and partly to that of aging anorexia. Our findings concerning obese rats are in accord with previous observations on anorexigenic effects of peripherally administered cholecystokinin: diet-induced obesity appeared to accelerate the development of age-related regulatory alterations. Similarly, our present data also raise the possibility that chronic diet-induced obesity promotes responsiveness to centrally applied leptin at least concerning anorexigenic effects. PMID- 27780784 TI - Comparative Effectiveness of Fluorescent Versus White Light Cystoscopy for Initial Diagnosis or Surveillance of Bladder Cancer on Clinical Outcomes: Systematic Review and Meta-Analysis. AB - PURPOSE: We systematically reviewed the comparative effectiveness of fluorescent vs white light cystoscopy on bladder cancer clinical outcomes. MATERIALS AND METHODS: Systematic literature searches of Ovid MEDLINE(r) (January 1990 through September 2015), Cochrane databases and reference lists were performed. A total of 14 randomized trials of fluorescent cystoscopy using 5-aminolevulinic acid or hexaminolevulinic acid vs white light cystoscopy for the diagnosis of initial or recurrent bladder cancer that reported bladder cancer recurrence, progression, mortality and harms were selected for review. RESULTS: Fluorescent cystoscopy was associated with a decreased risk of bladder cancer recurrence vs white light cystoscopy at short-term (less than 3 months, 10 trials, RR 0.59, 95% CI 0.40 to 0.88, I2=69%), intermediate-term (3 months to less than 1 year, 6 trials, RR 0.70, 95% CI 0.56 to 0.88, I2=19%) and long-term followup (1 year or more, 12 trials, RR 0.81, 95% CI 0.70 to 0.93, I2=49%). However, the findings were inconsistent, and potentially susceptible to performance and publication bias (strength of evidence low). There were no differences between cystoscopic methods in risk of mortality (3 trials, RR 1.28, 95% CI 0.55 to 2.95, I2=41%) (strength of evidence low) or progression (9 trials, RR 0.74, 95% CI 0.52 to 1.03, I2=0%) (strength of evidence moderate). Estimates for short-term recurrence (6 trials, RR 0.62, 95% CI 0.38 to 1.00), long-term recurrence (7 trials, RR 0.75, 95% CI 0.62 to 0.92) and progression (4 trials, RR 0.51, 95% CI 0.28 to 0.96) were statistically significant in the subgroup of trials that used hexaminolevulinic acid, but there were no statistically significant interactions based on the photosensitizer used. Fluorescent cystoscopy was not associated with a decreased risk of long-term recurrence in 3 trials that used methods to reduce performance bias with initial cystoscopy (RR 0.96, 95% CI 0.79 to 1.18, I2=36%). Data on harms were sparse. CONCLUSIONS: Fluorescent cystoscopy was associated with a reduced risk of bladder cancer recurrence vs white light cystoscopy. However, additional trials that adequately guard against performance bias are needed to confirm these findings. Fluorescent cystoscopy with hexaminolevulinic acid may be associated with a decreased risk of progression, but more studies with long-term followup are needed to better understand the effects of the photosensitizer used on progression. PMID- 27780786 TI - The Eighth Edition Lung Cancer Stage Classification. AB - Stage classification provides a nomenclature about the anatomic extent of a cancer; a consistent language provides the ability to communicate about a specific patient and about cohorts of patients in clinical studies. This paper summarizes the eighth edition of lung cancer stage classification, which is the worldwide standard as of January 1, 2017. This revision is based on a large global database, a sophisticated analysis, extensive internal validation as well as multiple assessments confirming generalizability. Practicing clinicians must be familiar with the stage classification system when managing contemporary patients with lung cancer. PMID- 27780785 TI - The audience eats more if a movie character keeps eating: An unconscious mechanism for media influence on eating behaviors. AB - Media's presentation of eating is an important source of influence on viewers' eating goals and behaviors. Drawing on recent research indicating that whether a story character continues to pursue a goal or completes a goal can unconsciously influence an audience member's goals, a scene from a popular movie comedy was manipulated to end with a character continuing to eat (goal ongoing) or completed eating (goal completed). Participants (N = 147) were randomly assigned to a goal status condition. As a reward, after viewing the movie clip viewers were offered two types of snacks: ChexMix and M&M's, in various size portions. Viewers ate more food after watching the characters continue to eat compared to watching the characters complete eating, but only among those manipulated to identify with a character. Viewers were more likely to choose savory food after viewing the ongoing eating scenes, but sweet dessert-like food after viewing the completed eating scenes. The results extend the notion of media influence on unconscious goal contagion and satiation to movie eating, and raise the possibility that completing a goal can activate a logically subsequent goal. Implications for understanding media influence on eating and other health behaviors are discussed. PMID- 27780787 TI - Polymorphisms in the prostaglandin receptor EP2 gene confers susceptibility to tuberculosis. AB - OBJECTIVES: Prostaglandin E2 (PGE2) is an important lipid mediator of the inflammatory immune response during acute and chronic infections. PGE2 modulates a variety of immune functions via four receptors (EP1-EP4), which mediate distinct PGE2 effects. Mice lacking EP2 are more susceptible to infection by Mycobacterium tuberculosis (M.tb), have a higher bacterial load, and increase size and number of granulomatous lesions. Our aim was to assess whether single nucleotide polymorphisms (SNPs) in EP2 increase the risk of tuberculosis. METHODS: DNA re-sequencing revealed five common EP2 variants in the Chinese Han population. We sequenced the EP2 gene from 600 patients and 572 healthy controls to measure SNP frequencies in association with tuberculosis infections (TB) within the population. RESULTS: The rs937337 polymorphism is associated with increased risk to tuberculosis (p=0.0044, odds ratio [OR], 1.67; 95% confidential interval,1.22-2.27). The rs937337 AA genotype and the rs1042618 CC genotype were significantly associated with TB. An estimation of the frequencies of haplotypes revealed a single protective haplotype GACGC for tuberculosis (p=0.00096, odds ratio [OR], 0.56; 95% confidential interval, 0.41-0.77). Furthermore, we determined that the remaining SNPs of EP2 were nominally associated with clinical patterns of disease. CONCLUSIONS: We identified genetic polymorphisms in EP2 associated with susceptibility to tuberculosis within a Chinese population. Our data support that EP2 SNPs are genetic predispositions of increased susceptibility to TB and to different clinical patterns of disease. PMID- 27780788 TI - Semiconductor technology in protein kinase research and drug discovery: sensing a revolution. AB - Since the discovery of protein kinase activity in 1954, close to 600 kinases have been discovered that have crucial roles in cell physiology. In several pathological conditions, aberrant protein kinase activity leads to abnormal cell and tissue physiology. Therefore, protein kinase inhibitors are investigated as potential treatments for several diseases, including dementia, diabetes, cancer and autoimmune and cardiovascular disease. Modern semiconductor technology has recently been applied to accelerate the discovery of novel protein kinase inhibitors that could become the standard-of-care drugs of tomorrow. Here, we describe current techniques and novel applications of semiconductor technologies in protein kinase inhibitor drug discovery. PMID- 27780789 TI - Drug repurposing by integrated literature mining and drug-gene-disease triangulation. AB - Drug design is expensive, time-consuming and becoming increasingly complicated. Computational approaches for inferring potentially new purposes of existing drugs, referred to as drug repositioning, play an increasingly important part in current pharmaceutical studies. Here, we first summarize recent developments in computational drug repositioning and introduce the utilized data sources. Afterwards, we introduce a new data fusion model based on n-cluster editing as a novel multi-source triangulation strategy, which was further combined with semantic literature mining. Our evaluation suggests that utilizing drug-gene disease triangulation coupled to sophisticated text analysis is a robust approach for identifying new drug candidates for repurposing. PMID- 27780790 TI - Association between HLA genes and dust mite sensitivity in a Brazilian population. AB - BACKGROUND: Type I hypersensitivity, also known as IgE-mediated allergy, is a complex, multifactorial condition whose onset and severity are influenced by both genetic and environmental factors. Mite allergens stimulate the production of humoral response (IgE), especially in children, which is closely involved in atopic asthma and rhinitis. OBJECTIVE: This study aimed to investigate the association between HLA class I (-A, -B, and -C), and HLA class II (-DRB1) genes in individuals sensitive to dust mites (Dermatophagoides farinae, Dermatophagoides pteronyssinus, or Blomia tropicalis) and mite-insensitive controls. METHODS: 396 participants were grouped as mite-sensitive and mite insensitive according to immediate hypersensitivity as determined by skin-prick tests, and to HLA genotyping by polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO). RESULTS: After chi-square heterogeneity testing no significant differences were observed in HLA-A, B, and C genes, except for the HLA-DRB1 locus, which, showed a negative association for DRB1*04, between mite sensitive and mite-insensitive individuals. In high resolution, DRB1*04:11 allele was significantly different from all other results (P=0.0042, OR=0.26, and 95%CI=0.09-0.70). The analysis stratified by etiologic agent confirmed these associations. CONCLUSION: Our results suggest a possible association between HLA DRB1 genes and hypersensitivity to dust mites. PMID- 27780791 TI - Early dose-dependent cortical thinning of the femoral neck in anal cancer patients treated with pelvic radiation therapy. AB - BACKGROUND AND PURPOSE: Anal cancer patients treated with radiation therapy (RT) have an increased risk of hip fractures after treatment. The mechanism of these fractures is unknown; however, femoral fractures have been correlated with cortical bone thinning. The objective of this study was to assess early changes in cortical bone thickness at common sites of femoral fracture in anal cancer patients treated with intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: RT treatment plans and computed tomography (CT) scans from 23 anal cancer patients who underwent IMRT between November 2012 and December 2014 were retrospectively reviewed. Cortical thickness (Ct.Th) was mapped at homologous vertices within the proximal femur using pre-RT and post-RT (<=4months) CT scans. The bone attenuation measurements were collected at homologous locations within the trabecular bone of the right femoral neck (FN). The percent change in Ct.Th and trabecular bone mineral density (trBMD) were assessed. FN cortical thinning was correlated to RT dose using linear regression. A logistic model for dose dependent cortical thinning was constructed. RESULTS: Twenty-two patients were analyzed. Significant post-treatment cortical thinning was observed in the intertrochanteric crest, subcapital and inferior FN (p<0.05). FN volume receiving >=40Gy (V40Gy) was a significant predictor of focal cortical thinning >=30% (p=0.03). A significant decrease in FN trBMD was observed (-6.4% [range -34.4 to 3.3%]; p=0.01). CONCLUSION: Significant early decrease in Ct.Th and trBMD occurs at the FN in patients treated with RT for anal cancer. FN V40Gy was predictive of clinically significant focal FN cortical thinning. PMID- 27780793 TI - A first higher-level time-calibrated phylogeny of antlions (Neuroptera: Myrmeleontidae). AB - In this study, we reconstruct the first time-calibrated phylogeny of the iconic antlion family, the Myrmeleontidae (Neuroptera: Myrmeleontiformia). We use maximum likelihood and Bayesian inference to analyse a molecular dataset based on seven mitochondrial and nuclear gene markers. The dataset encompasses 106 species of Neuroptera, including 94 antlion species. The resulting phylogenetic framework provides support for a myrmeleontid classification distinguishing four subfamilies: Acanthaclisinae, Myrmeleontinae, Palparinae, and Stilbopteryginae. Within Myrmeleontinae, Myrmecaelurini and Nemoleontini are recovered as monophyletic clades; Gepini also appears as a valid tribe, distinct from Myrmecaelurini whereas Myrmecaelurini and Nesoleontini on one hand and Brachynemurini and Dendroleontini on the other hand, appear closely related. Some preliminary information related to generic and specific levels are also implied from our results, such as the paraphyly of several genera. Dating analyses based on thoroughly evaluated fossil calibrations indicate that the antlion family likely originated in the Cretaceous, between 135 and 138 million years ago (depending on the set of fossil calibrations), and that all higher-level lineages appeared during the Early Cretaceous. This first phylogenetic hypothesis will provide a valuable basis to further expand the taxonomic coverage and molecular sampling, and to lay the foundations of future systematic revisions. PMID- 27780792 TI - Application of anti-Sclerostin therapy in non-osteoporosis disease models. AB - Sclerostin, a known inhibitor of the low density lipoprotein related protein 5 and 6 (LRP5 and LRP6) cell surface signaling receptors, is integral in the maintenance of normal bone mass and strength. Patients with loss of function mutations in SOST or missense mutations in LRP5 that prevent Sclerostin from binding and inhibiting the receptor, have significantly increased bone mass. This observation leads to the development of Sclerostin neutralizing therapies to increase bone mass and strength. Anti-Sclerostin therapy has been shown to be effective at increasing bone density and strength in animal models and patients with osteoporosis. Loss of function of Sost or treatment with a Sclerostin neutralizing antibody improves bone properties in animal models of Osteoporosis Pseudoglioma syndrome (OPPG), likely due to action through the LRP6 receptor, which suggests patients may benefit from these therapies. Sclerostin antibody is effective at improving bone properties in mouse models of Osteogenesis Imperfecta, a genetic disorder of low bone mass and fragility due to type I collagen mutations, in as little as two weeks after initiation of therapy. However, these improvements are due to increases in bone quantity as the quality (brittleness) of bone remains unaffected. Similarly, Sclerostin antibody treatment improves bone density in animal models of other diseases. Sclerostin neutralizing therapies are likely to benefit many patients with genetic disorders of bone, as well as other forms of metabolic bone disease. PMID- 27780794 TI - The Relationship Between Health Management and Information Behavior Over Time: A Study of the Illness Journeys of People Living With Fibromyalgia. AB - BACKGROUND: Over the course of a chronic illness, patients face many challenges, including understanding what is happening to them and developing an effective strategy for managing illness. While there is existing literature concerning how people seek health-related information and cope with chronic illnesses, there is a need for additional research on how information affects patients' understandings of their illness, and how changes in this understanding affect their health management strategies over time. OBJECTIVE: This study examined how health management, information seeking, and information consumption and use processes are related throughout an illness. METHODS: A diversified recruitment strategy involving multiple media channels was used to recruit participants for an interview study. During the interviews, participants were asked to draw an "illness journey" timeline. The data were analyzed using a qualitative approach drawn from Interpretative Phenomenological Analysis and Grounded Theory. RESULTS: The study identified four main health management features of illness journeys: onset, progression toward diagnosis, acceptance, and development of an effective management strategy. The study then focused on how information seeking changes over illness journeys, particularly in terms of a transition from active information seeking to monitoring with intermittent focused searching. Last, the paper describes the information consumption and use processes that patients engaged in throughout their journey. CONCLUSIONS: This study makes three important contributions to the field. First, it presents an integrated conceptualization of how health management and information behaviors are related on illness journeys. Second, it adds to our existing knowledge on health literacy and self-management of chronic illness. Third, the study has implications for health interface design. PMID- 27780795 TI - Economic Evaluation of Text-Messaging and Smartphone-Based Interventions to Improve Medication Adherence in Adolescents with Chronic Health Conditions: A Systematic Review. AB - BACKGROUND: The rate of chronic health conditions (CHCs) in children and adolescents has doubled in the past 20 years, with increased health care costs. Technology-based interventions have demonstrated efficacy to improving medication adherence. However, data to support the cost effectiveness of these interventions are lacking. OBJECTIVE: The objective of this study is to conduct an economic evaluation of text-messaging and smartphone-based interventions that focus on improving medication adherence in adolescents with CHCs. METHODS: Searches included PubMed MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Web of Science, and Inspec. Eligibility criteria included age (12-24 years old), original articles, outcomes for medication adherence, and economic outcomes. RESULTS: Our search identified 1118 unique articles that were independently screened. A total of 156 articles met inclusion criteria and were then examined independently with full-text review. A total of 15 articles met most criteria but lacked economic outcomes such as cost effectiveness or cost-utility data. No articles met all predefined criteria to be included for final review. Only 4 articles (text messaging [n=3], electronic directly observed therapy [n=1]) described interventions with possible future cost-saving but no formal economic evaluation. CONCLUSIONS: The evidence to support the cost effectiveness of text messaging and smartphone-based interventions in improving medication adherence in adolescents with CHCs is insufficient. This lack of research highlights the need for comprehensive economic evaluation of such interventions to better understand their role in cost-savings while improving medication adherence and health outcomes. Economic evaluation of technology-based interventions can contribute to more evidence-based assessment of the scalability, sustainability, and benefits of broader investment of such technology tools in adolescents with CHCs. PMID- 27780796 TI - Participant Recruitment and Engagement in Automated eHealth Trial Registration: Challenges and Opportunities for Recruiting Women Who Experience Violence. AB - BACKGROUND: Automated eHealth Web-based research trials offer people an accessible, confidential opportunity to engage in research that matters to them. eHealth trials may be particularly useful for sensitive issues when seeking health care may be accompanied by shame and mistrust. Yet little is known about people's early engagement with eHealth trials, from recruitment to preintervention autoregistration processes. A recent randomized controlled trial that tested the effectiveness of an eHealth safety decision aid for New Zealand women in the general population who experienced intimate partner violence (isafe) provided the opportunity to examine recruitment and preintervention participant engagement with a fully automated Web-based registration process. The trial aimed to recruit 340 women within 24 months. OBJECTIVE: The objective of our study was to examine participant preintervention engagement and recruitment efficiency for the isafe trial, and to analyze dropout through the registration pathway, from recruitment to eligibility screening and consent, to completion of baseline measures. METHODS: In this case study, data collection sources included the trial recruitment log, Google Analytics reports, registration and program metadata, and costs. Analysis included a qualitative narrative of the recruitment experience and descriptive statistics of preintervention participant engagement and dropout rates. A Koyck model investigated the relationship between Web-based online marketing website advertisements (ads) and participant accrual. RESULTS: The isafe trial was launched on September 17, 2012. Placement of ads in an online classified advertising platform increased the average number of recruited participants per month from 2 to 25. Over the 23-month recruitment period, the registration website recorded 4176 unique visitors. Among 1003 women meeting eligibility criteria, 51.55% (517) consented to participate; among the 501 women who enrolled (consented, validated, and randomized), 412 (82.2%) were accrued (completed baseline assessments). The majority (n=52, 58%) of the 89 women who dropped out between enrollment and accrual never logged in to the allocated isafe website. Of every 4 accrued women, 3 (314/412, 76.2%) identified the classified ad as their referral source, followed by friends and family (52/412, 12.6%). Women recruited through a friend or relative were more likely to self-identify as indigenous Maori and live in the highest-deprivation areas. Ads increased the accrual rate by a factor of 74 (95% CI 49-112). CONCLUSIONS: Print advertisements, website links, and networking were costly and inefficient methods for recruiting participants to a Web-based eHealth trial. Researchers are advised to limit their recruitment efforts to Web-based online marketplace and classified advertising platforms, as in the isafe case, or to social media. Online classified advertising in "Jobs-Other-volunteers" successfully recruited a diverse sample of women experiencing intimate partner violence. Preintervention recruitment data provide critical information to inform future research and critical analysis of Web-based eHealth trials. CLINICALTRIAL: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12612000708853; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261200070885 (Archived by WebCite at http://www.webcitation/6lMGuVXdK). PMID- 27780797 TI - Prognostic Value of E-Cadherin and beta-Catenin in Triple-Negative Breast Cancer. AB - Objectives: To analyze the expression of E-cadherin and beta-catenin in triple negative breast cancer (TNBC) to assess their prognostic significance. Methods: The expression of E-cadherin and beta-catenin was examined semiquantitatively and correlated with other pathologic factors and survival outcomes. Results: Of 72 consecutive TNBCs, 56% showed reduced membranous expression of E-cadherin or beta catenin, with a strong correlation to each other. Of the clinicopathologic factors analyzed, tumor size and nodal status were significantly associated with overall survival and disease-specific survival, while the latter remained an independent factor by multivariate analysis. Reduced E-cadherin and beta-catenin were both significantly associated with a poor overall survival and disease specific survival by univariate and multivariate analyses. Conclusions: E cadherin and beta-catenin expression provides discriminative prognostic power independent of conventional pathologic factors, thus further reinforcing the important role of cell adhesion molecules in the process of tumor metastasis, especially in TNBC. PMID- 27780798 TI - Status of physiology education in US Doctor of Pharmacy programs. AB - The purpose of the present study was to assess the current status of physiology education in US Doctor of Pharmacy (PharmD) programs. A survey instrument was developed and distributed through SurveyMonkey to American Association of Colleges of Pharmacy (AACP) Biological Sciences section members of 132 PharmD programs. Survey items focused on soliciting qualitative and quantitative information on the delivery of physiology curricular contents and faculty perceptions of physiology education. A total of 114 programs responded to the survey, resulting in a response rate of 86%. Out of 114 schools/colleges, 61 programs (54%) offered standalone physiology courses, and 53 programs (46%) offered physiology integrated with other courses. When integrated, the average contact hours for physiology contents were significantly reduced compared with standalone courses (30 vs. 84 h, P < 0.0001). Survey respondents identified diverse strategies in the delivery and assessment of physiology contents. Eighty percent of the responding faculty (n = 204) agree/strongly agree that physiology is underemphasized in PharmD curriculum. Moreover, 67% of the respondents agree/strongly agree that physiology should be taught as a standalone foundational course. A wide variation in the depth and breadth of physiology course offerings in US PharmD programs remains. The reduction of physiology contents is evident when physiology is taught as a component of integrated courses. Given current trends that favor integrated curricula, these data suggest that additional collaboration among basic and clinical science faculty is required to ensure that physiology contents are balanced and not underemphasized in a PharmD curriculum. PMID- 27780801 TI - Persistent User Bias in Case-Crossover Studies in Pharmacoepidemiology. AB - Studying the effect of chronic medication exposure by means of a case-crossover design may result in an upward-biased odds ratio. In this study, our aim was to assess the occurrence of this bias and to evaluate whether it is remedied by including a control group (the case-time-control design). Using Danish data resources from 1995-2012, we conducted case-crossover and case-time-control analyses for 3 medications (statins, insulin, and thyroxine) in relation to 3 outcomes (retinal detachment, wrist fracture, and ischemic stroke), all with assumed null associations. Controls were matched on age, sex, and index date, and exposure over the preceding 12 months was ascertained. For retinal detachment, the case-crossover odds ratio was 1.60 (95% confidence interval (CI): 1.42, 1.80) for statins, 1.40 (95% CI: 1.02, 1.92) for thyroxine, and 1.53 (95% CI: 1.04, 2.24) for insulin. Estimates for the retinal detachment controls were similar, leading to near-null case-time-control estimates for all 3 medication classes. For wrist fracture and stroke, the odds ratios were higher for cases than for controls, and case-time-control odds ratios were consistently above unity, thus implying significant residual bias. In case-crossover studies of medications, contamination by persistent users confers a moderate bias upward, which is partly remedied by using a control group. The optimal strategy for dealing with this problem is currently unknown. PMID- 27780802 TI - Association Between Short-Term Exposure to PM2.5 and PM10 and Mortality in Susceptible Subgroups: A Multisite Case-Crossover Analysis of Individual Effect Modifiers. AB - We performed a multisite study to evaluate demographic and clinical conditions as potential modifiers of the particulate matter (PM)-mortality association. We selected 228,619 natural deaths of elderly persons (ages >=65 years) that occurred in 12 Italian cities during the period 2006-2010. Individual data on causes of death, age, sex, location of death, and preexisting chronic and acute conditions from the previous 5 years' hospitalizations were collected. City specific conditional logistic regression models were applied within the case crossover "time-stratified" framework, followed by random-effects meta-analysis. Particulate matter less than or equal to 2.5 um in aerodynamic diameter (PM2.5) and particulate matter less than or equal to 10 um in aerodynamic diameter (PM10) were positively associated with natural mortality (1.05% and 0.74% increases in mortality risk for increments of 10 ug/m3 and 14.4 ug/m3, respectively), with greater effects being seen among older people, those dying out-of-hospital or during the warm season, and those affected by 2 or more chronic diseases. Limited associations were found among persons with no previous hospital admissions. Diabetes (1.98%, 95% confidence interval (CI): 0.54, 3.44) and cardiac arrhythmia (1.65%, 95% CI: 0.37, 2.95) increased risk of PM2.5-related mortality, while heart conduction disorders increased risk of mortality related to both PM2.5 (4.22%, 95% CI: 0.15, 8.46) and PM10 (4.19%, 95% CI: 0.38, 8.14). Among acute conditions, recent hospital discharge for heart failure modified the PM10 mortality association. The study found increases in natural mortality from PM exposure among people with chronic morbidity; diabetes and cardiac disorders were the main susceptibility factors. PMID- 27780803 TI - Emerging anticoagulant strategies. AB - Despite the introduction of direct oral anticoagulants (DOACs), the search for more effective and safer antithrombotic strategies continues. Better understanding of the pathogenesis of thrombosis has fostered 2 new approaches to achieving this goal. First, evidence that thrombin may be as important as platelets to thrombosis at sites of arterial injury and that platelets contribute to venous thrombosis has prompted trials comparing anticoagulants with aspirin for secondary prevention in arterial thrombosis and aspirin with anticoagulants for primary and secondary prevention of venous thrombosis. These studies will help identify novel treatment strategies. Second, emerging data that naturally occurring polyphosphates activate the contact system and that this system is critical for thrombus stabilization and growth have identified factor XII (FXII) and FXI as targets for new anticoagulants that may be even safer than the DOACs. Studies are needed to determine whether FXI or FXII is the better target and to compare the efficacy and safety of these new strategies with current standards of care for the prevention or treatment of thrombosis. Focusing on these advances, this article outlines how treatment strategies for thrombosis are evolving and describes the rationale and approaches to targeting FXII and FXI. These emerging anticoagulant strategies should address unmet needs and reduce the systemic underuse of anticoagulation because of the fear of bleeding. PMID- 27780804 TI - How I use anticoagulation in atrial fibrillation. AB - Atrial fibrillation is the most common cardiac arrhythmia and conveys a significant risk of morbidity and mortality due to related stroke and systemic embolism. Oral anticoagulation (OAC) is the mainstay of thromboembolism prevention, and management of anticoagulation can be challenging. For patients without significant valvular disease, decisions around anticoagulation therapy are first based on the presence of additional stroke risk factors, as measured by the CHA2DS2-VASc (congestive heart failure, hypertension, age >=75, diabetes, prior stroke or transient ischemic attack, vascular disease, age 65-74, and sex category [female]) score. Patients with increased CHA2DS2-VASc scores (by regional guidelines) should next be evaluated to determine if they are candidates for non-vitamin K antagonist oral anticoagulant (NOAC) therapy. This should focus on assessment of concomitant valve disease and/or impaired renal function. In eligible patients, the cumulative data support a preference for NOACs over warfarin, as NOACs appear safer and more effective as a group. However, there are no direct, randomized comparisons between NOACs, and therefore, selecting among them can be difficult. In addition, important patient groups remain underrepresented in major clinical trials, and their management is often left to clinician judgment. Data from emerging clinical trials will help guide physicians; however, patient engagement in decisions regarding OAC management will remain vital to ensuring appropriate balance of risks and optimizing health outcomes. PMID- 27780806 TI - Action is urged to improve physical health in severe mental illness. PMID- 27780805 TI - Ceritinib Outperforms Chemo as Second-Line Treatment. AB - Many oncologists have already adopted ceritinib as a second-line treatment for ALK-positive non-small cell lung cancer in patients who have developed resistance to crizotinib. The results of a randomized trial, presented at the European Society for Medical Oncology 2016 Congress, confirm that ceritinib is an effective option because it increases progression-free survival by 4 months over chemotherapy. PMID- 27780807 TI - A Way Forward for Cancer Chemoprevention: Think Local. AB - As cells progress through carcinogenesis, the associated exponential expansion of genetic and molecular aberrations and resultant heterogeneity make therapeutic success increasingly unattainable. Therapeutic intervention at early stages of carcinogenesis that occurs within the primary organ and in the face of a lower burden of molecular aberrations, constitutes a basic tenet of cancer chemoprevention, and provides a situation that favors a greater degree of therapeutic efficacy compared with that of advanced cancer. A longstanding barrier to chemoprevention relates to the requirement for essentially no systemic toxicity, and the fact that when large numbers of people are treated, the emergence of systemic toxicity is almost universal. A rational means to address this in fact relates to a second basic tenet of the chemopreventive strategy: the focus of therapeutic intervention is to disrupt a process that is in essence localized to a single organ. Based upon this consideration, a strategy which is based upon local delivery of therapeutics to an at-risk organ will achieve therapeutic efficacy while avoiding systemic delivery and its associated toxicity. This article will review the rationale for undertaking such an approach, describe successful clinical achievements based on this strategy, describe ongoing efforts to expand the impact of this approach, and together will highlight the high impact that this approach has already had on the field as well as its extremely high potential for future impact. Cancer Prev Res; 10(1); 14-35. (c)2016 AACR. PMID- 27780808 TI - Low intensity pulsed ultrasound for fractures of the tibial shaft. PMID- 27780809 TI - Letter to the Editor response: Nygaard et al. AB - The article by Nygaard and others (2016) proposes that applying batch correction approaches to microarray data from studies with unbalanced designs may inadvertently exaggerate the differences observed. In seeking to illustrate their point, Nygaard and others (2016) utilized a dataset (GSE61901) from a study we published (Towfic and others, 2014) and showed that one analysis pipeline utilizing the traditional approach to batch correction (ComBat) yielded over 1000 differentially expressed probesets, while an alternative approach proposed by Nygaard and others (2016). (utilizing batch as a fixed effect and averaging technical replicates) recovered 11 differentially expressed probesets. PMID- 27780810 TI - Clustering of mRNA-Seq data based on alternative splicing patterns. AB - Sequencing of messenger RNA (mRNA) can provide estimates of the levels of individual isoforms within the cell. It remains to adapt many standard statistical methods commonly used for analyzing gene expression levels to take advantage of this additional information. One novel question is whether we can find clusters of samples that are distinguished not by their gene expression but by their isoform usage. We propose a novel approach for clustering mRNA-Seq data that identifies such clusters. We show via simulation that our methods are more sensitive to finding clusters based on isoform usage than standard clustering techniques. We demonstrate its performance by finding a technical artifact that resulted in different batches having different isoform usage patterns, and illustrate its usage on several The Cancer Genome Atlas datasets. PMID- 27780811 TI - GP referral to weight loss programme is quick and effective, finds study. PMID- 27780812 TI - The Impact of Abdominal Contouring with Monsplasty on Sexual Function and Urogenital Distress in Women Following Massive Weight Loss. AB - BACKGROUND: Monsplasty treats massive weight loss (MWL) patients with redundant tissues in the mons region. Monsplasty, however, is not a routine component of abdominal contouring. OBJECTIVES: The goal of this study was to evaluate the changes in urinary and sexual functioning in patients who undergo abdominal contouring with monsplasty vs non-operated controls. METHODS: A prospective study was performed of patients who underwent abdominal contouring + monsplasty or no surgery. The Urogenital Distress Inventory Short Form (UDI-6) and the Female Sexual Function Index (FSFI) questionnaires were administered to both groups at baseline and then three months later. RESULTS: The surgical (n = 20) and nonsurgical groups (n = 20) were similar related to patient demographics, body mass index after MWL, parity, relationship status, hormonal status, and baseline UDI-6/FSFI scores (all P values >0.05). After three months, there was a statistically significant decrease in the UDI-6 score for the surgical groups vs the nonsurgical group: median UDI-6 score = -0.01 (interquartile range [IQR], 7.65-5.55) vs 0 (IQR, 0-11.11) (P = .03). There was no change for the Female Sexual Function Index in the surgical vs nonsurgical groups: median FSFI = 0.20 (IQR, -1.20-1.58) vs 0.95 (IQR, 0.08-2.58) (P = .11). CONCLUSIONS: Urinary dysfunction improved even at the early time point of three months following abdominal contouring procedures including monsplasty. At the early postoperative period of three months, however, there was no significant change in female sexual function. Monsplasty in conjunction with abdominal contouring is recommended in the MWL female patient. LEVEL OF EVIDENCE: 2 Therapeutic. PMID- 27780813 TI - Indonesian doctors risk losing licence if they castrate paedophiles. PMID- 27780815 TI - BMA calls for national prescription drug helpline. PMID- 27780816 TI - NHS must find ways to speed access to new drugs and technologies. PMID- 27780814 TI - Plant immunity against viruses: antiviral immune receptors in focus. AB - Background: Among the environmental limitations that affect plant growth, viruses cause major crop losses worldwide and represent serious threats to food security. Significant advances in the field of plant-virus interactions have led to an expansion of potential strategies for genetically engineered resistance in crops during recent years. Nevertheless, the evolution of viral virulence represents a constant challenge in agriculture that has led to a continuing interest in the molecular mechanisms of plant-virus interactions that affect disease or resistance. Scope and Conclusion: This review summarizes the molecular mechanisms of the antiviral immune system in plants and the latest breakthroughs reported in plant defence against viruses. Particular attention is given to the immune receptors and transduction pathways in antiviral innate immunity. Plants counteract viral infection with a sophisticated innate immune system that resembles the non-viral pathogenic system, which is broadly divided into pathogen associated molecular pattern (PAMP)-triggered immunity and effector-triggered immunity. An additional recently uncovered virus-specific defence mechanism relies on host translation suppression mediated by a transmembrane immune receptor. In all cases, the recognition of the virus by the plant during infection is central for the activation of these innate defences, and, conversely, the detection of host plants enables the virus to activate virulence strategies. Plants also circumvent viral infection through RNA interference mechanisms by utilizing small RNAs, which are often suppressed by co-evolving virus suppressors. Additionally, plants defend themselves against viruses through hormone-mediated defences and activation of the ubiquitin-26S proteasome system (UPS), which alternatively impairs and facilitates viral infection. Therefore, plant defence and virulence strategies co-evolve and co-exist; hence, disease development is largely dependent on the extent and rate at which these opposing signals emerge in host and non-host interactions. A deeper understanding of plant antiviral immunity may facilitate innovative biotechnological, genetic and breeding approaches for crop protection and improvement. PMID- 27780817 TI - Reallocating Time to Sleep, Sedentary Time, or Physical Activity: Associations with Waist Circumference and Body Mass Index in Breast Cancer Survivors. AB - BACKGROUND: Moderate-to-vigorous intensity physical activity (MVPA) is inversely associated with waist circumference and body mass index (BMI) among breast cancer survivors. Limited research has focused on behaviors that account for larger portions of the day [sleep, sedentary time, and light-intensity physical activity (LPA)]. We investigated the interdependent associations of self-reported sleep, objectively assessed prolonged and short bouts of sedentary time, total LPA, and total MVPA with waist circumference and BMI. METHODS: A cross-sectional sample of breast cancer survivors (N = 256, mean age = 60 years; mean time since diagnosis = 3 years) wore an Actigraph GT3X+ accelerometer during waking hours for 7 days. Participants completed the Pittsburgh Sleep Quality Index and self-reported their waist circumference, height, and weight. An isotemporal substitution approach was used in linear regression models to explore the associations of reallocating time to sleep, sedentary and active behaviors on waist circumference, and BMI, after adjusting for potential confounders. RESULTS: Reallocating 30 minutes to MVPA was significantly associated with lower waist circumference when allocated from sleep (-2.50 cm), prolonged sedentary time (-2.51 cm), or LPA (-2.71 cm). Reallocating 30 minutes of prolonged sedentary time to nonprolonged sedentary time was significantly associated with lower waist circumference (-0.94 cm). Similar results were observed for BMI. CONCLUSIONS: Reallocating 30 minutes to MVPA was associated with significantly lower waist circumference and BMI, as was reallocating 30 minutes of prolonged sedentary time to 30 minutes of nonprolonged sedentary time. IMPACT: Increasing MVPA levels and decreasing time spent in prolonged, unbroken sedentary bouts may be avenues for improving body composition in this population. Cancer Epidemiol Biomarkers Prev; 26(2); 254-60. (c)2016 AACR. PMID- 27780819 TI - Light-load resistance exercise increases muscle protein synthesis and hypertrophy signaling in elderly men. AB - The present study investigated whether well-tolerated light-load resistance exercise (LL-RE) affects skeletal muscle fractional synthetic rate (FSR) and anabolic intracellular signaling as a way to counteract age-related loss of muscle mass. Untrained healthy elderly (>65-yr-old) men were subjected to 13 h of supine rest. After 2.5 h of rest, unilateral LL-RE, consisting of leg extensions (10 sets, 36 repetitions) at 16% of 1 repetition maximum (RM), was conducted. Subsequently, the subjects were randomized to oral intake of 4 g of whey protein per hour (PULSE, n = 10), 28 g of whey protein at 0 h and 12 g of whey protein at 7 h postexercise (BOLUS, n = 10), or 4 g of maltodextrin per hour (placebo, n = 10). Quadriceps muscle biopsies were taken at 0, 3, 7, and 10 h postexercise from the resting and the exercised leg of each subject. Myofibrillar FSR and activity of select targets from the mechanistic target of rapamycin complex 1-signaling cascade were analyzed from the biopsies. LL-RE increased myofibrillar FSR compared with the resting leg throughout the 10-h postexercise period. Phosphorylated (T308) AKT expression increased in the exercised leg immediately after exercise. This increase persisted in the placebo group only. Levels of phosphorylated (T37/46) eukaryotic translation initiation factor 4E-binding protein 1 increased throughout the postexercise period in the exercised leg in the placebo and BOLUS groups and peaked at 7 h. In all three groups, phosphorylated (T56) eukaryotic elongation factor 2 decreased in response to LL RE. We conclude that resistance exercise at only 16% of 1 RM increased myofibrillar FSR, irrespective of nutrient type and feeding pattern, which indicates an anabolic effect of LL-RE in elderly individuals. This finding was supported by increased signaling for translation initiation and translation elongation in response to LL-RE. PMID- 27780818 TI - Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA. AB - Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension. PMID- 27780820 TI - Activation of beta3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats. AB - Activation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) present potential new therapies for obesity and type 2 diabetes. Here, we examined the effects of beta3-adrenergic stimulation on tissue-specific uptake and storage of free fatty acids (FFA) and its implications for whole body FFA metabolism in diet-induced obese rats using a multi-radiotracer technique. Male Wistar rats were high fat-fed for 12 wk and administered beta3-agonist CL316,243 (CL, 1 mg.kg-1.day-1) or saline via osmotic minipumps during the last 3 wk. The rats were then fasted and acutely infused with a tracer mixture ([14C]palmitate and the partially metabolized R-[3H]bromopalmitate) under anesthesia. CL infusion decreased body weight gain and fasting plasma glucose levels. While core body temperature was unaffected, infrared thermography showed an increase in tail heat dissipation following CL infusion. Interestingly, CL markedly increased both FFA storage and utilization in interscapular and perirenal BAT, whereas the flux of FFA to skeletal muscle was decreased. In this rat model of obesity, only sporadic populations of beige adipocytes were detected in the epididymal WAT depot of CL infused rats, and there was no change in FFA uptake or utilization in WAT following CL infusion. In summary, beta3-agonism robustly increased FFA flux to BAT coupled with enhanced utilization. Increased BAT activation most likely drove the increased tail heat dissipation to maintain thermostasis. Our results emphasize the quantitative role of brown fat as the functional target of beta3 agonism in obesity. PMID- 27780821 TI - Adult expression of PGC-1alpha and -1beta in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity. AB - Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1alpha and -1beta (iMyo PGC-1DKO), in which both PGC-1alpha and -beta can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1alpha and -1beta in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1alpha and -1beta expression. Taken together these data suggest that PGC-1alpha and -1beta expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms. PMID- 27780822 TI - Presleep protein ingestion does not compromise the muscle protein synthetic response to protein ingested the following morning. AB - Protein ingestion before sleep augments postexercise muscle protein synthesis during overnight recovery. It is unknown whether postexercise and presleep protein consumption modulates postprandial protein handling and myofibrillar protein synthetic responses the following morning. Sixteen healthy young (24 +/- 1 yr) men performed unilateral resistance-type exercise (contralateral leg acting as a resting control) at 2000. Participants ingested 20 g of protein immediately after exercise plus 60 g of protein presleep (PRO group; n = 8) or equivalent boluses of carbohydrate (CON; n = 8). The subsequent morning participants received primed, continuous infusions of l-[ring-2H5]phenylalanine and l-[1 13C]leucine combined with ingestion of 20 g intrinsically l-[1-13C]phenylalanine- and l-[1-13C]leucine-labeled protein to assess postprandial protein handling and myofibrillar protein synthesis in the rested and exercised leg in CON and PRO. Exercise increased postabsorptive myofibrillar protein synthesis rates the subsequent day (P < 0.001), with no differences between CON and PRO. Protein ingested in the morning increased myofibrillar protein synthesis in both the exercised and rested leg (P < 0.01), with no differences between treatments. Myofibrillar protein bound l-[1-13C]phenylalanine enrichments were greater in the exercised (0.016 +/- 0.002 and 0.015 +/- 0.002 MPE in CON and PRO, respectively) vs. rested (0.010 +/- 0.002 and 0.009 +/- 0.002 MPE in CON and PRO, respectively) leg (P < 0.05), with no differences between treatments (P > 0.05). The additive effects of resistance-type exercise and protein ingestion on myofibrillar protein synthesis persist for more than 12 h after exercise and are not modulated by protein consumption during acute postexercise recovery. This work provides evidence of an extended window of opportunity where presleep protein supplementation can be an effective nutrient timing strategy to optimize skeletal muscle reconditioning. PMID- 27780824 TI - KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1. AB - The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelial-mesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. (c)2016 AACR. PMID- 27780823 TI - Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms. AB - Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27-7.16; Ptrend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend = 0.21). Results were similar across cohorts (Pheterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18-2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160-7. (c)2016 AACR. PMID- 27780825 TI - Transglutaminase Interaction with alpha6/beta4-Integrin Stimulates YAP1-Dependent DeltaNp63alpha Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation. AB - Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with alpha6/beta4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized DeltaNp63alpha to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of DeltaNp63alpha, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265-76. (c)2016 AACR. PMID- 27780826 TI - A graphical model approach visualizes regulatory relationships between genome wide transcription factor binding profiles. AB - Integrated analysis of multiple genome-wide transcription factor (TF)-binding profiles will be vital to advance our understanding of the global impact of TF binding. However, existing methods for measuring similarity in large numbers of chromatin immunoprecipitation assays with sequencing (ChIP-seq), such as correlation, mutual information or enrichment analysis, are limited in their ability to display functionally relevant TF relationships. In this study, we propose the use of graphical models to determine conditional independence between TFs and showed that network visualization provides a promising alternative to distinguish 'direct' versus 'indirect' TF interactions. We applied four algorithms to measure 'direct' dependence to a compendium of 367 mouse haematopoietic TF ChIP-seq samples and obtained a consensus network known as a 'TF association network' where edges in the network corresponded to likely causal pairwise relationships between TFs. The 'TF association network' illustrates the role of TFs in developmental pathways, is reminiscent of combinatorial TF regulation, corresponds to known protein-protein interactions and indicates substantial TF-binding reorganization in leukemic cell types. With the rapid increase in TF ChIP-Seq data sets, the approach presented here will be a powerful tool to study transcriptional programmes across a wide range of biological systems. PMID- 27780827 TI - When water is thicker than blood: recognising a systemic cause of haemoptysis. AB - The case of an 11-year-old child presenting with acute haemoptysis and breathlessness is described. The girl was Malaysian and had recently arrived in the UK. She subsequently deteriorated, developing respiratory failure. The course of the illness is described, with reference to the diagnostic process at each stage. The case demonstrates the importance of having a broad investigatory approach in acute haemoptysis. PMID- 27780828 TI - Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. AB - We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA) mouse models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor grooves, inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR). Lurbinectedin-gemcitabine combination induced a synergistic effect on both MIA PaCa-2 [combination index (CI)=0.66] and SW-1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in four out of six patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-gamma-H2AX), cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAM depletion leading to cytidine deaminase (CDA) downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop 'molecularly targeted' combination strategies. PMID- 27780831 TI - Aspirin reduces cardiovascular events in primary prevention of cardiovascular disease but at a near equivalent risk of increased bleeding. PMID- 27780829 TI - Exposure to Fine Particulate Air Pollution Is Associated With Endothelial Injury and Systemic Inflammation. AB - RATIONALE: Epidemiological evidence indicates that exposures to fine particulate matter air pollution (PM2.5) contribute to global burden of disease, primarily as a result of increased risk of cardiovascular morbidity and mortality. However, mechanisms by which PM2.5 exposure induces cardiovascular injury remain unclear. PM2.5-induced endothelial dysfunction and systemic inflammation have been implicated, but direct evidence is lacking. OBJECTIVE: To examine whether acute exposure to PM2.5 is associated with endothelial injury and systemic inflammation. METHODS AND RESULTS: Blood was collected from healthy, nonsmoking, young adults during 3 study periods that included episodes of elevated PM2.5 levels. Microparticles and immune cells in blood were measured by flow cytometry, and plasma cytokine/growth factors were measured using multiplexing laser beads. PM2.5 exposure was associated with the elevated levels of endothelial microparticles (annexin V+/CD41-/CD31+), including subtypes expressing arterial-, venous-, and lung-specific markers, but not microparticles expressing CD62+. These changes were accompanied by suppressed circulating levels of proangiogenic growth factors (EGF [epidermal growth factor], sCD40L [soluble CD40 ligand], PDGF [platelet-derived growth factor], RANTES [regulated on activation, normal T-cell expressed and secreted], GROalpha [growth-regulated protein alpha], and VEGF [vascular endothelial growth factor]), and an increase in the levels of antiangiogenic (TNFalpha [tumor necrosis factor alpha], IP-10 [interferon gamma induced protein 10]), and proinflammatory cytokines (MCP-1 [monocyte chemoattractant protein 1], MIP-1alpha/beta [macrophage inflammatory protein 1alpha/beta], IL-6 [interleukin 6], and IL-1beta [interleukin 1beta]), and markers of endothelial adhesion (sICAM-1 [soluble intercellular adhesion molecule 1] and sVCAM-1 [soluble vascular cellular adhesion molecule 1]). PM2.5 exposure was also associated with an inflammatory response characterized by elevated levels of circulating CD14+, CD16+, CD4+, and CD8+, but not CD19+ cells. CONCLUSIONS: Episodic PM2.5 exposures are associated with increased endothelial cell apoptosis, an antiangiogenic plasma profile, and elevated levels of circulating monocytes and T, but not B, lymphocytes. These changes could contribute to the pathogenic sequelae of atherogenesis and acute coronary events. PMID- 27780830 TI - Can we predict relapse in Graves' disease? Results from a systematic review and meta-analysis. AB - BACKGROUND: Identification of pretreatment risk factors predicting relapse in patients with hyperthyroidism of Graves' disease after stopping anti-thyroid drugs (ATD) is decisive to guide therapeutic options. PURPOSE: We performed a systematic search and meta-analysis to study predictors for relapse after stopping ATD in patients with Graves' disease. METHODS: Based on a pre-specified protocol, we searched PubMed, EMBASE and Cochrane in July 2015 for case-control, controlled and randomized-controlled trials reporting risk factors for relapse after stopping ATD. The primary endpoint was relapse of disease until follow-up. PRISMA and SIGN statements were used for reviewing the data and assessing the quality of included trials. RESULTS: We included 54 trials with a total of 7595 participants. Most trials were small with moderate-to-high risk for bias. Ten trials were assessed only qualitatively (2227 patients), genomic data were reported in 13 trials (2178 patients) and 31 trials (4346 patients) were assessed quantitatively. In total, there were 3696 relapses in 7595 patients (48.7%). By using random-effects meta-analysis, orbitopathy, smoking, thyroid volume measured by sonography, goiter size, fT4, tT3, TRAb and TBII were significantly associated with relapse, whereas male vs female sex, age and initial tT4 level did not show significant associations. CONCLUSIONS: This analysis found several risk factors to predict relapse in Graves' disease, which can be combined in a risk score. Prospective studies should evaluate the prognostic accuracy of such a score to guide treatment decisions. PMID- 27780833 TI - Lung haemangioma presenting with air-crescent-sign like image in an extreme premature baby. PMID- 27780832 TI - Outcome of babies with no detectable heart rate before 10 minutes of age, and the effect of gestation. AB - OBJECTIVE: Current resuscitation guidelines suggest that it is reasonable to consider stopping resuscitation where no heart rate (cardiac activity) has been detected for 10 min in a newborn baby from birth. We aimed to determine the mortality rate and 2-year neurodevelopmental outcome of all babies born with no heart rate before 10 min of age where resuscitation was attempted in a tertiary referral centre over a 5-year period. DESIGN: To identify all babies with no heart rate before age 10 min we examined two groups:? All babies classified as live born who received cardiac massage at birth between January 2009 and December 2013.? All babies classified as stillborn between January 2009 and December 2013 where attempts were made at resuscitation beyond 10 min. RESULTS: 87 babies received cardiac massage. 81 babies were live born and 6 were classified as stillborn. Twenty-two babies had no heart rate before 10 min of age. Eight babies survived to 2-year follow-up. 6/11 term babies survived, 2/4 babies born between 32 weeks and 37 weeks survived, and no infants born less than 32 weeks survived (n=7). Of the survivors, 5/8 had a normal neurodevelopmental outcome at 2 years' age. One patient was lost to follow-up, while the other two patients had hemiplegia. CONCLUSIONS: Our results add to the body of evidence suggesting that having no heart rate before 10 min of age, in term babies, may not be an appropriate prompt to discontinue resuscitation. PMID- 27780834 TI - Stable Overexpression of the Constitutive Androstane Receptor Reduces the Requirement for Culture with Dimethyl Sulfoxide for High Drug Metabolism in HepaRG Cells. AB - Dimethylsulfoxide (DMSO) induces cellular differentiation and expression of drug metabolic enzymes in the human liver cell line HepaRG; however, DMSO also induces cell death and interferes with cellular activities. The aim of this study was to examine whether overexpression of the constitutive androstane receptor (CAR, NR1I3), the nuclear receptor controlling various drug metabolism genes, would sufficiently promote differentiation and drug metabolism in HepaRG cells, optionally without using DMSO. By stable lentiviral overexpression of CAR, HepaRG cultures were less affected by DMSO in total protein content and obtained increased resistance to acetaminophen- and amiodarone-induced cell death. Transcript levels of CAR target genes were significantly increased in HepaRG-CAR cultures without DMSO, resulting in increased activities of cytochrome P450 (P450) enzymes and bilirubin conjugation to levels equal or surpassing those of HepaRG cells cultured with DMSO. Unexpectedly, CAR overexpression also increased the activities of non-CAR target P450s, as well as albumin production. In combination with DMSO treatment, CAR overexpression further increased transcript levels and activities of CAR targets. Induction of CYP1A2 and CYP2B6 remained unchanged, whereas CYP3A4 was reduced. Moreover, the metabolism of low-clearance compounds warfarin and prednisolone was increased. In conclusion, CAR overexpression creates a more physiologically relevant environment for studies on hepatic (drug) metabolism and differentiation in HepaRG cells without the utilization of DMSO. DMSO still may be applied to accomplish higher drug metabolism, required for sensitive assays, such as low-clearance studies and identification of (rare) metabolites, whereas reduced total protein content after DMSO culture is diminished by CAR overexpression. PMID- 27780835 TI - Developmental Changes in Hepatic Organic Cation Transporter OCT1 Protein Expression from Neonates to Children. AB - Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinically important drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Knowledge of OCT1 protein expression in children, especially neonates and small infants, is currently very limited. Here, we report on the characterization of OCT1 protein expression in neonatal, infant, and pediatric liver samples performed using immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal days 1 and 2. This youngest group showed significantly lower OCT1 expression normalized by glyceraldehyde-6-phosphate dehydrogenase (values given as means +/- S.D. in arbitrary units; 0.03 +/- 0.02, n = 7) compared with samples from patients aged 3 to 4 weeks (0.08 +/- 0.03, n = 5, P < 0.01), 3 to 6 months (0.23 +/- 0.15, n = 7, P < 0.01), 11 months to 1 year (0.42 +/- 0.32, n = 6, P < 0.01), and 8 to 12 years (1.00 +/- 0.44, n = 7, P < 0.01). These data demonstrate an age-dependent increase in OCT1 expression from birth up to 8 to 12 years of age, and the findings of this study contribute to the understanding of OCT1 functional capacity and its effect upon the disposition of OCT1 substrates in neonates and small infants. PMID- 27780837 TI - Direct Exposure of Wheat Seeds to High-Voltage Electrostatic Fields Adversely Affects the Performance of Sitobion avenae (Hemiptera: Aphididae). AB - Exposing seeds to a high-voltage electrostatic field (HVEF) may influence the performance of herbivores and improve the germination rate by inducing biological and physiological changes in plants. In the current study, an age-stage, two-sex life table was established to evaluate the effects from directly exposing seeds to HVEFs on the performance of apterous Sitobion avenae (Fabricius) reared on winter wheat. We treated the wheat seeds by exposing them to an HVEF for 20 min at three intensities: 2, 4, or 6 KV/cm. Controls received no treatment (0 KV/cm). The results indicated that the parameters of the net reproductive rate (R0), the intrinsic rate of increase (r), and the mean generation span (T) of S. avenae were significantly reduced by HVEFs through multiple generations. In addition, the age-specific survival rate (lx) and comparison with the results of a Weibull equation analysis suggested that S. avenae had the shortest life span when seeds were exposed to an HVEF at 4 KV/cm. Overall, these findings indicated that direct exposure of wheat seeds to an HVEF at 4 KV/cm could adversely affect the performance of S. avenae. PMID- 27780836 TI - Variation in Hospital Use and Outcomes Associated With Pulmonary Artery Catheterization in Heart Failure in the United States. AB - BACKGROUND: There has been an increase in the use of pulmonary artery (PA) catheters in heart failure (HF) in the United States in recent years. However, patterns of hospital use and trends in patient outcomes are not known. METHODS AND RESULTS: In the National Inpatient Sample 2001 to 2012, using International Classification of Diseases-Ninth Revision codes, we identified 11 888 525 adult (>=18 years) HF hospitalizations nationally, of which an estimated 75 209 (SE 0.6%) received a PA catheter. In 2001, the number of hospitals with >=1 PA catheterization was 1753, decreasing to 1183 in 2011. The mean PA catheter use per hospital trended from 4.9 per year in 2001 (limits 1-133) to 3.8 per year in 2007 (limits 1-46), but increased to 5.5 per year in 2011 (limits 1-70). During 2001 to 2006, PA catheterization declined across hospitals; however, in 2007 to 2012, there was a disproportionate increase at hospitals with large bedsize, teaching programs, and advanced HF capabilities. The overall in-hospital mortality with PA catheter use was higher than without PA catheter use (13.1% versus 3.4%; P<0.0001); however, in propensity-matched analysis, differences in mortality between these groups have attenuated over time-risk-adjusted odds ratio for mortality for PA catheterization, 1.66 (95% confidence interval, 1.60-1.74) in 2001 to 2003 down to 1.04 (95% confidence interval, 0.97-1.12) in 2010 to 2012. CONCLUSIONS: There is substantial hospital-level variability in PA catheterization in HF along with increasing volume at fewer hospitals over represented by large, academic hospitals with advanced HF capabilities. This is accompanied by a decline in excess mortality associated with PA catheterization. PMID- 27780838 TI - Physiological Response of Orchids to Mealybugs (Hemiptera: Pseudococcidae) Infestation. AB - The harmfulness of mealybugs resulting from sucking plant sap, secreting honeydew, and transmitting plant viruses can give them the status of serious pests. This study documents the influence of Pseudococcus maritimus (Ehrhorn) and Pseudococcus longispinus (Targioni Tozzetti) infestation on alterations in selected physiological parameters of Phalaenopsis x hybridum 'Innocence'. The condition of the cytoplasmic membranes was expressed as the value of thiobarbituric acid reactive substances. We have determined changes in the activities of catalase and guaiacol peroxidase and measured the following chlorophyll fluorescence parameters: maximum quantum yield of photosystem II (Fv/Fm), effective quantum yield (Y), photochemical quenching (qP), and nonphotochemical quenching (qN). The strongest physiological response of orchids was recorded in the initial period of mealybugs infestation. Prolonged insect feeding suppressed lipid peroxidation, peroxidase and catalase activity, as well as photosynthesis photochemistry. The pattern of changes was dependent on mealybug species. This indicated the complexity of the processes responsible for plant tolerance. Data generated in this study have provided a better understanding of the impact of two mealybug species infestation on Phalaenopsis and should be useful in developing pest management strategies. PMID- 27780839 TI - Motivational Impact of Palatable Food Correlates With Functional Brain Responses to Food Images in Adolescents. AB - Objective: To examine associations between motivational impact of palatable foods and neural activity in brain regions involved in inhibitory control among adolescents. Methods: Thirty-four adolescents aged 14-20 years underwent functional magnetic resonance imaging while viewing images of high- and low energy foods. Participants completed the Power of Food Scale (PFS). Whole-brain analyses of variance tested for neural activation differences and correlations between brain activation and PFS scores were tested. Results: We found an interaction between food type (high energy vs. low energy) and PFS scores in the right dorsolateral prefrontal cortex and right inferior parietal lobule. We also found that PFS scores correlated negatively with activation to high-energy foods in prefrontal cortical and parietal regions. Conclusions: These findings suggest that individuals with high motivation for high-energy foods also demonstrate lower neural activation in inhibition-related brain regions when viewing images of high-energy foods, indicating that they may have difficulty inhibiting consumption impulses. PMID- 27780840 TI - Identifying Unbiased Items for Screening Preschoolers for Disruptive Behavior Problems. AB - Objective: Efficient identification and referral to behavioral services are crucial in addressing early-onset disruptive behavior problems. Existing screening instruments for preschoolers are not ideal for pediatric primary care settings serving diverse populations. Eighteen candidate items for a new brief screening instrument were examined to identify those exhibiting measurement bias (i.e., differential item functioning, DIF) by child characteristics. Method: Parents/guardians of preschool-aged children ( N = 900) from four primary care settings completed two full-length behavioral rating scales. Items measuring disruptive behavior problems were tested for DIF by child race, sex, and socioeconomic status using two approaches: item response theory-based likelihood ratio tests and ordinal logistic regression. Results: Of 18 items, eight were identified with statistically significant DIF by at least one method. Conclusions: The bias observed in 8 of 18 items made them undesirable for screening diverse populations of children. These items were excluded from the new brief screening tool. PMID- 27780842 TI - Voices of the Dying and Bereaved: Music Therapy Narratives. PMID- 27780841 TI - 'A band of brothers'-an exploration of the range of medical ethical issues faced by British senior military clinicians on deployment to Afghanistan: a qualitative study. AB - AIMS: To identify and explore features of ethical issues that senior clinicians faced as deployed medical directors (DMDs) to the British Field Hospital in Afghanistan as well as to determine the ethical training requirements for future deployments. METHOD: A qualitative study in two phases conducted from November 2014 to June 2015. Phase 1 analysed 60 vignettes of cases that had generated ethical dilemmas for DMDs. Phase 2 included focus groups and an interview with 13 DMDs. FINDINGS: Phase 1 identified working with limited resources, dual conflict of meeting both clinical and military obligations and consent of children as the most prevalent ethical challenges. Themes found in Phase 2 included sharing clinical responsibilities with clinicians from other countries and not knowing team members' ways of working, in addition to the themes from Phase 1. DISCUSSION: This study has drawn together examples of scenarios to form a repository that will aid future training. Recommendations included undertaking ethics training together as a team before, during and after deployment which must include all nationalities who are assigned to the same operational tour, so that different ethical views can be explored beforehand. PMID- 27780843 TI - Binding of anti-dsDNA antibodies to proximal tubular epithelial cells contributes to renal tubulointerstitial inflammation. AB - Immune deposits are often observed along the tubular basement membrane in patients with lupus nephritis, but the role of anti-dsDNA antibody (Ab) deposition on tubulointerstitial inflammation remains to be investigated. We examined the effect of human polyclonal anti-dsDNA Abs on inflammatory processes in cultured proximal renal tubular epithelial cells (PTEC, HK-2 cells) and their association with serum levels of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in patients. Binding of anti-dsDNA Abs to HK-2 cells was investigated by cellular ELISA, flow cytometry and immunohistochemistry. IL-6, IL-8 and MCP-1 secretion, mitogen-activated protein kinase (MAPK) activation and the effect of mycophenolic acid (MPA) were investigated by ELISAs and Western blot analysis. NZBWF1/J mice with active nephritis were randomized to receive either mycophenolate mofetil (MMF) (100 mg/kg per day) or vehicle for up to 12 weeks to study renal histopathology focusing on tubulointerstitial changes. Our results demonstrated that anti-dsDNA Abs bound to HK-2 cell surface and induced IL-6, IL-8 and MCP-1 secretion through distinct MAPK pathways. MPA inhibited anti-dsDNA Ab binding to HK-2 cells and suppressed apical and basolateral IL-6 and IL-8, but not MCP-1, secretion. Anti dsDNA Ab level correlated with serum and tubulointerstitial expression of IL-6, IL-8 and MCP-1. MMF treatment in NZBWF1/J mice reduced anti-dsDNA Ab production and MAPK activation in the renal tubulointerstitium, together with decreased IL-6 and MCP-1 expression. Our data demonstrate that anti-dsDNA Abs contribute to inflammatory processes in the tubulointerstitium in lupus nephritis through their binding to proximal renal tubular epithelial cells and induction of pro inflammatory mediators, and MPA ameliorates anti-dsDNA Ab induced IL-6 and IL-8 secretion in these cells. PMID- 27780844 TI - Mouse models of Casc3 reveal developmental functions distinct from other components of the exon junction complex. AB - The exon junction complex (EJC) is a multiprotein complex integral to mRNA metabolism. Biochemistry and genetic studies have concluded that the EJC is composed of four core proteins, MAGOH, EIF4A3, RBM8A, and CASC3. Yet recent studies in Drosophila indicate divergent physiological functions for Barentsz, the mammalian Casc3 ortholog, raising the question as to whether CASC3 is a constitutive component of the EJC. This issue remains poorly understood, particularly in an in vivo mammalian context. We previously found that haploinsufficiency for Magoh, Eif4a3, or Rbm8a disrupts neuronal viability and neural progenitor proliferation, resulting in severe microcephaly. Here, we use two new Casc3 mouse alleles to demonstrate developmental phenotypes that sharply contrast those of other core EJC components. Homozygosity for either null or hypomorphic Casc3 alleles led to embryonic and perinatal lethality, respectively. Compound embryos lacking Casc3 expression were smaller with proportionately reduced brain size. Mutant brains contained fewer neurons and progenitors, but no apoptosis, all phenotypes explained by developmental delay. This finding, which contrasts with severe neural phenotypes evident in other EJC mutants, indicates Casc3 is largely dispensable for brain development. In the developing brain, CASC3 protein expression is substoichiometric relative to MAGOH, EIF4A3, and RBM8A. Taken together, this argues that CASC3 is not an essential EJC component in brain development and suggests it could function in a tissue-specific manner. PMID- 27780845 TI - The C terminus of Pcf11 forms a novel zinc-finger structure that plays an essential role in mRNA 3'-end processing. AB - 3'-End processing of pre-mRNAs prior to packaging and export to the cytoplasm of the mature transcript is a highly regulated process executed by several tens of protein factors that recognize poorly conserved RNA signals. Among them is Pcf11, a highly conserved, multidomain protein that links transcriptional elongation, 3' end processing, and transcription termination. Here we report the structure and biochemical function of Pcf11's C-terminal domain, which is conserved from yeast to humans. We identify a novel zinc-finger fold, resembling a trillium flower. Structural, biochemical, and genetic analyses reveal a highly conserved surface that plays a critical role in both cleavage and polyadenylation. These findings provide further insight into this important protein and its multiple functional roles during cotranscriptional RNA processing. PMID- 27780846 TI - Clinical Utility of Multimarker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study Among Over 51 Thousand Individuals of European Ancestry. AB - BACKGROUND: We evaluated whether including multilocus genetic risk scores (GRSs) into the Framingham Risk Equation improves the predictive capacity, discrimination, and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. METHODS AND RESULTS: We performed a cohort study among 51 954 European-ancestry members of a Northern California integrated healthcare system (67% female; mean age 59) free of CHD at baseline (2007-2008). Four GRSs were constructed using between 8 and 51 previously identified genetic variants. After a mean (+/-SD) follow-up of 5.9 (+/-1.5) years, 1864 incident CHD events were documented. All GRSs were linearly associated with CHD in a model adjusted by individual risk factors: hazard ratio (95% confidence interval) per SD unit: 1.21 (1.15-1.26) for GRS_8, 1.20 (1.15-1.26) for GRS_12, 1.23 (1.17 1.28) for GRS_36, and 1.23 (1.17-1.28) for GRS_51. Inclusion of the GRSs improved the C statistic (DeltaC statistic =0.008 for GRS_8 and GRS_36; 0.007 for GRS_12; and 0.009 for GRS_51; all P<0.001). The net reclassification improvement was 5% for GRS_8, GRS_12, and GRS_36 and 4% for GRS_51 in the entire cohort and was (after correcting for bias) 9% for GRS_8 and GRS_12 and 7% for GRS_36 and GRS_51 when analyzing those classified as intermediate Framingham risk (10%-20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS_8 and GRS_12, 41 for GRS_36, and 43 for GRS_51. CONCLUSIONS: Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of 4 multilocus GRSs for incident CHD among subjects of European ancestry. PMID- 27780847 TI - Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data. AB - BACKGROUND: Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. METHODS AND RESULTS: We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities; n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [r]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=-0.44, P=0.005), high-density lipoprotein (rG= 0.48, P=0.005), systolic blood pressure (rG=0.44, P=0.02), and triglycerides (rG=0.38, P=0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors. CONCLUSIONS: The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease. PMID- 27780849 TI - Guideline-Appropriate Care and In-Hospital Outcomes in Patients With Heart Failure in Teaching and Nonteaching Hospitals: Findings From Get With The Guidelines-Heart Failure. AB - BACKGROUND: Despite increasing awareness regarding evidence-based guidelines, considerable gaps exist for heart failure (HF) quality of care at teaching hospitals (TH) and nonteaching hospitals (NTH). We analyzed data from Get With The Guidelines (GWTG)-HF to compare the rates and trends of guideline-recommended care at TH and NTH for patients with HF. METHOD AND RESULTS: Baseline patient characteristics, performance measures, and in-hospital outcomes were compared between 197 187 HF patients admitted to TH and 106 924 patients admitted to NTH between 2005 and 2014. Patients treated in TH were younger and were more likely to be black and uninsured. Defect-free care (defined as 100% compliance with performance measures) was similar in both group of hospitals (crude rates: 88% at TH versus 86% at NTH, adjusted odds ratio 0.99, 95% confidence interval 0.73 1.34) as were individual performance measures: discharge instruction, documentation of ejection fraction, use of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists, use of beta-blocker, and smoking cessation counseling. During the study period, there was improvement in adherence with performance measures over time, with no significant difference at TH (adjusted odds ratio 1.20, 95% confidence interval 1.11-1.30; P<0.01) and NTH (adjusted odds ratio 1.09, 95% confidence interval 1.02-1.17; P=0.01; interaction P value 0.07). CONCLUSIONS: Data from the GWTG-HF program suggest that there was improving and comparable adherence with HF performance measures and use of guideline-recommended therapies irrespective of hospital teaching status. PMID- 27780848 TI - Sucrose Nonfermenting-Related Kinase Enzyme-Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function. AB - BACKGROUND: Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months. METHODS AND RESULTS: We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits. CONCLUSIONS: Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart. PMID- 27780850 TI - Health Status Outcomes in Patients With Acute Myocardial Infarction After Rehospitalization. AB - BACKGROUND: Rehospitalizations after acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are common. However, despite the inclusion of these events in composite end points of many clinical trials, their association with health status has not been studied. METHODS AND RESULTS: We included 3283 patients with acute myocardial infarction enrolled in a prospective, 24-center US study who had rehospitalizations independently classified by experienced cardiologists. Health status was assessed using Seattle Angina Questionnaire and EuroQol-5D Visual Analog Scale. In the propensity matched cohorts, 1-year health status was compared between those who did and did not experience rehospitalization for UA or revascularization using a hierarchical linear model. Overall, mean age was 59 years, 33% were women, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 4.3% and 4.7%. One-year Seattle Angina Questionnaire summary scores were worse in patients with rehospitalizations for UA (mean difference, -10.1; 95% confidence interval, -12.4 to -7.9) and unplanned revascularization (mean difference, -5.7; 95% confidence interval, -8.8 to -2.5) when compared with patients without such rehospitalizations. Similarly, EuroQol-5D Visual Analog Scale scores were worse among patients with such readmissions. Individual Seattle Angina Questionnaire domains indicated worse 1-year angina and quality of life outcomes among patients rehospitalized for UA or unplanned revascularization. CONCLUSIONS: Within the first year after acute myocardial infarction, rehospitalizations for UA and unplanned revascularization are associated with worse health status. These findings highlight the impact of such events from a patient's perspective, beyond their economic impact and support the use of UA and unplanned revascularization as elements of composite end points. PMID- 27780851 TI - MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease. AB - BACKGROUND: The transcription factor GATA2 orchestrates the expression of many endothelial-specific genes, illustrating its crucial importance for endothelial cell function. The capacity of this transcription factor in orchestrating endothelial-important microRNAs (miRNAs/miR) is unknown. METHODS: Endothelial GATA2 was functionally analyzed in human endothelial cells in vitro. Endogenous short interfering RNA-mediated knockdown and lentiviral-based overexpression were applied to decipher the capacity of GATA2 in regulating cell viability and capillary formation. Next, the GATA2-dependent miR transcriptome was identified by using a profiling approach on the basis of quantitative real-time polymerase chain reaction. Transcriptional control of miR promoters was assessed via chromatin immunoprecipitation, luciferase promoter assays, and bisulfite sequencing analysis of sites in proximity. Selected miRs were modulated in combination with GATA2 to identify signaling pathways at the angiogenic cytokine level via proteome profiler and enzyme-linked immunosorbent assays. Downstream miR targets were identified via bioinformatic target prediction and luciferase reporter gene assays. In vitro findings were translated to a mouse model of carotid injury in an endothelial GATA2 knockout background. Nanoparticle-mediated delivery of proangiogenic miR-126 was tested in the reendothelialization model. RESULTS: GATA2 gain- and loss-of-function experiments in human umbilical vein endothelial cells identified a key role of GATA2 as master regulator of multiple endothelial functions via miRNA-dependent mechanisms. Global miRNAnome-screening identified several GATA2-regulated miRNAs including miR-126 and miR-221. Specifically, proangiogenic miR-126 was regulated by GATA2 transcriptionally and targeted antiangiogenic SPRED1 and FOXO3a contributing to GATA2-mediated formation of normal vascular structures, whereas GATA2 deficiency led to vascular abnormalities. In contrast to GATA2 deficiency, supplementation with miR-126 normalized vascular function and expression profiles of cytokines contributing to proangiogenic paracrine effects. GATA2 silencing resulted in endothelial DNA hypomethylation leading to induced expression of antiangiogenic miR-221 by GATA2 dependent demethylation of a putative CpG island in the miR-221 promoter. Mechanistically, a reverted GATA2 phenotype by endogenous suppression of miR-221 was mediated through direct proangiogenic miR-221 target genes ICAM1 and ETS1. In a mouse model of carotid injury, GATA2 was reduced, and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo. CONCLUSIONS: GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Hence, modulation of GATA2 and its targets miR-126 and miR-221 is a promising therapeutic strategy for treatment of many vascular diseases. PMID- 27780852 TI - High-Throughput Screening Identifies miR-451 as a Pleiotropic Modulator That Suppresses Gastric Cancer Metastasis. AB - MicroRNAs (miRNAs) are globally dysregulated in human carcinomas. However, the specific miRNAs that mediate gastric cancer metastasis have not been identified. We identified 100 miRNAs that are dysregulated in gastric cancer and used a self assembled cell microarray method to systematically evaluate their capacity to regulate cell migration. MiR-451, which is down-regulated in human gastric cancer samples, potently modulated multiple metastatic phenotypes including cell migration, invasion, proliferation, and epithelial-mesenchymal transition. These effects were achieved via down-regulation of the miR-451 target gene, ERK2. These findings provide new insight into the physiological effects of and potential therapeutic uses for miRNAs in gastric cancer. PMID- 27780853 TI - The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. AB - PURPOSE: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. EXPERIMENTAL DESIGN: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co structure was determined. RESULTS: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. CONCLUSIONS: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527-38. (c)2016 AACR. PMID- 27780855 TI - Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First Line Tyrosine Kinase Inhibitors. AB - Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53 mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively.Conclusions:TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195-202. (c)2016 AACR. PMID- 27780854 TI - T-cell Receptor Signaling Activates an ITK/NF-kappaB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy. AB - Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell-specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy.Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines.Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-kappaB, and GATA-3 and promotes chemotherapy resistance.Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506-15. (c)2016 AACR. PMID- 27780856 TI - Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer. AB - Purpose: Even if RAS-BRAF wild-type and HER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies.Experimental design: Twenty two RAS-BRAF wild-type, HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples.Results:RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade.Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC. Clin Cancer Res; 23(10); 2414-22. (c)2016 AACR. PMID- 27780857 TI - Enrolling Adolescents in Disease/Target-Appropriate Adult Oncology Clinical Trials of Investigational Agents. AB - The enrollment of adolescents with cancer in clinical trials is much lower than that of younger pediatric patients. For adolescents with "adult-type" cancers, lack of access to relevant trials is cited as one of the reasons for this discrepancy. Adolescents are generally not eligible for enrollment in adult oncology trials, and initial pediatric trials for many drugs are conducted years later, often after the drug is approved. As a result, accrual of adolescents to these trials may be slow due to off-label use, prospectively collected safety and efficacy data are lacking at the time of initial approval, and, most importantly, these adolescents have delayed access to effective therapies. To facilitate earlier access to investigational and approved drugs for adolescent patients with cancer, and because drug exposure is most often similar in adolescents and adults, we recommend the inclusion of adolescents (ages 12-17) in disease- and target-appropriate adult oncology trials. This approach requires careful monitoring for any differential safety signals, appropriate pharmacokinetic evaluations, and ensuring that ethical requirements are met. Inclusion of adolescents in adult oncology trials will require the cooperation of investigators, cooperative groups, industry, institutional review boards, and regulatory agencies to overcome real and perceived barriers. Clin Cancer Res; 23(1); 9-12. (c)2016 AACR. PMID- 27780860 TI - Individuals with Alzheimer's learn to play a tile placement game: Results of a pilot study. AB - With the ongoing need to determine effective memory interventions for persons with dementia and other memory impairments, the purpose of this study was to create a unique learning opportunity, where persons with early to moderate Alzheimer's engaged in game play activity. Six female participants, diagnosed with early to moderate dementia, were recruited from an adult day care center and participated in a 10-week study. The participants were placed in groups of three and were taught a tile placement game. Results indicate playing the game yielded inconsistent, but some significant, increases and eventual plateauing of knowing when it was their turn. The results also indicate the participant's maintained improvement in tile placement over the study period. Tile placement accuracy increased over rounds, which points to the importance of practice to maintain learned behavior. The game provided a platform for learning, social engagement, and occupied their time meaningfully. PMID- 27780859 TI - The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia. AB - Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug-target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528-41. (c)2016 AACR. PMID- 27780858 TI - 5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma. AB - Purpose: Locoregional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, that is, cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency.Experimental Design: Here, we evaluated the efficacy of MEDI0641, a novel antibody-drug conjugate targeted to 5T4 and carrying a DNA-damaging "payload" (pyrrolobenzodiazepine) in preclinical models of HNSCC.Results: Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4high tumors displayed lower overall survival than those with 5T4low tumors (P = 0.038). 5T4 is more highly expressed in head and neck CSC (ALDHhighCD44high) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM SCC-11B, UM-SCC-22B) in vitro Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in three patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by five-fold in the PDX-SCC-M1, and two-fold in the PDX-SCC-M11 model. Importantly, mice (n = 12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for more than 200 days, whereas the control group had 7 recurrences (in 12 mice; P = 0.0047).Conclusions: Collectively, these findings demonstrate that an anti-5T4 antibody-drug conjugate reduces the fraction of CSCs and prevents local recurrence and suggest a novel therapeutic approach for patients with HNSCC. Clin Cancer Res; 23(10); 2516-27. (c)2016 AACR. PMID- 27780861 TI - p70S6K1 (S6K1)-mediated Phosphorylation Regulates Phosphatidylinositol 4 Phosphate 5-Kinase Type I gamma Degradation and Cell Invasion. AB - Phosphatidylinositol 4-phosphate 5-kinase type I gamma (PIPKIgamma90) ubiquitination and subsequent degradation regulate focal adhesion assembly, cell migration, and invasion. However, it is unknown how upstream signals control PIPKIgamma90 ubiquitination or degradation. Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIgamma90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIgamma90 phosphorylation is essential for cell migration and invasion. Moreover, PIPKIgamma90 phosphorylation is required for the development of focal adhesions and invadopodia, key machineries for cell migration and invasion. Surprisingly, substitution of Thr-553 and Ser-555 with Ala promoted PIPKIgamma90 ubiquitination but enhanced the stability of PIPKIgamma90, and depletion of S6K1 also enhanced the stability of PIPKIgamma90, indicating that PIPKIgamma90 ubiquitination alone is insufficient for its degradation. These data suggest that S6K1-mediated PIPKIgamma90 phosphorylation regulates cell migration and invasion by controlling PIPKIgamma90 degradation. PMID- 27780862 TI - The Orai1 Store-operated Calcium Channel Functions as a Hexamer. AB - Orai channels mediate store-operated Ca2+ signals crucial in regulating transcription in many cell types, and implicated in numerous immunological and inflammatory disorders. Despite their central importance, controversy surrounds the basic subunit structure of Orai channels, with several biochemical and biophysical studies suggesting a tetrameric structure yet crystallographic evidence indicating a hexamer. We systematically investigated the subunit configuration of the functional Orai1 channel, generating a series of tdTomato tagged concatenated Orai1 channel constructs (dimers to hexamers) expressed in CRISPR-derived ORAI1 knock-out HEK cells, stably expressing STIM1-YFP. Surface biotinylation demonstrated that the full-length concatemers were surface membrane expressed. Unexpectedly, Orai1 dimers, trimers, tetramers, pentamers, and hexamers all mediated similar and substantial store-operated Ca2+ entry. Moreover, each Orai1 concatemer mediated Ca2+ currents with inward rectification and reversal potentials almost identical to those observed with expressed Orai1 monomer. In Orai1 tetramers, subunit-specific replacement with Orai1 E106A "pore inactive" subunits revealed that functional channels utilize only the N-terminal dimer from the tetramer. In contrast, Orai1 E106A replacement in Orai1 hexamers established that all the subunits can contribute to channel formation, indicating a hexameric channel configuration. The critical Ca2+ selectivity filter-forming Glu-106 residue may mediate Orai1 channel assembly around a central Ca2+ ion within the pore. Thus, multiple E106A substitutions in the Orai1 hexamer may promote an alternative "trimer-of-dimers" channel configuration in which the C terminal E106A subunits are excluded from the hexameric core. Our results argue strongly against a tetrameric configuration for Orai1 channels and indicate that the Orai1 channel functions as a hexamer. PMID- 27780864 TI - Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine. AB - In human urinary tract infections, host cells release the antimicrobial protein siderocalin (SCN; also known as lipocalin-2, neutrophil gelatinase-associated lipocalin, or 24p3) into the urinary tract. By binding to ferric catechol complexes, SCN can sequester iron, a growth-limiting nutrient for most bacterial pathogens. Recent evidence links the antibacterial activity of SCN in human urine to iron sequestration and metabolomic variation between individuals. To determine whether these metabolomic associations correspond to functional Fe(III)-binding SCN ligands, we devised a biophysical protein binding screen to identify SCN ligands through direct analysis of human urine. This screen revealed a series of physiologic unconjugated urinary catechols that were able to function as SCN ligands of which pyrogallol in particular was positively associated with high urinary SCN activity. In a purified, defined culture system, these physiologic SCN ligands were sufficient to activate SCN antibacterial activity against Escherichia coli In the presence of multiple SCN ligands, native mass spectrometry demonstrated that SCN may preferentially combine different ligands to coordinate iron, suggesting that availability of specific ligand combinations affects in vivo SCN antibacterial activity. These results support a mechanistic link between the human urinary metabolome and innate immune function. PMID- 27780863 TI - Protein 4.1R Influences Myogenin Protein Stability and Skeletal Muscle Differentiation. AB - Protein 4.1R (4.1R) isoforms are expressed in both cardiac and skeletal muscle. 4.1R is a component of the contractile apparatus. It is also associated with dystrophin at the sarcolemma in skeletal myofibers. However, the expression and function of 4.1R during myogenesis have not been characterized. We now report that 4.1R expression increases during C2C12 myoblast differentiation into myotubes. Depletion of 4.1R impairs skeletal muscle differentiation and is accompanied by a decrease in the levels of myosin heavy and light chains and caveolin-3. Furthermore, the expression of myogenin at the protein, but not mRNA, level is drastically decreased in 4.1R knockdown myocytes. Similar results were obtained using MyoD-induced differentiation of 4.1R-/- mouse embryonic fibroblast cells. von Hippel-Lindau (VHL) protein is known to destabilize myogenin via the ubiquitin-proteasome pathway. We show that 4.1R associates with VHL and, when overexpressed, reverses myogenin ubiquitination and stability. This suggests that 4.1R may influence myogenesis by preventing VHL-mediated myogenin degradation. Together, our results define a novel biological function for 4.1R in muscle differentiation and provide a molecular mechanism by which 4.1R promotes myogenic differentiation. PMID- 27780865 TI - Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION. AB - The relevance of mitochondrial phosphate carrier (PiC), encoded by SLC25A3, in bioenergetics is well accepted. However, little is known about the mechanisms mediating the cellular impairments induced by pathological SLC25A3 variants. To this end, we investigated the pathogenicity of a novel compound heterozygous mutation in SLC25A3 First, each variant was modeled in yeast, revealing that substituting GSSAS for QIP within the fifth matrix loop is incompatible with survival on non-fermentable substrate, whereas the L200W variant is functionally neutral. Next, using skin fibroblasts from an individual expressing these variants and HeLa cells with varying degrees of PiC depletion, PiC loss of ~60% was still compatible with uncompromised maximal oxidative phosphorylation (oxphos), whereas lower maximal oxphos was evident at ~85% PiC depletion. Furthermore, intact mutant fibroblasts displayed suppressed mitochondrial bioenergetics consistent with a lower substrate availability rather than phosphate limitation. This was accompanied by slowed proliferation in glucose replete medium; however, proliferation ceased when only mitochondrial substrate was provided. Both mutant fibroblasts and HeLa cells with 60% PiC loss showed a less interconnected mitochondrial network and a mitochondrial fusion defect that is not explained by altered abundance of OPA1 or MFN1/2 or relative amount of different OPA1 forms. Altogether these results indicate that PiC depletion may need to be profound (>85%) to substantially affect maximal oxphos and that pathogenesis associated with PiC depletion or loss of function may be independent of phosphate limitation when ATP requirements are not high. PMID- 27780866 TI - Identification of Two Phosphate Starvation-induced Wall Teichoic Acid Hydrolases Provides First Insights into the Degradative Pathway of a Key Bacterial Cell Wall Component. AB - The cell wall of most Gram-positive bacteria contains equal amounts of peptidoglycan and the phosphate-rich glycopolymer wall teichoic acid (WTA). During phosphate-limited growth of the Gram-positive model organism Bacillus subtilis 168, WTA is lost from the cell wall in a response mediated by the PhoPR two-component system, which regulates genes involved in phosphate conservation and acquisition. It has been thought that WTA provides a phosphate source to sustain growth during starvation conditions; however, WTA degradative pathways have not been described for this or any condition of bacterial growth. Here, we uncover roles for the Bacillus subtilis PhoP regulon genes glpQ and phoD as encoding secreted phosphodiesterases that function in WTA metabolism during phosphate starvation. Unlike the parent 168 strain, DeltaglpQ or DeltaphoD mutants retained WTA and ceased growth upon phosphate limitation. Characterization of GlpQ and PhoD enzymatic activities, in addition to X-ray crystal structures of GlpQ, revealed distinct mechanisms of WTA depolymerization for the two enzymes; GlpQ catalyzes exolytic cleavage of individual monomer units, and PhoD catalyzes endo-hydrolysis at nonspecific sites throughout the polymer. The combination of these activities appears requisite for the utilization of WTA as a phosphate reserve. Phenotypic characterization of the DeltaglpQ and DeltaphoD mutants revealed altered cell morphologies and effects on autolytic activity and antibiotic susceptibilities that, unexpectedly, also occurred in phosphate-replete conditions. Our findings offer novel insight into the B. subtilis phosphate starvation response and implicate WTA hydrolase activity as a determinant of functional properties of the Gram-positive cell envelope. PMID- 27780867 TI - Interferon-gamma Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells. AB - Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFNgamma promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFNgamma drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1 related markers HLA-DR and CD86, as well as of FcgammaRI, which mediates effector responses to therapeutic antibodies. Importantly, IFNgamma was able to up regulate CD38, the target of the therapeutic antibody daratumumab. Because the antigen (CD38) and effector receptor (FcgammaRI) were both simultaneously up regulated on the AML blasts, we tested whether IFNgamma treatment of the AML cell lines THP-1 and MV4-11 could stimulate them to target one another after the addition of daratumumab. Results showed that IFNgamma significantly increased daratumumab-mediated cytotoxicity, as measured both by 51Cr release and lactate dehydrogenase release assays. We also found that the combination of IFNgamma and activation of FcgammaR led to the release of granzyme B by AML cells. Finally, using a murine NSG model of subcutaneous AML, we found that treatment with IFNgamma plus daratumumab significantly attenuated tumor growth. Taken together, these studies show a novel mechanism of daratumumab-mediated killing and a possible new therapeutic strategy for AML. PMID- 27780870 TI - Virtual flow-diverter treatment planning: The effect of device placement on bifurcation aneurysm haemodynamics. AB - Bifurcation aneurysms account for a large fraction of cerebral aneurysms and often present morphologies that render traditional endovascular treatments, such as coiling, challenging and problematic. Flow-diverter stents offer a potentially elegant treatment option for such aneurysms, but clinical use of these devices remains controversial. Specifically, the deployment of a flow-diverter device in a bifurcation entails jailing one or more potentially vital vessels with a low porosity mesh designed to restrict the flow. When multiple device placement configurations exist, the most appropriate clinical decision becomes increasingly opaque. In this study, three bifurcation aneurysm geometries were virtually treated by flow-diverter device. Each aneurysm was selected to offer two possible device deployment positions. Flow-diverters similar to commercially available designs were deployed with a fast-deployment algorithm before transient and steady state computational fluid dynamics simulations were performed. Reductions in aneurysm inflow, mean wall shear stress and maximum wall shear stress, all factors often linked with aneurysm treatment outcome, were compared for different device configurations in each aneurysm. In each of the three aneurysms modelled, a particular preferential device placement was shown to offer superior performance with the greatest reduction in the flow metrics considered. In all the three aneurysm geometries, substantial variations in inflow reduction (up to 25.3%), mean wall shear stress reduction (up to 14.6%) and maximum wall shear stress reduction (up to 12.1%) were seen, which were all attributed to device placement alone. Optimal device placement was found to be non-trivial and highly aneurysm specific; in only one-third of the simulated geometries, the best overall performance was achieved by deploying a device in the daughter vessel with the highest flow rate. Good correspondence was seen between transient results and steady state computations that offered a significant reduction in simulation run time. If accurate steady state computations are combined with the fast-deployment algorithm used, the modest run time and corresponding hardware make a virtual treatment pipeline in the clinical setting a meaningful possibility. PMID- 27780868 TI - Inter-domain Synergism Is Required for Efficient Feeding of Cellulose Chain into Active Site of Cellobiohydrolase Cel7A. AB - Structural polysaccharides like cellulose and chitin are abundant and their enzymatic degradation to soluble sugars is an important route in green chemistry. Processive glycoside hydrolases (GHs), like cellobiohydrolase Cel7A of Trichoderma reesei (TrCel7A) are key components of efficient enzyme systems. TrCel7A consists of a catalytic domain (CD) and a smaller carbohydrate-binding module (CBM) connected through the glycosylated linker peptide. A tunnel-shaped active site rests in the CD and contains 10 glucose unit binding sites. The active site of TrCel7A is lined with four Trp residues with two of them, Trp-40 and Trp-38, in the substrate binding sites near the tunnel entrance. Although addressed in numerous studies the elucidation of the role of CBM and active site aromatics has been obscured by a complex multistep mechanism of processive GHs. Here we studied the role of the CBM-linker and Trp-38 of TrCel7A with respect to binding affinity, on- and off-rates, processivity, and synergism with endoglucanase. The CBM-linker increased the on-rate and substrate affinity of the enzyme. The Trp-38 to Ala substitution resulted in increased off-rates and decreased processivity. The effect of the Trp-38 to Ala substitution on on-rates was strongly dependent on the presence of the CBM-linker. This compensation between CBM-linker and Trp-38 indicates synergism between CBM-linker and CD in feeding the cellulose chain into the active site. The inter-domain synergism was pre-requisite for the efficient degradation of cellulose in the presence of endoglucanase. PMID- 27780869 TI - URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells. AB - URI (unconventional prefoldin RPB5 interactor protein) is an unconventional prefoldin, RNA polymerase II interactor that functions as a transcriptional repressor and is part of a larger nuclear protein complex. The components of this complex and the mechanism of transcriptional repression have not been characterized. Here we show that KAP1 (KRAB-associated protein 1) and the protein phosphatase PP2A interact with URI. Mechanistically, we show that KAP1 phosphorylation is decreased following recruitment of PP2A by URI. We functionally characterize the novel URI-KAP1-PP2A complex, demonstrating a role of URI in retrotransposon repression, a key function previously demonstrated for the KAP1-SETDB1 complex. Microarray analysis of annotated transposons revealed a selective increase in the transcription of LINE-1 and L1PA2 retroelements upon knockdown of URI. These data unveil a new nuclear function of URI and identify a novel post-transcriptional regulation of KAP1 protein that may have important implications in reactivation of transposable elements in prostate cancer cells. PMID- 27780871 TI - Pax8 controls thyroid follicular polarity through cadherin-16. AB - Organization of epithelial cells during follicular lumen formation is crucial for thyroid morphogenesis and function of the thyroid gland; however, the molecular mechanisms underlying this are poorly understood. To investigate this process, we established three-dimensional (3D) epithelial culture model systems using Fischer rat thyroid (FRT) cells or murine primary thyrocytes that developed polarized spherical structures with a central lumen, mimicking thyroid follicles. Using microarray-based differential expression analysis of FRT cells grown under 2D or 3D conditions, followed by RNA-mediated interference (RNAi) and morphogenetic analysis, we identified a key role for the thyroid transcription factor Pax8 and its target cadherin-16 (Cdh16) in the generation of polarized follicle-like structures. Silencing Pax8 expression inhibited the acquisition of apical-basal membrane polarity and impaired lumen formation. Both laminin and beta1-integrin (Itgb1) expression was reduced, and cell cytoskeleton polarized distribution was altered. Silencing Cdh16 expression also led to the formation of defective structures characterized by very low laminin expression at the follicle-matrix interface, downregulation of Itgb1, and unpolarized distribution of cell cytoskeleton. Our results demonstrate that Pax8 controls apical-basal follicular polarization and follicle formation through Cdh16. PMID- 27780872 TI - Direction and magnitude of head tilt alter postrotatory nystagmus. PMID- 27780873 TI - Effects of Eight-Week-Web-Based Mindfulness Training on Pain Intensity, Pain Acceptance, and Life Satisfaction in Individuals With Chronic Pain. AB - This study examined the effects of an eight-week-web-based mindfulness program designed for individuals with chronic pain. A sample of 107 participants with chronic pain (M = 51.0 years, SD = 9.3) were randomly assigned to a treatment group and a control group. The mindfulness program involved 20 minutes of training per day, six days a week, for eight weeks. During this period, the control group was invited to an online discussion forum involving pain-related topics. A total of 77 participants completed the postintervention assessment (n = 36 in the treatment group, n = 41 in the control group). The group assigned to mindfulness training showed increased mindfulness skills (Cohen's d = 1.18), reduced pain intensity (d = 0.47-0.82), reduced pain-related interference/suffering (d = 0.39-0.85), heightened pain acceptance (d = 0.66), reduced affective distress (d = 0.67), and higher ratings of life satisfaction (d = 0.54) following the training with no or minor changes up for the control group (d values 0.01-0.23), a pattern substantiated by significant group-by-time interactions. Despite limitations of this study, including a less than ideal control group to isolate effects of mindfulness and lack of a long-term follow up, the results appear promising and may motivate further investigations. PMID- 27780874 TI - Data Mining in the Exploration of Stressors Among NCAA Student Athletes. AB - Collegiate student athletes face psychological stressors in adjusting to campus life. This study used preexisting, nationally representative data administered by the National Collegiate Athletic Association for student athletes in 2010 to explore the conjunctive relationships among demographics, personal characteristics, social contexts, and physical condition in predicting perceived stress. The number of valid samples was 19,967 from 609 member institutions. A data mining methodology (i.e., SEARCH) was applied to model the distribution of the perceived stress. Results showed that significant stressors included the variables related to academics, physical well-being, and social contexts. Academic anxiety was the most important predictor, and its interactions with abusive coaching behavior and an inclusive team environment were shown to reduce perceived stress. Sufficient sleep was also found as a moderator in the positive relationship between perceived stress and academic anxiety. PMID- 27780875 TI - Molecular mechanisms of innate memory and tolerance to LPS. AB - LPS is a potent trigger of macrophage-mediated inflammation. However, prolonged exposure to LPS induces a state of tolerance that reprograms the inflammatory response, resulting in reduced inflammatory cytokine production in vitro and in vivo. Recent evidence suggests that LPS tolerance also increases the expression of a subset of genes that may protect animals from systemic infection while they are in the tolerized state. However, a molecular basis for these selective changes in inflammatory gene expression during LPS tolerance has remained elusive. In this review, we discuss the molecular mechanisms that may account for these effects, focusing on changes in LPS signaling, epigenetic markers, and chromatin remodeling that may be responsible for cellular memory and physiologic changes that comprise the LPS tolerance phenomenon. PMID- 27780877 TI - A mathematical model for assessing the effectiveness of protective devices in reducing risk of infection by inhalable droplets. AB - Respiratory protective devices (RPDs) are critical for reducing the spread of infection via inhalable droplets. In determining the type of RPD to deploy, it is important to know the reduction in the infection rate that the RPD enables for the given pathogen and population. This paper extends a previously developed susceptible-infected-recovered (SIR) epidemic model to analyse the effect of a protection strategy. An approximate solution to the modified SIR equations, which compares well with a full numerical solution to the equations, was used to derive a simple threshold equation for predicting when growth of the infected population will occur for a given protection strategy. The threshold equation is cast in terms of a generalized reproduction number, which contains the characteristics of the RPDs deployed by the susceptible and infected populations, as well as the degree of compliance in wearing the equipment by both populations. An example calculation showed that with 50% of the susceptible population deploying RPDs that transmit 15% of pathogens, and an unprotected infected population, an otherwise growing infection rate can be converted to one that decays. When the infected population deploys RPDs, the transmission rate for the RPDs worn by the susceptible population can be higher. PMID- 27780876 TI - Mechanisms of Resistance to Antibody-Drug Conjugates. AB - Drug resistance limits the effectiveness of cancer therapies. Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents. Antibody-drug conjugates (ADC) are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy; however, recent preclinical studies reveal potential mechanisms of resistance. Because ADCs are a combination of antibody and small molecule cytotoxin, multifactorial modes of resistance are emerging that are inherent to the structure and function of the ADC. Decreased cell-surface antigen reduces antibody binding, whereas elevated drug transporters such as MDR1 and MRP1 reduce effectiveness of the payload. Inherent to the uniqueness of the ADC, other novel resistance mechanisms are emerging, including altered antibody trafficking, ADC processing, and intracellular drug release. Most importantly, the modular nature of the ADC allows components to be switched and replaced, enabling development of second-generation ADCs that overcome acquired resistance. This review is intended to highlight recent progress in our understanding of ADC resistance, including approaches to create preclinical ADC-refractory models and to characterize their emerging mechanisms of resistance. Mol Cancer Ther; 15(12); 2825-34. (c)2016 AACR. PMID- 27780879 TI - Barriers and myths that limit the use of intrauterine contraception in nulliparous women: a survey of Brazilian gynaecologists. AB - OBJECTIVE: To understand the extent to which barriers and misperceptions about intrauterine contraception (IUC) remain among Brazilian gynaecologists, particularly for nulliparous women. METHODS: An online survey was developed to assess Brazilian gynaecologists' knowledge and attitudes towards IUC. Data collected included demographic and professional data, main barriers when considering IUC for women in general and/or nulliparous women, attitudes towards inclusion of IUC in contraceptive counselling, and opinions on what could increase IUC prescription for nulliparous women. A question regarding knowledge about WHO medical eligibility criteria (WHO MEC) was also included in the survey. RESULTS: 101 gynaecologists completed the survey. The insertion rate in nulliparous women was 79.2%. Brazilian gynaecologists were more likely to consider IUC in counselling or provide it on request for parous than for nulliparous women (p<0.05) and perceived more complications in nulliparous women. 74.2% of gynaecologists recognised a higher risk of pelvic inflammatory disease (PID)/infertility associated with IUC use in nulliparous women than in parous women. Difficult and painful insertion were also relevant for 83.2% and 77.3% of the gynaecologists, respectively. Respondents showed a high level of awareness of the WHO MEC classification. CONCLUSIONS: The three most commonly reported barriers to considering IUC as a contraceptive option for nulliparous woman were concerns about PID and difficult or painful insertion. The challenge is to ensure that gynaecologists understand the evidence and do not disregard IUC as a potential option for nulliparous women. PMID- 27780878 TI - Blocking mammalian target of rapamycin alleviates bladder hyperactivity and pain in rats with cystitis. AB - BACKGROUND: Bladder disorders associated with interstitial cystitis are frequently characterized by increased contractility and pain. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on the exaggerated bladder activity and pain evoked by cystitis and (2) the underlying mechanisms responsible for the role of mTOR in regulating cystic sensory activity. RESULTS: The expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4 E-binding protein 4 (p-4 E-BP1), as well as phosphatidylinositide 3-kinase (p-PI3K) pathway were amplified in cyclophosphamide rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated bladder hyperactivity and pain. In addition, blocking PI3K signal pathway attenuated activities of mTOR, which was accompanied with decreasing bladder hyperactivity and pain. Inhibition of either mTOR or PI3K blunted the enhanced spinal substance P and calcitonin gene-related peptide in cyclophosphamide rats. CONCLUSIONS: The data for the first time revealed specific signaling pathways leading to cyclophosphamide induced bladder hyperactivity and pain, including the activation of mTOR and PI3K. Inhibition of these pathways alleviates cystic pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of overactive bladder and pain often observed in cystitis. PMID- 27780880 TI - Behind the (bilateral) fungus ball. PMID- 27780881 TI - Twelve Committed Men: the feasibility of a community-based participatory HIV prevention intervention within a Canadian men's correctional facility. AB - OBJECTIVES: The intervention objectives were to evaluate and describe the feasibility of using a community-based research (CBR) approach to adapt and implement HIV-prevention materials and tools with incarcerated men. We found no prior published reports about CBR HIV-prevention education in Canadian correctional facilities. METHODS: Twelve members of the correctional Peer Education Committee (PEC) and Aboriginal PEC, whom a correctional nurse identified as being interested in preventive health, were purposively invited to participate. Eight participants were serving life sentences, three were Aboriginal and their education levels ranged from below grade 8 to 11 years of post-secondary education. The setting was a medium-security federal correctional facility, housing 324 men. The intervention was guided by CBR and 'greater involvement of people with AIDS' principles. Participants were invited to attend four workshops, over seven days in May 2014, and to provide their insights regarding future scaled-up CBR HIV prevention. Each workshop included an HIV prevention presentation and a focus group discussion, two of which were audio recorded. FINDINGS: All participants attended all sessions. Synthesis of mixed method findings, with quantitative and qualitative data triangulation, demonstrated two major outcomes: 'new knowledge was generated' regarding feasibility of CBR HIV prevention in a men's correction facility; and 'capacity building occurred' with increased participants' social capital. Thirty incarcerated men requested HIV testing following the intervention, because participants spread their knowledge about HIV prevention to others. Participants asked to become 'health ambassadors' - champion advisors for future scaled-up CBR HIV-prevention intervention for the entire correctional facility. CONCLUSION: CBR HIV prevention is feasible within a Canadian men's correctional facility. PMID- 27780883 TI - Human umbilical perivascular cells: a novel source of MSCs to support testicular niche regeneration. AB - The expansion of functional testicular biopsy-derived human spermatogonial stem cells (hSSC) ex-vivo may enable the restoration of fertility in pre-pubertal males having undergone gonadotoxic therapies or men with severe male factor infertility. Various somatic cells are known to regulate SSC homeostasis and spermatogenesis in the developing and adult testis. Prior attempts to recapitulate this niche demonstrated the requirement of feeder cells, such as endogenous testicular somatic cells, for germ cell expansion ex-vivo. However, this strategy has limitations for the expansion of hSSCs from tissue biopsies where spermatogenesis is absent or defective. Our aim was to evaluate first trimester human umbilical cord perivascular cells (FTM HUCPVCs), a novel source of mesenchymal stromal-like cells (MSCs), as potential human feeder cells for standardized hSSC expansion ex-vivo. Targeted RNA sequencing analysis demonstrated that CD90+ve FTM HUCPVCs expanded in vitro under germ cell culture conditions express a profile of targeted testicular-associated transcripts that is similar to cultured human CD90+ve testicular adherent cells (hTACs) and secrete LIF, FGF2 and BMP4, key growth factors known to regulate spermatogenesis. We also demonstrated that mitotically-inactivated FTM HUCPVCs support the expansion of mouse germ cells and putative SSCs ex-vivo, and that FTM HUCPVC transplantation promotes in vivo germ cell regeneration following mono-2- ethylhexyl phthalate (MEHP)-induced seminiferous tubule damage in a murine model, including a partial reconstitution of tubular cellular architecture and reestablishment of DAZL and acrosin+ve germ cell layers. Together, these data suggest that FTM HUCPVCs have phenotypical and functional properties that may support repair of the human testicular niche. PMID- 27780882 TI - Sickness absence among peer-supported drivers after occupational trauma. AB - Background: Psychological first aid is a common approach for providing support after potentially traumatic events (PTEs). In Germany, a peer support model is recommended by the German Statutory Accident Insurance (DGUV) to reduce sickness absence after occupational accidents, especially in public transportation. However, data on the effectiveness of peer support are very sparse. Aims: To analyse whether peer support has an impact on sickness absence after work-related traumatic events in public transportation. Methods: An analysis was conducted in two German public transportation corporations. Due to ethical requirements, we used a historical cohort study comparing peer support by colleagues (VAG-1), peer support at supervisor level (VGF) and a non-intervention group (VAG-0). The study period was from March 2003 to December 2012. We used a negative binominal regression model to estimate the relative risk associated with the interventions and potential confounders. Results: A total of 259 incident PTEs in employees were observed. A regression analysis identified the severity of PTE (severe and fatal events), VGF and age as significant factors in predicting duration of post event sickness absence. In a stratified analysis, the mode of peer support (VGF) and age predicted sickness absence for less severe PTEs but this was not significant for severe PTEs. Conclusions: Severe and fatal PTEs had the strongest impact on sickness absence after PTEs. For less severe PTE, peer support provided by colleagues may be superior to supervisor support. PMID- 27780884 TI - Strength of evidence for labeled dosing recommendations in renal impairment. AB - BACKGROUND/AIMS: Renally excreted medications often require dose adjustment in patients with kidney impairment. While drug development and approval in the United States are typically based on several Phase I and II studies and one or more larger Phase III randomized trials, the basis for labeled dosing recommendations for patients with renal impairment is less well known. In response, we aimed to quantify the level of evidence used to recommend labeled dosing adjustments for newly approved drugs in patients with renal impairment. METHODS: We reviewed publicly available drug labels and approval packages for new molecular entities approved in the United States between 2012 and 2014. The sample was restricted to 29 renally excreted new molecular entities that were not granted orphan drug status. We extracted data regarding approved indications, normal dosing, dosing adjustments for patients with mild (estimated glomerular filtration rate >60 mL/min/1.73 m2), moderate (estimated glomerular filtration rate 30-<60 mL/min/1.73 m2), and severe (estimated glomerular filtration rate <30 mL/min/1.73 m2) renal impairment, characteristics of studies used to justify dosing adjustments, and numbers of subjects in each study. RESULTS: In all, 14 of 29 (48%) new molecular entities had labels that recommended dosing adjustments for patients with mild, moderate, and/or severe renal impairment. Among these 14 new molecular entities, 4 (29%) used only pharmacokinetic studies to justify the recommendations, with no examination of clinical outcomes for patients with renal impairment. Where data were available, the median number of patients with renal impairment evaluated in studies used for dosing adjustment was 34 (range, 4 5976). Of the 15 new molecular entities with no recommended dosing adjustments for this population, 2 (13%) did not report assessing the effects of renal impairment. CONCLUSION: Nearly half of newly approved renally excreted drugs include dosing adjustments for kidney impairment on the label, but the recommendations are usually based on very small numbers of patients and often utilize pharmacokinetic studies alone. More research is needed to understand the benefits and risks of new drugs in patients with renal impairment. PMID- 27780885 TI - FutureTox III: Bridges for Translation. AB - Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making. PMID- 27780887 TI - Evaluation of a motivational pre-exercise music intervention. AB - While music has been found to motivate exercisers during workouts, its potential as a pre-exercise motivator has rarely been investigated. This study evaluated a self-selected, pre-exercise music intervention against implementation intentions (writing down 'if ... then ...' sentences relating to overcoming barriers) and a control condition. A total of 50 participants ( Mage = 43) took part in a longitudinal, randomised, between-participants study, from 99 recruited. For both interventions, participants had significantly more success meeting self-set exercise goals than the control group, and the music group exercised significantly more frequently than the control group. There was support for music as a comparable intervention to implementation intentions. PMID- 27780888 TI - Psychological factors associated with the use of weight management behaviours in young adults. AB - We modified the Weight Control Behaviours scale to explore unhealthy/healthy behaviours to increase, decrease or maintain weight in young adults ( N = 1082) and associations with body mass index, depression and body image. Females reported more use of all strategies except those which increase body size or exercising to exhaustion. Although the sample reported more use of healthy weight management strategies, the use of dangerous ones warrants attention by healthcare professionals. Feelings of fatness was an important predictor of weight management behaviours. Public health campaigns should focus on the harmfulness of unhealthy weight management practices as well as the importance of healthy ones. PMID- 27780886 TI - Development of an index to define overall disease severity in IBD. AB - BACKGROUND AND AIM: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. METHODS: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. RESULTS: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. CONCLUSIONS: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD. PMID- 27780889 TI - Decision-making on behalf of people living with dementia: how do surrogate decision-makers decide? AB - BACKGROUND: For people living with dementia, the capacity to make important decisions about themselves diminishes as their condition advances. As a result, important decisions (affecting lifestyle, medical treatment and end of life) become the responsibility of someone else, as the surrogate decision-maker. This study investigated how surrogate decision-makers make important decisions on behalf of a person living with dementia. METHODS: Semi-structured interviews were conducted with 34 family members who had formally or informally taken on the role of surrogate decision-maker. Thematic analysis of interviews was undertaken, which involved identifying, analysing and reporting themes arising from the data. RESULTS: Analysis revealed three main themes associated with the process of surrogate decision-making in dementia: knowing the person's wishes; consulting with others and striking a balance. Most participants reported that there was not an advance care plan in place for the person living with dementia. Even when the prior wishes of the person with dementia were known, the process of decision making was often fraught with complexity. DISCUSSION: Surrogate decision-making on behalf of a person living with dementia is often a difficult process. Advance care planning can play an important role in supporting this process. Healthcare professionals can recognise the challenges that surrogate decision-makers face and support them through advance care planning in a way that suits their needs and circumstances. PMID- 27780890 TI - Novel protective effects of pulsed electromagnetic field ischemia/reperfusion injury rats. AB - Extracorporeal pulsed electromagnetic field (PEMF) has shown the ability to regenerate tissue by promoting cell proliferation. In the present study, we investigated for the first time whether PEMF treatment could improve the myocardial ischaemia/reperfusion (I/R) injury and uncovered its underlying mechanisms.In our study, we demonstrated for the first time that extracorporeal PEMF has a novel effect on myocardial I/R injury. The number and function of circulating endothelial progenitor cells (EPCs) were increased in PEMF treating rats. The in vivo results showed that per-treatment of PEMF could significantly improve the cardiac function in I/R injury group. In addition, PEMF treatment also reduced the apoptosis of myocardial cells by up-regulating the expression of anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and down-regulating the expression of pro-apoptosis protein (Bax). In vitro, the results showed that PEMF treatment could significantly reduce the apoptosis and reactive oxygen species (ROS) levels in primary neonatal rat cardiac ventricular myocytes (NRCMs) induced by hypoxia/reoxygenation (H/R). In particular, PEMF increased the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS), which might be closely related to attenuated cell apoptosis by increasing the releasing of nitric oxide (NO). Therefore, our data indicated that PEMF could be a potential candidate for I/R injury. PMID- 27780893 TI - Work Site-Based Environmental Interventions to Reduce Sedentary Behavior: A Systematic Review. AB - OBJECTIVE: The purpose of this investigation was to systematically review work site-based, environmental interventions to reduce sedentary behavior following preferred reporting items for systematic reviews and meta-analyses guidelines. DATA SOURCE: Data were extracted from Medical Literature Analysis and Retrieval System Online, Cochrane Central Register of Controlled Trials, and Web of Science between January 2005 and December 2015. STUDY INCLUSION AND EXCLUSION CRITERIA: Inclusion criteria were work site interventions, published in peer-reviewed journals, employing environmental modalities, targeting sedentary behavior, and using any quantitative design. Exclusion criteria were noninterventions and non English publications. DATA EXTRACTION: Data extracted included study design, population, intervention dosage, intervention activities, evaluation measures, and intervention effects. DATA SYNTHESIS: Data were tabulated quantitatively and synthesized qualitatively. RESULTS: A total of 15 articles were identified for review and 14 reported statistically significant decreases in sedentary behavior. The majority of studies employed a randomized controlled trial design (n = 7), used inclinometers to measure sedentary behavior (n = 9), recruited predominantly female samples (n = 15), and utilized sit-to-stand desks as the primary intervention modality (n = 10). The mean methodological quality score was 6.2 out of 10. CONCLUSION: Environmental work site interventions to reduce sedentary behavior show promise because work sites often have more control over environmental factors. Limitations of this intervention stream include inconsistent measurement of sedentary behavior, absence of theoretical frameworks to guide program development, and absence of long-term evaluation. Future studies should include clear reporting of intervention strategies and explicit operationalization of theoretical constructs. PMID- 27780891 TI - SIN1 promotes the proliferation and migration of breast cancer cells by Akt activation. AB - Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential TORC2 component and a key regulator of Akt pathway that plays an important role in various pathological conditions including cancer. Whereas its functional role in breast cancer has not been well characterized. In the present study, SIN1 is associated with the progression and survival of breast cancer patients, as well as human breast cancer cell proliferation and migration. SIN1 mRNA level was significantly up-regulated in human breast cancer samples compared with their corresponding paracancerous histological normal tissues. Furthermore, the expression levels of SIN1 were also increased in three human breast cancer cell lines compared with human breast epithelial cell MCF10A. Overexpression of SIN1 promoted cell proliferation, colony formation and migration of breast cancer cells. Knockdown of SIN1 in MDA-MB-468 cells inhibited cell proliferation, colony formation and migration. In addition, SIN1 overexpression increased phosphorylation of Akt and knockdown of SIN1 inhibited phosphorylation of Akt in MDA-MB-468 cells. In a tumour xenograft model, overexpression of SIN1 promoted tumour growth of MDA-MB-468 cells in vivo, whereas SIN1 knockdown inhibits the tumour growth. Taken together, our results reveal that SIN1 plays an important role in breast cancer and SIN1 is a potential biomarker and a promising target in the treatment of breast cancer. PMID- 27780894 TI - Differences in Cardiovascular Disease Risk Factors and Health Behaviors Between Black and Non-Black Students Participating in a School-Based Health Promotion Program. AB - PURPOSE: To compare cardiovascular disease (CVD) risk factors of black and non black children participating in Project Healthy Schools (PHS), a school-based wellness program. DESIGN: Participants were surveyed and participated in physiological screenings pre- and post-PHS intervention. SETTING: Middle schools in 4 Michigan communities of varying socioeconomic status. PARTICIPANTS: A total of 3813 sixth-grade students comprised the survey sample, and 2297 sixth-grade students comprised the screening sample. INTERVENTION: Project Healthy Schools is a school-based intervention designed to reduce the risk of obesity and CVD in children through the promotion of healthy eating and physical activity. MEASURES: Physical examination, blood test, and self-reported survey data on dietary habits, physical activity, and sedentary behaviors were collected pre- and post PHS. ANALYSIS: Paired and independent t tests were used for physiologic variables. Wilcoxon sign-rank and rank-sum tests were used for survey variables. RESULTS: At baseline, blacks had a higher percentage of overweight/obese students (43% vs 34%; P < .0001) and demonstrated poorer health habits than non-blacks; however, non-blacks had poorer lipid profiles. At follow-up (post-PHS intervention), both groups demonstrated significant improvements in physiological measures and health behaviors. CONCLUSION: Despite disparities between the groups at both baseline and follow-up, changes seen post-PHS intervention were beneficial in both groups. These results suggest that early intervention for risk factor modification is possible and may be of great importance in the prevention of CVD, particularly in high-risk groups. PMID- 27780892 TI - Diabetes negatively affects cortical and striatal GABAergic neurons: an effect that is partially counteracted by exendin-4. AB - Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional gamma-aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R). We determined the effect of T2D on cortical and striatal GABAergic neurons positive for glutamic acid decarboxylase-67 (GAD67), calbindin (CB), parvalbumin (PV) and calretinin (CR) by using immunohistochemistry and quantitative microscopy. Young and middle-aged T2D Goto Kakizaki (GK) (a model of spontaneous T2D) and Wistar rats were used. Furthermore, we determined the therapeutic potential of the GLP1-R agonist exendin-4 (Ex-4) by treating middle-aged GK rats for 6 weeks with 0.1 MUg/kg Ex-4 twice daily. We show that T2D reduced the density of GAD67-positive neurons in the striatum and of CB-positive neurons in both striatum and neocortex. T2D also increased the average volume of PV-positive interneurons in the striatum. Ex-4 treatment increased the density of CB-positive neurons in the striatum of GK rats. Our data demonstrate that T2D negatively affects GAD67 and CB-positive GABAergic neurons in the brain during aging, potentially identifying some of the pathophysiological mechanisms to explain the increased prevalence of neurological complications in T2D. We also show a specific, positive effect of Ex-4 on striatal CB-positive neurons, which could be exploited in therapeutic perspective. PMID- 27780895 TI - Utilizing Lung Cancer Risk Prediction Models to Promote Smoking Cessation: Two Randomized Controlled Trials. AB - PURPOSE: The current project sought to examine whether delivery of lung cancer risk projections (calculated using the Liverpool Lung Project [LLP] risk model) predicted follow-up smoking status. DESIGN: Two single-blinded randomized controlled trials. SETTING: Stop Smoking Services in Liverpool (United Kingdom). PARTICIPANTS: Baseline current smokers (N = 297) and baseline recent former smokers (N = 216) were recruited. INTERVENTION: Participants allocated to intervention groups were provided with personalized lung cancer risk projections, calculated using the LLP risk model. MEASURES: Baseline and follow-up questionnaires explored sociodemographics, smoking behavior, and lung cancer risk perceptions. ANALYSIS: Bivariate analyses identified significant differences between randomization groups, and logistic regression models were developed to investigate the intervention effect on the outcome variables. RESULTS: Lung cancer risk projections were not found to predict follow-up smoking status in the trial of baseline current smokers; however, they did predict follow-up smoking status in the trial of baseline recent former smokers (odds ratio: 1.91; 95% confidence interval: 1.03-3.55). CONCLUSION: The current study suggests that lung cancer risk projections may help maintain abstinence among individuals who have quit smoking, but the results did not provide evidence to suggest that lung cancer risk projections motivate current smokers to quit. PMID- 27780897 TI - Effect of high rate rTMS on somatosensory evoked potential in migraine. AB - Background Sensitization and impaired habituation of cortical neurons have been reported in migraineurs. Repetitive transcranial magnetic stimulation (rTMS) may change these phenomena and be the basis of therapeutic response. We report the effect of 10 Hz rTMS on sensitization and habituation of median somatosensory evoked potential (SEP) in migraineurs, and correlate these changes with clinical response. Methods Migraineurs having four or more episodes of headache per month were included and their clinical details were noted. Three sessions of 10 Hz rTMS, 600 pulses in 412.4 seconds were delivered on the left frontal cortex corresponding to the hot spot of right abductor digiti minimi, on alternate days. Median SEP was done before and 30 minutes after the third rTMS session. Sensitization (block I N20 amplitude) and impaired habituation (if N20 amplitude of block 2 or 3 were not suppressed compared to block I) were noted. The reduction in frequency and severity of headache in the next month were noted and correlated with SEP changes. Results Ninety-four migraineurs were included; 56 received true rTMS and 38 sham stimulation. Following stimulation, reduction in N20 amplitude of block 1 correlated with a reduction in frequency and severity of headache at one month. The impaired habituation significantly improved in the true rTMS group compared to sham stimulation, and correlated with a reduction in the severity of headache but not with frequency. Conclusion In migraineurs, 10 Hz rTMS improves habituation and may be the biological basis of headache relief. PMID- 27780898 TI - American health care paradox-high spending on health care and poor health. AB - Background: For decades, US taxpayers have been lamenting the high cost of health care. Since the mid-1980s, Americans have had double-digit spending on health care. Despite this investment, Americans are less healthy than their European and Scandinavian counterparts across an array of health measures. Aim: We sought to explore how inadequate attention to the social, behavioral and environmental determinants of health may contribute to the American health care paradox of high health care spending and poor health outcomes. Design: Mixed methods. Methods: We report previous findings related from a 10-year analysis of national-level health and social service spending and health outcome data from the Organization of Economic and Cooperation and Development (OECD). We also put forth case studies representing different socioeconomic strata to illustrate the relationship between health care and social service spending and health. Results: Although the US spending more of its GDP on health care than any other country, it is not a high spender when one sums spending on both health care and social services. The U.S. however has the lowest ratio of our social service spending to health care spending in the OECD, and countries with lower ratios on average have worse health outcomes. Cases from diverse socioeconomic strata demonstrate how limited attention to the social determinants of health can result in extremely high health care costs and poor health outcomes. Conclusions: Greater investment in addressing the social, behavioral and environmental determinants of health may foster better health without accelerating health care costs in America. PMID- 27780896 TI - An E3 Ligase Affects the NLR Receptor Stability and Immunity to Powdery Mildew. AB - Following the detection of pathogen cognate effectors, plant Nod-like receptors (NLRs) trigger isolate-specific immunity that is generally associated with cell death. The regulation of NLR stability is important to ensure effective immunity. In barley (Hordeum vulgare), the allelic Mildew locus A (MLA) receptors mediate isolate-specific disease resistance against powdery mildew fungus (Blumeria graminis f. sp. hordei). Currently, how MLA stability is controlled remains unknown. Here, we identified an MLA-interacting RING-type E3 ligase, MIR1, that interacts with several MLAs. We showed that the carboxyl-terminal TPR domain of MIR1 mediates the interaction with the coiled-coil domain-containing region of functional MLAs, such as MLA1, MLA6, and MLA10, but not with that of the nonfunctional MLA18-1. MIR1 can ubiquitinate the amino-terminal region of MLAs in vitro and promotes the proteasomal degradation of MLAs in vitro and in planta. Both proteasome inhibitor treatment and virus-induced gene silencing-mediated MIR1 silencing significantly increased MLA abundance in barley transgenic lines. Furthermore, overexpression of MIR1 specifically compromised MLA-mediated disease resistance in barley, while coexpression of MIR1 and MLA10 attenuated MLA10 induced cell death signaling in Nicotiana benthamiana Together, our data reveal a mechanism for the control of the stability of MLA immune receptors and for the attenuation of MLA-triggered defense signaling by a RING-type E3 ligase via the ubiquitin proteasome system. PMID- 27780899 TI - Displayed Trees Do Not Determine Distinguishability Under the Network Multispecies Coalescent. AB - Recent work in estimating species relationships from gene trees has included inferring networks assuming that past hybridization has occurred between species. Probabilistic models using the multispecies coalescent can be used in this framework for likelihood-based inference of both network topologies and parameters, including branch lengths and hybridization parameters. A difficulty for such methods is that it is not always clear whether, or to what extent, networks are identifiable-that is whether there could be two distinct networks that lead to the same distribution of gene trees. For cases in which incomplete lineage sorting occurs in addition to hybridization, we demonstrate a new representation of the species network likelihood that expresses the probability distribution of the gene tree topologies as a linear combination of gene tree distributions given a set of species trees. This representation makes it clear that in some cases in which two distinct networks give the same distribution of gene trees when sampling one allele per species, the two networks can be distinguished theoretically when multiple individuals are sampled per species. This result means that network identifiability is not only a function of the trees displayed by the networks but also depends on allele sampling within species. We additionally give an example in which two networks that display exactly the same trees can be distinguished from their gene trees even when there is only one lineage sampled per species. [gene tree, hybridization, identifiability, maximum likelihood, species tree, phylogeny.]. PMID- 27780900 TI - Periodontal lesions in slaughtered cattle in the west of Scotland. PMID- 27780901 TI - Fentanyl and methadone used as adjuncts to bupivacaine for lumbosacral epidural analgesia in sheep. AB - Six healthy, female, mixed-breed 18-24-month-old sheep weighing 30-48 kg were submitted to lumbosacral epidural bupivacaine in combination with either methadone or fentanyl. Epidural catheters were placed in six sheep that were given three treatments: (Bup) bupivacaine (0.5 mg/kg) alone; (BupMet) bupivacaine (0.25 mg/kg) plus methadone (0.3 mg/kg); and (BupFent) bupivacaine (0.25 mg/kg) plus fentanyl (0.002 mg/kg). Haemodynamic variables, respiratory rate, rectal temperature, analgesia by applying a standard painful stimulus, motor block and sedative scores were compared among the three treatments. These parameters were determined before epidural administration and at 5, 10, 20, 30, 60, 90, 120 minutes after treatment administration, and then every 60 minutes thereafter until the end of analgesic effect. Parametrical data were analysed by proc glimmix (SAS) for repeated measures on time and means tested by ls-means. Non parametrical data were analysed by Fisher's exact test. Duration of analgesia was longer with BupMet (240 minutes) compared with BupFent (180 minutes; P=0.0127), but BupMet was similar to Bup (240 minutes). Both treatments with opioids produced moderate motor blockade. BupMet and BupFent produced mild sedation. Only treatment with bupivacaine alone induced cardiovascular and respiratory rate changes that stayed within acceptable limits. PMID- 27780902 TI - Cavitary lung cancer with cartilage tissues in the wall mimicking aspergilloma. PMID- 27780903 TI - Histopathologic Analysis of Retrieved Thrombi Associated With Successful Reperfusion After Acute Stroke Thrombectomy. AB - BACKGROUND AND PURPOSE: Histopathologic evaluation of occlusive thrombi retrieved from cerebral arteries using endovascular therapy is possible. We investigated the relationship between successful reperfusion after thrombectomy and histopathologic characteristics of retrieved thrombi. METHODS: Among consecutive patients with acute ischemic stroke treated with endovascular therapy at our institute from December 2010 to July 2015, we retrospectively reviewed those with acute major arterial occlusion from which retrieved thrombi were evaluated histopathologically. Obtained thrombi were assessed for the existence of atheromatous gruel, organization, and the ratios of erythrocyte and fibrin/platelet components. Successful reperfusion was defined as the modified Treatment in Cerebral Ischemia grade of 2b to 3. RESULTS: Of 83 patients studied, 58 (70%) underwent successful reperfusion. Atheromatous gruel was less frequently identified (3% versus 20%; P=0.024), and the proportion of erythrocyte components was higher (57+/-23% versus 47+/-24%; P=0.042) in thrombi retrieved from the reperfused than the unreperfused group. On multivariate logistic regression analysis, atheromatous gruel was inversely related (odds ratio, 0.062; 95% confidence interval, 0.002-0.864), and >64% erythrocyte components (cutoff obtained from receiver operating characteristic curve) were positively related (odds ratio, 4.352; 95% confidence interval, 1.185-19.363) to successful reperfusion. CONCLUSIONS: Successful reperfusion could be associated with the histopathology of occlusive thrombi, including the existence of atheromatous gruel and proportion of erythrocyte components. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02251665. PMID- 27780905 TI - Using Administrative Data to Explore the Effect of Survey Nonresponse in the UK Employment Retention and Advancement Demonstration. AB - BACKGROUND: Even a well-designed randomized control trial (RCT) study can produce ambiguous results. This article highlights a case in which full-sample results from a large-scale RCT in the United Kingdom differ from results for a subsample of survey respondents. OBJECTIVES: Our objective is to ascertain the source of the discrepancy in inferences across data sources and, in doing so, to highlight important threats to the reliability of the causal conclusions derived from even the strongest research designs. RESEARCH DESIGN: The study analyzes administrative data to shed light on the source of the differences between the estimates. We explore the extent to which heterogeneous treatment impacts and survey nonresponse might explain these differences. We suggest checks which assess the external validity of survey measured impacts, which in turn provides an opportunity to test the effectiveness of different weighting schemes to remove bias. The subjects included 6,787 individuals who participated in a large-scale social policy experiment. RESULTS: Our results were not definitive but suggest nonresponse bias is the main source of the inconsistent findings. CONCLUSIONS: The results caution against overconfidence in drawing conclusions from RCTs and highlight the need for great care to be taken in data collection and analysis. Particularly, given the modest size of impacts expected in most RCTs, small discrepancies in data sources can alter the results. Survey data remain important as a source of information on outcomes not recorded in administrative data. However, linking survey and administrative data is strongly recommended where possible. PMID- 27780906 TI - Synthesizing Evidence in Public Policy Contexts: The Challenge of Synthesis When There Are Only a Few Studies. AB - For a variety of reasons, researchers and evidence-based clearinghouses synthesizing the results of multiple studies often have very few studies that are eligible for any given research question. This situation is less than optimal for meta-analysis as it is usually practiced, that is, by employing inverse variance weights, which allows more informative studies to contribute relatively more to the analysis. This article outlines the choices available for synthesis when there are few studies to synthesize. As background, we review the synthesis practices used in several projects done at the behest of governmental agencies and private foundations. We then discuss the strengths and limitations of different approaches to meta-analysis in a limited information environment. Using examples from the U.S. Department of Education's What Works Clearinghouse as case studies, we conclude with a discussion of Bayesian meta-analysis as a potential solution to the challenges encountered when attempting to draw inferences about the effectiveness of interventions from a small number of studies. PMID- 27780907 TI - Design and Analysis Considerations for Cluster Randomized Controlled Trials That Have a Small Number of Clusters. AB - BACKGROUND: Cluster randomized controlled trials (CRCTs) often require a large number of clusters in order to detect small effects with high probability. However, there are contexts where it may be possible to design a CRCT with a much smaller number of clusters (10 or fewer) and still detect meaningful effects. OBJECTIVES: The objective is to offer recommendations for best practices in design and analysis for small CRCTs. RESEARCH DESIGN: I use simulations to examine alternative design and analysis approaches. Specifically, I examine (1) which analytic approaches control Type I errors at the desired rate, (2) which design and analytic approaches yield the most power, (3) what is the design effect of spurious correlations, and (4) examples of specific scenarios under which impacts of different sizes can be detected with high probability. RESULTS/CONCLUSIONS: I find that (1) mixed effects modeling and using Ordinary Least Squares (OLS) on data aggregated to the cluster level both control the Type I error rate, (2) randomization within blocks is always recommended, but how best to account for blocking through covariate adjustment depends on whether the precision gains offset the degrees of freedom loss, (3) power calculations can be accurate when design effects from small sample, spurious correlations are taken into account, and (4) it is very difficult to detect small effects with just four clusters, but with six or more clusters, there are realistic circumstances under which small effects can be detected with high probability. PMID- 27780904 TI - The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. AB - The cortical angioarchitecture is a key factor in controlling cerebral blood flow and oxygen metabolism. Difficulties in imaging the complex microanatomy of the cortex have so far restricted insight about blood flow distribution in the microcirculation. A new methodology combining advanced microscopy data with large scale hemodynamic simulations enabled us to quantify the effect of the angioarchitecture on the cerebral microcirculation. High-resolution images of the mouse primary somatosensory cortex were input into with a comprehensive computational model of cerebral perfusion and oxygen supply ranging from the pial vessels to individual brain cells. Simulations of blood flow, hematocrit and oxygen tension show that the wide variation of hemodynamic states in the tortuous, randomly organized capillary bed is responsible for relatively uniform cortical tissue perfusion and oxygenation. Computational analysis of microcirculatory blood flow and pressure drops further indicates that the capillary bed, including capillaries adjacent to feeding arterioles (d < 10 um), are the largest contributors to hydraulic resistance. PMID- 27780908 TI - Measuring Oxidative DNA Damage With 8-Hydroxy-2'-Deoxyguanosine Levels in Patients With Laryngeal Cancer. AB - OBJECTIVES: 8-Hydroxy-2'-deoxyguanosine is a biomolecule associated with DNA damage. We evaluated oxidative stress and DNA damage in patients with laryngeal cancer by measuring 8-hydroxy-2'-deoxyguanosine levels. METHODS: This study enrolled 117 subjects, including 64 controls and 53 patients who had benign vocal cord lesions or laryngeal cancer. The benign excised lesions, tumor tissue, noncancerous laryngeal tissue, blood, and urine were subjected to high performance liquid chromatography, and 8-hydroxy-2'-deoxyguanosine levels were compared between groups. RESULTS: Blood and urine 8-hydroxy-2'-deoxyguanosine levels in patients with laryngeal carcinoma were significantly higher than in the controls ( P = .00002, P = .00001). The 8-hydroxy-2'-deoxyguanosine level was significantly higher in tumor tissues than in non-tumor tissue and benign vocal cord lesion tissues ( P = .00002, P = .000001). CONCLUSIONS: We determined that laryngeal cancer was associated with oxidative stress, which may be quantified by measuring 8-hydroxy-2'-deoxyguanosine. For a patient with a suspicious laryngeal lesion, 8-hydroxy-2'-deoxyguanosine levels in blood and urine can provide advance information about the likely diagnosis. PMID- 27780909 TI - Benign Paroxysmal Positional Vertigo Secondary to Mild Head Trauma. AB - OBJECTIVES: We studied the clinical characteristics, nystagmographic findings, and treatment outcome of a group of patients with benign paroxysmal positional vertigo (BPPV) secondary to mild head trauma and compared them with a group of patients with idiopathic BPPV. METHODS: The medical records of 33 patients with BPPV associated with mild head trauma were reviewed. Data of a complete otolaryngological, audiological, neurotologic, and imaging evaluation were available for all patients. Three hundred and twenty patients with idiopathic BPPV were used as a control group. RESULTS: The patients with BPPV secondary to mild head trauma presented the following features, in which they differed from the patients with idiopathic BPPV: (1) lower mean age, with more intense symptoms; (2) increased rate of horizontal and anterior semicircular canal involvement and frequent multiple canal and bilateral involvement; (3) greater incidence of canal paresis and presence of spontaneous nystagmus; (4) poorer treatment results, attributed mainly to coexisting canal paresis in many patients, and higher rate of recurrence. CONCLUSIONS: Benign paroxysmal positional vertigo associated with mild head trauma differs from idiopathic BPPV in terms of several epidemiological and clinical features; it responds less effectively to treatment and is prone to recurrence. PMID- 27780910 TI - Radiological and NRT-Ratio-Based Estimation of Slim Straight Cochlear Implant Electrode Positions: A Multicenter Study. AB - OBJECTIVES: An intraoperative neural response telemetry-ratio (NRT-ratio) was established, which can provide information about the intraoperative intracochlear electrode array position for perimodiolar electrodes. METHODS: In a retrospective controlled study in 2 tertiary referral centers, the electrophysiological data sets of 50 patients with measured intraoperative auto-NRTs and postoperative radiological examinations were evaluated. All patients were implanted with Nucleus slim straight electrodes. The NRT-ratio was calculated by dividing the average auto-NRT data from electrodes 16 to 18 with the average from electrodes 5 to 7. Using a flat panel tomography system or a computed tomography, the position of the electrode array was certified radiological. RESULTS: Radiologically, 2 out of 50 patients were identified with an electrode translocated from the scala tympani into the scala vestibuli. The radiologically estimated electrodes indicating a scalar change showed a regular NRT-ratio but nonspecific NRT-level changes at the localization of translocation. PMID- 27780911 TI - False Vocal Fold Characteristics in Presbylarynges and Recurrent Laryngeal Neuropathy. AB - OBJECTIVE: Conflicting data exist regarding false vocal fold (FVF) anatomy; it is unclear if this structure is an extension of the thyroarytenoid muscle or an independent muscle system. This confusion is amplified by diverse clinical findings in the setting of unilateral recurrent laryngeal neuropathy and presbylarynges. We sought to characterize FVF behavior in these contexts. METHODS: Laryngoscopic/stroboscopic examinations from 11 patients with unilateral recurrent laryngeal nerve paresis and 12 patients with presbylarynges were reviewed by 4 laryngologists, blinded to the goal of the study but informed of diagnosis. Variables related to FVF structure and function at rest and during phonation were rated. RESULTS: In recurrent laryngeal neuropathy, no significant association between atrophic/paretic vocal fold (VF) and FVF size was observed at rest (P = .69). During phonation, FVF compression was noted bilaterally; contralateral FVF hypertrophy was more common (P = .002). In presbylarynges, neither FVF size at rest (P = .86) nor compression during phonation (P = .37) was associated with the more atrophic VF; FVF compression/hypertrophy was common. CONCLUSIONS: Consistent with clinical dogma, FVF compression was more common contralateral to VF neuropathy. This finding, however, was inconsistent and may suggest individual variability in FVF innervation and/or morphology. Intra- and interrater reliability of these clinical findings was poor. PMID- 27780912 TI - Improved treatment satisfaction after switching therapy to rituximab in relapsing remitting MS. AB - OBJECTIVE: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab. METHOD: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period. RESULTS: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression. CONCLUSION: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy. PMID- 27780913 TI - Hippocampal microstructural damage correlates with memory impairment in clinically isolated syndrome suggestive of multiple sclerosis. AB - OBJECTIVE: We investigated whether diffusion tensor imaging (DTI) could reveal early hippocampal damage and clinically relevant correlates of memory impairment in persons with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). METHODS: A total of 37 persons with CIS, 32 with MS and 36 controls prospectively included from 2011 to 2014 were tested for cognitive performances and scanned with 3T-magnetic resonance imaging (MRI) to assess volumetric and DTI changes within the hippocampus, whole brain volume and T2 lesion load. RESULTS: While there was no hippocampal atrophy in the CIS group, hippocampal fractional anisotropy (FA) was significantly decreased compared to controls. Decrease in hippocampal FA together with increased mean diffusivity (MD) was even more prominent in MS patients. In CIS, hippocampal MD was correlated with episodic verbal memory performance ( r = -0.57, p = 0.0002 and odds ratio (OR) = 0.058, 95% confidence interval (CI) = 0.0057-0.59, p = 0.016 adjusted for age, gender, depression and T2-lesion load), but not with cognitive tasks unrelated to hippocampal functions. Hippocampal MD was the only variable discriminating memory-impaired from memory-preserved persons with CIS (area under the curve (AUC) = 0.77, sensitivity = 90.0%, specificity = 70.3%, positive predictive value (PPV) = 52.9%, negative predictive value (NPV) = 95.0%). CONCLUSION: DTI alterations within the hippocampus might reflect early neurodegenerative processes that are correlated with episodic memory performance, discriminating persons with CIS according to their memory status. PMID- 27780914 TI - Excellence in Development of Health Care Providers: The Nicaragua Clinical Experience. AB - INTRODUCTION: According to the U.S. Census Bureau, 17% of the U.S. population is Latino, with an expected increase to 31% by 2060. It is imperative that we prepare students who will be future health care providers with the resources needed to care for the Latino population, specifically increasing the number of Spanish-speaking health care providers who have some understanding of the Latino culture. There is a lack of health care providers who are educated about the Latino culture and lack mentorship in the development of medical conversational Spanish. METHOD: The Nicaragua Clinical Experience is a service learning abroad program embedded in an academic setting through the scholarship of cultural immersion, language development, health care, and leadership development of students. CONCLUSION: The Nicaragua Clinical Experience is a unique academic program that prepares pre-health care majors to provide culturally congruent health care for the Latino population. CLINICAL IMPLICATIONS: Students are prepared to care for Latino patients through the cultural immersion program and are also introduced to working in "team-based care" multidisciplinary groups to improve health care outcomes. PMID- 27780915 TI - Efficacy of glycogen synthase kinase-3beta targeting against osteosarcoma via activation of beta-catenin. AB - Development of innovative more effective therapy is required for refractory osteosarcoma patients. We previously established that glycogen synthase kinase 3beta (GSK- 3beta) is a therapeutic target in various cancer types. In the present study, we explored the therapeutic efficacy of GSK-3beta inhibition against osteosarcoma and the underlying molecular mechanisms in an orthotopic mouse model. Expression and phosphorylation of GSK-3beta in osteosarcoma and normal osteoblast cell lines was examined, together with efficacy of GSK-3beta inhibition on cell survival, proliferation and apoptosis and on the growth of orthotopically-transplanted human osteosarcoma in nude mice. We also investigated changes in expression, phosphorylation and co-transcriptional activity of beta catenin in osteosarcoma cells following GSK-3beta inhibition. Expression of the active form of GSK- 3beta (tyrosine 216-phosphorylated) was higher in osteosarcoma than osteoblast cells. Inhibition of GSK-3beta activity by pharmacological inhibitors or of its expression by RNA interference suppressed proliferation of osteosarcoma cells and induced apoptosis. Treatment with GSK 3beta-specific inhibitors attenuated the growth of orthotopic osteosaroma in mice. Inhibition of GSK-3beta reduced phosphorylation at GSK- 3beta-phospho acceptor sites in beta-catenin and increased beta-catenin expression, nuclear localization and co-transcriptional activity. These results suggest the efficacy of GSK-3beta inhibitors is associated with activation of beta-catenin, a putative tumor suppressor in bone and soft tissue sarcoma and an important component of osteogenesis. Our study thereby demonstrates a critical role for GSK-3beta in sustaining survival and proliferation of osteosarcoma cells, and identifies this kinase as a potential therapeutic target against osteosarcoma. PMID- 27780916 TI - Efficient generation of antigen-specific CTLs by the BAFF-activated human B Lymphocytes as APCs: a novel approach for immunotherapy. AB - Efficient antigen presentation is indispensable for cytotoxic T lymphocyte (CTL) mediated immunotherapy. B-lymphocytes propagated with CD40L have been developed as antigen-presenting cells (APCs), but this capacity needs further optimization. Here, we aimed to expand human B-lymphocytes on a large scale while maintaining their antigen-presenting ability by using both CD40L and B-cell activating factor (BAFF). The addition of BAFF enhanced the expansion efficiency and prolonged the culture time without causing apoptosis of the expanded B-cells. This method thus provided an almost unlimited source of cellular adjuvant to achieve sufficient expansion of CTLs in cases where several rounds of stimulation are required. We also showed that the addition of BAFF significantly enhanced the expression of major costimulatory molecules, CD80 and CD86. Subsequently, the antigen presenting ability of the B-lymphocytes also increased. Consequently, these B lymphocytes showed robust CTL responses to inhibit tumor growth after tumor specific peptide pulses. A similar method induced potent antigen-specific CTL responses, which effectively eradicated human immunodeficiency virus type 1 (HIV 1) latency in CD4 T-lymphocytes isolated from patients receiving suppressive anti retroviral therapy (ART). Together, our findings indicate that potent antigen specific CTLs can be generated using BAFF-activated B-lymphocytes as APCs ex vivo. This approach can be applied for CTL-mediated immunotherapy in patients with cancers or chronic viral infections. PMID- 27780917 TI - The somite-secreted factor Maeg promotes zebrafish embryonic angiogenesis. AB - MAM and EGF containing gene (MAEG), also called Epidermal Growth Factor-like domain multiple 6 (EGFL6), belongs to the epidermal growth factor repeat superfamily. The role of Maeg in zebrafish angiogenesis remains unclear. It was demonstrated that maeg was dynamically expressed in zebrafish developing somite during a time window encompassing many key steps in embryonic angiogenesis. Maeg loss-of-function embryos showed reduced endothelial cell number and filopodia extensions of intersegmental vessels (ISVs). Maeg gain-of-function induced ectopic sprouting evolving into a hyperbranched and functional perfused vasculature. Mechanistically we demonstrate that Maeg promotes angiogenesis dependent on RGD domain and stimulates activation of Akt and Erk signaling in vivo. Loss of Maeg or Itgb1, augmented expression of Notch receptors, and inhibiting Notch signaling or Dll4 partially rescued angiogenic phenotypes suggesting that Notch acts downstream of Itgb1. We conclude that Maeg acts as a positive regulator of angiogenic cell behavior and formation of functional vessels. PMID- 27780918 TI - MicroRNA-3196 is inhibited by H2AX phosphorylation and attenuates lung cancer cell apoptosis by downregulating PUMA. AB - Histone H2AX is a tumor suppressor protein that plays an important role in apoptosis. However, the mechanism underlying the association of H2AX with apoptosis in cancer cells remains elusive. Here, we showed that H2AX knockdown in lung cancer A549 cells affected the expression of 16 microRNAs (miRNAs), resulting in the downregulation of 1 and the upregulation of 15 miRNAs. MicroRNA 3196 (miR-3196) was identified as a target of H2AX and shown to inhibit apoptosis in lung cancer cells by targeting p53 upregulated modulator of apoptosis (PUMA). Phosphorylated H2AX (gammaH2AX) was shown to bind to the promoter of miR-3196 and regulate its expression. In addition, H2AX phosphorylation increased H3K27 trimethylation in the promoter region of miR-3196 and inhibited the binding of RNA polymerase II to the promoter of miR-3196, leading to the inhibition of miR 3196 transcription. Taken together, these results indicated that H2AX phosphorylation regulates apoptosis in lung cancer cells via the miR-3196/PUMA pathway. PMID- 27780919 TI - MCM10 overexpression implicates adverse prognosis in urothelial carcinoma. AB - Urothelial carcinoma (UC) occurs in the upper urinary tract (UTUC) and the urinary bladder (UBUC). The molecular pathogenesis of UC has not been fully elucidated. Through data mining of a published transcriptome of UBUC (GSE31684), we identified Minichromosome Maintenance Complex Component 2 (MCM2) and MCM10 as the two most significantly upregulated genes in UC progression among the MCM gene family, the key factors for the initiation of DNA replication. To validate the clinical significance of MCM2 and MCM10, immunohistochemistry, evaluated by H score, was used in a pilot study of 50 UTUC and 50 UBUC samples. Only a high expression level of MCM10 predicted worse disease-specific survival (DSS) and inferior metastasis-free survival (MeFS) for both UTUC and UBUC. Correspondingly, evaluation of MCM10 mRNA expression in 36 UTUCs and 30 UBUCs showed significantly upregulated levels in high stage UC, suggesting its role in tumor progression. Evaluation of 340 UTUC and 296 UBUC tissue samples, respectively, demonstrated that high MCM10 immunoexpression was significantly associated with advanced primary tumors, nodal status, and the presence of vascular invasion in both groups of UCs. In multivariate Cox regression analyses, adjusted for standard clinicopathological features, MCM10 overexpression was independently associated with DSS (UTUC hazard ratio [HR]=2.401, P = 0.013; UBUC HR=4.323, P=0.001) and with MeFS (UTUC HR=3.294, P<0.001; UBUC HR=1.972, P=0.015). In vitro, knockdown of MCM10 gene significantly suppressed cell proliferation in both J82 and TCCSUP cells. In conclusion, MCM10 overexpression was associated with unfavorable clinicopathological characteristics and independent negative prognostic effects, justifying its potential theranostic value in UC. PMID- 27780920 TI - Prognostic value of plasma levels of HIF-1a and PGC-1a in breast cancer. AB - Cellular adaptive mechanisms are crucial for tumorigenesis and a common feature in solid tumor progression. Hypoxia-inducible factor-1alpha (HIF-1alpha) facilitates the biological response to hypoxia, advancing angiogenesis and metastatic potential of the tumor. The peroxisome proliferator-activated receptor gamma coactivators 1alpha (PGC-1alpha) enhances mitochondrial biogenesis, favored by migratory/invasive cancer cells. We conducted a prospective, long-term follow up study to determine whether HIF-1alpha and PGC-1alpha can be implemented as predictive biomarker in breast cancer. HIF-1alpha and PGC-1alpha plasma concentrations were measured in patients and in healthy controls by enzyme linked immune sorbent assay. Breast cancer patients had significantly higher HIF-1alpha and PGC-1alpha levels, which correlated with clinicopathological features, overall with more aggressive cancer characteristics. Disease free and overall survival of breast cancer patients with high HIF-1alpha and PGC-1alpha were significantly poorer than in patients with low plasma levels. In multivariate analysis, high amount of PGC-1alpha showed independent prognostic value. Our data suggests that HIF-1alpha and PGC-1alpha may be promising, noninvasive, biomarkers with a high potential for future clinical implication to identify subgroups of patients with poorer prognosis and to indicate early, subclinical metastasis. PMID- 27780921 TI - Serum carboxypeptidaseA4 levels predict liver metastasis in colorectal carcinoma. AB - Hepatic metastasis is the most critical prognostic factor for colorectal cancer (CRC), and early detection of CRC liver metastasis can significantly improve cancer patient outcomes. In this study, we examined the levels of CPA4 in CRC samples, and assessed the potential of serum CPA4 as a biomarker for predicting CRC liver metastasis. CPA4 positivity was observed in 68.4% (130/190) colorectal cancer tissues, and significantly correlated with Depth of invasion, Lymph node metastasis, Distant metastasis and Stage. In addition, high CPA4 expression was associated with poor overall survival, and was an independent prognostic marker in patients with CRC. In CRC serum samples, serum CPA4 concentrations in CRC M1(S) patients (3717.89 +/- 375.98 pg/mL) were significantly increased as compared to in CRC-M1(H) patients (3692.12 +/- 261.51 pg/mL), CRC patients without liver metastasis (2480.47 +/- 507.90 pg/mL) or healthy controls (2183.7 +/- 621.7 pg/mL) (P < 0.05). Furthermore, high CPA4 concentration was significantly correlated with Distant metastasis, Lymph node involvement, Stage and poor overall survival of the patients with CRC. Logistic regression analysis revealed that serum CPA4 level and Lymph node metastasis were the significant parameters for predicting CRC liver metastasis. In leave-one-out-cross validation, these two markers resulted in sensitivity (90.0%) and specificity (93.8%) for hepatic metastasis detection. Moreover, this combination could correctly classify 49 cases of the 50 CRC patients with heterochronous liver metastasis in an independent test set. Therefore, our results suggest that CPA4 is closely associated with CRC liver metastasis, and serum CPA4 concentration combined with lymph node involvement may be used as accurate predictors of liver metastasis in colorectal cancer. PMID- 27780922 TI - Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI. AB - Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR-PET/CT for detecting cardiac sarcoidosis in comparison to CMR.15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUVmean) and maximum standardized uptake values (SUVmax) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up.In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUVmean and SUVmax in inflamed areas were 2.0+/-1.2 and 2.6+/ 1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8+/-0.2 and 1.9+/-0.2 for SUVmean and 2.0+/-0.3 and 1.7+/-0.3 for SUVmax, respectively.Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series. PMID- 27780923 TI - Differential role of intravenous anesthetics in colorectal cancer progression: implications for clinical application. AB - Anesthetics are unavoidable to colorectal cancer (CRC) patients who underwent surgical treatment. Thus, the molecular mechanisms underlying the role of the intravenous anesthetics in CRC metastasis are still unclear. In this study, the effects of intravenous anesthetics, such as propofol, etomidate and dexmedetomidine, on cell migration were determined. The migration of CRC cells was inhibited by propofol in vitro, but not in vivo. Etomidate, however, promoted the migration of CRC cells both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) mediated the promotive effect of propofol and etomidate on the migration of CRC cells through PI3K/AKT signaling pathway. Dexmedetomidine alone or in combination with propofol or etomidate had minor effect on the migration of CRC cells. These findings indicate that propofol inhibites CRC cell migration in vitro. Etomidate playes a role for prompting CRC metastasis progression by activating (PI3K)/AKT signaling and inducing EMT. It provides an important hint for the clinical application of these anesthetics. PMID- 27780924 TI - CDDO-Me reveals USP7 as a novel target in ovarian cancer cells. AB - Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of alpha, beta-unsaturated ketones. Molecular docking studies showed that CDDO-Me fits well in the ubiquitin carboxyl terminus-binding pocket on USP7. Given that CDDO-Me is known to be effective against ovarian cancer cells, we speculated that CDDO-Me may target USP7 in ovarian cancer cells. We demonstrated that ovarian cancer cells have higher USP7 expression than their normal counterparts. Knockdown of USP7 inhibits the proliferation of ovarian cancer cells both in vitro and in vivo. Using the cellular thermal shift assay and the drug affinity responsive target stability assay, we further demonstrated that CDDO-Me directly binds to USP7 in cells, which leads to the decrease of its substrates such as MDM2, MDMX and UHRF1. CDDO-Me suppresses ovarian cancer tumor growth in an xenograft model. In conclusion, we demonstrate that USP7 is a novel target of ovarian cancer cells; targeting USP7 may contribute to the anti-cancer effect of CDDO-Me. The development of novel USP7 selective compounds based on the CDDO-Me-scaffold warrants further investigation. PMID- 27780925 TI - Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells. AB - The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA AKT1) decreased the PKC412's cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412's lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412's cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment. PMID- 27780926 TI - Resistance of glioma cells to nutrient-deprived microenvironment can be enhanced by CD133-mediated autophagy. AB - CD133 is a pentaspan transmembrane protein that can serve as a biomarker for cancer stem cells, although its biochemical mechanism remains unclear. Here we report that CD133 expression enhances glioma cell tolerance of a nutrient deprived microenvironment. Under starvation conditions, CD133-positive cells exhibited higher survival and decreased levels of apoptosis. These changes were dependent on activation of autophagy-associated gene signaling and were impaired by the autophagic inhibitor chloroquine. Furthermore, rapamycin up-regulated the level of autophagy and inversely reduced CD133 expression. Immunofluorescence confirmed that starvation promoted release of CD133 from the plasma membrane to the cytoplasm, with CD133 also partially co-localizing with LC3 upon starvation. Additionally, CD133 partially co-localized with Beclin1, Atg5, and lysosomes, indicating that CD133 directly participates in the autophagosome membrane fusion process and ultimately undergoes lysosomal degradation. Collectively, our results demonstrate that CD133 contributes to cell survival by regulating autophagy, and that targeting CD133-linked signaling and autophagy may be useful in improving anti-cancer treatments. PMID- 27780927 TI - Meta-analysis of the correlation between selenium and incidence of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common cancer type. There is a correlation between selenium (Se) deficiency and the incidence of HCC. To clarify the effects of Se level on the risk of HCC patients, a meta-analysis was performed. A total of 9 articles published between 1994 and 2016 worldwide were selected through searching PubMed, EMBASE, web of science, Cochrane Library, Springer Link, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM), and the information were analyzed using a meta-analysis method. Heterogeneity was assessed by using the I2 index. Publication bias was evaluated by Begg's Test analysis. Pooled analysis indicated that patients with HCC had lower Se levels than the healthy controls [standardized mean difference (SMD)= -1.08, 95% confidence intercal (CI) = (-0.136, -0.08), P < 0.001]. Further subgroup analysis showed this effect to be independent of the study design, race or sample collection. In conclusion, this meta-analysis suggested an inverse correlation between Se level and the risk of HCC in humans patients. PMID- 27780928 TI - SIN3A and SIN3B differentially regulate breast cancer metastasis. AB - SIN3 corepressor complexes play important roles in both normal development and breast cancer. Mammalian cells have two paralogs of SIN3 (SIN3A and SIN3B) that are encoded by distinct genes and have unique functions in many developmental processes. However, specific roles for SIN3A and SIN3B in breast cancer progression have not been characterized. We generated stable knockdown cells of SIN3 paralogs individually and in combination using three non-overlapping shRNA. Stable knockdown of SIN3B caused a significant decrease in transwell invasion through Matrigel and decreased the number of invasive colonies when grown in a 3D extracellular matrix. Conversely, stable knockdown of SIN3A significantly increased transwell invasion and increased the number of invasive colonies. These results were corroborated in vivo in which SIN3B knockdown significantly decreased and SIN3A knockdown increased experimental lung metastases. RNA sequencing was used to identify unique targets and biological pathways that were altered upon knockdown of SIN3A compared to SIN3B. Additionally, we analyzed microarray data sets to identify correlations of SIN3A and SIN3B expression with survival in patients with breast cancer. These data sets indicated that high mRNA expression of SIN3A as well as low mRNA expression of SIN3B correlates with longer relapse free survival specifically in patients with triple negative breast cancer which corresponds with our in vitro and in vivo data. These results demonstrate key functional differences between SIN3 paralogs in regulating the process of breast cancer metastasis and suggest metastasis suppressive roles of SIN3A and metastasis promoting roles of SIN3B. PMID- 27780929 TI - KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. AB - BACKGROUND: In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. Nitrogen-containing bisphosphonates inhibit prenylation of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS expressing human NSCLC cell lines. RESULTS: We confirmed that zoledronic acid was unable to inhibit the prenylation of mutant K-Ras unlike in the case of wild type K-Ras. In case of in vitro proliferation, the KRAS-mutant human NSCLC cell lines showed resistance to zoledronic acid wild-type KRAS-cells proved to be sensitive. Combinatory application of zoledronic acid enhanced the cytostatic effect of cisplatin. Zoledronic acid did not induce significant apoptosis. In xenograft model, zoledronic acid significantly reduced the weight of wild type KRAS-EGFR expressing xenograft tumor by decreasing the proliferative capacity. Futhermore, zoledronic acid induced VEGF expression and improved in vivo tumor vascularization. MATERIALS AND METHODS: Membrane association of K-Ras was examined by Western-blot. In vitro cell viability, apoptotic cell death and migration were measured in NSCLC lines with different molecular background. The in vivo effect of zoledronic acid was investigated in a SCID mouse subcutaneous xenograft model. CONCLUSIONS: The in vitro and in vivo inhibitory effect of zoledronic acid was based on the blockade of cell cycle in wild type KRAS expressing human NSCLC cells. The zoledronic acid induced vascularization supported in vivo cytostatic effect. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy. PMID- 27780930 TI - TGF-beta signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts. AB - Activation of TGF-beta signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-beta signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-beta signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-beta and its backup partner ERK represents an attractive strategy for treating mCRPC patients. PMID- 27780931 TI - Marital status is an independent prognostic factor for tracheal cancer patients: an analysis of the SEER database. AB - BACKGROUND: Although marital status is an independent prognostic factor in many cancers, its prognostic impact on tracheal cancer has not yet been determined. The goal of this study was to examine the relationship between marital status and survival in patients with tracheal cancer. RESULTS: Compared with unmarried patients (42.67%), married patients (57.33%) had better 5-year OS (25.64% vs. 35.89%, p = 0.009) and 5-year TCSS (44.58% vs. 58.75%, p = 0.004). Results of multivariate analysis indicated that marital status is an independent prognostic factor, with married patients showing better OS (hazard ratio [HR] = 0.78, 95% confidence interval [CI] 0.64-0.95, p = 0.015) and TCSS (HR = 0.70, 95% CI 0.54 0.91, p = 0.008). In addition, subgroup analysis suggested that marital status plays a more important role in the TCSS of patients with non-low-grade malignant tumors (HR = 0.71, 95% CI 0.53-0.93, p = 0.015). METHODS: We extracted 600 cases from the Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by Pearson chi-squared test, t-test, log-rank test, and multivariate Cox regression analysis. Overall survival (OS) and tracheal cancer specific survival (TCSS) were compared between subgroups with different pathologic features and tumor stages. CONCLUSIONS: Marital status is an independent prognostic factor for survival in patients with tracheal cancer. For that reason, additional social support may be needed for unmarried patients, especially those with non-low-grade malignant tumors. PMID- 27780932 TI - Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. AB - Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil * platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (>=0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy. PMID- 27780933 TI - Ampelopsin attenuates brain aging of D-gal-induced rats through miR-34a-mediated SIRT1/mTOR signal pathway. AB - The underlying molecular mechanisms for aging-related neurodegenerative diseases such as Alzheimer's disease (AD) are not fully understood. Currently, growing evidences have revealed that microRNAs (miRNAs) are involved in aging and aging related diseases. The up-regulation of miR-34a has been reported to be associated with aging-related diseases, and thus it should be a promising therapeutic target. Ampelopsin, also called dihydromyricetin (DHM), a natural flavonoid from Chinese herb Ampelopsis grossedentata, has been reported to possess multiple pharmacological functions including anti-inflammatory, anti-oxidative and anti cancer functions. Meanwhile, it has also gained tremendous attention against neurodegenerative diseases as an anti-aging compound. In the present study, the model rats with D-gal-induced brain aging revealed an obvious expression of miR 34a; in contrast, it could be significantly suppressed upon DHM treatment. In addition, target genes associated with miR-34a in the presence of DHM treatment were also explored. DHM supplementation inhibited D-gal-induced apoptosis and rescued impaired autophagy of neurons in hippocampus tissue. Moreover, DHM activated autophagy through up-regulated SIRT1 and down-regulated mTOR signal pathways due to the down-regulated miR-34a. In conclusion, DHM can execute the prevention and treatment of D-gal-induced brain aging by miR-34a-mediated SIRT1 mTOR signal pathway. PMID- 27780934 TI - Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease. AB - Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective beta-galactosylceramidase (GALC), a lysosomal enzyme responsible for cleavage of several key substrates including psychosine. Accumulation of psychosine to the cytotoxic levels in KD patients is thought to cause dysfunctions in myelinating glial cells based on a comprehensive study of demyelination in KD. However, recent evidence suggests myelin-independent neuronal death in the murine model of KD, thus indicating defective GALC in neurons as an autonomous mechanism for neuronal cell death in KD. These observations prompted us to generate induced neurons (iNeurons) from two adult onset KD patients carrying compound heterozygous mutations (p.[K563*];[L634S]) and (p.[N228_S232delinsTP];[G286D]) to determine the direct contribution of autonomous neuronal toxicity to KD. Here we report that directly converted KD iNeurons showed not only diminished GALC activity and increased psychosine levels, as expected, but also neurite fragmentation and abnormal neuritic branching. The lysosomal-associated membrane proteins 1 (LAMP1) was expressed at higher levels than controls, LAMP1-positive vesicles were significantly enlarged and fragmented, and mitochondrial morphology and its function were altered in KD iNeurons. Strikingly, we demonstrated that psychosine was sufficient to induce neurite defects, mitochondrial fragmentation, and lysosomal alterations in iNeurons derived in healthy individuals, thus establishing the causal effect of the cytotoxic GALC substrate in KD and the autonomous neuronal toxicity in KD pathology. PMID- 27780935 TI - Incidence and physiological mechanism of carboplatin-induced electrolyte abnormality among patients with non-small cell lung cancer. AB - To clarify the association between carboplatin and electrolyte abnormality, a pooled-analysis was performed with the adverse event reports of non-small cell lung cancer patients. A total of 19901 adverse events were retrieved from the FDA Adverse Event Reporting System (FAERS). Pooled reporting odds ratios (RORs) and 95% CIs suggested that carboplatin was significantly associated with hyponatremia (pooled ROR = 1.57, 95% CI 1.18-2.09, P = 1.99*10-3) and hypokalemia (pooled ROR = 2.37, 95% CI 1.80-3.10, P = 5.24*10-10) as compared to other therapies. In addition, we found that dehydration was frequently concurrent with carboplatin therapy (pooled ROR = 2.01, 95% CI 1.52-2.66, P = 8.37*10-7), which may prompt excessive water ingestion and decrease serum electrolyte concentrations. This information has not been mentioned in the FDA-approved drug label and could help explain the physiological mechanism of carboplatin-induced electrolyte abnormality. In conclusion, the above results will facilitate clinical management and prompt intervention of life-threatening electrolyte imbalance in the course of cancer treatment. PMID- 27780937 TI - CXC chemokine receptor 1 predicts postoperative prognosis and chemotherapeutic benefits for TNM II and III resectable gastric cancer patients. AB - : Backround: Abnormal expression of CXC chemokine receptor 1 (CXCR1) has shown the ability to promote tumor angiogensis, invasion and metastasis in several cancers. The purpose of our curret study is to discover the clinical prognostic significance of CXCR1 in resectable gastric cancer. METHODS: 330 gastric cancer patients who underwent R0 gastrectomy with standard D2 lymphadenectomy at Zhongshan Hospital, Fudan University between 2007 and 2008 were enrolled. CXCR1 expression was evaluated with use of immunohistochemical staining. The relation between CXCR1 expression and clinicopathological features and postoperative prognosis was respectively inspected. RESULTS: In both discovery and validation data sets, CXCR1 high expression indicated poorer overall survival (OS) in TNM II and III patients. Furthermore, multivariate analysis identified CXCR1 expression and TNM stage as two independent prognostic factors for OS. Incorporating CXCR1 expression into current TNM staging system could generate a novel clinical predictive model for gastric cancer, showing better prognostic accuracy with respect to patients' OS. More importantly, TNM II patients with higher CXCR1 expression were shown to significantly benefit from postoperative 5-fluorouracil (5-FU) based adjuvant chemotherapy (ACT). CONCLUSION: CXCR1 in gastric cancer was identified as an independent adverse prognostic factor. Combining CXCR1 expression with current TNM staging system could lead to better risk stratification and more accurate prognosis for gastric cancer patients. High expression of CXCR1 identified a subgroup of TNM stage II gastric cancer patients who appeared to benefit from 5-FU based ACT. PMID- 27780936 TI - Low dose angiostatic treatment counteracts radiotherapy-induced tumor perfusion and enhances the anti-tumor effect. AB - The extent of tumor oxygenation is an important factor contributing to the efficacy of radiation therapy (RTx). Interestingly, several preclinical studies have shown benefit of combining RTx with drugs that inhibit tumor blood vessel growth, i.e. angiostatic therapy. Recent findings show that proper scheduling of both treatment modalities allows dose reduction of angiostatic drugs without affecting therapeutic efficacy. We found that whilst low dose sunitinib (20 mg/kg/day) did not affect the growth of xenograft HT29 colon carcinoma tumors in nude mice, the combination with either single dose RTx (1x 5Gy) or fractionated RTx (5x 2Gy/week, up to 3 weeks) substantially hampered tumor growth compared to either RTx treatment alone. To better understand the interaction between RTx and low dose angiostatic therapy, we explored the effects of RTx on tumor angiogenesis and tissue perfusion. DCE-MRI analyses revealed that fractionated RTx resulted in enhanced perfusion after two weeks of treatment. This mainly occurred in the center of the tumor and was accompanied by increased tissue viability and decreased hypoxia. These effects were accompanied by increased expression of the pro-angiogenic growth factors VEGF and PlGF. DCE-MRI and contrast enhanced ultrasonography showed that the increase in perfusion and tissue viability was counteracted by low-dose sunitinib. Overall, these data give insight in the dynamics of tumor perfusion during conventional 2 Gy fractionated RTx and provide a rationale to combine low dose angiostatic drugs with RTx both in the palliative as well as in the curative setting. PMID- 27780938 TI - Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sezary syndrome. AB - Sezary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists. IFN-gamma was scarcely produced upon TLR activation in SS cells, albeit TLR 7/8 (CL097) enhanced their secretion at lower levels than the control group. TLR9 agonist efficiently induced IFN-I in SS patients, although this positive regulation was not observed for other cytokines, in direct contrast to the broad activity of CL097. Among the TLR agonists, TLR4 was able to induce pro-inflammatory, IL-10 and Th2 secretion, while TLR7-8 agonist induced the inflammatory cytokines, IFN-I and IFN-gamma. These findings reveal a dysfunctional cytokine response upon both extracellular and intracellular TLR activation in SS patients, which was partially restored by TLRs agonists. PMID- 27780940 TI - [Gastric Mucosa-associated Lymphoid Tissue Lymphoma Based on Outcome of Domestic Treatment]. AB - Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is associated with Helicobacter pylori infection. H. pylori eradication can be performed as a primary therapy regardless of H. pylori status. In Korea, six articles were published about low-grade gastric MALT lymphoma with H. pylori. Complete regression rate after H. pylori eradication is reported at 74.5% to 94.4%. Radiotherapy results in favorable clinical long-term outcomes in patients with early-stage gastric MALT lymphoma who fail H. pylori eradication therapy and those who are H. pylori negative. Chemotherapy could be reserved for patients with metastatic or high-grade lymphoma. In gastric MALT lymphoma, patients with polypoid type on initial endoscopy had a higher likelihood of recurrence than those with diffuse infiltration or ulceration types. The depth of invasion, location of lesions, and chromosomal abnormality with t(11;18) together are predictive factors for failure to remission by H. pylori eradication. PMID- 27780941 TI - Clinical Outcomes of Endoscopic Removal in Patients with Colorectal Polypoid Leiomyomas. AB - Background/Aims: Although polypoid leiomyomas in the colon and rectum are rare, they are increasingly detected during colonoscopy. The aim of this study was to evaluate the efficacy and clinical outcomes of endoscopic removal for colorectal polypoid leiomyoma. Methods: Data were retrospectively collected from 22 patients with polypoid leiomyoma arising from the muscularis mucosae in the colon and rectum who underwent endoscopic removal at single referral gastrointestinal endoscopy unit. Colonoscopic findings, endoscopic removal, success rates, complication rates (bleeding or perforation), pathologic characteristics, and recurrence rates were investigated. Results: Most polypoid leiomyomas were small asymptomatic lesions less than 1 cm. The tumors were located predominantly in the left colon. Ten leiomyomas were removed using cold biopsy forceps, and 12 were resected by conventional polypectomy or endoscopic mucosal resection. All tumors arose from or involved the muscularis mucosa. There were no complications, such as bleeding or perforation. No local remnant lesions were found in 19 patients who underwent at least one follow-up colonoscopy. Conclusions: This case series represent cases of small colorectal polypoid leiomyoma that were safely removed endoscopically. An awareness of their endoscopic and clinic-pathological characteristics may provide safe treatment strategy for colonic leiomyomatous tumors of similar size in capable hands. PMID- 27780939 TI - Chinese expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus: 2016 edition. AB - Hepatocellular carcinoma is the fourth leading cause of cancer-related morbidity and mortality in China. Portal vein tumor thrombus (PVTT) is common and it worsens prognosis of hepatocellular carcinoma (HCC). There is no internationally accepted consensus or guideline for diagnosis and treatment of HCC with PVTT. Based on existing evidences and common current practices, Chinese Experts on Multidisciplinary Diagnosis and Treatment of HCC with portal vein tumor thrombus met to develop a national consensus on diagnosis and treatment of HCC with PVTT. The meeting concluded with the First Edition (version 2016) of consensus statements with grades of evidence given as grades Ia, Ib, IIa, IIb, III and IV, and ranking as Classes A, B, C, D and I for quality of evidence and strength of recommendation by the United State Preventive Service Task Force, respectively. The consensus suggests recommended treatment to be based on patients' PVTT type and ECOG functional status; surgery being the preferred treatment for Child-Pugh A, PVTT type I/II, and ECOG PS 0-1; transcatheter arterial chemoembolization (TACE) for non-resectable PVTT I/II and Child-Pugh A; and radiotherapy for non resectable PVTT I/II/III and Child-Pugh A. Symptomatic treatment is recommended for Child-Pugh C, with massive ascites or gastrointestinal bleeding. By updating clinicians with treatment options for HCC with PVTT, the consensus statement aimed to prolong overall survival and to improve quality of life of patients with minimal treatment complication. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials, especially studies defining the role of traditional Chinese medicine and clarifying molecular aspects of HCC. PMID- 27780942 TI - [Role of Inhibitory Transforming Growth Factor-beta Signal Smad7 in Helicobacter pylori-associated Gastric Damage]. AB - Background/Aims: Transforming growth factor-beta (TGF-beta) is a cytokine implicated in the susceptibility, development, and progression of gastrointestinal cancer and certain other neoplasms. In the later stages of cancer, TGF-beta not only acts as a bystander of host-immune response, but also contributes to cell growth, invasion, and metastasis. In the current study, we generated gastric mucosal cells that stably express Smad7, and explored the Helicobacter pylori-associated biological changes between mock-transfected and Smad7-transfected RGM1 cells. Methods: RGM1 cells stably transfected with Smad7 were infected with H. pylori, and molecular changes in apoptotic markers and inflammatory mediators were examined. Several candidate genes were explored in Smad7-overexpressing cells after H. pylori infection. Results: Overexpression of Smad7 in RGM1 cells significantly increased the H. pylori-induced cytotoxicity compared to mock-transfected cells. Exaggerated increases in inflammatory mediators, cyclooxygenase 2, inducible NO synthase, and augmented apoptosis were noted in Smad7-overexpressing cells, whereas mitigated heme oxygenase 1 was noted in Smad7- overexpressing cells. These phenomena were reversed in cells transfected with Smad7 siRNA. Conclusions: These data suggest that inhibition of Smad7 is a possible target for mitigating H. pylori-associated inflammation. PMID- 27780943 TI - The Prevalence of Colonic Neoplasm in Cryptogenic Pyogenic Liver Abscess: A Prospectively Enrolled Cross-sectional Study. AB - Background/Aims: Several studies suggest that pyogenic liver abscess (PLA) is associated with colon neoplasm. A colonoscopic exam for cryptogenic PLA might detect a hidden colon neoplasm, through which intestinal flora can be transmitted into the liver. However, there are no prospectively enrolled cross-sectional data for colonic neoplasm in cryptogenic PLA. Methods: Patients with PLA were prospectively enrolled from two university hospitals. Among them, all the patients with cryptogenic PLA were recommended for colonoscopic exam to check for colonic neoplasm. Results: One hundred eighty-three patients with PLA were enrolled in the study for 22 months. One hundred and one (55.2%) patients did not have a definite cause of liver abscess at initial evaluation. The median diameter of the largest lesion was 5.7 cm (1.0-14.0 cm), and 74.3% of the patients were treated by percutaneous abscess drainage. Ninety-one percent of the patients who had an identified pathogen yielded Klebsiella. Sixty-two patients underwent colonoscopic exams, and no one had a colonic cancer, one had an adenomatous polyp with high grade dysplasia (1.6%), and 27 had adenomatous polyps with low grade dysplasia (43.5%; 41.0% in male and 43.5% in female). Of fifty patients who underwent an esophagogastroduodenoscopic exam, nine had gastric ulcers, one had an esophageal ulcer, and one had hemorrhagic gastritis. Conclusions: The prevalence of colonic neoplasm among the patients with cryptogenic PLA was not as high as that in previous studies. Further well-designed, large-scale studies are required to assess the association of the colon neoplasm and cryptogenic PLA. PMID- 27780944 TI - The Usefulness of Early Endoscopic Ultrasonography in Acute Biliary Pancreatitis with Undetectable Choledocholithiasis on Multidetector Computed Tomography. AB - Background/Aims: EUS can detect bile duct stones (BDS) that are undetectable on multidetector computed tomography (MDCT). BDS associated with acute biliary pancreatitis (ABP) are small and tend to be excreted spontaneously. This study evaluated the usefulness of early EUS in patients with ABP and undetectable BDS on MDCT. Methods: Forty-one patients with ABP and undetectable BDS on MDCT underwent EUS within 24 hours of admission and were diagnosed with BDS, sludge, dilated common bile duct (CBD), or normal CBD. ERCP was performed in patients with BDS, sludge, or clinical deterioration. The diagnostic yield and the effects of early EUS on morbidity, mortality, and the length of hospitalization were evaluated. Results: EUS detected BDS or sludge in 48.8% of patients examined. BDS was the diagnosis in 13 patients, sludge in seven, and neither for 21 patients. ERCP was performed in 20 patients with BDS or sludge, in two patients with coexisting cholangitis, and in one patient with worsening liver function tests. ERCP identified BDS in 12 patients and sludge in seven. No lesions were diagnosed in four patients by ERCP. All patients improved, and the length of hospitalization in patients with ERCP was 9.0 days, without ERCP 7.1 days. Two patients with major complications by ERCP were hospitalized for a prolonged time. Conclusions: Early EUS may be useful to select patients for therapeutic ERCP in cases of suspected ABP with undetectable BDS on MDCT. PMID- 27780945 TI - Endoscopic Resection of a Giant Esophageal Lipoma Causing Sudden Choking. AB - Most esophageal lipomas are discovered incidentally and are small and asymptomatic. However, large (>4 cm) lipomas may cause various symptoms, including dysphagia, regurgitation, or epigastric discomfort. We present a 45 year-old woman with intermittent sudden choking and globus pharyngeus. Upper gastrointestinal endoscopy and endoscopic ultrasound revealed an approximately 10.0*1.5 cm pedunculated subepithelial tumor in the upper esophagus, identified as the cause of her symptoms. A thoracic computed tomography scan revealed a fat attenuated longitudinal mass along the upper esophagus, suggestive of a lipoma. Endoscopic resection of the lesion was performed with a detachable snare to relieve her symptoms, and the pathologic findings were consistent with a lipoma. PMID- 27780946 TI - [A Case of Cecal Endometriosis Presenting as Subepithelial Tumor]. AB - Endometriosis is a benign gynecologic disease, characterized by the presence and growth of functional endometrial-like tissue outside uterus. This ectopic endometrial tissue is most commonly found in the peritoneum, ovaries and uterosacral ligaments, but extremely rarely there is involvement of the appendix or cecum. Here we report a case of cecal endometriosis presenting as a subepithelial tumor diagnosed by surgical excision. PMID- 27780947 TI - [A Case of Rectal Syphilis Incidentally Found at Regular Medical Check-up]. AB - Syphilis is a rare disease in the rectum. It is difficult to diagnose because the characteristics of the rectal syphilis rectal lesion are highly varied. The endoscopic findings of rectal syphilis are proctitis, ulcers, and masses. If rectal syphilis is suspected to be the cause for rectal lesions, it is important for physicians to consider the sexual history and sexual orientation of the patient. We report a case of incidental rectal syphilis in a 41-year-old man diagnosed during a regular medical check-up. PMID- 27780948 TI - Non-umbilical Cutaneous Metastasis of Pancreatic Adenocarcinoma as the First Clinical Manifestation: A Case Report. AB - Non-umbilical cutaneous metastases from pancreatic adenocarcinomas are extremely rare. Only a few cases have been reported in the literature. An 83-year-old Korean woman, with no previous medical history, presented with a painful nodule on her scalp. Histologic examination of the nodule revealed a metastatic adenocarcinoma, and immunohistochemical staining was positive for cytokeratin (CK) 7 and CK 19. These findings were consistent with a metastatic carcinoma of pancreatic origin. An abdominal computed tomography scan identified a mass on the pancreatic head and multiple enlarged lymph nodes. Pathological examination of an endoscopic ultrasound-guided fine needle biopsy of the pancreatic mass determined that it was a poorly differentiated carcinoma. The patient refused any treatment owing to her old age and short life expectancy. Four months later, the disease progressed rapidly, and the patient died. PMID- 27780949 TI - Alterations in Acetylation of Histone H4 Lysine 8 and Trimethylation of Lysine 20 Associated with Lytic Gene Promoters during Kaposi's Sarcoma-Associated Herpesvirus Reactivation. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with formation of Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Replication and transcription activator (RTA) genes are expressed upon reactivation of KSHV, which displays a biphasic life cycle consisting of latent and lytic replication phases. RTA protein expression results in KSHV genome amplification and successive viral lytic gene expression. Transcriptional activity of viral lytic genes is regulated through epigenetic modifications. In Raji cells latently infected with Epstein-Barr virus, various modifications, such as acetylation and methylation, have been identified at specific lysine residues in histone H4 during viral reactivation, supporting the theory that expression of specific lytic genes is controlled by histone modification processes. Data obtained from chromatin immunoprecipitation and quantitative real-time PCR analyses revealed alterations in the H4K8ac and H4K20me3 levels at lytic gene promoters during reactivation. Our results indicate that H4K20me3 is associated with the maintenance of latency, while H4K8ac contributes to KSHV reactivation in infected TREx BCBL-1 RTA cells. PMID- 27780950 TI - Hydrogen Treatment Protects against Cell Death and Senescence Induced by Oxidative Damage. AB - Hydrogen has potential for preventive and therapeutic applications as an antioxidant. However, micro- and macroparticles of hydrogen in water disappear easily over time. In order to eliminate reactive oxygen species (ROS) related with the aging process, we used functional water containing nanoparticle hydrogen. Nanoparticle hydrogen does not disappear easily and collapse under water after long periods of time. We used murine embryonic fibroblasts that were isolated from 12.5-day embryos of C57BL/6 mice. We investigated the ability of nanoparticle hydrogen in water to suppress hydroxyurea-induced ROS production, cytotoxicity, and the accumulation of beta-galactosidase (an indicator of aging), and promote cell proliferation. The accumulation of beta-galactosidase in the cytoplasm and the appearance of abnormal nuclei were inhibited by daily treatment of cells with hydrogen water. When the aging process was accelerated by hydroxyurea-induced oxidative stress, the effect of hydrogen water was even more remarkable. Thus, this study showed the antioxidant and anti-senescence effects of hydrogen water. Nanoparticle hydrogen water is potentially a potent anti-aging agent. PMID- 27780951 TI - Engineering CotA Laccase for Acidic pH Stability Using Bacillus subtilis Spore Display. AB - Bacillus subtilis spores can be used for protein display to engineer protein properties. This method overcomes viability and protein-folding concerns associated with traditional protein display methods. Spores remain viable under extreme conditions and the genotype/phenotype connection remains intact. In addition, the natural sporulation process eliminates protein-folding concerns that are coupled to the target protein traveling through cell membranes. Furthermore, ATP-dependent chaperones are present to assist in protein folding. CotA was optimized as a whole-cell biocatalyst immobilized in an inert matrix of the spore. In general, proteins that are immobilized have advantages in biocatalysis. For example, the protein can be easily removed from the reaction and it is more stable. The aim is to improve the pH stability using spore display. The maximum activity of CotA is between pH 4 and 5 for the substrate ABTS (ABTS = diammonium 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate). However, the activity dramatically decreases at pH 4. The activity is not significantly altered at pH 5. A library of approximately 3,000 clones was screened. A E498G variant was identified to have a half-life of inactivation (t1/2) at pH 4 that was 24.8 times greater compared with wt-CotA. In a previous investigation, a CotA library was screened for organic solvent resistance and a T480A mutant was found. Consequently, T480A/E498G-CotA was constructed and the t1/2 was 62.1 times greater than wt-CotA. Finally, E498G-CotA and T480A/E498G CotA yielded 3.7- and 5.3-fold more product than did wt-CotA after recycling the biocatalyst seven times over 42 h. PMID- 27780954 TI - Antimicrobial Activity of the Scolopendrasin V Peptide Identified from the Centipede Scolopendra subspinipes mutilans. AB - In a previous study, we analyzed the transcriptome of Scolopendra subspinipes mutilans using next-generation sequencing technology and identified several antimicrobial peptide candidates. One of the peptides, scolopendrasin V, was selected based on the physicochemical properties of antimicrobial peptides using a bioinformatics strategy. In this study, we assessed the antimicrobial activities of scolopendrasin V using the radial diffusion assay and colony count assay. We also investigated the mode of action of scolopendrasin V using flow cytometry. We found that scolopendrasin V's mechanism of action involved binding to the surface of microorganisms via a specific interaction with lipopolysaccharides, lipoteichoic acid, and peptidoglycans, which are components of the bacterial membrane. These results provide a basis for developing peptide antibiotics. PMID- 27780952 TI - Validation of Analytical Methods for Plasma Total Antioxidant Capacity by Comparing with Urinary 8-Isoprostane Level. AB - Although several analytical methods for measuring total antioxidant capacity (TAC) have been applied to biological samples, there were often dissimilar results due to the different principles of methods applied. Thus, this study aimed to validate four conventional analytical methods for measuring plasma TAC, including the ABTS assay, DPPH assay, FRAP assay, and ORAC assay, by comparing with urinary 8-isoprostane concentration. In addition, TAC results were compared with antioxidant enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase in erythrocyte, and catalase in plasma. Plasma TAC measure by ABTS assay was strongly correlated with the result by FRAP assay. Plasma TAC by FRAP and ORAC assays were negatively correlated with erythrocyte SOD activity. The agreement among the four TAC assay methods and 8-isoprostane was determined using 95% prediction limits of linear regression, expressed as the mean of 8 isoprostane +/- 95% prediction limits. The ABTS method better agreed with 8 isoprostane than the other methods, demonstrating narrow prediction of limits. Furthermore, only plasma TAC determined by the ABTS assay was inversely correlated with urinary 8-isoprostane (r = -0.35, p < 0.05). In summary, the ABTS assay would be an appropriate method to measure overall plasma antioxidant capacity and predict the body's antioxidant status. PMID- 27780953 TI - Kinetics of Horseradish Peroxidase-Catalyzed Nitration of Phenol in a Biphasic System. AB - The use of peroxidase in the nitration of phenols is gaining interest as compared with traditional chemical reactions. We investigated the kinetic characteristics of phenol nitration catalyzed by horseradish peroxidase (HRP) in an aqueous organic biphasic system using n-butanol as the organic solvent and NO2- and H2O2 as substrates. The reaction rate was mainly controlled by the reaction kinetics in the aqueous phase when appropriate agitation was used to enhance mass transfer in the biphasic system. The initial velocity of the reaction increased with increasing HRP concentration. Additionally, an increase in the substrate concentrations of phenol (0-2 mM in organic phase) or H2O2 (0-0.1 mM in aqueous phase) enhanced the nitration efficiency catalyzed by HRP. In contrast, high concentrations of organic solvent decreased the kinetic parameter Vmax/Km. No inhibition of enzyme activity was observed when the concentrations of phenol and H2O2 were at or below 10 mM and 0.1 mM, respectively. On the basis of the peroxidase catalytic mechanism, a double-substrate ping-pong kinetic model was established. The kinetic parameters were KmH2O2= 1.09 mM, KmPhOH = 9.45 mM, and Vmax = 0.196 mM/min. The proposed model was well fit to the data obtained from additional independent experiments under the suggested optimal synthesis conditions. The kinetic model developed in this paper lays a foundation for further comprehensive study of enzymatic nitration kinetics. PMID- 27780955 TI - Enzymatic Characteristics of a Highly Thermostable beta-(1-4)-Glucanase from Fervidobacterium islandicum AW-1 (KCTC 4680). AB - A highly thermostable beta-(1-4)-glucanase (NA23_08975) gene (fig) from Fervidobacterium islandicum AW-1, a native-feather degrading thermophilic eubacterium, was cloned and expressed in Escherichia coli. The recombinant FiG (rFiG) protein showed strong activity toward beta-D-glucan from barley (367.0 IU/mg), galactomannan (174.0 IU/mg), and 4-nitrophenyl-cellobioside (66.1 IU/mg), but relatively weak activity was observed with hydroxyethyl cellulose (5.3 IU/mg), carboxymethyl cellulose (2.4 IU/mg), and xylan from oat spelt (1.4 IU/mg). rFiG exhibited optimal activity at 90 degrees C and pH 5.0. In addition, this enzyme was extremely thermostable, showing a half-life of 113 h at 85 degrees C. These results indicate that rFiG could be used for hydrolysis of cellulosic and hemicellulosic biomass substrates for biofuel production. PMID- 27780956 TI - Cadaverine Production by Using Cross-Linked Enzyme Aggregate of Escherichia coli Lysine Decarboxylase. AB - Lysine decarboxylase (CadA) converts L-lysine into cadaverine (1,5 pentanediamine), which is an important platform chemical with many industrial applications. Although there have been many efforts to produce cadaverine through the soluble CadA enzyme or Escherichia coli whole cells overexpressing the CadA enzyme, there have been few reports concerning the immobilization of the CadA enzyme. Here, we have prepared a cross-linked enzyme aggregate (CLEA) of E. coli CadA and performed bioconversion using CadACLEA. CadAfree and CadACLEA were characterized for their enzymatic properties. The optimum temperatures of CadAfree and CadACLEA were 60 degrees C and 55 degrees C, respectively. The thermostability of CadACLEA was significantly higher than that of CadAfree. The optimum pH of both enzymes was 6.0. CadAfree could not be recovered after use, whereas CadACLEA was rapidly recovered and the residual activity was 53% after the 10th recycle. These results demonstrate that CadACLEA can be used as a potential catalyst for efficient production of cadaverine. PMID- 27780957 TI - Purification and Properties of Extracellular Lipases with Transesterification Activity and 1,3-Regioselectivity from Rhizomucor miehei and Rhizopus oryzae. AB - Rhizomucor miehei NRRL 5282 and Rhizopus oryzae NRRL 1526 can produce lipases with high synthetic activities in wheat bran-based solid-state culture. In this study, the purification and biochemical characterization of the lipolytic activities of these lipases are presented. SDS-PAGE indicated a molecular mass of about 55 and 35 kDa for the purified R. miehei and Rh. oryzae enzymes, respectively. p-Nitrophenyl palmitate (pNPP) hydrolysis was maximal at 40 degrees C and pH 7.0 for the R. miehei lipase, and at 30 degrees C and pH 5.2 for the Rh. oryzae enzyme. The enzymes showed almost equal affinity to pNPP, but the Vmax of the Rh. oryzae lipase was about 1.13 times higher than that determined for R. miehei using the same substrate. For both enzymes, a dramatic loss of activity was observed in the presence of 5 mM Hg2+, Zn2+, or Mn2+, 10 mM N bromosuccinimide or sodium dodecyl sulfate, and 5-10% (v/v) of hexanol or butanol. At the same time, they proved to be extraordinarily stable in the presence of n-hexane, cyclohexane, n-heptane, and isooctane. Moreover, isopentanol up to 10% (v/v) and propionic acid in 1 mM concentrations increased the pNPP hydrolyzing activity of R. miehei lipase. Both enzymes had 1,3 regioselectivity, and efficiently hydrolyzed p-nitrophenyl (pNP) esters with C8 C16 acids, exhibiting maximum activity towards pNP-caprylate (R. miehei) and pNP dodecanoate (Rh. oryzae). The purified lipases are promising candidates for various biotechnological applications. PMID- 27780958 TI - Molecular Characterization of Adenylyl Cyclase Complex Proteins Using Versatile Protein-Tagging Plasmid Systems in Cryptococcus neoformans. AB - In this study, we aimed to generate a series of versatile tagging plasmids that can be used in diverse molecular biological studies of the fungal pathogen Cryptococcus neoformans. We constructed 12 plasmids that can be used to tag a protein of interest with a GFP, mCherry, 4*FLAG, or 6*HA, along with nourseothricin-, neomycin-, or hygromycin-resistant selection markers. Using this tagging plasmid set, we explored the adenylyl cyclase complex (ACC), consisting of adenylyl cyclase (Cac1) and its associated protein Aca1, in the cAMP-signaling pathway, which is critical for the pathogenicity of C. neoformans. We found that Cac1-mCherry and Aca1-GFP were mainly colocalized as punctate forms in the cell membrane and nonnuclear cellular organelles. We also demonstrated that Cac1 and Aca1 interacted in vivo by coimmunoprecipitation, using Cac1-6*HA and Aca1-4*FLAG tagging strains. Bimolecular fluorescence complementation further confirmed the in vivo interaction of Cac1 and Aca1 in live cells. Finally, protein pull-down experiments using aca1Delta::ACA1-GFP and aca1Delta::ACA1- GFP cac1Delta strains and comparative mass spectrometry analysis identified Cac1 and a number of other novel ACC-interacting proteins. Thus, this versatile tagging plasmid system will facilitate diverse mechanistic studies in C. neoformans and further our understanding of its biology. PMID- 27780959 TI - Polyphasic Microbial Analysis of Traditional Korean Jeung-Pyun Sourdough Fermented with Makgeolli. AB - Jeung-pyun, a fermented rice cake, is prepared by fermenting rice sourdough using makgeolli, a traditional Korean rice wine, in the presence of yeast and lactic acid bacteria (LAB). The goal of this study was to conduct biochemical and microbial analyses of five different rice sourdoughs, each fermented with a different commercial makgeolli, using culture-dependent and culture-independent approaches. All sourdough samples fermented with different makgeolli for 6.5 h showed different profiles in pH, total titratable acidity, organic acid concentration, and microbial growth. LAB belonging to different genera were identified based on colony morphology on modified MRS and sourdough bacteria agar medium. PCR-denaturinggradient gel electrophoresis analyses of the five sourdoughs showed different bands corresponding to LAB and yeast. 16S/26S rRNA gene sequence analyses of the samples confirmed that the predominant LAB in the five fermented rice doughs was Lactobacillus plantarum, Lb. pentosus, and Lb. brevis. Various other Lactobacillus spp. and Saccharomyces cerevisiae were common in all five fermented samples. This study provides comprehensive and comparative information on the microflora involved in fermentation of rice sourdough and signifies the need to develop effective starters to enrich the quality of jeung pyun. PMID- 27780960 TI - An Analog of the Antimicrobial Peptide CopA5 Inhibits Lipopolysaccharide-Induced Macrophage Activation. AB - We previously reported that the CopA3 peptide (LLCIALRKK, D-form) originally isolated from the Korean dung beetle has antimicrobial and immunosuppressive effects. However, the high cost of producing the synthetic peptide, especially the D-form, has limited the development of CopA3 for therapeutic purposes. Here, we investigated whether the CopA3 deletion derivative, CopA5, which is composed of only five amino acids (LLCIA) and has the L-form structure, could inhibit the lipopolysaccharide (LPS)-induced activation of macrophages. Peritoneal exudate macrophages (PEM) were isolated from mice and exposed to LPS in the presence or absence of CopA5, and biomarkers of macrophage activation were measured. Our results revealed that LPS-induced nitric oxide (NO) production, tumor necrosis factor (TNF)-alpha secretion, and phagocytic activity of PEM were significantly inhibited by CopA5 treatment. Similar to CopA3, the structurally modified CopA5 peptide had no cell toxicity (as assessed by measurement of cell viability loss and apoptosis) in PEM. Moreover, the LPS-induced upregulation of the activating phosphorylation of signal transducer and activator of transcription 1 (STAT1) was markedly inhibited by CopA5 treatment. These results suggest that, similar to CopA3, CopA5 inhibits macrophage activation by inhibiting STAT1 phosphorylation and blocking the release of NO and TNF-alpha. CopA5 may therefore prove therapeutically useful in the realm of immune suppression. PMID- 27780961 TI - Biphasic Study to Characterize Agricultural Biogas Plants by High-Throughput 16S rRNA Gene Amplicon Sequencing and Microscopic Analysis. AB - Process surveillance within agricultural biogas plants (BGPs) was concurrently studied by high-throughput 16S rRNA gene amplicon sequencing and an optimized quantitative microscopic fingerprinting (QMF) technique. In contrast to 16S rRNA gene amplicons, digitalized microscopy is a rapid and cost-effective method that facilitates enumeration and morphological differentiation of the most significant groups of methanogens regarding their shape and characteristic autofluorescent factor 420. Moreover, the fluorescence signal mirrors cell vitality. In this study, four different BGPs were investigated. The results indicated stable process performance in the mesophilic BGPs and in the thermophilic reactor. Bacterial subcommunity characterization revealed significant differences between the four BGPs. Most remarkably, the genera Defluviitoga and Halocella dominated the thermophilic bacterial subcommunity, whereas members of another taxon, Syntrophaceticus, were found to be abundant in the mesophilic BGP. The domain Archaea was dominated by the genus Methanoculleus in all four BGPs, followed by Methanosaeta in BGP1 and BGP3. In contrast, Methanothermobacter members were highly abundant in the thermophilic BGP4. Furthermore, a high consistency between the sequencing approach and the QMF method was shown, especially for the thermophilic BGP. The differences elucidated that using this biphasic approach for mesophilic BGPs provided novel insights regarding disaggregated single cells of Methanosarcina and Methanosaeta species. Both dominated the archaeal subcommunity and replaced coccoid Methanoculleus members belonging to the same group of Methanomicrobiales that have been frequently observed in similar BGPs. This work demonstrates that combining QMF and 16S rRNA gene amplicon sequencing is a complementary strategy to describe archaeal community structures within biogas processes. PMID- 27780962 TI - Combined Treatment on the Inactivation of Naturally Existing Bacteria and Escherichia coli O157:H7 Inoculated on Fresh-Cut Kale. AB - An aqueous chlorine dioxide (ClO2) treatment combined with highly activated calcium oxide (CaO) and mild heat was tested for inactivating naturally existing bacteria and Escherichia coli O157:H7 inoculated on fresh-cut kale. Kale samples were treated with different concentrations of ClO2 (10, 30, and 50 ppm), CaO (0.01%, 0.05%, 0.1%, and 0.2%), and mild heat (25 degrees C, 45 degrees C, 55 degrees C, and 65 degrees C) as well with combinations of 30 or 50 ppm ClO2 and 0.2% CaO at 55 degrees C for 3 min. An increasing concentration of ClO2 and CaO significantly reduced the microbialpopulation compared with the control. In addition, mild heating at 55 degrees C elicited greater microbial reduction than the other temperatures. A combined treatment of 50 ppm ClO2 and 0.2% CaO at 55 degrees C reduced the population of naturally existing bacteria on kale by 3.10 logcolony forming units (CFU)/g, and the counts of E. coli O157:H7 were below the detection limit (1 log CFU/g). In addition, no significant differences in the Hunter color values were evident in any treatment during storage. Therefore, a combined treatment of ClO2 and active CaO at 55 degrees C can be an effective sanitizing method to improve the microbiological safety of fresh-cut kale without affecting its quality. PMID- 27780963 TI - Properties of a Fibrinolytic Enzyme Secreted by Bacillus amyloliquefaciens RSB34, Isolated from Doenjang. AB - Nine bacilli with fibrinolytic activities were isolated from doenjang, a traditional Korean fermented soy food. Among them, RSB34 showed the strongest activity and was identified as Bacillus amyloliquefaciens by 16S rRNA and recA gene sequencing. During growth on LB up to 96 h, RSB34 showed the highest fibrinolytic activity (83.23 mU/MUl) at 48 h. Three bands of 23, 27, and 42 kDa in size were observed when the culture supernatant was analyzed by SDS-PAGE and 27 and 42 kDa bands by fibrin zymography. The gene encoding the 27 kDa fibrinolytic enzyme AprE34 was cloned by PCR. BLAST analyses confirmed that the gene was a homolog to genes encoding AprE-type proteases. aprE34 was overexpressed in Escherichia coli BL21(DE3) using pET26b(+). Recombinant AprE34 was purified and examined for its properties. The Km and Vmax values of recombinant AprE34 were 0.131 +/- 0.026 mM and 16.551 +/- 0.316 MUM/l/min, respectively, when measured using an artificial substrate, N-succinyl-ala-ala-pro phe-p-nitroanilide. aprE34 was overexpressed in B. subtilis WB600 using pHY300PLK. B. subtilis transformants harboring pHYRSB34 (pHY300PLK with aprE34) showed higher fibrinolytic activity than B. amyloliquefaciens RSB34. PMID- 27780964 TI - Use of Multimedia Technology in the Doctor-Patient Relationship for Obtaining Patient Informed Consent. AB - Patient informed consent for surgery or for high-risk methods of treatment or diagnosis means that unlawful breach of the patient's personal interests is avoided and the patient accepts the risk of surgery and takes the brunt of it. Patient awareness - their knowledge of the condition and circumstances of continued therapeutic procedure, including offered and available methods of treatment and their possible complications - constitutes a particular aspect of the informed-consent process. The rapid development of technologies and methods of treatment may cause communication problems between the doctor and the patient regarding the scope and method of patient education prior to surgery. The use of multimedia technology (e.g., videos of surgical procedures, computer animation, and graphics), in addition to media used in preoperative patient education, may be a factor in improving the quality of the informed consent process. Studies conducted in clinical centers show that with use of multimedia technology, patients remember more of the information presented. The use of new technology also makes it possible to reduce the difference in the amount of information assimilated by patients with different levels of education. The use of media is a way to improve the quality of preoperative patient education and, at the same time, a step towards their further empowerment in the healing process. PMID- 27780965 TI - A Case of Birt-Hogg-Dube (BHD) Syndrome Harboring a Novel Folliculin (FLCN) Gene Mutation. AB - BACKGROUND Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disorder clinically characterized by pulmonary cysts, spontaneous pneumothorax, renal cell cancer, and skin fibrofolliculomas. The disorder is caused by germline mutations in the FLCN gene. CASE REPORT A 56-year-old female was admitted to our hospital with a diagnosis of bilateral spontaneous pneumothorax. A computed tomography (CT) scan of the chest revealed bilateral multiple bullae predominantly located in the subpleural and mediastinal areas in the bilateral upper and lower lobes. Although she was cured by thoracic cavity drainage, she underwent resection of bilateral lung bullae because she had a prior history of right pneumothorax at 37 and 45-years of age. She had no signs of renal tumor but had fibrofolliculoma in her face and a family history of pneumothorax, we therefore suspected BHD syndrome. DNA sequence analyses determined that there was a two base pair deletion in exon 4 of the FLCN gene, confirming the diagnosis of BHD syndrome. CONCLUSIONS Here we report a case of BHD syndrome with a previously unreported FLCN mutation. PMID- 27780966 TI - Isolation and identification of new macrocyclic lactones from a genetically engineered strain Streptomyces bingchenggensis BCJ60. PMID- 27780967 TI - Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target. AB - Acute myeloid leukemias (AMLs) result from a series of genetic events occurring in a stem or progenitor hematopoietic cell that gives rise to their clonal expansion and an impaired capacity to differentiate. To circumvent the genetic heterogeneity of AML patient cohorts, we have developed a model system, driven by the MLL-AF9 (MA9) oncogene, to generate multiple human leukemias using progenitor cells from a single healthy donor. Through stepwise RNA-sequencing data generated using this model and AML patients, we have identified consistent changes associated with MA9-driven leukemogenesis and demonstrate that no recurrent secondary mutations are required. We identify 39 biomarkers whose high expression level is specific to this genetic subtype of AML and validate that many of these have diagnostic utility. We further examined one biomarker, the receptor tyrosine kinase (RTK) RET, and show through shRNA knockdowns that its expression is essential for in vivo and in vitro growth of MA9-AML. These results highlight the value of novel human models of AML derived from single donors using specific oncogenic fusions to understand their biology and to uncover potential therapeutic targets. PMID- 27780968 TI - Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by 90Y ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499. PMID- 27780969 TI - From discovery to outbreak: the genetic evolution of the emerging Zika virus. PMID- 27780970 TI - Avian gyrovirus 2 in poultry, China, 2015-2016. PMID- 27780973 TI - Colorectal cancer: CRC endothelial regulation. PMID- 27780971 TI - Patient optimization for surgery relating to Crohn's disease. AB - The majority of patients with Crohn's disease require abdominal surgery during their lifetime, some of whom will require multiple operations. Postoperative complications are seen more frequently in patients requiring abdominal surgery for Crohn's disease than in patients requiring abdominal surgery for other conditions. In this article, we review the evidence supporting preoperative optimization, discussing strategies that potentially improve surgical outcomes and reduce perioperative morbidity and mortality. We discuss the roles of adequate cross-sectional imaging, nutritional optimization, appropriate adjustments of medical therapy, management of preoperative abscesses and phlegmons, smoking cessation and thromboembolic prophylaxis. We also review operation-related factors, and discuss their potential implications with respect to postoperative complications. Overall, the literature suggests that preoperative management has a major effect on postoperative outcomes. PMID- 27780974 TI - Mobile applications for obesity and weight management: current market characteristics. AB - Mobile-Health (mHealth) is the fastest-developing eHealth sector, with over 100 000 health applications (apps) currently available. Overweight/obesity is a problem of wide public concern that is potentially treatable/preventable through mHealth. This study describes the current weight-management app-market. Five app stores (Apple, Google, Amazon, Windows and Blackberry) in UK, US, Russia, Japan and Germany, Italy, France, China, Australia and Canada were searched for keywords: 'weight', 'calorie', 'weight-loss', 'slimming', 'diet', 'dietitian' and 'overweight' in January/February 2016 using App-Annie software. The 10 most downloaded apps in the lifetime of an app were recorded. Developers' lists and the app descriptions were searched to identify any professional input with keywords 'professional', 'dietitian' and 'nutritionist'. A total of 28 905 relevant apps were identified as follows: Apple iTunes=8559 (4634, 54% paid), Google Play=1762 (597, 33.9% paid), Amazon App=13569 (4821, 35.5% paid), Windows=2419 (819, 17% paid) and Blackberry=2596 (940, 36% paid). The 28 905 identified apps focused mainly on physical activity (34%), diet (31%), and recording/monitoring of exercise, calorie intake and body weight (23%). Only 17 apps (0.05%) were developed with identifiable professional input. Apps on weight management are widely available and very popular but currently lack professional content expertise. Encouraging app development based on evidence-based online approaches would assure content quality, allowing healthcare professionals to recommend their use. PMID- 27780975 TI - The role and possible mechanism of lncRNA U90926 in modulating 3T3-L1 preadipocyte differentiation. AB - BACKGROUND: Obesity is a risk factor for metabolic diseases, while preadipocyte differentiation or adipogenesis is closely related to obesity occurrence. Long noncoding RNAs (lncRNAs) are a unique class of transcripts in regulation of a variety of biological processes. Using cDNA microarray, we found lncRNA U90926 is negatively correlated with 3T3-L1 preadipocyte differentiation. OBJECTIVE: The aim of this study was to explore the role of lncRNA U90926 (lnc-U90926) in adipogenesis and the underlying mechanisms. METHODS: Quantitative real-time PCR (qPCR) was performed to determine lnc-U90926 expression in 3T3-L1 preadipocytes, differentiated adipocytes, and in adipose tissues form mice. RNA fluorescent in situ hybridization (FISH) was performed to determine the localization of lnc U90926 in 3T3-L1 preadipocytes. The effects of lnc-U90926 on 3T3-L1 adipogenesis were analyzed with lentivirus-mediated gain- and loss-of-function experiments. Lipid accumulation was evaluated by oil red O staining; several adipogenesis makers were analyzed by qPCR and western blotting. Dual luciferase assay was applied to explore the transactivation of target genes modulated by lnc-U90926. All measurements were performed at least for three times. RESULTS: Lnc-U90926 expression decreased along the differentiation of 3T3-L1 preadipocytes. In mice, lnc-U90926 is predominantly expressed in adipose tissue. Obese mice have lower lnc-U90926 expression in subcutaneous and visceral adipose tissue than non-obese mice. FISH results showed that lnc-U90926 was mainly located in the cytoplasm. Overexpression lnc-U90926 attenuated 3T3-L1 adipocyte differentiation as evidenced by its ability to inhibit lipid accumulation, to decrease the mRNA levels of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2), fatty acid binding protein 4 (FABP4) and adiponectin (AdipoQ) as well as to reduce the protein levels of PPARgamma and FABP4 (P<0.05). Knockdown of lnc-U90926 showed opposite effects, which increased mRNA expression of PPARgamma2, FABP4, CCAAT/enhancer-binding proteinalpha (C/EBPalpha) and AdipoQ. CONCLUSION: Lnc U90926 attenuates 3T3-L1 adipocyte differentiation via inhibiting the transactivation of PPARgamma2 or PPARgamma. PMID- 27780977 TI - Weight loss surgery in adolescents corrects high-density lipoprotein subspecies and their function. AB - BACKGROUND/OBJECTIVE: Youth with obesity have an altered high-density lipoprotein (HDL) subspecies profile characterized by depletion of large apoE-rich HDL particles and an enrichment of small HDL particles. The goal of this study was to test the hypothesis that this atherogenic HDL profile is reversible and that HDL function would improve with metabolic surgery. METHODS: Serum samples from adolescent males with severe obesity mean+/-s.d. age of 17.4+/-1.6 years were studied at baseline and 1 year following vertical sleeve gastrectomy (VSG). HDL subspecies and HDL function were evaluated pre and post VSG using paired t-tests. A lean group of adolescents was included as a reference group. RESULTS: After VSG, body mass index decreased by 32% and insulin resistance as estimated by homeostatic model assessment of insulin resistance decreased by 75% (both P<0.01). Large apoE-rich HDL subspecies increased following VSG (P<0.01) and approached that of lean adolescents despite participants with considerable residual obesity. In addition, HDL function improved compared with baseline (cholesterol efflux capacity increased by 12%, HDL lipid peroxidation potential decreased by 30% and HDL anti-oxidative capacity improved by 25%, all P<0.01). CONCLUSIONS: Metabolic surgery results in a significant improvement in the quantity of large HDL subspecies and HDL function. Our data suggest metabolic surgery may improve cardiovascular risk in adolescents and young adults. PMID- 27780976 TI - Impact of parental obesity on neonatal markers of inflammation and immune response. AB - BACKGROUND/OBJECTIVES: Maternal obesity may influence neonatal and childhood morbidities through increased inflammation and/or altered immune response. Less is known about paternal obesity. We hypothesized that excessive parental weight contributes to elevated inflammation and altered immunoglobulin (Ig) profiles in neonates. SUBJECTS/METHODS: In the Upstate KIDS Study maternal pre-pregnancy body mass index (BMI) was obtained from vital records and paternal BMI from maternal report. Biomarkers were measured from newborn dried blood spots (DBS) among neonates whose parents provided consent. Inflammatory scores were calculated by assigning one point for each of five pro-inflammatory biomarkers above the median and one point for an anti-inflammatory cytokine below the median. Linear regression models and generalized estimating equations were used to estimate mean differences (beta) and 95% confidence intervals (CI) in the inflammatory score and Ig levels by parental overweight/obesity status compared with normal weight. RESULTS: Among 2974 pregnancies, 51% were complicated by excessive maternal weight (BMI>25), 73% by excessive paternal weight and 28% by excessive gestational weight gain. Maternal BMI categories of overweight (BMI 25.0-29.9) and obese class II/III (BMI>=35) were associated with increased neonatal inflammation scores (beta=0.12, 95% CI: 0.02, 0.21; P=0.02 and beta=0.13, CI: 0.002, 0.26; P=0.05, respectively) but no increase was observed in the obese class I group (BMI 30-34.9). Mothers with class I and class II/III obesity had newborns with increased IgM levels (beta=0.11, CI: 0.04, 0.17; P=0.001 and beta=0.12, CI: 0.05, 0.19); P<0.001, respectively). Paternal groups of overweight, obese class I and obese class II/III had decreased neonatal IgM levels (beta=-0.08, CI: -0.13,-0.03, P=0.001; beta=-0.07, CI: -0.13, -0.01, P=0.029 and beta=-0.11, CI:-0.19,-0.04, P=0.003, respectively). CONCLUSIONS: Excessive maternal weight was generally associated with increased inflammation and IgM supporting previous observations of maternal obesity and immune dysregulation in offspring. The role of paternal obesity requires further study. PMID- 27780972 TI - Developmental origins of NAFLD: a womb with a clue. AB - Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation. PMID- 27780978 TI - Maternal obesity modulates intracellular lipid turnover in the human term placenta. AB - BACKGROUND: Obesity before pregnancy is associated with impaired metabolic status of the mother and the offspring later in life. These adverse effects have been attributed to epigenetic changes in utero, but little is known about the role of placental metabolism and its contribution to fetal development. OBJECTIVES: We examined the impact of maternal pre-pregnancy obesity on the expression of genes involved in placental lipid metabolism in lean and obese women. SUBJECTS/METHODS: Seventy-three lean and obese women with healthy pregnancy were recruited at term elective cesarean delivery. Metabolic parameters were measured on maternal venous blood samples. Expression of 88 genes involved in lipid metabolism was measured in whole placenta tissue. Proteins of genes differently expressed in response to maternal obesity were quantified, correlated with maternal parameters and immunolocalized in placenta sections. Isolated primary trophoblasts were used for in vitro assays. RESULTS: Triglyceride (TG) content was increased in placental tissue of obese (1.10, CI 1.04-1.24 mg g-1, P<0.05) vs lean (0.84, CI 0.72-1.02 mg g-1) women. Among target genes examined, six showed positive correlation (P<0.05) with maternal pre-pregnancy BMI, namely ATGL (PNPLA2), FATP1 (SLC27A1), FATP3 (SLC27A3), PLIN2, PPARG and CGI-58 (ABHD5). CGI-58 protein abundance was twofold higher (P<0.001) in placentas of obese vs lean women. CGI-58 protein levels correlated positively with maternal insulin levels and pre-pregnancy body mass index (R=0.63, P<0.001 and R=0.64, P<0.001, respectively). CGI-58 and PLIN2 were primarily located in the syncytiotrophoblast and, were upregulated (1.38- and 500-fold, respectively) upon oleic acid and insulin treatment of cultured trophoblast cells. CONCLUSION: Pre-gravid obesity significantly modifies the expression of placental genes related to transport and storage of neutral lipids. We propose that the upregulation of CGI-58, a master regulator of TG hydrolysis, contributes to the turnover of intracellular lipids in placenta of obese women, and is tightly regulated by metabolic factors of the mother. PMID- 27780980 TI - Genome organization: Add a TAD of duplication. PMID- 27780981 TI - Longitudinal observation of serum anti-Mullerian hormone in three girls after cancer treatment. AB - Gonadal dysfunction and infertility are major endocrinological late effects among childhood cancer survivors. Chemotherapy and radiation have gonadotoxic effects and diminish the ovarian reserve. The serum concentration of anti-Mullerian hormone (AMH) is a useful marker of ovarian reserve in survivors. We conducted a longitudinal study to investigate the variations of AMH in evaluating the acute and chronic effects of cancer therapy on the ovary. Three young female patients with different hematological diseases were registered, and their medical records were reviewed. Patient 1 with myelodysplastic syndrome received reduced-intensity hematopoietic stem cell transplantation (HSCT) at 10 yr of age. Breast development and menarche occurred spontaneously after HSCT; however, AMH level became undetectable and gonadotropin did not increase. Patient 2 with acute lymphoblastic leukemia had been receiving chemotherapy since 11 yr of age. AMH level became undetectable but increased after chemotherapy and was associated with regular menstruation. Patient 3 with acute myeloid leukemia received chemotherapy at 13 yr of age and myeloablative HSCT at 14 yr of age. AMH level became undetectable after HSCT, and the patient developed amenorrhea. These different patterns in the recovery phase demonstrated that the AMH level immediately after the end of cancer therapy is inappropriate for the evaluation of the ovarian reserve. PMID- 27780982 TI - A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation. AB - Pseudohypoaldosteronism type II (PHA II) is a renal tubular disease that causes hyperkalemia, hypertension, and metabolic acidosis. Mutations in four genes (WNK4, WNK1, KLHL3, and CUL3) are known to cause PHA II. We report a patient with PHA II carrying a KLHL3 mutation, who also had congenital hypopituitarism. The patient, a 3-yr-old boy, experienced loss of consciousness at age 10 mo. He exhibited growth failure, hypertension, hyperkalemia, and metabolic acidosis. We diagnosed him as having PHA II because he had low plasma renin activity with normal plasma aldosterone level and a low transtubular potassium gradient. Further investigations revealed defective secretion of GH and gonadotropins and anterior pituitary gland hypoplasia. Genetic analyses revealed a previously known heterozygous KLHL3 mutation (p.Leu387Pro), but no mutation was detected in 27 genes associated with congenital hypopituitarism. He was treated with sodium restriction and recombinant human GH, which normalized growth velocity. This is the first report of a molecularly confirmed patient with PHA II complicated by congenital hypopituitarism. We speculate that both GH deficiency and metabolic acidosis contributed to growth failure. Endocrinological investigations will help to individualize the treatment of patients with PHA II presenting with growth failure. PMID- 27780983 TI - A novel mutation in the human mineralocorticoid receptor gene in a Japanese family with autosomal-dominant pseudohypoaldosteronism type 1. PMID- 27780979 TI - Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression. AB - Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples - including Xist, which orchestrates X chromosome inactivation - has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus. PMID- 27780984 TI - A case of transient neonatal diabetes due to a novel mutation in ABCC8. PMID- 27780985 TI - Affordable Neurogenetic Screening as a Powerful Tool for Beti Bachao. PMID- 27780986 TI - Integrated Healthcare in India - A Conceptual Framework. PMID- 27780987 TI - Prediction of Outcome in Diabetic Acute Ischemic Stroke Patients: A Hospital Based Pilot Study Report. AB - BACKGROUND: Demographic and clinical characteristics are known to influence the outcome in acute ischemic stroke (AIS) patients. PURPOSE: This study is aimed at evaluating short- and long-term outcomes in diabetic AIS patients. In addition, the study also evaluates the impact of diabetes on the performance of indigenously reported biomarker, inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and known biomarkers, neuron-specific enolase (NSE) and glial-derived S 100 beta beta protein (S-100betabeta). METHODS: This study was performed on 29 diabetes and 75 non-diabetes AIS patients. Outcome of AIS patients was analyzed by using modified Rankin scale at discharge, then at 12 and 18 months after discharge. Based on the obtained scores, patients were classified as improved group (scales 1-3) and dependent/expired group (scales 3-6). Blood samples were collected during admission and at discharge/expired time. Levels of NSE, S100betabeta, and ITIH4 were analyzed in all samples. RESULTS: On discharge, frequencies of dependent/expired outcome were 4/29 (14%) and 19/75 (17%) in diabetic and non-diabetic AIS patients. However, follow-up outcome at 12 and 18 months showed higher dependent/expired cases of 43 and 41% among diabetic AIS patients compared to 27 and 21% in non-diabetic patients. Multivariate analysis revealed that diabetes is an independent risk factor for dependent/expired outcome in AIS patients (OR 0.484 (at discharge); 1.307 (at 12 months) and 1.675 (at 18 months)). NSE, S100betabeta, and ITIH4 showed a differential expression in both the outcome groups of AIS patients, irrespective of diabetes. CONCLUSION: Diabetes increases the risk of dependent/expired outcome in AIS patients. Also, serum NSE, S100betabeta, and ITIH4 are independent biomarkers for prognosis of outcome in AIS patients, irrespective of diabetes. PMID- 27780988 TI - A Bibliometric Assessment of Global Ice Bucket Challenge (Amyotrophic Lateral Sclerosis) Research. AB - BACKGROUND: This study is a quantitative and qualitative assessment of the global research trends on amyotrophic lateral sclerosis (ALS) (popularly known as Ice Bucket Challenge), through related literatures retrieved from SCOPUS multidisciplinary database for the period 1974-2013. PURPOSE: This study is aimed at analyzing the literature on ALS in terms of document type, language, annual growth, productive country, journal, authors, subject, and most cited articles. METHODS: The bibliographic data for this study was retrieved from the SCOPUS database using keywords 'amyotrophic lateral sclerosis', 'motor neurone disease', 'Charcot disease', 'Lou Gehrig's disease', 'Ice Bucket Challenge' available in title, abstract, and keyword fields of Scopus database from 1974 to 2013. RESULTS: The literature analysis included 21,750 articles during the period from 1974 to 2013 in different areas of ALS. USA was the most productive country in terms of literature produced, while Neurology was the most productive journal. CONCLUSION: An intensive awareness created by 'Ice Bucket Challenge' has attracted masses, and an intensive growth of literature is pertinent on ALS. The results of this study are expressed in terms of growth of literature, output of individual countries, and authors, and will be helpful in collaborative research in future. PMID- 27780989 TI - Exploring the Effect of Phyllanthus emblica L. on Cognitive Performance, Brain Antioxidant Markers and Acetylcholinesterase Activity in Rats: Promising Natural Gift for the Mitigation of Alzheimer's Disease. AB - Neurodegenerative diseases are incurable and debilitating conditions that result in the progressive degeneration of nerve cells, which affect the cognitive activity. Currently, as a result of multiple studies linking Alzheimer's disease (AD) to oxidative damage, the uses of natural antioxidant to prevent, delay, or enhance the pathological changes underlying the progression of AD has received considerable attention. Therefore, this study was aimed at examining the effect of ethanolic extracts of Phyllanthus emblica (EEPE) ripe (EEPEr) and EEPE unripe (EEPEu) fruits on cognitive functions, brain antioxidant enzymes, and acetylcholinesterase (AChE) activity in rat. The effects of EEPEr and EEPEu fruits (i.e., 100 and 200 mg/kg b.w.) were examined in Swiss albino male rats for 12 days and its effect on cognitive functions, brain antioxidant enzymes, and AChE activity determined. Learning and memory enhancing activity of EEPE fruit was examined by using passive avoidance test and rewarded alternation test. Antioxidant potentiality was evaluated by measuring the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase, reduced glutathione (GSH), glutathione-S-transferase, and the contents of thiobarbituric acid reactive substances (TBARS) in entire brain tissue homogenates. AChE activity was determined using colorimetric method. Administration of the highest dose (i.e., 200 mg/kg b.w.) of EEPEr fruit significantly (p < 0.01) and both lowest and highest doses (i.e., 100 and 200 mg/kg b.w.) of EEPEu fruit markedly (p < 0.05, p < 0.001) increased step-through latency in rats on 6th, 11th, and 12th day with respect to the control group. For aforementioned doses, the percentage of memory retention (MR) was considerably (p < 0.05, p < 0.01) increased in rats on 10th, 11th, and 12th days with respect to the control group. The extract, particularly highest dose (i.e., 200 mg/kg b.w.) of EEPEr fruit markedly (p < 0.05) and lowest and highest doses (i.e., 100 and 200 mg/kg b.w.) of EEPEu fruit significantly (p < 0.01) increased the correct responses in rats on 6th, and 12th day related to the control group. In case of this test, the percentage of MR was significantly (p < 0.05, p < 0.01) increased in rats treated with aforementioned doses on 12th day with respect to the control group. The highest dose (i.e., 200 mg/kg b.w.) of EEPEr fruit suggestively (p < 0.05) and both lowest and highest doses (i.e., 100 and 200 mg/kg b.w.) of EEPEu fruit suggestively (p < 0.05, p < 0.01, p < 0.001) increased the levels of SOD, CAT, GSH, GSH-Px and expressively (p < 0.01) decreased the TBARS level compared to the control group. Treatment with the highest dose (i.e., 200 mg/kg b.w.) of EEPEr fruit significantly (p < 0.05) and both lowest and highest doses (i.e., 100 and 200 mg/kg b.w.) of EEPEu fruit markedly (p < 0.01, p < 0.001) decreased the level of AChE activity compared to that of the control group. The present study shows that EEPE fruit possesses an excellent source for natural cognitive enhancer which could be developed in the treatment of AD and other neurodegenerative diseases. PMID- 27780990 TI - Association of Interictal Epileptiform Discharges with Sleep and Anti-Epileptic Drugs. AB - BACKGROUND: The presence of interictal epileptiform discharges (IEDs) in electroencephalogram (EEG) is diagnostic of epilepsy. Latent IEDs are activated during sleep. Anti-epileptic drugs (AEDs) improve sleep. AEDs, sleep, and IEDs may interact and affect epilepsy management. PURPOSE: To explore the occurrence of IEDs and its association with sleep and AED status in suspected patients of epilepsy. METHODS: EEG records were collected of suspected patients of epilepsy who reported to the electrophysiology laboratory of a tertiary care hospital during 1 year. The anthropometric details, clinical presentations, and AED status of the patients were recorded from the EEG records. Patients were divided into 2 categories based on whether AEDs had been started prior to the EEG evaluation (category-I) or not (category-II). The occurrences of IEDs in EEG recordings in both categories were analyzed. RESULTS: In 1 year, 138 patients were referred for diagnostic EEG evaluation. One-hundred-two patients fulfilled the inclusion criteria, of which 57 patients (53%) belonged to category-I and 45 patients (47%) belonged to category-II. Incidence of IEDs, suggestive of definite diagnosis of epilepsy in category-I was 88% and in category-II was 69%, and this difference was statistically significant (p = 0.02). CONCLUSION: The increased proportion of IEDs in category-I patients may be due to high clinical suspicion or compounding interaction of AEDs and sleep. More extensive studies are required to delineate the complex interaction of AEDs, sleep, and IEDs so that judicious yet prompt management of epilepsy can be carried out. PMID- 27780991 TI - Neuromodulation for Addiction by Transcranial Direct Current Stimulation: Opportunities and Challenges. AB - The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify the pathological activity within the nervous system to achieve a therapeutic effect. Therapy, including transcranial direct current stimulation, has shown promising results across a range of neurological and neuropsychiatric disorders. This article reviews the state-of-the-art of neuromodulation for addiction and discusses the opportunities and challenges available for clinicians and researchers interested in advancing the neuromodulation therapy. A neuromodulation-based approach for addiction has the advantage that the effects might be immediate and selective to the dysfunction. If an alteration in the mechanisms of brain plasticity indeed represents the proximal cause for nicotine-associated cognitive decline and is a critical contributor to the early pathogenesis of addiction, novel interventions that forestall the development of symptoms might be possible. PMID- 27780993 TI - In Memory of Leonid Gittik: Academic Readings, Dedicated to the Anniversary of Prominent Ukrainian Scientist. PMID- 27780994 TI - Glioblastoma Multiforme with Hemorrhage Mimicking an Aneurysm: Lessons Learnt. AB - BACKGROUND: A sudden onset of neurological symptoms in patients is conventionally thought to be due to vascular phenomenon, with one common differential diagnosis being subarachnoid hemorrhage. Another important differential diagnosis is ischemic stroke. An uncommon cause of such acute symptoms can be hemorrhage in a pre-existing tumor, that is, intratumoral hemorrhage (ITH). PURPOSE: ITH is an important, though uncommon differential diagnosis in cases of sudden onset of neurological deterioration. METHODS AND RESULT: A 60-year-old male presented with seizures and loss of consciousness 12 h prior to admission. The episode was sudden in onset. After detailed clinical and radiological investigations, the patient was diagnosed with glioma with bleed and was successfully operated upon. CONCLUSION: The combination of hemorrhage and ischemic stroke pointed more towards an aneurysm rather than a tumor bleed. There were pointers both in favor of and against both the diagnosis. Therefore, a complex hemorrhagic cerebral tumor with acute presentation and discordant finding on CT or CT angiography should be characterized preoperatively. A large thrombosed aneurysm remains an important differential diagnosis. PMID- 27780992 TI - Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets. AB - Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development. PMID- 27780995 TI - Developing a Human Rights-Based Approach to Tuberculosis. PMID- 27780996 TI - Falling Short of the Rights to Health and Scientific Progress: Inadequate TB Drug Research and Access. AB - The incorporation of human rights-based approaches into TB programs is gaining traction, but little work has explored the application of human rights norms and principles to TB research (a domain traditionally left to bioethics). TB research is gravely underfunded, and the scarcity of resources for TB drug development has contributed to the stubborn persistence of the TB epidemic and helped to create the conditions under which drug-resistant TB has developed and spread. This article shows how human rights-particularly human rights standards, norms, and principles related to the rights to health and benefits of scientific progress can provide insight into understanding how underfunding TB drug research undermines efforts to secure access to safe, effective, and optimized treatment for all people with TB. By analyzing TB research in relation to the rights to health and scientific progress, we aim to clarify the legal obligations of governments to improve the TB drug research system, fund TB research, and make medical advances that result from research available to all people with TB. PMID- 27780997 TI - Multidrug-Resistant TB: Implementing the Right to Health through the Right to Enjoy the Benefits of Scientific Progress. AB - The right to enjoy the benefits of scientific progress (REBSP) is a little-known but potentially valuable right that can contribute to rights-based approaches to addressing multidrug-resistant TB (MDR-TB). We argue that better understanding of the REBSP may help to advance legal and civil society action for health rights. While the REBSP does not provide an individual entitlement to have a new drug developed for MDR-TB, it sets up entitlements to expect a state to establish a legislative and policy framework aimed at developing scientific capacity to address the most important health issues and at disseminating the outcomes of scientific research. By making scientific findings available and accessible, people can be enabled to claim the use of science for social benefits. Inasmuch as the market fails to address neglected diseases such as MDR-TB, the REBSP provides a potential counterbalance to frame a positive obligation on states to both marshal their own resources and to coordinate the actions of multiple other actors towards this goal, including non-state actors. While the latter do not hold the same level of accountability as states, the REBSP can still enable the recognition of obligations at a level of "soft law" responsibilities. PMID- 27780998 TI - Detention of People Lost to Follow-Up on TB Treatment in Kenya: The Need for Human Rights-Based Alternatives. AB - Adherence to treatment is a key element for global TB control. Public health laws can be used to enforce isolation, adherence, and completion of TB treatment. However, the practical application of public health laws can potentially range from voluntary measures to involuntary detention approaches. This paper explores the potential risks and impacts of using detention approaches to enforce TB treatment adherence. In August 2015, we conducted a literature search regarding the application of public health laws to enforce adherence to TB treatment globally, and specifically in Kenya. Texts were analyzed using narrative synthesis. Results indicated that in Kenya, people lost to follow-up on TB treatment were frequently detained in prisons. However, incarceration and detention approaches curtail the rights to health, informed consent, privacy, freedom from non-consensual treatment, freedom from inhumane and degrading treatment, and freedom of movement of people lost to follow-up. Detention could also worsen social inequalities and lead to a paradoxical increase in TB incidence. We suggest the incorporation of less intrusive solutions in legislation and policies. These include strengthening health systems to reduce dependency on prisons as isolation spaces, decentralizing TB treatment to communities, enhancing treatment education, revising the public health laws, and addressing socioeconomic and structural determinants associated with TB incidence and loss to follow-up. PMID- 27780999 TI - TB in Vulnerable Populations: The Case of an Indigenous Community in the Peruvian Amazon. AB - This article analyzes the factors associated with vulnerability of the Ashaninka, the most populous indigenous Peruvian Amazonian people, to tuberculosis (TB). By applying a human rights-based analytical framework that assesses public policy against human rights standards and principles, and by offering a step-by-step framework for a full assessment of compliance, it provides evidence of the relationship between the incidence of TB among the Ashaninka and Peru's poor level of compliance with its human rights obligations. The article argues that one of the main reasons for the historical vulnerability of the Ashaninka to diseases such as TB is a lack of political will on the part of the national government to increase public health spending, ensure that resources reach the most vulnerable population, and adopt and invest in a culturally appropriate health system. PMID- 27781000 TI - Litigation as TB Rights Advocacy: A New Delhi Case Study. AB - One thousand people die every day in India as a result of TB, a preventable and treatable disease, even though the Constitution of India, government schemes, and international law guarantee available, accessible, acceptable, quality health care. Failure to address the spread of TB and to provide quality treatment to all affected populations constitutes a public health and human rights emergency that demands action and accountability. As part of a broader strategy, health activists in India employ Public Interest Litigation (PIL) to hold the state accountable for rights violations and to demand new legislation, standards for patient care, accountability for under-spending, improvements in services at individual facilities, and access to government entitlements in marginalized communities. Taking inspiration from right to health PIL cases (PILs), lawyers in a New Delhi-based rights organization used desk research, fact-findings, and the Right To Information Act to build a TB PIL for the Delhi High Court, Sanjai Sharma v. NCT of Delhi and Others (2015). The case argues that inadequate implementation of government TB schemes violates the Constitutional rights to life, health, food, and equality. Although PILs face substantial challenges, this paper concludes that litigation can be a crucial advocacy and accountability tool for people living with TB and their allies. PMID- 27781002 TI - Petition 329: A Legal Challenge to the Involuntary Confinement of TB Patients in Kenyan Prisons. PMID- 27781001 TI - Double Standards in Global Health: Medicine, Human Rights Law and Multidrug Resistant TB Treatment Policy. AB - The human rights arguments that underpinned the fight against HIV over the last three decades were poised, but ultimately failed, to provide a similar foundation for success against multidrug-resistant TB (MDR-TB) and other diseases of the poor. With more than 1.5 million deaths since 2000 attributed to strains of MDR TB, and with half a million new, and mostly untreated, MDR-TB cases in the world each year, the stakes could not be higher. The World Health Organization (WHO), whose mandate is to champion the attainment by all peoples of the highest possible level of health, recommended unsound medical treatment for MDR-TB patients in resource-poor settings from 1993-2002. Citing cost considerations, WHO did not recommend the available standard of care that had been successfully used to contain and defeat MDR-TB in rich countries. By acting as a strategic gatekeeper in its technical advisory role to donor agencies and countries, it also facilitated the global implementation of a double standard for TB care in low- and middle-income countries (LMICs), upending important legal and scientific priorities. This raises serious questions about whether the organization violated international human rights standards and those established in its own constitution. While calling for additional analysis and discussion on this topic, the authors propose that policymakers should reject double standards of this kind and instead embrace the challenge of implementing the highest standard of care on a global level. PMID- 27781003 TI - Rights-Based TB Programs for Migrants and Prisoners Needed in North Korea. PMID- 27781004 TI - Biosocial Approaches to the 2013-2016 Ebola Pandemic. AB - Despite more than 25 documented outbreaks of Ebola since 1976, our understanding of the disease is limited, in particular the social, political, ecological, and economic forces that promote (or limit) its spread. In the following study, we seek to provide new ways of understanding the 2013-2016 Ebola pandemic. We use the term, 'pandemic,' instead of 'epidemic,' so as not to elide the global forces that shape every localized outbreak of infectious disease. By situating life histories via a biosocial approach, the forces promoting or retarding Ebola transmission come into sharper focus. We conclude that biomedical and culturalist claims of causality have helped obscure the role of human rights failings (colonial legacies, structural adjustment, exploitative mining companies, enabled civil war, rural poverty, and the near absence of quality health care, to name but a few) in the genesis of the 2013-16 pandemic. From early 20th century smallpox and influenza outbreaks to 21st century Ebola, transnational relations of inequality continue to be embodied as viral disease in West Africa, resulting in the preventable deaths of hundreds of thousands of people. PMID- 27781005 TI - An Independent Review and Accountability Mechanism for the Sustainable Development Goals: The Possibilities of a Framework Convention on Global Health. AB - The Framework Convention on Global Health (FCGH), a proposed global treaty to be rooted in the right to health and aimed at health equity, could establish a nuanced, layered, and multi-faceted regime of compliance with, and accountability to, the right to health. In so doing, it would significantly strengthen accountability for the health-related Sustainable Development Goals (SDGs), which it would encompass. Legally binding, the FCGH could facilitate accountability through the courts and catalyze comprehensive domestic accountability regimes, requiring national strategies that include transparency, community and national mechanisms for accountability and participation and an enabling environment for social empowerment. A "Right to Health Capacity Fund" could ensure resources to implement these strategies. Inclusive national processes could establish targets, benchmarks, and indicators consistent with FCGH guidance, with regular reporting to a treaty body, which could also hear individual cases. State reports could be required to include plans to overcome implementation gaps, subjecting poorly complying states to penalties and targeted capacity building measures. Regional special rapporteurs could facilitate compliance through regular country visits, while also responding to serious violations. And reaching beyond government compliance, from capacity building to the courts and contractual obligations, the FCGH could establish nationally enforceable right to health obligations on the private sector. PMID- 27781006 TI - Essential Medicines in National Constitutions: Progress Since 2008. AB - A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states' legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions. PMID- 27781007 TI - Opening the Door to Zero New HIV Infections in Closed Settings. AB - Prisons and other closed settings are high-risk environments for HIV and tuberculosis (TB) transmission. Prisoners often experience overcrowded living conditions and violence-including sexual assault-increasing their vulnerability to HIV and TB. However, high infection rates in prisons affect both prisoners and prison employees. Both groups, in interacting with their families and their communities, represent a potential risk of HIV transmission outside the prison setting. National HIV and TB strategies should therefore include measures to prevent transmission and increase access to HIV-related services in prisons. Courts have progressively recognized the human rights of prisoners, including the right to health and access to HIV-related services. A number of national and regional court decisions have affirmed that prison authorities have a duty of care to prisoners and an obligation to ensure that prisoners have access to HIV prevention measures and treatment. Policies and programs on HIV, AIDS, and TB for prison workplaces that are aligned with the ILO's international labor standards can benefit both prisoners and prison employees. In particular, the ILO's HIV and AIDS Recommendation, 2010 (No. 200) affirms the principle of universal access to HIV services and provides guidance for the HIV/TB response in prison settings. PMID- 27781008 TI - The HIV and AIDS Tribunal of Kenya: An Effective Mechanism for the Enforcement of HIV-related Human Rights? AB - Established under Section 25 of the HIV Prevention and Control Act of 2006, the HIV and AIDS Tribunal of Kenya is the only HIV-specific statutory body in the world with the mandate to adjudicate cases relating to violations of HIV-related human rights. Yet, very limited research has been done on this tribunal. Based on findings from a desk research and semi-structured interviews of key informants conducted in Kenya, this article analyzes the composition, mandate, procedures, practice, and cases of the tribunal with the aim to appreciate its contribution to the advancement of human rights in the context of HIV. It concludes that, after a sluggish start, the HIV and AIDS Tribunal of Kenya is now keeping its promise to advance the human rights of people living with and affected by HIV in Kenya, notably through addressing barriers to access to justice, swift ruling, and purposeful application of the law. The article, however, highlights various challenges still affecting the tribunal and its effectiveness, and cautions about the replication of this model in other jurisdictions without a full appraisal. PMID- 27781009 TI - Human Trafficking Identification and Service Provision in the Medical and Social Service Sectors. AB - The medical sector presents a unique opportunity for identification and service to victims of human trafficking. In this article, we describe local and site specific efforts to develop an intervention tool to be used in an urban hospital's emergency department in the midwestern United States. In the development of our tool, we focused on both identification and intervention to assist trafficked persons, through a largely collaborative process in which we engaged local stakeholders for developing site-specific points of intervention. In the process of developing our intervention, we highlight the importance of using existing resources and services in a specific community to address critical gaps in coverage for trafficked persons. For example, we focus on those who are victims of labor trafficking, in addition to those who are victims of sex trafficking. We offer a framework informed by rights-based approaches to anti trafficking efforts that addresses the practical challenges of human trafficking victim identification while simultaneously working to provide resources and disseminate services to those victims. PMID- 27781010 TI - The Paradox of Happiness: Health and Human Rights in the Kingdom of Bhutan. AB - The Kingdom of Bhutan is seeking to progressively realize the human right to health without addressing the cross-cutting human rights principles essential to a rights-based approach to health. Through a landscape analysis of the Bhutanese health system, documentary review of Bhutanese reporting to the United Nations human rights system, and semi-structured interviews with health policymakers in Bhutan, this study examines the normative foundations of Bhutan's focus on "a more meaningful purpose for development than just mere material satisfaction." Under this development paradigm of Gross National Happiness, the Bhutanese health system meets select normative foundations of the right to health, seeking to guarantee the availability, accessibility, acceptability, and quality of health care and underlying determinants of health. However, where Bhutan continues to restrict the rights of minority populations-failing to address the ways in which human rights are indivisible, interdependent, and interrelated-additional reforms will be necessary to realize the right to health. Given the continuing prevalence of minority rights violations in the region, this study raises research questions for comparative studies in other rights-denying national contexts and advocacy approaches to advance principles of non-discrimination, participation, and accountability through health policy. PMID- 27781011 TI - The Judicialization of Health and the Quest for State Accountability: Evidence from 1,262 Lawsuits for Access to Medicines in Southern Brazil. AB - The impact of increasing numbers of lawsuits for access to medicines in Brazil is hotly debated. Government officials and scholars assert that the "judicialization of health" is driven by urban elites and private interests, and is used primarily to access high-cost drugs. Using a systematic sample of 1,262 lawsuits for access to medicines filed against the southern Brazilian state of Rio Grande do Sul, we assess these claims, offering empirical evidence that counters prevailing myths and affirms the heterogeneity of the judicialization phenomenon. Our findings show that the majority of patient-litigants are in fact poor and older individuals who do not live in major metropolitan areas and who depend on the state to provide their legal representation, and that the majority of medicines requested were already on governmental formularies. Our data challenge arguments that judicialization expands inequities and weakens the universal health care system. Our data also suggest that judicialization may serve as a grassroots instrument for the poor to hold the state accountable. Failing to acknowledge regional differences and attempting to fit all data into one singular narrative may be contributing to a biased interpretation of the nature of judicialization, and limiting the understanding of its drivers, consequences, and implications at local levels. PMID- 27781012 TI - Indigenous Child Health in Brazil: The Evaluation of Impacts as a Human Rights Issue. AB - Improving the health status of indigenous children is a long-standing challenge. Several United Nations committees have identified the health of indigenous peoples as a human rights concern. Addressing the health of indigenous children cannot be separated from their social, cultural, and historic contexts, and any related health program must offer culturally appropriate services and a community perspective broad enough to address the needs of children and the local worlds in which they live. Evaluations of programs must, therefore, address process as well as impacts. This paper assesses interventions addressing indigenous children's health in Brazil, ranging from those explicitly targeting indigenous children's health, such as the targeted immunization program for indigenous peoples, as well as more generalized programs, including a focus upon indigenous children, such as the Integrated Management of Childhood Illness. The paper discusses the tensions and complexities of ethnically targeted health interventions as well as the conceptual and methodological challenge of measuring the processes employed and their impact. The lessons learned, especially the need for countries to more systematically collect data and evaluate impacts using ethnicity as an analytical category, are drawn out with respect to ensuring human rights for all within health sector responses. PMID- 27781013 TI - Assessing and Improving Children's Rights in Hospitals: Case Studies from Kyrgyzstan, Tajikistan, and Moldova. AB - There is a recognized need to raise evidence on how to adopt human rights-based approaches (HRBAs) to health and to assess their impact. In 2013 and 2014, the World Health Organization (WHO) Regional Office for Europe used a set of tools to assess and improve the situation of children's rights in 11 hospitals in Kyrgyzstan, 10 hospitals in Tajikistan, and 21 hospitals in Moldova, by applying a HRBA to health, taking as a reference the Convention on the Rights of the Child (CRC). The assessment results show a similar situation across countries in some areas, and more or less significant variation in others. Common gaps include the need to improve adolescent-friendly health services, the rights to privacy and play; and infrastructure and equipment. In Kyrgyzstan and Tajikistan, a second round of assessment, was carried out, which showed an effective change in several areas, whilst other areas showed persistent gaps. Moldova did not carry out a second round of assessment. Involving children and parents in the assessment was crucial to obtain more reliable data; the project showed how to use the CRC as a framework to improve quality of care for children (QoC); and the tools were proven useful for self-assessment. PMID- 27781014 TI - Childhood Obesity and the Right to Health. AB - Childhood obesity is now a global health epidemic, yet the obligations of states to prevent obesity through fulfillment of the right to health have received limited consideration. This article examines the childhood obesity recommendations of the UN Committee on the Rights of the Child (the committee on the CRC), the Special Rapporteur on the right to health, and the UN High Commissioner on Human Rights. It suggests how their engagement might be strengthened. It concludes that the final report of the World Health Organization's Commission on Ending Childhood Obesity could provide the committee on the CRC with a more systematic basis for advising and assessing preventive measures taken by states. Moreover, while the interim report envisages a central role for states in childhood obesity prevention, it pays inadequate attention to their obligations under international human rights law. It is hoped that this will be remedied in the final report through the adoption of a child-centered approach inspired by the rights to health and play, and the general principles of the Convention on the Rights of the Child (CRC). PMID- 27781015 TI - Human Rights-Based Approaches to Mental Health: A Review of Programs. AB - The incidence of human rights violations in mental health care across nations has been described as a "global emergency" and an "unresolved global crisis." The relationship between mental health and human rights is complex and bidirectional. Human rights violations can negatively impact mental health. Conversely, respecting human rights can improve mental health. This article reviews cases where an explicitly human rights-based approach was used in mental health care settings. Although the included studies did not exhibit a high level of methodological rigor, the qualitative information obtained was considered useful and informative for future studies. All studies reviewed suggest that human rights based approaches can lead to clinical improvements at relatively low costs. Human rights-based approaches should be utilized for legal and moral reasons, since human rights are fundamental pillars of justice and civilization. The fact that such approaches can contribute to positive therapeutic outcomes and, potentially, cost savings, is additional reason for their implementation. However, the small sample size and lack of controlled, quantitative measures limit the strength of conclusions drawn from included studies. More objective, high quality research is needed to ascertain the true extent of benefits to service users and providers. PMID- 27781017 TI - Corruption, Proportionality, and their Challenges. PMID- 27781016 TI - Medical Hostages: Detention of Women and Babies in Hospitals. PMID- 27781018 TI - Tissue Engineering and Regenerative Medicine - New Initiatives for Individual Treatment Offers. PMID- 27781019 TI - Stem Cell-Mediated Regeneration of the Adult Brain. AB - Acute or chronic injury of the adult mammalian brain is often associated with persistent functional deficits as its potential for regeneration and capacity to rebuild lost neural structures is limited. However, the discovery that neural stem cells (NSCs) persist throughout life in discrete regions of the brain, novel approaches to induce the formation of neuronal and glial cells, and recently developed strategies to generate tissue for exogenous cell replacement strategies opened novel perspectives how to regenerate the adult brain. Here, we will review recently developed approaches for brain repair and discuss future perspectives that may eventually allow for developing novel treatment strategies in acute and chronic brain injury. PMID- 27781021 TI - The Use of Adipose Tissue-Derived Progenitors in Bone Tissue Engineering - a Review. AB - 2500 years ago, Hippocrates realized that bone can heal without scaring. The natural healing potential of bone is, however, restricted to small defects. Extended bone defects caused by trauma or during tumor resections still pose a huge problem in orthopedics and cranio-maxillofacial surgery. Bone tissue engineering strategies using stem cells, growth factors, and scaffolds could overcome the problems with the treatment of extended bone defects. In this review, we give a short overview on bone tissue engineering with emphasis on the use of adipose tissue-derived stem cells and small molecules. PMID- 27781022 TI - About ATMPs, SOPs and GMP: The Hurdles to Produce Novel Skin Grafts for Clinical Use. AB - BACKGROUND: The treatment of severe full-thickness skin defects represents a significant and common clinical problem worldwide. A bio-engineered autologous skin substitute would significantly reduce the problems observed with today's gold standard. METHODS: Within 15 years of research, the Tissue Biology Research Unit of the University Children's Hospital Zurich has developed autologous tissue engineered skin grafts based on collagen type I hydrogels. Those products are considered as advanced therapy medicinal products (ATMPs) and are routinely produced for clinical trials in a clean room facility following the guidelines for good manufacturing practice (GMP). This article focuses on hurdles observed for the translation of ATMPs from research into the GMP environment and clinical application. RESULTS AND CONCLUSION: Personalized medicine in the field of rare diseases has great potential. However, ATMPs are mainly developed and promoted by academia, hospitals, and small companies, which face many obstacles such as high financial burdens. PMID- 27781020 TI - Stem Cells in Functional Bladder Engineering. AB - Conditions impairing bladder function in children and adults, such as myelomeningocele, posterior urethral valves, bladder exstrophy or spinal cord injury, often need urinary diversion or augmentation cystoplasty as when untreated they may cause severe bladder dysfunction and kidney failure. Currently, the gold standard therapy of end-stage bladder disease refractory to conservative management is enterocystoplasty, a surgical enlargement of the bladder with intestinal tissue. Despite providing functional improvement, enterocystoplasty is associated with significant long-term complications, such as recurrent urinary tract infections, metabolic abnormalities, stone formation, and malignancies. Therefore, there is a strong clinical need for alternative therapies for these reconstructive procedures, of which stem cell-based tissue engineering (TE) is considered to be the most promising future strategy. This review is focused on the recent progress in bladder stem cell research and therapy and the challenges that remain for the development of a functional bladder wall. PMID- 27781023 TI - Quality Assurance in Biobanking for Pre-Clinical Research. AB - It is estimated that not less than USD 28 billion are spent each year in the USA alone on irreproducible pre-clinical research, which is not only a fundamental loss of investment and resources but also a strong inhibitor of efficiency for upstream processes regarding the translation towards clinical applications and therapies. The issues and cost of irreproducibility has mainly been published on pre-clinical research. In contrast to pre-clinical research, test material is often being transferred into humans in clinical research. To protect treated human subjects and guarantee a defined quality standard in the field of clinical research, the manufacturing and processing infrastructures have to strictly follow and adhere to certain (inter-)national quality standards. It is assumed and suggested by the authors that by an implementation of certain quality standards within the area of pre-clinical research, billions of USD might be saved and the translation phase of promising pre-clinical results towards clinical applications may substantially be improved. In this review, we discuss how an implementation of a quality assurance (QA) management system might positively improve sample quality and sustainability within pre-clinically focused biobank infrastructures. Biobanks are frequently positioned at the very beginning of the biomedical research value chain, and, since almost every research material has been stored in a biobank during the investigated life cycle, biobanking seems to be of substantial importance from this perspective. The role model of a QA-regulated biobank structure can be found in biobanks within the context of clinical research organizations such as in regenerative medicine clusters. PMID- 27781024 TI - Safety of Factor XIII Concentrate: Analysis of More than 20 Years of Pharmacovigilance Data. AB - BACKGROUND: Plasma-derived factor XIII (FXIII) concentrate is an effective treatment for FXIII deficiency. We describe adverse drug reactions (ADRs) reported during pharmacovigilance monitoring of Fibrogammin(r)/Corifact(r) and review published safety data. METHODS: Postmarketing safety reports recorded by CSL Behring from June 1993 to September 2013 were analyzed. Clinical studies published during the same period were also reviewed. RESULTS: Commercial data indicated that 1,653,450,333 IU FXIII concentrate were distributed over the review period, equivalent to 1,181,036 doses for a 70 kg patient. 75 cases were reported (one/15,700 standard doses or 22,046,000 IU). Reports of special interest included 12 cases of possible hypersensitivity reactions (one/98,400 doses or 137,787,500 IU), 7 with possible thromboembolic events (one/168,700 doses or 236,207,200 IU), 5 of possible inhibitor development (one/236,200 doses or 330,690,100 IU), and 20 of possible pathogen transmission (one/59,100 doses or 82,672,500 IU). 19 pathogen transmission cases involved viral infection; 4 could not be analyzed due to insufficient data, but for all others a causal relationship to the product was assessed as unlikely. A review of published literature revealed a similar safety profile. CONCLUSION: Assessment of ADRs demonstrated that FXIII concentrate carries a low risk of ADRs across various clinical situations, suggesting a favorable safety profile. PMID- 27781026 TI - Towards a Molecular Syndromology of the Epilepsies. PMID- 27781025 TI - Thrombopoietin Receptor Agonists Are Often Ineffective in Immune Thrombocytopenia and/or Cause Adverse Reactions: Results from One Hand. AB - BACKGROUND: Eltrombopag and romiplostim are thrombopoietin receptor agonists (TPOs) that have been increasingly used for the treatment of immune thrombocytopenia (ITP). Based on our experience, the incidence of abortive treatment with these drugs and the occurrence of adverse reactions that lead to therapy break-off despite response are higher than has been previously suggested. METHODS: During the last 8 years, a total of 65 patients were treated with eltrombopag and/or romiplostim at our institute. RESULTS: 36 of a total of 58 patients responded well to eltrombopag. In 12 patients that responded, treatment with eltrombopag was discontinued due to the development of adverse reactions. Eltrombopag was replaced by romiplostim in 23 cases (14 non-responders, 9 patients with adverse reactions). Of these patients, 83% responded to romiplostim. Among all patients treated with romiplostim (n = 32), 75% initially responded; however, 8 of these patients developed adverse reactions. Romiplostim was replaced by eltrombopag in 5 cases (4 due to adverse reactions, 1 non responsive patient), and only 3 (60%) of these patients were observed to respond to eltrombopag. CONCLUSION: TPOs often remain ineffective in ITP or result in adverse reactions, which lead to treatment stop or to drug switch. Therefore, alternative treatment options are required. PMID- 27781027 TI - Understanding Genotypes and Phenotypes in Epileptic Encephalopathies. AB - Epileptic encephalopathies are severe often intractable seizure disorders where epileptiform abnormalities contribute to a progressive disturbance in brain function. Often, epileptic encephalopathies start in childhood and are accompanied by developmental delay and various neurological and non-neurological comorbidities. In recent years, this concept has become virtually synonymous with a group of severe childhood epilepsies including West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and several other severe childhood epilepsies for which genetic factors are increasingly recognized. In the last 5 years, the field has seen a virtual explosion of gene discovery, raising the number of bona fide genes and possible candidate genes for epileptic encephalopathies to more than 70 genes, explaining 20-25% of all cases with severe early-onset epilepsies that had otherwise no identifiable causes. This review will focus on the phenotypic variability as a characteristic aspect of genetic epilepsies. For many genetic epilepsies, the phenotypic presentation can be broad, even in patients with identical genetic alterations. Furthermore, patients with different genetic etiologies can have seemingly similar clinical presentations, such as in Dravet syndrome. While most patients carry mutations in SCN1A, similar phenotypes can be seen in patients with mutations in PCDH19, CHD2, SCN8A, or in rare cases GABRA1 and STXBP1. In addition to the genotypic and phenotypic heterogeneity, both benign phenotypes and severe encephalopathies have been recognized in an increasing number of genetic epilepsies, raising the question whether these conditions represent a fluid continuum or distinct entities. PMID- 27781028 TI - Phenotypic Variability from Benign Infantile Epilepsy to Ohtahara Syndrome Associated with a Novel Mutation in SCN2A. AB - Mutations in SCN2A have been associated with benign familial neonatal-infantile seizures (BFNIS) as well as infantile-onset epileptic encephalopathy, such as Ohtahara syndrome (OS). We describe a family with 3 affected individuals carrying the novel SCN2A missense variant c.1147C>G, p.Q383E affecting a residue proximal to the highly conserved selectivity filter in the P-loop of the voltage-gated sodium channel (Nav1.2). All 3 individuals presented with seizures in early infancy. However, there were striking differences in the spectrum of clinical presentations, ranging from BFNIS to OS. A change of ion selectivity of Nav1.2 is considered to be the potential pathomechanism underlying this Nav1.2 channel dysfunction. The observation of benign and severe phenotypes due to an identical mutation within one family contradicts the hypothesis of different modes of inheritance as a mandatory feature discriminating BFNIS from SCN2A encephalopathy. PMID- 27781029 TI - Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures. AB - Benign familial neonatal seizures (BFNS) present a rare familial epilepsy syndrome caused by genetic alterations in the voltage-gated potassium channels Kv7.2 and Kv7.3, encoded by KCNQ2 and KCNQ3. While most BFNS families carry alterations in KCNQ2, mutations in KCNQ3 appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novel KCNQ3 variant, c.835G>T, cosegregating with seizures in 4 tested individuals. This variant results in a substitution of the highly conserved amino acid valine localized within the pore forming transmembrane segment S5 (p.V279F). Functional investigations in Xenopus laevis oocytes revealed a loss of function, which supports p.V279F as a pathogenic mutation. When p.V279F was coexpressed with the wild-type (WT) Kv7.2 subunits, the resulting potassium currents were about 10-fold reduced compared to the WT Kv7.3 and Kv7.2 coexpression. Genotype-phenotype correlation shows an incomplete penetrance of p.V279F. Response to antiepileptic treatment was variable, but evaluation of treatment response remained challenging due to the self-limiting character of the disease. The identification of the pathogenic variant helped to avoid unnecessary investigations in affected family members and allowed guided therapy. PMID- 27781030 TI - Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects. AB - Despite intensive research activity leading to many important discoveries, the pathophysiological mechanisms underlying seizures and epilepsy remain poorly understood. An important number of specific gene defects have been related to various forms of epilepsies, and autoimmunity and epilepsy have been associated for a long time. Certain central nervous system proteins have been involved in epilepsy or acute neurological diseases with seizures either due to underlying gene defects or immune dysfunction. Here, we focus on 2 of them that have been the object of particular attention and in-depth research over the past years: the N-methyl-D-aspartate receptor and the leucin-rich glioma-inactivated protein 1 (LGI1). We also describe illustrative examples of situations in which genetics and immunology meet in the complex pathways that underlie seizures and epilepsy. PMID- 27781033 TI - Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome. AB - Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected. PMID- 27781031 TI - Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies. AB - In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs. PMID- 27781034 TI - Generalized Epilepsy and Myoclonic Seizures in 22q11.2 Deletion Syndrome. AB - Prompted by the observations of juvenile myoclonic epilepsy (JME) in 22q11.2 deletion syndrome (22q11DS) and recurrent copy number variants in genetic generalized epilepsy (GGE), we searched for further evidence supporting a possible correlation of 22q11DS with GGE and with myoclonic seizures. Through routine diagnostics, we identified 3 novel individuals with the seemingly uncommon combination of 22q11DS and JME. We subsequently screened the literature for reports focussing on the epilepsy phenotype in 22q11DS. We additionally screened a database of 173 22q11DS patients and identified a fourth individual with JME as well as 2 additional cases with GGE. We describe 6 novel and 22 published cases with co-occurrence of 22q11DS and GGE. In many patients, GGE was associated with myoclonic seizures allowing for a diagnosis of JME in at least 6 individuals. Seventeen of the 173 22q11DS cases (10%) had a diagnosis of either focal or generalized epilepsy. In these cases, focal epilepsy could often be attributed to syndrome-associated hypocalcaemia, cerebral bleeds, or structural brain anomalies. However, the cause of GGE remained unclear. In this study, we describe and review 28 individuals with 22q11DS and GGE (especially JME), showing that both disorders frequently co-occur. Compared to the reported prevalence of 15-21%, in our case series only 10% of 22q11DS individuals were found to have epilepsy, often GGE. Since 22q11.2 does not contain convincing GGE candidate genes, we discuss the possibility of an aetiological correlation through a possibly disturbed interaction with the GABAB receptor. PMID- 27781032 TI - Genetic Basis of Brain Malformations. AB - Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly pachygyria-severe band heterotopia are diffuse neuronal migration disorders causing severe global neurological impairment. Abnormalities of the LIS1, DCX, ARX, RELN, VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5 genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes (TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, and DYNC1H1), regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes and cause neurological and cognitive impairment that vary from severe to mild deficits. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous, and only in a small minority of patients, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms. PMID- 27781035 TI - Decoding the Semantic Content of Natural Movies from Human Brain Activity. AB - One crucial test for any quantitative model of the brain is to show that the model can be used to accurately decode information from evoked brain activity. Several recent neuroimaging studies have decoded the structure or semantic content of static visual images from human brain activity. Here we present a decoding algorithm that makes it possible to decode detailed information about the object and action categories present in natural movies from human brain activity signals measured by functional MRI. Decoding is accomplished using a hierarchical logistic regression (HLR) model that is based on labels that were manually assigned from the WordNet semantic taxonomy. This model makes it possible to simultaneously decode information about both specific and general categories, while respecting the relationships between them. Our results show that we can decode the presence of many object and action categories from averaged blood-oxygen level-dependent (BOLD) responses with a high degree of accuracy (area under the ROC curve > 0.9). Furthermore, we used this framework to test whether semantic relationships defined in the WordNet taxonomy are represented the same way in the human brain. This analysis showed that hierarchical relationships between general categories and atypical examples, such as organism and plant, did not seem to be reflected in representations measured by BOLD fMRI. PMID- 27781036 TI - Modulation of Primary Immune Response by Different Vaccine Adjuvants. AB - Adjuvants contribute to enhancing and shaping the vaccine immune response through different modes of action. Here early biomarkers of adjuvanticity after primary immunization were investigated using four different adjuvants combined with the chimeric tuberculosis vaccine antigen H56. C57BL/6 mice were immunized by the subcutaneous route with different vaccine formulations, and the modulation of primary CD4+ T cell and B cell responses was assessed within draining lymph nodes, blood, and spleen, 7 and 12 days after priming. Vaccine formulations containing the liposome system CAF01 or a squalene-based oil-in-water emulsion (o/w squalene), but not aluminum hydroxide (alum) or CpG ODN 1826, elicited a significant primary antigen-specific CD4+ T cell response compared to antigen alone, 7 days after immunization. The effector function of activated CD4+ T cells was skewed toward a Th1/Th17 response by CAF01, while a Th1/Th2 response was elicited by o/w squalene. Differentiation of B cells in short-lived plasma cells, and subsequent early H56-specific IgG secretion, was observed in mice immunized with o/w squalene or CpG adjuvants. Tested adjuvants promoted the germinal center reaction with different magnitude. These results show that the immunological activity of different adjuvants can be characterized by profiling early immunization biomarkers after primary immunization. These data and this approach could give an important contribution to the rational development of heterologous prime-boost vaccine immunization protocols. PMID- 27781038 TI - Stent Retriever-Based Thrombectomy in Octogenarians. AB - BACKGROUND AND AIMS: Stent retriever-based thrombectomy (SRT) may be beneficial in patients with large hemispheric stroke. Previous studies concluded that favorable outcomes are far less frequent after endovascular therapy in older patients but have not explored outcomes in the era of newer-generation stent retrievers. MATERIALS AND METHODS: Consecutive patients with large hemispheric stroke treated with SRT were included. We compared neurological and functional outcomes between patients younger and older than 80. RESULTS: We included 16 patients older than 80 (22.5%, mean age 84.1 +/- 4.4, 56% females) and compared them to 55 patients that were younger than 80 (77.5%, mean age 63.1 +/- 12.5, 51% females). Risk factor profile, admission neurological severity, stroke etiology and procedure-related variables including excellent target vessel recanalization did not differ between the groups. Favorable outcome at 90 days (modified Rankin score <=2) was more common in younger patients (77 vs. 23%; p = 0.031). In contrast, mortality rates were higher in octogenarians (40 vs. 7%; p = 0.01). Logistic regression analysis adjusting for neurological severity and collateral state identified age over 80 (odds ratio, OR 0.15, 95% CI 0.03-0.75; p = 0.02) and reperfusion state (OR 7.4, 95% CI 1.1-49.9; p = 0.04) as significant modifiers of favorable outcome. Similarly, age over 80 was identified as a positive predictor of mortality (OR 8.1, 95% CI 1.8-36.7; p = 0.007). CONCLUSIONS: Octogenarians have higher chances of mortality and lower probability of achieving functional independence even after SRT. Nevertheless, because some elderly patients do achieve favorable outcomes, the cost-effectiveness of SRT in this population needs to be further studied. PMID- 27781037 TI - Rescue Thrombectomy in Large Vessel Occlusion Strokes Leads to Better Outcomes than Intravenous Thrombolysis Alone: A 'Real World' Applicability of the Recent Trials. AB - BACKGROUND: The Interventional Management of Stroke III (IMS-III) trial demonstrated no benefit for intravenous recombinant tissue plasminogen activator (IV rt-PA) followed by endovascular therapy versus IV rt-PA alone. However, IMS III mostly included earlier generation devices. The recent thrombectomy trials have incorporated the stent-retriever technology, but their generalizability remains unknown. METHODS: The North American Solitaire Acute Stroke (NASA) registry recruited patients treated with the Solitaire FRTM device between March 2012 and February 2013. The NASA-IMS-III-Like Group (NILG baseline NIHSS score >=10 who received IV rt-PA) was compared to the IV rt-PA and IV + intra-arterial (IA)-IMS-III groups and the MR CLEAN, ESCAPE, SWIFT Prime, and REVASCAT trial controls to assess the stent-retriever treatment in the 'real-world' setting. The NILG was also compared to non-IV rt-PA NASA patients to evaluate the impact of IV rt-PA on thrombectomy. RESULTS: A total of 136 of the 354 NASA patients fulfilled criteria for the NILG. Baseline characteristics were well balanced across groups. Time from onset to puncture was higher in NILG than IV+IA-IMS-III patients (274 +/- 112 vs. 208 +/- 47 min, p < 0.0001). Occlusions involving the intracranial ICA, MCA-M1, or basilar arteries were more common in NILG than IV+IA-IMS-III patients (91.2 vs. 47.2%, p < 0.00001). Modified thrombolysis in cerebral infarction >=2b reperfusion was higher in NILG than IV+IA-IMS-III patients (74.3 vs. 39.6%, p < 0.00001). A 90-day modified Rankin Scale score <=2 was more frequent in the NILG than IV+IA-IMS-III patients (51.9 vs. 40.8%, p = 0.03) and MR CLEAN (51.9 vs. 19.1%, p < 0.00001), ESCAPE (51.9 vs. 29.3%, p = 0.0002), SWIFT Prime (51.9 vs. 35.5%, p = 0.02), and REVASCAT (51.9 vs. 28.2%, p = 0.0003) controls. Symptomatic intracranial hemorrhage definitions varied across the different studies with rates ranging from 2.7% (ESCAPE) to 11.9% (NILG). The NILG 90-day mortality (24.4%) was higher than in SWIFT Prime but comparable to all other groups. IV rt-PA was an independent predictor of good outcome in NASA (OR = 2.3, 95% CI 1.2-4.7). CONCLUSION: Our results support the 'real-world' applicability of the recent thrombectomy trials. PMID- 27781039 TI - Recanalization and Angiographic Reperfusion Are Both Associated with a Favorable Clinical Outcome in the IMS III Trial. AB - BACKGROUND: Prompt revascularization is the main goal of acute ischemic stroke treatment. We examined which revascularization scale - reperfusion (modified Treatment in Cerebral Infarctions, mTICI) or recanalization (Arterial Occlusive Lesion, AOL) - better predicted the clinical outcome in ischemic stroke participants treated with endovascular therapy (EVT). Additionally, we determined the optimal thresholds for the predictive accuracy of each scale. METHODS: We included participants from the Interventional Management of Stroke (IMS) III trial with complete occlusion in the internal carotid artery terminus or proximal middle cerebral artery (M1 or M2) who completed EVT within 7 h of symptom onset. The abilities of the AOL and mTICI scales to predict a favorable outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) were compared by receiver operating characteristic analyses. The maximal sensitivity and specificity for each revascularization scale were established. RESULTS: Among 240 participants who met the study inclusion criteria, 79 (33%) achieved a favorable outcome. Higher scores of mTICI and AOL increased the likelihood of a favorable outcome (2.7% with mTICI 0 vs. 83.3% with mTICI 3, and 3.0% with AOL 0 vs. 43% with AOL 3). The accuracy of mTICI reperfusion and AOL recanalization for a favorable outcome prediction was similar, with optimal thresholds of mTICI 2b/3 and AOL 3, respectively. CONCLUSION: Reperfusion (mTICI) and recanalization (AOL) predicted a favorable clinical outcome with comparable accuracy in ischemic stroke participants treated with EVT. Optimal revascularization goals to maximize clinical outcome (modified Rankin Scale score of 0-2) consisted of complete recanalization (AOL 3) and reperfusion of at least 50% of the arterial tree of the symptomatic artery (mTICI 2b/3) in the IMS III trial setting. PMID- 27781040 TI - Safety Outcomes Using a Proximal Protection Device in Carotid Stenting of Long Carotid Stenoses. AB - BACKGROUND: Embolic protection devices can prevent atherosclerotic emboli during carotid stenting. Newer proximal protection devices reverse flow in the internal carotid artery (ICA), leading to reduction in perioperative microemboli. The risk of stroke is high for carotid stenting of ICA lesions with a length >10 mm and/or angiographic string sign. OBJECTIVE: We aimed to evaluate the safety outcomes of proximal embolic protection device usage in this high-risk group. METHODS: This is a retrospective analysis of patients who underwent carotid stenting procedures with proximal embolic protection devices at a tertiary care center. High-risk features for adverse events with carotid stenting were identified. Peri- and postprocedural outcomes were recorded. We further compared outcomes in patients with a carotid stenosis length >10 mm to those with shorter stenosis. RESULTS: From January 2011 to December 2014, we included 27 patients; 96.3% were symptomatic and 3.7% were asymptomatic. There was a stent placement technical success rate of 100%. No major stroke or coronary events were recorded. One minor stroke event developed in one patient. A carotid lesion length >10 mm and/or angiographic string sign was noted in 21/27 patients, with an average lesion length of 14.4 mm. One patient (4.8%) in this group developed a minor stroke event. Neither a coronary nor a major stroke event was recorded in this group. There was no significant difference in the complication rate between the long lesion and the control group. CONCLUSION: In our patient cohort, it was found that a proximal embolic protection device is safe for patients with carotid stenosis, including those with a carotid lesion length >10 mm and/or angiographic string sign. PMID- 27781041 TI - Visual Improvement after Intra-Arterial Thrombolysis for Central Retinal Artery Occlusion Does Not Correlate with Time to Treatment. AB - BACKGROUND: Intra-arterial thrombolysis (IAT) for the treatment of acute central retinal artery occlusion (CRAO) has demonstrated variable results for improving visual acuity and remains controversial. Despite limited evidence, time from symptom onset to thrombolysis is believed to be an important factor in predicting visual improvement after IAT. METHODS: A comprehensive review of the literature was conducted and individual subject level data were extracted from relevant studies. From these, a secondary analysis was performed. Initial and final logarithm of the minimum angle of resolution (logMAR) scores were either abstracted directly from relevant studies or converted from provided Snellen chart scores. Change in logMAR scores was used to determine overall treatment efficacy. RESULTS: Data on 118 patients undergoing IAT from five studies were evaluated. Median logMAR improvement in visual acuity was -0.400 (p < 0.001). There was no significant association between logMAR change and time to treatment when time (hours) was described as a continuous variable or described categorically [0-4, 4-8, 8-12, 12+ h; or 0-6, 6-12, 12+ h]. CONCLUSION: The visual improvement observed in this series had no relationship to the time from symptom onset to treatment with IAT. This suggests that patients may have the possibility for improvement even with delayed presentation to the neurointerventionalist. Other factors, such as completeness of retinal occlusion, may be more important than time to treatment. Additional studies to determine optimal patient selection criteria for the endovascular treatment of acute CRAO are needed. PMID- 27781042 TI - CBV_ASPECTS Improvement over CT_ASPECTS on Determining Irreversible Ischemic Lesion Decreases over Time. AB - : The Alberta Stroke Program Early CT Score (ASPECTS) is a useful scoring system for assessing early ischemic signs on noncontrast computed tomography (CT). Cerebral blood volume (CBV) on CT perfusion defines the core lesion assumed to be irreversibly damaged. We aim to explore the advantages of CBV_ASPECTS over CT_ASPECTS in the prediction of final infarct volume according to time. METHODS: Consecutive patients with anterior circulation stroke who underwent endovascular reperfusion according to initial CT_ASPECTS >=7 were studied. CBV_ASPECTS was assessed blindly later on. Recanalization was defined as thrombolysis in cerebral ischemia score 2b-3. Final infarct volumes were measured on follow-up imaging. We compared ASPECTS on CBV and CT images, and defined ASPECTS agreement as: CT_ASPECTS - CBV_ASPECTS <=1. RESULTS: Sixty-five patients, with a mean age of 67 +/- 14 years and a median National Institutes of Health Stroke Scale score of 16 (range 10-20), were studied. The recanalization rate was 78.5%. The median CT_ASPECTS was 9 (range 8-10), and the CBV_ASPECTS was 8 (range 8-10). The mean time from symptoms to CT was 219 +/- 143 min. Fifty patients (76.9%) showed ASPECTS agreement. The ASPECTS difference was inversely correlated to the time from symptoms to CT (r = -0.36, p < 0.01). A ROC curve defined 120 min as the best cutoff point after which the ASPECTS difference becomes more frequently <=1. After 120 min, 89.5% of the patients showed ASPECTS agreement (as compared with 37.5% for <120 min, p < 0.01). CBV_ASPECTS but not CT_ASPECTS correlated with final infarct (r = -0.33, p < 0.01). However, if CT was done >2 h after symptom onset, CT_ASPECTS also correlated to final infarct (r = -0.39, p = 0.01). CONCLUSIONS: In acute stroke, CBV_ASPECTS correlates with the final infarct volume. However, when CT is performed after 120 min from symptom onset, CBV_ASPECTS does not add relevant information to CT_ASPECTS. PMID- 27781043 TI - Treatment Strategies for Acute Ischemic Stroke Caused by Carotid Artery Occlusion. AB - Background: Acute ischemic stroke caused by internal carotid artery (ICA) occlusion usually has a poor prognosis, especially the T occlusion cases without functional collaterals. The efficacy of intravenous (IV) or intra-arterial (IA) thrombolysis with recombinant tissue plasminogen activator (rt-PA) remains ambiguous in these patients. Eendovascular recanalization of the occluded carotid has been attempted in recent years as a potential strategy. However, the different etiologies of ICA occlusion pose a significant challenge to neurointerventionists. Recently, several endovascular evolvements have been reported in treating carotid occlusion-related stroke. This review summarizes the current status of treatment for acute ICA occlusion. PMID- 27781044 TI - Clopidogrel plus Aspirin for Symptomatic Intracranial Atherosclerotic Stenosis: A Pilot Study. AB - BACKGROUND AND PURPOSE: There are limited data on the optimal duration of dual antiplatelet therapy for secondary stroke prevention in patients with symptomatic intracranial atherosclerotic disease. METHODS: Consecutive patients presenting with high-grade (70-99%) symptomatic intracranial stenosis from January 1, 2011, to December 31, 2013, and evaluated within 30 days of the index event were eligible for this analysis. All patients underwent treatment with aspirin plus clopidogrel for a target duration of 12 months along with aggressive medical management based on the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) protocol; all patients were given gastrointestinal prophylaxis for the duration of their aspirin and clopidogrel treatment. Clinical and safety outcomes of our cohort were compared with the medical arm of the SAMMPRIS trial cohort (n = 227). RESULTS: Our cohort included 25 patients that met the inclusion criteria. Achievement of blood pressure and LDL cholesterol targets were similar between our cohort and the SAMMPRIS cohort. At 1 year, the rates of stroke, myocardial infarction or vascular death were 0% in our cohort and 16% in the SAMMPRIS cohort (p = 0.03). At 1 year, major bleeding rates were similar between our cohort and the SAMMPRIS cohort (4 vs. 2.2%, p = 1.0). CONCLUSION: A prolonged course of dual antiplatelet therapy for symptomatic intracranial atherosclerotic disease may be associated with less vascular events with no increase in hemorrhagic complications. PMID- 27781045 TI - Local Fibrinolysis in Spontaneous Supratentorial Hematomas: Comparison with Surgical and Medical Treatment. AB - OBJECTIVE: To evaluate the effectiveness of minimally invasive craniopuncture with local fibrinolysis in the management of supratentorial spontaneous intracerebral hemorrhage (SICH). METHODS: The study included 218 consecutive patients with supratentorial SICH who were assigned to one of three groups: treated with minimally invasive craniopuncture with local fibrinolysis, treated with craniotomy or other minimally invasive techniques without local fibrinolysis, or receiving conservative management alone. RESULTS: Minimally invasive craniopuncture with local fibrinolysis was associated with a lower rate of assisted ventilation, a shorter period of in-hospital stay, a more frequent initiation of early rehabilitation, and a lower mortality rate at all periods of assessment. The overall mortality at 12 months was 19.4% (vs. 50.0 and 33.3% in the two other therapy groups). Lobar (subcortical and cortical) SICHs treated with local fibrinolysis had an overall mortality of 4.8% (vs. 43.5 and 41.7% in the two other therapy groups). On the other hand, SICHs having mixed (basal ganglia and lobar) locations treated with medical therapy alone had an overall mortality of 28.6%, while associated surgery with or without local fibrinolysis increased the overall mortality to over 65%. CONCLUSIONS: The study demonstrated the applicability of minimally invasive craniopuncture with local fibrinolysis for the management of supratentorial SICHs and the advantages it may have in certain categories of patients. The method proved particularly useful in lobar SICHs, being associated with the lowest mortality. Mixed SICHs do not represent a predilection for surgical interventions; however, the results related to mixed supratentorial locations need confirmation in larger cohorts. PMID- 27781046 TI - Is Intra-Arterial Treatment for Acute Ischemic Stroke Less Effective in Women than in Men? AB - INTRODUCTION: Stroke etiology and outcome after ischemic stroke differ between men and women. We examined if sex modifies the effect of intra-arterial treatment (IAT) in a randomized clinical trial of IAT for acute ischemic stroke in the Netherlands (MR CLEAN). PATIENTS AND METHODS: The primary outcome was the score on the modified Rankin scale at 90 days. We tested for interaction between sex and treatment and estimated the treatment effect by sex with multiple ordinal logistic regression with adjustment for prognostic factors. RESULTS: All 500 patients were included in the analysis; 292 (58.4%) were men. The treatment effect (adjusted common odds ratio) was 2.39 [95% confidence interval (CI) 1.55 3.68] in men and 0.99 (95% CI 0.60-1.66) in women (pinteraction = 0.016). In women, mortality was higher in the intervention group than in the control group (24 vs. 15%, p = 0.07). Serious adverse events occurred more often in women than in men undergoing intervention. There were no differences in neuro-imaging outcomes. DISCUSSION AND CONCLUSION: Contrary to other studies, we found a significant interaction between sex and treatment effect in the MR CLEAN trial. Pooled analyses of all published thrombectomy trials did not confirm this finding. In MR CLEAN, women seem to have a slightly more unfavorable profile, causing higher mortality and more serious adverse events, but insufficient to explain the absence of an overall effect. This suggests a play of chance and makes it clear that IAT should not be withheld in women. PMID- 27781047 TI - Functional Independence following Endovascular Treatment for Basilar Artery Occlusion despite Extensive Bilateral Pontine Infarcts on Diffusion-Weighted Imaging: Refuting a Self-Fulfilling Prophecy. AB - BACKGROUND AND PURPOSE: Extensive brainstem diffusion-weighted imaging (DWI) hyperintensity has been associated with poor outcomes. We aim at documenting a series of patients with extensive DWI pontine lesions who achieved independence following endovascular therapy and aggressive medical therapy in the setting of posterior circulation basilar artery occlusion (BAO). METHODS: This is a retrospective endovascular database review of a single-operator experience over a 9-year period for patients with (1) complete BAO, (2) extensive bilateral pontine DWI changes and (3) 90-day modified Rankin scale 0-2. RESULTS: Three out of a total of 40 patients met the inclusion criteria. Case 1 was an 18-year-old male with National Institutes of Health Stroke Scale (NIHSS) 32 on admission, treated 25 h after symptom onset. Case 2 was a 56-year-old male with NIHSS 19, treated 10 h after onset. Case 3 was a 73-year-old male with NIHSS 29, treated 6 h after onset. Full endovascular reperfusion was achieved in all 3 patients. A literature review identified 9 additional cases of extensive pontine DWI changes and good outcome. These patients were young (32 +/- 22 years), mostly males (69%), presented with a relatively low posterior circulation Acute Stroke Prognosis Early CT Score (6 +/- 1), were treated relatively late from last known normal (13 +/- 10 h) and were mostly (84%) treated with endovascular intervention. CONCLUSION: Extensive bilateral pontine DWI lesions among patients with BAO are not an unequivocal indicator of poor prognosis. We advise strong caution when considering these findings in the treatment decision algorithm. PMID- 27781049 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000443617.]. PMID- 27781048 TI - Internal Carotid Artery S-Shaped Curve as a Marker of Fibromuscular Dysplasia in Dissection-Related Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Craniocervical fibromuscular dysplasia (FMD) is associated with dissections and with S-shaped curves in the internal carotid artery (ICA). We evaluated the occurrence of S-curves in patients presenting with acute strokes due to ICA steno-occlusive dissections. METHODS: This was a retrospective review of the interventional databases of two academic tertiary care institutions. The presence of ICA S-shaped curves, C-shaped curves, 360 degree loops, as well as classic FMD and atherosclerotic changes at the ICA bulb and curve/loop was determined. Cases of carotid dissections were compared with a control group (consecutive non-tandem anterior circulation strokes). RESULTS: Twenty-four patients with carotid dissections were compared to 92 controls. Baseline characteristics and procedural variables were similar, with the exception of younger age, less frequent history of hypertension, diabetes, atrial fibrillation and stent retriever use in patients with dissections. The rates of mTICI2b-3 reperfusion, parenchymal hematoma, good outcome and mortality were similar amongst groups. The frequency of S-curves (any side without superimposed atherosclerosis) was 29% in the dissection group versus 7% in controls (p < 0.01). S-curves were typically mirror images within the dissection group (85% had bilateral occurrence). The frequency of C-shaped and 360-degree curves was similar between groups. FMD changes within the craniocervical arteries were statistically more common in dissection patients. Ten patients (41%) of the dissection group had S-curves or classic FMD changes. Multivariate analysis indicated that S-curves were independently associated with the presence of dissections. CONCLUSION: S-shaped ICA curves are predictably bilateral, highly associated with carotid dissections in patients with moderate to severe strokes, and may suggest an underlying presence of FMD. PMID- 27781050 TI - The Role of Catheter Angiography in the Diagnosis of Central Nervous System Vasculitis. AB - BACKGROUND: Central nervous system vasculitis (CNSV) is a rare disorder, the pathophysiology of which is not fully understood. It involves a combination of inflammation and thrombosis. CNSV is most commonly associated with headache, gradual changes in mental status, and focal neurological symptoms. Diagnosis requires the effective use of history, laboratory testing, imaging, and biopsy. Catheter angiography can be a powerful tool in the diagnosis when common and low frequency angiographic manifestations of CNSV are considered. We review these manifestations and their place in the diagnostic algorithm of CNSV. SUMMARY: We reviewed the PubMed database for case series of CNSV that included 5 or more patients. Demographic and angiographic findings were collected. Angiographic findings were dichotomized between common and low-frequency findings. A system for incorporating these findings into clinical decision-making is proposed. KEY MESSAGE: CNSV is a diagnostic challenge due to the absence of a true gold standard test. In the absence of such a test, catheter angiography remains a central piece of the diagnostic puzzle when appropriately employed and interpreted. PMID- 27781051 TI - Improving the Evaluation of Collateral Circulation by Multiphase Computed Tomography Angiography in Acute Stroke Patients Treated with Endovascular Reperfusion Therapies. AB - : Good collateral circulation (CC) is associated with favorable outcomes in acute stroke, but the best technique to evaluate collaterals is controversial. Single phase computed tomography angiography (sCTA) is widely used but lacks temporal resolution. We aim to compare CC evaluation by sCTA and multiphase CTA (mCTA) as predictors of outcome in endovascular treated patients. METHODS: Consecutive endovascular treated patients with M1 middle cerebral artery (MCA) or terminal intracranial carotid artery (TICA) occlusion confirmed by sCTA were included. Two more CTA acquisitions with 8- and 16-second delays were performed for mCTA. Endovascular thrombectomy was performed independently of the CC status according to a local protocol [Alberta Stroke Program Early CT score (ASPECTS) >6, modified Rankin scale (mRS) score <3]. CC on sCTA and mCTA were compared. RESULTS: 108 patients were included. Their mean age was 69.6 +/- 13 years and their median National Institutes of Health Stroke Scale (NIHSS) score was 17 (interquartile range 8). 79 (73.1%) had M1 MCA and 29 (26.9%) TICA occlusions. The mean time from symptom onset to CTA was 146.8 +/- 96.5 min. On sCTA, 50.9% patients presented good CC vs. 57.5% on mCTA. Good CC status in both sCTA and mCTA had a lower 24-hour infarct volume (27.4 vs. 74.8 cm3 on sCTA, p = 0.04; 17.2 vs. 97.8 cm3 on mCTA, p < 0.01). However, only good CC on mCTA was associated with lower 24-hour (5 vs. 8.5, p = 0.04) and median discharge NIHSS (2 vs. 4.5, p = 0.04) scores and functional independency (mRS score <3) at 3 months (76.9 vs. 23.1%, p < 0.01). In a logistic regression model including age, NIHSS, ASPECTS and recanalization, only age (OR 0.96, 95% CI 0.93-0.99, p = 0.02) and good CC on mCTA (OR 5, 95% CI 1.99-12.6, p < 0.01) were independent predictors of functional outcome at 3 months. CONCLUSION: CC evaluation by mCTA is a better prognostic marker than CC evaluation by sCTA for clinical and functional endpoints in acute stroke patients treated with endovascular thrombectomy. PMID- 27781052 TI - Arteriovenous Malformations in the Pediatric Population: Review of the Existing Literature. AB - Arteriovenous malformations (AVMs) in the pediatric population are relatively rare but reportedly carry a higher rate of rupture than in adults. This could be due to the fact that most pediatric AVMs are only detected after rupture. We aimed to review the current literature regarding the natural history and the clinical outcome after multimodality AVM treatment in the pediatric population, as optimal management for pediatric AVMs remains controversial. A multidisciplinary approach using multimodality therapy if needed has been proved to be beneficial in approaching these lesions in all age groups. Microsurgical resection remains the gold standard for the treatment of all accessible pediatric AVMs. Embolization and radiosurgery should be considered as an adjunctive therapy. Embolization provides a useful adjunct therapy to microsurgery by preventing significant blood loss and to radiosurgery by decreasing the volume of the AVM. Radiosurgery has been described to provide an alternative treatment approach in certain circumstances either as a primary or adjuvant therapy. PMID- 27781053 TI - Electrophysiology and heart rhythm disorders in older adults. PMID- 27781054 TI - Left atrial area index predicts adverse cardiovascular events in patients with unstable angina pectoris. AB - BACKGROUND: The left atrial size has been considered as a useful marker of adverse cardiovascular outcomes. However, it is not well known whether left atrial area index (LAAI) has predictive value for prognosis in patients with unstable angina pectoris (UAP). This study was aimed to assess the association between LAAI and outcomes in UAP patients. METHODS: We enrolled a total of 391 in hospital patients diagnosed as UAP. Clinical and echocardiographic data at baseline were collected. The patients were followed for the development of adverse cardiovascular (CV) events, including hospital readmission for angina pectoris, acute myocardial infarction (AMI), congestive heart failure (CHF), stroke and all-cause mortality. RESULTS: During a mean follow-up time of 26.3 +/- 8.6 months, 98 adverse CV events occurred (84 hospital readmission for angina pectoris, four AMI, four CHF, one stroke and five all-cause mortality). In a multivariate Cox model, LAAI [OR: 1.140, 95% CI: 1.016-1.279, P = 0.026], diastolic blood pressure (OR: 0.976, 95% CI: 0.956-0.996, P = 0.020) and pulse pressure (OR: 1.020, 95% CI: 1.007-1.034, P = 0.004) were independent predictors for adverse CV events in UAP patients. CONCLUSIONS: LAAI is a predictor of adverse CV events independent of clinical and other echocardiographic parameters in UAP patients. PMID- 27781055 TI - Total ischemic time and outcomes for patients with ST-elevation myocardial infarction: does time of admission make a difference? AB - OBJECTIVE: To investigate whether admission time was associated with the delay of reperfusion therapy and in-hospital death in patients with ST-elevation myocardial infarction (STEMI). METHODS: All patients with STEMI who were admitted to the emergency department and underwent primary percutaneous coronary intervention at Peking University People's Hospital between April 2012 and March 2015 were included. We examined differences in clinical characteristics, total ischemic time, and in-hospital death between patients admitted during off-hours and those admitted during regular hours. Multivariate logistic regression was used to estimate the relationship between off-hours admission and clinical outcome. RESULTS: The sample comprised 184 and 105 patients with STEMI admitted to hospital during off-hours and regular hours, respectively. Total ischemic and onset-to-door times were significantly shorter in patients admitted during off hours than among those admitted during regular hours (all P < 0.05). Door-to balloon (DTB) time, the rate of DTB time <= 90 min, and in-hospital death were comparable between groups. Multivariate logistic regression showed that age and creatinine level, but not off-hours admission, were associated independently with increased in-hospital death. CONCLUSIONS: Off-hours admission did not result in delayed reperfusion therapy or increased in-hospital mortality in patients with STEMI. Further efforts should focus on identifying pivotal factors associated with the pre-hospital and in-hospital delay of reperfusion therapy, and implementing quality improvement initiatives for reperfusion programs. PMID- 27781056 TI - Clinical characteristics and one year outcomes in Chinese atrial fibrillation patients with stable coronary artery disease: a population-based study. AB - BACKGROUND: Atrial fibrillation (AF) and coronary artery disease (CAD) often coexist, however, the clinical characteristics and the impact of stable CAD on the outcomes in Chinese patients with AF has not been well understood. METHODS: Consecutive AF patients in 20 hospitals in China from November 2008 to October 2011 were enrolled. The primary endpoints included 1-year all-cause mortality, stroke, non-central nervous system (non-CNS) embolism, and major bleeding. RESULTS: A total of 1947 AF patients were analyzed, of whom 40.5% had stable CAD. The mean CHADS2 scores in CAD patients were significantly higher than that of non CAD patients (2.4 +/- 1.4 vs. 1.4 +/- 1.2, P < 0.001). During follow-up period, warfarin use is low in both groups, with relatively higher proportion in non-CAD patients compared with CAD patients (22.3% vs. 10.7%, P < 0.001). Compared with non-CAD patients, CAD patients had higher one-year all-cause mortality (16.8% vs. 12.9%, P = 0.017) and incidence of stroke (9.0% vs. 6.4%, P = 0.030), while the non-CNS embolism and major bleeding rates were comparable between the two groups. After multivariate adjustment, stable CAD was independently associated with increased risk of 1-year all-cause mortality (HR = 1.35, 95% CI: 1.01-1 .80, P = 0.040), but not associated with stroke (HR = 1.07, 95% CI: 0.72-1.58, P = 0.736). CONCLUSIONS: Stable CAD was prevalent in Chinese AF patients and was independently associated with increased risk of 1-year all-cause mortality. Chinese AF patients with stable CAD received inadequate antithrombotic therapy and this grim status of antithrombotic therapy needed to be improved urgently. PMID- 27781057 TI - Uncontrolled hypertension in older patients: markers and associated factors to masked and white-coat effect. AB - BACKGROUND: Hypertension is the main risk factor for cardiovascular diseases, affecting more than half the elderly population. It is essential to know if they have proper control of hypertension. The aim of this study was to identify the associated factors to masked uncontrolled hypertension and false uncontrolled hypertension in older patients. METHODS: Two-hundred seventy-three individuals (70.1 +/- 6.7 years-old) had blood pressure (BP) measured at the office and by ambulatory BP monitoring (ABPM), with the definition of controlled group (C), individuals with high office BP and adequate ABPM, called white-coat effect group (WCE), uncontrolled (UC), and subjects with appropriate office BP and elevated ABPM denominated masked effect group (ME). Age, body mass index, diabetes, pulse pressure (PP) and BP dipping during sleep were evaluated (Kruskal-Wallis test and logistic regression models). RESULTS: Age was higher in UC than in C and ME (P < 0.01), and 24-h ABPM PP was lower in C (48 +/- 7 mmHg) and WCE (51 +/- 6 mmHg) than in UC (67 +/- 12 mmHg) and ME (59 +/- 8 mmHg) (P < 0.01). Sleep systolic BP dipping was lower in ME than in C (P = 0.03). Female gender was associated with a greater chance of being of ME group, which showed a higher PP and lower BP dipping during sleep. CONCLUSIONS: In older individuals, office BP measurements did not allow the detection of associated factors that would permit to differentiate WCE from UC group and C from ME group. ABPM favored the identification of a higher PP and a lower BP dipping during sleep in the masked effect and uncontrolled groups. PMID- 27781058 TI - Predictors and in-hospital outcomes of preoperative acute kidney injury in patients with type A acute aortic dissection. AB - BACKGROUND: Acute kidney injury (AKI) is common after surgery for acute aortic dissection (AAD) and increases in-hospital and long-term mortality. However, few data exist on the clinical and prognostic relevance of early preoperative AKI in patients with type A AAD. We aimed to determine the incidence and predictors of preoperative AKI and the impact of AKI on in-hospital outcomes in patients with type A AAD. METHODS: From May 2009 to June 2014, we retrospectively enrolled 178 patients admitted to our hospital within 48 h from symptom onset and receiving open surgery for type A AAD. The patients were divided into no AKI and AKI groups and staged with AKI severity according to the KDIGO criteria before surgery. RESULTS: AKI occurred in 41 patients (23.0%). The incidence of in-hospital complications was significantly higher in patients with preoperative AKI compared to no AKI (41.5% vs. 9.5%, P < 0.001), including renal infarction (7.3% vs. 0, P = 0.012), and it increased with AKI severity (Ptrend < 0.001). Patients with AKI had higher in-hospital mortality compared with patients without AKI, although no significant difference was found (14.6% vs. 5.1%, P = 0.079). Multivariate analysis indicated that male gender, diastolic blood pressure on admission and bilateral renal artery involvement were independent predictors of preoperative AKI in patients with type A AAD. CONCLUSIONS: Early AKI before surgery was common in patients with type A AAD, and was associated with increased in-hospital complications. Male gender, diastolic blood pressure on admission and bilateral renal artery involvement were major predictors for preoperative AKI. PMID- 27781059 TI - Relationship of lipid and lipoprotein ratios with coronary severity in patients with new on-set coronary artery disease complicated with type 2 diabetics. AB - BACKGROUND: Diabetes mellitus (DM) is associated with coronary artery disease (CAD) progression. Although previous studies have demonstrated the association of lipid and lipoprotein ratios with CAD, no data are currently available concerning the relationship between lipid and lipoprotein ratios and the severity of new on set CAD in diabetics. Therefore, the aim of the present study was to investigate the usefulness of lipid and lipoprotein ratios in predicting the severity of CAD in patients with type 2 DM (T2DM). METHODS: A total of 380 consecutive T2DM patients with new on-set CAD were enrolled in the present study. Then, they were classified into the three groups according to Gensini score (GS) tertiles. The relationship between lipid and lipoprotein ratios currently used and the GS was investigated. RESULTS: Positive correlations of natural log-transformed GS (lnGS) with apolipoprotein B to apoA-I ratio (apoB/apoA-I), non-high-density lipoprotein cholesterol to apoA-I ratio (non-HDL-C/apoA-I), and low-density lipoprotein cholesterol to apoA-I ratio (LDL-C/apoA-I) were found (r = 0.18, 0.13, 0.12, respectively, all P < 0.05). Multivariate logistic analysis indicated apoB/apoA-I as the strongest predictor for high GS (OR = 5.67, 95% CI: 1.45-23.92, P = 0.003). Area under receivers operating characteristic curve of apoB/apoA-I was 0.63 (95% CI: 0.60-0.66, P = 0.001) for predicting high GS. The optimal cutoff value of apoB/apoA-I to predict high GS was 0.72 with the sensitivity of 61.2% and the specificity of 62.1%. CONCLUSIONS: Lipid and lipoprotein ratios might be useful for predicting the severity of new on-set CAD in T2DM patients, and the apoB/apoA-I appeared as the most significant predictor in this population. PMID- 27781060 TI - Cancer risk in older people receiving statin therapy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Although statins are well tolerated by most aged people, their potential carcinogenicity is considered as one of the biggest factors limiting the use of statins. The aim of the present study was to determine the risk of cancer in people aged over 60 years receiving statin therapy. METHODS: A comprehensive search for articles published up to December 2015 was performed, reviews of each randomized controlled trials (RCTs) that compared the effects of statin mono-therapy with placebo on the risk of cancer in people aged > 60 years were conducted and data abstracted. All the included studies were evaluated for publication bias and heterogeneity. Pooled odds ratios (OR) estimates and 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: A total of 12 RCTs, involving 62,927 patients (31,517 in statin therapy group and 31,410 in control group), with a follow-up duration of 1.9-5.4 years, contributed to the analysis. The statin therapy did not affect the overall incidence of cancer (OR = 1.03, 95% CI: 0.94-1.14, P = 0.52); subgroup analyses showed that neither the variety nor the chemical properties of the statins accounted for the incidence of cancer in older people. CONCLUSIONS: Our meta analysis findings do not support a potential cancer risk of statin treatment in people over 60 years old. Further targeted researches with a longer follow-up duration are warranted to confirm this issue. PMID- 27781061 TI - Decreased expression of Klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease. AB - BACKGROUND: Klotho proteins (alpha- and beta) are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors (FGFs). Recent data has shown that higher plasma circulating Klotho levels reduce cardiovascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and FGFs, and whether high cardiovascular risk could affect cardiac expression of Klotho, FGFs and other molecules. METHODS: We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyocytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxidative stress, inflammation and fibrosis. RESULTS: Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis. CONCLUSIONS: This study showed for the first time that Klotho proteins are expressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress related molecules were significantly increased. PMID- 27781062 TI - Pentraxin 3 (PTX3) promoter methylation associated with PTX3 plasma levels and neutrophil to lymphocyte ratio in coronary artery disease. AB - BACKGROUND: Pentraxin 3 (PTX3) is expressed in the heart under inflammatory conditions and plays an important role in atherogenesis. Patients with increased PTX3 levels may suffer from higher rates of cardiac events. Regulation of specific genes by promoter methylation is important in atherogenesis. The factors influencing PTX3 levels and the association between epigenetics and PTX3 levels have not been investigated. METHODS: Blood samples were collected from 64 patients admitted to the Department of Cardiology, 35 who had coronary artery disease (CAD), and 29 who were CAD-free. Plasma levels of PTX3 were measured by ELISA. PTX3 promoter methylation was evaluated via methyl-specific PCR. The severity of coronary artery lesion was evaluated by angiography. RESULTS: The level of PTX3 promoter methylation in the CAD group was 62.69% +/- 20.57%, significantly lower than that of the CAD-free group, which was 72.45% +/- 11.84% (P = 0.03). Lower PTX3 promoter methylation levels in the CAD group were associated with higher plasma PTX3 concentrations (r = -0.29, P = 0.02). Furthermore, lower PTX3 promoter methylation levels were associated with higher neutrophil to lymphocyte ratio (NLR) in men (r = -0.58, P = 0.002). CONCLUSIONS: The present study provides new evidence that methylation of the PTX3 promoter is associated with PTX3 plasma levels and NLR in coronary artery disease. This study also shows that modification of epigenetics by chronic inflammation might be a significant molecular mechanism in the atherosclerotic processes that influence plasma PTX3 concentrations. PMID- 27781064 TI - Double-edged blinde, hemorrhagic or cardioembolic cognitive impairment. PMID- 27781063 TI - Efficacy and safety of novel anticoagulants in the elderly. AB - Atrial fibrillation and venous thromboembolism (VTE) are common disorders associated with maleficent thrombotic events, particularly in the elderly patients. Polypharmacy, co-morbidities, and altered pharmacokinetics, often present in these patients, render the use of anticoagulants quite challenging. Novel oral anticoagulants (NOACs) have recently emerged as alternatives to Vitamin K Antagonists (VKAs) and are gradually increasing their popularity mainly because of their fewer drug and food interactions and ease of use. Their effectiveness and safety has been well-established in the general population but the balance between benefit and harm in the elderly is still unclear. Routine use in these patients is uncommon. Accumulating data have shown that the benefit of NOACs is consistent among all age groups, featuring equal or greater efficacy in preventing thrombotic events. Excess bleedings were lower with NOACs in comparison to VKAs, but bleeding patterns were disparate among them and head to head comparison is not available. The present review highlights on the efficacy and safety of novel anticoagulants in the elderly population. PMID- 27781065 TI - Prognostic Importance of Cell Cycle Regulators Cyclin D1 (CCND1) and Cyclin Dependent Kinase Inhibitor 1B (CDKN1B/p27) in Sporadic Gastric Cancers. AB - Background. Gastric cancer is known for a notable variety in the course of the disease. Clinical factors, such as tumor stage, grade, and localization, are key in patient survival. It is expected that molecular factors such as somatic mutations and gene amplifications are also underlying tumor biological behavior and may serve as factors for prognosis estimation. Aim. The purpose of this study was to examine gene amplifications from a panel of genes to uncover potential prognostic marker candidates. Methods. A panel of gene amplifications including 71 genes was tested by multiplex ligation-dependent probe amplification (MLPA) technique in 76 gastric cancer samples from a Caucasian population. The correlation of gene amplification status with patient survival was determined by the Kaplan-Meier method. Results. The amplification of two cell cycle regulators, CCND1 and CDKN1B, was identified to have a negative prognostic role. The medial survival of patients with gastric cancer displaying amplification compared to patients without amplification was 192 versus 725 days for CCND1 (P = 0.0012) and 165 versus 611 days for CDKN1B (P = 0.0098). Conclusion. Gene amplifications of CCND1 and CDKN1B are potential candidates to serve as prognostic markers for the stratification of patients based on the estimate of survival in the management of gastric cancer patients. PMID- 27781067 TI - Quantitative Scrutinization of Aflatoxins in Different Spices from Pakistan. AB - The current research work aimed to access the contamination level of aflatoxins B1, B2, G1, and G2 in the household spices that are widely consumed in huge amounts. 200 different spice samples, 100 packed and 100 unpacked, were analyzed for the aflatoxins profile by HPLC with an incidence of 61.5% contamination out of which 53.66% samples exceed the EU limit. The results disclosed that the unpacked samples are more contaminated as compared to the packed samples except for white cumin seeds. Among packed and unpacked samples of spices, the maximum value of aflatoxins was detected in fennel, that is, 27.93 MUg/kg and 67.04 MUg/kg, respectively. The lowest concentration of aflatoxin was detected in cinnamon in packed form (0.79 MUg/kg) and in the unpacked samples of white cumin seeds which is 1.75 MUg/kg. Caraway seeds and coriander in its unpacked form showed positive results whereas black pepper (packed and unpacked) was found free from aflatoxins. This is the first report on the occurrence of aflatoxins in packed and unpacked samples of spices from Pakistan. To ensure safe consumption of spices, there should be constant monitoring of aflatoxin and more studies need to be executed with the intention of preventing mycotoxin accretion in this commodity. PMID- 27781066 TI - Diagnostic Features of Common Oral Ulcerative Lesions: An Updated Decision Tree. AB - Diagnosis of oral ulcerative lesions might be quite challenging. This narrative review article aims to introduce an updated decision tree for diagnosing oral ulcerative lesions on the basis of their diagnostic features. Various general search engines and specialized databases including PubMed, PubMed Central, Medline Plus, EBSCO, Science Direct, Scopus, Embase, and authenticated textbooks were used to find relevant topics by means of MeSH keywords such as "oral ulcer," "stomatitis," and "mouth diseases." Thereafter, English-language articles published since 1983 to 2015 in both medical and dental journals including reviews, meta-analyses, original papers, and case reports were appraised. Upon compilation of the relevant data, oral ulcerative lesions were categorized into three major groups: acute, chronic, and recurrent ulcers and into five subgroups: solitary acute, multiple acute, solitary chronic, multiple chronic, and solitary/multiple recurrent, based on the number and duration of lesions. In total, 29 entities were organized in the form of a decision tree in order to help clinicians establish a logical diagnosis by stepwise progression. PMID- 27781068 TI - Chondrogenic Potency Analyses of Donor-Matched Chondrocytes and Mesenchymal Stem Cells Derived from Bone Marrow, Infrapatellar Fat Pad, and Subcutaneous Fat. AB - Autologous chondrocyte implantation (ACI) is a cell-based therapy that has been used clinically for over 20 years to treat cartilage injuries more efficiently in order to negate or delay the need for joint replacement surgery. In this time, very little has changed in the ACI procedure, but now many centres are considering or using alternative cell sources for cartilage repair, in particular mesenchymal stem cells (MSCs). In this study, we have tested the chondrogenic potential of donor-matched MSCs derived from bone marrow (BM), infrapatellar fat pad (FP), and subcutaneous fat (SCF), compared to chondrocytes. We have confirmed that there is a chondrogenic potency hierarchy ranging across these cell types, with the most potent being chondrocytes, followed by FP-MSCs, BM-MSCs, and lastly SCF-MSCs. We have also examined gene expression and surface marker profiles in a predictive model to identify cells with enhanced chondrogenic potential. In doing so, we have shown that Sox-9, Alk-1, and Coll X expressions, as well as immunopositivity for CD49c and CD39, have predictive value for all of the cell types tested in indicating chondrogenic potency. The findings from this study have significant clinical implications for the refinement and development of novel cell-based cartilage repair strategies. PMID- 27781069 TI - Expression of Vascular Endothelial Growth Factor in Nasal Polyp and Chronic Rhinosinusitis. AB - BACKGROUND: Nasal inflammatory disorders such as chronic rhinosinusitis and nasal polyp are among the most prevalent complications with high socioeconomic costs. Vascular Endothelial Growth Factor (VEGF) plays a key role in angiogenesis and cell proliferation. In the present study the effect of VEGF on the development and prognosis of chronic rhinosinusitis and nasal polyp was investigated. METHODS: This cross sectional study was performed on the nasal histological specimens of two groups of patients suffering from nasal polyp or chronic rhinosinusitis, and the expression of VEGF in the two groups was compared immunohistochemically. Based on the percentage of VEGF-positive cells the specimens were classified into four scores. Furthermore, the relations between the VEGF expression and some demographic characteristics were evaluated. RESULTS: The VEGF immunohistochemistry findings indicated a significantly higher expression of VEGF in nasal polyp group compared to chronic rhinosinusitis without nasal polyp group. In terms of VEGF-expression scoring, in both groups most of the specimens were classified as score-2, namely indicating 10-50% of VEGF-positive epithelial cells. In both groups no significant relation between VEGF expression and age or sex of the patients could be seen. CONCLUSION: Local modulation of VEGF expression might be taken as a putative therapeutic strategy in management of sinunasal inflammatory disorders, especially nasal polyps. PMID- 27781070 TI - Identification of a New Antibacterial Sulfur Compound from Raphanus sativus Seeds. AB - Raphanus sativus L. (radish), a member of Brassicaceae, is widely used in traditional medicine in various cultures for treatment of several diseases and disorders associated with microbial infections. The antibacterial activity of the different plant parts has been mainly attributed to several isothiocyanate (ITC) compounds. However, the low correlation between the ITC content and antibacterial activity suggests the involvement of other unknown compounds. The objective of this study was to investigate the antibacterial potential of red radish seeds and identify the active compounds. A crude ethanol seed extract was prepared and its antibacterial activity was tested against five medically important bacteria. The ethanol extract significantly inhibited the growth of all tested strains. However, the inhibitory effect was more pronounced against Streptococcus pyogenes and Escherichia coli. Bioassay-guided fractionation of the ethanol extract followed by HPLC, 1H-NMR, 13C-NMR, 15N-NMR, and HMBC analysis revealed that the active fraction consisted of a single new compound identified as [5 methylsulfinyl-1-(4-methylsulfinyl-but-3-enyl)-pent-4-enylidene]-sulfamic acid, which consisted of two identical sulfur side chains similar to those found in ITCs. The minimal inhibitory concentration values of the isolated compound were in the range of 0.5-1 mg/mL. These results further highlight the role of radish as a rich source of antibacterial compounds. PMID- 27781071 TI - Bioactive Natural Molecules and Traditional Herbal Medicine in the Treatment of Airways Diseases. PMID- 27781072 TI - Regional Differences in the Concentrations of Metabolites in the Brain of Healthy Children: A Proton Magnetic Resonance Spectroscopy (1HMRS) Study. AB - BACKGROUND: The aim of this 1HMRS study was to identify any potential regional differences in the metabolic spectrum in the brains of healthy children. MATERIAL/METHODS: Forty-nine healthy children aged 6-15 years (mean 11.6 years) were examined, including 21 girls and 28 boys. A 1.5T MR system (xi Signa HD 1.5T General Electric) was used in patient examinations. The VOI (Volume of Interest) was defined in 7 locations: the frontal lobe in the right and left hemispheres, the basal ganglia in the right and left hemispheres, hippocampus in the right and left hemispheres and cerebellum. SAGE 7.0 software was used for the analysis of data obtained from the 1HMRS study. Differences in the concentrations of metabolites in various regions of the brain in children were verified using the t test for independent samples. RESULTS: There were significant differences in concentration levels between various brain regions for all the examined metabolites. NAA was the metabolite characterized by the greatest regional variation with significant differences being observed between all locations. Only in the case of Lip/Cr and the ratio of the Lip concentration to the sum of the concentrations of all the metabolites no significant differences could be observed. CONCLUISONS: The results of the study show that a child's brain is inhomogeneous. The results underline the need of the regional differences in the concentrations of metabolites being taken into account when comparing the results of 1HMRS studies in children. PMID- 27781073 TI - A Classic Case of Subcutaneous Cysticercosis: A Rare Case with Sonological Findings and Review of Literature. AB - BACKGROUND: Cysticercosis is a parasitic infection caused by the larval stages of the pork tapeworm, Taenia solium. The subcutaneous form of the disease is a relatively rare clinical entity. Despite its rarity, it is imperative for a radiologist to be aware of this subcutaneous form of the disease and its various radiological patterns while evaluating any subcutaneous swelling. In this paper, we aimed to describe a typical case of 'subcutaneous cysticercosis involving the left anterior chest wall' with high resolution ultrasound findings. We also discussed the role of other imaging modalities in a case of subcutaneous cysticercosis. To the best of our knowledge, our case is only the second documented case report of sonological evaluation of subcutaneous cysticercosis involving the left anterior chest wall and the first case with high resolution ultrasound images of the lesion. CASE REPORT: An 11-year-old male presented with a painless, subcutaneous swelling over the left anterior chest wall for the last 2 months. High resolution ultrasound showed a well-defined, thin-walled, cystic lesion with an eccentric, echogenic focus in the subcutaneous plane. On change of the posture of the patient, this focus showed mobility. The hypoechoic area surrounding this cyst showed significant exudative fluid collection with diffuse, floating echoes and thin, incomplete internal septations. The adjacent soft tissues were thickened and irregular, suggestive of edema. This was followed by an excision biopsy. Histopathological examination revealed cysticercus cellulose parasite with an extensive mixed inflammatory cell infiltrate in the surrounding tissue. The patient was also administered oral antihelminthic therapy. Repeat ultrasound examination at the end of this management regimen showed complete healing with no e/o any remnant or recurrent cystic lesion, abscess or edema in the subcutaneous plane. CONCLUSIONS: Subcutaneous cysticercosis is a relatively rare form of cysticercosis but should always be born in mind during the evaluation of subcutaneous swellings. High resolution ultrasound is a valuable, safe, nonionizing, cost-effective, widely-available, and easily-reproducible imaging tool for diagnosis of subcutaneous cysticercosis. There is a wide spectrum of ultrasound patterns of subcutaneous cysticercosis. In classic cases with a cyst containing a scolex within and with a surrounding abscess, high resolution ultrasound should always be the primary mode of diagnosis, thus avoiding unnecessary fine needle aspiration cytologies. PMID- 27781074 TI - Heuber Maneuver in Evaluation of Direct Carotid-Cavernous Fistula. AB - Carotid-cavernous fistulas are abnormal communications between the carotid system and the cavernous sinus. Elevated venous pressure produces congestion in the orbit with resultant transudation of fluid and increased intraocular pressure, thereby leading to secondary glaucoma which may result in visual loss. Immediate treatment is hence, warranted in these cases. The planning of endovascular management is dependent on many parameters, the most important of which are the size and location of the fistula. Since these are high-flow fistulas, assessment requires certain manoeuvers. Heuber manoeuver is one of the manoeuvers used to demonstrate the size of the fistula. PMID- 27781076 TI - Reactive Oxygen Species in Cancer Biology and Anticancer Therapy. PMID- 27781075 TI - Metformin Prevents Renal Stone Formation through an Antioxidant Mechanism In Vitro and In Vivo. AB - Oxidative stress is a causal factor and key promoter of urolithiasis associated with renal tubular epithelium cell injury. The present study was designed to investigate the preventive effects of metformin on renal tubular cell injury induced by oxalate and stone formation in a hyperoxaluric rat model. MTT assays were carried out to determine the protection of metformin from oxalate-induced cytotoxicity. The intracellular superoxide dismutase (SOD) activities and malondialdehyde (MDA) levels were measured in vitro. Male Sprague-Dawley rats were divided into control group, ethylene glycol (EG) treated group, and EG + metformin treated group. Oxidative stress and crystal formations were evaluated in renal tissues after 8-week treatment. Metformin significantly inhibited the decrease of the viability in MDCK cells and HK-2 cells induced by oxalate. Besides, metformin markedly prevented the increased concentration of MDA and the decreased tendency of SOD in oxalate-induced MDCK cells and HK-2 cells. In vivo, the increased MDA levels and the reduction of SOD activity were detected in the EG treated group compared with controls, while these parameters reversed in the EG + metformin treated group. Kidney crystal formation in the EG + metformin treated group was decreased significantly compared with the EG treated group. Metformin suppressed urinary crystal deposit formation through renal tubular cell protection and antioxidative effects. PMID- 27781078 TI - Exposure to Hookah and Cigarette Smoke in Children and Adolescents According to Their Socio-Economic Status: The CASPIAN-IV Study. AB - BACKGROUND: Exposure to smoking or passive smoking is one of serious health problems especially in the pediatric age group. OBJECTIVES: To compare the prevalence and determinants of passive smoking in a nationally representative sample of Iranian children and adolescents according to their socioeconomic status (SES). MATERIALS AND METHODS: This nationwide study was conducted in 2011 2012 among 14880 students aged 6 - 18 years, living in 30 provinces in Iran. Exposure to the smoke of hookah or cigarette was documented by using validated questionnaires. Possible influencing factors were determined and the frequency of passive smoking was compared according to the regional and familial SES. RESULTS: Participants consisted of 13,486 children and adolescents including 49.2% girls and 75.6% urban inhabitants (90.6% participation rate). The mean age of participants was 12.47 +/- 3.36 years. Overall, 43.87% of them (44.07% of boys and 43.66% of girls) were exposed to second hand smoke at home. Exposures to hookah or cigarette smoke at home were respectively reported in 21.46% and 34.49% of participants. The prevalence of passive smoking was lower in children of families with higher SES level, but higher in high SES regions of the country than in low SES ones, and ranged from 39.2% in the region with lowest SES to 49.05% in the highest SES region. Higher education levels of fathers and mothers were significantly associated with lower frequency of passive smoking. CONCLUSIONS: Exposure to second hand smoke is a major problem among Iranian children and adolescents. Low family SES and low parental education increased the frequency of passive smoking. Appropriate public health education and legislation for smoke free home as well as family-centered counseling should be strengthened. PMID- 27781079 TI - Atypical Hemolytic Uremic Syndrome Secondary to Lupus Nephritis, Responsive to Eculizumab. AB - Among the spectrum of disease manifestations associated with systemic lupus erythematosus, lupus nephritis is particularly concerning due to the potential for renal failure. This autoimmune attack may not, however, be limited to the kidney and is increasingly being recognized as a trigger for atypical Hemolytic Uremic Syndrome (aHUS). Atypical HUS falls under the spectrum of the thrombotic microangiopathies (TMAs) - a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. Although plasma exchange is considered first-line therapy for thrombotic thrombocytopenic purpura - a TMA classically associated with autoimmune depletion of ADAMTS-13 - aHUS demonstrates less reliable responsiveness to this modality. Instead, use of the late complement inhibitor Eculizumab has emerged as an effective modality for the management of such patients. Diagnosis of aHUS, however, is largely clinically based, relying heavily upon a multidisciplinary approach. Herein we present the case of a patient with atypical HUS successfully treated with Eculizumab in the setting of Class IV-G (A) lupus nephritis and hypocomplementemia. PMID- 27781077 TI - Neuroprotective Effects of Acai (Euterpe oleracea Mart.) against Rotenone In Vitro Exposure. AB - Neuropsychiatric diseases, such as bipolar disorder (BD) and schizophrenia (SCZ), have a very complex pathophysiology. Several current studies describe an association between psychiatric illness and mitochondrial dysfunction and consequent cellular modifications, including lipid, protein, and DNA damage, caused by cellular oxidative stress. Euterpe oleracea (acai) is a powerful antioxidant fruit. Acai is an Amazonian palm fruit primarily found in the lowlands of the Amazonian rainforest, particularly in the floodplains of the Amazon River. Given this proposed association, this study analyzed the potential in vitro neuropharmacological effect of Euterpe oleracea (acai) extract in the modulation of mitochondrial function and oxidative metabolism. SH-SY5Y cells were treated with rotenone to induce mitochondrial complex I dysfunction and before and after we exposed the cells to acai extract at 5 MUg/mL. Treated and untreated cells were then analyzed by spectrophotometric, fluorescent, immunological, and molecular assays. The results showed that acai extract can potentially increase protein amount and enzyme activity of mitochondrial complex I, mainly through NDUFS7 and NDUFS8 overexpression. Acai extract was also able to decrease cell reactive oxygen species levels and lipid peroxidation. We thus suggest acai as a potential candidate for drug development and a possible alternative BD therapy. PMID- 27781080 TI - wigExplorer, a BioJS component to visualise wig data. AB - wigExplorer is a BioJS component whose main purpose is to provide a platform for visualisation of wig-formatted data. Wig files are extensively used by genome browsers such as the UCSC Genome Browser. wigExplorer follows the BioJS standard specification, requiring a simple configuration and installation. wigExplorer provides an easy way to navigate the visible region of the canvas and allows interaction with other components via predefined events. Availability: http://github.com/biojs/biojs; http://dx.doi.org/10.5281/zenodo.7721. PMID- 27781081 TI - Finding the shortest path with PesCa: a tool for network reconstruction. AB - Network analysis is of growing interest in several fields ranging from economics to biology. Several methods have been developed to investigate different properties of physical networks abstracted as graphs, including quantification of specific topological properties, contextual data enrichment, simulation of pathway dynamics and visual representation. In this context, the PesCa app for the Cytoscape network analysis environment is specifically designed to help researchers infer and manipulate networks based on the shortest path principle. PesCa offers different algorithms allowing network reconstruction and analysis starting from a list of genes, proteins and in general a set of interconnected nodes. The app is useful in the early stage of network analysis, i.e. to create networks or generate clusters based on shortest path computation, but can also help further investigations and, in general, it is suitable for every situation requiring the connection of a set of nodes that apparently do not share links, such as isolated nodes in sub-networks. Overall, the plugin enhances the ability of discovering interesting and not obvious relations between high dimensional sets of interacting objects. PMID- 27781083 TI - The 2016 Bioinformatics Open Source Conference (BOSC). AB - Message from the ISCB: The Bioinformatics Open Source Conference (BOSC) is a yearly meeting organized by the Open Bioinformatics Foundation (OBF), a non profit group dedicated to promoting the practice and philosophy of Open Source software development and Open Science within the biological research community. BOSC has been run since 2000 as a two-day Special Interest Group (SIG) before the annual ISMB conference. The 17th annual BOSC ( http://www.open bio.org/wiki/BOSC_2016) took place in Orlando, Florida in July 2016. As in previous years, the conference was preceded by a two-day collaborative coding event open to the bioinformatics community. The conference brought together nearly 100 bioinformatics researchers, developers and users of open source software to interact and share ideas about standards, bioinformatics software development, and open and reproducible science. PMID- 27781084 TI - Recent progress and future challenges in algal biofuel production. AB - Modern society is fueled by fossil energy produced millions of years ago by photosynthetic organisms. Cultivating contemporary photosynthetic producers to generate energy and capture carbon from the atmosphere is one potential approach to sustaining society without disrupting the climate. Algae, photosynthetic aquatic microorganisms, are the fastest growing primary producers in the world and can therefore produce more energy with less land, water, and nutrients than terrestrial plant crops. We review recent progress and challenges in developing bioenergy technology based on algae. A variety of high-value products in addition to biofuels can be harvested from algal biomass, and these may be key to developing algal biotechnology and realizing the commercial potential of these organisms. Aspects of algal biology that differentiate them from plants demand an integrative approach based on genetics, cell biology, ecology, and evolution. We call for a systems approach to research on algal biotechnology rooted in understanding their biology, from the level of genes to ecosystems, and integrating perspectives from physical, chemical, and social sciences to solve one of the most critical outstanding technological problems. PMID- 27781082 TI - Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways. AB - Tissue injury, whether by trauma, surgical intervention, metabolic dysfunction, ischemia, or infection, evokes a complex cellular response (inflammation) that is associated with painful hyperalgesic states. Although in the acute stages it is necessary for protective reflexes and wound healing, inflammation may persist well beyond the need for tissue repair or survival. Prolonged inflammation may well represent the greatest challenge mammalian organisms face, as it can lead to chronic painful conditions, organ dysfunction, morbidity, and death. The complexity of the inflammatory response reflects not only the inciting event (infection, trauma, surgery, cancer, or autoimmune) but also the involvement of heterogeneous cell types including neuronal (primary afferents, sensory ganglion, and spinal cord), non-neuronal (endothelial, keratinocytes, epithelial, and fibroblasts), and immune cells. In this commentary, we will examine 1.) the expression and regulation of two members of the transient receptor potential family in primary afferent nociceptors and their activation/regulation by products of inflammation, 2.) the role of innate immune pathways that drive inflammation, and 3.) the central nervous system's response to injury with a focus on the activation of spinal microglia driving painful hyperalgesic states. PMID- 27781087 TI - Report on noninvasive prenatal testing: classical and alternative approaches. AB - Concerns of traditional prenatal aneuploidy testing methods, such as low accuracy of noninvasive and health risks associated with invasive procedures, were overcome with the introduction of novel noninvasive methods based on genetics (NIPT). These were rapidly adopted into clinical practice in many countries after a series of successful trials of various independent submethods. Here we present results of own NIPT trial carried out in Moscow, Russia. 1012 samples were subjected to the method aimed at measuring chromosome coverage by massive parallel sequencing. Two alternative approaches are ascertained: one based on maternal/fetal differential methylation and another based on allelic difference. While the former failed to provide stable results, the latter was found to be promising and worthy of conducting a large-scale trial. One critical point in any NIPT approach is the determination of fetal cell-free DNA fraction, which dictates the reliability of obtained results for a given sample. We show that two different chromosome Y representation measures-by real-time PCR and by whole genome massive parallel sequencing-are practically interchangeable (r=0.94). We also propose a novel method based on maternal/fetal allelic difference which is applicable in pregnancies with fetuses of either sex. Even in its pilot form it correlates well with chromosome Y coverage estimates (r=0.74) and can be further improved by increasing the number of polymorphisms. PMID- 27781085 TI - Biology and structure of leukocyte beta 2 integrins and their role in inflammation. AB - Integrins comprise a large family of alphabeta heterodimeric cell adhesion receptors that are expressed on all cells except red blood cells and that play essential roles in the regulation of cell growth and function. The leukocyte integrins, which include members of the beta 1, beta 2, beta 3, and beta 7 integrin family, are critical for innate and adaptive immune responses but also can contribute to many inflammatory and autoimmune diseases when dysregulated. This review focuses on the beta 2 integrins, the principal integrins expressed on leukocytes. We review their discovery and role in host defense, the structural basis for their ligand recognition and activation, and their potential as therapeutic targets. PMID- 27408698 TI - Mechanisms of low back pain: a guide for diagnosis and therapy. AB - Chronic low back pain (CLBP) is a chronic pain syndrome in the lower back region, lasting for at least 3 months. CLBP represents the second leading cause of disability worldwide being a major welfare and economic problem. The prevalence of CLBP in adults has increased more than 100% in the last decade and continues to increase dramatically in the aging population, affecting both men and women in all ethnic groups, with a significant impact on functional capacity and occupational activities. It can also be influenced by psychological factors, such as stress, depression and/or anxiety. Given this complexity, the diagnostic evaluation of patients with CLBP can be very challenging and requires complex clinical decision-making. Answering the question "what is the pain generator" among the several structures potentially involved in CLBP is a key factor in the management of these patients, since a mis-diagnosis can generate therapeutical mistakes. Traditionally, the notion that the etiology of 80% to 90% of LBP cases is unknown has been mistaken perpetuated across decades. In most cases, low back pain can be attributed to specific pain generator, with its own characteristics and with different therapeutical opportunity. Here we discuss about radicular pain, facet Joint pain, sacro-iliac pain, pain related to lumbar stenosis, discogenic pain. Our article aims to offer to the clinicians a simple guidance to identify pain generators in a safer and faster way, relying a correct diagnosis and further therapeutical approach. PMID- 27781088 TI - Ability of device to collect bacteria from cough aerosols generated by adults with cystic fibrosis. AB - Background: Identifying lung pathogens and acute spikes in lung counts remain a challenge in the treatment of patients with cystic fibrosis (CF). Bacteria from the deep lung may be sampled from aerosols produced during coughing. Methods: A new device was used to collect and measure bacteria levels from cough aerosols of patients with CF. Sputum and oral specimens were also collected and measured for comparison. Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus mitis were detected in specimens using Real-Time Polymerase Chain Reaction (RT-PCR) molecular assays. Results: Twenty adult patients with CF and 10 healthy controls participated. CF related bacteria (CFRB) were detected in 13/20 (65%) cough specimens versus 15/15 (100%) sputum specimens. Commensal S. mitis was present in 0/17 (0%, p=0.0002) cough specimens and 13/14 (93%) sputum samples. In normal controls, no bacteria were collected in cough specimens but 4/10 (40%) oral specimens were positive for CFRB. Conclusions: Non-invasive cough aerosol collection may detect lower respiratory pathogens in CF patients, with similar specificity and sensitivity to rates detected by BAL, without contamination by oral CFRB or commensal bacteria. PMID- 27781089 TI - Collecting clinical data in primary ciliary dyskinesia- challenges and opportunities. AB - Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research. PMID- 27781090 TI - Plant expression systems, a budding way to confront chikungunya and Zika in developing countries? AB - Plant expression systems could be used as biofactories of heterologous proteins that have the potential to be used with biopharmaceutical aims and vaccine design. This technology is scalable, safe and cost-effective and it has been previously proposed as an option for vaccine and protein pharmaceutical development in developing countries. Here we present a proposal of how plant expression systems could be used to address Zika and chikungunya outbreaks through development of vaccines and rapid diagnostic kits. PMID- 27781092 TI - An annotation of cuts, depicted locations, and temporal progression in the motion picture "Forrest Gump". AB - Here we present an annotation of locations and temporal progression depicted in the movie "Forrest Gump", as an addition to a large public functional brain imaging dataset ( http://studyforrest.org). The annotation provides information about the exact timing of each of the 870 shots, and the depicted location after every cut with a high, medium, and low level of abstraction. Additionally, four classes are used to distinguish the differences of the depicted time between shots. Each shot is also annotated regarding the type of location (interior/exterior) and time of day. This annotation enables further studies of visual perception, memory of locations, and the perception of time under conditions of real-life complexity using the studyforrest dataset. PMID- 27781091 TI - Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model. AB - Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model ( Mecp2 A140V "knock-in" mutant) expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant ( Mecp2A140V/y) and wild type ( Mecp2+/y) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant (maternal allele) and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor 1) treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2 mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype ("phenotypic assay"). PMID- 27781093 TI - Gut chemosensing: implications for disease pathogenesis. AB - The ability of humans to sense chemical signals in ingested substances is implicit in the ability to detect the five basic tastes; sweet, sour, bitter, salty, and umami. Of these, sweet, bitter, and umami tastes are detected by lingual G-protein-coupled receptors (GPCRs). Recently, these receptors were also localized to the gut mucosa. In this review, we will emphasize recent advances in the understanding of the mechanisms and consequences of foregut luminal chemosensing, with special emphasis on cell surface GPCRs such as the sweet and proteinaceous taste receptors (TASRs), short- and long-chain fatty acid (FA) receptors, and bile acid receptors. The majority of these luminal chemosensors are expressed on enteroendocrine cells (EECs), which are specialized endocrine cells in the intestine and pancreas that release gut hormones with ligand activation. These gut hormones are responsible for a wide variety of physiologic and homeostatic mechanisms, including glycemic control, appetite stimulation and suppression, regulation of gastric emptying, and trophic effects on the intestinal epithelium. Released from the EECs, the gut peptides have paracrine, autocrine, and endocrine effects. Additionally, EECs have unique direct connections to the enteric nervous system enabling precise transmission of sensory data to and communication with the central nervous system. We will also describe how gut sensors are implicated in gut hormone release, followed by examples of how altered gut chemosensing has been implicated in pathological conditions such as metabolic diseases including diabetes and obesity, functional dyspepsia, helminthic infections, colitis, gastric bypass surgery, and gastric inflammation and cancer. PMID- 27781095 TI - Recent advances in understanding hepatic drug transport. AB - Cells need to strictly control their internal milieu, a function which is performed by the plasma membrane. Selective passage of molecules across the plasma membrane is controlled by transport proteins. As the liver is the central organ for drug metabolism, hepatocytes are equipped with numerous drug transporters expressed at the plasma membrane. Drug disposition includes absorption, distribution, metabolism, and elimination of a drug and hence multiple passages of drugs and their metabolites across membranes. Consequently, understanding the exact mechanisms of drug transporters is essential both in drug development and in drug therapy. While many drug transporters are expressed in hepatocytes, and some of them are well characterized, several transporters have only recently been identified as new drug transporters. Novel powerful tools to deorphanize (drug) transporters are being applied and show promising results. Although a large set of tools are available for studying transport in vitro and in isolated cells, tools for studying transport in living organisms, including humans, are evolving now and rely predominantly on imaging techniques, e.g. positron emission tomography. Imaging is an area which, certainly in the near future, will provide important insights into "transporters at work" in vivo. PMID- 27781096 TI - Abortion, substance abuse and mental health in early adulthood: Thirteen-year longitudinal evidence from the United States. AB - OBJECTIVE: To examine the links between pregnancy outcomes (birth, abortion, or involuntary pregnancy loss) and mental health outcomes for US women during the transition into adulthood to determine the extent of increased risk, if any, associated with exposure to induced abortion. METHOD: Panel data on pregnancy history and mental health history for a nationally representative cohort of 8005 women at (average) ages 15, 22, and 28 years from the National Longitudinal Study of Adolescent to Adult Health were examined for risk of depression, anxiety, suicidal ideation, alcohol abuse, drug abuse, cannabis abuse, and nicotine dependence by pregnancy outcome (birth, abortion, and involuntary pregnancy loss). Risk ratios were estimated for time-dynamic outcomes from population averaged longitudinal logistic and Poisson regression models. RESULTS: After extensive adjustment for confounding, other pregnancy outcomes, and sociodemographic differences, abortion was consistently associated with increased risk of mental health disorder. Overall risk was elevated 45% (risk ratio, 1.45; 95% confidence interval, 1.30-1.62; p < 0.0001). Risk of mental health disorder with pregnancy loss was mixed, but also elevated 24% (risk ratio, 1.24; 95% confidence interval, 1.13-1.37; p < 0.0001) overall. Birth was weakly associated with reduced mental disorders. One-eleventh (8.7%; 95% confidence interval, 6.0 11.3) of the prevalence of mental disorders examined over the period were attributable to abortion. CONCLUSION: Evidence from the United States confirms previous findings from Norway and New Zealand that, unlike other pregnancy outcomes, abortion is consistently associated with a moderate increase in risk of mental health disorders during late adolescence and early adulthood. PMID- 27781094 TI - Current status and future prospects for enabling chemistry technology in the drug discovery process. AB - This review covers recent advances in the implementation of enabling chemistry technologies into the drug discovery process. Areas covered include parallel synthesis chemistry, high-throughput experimentation, automated synthesis and purification methods, flow chemistry methodology including photochemistry, electrochemistry, and the handling of "dangerous" reagents. Also featured are advances in the "computer-assisted drug design" area and the expanding application of novel mass spectrometry-based techniques to a wide range of drug discovery activities. PMID- 27781097 TI - Understanding the relationship transitions and associated end of life clinical needs of young adults with life-limiting illnesses: A triangulated longitudinal qualitative study. AB - BACKGROUND: Care of young adults with life-limiting illnesses can often be complex due to the fact that they are growing and developing within the continuing presence of their illness. There is little research conducted nationally and internationally, which has examined the life issues of young adults or taken a longitudinal approach to understand such issues over a period of time. AIM: To gain clear understanding of one particular and pertinent life issue-relationship transition-occurring in the context of being a young adult with a life-limiting illness and the clinical needs arising from this. DESIGN: This was a triangulated, longitudinal, qualitative study involving young adults with life-limiting illnesses and their significant others, namely, family members and healthcare professionals. Semi-structured interviews were conducted with participants and analysed using thematic analysis. Clinical case note reviews were also carried out. SETTING/PARTICIPANTS: A total of 12 young adults (aged between 17 and 23 years) from 2 hospices and 22 nominated significant others participated in a total of 58 interviews. RESULTS: Thematic analysis revealed 4 main themes and 11 subthemes. The main themes were 'Dependence dichotomy', 'In it together', 'Biographical uncertainty', and 'Conserving integrity'. These themes helped to establish the nature of relationship transitions that the young adult participants from the study experienced and additionally allowed insight into their possible needs at their end of life. CONCLUSION: This study has identified the nature of relationship transitions pertinent to young adults and has highlighted associated end of life clinical needs. This study can influence further research into the transitions and end of life needs of this particular patient group receiving palliative care, while informing the lacking evidence base which exists internationally. PMID- 27781098 TI - Recurrent pyriform sinus fistula successfully treated by endoscopic Glubran 2 sealing: A rare case and literature review. AB - OBJECTIVES: The authors present the case of a 3-year-old girl with a history of complicated surgery for removing a third branchial cleft fistula. METHODS: An endoscopic approach using N-butyl-2-acrylate and metacrilosisolfolane glue (GLUBRAN 2) to seal the fistula was performed. RESULTS: The clinical and radiological 6-year follow-up confirmed the absence of the fistulous orifice and the persistence of scar due to previous open-neck surgical procedures. CONCLUSION: endoscopic Glubran 2 sealing has been an effective treatment procedure for branchial fistula. PMID- 27781099 TI - Related or not? Development of spontaneous Creutzfeldt-Jakob disease in a patient with chronic, well-controlled HIV: A case report and review of the literature. AB - BACKGROUND: We report a novel case of a rare disease: spontaneous Creutzfeldt Jakob disease in a patient with well-controlled HIV. We explore the relationship between spontaneous Creutzfeldt-Jakob disease and HIV. CASE REPORT: A 66-year-old man with long-standing, well-controlled HIV infection presented with 3 months of progressive, subacute neurocognitive decline. His symptoms included conceptual apraxia, apathy, memory impairment, and gait disturbance, and were initially attributed to depressive "pseudo-dementia." Unfortunately, the patient's symptoms rapidly progressed and he ultimately succumbed to his illness. Autopsy confirmed the clinical diagnosis of spontaneous Creutzfeldt-Jakob disease. DISCUSSION: This case highlights spontaneous Creutzfeldt-Jakob disease as a rare terminal illness in the setting of well-controlled chronic HIV. To our knowledge, this is the first report of a patient with chronic and previously well-controlled HIV infection dying from a prion disease. Despite the very different epidemiology and pathophysiology of HIV and spontaneous Creutzfeldt-Jakob disease, this case does raise questions of whether certain host genetic factors could predispose to both conditions, albeit currently, there is no clear causal link between HIV and spontaneous Creutzfeldt-Jakob disease. PMID- 27781100 TI - How can we achieve universal access to low-cost treatment for HIV? AB - Mass production of low-cost antiretrovirals (ARVs) has already allowed over 17 million individuals to access treatment for HIV infection, mainly in low-income countries. It is possible to manufacture combination ARVs for $110 per person year, using tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV). New combinations of ARVs costing as little as $60 per person-year will be available in the near future. Pre-exposure prophylaxis using TDF in combination with either 3TC or emtricitabine (FTC) could also be provided for less than $90 per person year. Voluntary licensing allows people in the poorest countries to access new ARVs at prices close to manufacturing costs. Patents on several key ARVs will expire by 2018 and should allow worldwide access to high-quality, low-cost triple combination therapy, such as TDF/3TC/EFV. Several protease inhibitors will also become available as generics by 2018. However, ongoing patent restrictions will lead to sustained high prices for the most recently developed ARVs in most middle and high-income countries. These include the nucleotide tenofovir alafenamide, the integrase strand inhibitor dolutegravir and several single combination tablet regimens. We suggest that as patents for ARVs expire, health authorities first need to rapidly import and introduce generic versions of drugs such as abacavir, 3TC, EFV and TDF. Once these low prices have been established for these generics, cost-effectiveness of patented ARVs needs to be re-evaluated. It may no longer be justified to pay high prices for these drugs. A strategy of low-cost generic ARVs for most people, with higher-cost patented alternatives used as switch options, could allow for an increased number of people to receive ARVs in the context of fixed health budgets. PMID- 27781101 TI - Cytomegalovirus vaccines under clinical development. AB - Congenital cytomegalovirus (CMV) infection is the most common infectious cause of disability in newborn infants. CMV also causes serious disease in solid organ (SOT) and haematopoietic stem cell transplant (HSCT) recipients. In otherwise healthy children and adults, primary CMV infection rarely causes illness. However, even asymptomatic CMV infections may predispose an individual towards an increased risk of atherosclerosis, cancer and immune senescence over the life course, although such associations remain controversial. Thus, although a vaccine against congenital CMV infection would have the greatest public health impact and cost-effectiveness, arguably all populations could benefit from an effective immunisation against this virus. Currently there are no licensed CMV vaccines, but there is increased interest in developing and testing potential candidates, driven by the demonstration that a recombinant CMV glycoprotein B (gB) vaccine has some efficacy in prevention of infection in young women and adolescents, and in CMV-seronegative SOT recipients. In this review, the recent and current status of candidate CMV vaccines is discussed. Evolving concepts about proposed correlates of protective immunity in different target populations for CMV vaccination, and how these differences impact current clinical trials, are also reviewed. PMID- 27781103 TI - Ageing and menopause considerations for women with HIV in the UK. AB - OBJECTIVES: Treatment rollout has dramatically improved life expectancy for people with HIV and AIDS. Women represent a substantial proportion of patients in the UK (approximately one-third of patients in care are female according to the HIV Annual Report 2014). This study examines psychosocial and biomedical issues for women diagnosed with HIV in the UK, comparing those above and below 45 years of age to examine menopause and ageing issues. METHODS: Consecutive clinic attenders in a large outpatient London HIV clinic were invited to participate in the study. Data were available for 170 (68%) women. In 57 women above the age of 45 data were available regarding menopause detailed insights. RESULTS: Compared with women aged under 45, women >45 years old were significantly less likely to be in a relationship (P=0.01), had higher anxiety scores (P=0.002), more likely to be classified as moderate to severe (25.9% vs 9.1%; chi2=6.1, P=0.01). There were no differences in terms of suicidal ideation, which was high for both groups of women (56.6%). Older women had higher psychological symptoms on the MSAS scale form and significantly higher PHQ-9 depression levels. A higher proportion of older women scored above the cut-off point for moderate to severe depression (9.2% vs 21.8%; chi2=3.7, P=0.048). Fewer older women had no mental health challenges (26.1% vs 42.4%) and more had multiple comorbidities (P=0.07). CONCLUSIONS: The vast majority of women reported experiencing a variety of physical and psychological menopause-related symptoms and there was a high suicide ideation rate in both groups of women. Over half of the group of menopausal women recorded distressing symptoms such as hot flushes, sweating, decreased sexual desire, back pain, night sweats, avoiding intimacy, involuntary urination and skin changes, yet few sought help. Age-specific, psychosexual and menopause services should be routinely available for women with HIV. PMID- 27781102 TI - Cytomegalovirus and paediatric HIV infection. AB - Cytomegalovirus (CMV) was among the most common AIDS-defining illnesses prior to the advent of combination antiretroviral therapy (ART). In the ART era, CMV disease remains a significant public health threat among HIV-infected adults and children with delayed HIV diagnosis. CMV co-infection may additionally contribute to accelerated HIV progression, development of inflammation-related comorbidities, immune senescence and developmental deficits. Elimination of CMV would have tremendous public health significance and is an important priority; however, current vaccine strategies are not targeted at HIV-infected individuals. Antivirals active against CMV may be a novel strategy to prevent acquisition and improve outcomes, but haematological side effects are common and necessitate cautious use in pregnant women and infants. Studies in HIV-infected children on ART lag behind adults, and the clinical significance of CMV in this population is not well understood. Furthermore, the effects of CMV in HIV-exposed uninfected (HEU) children need to be clarified to understand whether CMV interventions should also be a priority for this growing population. This review discusses our current understanding of CMV transmission and pathogenesis in HIV-exposed children and highlights unanswered questions for future research. PMID- 27781104 TI - Quantifying integrated SIV-DNA by repetitive-sampling Alu-gag PCR. AB - OBJECTIVES: Although antiretroviral therapy (ART) effectively suppresses HIV-1 replication, it does not eradicate the virus and ART interruption consistently results in rebound of viraemia, demonstrating the persistence of a long-lived viral reservoir. Several approaches aimed at reducing virus persistence are being developed, and accurate measurements of the latent reservoir (LR) are necessary to assess the effectiveness of anti-latency interventions. We sought to measure the LR in SIV/SHIV-infected rhesus macaques (RMs) by quantifying integrated SIV DNA. METHODS: We optimised a repetitive sampling Alu-gag PCR to quantify integrated SIV-DNA ex vivo in ART-naive and ART-experienced SIV/SHIV-infected RMs. RESULTS: In ART-naive RMs, we found the median level of integrated SIV-DNA to be 1660 copies and 866 copies per million PBMC during untreated acute and chronic SHIV infection, respectively. Integrated and total SIV-DNA levels were positively correlated with one another. In ART-treated RMs, integrated SIV-DNA was readily detected in lymph nodes and spleen and levels of total (3319 copies/million cells) and integrated (3160 copies/million cells) SIV-DNA were similar after a median of 404 days of ART. In peripheral blood CD4+ T cells from ART-treated RMs, levels of total (3319 copies/million cells) and integrated (2742 copies/million cells) SIV-DNA were not significantly different and were positively correlated. CONCLUSIONS: The assay described here is validated and can be used in interventional studies testing HIV/SIV cure strategies in RMs. Measurement of integrated SIV-DNA in ART-treated RMs, along with other reservoir analyses, gives an estimate of the size of the LR. PMID- 27781107 TI - The latest science from the IAS Towards an HIV Cure Symposium: 16-17 July 2016, Durban, South Africa. PMID- 27781106 TI - Twin pregnancy in a liver transplant recipient with HIV infection. AB - We are not aware of a report detailing the complex obstetrical and medical management of twin pregnancy in the context of HIV infection and early post-liver transplantation period. Here we describe the successful outcome of a twin pregnancy in a 28-year-old HIV-positive female receiving antiretroviral therapy and immunosuppressive therapy who was the recipient of a liver transplant for previous drug-induced liver failure. PMID- 27781105 TI - Impact of orphan status on HIV treatment outcomes and retention in care of children and adolescents in Asia. AB - An analysis of the impact of orphanhood at antiretroviral therapy (ART) initiation on HIV outcomes in Asia included 4300 children; 51% were male. At ART initiation, 1805 (42%) were non-orphans (median age: 3 years), 1437 (33%) were single orphans (6 years) and 1058 (25%) were double orphans (7 years). Ten-year post-ART survival was 93.4-95.2% across orphan categories. Clinic transfers were higher among single and double orphans than non-orphans (41% vs 11%, P<0.001). On multivariate analysis, children >=3 years at ART initiation (hazard ratio 1.58 vs <3 years, 95% confidence interval: 1.11-2.24) were more likely to be lost to follow-up. Although post-ART mortality and retention did not differ by orphan status, orphans were at greater risk of starting ART at older ages, and with more severe immunosuppression and poorer growth. PMID- 27781108 TI - HIV persistence in the CNS: the final frontier for a cure? PMID- 27781110 TI - Why Fever Phobia Is Still Common? AB - BACKGROUND: Fever is a reliable sign of illness, but it also evokes fear and anxiety. It is not the fever itself but the fear of possible complications and accompanying symptoms that is important for pediatricians and parents. OBJECTIVES: We aimed to investigate maternal understanding of fever, its potential consequences, and impacts on the treatment of children. PATIENTS AND METHODS: A questionnaire was use to explore the attitudes, knowledge, and practices of mothers of 861 children brought to four medical centers in different regions of Turkey in 2012, with fever being the chief complaint. All the children were aged 3 months - 15 years. RESULTS: Among the 861 mothers, 92.2% favored antipyretics for fever, either alone or in addition to external cooling measures. Most favored paracetamol or ibuprofen. In this study, the appropriate use of antipyretics was 75.2%, which was higher than that reported in the literature. In common with previous reports, seizures and brain damage were perceived as the most frightening and harmful effects of fever. All the mothers expressed concerns about fever, but they were most common among the highly educated or those with one child. CONCLUSIONS: Fever phobia remains common, not only among low socioeconomic status mothers but also among those of high socioeconomic status. Healthcare providers should take fever phobia into account and provide correct information to caregivers about fever at all visits. PMID- 27781109 TI - Highlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA. AB - CSF HIV escape is a recently recognised phenomenon that suggests that despite suppressive treatment, HIV RNA may be detected in the CNS compartment in some individuals. In rare cases this is associated with clinical neurological disease, while in most cases, neurological consequences are not apparent. Attempts at characterising the biological substrates of CSF escape and further investigating the neurological consequences need to be made to better understand the implications of this condition for the HIV cure agenda as well as for clinical outcomes. The Global CSF HIV-1 Escape Consortium meeting, convened by the US National Institute of Mental Health, was a first step to gather investigators from diverse sites to discuss opportunities for future collaborative work on this emerging issue. To better understand CSF HIV escape and allow cross-site data reconciliation, it will be useful to reach a consensus set of definitions of the distinct forms of CSF escape, without which concerted cross-site efforts are difficult. PMID- 27781111 TI - Comparison of Hydrogel Produced by Radiation as Applied at the Research Center (Yazd Branch) With MaxGel and Routine Dressing for Second-Degree Burn Repair in Yazd Burn Hospital. AB - BACKGROUND: Recently, the radiation application research center for the atomic energy organization of Yazd (Iran) has developed a hydrogel dressing which was evaluated for quality and safety in 2008. Its efficacy for assisting in the wound healing process was approved for animal use, and its use has proven to be more effective than a related Syrian material. OBJECTIVES: We have already confirmed the safety and efficacy of Irgel use on mice (1, 2), so this study was conducted in order to further evaluate its effectiveness on human burn wounds, and to compare its efficacy with MaxGel, another hydrogel. A randomized clinical trial study was conducted to compare the efficacy of hydrogel produced by the radiation application research center (Yazd Branch) with MaxGel and routine dressing on burn repair in the Yazd Burn hospital. MATERIALS AND METHODS: In this study, 90 patients with second-degree burn injuries who were admitted to the Yazd Burn hospital were randomly divided into three equal groups. In the negative control group, the wounds were covered with sterile vaseline gauze followed by double sterile dry gauze and ultimately bandaged. In the test group, the wounds were covered by an Iranian hydrogel sheet (Irgel) instead of vaseline gauze, while in the positive control group, the wounds were covered by MaxGel instead of Irgel. At each visit (every other day), each dressing was renewed by its respective method and the wound area, pain score, and body temperature were recorded. At the beginning and at the end of the first and second week, five milliliters of venous blood were taken from all patients to evaluate hematologic parameters such as peripheral blood cell count, liver function, blood urea nitrogen, and creatinine. RESULTS: Before the intervention, the extent of the burns and pain sensations were quite similar among the different groups, but at the second week, the burn areas and pain scores for the Irgel group were significantly less than those of the normal control and the positive control groups (P < 0.05). CONCLUSIONS: Based on our findings, both gels assist in the process of burn wound healing and pain reduction more effectively as compared with routine dressing. However, Irgel had better effects on wound healing and pain relief than MaxGel, which indicates a better quality of Irgel for this particular kind of treatment. PMID- 27781112 TI - Nutritional Education Needs in Relation to Ramadan Fasting and Its Complications in Tehran, Iran. AB - BACKGROUND: Ramadan fasting is associated with some lifestyle changes. A lack of nutritional needs knowledge or the improper performance of fasting, particularly in relation to time, type and amount of food intake, can cause disorders such as indigestion, bloating, constipation, headaches and other clinical problems. OBJECTIVES: To investigate the general knowledge regarding dietary factors associated with Ramadan fasting and its related complications. PATIENTS AND METHODS: This prospective, non-interventional, observational study was conducted from April to July, 2012 to coincide with the month before and the month of Ramadan. The initial participants were 600 fasting and 588 non-fasting people (aged 18 - 65 years, BMI 18.5 - 40 kg/m2) chosen by random cluster sampling in Tehran, Iran. A questionnaire of Ramadan fasting nutritional knowledge was developed and validated in a pilot study. The Likert scale was used two weeks before Ramadan and during the third and fourth weeks of Ramadan to estimate Ramadan-related complications. Seven-day, 24 - hour food recalls were used to assess food intakes. RESULTS: The lowest level of general knowledge was identified in the context of foods associated with hunger (22.1%) and hypoglycemia (24.8%) and the highest level of general knowledge was identified in reference to unsuitable foods for Sahar (91.4%). During Ramadan, all attributed complications increased in fasting subjects (P < 0.001). High calorie, carbohydrate, fat and protein intakes in the Ramadan diet were associated with some gastrointestinal and sleep complications (P < 0.05). CONCLUSIONS: Despite the relatively high level of knowledge in the context of the general principles of a diet to prevent Ramadan-related complications, practical training in regard to the amounts of nutrients associated with Ramadan-related complications is both necessary and recommended. PMID- 27781113 TI - Familial Aggregation of Metabolic Syndrome With Different Socio-Behavioral Characteristics: The Fourth Phase of Tehran Lipid and Glucose Study. AB - BACKGROUND: Since genetic and most environmental factors shape the context of families, some studies have been initiated to investigate the role of familial relationships in metabolic syndrome (MetS). OBJECTIVES: To estimate the familial aggregation of MetS and its components by identifying both case and control probands among Tehranian adults with different socio-behavioral and reproductive characteristics. PATIENTS AND METHODS: This case-controlled/family-based study was conducted on 1,777 families (635 case probands) who participated in the Tehran Lipid and Glucose Study (TLGS). Socio-demographic and reproductive information including levels of education, marital status, occupation status, age at menarche, number of abortions, number of children, and lifestyle habits such as smoking, physical activity and regular diet were obtained from the TLGS data bank. Metabolic syndrome was defined according to the joint interim statement (JIS) criteria. To estimate the regression co-efficient for familial aggregation and environmental factors, the generalized estimation equation method was used. RESULTS: The risk of having MetS among family members for case versus control probands was 2.19 (95% CI: 1.68 - 2.84), which, after adjusting for potential confounders including age, sex, educational level, marital status, occupation, age at menarche and energy, soft drink and starchy vegetable intake, increased to 2.31 (95% CI: 1.81 - 2.94; P < 0.05). Compared to control probands, the risk of having MetS components increased significantly from OR = 1.28 for both high waist circumference (WC) and blood pressure (BP) to OR = 1.72 for high triglycerides in cases. Familial aggregation inherited from the father was significantly observed in all MetS components, from adjusted OR = 1.63 for hyperglycemia to adjusted OR = 2.69 for high WC, except for low HDL, after controlling for potential confounders. CONCLUSIONS: Considering spouses and siblings, there was a higher risk for MetS components among families whose fathers and offspring had MetS components, implying the pivotal role of genetic inheritance in the incidence of the syndrome and its components. PMID- 27781114 TI - Coenzyme Q10 Ameliorates Trimethyltin Chloride Neurotoxicity in Experimental Model of Injury in Dentate Gyrus of Hippocampus: A Histopathological and Behavioral Study. AB - BACKGROUND: Coenzyme Q10 has antioxidative and free radical scavenging effects. CoQ10 supplementation is known to have neuroprotective effects in some neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. OBJECTIVES: The aim of this study was to evaluate both histopathologic and behavioral whether Coenzyme Q10 is protective against trimethyltin chloride (TMT) induced hippocampal damage. MATERIALS AND METHODS: This was an experimental study. Thirty-six Balb/c mice were divided into four groups, as follows: 1) control group; 2) sham group of mice that received a 100 uL intraperitoneal injection (IP) of sesame oil; 3) TMT group of mice that received a single 2.5 mg/kg/day IP injection of TMT; and 4) TMT + CoQ10 group of mice that received a 10 mg/kg IP injection of CoQ10. Body weight and Morris water maze (MWM) responses were investigated. In addition, the dentate gyrus neurons of the hippocampus were evaluated histopathologically by light and electron microscopes. RESULTS: This study revealed that the body weight scale was found to be significantly higher in the CoQ10 group (21.39 +/- 2.70), compared to the TMT group (19.39 +/- 2.74) (P < 0.05). In the TMT group, the animals showed body a weight loss that was significantly lower than that of the control group (22.33 +/- 3.06) (P < 0.05). Our results showed that CoQ10 provided protection against MWM deficits. Furthermore, TMT impaired the ability of mice to locate the hidden platform, compared to the control group (P < 0.05). Microscopic studies showed that TMT caused histopathological changes in the dentate gyrus and increased the number of necrotic neurons (476 +/- 78.51), compared to the control group (208 +/- 40.84) (P < 0.001). But, CoQ10 significantly attenuated (31 9 +/- 60.08) the density of necrotic neurons compared to TMT (P < 0.05). CONCLUSIONS: The results of the present study indicate that Coenzyme Q10 diminished neuronal necrosis and improved learning memory. Part of its beneficial effect is due to its potential to discount oxidative stress. PMID- 27781115 TI - Unexpected Rupture of a Giant Lobulated Thrombotic Middle Cerebral Artery Aneurysm and Emergency Surgical Treatment With Thrombectomy: A Case Report and Review of the Literature. AB - INTRODUCTION: The treatment of giant intracranial aneurysms is one of the most challenging cerebrovascular problems of neurosurgery. We report the rupture of a giant, lobulated, and almost completely thrombosed middle cerebral artery (MCA) aneurysm that is the ninth such report in the literature. We also investigated additional solutions used in the treatment of this patient. CASE PRESENTATION: A 58-year-old man had been admitted with headache 8 years previously (in 2005), and a giant MCA aneurysm was detected. Two separate endovascular interventions were performed, and both failed. The patient began to live with the giant aneurysm. As there was a large thrombosis filling the aneurysm lumen during the previous endovascular procedures, the aneurysm was not expected to rupture. However, a rupture eventually occurred, in 2013. Even if an aneurysm is very large, lobulated, old, and almost completely thrombosed, it can suddenly bleed. During surgery on this patient, we observed severe cerebral vasospasm caused by a giant thrombosed aneurysmal rupture. Despite the complications, surgery is a life saving treatment for this emergency when other strategies are not possible. Thrombectomy and clipping are approaches that require a great deal of courage for the neurosurgeon, in terms of entering the risky area within the aneurysm. CONCLUSIONS: We believe that it would be more appropriate to plan for combined treatment with surgical and endovascular approaches before the emergency condition could occur. PMID- 27781116 TI - Case Report of a Patient Undergoing Peritoneal Dialysis with Encapsulating Peritoneal Sclerosis Superimposed With Calciphylaxis. AB - INTRODUCTION: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis (PD). Tamoxifen has been generally well tolerated, even without randomized controlled trials. CASE PRESENTATION: Herein, we report a case of a patient undergoing 12 years of PD who developed EPS and calciphylaxis simultaneously. We also provide a comprehensive discussion about the association between EPS and calciphylaxis. Moreover, although tamoxifen is used in EPS due to its inhibition of fibroblast-transforming growth factor beta (TGFbeta) production, it may worsen the calciphylaxis due to a hypercoagulable state. CONCLUSIONS: We suggest avoiding the use of tamoxifen for EPS in patients with superimposed calciphylaxis. PMID- 27781117 TI - Determinants of Tobacco and Hookah Smoking in a Nationally Representative Sample of Iranian Children and Adolescents: The CASPIAN-IV Study. AB - BACKGROUND: The consumption of tobacco through a hookah is growing in popularity, especially among children and adolescents, but little is known about the determinants of hookah smoking. OBJECTIVES: The current study aimed to assess the determinants of tobacco smoking and hookah smoking in a nationally representative sample of Iranian children and adolescents. PATIENTS AND METHODS: This study was conducted as part of the fourth cross-sectional survey of a national school-based program. Using a cluster random sampling method, a validated questionnaire was completed anonymously by 14,880 students who were aged 6 - 18 years and living in urban and rural areas of 30 provinces in Iran. RESULTS: The final study group consisted of 13,486 children and adolescents (participation rate of 90.6%), of whom 49.2% were girls and 75.6% were urban residents. The mean age was 12.47 +/- 3.36 years. According to the self-reports of the students, 2.6% (3.5% of boys and 1.7% of girls) were current tobacco smokers, 5.9% (7.5% of boys and 4.2% of girls) were ever tobacco smokers, and 1.8% (2.49% of boys and 1.14% of girls) were current hookah smokers. Based on a multiple logistic regression (MLR) model, the following factors increased the risk of current smoking: age, number of days spent with friends per week, hookah smoking or cigarette smoking by the father, hookah smoking by siblings, hookah smoking by other members of the family, and screen time. The age, number of days spent with friends, hookah or cigarette smoking by the father, hookah smoking by siblings, and screen time increased the risk of hookah smoking. Female gender and living in rural areas decreased the risk of current tobacco and hookah smoking. CONCLUSIONS: Preventive measures against tobacco use should be underscored for Iranian families. The preparation of strategies on the promotion of a healthy lifestyle should be considered a health priority. PMID- 27781118 TI - Optimal Glycemic and Hemoglobin A1c Thresholds for Diagnosing Diabetes Based on Prevalence of Retinopathy in an Iranian Population. AB - BACKGROUND: The use of glycemic thresholds for diabetes diagnosis is controversial. However, no information is available regarding glycemic and glycated hemoglobin (HbA1c) thresholds for detecting diabetic retinopathy (DR) in the Iranian population. OBJECTIVES: The main purpose of the current investigation was to examine the association of fasting plasma glucose (FPG) and HbA1c levels with diabetic retinopathy (DR), and to determine the relevant cut-off levels in an Iranian population. PATIENTS AND METHODS: This cross-sectional, population based study was performed during 2012-2013 in Urmia, the capital of West Azerbaijan province, Iran. The subjects were 3,010 Iranians aged 40-81 years. The FPG levels were determined using the glucose oxidase method whereas, the HbA1c values were measured using a standardized assay by high performance liquid chromatography. DR was evaluated by an examination of the fundus photograph of each eye. The photographs were graded according to the international clinical diabetic retinopathy disease severity scale by photograph graders who were masked to the clinical information. RESULTS: Of the subjects, 59 had DR. The prevalence of DR increased steeply between the ninth and the tenth deciles for both variables. The ROC curve analysis showed overall glycemic thresholds for DR of 6.5 mmol/L (117 mg/dL) for FPG and 6.2% (44 mmol/mol) for HbA1c. The sensitivities and specificities were 78.0% and 87.1% for FPG and 89.8% and 89.5% for HbA1c, respectively. The areas under the ROC curves indicated that HbA1c was a stronger discriminator of retinopathy: the area under curve was 0.880 for FPG and 0.946 for HbA1c P < 0.001). However, the thresholds for detecting DR for the two measures showed no significant differences after excluding individuals receiving anti-hyperglycemic medication. CONCLUSIONS: These findings suggest that the HbA1c and FPG thresholds for detecting diabetes in the Iranian population are lower than the current diagnostic criteria. PMID- 27781119 TI - The Effect of Orem's Self-Care Model on Fatigue in Patients With Multiple Sclerosis: A Single Blind Randomized Clinical Trial Study. AB - BACKGROUND: Orem's self-care model is a nursing model that was introduced with the purpose of improving the self-care of individuals, especially patients suffering from chronic diseases. OBJECTIVES: To determining the effect of Orem's self-care model on fatigue in multiple sclerosis patients. PATIENTS AND METHODS: This research involved a clinical trial. Sixty-three multiple sclerosis patients at the vice-chancellor in treatment affairs of Yasuj University of Medical Sciences were selected based on nonrandom sampling, but they were allocated to the two groups based on random allocation. In the intervention group, Orem's model was applied during six sessions of 45 - 60 minutes in length, and the process continued for 1 month. The data were collected 1 week before and 7 weeks after the end of the intervention using the Orem's self-care model-based assessment form and fatigue severity scale, the validity and reliability of which have been. RESULTS: Before the intervention, 11.11% of the participants had a good knowledge of self-care. In addition, self-care willingness and skills were observed in 76.19% and 4.76% of participants, respectively. The mean difference in fatigue reduced significantly in the intervention group after the intervention (P < 0.05). After the intervention, a statistically significant difference was observed in the mean difference of fatigue between the two groups (P < 0.05). CONCLUSIONS: Orem's self-care model is significantly effective in reducing the fatigue of multiple sclerosis patients. PMID- 27781120 TI - Effective Factors on Health-Promoting Lifestyle Among Iranian Chemical Veterans in 2014 Based on Health Promotion Model: A Path Analysis. AB - BACKGROUND: Health-promoting behaviors can enhance physical and mental health among individuals with disability, particularly veterans. OBJECTIVES: The current study aimed to examine both one-way direct and indirect effects of the factors of the Health Promotion Model (HPM) on health-promoting behaviors in chemical veterans from Ilam province in Iran. MATERIALS AND METHODS: This cross-sectional study was conducted in 2014. In this study, 239 moderate-to-severe chemical veterans from Illam province supported by the veterans' affairs department of Ilam were evaluated via census sampling. Data including health-promoting behaviors, perceived self-efficacy, perceived barriers and benefits, perceived social support, and perceived health status were collected using standard questionnaires. RESULTS: The results show that the HPM is a poor predictor of the health-promoting lifestyles of chemical veterans (R2 = 15%). Social support (factor loading = 0.38) is the strongest predictor of health-promoting behaviors and it influences such behaviors directly, while perceived barriers (factor loading = -0.11) and perceived self-efficacy (factor loading = 0.02) indirectly predict behavior through social support. CONCLUSIONS: Perceived social support is the most important factor that influences health-promoting behaviors. Increasing social support by enhancing self-efficacy and decreasing perceived barriers can improve health-promoting behaviors among veterans. PMID- 27781121 TI - The Effect of Cumin cyminum L. Plus Lime Administration on Weight Loss and Metabolic Status in Overweight Subjects: A Randomized Double-Blind Placebo Controlled Clinical Trial. AB - BACKGROUND: Limited data are available regarding the effects of combined administration of Cumin cyminum L. and lime on weight loss and metabolic profiles among subjects with overweight subjects. OBJECTIVES: The current study aimed to assess the effects of combined administration of Cumin cyminum L. and lime on weight loss and metabolic profiles among subjects with overweight. PATIENTS AND METHODS: This randomized double-blind placebo-controlled clinical trial was conducted on 72 subjects with overweight, aged 18 - 50 years old. Participants were randomly divided into three groups: Group A received high-dose Cumin cyminum L. and lime capsules (75 mg each, n = 24), group B low-dose Cumin cyminum L. and lime capsules (25 mg each, n = 24) and group C placebos (n = 24) twice daily for eight weeks. RESULTS: After eight weeks of intervention, compared with low-dose C. cyminum L. plus lime and placebo, taking high-dose C. cyminum L. plus lime resulted in significant weight loss (in the high-dose group: -2.1 +/- 1.7 vs. in the low-dose group: -1.2 +/- 1.5 and in the placebo group: + 0.2 +/- 1.3 kg, respectively; P < 0.001) and body mass index (-0.8 +/- 0.6 vs. -0.5 +/- 0.5 and +0.1 +/- 0.5 kg/m2, respectively; P < 0.001). In addition, administration of high dose C. cyminum L. plus lime compared with low-dose C. cyminum L. plus lime and placebo, led to a significant reduction in fasting plasma glucose (FPG) (P < 0.001) and a significant rise in quantitative insulin sensitivity check index (QUICKI) (+ 0.02 +/- 0.02 vs. + 0.01 +/- 0.02 and 0.01 +/- 0.01, respectively; P = 0.01). Moreover, a significant decrease in serum triglycerides (-14.1 +/- 56.2 vs. +13.9 +/- 36.8 and + 10.6 +/- 25.1 mg/dL; respectively; P = 0.03), total cholesterol (-18.4 +/- 28.6 vs. +8.6 +/- 28.5 and -1.0 +/- 24.8 mg/dL; respectively; P = 0.004) and low density lipoproteins- (LDL)-cholesterol levels ( 11.8 +/- 20.7 vs. +6.5 +/- 23.2 and -2.9 +/- 20.4 mg/dL, respectively; P = 0.01) was observed following the consumption of high-dose C. cyminum L. plus lime compared with low-dose C. cyminum L. plus lime and placebo. CONCLUSIONS: Results of the current study indicated that taking high-dose C. cyminum L. plus lime for eight weeks among subjects with overweight had beneficial effects on weight, BMI, FPG, QUICKI, triglycerides, total-cholesterol and LDL-cholesterol levels. PMID- 27781122 TI - The Effect of Slow-Stroke Back Massage on the Anxiety Levels of Iranian Women on the First Postpartum Day. AB - BACKGROUND: Anxiety disorder is common during the postpartum period. Back massage relaxation techniques are one of the most important nonpharmacological interventions to prevent and control postpartum-related anxiety. OBJECTIVES: To determine the effectiveness of slow-stroke back massage on the anxiety levels of primiparous mothers in the first days after delivery. MATERIALS AND METHODS: This single-blind controlled clinical trial consisted of 100 primiparous mothers with normal deliveries. The mothers were randomly allocated to interventional (n = 50) or control (n = 50) groups using binary blocks. Both groups were followed up just before, immediately after, and the morning after the intervention. Data were collected using a demographic questionnaire and Spielberger's state anxiety inventory (STAI) questionnaire. RESULTS: The mean age of the mothers was 22 years. There were no significant between-group differences in age (P = 0.333), education (P = 0.427), and medication during labor and the postpartum period (P = 0.412). There was no statistically significant difference between the mean anxiety scores of the experimental (6.66 +/- 35.48) and control groups (9.05 +/- 37.42) before the intervention (P = 0.268). Immediately after the massage and the next morning, there was a significant between-group difference in the anxiety scores (P < 0.001). CONCLUSIONS: The findings demonstrate that slow-stroke back massage is a simple, inexpensive, noninvasive, and effective method to reduce the anxiety levels of primiparous women during the first postpartum day. PMID- 27781123 TI - Septic Cavernous Sinus Thrombosis: A Case Report. AB - INTRODUCTION: Septic cavernous sinus thrombosis (CST) is a rare condition that can result in high mortality and morbidity rates if not treated immediately. CST may be aseptic or septic. Less common primary sites of infection include the tonsils, soft palate, middle ear, and orbit. Reported cases of middle ear infection are very rare, and response to treatment is poor. CASE PRESENTATION: The present study is a case report of acute otitis media which led to septic cavernous sinus thrombosis in a 56-year-old woman in Bojnord city, North Khorasan, Iran. CONCLUSIONS: Findings of laboratory tests and magnetic resonance imaging (MRI) confirmed the clinical diagnosis. Clinical-based medical care led to successful management of the patient with broad spectrum intravenous antibiotics that prevented serious complications. PMID- 27781124 TI - Systemic Manifestation of Rotavirus Infection in Children: A Report of Three Cases. AB - INTRODUCTION: Rotavirus is a leading cause of acute gastroenteritis in children. Although the clinical complaints associated with rotavirus are generally gastrointestinal, including vomiting and diarrhea, data suggest that it can also cause symptoms that extend beyond the gastrointestinal tract. CASE PRESENTATIONS: We report three pediatric cases of rotavirus infection: one accompanied by encephalopathy and two with elevated hepatic transaminase activity. The patients were admitted to Dr. Sami Ulus maternity and children's health and diseases training and research hospital, Ankara, Turkey, from 2012 - 2014. The presented patients' aspartate aminotransferase (AST) (1765-2614 IU L-1) and alanine aminotransferase (ALT) (1448-3558 IU L-1) levels are, to date, the highest reported levels associated with rotavirus infections, and suggest that the rotavirus can cause severe hepatic transaminase elevation. CONCLUSIONS: This report aimed to increase awareness of the occurrence of extra-intestinal systemic manifestations of rotavirus infection. Although such cases may be rare, they still suggest that that rotavirus is a systemic viral infection. PMID- 27781125 TI - Torsion of a Giant Pedunculated Hemangioma of the Liver Presenting With Acute Abdomen: A Case Report. AB - INTRODUCTION: Hemangioma is the most common benign tumor of the liver. Most cases are asymptomatic and do not require treatment. A hemangioma can rarely be pedunculated; as a result, it may undergo torsion and infarction, which can make it symptomatic. CASE PRESENTATION: We report the case of a 45-year-old woman with acute abdominal pain due to torsion of a giant pedunculated hepatic hemangioma around its vascular stalk. CONCLUSIONS: Pedunculated hemangioma of the liver is an uncommon benign tumor, a rare differential diagnosis for a mass located in the upper abdomen. All incidentally detected pedunculated hemangiomas must be surgically managed, as these have a tendency to become torsioned, and there is also a risk of malignancy or rupture. PMID- 27781126 TI - Fuchs' Heterochromic Iridocyclitis in an Italian Tertiary Referral Centre: Epidemiology, Clinical Features, and Prognosis. AB - Purpose. To study epidemiology, clinical findings and visual prognosis of patients with Fuchs' Heterochromic Iridocyclitis (FHI). Methods. A retrospective analysis was performed on 158 patients with FHI. Thirty-five patients were observed only once; the remaining 123 had a mean follow-up of 30.7 months (50 of them had a mean follow-up of 63.5 months) and in those we assessed complications, medical and surgical treatment, and long-term visual prognosis. Results. Average age at uveitis diagnosis was 27.2 years and 18.3% of patients were children. Blurred vision (54.5%) and floaters (40.5%) were the most frequent presenting symptoms. Small to medium-sized keratic precipitates (95.6%), iris atrophy (86.8%), and vitreous opacities (91.2%) were the most common signs; the prevalence of cataract and IOP increase was 63.5% and 20.1%, respectively, and their incidence was 0.1 and 0.06 eye/year. Significant risk factor for visual loss was IOP increase at presentation (p = 0.02). At final examination 98% of the eye had a visual acuity >= 0.6, and topical (p < 0.001) and systemic (p < 0.001) corticosteroids therapy were used less frequently than before referral. Conclusions. FHI has a good visual prognosis, despite the significant incidence of cataract and glaucoma. A correct and prompt diagnosis might avoid unnecessary therapies and provide excellent visual outcomes. PMID- 27781128 TI - Removal of Separated Endodontic K-File with the Aid of Hypodermic Needle and Cyanoacrylate. AB - A wide range of accidents might happen during the treatment of the root canal system, where the instrument separation is one of the most unpleasant occurrences. Several techniques have been developed to facilitate the removal of the fragments; however, they generally require specific devices that not always are available to the clinician. The aim of this case report is to present a simple alternative technique to remove from the root canals manual instruments fractured during the treatment. The case has its outline based on a 31-year-old patient who sought the clinic to have her maxillary first left premolar rehabilitated. The clinic and radiographic examinations revealed the need of endodontic retreatment and the presence of a fragment of a K-file instrument localized at the apical third of the palatine canal. The retreatment was initiated by the removal of the obturation materials followed by several unsuccessful attempts to take out the fractured instrument. Hence, it was chosen to perform the fragment removal using a hypodermic needle and cyanoacrylate adhesive. The fragment easily came out, which reinforces the technique adopted as a safe, simple, and low cost mean to solve the problem of fractured instruments using only items already present in the endodontic arsenal. PMID- 27781129 TI - Giant Inflammatory Fibroid Polyp of the Hepatic Flexure of Colon Presenting with an Acute Abdomen. AB - Background. Inflammatory Fibroid Polyp (IFP) of the colon is an exceedingly rare condition. Since 1952 till now only 32 cases have been reported worldwide of which only 5 were giant (>4 cm) polyps mostly found in the caecum (15 cases) with only 3 in the descending colon. Case Presentation. A 36-year-old female with no previous illness presented to the emergency unit with an acute onset pain over the right hypochondrium for 3 days associated with intermittent fever and anorexia. As she had evidence of localized peritonitis she underwent a diagnostic laparoscopy and subsequently an exploratory laparotomy. A mass measuring 8 * 7 * 5 cm arising from the hepatic flexure of colon was noted. Right hemicolectomy with ileotransverse anastomosis was performed. The mass was subsequently reported to be IFP. Conclusion. IFP is a very rare condition with clinical presentation depending upon its size and location. Definitive diagnosis is possible with histopathological examination of tissue aided by immunohistochemical studies. Surgical resection has been the most common method of treatment especially for large and giant colonic IFPs owing to challenges in terms of diagnosis and technical difficulties associated with endoscopic methods. PMID- 27781127 TI - Timing of Pars Plana Vitrectomy in Management of Gunshot Perforating Eye Injury: Observational Study. AB - The aim of this study is to report the difference in either anatomical or functional outcome of vitreoretinal intervention in cases of gunshot perforating eye injury if done 2-4 weeks or after the 4th week after the original trauma. Patients were treated with pars plana vitrectomy and silicon oil. Surgeries were performed in the period from February 2011 until the end of December 2014. 253 eyes of 237 patients were reviewed. 46 eyes were excluded. 207 eyes of 197 patients were analyzed. The included eyes were classified based on the timing of vitrectomy in relation to the initial trauma into two groups: 149 eyes (the first group) operated on between the 3rd and the 4th week and 58 eyes (the second group) operated on after the 4th week after the trauma. Following one surgical intervention, in the first group, attached retina was achieved in 93.28% of patients. In the second group, attached retina was achieved in 96.55% of patients. All RD cases could be attached by a second surgery. Visual acuity improved in 81.21% of patients, did not change in 15.43% of patients, and declined in 3.35% of patients. In the second group, visual acuity improved in 81.03% of patients, did not change in 12.06% of patients, and worsened in 6.89% of patients. There was no statistically significant difference between the two groups in either anatomical or functional results. We recommend interfering before the 5th week after the trauma as retinal detachment is encountered more in cases operated on after the 4th week. The visual outcome depends on the site of entry and exit (the route of gunshot). PMID- 27781131 TI - Cystic Lung Disease in Down Syndrome: A Case Report and Literature Review. AB - Subpleural lung cysts (SPC) are seen in children with Down syndrome (DS). The incidence and the long term course of these lesions are not known. It is important for pediatricians and pediatric radiologists to be aware of these lung lesions since the DS patients' longevity has increased and they have greater frequency to encounter the clinicians. Autopsy and the radiology series have shown that these lesions are often found in association with congenital heart disease, particularly the endocardial cushion defect and prematurity. PMID- 27781130 TI - Single Jejunum Metastasis from Breast Cancer Arising Twelve Years after the Initial Treatment. AB - Metastatic involvement of gastrointestinal tract from breast cancer is a rare event. We report the case of a 61-year-old woman presenting with bowel obstruction, related to metastasis of a primary breast cancer she had 12 years earlier (a triple-negative invasive ductal carcinoma treated with surgery and chemotherapy). Bowel obstruction was caused by a 20-centimeter tumor in the jejunum, involving also the transverse colon. The patient underwent en bloc resection of tumor with jejunum and transverse bowel segment and received adjuvant chemotherapy with carboplatin and paclitaxel. Twenty months later, she was alive without disease recurrence. PMID- 27781132 TI - Immunomodulation of inflammatory leukocyte markers during intravenous immunoglobulin treatment associated with clinical efficacy in chronic inflammatory demyelinating polyradiculoneuropathy. AB - OBJECTIVE: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy. METHODS: Response to IVIg treatment in newly diagnosed IVIg-naive and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response. RESULTS: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185+ follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16+ myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16+ dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response. CONCLUSIONS: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome. PMID- 27781134 TI - Genetic and environmental components of female depression as a function of the severity of the disorder. AB - BACKGROUND: Both clinical care and genome-wide studies need to account for levels of severity in the etiology of depression. The purpose of the study is to estimate the genetic and environmental components of female depression as a function of the severity of the disorder. METHODS: A genetic and environmental model analysis of depression incidence was made using the IOP Depression Severity Measure (IDSM). Details of lifetime depression incidence were obtained by questionnaire from twins on the DTR registry. Data from 1449 matched female twin pairs in the age range 19-85 years in four ordinal categories of increasing severity were employed in the analysis. RESULTS: Estimates of additive and dominance genetic components of 27% and 25% were found when all three levels of depression were included, and near zero and 33% when the recurrent/severe level was excluded. Shared environmental effects were not significant in either case, but the estimate for random environmental effects was greater when the severe level was excluded. CONCLUSIONS: These results suggest that the incidence of severe depression is associated with homozygotic alleles and the less severe with heterozygotic alleles. This is in accord with the finding that the hereditary component of severe depression is relatively high and that milder forms are more dependent on life-time environmental factors. Such conclusions have clinical implications for the diagnosis and treatment of the disorder by practicing psychiatrists. They also lead to the importance of focusing future genome-wide and linkage studies on those females with severe levels of depression if progress in identifying genetic risk loci is to be made. PMID- 27781133 TI - Hippocampal lipid differences in Alzheimer's disease: a human brain study using matrix-assisted laser desorption/ionization-imaging mass spectrometry. AB - INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia, is pathologically characterized by beta-amyloid plaques and tau tangles. However, there is also evidence of lipid dyshomeostasis-mediated AD pathology. Given the structural diversity of lipids, mass spectrometry is a useful tool for studying lipid changes in AD. Although there have been a few studies investigating lipid changes in the human hippocampus in particular, there are few reports on how lipids change in each hippocampal subfield (e.g., Cornu Ammonis [CA] 1-4, dentate gyrus [DG] etc.). Since each subfield has its own function, we postulated that there could be lipid changes that are unique to each. METHODS: We used matrix assisted laser desorption/ionization-imaging mass spectrometry to investigate specific lipid changes in each subfield in AD. Data from the hippocampus region of six age- and gender-matched normal and AD pairs were analyzed with SCiLS lab 2015b software (SCiLS GmbH, Germany; RRID:SCR_014426), using an analysis workflow developed in-house. Hematoxylin, eosin, and luxol fast blue staining were used to precisely delineate each anatomical hippocampal subfield. Putative lipid identities, which were consistent with published data, were assigned using MS/MS. RESULTS: Both positively and negatively charged lipid ion species were abundantly detected in normal and AD tissue. While the distribution pattern of lipids did not change in AD, the abundance of some lipids changed, consistent with trends that have been previously reported. However, our results indicated that the majority of these lipid changes specifically occur in the CA1 region. Additionally, there were many lipid changes that were specific to the DG. CONCLUSIONS: Matrix-assisted laser desorption/ionization-imaging mass spectrometry and our analysis workflow provide a novel method to investigate specific lipid changes in hippocampal subfields. Future work will focus on elucidating the role that specific lipid differences in each subfield play in AD pathogenesis. PMID- 27781135 TI - Adjunctive brexpiprazole in patients with major depressive disorder and anxiety symptoms: an exploratory study. AB - BACKGROUND: Major depressive disorder (MDD) with concurrent anxiety symptoms may signal a difficult-to-treat patient. Brexpiprazole is a serotonin-dopamine activity modulator: a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. The objective of this Phase IIIb study was to explore effectiveness, safety, and tolerability of brexpiprazole adjunctive to antidepressant (ADT) monotherapy in patients with MDD and anxiety symptoms (NCT02013531). METHODS: Patients with MDD, Hamilton Anxiety Rating Scale (HAM-A) total score >= 20, and inadequate response to current ADT received open-label brexpiprazole 1-3 mg day-1 (target dose 2 mg day-1) + ADT for 6 weeks. Efficacy endpoints included change from baseline at Week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score, HAM-A total score, and Sheehan Disability Scale (SDS). Safety and tolerability assessments included adverse events (AEs). RESULTS: Of 37 participants enrolled, 32 (86.5%) completed the study. Baseline mean (SD) MADRS total score was 30.1 (5.1); mean HAM-A total score was 26.9 (5.0). Improvements from baseline were observed at Week 6 for least squares mean change in MADRS total score (-19.6, p < .0001 vs. baseline), HAM-A total score (-17.8, p < .0001) and mean (SD) SDS mean score [-3.6 (2.6)]. Brexpiprazole was well tolerated. The most frequent treatment-emergent AEs were increased appetite (13.5%) and diarrhea, dry mouth, and dizziness (all 10.8%). CONCLUSIONS: These open-label results support the anxiolytic effects of adjunctive brexpiprazole in the treatment of patients with MDD. PMID- 27781137 TI - Epidemiology of persistent iatrogenic spinal cord injuries in Western Norway. AB - OBJECTIVES: Iatrogenic spinal cord injuries (SCIs) caused by invasive procedures or surgical interventions have previously been reported as case studies. The primary objective of this study was to investigate and analyze the incidence, etiology, and prognosis of iatrogenic SCI in Western Norway. METHODS: Medical records of all 183 patients admitted to the SCU between 01.01.2004 and 31.12.2013 were reviewed. Gender, age, diagnosis, iatrogenic medical procedure, symptoms and findings before and after injury, mechanism of injury, level of injury, and ASIA Impairment Scale (AIS) score prior iatrogenic SCI, at admittance and discharge were recorded, as were the length of the period prior to admittance and the length of stay. RESULTS: Twenty-three (12.5%; 14 men, nine women) of 183 patients met the criteria for iatrogenic SCI. The annual incidence rate was estimated 2,3 per 1,000,000 (SD +/-1.0). Mean age at iatrogenic SCI was 55.5 years (range 16-79 years). Intervention for cervical spinal stenosis was the leading cause of iatrogenic SCI, followed by operations on the aorta and spine. Iatrogenic SCIs was most frequently located on the thoracic level. The patients suffered from clinical incomplete injuries (AIS score C and D) both at admittance and discharge from the SCU. Most patients improved, but no patient recovered completely after SCI. CONCLUSION: Although the annual incidence rate of iatrogenic SCI is low in Norway, individual consequences are serious. Increased awareness of the causes of SCI may decrease the risk of iatrogenic SCI. PMID- 27781136 TI - Altered regional brain function in the treatment-naive patients with somatic symptom disorder: a resting-state fMRI study. AB - INTRODUCTION: Somatic symptom disorder (SSD) is an illness that occurs over a long time and results in significant disruption in daily life. Clinically, SSD patients typically express complaints that involve a variety of organ systems. However, the neural mechanism of SSD remains poorly understood. METHODS: Using resting-state functional magnetic resonance imaging, we investigated the characteristics of the regional basal brain function during resting state in patients with SSD. Eleven treatment-naive SSD patients and 12 age-matched healthy controls were recruited in this study. Between-group differences in regional homogeneity values were analyzed. RESULTS: Compared with the healthy control group, the SSD group showed significant increases in regional homogeneity values in the right medial prefrontal cortex, anterior cingulate cortex and supramarginal gyrus, and significant decreases in the bilateral middle occipital gyrus, superior occipital gyrus and right cuneus and left postcentral gyrus and cerebellum. Meanwhile, the regional homogeneity value of the right medial prefrontal cortex positively correlated with the total duration of SSD. CONCLUSIONS: The abnormal resting-state patterns in regional brain activity may contribute to understanding the mechanism of SSD. PMID- 27781138 TI - Depressive symptoms associated with concerns about falling in Parkinson's disease. AB - BACKGROUND: Concerns about falling, a construct related to fear of falling, is increased in people with Parkinson's disease (PD) and is recognized as a barrier for exercise, negatively affecting health-related quality of life and participation. AIM: To investigate modifiable factors associated with concerns about falling in elderly with mild-to-moderate PD. METHODS: Eighty-nine elderly (39 females, mean age 73 years) with mild-to-moderate PD were recruited. Concerns about falling were assessed with the Falls Efficacy Scale-international, that is, the dependent variable in multiple linear regression analysis. Independent variables included both motor (e.g., objective measures of physical activity and gait) and nonmotor aspects such as depressive symptoms. RESULTS: A model with three significant independent variables explained 33% of the variance in concerns about falling. According to the standardized regression coefficients (beta), the strongest contributing factor was depressive symptoms (0.40), followed by balance performance (-0.25), and use of mobility devices (0.24). CONCLUSIONS: The findings imply that factors associated with concerns about falling are a multifactorial phenomenon. For its management in elderly with mild-to-moderate PD, one should consider depressive symptoms, balance deficits, and mobility devices. PMID- 27781139 TI - Mandarin functional MRI Language paradigms. AB - OBJECTIVE: The objective of this study was to implement convenient, fast, and accurate Mandarin task paradigms for functional MRI, and to locate the Chinese language functional areas in frontal and temporal lobes. MATERIALS AND METHODS: Nineteen healthy Chinese volunteers participated in this study, which utilized a block design with four language tasks: auditory naming (AN), picture naming (PN), verbal fluency-character (VFC), and verbal fluency-letter (VFL). All functional images were preprocessed by SPM 8, followed by first- and second-level analyses and lateralization index calculation. RESULTS: Group analyses showed that for AN and PN, maximal responses were located in the right superior temporal gyrus. The picture naming-scrambled pictures and faces contrast gave maximal responses in the left fusiform gyrus; VFC in the left middle frontal gyrus and the left superior frontal gyrus. For VFL the maximal response was in the left superior temporal gyrus. There was some inconsistency of activations for individual subjects. At a threshold of Z > 2.5, 10 voxels extent, activations were seen in >50% subjects for AN in the right superior temporal gyrus, the right middle frontal gyrus, and the left middle temporal gyrus, for PN in the right superior temporal gyrus and for picture naming-scrambled pictures and faces in left inferior frontal gyrus. As a group, the lateralization index of all contrasts were left hemisphere dominant in the frontal lobes. In the temporal lobe, the hemispheric dominance differed for different contrasts. CONCLUSION: These Chinese language stimulus paradigms activated language areas, and the functional regions of brain in different language tasks, and can now be piloted in clinical studies. PMID- 27781140 TI - Mesenchymal stem cell-based treatments for stroke, neural trauma, and heat stroke. AB - BACKGROUND: Mesenchymal stem cell (MSC) transplantation has been reported to improve neurological function following neural injury. Many physiological and molecular mechanisms involving MSC therapy-related neuroprotection have been identified. METHODS: A review is presented of articles that pertain to MSC therapy and diverse brain injuries including stroke, neural trauma, and heat stroke, which were identified using an electronic search (e.g., PubMed), emphasize mechanisms of MSC therapy-related neuroprotection. We aim to discuss neuroprotective mechanisms that underlie the beneficial effects of MSCs in treating stroke, neural trauma, and heatstroke. RESULTS: MSC therapy is promising as a means of augmenting brain repair. Cell incorporation into the injured tissue is not a prerequisite for the beneficial effects exerted by MSCs. Paracrine signaling is believed to be the most important mediator of MSC therapy in brain injury. The multiple mechanisms of action of MSCs include enhanced angiogenesis and neurogenesis, immunomodulation, and anti-inflammatory effects. Microglia are the first source of the inflammatory cascade during brain injury. Cytokines, including tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, are significantly produced by microglia in the brain after experimental brain injury. The proinflammatory M1 phenotype of microglia is associated with tissue destruction, whereas the anti-inflammatory M2 phenotype of microglia facilitates repair and regeneration. MSC therapy may improve outcomes of ischemic stroke, neural trauma, and heatstroke by inhibiting the activity of M1 phenotype of microglia but augmenting the activity of M2 phenotype of microglia. CONCLUSION: This review offers a testable platform for targeting microglial-mediated cytokines in clinical trials based upon the rational design of MSC therapy in the future. MSCs that are derived from the placenta provide a great choice for stem cell therapy. Although targeting the microglial activation is an important approach to reduce the burden of the injury, it is not the only one. This review focuses on this specific aspect. PMID- 27781141 TI - Characterizing neurocognitive impairment in young people with major depression: state, trait, or scar? AB - BACKGROUND: Major depressive disorder (MDD) affects a quarter of adolescents and young adults and is associated with the greatest global burden of disease in this population. There is a growing literature, mostly in adults, showing that significant neurocognitive impairments are common in MDD. It remains unclear whether these impairments are pre-existing trait markers of MDD, state-related impairments that fluctuate with depressive symptoms, or 'scar' impairments that worsen with illness progression. The aim of this study is to provide a conceptual framework for understanding MDD and neurocognitive impairment in adolescence and young adulthood (ages 12-25 years). METHOD: Examination of the evidence for neurocognitive deficits as trait, state, and scar features of MDD according to different study designs (family studies, premorbid studies, current depression, remitted depression, and longitudinal studies with repeated assessment) was conducted. RESULTS: The few premorbid and family studies conducted in youth provide equivocal evidence for neurocognitive impairments as trait markers of MDD. The presence of state-based neurocognitive impairment remains unclear as evidence comes mostly from cross-sectional studies. There are a limited, but growing number of longitudinal studies with repeated neurocognitive assessment in youth. Studies that examined neurocognition prior to the onset of MDD and with long-term follow-up provide tentative evidence for neurocognitive scarring. CONCLUSION: Neurocognitive impairment is a feature of MDD in adolescents and young adults. To better understand the nature, timing, and pattern of impairment, longitudinal studies that examine neurocognition before and after the development of full-threshold MDD, including following recurrence are needed. This knowledge will have important implications for mechanisms, prevention, and treatment of MDD in youth. PMID- 27781142 TI - Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants. AB - INTRODUCTION: The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. METHODS: C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. RESULTS: Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. CONCLUSIONS: Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function. PMID- 27781143 TI - Temporal regularity of intrinsic cerebral activity in patients with chronic primary insomnia: a brain entropy study using resting-state fMRI. AB - INTRODUCTION: Several neuroimaging studies have suggested that patients with chronic primary insomnia (CPI) exhibit anatomical and functional alterations of the brain, but the temporal regularity in spontaneous neuronal activity remains unknown. Here, brain entropy (BEN), a data-driven method used to measure the signal regularity of a time series, was applied for the first time to investigate changes in the entire brain at the voxel level. METHODS: Resting-state functional MRI data were used to investigate insomnia-related BEN alterations and the resting-state functional connectivity (rsFC) pattern in seed regions with altered BEN in 29 patients with identified and untreated CPI and 29 matched healthy controls. Subsequently, within the CPI group, correlation analysis was conducted to evaluate the relationship between the clinical variables and the BEN and rsFC of the abnormal regions. RESULTS: Chronic primary insomnia patients showed significant increase in BEN in the central part of the default-mode network (DMN), the anterior regions of the task-positive network (TPN), the hippocampus (Hipp), and basal ganglia (BG), and decreases in BEN in the right postcentral gyrus (PoCG) and right temporal-occipital junction (TOJ). We also demonstrated that three altered resting-state functional connectivity (rsFC) patterns were associated with abnormal BEN regions in CPI patients. Correlation analysis identified an association between the altered rsFC and clinical variables, such as the Pittsburgh Sleep Quality Index (PSQI), in CPI patients. CONCLUSIONS: Together, these findings suggest that abnormal BEN-related intrinsic functional plasticity in CPI patients corresponds to poor sleep quality during chronic insomnia. Alterations in both BEN and its affected connectivity may improve our understanding of treatment-naive CPI patients and promote the future development of new therapeutic strategies. PMID- 27781145 TI - The feasibility of 11C-PIB-PET/CT for amyloid plaque burden: validation of the effectiveness of CT-based partial volume correction. AB - INTRODUCTION: Amyloid positron-emission tomography (PET) imaging with 11C Pittsburgh compound B (PiB) is an effective tool for assessing brain amyloid deposits. PET imaging, however, can suffer from the partial volume effect (PVE). PVE has been corrected using MRI (magnetic resonance imaging) image data. However, correction of the PVE of PET using MRI usually requires two separate procedures, imposing a burden on patients and leading to low throughput and inefficient diagnoses. The advent of PET/computed tomography (PET/CT) may potentially overcome these problems and offer higher throughput and reliable quantification of amyloid plaques and assessment of Alzheimer disease (AD). METHODS: We investigated the feasibility of correcting PVE in amyloid PET using CT, obtained by PET/CT, instead of MRI. We demonstrated the efficacy of partial volume correction (PVC) based on CT by comparing the results of CT-based PVC and those of MRI-based PVC using images acquired from AD patients and controls. RESULTS: Both methods were able to perform PVC. Slight but significant differences between standard uptake volume ratio (SUVR) values were noted between the two modalities; these were attenuated by constant multiplication. CONCLUSION: CT will potentially replace MRI for PVC, allowing the use of a single PET/CT scanner for amyloid plaque quantitation. PMID- 27781146 TI - Prevalence and impact of autoimmune thyroid disease on myasthenia gravis course. AB - OBJECTIVES: Autoimmune thyroid diseases (ATDs) frequently accompany myasthenia gravis (MG) and may influence its course. We aimed to determine the association and impact of ATD with early- (<50 years), late-onset MG, or thymoma-MG. MATERIALS AND METHODS: Prevalence of ATD was measured in a cross-sectional study of 343 consecutive patients with MG (236 F, 107 M) aged 4-89 years; 83.8% were seropositive, in 2.9%, anti-MuSK antibodies were detected. Concentrations of antithyroid peroxidase antibodies, antithyroglobulin antibodies, antithyrotropin receptor antibodies, and TSH level were measured in all patients. MG clinical course, treatment received, and treatment results were evaluated. RESULTS: Autoimmune thyroid diseases were diagnosed in 92 (26.8%) of MG patients including 4.4% with Graves (GD), 9% with Hashimoto thyroiditis (HT), and 13.4% with antithyroid antibodies only. GD patients had ocular symptoms more often than patients with antithyroid antibodies or HT (p = .008). ATD prevalence was comparable in MG with early and late onset, while non-ATDs were more frequent in thymoma-MG (p = .049). Immunosuppressive therapy was less frequently needed in the patients with MG and ATD, indirectly indicating milder MG course (p = .005). Risk of myasthenic crisis and the results of treatment did not differ between patients with and without ATD. CONCLUSIONS: Autoimmune thyroid diseases are frequently accompanied by early-and late-onset MG, while thymoma-MG is related to higher risk of non-ATD. Myasthenia coexisting with ATD follows milder course than MG alone. PMID- 27781144 TI - Socioeconomic status, white matter, and executive function in children. AB - BACKGROUND: A growing body of evidence links socioeconomic status (SES) to children's brain structure. Few studies, however, have specifically investigated relations of SES to white matter structure. Further, although several studies have demonstrated that family SES is related to development of brain areas that support executive functions (EF), less is known about the role that white matter structure plays in the relation of SES to EF. One possibility is that white matter differences may partially explain SES disparities in EF (i.e., a mediating relationship). Alternatively, SES may differentially shape brain-behavior relations such that the relation of white matter structure to EF may differ as a function of SES (i.e., a moderating relationship). METHOD: In a diverse sample of 1082 children and adolescents aged 3-21 years, we examined socioeconomic disparities in white matter macrostructure and microstructure. We further investigated relations between family SES, children's white matter volume and integrity in tracts supporting EF, and performance on EF tasks. RESULTS: Socioeconomic status was associated with fractional anisotropy (FA) and volume in multiple white matter tracts. Additionally, family income moderated the relation between white matter structure and cognitive flexibility. Specifically, across multiple tracts of interest, lower FA or lower volume was associated with reduced cognitive flexibility among children from lower income families. In contrast, children from higher income families showed preserved cognitive flexibility in the face of low white matter FA or volume. SES factors did not mediate or moderate links between white matter and either working memory or inhibitory control. CONCLUSIONS: This work adds to a growing body of literature suggesting that the socioeconomic contexts in which children develop not only shape cognitive functioning and its underlying neurobiology, but may also shape the relations between brain and behavior. PMID- 27781147 TI - Fatigue in myasthenia gravis: risk factors and impact on quality of life. AB - OBJECTIVES: Emerging evidence suggests that fatigue in myasthenia gravis (MG) is a relevant problem that negatively impacts activities of daily living (ADL). The relationship between fatigue and quality of life (QoL) has never been systematically explored in MG patients. The study aimed to assess the prevalence of fatigue and its relation to ADL and QoL as well as to identify factors associated with fatigue in MG. MATERIAL AND METHODS: This was a cross-sectional observational study in patients with confirmed diagnosis of MG independent of disease severity. Prevalence of fatigue was assessed using the Chalder Fatigue Scale (CFQ). Impact of fatigue on ADL and QoL was assessed by the MG activities of daily living profile (MG-ADL) and the MG-specific quality-of-life instrument (MG-QoL), respectively. Association of fatigue with sociodemographics, clinical characteristics of MG, and comorbidities including mood and anxiety disorders as well as sleep disorders was investigated using multivariable logistic regression analyses. RESULTS: Overall, 200 MG patients were included. The observed rate of fatigue was 56.1%, of those 70.4% fulfilled the criteria of chronic fatigue (CF) with a duration of >=6 months. Relevant fatigue was strongly associated to ADL and QoL. Factors associated with relevant fatigue were disease severity and depressive state. Furthermore, positive muscle-specific tyrosine kinase (MuSK) antibody status showed a strong association with relevant fatigue. CONCLUSIONS: MG patients have a high prevalence of fatigue which negatively impacts ADL and QoL. MG-specific clinical characteristics are related to fatigue and might help to identify MG patients at risk for fatigue. PMID- 27781148 TI - Functional neuroimaging of visual creativity: a systematic review and meta analysis. AB - INTRODUCTION: The generation of creative visual imagery contributes to technological and scientific innovation and production of visual art. The underlying cognitive and neural processes are, however, poorly understood. METHODS: This review synthesizes functional neuroimaging studies of visual creativity. Seven functional magnetic resonance imaging (fMRI) and 19 electroencephalography (EEG) studies were included, comprising 27 experiments and around 800 participants. RESULTS: Activation likelihood estimation meta-analysis of the fMRI studies comparing visual creativity to non-rest control tasks yielded significant clusters in thalamus, left fusiform gyrus, and right middle and inferior frontal gyri. The EEG studies revealed a tendency for decreased alpha power during visual creativity compared to baseline, but comparisons of visual creativity to non-rest control tasks revealed inconsistent findings. CONCLUSIONS: The findings are consistent with suggested contributions to visual creativity of prefrontally mediated inhibition, evaluation, and working memory, as well as visual imagery processes. Findings are discussed in relation to prominent theories of the neural basis of creativity. PMID- 27781149 TI - Prognostic value of plasma galectin-3 levels after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Inflammatory responses are correlated with secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Galectin-3 (Gal-3) is a novel biomarker reflecting inflammation status, and its elevated circulating levels are associated with poor prognosis of some inflammatory diseases. The aim of this study was to evaluate the relationship between Gal-3 plasma levels and prognosis in a group of aSAH patients. MATERIALS AND METHODS: We assessed plasma Gal-3 levels in 120 patients and 120 healthy individuals. 6-month clinical outcomes included mortality and unfavorable outcome (Glasgow Outcome Scale score of 1-3). Associations of plasma Gal-3 levels with clinical outcomes were investigated using multivariate analysis. RESULTS: Patients showed significantly higher Gal-3 levels as compared to controls. Circulating Gal-3 was significantly and independently associated with 6-month clinical outcomes in the logistic regression analysis. Moreover, we observed a significant correlation between circulating Gal-3 and World Federation of Neurological Surgeons scores and modified Fisher scores. Furthermore, Gal-3 possessed high area under receiver operating characteristic curve for prognostic assessment. CONCLUSION: Our findings indicate the associations between Gal-3 levels and the severity and poor prognosis following aSAH. This suggests the possible role of Gal-3 in the prognostic prediction after aSAH. PMID- 27781150 TI - Brain metabolite levels and language abilities in preschool children. AB - INTRODUCTION: Language acquisition occurs rapidly during early childhood and lays the foundation for future reading success. However, little is known about the brain-language relationships in young children. The goal of this study was to investigate relationships between brain metabolites and prereading language abilities in healthy preschool-aged children. METHODS: Participants were 67 healthy children aged 3.0-5.4 years scanned on a 3T GE MR750w MRI scanner using short echo proton spectroscopy with a voxel placed in the anterior cingulate gyrus (n = 56) and/or near the left angular gyrus (n = 45). Children completed the NEPSY-II Phonological Processing and Speeded Naming subtests at the same time as their MRI scan. We calculated glutamate, glutamine, creatine/phosphocreatine, choline, inositol, and NAA concentrations, and correlated these with language skills. RESULTS: In the anterior cingulate, Phonological Processing Scaled Scores were significantly correlated with glutamate, creatine, and inositol concentrations. In the left angular gyrus, Speeded Naming Combined Scaled Scores showed trend correlations with choline and glutamine concentrations. CONCLUSIONS: For the first time, we demonstrate relationships between brain metabolites and prereading language abilities in young children. Our results show relationships between language and inositol and glutamate that may reflect glial differences underlying language function, and a relationship of language with creatine. The trend between Speeded Naming and choline is consistent with previous research in older children and adults; however, larger sample sizes are needed to confirm whether this relationship is indeed significant in young children. These findings help understand the brain basis of language, and may ultimately lead to earlier and more effective interventions for reading disabilities. PMID- 27781152 TI - Expression and characterization of thermotolerant lipase with broad pH profiles isolated from an Antarctic Pseudomonas sp strain AMS3. AB - A gene encoding a thermotolerant lipase with broad pH was isolated from an Antarctic Pseudomonas strain AMS3. The recombinant lipase AMS3 was purified by single-step purification using affinity chromatography, yielding a purification fold of approximately 1.52 and a recovery of 50%. The molecular weight was approximately ~60 kDa including the strep and affinity tags. Interestingly, the purified Antarctic AMS3 lipase exhibited broad temperature profile from 10-70 degrees C and stable over a broad pH range from 5.0 to pH 10.0. Various mono and divalent metal ions increased the activity of the AMS3 lipase, but Ni2+ decreased its activity. The purified lipase exhibited the highest activity in the presence of sunflower oil. In addition, the enzyme activity in 25% v/v solvents at 50 degrees C particularly to n-hexane, DMSO and methanol could be useful for catalysis reaction in organic solvent and at broad temperature. PMID- 27781151 TI - Dose-dependent short- and long-term effects of ionizing irradiation on neural stem cells in murine hippocampal tissue cultures: neuroprotective potential of resveratrol. AB - INTRODUCTION: Radiation therapy plays an essential role in the treatment of brain tumors, but neurocognitive deficits remain a significant risk, especially in pediatric patients. In recent trials, hippocampal sparing techniques are applied to reduce these adverse effects. Here, we investigate dose-dependent effects of ionizing radiation (IR) on juvenile hippocampal neurogenesis. Additionally, we evaluate the radioprotective potential of resveratrol, a plant polyphenol recognized for its bifunctional tumor-preventive and anticancer effects. METHODS: Organotypic entorhinal-hippocampal slice cultures from transgenic nestin-CFPnuc C57BL/J6 mice, postnatal days 3-6, were irradiated on a X-ray machine (4.5, 8, 12, and 16 Gy, single doses) after about 2 weeks. Nestin-positive neural stem cells were counted at a confocal live imaging microscope 0, 2, 4, 14, 25, and 42 days after IR. Resveratrol (15 MUmol/L) was added 2 hr before and 24 hr after IR. Proliferation and cell death were assessed by BrdU pulse label, 48 hr after and by propidium iodide staining 96 hr after IR. GFAP- and NeuN-positive cells were counted 42 days after IR in cryosectioned immunofluorescence-stained slices. RESULTS: The observed age-related changes of nestin-positive stem cells in the organotypic slice culture model resembled the reduction of neural stem cells in vivo. IR (4.5-16 Gy) led to a dose-dependent damage of the neural stem cell pool in the dentate gyrus. No recovery was seen within 42 days after doses from 4.5 Gy onward. The decline of nestin-positive cells was paralleled by increased cell death and decreased proliferation. The number of GFAP-positive cells was significantly enhanced. No significant change was detected in the overall NeuN positive cell population, whereas the number of newborn, NeuN/BrdU double positive neurons was reduced. Resveratrol treatment reversed the irradiation induced decline of neural stem cells. CONCLUSION: The neuroprotective action of resveratrol on irradiated hippocampal tissue warrants further investigation as a possible supplement to hippocampal sparing procedures. PMID- 27781153 TI - Does regional diversity recover after disturbance? A field experiment in constructed ponds. AB - The effects of disturbance on local species diversity have been well documented, but less recognized is the possibility that disturbances can alter diversity at regional spatial scales. Since regional diversity can dictate which species are available for recolonization of degraded sites, the loss of diversity at regional scales may impede the recovery of biodiversity following a disturbance. To examine this we used a chemical disturbance of rotenone, a piscicide commonly used for fish removal in aquatic habitats, on small fishless freshwater ponds. We focused on the non-target effects of rotenone on aquatic invertebrates with the goal of assessing biodiversity loss and recovery at both local (within-pond) and regional (across ponds) spatial scales. We found that rotenone caused significant, large, but short-term losses of species at both local and regional spatial scales. Using a null model of random extinction, we determined that species were selectively removed from communities relative to what would be expected if species loss occurred randomly. Despite this selective loss of biodiversity, species diversity at both local and regional spatial scales recovered to reference levels one year after the addition of rotenone. The rapid recovery of local and regional diversity in this study was surprising considering the large loss of regional species diversity, however many aquatic invertebrates disperse readily or have resting stages that may persist through disturbances. We emphasize the importance of considering spatial scale when quantifying the impacts of a disturbance on an ecosystem, as well as considering how regional species loss can influence recovery from disturbance. PMID- 27781154 TI - Intranodal signal suppression in pelvic MR lymphography of prostate cancer patients: a quantitative comparison of ferumoxtran-10 and ferumoxytol. AB - OBJECTIVES: The key to MR lymphography is suppression of T2* MR signal in normal lymph nodes, while retaining high signal in metastatic nodes. Our objective is to quantitatively compare the ability of ferumoxtran-10 and ferumoxytol to suppress the MR signal in normal pelvic lymph nodes. METHODS: In 2010, a set of consecutive patients who underwent intravenous MR Lymphography (MRL) were included. Signal suppression in normal lymph nodes in T2*-weighted images due to uptake of USPIO (Ultra-Small Superparamagnetic Particles of Iron Oxide) was quantified. Signal suppression by two USPIO contrast agents, ferumoxtran-10 and ferumoxytol was compared using Wilcoxon's signed rank test. RESULTS: Forty-four patients were included, of which all 44 had a ferumoxtran-10 MRL and 4 had additionally a ferumoxytol MRL. A total of 684 lymph nodes were identified in the images, of which 174 had been diagnosed as metastatic. USPIO-induced signal suppression in normal lymph nodes was significantly stronger in ferumoxtran-10 MRL than in ferumoxytol MRL (p < 0.005). CONCLUSIONS: T2* signal suppression in normal pelvic lymph nodes is significantly stronger with ferumoxtran-10 than with ferumoxytol, which may affect diagnostic accuracy. PMID- 27781155 TI - The influence of flight style on the aerodynamic properties of avian wings as fixed lifting surfaces. AB - The diversity of wing morphologies in birds reflects their variety of flight styles and the associated aerodynamic and inertial requirements. Although the aerodynamics underlying wing morphology can be informed by aeronautical research, important differences exist between planes and birds. In particular, birds operate at lower, transitional Reynolds numbers than do most aircraft. To date, few quantitative studies have investigated the aerodynamic performance of avian wings as fixed lifting surfaces and none have focused upon the differences between wings from different flight style groups. Dried wings from 10 bird species representing three distinct flight style groups were mounted on a force/torque sensor within a wind tunnel in order to test the hypothesis that wing morphologies associated with different flight styles exhibit different aerodynamic properties. Morphological differences manifested primarily as differences in drag rather than lift. Maximum lift coefficients did not differ between groups, whereas minimum drag coefficients were lowest in undulating flyers (Corvids). The lift to drag ratios were lower than in conventional aerofoils and data from free-flying soaring species; particularly in high frequency, flapping flyers (Anseriformes), which do not rely heavily on glide performance. The results illustrate important aerodynamic differences between the wings of different flight style groups that cannot be explained solely by simple wing-shape measures. Taken at face value, the results also suggest that wing shape is linked principally to changes in aerodynamic drag, but, of course, it is aerodynamics during flapping and not gliding that is likely to be the primary driver. PMID- 27781156 TI - Climate-related environmental stress in intertidal grazers: scaling-up biochemical responses to assemblage-level processes. AB - BACKGROUND: Organisms are facing increasing levels of environmental stress under climate change that may severely affect the functioning of biological systems at different levels of organization. Growing evidence suggests that reduction in body size is a universal response of organisms to global warming. However, a clear understanding of whether extreme climate events will impose selection directly on phenotypic plastic responses and how these responses affect ecological interactions has remained elusive. METHODS: We experimentally investigated the effects of extreme desiccation events on antioxidant defense mechanisms of a rocky intertidal gastropod (Patella ulyssiponensis), and evaluated how these effects scaled-up at the population and assemblage levels. RESULTS: With increasing levels of desiccation stress, limpets showed significant lower levels of total glutathione, tended to grow less and had reduced per capita interaction strength on their resources. DISCUSSION: Results suggested that phenotypic plasticity (i.e., reduction in adults' body size) allowed buffering biochemical responses to stress to scale-up at the assemblage level. Unveiling the linkages among different levels of biological organization is key to develop indicators that can anticipate large-scale ecological impacts of climate change. PMID- 27781157 TI - The cranial endocast of Dipnorhynchus sussmilchi (Sarcopterygii: Dipnoi) and the interrelationships of stem-group lungfishes. AB - The first virtual cranial endocast of a lungfish from the Early Devonian, Dipnorhynchus sussmilchi, is described. Dipnorhynchus, only the fourth Devonian lungfish for which a near complete cranial endocast is known, is a key taxon for clarifying primitive character states within the group. A ventrally-expanded telencephalic cavity is present in the endocast of Dipnorhynchus demonstrating that this is the primitive state for "true" Dipnoi. Dipnorhynchus also possesses a utricular recess differentiated from the sacculolagenar pouch like that seen in stratigraphically younger lungfish (Dipterus, Chirodipterus, Rhinodipterus), but absent from the dipnomorph Youngolepis. We do not find separate pineal and para pineal canals in contrast to a reconstruction from previous authors. We conduct the first phylogenetic analysis of Dipnoi based purely on endocast characters, which supports a basal placement of Dipnorhynchus within the dipnoan stem group, in agreement with recent analyses. Our analysis demonstrates the value of endocast characters for inferring phylogenetic relationships. PMID- 27781159 TI - Single-agent maintenance therapy for advanced non-small cell lung cancer (NSCLC): a systematic review and Bayesian network meta-analysis of 26 randomized controlled trials. AB - BACKGROUND: The benefit of maintenance therapy has been confirmed in patients with non-progressing non-small cell lung cancer (NSCLC) after first-line therapy by many trials and meta-analyses. However, since few head-to-head trials between different regimens have been reported, clinicians still have little guidance on how to select the most efficacious single-agent regimen. Hence, we present a network meta-analysis to assess the comparative treatment efficacy of several single-agent maintenance therapy regimens for stage III/IV NSCLC. METHODS: A comprehensive literature search of public databases and conference proceedings was performed. Randomized clinical trials (RCTs) meeting the eligible criteria were integrated into a Bayesian network meta-analysis. The primary outcome was overall survival (OS) and the secondary outcome was progression free survival (PFS). RESULTS: A total of 26 trials covering 7,839 patients were identified, of which 24 trials were included in the OS analysis, while 23 trials were included in the PFS analysis. Switch-racotumomab-alum vaccine and switch-pemetrexed were identified as the most efficacious regimens based on OS (HR, 0.64; 95% CrI, 0.45 0.92) and PFS (HR, 0.54; 95% CrI, 0.26-1.04) separately. According to the rank order based on OS, switch-racotumomab-alum vaccine had the highest probability as the most effective regimen (52%), while switch-pemetrexed ranked first (34%) based on PFS. CONCLUSIONS: Several single-agent maintenance therapy regimens can prolong OS and PFS for stage III/IV NSCLC. Switch-racotumomab-alum vaccine maintenance therapy may be the most optimal regimen, but should be confirmed by additional evidence. PMID- 27781160 TI - Predictions of potential geographical distribution and quality of Schisandra sphenanthera under climate change. AB - Climate change will significantly affect plant distribution as well as the quality of medicinal plants. Although numerous studies have analyzed the effect of climate change on future habitats of plants through species distribution models (SDMs), few of them have incorporated the change of effective content of medicinal plants. Schisandra sphenanthera Rehd. et Wils. is an endangered traditional Chinese medical plant which is mainly located in the Qinling Mountains. Combining fuzzy theory and a maximum entropy model, we obtained current spatial distribution of quality assessment for S. spenanthera. Moreover, the future quality and distribution of S. spenanthera were also projected for the periods 2020s, 2050s and 2080s under three different climate change scenarios (SRES-A1B, SRES-A2 and SRES-B1 emission scenarios) described in the Special Report on Emissions Scenarios (SRES) of IPCC (Intergovernmental Panel on Climate Change). The results showed that the moderately suitable habitat of S. sphenanthera under all climate change scenarios remained relatively stable in the study area. The highly suitable habitat of S. sphenanthera would gradually decrease in the future and a higher decline rate of the highly suitable habitat area would occur under climate change scenarios SRES-A1B and SRES-A2. The result suggested that in the study area, there would be no more highly suitable habitat areas for S. sphenanthera when the annual mean temperature exceeds 20 degrees C or its annual precipitation exceeds 1,200 mm. Our results will be influential in the future ecological conservation and management of S. sphenanthera and can be taken as a reference for habitat suitability assessment research for other medicinal plants. PMID- 27781158 TI - Formal modeling and analysis of ER-alpha associated Biological Regulatory Network in breast cancer. AB - BACKGROUND: Breast cancer (BC) is one of the leading cause of death among females worldwide. The increasing incidence of BC is due to various genetic and environmental changes which lead to the disruption of cellular signaling network(s). It is a complex disease in which several interlinking signaling cascades play a crucial role in establishing a complex regulatory network. The logical modeling approach of Rene Thomas has been applied to analyze the behavior of estrogen receptor-alpha (ER-alpha) associated Biological Regulatory Network (BRN) for a small part of complex events that leads to BC metastasis. METHODS: A discrete model was constructed using the kinetic logic formalism and its set of logical parameters were obtained using the model checking technique implemented in the SMBioNet software which is consistent with biological observations. The discrete model was further enriched with continuous dynamics by converting it into an equivalent Petri Net (PN) to analyze the logical parameters of the involved entities. RESULTS: In-silico based discrete and continuous modeling of ER-alpha associated signaling network involved in BC provides information about behaviors and gene-gene interaction in detail. The dynamics of discrete model revealed, imperative behaviors represented as cyclic paths and trajectories leading to pathogenic states such as metastasis. Results suggest that the increased expressions of receptors ER-alpha, IGF-1R and EGFR slow down the activity of tumor suppressor genes (TSGs) such as BRCA1, p53 and Mdm2 which can lead to metastasis. Therefore, IGF-1R and EGFR are considered as important inhibitory targets to control the metastasis in BC. CONCLUSION: The in-silico approaches allow us to increase our understanding of the functional properties of living organisms. It opens new avenues of investigations of multiple inhibitory targets (ER-alpha, IGF-1R and EGFR) for wet lab experiments as well as provided valuable insights in the treatment of cancers such as BC. PMID- 27781161 TI - Determining the distribution loss of brown eared-pheasant (Crossoptilon mantchuricum) using historical data and potential distribution estimates. AB - We analyzed the synchronous relationship between forest cover and species distribution to explain the contraction in the distribution range of the brown eared-pheasant (Crossoptilon mantchuricum) in China. Historical resources can provide effective records for reconstructing long-term distribution dynamics. The brown eared-pheasant's historical distribution from 25 to 1947 CE, which included the three provinces of Shaanxi, Shanxi, and Hebei based on this species' habitat selection criteria, the history of the forests, ancient climate change records, and fossil data. The current species distribution covers Shaanxi, Shanxi, and Hebei provinces, as well as Beijing city, while Shanxi remains the center of the distribution area. MaxEnt model indicated that the suitable conditions of the brown eared-pheasant had retreated to the western regions of Shanxi and that the historical distribution area had reduced synchronously with the disappearance of local forest cover in Shanxi. We built a correlative relationship between the presence/absence of brown eared-pheasants and forest coverage and found that forest coverage in the north, northeast, central, and southeast areas of the Shanxi province were all less than 10% in 1911. Wild brown eared-pheasants are stable in the Luliang Mountains, where forest coverage reached 13.2% in 2000. Consequently, we concluded that the distribution of this species is primarily determined by vegetation conditions and that forest cover was the most significant determining factor. PMID- 27781162 TI - Beech cupules as keystone structures for soil fauna. AB - Facilitative or positive interactions are ubiquitous in nature and play a fundamental role in the configuration of ecological communities. In particular, habitat modification and niche construction, in which one organism locally modifies abiotic conditions and favours other organisms by buffering the effects of adverse environmental factors, are among the most relevant facilitative interactions. In line with this, 'keystone structures', which provide resources, refuge, or advantageous services decisive for other species, may allow the coexistence of various species and thus considerably contribute to diversity maintenance. Beech cupules are woody husks harbouring beech fruits that remain in the forest soil for relatively long periods of time. In this study, we explored the potential role of these cupules in the distribution and maintenance of the soil fauna inhabiting the leaf litter layer. We experimentally manipulated cupule availability and soil moisture in the field to determine if such structures are limiting and can provide moist shelter to soil animals during drought periods, contributing to minimize desiccation risks. We measured invertebrate abundances inside relative to outside the cupules, total abundances in the leaf litter and animal body sizes, in both dry and wet experimental plots. We found that these structures are preferentially used by the most abundant groups of smaller soil animals-springtails, mites and enchytraeids-during droughts. Moreover, beech cupules can be limiting, as an increase in use was found with higher cupule densities, and are important resources for many small soil invertebrates, driving the spatial structure of the soil community and promoting higher densities in the leaf litter, probably through an increase in habitat heterogeneity. We propose that fruit woody structures should be considered 'keystone structures' that contribute to soil community maintenance. Therefore, beech trees may indirectly facilitate soil fauna activities through their decaying fruit husks, hence acting as ecosystem engineers. PMID- 27781163 TI - Molecular phylogeny of the megadiverse insect infraorder Bibionomorpha sensu lato (Diptera). AB - The phylogeny of the insect infraorder Bibionomorpha (Diptera) is reconstructed based on the combined analysis of three nuclear (18S, 28S, CAD) and three mitochondrial (12S, 16S, COI) gene markers. All the analyses strongly support the monophyly of Bibionomorpha in both the narrow (sensu stricto) and the broader (sensu lato) concepts. The major lineages of Bibionomorpha sensu lato (Sciaroidea, Bibionoidea, Anisopodoidea, and Scatopsoidea) and most of the included families are supported as monophyletic groups. Axymyiidae was not found to be part of Bibionomorpha nor was it found to be its sister group. Bibionidae was paraphyletic with respect to Hesperinidae and Keroplatidae was paraphyletic with respect to Lygistorrhinidae. The included Sciaroidea incertae sedis (except Ohakunea Edwards) were found to belong to one clade, but the relationships within this group and its position within Sciaroidea require further study. PMID- 27781164 TI - A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer's disease. AB - A small molecule named ISRIB has recently been described to enhance memory in rodents. In this study we aimed to test whether ISRIB would reverse learning and memory deficits in the J20 mouse model of human amyloid precursor protein (hAPP) overexpression, a model that simulates many aspects of Alzheimer's disease in which memory deficits are a hallmark feature. We did not observe a significant rescue effect with ISRIB treatment on spatial learning and memory as assessed in the Morris water maze in J20 mice. We also did not observe a significant enhancement of spatial learning or memory in nontransgenic mice with ISRIB treatment, although a trend emerged for memory enhancement in one cohort of mice. Future preclinical studies with ISRIB would benefit from additional robust markers of target engagement in the brain. PMID- 27781165 TI - Systematic review on the conservation genetics of African savannah elephants. AB - BACKGROUND: In this paper we review the conservation genetics of African savannah elephants, aiming to understand the spatio-temporal research trends and their underlying factors. As such, we explore three questions associated to the conservation genetics and molecular ecology of these elephants: (1) what are the research trends concerning the conservation genetics of Loxodonta africana? (2) Do richer countries conduct more research on the genetics of African elephants? (3) Which attributes influence where scholars conduct their research? MATERIALS AND METHODS: We examined available peer-reviewed publications from 1993 to 2014 in complementary online databases, including the ISI/Web of Science (WoS), Scopus and Google Scholar (GS), and searched for publications in scientific journals as well as in the reference section of these publications. We analyzed the annual trend of publications in this field of research, including the number of authors, levels of collaboration among authors, year of publication, publishing journal and the countries from where genetic samples were collected. Additionally, we identified main research clusters, authors, and institutional collaborations, based on co-citation and co-occurrence networks. RESULTS: We found that during the study period there was a positive trend in the number of publications and a reduction in the number of authors per paper. Twenty-five countries contributed, with the majority of publications authored by researchers in the USA, Kenya and South Africa. The majority of samples were collected in Kenya, Tanzania and South Africa. Research outputs are associated with the existence of long-term conservation/research projects and research potential as measured by the literacy rate and the number of higher education institutions in a country. Five research clusters were identified, focusing on the origin and evolution of the species, methodological issues and the relatedness among elephant species. CONCLUSIONS: Research in this field should be expanded to additional countries harboring elephant populations to enable a more comprehensive understanding of the population structure and genetic differentiation of the species, and to cope with challenges associated with the conservation of the species such as illegal hunting, habitat fragmentation, species reintroduction and climate change. PMID- 27781167 TI - Divergent relationship of circulating CTRP3 levels between obesity and gender: a cross-sectional study. AB - : C1q TNF Related Protein 3 (CTRP3) is a novel adipose tissue derived secreted factor, or adipokine, which has been linked to a number of beneficial biological effects on metabolism, inflammation, and survival signaling in a variety of tissues. However, very little is known about CTRP3 in regards to human health. The purpose of this project was to examine circulating CTRP3 levels in a clinical population, patients with symptoms requiring heart catheterization in order to identify the presence of obstructive coronary artery disease (CAD). It was hypothesized that serum CTRP3 levels would be decreased in the presence of CAD. METHODS: Body mass index (BMI), diabetes status, and plasma samples were collected from 100 patients who were >30 years of age and presented at the East Tennessee State University Heart Clinic with symptoms requiring heart catheterization in order to identify the presence of cardiovascular blockages (n = 52 male, n = 48 female). Circulating CTRP3 levels were quantified using commercially available ELISA. RESULTS: Circulating CTRP3 levels had no relationship to the presence of CAD regardless of gender. However, circulating concentrations of CTRP3 were significantly higher in normal weight (BMI < 30) females (0.88 +/- 0.12 ug/ml) compared with males (0.54 +/- 0.06 ug/ml). Further, obesity (BMI > 30) resulted in an increase in circulating CTRP3 levels in male subjects (0.74 +/- 0.08 ug/ml) but showed a significant decrease in female subjects (0.58 +/- 0.07 ug/ml). Additionally, there was a significant reduction in circulating CTRP3 levels in female subjects who were diagnosed with Type 2 diabetes compared with patients without (0.79 +/- 0.08 vs. 0.42 +/- 0.10 ug/ml). There was no relationship between diabetes status and circulating CTRP3 levels in male subjects. CONCLUSION: Circulating CTRP3 levels had a different relationship with diabetes and obesity status between male and female patients. It is possible that circulating CTRP3 levels are controlled by hormonal status, however more research is needed to explore this relationship. Nevertheless, future studies examining the relationship between CTRP3 levels and disease status should treat gender as an independent variable. PMID- 27781168 TI - A revision of Sanpasaurus yaoi Young, 1944 from the Early Jurassic of China, and its relevance to the early evolution of Sauropoda (Dinosauria). AB - The Early Jurassic of China has long been recognized for its diverse array of sauropodomorph dinosaurs. However, the contribution of this record to our understanding of early sauropod evolution is complicated by a dearth of information on important transitional taxa. We present a revision of the poorly known taxon Sanpasaurus yaoi Young, 1944 from the late Early Jurassic Ziliujing Formation of Sichuan Province, southwest China. Initially described as the remains of an ornithopod ornithischian, we demonstrate that the material catalogued as IVPP V156 is unambiguously referable to Sauropoda. Although represented by multiple individuals of equivocal association, Sanpasaurus is nonetheless diagnosable with respect to an autapomorphic feature of the holotypic dorsal vertebral series. Additional material thought to be collected from the type locality is tentatively referred to Sanpasaurus. If correctly attributed, a second autapomorphy is present in a referred humerus. The presence of a dorsoventrally compressed pedal ungual in Sanpasaurus is of particular interest, with taxa possessing this typically 'vulcanodontid' character exhibiting a much broader geographic distribution than previously thought. Furthermore, the association of this trait with other features of Sanpasaurus that are broadly characteristic of basal eusauropods underscores the mosaic nature of the early sauropod-eusauropod transition. Our revision of Sanpasaurus has palaeobiogeographic implications for Early Jurassic sauropods, with evidence that the group maintained a cosmopolitan Pangaean distribution. PMID- 27781166 TI - The single-species metagenome: subtyping Staphylococcus aureus core genome sequences from shotgun metagenomic data. AB - In this study we developed a genome-based method for detecting Staphylococcus aureus subtypes from metagenome shotgun sequence data. We used a binomial mixture model and the coverage counts at >100,000 known S. aureus SNP (single nucleotide polymorphism) sites derived from prior comparative genomic analysis to estimate the proportion of 40 subtypes in metagenome samples. We were able to obtain >87% sensitivity and >94% specificity at 0.025X coverage for S. aureus. We found that 321 and 149 metagenome samples from the Human Microbiome Project and metaSUB analysis of the New York City subway, respectively, contained S. aureus at genome coverage >0.025. In both projects, CC8 and CC30 were the most common S. aureus clonal complexes encountered. We found evidence that the subtype composition at different body sites of the same individual were more similar than random sampling and more limited evidence that certain body sites were enriched for particular subtypes. One surprising finding was the apparent high frequency of CC398, a lineage often associated with livestock, in samples from the tongue dorsum. Epidemiologic analysis of the HMP subject population suggested that high BMI (body mass index) and health insurance are possibly associated with S. aureus carriage but there was limited power to identify factors linked to carriage of even the most common subtype. In the NYC subway data, we found a small signal of geographic distance affecting subtype clustering but other unknown factors influence taxonomic distribution of the species around the city. PMID- 27781169 TI - Performance of joint modelling of time-to-event data with time-dependent predictors: an assessment based on transition to psychosis data. AB - Joint modelling has emerged to be a potential tool to analyse data with a time-to event outcome and longitudinal measurements collected over a series of time points. Joint modelling involves the simultaneous modelling of the two components, namely the time-to-event component and the longitudinal component. The main challenges of joint modelling are the mathematical and computational complexity. Recent advances in joint modelling have seen the emergence of several software packages which have implemented some of the computational requirements to run joint models. These packages have opened the door for more routine use of joint modelling. Through simulations and real data based on transition to psychosis research, we compared joint model analysis of time-to-event outcome with the conventional Cox regression analysis. We also compared a number of packages for fitting joint models. Our results suggest that joint modelling do have advantages over conventional analysis despite its potential complexity. Our results also suggest that the results of analyses may depend on how the methodology is implemented. PMID- 27781170 TI - VSEARCH: a versatile open source tool for metagenomics. AB - BACKGROUND: VSEARCH is an open source and free of charge multithreaded 64-bit tool for processing and preparing metagenomics, genomics and population genomics nucleotide sequence data. It is designed as an alternative to the widely used USEARCH tool (Edgar, 2010) for which the source code is not publicly available, algorithm details are only rudimentarily described, and only a memory-confined 32 bit version is freely available for academic use. METHODS: When searching nucleotide sequences, VSEARCH uses a fast heuristic based on words shared by the query and target sequences in order to quickly identify similar sequences, a similar strategy is probably used in USEARCH. VSEARCH then performs optimal global sequence alignment of the query against potential target sequences, using full dynamic programming instead of the seed-and-extend heuristic used by USEARCH. Pairwise alignments are computed in parallel using vectorisation and multiple threads. RESULTS: VSEARCH includes most commands for analysing nucleotide sequences available in USEARCH version 7 and several of those available in USEARCH version 8, including searching (exact or based on global alignment), clustering by similarity (using length pre-sorting, abundance pre sorting or a user-defined order), chimera detection (reference-based or de novo), dereplication (full length or prefix), pairwise alignment, reverse complementation, sorting, and subsampling. VSEARCH also includes commands for FASTQ file processing, i.e., format detection, filtering, read quality statistics, and merging of paired reads. Furthermore, VSEARCH extends functionality with several new commands and improvements, including shuffling, rereplication, masking of low-complexity sequences with the well-known DUST algorithm, a choice among different similarity definitions, and FASTQ file format conversion. VSEARCH is here shown to be more accurate than USEARCH when performing searching, clustering, chimera detection and subsampling, while on a par with USEARCH for paired-ends read merging. VSEARCH is slower than USEARCH when performing clustering and chimera detection, but significantly faster when performing paired-end reads merging and dereplication. VSEARCH is available at https://github.com/torognes/vsearch under either the BSD 2-clause license or the GNU General Public License version 3.0. DISCUSSION: VSEARCH has been shown to be a fast, accurate and full-fledged alternative to USEARCH. A free and open-source versatile tool for sequence analysis is now available to the metagenomics community. PMID- 27781172 TI - Residency in white-eared hummingbirds (Hylocharis leucotis) and its effect in territorial contest resolution. AB - BACKGROUND: Territory owners usually defeat intruders. One explanation for this observation is the uncorrelated asymmetry hypothesis which argues that contests might be settled by an arbitrary convention such as "owners win." We studied the effect of territorial residency on contest asymmetries in the white-eared hummingbird (Hylocharis leucotis) in a fir forest from central Mexico. METHODS: Twenty white-eared male adult hummingbird territories were monitored during a winter season, recording the territorial behavior of the resident against intruding hummingbirds. The size and quality of the territory were related to the probability that the resident would allow the use of flowers by the intruder. Various generalized models (logistical models) were generated to describe the probabilities of victory for each individual resident depending on the different combinations of three predictor variables (territory size, territory quality, and intruder identity). RESULTS: In general, small and low quality territory owners tend to prevent conspecific intruders from foraging at a higher rate, while they frequently fail to exclude heterospecific intruders such as the magnificent hummingbird (Eugenes fulgens) or the green violetear hummingbird (Colibri thalassinus) on any territory size. Our results showed that the identity of the intruder and the size and quality of the territory determined the result of the contests, but not the intensity of defense. DISCUSSION: Initially, the rule that "the resident always wins" was supported, since no resident was expelled from its territory during the study. Nevertheless, the resident-intruder asymmetries during the course of a day depended on different factors, such as the size and quality of the territory and, mainly, the identity of the intruders. Our results showed that flexibility observed in contest tactics suggests that these tactics are not fixed but are socially plastic instead and they can be adjusted to specific circumstances. PMID- 27781171 TI - Viral recombination blurs taxonomic lines: examination of single-stranded DNA viruses in a wastewater treatment plant. AB - Understanding the structure and dynamics of microbial communities, especially those of economic concern, is of paramount importance to maintaining healthy and efficient microbial communities at agricultural sites and large industrial cultures, including bioprocessors. Wastewater treatment plants are large bioprocessors which receive water from multiple sources, becoming reservoirs for the collection of many viral families that infect a broad range of hosts. To examine this complex collection of viruses, full-length genomes of circular ssDNA viruses were isolated from a wastewater treatment facility using a combination of sucrose-gradient size selection and rolling-circle amplification and sequenced on an Illumina MiSeq. Single-stranded DNA viruses are among the least understood groups of microbial pathogens due to genomic biases and culturing difficulties, particularly compared to the larger, more often studied dsDNA viruses. However, the group contains several notable well-studied examples, including agricultural pathogens which infect both livestock and crops (Circoviridae and Geminiviridae), and model organisms for genetics and evolution studies (Microviridae). Examination of the collected viral DNA provided evidence for 83 unique genotypic groupings, which were genetically dissimilar to known viral types and exhibited broad diversity within the community. Furthermore, although these genomes express similarities to known viral families, such as Circoviridae, Geminiviridae, and Microviridae, many are so divergent that they may represent new taxonomic groups. This study demonstrated the efficacy of the protocol for separating bacteria and large viruses from the sought after ssDNA viruses and the ability to use this protocol to obtain an in-depth analysis of the diversity within this group. PMID- 27781173 TI - Green synthesis of silver nanoparticles in aloe vera plant extract prepared by a hydrothermal method and their synergistic antibacterial activity. AB - BACKGROUND: There is worldwide interest in silver nanoparticles (AgNPs) synthesized by various chemical reactions for use in applications exploiting their antibacterial activity, even though these processes exhibit a broad range of toxicity in vertebrates and invertebrates alike. To avoid the chemical toxicity, biosynthesis (green synthesis) of metal nanoparticles is proposed as a cost-effective and environmental friendly alternative. Aloe vera leaf extract is a medicinal agent with multiple properties including an antibacterial effect. Moreover the constituents of aloe vera leaves include lignin, hemicellulose, and pectins which can be used in the reduction of silver ions to produce as AgNPs@aloe vera (AgNPs@AV) with antibacterial activity. METHODS: AgNPs were prepared by an eco-friendly hydrothermal method using an aloe vera plant extract solution as both a reducing and stabilizing agent. AgNPs@AV were characterized using XRD and SEM. Additionally, an agar well diffusion method was used to screen for antimicrobial activity. MIC and MBC were used to correlate the concentration of AgNPs@AV its bactericidal effect. SEM was used to investigate bacterial inactivation. Then the toxicity with human cells was investigated using an MTT assay. RESULTS: The synthesized AgNPs were crystalline with sizes of 70.70 +/- 22 192.02 +/- 53 nm as revealed using XRD and SEM. The sizes of AgNPs can be varied through alteration of times and temperatures used in their synthesis. These AgNPs were investigated for potential use as an antibacterial agent to inhibit pathogenic bacteria. Their antibacterial activity was tested on S. epidermidis and P. aeruginosa. The results showed that AgNPs had a high antibacterial which depended on their synthesis conditions, particularly when processed at 100 oC for 6 h and 200 oC for 12 h. The cytotoxicity of AgNPs was determined using human PBMCs revealing no obvious cytotoxicity. These results indicated that AgNPs@AV can be effectively utilized in pharmaceutical, biotechnological and biomedical applications. DISCUSSION: Aloe vera extract was processed using a green and facile method. This was a hydrothermal method to reduce silver nitrate to AgNPs@AV. Varying the hydrothermal temperature provided the fine spherical shaped nanoparticles. The size of the nanomaterial was affected by its thermal preparation. The particle size of AgNPs could be tuned by varying both time and temperature. A process using a pure AG phase could go to completion in 6 h at 200 oC, whereas reactions at lower temperatures required longer times. Moreover, the antibacterial effect of this hybrid nanomaterial was sufficient that it could be used to inhibit pathogenic bacteria since silver release was dependent upon its particle size. The high activity of the largest AgNPs might have resulted from a high concentration of aloe vera compounds incorporated into the AgNPs during hydrothermal synthesis. PMID- 27781174 TI - A reappraisal of Theroteinus (Haramiyida, Mammaliaformes) from the Upper Triassic of Saint-Nicolas-de-Port (France). AB - The earliest mammaliaforms are difficult to assess because the fossil record is poor and because their distinctive morphologies cannot be directly compared with more recent mammaliaforms. This is especially true for the haramiyid genus Theroteinus, only known in the Saint-Nicolas-de-Port locality (Rhaetian, France). This study presents a new definition of the type-species Theroteinus nikolai. A new species Theroteinus rosieriensis, sp. nov., is named and distinguished by the lingual shift of distal cusps, a larger size, and a stockier occlusal outline. Comparisons with Eleutherodon, Megaconus and Millsodon suggest that Theroteinus has potential close relatives among the Jurassic haramiyids. PMID- 27781175 TI - Spotted hyaena space use in relation to human infrastructure inside a protected area. AB - Increasing human population growth has led to elevated levels of human-carnivore conflict. However, some carnivore populations have adapted to urban environments and the resources they supply. Such associations may influence carnivore ecology, behaviour and life-history. Pockets of urbanisation sometimes occur within protected areas, so that anthropogenic influences on carnivore biology are not necessarily confined to unprotected areas. In this study we evaluated associations between human infrastructure and related activity and space use of spotted hyaenas within one of the largest protected areas in South Africa, the Kruger National Park. Home range size was smaller for the dominant female of a clan living in close proximity to humans than that of the dominant female of a clan without direct access to human infrastructure. The home range including human infrastructure was also used less evenly during the night, presumably when the animals were active. Within this home range, a village area was preferred during the night, when the least modified areas within the village were preferred and administration and highly modified areas were avoided. During the day, however, there were no preference or avoidance of the village area, but all habitats except unmodified habitats within the village area were avoided. We suggest that human infrastructure and associated activity influenced hyaena space use, primarily through alterations in the spatial distribution of food. However, these effects may have been indirectly caused by habitat modification that generated favourable hunting habitat rather than a direct effect caused by access to human food such as garbage. Because of the often pivotal effects of apex predators in terrestrial ecosystems, we encourage further work aimed to quantify how human presence influences large carnivores and associated ecosystem processes within protected areas. PMID- 27781176 TI - Ecological solutions to reef degradation: optimizing coral reef restoration in the Caribbean and Western Atlantic. AB - Reef restoration activities have proliferated in response to the need to mitigate coral declines and recover lost reef structure, function, and ecosystem services. Here, we describe the recent shift from costly and complex engineering solutions to recover degraded reef structure to more economical and efficient ecological approaches that focus on recovering the living components of reef communities. We review the adoption and expansion of the coral gardening framework in the Caribbean and Western Atlantic where practitioners now grow and outplant 10,000's of corals onto degraded reefs each year. We detail the steps for establishing a gardening program as well as long-term goals and direct and indirect benefits of this approach in our region. With a strong scientific basis, coral gardening activities now contribute significantly to reef and species recovery, provide important scientific, education, and outreach opportunities, and offer alternate livelihoods to local stakeholders. While challenges still remain, the transition from engineering to ecological solutions for reef degradation has opened the field of coral reef restoration to a wider audience poised to contribute to reef conservation and recovery in regions where coral losses and recruitment bottlenecks hinder natural recovery. PMID- 27781177 TI - Effects of 14-day oral low dose selenium nanoparticles and selenite in rat-as determined by metabolite pattern determination. AB - Selenium (Se) is an essential element with a small difference between physiological and toxic doses. To provide more effective and safe Se dosing regimens, as compared to dosing with ionic selenium, nanoparticle formulations have been developed. However, due to the nano-formulation, unexpected toxic effects may occur. We used metabolite pattern determination in urine to investigate biological and/or toxic effects in rats administered nanoparticles and for comparison included ionic selenium at an equimolar dose in the form of sodium selenite. Low doses of 10 and 100 fold the recommended human high level were employed to study the effects at borderline toxicity. Evaluations of all significantly changed putative metabolites, showed that Se nanoparticles and sodium selenite induced similar dose dependent changes of the metabolite pattern. Putative identified metabolites included increased decenedioic acid and hydroxydecanedioic acid for both Se formulations whereas dipeptides were only increased for selenite. These effects could reflect altered fatty acid and protein metabolism, respectively. PMID- 27781178 TI - Taxonomy of Platypterygius campylodon and the diversity of the last ichthyosaurs. AB - A complex and confusing taxonomy has concealed the diversity dynamics of Cretaceous ichthyosaurs (Reptilia) for decades. The near totality of Albian Cenomanian remains from Eurasia has been assigned, by default, to the loosely defined entity Platypterygius campylodon, whose holotype was supposed to be lost. By thoroughly examining the Cenomanian ichthyosaur collections from the UK, I redescribe the syntypic series of Platypterygius campylodon. This material, along with a handful of other coeval remains, is diagnostic and seemingly differs from the vast majority of Cretaceous remains previously assigned to this taxon. A lectotype for Platypterygius campylodon is designated and I reassign this species to Pervushovisaurus campylodon nov. comb. The feeding ecology of this species is assessed and conforms to the scenario of an early Cenomanian diversity drop prior to the latest Cenomanian final extinction. PMID- 27781179 TI - Nonlinear temperature effects on multifractal complexity of metabolic rate of mice. AB - Complex physiological dynamics have been argued to be a signature of healthy physiological function. Here we test whether the complexity of metabolic rate fluctuations in small endotherms decreases with lower environmental temperatures. To do so, we examine the multifractal temporal scaling properties of the rate of change in oxygen consumption r(VO2), in the laboratory mouse Mus musculus, assessing their long range correlation properties across seven different environmental temperatures, ranging from 0 degrees C to 30 degrees C. To do so, we applied multifractal detrended fluctuation analysis (MF-DFA), finding that r(VO2) fluctuations show two scaling regimes. For small time scales below the crossover time (approximately 102 s), either monofractal or weak multifractal dynamics are observed depending on whether Ta < 15 degrees C or Ta > 15 degrees C respectively. For larger time scales, r(VO2) fluctuations are characterized by an asymptotic scaling exponent that indicates multifractal anti-persistent or uncorrelated dynamics. For both scaling regimes, a generalization of the multiplicative cascade model provides very good fits for the Renyi exponents tau(q), showing that the infinite number of exponents h(q) can be described by only two independent parameters, a and b. We also show that the long-range correlation structure of r(VO2) time series differs from randomly shuffled series, and may not be explained as an artifact of stochastic sampling of a linear frequency spectrum. These results show that metabolic rate dynamics in a well studied micro-endotherm are consistent with a highly non-linear feedback control system. PMID- 27781181 TI - Perioperative Complications of Pedicle Subtraction Osteotomy. AB - Study Design Retrospective case series. Objective To describe the perioperative complications (0 to 90 days) associated with pedicle subtraction osteotomies (PSOs) performed at a tertiary spine center by two experienced spine surgeons who recently adopted the technique. Methods We reviewed all 65 patients (47 women and 18 men; mean age 60 years, range 24 to 80) who underwent a PSO at our institution. Descriptive data and analysis of complications were limited to the perioperative time (within 90 days of surgery). Data analyzed included operative time, length of stay (LOS), estimated blood loss (EBL), blood products, comorbidities, neurologic complications, and medical complications. Complications were rated as major and minor. Radiographic data was also analyzed. Results Ten patients (15.4%) had a major complication, and 15 (23%) had a minor complication. There were three perioperative deaths. The most common major complication was neurologic deficit (6.2%, 4/65), three with a permanent foot drop, and one with paraplegia secondary to postoperative hematoma. There were no differences between patients with and without a major complication in regard to age, gender, comorbidities, operative time, number of levels fused, and EBL (p > 0.05). Patients with a major complication had a longer intensive care unit stay (p = 0.04). There was no difference in the rate of major complications between the initial and later cases performed. Conclusion The major complication rate for pedicle subtraction osteotomy was 15% and the minor complication rate was 23%. The most common major complication was neurologic deficit in 6.2%. The complication rate did not change with increased surgeon experience. PMID- 27781180 TI - A pilot study examining the effects of low-volume high-intensity interval training and continuous low to moderate intensity training on quality of life, functional capacity and cardiovascular risk factors in cancer survivors. AB - PURPOSE: The aim of this study was to evaluate the effects of low-volume high intensity interval training and continuous low to moderate intensity training on quality of life, functional capacity and cardiovascular disease risk factors in cancer survivors. METHODS: Cancer survivors within 24 months post-diagnosis were randomly assigned into the low-volume high-intensity interval training group (n = 8) or the continuous low to moderate intensity training group (n = 8) group for 36 sessions (12 weeks) of supervised exercise. The low-volume high-intensity interval training (LVHIIT) group performed 7 * 30 s intervals (>=85% maximal heart rate) and the continuous low to moderate intensity training (CLMIT) group performed continuous aerobic training for 20 min (<=55% maximal heart rate) on a stationary bike or treadmill. RESULTS: Significant improvements (time) were observed for 13 of the 23 dependent variables (ES 0.05-0.61, p <= 0.05). An interaction effect was observed for six minute walk test (18.53% [32.43-4.63] ES 0.50, p <= 0.01) with the LVHIIT group demonstrating greater improvements. CONCLUSION: These preliminary findings suggest that both interventions can induce improvements in quality of life, functional capacity and selected cardiovascular disease risk factors. The LVHIIT program was well tolerated by the participants and our results suggest that LVHIIT is the preferred modality to improve fitness (6MWT); it remains to be seen which intervention elicits the most clinically relevant outcomes for patients. A larger sample size with a control group is required to confirm the significance of these findings. PMID- 27781182 TI - Validation of a Russian Language Oswestry Disability Index Questionnaire. AB - Study Design Retrospective reliability and validity study. Objective To validate a recently translated Russian language version of the Oswestry Disability Index (R-ODI) using standardized methods detailed from previous validations in other languages. Methods We included all subjects who were seen in our spine surgery clinic, over the age of 18, and fluent in the Russian language. R-ODI was translated by six bilingual people and combined into a consensus version. R-ODI and visual analog scale (VAS) questionnaires for leg and back pain were distributed to subjects during both their initial and follow-up visits. Test validity, stability, and internal consistency were measured using standardized psychometric methods. Results Ninety-seven subjects participated in the study. No change in the meaning of the questions on R-ODI was noted with translation from English to Russian. There was a significant positive correlation between R-ODI and VAS scores for both the leg and back during both the initial and follow-up visits (p < 0.01 for all). The instrument was shown to have high internal consistency (Cronbach alpha = 0.82) and moderate test-retest stability (interclass correlation coefficient = 0.70). Conclusions The R-ODI is both valid and reliable for use among the Russian-speaking population in the United States. PMID- 27781183 TI - Perioperative Complications of Cervical Spine Surgery: Analysis of a Prospectively Gathered Database through the Association for Collaborative Spinal Research. AB - Study Design Retrospective review of prospectively gathered data. Objective To report the rate and impact of perioperative complications in cervical spine surgery. To our knowledge, no prior study of the cervical spine has analyzed a large prospectively gathered data set for adverse events, based on surgical subgroup. Methods The ProSTOS database features prospectively documented perioperative adverse events for 1,269 patients who had cervical spine surgery at multiple centers in North America between 2008 and 2011. We subgrouped patients by approach, whether surgery was a primary or revision operation, and by the number of levels involved. Multivariate analysis with stepwise logistic regression was used to relate complication rates to gender, age, smoking status, body mass index, approach, revision status, and number of levels involved. Follow up was 41%. Results Adverse events occurred significantly more frequently in posterior and combined procedures than in anterior procedures. Revision surgery had significantly more complications than primary surgery. For patients who had anterior surgery, those who had one, two, and three or more levels operated had no significant difference in complication rates. Patients who had posterior surgery had significantly more complications if they had two or more levels operated compared with one level. The lowest rates of complications were for one level primary surgery (<5%), and multilevel posterior, revision posterior, and revision combined surgery had complication rates over 6 times higher (>28%). Patients who had complications were significantly older than patients who did not. The most common adverse events were dysphagia and cardiac complications. The most severe morbid complications, in terms of increased treatment needs and hospital stay, were paraparesis and seizure. Conclusions Perioperative complication rates in cervical spine surgery are significantly lower in younger patients, surgery performed through an anterior approach (compared with a posterior or combined approach), with fewer levels involved (particularly in posterior surgery), and in primary (compared with revision) procedures. PMID- 27781184 TI - Change in Off-Label Use of Bone Morphogenetic Protein in Spine Surgery and Associations with Adverse Outcome. AB - Study Design Retrospective cohort study. Objective The U.S. Food and Drug Administration issued a warning in 2008 against off-label bone morphogenetic protein (BMP-2) use. We aimed to determine (off-label) BMP-2 use in two periods and associations with complications. Methods We included 340,393 patients undergoing spinal fusions from the Premier Perspective database (2006 to 2012). BMP-2 use was determined from billing in 2006 to 2008 versus 2009 to 2012. Outcomes included revisions, length of hospital stay (LOHS), and cost of hospital stay (COH). Multilevel regressions measured associations between BMP-2 and outcomes; odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Results BMP-2 use decreased from 18.7% in 2006 to 11.5% in 2012. Off-label use remains but is decreasing, particularly for cervical anterior (5.1 versus 2.0%) and cervical posterior procedures (15.3 versus 8.5%; both p < 0.01 comparing 2006 to 2008 with 2009 to 2012). BMP-2 remains associated with increased LOHS (median 2 versus 3 days; both periods) and COH (median $15,455 versus $27,881 in 2006 to 2008; $17,007 versus $30,331 in 2009 to 2012). Adjusted ORs for the association between BMP-2 and adverse outcomes were generally lower in 2009 to 2012 compared with 2006 to 2008. Most notably, we demonstrate lower ORs for revision after cervical fusions in 2009 to 2012 (OR 1.67, CI 1.01 to 2.78) compared with 2006 to 2008 (OR 2.43, CI 1.66 to 3.54). Conclusions Using a previously untapped data source, we show decreased (off-label) BMP-2 use in spinal fusions, particularly in cervical fusions. Although there was a tendency of decreased odds in 2009 to 2012, higher resource utilization and odds for complications remain in patients using BMP-2. A national registry or prospective observational studies will benefit the ongoing discussion. PMID- 27781185 TI - Clinical and Radiographic Outcomes of Transforaminal Lumbar Interbody Fusion in Patients with Osteoporosis. AB - Study Design Retrospective review. Objective To compare clinical outcomes after transforaminal lumbar interbody fusion (TLIF) in patients with and patients without osteoporosis. Methods We reviewed all patients with 6-month postoperative radiographs and computed tomography (CT) scans for evaluation of the interbody cage. CT Hounsfield unit (HU) measurements of the instrumented vertebral body were used to determine whether patients had osteoporosis. Radiographs and CT scans were evaluated for evidence of implant subsidence, migration, interbody fusion, iatrogenic fracture, or loosening of posterior pedicle screw fixation. Medical records were reviewed for persistence of symptoms or recurrence of symptoms. Results The final data analysis included 18 (20.5%) patients with osteoporosis and 70 (79.5%) patients without osteoporosis. Males comprised 50% of patients with osteoporosis, and 64.3% of patients without osteoporosis. The mean age was significantly higher in the osteoporotic group (65.2 years) versus the nonosteoporotic group (56.9 years; p < 0.0001). We found significantly higher rates of subsidence (72.2 versus 45.7%, p = 0.05) and iatrogenic fractures (16.7% versus 1.4%, p = 0.03) in the osteoporotic group. In addition, the osteoporotic group had significantly higher radiographic complication rates compared with the nonosteoporotic group (77.8 versus 48.6%, p = 0.03). There was no difference between groups for revision surgery (16.6 versus 14.3%, p = 0.78) or postoperative symptoms (44.4% versus 50.0%, p = 0.69). Conclusions Our data demonstrated significantly increased rates of cage subsidence, iatrogenic fracture, and overall radiographic complications in patients with osteoporosis. However, these radiographic complications did not predispose patients with osteoporosis to an increased risk of surgical revision or worse clinical outcomes. PMID- 27781186 TI - Clinical Outcomes of Posterior Lumbar Interbody Fusion for Patients 80 Years of Age and Older with Lumbar Degenerative Disease: Minimum 2 Years' Follow-Up. AB - Study Design Retrospective study. Objective To compare clinical outcomes, radiographic evaluations including bony union rate and incidence of osteoporotic vertebral fractures (OVFxs), and perioperative complications following posterior lumbar interbody fusion (PLIF) between patients >=80 years of age and those <80 years. Methods Ninety-six patients >=70 years old who underwent PLIF were reviewed. We divided the patients into the two age groups, >=80 group (n = 19) and <80 group (n = 77), and compared the clinical outcomes using Japanese Orthopaedics Association (JOA) scores and the Short-Form Health Survey (SF-36). We also evaluated bony union and the incidence of OVFxs in the both groups. Results The JOA score improved 47.6% in the >=80 group and 49.1% in the <80 group. There were no significant differences between the two groups. Only the bodily pain component of the SF-36 improved significantly in the >=80 group, and seven of eight components (exception was general health) improved significantly in the <80 group. Bony union rate was significantly superior in the <80 group (94.8%) compared with that of the >=80 group (73.7%, p = 0.013). OVFx prevalence and incidence were not significantly different between the two groups, although postoperative OVFx worsened the JOA score improvement in the >=80 group (38.8%, p = 0.02). Conclusions The present study indicated that surgical outcomes of PLIF in patients >=80 years were comparable to those < 80 years. However, bony union rate was significantly lower and postoperative OVFx worsened the clinical outcomes in patients >=80 years. PMID- 27781187 TI - Kinematic Magnetic Resonance Imaging Assessment of the Degenerative Cervical Spine: Changes after Anterior Decompression and Cage Fusion. AB - Study Design A prospective cohort study. Objective Decompression and fusion of cervical vertebrae is a combined procedure that has a high success rate in relieving radicular symptoms and stabilizing or improving cervical myelopathy. However, fusion may lead to increased motion of the adjacent vertebrae and cervical deformity. Both have been postulated to lead to adjacent segment pathology (ASP). Kinematic magnetic resonance imaging (MRI) has been increasingly used to evaluate range of motion (ROM) of the cervical spine and ASP. Our objective was to measure ASP, cervical curvature, and ROM of individual segments of the cervical spine using kinematic MRI before and 24 months after monosegmental cage fusion. Methods Eighteen patients who had single-level interbody fusion were included. ROM (using kinematic MRI) and degeneration, spinal stenosis, and cervical curvature were measured preoperatively and 24 months postoperatively. Results Using kinematic MRI, segmental motion of the cervical segments was measured with a precision of less than 3 degrees. The cervical fusion did not affect the ROM of adjacent levels. However, pre- and postoperative ROM was higher at the levels immediately adjacent to the fusion level compared with those further away. In addition, at 24 months postoperatively, the number of cases with ASP was higher at the levels immediately adjacent to fusion level. Conclusions Using kinematic MRI, ROM after spinal fusion can be measured with high precision. Kinematic MRI can be used not only in clinical practice, but also to study intervention and its effect on postoperative biomechanics and ASP of cervical vertebrae. PMID- 27781188 TI - Blunt Cerebrovascular Injury in Cervical Spine Fractures: Are More-Liberal Screening Criteria Warranted? AB - Study Design Retrospective comparative study. Objective To compare strict Biffl criteria to more-liberal criteria for computed tomography angiography (CTA) when screening for blunt cerebrovascular injury (BCVI). Methods All CTAs performed for blunt injury between 2009 and 2011 at our institution were reviewed. All patients with cervical spine fractures who were evaluated with CTA were included; patients with penetrating trauma and atraumatic reasons for imaging were excluded. We then categorized the patients' fractures based on the indications for CTA as either within or outside Biffl criteria. For included subjects, the percentage of studies ordered for loose versus strict Biffl criteria and the resulting incidences of BCVI were determined. Results During our study period, 1,000 CTAs were performed, of which 251 met inclusion criteria. Of the injuries, 192 met Biffl criteria (76%). Forty-nine were found to have BCVIs (19.5%). Forty-one injuries were related to fractures meeting Biffl criteria (21.4%), and 8 were related to fractures not meeting those criteria (13.6%). The relative risk of a patient with a Biffl criteria cervical spine injury having a vascular injury compared with those imaged outside of Biffl criteria was 1.57 (p = 0.19). Conclusions Our data demonstrates that although cervical spine injuries identified by the Biffl criteria trend toward a higher likelihood of concomitant BCVI (21.4%), a significant incidence of 13.6% also exists within the non-Biffl fracture cohort. As a result, a more-liberal screening than proposed by Biffl may be warranted. PMID- 27781189 TI - The Development of a Universally Accepted Sacral Fracture Classification: A Survey of AOSpine and AOTrauma Members. AB - Study Design Survey study. Objective To determine the global perspective on controversial aspects of sacral fracture classifications. Methods While developing the AOSpine Sacral Injury Classification System, a survey was sent to all members of AOSpine and AOTrauma. The survey asked four yes-or-no questions to help determine the best way to handle controversial aspects of sacral fractures in future classifications. Chi-square tests were initially used to compare surgeons' answers to the four key questions of the survey, and then the data was modeled through multivariable logistic regression analysis. Results A total of 474 surgeons answered all questions in the survey. Overall 86.9% of respondents felt that the proposed hierarchical nature of injuries was appropriate, and 77.8% of respondents agreed that that the risk of neurologic injury is highest in a vertical fracture through the foramen. Almost 80% of respondents felt that the separation of injuries based on the integrity of L5-S1 facet was appropriate, and 83.8% of surgeons agreed that a nondisplaced sacral U fracture is a clinically relevant entity. Conclusion This study determines the global perspective on controversial areas in the injury patterns of sacral fractures and demonstrates that the development of a comprehensive and universally accepted sacral classification is possible. PMID- 27781191 TI - Outcomes following Laminoplasty or Laminectomy and Fusion in Patients with Myelopathy Caused by Ossification of the Posterior Longitudinal Ligament: A Systematic Review. AB - Study Design Systematic review. Objective To compare laminoplasty versus laminectomy and fusion in patients with cervical myelopathy caused by OPLL. Methods A systematic review was conducted using PubMed/Medline, Cochrane database, and Google scholar of articles. Only comparative studies in humans were included. Studies involving cervical trauma/fracture, infection, and tumor were excluded. Results Of 157 citations initially analyzed, 4 studies ultimately met our inclusion criteria: one class of evidence (CoE) II prospective cohort study and three CoE III retrospective cohort studies. The prospective cohort study found no significant difference between laminoplasty and laminectomy and fusion in the recovery rate from myelopathy. One CoE III retrospective cohort study reported a significantly higher recovery rate following laminoplasty. Another CoE III retrospective cohort study reported a significantly higher recovery rate in the laminectomy and fusion group. One CoE II prospective cohort study and one CoE III retrospective cohort study found no significant difference in pain improvement between patients treated with laminoplasty versus patients treated with laminectomy and fusion. All four studies reported a higher incidence of C5 palsy following laminectomy and fusion than laminoplasty. One CoE II prospective cohort and one CoE III retrospective cohort reported that there was no significant difference in axial neck pain between the two procedures. One CoE III retrospective cohort study suggested that there was no significant difference between groups in OPLL progression. Conclusion Data from four comparative studies was not sufficient to support the superiority of laminoplasty or laminectomy and fusion in treating cervical myelopathy caused by OPLL. PMID- 27781190 TI - The Effects of Smoking and Smoking Cessation on Spine Surgery: A Systematic Review of the Literature. AB - Study Design Literature review. Objective The aim of this literature review was to detail the effects of smoking in spine surgery and examine whether perioperative smoking cessation could mitigate these risks. Methods A review of the relevant literature examining the effects of smoking and cessation on surgery was conducted using PubMed, Google Scholar, and Cochrane databases. Results Current smokers are significantly more likely to experience pseudarthrosis and postoperative infection and to report lower clinical outcomes after surgery in both the cervical and lumbar spines. Smoking cessation can reduce the risks of these complications depending on both the duration and timing of tobacco abstinence. Conclusion Smoking negatively affects both the objective and subjective outcomes of surgery in the lumbar and cervical spine. Current literature supports smoking cessation as an effective tool in potentially mitigating these unwanted outcomes. Future investigations in this field should be directed toward developing a better understanding of the complex relationship between smoking and poorer outcomes in spine surgery as well as developing more efficacious cessation strategies. PMID- 27781192 TI - Staged Correction of Severe Thoracic Kyphosis in Patients with Multilevel Osteoporotic Vertebral Compression Fractures. AB - Study Design Technical report. Objective Multilevel osteoporotic vertebral compression fractures may lead to considerable thoracic deformity and sagittal imbalance, which may necessitate surgical intervention. Correction of advanced thoracic kyphosis in patients with severe osteoporosis remains challenging, with a high rate of failure. This study describes a surgical technique of staged vertebral augmentation with osteotomies for the treatment of advanced thoracic kyphosis in patients with osteoporotic multilevel vertebral compression fractures. Methods Five patients (average age 62 +/- 6 years) with multilevel osteoporotic vertebral compression fractures and severe symptomatic thoracic kyphosis underwent staged vertebral augmentation and surgical correction of their sagittal deformity. Clinical and radiographic outcomes were assessed retrospectively at a mean postoperative follow-up of 34 months. Results Patients' self-reported back pain decreased from 7.2 +/- 0.8 to 3.0 +/- 0.7 (0 to 10 numerical scale; p < 0.001). Patients' back-related disability decreased from 60 +/- 10% to 29 +/- 10% (0 to 100% Oswestry Disability Index; p < 0.001). Thoracic kyphosis was corrected from 89 +/- 5 degrees to 40 +/- 4 degrees (p < 0.001), and the sagittal vertical axis was corrected from 112 +/- 83 mm to 38 +/- 23 mm (p = 0.058). One patient had cement leakage without subsequent neurologic deficit. Decreased blood pressure was observed in another patient during the cement injection. No correction loss, hardware failure, or neurologic deficiency was seen in the other patients. Conclusion The surgical technique described here, despite its complexity, may offer a safe and effective method for the treatment of advanced thoracic kyphosis in patients with osteoporotic multilevel vertebral compression fractures. PMID- 27781194 TI - Mucoepidermoid Carcinoma of Palatal Minor Salivary Glands with Intracranial Extension: A Case Report and Literature Review. AB - Mucoepidermoid carcinoma (MEC) is one of the most common malignant tumors of both major and minor salivary glands. Although there are reports of parotid MEC tumors extending intracranially via the facial nerve, intracranial extension from MEC originating from minor salivary glands in the palate has not previously been reported. This report presents a case of MEC arising from the minor salivary glands of the palate and extending into the middle fossa via the foramen rotundum with perineural invasion of the maxillary division of the trigeminal nerve. The patient received surgical intervention via a combined otolaryngology and neurosurgery approach to achieve gross total resection of the tumor. This was followed by adjuvant radiotherapy. The epidemiology, histopathology, and treatment of MEC originating from salivary glands are discussed. PMID- 27781193 TI - Catastrophic Cervical Spine Injuries in Contact Sports. AB - Study Design Systematic review. Objectives To determine the incidence of catastrophic cervical spine injuries (CCSIs) among elite athletes participating in contact team sports and whether the incidence varies depending on the use of protective gear or by player position. Methods Electronic databases and reference lists of key articles published from January 1, 2000, to January 29, 2016, were searched. Results Fourteen studies were included that reported CCSI in rugby (n = 10), American football (n = 3), and Irish hurling (n = 1). Among Rugby Union players, incidence of CCSI was 4.1 per 100,000 player-hours. Among National Football League players, the CCSI rate was 0.6 per 100,000 player-exposures. At the collegiate level, the CCSI rate ranged from 1.1 to 4.7 per 100,000 player years. Mixed populations of elite and recreational rugby players in four studies report a CCSI rate of 1.4 to 7.2 per 100,000 player-years. In this same population, the scrum accounted for 30 to 51% of total reported CCSIs in Rugby Union versus 0 to 4% in Rugby League. The tackle accounted for 29 to 39% of injuries in Rugby Union and 78 to 100% of injuries in Rugby League. Making a tackle was responsible for 29 to 80% of injuries in American football. Conclusion CCSIs are infrequent among elite athletes. There is insufficient evidence to determine the effect of protective gear (e.g., helmets, padding) on CCSI incidence. Scrum and tackle in rugby and tackling in American football account for the majority of CCSIs in each respective sport. PMID- 27781196 TI - Regorafenib as Second-Line Systemic Therapy May Change the Treatment Strategy and Management Paradigm for Hepatocellular Carcinoma. PMID- 27781195 TI - Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis. AB - The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis - providing D2HG interstitial fluid concentrations - sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 +/- 74.8 MUM awake and 117.6 +/- 98.6 MUM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 +/- 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis. PMID- 27781197 TI - Surgery for Intermediate and Advanced Hepatocellular Carcinoma: A Consensus Report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014). AB - BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy does not recommended surgery for treating BCLC stage B and C hepatocellular carcinoma (HCC). However, numerous Asia-Pacific institutes still perform surgery for this patient group. This consensus report from the 5th Asia Pacific Primary Liver Cancer Expert Meeting aimed to share opinions and experiences pertaining to liver resection for intermediate and advanced HCCs and to provide evidence to issue recommendations for surgery in this patient group. SUMMARY: Thirteen experts from five Asia-Pacific regions were invited to the meeting; 10 of them (Japan: 2, Taiwan: 3, South Korea: 2, Hong Kong: 1, and China: 2) voted for the final consensus. The discussion focused on evaluating the preoperative liver functional reserve and surgery for large tumors, multiple tumors, HCCs with vascular invasion, and HCCs with distant metastasis. The feasibility of future prospective randomized trials comparing surgery with transarterial chemoembolization for intermediate HCC and with sorafenib for advanced HCC was also discussed. The Child-Pugh score (9/10 experts) and indocyanine green retention rate at 15 min (8/10) were the most widely accepted methods for evaluating the preoperative liver functional reserve. All (10/10) experts agreed that portal hypertension, tumor size >5 cm, portal venous invasion, hepatic venous invasion, and extrahepatic metastasis are not absolute contraindications for the surgical resection of HCC. Furthermore, 9 of the 10 experts agreed that tumor resection may be performed for patients with >3 tumors. The limitations of surgery are associated with a poor liver functional reserve, incomplete tumor resection, and a high probability of recurrence. KEY MESSAGES: Surgery provides significant survival benefits for Asian-Pacific patients with intermediate and advanced HCCs, particularly when the liver functional reserve is favorable. However, prospective randomized controlled trials are difficult to conduct because of technical and ethical considerations. PMID- 27781198 TI - Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment. AB - OBJECTIVES: This study aimed to build a prediction score of prognosis for patients with advanced hepatocellular carcinoma (HCC) after sorafenib treatment. METHODS: A total of 165 patients with advanced HCC who were treated with sorafenib were analyzed. Readily available baseline factors were used to establish a scoring system for the prediction of survival. RESULTS: The median survival time (MST) was 14.2 months. The independent prognostic factors were C reactive protein (CRP) <1.0 mg/dL [hazard ratio (HR) =0.51], albumin >3.5 g/dL (HR =0.55), alpha-fetoprotein <200 ng/mL (HR =0.45), and a lack of major vascular invasion (HR =0.39). Each of these factors had a score of 1, and after classifying the patients into five groups, the total scores ranged from 0 to 4. Higher scores were linked to significantly longer survival (p<0.0001). Twenty nine patients (17.6%) with a score of 4 had a MST as long as 36.5 months, whereas MST was as short as 2.4 and 3.7 months for seven (4.2%) and 22 (13.3%) patients with scores of 0 and 1, respectively. CONCLUSIONS: A novel prognostic scoring system, which includes the CRP level, has the ability to stratify the prognosis of patients with advanced stage HCC after treatment with sorafenib. PMID- 27781199 TI - Feasibility of Extracted-Overlay Fusion Imaging for Intraoperative Treatment Evaluation of Radiofrequency Ablation for Hepatocellular Carcinoma. AB - BACKGROUND AND AIMS: Extracted-overlay fusion imaging is a novel computed tomography/magnetic resonance-ultrasonography (CT/MR-US) imaging technique in which a target tumor with a virtual ablative margin is extracted from CT/MR volume data and synchronously overlaid on US images. We investigated the applicability of the technique to intraoperative evaluation of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: This retrospective study analyzed 85 HCCs treated with RFA using extracted-overlay fusion imaging for guidance and evaluation. To perform RFA, an electrode was inserted targeting the tumor and a virtual 5-mm ablative margin overlaid on the US image. Following ablation, contrast-enhanced US (CEUS) was performed to assess the ablative margin, and the minimal ablative margins were categorized into three groups: (I) margin <0 mm (protrusion), (II) margin 0 to <5 mm, and (III) margin >=5 mm. Margin assessment was based on the positional relationship between the overlaid tumor plus margin and the perfusion defect of the ablation zone. Tumors in group I underwent repeat ablation until they were in groups II or III. The final classifications were compared with those obtained by retrospectively created fusion images of pre- and post-RFA CT or MR imaging (CT-CT/MR-MR fusion imaging). RESULTS: Treatment evaluation was impossible using CEUS in six HCCs because the tumors were located far below the body surface. Of the remaining 79 HCCs, the categorizations of minimal ablative margins between CEUS extracted-overlay fusion imaging and CT-CT/MR-MR fusion imaging were in agreement for 72 tumors (91.1%) (Cohen's quadratic-weighted kappa coefficient 0.66, good agreement, p<0.01). CONCLUSIONS: Extracted-overlay fusion imaging combined with CEUS is feasible for the evaluation of RFA and enables intraoperative treatment evaluation without the need to perform contrast-enhanced CT. PMID- 27781200 TI - Is Surgical Resection Justified for Advanced Intrahepatic Cholangiocarcinoma? AB - BACKGROUNDS: Prognosis for patients with advanced intrahepatic cholangiocarcinoma (ICC) with intrahepatic metastasis (IM), vascular invasion (VI), or regional lymph node metastasis (LM) remains poor. The aim of this study was to clarify the indications for surgical resection for advanced ICC. METHODS: We retrospectively divided 213 ICC patients treated at Kyoto University Hospital between 1993 and 2013 into a resection (n=164) group and a non-resection (n=49) group. Overall survival was assessed after stratification for the presence of IM, VI, or LM. RESULTS: Overall median survival times (MSTs) for the resection and non-resection groups were 26.0 and 7.1 months, respectively (p<0.001). After stratification, MSTs in the resection and non-resection groups, respectively, were 18.7 vs. 7.0 months for patients with IM (p<0.001), 23.4 vs. 5.7 months for those with VI (p<0.001), and 12.8 vs. 5.5 months for those with LM (p<0.001). CONCLUSION: When macroscopic curative resection is possible, surgical resection can be justified for some advanced ICC patients with IM, VI, or LM. PMID- 27781201 TI - Molecular Pathogenesis of Hepatocellular Carcinoma. AB - The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process involving the progressive accumulation of molecular alterations pinpointing different molecular and cellular events. The next-generation sequencing technology is facilitating the global and systematic evaluation of molecular landscapes in HCC. There is emerging evidence supporting the importance of cancer metabolism and tumor microenvironment in providing a favorable and supportive niche to expedite HCC development. Moreover, recent studies have identified distinct surface markers of cancer stem cell (CSC) in HCC, and they also put forward the profound involvement of altered signaling pathways and epigenetic modifications in CSCs, in addition to the concomitant drug resistance and metastasis. Taken together, multiple key genetic and non-genetic factors, as well as liver CSCs, result in the development and progression of HCC. PMID- 27781202 TI - Selective Internal Radiation Therapy (SIRT) as Conversion Therapy for Unresectable Primary Liver Malignancies. AB - BACKGROUND: Many patients with primary liver cancers are not candidates for surgery, and systemic therapies are seldom effective. Selective internal radiation therapy (SIRT) has been shown to obtain partial and even complete response in unresectable primary tumors. As a "side effect", SIRT can induce contra-lateral liver hypertrophy. Tumor response to SIRT can be sufficient to allow disengagement from normal vital structures whose involvement is the cause of the initial unresectability. The contra-lateral hypertrophy can thereby increase the future liver remnant (FLR) volume to over the safe threshold so that extended hepatectomy can be performed. SUMMARY: A review of the available literature was performed to assess the tumor response and liver hypertrophy that can be expected after SIRT, in order to delineate whether SIRTcan play a role in conversion therapy for resectability of primary liver malignancies. KEY MESSAGE: Available data suggest that SIRT in unresectable hepatocellular and cholangiocellular carcinomas can provide a considerable down-sizing of the tumors to possibly allow resection. Hypertrophy of the contra-lateral lobe represents a favorable collateral effect that can help in achieving safer subsequent major hepatectomy. In patients whose FLR volume represents the only surgical concern, portal vein embolization remains the treatment of choice. PMID- 27781204 TI - Why Economic Analysis of Health System Improvement Interventions Matters. AB - There is little evidence to direct health systems toward providing efficient interventions to address medical errors, defined as an unintended act of omission or commission or one not executed as intended that may or may not cause harm to the patient but does not achieve its intended outcome. We believe that lack of guidance on what is the most efficient way to reduce medical errors and improve the quality of health-care limits the scale-up of health system improvement interventions. Challenges to economic evaluation of these interventions include defining and implementing improvement interventions in different settings with high fidelity, capturing all of the positive and negative effects of the intervention, using process measures of effectiveness rather than health outcomes, and determining the full cost of the intervention and all economic consequences of its effects. However, health system improvement interventions should be treated similarly to individual medical interventions and undergo rigorous economic evaluation to provide actionable evidence to guide policy makers in decisions of resource allocation for improvement activities among other competing demands for health-care resources. PMID- 27781205 TI - A Unique Cause of Proteinuria in Pregnancy: Class II Lupus Nephritis with Concomitant Minimal Change Disease. AB - We report the case of a 22-year-old African American female who presented to another facility for routine follow-up in the 34th week of pregnancy with lower extremity swelling and nephrotic-range proteinuria. Although she was normotensive, it was initially thought that she had preeclampsia. She was monitored carefully and delivery was induced at 37 weeks of gestation. She was transferred to our hospital, where she was diagnosed with systemic lupus erythematosus (SLE) based on clinical and laboratory criteria. Renal biopsy revealed a surprising finding of minimal change disease (MCD) concomitant with class II lupus nephritis (LN). She was managed with pulses and then tapering doses of steroid therapy with dramatic resolution of the nephrotic syndrome. This case demonstrates not only the rare de novo occurrence of SLE in pregnancy, but the unique finding of MCD coexisting with class II LN. We propose that altered T cell activity may be the link between these seemingly distinct entities. PMID- 27781203 TI - Real-Life Treatment Paradigms Show Adalimumab Is Cost-Effective for the Management of Ulcerative Colitis. AB - Background. Adalimumab is effective for the maintenance of remission in patients with moderate-to-severe ulcerative colitis (UC). Currently, biologic therapies are used in cases where patients fail conventional medical therapies. If biologic therapies are not available, patients often choose to remain in an unwell state rather than undergo colectomy. Objective. The aim of the study was to evaluate the cost-effectiveness of adalimumab in patients with UC where adalimumab was readily available compared to not available. Methods. A previously validated Markov model was used to simulate disease progression of patients with UC who are corticosteroid-dependent and/or did not respond to thiopurine therapy. Utility scores and transition probabilities between health states were determined by using data from randomized controlled trials and real-life observational studies. Costs were obtained from the Ontario Case Costing Initiative and the Alberta Health Schedule of Medical Benefits. Results. The incremental cost-effectiveness ratios for readily available adalimumab treatment of UC were $40,000 and $59,000 per quality-adjusted life year, compared with ongoing medical therapy in an unwell state, at 5-year and 10-year treatment time horizons, respectively. Conclusion. Considering real-life patient preferences to avoid colectomy, adalimumab is cost-effective according to a willingness-to-pay threshold of $80,000 for treatment of UC. PMID- 27781206 TI - A Case of Transforming Growth Factor-beta-Induced Gene-Related Oculorenal Syndrome: Granular Corneal Dystrophy Type II with a Unique Nephropathy. AB - Many types of inherited renal diseases have ocular features that occasionally support a diagnosis. The following study describes an unusual example of a 40 year-old woman with granular corneal dystrophy type II complicated by renal involvement. These two conditions may coincidentally coexist; however, there are some reports that demonstrate an association between renal involvement and granular corneal dystrophy type II. Granular corneal dystrophy type II is caused by a mutation in the transforming growth factor-beta-induced (TGFBI) gene. The patient was referred to us because of the presence of mild proteinuria without hematuria that was subsequently suggested to be granular corneal dystrophy type II. A kidney biopsy revealed various glomerular and tubular basement membrane changes and widening of the subendothelial space of the glomerular basement membrane by electron microscopy. However, next-generation sequencing revealed that she had no mutation in a gene that is known to be associated with monogenic kidney diseases. Conversely, real-time polymerase chain reaction, using a simple buccal swab, revealed TGFBI heteromutation (R124H). The TGFBI protein plays an important role in cell-collagen signaling interactions, including extracellular matrix proteins which compose the renal basement membrane. This mutation can present not only as corneal dystrophy but also as renal disease. TGFBI-related oculorenal syndrome may have been unrecognized. It is difficult to diagnose this condition without renal electron microscopic studies. To the best of our knowledge, this is the first detailed report of nephropathy associated with a TGFBI mutation. PMID- 27781207 TI - Reversal of Gastric Bypass Resolves Hyperoxaluria and Improves Oxalate Nephropathy Secondary to Roux-en-Y Gastric Bypass. AB - Hyperoxaluria after Roux-en-Y gastric bypass (RYGB) increases the risk for kidney injury. Medical therapies for hyperoxaluria have limited efficacy. A 65-year-old female was evaluated for acute kidney injury [AKI, serum creatinine (Cr) 2.1 mg/dl, baseline Cr 1.0 mg/dl]. She did not have any urinary or gastrointestinal symptoms or exposure to nephrotoxic agents. Sixteen months prior to this evaluation, she underwent RYGB for morbid obesity. Her examination was unremarkable for hypertension or edema and there was no protein or blood on urine dipstick. Kidney biopsy revealed acute tubulointerstitial nephritis with oxalate crystals in tubules. The concurrent finding of severe hyperoxaluria (urine oxalate 150 mg/day) confirmed the diagnosis of oxalate nephropathy. Despite medical management of hyperoxaluria, her AKI worsened. Laparoscopic reversal of RYGB was performed and within 1 month, her hyperoxaluria resolved (urine oxalate 20 mg/day) and AKI improved (Cr 1.7 mg/dl). Surgical reversal of RYGB may be considered in patients with oxalate nephropathy at high risk of progression who fail medical therapy. Physicians need to be aware of the possibility of oxalate nephropathy after RYGB and promptly treat the hyperoxaluria to halt further kidney damage. PMID- 27781208 TI - Detection of Astrovirus in Historical Cases of European Sporadic Bovine Encephalitis, Switzerland 1958-1976. AB - European sporadic bovine encephalitis is a frequent diagnosis in neurologically diseased cattle, but its etiology remained unresolved. Using in situ hybridization, we have detected a recently discovered neurotropic bovine astrovirus in historical tissues in a high proportion of brain samples of affected cattle. Our results suggest that astroviruses were already involved in the pathogenesis of the disease several decades ago, but have gone undetected. PMID- 27781209 TI - Expression Profiling of Genes Related to Endothelial Cells Biology in Patients with Type 2 Diabetes and Patients with Prediabetes. AB - Endothelial dysfunction appears to be an early sign indicating vascular damage and predicts the progression of atherosclerosis and cardiovascular disorders. Extensive clinical and experimental evidence suggests that endothelial dysfunction occurs in Type 2 Diabetes Mellitus (T2DM) and prediabetes patients. This study was carried out with an aim to appraise the expression levels in the peripheral blood of 84 genes related to endothelial cells biology in patients with diagnosed T2DM or prediabetes, trying to identify new genes whose expression might be changed under these pathological conditions. The study covered a total of 45 participants. The participants were divided into three groups: group 1, patients with T2DM; group 2, patients with prediabetes; group 3, control group. The gene expression analysis was performed using the Endothelial Cell Biology RT2 Profiler PCR Array. In the case of T2DM, 59 genes were found to be upregulated, and four genes were observed to be downregulated. In prediabetes patients, increased expression was observed for 49 genes, with two downregulated genes observed. Our results indicate that diabetic and prediabetic conditions change the expression levels of genes related to endothelial cells biology and, consequently, may increase the risk for occurrence of endothelial dysfunction. PMID- 27781210 TI - Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies. AB - Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin aldosterone system (RAAS) and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment. PMID- 27781211 TI - Allogeneic Antigen Composition for Preparing Universal Cancer Vaccines. AB - Recently it was demonstrated that tumors induce specific changes to the surface of human endothelial cells thereby providing the basis for designing endothelial cell-based vaccines that directly target antigens expressed by the tumor endothelium. The present report extends these studies in vitro by investigating the efficacy of allogeneic antigens with regard to their ability to target immune responses against the tumor vasculature since alloantigens simplify vaccine development and implementation in clinical practice. We demonstrated that allogeneic SANTAVAC (Set of All Natural Target Antigens for Vaccination Against Cancer), which presents a specifically prepared composition of cell surface antigens from tumor-stimulated endothelial cells, allows targeting of the tumor vasculature with efficacy of 17, where efficacy represents the killing rate of target cells before normal cells are adversely affected, and efficacy of 60, where efficacy represents the fold decrease in the number of target cells and directly relates to tumor growth arrest. These data suggest that allogeneic SANTAVAC may be considered an antigenic composition that following administration in the presence of respective adjuvants may be clinically tested as a therapeutic or prophylactic universal cancer vaccine without adverse side effects to the normal vasculature. PMID- 27781213 TI - Erratum: Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48). AB - [This corrects the article on p. e98 in vol. 2, PMID: 27606357.]. PMID- 27781212 TI - Acute Ultrasonography Investigation to Predict Reruptures and Outcomes in Patients With an Achilles Tendon Rupture. AB - BACKGROUND: The optimal treatment for acute Achilles tendon ruptures is still an ongoing debate. Acute ultrasonography (US) investigation to measure the diastasis between the tendon ends has previously been used to classify acute Achilles tendon ruptures; however, no study has used US to predict reruptures and functional outcomes. PURPOSE: To investigate whether acute US can be used to predict the risk of reruptures and outcomes after treatment of an acute Achilles tendon rupture. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Forty five patients (37 men, 8 women) with a mean age of 39 +/- 9.2 years (range, 23-59 years) from a cohort of 97 patients participating in a randomized controlled study comparing surgical and nonsurgical treatment were included. US was performed within 72 hours from the index injury. Diastasis between the tendon ends was documented. Reruptures were documented, and the patients' functional outcomes were measured 12 months after injury. RESULTS: Patients with a diastasis of >10 mm treated nonsurgically had a higher degree of rerupture. In the nonsurgically treated group, 3 of 4 patients with a diastasis of >10 mm suffered from rerupture (P < .001). Moreover, in the nonsurgical group, there was significantly worse outcomes in patients with a diastasis of >5 mm in terms of patient-reported outcomes using the Achilles tendon Total Rupture Score (ATRS) (P = .004) and heel-rise height at 12 months (P = .048) compared with the group with a lesser degree of tendon separation. CONCLUSION: US may be a useful tool to predict the risk of rerupture and greater degree of functional deficit. It may be an important measure in a clinical treatment algorithm for deciding whether a patient will benefit from surgical intervention after an acute Achilles tendon rupture. PMID- 27781214 TI - Giant spin-orbit effects on 1H and 13C NMR shifts for uranium(vi) complexes revisited: role of the exchange-correlation response kernel, bonding analyses, and new predictions. AB - Previous relativistic quantum-chemical predictions of unusually large 1H and 13C NMR chemical shifts for ligand atoms directly bonded to a diamagnetic uranium(vi) center (P. Hrobarik, V. Hrobarikova, A. H. Greif and M. Kaupp, Angew. Chem., Int. Ed., 2012, 51, 10884) have been revisited by two- and four-component relativistic density functional methods. In particular, the effect of the exchange-correlation response kernel, which had been missing in the previously used two-component version of the Amsterdam Density Functional program, has been examined. Kernel contributions are large for cases with large spin-orbit (SO) contributions to the NMR shifts and may amount to up to ~30% of the total shifts, which means more than a 50 ppm difference for the metal-bonded carbon shifts in some extreme cases. Previous calculations with a PBE-40HF functional had provided overall reasonable predictions, due to cancellation of errors between the missing kernel contributions and the enhanced exact-exchange (EXX) admixture of 40%. In the presence of an exchange-correlation kernel, functionals with lower EXX admixtures give already good agreement with experiments, and the PBE0 functional provides reasonable predictive quality. Most importantly, the revised approach still predicts unprecedented giant 1H NMR shifts between +30 ppm and more than +200 ppm for uranium(vi) hydride species. We also predict uranium-bonded 13C NMR shifts for some synthetically known organometallic U(vi) complexes, for which no corresponding signals have been detected to date. In several cases, the experimental lack of these signals may be attributed to unexpected spectral regions in which some of the 13C NMR shifts can appear, sometimes beyond the usual measurement area. An extremely large uranium-bonded 13C shift above 550 ppm, near the upper end of the diamagnetic 13C shift range, is predicted for a known pincer carbene complex. Bonding analyses allow in particular the magnitude of the SO shifts, and of their dependence on the functional, on the ligand position in the complex, and on the overall electronic structure to be better appreciated, and improved confidence ranges for predicted shifts have been obtained. PMID- 27781215 TI - Strong shear-driven large scale formation of hybrid shish-kebab in carbon nanofiber reinforced polyethylene composites during the melt second flow. AB - The formation of a hybrid shish-kebab (HSK) structure with different degrees of lamellar orientations was first observed in the solution crystallization of polyethylene (PE) in the presence of carbon nanofibers (CNFs). In this study, PE crystal lamellae were periodically decorated on the surface of CNFs and were aligned approximately perpendicular to the long axes of the CNFs, forming aligned hybrid shish-kebab nanostructures. More importantly, the fascinating structure was directly formed in all regions of the injection molded bars of HDPE/CNF composites, via a gas-assisted injection molding (GAIM), instead of the shell core structure. In the GAIM process, an intense shear was imposed onto the melt during the melt second flow and drove PE chains to orient along the axes of the CNFs. Then the entropy penalty for PE chains deposited on the CNF surface was drastically decreased. Although the attractive van der Waals interactions were weak, the oriented PE chains could successfully adsorb on the CNF surface due to the decrease of the entropy penalty, therewith the underlayer coating was formed along the axis based on a two-dimensional mode for early nucleation on the CNF surface. Subsequently, subglobules appeared on the ordered structure, which could be regarded as the crystal nucleus. Finally, the oriented PE chains began to epitaxially grow from the subglobules with a folded-chain shape to decrease the polymer surface energy and grew perpendicular to the CNFs long axis, abiding by the "soft epitaxy" crystallization mechanism regardless of strict lattice matching. PMID- 27781216 TI - Dynamic viscosity mapping of the oxidation of squalene aerosol particles. AB - Organic aerosols (OAs) play important roles in multiple atmospheric processes, including climate change, and can impact human health. The physico-chemical properties of OAs are important for all these processes and can evolve through reactions with various atmospheric components, including oxidants. The dynamic nature of these reactions makes it challenging to obtain a true representation of their composition and surface chemistry. Here we investigate the microscopic viscosity of the model OA composed of squalene, undergoing chemical aging. We employ Fluorescent Lifetime Imaging Microscopy (FLIM) in conjunction with viscosity sensitive probes termed molecular rotors, in order to image the changes in microviscosity in real time during oxidation with ozone and hydroxyl radicals, which are two key oxidising species in the troposphere. We also recorded the Raman spectra of the levitated particles to follow the reactivity during particle ozonolysis. The levitation of droplets was achieved via optical trapping that enabled simultaneous levitation and measurement via FLIM or Raman spectroscopy and allowed the true aerosol phase to be probed. Our data revealed a very significant increase in viscosity of the levitated squalene droplets upon ozonolysis, following their transformation from the liquid to solid phase that was not observable when the oxidation was carried out on coverslip mounted droplets. FLIM imaging with sub-micron spatial resolution also revealed spatial heterogeneity in the viscosity distribution of oxidised droplets. Overall, a combination of molecular rotors, FLIM and optical trapping is able to provide powerful insights into OA chemistry and the microscopic structure that enables the dynamic monitoring of microscopic viscosity in aerosol particles in their true phase. PMID- 27781217 TI - Label-free spectroscopic characterization of live liver sinusoidal endothelial cells (LSECs) isolated from the murine liver. AB - Liver sinusoidal endothelial cells (LSECs) represent a highly specialized and unique type of endothelial cell in terms of their morphology and function. The biochemical and functional characterization of LSECs in vitro is restrained by the rapid change of LSECs' phenotype upon culturing under classical experimental conditions. In this work, we present a novel approach to characterize the biochemical content of murine LSECs, freshly isolated from the liver, with the use of microspectroscopic analysis. For comparison, hepatocytes and Hepatic Stellate Cells (HSCs) were analyzed. Our approach, based on label-free confocal Raman imaging of live cells combined with chemometric analysis, provided insight into the biochemical content of freshly isolated LSECs on a subcellular level. LSECs were featured by a distinct biochemical signature in comparison with other major cell types of the liver. Based on our work we claim that the non-invasive and non-destructive confocal Raman imaging may assist in obtaining chemical information spatially distributed within the cells that characterize the phenotype of primary LSECs as well as other types of liver cells. Furthermore, our approach provides a unique insight into LSECs' morphology and chemical composition that may help to understand their functions. PMID- 27781218 TI - Amyloid beta peptides inside a reconstituted cell-like liposomal system: aggregation, FRET, fluorescence oscillations and solvation dynamics. AB - Aggregations of amyloid-beta (Abeta) peptides were studied inside a reconstituted cell like liposomal system using time-resolved confocal microscopy. Fluorescence correlation spectroscopy (FCS) and confocal images indicate that Abeta forms a very large aggregate in bulk and more efficiently, in the bilayer region of the liposome, respectively. The aggregates formed inside the liposome gradually migrate out to bulk water. FRET, from HiLyte Fluor 488 (covalently attached to an Abeta peptide) to TRITC (tetramethylrhodamine isothiocyanate) covalently attached to a DHPE lipid present in the bilayer, reveals intermittent oscillations in the time scale of ~0.5 s. This is attributed to the structural fluctuations of the membrane of the liposome. The solvation dynamics of Abeta in monomer and in oligomeric state is studied by monitoring the emission of HiLyte Fluor 488. The solvation dynamics of the Abeta monomer is similar to that of oligomeric aggregates in the liposome. PMID- 27781219 TI - Specific effects of monovalent counterions on the structural and interfacial properties of dodecyl sulfate monolayers. AB - A series of molecular dynamics simulations have been conducted in order to study the specific ion effects of Li+, Na+, Cs+ and NH4+ cations on dodecyl sulfate (DS ) monolayers. Varying the counterion had no appreciable effect on the structure of the surfactant molecules within the different monolayers. However, the different counterions have a significant effect on the interfacial properties of the monolayer. In particular, we have investigated to what extent each of the counterions is dehydrated when interacting with the DS- headgroup, the specific interactions between the counterions and the headgroup and the salt bridging of the headgroups caused by each counterion. The NH4+ ions are found to directly compete with water molecules to form hydrogen bonds with the DS- headgroup and as a result the ammonium dodecyl sulfate monolayer is the least hydrated of any of those studied. The Cs+ ions are strongly bound to the headgroup and weakly hydrated, such that they would prefer to displace water in the DS- hydration shell to interact with the headgroups. In the case of the Li+ ions, they interact almost as strongly with the DS- headgroups as the Na+ ions, but are generally less hydrated than the Na+ ions and consequently the lithium dodecyl sulfate monolayers are less hydrated than the sodium dodecyl sulfate monolayers. Therefore, by changing the counterion, one can modify the interfacial properties of the surfactant monolayer, and thus affect their ability to encapsulate poorly water soluble drug molecules, which we discuss further in the manuscript. PMID- 27781220 TI - Template-free synthesis of ordered ZnO@ZnS core-shell arrays for high performance supercapacitors. AB - In this article, ordered ZnO@ZnS core-shell structures have been produced on a stainless mesh by a two-step approach without using a template. ZnO nanorods fabricated by a chemical vapor method are transferred into a 50 ml autoclave for a second stage ion-exchange reaction followed by heating at 120 degrees C for 4 16 h. The ZnO core is prepared as the conducting channel and ZnS as the active material. Such unique architecture exhibits remarkable electrochemical performance with high capacitance and desirable cycle life. When evaluating as the electrode for supercapacitors, the ZnO@ZnS core-shell structure delivers a high specific capacitance of 603.8 F g-1 at a current density of 2 A g-1, with 9.4% capacitance loss after cycling 3000 times. The fabrication strategy presented here is simple and cost-effective, which can open new avenues for large scale applications of the novel materials in energy storage. PMID- 27781221 TI - On the wavelength dependence of UV induced thymine photolesions: a synchrotron radiation circular dichroism study. AB - Solar mutagenesis via the formation of thymine dimer photoproducts is a primary cause of skin cancer. The aim of this study is to provide a direct method for following the development of photolesions in thymine single strands and to determine how the formation of these photoproducts depends on the excitation wavelength in the ultraviolet (UV) between 210 nm and 325 nm. Experiments were performed both with a 20 Hz pulsed, intense, tunable laser as well as UV lamps (at 254 nm and 302 nm), but we find that only the dose matters at these wavelengths for the yield of photoproducts. Hence in both cases the lesion process is due to one-photon absorption. The formation and yields of the photoproducts as the irradiation dose is increased is followed through measurement of synchrotron radiation circular dichroism (SRCD) spectra. A principal component analysis (PCA) of the SRCD data yields CD signatures for each of the resulting photoproducts and reveals a strong irradiation wavelength dependence upon which products are formed; cyclobutane pyrimidine dimers (CPDs) are formed primarily at higher irradiation wavelengths (from 250 to 300 nm); the 6,4 pyrimidine-pyrimidone photoadduct (64PP) is formed in the range 210 to 285 nm, with a higher rate of formation in the lower part of that range, while in the very lowest irradiation wavelength range (210 to 240 nm) we find thymidine monophosphate (dTMP), which indicates cleavage of the DNA backbone. Our work demonstrates the strength of SRCD spectroscopy compared to ordinary absorption spectroscopy, as the latter is not sufficient to obtain fingerprints of the thymine photoproducts. PMID- 27781222 TI - Cationic CHpi interactions as a function of solvation. AB - The energy (DeltaG) of a cationic CHpi interaction was measured experimentally through the conformational studies of new molecular torsion balances using proton NMR spectroscopy. Each of the molecular balance adopted folded and unfolded conformations for which the ratio of the conformational equilibrium (i.e., folded/unfolded ratio) provided a quantitative measure of the DeltaG as a function of solvation. An excellent linear solvation energy relationship between the DeltaG values and the Hunter's solvent hydrogen-bond parameters (alphas and betas) revealed that electrostatic interaction is the physical origin of the observed conformational preferences in solution. PMID- 27781223 TI - The magnetic structure of beta-cobalt hydroxide and the effect of spin orientation. AB - Synchrotron X-ray and neutron diffraction experiments at various temperatures, down to 3 K, along with ab initio calculations, are carried out to elucidate the magnetic order of layered beta-cobalt-hydroxide. This combination of techniques allows for the unambiguous assignment of the magnetic structure of this material. Our results confirm that below the Neel temperature high-spin cobalt centers are ferromagnetically coupled within a layer, and antiferromagnetically coupled across layers (magnetic propagation vector k = (0,0,1/2)), in agreement with the indirect interpretation based on magnetic susceptibility measurements. A paramagnetic/antiferromagnetic transition is observed at around 15 K. Moreover, the thermal expansion behavior along the c-lattice direction, perpendicular to the layers, shows an inflection slightly above this temperature, at around 30 K. The neutron diffraction patterns and the non-collinear DFT+U calculations indicate that the magnetization forms an angle of about 35 degrees with the cobalt planes. In particular, for an isolated ferromagnetic layer, the electronic structure calculations reveal sharp cusps on the potential energy surface when the spins point parallel or perpendicular to the planes, suggesting that the ferromagnetic superexchange mechanism is strongly sensitive to the orientation of the magnetic moment. PMID- 27781224 TI - Kinetic and thermodynamic determinants of trace metal partitioning at biointerphases: the role of intracellular speciation dynamics. AB - There is a large body of work evidencing the necessity to evaluate chemical speciation dynamics of trace metals in solution for an accurate definition of their bioavailability to microorganisms. In contrast, the integration of intracellular metal speciation dynamics in biouptake formalisms is still in its early stages. Accordingly, we elaborate here a rationale for the interplay between chemodynamics of intracellular metal complexes and dynamics of processes governing metal biouptake under non-complexing outer medium conditions. These processes include the conductive diffusion of metal ions to the charged soft biointerphase, metal internalisation, excretion of intracellular free metal species and metal depletion from bulk solution. The theory is formulated from Nernst-Planck equations corrected for electrostatic and reaction kinetic terms applied at the biosurface and in the intracellular volume. Computational illustrations demonstrate how biointerfacial metal distribution dynamics inherently reflects the chemodynamic properties of intracellular complexes. In the practical limits of high and weak metal affinity to biosurface internalisation sites, the metal concentration profile is explicitly solved under conditions of strong intracellular complexing agents. Exact analytical expression is further developed for metal partitioning at equilibrium. This provides a way to evaluate the metal biopartition coefficient from refined analysis of bulk metal depletion measured at various cell concentrations. Depending on here defined dimensionless parameters involving rates of metal internalisation excretion and complex formation, the formalism defines the nature of the different kinetic regimes governing bulk metal depletion and biouptake. In particular, the conditions leading to an internalisation flux limited by diffusion as a result of demanding intracellular metal complexation are identified. PMID- 27781225 TI - White luminescence achieved by a multiple thermochromic emission in a hybrid organic-inorganic compound based on 3-picolylamine and copper(i) iodide. AB - Three copper(i) complexes have been obtained by the reaction of CuI with 3 picolylamine in acetonitrile solution and characterized by X-ray powder diffraction, both from synchrotron and laboratory radiation. Photophysical investigations in the solid state revealed highly efficient thermally-activated delayed fluorescence (TADF) with photoluminescence quantum yields (PLQYs) up to 18%. Notably, the complex [Cu2I2(3pica)]infinity displays a strong luminescence thermochromism due to the presence of both 1,3(X + M)LCT excited states and a lower-lying cluster-centered (3CC) one, leading to multiple emission at room temperature; as a result, a white luminescence is achieved with a PLQY of 4.5%. PMID- 27781226 TI - Synthesis and structure of pseudo-three dimensional hybrid iodobismuthate semiconductors. AB - The synthesis, structures and semiconducting properties of three isostructural, piperazinium-cation based iodobismuthates, [NH2(CH2)4NH2][BiI4]2.4H2O, [CH3NH(CH2)4NH2][BiI4]2.3H2O and [CH3NH(CH2)4HNCH3][BiI4]2.2H2O, are reported. The materials have pseudo-three dimensional structures consisting of infinite chains formed from edge/face sharing [BiI6] octahedra with short interchain II interactions of <3.8 A. The materials have band gaps of ~1.9-2.0 eV and show variable optoelectronic properties based on the degree of methylation of the templating piperazinium ring-based organic species and the accordingly associated level of solvation in the structure. PMID- 27781227 TI - On the tree-like structure of rings in dense solutions. AB - One of the most challenging problems in polymer physics is providing a theoretical description for the behaviour of rings in dense solutions and melts. Although it is nowadays well established that the overall size of a ring in these conditions scales like that of a collapsed globule, there is compelling evidence that rings may exhibit ramified and tree-like conformations. In this work I show how to characterise these local tree-like structures by measuring the local writhing of the rings' segments and by identifying the patterns of intra-chain contacts. These quantities reveal two major topological structures: loops and terminal branches which strongly suggest that the strictly double-folded "lattice animal" picture for rings in the melt may be replaced by a more relaxed tree-like structure accommodating loops. In particular, I show that one can identify hierarchically looped structures whose degree increases linearly with the size of a ring, and that terminal branches are found to store about 30% of the whole ring mass, irrespectively of its length. Finally, I draw an analogy between rings in the melt and slip-linked chains, where contact points are enforced by mobile slip links and for which a field-theoretic treatment can be employed to get some insight into their typical conformations. These findings are ultimately discussed in the light of recent works on the static structure of rings and on the existence of inter-ring threadings. PMID- 27781228 TI - AXXTe12 (A = Rb, Cs; XII = Mn, Zn, Cd; XIII = Ga, In): quaternary semiconducting tellurides with very low thermal conductivities. AB - The discovery of novel materials with very low thermal conductivity is paramount to improving the efficiency of thermoelectric devices. Here we present a series of quaternary semiconducting tellurides AXXTe12 (A = Rb, Cs; XII = Mn, Zn, Cd; XIII = Ga, In) with three-dimensional (3D) diamond-like frameworks (DLFs) and they exhibit a very low thermal conductivity (ca. 0.26-0.42 W m-1 K-1) around 800 K. PMID- 27781229 TI - Electrostatics-mediated alpha-chymotrypsin inhibition by functionalized single walled carbon nanotubes. AB - The alpha-chymotrypsin (alpha-ChT) enzyme is extensively used for studying nanomaterial-induced enzymatic activity inhibition. A recent experimental study reported that carboxylized carbon nanotubes (CNTs) played an important role in regulating the alpha-ChT activity. In this study, parallel tempering Monte Carlo and molecular dynamics simulations were combined to elucidate the interactions between alpha-ChT and CNTs in relation to the CNT functional group density. The simulation results indicate that the adsorption and the driving force of alpha ChT on different CNTs are contingent on the carboxyl density. Meanwhile, minor secondary structural changes are observed in adsorption processes. It is revealed that alpha-ChT interacts with pristine CNTs through hydrophobic forces and exhibits a non-competitive characteristic with the active site facing towards the solution; while it binds to carboxylized CNTs with the active pocket through a dominant electrostatic association, which causes enzymatic activity inhibition in a competitive-like mode. These findings are in line with experimental results, and well interpret the activity inhibition of alpha-ChT at the molecular level. Moreover, this study would shed light on the detailed mechanism of specific recognition and regulation of alpha-ChT by other functionalized nanomaterials. PMID- 27781230 TI - Bio-inspired photonic crystals with superwettability. AB - Photonic crystals (PCs) have attracted enormous research interest due to their unique light manipulation and potential applications in sensing, catalysts, detection, displays, solar cells and other fields. In particular, many novel applications of PCs are derived from their surface wettability. Generally, the wettability of PCs is determined by a combination of its surface geometrical structures and surface chemical compositions. This review focuses on the recent developments in the mechanism, fabrication and application of bio-inspired PCs with superwettability. It includes information on constructing superwetting PCs based on designing the topographical structure and regulating the surface chemical composition, and information on extending the practical applications of superwetting PCs in humidity/oil/solvent sensing, actuating, anti-fouling and liquid-impermeable surface, chemical detection, etc. PMID- 27781231 TI - Genistein promotes the metabolic transformation of acetaminophen to glucuronic acid in human L-O2, HepG2 and Hep3b cells via the Nrf2/Keap1 pathway. AB - This study aimed to explore the effects of genistein on regulating the activation of UGTs via the Nrf2/Keap1 pathway and to elucidate the underlying mechanisms of detoxification and hepatic protection. Experiments monitoring genistein-induced protection against acetaminophen-induced cell damage were performed in L-02, HepG2 and Hep3b cells. The results of the MTT, AST, ALT, LDH, GSH and GSSG assays showed that genistein evidently protected the cells from acetaminophen-induced injury in a dose-dependent manner. The control cells were treated with 10 mM acetaminophen without genistein to compare with the effects of the combination of acetaminophen and genistein on the expression of UGT1A1, 1A6 and 1A9, Nrf2 and Keap1 mRNAs, as well as the expression of Nrf2 and Keap1 proteins, which were tested by western blotting. The results showed that the expression of the Nrf2 mRNA and protein increased; in contrast, the expression levels of the Keap1 mRNA and protein were obviously reduced by genistein in a dose-dependent manner. Meanwhile, the expression of the UGT mRNA was increased, and UGT1A9 exhibited the highest expression among the three UGTs. Accordingly, the residual acetaminophen content was obviously reduced and acetaminophen glucuronidation increased after 24 hours of treatment with genistein in a dose-dependent manner. PMID- 27781232 TI - Fabrication and notable optical nonlinearities of ultrathin composite films derived from water-soluble Keggin-type polyoxometalates and water-insoluble phthalocyanine. AB - Composite films with the general formula (POM/CuTAPc)n derived from water-soluble Keggin-type polyoxometalates (POMs = H5PMo10V2O40, H4SiW12O40, H3PMo12O40 and H3PW12O40) and water-insoluble 4,9,16,23-copper tetraaminophthalocyanine (denoted CuTAPc) are successfully fabricated by a layer-by-layer self-assembly technique and systematically characterized. The structure of the polyoxometalate anions in the multilayers is kept intact; the deposition amounts of POM and CuTAPc remain constant in every adsorption cycle of the composite film assembly process. The nonlinear optical properties of the composite films were studied by a Z-scan technique at a wavelength of 532 nm and a pulse width of 7 ns. The results not only show that the composite films exhibit notable optical nonlinear self defocusing behavior and a saturated absorption effect with the nonlinear optical absorption co-efficient beta, refractive index n2, and third-order NLO susceptibility chi(3) of the films increasing with the increase in number of layers of the films, but also reveal importantly that the discrepancy of LUMO levels between CuTAPc and POMs is proportional to their third-order NLO response. PMID- 27781233 TI - Should "anion-pi interactions" be called "anion-sigma interactions"? A revision of the origin of some hole-bonds and their nomenclature. AB - The so-called anion-pi interactions are dissected to test if indeed the pi system of the aromatic ring is the reason for the bond. In contrast, due to sigma-holes the sigma system is found to be responsible for a "pseudo-pi hole" interaction. Models that form genuine anion-pi bonds are discussed. PMID- 27781234 TI - 1-(3,5-Dinitro-1H-pyrazol-4-yl)-3-nitro-1H-1,2,4-triazol-5-amine (HCPT) and its energetic salts: highly thermally stable energetic materials with high performance. AB - A novel energetic heat-resistant explosive, 1-(3,5-dinitro-1H-pyrazol-4-yl)-3 nitro-1H-1,2,4-triazol-5-amine (HCPT), has been synthesized along with its salts. An intensive characterization of the compounds is given, including 1H and 13C NMR spectroscopy, IR spectroscopy, and elemental analysis. The crystal structures of neutral HCPT (3), its triaminoguanidinium salt (10), 3,4,5-triamino-1,2,4 triazolium salt (12), and copper(ii) complex (16) were determined by single crystal X-ray diffraction. The physicochemical properties of the compounds, such as density, thermal stability, and sensitivity towards impact and friction were evaluated; all energetic compounds exhibited excellent thermal stabilities with decomposition temperatures ranging from 215 degrees C to 340 degrees C, and high positive heats of formation between 622.8 kJ mol-1 and 1211.7 kJ mol-1. The detonation pressures and velocities for the energetic compounds were calculated using EXPLO5 (V6.01) based on experimental densities and calculated heats of formation, and the corresponding values were in the ranges of 26.5 GPa to 37.8 GPa and 8236 m s-1 to 9167 m s-1. Based on thermal stability values and energetic parameters, compounds 3 and 7 were superior to those of all of the commonly used heat-resistant explosives, which may find potential application as heat-resistant energetic materials. PMID- 27781235 TI - Alcohol oxidation with H2O2 catalyzed by a cheap and promptly available imine based iron complex. AB - We previously reported that the iminopyridine iron(ii) complex 1, easily and quantitatively obtainable in situ, can activate H2O2 to form a powerful oxidant, capable of aliphatic C-H bond hydroxylation. In the present study we expand the application of this catalyst to the oxidation of a series of alcohols to the corresponding carbonyl compounds. The oxidation of aliphatic alcohols proceeds smoothly, while that of benzylic alcohols is shown to be challenging. Some collected pieces of evidence suggest a preference of the oxidizing species for the aromatic ring instead for the alcoholic moiety. The decrease of the electron density in the aromatic ring shifts the oxidation from the aromatic towards the alcoholic moiety. Quite surprisingly, preferential oxidation of cyclohexanol versus benzylic alcohol was achieved, showing unprecedented selectivity. PMID- 27781236 TI - Synthesis and structural characterization of iron complexes bearing N-aryl phenanthren-o-iminoquinone ligands. AB - Treatments of N-aryl-phenanthren-o-iminoquinone (aryl = 2,6-Me2C6H3 (MeL); 2,6 iPr2C6H3 (iPrL)) with iron powder in THF at 75 degrees C generate complexes [eta2L]2Fe[eta1LH] (1a, L = MeL; 1b, L = iPrL) in moderate yields. The X-ray crystallography analysis reveals that the molecule of 1b consists of a Fe(iii) center coordinated by three phenanthren-o-iminosemiquinone ligands, two of which are in an eta2 fashion while the remaining one is in an eta1 fashion. The analysis of the bond parameters of ligands indicates that the eta2-fashioned ligands are radical anions and the eta1-fashioned one is in an aminephenolato form. Reactions of MeL and iPrL with FeCl2 in THF produce Fe(iii) complexes [L]2FeCl (2a, L = MeL; 2b, L = iPrL) with the two ligands in the radical anionic form. However, similar reactions of PIQ ligands with FeCl2 in CH2Cl2 yield ion pair complexes {[L]2FeCl}+[FeCl4]- (3a, L = MeL; 3b, L = iPrL), in which the iron center chelated by two neutral ligands can be formulated as Fe(ii). Reduction of 2b with sodium provides a salt-type complex [iPrL2-]2Fe(ii)Na2 (4), in which a high spin Fe(ii) atom is ligated by two amidophenolate ligands, and the sodium atoms attached to the oxygen atoms of ligands are eta3-coordinated by the aryl ring in amido moieties. PMID- 27781237 TI - Comparison of clonogenic cell survival and DNA damage induced by 188Re and X-rays in rat thyroid cells. AB - AIM: Ionizing radiation produces DNA lesions among which DNA double strand breaks (DSB) are the most critical events. Radiation of various energy types might differ in their biological effectiveness. Here, we compared cell survival and DNA damage induced by 188Re and X-rays using gammaH2AX foci as a measure of DSB. The correlation between survival and residual foci was also analyzed. METHODS: PCCl3 cells were irradiated with 200 kV X-rays (1.2 Gy/min) or 0.5-25 MBq/ml 188Re (1 h irradiation) achieving doses up to 10 Gy. By blocking of sodium iodide symporter (NIS) essentially extracellular activity could be guaranteed. Survival fractions (SF) were detected by colony forming assay. Initial and residual gammaH2AX foci (15 min and 24 h after irradiation) were assessed by immunostaining. The relationship between SF and residual radiation induced gammaH2AX foci (RIF) was evaluated by Spearman and Pearson correlation tests. RESULTS: We did not find significant differences between the survival curves in terms of the radiation quality. The D37 values were 4.6 Gy and 4.2 Gy for 188Re or X-ray, respectively. The initial foci numbers were in the same range for 188Re and X-ray, but higher levels of residual foci persisted after X-rays in comparison to 188Re (1 GyX-ray 6.5 +/- 0.2; 1 GyRe-188 4.8 +/- 0.2 RIF). Accordingly, for 188Re a higher extent of DSB repair was found. The Spearman test revealed a significant (p < 0.01) correlation between SF and residual RIF for both radiation modalities. CONCLUSION: No differences in terms of radiation were found for SF and initial foci. However, residual foci were lower for 188Re than for X-rays. A prediction of SF by residual foci should consider the properties of the radiation qualities that influence foci removal and DSB repair. PMID- 27781239 TI - [The third component in surgical anatomy and its impacts]. AB - Surgical or local anatomy consists of two components conventionally, organs and their blood supply. In fact, they are enveloped by the fascia membrane and serous membrane. This is the third component in surgical or local anatomy, which is omitted by surgeons for many years. The omitted reasons are failed recognition and unknown function. Re-understanding of the third component in surgical or local anatomy will make some changes in the local anatomy, tumor pathology, oncology surgery and operations. Firstly, the third component makes surgical anatomy developed from organ anatomy, blood vessel anatomy to membrane anatomy, which consists of the mesentery in broad sense and its bed, both include serous membrane and fascia membrane. Secondly, the third component provides the basic membrane anatomy of envelop cavity of metastasis V, and the impairment of its integrity will induce the mesentery cancer leakage of metastasis V in the operation field. Thirdly, based on the development of anatomy and pathology of the third component, cancer of alimentary tract can be divided into 3 types, the cancer in the mesentery, the cancer at the mesentery edge and the cancer outside the mesentery. Cancer outside the mesentery is in the field of oncology except complication of primary lesion, such as bleeding, perforation and obstruction. The main task of surgeons is to prevent the cancer leakage during operation, improve the cancer at the mesentery edge and perform radical operation for the cancer in the mesentery. Finally, the principle of radical operation for the cancer of alimentary tract should include the primary lesion resection, systematical lymphadenectomy and complete mesentery excision. Therefore, these principles should be classified into three kinds:(1) D type operation, which is only the concern about lymphadenectomy at D2 or D3 level and does not care about the completeness of the mesentery; (2) C type operation, which is only the concern about completeness of the mesentery, with only high tie of blood vessels, which does not care about ligation at the bifurcation; (3) D+C type operation, which is not only the concern about ligation at the bifurcation, but also about the completeness of the mesentery. Many aspects will change with surgical developments, especially with the membrane anatomy, the third component. PMID- 27781238 TI - Improving Individual Acceptance of Health Clouds through Confidentiality Assurance. AB - BACKGROUND: Cloud computing promises to essentially improve healthcare delivery performance. However, shifting sensitive medical records to third-party cloud providers could create an adoption hurdle because of security and privacy concerns. OBJECTIVES: This study examines the effect of confidentiality assurance in a cloud-computing environment on individuals' willingness to accept the infrastructure for inter-organizational sharing of medical data. METHODS: We empirically investigate our research question by a survey with over 260 full responses. For the setting with a high confidentiality assurance, we base on a recent multi-cloud architecture which provides very high confidentiality assurance through a secret-sharing mechanism: Health information is cryptographically encoded and distributed in a way that no single and no small group of cloud providers is able to decode it. RESULTS: Our results indicate the importance of confidentiality assurance in individuals' acceptance of health clouds for sensitive medical data. Specifically, this finding holds for a variety of practically relevant circumstances, i.e., in the absence and despite the presence of conventional offline alternatives and along with pseudonymization. On the other hand, we do not find support for the effect of confidentiality assurance in individuals' acceptance of health clouds for non-sensitive medical data. These results could support the process of privacy engineering for health cloud solutions. PMID- 27781240 TI - [Anatomical structures relevant to complete mesocolic excision: mesentery, fascia and space]. AB - Anatomy is the foundation of surgical techniques. With the development of surgery, anatomy also divided into traditional anatomy, surgical anatomy and embryonic development anatomy. Complete mesocolic excision (CME) is one of classic radical operation for colon cancer, based on the modern anatomy. CME advocates correct operation plane, and describes the mobilization and separation of the colon together with the entire regional mesocolon. With the evolution of anatomy, the definition and content of CME-related anatomic landmarks such as mesentery, fascia and space have been changed. This article elaborates theses anatomical structures and their distribution, in order to improve the understanding of colorectal surgeons on CME-related traditional anatomy, surgical anatomy and embryonic developmental anatomy. PMID- 27781242 TI - [The further understanding of Denonvilliers fascia based on "Fascial Surgery"]. AB - Denonvilliers fascia is a dense structure between the rectum and the genitourinary system, and plays as a barrier. In recent years, along with in depth study of TME, scholars have taken many discussions on Denonvilliers fascia structure and the dissection plane. On the one hand, some consensus have been made on Denonvilliers fascia structure, but still needs to further clarify its microstructure. On the other hand, scholars have generally recognized the neurovascular bundles are on Denonvilliers fascia sides. They should be protected during rectal surgery, however, the details should be clarified. Based on "Fascial Surgery" theory, this article describes Denonvilliers fascia structure and clinical application combined with previous research and our research results. PMID- 27781241 TI - [Laparoscopic total mesorectum excision with the guidance of membrane anatomy]. AB - The efficacy of laparoscopic total mesorectum excision (TME) has been confirmed by many clinical trials and guidelines. But two issues on laparoscopic TME are still questioned, including the integrity of specimen membrane of TME and the incidence of postoperative sexual dysfunction. According to my experiences and the primary results of the multicenter clinical trial (LASRE, clinicaltrials.gov identifier: NCT01899547) conducted by me, the integrity of the specimen membrane of laparoscopic TME is not inferior to the open TME. With the further understanding of surgical membrane anatomy, the quality of surgical specimen after laparoscopic TME could be improved, and the incidence of postoperative sexual dysfunction could be lowered. With the combination of my laparoscopic experiences and the theory of surgical membrane anatomy, this article introduces the peri-rectal space dissection during TME and its relationship with the membrane anatomy for reference. It suggests that laparoscopic TME should be performed with the guidelines of surgical membrane anatomy: (1) To cut membrane bridge of left para-rectal furrow and enter left retroperitoneal space; (2) Along the autonomic nerve, to separate retrorectal space first, then rectal front space, and bilateral rectal space finally; (3) To cut anterior lobe of Denonvilliers fascia using U shape 0.5 to 1 cm away from the bottom of seminal vesicle, if existence of tumor invasion in fascia, to separate downward in front; (4) To separate mesorectum to the edge of hiatus of levator ani muscle and then bare. PMID- 27781243 TI - [Application of en-bloc mesogastric excision in the treatment of advanced gastric cancer]. AB - OBJECTIVE: To evaluate the value of en-bloc mesogastric excision (EME) in the treatment of advanced gastric cancer. METHODS: A retrospective analysis on clinical data of 98 gastric cancer patients who underwent total gastrectomy in China-Japan Union Hospital of Jilin University from January 2013 to December 2015 was carried out, including EME group of 48 cases (according to the mesangial space) and D2 radical group of 50 cases(D2 lymphadenectomy according to the vascular markers). Operations were performed by the same single surgeon team. Surgical indexes and recent efficacy indexes were compared between two groups. RESULTS: General informations pertaining to two groups were comparable (P>0.05). All the operations were performed successfully. Compared with D2 radical group, EME group had a shorter operative time [(155.3+/-13.6) vs. (171.2+/-14.9) minutes, P=0.012] and less intraoperative blood loss [(95.1+/-19.5) vs.(122.6+/ 28.0) milliliters, P=0.011]. There were no significant differences in the number of harvested lymph node (30.8+/-3.9 vs. 31.5+/-4.7, P=0.675), time to postoperative bowel function return [(3.2+/-1.2) vs.(3.9+/-1.4) days, P=0.179], postoperative hospital stay [(10.9+/-2.7) vs.(11.3+/-3.2) days, P=0.788], and the incidence of postoperative complication [8.3% vs. 10.0%, P=0.775]. During the follow-up of 1 year, all the patients had no long-term complications, no tumor recurrence or death. CONCLUSIONS: For advanced gastric cancer, EME result in the same clinical efficacy compared with standard D2 resection. At the same time, EME can shorten the operative time and reduce the intraoperative blood loss, which is a new technology and worthy promoting. PMID- 27781244 TI - [Efficacy of complete mesocolic excision in radical operation for right colon cancer]. AB - OBJECTIVE: To investigate the efficacy of complete mesocolic excision (CME) in the radical operation for right hemicolon cancer. METHODS: Clinical data of 336 cases of right hemicolon cancer undergoing radical resection, including 218 cases of CME surgery group and 118 cases of traditional surgery group, from January 2005 to December 2014 in Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University were retrospectively analyzed. Intraoperational events, perioperative status and postoperative survival were compared between the two groups. RESULTS: The baseline information was not significantly different between the two groups (all P>0.05). The number of harvested lymph nodes in CME and traditional group was 11.4+/-0.3 and 9.3+/-0.5 respectively(P=0.000) and the proportion of greater than or equal to 12 lymph nodes per case was 47.3%(103/218) and 28.8%(34/118)(P=0.002), which both were significantly different. The operation time in CME and traditional group was (147.2+/-2.9) and (148.8+/-3.9) minutes, which was not significantly different (P>0.05), whereas operative blood loss was (125.7+/-7.5) and (305.1+/-20.5) milliliters in CME and traditional group with significant difference (P=0.000). Postoperative hospital stay was (12.9+/-0.9) and (16.3+/-1.0) days in CME and traditional group with significant difference (P=0.018), while the time to postoperative liquid intake and normal diet was not significantly different between two groups (both P>0.05). The morbidity of postoperative complication of CME group was lower compared to traditional group (14.2%, 31/218 vs. 24.6%, 29/118), which was significantly different (P=0.018). Among them, infection occurred in 19 (8.7%) cases and 21 (17.8%) cases with significant difference between the two groups (P=0.014). The average time of follow-up was (34.5+/-1.2) months and (27.9+/-1.5) months in CME and traditional group, and the five-year survival rate was 85.6% and 78.0% with significant difference(P=0.043). Moreover, 102 cases underwent laparoscopic-assisted CME and 116 cases underwent open CME in CME group. The 5-year survival rate was 89.8% and 82.2% in laparoscopic and open group with significant difference (P=0.048). CONCLUSION: Compared with traditional radical resection, CME radical resection for right hemicolon cancer can harvest more lymph nodes, decrease operative blood loss, lower the riskof postoperative complication, shorten the postoperative hospital stay, and increase the 5-year survival rate. Furthermore, laparoscopic-assisted CME has more advantages. PMID- 27781245 TI - [Comparison of three lymph node staging systems in predicting overall survival for gastric cancer patients after radical resection]. AB - OBJECTIVES: To compare the prognostic value of three lymph node(N) staging systems, including the number of metastatic lymph nodes(pN), the metastatic lymph node ratio (Nr) and the log odds of positive lymph nodes (LODDS), in gastric cancer patients after radical resection. METHODS: Clinical and pathological data of 1 796 patients who underwent gastric cancer radical resection with complete follow-up information from January 2000 to December 2010 at Sun Yat-sen University Cancer Center were retrospectively analyzed. For each patient, N stages were classified according to three lymph node staging systems (pN, Nr, and LODDS). The relationship between each N staging was examined. Survival was analyzed using the Cox's proportional hazard model, and discrimination of staging system was determined using the change value of Chi squared statistic (?chi2) from the log-likelihood test. A larger ?chi2 value indicates a better discriminatory ability. The homogeneity of 5-year overall survival across each pN stage within each Nr and LODDS stage was compared by using the log-rank test. The subgroup analysis was performed to evaluate whether each of the competing system was affected by the number of lymph nodes retrieved. RESULTS: The mean number of lymph node examined and positive nodes in the entire cohort was 21.1+/-12.1 and 7.9+/-8.2,respectively. The median overall survival of all the patients was 45 months (95% CI: 42.6 to 47.4 months), and the 5-year survival rate was 55.0%(95% CI: 52.6% to 57.4%). The ?chi2 of Nr system was 198.546, which was higher than that of pN(191.255) and LODDS(196.557) system. Except for the pN3b stage, significant heterogeneity was found among patients of different Nr subcategories in 5-year overall survival rate (all P<0.05) within each pN stage. While there was no significant difference in overall survival when any of the Nr stages was stratified by pN stages(all P>0.05). Significant difference in survival among patients of different LODDS subcategories was also seen within each pN stage. But for the LODDS system, the survival rate was similar among patients of different pN subcategories (all P>0.05) apart from the LODDS3 stage. The hazard ratios of patients with insufficient lymph nodes examined (<=15) were higher than those with sufficient nodes examined (>15) when the pN classification was used (all P<0.05), whereas similar results were not found if the Nr or LODDS classification was applied. CONCLUSION: Compared with the pN staging system, both the Nr and LODDS staging system, especially the former, have a higher degree of discrimination ability and robustness to predict the prognosis in patients with gastric cancer after radical resection. PMID- 27781246 TI - [Influences of inferior mesenteric artery types and Riolan artery arcade absence on the incidence of anastomotic leakage after laparoscopic resection of rectal cancer]. AB - OBJECTIVE: To evaluate the influences of inferior mesenteric artery (IMA) types and Riolan artery arcade absence on the incidence of anastomotic leakage(AL) after laparoscopic resection of rectal cancer. METHODS: Clinical data of 116 local advanced rectal cancer patients who underwent laparoscopic resection in The Sixth Affiliated Hospital of Sun Yat-sen University from January 2012 to December 2014 were analyzed retrospectively. IMA and Riolan artery arcade were examined by preoperative computed tomography angiography (CTA) reconstruction. The influences of IMA type, Riolan artery arcade absence and ligation site (high or low) on AL were analyzed by Logistic regression. RESULTS: The proportion of IMA types(I( IIII() was 57.8%(67/116), 10.3%(12/116), 31.0%(36/116) and 0.9%(1/116), respectively. Riolan artery arcade absence was found in 60.3%(70/116). Eight (6.9%) patients suffered from AL. IMA type III( had significantly higher AL incidence as compared to other IMA types [19.4%(7/36) vs. 1.2%(1/80), P=0.001]. Meanwhile, patients with Riolan artery arcade absence also had significantly higher AL incidence[11.4%(8/70) vs. 0.0%(0/46), P=0.030]. However, the difference in AL incidence between high and Low IMA ligation was not statistically significant [8.0%(7/87) vs. 3.4%(1/29), P=0.531]. Seven of these 8 AL patients were found in IMA type III( with Riolan artery arcade absence and high ligation. Multivariate analysis showed that IMA type III( (P=0.001) and Riolan artery arcade absence (P=0.002) were independent risk factors of AL. CONCLUSIONS: IMA type III( with Riolan artery arcade absence increases AL incidence significantly in laparoscopic resection of rectal cancer. IMA type and Riolan aretry arcade absence or not contribute to the selection of IMA ligation site in the operation. For the colorectal cancer patients with IMA type III( and Riolan artery arcade absence, selective low IMA ligation with root lymph node dissection should be recommended. PMID- 27781247 TI - [Difference analysis of chemotherapy efficacy among different primary tumor sites in metastatic colorectal cancer]. AB - OBJECTIVE: To analyze the relationship between primary tumor location and clinical response of chemotherapy in patients with metastatic colorectal cancer(mCRC). METHODS: Clinical data of 721 mCRC patients who received first-line and second-line chemotherapy in Peking University Cancer Hospital between January 1996 and December 2011 were collected. All the patients were divided into 5 groups according to primary tumor location: ileocecum in 61 patients(8.5%), ascending colon or hepatic flexure in 126 patients (17.5%), transverse colon or splenic flexure in 26 patients (3.6%), descending or sigmoid colon in 172 patients (23.9%), rectum in 336 patients (46.6%). Outcomes of chemotherapy were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), including complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The overall response rate (ORR) was counted with the total number of patients divided by the number of CR+PR. Differences in first line and second-line chemotherapy efficacy among different primary tumor sites in metastatic colorectal cancer were compared by using Chi-square test. RESULTS: Of the 571 patients receiving first-line chemotherapy, no one patient was classified as CR, while there were 190 as PR (33.3%), 277 as SD (48.5%) and 104 as PD (18.2%), with ORR 33.3% (190/571). The ORRs of patients with primary tumor located at ileocecum, ascending colon or hepatic flexure, transverse colon or splenic flexure, descending or sigmoid colon, rectum were 21.3% (10/47), 35.3% (36/102), 14.3% (3/21), 41.3% (57/138) and 31.9% (84/263), respectively, with statistically significant difference(P = 0.028). Difference of oxaliplatin-based first-line chemotherapy efficacy among different tumor sites was statistically significant(P = 0.009), while differences in irinotecan-based or single-agent 5 fluorouracil chemotherapy efficacy were not statistically significant (all P>0.05). In patients with primary tumor located at transverse colon or splenic flexure, irinotecan-based first-line chemotherapy had higher ORR than oxaliplatin based or single-agent 5-fluorouracil chemotherapy, and the difference was statistically significant (P=0.042). There was no significant difference in the efficacy of different first-line chemotherapy regimens in patients with primary tumor located at other sites (all P>0.05). Of the 353 patients receiving second line chemotherapy, no one patient was classified as CR, while there were 43 as PR (12.2%), 187 as SD (53.0%) and 123 as PD (34.8%), with ORR 12.2%(43/353). The ORRs of patients with primary tumor located at the ileocecum, the ascending colon or the hepatic flexure, the transverse colon or the splenic flexure, the descending or sigmoid colon, the rectum were 4.2%(1/24), 12.1%(8/66), 8.3%(1/12), 15.2%(12/79) and 12.3%(21/171) respectively, without statistically significant difference (P=0.686). Differences in second-line chemotherapy efficacy with the same regimen among different tumor sites were not statistically significant, and there were also no significant differences of efficacy of different second-line chemotherapy regimens in patients with the same tumor site (all P>0.05). CONCLUSION: There are differences in first-line chemotherapy efficacy among different primary tumor sites in metastatic colorectal cancer, while their second line chemotherapy efficacy is equivalent. PMID- 27781248 TI - [Application of multidisciplinary treatment in patients with liver metastasis of colorectal cancer]. AB - OBJECTIVE: To evaluate the application of multidisciplinary treatment (MDT) in patients with liver metastasis of colorectal cancer(CLM). METHODS: Clinical data of 118 patients with liver metastasis of colorectal cancer, including 32 patients with MDT (MDT group) and 86 patients without MDT (control group), from February 2014 to April 2015 in PLA General Hospital were analyzed retrospectively. Compliance of preoperative examination and adjuvant therapy, and efficacy associated indexes were compared between the two groups. RESULTS: (1) As compared to control group, statistically significant increase in imaging examination ratio was found in MDT group: chest CT [87.5%(28/32) vs. 40.7%(35/86), P=0.0000], abdominal MRI [84.4%(27/32) vs.61.6%(53/86), P=0.019], pelvic MRI [63.7%(7/11) vs. 24.3%(8/33), P=0.017]. The preoperative assessment of TNM staging was also higher in MDT group [100%(32/32) vs. 20.9%(18/86), P=0.0000], while there was no significant difference in accuracy rate of TNM staging between the two groups [81.3%(26/32) vs. 66.7%(12/18), P=0.2465]. (2) Rates of preoperative chemotherapy and chemotherapy completion were also higher in MDT group than those in control group [90.6%(29/32) vs. 62.8%(54/86), P=0.0033; 82.8% (24/29) vs. 57.4% (31/54), P=0.000], but conversion rate of unresectable CLM showed no significant difference [24.0% (6/25) vs. 14.3% (7/49), P=0.299 ]. (3) Rate of one-stage resection or ablation was higher in MDT group compared to control group [76.9%(10/13) vs. 36.0%(9/25), P=0.038], and resection rate of metastasis nidus was also higher in MDT group [77.0%(20/26) vs. 44.9%(13/29), P=0.015]. No significant differences were observed in rates of R0 resection, positive surgical margin, lymph node clearance, ablation of metastasis nidus, pathological complete response, postoperative chemotherapy or postoperative complications (all P>0.05). CONCLUSION: MDT has the advantages on standardization of preoperative examination and perioperative chemotherapy, and can improve the rate of one-stage resection or ablation, as well as resection of metastasis nidus. PMID- 27781249 TI - [Can the weekday of surgery influence the prognosis of colorectal cancer patients? A retrospective study based on a single-center of large sample]. AB - OBJECTIVE: To investigate the impact of the weekday of surgery on the prognosis of patients with colorectal cancer. METHODS: A retrospective analysis was conducted in patients with colorectal cancer who underwent radical resection in Fudan University Shanghai Cancer Center(FUSCC) between January 2007 and December 2013, and 4 971 patients were identified eligible. Statistical analyses were carried out between patients who received surgery on Monday to Thursday and those who received surgery on Friday. Chi-square test was used to analyze the relationship between clinicopathological parameters and day of surgery. T test was used to compare continuous variables between groups. The 5-year overall survival (OS) and disease-free survival (DFS) were calculated by the Kaplan-Meier method, and compared by log-rank test. RESULTS: There were no statistically significant differences between two groups in age, gender and pathological grade et al (all P>0.05). However, the number of dissected lymph node was higher in patients who received surgery on Monday to Thursday (median 16) compared with patients who received surgery on Friday (median 14), with statistically significant difference (P=0.038). The 5-year OS and DFS in all eligible patients were 78.0% and 55.0%, respectively. 5-year OS of patients in Monday to Thursday surgery group and Friday surgery group was 79.6% and 77.2%, while 5-year DFS in two groups was 57.8% and 50.4%. There were no significant differences in OS and DFS between two group, with P=0.882 and P=0.210, respectively. Subgroup analyses were conducted according to different pathological stages. 5-year OS of patients at stage I( in Monday to Thursday surgery group and Friday surgery group was 94.7% and 90.6% (P=0.742) and 5-year DFS was 85.1% and 78.2% (P=0.765). 5-year OS of patients at stage II( in two groups was 85.5% and 83.7% (P=0.496) and 5-year DFS was 72.7% and 62.8% (P=0.121). 5-year OS of patients at stage III( in two groups was 69.7% and 69.4%(P=0.354) and 5-year DFS was 41.8% and 37.4% (P=0.976). No statistically significant differences manifested in subgroup analyses. CONCLUSION: Patients with colorectal cancer undergoing surgery on Monday to Thursday have similar long-term prognosis with those on Friday. PMID- 27781250 TI - [Predictive value of Glasgow prognostic score in patients with colorectal cancer undergoing laparoscopic radical resection]. AB - OBJECTIVE: To investigate the predictive value of preoperative Glasgow prognostic score (GPS) for the postoperative complications and survival in patients with colorectal cancer (CRC) undergoing laparoscopic radical resection. METHODS: This retrospective study was conducted in the Beijing Hospital between January 2009 and January 2012. A total of 228 patients with primary CRC undergoing laparoscopic radical resection were analyzed. The GPS was constructed based on routine preoperative blood tests of C-reactive protein and serum albumin. The patients were classified into three groups according to GPS (GPS 0, 1, 2 groups). Survival curves were described by the Kaplan-Meier method and compared by the Log rank test. The univariate and multivariate analyses were performed with the Cox proportional hazard model to identify the influence of GPS on prognosis in patients with CRC undergoing laparoscopic radical resection. RESULTS: Preoperative CRP level was increased in 48 cases (21.1%), and preoperative serum albumin level was decreased in 104 cases (45.6%) in the whole group. These 228 patients were classified into 99, 105 and 24 patients in GPS 0, 1, 2 group respectively. GPS was significantly associated with age, preoperative body mass index (BMI), carcinoembryonic antigen (CEA), CA19-9, tumor location, tumor differentiation and TNM stage (all P<0.05). Postoperative complication rates of GPS 0, 1, 2 group were 6.1%, 14.3% and 70.8% respectively (chi2=59.147, P=0.000). Serious postoperative complication rates were 3.0%, 6.7% and 58.3% respectively (chi2=65.807, P=0.000). Univariate and multivariate analyses revealed that GPS was an independent risk factor of postoperative complications(HR=21.611, 95%CI: 5.936-78.681, P=0.000) and severe complications (HR=35.833, 95%CI: 7.364-174.355, P = 0.000). The 5-year survival rate was 50% and the average total survival time was 58.2 (95% CI: 54.6-61.7) months in the whole group. The median overall survival time in GPS 0, 1, 2 group was 74.6(95%CI: 70.4-78.7) months, 49.8(95%CI: 45.2-54.4) months and 27.8 (95%CI: 21.8-33.8) months respectively(chi2=98.425, P=0.000). The median disease-free survival time was 73.9(95%CI: 69.2-78.7) months, 47.4 (95% CI: 41.6-53.1) months and 19.9 (95%CI: 14.8-25.0) months respectively (chi2=91.305, P=0.000). GPS was an independent risk factor of disease-free survival (HR=4.840, 95%CI: 2.413-9.709, P=0.000) and overall survival (HR=6.267, 95%CI: 3.073-12.784, P=0.000). CONCLUSIONS: GPS can be used as an effective predictor of the prognosis for patients with CRC undergoing laparoscopic radical surgery. Higher GPS suggests more postoperative complications and worse prognosis. PMID- 27781251 TI - [Analysis of screening for colorectal cancer high-risk groups in Harbin, China 2012-2015]. AB - OBJECTIVE: To evaluate the result of colorectal cancer screening for high-risk groups in Harbin, China from 2012 to 2015. METHODS: According to the Project of National Colorectal Cancer Screening in Urban Area, epidemiological investigation and cancer risk evaluation established by National Cancer Center were performed among 40-69 years old residents in Harbin. Questionnaires were issued to assess high-risk groups for clinical screening, including colonoscope examination. The results of colorectal screening were evaluated in detail. RESULTS: Project of Colorectal Cancer Screening in Urban Area was completed successfully from 2012 to 2015 in various districts of Harbin. The accomplishment of high-risk assessment included 3 017 people, while 2 996 people received the clinical screening, including 1 376 males and 1 629 females, from 40 to 69 (53.3+/-7.1) years old. Among 2 996 people, 1 158 cases of colorectal polyps(38.7%) were screened, including 36.6%(901/2 465) cases of age<60 and 48.4%(257/531) cases of age>60 years old with significant difference (chi2=19.19, P<0.01), and 47.6% (651/1 367) cases of male and 31.1%(507/1 629) cases of female with significant difference (chi2=85.33, P<0.01). Of 1 158 polyps patients, 141 received the pathological examination and 11 patients were diagnosed as colorectal cancer, accounting for 0.4% of overall screening people (11/2 996). All these 11 patients underwent operation by advice and the postoperative pathology results all indicated early adenocarcinoma. Furthermore, among 141 polyps patients, 97 cases of tubular adenoma were found, which were distributed as follows: 2 cases of cecum (2.1%), 14 cases of ascending colon(14.4%), 12 cases of transverse colon (12.4%), 15 cases of descending colon (15.5%), 35 cases of sigmoid colon (36.1%) and 19 cases of rectum(19.6%). CONCLUSION: With the increase in age, the risk of colorectal polyps is significantly elevated. The males have higher incidence of colorectal polyps than the females. Adenoma mainly locates in the distal colon and rectum, especially in the sigmoid colon. Early screening for high-risk group can find out colorectal precancerosis and cancer, so the patients can receive early treatment. PMID- 27781252 TI - [Impact of preoperative lymphocyte to monocyte ratio on the prognosis of the elderly patients with stage II(-III( gastric cancer]. AB - OBJECTIVE: To investigate the impact of preoperative lymphocyte to monocyte ratio on the prognosis of elderly patients with stage II(-III( gastric cancer. METHODS: Clinicopathological data of 188 patients with stage II(-III( gastric cancer aged>=75 years undergoing radical gastrectomy in our department from January 2007 to December 2011 were analyzed retrospectively. The optimal critical value of preoperative peripheral blood LMR in prediction of overall survival was determined through the receiver-operating characteristic (ROC) curve analysis. According to the critical value, patients were divided into the low LMR group and high LMR group. Clinicopathological features and prognosis were compared between the two groups. Univariate and multivariate analyses were performed to evaluate the clinical factors affecting prognosis with Cox proportional hazard model. RESULTS: ROC curve revealed the optimal critical value of preoperative peripheral blood LMR in prediction of overall survival was 4.34, then 71 cases were divided into the low LMR group (<4.34) and 117 cases into high LMR group (>=4.34). The low LMR group had greater tumor size (P=0.015) and higher level of carcinoembryonic antigen (CEA) (P=0.018) as compared to the high LMR group, and other clinicopathological parameters were not significantly different (all P>0.05). Median follow-up time of all the 188 patients was 21.8 (1.3 to 92.9) months. The 3-year survival rate of the low and high LMR groups was 36.8% and 45.1% respectively with significant difference (P=0.001). Univariate analysis revealed that the postoperative overall survival was associated with the preoperative LMR (P<0.001), absolute count of lymphocyte (P=0.002), absolute count of monocyte (P=0.016), CEA level (P=0.011), CA199 level (P=0.003), lymph node metastasis (P<0.001), tumor maximal size (P<0.001), TNM stage (P<0.001), postoperative adjuvant chemotherapy (P=0.004). Multivariate analysis revealed that the TNM stage III( (HR:2.708, 95%CI:1.356 to 5.411, P=0.005), tumor maximal size>=50 mm (HR: 1.737, 95%CI: 1.114 to 2.709, P=0.015), without postoperative adjuvant chemotherapy (HR: 0.651, 95%CI: 0.440 to 0.961, P=0.031), and preoperative peripheral blood LMR<4.34 (HR: 0.600, 95%CI: 0.376 to 0.958, P=0.032) were independent risk factors of prognosis. CONCLUSIONS: Preoperative peripheral blood LMR level possesses good predictive value of prognosis for the elderly patients with stage II(-III( gastric cancer. Low LMR is associated with poor outcomes. PMID- 27781253 TI - [Value of CT perfusion imaging in differential diagnosis between Borrmann types II( and III( gastric cancer]. AB - OBJECTIVE: To investigate the value of CT perfusion imaging in differential diagnosis between Borrmann types II( and III( gastric cancer. METHODS: All the patients were proven as ulcerated gastric cancer by preoperative gastroscopy and underwent CT perfusion scanning with Aquilion ONE 320 spiral CT from October 2013 to June 2014 in The First Affiliated Hospital of Zhengzhou University, including 19 patients as Borrmann type II( gastric cancer and 23 patients as Borrmann type III( gastric cancer by pathology. Lesions were divided into three parts by two tangent lines perpendicular to the gastric wall of the ulcer edge, including proximal part (close to cardia), ulcer part and distal part (close to pylorus). All the perfusion images were analyzed in the Toshiba 4.7 post processing workstation. Blood flow (BF), blood volume (BV), and clearance (CL) were measured according to Patlak-plot mode, and arterial flow (AF) was measured according to Single-input maximum mode. Differences in all the parameters between Borrmann type II( and III( groups were analyzed. Receiver operating characteristic (ROC) curve was used to determine the threshold of perfusion parameters for differentiating Borrmann type II( and III( gastric cancer. RESULTS: There were no significant differences in AF, BV and BF of ulcer part between the two groups (all P>0.05). While the CL of ulcer part in Borrmann type III( group was (7.17+/ 2.41) L/s, which was significantly higher than (4.82+/-2.26) L/s in Borrmann type II( group (P=0.00). There were no significant differences for all the parameters at proximal part and distal part between the two types (all P>0.05). According to the ROC curve, area under the curve of CL was 0.78. Taking 0.59 L/s as the threshold of CL value, the corresponding sensitivity and specificity for diagnosing Borrmann type III( were 70% and 80%, respectively. CONCLUSION: The CL value has certain diagnostic value in differential diagnosis between Borrmann types II( and III( gastric cancer. PMID- 27781254 TI - [Application of Bishop-Koop stoma in refractory congenital intestinal atresia]. AB - OBJECTIVE: To explore the feasibility and safety of Bishop-Koop stoma procedure in the treatment of neonates with refractory congenital intestinal atresia. METHODS: Clinical and follow-up data of 25 neonates with refractory congenital intestinal atresia undergoing Bishop-Koop stoma procedure in our center from January 2011 to December 2014 were retrospectively analyzed. Of 25 neonates, 13 (52%) were male, 12(48%) were female, the birth weight was 1600-3800 g (mean 2920 g), the age of admission was 10 hours to 20 days, and the age of operation was 1 58 d (mean 7 d). Diameter ratio of proximal atresia intestine to distal atresia intestine was all greater than 4. Eleven cases(44%) were high jejunal atresia, 3 cases(12%) type III( b, 7 cases(28%) type IIII(, 14 cases(56%) were identified as complex meconium peritonitis, and 3 cases (12%) received reoperation. RESULTS: All the cases completed their Bishop-Koop stoma operations successfully with median operative time of 3 (1.2-4.5) hours and median intra-operative blood loss of 3.5(1-18) ml. The postoperative complication rate was 20%(5/25), including 3 cases of cholestasis, 1 case of ileus, and 1 case of neonatal necrotizing enterocolitis with septicemia who died 6 days after operation resulting in the mortality of 4%. Besides, 1 case gave up treatment because of economic reason. For the rest 23 neonates, the median first feeding time was 11 days and mean time was 11(5 to 20) days; the median time of postoperative total parenteral nutrition (TPN) was 15 days and mean time was 21 (5 to 68) days; the median hospital stay was 33 days and mean hospital stay was 25(12 to 81) days, respectively. Two-stage stoma closure operations were performed in all the 23 cases afterwards and no postoperative associated complications were found. When discharge after Bishop Koop stoma operations, Z score of body weight was normal in 3 cases(13.0%) and lower than normal in 20 cases(87.0%), while in hospitalization for stoma closure, Z score of body weight was normal in 19 cases(82.6%) and lower than normal in 4 cases (17.4%). Of 23 cases, serum albumin level was normal in 9 cases(39.1%) before operation, in 3 cases (13.0%) when discharge and in 22 cases(95.7%) in hospitalization for stoma closure. CONCLUSION: Bishop-Koop stoma procedure is safe and feasible in the treatment of neonates with refractory congenital intestinal atresia, and can obviously improve the nutritional status. PMID- 27781256 TI - [Expression of tumor necrosis factor-like weak inducer of apoptosis in patients with gastric cancer and its relationship with nutritional status]. AB - OBJECTIVE: To investigate the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the serum and the rectus abdominis muscle in patients with gastric cancer and its relationship with the nutritional status. Method Clinical data of 102 patients with gastric cancer (gastric cancer group) and 53 patients with benign abdominal disease (control group) who were admitted to Zhejiang Province People's Hospital from January 2008 to October 2013 were analyzed retrospectively. Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum expression of TWEAK. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot were used to detect the mRNA and protein expression of TWEAK in the rectus abdominis muscle. Relationship between TWEAK expression and nutritional status of gastric cancer patients was examined. RESULTS: The relative expression level of TWEAK protein in serum of gastric cancer group and control group was 0.403+/-0.065 and 0.148+/-0.036 respectively. The relative expression of TWEAK mRNA in the rectus abdominis muscle tissue was 0.313+/-0.089 (gastric cancer group) and 0.118+/-0.005 (control group). The relative expression of TWEAK protein in the rectus abdominis muscle tissue was 0.197+/-0.064 (gastric cancer group) and 0.066+/-0.014 (control group), and the differences were statistically significant (both P=0.000). The high expression of TWEAK (high than median) in rectus abdominis muscle of gastric cancer patients was related to the percentage of more than 10% decline in body weight (P=0.000), the small percentage of ideal body weight at the time of admission (P=0.000), BMI<20 kg/m2(P=0.023), higher NRS2002 nutritional risk screening score (P=0.000), lower prognostic nutrition index (P=0.000) and serum albumin <35 g/L (P=0.000). CONCLUSIONS: The expression of TWEAK in serum and rectus abdominis muscle of gastric cancer patients up-regulates compared to non-tumor patients. The expression level of TWEAK in the rectus abdominis muscle of gastric cancer patients is closely related to poor nutritional status, suggesting that TWEAK may play a key role in the process of cachexia of gastric cancer patients. PMID- 27781255 TI - [Timing investigation of single-stage definitive surgery for newborn with Hirschsprung's disease]. AB - OBJECTIVE: To investigate the operation timing of newborns with rectosigmoid Hirschsprung's disease (HD). METHODS: From March 2013 to September 2015, 35 newborns diagnosed as rectosigmoid HD in our department were prospectively and randomly divided into 2 groups: less than 3 months treatment group (18 cases) and more than 3 months treatment group (17 cases, conservative treatment for 3 months). They all underwent laparoscopic-assisted transanal endorectal pull through (LATEP) (modified Soave) procedure. Clinical data, perioperative conditions, postoperative complication, postoperative anal function evaluated by Wingspread score and barium enema were compared between two groups. RESULTS: The baseline data of two groups were comparable (all P>0.05). All the cases completed single-stage LATEP procedure successfully without conversion to open operation. Compared with more than 3 months treatment group, preoperative bowel preparation time and operation time were significantly shorter [(6.2+/-3.3) vs. (9.3+/-4.1) days, P=0.042; (95+/-15) vs.(121+/-23) minutes, P=0.029, respectively], intra operative blood loss was significantly less [(13+/-3) ml vs. (22+/-5) ml, P=0.036], length of resected bowel was significantly shorter [(16+/-5) cm vs.(23+/-8) cm, P=0.033], and bowel movement recovery time, parenteral nutrition time, hospital stay were also significantly shorter [(2.3+/-0.5) vs. (2.9+/-0.6) days, P=0.046; (5.1+/-2.1) vs. (5.9+/-2.3) days, P=0.048; (12.9+/-3.3) vs. (15.8+/-4.3) days, P=0.049, respectively] in less than 3 months treatment group. No short-term complications, such as anastomotic leak, interlayer infection and abdominal infection occurred in both groups. The follow-up period ranged from 2 months to 24 months. Only the incidence of perianal excoriation was significantly higher in less than 3 months treatment group compared with more than 3 months treatment group [50.0%(9/18) vs. 23.5%(4/17), P=0.045]. Wingspread score results at 6 and 12 months after operation showed excellent rate of postoperative anal function, which was not significantly different between two groups[ <3 months group : 81.3%(13/16) and 92.9%(13/14); >3 months group: 85.7%(12/14) and 92.3%(12/13), all P>0.05]. Postoperative barium enema results at 6 and 12 months after operation all showed normal shape of colon without residue of barium. CONCLUSIONS: For newborns with rectosigmoid HD, single-stage definitive operation performed at the age less than 3 months has the advantages of shorter preoperative preparation time, less operating injury, shorter resected bowel, and faster postoperative recovery as compared to the age more than 3 months. If rectosigmoid HD is definitively diagnosed, early operation is suggested to perform at the age less than 3 months. PMID- 27781257 TI - [Role and mechanism research on reversal of 5-fluorouracil resistance by epigallocatechin gallate in gastric cancer drug-resistance cells lines SGC-7901/5 FU]. AB - : To study the role and molecular mechanism of epigallocatechin gallate (EGCG) in reversing drug-resistance to 5-fluorouracil (5-FU) in gastric cancer drug resistant cell line SGC-7901/5-FU. METHODS: Drug-resistance gastric cancer cell line (SGC-7901/5-FU) was established by high doses of repeated impact joint drug concentration increment methods. The cell viability of the parent cell line and the drug-resistance cell line were determined by standard MTT assay. Cell survival rate of drug-resistance was calculated by the formula [(A490 of the treatment group / A490 of the control group) * 100%]. Cell half inhibitory concentration (IC50) and resistance index (RI) were calculated by the Graphpad prime 6.0 software(RI=IC50 value of drug-resistance cells / IC50 value of parent cells). The apoptosis rate of SGC-7901/5-FU cells was quantified by flow cytometry after staining with annexin-V and PI. Western blot was used to detect the protein expression of drug-resistance-related proteins (ABCG2, P-gp, MDR-1 and GST-pi) and apoptosis-related proteins (PARP, Survivin, Bax and bcl-2). RESULTS: IC50 value was significantly increased in drug-resistant cells compared with parental cells [(64.7+/-3.9) mg/L and (4.1+/-0.3) mg/L, respectively, t=26.46, P=0.000], and the RI was 15.6. Proliferation activity in the drug resistant cells was higher than that in parental cells at different 5-FU concentrations (all P<0.05). In drug-resistant cells, the IC50 value of 5-FU combined with EGCG group obviously decreased compared with 5-FU group [(7.3+/ 0.1) mg/L and (63.1+/-1.4) mg/L respectively, t=40.84, P=0.000], and the RI was 0.12. Proliferation activity in drug-resistant cells was significantly decreased after EGCG treatment at different 5-FU concentrations (all P<0.05). Cell apoptosis rates in control group, 5-FU group, EGCG group and 5-FU combined with EGCG group were (3.0+/-1.0)%, (7.0+/-1.3)%, (6.0+/-1.2)% and (18.0+/-1.4)%, while apoptosis rate in 5-FU combined with EGCG group was significantly higher than those of other 3 groups(F=129.5, P=0.000). Western blot revealed that after EGCG treatment, the expression levels of drug-resistance-related proteins (ABCG2, P gp, MDR-1 and GST-pi) in the drug-resistant cell line SGC-7901/5-FU decreased significantly; the expression levels of apoptosis marker protein PARP and pro apoptotic protein Bax increased significantly; and the expression levels of anti apoptotic protein Survivin and Bcl-2 decreased significantly (all P<0.05). CONCLUSION: EGCG can reduce the resistance of gastric cancer resistant cell line SGC-7901/5-FU, whose role may be via the inhibition of the expression of drug resistance-related proteins, and the elevation of the protein expression ratio of PARP/Survivin and Bax/Bcl-2. PMID- 27781258 TI - [Research status quo and progression in targeted therapy for advanced gastric cancer]. AB - With the deeper research of the proliferation, invasion and metastasis mechanisms of the gastric cancer, targeted therapy has become a hot spot in this field. The exploration of targeted agents for gastric cancer is mainly concentrated upon the drugs that target human epidermal growth factor receptor (HER) family, the vascular endothelial growth factor (VEGF), the phosphatidylinositol 3-kinase protein kinase/mammalian target of rapamycin (PI3K/mTOR) and the NF-kappaB signaling pathways. The targeted drugs relevant to HER family include the Cetuximab, Nimotuzumab, Matuzumab, Panitumumab and Erlotinib which are aimed at HER-1, the Trastuzumab, Pertuzumab and T-DM1 (trastuzumab emtansine) which are aimed at HER-2, and the Lapatinib and Afatinib which are the multi-target agents of HER. The agents which target VEGF signaling pathway include the anti-VEGF monoclonal antibody (Bevacizumab), the anti-VEGFR drugs (Ramucirumab, Apatinib, Sorafenib, Sunitinib and cediranib), and the recombinant fusion protein (Aflibercept). The LY294002, BEZ235 and Everolimus which are aimed at PI3K/mTOR signaling pathway have shown great promise. Bortezomib has been researched more as a new agent which targets NF-kappaB signaling pathway. Currently, only Trastuzumab, Ramucirumab and Apatinib have been completed the stage 3 clinical trials and succeeded. In future, researches should focus on multi-target agents or applications in combination treatment. This review collects the recent researches and the clinical trials to summarize the current state and progress of research on gastric cancer targeted therapy. PMID- 27781259 TI - [Research progress of serrated polyposis syndrome]. AB - Serrated polyposis syndrome (SPS) is closely associated with the initiation and development of colorectal cancer (CRC), however, there is few research on SPS in China. Serrated polyps can be divided into hyperplastic polyps, sessile serrated polyps and traditional serrated polyps. The diagnosis standard of SPS is as following: (1) There are at least 5 serrated lesions in proximal colon, and diameter of more than 2 lesions is >10 mm; (2) The patient has one serrated polyp with family history of SPS; (3) More than 20 serrated polyps can be found in the entire large bowel. The risk of SPS is relatively high in the development of colorectal cancer and 25%-70% of the SPS patients is diagnosed with synchronous or metachronous colorectal cancer during following-up. The clinical characteristics of SPS include that patients are relatively old; no significant racial difference exists in the morbidity; patients have family history of colorectal cancer. The mutation of BRAF or KRAS gene, which induces colorectal cancer through the RAS-RAF-MAPK signaling pathway, is often found in SPS as well as CpG island methylation phenotype (CIMP) and microsatellite instability (MSI). The difference between SPS and traditional familial adenomatous polyposis (FAP) should be noted because of the different pathology mechanism, clinical characteristics and the risk of malignancy. Nowadays, the common technologies of detecting serrated polyps are auto-fluorescence imaging (AFI) and narrow-band imaging (NBI), whose detective rate is around 55%. The SPS patients are advised to undergo the resection of all the serrated polyps with diameter larger than 3-5 mm and receive the colonoscopy examination every 1 or 2 year. Not only the research about SPS is on the initiation step and the molecular mechanism is still unknown, but also the scholars do not come to achieve agreement about the risk of SPS in the malignancy of colorectal cancer, which is essential for further research therefore. PMID- 27781260 TI - Environmental drivers of diurnal visits by transient predatory fishes to Caribbean patch reefs. AB - Video cameras recorded the diurnal visitation rates of transient (large home range) piscivorous fishes to coral patch reefs in The Bahamas and identified 11 species. Visits by bar jack Caranx ruber, mutton snapper Lutjanus analis, yellowtail snapper Ocyurus chrysurus, barracuda Sphyraena barracuda and cero Scomberomorus regalis were sufficiently frequent to correlate with a range of biophysical factors. Patch-reef visitation rates and fish abundances varied with distance from shore and all species except S. regalis were seen more frequently inshore. This pattern is likely to be caused by factors including close proximity to additional foraging areas in mangroves and on fore-reefs and higher abundances close to inshore nursery habitats. Visitation rates and abundances of C. ruber, L. analis, O. chrysurus and S. regalis also varied seasonally (spring v. winter), possibly as fishes responded to temperature changes or undertook spawning migrations. The abundance of each transient predator species on the patch reefs generally exhibited limited diurnal variability, but L. analis was seen more frequently towards dusk. This study demonstrates that the distribution of transient predators is correlated spatially and temporally with a range of factors, even within a single lagoon, and these drivers are species specific. Transient predators are considered an important source of mortality shaping reef fish assemblages and their abundance, in combination with the biomass of resident predators, was negatively correlated with the density of prey fishes. Furthermore, transient predators are often targeted by fishers and understanding how they utilize seascapes is critical for protecting them within reserves. PMID- 27781261 TI - Psychometric properties of the mutuality scale in Swedish dyads with Parkinson's disease. AB - OBJECTIVES: The 15-item mutuality scale (MS) has been used in several neurological conditions assessing the quality of relationship associations with negative effects of the caregiving situation. The aim of this study was to translate the original MS into Swedish and assess its psychometric properties in Parkinson's disease (PD). MATERIALS AND METHODS: Following the forward-backward translation method, the scale was evaluated regarding linguistic correctness at a conceptual level and user-friendliness. The scale was filled out by a sample of 50 care dyads where one was having PD. Scale assumptions and scale structure were evaluated using floor/ceiling effect and principal component analyses (PCA) with promax rotation. Internal consistency was evaluated using Cronbach's alpha and mean inter-item correlation coefficients. RESULTS: The Swedish MS was evaluated as user-friendly and relevant by the participants. The scale demonstrated no floor/ceiling effect and showed high internal consistency (alpha>=0.93) with a mean inter-item correlation coefficient of >=0.5. Through the PCA, a two factor solution emerged, which accounted for 67% and 64% of the variance of the MS score by PD-partners and PD-patients, respectively. However, some variables were complex and discarded in the final solution. CONCLUSION: Our findings provide initial support of the Swedish MS as a user-friendly and useful instrument with acceptable psychometric properties even though more research is needed to evaluate the existence of subscales. PMID- 27781262 TI - Risk of Parkinson disease after organophosphate or carbamate poisoning. AB - AIMS: Parkinson disease (PD) is a common neurodegenerative disease. The aim of this study was to evaluate the risk of PD in patients with organophosphate (OP) or carbamate (CM) poisoning by using the Taiwan National Health Insurance Research Database. METHODS: We conducted a retrospective study involving a cohort of 45 594 patients (9128 patients with a history of OP or CM poisoning and 36 466 control patients) who were selected from the Taiwan National Health Insurance Research Database. The patients were observed for a maximum of 12 years to determine the rates of new-onset PD, and a Poisson regression model was used to identify the predictors of PD. The cumulative incidence of PD between the two cohorts was plotted through Kaplan-Meier analysis. RESULTS: During the study period, the incidence rate ratio (IRR) of PD in the OP or CM poisoning patients was 1.36-fold [95% confidence interval (CI)=1.26-1.47] higher than that in the control patients in the multivariable model. The absolute incidence of PD was the highest for the group aged >=75 years in both cohorts (77.4 vs 43.7 per 10 000 person-years). However, the age-specific relative risk was higher for the group aged <50 years (adjusted IRR=3.88; 95% CI=3.44-4.39). CONCLUSION: Our results suggest that the likelihood of developing PD is greater in patients with OP or CM poisoning than in those without poisoning. OP or CM poisoning may be an independent risk factor for PD. PMID- 27781263 TI - A review of medication adherence in people with epilepsy. AB - People with epilepsy (PWE) have a higher risk of mortality in comparison with the general population. This in part reflects intrinsic factors or associated comorbidities, but poor adherence to anti-epileptic drugs (AED) has also been shown to contribute to increased risk of death and increased utilization of unscheduled care. The aim of this review was to determine the prevalence of non adherence to AED in PWE, evaluate whether specific clinical and demographic features can allow clinicians to identify those at highest risk and identify the methods and techniques that can be used to improve adherence in clinical settings. We identified relevant studies for the prevalence of medication non adherence in PWE by searching MEDLINE (1946-7 Dec 2015), EMBASE (1947-7 Dec 2015) and Cochrane Library (1946-7 Dec 2015) as per predefined inclusion and exclusion criteria. We included 17 research studies from our review of the medical literature to determine the prevalence of medication non-adherence in epilepsy. The prevalence of significant medication non-adherence in epilepsy has been reported to vary between 26% and 79%. This variation partly reflects the differences in defining what clinically significant medication adherence is, the methods used to estimate the scale of the problem and the underlying population heterogeneity. A number of clinical and demographic features have been associated with poor adherence allowing clinicians to identify those at greatest risk. Educating patients and their carers about the risks associated with poor adherence, certain behavioural interventions and simplifying their drug regimens have been shown to improve adherence. PMID- 27781264 TI - Spatio-temporal patterns of genetic variations in populations of yellowtail kingfish Seriola lalandi from the south-eastern Pacific Ocean and potential implications for its fishery management. AB - The genetic population structure and genetic diversity of yellowtail kingfish Seriola lalandi from the coastal south-eastern Pacific Ocean (SEP) were evaluated at spatiotemporal scale in order to understand the ecology of this species. Between 2012 and 2015, temporal and spatial population genetic structure and a low genetic diversity were detected in S. lalandi from SEP. These results suggest that S. lalandi specimens arriving annually from offshore to the SEP coast could come from at least two genetically distinct populations, revealing a particular life strategy (i.e. reproductive or habitat segregation) for this fish species. Therefore, the SEP coast might constitute a point of population mixing for this species. Additionally, the low genetic diversity of S. lalandi in the SEP could be a result of a founder effect or overfishing. Regardless of the process explaining the genetic diversity and structure of S. lalandi in this geographical area, this new information should be considered in order to implement successful fishery management of this resource in the South Pacific. PMID- 27781265 TI - Fenestration of the Basilar Artery With Associated Aneurysm-A Case Report. PMID- 27781266 TI - Case Outcomes in a Communication-and-Resolution Program in New York Hospitals. AB - OBJECTIVE: To determine case outcomes in a communication-and-resolution program (CRP) implemented to respond to adverse events in general surgery. STUDY SETTING: Five acute-care hospitals in New York City. STUDY DESIGN: Following CRP implementation, hospitals recorded information about each CRP event for 22 months. DATA COLLECTION METHODS: Risk managers prospectively collected data in collaboration with representatives from the hospital's insurer. External researchers administered an online satisfaction survey to clinicians involved in CRP events. PRINCIPAL FINDINGS: Among 125 CRP cases, disclosure conversations were carried out in 92 percent, explanations were conveyed in 88 percent, and apologies were offered in 72.8 percent. Three quarters of events did not involve substandard care. Compensation offers beyond bill waivers were deemed appropriate in 9 of 30 of cases in which substandard care caused harm and communicated in six such cases. In 44 percent of cases, hospitals identified steps that could be taken to improve safety. Clinicians had low awareness of the workings of the CRP, but high satisfaction with their experiences. CONCLUSIONS: The bulk of CRPs' work is in investigating and communicating about events not caused by substandard care. These CRPs were quite successful in handling such events, but less consistent in offering compensation in cases involving substandard care. PMID- 27781268 TI - Safety and efficacy of a combination of paromomycin and miltefosine for two vs. three courses in patients with post-kala-azar dermal leishmaniasis: an observational pilot study. PMID- 27781267 TI - Maternal health in pregnancy and associations with adverse birth outcomes: Evidence from Growing Up in New Zealand. AB - OBJECTIVE: To examine prospectively multiple indicators of pregnancy health and associations with adverse birth outcomes within a large, diverse sample of contemporary women. DESIGN: A cohort of pregnant women who gave birth during 2009 10. POPULATION: We enrolled a sample of 6822 pregnant New Zealand (NZ) women: 11% of all births in NZ during the recruitment period. METHODS: We analysed a number of maternal health indicators and behaviours during pregnancy in relation to birth outcomes using multivariable logistic regression. Associations were described using adjusted odds ratios and 95% confidence intervals. MAIN OUTCOME MEASURES: Three birth outcomes, low birth weight (LBW), pre-term birth (PTB) and delivery type, were measured via linkage with maternity hospital perinatal databases. Small for gestational age (SGA) was then defined as below the 10th percentile by week of gestation. RESULTS: Modelling of birth outcomes after adjusting for confounders indicated patterns of increased risk of LBW and PTB for women who smoke, have elevated pre-pregnancy body mass index (BMI), or with insufficient pregnancy weight gain. SGA was associated with maternal smoking, alcohol use, insufficient weight gain and nausea and vomiting during pregnancy. Risk of caesarean section was associated with having a diagnosed illness before pregnancy, elevated BMI, greater pregnancy weight gain and less pregnancy exercise. Number of risk factor variables were then used to model birth outcomes. Women with multiple risk factors were at increased risk compared with those who had no risk factors. CONCLUSIONS: Women with multiple health risks are at particular risk of adverse birth outcomes. PMID- 27781269 TI - Migraine-Like Headache as Presentation Symptom in Susac Syndrome. PMID- 27781270 TI - The effects of entanglement concentration on the hydrodynamic properties of cereal starches. AB - BACKGROUND: The hydrodynamic properties of four cereal starches in dilute and semi-dilute aqueous solutions were investigated using an Ubbelohde viscometer, a transmission electron microscope and steady shear rheological measurements. RESULTS: The results indicated that the starch solutions showed the nonlinear shape of the etasp /c versus c curves in dilute solutions, followed by a linear increase to different extents thereafter. The intrinsic viscosity might be positively correlated with the entanglement concentration (ce ). Compared to normal maize and wheat starch solutions, ce influences more significantly the network formation of normal and waxy rice starch solutions. At concentrations <= ce , the gelatinized cereal starch solutions hardly exhibit shear thinning behavior, whereas shear thinning behavior developed at concentrations > ce , at which the solutions were pseudoplastic and thixotropic. CONCLUSION: The obtained information will be very useful, based on ce as a reference value, in regulating the starch concentration suitable for different industrial applications. (c) 2016 Society of Chemical Industry. PMID- 27781271 TI - Prevalence of spinous process impingement in thoracic vertebrae on radiographs of clinically-unaffected dogs. AB - OBJECTIVES: To assess the prevalence of impinged spinous processes in asymptomatic dogs. METHODS: One hundred and ninety lateral thoracic radiographs of asymptomatic dogs radiographed for reasons other than spinal pain, were retrospectively reviewed by two board-certified radiologists. Images were assessed for impinged spinous processes and graded for narrowing, sclerosis or remodelling of the spinous processes. RESULTS: The prevalence of impinged spinous processes in unaffected dogs was 33.2%. Seventy-five of 79 (95%) lesions were located between T8 and T11. Impingement of the spinous processes was more common in older dogs and larger dogs displayed more frequent and more severe impingement of the spinous processes compared with smaller breeds. CLINICAL SIGNIFICANCE: Spinous process impingement is common in animals with no history of spinal pain, indicating that this radiographic finding should be interpreted with caution. PMID- 27781272 TI - Gingival crevicular fluid tissue/blood vessel-type plasminogen activator and plasminogen activator inhibitor-2 levels in patients with rheumatoid arthritis: effects of nonsurgical periodontal therapy. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the effect of nonsurgical periodontal therapy on clinical parameters and gingival crevicular fluid levels of tissue/blood vessel-type plasminogen activator (t-PA) and plasminogen activator inhibitor-2 (PAI-2) in patients with periodontitis, with or without rheumatoid arthritis (RA). MATERIAL AND METHODS: Fifteen patients with RA and chronic periodontitis (RA-P), 15 systemically healthy patients with chronic periodontitis (H-P) and 15 periodontally and systemically healthy volunteers (C) were included in the study. Plaque index, gingival index, probing pocket depth, clinical attachment level, bleeding on probing, gingival crevicular fluid t-PA and PAI-2 levels, erythrocyte sedimentation rate, serum C-reactive protein and disease activity score were evaluated at baseline and 3 mo after mechanical nonsurgical periodontal therapy. RESULTS: All periodontal clinical parameters were significantly higher in the RA-P and H-P groups compared with the C group (p < 0.001) and decreased significantly after treatment (p < 0.001). Pretreatment t PA levels were highest in the RA-P group and significantly decreased post treatment (p = 0.047). Pre- and post-treatment PAI-2 levels were significantly lower in controls compared with both periodontitis groups (p < 0.05). Gingival crevicular fluid volume and the levels of t-PA and PAI-2 were significantly correlated. CONCLUSION: In patients with periodontitis and RA, nonsurgical periodontal therapy reduced the pretreatment gingival crevicular fluid t-PA levels, which were significantly correlated with gingival crevicular fluid PAI-2 levels. The significantly higher t-PA and PAI-2 gingival crevicular fluid levels in periodontal patients, regardless of systemic status, suggest that the plasminogen activating system plays a role in the disease process of periodontitis. PMID- 27781274 TI - Elevated carbon dioxide has limited acute effects on Lepomis macrochirus behaviour. AB - The current study investigated the behavioural response of Lepomis macrochirus following exposures to elevated carbon dioxide (CO2 ). For this, L. macrochirus were held at ambient pCO2 (160 MUatm pCO2 ) for 7 days, then exposed to elevated pCO2 (8300 MUatm pCO2 ) for 5 days, and then returned to ambient conditions for a further 5 days to recover. At the end of each exposure period, several behavioural metrics were quantified (boldness, lateralization and activity). Data showed no change in lateralization and most metrics associated with performance and boldness. During the boldness test, however, average velocity, velocity in the thigmotaxis (outer) zone and proportion of activity in the thigmotaxis zone increased with pCO2 exposure. During post-exposure, average velocity of L. macrochirus decreased. In addition, individual rank was repeatable during the pre exposure and post-exposure period in three of the 17 metrics investigated (average velocity in the middle zone, average velocity near object and total shuttles to the object zone), but not during the CO2 exposure period, suggesting that elevated pCO2 disrupted some behavioural performances. Overall, this study found elevated pCO2 caused disruption to behaviours of freshwater fishes such as L. macrochirus and effects do not appear to be as serious as has been shown for marine fishes. PMID- 27781273 TI - Forecasting oral absorption across biopharmaceutics classification system classes with physiologically based pharmacokinetic models. AB - OBJECTIVES: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success. METHODS: Simcyp Simulator, GastroPlusTM and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters. Simulation success was evaluated with the average fold error (AFE) and absolute average fold error (AAFE). Parameter sensitivity analysis (PSA) to selected parameters was performed. KEY FINDINGS: Plasma concentration-time profiles after intravenous administration were forecast within an AAFE < 3. The addition of absorption processes resulted in more variability in the prediction of the plasma profiles, irrespective of biopharmaceutics classification system (BCS) class. The reliability of literature permeability data was identified as a key issue in the accuracy of predicting oral drug absorption. CONCLUSION: For the four drugs studied, it appears that the forecasting accuracy of the PBPK models is related to the BCS class (BCS I > BCS II, BCS III > BCS IV). These results will need to be verified with additional drugs. PMID- 27781275 TI - Follicle cell processes: a shark thing? AB - Follicle cell processes (FCP) are identified in two species of carcharhinid shark (Selachii) but are absent in the little skate Leucoraja erinacea (Batoidea). This suggests that FCPs are either a unique structure that evolved in selachians or were lost by the batoids after their divergence, some 280 mya. The presence of FCPs in the selachians would be consistent with the evolution of large oocytes in this group of animals. PMID- 27781276 TI - Effect of ball milling on the physicochemical properties of atorvastatin calcium sesquihydrate: the dissolution kinetic behaviours of milled amorphous solids. AB - OBJECTIVES: The purposes of this study were to clarify the amorphization by ball milling of atorvastatin calcium sesquihydrate (AT) and to analyse the change in dissolution kinetics. METHODS: The amorphous AT was prepared from crystal AT by ball milling and analysed in terms of the changes of its physicochemical properties by powder X-ray diffraction analysis (XRD), thermal analysis and infrared spectroscopy (IR). Moreover, to evaluate the usefulness of the amorphous form for pharmaceutical development, intrinsic solubility of the ground product was evaluated using a dissolution kinetic method. KEY FINDINGS: The XRD results indicated that crystalline AT was transformed into amorphous solids by more than 30-min milling. The thermal analysis result suggested that chemical potential of the ground AT are changed significantly by milling. The IR spectra of the AT showed the band shift from the amide group at 3406 cm-1 with an intermolecular hydrogen bond to a free amide group at 3365 cm-1 by milling. The dissolution of amorphous AT follows a dissolution kinetic model involving phase transformation. CONCLUSIONS: The initial dissolution rate of the ground product increased with the increase in milling time to reflect the increase in the intrinsic solubility based on the amorphous state. PMID- 27781277 TI - Never mind the length, feel the quality. PMID- 27781278 TI - Improving the oral bioavailability of buprenorphine: an in-vivo proof of concept. AB - OBJECTIVES: The aim of this study was to improve the oral bioavailability of buprenorphine by inhibiting presystemic metabolism via the oral co-administration of 'Generally Recognized as Safe' compounds, thus providing an orally administered drug product with less variability and comparable or higher exposure compared with the sublingual route. METHODS: The present studies were performed in Sprague Dawley rats following either intravenous or oral administration of buprenorphine/naloxone and oral co-administration of 'Generally Recognized as Safe' compounds referred to as 'adjuvants'. Plasma samples were collected up to 22 h postdosing followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis. KEY FINDINGS: The adjuvants increased Cmax (21 +/- 16 ng/ml vs 75 +/- 33 ng/ml; 3.6-fold) and AUC(0-22 h) (10.6 +/- 8.11 MUg min/ml vs 22.9 +/- 11.7 MUg min/ml; 2.2-fold) values of buprenorphine (control vs adjuvant-treated, respectively). The absolute oral bioavailability of buprenorphine doubled (from 1.24% to 2.68%) in the presence of the adjuvants. CONCLUSIONS: One may suggest that the adjuvant treatment most likely inhibited the presystemic metabolic enzymes, thus decreasing the intestinal 'first-pass effect' on buprenorphine. Additional studies are now required to further explore the concept of inhibiting presystemic metabolism of buprenorphine by adjuvants to potentially increase the oral bioavailability of buprenorphine. PMID- 27781279 TI - Immunoregulatory effects of 4-(4-chlorophenyl)-1-(5-amino-3-methylisoxazole-4 carbonyl)-thiosemicarbazide (06K) in non-immunized and SRBC-immunized mice. AB - OBJECTIVES: Immunoregulatory properties of 06K derivative (4-(4-chlorophenyl)-1 (5-amino-3-methylisoxazole-4-carbonyl)-thiosemicarbazide) in mouse in vivo models were investigated. METHODS: Several in vivo models were used: humoral and cellular immune response, carrageenan inflammatory reaction and determination of lymphocyte subsets in non-immunized mice. KEY FINDINGS: The compound administered before or after immunization with sheep erythrocytes (sheep red blood cell (SRBC)) elevated the number of plaque-forming cells (PFC), and this effect was stronger at lower doses. Although total haemagglutinin titres to SRBC decreased upon postimmunization treatment, IgG titre increased. In the model of delayed type hypersensitivity (DTH) to ovalbumin (OVA), the compound, applied intraperitoneally before an eliciting dose of an antigen but not before immunization, inhibited the magnitude of a cutaneous reaction. Further, 06K significantly diminished carrageenan-induced foot pad inflammation when administered 1 h before carrageenan. The compound, administered intraperitoneally to naive mice, elicited changes in weight, cell number in lymphoid organs and content of lymphocyte subsets, depending on the dose and number of applications. Phenotypic changes included increased turnover of thymocytes, changes in B-cell distribution in spleens and lymph nodes, increased percentage of CD8+ cells and regulatory CD4+ CD25+ Foxp3+ T cells. CONCLUSIONS: Immunoregulatory properties of 06K involve mobilization of lymphopoiesis and generation of regulatory T cells. PMID- 27781280 TI - Improving Patient Safety through Video Monitoring. AB - PURPOSE: Falls are a major safety issue in rehabilitation settings. Patients receive mixed messages-try to be as independent as possible, but don't do anything in your room without calling for assistance. Despite the use of multiple falls interventions at this facility, the fall rate remained high. To impact this rate, the facility implemented a video monitoring system. This system allows for patients at risk for falling to be monitored from a remote location. The monitor technician is able to speak to the patient directly and/or contact staff members to respond to the room, preventing a fall. DESIGN: Sequential cohort design. METHOD: Fifteen video monitoring units were installed on high risk units in a 115 bed Inpatient Rehabilitation Facility. Total falls and falls rates were tracked and reported pre- and postimplementation. FINDINGS: Over a 21-month period prior to implementing the video monitoring system, the average hospital-wide rate of falls was 6.34 per 1,000 patient-days (SD = 1.7488). After a year of usage that average has decreased to 5.099 falls per 1,000 patient-days (SD = 1.524). The reduction in falls was statistically significant. In addition, there have been significant cost savings by reducing sitter usage. CONCLUSIONS: Video monitoring can improve patient safety by decreasing falls, decreasing sitter usage and cost, and improving patient, family, and staff satisfaction. CLINICAL RELEVANCE: Falls are a significant issue in rehabilitation settings and current fall prevention strategies fall short of reducing fall rates. Implementation of new video monitoring technology can help reduce fall rates in inpatient rehabilitation settings. PMID- 27781281 TI - Feedback negativity and decision-making behavior in the Balloon Analogue Risk Task (BART) in adolescents is modulated by peer presence. AB - Adolescent risk taking is strongly influenced by peer presence. The aim of the present study was to investigate the effect of peer presence on the ERP after negative and positive feedback in the time range of the feedback-related negativity (FRN). Eighteen male adolescents completed a version of the Balloon Analogue Risk Task (BART) under two conditions: playing alone and while observed by a peer. We recorded the ERPs after success or failure feedback and analyzed risk-taking behavior under both conditions. Behavioral results show that the participants were more cautious when being watched by a peer, especially after success. ERPs show that participants under peer presence exhibit more negative FRN after failure feedback than in the single condition, but no greater positivities after success feedback in the observed condition compared to the single condition. Results are in line with reinforcement learning theory and psychological aspects of loss prevention. The results suggest that the effect of peer presence on risk-taking behavior depends on the specific situational context. PMID- 27781282 TI - The role of religious context in children's differentiation between God's mind and human minds. AB - The current study examined the cultural factors (i.e., religious background, religious participation, parents' views of prayer, and parents' concepts of God) that contribute to children's differentiation between the capabilities of human minds and God's mind. Protestant Christian, Roman Catholic, Muslim, and Religiously Non-Affiliated parents and their preschool-aged children were interviewed (N = 272). Children of Muslim parents differentiated the most between God's mind and human minds (i.e., human minds are fallible but God's is not), and children who had greater differentiation between God's and humans' minds had parents who had the least anthropomorphic conceptions of God. Additionally, there was a unique effect of being raised in a Religiously Non-Affiliated home on the degree of children's differentiation between God's and human minds after religious context factors had been accounted for; in other words, children of Religious Non-Affiliates differentiated between humans and God the least and their differentiation was unrelated to religious context factors. These findings delineate the ways in which religious context differences influence concepts of God from the earliest formation. Statement of contribution What is already known on this subject? Children's concept of God develops during the preschool years. The degree of anthropomorphism in children's concept of God varies. What does this study add? Muslim children have a strong differentiation between what God's mind and human minds can do. Religiously Non-Affiliated children have almost no differentiation between God's and human minds. Parent anthropomorphism explains variance in children's God concepts, both within and across religious groups. PMID- 27781283 TI - The relationship between approaches to study and academic performance among Australian undergraduate occupational therapy students. AB - BACKGROUND/AIM: The academic success and degree completion of tertiary students depends on their academic performance (AP), commonly measured by the percentage grades for the units they complete. No research has examined whether occupational therapy students' approaches to study are predictive of their AP. This study investigated whether approaches to study were predictive of the AP among a group of Australian undergraduate occupational therapy students. METHODS: A total of 376 undergraduate occupational therapy students completed the Approaches and Study Skills Inventory for Students (ASSIST). Regression analysis was conducted using a range of demographic characteristics and the ASSIST scores as independent variables with students' self-reported by their self-reported mean percentage grade range (as a proxy indicator of their AP) as the dependent variable. RESULTS: The deep and the strategic approaches to study were not significantly correlated with occupational therapy students' AP. The ASSIST fear of failure subscale of the surface approach to study had a unique contribution to AP, accounting for 1.3% of its total variance. Occupational therapy students' year level of enrolment made a unique contribution to their AP, accounting for 4.2% of the total variance. Age and gender made a unique contribution to AP as well although their impact was small. CONCLUSIONS: Undergraduate occupational therapy students' approaches to study were predictive of their AP to a very limited degree. However, their AP was predicted by a number of demographic variables, including age, gender and year level of enrolment. Further study in this area is recommended. PMID- 27781284 TI - Effects of four commercial fungal formulations on mortality and sporulation in house flies (Musca domestica) and stable flies (Stomoxys calcitrans). AB - The house fly Musca domestica L. (Diptera: Muscidae) and stable fly Stomoxys calcitrans (L.) (Diptera: Muscidae) are major pests of livestock. Biological control is an important tool in an integrated control framework. Increased mortality in filth flies has been documented with entomopathogenic fungi, several strains of which are commercially available. Three strains of Beauveria bassiana (Balsamo-Crivelli) Vuillemin (Hypocreales: Cordycipitaceae) and one strain of Metarhizium brunneum (Petch) (Hypocreales: Clavicipitaceae) were tested in commercial formulations for pathogenicity against house flies and stable flies. There was a significant increase in mortality of house flies with three of the formulations, BotaniGard(r) ES, Mycotrol(r) O, and Met52(r) EC, during days 4-9 in comparison with balEnceTM and the control. In stable flies, mortality rates were highest with Met52(r) EC, followed by Mycotrol(r) O, BotaniGard(r) ES and, finally, balEnceTM. There was a significant fungal effect on sporulation in both house flies and stable flies. Product formulation, species differences and fungal strains may be responsible for some of the differences observed. Future testing in field situations is necessary. These commercial biopesticides may represent important tools in integrated fly management programmes. PMID- 27781285 TI - Impact of an international workplace learning placement on personal and professional development. AB - BACKGROUND/AIM: Workplace learning (WPL) placements are a mandatory part of occupational therapy courses. There is some evidence that suggests WPL placements in international settings are beneficial for students' learning, and personal and professional development. The aim of this study was to explore the impact an international WPL placement in Vietnam had on the perceived personal and professional development of a group of Australian occupational therapy graduates. METHODS: Interpretative phenomenological analysis was used to explore the perceptions of how participation in the Charles Sturt University School of Community Health's Vietnam placement influenced the personal and professional development of occupational therapy graduates. Individual semi-structured interviews were conducted with nine graduates who participated in the Vietnam placement when they were final year occupational therapy students. Interviews were audio-recorded, transcribed verbatim and individually analysed to identify key themes. FINDINGS: Two major themes emerged from the analysis: becoming resourceful, resilient and confident, and becoming respectful of difference. The participants indicated that participation in the Vietnam placement had a positive impact on their personal and professional development. CONCLUSION: Participants indicated that the Vietnam placement enabled them to develop their resourcefulness, resilience, reasoning skills, cultural competence, confidence and independence, beyond what they felt would have achieved on a domestic placement. For these reason these participants found the placement a beneficial and worthwhile experience. PMID- 27781286 TI - Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014. AB - BACKGROUND: Management of inflammatory bowel disease (IBD) has evolved in the last decade. AIM: To assess IBD therapeutic management, including treatment withdrawal and early treatment use in the current era of anti-TNF agents (anti TNFs). METHODS: All patients affiliated to the French national health insurance diagnosed with IBD were included from 2009 to 2013 and followed up until 31 December 2014. Medication uses, treatment sequences after introduction of thiopurine or anti-TNF monotherapies or both (combination therapy), surgical procedures and hospitalisations were assessed. RESULTS: A total of 210 001 patients were diagnosed with IBD [Crohn's disease (CD), 100 112; ulcerative colitis (UC), 109 889]. Five years after diagnosis, cumulative probabilities of anti-TNF monotherapy and combination therapy exposures were 33.8% and 18.3% in CD patients and 12.9% and 7.4% in UC patients, respectively. Among incident patients who received thiopurines or anti-TNFs, the first treatment was thiopurine in 69.1% of CD and 78.2% of UC patients. Among patients treated with anti-TNFs, 45.2% and 54.5% of CD patients and 38.2% and 39.9% of UC patients started monotherapy and combination therapy within 3 months after diagnosis, respectively; 31.3% of CD and 27.1% of UC incident patients withdrew from thiopurine or anti-TNFs for more than 3 months after their first course of treatment. Five years after diagnosis, the cumulative risks of first intestinal resection in CD patients and colectomy in UC patients were 11.9% and 5.7%, respectively. CONCLUSIONS: Step-up approach remains the predominant strategy, while exposure to anti-TNFs is high. Surgery rates are low. Treatment withdrawal in IBD is more common than expected. PMID- 27781287 TI - Sex and seasonal differences in diet and nutrient intake in Verreaux's sifakas (Propithecus verreauxi). AB - Fluctuations in food availability are a major challenge faced by primates living in seasonal climates. Variation in food availability can be especially challenging for females, because of the high energetic costs of reproduction. Therefore, females must adapt the particular demands of the different reproductive stages to the seasonal availability of resources. Madagascar has a highly seasonal climate, where food availability can be extremely variable. We investigated the seasonal changes in diet composition, nutrient and energy intake of female and male sifakas (Propithecus verreauxi) in a dry deciduous forest in western Madagascar. We examined how females adjust their diet to different reproductive stages. Seasonality affected the diet of both sexes; particularly in the dry season (Apr-Oct) with low availability of food items, especially fruits, males and females had a reduced nutrient and energy intake compared to the wet season (Nov-Mar) with higher food and fruit availability. The comparison of the diet between sexes in different reproductive stages showed that during the late stage of lactation (Nov-Jan) females had higher food intake, and as a result they had a higher intake of macronutrients (crude protein, fat and non-structured carbohydrates (TNC)) and energy than males. These differences were not present during the pregnancy of females, with both sexes having similar intake of macronutrients and energy during that stage. The increase in the intake of macronutrients observed for females during late lactation could be related to the higher energetic demands of this stage of reproduction. Thus, the observed pattern in the diet indicates that sifaka females are following a capital breeding strategy, whereby females potentially store enough nutrients to cope with the reproduction costs in periods of low food availability. PMID- 27781288 TI - Reliability of the Timed Up and Go Test in Fibromyalgia. AB - PURPOSE: The aim of the study was to evaluate the test-retest reliability of the timed up and go test using manual and automatic chronometer (chronopic) in women with fibromyalgia. DESIGN: Cross-sectional study with convenience sample. METHOD: A total of 49 women with fibromyalgia, aged 50.20 +/- 10.01 participated in the study. FINDINGS: The intraclass correlation coefficient was .935 with the manual stopwatch and .955 with the chronopic. The smallest real difference using manual stopwatch was 9.327%, whereas for the timed up and go using the chronopic it was 7.708%. Mean of the three repetitions was significantly different (p = .005) between both chronometers. CONCLUSION: Timed up and go is a reliable physical fitness test for assessing agility/dynamic balance in women with fibromyalgia. CLINICAL RELEVANCE: The reliability is higher when the time is tracked using an automatic chronometer, which is easy to use and not expensive in terms of time and money, the use of this device is recommended in the nursing practice. PMID- 27781289 TI - Describing the Shape of the Relationship Between Gestational Age at Birth and Cognitive Development in a Nationally Representative U.S. Birth Cohort. AB - BACKGROUND: Preterm children face higher risk of cognitive and academic deficits compared with their full-term peers. The objective of this study was to describe early childhood cognitive ability and kindergarten academic achievement across gestational age at birth in a population-based longitudinal cohort. METHODS: The study population included singletons born at 24-42 weeks gestation enrolled in the Early Childhood Longitudinal Study-Birth Cohort (n = 6150 for 2-year outcome, n = 4450 for kindergarten outcome). Home-based assessments measured cognitive ability at 2 years and reading and mathematics achievement at kindergarten age. Linear regression models estimated the association between gestational age and cognitive and academic scores using four different ways of modelling gestational age: continuous variable in linear and quadratic terms; categories for individual weeks; and clinical categories for early preterm, moderate preterm, late preterm, early term, full term, late term, and post-term. RESULTS: Children born at early preterm (24-27 weeks), moderate preterm (28-33 weeks), and late preterm (34-36 weeks) scored significantly worse than full-term (39-40 weeks) peers on 2-year and kindergarten assessments; however, no deficits were observed for early term (37-38 weeks). These categories were a clinically useful and parsimonious approach to stratifying risk of adverse cognitive and academic outcomes. CONCLUSIONS: This study estimated the relative performance of children born at 24 42 weeks in a population-based birth cohort using multiple approaches to modelling gestational age, providing a more rigorous understanding of the relationships between the full spectrum of gestational age and cognitive and academic outcomes in early childhood and at school age. PMID- 27781290 TI - Low-dose radiotherapy in diffuse large B-cell lymphoma. AB - Low-dose radiotherapy (LDRT) given in 2 * 2 Gy is a highly effective and safe treatment for palliation of indolent lymphomas. Otherwise, very little regarding the use of LDRT for diffuse large B-cell lymphoma (DLBCL) has been investigated. We designed a phase 2 trial of LDRT in patients with DLBCL with indication for palliative radiation. Low-dose radiotherapy was administered on symptomatic areas only. Clinical response was assessed 21 days after LDRT and defined as reduction >50% of maximum diameter of the radiated lesions. Quality of life was scored by the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Tumor subtype (germinal center B-cell type versus activated B-cell type) and the presence of TP53 mutations in pathologic specimens of the target lesion were also evaluated. Twenty-three of twenty-five radiated patients were evaluable for response, and 2 died of disease before the visit at 21 days. The overall response rate was 70% (16 of 23 patients), with 7 complete responses and 9 partial responses (mean duration of response, 6 months; range, 1-39 months). Fifteen patients answered to the QLQ-C30 questionnaires, and an improved quality of life was documented in 9 cases. TP53 mutations were detected in 2 of 6 (33%) nonresponders and in none of the responders (P = .12). Germinal center B-cell type responded better than activated B-cell type (response rate was 83% and 29%, respectively, P = .01). These findings indicate that LDRT is effective for palliation in patients with DLBCL. PMID- 27781291 TI - Expressed microRNA associated with high rate of egg production in chicken ovarian follicles. AB - MicroRNA (miRNA) is a highly conserved class of small noncoding RNA about 19-24 nucleotides in length that function in a specific manner to post transcriptionally regulate gene expression in organisms. Tissue miRNA expression studies have discovered a myriad of functions for miRNAs in various aspects, but a role for miRNAs in chicken ovarian tissue at 300 days of age has not hitherto been reported. In this study, we performed the first miRNA analysis of ovarian tissues in chickens with low and high rates of egg production using high throughput sequencing. By comparing low rate of egg production chickens with high rate of egg production chickens, 17 significantly differentially expressed miRNAs were found (P < 0.05), including 11 known and six novel miRNAs. We found that all 11 known miRNAs were involved mainly in pathways of reproduction regulation, such as steroid hormone biosynthesis and dopaminergic synapse. Additionally, expression profiling of six randomly selected differentially regulated miRNAs were validated by quantitative real-time polymerase chain reaction (RT-qPCR). Some miRNAs, such as gga-miR-34b, gga-miR-34c and gga-miR-216b, were reported to regulate processes such as proliferation, cell cycle, apoptosis and metastasis and were expressed differentially in ovaries of chickens with high rates of egg production, suggesting that these miRNAs have an important role in ovary development and reproductive management of chicken. Furthermore, we uncovered that a significantly up-regulated miRNA-gga-miR-200a-3p-is ubiquitous in reproduction-regulation-related pathways. This miRNA may play a special central role in the reproductive management of chicken, and needs to be further studied for confirmation. PMID- 27781292 TI - Implementation Strategies to Improve Knowledge and Adherence to Spinal Cord Injury Guidelines. AB - PURPOSE: The purpose of this study was to evaluate a bundle of implementation strategies (local opinion leaders, printed educational materials, and educational outreach) to increase neurocritical care nurses' knowledge of and adherence to spinal cord injury guidelines. DESIGN: A preprogram, postprogram, and follow-up design was used to evaluate outcomes. METHODS: Adherence was measured via self reported anticipatory adherence; knowledge was measured by an author-developed assessment. Repeated-measures ANOVA was used for data analysis. FINDINGS: Improvements in nursing knowledge and adherence were found from preprogram to postprogram to follow-up time points. CONCLUSIONS: Outcomes noted in this study provide additional support for using this bundle of implementation strategies and were consistent with previous research documenting the usefulness of these strategies. CLINICAL RELEVANCE: Although further research is needed, this study highlighted a systematic way of implementing evidence-based practices to improve neurocritical care nurses' knowledge of and adherence to spinal cord injury guidelines. PMID- 27781293 TI - Methotrexate elimination and toxicity: MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high-dose methotrexate. AB - The genetic association of the methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism with methotrexate (MTX)-associated toxicity has been evaluated and conflicting results have been reported. The substantial heterogeneity of the studied population was suggested to be a possible explanation because ethnicity, MTX dose, coadministered chemotherapeutic agents, and folinate rescue dosage regimen could alter the MTX toxicity profile. The patient population was homogenized by limiting the cancer type to primary central nervous system lymphoma and chemotherapy protocol to a high-dose MTX monotherapy regimen. A total of 111 patients with 402 chemotherapy courses were analyzed. MTHFR 677C>T polymorphism was identified as an independent predictive marker for MTX-associated hematologic toxicity (odds ratio, 2.60; 95% confidence interval, 1.32-5.09; P = .0055). Clinically significant nephrotoxicity occurred in patients without delayed elimination, suggesting roles for factors other than serum MTX levels. MTX-induced hepatotoxicity and oral mucositis occurred independently of plasma MTX levels. PMID- 27781294 TI - Response to Re: Associations between choroidal thickness, axial length and spherical equivalent in a paediatric population. PMID- 27781296 TI - Complementary echo and CCTA findings with superior sinus venosus atrial septal defect. AB - A young female developed progressive dyspnea on minimal exertion. Echocardiography demonstrated a large right heart with severe pulmonary hypertension. Cardiac computed tomographic angiography then demonstrated a superior sinus venosus atrial septal defect with an anomalous right upper pulmonary venous drainage. Echo and CCTA were complementary in making a proper diagnosis. PMID- 27781295 TI - 3D Cohort Study: The Integrated Research Network in Perinatology of Quebec and Eastern Ontario. AB - BACKGROUND: The 3D Cohort Study (Design, Develop, Discover) was established to help bridge knowledge gaps about the links between various adverse exposures during pregnancy with birth outcomes and later health outcomes in children. METHODS: Pregnant women and their partners were recruited during the first trimester from nine sites in Quebec and followed along with their children through to 2 years of age. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, mental health and life style, medical history, psychosocial measures, diet, infant growth, and neurodevelopment. Information on the delivery and newborn outcomes were abstracted from medical charts. Biological specimens were collected from mothers during each trimester, fathers (once during the pregnancy), and infants (at delivery and 2 years of age) for storage in a biological specimen bank. RESULTS: Of the 9864 women screened, 6348 met the eligibility criteria and 2366 women participated in the study (37% of eligible women). Among women in the 3D cohort, 1721 of their partners (1704 biological fathers) agreed to participate (73%). Two thousand two hundred and nineteen participants had a live singleton birth (94%). Prenatal blood and urine samples as well as vaginal secretions were collected for >=98% of participants, cord blood for 81% of livebirths, and placental tissue for 89% of livebirths. CONCLUSIONS: The 3D Cohort Study combines a rich bank of multiple biological specimens with extensive clinical, life style, and psychosocial data. This data set is a valuable resource for studying the developmental etiology of birth and early childhood neurodevelopmental outcomes. PMID- 27781298 TI - Why chronically ill children face challenges in regular classrooms: perspectives from nursing teachers in Japan. AB - BACKGROUND: Chronically ill children are increasingly expected to join their peers in regular classrooms. However, sometimes schools do not provide adequate assistance. This study explores nursing teachers' thoughts and experiences on integrating such students into regular classrooms in Japan. METHODS: We analysed 79 essays written by nursing teachers collectively titled 'The challenges of having chronically ill children in regular classrooms'. We conducted a qualitative study using Kinoshita's Modified Grounded Theory Approach. RESULTS: Nursing teachers identified three main obstacles: insufficient resources to support chronically ill students, parents not playing a supporting role in aiding them at school and a regular classroom not being suitable for them. However, collaborating with the children's medical staff proved successful at integrating them into regular classrooms. CONCLUSIONS: Given these obstacles, it seems very difficult for nursing teachers to lead the way toward establishing cooperative support systems for the children. Instructions from medical staff could empower teachers to set up such systems. PMID- 27781297 TI - Safety and Efficacy of Using a Single Transradial MAC Guiding Catheter for Coronary Angiography and Intervention in Patients with ST Elevation Myocardial Infarction. AB - BACKGROUND: There are limited data on the impact of using a single dedicated radial guiding catheter in primary percutaneous coronary intervention (PCI) via radial access. OBJECTIVES: To investigate the effect of using a single guiding catheter (MAC 3.5) for left and right coronary angiography and intervention on catheterization laboratory door to balloon (C2B) time in patients with ST elevation myocardial infarction (STEMI). METHODS: Three hundred and sixty patients were randomized (1:1) to using a single MAC3.5 guiding catheter (MAC group) or diagnostic Tiger catheter first for coronary angiography followed by guiding catheter selection (control group) for intervention. The primary outcomes were C2B. The secondary outcomes were major adverse cardiac events (MACE) at 30 days and 6 months. RESULTS: Median C2B time (16.6 min, interquartile range [IQR] 14.3-20.2 min vs 19.0 min, IQR 14.3-23.1 min; P < 0.001), total procedure time (31.0 min, IQR 26.4-37.7 min vs 34.8 min, IQR 29.7-42.5 min, P < 0.001), and overall fluoroscopy time (8.0 min, IQR 6.4-10.4 min vs 8.8 min, IQR 6.5-12.2, P = 0.04) were significantly reduced in MAC Group. Contrast consumption were similar among both groups (103 +/- 37 ml vs 110 +/- 41 ml, P = 0.16). The MACE rate in MAC group and control group was 3.3 versus 4.4% (P = 0.586) at 30 days and 3.3 versus 5.0% (P = 0.429) at 6 months, respectively. CONCLUSIONS: A single MAC3.5 guiding catheter for coronary angiography and intervention can shorten C2B time, procedure time, and fluoroscopy time. (RAPID study; NCT01759043). PMID- 27781300 TI - Functional Synergy Between Postural and Visual Behaviors When Performing a Difficult Precise Visual Task in Upright Stance. AB - Previous works usually report greater postural stability in precise visual tasks (e.g., gaze-shift tasks) than in stationary-gaze tasks. However, existing cognitive models do not fully support these results as they assume that performing an attention-demanding task while standing would alter postural stability because of the competition of attention between the tasks. Contrary to these cognitive models, attentional resources may increase to create a synergy between visual and postural brain processes to perform precise oculomotor behaviors. To test this hypothesis, we investigated a difficult searching task and a control free-viewing task. The precise visual task required the 16 young participants to find a target in densely furnished images. The free-viewing task consisted of looking at similar images without searching anything. As expected, the participants exhibited significantly lower body displacements (linear, angular) and a significantly higher cognitive workload in the precise visual task than in the free-viewing task. Most important, our exploration showed functional synergies between visual and postural processes in the searching task, that is, significant negative relationships showing lower head and neck displacements to reach more expended zones of fixation. These functional synergies seemed to involve a greater attentional demand because they were not significant anymore when the cognitive workload was controlled (partial correlations). In the free viewing task, only significant positive relationships were found and they did not involve any change in cognitive workload. An alternative cognitive model and its potential subtended neuroscientific circuit are proposed to explain the supposedly cognitively grounded functional nature of vision-posture synergies in precise visual tasks. PMID- 27781301 TI - Supermicrosurgical lymphatico comitantes perforator venule anastomosis for the treatment of peripheral lymphedema: A new configuration for patients with superficial vein insufficiency? PMID- 27781299 TI - Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. AB - Cell therapy has emerged as a potential treatment for many neurodegenerative diseases including stroke and neonatal ischemic brain injury. Delayed intranasal administration of mesenchymal stem cells (MSCs) after experimental hypoxia ischemia and after a transient middle cerebral artery occlusion (tMCAO) in neonatal rats has shown improvement in long-term functional outcomes, but the effects of MSCs on white matter injury (WMI) are insufficiently understood. In this study we used longitudinal T2-weighted (T2W) and diffusion tensor magnetic resonance imaging (MRI) to characterize chronic injury after tMCAO induced in postnatal day 10 (P10) rats and examined the effects of delayed MSC administration on WMI, axonal coverage, and long-term somatosensory function. We show unilateral injury- and region-dependent changes in diffusion fraction anisotropy 1 and 2 weeks after tMCAO that correspond to accumulation of degraded myelin basic protein, astrocytosis, and decreased axonal coverage. With the use of stringent T2W-based injury criteria at 72 hr after tMCAO to randomize neonatal rats to receive intranasal MSCs or vehicle, we show that a single MSC administration attenuates WMI and enhances somatosensory function 28 days after stroke. A positive correlation was found between MSC-enhanced white matter integrity and functional performance in injured neonatal rats. Collectively, these data indicate that the damage induced by tMCAO progresses over time and is halted by administration of MSCs. (c) 2016 Wiley Periodicals, Inc. PMID- 27781302 TI - The two faces of the translaminar pressure difference: the biomechanical one and the biochemical one. PMID- 27781303 TI - Long-term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis. AB - Neurogenesis is a well-characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of chronic inflammation remains controversial. In this study the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis was used to investigate the long-term effects of T cell-mediated central nervous system inflammation on hippocampal neurogenesis. 5-Bromodeoxyuridine (BrdU)-labeled subpopulations of hippocampal cells in EAE and control mice (coexpressing GFAP, doublecortin, NeuN, calretinin, and S100) were quantified at the recovery phase, 21 days after BrdU administration, to estimate alterations on the rate and differentiation pattern of the neurogenesis process. The core features of EAE mice DG are (i) elevated number of newborn (BrdU+) cells indicating vigorous proliferation, which in the long term subsided; (ii) enhanced migration of newborn cells into the granule cell layer; (iii) increased level of immature neuronal markers (including calretinin and doublecortin); (iv) trending decrease in the percentage of newborn mature neurons; and (v) augmented gliogenesis and differentiation of newborn neural precursor cells (NPCs) to mature astrocytes (BrdU+/S100+). Although the inflammatory environment in the brain of EAE mice enhances the proliferation of hippocampal NPCs, in the long term neurogenesis is progressively depleted, giving prominence to gliogenesis. The discrepancy between the high number of immature cells and the low number of mature newborn cells could be the result of a caused defect in the maturation pathway. (c) 2016 Wiley Periodicals, Inc. PMID- 27781305 TI - New onset of few atrophic white papules of the trunk and limbs. PMID- 27781304 TI - Poly(phosphorodiamidate)s by Olefin Metathesis Polymerization with Precise Degradation. AB - Degradable polymers are a currently growing field of research for biomedical and materials science applications. The majority of such compounds are based on polyesters and polyamides. In contrast, their phosphorus-containing counterparts are much less studied, in spite of their potential precise degradation profile and biocompatibility. Herein, the first library of poly(phosphorodiamidate)s (PPDAs) with two P-N bonds forming the polymer backbone and a pendant P-OR group is prepared through acyclic diene metathesis polymerization. They are designed to vary in their hydrophilicity and are compared with the structural analogues poly(phosphoester)s (PPEs) with respect to their thermal properties and degradation profiles. The degradation of PPDAs can be controlled precisely by the pH: under acidic conditions the P-N linkages in the polymer backbone are cleaved, whereas under basic conditions the pendant ester is cleaved selectively and almost no backbone degradation occurs. The PPDAs exhibit distinctively higher thermal stability (from thermogravimetric analysis (TGA)) and higher glass transition and/or melting temperatures (from differential scanning calorimetry (DSC)) compared with analogous PPEs. This renders this exotic class of phosphorus containing polymers as highly promising for the development of future drug carriers or tissue engineering scaffolds. PMID- 27781306 TI - Flexibility is associated with motor competence in schoolchildren. AB - Available data on the associations between motor competence (MC) and flexibility are limited and result inconclusive. This study aims to examine the relationship between flexibility and MC in children. The sample comprised 596 Portuguese children (47.1% girls) aged 9.7 +/- 0.6 years. Motor competence was evaluated with the body coordination test, Korperkoordination Test fur Kinder. Cardiorespiratory fitness (20-m shuttle run), muscular strength (curl-up and push up tests), and flexibility (back-saver sit and reach and trunk-lift tests) were evaluated using the Fitnessgram Test Battery. Z-scores by age and gender for the physical fitness tests were constructed. Analysis of variance and regression analysis were performed. Participants in the healthy zone groups of both flexibility tests exhibited significantly better scores of MC than the participants under the healthy zone (P < 0.001). Back-saver sit and reach and trunk-lift Z-scores, either individually or as a sum, were significant predictors of MC (P < 0.05 for all) after adjustments for the other physical fitness components, age, body mass index, and socioeconomic status, in both genders. Our findings highlight the importance of promoting and developing flexibility, as well as the other health-related physical fitness components in schoolchildren to reach adequate levels of MC. PMID- 27781307 TI - Composition and adaptation of human myotendinous junction and neighboring muscle fibers to heavy resistance training. AB - The myotendinous junction (MTJ) is a common site of strain injury and yet understanding of its composition and ability to adapt to loading is poor. The main aims of this study were to determine the profile of selected collagens and macrophage density in human MTJ and adjoining muscle fibers, and to investigate whether heavy exercise loading would alter this profile. Fifteen individuals scheduled for anterior cruciate ligament repair surgery were randomized into three groups: control, acute or 4 weeks heavy resistance training. MTJ samples were collected from the semitendinosus and gracilis muscles and were sectioned and stained immunohistochemically for collagen types I, III, VI, XII, XIV, XXII, Tenascin-C and CD68. Macrophage density and distribution was evaluated and the amount of each collagen type in muscle and MTJ was graded. Collagen XXII was observed solely at the MTJ, while all other collagens were abundant at the MTJ and in muscle perimysium or endomysium. The endomysial content of collagen XIV, macrophages and Tenascin-C increased following 4 weeks of training. These findings illustrate the heterogeneity of collagen type composition of human MTJ. The increase in collagen XIV following 4 weeks of training may reflect a training induced protection against strain injuries in this region. PMID- 27781309 TI - Ir-Catalyzed C-H Amidation of Aldehydes with Stoichiometric/Catalytic Directing Group. AB - Ir-catalyzed sp2 C-H amidation of aldehydes with various anilines as stoichiometric or catalytic directing groups was accomplished. A wide range of substrates were selectively amidated in good to excellent yields with broad functional group tolerance. The iridacycle complexes were isolated, characterized, and proved as key intermediates. Kinetic studies and Hammett plots provided detailed understandings of this amidation. According to the mechanism, the electron-rich ArSO2 N3 was proved effective for intermolecular sp3 C-H amidation. PMID- 27781308 TI - Clinical Outcomes Following Covered Stent for the Treatment of Coronary Artery Perforation. AB - BACKGROUND: This study aimed to evaluate short- and long-term outcomes of polytetrafluoroethylene covered stent for patients with coronary artery perforation. METHODS: During April 2004 and February 2016, a total 48 patients underwent implantation using polytetrafluoroethylene-covered JOSTENT GraftMaster stents (Abbott Vascular, Santa Clara, CA) in the native coronary arteries implantation for coronary artery perforation. Clinical outcomes such as target lesion revascularization (TLR), myocardial infarction (MI), definite or possible stent thrombosis, cardiovascular mortality, and all-cause mortality were analyzed. RESULTS: The average age of study patients was 68.02 +/- 13.49 years, and the majorities were men (76.6%). The most frequent devices cause of perforation were stents (37.5%). Eighteen patients (37.5%) experienced cardiac tamponade and 20 patients (41.7%) underwent emergent pericardiocentesis. Only 1 patient (2.1%) experienced emergent surgical repair after covered stent. At the 30-day follow-up, the rate of all-cause mortality was 16.7% and cardiovascular mortality was 13.0%. At the 1-year follow-up, the rate of MI was 6.1%, the rate of TLR was 21.9%, the rate of definite or possible stent thrombosis was 15.6%, the rate of cardiovascular mortality was 22.0%, and the rate of all-cause mortality was 26.2%. Between the patients with and without cardiac tamponade, patients with cardiac tamponade had higher cardiovascular mortality in 30-day and also higher all-cause mortality in 30-day and 1-year follow-up. CONCLUSION: The covered stent could solve emergent condition for patients with coronary artery perforation with high TLR and stent thrombosis rate at long-term follow-up. The patients with cardiac tamponade had worse clinical outcomes in 30-day and 1-year follow-up. PMID- 27781310 TI - Double-Negative Mechanical Metamaterials Displaying Simultaneous Negative Stiffness and Negative Poisson's Ratio Properties. AB - A scalable mechanical metamaterial simultaneously displaying negative stiffness and negative Poisson's ratio responses is presented. Interlocking hexagonal subunit assemblies containing 3 alternative embedded negative stiffness (NS) element types display Poisson's ratio values of -1 and NS values over two orders of magnitude (-1.4 N mm-1 to -160 N mm-1 ), in good agreement with model predictions. PMID- 27781311 TI - Phellinus species: An emerging cause of refractory fungal infections in patients with X-linked chronic granulomatous disease. AB - Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing. He improved with amphotericin B and isavuconazole but required haematopoietic stem cell transplantation (HSCT). We review the literature on Phellinus infections in CGD and conclude that: (i) these infections emerge on mould-active prophylaxis and are indolent; (ii) they typically cause locally destructive disease but can disseminate; (iii) diagnosis is delayed and requires molecular methods; (iv) amphotericin B is most active in vitro; and (v) treatment is protracted and requires surgery and possibly HSCT. In conclusion, Phellinus spp. are emerging pathogens in CGD. Every effort should be made to establish the diagnosis of non-Aspergillus IFIs in patients with CGD by sending tissue specimens for molecular diagnostics. PMID- 27781313 TI - High-Capacity Aqueous Potassium-Ion Batteries for Large-Scale Energy Storage. AB - A potassium iron (II) hexacyanoferrate nanocube cathode material is reported, which operates with an aqueous electrolyte to deliver exceptionally high capacities (up to 120 mA h g-1 ). The cathode material exhibits excellent structural integrity, leading to fast kinetics and highly reversible properties. All of the battery materials are safe, inexpensive, and provide superior high rate, long-cycle-life electrochemical performance. PMID- 27781312 TI - Predictors of Beagley-Gibson skin cast grade in older adults. AB - BACKGROUND AND PURPOSE: The Beagley-Gibson (BG) grading system utilizes microtopographical skin changes to generate an individualized, objective estimate of cumulative, lifetime ultraviolet radiation (UVR) exposure. However, predictors of BG grade are ill-defined, particularly in older populations. The aim of this cross-sectional study was to describe the factors associated with skin damage as measured by the BG method in 835 community-dwelling older adults. METHODS: Study participants aged 53-83 years had silicone casts taken from the dorsum of both hands and graded by the BG method. Lifetime sun exposure, skin phenotypic traits and smoking status were assessed by questionnaire. 25-hydroxyvitamin D and melanin density were measured using radioimmunoassay and spectrophotometry, respectively. Ordered logistic regression was used to compute a single odds ratio (OR) by taking BG grade as the outcome variable. RESULTS: Higher 25 hydroxyvitamin D was associated with increasing BG grade (OR = 1.39, P = 0.02) in adjusted analysis. Age (OR = 1.14, P < 0.001), occupational sun exposure (OR = 1.62, P < 0.001), ability to tan (OR = 1.40, P < 0.001), melanin density (OR=0.79, P = 0.001), lifetime leisure time sun exposure (OR = 1.21, P = 0.004), current smoking (OR = 1.82, P = 0.007), propensity to sunburn (OR = 1.18, P = 0.016), and waist-hip ratio (OR = 1.10, P = 0.02) were independent predictors of BG grade. Hair colour, number of sunburns, body mass index and gender were not independent predictors of BG grade. CONCLUSIONS: Beagley-Gibson skin cast grade is a biologically relevant marker of UVR exposure in older adults influenced by both intrinsic and extrinsic factors. PMID- 27781314 TI - Changes in physical activity and sedentary time in the Finnish Schools on the Move program: a quasi-experimental study. AB - The aim of the Finnish Schools on the Move program is to create a more active and pleasant school day through physical activity (PA). In this quasi-experimental design, we compared changes in moderate-to-vigorous-intensity physical activity (MVPA) and sedentary time (ST) during the school day and outside school hours for Grades 1-9 over two academic years in four program schools and two reference schools. Altogether 319 girls and boys aged 7-15 participated in the study between 2010 and 2012. MVPA and ST were measured four times over the 1.5-year follow-up period for seven consecutive days, using a hip-worn ActiGraph accelerometer. Linear growth curve modeling was used to examine the effect of the program on MVPA and ST during follow-up. School day MVPA increased (P = 0.010) and school day ST decreased (P = 0.008) in program primary schools (Grades 1-6) more compared with the reference schools. The effect sizes (Cohen's d) for the difference in change (from the first to the last measurement) were small (d = 0.18 and d = -0.27, respectively). No differences in the changes of leisure-time or whole-day MVPA and ST between the program and reference schools were observed during follow-up. In conclusion, the changes in school day MVPA and ST did not translate into positive effects across the whole day. More effective and longer promotion actions are needed for positive changes in PA and ST, especially in lower secondary schools and for all daily segments. PMID- 27781315 TI - Micro-Nanocomposites in Environmental Management. AB - Water pollution, a worldwide issue for the human society, has raised global concerns on environmental sustainability, calling for high-performance materials for effective treatments. Since the traditional techniques have inherent limitations in treatment speed and efficiency, nanotechnology is subsequently used as an environmental technology to remove pollutants through a rapid adsorption and degradation process. Therefore, here, various adsorbent and photodegradation composite materials leading to effective water remediation are summarized and predicted. Notably, recent advances in simultaneous adsorption and photodegradation micro-nanocomposites are outlined. Such materials can not only completely adsorb and remove contaminants, but the micro-nanocomposites can also be directly reused without further treatment. Finally, the future development of this unique system is discussed. PMID- 27781316 TI - Stillbirth and intrauterine fetal death: role of routine histological organ sampling to determine cause of death. AB - OBJECTIVES: Guidelines for the investigation of intrauterine death and sudden unexpected death in infancy (SUDI) recommend, based on expert opinion, autopsy procedures and tissue sampling strategies for histological analysis. Although stillbirth is much more common than SUDI, there have been no large-scale studies published which evaluate the usefulness of histological evaluation of specific organs in stillbirth for determining cause of death. Our aim was to evaluate the use of macroscopic and microscopic assessment of internal organs to determine cause of intrauterine death. METHODS: As part of a larger study evaluating several aspects of autopsy findings in intrauterine death, a dedicated database was used to collate antenatal and postmortem examination details for cases of intrauterine death examined between 2005 and 2013 at two tertiary specialist centers in London, UK. Histological findings for all organs were examined in relation to the final cause of death, as determined by objective criteria. RESULTS: Among 1064 intrauterine deaths, the majority (> 80%) of cases had internal organs that were normal on both macroscopic and microscopic examination. There was no case in which histological cardiac examination provided the cause of death when the macroscopic appearance of the heart was normal. Microscopic examination of lung tissue revealed 13 (1%) cases with histological abnormalities that provided the cause of death when the macroscopic appearance was normal, but there was only one (0.1%) case in which the diagnosis would not have been apparent on placental examination: a case of congenital cytomegalovirus infection. There was no case in which microscopic examination of macroscopically normal liver, kidneys, adrenals, spleen, thymus, intestines, pancreas, brain or thyroid provided the cause of death. CONCLUSION: In this large series of autopsies in cases of intrauterine death, only around 1% of cases demonstrated histological abnormalities which provided the cause of death when the internal organs appeared normal macroscopically. There was no case in which routine histological examination of most tissues provided diagnostically useful information that was not apparent from other examinations, such as placental pathology. There is little benefit, purely in terms of determining cause of death, in obtaining tissue from most macroscopically normal organs for routine histological examination. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27781317 TI - Stillbirth and intrauterine fetal death: factors affecting determination of cause of death at autopsy. AB - OBJECTIVES: There have been several attempts to classify cause of death (CoD) in stillbirth; however, all such systems are subjective, allowing for observer bias and making comparisons between systems challenging. This study aimed to examine factors relating to determination of CoD using a large dataset from two specialist centers in which observer bias had been reduced by classifying findings objectively and assigning CoD based on predetermined criteria. METHODS: Detailed autopsy reports from intrauterine deaths in the second and third trimesters during 2005-2013 were reviewed and findings entered into a specially designed database, in which CoD was assigned using predefined objective criteria. Data regarding CoD categories and factors affecting determination of CoD were examined. RESULTS: There were 1064 intrauterine deaths, including 246 early intrauterine fetal deaths (IUFD) (< 20 weeks), 179 late IUFDs (20-23 weeks) and 639 stillbirths (>= 24 weeks' gestation). Overall, around 40% (n = 412) had a clear CoD identified, whilst around 60% (n = 652) were classified as 'unexplained', including around half with identified risk factors or lesions of uncertain significance, with the remaining half (n = 292 (45%)) being entirely unexplained. A stepwise increase in the proportion of unexplained deaths was observed with increasing maceration. Black and Asian women had significantly greater proportions of deaths due to ascending infection, whilst women aged over 40 years had significantly increased placenta-related CoDs. There was no significant difference in CoD distribution according to maternal body mass index or with increasing postmortem interval. Around half of those with an identifiable CoD could be identified from clinical review and external fetal examination or imaging, with most of the remainder being determined following placental examination. CONCLUSIONS: Based on objective criteria, many intrauterine deaths throughout gestation remain unexplained despite autopsy examination. The rate of unexplained death varies from around 30% to 60% depending on interpretation of the significance of features. CoD determination is dependent on both the classification system used and subjective interpretation, such that variation in the proportion of 'unexplained' cases is based largely on speculation regarding mechanisms of death. Novel methods to determine objectively the mechanism of death at postmortem examination are required. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27781318 TI - Cytotoxicity of Exfoliated Layered Vanadium Dichalcogenides. AB - Transition-metal Group 5 vanadium dichalcogenides have shown promising properties for many applications, such as batteries, capacitors, electrocatalysts for hydrogen production and many more. However, their toxicological effects have not yet been well understood. Here, we studied the cytotoxicity of exfoliated VS2 , VSe2 and VTe2 by incubating various concentrations of the materials with human lung carcinoma (A549) cells for 24 h and measuring the remaining cell viabilities after the treatment. We found that these vanadium dichalcogenides are relatively more toxic compared to Group 6 transition-metal dichalcogenides (TMDs), namely MoS2 , WS2 and WSe2 . This study is important for a better understanding of the toxicity of TMDs in preparation for their actual commercialisation in the future. PMID- 27781319 TI - Stillbirth and intrauterine fetal death: role of routine histopathological placental findings to determine cause of death. AB - OBJECTIVES: Placental abnormalities are a common cause of death in stillbirth, ranking second only to unexplained deaths, though there is wide variation in the proportion attributed to placental disease. In clinical practice, interpretation of the significance of placental findings is difficult, since many placental features in stillbirths overlap with those in live births. Our aim was to examine objectively classified placental findings from a series of > 1000 autopsies following intrauterine death in order to evaluate the role of placental histological examination in determining the cause of death. METHODS: As part of a larger study evaluating several aspects of autopsy findings in intrauterine death, a dedicated database was used to collate antenatal and postmortem examination details for all cases examined between 2005 and 2013 at two tertiary specialist centers in London, UK. Histological findings for placentas were evaluated in relation to the final cause of death. RESULTS: Among 1064 intrauterine deaths, 946 (89%) cases had the placenta submitted for examination as part of the autopsy. Of these, 307 (32%) cases had the cause of death assigned to abnormalities of the placenta, cord or membranes. Around one third of stillbirths (>= 24 weeks) had some isolated placental histological abnormality identified, many of uncertain significance, a significantly greater proportion than in cases of second-trimester intrauterine fetal demise (P < 0.0001). The cause of death was ascending infection in 176/946 (19%) cases, peaking at 22 weeks' gestation, with significantly more black mothers having ascending infection compared with other ethnicities (P < 0.0001). Maternal vascular malperfusion was the largest category of placental abnormalities in stillbirth, with peak prevalence in the early third trimester. There were 18 (2%) cases with specific histological abnormalities, including chronic histiocytic intervillositis and massive perivillous fibrin deposition. CONCLUSIONS: Placental pathologies represent the largest category of cause of intrauterine death. Placental histological examination is the single most useful component of the autopsy process in this clinical setting. A minority of cases are associated with specific placental pathologies, often with high recurrence rates, that can be diagnosed only on microscopic examination of the placenta. Many deaths remain unexplained, although placental histological lesions may be present which are of uncertain significance. A rigorous, systematic approach to placental pathology research and classification may yield better understanding of the significance of placental findings and reduce the rate of unexplained intrauterine deaths. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27781320 TI - Contribution of Energy Transfer from the Singlet State to the Sensitization of Eu3+ and Tb3+ Luminescence by Sulfonylamidophosphates. AB - A series of stable lanthanide complexes Na[Ln(L)4 ] (Ln=La3+ , Eu3+ , Gd3+ , Tb3+ , with L=dimethyl(4-methylphenylsulfonyl)amidophosphate and dimethyl-2 naphthylsulfonylamidophosphate) were synthesized. The compounds were characterized by single-crystal X-ray diffraction, IR, absorption, and emission spectroscopy at 293 and 77 K. In contrast to the usual and well-known dominant role of the ligand triplet state in intramolecular energy transfer processes in Ln complexes, in this particular new class of Ln compounds with sulphonylamidophosphate ligands, strong experimental and detailed theoretical evidence suggest a dominant role is played by the ligand first excited singlet state. The importance of the role played by the 7 F5 level in the case of the Tb3+ compound in this process is shown. The theoretical approach for the energy transfer rates was successfully applied to the rationalization of the experimental data. The higher-lying excited levels of Eu (5 DJ , 5 LJ , 5 GJ ) and Tb (5 DJ , 5 GJ , 5 LJ , 5 HJ , 5 FJ , 5 IJ ) were included in the calculations for the first time. Both the multipolar and exchange mechanisms were taken into account. The experimental intensity parameters (Omegalambda ), emission lifetimes (tau), radiative (Arad ) and non-radiative (Anrad ) decay rates, and quantum yields (theoretical and experimental) were determined and are discussed in detail. PMID- 27781321 TI - Effects of intrauterine retention and postmortem interval on body weight following intrauterine death: implications for assessment of fetal growth restriction at autopsy. AB - OBJECTIVE: According to the classification system used, 15-60% of stillbirths remain unexplained, despite undergoing recommended autopsy examination, with variable attribution of fetal growth restriction (FGR) as a cause of death. Distinguishing small-for-gestational age (SGA) from pathological FGR is a challenge at postmortem examination. This study uses data from a large, well characterized series of intrauterine death autopsies to investigate the effects of secondary changes such as fetal maceration, intrauterine retention and postmortem interval on body weight. METHODS: Autopsy findings from intrauterine death investigations (2005-2013 inclusive, from Great Ormond Street Hospital and St George's Hospital, London) were collated into a research database. Growth charts published by the World Health Organization were used to determine normal expected weight centiles for fetuses born >= 24 weeks' gestation, and the effects of intrauterine retention (maceration) and postmortem interval were calculated. RESULTS: There were 1064 intrauterine deaths, including 533 stillbirths >= 24 weeks' gestation with a recorded birth weight. Of these, 192 (36%) had an unadjusted birth weight below the 10th centile and were defined as SGA. The majority (86%) of stillborn SGA fetuses demonstrated some degree of maceration, indicating a significant period of intrauterine retention after death. A significantly greater proportion of macerated fetuses were present in the SGA population compared with the non-SGA population (P = 0.01). There was a significant relationship between increasing intrauterine retention interval and both more severe maceration and reduction in birth weight (P < 0.0001 for both), with an average artifactual reduction in birth weight of around -0.8 SD of expected weight. There was an average 12% reduction in fetal weight between delivery and autopsy and, as postmortem interval increased, fetal weight loss increased (P = 0.0001). CONCLUSION: Based on birth weight alone, 36% of stillbirths are classified as SGA. However, fetuses lose weight in utero with increasing intrauterine retention and continue to lose weight between delivery and autopsy, resulting in erroneous overestimation of FGR. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27781322 TI - Stillbirth and intrauterine fetal death: contemporary demographic features of >1000 cases from an urban population. AB - OBJECTIVES: Of 780 000 births annually in the UK, around 3300 are stillborn, a rate of approximately 4 per 1000 births. Traditional epidemiological associations are based on historic data. The aim of this study was to document contemporary demographic findings in a large series of > 1000 deaths in utero in London and compare these with national datasets. METHODS: From a dedicated database, including > 400 data fields per case, of fetal, infant and pediatric autopsies performed at Great Ormond Street Hospital and St George's Hospital, London, we extracted information on all intrauterine deaths, excluding terminations of pregnancy, from 2005 to 2013, inclusive. Demographic data were analyzed according to the gestational age at which fetal death occurred (second-trimester intrauterine fetal death (IUFD), subdivided into early (< 20 weeks) and late (20 23 weeks) IUFD, and third-trimester stillbirth (>= 24 weeks)) and compared with national datasets when available, using Mann-Whitney U-test and comparison of proportions testing as appropriate. RESULTS: Data were available from 1064 individual postmortem reports examining intrauterine deaths delivered between 12 and 43 weeks' gestation, including 425 IUFDs (246 early and 179 late) and 639 stillbirths. Compared with the overall UK pregnant population, women in whom an intrauterine death occurred were significantly older and more obese. White mothers had a higher proportion of stillbirths (as opposed to IUFDs) than did non white mothers, whereas black mothers had a higher proportion of IUFDs relative to stillbirths. Increased body mass index was associated with increased risk across all groups. Women who had uterine fibroids, those who had a history of vaginal bleeding in early pregnancy and those who had undergone assisted conception had a relatively higher proportion of IUFDs than stillbirths. CONCLUSIONS: Based on a large series of >1000 autopsies in cases of intrauterine death, these data highlight the increased risk for fetal loss associated with maternal demographic factors in contemporary clinical practice, particularly associations with increased maternal age and body mass index. Among women in whom an intrauterine death occurs, maternal ethnicity, mode of conception and gynecological history are associated with differing timing of fetal loss. Further research is required to understand the mechanisms involved in such maternal factors in order to develop preventative strategies. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27781323 TI - Therapeutic Potential for Targeting the Suppressor of Cytokine Signalling-1 Pathway for the Treatment of SLE. AB - Although the specific events dictating systemic lupus erythematosus (SLE) pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signalling in disease progression. Notably, the suppressor of cytokine signalling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, plays a critical role in regulating cytokine signalling. To assess a relationship between SOCS1/SOCS3 expression and SLE, the goals of this study were to (1) evaluate the time kinetics of SOCS1/SOCS3 message and protein expression based on SLE-associated stimulations, (2) compare levels of SOCS1 and SOCS3 present in SLE patients and healthy controls by message and protein, (3) relate SOCS1/SOCS3 expression to inflammatory markers in SLE patients and (4) correlate SOCS1/SOCS3 levels to current treatments. We found that SOCS1 and SOCS3 were most abundant in murine splenic samples at 48 h subsequent to stimulation by anti-CD3, LPS or interferon gamma. In addition, significant reductions in SOCS1 and SOCS3 were present within PMBCs of SLE patients compared to controls by both mRNA and protein expression. We also found that decreased levels of SOCS1 in SLE patients were correlated with enhanced levels of inflammatory markers and upregulated expression of MHC class II. Finally, we show that patients receiving steroid treatment possessed higher levels SOCS1 compared to SLE patient counterparts and that steroid administration to human PBMCs upregulated SOCS1 message in a dose- and time-dependent manner. Together, these results suggest that therapeutic strategies focused on SOCS1 signalling may have efficacy in the treatment of SLE. PMID- 27781324 TI - Tracing trajectories of audio-visual learning in the infant brain. AB - Although infants begin learning about their environment before they are born, little is known about how the infant brain changes during learning. Here, we take the initial steps in documenting how the neural responses in the brain change as infants learn to associate audio and visual stimuli. Using functional near infrared spectroscopy (fNRIS) to record hemodynamic responses in the infant cortex (temporal, occipital, and frontal cortex), we find that across the infant brain, learning is characterized by an increase in activation followed by a decrease. We take this U-shaped response as evidence of repetition enhancement during early stages of learning and repetition suppression during later stages, a result that mirrors the Hunter and Ames model of infant visual preference. Furthermore, we find that the neural response to violations of the learned associations can be predicted by the shape of the learning curve in temporal and occipital cortex. These data provide the first look at the shape of the neural response during audio-visual associative learning in infancy establishing that diverse regions of the infant brain exhibit systematic changes across the time course of learning. PMID- 27781325 TI - Beyond the Storm: Comparison of Clinical Factors, Arrhythmogenic Substrate, and Catheter Ablation Outcomes in Structural Heart Disease Patients With versus Those Without a History of Ventricular Tachycardia Storm. AB - AIMS: Catheter ablation can be lifesaving in ventricular tachycardia (VT) storm, but the underlying substrate in patients with storm is not well characterized. We sought to compare the clinical factors, substrate, and outcomes differences in patients with sustained monomorphic VT who present for catheter ablation with VT storm versus those with a nonstorm presentation. METHODS: Consecutive ischemic (ICM; n = 554) or nonischemic cardiomyopathy patients (NICM; n = 369) with a storm versus nonstorm presentation were studied (ICM storm 186; NICM storm 101). RESULTS: In ICM, storm compared with nonstorm patients had significantly lower left ventricular (LV) ejection fraction (EF), greater number of antiarrhythmic drug (AAD) failures, slower VTs, greater number of scarred LV segments, higher incidence of anterior, septal, and apical endocardial LV scar (all P < 0.05). However, outcomes in follow-up were similar (12-month ventricular arrhythmia [VA] free survival: 51% vs. 52%, P = 0.6; survival free of death/transplant 75% vs. 87%, P = 0.7). In addition to the above differences, NICM storm patients were also older; however, the extent and distribution of scar was similar except for a higher incidence of lateral endocardial scar in storm patients (P = 0.05). VA free survival (36% vs. 47%, P = 0.004) and survival free of death/transplant, however, were worse in NICM storm than nonstorm patients (72% vs. 88%, P = 0.001). NICM storm patients had worse VA-free survival than ICM storm patients. CONCLUSION: There are differences in clinical factors and scar patterns in patients undergoing VT ablation who present with VT storm versus those with a nonstorm presentation. Clinical outcomes are worse in NICM storm patients. PMID- 27781328 TI - Preferential Conduction During Posterior Papillary Muscle Origin Premature Ventricular Contractions Demonstrated by Pace Mapping. PMID- 27781327 TI - Developing tailored positive parenting messages for a clinic-based communication programme. AB - BACKGROUND: Health care providers fill a central role in the prevention of both child abuse and neglect (CA/N) and unintentional childhood injury. Health communication interventions hold promise for promoting attitudes and behaviours among parents that increase positive parenting practices, which may be linked to decreased rates of intentional and unintentional childhood injuries. This manuscript describes the development of 'RISE Up', an ambulatory clinic-based childhood injury prevention programme that provides tailored, injury prevention print materials to parents of children ages 0-5. METHODS: Fifteen semi-structured key informant interviews were conducted with clinic healthcare providers and staff to develop communication strategies and materials for caregivers. Cognitive response testing was then conducted with 20 caregivers of the priority population to assess all materials. Interviews were recorded, transcribed and analyzed using thematic coding methods. RESULTS: Formative research revealed that health care providers and caregivers were very responsive to messages and materials. Health care providers reported that abuse and neglect were particularly relevant to their patients and noted several benefits to implementing the RISE Up programme in a health care setting. Caregivers generally found messages on reducing the risks of injuries, as well as the graphics displayed in the RISE Up programme to be helpful. CONCLUSIONS: Addressing the common determinants of both intentional and unintentional childhood injury through customized print materials may be a useful component of comprehensive prevention efforts to address childhood injury risk with greater impact. Providers and parents responded favourably to this communication strategy. PMID- 27781326 TI - Organ weights and ratios for postmortem identification of fetal growth restriction: utility and confounding factors. AB - OBJECTIVES: The postmortem fetal brain:liver weight ratio is commonly used as a marker of nutrition for diagnosis of fetal growth restriction (FGR). However, there are limited data regarding the effects of intrauterine retention, fetal maceration and postmortem interval on organ weights and their ratios at autopsy. Our aims were to examine the relationships between gestational-age-adjusted and sex-adjusted fetal organ weights at autopsy, cause of intrauterine death and effects of intrauterine retention, and to determine whether the brain:liver weight ratio is a reliable marker of FGR in intrauterine death. METHODS: As part of a larger study examining autopsy findings in intrauterine death, data from two specialist centers in London were collated in a specially designed database. Autopsy and clinical information for > 1000 intrauterine deaths between 2005 and 2013 were extracted. Adjusted (delta) organ weights were calculated by plotting against gestational age female and male brain, liver, thymus, heart, combined kidney, combined lung, spleen and combined adrenal gland weights. Polynomial regression was used to determine best fit and to calculate expected (50th centile) organ weights and deviations from expected. We compared adjusted organ weights and body:organ weight ratios in fetuses which were small-for-gestational age (SGA) at autopsy (birth weight < 10th centile for normal live births) vs those in fetuses which were not, and in macerated vs non-macerated fetuses. RESULTS: The majority of fetal organs (brain, liver, heart, thymus, lungs, kidneys and thyroid) in SGA fetuses were significantly lighter than those in non SGA fetuses. Body:organ weight ratios for thymus, liver and spleen were significantly greater in SGA fetuses, indicating these organs to be disproportionately small. The majority of organs were significantly lighter in macerated compared with non-macerated fetuses and body:organ weight ratios for most organs (liver, thymus, lung, pancreas, adrenal gland, kidney, heart) were significantly greater in macerated compared with non-macerated fetuses. When SGA cases with demonstrable placental histological abnormalities were compared with other SGA cases, there was a significant difference in the brain:liver weight ratio (median, 6 vs 3.5). CONCLUSION: Changes after intrauterine death lead to loss of fetal weight, with preferential weight loss of visceral organs such as the liver. Maceration therefore affects the brain:liver weight ratio and adjustment should be made for such changes during interpretation of ratios. Fetal organ weights may be affected significantly by mechanism of death and postmortem changes. The fetal brain:liver weight ratio may provide useful information regarding intrauterine growth status at time of death, provided that adjustment is made for effects of intrauterine retention and that appropriate cut-off values are used. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27781329 TI - The Magic Wand Question and Recovery-Focused Practice in Child and Adolescent Mental Health Services. AB - BACKGROUND: This paper uses a case study to describe the implementation of the Magic Wand Question (MWQ), also known as the miracle question, in a child and adolescent mental health service (CAMHS) in Scotland. The MWQ, a common intervention, is based on a Solution-Focused Brief Therapy (SFBT) approach. This intervention was undertaken by a third year student nurse with the intention of demonstrating how practice can be more closely aligned to a recovery-focused, strengths-based approach, which is in line with national policy. METHODS: SFBT has a growing evidence base for use with children and young people. However, there are still some common uncertainties about its use; therefore, a literature review has been undertaken to further explore the evidence base for the use of SFBT, with a focus on the MWQ. Furthermore, an exploration of the planning, implementation, and evaluation of the effectiveness of the MWQ is provided with a 15-year-old girl experiencing symptoms of low mood. RESULTS: Although limitations have been identified, giving careful consideration to posing the MWQ, through detailed planning prior to implementation, led to an increased understanding of factors supporting the use of the MWQ and reduced any uncertainty around when to use the MWQ in practice. In this clinical intervention, with a 15-year-old girl experiencing symptoms of low mood, the use of the MWQ was successful. CONCLUSION: The effectiveness of any treatment is best judged by the individual receiving care, and positive results have been achieved in this case study. Use of this approach ensured professionals were looking beyond diagnosis, illness, and problems in line with the principles of recovery-focused practice (Scottish Recovery Network [SRN] and NHS Education for Scotland [NES], 2007). The use of the MWQ in this case enhanced the knowledge of evidence-based practices, in line with the Nursing and Midwifery Council (NMC, ) and improved overall outcomes for individuals receiving care. PMID- 27781330 TI - Investigating looking and social looking measures as an index of infant violation of expectation. AB - Accumulated looking time has been widely used to index violation of expectation (VoE) response in young infants. But there is controversy concerning the validity of this measure, with some interpreting infant looking behaviour in terms of perceptual preferences (Cohen & Marks, ; Haith, ). The current study aimed to compare the use of looking time with a recently used measure of social looking (Walden et al., ) in distinguishing between 6-month-old infants' response to novelty/familiarity and a condition in which the object was covertly switched for a different object. Following habituation, infants showed more social looking in response to the object-switch condition than the novel object change, whereas the more commonly used accumulated looking time measure did not distinguish between the two, showing an increase for both. Thus, social looking is a more valid measure of infant VoE than looking time. PMID- 27781331 TI - Anesthetic management of premature conjoined twins posted for nonseparation emergency surgery. AB - Craniopagus conjoined twins are rare, and the chance that an anesthesiologist might face the challenge of providing anesthesia for this condition is very rare. The incidence of conjoined twins ranges from 1 : 50 000 to 1 : 200 000 births. We describe the anesthetic management of a pair of premature craniopagus conjoined twins posted for emergency surgery prior to their separation. PMID- 27781332 TI - The impact of irritable bowel syndrome on daily functioning: Characterizing and understanding daily consequences of IBS. AB - BACKGROUND: Despite the well-documented economic and psychosocial burden of irritable bowel syndrome (IBS), few studies have focused on the impact of IBS on daily activities. This study aims to quantitate impairment in daily activities among IBS patients and to evaluate the relationship between impairment, IBS, quality of life, and psychiatric symptoms. METHODS: A total of 179 participants meeting ROME-III criteria for IBS completed an online research survey evaluating the following variables: (i) the impact of IBS on daily activities, (ii) comorbid psychiatric diagnoses, (iii) symptom severity, (iv) quality of life, and (v) symptom-specific cognitive affective factors related to IBS. KEY RESULTS: This sample reported a high degree of impairment due to IBS, with 76% of the sample reporting some degree of IBS-related impairment in at least five different domains of daily life. Rates of impairment were significantly higher for participants who met criteria for anxiety, depression, and/or panic disorder. CONCLUSIONS & INFERENCES: This study contributes to existing literature by demonstrating a high level of daily impairment among patients with IBS, particularly those who meet criteria for anxiety, depression, and panic disorder. These findings support the importance of integrated psychosocial and medical care for IBS patients, and highlight the utility of evaluation and intervention for behavioral avoidance/impairment especially among those who exhibit signs or symptoms of psychiatric diagnoses. PMID- 27781333 TI - Plasticity of gastrointestinal vagal afferent satiety signals. AB - The vagal link between the gastrointestinal tract and the central nervous system (CNS) has numerous vital functions for maintaining homeostasis. The regulation of energy balance is one which is attracting more and more attention due to the potential for exploiting peripheral hormonal targets as treatments for conditions such as obesity. While physiologically, this system is well tuned and demonstrated to be effective in the regulation of both local function and promoting/terminating food intake the neural connection represents a susceptible pathway for disruption in various disease states. Numerous studies have revealed that obesity in particularly is associated with an array of modifications in vagal afferent function from changes in expression of signaling molecules to altered activation mechanics. In general, these changes in vagal afferent function in obesity further promote food intake instead of the more desirable reduction in food intake. It is essential to gain a comprehensive understanding of the mechanisms responsible for these detrimental effects before we can establish more effective pharmacotherapies or lifestyle strategies for the treatment of obesity and the maintenance of weight loss. PMID- 27781334 TI - International Session Poster. PMID- 27781335 TI - International Session Award Candidates. PMID- 27781336 TI - International Session Mini Workshop. PMID- 27781337 TI - A simple attention test in the acute phase of a major depressive episode is predictive of later functional remission. AB - BACKGROUND: Functional recovery after a major depressive episode (MDE) requires both clinical remission and preservation of cognitive skills. As attentional deficit may persist after remission, leading to functional impairment, its role as a prognosis marker needs to be considered. METHODS: Five hundred eight depressed outpatients (DSM-IV) were assessed at baseline for clinical symptoms (QIDS-SR), social functioning (Sheehan Disability Scale, SDS) and attention through the d2 test of attention and the trail making test, simple tests, respectively, requiring to quote or to interconnect relevant items. All patients were treated by agomelatine, and examined 6 to 8 weeks after baseline to assess clinical remission (QIDS-SR <= 5) and/or functional remission (SDS <= 6). RESULTS: At follow up, 154 patients (31%) were in clinical and functional remission. Shorter cumulative duration of prior depression, shorter present MDE, and two parameters of the d2 test of attention were predictive of such positive outcome, the number of omission mistakes (F1) being the only one still significantly predictive (P < .05) with a multivariate approach. F1 was unchanged after remission, patients with less than 11 mistakes had a 2.27 times increased chance to reach full remission, and a dose-response relationship was observed, with a regular increase of positive outcome for less mistakes. CONCLUSIONS: The number of omission mistakes (F1) of the d2 test of attention was a stable marker, being predictive of, and with a dose-effect for, clinical plus functional remission. It may constitute a specific marker of attentional deficit, involved in the resilience process that enables individuals to develop more adequate strategies to cope with everyday functional activities. PMID- 27781338 TI - Does induced masseter muscle pain affect integrated jaw-neck movements similarly in men and women? AB - Normal jaw opening-closing involves simultaneous jaw and head-neck movements. We previously showed that, in men, integrated jaw-neck movements during jaw function are altered by induced masseter muscle pain. The aim of this study was to investigate possible sex-related differences in integrated jaw-neck movements following experimental masseter muscle pain. We evaluated head-neck and jaw movements in 22 healthy women and 16 healthy men in a jaw opening-closing task. The participants performed one control trial and one trial with masseter muscle pain induced by injection of hypertonic saline. Jaw and head movements were registered using a three-dimensional optoelectronic recording system. There were no significant sex-related differences in jaw and head movement amplitudes. Head movement amplitudes were significantly greater in the pain trials for both men and women. The proportional involvement of the neck motor system during jaw movements increased in pain trials for 13 of 16 men and for 18 of 22 women. Thus, acute pain may alter integrated jaw-neck movements, although, given the similarities between men and women, this interaction between acute pain and motor behaviour does not explain sex differences in musculoskeletal pain in the jaw and neck regions. PMID- 27781341 TI - Our multidisciplinary journal: November 2016 issue takes us from spirituality to long-term survivors of childhood cancer. PMID- 27781340 TI - P2X3 receptor-mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD-like stress in the dorsal root ganglia of rats. AB - BACKGROUND: Patients with posttraumatic stress disorder (PTSD) often share co morbidity with chronic pain conditions. Recent studies suggest a role of P2X3 receptors and ATP signaling in pain conditions. However, the underlying mechanisms of visceral hyperalgesia following exposure to PTSD-like stress conditions remain unclarified. METHODS: The behavior and hormones relevant for PTSD were studied. Visceromotor responses (VMR) and the abdominal withdrawal reflexes (AWR) to colorectal distention (CRD) were recorded to determine P2X3 receptor-mediated alteration of hyperalgesia following single-prolonged stress (SPS) exposure. Immunofluorescence, Western blotting, and patch-clamp were used. KEY RESULTS: The escape latency, adrenocorticotropic hormone and cortisol were increased on days 7-14. Visceromotor responses and AWR was reduced at day 1 in SPS rats but increased to higher levels than in controls after exposure to day 7. Intrathecal administration of the P2X3-receptor antagonist TNP-ATP abolished the CRD response. Based on immunofluorescence and Western blotting analysis, SPS treated rats exhibited reduced P2X3 expression in dorsal root ganglia (DRG) after day 1 compared with controls. P2X3 expression in DRG was enhanced on day 7 after SPS and the increase of the P2X3 expression was maintained on day 14 and 21 compared with controls. The P2X3-receptor agonist alpha,beta-me ATP (10 MUM) induced a fast desensitizing inward current in DRG neurons of both control and SPS-treated rats. The average peak current densities in SPS-treated group were increased 3.6-fold. TNP-ATP (100 nM) markedly blocked all fast alpha,beta-me ATP induced inward currents in the DRG neurons both in control and SPS-treated rats. CONCLUSIONS & INFERENCES: The data indicate an important role of P2X3 signaling in visceral hyperalgesia following PTSD-like stress. PMID- 27781339 TI - Tumor necrosis factor alpha derived from classically activated "M1" macrophages reduces interstitial cell of Cajal numbers. AB - BACKGROUND: Delayed gastric emptying in diabetic mice and humans is associated with changes in macrophage phenotype and loss of interstitial cells of Cajal (ICC) in the gastric muscle layers. In diabetic mice, classically activated M1 macrophages are associated with delayed gastric emptying, whereas alternatively activated M2 macrophages are associated with normal gastric emptying. This study aimed to determine if secreted factors from M1 macrophages could injure mouse ICC in primary culture. METHODS: Cultures of gastric ICC were treated with conditioned medium (CM) from activated bone marrow-derived macrophages (BMDMs) and the effect of CM was quantified by counting ICC per high-powered field. KEY RESULTS: Bone marrow-derived macrophages were activated to a M1 or M2 phenotype confirmed by qRT-PCR. Conditioned medium from M1 macrophages reduced ICC numbers by 41.1%, whereas M2-CM had no effect as compared to unconditioned, control media. Immunoblot analysis of 40 chemokines/cytokines found 12 that were significantly increased in M1-CM, including tumor necrosis factor alpha (TNF alpha). ELISA detected 0.697+/-0.03 ng mL-1 TNF-alpha in M1-CM. Recombinant mouse TNF-alpha reduced Kit expression and ICC numbers in a concentration-dependent manner (EC50 = 0.817 ng mL-1 ). Blocking M1-CM TNF-alpha with a neutralizing antibody preserved ICC numbers. The caspase inhibitor Z-VAD.fmk partly preserved ICC numbers (cells/field; 6.63+/-1.04, 9.82+/-1.80 w/Z-VAD.fmk, n=6, P<.05). CONCLUSIONS & INFERENCES: This work demonstrates that TNF-alpha secreted from M1 macrophages can result in Kit loss and directly injure ICC in vitro partly through caspase-dependent apoptosis and may play an important role in ICC depletion in diabetic gastroparesis. PMID- 27781343 TI - Substrate-Modulated Reductive Graphene Functionalization. AB - Covalently functionalizing mechanical exfoliated mono- and bilayer graphenides with lambda-iodanes led to the discovery that the monolayers supported on a SiO2 substrate are considerably more reactive than bilayers as demonstrated by statistical Raman spectroscopy/microscopy. Supported by DFT calculations we show that ditopic addend binding leads to much more stable products than the corresponding monotopic reactions as a result of the much lower lattice strain of the reactions products. The chemical nature of the substrate (graphene versus SiO2 ) plays a crucial role. PMID- 27781342 TI - Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water load testing. AB - BACKGROUND: Early satiety (ES) and postprandial fullness (PPF) are often present in gastroparesis, but the importance of these symptoms in gastroparesis has not been well-described. The aims were: (i) Characterize ES and PPF in patients with gastroparesis. (ii) Assess relationships of ES and PPF with etiology of gastroparesis, quality of life, body weight, gastric emptying, and water load testing. METHODS: Gastroparetic patients filled out questionnaires assessing symptoms (PAGI-SYM) and quality of life (PAGI-QOL, SF-36v2). Patients underwent gastric emptying scintigraphy and water load testing. KEY RESULTS: 198 patients with gastroparesis (134 IG, 64 DG) were evaluated. Early satiety was severe or very severe in 50% of patients. Postprandial fullness was severe or very severe in 60% of patients. Severity scores for ES and PPF were similar between idiopathic and diabetic gastroparesis. Increasing severity of ES and PPF were associated with other gastroparesis symptoms including nausea/vomiting, satiety/early fullness, bloating, and upper abdominal pain and GERD subscores. Increasing severity of ES and PPF were associated with increasing gastroparesis severity, decreased BMI, decreased quality of life from PAGI-QOL and SF-36 physical health. Increasing severity of ES and PPF were associated with increasing gastric retention of a solid meal and decreased volume during water load test. CONCLUSIONS & INFERENCES: Early satiety and PPF are commonly severe symptoms in both diabetic and idiopathic gastroparesis. Early satiety and PPF severity are associated with other gastroparesis symptom severities, body weight, quality of life, gastric emptying, and water load testing. Thus, ES and PPF are important symptoms characterizing gastroparesis. ClinicalTrials.gov number: NCT NCT01696747. PMID- 27781344 TI - Endoscopic antireflux surgery leading to obstruction in pediatric renal transplant patients. AB - To describe a multicenter experience with management of ureteral obstruction after injection of Dx/HA for VUR in pediatric renal transplant patients. The records of all pediatric renal transplant patients who underwent Dx/HA injection for VUR and had subsequent obstruction were identified, and the management and outcomes were reviewed. Follow-up ranged from 1 to 10 years. There were four patients identified, all of whom had a history of rising creatinine, recurrent UTI, and increasing hydronephrosis which led to the diagnosis of high-grade VUR. Obstruction was diagnosed within 24-72 hours after injection in three patients. One patient was asymptomatic, and rising creatinine and hydronephrosis were noted 1 month after injection. One patient was managed expectantly, while three patients underwent ureteral stent placement. After the stent was removed, one patient went on to open reimplant due to delayed obstruction, the second patient with voiding dysfunction is currently managed with an indwelling ureteral stent and may require further definitive surgery, the third patient recovered, and the fourth is being observed. Our cases illustrate that despite initial successful management of the obstruction in some, delayed obstruction is possible and may necessitate open reimplant. It is imperative that these patients have close follow-up after Dx/HA. PMID- 27781345 TI - Immobilization of a Bacterial Cytochrome P450 Monooxygenase System on a Solid Support. AB - Bacterial cytochrome P450s (P450s), which catalyze regio- and stereoselective oxidations of hydrocarbons with high turnover rates, are attractive biocatalysts for fine chemical production. Enzyme immobilization is needed for cost-effective industrial manufacturing. However, immobilization of P450s is difficult because electron-transfer proteins are involved in catalysis and anchoring these can prevent them from functioning as shuttle molecules for carrying electrons. We studied a heterotrimeric protein-mediated co-immobilization of a bacterial P450, and its electron-transfer protein and reductase. Fusion with subunits of a heterotrimeric Sulfolobus solfataricus proliferating cell nuclear antigen (PCNA) enabled immobilization of the three proteins on a solid support. The co immobilized enzymes catalyzed monooxygenation because the electron-transfer protein fused to PCNA via a single peptide linker retained its electron-transport function. PMID- 27781347 TI - Abstracts for the 42nd Annual Meeting of the International Society for Pediatric and Adolescent Diabetes (ISPAD), 26-29 October 2016, Valencia, Spain. PMID- 27781346 TI - Slow Molecular Motions in Ionic Liquids Probed by Cross-Relaxation of Nuclear Spins During Overhauser Dynamic Nuclear Polarization. AB - Solution-state Overhauser dynamic nuclear polarization (ODNP) at moderate fields, performed by saturating the electron spin resonance (ESR) of a free radical added to the sample of interest, is well known to lead to significant NMR signal enhancements in the steady state, owing to electron-nuclear cross-relaxation. Here it is shown that under conditions which limit radical access to the molecules of interest, the time course of establishment of ODNP can provide a unique window into internuclear cross-relaxation, and reflects relatively slow molecular motions. This behavior, modeled mathematically by a three-spin version of the Solomon equations (one unpaired electron and two nuclear spins), is demonstrated experimentally on the 19 F/1 H system in ionic liquids. Bulky radicals in these viscous environments turn out to be just the right setting to exploit these effects. Compared to standard nuclear Overhauser effect (NOE) work, the present experiment offers significant improvement in dynamic range and sensitivity, retains usable chemical shift information, and reports on molecular motions in the sub-megahertz (MHz) to tens of MHz range-motions which are not accessed at high fields. PMID- 27781348 TI - cyclo-P4 Building Blocks: Achieving Non-Classical Fullerene Topology and Beyond. AB - The cyclo-P4 complexes [CpR Ta(CO)2 (eta4 -P4 )] (CpR : Cp''=1,3-C5 H3 tBu2 , Cp'''=1,2,4-C5 H2 tBu3 ) turned out to be predestined for the formation of hollow spherical supramolecules with non-classical fullerene-like topology. The resulting assemblies constructed with CuX (X=Cl, Br) showed a highly symmetric 32 vertex core of solely four- and six-membered rings. In some supramolecules, the inner cavity was occupied by an additional CuX unit. On the other hand, using CuI, two different supramolecules with either peanut- or pear-like shapes and outer diameters in the range of 2-2.5 nm were isolated. Furthermore, the spherical supramolecules containing Cp''' ligands at tantalum are soluble in CH2 Cl2 . NMR spectroscopic investigations in solution revealed the formation of isomeric supramolecules owing to the steric hindrance caused by the third tBu group on the Cp''' ligand. In addition, a 2D coordination polymer was obtained and structurally characterized. PMID- 27781349 TI - Stillbirths and fetal deaths-Better definitions to monitor practice and policy across countries. PMID- 27781350 TI - Total Synthesis of Camptothecin and Related Natural Products by a Flexible Strategy. AB - A flexible strategy for constructing natural products containing indolizinone or quinolizinone scaffolds and their analogues was developed, which was based on a cascade exo hydroamination followed by spontaneous lactamization. This method was applied in the total synthesis of camptothecin in nine steps in a new ring forming approach. It was also used to efficiently prepare five biogenetically or structurally related natural alkaloids, including 22-hydroxyacuminatine, oxypalmatine, norketoyobyrine, naucleficine, and nauclefine, as well as 35 natural-product-like molecules. We believe that this method and the small molecule library prepared with it can open new avenues for studying the bioactivity of camptothecin and Nauclea natural products. PMID- 27781351 TI - Hydrogen-Abstraction/Acetylene-Addition Exposed. AB - Polycyclic aromatic hydrocarbons (PAHs) are omnipresent in the interstellar medium (ISM) and also in carbonaceous meteorites (CM) such as Murchison. However, the basic reaction routes leading to the formation of even the simplest PAH naphthalene (C10 H8 )-via the hydrogen-abstraction/acetylene-addition (HACA) mechanism still remain ambiguous. Here, by revealing the uncharted fundamental chemistry of the styrenyl (C8 H7 ) and the ortho-vinylphenyl radicals (C8 H7 ) key transient species of the HACA mechanism-with acetylene (C2 H2 ), we provide the first solid experimental evidence on the facile formation of naphthalene in a simulated combustion environment validating the previously postulated HACA mechanism for these two radicals. This study highlights, at the molecular level spanning combustion and astrochemistry, the importance of the HACA mechanism to the formation of the prototype PAH naphthalene. PMID- 27781352 TI - Terminal-Selective Functionalization of Alkyl Chains by Regioconvergent Cross Coupling. AB - Hydrocarbons are still the most important precursors of functionalized organic molecules, which has stirred interest in the discovery of new C-H bond functionalization methods. We describe herein a new step-economical approach that enables C-C bonds to be constructed at the terminal position of linear alkanes. First, we show that secondary alkyl bromides can undergo in situ conversion into alkyl zinc bromides and regioconvergent Negishi coupling with aryl or alkenyl triflates. The use of a suitable phosphine ligand favoring Pd migration enabled the selective formation of the linear cross-coupling product. Subsequently, mixtures of secondary alkyl bromides were prepared from linear alkanes by standard bromination, and regioconvergent cross-coupling then provided access to the corresponding linear arylation product in only two steps. PMID- 27781353 TI - Bi-P Bond Homolysis as a Route to Reduced Bismuth Compounds and Reversible Activation of P4. AB - Bismuth diphenylphosphanides Bi(NONR )(PPh2 ) (NONR =[O(SiMe2 NR)2 ], R=tBu, 2,6 iPr2 C6 H3 , Aryl) undergo facile decomposition via single-electron processes to form reduced Bi and P species. The corresponding derivatives Bi(NONR )(PCy2 ) are stable. Reaction of the isolated BiII radical . Bi(NONAr ) with white phosphorus (P4 ) proceeds with the reversible and selective activation of a single P-P bond to afford the bimetallic MU,eta1:1 -bicyclo[1.1.0]tetraphosphabutane compound. PMID- 27781354 TI - Enhanced Peroxidase-Like Properties of Graphene-Hemin-Composite Decorated with Au Nanoflowers as Electrochemical Aptamer Biosensor for the Detection of K562 Leukemia Cancer Cells. AB - Graphene composites with hemin and gold nanoparticles show a better performance for hydrogen peroxide decomposition compared to that of the three components alone or duplex/hybrid complexes. Our previous studies showed that the morphology of the Au nanoparticles may greatly influence the catalytic activity of graphene family peroxidase mimics. Recently, we found that Au nanoflowers could grow in situ and form on the surface of hemin/RGO (reduced graphene oxide). The prickly morphology of this Au nanoflower brought a higher catalytic ability with enhanced kinetic parameters than traditional Au nanoparticles that showed a smooth surface. Therefore, based on this discovery, a smart electrochemical aptamer biosensor for K562 leukemia cancer cells was further presented with good performance in selectivity and sensitivity attributed to the excellent mimetic peroxidase catalytic activity of this newly synthesized Au nanoflower decorated graphene-hemin composite (H-RGO-Au NFs). PMID- 27781355 TI - Reversible Dimerization and Polymerization of a Janus Diradical To Produce Labile C-C Bonds and Large Chromic Effects. AB - Conducting polymers can be synthesized by irreversible diradical monomer polymerization. A reversible version of this reaction consisting of the formation/dissociation of sigma-dimers and sigma-polymers from a stable quinonoidal diradical precursor is described. The reaction reversibility is made by a quinonoidal molecule which changes its structure to an aromatic species by forming weak and long intermolecular C-C single bonds. The reaction provokes a giant chromic effect of about 2.5 eV. The two opposite but complementary quinonoidal and aromatic tautomers provide the Janus faces of the reactants and products which produces the observed chromic effect. A reaction mechanism is proposed to explain the variety of final products starting with structurally very similar reactants. These reversible reactions, covering an unusual regime of weak covalent supramolecular bonding, yield products which might be envisaged as novel molecular and polymeric soft matter phases. PMID- 27781357 TI - [Cu13 {S2 CNn Bu2 }6 (acetylide)4 ]+ : A Two-Electron Superatom. AB - The first structurally characterized copper cluster with a Cu13 centered cuboctahedral arrangement, a model of the bulk copper fcc structure, was observed in [Cu13 (S2 CNn Bu2 )6 (C=CR)4 ](PF6 ) (R=C(O)OMe, C6 H4 F) nanoclusters. Four of the eight triangular faces of the cuboctahedron are capped by acetylide groups in MU3 fashion, and each of the six square faces is bridged by a dithiolate ligand in MU2 ,MU2 fashion, which leads to a truncated tetrahedron of twelve sulfur atoms. DFT calculations are fully consistent with the description of these Cu13 clusters as two-electron superatoms, that is, a [Cu13 ]11+ core passivated by ten monoanionic ligands, with an a1 HOMO containing two 1S jellium electrons. PMID- 27781356 TI - Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and Sch 725674. AB - 1,2-Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3 bis(boronic esters), which can be subsequently oxidized to the corresponding secondary-secondary and secondary-tertiary 1,3-diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14-membered macrolactone, Sch 725674. The nine-step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high-yielding late-stage cross-metathesis and Yamaguchi macrolactonization reactions. PMID- 27781358 TI - Pseudo-Contact NMR Shifts over the Paramagnetic Metalloprotein CoMMP-12 from First Principles. AB - Long-range pseudo-contact NMR shifts (PCSs) provide important restraints for the structure refinement of proteins when a paramagnetic metal center is present, either naturally or introduced artificially. Here we show that ab initio quantum chemical methods and a modern version of the Kurland-McGarvey approach for paramagnetic NMR (pNMR) shifts in the presence of zero-field splitting (ZFS) together provide accurate predictions of all PCSs in a metalloprotein (high-spin cobalt-substituted MMP-12 as a test case). Computations of 314 13 C PCSs using g- and ZFS tensors based on multi-reference methods provide a reliable bridge between EPR-parameter- and susceptibility-based pNMR formalisms. Due to the high sensitivity of PCSs to even small structural differences, local structures based either on X-ray diffraction or on various DFT optimizations could be evaluated critically by comparing computed and experimental PCSs. Many DFT functionals provide insufficiently accurate structures. We also found the available 1RMZ PDB X-ray structure to exhibit deficiencies related to binding of a hydroxamate inhibitor. This has led to a newly refined PDB structure for MMP-12 (5LAB) that provides a more accurate coordination arrangement and PCSs. PMID- 27781359 TI - Analysis of Ca2+ mediated signaling regulating Toxoplasma infectivity reveals complex relationships between key molecules. AB - Host cell invasion, exit and parasite dissemination is critical to the pathogenesis of apicomplexan parasites such as Toxoplasma gondii and Plasmodium spp. These processes are regulated by intracellular Ca2+ signaling although the temporal dynamics of Ca2+ fluxes and down-stream second messenger pathways are poorly understood. Here, we use a genetically encoded biosensor, GFP-Calmodulin M13-6 (GCaMP6), to capture Ca2+ flux in live Toxoplasma and investigate the role of Ca2+ signaling in egress and motility. Our analysis determines how environmental cues and signal activation influence intracellular Ca2+ flux, allowing placement of effector molecules within this pathway. Importantly, we have identified key interrelationships between cGMP and Ca2+ signaling that are required for activation of egress and motility. Furthermore, we extend this analysis to show that the Ca2+ Dependent Protein Kinases-TgCDPK1 and TgCDPK3-play a role in signal quenching before egress. This work highlights the interrelationships of second messenger pathways of Toxoplasma in space and time, which is likely required for pathogenesis of all apicomplexan species. PMID- 27781360 TI - Nurse faculty as international research collaborators. AB - Nursing faculty who desire to expand their research portfolios will benefit from collaboration with researchers with complimentary interests from different universities across the world. International collaboration can enhance the productivity of researchers who seek to conduct studies with similar populations in different environments, and who desire a larger impact based on the findings of their studies. International collaborative teams have the potential to make important discoveries that affect the health of populations across the world. Communication is a critical step in defining the roles and professional relationships of researchers involved in international collaboration. Researchers need to be cognizant of rules affecting data security, intellectual property, data ownership, and funding sources in each country. International collaborative research can be exciting and rewarding, especially when participants are culturally aware, respect universities' policies, and are mindful of the ethical and legal principles for the countries in which the research is conducted. This article describes ways to enhance the success of nursing faculty who desire a rich experience with international research collaborators. PMID- 27781361 TI - Radical Enantioselective C(sp3 )-H Functionalization. AB - Radical style: Several breakthroughs have recently been achieved in enantioselective C(sp3 )-H functionalization through radical activation. These new strategies show how radical chemistry can be used to convert alkanes into functionalized chiral molecules (see scheme; HAT=hydrogen atom transfer). PMID- 27781362 TI - Spared internal but impaired external reward prediction error signals in major depressive disorder during reinforcement learning. AB - BACKGROUND: Major depressive disorder (MDD) creates debilitating effects on a wide range of cognitive functions, including reinforcement learning (RL). In this study, we sought to assess whether reward processing as such, or alternatively the complex interplay between motivation and reward might potentially account for the abnormal reward-based learning in MDD. METHODS: A total of 35 treatment resistant MDD patients and 44 age matched healthy controls (HCs) performed a standard probabilistic learning task. RL was titrated using behavioral, computational modeling and event-related brain potentials (ERPs) data. RESULTS: MDD patients showed comparable learning rate compared to HCs. However, they showed decreased lose-shift responses as well as blunted subjective evaluations of the reinforcers used during the task, relative to HCs. Moreover, MDD patients showed normal internal (at the level of error-related negativity, ERN) but abnormal external (at the level of feedback-related negativity, FRN) reward prediction error (RPE) signals during RL, selectively when additional efforts had to be made to establish learning. CONCLUSIONS: Collectively, these results lend support to the assumption that MDD does not impair reward processing per se during RL. Instead, it seems to alter the processing of the emotional value of (external) reinforcers during RL, when additional intrinsic motivational processes have to be engaged. PMID- 27781364 TI - The eplet load concept in clinical transplantation. PMID- 27781363 TI - The tip of the iceberg: outcomes after liver transplantation for very young infants. PMID- 27781365 TI - Asynchronous demographic responses to Pleistocene climate change in Eastern Nearctic vertebrates. AB - Pleistocene climatic cycles altered species distributions in the Eastern Nearctic of North America, yet the degree of congruent demographic response to the Pleistocene among codistributed taxa remains unknown. We use a hierarchical approximate Bayesian computational approach to test if population sizes across lineages of snakes, lizards, turtles, mammals, birds, salamanders and frogs in this region expanded synchronously to Late Pleistocene climate changes. Expansion occurred in 75% of 74 lineages, and of these, population size trajectories across the community were partially synchronous, with coexpansion found in at least 50% of lineages in each taxonomic group. For those taxa expanding outside of these synchronous pulses, factors related to when they entered the community, ecological thresholds or biotic interactions likely condition their timing of response to Pleistocene climate change. Unified timing of population size change across communities in response to Pleistocene climate cycles is likely rare in North America. PMID- 27781366 TI - Hepatic Vitamin A Content Investigation Using Coherent Anti-Stokes Raman Scattering Microscopy. AB - Standard techniques for examining the distribution of vitamin A in liver either require staining or lead to rapid photobleaching of the molecule. A potentially better alternative approach is to use coherent anti-Stokes Raman scattering (CARS) microscopy; a fast, label-free, non-disruptive imaging method that provides contrast based on molecular vibrations. This contribution evaluates the viability of CARS microscopy for imaging vitamin A within thick hepatic tissue under physiological conditions by tuning into its characteristic vibrational band in the fingerprint region. Additional information about the morphology and architecture of the tissue was acquired using second harmonic generation (SHG) and multi-photon excited fluorescence (MPEF) to help mapping the intra-lobular positions of the vitamin A droplets. We demonstrate the capability of our multimodal imaging framework to selectively image lipid-soluble vitamin A droplets deep in bulk liver tissue with a high contrast while co-registering a complementary morphological background that clearly visualizes hepatic lobules. The results obtained envisage the good prospect of the technique for in vivo studies assessing vitamin A distribution heterogeneity and how it is affected by the progression of hepatic diseases. PMID- 27781367 TI - Rich Athermal Ground-State Chemistry Triggered by Dynamics through a Conical Intersection. AB - A fundamental tenet of statistical rate theories (such as transition state theory and RRKM) is the rapidity of vibrational relaxation. Excited-state reactions happen quite quickly (sub-picosecond) and thus can exhibit nonstatistical behavior. However, it is often thought that any diversity of photoproducts results from different conical intersections connecting the excited and ground electronic states. It is also conceivable that the large energy of the photon, which is converted to vibrational energy after electronic transitions could lead to athermal hot ground state reactions and that these might be responsible for the diversity of photoproducts. Here we show that this is the case for sulfines, where a single conical intersection is implicated in the electronic transition but the excited state reaction leads to nine different products within less than a picosecond. PMID- 27781368 TI - Pyridyl-Endcapped Polyynes: Stabilized Wire-like Molecules. AB - A 4-ethynylpyridyl derivative with sterically shielding phenyl groups in the 3- and 5-positions has been synthesized and used to terminate a series of polyynes. This approach allows for the synthesis of stable polyynes up to an octayne, twice as long as previous accessible for "unstabilized" pyridyl-endcapped polyynes. The potential of these polyynes as wire-like linkers to metal centers is demonstrated by axial coordination of pyridyl groups to zinc- and ruthenium-metalloporphyrins. PMID- 27781369 TI - Ion channels, ion channel receptors, and visceral hypersensitivity in irritable bowel syndrome. AB - Ion channels are expressed throughout the gastrointestinal system and regulate nearly every aspect of digestion, including fluid secretion and absorption, motility, and visceral sensitivity. It is therefore not surprising that in the setting of functional bowel disorders, such as irritable bowel syndrome (IBS), ion channels are often altered in terms of expression level and function and are a target of pharmacological intervention. This is particularly true of their role in driving abdominal pain through visceral hypersensitivity (VH), which is the main reason IBS patients seek medical care. In the study by Scanzi et al., in the current issue of this journal, they provide evidence that the T-type voltage gated calcium channel (Cav ) Cav 3.2 is upregulated in human IBS patients, and is necessary for the induction of an IBS-like disease state in mice. In this mini review, we will discuss the contribution of specific ion channels to VH in IBS, both in human patients and rodent models. We will also discuss how Cav 3.2 may play a role as an integrator of multiple environmental stimuli contributing toward VH. PMID- 27781370 TI - Mechanically Induced Opening-Closing Action of Binaphthyl Molecular Pliers: Digital Phase Transition versus Continuous Conformational Change. AB - Reversible dynamic control of structure is a significant challenge in molecular nanotechnology. Previously, we have reported a mechanically induced continuous (analog) conformational variation in an amphiphilic binaphthyl, where closing of molecular pliers was achieved by compression of a molecular monolayer composed of these molecules at the air-water interface. In this work we report that a phase transition induced by an applied mechanical stress enables discontinuous digital (1/0) opening of simple binaphthyl molecular pliers. A lipid matrix at the air water interface promotes the formation of quasi-stable nanocrystals, in which binaphthyl molecules have an open transoid configuration. The crystallization/dissolution of quasi-stable binaphthyl crystals with accompanying conformational change is reversible and repeatable. PMID- 27781371 TI - Acute cardiorespiratory responses in participants with heart disease during cycling at different immersion levels. AB - Physical activity is often avoided or practised at a low-intensity level because of the limited ability of patients with heart disease (HD) to provide sustained effort. Immersible training has been suggested as a possible alternative as hydrostatic pressure can modify some hemodynamic parameters in healthy patients and potentially increase the exercise capacity in patients with HD. The purpose of this study was to examine the acute cardiorespiratory adaptations at different levels of immersion using an immersible ergometer (IE) in patients with HD. Twenty-one patients and 13 healthy controls (HC) participated in this study. Several cardiorespiratory parameters were assessed at two levels of immersion (hips and xiphoid) for five different pedalling rates (40, 50, 60, 70 and peak rpm). At submaximal intensity, HD and HC participants did not differ significantly for most variables. However, for nearly and/or maximal workload, HD participants showed significantly lower values for VO2 and higher values for VE /VO2 and VE /VCO2 for both immersion levels. The increase in immersion level from hips to xiphoid resulted in a significant decrease in VO2 in both HC and HD groups at the same exercise intensity. In addition, the increase in the effects of size values based on the exercise workload indicates that group differences are accentuated with the highest pedalling rates. Our data suggest that participants with HD may benefit from the hydrostatic effect during IE cycling by allowing them to alleviate their submaximal efforts and increasing their maximal cardiorespiratory capacity during hip immersion. PMID- 27781372 TI - Sufentanil Sublingual Tablet 30 mcg for the Management of Pain Following Abdominal Surgery: A Randomized, Placebo-Controlled, Phase-3 Study. AB - BACKGROUND: Results from a phase-3, prospective, randomized, double-blind, placebo-controlled trial evaluating sufentanil sublingual tablet 30 mcg (SST) for the management of pain after ambulatory abdominal surgery are presented. METHODS: Adults with American Society of Anesthesiologists status 1 to 3 scheduled to undergo abdominoplasty, open tension-free inguinal hernioplasty, or laparoscopic abdominal surgery under general or spinal anesthesia that did not include intrathecal opioids during the operation were eligible. Opioid-tolerant patients were excluded. The primary endpoint was the time-weighted summed pain intensity difference to baseline (SPID) over 12 hours. Secondary endpoints included SPID over 24 and 48 hours, total pain relief, and patient and healthcare professional (HCP) global assessments. RESULTS: Overall, 161 patients were randomized to SST (N = 107) or placebo (N = 54); pain scores were recorded for up to 48 hours. SPID 12 was higher (greater pain intensity reduction from baseline) in the SST group compared with placebo (25.8 vs. 13.1; P < 0.001, with a difference of 12.7 [95% confidence interval 7.16, 18.23]). In the SST group, a greater proportion of patients and HCPs responded "good" or "excellent" on the global assessments compared with placebo (P < 0.001 for both). There was a numerically, but not statistically, higher incidence of nausea and headache in the SST group. CONCLUSIONS: In patients following abdominal surgery in an ambulatory care setting, SST was an effective opioid analgesic in postoperative pain management. In addition, SST was well tolerated with mild-to-moderate side effects, similar to those found in placebo-treated patients. PMID- 27781373 TI - Home hemodialysis associated infection-The "Achilles' Heel" of intensive hemodialysis. AB - Home hemodialysis (HHD) is emerging as an important alternate renal replacement therapy. Although there are multiple clinical advantages with HHD, concerns surrounding increased risks of infection in this group of patients remain a major barrier to its implementation. In contrast to conventional hemodialysis, infection related complication represents the major morbidity in this mode of renal replacement therapy. Vascular access related infection is an important cause of infection in this population. Use of central vein catheters and buttonhole cannulation in HHD are important modifiable risk factors for HHD associated infection. Several preventive measures are suggested in the literature, which will require further prospective validation. PMID- 27781374 TI - Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy? AB - Homologous recombination (HR) is an evolutionarily conserved DNA repair process. Overexpression of the key HR protein RAD51 is a common feature of malignant cells. RAD51 plays two distinct genome-stabilizing roles, including HR-mediated repair of double-strand breaks (DSBs) and the promotion of replication fork stability during replication stress. Because upregulation of RAD51 in cancer cells can promote tumor resistance to DNA-damaging oncologic therapies, we and others have worked to develop cancer therapeutics that target various aspects of RAD51 protein function. Herein, we provide an overview of recent developments in this field, together with our perspectives on the challenges associated with these evolving anticancer strategies. PMID- 27781375 TI - Multidisciplinary management of hepatoblastoma in children: Experience from a developing country. AB - BACKGROUND: Advances in chemotherapy, liver resection techniques, and pediatric liver transplantation have vastly improved survival in children with hepatoblastoma (HB). These are best managed by a multidisciplinary team (MDT) in a setting where all treatment options are available. Until recently, this was difficult to achieve in India. METHODS: All children (<16 years) with HB treated in a pediatric liver surgery and transplantation unit between January 2011 and July 2016 were reviewed. Data regarding the clinical presentation, preoperative management, surgical treatment, postoperative course, and outcomes were extracted from a prospectively managed database. RESULTS: Thirty children were treated for HB during the study period. Nine children were PRETEXT 4, 7 were PRETEXT 3, 13 were PRETEXT 2, and 1 was PRETEXT 1 (where PRETEXT is pretreatment extension). All children received a neoadjuvant chemotherapy before surgery followed by an adjuvant chemotherapy. Nineteen children had complete resection, while six underwent primary living donor liver transplantation. There were six mortalities including five children who poorly responded to chemotherapy with progressive tumor extension. At a median follow-up of 30 months, two children who underwent resection and one child who underwent liver transplant had disease recurrence. CONCLUSION: Improved outcomes can be achieved in children with HB even in countries with limited resources when they are managed by MDTs with expertise in pediatric oncology, liver resection, and liver transplantation. PMID- 27781376 TI - Safety and Efficacy of a Pharmacist-Managed Patient-Controlled Analgesia Service in Postsurgical Patients. AB - PURPOSE: To compare the safety and efficacy of a pharmacist-managed patient controlled analgesia (PCA) service with physician/midlevel provider-managed (standard) PCA services in postsurgical patients. METHODS: This was a multicenter, retrospective cohort study performed at 3 major hospitals in the Detroit, Michigan, metropolitan area. Postsurgical patients from October 2012 to December 2013 were included. The primary outcome compared the pain area under the curve adjusted for time on PCA (AUC/T) of patients receiving pharmacist-managed PCA services vs. standard care, up to 72 hours after initiation of PCA. Secondary outcomes included initial opioid selection, programmed PCA settings, duration of PCA use, frequency of adjunct analgesia utilization, and frequency of breakthrough analgesia utilization. Safety outcomes were assessed as a composite safety endpoint and individually. RESULTS: Total pain AUC/T scores did not differ between the pharmacist-managed and standard-managed groups (3.25 vs. 3.25, respectively; P = 0.98). Adjunct pain medications were given with similar frequency in the 2 groups; however, significantly fewer patients required breakthrough pain medication in the pharmacist-managed group (11% vs. 36%, respectively; P < 0.0001). A composite endpoint of any adverse event occurring was found to be greater in the pharmacist-managed group. This was driven by a higher proportion of patients requiring antiemetic use (46% vs. 32%; P = 0.04). CONCLUSION: A pharmacist-managed PCA service provided no difference in pain control compared to standard management. The requirement for breakthrough analgesia was decreased in the pharmacist group, while the need for antiemetic use was increased. Further research should be conducted to evaluate different PCA management strategies. PMID- 27781377 TI - A variant c-KIT mutation, D816H, fundamental to the sequential development of an ovarian mixed germ cell tumor and systemic mastocytosis with chronic myelomonocytic leukemia. AB - An activating point mutation of the c-KIT tyrosine kinase receptor gene, D816H, has been described in germ cell tumors (GCTs). We report an adolescent diagnosed with an ovarian mixed GCT and systemic mastocytosis with chronic myelomonocytic leukemia (SM-CMML). The teratoma and dysgerminoma differed by copy number aberrations via single nucleotide polymorphism (SNP) microarray, but were inclusive of the same c-KIT D816H point mutation (c.2446G>C) also identified in blood and bone marrow mast cells. These findings indicate not only a clonal origin of the GCT and hematologic malignancy, but also suggest a rare KIT mutation may be playing a fundamental role in malignancy development. PMID- 27781378 TI - Mass cytometry reveals a distinct immunoprofile of operational tolerance in pediatric liver transplantation. AB - Long-term IS in transplant patients has significant morbidity, poorer quality of life, and substantial economic costs. TOL, defined as graft acceptance without functional impairment in the absence of IS, has been achieved in some pediatric LT recipients. Using mass cytometry, peripheral blood immunotyping was performed to characterize differences between tolerant patients and patients who are stable on single-agent IS. Single-cell mass cytometry was performed using blood samples from a single-center pediatric LT population of operationally tolerant patients to comprehensively characterize the immune cell populations in the tolerant state compared with patients on chronic low-dose IS. Specific T-cell populations of interest were confirmed by flow cytometry. This high-dimensional phenotypic analysis revealed distinct immunoprofiles between transplant populations as well as a CD4+ TOT (CD4+ CD5+ CD25+ CD38-/lo CD45RA) that correlates with tolerance in pediatric LT recipients. In TOL patients, the TOT was significantly increased as compared to patients stable on low levels of IS. This TOT cell was confirmed by flow cytometry and is distinct from classic Treg cells. These results demonstrate the power of mass cytometry to discover significant immune cell signatures that have diagnostic potential. PMID- 27781379 TI - Hypertension Attitude PersPEctives and Needs (HAPPEN): A Real-World Survey of Physicians and Patients With Hypertension in China. AB - The Hypertension Attitude PersPEctives and Needs (HAPPEN) survey was a real-world survey of cardiologists, nephrologists, and patients with treated hypertension at level 3 hospitals in China. It aimed to characterize the attitudes and behavior of physicians and patients and to identify possible causes of poor blood pressure (BP) control. Randomly selected participants (100 cardiologists, 30 nephrologists, 400 patients) completed face-to-face interviews investigating BP control rates, consulting behavior, prescribing patterns, and attitudes toward hypertension management. Perceived levels of BP control were high; 70% of physicians and 85% of patients believed that BP targets were achieved, despite only 31% of patients achieving targets. Physician satisfaction with control rates and patient satisfaction with treatment were high. Differences in perceived and actual levels of BP control may be driving therapeutic inertia. In combination with inadequate patient evaluation and support services, therapeutic inertia may contribute to poor BP control among patients with treated hypertension in China. PMID- 27781380 TI - Hodgkin lymphoma, HIV, and Epstein-Barr virus in Malawi: Longitudinal results from the Kamuzu Central Hospital Lymphoma study. AB - BACKGROUND: Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub-Saharan Africa where human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) are prevalent. METHODS: We describe a prospective cHL cohort in Malawi enrolled from 2013 to 2015. Patients received standardized treatment and evaluation, including HIV status and EBV testing of tumors and plasma. RESULTS: Among 31 patients with confirmed cHL, the median age was 19 years (range, 2-51 years) and 22 (71%) were male. Sixteen patients (52%) had stage III/IV, 25 (81%) B symptoms, and 16 (52%) performance status impairment. Twenty-three patients (74%) had symptoms >6 months, and 11 of 29 (38%) had received empiric antituberculosis treatment. Anemia was common with median hemoglobin 8.2 g/dL (range, 3.1-17.1 g/dL), which improved during treatment. No children and 5 of 15 adults (33%) were HIV+. All HIV+ patients were on antiretroviral therapy for a median 15 months (range, 2-137 months), with median CD4 count 138 cells/MUL (range, 23-329 cells/MUL) and four (80%) having undetectable HIV. EBV was present in 18 of 24 (75%) tumor specimens, including 14 of 20 (70%) HIV- and 4 of 4 (100%) HIV+. Baseline plasma EBV DNA was detected in 25 of 28 (89%) patients, with median viral load 4.7 (range, 2.0-6.7) log10 copies/mL, and subsequently declined in most patients. At 12 months, overall survival was 75% (95% confidence interval [CI], 55%-88%) and progression-free survival 65% (95% CI, 42%-81%). Baseline plasma EBV DNA and persistent viremia during treatment were associated with poorer outcomes. CONCLUSION: cHL in Malawi is characterized by delayed diagnosis and advanced disease. Most cases were EBV associated and one-third of adults were HIV+. Despite resource limitations, 12 month outcomes were good. PMID- 27781381 TI - Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database. AB - OBJECTIVE: To examine patient characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver (UESL) using a multi institutional database. SUMMARY BACKGROUND DATA: UESL is a rare disease (incidence is one per million). Therefore, the current literature is mostly limited to small case series. METHODS: The National Cancer Database was queried for primary UESL diagnosed between 1998 and 2012. RESULTS: A total of 103 patients (<18 years) were identified. The 5-year overall survival of the entire group was 86%. The best outcomes were seen in children who had tumors smaller than 15 cm and were able to undergo surgical resection with or without chemotherapy. Margin status did not appear to significantly affect survival. The most common type of resection was hemihepatectomy (37%), followed by sectionectomy (10%) and trisectionectomy (10%). Orthotopic liver transplant was performed in 10 children, all of whom survived to 5 years. CONCLUSION: Surgical resection with or without chemotherapy should be the mainstay of treatment in children with UESL, and is associated with very favorable outcomes. Negative surgical margins were not associated with improved survival. Orthotopic liver transplantation may be a viable method of attaining local control in tumors, which would otherwise be unresectable. PMID- 27781382 TI - Hepatocellular adenoma among adult survivors of childhood and young adult cancer. AB - Hepatocellular adenoma (HCA) is a rare benign epithelial neoplasm with potential for hemorrhage, rupture, or malignant transformation. Reported annual incidence of HCA is approximately 1/1,000,000. We identified 12 cases of HCA among adults with a history of childhood or young adult cancer. The most common cancer diagnosis was leukemia (N = 4). Five had undergone allogeneic hematopoietic stem cell transplant with total body irradiation. All 11 females had prior estrogen therapy; the male case was hypogonadal. This report suggests childhood and young adult cancer survivors may be at increased risk for HCA, but further investigation is needed. PMID- 27781383 TI - Topographic, tomographic and biomechanical corneal changes during pregnancy in patients with keratoconus: a cohort study. AB - PURPOSE: This study aimed at evaluating the effect of pregnancy on topographic, tomographic and biomechanical parameters of patients with keratoconus (KC) in comparison with non-pregnant patients with KC. METHOD: In a cohort study, patients with KC, whose disease was stable for at least 2 years, were evaluated before pregnancy, at their third trimester of pregnancy (34th week of pregnancy) and 6 months after pregnancy. As the control group, an equivalent number of age- and severity-matched non-pregnant female patients with KC were evaluated at the corresponding times. All subjects were evaluated with respect to central and thinnest corneal thickness (CCT and TCT), keratometry values, and maximum anterior and posterior elevation measurements (AE and PE) by Pentacam. Furthermore, corneal biomechanical properties including corneal hysteresis (CH) and corneal resistance factor (CRF) were measured using the ocular response analyser. RESULTS: Twenty-two eyes of 11 patients were equally enrolled in each group. The results revealed that there was a statistically significant difference between the means of all measurements during the course of study (p < 0.001, repeated measures analysis of variance). The values of CCT, TCT, CH, CRF, IOPg and IOPcc were significantly decreased; however, keratometry values, AE, PE and refraction measurements were significantly increased during the study period (p < 0.001). In contrast, no significant differences were observed regarding the study variables in the control group (p > 0.05). According to the Amsler-Krumeich classification, severity of KC increased during the pregnancy and postpregnancy periods (p = 0.038). CONCLUSION: The obtained results revealed that KC progressed during the pregnancy period and continued to the post-partum period, indicating that pregnancy may be a risk factor for KC progression. Patients with KC, who intend to become pregnant, may consider corneal cross-linking treatment in an attempt to stop KC progression. PMID- 27781384 TI - Comment on: Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease. PMID- 27781385 TI - An Epigenetic Perspective on the Midwife Toad Experiments of Paul Kammerer (1880 1926). AB - Paul Kammerer was the most outstanding neo-Lamarckian experimentalist of the early 20th century. He reported spectacular results in the midwife toad, including crosses of environmentally modified toads with normal toads, where acquired traits were inherited in Mendelian fashion. Accusations of fraud generated a great scandal, ending with Kammerer's suicide. Controversy reignited in the 1970s, when journalist Arthur Koestler argued against these accusations. Since then, others have argued that Kammerer's results, even if real, were not groundbreaking and could be explained by somatic plasticity, inadvertent selection, or conventional genetics. More recently, epigenetics has uncovered mechanisms by which inheritance can respond directly to environmental change, inviting a reanalysis of Kammerer's descriptions. Previous arguments for mere somatic plasticity have ignored the description of experiments showing heritable germ line modification. Alleged inadvertent selection associated with egg mortality can be discarded, since mortality decreased in a single generation, upon repeated exposures. The challenging implications did not escape the attention of Kammerer's noted contemporary, William Bateson, but he reacted with disbelief, thus encouraging fraud accusations. Nowadays, formerly puzzling phenomena can be explained by epigenetic mechanisms. Importantly, Kammerer described parent-of-origin effects, an effect of parental sex on dominance. Epigenetic mechanisms underlie these effects in genomic imprinting and experiments of transgenerational epigenetic inheritance. In the early 20th century, researchers had no reason to link them with the inheritance of acquired traits. Thus, the parent-of-origin effects in Kammerer's experiments specifically suggest authenticity. Ultimate proof should come from renewed experimentation. To encourage further research, we present a model of possible epigenetic mechanisms. PMID- 27781386 TI - HULC: an oncogenic long non-coding RNA in human cancer. AB - Highly up-regulated in liver cancer (HULC) was originally identified as the most overexpressed long non-coding RNA in hepatocellular carcinoma. Since its discovery, the aberrant up-regulation of HULC has been demonstrated in other cancer types, including gastric cancer, pancreatic cancer, osteosarcoma and hepatic metastasis of colorectal cancer. Recent discoveries have also shed new light on the upstream molecular mechanisms underlying HULC deregulation. As an oncogene, HULC promotes tumorigenesis by regulating multiple pathways, such as down-regulation of EEF1E1, promotion of abnormal lipid metabolism, and up regulation of sphingosine kinase 1. Pertinent to clinical practice, a genetic variant in the HULC gene has been found to alter the risk for hepatocellular carcinoma and oesophageal cancer, whereas cancer patients with high or low expression of HULC exhibit different clinical outcome. These findings highlighted the pathogenic role and clinical utility of HULC in human cancers. Further efforts are warranted to promote the development of HULC-directed therapeutics. PMID- 27781387 TI - Clinical presentation and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in China: A retrospective multicenter study. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous disease with major diagnostic and therapeutic difficulties. A large-scale multicenter study of pediatric HLH is still lacking in China. PROCEDURE: The Histiocytosis Study Group of the Chinese Pediatric Society conducted this retrospective study in 2014. A total of 323 patients diagnosed with HLH between 2011 and 2013 from 12 hospitals were registered. RESULTS: The median age at diagnosis was 2.2 years (range, 0-14.6 years), with a peak age of HLH onset at 0 to 3 years (63%). Mutations in HLH-related genes were found in 27.9% (24/86) patients who underwent genetic testing. PRF1, UNC13D, STXBP2 and LYST were the predominant genes involved. Sixteen patients (66.7%) presented with only monoallelic mutations in one gene. Epstein-Barr virus (EBV) infection was the major condition related to HLH, which was documented in 74.4% (201/270) of the patients who underwent EBV detection. Of 252 evaluable patients, 64.7% (163) achieved non-active disease at the eighth week and patients treated with a protocol containing etoposide presented higher remission rates (75.6% vs. 46.8%, P < 0.001). In multivariate analysis, a younger age at diagnosis (<12 months), platelet count less than 80*109 /L, central nervous system involvement, and initial treatment using a protocol without etoposide (not HLH-94/04) were independent prognostic factors indicating resistant disease. DISCUSSION: This study first multicenter assessment of HLH in China shows some different features in Chinese children with HLH compared with those in western countries, including older age, vulnerability to EBV infection, and a high proportion of patients with single monoallelic genetic mutations. PMID- 27781388 TI - The Dialysis Outcomes and Practice Patterns Study (DOPPS) in Turkey. AB - INTRODUCTION: Turkey has one of the largest treated end-stage renal disease (ESRD) patient populations in Europe (N = 66,711). In 2013, the international Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective study of hemodialysis (HD) practices and outcomes, initiated data collection in Turkey. Here we provide comparisons of HD patients in DOPPS-Turkey with other international regions and with patients in the Registry of Turkish Nephrology, Dialysis and Transplantation. METHODS: DOPPS-Turkey study sites were randomly selected from all Turkish HD units treating >=25 in-center chronic HD patients. Detailed patient- and facility-level data were collected for 20-30 randomly selected prevalent HD patients per facility. FINDINGS: Demographic and comorbidity profiles for DOPPS-Turkey patients were similar to HD patients overall in the 2013 Turkish Registry Report. In Turkey: diabetes was the most common ESRD cause (37%); arteriovenous fistula use was 83%; mean single pool Kt/V was 1.61. Compared with other international regions, Turkey had the highest mean hemoglobin (11.5 g/dL), ferritin (771 ng/mL), and interdialytic weight gain (3.28%), while Turkey had the lowest mean systolic blood pressure (127 mmHg) and erythropoiesis stimulating agent prescription (57%). Turkish patients also reported the highest depression scores. DISCUSSION: In this first DOPPS-Turkey report, the DOPPS sample agrees well with national Turkish Registry data. Treatment and laboratory data, and patient-reported outcomes, demonstrate similarities and previously unrecognized contrasts to DOPPS findings in Europe, Japan, and North America. Long-term follow-up of these patients will describe how these differences relate to clinical outcomes within Turkey. PMID- 27781390 TI - A multicenter, placebo-controlled, double-blind clinical trial assessing the effects of a multicomponent nutritional supplement for treating photoaged skin in healthy women. AB - BACKGROUND: Dietary or supplementary intake of nutrients and other ingredients positively affects skin appearance. AIMS: Evaluate a multicomponent nutritional supplement on photoaged skin. PATIENTS/METHODS: This multicenter, double-blind, placebo-controlled trial randomized healthy 35- to 65-year-old women with Fitzpatrick skin types I-IV and Glogau classification types II-III to a multicomponent nutritional supplement or placebo for 24 weeks. The primary endpoint was Investigator Global Assessment of overall facial appearance at week 24. Secondary endpoints included investigator- and subject-rated assessments of the face, decolletage, and hands; facial photography assessments (conducted by an independent panel of dermatologists); and instrumental measures. Analysis of variance was used to assess between-group differences (P <= 0.05). RESULTS: Of 194 randomized subjects, 171 completed the study. Subjects had a mean age of 53 years and were primarily white (81%), had Glogau II (58%) and Fitzpatrick III (45%; significantly more supplement subjects had Fitzpatrick III [54%] vs. placebo [35%]; P = 0.039). At week 24, Investigator Global Assessment of overall facial appearance was numerically but not statistically better for supplement over placebo (mean difference: 0.14 [95% confidence interval: -0.16-0.44]; P = 0.358). A significant treatment-by-site interaction (P = 0.073) was observed; by site analyses revealed a significant difference at one of three geographical sites for supplement vs. placebo (P = 0.001). Differences on secondary endpoints were generally not significant. CONCLUSIONS: In the first multicenter study conducted with this multicomponent nutritional supplement, no significantly greater effects vs. placebo were observed on the primary endpoint, perhaps because of significant between-site variability. PMID- 27781391 TI - Effective cleanup for the determination of six quinolone residues in shrimp before HPLC with diode array detection in compliance with the European Union Decision 2002/657/EC. AB - A high-performance liquid chromatographic method was developed for the determination of six quinolone residues (ciprofloxacin, enrofloxacin, sarafloxacin, oxolinic acid, nalidixic acid, and flumequine) in shrimp tissue samples. Separation was carried out by a LiChrospher(r) 100 RP-8e column, running at a 22 min gradient elution program, and the mobile phase consisted of citric acid (0.4 mol/L), acetonitrile and methanol. Detection was achieved by a diode array detector, monitoring at 255 and 275 nm. Sample preparation included initial extraction with citric acid solution and further clean-up by solid-phase extraction, employing Lichrolut RP-18 cartridges. Validation was performed according to the European Union Decision 2002/657/EC. The detection capability was 127.2 MUg/kg for ciprofloxacin, 115.2 MUg/kg for enrofloxacin, 126.2 MUg/kg for sarafloxacin, 113.1 MUg/kg for oxolinic acid, 125.2 MUg/kg for nalidixic acid, and 239.0 MUg/kg for flumequine. Recoveries ranged between 83.0 and 121.6%. The Youden test was applied to study the method ruggedness. PMID- 27781389 TI - Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife: The Atherosclerosis Risk in Communities Study. AB - Alzheimer's disease (AD) is the most common form of dementia and is characterized by impairment in memory, behavioral changes, and gradual loss of autonomy. Since there is a long latent period prior to diagnosis, the aim of this study was to determine whether twenty single nucleotide polymorphisms identified in genome wide association analyses of AD are associated with cognitive change in 8,320 white and 2,039 African-American middle-aged adults enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), Digit Symbol Substitution Test (DSST; processing speed), and Word Fluency Test (WFT; executive function). General linear models were used to assess mean differences in 6-year change in test scores among individuals categorized by genotype after adjusting for age, gender, and years of education. Addition of the minor allele for rs670139 (MS4A4E), rs9331896 (CLU), and rs12155159 (NME8) was nominally associated with change on the DWRT, DSST, and WFT, respectively, in whites. The ZCWPW1 (rs1476679) and CDS33 (rs3865444) variants were nominally associated with change on the DWRT and WFT in African-Americans. For rs670139 and rs9331896 the association was only significant in individuals bearing at least one APOE epsilon4 allele in stratified analyses. An unweighted genetic risk score aggregating the risk alleles for 15 polymorphisms was not associated with change in cognitive function. Although the AD-associated genetic variants appear to have small effects on early cognitive change, replication will be required to establish whether there is a discernible influence on cognitive status in midlife. (c) 2016 Wiley Periodicals, Inc. PMID- 27781392 TI - Increasing observation rates in low-risk pediatric immune thrombocytopenia using a standardized clinical assessment and management plan (SCAMP(r) ). AB - An observational approach is recommended in newly diagnosed children with immune thrombocytopenia (ITP) at low risk of bleeding; however, there is no standard definition of risk. A standardized clinical assessment and management plan (SCAMP(r) ), a modifiable practice guideline, was implemented and revised (SCAMP 1 and SCAMP-2) and applied to 71 newly diagnosed patients with ITP. The Buchanan and Adix bleeding score guided treatment and was modified by stratifying by low- and high-risk grade 3 bleeding in SCAMP-2. Observation rates increased from 40% to 74% from SCAMP-1 to SCAMP-2 (P < 0.05) with no bleeding complications. We propose a modified bleeding score that increased observation rates in low-risk patients with ITP. PMID- 27781393 TI - T-cell-rich HLA-haploidentical hematopoietic stem cell transplantation for relapsed/refractory pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia without posttransplant tyrosine kinase inhibitor therapy. AB - Intensive chemotherapy with tyrosine kinase inhibitor (TKI) improves the prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL). However, the prognosis of cases of relapsed or refractory Ph ALL remains poor. Here, we aimed to assess the efficacy of T-cell-rich HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) in eight patients with relapsed or refractory pediatric Ph-ALL. Transplant-related mortality was observed in two patients. All patients discontinued TKI after receiving TCR-haplo-HSCT. The 3-year probability of overall survival and event free survival was 75.0 and 62.5%, respectively. These results indicate the efficacy of TCR-haplo-HSCT for relapsed/refractory pediatric Ph-ALL. PMID- 27781395 TI - The effects of temperature and mobile phase on the retention of aliphatic carboxylic acids in hydrophilic interaction chromatography on zwitterionic stationary phases. AB - The influence of the mobile phase and temperature, on the retention behavior of seven aliphatic acids (pyruvic, gluconic, 2-oxoglutaric, tartaric, malic, oxalic, and citric acid) in hydrophilic interaction liquid chromatography on zwitterionic stationary phases with sulfobetaine and phosphorylcholine ligands is investigated. In agreement with the van't Hoff model, most acids show linear ln k versus 1/T plots. However, the retention of structurally symmetrical oxalic and tartaric dicarboxylic acids is almost independent of temperature, or slightly increases at rising temperature. The experimental parameters of the van't Hoff plots suggest positive entropic contributions to the retention of these symmetrical acids, possibly connected with changes in molecular symmetry on their adsorption. The type of the zwitterionic stationary phase and the mobile phase composition (the molar concentration of acetate buffer and the volume fraction of acetonitrile) affect the retention and the selectivity of the separation of the acids. PMID- 27781394 TI - A Tandem Green-Red Heterodimeric Fluorescent Protein with High FRET Efficiency. AB - The tetrameric red fluorescent protein from Discosoma sp. coral (DsRed) has previously been engineered to produce dimeric and monomeric fluorescent variants with excitation and emission profiles that span the visible spectrum. The brightest of the effectively monomeric DsRed variants is tdTomato-a tandem fusion of a dimeric DsRed variant. Here we describe the engineering of brighter red (RRvT), green (GGvT), and green-red heterodimeric (GRvT) tdTomato variants. GRvT exhibited 99 % intramolecular FRET efficiency, resulting in long Stokes shift red fluorescence. These new variants could prove useful for multicolor live-cell imaging applications. PMID- 27781397 TI - Assessment of reduced-order unscented Kalman filter for parameter identification in 1-dimensional blood flow models using experimental data. AB - This work presents a detailed investigation of a parameter estimation approach on the basis of the reduced-order unscented Kalman filter (ROUKF) in the context of 1-dimensional blood flow models. In particular, the main aims of this study are (1) to investigate the effects of using real measurements versus synthetic data for the estimation procedure (i.e., numerical results of the same in silico model, perturbed with noise) and (2) to identify potential difficulties and limitations of the approach in clinically realistic applications to assess the applicability of the filter to such setups. For these purposes, the present numerical study is based on a recently published in vitro model of the arterial network, for which experimental flow and pressure measurements are available at few selected locations. To mimic clinically relevant situations, we focus on the estimation of terminal resistances and arterial wall parameters related to vessel mechanics (Young's modulus and wall thickness) using few experimental observations (at most a single pressure or flow measurement per vessel). In all cases, we first perform a theoretical identifiability analysis on the basis of the generalized sensitivity function, comparing then the results owith the ROUKF, using either synthetic or experimental data, to results obtained using reference parameters and to available measurements. PMID- 27781396 TI - Descriptors and Thermodynamic Limitations of Electrocatalytic Carbon Dioxide Reduction on Rutile Oxide Surfaces. AB - A detailed understanding of the electrochemical reduction of CO2 into liquid fuels on rutile metal oxide surfaces is developed by using DFT calculations. We consider oxide overlayer structures on RuO2 (1 1 0) surfaces as model catalysts to elucidate the trends and limitations in the CO2 reduction reaction (CO2RR) based on thermodynamic analysis. We aim to specify the requirements for CO2RR catalysts to establish adsorbate scaling relations and use these to derive activity volcanoes. Computational results show that the OH* binding free energy is a good descriptor of the thermodynamic limitations and it defines the left leg of the activity volcano for CO2RR. HCOOH* is a key intermediate for products formed through further reduction, for example, methanediol, methanol, and methane. The surfaces that do not bind HCOOH* are selective towards formic acid (HCOOH) production, but hydrogen evolution limits their suitability. We determine the ideal binding free energy for H* and OH* to facilitate selective CO2RR over H2 /CO evolution to be DeltaGB [H]>0.5 eV and -0.5 eV0.3 mg dl-1 ) CRP, but above median MVPA (OR = 0.62; 95% CI: 0.40-0.97) and above median VO2max (OR = 0.61; 95% CI: 0.40-0.93) were associated with a reduced odds of having an elevated CRP. With regard to the additive model, and after adjustment, the odds ratios (95% CI) for the PACS score of 1 (versus 0), 2 (versus 0) and 3 (versus 0), respectively, were 0.59 (0.34-1.05; P = 0.07), 0.60 (0.31-1.15; P = 0.11) and 0.34 (0.12-0.97; P = 0.04). CONCLUSION: Cardiorespiratory fitness and MVPA, but not sedentary behaviour, were independently associated with reduced odds of elevated CRP. Adults with all three characteristics, however, had the lowest odds of elevated CRP. PMID- 27781403 TI - Keeping it in the family: Coevolution of latrunculid sponges and their dominant bacterial symbionts. AB - The Latrunculiidae are a family of cold water sponges known for their production of bioactive pyrroloiminoquinone alkaloids. Previously it was shown that the bacterial community associated with a Tsitsikamma sponge species comprises unusual bacterial taxa and is dominated by a novel Betaproteobacterium. Here, we have characterized the bacterial communities associated with six latrunculid species representing three genera (Tsitsikamma, Cyclacanthia, and Latrunculia) as well as a Mycale species, collected from Algoa Bay on the South African southeast coast. The bacterial communities of all seven sponge species were dominated by a single Betaproteobacterium operational taxonomic unit (OTU0.03 ), while a second OTU0.03 was dominant in the Mycale sp. The Betaproteobacteria OTUs from the different latrunculid sponges are closely related and their phylogenetic relationship follows that of their hosts. We propose that the latrunculid Betaproteobacteria OTUs are members of a specialized group of sponge symbionts that may have coevolved with their hosts. A single dominant Spirochaetae OTU0.03 was present in the Tsitsikamma and Cyclacanthia sponge species, but absent from the Latrunculia and Mycale sponges. This study sheds new light on the interactions between latrunculid sponges and their bacterial communities and may point to the potential involvement of dominant symbionts in the biosynthesis of the bioactive secondary metabolites. PMID- 27781405 TI - Valproic acid enhances the neural differentiation of human placenta derived mesenchymal stem cells in vitro. AB - Mesenchymal stem cells (MSCs) are known to express a wide range of markers belonging to all the three lineages: mesodermal, ectodermal and endodermal. Therefore, the possibility of their transdifferentiation towards a neural lineage has been an aspect of active research. In the present study, MSCs were isolated from human placental tissue (P-MSC) and subjected them to neural differentiation. It was found that the P-MSCs differentiated towards neural lineage in appropriate differentiation conditions. However, when a histone deacetylase (HDAC) inhibitor valproic acid (VPA) - was incorporated in the medium, there was a further increase in their neural differentiation potential. The increase in the number of neurites and neural lineage specific markers was notable. The VPA-treated cells showed a significantly elevated membrane potential compared with the cells grown in only differentiation medium. When the molecular mechanism was studied, the enhancement in the neuronal lineage specification was caused by the inhibition of bone morphogenetic protein (BMP) 2 and an increase in BMP4 under both conditions. The target of VPA (HDAC2) was reduced in the VPA set, whereas HDAC1 remained unchanged. Concurrent reduction in the levels of Stat3 was observed, leading to an upregulation of betaIII tubulin, which is a neuronal lineage-specific marker. The components of Notch signalling (i.e. decreased notch 1 and increased notch 3) also supported differentiation towards the neuronal lineage. Thus, the VPA treated P-MSCs can serve as an alternative source for deriving neural cells for use in both research and in clinics. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27781406 TI - A novel allele, HLA-A*33:97 was identified in a Chinese bone marrow donor. AB - HLA-A*33:97 has one base substitution at position 287 A>T in exon 2 compared to HLA-A*33:03:01. PMID- 27781407 TI - The Contribution of the Rasch Model to the Clinical Validation of Nursing Diagnoses: Integrative Literature Review. AB - PURPOSE: To analyze the knowledge related to the use of the Rasch model in validation of nursing diagnoses. METHODS: Integrative literature review with search in LILACS, PUBMED, CINAHL, and SCOPUS. FINDINGS: Five studies comprised the sample, which analyzed unidimensionality, local independence, item calibration, item reliability, separation of items and people, and differential item functioning for analyzing nursing diagnoses. CONCLUSIONS: The Rasch model seems to be a useful method to validate nursing diagnoses and probably also for the validation of nursing outcomes in the Nursing Outcomes Classification. The use of this model is promising, considering the advantages that it can be used in studies with several methodological designs. IMPLICATIONS FOR NURSING: Methods that are able to provide more robust evidence of nursing diagnosis validity are needed to support highly accurate diagnostic findings in clinical practice. PMID- 27781408 TI - Pathology of healing: what else might we look at? AB - Several aspects of the article by Morita et al. (Cancer Medicine 5:1607-18, 2016), examining the spontaneous healing phenomenon with reference to tumor infiltrating lymphocytes (TILs), require clarification. The concept of "healing", which can perhaps be more accurately termed "regressive change", remains controversial due to a lack of concrete evidence. Since regressive change is characterized by fibrosis and lymphocytes, a cancer nest that appears to lack a distinct basement membrane, surrounded only by lymphocytes, as in Morita et al's Figure 2F, should be meticulously examined because the appearance may correspond to a tumor having just completed the process of invasion. In our experience, a layer of myoepithelial cells in such foci is often difficult to detect even with immunohistochemistry. Thus, we suggest evaluating the viability of cancer cells within the nest by employing several markers, such as Ki67 and apoptotic markers, to judge whether the tumor is intraductal. It might also be useful to compare cases with versus without regressive change to elucidate the biology of such tumors. For these reasons, a tumor, floating within a pool of TILs and lacking obvious fibrous bands, might be an interesting material to examine in future studies. PMID- 27781409 TI - TreeExp1.0: R Package for Analyzing Expression Evolution Based on RNA-Seq Data. AB - Recent innovation of RNA-seq technology has shed insightful light on the transcriptomic evolution studies, especially on researches of tissue-specific expression evolution. Phylogenetic analysis of transcriptome data may help to identify causal gene expression differences underlying the evolutionary changes in morphological, physiological, and developmental characters of interest. However, there is a deficiency of software to phylogenetically analyze transcriptome data. To address this need, we have developed an R package TreeExp that can perform comparative expression evolution analysis based on RNA-seq data, which includes optimized input formatting, normalization, pairwise expression distance estimation, expression character tree inference, and preliminary expression phylogenetic network analysis. TreeExp also enables user to map expression distance onto a customized phylogenetic tree. By applying TreeExp on two cases of mammalian gene expression evolution, we observed that (1) expression trees of brain and testis are largely consistent with known mammalian species tree with minor discrepancies; (2) intertissues expression divergences (brain and testis) are more substantial than interspecies expression divergences across mammalian species; and (3) expression pattern of gene modules related to nervous system development exhibits specific expression pattern in brain of primates compared to housekeeping genes. These tissue-specific expression patterns might give insights underlying evo-devo mechanisms of complex organisms. TreeExp is released under the GPL v3 open source license, and its current stable version 1.0 is freely available at the Github developer site (https://github.com/hr1912/TreeExp). PMID- 27781411 TI - Glycerol as a Building Block for Prochiral Aminoketone, N-Formamide, and N-Methyl Amine Synthesis. AB - Prochiral aminoketones are key intermediates for the synthesis of optically active amino alcohols, and glycerol is one of the main biomass-based alcohols available in industry. In this work, glycerol was catalytically activated and purposefully converted with amines to generate highly valuable prochiral aminoketones, as well as N-formamides and N-methyl amines, over CuNiAlOx catalyst. The catalyst structure can be anticipated as nano-Ni species on or in CuAlOx via the formation of nano- Cu-Ni alloy particles. This concept may present a novel and valuable methodology for glycerol utilization. PMID- 27781410 TI - Expression profile of E-cadherin, estrogen receptors, and P53 in early-onset gastric cancers. AB - Early-onset gastric cancer (EOGC) is predominant in females, diffuse histology, and hereditary pattern. Germline mutation of CDH1 and p53 has been reported previously and female dominance was speculated to be associated with estrogen and its receptors. Expression of E-cadherin, estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), and p53 in EOGC remains unclear, which was the focus of this study, to assess clinical significance of their expression in EOGC. The expression of E-cadherin, ERalpha, ERbeta, and p53 in tumors and normal tissues from surgically resected EOGCs was assessed by immunohistochemistry (n = 139) and Western blot (n = 7) methods, respectively. The expression in tumor tissues was significantly higher for ERalpha, ERbeta, and p53, but lower for E cadherin, compared to uninvolved mucosa. Positive staining of ERbeta and p53 was more frequently observed in younger patients with advanced TNM stages. For E cadherin, significant correlation was observed between the immunopositivity and TNM stages IA+IB. P53-negative patients had significantly better outcomes than p53-positive patients. Significant association between expression of E-cadherin and histologic types was found in familial, but not in sporadic, EOGC. In conclusion, our results demonstrated E-cadherin may have a role in initiation of EOGC and positive ERbeta and p53 expression may partially explained early-onset and tumor progression of EOGC. PMID- 27781412 TI - Causes of false-negative for high-grade urothelial carcinoma in urine cytology. AB - INTRODUCTION: The Paris System for classifying urine cytology emphasizes identification of high-grade urothelial carcinoma (HGUC). The causes of false negative urine cytologies (UC) within this system are not well described. MATERIAL AND METHODS: We identified 660 cases between 2005 and 2013 with both UC and subsequent cystoscopic biopsies. UC were classified as either Negative for HGUC or "Abnormal" ("Atypical", "Suspicious", and "Malignant"). Apparent false negative cases were reviewed in a nonblinded fashion by two cytopathologists and two subspecialized genitourinary pathologists. RESULTS: A total of 199 of the 660 cases (30%) were histologically diagnosed as HGUC. The UC were "Abnormal" in 170/199 cases (sensitivity/specificity of 86%/71%). Twenty four apparent false negative cases were available for retrospective review. Five of 24 (21%) cystoscopic biopsies were found not to be HGUC on review (one false positive and four low-grade urothelial carcinoma (LGUC on review). Of the remaining 19 UC, 7 (29%) cytology samples were found to be truly negative on review, 11 (46%) were found to be Atypical, and 1 (4%) suspicious. Of the 12 UC that were at least "Atypical" with histologic HGUC on review: six misses (half) were attributed to obscuring inflammation/blood, four to poor preservation, eight to paucity of abnormal cells, and 1 case to interpretive error; many cases demonstrated overlapping reasons. CONCLUSION: About one fifth of apparent false negative diagnoses for HGUC can be because of overdiagnosis of HGUC by surgical pathologists. If poor preservation or obscured samples are called nondiagnostic, the sensitivity/specificity of UC for HGUC can be as high as 94%/71%. Diagn. Cytopathol. 2016;44:994-999. (c) 2016 Wiley Periodicals, Inc. PMID- 27781413 TI - Unprecedented Charge-Transfer Complex of Fused Diporphyrin as Near-Infrared Absorption-Induced High-Aspect-Ratio Nanorods. AB - Charge-transfer (CT) complexes of near-infrared absorbing systems have been unknown until now. Consequently, structural similarities between donor and acceptor are rather important to achieve this phenomenon. Herein, we report electron donors such as non-fused diporphyrin-anthracene (DP), zinc diporphyrin anthracene (ZnDP) and fused zinc diporphyrin-anthracene (FZnDP) in which FZnDP absorbs in NIR region and permits a CT complex with the electron acceptor, perylene diimide (PDI) in CHCl3 exclusively. UV/Vis-NIR absorption, 1 H NMR, NOESY and powder X-ray diffraction analysis demonstrated that the CT complex formation occurs by pi-pi stacking between perylene units in FZnDP and PDI upon mixing together in a 1:1 molar concentration in CHCl3 , unlike non-fused ZnDP and DP. TEM and AFM images revealed that the CT complex initially forms nanospheres leading to nanorods by diffusion of CH3 OH vapors into the CHCl3 solution of FZnDP/PDI (1:1 molar ratio). Therefore, these CT nanorods could lead to significant advances in optical, biological and ferroelectric applications. PMID- 27781414 TI - Genomic full-length sequence of two new HLA-C alleles, HLA-C*04:239 and HLA C*05:137. AB - Two novel HLA-C alleles, C*04:239 and C*05:137, were characterized in Spanish individuals. PMID- 27781415 TI - Overexpression of SRC-3 promotes esophageal squamous cell carcinoma aggressiveness by enhancing cell growth and invasiveness. AB - Steroid receptor coactivator-3 (SRC-3), a transcriptional coactivator for nuclear receptors and other transcription factors, plays an important role in the genesis and progression of several cancers. However, studies investigated the role of SRC 3 in esophageal squamous cell carcinomas (ESCCs) are limited, and the role of SRC 3 in tumor progression remains unclear. We examined the expression of SRC-3 in 8 ESCC cell lines and 302 human ESCC tissues by qPCR, Western blot, and immunohistochemistry. In addition, ESCC cell lines were subjected to proliferation and invasion assays, tumorigenicity assay, flow cytometry assay, qPCR, Western blot, and Chromatin Immunoprecipitation assay to investigate the role of SRC-3 in cancer progression. SRC-3 was overexpressed in 48% of cases and correlated with poor overall (P = 0.0076) and progression-free (P = 0.0069) survival of surgically resected ESCC patient. Cox regression analysis revealed that SRC-3 is an independent prognostic marker. Furthermore, we found that activation of insulin-like growth factor (IGF)/AKT) was involved in the SRC-3 on the cell growth and invasiveness in two ESCC cell lines, Eca109 and EC18 cells. SRC-3 overexpression is clinically and functionally relevant to the progression of human ESCC, and might be a useful molecular target for ESCC prognosis and treatment. PMID- 27781417 TI - Upgrading Electroresistive Memory from Binary to Ternary Through Single-Atom Substitution in the Molecular Design. AB - Herein, two molecules based on urea and thiourea, which differ by only a single atom, were designed, successfully synthesized, and fabricated into resistive random-access memory devices (RRAM). The urea-based molecule showed binary write once-read-many (WORM) storage behavior, whereas the thiourea-based molecule demonstrated ternary storage behavior. Atomic-force microscopy (AFM) and X-ray diffraction (XRD) patterns show that both molecules have smooth morphology and ordered layer-by-layer lamellar packing, which is beneficial for charge transportation and, consequently, device performance. Additionally, the optical and electrochemical properties indicate that the thiourea-based molecule has a lower bandgap and may be polarized by trapped charges, thus the formation of a continuous conductive channel and electric switching occurs at lower bias voltage, which results in ternary WORM behavior. This study, together with our previous work on single-atom substitution, may be useful to tune and improve device performance in the future design of organic memory. PMID- 27781416 TI - MicroRNA-379 suppresses osteosarcoma progression by targeting PDK1. AB - Osteosarcoma is the most common primary bone tumour. Increasing evidence has demonstrated the pathogenic role of microRNA (miRNAs) dysregulation in tumour development. miR-379 was previously reported to function as an oncogenic or tumour-suppressing miRNA in a tissue-dependent manner. However, its function in osteosarcoma remains unknown. In this study, we found that the expression of miR 379 was downregulated in osteosarcoma tissues and cell lines. Further functional characterization revealed that miR-379 suppressed osteosarcoma cell proliferation and invasion in vitro and retarded the growth of osteosarcoma xenografts in vivo. Mechanistically, PDK1 was identified as the direct target of miR-379 in osteosarcoma, in which PDK1 expression was up-regulated and showed inverse correlation with miR-379. Enforced expression of PDK1 promoted osteosarcoma cell proliferation and rescued the anti-proliferative effect of miR-379. These data suggest that miR-379 could function as a tumour-suppressing miRNA via targeting PDK1 in osteosarcoma. PMID- 27781418 TI - d-Glucose: An Efficient Reducing Agent for a Copper(II)-Mediated Arylation of Primary Amines in Water. AB - A copper-catalyzed Ullmann-type amination with primary amines in water with a combination of copper(II) triflate [Cu(OTf)2 ], dipivaloylmethane, and d-glucose is reported. The mild conditions and the use of an inexpensive catalyst as well as a renewable feedstock (d-glucose and the surfactant TPGS-750-M, which is derived from vitamin E) make this protocol a safe and convenient strategy for efficient C-N bond formation. This easy-to-handle procedure is extremely competitive compared to palladium-based reactions and may be used to synthesize N containing molecules, such as drugs or organic light-emitting diodes (OLEDs). PMID- 27781419 TI - Low-dose mycophenolate mofetil in tablet form or capsule form combined with tacrolimus in the early period after kidney transplantation: a prospective randomized trial?. AB - AIMS: The tablet form (500 mg) of mycophenolate mofetil (MMF) provides more convenience of taking drugs and cost-effectiveness than the capsule form (250 mg). We examined the efficacy and safety of MMF in its different forms combined with tacrolimus in kidney transplant recipients. METHODS: This multicenter, 26 week, randomized trial was performed to compare the efficacy and safety of the tablet form of MMF versus the capsule form of MMF in 156 kidney transplant recipients. Allograft function, the incidence of efficacy failure (biopsy-proven acute rejection (BPAR), death, graft loss, or loss to follow-up), and adverse events were compared. RESULTS: The mean dose (mg/day) of MMF at 26 weeks was comparable: 1,052.6 +/- 194.2 in the tablet group vs. 1,155.6 +/- 298.1 in the capsule group (p = 0.063). Trough levels of tacrolimus at 26 weeks were comparable. The mean estimated glomerular filtration rate of the tablet group at 26 weeks post-transplant was not inferior to that of the capsule group. The incidence of efficacy failure was similar in the two groups: tablet group, 5.2% and capsule group, 7.7% (difference -2.5%; 95% confidence interval -5.22 - 10.21%). The incidence of BPAR until 26 weeks post-transplant in the tablet group was 3.9%, compared to 7.7% in the capsule group (p = 0.346). There was no significant difference in the incidence of discontinuations and serious adverse events between the groups. CONCLUSION: Low-dose MMF in tablet form combined with tacrolimus can be considered as an efficacious and safe immunosuppressive regimen in the early period after kidney transplantation.?. PMID- 27781420 TI - Circadian pharmacokinetics and limited sampling strategy of everolimus in heart transplant patients?. AB - OBJECTIVE: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration-time curve (AUC) of EVL in heart transplant patients. METHODS: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00 AM to 9:00 PM) and resting periods (9:00 PM to 9:00 AM). RESULTS: AUC0-4h, peak concentration (Cmax), Cmax/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p = 0.008, 0.017, 0.022, and 0.011, respectively). Half-life and mean residence time were significantly longer in the resting period than in the active period (p = 0.002 and 0.002, respectively). AUC0-12h in the active period was similar (p = 0.154) and correlated with that in the resting period (r2 = 0.93). Two-point blood samplings, C0 and C2, correlated more strongly with AUC0-12h for EVL, compared with C0 alone (0.92 vs. 0.79, respectively, for r2 in the active period). CONCLUSIONS: EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC0-12h. A 2-time-point model that included C0 and C2 was more accurate for predicting the AUC0-12h of EVL than C0 alone in heart transplant patients.?. PMID- 27781421 TI - Pharmacokinetics and food-effect of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, in healthy adult Caucasian and Japanese subjects?. AB - OBJECTIVE: Fosdagrocorat (PF-04171327) is a pro-drug form of PF-00251802, a dissociated agonist of the glucocorticoid receptor, under investigation for the treatment of rheumatoid arthritis. This study investigates the pharmacokinetics (PK) of single and multiple doses of fosdagrocorat in healthy Japanese and Western volunteers, the effect of food on fosdagrocorat PK, and the effect of fosdagrocorat on bone biomarkers. METHODS: This was a phase 1, randomized, placebo-controlled, dose-escalation study. For single-escalating-dose evaluation, Japanese (n = 9) and Western (n = 9) subjects were randomized (1 : 1 : 1) to treatment sequences including 3 doses of fosdagrocorat (5, 10, or 30 mg) or placebo. For multiple-dose evaluation, Japanese subjects were randomized (3 : 1) to receive fosdagrocorat 20 mg or placebo once daily (QD) for 12 days. Subjects were aged 18 - 55 years; body mass index 17.5 - 30.5 kg/m2; total body weight > 45 kg. RESULTS: Following single doses of fosdagrocorat, the PK of PF 00251802 and its metabolite PF-04015475 were similar between Japanese (PF 00251802: mean area under the curve (AUC)inf (range across doses), 791 - 3,460 ng*h/mL; individual half-life (t1/2) 14.1 - 28.9 hours; PF 04015475: mean AUCinf, 395 - 1,740 ng*h/mL; individual t1/2 21.6 - 40.3 hours) and Western (PF-00251802: mean AUCinf, 750 - 4,150 ng*h/mL; individual t1/2 17.7 - 40.4 hours; PF-04015475: mean AUCinf, 394 - 2,160 ng*h/mL; individual t1/2 24.5 - 63.7 hours) subjects. Steady-state concentrations were reached within 9 days following multiple doses of fosdagrocorat. Food did not affect total exposure of PF 00251802 and PF-04015475. Multiple-dose administration of fosdagrocorat 20 mg QD resulted in suppression of bone formation markers and cortisol and increased bone resorption markers vs. placebo. Adverse events (AEs) were mild in severity and no serious AEs, deaths, or severe AEs were reported. CONCLUSIONS: The PK profile of fosdagrocorat was similar between Japanese and Western subjects, with little effect of food on PK parameters. Fosdagrocorat was well tolerated in both Japanese and Western subjects.?. PMID- 27781422 TI - Evaluation of the area under the curve of enteric-coated mycophenolate sodium using a limited sampling strategy in Chinese kidney transplant recipients?. AB - AIMS: To investigate the area under the curve (AUC) of mycophenolic acid (MPA) in adult Chinese renal allograft recipients receiving concomitant enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine (CsA) during the early post transplant phase and to develop optimal model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC0 12h) using a limited-sampling strategy (LSS). METHODS: The present study enrolled 24 Chinese renal recipients treated with EC-MPS, CsA, and corticosteroid, from whom 24 serial blood samples were collected over 12 hours. MPA concentration was evaluated with enzyme multiplied immunoassay technique (EMIT). LSS was developed by multiple stepwise regression analysis using a two group method (test group, n = 12; and validation group, n = 12). RESULTS: The MPA predose concentration had a poor correlation with MPA AUC0-12h, and the best equations obtained from the test group were the following: 25.73 + 0.59 * C1.5 + 0.79 * C2 + 2.03 * C4 (for three time points, r2 = 0.761) and 22.13 + 1.7 * C0.5 + 0.61 * C1.5 + 0.78 * C2 + 1.83 * C4 (for four time points, r2 = 0.853). When these equations were tested in the validation group, there were no significant differences in prediction errors. CONCLUSION: An LSS using time points at 1.5, 2, and 4 hours or 0.5, 1.5, 2, and 4 hours provides the most accurate and reliable estimation of the MPA AUC0-12h in Chinese adult renal recipients treated concomitantly with EC-MPS and CsA during the early post-transplant phase.?. PMID- 27781423 TI - Malignant glioma with primitive neuroectodermal tumor-like component (MG-PNET): novel microarray findings in a pediatric patient. AB - Central nervous system (CNS) tumors exhibiting dual features of malignant glioma (MG) and primitive neuroectodermal tumor (PNET) are rare and diagnostically challenging. Previous studies have shown that MG-PNET carry MYCN or MYC gene amplifications within the PNET component concomitant with glioma-associated alterations, most commonly 10q loss, in both components [9]. Here we confirm and extend the profile of molecular genetic findings in a MG-PNET involving the left frontal lobe of a 12-year-old male. Histologically, the PNET-like component showed morphological features akin to anaplastic medulloblastoma highlighted by widespread immunoreactivity for betaIII-tubulin (TUBB3) and nonphosphorylated neurofilament protein, and to a lesser degree, Neu-N, synaptophysin, and CD99, whereas the gliomatous component was demarcated by glial fibrillary acidic protein (GFAP) labeling. Immunohistochemical labeling with an anti-H3K27M mutant specific antibody was not detectable in either gliomatous and/or PNET-like areas. Interphase fluorescent in situ hybridization (FISH) study on touch preparations from frozen tumor and formaldehyde-fixed, paraffin-embedded histological sections showed amplification of MYC in both PNET-like and gliomatous areas. Single nucleotide polymorphism (SNP) microarray analysis revealed that the tumor carried gains of multiple chromosomes and chromosome arms, losses of multiple chromosomes and chromosome arms, gains of multiple chromosomal segments (not limited to amplification of chromosomal segments 4q12 including PDGFRA, and 8q24.21 including MYC), and a hitherto unreported chromothripsis-like abnormality on chromosome 8. No mutations were identified for IDH1, IDH2, or BRAF genes by sequence analysis. The molecular genetic findings support the presence of a CNS PNET as an integral part of the tumor coupled with overlapping genetic alterations found in both adult and pediatric high-grade gliomas/glioblastoma. Collectively, microarray data point to a complex underpinning of genetic alterations associated with the MG-PNET tumor phenotype.?. PMID- 27781425 TI - Spinal T-cell-rich B-cell lymphoma. PMID- 27781424 TI - Update on the integrated histopathological and genetic classification of medulloblastoma - a practical diagnostic guideline. AB - The revised WHO classification of tumors of the CNS 2016 has introduced the concept of the integrated diagnosis. The definition of medulloblastoma entities now requires a combination of the traditional histological information with additional molecular/genetic features. For definition of the histopathological component of the medulloblastoma diagnosis, the tumors should be assigned to one of the four entities classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component comprises the four entities WNT-activated, SHH-activated and TP53 wildtype, SHH-activated and TP53 mutant, or non-WNT/non-SHH medulloblastoma. Robust and validated methods are available to allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification, and for differential diagnostic purposes. A combination of immunohistochemical markers including beta-catenin, Yap1, p75-NGFR, Otx2, and p53, in combination with targeted sequencing and copy number assessment such as FISH analysis for MYC genes allows a precise assignment of patients for risk-adapted stratification. It also allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement.?. PMID- 27781426 TI - Tunable Surface Structuration of Silicon by Metal Assisted Chemical Etching with Pt Nanoparticles under Electrochemical Bias. AB - An in-depth study of metal assisted chemical etching (MACE) of p-type c-Si in HF/H2O2 aqueous solutions using Pt nanoparticles as catalysts is presented. Combination of cyclic voltammetry, open circuit measurements, chronoamperometry, impedance spectroscopy, and 2D band bending modeling of the metal/semiconductor/electrolyte interfaces at the nanoscale and under different etching conditions allows gaining physical insights into this system. Additionally, in an attempt to mimic the etching conditions, the modeling has been performed with a positively biased nanoparticle buried in the Si substrate. Following these findings, the application of an external polarization during etching is introduced as a novel efficient approach for achieving straightforward control of the pore morphology by acting upon the band bending at the Si/electrolyte junction. In this way, nanostructures ranging from straight mesopores to cone-shaped macropores are obtained as the Si sample is biased from negative to positive potentials. Remarkably, macroscopic cone-shaped pores in the 1-5 MUm size range with a high aspect ratio (L/W ~ 1.6) are obtained by this method. This morphology leads to a reduction of the surface reflectance below 5% over the entire VIS-NIR domain, which outperforms macrostructures made by state of the art texturization techniques for Si solar cells. PMID- 27781427 TI - Ultrastable Quantum-Dot Light-Emitting Diodes by Suppression of Leakage Current and Exciton Quenching Processes. AB - A study of hybrid inverted quantum-dot (QD) light-emitting diodes constructed with and without Al2O3 interlayers is presented. The Al2O3 interlayers are deposited at ZnO/QDs or/and QDs/4,4'-bis(carbazol-9-yl)biphenyl interfaces, resulting in large improvement of device performance, including luminance, current efficiency, and device lifetime. Especially, the devices with QD emitters sandwiched by two Al2O3 layers exhibits outstanding performance, the longest operation lifetime, and mediate efficiency. The maximum current efficiency of 15.3 cd/A is obtained, an enhancement factor of 35% in comparison to that (11.3 cd/A) of conventional device without Al2O3 layer. Moreover, device lifetime is also largely enhanced, over 110 000 h for the device containing two Al2O3 interlayers, nearly 40% enhancement relative to that of conventional device that shows a lifetime of only 80 000 h. On the basis of electrical property and photoluminescence spectroscopy studies, we demonstrate that the Al2O3 interlayers play crucial roles in suppressing the leakage current across the device and reducing exciton quenching induced by ZnO. PMID- 27781428 TI - High Pressure ZZ-Exchange NMR Reveals Key Features of Protein Folding Transition States. AB - Understanding protein folding mechanisms and their sequence dependence requires the determination of residue-specific apparent kinetic rate constants for the folding and unfolding reactions. Conventional two-dimensional NMR, such as HSQC experiments, can provide residue-specific information for proteins. However, folding is generally too fast for such experiments. ZZ-exchange NMR spectroscopy allows determination of folding and unfolding rates on much faster time scales, yet even this regime is not fast enough for many protein folding reactions. The application of high hydrostatic pressure slows folding by orders of magnitude due to positive activation volumes for the folding reaction. We combined high pressure perturbation with ZZ-exchange spectroscopy on two autonomously folding protein domains derived from the ribosomal protein, L9. We obtained residue specific apparent rates at 2500 bar for the N-terminal domain of L9 (NTL9), and rates at atmospheric pressure for a mutant of the C-terminal domain (CTL9) from pressure dependent ZZ-exchange measurements. Our results revealed that NTL9 folding is almost perfectly two-state, while small deviations from two-state behavior were observed for CTL9. Both domains exhibited large positive activation volumes for folding. The volumetric properties of these domains reveal that their transition states contain most of the internal solvent excluded voids that are found in the hydrophobic cores of the respective native states. These results demonstrate that by coupling it with high pressure, ZZ-exchange can be extended to investigate a large number of protein conformational transitions. PMID- 27781429 TI - Microvessels-on-a-Chip to Assess Targeted Ultrasound-Assisted Drug Delivery. AB - Microbubbles have been used in ultrasound-assisted drug delivery to help target solid tumors via blood vessels in vivo; however, studies to understand the phenomena at the cellular level and to optimize parameters for ultrasound or microbubbles in vivo are challenging and expensive to perform. Here, we utilize microfluidic microvessels-on-a-chip that enable visualization of microbubble/ultrasound-dependent drug delivery to microvasculature. When exposed to pulsed ultrasound, microbubbles perfused through microvessels-on-a-chip were observed to stably oscillate. Minimal cellular damage was observed for both microbubbles and untargeted doxorubicin-encapsulating liposomes (DOX-liposomes) perfused through chip microvessels. In contrast, passive and ultrasound-assisted perfusion of integrin-targeted DOX-liposomes induced cytotoxicity, which was only significantly enhanced for ultrasound-assisted perfusion when microbubbles were coperfused. These results suggest that stably oscillating microbubbles enhance targeted DOX-liposome internalization/cytotoxicity largely by stimulating integrin receptor endocytosis. Furthermore, our study demonstrates the utility of our microvessels-on-a-chip as a screening platform for optimizing drug dosage, targeting ligands and drugs. PMID- 27781430 TI - Organic Dye-Sensitized CH3NH3PbI3 Hybrid Flexible Photodetector with Bulk Heterojunction Architectures. AB - A flexible photodetector based on the bulk heterojunction of an organometallic halide perovskites CH3NH3PbI3 and an organic dye Rhodamine B (RhB) has been fabricated via a solution casting process. It showed a high responsivity (Rmax = 43.6 mA/W) to visible lights, short response time (tr ~ 60 ms, td ~ 40 ms), high on-off ratio (Ion/Ioff ~ 287) and satisfactory stability because of its Schottky barrier structure and the dye enhanced light absorption. PMID- 27781431 TI - Na+ Binding Is Ineffective in Forming a Primary Substrate Pocket of Thrombin. AB - Thrombin is a serine protease involved in the blood coagulation reaction, and it shows maximum enzymatic activity in the presence of Na+. It has been supposed that Na+ binding promotes conversion from the inactive form, with a collapsed primary substrate pocket (S1 pocket), to the active form, with a properly formed S1 pocket. However, the evidence supporting this activation mechanism was derived from the X-ray crystallographic structures solved under nonphysiological conditions and using thrombin mutants; thus, it still remains elusive whether the activation mechanism is actually attributed to Na+ binding. To address the problem, we employed all-atom molecular dynamics simulations for both active and inactive forms of thrombin in the presence and absence of Na+ binding and examined the effect of Na+ binding on S1-pocket formation. In contrast to the conventional supposition, we revealed that Na+ binding does not prevent S1-pocket collapse virtually, but rather, the bound Na+ can move to the S1 pocket, thus blocking substrate access directly. Additionally, it was clarified that Na+ binding does not promote S1-pocket formation. According to these insights, we concluded that Na+ binding is irrelevant to the interconversion between the inactive and active forms of thrombin. PMID- 27781432 TI - Reloadable Silk-Hydrogel Hybrid Scaffolds for Sustained and Targeted Delivery of Molecules. AB - Tunable repeated drug administration is often inevitable in a number of pathological cases. Reloadable 3D matrices for sustained drug delivery are predicted as a prospective avenue to realize this objective. This study was directed toward sonication-induced fabrication of novel reloadable Bombyx mori silk fibroin (SF) (4, 6, and 8 wt %) hydrogel, injected within 3D porous (8 wt %) scaffolds. The focus was to develop a dual-barrier reloadable depot system for sustained molecular cargo release. Both the varying SF concentration (4, 6, and 8 wt %) and the sonication time (30, 45, and 60 s) dictated the extent of cross linking, beta-sheet content, and porosity (1-10 MUm) influencing the release behavior of model molecules. Release studies of model molecules (trypan blue, TB, 961 Da and bovine serum albumin, BSA, 66 kDa) for 28 days attested that the variations in their molecular weight, the matrix cross-linking density, and the scaffold-hydrogel interactions dictated the release behavior. The Ritger and Peppas equation was further fitted into the release behavior of model molecules from various SF matrices. The hybrid constructs exhibited high compressive strength along with in vitro compatibility using primary porcine chondrocytes and tunable enzymatic degradation as assessed for 28 days. The aptness of the constructs was evinced as a reloadable model molecule (BSA and fluorescein isothiocyanate-inulin, 3.9 kDa) depot system through UV-visible and fluorescence spectroscopic analyses. The novel affordable platform developed using silk scaffold-hydrogel hybrid constructs could serve as a sustained and reloadable drug depot system for administration of multiple and repeated drugs. PMID- 27781433 TI - Controlling Structural Transitions in AuAg Nanoparticles through Precise Compositional Design. AB - We present a study of the transitional pathways between high-symmetry structural motifs for AgAu nanoparticles, with a specific focus on controlling the energetic barriers through chemical design. We show that the barriers can be altered by careful control of the elemental composition and chemical arrangement, with core@shell and vertex-decorated arrangements being specifically influential on the barrier heights. We also highlight the complexity of the potential and free energy landscapes for systems where there are low-symmetry geometric motifs that are energetically competitive to the high-symmetry arrangements. In particular, we highlight that some core@shell arrangements preferentially transition through multistep restructuring of low-symmetry truncated octahedra and rosette icosahedra, instead of via the more straightforward square-diamond transformations, due to lower energy barriers and competitive energetic minima. Our results have promising implications for the continuing efforts in bespoke nanoparticle design for catalytic and plasmonic applications. PMID- 27781434 TI - Complex Coacervation-Integrated Hybrid Nanoparticles Increasing Plasmid DNA Delivery Efficiency in Vivo. AB - Many polycation-based gene delivery vehicles have limited in vivo transfection efficiency because of their excessive exterior positive charges and/or PEGylation, both of which could result in premature dissociation and poor cellular uptake and trafficking. Here, we reported novel hybrid PEGylated nanoparticles (HNPs) that are composed of (a) poly(ethylene glycol)-b poly(aspartate)-adamantane (PEG-P(asp)-Ad) constituting the outer PEG layer to provide colloidal stability; (b) poly(ethylenimine)10K (PEI10K) forming complex coacervate with P(asp) as the cross-linked cage preventing premature dissociation; (c) cyclodextrin-decorated PEI10K (PEI10K-CD) forming the core with reporter plasmid DNA (pDNA). These HNPs exhibited an increased stability and higher in vitro transfection efficiency compared to traditional PEGylated nanoparticles (PEG-NP). Intratumoral injections further demonstrated that HNPs were able to successfully deliver pDNAs into tumors, while PEG-NP and PEI25K had only negligible delivery efficiencies. Moreover, HNPs' in vivo stability and pDNA delivery capability post intravenous injection were also confirmed by live animal bioluminescence and fluorescence image analysis. It is likely that the coacervation integration at the interface of PEI10K-CD/pDNA core and the PEG shell attributed to the significantly improved in vivo transfection efficiency of HNPs over PEG-NP and PEI25K. This study suggests that the HNP has the potential for in vivo gene delivery applications with significantly improved gene transfection efficiency. PMID- 27781435 TI - Detecting Beer Intake by Unique Metabolite Patterns. AB - Evaluation of the health related effects of beer intake is hampered by the lack of accurate tools for assessing intakes (biomarkers). Therefore, we identified plasma and urine metabolites associated with recent beer intake by untargeted metabolomics and established a characteristic metabolite pattern representing raw materials and beer production as a qualitative biomarker of beer intake. In a randomized, crossover, single-blinded meal study (MSt1), 18 participants were given, one at a time, four different test beverages: strong, regular, and nonalcoholic beers and a soft drink. Four participants were assigned to have two additional beers (MSt2). In addition to plasma and urine samples, test beverages, wort, and hops extract were analyzed by UPLC-QTOF. A unique metabolite pattern reflecting beer metabolome, including metabolites derived from beer raw material (i.e., N-methyl tyramine sulfate and the sum of iso-alpha-acids and tricyclohumols) and the production process (i.e., pyro-glutamyl proline and 2 ethyl malate), was selected to establish a compliance biomarker model for detection of beer intake based on MSt1. The model predicted the MSt2 samples collected before and up to 12 h after beer intake correctly (AUC = 1). A biomarker model including four metabolites representing both beer raw materials and production steps provided a specific and accurate tool for measurement of beer consumption. PMID- 27781437 TI - Co-existence of periodic bursts and death of cycles in a population dynamics system. AB - We study the dynamics of a discrete-time tritrophic model which mimics the observed periodicity in the population cycles of the larch budmoth insect which causes widespread defoliation of larch forests at high altitudes periodically. Our model employs q-deformation of numbers to model the system comprising the budmoth, one or more parasitoid species, and larch trees. Incorporating climate parameters, we introduce additional parasitoid species and show that their introduction increases the periodicity of the budmoth cycles as observed experimentally. The presence of these additional species also produces other interesting dynamical effects such as periodic bursting and oscillation quenching via oscillation death, amplitude death, and partial oscillation death which are also seen in nature. We suggest that introducing additional parasitoid species provides an alternative explanation for the collapse of the nine year budmoth outbreak cycles observed in the Swiss Alps after 1981. A detailed exploration of the parameter space of the system is performed with movies of bifurcation diagrams which enable variation of two parameters at a time. Limit cycles emerge through a Neimark-Sacker bifurcation with respect to all parameters in all the five and higher dimensional models we have studied. PMID- 27781438 TI - Chimera and chimera-like states in populations of nonlocally coupled homogeneous and heterogeneous chemical oscillators. AB - Chimera and chimera-like states are characterized in populations of photochemically coupled Belousov-Zhabotinsky (BZ) oscillators. Simple chimeras and chimera states with multiple and traveling phase clusters, phase-slip behavior, and chimera-like states with phase waves are described. Simulations with a realistic model of the discrete BZ system of populations of homogeneous and heterogeneous oscillators are compared with each other and with experimental behavior. PMID- 27781436 TI - Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines. AB - The clinical value of current and future nanomedicines can be improved by introducing patient selection strategies based on noninvasive sensitive whole body imaging techniques such as positron emission tomography (PET). Thus, a broad method to radiolabel and track preformed nanomedicines such as liposomal drugs with PET radionuclides will have a wide impact in nanomedicine. Here, we introduce a simple and efficient PET radiolabeling method that exploits the metal chelating properties of certain drugs (e.g., bisphosphonates such as alendronate and anthracyclines such as doxorubicin) and widely used ionophores to achieve excellent radiolabeling yields, purities, and stabilities with 89Zr, 52Mn, and 64Cu, and without the requirement of modification of the nanomedicine components. In a model of metastatic breast cancer, we demonstrate that this technique allows quantification of the biodistribution of a radiolabeled stealth liposomal nanomedicine containing alendronate that shows high uptake in primary tumors and metastatic organs. The versatility, efficiency, simplicity, and GMP compatibility of this method may enable submicrodosing imaging studies of liposomal nanomedicines containing chelating drugs in humans and may have clinical impact by facilitating the introduction of image-guided therapeutic strategies in current and future nanomedicine clinical studies. PMID- 27781439 TI - Synchronization of mobile chaotic oscillator networks. AB - We study synchronization of systems in which agents holding chaotic oscillators move in a two-dimensional plane and interact with nearby ones forming a time dependent network. Due to the uncertainty in observing other agents' states, we assume that the interaction contains a certain amount of noise that turns out to be relevant for chaotic dynamics. We find that a synchronization transition takes place by changing a control parameter. But this transition depends on the relative dynamic scale of motion and interaction. When the topology change is slow, we observe an intermittent switching between laminar and burst states close to the transition due to small noise. This novel type of synchronization transition and intermittency can happen even when complete synchronization is linearly stable in the absence of noise. We show that the linear stability of the synchronized state is not a sufficient condition for its stability due to strong fluctuations of the transverse Lyapunov exponent associated with a slow network topology change. Since this effect can be observed within the linearized dynamics, we can expect such an effect in the temporal networks with noisy chaotic oscillators, irrespective of the details of the oscillator dynamics. When the topology change is fast, a linearized approximation describes well the dynamics towards synchrony. These results imply that the fluctuations of the finite-time transverse Lyapunov exponent should also be taken into account to estimate synchronization of the mobile contact networks. PMID- 27781440 TI - Multistability and complex basins in a nonlinear duopoly with price competition and relative profit delegation. AB - In this article, we investigate the local and global dynamics of a nonlinear duopoly model with price-setting firms and managerial delegation contracts (relative profits). Our study aims at clarifying the effects of the interaction between the degree of product differentiation and the weight of manager's bonus on long-term outcomes in two different states: managers behave more aggressively with the rival (competition) under product complementarity and less aggressively with the rival (cooperation) under product substitutability. We combine analytical tools and numerical techniques to reach interesting results such as synchronisation and on-off intermittency of the state variables (in the case of homogeneous attitude of managers) and the existence of chaotic attractors, complex basins of attraction, and multistability (in the case of heterogeneous attitudes of managers). We also give policy insights. PMID- 27781441 TI - Chaos in generically coupled phase oscillator networks with nonpairwise interactions. AB - The Kuramoto-Sakaguchi system of coupled phase oscillators, where interaction between oscillators is determined by a single harmonic of phase differences of pairs of oscillators, has very simple emergent dynamics in the case of identical oscillators that are globally coupled: there is a variational structure that means the only attractors are full synchrony (in-phase) or splay phase (rotating wave/full asynchrony) oscillations and the bifurcation between these states is highly degenerate. Here we show that nonpairwise coupling-including three and four-way interactions of the oscillator phases-that appears generically at the next order in normal-form based calculations can give rise to complex emergent dynamics in symmetric phase oscillator networks. In particular, we show that chaos can appear in the smallest possible dimension of four coupled phase oscillators for a range of parameter values. PMID- 27781442 TI - Synchronization of multi-agent systems with metric-topological interactions. AB - A hybrid multi-agent systems model integrating the advantages of both metric interaction and topological interaction rules, called the metric-topological model, is developed. This model describes planar motions of mobile agents, where each agent can interact with all the agents within a circle of a constant radius, and can furthermore interact with some distant agents to reach a pre-assigned number of neighbors, if needed. Some sufficient conditions imposed only on system parameters and agent initial states are presented, which ensure achieving synchronization of the whole group of agents. It reveals the intrinsic relationships among the interaction range, the speed, the initial heading, and the density of the group. Moreover, robustness against variations of interaction range, density, and speed are investigated by comparing the motion patterns and performances of the hybrid metric-topological interaction model with the conventional metric-only and topological-only interaction models. Practically in all cases, the hybrid metric-topological interaction model has the best performance in the sense of achieving highest frequency of synchronization, fastest convergent rate, and smallest heading difference. PMID- 27781443 TI - Approximate cluster synchronization in networks with symmetries and parameter mismatches. AB - We study cluster synchronization in networks with symmetries in the presence of small generic parametric mismatches of two different types: mismatches affecting the dynamics of the individual uncoupled systems and mismatches affecting the network couplings. We perform a stability analysis of the nearly synchronous cluster synchronization solution and reduce the stability problem to a low dimensional form. We also show how under certain conditions the low dimensional analysis can be used to predict the overall synchronization error, i.e., how close the individual nearly synchronous trajectories are to each other. PMID- 27781444 TI - Discrimination of coupling structures using causality networks from multivariate time series. AB - Measures of Granger causality on multivariate time series have been used to form the so-called causality networks. A causality network represents the interdependence structure of the underlying dynamical system or coupled dynamical systems, and its properties are quantified by network indices. In this work, it is investigated whether network indices on networks generated by an appropriate Granger causality measure can discriminate different coupling structures. The information based Granger causality measure of partial mutual information from mixed embedding (PMIME) is used to form causality networks, and a large number of network indices are ranked according to their ability to discriminate the different coupling structures. The evaluation of the network indices is done with a simulation study based on two dynamical systems, the coupled Mackey-Glass delay differential equations and the neural mass model, both of 25 variables, and three prototypes of coupling structures, i.e., random, small-world, and scale-free. It is concluded that the setting of PMIME combined with a network index attains high level of discrimination of the coupling structures solely on the basis of the observed multivariate time series. This approach is demonstrated to identify epileptic seizures emerging during electroencephalogram recordings. PMID- 27781445 TI - Diffusion and transport in locally disordered driven lattices. AB - We study the effect of disorder on the particle density evolution in a classical Hamiltonian driven lattice setup. If the disorder is localized within a finite sub-domain of the lattice, the emergence of strong tails in the density distribution which even increases towards larger positions is shown, thus yielding a highly non-Gaussian particle density evolution. As the key underlying mechanism, we identify the conversion between different components of the unperturbed systems mixed phase space which is induced by the disorder. Based on the introduction of individual conversion rates between chaotic and regular components, a theoretical model is developed which correctly predicts the scaling of the particle density. The effect of disorder on the transport properties is studied where a significant enhancement of the transport for cases of localized disorder is shown, thereby contrasting strongly the merely weak modification of the transport for global disorder. PMID- 27781446 TI - Distinguishing between direct and indirect directional couplings in large oscillator networks: Partial or non-partial phase analyses? AB - We investigate the relative merit of phase-based methods for inferring directional couplings in complex networks of weakly interacting dynamical systems from multivariate time-series data. We compare the evolution map approach and its partialized extension to each other with respect to their ability to correctly infer the network topology in the presence of indirect directional couplings for various simulated experimental situations using coupled model systems. In addition, we investigate whether the partialized approach allows for additional or complementary indications of directional interactions in evolving epileptic brain networks using intracranial electroencephalographic recordings from an epilepsy patient. For such networks, both direct and indirect directional couplings can be expected, given the brain's connection structure and effects that may arise from limitations inherent to the recording technique. Our findings indicate that particularly in larger networks (number of nodes ?10), the partialized approach does not provide information about directional couplings extending the information gained with the evolution map approach. PMID- 27781448 TI - Super-transient scaling in time-delay autonomous Boolean network motifs. AB - Autonomous Boolean networks are commonly used to model the dynamics of gene regulatory networks and allow for the prediction of stable dynamical attractors. However, most models do not account for time delays along the network links and noise, which are crucial features of real biological systems. Concentrating on two paradigmatic motifs, the toggle switch and the repressilator, we develop an experimental testbed that explicitly includes both inter-node time delays and noise using digital logic elements on field-programmable gate arrays. We observe transients that last millions to billions of characteristic time scales and scale exponentially with the amount of time delays between nodes, a phenomenon known as super-transient scaling. We develop a hybrid model that includes time delays along network links and allows for stochastic variation in the delays. Using this model, we explain the observed super-transient scaling of both motifs and recreate the experimentally measured transient distributions. PMID- 27781447 TI - Average activity of excitatory and inhibitory neural populations. AB - We develop an extension of the Ott-Antonsen method [E. Ott and T. M. Antonsen, Chaos 18(3), 037113 (2008)] that allows obtaining the mean activity (spiking rate) of a population of excitable units. By means of the Ott-Antonsen method, equations for the dynamics of the order parameters of coupled excitatory and inhibitory populations of excitable units are obtained, and their mean activities are computed. Two different excitable systems are studied: Adler units and theta neurons. The resulting bifurcation diagrams are compared with those obtained from studying the phenomenological Wilson-Cowan model in some regions of the parameter space. Compatible behaviors, as well as higher dimensional chaotic solutions, are observed. We study numerical simulations to further validate the equations. PMID- 27781449 TI - Control and prediction for blackouts caused by frequency collapse in smart grids. AB - The electric power system is one of the cornerstones of modern society. One of its most serious malfunctions is the blackout, a catastrophic event that may disrupt a substantial portion of the system, playing havoc to human life and causing great economic losses. Thus, understanding the mechanisms leading to blackouts and creating a reliable and resilient power grid has been a major issue, attracting the attention of scientists, engineers, and stakeholders. In this paper, we study the blackout problem in power grids by considering a practical phase-oscillator model. This model allows one to simultaneously consider different types of power sources (e.g., traditional AC power plants and renewable power sources connected by DC/AC inverters) and different types of loads (e.g., consumers connected to distribution networks and consumers directly connected to power plants). We propose two new control strategies based on our model, one for traditional power grids and another one for smart grids. The control strategies show the efficient function of the fast-response energy storage systems in preventing and predicting blackouts in smart grids. This work provides innovative ideas which help us to build up a robuster and more economic smart power system. PMID- 27781450 TI - Stability regions for synchronized tau-periodic orbits of coupled maps with coupling delay tau. AB - Motivated by the chaos suppression methods based on stabilizing an unstable periodic orbit, we study the stability of synchronized periodic orbits of coupled map systems when the period of the orbit is the same as the delay in the information transmission between coupled units. We show that the stability region of a synchronized periodic orbit is determined by the Floquet multiplier of the periodic orbit for the uncoupled map, the coupling constant, the smallest and the largest Laplacian eigenvalue of the adjacency matrix. We prove that the stabilization of an unstable tau-periodic orbit via coupling with delay tau is possible only when the Floquet multiplier of the orbit is negative and the connection structure is not bipartite. For a given coupling structure, it is possible to find the values of the coupling strength that stabilizes unstable periodic orbits. The most suitable connection topology for stabilization is found to be the all-to-all coupling. On the other hand, a negative coupling constant may lead to destabilization of tau-periodic orbits that are stable for the uncoupled map. We provide examples of coupled logistic maps demonstrating the stabilization and destabilization of synchronized tau-periodic orbits as well as chaos suppression via stabilization of a synchronized tau-periodic orbit. PMID- 27781451 TI - Early-warning indicators for rate-induced tipping. AB - A dynamical system is said to undergo rate-induced tipping when it fails to track its quasi-equilibrium state due to an above-critical-rate change of system parameters. We study a prototypical model for rate-induced tipping, the saddle node normal form subject to time-varying equilibrium drift and noise. We find that both most commonly used early-warning indicators, increase in variance and increase in autocorrelation, occur not when the equilibrium drift is fastest but with a delay. We explain this delay by demonstrating that the most likely trajectory for tipping also crosses the tipping threshold with a delay, and therefore, the tipping itself is delayed. We find solutions of the variational problem determining the most likely tipping path using numerical continuation techniques. The result is a systematic study of the most likely tipping time in the plane of two parameters, distance from tipping threshold and noise intensity. PMID- 27781452 TI - Restoring oscillatory behavior from amplitude death with anti-phase synchronization patterns in networks of electrochemical oscillations. AB - The dynamical behavior of delay-coupled networks of electrochemical reactions is investigated to explore the formation of amplitude death (AD) and the synchronization states in a parameter region around the amplitude death region. It is shown that difference coupling with odd and even numbered ring and random networks can produce the AD phenomenon. Furthermore, this AD can be restored by changing the coupling type from difference to direct coupling. The restored oscillations tend to create synchronization patterns in which neighboring elements are in nearly anti-phase configuration. The ring networks produce frozen and rotating phase waves, while the random network exhibits a complex synchronization pattern with interwoven frozen and propagating phase waves. The experimental results are interpreted with a coupled Stuart-Landau oscillator model. The experimental and theoretical results reveal that AD behavior is a robust feature of delayed coupled networks of chemical units; if an oscillatory behavior is required again, even a small amount of direct coupling could be sufficient to restore the oscillations. The restored nearly anti-phase oscillatory patterns, which, to a certain extent, reflect the symmetry of the network, represent an effective means to overcome the AD phenomenon. PMID- 27781453 TI - Patterns of patterns of synchronization: Noise induced attractor switching in rings of coupled nonlinear oscillators. AB - Following the long-lived qualitative-dynamics tradition of explaining behavior in complex systems via the architecture of their attractors and basins, we investigate the patterns of switching between distinct trajectories in a network of synchronized oscillators. Our system, consisting of nonlinear amplitude-phase oscillators arranged in a ring topology with reactive nearest-neighbor coupling, is simple and connects directly to experimental realizations. We seek to understand how the multiple stable synchronized states connect to each other in state space by applying Gaussian white noise to each of the oscillators' phases. To do this, we first analytically identify a set of locally stable limit cycles at any given coupling strength. For each of these attracting states, we analyze the effect of weak noise via the covariance matrix of deviations around those attractors. We then explore the noise-induced attractor switching behavior via numerical investigations. For a ring of three oscillators, we find that an attractor-switching event is always accompanied by the crossing of two adjacent oscillators' phases. For larger numbers of oscillators, we find that the distribution of times required to stochastically leave a given state falls off exponentially, and we build an attractor switching network out of the destination states as a coarse-grained description of the high-dimensional attractor-basin architecture. PMID- 27781454 TI - Graph partitions and cluster synchronization in networks of oscillators. AB - Synchronization over networks depends strongly on the structure of the coupling between the oscillators. When the coupling presents certain regularities, the dynamics can be coarse-grained into clusters by means of External Equitable Partitions of the network graph and their associated quotient graphs. We exploit this graph-theoretical concept to study the phenomenon of cluster synchronization, in which different groups of nodes converge to distinct behaviors. We derive conditions and properties of networks in which such clustered behavior emerges and show that the ensuing dynamics is the result of the localization of the eigenvectors of the associated graph Laplacians linked to the existence of invariant subspaces. The framework is applied to both linear and non-linear models, first for the standard case of networks with positive edges, before being generalized to the case of signed networks with both positive and negative interactions. We illustrate our results with examples of both signed and unsigned graphs for consensus dynamics and for partial synchronization of oscillator networks under the master stability function as well as Kuramoto oscillators. PMID- 27781455 TI - Nonlinear behavior of the tarka flute's distinctive sounds. AB - The Andean tarka flute generates multiphonic sounds. Using spectral techniques, we verify two distinctive musical behaviors and the nonlinear nature of the tarka. Through nonlinear time series analysis, we determine chaotic and hyperchaotic behavior. Experimentally, we observe that by increasing the blow pressure on different fingerings, peculiar changes from linear to nonlinear patterns are produced, leading ultimately to quenching. PMID- 27781456 TI - Experimental observation of chimera and cluster states in a minimal globally coupled network. AB - A "chimera state" is a dynamical pattern that occurs in a network of coupled identical oscillators when the symmetry of the oscillator population is broken into synchronous and asynchronous parts. We report the experimental observation of chimera and cluster states in a network of four globally coupled chaotic opto electronic oscillators. This is the minimal network that can support chimera states, and our study provides new insight into the fundamental mechanisms underlying their formation. We use a unified approach to determine the stability of all the observed partially synchronous patterns, highlighting the close relationship between chimera and cluster states as belonging to the broader phenomenon of partial synchronization. Our approach is general in terms of network size and connectivity. We also find that chimera states often appear in regions of multistability between global, cluster, and desynchronized states. PMID- 27781457 TI - Is there an impact of small phase lags in the Kuramoto model? AB - We discuss the influence of small phase lags on the synchronization transitions in the Kuramoto model for a large inhomogeneous population of globally coupled phase oscillators. Without a phase lag, all unimodal distributions of the natural frequencies give rise to a classical synchronization scenario, where above the onset of synchrony at the Kuramoto threshold, there is an increasing synchrony for increasing coupling strength. We show that already for arbitrarily small phase lags, there are certain unimodal distributions of natural frequencies such that for increasing coupling strength synchrony may decrease and even complete incoherence may regain stability. Moreover, our example allows a qualitative understanding of the mechanism for such non-universal synchronization transitions. PMID- 27781458 TI - Analysis of vibrational resonance in bi-harmonically driven plasma. AB - The phenomenon of vibrational resonance (VR) is examined and analyzed in a bi harmonically driven two-fluid plasma model with nonlinear dissipation. An equation for the slow oscillations of the system is analytically derived in terms of the parameters of the fast signal using the method of direct separation of motion. The presence of a high frequency externally applied electric field is found to significantly modify the system's dynamics, and consequently, induce VR. The origin of the VR in the plasma model has been identified, not only from the effective plasma potential but also from the contributions of the effective nonlinear dissipation. Beside several dynamical changes, including multiple symmetry-breaking bifurcations, attractor escapes, and reversed period-doubling bifurcations, numerical simulations also revealed the occurrence of single and double resonances induced by symmetry breaking bifurcations. PMID- 27781459 TI - Devaney chaos plus shadowing implies distributional chaos. AB - We explore connections among the regional proximal relation, the asymptotic relation, and the distal relation for a topological dynamical system with the shadowing property and show that if a Devaney chaotic system has the shadowing property then it is distributionally chaotic. PMID- 27781460 TI - Chimera states in networks of Van der Pol oscillators with hierarchical connectivities. AB - Chimera states are complex spatio-temporal patterns that consist of coexisting domains of coherent and incoherent dynamics. We analyse chimera states in ring networks of Van der Pol oscillators with hierarchical coupling topology. We investigate the stepwise transition from a nonlocal to a hierarchical topology and propose the network clustering coefficient as a measure to establish a link between the existence of chimera states and the compactness of the initial base pattern of a hierarchical topology; we show that a large clustering coefficient promotes the occurrence of chimeras. Depending on the level of hierarchy and base pattern, we obtain chimera states with different numbers of incoherent domains. We investigate the chimera regimes as a function of coupling strength and nonlinearity parameter of the individual oscillators. The analysis of a network with larger base pattern resulting in larger clustering coefficient reveals two different types of chimera states and highlights the increasing role of amplitude dynamics. PMID- 27781461 TI - A model of economic growth with physical and human capital: The role of time delays. AB - This article aims at analysing a two-sector economic growth model with discrete delays. The focus is on the dynamic properties of the emerging system. In particular, this study concentrates on the stability properties of the stationary solution, characterised by analytical results and geometrical techniques (stability crossing curves), and the conditions under which oscillatory dynamics emerge (through Hopf bifurcations). In addition, this article proposes some numerical simulations to illustrate the behaviour of the system when the stationary equilibrium is unstable. PMID- 27781462 TI - Rigid patterns of synchrony for equilibria and periodic cycles in network dynamics. AB - We survey general results relating patterns of synchrony to network topology, applying the formalism of coupled cell systems. We also discuss patterns of phase locking for periodic states, where cells have identical waveforms but regularly spaced phases. We focus on rigid patterns, which are not changed by small perturbations of the differential equation. Symmetry is one mechanism that creates patterns of synchrony and phase-locking. In general networks, there is another: balanced colorings of the cells. A symmetric network may have anomalous patterns of synchrony and phase-locking that are not consequences of symmetry. We introduce basic notions on coupled cell networks and their associated systems of admissible differential equations. Periodic states also possess spatio-temporal symmetries, leading to phase relations; these are classified by the H/K theorem and its analog for general networks. Systematic general methods for computing the stability of synchronous states exist for symmetric networks, but stability in general networks requires methods adapted to special classes of model equations. PMID- 27781464 TI - Correlation analysis of the coherence-incoherence transition in a ring of nonlocally coupled logistic maps. AB - We present numerical results for a set of bifurcations occurring at the transition from complete chaotic synchronization to spatio-temporal chaos in a ring of nonlocally coupled chaotic logistic maps. The regularities are established for the evolution of cross-correlations of oscillations in the network elements at the bifurcations related to the coupling strength variation. We reveal the distinctive features of cross-correlations for phase and amplitude chimera states. It is also shown that the effect of time intermittency between the amplitude and phase chimeras can be realized in the considered ensemble. PMID- 27781463 TI - Optimal synchronization of directed complex networks. AB - We study optimal synchronization of networks of coupled phase oscillators. We extend previous theory for optimizing the synchronization properties of undirected networks to the important case of directed networks. We derive a generalized synchrony alignment function that encodes the interplay between the network structure and the oscillators' natural frequencies and serves as an objective measure for the network's degree of synchronization. Using the generalized synchrony alignment function, we show that a network's synchronization properties can be systematically optimized. This framework also allows us to study the properties of synchrony-optimized networks, and in particular, investigate the role of directed network properties such as nodal in- and out-degrees. For instance, we find that in optimally rewired networks, the heterogeneity of the in-degree distribution roughly matches the heterogeneity of the natural frequency distribution, but no such relationship emerges for out degrees. We also observe that a network's synchronization properties are promoted by a strong correlation between the nodal in-degrees and the natural frequencies of oscillators, whereas the relationship between the nodal out-degrees and the natural frequencies has comparatively little effect. This result is supported by our theory, which indicates that synchronization is promoted by a strong alignment of the natural frequencies with the left singular vectors corresponding to the largest singular values of the Laplacian matrix. PMID- 27781465 TI - Adjoint eigenfunctions of temporally recurrent single-spiral solutions in a simple model of atrial fibrillation. AB - This paper introduces a numerical method for computing the spectrum of adjoint (left) eigenfunctions of spiral wave solutions to reaction-diffusion systems in arbitrary geometries. The method is illustrated by computing over a hundred eigenfunctions associated with an unstable time-periodic single-spiral solution of the Karma model on a square domain. We show that all leading adjoint eigenfunctions are exponentially localized in the vicinity of the spiral tip, although the marginal modes (response functions) demonstrate the strongest localization. We also discuss the implications of the localization for the dynamics and control of unstable spiral waves. In particular, the interaction with no-flux boundaries leads to a drift of spiral waves which can be understood with the help of the response functions. PMID- 27781466 TI - Network-complement transitions, symmetries, and cluster synchronization. AB - Synchronization in networks of coupled oscillators is known to be largely determined by the spectral and symmetry properties of the interaction network. Here, we leverage this relation to study a class of networks for which the threshold coupling strength for global synchronization is the lowest among all networks with the same number of nodes and links. These networks, defined as being uniform, complete, and multi-partite (UCM), appear at each of an infinite sequence of network-complement transitions in a larger class of networks characterized by having near-optimal thresholds for global synchronization. We show that the distinct symmetry structure of the UCM networks, which by design are optimized for global synchronizability, often leads to formation of clusters of synchronous oscillators, and that such states can coexist with the state of global synchronization. PMID- 27781467 TI - Digit replacement: A generic map for nonlinear dynamical systems. AB - A simple discontinuous map is proposed as a generic model for nonlinear dynamical systems. The orbit of the map admits exact solutions for wide regions in parameter space and the method employed (digit manipulation) allows the mathematical design of useful signals, such as regular or aperiodic oscillations with specific waveforms, the construction of complex attractors with nontrivial properties as well as the coexistence of different basins of attraction in phase space with different qualitative properties. A detailed analysis of the dynamical behavior of the map suggests how the latter can be used in the modeling of complex nonlinear dynamics including, e.g., aperiodic nonchaotic attractors and the hierarchical deposition of grains of different sizes on a surface. PMID- 27781469 TI - Frequency spirals. AB - We study the dynamics of coupled phase oscillators on a two-dimensional Kuramoto lattice with periodic boundary conditions. For coupling strengths just below the transition to global phase-locking, we find localized spatiotemporal patterns that we call "frequency spirals." These patterns cannot be seen under time averaging; they become visible only when we examine the spatial variation of the oscillators' instantaneous frequencies, where they manifest themselves as two armed rotating spirals. In the more familiar phase representation, they appear as wobbly periodic patterns surrounding a phase vortex. Unlike the stationary phase vortices seen in magnetic spin systems, or the rotating spiral waves seen in reaction-diffusion systems, frequency spirals librate: the phases of the oscillators surrounding the central vortex move forward and then backward, executing a periodic motion with zero winding number. We construct the simplest frequency spiral and characterize its properties using analytical and numerical methods. Simulations show that frequency spirals in large lattices behave much like this simple prototype. PMID- 27781468 TI - Effects of quasiperiodic forcing in epidemic models. AB - We study changes in the bifurcations of seasonally driven compartmental epidemic models, where the transmission rate is modulated temporally. In the presence of periodic modulation of the transmission rate, the dynamics varies from periodic to chaotic. The route to chaos is typically through period doubling bifurcation. There are coexisting attractors for some sets of parameters. However in the presence of quasiperiodic modulation, tori are created in place of periodic orbits and chaos appears via finite torus doublings. Strange nonchaotic attractors (SNAs) are created at the boundary of chaotic and torus dynamics. Multistability is found to be reduced as a function of quasiperiodic modulation strength. It is argued that occurrence of SNAs gives an opportunity of asymptotic predictability of epidemic growth even when the underlying dynamics is strange. PMID- 27781470 TI - Enhancing multivariate singular spectrum analysis for phase synchronization: The role of observability. AB - Multivariate singular spectrum analysis (M-SSA) was recently adapted to study systems of coupled oscillators. It does not require an a priori definition for phase nor detailed knowledge of the individual oscillators, but it uses all the variables of each system. This aspect could be restrictive for practical applications, since usually just a few (sometimes only one) variables are measured. Based on dynamical systems and observability theories, we first show how to apply the M-SSA with only one variable and show the conditions to achieve good performance. Next, we provide numerical evidence that this single-variable approach enhances the explanatory power compared to the original M-SSA when computed with all the system variables. This could have important practical implications, as pointed out using benchmark oscillators. PMID- 27781471 TI - Chimera states in two populations with heterogeneous phase-lag. AB - The simplest network of coupled phase-oscillators exhibiting chimera states is given by two populations with disparate intra- and inter-population coupling strengths. We explore the effects of heterogeneous coupling phase-lags between the two populations. Such heterogeneity arises naturally in various settings, for example, as an approximation to transmission delays, excitatory-inhibitory interactions, or as amplitude and phase responses of oscillators with electrical or mechanical coupling. We find that breaking the phase-lag symmetry results in a variety of states with uniform and non-uniform synchronization, including in phase and anti-phase synchrony, full incoherence (splay state), chimera states with phase separation of 0 or pi between populations, and states where both populations remain desynchronized. These desynchronized states exhibit stable, oscillatory, and even chaotic dynamics. Moreover, we identify the bifurcations through which chimeras emerge. Stable chimera states and desynchronized solutions, which do not arise for homogeneous phase-lag parameters, emerge as a result of competition between synchronized in-phase, anti-phase equilibria, and fully incoherent states when the phase-lags are near +/-pi2 (cosine coupling). These findings elucidate previous experimental results involving a network of mechanical oscillators and provide further insight into the breakdown of synchrony in biological systems. PMID- 27781472 TI - On controlling networks of limit-cycle oscillators. AB - The control of network-coupled nonlinear dynamical systems is an active area of research in the nonlinear science community. Coupled oscillator networks represent a particularly important family of nonlinear systems, with applications ranging from the power grid to cardiac excitation. Here, we study the control of network-coupled limit cycle oscillators, extending the previous work that focused on phase oscillators. Based on stabilizing a target fixed point, our method aims to attain complete frequency synchronization, i.e., consensus, by applying control to as few oscillators as possible. We develop two types of controls. The first type directs oscillators towards larger amplitudes, while the second does not. We present numerical examples of both control types and comment on the potential failures of the method. PMID- 27781474 TI - Travelling waves in arrays of delay-coupled phase oscillators. AB - We consider the effects of several forms of delays on the existence and stability of travelling waves in non-locally coupled networks of Kuramoto-type phase oscillators and theta neurons. By passing to the continuum limit and using the Ott/Antonsen ansatz, we derive evolution equations for a spatially dependent order parameter. For phase oscillator networks, the travelling waves take the form of uniformly twisted waves, and these can often be characterised analytically. For networks of theta neurons, the waves are studied numerically. PMID- 27781473 TI - Resynchronization of circadian oscillators and the east-west asymmetry of jet lag. AB - Cells in the brain's Suprachiasmatic Nucleus (SCN) are known to regulate circadian rhythms in mammals. We model synchronization of SCN cells using the forced Kuramoto model, which consists of a large population of coupled phase oscillators (modeling individual SCN cells) with heterogeneous intrinsic frequencies and external periodic forcing. Here, the periodic forcing models diurnally varying external inputs such as sunrise, sunset, and alarm clocks. We reduce the dimensionality of the system using the ansatz of Ott and Antonsen and then study the effect of a sudden change of clock phase to simulate cross-time zone travel. We estimate model parameters from previous biological experiments. By examining the phase space dynamics of the model, we study the mechanism leading to the difference typically experienced in the severity of jet-lag resulting from eastward and westward travel. PMID- 27781476 TI - Bistability of patterns of synchrony in Kuramoto oscillators with inertia. AB - We study the co-existence of stable patterns of synchrony in two coupled populations of identical Kuramoto oscillators with inertia. The two populations have different sizes and can split into two clusters where the oscillators synchronize within a cluster while there is a phase shift between the dynamics of the two clusters. Due to the presence of inertia, which increases the dimensionality of the oscillator dynamics, this phase shift can oscillate, inducing a breathing cluster pattern. We derive analytical conditions for the co existence of stable two-cluster patterns with constant and oscillating phase shifts. We demonstrate that the dynamics, that governs the bistability of the phase shifts, is described by a driven pendulum equation. We also discuss the implications of our stability results to the stability of chimeras. PMID- 27781475 TI - Reviving oscillation with optimal spatial period of frequency distribution in coupled oscillators. AB - The spatial distributions of system's frequencies have significant influences on the critical coupling strengths for amplitude death (AD) in coupled oscillators. We find that the left and right critical coupling strengths for AD have quite different relations to the increasing spatial period m of the frequency distribution in coupled oscillators. The left one has a negative linear relationship with m in log-log axis for small initial frequency mismatches while remains constant for large initial frequency mismatches. The right one is in quadratic function relation with spatial period m of the frequency distribution in log-log axis. There is an optimal spatial period m0 of frequency distribution with which the coupled system has a minimal critical strength to transit from an AD regime to reviving oscillation. Moreover, the optimal spatial period m0 of the frequency distribution is found to be related to the system size N. Numerical examples are explored to reveal the inner regimes of effects of the spatial frequency distribution on AD. PMID- 27781477 TI - Synchronizing noisy nonidentical oscillators by transient uncoupling. AB - Synchronization is the process of achieving identical dynamics among coupled identical units. If the units are different from each other, their dynamics cannot become identical; yet, after transients, there may emerge a functional relationship between them-a phenomenon termed "generalized synchronization." Here, we show that the concept of transient uncoupling, recently introduced for synchronizing identical units, also supports generalized synchronization among nonidentical chaotic units. Generalized synchronization can be achieved by transient uncoupling even when it is impossible by regular coupling. We furthermore demonstrate that transient uncoupling stabilizes synchronization in the presence of common noise. Transient uncoupling works best if the units stay uncoupled whenever the driven orbit visits regions that are locally diverging in its phase space. Thus, to select a favorable uncoupling region, we propose an intuitive method that measures the local divergence at the phase points of the driven unit's trajectory by linearizing the flow and subsequently suppresses the divergence by uncoupling. PMID- 27781478 TI - Horizontal stability of a bouncing ball. AB - We present an investigation of a partially elastic ball bouncing on a vertically vibrated concave parabolic surface in two dimensions. In particular, we demonstrate that simple vertical motion, wherein the ball bounces periodically at the parabola's vertex, is unstable to horizontal perturbations when the parabolic coefficient defining the surface shape exceeds a critical value. The result is a new periodic solution where the ball bounces laterally over the vertex. As the parabola is further steepened, this new solution also becomes unstable which gives rise to other complex periodic and chaotic bouncing states, all characterized by persistent lateral motion. PMID- 27781479 TI - Phase-locked patterns of the Kuramoto model on 3-regular graphs. AB - We consider the existence of non-synchronized fixed points to the Kuramoto model defined on sparse networks: specifically, networks where each vertex has degree exactly three. We show that "most" such networks support multiple attracting phase-locked solutions that are not synchronized and study the depth and width of the basins of attraction of these phase-locked solutions. We also show that it is common in "large enough" graphs to find phase-locked solutions where one or more of the links have angle difference greater than pi/2. PMID- 27781480 TI - A classification scheme for chimera states. AB - We present a universal characterization scheme for chimera states applicable to both numerical and experimental data sets. The scheme is based on two correlation measures that enable a meaningful definition of chimera states as well as their classification into three categories: stationary, turbulent, and breathing. In addition, these categories can be further subdivided according to the time stationarity of these two measures. We demonstrate that this approach is both consistent with previously recognized chimera states and enables us to classify states as chimeras which have not been categorized as such before. Furthermore, the scheme allows for a qualitative and quantitative comparison of experimental chimeras with chimeras obtained through numerical simulations. PMID- 27781481 TI - Introduction to focus issue: Patterns of network synchronization. AB - The study of synchronization of coupled systems is currently undergoing a major surge fueled by recent discoveries of new forms of collective dynamics and the development of techniques to characterize a myriad of new patterns of network synchronization. This includes chimera states, phenomena determined by symmetry, remote synchronization, and asymmetry-induced synchronization. This Focus Issue presents a selection of contributions at the forefront of these developments, to which this introduction is intended to offer an up-to-date foundation. PMID- 27781482 TI - Multiple absolute negative mobilities. AB - In this paper, we investigate transport of an inertial particle in a spatially symmetric potential and subjected to two harmonic signals with different frequencies in both deterministic and stochastic cases. Numerical results indicate that: (i) In the deterministic case, the two harmonic signals can induce many (up to six) segments of negative slopes in the curve of mean velocity vs. external constant force, i.e., a multiple absolute negative mobilities (ANMs) effect. But the occurrence of the effect depends on their frequencies and amplitudes. (ii) For the stochastic case, the multiple ANMs relay on stable index and symmetry parameter of the Levy noise. In the case of symmetric noise, appropriate stable index makes the multiple ANMs be the strongest. Our further investigations indicate that an indispensable condition for the multiple ANMs to occur in the system is the temporal symmetry breaking by one multiplicative periodic signal and one additive periodic signal. PMID- 27781483 TI - Synchronization failure caused by interplay between noise and network heterogeneity. AB - We investigate synchronization in complex networks of noisy phase oscillators. We find that, while too weak a coupling is not sufficient for the whole system to synchronize, too strong a coupling induces a nontrivial type of phase slip among oscillators, resulting in synchronization failure. Thus, an intermediate coupling range for synchronization exists, which becomes narrower when the network is more heterogeneous. Analyses of two noisy oscillators reveal that nontrivial phase slip is a generic phenomenon when noise is present and coupling is strong. Therefore, the low synchronizability of heterogeneous networks can be understood as a result of the difference in effective coupling strength among oscillators with different degrees; oscillators with high degrees tend to undergo phase slip while those with low degrees have weak coupling strengths that are insufficient for synchronization. PMID- 27781485 TI - Big Data in radiation therapy: challenges and opportunities. AB - Data collected and generated by radiation oncology can be classified by the Volume, Variety, Velocity and Veracity (4Vs) of Big Data because they are spread across different care providers and not easily shared owing to patient privacy protection. The magnitude of the 4Vs is substantial in oncology, especially owing to imaging modalities and unclear data definitions. To create useful models ideally all data of all care providers are understood and learned from; however, this presents challenges in the guise of poor data quality, patient privacy concerns, geographical spread, interoperability and large volume. In radiation oncology, there are many efforts to collect data for research and innovation purposes. Clinical trials are the gold standard when proving any hypothesis that directly affects the patient. Collecting data in registries with strict predefined rules is also a common approach to find answers. A third approach is to develop data stores that can be used by modern machine learning techniques to provide new insights or answer hypotheses. We believe all three approaches have their strengths and weaknesses, but they should all strive to create Findable, Accessible, Interoperable, Reusable (FAIR) data. To learn from these data, we need distributed learning techniques, sending machine learning algorithms to FAIR data stores around the world, learning from trial data, registries and routine clinical data rather than trying to centralize all data. To improve and personalize medicine, rapid learning platforms must be able to process FAIR "Big Data" to evaluate current clinical practice and to guide further innovation. PMID- 27781484 TI - Molecular characterization of pathogenic and nonpathogenic fowl aviadenovirus serotype 11 isolates. AB - Fowl aviadenoviruses, many of which are of importance in veterinary medicine, are classified into 5 species. In this study, a pathogenic isolate and a nonpathogenic isolate of fowl aviadenovirus serotype 11 (FAdV-11) of species Fowl aviadenovirus D were characterized. Growth rates were analyzed for the 2 isolates, showing notable differences. The complete genomic sequences of the viruses were fully determined and were analyzed. The genomes of the 2 isolates showed 98.1% sequence identity and revealed 6 nonsynonymous mutations between the Ontario isolates. Two of the 6 mutations were also found in the sequences of recently published pathogenic Chinese fowl aviadenovirus 11 isolates, suggesting potential molecular markers that could be associated with pathogenesis. Deletions were found in the L5 region within the overlapping coding sequences for the 100, 22, and 33 kDa proteins, and these were found in only the nonpathogenic isolates. This molecular pattern was identified in FAdV-9, another nonpathogenic FAdV-D species virus. Furthermore, the tandem repeat regions varied dramatically; the pathogenic isolates contained a reduced number of tandem repeats compared with the nonpathogenic isolates. Lastly, a protein produced early in infection was analyzed using bioinformatics to determine its role in disease. This study highlights several candidate molecular determinants of avian adenovirus genomes related to pathogenicity. PMID- 27781487 TI - Kernohan-Woltman notch phenomenon: a review article. AB - Kernohan-Woltman notch phenomenon (KWNP) is a false localising sign which may still cause diagnostic confusion. It was first described by Kernohan and Woltman in 1929, through post-mortem studies on 297 patients following cases of false localisation. They proposed that raised intracranial pressure causes uncal herniation, which can compress the contralateral cerebral peduncle against the tough tentorium, manifesting as hemiparesis ipsilateral to the primary brain lesion. A number of case reports have been written since the original description of this phenomenon, primarily secondary to intracranial bleeds, and little has been written about long-term outcome of patients who develop KNWP. We performed a literature search of all published cases of KWNP, and reviewed its clinical, pathophysiological, imaging and neurophysiological characteristics. Furthermore, we summarise the long-term outcomes of these patients as described by case reports, with the aim to improve understanding of rehabilitation potential. Thirty-eight cases were found through a PubMed search. We also included a case from our own Trust, making the total number of cases in the analysis 39. Thirty six cases were secondary to intracranial bleeds (22 of which were traumatic), the remainder were due to an arachnoid cyst, high grade glioma, and reabsorption bone syndrome. Additional clinical manifestations to hemibrachiocrural syndrome included third nerve palsy, mydriasis of the contralateral and ipsilateral pupils, facial nerve palsies, and parkinsonism. Twenty-six (67%) patients had improvement in motor function of varying degrees, with twelve (31%) patients attaining complete motor recovery or independence. More studies on long-term outcome of patients who develop KWNP are needed to understand rehabilitation potential. PMID- 27781486 TI - Quality of tri-Co-60 MR-IGRT treatment plans in comparison with VMAT treatment plans for spine SABR. AB - OBJECTIVE: To investigate the plan quality of tri-Co-60 intensity-modulated radiation therapy (IMRT) plans for spine stereotactic ablative radiotherapy (SABR). METHODS: A total of 20 patients with spine metastasis were retrospectively selected. For each patient, a tri-Co-60 IMRT plan and a volumetric-modulated arc therapy (VMAT) plan were generated. The spinal cords were defined based on MR images for the tri-Co-60 IMRT, while isotropic 1-mm margins were added to the spinal cords for the VMAT plans. The VMAT plans were generated with 10-MV flattening filter-free photon beams of TrueBeam STxTM (Varian Medical Systems, Palo Alto, CA), while the tri-Co-60 IMRT plans were generated with the ViewRayTM system (ViewRay inc., Cleveland, OH). The initial prescription dose was 18 Gy (1 fraction). If the tolerance dose of the spinal cord was not met, the prescription dose was reduced until the spinal cord tolerance dose was satisfied. RESULTS: The mean dose to the target volumes, conformity index and homogeneity index of the VMAT and tri-Co-60 IMRT were 17.8 +/- 0.8 vs 13.7 +/- 3.9 Gy, 0.85 +/- 0.20 vs 1.58 +/- 1.29 and 0.09 +/- 0.04 vs 0.24 +/- 0.19, respectively. The integral doses and beam-on times were 16,570 +/- 1768 vs 22,087 +/- 2.986 Gy cm3 and 3.95 +/- 1.13 vs 48.82 +/- 10.44 min, respectively. CONCLUSION: The tri-Co-60 IMRT seems inappropriate for spine SABR compared with VMAT. Advances in knowledge: For spine SABR, the tri-Co-60 IMRT is inappropriate owing to the large penumbra, large leaf width and low dose rate of the ViewRay system. PMID- 27781488 TI - Current challenges in the pharmacological management of thyroid dysfunction in pregnancy. AB - INTRODUCTION: Thyroid dysfunction is common in pregnancy and has adverse fetal and maternal health consequences. A number of challenges in the management of gestational thyroid dysfunction remain unresolved including uncertainties in optimal thresholds for correction of hypothyroidism and strategies for pharmacological management of hyperthyroidism. Areas covered: We addressed key challenges and areas of uncertainty in the management of thyroid dysfunction in pregnancy. Expert commentary: Gestational thyroid hormone reference intervals vary according to population ethnicity, iodine nutrition, and assay method and each population should derive trimester specific reference intervals for use in pregnancy. Subclinical hypothyroidism and isolated hypothyroxinaemia are common in pregnancy but there is no consensus on the benefits of correcting these conditions. Although observational studies show potential benefits of levothyroxine on child neurocognitive function these benefits are have not been supported by two controlled trials. Carbimazole should be avoided in the first trimester of pregnancy due to risk of congenital anomalies but recent studies would suggest that this risk is present to a lesser magnitude with propylthiouracil. Current international guidelines recommend the use of propylthiouracil in the first trimester and switching to carbimazole for the remainder of pregnancy but the benefits and practicalities of this approach is unproven. PMID- 27781489 TI - Altered glycosyltransferases in colorectal cancer. PMID- 27781490 TI - Dabrafenib in BRAFV600-mutated anaplastic pleomorphic xanthoastrocytoma. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor. Anaplastic features are found in 20-30% of cases of PXA and are associated with poor outcomes. Typical treatment is with gross total resection, followed by radiation therapy and cytotoxic chemotherapy at relapse. BRAFV600 mutations have been identified in 38-60% of patients with PXA. Several case reports and small case series have identified clinical benefit with BRAF inhibition in patients with BRAFV600 mutated PXA. We report the second published case of successful treatment with the BRAF inhibitor dabrafenib in a female patient with relapsed anaplastic PXA with a BRAFV600 mutation, and the first published case of dabrafinib treatment following intolerance to vemurafenib. PMID- 27781491 TI - Feasibility of offline head & neck adaptive radiotherapy using deformed planning CT electron density mapping on weekly cone beam computed tomography. AB - OBJECTIVE: The purpose of the study was to use deformable mapping of planning CT (pCT) electron density values on weekly cone-beam CT (CBCT) to quantify the anatomical changes and determine the dose-volume relationship in offline adaptive volumetric-modulated arc therapy. METHODS: 10 patients treated with RapidArc plans who had weekly CBCTs were selected retrospectively. The pCT was deformed to weekly CBCTs and the deformed contours were checked for any discrepancies. Clinical target volume 66 Gy and 60 Gy (CTV66 and CTV60), parotids and spinal cord were the structures selected for analysis. Volume reduction and dice similarity index (DSI) were determined. Hybrid RapidArc plans were created and the cumulative dose-volume histograms for selected structures were analyzed. RESULTS: Results showed a mean volume reduction of 18.82 +/- 6.08% and 18.22 +/- 6.1% for Clinical target volume 66 Gy and 60 Gy (CTV66 and CTV60), respectively, and their corresponding DSI values were 0.94 +/- 0.03 and 0.95 +/- 0.01. Mean volume reductions of left and right parotids were 32.79 +/- 10.28% and 29.46 +/- 8.78%, respectively, and their corresponding mean DSI values were 0.90 +/- 0.05 and 0.89 +/- 0.05. The cumulative mean dose difference for Planning target volume 66 Gy (PTV66) was -1.35 +/- 1.71% and for Planning target volume 60 Gy (PTV60), it was -0.69 +/- 1.37%. Spinal cord doses varied for all patients over the course. CONCLUSION: The results from the study showed that it is clinically feasible to estimate the dose-volume relationship using deformed pCT. Monitoring of patient anatomic changes and incorporating patient-specific replanning strategy are necessary to avoid critical structure complications. Advances in knowledge: Deformable mapping of pCT electron density values on weekly CBCTs has been performed to establish the volumetric and dosimetric changes. The anatomical changes differ among the patients and hence, the choice for adaptive radiotherapy should be strictly patient specific rather than time specific. PMID- 27781492 TI - Presenting concerns of emerging adults seeking treatment at an early intervention outpatient mood and anxiety program. AB - This study examined presenting concerns and characteristics of emerging adults (EAs) seeking treatment at an early intervention program for mood and anxiety disorders to better understand presenting concerns when treatment is needed. During an intake assessment conducted by a social worker or clinical psychologist, participants (N = 548; 62% female, 38% male) reported their top three current life concerns, which were analyzed qualitatively using thematic analysis. Participants completed a battery of questionnaires assessing demographic information, symptomatology, and daily functioning. Females presented with significantly higher levels of anxiety, and both females and younger individuals (age 16-18) presented with significantly higher levels of depression compared to males and older individuals (age 19-26), respectively. The two most commonly reported presenting concerns were problems in interpersonal relationships and academics, and females were more likely to report academic concerns than males. The majority of participants reported seeking help for a wide range of problems commonly faced by EAs (83.7%), and participants rarely expressed concerns about particular symptoms of mood and/or anxiety disorders (16.3%). EAs and those supporting EAs may benefit from learning when psychosocial concerns are indicative of mental health challenges warranting professional attention. PMID- 27781494 TI - Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency. AB - A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly's advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides). To our surprise, while seven of nine compounds were found to be inactive (likely due to the decrease in lipophilicity, which is known to be detrimental to FFA1 ligand affinity), two compounds containing 2-pyridyloxy and 2-pyrimidinyloxy groups were found to have EC50 of 1.621 and 0.904 uM, respectively. This result is significant in the context of the worldwide quest for more polar FFA1 agonists, which would be devoid of liver toxicity effects earlier observed for a FFA1 agonist fasiglifam (TAk-875) in clinical studies. PMID- 27781493 TI - Systematic review and meta-analysis on laparoscopic pancreatic resections for neuroendocrine neoplasms (PNENs). AB - INTRODUCTION: The safety of laparoscopic resections (LPS) of pancreatic neuroendocrine neoplasms (PNENs) has been well established in the literature. Areas covered: Studies conducted between January 2003 and December 2015 that reported on LPS and open surgery (OPS) were reviewed. The primary outcomes were the rate of post-operative complications and the length of hospital stay (LoS) after laparoscopic and open surgical resection. The rate of recurrence was the secondary outcome. Eleven studies were included with a total of 907 pancreatic resections for PNENs, of whom, 298 (32.8%) underwent LPS and 609 (67.2%) underwent open surgery. LPS resulted in a significantly shorter LoS (p < 0.0001) and lower blood loss (p < 0.0001). The meta-analysis did not show any significant difference in the pancreatic fistula rate, recurrence rate or post-operative mortality between the two groups. Expert commentary: LPS is a safe approach even for PNENs and it is associated with a shorter LoS. PMID- 27781495 TI - Prevalence of oral cancer, oral potentially malignant disorders and other oral mucosal lesions in Cambodia. AB - OBJECTIVES: To obtain data on the prevalence of oral mucosal lesions (OMLs) among Cambodians, and to assess the relationship between known risk habits of oral diseases with prevalence of oral potentially malignant disorders (OPMDs). DESIGN: This was a population-based, cross-sectional study whereby subjects were adults aged 18 years old and above. A workshop on the identification of OML was held to train and calibrate dental officers prior to data collection in the field. Sociodemographic and risk habits data were collected via face-to-face interview, whilst presence of OML and clinical details of lesions such as type and site were collected following clinical oral examination by the examiners. Data analysis was carried out using the Statistical Package for Social Science (SPSS) version 12.0. The association between risk habits and risk of OPMD was explored using logistic regression analysis. RESULTS: A total of 1634 subjects were recruited. Prevalence of OML for this population was 54.1%. Linea alba was the most common lesion seen (28.7%). This study showed an overall OPMD prevalence of 5.6%. The most common type of OPMD was leukoplakia (64.8%), followed by lichen planus (30.8%). Subjects who only smoked were found to have an increased risk for OPMD of almost four-fold (RR 3.74, 95%CI 1.89-7.41). The highest risk was found for betel quid chewers, where the increased risk observed was more than six times (RR 6.75, 95%CI 3.32 13.72). Alcohol consumption on its own did not seem to confer an increased risk for OPMD, however when practiced concurrently with smoking, a significant risk of more than five times was noted (RR 5.69 95%CI 3.14-10.29). CONCLUSION: The prevalence of OML was 54.1%, with linea alba being the most commonly occurring lesion. Smoking, alcohol consumption and betel quid chewing were found to be associated with the prevalence of OPMD, which was 5.6%. PMID- 27781496 TI - The interprocess NIR sampling as an alternative approach to multivariate statistical process control for identifying sources of product-quality variability. AB - We are presenting a new approach of identifying sources of variability within a manufacturing process by NIR measurements of samples of intermediate material after each consecutive unit operation (interprocess NIR sampling technique). In addition, we summarize the development of a multivariate statistical process control (MSPC) model for the production of enteric-coated pellet product of the proton-pump inhibitor class. By developing provisional NIR calibration models, the identification of critical process points yields comparable results to the established MSPC modeling procedure. Both approaches are shown to lead to the same conclusion, identifying parameters of extrusion/spheronization and characteristics of lactose that have the greatest influence on the end-product's enteric coating performance. The proposed approach enables quicker and easier identification of variability sources during manufacturing process, especially in cases when historical process data is not straightforwardly available. In the presented case the changes of lactose characteristics are influencing the performance of the extrusion/spheronization process step. The pellet cores produced by using one (considered as less suitable) lactose source were on average larger and more fragile, leading to consequent breakage of the cores during subsequent fluid bed operations. These results were confirmed by additional experimental analyses illuminating the underlying mechanism of fracture of oblong pellets during the pellet coating process leading to compromised film coating. PMID- 27781497 TI - Solvents effects on crystallinity and dissolution of beta-artemether. AB - beta-artemether (ARM) is a widely used anti-malarial drug isolated from the Chinese antimalarial plant, Artemisia annua. The solvent effects on crystal habits and dissolution of ARM were thoroughly investigated and discussed herein. The ARM was recrystallized in nine different solvents of varied polarity, namely, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, trichloromethane, ethyl acetate, acetone and hexane by solvent evaporation method. The obtained crystals were morphologically characterized using scanning electron microscope (SEM). The average sizes of crystals were 1.80-2.64 MUm calculated from microscopic images using Image-Pro software. No significant change in chemical structure was noticed after recrystallization and the specific band at 875 cm-1 wavenumber (C-O-O-C) confirmed the presence of most sensitive functional group in the ARM chemical structure. The existence and production of two polymorphic forms, polymorph A and polymorph B, was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The data suggested that the fabrication of polymorph B can be simply obtained from the recrystallization of ARM in a specific solvent. Significant effects of solvent polarity, crystals shapes and sizes on drug dissolution were noticed during in vitro dissolution test. The release kinetics were calculated and well fitted by the Higuchi and Hixon-Crowell models. The ARM-methanol and ARM-hexane showed highest and slowest dissolution, respectively, due to the effects of solvent polarity and crystal morphologies. Overall, proper selection of the solvents for the final crystallization of ARM helps to optimize dissolution and bioavailability for a better delivery of anti-malarial drug. PMID- 27781498 TI - Infliximab therapy reverses the increase of allograft inflammatory factor-1 in serum and colonic mucosa of rats with inflammatory bowel disease. AB - OBJECTIVE: Our purpose was to study the molecular basis of infliximab (IFX) effect on colon mucosa in a colitis model and to identify new biomarkers of mucosal healing. METHODS: Healthy rats and rats which were subjected to experimental colitis induced by dextran sulfate sodium, with or without IFX treatment (in the short- and long-term), were studied along with forty-seven IBD patients. Colon mucosal integrity by periodic acid Schiff (PAS) staining, intestinal damage by immunohistochemistry (proliferating cell nuclear antigen, beta-catenin, E-cadherin, phosphotyrosine, p-p38, allograft inflammatory factor-1 (AIF-1) and colonic mucosal apoptosis by TUNEL staining were evaluated in rats while serum and colon AIF-1 levels were determined in IBD patients. RESULTS: In rats with colitis, IFX reestablished the epithelial barrier integrity, recovered mucus production and decreased colon inflammation, as verified by reduced serum and colon AIF-1 levels; colon and serum AIF-1 levels were also lower in inactive IBD patients compare to active ones. P38 activation after IFX treatment tended to induce differentiation/proliferation of epithelial cells along the colonic crypt villous axis. CONCLUSIONS: These findings support AIF-1 as a new biomarker of mucosal healing in experimental colitis and suggest that p38 activation is involved in the mucosal healing intracellular mechanism induced by IFX treatment. PMID- 27781499 TI - A quantitative study of shape descriptors from glioblastoma multiforme phenotypes for predicting survival outcome. AB - OBJECTIVE: Predicting the survival outcome of patients with glioblastoma multiforme (GBM) is of key importance to clinicians for selecting the optimal course of treatment. The goal of this study was to evaluate the usefulness of geometric shape features, extracted from MR images, as a potential non-invasive way to characterize GBM tumours and predict the overall survival times of patients with GBM. METHODS: The data of 40 patients with GBM were obtained from the Cancer Genome Atlas and Cancer Imaging Archive. The T1 weighted post-contrast and fluid-attenuated inversion-recovery volumes of patients were co-registered and segmented into delineate regions corresponding to three GBM phenotypes: necrosis, active tumour and oedema/invasion. A set of two-dimensional shape features were then extracted slicewise from each phenotype region and combined over slices to describe the three-dimensional shape of these phenotypes. Thereafter, a Kruskal-Wallis test was employed to identify shape features with significantly different distributions across phenotypes. Moreover, a Kaplan-Meier analysis was performed to find features strongly associated with GBM survival. Finally, a multivariate analysis based on the random forest model was used for predicting the survival group of patients with GBM. RESULTS: Our analysis using the Kruskal-Wallis test showed that all but one shape feature had statistically significant differences across phenotypes, with p-value < 0.05, following Holm Bonferroni correction, justifying the analysis of GBM tumour shapes on a per phenotype basis. Furthermore, the survival analysis based on the Kaplan-Meier estimator identified three features derived from necrotic regions (i.e. Eccentricity, Extent and Solidity) that were significantly correlated with overall survival (corrected p-value < 0.05; hazard ratios between 1.68 and 1.87). In the multivariate analysis, features from necrotic regions gave the highest accuracy in predicting the survival group of patients, with a mean area under the receiver-operating characteristic curve (AUC) of 63.85%. Combining the features of all three phenotypes increased the mean AUC to 66.99%, suggesting that shape features from different phenotypes can be used in a synergic manner to predict GBM survival. CONCLUSION: Results show that shape features, in particular those extracted from necrotic regions, can be used effectively to characterize GBM tumours and predict the overall survival of patients with GBM. Advances in knowledge: Simple volumetric features have been largely used to characterize the different phenotypes of a GBM tumour (i.e. active tumour, oedema and necrosis). This study extends previous work by considering a wide range of shape features, extracted in different phenotypes, for the prediction of survival in patients with GBM. PMID- 27781554 TI - Gut-lung axis: The microbial contributions and clinical implications. AB - Gut microbiota interacts with host immune system in ways that influence the development of disease. Advances in respiratory immune system also broaden our knowledge of the interaction between host and microbiome in the lung. Increasing evidence indicated the intimate relationship between the gastrointestinal tract and respiratory tract. Exacerbations of chronic gut and lung disease have been shown to share key conceptual features with the disorder and dysregulation of the microbial ecosystem. In this review, we discuss the impact of gut and lung microbiota on disease exacerbation and progression, and the recent understanding of the immunological link between the gut and the lung, the gut-lung axis. PMID- 27781555 TI - Who should be treated surgically for a displaced clavicle fracture? PMID- 27781557 TI - Characterisation and in vitro antimicrobial activity of biosynthetic silver loaded bacterial cellulose hydrogels. AB - Wounds that remain in the inflammatory phase for a prolonged period of time are likely to be colonised and infected by a range of commensal and pathogenic microorganisms. Treatment associated with these types of wounds mainly focuses on controlling infection and providing an optimum environment capable of facilitating re-epithelialisation, thus promoting wound healing. Hydrogels have attracted vast interest as moist wound-responsive dressing materials. In the current study, biosynthetic bacterial cellulose hydrogels synthesised by Gluconacetobacter xylinus and subsequently loaded with silver were characterised and investigated for their antimicrobial activity against two representative wound infecting pathogens, namely S. aureus and P. aeruginosa. Silver nitrate and silver zeolite provided the source of silver and loading parameters were optimised based on experimental findings. The results indicate that both AgNO3 and AgZ loaded biosynthetic hydrogels possess antimicrobial activity (p < .05) against both S. aureus and P. aeruginosa and may therefore be suitable for wound management applications. PMID- 27781558 TI - Lipid-based nanocarriers for the oral administration of biopharmaceutics. AB - Biopharmaceutics have been recognized as the drugs of choice for the treatment of several diseases, mainly due to their high selectivity and potent action. Nonetheless, their oral administration is a rather challenging problem, since their bioavailability is significantly hindered by various physiological barriers along the GI tract, including their acid-induced hydrolysis in the stomach, their enzymatic degradation throughout the GI tract and their poor mucosa permeability. Lipid-based nanocarriers represent a viable means for enhancing the oral bioavailability of biomolecules while diminishing toxicity-related issues. The present review describes the main physiological barriers limiting the oral bioavailability of macromolecules and highlights recent advances in the field of lipid-based carriers as well as the respective lipid intestinal absorption mechanisms. PMID- 27781560 TI - Precision medicine in genetic epilepsies: break of dawn? AB - INTRODUCTION: Therapy with current antiepileptic drugs aims at reducing the likelihood of seizure occurrence rather than influencing the underlying disease process. Therefore, antiepileptic drugs have an anticonvulsant rather than antiepileptic property. Areas covered: The increasing identification of genetic causes for epilepsy over the recent years improves the understanding of the underlying epileptogenic process and allows for the possibility of directed therapeutic approaches. An ideal antiepileptic therapy consists of a drug which is able to influence the functional changes caused by a specific pathogenic variant. In this review we will describe the current precision medicine approaches in genetic epilepsies in reference to the identified genetic etiologies. References for this review were identified through searches of PubMed and the authors' own files. Expert commentary: Currently established or investigated precision medicine treatments include the ketogenic diet in patients with GLUT1 deficiency, sodium channel blockers in patients with KCNQ2, SCN2A and SCN8A mutations as well as mTOR-inhibitors in mTORopathies. These predominantly represent already available treatments that were repurposed for use in epilepsy. The development of new therapeutic agents aiming at targets identified in genetic epilepsies will advance epilepsy treatment considerably. PMID- 27781556 TI - Mood Therapeutics: Novel Pharmacological Approaches for Treating Depression. AB - INTRODUCTION: Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders. Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States. Expert commentary: Of these novel targets, the most promising - and the ones for whom the most evidence exists - appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders. PMID- 27781559 TI - Folic acid-decorated polyamidoamine dendrimer mediates selective uptake and high expression of genes in head and neck cancer cells. AB - AIM: Folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) was synthesized and studied for targeted delivery of genes to head and neck cancer cells expressing high levels of folate receptors (FRs). METHODS: Cellular uptake, targeting specificity, cytocompatibility and transfection efficiency were evaluated. RESULTS: G4-FA competes with free FA for the same binding site. G4-FA facilitates the cellular uptake of DNA plasmids in a FR-dependent manner and selectively delivers plasmids to FR-high cells, leading to enhanced gene expression. CONCLUSION: G4-FA is a suitable vector to deliver genes selectively to head and neck cancer cells. The fundamental understandings of G4-FA as a vector and its encouraging transfection results for head and neck cancer cells provided support for its further testing in vivo. PMID- 27781563 TI - Are engineered nano iron oxide particles safe? an environmental risk assessment by probabilistic exposure, effects and risk modeling. AB - Nano iron oxide particles are beneficial to our daily lives through their use in paints, construction materials, biomedical imaging and other industrial fields. However, little is known about the possible risks associated with the current exposure level of engineered nano iron oxides (nano-FeOX) to organisms in the environment. The goal of this study was to predict the release of nano-FeOX to the environment and assess their risks for surface waters in the EU and Switzerland. The material flows of nano-FeOX to technical compartments (waste incineration and waste water treatment plants) and to the environment were calculated with a probabilistic modeling approach. The mean value of the predicted environmental concentrations (PECs) of nano-FeOX in surface waters in the EU for a worst-case scenario (no particle sedimentation) was estimated to be 28 ng/l. Using a probabilistic species sensitivity distribution, the predicted no effect concentration (PNEC) was determined from ecotoxicological data. The risk characterization ratio, calculated by dividing the PEC by PNEC values, was used to characterize the risks. The mean risk characterization ratio was predicted to be several orders of magnitude smaller than 1 (1.4 * 10-4). Therefore, this modeling effort indicates that only a very limited risk is posed by the current release level of nano-FeOX to organisms in surface waters. However, a better understanding of the hazards of nano-FeOX to the organisms in other ecosystems (such as sediment) needs to be assessed to determine the overall risk of these particles to the environment. PMID- 27781564 TI - Improvements in physical function and pain sustained for up to 10 years after knee or hip arthroplasty irrespective of mental health status before surgery. AB - Background and purpose - There are concerns that mental health (MH) may influence outcomes of total knee arthroplasty (TKA) or total hip arthroplasty (THA). We examined effects of poor MH before surgery on long-term outcomes of osteoarthritis-related TKA or THA in women. Patients and methods - The data were from 9,737 middle-aged participants (47-52 years) and 9,292 older participants (73-78 years) in the Australian Longitudinal Study on Women's Health who completed surveys between 1998 and 2013. Dates of arthroplasties were obtained from the Australian Orthopaedics Association National Joint Replacement Registry. Participants without procedures were matched with participants with procedures. Trajectories of the Short-Form 36 scores for physical functioning, bodily pain, social functioning, and mental health based on mixed modeling were plotted for participants with and without surgery (stratified according to mental health, separately for TKA and THA, and for middle-aged and older participants). Results In middle-aged women with poor and good MH, TKA improved physical function and reduced bodily pain, with improvements sustained up to 10 years after surgery. TKA contributed to restoration of social function in women with good MH, but this was less clear in women with poor MH. In both MH groups, mental health appeared to be unaffected by TKA. Similar patterns were observed after THA, and in older women. Interpretation - Recovery of physical and social function and reductions in pain were sustained for up to 10 years after surgery. Improvements in physical function and pain were also observed in women with poor mental health. Thus, in our view poor mental health should not be a contraindication for arthroplasty. PMID- 27781565 TI - Could multiresponsive hollow shell-shell nanocontainers offer an improved strategy for drug delivery? PMID- 27781566 TI - Persistence of chloramphenicol residues in chicken muscle tissue after a therapeutic dose administration. AB - One-day-old chickens were individually orally treated with chloramphenicol at a dose of 100 mg per kg of body weight per day for three consecutive days. After the final treatment, the groups of six birds were sacrificed in seven-day intervals up to 42 days. The muscle tissue collected from the breasts and legs of each bird was individually examined for the presence of chloramphenicol residues using a GC/MS-NCI analytical method, which was validated according to Commission Decision 2002/657/EC. The decision limit (CCalpha) obtained for the method was 0.05 ng g-1. The results showed a rapid decrease of chloramphenicol concentration in the muscle tissue after termination of the treatment, but also showed a relatively long persistence of low residue concentrations. Levels of chloramphenicol in muscle tissue averaged 64 ng g-1 seven days after the final treatment and fell to 0.21 ng g-1 after 35 days. All animals tested on the 35th day after the final treatment showed detectable chloramphenicol concentrations above the decision limit of the method used. No residues were detected in the animal tissues 42 days after the end of the treatment. PMID- 27781567 TI - Dynamic adjustment of lexical processing in the lexical decision task: Cross trial sequence effects. AB - There has been growing interest in dynamic changes in the lexical processing system across trials, which have typically been assessed via linear mixed effect modelling. In the current study, we explore the influence of previous trial lexicality and previous trial perceptual degradation on the effect of lexicality and degradation on the current trial. The results of analyses of three datasets (two previously published studies and a new study) provide evidence for a robust four-way interaction among previous trial lexicality and degradation and current trial lexicality and degradation effects. Discussion emphasizes how priming of relevant dimensions (clear vs. degraded or word vs. nonword) within the experimental context modulates the influence of degradation on the current trial as a function of lexicality. These results suggest that in lexical decision there are robust lingering effects of the previous stimulus and response that carry over to the current stimulus and response, and participants cannot tune task related systems to only the present trial. Importantly, although these complex relationships are theoretically important regarding lexical and decision level processes, these complexities also reinforce Keith Rayner's emphasis on on-line eye-tracking measures during reading as the most straightforward window into word level processes engaged during reading. PMID- 27781568 TI - Delivering solid treatments on shaky ground: Feasibility study of an online therapy for child anxiety in the aftermath of a natural disaster. AB - OBJECTIVE: To assess feasibility of online cognitive behaviour therapy (CBT) for children and adolescents with anxiety in the aftermath of a natural disaster. METHOD: 42 children and adolescents with clinical anxiety referred from primary care were invited to complete an internet CBT program (BRAVE-ONLINE). Outcome measures and assessment timelines were chosen to allow a comparison of the results with the program developers' randomised controlled trials. RESULTS: At 6 month post intervention, more than half (55%) of the 33 participants assessed, no longer met criteria for their primary anxiety disorder. The mean number of anxiety diagnoses dropped from 2.76 (SD = 0.85) at baseline to 1.06 (SD = 1.25) at follow-up (z = -4.51, p < .001). Participants' anxiety and mood symptoms reduced and health-related quality of life improved significantly by follow-up. Satisfaction ratings were moderate to high. On average, by 6-month follow-up, children and adolescents had completed 6 of 10 sessions and parents had completed 5/6 (child parent program) and 3/5 sessions (adolescent parent program). CONCLUSIONS: Following a natural disaster (the Canterbury earthquakes), children and adolescents showed clinically significant improvement in anxiety and mood when they used BRAVE-ONLINE. This approach was both feasible and acceptable to families and offered a solution when mental health services were under pressure. PMID- 27781569 TI - The complete mitochondrial genome of great cormorant, Phalacrocorax carbo (Phalacrocorax, Phalacrocoracidae). AB - The great cormorant (Phalacrocorax carbo) is widely distributed in the world. Here, we report the complete mitogenome sequence of P. carbo, which was 18,995 bp long and composed of 15 protein-coding genes, 25 tRNA genes, 2 rRNA genes and 2 control regions. Most genes were located on H-strand except for 10 tRNAs and 2 ND6 genes. In protein-coding genes, ATG, ATC and GTG were used as initiation codons, and TAA, AGA, AGG and TAG were used as stop codons. The 25 tRNA genes ranged in size from 67 to 75 bp. And 12S and 16S rRNA were respectively 983 and 1517 bp. Except for a tRNA-Ala in P. carbo which was different from the tRNA-Lys annotated in P. chalconotus, both species of Phalacrocorax had the same order of other genes. In addition, a phylogenetic analysis may help us understand the evolutionary status of this widespread species better. PMID- 27781570 TI - Quantum ergonomics: shifting the paradigm of the systems agenda. AB - A paradigm is an accepted world view. If we do not continually question our paradigm then wider trends and movements will overtake the discipline leaving it ill adapted to future challenges. This Special Issue is an opportunity to keep systems thinking at the forefront of ergonomics theory and practice. Systems thinking prompts us to ask whether ergonomics, as a discipline, has been too timid? Too preoccupied with the resolution of immediate problems with industrial age methods when, approaching fast, are developments which could render these operating assumptions an irrelevance. Practical case studies are presented to show how abstract systems problems can be tackled head-on to deliver highly innovative and cost-effective insights. The strategic direction of the discipline foregrounds high-quality systems problems. These are something the discipline is well able to respond to provided that the appropriate operating paradigms are selected. Practitioner Summary: High-quality systems problems are the future of the discipline. How do we convert obtuse sounding systems concepts into practical interventions? In this paper, the essence of systems thinking is distilled and practical case studies used to demonstrate the benefits of this new paradigm. PMID- 27781936 TI - Editorial: Antibody Phage Display: The Evolution of Antibody Therapeutics. PMID- 27781667 TI - Peripheral snap-fit locking mechanisms and smooth surface finish of tibial trays reduce backside wear in fixed-bearing total knee arthroplasty. AB - Background and purpose - Severe backside wear, observed in older generations of total knee replacements (TKRs), led to redesign of locking mechanisms to reduce micromotions between tibial tray and inlay. Since little is known about whether this effectively reduces backside wear in modern designs, we examined backside damage in retrievals of various contemporary fixed-bearing TKRs. Patients and methods - A consecutive series of 102 inlays with a peripheral (Stryker Triathlon, Stryker Scorpio, DePuy PFC Sigma, Aesculap Search Evolution) or dovetail locking mechanism (Zimmer NexGen, Smith and Nephew Genesis II) was examined. Articular and backside surface damage was evaluated using the semiquantitative Hood scale. Inlays were examined using scanning electron microscopy (SEM) to determine backside wear mechanisms. Results - Mean Hood scores for articular (A) and backside (B) surfaces were similar in most implants Triathlon (A: 46, B: 22), Genesis II (A: 55, B: 24), Scorpio (A: 57, B: 24), PFC (A: 52, B: 20); Search (A: 56, B: 24)-except the NexGen knee (A: 57, B: 60), which had statistically significantly higher backside wear scores. SEM studies showed backside damage caused by abrasion related to micromotion in designs with dovetail locking mechanisms, especially in the unpolished NexGen trays. In implants with peripheral liner locking mechanism, there were no signs of micromotion or abrasion. Instead, "tray transfer" of polyethylene and flattening of machining was observed. Interpretation - Although this retrieval study may not represent well-functioning TKRs, we found that a smooth surface finish and a peripheral locking mechanism reduce backside wear in vivo, but further studies are required to determine whether this actually leads to reduced osteolysis and lower failure rates. PMID- 27781937 TI - A new computational approach to the classification of fluoroquinolones according to the Biopharmaceutical Classification System. AB - BACKGROUND: Two main factors, which have an influence on oral absorption from solid, immediate release dosage form, are solubility and permeability. These are considered the main fundamental properties that govern the rate and extent of oral absorption. The significance of these properties has been highlighted in the Biopharmaceutics Classification System (BCS). OBJECTIVE: The concept of this paper was to predict the solubility and permeability of fluoroquinolones using in silico methods based on the assumptions of the BCS. An attempt was also made to determine the place within this system for drugs from the fluoroquinolone group. METHOD: The study was carried out with the use of modern computational techniques which developed based on Artificial Neural Network Ensembles for Binary Classification. RESULTS: Using the values of the physicochemical descriptors of medicinal compounds with labeled BCS class, two classification models were elaborated for solubility and permeability. CONCLUSION: The obtained models helped to predict the provisional class for the following drugs in the BCS. Continuous improvement of computational models may support and can be treated equally with the in vivo data. PMID- 27781938 TI - Editorial: Limited Utility of the Handgrip Test for the Diagnosis of Diabetic Cardiovascular Autonomic Neuropathy: "There's Time Enough, But None to Spare". PMID- 27781939 TI - Editorial : Full Blood Count and Peripheral Arterial Disease Severity and Prognosis. PMID- 27781940 TI - Mesenchymal Stem Cells in Renal Ischemia-Reperfusion Injury: Biological and Therapeutic Perspectives. AB - Acute renal failure (ARF) is a syndrome of abrupt decline in renal function induced by a number of different insults. In clinic, the common etiology for ARF is ischemia-reperfusion injury (IRI). The pathophysiological process of renal IRI is complex, there is no good treatment. Stem cell therapy is a new and promising treatment for renal IRI. Mesenchymal stem cells (MSCs) have the ability to differentiate into tissues of mesodermal lineages. MSCs are under intensive study as potential therapeutic strategy for renal IRI. MSCs have been investigated with immunomodulatory, anti-inflammatory and tissue repair properties which could attenuate ischemic injury and accelerate the regeneration process in the condition of renal IRI. Moreover, the MSCs have the ability to migrate to the injury sites and to stimulate repair by paracrine mechanisms rather by differentiating into the injured cells. Here we review the latest information on MSCs, their biological characteristics, including their therapeutic perspectives, and envisage their putative role in renal ischaemic conditioning. PMID- 27781941 TI - Microwave Assisted Synthesis of Biorelevant Benzazoles. AB - The benzazole scaffolds are present in various therapeutic agents and have been recognized as the essential pharmacophore for diverse biological activities. These have generated interest and necessity to develop efficient synthetic methods of these privileged classes of compounds to generate new therapeutic leads for various diseases. The biological activities of the benzazoles and efforts towards their synthesis have been summarized in a few review articles. In view of these, the aim of this review is to provide an account of the developments that have taken place in the synthesis of biorelevant benzazoles under microwave irradiation as the application of microwave heating has long been recognized as a green chemistry tool for speedy generation of synthetic targets. Attention has been focused to those literature reports wherein the use of microwave irradiation is the key step in the formation of the heterocyclic ring system or in functionalization of the benzazole ring system to generate the essential pharmacophoric feature. The convenient and economic way to synthesize these privileged class of heterocycles through the use of microwave irradiation that would be beneficial for the drug discovery scientist to synthesize biologically active benzazoles and provide access to wide range of reactions for the synthesis of benzazoles constitute the theme of this review. Examples have been drawn wherein the use of microwave heating offers distinct advantage in terms of improved product yields and reduction of reaction time as compared to those observed for the synthesis under conventional heating. PMID- 27781942 TI - Expression and Regulation of Drug Transporters and Metabolizing Enzymes in the Human Gastrointestinal Tract. AB - Orally administered drugs must pass through the intestinal wall and then through the liver before reaching systemic circulation. During this process drugs are subjected to different processes that may determine the therapeutic value. The intestinal barrier with active drug metabolizing enzymes and drug transporters in enterocytes plays an important role in the determination of drug bioavailability. Accumulating information demonstrates variable distribution of drug metabolizing enzymes and transporters along the human gastrointestinal tract (GI), that creates specific barrier characteristics in different segments of the GI. In this review, expression of drug metabolizing enzymes and transporters in the healthy and diseased human GI as well as their regulatory aspects: genetic, miRNA, DNA methylation are outlined. The knowledge of unique interplay between drug metabolizing enzymes and transporters in specific segments of the GI tract allows more precise definition of drug release sites within the GI in order to assure more complete bioavailability and prediction of drug interactions. PMID- 27781943 TI - A Short Overview on the Biomedical Applications of Silica, Alumina and Calcium Phosphate-based Nanostructured Materials. AB - This article reviews the use of silica, alumina and calcium phosphate-based nanostructured materials with biomedical applications. A short introduction on the use of the materials in Science, Nanotechnology and Health is included followed by a revision of each of the selected materials. A description of the principal synthetic methods used in the preparation of the materials in nanostructured form is included. The most widely used applications in biomedicine are reviewed including, for example drug-delivery, bone regeneration, imaging, sensoring amongst others. Finally, a short description of the toxicity and cytotoxicity associated with each of the materials of this revision is presented. This short literature revision serves to demonstrate the very promising future ahead of nanosystems based on silica, alumina and calcium phosphate for biological and biomedical applications. PMID- 27781944 TI - Multitarget Opioid/Non-opioid Ligands: A Potential Approach in Pain Management. AB - Polypharmacology, or the associations between two or more drugs producing biological effects on two or more different sites of action could represent a possible therapeutic approach for the clinical management of acute and chronic pain. The multitude and complexity of neuronal mechanisms that contribute to pain transmission provide several possible targets for pharmacological intervention. Thus, multitarget ligands possessing opioid-opioid or non-opioid-opioid mechanisms of action are potential drug candidates for pain relief. In this perspective, the past medicinal chemistry paradigm "one-target, one-disease" has been reconsidered and converted into "one-molecule, multiple targets". Multitarget ligands in comparison with cocktail drugs, besides an improved analgesic effect, display a more predictable pharmacokinetic and pharmacodynamic profile coupled to a less incidence of side-effects. Thus, they ameliorate patient compliance and decrease the risk of drug-drug interactions. In our previous review multitarget ligands with an opioid-opioid mechanism of action were described. Here, we deal with multitarget ligands with opioid-non opioid mechanism of action as potential drug candidates for the management of different pain states. PMID- 27781945 TI - Resveratrol and Lifespan in Model Organisms. AB - BACKGROUND: Resveratrol may possess life-prolonging and health-benefitting properties, some of which may resemble the effect of caloric restriction (CR). CR appears to prolong the lifespan of model organisms in some studies and may benefit human health. However, for humans, restricting food intake for an extended period of time seems impracticable and substances imitating the beneficial effects of CR without having to reduce food intake could improve health in an aging and overweight population. METHODS: We have reviewed the literature studying the influence of resveratrol on the lifespan of model organisms including yeast, flies, worms, and rodents. We summarize the in vivo findings, describe modulations of molecular targets and gene expression observed in vivo and in vitro, and discuss how these changes may contribute to lifespan extension. Data from clinical studies are summarized to provide an insight about the potential of resveratrol supplementation in humans. RESULTS: Resveratrol supplementation has been shown to prolong lifespan in approximately 60% of the studies conducted in model organisms. However, current literature is contradictory, indicating that the lifespan effects of resveratrol vary strongly depending on the model organism. While worms and killifish seemed very responsive to resveratrol, resveratrol failed to affect lifespan in the majority of the studies conducted in flies and mice. Furthermore, factors such as dose, gender, genetic background and diet composition may contribute to the high variance in the observed effects. CONCLUSION: It remains inconclusive whether resveratrol is indeed a CR mimetic and possesses life-prolonging properties. The limited bioavailability of resveratrol may further impede its potential effects. PMID- 27781946 TI - The Role of Clusterin in Carcinogenesis and its Potential Utility as Therapeutic Target. AB - Clusterin is a glycoprotein that has been implicated in many processes, including apoptosis, cell cycle regulation and DNA repair. Since clusterin expression has also been associated with tumorigenesis and the progression of various malignancies including prevalent tumors like prostate, colon, bladder and breast, this protein has been proposed as a good candidate for future treatments. There have been numerous studies conducted in cell lines and xenograft models with successful results that, in general, justify the use of clusterin as a therapeutic target. However, it is still necessary to continue with these studies in order to achieve a better understanding of the role of this protein in carcinogenesis and to determine those specific situations in which its therapeutic use may be more favorable. In this review, we will make a brief description of clusterin structure and genetics, its implication in tumorigenesis and cancer progression and its prognosis utility. Finally, we will analyze the effects of clusterin inhibition in different types of cancer. PMID- 27781947 TI - Synthetic Lipoproteins as Carriers for Drug Delivery. AB - Synthetic lipoprotein is an effective carrier of targeted delivery for drugs. It has the very small size, good biocompatibility, suitable half-life, and specific lipoprotein receptorbinding capacity. Compared with the traditional natural lipoprotein, synthetic lipoprotein not only retains the original biological characteristics and functions, but also exhibits the excellent characteristics in drug delivery. Herein, the advantages, development, applications, and prospect of synthetic lipoproteins as drug carriers were summarized. PMID- 27781948 TI - Plant Anti-cancer Agents and their Biotechnological Production in Plant Cell Biofactories. AB - BACKGROUND: Bioactive plant secondary metabolites have complex chemical structures, which are specific to each plant species/family, and accumulate in tiny amounts. The growing market demand for many phytochemicals can lead to the over-harvesting of medicinal plants in their natural habitat, endangering species in the process. OBJECTIVE: An ongoing challenge for our society is therefore to develop a bio-sustainable production of phytochemicals, among other natural resources. Cancer is currently a major health problem, responsible for approximately 8.2 million deaths per year worldwide. We therefore focused this review on cancer therapeutic agents from plants and their biotechnological production. METHOD AND RESULTS: An extensive review of the literature shows that although a wide range of phytochemicals have demonstrated anti-proliferative activity in vitro, only a few examples of plant-based drugs are included in the Anatomical Therapeutic Chemical (ATC) classification as antineoplastic agents. These include vinca alkaloids and their derivatives (L01CA), podophyllotoxin derivatives (L01CB), and paclitaxel and its derivatives (L01CD), as well as camptothecin derivatives (L01XX). These compounds all have in common a complex chemical structure, a scarce distribution in nature, and a high added value. After describing the chemical structures, natural sources and biological activities of these anticancer compounds, we focus on the state of the art in their biotechnological production in plant cell biofactories. CONCLUSION: More in depth studies are required on the biosynthesis of target plant metabolites and its regulation in order to increase their biotechnological production in plant cell factories and ultimately implement these biosustainable processes at an industrial level. PMID- 27781949 TI - Current and Future Perspectives on the Major Depressive Disorder: Focus on the New Multimodal Antidepressant Vortioxetine. AB - BACKGROUND: Vortioxetine (VRX) is a multimodal antidepressant that acts as serotonin (5HT) transporter inhibitor as well as 5HT3A and 5HT7 receptors antagonist, 5HT1A and 5HT1B receptors partial agonist. It was recently approved in the US and the EU for the treatment of adult patients with Major Depressive Disorder (MDD). OBJECTIVE: The present article aims at systematically reviewing findings of the published and unpublished research on the pharmacological properties, efficacy, safety and tolerability of oral VRX in the treatment of MDD. METHOD: A systematic review, in accordance with the Cochrane Collaboration and the PRISMA guidelines, was conducted searching the electronic databases MEDLINE, by combining the following keyterms: ((vortioxetine OR LU AA21004 OR brintellix) AND (antidepressant OR depression OR major depressive disorder), without language/time restrictions. Further studies were retrieved from reference listing of relevant articles or manual search. Preclinical and clinical studies (RCT and open label trials) were here retrieved. RESULTS: Several placebo controlled and active-treatment studies demonstrated the antidepressant efficacy and tolerability of VRX in adult patients affected with MDD. In addition, VRX seems to own procognitive activity. VRX seems generally well tolerated, without significant cardiovascular or weight gain effects. The most common adverse events reported included nausea, vomiting, hyperhidrosis, headache, dizziness, somnolence, diarrhoea and dry mouth. CONCLUSION: Overall, placebo controlled and active treatment trials support that VRX is effective and well tolerated in MDD. Its combined serotonin reuptake inhibition with agonism, partial agonism and antagonism of a number of receptors might provide a broader spectrum of antidepressant activity than currently available agents. PMID- 27781950 TI - The Differential Diagnosis of Multiple Sclerosis Using Convex Combination of Infinite Kernels. AB - Our purpose is to develop a clinical decision support system to classify the patients' diagnostics based on features gathered from Magnetic Resonance Imaging (MRI) and Expanded Disability Status Scale (EDSS). We studied 120 patients and 19 healthy individuals (not afflicted with MS) have been studied for this study. Healthy individuals in the control group do not have any complaint or drug use history. For the kernel trick, efficient performance in non-linear classification, the Convex Combination of Infinite Kernels model was developed to measure the health status of patients based on features gathered from MRI and EDSS. Our calculations show that our proposed model classifies the multiple sclerosis (MS) diagnosis level with better accuracy than single kernel, artificial neural network and other machine learning methods, and it can also be used as a decision support system for identifying MS health status of patients. PMID- 27781951 TI - Stationary Wavelet Transform and AdaBoost with SVM Based Pathological Brain Detection in MRI Scanning. AB - This paper presents an automatic classification system for segregating pathological brain from normal brains in magnetic resonance imaging scanning. The proposed system employs contrast limited adaptive histogram equalization scheme to enhance the diseased region in brain MR images. Two-dimensional stationary wavelet transform is harnessed to extract features from the preprocessed images. The feature vector is constructed using the energy and entropy values, computed from the level- 2 SWT coefficients. Then, the relevant and uncorrelated features are selected using symmetric uncertainty ranking filter. Subsequently, the selected features are given input to the proposed AdaBoost with support vector machine classifier, where SVM is used as the base classifier of AdaBoost algorithm. To validate the proposed system, three standard MR image datasets, Dataset-66, Dataset-160, and Dataset- 255 have been utilized. The 5 runs of k fold stratified cross validation results indicate the suggested scheme offers better performance than other existing schemes in terms of accuracy and number of features. The proposed system earns ideal classification over Dataset-66 and Dataset-160; whereas, for Dataset- 255, an accuracy of 99.45% is achieved. PMID- 27781952 TI - Novel Mutation of the NOTCH3 Gene in a Chinese Pedigree with CADASIL. AB - BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) results from NOTCH3 gene mutations, which lead to the degeneration of vascular smooth muscle cells (VSMCs). The clinical presentation of CADASIL patients is dependent on the impact of other vascular risk factors and the type of NOTCH3 mutation present. METHODS: Here, we report a rare pathogenic mutation on exon 14 of the NOTCH3 gene in a Chinese family affected by CADASIL with phenotypic peculiarities. We performed genetic testing, clinical and neuropsychological examination, brain magnetic resonance images (MRI), and electron microscopy (EM) in skin biopsies. RESULTS: NOTCH3 gene analysis revealed a c.2182CT substitution on exon 14, which is the first example of this mutation in a Chinese individual from the Han ancestry. Granular osmiophilic material (GOM) was found in the proband, and all patients had migraine, subcortical ischemic events, and mood disturbances, without progressive cognitive impairment. Cranial MRI further showed white matter hyperintensity, involving bilateral basal ganglia and multiple microbleeds (MBs), in the thalamus and brain stem. CONCLUSIONS: This study suggests that different missense mutations in NOTCH3 might contribute to atypical clinical features of CADASIL. This report also indicates that for individuals with a positive family history having clinical and neuroradiological findings suggestive of CADASIL, genetic testing and GOM detection should be performed. PMID- 27781953 TI - Identification of Egg White Proteins and Divergence in the Regulatory Region of the Ovalbumin Gene in Avians. AB - Egg white proteins play an important role in avian reproductive systems and are an ideal resource for bioreactor construction. In this study, 1D electrophoresis and MALDI-TOF-MS were performed to analyze egg white proteins in four species. In total, 18, 11, 28, and 13 proteins were identified in the egg whites of the chicken, duck, goose, and pigeon, respectively. Egg white proteins in chickens have been studied previously; therefore, we focused on the proteins in goose and duck egg whites. Based on the amino acid sequence analysis and a comparison of the unique peptides, high similarity was observed between the goose and duck egg whites. Diversity in the regulatory region of the ovalbumin gene explained the higher ovalbumin expression in the duck and goose than in the chicken. These data clarify the evolutionary processes underlying to the unique peptides contributing to the differential expression of ovalbumin in avians. PMID- 27781954 TI - Biophysical Characterization of Alanine Aminotransferase from Trypanosoma cruzi. AB - Aminotransferases are an important group of enzymes that catalyze the transfer of an amino group of an amino acid into a keto acid. Alanine aminotransferase from Trypanosoma cruzi (TcALAT) was cloned, overexpressed and purified. Far-UV Circular Dichroism (CD), Dynamic Light Scattering (DLS), Analytical Size Exclusion Chromatography (aSEC) and Small Angle X-ray Scattering (SAXS) provide data concerning TcALAT biophysical behavior. CD analysis displayed a typical spectrum of alpha-beta proteins analogously as observed for other alanine aminotransferases. The protein is stable until 40oC and above that temperature starts to denatured. Its temperature of melting is equal to 50oC. DLS, aSEC and SAXS data show that protein is monomeric in solution. All these gather initial information on secondary and quaternary structures of TcALAT. PMID- 27781955 TI - MMP14 Regulates VEGFR3 Expression on Corneal Epithelial Cells. AB - Vascular endothelial growth factor receptor 3 (VEGFR3) regulates the growth and differentiation of blood and lymphatic vessels. To determine whether matrix metalloproteinase 14 (MMP14) modulates VEGFR3 expression in the corneal epithelium to influence the avascularity of the cornea, VEGFR3 expression was compared between wild-type and MMP14-deficient (MMP14 Deltaexon4) corneal epithelial cells. Western blot analysis showed that VEGFR3 protein expression was higher on MMP14 Deltaexon4 corneal epithelial cells than on wild-type cells, and quantitative RT-PCR analysis showed that VEGFR3 gene expression was highly induced in MMP14 Deltaexon4 corneal epithelial cells but not in wild-type corneal epithelial cells or wild-type and MMP14 Deltaexon4 corneal keratocytes. Unlike in epithelial cells, MMP14 Deltaexon4 keratocytes did not express relatively higher levels of VEGFR3 than wild-type keratocytes. Interestingly, in vitro proteolysis experiments showed that MMP14 does not cleave VEGFR3 in vitro as it does VEGFR1, indicating that other genes may be involved in the modulation of VEGFR3 expression by MMP14. Using proteomic analysis to identify candidate factors, we found that 39 nuclear proteins were differentially expressed between wildtype and MMP14 Deltaexon4 corneal epithelial cells. These findings suggest that MMP14 may regulate VEGFR3 expression at the transcriptional level on corneal epithelial cells but not on corneal keratocytes. PMID- 27781956 TI - Influence of a High-Fat Diet on Cardiac iNOS in Female Rats. AB - BACKGROUND: Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular disease. Oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. METHODS: In the present study, female Wistar rats were fed a standard diet or a HF diet (42% fat) for 10 weeks. iNOS gene and protein expressions were measured in heart tissue. HF-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF-fed rats. Expression of the p50 subunit of nuclear factor-kB (NFkB-p50) in heart was increased by 77% (p<0.01) in HF-fed rats. Expression of protein kinase B (Akt) and extracellular signalregulated kinases 1/2 (ERK1/2) were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho ERK1/2/total ERK1/2 in HF-fed rats. Estrogen receptor-alpha levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were shown to be significantly reduced in HF-fed rats. RESULTS AND CONCLUSION: Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFkappaB-p50 proteins. Decreased levels of oestradiol and ERalpha protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression. PMID- 27781957 TI - Valsartan Protects Against Contrast-Induced Acute Kidney Injury in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Apoptosis. AB - BACKGROUND AND OBJECTIVE: Contrast-induced acute kidney injury (CI-AKI) is a serious complication of the administration of iodinated contrast media (CM) for diagnostic and interventional cardiovascular procedures and is associated with substantial morbidity and mortality. While the preventative measures can mitigate the risk of CI-AKI, there remains a need for novel and effective therapeutic approaches. The pathogenesis of CI-AKI is complex and not completely understood. CM-induced renal tubular cell apoptosis caused by the activation of endoplasmic reticulum (ER) stress is involved in CIAKI. We previously demonstrated that valsartan alleviated CM-induced human renal tubular cell apoptosis by inhibiting ER stress in vitro. However, the nephroprotective effect of valsartan on CI-AKI in vivo has not been investigated. Therefore, the aim of this study was to explore the protective effect of valsartan in a rat model of CI-AKI by measuring the amelioration of renal damage and the changes in ER stressrelated biomarkers. METHOD AND RESULTS: Our results showed that the radiocontrast agent meglumine diatrizoate caused significant renal insufficiency, renin-angiotensin system (RAS) activation, and renal tubular apoptosis by triggering ER stress through activation of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), caspase 12, CCAAT/enhancer-binding protein-homologous protein (CHOP) and c-Jun N-terminal protein kinase (JNK) (P<0.05; n=6 in each group). Pre treatment with valsartan significantly alleviated renal dysfunction, pathological injury, and apoptosis along with the inhibition of ER stressrelated biomarkers (P<0.05; n=8 in each group). CONCLUSION: Valsartan could protect against meglumine diatrizoate-induced kidney injury in rats by inhibiting the ER stress induced apoptosis, making it a promising strategy for preventing CI-AKI. PMID- 27781958 TI - Metalloproteinase 2 and 9 Activity Increase in Epicardial Adipose Tissue of Patients with Coronary Artery Disease. AB - BACKGROUND: Epicardial adipose tissue (EAT) is a visceral adipose tissue (AT) surrounding and infiltrating myocardium and coronary arteries. Increased EAT may represent a chronic inflammatory injury and a link with coronary artery disease (CAD). Metalloproteinases (MMPs) are involved in expansion of AT. OBJECTIVE: To evaluate MMP-2 and -9 behaviour in EAT from CAD patients. METHODS: In EAT and subcutaneous AT (SAT) from patients undergoing coronary artery bypass graft (CABG, n=26) or valve replacement (No CABG, n=18), MMP-2 and -9 activity and localization, inflammatory cells and vascular endothelial growth factor (VEGF) levels were determined. RESULTS: In EAT from CABG, MMP-2 and -9 activity was increased compared with No CABG (p=0.041 and p=0.027, respectively) and compared with SAT (p=0.005 and p=0.048, respectively). In CABG patients EAT showed higher infiltration of macrophages and T lymphocytes than SAT (p=0.01 and p=0.002, respectively). In No CABG patients no sign of cellular retention was observed in EAT or SAT. Vascular density was higher in EAT from CABG than No CABG (p=0.015) and it was directly correlated with MMP-2 (p=0.006) and MMP-9 (p=0.02). VEGF levels in EAT were directly associated with MMP-2 (p=0.016). CONCLUSION: In EAT from CABG patients the increase of MMP-2 and -9 activity and the presence of inflammatory cells would be partially responsible for extracellular matrix (ECM) remodeling and major vascular density necessary for EAT expansion. Improved knowledge of EAT behaviour may allow to identify new therapeutic targets for the treatment of CAD. PMID- 27781959 TI - Relationships Between Alcohol Consumption, Smoking Status and Food Habits in Greek Adolescents. Vascular Implications for the Future. AB - BACKGROUND: Addictive behaviours in adolescents such as alcohol consumption and smoking are rapidly increasing worldwide. OBJECTIVE: No previous study has examined smoking status and alcohol consumption in adolescents of Northern Greece in relation to their food habits. Therefore, we assessed the smoking status and alcohol consumption, as well the food habits, of this population. METHOD: Adolescents (495 boys and 508 girls) aged 15+/-1 years old and 15+/-2 years old respectively, completed questionnaires regarding smoking, alcohol and food habits. RESULTS: Tobacco use and alcohol consumption were reported by 9.2% and 48.1% of them, respectively. Of those that drank alcohol, 13.9% were also smokers. Older adolescents were more likely to consume foods high in fat and sugar, low in vitamins and minerals as well as foods, considered by them to be less healthy and prepared in a less healthy way. Moreover, smoker adolescents were less likely to choose foods considered to be healthy and prepared in a healthy way, whereas they were more likely to choose foods high in fat content. CONCLUSIONS: Both smoking and alcohol consumption may affect cardiovascular risk and the vasculature. Poor lifestyle (and risk of vascular events) can start at an early age. PMID- 27781960 TI - Angiotensin Mediated Oxidative Stress and Neuroprotective Potential of Antioxidants and AT1 Receptor Blockers. AB - Oxidative stress in brain underlies the major neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). Peripherally, Angiotensin II is a major effector of inflammation. Identification of its capacity to access brain during hypertension, as well as location of central renin angiotensin system have led to its recognition as the major effector of oxidative stress in brain. Clinical uses of antioxidants to antagonize this oxidative stress have mostly failed. In this scenario, AT1 blockers have been investigated to prevent neurodegeneration. Although it has shown promise, clinical efficacy is limited to few drugs including telmisartan mainly due to the poor brain availability of others. In this review we aim to analyze the potential of antioxidants to reduce oxidative stress in brain. We have given critical analysis of the approaches for re-purposing of AT1 blockers against oxidative stress induced neurodegeneration. PMID- 27781961 TI - Microbe-bio-Chemical Insight: Reviewing Interactions between Dietary Polyphenols and Gut Microbiota. AB - OBJECTIVE: Polyphenols are widespread constituents of different food commodities. These are regarded as essential micronutrients because of their well-documented health benefits. These health benefits depend on the amount of polyphenols consumed and their bioavailability in the gut. The microbial transformation of polyphenols in gut is poorly characterized, where, these polyphenols may act as promoting factors for proliferation of beneficial gut inhabitants and inhibiting the pathogenic species. CONCLUSION: The aim of this review is to present a holistic view on occurrence of polyphenols, their health benefits and influence of dietary polyphenols on gut microbiota. PMID- 27781963 TI - Bioactive Natural Products from Animal Associated-Microbes. AB - OBJECTIVE: Animal associated-microbes are miroorganisms living inside animal hosts during some parts of their life. In view of the special environment, it is considered that the unique microbes might be the producer of new compounds with diversity biological activities. CONCLUSION: This review summarizes new findings (mainly described since 2011) concerning the characteristics of various natural products that can be extracted from animal associated-microbes, highlighting that animal related microorganisms represent an underexplored reservoir for the discovery of molecules with unique scaffolds and promising biological activities. PMID- 27781964 TI - [Tinnitus in patients with hemifacial spasm: a treatable combination?] AB - BACKGROUND: About 5-15% of people in the Western world will suffer from an extended period of tinnitus during their lifetime. This is often a non-treatable, disabling disorder. Tinnitus can be classified as pulsatile or non-pulsatile. Pulsatile tinnitus can be caused by a treatable neurovascular compression. CASE DESCRIPTION: Here we describe two patients, a 68-year old woman and 40-year old man suffering from pulsatile tinnitus and hemifacial spams due to neurovascular compression of the facial and acoustic nerve in the anterior cranial fossa. After microvascular decompression using the Jannetta procedure, in which a sponge was placed between the blood vessel and the nerve, the tinnitus and hemifacial spasm disappeared. CONCLUSION: Recognition of hemifacial spasm in patients with tinnitus is important because the symptoms are treatable when it is due to neurovascular compression. Because hemifacial spasm can manifest in subtle forms for instance unilateral blinking - this important symptom can easily be overlooked. PMID- 27781965 TI - [A patient with Melkersson-Rosenthal syndrome]. AB - BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a relatively rare syndrome characterised by the clinical triad of persisting or recurrent facial oedema, recurrent peripheral facial palsy, and a fissured tongue. CASE DESCRIPTION: A 30 year-old male patient presented with a left peripheral facial palsy spreading to the right side of the face. The left-sided facial paralysis recurred twice after initial recovery. The patient had also suffered from oedema of the lip and face, which sometimes occurred simultaneously with the paralysis, and he had always had a fissured tongue. Extensive biochemical tests, tests for infection and imaging tests revealed no abnormalities, and MRS was diagnosed. No treatment was required as the symptoms always disappeared spontaneously. CONCLUSION: Patients with MRS can present to the general practitioner, dermatologist, or ENT-specialist as well as to the neurologist. As this is a relatively unknown syndrome, the diagnosis is often made late, and it is often over-diagnosed and over-treated. There is no proven effective treatment, but systemic corticosteroids can be considered. PMID- 27781966 TI - [Financial compensation for asbestosis patients]. AB - Asbestosis in the Netherlands is a rare work-related form of pulmonary fibrosis caused by long-term, intensive exposure to asbestos. It can have a great impact on patients' quality of life and life expectancy even 20-30 years after initial exposure. The Dutch Institute of Asbestos Victims (IAS) mediates between the victims and their employers or former employers about payment of compensation. Liability procedures against a previous employer are long and stressful. Since 1 April 2014 it has, therefore, been possible to receive financial aid from the state. The IAS and the Netherlands Asbestosis Panel determine who is eligible for this. In this article we look in detail at the conditions for, and the process of, application for this financial aid. Since the introduction of this arrangement, more than 250 asbestosis victims have applied for aid; so far, 65 applicants have met the required conditions. PMID- 27781967 TI - [Renal denervation as treatment option for hypertension]. AB - The rationale behind catheter-based renal denervation is that afferent and efferent renal nerves play a role in the pathogenesis and maintenance of high blood pressure, and that this can be prevented by blocking the function of the renal nerves. Since the introduction of catheter-based renal denervation, several observational and a small number of randomised controlled trials have been conducted. The available evidence does not allow for a definitive conclusion regarding its efficacy. There have been no serious side-effects reported. The development of this treatment concept has not been finalised; new trials have just commenced or will start in the near future. PMID- 27781968 TI - [Complex interventions in elderly - how do we determine the effect?] AB - The care for frail elderly is challenging and requires an individualised approach. To meet the complex care needs of these patients, interventions aimed at improving care often consist of multiple interacting components. Several recent RCTs investigating such complex interventions in a primary care setting were unable to show an effect. In this paper the challenges that arise when examining complex interventions in experimental trials are discussed. Standardisation of the content of the intervention is often not desirable. The context in which the intervention takes place cannot be controlled and is in itself complex. A thorough process evaluation is essential in order to interpret the findings correctly. The relevant outcomes in such trials are often multidimensional and difficult to capture with a quantitative instrument. Such complex interventions, therefore, require a combination of quantitative and qualitative research methods. PMID- 27781969 TI - [A blood culture containing coagulase-negative staphylococci: not always due to contamination]. AB - Staphylococcus lugdunensis (SL) is a species belonging to the group of coagulase negative staphylococci (CNS). It can cause severe infections such as endocarditis. Three cases of endocarditis caused by SL are presented. The first case describes a 71-year-old man with a fever and endogenous endophthalmitis. The second case describes delirium in an 87-year-old woman, thought to be due to pneumonia. The third case describes a 76-year-old man with an infection of unknown origin. In all cases, the first blood cultures drawn were positive for CNS and considered to be contaminated. However, all three patients were finally diagnosed as having severe endocarditis caused by SL. Two patients underwent valve replacement, one patient died due to ongoing sepsis. The first CNS-positive blood cultures drawn were wrongly denoted as being contaminated. Physicians should be aware of the pathogenic potential of SL and rule out contamination. PMID- 27781970 TI - SGEM Hot Off the Press: ultrasound during critical care simulation: a randomized crossover study. AB - As part of the Canadian Journal of Emergency Medicine's (CJEM) developing social media strategy, 1 we are collaborating with the Skeptics' Guide to Emergency Medicine (SGEM) to summarize and critically appraise the current emergency medicine (EM) literature using evidence-based medicine principles. In the "Hot Off the Press" series, we select original research manuscripts published in CJEM to be featured on the SGEM website/podcast 2 and discussed by the study authors and the online EM community. A similar collaboration is underway between the SGEM and Academic Emergency Medicine. What follows is a summary of the selected article the immediate post-publication synthesis from the SGEM podcast, commentary by the first author, and the subsequent discussion from the SGEM blog and other social media. Through this series, we hope to enhance the value, accessibility, and application of important, clinically relevant EM research. In this, the third SGEM HOP hosted collaboratively with CJEM, we discuss Olszynski et al.'s randomized crossover study evaluating the use of ultrasound simulator devices during critical care simulation. 3. PMID- 27781974 TI - A new heading in our journal. PMID- 27781975 TI - IFSSH scientific committee on skin coverage: 2015 report. AB - Skin coverage in hand reconstruction is a challenging and vast chapter in hand surgery; covering every aspect of it in a report is simply not feasible. Therefore, this report focuses on a few specific topics. The coverage of anatomical regions like the fingertips is common ground for hand surgeons worldwide, but in the last 10 years, various refinements have been published in order to optimize the reconstruction of this organ. Nevertheless, in many emergency departments, the amputation of badly injured fingertips, including the thumb, remains the preferred treatment. The main focus of this report is to counter this tendency by providing alternatives to surgeons. Large defects in the fingers involving more than one segment, defects in the palm and in the dorsum of the hand are currently debated in international meetings. The use of skin substitutes vs. the use of extremely refined microsurgical procedures vs. classic island flaps has generated animated discussions, which are also influenced by cultural and socioeconomic factors around the world. This report offers the views of six surgeons from four different countries, in the hope of animating discussions and suggesting new approaches. PMID- 27781976 TI - The role of imaging in isolated benign peripheral nerve tumors: A practical review for surgeons. AB - The diagnosis of nerve tumor(s) must be suspected in all cases of tumefaction or pain on the path of a nerve exacerbated by percussion. Solitary nerve tumors are primarily schwannomas, but other rare tumors may be present such as intraneural ganglion cysts of controversial origin. Preservation of nerve continuity is the underlying goal for any surgical procedure, irrespective of the type of tumor. Therapeutic outcomes are closely linked to tumor resectability; in most patients, the resectability of the tumor, its type and benignity can be predicted based on medical imaging. Comparison with the clinical examination and case-based reasoning is crucial. Consequently, the aim of this review was to examine the role of imaging in isolated benign peripheral nerve tumors, and provide the surgeon with a practical guide for its application in predicting the nature and resectability of nerve tumors. PMID- 27781977 TI - Treatment of unstable distal phalanx fractures by extra-articular DIP pinning: A series of 12 cases. AB - : Unstable distal phalanx fractures are typically treated by pinning of the distal phalanx or the distal interphalangeal joint (DIP). Complications include unstable fixation, K-wire migration, septic arthritis and osteoarthritis. To limit these complications, we wanted to explore the benefits of using locked extra-articular DIP pinning. The cohort consisted of 12 patients (mean age 36.3 years) who had an extra-articular (6 cases) or intra-articular distal phalanx fracture (6 cases). All patients were treated surgically with a construct consisting of two connected K-wires: one was placed inside the shaft of the distal phalanx and the other was placed perpendicular to the middle phalanx. The K-wires were removed after 1 month. After an average follow-up of 19.9 weeks, pain was 0.4/10 and the QuickDASH score was 7.41/100 on average. The range of motion was, on average, 30.0 degrees less than the contralateral uninjured side for active flexion, 8.8 degrees less for active extension, 32.0 degrees less for passive flexion and 4.1 degrees less for passive extension. The overall hand strength averaged 85.2% of the contralateral one. One secondary displacement occurred but there were no infections. In all, these findings suggest that locked extra-articular DIP pinning is a simple and reproducible surgical treatment for distal phalanx fractures. LEVEL OF EVIDENCE: IV. PMID- 27781978 TI - Modified Suzuki frame for the treatment of difficult Rolando fractures. AB - Fifteen consecutive patients with severely comminuted Rolando fractures were treated by closed reduction and fixation with a modified Suzuki frame without rubber bands, followed by immediate mobilization. All the fractures healed within 5 weeks. At 3 months, no rotational deformity was observed. The Kapandji score was equal that of the contralateral thumb in eight cases. No residual pain was recorded. Grip strength was 78% and pinch strength was 78% of the contralateral hand. One patient needed the frame tension modified. One patient developed a sensory deficit in the area of the superficial branch of the radial nerve that resolved spontaneously in 3 months. One patient healed with a 2-mm articular step off, but the clinical outcome was good. Our retrospective study suggests that the small modification we made to the Suzuki frame provides a relatively simple and minimally invasive technique for the treatment of comminuted Rolando fractures. PMID- 27781979 TI - Scapholunate interosseous ligament injury in professional volleyball players. AB - Injuries to the scapholunate interosseous ligament (SLIL) are the most common cause of carpal instability. A SLIL injury typically follows a fall on an outstretched hand, with the wrist in hyperextension, ulnar deviation and intercarpal supination. We hypothesize that repetitive axial loading on the wrist in hyperextension, during the reception and digging motions of volleyball, can lead to functional overloading of the SLIL. To identify patients and to determine the clinical history and surgical treatment performed, we analyzed hospital records, X-rays, electronic databases containing all the operations performed, and image files (including before and after surgery and follow-up). We identified three SLIL injury cases in national volleyball team players, also at the libero position, who were treated at our clinic between 2007 and 2013 for scapholunate instability. Open reduction and Berger capsulodesis was performed in all cases. At a mean follow-up of 3 years (range, 22-50 months), the mean pain level on VAS was 0.3 (range, 0-1) at rest and 1.7 (range 1-2) during sport activities. The mean DASH score was 4 (range 2-5). The mean wrist flexion was 60 degrees (range 55-70 degrees ) and extension was 80 degrees (range 75-85 degrees ). Given the greater susceptibility of these players for developing a SLIL injury, a high index of suspicion is needed when managing athletes presenting with wrist pain or instability. PMID- 27781980 TI - Hypothenar fat pad flap surgery for end stage and recurrent carpal tunnel syndrome. AB - One year follow-up results after hypothenar fat pad flap surgery for recurrent and end stage carpal tunnel syndrome (CTS) are reported. Before surgery, the patients' complaints with a recurrent CTS were mainly pain and return of pathological symptoms (tingling, nocturnal pain, etc.) whereas the patients with end stage CTS reported problems of loss of sensation. Both groups (8 patients in each group) reported a limited functional status for activity of daily living (ADL) prior to surgery. Evaluations of sensibility, strength, pain and Boston Carpal Tunnel Questionnaire were made preoperatively and postoperatively at 3, 6 and 12 months. The major clinical issues for both groups were statistically significantly improved after one year, but already significant results were noted after 3 months. We confirm that the hypothenar fat pad flap is a good solution for recurrent CTS. Moreover, end stage CTS could be a new and promising indication for the use of this vascularized flap. PMID- 27781981 TI - The place of occupational therapy in rehabilitation strategies of complex regional pain syndrome: Comparative study of 60 cases. AB - The purpose of the study was to assess the value of combining occupational therapy (OT) with physical therapy (PT) for the rehabilitation of complex regional pain syndrome (CRPS) and to measure its effectiveness on activities of daily life. Sixty patients with CRPS type 1 were recruited and interviewed between September 1, 2014 and February 1, 2015. Thirty patients had undergone PT and thirty had undergone PT+OT. They were administered the short-form of the "Assessment of Life Habits" questionnaire (v.3.0 LIFE-H) created in Canada. This questionnaire consists of 16 items exploring activities of daily living, which were used to compare the effectiveness of the two rehabilitation protocols. The results of each test were submitted to the Wilcoxon test. After confirming the complexity of CRPS in terms of its etiology, clinical signs and progression, rehabilitation was effective, especially for pain. The patients who received PT+OT had on average 10% better dressing and undressing function, 25% better for meal preparation, and 20% better on personal care than those who underwent PT only. In CRPS, OT combined with PT brings a real benefit in restoring the essential activities of daily life. This strategy could be implemented as soon the diagnosis confirmed and continued for a very long time. It helps to avoid the risk of dependence on third parties. PMID- 27781982 TI - Rhomboid nerve transfer to the suprascapular nerve for shoulder reanimation in brachial plexus palsy: A clinical report. AB - Recovery of shoulder function is a real challenge in cases of partial brachial plexus palsy. Currently, in C5-C6 root injuries, transfer of the long head of the triceps brachii branch is done to revive the deltoid muscle. Spinal accessory nerve transfer is typically used for reanimation of the suprascapular nerve. We propose an alternative technique in which the nerve of the rhomboid muscles is transferred to the suprascapular nerve. A 33-year-old male patient with a C5-C6 brachial plexus injury with shoulder and elbow flexion palsy underwent surgery 7 months after the injury. The rhomboid nerve was transferred to the suprascapular nerve and the long head of the triceps brachii branch to the axillary nerve for shoulder reanimation. A double transfer of fascicles was performed, from the ulnar and median nerves to the biceps brachii branch and brachialis branch, respectively, for elbow flexion. At 14 months' follow-up, elbow flexion was rated M4. Shoulder elevation was 85 degrees and rated M4, and external rotation was 80 degrees and rated M4. After performing a cadaver study showing that transfer of the rhomboid nerve to the suprascapular nerve is technically possible, here we report and discuss the clinical outcomes of this new transfer technique. PMID- 27781983 TI - Idiopathic bilateral lunate and triquetrum avascular necrosis: A case report. AB - We report on the case of bilateral avascular osteonecrosis (AVN) of the lunate and triquetrum in a 45-year-old woman without any relevant medical history for which the cause could not be established. She was treated conservatively with splinting and analgesics. The patient was able to pursue her work and hobbies with subnormal range of motion at 1-year follow-up. AVN of the triquetrum is very rare, as it is a richly vascularized bone. The presence of AVN in multiple carpal bones has only been described in patients receiving high doses of corticosteroids. To our knowledge, there are no other cases of idiopathic AVN of multiple carpal bones in the literature. PMID- 27781984 TI - An articular spacer for metacarpophalangeal fracture: The story of a crocodile bite. AB - Choosing the best option for reconstructing comminuted joint fractures in hand surgery raises technical challenges due to the small size of the anatomical structures and the required early mobilization. Single-stage reconstructions are clearly preferable, but when the infection risk is high, two-stage alternatives are needed. We report a case of fracture of the head of the 2nd metacarpal resulting from a crocodile bite treated by implanting an articular spacer. PMID- 27781985 TI - Our journal will now focus exclusively on surgery and rehabilitation of hand, wrist, forearm and nerves of upper limb. PMID- 27781986 TI - Surgery for trapeziometacarpal osteoarthritis. AB - Trapeziometacarpal (TMC) osteoarthritis is a common, disabling condition that mostly affects women. The demand for surgical treatment is growing and the patients are becoming younger, adding to the challenge. Surgery can only be proposed after failure of well-conducted conservative treatment and requires a complete X-ray assessment. In the early stages, conservative surgery measures can be used to stabilize the joint or realign it in cases of dysplasia, but in most cases, patients are seen with more advanced arthritis and joint replacement must be considered. The ideal arthroplasty technique has yet to be defined but nevertheless, the chosen technique must be well-suited to the patient's condition. Although many studies have been published on this topic, they do not help us define the treatment indications. Prospective studies focusing on the patient rather than evaluating a certain surgical technique are needed. Trapeziectomy with or without ligament reconstruction is still considered the gold standard, but the challenges associated with treating its complications limit its indications. Arthrodesis, interposition or arthroplasty are also viable therapeutic options. The patient must be sufficiently informed to be able to contribute to choosing the indication. PMID- 27781987 TI - Balloon humeroplasty reconstruction for acute Hill-Sachs injury: A technical note. AB - Posterior Hill-Sachs humeral defects are present in 80% to 100% of cases of anterior shoulder dislocation and are a factor in recurrent instability. Several techniques have been described to fill the defect and avoid recurrence. We developed a percutaneous technique to fill the newly created defect in which a percutaneous balloon, analogous to the one used in vertebral kyphoplasty, is used to reduce the defect, which is then filled with calcium phosphate cement. One patient with an acute anterior dislocation of the shoulder with no previous history was treated using this method. Early imaging results showed adequate reduction of the defect and no cement resorption. The patient was followed for 12 months; he had normal function of the shoulder and no recurrent dislocation. Shoulder computed tomography (CT) arthrography with contrast after 3 months showed an intact capsule and no recurrence of the defect. While this technique is certainly in its infancy, we have demonstrated that emergency reduction of the defect in acute first occurrence anterior shoulder dislocation is feasible, helps to restore normal anatomy of the humeral head and leads to good clinical results. Whether it can improve clinical results and prevent recurrent shoulder dislocation remains to be evaluated. PMID- 27781988 TI - A ten-year prospective outcome study of Pi2 pyrocarbon spacer arthroplasty in carpometacarpal joint osteoarthritis. AB - Surgical management of carpometacarpal osteoarthritis may use many techniques. Pi2 (pyrocarbon interposition implant) arthroplasty is one possible solution after total trapeziectomy. The present study assessed clinical and radiological results in Pi2 arthroplasty at a minimum 10years' follow-up. Forty-two consecutive cases underwent surgery between March 2003 and April 2005; 29 were followed up for a mean of 125.49months (10.5years). A total of 96.6% of patients were very satisfied or satisfied. Range of motion improved, especially in opposition (mean Kapandji score, 9.60), with no major aggravation of metacarpophalangeal extension. Postoperative pinch strength was 5.9kg and grip 24.2kg. Mean time to resuming daily activities was 76days (range, 30-240days). At last follow-up, mean QuickDash score was 19.9 and overall PWRE score 16.4 out of 100. Bone remodeling, mainly in the scaphoid, was found in 48.2% of cases, and was stable between 5 and 10years, with no clinical or functional significance. Two implant dislocations (4.6%) occurred, not requiring surgical revision. Implant survival was 100%. The results of free Pi2 arthroplasty at more than 10years confirmed that this is a valid solution for the treatment of advanced carpometacarpal osteoarthritis, on condition that surgical technique is very precise. PMID- 27781989 TI - Proximodistal interphalangeal arthrodesis of the little finger: A series of 7 cases. AB - As an alternative to amputation of the little finger, we report here seven cases of shortening arthrodesis carried out by resecting the middle phalanx and proximodistal interphalangeal (PDIP) arthrodesis. Our cohort consisted of 6 males and 1 female (58years average age), with a stiff little finger secondary to Dupuytren's disease or trauma. All fingers were approached dorsally; after resection of the middle phalanx and decortication of the subchondral bone, fusion of the remaining phalanges was performed using an intramedullary self-breaking screw-pin. At a mean follow-up of 34.9months, pain decreased significantly (1.4/10 versus 5.4/100 preoperatively), the QuickDASH score improved significantly (33/100 versus 51/100 preoperatively) and all the joints had fused. One patient suffered from cold intolerance. PDIP arthrodesis is an alternative salvage procedure to amputation for multioperated stiff little fingers that does not burn any bridges if it fails. PMID- 27781990 TI - Contaminated wounds: Effectiveness of debridement for reducing bacterial load. AB - Surgical management of contaminated hand wounds may seem anecdotal, but such injuries actually account for an appreciable amount of the activity in emergency hand centers, and recommendations put forward by scientific societies differ. Dealing effectively with this public health issue calls for clarifying the usefulness of the various available treatments. Our study's objective was to determine the effectiveness of surgical debridement. In this prospective study, 92 patients with contaminated hand wounds underwent surgical debridement. Selection criteria included the length of time between injury and treatment, and the mechanism of injury. Patients with infected wounds, those treated by antibiotics, who were immunosuppressed or had osteoarthritis were excluded. Skin samples were collected both before and after debridement. In 62% of cases, the wounds were contaminated before debridement. Following the procedure, 87% of the bacterial smears were negative. The comparison between debridement and smear results was statistically significant (Student's t test, P<0.001). Surgical debridement, with appropriate irrigation, can effectively eradicate bacterial flora due to contamination. PMID- 27781991 TI - A prospective study of 100 cases of sterile T-RINGTM digital tourniquet application. AB - The ideal finger tourniquet must be easy to use and provide a completely bloodless field with control of the pressure exerted at the compression site. The primary objective of this study was to evaluate the effectiveness of the T-RINGTM digital tourniquet in emergency hand surgery; the secondary objective was to define the optimal indications and possible contraindications. This prospective study, undertaken between May 4 and July 30, 2015, comprised the application of 100 finger tourniquets in the following indications: all single or multiple digital wounds, distal from the base of the proximal phalanx, irrespective of their nature and the suspected structural damage. Data were collected with a questionnaire at the end of each surgical use of the finger tourniquet. An overall grade out of 30 was obtained by combining these scores. The facility of opening the packing was rated on average at 4/4, the facility of applying the finger tourniquet was rated at 3.8/4, the quality of the exsanguination at the beginning and at the end of the procedure were rated at 3.4/4 and 3.1/4, respectively, the difficulty related to positioning of the finger tourniquet was rated at 2.7/3, the facility of removing the finger tourniquet was rated at 3.6/4, the risk of forgetting the finger tourniquet at the end of the procedure was rated to 2.8/3, the comparison with an arm tourniquet was rated at 1.9/4. The overall grade was 25.1/30 on average. In current practice, use of the T-RingTM tourniquet did not cause any difficulty. The tourniquet was never forgotten and the risk of forgetting it was considered low by the surgeons. The exsanguination appeared satisfactory, with a reduction in its effectiveness over time. We identified specific situations where its use could be indispensable: contraindication to trunk or plexus regional anesthesia, or as a relay to a pneumatic arm tourniquet after more than 2hours. PMID- 27781992 TI - Resistance of primary microsurgical repair of palmar digital nerves to finger mobilization: A cadaver study. AB - The aim of this study was to assess the resistance of microsurgically repaired proper palmar digital nerves (PPDN) to mobilization. Thirty-nine PPDN from fresh forearms cadavers were transected and then sutured using 10/0 nylon. After skin closure, each finger was forcefully flexed and extended 10 times. Out of the 39 repaired nerves, two were elongated and four were ruptured; this amounts to a 15.38% complication rate. We recommend immobilization of nerve repairs, although this contradicts most recent studies. PMID- 27781993 TI - Restoration of elbow and hand function in total brachial plexus palsy with intercostal nerves and C5 root neurotization. Results in 21 patients. AB - Consensus opinion is that active movement of the elbow is a priority in the surgical treatment of total brachial plexus injuries. But the indications and neurotization techniques used to restore motor function of the hand are the subject of discussion. The aim of this retrospective study was to evaluate, in adult patients with complete post-traumatic paralysis of the brachial plexus, the functional results of neurotization of four intercostal nerves on the musculocutaneous nerve and grafting of the C5 root by one strand on the nerve to the long head of triceps and three strands on the medial component of the median nerve. The cohort included 21 patients (mean age 21years). The average time between the trauma and surgical treatment was 4.8months. At a mean follow-up of 22months, 67% of patients achieved>=M3 elbow flexion, and 62% achieved>=M3 active elbow extension. Of the patients who had the required follow-up of 2years to assess motor recovery of the median nerve, 40% achieved function>=M3. Based on our results, use of the C5 root is suitable for surgically restoring elbow extension and finger flexion. PMID- 27781994 TI - Trapeziometacarpal joint dislocation complicated by a trapezium fracture: A case report and literature review. AB - The authors report and discuss the management of a 25-year-old male patient with a trapeziometacarpal joint dislocation complicated by a trapezium fracture. This injury combination is rare with only reported 15 cases. After closed reduction resulted in dorsal instability, anatomical reduction of the trapezium fracture and internal screw fixation were performed using an open approach. This fixation stabilized the joint but was fragile due to the small fragment size. For this reason, ligament reconstruction using half of the flexor carpi radialis tendon was added. At the last follow-up, 16 months later, the trapeziometacarpal joint was stable with a normal range of motion, but the patient had slight pain during physical effort and decreased pinch strength. PMID- 27781995 TI - Spontaneous flexor tendon rupture secondary to capitate non-union. A case report and review of literature. AB - Rupture of the flexor digitorum profundus and superficialis tendons of the index finger secondary to non-union of the capitate has not yet been reported to our knowledge. We describe the case of a 48-year-old man with rupture of both flexor tendons of the index finger that occurred 15 years after a capitate fracture. The patient was completely asymptomatic before the rupture. Tendon reconstruction was performed using the palmaris longus. One year after surgery, the patient had acceptable range of motion and was pain-free. PMID- 27781996 TI - Osteoid osteoma of the pisiform bone: A rare cause of wrist pain. AB - Non-traumatic wrist pain remains a diagnostic challenge. An accurate diagnosis is crucial in order to choose the appropriate treatment. We report the case of a 23 year-old female with a four-month history of mainly nocturnal wrist pain. There was no history of trauma or prior surgery. Radiographs and CT scans showed a lytic lesion with central nidus and sclerotic margins in the pisiform bone. Bone scan showed increased uptake in the pisiform bone. The diagnosis of osteoid osteoma was confirmed by histopathological analysis after complete surgical resection. Osteoid osteoma of the carpal bones is a rare cause of wrist pain and can raise diagnostic issues. Diagnosis is based on both clinical and radiological features; histopathological analysis can confirm the diagnosis. Treatment depends on several criteria and multiple options are possible, but surgical excision is often preferred for the wrist. Osteoid osteoma should always be considered in young patients presenting with chronic unexplained wrist pain. PMID- 27781997 TI - Custom-made silicone hand prosthesis: A case study. AB - Up to now, a cosmetic glove was the most common method for managing transmetacarpal (TMC) and carpometacarpal (CMC) amputations, but it is devoid of markings and body color. At this amputation level, it is very difficult to fit a functional prosthesis because of the short available length, unsightly shape, grafted skin, contracture and lack of functional prosthetic options. A 30-year old male came to our clinic with amputation at the 1st to 4th carpometacarpal level and a 5th metacarpal that was projected laterally and fused with the carpal bone. The stump had grafted skin, redness, and an unhealed suture line. He complained of pain projected over the metacarpal and suture area. The clinical team members decided to fabricate a custom-made silicone hand prosthesis to accommodate the stump, protect the grafted skin, improve the hand's appearance and provide some passive function. The custom silicone hand prosthesis was fabricated with modified flexible wires to provide passive interphalangeal movement. Basic training, care and maintenance instructions for the prosthesis were given to the patient. The silicone hand prosthesis was able to restore the appearance of the lost digits and provide some passive function. His pain (VAS score) was reduced. Improvement in activities of daily living was found in the DASH questionnaire and Jebsen-Taylor Hand Function test. A silicone glove is a good option for more distal amputations, as it can accommodate any deformity, protect the skin, enhance the appearance and provide functional assistance. This case study provides a simple method to get passively movable fingers after proximal hand amputation. PMID- 27781998 TI - Ultra-lightweight pressure sensor based on graphene aerogel decorated with piezoelectric nanocrystalline films. AB - In this paper, we report on a pressure sensor based on graphene aerogel functionalized with SnO2 or GaN thin films deposited by magnetron sputtering. Decoration by nanocrystalline SnO2 or GaN was found to enhance the piezoresistive response of the bare aerogel. The responsivity and pressure sensing range (from 1 5 atm) of the sensor are shown to be higher than those inherent in pressure sensors based on graphene membranes. PMID- 27781999 TI - Inter-comparison of relative stopping power estimation models for proton therapy. AB - Theoretical stopping power values were inter-compared for the Bichsel, Janni, ICRU and Schneider relative stopping power (RSP) estimation models, for a variety of tissues and tissue substitute materials taken from the literature. The RSPs of eleven plastic tissue substitutes were measured using Bragg peak shift measurements in water in order to establish a gold standard of RSP values specific to our centre's proton beam characteristics. The theoretical tissue substitute RSP values were computed based on literature compositions to assess the four different computation approaches. The Bichsel/Janni/ICRU approaches led to mean errors in the RSP of -0.1/+0.7/-0.8%, respectively. Errors when using the Schneider approach, with I-values from the Bichsel, Janni and ICRU sources, followed the same pattern but were generally larger. Following this, the mean elemental ionisation energies were optimized until the differences between theoretical RSP values matched measurements. Failing to use optimized I-values when applying the Schneider technique to 72 human tissues could introduce errors in the RSP of up to -1.7/+1.1/-0.4% when using Bichsel/Janni/ICRU I-values, respectively. As such, it may be necessary to introduce an additional step in the current stoichiometric calibration procedure in which tissue insert RSPs are measured in a proton beam. Elemental I-values can then optimized to match these measurements, reducing the uncertainty when calculating human tissue RSPs. PMID- 27782000 TI - Superconductivity in highly disordered NbN nanowires. AB - The topic of superconductivity in strongly disordered materials has attracted significant attention. These materials appear to be rather promising for fabrication of various nanoscale devices such as bolometers and transition edge sensors of electromagnetic radiation. The vividly debated subject of intrinsic spatial inhomogeneity responsible for the non-Bardeen-Cooper-Schrieffer relation between the superconducting gap and the pairing potential is crucial both for understanding the fundamental issues of superconductivity in highly disordered superconductors, and for the operation of corresponding nanoelectronic devices. Here we report an experimental study of the electron transport properties of narrow NbN nanowires with effective cross sections of the order of the debated inhomogeneity scales. The temperature dependence of the critical current follows the textbook Ginzburg-Landau prediction for the quasi-one-dimensional superconducting channel I c ~ (1-T/T c)3/2. We find that conventional models based on the the phase slip mechanism provide reasonable fits for the shape of R(T) transitions. Better agreement with R(T) data can be achieved assuming the existence of short 'weak links' with slightly reduced local critical temperature T c. Hence, one may conclude that an 'exotic' intrinsic electronic inhomogeneity either does not exist in our structures, or, if it does exist, it does not affect their resistive state properties, or does not provide any specific impact distinguishable from conventional weak links. PMID- 27782001 TI - Anomalous transport properties in boron and phosphorus co-doped armchair graphene nanoribbons. AB - Multi-element doping of graphene could potentially provide functionalities that are not available in the single-element doping approach, but it has not been actively studied so far. Carrying out first-principles calculations, we study the structural, electronic, and transport properties of B-P edge-co-doped armchair graphene nanoribbons (aGNRs). We find that the B, P-complex edge-doped aGNRs exhibit an n-type transport behavior, which is counterintuitive considering the p type and bipolar characters of the corresponding B- and P-doped aGNRs, respectively. Moreover, we show that the n-type property of B, P co-doped aGNRs is superior to that of representative N-doped aGNRs in terms of preserving the valence band edge conductance spectrum. Analyzing the mechanisms, we demonstrate that the structural distortion rather than chemical valence induces the anomalous donor character of B, P co-doped aGNRs. We thus propose a systematic modification of GNR atomic structures via co-doping as a novel approach to control charge transport characteristics of GNRs. PMID- 27782002 TI - Temperature-controlled transparent-film heater based on silver nanowire-PMMA composite film. AB - We fabricated a high-performance film heater based on a silver nanowire and polymethyl methacrylate (Ag NW-PMMA) composite film, which was synthesized with the assistance of mechanical lamination and an in situ transfer method. The films exhibit excellent conductivity, high figure of merit, and strong adhesion of percolation network to substrate. By controlling NW density, we prepared the films with a transmittance of 44.9-85.0% at 550 nm and a sheet resistance of 0.13 1.40 Omega sq-1. A stable temperature ranging from 130 degrees C-40 degrees C was generated at 3.0 V within 10-30 s, indicating that the resulting film heaters show a rapid thermal response, low driving voltage and stable temperature recoverability. Furthermore, we demonstrated the applications of the film heater in defrosting and a physical therapeutic instrument. A fast defrosting on the composite film with a transmittance of 88% was observed by applying a 9 V driving voltage for 20 s. Meanwhile, we developed a physical therapeutic instrument with two modes of thermotherapy and electronic-pulse massage by using the composite films as two electrodes, greatly decreasing the weight and power consumption compared to a traditional instrument. Therefore, Ag NW-PMMA film can be a promising candidate for diversified heating applications. PMID- 27782003 TI - Electromechanical wave imaging (EWI) validation in all four cardiac chambers with 3D electroanatomic mapping in canines in vivo. AB - Characterization and mapping of arrhythmias is currently performed through invasive insertion and manipulation of cardiac catheters. Electromechanical wave imaging (EWI) is a non-invasive ultrasound-based imaging technique, which tracks the electromechanical activation that immediately follows electrical activation. Electrical and electromechanical activations were previously found to be linearly correlated in the left ventricle, but the relationship has not yet been investigated in the three other chambers of the heart. The objective of this study was to investigate the relationship between electrical and electromechanical activations and validate EWI in all four chambers of the heart with conventional 3D electroanatomical mapping. Six (n = 6) normal adult canines were used in this study. The electrical activation sequence was mapped in all four chambers of the heart, both endocardially and epicardially using the St Jude's EnSite 3D mapping system (St. Jude Medical, Secaucus, NJ). EWI acquisitions were performed in all four chambers during normal sinus rhythm, and during pacing in the left ventricle. Isochrones of the electromechanical activation were generated from standard echocardiographic imaging views. Electrical and electromechanical activation maps were co-registered and compared, and electrical and electromechanical activation times were plotted against each other and linear regression was performed for each pair of activation maps. Electromechanical and electrical activations were found to be directly correlated with slopes of the correlation ranging from 0.77 to 1.83, electromechanical delays between 9 and 58 ms and R 2 values from 0.71 to 0.92. The linear correlation between electrical and electromechanical activations and the agreement between the activation maps indicate that the electromechanical activation follows the pattern of propagation of the electrical activation. This suggests that EWI may be used as a novel non-invasive method to accurately characterize and localize sources of arrhythmias. PMID- 27782005 TI - A handheld SPIO-based sentinel lymph node mapping device using differential magnetometry. AB - Sentinel lymph node biopsy has become a staple tool in the diagnosis of breast cancer. By replacing the morbidity-plagued axillary node clearance with removing only those nodes most likely to contain metastases, it has greatly improved the quality of life of many breast cancer patients. However, due to the use of ionizing radiation emitted by the technetium-based tracer material, the current sentinel lymph node biopsy has serious drawbacks. Most urgently, the reliance on radioisotopes limits the application of this procedure to small parts of the developed world, and it imposes restrictions on patient planning and hospital logistics. Magnetic alternatives have been tested in recent years, but all have their own drawbacks, mostly related to interference from metallic instruments and electromagnetic noise coming from the human body. In this paper, we demonstrate an alternative approach that utilizes the unique nonlinear magnetic properties of superparamagnetic iron oxide nanoparticles to eliminate the drawbacks of both the traditional gamma-radiation centered approach and the novel magnetic techniques pioneered by others. Contrary to many other nonlinear magnetic approaches however, field amplitudes are limited to 5 mT, which enables handheld operation without additional cooling. We show that excellent mass sensitivity can be obtained without the need for external re-balancing of the probe to negate any influences from the human body. Additionally, we show how this approach can be used to suppress artefacts resulting from the presence of metallic instruments, which are a significant dealbreaker when using conventional magnetometry-based approaches. PMID- 27782004 TI - Robust dynamic myocardial perfusion CT deconvolution for accurate residue function estimation via adaptive-weighted tensor total variation regularization: a preclinical study. AB - Dynamic myocardial perfusion computed tomography (MPCT) is a promising technique for quick diagnosis and risk stratification of coronary artery disease. However, one major drawback of dynamic MPCT imaging is the heavy radiation dose to patients due to its dynamic image acquisition protocol. In this work, to address this issue, we present a robust dynamic MPCT deconvolution algorithm via adaptive weighted tensor total variation (AwTTV) regularization for accurate residue function estimation with low-mA s data acquisitions. For simplicity, the presented method is termed 'MPD-AwTTV'. More specifically, the gains of the AwTTV regularization over the original tensor total variation regularization are from the anisotropic edge property of the sequential MPCT images. To minimize the associative objective function we propose an efficient iterative optimization strategy with fast convergence rate in the framework of an iterative shrinkage/thresholding algorithm. We validate and evaluate the presented algorithm using both digital XCAT phantom and preclinical porcine data. The preliminary experimental results have demonstrated that the presented MPD-AwTTV deconvolution algorithm can achieve remarkable gains in noise-induced artifact suppression, edge detail preservation, and accurate flow-scaled residue function and MPHM estimation as compared with the other existing deconvolution algorithms in digital phantom studies, and similar gains can be obtained in the porcine data experiment. PMID- 27782006 TI - Wrinkled single-layer graphenes fabricated by silicon nanopillar arrays. AB - The degree of crumpling affects the optoelectronic properties of graphene, which are very important for the performance of graphene-based devices and materials. In this article, we report an approach to tune the formation of wrinkles on single-layer graphene (SLG) by silicon nanopillar (SNP) arrays. By using gold nanoparticles as an etching mask, SNP arrays with different heights could be prepared by tuning the duration of etching. The formation of wrinkles on these SNP arrays was studied systematically. We found that thermal treatment could lead to a wrapping behavior of graphene around SNP arrays, which was accompanied by the emergence of many more wrinkles. Controllable wettability, conductivity and transmittance were demonstrated. This ability to tune wrinkles using SNP arrays can be employed to engineer the fabrication of graphene-related devices and other optoelectronic applications. PMID- 27782007 TI - Methods of Ga droplet consumption for improved GaAs nanowire solar cell efficiency. AB - We describe methods of Ga droplet consumption in Ga-assisted GaAs nanowires, and their impact on the crystal structure at the tip of nanowires. Droplets are consumed under different group V flux conditions and the resulting tip crystal structure is examined by transmission electron microscopy. The use of GaAsP marker layers provides insight into the behavior of the Ga droplet during different droplet consumption conditions. Lower group V droplet supersaturations lead to a pure zincblende stacking-fault-free tip crystal structure, which improved the performance of a nanowire-based photovoltaic device. PMID- 27782008 TI - Carbon nanotube modified probes for stable and high sensitivity conductive atomic force microscopy. AB - Conductive atomic force microscopy (C-AFM) is used to characterise the nanoscale electrical properties of many conducting and semiconducting materials. We investigate the effect of single walled carbon nanotube (SWCNT) modification of commercial Pt/Ir cantilevers on the sensitivity and image stability during C-AFM imaging. Pt/Ir cantilevers were modified with small bundles of SWCNTs via a manual attachment procedure and secured with a conductive platinum pad. AFM images of topography and current were collected from heterogeneous polymer and nanomaterial samples using both standard and SWCNT modified cantilevers. Typically, achieving a good current image comes at the cost of reduced feedback stability. In part, this is due to electrostatic interaction and increased tip wear upon applying a bias between the tip and the sample. The SWCNT modified tips displayed superior current sensitivity and feedback stability which, combined with superior wear resistance of SWCNTs, is a significant advancement for C-AFM. PMID- 27782009 TI - Visualizing the interface state of PTCDA on Au(111) by scanning tunneling microscopy. AB - We have investigated by means of scanning tunneling microscopy (STM) and spectroscopy (STS) the electronic structure of PTCDA (3,4,9,10-perylene tetracarboxylic-dianhydride) molecular monolayers grown on Au(111). Thanks to our STM/STS measurements, performed under ultra-high vacuum conditions and low temperature, an interface state directly derived from the Shockley-type surface state of pristine Au(111) has been detected. Low bias voltage STM images show the formation of standing wave patterns both on Au(111) and on Au(111) covered by a PTCDA monolayer. These patterns result from the scattering of quasi-free 2D electron surface states with surface defects. By Fourier transforming STM images, the corresponding wavevectors have been extracted. In particular, the simultaneous imaging of both pristine and PTCDA covered Au(111) areas has allowed to measure the Fermi contours and the Fermi wavevectors of both systems. These measurements show that one monolayer PTCDA on Au(111) presents an interface state with an isotropic circular Fermi contour and smaller Fermi wavector ([Formula: see text]) than the corresponding Fermi wavector of pristine Au(111) ([Formula: see text]). This picture is consistent with an upward shift of the Shockley-type surface state due to the presence of the molecular monolayer. PMID- 27782010 TI - Passive RFID Localisation Framework in Smart Homes Healthcare Settings. AB - In recent years, Smart Homes have become a solution to benefit impaired individuals and elderly in their daily life settings. In healthcare applications, pervasive technologies have enabled the practicality of personal monitoring using Indoor positioning technologies. Radio-Frequency Identification (RFID) is a promising technology, which is useful for non-invasive tracking of activities of daily living. Many implementations have focused on using battery-enabled tags like in RFID active tags, which require frequent maintenance and they are costly. Other systems can use wearable sensors requiring individuals to wear tags which may be inappropriate for elders. Successful implementations of a tracking system are dependent on multiple considerations beyond the physical performance of the solution, such as affordability and human acceptance. This paper presents a localisation framework using passive RFID sensors. It aims to provide a low cost solution for subject location in Smart Homes healthcare. PMID- 27782011 TI - Reviewing the Evidence: In Pursuit of a Framework for Parkinson Disease Rehabilitation with Games. AB - Exercise gaming has been receiving a significant interest from both consumers and researchers. Be it for the purposes of weight loss, physical fitness or even just enjoyment, the potential of games to support rehabilitation has also been under investigation for a while. Due to our aging society, game based therapies could be a solution for optimizing resources and reducing rehabilitation costs. This paper aims to discuss the potential capacity of games as systems to enhance the relation of physical exercise and cognition for the rehabilitation of Parkinson Disease. Our investigation demonstrates that there is no established methodology for games in rehabilitation of Parkinson's addressing how games can encapsulate physical exercise strategies while providing safety, continuous monitoring and cognitive development exercises in facilitation of rehabilitation. Since rehabilitation with games is trending, yet to be developed rehabilitation strategies would benefit from new insights into the relationship between game worlds, physical exercise and motor-cognitive training. Therefore, it is useful to do further research into realizing (1) a relational model that demonstrates the relation between game world (composed of game features including formal game elements, audio-visual features, mechanics and dynamics), motor skills, cognition and physical exercise for both generic and specific rehabilitation purposes, (2) a structured task creation approach for game features that reconciles specific rehabilitation outcomes, correct level of engagement, task difficulty and safety requirements for target demographic. PMID- 27782012 TI - Emergency Data Management - Overcoming (Information) Borders. AB - BACKGROUND: In order to improve access to critical patient data in case of emergency, many countries have begun or intend to implement emergency datasets. In Germany, the German Medical Association developed a medical emergency dataset (MED), which provides the possibility to store information on prior diagnoses, medications, allergies and other emergency-relevant information on the German Electronic Health Card. OBJECTIVES: The aim of the study is to evaluate how the MED can be used internationally. METHODS: A total of 64 paper-based emergency data sets were completed by primary care physicians in Germany, and were then evaluated by German clinicians, emergency physicians, and paramedics on the basis of fictitious emergency scenarios. Thirty randomly selected MEDs were then translated into English and will be evaluated by international emergency physicians and paramedics. RESULTS: In Germany, clinicians, emergency physicians and paramedics rated the emergency data set as very useful or useful in more than 70% of the reviewed cases. The international evaluation will start in September 2016, so these results are pending at this time. CONCLUSION: The first study results from Germany indicate high potential benefits of the emergency data set in real patient care situations. The subsequent tests will show whether the MED is also suitable for international use. PMID- 27782013 TI - How Nurses Use Telehealth to Support Health Transitions of Older Adults. AB - : When people with long term health issues transition from illness to health, or move from hospital to home after an exacerbation they feel vulnerable, unsafe, uncertain, lost, and unsupported. Transitions are life experiences that result in change. Telehealth gives easier access to care and increases patient involvement and self-awareness for self-care and improved outcomes. The purpose of our research was to explore how telehealth tools and processes lend themselves to nursing of patients through transitions. METHODS: A multimethod study with before and after questionnaires consisting of validated questionnaires. These were triangulated with nurse field notes, nurse assessment of each participant, exit interviews with participants, and questionnaire for referring clinicians about their experience of the service. Twenty patients, their five doctors, and two telehealth nurses, participated. RESULTS: PACIC questions revealed that participants felt more involved in decision making, self-care planning, referrals to other services, and understood more clearly their health issues. The Quality of Life questions showed improvement, and their health issues bothered them less after telehealth. The Perceived Health Competence questions showed an improvement in how they rated their health, and their ability to influence their health. Clinicians indicated that the service worked well, was appropriate and useful, and should continue. The interviews revealed that participants learned how to do self-care with insight, made the transition from hospital to home and from illness to a new way of being well, and referred the service to others like them. DISCUSSION AND CONCLUSION: We conclude that our experienced nurses used the tools of telehealth (monitoring of self-care and videoconferencing) to coach, supervise, guide, and accompany patients through an organizational transition for half our participants (from hospital to home) and all the participants through an illness to a new way of being well. PMID- 27782014 TI - Current Trends in Electronic Medication Reminders for Self Care. AB - Poor adherence to medication can lead to negative health outcomes and increased financial burdens. We present a literature review on electronic medication reminders used for medication adherence in self care settings, to identify current and possible future trends. A structured PubMed search based on extracted MeSH terms provided a total of 45 publications which were identified as most relevant. Three main categories of electronic solutions were identified: mobile phone reminders, in-home electronic reminder devices, and portable reminder devices. PMID- 27782015 TI - Improving Patient Safety, Health Data Accuracy, and Remote Self-Management of Health Through the Establishment of a Biometric-Based Global UHID. AB - Healthcare systems globally continue to face challenges surrounding patient identification. Consequences of misidentification include incomplete and inaccurate electronic patient health records potentially jeopardizing patients' safety, a significant amount of cases of medical fraud because of inadequate identification mechanisms, and difficulties affiliated with the value of remote health self-management application data being aggregated accurately into the user's Electronic Health Record (EHR). We introduce a new technique of user identification in healthcare capable of establishing a global identifier. Our research has developed algorithms capable of establishing a Unique Health Identifier (UHID) based on the user's fingerprint biometric, with the utilization of facial-recognition as a secondary validation step before health records can be accessed. Biometric captures are completed using standard smartphones and Web cameras in a touchless method. We present a series of experiments to demonstrate the formation of an accurate, consistent, and scalable UHID. We hope our solution will aid in the reduction of complexities associated with user misidentification in healthcare resulting in lowering costs, enhancing population health monitoring, and improving patient-safety. PMID- 27782016 TI - Applying the Resilient Health System Framework for Universal Health Coverage. AB - Since the 1978 Declaration of Alma-Ata affirming health as a fundamental human right, policy-makers and stakeholders have proposed many different strategies to achieve the goal of 'health for all'. However, globally there still remains a lack of access to health information and quality health care, especially in low- and middle-income countries (LMIC). Digital health holds great promise to improve access and quality of care. We propose using the "resilient health system framework" as a guide to scale-up digital health as a means to achieve universal health care (UHC) and health for all. This article serves as a call to action for all governments to include population-based digital health tools as a foundational element in on-going health system priorities and service delivery. PMID- 27782017 TI - Family and Practitioner Perspectives on Telehealth for Services to Young Children with Autism. AB - Telehealth offers the potential to address inequalities in autism service access for young children living in regional and rural areas with limited access to autism specialists. Our aim was to explore parent and practitioner uses of technology, and views about telehealth, including perceived barriers, for autism early intervention service delivery in a regional town in Australia. Fifteen mothers and 19 front-line autism practitioners completed surveys distributed by local autism service and support providers in the regional town; eight front-line practitioners from one service participated in interviews. Mothers and practitioners had access to technology that could be used for video communication, but had little or no experience with telehealth. Mothers appeared more willing to try telehealth for receiving autism services than practitioners appeared to believe, and practitioners preferred to use it for consulting with other professionals and professional development. Barriers to telehealth included limited experience and practitioners not knowing what a telehealth service would look like, poor access to reliable and high speed internet, lack of skill and technical supports, and practitioners believing families preferred face-to-face services. The success of telehealth in this regional town will rely on better infrastructure, and upskilling practitioners in evidence-based autism interventions so they can provide the required support remotely. Use of telehealth to upskill practitioners in evidence-based practice could provide a first step in ensuring equitable access to expert autism services to regional and rural families. PMID- 27782018 TI - Assessment of Computer-Assisted Screening Technology for Diabetic Retinopathy Screening in India - Preliminary Results and Recommendations from a Pilot Study. AB - BACKGROUND: Diabetic retinopathy (DR) is regarded as a major cause of preventable blindness, which can be detected and treated if the cases are identified by screening. Screening for DR is therefore being practiced in developed countries, and tele screening has been a prominent model of delivery of eye care for screening DR. AIM: Our study has been designed to provide inputs on the suitability of a computer-assisted DR screening solution, for use in a larger prospective study. METHODS: Computer-assisted screening technology for grading diabetic retinopathy from fundus images by a set of machine learning algorithms. RESULTS: The preliminary recommendations from a pilot study of a system built using the public datasets and retrospective images, showed a good sensitivity and specificity. CONCLUSION: The machine learning algorithms has to be validated on a larger dataset of a population level study. PMID- 27782019 TI - WhatsApp in Clinical Practice: A Literature Review. AB - : Several spontaneous telemedicine services using WhatsApp Messenger have started in South Africa raising issues of confidentiality, data security and storage, record keeping and reporting. This study reviewed the literature on WhatsApp in clinical practice, to determine how it is used, and users' satisfaction. METHODS: Pubmed, Scopus, Science Direct and IEE Expert databases were searched using the search term WhatsApp and Google Scholar using the terms WhatsApp Telemedicine and WhatsApp mHealth. RESULTS: Thirty-two papers covering 17 disciplines were relevant with the most papers, 12, from India. Seventeen papers reported the use of WhatsApp Groups within departments, 14 of which were surgery related disciplines. Groups improved communication and advice given on patient management. Confidentiality was mentioned in 19 papers and consent in five. Data security was partially addressed in 11 papers with little understanding of how data are transmitted and stored. Telemedicine services outside of departmental groups were reported in seven papers and covered emergency triage in maxillofacial, plastic, neuro and general surgery, and cardiology and telestroke. CONCLUSIONS: WhatsApp is seen to be a simple, cheap and effective means of communication within the clinical health sector and its use will grow. Users have paid little attention to confidentiality, consent and data security. Guidelines for using WhatsApp for telemedicine are required including downloading. WhatsApp messages to computer for integration with electronic medical records. PMID- 27782020 TI - Health Behaviour Change Through Computer Games: Characterising Interventions. AB - Recently games in the form of video, computer, or mobile apps have been utilised as an effective component of interventions for health behaviour change. This paper provides an overview of related projects reported in peer-review literature in the period 2006 to 2016. Nine highly relevant references were considered for analysis. The findings are presented according to 3 dimensions of characterisation: health intention, behaviour change principle, and health purpose. PMID- 27782021 TI - The Same Language Speak We Do - Consensus Terminology for Telehealth. AB - : e-Health has grown to become interjurisdictional in scope and in practice. Central to successful implementation and scaling of e-heath solutions is clear and concise communication of ideas and principles, and instructions during construction. This paper addresses the need for an agreed taxonomy and terminology and focuses on explaining, proposing, and recommending terms and action for an international consensus-based terminology for telehealth. METHODS: Two structured database literature searches were performed to identify literature relevant to telehealth/telemedicine taxonomy or terminology. RESULTS: The terminology search identified 162 resources of which 4 met the inclusion criteria, while the taxonomy search identified 447 resources of which 5 met the inclusion criteria. Using these literature sources, a telehealth terminology was developed. DISCUSSION: The literature shows clear lack of and need for a common telehealth taxonomy and terminology. Of those proposed in the literature none has been universally adopted or applied. CONCLUSIONS: Proponents of telehealth and those working in or aligned with the field, must develop, agree upon, adopt, and use clear and accurate telehealth terminology to ensure concise and accurate communication in the application of telehealth globally. PMID- 27782022 TI - Interactive Games for Home Delivery of Exercise and Rehabilitation Interventions for Older Adults: An Australian Perspective. AB - Over the past few decades there has been a wealth of published scientific evidence for the physical, cognitive and social health-related benefits of increased physical activity, especially in older adults and people living with chronic disease. Despite the clear evidence base demonstrating the health-related benefits of physical activity, uptake and adherence is often disappointing. Therefore, methods for remote delivery of guided exercise programs are required, both to maximise the reach of physical activity promotion initiatives and programs across the older community and to minimise attrition once people begin to be physically active. One method by which we can increase understanding of the importance of, and compliance with, exercise programs involves the use of fun and engaging videogames. In the following we outline two ways in which we are using games technology in an Australian context. PMID- 27782023 TI - An Integrated Patient Information and In-Home Health Monitoring System Using Smartphones and Web Services. AB - Modern healthcare systems are undergoing a paradigm shift from in-hospital care to in-home monitoring, leveraging the emerging technologies in the area of bio sensing, wireless communication, mobile computing, and artificial intelligence. In-home monitoring promises to significantly reduce healthcare spending by preventing unnecessary hospital admissions and visits to healthcare professionals. Most of the in-home monitoring systems, proposed in the literature, focus on monitoring a set of specific vital signs. However, from the perspective of caregivers it is infeasible to maintain a collection of specialized monitoring systems. In this paper, we view the problem of in-home monitoring from the perspective of caregivers and present a framework that supports various monitoring capabilities while making the complexity transparent to the end users. The essential idea of the framework is to define a 'general purpose architecture' where the system specifies a particular protocol for communication and makes it public. Then any bio-sensing system can communicate with the system as long as it conforms to the protocol. We then argue that as the system grows in terms of number of patients and bio-sensing systems, artificial intelligence technologies need to be employed for patients' risk assessment, prioritization, and recommendation. Finally, we present an initial prototype of the system designed according to the proposed framework. PMID- 27782024 TI - Cost and Time Effectiveness Analysis of a Telemedicine Service in Bangladesh. AB - Telemedicine has great potential to overcome geographical barriers to providing access to equal health care services, particularly for people living in remote and rural areas in developing countries like Bangladesh. A number of telemedicine systems have been implemented in Bangladesh. However, no significant studies have been conducted to determine either their cost effectiveness or efficiency in reducing travel time required by patients. In addition, very few studies have analyzed the attitude and level of satisfaction of telemedicine service recipients in Bangladesh. The aim of this study was to analyze the cost and time effectiveness of a telemedicine service, implemented through locally developed PC based diagnostic equipment and software in Bangladesh, compared to conventional means of providing those services. The study revealed that the introduced telemedicine service reduced cost and travel time on average by 56% and 94% respectively compared to its counterpart conventional approach. The study also revealed that majority of users were highly satisfied with the newly introduced telemedicine service. Therefore, the introduced telemedicine service can be considered as a low cost and time efficient health service solution to improve health care facilities in the remote rural areas in Bangladesh. PMID- 27782025 TI - Improving the Quality of Informed Consent in Clinical Research with Information Technology. AB - The clinical research industry has yet to fully embrace information technology (IT) for informed consent purposes, even though it is used indispensably in our everyday lives and in other areas of clinical research and healthcare. This paper presents findings of a meta-narrative literature review to discuss the potential for IT to improve the quality of clinical research informed consent. The review reveals three main rationales for including IT in research consent. First, in the current context consent documents frequently fail to be effective decision aids for patients, and the lack of patient centricity in the process. Second, social media provides opportunities for patients to consult with a broader community during research consent to seek broader support, and potential to participate in creating a more patient centric process. Third, multimedia tools provide opportunities for improved patient education, engagement and decision making during research consent. IT offers opportunities to achieve more meaningful research consent, but more research is needed to create an evidence base, policies and economic analyses on the return on investment of using IT in the process. PMID- 27782026 TI - A Review and Critique of Teledermatology in the South African Public Health Sector. AB - : Nearly 80% of the world's population live in developing countries in Asia, Africa, and Latin America. Many of these countries must face a triple or quadruple burden of disease with severely limited resources and health systems. South Africa (SA) is one such country, and recognises the potential for e-health to moderate these limitations. Dermatological issues remain a concern in SA and globally. Indeed, the World Health Organisation (WHO) has recognised that a number of diseases are most likely to manifest themselves through a dermatological problem before becoming full-blown. However, there is an acute shortage of dermatologists in SA. Teledermatology has promise as a service delivery intervention. This study reports on the current status of teledermatology services in the public health sector of SA. METHODS: The study adopted a qualitative, inductive research approach based on a structured literature review of teledermatology in SA. A modified Momentum-Treat tool was used to critique identified teledermatology services. RESULTS: 159 resources were identified, of which 68 were excluded. The remaining 91 resources revealed a history of ad hoc teledermatology services, of which few remained active. Requests for teledermatology service confirmations provided some feedback, together with follow-up meetings and interviews. DISCUSSION: No evidence of scaling of teledermatology services and integration into routine healthcare was found. Of eight services, 4 remain active. Review and modified Momentum-Treat critique showed opportunities for improved readiness assessment, programme governance, and alignment to government policy direction, in order to improve scaling and sustainability. CONCLUSIONS: Full-scale teledermatology integration is possible, but stronger programme development is needed. Findings will inform development of a teledermatology scale-up framework to assist with future integration of teledermatology into routine healthcare. PMID- 27782027 TI - A Population-Level Data Analytics Portal for Self-Administered Lifestyle and Mental Health Screening. AB - This paper describes development of a prototype data analytics portal for analysis of accumulated screening results from eCHAT (electronic Case-finding and Help Assessment Tool). eCHAT allows individuals to conduct a self-administered lifestyle and mental health screening assessment, with usage to date chiefly in the context of primary care waiting rooms. The intention is for wide roll-out to primary care clinics, including secondary school based clinics, resulting in the accumulation of population-level data. Data from a field trial of eCHAT with sexual health questions tailored to youth were used to support design of a data analytics portal for population-level data. The design process included user personas and scenarios, screen prototyping and a simulator for generating large scale data sets. The prototype demonstrates the promise of wide-scale self administered screening data to support a range of users including practice managers, clinical directors and health policy analysts. PMID- 27782031 TI - Correction: Sun, Y.; et al. Bi-Objective Modelling for Hazardous Materials Road Rail Multimodal Routing Problem with Railway Schedule-Based Space-Time Constraints. Int. J. Environ. Res. Public Health 2016, 13, 762. AB - Bi-Objective Modelling for Hazardous Materials Road-Rail Multimodal Routing Problem with Railway Schedule-Based Space-Time Constraints.[...]. PMID- 27782032 TI - An Exploration of the Metal Dependent Selectivity of a Metalloporphyrins Coated Quartz Microbalances Array. AB - Several studies in the last two decades have demonstrated that metalloporphyrins coated quartz microbalances can be fruitfully used in many diverse applications, spanning from medical diagnosis to environmental control. This large versatility is due to the combination of the flexibility of metalloporphyrins molecular design with the independence of the quartz microbalance signal from the interaction mechanisms. The nature of the metal atom in the metalloporphyrins is often indicated as one of the most effective tools to design differently selective sensors. However, the properties of sensors are also strongly affected by the characteristics of the transducer. In this paper, the role of the metal atom is investigated studying the response, to various volatile compounds, of six quartz microbalance sensors that are based on the same porphyrin but with different metals. Results show that, since quartz microbalances (QMB) transducers can sense all the interactions between porphyrin and volatile compounds, the metal ion does not completely determine the sensor behaviour. Rather, the sensors based on the same molecular ring but with different metal ions show a non negligible common behaviour. However, even if limited, the different metals still confer peculiar properties to the sensors and might drive the sensor array identification of the pool of tested volatile compounds. PMID- 27782033 TI - Eddy-Current Sensors with Asymmetrical Point Spread Function. AB - This paper concerns a special type of eddy-current sensor in the form of inductive loops. Such sensors are applied in the measuring systems classifying road vehicles. They usually have a rectangular shape with dimensions of 1 * 2 m, and are installed under the surface of the traffic lane. The wide Point Spread Function (PSF) of such sensors causes the information on chassis geometry, contained in the measurement signal, to be strongly averaged. This significantly limits the effectiveness of the vehicle classification. Restoration of the chassis shape, by solving the inverse problem (deconvolution), is also difficult due to the fact that it is ill-conditioned. An original approach to solving this problem is presented in this paper. It is a hardware-based solution and involves the use of inductive loops with an asymmetrical PSF. Laboratory experiments and simulation tests, conducted with models of an inductive loop, confirmed the effectiveness of the proposed solution. In this case, the principle applies that the higher the level of sensor spatial asymmetry, the greater the effectiveness of the deconvolution algorithm. PMID- 27782034 TI - Research on High Sensitive D-Shaped FBG Hydrogen Sensors in Power Transformer Oil. AB - Dissolved hydrogen is a symbol gas decomposed by power transformer oil for electrical faults such as overheat or partial discharges. A novel D-shaped fiber Bragg grating (D-FBG) sensor is herein proposed and was fabricated with magnetron sputtering to measure the dissolved hydrogen concentration in power transformer oil in this paper. Different from the RI (refractive index)-based effect, D-FBG in this case is sensitive to curvature caused by stress from sensing coating, leading to Bragg wavelength shifts accordingly. The relationship between the D FBG wavelength shift and dissolved hydrogen concentration in oil was measured experimentally in the laboratory. The detected sensitivity could be as high as 1.96 MUL/L at every 1-pm wavelength shift. The results proved that a simple, polished FBG-based hydrogen sensor provides a linear measuring characteristic in the range of low hydrogen concentrations in transformer oil. Moreover, the stable hydrogen sensing performance was investigated by X-ray diffraction analysis. PMID- 27782036 TI - HPLC Separation of Diastereomers: Chiral Molecular Tools Useful for the Preparation of Enantiopure Compounds and Simultaneous Determination of Their Absolute Configurations. AB - To obtain enantiopure compounds, the so-called chiral high performance liquid chromatography (HPLC) method, i.e., HPLC using a chiral stationary phase, is very useful, as reviewed in the present Special Issue. On the other hand, normal HPLC (on silica gel) separation of diastereomers is also useful for the preparation of enantiopure compounds and also for the simultaneous determination of their absolute configurations (ACs). The author and coworkers have developed some chiral molecular tools, e.g., camphorsultam dichlorophthalic acid (CSDP acid), 2 methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid), and others suitable for this purpose. For example, a racemic alcohol is esterified with (S)-(+)-MalphaNP acid, yielding diastereomeric esters, which are easily separable by HPLC on silica gel. The ACs of the obtained enantiopure MalphaNP esters can be determined by the 1H-NMR diamagnetic anisotropy method. In addition, MalphaNP or CSDP esters have a high probability of giving single crystals suitable for X-ray crystallography. From the X-ray Oak Ridge thermal ellipsoid plot (ORTEP) drawing, the AC of the alcohol part can be unambiguously determined because the AC of the acid part is already known. The hydrolysis of MalphaNP or CSDP esters yields enantiopure alcohols with the established ACs. The mechanism and application examples of these methods are explained. PMID- 27782037 TI - Atypical Porcine Pestivirus: A Possible Cause of Congenital Tremor Type A-II in Newborn Piglets. AB - Congenital tremor type A-II in piglets has been regarded as a transmissible disease since the 1970s, possibly caused by a very recently-described virus: atypical porcine pestivirus (APPV). Here, we describe several strains of APPV in piglets with clinical signs of congenital tremor (10 of 10 farms tested). Piglets on a farm with no history of congenital tremor were PCR-negative for the virus. To demonstrate a causal relationship between APPV and disease, three gilts were inoculated via intramuscular injection at day 32 of pregnancy. In two of the three litters, vertical transmission of the virus occurred. Clinical signs of congenital tremor were observed in APPV-infected newborns, yet also two asymptomatic carriers were among the offspring. Piglets of one litter were PCR negative for the virus, and these piglets were all without congenital tremors. Long-term follow up of farm piglets born with congenital tremors showed that the initially high viremia in serum declines at five months of age, but shedding of the virus in feces continues, which explains why the virus remains present at affected farms and causes new outbreaks. We conclude that trans-placental transmission of APPV and subsequent infection of the fetuses is a very likely cause of congenital tremor type A-II in piglets. PMID- 27782035 TI - Cancer Cell Colonisation in the Bone Microenvironment. AB - Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow. PMID- 27782038 TI - The Effect of Zinc and Selenium Supplementation Mode on Their Bioavailability in the Rat Prostate. Should Administration Be Joint or Separate? AB - It is thought that zinc and selenium deficiency may play a significant role in the etiology of prostate cancer. Although joint zinc and selenium supplementation is frequently applied in the prevention of prostate diseases, the bioavailability of these elements in the prostate after co-administration is still unknown. The study examines the effect of subchronic supplementation of zinc gluconate and selenium compounds (sodium selenite or selenomethionine), administered together or separately, on their bioavailability in the prostate, as well as the induction of metallothionein-like proteins (MTs) bound to zinc in the prostate and liver. Zinc concentration in the dorso-lateral lobe of the prostate was significantly elevated already after the first month of supplementation of zinc alone. In the supplementation period, the MTs level increased together with zinc concentration. In contrast, the ventral lobe of the prostate did not demonstrate significantly higher levels of zinc until after three months of supplementation, despite the MTs induction noted after one-month supplementation. Increased selenium levels in the dorsolateral lobe were observed throughout the administration and post administration periods, regardless of the selenium compound used or whether zinc was co-administered. The results of our studies suggested for the first time that these elements should not be administered jointly in supplementation. PMID- 27782039 TI - Performance of Two Bioelectrical Impedance Analyses in the Diagnosis of Overweight and Obesity in Children and Adolescents: The FUPRECOL Study. AB - This study aimed to determine thresholds for percentage of body fat (BF%) corresponding to the cut-off values for overweight/obesity as recommended by the International Obesity Task Force (IOTF), using two bioelectrical impedance analyzers (BIA), and described the likelihood of increased cardiometabolic risk in our cohort defined by the IOTF and BF% status. Participants included 1165 children and adolescents (54.9% girls) from Bogota (Colombia). Body mass index (BMI) was calculated from height and weight. BF% of each youth was assessed first using the Tanita BC-418(r) followed by a Tanita BF-689(r). The sensitivity and specificity of both devices and their ability to correctly classify children as overweight/obesity (>=2 standard deviation), as defined by IOTF, was investigated using receiver operating characteristic (ROC) by sex and age groups (9-11, 12-14, and 13-17 years old); Area under curve (AUC) values were also reported. For girls, the optimal BF% threshold for classifying into overweight/obesity was found to be between 25.2 and 28.5 (AUC = 0.91-0.97) and 23.9 to 26.6 (AUC = 0.90 0.99) for Tanita BC-418(r) and Tanita BF-689(r), respectively. For boys, the optimal threshold was between 16.5 and 21.1 (AUC = 0.93-0.96) and 15.8 to 20.6 (AUC = 0.92-0.94) by Tanita BC-418(r) and Tanita BF-689(r), respectively. All AUC values for ROC curves were statistically significant and there were no differences between AUC values measured by both BIA devices. The BF% values associated with the IOTF-recommended BMI cut-off for overweight/obesity may require age- and sex-specific threshold values in Colombian children and adolescents aged 9-17 years and could be used as a surrogate method to identify individuals at risk of excess adiposity. PMID- 27782040 TI - Total Water Intake from Beverages and Foods Is Associated with Energy Intake and Eating Behaviors in Korean Adults. AB - Water is essential for the proper functioning of the body. Even though a recommendation exists for adequate water intake for Koreans, studies identifying actual water intake from all beverages and foods consumed daily in the Korean population are limited. Thus, we estimated total water intake from both beverages and foods and its association with energy intake and eating behaviors in Korean adults. We used a nationally representative sample of 25,122 Korean adults aged >=19 years, from the Korean National Health and Nutrition Examination Survey 2008 2012. We performed multiple regression analyses, adjusting for sociodemographic and health-related variables to investigate the contribution of overall energy and dietary intakes and eating behaviors to total water intake. The mean total water intake excluding plain water was 1071 g (398 g from beverages and 673 g from foods) and the estimated plain water intake was 1.3 L. Among Korean adults, 82% consumed beverages (excluding plain water) and these beverages contributed to 10% of daily energy intake and 32% of total water intake from beverages and foods. For every 100 kcal/day in energy intake, water intake consumed through beverages and foods increased by 18 g and 31 g, respectively. Water intake from beverages and foods was positively associated with energy from fat and dietary calcium, but inversely associated with energy density and energy from carbohydrates. When there was a 5% increase in energy intake from snacks and eating outside the home, there was an increase in water intake from beverages of 13 g and 2 g, respectively. Increased daily energy intake, the number of eating episodes, and energy intake from snacks and eating outside the home predicted higher water intake from beverages and foods. Our results provide evidence suggesting that various factors, including sociodemographic status, dietary intakes, and eating behaviors, could be important contributors to the water intake of Korean adults. Findings from this cross-sectional analysis may provide insight into strategies for promoting adequate water intake among Koreans. PMID- 27782041 TI - Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum. AB - Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to children's health. Here we examined the effects of longterm (14 days) and low dose (1 MUM) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, >=1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain. PMID- 27782042 TI - Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage. AB - Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF. PMID- 27782043 TI - Photodynamic Therapy for Non-Melanoma Skin Cancers. AB - Non-melanoma skin cancer (NMSC) is traditionally treated with surgical excision. Nonsurgical methods such as cryotherapy and topical chemotherapeutics, amongst other treatments, are other options. Actinic keratosis (AKs) are considered precancerous lesions that eventually may progress to squamous cell carcinoma (SCC). Photodynamic therapy (PDT) offers an effective treatment for AKs, and is also effective for superficial basal cell carcinoma (BCC). Nodular BCC and Bowen's disease (SCC in situ) have shown acceptable response rates with PDT, although recurrence rates are higher for these two NMSC subtypes. Methylaminolevulinate (MAL) PDT is a more effective treatment option than 5 aminolevulinic acid (ALA) PDT for nodular BCC. Several studies have shown that PDT results in superior cosmetic outcomes compared to surgical treatment. PDT is overall well-tolerated, with pain being the most common side effect. PMID- 27782044 TI - Normal Levels of Urinary CC16 Protein. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. AB - In 1937, Max Clara described a new type of cell in the human lung, which was later determined to be an exocrine secretory cell type containing granules composed of proteins [1].[...]. PMID- 27782045 TI - Response to Garcia-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. AB - We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. Garcia Nieto.[...]. PMID- 27782046 TI - A Viral Noncoding RNA Complements a Weakened Viral RNA Silencing Suppressor and Promotes Efficient Systemic Host Infection. AB - Systemic movement of beet necrotic yellow vein virus (BNYVV) in Beta macrocarpa depends on viral RNA3, whereas in Nicotiana benthamiana this RNA is dispensable. RNA3 contains a coremin motif of 20 nucleotides essential for the stabilization of noncoding RNA3 (ncRNA3) and for long-distance movement in Beta species. Coremin mutants that are unable to accumulate ncRNA3 also do not achieve systemic movement in Beta species. A mutant virus carrying a mutation in the p14 viral suppressor of RNA silencing (VSR), unable to move long distances, can be complemented with the ncRNA3 in the lesion phenotype, viral RNA accumulation, and systemic spread. Analyses of the BNYVV VSR mechanism of action led to the identification of the RNA-dependent RNA polymerase 6 (RDR6) pathway as a target of the virus VSR and the assignment of a VSR function to the ncRNA3. PMID- 27782047 TI - Occupational Safety and Related Impacts on Health and the Environment. AB - The inter-relationship between safety, health and the 'environment' is a complex and at times a relatively neglected topic. In this issue, 'safety' is often viewed by contributors as 'health and safety' and includes occupationally-related ill health as well as injury or harm to employees and the wider public. 'Environment' is also interpreted in the widest sense covering both physical and work environments with upstream work hazards presenting risks to downstream communities. The focus is very much on exploring and where possible addressing the challenges, some old and some facing workers in a range of public and private settings and also at times their nearby communities. The 19 papers in the issue cover public and private sectors, global and very local populations, macro theoretical perspectives, large epidemiological and some single factory or hospital site small case studies. A number of the papers are just beginning to explore and draw out for the first time the risks from hazards in their part of the world. The methodologies adopted also range from lab-based studies through ergonomic assessments and interventions to therapeutic approaches. PMID- 27782048 TI - Saponins from Chinese Medicines as Anticancer Agents. AB - Saponins are glycosides with triterpenoid or spirostane aglycones that demonstrate various pharmacological effects against mammalian diseases. To promote the research and development of anticancer agents from saponins, this review focuses on the anticancer properties of several typical naturally derived triterpenoid saponins (ginsenosides and saikosaponins) and steroid saponins (dioscin, polyphyllin, and timosaponin) isolated from Chinese medicines. These saponins exhibit in vitro and in vivo anticancer effects, such as anti proliferation, anti-metastasis, anti-angiogenesis, anti-multidrug resistance, and autophagy regulation actions. In addition, related signaling pathways and target proteins involved in the anticancer effects of saponins are also summarized in this work. PMID- 27782049 TI - Rapid On-Site Formation of a Free-Standing Flexible Optical Link for Sensing Applications. AB - An optical link, based on a conventional Scotch tape waveguide, for sensing applications requiring rapid on-site assembly is proposed and demonstrated. The flexible waveguide contains an integrated aluminum one-dimensional grating coupler that, when stuck on the radiative surface of a light emitting device, allows light to be coupled in and transmitted through the tape, whose tip end is, in turn, adhered onto the photosensitive surface of a photodetector. The (de)coupling approaches exhibit high alignment tolerances that permit the formation of a free-standing flexible optical connection between surface-normal optoelectronic devices without the need of specialized equipment. As the first demonstration of a sensing application, the proposed optical link is easily configured as a cost-effective intensity-based refractometric sensor for liquid detection, which can be applicable to on-site quality and process control of, for example, beverages. PMID- 27782050 TI - A Combinational Strategy upon RNA Sequencing and Peptidomics Unravels a Set of Novel Toxin Peptides in Scorpion Mesobuthus martensii. AB - Scorpion venom is deemed to contain many toxic peptides as an important source of natural compounds. Out of the two hundred proteins identified in Mesobuthus martensii (M. martensii), only a few peptide toxins have been found so far. Herein, a combinational approach based upon RNA sequencing and Liquid chromatography-mass spectrometry/mass spectrometry (LC MS/MS) was employed to explore the venom peptides in M. martensii. A total of 153 proteins were identified from the scorpion venom, 26 previously known and 127 newly identified. Of the novel toxins, 97 proteins exhibited sequence similarities to known toxins, and 30 were never reported. Combining peptidomic and transcriptomic analyses, the peptide sequence of BmKKx1 was reannotated and four disulfide bridges were confirmed within it. In light of the comparison of conservation and variety of toxin amino acid sequences, highly conserved and variable regions were perceived in 24 toxins that were parts of two sodium channel and two potassium channel toxins families. Taking all of this evidences together, the peptidomic analysis on M. martensii indeed identified numerous novel scorpion peptides, expanded our knowledge towards the venom diversity, and afforded a set of pharmaceutical candidates. PMID- 27782051 TI - pMPES: A Modular Peptide Expression System for the Delivery of Antimicrobial Peptides to the Site of Gastrointestinal Infections Using Probiotics. AB - Antimicrobial peptides are a promising alternative to traditional antibiotics, but their utility is limited by high production costs and poor bioavailability profiles. Bacterial production and delivery of antimicrobial peptides (AMPs) directly at the site of infection may offer a path for effective therapeutic application. In this study, we have developed a vector that can be used for the production and secretion of seven antimicrobial peptides from both Escherichia coli MC1061 F' and probiotic E.coli Nissle 1917. The vector pMPES (Modular Peptide Expression System) employs the Microcin V (MccV) secretion system and a powerful synthetic promoter to drive AMP production. Herein, we demonstrate the capacity of pMPES to produce inhibitory levels of MccV, Microcin L (MccL), Microcin N (McnN), Enterocin A (EntA), Enterocin P (EntP), Hiracin JM79 (HirJM79) and Enterocin B (EntB). To our knowledge, this is the first demonstration of such a broadly-applicable secretion system for AMP production. This type of modular expression system could expedite the development of sorely needed antimicrobial technologies. PMID- 27782052 TI - A Review on Internet of Things for Defense and Public Safety. AB - The Internet of Things (IoT) is undeniably transforming the way that organizations communicate and organize everyday businesses and industrial procedures. Its adoption has proven well suited for sectors that manage a large number of assets and coordinate complex and distributed processes. This survey analyzes the great potential for applying IoT technologies (i.e., data-driven applications or embedded automation and intelligent adaptive systems) to revolutionize modern warfare and provide benefits similar to those in industry. It identifies scenarios where Defense and Public Safety (PS) could leverage better commercial IoT capabilities to deliver greater survivability to the warfighter or first responders, while reducing costs and increasing operation efficiency and effectiveness. This article reviews the main tactical requirements and the architecture, examining gaps and shortcomings in existing IoT systems across the military field and mission-critical scenarios. The review characterizes the open challenges for a broad deployment and presents a research roadmap for enabling an affordable IoT for defense and PS. PMID- 27782054 TI - Ultraviolet Imaging with Low Cost Smartphone Sensors: Development and Application of a Raspberry Pi-Based UV Camera. AB - Here, we report, for what we believe to be the first time, on the modification of a low cost sensor, designed for the smartphone camera market, to develop an ultraviolet (UV) camera system. This was achieved via adaptation of Raspberry Pi cameras, which are based on back-illuminated complementary metal-oxide semiconductor (CMOS) sensors, and we demonstrated the utility of these devices for applications at wavelengths as low as 310 nm, by remotely sensing power station smokestack emissions in this spectral region. Given the very low cost of these units, ~ USD 25, they are suitable for widespread proliferation in a variety of UV imaging applications, e.g., in atmospheric science, volcanology, forensics and surface smoothness measurements. PMID- 27782055 TI - Quantitative Determination of 3-O-Acetyl-11-Keto-betaBoswellic Acid (AKBA) and Other Boswellic Acids in Boswellia sacra Flueck (syn. B. carteri Birdw) and Boswellia serrata Roxb. AB - Boswellia serrata and Boswellia sacra (syn. B. carteri) are important medicinal plants widely used for their content of bioactive lipophilic triterpenes. The qualitative and quantitative determination of boswellic acids (BAs) is important for their use in dietary supplements aimed to provide a support for osteoarthritic and inflammatory diseases. We used High Performance Liquid Chromatography (HPLC)-Diode Array Detector (DAD) coupled to ElectroSpray Ionization and tandem Mass Spectrometry (ESI-MS/MS) for the qualitative and quantitative determination of BAs extracted from the gum resins of B. sacra and B. serrata. Limit of detection (LOD), limit of quantification (LOQ), and Matrix Effect were assessed in order to validate quantitative data. Here we show that the BAs quantitative determination was 491.20 g.kg-1 d. wt (49%) in B. sacra and 295.25 g.kg-1 d. wt (30%) in B. serrata. Lower percentages of BAs content were obtained when BAs were expressed on the gum resin weight (29% and 16% for B. sacra and B. serrata, respectively). The content of Acetyl-11-Keto-beta-Boswellic Acid (AKBA) was higher in B. sacra (70.81 g.kg-1 d. wt; 7%) than in B. serrata (7.35 g.kg-1 d. wt; 0.7%). Our results show that any claim of BAs content in either B. sacra or B. serrata gum resins equal to or higher than 70% or AKBA contents of 30% are simply unrealistic or based on a wrong quantitative determination. PMID- 27782056 TI - Analysis of Crack Image Recognition Characteristics in Concrete Structures Depending on the Illumination and Image Acquisition Distance through Outdoor Experiments. AB - The effects of illumination and shooting distance on crack image recognition were investigated by examining cracks in images taken with a camera. In order to examine the effects, images of cracks in a concrete structure taken while varying the illumination and shooting distance in an outdoor environment were analyzed. The images were acquired at a daytime illumination of 52,000 lx and a night illumination of 13 lx. The crack specimen images produced for the experiment were taken by increasing the shooting distance from 5 m to 100 m in each illumination. On the basis of the analysis on the modulation transfer function (MTF) and contrast sensitivity of the crack images, the effects of illumination and shooting distance on the sharpness of the crack images were investigated. The minimum crack widths that can be identified under each illumination were analyzed using MTF10 and Weber contrast 0.1, respectively. It was found that as the shooting distance increases, the effects of illumination on crack recognition become greater. PMID- 27782053 TI - Circulating MicroRNAs as Potential Biomarkers of Exercise Response. AB - Systematic physical activity increases physical fitness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and monitoring health-related adaptation changes. Recent advances in OMICS technologies have opened new opportunities in the detection of genetic, epigenetic and transcriptomic biomarkers. Very promising are mainly small non-coding microRNAs (miRNAs). miRNAs post-transcriptionally regulate gene expression by binding to mRNA and causing its degradation or inhibiting translation. A growing body of evidence suggests that miRNAs affect many processes and play a crucial role not only in cell differentiation, proliferation and apoptosis, but also affect extracellular matrix composition and maintaining processes of homeostasis. A number of studies have shown changes in distribution profiles of circulating miRNAs (c-miRNAs) associated with various diseases and disorders as well as in samples taken under physiological conditions such as pregnancy or physical exercise. This overview aims to summarize the current knowledge related to the response of blood c-miRNAs profiles to different modes of exercise and to highlight their potential application as a novel class of biomarkers of physical performance capacity and training adaptation. PMID- 27782057 TI - Device Centric Throughput and QoS Optimization for IoTsin a Smart Building Using CRN-Techniques. AB - The Internet of Things (IoT) has gained an incredible importance in the communication and networking industry due to its innovative solutions and advantages in diverse domains. The IoT' network is a network of smart physical objects: devices, vehicles, buildings, etc. The IoT has a number of applications ranging from smart home, smart surveillance to smart healthcare systems. Since IoT consists of various heterogeneous devices that exhibit different traffic patterns and expect different quality of service (QoS) in terms of data rate, bit error rate and the stability index of the channel, therefore, in this paper, we formulated an optimization problem to assign channels to heterogeneous IoT devices within a smart building for the provisioning of their desired QoS. To solve this problem, a novel particle swarm optimization-based algorithm is proposed. Then, exhaustive simulations are carried out to evaluate the performance of the proposed algorithm. Simulation results demonstrate the supremacy of our proposed algorithm over the existing ones in terms of throughput, bit error rate and the stability index of the channel. PMID- 27782058 TI - From WSN towards WoT: Open API Scheme Based on oneM2M Platforms. AB - Conventional computing systems have been able to be integrated into daily objects and connected to each other due to advances in computing and network technologies, such as wireless sensor networks (WSNs), forming a global network infrastructure, called the Internet of Things (IoT). To support the interconnection and interoperability between heterogeneous IoT systems, the availability of standardized, open application programming interfaces (APIs) is one of the key features of common software platforms for IoT devices, gateways, and servers. In this paper, we present a standardized way of extending previously existing WSNs towards IoT systems, building the world of the Web of Things (WoT). Based on the oneM2M software platforms developed in the previous project, we introduce a well-designed open API scheme and device-specific thing adaptation software (TAS) enabling WSN elements, such as a wireless sensor node, to be accessed in a standardized way on a global scale. Three pilot services are implemented (i.e., a WiFi-enabled smart flowerpot, voice-based control for ZigBee connected home appliances, and WiFi-connected AR.Drone control) to demonstrate the practical usability of the open API scheme and TAS modules. Full details on the method of integrating WSN elements into three example systems are described at the programming code level, which is expected to help future researchers in integrating their WSN systems in IoT platforms, such as oneM2M. We hope that the flexibly-deployable, easily-reusable common open API scheme and TAS-based integration method working with the oneM2M platforms will help the conventional WSNs in diverse industries evolve into the emerging WoT solutions. PMID- 27782059 TI - Highly Selective and Ultrasensitive Turn-on Luminescence Chemosensor for Mercury (II) Determination Based on the Rhodamine 6G Derivative FC1 and Au Nanoparticles. AB - A method for the detection and quantitation of Hg2+ in aqueous samples by fluorescence spectroscopy is presented. It consists of a turn-on sensor developed by coupling Gold nanoparticles (AuNPs) with the rhodamine 6G derivative FC1, in which the response is generated by a mercury-induced ring-opening reaction. The AuNPs were included in order to improve the sensitivity of the method towards the analyte, maintaining its high selectivity. The method was validated in terms of linearity, precision and accuracy, and applied to the quantitation of Hg2+ in Milli-Q and tap water with and without spiked analyte. The limit of detection and quantitation were 0.15 MUg.L-1 and 0.43 MUg.L-1, respectively, constituting a substantial improvement of sensitivity in comparison with the previously reported detection of Hg2+ with free FC1. PMID- 27782061 TI - A Single Lineage of Hepatitis E Virus Causes Both Outbreaks and Sporadic Hepatitis in Sudan. AB - Few studies have reported sporadic hepatitis E virus (HEV) infections during non outbreak periods in Africa. In this study, the prevalence of HEV infection in Sudan was investigated in 432 patients with acute hepatitis from 12 localities in North Kordofan, and from 152 patients involved in smaller outbreaks of hepatitis in the neighbouring Darfur. HEV infection was diagnosed in 147 (25%) patients: 98 from Kordofan and 49 from Darfur. The mortality was 10%; six of the patients who died from the infection were pregnant women. HEV RNA was detected by quantitative real-time polymerase chain reaction (RT-qPCR) in 38 (26%) patients: 22 from Kordofan and 16 from Darfur. Partial open reading frame (ORF) 1 and ORF2 were sequenced from HEV from nine and three patients, respectively. Phylogenetic analysis showed that the Sudanese strains belonged to genotype 1 (HEV1), and confirmed the segregation of African HEV1 strains into one branch divergent from Asian HEV1. It also revealed that the Sudanese strains from this study and from an outbreak in 2004 formed a separate clade with a common ancestor, distinct from strains from the neighbouring Chad and Egypt. This HEV strain has thus spread in a large area of Sudan, where it has caused both sporadic hepatitis E and outbreaks from at least 2004 and onwards. These data demonstrate that hepatitis E is a constant, on-going public health problem in Sudan and that there is a need for hepatitis E surveillance, outbreak preparedness, and general improvements of the sanitation in these remote areas of the country. PMID- 27782060 TI - Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors. AB - While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM. PMID- 27782062 TI - A Steel Wire Stress Measuring Sensor Based on the Static Magnetization by Permanent Magnets. AB - A new stress measuring sensor is proposed to evaluate the axial stress in steel wires. Without using excitation and induction coils, the sensor mainly consists of a static magnetization unit made of permanent magnets and a magnetic field measurement unit containing Hall element arrays. Firstly, the principle is illustrated in detail. Under the excitation of the magnetization unit, a spatially varying magnetized region in the steel wire is utilized as the measurement region. Radial and axial magnetic flux densities at different lift offs in this region are measured by the measurement unit to calculate the differential permeability curve and magnetization curve. Feature parameters extracted from the curves are used to evaluate the axial stress. Secondly, the special stress sensor for Phi5 and Phi7 steel wires is developed accordingly. At last, the performance of the sensor is tested experimentally. Experimental results show that the sensor can measure the magnetization curve accurately with the error in the range of +/-6%. Furthermore, the obtained differential permeability at working points 1200 A/m and 10000 A/m change almost linearly with the stress in steel wires, the goodness of linear fits are all higher than 0.987. Thus, the proposed steel wire stress measuring sensor is feasible. PMID- 27782063 TI - Automatic Extraction of Tunnel Lining Cross-Sections from Terrestrial Laser Scanning Point Clouds. AB - Tunnel lining (bare-lining) cross-sections play an important role in analyzing deformations of tunnel linings. The goal of this paper is to develop an automatic method for extracting bare-lining cross-sections from terrestrial laser scanning (TLS) point clouds. First, the combination of a 2D projection strategy and angle criterion is used for tunnel boundary point detection, from which we estimate the two boundary lines in the X-Y plane. The initial direction of the cross-sectional plane is defined to be orthogonal to one of the two boundary lines. In order to compute the final cross-sectional plane, the direction is adjusted twice with the total least squares method and Rodrigues' rotation formula, respectively. The projection of nearby points is made onto the adjusted plane to generate tunnel cross-sections. Finally, we present a filtering algorithm (similar to the idea of the morphological erosion) to remove the non-lining points in the cross-section. The proposed method was implemented on railway tunnel data collected in Sichuan, China. Compared with an existing method of cross-sectional extraction, the proposed method can offer high accuracy and more reliable cross-sectional modeling. We also evaluated Type I and Type II errors of the proposed filter, at the same time, which gave suggestions on the parameter selection of the filter. PMID- 27782065 TI - Synthesis of Thioethers by InI3-Catalyzed Substitution of Siloxy Group Using Thiosilanes. AB - The substitution of a siloxy group using thiosilanes smoothly occurred in the presence of InI3 catalyst to yield the corresponding thioethers. InI3 was a specifically effective catalyst in this reaction system, while other typical Lewis acids such as BF3?OEt2, AlCl3, and TiCl4 were ineffective. Various silyl ethers such as primary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic, and propargylic types were applicable. In addition, bulky OSitBuMe2 and OSiiPr3 groups, other than the OSiMe3 group, were successfully substituted. The substitution reaction of enantiopure secondary benzylic silyl ether yielded the corresponding racemic thioether product, which suggested that the reaction of tertiary alkyl, secondary alkyl, benzylic, and propargylic silyl ethers would proceed via a SN1 mechanism. PMID- 27782064 TI - Influence of Bisphenol A on Type 2 Diabetes Mellitus. AB - Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies. PMID- 27782066 TI - Boosting Tumor-Specific Immunity Using PDT. AB - Photodynamic therapy (PDT) is a cancer treatment with a long-standing history. It employs the application of nontoxic components, namely a light-sensitive photosensitizer and visible light, to generate reactive oxygen species (ROS). These ROS lead to tumor cell destruction, which is accompanied by the induction of an acute inflammatory response. This inflammatory process sends a danger signal to the innate immune system, which results in activation of specific cell types and release of additional inflammatory mediators. Activation of the innate immune response is necessary for subsequent induction of the adaptive arm of the immune system. This includes the priming of tumor-specific cytotoxic T lymphocytes (CTL) that have the capability to directly recognize and kill cells which display an altered self. The past decades have brought increasing appreciation for the importance of the generation of an adaptive immune response for long-term tumor control and induction of immune memory to combat recurrent disease. This has led to considerable effort to elucidate the immune effects PDT treatment elicits. In this review we deal with the progress which has been made during the past 20 years in uncovering the role of PDT in the induction of the tumor-specific immune response, with special emphasis on adaptive immunity. PMID- 27782067 TI - One Step Assembly of Thin Films of Carbon Nanotubes on Screen Printed Interface for Electrochemical Aptasensing of Breast Cancer Biomarker. AB - Thin films of organic moiety functionalized carbon nanotubes (CNTs) from a very well-dispersed aqueous solution were designed on a screen printed transducer surface through a single step directed assembly methodology. Very high density of CNTs was obtained on the screen printed electrode surface, with the formation of a thin and uniform layer on transducer substrate. Functionalized CNTs were characterized by X-ray diffraction spectroscopy (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and Brunauer-Emmett- Teller (BET) surface area analyzer methodologies, while CNT coated screen printed transducer platform was analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The proposed methodology makes use of a minimum amount of CNTs and toxic solvents, and is successfully demonstrated to form thin films over macroscopic areas of screen printed carbon transducer surface. The CNT coated screen printed transducer surface was integrated in the fabrication of electrochemical aptasensors for breast cancer biomarker analysis. This CNT coated platform can be applied to immobilize enzymes, antibodies and DNA in the construction of biosensor for a broad spectrum of applications. PMID- 27782068 TI - The Anti-Inflammatory Effect of Spray-Dried Plasma Is Mediated by a Reduction in Mucosal Lymphocyte Activation and Infiltration in a Mouse Model of Intestinal Inflammation. AB - Spray-dried preparations from porcine and bovine plasma can alleviate mucosal inflammation in experimental models and improve symptoms in patients with enteropathy. In rodents, dietary supplementation with porcine spray-dried plasma (SDP) attenuates intestinal inflammation and improves the epithelial barrier function during intestinal inflammation induced by Staphylococcus aureus enterotoxin B (SEB). The aim of this study was to discern the molecular mechanisms involved in the anti-inflammatory effects of SDP. Male C57BL/6 mice were fed with 8% SDP or control diet (based on milk proteins) for two weeks, from weaning until day 33. On day 32, the mice were given a SEB dose (i.p., 25 ug/mouse) or vehicle. SEB administration increased cell recruitment to mesenteric lymph nodes and the percentage of activated Th lymphocytes and SDP prevented these effects). SDP supplementation increased the expression of interleukin 10 (IL-10) or transforming growth factor- beta (TGF-beta) compared to the SEB group. The SEB challenge increased six-fold the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and intercellular adhesion molecule 1 (ICAM-1); and these effects were attenuated by SDP supplementation. SEB also augmented NF kappaB phosphorylation, an effect that was prevented by dietary SDP. Our results indicate that the anti-inflammatory effects of SDP involve the regulation of transcription factors and adhesion molecules that reduce intestinal cell infiltration and the degree of the inflammatory response. PMID- 27782070 TI - Vitamin D Status during Pregnancy in a Multi-Ethnic Population-Representative Swedish Cohort. AB - There is currently little information on changes in vitamin D status during pregnancy and its predictors. The aim was to study the determinants of change in vitamin D status during pregnancy and of vitamin D deficiency (<30 nmol/L) in early pregnancy. Blood was drawn in the first (T1) and third trimester (T3). Serum 25-hydroxyvitamin D (25(OH)D) (N = 1985) was analysed by liquid chromatography tandem-mass spectrometry. Season-corrected 25(OH)D was calculated by fitting cosine functions to the data. Mean (standard deviation) 25(OH)D was 64.5(24.5) nmol/L at T1 and 74.6(34.4) at T3. Mean age was 31.3(4.9) years, mean body mass index (BMI) was 24.5(4.2) kg/m2 and 74% of the women were born in Sweden. Vitamin D deficiency was common among women born in Africa (51%) and Asia (46%) and prevalent in 10% of the whole cohort. Determinants of vitamin D deficiency at T1 were of non-North European origin, and had less sun exposure, lower vitamin D intake and lower age. Season-corrected 25(OH)D increased by 11(23) nmol/L from T1 to T3. The determinants of season-corrected change in 25(OH)D were origin, sun-seeking behaviour, clothing style, dietary vitamin D intake, vitamin D supplementation and recent travel <35 degrees N. In conclusion, season-corrected 25(OH)D concentration increased during pregnancy and depended partly on lifestyle factors. The overall prevalence of vitamin D deficiency was low but common among women born in Africa and Asia. Among them, the determinants of both vitamin D deficiency and change in season-corrected vitamin D status were fewer, indicating a smaller effect of sun exposure. PMID- 27782069 TI - What Is Breast in the Bone? AB - The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%-50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural "recycling" of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle. PMID- 27782072 TI - The Association between the Lipids Levels in Blood and Risk of Age-Related Macular Degeneration. AB - Lipid metabolism may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with blood lipids. We performed a meta-analysis including a total of 19 studies to evaluate associations between blood lipids and this disease. The result reported that the high level of high-density lipoprotein cholesterol (HDL-C) obtained with an increment of 1 mmol/L could result in a significantly increase in the AMD risk of approximately 18% (relative risk (RR), 1.18; 95% confidence interval (CI), 1.01 to 1.35; I2 = 53.8%; p = 0.007). High levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were significantly associated with a decreased risk of AMD (RRs ranging from 0.92 to 0.95; all p < 0.05). The stratified analysis based on AMD subtypes showed that these blood lipids were only significantly associated with the risk of early AMD (all p < 0.05). The association between the blood lipids and AMD risk did not differ substantially based on the other characteristics of the participants. A high HDL-C level was associated with an increased AMD risk, whereas participants with high TC, LDL-C, and TG concentrations may show a decreased risk for this disease. Further well-designed large studies are warranted to confirm the conclusions. PMID- 27782071 TI - Effect of Bifidobacterium breve on the Intestinal Microbiota of Coeliac Children on a Gluten Free Diet: A Pilot Study. AB - Coeliac disease (CD) is associated with alterations of the intestinal microbiota. Although several Bifidobacterium strains showed anti-inflammatory activity and prevention of toxic gliadin peptides generation in vitro, few data are available on their efficacy when administered to CD subjects. This study evaluated the effect of administration for three months of a food supplement based on two Bifidobacterium breve strains (B632 and BR03) to restore the gut microbial balance in coeliac children on a gluten free diet (GFD). Microbial DNA was extracted from faeces of 40 coeliac children before and after probiotic or placebo administration and 16 healthy children (Control group). Sequencing of the amplified V3-V4 hypervariable region of 16S rRNA gene as well as qPCR of Bidobacterium spp., Lactobacillus spp., Bacteroides fragilis group Clostridiumsensu stricto and enterobacteria were performed. The comparison between CD subjects and Control group revealed an alteration in the intestinal microbial composition of coeliacs mainly characterized by a reduction of the Firmicutes/Bacteroidetes ratio, of Actinobacteria and Euryarchaeota. Regarding the effects of the probiotic, an increase of Actinobacteria was found as well as a re-establishment of the physiological Firmicutes/Bacteroidetes ratio. Therefore, a three-month administration of B. breve strains helps in restoring the healthy percentage of main microbial components. PMID- 27782074 TI - In-Field, In Situ, and In Vivo 3-Dimensional Elemental Mapping for Plant Tissue and Soil Analysis Using Laser-Induced Breakdown Spectroscopy. AB - Sensing and mapping element distributions in plant tissues and its growth environment has great significance for understanding the uptake, transport, and accumulation of nutrients and harmful elements in plants, as well as for understanding interactions between plants and the environment. In this study, we developed a 3-dimensional elemental mapping system based on laser-induced breakdown spectroscopy that can be deployed in- field to directly measure the distribution of multiple elements in living plants as well as in the soil. Mapping is performed by a fast scanning laser, which ablates a micro volume of a sample to form a plasma. The presence and concentration of specific elements are calculated using the atomic, ionic, and molecular spectral characteristics of the plasma emission spectra. Furthermore, we mapped the pesticide residues in maize leaves after spraying to demonstrate the capacity of this method for trace elemental mapping. We also used the system to quantitatively detect the element concentrations in soil, which can be used to further understand the element transport between plants and soil. We demonstrate that this method has great potential for elemental mapping in plant tissues and soil with the advantages of 3-dimensional and multi-elemental mapping, in situ and in vivo measurement, flexible use, and low cost. PMID- 27782073 TI - A Comprehensive View of the Structural and Functional Alterations of Extracellular Matrix by Snake Venom Metalloproteinases (SVMPs): Novel Perspectives on the Pathophysiology of Envenoming. AB - Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics analysis of exudates collected in the vicinity of tissues affected by SVMPs has provided novel and exciting information on SVMP induced ECM alterations. The presence of fragments of an array of ECM proteins, including those of the basement membrane, has revealed a complex pathological scenario caused by the direct action of SVMPs. In addition, the time-course analysis of these changes has underscored that degradation of some fibrillar collagens is likely to depend on the action of endogenous proteinases, such as matrix metalloproteinases (MMPs), synthesized as a consequence of the inflammatory process. The action of SVMPs on the ECM also results in the release of ECM-derived biologically-active peptides that exert diverse actions in the tissue, some of which might be associated with reparative events or with further tissue damage. The study of the effects of SVMP on the ECM is an open field of research which may bring a renewed understanding of snake venom-induced pathology. PMID- 27782076 TI - A Portable Farmland Information Collection System with Multiple Sensors. AB - Precision agriculture is the trend of modern agriculture, and it is also one of the important ways to realize the sustainable development of agriculture. In order to meet the production requirements of precision agriculture-efficient use of agricultural resources, and improving the crop yields and quality-some necessary field information in crop growth environment needs to be collected and monitored. In this paper, a farmland information collection system is developed, which includes a portable farmland information collection device based on STM32 (a 32-bit comprehensive range of microcontrollers based on ARM Crotex-M3), a remote server and a mobile phone APP. The device realizes the function of portable and mobile collecting of multiple parameters farmland information, such as chlorophyll content of crop leaves, air temperature, air humidity, and light intensity. UM220-III (Unicore Communication Inc., Beijing, China) is used to realize the positioning based on BDS/GPS (BeiDou Navigation Satellite System, BDS/Global Positioning System, GPS) dual-mode navigation and positioning system, and the CDMA (Code Division Multiple Access, CDMA) wireless communication module is adopted to realize the real-time remote transmission. The portable multi function farmland information collection system is real-time, accurate, and easy to use to collect farmland information and multiple information parameters of crops. PMID- 27782078 TI - A Comparative Study of the Application of Fluorescence Excitation-Emission Matrices Combined with Parallel Factor Analysis and Nonnegative Matrix Factorization in the Analysis of Zn Complexation by Humic Acids. AB - The main aim of this study was the application of excitation-emission fluorescence matrices (EEMs) combined with two decomposition methods: parallel factor analysis (PARAFAC) and nonnegative matrix factorization (NMF) to study the interaction mechanisms between humic acids (HAs) and Zn(II) over a wide concentration range (0-50 mg.dm-3). The influence of HA properties on Zn(II) complexation was also investigated. Stability constants, quenching degree and complexation capacity were estimated for binding sites found in raw EEM, EEM PARAFAC and EEM-NMF data using mathematical models. A combination of EEM fluorescence analysis with one of the proposed decomposition methods enabled separation of overlapping binding sites and yielded more accurate calculations of the binding parameters. PARAFAC and NMF processing allowed finding binding sites invisible in a few raw EEM datasets as well as finding totally new maxima attributed to structures of the lowest humification. Decomposed data showed an increase in Zn complexation with an increase in humification, aromaticity and molecular weight of HAs. EEM-PARAFAC analysis also revealed that the most stable compounds were formed by structures containing the highest amounts of nitrogen. The content of oxygen-functional groups did not influence the binding parameters, mainly due to fact of higher competition of metal cation with protons. EEM spectra coupled with NMF and especially PARAFAC processing gave more adequate assessments of interactions as compared to raw EEM data and should be especially recommended for modeling of complexation processes where the fluorescence intensities (FI) changes are weak or where the processes are interfered with by the presence of other fluorophores. PMID- 27782075 TI - Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort. AB - Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6 marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 * 10-6 for the European controls; odds ratio = 2.42, p-value = 6.33 * 10-3 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence. PMID- 27782077 TI - Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways. AB - An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, p < 0.05) between CR-CD offspring (264 up-regulated genes, 199 down-regulated genes) and control offspring. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis revealed that the insulin signaling pathway and Wnt signaling pathway were in the center of the gene network. Our study provides the first evidence that maternal chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways. PMID- 27782079 TI - Organ-Specific Gene Expression Changes in the Fetal Liver and Placenta in Response to Maternal Folate Depletion. AB - Growing evidence supports the hypothesis that the in utero environment can have profound implications for fetal development and later life offspring health. Current theory suggests conditions experienced in utero prepare, or "programme", the fetus for its anticipated post-natal environment. The mechanisms responsible for these programming events are poorly understood but are likely to involve gene expression changes. Folate is essential for normal fetal development and inadequate maternal folate supply during pregnancy has long term adverse effects for offspring. We tested the hypothesis that folate depletion during pregnancy alters offspring programming through altered gene expression. Female C57BL/6J mice were fed diets containing 2 mg or 0.4 mg folic acid/kg for 4 weeks before mating and throughout pregnancy. At 17.5 day gestation, genome-wide gene expression was measured in male fetal livers and placentas. In the fetal liver, 989 genes were expressed differentially (555 up-regulated, 434 down-regulated) in response to maternal folate depletion, with 460 genes expressed differentially (250 up-regulated, 255 down-regulated) in the placenta. Only 25 differentially expressed genes were common between organs. Maternal folate intake during pregnancy influences fetal gene expression in a highly organ specific manner which may reflect organ-specific functions. PMID- 27782080 TI - In Vitro and In Vivo Models for the Study of Human Polyomavirus Infection. AB - Developments of genome amplification techniques have rapidly expanded the family of human polyomaviruses (PyV). Following infection early in life, PyV persist in their hosts and are generally of no clinical consequence. High-level replication of PyV can occur in patients under immunosuppressive or immunomodulatory therapy and causes severe clinical entities, such as progressive multifocal leukoencephalopathy, polyomavirus-associated nephropathy or Merkel cell carcinoma. The characterization of known and newly-discovered human PyV, their relationship to human health, and the mechanisms underlying pathogenesis remain to be elucidated. Here, we summarize the most widely-used in vitro and in vivo models to study the PyV-host interaction, pathogenesis and anti-viral drug screening. We discuss the strengths and limitations of the different models and the lessons learned. PMID- 27782082 TI - Transcriptome Sequencing and De Novo Assembly of Golden Cuttlefish Sepia esculenta Hoyle. AB - Golden cuttlefish Sepia esculenta Hoyle is an economically important cephalopod species. However, artificial hatching is currently challenged by low survival rate of larvae due to abnormal embryonic development. Dissecting the genetic foundation and regulatory mechanisms in embryonic development requires genomic background knowledge. Therefore, we carried out a transcriptome sequencing on Sepia embryos and larvae via mRNA-Seq. 32,597,241 raw reads were filtered and assembled into 98,615 unigenes (N50 length at 911 bp) which were annotated in NR database, GO and KEGG databases respectively. Digital gene expression analysis was carried out on cleavage stage embryos, healthy larvae and malformed larvae. Unigenes functioning in cell proliferation exhibited higher transcriptional levels at cleavage stage while those related to animal disease and organ development showed increased transcription in malformed larvae. Homologs of key genes in regulatory pathways related to early development of animals were identified in Sepia. Most of them exhibit higher transcriptional levels in cleavage stage than larvae, suggesting their potential roles in embryonic development of Sepia. The de novo assembly of Sepia transcriptome is fundamental genetic background for further exploration in Sepia research. Our demonstration on the transcriptional variations of genes in three developmental stages will provide new perspectives in understanding the molecular mechanisms in early embryonic development of cuttlefish. PMID- 27782081 TI - The Role of Nuclear Antiviral Factors against Invading DNA Viruses: The Immediate Fate of Incoming Viral Genomes. AB - In recent years, it has been suggested that host cells exert intrinsic mechanisms to control nuclear replicating DNA viruses. This cellular response involves nuclear antiviral factors targeting incoming viral genomes. Herpes simplex virus 1 (HSV-1) is the best-studied model in this context, and it was shown that upon nuclear entry HSV-1 genomes are immediately targeted by components of promyelocytic leukemia nuclear bodies (PML-NBs) and the nuclear DNA sensor IFI16 (interferon gamma inducible protein 16). Based on HSV-1 studies, together with limited examples in other viral systems, these phenomena are widely believed to be a common cellular response to incoming viral genomes, although formal evidence for each virus is lacking. Indeed, recent studies suggest that the case may be different for adenovirus infection. Here we summarize the existing experimental evidence for the roles of nuclear antiviral factors against incoming viral genomes to better understand cellular responses on a virus-by-virus basis. We emphasize that cells seem to respond differently to different incoming viral genomes and discuss possible arguments for and against a unifying cellular mechanism targeting the incoming genomes of different virus families. PMID- 27782083 TI - Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies. AB - Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data. PMID- 27782086 TI - Laurus nobilis, Zingiber officinale and Anethum graveolens Essential Oils: Composition, Antioxidant and Antibacterial Activities against Bacteria Isolated from Fish and Shellfish. AB - Several bacterial strains were isolated from wild and reared fish and shellfish. The identification of these strains showed the dominance of the Aeromonas hydrophila species in all seafood samples, followed by Staphylococcus spp., Vibrio alginolyticus, Enterobacter cloacae, Klebsiella ornithinolytica, Klebsiella oxytoca and Serratia odorifera. The isolates were studied for their ability to produce exoenzymes and biofilms. The chemical composition of the essential oils from Laurus nobilis leaves, Zingiber officinale rhizomes and Anethum graveolens aerial parts was studied by GC and GC/MS. The essential oils' antioxidant and antibacterial activities against the isolated microorganisms were studied. Low concentrations of the three essential oils were needed to inhibit the growth of the selected bacteria and the lowest MBCs values were obtained for the laurel essential oil. The selected essential oils can be used as a good natural preservative in fish food due to their antioxidant and antibacterial activities. PMID- 27782087 TI - A Nanoporous Alumina Membrane Based Electrochemical Biosensor for Histamine Determination with Biofunctionalized Magnetic Nanoparticles Concentration and Signal Amplification. AB - Histamine is an indicator of food quality and indispensable in the efficient functioning of various physiological systems. Rapid and sensitive determination of histamine is urgently needed in food analysis and clinical diagnostics. Traditional histamine detection methods require qualified personnel, need complex operation processes, and are time-consuming. In this study, a biofunctionalized nanoporous alumina membrane based electrochemical biosensor with magnetic nanoparticles (MNPs) concentration and signal amplification was developed for histamine determination. Nanoporous alumina membranes were modified by anti histamine antibody and integrated into polydimethylsiloxane (PDMS) chambers. The specific antibody modified MNPs were used to concentrate histamine from samples and transferred to the antibody modified nanoporous membrane. The MNPs conjugated to histamine were captured in the nanopores via specific reaction between histamine and anti-histamine antibody, resulting in a blocking effect that was amplified by MNPs in the nanopores. The blockage signals could be measured by electrochemical impedance spectroscopy across the nanoporous alumina membrane. The sensing platform had great sensitivity and the limit of detection (LOD) reached as low as 3 nM. This biosensor could be successfully applied for histamine determination in saury that was stored in frozen conditions for different hours, presenting a potentially novel, sensitive, and specific sensing system for food quality assessment and safety support. PMID- 27782084 TI - Measles to the Rescue: A Review of Oncolytic Measles Virus. AB - Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and "blinding" the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated. PMID- 27782088 TI - Experimental Study on Damage Detection in Timber Specimens Based on an Electromechanical Impedance Technique and RMSD-Based Mahalanobis Distance. AB - In the electromechanical impedance (EMI) method, the PZT patch performs the functions of both sensor and exciter. Due to the high frequency actuation and non model based characteristics, the EMI method can be utilized to detect incipient structural damage. In recent years EMI techniques have been widely applied to monitor the health status of concrete and steel materials, however, studies on application to timber are limited. This paper will explore the feasibility of using the EMI technique for damage detection in timber specimens. In addition, the conventional damage index, namely root mean square deviation (RMSD) is employed to evaluate the level of damage. On that basis, a new damage index, Mahalanobis distance based on RMSD, is proposed to evaluate the damage severity of timber specimens. Experimental studies are implemented to detect notch and hole damage in the timber specimens. Experimental results verify the availability and robustness of the proposed damage index and its superiority over the RMSD indexes. PMID- 27782089 TI - Plantar Pressure Detection with Fiber Bragg Gratings Sensing System. AB - In this paper, a novel fiber-optic sensing system based on fiber Bragg gratings (FBGs) to measure foot plantar pressure is proposed. This study first explores the Pedar-X insole foot pressure types of the adult-size chart and then defines six measurement areas to effectively identify four foot types: neutral foot, cavus foot, supinated foot and flat foot. The plantar pressure signals are detected by only six FBGs, which are embedded in silicone rubber. The performance of the fiber optic sensing is examined and compared with a digital pressure plate of i-Step P1000 with 1024 barometric sensors. In the experiment, there are 11 participants with different foot types to participate in the test. The Pearson correlation coefficient, which is determined from the measured results of the homemade fiber-optic plantar pressure system and i-Step P1000 plantar pressure plate, reaches up to 0.671 (p < 0.01). According to the measured results from the plantar pressure data, the proposed fiber optic sensing system can successfully identify the four different foot types. Measurements of this study have demonstrated the feasibility of the proposed system so that it can be an alternative for plantar pressure detection systems. PMID- 27782085 TI - Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria. AB - Bacterial toxin-antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein-protein interactions. Accumulating knowledge about the structure-function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems. PMID- 27782091 TI - An Improved Map-Matching Technique Based on the Frechet Distance Approach for Pedestrian Navigation Services. AB - Wearable and smartphone technology innovations have propelled the growth of Pedestrian Navigation Services (PNS). PNS need a map-matching process to project a user's locations onto maps. Many map-matching techniques have been developed for vehicle navigation services. These techniques are inappropriate for PNS because pedestrians move, stop, and turn in different ways compared to vehicles. In addition, the base map data for pedestrians are more complicated than for vehicles. This article proposes a new map-matching method for locating Global Positioning System (GPS) trajectories of pedestrians onto road network datasets. The theory underlying this approach is based on the Frechet distance, one of the measures of geometric similarity between two curves. The Frechet distance approach can provide reasonable matching results because two linear trajectories are parameterized with the time variable. Then we improved the method to be adaptive to the positional error of the GPS signal. We used an adaptation coefficient to adjust the search range for every input signal, based on the assumption of auto-correlation between consecutive GPS points. To reduce errors in matching, the reliability index was evaluated in real time for each match. To test the proposed map-matching method, we applied it to GPS trajectories of pedestrians and the road network data. We then assessed the performance by comparing the results with reference datasets. Our proposed method performed better with test data when compared to a conventional map-matching technique for vehicles. PMID- 27782090 TI - Association of the Host Immune Response with Protection Using a Live Attenuated African Swine Fever Virus Model. AB - African swine fever (ASF) is a lethal hemorrhagic disease of swine caused by a double-stranded DNA virus, ASF virus (ASFV). There is no vaccine to prevent the disease and current control measures are limited to culling and restricting animal movement. Swine infected with attenuated strains are protected against challenge with a homologous virulent virus, but there is limited knowledge of the host immune mechanisms generating that protection. Swine infected with Pretoriuskop/96/4 (Pret4) virus develop a fatal severe disease, while a derivative strain lacking virulence-associated gene 9GL (Pret4Delta9GL virus) is completely attenuated. Swine infected with Pret4Delta9GL virus and challenged with the virulent parental virus at 7, 10, 14, 21, and 28 days post infection (dpi) showed a progressive acquisition of protection (from 40% at 7 dpi to 80% at 21 and 28 dpi). This animal model was used to associate the presence of host immune response (ASFV-specific antibody and interferon (IFN)-gamma responses, or specific cytokine profiles) and protection against challenge. With the exception of ASFV-specific antibodies in survivors challenged at 21 and 28 dpi, no association between the parameters assessed and protection could be established. These results, encompassing data from 65 immunized swine, underscore the complexity of the system under study, suggesting that protection relies on the concurrence of different host immune mechanisms. PMID- 27782093 TI - Effects of Hyponatremia Normalization on the Short-Term Mortality and Rehospitalizations in Patients with Recent Acute Decompensated Heart Failure: A Retrospective Study. AB - Background: Several studies have shown that hyponatremia is associated with increased risk of rehospitalization and death in patients with heart failure. In these studies, chronic heart failure (CHF) patients with persistent hyponatremia were compared only with CHF patients with a normal sodium level at hospital admission. Aims: In the present retrospective study, conducted in a cohort of patients with recent acute decompensated heart failure (ADHF), all with hyponatremia ascertained at the time of hospital admission, we aimed to evaluate the effect of the normalization of serum sodium on the composite endpoint of short-term rehospitalization and mortality. Methods: A retrospective study centered on medical records of patients hospitalized for ADHF in the period April 2013 to April 2016 was performed. Data regarding serum sodium measurements had to be collected from medical records of cardiology wards of two hospitals, and were then processed for statistical analysis. As an inclusion criterion for enrollment, patients had to be suffering from heart failure that had required at least one hospitalization. Moreover, they had to be suffering from a state of hyponatremia (serum sodium < 135 mEq/L) at admission on the occasion of the index hospitalization. Patients with hyponatremia at admission were divided into two groups, one comprising patients with hyponatremia that persisted at the time of discharge (persistent hyponatremia) and a second including patients who had achieved normalization of their serum sodium levels (serum Na+ >= 135 mEq/L) during hospitalization until discharge. For both groups, the risk of mortality and rehospitalization during a 30-day follow-up was assessed. Results: One hundred and sixty CHF patients with various degrees of functional impairment were enrolled in the study. Among them, 56 (35%) had persistent hyponatremia over the course of hospitalization. At multivariable Cox proportional-hazards regression analysis, the risk of having a 30-day unplanned readmission or death was significantly higher in patients with persistent hyponatremia compared to those who exhibited a sodium level normalized at discharge (adjusted hazard ratio = 3.0743; 95% CI: 1.3981-6.7601; p = 0.0054). Among the other variables included in the Cox regression model, the number of admissions in the last 12 months (p < 0.0001), the length of stay of the index admission (p = 0.0015) and the New York Heart Association (NYHA) class III at discharge (p = 0.0022) were also identified as risk factors associated with the composite endpoint of 30-day unplanned readmission or death. Conclusions: In the present retrospective study, the risk of 30-day rehospitalization or death was significantly higher in patients with recent ADHF and persistent hyponatremia in comparison with ADHF patients who had had their serum sodium normalized during the hospital stay. This association seemed to be independent of the heart failure severity. PMID- 27782092 TI - Annexin-1 Mediates Microglial Activation and Migration via the CK2 Pathway during Oxygen-Glucose Deprivation/Reperfusion. AB - Annexin-1 (ANXA1) has shown neuroprotective effects and microglia play significant roles during central nervous system injury, yet the underlying mechanisms remain unclear. This study sought to determine whether ANXA1 regulates microglial response to oxygen-glucose deprivation/reperfusion (OGD/R) treatment and to clarify the downstream molecular mechanism. In rat hippocampal slices, OGD/R treatment enhanced the ANXA1 expression in neuron, the formyl peptide receptor (FPRs) expression in microglia, and the microglial activation in the CA1 region (cornu ammonis 1). These effects were reversed by the FPRs antagonist Boc1. The cell membrane currents amplitude of BV-2 microglia (the microglial like cell-line) was increased when treated with Ac2-26, the N-terminal peptide of ANXA1. Ac2-26 treatment enhanced BV-2 microglial migration whereas Boc1 treatment inhibited the migration. In BV-2 microglia, both the expression of the CK2 target phosphorylated alpha-E-catenin and the binding of casein kinase II (CK2) with alpha-E-catenin were elevated by Ac2-26, these effects were counteracted by the CK2 inhibitor TBB and small interfering (si) RNA directed against transcripts of CK2 and FPRs. Moreover, both TBB and siRNA-mediated inhibition of CK2 blocked Ac2 26-mediated BV-2 microglia migration. Our findings indicate that ANXA1 promotes microglial activation and migration during OGD/R via FPRs, and CK2 target alpha-E catenin phosphorylation is involved in this process. PMID- 27782095 TI - Underwater Communications for Video Surveillance Systems at 2.4 GHz. AB - Video surveillance is needed to control many activities performed in underwater environments. The use of wired media can be a problem since the material specially designed for underwater environments is very expensive. In order to transmit the images and videos wirelessly under water, three main technologies can be used: acoustic waves, which do not provide high bandwidth, optical signals, although the effect of light dispersion in water severely penalizes the transmitted signals and therefore, despite offering high transfer rates, the maximum distance is very small, and electromagnetic (EM) waves, which can provide enough bandwidth for video delivery. In the cases where the distance between transmitter and receiver is short, the use of EM waves would be an interesting option since they provide high enough data transfer rates to transmit videos with high resolution. This paper presents a practical study of the behavior of EM waves at 2.4 GHz in freshwater underwater environments. First, we discuss the minimum requirements of a network to allow video delivery. From these results, we measure the maximum distance between nodes and the round trip time (RTT) value depending on several parameters such as data transfer rate, signal modulations, working frequency, and water temperature. The results are statistically analyzed to determine their relation. Finally, the EM waves' behavior is modeled by a set of equations. The results show that there are some combinations of working frequency, modulation, transfer rate and temperature that offer better results than others. Our work shows that short communication distances with high data transfer rates is feasible. PMID- 27782096 TI - GNSS Spoofing Network Monitoring Based on Differential Pseudorange. AB - Spoofing is becoming a serious threat to various Global Navigation Satellite System (GNSS) applications, especially for those that require high reliability and security such as power grid synchronization and applications related to first responders and aviation safety. Most current works on anti-spoofing focus on spoofing detection from the individual receiver side, which identifies spoofing when it is under an attack. This paper proposes a novel spoofing network monitoring (SNM) mechanism aiming to reveal the presence of spoofing within an area. Consisting of several receivers and one central processing component, it keeps detecting spoofing even when the network is not attacked. The mechanism is based on the different time difference of arrival (TDOA) properties between spoofing and authentic signals. Normally, TDOAs of spoofing signals from a common spoofer are identical while those of authentic signals from diverse directions are dispersed. The TDOA is measured as the differential pseudorange to carrier frequency ratio (DPF). In a spoofing case, the DPFs include those of both authentic and spoofing signals, among which the DPFs of authentic are dispersed while those of spoofing are almost overlapped. An algorithm is proposed to search for the DPFs that are within a pre-defined small range, and an alarm will be raised if several DPFs are found within such range. The proposed SNM methodology is validated by simulations and a partial field trial. Results show 99.99% detection and 0.01% false alarm probabilities are achieved. The SNM has the potential to be adopted in various applications such as (1) alerting dedicated users when spoofing is occurring, which could significantly shorten the receiver side spoofing cost; (2) in combination with GNSS performance monitoring systems, such as the Continuous Operating Reference System (CORS) and GNSS Availability, Accuracy, Reliability anD Integrity Assessment for Timing and Navigation (GAARDIAN) System, to provide more reliable monitoring services. PMID- 27782094 TI - Photodynamic Therapy and Non-Melanoma Skin Cancer. AB - Non-melanoma skin cancer (NMSC) is the most common malignancy among the Caucasian population. Photodynamic therapy (PDT) is gaining popularity for the treatment of basal cell carcinoma (BCC), Bowen's disease (BD) and actinic keratosis (AK). A topical or systemic exogenous photosensitiser, results in selective uptake by malignant cells. Protoporphyrin IX (PpIX) is produced then activated by the introduction of a light source. Daylight-mediated MAL (methyl aminolaevulinate) PDT for AKs has the advantage of decreased pain and better patient tolerance. PDT is an effective treatment for superficial BCC, BD and both individual and field treatment of AKs. Excellent cosmesis can be achieved with high patient satisfaction. Variable results have been reported for nodular BCC, with improved outcomes following pretreatment and repeated PDT cycles. The more aggressive basisquamous, morphoeic infiltrating subtypes of BCC and invasive squamous cell carcinoma (SCC) are not suitable for PDT. Prevention of "field cancerization" in organ transplant recipients on long-term immunosuppression and patients with Gorlin syndrome (naevoid basal cell carcinoma syndrome) is a promising development. The optimisation of PDT techniques with improved photosensitiser delivery to target tissues, new generation photosensitisers and novel light sources may expand the future role of PDT in NMSC management. PMID- 27782097 TI - Association between Low Dietary Protein Intake and Geriatric Nutrition Risk Index in Patients with Chronic Kidney Disease: A Retrospective Single-Center Cohort Study. AB - Reduced dietary protein intake in malnourished patients with chronic kidney disease (CKD) may be associated with adverse clinical outcomes, which may mask any efficacy of a low-protein diet. The study included 126 patients with CKD who attended a dedicated dietary counseling clinic in 2005-2009 and were systematically followed until January 2015. Of these patients, 20 (15.9%) had moderate or severe nutrition-related risk of geriatric nutritional risk index (GNRI) < 92; these patients were more likely to be older, have a greater proteinuria, and have lower body mass index and serum albumin concentration. Dietary protein intake was significantly lower in older patients (r = -0.33, p < 0.001) and those with lower glomerular filtration rate (r = 0.47, p < 0.001). The non-protein to nitrogen calorie ratio was independently associated with GNRI. Reduced GNRI was significantly associated with mortality (hazard ratio (HR) = 4.94; 95% confidence interval (CI) = 1.61-15.42, p = 0.012) and cardiovascular events (HR = 9.37; 95% CI = 2.49-37.34, p = 0.006), but not with adverse renal outcomes. Restricting protein intake may be harmful to patients with any nutrition-related risk, suggesting that improvement of nutritional status should be a high priority. PMID- 27782098 TI - Does Human Milk Modulate Body Composition in Late Preterm Infants at Term Corrected Age? AB - (1) Background: Late preterm infants account for the majority of preterm births and are at risk of altered body composition. Because body composition modulates later health outcomes and human milk is recommended as the normal method for infant feeding, we sought to investigate whether human milk feeding in early life can modulate body composition development in late preterm infants; (2) Methods: Neonatal, anthropometric and feeding data of 284 late preterm infants were collected. Body composition was evaluated at term-corrected age by air displacement plethysmography. The effect of human milk feeding on fat-free mass and fat mass content was evaluated using multiple linear regression analysis; (3) Results: Human milk was fed to 68% of the infants. According to multiple regression analysis, being fed any human milk at discharge and at term-corrected and being fed exclusively human milk at term-corrected age were positively associated with fat-free mass content(beta = -47.9, 95% confidence interval (CI) = -95.7; -0.18; p = 0.049; beta = -89.6, 95% CI = -131.5; -47.7; p < 0.0001; beta = -104.1, 95% CI = -151.4; -56.7, p < 0.0001); (4) Conclusion: Human milk feeding appears to be associated with fat-free mass deposition in late preterm infants. Healthcare professionals should direct efforts toward promoting and supporting breastfeeding in these vulnerable infants. PMID- 27782099 TI - Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5 dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors. AB - Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6 dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6 (2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30.2 nM. PMID- 27782100 TI - Isobutylhydroxyamides from Zanthoxylum bungeanum and Their Suppression of NO Production. AB - Four new unsaturated aliphatic acid amides, named zanthoamides A-D (1-4), and eight known ones-tetrahydrobungeanool (5), ZP-amide A (6), ZP-amide B (7), ZP amide C (8), ZP-amide D (9), ZP-amide E (10), bugeanumamide A (11), and (2E,7E,9E)-N-(2-hydroxy-2-methylpropyl)-6,11-dioxo-2,7,9-dodecatrienamide (12) were isolated from the pericarps of Zanthoxylum bungeanum. The structures of these compounds were elucidated by extensive use of spectroscopic methods, including HRESIMS, 1D and 2D NMR analyses and comparison with previously reported data. Compound 4 contained a rare C6 fatty acid unit with an acetal group. Results revealed that compounds 1, 5, 6, and 12 showed inhibitory effects on nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages, with IC50values of 48.7 +/- 0.32, 27.1 +/- 1.15, 49.8 +/- 0.38, and 39.4 +/- 0.63 uM, respectively, while the other compounds were inactive (IC50 > 60 MUM). They could contribute to the anti-inflammatory effects of Z. bungeanum by suppression of NO production. PMID- 27782101 TI - Angiotensin II Promotes the Development of Carotid Atherosclerosis in Type 2 Diabetes Patients via Regulating the T Cells Activities: A Cohort Study. AB - BACKGROUND Specific T cell phenotype has been reported to potentially contribute to the development of angiotensin II (Ang II)-induced several vascular disorders. Type 2 diabetes mellitus (T2DM) is intimately associated with cardiovascular disease. The present study aimed to investigate the relationship between T cell phenotypes and Ang II in T2DM patients combined with carotid atherosclerosis (CA). MATERIAL AND METHODS This study was performed on 50 patients with T2DM in our hospital. Based on the presence of CA, they were divided into CA group (presence of CA, n=30) or T2DM group (absence of CA, n=20). Additionally, 10 healthy participants were selected as controls. Basic characteristics of all participants were collected and recorded. Peripheral blood mononuclear cells (PBMCs) isolated from patients and controls with or without Ang II and Ang II receptor blocker (ARB) treatment were used to detect Th1, Th2, and Th17 cell proportions, mRNA levels of T-bet, GATA3, and RORgammat as well as the expression of IFN-gamma, IL-4, and IL-17 by flow cytometry, ELISA, and Real-Time PCR. RESULTS Ang II levels were notably higher in patients in the CA group than those in the T2DM and control group (p<0.05). Th1 and Th17 positive cells, mRNA levels of T-bet and RORgt as well as the expression of IFN-gamma and IL-17 were significantly increased in the CA group compared with the T2DM group and control group (p<0.05). Moreover, the activities of T cells and related cytokines were significantly increased of healthy controls after Ang II treatment (p<0.05), while these changes were notably weakened by ARB treatment (p<0.05). CONCLUSIONS Ang II promotes the development of CA in T2DM patients by regulating T cells activities. PMID- 27782103 TI - The Southampton-York Natural Scenes (SYNS) dataset: Statistics of surface attitude. AB - Recovering 3D scenes from 2D images is an under-constrained task; optimal estimation depends upon knowledge of the underlying scene statistics. Here we introduce the Southampton-York Natural Scenes dataset (SYNS: https://syns.soton.ac.uk), which provides comprehensive scene statistics useful for understanding biological vision and for improving machine vision systems. In order to capture the diversity of environments that humans encounter, scenes were surveyed at random locations within 25 indoor and outdoor categories. Each survey includes (i) spherical LiDAR range data (ii) high-dynamic range spherical imagery and (iii) a panorama of stereo image pairs. We envisage many uses for the dataset and present one example: an analysis of surface attitude statistics, conditioned on scene category and viewing elevation. Surface normals were estimated using a novel adaptive scale selection algorithm. Across categories, surface attitude below the horizon is dominated by the ground plane (0 degrees tilt). Near the horizon, probability density is elevated at 90 degrees /270 degrees tilt due to vertical surfaces (trees, walls). Above the horizon, probability density is elevated near 0 degrees slant due to overhead structure such as ceilings and leaf canopies. These structural regularities represent potentially useful prior assumptions for human and machine observers, and may predict human biases in perceived surface attitude. PMID- 27782104 TI - Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation. AB - The exceptionally large SYNE1 (spectrin repeat-containing nuclear envelope protein 1) gene encodes different nesprin-1 isoforms, which are differentially expressed in striated muscle and in cerebellar and cerebral neurons. Nesprin-1 isoforms can function in cytoskeletal, nuclear, and vesicle anchoring. SYNE1 variants have been associated with a spectrum of neurological and neuromuscular disease. Homozygosity mapping combined with exome sequencing identified a disease causing nonsense mutation in the ultimate exon of full-length SYNE1 transcript in an 8-year-old boy with distal arthrogryposis and muscular hypotonia. mRNA analysis showed that the mutant transcript is expressed at wild-type levels. The variant truncates nesprin-1 isoforms for the C-terminal KASH (Klarsicht-ANC-Syne homology) domain. This is the third family with recessive arthrogryposis caused by homozygous distal-truncating SYNE1 variants. There is a SYNE1 genotype phenotype correlation emerging, with more proximal homozygous SYNE1 variants causing recessive cerebellar ataxia of variable onset (SCAR8; ARCA-1). PMID- 27782102 TI - Disulfide-activated protein kinase G Ialpha regulates cardiac diastolic relaxation and fine-tunes the Frank-Starling response. AB - The Frank-Starling mechanism allows the amount of blood entering the heart from the veins to be precisely matched with the amount pumped out to the arterial circulation. As the heart fills with blood during diastole, the myocardium is stretched and oxidants are produced. Here we show that protein kinase G Ialpha (PKGIalpha) is oxidant-activated during stretch and this form of the kinase selectively phosphorylates cardiac phospholamban Ser16-a site important for diastolic relaxation. We find that hearts of Cys42Ser PKGIalpha knock-in (KI) mice, which are resistant to PKGIalpha oxidation, have diastolic dysfunction and a diminished ability to couple ventricular filling with cardiac output on a beat to-beat basis. Intracellular calcium dynamics of ventricular myocytes isolated from KI hearts are altered in a manner consistent with impaired relaxation and contractile function. We conclude that oxidation of PKGIalpha during myocardial stretch is crucial for diastolic relaxation and fine-tunes the Frank-Starling response. PMID- 27782105 TI - Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy. AB - Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy. PMID- 27782106 TI - A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder with a range of cardiovascular, skeletal, craniofacial and cutaneous manifestations. LDS type 4 is caused by mutations in TGFbeta ligand 2 (TGFB2) and based on the family pedigrees described to date, appears to have a milder clinical phenotype, often presenting with isolated aortic disease. We sought to investigate its molecular basis in a new pedigree. We identified a missense variant p.(Arg320Cys) (NM_003238.3) in a highly evolutionary conserved region of TGFB2 in a new LDS type 4 pedigree with multiple cases of aortic aneurysms and dissections. There was striking upregulation of TGFB1 and TGFB2 expression on immunofluorescent staining, and western blotting of the aortic tissue from the index case confirming the functional importance of the variant. This case highlights the striking paradox of predicted loss-of-function mutations in TGFB2 causing enhanced TGFbeta signaling in this emerging familial aortopathy. PMID- 27782107 TI - 'IRDiRC Recognized Resources': a new mechanism to support scientists to conduct efficient, high-quality research for rare diseases. AB - The International Rare Diseases Research Consortium (IRDiRC) has created a quality label, 'IRDiRC Recognized Resources', formerly known as 'IRDiRC Recommended'. It is a peer-reviewed quality indicator process established based on the IRDiRC Policies and Guidelines to designate resources (ie, standards, guidelines, tools, and platforms) designed to accelerate the pace of discoveries and translation into clinical applications for the rare disease (RD) research community. In its first year of implementation, 13 resources successfully applied for this designation, each focused on key areas essential to IRDiRC objectives and to the field of RD research more broadly. These included data sharing for discovery, knowledge organisation and ontologies, networking patient registries, and therapeutic development. 'IRDiRC Recognized Resources' is a mechanism aimed to provide community-approved contributions to RD research higher visibility, and encourage researchers to adopt recognised standards, guidelines, tools, and platforms that facilitate research advances guided by the principles of interoperability and sharing. PMID- 27782108 TI - Whole-exome sequencing of Finnish hereditary breast cancer families. AB - A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16-2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC related pathways and an excellent premise for future studies. PMID- 27782109 TI - Joint association analysis of a binary and a quantitative trait in family samples. AB - In recent years, improved genotyping and sequencing technologies have enabled the discovery of new loci associated with various diseases or traits. For instance, by testing the association with each single-nucleotide variant (SNV) separately, genome-wide association studies (GWAS) have achieved tremendous success in identifying SNVs associated with specific traits. However, little is known about the common genetic basis of multiple traits owing to lack of efficient methods. With the use of extended quasi-likelihood, a Wald test has been proposed to perform a bivariate analysis of a continuous and a binary trait in unrelated samples. However, owing to its low computational efficiency, it has not been implemented in real applications to large-scale genetic studies. In this paper, we propose an efficient bivariate robust score test for two traits, one continuous and one binary, based on extended generalized estimating equations. Our approach is applicable to both family-based and unrelated study designs and can be extended to test the association of multiple traits. Our simulation studies demonstrate the type-I error rate of our approach is well controlled in all minor allele frequency (MAF) scenarios, with MAF ranging from 1 to 30%, and the method is more powerful in certain MAF scenarios than univariate testing with correction for multiple testing. Because of the computational advantage of score tests, our approach is readily applicable to GWAS or sequencing studies. Finally, we present a real application to uncover genetic variants associated with body mass index and type-2 diabetes in the Framingham Heart Study. PMID- 27782110 TI - Multi-omic data integration enables discovery of hidden biological regularities. AB - Rapid growth in size and complexity of biological data sets has led to the 'Big Data to Knowledge' challenge. We develop advanced data integration methods for multi-level analysis of genomic, transcriptomic, ribosomal profiling, proteomic and fluxomic data. First, we show that pairwise integration of primary omics data reveals regularities that tie cellular processes together in Escherichia coli: the number of protein molecules made per mRNA transcript and the number of ribosomes required per translated protein molecule. Second, we show that genome scale models, based on genomic and bibliomic data, enable quantitative synchronization of disparate data types. Integrating omics data with models enabled the discovery of two novel regularities: condition invariant in vivo turnover rates of enzymes and the correlation of protein structural motifs and translational pausing. These regularities can be formally represented in a computable format allowing for coherent interpretation and prediction of fitness and selection that underlies cellular physiology. PMID- 27782113 TI - Association between lutein intake and lutein concentrations in human milk samples from lactating mothers in South Korea. PMID- 27782112 TI - Donor polymer design enables efficient non-fullerene organic solar cells. AB - To achieve efficient organic solar cells, the design of suitable donor-acceptor couples is crucially important. State-of-the-art donor polymers used in fullerene cells may not perform well when they are combined with non-fullerene acceptors, thus new donor polymers need to be developed. Here we report non-fullerene organic solar cells with efficiencies up to 10.9%, enabled by a novel donor polymer that exhibits strong temperature-dependent aggregation but with intentionally reduced polymer crystallinity due to the introduction of a less symmetric monomer unit. Our comparative study shows that an analogue polymer with a C2 symmetric monomer unit yields highly crystalline polymer films but less efficient non-fullerene cells. Based on a monomer with a mirror symmetry, our best donor polymer exhibits reduced crystallinity, yet such a polymer matches better with small molecular acceptors. This study provides important insights to the design of donor polymers for non-fullerene organic solar cells. PMID- 27782111 TI - Inflammatory cues enhance TGFbeta activation by distinct subsets of human intestinal dendritic cells via integrin alphavbeta8. AB - Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-beta (TGFbeta), which is secreted by cells as a latent complex that requires activation to function. However, how TGFbeta activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFbeta, integrin alphavbeta8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c+ but not the CD141+ intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGFbeta-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin alphavbeta8 expression and TGFbeta activation by human DC. We also show that DC expression of integrin alphavbeta8 enhanced induction of FOXP3 in CD4+ T cells, suggesting functional importance of integrin alphavbeta8 expression by human DC. These results show that microbial signals enhance the TGFbeta-activating ability of human DC via regulation of integrin alphavbeta8 expression, and that intestinal inflammation may drive this pathway in patients with IBD. PMID- 27782114 TI - Less-than-expected weight loss in normal-weight women undergoing caloric restriction and exercise is accompanied by preservation of fat-free mass and metabolic adaptations. AB - BACKGROUND/OBJECTIVES: Normal-weight women frequently restrict their caloric intake and exercise, but little is known about the effects on body weight, body composition and metabolic adaptations in this population. SUBJECTS/METHODS: We conducted a secondary analysis of data from a randomized controlled trial in sedentary normal-weight women. Women were assigned to a severe energy deficit (SEV: -1062+/-80 kcal per day; n=9), a moderate energy deficit (MOD: -633+/-71 kcal per day; n=7) or energy balance (BAL; n=9) while exercising five times per week for 3 months. Outcome variables included changes in body weight, body composition, resting metabolic rate (RMR) and metabolic hormones associated with energy conservation. RESULTS: Weight loss occurred in SEV (-3.7+/-0.9 kg, P<0.001) and MOD (-2.7+/-0.8 kg; P=0.003), but weight loss was significantly less than predicted (SEV: -11.1+/-1.0 kg; MOD: -6.5+/-1.1 kg; both P<0.001 vs actual). Fat mass declined in SEV (P<0.001) and MOD (P=0.006), whereas fat-free mass remained unchanged in all groups (P>0.33). RMR decreased by -6+/-2% in MOD (P=0.020). In SEV, RMR did not change on a group level (P=0.66), but participants whose RMR declined lost more weight (P=0.020) and had a higher baseline RMR (P=0.026) than those whose RMR did not decrease. Characteristic changes in leptin (P=0.003), tri-iodothyronine (P=0.013), insulin-like growth factor-1 (P=0.016) and ghrelin (P=0.049) occurred only in SEV. The energy deficit and adaptive changes in RMR explained 54% of the observed weight loss. CONCLUSIONS: In normal weight women, caloric restriction and exercise resulted in less-than-predicted weight loss. In contrast to previous literature, weight loss consisted almost exclusively of fat mass, whereas fat-free mass was preserved. PMID- 27782115 TI - Body mass index and the risk of all-cause mortality among patients with nonvalvular atrial fibrillation: a multicenter prospective observational study in China. AB - BACKGROUND/OBJECTIVES: High body mass index (BMI) is associated with increased incident atrial fibrillation (AF) and mortality rate. In patients presenting with nonvalvular AF (NVAF), the prognostic relevance of BMI remains unclear. SUBJECTS/METHODS: In this prospective observational study, a total of 1759 patients with NVAF (69.9+/-12.9 years old, 47.9% male) were divided into three clinical settings according to estimated stroke risks (CHADS2 score ?1 (low), =2 (moderate) and ?3 (high)). The primary outcome was all-cause mortality, and the secondary outcomes included thromboembolism and major bleeding. Cox-proportional hazard models were used to estimate the association between BMI levels and clinical outcomes. RESULTS: During a mean follow-up of 1 year representing 1974 patient-years at risk, 256 patients died, 142 suffered from thromboembolism and 17 developed major bleeding. Multivariate adjusted Cox analysis indicated that a BMI of 24.0-27.9 kg/m2 was independently associated with improved survival among all patients (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.512-0.928; P=0.018) and patients at high stroke risk (HR 0.622, 95% CI 0.410-0.943; P=0.024), but not among those at low or moderate stroke risks. No associations were observed between BMI levels and the incidence of thromboembolic events in various clinical settings. CONCLUSIONS: A paradoxical BMI-all-cause mortality risk association was observed in Chinese patients with NVAF, and this association was pronounced among patients at high stroke risk rather than in those at low stroke risk. PMID- 27782116 TI - Screening for muscle loss in patients established on peritoneal dialysis using bioimpedance. AB - : Background/objectivesKidney dialysis patients with sarcopenia have increased mortality. Screening for low muscle mass may allow interventions at an earlier stage to help improve outcomes. We wished to determine the prevalence of low muscle mass in a cohort of peritoneal dialysis (PD) patients.Subjects/methodsWe measured lean body mass index (LBMI) in 490 PD patients by bioimpedance, grading patients using two different classifications of sarcopenia. RESULTS: LBMI was 9.7+/-1.9 kg/m2, mean age was 55.3+/-16.4 years, 53.1% were male, 33.7% were diabetic and 51% were Caucasoid. 98.5% of patients were classified as having sarcopenia based on LBMI cutoffs from NHANES data, whereas 28.8% had moderate and 6.3% severe sarcopenia using a grading correlated with functional disability. Lower muscle mass was associated with increasing co-morbidity (beta=0.34, P=0.02) and age (beta=0.01, P=0.006), and negatively with body mass index (beta=-0.23, P<0.001), log serum creatinine (beta=-0.231, P<0.001), normalised protein nitrogen appearance (beta=-1.33, P<0.001) and log urine volume (beta=-0.28, P=0.002). There was no association with duration of PD, dialysis prescription, residual renal function or solute clearances. CONCLUSIONS: There is currently no agreed universal definition for sarcopenia, and prevalence varied markedly depending on the scoring system. Prevalence was not associated with small solute clearances, but was associated with sex, age co-morbidity, BMI and ethnicity. There was an association with dietary protein intake and urine volume, which may allow for dietary interventions and strategies to preserve urine output to reduce muscle loss in PD patients. PMID- 27782117 TI - Detection of genetic incompatibilities in non-model systems using simple genetic markers: hybrid breakdown in the haplodiploid spider mite Tetranychus evansi. AB - When two related species interbreed, their hybrid offspring frequently suffer from reduced fitness. The genetics of hybrid incompatibility are described by the Bateson-Dobzhansky-Muller (BDM) model, where fitness is reduced by epistatic interactions between alleles of heterospecific origin. Unfortunately, most empirical evidence for the BDM model comes from a few well-studied model organisms, restricting our genetic understanding of hybrid incompatibilities to limited taxa. These systems are predominantly diploid and incompatibility is often complete, which complicates the detection of recessive allelic interactions and excludes the possibility to study viable or intermediate stages. Here, we advocate research into non-model organisms with haploid or haplodiploid reproductive systems and incomplete hybrid incompatibility because (1) dominance is absent in haploids and (2) incomplete incompatibility allows comparing affected with unaffected individuals. We describe a novel two-locus statistic specifying the frequency of individuals for which two alleles co-occur. This approach to studying BDM incompatibilities requires genotypic characterization of hybrid individuals, but not genetic mapping or genome sequencing. To illustrate our approach, we investigated genetic causes for hybrid incompatibility between differentiated lineages of the haplodiploid spider mite Tetranychus evansi, and show that strong, but incomplete, hybrid breakdown occurs. In addition, by comparing the genotypes of viable hybrid males and inviable hybrid male eggs for eight microsatellite loci, we show that nuclear and cytonuclear BDM interactions constitute the basis of hybrid incompatibility in this species. Our approach opens up possibilities to study BDM interactions in non-model taxa, and may give further insight into the genetic mechanisms behind hybrid incompatibility. PMID- 27782118 TI - An assessment of the reliability of quantitative genetics estimates in study systems with high rate of extra-pair reproduction and low recruitment. AB - Quantitative genetics approaches, and particularly animal models, are widely used to assess the genetic (co)variance of key fitness related traits and infer adaptive potential of wild populations. Despite the importance of precision and accuracy of genetic variance estimates and their potential sensitivity to various ecological and population specific factors, their reliability is rarely tested explicitly. Here, we used simulations and empirical data collected from an 11 year study on tree swallow (Tachycineta bicolor), a species showing a high rate of extra-pair paternity and a low recruitment rate, to assess the importance of identity errors, structure and size of the pedigree on quantitative genetic estimates in our dataset. Our simulations revealed an important lack of precision in heritability and genetic-correlation estimates for most traits, a low power to detect significant effects and important identifiability problems. We also observed a large bias in heritability estimates when using the social pedigree instead of the genetic one (deflated heritabilities) or when not accounting for an important cause of resemblance among individuals (for example, permanent environment or brood effect) in model parameterizations for some traits (inflated heritabilities). We discuss the causes underlying the low reliability observed here and why they are also likely to occur in other study systems. Altogether, our results re-emphasize the difficulties of generalizing quantitative genetic estimates reliably from one study system to another and the importance of reporting simulation analyses to evaluate these important issues. PMID- 27782119 TI - Evolution of nickel hyperaccumulation and serpentine adaptation in the Alyssum serpyllifolium species complex. AB - Metal hyperaccumulation is an uncommon but highly distinctive adaptation found in certain plants that can grow on metalliferous soils. Here we review what is known about evolution of metal hyperaccumulation in plants and describe a population genetic analysis of the Alyssum serpyllifolium (Brassicaceae) species complex that includes populations of nickel-hyperaccumulating as well as non-accumulating plants growing on serpentine (S) and non-serpentine (NS) soils, respectively. To test whether the S and NS populations belong to the same or separate closely related species, we analysed genetic variation within and between four S and four NS populations from across the Iberian peninsula. Based on microsatellites, genetic variation was similar in S and NS populations (average Ho=0.48). The populations were significantly differentiated from each other (overall FST=0.23), and the degree of differentiation between S and NS populations was similar to that within these two groups. However, high S versus NS differentiation was observed in DNA polymorphism of two genes putatively involved in adaptation to serpentine environments, IREG1 and NRAMP4, whereas no such differentiation was found in a gene (ASIL1) not expected to play a specific role in ecological adaptation in A. serpyllifolium. These results indicate that S and NS populations belong to the same species and that nickel hyperaccumulation in A. serpyllifolium appears to represent a case of adaptation to growth on serpentine soils. Further functional and evolutionary genetic work in this system has the potential to significantly advance our understanding of the evolution of metal hyperaccumulation in plants. PMID- 27782120 TI - Genetic hitchhiking and resistance evolution to transgenic Bt toxins: insights from the African stalk borer Busseola fusca (Noctuidae). AB - Since transgenic crops expressing Bacillus thuringiensis (Bt) toxins were first released, resistance evolution leading to failure in control of pests populations has been observed in a number of species. Field resistance of the moth Busseola fusca was acknowledged 8 years after Bt maize was introduced in South Africa. Since then, field resistance of this corn borer has been observed at several locations, raising questions about the nature, distribution and dynamics of the resistance trait. Using genetic markers, our study identified four outlier loci clearly associated with resistance. In addition, genetic structure at neutral loci reflected extensive gene flow among populations. A realistically parameterised model suggests that resistance could travel in space at speed of several kilometres a year. Markers at outlier loci delineated a geographic region associated with resistance spread. This was an area of approximately 100 km radius, including the location where resistance was first reported. Controlled crosses corroborated these findings and showed significant differences of progeny survival on Bt plants depending on the origin of the resistant parent. Last, our study suggests diverse resistance mutations, which would explain the widespread occurrence of resistant larvae in Bt fields across the main area of maize production in South Africa. PMID- 27782122 TI - Specific inhibition of ICAM-1 effectively reduces bladder inflammation in a rat model of severe non-bacterial cystitis. AB - The development and progression of bladder pain syndrome/interstitial cystitis (BPS/IC) is closely related to bladder inflammation. Intercellular adhesion molecule 1 (ICAM-1) is associated with bladder inflammation in BPS/IC. We investigated the effect of specific inhibition of ICAM-1 using an anti-ICAM-1 antibody (AIA) on bladder inflammation in a rat model of severe non-bacterial cystitis (NBC) resembling BPS/IC by evaluating the bladder inflammation grade, mast cell infiltration and related cytokines and receptors. We also compared the effects of AIA with the COX-2 inhibitor celecoxib and the neurokinin-1 receptor (NK1R) inhibitor aprepitant. Our NBC model was established by intraperitoneal injection of cyclophosphamide combined with intravesical protamine/lipopolysaccharide, which resulted in severe bladder inflammation and increased mast cell infiltration, similar to the pathological changes of BPS/IC. Inhibition of ICAM-1 by AIA significantly decreased the bladder inflammation grade and mast cell counts, which was accompanied by a reduction of purinergic receptors (P2X2/P2X3), prostaglandin E2, EP1/EP2 receptors, TNF-alpha, NK1R, and ICAM-1. Moreover, AIA showed superior effects to those of celecoxib and aprepitant treatment in improving the bladder inflammatory response. Our results suggest that ICAM-1 may play a critical role in bladder inflammation in severe NBC and may be used as a novel therapeutic target in non-bacterial bladder inflammation such as BPS/IC. PMID- 27782123 TI - Permanent ferroelectric retention of BiFeO3 mesocrystal. AB - Non-volatile electronic devices based on magnetoelectric multiferroics have triggered new possibilities of outperforming conventional devices for applications. However, ferroelectric reliability issues, such as imprint, retention and fatigue, must be solved before the realization of practical devices. In this study, everlasting ferroelectric retention in the heteroepitaxially constrained multiferroic mesocrystal is reported, suggesting a new approach to overcome the failure of ferroelectric retention. Studied by scanning probe microscopy and transmission electron microscopy, and supported via the phase-field simulations, the key to the success of ferroelectric retention is to prevent the crystal from ferroelastic deformation during the relaxation of the spontaneous polarization in a ferroelectric nanocrystal. PMID- 27782121 TI - De novo transcriptome assembly facilitates characterisation of fast-evolving gene families, MHC class I in the bank vole (Myodes glareolus). AB - The major histocompatibility complex (MHC) plays a central role in the adaptive immune response and is the most polymorphic gene family in vertebrates. Although high-throughput sequencing has increasingly been used for genotyping families of co-amplifying MHC genes, its potential to facilitate early steps in the characterisation of MHC variation in nonmodel organism has not been fully explored. In this study we evaluated the usefulness of de novo transcriptome assembly in characterisation of MHC sequence diversity. We found that although de novo transcriptome assembly of MHC I genes does not reconstruct sequences of individual alleles, it does allow the identification of conserved regions for PCR primer design. Using the newly designed primers, we characterised MHC I sequences in the bank vole. Phylogenetic analysis of the partial MHC I coding sequence (2-4 exons) of the bank vole revealed a lack of orthology to MHC I of other Cricetidae, consistent with the high gene turnover of this region. The diversity of expressed alleles was characterised using ultra-deep sequencing of the third exon that codes for the peptide-binding region of the MHC molecule. High allelic diversity was demonstrated, with 72 alleles found in 29 individuals. Interindividual variation in the number of expressed loci was found, with the number of alleles per individual ranging from 5 to 14. Strong signatures of positive selection were found for 8 amino acid sites, most of which are inferred to bind antigens in human MHC, indicating conservation of structure despite rapid sequence evolution. PMID- 27782125 TI - Time-resolved single dopant charge dynamics in silicon. AB - As the ultimate miniaturization of semiconductor devices approaches, it is imperative that the effects of single dopants be clarified. Beyond providing insight into functions and limitations of conventional devices, such information enables identification of new device concepts. Investigating single dopants requires sub-nanometre spatial resolution, making scanning tunnelling microscopy an ideal tool. However, dopant dynamics involve processes occurring at nanosecond timescales, posing a significant challenge to experiment. Here we use time resolved scanning tunnelling microscopy and spectroscopy to probe and study transport through a dangling bond on silicon before the system relaxes or adjusts to accommodate an applied electric field. Atomically resolved, electronic pump probe scanning tunnelling microscopy permits unprecedented, quantitative measurement of time-resolved single dopant ionization dynamics. Tunnelling through the surface dangling bond makes measurement of a signal that would otherwise be too weak to detect feasible. Distinct ionization and neutralization rates of a single dopant are measured and the physical process controlling those are identified. PMID- 27782124 TI - Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. AB - The development of in vitro culture systems quantitatively and qualitatively recapitulating normal breast biology is key to the understanding of mammary gland biology. Current three-dimensional mammary culture systems have not demonstrated concurrent proliferation and functional differentiation ex vivo in any system for longer than 2 weeks. Here, we identify conditions including Neuregulin1 and R spondin 1, allowing maintenance and expansion of mammary organoids for 2.5 months in culture. The organoids comprise distinct basal and luminal compartments complete with functional steroid receptors and stem/progenitor cells able to reconstitute a complete mammary gland in vivo. Alternative conditions are also described that promote enrichment of basal cells organized into multiple layers surrounding a keratinous core, reminiscent of structures observed in MMTV-Wnt1 tumours. These conditions comprise a unique tool that should further understanding of normal mammary gland development, the molecular mechanism of hormone action and signalling events whose deregulation leads to breast tumourigenesis. PMID- 27782126 TI - Stretching magnetism with an electric field in a nitride semiconductor. AB - The significant inversion symmetry breaking specific to wurtzite semiconductors, and the associated spontaneous electrical polarization, lead to outstanding features such as high density of carriers at the GaN/(Al,Ga)N interface-exploited in high-power/high-frequency electronics-and piezoelectric capabilities serving for nanodrives, sensors and energy harvesting devices. Here we show that the multifunctionality of nitride semiconductors encompasses also a magnetoelectric effect allowing to control the magnetization by an electric field. We first demonstrate that doping of GaN by Mn results in a semi-insulating material apt to sustain electric fields as high as 5 MV cm-1. Having such a material we find experimentally that the inverse piezoelectric effect controls the magnitude of the single-ion magnetic anisotropy specific to Mn3+ ions in GaN. The corresponding changes in the magnetization can be quantitatively described by a theory developed here. PMID- 27782127 TI - Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control. AB - Alhough the glucagon-like peptide-1 (GLP-1) system is critical to energy balance control and is a target for obesity pharmacotherapies, the receptor-population mediating effects of endogenous GLP-1 signaling are not fully understood. To address this, we developed a novel adeno-associated virus (AAV-GLP-1R) that utilizes short hairpin RNA to chronically knock down GLP-1 receptors (GLP-1R) in rats. As pharmacological studies highlight the hindbrain nucleus tractus solitarius (NTS) as a brain region important for GLP-1R-mediated effects on energy balance, AAV-GLP-1R was injected into the NTS to examine the role of endogenous NTS GLP-1R signaling in energy balance control. Chow intake and meal size were significantly increased following chronic NTS GLP-1R knockdown. In addition, NTS GLP-1R knockdown significantly increased self-administration of palatable food under both fixed and progressive ratio schedules of reinforcement. Collectively, these data demonstrate that endogenous NTS GLP-1R signaling is required for the control of food intake and motivation to feed, and provide a new strategy to investigate the importance of distinct GLP-1R populations in the control of a variety of functions. PMID- 27782129 TI - Diverse Colletotrichum species cause anthracnose of tea plants (Camellia sinensis (L.) O. Kuntze) in China. AB - Anthracnose caused by Colletotrichum is one of the most severe diseases that can afflict Camellia sinensis. However, research on the diversity and geographical distribution of Colletotrichum in China remain limited. In this study, 106 Colletotrichum isolates were collected from diseased leaves of Ca. sinensis cultivated in the 15 main tea production provinces in China. Multi-locus phylogenetic analysis coupled with morphological identification showed that the collected isolates belonged to 11 species, including 6 known species (C. camelliae, C. cliviae, C. fioriniae, C. fructicola, C. karstii, and C. siamense), 3 new record species (C. aenigma, C. endophytica, and C. truncatum), 1 novel species (C. wuxiense), and 1 indistinguishable strain, herein described as Colletotrichum sp. Of these species, C. camelliae and C. fructicola were the dominant species causing anthracnose in Ca. sinensis. In addition, our study provided further evidence that phylogenetic analysis using a combination of ApMat and GS sequences can be used to effectively resolve the taxonomic relationships within the C. gloeosporioides species complex. Finally, pathogenicity tests suggested that C. camelliae, C. aenigma, and C. endophytica are more invasive than other species after the inoculation of the leaves of Ca. sinensis. PMID- 27782128 TI - Network-Level Dysconnectivity in Drug-Naive First-Episode Psychosis: Dissociating Transdiagnostic and Diagnosis-Specific Alterations. AB - The neuroimaging literature provides compelling evidence for functional dysconnectivity in people with psychosis. However, it is likely that at least some of the observed alterations represent secondary effects of illness chronicity and/or antipsychotic medication. In addition, the extent to which these alterations are specific to psychosis or represent a transdiagnostic feature of psychiatric illness remains unclear. The aim of this study was therefore to examine the diagnostic specificity of functional dysconnectivity in drug-naive first-episode psychosis (FEP). We used resting-state functional magnetic resonance imaging and functional connectivity analysis to estimate network-level connectivity in 50 patients with FEP, 50 patients with major depressive disorder (MDD), 50 patients with post-traumatic stress disorder (PTSD), and 122 healthy controls (HCs). The FEP, MDD, and PTSD groups showed reductions in intranetwork connectivity of the default mode network relative to the HC group (p<0.05 corrected); therefore, intranetwork alterations were expressed across the three diagnostic groups. In addition, the FEP group showed heightened internetwork connectivity between the default mode network, particularly the anterior cingulate cortex, and the central executive network relative to the MDD, PTSD, and HC groups (p<0.05 corrected); therefore, internetwork alterations were specific to the FEP. These findings suggest that network-level alterations are present in individuals with a first episode of psychosis who have not been exposed to antipsychotic medication. In addition, they suggest a dissociation between aberrant internetwork connectivity as a distinctive feature of psychosis and aberrant intranetwork connectivity as a transdiagnostic feature of psychiatric illness. PMID- 27782130 TI - Transcriptome analyses provide insights into the phylogeny and adaptive evolution of the mangrove fern genus Acrostichum. AB - The mangrove fern genus Acrostichum grows in the extremely unstable marine intertidal zone under harsh conditions, such as high salt concentrations, tidal rhythms and long-term climate changes. To explore the phylogenetic relationships and molecular mechanisms underlying adaptations in this genus, we sequenced the transcriptomes of two species of Acrostichum, A. aureum and A. speciosum, as well as a species in the sister genus, Ceratopteris thalictroides. We obtained 47,517, 36,420 and 60,823 unigenes for the three ferns, of which 24.39-45.63% were annotated using public databases. The estimated divergence time revealed that Acrostichum adapted to the coastal region during the late Cretaceous, whereas the two mangrove ferns from the Indo West-Pacific (IWP) area diverged more recently. Two methods (the modified branch-site model and the Kh method) were used to identify several positively selected genes, which may contribute to differential adaptation of the two Acrostichum species to different light and salt conditions. Our study provides abundant transcriptome data and new insights into the evolution and adaptations of mangrove ferns in the inhospitable intertidal zone. PMID- 27782131 TI - In vivo correction of anaemia in beta-thalassemic mice by gammaPNA-mediated gene editing with nanoparticle delivery. AB - The blood disorder, beta-thalassaemia, is considered an attractive target for gene correction. Site-specific triplex formation has been shown to induce DNA repair and thereby catalyse genome editing. Here we report that triplex-forming peptide nucleic acids (PNAs) substituted at the gamma position plus stimulation of the stem cell factor (SCF)/c-Kit pathway yielded high levels of gene editing in haematopoietic stem cells (HSCs) in a mouse model of human beta-thalassaemia. Injection of thalassemic mice with SCF plus nanoparticles containing gammaPNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood haemoglobin levels into the normal range, reduced reticulocytosis, reversal of splenomegaly and up to 7% beta-globin gene correction in HSCs, with extremely low off-target effects. The combination of nanoparticle delivery, next generation gammaPNAs and SCF treatment may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration. PMID- 27782132 TI - AtSWEET13 and AtSWEET14 regulate gibberellin-mediated physiological processes. AB - Transmembrane transport of plant hormones is required for plant growth and development. Despite reports of a number of proteins that can transport the plant hormone gibberellin (GA), the mechanistic basis for GA transport and the identities of the transporters involved remain incomplete. Here, we provide evidence that Arabidopsis SWEET proteins, AtSWEET13 and AtSWEET14, which are members of a family that had previously been linked to sugar transport, are able to mediate cellular GA uptake when expressed in yeast and oocytes. A double sweet13 sweet14 mutant has a defect in anther dehiscence and this phenotype can be reversed by exogenous GA treatment. In addition, sweet13 sweet14 exhibits altered long distant transport of exogenously applied GA and altered responses to GA during germination and seedling stages. These results suggest that AtSWEET13 and AtSWEET14 may be involved in modulating GA response in Arabidopsis. PMID- 27782133 TI - Problems and Solutions in Click Chemistry Applied to Drug Probes. AB - Small-molecule fluorescent probes have been widely used in target identification, but this method has many disadvantages. For example, the identified proteins are usually complex, and additional biochemical studies are needed to distinguish real targets from interference results. To address this problem, we propose a series of strategies for improving the efficiency of target identification. First, pretreatment with a lower concentration of hydrogen peroxide can shield against thiol interference. Second, the use of benzophenone as a photo-affinity group is not appropriate, and diazirines are preferred. Third, if cytoskeleton proteins or stress proteins are captured, the interference must be carefully eliminated. The specificity of target identification can be improved by optimizing these three strategies. In this paper, we discuss the problems associated with the use of the click reaction in living cells and provide important complementary techniques for photo-affinity probes based on the click chemistry reaction. PMID- 27782135 TI - Surpassing the no-cloning limit with a heralded hybrid linear amplifier for coherent states. AB - The no-cloning theorem states that an unknown quantum state cannot be cloned exactly and deterministically due to the linearity of quantum mechanics. Associated with this theorem is the quantitative no-cloning limit that sets an upper bound to the quality of the generated clones. However, this limit can be circumvented by abandoning determinism and using probabilistic methods. Here, we report an experimental demonstration of probabilistic cloning of arbitrary coherent states that clearly surpasses the no-cloning limit. Our scheme is based on a hybrid linear amplifier that combines an ideal deterministic linear amplifier with a heralded measurement-based noiseless amplifier. We demonstrate the production of up to five clones with the fidelity of each clone clearly exceeding the corresponding no-cloning limit. Moreover, since successful cloning events are heralded, our scheme has the potential to be adopted in quantum repeater, teleportation and computing applications. PMID- 27782136 TI - Bacterial evolution: Genomics of metabolic trade-offs. PMID- 27782137 TI - Structural biology: Variability without change. PMID- 27782140 TI - Environmental microbiology: Viral diversity on the global stage. PMID- 27782134 TI - Gap junctions and cancer: communicating for 50 years. AB - Fifty years ago, tumour cells were found to lack electrical coupling, leading to the hypothesis that loss of direct intercellular communication is commonly associated with cancer onset and progression. Subsequent studies linked this phenomenon to gap junctions composed of connexin proteins. Although many studies support the notion that connexins are tumour suppressors, recent evidence suggests that, in some tumour types, they may facilitate specific stages of tumour progression through both junctional and non-junctional signalling pathways. This Timeline article highlights the milestones connecting gap junctions to cancer, and underscores important unanswered questions, controversies and therapeutic opportunities in the field. PMID- 27782141 TI - Resistance ascends the political summit. PMID- 27782138 TI - Optical and force nanoscopy in microbiology. AB - Microbial cells have developed sophisticated multicomponent structures and machineries to govern basic cellular processes, such as chromosome segregation, gene expression, cell division, mechanosensing, cell adhesion and biofilm formation. Because of the small cell sizes, subcellular structures have long been difficult to visualize using diffraction-limited light microscopy. During the last three decades, optical and force nanoscopy techniques have been developed to probe intracellular and extracellular structures with unprecedented resolutions, enabling researchers to study their organization, dynamics and interactions in individual cells, at the single-molecule level, from the inside out, and all the way up to cell-cell interactions in microbial communities. In this Review, we discuss the principles, advantages and limitations of the main optical and force nanoscopy techniques available in microbiology, and we highlight some outstanding questions that these new tools may help to answer. PMID- 27782139 TI - Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. AB - The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice. PMID- 27782142 TI - Fungal physiology: Robbing the bank of haem iron. PMID- 27782143 TI - Structural biology: A picornavirus unlike the others. PMID- 27782145 TI - Tumour immunology: Suppressive metabolites. PMID- 27782144 TI - Cell-to-cell spread of microsporidia causes Caenorhabditis elegans organs to form syncytia. AB - The growth of pathogens is dictated by their interactions with the host environment1. Obligate intracellular pathogens undergo several cellular decisions as they progress through their life cycles inside host cells2. We have studied this process for microsporidian species in the genus Nematocida as they grew and developed inside their co-evolved animal host, Caenorhabditis elegans3-5. We found that microsporidia can restructure multicellular host tissues into a single contiguous multinucleate cell. In particular, we found that all three Nematocida species we studied were able to spread across the cells of C. elegans tissues before forming spores, with two species causing syncytial formation in the intestine and one species causing syncytial formation in the muscle. We also found that the decision to switch from replication to differentiation in Nematocida parisii was altered by the density of infection, suggesting that environmental cues influence the dynamics of the pathogen life cycle. These findings show how microsporidia can maximize the use of host space for growth and that environmental cues in the host can regulate a developmental switch in the pathogen. PMID- 27782146 TI - Regulatory T CELLS: Suppressing antibody production. PMID- 27782147 TI - T cell development: Shaping organ-specific gammadelta T cells. PMID- 27782148 TI - Antibodies: Marking disease states in tuberculosis. PMID- 27782149 TI - Solution conformation and flexibility of capsular polysaccharides from Neisseria meningitidis and glycoconjugates with the tetanus toxoid protein. AB - The structural integrity of meningococcal native, micro-fluidized and activated capsular polysaccharides and their glycoconjugates - in the form most relevant to their potential use as vaccines (dilute solution) - have been investigated with respect to their homogeneity, conformation and flexibility. Sedimentation velocity analysis showed that the polysaccharide size distributions were generally bimodal with some evidence for higher molar mass forms at higher concentration. Weight average molar masses Mw where lower for activated polysaccharides. Conjugation with tetanus toxoid protein however greatly increased the molar mass and polydispersity of the final conjugates. Glycoconjugates had an approximately unimodal log-normal but broad and large molar mass profiles, confirmed by sedimentation equilibrium "SEDFIT MSTAR" analysis. Conformation analysis using HYDFIT (which globally combines sedimentation and viscosity data), "Conformation Zoning" and Wales-van Holde approaches showed a high degree of flexibility - at least as great as the unconjugated polysaccharides, and very different from the tetanus toxoid (TT) protein used for the conjugation. As with the recently published finding for Hib TT complexes, it is the carbohydrate component that dictates the solution behaviour of these glycoconjugates, although the lower intrinsic viscosities suggest some degree of compaction of the carbohydrate chains around the protein. PMID- 27782150 TI - A robust gene-stacking method utilizing yeast assembly for plant synthetic biology. AB - The advent and growth of synthetic biology has demonstrated its potential as a promising avenue of research to address many societal needs. However, plant synthetic biology efforts have been hampered by a dearth of DNA part libraries, versatile transformation vectors and efficient assembly strategies. Here, we describe a versatile system (named jStack) utilizing yeast homologous recombination to efficiently assemble DNA into plant transformation vectors. We demonstrate how this method can facilitate pathway engineering of molecules of pharmaceutical interest, production of potential biofuels and shuffling of disease-resistance traits between crop species. Our approach provides a powerful alternative to conventional strategies for stacking genes and traits to address many impending environmental and agricultural challenges. PMID- 27782151 TI - Direct penetration of spin-triplet superconductivity into a ferromagnet in Au/SrRuO3/Sr2RuO4 junctions. AB - Efforts have been ongoing to establish superconducting spintronics utilizing ferromagnet/superconductor heterostructures. Previously reported devices are based on spin-singlet superconductors (SSCs), where the spin degree of freedom is lost. Spin-polarized supercurrent induction in ferromagnetic metals (FMs) is achieved even with SSCs, but only with the aid of interfacial complex magnetic structures, which severely affect information imprinted to the electron spin. Use of spin-triplet superconductors (TSCs) with spin-polarizable Cooper pairs potentially overcomes this difficulty and further leads to novel functionalities. Here, we report spin-triplet superconductivity induction into a FM SrRuO3 from a leading TSC candidate Sr2RuO4, by fabricating microscopic devices using an epitaxial SrRuO3/Sr2RuO4 hybrid. The differential conductance, exhibiting Andreev reflection features with multiple energy scales up to around half tesla, indicates the penetration of superconductivity over a considerable distance of 15 nm across the SrRuO3 layer without help of interfacial complex magnetism. This demonstrates potential utility of FM/TSC devices for superspintronics. PMID- 27782152 TI - HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2. AB - The dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Our results demonstrate HULC, MALAT1 and TRF2 are highly expressed in human hepatocellular carcinoma tissues, and HULC plus MALAT1 overexpression drastically promotes the growth of liver cancer stem cells. Mechanistically, both HULC and MALAT1 overexpression enhanced RNA polII, P300, CREPT to load on the promoter region of telomere repeat-binding factor 2(TRF2), triggering the overexpression, phosphorylation and SUMOylation of TRF2. Strikingly, the excessive TRF2 interacts with HULC or MALAT1 to form the complex that loads on the telomeric region, replacing the CST/AAF and recruiting POT1, pPOT1, ExoI, SNM1B, HP1 alpha. Accordingly, the telomere is greatly protected and enlonged. Furthermore, the excessive HULC plus MALAT1 reduced the methylation of the TERC promoter dependent on TRF2, increasing the TERC expression that causes the increase of interplay between TRET and TERC. Ultimately, the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the liver cancer stem cells. Our demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell. PMID- 27782153 TI - Terahertz reflectometry imaging for low and high grade gliomas. AB - Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes. PMID- 27782154 TI - Expression of varied GFPs in Saccharomyces cerevisiae: codon optimization yields stronger than expected expression and fluorescence intensity. AB - Green fluorescent protein (GFP), which was originally isolated from jellyfish, is a widely used tool in biological research, and homologs from other organisms are available. However, researchers must determine which GFP is the most suitable for a specific host. Here, we expressed GFPs from several sources in codon-optimized and non-codon-optimized forms in the yeast Saccharomyces cerevisiae, which represents an ideal eukaryotic model. Surprisingly, codon-optimized mWasabi and mNeonGreen, which are typically the brightest GFPs, emitted less green fluorescence than did the other five codon-optimized GFPs tested in S. cerevisiae. Further, commercially available GFPs that have been optimized for mammalian codon usage (e.g., EGFP, AcGFP1 and TagGFP2) unexpectedly exhibited extremely low expression levels in S. cerevisiae. In contrast, codon-optimization of the GFPs for S. cerevisiae markedly increased their expression levels, and the fluorescence intensity of the cells increased by a maximum of 101-fold. Among the tested GFPs, the codon-optimized monomeric mUkG1 from soft coral showed the highest levels of both expression and fluorescence. Finally, the expression of this protein as a fusion-tagged protein successfully improved the reporting system's ability to sense signal transduction and protein-protein interactions in S. cerevisiae and increased the detection rates of target cells using flow cytometry. PMID- 27782155 TI - Structural elucidation of estrus urinary lipocalin protein (EULP) and evaluating binding affinity with pheromones using molecular docking and fluorescence study. AB - Transportation of pheromones bound with carrier proteins belonging to lipocalin superfamily is known to prolong chemo-signal communication between individuals belonging to the same species. Members of lipocalin family (MLF) proteins have three structurally conserved motifs for delivery of hydrophobic molecules to the specific recognizer. However, computational analyses are critically required to validate and emphasize the sequence and structural annotation of MLF. This study focused to elucidate the evolution, structural documentation, stability and binding efficiency of estrus urinary lipocalin protein (EULP) with endogenous pheromones adopting in-silico and fluorescence study. The results revealed that: (i) EULP perhaps originated from fatty acid binding protein (FABP) revealed in evolutionary analysis; (ii) Dynamic simulation study shows that EULP is highly stable at below 0.45 A of root mean square deviation (RMSD); (iii) Docking evaluation shows that EULP has higher binding energy with farnesol and 2-iso butyl-3-methoxypyrazine (IBMP) than 2-naphthol; and (iv) Competitive binding and quenching assay revealed that purified EULP has good binding interaction with farnesol. Both, In-silico and experimental studies showed that EULP is an efficient binding partner to pheromones. The present study provides impetus to create a point mutation for increasing longevity of EULP to develop pheromone trap for rodent pest management. PMID- 27782156 TI - Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma. AB - Lung cancer is the number one cause of cancer-related deaths worldwide. DNA methylation is an epigenetic mechanism that regulates gene expression, and disease-specific methylation changes can be targeted as biomarkers. We have compared the genome-wide methylation pattern in tumor and tumor-adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32 patients by methylation-sensitive high resolution melting (MS-HRM) analysis. Significant increases in methylation were confirmed for 15 DMRs associated with the genes and genomic regions: OSR1, SIM1, GHSR, OTX2, LOC648987, HIST1H3E, HIST1H3G/HIST1H2BI, HIST1H2AJ/HIST1H2BM, HOXD10, HOXD3, HOXB3/HOXB4, HOXA3, HOXA5, Chr1(q21.1).A, and Chr6(p22.1). In particular the OSR1, SIM1 and HOXB3/HOXB4 regions demonstrated high potential as biomarkers in LAC. For OSR1, hypermethylation was detected in 47/48 LAC cases compared to 1/31 tumor-adjacent normal lung samples. Similarly, 45/49 and 36/48 LAC cases compared to 3/31 and 0/31 tumor-adjacent normal lung samples showed hypermethylation of the SIM1 and HOXB3/HOXB4 regions, respectively. In conclusion, this study has identified and validated 15 DMRs that can be targeted as biomarkers in LAC. PMID- 27782157 TI - Albumin Homodimers in Patients with Cirrhosis: Clinical and Prognostic Relevance of a Novel Identified Structural Alteration of the Molecule. AB - Decompensated cirrhosis is associated to extensive post-transcriptional changes of human albumin (HA). This study aims to characterize the occurrence of HA homodimerization in a large cohort of patients with decompensated cirrhosis and to evaluate its association with clinical features and prognosis. HA monomeric and dimeric isoforms were identified in peripheral blood by using a HPLC-ESI-MS technique in 123 cirrhotic patients hospitalized for acute decompensation and 50 age- and sex-comparable healthy controls. Clinical and biochemical parameters were recorded and patients followed up to one year. Among the monomeric isoforms identified, the N- and C-terminal truncated and the native HA underwent homodimerization. All three homodimers were significantly more abundant in patients with cirrhosis, acute-on-chronic liver failure and correlate with the prognostic scores. The homodimeric N-terminal truncated isoform was independently associated to disease complications and was able to stratify 1-year survival. As a result of all these changes, the monomeric native HA was significantly decreased in patients with cirrhosis, being also associated with a poorer prognosis. In conclusion homodimerization is a novel described structural alteration of the HA molecule in decompensated cirrhosis and contributes to the progressive reduction of the monomeric native HA, the only isoform provided of structural and functional integrity. PMID- 27782159 TI - Particulate matter emissions from biochar-amended soils as a potential tradeoff to the negative emission potential. AB - Novel carbon sequestration strategies such as large-scale land application of biochar may provide sustainable pathways to increase the terrestrial storage of carbon. Biochar has a long residence time in the soil and hence comprehensive studies are urgently needed to quantify the environmental impacts of large-scale biochar application. In particular, black carbon emissions from soils amended with biochar may counteract the negative emission potential due to the impacts on air quality, climate, and biogeochemical cycles. We investigated, using wind tunnel experiments, the particulate matter emission potential of a sand and two agriculturally important soils amended with different concentrations of biochar, in comparison to control soils. Our results indicate that biochar application considerably increases particulate emissions possibly by two mechanisms-the accelerated emission of fine biochar particles and the generation and emission of fine biochar particles resulting from abrasion of large biochar particles by sand grains. Our study highlights the importance of considering the background soil properties (e.g., texture) and geomorphological processes (e.g., aeolian transport) for biochar-based carbon sequestration programs. PMID- 27782158 TI - Analyses of RNA-Seq and sRNA-Seq data reveal a complex network of anti-viral defense in TCV-infected Arabidopsis thaliana. AB - In order to identify specific plant anti-viral genes related to the miRNA regulatory pathway, RNA-Seq and sRNA-Seq were performed using Arabidopsis WT and dcl1-9 mutant line. A total of 5,204 DEGs were identified in TCV-infected WT plants. In contrast, only 595 DEGs were obtained in the infected dcl1-9 mutant plants. GO enrichment analysis of the shared DEGs and dcl1-9 unique DEGs showed that a wide range of biological processes were affected in the infected WT plants. In addition, miRNAs displayed different patterns between mock and infected WT plants. This is the first global view of dcl1-9 transcriptome which provides TCV responsive miRNAs data. In conclusion, our results indicated the significance of DCL1 and suggested that PPR genes may play an important role in plant anti-viral defense. PMID- 27782160 TI - Global-scale river flood vulnerability in the last 50 years. AB - The impacts of flooding are expected to rise due to population increases, economic growth and climate change. Hence, understanding the physical and spatiotemporal characteristics of risk drivers (hazard, exposure and vulnerability) is required to develop effective flood mitigation measures. Here, the long-term trend in flood vulnerability was analysed globally, calculated from the ratio of the reported flood loss or damage to the modelled flood exposure using a global river and inundation model. A previous study showed decreasing global flood vulnerability over a shorter period using different disaster data. The long-term analysis demonstrated for the first time that flood vulnerability to economic losses in upper-middle, lower-middle and low-income countries shows an inverted U-shape, as a result of the balance between economic growth and various historical socioeconomic efforts to reduce damage, leading to non significant upward or downward trends. We also show that the flood-exposed population is affected by historical changes in population distribution, with changes in flood vulnerability of up to 48.9%. Both increasing and decreasing trends in flood vulnerability were observed in different countries, implying that population growth scenarios considering spatial distribution changes could affect flood risk projections. PMID- 27782161 TI - Maltodextrin enhances biofilm elimination by electrochemical scaffold. AB - Electrochemical scaffolds (e-scaffolds) continuously generate low concentrations of H2O2 suitable for damaging wound biofilms without damaging host tissue. Nevertheless, retarded diffusion combined with H2O2 degradation can limit the efficacy of this potentially important clinical tool. H2O2 diffusion into biofilms and bacterial cells can be increased by damaging the biofilm structure or by activating membrane transportation channels by exposure to hyperosmotic agents. We hypothesized that e-scaffolds would be more effective against Acinetobacter baumannii and Staphylococcus aureus biofilms in the presence of a hyperosmotic agent. E-scaffolds polarized at -600 mVAg/AgCl were overlaid onto preformed biofilms in media containing various maltodextrin concentrations. E scaffold alone decreased A. baumannii and S. aureus biofilm cell densities by (3.92 +/- 0.15) log and (2.31 +/- 0.12) log, respectively. Compared to untreated biofilms, the efficacy of the e-scaffold increased to a maximum (8.27 +/- 0.05) log reduction in A. baumannii and (4.71 +/- 0.12) log reduction in S. aureus biofilm cell densities upon 10 mM and 30 mM maltodextrin addition, respectively. Overall ~55% decrease in relative biofilm surface coverage was achieved for both species. We conclude that combined treatment with electrochemically generated H2O2 from an e-scaffold and maltodextrin is more effective in decreasing viable biofilm cell density. PMID- 27782162 TI - Diagnostic Value and Surgical Implications of the 3D DW-SSFP MRI On the Management of Patients with Brachial Plexus Injuries. AB - Three-dimensional diffusion-weighted steady-state free precession (3D DW-SSFP) of high-resolution magnetic resonance has emerged as a promising method to visualize the peripheral nerves. In this study, the application value of 3D DW-SSFP brachial plexus imaging in the diagnosis of brachial plexus injury (BPI) was investigated. 33 patients with BPI were prospectively examined using 3D DW-SSFP MR neurography (MRN) of brachial plexus. Results of 3D DW-SSFP MRN were compared with intraoperative findings and measurements of electromyogram (EMG) or somatosensory evoked potentials (SEP) for each injured nerve root. 3D DW-SSFP MRN of brachial plexus has enabled good visualization of the small components of the brachial plexus. The postganglionic section of the brachial plexus was clearly visible in 26 patients, while the preganglionic section of the brachial plexus was clearly visible in 22 patients. Pseudomeningoceles were commonly observed in 23 patients. Others finding of MRN of brachial plexus included spinal cord offset (in 16 patients) and spinal cord deformation (in 6 patients). As for the 3D DW SSFP MRN diagnosis of preganglionic BPI, the sensitivity, the specificity and the accuracy were respectively 96.8%, 90.29%, and 94.18%. 3D DW-SSFP MRN of brachial plexus improve visualization of brachial plexus and benefit to determine the extent of injury. PMID- 27782163 TI - Oocyte aging-induced Neuronatin (NNAT) hypermethylation affects oocyte quality by impairing glucose transport in porcine. AB - DNA methylation plays important roles in regulating many physiological behaviors; however, few studies were focused on the changes of DNA methylation during oocyte aging. Early studies showed that some imprinted genes' DNA methylation had been changed in aged mouse oocytes. In this study, we used porcine oocytes to test the hypothesis that oocyte aging would alter DNA methylation pattern of genes and disturb their expression in age oocytes, which affected the developmental potential of oocytes. We compared several different types of genes and found that the expression and DNA methylation of Neuronatin (NNAT) were disturbed in aged oocytes significantly. Additional experiments demonstrated that glucose transport was impaired in aged oocytes and injection of NNAT antibody into fresh oocytes led to the same effects on glucose transport. These results suggest that the expression of NNAT was declined by elevating DNA methylation, which affected oocyte quality by decreasing the ability of glucose transport in aged oocytes. PMID- 27782164 TI - Domestication and ontogeny effects on the stress response in young chickens (Gallus gallus). AB - Domestication is thought to increase stress tolerance. The connection between stressor exposure, glucocorticoids and behavioural responses has been studied in adults, where domestication effects are evident. Early stress exposure may induce detrimental effects both in short-and long term. Previous research has reported a lack of glucocorticoid response in newly hatched chickens (Gallus gallus), whereas others have found opposite results. Hence it remains unclear whether the HPA-axis is functional from hatch, and if domestication has affected the early post-hatch ontogeny of the stress response. Our aims were to investigate the early ontogeny of the HPA-axis and characterize behavioural and hormonal stress responses in ancestral Red Junglefowl and in two domestic layer strains. Plasma corticosteone and behavioural responses before and after physical restraint was measured on day one, nine, 16 and 23 post hatch. The results showed significant increases of corticosterone after stress in all three breeds at all the different ages. The HPA-response decreased with age and was lower in Red Junglefowl. Behavioural responses also decreased with age, and tended to be stronger in Red Junglefowl. In summary, the HPA-axis is reactive from day one, and domestication may have affected its development and reactivity, alongside with related behaviour responses. PMID- 27782165 TI - beta-Arrestin 1's Interaction with TC45 Attenuates Stat signaling by dephosphorylating Stat to inhibit antimicrobial peptide expression. AB - Impaired phosphatase activity leads to the persistent activation of signal transducers and activators of transcription (Stat). In mammals, Stat family members are often phosphorylated or dephosphorylated by the same enzymes. To date, only one Stat similar to mammalian Stat5a/b has been found in crustaceans and there have been few studies in Stat signal regulation in crustaceans. Here, we report that beta-arrestin1 interacts with TC45 (45-kDa form of T cell protein tyrosine phosphatase) in the nucleus to attenuate Stat signaling by promoting dephosphorylation of Stat. Initially, we showed that Stat translocates into the nucleus to induce antimicrobial peptide (AMP) expression after bacterial infection. betaArr1 enters the nucleus of hemocytes and recruits TC45 to form the betaarr1-TC45-Stat complex, which dephosphorylates Stat efficiently. The interaction of TC45 with Stat decreased and Stat phosphorylation increased in betaarr1-silenced shrimp (Marsupenaeus japonicus) after challenge with Vibrio anguillarum. betaArr1 directly interacts with Stat in nucleus and accelerates Stat dephosphorylation by recruiting TC45 after V. anguillarum challenge. Further study showed that betaarr1 and TC45 also affect AMP expression, which is regulated by Stat. Therefore, betaarr1 and TC45 are involved in the anti-V. anguillarum immune response by regulating Stat activity negatively to decrease AMP expression in shrimp. PMID- 27782166 TI - Modeling analysis of secondary inorganic aerosols over China: pollution characteristics, and meteorological and dust impacts. AB - Secondary inorganic aerosols (SIA) are the predominant components of fine particulate matter (PM2.5) and have significant impacts on air quality, human health, and climate change. In this study, the Community Multiscale Air Quality modeling system (CMAQ) was modified to incorporate SO2 heterogeneous reactions on the surface of dust particles. The revised model was then used to simulate the spatiotemporal characteristics of SIA over China and analyze the impacts of meteorological factors and dust on SIA formation. Including the effects of dust improved model performance for the simulation of SIA concentrations, particularly for sulfate. The simulated annual SIA concentration in China was approximately 10.1 MUg/m3 on domain average, with strong seasonal variation: highest in winter and lowest in summer. High SIA concentrations were concentrated in developed regions with high precursor emissions, such as the North China Plain, Yangtze River Delta, Sichuan Basin, and Pearl River Delta. Strong correlations between meteorological factors and SIA pollution levels suggested that heterogeneous reactions under high humidity played an important role on SIA formation, particularly during severe haze pollution periods. Acting as surfaces for heterogeneous reactions, dust particles significantly affected sulfate formation, suggesting the importance of reducing dust emissions for controlling SIA and PM2.5 pollution. PMID- 27782167 TI - Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 &2 and AMP-activated Protein Kinase in the Kidney. AB - The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3 day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs). To test whether the effects of metformin in the kidney are dependent on these transporters, we tested metformin treatment in OCT1/2-/- mice. Even though exposure of metformin in the kidney was severely decreased in OCT1/2-/- mice when evaluated with [11C]-Metformin and PET/MRI, we found that the protective effects of metformin were OCT1/2 independent when tested in this model. AMP-activated protein kinase (AMPK) has been suggested as a key mediator of the effects of metformin. When using an AMPK beta1 KO mouse model, the protective effects of metformin still occurred in the 3dUUO model. In conclusion, these results show that metformin has a beneficial effect in early stages of renal disease induced by 3dUUO. Furthermore, these effects appear to be independent of the expression of OCT1/2 and AMPK-beta1, the most abundant AMPK-beta isoform in the kidney. PMID- 27782168 TI - Fluorescent protein tagging of endogenous protein in brain neurons using CRISPR/Cas9-mediated knock-in and in utero electroporation techniques. AB - Genome editing is a powerful technique for studying gene functions. CRISPR/Cas9 mediated gene knock-in has recently been applied to various cells and organisms. Here, we successfully knocked in an EGFP coding sequence at the site immediately after the first ATG codon of the beta-actin gene in neurons in the brain by the combined use of the CRISPR/Cas9 system and in utero electroporation technique, resulting in the expression of the EGFP-tagged beta-actin protein in cortical layer 2/3 pyramidal neurons. We detected EGFP fluorescence signals in the soma and neurites of EGFP knock-in neurons. These signals were particularly abundant in the head of dendritic spines, corresponding to the localization of the endogenous beta-actin protein. EGFP knock-in neurons showed no detectable changes in spine density and basic electrophysiological properties. In contrast, exogenously overexpressed EGFP-beta-actin showed increased spine density and EPSC frequency, and changed resting membrane potential. Thus, our technique provides a potential tool to elucidate the localization of various endogenous proteins in neurons by epitope tagging without altering neuronal and synaptic functions. This technique can be also useful for introducing a specific mutation into genes to study the function of proteins and genomic elements in brain neurons. PMID- 27782170 TI - A Reduction-Based Sensor for Acrolein Conjugates with the Inexpensive Nitrobenzene as an Alternative to Monoclonal Antibody. AB - Acrolein, a highly toxic alpha, beta-unsaturated aldehyde, has been a longstanding key biomarker associated with a range of disorders related to oxidative stresses. One of the most promising methods for detecting acrolein involves the use of antibodies that can recognize the acrolein-lysine conjugate, 3-formyl-3, 4-dehydropiperidines (FDP), within oxidatively stressed cells and tissues from various disease states. We have uncovered here that FDP could reduce nitroarenes in high yields at 100 degrees C in the presence of excess CaCl2 as a Lewis acid promoter. This unique transformation allowed for the development of a de novo method for detecting levels of FDPs generated from proteins in urine or blood serum samples. Thus we successfully converted a non-fluorescent and inexpensive 4-nitrophthalonitrile probe to the corresponding fluorescent aniline, thereby constituting the concept of fluorescent switching. Its sensitivity level (0.84 nmol/mL) is more than that of ELISA assays (3.13 nmol/mL) and is already equally reliable and reproducible at this early stage of development. More importantly, this method is cost effective and simple to operate, requiring only mixing of samples with a kit solution. Our method thus possesses potential as a future alternative to the more costly and operatively encumbered conventional antibody-based methods. PMID- 27782169 TI - Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae. AB - The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression. We further investigated the impact of VPA on selected processes and found that this drug: i) activates markers of the unfolded protein stress response such as Hac1 mRNA splicing; ii) modulates the cell wall integrity pathway by inhibiting the activation of the Slt2 MAP kinase, and synergizes with cell wall stressors such as micafungin and calcofluor white in preventing yeast growth; iii) prevents activation of the Kss1 and Fus3 MAP kinases of the mating pheromone pathway, which in turn abolishes cellular responses to alpha factor; and iv) blocks cell cycle progression and DNA replication. Overall, our data identify heretofore unknown biological responses to VPA in budding yeast, and highlight the broad spectrum of cellular pathways influenced by this chemical in eukaryotes. PMID- 27782171 TI - Integrated presentation of ecological risk from multiple stressors. AB - Current environmental risk assessments (ERA) do not account explicitly for ecological factors (e.g. species composition, temperature or food availability) and multiple stressors. Assessing mixtures of chemical and ecological stressors is needed as well as accounting for variability in environmental conditions and uncertainty of data and models. Here we propose a novel probabilistic ERA framework to overcome these limitations, which focusses on visualising assessment outcomes by construct-ing and interpreting prevalence plots as a quantitative prediction of risk. Key components include environmental scenarios that integrate exposure and ecology, and ecological modelling of relevant endpoints to assess the effect of a combination of stressors. Our illustrative results demonstrate the importance of regional differences in environmental conditions and the confounding interactions of stressors. Using this framework and prevalence plots provides a risk-based approach that combines risk assessment and risk management in a meaningful way and presents a truly mechanistic alternative to the threshold approach. Even whilst research continues to improve the underlying models and data, regulators and decision makers can already use the framework and prevalence plots. The integration of multiple stressors, environmental conditions and variability makes ERA more relevant and realistic. PMID- 27782172 TI - Procedural performance following sleep deprivation remains impaired despite extended practice and an afternoon nap. AB - The negative impact of sleep loss on procedural memory is well established, yet it remains unclear how extended practice opportunities or daytime naps can modulate the effect of a night of sleep deprivation. Here, participants underwent three training and test conditions on a sequential finger tapping task (SFTT) separated by at least one week. In the first condition they were trained in the evening followed by a night of sleep. Two further conditions took place where evening training was followed by a night of total sleep deprivation (TSD). One of the TSD conditions included a one-hour nap opportunity (15:00). Compared to the condition in which sleep was permitted, a night of TSD resulted in poorer performance across 4 practices the following day (10:00-19:00). The deleterious effect of a single night of TSD on procedural performance, was neither clearly alleviated by an afternoon nap nor by multiple practice opportunities. Interestingly, significant gains in performance were observed in all conditions after a one-week delay. Recovery sleep on subsequent nights thus appeared to nullify the effect of a single night of sleep deprivation, underscoring the importance of offline consolidation on the acquisition of procedural skill. PMID- 27782173 TI - Mesenchymal stem cells with Sirt1 overexpression suppress breast tumor growth via chemokine-dependent natural killer cells recruitment. AB - Mesenchymal stem cells (MSCs) are generally used in regenerative medicine, tissue engineering and therapy for immune disorder diseases. However, due to the immunosuppressive function of MSCs, the application of MSCs in breast cancer therapy remains limited. Sirt1 is the closest mammalian homologue of the yeast enzyme Sir2 which has an established capacity to influence yeast replicative lifespan. In this study, we demonstrated the effect of MSCs with Sirt1 overexpression (MSCs-Sirt1) in mice bearing 4T1 breast cancer and investigated the underlying mechanism. Firstly, we found that MSCs could accelerate breast tumor growth with promoted proliferation and inhibited apoptosis, whereas MSCs Sirt1 significantly suppressed tumor growth with proliferation inhibition and apoptosis promotion. Moreover, we detected that NK cells were the prominent antitumor effectors for the MSCs-Sirt1-induced antitumor activity. Besides that, CXCL10 and IFN-gamma showed the high level expression in MSCs-Sirt1 treatment group. The impulsive effect of MSCs-Sirt1 on 4T1 cells in vivo could be reversed by inhibition of CXCL10 and IFN-gamma. Overall, our results suggest that MSCs Sirt1 can effectively inhibit breast tumor growth via the recruitment of NK cells in tumor inflammatory microenvironment. PMID- 27782174 TI - Phylogenetic and functional potential links pH and N2O emissions in pasture soils. AB - Denitrification is mediated by microbial, and physicochemical, processes leading to nitrogen loss via N2O and N2 emissions. Soil pH regulates the reduction of N2O to N2, however, it can also affect microbial community composition and functional potential. Here we simultaneously test the link between pH, community composition, and the N2O emission ratio (N2O/(NO + N2O + N2)) in 13 temperate pasture soils. Physicochemical analysis, gas kinetics, 16S rRNA amplicon sequencing, metagenomic and quantitative PCR (of denitrifier genes: nirS, nirK, nosZI and nosZII) analysis were carried out to characterize each soil. We found strong evidence linking pH to both N2O emission ratio and community changes. Soil pH was negatively associated with N2O emission ratio, while being positively associated with both community diversity and total denitrification gene (nir &nos) abundance. Abundance of nosZII was positively linked to pH, and negatively linked to N2O emissions. Our results confirm that pH imposes a general selective pressure on the entire community and that this results in changes in emission potential. Our data also support the general model that with increased microbial diversity efficiency increases, demonstrated in this study with lowered N2O emission ratio through more efficient conversion of N2O to N2. PMID- 27782175 TI - Angiotensin II type-1 receptor (AT1R) regulates expansion, differentiation, and functional capacity of antigen-specific CD8+ T cells. AB - Angiotensin II (Ang II) and its receptor AT1 (AT1R), an important effector axis of renin-angiotensin system (RAS), have been demonstrated to regulate T-cell responses. However, these studies characterized Ang II and AT1R effects using pharmacological tools, which do not target only Ang II/AT1R axis. The specific role of AT1R expressed by antigen-specific CD8+ T cells is unknown. Then we immunized transgenic mice expressing a T-cell receptor specific for SIINFEKL epitope (OT-I mice) with sporozoites of the rodent malaria parasite Plasmodium berghei expressing the cytotoxic epitope SIINFEKL. Early priming events after immunization were not affected but the expansion and contraction of AT1R deficient (AT1R-/-) OT-I cells was decreased. Moreover, they seemed more activated, express higher levels of CTLA-4, PD-1, LAG-3, and have decreased functional capacity during the effector phase. Memory AT1R-/- OT-I cells exhibited higher IL-7Ralpha expression, activation, and exhaustion phenotypes but less cytotoxic capacity. Importantly, AT1R-/- OT-I cells show better control of blood parasitemia burden and ameliorate mice survival during lethal disease induced by blood-stage malaria. Our study reveals that AT1R in antigen-specific CD8+ T cells regulates expansion, differentiation, and function during effector and memory phases of the response against Plasmodium, which could apply to different infectious agents. PMID- 27782177 TI - System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder mainly caused by mutation in PKD1/PKD2. However, ethnic differences in mutations, the association between mutation genotype/clinical phenotype, and the clinical applicable value of mutation detection are poorly understood. We made systematically analysis of Chinese ADPKD patients based on a next-generation sequencing platform. Among 148 ADPKD patients enrolled, 108 mutations were detected in 127 patients (85.8%). Compared with mutations in Caucasian published previously, the PKD2 mutation detection rate was lower, and patients carrying the PKD2 mutation invariably carried the PKD1 mutation. The definite pathogenic mutation detection rate was lower, whereas the multiple mutations detection rate was higher in Chinese patients. Then, we correlated PKD1/PKD2 mutation data and clinical data: patients with mutation exhibited a more severe phenotype; patients with >1 mutations exhibited a more severe phenotype; patients with pathogenic mutations exhibited a more severe phenotype. Thus, the PKD1/PKD2 mutation status differed by ethnicity, and the PKD1/PKD2 genotype may affect the clinical phenotype of ADPKD. Furthermore, it makes sense to detect PKD1/PKD2 mutation status for early diagnosis and prognosis, perhaps as early as the embryo/zygote stage, to facilitate early clinical intervention and family planning. PMID- 27782178 TI - Being overweight in early adulthood is associated with increased mortality in middle age. AB - Observational analyses of the association between body mass index (BMI) and all cause mortality often suggest that overweight is neutral or beneficial, but such analyses are potentially confounded by smoking or by reverse causation. The use of BMI measured in early adulthood offers one means of reducing the latter problem. We used a cohort who were first measured while 16-24 year old students at Glasgow University in 1948-1968 and subsequently re-measured in 2000-2003, offering a rare opportunity to compare BMI measured at different ages as a predictor of mortality. Analysis of the later BMI measurements suggested that overweight was beneficial to survival, while analysis of BMI measured in early adulthood suggested that overweight was harmful and that the optimum BMI lay towards the lower end of the recommended range of 18.5-25 kg m-2. We interpret the association with later BMI as being probably distorted by reverse causality, although it remains possible instead that the optimum BMI increases with age. Differences when analyses were restricted to healthy non-smokers also suggested some residual confounding by smoking. These results suggest that analyses of BMI recorded in middle or old age probably over-estimate the optimum BMI for survival and should be treated with caution. PMID- 27782179 TI - Biocatalysis on the surface of Escherichia coli: melanin pigmentation of the cell exterior. AB - Today, it is considered state-of-the-art to engineer living organisms for various biotechnology applications. Even though this has led to numerous scientific breakthroughs, the enclosed interior of bacterial cells still restricts interactions with enzymes, pathways and products due to the mass-transfer barrier formed by the cell envelope. To promote accessibility, we propose engineering of biocatalytic reactions and subsequent product deposition directly on the bacterial surface. As a proof-of-concept, we used the AIDA autotransporter vehicle for Escherichia coli surface expression of tyrosinase and fully oxidized externally added tyrosine to the biopolymer melanin. This resulted in a color change and creation of a black cell exterior. The capture of ninety percent of a pharmaceutical wastewater pollutant followed by regeneration of the cell bound melanin matrix through a simple pH change, shows the superior function and facilitated processing provided by the surface methodology. The broad adsorption spectrum of melanin could also allow removal of other micropollutants. PMID- 27782176 TI - Functional kinomics establishes a critical node of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain. AB - Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr991/Thr1048 phosphorylation - a key signaling event in cell swelling-induced regulatory volume decrease (RVD). In the mammalian brain, we found the Cl--sensitive WNK3 SPAK kinase complex, required for cell shrinkage-induced regulatory volume decrease (RVI) via the stimulatory phosphorylation of NKCC1 (Thr203/Thr207/Thr212), is also essential for the inhibitory phosphorylation of KCC3 (Thr991/Thr1048). This is mediated in vivo by an interaction between the CCT domain in SPAK and RFXV/I domains in WNK3 and NKCC1/KCC3. Accordingly, genetic or pharmacologic WNK3-SPAK inhibition prevents cell swelling in response to osmotic stress and ameliorates post-ischemic brain swelling through a simultaneous inhibition of NKCC1-mediated Cl- uptake and stimulation of KCC3-mediated Cl- extrusion. We conclude that WNK3-SPAK is an integral component of the long-sought "Cl-/volume-sensitive kinase" of the cation-Cl- cotransporters, and functions as a molecular rheostat of cell volume in the mammalian brain. PMID- 27782180 TI - HASE: Framework for efficient high-dimensional association analyses. AB - High-throughput technology can now provide rich information on a person's biological makeup and environmental surroundings. Important discoveries have been made by relating these data to various health outcomes in fields such as genomics, proteomics, and medical imaging. However, cross-investigations between several high-throughput technologies remain impractical due to demanding computational requirements (hundreds of years of computing resources) and unsuitability for collaborative settings (terabytes of data to share). Here we introduce the HASE framework that overcomes both of these issues. Our approach dramatically reduces computational time from years to only hours and also requires several gigabytes to be exchanged between collaborators. We implemented a novel meta-analytical method that yields identical power as pooled analyses without the need of sharing individual participant data. The efficiency of the framework is illustrated by associating 9 million genetic variants with 1.5 million brain imaging voxels in three cohorts (total N = 4,034) followed by meta analysis, on a standard computational infrastructure. These experiments indicate that HASE facilitates high-dimensional association studies enabling large multicenter association studies for future discoveries. PMID- 27782181 TI - A fully functionalized metamaterial perfect absorber with simple design and implementation. AB - Broadband perfect metamaterial absorbers have been drawing significant attention in recent years. A close-to-unity absorption over a broad spectral range is established and this facilitates many photonic applications. A more challenging goal is to construct a broadband absorber with a tailored spectral absorption. The spectral absorption control and spectral shaping are very critical in many applications, such as thermal-photovoltaic, thermal emitters, spectrum imaging system, biomedical and extraterrestrial sensing, and refractive index sensor. In this work, one-dimensional (1D) planar stacking structure is designed to achieve the ultimate goal of a functionalized absorber with a fully tailorable spectral absorption. The lithography and etching process are totally eliminated in this proposed structure, and the fabrication is fully compatible with the regular silicon IC processing. By using ~2 nm ultra-thin metallic layers with a 10-pair (10X) SiO2/Si3N4 integrated dielectric filter, we can achieve decent spectral response shaping. The planar configuration of the ultra-thin-metal metamaterial perfect absorber (MPA) is the key to the easy design/integration of the dielectric filters on top of the MPA. Specifically, band-rejected, high-pass, low pass and band-pass structure are constructed successfully. Finally, experimental evidence to support our simulation result is also provided, which proves the feasibility of our proposal. PMID- 27782182 TI - Opportunistic fungal pathogen Candida glabrata circulates between humans and yellow-legged gulls. AB - The opportunistic pathogenic yeast Candida glabrata is a component of the mycobiota of both humans and yellow-legged gulls that is prone to develop fluconazole resistance. Whether gulls are a reservoir of the yeast and facilitate the dissemination of human C. glabrata strains remains an open question. In this study, MLVA genotyping highlighted the lack of genetic structure of 190 C. glabrata strains isolated from either patients in three hospitals or fecal samples collected from gull breeding colonies located in five distinct areas along the French Mediterranean littoral. Fluconazole-resistant isolates were evenly distributed between both gull and human populations. These findings demonstrate that gulls are a reservoir of this species and facilitate the diffusion of C. glabrata and indirect transmission to human or animal hosts via environmental contamination. This eco-epidemiological view, which can be applied to other vertebrate host species, broadens our perspective regarding the reservoirs and dissemination patterns of antifungal-resistant human pathogenic yeast. PMID- 27782183 TI - Evaluating the transferability of 15 European-derived fasting plasma glucose SNPs in Mexican children and adolescents. AB - Genome wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) that are associated with fasting plasma glucose (FPG) in adult European populations. The contribution of these SNPs to FPG in non Europeans and children is unclear. We studied the association of 15 GWAS SNPs and a genotype score (GS) with FPG and 7 metabolic traits in 1,421 Mexican children and adolescents from Mexico City. Genotyping of the 15 SNPs was performed using TaqMan Open Array. We used multivariate linear regression models adjusted for age, sex, body mass index standard deviation score, and recruitment center. We identified significant associations between 3 SNPs (G6PC2 (rs560887), GCKR (rs1260326), MTNR1B (rs10830963)), the GS and FPG level. The FPG risk alleles of 11 out of the 15 SNPs (73.3%) displayed significant or non-significant beta values for FPG directionally consistent with those reported in adult European GWAS. The risk allele frequencies for 11 of 15 (73.3%) SNPs differed significantly in Mexican children and adolescents compared to European adults from the 1000G Project, but no significant enrichment in FPG risk alleles was observed in the Mexican population. Our data support a partial transferability of European GWAS FPG association signals in children and adolescents from the admixed Mexican population. PMID- 27782184 TI - Interspecific variation of warning calls in piranhas: a comparative analysis. AB - Fish sounds are known to be species-specific, possessing unique temporal and spectral features. We have recorded and compared sounds in eight piranha species to evaluate the potential role of acoustic communication as a driving force in clade diversification. All piranha species showed the same kind of sound producing mechanism: sonic muscles originate on vertebrae and attach to a tendon surrounding the bladder ventrally. Contractions of the sound-producing muscles force swimbladder vibration and dictate the fundamental frequency. It results the calling features of the eight piranha species logically share many common characteristics. In all the species, the calls are harmonic sounds composed of multiple continuous cycles. However, the sounds of Serrasalmus elongatus (higher number of cycles and high fundamental frequency) and S. manueli (long cycle periods and low fundamental frequency) are clearly distinguishable from the other species. The sonic mechanism being largely conserved throughout piranha evolution, acoustic communication can hardly be considered as the main driving force in the diversification process. However, sounds of some species are clearly distinguishable despite the short space for variations supporting the need for specific communication. Behavioural studies are needed to clearly understand the eventual role of the calls during spawning events. PMID- 27782185 TI - Fine-scale partitioning of genomic variation among recruits in an exploited fishery: causes and consequences. AB - Conservation and management of exploited species depends on accurate knowledge of how genetic variation is partitioned across a fishery, especially as it relates to recruitment. Using double-digest restriction-site associated DNA sequencing, we surveyed variation in 7,382 single nucleotide polymorphisms (SNPs) in red snapper (Lutjanus campechanus) young-of-the-year (YOY) sampled at six localities and in adults sampled at two localities in the northern Gulf of Mexico. Significant genetic heterogeneity was detected between the two adult samples, separated by ~600 km, and at spatial scales less than five kilometers among samples of YOY. Genetic differences between YOY samples and between YOY samples and adult samples were not associated with geographic distance, and a genome scan revealed no evidence of loci under selection. Estimates of the effective number of breeders, allelic richness, and relatedness within YOY samples were not consistent with sweepstakes recruitment. Instead, the data demonstrate, at least within one recruitment season, that multiple pulses of recruits originate from distinct groups of spawning adults, even at small spatial scales. For exploited species with this type of recruitment pattern, protection of spawning adults over wide geographic areas may be critical for ensuring productivity and stability of the fishery by maintaining larval supply and connectivity. PMID- 27782187 TI - Pure spin current devices based on ferromagnetic topological insulators. AB - Two-dimensional topological insulators possess two counter propagating edge channels with opposite spin direction. Recent experimental progress allowed to create ferromagnetic topological insulators realizing a quantum anomalous Hall (QAH) state. In the QAH state one of the two edge channels disappears due to the strong ferromagnetic exchange field. We investigate heterostructures of topological insulators and ferromagnetic topological insulators by means of numerical transport calculations. We show that spin current flow in such heterostructures can be controlled with high fidelity. Specifically, we propose spintronic devices that are capable of creating, switching and detecting pure spin currents using the same technology. In these devices electrical currents are directly converted into spin currents, allowing a high conversion efficiency. Energy independent transport properties in combination with large bulk gaps in some topological insulator materials may allow operation even at room temperature. PMID- 27782186 TI - Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis. AB - Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits. PMID- 27782190 TI - Current controlled switching of impedance in magnetic conductor with tilted anisotropy easy axis and its applications. AB - We present a concept and prototype of a memory element based on current driven magneto-impedance (MI) effect that stores the binary data (0, 1) as the orientation of the magnetization. The magnetization orientation in the surface layer with tilted anisotropy easy axis can be switched controllably between two stable states by applying current pulses of the appropriate sign, and can be detected by sensing the impedance. We demonstrated the functioning of a non volatile magnetic memory with a read speed performance up to and above 2 GHz. A prototype of a memory element was realized on a short piece of amorphous microwire, as this material exhibits the highest MI effect, and the required anisotropy can be quite easily obtained. Nevertheless, this concept can be extended to other materials and geometries exhibiting MI effect and possessing a required magnetic anisotropy. PMID- 27782189 TI - Molecular phylogeny of Polyneoptera (Insecta) inferred from expanded mitogenomic data. AB - The Polyneoptera represents one of the earliest insect radiations, comprising the majority of hemimetabolous orders, in which many species have great economic importance. Here, we sequenced eleven mitochondrial genomes of the polyneopteran insects by using high throughput pooled sequencing technology, and presented a phylogenetic reconstruction for this group based on expanded mitochondrial genome data. Our analyses included 189 taxa, of which 139 species represent all the major polyneopteran lineages. Multiple results support the monophyly of Polyneoptera, the monophyly of Dictyoptera, and the monophyly of Orthoptera. Sister taxon relationships Plecoptera + Dermaptera, and Zoraptera + Embioptera are also supported by most analyses. Within Dictyoptera, the Blattodea is consistently retrieved as paraphyly due to the sister group relationship of Cryptocercus with Isoptera. In addition, the results demonstrate that model selection, data treatment, and outgroup choice can have significant effects on the reconstructed phylogenetic relationships of Polyneoptera. PMID- 27782188 TI - Comprehensive analysis of trihelix genes and their expression under biotic and abiotic stresses in Populus trichocarpa. AB - Trihelix genes play important roles in plant growth and development and responses to biotic and abiotic stresses. Here, we identified 56 full-length trihelix genes in Populus trichocarpa and classified them into five groups. Most genes within a given group had similar gene structures and conserved motifs. The trihelix genes were unequally distributed across 19 different linkage groups. Fifteen paralogous pairs were identified, 14 of which have undergone segmental duplication events. Promoter cis-element analysis indicated that most trihelix genes contain stress- or phytohormone-related cis-elements. The expression profiles of the trihelix genes suggest that they are primarily expressed in leaves and roots. Quantitative real-time reverse transcription polymerase chain reaction analysis indicated that members of the trihelix gene family are significantly induced in response to osmotic, abscisic acid, salicylic acid, methyl jasmonate and pathogen infection. PtrGT10 was identified as a target gene of miR172d, which is involved in the osmotic response. Repression of PtrGT10 could increase reactive oxygen species scavenging ability and decrease cell death. This study provides novel insights into the phylogenetic relationships and functions of the P. trichocarpa trihelix genes, which will aid future functional studies investigating the divergent roles of trihelix genes belonging to other species. PMID- 27782191 TI - Synchronization in flickering of three-coupled candle flames. AB - When two or more candle flames are fused by approaching them together, the resulting large flame often exhibits flickering, i.e., prolonged high-frequency oscillation in its size and luminance. In the present work, we investigate the collective behaviour of three-coupled candle flame oscillators in a triangular arrangement. The system showed four distinct types of syncronised modes as a consequence of spontaneous symmetry breaking. The modes obtained include the in phase mode, the partial in-phase mode, the rotation mode, and an anomalous one called the "death" mode that causes a sudden stop of the flame oscillation followed by self-sustained stable combustion. We also clarified the correlation between the inter-flame distance and the frequency with which the modes occur. PMID- 27782192 TI - Responses of bacterial community structure and denitrifying bacteria in biofilm to submerged macrophytes and nitrate. AB - Submerged macrophytes play important roles in constructed wetlands and natural water bodies, as these organisms remove nutrients and provide large surfaces for biofilms, which are beneficial for nitrogen removal, particularly from submerged macrophyte-dominated water columns. However, information on the responses of biofilms to submerged macrophytes and nitrogen molecules is limited. In the present study, bacterial community structure and denitrifiers were investigated in biofilms on the leaves of four submerged macrophytes and artificial plants exposed to two nitrate concentrations. The biofilm cells were evenly distributed on artificial plants but appeared in microcolonies on the surfaces of submerged macrophytes. Proteobacteria was the most abundant phylum in all samples, accounting for 27.3-64.8% of the high-quality bacterial reads, followed by Chloroflexi (3.7-25.4%), Firmicutes (3.0-20.1%), Acidobacteria (2.7-15.7%), Actinobacteria (2.2-8.7%), Bacteroidetes (0.5-9.7%), and Verrucomicrobia (2.4 5.2%). Cluster analysis showed that bacterial community structure can be significantly different on macrophytes versus from those on artificial plants. Redundancy analysis showed that electrical conductivity and nitrate concentration were positively correlated with Shannon index and operational taxonomic unit (OTU) richness (log10 transformed) but somewhat negatively correlated with microbial density. The relative abundances of five denitrifying genes were positively correlated with nitrate concentration and electrical conductivity but negatively correlated with dissolved oxygen. PMID- 27782194 TI - Effects of Pore-Scale Disorder on Fluid Displacement in Partially-Wettable Porous Media. AB - We present a systematic, quantitative assessment of the impact of pore size disorder and its interplay with flow rates and wettability on immiscible displacement of a viscous fluid. Pore-scale simulations and micromodel experiments show that reducing disorder increases the displacement efficiency and compactness, minimizing the fluid-fluid interfacial area, through (i) trapping at low rates and (ii) viscous fingering at high rates. Increasing the wetting angle suppresses both trapping and fingering, hence reducing the sensitivity of the displacement to the underlying disorder. A modified capillary number Ca* that includes the impact of disorder lambda on viscous forces (through pore connectivity) is direct related to lambda, in par with previous works. Our findings bear important consequences on sweep efficiency and fluid mixing and reactions, which are key in applications such as microfluidics to carbon geosequestration, energy recovery, and soil aeration and remediation. PMID- 27782196 TI - Intrinsic and extrinsic pinning in NdFeAs(O,F): vortex trapping and lock-in by the layered structure. AB - Fe-based superconductors (FBS) present a large variety of compounds whose properties are affected to different extents by their crystal structures. Amongst them, the REFeAs(O,F) (RE1111, RE being a rare-earth element) is the family with the highest critical temperature Tc but also with a large anisotropy and Josephson vortices as demonstrated in the flux-flow regime in Sm1111 (Tc ~ 55 K). Here we focus on the pinning properties of the lower-Tc Nd1111 in the flux-creep regime. We demonstrate that for H//c critical current density Jc at high temperatures is dominated by point-defect pinning centres, whereas at low temperatures surface pinning by planar defects parallel to the c-axis and vortex shearing prevail. When the field approaches the ab-planes, two different regimes are observed at low temperatures as a consequence of the transition between 3D Abrikosov and 2D Josephson vortices: one is determined by the formation of a vortex-staircase structure and one by lock-in of vortices parallel to the layers. This is the first study on FBS showing this behaviour in the full temperature, field, and angular range and demonstrating that, despite the lower Tc and anisotropy of Nd1111 with respect to Sm1111, this compound is substantially affected by intrinsic pinning generating a strong ab-peak in Jc. PMID- 27782197 TI - High efficiency holographic Bragg grating with optically prolonged memory. AB - In this paper, we show that photosensitive azo-dye doped Blue-phase liquid crystals (BPLC) formed by natural molecular self-assembly are capable of high diffraction efficiency holographic recording with memory that can be prolonged from few seconds to several minutes by uniform illumination with the reference beam. Operating in the Bragg regime, we have observed 50 times improvement in the grating diffraction efficiency and shorter recording time compared to previous investigations. The enabling mechanism is BPLC's lattice distortion and index modulation caused by the action of light on the azo-dopant; upon photo excitation, the azo-molecules undergo transformation from the oblong-shaped Trans state to the bent-shaped Cis-state, imparting disorder and also cause the surrounding BPLC molecules to undergo coupled flow &reorientation leading to lattice distortion and index modulation. We also showed that the same mechanism at work here that facilitates lattice distortion can be used to frustrate free relaxation of the lattice distortion, thereby prolonging the lifetime of the written grating, provided the reference beam is kept on after recording. Due to the ease in BPLC fabrication and the availability of azo-dopants with photosensitivity throughout the entire visible spectrum, one can optimize the controlling material and optical parameters to obtain even better performance. PMID- 27782195 TI - Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase DCST1 as a novel negative regulator of Type-I interferon signaling. AB - Type I interferon (IFN-I) mediated innate immune response controls virus infections by inducing the expression of interferon stimulated genes (ISGs). Although ubiquitination plays key roles in immune signaling regulation, a human genome-wide understanding of the role of E3 ubiquitin ligases in interferon mediated ISG induction is lacking. Here, we report a genome-wide profiling of the effect of ectopic expression of 521 E3 ubiquitin ligases and substrate recognition subunits encoded in the human genome (which constitutes 84.4% of all ubiquitination related genes encoded in the human genome, hereafter termed Human Ubiquitome) on IFNbeta mediated induction of interferon stimulated DNA response element (ISRE) driven reporter activity. We identified 96 and 42 genes of the human ubiquitome as novel negative and positive regulators of interferon signaling respectively. Furthermore, we characterized DCST1 as a novel E3 ubiquitin ligase negatively regulating interferon response. Ectopic expression and gene silencing of DCST1 respectively attenuated and increased ISRE reporter activity. DCST1 regulated Type I interferon signaling by interacting with and promoting ubiquitination-mediated degradation of STAT2, an essential component of antiviral gene induction. In summary, this study provided a systems level view on the role of human ubiquitination associated genes in Type I interferon response. PMID- 27782193 TI - Lipocalin 2 (LCN2) is a promising target for cholangiocarcinoma treatment and bile LCN2 level is a potential cholangiocarcinoma diagnostic marker. AB - Cholangiocarcinoma (CCA) is a devastating disease due to resistance to traditional chemotherapies and radiotherapies. New therapeutic strategies against CCA are urgently needed. This study investigated the role of lipocalin-2 (LCN2) in human cholangiocarcinoma as a potential therapeutic target and diagnostic marker. So far, the role of LCN2 in cancer is still controversial and studies regarding the role of LCN2 in CCA are limited. LCN2 knockdown inhibited CCA cell growth in vitro and in vivo through induction of cell cycle arrest at G0/G1 phases and decreased metastatic potential due to repression of epithelial mesenchymal transition (EMT). Overexpression of LCN2 in CCA cells increased cell metastatic potential. We showed for the first time that the N-myc downstream regulated gene 1 (NDRG1) and NDRG2, known as tumor suppressor genes, are negatively regulated by LCN2 in CCA cells. LCN2 concentration in bile was higher in patients with CCA than that in patients with gallstones, with a cutoff value of 20.08 ng/ml making this a potential diagnostic marker. Higher LCN2 expression was associated with worse survival in patients with CCA. LCN2 is a promising target for CCA treatment and bile LCN2 level is a potential diagnostic marker for CCA. PMID- 27782198 TI - Hydrogen-doped Brookite TiO2 Nanobullets Array as a Novel Photoanode for Efficient Solar Water Splitting. AB - As a representative photocatalyst for photoelectrochemical solar water splitting, TiO2 has been intensively studied but most researches have focused on the rutile and anatsase phases because brookite, another important crystalline polymorph of TiO2, rarely exists in nature and is difficult to synthesize. In this work, hydrogen doped brookite (H:brookite) nanobullet arrays were synthesized via a well-designed solution reaction for the first time. H:brookite shows highly improved PEC properties with excellent stability, enhanced photocurrent, and significantly high Faradaic efficiency for overall solar water splitting. To support the experimental data, ab initio density functional theory calculations were also conducted. At the interstitial doping site that has minimum formation energy, the hydrogen atoms act as shallow donors and exist as H+. which has the minimum formation energy among three states of hydrogen (H+. H0, and H-). The calculated density of states of H:brookite shows a narrowed bandgap and an increased electron density compared to the pristine brookite. The combined experimental and theoretical results provide frameworks for the exploration of the PEC properties of doped brookite and extend our knowledge regarding the undiscovered properties of brookite of TiO2. PMID- 27782200 TI - In situ Scanning Electron Microscopy of Silicon Anode Reactions in Lithium-Ion Batteries during Charge/Discharge Processes. AB - A comprehensive understanding of the charge/discharge behaviour of high-capacity anode active materials, e.g., Si and Li, is essential for the design and development of next-generation high-performance Li-based batteries. Here, we demonstrate the in situ scanning electron microscopy (in situ SEM) of Si anodes in a configuration analogous to actual lithium-ion batteries (LIBs) with an ionic liquid (IL) that is expected to be a functional LIB electrolyte in the future. We discovered that variations in the morphology of Si active materials during charge/discharge processes is strongly dependent on their size and shape. Even the diffusion of atomic Li into Si materials can be visualized using a back scattering electron imaging technique. The electrode reactions were successfully recorded as video clips. This in situ SEM technique can simultaneously provide useful data on, for example, morphological variations and elemental distributions, as well as electrochemical data. PMID- 27782201 TI - The mechanical behavior dependence on the TiB whisker realignment during hot working in titanium matrix composites. AB - Low-cost TiB whiskers reinforced titanium matrix composite (TMCs) was fabricated with enhanced mechanical performances using in situ technologies and hot working. Morphologies observation indicates that needle-like TiB whiskers with a hexagonal transverse section grow along the [010] direction due to B27 crystal structure and its growth mechanism. Mechanical properties tests show that the mechanical behavior of the TiB whiskers reinforced TMCs is dependent on the deformation amplitudes applied in hot-working. The improvement in yield strength by hot working is attributed to the TiB whiskers realignment and the refinement of microstructure. Models are constructed to evaluate the realignment of TiB whisker during deformation and the increase in yield strength of the composite at elevated temperatures. These models clarify the alignment effect of TiB whiskers under various deformation amplitudes applied in hot-workings and reveals the yield strength dependence on TiB whiskers orientation. PMID- 27782199 TI - Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study. AB - The current study examined risk factors for sporadic pancreatic neuroendocrine tumors (PNETs), including smoking, alcohol use, first-degree family history of any cancer (FHC), and diabetes in the Han Chinese ethnic group. In this clinic based case-control analysis on 385 patients with sporadic PNETs and 614 age- and sex-matched controls, we interviewed subjects using a specific questionnaire on demographics and potential risk factors. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). No significant differences were found between patients and controls in terms of demographic variables. Most of the patients with PNETs had well-differentiated PNETs (G1, 62.9%) and non-advanced European Neuroendocrine Tumor Society (ENETS) stage (stage I or II, 83.9%). Ever/heavy smoking, a history of diabetes and a first-degree FHC were independent risk factors for non-functional PNETs. Only heavy drinking was found to be an independent risk factor for functional PNETs (AOR = 1.87; 95% confidence interval [CI], 1.01-3.51). Ever/heavy smoking was also associated with advanced ENETS staging (stage III or IV) at the time of diagnosis. This study identified first-degree FHC, ever/heavy smoking, and diabetes as risk factors for non-functional PNETs, while heavy drinking as a risk factor for functional PNETs. PMID- 27782202 TI - Exploring the Influence of Environmental Factors on Bacterial Communities within the Rhizosphere of the Cu-tolerant plant, Elsholtzia splendens. AB - Bacterial communities of rhizospheric soils play an important role in the tolerance and uptake of metal-tolerant/hyperaccumulating plants to metals, e.g. the Cu-tolerant Elsholtzia splendens native to China. In this work, pyrosequencing of the bacterial 16S rRNA gene was firstly applied to investigate the rhizospheric bacterial community of E. splendens grown at Cu contaminated sites. The 47 phyla including 11 dominant phyla (>1%) in E. splendens rhizosphere were presented. The effects of Cu and other environmental factors (total organic carbon, total nitrogen and pH) on the rhizospheric bacterial community were studied comprehensively. The phyla abundances were affected by the environmental factors to different extent, and we found pH, instead of Cu concentration, influenced UniFrac distance significantly and was identified as the most important environmental factor affecting bacterial community. In addition, the influence of environmental factors on gene profiles was explored according to the predicted metagenomes obtained by PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states). Our study illustrates a view about Cu-tolerant E. splendens rhizospheric bacterial communities (composition, diversity and gene profiles) and their influencing factors, giving a hand for the understanding on bacterial community is formed and affected in rhizosphere. PMID- 27782203 TI - Super-resolution imaging of fluorescently labeled, endogenous RNA Polymerase II in living cells with CRISPR/Cas9-mediated gene editing. AB - Live cell imaging of mammalian RNA polymerase II (Pol II) has previously relied on random insertions of exogenous, mutant Pol II coupled with the degradation of endogenous Pol II using a toxin, alpha-amanitin. Therefore, it has been unclear whether over-expression of labeled Pol II under an exogenous promoter may have played a role in reported Pol II dynamics in vivo. Here we label the endogenous Pol II in mouse embryonic fibroblast (MEF) cells using the CRISPR/Cas9 gene editing system. Using single-molecule based super-resolution imaging in the living cells, we captured endogenous Pol II clusters. Consistent with previous studies, we observed that Pol II clusters were short-lived (cluster lifetime ~8 s) in living cells. Moreover, dynamic responses to serum-stimulation, and drug mediated transcription inhibition were all in agreement with previous observations in the exogenous Pol II MEF cell line. Our findings suggest that previous exogenously tagged Pol II faithfully recapitulated the endogenous polymerase clustering dynamics in living cells, and our approach may in principle be used to directly label transcription factors for live cell imaging. PMID- 27782204 TI - Dynamics of soil organic and inorganic carbon in the cropland of upper Yellow River Delta, China. AB - Soil inorganic carbon (SIC) and organic carbon (SOC) are important carbon reservoirs in terrestrial ecosystems. However, little attention was paid to SIC dynamics in cropland. We conducted a survey in the upper Yellow River Delta of North China Plain. We collected 155 soil samples from 31 profiles, and measured SOC, SIC and soluble Ca2+ and Mg2+ contents. Our results showed that mean SOC content decreased from 9.30 g kg-1 near the surface to 2.36 g kg-1 in 80-100 cm whereas mean SIC content increased from 10.48 to 12.72 g kg-1. On average, SOC and SIC stocks over 0-100 cm were 5.73 kg C m-2 and 16.89 kg C m-2, respectively. There was a significantly positive correlation (r = 0.88, P < 0.001) between SOC and SIC in the cropland. We also found that SIC had a significantly positive correlation with both soluble Ca2+ (r = 0.57, P < 0.01) and Mg2+ (r = 0.43, P < 0.05). Our study suggested that increasing SOC might lead to an increase in SIC stocks in the cropland of North China Plain. This study highlights the importance of SIC in the carbon cycle of China's semi-arid region. PMID- 27782205 TI - Discrimination of transgenic soybean seeds by terahertz spectroscopy. AB - Discrimination of genetically modified organisms is increasingly demanded by legislation and consumers worldwide. The feasibility of a non-destructive discrimination of glyphosate-resistant and conventional soybean seeds and their hybrid descendants was examined by terahertz time-domain spectroscopy system combined with chemometrics. Principal component analysis (PCA), least squares support vector machines (LS-SVM) and PCA-back propagation neural network (PCA BPNN) models with the first and second derivative and standard normal variate (SNV) transformation pre-treatments were applied to classify soybean seeds based on genotype. Results demonstrated clear differences among glyphosate-resistant, hybrid descendants and conventional non-transformed soybean seeds could easily be visualized with an excellent classification (accuracy was 88.33% in validation set) using the LS-SVM and the spectra with SNV pre-treatment. The results indicated that THz spectroscopy techniques together with chemometrics would be a promising technique to distinguish transgenic soybean seeds from non-transformed seeds with high efficiency and without any major sample preparation. PMID- 27782206 TI - NPNT is Expressed by Osteoblasts and Mediates Angiogenesis via the Activation of Extracellular Signal-regulated Kinase. AB - Angiogenesis plays an important role in bone development and remodeling and is mediated by a plethora of potential angiogenic factors. However, data regarding specific angiogenic factors that are secreted within the bone microenvironment to regulate osteoporosis is lacking. Here, we report that Nephronectin (NPNT), a member of the epidermal growth factor (EGF) repeat superfamily proteins and a homologue of EGFL6, is expressed in osteoblasts. Intriguingly, the gene expression of NPNT is reduced in the bone of C57BL/6J ovariectomised mice and in osteoporosis patients. In addition, the protein levels of NPNT and CD31 are also found to be reduced in the tibias of OVX mice. Exogenous addition of mouse recombinant NPNT on endothelial cells stimulates migration and tube-like structure formation in vitro. Furthermore, NPNT promotes angiogenesis in an ex vivo fetal mouse metatarsal angiogenesis assay. We show that NPNT stimulates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated kinase (MAPK) in endothelial cells. Inhibition of ERK1/2 impaired NPNT-induced endothelial cell migration, tube-like structure formation and angiogenesis. Taken together, these results demonstrate that NPNT is a paracrine angiogenic factor and may play a role in pathological osteoporosis. This may lead to new targets for treatment of bone diseases and injuries. PMID- 27782207 TI - Collective Influence of Multiple Spreaders Evaluated by Tracing Real Information Flow in Large-Scale Social Networks. AB - Identifying the most influential spreaders that maximize information flow is a central question in network theory. Recently, a scalable method called "Collective Influence (CI)" has been put forward through collective influence maximization. In contrast to heuristic methods evaluating nodes' significance separately, CI method inspects the collective influence of multiple spreaders. Despite that CI applies to the influence maximization problem in percolation model, it is still important to examine its efficacy in realistic information spreading. Here, we examine real-world information flow in various social and scientific platforms including American Physical Society, Facebook, Twitter and LiveJournal. Since empirical data cannot be directly mapped to ideal multi-source spreading, we leverage the behavioral patterns of users extracted from data to construct "virtual" information spreading processes. Our results demonstrate that the set of spreaders selected by CI can induce larger scale of information propagation. Moreover, local measures as the number of connections or citations are not necessarily the deterministic factors of nodes' importance in realistic information spreading. This result has significance for rankings scientists in scientific networks like the APS, where the commonly used number of citations can be a poor indicator of the collective influence of authors in the community. PMID- 27782208 TI - Differential expression of lncRNAs during the HIV replication cycle: an underestimated layer in the HIV-host interplay. AB - Studying the effects of HIV infection on the host transcriptome has typically focused on protein-coding genes. However, recent advances in the field of RNA sequencing revealed that long non-coding RNAs (lncRNAs) add an extensive additional layer to the cell's molecular network. Here, we performed transcriptome profiling throughout a primary HIV infection in vitro to investigate lncRNA expression at the different HIV replication cycle processes (reverse transcription, integration and particle production). Subsequently, guilt by-association, transcription factor and co-expression analysis were performed to infer biological roles for the lncRNAs identified in the HIV-host interplay. Many lncRNAs were suggested to play a role in mechanisms relying on proteasomal and ubiquitination pathways, apoptosis, DNA damage responses and cell cycle regulation. Through transcription factor binding analysis, we found that lncRNAs display a distinct transcriptional regulation profile as compared to protein coding mRNAs, suggesting that mRNAs and lncRNAs are independently modulated. In addition, we identified five differentially expressed lncRNA-mRNA pairs with mRNA involvement in HIV pathogenesis with possible cis regulatory lncRNAs that control nearby mRNA expression and function. Altogether, the present study demonstrates that lncRNAs add a new dimension to the HIV-host interplay and should be further investigated as they may represent targets for controlling HIV replication. PMID- 27782209 TI - Carbon nanotubes allow capture of krypton, barium and lead for multichannel biological X-ray fluorescence imaging. AB - The desire to study biology in situ has been aided by many imaging techniques. Among these, X-ray fluorescence (XRF) mapping permits observation of elemental distributions in a multichannel manner. However, XRF imaging is underused, in part, because of the difficulty in interpreting maps without an underlying cellular 'blueprint'; this could be supplied using contrast agents. Carbon nanotubes (CNTs) can be filled with a wide range of inorganic materials, and thus can be used as 'contrast agents' if biologically absent elements are encapsulated. Here we show that sealed single-walled CNTs filled with lead, barium and even krypton can be produced, and externally decorated with peptides to provide affinity for sub-cellular targets. The agents are able to highlight specific organelles in multiplexed XRF mapping, and are, in principle, a general and versatile tool for this, and other modes of biological imaging. PMID- 27782210 TI - Multiple and diverse structural changes affect the breakpoint regions of polymorphic inversions across the Drosophila genus. AB - Chromosomal polymorphism is widespread in the Drosophila genus, with extensive evidence supporting its adaptive character in diverse species. Moreover, inversions are the major contributors to the genus chromosomal evolution. The molecular characterization of a reduced number of polymorphic inversion breakpoints in Drosophila melanogaster and Drosophila subobscura supports that their inversions would have mostly originated through a mechanism that generates duplications -staggered double-strand breaks- and has thus the potential to contribute to their adaptive character. There is also evidence for inversion breakpoint reuse at different time scales. Here, we have characterized the breakpoints of two inversions of D. subobscura -O4 and O8- involved in complex arrangements that are frequent in the warm parts of the species distribution area. The duplications detected at their breakpoints are consistent with their origin through the staggered-break mechanism, which further supports it as the prevalent mechanism in D. subobscura. The comparative analysis of inversions breakpoint regions across the Drosophila genus has revealed several genes affected by multiple disruptions due not only to inversions but also to single gene transpositions and duplications. PMID- 27782211 TI - von Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage. AB - Spontaneous intracerebral haemorrhage (ICH) is the most devastating stroke subtype and has no proven treatment. von Willebrand factor (VWF) has recently been demonstrated to promote inflammation processes. The present study investigated the pathophysiological role of VWF after experimental ICH. Functional outcomes, brain edema, blood-brain barrier (BBB) permeability, cerebral inflammation and levels of intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) were measured in a mouse model of ICH induced by autologous blood injection. We show that VWF were increased in the plasma and was accumulated in the perihematomal regions of mice subjected to ICH. Injection of VWF resulted in incerased expression of proinflammatory mediators and activation of ICAM-1 and MMP-9, associated with elevated myeloperoxidase, recruitment of neutrophils and microglia. Moreover, mice treated with VWF showed dramatically decreased pericyte coverage, more severe BBB damage and edema formation, and neuronal injury was increased compared with controls. In contrast, blocking antibodies against VWF reduced BBB damage and edema formation and improved neurological function. Together, these data identify a critical role for VWF in cerebral inflammation and BBB damage after ICH. The therapeutic interventions targeting VWF may be a novel strategy to reduce ICH-related injury. PMID- 27782213 TI - Biotic and abiotic controls on co-occurring nitrogen cycling processes in shallow Arctic shelf sediments. AB - The processes that convert bioavailable inorganic nitrogen to inert nitrogen gas are prominent in continental shelf sediments and represent a critical global sink, yet little is known of these pathways in the Arctic where 18% of the world's continental shelves are located. Moreover, few data from the Arctic exist that separate loss processes like denitrification and anaerobic ammonium oxidation (anammox) from recycling pathways like dissimilatory nitrate reduction to ammonium (DNRA) or source pathways like nitrogen fixation. Here we present measurements of these co-occurring processes using 15N tracers. Denitrification was heterogeneous among stations and an order of magnitude greater than anammox and DNRA, while nitrogen fixation was undetectable. No abiotic factors correlated with interstation variability in biogeochemical rates; however, bioturbation potential explained most of the variation. Fauna-enhanced denitrification is a potentially important but overlooked process on Arctic shelves and highlights the role of the Arctic as a significant global nitrogen sink. PMID- 27782212 TI - A Carbonaceous Membrane based on a Polymer of Intrinsic Microporosity (PIM-1) for Water Treatment. AB - As insufficient access to clean water is expected to become worse in the near future, water purification is becoming increasingly important. Membrane filtration is the most promising technologies to produce clean water from contaminated water. Although there have been many studies to prepare highly water permeable carbon-based membranes by utilizing frictionless water flow inside the carbonaceous pores, the carbon-based membranes still suffer from several issues, such as high cost and complicated fabrication as well as relatively low salt rejection. Here, we report for the first time the use of microporous carbonaceous membranes via controlled carbonization of polymer membranes with uniform microporosity for high-flux nanofiltration. Further enhancement of membrane performance is observed by O2 plasma treatment. The optimized membrane exhibits high water flux (13.30 LMH Bar-1) and good MgSO4 rejection (77.38%) as well as antifouling properties. This study provides insight into the design of microporous carbonaceous membranes for water purification. PMID- 27782214 TI - The uronic acid content of coccolith-associated polysaccharides provides insight into coccolithogenesis and past climate. AB - Unicellular phytoplanktonic algae (coccolithophores) are among the most prolific producers of calcium carbonate on the planet, with a production of ~1026 coccoliths per year. During their lith formation, coccolithophores mainly employ coccolith-associated polysaccharides (CAPs) for the regulation of crystal nucleation and growth. These macromolecules interact with the intracellular calcifying compartment (coccolith vesicle) through the charged carboxyl groups of their uronic acid residues. Here we report the isolation of CAPs from modern day coccolithophores and their prehistoric predecessors and we demonstrate that their uronic acid content (UAC) offers a species-specific signature. We also show that there is a correlation between the UAC of CAPs and the internal saturation state of the coccolith vesicle that, for most geologically abundant species, is inextricably linked to carbon availability. These findings suggest that the UAC of CAPs reports on the adaptation of coccolithogenesis to environmental changes and can be used for the estimation of past CO2 concentrations. PMID- 27782216 TI - Broadband Focusing Acoustic Lens Based on Fractal Metamaterials. AB - Acoustic metamaterials are artificial structures which can manipulate sound waves through their unconventional effective properties. Different from the locally resonant elements proposed in earlier studies, we propose an alternate route to realize acoustic metamaterials with both low loss and large refractive indices. We describe a new kind of acoustic metamaterial element with the fractal geometry. Due to the self-similar properties of the proposed structure, broadband acoustic responses may arise within a broad frequency range, making it a good candidate for a number of applications, such as super-resolution imaging and acoustic tunneling. A flat acoustic lens is designed and experimentally verified using this approach, showing excellent focusing abilities from 2 kHz and 5 kHz in the measured results. PMID- 27782215 TI - Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents. AB - Maleimides remain the reagents of choice for the preparation of therapeutic and imaging protein conjugates despite the known instability of the resulting products that undergo thiol-exchange reactions in vivo. Here we present the rational design of carbonylacrylic reagents for chemoselective cysteine bioconjugation. These reagents undergo rapid thiol Michael-addition under biocompatible conditions in stoichiometric amounts. When using carbonylacrylic reagents equipped with PEG or fluorophore moieties, this method enables access to protein and antibody conjugates precisely modified at pre-determined sites. Importantly, the conjugates formed are resistant to degradation in plasma and are biologically functional, as demonstrated by the selective imaging and detection of apoptotic and HER2+ cells, respectively. The straightforward preparation, stoichiometric use and exquisite cysteine selectivity of the carbonylacrylic reagents combined with the stability of the products and the availability of biologically relevant cysteine-tagged proteins make this method suitable for the routine preparation of chemically defined conjugates for in vivo applications. PMID- 27782217 TI - Genome-wide methylation analysis identified sexually dimorphic methylated regions in hybrid tilapia. AB - Sexual dimorphism is an interesting biological phenomenon. Previous studies showed that DNA methylation might play a role in sexual dimorphism. However, the overall picture of the genome-wide methylation landscape in sexually dimorphic species remains unclear. We analyzed the DNA methylation landscape and transcriptome in hybrid tilapia (Oreochromis spp.) using whole genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq). We found 4,757 sexually dimorphic differentially methylated regions (DMRs), with significant clusters of DMRs located on chromosomal regions associated with sex determination. CpG methylation in promoter regions was negatively correlated with the gene expression level. MAPK/ERK pathway was upregulated in male tilapia. We also inferred active cis regulatory regions (ACRs) in skeletal muscle tissues from WGBS datasets, revealing sexually dimorphic cis-regulatory regions. These results suggest that DNA methylation contribute to sex-specific phenotypes and serve as resources for further investigation to analyze the functions of these regions and their contributions towards sexual dimorphisms. PMID- 27782219 TI - Learning robust pulses for generating universal quantum gates. AB - Constructing a set of universal quantum gates is a fundamental task for quantum computation. The existence of noises, disturbances and fluctuations is unavoidable during the process of implementing quantum gates for most practical quantum systems. This paper employs a sampling-based learning method to find robust control pulses for generating a set of universal quantum gates. Numerical results show that the learned robust control fields are insensitive to disturbances, uncertainties and fluctuations during the process of realizing universal quantum gates. PMID- 27782218 TI - Cattle encephalon glycoside and ignotin reduced white matter injury and prevented post-hemorrhagic hydrocephalus in a rat model of intracerebral hemorrhage. AB - The morbidity, mortality, and disability associated with intraventricular hemorrhage (IVH) secondary to intracerebral hemorrhage (ICH) represent a global burden. To date, there is no effective therapy for ICH other than supportive care. In this study, we assessed the neuroprotective effects of Cattle encephalon glycoside and ignotin (CEGI) injection in a rat model of ICH with ventricular extension (IVH/ICH). The IVH/ICH rat model was induced via injection of type IV collagenase in the caudate nucleus of Sprague-Dawley rats. The experimental animals were randomized to receive CEGI, monosialotetrahexosyl ganglioside (GM 1), or normal saline. The modified Garcia scale, corner turn test, immunofluorescence staining for myelin basic protein (MBP) and microtubule associated protein 2 (MAP-2), transmission electron microscopy (TEM), and magnetic resonance imaging were employed to evaluate the neuroprotective effect of CEGI in the IVH/ICH rat model. CEGI treatment significantly alleviated the neurobehavioral dysfunction, reduced the lateral ventricular enlargement, promoted hematoma absorption, effectively up-regulated MBP/MAP-2 expression, and ameliorated white matter fiber damage post-ICH induction. Our results demonstrate that CEGI has significant neuroprotective effects in a rat model of IVH/ICH. Therefore, it can be used as a candidate drug for the clinical treatment of IVH/ICH. PMID- 27782220 TI - Improvement of Terahertz Wave Radiation for InAs Nanowires by Simple Dipping into Tap Water. AB - We report improvement of terahertz (THz) wave radiation for Si-based catalyst free InAs nanowires (NWs) by simple dipping into tap water (DTW). In addition, the possibility of using InAs NWs as a cost-effective method for biomedical applications is discussed by comparison to bulk InAs. The peak-to-peak current signals (PPCSs) of InAs NWs measured from THz time-domain spectroscopy increased with increasing NW height. For example, the PPCS of 10 MUm-long InAs NWs was 2.86 times stronger than that of 2.1 MUm-long NWs. The THz spectra of the InAs NWs obtained by applying a fast Fourier transformation to the current signals showed a main frequency of 0.5 THz, which can be applied to a variety of medical imaging systems. After the DTW process, structural variation was not observed for 2.1 MUm long InAs NWs. However, the top region of several InAs NWs with heights of 4.6 and 5.8 MUm merged into a conical structure. InAs NWs with a height of 10 MUm resulted in a bundle feature forming above the conical shape, where the length of bundle region was 4 MUm. After the DTW process, the PPCS for 10 MUm-long InAs NWs increased by 15 percent compared to that of the as-grown case. PMID- 27782222 TI - ? PMID- 27782223 TI - ? PMID- 27782224 TI - [Epidemiology of cancer in Italy: from real data to the need for cancer networks.] AB - The Italian Association of Medical Oncology (AIOM) and the Italian Association of Cancer Registries (AIRTUM) provide a reliable estimation of the incidence of cancer in Italy. The most outstanding data point to the steadily increasing efficacy of novel therapies, allowing patients to live longer and have a better quality of life, and the number of citizens being diagnosed with cancer - more than three million people, 4.9% of the population. Over the last years, a significant reduction in cancer incidence has been recorded among men with an opposite tendency among women. However, decreased mortality rates are observed in both sexes as a result of primary prevention measures and the promotion of large scale national screening programs. In this scenario, cancer networks may play a key role. Quality of care could be substantially improved only if regional cancer networks are implemented on the basis of shared pathways, so as to guarantee equity of access in every phase of the disease. PMID- 27782221 TI - Visceral Adiposity and Anthropometric Indicators as Screening Tools of Metabolic Syndrome among Low Income Rural Adults in Xinjiang. AB - Most previous studies on metabolic syndrome (MetS) examined urban and high income settings. We thus investigated the prevalence of MetS among a multi-ethnic population living in a low income rural area and explored the use of visceral adiposity and anthropometric indicators to identify men and women with MetS. We recruited 10,029 individuals of nomadic Kazakhs, rural Uyghur and Han residents in Xinjiang, China. MetS was defined by the Joint Interim Statement criteria. The receiver operating characteristic curve (ROC) was used to compare the area under the ROC curve (AUC) of each index. The age-adjusted prevalence of MetS was 21.8%. The visceral adiposity index (VAI), lipid accumulation product (LAP), body adiposity index (BAI) and the waist-to-height ratio (WHtR) were significantly associated with MetS, independent of ethnic, age, and other covariates. The AUC of VAI, LAP and WHtR were all greater than 0.7, and the LAP was the index that most accurately identified MetS status in men (AUC = 0.853) and women (AUC = 0.817), with the optimal cut-offs of 34.7 and 27.3, respectively. In conclusion, the prevalence of MetS in low income rural adults of Xinjiang was high and the LAP was an effective indicator for the screening of MetS. PMID- 27782225 TI - [Biomedical research from philanthropy to scarcity.] AB - Some huge information technology companies have increased investment in biomedical research: recently Google, Microsoft, and Facebook. The latter presented the ambitious Zuckerberg-Chan Initiative involving three major Californian universities: UC San Francisco, Berkeley and Stanford. These important private investments arouse reflections. First, investing in scientific research improves the corporate image of the most generous companies and it is a great marketing strategy. Second, the availability of private funds is surely useful, especially if these funds are directed to relevant projects, and produce studies conducted and disseminated in a transparent way. Third, private funding should not replace public ones, representing an integration that will not likely affect the determination of the research agenda, which should remain the prerogative of public institutions. Fourth, the researchers involved in public funded projects should benefit from the margin of freedom that private industry promises, both in the decision of research pathways and in their course. Finally, the scarcity of resources is likely to divert energy and attention of the public researchers and this aspect should be considered by decision makers when determining size and recipients of research funding. PMID- 27782226 TI - [The evolution of the treatment of advanced NSCLC.] AB - The therapeutic scenario of patients with advanced non-small-cell lung cancer (NSCLC) has dramatically changed in recent years, thanks to the improvement in the knowledge of the biology of NSCLC, the discovery of targetable oncogenic drivers, and the availability of new effective drugs also for non oncogenic addicted patients, defined "wild-type" (WT). NSCLC has been the first epithelial neoplasm treated with a targeted first-line therapy in patients harbouring EGFR activating mutations or ALK rearrangements, and new targeted-based agents directed versus other molecular alterations are currently in development. The recognition of the importance of histology for the definition of a first-line therapy of WT tumors has led to the adoption of different regimens for patients with squamous and non-squamous histology. In particular, in case of WT NSCLC with non-squamous histology, the use of platinum-based combinations including pemetrexed or bevacizumab became the standard treatment and the maintenance therapy with pemetrexed a further opportunity for selected patients. Recently, new active drugs with different mechanisms of action, including angiogenesis inhibitors, such as nintedanib or ramucirumab, and immune checkpoint inhibitors, such as nivolumab, pembrolizumab and atezolizumab, have shown relevant overall survival improvement in pretreated patients, modifying the landscape also of the second line treatment that became more rich and complex. The improvement and the application of novel technologies of molecular analysis and the identification of predictive biomarkers for new agents and in particular for immunotherapy will allow a more comprehensive molecular profiling of NSCLC and a better customization of treatments. PMID- 27782227 TI - [Cancer cachexia assessment: new tools for oncologists.] AB - The cancer anorexia-cachexia syndrome (CACS) is considered a multifactorial syndrome that leads a general decline of the cancer patient conditions, prognosis and survival, and characterized by progressive loss of body mass and functional impairment, due to marked energy metabolism imbalance and immunological disorders. It is the cause of death in almost one out of five advanced cancer patients. CACS is also accompanied with loss of quality of life, reduced response and tolerance to anticancer therapies and affected outcome. This condition arises by acute-chronic inflammation, hypercatabolism and resulting in an increased energy expenditure, anorexia and negative caloric balance. Although the international scientific community has reached some important findings in last years regarding CACS, a precise definition agreement for CACS in order to a precise patients assessment is still lacking. In light of the advances in pathogenesis and evaluation of CACS, as well as those reached in the therapy, this review aims to draft a list of key points that could be useful for the oncologist to recognize the different signs and symptoms of this syndrome, in order to evaluate and stage the cancer patients in attempt to target an early multimodal pharmacological-nutritional treatment strategy to improve his outcome and his quality of life. PMID- 27782229 TI - ? PMID- 27782230 TI - [The development of advanced competences in the nursing profession]. PMID- 27782228 TI - [Treating HIV disease: back to the patient?] AB - HIV disease has dramatically changed in the last two decades from a progressive, lethal disease to a chronic manageable condition. These changes are due to the availability of potent antiretroviral combination therapy, which also have the potential to contribute significantly to the control of the epidemic. Among persons living with HIV, incidence of immunosuppression-related opportunistic illnesses has clearly decreased, while an increase was observed in the prevalence of age-related noncommunicable comorbidities, including cardiovascular, metabolic, renal, bone and hepatic disease, due to chronic inflammatory state and to an overall aging of the population of persons with HIV. It has been predicted that by 2030 more than 80% of older persons with HIV will have at least one comorbidity, compared to 19% of non HIV-infected persons, and that one fourth of these persons will have three or more comorbidities. Among persons with HIV, the prevalence of frailty is increasing. Choice of therapeutic approach to HIV disease should take into account, in addition to the ability of drug combination to suppress viral replication, the potential for long term adherence to treatment, the lack of long term toxicity, the possibility to fully restore immune function and prevent immune activation, thus reducing the risk of chronic inflammation related disease. In addition the overall impact of treatment on patients' well-being must be considered, and patients related outcomes should be used to measure this impact. PMID- 27782231 TI - [The debate on the development of advanced competences]. AB - . The debate on the development of advanced nursing competences. The dossier aims to describe and disentagle the present Italian and international debate on the development and recognition of advanced nursing competences. Following a general brief description of the legislative national background, the attention is first of all focused on the lack of clarity on the definition of advanced competence, which is further complicated by the issue of their formal, contractual and economic recognition. To explore these issues a list of contributions is presented and some proposals are formulated to favor a better oriented development of the debate: a. A convenience sample of 139 nurses were interviewed asking to describe problems occurred in the last month that could prompt the intervention of an expert nurse and to list the clinical, managerial and educational competences of a specialized nurse in their ward. The results document the quality and the dispersion of the definitions which are perceived and applied in the general settings of care. b. The issue the post basic courses (master, specialization) offered to nurses in 2015-2016 by Italian universities were described and their aims. While the contribution of the courses in increasing the theoretical knowledge is well defined, the aims and the description of the clinical training are badly developed and an acquisition of advanced competences would seem unlikely. c. The definition of advanced competences was explored in the international literature: while evidences are available on the impact of advanced nursing on patients' outcomes, what is advanced nursing is far from being clear, and an impressive list of roles, activities and functions are considered advanced. d. Although at national level there is no formal recognition for nurses with advanced competences (with the exception of the head nurse that holds mostly an organizational rather than clinical role), the opportunities for promoting the role of specialistic/advanced nurses were described. An interview to 20 nursing managers representing 23 Italian hospitals and districts shows the huge variability of what is recognized and considered specialistic/advanced competence. Competences in stoma care, venous catheters, pressure sores, do not necessarily cover the concept of advanced competence. e. Two further contributions explore how the challenge of what is ill-defined (or cannot be defined) can be transformed in a methodological opportunity and how the growth of an health profession may break the delicate balance of the boundaries between professions. PMID- 27782232 TI - [The nurses' perception of the need of advanced competences]. PMID- 27782233 TI - [The post-basic courses for nurses offered by Italian Universities]. PMID- 27782234 TI - [The advanced nursing practice in other countries]. PMID- 27782235 TI - [The impact of the advanced clinical practice: methods, outcomes and literature research results]. PMID- 27782236 TI - [The evolution of the assessment and development of nursing competences in the Italian health-care system]. AB - . The evolution of the assessment and development of nursing competences in the Italian health-care system. The issue of the skills, in health care organizations, received a boost in the last 15 years as a result of contractual innovations that recognized different career levels in the nursing profession, and of the widespread dissemination of quality systems for certification or accreditation for excellence. These events prompted organizations to assess the competence of their professionals. A further stimulus was given by the recent debate on nursing sensitive outcomes, by the changes in patients' needs and by the increased production of knowledge from the nursing profession which contributed to an increase of competences and to their expanded role. To improve patients' care and avoid conflicts, and to maximize the benefits to users, professionals need to learn to work together, integrating and respecting roles and competences. PMID- 27782237 TI - [Specialist nursing roles in a sample of Italian hospitals and districts]. PMID- 27782238 TI - [Conclusions and reflections for a debate]. PMID- 27782239 TI - [The accreditation of professional competence: the analysis of nursing
interventions to control anxiety in surgical patients]. AB - : . The accreditation of professional competence: the analysis of nursing interventions to control anxiety in surgical patients. INTRODUCTION: The preoperative anxiety is a state of discomfort or unpleasant tension resulting from concerns about illness, hospitalization, anesthesia, surgery or the unknown. Nurses play a vital role reducing preoperative anxiety. An accreditation program was developed in Andalusia (Spain) to measure nurses' competences in this and others fields. AIMS: To analyze the accredited nurses' interventions spectrum to reduce anxiety in surgical patients and to check if their range of interventions depends upon their professional skills accreditation level. METHODS: Cross sectional study. From 20016 to 2014, 1.282 interventions performed by 303 operating room nurses accredited through the Professional Skills Accreditation Program of the Andalusian Agency for Health Care Quality (ACSA) were analyzed with the latent class analysis (LCA) and multinomial logistic regression. RESULTS: Two-thirds of the sample was accredited in Advanced level, about 31% in Expert level and 2.6% in Excellent level. Mean age of patients was 58.5+/-19.8 years. Three professional profiles were obtained from the LCA. Those nurses classified in Class I (22.4% of the sample) were more likely to be women, to can for younger patients, and to be accredited in Expert or Excellent Level and to perform the larger range of interventions, becoming therefore the most complete professional profile. CONCLUSION: Those nurses who perform a wider range of interventions and specifically two evidence based interventions such Calming Technique and Coping Enhancement are those who have a higher level of accreditation level. PMID- 27782240 TI - [What is not, and cannot be, defined as a challenging methodological opportunity:
talking of advanced competences]. PMID- 27782241 TI - [The mobile boundaries of health professions]. PMID- 27782242 TI - Control of morphology and defect density in zinc oxide for improved dye sensitized solar cells. AB - While zinc oxide (ZnO) with a mesoporous network has long been explored for adsorption of dyes and as an electron-transporting medium in dye-sensitized solar cells (DSSCs), the performance of ZnO-based DSSCs remains unsatisfactory. Despite the importance of understanding the surface characteristics of ZnO in DSSC applications, most of the studies relevant to ZnO-based DSSCs are focused on the synthesis of unique nanostructures of ZnO. In this study, we not only introduce a novel disk-shaped ZnO nanostructure, but also provide insight into the distinctive surface properties of ZnO and its influence on DSSC performance. When utilized in DSSCs, the mesoporous ZnO nanodisk yields 60% better power conversion efficiency (PCE) compared to commercial ZnO nanoparticles, which is attributed to less surface and bulk trap densities as concluded by an in-depth open-circuit voltage decay (OCVD) analysis and electrochemical impedance spectroscopy (EIS). Another aspect that contributes to the higher PCE is the better connectivity of primary particles that join together to form secondary disk-shaped particles. Furthermore, a 40% improvement in the PCE was observed by coating the mesoporous ZnO nanodisk with TiO2, which results from the passivation of the surface defects that aid in suppressing the interfacial charge recombination. PMID- 27782243 TI - Construction of a temperature-responsive terpolymer coating with recyclable bactericidal and self-cleaning antimicrobial properties. AB - Once a biomedical implant is implanted into a human body, proteins and bacteria can easily colonize the implant, and subsequently, a biofilm can grow on the surface. A biofilm can protect the inhabiting bacteria against macrophages and neutrophil cell attack from the host immune system. The most important issue for artificial antibacterial surfaces is the accumulation of the bacteria corpse after they are killed by contact, which promotes further adhesion of bacteria and biofilm formation. Therefore, we constructed a novel multifunctional bactericidal and fouling release antibacterial surface through the combination of temperature responsive N-vinylcaprolactam (VCL), hydrophilic 2-methacryloyloxyethyl phosphorylcholine (MPC) and a bactericidal quaternary ammonium salt (2 (dimethylamino)-ethyl methacrylate (DMAEMA+)). The terpolymer coating was prepared through surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization and characterized using water contact angle measurements, atomic force microscopy and spectroscopic ellipsometry. At a temperature above the lower critical solution temperature (LCST), the P(VCL-co DMAEMA+-co-MPC) terpolymer coating was in a compressed and hydrophobic state with low moisture content, which displayed bactericidal efficiency against Gram positive Staphylococcus aureus. The coating could be switched into a relatively hydrophilic surface at a temperature below the LCST, which showed self-cleaning properties against both bacteria and bovine serum albumin. The functionalized surface showed good biocompatibility against human lens epithelial cells as evaluated by morphology studies and activity measurements. PMID- 27782244 TI - Aun (n = 1-16) clusters on the ZrO2(111) surface: a DFT+U investigation. AB - The growth patterns and electronic structures of Aun clusters (n = 1-16) supported on the monoclinic ZrO2(111) surface were investigated using a DFT+U approach. We found that the supported Aun clusters prefer quasi-planar structures and lay flat on the ZrO2 surface. This result agrees well with the experimental results. Both orbital overlap and dispersion interactions contribute to the interaction between the Aun cluster and the ZrO2 surface. Electrons were transferred from the ZrO2 surface to the Aun cluster. Small energy gaps between unoccupied states in the Aun clusters and occupied states in the ZrO2 surface were found, especially for the supported Aun clusters with odd n, which may indicate that more electrons are excited from the ZrO2 surface to the Aun cluster even under visible-light irradiation. In other words, the ZrO2 support may be involved in the photocatalytic process when Aun/ZrO2 is used as a photocatalyst. PMID- 27782245 TI - Particle size-independent induction of leucism in Drosophila melanogaster by silver: nano vs. micro. AB - With the discovery of nanoscience, silver nanoparticles (AgNPs) now appear on the ingredient lists of commercial products along with bulk silver or silver microparticles (AgMPs). In the present study, we have compared the effects of silver in both nano and micro forms to assess whether particle size plays a role in the pigmentation pathway, using Drosophila melanogaster as a model organism. AgNPs were synthesized, characterized and validated. Internalization of the AgNPs and AgMPs was confirmed by atomic absorption spectroscopy. Analysis of phenol oxidase (PO) enzyme and total melanin as well as quantification of tyrosine and dihydroxy phenylalanine (dopa) were carried out to understand the perturbation of the melanization pathway. The interactions of AgNP/MP with tyrosine and dopa were investigated using various spectrometric techniques. The absence of PO activity, reduced levels of melanin, tyrosine, and dopa, and the absence of local dissemination of melanin upon cuticle injury confirmed that the AgNPs and AgMPs mediated leucism in Drosophila. The reduction of bulk silver to the nano form upon internalization was found to be the modus operandi for the AgMPs. The actions of the AgNPs and AgMPs were attributed to their binding and interaction with tyrosine and dopa via their phenolic hydroxyl groups. Silver, irrespective of its size, induced leucism in Drosophila melanogaster by binding and interacting with precursor metabolites of the melanization pathway, such as tyrosine and dopa. PMID- 27782246 TI - Co-percolation to tune conductive behaviour in dynamical metallic nanowire networks. AB - Nanowire networks act as self-healing smart materials, whose sheet resistance can be tuned via an externally applied voltage stimulus. This memristive response occurs due to modification of junction resistances to form a connectivity path across the lowest barrier junctions in the network. While most network studies have been performed on expensive noble metal nanowires like silver, networks of inexpensive nickel nanowires with a nickel oxide coating can also demonstrate resistive switching, a common feature of metal oxides with filamentary conduction. However, networks made from solely nickel nanowires have high operation voltages which prohibit large-scale material applications. Here we show, using both experiment and simulation, that a heterogeneous network of nickel and silver nanowires allows optimization of the activation voltage, as well as tuning of the conduction behavior to be either resistive switching, memristive, or a combination of both. Small percentages of silver nanowires, below the percolation threshold, induce these changes in electrical behaviour, even for low area coverage and hence very transparent films. Silver nanowires act as current concentrators, amplifying conductivity locally as shown in our computational dynamical activation framework for networks of junctions. These results demonstrate that a heterogeneous nanowire network can act as a cost effective adaptive material with minimal use of noble metal nanowires, without losing memristive behaviour that is essential for smart sensing and neuromorphic applications. PMID- 27782247 TI - Field-induced self-assembly of iron oxide nanoparticles investigated using small angle neutron scattering. AB - The magnetic-field-induced assembly of magnetic nanoparticles (NPs) provides a unique and flexible strategy in the design and fabrication of functional nanostructures and devices. We have investigated the field-induced self-assembly of core-shell iron oxide NPs dispersed in toluene by means of small-angle neutron scattering (SANS). The form factor of the core-shell NPs was characterized and analyzed using SANS with polarized neutrons. Large-scale aggregates of iron oxide NPs formed above 0.02 T as indicated by very-small-angle neutron scattering measurements. A three-dimensional long-range ordered superlattice of iron oxide NPs was revealed under the application of a moderate magnetic field. The crystal structure of the superlattice has been identified to be face-centred cubic. PMID- 27782248 TI - Synthesis of a monomolecular anionic FLP complex. AB - Despite intense research in FLP chemistry, nothing is known about monomolecular anionic FLPs and/or complexes thereof. Herein, synthesis and reaction of the first anionic FLP complex is described using [(OC)5W{(Me3Si)2HCP(H)OLi(12-crown 4)}], Cy2BCl and subsequent deprotonation by KHMDS. The obtained anionic FLP complex reacts readily with CO2 in a concerted manner. PMID- 27782249 TI - Investigation of the effect of cucurbit[7]uril complexation on the photophysical and acid-base properties of the antimalarial drug quinine. AB - Host-guest complexation of mono and dicationic quinine with cucurbit[7]uril (CB7), a water-soluble macrocyclic host molecule, has been investigated. Job's plot, time-resolved anisotropy as well as concentration dependent NMR titration confirm the binding of two CB7 macrocycles with one quinine molecule. The binding affinity of dicationic quinine with CB7 is one order of magnitude higher than the binding constant of mono-cationic quinine. Such preferential binding results in one unit pKa shift in the ground-state of the quinoline ring. However, using fluorescence spectroscopy we have obtained two acid-dissociation constants, one for quinoline ring nitrogen and the other for the nitrogen of the quinuclidine moiety. In the excited state, CB7 complexation causes one unit pKa shift for the quinoline ring and 1.9 unit shift for the quinuclidine moiety. Interestingly, a large enhancement of fluorescence lifetime and anisotropy of quinine at pH 2.7 and pH 9.0 upon CB7 complexation was observed due to the restriction of conformational flexibility. Moreover, at pH 3.0, a large fluorescence enhancement of quinine due to CB7 complexation was observed and it was quite significant as compared to that of quinine in 0.1 (M) HCl without CB7. We believe that this study of quinine complexation with CB7 will reduce phototoxicity, increase bioavailability and offer an alternative standard for quantum yield measurements in an amiable condition. PMID- 27782250 TI - A highly sensitive compact liquid sensor based on slotted phononic crystal plates. AB - Liquid sensing is achieved by using slotted phononic crystal plates (SPCP). The sensing mechanism is based on the fact that an acoustic wave confined in a small liquid slot intensively interacts with the liquid sample in the slot, and the acoustic energy flux transmission spectrum of the SPCP system strongly depends on the acoustic properties of the liquid in the slot. Consequently, the resonance frequency of the sensing system varies with the density and sound velocity of the liquid sample. Compared with the traditional Lamb wave sensor, the SPCP sensor exhibits a higher sensitivity and requires a minimal amount of liquid sample. These attractive advantages may allow the SPCP liquid sensor to be easily integrated into a chip for broad lab-on-chip biochemical sensing applications. PMID- 27782251 TI - An ultrahigh volumetric capacitance of squeezable three-dimensional bicontinuous nanoporous graphene. AB - Graphene with a large specific surface area and high conductivity has a large specific capacitance. However, its volumetric capacitance is usually very low because the restacking of 2D graphene sheets leads to the loss of the large ion accessible surface area. Here we report squeezable bicontinuous nanoporous nitrogen-doped graphene, which is extremely flexible and can tolerate large volume contraction by mechanical compression without the face-to-face restacking occurring. The compressed nanoporous N-doped graphene with a large ion accessible surface area and high conductivity shows an ultrahigh volumetric capacitance of ~300 F cm-3 together with excellent cycling stability and high rate performance. PMID- 27782252 TI - Understanding charge transport in non-doped pristine and surface passivated hematite (Fe2O3) nanorods under front and backside illumination in the context of light induced water splitting. AB - Hematite (Fe2O3) nanorods on FTO substrates have been proven to be promising photoanodes for solar fuel production but only with high temperature thermal activation which allows diffusion of tin (Sn) ions from FTO, eventually enhancing their conductivity. Hence, there is a trade-off between the conductivity of Fe2O3, and the degradation of FTO occurring at high annealing temperatures (>750 degrees C). Here, we present a comprehensive study on undoped Fe2O3 nanorods under front and back illumination to find the optimum annealing temperature. Bulk/surface charge transport efficiency analysis demonstrates minimum bulk recombination indicating overall high quality crystalline Fe2O3 and the preservation of FTO conductivity. Surface recombination is further improved by growing a TiOx overlayer, which improves the photocurrent density from 0.2 mA cm 2 (backside) to 1.2 mA cm-2 under front side and 0.8 mA cm-2 under backside illumination. It is evident from this study that the performance of undoped and unpassivated hematite nanorods is limited by electron transport, whereas that of doped/passivated hematite nanorods is limited by hole transport. PMID- 27782253 TI - An ab initio anharmonic approach to study vibrational spectra of small ammonia clusters. AB - Fermi resonance between the N-H stretching (nu1 and nu3) and the overtone of N-H bending (2nu4) in ammonia has hindered the interpretation and assignments of experimental spectra of small ammonia clusters. In this work, we carried out anharmonic vibrational calculations using MP2/aug-cc-pVDZ to examine the vibrational spectra of (NH3)n=1-5 with a focus on the size evolution. The enhancement of hydrogen bond strength due to cooperative effects will cause nu1 and nu4 to red-shift and blue-shift, respectively, when the size of the cluster increases. Our calculations show that the energy order of fundamental of nu1 and overtone of nu4 is reversed between n = 3 and n = 4. Therefore, while the resultant mixed levels do not show remarkable shifts in their peak positions, the main identity of these mixed levels changes and this causes significant re distribution of their intensities. Furthermore, our ab initio anharmonic calculation scheme can directly evaluate the coupling strength between different N-H stretching and overtone of N-H bending without any experimental parameters, thus leading us to a simpler picture to understand the Fermi resonance in (NH3)n. PMID- 27782254 TI - Phenols as probes of chemical composition of graphene oxide. AB - Graphene oxide (GO) can be conveniently used as a starting material for the preparation of selective and sensitive electrochemical sensing systems. The amount of oxygen groups present on the material can be precisely tuned by reduction methodologies which allow the selection of the optimal C/O ratio for specific analytes. An electrochemical reduction procedure is used in this work to alter the oxygen content of the GO starting material and investigate the effects on the electrochemical detection of phenolic compounds selected with different hydroxyl groups: phenol, catechol, hydroquinone and phloroglucinol. Cyclic voltammetry has been used to measure the alteration of the oxidation signal upon tuning the oxygen content of the graphene based electrode material. PMID- 27782255 TI - Systemic lupus erythematosus: molecular cloning and analysis of recombinant monoclonal kappa light chain NGTA1-Me-pro with two metalloprotease active centers. AB - It was shown previously that approximately 30% +/- 5% of antibodies against myelin basic protein (MBP) and the DNA of patients with systemic lupus erythematosus (SLE) and multiple sclerosis (MS) possess catalytic activities that play an important negative role in the pathogenesis of MS and SLE. An immunoglobulin light chain phagemid library derived from peripheral blood lymphocytes of patients with SLE was used. The small pools of phage particles displaying light chains with different affinity for MBP were isolated by affinity chromatography on MBP-Sepharose, and the fraction eluted with 0.5 M NaCl was used for preparation of individual monoclonal light chains (MLChs, 26-27 kDa). The clones were expressed in E. coli in a soluble form. MLChs were purified by metal chelating chromatography followed by FPLC-gel filtration. The activity of one MLCh (NGTA1-Me-pro) was inhibited only by EDTA, and it efficiently hydrolyzed MBP (but not other proteins) and four different oligopeptides corresponding to four known immunodominant sequences containing cleavage sites of MBP only in the presence of several different metal ions. An unexpected result was obtained: NGTA1-Me-pro demonstrated two pH optima, two optimal concentrations of Me2+ ions, and two Km values for MBP. The protein sequence of NGTA1-Me-pro, having two metalloprotease active centers, has homology with several mammalian metalloproteases. Recently, it was shown that one other MLCh possesses serine like and metalloprotease activity. The principal possibility of the existence of MLChs with several different active centers is unexpected, but very important for the further understanding of unknown possibilities for immune systems and the biological functions of antibodies. PMID- 27782256 TI - The synergistic effects of carbon coating and micropore structure on the microwave absorption properties of Co/CoO nanoparticles. AB - 25 nm carbon-coated microporous Co/CoO nanoparticles (NPs) were synthesized by integrating chemical de-alloying and chemical vapor deposition (CVD) methods. The NPs possess micropores of 0.8-1.5 nm and display a homogeneous carbon shell of about 4 nm in thickness with a low graphitization degree. The saturation magnetization (MS) and coercivity (HC) of the NPs were 70.3 emu g-1 and 398.4 Oe, respectively. The microporous Co/CoO/C NPs exhibited enhanced microwave absorption performance with a minimum reflection coefficient (RC) of -78.4 dB and a wide absorption bandwidth of 8.1 GHz (RC <= -10 dB), larger than those of the nonporous counterparts of -68.3 dB and 5.8 GHz. The minimum RC values of the microporous Co/CoO/C NPs at different thicknesses were much smaller than the nonporous counterparts. The high microwave absorption mechanism of the microporous Co/CoO/C nanocomposite can be interpreted in terms of the interfacial polarization relaxation of the core/shell and micropore structures, the effective permittivity modification of the air in the micropores and the polarization relaxation of the defects in the low-graphitization carbon shell and the porous Co NPs. Our study demonstrates that the microporous Co/CoO/C nanocomposite is an efficient microwave absorber with high absorption intensity and wide absorption bandwidth. PMID- 27782257 TI - Characteristics and determinants of ambient volatile organic compounds in primary schools. AB - This study evaluates the effects of a sampling strategy that includes the sampling season, time period, ambient environment, and location on determining the concentrations and species of ambient volatile organic compounds (VOCs) that may affect children in primary schools. Air samples were collected from playgrounds in primary schools, with four sites near an oil refinery plant in Taoyuan and two sites in Zhongli (one site near a bus terminal and the other site in a suburban area) in Taiwan. The samples were obtained on eight occasions from August 2010 to June 2011. One sample was collected from 09:00 to 11:00 and the other was collected from 13:00 to 15:00 on each occasion using passive flow controller canisters (40 mL min-1 flow rate) assembled with silica-coated stainless steel. The United States Environmental Protection Agency Method TO-15 with Photochemical Assessment Monitoring System and Urban Air Toxics standards was used to analyze the samples. The ratios of benzene, toluene, ethylbenzene, and xylenes (BTEXs) were also estimated. This study found that the sampling location and wind direction are the main determinants to monitor the concentrations and species of ambient VOCs, and the effects from the sampling season and time period are minor. Alkane, ketone, and aromatics have been ranked as the top three categories with high concentrations, and toluene, 2-butanone, and acetone have been detected with the highest concentrations among the investigated VOCs. Several VOCs emitted from stationary sources, including propane, isoprene, n-decane, chloromethane, chloroethene, chloroethane and 1,2 dichloroethane, were detected only in Taoyuan. Higher concentrations of VOC species associated with automobiles and common community sources were detected in Zhongli but not in Taoyuan. Among BTEXs ratios, toluene/ethylbenzene ratios were as high as 31.52 (standard deviation [S.D.] = 13.53) in Taoyuan and 13.66 (S.D. = 3.87) in Zhongli. Toluene/benzene ratios were as high as 15.7 in Taoyuan and 4.30 in Zhongli. This study suggests that the susceptible population exposed to ambient VOCs should be considered in planning public service facilities and the presence of VOCs should be investigated regularly. PMID- 27782258 TI - In situ dual-functional water purification with simultaneous oil removal and visible light catalysis. AB - Dual purification of both oily wastewater and dye-polluted water for enhancing the use of freshwater is an urgent task. We report herein, the facile synthesis of inorganic semiconductor nanomaterials anchored mesh for in situ dual functional water purification. This resultant mesh combines the excellent capacity of oil removal and the advantage of photocatalytic performance for dye degradation under visible light irradiation at the same time. In addition, the mesh was easily regenerated and remained unaltered in photocatalytic performance over five successive dye degradation cycles. Given the innovative integration of special wettability and photocatalytic activity of such a semiconductor material under visible light for dual elimination of various pollutants from water, we anticipate that this approach will provide a promising pathway for versatile applications in oily wastewater treatment, water purification and so on. PMID- 27782259 TI - Improving O2 reduction at an enzymatic biocathode: mimicking the lungs. AB - Here, we demonstrate the use of phospholipid micelles to enhance O2 concentrations by two-fold at the surface of a bilirubin oxidase biocathode. Specifically, 1,2-diarachidoyl-sn-glycero-3-phosphocholine was used in a glucose enzymatic fuel cell to limit power losses due to O2 transport, even in a quiescent solution. PMID- 27782260 TI - Microwave-gated dynamic nuclear polarization. AB - Dissolution dynamic nuclear polarization (D-DNP) has become a method of choice to enhance signals in nuclear magnetic resonance (NMR). Recently, we have proposed to combine cross-polarization (CP) with D-DNP to provide high polarization P(13C) in short build-up times. In this paper, we show that switching microwave irradiation off for a few hundreds of milliseconds prior to CP can significantly boost the efficiency. By implementing microwave gating, 13C polarizations on sodium [1-13C]acetate as high as 64% could be achieved with a polarization build up time constant as short as 160 s. A polarization of P(13C) = 78% could even be reached for [13C]urea. PMID- 27782261 TI - Controllable stationary photocurrents generated from a bacteriorhodopsin/upconversion nanoparticle-based bionanosystem under NIR illumination. AB - In the past few decades, tremendous effort has been dedicated to develop bacteriorhodopsin (bR)-based photo-electronic devices for generating a stationary photocurrent and further for use as a component of artificial retinas in constant illumination sensing. However, an IR-triggered stationary photocurrent with controllable amplitudes has never been realized to date. Herein, NaYF4:Yb,Er and NaYF4:Yb,Tm upconversion nanoparticles (UCNPs) with green and blue emissions, respectively, were synthesized and further incorporated with bR to build a bionanosystem. Under 980 nm NIR irradiation the UCNPs function as internal green and blue light sources to initiate the photocycle and speed up the transition of bR from M410 to the ground state, consequently accelerating the bR photocycle for the generation of a stationary photocurrent. Moreover, the photocurrent profile could be tailored by changing the blue/green emission intensity ratio. The mechanism is analysed to explore the scientific insights. The system consisting of controllable blue and green light sources may not only hold great promise to construct new types of bR-based optical devices, but also offers a useful setup to investigate the fundamental science underlying the bR photoresponse. PMID- 27782262 TI - Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis. AB - Covering: 2013 up to the end of 2015This review covers the isolation and structure of new pyrrolizidines; pyrrolizidine biosynthesis; biological activity, including the occurrence of pyrrolizidines as toxic components or contaminants in foods and beverages; and formal and total syntheses of naturally-occurring pyrrolizidine alkaloids and closely related non-natural analogues. PMID- 27782263 TI - Conjugation of a photosensitizer to near infrared light renewable persistent luminescence nanoparticles for photodynamic therapy. AB - We report 808 nm NIR light renewable NIR persistent luminescence sensitized photodynamic therapy (PDT). Persistent luminescence provides an internal light source to generate singlet oxygen for PDT. This work paves the way for the next generation of PDT without any need for continuous external light irradiation. PMID- 27782264 TI - Metal homeostasis disruption and mitochondrial dysfunction in hepatocytes exposed to sub-toxic doses of zinc oxide nanoparticles. AB - Increased production and use of zinc oxide nanoparticles (ZnO-NPs) in consumer products has prompted the scientific community to investigate their potential toxicity, and understand their impact on the environment and organisms. Molecular mechanisms involved in ZnO-NP toxicity are still under debate and focus essentially on high dose expositions. In our study, we chose to evaluate the effect of sub-toxic doses of ZnO-NPs on human hepatocytes (HepG2) with a focus on metal homeostasis and redox balance disruptions. We showed massive dissolution of ZnO-NPs outside the cell, transport and accumulation of zinc ions inside the cell but no evidence of nanoparticle entry, even when analysed by high resolution TEM microscopy coupled with EDX. Gene expression analysis highlighted zinc homeostasis disruptions as shown by metallothionein 1X and zinc transporter 1 and 2 (ZnT1, ZnT2) over-expression. Major oxidative stress response genes, such as superoxide dismutase 1, 2 and catalase were not induced. Phase 2 enzymes in term of antioxidant response, such as heme oxygenase 1 (HMOX1) and the regulating subunit of the glutamate-cysteine ligase (GCLM) were slightly upregulated, but these observations may be linked solely to metal homeostasis disruptions, as these actors are involved in both metal and ROS responses. Finally, we observed abnormal mitochondria morphologies and autophagy vesicles in response to ZnO-NPs, indicating a potential role of mitochondria in storing and protecting cells from zinc excess but ultimately causing cell death at higher doses. PMID- 27782265 TI - Achieving regio- and stereo-control in the fluorination of aziridines under acidic conditions. AB - We developed an efficient fluorination protocol that converts easily accessible aziridines into beta-fluoroamines, which are important motifs in biologically active molecules. In contrast with traditional fluorination approaches, DMPU-HF has shown both higher reactivity and regioselectivity and good functional group tolerance; thus, a wide scope of beta-fluoroamines can now be accessed conveniently. The stereochemical behavior of the ring opening depends on the substitution pattern of the aziridine substrate. PMID- 27782266 TI - Ultrafast ion migration in hybrid perovskite polycrystalline thin films under light and suppression in single crystals. AB - Understanding the influence of light on ion migration in organic-inorganic halide perovskite (OIHP) materials is important to understand the photostability of perovskite solar cells. We reveal that light could greatly reduce the ion migration energy barrier in both polycrystalline and single crystalline OIHP. The activation energies derived from conductivity measurement under 0.25 Sun decrease to less than one half of the values in the dark. A typical ion drift velocity in CH3NH3PbI3 polycrystalline films is 1.2 MUm s-1 under 1 Sun, compared with 0.016 MUm s-1 under 0.02 Sun. Ion migration across the photoactive layers in most OIHP devices thus takes only subseconds under 1 Sun illumination, which is much shorter than what it was thought to take. Most important of all, ion migration through a single crystal surface is still too slow to be observed even after illumination for two days due to the large ion diffusion activation energy, >0.38 eV. PMID- 27782267 TI - Tough and strong bioinspired nanocomposites with interfacial cross-links. AB - Strength and toughness are two mechanical properties that are generally mutually exclusive but highly sought-after in the design of advanced composite materials. There has only been limited progress in achieving both high strength and toughness in composite materials. However, the fundamental underlying mechanics remain largely unexplored, especially at the nanoscale. Inspired by the lamellar structure of nacre, here a layered graphene and polyethylene nanocomposite with tunable interfacial cross-links is studied via coarse-grained molecular dynamics simulations in order to achieve both high strength and toughness. Our simulations indicate that, as the cross-link density increases from 0 to about 25%, strength and toughness of the nanocomposite experience a surprising 91% and 76% increase respectively. This strengthening mechanism can be well explained by the extent of increased nonbonded contacts between polymer chains (van der Waals interaction) during the stretch and exceptional stretchability of each polymer chain (dihedral interaction) due to interfacial cross-links by comparing nanocomposites with and without cross-links. As the strength of cross-links increases, both mechanical strength and toughness of graphene-based polymer nanocomposite increase as expected. This may be attributed to the intra-chain bond and angle interactions among polymer chains, which may be negligible for nanocomposites with weak cross links but play a key role in enhancing both strength and toughness for nanocomposites with strong cross-links. Overall, our findings unveil the fundamental mechanism at the nanoscale for tough-and-strong polymer composites via interfacial cross-linking as well as offer a novel way to design bioinspired nanocomposites with targeted properties via tunable interfacial cross-linking. PMID- 27782268 TI - Enhanced luminescence of Au22(SG)18 nanoclusters via rational surface engineering. AB - We report design strategies for the preparation of highly luminescent Au22(SG)18 clusters, where SG is glutathione, by the functionalization of the cluster shell. In these strategies, the cluster shell was covalently modified with small aromatic molecules and pyrene chromophores that led to a 5-fold PL enhancement by rigidifying the shell-gold. Highly luminescent water-soluble gold clusters with a PL quantum yield of 30% were obtained at room temperature. To further enhance the luminescence, the pyrene chromophores in the functionalized Au22 clusters were photoexcited at 350 nm to induce energy transfer from pyrene to the Au22 cluster. Steady-state and time-resolved PL measurements have shown evidence of enhanced rigidity with increased PL lifetimes for the functionalized Au22 clusters. However, the energy transfer efficiency was found to be only 14% because of the competing electron transfer deactivation pathway as evidenced by the formation of the pyrene anion radical revealed in the ultrafast transient absorption measurements. To suppress the electron transfer pathway, the pyrene functionalized Au22 clusters were ion-paired with tetraoctylammonium (TOA) cations that could break the electron transfer pathway, leading to a dramatic 37 fold increase in PL brightness with the resonance energy transfer efficiency of ca. 80%. This work presents effective design strategies for the preparation of highly luminescent gold clusters by the combination of rigidifying effect and energy transfer sensitization. PMID- 27782269 TI - Highly active nickel-cobalt/nanocarbon thin films as efficient water splitting electrodes. AB - Developing low cost, highly active and stable electrocatalysts for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) using the same electrolyte has remained a major challenge. Herein, we report a novel and robust material comprised of nickel-cobalt nanoparticles coated on a porous nitrogen-doped carbon (NC) thin film synthesized via a two-step pulsed laser deposition technique. The optimized sample (Ni0.5Co0.5/NC) achieved the lowest overpotentials of 176 mV and 300 mV at a current density of 10 mA cm-2 for HER and OER, respectively. The optimized OER activity might be attributed to the available metal oxide nanoparticles with an effective electronic structure configuration and enhanced mass/charge transport capability. At the same time, the porous nitrogen doped carbon incorporated with cobalt and nickel species can serve as an excellent HER catalyst. As a result, the newly developed electrocatalysts manifest high current densities and strong electrochemical stability in overall water splitting, outperforming most of the previously reported non-precious metal-based catalysts. PMID- 27782270 TI - Enhanced bone morphogenic property of parylene-C. AB - The ability to induce osteointegration was introduced to a parylene-C surface via the simple and intuitive process of protein adsorption mediated by hydrophobic interactions. In this way, bone morphogenetic protein (BMP)-2, fibronectin, and platelet-rich plasma (PRP) could be immobilized on parylene-C surfaces. This approach alleviates concerns related to the use of potentially harmful substances in parylene-C modification processes. The adsorbed protein molecules were quantitatively characterized with respect to adsorption efficacy and binding affinity, and the important biological activities of the proteins were also examined using both early and late markers of osteogenetic activity, including alkaline phosphatase expression, calcium mineralization and marker gene expression. Additionally, the adsorbed PRP exhibited potential as a substitute for expensive recombinant growth factors by effectively inducing comparable osteogenetic activity. In addition to the excellent biocompatibility of parylene C and its ability to coat a wide variety of substrate materials, the modification of parylene-C via protein adsorption provides unlimited possibilities for installing specific biological functions, expanding the potential applications of this material to include various biointerface platforms. PMID- 27782271 TI - Efficient electro/photocatalytic water reduction using a [NiII(N2Py3)]2+ complex. AB - The pyridine-rich complex [NiII(LN2Py3)(MeCN)](ClO4)2 (1) acts as an efficient electro- and photocatalyst in the generation of H2 from water. Observed TONs reach 1050 for electrocatalysis and a remarkable 3500 for photocatalysis. Experimental and DFT data support the ligand-reduced [NiIL] as the catalytically active species, contrasting with the [CoIL] observed for cobalt catalysts. PMID- 27782272 TI - C8-H bond activation vs. C2-H bond activation: from naphthyl amines to lactams. AB - Pd-catalyzed selective amine-oriented C8-H bond functionalization/N-dealkylative carbonylation of naphthyl amines has been achieved. The amine group from dealkylation is proposed to be the directing group for promoting this process. It represents a straightforward and easy method to access various biologically important benzo[cd]indol-2(1H)-one derivatives. PMID- 27782273 TI - A plasmonic liquid junction photovoltaic cell with greatly improved power conversion efficiency. AB - A plasmonic liquid junction photovoltaic cell with greatly improved power conversion efficiency is described. When illuminated with simulated sunlight, the device (Au-TiO2/V3+(0.018 M), V2+(0.182 M)/Pt) reproducibly and sustainably produces an VOC of 0.50 V and a JSC of 0.5 mA cm-2, corresponding to a power conversion efficiency of 0.095%. PMID- 27782274 TI - Simultaneous measurement of dynamic force and spatial thin film thickness between deformable and solid surfaces by integrated thin liquid film force apparatus. AB - Interactions involving deformable surfaces reveal a number of distinguishing physicochemical characteristics that do not exist in interactions between rigid solid surfaces. A unique fully custom-designed instrument, referred to as integrated thin liquid film force apparatus (ITLFFA), was developed to study the interactions between one deformable and one solid surface in liquid. Incorporating a bimorph force sensor with interferometry, this device allows for the simultaneous measurement of the time-dependent interaction force and the corresponding spatiotemporal film thickness of the intervening liquid film. The ITLFFA possesses the specific feature of conducting measurement under a wide range of hydrodynamic conditions, with a displacement velocity of deformable surfaces ranging from 2 MUm s-1 to 50 mm s-1. Equipped with a high speed camera, the results of a bubble interacting with hydrophilic and partially hydrophobic surfaces in aqueous solutions indicated that ITLFFA can provide information on interaction forces and thin liquid film drainage dynamics not only in a stable film but also in films of the quick rupture process. The weak interaction force was extracted from a measured film profile. Because of its well-characterized experimental conditions, ITLFFA permits the accurate and quantitative comparison/validation between measured and calculated interaction forces and temporal film profiles. PMID- 27782275 TI - Zirconocene-assisted remote cleavage of C-C and C-O bonds: application to acyclic stereodefined metalated hydrocarbons. AB - The molding of molecules through remote functionalisation has increasingly become popular as it provides original and flexible synthetic alternatives to classical retrosynthetic analysis. In this Perspective article, we summarise more than a decade of studies in the specific field of remote activation of inert C-C and C-O bonds using the unique abilities of organozirconocene species mainly from our own research group. By demonstrating that these reactions represent novel and powerful entries towards acyclic stereodefined reactive organometallic species, we aim to show the vast opportunities this concept-driven methodology discovery offers. PMID- 27782276 TI - Regioselective synthesis of naphthoquinone/naphthoquinol-carbohydrate hybrids by [4 + 2] anionic annulations and studies on their cytotoxicity. AB - An efficient and regioselective synthetic route to naphthoquinone/naphthoquinol carbohydrate hybrids has been developed. It is based upon anionic annulation of 3 nucleofugalphthalides with an acrylate appended sugar moiety. In each of the annulations studied, the arene-carbohydrate hybrids were obtained in good to excellent yields. The in vitro cytotoxic activity of the synthetic naphthoquinone/naphthonol-carbohydrate hybrids were evaluated against the human cervical cancer cell line (HeLa), and a few of them were found to exhibit potent anticancer activity against the cell line. PMID- 27782277 TI - Relating microstructure and particle-level stress in colloidal crystals under increased confinement. AB - The mechanical properties of crystalline materials can be substantially modified under confinement. Such modified macroscopic properties are usually governed by the altered microstructures and internal stress fields. Here, we use a parallel plate geometry to apply a quasi-static squeeze flow crushing a colloidal polycrystal while simultaneously imaging it with confocal microscopy. The confocal images are used to quantify the local structure order and, in conjunction with Stress Assessment from Local Structural Anisotropy (SALSA), determine the stress at the single-particle scale. We find that during compression, the crystalline regions break into small domains with different geometric packing. These domains are characterized by a pressure and deviatoric stress that are highly localized with correlation lengths that are half those found in bulk. Furthermore, the mean deviatoric stress almost doubles, suggesting a higher brittleness in the highly-confined samples. PMID- 27782278 TI - Synthesis of quinazolines from 2-aminobenzylamines with benzylamines and N substituted benzylamines under transition metal-free conditions. AB - This work reports the synthesis of quinazolines from 2-aminobenzylamines with N substituted benzylamines in the presence of molecular iodine. The developed methodology works smoothly under transition-metal free, additive free and solvent free conditions. The use of O2 as a green oxidant makes it a greatly economical, green and sustainable protocol. Moreover, no aqueous work up is required thereby enhancing the efficiency. A series of quinazoline derivatives were synthesized successfully in good to excellent yields. PMID- 27782280 TI - A metal-free cyclic iminium induced one-pot double annulation cascade: access to dihydroisoquinolinium (DHIQ) salts. AB - A reactive cyclic iminium induced one-pot Groebke-Blackburn-Bienayme (GBB) double annulation cascade (DAC) for the synthesis of skeletally diverse DHIQ salts has been described. The key features of this protocol are transition-metal and solvent-free, mild reaction conditions, robust method, one-step construction of two privileged heterocyclic rings, clean reaction profile and operational simplicity. PMID- 27782283 TI - An overview of the synthesis of acyl hydrazides from aldehydes and reactions of the products thereof. AB - Herein a review on the methods for the formation and reaction of acyl hydrazides will be given. There is particular focus on the synthesis of acyl hydrazides from aldehyde precursors with examination of the various approaches (e.g. metal-based (rhodium, copper) and non-metal-based (aerobically- and photoorganocatalytically initiated)) that have been used to achieve this. Finally, strategies to utilise acyl hydrazides for the formation of an array of useful entities will be detailed. PMID- 27782284 TI - Silver-catalyzed nucleophilic substitution of aminals with ethyl diazoacetate: a new pathway to beta-amino-alpha-diazoesters. AB - A novel silver-catalyzed nucleophilic substitution of aminals with ethyl diazoacetate producing beta-amino-alpha-diazoesters has been developed. A series of aminals with different amino moieties and substituents were successfully incorporated in this reaction, which delivered a wide range of beta-amino-alpha diazocarbonyl compounds in the presence of a lower catalyst loading in 2 hours. PMID- 27782279 TI - Stereoselective alkyne semihydrogenations with an air-stable copper(i) catalyst. AB - An air-stable and preactivated copper(i) hydroxide/N-heteroyclic carbene (NHC) complex for alkyne semihydrogenations is reported. Next to an enhanced practicability of the process, the resulting alkenes are obtained with high Z selectivities and no overreduction to the corresponding alkanes. PMID- 27782282 TI - Synthetic methods for 1,3-diamines. AB - 1,3-Diamines not only are significant motifs in natural products, but also serve as building blocks in synthetic organic chemistry. However, unlike their 1,2 diamine counterparts, limited efforts have been devoted to the development of an effective synthetic approach to 1,3-diamines. In this review, the synthetic methods for the preparation of 1,3-diamines are summarized. PMID- 27782285 TI - Micelle response to changes in solvent properties. AB - The dynamics of co-polymer systems play an important role in the preparation and stability of formulations, as well as on their capability to function in drug delivery systems. Micelle inversion can occur as a result of a change in concentration when a solvent is very volatile and evaporates, or as a result of a change in solvent quality upon addition of another solvent to the original solution, or upon changes in pH. In this work, dissipative particle dynamics (DPD) is used to examine the dynamics of micelle inversion in concentrated systems of diblock and triblock amphiphiles, where interactions between neighboring aggregates are observed. Significant differences were observed in the inversion process of different amphiphilic molecules, with a large amount of co polymer exchange between inverting aggregates made of diblock amphiphiles, and practically no exchange of molecules between aggregates during the inversion of triblock copolymer aggregates. Fundamental mechanisms of inversion are revealed that provide information which can be used to help design micelles for targeted drug release and allow understanding of history dependant formulations. PMID- 27782286 TI - Progress in aminosugar derived asymmetric organocatalysis. AB - In the last decade aminosugars, especially d-glucoamine based organocatalysts, have been applied to catalyze various asymmetric reactions such as aldol reactions, Michael addition, Strecker reactions, Biginelli reactions, epoxidation, fluorination, and imine reduction, and for the synthesis of various biologically important molecules such as 3-alkylnitro-2-hydroxynaphthoquinones, trans-dihydrobenzofurans etc. Immense growth has been also observed in the structural modification of aminosugar based organocatalysts to obtain the best results from them. This review sheds light on such organocatalytic transformations reported in last the decade including the effect of the structural modification of sugar amines on their catalytic efficiency and the stereoselectivity of the reaction. PMID- 27782281 TI - Carbohydrate receptors combining both a macrocyclic building block and flexible side arms as recognition units: binding properties of compounds with CH2OH groups as side arms. AB - New representatives of compounds combining both a macrocyclic building block and two flexible side arms as recognition units were prepared and their binding properties toward selected carbohydrates were evaluated. The aim of this study was to examine the effects of the replacement of the heterocycle-bearing side arms by smaller units, such as hydroxy groups, on the binding capability. The design of this type of receptor was inspired by the participation of the side chain hydroxy group of serine and threonine in the biorecognition of carbohydrates. Such structural modifications enable the recognition of structure activity relationships, which are of high importance in the development of carbohydrate receptors with predictable binding strength and selectivity. PMID- 27782291 TI - Person-generated Data in Self-quantification. A Health Informatics Research Program. AB - OBJECTIVES: The availability of internet-connected mobile, wearable and ambient consumer technologies, direct-to-consumer e-services and peer-to-peer social media sites far outstrips evidence about the efficiency, effectiveness and efficacy of using them in healthcare applications. The aim of this paper is to describe one approach to build a program of health informatics research, so as to generate rich and robust evidence about health data and information processing in self-quantification and associated healthcare and health outcomes. METHODS: The paper summarises relevant health informatics research approaches in the literature and presents an example of developing a program of research in the Health and Biomedical Informatics Centre (HaBIC) at the University of Melbourne. The paper describes this program in terms of research infrastructure, conceptual models, research design, research reporting and knowledge sharing. RESULTS: The paper identifies key outcomes from integrative and multiple-angle approaches to investigating the management of information and data generated by use of this Centre's collection of wearable, mobiles and other devices in health self monitoring experiments. These research results offer lessons for consumers, developers, clinical practitioners and biomedical and health informatics researchers. CONCLUSIONS: Health informatics is increasingly called upon to make sense of emerging self-quantification and other digital health phenomena that are well beyond the conventions of healthcare in which the field of informatics originated and consolidated. To make a substantial contribution to optimise the aims, processes and outcomes of health self-quantification needs further work at scale in multi-centre collaborations for this Centre and for health informatics researchers generally. PMID- 27782287 TI - Graphical Presentation of Patient-Treatment Interaction Elucidated by Continuous Biomarkers. Current Practice and Scope for Improvement. AB - BACKGROUND: Biomarkers providing evidence for patient-treatment interaction are key in the development and practice of personalized medicine. Knowledge that a patient with a specific feature - as demonstrated through a biomarker - would have an advantage under a given treatment vs. a competing treatment can aid immensely in medical decision-making. Statistical strategies to establish evidence of continuous biomarkers are complex and their formal results are thus not easy to communicate. Good graphical representations would help to translate such findings for use in the clinical community. Although general guidelines on how to present figures in clinical reports are available, there remains little guidance for figures elucidating the role of continuous biomarkers in patient treatment interaction (CBPTI). OBJECTIVES: To combat the current lack of comprehensive reviews or adequate guides on graphical presentation within this topic, our study proposes presentation principles for CBPTI plots. In order to understand current practice, we review the development of CBPTI methodology and how CBPTI plots are currently used in clinical research. METHODS: The quality of a CBPTI plot is determined by how well the presentation provides key information for clinical decision-making. Several criteria for a good CBPTI plot are proposed, including general principles of visual display, use of units presenting absolute outcome measures, appropriate quantification of statistical uncertainty, correct display of benchmarks, and informative content for answering clinical questions especially on the quantitative advantage for an individual patient with regard to a specific treatment. We examined the development of CBPTI methodology from the years 2000 - 2014, and reviewed how CBPTI plots were currently used in clinical research in six major clinical journals from 2013 - 2014 using the principle of theoretical saturation. Each CBPTI plot found was assessed for appropriateness of its presentation and clinical utility. RESULTS: In our review, a total of seven methodological papers and five clinical reports used CBPTI plots which we categorized into four types: those that distinguish the outcome effect for each treatment group; those that show the outcome differences between treatment groups (by either partitioning all individuals into subpopulations or modelling the functional form of the interaction); those that evaluate the proportion of population impact of the biomarker; and those that show the classification accuracy of the biomarker. The current practice of utilizing CBPTI plots in clinical reports suffers from methodological shortcomings: the lack of presentation of statistical uncertainty, the outcome measure scaled by relative unit instead of absolute unit, incorrect use of benchmarks, and being non informative in answering clinical questions. CONCLUSIONS: There is considerable scope for improvement in the graphical representation of CBPTI in clinical reports. The current challenge is to develop instruments for high-quality graphical plots which not only convey quantitative concepts to readers with limited statistical knowledge, but also facilitate medical decision-making. PMID- 27782288 TI - Development of a Standardized Rating Tool for Drug Alerts to Reduce Information Overload. AB - BACKGROUND: A well-known problem in current clinical decision support systems (CDSS) is the high number of alerts, which are often medically incorrect or irrelevant. This may lead to the so-called alert fatigue, an overriding of alerts, including those that are clinically relevant, and underuse of CDSS in general. OBJECTIVES: The aim of our study was to develop and to apply a standardized tool that allows its users to evaluate the quality of system generated drug alerts. The users' ratings can subsequently be used to derive recommendations for developing a filter function to reduce irrelevant alerts. METHODS: We developed a rating tool for drug alerts and performed a web-based evaluation study that also included a user review of alerts. In this study the following categories were evaluated: "data linked correctly", "medically correct", "action required", "medication change", "critical alert", "information gained" and "show again". For this purpose, 20 anonymized clinical cases were randomly selected and displayed in our customized CDSS research prototype, which used the summary of product characteristics (SPC) for alert generation. All the alerts that were provided were evaluated by 13 physicians. The users' ratings were used to derive a filtering algorithm to reduce overalerting. RESULTS: In total, our CDSS research prototype generated 399 alerts. In 98 % of all alerts, medication data were rated as linked correctly to drug information; in 93 %, the alerts were assessed as "medically correct"; 19.5 % of all alerts were rated as "show again". The interrater-agreement was, on average, 68.4 %. After the application of our filtering algorithm, the rate of alerts that should be shown again decreased to 14.8 %. CONCLUSIONS: The new standardized rating tool supports a standardized feedback of user-perceived clinical relevance of CDSS alerts. Overall, the results indicated that physicians may consider the majority of alerts formally correct but clinically irrelevant and override them. Filtering may help to reduce overalerting and increase the specificity of a CDSS. PMID- 27782290 TI - Technology in Rehabilitation: Evaluating the Single Leg Squat Exercise with Wearable Inertial Measurement Units. AB - BACKGROUND: The single leg squat (SLS) is a common lower limb rehabilitation exercise. It is also frequently used as an evaluative exercise to screen for an increased risk of lower limb injury. To date athlete / patient SLS technique has been assessed using expensive laboratory equipment or subjective clinical judgement; both of which are not without shortcomings. Inertial measurement units (IMUs) may offer a low cost solution for the objective evaluation of athlete / patient SLS technique. OBJECTIVES: The aims of this study were to determine if in combination or in isolation IMUs positioned on the lumbar spine, thigh and shank are capable of: (a) distinguishing between acceptable and aberrant SLS technique; (b) identifying specific deviations from acceptable SLS technique. METHODS: Eighty-three healthy volunteers participated (60 males, 23 females, age: 24.68 + / - 4.91 years, height: 1.75 + / - 0.09 m, body mass: 76.01 + / - 13.29 kg). All participants performed 10 SLSs on their left leg. IMUs were positioned on participants' lumbar spine, left shank and left thigh. These were utilized to record tri-axial accelerometer, gyroscope and magnetometer data during all repetitions of the SLS. SLS technique was labelled by a Chartered Physiotherapist using an evaluation framework. Features were extracted from the labelled sensor data. These features were used to train and evaluate a variety of random-forests classifiers that assessed SLS technique. RESULTS: A three IMU system was moderately successful in detecting the overall quality of SLS performance (77 % accuracy, 77 % sensitivity and 78 % specificity). A single IMU worn on the shank can complete the same analysis with 76 % accuracy, 75 % sensitivity and 76 % specificity. Single sensors also produce competitive classification scores relative to multi-sensor systems in identifying specific deviations from acceptable SLS technique. CONCLUSIONS: A single IMU positioned on the shank can differentiate between acceptable and aberrant SLS technique with moderate levels of accuracy. It can also capably identify specific deviations from optimal SLS performance. IMUs may offer a low cost solution for the objective evaluation of SLS performance. Additionally, the classifiers described may provide useful input to an exercise biofeedback application. PMID- 27782296 TI - The International Committee of Medical Journal Editors trial data sharing requirement and participants' consent. AB - The International Committee of Medical Journal Editors (ICMJE) has published a draft proposal on de-identified individual clinical trial participant data (IPD) sharing, stating that sharing trial data requires planning to ensure appropriate research ethics committee approval and participants' informed consent. This is why its implementation will be deferred for 1 year after the publication of the final version of the policy. When conducting research with anonymous data, it is not feasible to obtain the informed consent from research participants. De identified IPD are anonymous to the investigator who is performing the secondary analysis. De-identified IPD meta-analyses have been conducted for decades. Public funders, industry and foundations have recently implemented new IPD sharing procedures; almost all trials used for secondary analyses so far were conducted without participant's consent to de-identified IPD. As stated by the ICMJE, de identified IPD protects participant's confidentiality. It follows that publishing secondary analyses from completed trials without participant's consent is ethically acceptable. From the ethical perspective, the ICMJE requirement on de identified IPD sharing should be implemented from the day the policy is published. PMID- 27782289 TI - Unobtrusive and Continuous Monitoring of Alcohol-impaired Gait Using Smart Shoes. AB - BACKGROUND: Alcohol ingestion influences sensory-motor function and the overall well-being of individuals. Detecting alcohol-induced impairments in gait in daily life necessitates a continuous and unobtrusive gait monitoring system. OBJECTIVES: This paper introduces the development and use of a non-intrusive monitoring system to detect changes in gait induced by alcohol intoxication. METHODS: The proposed system employed a pair of sensorized smart shoes that are equipped with pressure sensors on the insole. Gait features were extracted and adjusted based on individual's gait profile. The adjusted gait features were used to train a machine learning classifier to discriminate alcohol-impaired gait from normal walking. In experiment of pilot study, twenty participants completed walking trials on a 12 meter walkway to measure their sober walking and alcohol impaired walking using smart shoes. RESULTS: The proposed system can detect alcohol-impaired gait with an accuracy of 86.2 % when pressure value analysis and person-dependent model for the classifier are applied, while statistical analysis revealed that no single feature was discriminative for the detection of gait impairment. CONCLUSIONS: Alcohol-induced gait disturbances can be detected with smart shoe technology for an automated monitoring in ubiquitous environment. We demonstrated that personal monitoring and machine learning-based prediction could be customized to detect individual variation rather than applying uniform boundary parameters of gait. PMID- 27782295 TI - Nitrergic and opioidergic systems affect radiographic density and histomorphometric indices in bile-duct-ligated cirrhotic rats. AB - Metabolic bone disease is a major issue in chronic liver disease. Increased production of nitric oxide (NO) and elevation of endogenous opioids have been suggested to occur during cholestasis/cirrhosis. We aimed to investigate the involvement of nitrergic and opioidergic systems in bone loss after bile-duct ligation (BDL) in rats using optical density (OD) evaluation and histomorphometric analysis. BDL- and sham-operated (SO) rats received injections of 3 mg/kg Nomega-Nitro-L-arginine methyl-ester-hydrochloride (L-NAME) as an NO synthase inhibitor, 10 mg/kg naltrexone (NTX) as an opioid-receptors antagonist or saline once daily for 28 days. Lateral cephalometric radiographs were taken on days 0 and 28 and histomorphometric and biochemical indices were measured. Plasma levels of total bilirubin and alkaline-phosphate were markedly increased in BDL compared with SO rats (p<=0.05). Among the studied variables, osteoclast number/mm trabecular surface showed significant increase in BDL animals compared to controls, which was significantly reduced following NO-synthase inhibition (p<=0.05). Similarly, cortical area slightly decreased in BDL animals in comparison to controls, whereas both L-NAME and NTX significantly increased this variable. Following BDL, optical density increased in the skulls of cirrhotic animals and showed a significant decrease after blocking opioid-receptors (p<=0.05). Inhibition of NO-synthase and/or opioid receptors caused significant changes in OD and histomorphometric parameters in BDL rats, both in favor of reducing bone loss. If confirmed by further studies, it seems that manipulation of these systems might be able to improve bone problems in subjects with cholestasis/cirrhosis. PMID- 27782301 TI - Clinical manifestations and pathogenesis of cutaneous lymphomas: current status and future directions. AB - The primary cutaneous lymphomas are a heterogeneous group of T-, Natural Killer- and B- cell neoplasms with a wide range of clinical and pathological presentations, and with very different prognoses compared to systemic lymphomas. Recent studies have shown that the skin microenvironment, which is composed of various immune cell subsets as well as their spatial distribution and T-cell interactions through different chemokines and cytokines, has an important role in the development and pathogenesis of cutaneous lymphomas and has assisted in the development of novel and more effective immunotherapies. The following review will focus on the major subtypes of primary cutaneous lymphomas, including the clinical and histological patterns, molecular hallmarks, and current and future treatment strategies. PMID- 27782298 TI - Traumatization, Marital Adjustment, and Parenting among Veterans and Their Spouses: A Longitudinal Study of Reciprocal Relations. AB - Despite considerable research on secondary traumatization, the ramifications of veterans' and their wives' posttraumatic stress symptoms (PTSS) for the family system remain largely uninvestigated. Beginning to fill this gap, the current study aims to investigate the reciprocal relations between both spouses' PTSS and marital adjustment, and the implications these bear for their parental functioning. Two hundred and twenty-five Israeli veterans (mean age = 58.62, SD = 7.6) from the 1973 Yom Kippur War and their wives (mean age = 58.28, SD = 5.79) were examined at two points in time: 30 (T1) and 35-37 years after the war (T2). Analysis included longitudinal actor-partner interdependence modeling and sequential mediation analyses. The results show that higher PTSS among the wives at T1 predicted higher PTSS among husbands at T2, and vice versa, and predicted their husbands' marital adjustment at T2. Moreover, wives' PTSS at T1 had a significant effect on parental overinvolvement of both parents at T2, but neither their PTSS nor their husbands' PTSS had an impact on positive parenting. In the intrapersonal domain, better marital adjustment at T1 predicted positive parenting among both spouses in subsequent measurement. Interpersonally, wives' lower marital adjustment at T1 predicted husbands' higher parental functioning, but not vice versa. Furthermore, marital adjustment mediated the association between PTSS and positive parenting for both spouses. The results emphasize the detrimental ramifications of war trauma on the interpersonal domains in veterans' families. Hence, both marital and parental consequences of trauma should be considered in clinical family interventions. PMID- 27782299 TI - Association between irritability and bias in attention orienting to threat in children and adolescents. AB - BACKGROUND: Irritability, a frequent complaint in children with psychiatric disorders, reflects increased predisposition to anger. Preliminary work in pediatric clinical samples links irritability to attention bias to threat, and the current study examines this association in a large population-based sample. METHODS: We studied 1,872 children (ages 6-14) using the Development and Well Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL), and dot-probe tasks. Irritability was defined using CBCL items that assessed temper tantrums and hot temper. The dot-probe task assessed attention biases for threat-related (angry face) stimuli. Multiple regression analysis was used to assess specificity of associations to irritability when adjusting for demographic variables and co occurring psychiatric traits. Propensity score matching analysis was used to increase causal inference when matching for demographic variables and co occurring psychiatric traits. RESULTS: Irritability was associated with increased attention bias toward threat-related cues. Multiple regression analysis suggests associations between irritability and threat bias are independent from demographic variables, anxiety, and externalizing traits (attention deficit/hyperactivity, conduct, and headstrong/hurtful), but not from broad internalizing symptoms. Propensity score matching analysis indicated that this association was found for irritable versus nonirritable groups matched on demographic and co-occurring traits including internalizing symptoms. CONCLUSIONS: Irritability in children is associated with biased attention toward threatening information. This finding, if replicated, warrants further investigation to examine the extent to which it contributes to chronic irritability and to explore possible treatment implications. PMID- 27782292 TI - N,N-Dimethylacetamide Significantly Attenuates LPS- and TNFalpha-Induced Proinflammatory Responses Via Inhibition of the Nuclear Factor Kappa B Pathway. AB - Previously, we have shown that N,N-dimethylacetamide (DMA) prevents inflammation induced preterm birth in a murine model, inhibits LPS-induced increases in placental pro-inflammatory cytokines and up-regulates the anti-inflammatory cytokine Interleukin-10 (IL-10). However, DMA's mechanism of action remains to be elucidated. In the current study we investigate how DMA produces its anti inflammatory effect. Using in vitro and ex vivo models, we show that DMA suppresses secretion of pro-inflammatory cytokines in lipopolysaccharide (LPS) induced RAW 264.7 cells, TNFalpha-challenged JEG-3 cells and LPS-stimulated human placental explants. DMA significantly attenuated the secretion of TNFalpha, IL-6, IL-10, and granulocyte macrophage colony stimulating factor (GM-CSF) from LPS stimulated RAW 264.7 cells, IL-6 secretion from TNFalpha-stimulated JEG-3 cells and TNFalpha, IL-6, IL-10, GM-CSF and Interleukin-8 (IL-8) from LPS-stimulated human placental explants. We further investigated if DMA's effect on cytokine expression involves the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways. DMA (10 mM) significantly inhibited nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaBalpha) degradation in LPS-stimulated RAW 264.7 cells, but there was no significant change in the expression of phosphorylated or native forms of downstream proteins in the MAPK pathway. In addition, DMA significantly attenuated luciferase activity in cells co transfected with NF-kappaB-Luc reporter plasmid, but not with AP-1-Luc or CEBP Luc reporters. Overall, our findings suggest that the anti-inflammatory activity of DMA is mediated by inhibition of the NF-kappaB pathway via decreased IkappaBalpha degradation. PMID- 27782297 TI - Botulinum toxin type A versus botulinum toxin type B for cervical dystonia. AB - BACKGROUND: This is an update of a Cochrane review first published in 2003. Cervical dystonia is the most common form of focal dystonia and is a disabling disorder characterised by painful involuntary head posturing. There are two available formulations of botulinum toxin, with botulinum toxin type A (BtA) usually considered the first line therapy for this condition. Botulinum toxin type B (BtB) is an alternative option, with no compelling theoretical reason why it might not be as- or even more effective - than BtA. OBJECTIVES: To compare the efficacy, safety and tolerability of botulinum toxin type A (BtA) versus botulinum toxin type B (BtB) in people with cervical dystonia. SEARCH METHODS: To identify studies for this review we searched the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, reference lists of articles and conference proceedings. All elements of the search, with no language restrictions, were last run in October 2016. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) comparing BtA versus BtB in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two independent authors assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third author. We performed meta-analyses using the random-effects model, for the comparison BtA versus BtB to estimate pooled effects and corresponding 95% confidence intervals (95% CI). No prespecified subgroup analyses were carried out. The primary efficacy outcome was improvement on any validated symptomatic rating scale, and the primary safety outcome was the proportion of participants with adverse events. MAIN RESULTS: We included three RCTs, all new to this update, of very low to low methodological quality, with a total of 270 participants.Two studies exclusively enrolled participants with a known positive response to BtA treatment. This raises concerns of population enrichment, with a higher probability of benefit from BtA treatment. None of the trials were free of for-profit bias, nor did they provide information regarding registered study protocols. All trials evaluated the effect of a single Bt treatment session, and not repeated treatment sessions, using doses from 100 U to 250 U of BtA (all onabotulinumtoxinA, or Botox, formulations) and 5000 U to 10,000 U of BtB (rimabotulinumtoxinB, or Myobloc/Neurobloc).We found no difference between the two types of botulinum toxin in terms of overall efficacy, with a mean difference of -1.44 (95% CI -3.58 to 0.70) points lower on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for BtB-treated participants, measured at two to four weeks after injection. The proportion of participants with adverse events was also not different between BtA and BtB (BtB versus BtA risk ratio (RR) 1.40; 95% CI 1.00 to 1.96). However, when compared to BtA, treatment with BtB was associated with an increased risk of one adverse events of special interest, namely treatment-related sore throat/dry mouth (BtB versus BtA RR of 4.39; 95% CI 2.43 to 7.91). Treatment-related dysphagia (swallowing difficulties) was not different between BtA and BtB (RR 2.89; 95% CI 0.80 to 10.41). The two types of botulinum toxin were otherwise clinically non-distinguishable in all the remaining outcomes. AUTHORS' CONCLUSIONS: The previous version of this review did not include any trials, since these were still ongoing at the time. Therefore, with this update we are able to change the conclusions of this review. There is low quality evidence that a single treatment session of BtA (specifically onabotulinumtoxinA) and a single treatment session of BtB (rimabotulinumtoxinB) are equally effective and safe in the treatment of adults with certain types of cervical dystonia. Treatment with BtB appears to present an increased risk of sore throat/dry mouth, compared to BtA. Overall, there is no clinical evidence from these single-treatment trials to support or contest the preferential use of one form of botulinum toxin over the other. PMID- 27782302 TI - Palladium-Catalyzed Direct Cross-Coupling of Carboranyllithium with (Hetero)Aryl Halides. AB - A palladium-catalyzed direct C-arylation reaction of readily available cage carboranyllithium reagents with aryl halides has been developed for the first time. This method is applicable to a wide range of aryl halide substrates including aryl iodides, aryl bromides, and heteroaromatic halides. PMID- 27782300 TI - Resident and student education in otolaryngology: A 10-year update on e-learning. AB - OBJECTIVES/HYPOTHESIS: E-learning, in its most rudimentary form, is the use of Internet-based resources for teaching and learning purposes. In surgical specialties, this definition encompasses the use of virtual patient cases, digital modeling, and online tutorials, as well as standardized video and imaging. As new technological frontiers rapidly emerge within otolaryngology, e learning may be an effective alternative to traditional teaching. Here we present a systematic review of the literature assessing the efficacy of e-learning for otolaryngology education and a discussion of the relevance of these programs for both medical students and residents within the field. STUDY DESIGN: Systematic review. METHODS: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted according to the guidelines defined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Twelve studies met inclusion criteria. These studies measured a range of outcomes from basic science anatomical knowledge to clinically relevant endpoints such as diagnostic accuracy. Nearly all of the studies reported greater satisfaction and/or significantly increased objective knowledge using the e learning intervention compared to traditional techniques. CONCLUSIONS: E-learning proves to be a powerful alternative to standard teaching techniques within otolaryngology education for both residents and medical students. Future work should focus on validating specific e-learning programs and accessing long-term knowledge retention using these innovative platforms. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E219-E224, 2017. PMID- 27782303 TI - Change-point detection of cognitive states across multiple trials in functional neuroimaging. AB - Many functional neuroimaging-based studies involve repetitions of a task that may require several phases, or states, of mental activity. An appealing idea is to use relevant brain regions to identify the states. We developed a novel change point methodology that adapts to the repeated trial structure of such experiments by assuming the number of states stays fixed across similar trials while allowing the timing of change-points to change across trials. Model fitting is based on reversible-jump MCMC. Simulation studies verified its ability to identify change points successfully. We applied this technique to data collected via functional magnetic resonance imaging (fMRI) while each of 20 subjects solved unfamiliar arithmetic problems. Our methodology supplies both a summary of state dimensionality and uncertainty assessments about number of states and the timing of state transitions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27782305 TI - Pulse Oximeter Derived Blood Pressure Measurement in Patients With a Continuous Flow Left Ventricular Assist Device. AB - Currently, blood pressure (BP) measurement is obtained noninvasively in patients with continuous flow left ventricular assist device (LVAD) by placing a Doppler probe over the brachial or radial artery with inflation and deflation of a manual BP cuff. We hypothesized that replacing the Doppler probe with a finger-based pulse oximeter can yield BP measurements similar to the Doppler derived mean arterial pressure (MAP). We conducted a prospective study consisting of patients with contemporary continuous flow LVADs. In a small pilot phase I inpatient study, we compared direct arterial line measurements with an automated blood pressure (ABP) cuff, Doppler and pulse oximeter derived MAP. Our main phase II study included LVAD outpatients with a comparison between Doppler, ABP, and pulse oximeter derived MAP. A total of five phase I and 36 phase II patients were recruited during February-June 2014. In phase I, the average MAP measured by pulse oximeter was closer to arterial line MAP rather than Doppler (P = 0.06) or ABP (P < 0.01). In phase II, pulse oximeter MAP (96.6 mm Hg) was significantly closer to Doppler MAP (96.5 mm Hg) when compared to ABP (82.1 mm Hg) (P = 0.0001). Pulse oximeter derived blood pressure measurement may be as reliable as Doppler in patients with continuous flow LVADs. PMID- 27782293 TI - Peroxisome proliferator activated receptor gamma 2 modulates late pregnancy homeostatic metabolic adaptations. AB - Pregnancy requires the adaptation of maternal energy metabolism including expansion and functional modifications of adipose tissue. Insulin resistance (IR), predominantly during late gestation, is a physiological metabolic adaptation that serves to support the metabolic demands of fetal growth. The molecular mechanisms underlying these adaptations are not fully understood and may contribute to gestational diabetes mellitus. Peroxisome proliferator activated receptor gamma (PPARgamma) controls adipogenesis, glucose and lipid metabolism and insulin sensitivity. The PPARgamma2 isoform is mainly expressed in adipocytes and is thus likely to contribute to adipose tissue adaptation during late pregnancy. In the present study, we investigated the contribution of PPARgamma2 to the metabolic adaptations occurring during the late phase of pregnancy in the context of IR. Using a model of late pregnancy in PPARgamma2 knockout (KO) mice, we found that deletion of PPARgamma2 exacerbated IR in association with lower serum adiponectin levels, increased body weight and enhanced lipid accumulation in liver. Lack of PPARgamma2 provoked changes in the distribution of fat mass and preferentially prevented the expansion of the perigonadal depot while at the same time exacerbating inflammation. PPARgamma2KO pregnant mice presented adipose tissue depot-dependent decreased expression of genes involved in lipid metabolism. Collectively, these data indicate that PPARgamma2 is essential to promote healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term. PMID- 27782307 TI - Estimation of relative free energies of binding using pre-computed ensembles based on the single-step free energy perturbation and the site-identification by Ligand competitive saturation approaches. AB - Accurate and rapid estimation of relative binding affinities of ligand-protein complexes is a requirement of computational methods for their effective use in rational ligand design. Of the approaches commonly used, free energy perturbation (FEP) methods are considered one of the most accurate, although they require significant computational resources. Accordingly, it is desirable to have alternative methods of similar accuracy but greater computational efficiency to facilitate ligand design. In the present study relative free energies of binding are estimated for one or two non-hydrogen atom changes in compounds targeting the proteins ACK1 and p38 MAP kinase using three methods. The methods include standard FEP, single-step free energy perturbation (SSFEP) and the site identification by ligand competitive saturation (SILCS) ligand grid free energy (LGFE) approach. Results show the SSFEP and SILCS LGFE methods to be competitive with or better than the FEP results for the studied systems, with SILCS LGFE giving the best agreement with experimental results. This is supported by additional comparisons with published FEP data on p38 MAP kinase inhibitors. While both the SSFEP and SILCS LGFE approaches require a significant upfront computational investment, they offer a 1000-fold computational savings over FEP for calculating the relative affinities of ligand modifications once those pre computations are complete. An illustrative example of the potential application of these methods in the context of screening large numbers of transformations is presented. Thus, the SSFEP and SILCS LGFE approaches represent viable alternatives for actively driving ligand design during drug discovery and development. (c) 2016 Wiley Periodicals, Inc. PMID- 27782306 TI - Prognostic stratification of oestrogen receptor-positive HER2-negative lymph node negative class of breast cancer. AB - AIMS: Multigene assay is recommended currently for prognostic stratification of the clinically indeterminate group of breast cancer (BC) patients defined as lymph node (LN)-negative, oestrogen receptor (ER)-positive, HER2-negative (LN- /ER+ /HER2- ) to determine the use of chemotherapy. However, this cohort, comprising approximately 40% of BC, is not a homogeneous group and shows variable outcome. This study aims to determine the prognostic value of routinely assessed variables, singly and in combination, in LN- /ER+ /HER2- BC patients. METHODS AND RESULTS: A total of 830 LN- /ER+ /HER2- chemotherapy-naive BCs were investigated. The prognostic value of histological grade, tumour size, lymphovascular invasion (LVI), progesterone receptor (PgR) and Ki67 labelling index (Ki67LI) was assessed. In this series, only 25% of patients received hormone therapy. Median follow-up was 172 months. In the whole cohort, tumour grade, size, LVI, PgR and Ki67LI were correlated highly with outcome in a time-dependent manner. The outcome of this group varied widely from 97% (20% of cases) to 50% survival rate after 10-year follow-up using a combination of these markers. A prognostic index (Nottingham Px) incorporating grade, size, PgR and Ki67LI, was developed. The index can stratify the whole cohort robustly as well as the higher-risk subgroup (NPI score >3.4) into distinct prognostic classes. CONCLUSION: Current routinely assessed variables can provide additional prognostic information in LN- /ER+ /HER2- BC. The proposed (Nottingham Px) index can stratify the BC clinically indeterminate group of patients into excellent and poor prognostic subgroups and can be used to identify reliably patients for systemic chemotherapy or further multigene prognostic testing. Performance of prognostic variables in these tumours is time-dependent, and should be considered in future studies. PMID- 27782304 TI - Nanomedicine and personalised medicine: understanding the personalisation of health care in the molecular era. AB - Globally supported by public policy and investment, nanomedicine is presented as an ongoing medical revolution that will radically change the practice of health care from diagnostic to therapeutic, and everything in between. One of nanomedicine's major promises is that of personalised medicine, enabling diagnostics and therapeutics tailored to individual needs and developing a truly 'patient-friendly' medical approach. Based on qualitative interviews with nanomedicine researchers in Canada, this article explores the emerging concept of personalised medicine as it becomes entangled with nanomedical research. More precisely, drawing on insights from science studies and the sociology of expectations, it analyses researchers' perceptions of personalised medicine in the cutting edge of current nanomedicine research. Two perceptions of personalisation are identified; a molecular conception of individuality and a technical conception of personalisation. The article concludes by examining the relationship between the two conceptions and contrasts them with the normative reflex of a more expansive conception of personalised medicine. PMID- 27782311 TI - Ageing, masculinity and Parkinson's disease: embodied perspectives. AB - Parkinson's disease (PD) presents as an illness which predominantly affects older men. However older men's lived experiences of PD, including how they are influenced by age and gender relations has seen little empirical study. Drawing on Watson's male body schema, this paper explores how men engage with masculinities and ageing in order to make sense and meaning from PD. Data is presented from 30 narrative and semi structured interviews with 15 men of various ages who were living with PD. Findings suggest that PD threatens a visceral embodiment located in the body's basic movements and intimate functions; a pragmatic embodiment expressed through men's everyday occupations and an experiential embodiment concerned with emotions and sensations felt within and through the body. In addition, each dimension of men's embodiment also intersected with the ageing process, a process also shaped in turn by broader social and cultural concerns regarding the positions and possibilities of men's lives as they move through the life course. This paper concludes by discussing the implications of gender and ageing in understanding men's experiences of PD. PMID- 27782317 TI - What is my impact? Another rant against the undead? No! PMID- 27782312 TI - Weighted analysis of composite endpoints with simultaneous inference for flexible weight constraints. AB - Composite endpoints are widely used as primary endpoints of randomized controlled trials across clinical disciplines. A common critique of the conventional analysis of composite endpoints is that all disease events are weighted equally, whereas their clinical relevance may differ substantially. We address this by introducing a framework for the weighted analysis of composite endpoints and interpretable test statistics, which are applicable to both binary and time-to event data. To cope with the difficulty of selecting an exact set of weights, we propose a method for constructing simultaneous confidence intervals and tests that asymptotically preserve the family-wise type I error in the strong sense across families of weights satisfying flexible inequality or order constraints based on the theory of chi-2-distributions. We show that the method achieves the nominal simultaneous coverage rate with substantial efficiency gains over Scheffe's procedure in a simulation study and apply it to trials in cardiovascular disease and enteric fever. (c) 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 27782310 TI - Reflectance confocal microscopy for the evaluation of sensitive skin. AB - BACKGROUND: Nowadays, the diagnosis for sensitive skin relies on subjective assessment or on the combination of subjective and objective evaluation. No quantitative evaluation is available. It could be expected that confocal microscopy imaging could be of interest to better define the condition. METHODS: Total 166 healthy female subjects were recruited in this study. Firstly, all subjects completed the sensitive questionnaire. Then, the cutaneous structures were measured by the reflectance confocal microscopy (RCM) on the face and fossa cubitalia. The lactic acid sting test was conducted finally. According to the results of self-perception sensitive skin questionnaire and lactic acid stinging test to evaluate facial skin sensitivity the both positive subjects were regarded as sensitive skin group and both negative group as healthy control group. RESULT: The results of RCM indicating that the proportion of 'disarranged honeycomb pattern' and 'spongiform edema' in the sensitive group and healthy control group were statistically different (P < 0.05), respectively; The following report 'damaged dermal papilla rings' was not a distinctive pattern, with no significant statistical difference (P > 0.05). The epidermal thickness was 38.88 +/- 6.81 MUm, healthy control group was 40.31 +/- 9.37 MUm in, respectively, sensitive skin group and healthy control group, there was no significant statistical difference between the two groups (P > 0.05). The honeycomb structure depth of sensitive group was 20.57 +/- 4.86 MUm. It was for 23.27 +/- 6.38 MUm, healthy control group the difference being statistically different between the two groups (P < 0.05). CONCLUSION: Based on the RCM results, 'epidermal honeycomb structure' and 'spongiform edema' may be used as new skin signs of RCM evaluation of sensitive skin effectively. Indeed, sensitive skin honeycomb structure depth was thinner compared with healthy control group. Such a specific pattern has good clinical and monitoring value for the further exploration. RCM could provide new data and patterns for the evaluation of sensitive skin. PMID- 27782294 TI - A Novel Role for Programmed Cell Death Receptor Ligand-1 (PD-L1) in Sepsis Induced Intestinal Dysfunction. AB - Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, co-inhibitory molecule, programmed death ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it isn't known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability, tissue cytokine levels were assessed. Subsequently, septic or non-septic patient colonic samples (assigned by pathology report) were immunohistochemically stained for PD L1 I a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly up-regulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed an increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability, tissue levels of IL 6, TNF-alpha and MCP-1, and prevented ileal tight junction protein loss compared to WT after sepsis. Comparatively, while Caco2 cell monolayers responded to inflammatory cytokine stimulation also with elevated PD-L1 expression, increased monolayer permeability and altering/decreasing monolayer tight junction protein morphology/expression; these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of ICE PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction. PMID- 27782309 TI - Individual changes in preclinical spinocerebellar ataxia identified via increased motor complexity. AB - BACKGROUND: Movement changes in autosomal-dominant spinocerebellar ataxias are suggested to occur many years before clinical manifestation. Detecting and quantifying these changes in the preclinical phase offers a window for future treatment interventions and allows the clinician to decipher the earliest dysfunctions starting the evolution of spinocerebellar ataxia. We hypothesized that quantitative movement analysis of complex stance and gait tasks allows to (i) reveal movement changes already at early stages of the preclinical phase when clinical ataxia signs are still absent and to (ii) quantify motor progression in this phase. METHODS: A total of 46 participants (14 preclinical spinocerebellar ataxia mutation carriers [spinocerebellar ataxias 1,2,3,6], 9 spinocerebellar ataxia patients at an early stage; 23 healthy controls) were assessed by quantitative movement analyses of increasingly complex stance and walking tasks in a cross-sectional design. RESULTS: Body sway in stance and spatiotemporal variability in tandem walking differentiated between preclinical mutation carriers and healthy controls (P < .01). Complex movement conditions allowed one to discriminate even those mutation carriers without any clinical signs in posture and gait (SARAposture&gait = 0; P < .04). Multivariate regression analysis categorized preclinical mutation carriers on a single-subject level with 100% accuracy within a range of 10 years to the estimated onset. Movement features in stance and gait correlated significantly with genetically estimated time to onset, indicating a gradual increase of motor changes with increasing proximity to disease manifestation. CONCLUSION: Our results provide evidence for subclinical motor changes in spinocerebellar ataxia, which allow to discriminate patients without clinical signs even on a single-subject basis and may help capture disease progression in the preclinical phase. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27782313 TI - Cytotoxic Epstein-Barr virus-positive large B cell lymphoma: a regulatory B cell derived neoplasia? AB - AIMS: A new subtype of granzyme B (GrB)-producing regulatory B cells (Bregs ) has been described recently; these peculiar cytotoxic B cells are increased significantly in interleukin (IL)-21-rich settings, and in particular during HIV and Epstein-Barr virus (EBV) infection. Our aim is to report a unique case of an EBV-positive diffuse large B cell lymphoma (DLBCL) with cytotoxic features arisen in an HIV+ patient, and to understand if this lesion may represent a proliferation of neoplastic cytotoxic Bregs . METHODS AND RESULTS: We describe a 66-year-old male patient who presented with cervical lymph node enlargement and B symptoms; subsequently, HIV infection was diagnosed. Histopathological, immunohistochemical and molecular studies were performed, and revealed an EBV positive DLBCL with cytotoxic features. Considering the immunological setting and unconventional phenotype observed, we tried to evaluate further the expression of GrB and IL-21 in another 150 aggressive B cell lymphomas (17 of 150 EBV+ , two of 150 EBV+ /HIV+ ). Minimal dot-like expression of GrB was found in seven lymphomas (in fewer than 1% of tumour cells), three of which were EBV-positive. CONCLUSIONS: Breg origin has never been reported in B cell lymphomas. We describe an exceptional case of EBV-positive DLBCL with aberrant expression of cytotoxic markers in a patient with a previously unknown HIV infection. We propose cytotoxic Bregs as a possible normal counterpart for this unusual tumour. PMID- 27782315 TI - Minimally Circulatory-Assisted On-Pump Beating Coronary Artery Bypass Grafting for Patients With Complex Conditions for Off-Pump Surgery. AB - Off-pump coronary artery bypass grafting (OPCAB) in patients with acute myocardial infarction (AMI) is difficult because of circulatory deterioration during displacement of the heart. At our institution, we performed minimally circulatory-assisted on-pump beating coronary artery bypass grafting (MICAB) in these patients. During MICAB, support flow was controlled at a minimal level to maintain a systemic blood pressure of approximately 100 mm Hg and a pulmonary arterial systolic pressure of <30 mm Hg, providing optimal pulsatile circulation for end-organ perfusion and prevention of heart congestion. From September 2006 to March 2012, MICAB was performed in 37 patients. Either emergent or urgent MICAB was performed in 27 patients following AMI because of hemodynamic instability during reconstruction. Elective MICAB was performed in the remaining 10 patients because of dilated left ventricle (LV) or small target coronary arteries. The details of bypass grafts, perioperative renal function, and early and mid-term morbidity and mortality were compared between the patients who received MICAB and the 37 consecutive patients who underwent OPCAB during the study period at our hospital. The assist flow indices (actual support flow/body surface area) during anastomosis to the left anterior descending artery, left circumflex artery, and right coronary artery were 0.95 +/- 0.48 L/min/m2 , 1.32 +/- 0.53 L/min/m2 , and 1.15 +/- 0.47 L/min/m2 , respectively, in the emergent and urgent patients following AMI, and 0.44 +/- 0.39 L/min/m2 , 1.25 +/- 0.39 L/min/m2 , and 1.14 +/- 0.43 L/min/m2 , respectively, in the elective patients with either dilated LVs or small target vessels. The lowest mixed venous oxygen saturation during pump support in the MICAB group was significantly higher than that in the OPCAB group (83.8 +/- 10.8%, 71.6 +/- 7.5%, P < 0.001). Comparing MICAB and OPCAB, the median number of distal bypass grafts for both groups was 4 (25th, 75th percentile: 3, 4) (P = 0.558); the complete revascularization rates were 94.6 and 97.3%, respectively (not significant [NS]); the acute patency rates were 98.9 and 99.2%, respectively (NS); and the 30-day mortality rates were 2.7 and 0%, respectively (NS). No instances of either cerebrovascular complications or newly occurring postoperative renal failure were noted in either group. There were no statistically significant differences between the groups with respect to early and mid-term results (freedom from all-cause death: 82.9 vs. 86.5%, respectively, and freedom from cardiac events at 3 years: 96.4 vs. 96.4%, respectively). MICAB is a safe alternative to OPCAB, particularly in patients with AMI and dilated LV. MICAB is associated with high rates of complete revascularization and acute graft patency, adequate preservation of end-organ function, and early and mid-term results comparable with those observed following OPCAB. PMID- 27782308 TI - Factors affecting SPF in vitro measurement and correlation with in vivo results. AB - OBJECTIVE: The in vitro evaluation of SPF is still a problem due to the lack of repeatability and correlation between the in vitro and in vivo data, and many authors are currently working to develop an internationally harmonized method. Very recently, the use of several "adjuvant" ingredients such as boosters, antioxidants, immunomodulators, solvents and film-forming ingredients have further complicated the pattern for product developers that should frequently run in vivo test. The aim of this study was to understand whether a simple and cheap in vitro method could be optimized in order to provide both statistically repeatable and predictive SPF measurement. METHODS: In vitro SPF assessments were carried out on 75 commercial products. The SPF was measured according to two laboratory methods (A and B), using different substrates (PMMA and surgical tape TransporeTM), quantity of product and spectrophotometers. In order to evaluate whether a standard technique of spreading could lead to a statistically reliable result, we applied different spreading pressure (100 g and 200 g). Furthermore, we investigate whether other parameters characterizing the product (SPF category, filter and texture) might represent statically significant variables affecting the measures. We then compared the results obtained from in vitro SPF measure of 11 products to in vivo SPF, in order to assess the predictability of in vitro methods. RESULTS: Several problems were encountered in confirming the weakness of the in vitro procedures. Pressure, SPF category, filter and texture did not affect significantly the results. Overall best results were obtained with the B2 method that in terms of repeatability and predictivity provided statistically better results. Method A with TransporeTM tape showed better in vitro-in vivo correlation than Method B with PMMA plates. CONCLUSION: In our investigation, we demonstrated that it is possible for a single laboratory to optimize internal methods and protocols to achieve repeatable and predictive in vitro results, but it is extremely difficult to develop methods reproducible and equally reliable in different laboratories, probably due to "external variables" (e.g. environmental, operator), which are difficult to control. PMID- 27782314 TI - A Novel Blood Viscosity Estimation Method Based on Pressure-Flow Characteristics of an Oxygenator During Cardiopulmonary Bypass. AB - During cardiopulmonary bypass (CPB), blood viscosity conspicuously increases and decreases due to changes in hematocrit and blood temperature. Nevertheless, blood viscosity is typically not evaluated, because there is no technology that can provide simple, continuous, noncontact monitoring. We modeled the pressure-flow characteristics of an oxygenator in a previous study, and in that study we quantified the influence of viscosity on oxygenator function. The pressure-flow monitoring information in the oxygenator is derived from our model and enables the estimation of viscosity. The viscosity estimation method was proposed and investigated in an in vitro experiment. Three samples of whole bovine blood with different hematocrit levels (21.8, 31.0, and 39.8%) were prepared and perfused into the oxygenator. As the temperature changed from 37 degrees C to 27 degrees C, the mean inlet pressure (Pin ) and outlet pressure (Pout ) of the oxygenator and the flow (Q) and viscosity of the blood were measured. The estimated viscosity was calculated from the pressure gradient (DeltaP = Pin - Pout ) and Q and was compared to the measured blood viscosity. A strong correlation was found between the two methods for all samples. Bland-Altman analysis revealed a mean bias of -0.0263 mPa.s, a standard deviation of 0.071 mPa.s, limits of agreement of -0.114-0.166 mPa.s, and a percent error of 5%. Therefore, this method is considered compatible with the torsional oscillation viscometer that has plus or minus 5% measurement accuracy. Our study offers the possibility of continuously estimating blood viscosity during CPB. PMID- 27782316 TI - 99m Tc-tricarbonyl labeling of paclitaxel as an antimicrotubule agent and its evaluation in B16-F10 melanoma tumor-bearing mice. AB - In the present study paclitaxel (taxol) was labeled with [99m Tc(CO)3 (H2 O)3 ]+ core. Labeling was optimized, and radiochemical analysis was determined by thin layer chromatography and high performance liquid chromatography. Radiocomplex was evaluated and verified further as a tumor characterization agent in B16-F10 melanoma tumor-bearing mice. The [99m Tc(CO)3 (H2 O)3 ]+ -paclitaxel complex with high specific activity (0.77 GBq/MUmol) and labeling yield (96.8 +/- 1.3) was obtained. No decrease in labeling was observed up to 6 hours, and the stability of the radiocomplex was found adequate. Our main achievement was high accumulation of radiolabeled paclitaxel in tumor (4.51 +/- 0.65 percentage injected dose per gram [%ID/g] at 2-h postinjection) followed by significant reduction (1.86 +/- 0.27%ID/g) at 4-hour postinjection. Because paclitaxel is a substrate for multidrug resistance, 99m Tc-tricarbonyl-paclitaxel imaging would be useful for tumor characterization rather than tumor detection. PMID- 27782318 TI - The emerging roles of mannose-binding lectin-associated serine proteases (MASPs) in the lectin pathway of complement and beyond. AB - Mannose-binding lectin (MBL)-associated serine proteases (MASPs) are the enzymatic constituents of the lectin pathway of the complement system. They are complexed with large pattern recognition molecules (PRMs) such as MBL, other collectins, and ficolins. The main function of two of the three MASPs has crystallized lately: MASP-1 autoactivates first, then it activates MASP-2, and finally both participate in the formation of the C4b2a convertase. In addition to this, both enzymes are involved in several other processes which are subject to intense research nowadays. Notably, MASP-1, as a promiscuous enzyme, has been implicated in the coagulation cascade, in the kinin generating contact system, and in cellular activation through protease-activated receptor (PAR) cleavage on endothelial cells. The third protease MASP-3 has emerged recently as the protease responsible for pro-factor D activation in resting blood, providing a fundamental link between two complement pathways. At present all three MASPs have at least one well-defined role and several other possible functions were implicated. Defect or more likely over-activation of MASPs may culminate into diseases such as ischemia-reperfusion injury (IRI); hence, MASPs are all potential targets of drug development. PMID- 27782319 TI - Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. AB - Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities. PMID- 27782320 TI - Innate immune mediators in cancer: between defense and resistance. AB - Chronic inflammation in the tumor microenvironment and evasion of the antitumor effector immune response are two of the emerging hallmarks required for oncogenesis and cancer progression. The innate immune system not only plays a critical role in perpetuating these tumor-promoting hallmarks but also in developing antitumor adaptive immune responses. Thus, understanding the dual role of the innate system in cancer immunology is required for the design of combined immunotherapy strategies able to tackle established tumors. Here, we review recent advances in the understanding of the role of cell populations and soluble components of the innate immune system in cancer, with a focus on complement, the adapter molecule Stimulator of Interferon Genes, natural killer cells, myeloid cells, and B cells. PMID- 27782323 TI - A journey through the lectin pathway of complement-MBL and beyond. AB - Mannose-binding lectin (MBL), collectin-10, collectin-11, and the ficolins (ficolin-1, ficolin-2, and ficolin-3) are soluble pattern recognition molecules in the lectin complement pathway. These proteins act as mediators of host defense and participate in maintenance of tissue homeostasis. They bind to conserved pathogen-specific structures and altered self-antigens and form complexes with the pentraxins to modulate innate immune functions. All molecules exhibit distinct expression in different tissue compartments, but all are found to a varying degree in the circulation. A common feature of these molecules is their ability to interact with a set of serine proteases named MASPs (MASP-1, MASP-2, and MASP-3). MASP-1 and -2 trigger the activation of the lectin pathway and MASP 3 may be involved in the activation of the alternative pathway of complement. Furthermore, MASPs mediate processes related to coagulation, bradykinin release, and endothelial and platelet activation. Variant alleles affecting expression and structure of the proteins have been associated with a variety of infectious and non-infectious diseases, most commonly as disease modifiers. Notably, the severe 3MC (Malpuech, Michels, Mingarelli, and Carnevale) embryonic development syndrome originates from rare mutations affecting either collectin-11 or MASP-3, indicating a broader functionality of the complement system than previously anticipated. This review summarizes the characteristics of the molecules in the lectin pathway. PMID- 27782322 TI - Preformed mediators of defense-Gatekeepers enter the spotlight. PMID- 27782324 TI - Endothelial cells: source, barrier, and target of defensive mediators. AB - Endothelium is strategically located at the interface between blood and interstitial tissues, placing thus endothelial cell as a key player in vascular homeostasis. Endothelial cells are in a dynamic equilibrium with their environment and constitute concomitantly a source, a barrier, and a target of defensive mediators. This review will discuss the recent advances in our understanding of the complex crosstalk between the endothelium, the complement system and the hemostasis in health and in disease. The first part will provide a general introduction on endothelial cells heterogeneity and on the physiologic role of the complement and hemostatic systems. The second part will analyze the interplay between complement, hemostasis and endothelial cells in physiological conditions and their alterations in diseases. Particular focus will be made on the prototypes of thrombotic microangiopathic disorders, resulting from complement or hemostasis dysregulation-mediated endothelial damage: atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Novel aspects of the pathophysiology of the thrombotic microangiopathies will be discussed. PMID- 27782329 TI - Complement in removal of the dead - balancing inflammation. AB - Recognition and removal of apoptotic and necrotic cells must be efficient and highly controlled to avoid excessive inflammation and autoimmune responses to self. The complement system, a crucial part of innate immunity, plays an important role in this process. Thus, apoptotic and necrotic cells are recognized by complement initiators such as C1q, mannose binding lectin, ficolins, and properdin. This triggers complement activation and opsonization of cells with fragments of C3b, which enhances phagocytosis and thus ensures silent removal. Importantly, the process is tightly controlled by the binding of complement inhibitors C4b-binding protein and factor H, which attenuates late steps of complement activation and inflammation. Furthermore, factor H becomes actively internalized by apoptotic cells, where it catalyzes the cleavage of intracellular C3 to C3b. The intracellularly derived C3b additionally opsonizes the cell surface further supporting safe and fast clearance and thereby aids to prevent autoimmunity. Internalized factor H also binds nucleosomes and directs monocytes into production of anti-inflammatory cytokines upon phagocytosis of such complexes. Disturbances in the complement-mediated clearance of dying cells result in persistence of autoantigens and development of autoimmune diseases like systemic lupus erythematosus, and may also be involved in development of age related macula degeneration. PMID- 27782330 TI - Old dogs-new tricks: immunoregulatory properties of C3 and C5 cleavage fragments. AB - The activation of the complement system by canonical and non-canonical mechanisms results in the generation of multiple C3 and C5 cleavage fragments including anaphylatoxins C3a and C5a as well as opsonizing C3b/iC3b. It is now well appreciated that anaphylatoxins not only act as pro-inflammatory mediators but as immunoregulatory molecules that control the activation status of cells and tissue at several levels. Likewise, C3b/iC3b is more than the opsonizing fragment that facilitates engulfment and destruction of targets by phagocytes. In the circulation, it also facilitates the transport and delivery of bacteria and immune complexes to phagocytes, through a process known as immune adherence, with consequences for adaptive immunity. Here, we will discuss non-classical immunoregulatory properties of C3 and C5 cleavage fragments. We highlight the influence of anaphylatoxins on Th2 and Th17 cell development during allergic asthma with a particular emphasis on their role in the modulation of CD11b+ conventional dendritic cells and monocyte-derived dendritic cells. Furthermore, we discuss the control of anaphylatoxin-mediated activation of dendritic cells and allergic effector cells by adaptive immune mechanisms that involve allergen specific IgG1 antibodies and plasma or regulatory T cell-derived IL-10 production. Finally, we take a fresh look at immune adherence with a particular focus on the development of antibacterial cytotoxic T-cell responses. PMID- 27782334 TI - Terminal complexes of the complement system: new structural insights and their relevance to function. AB - Complement is a key component of innate immunity in health and a powerful driver of inflammation and tissue injury in disease. The biological and pathological effects of complement activation are mediated by activation products. These come in two flavors: (i) proteolytic fragments of complement proteins (C3, C4, C5) generated during activation that bind specific receptors on target cells to mediate effects; (ii) the multimolecular membrane attack complex generated from the five terminal complement proteins that directly binds to and penetrates target cell membranes. Several recent publications have described structural insights that have changed perceptions of the nature of this membrane attack complex. This review will describe these recent advances in understanding of the structure of the membrane attack complex and its by-product the fluid-phase terminal complement complex and relate these new structural insights to functional consequences and cell responses to complement membrane attack. PMID- 27782332 TI - The complement factor H-related proteins. AB - The role of the complement factor H-related (FHR) proteins in homeostasis, pathogen defense, and autoimmune disease has recently attracted considerable interest. We highlight the exciting research that has contributed to our understanding of the FHR protein family. Unlike factor H, a potent negative regulator of complement C3 activation, the FHR proteins appear to promote C3 activation. These data have important implications for understanding complement mediated diseases because, depending on the context, the balance between the actions of factor H and the FHR proteins determines the degree of complement activation. PMID- 27782326 TI - Injury site-specific targeting of complement inhibitors for treating stroke. AB - Cumulative evidence indicates a role for the complement system in both pathology and recovery after ischemic stroke. Here, we review the current understanding of the dual role of complement in poststroke injury and recovery, and discuss the challenges of anti-complement therapies. Most complement directed therapeutics currently under investigation or development systemically inhibit the complement system, but since complement is important for immune surveillance and is involved in various homeostatic activities, there are potential risks associated with systemic inhibition. Depending on the target within the complement pathway, other concerns are high concentrations of inhibitor required, low efficacy and poor bioavailability. To overcome these limitations, approaches to target complement inhibitors to specific sites have been investigated. Here, we discuss targeting strategies, with a focus on strategies developed in our lab, to specifically localize complement inhibition to sites of tissue injury and complement activation, and in particular to the postischemic brain. We discuss various injury site-specific targeted complement inhibitors as potential therapeutic agents for the treatment of ischemic stroke treatment, as well as their use as investigative tools for probing complement-dependent pathophysiological processes. PMID- 27782328 TI - More than complementing Tolls: complement-Toll-like receptor synergy and crosstalk in innate immunity and inflammation. AB - Complement and Toll-like receptors (TLRs) play key roles in the host immune response and are swiftly activated by infection or other types of immunological stress. This review focuses on the capacity of complement and TLRs to engage in signaling crosstalk, ostensibly to coordinate immune and inflammatory responses through synergistic or antagonistic (regulatory) interactions. However, overactivation or dysregulation of either system may lead-often synergistically to exaggerated inflammation and host tissue injury. Intriguingly, moreover, certain pathogens can manipulate complement-TLR crosstalk pathways in ways that undermine host immunity and favor their persistence. In the setting of polymicrobial inflammatory disease, subversion of complement-TLR crosstalk by keystone pathogens can promote dysbiosis. Knowledge of the molecular mechanisms underlying complement-TLR crosstalk pathways can, therefore, be used productively for tailored therapeutic approaches, such as, to enhance host immunity, mitigate destructive inflammation, or counteract microbial subversion of the host response. PMID- 27782327 TI - Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. AB - The complement system is an evolutionarily ancient component of immunity that revolves around the central component C3. With the recent description of intracellular C3 stores in many types of human cells, our view of the complement system has expanded. In this article, we hypothesize that a primitive version of C3 comprised the first element of the original complement system and initially functioned intracellularly and on the membrane of single-celled organisms. With increasing specialization and multicellularity, C3 evolved a secretory capacity that allowed it to play a protective role in the interstitial space. Upon development of a pumped circulatory system, C3 was synthesized in large amounts and secreted by the liver to protect the intravascular space. Recent discoveries of intracellular C3 activation, a C3-based recycling pathway and C3 being a driver and programmer of cell metabolism suggest that the complement system utilizes C3 to guard not only extracellular but also the intracellular environment. We predict that the major functions of C3 in all four locations (i.e. intracellular, membrane, interstitium and circulation) are similar: opsonization, membrane perturbation, triggering inflammation, and metabolic reprogramming. PMID- 27782321 TI - Protection of host cells by complement regulators. AB - The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation. Although the other two canonical complement activation routes, the classical and lectin pathways, initiate the cascade more specifically through pattern recognition, their activity still needs to be tightly controlled to avoid excessive reactivity. It is the perpetual duty of complement regulators to protect the self from damage inflicted by inadequate complement activation. Here, we review the role of complement regulators as preformed mediators of defense, explain their common and specialized functions, and discuss selected cases in which alterations in complement regulators lead to disease. Finally, rational engineering approaches using natural complement inhibitors as potential therapeutics are highlighted. PMID- 27782336 TI - Structural insight into proteolytic activation and regulation of the complement system. AB - The complement system is a highly complex and carefully regulated proteolytic cascade activated through three different pathways depending on the activator recognized. The structural knowledge regarding the intricate proteolytic enzymes that activate and control complement has increased dramatically over the last decade. This development has been pivotal for understanding how mutations within complement proteins might contribute to pathogenesis and has spurred new strategies for development of complement therapeutics. Here we describe and discuss the complement system from a structural perspective and integrate the most recent findings obtained by crystallography, small-angle X-ray scattering, and electron microscopy. In particular, we focus on the proteolytic enzymes governing activation and their products carrying the biological effector functions. Additionally, we present the structural basis for some of the best known complement inhibitors. The large number of accumulated molecular structures enables us to visualize the relative size, position, and overall orientation of many of the most interesting complement proteins and assembled complexes on activator surfaces and in membranes. PMID- 27782341 TI - Highly Selective Zeolite Topologies for Flue Gas Separation. AB - The separation of carbon dioxide from flue gas is essential for the reduction of greenhouse gas emissions. In adsorptive methods, the challenge lies in the choice of suitable porous materials. Among all zeolite topologies, a number of adsorbents with pore dimensions in the range of the guest molecules were identified to allow an excellent separation by diffusion, and MRE and AFO zeolite topologies appear to be the best candidates based on equilibrium adsorption. Also, it was found that the behavior of this gas mixture in DFT and APD zeolites differed from the normal behavior. PMID- 27782338 TI - The versatile functions of complement C3-derived ligands. AB - The complement system is a major component of immune defense. Activation of the complement cascade by foreign substances and altered self-structures may lead to the elimination of the activating agent, and during the enzymatic cascade, several biologically active fragments are generated. Most immune regulatory effects of complement are mediated by the activation products of C3, the central component. The indispensable role of C3 in opsonic phagocytosis as well as in the regulation of humoral immune response is known for long, while the involvement of complement in T-cell biology have been revealed in the past few years. In this review, we discuss the immune modulatory functions of C3-derived fragments focusing on their role in processes which have not been summarized so far. The importance of locally synthesized complement will receive special emphasis, as several immunological processes take place in tissues, where hepatocyte-derived complement components might not be available at high concentrations. We also aim to call the attention to important differences between human and mouse systems regarding C3-mediated processes. PMID- 27782343 TI - Metformin use and asthma: Further investigations. PMID- 27782346 TI - A new era in idiopathic interstitial pneumonias: Epilogue to a review series. PMID- 27782344 TI - The role of 'social support' in the experience of fibromyalgia - narratives from South Africa. AB - This paper focuses on the role of 'social support' in the experience of fibromyalgia (a musculoskeletal pain disorder) in South Africa. In-depth semi structured interviews were used to collect narratives from 15 participants. Sources of social support constitute important mechanisms for coping with the illness experience of fibromyalgia. In providing a space for consultation and validation of the diagnosis of fibromyalgia, and the person living with the condition, people giving support fulfil a critical role in shaping the experience. The findings show how support from family, partners, and peers plays an integral role in the process of accepting fibromyalgia diagnosis, adapting to the demands of the condition, and seeking help from healthcare providers. The findings also show the ways in which people with fibromyalgia provide support for others with the condition, and the importance of this peer network in shaping the paths and outcomes of this illness experience. The findings of this study corroborate existing evidence that show fibromyalgia to be a complex condition to manage, due to the multiplicity, uncertainty and contestation that feature in the experience of the illness. Additionally, this study presents the challenges related to the limitations of access to healthcare in the South African context, and the utility of narrative approaches in garnering insight into the ways in which social support is harnessed in this environment. PMID- 27782339 TI - The complement and contact activation systems: partnership in pathogenesis beyond angioedema. AB - The blood plasma contains four biologically important proteolytic cascades, which probably evolved from the same ancestral gene. This in part may explain why each cascade has very similar "initiating trigger" followed by sequential and cascade like downstream enzymatic activation pattern. The four cascades are: the complement system, the blood clotting cascade, the fibrinolytic system, and the kallikrein-kinin system. Although much has been written about the interplay between all these enzymatic cascades, the cross-talk between the complement and the kinin generating systems has become particularly relevant as this interaction results in the generation of nascent molecules that have significant impact in various inflammatory diseases including angioedema and cancer. In this review, we will focus on the consequences of the interplay between the two systems by highlighting the role of a novel molecular link called gC1qR. Although this protein was first identified as a receptor for C1q, it is now recognized as a multiligand binding cellular protein, which serves not only as C1q receptor, but also as high affinity (KD <= 0.8 nM) binding site for both high molecular weight kininogen (HK) and factor XII (FXII). At inflammatory sites, where atherogenic factors such as immune complexes and/or pathogens can activate the endothelial cell into a procoagulant and proinflammatory surface, the two pathways are activated to generate vasoactive peptides that contribute in various ways to the inflammatory processes associated with numerous diseases. More importantly, since recent observations strongly suggest an important role for both pathways in cancer, we will focus on how a growing tumor cluster can employ the byproducts derived from the two activation systems to ensure not only its survival and growth, but also its escape into distal sites of colonization. PMID- 27782340 TI - The priming molecule beta-aminobutyric acid is naturally present in plants and is induced by stress. AB - The defense system of a plant can be primed for increased defense, resulting in an augmented stress resistance and/or tolerance. Priming can be triggered by biotic and abiotic stimuli, as well as by chemicals such as beta-aminobutyric acid (BABA), a nonprotein amino acid considered so far a xenobiotic. Since the perception mechanism of BABA has been recently identified in Arabidopsis thaliana, in the present study we explored the possibility that plants do synthesize BABA. After developing a reliable method to detect and quantify BABA in plant tissues, and unequivocally separate it from its two isomers alpha- and gamma-aminobutyric acid, we measured BABA levels in stressed and nonstressed A. thaliana plants, and in different plant species. We show that BABA is a natural product of plants and that the endogenous levels of BABA increase rapidly after infection with necrotrophic, biotrophic and hemibiotrophic pathogens, as well as after salt stress and submergence. Our results place the rise in endogenous BABA levels to a point of convergence in plant stress response and provide biological significance to the presence of a receptor in plants. These findings can explain the extremely widespread efficacy of BABA and open the way to unravel the early steps of priming. PMID- 27782342 TI - A qualitative follow-up study of diabetes patients' appraisal of an integrated diabetes service in primary care. AB - As the prevalence of type 2 diabetes continues to escalate, health system reform is seeking better patient outcomes through new models of care that aim to provide the most appropriate care when needed. Patients' experiences of service innovations can shed light on the successes and challenges of implementing change. This paper explores patients' views of a new model of integrated care for patients with type 2 diabetes. A mixed-methods, randomised control trial evaluated a beacon clinic model of care for complex type 2 diabetes led by specialist general practitioners (GPs) in primary care settings in Brisbane, Australia. In this qualitative sub-study conducted between May 2014 and January 2015, 25 consenting participants were re-interviewed after 12 months using semi structured questions, to explore their experiences of the new model of care. Interview transcripts were analysed thematically. In the first theme, Organised for patient-centred care, patients appraised the structural elements of the clinic. For most, it was an enabling experience which included convenience, flexibility and prompt communication back to the referring GPs. The preferences of a minority were partly realised, as they tried to understand the clinical purpose in comparison with traditional care. The second theme, Positioned as partners in care, revealed the pivotal role of patient-clinician relationships in patients' engagement with advice and self-care. Most found clinicians' collaborative approach engaging and motivating. A small minority with contextual concerns were disappointed with the focus on diabetes and struggled to engage fully with the model. Most participants valued this model of care, which reflects a capacity to manage the variable and complex needs of most patients referred for care. However, multi-level strategies are also needed to enhance patients' engagement with care and the sustainability of integrated diabetes care. PMID- 27782348 TI - (C6 F5 )3 B Catalyzed Chemoselective and ortho-Selective Substitution of Phenols with alpha-Aryl alpha-Diazoesters. AB - The development of an efficient method for the site-selective substitution of unprotected phenols has long been considered as an attractive but challenging task. Herein, we describe a highly chemo- and ortho-selective substitution reaction of phenols with alpha-aryl alpha-diazoacetates with commercially available (C6 F5 )3 B as the catalyst. This reaction proceeds under simple and mild conditions with high efficiency, it features a wide substrate scope and can be easily scaled up. PMID- 27782347 TI - Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram Negative Pathogen Salmonella by Attenuating Cellular Stress Response. AB - Gram-negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural-product-derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against Salmonella Typhimurium was identified, and the target enzymes were unraveled by quantitative chemical proteomics. Importantly, two protein hits were linked to bacterial stress response, and corresponding assays revealed an elevated susceptibility to reactive oxygen species upon compound treatment. The consolidated inhibition of these targets provides a rationale for antibacterial activity and highlights epoxycyclohexenones as natural product scaffolds with suitable properties for killing Gram-negative Salmonella. PMID- 27782331 TI - Properdin: a tightly regulated critical inflammatory modulator. AB - The complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate and positively regulate alternative pathway activity. Properdin is produced by many different leukocyte subsets and circulates as cyclic oligomers of monomeric subunits. While the formation of non-physiological aggregates in purified properdin preparations and the presence of potential properdin inhibitors in serum have complicated studies of its function, properdin has, regardless, emerged as a key player in various inflammatory disease models. Here, we review basic properdin biology, emphasizing the major hurdles that have complicated the interpretation of results from properdin-centered studies. In addition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potential utility of properdin inhibitors as long-term therapeutic options to treat diseases marked by increased formation of platelet/granulocyte aggregates. Finally, we describe the interplay between properdin and the alternative pathway negative regulator, Factor H, and how aiming to understand these interactions can provide scientists with the most effective ways to manipulate alternative pathway activation in complex systems. PMID- 27782337 TI - Pentraxins in the activation and regulation of innate immunity. AB - Humoral fluid phase pattern recognition molecules (PRMs) are a key component of the activation and regulation of innate immunity. Humoral PRMs are diverse. We focused on the long pentraxin PTX3 as a paradigmatic example of fluid phase PRMs. PTX3 acts as a functional ancestor of antibodies and plays a non-redundant role in resistance against selected microbes in mouse and man and in the regulation of inflammation. This molecule interacts with complement components, thus modulating complement activation. In particular, PTX3 regulates complement-driven macrophage mediated tumor progression, acting as an extrinsic oncosuppressor in preclinical models and selected human tumors. Evidence collected over the years suggests that PTX3 is a biomarker and potential therapeutic agent in humans, and pave the way to translation of this molecule into the clinic. PMID- 27782350 TI - Carbon emissions from agricultural expansion and intensification in the Chaco. AB - Carbon emissions from land-use changes in tropical dry forest systems are poorly understood, although they are likely globally significant. The South American Chaco has recently emerged as a hot spot of agricultural expansion and intensification, as cattle ranching and soybean cultivation expand into forests, and as soybean cultivation replaces grazing lands. Still, our knowledge of the rates and spatial patterns of these land-use changes and how they affected carbon emissions remains partial. We used the Landsat satellite image archive to reconstruct land-use change over the past 30 years and applied a carbon bookkeeping model to quantify how these changes affected carbon budgets. Between 1985 and 2013, more than 142 000 km2 of the Chaco's forests, equaling 20% of all forest, was replaced by croplands (38.9%) or grazing lands (61.1%). Of those grazing lands that existed in 1985, about 40% were subsequently converted to cropland. These land-use changes resulted in substantial carbon emissions, totaling 824 Tg C between 1985 and 2013, and 46.2 Tg C for 2013 alone. The majority of these emissions came from forest-to-grazing-land conversions (68%), but post-deforestation land-use change triggered an additional 52.6 Tg C. Although tropical dry forests are less carbon-dense than moist tropical forests, carbon emissions from land-use change in the Chaco were similar in magnitude to those from other major tropical deforestation frontiers. Our study thus highlights the urgent need for an improved monitoring of the often overlooked tropical dry forests and savannas, and more broadly speaking the value of the Landsat image archive for quantifying carbon fluxes from land change. PMID- 27782345 TI - Safety and Clinical Outcomes of Catheter Ablation of Atrial Fibrillation in Patients With Chronic Kidney Disease. AB - INTRODUCTION: Data regarding catheter ablation of atrial fibrillation (AF) in patients with chronic kidney disease (CKD) is limited. We therefore assessed the association of CKD with common safety and clinical outcomes in a nationwide sample of ablation recipients. METHODS: Using MarketScan(r) Commercial Claims and Medicare Supplemental Databases, we evaluated 30-day safety and 1-year clinical outcomes in patients who underwent a first AF ablation procedure between 2007 and 2011. We calculated frequency of common 30-day complications and calculated frequencies, incidence rates, and Cox proportional hazards for outcomes at 1-year postablation. RESULTS: Of 21,091 patients included, 1,593 (7.6%) had CKD. Patients with CKD were older (64 years vs. 59 years, P < 0.001) with higher CHA2 DS2 -VASc scores (3.2 vs. 1.8, P < 0.001). At 30 days postablation, patients with CKD had similar rates of stroke/TIA (0.13% vs. 0.13%, P = 0.99), perforation/tamponade (3.2% vs. 3.1%, P = 0.83), and vascular complications (2.4% vs. 2.2%, P = 0.59) as patients without CKD, but were more likely to be hospitalized for heart failure (2.1% vs. 0.4%, P < 0.001). In multivariate analysis, there were no significant differences in hazards of AF hospitalization (adjusted HR: 1.02, 95%CI: 0.87-1.20), cardioversion (adjusted HR: 0.99, 95%CI: 0.87-1.12), or repeat AF ablation (adjusted HR: 0.89, 95%CI: 0.76-1.06) at 1 year. CONCLUSIONS: Among patients selected for AF ablation, those with and without CKD had similar rates of postprocedural complications although they were more likely to be re-admitted for heart failure. CKD was not independently associated with AF hospitalization, cardioversion, and repeat ablation. These findings can inform clinical decision-making in patients with AF and CKD. PMID- 27782352 TI - Mild and Selective Cobalt-Catalyzed Chemodivergent Transfer Hydrogenation of Nitriles. AB - Herein, we describe a selective cobalt-catalyzed chemodivergent transfer hydrogenation of nitriles to synthesize primary, secondary, and tertiary amines. The solvent effect plays a key role for the selectivity control. The general applicability of this procedure was highlighted by the synthesis of more than 70 amine products bearing various functional groups in high chemoselectivity. Moreover, this mild system achieved >2000 TONs (turnover numbers) for the transfer hydrogenation of nitriles. PMID- 27782335 TI - The "ins and outs" of complement-driven immune responses. AB - The complement system represents an evolutionary old and critical component of innate immunity where it forms the first line of defense against invading pathogens. Originally described as a heat-labile fraction of the serum responsible for the opsonization and subsequent lytic killing of bacteria, work over the last century firmly established complement as a key mediator of the general inflammatory response but also as an acknowledged vital bridge between innate and adaptive immunity. However, recent studies particularly spanning the last decade have provided new insights into the novel modes and locations of complement activation and highlighted unexpected additional biological functions for this ancient system, for example, in regulating basic processes of the cell. In this review, we will cover the current knowledge about complement's established and novel roles in innate and adaptive immunity with a focus on the functional differences between serum circulating and intracellularly active complement and will describe and discuss the newly discovered cross-talks of complement with other cell effector systems particularly during T-cell induction and contraction. PMID- 27782325 TI - Complement component C3 - The "Swiss Army Knife" of innate immunity and host defense. AB - As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target. PMID- 27782349 TI - Quantifying the risk of nosocomial infection within Ebola Holding Units: a retrospective cohort study of negative patients discharged from five Ebola Holding Units in Western Area, Sierra Leone. AB - OBJECTIVES: A central pillar in the response to the 2014 Ebola virus disease (EVD) epidemic in Sierra Leone was the role of Ebola Holding Units (EHUs). These units isolated patients meeting a suspect case definition, tested them for EVD, initiated appropriate early treatment and discharged negative patients to onward inpatient care or home. Positive patients were referred to Ebola Treatment Centres. We aimed to estimate the risk of nosocomial transmission within these EHUs. METHODS: We followed up a cohort of 543 patients discharged with a negative EVD test from five EHUs in the Western Area, Sierra Leone, and examined all line listed subsequent EVD tests from any facility in the Western Area to see whether the patient was retested within 30 days, matching by name, age and address. We defined possible readmissions as having the same name and age but uncertain address, and confirmed readmissions where name, age and address matched. RESULTS: We found a positive readmission rate of 3.3% (18 cases), which included 1.5% confirmed readmissions (8 cases) and 1.8% possible readmissions (10 cases). This is lower than rates previously reported. We cannot ascertain whether EVD was acquired within the EHUs or from re-exposure in the community. No demographic or clinical variables were identified as risk factors for positive readmission, likely due to our small sample size. CONCLUSIONS: These findings support the EHU model as a safe method for isolation of suspect EVD patients and their role in limiting the spread of EVD. PMID- 27782358 TI - Metformin use and asthma: Further investigations - Reply. PMID- 27782353 TI - Predicting vegetation type through physiological and environmental interactions with leaf traits: evergreen and deciduous forests in an earth system modeling framework. AB - Earth system models are incorporating plant trait diversity into their land components to better predict vegetation dynamics in a changing climate. However, extant plant trait distributions will not allow extrapolations to novel community assemblages in future climates, which will require a mechanistic understanding of the trade-offs that determine trait diversity. In this study, we show how physiological trade-offs involving leaf mass per unit area (LMA), leaf lifespan, leaf nitrogen, and leaf respiration may explain the distribution patterns of evergreen and deciduous trees in the temperate and boreal zones based on (1) an evolutionary analysis of a simple mathematical model and (2) simulation experiments of an individual-based dynamic vegetation model (i.e., LM3-PPA). The evolutionary analysis shows that these leaf traits set up a trade-off between carbon- and nitrogen-use efficiency at the scale of individual trees and therefore determine competitively dominant leaf strategies. As soil nitrogen availability increases, the dominant leaf strategy switches from one that is high in nitrogen-use efficiency to one that is high in carbon-use efficiency or, equivalently, from high-LMA/long-lived leaves (i.e., evergreen) to low-LMA/short lived leaves (i.e., deciduous). In a region of intermediate soil nitrogen availability, the dominant leaf strategy may be either deciduous or evergreen depending on the initial conditions of plant trait abundance (i.e., founder controlled) due to feedbacks of leaf traits on soil nitrogen mineralization through litter quality. Simulated successional patterns by LM3-PPA from the leaf physiological trade-offs are consistent with observed successional dynamics of evergreen and deciduous forests at three sites spanning the temperate to boreal zones. PMID- 27782354 TI - Effects of enhanced external counterpulsation on skeletal muscle gene expression in patients with severe heart failure. AB - Enhanced external counterpulsation (EECP) is a non-invasive treatment in which leg cuff compressions increase diastolic aortic pressure and coronary perfusion. EECP is offered to patients with refractory angina pectoris and increases physical capacity. Benefits in heart failure patients have been noted, but EECP is still considered to be experimental and its effects must be confirmed. The mechanism of action is still unclear. The aim of this study was to evaluate the effect of EECP on skeletal muscle gene expression and physical performance in patients with severe heart failure. Patients (n = 9) in NYHA III-IV despite pharmacological therapy were subjected to 35 h of EECP during 7 weeks. Before and after, lateral vastus muscle biopsies were obtained, and functional capacity was evaluated with a 6-min walk test. Skeletal muscle gene expression was evaluated using Affymetrix Hugene 1.0 arrays. Maximum walking distance increased by 15%, which is in parity to that achieved after aerobic exercise training in similar patients. Skeletal muscle gene expression analysis using Ingenuity Pathway Analysis showed an increased expression of two networks of genes with FGF-2 and IGF-1 as central regulators. The increase in gene expression was quantitatively small and no overlap with gene expression profiles after exercise training could be detected despite adequate statistical power. EECP treatment leads to a robust improvement in walking distance in patients with severe heart failure and does induce a skeletal muscle transcriptional response, but this response is small and with no significant overlap with the transcriptional signature seen after exercise training. PMID- 27782357 TI - Global meta-analysis of native and nonindigenous trophic traits in aquatic ecosystems. AB - Ecologists have recently devoted their attention to the study of species traits and their role in the establishment and spread of nonindigenous species (NIS). However, research efforts have mostly focused on studies of terrestrial taxa, with lesser attention being dedicated to aquatic species. Aquatic habitats comprise of interconnected waterways, as well as exclusive introduction vectors that allow unparalleled artificial transport of species and their propagules. Consequently, species traits that commonly facilitate biological invasions in terrestrial systems may not be as represented in aquatic environments. We provide a global meta-analysis of studies conducted in both marine and freshwater habitats. We selected studies that conducted experiments with native and NIS under common environmental conditions to allow detailed comparisons among species traits. In addition, we explored whether different factors such as species relatedness, functional feeding groups, latitude, climate, and experimental conditions could be linked to predictive traits. Our results show that species with traits that enhance consumption and growth have a substantially increased probability of establishing and spreading when entering novel ecosystems. Moreover, traits associated with predatory avoidance were more prevalent in NIS and therefore favour invasive species in aquatic habitats. When we analysed NIS interacting with taxonomically distinctive native taxa, we found that consumption and growth were particularly important traits. This suggests that particular attention should be paid to newly introduced species for which there are no close relatives in the local biota. Finally, we found a bias towards studies conducted in temperate regions, and thus, more studies in other climatic regions are needed. We conclude that studies aiming at predicting future range shifts should consider trophic traits of aquatic NIS as these traits are indicative of multiple interacting mechanisms involved in promoting species invasions. PMID- 27782355 TI - Pain-processing abnormalities in bipolar I disorder, bipolar II disorder, and schizophrenia: A novel trait marker for psychosis proneness and functional outcome? AB - OBJECTIVES: Overlapping neural system dysfunctions, mainly involving the secondary somatosensory cortex (S2), the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC), seem to be related to both pain-perception abnormalities and psychotic symptoms in schizophrenia (SCZ) and bipolar disorder (BD). Laser-evoked potentials (LEPs) were used to investigate pain-perception and central pain-processing abnormalities in SCZ, bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and to evaluate their relationship with history of psychosis, and social-cognitive and functional impairments. METHODS: Twenty patients with SCZ, 17 patients with BD-I, and 21 patients with BD-II who were all under similar pharmacological treatment underwent clinical, functional, and neuro psychological assessment. LEPs were analyzed in patients and 19 healthy subjects (HS). LEPs elicit responses reflecting the activity of the S2 (N1 wave) and the ACC/AIC cortices (N2/P2 complex). A four-group ANOVA was conducted between patients and HS to compare pain-perceptive thresholds (PThs), N1, and N2/P2-LEP components. RESULTS: Compared to HS: (i) patients with SCZ showed pain-processing and pain-perception abnormalities, as revealed by significantly higher PTh (P<.01), and lower N1 (P<.01) and N2/P2 (P<.01) amplitudes, (ii) patients with BD I showed only pain-processing abnormalities, as revealed by significantly lower N1 (P<.05) and N2 (P<.01) amplitudes; and patients with BD-II did not differ for any of the LEP variables investigated. N1 and N2 amplitudes negatively correlated to history of psychosis (P<.01), social-cognition (P<.05), and real-world functioning (P<.01) measures in the whole group of patients. CONCLUSIONS: To the best of our knowledge, this is the first study comparing central pain processing in patients with SCZ, BD-I, and BD-II. Our results suggest that pain-processing abnormalities may represent a novel locus of interest for research investigating trait markers of the psychosis spectrum. PMID- 27782351 TI - A Fluorescent Probe for Neural Stem/Progenitor Cells with High Differentiation Capability into Neurons. AB - Selection of a specific neural stem/progenitor cells (NSPCs) has attracted broad attention in regenerative medicine for neurological disorders. Here, we report a fluorescent probe, CDg13, and its application for isolating strong neurogenic NSPCs. In comparison to the NSPCs isolated by other biomarkers, CDg13-stained NSPCs showed higher capability to differentiate into neurons. Target identification revealed that the fluorescence intensity of the probe within cells is inversely proportional to the expression levels of mouse and human Abcg2 transporters. These findings suggest that low Abcg2 expression is a biomarker for neurogenic NSPCs in mouse brain. Furthermore, CDg13 can be used to isolate Abcg2low cells from heterogeneous cell populations. PMID- 27782359 TI - Iceberg killing fields limit huge potential for benthic blue carbon in Antarctic shallows. AB - Climate-forced ice losses are increasing potential for iceberg-seabed collisions, termed ice scour. At Ryder Bay, West Antarctic Peninsula (WAP) sea ice, oceanography, phytoplankton and encrusting zoobenthos have been monitored since 1998. In 2003, grids of seabed markers, covering 225 m2 , were established, surveyed and replaced annually to measure ice scour frequency. Disturbance history has been recorded for each m2 of seabed monitored at 5-25 m for ~13 years. Encrusting fauna, collected from impacted and nonimpacted metres each year, show coincident benthos responses in growth, mortality and mass of benthic immobilized carbon. Encrusting benthic growth was mainly determined by microalgal bloom duration; each day, nanophytoplankton exceeded 200 MUg L-1 produced ~0.05 mm radial growth of bryozoans, and sea temperature >0 degrees C added 0.002 mm day-1 . Mortality and persistence of growth, as benthic carbon immobilization, were mainly influenced by ice scour. Nearly 30% of monitored seabed was hit each year, and just 7% of shallows were not hit. Hits in deeper water were more deadly, but less frequent, so mortality decreased with depth. Five-year recovery time doubled benthic carbon stocks. Scour-driven mortality varied annually, with two-thirds of all monitored fauna killed in a single year (2009). Reduced fast ice after 2006 ramped iceberg scouring, killing half the encrusting benthos each year in following years. Ice scour coupled with low phytoplankton biomass drove a phase shift to high mortality and depressed zoobenthic immobilized carbon stocks, which has persevered for 10 years since. Stocks of immobilized benthic carbon averaged nearly 15 g m-2 . WAP ice scouring may be recycling 80 000 tonnes of carbon yr-1 . Without scouring, such carbon would remain immobilized and the 2.3% of shelf which are shallows could be as productive as all the remaining continental shelf. The region's future, when glaciers reach grounding lines and iceberg production diminishes, is as a major global sink of carbon storage. PMID- 27782356 TI - Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma. AB - BACKGROUND AND OBJECTIVE: Statins have been widely used in inflammatory diseases including asthma, because of their anti-inflammatory and immunomodulatory properties. It has been shown that simvastatin induces autophagy and cell death in some circumstances. However, the possible cross-talk between simvastatin and autophagic processes in lung disease is largely unknown. Thus, we investigated the impact of simvastatin on airway inflammation and airway remodelling and the possible relationship of these processes to a simvastatin-induced autophagic pathway in mouse models of asthma. METHODS: Ovalbumin (OVA)-sensitized and challenged mice were treated with simvastatin and sacrificed. The autophagy related proteins Atg5, LC3B and Beclin1 were quantified, as well as the autophagy flux in bronchial smooth muscle cells (BSMCs). The relationship between airway inflammation and the autophagic process was investigated. RESULTS: We show that simvastatin treatment mediates activation of autophagy in BSMCs, which is correlated with airway inflammation and airway remodelling in mouse models of asthma. Simvastatin increases autophagy-related protein Atg5, LC3B and Beclin1 expression and autophagosome formation in lung tissue. Simvastatin-induced autophagy is associated with increased interferon-gamma (IFN-gamma) and decreased IL-4, IL-5 and IL-13 cytokines production in BSMCs, as well as reversed extracellular matrix (ECM) deposition. In contrast, autophagy inhibitor 3 methyladenine (3-MA) eliminates the therapeutic effect of simvastatin. CONCLUSION: These findings demonstrate that simvastatin inhibits airway inflammation and airway remodelling through an activated autophagic process in BSMCs. We propose a crucial function of autophagy in statin-based therapeutic approaches in asthma. PMID- 27782333 TI - The immune system's role in sepsis progression, resolution, and long-term outcome. AB - Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long term sepsis mortality. PMID- 27782360 TI - Improved catalytic and antifungal activities of Bacillus thuringiensis cells with surface display of Chi9602DeltaSP. AB - AIMS: The cell-surface display of chitinase Chi9602DeltaSP was constructed on Bacillus thuringiensis BMB171 by using two repeat N-terminal regions of autolysin (Mbgn)2 as the anchoring motif. This study aimed to prepare a chitinolytic whole cell B. thuringiensis biocatalyst with improved catalytic and antifungal activities. METHODS AND RESULTS: The chitinase Chi9602DeltaSP was displayed on the cell surface of B. thuringiensis BMB171 by using (Mbgn)2 as the anchoring motif. Immunofluorescence microscopic assays and flow cytometry confirmed that Chi9602DeltaSP was anchored onto the surface of vegetative cells and spores. Western blot analysis further confirmed that the (Mbgn)2 -Chi9602DeltaSP fusion protein was of the predicted molecular size of 94.2 kDa. A whole-cell-specific chitinase activity assay demonstrated that catalytic activities towards colloidal chitin of the recombinant strain (MB333) were significantly improved compared with those of wild inactive B. thuringiensis BMB171. The pH tolerance, thermostability and ultraviolet (UV) radiation resistance of Chi9602DeltaSP also slightly improved compared with the unanchored Chi9602DeltaSP displayed on the surface of MB333 cells and cultured for 24 h. After continuous culturing for 120 h, MB333 chitinase activity showed narrow pH tolerance and slightly decreased thermostability. In contrast, the UV radiation resistance capacity was obviously enhanced. An antifungal assay indicated that the recombinant strain exhibited a high inhibitory effect towards the mycelial growth of two phytopathogenic fungi, Fusarium oxysporum FB012 and Physalospora piricola FB016. CONCLUSIONS: We successfully developed a cell-surface display system for Chi9602DeltaSP on the surface of B. thuringiensis BMB171. The cell-surface display system can enhance the stability of Chi9602DeltaSP and has the potential of becoming a whole-cell biocatalyst for agricultural applications. SIGNIFICANCE AND IMPACT OF THE STUDY: Results demonstrated that the bacterial cell display system can be used to express biocontrol agents on the cell surface of B. thuringiensis and provides an attractive method for inhibiting phytopathogenic fungi. PMID- 27782364 TI - Survival at 2 years among liver cirrhotic patients is influenced by left atrial volume and left ventricular mass. AB - BACKGROUND & AIMS: Cirrhotic cardiomyopathy (CC) may interact with the clinical course of cirrhosis and can be implicated in the development of several complications in advanced liver disease. The best and easiest parameters which should define a condition of reduced cardiac reserve in cirrhosis are still controversial. This study was aimed at selecting the cardiac parameters, derived by Doppler echocardiography, predictive of survival during follow-up. METHODS: This study included cirrhotic patients without cardiovascular or pulmonary diseases. Patients were studied in stable conditions. Doppler echocardiography was used to select parameters associated with survival. Among the others, left atrial volume (LAVi) and left ventricular mass indexed to body surface area (LVMi) were evaluated. A comparison was performed with the parameters presently applied for the definition of CC according to the Montreal criteria. RESULTS: Ninety cirrhotic patients have been included (males 66%, alcohol origin 31%, post viral 54%, Child-Pugh A 53%, B 29% and C 18%). Patients were followed up for at least 24 months. Twenty-six patients had a diagnosis of CC according to the Montreal criteria. During follow-up, 24 patients died. Overall mortality was 26.7%. Patients presenting higher LAVi and lower LVMi were those at higher risk to die (P=.04 and P=.007 respectively). No difference in survival was seen in patients with a diagnosis of CC. CONCLUSIONS: An increased LAVi and a decreased LVMi were able to differentiate among patients with a lower survival at 2 years. These parameters need to be considered for prognostic evaluation in cirrhotics. PMID- 27782367 TI - The "Tears of the Virgin" at Lakes Entrance, southeast Australia were made by the intertidal barnacle Chthamalus antennatus (Cirripedia: Thoracica) and cyanobacteria. AB - Curious eroded depressions, most resembling an eye shedding an elongate tear, are found in gently sloping, intertidal, carbonate-rich arenite outcropping on the sea coast near Lakes Entrance, Victoria, southeast Australia. The depressions, known locally as "Tears of the Virgin," are evidently formed by multiple generations of a barnacle, Chthamalus antennatus Darwin, 1854 in association with cyanobacteria. While the round part of a depression offers the barnacle a modicum of protection from impacts during high tides, it is also partially inhabited by cyanobacteria, which extend into and tend to fill the elongate tear. As such, this appears to be the first case of mutualism between a higher invertebrate and cyanobacteria, with the cyanobacteria reducing the barnacle's risk of desiccation while receiving metabolic wastes from it during low tides. It is also the first record of a balanomorph barnacle eroding calcareous arenite beneath its shell, the net effect of which would be expected to reduce its adhesion to the substrate. However, the siliceous residue, resulting from the barnacle's dissolution of the more than 80% of the calcite-rich sedimentary rock, is sequestered in delicate folds on the inside of the shell wall as it grows. A brief review of cirripedes capable of excavation includes the first photographic documentation of excavation of a mollusc shell by a verrucomorph. PMID- 27782366 TI - Chronic Pain Features Relate to Quality of Life More than Physiopathology: A Cross-Sectional Evaluation in Pain Clinics. AB - OBJECTIVE: To compare the impact of chronic pain physiopathology on health related quality of life (HR-QoL), considering the influence of pain features and psychosocial adjustment (intensity, interference, psychological comorbidities, and sleep quality). DESIGN: A cross-sectional study involving 1,025 noncancer patients with predominantly neuropathic, nociceptive, or mixed chronic pain conditions was conducted in 88 pain clinics within Spain. The EuroQol-5 Dimensions instrument (EQ-5D) was used to measure HR-QoL. The Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS), and sleep scale developed for the MOS study (MOS-SQ) were used to measure pain features and psychosocial adjustment. Multivariate analyses were used to model HR-QoL measures. RESULTS: All patients reported very low HR-QoL. The mean EQ-5D index scores were 0.33, 0.36, and 0.37 in the mixed, neuropathic, and nociceptive pain groups, respectively. The differences did not reach statistical significance (P = 0.057). Patients with nociceptive pain had less pain (least pain intensity score: 4.7 vs. 5.2 in the other groups; P = 0.006), less interference with daily activities (BPI average interference score: 6.3 vs. 6.6 and 6.7 in the neuropathic and mixed pain groups, respectively; P = 0.013), less anxiety (HADS score: 8.5 vs. 9.6 and 9.7 in the same respective groups; P = 0.001), and fewer sleep problems (MOS-SQ sleep problems index: 46.8 vs. 52.2 and 50.2 in the same respective groups; P = 0.005). In the adjusted analyses, HR-QoL measures were explained by pain intensity, anxiety, and sleep quality, but not by physiopathological pain type. CONCLUSIONS: Pain features, particularly intensity, have a greater impact than pain physiopathology on HR-QoL. Distinct physiopathological mechanisms give rise to different pain features that, in turn, may mediate the HR-QoL of patients with chronic pain. This could be used to improve pain management strategies. PMID- 27782368 TI - Issues related to diagnosing oral lichen planus among oral pathologists in South India: A pilot survey. AB - AIM: In the present study, we simulated clinical scenarios by explicitly describing the history and clinical and histological features of hypothetical patients presenting with oral lichen planus (OLP), oral lichenoid lesion, and epithelial dysplasia in a self-designed questionnaire. By doing so, we aimed to elicit a diagnosis from oral pathologists and trainees, analyze their responses, appraise issues, and propose solutions regarding the diagnosis of OLP. METHODS: The questionnaire was distributed to 100 oral pathologists and trainees in South India. Six questions were designed to assess awareness of the diagnostic aspects of OLP. Ten questions were hypothetical clinical scenarios (HCS) devised to evaluate respondents' knowledge of diagnostic guidelines and the criteria used by the respondents to render a diagnosis. RESULTS: There were 60 of 100 responses to the questionnaire. More than half the respondents were aware of the World Health Organization and modified guidelines of OLP. We observed considerable variations in diagnoses for the HCS. CONCLUSIONS: Our study illustrates the ambiguity in rendering an accurate diagnosis, despite adequate guidelines. Based on the responses for the HCS, we hypothesized that changes in the distribution (unilateral or bilateral) and clinical characteristic of OLP, and habits of patients, have a significant bearing on the clinical and final diagnoses of the lesion. PMID- 27782365 TI - Evaluation of an alcohol screening and brief advice training programme for NHS general dental practitioners. AB - INTRODUCTION: Primary care dentists are in a unique position to screen for alcohol misuse and provide brief advice to patients; however, lack of knowledge and confidence are some of the barriers cited for their reluctance to do so. AIMS: This study describes the evaluation of a novel brief alcohol advice training programme specifically designed and tailored to the needs of NHS general dental practitioners. MATERIALS AND METHODS: The training programme was developed as part of a feasibility trial and included a mixture of theoretical and practical elements. During 8 h of highly interactive sessions, participants took part in role-plays, including scenarios of patients of varying age groups, oral health status, dental attendance and different levels of motivation. Training manuals and other resources were also given. Knowledge, attitudes and confidence scores were assessed before and after the sessions. Wilcoxon matched-pairs signed ranks and McNemar's tests were used to compare participants' performance before and after the completion of the programme. RESULTS: Significant positive changes were observed in all training objectives. There was an overall improvement of 23% in levels of knowledge, a 40% increase in positive attitudes towards alcohol screening and intervention and 80% increase in confidence scores. Fidelity assessments of the implementation of the intervention in the trial showed that dentists who completed the training successfully went on to screen for alcohol misuse and provide brief advice to patients. CONCLUSION: NHS dentists can be successfully trained with the relevant knowledge, attitudes and confidence needed to deliver alcohol screening and brief advice to patients. PMID- 27782362 TI - Assessing forest vulnerability to climate warming using a process-based model of tree growth: bad prospects for rear-edges. AB - Growth models can be used to assess forest vulnerability to climate warming. If global warming amplifies water deficit in drought-prone areas, tree populations located at the driest and southernmost distribution limits (rear-edges) should be particularly threatened. Here, we address these statements by analyzing and projecting growth responses to climate of three major tree species (silver fir, Abies alba; Scots pine, Pinus sylvestris; and mountain pine, Pinus uncinata) in mountainous areas of NE Spain. This region is subjected to Mediterranean continental conditions, it encompasses wide climatic, topographic and environmental gradients, and, more importantly, it includes rear-edges of the continuous distributions of these tree species. We used tree-ring width data from a network of 110 forests in combination with the process-based Vaganov-Shashkin Lite growth model and climate-growth analyses to forecast changes in tree growth during the 21st century. Climatic projections were based on four ensembles CO2 emission scenarios. Warm and dry conditions during the growing season constrain silver fir and Scots pine growth, particularly at the species rear-edge. By contrast, growth of high-elevation mountain pine forests is enhanced by climate warming. The emission scenario (RCP 8.5) corresponding to the most pronounced warming (+1.4 to 4.8 degrees C) forecasted mean growth reductions of -10.7% and 16.4% in silver fir and Scots pine, respectively, after 2050. This indicates that rising temperatures could amplify drought stress and thus constrain the growth of silver fir and Scots pine rear-edge populations growing at xeric sites. Contrastingly, mountain pine growth is expected to increase by +12.5% due to a longer and warmer growing season. The projections of growth reduction in silver fir and Scots pine portend dieback and a contraction of their species distribution areas through potential local extinctions of the most vulnerable driest rear-edge stands. Our modeling approach provides accessible tools to evaluate forest vulnerability to warmer conditions. PMID- 27782363 TI - DNA Damage Potential of Engine Emissions Measured In Vitro by Micronucleus Test in Human Bronchial Epithelial Cells. AB - Internal combustion engine emissions belong among the major anthropogenic sources of air pollution in urban areas. According to the International Agency for Research on Cancer, there is sufficient evidence of the carcinogenicity of diesel exhaust in human beings. Although alternative fuels, mainly biodiesel, have recently become popular, little is still known about the genotoxicity of emissions from these fuels. We analysed DNA damage expressed as the frequency of micronuclei (MN) in human bronchial epithelial cells (BEAS-2B), induced by extractable organic matter (EOM; tested concentrations: 1, 10 and 25 MUg/ml) obtained from particle emissions from various blends of biodiesel with diesel fuels (including neat diesel fuel (B0), a blend of 70% B0 and 30% biodiesel (B30) and neat biodiesel (B100)). We also tested the effect of selected diesel exhaust organic/genotoxic components [benzo[a]pyrene (B[a]P) concentrations: 25, 100 and 200 MUM; 1-nitropyrene (1-NP) concentrations: 1, 5 and 10 MUM; 3 nitrobenzanthrone (3-NBA) concentrations: 1, 5 and 50 MUM]. The cells were treated with the compounds for 28 and 48 hr. Our results showed that most of the tested compounds (except for the 25 MUM B[a]P, 28-hr treatment) significantly increased MN frequency. The genotoxicity of EOMs from the engine emissions of diesel and biodiesel engines was comparable. Both nitro-PAH compounds demonstrated higher genotoxic potential in comparison with B[a]P. Considering our results and due to increasing popularity of alternative fuels, it is prudent that the potential genotoxic effects of various fuels are investigated across engine technologies and operating conditions in a relevant model system. PMID- 27782361 TI - YKL-40, CCL18 and SP-D predict mortality in patients hospitalized with community acquired pneumonia. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the prognostic value of four biomarkers, YKL-40, chemokine (C-C motif) ligand 18 (CCL18), surfactant protein-D (SP-D) and CA 15-3, in patients admitted with community acquired pneumonia (CAP). These markers have been studied extensively in chronic pulmonary disease, but in acute pulmonary disease their prognostic value is unknown. METHODS: A total of 289 adult patients who were hospitalized with CAP and participated in a randomized controlled trial were enrolled. Biomarker levels were measured on the day of admission. Intensive care unit admission, 30-day, 1 year and long-term mortality (median follow-up of 5.4 years, interquartile range (IQR): 4.7-6.1) were recorded as outcomes. RESULTS: Median YKL-40 and CCL18 levels were significantly higher and levels of SP-D were significantly lower in CAP patients compared to healthy controls. Significantly higher YKL-40, CCL18 and SP-D levels were found in patients classified in pneumonia severity index classes 4-5 and with a CURB-65 score >=2 compared to patients with less severe pneumonia. Furthermore, these three markers were significant predictors for long-term mortality in multivariate analysis and compared with C-reactive protein and procalcitonin level on admission, area under the curves were higher for 30-day, 1 year and long-term mortality. CA 15-3 levels were less predictive. CONCLUSION: YKL-40, CCL18 and SP-D levels were higher in patients with more severe pneumonia, possibly reflecting the extent of pulmonary inflammation. Of these, YKL-40 most significantly predicts mortality for CAP. PMID- 27782371 TI - A Pharmacokinetic Model of a Tissue Implantable Cortisol Sensor. AB - Cortisol is an important glucocorticoid hormone whose biochemistry influences numerous physiological and pathological processes. Moreover, it is a biomarker of interest for a number of conditions, including posttraumatic stress disorder, Cushing's syndrome, Addison's disease, and others. An implantable biosensor capable of real time monitoring of cortisol concentrations in adipose tissue may revolutionize the diagnosis and treatment of these disorders, as well as provide an invaluable research tool. Toward this end, a mathematical model, informed by the physiological literature, is developed to predict dynamic cortisol concentrations in adipose, muscle, and brain tissues, where a significant number of important processes with cortisol occur. The pharmacokinetic model is applied to both a prototypical, healthy male patient and a previously studied Cushing's disease patient. The model can also be used to inform the design of an implantable sensor by optimizing the sensor dissociation constant, apparent delay time, and magnitude of the sensor output versus system dynamics. Measurements from such a sensor would help to determine systemic cortisol levels, providing much needed insight for proper medical treatment for various cortisol-related conditions. PMID- 27782369 TI - The structure of brain glycogen phosphorylase-from allosteric regulation mechanisms to clinical perspectives. AB - Glycogen phosphorylase (GP) is the key enzyme that regulates glycogen mobilization in cells. GP is a complex allosteric enzyme that comprises a family of three isozymes: muscle GP (mGP), liver GP (lGP), and brain GP (bGP). Although the three isozymes display high similarity and catalyze the same reaction, they differ in their sensitivity to the allosteric activator adenosine monophosphate (AMP). Moreover, inactivating mutations in mGP and lGP have been known to be associated with glycogen storage diseases (McArdle and Hers disease, respectively). The determination, decades ago, of the structure of mGP and lGP have allowed to better understand the allosteric regulation of these two isoforms and the development of specific inhibitors. Despite its important role in brain glycogen metabolism, the structure of the brain GP had remained elusive. Here, we provide an overview of the human brain GP structure and its relationship with the two other members of this key family of the metabolic enzymes. We also summarize how this structure provides valuable information to understand the regulation of bGP and to design specific ligands of potential pharmacological interest. PMID- 27782374 TI - Effect of disinfection and sterilization on the tensile strength, surface roughness, and wettability of elastomers. AB - AIM: The aim of the present study was to evaluate the effect of chemical disinfection, autoclave, and microwave sterilization on some of the key properties of elastomers. METHODS: Five polyvinylsiloxane elastomeric impression materials were evaluated. Forty samples were fabricated from each material. The samples were randomly selected and assigned to four experimental groups with 50 samples each: group I, control; group II,chemical disinfection; group III, autoclave sterilization; and group IV, microwave sterilization. The differences in the mean values were contrasted and compared with the control group and analyzed using two-way analysis of variance (P < 0.05). RESULTS: The results showed that chemical disinfection and autoclave sterilization had no significant effect on the tensile strength and surface roughness, whereas microwave sterilization showed a statistically-significant reduction in tensile strength, and an increase in surface roughness. None of the disinfection and sterilization techniques had a significant effect on wettability. However, autoclave and microwave sterilization resulted in an increase in hydrophilicity of all the materials tested. CONCLUSION: Chemical disinfection and autoclave sterilization had no statistically-significant effect on the tested properties of elastomers, thus autoclave sterilization can be considered as an alternative and an effective mode of disinfection and sterilization to eliminate all forms of disease causing microorganisms from dental impressions. PMID- 27782372 TI - Theoretical Calculations on the Feasibility of Microalgal Biofuels: Utilization of Marine Resources Could Help Realizing the Potential of Microalgae. AB - Microalgae have long been considered as one of most promising feedstocks with better characteristics for biofuels production over conventional energy crops. There have been a wide range of estimations on the feasibility of microalgal biofuels based on various productivity assumptions and data from different scales. The theoretical maximum algal biofuel productivity, however, can be calculated by the amount of solar irradiance and photosynthetic efficiency (PE), assuming other conditions are within the optimal range. Using the actual surface solar irradiance data around the world and PE of algal culture systems, maximum algal biomass and biofuel productivities were calculated, and feasibility of algal biofuel were assessed with the estimation. The results revealed that biofuel production would not easily meet the economic break-even point and may not be sustainable at a large-scale with the current algal biotechnology. Substantial reductions in the production cost, improvements in lipid productivity, recycling of resources, and utilization of non-conventional resources will be necessary for feasible mass production of algal biofuel. Among the emerging technologies, cultivation of microalgae in the ocean shows great potentials to meet the resource requirements and economic feasibility in algal biofuel production by utilizing various marine resources. PMID- 27782379 TI - Inpatient inherited thrombophilia testing. PMID- 27782378 TI - Integration of complementary and alternative medicine into cancer-specific supportive care programs in Australia: A scoping study. AB - AIM: The main aim of this research was to describe the availability and integration of supportive care programs (SCPs), particularly complementary and alternative medicine (CAM) services, for adults in Australian oncology treatment centers. METHODS: We systematically searched 124 Australian hospitals listed as having an oncology department out of a total of 1157 hospitals listed in the Australian Hospitals and Aged Care Databases (2014), and assessed their website and relevant leaflets. Direct contact was made with a relevant staff member in each hospital. Data were collected regarding the range of SCP and CAM services available. RESULTS: Of the 124 hospitals, 89 (72%) provide nonspecific guidance to SCP or a staff member (e.g. social worker or care coordinator) who directs patients, advising them about SCP; 35 hospitals (28%) provide active referral to SCP, of which 24 of 35 (69%) include CAM in their service, with individual variation in how it is incorporated. Only 11 (46%) of these 24 CAM incorporated oncology centers in Australia provided systematically integrated CAM programs. CONCLUSION: The majority of Australian oncology departments do not have CAM incorporated into their services. In those that do, less than half had systemically integrated CAM. The types of CAM available, how they are accessed and how they are integrated varied across hospitals. Further research is required to understand how to successfully and systematically integrate cancer-specific supportive care such as CAM into Australian cancer services. PMID- 27782370 TI - Pericyte Seeded Dual Peptide Scaffold with Improved Endothelialization for Vascular Graft Tissue Engineering. AB - The development of synthetic vascular grafts for coronary artery bypass is challenged by insufficient endothelialization, which increases the risk of thrombosis, and the lack of native cellular constituents, which favors pathological remodeling. Here, a bifunctional electrospun poly(epsilon caprolactone) (PCL) scaffold with potential for synthetic vascular graft applications is presented. This scaffold incorporates two tethered peptides: the osteopontin-derived peptide (Adh) on the "luminal" side and a heparin-binding peptide (Hep) on the "abluminal" side. Additionally, the "abluminal" side of the scaffold is seeded with saphenous vein-derived pericytes (SVPs) as a source of proangiogenic growth factors. The Adh peptide significantly increases endothelial cell adhesion, while the Hep peptide promotes accumulation of vascular endothelial growth factor secreted by SVPs. SVPs increase endothelial migration both in a transwell assay and a modified scratch assay performed on the PCL scaffold. Seeding of SVPs on the "abluminal"/Hep side of the scaffold further increases endothelial cell density, indicating a combinatory effect of the peptides and pericytes. Finally, SVP-seeded scaffolds are preserved by freezing in a xeno-free medium, maintaining good cell viability and function. In conclusion, this engineered scaffold combines patient-derived pericytes and spatially organized functionalities, which synergistically increase endothelial cell density and growth factor retention. PMID- 27782376 TI - Synergistic Anticancer Effect of Peptide-Docetaxel Nanoassembly Targeted to Tubulin: Toward Development of Dual Warhead Containing Nanomedicine. AB - Microtubule dynamics play a crucial role in cancer cell division. Various drugs are developed to target microtubule. Although a few of them show potential in treatment of cancer, but success rate is limited due to their poor bioavailability and lack of specificity. Thus, development of highly bioavailable and target specific anticancer drug is extremely necessary. To address these key issues, here, a combination of approaches such as development of a dodecapeptide docetaxel nanoassembly targeted to tubulin and MUC1 (mucin 1, cell surface associated glycoprotein) targeting oligonucleotide aptamer conjugated liposome for delivering peptide-docetaxel nanoassembly into the breast cancer cell have been demonstrated. These studies reveal that the peptide forms nanoassembly and entraps docetaxel drug. Further, the liposomal formulation of peptide-docetaxel exerts synergistic anticancer effect, activates key mitotic check point proteins, and inhibits bipolar spindle formation, metastatic cancer cell migration, and growth of tumor mimicking 3D multicellular spheroid. PMID- 27782383 TI - UV Cross-Linkable Graphene/Poly(trimethylene Carbonate) Composites for 3D Printing of Electrically Conductive Scaffolds. AB - Conductive, flexible graphene/poly(trimethylene carbonate) (PTMC) composites were prepared. Addition of just 3 wt % graphene to PTMC oligomers functionalized with methacrylate end-groups followed by UV cross-linking resulted in more than 100% improvement in tensile strength and enhanced electrical conductivity by orders of magnitude without altering the processability of the host material. The addition of graphene also enhanced mesenchymal stem cell (MSC) attachment and proliferation. When electrical stimulation via the composite material was applied, MSC viability was not compromised, and osteogenic markers were upregulated. Using additive fabrication techniques, the material was processed into multilayer 3D scaffolds which supported MSC attachment. These conducting composites with excellent processability and compatibility with MSCs are promising biomaterials to be used as versatile platforms for biomedical applications. PMID- 27782373 TI - Efficacy and safety of sofosbuvir/simeprevir plus flat dose ribavirin in genotype 1 elderly cirrhotic patients: A real-life study. AB - BACKGROUND & AIMS: The proportion of HCV-infected patients over age 65 years in Western countries is increasing. This growth and the advent of new antiviral therapy bring into the question the real-world efficacy and safety of the combination of sofosbuvir (SOF) and simeprevir (SMV) plus a flat dose of 800 mg/d ribavirin (RBV) in elderly patients with cirrhosis compared to younger patients. METHODS: Retrospective observational multicentre real-life investigation study of SOF/SMV/RBV for a duration of 12 weeks in HCV genotype 1-infected patients with cirrhosis. RESULTS: Of the 270 patients enrolled in this study, with compensated cirrhosis, 133 (49.2%) were >=65 years of age. Sustained virological response at 12 weeks (SVR12) was achieved by 94.2% (129/137) of those aged <65 years and 97.7% (130/133) of those >=65 years. Diabetes was the most common comorbidity in patients >=65 years compared to younger patients (26.3% vs 12.4% P<.003). The most common adverse event (AE) in elderly patients was a grade 2 anaemia (35.3% vs 19.9% P<.004). CONCLUSIONS: Sofosbuvir/simeprevir plus a daily flat dose of RBV 800 mg for 12 weeks was highly effective and safe in genotype 1 elderly patients with compensated cirrhosis. PMID- 27782382 TI - Influence of High pH and Cholesterol on Single Arginine-Containing Transmembrane Peptide Helices. AB - An essential component of mammalian cells, cholesterol exerts significant influence on the physical properties of the cell membrane and in turn its constituents, including membrane proteins. Although sparse, polar amino acid residues are highly conserved in membrane proteins and play pivotal roles in determining specific structural and functional properties. To improve our understanding of particular polar residues in the membrane environment, we have examined two specific "guest" Arg residues within a well-defined and deuterium labeled "host" framework provided by the transmembrane helical peptide GWALP23 (acetyl-GGALWLALALALALALALWLAGA-amide). Solid-state 2H nuclear magnetic resonance (NMR) spectra from aligned bilayer membrane samples effectively report changes in the host helix properties because of the incorporation of the guest residues. The focus of this work is two-pronged. First, GWALP23-R14 was examined over a pH range of 2-13 in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) ester- or ether linked bilayer membranes. Our findings indicate that the Arg guanidinium side chain remains charged over this entire range, in agreement with numerous molecular dynamics simulations. Second, GWALP23-R12 and GWALP23-R14 peptides were characterized in DOPC bilayers with varying cholesterol content. Our findings suggest that 10 or 20% cholesterol content has minimal impact on the orientation of the R14 peptide. Although the NMR signals are broader and weaker in the presence of 20% cholesterol, the deuterium quadrupolar splittings for [2H]Ala residues in GWALP23-R14 change very little. Conversely, cholesterol appears to modulate the multistate behavior of GWALP23-R12 and to favor a major interfacial state for the helix, bound at the bilayer surface. These results indicate a conditional sensitivity of a complex multistate transmembrane Arg-containing peptide helix to the presence of cholesterol. PMID- 27782385 TI - Bioinspired Graphene Oxide/Polymer Nanocomposite Paper with High Strength, Toughness, and Dielectric Constant. AB - Graphene/graphene oxide (GO)-based paper is attracting great interest owing to its multiple functionalities. In this study, we successfully synthesized a triblock copolymer by atom transfer radical polymerization method in terms of molecular design. The copolymer was comprised of polydimethylsiloxane (PDMS) and poly(glycidyl methacrylate) (PGMA) segments. To the copolymer, the PDMS segments provided flexible characteristic, and the PGMA segments provided reactive groups and adhesiveness. Because of the above characteristics, the copolymer was used as an adhesive between the adjacent GO nanosheets for fabrication of GO/PDMS-PGMA papers. The papers showed a good combination of high tensile strength and toughness. The tensile strength and toughness of GO/PDMS-PGMA (85/15) paper reached as high as 309 MPa and 6.55 MJ.m-3, which were 3.4 and 8.2 times higher than that of pure GO paper. Furthermore, the papers also had high dielectric constant, which may enable this kind of material to be used in electronic and engineering fields. PMID- 27782390 TI - TMFF-A Two-Bead Multipole Force Field for Coarse-Grained Molecular Dynamics Simulation of Protein. AB - Coarse-grained (CG) models are desirable for studying large and complex biological systems. In this paper, we propose a new two-bead multipole force field (TMFF) in which electric multipoles up to the quadrupole are included in the CG force field. The inclusion of electric multipoles in the proposed CG force field enables a more realistic description of the anisotropic electrostatic interactions in the protein system and, thus, provides an improvement over the standard isotropic two-bead CG models. In order to test the accuracy of the new CG force field model, extensive molecular dynamics simulations were carried out for a series of benchmark protein systems. These simulation studies showed that the TMFF model can realistically reproduce the structural and dynamical properties of proteins, as demonstrated by the close agreement of the CG results with those from the corresponding all-atom simulations in terms of root-mean square deviations (RMSDs) and root-mean-square fluctuations (RMSFs) of the protein backbones. The current two-bead model is highly coarse-grained and is 50 fold more efficient than all-atom method in MD simulation of proteins in explicit water. PMID- 27782380 TI - Highly Oriented Growth of Piezoelectric Thin Films on Silicon Using Two Dimensional Nanosheets as Growth Template Layer. AB - Ca2Nb3O10 (CNOns) and Ti0.87O2 (TiOns) metal oxide nanosheets (ns) are used as a buffer layer for epitaxial growth of piezoelectric capacitor stacks on Si and Pt/Ti/SiO2/Si (Pt/Si) substrates. Highly (001)- and (110)-oriented Pb(Zr0.52Ti0.48)O3 (PZT) films are achieved by utilizing CNOns and TiOns, respectively. The piezoelectric capacitors are characterized by polarization and piezoelectric hysteresis loops and by fatigue measurements. The devices fabricated with SrRuO3 top and bottom electrodes directly on nanosheets/Si have ferroelectric and piezoelectric properties well comparable with devices that use more conventional oxide buffer layers (stacks) such as YSZ, CeO2/YSZ, or SrTiO3 on Si. The devices grown on nanosheets/Pt/Si with Pt top electrodes show significantly improved polarization fatigue properties over those of similar devices grown directly on Pt/Si. The differences in properties are ascribed to differences in the crystalline structures and the density of the films. These results show a route toward the fabrication of single crystal piezoelectric thin films and devices with high quality, long-lifetime piezoelectric capacitor structures on nonperovskite and even noncrystalline substrates such as glass or polished metal surfaces. PMID- 27782381 TI - Apoferritin Nanocage Delivers Combination of Microtubule and Nucleus Targeting Anticancer Drugs. AB - An ideal nano drug delivery agent must be potent enough to carry high dose of therapeutics and competent enough in targeting specific cell of interest, having adequate optimized physiochemical properties and biocompatibility. Carrying differentially polar therapeutics simultaneously will make them superior in their class. However, it is of enormous challenge to the researchers to find such a unique nanocarrier and to engineer all of the above-mentioned features into it. In this manuscript, we have shown for the first time that apoferritin (Apf) can carry and deliver high dose of doxorubicin (Dox), docetaxel (Doc), and combination of both Dox and Doc specifically into the cancer cell and enhances killing compared to free drug without any functionalization or property modulation. In addition, we have shown that Apf alone is noncytotoxic in nature and interacts with intracellular tubulin/microtubule. Drug loaded Apf specifically bound and consequently internalized into the human breast cancer cell line (MCF7) and human cervical cancer cell line (HeLa) through receptor mediated endocytosis process and releases either single or combination of drugs in the endosome. We have also checked the binding efficacy of both drugs using molecular docking. Further, using fluorescence microscopy, we have shown that Apf can deliver combination of drugs inside cancer cells and the drugs exerts their effect thereof. Finally, we have studied the efficacy of Apf complexes with individual drugs and in combination compared to free drugs in a tumor mimicking 3D multicellular spheroid model of HeLa cell. PMID- 27782384 TI - Use of Ion Chromatography/Mass Spectrometry for Targeted Metabolite Profiling of Polar Organic Acids. AB - Organic acids (OAs) serve as metabolites that play pivotal roles in a host of different metabolic and regulatory pathways. The polar nature of many OAs poses a challenge to their measurement using widely practiced analytical methods. In this study, a targeted metabolomics method was developed using ion chromatography/triple quadrupole mass spectrometry (IC/MS) to quantitate 28 polar OAs with limits of quantitation ranging from 0.25 to 50 MUM. The interday assay precisions ranged from 1% to 19%, with accuracies ranging from 82% to 115%. The IC/MS assay was used to quantitate OAs in quadriceps muscle from sedentary mice compared to fatigued mice subjected to either a low intensity, long duration (LILD) or high intensity, short duration (HISD) forced treadmill regimen. Among the OAs examined, significant differences were detected for hippuric acid, malic acid, fumaric acid, and 2-ketoglutaric acid between the sedentary and fatigued mice. In conclusion, the IC/MS method enabled the separation and quantitative survey of a broad range of polar OAs that are difficult to analyze by chromatographic techniques. PMID- 27782387 TI - Proton Probability Distribution in the O...H...O Low-Barrier Hydrogen Bond: A Combined Solid-State NMR and Quantum Chemical Computational Study of Dibenzoylmethane and Curcumin. AB - We report a combined solid-state (1H, 2H, 13C, 17O) NMR and plane-wave density functional theory (DFT) computational study of the O...H...O low-barrier hydrogen bonds (LBHBs) in two 1,3-diketone compounds: dibenzoylmethane (1) and curcumin (2). In the solid state, both 1 and 2 exist in the cis-keto-enol tautomeric form, each exhibiting an intramolecular LBHB with a short O...O distance (2.435 A in 1 and 2.455 A in 2). Whereas numerous experimental (structural and spectroscopic) and computational studies have been reported for the enol isomers of 1,3 diketones, a unified picture about the proton location within an LBHB is still lacking. This work reports for the first time the solid-state 17O NMR data for the O...H...O LBHBs in 1,3-diketones. The central conclusion of this work is that detailed information about the probability density distribution of the proton (nuclear zero-point motion) across an LBHB can be obtained from a combination of solid-state NMR and plane-wave DFT computations (both NMR parameter calculations and ab initio molecular dynamics simulations). We propose that the precise proton probability distribution across an LBHB should provide a common basis on which different and sometimes seemingly contradicting experimental results obtained from complementary techniques, such as X-ray diffraction, neutron diffraction, and solid-state NMR, can be reconciled. PMID- 27782375 TI - Water Soluble Melanin Derivatives for Dynamic Contrast Enhanced Photoacoustic Imaging of Tumor Vasculature and Response to Antiangiogenic Therapy. AB - A dynamic contrast enhanced (DCE) approach for tumor photoacoustic (PA) imaging is described. Novel water soluble melanin-based derivatives are synthesized that exhibit good PA properties, stability, safety and accumulation in tumor bearing mice. This melanin derivative is capable to characterize tumor vasculature and to monitor vessel permeability changes upon antiangiogenic treatment. DCE-PA imaging can assess functional response to cancer treatments. PMID- 27782389 TI - Pulsed Nano-ESI Atmospheric-Pressure Ion Mobility Mass Spectrometry with Enhanced Ion Sampling. AB - Ion mobility-mass spectrometry (IM-MS) has gained considerable attention for detection of clusters and weakly bound species created by electrospray ionization (ESI). Atmospheric-pressure (AP) IM-MS offers an advantage in these studies compared to its low-pressure counterpart, owing to soft introduction of ions into the mobility cell with minimal ion activation. Here, we report new approaches to improve the sensitivity and soft ion introduction in AP-IM-MS. For the former, we demonstrate enhanced aerodynamic sampling of ions from the mobility cell into the MS using pulsed-field sampling. In this approach, ions are driven toward the MS, and the field is shut down once the ions reach the vicinity of the MS inlet orifice. The pulsed-field operation provides arrival times without the need for an exit ion gate in the mobility cell and leads to improvements in sensitivity of up to 1 order of magnitude. For soft ion generation, we report a pulsed nano-ESI source to introduce a packet of ions into the room-temperature mobility cell without induced desolvation. Further, we demonstrate the application of the pulsed nano-ESI AP-IM-MS with enhanced ion sampling for detection of solvent clusters of amines and peptide aggregates. PMID- 27782386 TI - Stabilization of Natural Organic Matter by Short-Range-Order Iron Hydroxides. AB - Dissolved organic matter (DOM) is capable of modifying the surfaces of soil minerals (e.g., Fe hydroxides) or even forming stable co-precipitates with Fe(III) in a neutral environment. The DOM/Fe co-precipitation may alter biogeochemical carbon cycling in soils if the relatively mobile DOM is sorbed by soil minerals against leaching, runoff, and biodegradation. In this study, we aimed to determine the structural development of DOM/Fe co-precipitates in relation to changes in pH and C/(C + Fe) ratios using XRD, XPS, Fe K-edge XAS, FTIR, and C-NEXAFS techniques. The results showed that in the system with bulk C/(C + Fe) molar ratios <=0.65, the ferrihydrite-like Fe domains were precipitated as the core and covered by the C shells. When the C/(C + Fe) molar ratio ranged between 0.71 and 0.89, the emerging Fe-C bonding suggested a more substantial association between Fe domains including edge- and corner-sharing FeO6 octahedra and DOM. With C/(C + Fe) bulk molar ratios >=0.92, only corner sharing FeO6 octahedra along with Fe-C bonding were found. The homogeneously distributed C and Fe domains caused the enhancement of Fe and C solubilization from co-precipitates. The C/(C + Fe) ratios dominated structural compositions and stabilities of C/Fe co-precipitates and may directly affect the Fe and C cycles in soils. PMID- 27782392 TI - Omics Approaches To Probe Microbiota and Drug Metabolism Interactions. AB - The drug metabolism field has long recognized the beneficial and sometimes deleterious influence of microbiota in the absorption, distribution, metabolism, and excretion of drugs. Early pioneering work with the sulfanilamide precursor prontosil pointed toward the necessity not only to better understand the metabolic capabilities of the microbiota but also, importantly, to identify the specific microbiota involved in the generation and metabolism of drugs. However, technological limitations important for cataloging the microbiota community as well as for understanding and/or predicting their metabolic capabilities hindered progress. Current advances including mass spectrometry-based metabolite profiling as well as culture-independent sequence-based identification and functional analysis of microbiota have begun to shed light on microbial metabolism. In this review, case studies will be presented to highlight key aspects (e.g., microbiota identification, metabolic function and prediction, metabolite identification, and profiling) that have helped to clarify how the microbiota might impact or be impacted by drug metabolism. Lastly, a perspective of the future of this field is presented that takes into account what important knowledge is lacking and how to tackle these problems. PMID- 27782391 TI - Emerging and Legacy Flame Retardants in UK Indoor Air and Dust: Evidence for Replacement of PBDEs by Emerging Flame Retardants? AB - Concentrations of 27 emerging (EFRs) and legacy flame retardants (LFRs) were measured in samples of indoor air (n = 35) and indoor dust (n = 77) from UK homes and offices. All target compounds were detected in indoor air and dust samples. Relatively volatile EFRs (e.g., tetrabromoethylcyclohexane-DBE-DBCH) were more frequently detected in indoor air (detection frequencies >60%), while less volatile EFRs (e.g., tetrabromobisphenolA-bis(2,3-dibromopropyl ether (TBBPA BDBPE) and decabromodiphenyl ethane (DBDPE)) were predominant in dust. Concentrations of some EFRs (e.g., DBDPE) exceeded significantly those reported previously in UK dust (p < 0.05), while concentrations of BDE-209 in office dust were significantly lower (p < 0.05) than those reported previously in UK offices, consistent with the application of DBDPE as an alternative to the Deca-BDE formulation, of which BDE-209 is the principal constituent. Moreover, concentrations of BDEs-47 and -99 (both major constituents of the Penta-BDE product) in office air were significantly lower (p < 0.05) than those in previous UK studies. Our results constitute important early evidence that restrictions on PBDEs have increased demand for EFRs in the UK, with the result that human exposure to PBDEs in UK homes and offices has decreased while exposure to EFRs has risen. PMID- 27782377 TI - Influence of WFIKKN1 on BMP1-mediated activation of latent myostatin. AB - : The NTR domain of WFIKKN1 protein has been shown to have significant affinity for the prodomain regions of promyostatin and latent myostatin but the biological significance of these interactions remained unclear. In view of its role as a myostatin antagonist, we tested the assumption that WFIKKN1 inhibits the release of myostatin from promyostatin and/or latent myostatin. WFIKKN1 was found to have no effect on processing of promyostatin by furin, the rate of cleavage of latent myostatin by BMP1, however, was significantly enhanced in the presence of WFIKKN1 and this enhancer activity was superstimulated by heparin. Unexpectedly, WFIKKN1 was also cleaved by BMP1 and our studies have shown that the KKN1 fragment generated by BMP1-cleavage of WFIKKN1 contributes most significantly to the observed enhancer activity. Analysis of a pro-TGF-beta -based homology model of homodimeric latent myostatin revealed that the BMP1-cleavage sites are buried and not readily accessible to BMP1. In view of this observation, the most plausible explanation for the BMP1-enhancer activity of the KKN1 fragment is that it shifts a conformational equilibrium of latent myostatin from the closed circular structure of the homodimer to a more open form, making the cleavage sites more accessible to BMP1. On the other hand, the observation that the enhancer activity of KKN1 is superstimulated in the presence of heparin is explained by the fact KKN1, latent myostatin, and BMP1 have affinity for heparin and these interactions with heparin increase the local concentrations of the reactants thereby facilitating the action of BMP1. ENZYMES: Furin: EC 3.4.21.75; BMP1, bone morphogentic protein 1 or procollagen C-endopeptidase: EC 3.4.24.19. PMID- 27782388 TI - Ambient Ionization and FAIMS Mass Spectrometry for Enhanced Imaging of Multiply Charged Molecular Ions in Biological Tissues. AB - Ambient ionization mass spectrometry imaging (MSI) has been increasingly used to investigate the molecular distribution of biological tissue samples. Here, we report the integration and optimization of desorption electrospray ionization (DESI) and liquid-microjunction surface sampling probe (LMJ-SSP) with a chip based high-field asymmetric waveform ion mobility spectrometry (FAIMS) device to image metabolites, lipids, and proteins in biological tissue samples. Optimized FAIMS parameters for specific molecular classes enabled semitargeted detection of multiply charged molecular species at enhanced signal-to-noise ratios (S/N), improved visualization of spatial distributions, and, most importantly, allowed detection of species which were unseen by ambient ionization MSI alone. Under static DESI-FAIMS conditions selected for transmission of doubly charged cardiolipins (CL), for example, detection of 71 different CL species was achieved in rat brain, 23 of which were not observed by DESI alone. Diagnostic CL were imaged in a human thyroid tumor sample with reduced interference of isobaric species. LMJ-SSP-FAIMS enabled detection of 84 multiply charged protein ions in rat brain tissue, 66 of which were exclusive to this approach. Spatial visualization of proteins in substructures of rat brain, and in human ovarian cancerous, necrotic, and normal tissues was achieved. Our results indicate that integration of FAIMS with ambient ionization MS allows improved detection and imaging of selected molecular species. We show that this methodology is valuable in biomedical applications of MSI for detection of multiply charged lipids and proteins from biological tissues. PMID- 27782393 TI - Structure and Dynamics of Ionic Liquid [MMIM][Br] Confined in Hydrophobic and Hydrophilic Porous Matrices: A Molecular Dynamics Simulation Study. AB - The effects of confinement on the structural and dynamical properties of the ionic liquid (IL) 1,3-dimethylimidazolium bromide ([MMIM][Br]) have been investigated by molecular dynamics simulations. We used zeolite faujasite (NaY) as a hydrophilic confinement and dealuminated faujasite (DAY) as a hydrophobic confinement. The presence of an extra framework cation, [Na+], in NaY makes the host hydrophilic, whereas DAY, with no extra framework cation, is hydrophobic. Although both NaY and DAY have almost similar structures, the IL showed markedly different structural and dynamical properties in these confinements and in bulk. In the confinements, the cation-cation radial distribution function, which strongly depends on temperature, exhibits a layer-like structure, whereas in bulk, it shows a liquid-like structure that hardly depends on temperature. Although the interaction between [MMIM]+ and Br- in DAY is stronger than that in both NaY and bulk, the strength of the interaction between them is almost invariant with temperature. Both [MMIM]+ and Br- strongly interact with Na+ of the host, and their interaction strongly depends on temperature, whereas the interaction of the IL with Si and O is very weak and invariant with temperature. In bulk, the self-diffusion coefficient, [D], of both [MMIM]+ and Br- increases exponentially with temperature, and the D of the cation is slightly higher than that of the anion at all studied temperatures, whereas in the confinements, [MMIM]+ moves much faster than Br-. For example, in the hydrophilic confinement, the D of the cation is 20-30 times higher than that of the anion. The D of both the ions decreases significantly in the confinements as compared to that in bulk. During diffusion, [MMIM]+ diffuses closer to the inner surface in the hydrophilic confinement than that in the hydrophobic confinement. The diffusion pathway imperceptibly depends on temperature but strongly depends on the nature of the confinement. The self part of the time-dependent van Hoove correlation function of [MMIM]+ in the hydrophilic confinement shows a larger deviation from its Gaussian form than that in the hydrophobic confinement at all temperatures, indicating that the long-time dynamics of [MMIM]+ in NaY is more heterogeneous than that in DAY. Although the orientational relaxation time scales of [MMIM]+ in the confinements significantly slowed as compared to those in bulk, confinement does not affect the librational motion of the collective hydrogen-bond network present in the IL. PMID- 27782394 TI - Evaluating the Optoelectronic Quality of Hybrid Perovskites by Conductive Atomic Force Microscopy with Noise Spectroscopy. AB - Organic-inorganic hybrid perovskite solar cells have emerged as promising candidates for next-generation solar cells. To attain high photovoltaic efficiency, reducing the defects in perovskites is crucial along with a uniform coating of the films. Also, evaluating the quality of synthesized perovskites via facile and adequate methods is important as well. Herein, CH3NH3PbI3 perovskites were synthesized by applying second solvent dripping to nonstoichiometric precursors containing excess CH3NH3I. The resulting perovskite films exhibited a larger average grain size with a better crystallinity compared to that from stoichiometric precursors. As a result, the performance of planar perovskite solar cells was significantly improved, achieving an efficiency of 14.3%. Furthermore, perovskite films were effectively analyzed using a conductive AFM and noise spectroscopy, which have been uncommon in the field of perovskite solar cells. Comparing the topography and photocurrent maps, the variation of photocurrents in nanoscale was systematically investigated, and a linear relationship between the grain size and photocurrent was revealed. Also, noise analyses with a conductive probe enabled examination of the defect density of perovskites at specific grain interiors by excluding the grain-boundary effect, and reduced defects were clearly observed for the perovskites using CH3NH3I-rich precursors. PMID- 27782395 TI - beta-Stereoselective Mannosylation Using 2,6-Lactones. AB - beta-Stereoselective mannosylation using donors bearing the 2,6-lactone moiety is described. In general, glycosylation is a nucleophilic substitution reaction between an alcoholic nucleophile and a sugar moiety containing a leaving group at the anomeric position. Owing to stereoelectronic effects, the reaction tends to proceed via an SN1 mechanism to afford alpha-glycosides. We found that the introduction of a 2,6-lactone bridge can circumvent the competing SN1 reaction, affording beta-glycosides with stereoinversion via SN2(-like) mechanisms. Glycosyl trichloroacetimidates are particularly efficient when activated by a combined catalyst of AuCl3 and 3,5-bis(trifluoromethyl)phenyl thiourea. In addition, the product stereoselectivity was highly dependent on the concentration of the reaction. Moreover, even when the reaction proceeds via an SN1 mechanism, the corresponding glycosyl cation appears to present sterically a beta-directing nature. Overall, 2,6-lactones were promising structures for achieving beta mannosylations. PMID- 27782396 TI - Phenyl Glycolipids with Different Glycosyl Groups Exhibit Marked Differences in Murine and Human iNKT Cell Activation. AB - Glycosphingolipids (GSLs) bearing the alpha-galactosyl headgroup and the acyl chain terminated with a phenyl derivative were found to be more potent than alpha galactosyl ceramide (alphaGalCer) to stimulate both murine and human invariant natural killer T (iNKT) cells and to induce an antibody isotope switch to IgG. In this study, we replaced the galactosyl group with glucose (alphaGlc) and its fluoro-analogs and found that phenyl GSLs with alphaGlc (C34-Glc) and its fluoro analog 6F-C34-Glc were stronger than those with alphaGal in stimulating human iNKT cells but weaker in mice. Their activities have a strong correlation with the binding avidities of the ternary interaction between the iNKT-cell receptor (iNKTCR) and CD1d-GSL complex. It was the iNKTCR rather than CD1d that dictated the species-specific responses. C34-Glc was further used as an adjuvant for a SSEA4-crm-197 vaccine, and after immunization in mice, the vaccine was highly effective against Lewis lung carcinoma. PMID- 27782397 TI - Monosaccharides as Potential Chiral Probes for the Determination of the Absolute Configuration of Secondary Alcohols. AB - Herein, a new method for the elucidation of the absolute configuration of chiral secondary alcohols is proposed. This method is an alternative for a widely used approach reported by Mosher and Dale and similar methods that are based on the 1H NMR shift (delta) changes of protons that are attached to the substituents of the oxymethine carbon atom. The presented method is not based on tracking the chemical shift changes and utilizes stereochemically defined monosaccharides as chiral probes. A secondary alcohol is glycosylated, and the resulting glycoside is subjected to NMR studies. The observation of dipolar couplings between the protons of the monosaccharide moiety and the protons of the secondary alcohol moiety via the NOESY/ROESY spectra enables the determination of the absolute configuration of the oxymethine carbon atom. PMID- 27782398 TI - Microcontact Printing of Thiol-Functionalized Ionic Liquid Microarrays for "Membrane-less" and "Spill-less" Gas Sensors. AB - Lab-on-a-chip systems have gained significant interest for both chemical synthesis and assays at the micro-to-nanoscale with a unique set of benefits. However, solvent volatility represents one of the major hurdles to the reliability and reproducibility of the lab-on-a-chip devices for large-scale applications. Here we demonstrate a strategy of combining nonvolatile and functionalized ionic liquids with microcontact printing for fabrication of "wall less" microreactors and microfluidics with high reproducibility and high throughput. A range of thiol-functionalized ionic liquids have been synthesized and used as inks for microcontact printing of ionic liquid microdroplet arrays onto gold chips. The covalent bonds formed between the thiol-functionalized ionic liquids and the gold substrate offer enhanced stability of the ionic liquid microdroplets, compared to conventional nonfunctionalized ionic liquids, and these microdroplets remain stable in a range of nonpolar and polar solvents, including water. We further demonstrate the use of these open ionic liquid microarrays for fabrication of "membrane-less" and "spill-less" gas sensors with enhanced reproducibility and robustness. Ionic-liquid-based microarray and microfluidics fabricated using the described microcontact printing may provide a versatile platform for a diverse number of applications at scale. PMID- 27782399 TI - Tunable Yellow-Red Photoluminescence and Persistent Afterglow in Phosphors Ca4LaO(BO3)3:Eu3+ and Ca4EuO(BO3)3. AB - In most Eu3+ activated phosphors, only red luminescence from the 5D0 is obtainable, and efficiency is limited by concentration quenching. Herein we report a new phosphor of Ca4LaO(BO3)3:Eu3+ (CLBO:Eu) with advanced photoluminescence properties. The yellow luminescence emitted from the 5D1,2 states is not thermally quenched at room temperature. The relative intensities of the yellow and red emission bands depend strongly on the Eu3+ doping concentration. More importantly, concentration quenching of Eu3+ photoluminescence is absent in this phosphor, and the stoichiometric compound of Ca4EuO(BO3)3 emits stronger luminescence than the Eu3+ doped compounds of CLBO:Eu; it is three times stronger than that of a commercial red phosphor of Y2O3:Eu3+. Another beneficial phenomenon is that ligand-to-metal charge transfer (CT) transitions occur in the long UV region with the lowest charge transfer band (CTB) stretched down to about 3.67 eV (~330 nm). The CT transitions significantly enhance Eu3+ excitation, and thus result in stronger photoluminescence and promote trapping of excitons for persistent afterglow emission. Along with structure characterization, optical spectra and luminescence dynamics measured under various conditions as a function of Eu3+ doping, temperature, and excitation wavelength are analyzed for a fundamental understanding of electronic interactions and for potential applications. PMID- 27782400 TI - Regioselectivity in the Controversial Scholl Reaction of 1-Benzoylpyrene: Formation of a Five-Member Ring Is Not Unexpected. AB - Intramolecular Scholl reaction of 1-benzoylpyrene (1) gave 8H dibenzo[def,qr]chrysen-8-one (2) and 11H-indeno[2,1-a]pyren-11-one (3) in a 1:2 ratio. The structures of 2 and 3 were determined, using 1H NMR, 13C NMR, and IR spectroscopies. A DFT B3LYP/6-311G(d,p) study of the reaction's arenium-cation mechanism of (E)-1 and (Z)-1 giving 2 and 3, respectively, indicated the reaction's regioselectivity and kinetic control. The analogous reaction of 1-(1' naphthoyl)pyrene gave exclusively 13H-benz[4,5]indeno[2,1-a]pyren-13-one. Contrary to previous claims, the preferred formation of five-member rings in Scholl reactions is not unexpected. PMID- 27782401 TI - Unconventional Tough Double-Network Hydrogels with Rapid Mechanical Recovery, Self-Healing, and Self-Gluing Properties. AB - Hydrogels are polymeric materials that have a relatively high capacity for holding water. Recently, a double network (DN) technique was developed to fabricate hydrogels with a toughness comparable to rubber. The mechanical properties of DN hydrogels may be attributed to the brittle sacrificial bonding network of one hydrogel, facilitating stress dispersion, combined with ductile polymer chains of a second hydrogel. Herein, we report a novel class of tunable DN hydrogels composed of a polyurethane hydrogel and a stronger, dipole-dipole and H-bonding interaction reinforced (DHIR) hydrogel. Compared to conventional DN hydrogels, these materials show remarkable improvements in mechanical recovery, modulus, and yielding, with excellent self-healing and self-gluing properties. In addition, the new DN hydrogels exhibit excellent tensile and compression strengths and possess shape-memory properties, which make them promising for applications in engineering, biomedicine, and other domains where load bearing is required. PMID- 27782402 TI - Three-Dimensional Printing of Photoresponsive Biomaterials for Control of Bacterial Microenvironments. AB - Advances in microscopic three-dimensional (MU3D) printing provide a means to microfabricate an almost limitless range of arbitrary geometries, offering new opportunities to rapidly prototype complex architectures for microfluidic and cellular applications. Such 3D lithographic capabilities present a tantalizing prospect for engineering micromechanical components, for example, pumps and valves, for cellular environments composed of smart materials whose size, shape, permeability, stiffness, and other attributes might be modified in real time to precisely manipulate ultralow-volume samples. Unfortunately, most materials produced using MU3D printing are synthetic polymers that are inert to biologically tolerated chemical and light-based triggers and provide low compatibility as materials for cell culture and encapsulation applications. We previously demonstrated feasibility for MU3D printing environmentally sensitive, microstructured protein hydrogels that undergo volume changes in response to pH, ionic strength, and thermal triggers, cues that may be incompatible with sensitive chemical and biological systems. Here, we report the systematic investigation of photoillumination as a minimally invasive and remotely applied means to trigger morphological change in protein-based MU3D-printed smart materials. Detailed knowledge of material responsiveness is exploited to develop individually addressable "smart" valves that can be used to capture, "farm", and then dilute motile bacteria at specified times in multichamber picoliter edifices, capabilities that offer new opportunities for studying cell-cell interactions in ultralow-volume environments. PMID- 27782403 TI - Structural Modulation from 1D Chain to 3D Framework: Improved Thermostability, Insensitivity, and Energies of Two Nitrogen-Rich Energetic Coordination Polymers. AB - Two new energetic coordination polymers (CPs) [Pb(BT)(H2O)3]n (1) and [Pb3(DOBT)3(H2O)2]n.(4H2O)n (2) with 1D and 3D structures were synthesized by employing two rational designed ligands, 1H,1'H-5,5'-bitetrazole (H2BT) and 1H,1'H-[5,5'-bitetrazole]-1,1'-diol ligands (DHBT), respectively. Thermal analyses and sensitivity tests show that the 3D architecture reinforces the network of 2 which has higher thermal stability and lower sensitivity than that of 1. Through oxygen-bomb combustion calorimetry the molar enthalpy of formation of 2 is derived to be much higher than that of 1 as well as the reported CPs. Herein, more importantly, the heats of detonation (DeltaHdet) were calculated according to the decomposition products of TG-DSC-MS-FTIR simultaneous analyses for the first time. The calculated results show that DeltaHdet of 2 is 23% higher than that of 1. This research demonstrates that 3D energetic CP with outstanding energetic properties can be obtained through efficient and reasonable design. PMID- 27782405 TI - Au@MoS2 Core-Shell Heterostructures with Strong Light-Matter Interactions. AB - There are emerging opportunities to harness diverse and complex geometric architectures based on nominal two-dimensional atomically layered structures. Herein we report synthesis and properties of a new core-shell heterostructure, termed Au@MoS2, where the Au nanoparticle is snugly and contiguously encapsulated by few shells of MoS2 atomic layers. The heterostructures were synthesized by direct growth of multilayer fullerene-like MoS2 shell on Au nanoparticle cores. The Au@MoS2 heterostructures exhibit interesting light-matter interactions due to the structural curvature of MoS2 shell and the plasmonic effect from the underlying Au nanoparticle core. We observed significantly enhanced Raman scattering and photoluminescence emission on these heterostructures. We attribute these enhancements to the surface plasmon-induced electric field, which simulations show to mainly localize within the MoS2 shell. We also found potential evidence for the charge transfer-induced doping effect on the MoS2 shell. The DFT calculations further reveal that the structural curvature of MoS2 shell results in a modification of its electronic structure, which may facilitate the charge transfer from MoS2 to Au. Such Au@MoS2 core-shell heterostructures have the potential for future optoelectronic devices, optical imaging, and other energy-environmental applications. PMID- 27782404 TI - Membrane Fluidity Modulates Thermal Stability and Ligand Binding of Cytochrome P4503A4 in Lipid Nanodiscs. AB - Cytochrome P4503A4 (CYP3A4) is a peripheral membrane protein that plays a major role in enzymatic detoxification of many drugs and toxins. CYP3A4 has an integral membrane N-terminal helix and a localized patch comprised of the G' and F' helix regions that are embedded in the membrane, but the effects of membrane composition on CYP3A4 function are unknown. Here, circular dichroism and differential scanning calorimetry were used to compare the stability of CYP3A4 in lipid bilayer nanodiscs with varying ratios of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine to 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). These lipids differ in the acyl-chain length and their degree of unsaturation. The thermal denaturation of CYP3A4 in nanodiscs occurs in a temperature range distinct from that of the nanodisc denaturation so it can be monitored calorimetrically. Melting temperatures (Tm), heat capacities (DeltaCp), and calorimetric enthalpies (DeltaHcal) for denaturation of CYP3A4 each increased with an increasing fraction of DMPC, with a maximum at 50% DMPC, before decreasing at 75% DMPC. Addition of the inhibitor ketoconazole results in increased thermal stability, and larger DeltaCp and DeltaHcal values, with different sensitivities to lipid composition. Effects of lipid composition on ligand binding dynamics were also studied. Equilibrium binding affinities of both ketoconazole (KTZ) and testosterone (TST) were minimally affected by lipid composition. However, stopped-flow analyses indicate that the rates of KTZ binding reach a maximum in membranes containing 50% DMPC, whereas the rate of TST binding decreases continuously with an increasing DMPC concentration. These results indicate that CYP3A4 is highly sensitive to the acyl-chain composition of the lipids and fluidity of the membrane in which it is embedded. PMID- 27782406 TI - Bronsted Acid Catalyzed [3 + 2]-Cycloaddition of Cyclic Enamides with in Situ Generated 2-Methide-2H-indoles: Enantioselective Synthesis of Indolo[1,2 a]indoles. AB - An efficient formal [3 + 2]-cycloaddition toward the highly diastereo- and enantioselective synthesis of indolo[1,2-a]indoles is disclosed. A chiral BINOL derived phosphoric acid catalyzed the highly enantioselective conjugate addition of cyclic enamides to in situ generated 2-methide-2H-indoles and subsequent aminalization to give rise to acetamide-substituted indolo[1,2-a]indoles carrying three contiguous stereogenic centers. Importantly, these products were formed as single diastereomers and with excellent yields and enantioselectivities. Mild reaction conditions at ambient temperatures, the facile removal of the acetamido group, and the possibility of a scale-up highlight the practicality of this methodology. PMID- 27782407 TI - Effects of High Pressure on Internally Self-Assembled Lipid Nanoparticles: A Synchrotron Small-Angle X-ray Scattering (SAXS) Study. AB - We present the first report on the effects of hydrostatic pressure on colloidally stabilized lipid nanoparticles enveloping inverse nonlamellar self-assemblies in their interiors. These internal self-assemblies were systematically tuned into bicontinuous cubic (Pn3m and Im3m), micellar cubic (Fd3m), hexagonal (H2), and inverse micellar (L2) phases by regulating the lipid/oil ratio as the hydrostatic pressure was varied from atmospheric pressure to 1200 bar and back to atmospheric pressure. The effects of pressure on these lipid nanoparticles were compared with those on their equilibrium bulk, nondispersed counterparts, namely, inverse nonlamellar liquid-crystalline phases and micellar solutions under excess-water conditions, using the synchrotron small-angle X-ray scattering (SAXS) technique. In the applied pressure range, induced phase transitions were observed solely in fully hydrated bulk samples, whereas the internal self-assemblies of the corresponding lipid nanoparticles displayed only pressure-modulated single phases. Interestingly, both the lattice parameters and the linear pressure expansion coefficients were larger for the self-assemblies enveloped inside the lipid nanoparticles as compared to the bulk states. This behavior can, in part, be attributed to enhanced lipid layer undulations in the lipid particles in addition to induced swelling effects in the presence of the triblock copolymer F127. The bicontinuous cubic phases both in the bulk state and inside lipid cubosome nanoparticles swell on compression, even as both keep swelling further upon decompression at relatively high pressures before shrinking again at ambient pressures. The pressure dependence of the phases is also modulated by the concentration of the solubilized oil (tetradecane). These studies demonstrate the tolerance of lipid nanoparticles [cubosomes, hexosomes, micellar cubosomes, and emulsified microemulsions (EMEs)] for high pressures, confirming their robustness for various technological applications. PMID- 27782408 TI - Explicitly correlated coupled-cluster theory for static polarizabilities. AB - A method of calculation of static polarizabilities with wavefunctions, corresponding to linearly approximated explicitly correlated coupled-cluster singles and doubles [CCSD(F12)] model, has been formulated and implemented. For the proper description of the response of system on applied electric field, modified ansatz is introduced for geminal part of cluster operators. Such extension of CCSD(F12) model provides balanced description of both perturbed and unperturbed wave functions, what leads to the increase of the accuracy of target polarizabilities. As a part of algorithm, explicitly correlated version of coupled-perturbed CCSD equations has also been derived and implemented. Numerical tests conducted for the set of eight molecules show good agreement between static polarizabilities, calculated with developed explicitly correlated approach and corresponding complete basis set results in regular CCSD already at triple-zeta level. PMID- 27782409 TI - Mode-specific multi-channel dynamics of the F- + CHD2Cl reaction on a global ab initio potential energy surface. AB - We report a detailed quasiclassical trajectory study for the dynamics of the ground-state and CH/CD stretching-excited F- + CHD2Cl(vCH/CD = 0, 1) -> Cl- + CHD2F, HF + CD2Cl-, and DF + CHDCl- SN2, proton-, and deuteron-abstraction reactions using a full-dimensional global ab initio analytical potential energy surface. The simulations show that (a) CHD2Cl(vCH/CD = 1), especially for vCH = 1, maintains its mode-specific excited character prior to interaction, (b) the SN2 reaction is vibrationally mode-specific, PMID- 27782410 TI - Dual binding mode in cohesin-dockerin complexes as assessed through stretching studies. AB - A recent experimental study by Jobst et al. of stretching of a wild-type (WT) cohesin-dockerin complex has identified two kinds of the force-displacement patterns, with a single or double-peaked final rupture, which are termed "short" and "long" here. This duality has been interpreted as arising from the existence of two kinds of binding. Here, we analyze the separation of two cohesin-dockerin complexes of C. thermocellum theoretically. We use a coarse-grained structure based model and the values of the pulling speeds are nearly experimental. In their native states, the two systems differ in the mutual binding orientations of the molecules in the complex. We demonstrate that the WT complex (PDB:1OHZ) unravels along two possible pathways that are qualitatively consistent with the presence of the short and long patterns observed experimentally. On the other hand, the mutated complex (PDB:2CCL) leads only to short trajectories. The short and long stretching pathways also appear in the cohesin-dockerin-Xmodule complex (PDB:4IU3, WT) of R. flavefaciens. Thus the duality in the stretching patterns need not be necessarily due to the duality in binding. PMID- 27782411 TI - Growth kinetics of racemic heptahelicene-2-carboxylic acid nanowires on calcite (104). AB - Molecular self-assembly of racemic heptahelicene-2-carboxylic acid on a dielectric substrate at room temperature can be used to generate wire-like organic nanostructures consisting of single and double molecular rows. By means of non-contact atomic force microscopy, we investigate the growth of the wire like pattern after deposition by experimental and theoretical means. From analyzing the time dependence of the mean row length, two distinct regimes were found. At the early post-deposition stage, the mean length grows in time. Subsequently, a crossover to a second regime is observed, where the mean row length remains nearly constant. We explain these findings by a mean-field rate equation approach providing a comprehensive picture of the growth kinetics. As a result, we demonstrate that the crossover between the two distinct regimes is accomplished by vanishing of the homochiral single rows. At later stages only heterochiral double row structures remain. PMID- 27782412 TI - Communication: Thermal unimolecular decomposition of syn-CH3CHOO: A kinetic study. AB - The thermal decomposition of syn-ethanal-oxide (syn-CH3CHOO) through vinyl hydrogen peroxide (VHP) leading to hydroxyl radical is characterized using a modification of the HEAT thermochemical protocol. The isomerization step of syn CH3CHOO to VHP via a 1,4 H-shift, which involves a moderate barrier of 72 kJ/mol, is found to be rate determining. A two-dimensional master equation approach, in combination with semi-classical transition state theory, is employed to calculate the time evolution of various species as well as to obtain phenomenological rate coefficients. This work suggests that, under boundary layer conditions in the atmosphere, thermal unimolecular decomposition is the most important sink of syn CH3CHOO. Thus, the title reaction should be included into atmospheric modeling. The fate of cold VHP, the intermediate stabilized by collisions with a third body, has also been investigated. PMID- 27782413 TI - Infrared absorption of 1-chloro-2-methyl-2-propyl [?C(CH3)2CH2Cl] and 2-chloro-2 methylpropyl [?CH2C(CH3)2Cl] radicals produced in the addition reactions of Cl with isobutene (i-C4H8) in solid para-hydrogen. AB - The addition reactions of chlorine atom with isobutene (i-C4H8) in solid para hydrogen (p-H2) were investigated with infrared (IR) absorption spectra. When a p H2 matrix containing Cl2 and isobutene was irradiated with ultraviolet light at 365 nm, intense lines in a set at 534.5, 1001.0, 1212.9, 1366.0, 2961.6, and 2934.7 cm-1, and several weaker others due to the 1-chloro-2-methyl-2-propyl radical, ?C(CH3)2CH2Cl, and those in a second set including intense ones at 642.7, 799.2, 1098.2, 1371.8, and 3027.3 cm-1 due to the 2-chloro-2-methylpropyl radical, ?CH2C(CH3)2Cl, appeared; the ratio of ?C(CH3)2CH2Cl to ?CH2C(CH3)2Cl was approximately (3 +/- 1):1. The observed wavenumbers and relative intensities agree with the vibrational wavenumbers and IR intensities predicted with the B3PW91/aug-cc-pVTZ method. That the Cl atom adds to both carbons of the C=C bond of isobutene with the terminal site slightly favored is consistent with the energies of products predicted theoretically, but is in contrast to the reaction of Cl + propene in solid p-H2 in which the addition of Cl to mainly the central C atom was previously reported. The role of the p-H2 matrix in affecting the reaction paths is discussed. Absorption lines of the complex i-C4H8?Cl2 and the dichloro-product anti-1,2-dichloro-2-methylpropane, a-CH2ClCCl(CH3)2, are also characterized. PMID- 27782415 TI - Markov state model of the two-state behaviour of water. AB - With the help of a Markov State Model (MSM), two-state behaviour is resolved for two computer models of water in a temperature range from 255 K to room temperature (295 K). The method is first validated for ST2 water, for which the so far strongest evidence for a liquid-liquid phase transition exists. In that case, the results from the MSM can be cross-checked against the radial distribution function g5(r) of the 5th-closest water molecule around a given reference water molecule. The latter is a commonly used local order parameter, which exhibits a bimodal distribution just above the liquid-liquid critical point that represents the low-density form of the liquid (LDL) and the high density liquid. The correlation times and correlation lengths of the corresponding spatial domains are calculated and it is shown that they are connected via a simple diffusion model. Once the approach is established, TIP4P/2005 will be considered, which is the much more realistic representation of real water. The MSM can resolve two-state behavior also in that case, albeit with significantly smaller correlation times and lengths. The population of LDL-like water increases with decreasing temperature, thereby explaining the density maximum at 4 degrees C along the lines of the two-state model of water. PMID- 27782414 TI - Thermodiffusion, molecular diffusion and Soret coefficients of aromatic+n-alkane binary mixtures. AB - In the present work, we have measured the thermodiffusion coefficient of 51 binary liquid mixtures at 25 oC. These mixtures correspond to the series of the aromatics toluene and 1-methylnaphthalene with n-alkanes nCi (i = 6, 8, 10, 12, and 14) at different mass fractions in the whole range. For that, we have used the thermogravitational technique. It is shown that the thermodiffusion coefficient is a linear function of the mass fraction in all the mixtures. Extrapolating the lines, we obtain the thermodiffusion coefficient in dilute solutions of n-alkanes for both toluene and 1-methylnaphthalene. These limiting values show a linear dependence with the inverse of the product of the molecular weights. In addition, we have measured the molecular diffusion coefficient of all the mixtures at 0.5 of mass fraction and at 25 oC, by the sliding symmetric tubes technique. It is observed that the product of this coefficient with the viscosity at the same concentrations takes a constant value for each of the series considered. Finally, we have also determined the Soret coefficient of the equimass mixtures by the combination of the measurements of thermodiffusion and molecular diffusion coefficients. PMID- 27782416 TI - Recoupling the singlet- and triplet-pairing channels in single-reference coupled cluster theory. AB - It is well known that single-reference coupled cluster theory truncated to low orders of excitations gives the right answer for the right reason when systems are dominated by dynamical or weak correlation. Static or strong correlation is more problematic, causing often catastrophic breakdown of restricted coupled cluster. This failure can be remedied, e.g., by allowing symmetry breaking in the reference or taking a multi-reference approach, but poses an interesting theoretical problem, especially since many groups have found that simplifying the T2 operator or the doubles amplitude equations gives better results. In singlet paired coupled cluster, eliminating the triplet-pairing channel recovers reasonable qualitative behavior for strong correlation at the cost of a decreased description of dynamical correlation in weakly correlated situations. This behavior seems to hold for both closed- and open-shell systems. In this work, we explore the coupling of the singlet- and triplet-pairing channels of T2 and attempt to recouple them in order to recover dynamical correlation without reintroducing catastrophic failure due to strong correlation. In the weakly correlated regime, these pairing channels are only weakly coupled, and a simple recoupling gives good results. However, as strong correlation dominates, the coupling strength between the singlet- and triplet-pairing channels increases, making it difficult to perturbatively recouple the singlet- and triplet-pairing channels in this regime. PMID- 27782417 TI - Determination of nuclear quadrupolar parameters using singularities in field swept NMR patterns. AB - We propose a simple data-analysis scheme to determine the coupling constant and the asymmetry parameter of nuclear quadrupolar interactions in field-swept nuclear magnetic resonance (NMR) for static powder samples. This approach correlates the quadrupolar parameters to the positions of the singularities, which can readily be found out as sharp peaks in the field-swept pattern. Moreover, the parameters can be determined without quantitative acquisition and elaborate calculation of the overall profile of the pattern. Since both experimental and computational efforts are significantly reduced, the approach presented in this work will enhance the power of the field-swept NMR for yet unexplored quadrupolar nuclei. We demonstrate this approach in 33S in alpha-S8 and 35Cl in chloranil. The accuracy of the obtained quadrupolar parameters is also discussed. PMID- 27782418 TI - The behavior of active diffusiophoretic suspensions: An accelerated Laplacian dynamics study. AB - Diffusiophoresis is the process by which a colloidal particle moves in response to the concentration gradient of a chemical solute. Chemically active particles generate solute concentration gradients via surface chemical reactions which can result in their own motion - the self-diffusiophoresis of Janus particles - and in the motion of other nearby particles - normal down-gradient diffusiophoresis. The long-range nature of the concentration disturbance created by a reactive particle results in strong interactions among particles and can lead to the formation of clusters and even coexisting dense and dilute regions often seen in active matter systems. In this work, we present a general method to determine the many-particle solute concentration field allowing the dynamic simulation of the motion of thousands of reactive particles. With the simulation method, we first clarify and demonstrate the notion of "chemical screening," whereby the long ranged interactions become exponentially screened, which is essential for otherwise diffusiophoretic suspensions would be unconditionally unstable. Simulations show that uniformly reactive particles, which do not self-propel, form loosely packed clusters but no coexistence is observed. The simulations also reveal that there is a stability threshold - when the "chemical fuel" concentration is low enough, thermal Brownian motion is able to overcome diffusiophoretic attraction. Janus particles that self-propel show coexistence, but, interestingly, the stability threshold for clustering is not affected by the self-motion. PMID- 27782419 TI - Structure and dynamics of binary liquid mixtures near their continuous demixing transitions. AB - The dynamic and static critical behavior of a family of binary Lennard-Jones liquid mixtures, close to their continuous demixing points (belonging to the so called model H' dynamic universality class), are studied computationally by combining semi-grand canonical Monte Carlo simulations and large-scale molecular dynamics (MD) simulations, accelerated by graphic processing units (GPU). The symmetric binary liquid mixtures considered cover a variety of densities, a wide range of compressibilities, and various interactions between the unlike particles. The static quantities studied here encompass the bulk phase diagram (including both the binodal and the lambda-line), the correlation length, and the concentration susceptibility, of the finite-sized systems above the bulk critical temperature Tc, the compressibility and the pressure at Tc. Concerning the collective transport properties, we focus on the Onsager coefficient and the shear viscosity. The critical power-law singularities of these quantities are analyzed in the mixed phase (above Tc) and non-universal critical amplitudes are extracted. Two universal amplitude ratios are calculated. The first one involves static amplitudes only and agrees well with the expectations for the three dimensional Ising universality class. The second ratio includes also dynamic critical amplitudes and is related to the Einstein-Kawasaki relation for the interdiffusion constant. Precise estimates of this amplitude ratio are difficult to obtain from MD simulations, but within the error bars our results are compatible with theoretical predictions and experimental values for model H'. Evidence is reported for an inverse proportionality of the pressure and the isothermal compressibility at the demixing transition, upon varying either the number density or the repulsion strength between unlike particles. PMID- 27782420 TI - Characterization of the primary hydration shell of the hydroxide ion with H2 tagging vibrational spectroscopy of the OH- ? (H2O)n=2,3 and OD- ? (D2O)n=2,3 clusters. AB - We report the isotope-dependent vibrational predissociation spectra of the H2 tagged OH- ? (H2O)n=2,3 clusters, from which we determine the strongly coordination-dependent energies of the fundamentals due to the OH groups bound to the ion and the intramolecular bending modes of the water molecules. The HOH bending fundamental is completely missing in the delocalized OH- ? (H2O) binary complex but is recovered upon adding the second water molecule, thereby establishing that the dihydrate behaves as a hydroxide ion solvated by two essentially intact water molecules. The energies of the observed OH stretches are in good agreement with the values predicted by Takahashi and co-workers [Phys. Chem. Chem. Phys. 17, 25505 (2015); 15, 114 (2013)] with a theoretical model that treats the strong anharmonicities at play in this system with explicit coupling between the bound OH groups and the O-O stretching modes on an extended potential energy surface. We highlight a surprising similarity between the spectral signatures of OH- ? (H2O)3 and the excess proton analogue, H3O+ ? (H2O)3, both of which correspond to completed hydration shells around the proton defect. We discuss the origin of the extreme solvatochromicity displayed by both OH- and H+ in the context of the anomalously large "proton polarizabilities" of the H5O2+ and H3O2- binary complexes. PMID- 27782421 TI - Communication: Equivalence between symmetric and antisymmetric stretching modes of NH3 in promoting H + NH3 -> H2 + NH2 reaction. AB - Vibrational excitations of reactants sometimes promote reactions more effectively than the same amount of translational energy. Such mode specificity provides insights into the transition-state modulation of reactivity and might be used to control chemical reactions. We report here a state-of-the-art full-dimensional quantum dynamical study of the hydrogen abstraction reaction H + NH3 -> H2 + NH2 on an accurate ab initio based global potential energy surface. This reaction serves as an ideal candidate to study the relative efficacies of symmetric and degenerate antisymmetric stretching modes. Strong mode specificity, particularly for the NH3 stretching modes, is demonstrated. It is further shown that nearly identical efficacies of the symmetric and antisymmetric stretching modes of NH3 in promoting the reaction can be understood in terms of local-mode stretching vibrations of the reactant molecule. PMID- 27782422 TI - The excited-state structure, vibrations, lifetimes, and nonradiative dynamics of jet-cooled 1-methylcytosine. AB - We have investigated the S0 -> S1 UV vibronic spectrum and time-resolved S1 state dynamics of jet-cooled amino-keto 1-methylcytosine (1MCyt) using two-color resonant two-photon ionization, UV/UV holeburning and depletion spectroscopies, as well as nanosecond and picosecond time-resolved pump/delayed ionization measurements. The experimental study is complemented with spin-component-scaled second-order coupled-cluster and multistate complete active space second order perturbation ab initio calculations. Above the weak electronic origin of 1MCyt at 31 852 cm-1 about 20 intense vibronic bands are observed. These are interpreted as methyl group torsional transitions coupled to out-of-plane ring vibrations, in agreement with the methyl group rotation and out-of-plane distortions upon 1pipi* excitation predicted by the calculations. The methyl torsion and nu1' (butterfly) vibrations are strongly coupled, in the S1 state. The S0 -> S1 vibronic spectrum breaks off at a vibrational excess energy Eexc ~ 500 cm-1, indicating that a barrier in front of the ethylene-type S1?S0 conical intersection is exceeded, which is calculated to lie at Eexc = 366 cm-1. The S1?S0 internal conversion rate constant increases from kIC = 2 ? 109 s-1 near the S1(v = 0) level to 1 ? 1011 s 1 at Eexc = 516 cm-1. The 1pipi* state of 1MCyt also relaxes into the lower-lying triplet T1 (3pipi*) state by intersystem crossing (ISC); the calculated spin orbit coupling (SOC) value is 2.4 cm-1. The ISC rate constant is 10-100 times lower than kIC; it increases from kISC = 2 ? 108 s-1 near S1(v = 0) to kISC = 2 ? 109 s-1 at Eexc = 516 cm-1. The T1 state energy is determined from the onset of the time-delayed photoionization efficiency curve as 25 600 +/- 500 cm-1. The T2 (3npi*) state lies >1500 cm-1 above S1(v = 0), so S1?T2 ISC cannot occur, despite the large SOC parameter of 10.6 cm-1. An upper limit to the adiabatic ionization energy of 1MCyt is determined as 8.41 +/- 0.02 eV. Compared to cytosine, methyl substitution at N1 lowers the adiabatic ionization energy by >=0.32 eV and leads to a much higher density of vibronic bands in the S0 -> S1 spectrum. The effect of methylation on the radiationless decay to S0 and ISC to T1 is small, as shown by the similar break-off of the spectrum and the similar computed mechanisms. PMID- 27782423 TI - Memory effects in nanoparticle dynamics and transport. AB - In this work, we use the generalized Langevin equation (GLE) to characterize and understand memory effects in nanoparticle dynamics and transport. Using the GLE formulation, we compute the memory function and investigate its scaling with the mass, shape, and size of the nanoparticle. It is observed that changing the mass of the nanoparticle leads to a rescaling of the memory function with the reduced mass of the system. Further, we show that for different mass nanoparticles it is the initial value of the memory function and not its relaxation time that determines the "memory" or "memoryless" dynamics. The size and the shape of the nanoparticle are found to influence both the functional-form and the initial value of the memory function. For a fixed mass nanoparticle, increasing its size enhances the memory effects. Using GLE simulations we also investigate and highlight the role of memory in nanoparticle dynamics and transport. PMID- 27782424 TI - Density-fitted open-shell symmetry-adapted perturbation theory and application to pi-stacking in benzene dimer cation and ionized DNA base pair steps. AB - Symmetry-Adapted Perturbation Theory (SAPT) is one of the most popular approaches to energy component analysis of non-covalent interactions between closed-shell systems, yielding both accurate interaction energies and meaningful interaction energy components. In recent years, the full open-shell equations for SAPT up to second-order in the intermolecular interaction and zeroth-order in the intramolecular correlation (SAPT0) were published [P. S. Zuchowski et al., J. Chem. Phys. 129, 084101 (2008); M. Hapka et al., ibid. 137, 164104 (2012)]. Here, we utilize density-fitted electron repulsion integrals to produce an efficient computational implementation. This approach is used to examine the effect of ionization on pi-pi interactions. For the benzene dimer radical cation, comparison against reference values indicates a good performance for open-shell SAPT0, except in cases with substantial charge transfer. For pi stacking between hydrogen-bonded pairs of nucleobases, dispersion interactions still dominate binding, in spite of the creation of a positive charge. PMID- 27782425 TI - The intermolecular interaction in D2 - CX4 and O2 - CX4 (X = F, Cl) systems: Molecular beam scattering experiments as a sensitive probe of the selectivity of charge transfer component. AB - Gas phase collisions of a D2 projectile by CF4 and by CCl4 targets have been investigated with the molecular beam technique. The integral cross section, Q, has been measured for both collisional systems in the thermal energy range and oscillations due to the quantum "glory" interference have been resolved in the velocity dependence of Q. The analysis of the measured Q(v) data provided novel information on the anisotropic potential energy surfaces of the studied systems at intermediate and large separation distances. The relative role of the most relevant types of contributions to the global interaction has been characterized. Extending the phenomenology of a weak intermolecular halogen bond, the present work demonstrates that while D2 - CF4 is basically bound through the balance between size (Pauli) repulsion and dispersion attraction, an appreciable intermolecular bond stabilization by charge transfer is operative in D2 - CCl4. We also demonstrated that the present analysis is consistent with that carried out for the F(2P)-D2 and Cl(2P)-D2 systems, previously characterized by scattering experiments performed with state-selected halogen atom beams. A detailed comparison of the present and previous results on O2-CF4 and O2-CCl4 systems pinpointed striking differences in the behavior of hydrogen and oxygen molecules when they interact with the same partner, mainly due to the selectivity of the charge transfer component. The present work contributes to cast light on the nature and role of the intermolecular interaction in prototype systems, involving homo-nuclear diatoms and symmetric halogenated molecules. PMID- 27782426 TI - Probing dissociative electron attachment through heavy-Rydberg ion-pair production in Rydberg atom collisions. AB - Electron transfer in collisions between low-n, n = 12, Rydberg atoms and targets that attach low-energy electrons can lead to the formation of heavy-Rydberg ion pair states comprising a weakly-bound positive-negative ion pair that orbit each other at large separations. Measurements of the velocity and angular distribution of ion-pair states produced in collisions with 1,1,1-C2Cl3F3, CBrCl3, BrCN, and Fe(CO)5 are used to show that electron transfer reactions furnish a new technique with which to examine the lifetime and decay energetics of the excited intermediates formed during dissociative electron capture. The results are analyzed with the aid of Monte Carlo simulations based on the free electron model of Rydberg atom collisions. The data further highlight the capabilities of Rydberg atoms as a microscale laboratory in which to probe the dynamics of electron attachment reactions. PMID- 27782427 TI - Tree based machine learning framework for predicting ground state energies of molecules. AB - We present an application of the boosted regression tree algorithm for predicting ground state energies of molecules made up of C, H, N, O, P, and S (CHNOPS). The PubChem chemical compound database has been incorporated to construct a dataset of 16 242 molecules, whose electronic ground state energies have been computed using density functional theory. This dataset is used to train the boosted regression tree algorithm, which allows a computationally efficient and accurate prediction of molecular ground state energies. Predictions from boosted regression trees are compared with neural network regression, a widely used method in the literature, and shown to be more accurate with significantly reduced computational cost. The performance of the regression model trained using the CHNOPS set is also tested on a set of distinct molecules that contain additional Cl and Si atoms. It is shown that the learning algorithms lead to a rich and diverse possibility of applications in molecular discovery and materials informatics. PMID- 27782428 TI - Diffusion of helical particles in the screw-like nematic phase. AB - The mechanism of diffusion of helical particles in the new screw-like nematic phase is studied by molecular dynamics numerical simulation. Several dynamical indicators are reported that evidence and microscopically characterise the special translo-rotational motion by which helical particles move in this chiral liquid-crystalline phase. Besides mean square displacements and diffusion coefficients resolved parallel and perpendicular to the nematic director, a suitable translo-rotational van Hove self-correlation function and a sequence of translational and rotational velocity, self- and distinct-, time correlation functions are calculated. The analysis of all these correlation functions elicits the operativeness of the aforementioned coupled mechanism and allows its short- and long-time quantitative characterisation. PMID- 27782429 TI - Intermolecular associations in an equimolar formamide-water solution based on neutron scattering and DFT calculations. AB - In the present work, we have investigated the intermolecular associations of formamide with water in an equimolar formamide-water solution (FA-Water) by means of neutron scattering in combination with density functional theory calculations. The neutron scattering data were analyzed to deduce the structure factor SM(q) and the intermolecular pair correlation function gL(r). By considering different hydrogen bonded FA-Water associations, it has been shown that some of them describe well the local order in the solution. Natural bond orbital and atoms in molecules analyses have been performed to give more insight into the properties of hydrogen bonds involved in the more probable models. PMID- 27782430 TI - Perspective: Kohn-Sham density functional theory descending a staircase. AB - This article presents a perspective on Kohn-Sham density functional theory (KS DFT) for electronic structure calculations in chemical physics. This theory is in widespread use for applications to both molecules and solids. We pay special attention to several aspects where there are both concerns and progress toward solutions. These include: 1. The treatment of open-shell and inherently multiconfigurational systems (the latter are often called multireference systems and are variously classified as having strong correlation, near-degeneracy correlation, or high static correlation; KS-DFT must treat these systems with broken-symmetry determinants). 2. The treatment of noncovalent interactions. 3. The choice between developing new functionals by parametrization, by theoretical constraints, or by a combination. 4. The ingredients of the exchange-correlation functionals used by KS-DFT, including spin densities, the magnitudes of their gradients, spin-specific kinetic energy densities, nonlocal exchange (Hartree Fock exchange), nonlocal correlation, and subshell-dependent corrections (DFT+U). 5. The quest for a universal functional, where we summarize some of the success of the latest Minnesota functionals, namely MN15-L and MN15, which were obtained by optimization against diverse databases. 6. Time-dependent density functional theory, which is an extension of DFT to treat time-dependent problems and excited states. The review is a snapshot of a rapidly moving field, and-like Marcel Duchamp-we hope to convey progress in a stimulating way. PMID- 27782431 TI - Asymmetry in structural response of inner and outer transmembrane segments of CorA protein by a coarse-grain model. AB - Structure of CorA protein and its inner (i.corA) and outer (o.corA) transmembrane (TM) components are investigated as a function of temperature by a coarse-grained Monte Carlo simulation. Thermal response of i.corA is found to differ considerably from that of the outer component, o.corA. Analysis of the radius of gyration reveals that the inner TM component undergoes a continuous transition from a globular conformation to a random coil structure on raising the temperature. In contrast, the outer transmembrane component exhibits an abrupt (nearly discontinuous) thermal response in a narrow range of temperature. Scaling of the structure factor shows a globular structure of i.corA at a low temperature with an effective dimension D ~ 3 and a random coil at a high temperature with D ~ 2. The residue distribution in o.corA is slightly sparser than that of i.corA in a narrow thermos-responsive regime. The difference in thermos-response characteristics of these components (i.corA and o.corA) may reflect their unique transmembrane functions. PMID- 27782432 TI - Phonon thermal properties of graphene from molecular dynamics using different potentials. AB - Phonon thermal transport in graphene has attracted significant interest in recent years. Phonon thermal properties of graphene are investigated by molecular dynamics simulations using the Tersoff, Tersoff-2010, REBO, and AIREBO potentials. By calculating the phonon properties and thermal conductivity of graphene, the performance of the potentials is evaluated based on comparisons with experimental data. It shows that the Tersoff-2010 and REBO display better dispersion curves for graphene than the original Tersoff and AIREBO. The Tersoff 2010 correctly provides the Gamma point phonon velocities of the LA and TA branches as well as the G peak frequency with a value of 46 THz. In addition, the acoustic phonon relaxation time derived from the Tersoff-2010 satisfies the ideal relation "tau-1 ? nu2." It is also found that the Tersoff-2010 provides the highest graphene thermal conductivity among the used potentials, and estimates about 30.0% contribution for flexural phonons to the total thermal conductivity. By comparison, the Tersoff-2010 potential is demonstrated to be the most suitable one to describe the phonon thermal properties of graphene. PMID- 27782433 TI - Lattice model of spatial correlations in catalysis. AB - Optically detected single-turnover measurements of biological and inorganic catalysts provide a detailed picture of structural and dynamical influences on catalytic activity. Measurement at the single-molecule level of catalysis of a fluorogenic reaction (or its reverse) yields a stochastic fluorescence trajectory reflecting the statistics of individual reaction and product dissociation events. Analysis of time correlations displayed by this trajectory reveals reaction details inaccessible in a bulk measurement of averaged dynamics. Superresolution optical detection techniques can provide a spatial resolution over which correlations could be observed in space as well as time. A model is constructed here for spatial correlations in catalytic activity produced by an entity transported among multiple active sites. An approximation strategy based on perturbation theory in the coupling between transport and reaction dynamics is applied to calculate the mean dwell time of a reactant on an active site and the correlation between dwell times of reactants at different locations. PMID- 27782434 TI - The Cassie-Wenzel transition of fluids on nanostructured substrates: Macroscopic force balance versus microscopic density-functional theory. AB - Classical density functional theory is applied to investigate the validity of a phenomenological force-balance description of the stability of the Cassie state of liquids on substrates with nanoscale corrugation. A bulk free-energy functional of third order in local density is combined with a square-gradient term, describing the liquid-vapor interface. The bulk free energy is parameterized to reproduce the liquid density and the compressibility of water. The square-gradient term is adjusted to model the width of the water-vapor interface. The substrate is modeled by an external potential, based upon the Lennard-Jones interactions. The three-dimensional calculation focuses on substrates patterned with nanostripes and square-shaped nanopillars. Using both the force-balance relation and density-functional theory, we locate the Cassie-to Wenzel transition as a function of the corrugation parameters. We demonstrate that the force-balance relation gives a qualitatively reasonable description of the transition even on the nanoscale. The force balance utilizes an effective contact angle between the fluid and the vertical wall of the corrugation to parameterize the impalement pressure. This effective angle is found to have values smaller than the Young contact angle. This observation corresponds to an impalement pressure that is smaller than the value predicted by macroscopic theory. Therefore, this effective angle embodies effects specific to nanoscopically corrugated surfaces, including the finite range of the liquid solid potential (which has both repulsive and attractive parts), line tension, and the finite interface thickness. Consistently with this picture, both patterns (stripes and pillars) yield the same effective contact angles for large periods of corrugation. PMID- 27782435 TI - Insight into the mechanism for the methanol synthesis via the hydrogenation of CO2 over a Co-modified Cu(100) surface: A DFT study. AB - A comprehensive density functional theory calculation was employed to investigate the reaction mechanism of methanol synthesis on a Co-modified Cu(100) surface via CO2 hydrogenation. The Cu(100) surface with embedded small Co clusters prepared experimentally was employed as a model system to explore the effects of Co dopant on the catalytic performance of Cu(100) surface towards CH3OH synthesis. The activation energy barriers and the reaction energies of 16 elementary surface reactions were determined. Our calculated results show that the most favorable reaction pathway for the hydrogenation of CO2 to CH3OH follows the sequence of CO2 -> HCOO* ->H2COO* ->H2COOH* ->H2CO* ->H3CO* ->H3COH*, and the OH* group hydrogenation to H2 O* is the rate-limiting step with an activation barrier of 112.3 kJ/mol. It is noted that, since the strength of Co-O bond is stronger than that of Cu-O bond, the introducing of Co dopant on the Cu surface can facilitate the formation of key intermediates for the CH3OH synthesis. Especially, the stability of the unstable dioxomethylene intermediate (H2COO*) found on the pure Cu(100) surface can be obviously enhanced on the Co-doped Cu(100) surface. As a result, with respect to the undoped surface, the productivity and selectivity towards CH3OH production on the Cu(100) surface will be improved after dispersing small Co clusters on the surface. PMID- 27782436 TI - The structural validity of various thermodynamical models of supercooled water. AB - The thermodynamic response functions of water exhibit an anomalous increase upon cooling that becomes strongly amplified in the deeply supercooled regime due to structural fluctuations between disordered and tetrahedral local structures. Here, we compare structural data from recent x-ray laser scattering measurements of water at 1 bar and temperatures down to 227 K with structural properties computed for several different water models using molecular dynamics simulations. Based on this comparison, we critically evaluate four different thermodynamic scenarios that have been invoked to explain the unusual behavior of water. The critical point-free model predicts small variations in the tetrahedrality with decreasing temperature, followed by a stepwise change at the liquid-liquid transition around 228 K at ambient pressure. This scenario is not consistent with the experimental data that instead show a smooth and accelerated variation in structure from 320 to 227 K. Both the singularity-free model and ice coarsening hypothesis give trends that indirectly indicate an increase in tetrahedral structure with temperature that is too weak to be consistent with experiment. A model that includes an apparent divergent point (ADP) at high positive pressure, however, predicts structural development consistent with our experimental measurements. The terminology ADP, instead of the commonly used liquid-liquid critical point, is more general in that it focuses on the growing fluctuations, whether or not they result in true criticality. Extrapolating this model beyond the experimental data, we estimate that an ADP in real water may lie around 1500 +/- 250 bars and 190 +/- 6 K. PMID- 27782437 TI - Ionic profiles close to dielectric discontinuities: Specific ion-surface interactions. AB - We study, by incorporating short-range ion-surface interactions, ionic profiles of electrolyte solutions close to a non-charged interface between two dielectric media. In order to account for important correlation effects close to the interface, the ionic profiles are calculated beyond mean-field theory, using the loop expansion of the free energy. We show that how it is possible to overcome the well-known deficiency of the regular loop expansion close to the dielectric jump and treat the non-linear boundary conditions within the framework of field theory. The ionic profiles are obtained analytically to one-loop order in the free energy, and their dependence on different ion-surface interactions is investigated. The Gibbs adsorption isotherm as well as the ionic profiles is used to calculate the surface tension, in agreement with the reverse Hofmeister series. Consequently, from the experimentally measured surface tension, one can extract a single adhesivity parameter, which can be used within our model to quantitatively predict hard to measure ionic profiles. PMID- 27782438 TI - State-to-state differential cross sections for a four-atom reaction: H2 + OH -> H2O + H in full dimensions. AB - The time-dependent wave packet method has been employed to calculate state-to state differential cross sections for the title reaction in full dimensions. It is found that the majority of H2O is produced in the first stretching excited states, with a large fraction of available energy for the reaction ending up as product internal motion. The differential cross sections for collision energy up to 0.4 eV are all peaked in the backward direction, but the width of the angular distribution increases considerably as the increase of collision energy. The isotope effect was also examined by comparing the scattering angular distribution for the title reaction with those for the HD + OH and D2 + OH reactions obtained in our previous work. PMID- 27782439 TI - Cost-effective description of strong correlation: Efficient implementations of the perfect quadruples and perfect hextuples models. AB - Novel implementations based on dense tensor storage are presented for the singlet reference perfect quadruples (PQ) [J. A. Parkhill et al., J. Chem. Phys. 130, 084101 (2009)] and perfect hextuples (PH) [J. A. Parkhill and M. Head-Gordon, J. Chem. Phys. 133, 024103 (2010)] models. The methods are obtained as block decompositions of conventional coupled-cluster theory that are exact for four electrons in four orbitals (PQ) and six electrons in six orbitals (PH), but that can also be applied to much larger systems. PQ and PH have storage requirements that scale as the square, and as the cube of the number of active electrons, respectively, and exhibit quartic scaling of the computational effort for large systems. Applications of the new implementations are presented for full-valence calculations on linear polyenes (CnHn+2), which highlight the excellent computational scaling of the present implementations that can routinely handle active spaces of hundreds of electrons. The accuracy of the models is studied in the pi space of the polyenes, in hydrogen chains (H50), and in the pi space of polyacene molecules. In all cases, the results compare favorably to density matrix renormalization group values. With the novel implementation of PQ, active spaces of 140 electrons in 140 orbitals can be solved in a matter of minutes on a single core workstation, and the relatively low polynomial scaling means that very large systems are also accessible using parallel computing. PMID- 27782440 TI - Origin of the effective mobility in non-linear active micro-rheology. AB - The distinction between the damping coefficient and the effective non-linear mobility of driven particles in active micro-rheology of supercooled liquids is explained in terms of individual and collective dynamics. The effective mobility arises as a collective effect which gives insight into the energy landscape of the system. On the other hand, the damping coefficient is a constant that modulates the effect of external forces over the thermal energy which particles have at their disposition to perform Brownian motion. For long times, these thermal fluctuations become characterized in terms of an effective temperature that is a consequence of the dynamic coupling between kinetic and configurational degrees of freedom induced by the presence of the strong external force. The interplay between collective mobility and effective temperature allows to formulate a generalized Stokes-Einstein relation that may be used to determine the collective diffusion coefficient. The explicit relations we deduce reproduce simulation data remarkably well. PMID- 27782441 TI - Efficiency in nonequilibrium molecular dynamics Monte Carlo simulations. AB - Hybrid algorithms combining nonequilibrium molecular dynamics and Monte Carlo (neMD/MC) offer a powerful avenue for improving the sampling efficiency of computer simulations of complex systems. These neMD/MC algorithms are also increasingly finding use in applications where conventional approaches are impractical, such as constant-pH simulations with explicit solvent. However, selecting an optimal nonequilibrium protocol for maximum efficiency often represents a non-trivial challenge. This work evaluates the efficiency of a broad class of neMD/MC algorithms and protocols within the theoretical framework of linear response theory. The approximations are validated against constant pH-MD simulations and shown to provide accurate predictions of neMD/MC performance. An assessment of a large set of protocols confirms (both theoretically and empirically) that a linear work protocol gives the best neMD/MC performance. Finally, a well-defined criterion for optimizing the time parameters of the protocol is proposed and demonstrated with an adaptive algorithm that improves the performance on-the-fly with minimal cost. PMID- 27782442 TI - A molecular dynamics study of the role of molecular water on the structure and mechanics of amorphous geopolymer binders. AB - In this paper, molecular dynamics simulations are used to study the effect of molecular water and composition (Si/Al ratio) on the structure and mechanical properties of fully polymerized amorphous sodium aluminosilicate geopolymer binders. The X-ray pair distribution function for the simulated geopolymer binder phase showed good agreement with the experimentally determined structure in terms of bond lengths of the various atomic pairs. The elastic constants and ultimate tensile strength of the geopolymer binders were calculated as a function of water content and Si/Al ratio; while increasing the Si/Al ratio from one to three led to an increase in the respective values of the elastic stiffness and tensile strength, for a given Si/Al ratio, increasing the water content decreased the stiffness and strength of the binder phase. An atomic-scale analysis showed a direct correlation between water content and diffusion of alkali ions, resulting in the weakening of the AlO4 tetrahedral structure due to the migration of charge balancing alkali ions away from the tetrahedra, ultimately leading to failure. In the presence of water molecules, the diffusion behavior of alkali cations was found to be particularly anomalous, showing dynamic heterogeneity. This paper, for the first time, proves the efficacy of atomistic simulations for understanding the effect of water in geopolymer binders and can thus serve as a useful design tool for optimizing composition of geopolymers with improved mechanical properties. PMID- 27782443 TI - Unphysical divergences in response theory. AB - Transition densities between excited states are key for nonlinear theoretical spectroscopy and multi-state non-adiabatic molecular dynamics (NAMD) simulations. In the framework of response theory, these transition densities are accessible from poles of the quadratic response function. It was shown recently that the thus obtained transition densities within time-dependent Hartree-Fock (TDHF) and adiabatic time-dependent density functional theory (TDDFT) exhibit unphysical divergences when the difference in excitation energy of the two states of interest matches another excitation energy. This unphysical behavior is a consequence of spurious poles in the quadratic response function. We show that the incorrect pole structure of the quadratic response is not limited to TDHF and adiabatic TDDFT, but is also present in many other approximate many-electron response functions, including those from coupled cluster and multiconfigurational self-consistent field response theory. The divergences appear in regions of the potential energy surface where the ground state is perfectly well behaved, and they are frequently encountered in NAMD simulations of photochemical reactions. The origin of the divergences is traced to an incorrect instantaneous time dependence of the effective Hamiltonian. The implications for computations of frequency-dependent response properties are considerable and call into question the validity of conventional approximate many-electron response theories beyond linear response. PMID- 27782444 TI - State-to-state differential cross sections for D2 + OH -> D + DOH reaction: Influence of vibrational excitation of OH reactant. AB - State-to-state differential cross sections (DCSs) are computed quantum mechanically in full dimensionality for the title reaction using a reactant product decoupling scheme. The DCSs are calculated at three collision energies of 0.25, 0.28, and 0.34 eV, corresponding to the existing experimental results. In good agreement with experiment, the calculated DCSs are dominated by backward scattering, thanks to the direct rebound mechanism, and the DOH product has two quanta of OD stretching vibration in the newly formed OD bond. In addition, the vibrational excitation of the OH reactant is found to result in a very different but predictable vibrational distribution of the DOH product. It is further shown at the state-to-state level that the DCSs of the DOH(vOD, vb, vOH) product state from the OH(v = 1) reactant state resemble the ones of the DOH(vOD, vb, vOH-1) product state from the OH(v = 0) reactant state, thanks to the spectator nature of the OH moiety. PMID- 27782445 TI - Removing the barrier to the calculation of activation energies. AB - Approaches for directly calculating the activation energy for a chemical reaction from a simulation at a single temperature are explored with applications to both classical and quantum systems. The activation energy is obtained from a time correlation function that can be evaluated from the same molecular dynamics trajectories or quantum dynamics used to evaluate the rate constant itself and thus requires essentially no extra computational work. PMID- 27782446 TI - Orientational distribution functions and order parameters in "de Vries"-type smectics: A simulation study. AB - Simple smectic A liquid crystal phases with different types of prescribed orientational distribution functions have been simulated and compared in order to study the possibility to distinguish between the Maier-Saupe type and cone-like orientational distributions using the popular method of Davidson et al. [J. Phys. II 5, 113 (1995)]. This method has been used to extract the orientational distribution functions from simulated diffraction patterns, and the results have been compared with actual distribution functions which have been prescribed during simulations. It has been shown that it is indeed possible to distinguish between these two qualitatively different types of orientational distribution already from the shape of the 2D diffraction pattern. Moreover, typical experimental diffraction patterns for "de Vries"-type smectic liquid crystals appear to be close to the ones which have been simulated using the prescribed Maier-Saupe orientational distribution function. PMID- 27782447 TI - Dynamics of proteins aggregation. I. Universal scaling in unbounded media. AB - It is well understood that in some cases proteins do not fold correctly and, depending on their environment, even properly-folded proteins change their conformation spontaneously, taking on a misfolded state that leads to protein aggregation and formation of large aggregates. An important factor that contributes to the aggregation is the interactions between the misfolded proteins. Depending on the aggregation environment, the aggregates may take on various shapes forming larger structures, such as protein plaques that are often toxic. Their deposition in tissues is a major contributing factor to many neuro degenerative diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and prion. This paper represents the first part in a series devoted to molecular simulation of protein aggregation. We use the PRIME, a meso-scale model of proteins, together with extensive discontinuous molecular dynamics simulation to study the aggregation process in an unbounded fluid system, as the first step toward MD simulation of the same phenomenon in crowded cellular environments. Various properties of the aggregates have been computed, including dynamic evolution of aggregate-size distribution, mean aggregate size, number of peptides that contribute to the formation of beta sheets, number of various types of hydrogen bonds formed in the system, radius of gyration of the aggregates, and the aggregates' diffusivity. We show that many of such quantities follow dynamic scaling, similar to those for aggregation of colloidal clusters. In particular, at long times the mean aggregate size S(t) grows with time as, S(t) ~ tz, where z is the dynamic exponent. To our knowledge, this is the first time that the qualitative similarity between aggregation of proteins and colloidal aggregates has been pointed out. PMID- 27782448 TI - Pressure-dependent morphology of trihexyl(tetradecyl)phosphonium ionic liquids: A molecular dynamics study. AB - In the present molecular dynamics study, we investigate the effects of increasing pressure on the structural morphology of trihexyl(tetradecyl)phosphonium bromide (P666,14+/Br-) and trihexyl(tetradecyl)phosphonium dicyanamide (P666,14+/DCA-) ionic liquids (ILs). Special attention was paid to how charge and polarity orderings, which are present in the microscopic structure of these ILs at ambient conditions, respond to very high external pressure. The simulated X-ray scattering structure functions, S(q)s, of the two systems reveal that both the characteristic orderings show appreciable responsiveness towards the applied pressure change. At a given pressure, a slight difference between the polarity ordering (PO), charge ordering (CO), and adjacency correlations (AC) for both the systems points towards different microscopic structure of the two ILs due to change in anion. Beyond a certain pressure, we observe emergence of a new low-q peak in the S(q)s of both the systems. The new peak is associated with formation of crystalline order in these systems at higher pressures and the real space length-scale corresponding to the crystalline order lies in between those of polarity- and charge-ordering. Beyond the transition pressure, the crystallinity of both the systems increases with increasing pressure and the corresponding length-scale shifts towards smaller values upon increasing pressure. We also observe that the extent of the usual polarity ordering decreases upon increasing pressure for both the P666,14+/Br- and P666,14+/DCA- systems. We demonstrate that the disappearance of the usual polarity peak is due to decreased polar-polar and apolar-apolar correlations and enhanced correlations between the charged and uncharged groups of the ions. This scenario is completely reversed for the components corresponding to the crystalline order, the polar-polar and apolar apolar correlations are enhanced and polar-apolar correlations are diminished at higher pressure. In addition, the charge ordering peak, which is not so obvious from the total S(q) but from ionic and sub-ionic partial components of it, shifts towards lower q values for P666,14+/Br-. Instead, for the P666,14+/DCA-, at the highest pressure studied the CO peak occurs at a q-value higher than that at the ambient pressure. PMID- 27782449 TI - Ordering effects of conjugate thermal fields in simulations of molecular liquids: Carbon dioxide and water. AB - As shown previously, it is possible to apply configurational and kinetic thermostats simultaneously in order to induce a steady thermal flux in molecular dynamics simulations of many-particle systems. This flux appears to promote motion along potential gradients and can be utilized to enhance the sampling of ordered arrangements, i.e., it can facilitate the formation of a critical nucleus. Here we demonstrate that the same approach can be applied to molecular systems, and report a significant enhancement of the homogeneous crystal nucleation of a carbon dioxide (EPM2 model) system. Quantitative ordering effects and reduction of the particle mobilities were observed in water (TIP4P-2005 model) and carbon dioxide systems. The enhancement of the crystal nucleation of carbon dioxide was achieved with relatively small conjugate thermal fields. The effect is many orders of magnitude bigger at milder supercooling, where the forward flux sampling method was employed, than at a lower temperature that enabled brute force simulations of nucleation events. The behaviour exhibited implies that the effective free energy barrier of nucleation must have been reduced by the conjugate thermal field in line with our interpretation of previous results for atomic systems. PMID- 27782450 TI - Surface roughness stabilizes the clustering of self-propelled triangles. AB - Self-propelled particles can spontaneously form dense phases from a dilute suspension in a process referred to as motility-induced phase separation. The properties of the out-of-equilibrium structures that are formed are governed by the specifics of the particle interactions and the strength of the activity. Thus far, most studies into the formation of these structures have focused on spherical colloids, dumbbells, and rod-like particles endowed with various interaction potentials. Only a few studies have examined the collective behavior of more complex particle shapes. Here, we increase the geometric complexity and use molecular dynamics simulations to consider the structures formed by triangular self-propelled particles with surface roughness. These triangles either move towards their apex or towards their base, i.e., they possess a polarity. We find that apex-directed triangles cluster more readily, more stably, and have a smoother cluster interface than their base-directed counterparts. A difference between the two polarities is in line with the results of Wensink et al. [Phys. Rev. E 89, 010302 (2014)]; however, we obtain the reversed result when it comes to clustering, namely, that apex-directed triangles cluster more successfully. We further show that reducing the surface roughness negatively impacts the stability of the base-directed structures, suggesting that their formation is in large part due to surface roughness. Our results lay a solid foundation for future experimental and computational studies into the effect of roughness on the collective dynamics of swimmers. PMID- 27782451 TI - New insights into the Mo/Cu(In,Ga)Se2 interface in thin film solar cells: Formation and properties of the MoSe2 interfacial layer. AB - Being at the origin of an ohmic contact, the MoSe2 interfacial layer at the Mo/Cu(In,Ga)Se2 interface in CIGS (Cu(In,Ga)Se2 and related compounds) based solar cells has allowed for very high light-to-electricity conversion efficiencies up to 22.3%. This article gives new insights into the formation and the structural properties of this interfacial layer. Different selenization-steps of a Mo covered glass substrate prior to the CIGS deposition by co-evaporation led to MoSe2 interfacial layers with varying thickness and orientation, as observed by x-ray diffraction and atomic resolution transmission electron microscopy. A novel model based on the anisotropy of the Se diffusion coefficient in MoSe2 is proposed to explain the results. While the series resistance of finished CIGS solar cells is found to correlate with the MoSe2 orientation, the adhesion forces between the CIGS absorber layer and the Mo substrate stay constant. Their counter-intuitive non-correlation with the configuration of the MoSe2 interfacial layer is discussed and related to work from the literature. PMID- 27782452 TI - On the origin of multiexponential fluorescence decays from 2-aminopurine-labeled dinucleotides. AB - The fluorescent probe 2-aminopurine (2Ap) has been used for decades to study local conformational fluctuations in DNA. Steady-state and time-resolved measurements of 2Ap fluorescence have been used to predict specific conformational states through suitable modeling of the quenching of the fluorescence of a 2Ap residue incorporated site-specifically into a DNA strand. The success of this approach has been limited by a lack of understanding of the precise factors responsible for the complex, multiexponential decays observed experimentally. In this study, dinucleotides composed of 2Ap and adenine were studied by the time-correlated single-photon counting technique to investigate the causes of heterogeneous emission kinetics. Contrary to previous reports, we argue that emission from 2Ap that is stacked with a neighboring base contributes negligibly to the emission signals recorded more than 50 ps after excitation, which are instead dominated by emission from unstacked 2Ap. We find that the decay kinetics can be modeled using a continuous lifetime distribution, which arises from the inherent distance dependence of electron transfer rates without the need to postulate a small number of discrete states with decay times derived from multiexponential fits. These results offer a new perspective on the quenching of 2Ap fluorescence and expand the information that can be obtained from experiments. PMID- 27782453 TI - Chebyshev polynomial filtered subspace iteration in the discontinuous Galerkin method for large-scale electronic structure calculations. AB - The Discontinuous Galerkin (DG) electronic structure method employs an adaptive local basis (ALB) set to solve the Kohn-Sham equations of density functional theory in a discontinuous Galerkin framework. The adaptive local basis is generated on-the-fly to capture the local material physics and can systematically attain chemical accuracy with only a few tens of degrees of freedom per atom. A central issue for large-scale calculations, however, is the computation of the electron density (and subsequently, ground state properties) from the discretized Hamiltonian in an efficient and scalable manner. We show in this work how Chebyshev polynomial filtered subspace iteration (CheFSI) can be used to address this issue and push the envelope in large-scale materials simulations in a discontinuous Galerkin framework. We describe how the subspace filtering steps can be performed in an efficient and scalable manner using a two-dimensional parallelization scheme, thanks to the orthogonality of the DG basis set and block sparse structure of the DG Hamiltonian matrix. The on-the-fly nature of the ALB functions requires additional care in carrying out the subspace iterations. We demonstrate the parallel scalability of the DG-CheFSI approach in calculations of large-scale two-dimensional graphene sheets and bulk three-dimensional lithium ion electrolyte systems. Employing 55 296 computational cores, the time per self consistent field iteration for a sample of the bulk 3D electrolyte containing 8586 atoms is 90 s, and the time for a graphene sheet containing 11 520 atoms is 75 s. PMID- 27782454 TI - Thermodynamic balance of perylene self-assembly on Ag(110). AB - We present a room temperature STM study of perylene adsorption on Ag(110) at the monolayer coverage regime. We found that structure and symmetry of the perylene monolayer are settled by thermodynamic balance of the three factors: (i) the ability of perylene molecules to recognize specific adsorption sites on the (110) lattice, (ii) the intermolecular interaction, and (iii) the accommodation of thermal motion of the molecules. The moderate strength of the site recognition and the intermolecular interaction, of the same order of magnitude as kT ~ 25 meV, represents a key feature of the thermodynamic balance. It bestows to this system the unique quality to form the quasi-liquid monolayer of epitaxial as well as self-assembling character. The perylene monolayer accommodates the short-range motion of the molecules instead of quenching it. It precludes the formation of possible solid nuclei and maintains common registry of the included molecules. The surface registry of the quasi-liquid phase is provided by locking of a structure-related fraction of the perylene molecules into specific adsorption sites of the (110) lattice favorable in terms of intermolecular interaction. PMID- 27782455 TI - Translocation is a nonequilibrium process at all stages: Simulating the capture and translocation of a polymer by a nanopore. AB - Langevin dynamics simulations of the capture of polymers by a nanopore and the subsequent translocation through the nanopore are performed. These simulations are conducted for several polymer lengths at two different values for the Peclet number, which quantifies the drift-diffusion balance of the system. The capture translocation process is divided into several stages, and the dynamics of translocation are characterized by measuring the average time for each stage and also the average conformation of the polymer at each stage. Comparison to the standard simulation approach of simulating only the translocation process reveals several important differences. While in the standard protocol, the polymer is essentially equilibrated at the start of translocation, simulations of the capture process reveal a polymer that is elongated when it approaches the pore and either remains elongated or becomes compressed at the start of translocation depending on the drift-diffusion balance. These results demonstrate that translocation is a non-equilibrium process at all stages and that simulations assuming equilibration could yield improper results, even at a qualitative level. The scaling of the translocation time with polymer length is found to be significantly different between the two simulation protocols thus demonstrating that the capture step is an essential part of modeling the translocation process. PMID- 27782456 TI - Coverage-dependent structural phase transformations in the adsorption of pentacene on an aperiodically modulated Cu film. AB - Surface ordering of pentacene molecules adsorbed on an aperiodic Cu surface has been studied with density functional theory (DFT) and scanning tunnelling microscopy as a function of coverage. Below 0.73 ML (5.3 * 1013 molecules cm-2), the adsorbate structure is row-like with the molecular axes aligned with the rows in the Cu structure. Between this coverage and 1 ML (7.3 * 1013 molecules cm-2), a structural phase with a checkerboard structure is seen. At this coverage region, the molecules are very close to each other which leads to unusual bending. At higher coverages, a further phase transition to a high-density row structure is seen for most of the film. DFT with van der Waals functionals is employed to study how the molecule-molecule and molecule-surface interactions evolve as a function of coverage. PMID- 27782457 TI - Communication: A multiscale Bayesian inference approach to analyzing subdiffusion in particle trajectories. AB - Anomalous diffusion is characterized by its asymptotic behavior for t -> infinity. This makes it difficult to detect and describe in particle trajectories from experiments or computer simulations, which are necessarily of finite length. We propose a new approach using Bayesian inference applied directly to the observed trajectories sampled at different time scales. We illustrate the performance of this approach using random trajectories with known statistical properties and then use it for analyzing the motion of lipid molecules in the plane of a lipid bilayer. PMID- 27782458 TI - Understanding decomposition and encapsulation energies of structure I and II clathrate hydrates. AB - When compressed with water or ice under high pressure and low temperature conditions, some gases form solid gas hydrate inclusion compounds which have higher melting points than ice under those pressures. In this work, we study the balance of the guest-water and water-water interaction energies that lead to the formation of the clathrate hydrate phases. In particular, molecular dynamics simulations with accurate water potentials are used to study the energetics of the formation of structure I (sI) and II (sII) clathrate hydrates of methane, ethane, and propane. The dissociation enthalpy of the clathrate hydrate phases, the encapsulation enthalpy of methane, ethane, and propane guests in the corresponding phases, and the average bonding enthalpy of water molecules are calculated and compared with accurate calorimetric measurements and previous classical and quantum mechanical calculations, when available. The encapsulation energies of methane, ethane, and propane guests stabilize the small and large sI and sII hydrate cages, with the larger molecules giving larger encapsulation energies. The average water-water interactions are weakened in the sI and sII phases compared to ice. The relative magnitudes of the van der Waals potential energy in ice and the hydrate phases are similar, but in the ice phase, the electrostatic interactions are stronger. The stabilizing guest-water "hydrophobic" interactions compensate for the weaker water-water interactions and stabilize the hydrate phases. A number of common assumptions regarding the guest cage water interactions are used in the van der Waals-Platteeuw statistical mechanical theory to predict the clathrate hydrate phase stability under different pressure-temperature conditions. The present calculations show that some of these assumptions may not accurately reflect the physical nature of the interactions between guest molecules and the lattice waters. PMID- 27782459 TI - Sensitivity measurement of a cantilever-based surface stress sensor. AB - A detailed analysis of the temporal surface stress evolution for potential-driven adsorption of ions is discussed. A gold-coated cantilever is used to simultaneously measure the change in surface stress as well as the current response during an applied potential step. In this electrochemical configuration, the cantilever acts as the working electrode, a platinum wire as the counter electrode, and the Ag/AgCl (sat. KCl) electrode as the reference electrode. To study the time-dependent signal and the sensitivity of the cantilever response, the frequency of the potential step applied to the cantilever is varied from 1 s to 0.1 ms. First, a comparison between a strong adsorbing (chloride Cl-) and a weak adsorbing ion (perchlorate ClO4-) in a 1 mM solution is presented. Next, the linear relationship between surface stress and charge density is measured for these fast potential steps. The slope of this fit is defined as the sensitivity of the system and is shown to increase for shorter potential pulses. Finally, the behaviour of the surface stress and current for consecutive applied potential steps is studied. PMID- 27782460 TI - Collective concerted motion in a molecular adlayer visualized through the surface diffusion of isolated vacancies. AB - We have measured STM movies to study the diffusion of individual vacancies in a self-assembled layer of a tetrathiafulvalene derivative (exTTF) on Au(111) at room temperature. The diffusion is anisotropic, being faster along the compact direction of the molecular lattice. A detailed analysis of the anisotropic displacement distribution of the single vacancies shows that the relative abundance of double jumps (that is, the collective motion of molecular dimers) with respect to single jumps is rather large, the number of double jumps being more than 20% of the diffusion events. We conjecture that the relative abundances of long jumps might be related to the strength of the intermolecular bonding and the misfit of the molecular overlayer with the substrate lattice. PMID- 27782461 TI - Spin-orbit coupling with approximate equation-of-motion coupled-cluster method for ionization potential and electron attachment. AB - Various approximate approaches to calculate cluster amplitudes in equation-of motion coupled-cluster (EOM-CC) approaches for ionization potentials (IP) and electron affinities (EA) with spin-orbit coupling (SOC) included in post self consistent field (SCF) calculations are proposed to reduce computational effort. Our results indicate that EOM-CC based on cluster amplitudes from the approximate method CCSD-1, where the singles equation is the same as that in CCSD and the doubles amplitudes are approximated with MP2, is able to provide reasonable IPs and EAs when SOC is not present compared with CCSD results. It is an economical approach for calculating IPs and EAs and is not as sensitive to strong correlation as CC2. When SOC is included, the approximate method CCSD-3, where the same singles equation as that in SOC-CCSD is used and the doubles equation of scalar-relativistic CCSD is employed, gives rise to IPs and EAs that are in closest agreement with those of CCSD. However, SO splitting with EOM-CC from CC2 generally agrees best with that with CCSD, while that of CCSD-1 and CCSD-3 is less accurate. This indicates that a balanced treatment of SOC effects on both single and double excitation amplitudes is required to achieve reliable SO splitting. PMID- 27782462 TI - On the calculation of solubilities via direct coexistence simulations: Investigation of NaCl aqueous solutions and Lennard-Jones binary mixtures. AB - Direct coexistence molecular dynamics simulations of NaCl solutions and Lennard Jones binary mixtures were performed to explore the origin of reported discrepancies between solubilities obtained by direct interfacial simulations and values obtained from the chemical potentials of the crystal and solution phases. We find that the key cause of these discrepancies is the use of crystal slabs of insufficient width to eliminate finite-size effects. We observe that for NaCl crystal slabs thicker than 4 nm (in the direction perpendicular to the interface), the same solubility values are obtained from the direct coexistence and chemical potential routes, namely, 3.7 +/- 0.2 molal at T = 298.15 K and p = 1 bar for the JC-SPC/E model. Such finite-size effects are absent in the Lennard Jones system and are likely caused by surface dipoles present in the salt crystals. We confirmed that MUs-long molecular dynamics runs are required to obtain reliable solubility values from direct coexistence calculations, provided that the initial solution conditions are near the equilibrium solubility values; even longer runs are needed for equilibration of significantly different concentrations. We do not observe any effects of the exposed crystal face on the solubility values or equilibration times. For both the NaCl and Lennard-Jones systems, the use of a spherical crystallite embedded in the solution leads to significantly higher apparent solubility values relative to the flat-interface direct coexistence calculations and the chemical potential values. Our results have broad implications for the determination of solubilities of molecular models of ionic systems. PMID- 27782463 TI - Molecular and electronic structures of cerium and cerium suboxide clusters. AB - The anion photoelectron (PE) spectra of Ce2Oy- (y = 1, 2), Ce3Oy- (y = 0-4), Ce4Oy- (y = 0-2), and Ce5Oy- (y = 1, 2) are reported and analyzed with supporting results from density functional theory calculations. The PE spectra all exhibit an intense electronic transition to the neutral ground state, all falling in the range of 0.7 to 1.1 eV electron binding energy, with polarization dependence consistent with detachment from diffuse Ce 6s-based molecular orbitals. There is no monotonic increase in electron affinity with increasing oxidation. A qualitative picture of how electronic structure evolves with an oxidation state emerges from comparison between the spectra and the computational results. The electronic structure of the smallest metallic cluster observed in this study, Ce3, is similar to the bulk structure in terms of atomic orbital occupancy (4f 5d2 6s). Initial cerium cluster oxidation involves largely ionic bond formation via Ce 5d and O 2p orbital overlap (i.e., larger O 2p contribution), with Ce-O-Ce bridge bonding favored over Ce=O terminal bond formation. With subsequent oxidation, the Ce 5d-based molecular orbitals are depleted of electrons, with the highest occupied orbitals described as diffuse Ce 6s based molecular orbitals. In the y <= (x + 1) range of oxidation states, each Ce center has a singly occupied non-bonding 4f orbital. The PE spectrum of Ce3O4- is unique in that it exhibits a single nearly vertical transition. The highly symmetric structure predicted computationally is the same structure determined from Ce3O4+ IR predissociation spectra [A. M. Burow et al., Phys. Chem. Chem. Phys. 13, 19393 (2011)], indicating that this structure is stable in -1, 0, and +1 charge states. Spectra of clusters with x >= 3 exhibit considerable continuum signal above the ground state transition; the intensity of the continuum signal decreases with increasing oxidation. This feature is likely the result of numerous quasi-bound anion states or two-electron transitions possible in molecules with abundant nearly degenerate partially occupied orbitals. PMID- 27782464 TI - Towards understanding photomigration: Insights from atomistic simulations of azopolymer films explicitly including light-induced isomerization dynamics. AB - The light-induced surface modification of a thin film of poly-(disperse orange-3 methylmethacrylate) is investigated computationally using atomistic molecular dynamics simulations specifically tailored to include photoisomerization dynamics. For a model surface consisting of a periodic pattern of alternating irradiated and dark spots, it is shown that repeated photoisomerization in the irradiated areas initially leads to a local temperature increase and a raised surface profile accompanied by a migration of molecules away from the bright spots. After switching off the light source and letting the system cool down, this leads to an inversion of the surface profile, i.e., dips in the bright spots and bumps in the dark spots. To separate the effect of photoisomerization from the pure heating effect, a second simulation is performed in which no photoisomerization is allowed to occur in the bright spots, but the equivalent amount of energy is introduced there locally in the form of heat. This also leads to a raised surface in these areas; however, no outward migration of molecules is observed and the surface pattern practically vanishes when the system is subsequently cooled back to room temperature. PMID- 27782466 TI - Miming the cancer-immune system competition by kinetic Monte Carlo simulations. AB - In order to mimic the interactions between cancer and the immune system at cell scale, we propose a minimal model of cell interactions that is similar to a chemical mechanism including autocatalytic steps. The cells are supposed to bear a quantity called activity that may increase during the interactions. The fluctuations of cell activity are controlled by a so-called thermostat. We develop a kinetic Monte Carlo algorithm to simulate the cell interactions and thermalization of cell activity. The model is able to reproduce the well-known behavior of tumors treated by immunotherapy: the first apparent elimination of the tumor by the immune system is followed by a long equilibrium period and the final escape of cancer from immunosurveillance. PMID- 27782465 TI - Effect of the surface charge distribution on the fluid phase behavior of charged colloids and proteins. AB - A generic but simple model is presented to evaluate the effect of the heterogeneous surface charge distribution of proteins and zwitterionic nanoparticles on their thermodynamic phase behavior. By considering surface charges as continuous "patches," the rich set of surface patterns that is embedded in proteins and charged patchy particles can readily be described. This model is used to study the fluid phase separation of charged particles where the screening length is of the same order of magnitude as the particle size. In particular, two types of charged particles are studied: dipolar fluids and protein-like fluids. The former represents the simplest case of zwitterionic particles, whose charge distribution can be described by their dipole moment. The latter system corresponds to molecules/particles with complex surface charge arrangements such as those found in biomolecules. The results for both systems suggest a relation between the critical region, the strength of the interparticle interactions, and the arrangement of charged patches, where the critical temperature is strongly correlated to the magnitude of the dipole moment. Additionally, competition between attractive and repulsive charge-charge interactions seems to be related to the formation of fluctuating clusters in the dilute phase of dipolar fluids, as well as to the broadening of the binodal curve in protein-like fluids. Finally, a variety of self-assembled architectures are detected for dipolar fluids upon small changes to the charge distribution, providing the groundwork for studying the self-assembly of charged patchy particles. PMID- 27782467 TI - A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4. AB - In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 MUs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a -3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class. PMID- 27782468 TI - Ab initio investigation of structure, stability, thermal behavior, bonding, and infrared spectra of ionized water cluster (H2O)6. AB - The low-lying isomers of cationic water cluster (H2O)6+ have been globally explored by using particle swarm optimization algorithm in conjunction with quantum chemical calculations. Compared with previous results, our searching method covers a wide range of structural isomers of (H2O)6+ and therefore turns out to be more effective. With these local minima, geometry optimization and vibrational analysis are performed for the most interesting clusters at second order Moller-Plesset (MP2)/aug-cc-pVDZ level, and their energies are further refined at MP2/aug-cc-pVTZ and coupled-cluster theory with single, double, and perturbative triple excitations/aug-cc-pVDZ level. The interaction energies using the complete basis set limits at MP2 level are also reported. The relationships between their structure arrangement and their energies are discussed. Based on the results of thermal simulation, structural change from a four-numbered ring to a tree-like structure occurs at T ~ 45 K, and the relative population of six lowest-free-energy isomers is found to exceed 4% at some point within the studied temperature range. Studies reveal that, among these six isomers, two new-found isomers constitute 10% of isomer population at 180 K, and the experimental spectra can be better explained with inclusions of the two isomers. The molecular orbitals for six representative cationic water clusters are also studied. Through topological and reduced density gradient analysis, we investigated the structural characteristics and the bonding strengths of these water cluster radical cations. PMID- 27782469 TI - Why many polymers are so fragile: A new perspective. AB - Many polymers exhibit much steeper temperature dependence of their structural relaxation time (higher fragility) than liquids of small molecules, and the mechanism of this unusually high fragility in polymers remains a puzzle. To reveal additional hints for understanding the underlying mechanism, we analyzed correlation of many properties of polymers to their fragility on example of model polymer polystyrene with various molecular weights (MWs). We demonstrate that these correlations work for short chains (oligomers), but fail progressively with increase in MW. Our surprising discovery is that the steepness of the temperature dependence (fragility) of the viscosity that is determined by chain relaxation follows the correlations at all molecular weights. These results suggest that the molecular level relaxation still follows the behavior usual for small molecules even in polymers, and its fragility (chain fragility) falls in the range usual for molecular liquids. It is the segmental relaxation that has this unusually high fragility. We speculate that many polymers cannot reach an ergodic state on the time scale of segmental dynamics due to chain connectivity and rigidity. This leads to sharper decrease in accessible configurational entropy upon cooling and results in steeper temperature dependence of segmental relaxation. The proposed scenario provides a new important insight into the specifics of polymer dynamics: the role of ergodicity time and length scale. At the end, we suggest that a similar scenario can be applicable also to other molecular systems with slow intra-molecular degrees of freedom and to chemically complex systems where the time scale of chemical fluctuations can be longer than the time scale of structural relaxation. PMID- 27782470 TI - Structure and dynamics of aqueous solutions from PBE-based first-principles molecular dynamics simulations. AB - Establishing an accurate and predictive computational framework for the description of complex aqueous solutions is an ongoing challenge for density functional theory based first-principles molecular dynamics (FPMD) simulations. In this context, important advances have been made in recent years, including the development of sophisticated exchange-correlation functionals. On the other hand, simulations based on simple generalized gradient approximation (GGA) functionals remain an active field, particularly in the study of complex aqueous solutions due to a good balance between the accuracy, computational expense, and the applicability to a wide range of systems. Such simulations are often performed at elevated temperatures to artificially "correct" for GGA inaccuracies in the description of liquid water; however, a detailed understanding of how the choice of temperature affects the structure and dynamics of other components, such as solvated ions, is largely unknown. To address this question, we carried out a series of FPMD simulations at temperatures ranging from 300 to 460 K for liquid water and three representative aqueous solutions containing solvated Na+, K+, and Cl- ions. We show that simulations at 390-400 K with the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional yield water structure and dynamics in good agreement with experiments at ambient conditions. Simultaneously, this computational setup provides ion solvation structures and ion effects on water dynamics consistent with experiments. Our results suggest that an elevated temperature around 390-400 K with the PBE functional can be used for the description of structural and dynamical properties of liquid water and complex solutions with solvated ions at ambient conditions. PMID- 27782471 TI - Silicon 1s near edge X-ray absorption fine structure spectroscopy of functionalized silicon nanocrystals. AB - Silicon 1s Near Edge X-ray Absorption Fine Structure (NEXAFS) spectra of silicon nanocrystals have been examined as a function of nanocrystal size (3-100 nm), varying surface functionalization (hydrogen or 1-pentyl termination), or embedded in oxide. The NEXAFS spectra are characterized as a function of nanocrystal size and surface functionalization. Clear spectroscopic evidence for long range order is observed silicon nanocrystals that are 5-8 nm in diameter or larger. Energy shifts in the silicon 1s NEXAFS spectra of covalently functionalized silicon nanocrystals with changing size are attributed to surface chemical shifts and not to quantum confinement effects. PMID- 27782472 TI - Development of an interatomic potential for the simulation of defects, plasticity, and phase transformations in titanium. AB - New interatomic potentials describing defects, plasticity, and high temperature phase transitions for Ti are presented. Fitting the martensitic hcp-bcc phase transformation temperature requires an efficient and accurate method to determine it. We apply a molecular dynamics method based on determination of the melting temperature of competing solid phases, and Gibbs-Helmholtz integration, and a lattice-switch Monte Carlo method: these agree on the hcp-bcc transformation temperatures to within 2 K. We were able to develop embedded atom potentials which give a good fit to either low or high temperature data, but not both. The first developed potential (Ti1) reproduces the hcp-bcc transformation and melting temperatures and is suitable for the simulation of phase transitions and bcc Ti. Two other potentials (Ti2 and Ti3) correctly describe defect properties and can be used to simulate plasticity or radiation damage in hcp Ti. The fact that a single embedded atom method potential cannot describe both low and high temperature phases may be attributed to neglect of electronic degrees of freedom, notably bcc has a much higher electronic entropy. A temperature-dependent potential obtained from the combination of potentials Ti1 and Ti2 may be used to simulate Ti properties at any temperature. PMID- 27782473 TI - Fast, accurate 2D-MR relaxation exchange spectroscopy (REXSY): Beyond compressed sensing. AB - Previously, we showed that compressive or compressed sensing (CS) can be used to reduce significantly the data required to obtain 2D-NMR relaxation and diffusion spectra when they are sparse or well localized. In some cases, an order of magnitude fewer uniformly sampled data were required to reconstruct 2D-MR spectra of comparable quality. Nonetheless, this acceleration may still not be sufficient to make 2D-MR spectroscopy practicable for many important applications, such as studying time-varying exchange processes in swelling gels or drying paints, in living tissue in response to various biological or biochemical challenges, and particularly for in vivo MRI applications. A recently introduced framework, marginal distributions constrained optimization (MADCO), tremendously accelerates such 2D acquisitions by using a priori obtained 1D marginal distribution as powerful constraints when 2D spectra are reconstructed. Here we exploit one important intrinsic property of the 2D-MR relaxation exchange spectra: the fact that the 1D marginal distributions of each 2D-MR relaxation exchange spectrum in both dimensions are equal and can be rapidly estimated from a single Carr-Purcell Meiboom-Gill (CPMG) or inversion recovery prepared CPMG measurement. We extend the MADCO framework by further proposing to use the 1D marginal distributions to inform the subsequent 2D data-sampling scheme, concentrating measurements where spectral peaks are present and reducing them where they are not. In this way we achieve compression or acceleration that is an order of magnitude greater than that in our previous CS method while providing data in reconstructed 2D-MR spectral maps of comparable quality, demonstrated using several simulated and real 2D T2 - T2 experimental data. This method, which can be called "informed compressed sensing," is extendable to other 2D- and even ND-MR exchange spectroscopy. PMID- 27782475 TI - Perspective: Ultracold molecules and the dawn of cold controlled chemistry. AB - Ultracold molecules offer unprecedented opportunities for the controlled interrogation of molecular events, including chemical reactivity in the ultimate quantum regime. The proliferation of methods to create, cool, and confine them has allowed the investigation of a diverse array of molecular systems and chemical reactions at temperatures where only a single partial wave contributes. Here we present a brief account of recent progress on the experimental and theoretical fronts on cold and ultracold molecules and the opportunities and challenges they provide for a fundamental understanding of bimolecular chemical reaction dynamics. PMID- 27782474 TI - Novel mixture model for the representation of potential energy surfaces. AB - We demonstrate that knowledge of chemical physics on a materials system can be automatically extracted from first-principles calculations using a data mining technique; this information can then be utilized to construct a simple empirical atomic potential model. By using unsupervised learning of the generative Gaussian mixture model, physically meaningful patterns of atomic local chemical environments can be detected automatically. Based on the obtained information regarding these atomic patterns, we propose a chemical-structure-dependent linear mixture model for estimating the atomic potential energy. Our experiments show that the proposed mixture model significantly improves the accuracy of the prediction of the potential energy surface for complex systems that possess a large diversity in their local structures. PMID- 27782476 TI - Monte Carlo explicitly correlated second-order many-body perturbation theory. AB - A stochastic algorithm is proposed and implemented that computes a basis-set incompleteness (F12) correction to an ab initio second-order many-body perturbation energy as a short sum of 6- to 15-dimensional integrals of Gaussian type orbitals, an explicit function of the electron-electron distance (geminal), and its associated excitation amplitudes held fixed at the values suggested by Ten-no. The integrals are directly evaluated (without a resolution-of-the identity approximation or an auxiliary basis set) by the Metropolis Monte Carlo method. Applications of this method to 17 molecular correlation energies and 12 gas-phase reaction energies reveal that both the nonvariational and variational formulas for the correction give reliable correlation energies (98% or higher) and reaction energies (within 2 kJ mol-1 with a smaller statistical uncertainty) near the complete-basis-set limits by using just the aug-cc-pVDZ basis set. The nonvariational formula is found to be 2-10 times less expensive to evaluate than the variational one, though the latter yields energies that are bounded from below and is, therefore, slightly but systematically more accurate for energy differences. Being capable of using virtually any geminal form, the method confirms the best overall performance of the Slater-type geminal among 6 forms satisfying the same cusp conditions. Not having to precompute lower-dimensional integrals analytically, to store them on disk, or to transform them in a nonscalable dense-matrix-multiplication algorithm, the method scales favorably with both system size and computer size; the cost increases only as O(n4) with the number of orbitals (n), and its parallel efficiency reaches 99.9% of the ideal case on going from 16 to 4096 computer processors. PMID- 27782477 TI - General theory for environmental effects on (vertical) electronic excitation energies. AB - Almost 70 years ago, the first theoretical model for environmental effects on electronic excitation energies has been derived. Since then, several different interpretations and refined models have been proposed for the perichromic shift of a chromophore due to its surrounding medium. Some of these models are contradictory. Here, the contributing terms are derived within the framework of long-range perturbation theory with the least approximations so far. The derivation is based on a state-specific interpretation of the interaction energies and all terms can be identified with individual properties of either the chromophore or the surroundings, respectively. Further, the much debated contribution due to transition moments coupled to the environment can be verified in the form of a non-resonant excitonic coupling to the dynamic polarizabilities in the environment. These general insights should clarify discussions and interpretations of environmental effects on electronic excitations and should foster the development of new models for the computation of these effects. PMID- 27782478 TI - Accelerating the search for global minima on potential energy surfaces using machine learning. AB - Controlling molecule-surface interactions is key for chemical applications ranging from catalysis to gas sensing. We present a framework for accelerating the search for the global minimum on potential surfaces, corresponding to stable adsorbate-surface structures. We present a technique using Bayesian inference that enables us to predict converged density functional theory potential energies with fewer self-consistent field iterations. We then discuss how this technique fits in with the Bayesian Active Site Calculator, which applies Bayesian optimization to the problem. We demonstrate the performance of our framework using a hematite (Fe2O3) surface and present the adsorption sites found by our global optimization method for various simple hydrocarbons on the rutile TiO2 (110) surface. PMID- 27782479 TI - Five dimensional binary hard hypersphere mixtures: A Monte Carlo study. AB - Additive binary mixtures of five dimensional hyperspheres were investigated by Monte Carlo simulations. Both equal packing fraction and equal mole fraction systems with diameter ratios of 0.4 and 0.5 were examined. A range of total densities were studied, spanning low to moderate density fluids. The pair correlation functions and the equations of state were determined and compared with molecular dynamics data and a variety of theoretical predictions. A significant result of the equal packing fraction simulations was the discovery of how quickly the larger hyperspheres reorganized into a dense fluid after a random initial placement. In the equal mole fraction case, the pair correlation functions for the larger hypersphere agree with the pair correlation function of a pure fluid at an appropriately scaled density. The theoretical results for the equation of state compare well to the Monte Carlo calculations for all but the highest densities studied. PMID- 27782480 TI - Domain overlap matrices from plane-wave-based methods of electronic structure calculation. AB - Plane waves are one of the most popular and efficient basis sets for electronic structure calculations of solids; however, their delocalized nature makes it difficult to employ for them classical orbital-based methods of chemical bonding analysis. The quantum chemical topology approach, introducing chemical concepts via partitioning of real space into chemically meaningful domains, has no difficulties with plane-wave-based basis sets. Many popular tools employed within this approach, for instance delocalization indices, need overlap integrals over these domains-the elements of the so called domain overlap matrices. This article reports an efficient algorithm for evaluation of domain overlap matrix elements for plane-wave-based calculations as well as evaluation of its implementation for one of the most popular projector augmented wave (PAW) methods on the small set of simple and complex solids. The stability of the obtained results with respect to PAW calculation parameters has been investigated, and the comparison of the results with the results from other calculation methods has also been made. PMID- 27782481 TI - Improved evolutionary algorithm for the global optimization of clusters with competing attractive and repulsive interactions. AB - We propose improvements to our evolutionary algorithm (EA) [J. M. C. Marques and F. B. Pereira, J. Mol. Liq. 210, 51 (2015)] in order to avoid dissociative solutions in the global optimization of clusters with competing attractive and repulsive interactions. The improved EA outperforms the original version of the method for charged colloidal clusters in the size range 3 <= N <= 25, which is a very stringent test for global optimization algorithms. While the Bernal spiral is the global minimum for clusters in the interval 13 <= N <= 18, the lowest energy structure is a peculiar, so-called beaded-necklace, motif for 19 <= N <= 25. We have also applied the method for larger sizes and unusual quasi-linear and branched clusters arise as low-energy structures. PMID- 27782483 TI - Comment on "Communication: Simple and accurate uniform electron gas correlation energy for the full range of densities" [J. Chem. Phys. 145, 021101 (2016)]. PMID- 27782482 TI - Theoretical predictions on efficiency of bi-exciton formation and dissociation in chiral carbon nanotubes. AB - Efficient multiple exciton generation (MEG) in chiral single-wall carbon nanotubes (SWCNTs) is present within the solar spectrum range as shown by the many-body perturbation theory calculations combined with the density functional theory simulations. To describe the impact ionization process, we calculate exciton-to-biexciton decay rates R1->2 and biexciton-to-exciton rates R2->1 in the (6,2) and (10,5) SWCNTs. Within the solar energy range, we predict R1->2 ~ 1014 s-1, while biexciton-to-exciton recombination is weak with R2->1/R1->2 <= 10 2. Also we calculate quantum efficiency (QE), the average number of excitons created by a single absorbed photon, for which we find QE ? 1.2-1.6, that is 20% 60%. However, MEG strength in these SWCNTs varies strongly with the excitation energy due to highly non-uniform density of states at the low energy. We hypothesize that MEG efficiency in the chiral SWCNTs can be enhanced by altering the low-energy electronic spectrum via surface functionalization, or by mixing SWCNTs of different chiralities. PMID- 27782484 TI - Structure and dynamics of liquid CS2: Going from ambient to elevated pressure conditions. AB - Molecular dynamics simulation studies were performed to investigate the structural and dynamic properties of liquid carbon disulfide (CS2) from ambient to elevated pressure conditions. The results obtained have revealed structural changes at high pressures, which are related to the more dense packing of the molecules inside the first solvation shell. The calculated neutron and X-ray structure factors have been compared with available experimental diffraction data, also revealing the pressure effects on the short-range structure of the liquid. The pressure effects on the translational, reorientational, and residence dynamics are very strong, revealing a significant slowing down when going from ambient pressure to 1.2 GPa. The translational dynamics of the linear CS2 molecules have been found to be more anisotropic at elevated pressures, where cage effects and librational motions are reflected on the shape of the calculated time correlation functions and their corresponding spectral densities. PMID- 27782485 TI - Replica exchange enveloping distribution sampling (RE-EDS): A robust method to estimate multiple free-energy differences from a single simulation. AB - In molecular dynamics (MD) simulations, free-energy differences are often calculated using free energy perturbation or thermodynamic integration (TI) methods. However, both techniques are only suited to calculate free-energy differences between two end states. Enveloping distribution sampling (EDS) presents an attractive alternative that allows to calculate multiple free-energy differences in a single simulation. In EDS, a reference state is simulated which "envelopes" the end states. The challenge of this methodology is the determination of optimal reference-state parameters to ensure equal sampling of all end states. Currently, the automatic determination of the reference-state parameters for multiple end states is an unsolved issue that limits the application of the methodology. To resolve this, we have generalised the replica exchange EDS (RE-EDS) approach, introduced by Lee et al. [J. Chem. Theory Comput. 10, 2738 (2014)] for constant-pH MD simulations. By exchanging configurations between replicas with different reference-state parameters, the complexity of the parameter-choice problem can be substantially reduced. A new robust scheme to estimate the reference-state parameters from a short initial RE-EDS simulation with default parameters was developed, which allowed the calculation of 36 free energy differences between nine small-molecule inhibitors of phenylethanolamine N methyltransferase from a single simulation. The resulting free-energy differences were in excellent agreement with values obtained previously by TI and two-state EDS simulations. PMID- 27782486 TI - Preparation of a selected high vibrational energy level of isolated molecules. AB - Stark induced adiabatic Raman passage (SARP) allows us to prepare an appreciable concentration of isolated molecules in a specific, high-lying vibrational level. The process has general applicability, and, as a demonstration, we transfer nearly 100 percent of the HD (v = 0, J = 0) in a supersonically expanded molecular beam of HD molecules to HD (v = 4, J = 0). This is achieved with a sequence of partially overlapping nanosecond pump (355 nm) and Stokes (680 nm) single-mode laser pulses of unequal intensities. By comparing our experimental data with our theoretical calculations, we are able to draw two important conclusions: (1) using SARP a large population (>1010 molecules per laser pulse) is prepared in the (v = 4, J = 0) level of HD and (2) the polarizability alpha00,40 (?0.6 * 10-41 C m2 V-1) for the (v = 0, J = 0) to (v = 4, J = 0) Raman overtone transition is only about five times smaller than alpha00,10 for the (v = 0, J = 0) to (v = 1, J = 0) fundamental Raman transition. Moreover, the SARP process selects a specific rotational level in the vibrational manifold and can prepare one or a phased linear combination of magnetic sublevels (M states) within the selected vibrational-rotational level. This capability of preparing selected, highly excited vibrational levels of molecules under collision-free conditions opens new opportunities for fundamental scattering experiments. PMID- 27782487 TI - Elastic X-ray scattering from state-selected molecules. AB - The characterization of electronic, vibrational, and rotational states using elastic (coherent) X-ray scattering is considered. The scattering is calculated directly from complete active space self-consistent field level ab initio wavefunctions for H2 molecules in the ground-state X1Sigmag+ and first-excited EF1Sigmag+ electronic states. The calculated scattering is compared to recent experimental measurements [Y.-W. Liu et al., Phys. Rev. A 89, 014502 (2014)], and the influence of vibrational and rotational states on the observed signal is examined. The scaling of the scattering calculations with basis set is quantified, and it is found that energy convergence of the ab initio calculations is a good indicator of the quality of the scattering calculations. PMID- 27782488 TI - Photoelectron spectroscopic study of carbon aluminum hydride cluster anions. AB - Numerous previously unknown carbon aluminum hydride cluster anions were generated in the gas phase, identified by time-of-flight mass spectrometry and characterized by anion photoelectron spectroscopy, revealing their electronic structure. Density functional theory calculations on the CAl5-9H- and CAl5-7H2- found that several of them possess unusually high carbon atom coordination numbers. These cluster compositions have potential as the basis for new energetic materials. PMID- 27782489 TI - Statistical field theory description of inhomogeneous polarizable soft matter. AB - We present a new molecularly informed statistical field theory model of inhomogeneous polarizable soft matter. The model is based on fluid elements, referred to as beads, that can carry a net monopole of charge at their center of mass and a fixed or induced dipole through a Drude-type distributed charge approach. The beads are thus polarizable and naturally manifest attractive van der Waals interactions. Beyond electrostatic interactions, beads can be given soft repulsions to sustain fluid phases at arbitrary densities. Beads of different types can be mixed or linked into polymers with arbitrary chain models and sequences of charged and uncharged beads. By such an approach, it is possible to construct models suitable for describing a vast range of soft-matter systems including electrolyte and polyelectrolyte solutions, ionic liquids, polymerized ionic liquids, polymer blends, ionomers, and block copolymers, among others. These bead models can be constructed in virtually any ensemble and converted to complex-valued statistical field theories by Hubbard-Stratonovich transforms. One of the fields entering the resulting theories is a fluctuating electrostatic potential; other fields are necessary to decouple non-electrostatic interactions. We elucidate the structure of these field theories, their consistency with macroscopic electrostatic theory in the absence and presence of external electric fields, and the way in which they embed van der Waals interactions and non uniform dielectric properties. Their suitability as a framework for computational studies of heterogeneous soft matter systems using field-theoretic simulation techniques is discussed. PMID- 27782490 TI - Molecular model for chirality phenomena. AB - Chirality is a hallmark feature for molecular recognition in biology and chemical physics. We present a three-dimensional continuum model for studying chirality phenomena in condensed phases using molecular simulations. Our model system is based upon a simple four-site molecule and incorporates non-trivial kinetic behavior, including the ability to switch chirality or racemize, as well as thermodynamics arising from an energetic preference for specific chiral interactions. In particular, we introduce a chiral renormalization parameter that can locally favor either homochiral or heterochiral configurations. Using this model, we explore a range of chirality-specific phenomena, including the kinetics of chiral inversion, the mechanism of spontaneous chiral symmetry breaking in the liquid, chirally driven liquid-liquid phase separation, and chiral crystal structures. PMID- 27782491 TI - Kondo screening and spin excitation in few-layer CoPc molecular assembly stacking on Pb(111) surface: A DFT+HEOM study. AB - Transition metal phthalocyanine molecules adsorbed on a metal substrate exhibit rich spin-related phenomena such as magnetic anisotropy, spin excitation, and Kondo effect. In this work, we investigate theoretically few-layer cobalt phthalocyanine (CoPc) molecular assembly stacking on Pb(111) surface with the use of a combined density functional theory (DFT) and hierarchical equations of motion (HEOM) approach. Calculation results indicate that the local spin properties of CoPc/Pb(111) composites depend critically on the number of adsorption layers. The first layer of CoPc on the Pb(111) surface serves as a spin-insulating buffer, while the CoPc molecules in the second layer exhibit spin 1/2 Kondo effect with a Kondo temperature of about 22 K. In a triple-layer CoPc assembly stacking on Pb(111), the antiferromagnetic coupling between the second and third layers leads to local spin-flip excitations under finite bias voltages, which gives rise to characteristic signatures in the differential conductance spectra. The DFT+HEOM approach thus provides a practical means for investigating the local electronic and spin properties of two-dimensional molecular assemblies adsorbed on the metal surface. The insights obtained from the first-principles based simulations could be useful for experimental manipulation or design of magnetic composite systems. PMID- 27782492 TI - Molecular modeling and assignment of IR spectra of the hydrated excess proton in isotopically dilute water. AB - Infrared (IR) spectroscopy of the water O-H stretch has been widely used to probe both the local hydrogen-bonding structure and dynamics of aqueous systems. Although of significant interest, the IR spectroscopy of excess protons in water remains difficult to assign as a result of extensive and strong intermolecular interactions in hydrated proton complexes. As an alternate approach, we develop a mixed quantum-classical model for the vibrational spectroscopy of the excess proton in isotopically dilute water that draws on frozen proton-water clusters taken from reactive molecular dynamics trajectories of the latest generation multi-state empirical valence bond proton model (MS-EVB 3.2). A semi-empirical single oscillator spectroscopic map for the instantaneous transition frequency and transition dipole moment is constructed using potential energy surfaces for the O-H stretch coordinate of the excess proton using electronic structure calculations. Calculated spectra are compared with experimental spectra of dilute H+ in D2O obtained from double-difference FTIR to demonstrate the validity of the map. The model is also used to decompose IR spectra into contributions from different aqueous proton configurations. We find that the O-H transition frequency continuously decreases as the oxygen-oxygen length for a special pair proton decreases, shifting from Eigen- to Zundel-like configurations. The same shift is accompanied by a shift of the flanking water stretches of the Zundel complex to higher frequency than the hydronium O-H vibrations. PMID- 27782493 TI - Properties of iron sulfide, hydrosulfide, and mixed sulfide/hydrosulfide cluster anions through photoelectron spectroscopy and density functional theory calculations. AB - A new magnetic-bottle time-of-flight photoelectron spectroscopy (PES) apparatus is constructed in our laboratory. The PES spectra of iron sulfide, hydrosulfide, and mixed sulfide/hydrosulfide [FeSm(SH)n-; m, n = 0-3, 0 < (m + n) <= 3] cluster anions, obtained at 2.331 eV (532 nm) and 3.492 eV (355 nm) photon energies, are reported. The electronic structure and bonding properties of these clusters are additionally investigated at different levels of density functional theory. The most probable structures and ground state spin multiplicity for these cluster anions are tentatively assigned by comparing their theoretical first vertical detachment energies (VDEs) with their respective experiment values. The behavior of S and (SH) as ligands in these iron sulfide, hydrosulfide, and mixed sulfide/hydrosulfide cluster anions is investigated and compared. The experimental first VDEs for Fe(SH)1-3- cluster anions are lower than those found for their respective FeS1-3- cluster anions. The experimental first VDEs for FeS1 3- clusters are observed to increase for the first two S atoms bound to Fe-; however, due to the formation of an S-S bond for the FeS3- cluster, its first VDE is found to be ~0.41 eV lower than the first VDE for the FeS2- cluster. The first VDEs of Fe(SH)1-3- cluster anions are observed to increase with the increasing numbers of SH groups. The calculated partial charges of the Fe atom for ground state FeS1-3- and Fe(SH)1-3- clusters are apparently related to and correlated with their determined first VDEs. The higher first VDE is correlated with a higher, more positive partial charge for the Fe atom of these cluster anions. Iron sulfide/hydrosulfide mixed cluster anions are also explored in this work: the first VDE for FeS(SH)- is lower than that for FeS2-, but higher than that for Fe(SH)2-; the first VDEs for FeS2(SH)- and FeS(SH)2- are close to that for FeS3-, but higher than that for Fe(SH)3-. The first VDEs of general iron sulfide, hydrosulfide, and mixed sulfide/hydrosulfide clusters [FeSm(SH)n-; m, n = 0-3, 0 < (m + n) <= 3] are dependent on three properties of these anions: 1. the partial charge on the Fe atom, 2. disulfide bond formation (S-S) in the cluster, and 3. the number of hydrosulfide ligands in the cluster. The higher the partial charge on the Fe atom of these clusters, the larger the first VDE; however, cluster S-S bonding and more (SH) ligands in the cluster lower the cluster anion first VDE. PMID- 27782494 TI - Multi-mode heterodyned 5th-order infrared spectroscopy. AB - Fifth-order multidimensional infrared spectroscopy with heterodyned detection was carried out in the three-beam dual-frequency configuration. Numerous 5th-order cross peaks were detected for the 4-azidobutyrate-N-hydroxysuccinimide ester compound in solution involving several vibrational modes ranging in frequency from 1045 to 2100 cm-1. Cross peaks involving overtones (2X/Z) and combination bands (XY/Z) among the tags, modes X and Y excited by the first two mid-IR laser pulses, and the reporter, modes Z excited by the third laser pulse, were acquired and the factors affecting the amplitude of 5th-order cross peaks are discussed. The 5th-order cross peaks were detected among modes that are spatially close (a few bonds apart) as well as for modes spatially separated by ca. 12 A (eight bonds apart). In both cases, the waiting time dependences for the 3rd and 5th order cross peaks were found to be different. In particular, the waiting time at which the cross-peak maximum is reached, the decay time, and the value of a plateau at large waiting times were all differing strongly. The differences are explained by reduced sensitivity of the 5th-order signals to modes coupled weakly to the reporter mode and different relaxation dynamics involving overtone state of the tag. The ability of the 5th-order peaks to single out the modes coupled strongly to the reporter can help identifying specific energy relaxation and transport pathways, which will be useful for understanding energy transport dynamics in molecules. The absorptive 5th-order cross peaks were constructed which report on three-point correlation functions. It is shown that in addition to the triple-frequency correlation functions, a correlation of the frequencies with the mode coupling (anharmonicity) can be naturally measured by the 5th-order spectroscopy. The current limit for detecting 5th-order signals was estimated at the level of 1 * 10-3 in reduced anharmonicity, which is determined by the corresponding two-state anharmonicity divided by the reporter mode spectral width. Given the simplicity of recording the 5th-order cross peaks in the three beam configuration, the approach carries a potential for a broad use. PMID- 27782495 TI - Infrared spectral identification of the Criegee intermediate (CH3)2COO. AB - Criegee intermediates are carbonyl oxides that play critical roles in the ozonolysis of alkenes in the atmosphere. So far, the infrared spectra of only the simplest Criegee intermediates CH2OO and CH3CHOO are reported. We report the transient infrared spectrum of the next member (CH3)2COO, produced from ultraviolet irradiation of a mixture of (CH3)2CI2 + O2 in a flow reactor and detected with a step-scan Fourier-transform spectrometer. The four observed bands near 1424, 1368, 1040, and 887.4 cm-1 provide definitive identification of (CH3)2COO. The observed vibrational wavenumbers and rotational contours agree with those predicted with quantum-chemical calculations; contributions of the hot bands from excited states of the low-lying torsional modes are significant. The rapid decay yields an estimate of the rate coefficient ~1.6 * 10-10 cm3 molecule 1 s-1 for the self-reaction of (CH3)2COO. The direct IR detection of (CH3)2COO should prove useful for field measurements and laboratory investigations of related Criegee mechanism. PMID- 27782496 TI - Nanocerium oxide increases the survival of adult rod and cone photoreceptor in culture by abrogating hydrogen peroxide-induced oxidative stress. AB - In vitro cell culture system for adult rod and cone photoreceptor (PR) is an effective and economical model for screening drug candidates against all kinds of age related retinal blindness. Interestingly, adult PR cells have a limited survival in the culture system, thus preventing full exploitation of this in vitro approach for drug screening applications. The limited survival of the adult PR cells in culture is due to their inherently high oxidative stress and photic injury. Mixed valence-state ceria nanoparticles have the ability to scavenge free radicals and reduce oxidative stress. Here, ceria nanoparticles of 5-10 nm dimensions have been synthesized, possessing dual oxidation state (+3 and +4) as evident from x-ray photoelectron spectroscopy and exhibiting real time reduction of hydrogen peroxide (H2O2) as quantified by absorbance spectroscopy and cyclic voltammogram analysis. Using flow cytometry and cell culture assay, it has been shown that, upon one time addition of 10 nM of nanoceria in the PR culture of the 18 months old adult common carp (Cyprinus carpio) at the time of plating the cells, the oxidative stress caused due to hydrogen peroxide assault could be abrogated. A further single application of nanoceria significantly increases the survival of these fragile cells in the culture, thus paving way for developing a more robust photoreceptor culture model to study the aging photoreceptor cells in a defined condition. PMID- 27782498 TI - Formation of planar unilamellar phospholipid membranes on oxidized gold substrate. AB - Supported planar phospholipid membranes are used in a range of biophysical measurements, typically for characterizing protein-membrane interactions. Liposome deposition is the most common method to create such membranes. The ability of liposomes to fuse into a lamellar membrane during deposition is strongly dependent on the surface chemistry; some important substrate materials such as oxidized gold do not promote liposome fusion. Circumventing this determinism poses an enduring challenge to membrane biophysics. Here, the authors show that the effect of surface chemistry can be overcome by using osmotic stress. Reproducible single bilayer coverage was achieved on oxidized gold surface from liposomes of a variety of lipid compositions, as demonstrated by quartz crystal microbalance measurements and confirmed via fluorescence microscopy imaging. The continuity of the deposit was confirmed by fluorescence recovery after photobleaching. Using mixtures of di-myristoyl and di-palmitoyl lipids, it was also demonstrated that the formation of fused lamellar membranes upon osmotic stress is a sensitive function of the thermodynamic phase of the membrane. PMID- 27782499 TI - Sufficient minimal model for DNA denaturation: Integration of harmonic scalar elasticity and bond energies. AB - We study DNA denaturation by integrating elasticity - as described by the Gaussian network model - with bond binding energies, distinguishing between different base pairs and stacking energies. We use exact calculation, within the model, of the Helmholtz free-energy of any partial denaturation state, which implies that the entropy of all formed "bubbles" ("loops") is accounted for. Considering base pair bond removal single events, the bond designated for opening is chosen by minimizing the free-energy difference for the process, over all remaining base pair bonds. Despite of its great simplicity, for several known DNA sequences our results are in accord with available theoretical and experimental studies. Moreover, we report free-energy profiles along the denaturation pathway, which allow to detect stable or meta-stable partial denaturation states, composed of bubble, as local free-energy minima separated by barriers. Our approach allows to study very long DNA strands with commonly available computational power, as we demonstrate for a few random sequences in the range 200-800 base-pairs. For the latter, we also elucidate the self-averaging property of the system. Implications for the well known breathing dynamics of DNA are elucidated. PMID- 27782500 TI - Self-consistent double-hybrid density-functional theory using the optimized effective-potential method. AB - We introduce an orbital-optimized double-hybrid (DH) scheme using the optimized effective-potential (OEP) method. The orbitals are optimized using a local potential corresponding to the complete exchange-correlation energy expression including the second-order Moller-Plesset correlation contribution. We have implemented a one-parameter version of this OEP-based self-consistent DH scheme using the BLYP density-functional approximation and compared it to the corresponding non-self-consistent DH scheme for calculations on a few closed shell atoms and molecules. While the OEP-based self-consistency does not provide any improvement for the calculations of ground-state total energies and ionization potentials, it does improve the accuracy of electron affinities and restores the meaning of the LUMO orbital energy as being connected to a neutral excitation energy. Moreover, the OEP-based self-consistent DH scheme provides reasonably accurate exchange-correlation potentials and correlated densities. PMID- 27782501 TI - Communication: Polymer entanglement dynamics: Role of attractive interactions. AB - The coupled dynamics of entangled polymers, which span broad time and length scales, govern their unique viscoelastic properties. To follow chain mobility by numerical simulations from the intermediate Rouse and reptation regimes to the late time diffusive regime, highly coarse grained models with purely repulsive interactions between monomers are widely used since they are computationally the most efficient. Here using large scale molecular dynamics simulations, the effect of including the attractive interaction between monomers on the dynamics of entangled polymer melts is explored for the first time over a wide temperature range. Attractive interactions have little effect on the local packing for all temperatures T and on the chain mobility for T higher than about twice the glass transition Tg. These results, across a broad range of molecular weight, show that to study the dynamics of entangled polymer melts, the interactions can be treated as pure repulsive, confirming a posteriori the validity of previous studies and opening the way to new large scale numerical simulations. PMID- 27782502 TI - Systematic study of glass transition in low-molecular phthalonitriles: Insight from computer simulations. AB - Phthalonitrile compounds with Si bridges were recently suggested for producing thermosetting polymer composites with reduced Tg and thus expanded processing range. The detailed experimental investigation of this class of phthalonitriles is still difficult due to development time and costs limitations and the need to take into account the structural changes during the crosslinking. In this paper, we try to overcome these limitations using computer simulations. We performed full-atomistic molecular dynamics simulations of various phthalonitrile compounds to understand the influence of molecular structure on the bulk glass temperature Tg. Two molecular properties affect Tg of the resulting bulk compound: the size of the residue and the length of the Si bridge. The larger residues lead to higher Tgs, while compounds with longer Si bridges have lower Tgs. We have also studied relaxation mechanisms involved in the classification of the samples. Two different factors influence the relaxation mechanisms: energetic, which is provided by the rigidity of molecules, and entropic, connected with the available volume of the conformational space of the monomer. PMID- 27782503 TI - Intermolecular modulation of IR intensities in the solid state. The role of weak interactions in polyethylene crystal: A computational DFT study. AB - Density functional theory calculations with periodic boundary conditions are exploited to study the infrared spectrum of crystalline polyethylene. Spectral changes lead by the intermolecular packing in the orthorhombic three-dimensional crystal are discussed by means of a careful comparison with calculations carried out for an isolated polymer chain in the all-trans conformation, described as an ideal one-dimensional crystal. The results are analyzed in the framework of the "oligomer approach" through the modelling of the IR spectrum of n-alkanes of different lengths. The study demonstrates that a relevant absorption intensity modulation of CH2 deformation transitions takes place in the solid state. This finding suggests a new interpretation for the experimental evidences collected in the past by means of IR intensity measurement during thermal treatment. Moreover, the comparison between calculations for 3-D crystal and for the isolated polyethylene chain (1-D crystal) allows to put in evidence the effect of the local electric field on the computed infrared intensities. This observation provides guidelines for the comparison between infrared absorption intensities predicted for an isolated unit and for a molecule belonging to a crystal, through the introduction of suitable correction factors based on the refraction index of the material and depending on the dimensionality of such units (0D-molecule; 1D polymer; 2D-slab). PMID- 27782504 TI - cDPD: A new dissipative particle dynamics method for modeling electrokinetic phenomena at the mesoscale. AB - We develop a "charged" dissipative particle dynamics (cDPD) model for simulating mesoscopic electrokinetic phenomena governed by the stochastic Poisson-Nernst Planck and the Navier-Stokes equations. Specifically, the transport equations of ionic species are incorporated into the DPD framework by introducing extra degrees of freedom and corresponding evolution equations associated with each DPD particle. Diffusion of ionic species driven by the ionic concentration gradient, electrostatic potential gradient, and thermal fluctuations is captured accurately via pairwise fluxes between DPD particles. The electrostatic potential is obtained by solving the Poisson equation on the moving DPD particles iteratively at each time step. For charged surfaces in bounded systems, an effective boundary treatment methodology is developed for imposing both the correct hydrodynamic and electrokinetics boundary conditions in cDPD simulations. To validate the proposed cDPD model and the corresponding boundary conditions, we first study the electrostatic structure in the vicinity of a charged solid surface, i.e., we perform cDPD simulations of the electrostatic double layer and show that our results are in good agreement with the well-known mean-field theoretical solutions. We also simulate the electrostatic structure and capacity densities between charged parallel plates in salt solutions with different salt concentrations. Moreover, we employ the proposed methodology to study the electro osmotic and electro-osmotic/pressure-driven flows in a micro-channel. In the latter case, we simulate the dilute poly-electrolyte solution drifting by electro osmotic flow in a micro-channel, hence demonstrating the flexibility and capability of this method in studying complex fluids with electrostatic interactions at the micro- and nano-scales. PMID- 27782505 TI - Comment on "Construction of the landscape for multi-stable systems: Potential landscape, quasi-potential, A-type integral and beyond" [J. Chem. Phys. 144, 094109 (2016)]. AB - Connections between a "SDE decomposition" to other frameworks constructing landscape in non-equilibrium processes were discussed by Zhou and Li [J. Chem. Phys. 144, 094109 (2016)]. It was speculated that the SDE decomposition would not be generally unique. In this comment, we demonstrate both mathematically and physically that the speculation is incorrect and the uniqueness is guaranteed under appropriate conditions. A few related issues are also clarified, such as the limitation of obtaining potential function from steady state distribution. Current demonstration may lead to a better understanding on the structure and robustness of the decomposition framework. PMID- 27782506 TI - Coherent control using kinetic energy and the geometric phase of a conical intersection. AB - Conical intersections (CIs) between molecular potential energy surfaces with non vanishing non-adiabatic couplings generally occur in any molecule consisting of at least three atoms. They play a fundamental role in describing the molecular dynamics beyond the Born-Oppenheimer approximation and have been used to understand a large variety of effects, from photofragmentation and isomerization to more exotic applications such as exciton fission in semiconductors. However, few studies have used the features of a CI as a tool for coherent control. Here we demonstrate two modes of control around a conical intersection. The first uses a continuous light field to control the population on the two intersecting electronic states in the vicinity of a CI. The second uses a pulsed light field to control wavepackets that are subjected to the geometric phase shift in transit around a CI. This second technique is likely to be useful for studying the role of nuclear dynamics in electronic coherence phenomena. PMID- 27782507 TI - A new symmetrical quasi-classical model for electronically non-adiabatic processes: Application to the case of weak non-adiabatic coupling. AB - Previous work has shown how a symmetrical quasi-classical (SQC) windowing procedure can be used to quantize the initial and final electronic degrees of freedom in the Meyer-Miller (MM) classical vibronic (i.e, nuclear + electronic) Hamiltonian, and that the approach provides a very good description of electronically non-adiabatic processes within a standard classical molecular dynamics framework for a number of benchmark problems. This paper explores application of the SQC/MM approach to the case of very weak non-adiabatic coupling between the electronic states, showing (as anticipated) how the standard SQC/MM approach used to date fails in this limit, and then devises a new SQC windowing scheme to deal with it. Application of this new SQC model to a variety of realistic benchmark systems shows that the new model not only treats the weak coupling case extremely well, but it is also seen to describe the "normal" regime (of electronic transition probabilities ? 0.1) even more accurately than the previous "standard" model. PMID- 27782508 TI - Comment on "Are polynuclear superhalogens without halogen atoms probable? A high level ab initio case study on triple-bridged binuclear anions with cyanide ligands" [J. Chem. Phys. 140, 094301 (2014)]. AB - For the vertical electron detachment energies of triply-bridged Mg2(CN)5- superhalides, the Outer Valence Green Function (OVGF) yields results similar to those of the coupled-cluster singles and doubles plus approximate triples, or CCSD(T), method. Invalid comparisons between states with different symmetry or localization properties underlie the assertion of Yin et al that OVGF produces large discrepancies with respect to CCSD(T) for several isomers of Mg2(CN)5-. PMID- 27782509 TI - Lattice model for water-solute mixtures. AB - A lattice model for the study of mixtures of associating liquids is proposed. Solvent and solute are modeled by adapting the associating lattice gas (ALG) model. The nature of interaction of solute/solvent is controlled by tuning the energy interactions between the patches of ALG model. We have studied three set of parameters, resulting in, hydrophilic, inert, and hydrophobic interactions. Extensive Monte Carlo simulations were carried out, and the behavior of pure components and the excess properties of the mixtures have been studied. The pure components, water (solvent) and solute, have quite similar phase diagrams, presenting gas, low density liquid, and high density liquid phases. In the case of solute, the regions of coexistence are substantially reduced when compared with both the water and the standard ALG models. A numerical procedure has been developed in order to attain series of results at constant pressure from simulations of the lattice gas model in the grand canonical ensemble. The excess properties of the mixtures, volume and enthalpy as the function of the solute fraction, have been studied for different interaction parameters of the model. Our model is able to reproduce qualitatively well the excess volume and enthalpy for different aqueous solutions. For the hydrophilic case, we show that the model is able to reproduce the excess volume and enthalpy of mixtures of small alcohols and amines. The inert case reproduces the behavior of large alcohols such as propanol, butanol, and pentanol. For the last case (hydrophobic), the excess properties reproduce the behavior of ionic liquids in aqueous solution. PMID- 27782510 TI - Erratum: "Communication: X-ray absorption spectra and core-ionization potentials within a core-valence separated coupled cluster framework" [J. Chem. Phys. 143, 181103 (2015)]. PMID- 27782511 TI - Differential steric effects in Cl reactions with aligned CHD3(v1 = 1) by the R(0) and Q(1) transitions. I. Attacking the excited C-H bond. AB - When a CHD3 molecule is pumped to the C-H stretching-excited state by absorbing a linearly polarized infrared (IR) photon via the R(0) branch of the v1 = 1<-0 transition, the rotational angular momentum j of the prepared state jK=10 preferentially lies in a plane perpendicular to the IR polarization axis epsilonIR. By way of contrast, when the Q(1) branch is used, the state of jK=1+/ 1 is prepared with j aligned along the direction of epsilonIR. Reported here is a detailed study of the title reaction by actively controlling the collision geometries under these two IR-excitation schemes at collision energy Ec = 8.6 kcal mol-1, using a crossed molecular beam, product imaging approach. We found that under the R(0) excitation, the polarization-dependent differential cross sections for the HCl(v = 0) + CD3(00) channel can largely be understood by invoking dual reaction mechanisms. The forward-scattered products are most likely mediated by a time-delayed resonance mechanism-as the formation of the HCl(v = 1) + CD3(00) channel, whereas the backward/sideways scattered products are governed by a direct abstraction mechanism. Compared to the previous results at lower Ec of 3.8 kcal mol-1, the sighting of opening-up the attack angle at the transition state of the direct pathway is proposed. Results under the Q(1) excitation are, however, perplexing and bear no obvious correlation to the corresponding ones for the R(0) excitation, defying simple intuitive interpretation. Possible reasons are put forward, which call for theoretical investigations for deeper insights. The results on the alternative isotope channel, DCl + CHD2, will be reported in the following paper. PMID- 27782512 TI - Response to "Comment on 'Gauge-invariant expectation values of the energy of a molecule in an electromagnetic field"' [J. Chem. Phys. 145, 147102 (2016)]. PMID- 27782513 TI - Communication: Kirkwood-Buff integrals in the thermodynamic limit from small sized molecular dynamics simulations. AB - We present an accurate and efficient method to obtain Kirkwood-Buff (KB) integrals in the thermodynamic limit from small-sized molecular dynamics simulations. By introducing finite size effects into integral equations of statistical mechanics, we derive an analytical expression connecting the KB integrals of the bulk system with the fluctuations of the number of molecules in the corresponding closed system. We validate the method by calculating the activity coefficients of aqueous urea mixtures and the KB integrals of Lennard Jones fluids. Moreover, our results demonstrate how to identify simulation conditions under which computer simulations reach the thermodynamic limit. PMID- 27782514 TI - Quadrupole splittings in the near-infrared spectrum of 14NH3. AB - Sub-Doppler, saturation dip, spectra of lines in the v1 + v3, v1 + 2v4, and v3 + 2v4 bands of 14NH3 have been measured by frequency comb-referenced diode laser absorption spectroscopy. The observed spectral line widths are dominated by transit time broadening and show resolved or partially-resolved hyperfine splittings that are primarily determined by the 14N quadrupole coupling. Modeling of the observed line shapes based on the known hyperfine level structure of the ground state of the molecule shows that, in nearly all cases, the excited state level has hyperfine splittings similar to the same rotational level in the ground state. The data provide accurate frequencies for the line positions and easily separate lines overlapped in Doppler-limited spectra. The observed hyperfine splittings can be used to make and confirm rotational assignments and ground state combination differences obtained from the measured frequencies are comparable in accuracy to those obtained from conventional microwave spectroscopy. Several of the measured transitions do not show the quadrupole hyperfine splittings expected based on their existing rotational assignments. Either the assignments are incorrect or the upper levels involved are perturbed in a way that affects the nuclear hyperfine structure. PMID- 27782515 TI - Heterogeneous melting of methane confined in nano-pores. AB - The melting transition of methane adsorbed in nanopores has been studied and compared in two types of structures: carbon slits pores and square shaped channels. We show that the nano-confinement not only modifies the temperatures of phase transformation but also induces strong space heterogeneity of the adsorbate. We emphasize the role of the structural heterogeneity on the mechanism of melting: in nanometric pores, each adsorbed layer exhibits different mechanisms of structural transformation and the notion of a unique transition temperature is not well defined. PMID- 27782517 TI - Differential steric effects in Cl reactions with aligned CHD3(v1 = 1) by the R(0) and Q(1) transitions. II. Abstracting the unexcited D-atoms. AB - A complete set of four polarization-dependent differential cross sections in the reactions of Cl + aligned-CHD3(v1=1,jK)->DCl(v=0)+CHD2(v1=1) is reported here for two different, rotationally polarized states with j = 1: specifically the jK=10 state prepared via the R(0) excitation and the 1+/-1 state via Q(1). In stark contrast to the complicated situation of the HCl(v) + CD3(v = 0) channel reported in Paper-I, the stereo-requirement of this isotopic channel for both polarized reactants appears quite straightforward and consistent with a direct rebound mechanism. The extent of steric effects is moderate and relatively smaller than the alternative H-atom abstraction channel. All major findings reported here can qualitatively be understood by first noting that the present reaction invokes abstracting a D-atom, which is the spectator in the IR-excitation process. Next, it is recognized that the directional properties of two polarized states of CHD3(v1=1, jK) should manifest primarily in the IR-excited C-H bond, leaving secondary imprints in the unexcited CD3-moiety. The stereo-specificity of the DCl + CHD2 product channel is further reduced by the fact that the abstraction can occur with any one of the three spatially distinct D-atoms. PMID- 27782518 TI - Response to "Comment on 'Construction of the landscape for multi-stable systems: Potential landscape, quasi-potential, A-type integral and beyond"' [J. Chem. Phys. 145, 147104 (2016)]. AB - The uniqueness issue of SDE decomposition theory proposed by Ao and his co workers has recently been discussed. A comprehensive study to investigate connections among different landscape theories [J. Chem. Phys. 144, 094109 (2016)] has pointed out that the decomposition is generally not unique, while Ao et al. recently argue that such conclusions are "incorrect" because the uniqueness of the decomposition for Ornstein-Uhlenbeck (O-U) process has been claimed before. In this response, we will demonstrate that the claimed "uniqueness" of the O-U process decomposition is invalid to serve as a counterexample according to the original definition of SDE decomposition. The absence of effective and concrete boundary conditions in previous SDE decomposition papers will be pointed out, and some other issues in the comment will also be responded. PMID- 27782519 TI - Comment on "Gauge-invariant expectation values of the energy of a molecule in an electromagnetic field" [J. Chem. Phys. 144, 044109 (2016)]. AB - The 'problem' identified in the paper [J. Chem.Phys. 144, 044109 (2016)] does not arise in a properly formulated non-relativistic Hamiltonian formalism for both classical and quantum electrodynamics. PMID- 27782520 TI - Communication: Finite size correction in periodic coupled cluster theory calculations of solids. AB - We present a method to correct for finite size errors in coupled cluster theory calculations of solids. The outlined technique shares similarities with electronic structure factor interpolation methods used in quantum Monte Carlo calculations. However, our approach does not require the calculation of density matrices. Furthermore we show that the proposed finite size corrections achieve chemical accuracy in the convergence of second-order Moller-Plesset perturbation and coupled cluster singles and doubles correlation energies per atom for insulating solids with two atomic unit cells using 2 * 2 * 2 and 3 * 3 * 3 k point meshes only. PMID- 27782521 TI - Gaussian polarizable-ion tight binding. AB - To interpret ultrafast dynamics experiments on large molecules, computer simulation is required due to the complex response to the laser field. We present a method capable of efficiently computing the static electronic response of large systems to external electric fields. This is achieved by extending the density functional tight binding method to include larger basis sets and by multipole expansion of the charge density into electrostatically interacting Gaussian distributions. Polarizabilities for a range of hydrocarbon molecules are computed for a multipole expansion up to quadrupole order, giving excellent agreement with experimental values, with average errors similar to those from density functional theory, but at a small fraction of the cost. We apply the model in conjunction with the polarizable-point-dipoles model to estimate the internal fields in amorphous poly(3-hexylthiophene-2,5-diyl). PMID- 27782516 TI - Perspective: Quantum mechanical methods in biochemistry and biophysics. AB - In this perspective article, I discuss several research topics relevant to quantum mechanical (QM) methods in biophysical and biochemical applications. Due to the immense complexity of biological problems, the key is to develop methods that are able to strike the proper balance of computational efficiency and accuracy for the problem of interest. Therefore, in addition to the development of novel ab initio and density functional theory based QM methods for the study of reactive events that involve complex motifs such as transition metal clusters in metalloenzymes, it is equally important to develop inexpensive QM methods and advanced classical or quantal force fields to describe different physicochemical properties of biomolecules and their behaviors in complex environments. Maintaining a solid connection of these more approximate methods with rigorous QM methods is essential to their transferability and robustness. Comparison to diverse experimental observables helps validate computational models and mechanistic hypotheses as well as driving further development of computational methodologies. PMID- 27782522 TI - Accurate and efficient calculation of excitation energies with the active-space particle-particle random phase approximation. AB - An efficient method for calculating excitation energies based on the particle particle random phase approximation (ppRPA) is presented. Neglecting the contributions from the high-lying virtual states and the low-lying core states leads to the significantly smaller active-space ppRPA matrix while keeping the error to within 0.05 eV from the corresponding full ppRPA excitation energies. The resulting computational cost is significantly reduced and becomes less than the construction of the non-local Fock exchange potential matrix in the self consistent-field (SCF) procedure. With only a modest number of active orbitals, the original ppRPA singlet-triplet (ST) gaps as well as the low-lying single and double excitation energies can be accurately reproduced at much reduced computational costs, up to 100 times faster than the iterative Davidson diagonalization of the original full ppRPA matrix. For high-lying Rydberg excitations where the Davidson algorithm fails, the computational savings of active-space ppRPA with respect to the direct diagonalization is even more dramatic. The virtues of the underlying full ppRPA combined with the significantly lower computational cost of the active-space approach will significantly expand the applicability of the ppRPA method to calculate excitation energies at a cost of O(K4), with a prefactor much smaller than a single SCF Hartree-Fock (HF)/hybrid functional calculation, thus opening up new possibilities for the quantum mechanical study of excited state electronic structure of large systems. PMID- 27782523 TI - Influence of TiO2(110) surface roughness on growth and stability of thin organic films. AB - We have investigated the growth and stability of molecular ultra-thin films, consisting of rod-like semiconducting para-hexaphenyl (6P) molecules vapor deposited on ion beam modified TiO2(110) surfaces. The ion bombarded TiO2(110) surfaces served as growth templates exhibiting nm-scale anisotropic ripple patterns with controllable parameters, like ripple depth and length. In turn, by varying the ripple depth one can tailor the average local slope angle and the local step density/terrace width of the stepped surface. Here, we distinguish three types of substrates: shallow, medium, and deep rippled surfaces. On these substrates, 6P sub-monolayer deposition was carried out in ultra-high vacuum by organic molecular beam evaporation (OMBE) at room temperature leading to the formation of islands consisting of upright standing 6P molecules, which could be imaged by scanning electron microscopy and atomic force microscopy (AFM). It has been found that the local slope and terrace width of the TiO2 template strongly influences the stability of OMBE deposited 6P islands formed on the differently rippled substrates. This effect is demonstrated by means of tapping mode AFM, where an oscillating tip was used as a probe for testing the stability of the organic structures. We conclude that by increasing the local slope of the TiO2(110) surface the bonding strength between the nearest neighbor standing molecules is weakened due to the presence of vertical displacement in the molecular layer in correspondence to the TiO2 atomic step height. PMID- 27782524 TI - Excited state X-ray absorption spectroscopy: Probing both electronic and structural dynamics. AB - We investigate the sensitivity of X-ray absorption spectra, simulated using a general method, to properties of molecular excited states. Recently, Averbukh and co-workers [M. Ruberti et al., J. Chem. Phys. 140, 184107 (2014)] introduced an efficient and accurate L2 method for the calculation of excited state valence photoionization cross-sections based on the application of Stieltjes imaging to the Lanczos pseudo-spectrum of the algebraic diagrammatic construction (ADC) representation of the electronic Hamiltonian. In this paper, we report an extension of this method to the calculation of excited state core photoionization cross-sections. We demonstrate that, at the ADC(2)x level of theory, ground state X-ray absorption spectra may be accurately reproduced, validating the method. Significantly, the calculated X-ray absorption spectra of the excited states are found to be sensitive to both geometric distortions (structural dynamics) and the electronic character (electronic dynamics) of the initial state, suggesting that core excitation spectroscopies will be useful probes of excited state non adiabatic dynamics. We anticipate that the method presented here can be combined with ab initio molecular dynamics calculations to simulate the time-resolved X ray spectroscopy of excited state molecular wavepacket dynamics. PMID- 27782525 TI - The microscopic structure of cold aqueous methanol mixtures. AB - The evolution of the micro-segregated structure of aqueous methanol mixtures, in the temperature range 300 K-120 K, is studied with computer simulations, from the static structural point of view. The structural heterogeneity of water is reinforced at lower temperatures, as witnessed by a pre-peak in the oxygen-oxygen structure factor. Water tends to form predominantly chain-like clusters at lower temperatures and smaller concentrations. Methanol domains have essentially the same chain-like cluster structure as the pure liquid at high concentrations and becomes monomeric at smaller ones. Concentration fluctuations decrease with temperature, leading to quasi-ideal Kirkwood-Buff integrals, despite the enhanced molecular interactions, which we interpret as the signature of non-interacting segregated water and methanol clusters. This study throws a new light on the nature of the micro-heterogeneous structure of this mixture: the domain segregation is essentially based on the appearance of linear water clusters, unlike other alcohol aqueous mixtures, such as with propanol or butanol, where the water domains are more bulky. PMID- 27782526 TI - Consequences of electron correlation for XPS binding energies: Representative case for C(1s) and O(1s) XPS of CO. AB - In this paper, we present a study of the signs and the magnitudes of the errors of theoretical binding energies, BE's, of the C(1s) and O(1s) core-levels compared to BE's measured in X-Ray photoemission, XPS, experiments. In particular, we explain the unexpected sign of the error of the Hartree-Fock C(1s) BE, which is larger than experiment, in terms of correlation effects due to the near degeneracy of the CO(1pi) and CO(2pi) levels and show how taking this correlation into account leads to rather accurate predicted BE's. We separate the initial state contributions of this near degeneracy, present for the ground state wavefunction, from the final state near degeneracy effects, present for the hole state wavefunctions. Thus, we are able to establish the importance for the core level BE's of initial state charge redistribution due to the pi near-degeneracy. While the results for CO are interesting in their own right, we also consider whether our conclusions for CO are relevant for the analysis of XPS spectra of a wider range of molecules. PMID- 27782527 TI - Nucleation of the BCC phase from disorder in a diblock copolymer melt: Testing approximate theories through simulation. AB - We examine nucleation of the stable body-centred-cubic (BCC) phase from the metastable uniform disordered phase in an asymmetric diblock copolymer melt. Our comprehensive, large-scale simulations of the time-dependent, mean-field Landau Brazovskii model find that spherical droplets of the BCC phase nucleate directly from disorder. Near the order-disorder transition, the critical nucleus is large and has a classical profile, attaining the bulk BCC phase in an interior that is separated from disorder by a sharp interface. At greater undercooling, the amplitude of BCC order in the interior decreases and the nucleus interface broadens, leading to a diffuse critical nucleus. This diffuse nucleus becomes large as the simulation approaches the disordered phase spinodal. We show that our simulation follows the same nucleation pathway that Cahn and Hilliard found for an incompressible two-component fluid, across the entire metastable region. In contrast, a classical nucleation theory calculation based on the free energy of a planar interface between coexisting BCC and disordered phases agrees with simulation only in the limit of very small undercooling; we can expand this region of validity somewhat by accounting for the curvature of the droplet interface. A nucleation pathway involving a classical droplet persists, however, to deep undercooling in our simulation, but this pathway is energetically unfavourable. As a droplet grows in the simulation, its interface moves with a constant speed, and this speed is approximately proportional to the undercooling. PMID- 27782528 TI - The importance of the pre-exponential factor in semiclassical molecular dynamics. AB - This paper deals with the critical issue of approximating the pre-exponential factor in semiclassical molecular dynamics. The pre-exponential factor is important because it accounts for the quantum contribution to the semiclassical propagator of the classical Feynman path fluctuations. Pre-exponential factor approximations are necessary when chaotic or complex systems are simulated. We introduced pre-exponential factor approximations based either on analytical considerations or numerical regularization. The approximations are tested for power spectrum calculations of more and more chaotic model systems and on several molecules, for which exact quantum mechanical values are available. The results show that the pre-exponential factor approximations introduced are accurate enough to be safely employed for semiclassical simulations of complex systems. PMID- 27782529 TI - Predicting kinetic nanocrystal shapes through multi-scale theory and simulation: Polyvinylpyrrolidone-mediated growth of Ag nanocrystals. AB - In the shape-controlled synthesis of colloidal Ag nanocrystals, structure directing agents, particularly polyvinylpyrrolidone (PVP), are known to be a key additive in making nanostructures with well-defined shapes. Although many Ag nanocrystals have been successfully synthesized using PVP, the mechanism by which PVP actuates shape control remains elusive. Here, we present a multi-scale theoretical framework for kinetic Wulff shape predictions that accounts for the chemical environment, which we used to probe the kinetic influence of the adsorbed PVP film. Within this framework, we use umbrella-sampling molecular dynamics simulations to calculate the potential of mean force and diffusion coefficient profiles of Ag atom deposition onto Ag(100) and Ag(111) in ethylene glycol solution with surface-adsorbed PVP. We use these profiles to calculate the mean-first passage times and implement extensive Brownian dynamics simulations, which allows the kinetic effects to be quantitatively evaluated. Our results show that PVP films can regulate the flux of Ag atoms to be greater towards Ag(111) than Ag(100). PVP's preferential binding towards Ag(100) over Ag(111) gives PVP its flux-regulating capabilities through the lower free-energy barrier of Ag atoms to cross the lower-density PVP film on Ag(111) and enhanced Ag trapping by the extended PVP film on Ag(111). Under kinetic control, {100}-faceted nanocrystals will be formed when the Ag flux is greater towards Ag(111). The predicted kinetic Wulff shapes are in agreement with the analogous experimental system. PMID- 27782530 TI - Dynamics of H2 dissociation on the close-packed (111) surface of the noblest metal: H2 + Au(111). AB - We have performed calculations on the dissociative chemisorption of H2 on un reconstructed and reconstructed Au(111) with density functional theory, and dynamics calculations on this process on un-reconstructed Au(111). Due to a very late barrier for dissociation, H2 + Au(111) is a candidate H2-metal system for which the dissociative chemisorption could be considerably affected by the energy transfer to electron-hole pairs. Minimum barrier geometries and potential energy surfaces were computed for six density functionals. The functionals tested yield minimum barrier heights in the range of 1.15-1.6 eV, and barriers that are even later than found for the similar H2 + Cu(111) system. The potential energy surfaces have been used in quasi-classical trajectory calculations of the initial (v,J) state resolved reaction probability for several vibrational states v and rotational states J of H2 and D2. Our calculations may serve as predictions for state-resolved associative desorption experiments, from which initial state resolved dissociative chemisorption probabilities can be extracted by invoking detailed balance. The vibrational efficacy etav=0->1 reported for D2 dissociating on un-reconstructed Au(111) (about 0.9) is similar to that found in earlier quantum dynamics calculations on H2 + Ag(111), but larger than found for D2 + Cu(111). With the two functionals tested most extensively, the reactivity of H2 and D2 exhibits an almost monotonic increase with increasing rotational quantum number J. Test calculations suggest that, for chemical accuracy (1 kcal/mol), the herringbone reconstruction of Au(111) should be modeled. PMID- 27782531 TI - Nature of the cubic to tetragonal phase transition in methylammonium lead iodide perovskite. AB - Hybrid organic-inorganic perovskites, as well as the perovskites in general, are known for their phase complexity evidenced by the stabilization of different polymorphs, and thus an understanding of their regions of stability and transitions can be important for their photovoltaic and optoelectronic technologies. Here we use a multiscale approach based on first-principles calculations with van der Waals corrections and classical force-field molecular dynamics to determine the finite-temperature properties of the tetragonal and cubic phases of CH3NH3PbI3. Temperature effects are implicitly included using the quasi-harmonic approximation that can describe anharmonic behavior due to thermal expansion through the dependence of the harmonic frequencies on structural parameters. Our finite-temperature free-energy surfaces predict the lattice and elastic moduli evolution with temperature, and show in particular that the calculated lattice parameters of the cubic and tetragonal phases are to within 1% of experimental values. Further, our results show that the phonons are the major contributing factor for stabilizing the cubic phase at high temperatures mainly due to the low-energy phonon modes that are associated with the inorganic lattice. On the other hand, the configurational entropy due to CH3NH3+ rotational degrees of freedom is slightly more favored in the cubic phase and amounts to less than 0.2% of the T = 0 K free-energy difference between the two phases. PMID- 27782532 TI - Single chains of strong polyelectrolytes in aqueous solutions at extreme dilution: Conformation and counterion distribution. AB - The molecular conformation of two typical polyelectrolytes, sodium polystyrene sulfonate (NaPSS) and quarternized poly-4-vinylpyridine (QP4VP), was studied in aqueous solutions without salt addition at the single molecular level. By fluorescence correlation spectroscopy, the hydrodynamic radius (Rh) of NaPSS and QP4VP with the molecular weight ranging more than one order of magnitude was measured. The scaling analysis of Rh exhibits scaling exponent of 0.70 and 0.86 for NaPSS and QP4VP in solutions without added salts, respectively, showing the conformation is much more expanded than random coil. Numerical fittings using the model of diffusion of a rod molecule agree with the data well, indicating that the polyelectrolyte chains take the rod-like conformation under the condition without salt addition. Further investigations by determining the electric potential of single PSS- chains using the photon counting histogram technique demonstrate the enhanced counterion adsorption to the charged chain at higher molecular weight. PMID- 27782533 TI - Spectroscopic characterization of the ethyl radical-water complex. AB - An ab initio investigation has been employed to determine the structural and spectroscopic parameters, such as rotational constants, vibrational frequencies, vertical excitation energies, and the stability of the ethyl-water complex. The ethyl-water complex has a binding energy of 1.15 kcal?mol-1. The interaction takes place between the hydrogen of water and the unpaired electron of the radical. This interaction is found to produce a red shift in the OH stretching bands of water of ca. 84 cm-1, and a shift of all UV absorption bands to higher energies. PMID- 27782534 TI - Using an expanding nondirect product harmonic basis with an iterative eigensolver to compute vibrational energy levels with as many as seven atoms. AB - We demonstrate that it is possible to use a variational method to compute 50 vibrational levels of ethylene oxide (a seven-atom molecule) with convergence errors less than 0.01 cm-1. This is done by beginning with a small basis and expanding it to include product basis functions that are deemed to be important. For ethylene oxide a basis with fewer than 3 * 106 functions is large enough. Because the resulting basis has no exploitable structure we use a mapping to evaluate the matrix-vector products required to use an iterative eigensolver. The expanded basis is compared to bases obtained from pre-determined pruning condition. Similar calculations are presented for molecules with 3, 4, 5, and 6 atoms. For the 6-atom molecule, CH3CH, the required expanded basis has about 106 000 functions and is about an order of magnitude smaller than bases made with a pre-determined pruning condition. PMID- 27782535 TI - A simple AC calorimeter for specific heat measurement of liquids confined in porous materials: A study of hydrated Vycor. AB - Nanometric confinement of fluids in porous media is a classical way to stabilize metastable states. Calorimetric studies give insight on the behavior of confined liquids compared to bulk liquids. We have developed and built a simple quasi adiabatic AC calorimeter for heat capacity measurement of confined liquids in porous media in a temperature range between 150 K and 360 K. Taking the fully hydrated porous medium as a reference, we address the thermal behavior of water as a monolayer on the surface of a porous silica glass (Vycor). For temperature ranging between 160 K and 325 K, this interfacial water shows a surprisingly large heat capacity. We describe the interfacial Hbond network in the framework of a mean field percolation model, to show that at 160 K interfacial water experiences a transformation from low density amorphous ice to a heterogeneous system where transient low and high density water patches coexist. The fraction of each species is controlled by the temperature. We identify the large entropy of the interfacial water molecules as the cause of this behaviour. PMID- 27782536 TI - A single-mode external cavity diode laser using an intra-cavity atomic Faraday filter with short-term linewidth <400 kHz and long-term stability of <1 MHz. AB - We report on the development of a diode laser system - the "Faraday laser" - using an atomic Faraday filter as the frequency-selective element. In contrast to typical external-cavity diode laser systems which offer tunable output frequency but require additional control systems in order to achieve a stable output frequency, our system only lases at a single frequency, set by the peak transmission frequency of the internal atomic Faraday filter. Our system has both short-term and long-term stability of less than 1 MHz, which is less than the natural linewidth of alkali-atomic D-lines, making similar systems suitable for use as a "turn-key" solution for laser-cooling experiments. PMID- 27782537 TI - High speed, intermediate resolution, large area laser beam induced current imaging and laser scribing system for photovoltaic devices and modules. AB - We have developed a laser beam induced current imaging tool for photovoltaic devices and modules that utilizes diode pumped Q-switched lasers. Power densities on the order of one sun (100 mW/cm2) can be produced in a ~40 MUm spot size by operating the lasers at low diode current and high repetition rate. Using galvanostatically controlled mirrors in an overhead configuration and high speed data acquisition, large areas can be scanned in short times. As the beam is rastered, focus is maintained on a flat plane with an electronically controlled lens that is positioned in a coordinated fashion with the movements of the mirrors. The system can also be used in a scribing mode by increasing the diode current and decreasing the repetition rate. In either mode, the instrument can accommodate samples ranging in size from laboratory scale (few cm2) to full modules (1 m2). Customized LabVIEW programs were developed to control the components and acquire, display, and manipulate the data in imaging mode. PMID- 27782538 TI - Precision atomic beam density characterization by diode laser absorption spectroscopy. AB - We provide experimental and theoretical details of a simple technique to determine absolute line-of-sight integrated atomic beam densities based on resonant laser absorption. In our experiments, a thermal lithium beam is chopped on and off while the frequency of a laser crossing the beam at right angles is scanned slowly across the resonance transition. A lock-in amplifier detects the laser absorption signal at the chop frequency from which the atomic density is determined. The accuracy of our experimental method is confirmed using the related technique of wavelength modulation spectroscopy. For beams which absorb of order 1% of the incident laser light, our measurements allow the beam density to be determined to an accuracy better than 5% and with a precision of 3% on a time scale of order 1 s. Fractional absorptions of order 10-5 are detectable on a one-minute time scale when we employ a double laser beam technique which limits laser intensity noise. For a lithium beam with a thickness of 9 mm, we have measured atomic densities as low as 5 * 104 atoms cm-3. The simplicity of our technique and the details we provide should allow our method to be easily implemented in most atomic or molecular beam apparatuses. PMID- 27782539 TI - Note: Characterization and test of a high input impedance RF amplifier for series nanowire detector. AB - We designed a high input impedance RF amplifier based on Tower Jazz's 0.18 MUm SiGe BiCMOS process for series nanowire detector. The characterization of its gain and input impedance with a vector network analyzer is described in detail for its specificity. The actual 15 dB gain should be the measured value subtracts 6 dB, which is easy to be ignored. Its input impedance can be equivalent to 6.7 kOmega ? 3.4 pF though fitting the measurement, whose accuracy is verified. The process of measurement provides a good reference to characterize the similar special amplifier with unmatched impedance. PMID- 27782540 TI - Distributed state machine supervision for long-baseline gravitational-wave detectors. AB - The Laser Interferometer Gravitational-wave Observatory (LIGO) consists of two identical yet independent, widely separated, long-baseline gravitational-wave detectors. Each Advanced LIGO detector consists of complex optical-mechanical systems isolated from the ground by multiple layers of active seismic isolation, all controlled by hundreds of fast, digital, feedback control systems. This article describes a novel state machine-based automation platform developed to handle the automation and supervisory control challenges of these detectors. The platform, called Guardian, consists of distributed, independent, state machine automaton nodes organized hierarchically for full detector control. User code is written in standard Python and the platform is designed to facilitate the fast paced development process associated with commissioning the complicated Advanced LIGO instruments. While developed specifically for the Advanced LIGO detectors, Guardian is a generic state machine automation platform that is useful for experimental control at all levels, from simple table-top setups to large-scale multi-million dollar facilities. PMID- 27782541 TI - BabyMEG: A whole-head pediatric magnetoencephalography system for human brain development research. AB - We developed a 375-channel, whole-head magnetoencephalography (MEG) system ("BabyMEG") for studying the electrophysiological development of human brain during the first years of life. The helmet accommodates heads up to 95% of 36 month old boys in the USA. The unique two-layer sensor array consists of: (1) 270 magnetometers (10 mm diameter, ~15 mm coil-to-coil spacing) in the inner layer, (2) thirty-five three-axis magnetometers (20 mm * 20 mm) in the outer layer 4 cm away from the inner layer. Additionally, there are three three-axis reference magnetometers. With the help of a remotely operated position adjustment mechanism, the sensor array can be positioned to provide a uniform short spacing (mean 8.5 mm) between the sensor array and room temperature surface of the dewar. The sensors are connected to superconducting quantum interference devices (SQUIDs) operating at 4.2 K with median sensitivity levels of 7.5 fT/?Hz for the inner and 4 fT/?Hz for the outer layer sensors. SQUID outputs are digitized by a 24-bit acquisition system. A closed-cycle helium recycler provides maintenance free continuous operation, eliminating the need for helium, with no interruption needed during MEG measurements. BabyMEG with the recycler has been fully operational from March, 2015. Ongoing spontaneous brain activity can be monitored in real time without interference from external magnetic noise sources including the recycler, using a combination of a lightly shielded two-layer magnetically shielded room, an external active shielding, a signal-space projection method, and a synthetic gradiometer approach. Evoked responses in the cortex can be clearly detected without averaging. These new design features and capabilities represent several advances in MEG, increasing the utility of this technique in basic neuroscience as well as in clinical research and patient studies. PMID- 27782542 TI - Surface plasmon resonance microscopy: Achieving a quantitative optical response. AB - Surface plasmon resonance (SPR) imaging allows real-time label-free imaging based on index of refraction and changes in index of refraction at an interface. Optical parameter analysis is achieved by application of the Fresnel model to SPR data typically taken by an instrument in a prism based figuration. We carry out SPR imaging on a microscope by launching light into a sample and collecting reflected light through a high numerical aperture microscope objective. The SPR microscope enables spatial resolution that approaches the diffraction limit and has a dynamic range that allows detection of subnanometer to submicrometer changes in thickness of biological material at a surface. However, unambiguous quantitative interpretation of SPR changes using the microscope system could not be achieved using the Fresnel model because of polarization dependent attenuation and optical aberration that occurs in the high numerical aperture objective. To overcome this problem, we demonstrate a model to correct for polarization diattenuation and optical aberrations in the SPR data and develop a procedure to calibrate reflectivity to index of refraction values. The calibration and correction strategy for quantitative analysis was validated by comparing the known indices of refraction of bulk materials with corrected SPR data interpreted with the Fresnel model. Subsequently, we applied our SPR microscopy method to evaluate the index of refraction for a series of polymer microspheres in aqueous media and validated the quality of the measurement with quantitative phase microscopy. PMID- 27782543 TI - X-ray backlighting of imploding aluminium liners on PTS facility. AB - The x-ray backlighting systems, including a 1.865 keV (Si Healpha line) spherically bent crystal imaging system and an ~8.3 keV (Cu Healpha line) point projection imaging system, newly fielded on the Primary Test Stand facility are introduced and its preliminary experimental results in radiography of the aluminium (Al) liners with seeded sinusoidal perturbations are presented. The x ray backlighter source is created using a 1 TW, 1 kJ Nd: glass high power laser, kilo-joule laser system, recently constructed at China Academy of Engineering Physics. The ablation melt and instability of the imploding Al liner outer edge under the driving current of ~7.5 MA are successfully observed using these two backlighting systems, respectively. PMID- 27782544 TI - Moving target detection for frequency agility radar by sparse reconstruction. AB - Frequency agility radar, with randomly varied carrier frequency from pulse to pulse, exhibits superior performance compared to the conventional fixed carrier frequency pulse-Doppler radar against the electromagnetic interference. A novel moving target detection (MTD) method is proposed for the estimation of the target's velocity of frequency agility radar based on pulses within a coherent processing interval by using sparse reconstruction. Hardware implementation of orthogonal matching pursuit algorithm is executed on Xilinx Virtex-7 Field Programmable Gata Array (FPGA) to perform sparse optimization. Finally, a series of experiments are performed to evaluate the performance of proposed MTD method for frequency agility radar systems. PMID- 27782545 TI - Magnetic tweezers force calibration for molecules that exhibit conformational switching. AB - High spatial and temporal resolution magnetic tweezers experiments allow for the direct calibration of pulling forces applied to short biomolecules. In one class of experiments, a force is applied to a structured RNA or protein to induce an unfolding transition; when the force is maintained at particular values, the molecule can exhibit conformational switching between the folded and unfolded states or between intermediate states. Here, we analyze the degree to which common force calibration approaches, involving the fitting of model functions to the Allan variance or power spectral density of the bead trajectory, are biased by this conformational switching. We find significant effects in two limits: that of large molecular extension changes between the two states, in which alternative fitting functions must be used, and that of very fast switching kinetics, in which the force calibration cannot be recovered due to the slow diffusion time of the magnetic bead. We use simulations and high-resolution RNA hairpin data to show that most biophysical experiments do not occur in either of these limits. PMID- 27782546 TI - X-ray reflectivity imager with 15 W power X-ray source. AB - X-ray reflectivity is usually used for the routine analysis of layered structures of uniform thin films. So far, the technique has some limitations in the application to more practical inhomogeneous/patterned samples. X-ray reflectivity imaging is recently developed technique and can give the reconstructed image from many X-ray reflection projections. The present article gives the instrumental details of the compact X-ray reflectivity imager. Though the power of X-ray source is only 15 W, it works well. The calibration of the system has been discussed, because it is particularly important for the present grazing incidence geometry. We also give a visualization example of the buried interface, physical meaning of the reconstructed image, and discussions about possibilities for improvement. PMID- 27782547 TI - Piezoelectric energy harvesting computer controlled test bench. AB - In this paper a new computer controlled (C.C.) laboratory test bench is presented. The patented test bench is made up of a C.C. road traffic simulator, C.C. electronic hardware involved in automating measurements, and test bench control software interface programmed in LabVIEWTM. Our research is focused on characterizing electronic energy harvesting piezoelectric-based elements in road traffic environments to extract (or "harvest") maximum power. In mechanical to electrical energy conversion, mechanical impacts or vibrational behavior are commonly used, and several major problems need to be solved to perform optimal harvesting systems including, but no limited to, primary energy source modeling, energy conversion, and energy storage. It is described a novel C.C. test bench that obtains, in an accurate and automatized process, a generalized linear equivalent electrical model of piezoelectric elements and piezoelectric based energy store harvesting circuits in order to scale energy generation with multiple devices integrated in different topologies. PMID- 27782548 TI - Broadband UV-Vis vibrational coherence spectrometer based on a hollow fiber compressor. AB - We describe a broadband transient absorption (TA) spectrometer devised to excite and probe, in the blue to UV range, vibrational coherence dynamics in organic molecules in condensed phase. A 800-nm Ti:Sa amplifier and a hollow fiber compressor are used to generate a 6-fs short pulse at 1 kHz. Broadband sum frequency generation with the fundamental pulse is implemented to produce a 400 nm, 8-fs Fourier limited short pulse. A UV-Vis white-light supercontinuum is implemented as a probe with intensity self-referencing to achieve a shot-noise limited sensitivity. Rapid scanning of the pump-probe delay is shown very efficient in suppressing the noise resulting from low-frequency pump intensity fluctuations. Using either of the 800-nm or 400-nm broadband pulses as the pump for TA spectroscopy of organic molecules in solution, we resolve oscillatory signals down to the 320 nm probing wavelength with a 3200 cm-1 FWHM bandwidth. Their Fourier transformation reveals the corresponding molecular vibrational spectra. Finally, we demonstrate the use of this setup as a vibrational coherence spectrometer for the investigation of the vibrational dynamics accompanying the sub-ps C=C photoisomerization of a retinal-like molecular switch through a conical intersection. PMID- 27782549 TI - Quantitative analysis of effective height of probes in microwave impedance microscopy. AB - A quantitative approach is used to determine an effective height of probe beyond which the capacitance contribution is not significant in microwave impedance microscopy (MIM). We compare the effective height for three different modes of measurement, i.e., capacitance C(l) (l is the tip-sample distance), derivative of capacitance (C'(l)), and second derivative of capacitance (C"(l)). We discuss the effects of tip geometry and sample properties such as relative permittivity and sample height on the effective height with examples and analyze the implication on the spatial resolution of MIM. Finally, our results are verified by microwave impedance microscopy (MIM) measurement. PMID- 27782550 TI - Electron cyclotron emission spectra in X- and O-mode polarisation at JET: Martin Puplett interferometer, absolute calibration, revised uncertainties, inboard/outboard temperature profile, and wall properties. AB - At the tokamak Joint European Torus (JET), the electron cyclotron emission spectra in O-mode and X-mode polarisations are diagnosed simultaneous in absolute terms for several harmonics with two Martin-Puplett interferometers. From the second harmonic range in X-mode polarisation, the electron temperature profile can be deduced for the outboard side (low magnetic field strength) of JET but only for some parts of the inboard side (high magnetic field strength). This spatial restriction can be bypassed, if a cutoff is not present inside the plasma for O-mode waves in the first harmonic range. Then, from this spectral domain, the profile on the entire inboard side is accessible. The profile determination relies on the new absolute and independent calibration for both interferometers. During the calibration procedure, the antenna pattern was investigated as well, and, potentially, an increase in the diagnostic responsivity of about 5% was found for the domain 100-300 GHz. This increase and other uncertainty sources are taken into account in the thorough revision of the uncertainty for the diagnostic absolute calibration. The uncertainty deduced and the convolution inherent for Fourier spectroscopy diagnostics have implications for the temperature profile inferred. Having probed the electron cyclotron emission spectra in orthogonal polarisation directions for the first harmonic range, a condition is derived for the reflection and polarisation-scrambling coefficients of the first wall on the outboard side of JET. PMID- 27782551 TI - Q-band 4-state phase shifter in planar technology: Circuit design and performance analysis. AB - A 30% bandwidth phase shifter with four phase states is designed to be integrated in a radio astronomy receiver. The circuit has two 90 degrees out-of-phase microwave phase-shifting branches which are combined by Wilkinson power dividers. Each branch is composed of a 180 degrees phase shifter and a band-pass filter. The 180 degrees phase shifter is made of cascaded hybrid rings with microwave PIN diodes as switching devices. The 90 degrees phase shift is achieved with the two band-pass filters. Experimental characterization has shown significant results, with average phase shift values of -90.7 degrees , -181.7 degrees , and 88.5 degrees within the operation band, 35-47 GHz, and mean insertion loss of 7.4 dB. The performance of its integration in a polarimetric receiver for radio astronomy is analyzed, which validates the use of the presented phase shifter in such type of receiver. PMID- 27782552 TI - Design of a high-bunch-charge 112-MHz superconducting RF photoemission electron source. AB - High-bunch-charge photoemission electron-sources operating in a continuous wave (CW) mode are required for many advanced applications of particle accelerators, such as electron coolers for hadron beams, electron-ion colliders, and free electron lasers. Superconducting RF (SRF) has several advantages over other electron-gun technologies in CW mode as it offers higher acceleration rate and potentially can generate higher bunch charges and average beam currents. A 112 MHz SRF electron photoinjector (gun) was developed at Brookhaven National Laboratory to produce high-brightness and high-bunch-charge bunches for the coherent electron cooling proof-of-principle experiment. The gun utilizes a quarter-wave resonator geometry for assuring beam dynamics and uses high quantum efficiency multi-alkali photocathodes for generating electrons. PMID- 27782553 TI - A heat-sinking self-referencing fiber optic emission probe. AB - A novel heat-sinking, self-referencing fiber optic emission probe having a sapphire fiber probe head is described. The laser heating effect in a GaAs wafer (on a polytetrafluoroethylene (PTFE) platform) has been measured with the probe in both the noncontact proximity mode and the contact mode. The GaAs/PTFE composite was selected to simulate the thermal conductivity of animal tissues. It was found that for the same laser power delivered to the wafer, the temperature rise in the contact mode was only 42% of that in the proximity mode. Additionally, a demonstration of the self-referencing capability of the probe is also presented. PMID- 27782554 TI - Picosecond X-ray streak camera dynamic range measurement. AB - Streak cameras are widely used to record the spatio-temporal evolution of laser induced plasma. A prototype of picosecond X-ray streak camera has been developed and tested by Commissariat a l'Energie Atomique et aux Energies Alternatives to answer the Laser MegaJoule specific needs. The dynamic range of this instrument is measured with picosecond X-ray pulses generated by the interaction of a laser beam and a copper target. The required value of 100 is reached only in the configurations combining the slowest sweeping speed and optimization of the streak tube electron throughput by an appropriate choice of high voltages applied to its electrodes. PMID- 27782555 TI - Modular time division multiplexer: Efficient simultaneous characterization of fast and slow transients in multiple samples. AB - A modular time division multiplexer (MTDM) device is introduced to enable parallel measurement of multiple samples with both fast and slow decay transients spanning from millisecond to month-long time scales. This is achieved by dedicating a single high-speed measurement instrument for rapid data collection at the start of a transient, and by multiplexing a second low-speed measurement instrument for slow data collection of several samples in parallel for the later transients. The MTDM is a high-level design concept that can in principle measure an arbitrary number of samples, and the low cost implementation here allows up to 16 samples to be measured in parallel over several months, reducing the total ensemble measurement duration and equipment usage by as much as an order of magnitude without sacrificing fidelity. The MTDM was successfully demonstrated by simultaneously measuring the photoconductivity of three amorphous indium-gallium zinc-oxide thin films with 20 ms data resolution for fast transients and an uninterrupted parallel run time of over 20 days. The MTDM has potential applications in many areas of research that manifest response times spanning many orders of magnitude, such as photovoltaics, rechargeable batteries, amorphous semiconductors such as silicon and amorphous indium-gallium-zinc-oxide. PMID- 27782556 TI - Piezoelectric tunable microwave superconducting cavity. AB - In the context of engineered quantum systems, there is a demand for superconducting tunable devices, able to operate with high-quality factors at power levels equivalent to only a few photons. In this work, we developed a 3D microwave re-entrant cavity with such characteristics ready to provide a very fine-tuning of a high-Q resonant mode over a large dynamic range. This system has an electronic tuning mechanism based on a mechanically amplified piezoelectric actuator, which controls the resonator dominant mode frequency by changing the cavity narrow gap by very small displacements. Experiments were conducted at room and dilution refrigerator temperatures showing a large dynamic range up to 4 GHz and 1 GHz, respectively, and were compared to a finite element method model simulated data. At elevated microwave power input, nonlinear thermal effects were observed to destroy the superconductivity of the cavity due to the large electric fields generated in the small gap of the re-entrant cavity. PMID- 27782557 TI - Scanning SQUID susceptometers with sub-micron spatial resolution. AB - Superconducting QUantum Interference Device (SQUID) microscopy has excellent magnetic field sensitivity, but suffers from modest spatial resolution when compared with other scanning probes. This spatial resolution is determined by both the size of the field sensitive area and the spacing between this area and the sample surface. In this paper we describe scanning SQUID susceptometers that achieve sub-micron spatial resolution while retaining a white noise floor flux sensitivity of ~2MUPhi0/Hz1/2. This high spatial resolution is accomplished by deep sub-micron feature sizes, well shielded pickup loops fabricated using a planarized process, and a deep etch step that minimizes the spacing between the sample surface and the SQUID pickup loop. We describe the design, modeling, fabrication, and testing of these sensors. Although sub-micron spatial resolution has been achieved previously in scanning SQUID sensors, our sensors not only achieve high spatial resolution but also have integrated modulation coils for flux feedback, integrated field coils for susceptibility measurements, and batch processing. They are therefore a generally applicable tool for imaging sample magnetization, currents, and susceptibilities with higher spatial resolution than previous susceptometers. PMID- 27782559 TI - The first measurement of plasma density in an ECRIS-like device by means of a frequency-sweep microwave interferometer. AB - The note presents the first plasma density measurements collected by a novel microwave interferometer in a compact Electron Cyclotron Resonance Ion Sources (ECRIS). The developed K-band (18.5 / 26.5 GHz) microwave interferometry, based on the Frequency-Modulated Continuous-Wave method, has been able to discriminate the plasma signal from the spurious components due to the reflections at the plasma chamber walls, when working in the extreme unfavorable condition lambdap ? Lp ? Lc (lambdap, Lp, and Lc being the probing signal wavelength, the plasma dimension and the plasma chamber length, respectively). The note describes the experimental procedure when probing a high density plasma (ne > 1 ? 1018 cm-3) produced by an ECRIS prototype operating at 3.75 GHz. PMID- 27782560 TI - A new flexible titanium foil cell for hydrothermal experiments and fluid sampling. AB - This paper describes the design of a flexible titanium foil cell, as well as its applications in hydrothermal experiments and in non-contaminating storage of seafloor hydrothermal fluids. A flexible cell constructed totally from pure titanium (Grade 1) can be used in corrosive environment because of the excellent chemical stability and temperature tolerance of the material. Theoretical calculation and finite element analysis of the titanium foil cell have been conducted to identify its flexibility and deformation mode. Two applications, i.e., hydrothermal reaction and non-contaminating fluid sampling, were introduced subsequently. The flexible titanium foil cell was successfully tested at elevated temperature and pressure of up to 400 degrees C and 40 MPa, respectively, demonstrating that it could be widely used under supercritical water conditions. PMID- 27782561 TI - Note: A manifold ranking based saliency detection method for camera. AB - Research focused on salient object region in natural scenes has attracted a lot in computer vision and has widely been used in many applications like object detection and segmentation. However, an accurate focusing on the salient region, while taking photographs of the real-world scenery, is still a challenging task. In order to deal with the problem, this paper presents a novel approach based on human visual system, which works better with the usage of both background prior and compactness prior. In the proposed method, we eliminate the unsuitable boundary with a fixed threshold to optimize the image boundary selection which can provide more precise estimations. Then, the object detection, which is optimized with compactness prior, is obtained by ranking with background queries. Salient objects are generally grouped together into connected areas that have compact spatial distributions. The experimental results on three public datasets demonstrate that the precision and robustness of the proposed algorithm have been improved obviously. PMID- 27782562 TI - Propagator based formalism for optimizing in-line phase contrast imaging in laboratory X-ray setups. AB - We derive a propagator based formalism for optimizing phase contrast imaging in laboratory setups as well as in synchrotron setups. We confirm based on five different setups the well known existence of an optimum position for the sample in terms of phase contrast by measuring two types of fibers and evaluating the fringe contrast. Furthermore, we demonstrate for these setups a correlation of our formula and the fringe contrast. Hence, an estimate of this optimum position is given by our formalism which only depends on the source size, the detector blurring, and the total distance between source and detector. PMID- 27782563 TI - 4D x-ray phase contrast tomography for repeatable motion of biological samples. AB - X-ray phase contrast tomography based on a grating interferometer was applied to fast and dynamic measurements of biological samples. To achieve this, the scanning procedure in the tomographic scan was improved. A triangle-shaped voltage signal from a waveform generator to a Piezo stage was used for the fast phase stepping in the grating interferometer. In addition, an optical fiber coupled x-ray scientific CMOS camera was used to achieve fast and highly efficient image acquisitions. These optimizations made it possible to perform an x-ray phase contrast tomographic measurement within an 8 min scan with density resolution of 2.4 mg/cm3. A maximum volume size of 13 * 13 * 6 mm3 was obtained with a single tomographic measurement with a voxel size of 6.5 MUm. The scanning procedure using the triangle wave was applied to four-dimensional measurements in which highly sensitive three-dimensional x-ray imaging and a time-resolved dynamic measurement of biological samples were combined. A fresh tendon in the tail of a rat was measured under a uniaxial stretching and releasing condition. To maintain the freshness of the sample during four-dimensional phase contrast tomography, the temperature of the bathing liquid of the sample was kept below 10 degrees using a simple cooling system. The time-resolved deformation of the tendon and each fascicle was measured with a temporal resolution of 5.7 Hz. Evaluations of cross-sectional area size, length of the axis, and mass density in the fascicle during a stretching process provided a basis for quantitative analysis of the deformation of tendon fascicle. PMID- 27782564 TI - An algorithm for circular test and improved optical configuration by two dimensional (2D) laser heterodyne interferometer. AB - Circular test is an important tactic to assess motion accuracy in many fields especially machine tool and coordinate measuring machine. There are setup errors due to using directly centring of the measuring instrument for both of contact double ball bar and existed non-contact methods. To solve this problem, an algorithm for circular test using function construction based on matrix operation is proposed, which is not only used for the solution of radial deviation (F) but also should be applied to obtain two other evaluation parameters especially circular hysteresis (H). Furthermore, an improved optical configuration with a single laser is presented based on a 2D laser heterodyne interferometer. Compared with the existed non-contact method, it has a more pure homogeneity of the laser sources of 2D displacement sensing for advanced metrology. The algorithm and modeling are both illustrated. And error budget is also achieved. At last, to validate them, test experiments for motion paths are implemented based on a gantry machining center. Contrast test results support the proposal. PMID- 27782565 TI - Chlorine measurement in the jet singlet oxygen generator considering the effects of the droplets. AB - A new method is presented to measure chlorine concentration more accurately than conventional method in exhaust gases of a jet-type singlet oxygen generator. One problem in this measurement is the existence of micrometer-sized droplets. In this article, an empirical method is reported to eliminate the effects of the droplets. Two wavelengths from a fiber coupled LED are adopted and the measurement is made on both selected wavelengths. Chlorine is measured by the two wavelength more accurately than the one-wavelength method by eliminating the droplet term in the equations. This method is validated without the basic hydrogen peroxide injection in the reactor. In this case, a pressure meter value in the diagnostic cell is compared with the optically calculated pressure, which is obtained by the one-wavelength and the two-wavelength methods. It is found that chlorine measurement by the two-wavelength method and pressure meter is nearly the same, while the one-wavelength method has a significant error due to the droplets. PMID- 27782566 TI - Pulse shaping techniques for a high-g shock tester based on collision principle. AB - Pulse shaping techniques are discussed in this paper for the practicability of a developed high-g shock tester. The tester is based on collision principle where there is a one-level velocity amplifier. A theoretical and experimental study of pulse shaping techniques is presented. A model was built and theoretical formulae were deduced for the shock peak acceleration and its duration. Then theoretical analysis and some experiments were conducted. The test results verify the validity of theoretical model and show that the shock tester can generate the expected high-g shock pulses by integrated usage of different impact velocities and pulse shapers made from different materials. This is important in practical applications where the items under test can be shown to excite specific resonances at predetermined acceleration levels using the shock tester. PMID- 27782567 TI - Systematic effects from an ambient-temperature, continuously rotating half-wave plate. AB - We present an evaluation of systematic effects associated with a continuously rotating, ambient-temperature half-wave plate (HWP) based on two seasons of data from the Atacama B-Mode Search (ABS) experiment located in the Atacama Desert of Chile. The ABS experiment is a microwave telescope sensitive at 145 GHz. Here we present our in-field evaluation of celestial (Cosmic Microwave Background (CMB) plus galactic foreground) temperature-to-polarization leakage. We decompose the leakage into scalar, dipole, and quadrupole leakage terms. We report a scalar leakage of ~0.01%, consistent with model expectations and an order of magnitude smaller than other CMB experiments have been reported. No significant dipole or quadrupole terms are detected; we constrain each to be <0.07% (95% confidence), limited by statistical uncertainty in our measurement. Dipole and quadrupole leakage at this level lead to systematic error on r ? 0.01 before any mitigation due to scan cross-linking or boresight rotation. The measured scalar leakage and the theoretical level of dipole and quadrupole leakage produce systematic error of r < 0.001 for the ABS survey and focal-plane layout before any data correction such as so-called deprojection. This demonstrates that ABS achieves significant beam systematic error mitigation from its HWP and shows the promise of continuously rotating HWPs for future experiments. PMID- 27782569 TI - In situ electron microscopy studies of electromechanical behavior in metals at the nanoscale using a novel microdevice-based system. AB - Electrically assisted deformation (EAD) is an emerging technique to enhance formability of metals by applying an electric current through them. Despite its increasing importance in manufacturing applications, there is still an unresolved debate on the nature of the fundamental deformation mechanisms underlying EAD, mainly between electroplasticity (non-thermal effects) and resistive heating (thermal effects). This status is due to two critical challenges: (1) a lack of experimental techniques to directly observe fundamental mechanisms of material deformation during EAD, and (2) intrinsic coupling between electric current and Joule heating giving rise to unwanted thermally activated mechanisms. To overcome these challenges, we have developed a microdevice-based electromechanical testing system (MEMTS) to characterize nanoscale metal specimens in transmission electron microscopy (TEM). Our studies reveal that MEMTS eliminates the effect of Joule heating on material deformation, a critical advantage over macroscopic experiments, owing to its unique scale. For example, a negligible change in temperature (<0.02 degrees C) is predicted at ~3500 A/mm2. Utilizing the attractive features of MEMTS, we have directly investigated potential electron dislocation interactions in single crystal copper (SCC) specimens that are simultaneously subjected to uniaxial loading and electric current density up to 5000 A/mm2. Our in situ TEM studies indicate that for SCC, electroplasticity does not play a key role as no differences in dislocation activities, such as depinning and movement, are observed. PMID- 27782568 TI - Plasmakristall-4: New complex (dusty) plasma laboratory on board the International Space Station. AB - New complex-plasma facility, Plasmakristall-4 (PK-4), has been recently commissioned on board the International Space Station. In complex plasmas, the subsystem of MUm-sized microparticles immersed in low-pressure weakly ionized gas discharge plasmas becomes strongly coupled due to the high (103-104 e) electric charge on the microparticle surface. The microparticle subsystem of complex plasmas is available for the observation at the kinetic level, which makes complex plasmas appropriate for particle-resolved modeling of classical condensed matter phenomena. The main purpose of PK-4 is the investigation of flowing complex plasmas. To generate plasma, PK-4 makes use of a classical dc discharge in a glass tube, whose polarity can be switched with the frequency of the order of 100 Hz. This frequency is high enough not to be felt by the relatively heavy microparticles. The duty cycle of the polarity switching can be also varied allowing to vary the drift velocity of the microparticles and (when necessary) to trap them. The facility is equipped with two videocameras and illumination laser for the microparticle imaging, kaleidoscopic plasma glow observation system and minispectrometer for plasma diagnostics and various microparticle manipulation devices (e.g., powerful manipulation laser). Scientific experiments are programmed in the form of scripts written with the help of specially developed C scripting language libraries. PK-4 is mainly operated from the ground (control center CADMOS in Toulouse, France) with the support of the space station crew. Data recorded during the experiments are later on delivered to the ground on the removable hard disk drives and distributed to participating scientists for the detailed analysis. PMID- 27782570 TI - Research of optical rotation measurement system based on centroid algorithm. AB - An optical rotation measurement system based on digital signal processor, modulated laser, and step motor rotating stage is established. Centroid algorithm featured fast and simple calculation is introduced to process light signals with or without sample to obtain the optical rotating angle through the step difference between two centroids. The system performance is proved experimentally with standard quartz tubes and glucose solutions. After various measurements, the relative error and precision of the system are determined to 0.4% and 0.004 degrees , which demonstrates the reliable repeatability and high accuracy of whole measurement system. PMID- 27782571 TI - Development and calibration of an air-floating six-axis force measurement platform using self-calibration. AB - This paper describes the design, working principle, as well as calibration of an air-floating six-axis force measurement platform, where the floating plate and nozzles were connected without contact, preventing inter-dimensional coupling and increasing precision significantly. The measurement repeatability error of the force size in the platform is less than 0.2% full scale (FS), which is significantly better than the precision of 1% FS in the six-axis force sensors on the current market. We overcame the difficulties of weight loading device in high precision calibration by proposing a self-calibration method based on the floating plate gravity and met the calibration precision requirement of 0.02% FS. This study has general implications for the development and calibration of high precision multi-axis force sensors. In particular, the air-floating six-axis force measurement platform could be applied to the calibration of some special sensors such as flexible tactile sensors and may be used as a micro-nano mechanical assembly platform for real-time assembly force testing. PMID- 27782572 TI - The supersonic molecular beam injector as a reliable tool for plasma fueling and physics experiment on HL-2A. AB - On HL-2A tokamak, supersonic molecular beam injection (SMBI) has been developed as a routine refueling method. The key components of the system are an electromagnetic valve and a conic nozzle. The valve and conic nozzle are assembled to compose the simplified Laval nozzle for generating the pulsed beam. The appurtenance of the system includes the cooling system serving the cooled SMBI generation and the in situ calibration component for quantitative injection. Compared with the conventional gas puffing, the SMBI features prompt response and larger fueling flux. These merits devote the SMBI a good fueling method, an excellent plasma density feedback control tool, and an edge localized mode mitigation resource. PMID- 27782573 TI - The cold neutron chopper spectrometer at the Spallation Neutron Source-A review of the first 8 years of operation. AB - The first eight years of operation of the Cold Neutron Chopper Spectrometer (CNCS) at the Spallation Neutron Source in Oak Ridge is being reviewed. The instrument has been part of the facility user program since 2009, and more than 250 individual user experiments have been performed to date. CNCS is an extremely powerful and versatile instrument and offers leading edge performance in terms of beam intensity, energy resolution, and flexibility to trade one for another. Experiments are being routinely performed with the sample at extreme conditions: T ? 0.05 K, p ? 2 GPa, and B = 8 T can be achieved individually or in combination. In particular, CNCS is in a position to advance the state of the art with inelastic neutron scattering under pressure, and some of the recent accomplishments in this area will be presented in more detail. PMID- 27782574 TI - Ultrasonic micro-motor with multilayer piezoelectric ceramic and chamfered driving tips. AB - In this study, an oblate-type ultrasonic micro-motor with multilayer piezoelectric ceramic and chamfered driving tips was proposed and experimentally researched. The micro-motor works based on the standing-wave principle and has a higher rotary speed than the traditional standing-wave one in principle, reaching a rotary speed of 2100 r/min in this study at the voltage of 20 Vp-p. When the micro-motor rotates, single phase alternating current is required, namely, V=Asinomegat, and exchanging the signal wire and ground wire will not change the rotary direction of the motor, which reinforces the safety and the compaction of this motor. The ratio of the maximum displacement value of the speed feeding direction and the preload direction is approximately 4, showing a characteristic of high speed and low ability to load. PMID- 27782575 TI - Tomography and imaging at the PSICHE beam line of the SOLEIL synchrotron. AB - PSICHE (Pressure, Structure and Imaging by Contrast at High Energy) is the high energy beam line of the SOLEIL synchrotron. The beam line is designed to study samples at extreme pressures, using diffraction, and to perform imaging and tomography for materials science and other diverse applications. This paper presents the tomograph and the use of the beam line for imaging, with emphasis on developments made with respect to existing instruments. Of particular note are the high load capacity rotation stage with free central aperture for installing large or complex samples and sample environments, x-ray mirror and filter optics for pink beam imaging, and multiple options for combining imaging and diffraction measurement. We describe how x-ray imaging techniques have been integrated into high-pressure experiments. The design and the specifications of the beam line are described, and several case studies drawn from the first user experiments are presented. PMID- 27782576 TI - Droplet sensing using small and compact high-Q planar resonator based on impedance matching technique. AB - In this paper, we demonstrate the sensing feasibility of the proposed high-Q resonator using a phosphate-buffered saline droplet at microwave frequencies. In the experimental results, the resonant frequency, signal level, and Q-factor of the S21-parameter with and without a 1-MUl droplet were changed to about 230 MHz, 32 dB, and 1500, respectively. The resonator system was found to be suitable for droplet sensing with a small volume due to its small and compact scheme. This resonator system is expected to play an important role in droplet sensing with different dielectric constants. PMID- 27782577 TI - Low power RF amplifier circuit for ion trap applications. AB - A low power RF amplifier circuit for ion trap applications is presented and described. The amplifier is based on a class-D half-bridge amplifier with a voltage mirror driver. The RF amplifier is composed of an RF class-D amplifier, an envelope modulator to ramp up the RF voltage during the ion analysis stage, a detector or amplitude demodulation circuit for sensing the output signal amplitude, and a feedback amplifier that linearizes the steady state output of the amplifier. The RF frequency is set by a crystal oscillator and the series resonant circuit is tuned to the oscillator frequency. The resonant circuit components have been chosen, in this case, to operate at 1 MHz. In testings, the class-D stage operated at a maximum of 78 mW at 1.1356 MHz producing 225 V peak. PMID- 27782578 TI - A microfabricated sun sensor using GaN-on-sapphire ultraviolet photodetector arrays. AB - A miniature sensor for detecting the orientation of incident ultraviolet light was microfabricated using gallium nitride (GaN)-on-sapphire substrates and semi transparent interdigitated gold electrodes for sun sensing applications. The individual metal-semiconductor-metal photodetector elements were shown to have a stable and repeatable response with a high sensitivity (photocurrent-to-dark current ratio (PDCR) = 2.4 at -1 V bias) and a high responsivity (3200 A/W at -1 V bias) under ultraviolet (365 nm) illumination. The 3 * 3 GaN-on-sapphire ultraviolet photodetector array was integrated with a gold aperture to realize a miniature sun sensor (1.35 mm * 1.35 mm) capable of determining incident light angles with a +/-45 degrees field of view. Using a simple comparative figure of merit algorithm, measurement of incident light angles of 0 degrees and 45 degrees was quantitatively and qualitatively (visually) demonstrated by the sun sensor, supporting the use of GaN-based sun sensors for orientation, navigation, and tracking of the sun within the harsh environment of space. PMID- 27782579 TI - Note: Localization based on estimated source energy homogeneity. AB - Acoustic signal localization is a complex problem with a wide range of industrial and academic applications. Herein, we propose a localization method based on energy attenuation and inverted source amplitude comparison (termed estimated source energy homogeneity, or ESEH). This inversion is tested on both synthetic (numerical) data using a Lamb wave propagation model and experimental 2D plate data (recorded with 4 accelerometers sensitive up to 26 kHz). We compare the performance of this technique with classic source localization algorithms: arrival time localization, time reversal localization, and localization based on energy amplitude. Our technique is highly versatile and out-performs the conventional techniques in terms of error minimization and cost (both computational and financial). PMID- 27782580 TI - A single-step lithography system based on an enhanced robotic adhesive dispenser. AB - In the paper, we present a single-step lithography system whereby the robotically controlled micro-extrusion of resist adhesive onto a substrate surface to directly create resist adhesive patterns of interest. This system is modified from a robotic adhesive dispenser by shrinking the aperture of the nozzle to a few micrometers aiming to realize patterns at microscale. From experimental investigation, it is found that working factors including writing speed, working time, and applied pressure can be adopted to conveniently regulate the feature size (the width of the line features and the diameter of the dot features). To test its functionality, the system was used to pattern line features on silicon dioxide (SiO2) and generate an array of square-like silicon microstructure by combining with wet etching. It provides a simple and flexible alternative tool to facilitate the development of microfabrication. PMID- 27782581 TI - Quartz crystal microbalance and photoacoustic measurements in dental photocuring. AB - Photocured dental resins are used extensively in restorative procedures in dentistry. Inadequate curing reduces the lifetime of the dental restoration, and consequently it is essential to precisely measure the polymerisation kinetics. In this study, two techniques, Quartz Crystal Microbalance (QCM) and Photoacoustic Spectroscopy (PAS), were used to monitor the real-time cure and to obtain the optical absorption spectra of resins, respectively. From the PAS measurements, the precise peaks of absorption were identified, and were used as the appropriate wavelength of the photocuring light in the QCM monitoring. The combined use of these techniques allows reliable determination of the duration of the phases of physical and chemical changes that occur during photocuring. Two commercial dental resins were tested, and the results confirmed the advantages of using PAS and QCM to study polymerisation kinetics. PMID- 27782582 TI - High-power ultrafast Yb:fiber laser frequency combs using commercially available components and basic fiber tools. AB - We present a detailed description of the design, construction, and performance of high-power ultrafast Yb:fiber laser frequency combs in operation in our laboratory. We discuss two such laser systems: an 87 MHz, 9 W, 85 fs laser operating at 1060 nm and an 87 MHz, 80 W, 155 fs laser operating at 1035 nm. Both are constructed using low-cost, commercially available components, and can be assembled using only basic tools for cleaving and splicing single-mode fibers. We describe practical methods for achieving and characterizing low-noise single pulse operation and long-term stability from Yb:fiber oscillators based on nonlinear polarization evolution. Stabilization of the combs using a variety of transducers, including a new method for tuning the carrier-envelope offset frequency, is discussed. High average power is achieved through chirped-pulse amplification in simple fiber amplifiers based on double-clad photonic crystal fibers. We describe the use of these combs in several applications, including ultrasensitive femtosecond time-resolved spectroscopy and cavity-enhanced high order harmonic generation. PMID- 27782583 TI - Development of low temperature atomic force microscopy with an optical beam deflection system capable of simultaneously detecting the lateral and vertical forces. AB - The atomic force microscopy (AFM) is a very important tool for imaging and investigating the complex force interactions on sample surfaces with high spatial resolution. In the AFM, two types of detection systems of the tip-sample interaction forces have been used: an optical detection system and an electrical detection system. In optical detection systems, such as optical beam deflection system or optical fiber interferometer system, both the lateral and the vertical tip-sample forces can be measured simultaneously. In electrical detection systems, such as qPlus or Kolibri sensors, either the lateral or vertical forces can be measured. Simultaneous measurement of the lateral and vertical interaction forces effectively allows investigation of force interactions because the force is a vector with magnitude and direction. In this study, we developed a low temperature, frequency-modulation AFM using an optical beam deflection system to simultaneously measure the vertical and lateral forces. In this system, the heat sources, such as a laser diode and a current-to-voltage converter, for measuring the photocurrent of the four-segmented photodiode are located outside the observation chamber to avoid a temperature increase of the AFM unit. The focused optical beam is three-dimensionally adjustable on the back side of the cantilever. We demonstrate low-noise displacement measurement of the cantilever and successful atomic resolution imaging using the vertical and lateral forces at low temperatures. PMID- 27782584 TI - A kind of fast shutter for Z pinch diagnosis device. AB - A kind of fast shutter for protecting the diagnosis devices in Z pinch experiments is introduced in this paper. The shutter is composed of a pulling rod, a magnetic core, and a solenoid. Different from the traditional coils which were used at the voltage of 220 V, the solenoid we used must endure the high voltage of 5-10 kV and the deformation which maybe caused by the 5-10 T intense magnetic field. A creative configuration for the solenoid is developed including the winding guide, insulating sleeve, and stainless-steel sleeve. The experimental results show that the configuration of the solenoid is effective. The velocity of the valve is nearly 19 m/s and the time jitter of the shutdown is within 75 MUs. PMID- 27782585 TI - A wide-field TCSPC FLIM system based on an MCP PMT with a delay-line anode. AB - We report on the implementation of a wide-field time-correlated single photon counting (TCSPC) method for fluorescence lifetime imaging (FLIM). It is based on a 40 mm diameter crossed delay line anode detector, where the readout is performed by three standard TCSPC boards. Excitation is performed by a picosecond diode laser with 50 MHz repetition rate. The photon arrival timing is obtained directly from the microchannel plates, with an instrumental response of ~190 to 230 ps full width at half maximum depending on the position on the photocathode. The position of the photon event is obtained from the pulse propagation time along the two delay lines, one in x and one in y. One end of a delay line is fed into the "start" input of the corresponding TCSPC board, and the other end is delayed by 40 ns and fed into the "stop" input. The time between start and stop is directly converted into position, with a resolution of 200-250 MUm. The data acquisition software builds up the distribution of the photons over their spatial coordinates, x and y, and their times after the excitation pulses, typically into 512 * 512 pixels and 1024 time channels per pixel. We apply the system to fluorescence lifetime imaging of cells labelled with Alexa 488 phalloidin in an epi-fluorescence microscope and discuss the application of our approach to other fluorescence microscopy methods. PMID- 27782586 TI - An improved correlation method for amplitude estimation of gravitational background signal with time-varying frequency. AB - In the measurement of the gravitational constant G with angular acceleration method, the accurate estimation of the amplitude of the useful angular acceleration generated by source masses depends on the effective subtraction of the spurious gravitational signal caused by room fixed background masses. The gravitational background signal is of time-varying frequency, and mainly consists of the prominent fundamental frequency and second harmonic components. We propose an improved correlation method to estimate the amplitudes of the prominent components of the gravitational background signal with high precision. The improved correlation method converts a sinusoidal signal with time-varying frequency into a standard sinusoidal signal by means of the stretch processing of time. Based on Gaussian white noise model, the theoretical result shows the uncertainty of the estimated amplitude is proportional to sigmaNT, where sigma and N are the standard deviation of noise and the number of the useful signal period T, respectively. PMID- 27782587 TI - A virtual instrument to standardise the calibration of atomic force microscope cantilevers. AB - Atomic force microscope (AFM) users often calibrate the spring constants of cantilevers using functionality built into individual instruments. This calibration is performed without reference to a global standard, hindering the robust comparison of force measurements reported by different laboratories. Here, we describe a virtual instrument (an internet-based initiative) whereby users from all laboratories can instantly and quantitatively compare their calibration measurements to those of others-standardising AFM force measurements-and simultaneously enabling non-invasive calibration of AFM cantilevers of any geometry. This global calibration initiative requires no additional instrumentation or data processing on the part of the user. It utilises a single website where users upload currently available data. A proof-of-principle demonstration of this initiative is presented using measured data from five independent laboratories across three countries, which also allows for an assessment of current calibration. PMID- 27782588 TI - A novel instrument to measure differential ablation of meteorite samples and proxies: The Meteoric Ablation Simulator (MASI). AB - On entering the Earth's atmosphere, micrometeoroids partially or completely ablate, leaving behind layers of metallic atoms and ions. The relative concentration of the various metal layers is not well explained by current models of ablation. Furthermore, estimates of the total flux of cosmic dust and meteoroids entering the Earth's atmosphere vary over two orders of magnitude. To better constrain these estimates and to better model the metal layers in the mesosphere, an experimental Meteoric Ablation Simulator (MASI) has been developed. Interplanetary Dust Particle (IDP) analogs are subjected to temperature profiles simulating realistic entry heating, to ascertain the differential ablation of relevant metal species. MASI is the first ablation experiment capable of simulating detailed mass, velocity, and entry angle specific temperature profiles whilst simultaneously tracking the resulting gas phase ablation products in a time resolved manner. This enables the determination of elemental atmospheric entry yields which consider the mass and size distribution of IDPs. The instrument has also enabled the first direct measurements of differential ablation in a laboratory setting. PMID- 27782589 TI - Acoustic buffeting by infrasound in a low vibration facility. AB - Measurement instruments and fabrication tools with spatial resolution on the atomic scale require facilities that mitigate the impact of vibration sources in the environment. One approach to protection from vibration in a building's foundation is to place the instrument on a massive inertia block, supported on pneumatic isolators. This opens the questions of whether or not a massive floating block is susceptible to acoustic forces, and how to mitigate the effects of any such acoustic buffeting. Here this is investigated with quantitative measurements of vibrations and sound pressure, together with finite element modeling. It is shown that a particular concern, even in a facility with multiple acoustic enclosures, is the excitation of the lowest fundamental acoustic modes of the room by infrasound in the low tens of Hz range, and the efficient coupling of the fundamental room modes to a large inertia block centered in the room. PMID- 27782590 TI - Measurement of the lifetime of individual foam lamellae. AB - Foams play a crucial role in a number of practical applications. Their analysis in terms of stability is subject to a large number of parameters. An automated, light reflection based device for the measurement of the lifetime of a single foam lamella of aqueous surfactant solutions in contact with the liquid and gas phases is proposed. The capability of the method is shown for the analysis of the cationic and anionic model surfactants hexadecyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS) with saturated humidity, respectively. A statistical approach for analysis of the individual foam lamella lifetimes is presented and a comparison to the foam stability parameters obtained from a foam column device is presented. PMID- 27782591 TI - A new system for continuous and remote monitoring of patients receiving home mechanical ventilation. AB - Home mechanical ventilation is the treatment of patients with respiratory failure or insufficiency by means of a mechanical ventilator at a patient's home. In order to allow remote patient monitoring, several tele-monitoring systems have been introduced in the last few years. However, most of them usually do not allow real-time services, as they have their own proprietary communication protocol implemented and some ventilation parameters are not always measured. Moreover, they monitor only some breaths during the whole day, despite the fact that a patient's respiratory state may change continuously during the day. In order to reduce the above drawbacks, this work reports the development of a novel remote monitoring system for long-term, home-based ventilation therapy; the proposed system allows for continuous monitoring of the main physical quantities involved during home-care ventilation (e.g., differential pressure, volume, and air flow rate) and is developed in order to allow observations of different remote therapy units located in different places of a city, region, or country. The developed remote patient monitoring system is able to detect various clinical events (e.g., events of tube disconnection and sleep apnea events) and has been successfully tested by means of experimental tests carried out with pulmonary ventilators typically used to support sick patients. PMID- 27782592 TI - Thermal conductivity measurements of non-metals via combined time- and frequency domain thermoreflectance without a metal film transducer. AB - The thermoreflectance-based techniques time- and frequency-domain thermoreflectance (TDTR and FDTR, respectively) have emerged as robust platforms to measure the thermophysical properties of a wide array of systems on varying length scales. Routine in the implementation of these techniques is the application of a thin metal film on the surface of the sample of interest to serve as an opto-thermal transducer ensuring the measured modulated reflectivity is dominated by the change in thermoreflectance of the sample. Here, we outline a method to directly measure the thermal conductivities of bulk materials without using a metal transducer layer using a standard TDTR/FDTR experiment. A major key in this approach is the use of a thermal model with z-dependent heat source when the optical penetration depth is comparable to the beam sizes and measuring the FDTR response at a long delay time to minimize non-thermoreflectivity contributions to the modulated reflectance signals (such as free carrier excitations). Using this approach, we demonstrate the ability to measure the thermal conductivity on three semiconductors, intrinsic Si (100), GaAs (100), and InSb (100), the results of which are validated with FDTR measurements on the same wafers with aluminum transducers. We outline the major sources of uncertainty in this approach, including frequency dependent heating and precise knowledge of the pump and probe spot sizes. As a result, we discuss appropriate pump-frequency ranges in which to implement this TDTR/FDTR approach and present a procedure to measure the effective spot sizes by fitting the FDTR data of an 80 nm Al/SiO2 sample at a time delay in which the spot size sensitivity dominates an FDTR measurement over the substrate thermal properties. Our method provides a more convenient way to directly measure the thermal conductivities of semiconductors. PMID- 27782593 TI - Quantum limited heterodyne detection of spin noise. AB - Spin noise spectroscopy is a powerful technique for studying spin relaxation in semiconductors. In this article, we propose an extension of this technique based on optical heterodyne detection of spin noise, which provides several key advantages compared to conventional spin noise spectroscopy: detection of high frequency spin noise not limited by detector bandwidth or sampling rates of digitizers, quantum limited sensitivity even in case of very weak probe power, and possible amplification of the spin noise signal. Heterodyne detection of spin noise is demonstrated on insulating n-doped GaAs. From measurements of spin noise spectra up to 0.4 Tesla, we determined the distribution of g-factors, Deltag/g = 0.49%. PMID- 27782594 TI - Improvement of density resolution in short-pulse hard x-ray radiographic imaging using detector stacks. AB - We demonstrate that stacking several imaging plates (IPs) constitutes an easy method to increase hard x-ray detection efficiency. Used to record x-ray radiographic images produced by an intense-laser driven hard x-ray backlighter source, the IP stacks resulted in a significant improvement of the radiograph density resolution. We attribute this to the higher quantum efficiency of the combined detectors, leading to a reduced photon noise. Electron-photon transport simulations of the interaction processes in the detector reproduce the observed contrast improvement. Increasing the detection efficiency to enhance radiographic imaging capabilities is equally effective as increasing the x-ray source yield, e.g., by a larger drive laser energy. PMID- 27782595 TI - Note: An in situ method for measuring the non-linear response of a Fabry-Perot cavity. AB - The transfer cavity is a very important frequency reference for laser stabilization and is widely used for applications such as precision measurements and laser cooling of ions or molecules. But the non-linear response of the piezoelectric ceramic transducer (PZT) in the Fabry-Perot cavity limits the performance of the laser stabilization. Thus, measuring and controlling such non linearity is essential. Here we report an in situ, optical method to characterize this non-linearity by measuring the resonant signals of a dual-frequency laser. The differential measurement makes it insensitive to the laser and cavity drifts, while maintaining a very high sensitivity. It can be applied for various applications with PZTs, especially in an optical lab. PMID- 27782596 TI - Ultra-high resolution steady-state micro-thermometry using a bipolar direct current reversal technique. AB - The suspended micro-thermometry measurement technique is one of the most prominent methods for probing the in-plane thermal conductance of low dimensional materials, where a suspended microdevice containing two built-in platinum resistors that serve as both heater and thermometer is used to measure the temperature and heat flow across a sample. The presence of temperature fluctuations in the sample chamber and background thermal conductance through the device, residual gases, and radiation are dominant sources of error when the sample thermal conductance is comparable to or smaller than the background thermal conductance, on the order of 300 pW/K at room temperature. In this work, we present a high resolution thermal conductance measurement scheme in which a bipolar direct current reversal technique is adopted to replace the lock-in technique. We have demonstrated temperature resolution of 1.0-2.6 mK and thermal conductance resolution of 1.7-26 pW/K over a temperature range of 30-375 K. The background thermal conductance of the suspended microdevice is determined accurately by our method and allows for straightforward isolation of this parasitic signal. This simple and high-throughput measurement technique yields an order of magnitude improvement in resolution over similarly configured lock-in amplifier techniques, allowing for more accurate investigation of fundamental phonon transport mechanisms in individual nanomaterials. PMID- 27782597 TI - Comb mode filtering silver mirror cavity for spectroscopic distance measurement. AB - In this work we present a design of an external optical cavity based on Fabry Perot etalons applied to a 100 MHz Er-doped fiber optical frequency comb working at 1560 nm to increase its repetition frequency. A Fabry-Perot cavity is constructed based on a transportable cage system with two silver mirrors in plano concave geometry including the mode-matching lenses, fiber coupled collimation package and detection unit. The system enables full 3D angle mirror tilting and x y off axis movement as well as distance between the mirrors. We demonstrate the increase of repetition frequency by direct measurement of the beat frequency and spectrally by using the virtually imaged phased array images. PMID- 27782598 TI - Design and construction of Keda Space Plasma Experiment (KSPEX) for the investigation of the boundary layer processes of ionospheric depletions. AB - In this work, the design and construction of the Keda Space Plasma EXperiment (KSPEX), which aims to study the boundary layer processes of ionospheric depletions, are described in detail. The device is composed of three stainless steel sections: two source chambers at both ends and an experimental chamber in the center. KSPEX is a steady state experimental device, in which hot filament arrays are used to produce plasmas in the two sources. A Macor-mesh design is adopted to adjust the plasma density and potential difference between the two plasmas, which creates a boundary layer with a controllable electron density gradient and inhomogeneous radial electric field. In addition, attachment chemicals can be released into the plasmas through a tailor-made needle valve which leads to the generation of negative ions plasmas. Ionospheric depletions can be modeled and simulated using KSPEX, and many micro-physical processes of the formation and evolution of an ionospheric depletion can be experimentally studied. PMID- 27782599 TI - Note: A dual-chip stroboscopic pulsed RADAR for probing passive sensors. AB - Stroboscopy provides an energy and computationally efficient means of sampling radiofrequency and microwave signals assumed to be reproducible under external excitation. While well known for impulse mode RADAR receivers, we here investigate its use for interrogating surface acoustic wave (SAW) transducers acting as passive cooperative targets. Amongst the originality of the implementation is the need to keep phase coherence between successive pulse generations which last up to tens of the radiofrequency periods to optimally transfer energy to the transducer. A two-chip receiver architecture is demonstrated, with a trigger signal compatible either with single-period avalanche transistor pulse excitation or frequency-agile direct digital synthesizer source. PMID- 27782600 TI - Super-resolution for scanning light stimulation systems. AB - Super-resolution (SR) is a technique used in digital image processing to overcome the resolution limitation of imaging systems. In this process, a single high resolution image is reconstructed from multiple low resolution images. SR is commonly used for CCD and CMOS (Complementary Metal-Oxide-Semiconductor) sensor images, as well as for medical applications, e.g., magnetic resonance imaging. Here, we demonstrate that super-resolution can be applied with scanning light stimulation (LS) systems, which are common to obtain space-resolved electro optical parameters of a sample. For our purposes, the Projection Onto Convex Sets (POCS) was chosen and modified to suit the needs of LS systems. To demonstrate the SR adaption, an Optical Beam Induced Current (OBIC) LS system was used. The POCS algorithm was optimized by means of OBIC short circuit current measurements on a multicrystalline solar cell, resulting in a mean square error reduction of up to 61% and improved image quality. PMID- 27782601 TI - Integrated four-channel all-fiber up-conversion single-photon-detector with adjustable efficiency and dark count. AB - Up-conversion single photon detector (UCSPD) has been widely used in many research fields including quantum key distribution, lidar, optical time domain reflectrometry, and deep space communication. For the first time in laboratory, we have developed an integrated four-channel all-fiber UCSPD which can work in both free-running and gate modes. This compact module can satisfy different experimental demands with adjustable detection efficiency and dark count. We have characterized the key parameters of the UCSPD system. PMID- 27782602 TI - Time-resolved single-shot terahertz time-domain spectroscopy for ultrafast irreversible processes. AB - Pulsed terahertz spectroscopy is suitable for spectroscopic diagnostics of ultrafast events. However, the study of irreversible or single shot ultrafast events requires ability to record transient properties at multiple time delays, i.e., time resolved at single shot level, which is not available currently. Here by angular multiplexing use of femtosecond laser pulses, we developed and demonstrated a time resolved, transient terahertz time domain spectroscopy technique, where burst mode THz pulses were generated and then detected in a single shot measurement manner. The burst mode THz pulses contain 2 sub-THz pulses, and the time gap between them is adjustable up to 1 ns with picosecond accuracy, thus it can be used to probe the single shot event at two different time delays. The system can detect the sub-THz pulses at 0.1 THz-2.5 THz range with signal to noise ratio (SNR) of ~400 and spectrum resolution of 0.05 THz. System design was described here, and optimizations of single shot measurement of THz pulses were discussed in detail. Methods to improve SNR were also discussed in detail. A system application was demonstrated where pulsed THz signals at different time delays of the ultrafast process were successfully acquired within single shot measurement. This time resolved transient terahertz time domain spectroscopy technique provides a new diagnostic tool for irreversible or single shot ultrafast events where dynamic information can be extracted at terahertz range within one-shot experiment. PMID- 27782603 TI - Validations of calibration-free measurements of electron temperature using double pass Thomson scattering diagnostics from theoretical and experimental aspects. AB - This paper evaluates the accuracy of electron temperature measurements and relative transmissivities of double-pass Thomson scattering diagnostics. The electron temperature (Te) is obtained from the ratio of signals from a double pass scattering system, then relative transmissivities are calculated from the measured Te and intensity of the signals. How accurate the values are depends on the electron temperature (Te) and scattering angle (theta), and therefore the accuracy of the values was evaluated experimentally using the Large Helical Device (LHD) and the Tokyo spherical tokamak-2 (TST-2). Analyzing the data from the TST-2 indicates that a high Te and a large scattering angle (theta) yield accurate values. Indeed, the errors for scattering angle theta = 135 degrees are approximately half of those for theta = 115 degrees . The method of determining the Te in a wide Te range spanning over two orders of magnitude (0.01-1.5 keV) was validated using the experimental results of the LHD and TST-2. A simple method to provide relative transmissivities, which include inputs from collection optics, vacuum window, optical fibers, and polychromators, is also presented. The relative errors were less than approximately 10%. Numerical simulations also indicate that the Te measurements are valid under harsh radiation conditions. This method to obtain Te can be considered for the design of Thomson scattering systems where there is high-performance plasma that generates harsh radiation environments. PMID- 27782604 TI - Accurate and fast fiber transfer delay measurement based on phase discrimination and frequency measurement. AB - An accurate and fast fiber transfer delay measurement method is demonstrated. As a key technique, a simple ambiguity resolving process based on phase discrimination and frequency measurement is used to overcome the contradiction between measurement accuracy and system complexity. The system achieves a high measurement accuracy of 0.2 ps with a 0.1 ps measurement resolution and a large dynamic range up to 50 km as well as no dead zone. PMID- 27782605 TI - Note: Electro-optic coefficients of Li-deficient MgO-doped LiNbO3 crystal. AB - A number of Li-deficient MgO-doped LiNbO3 (LN) crystals with different Li2O contents ranging from 43.4 mol. % to 44.5 mol. % were prepared by carrying out the Li-poor vapor transport equilibration treatment on 5 mol. % (in growth melt) MgO-doped LN crystals. Unclamped electro-optic (EO) coefficients gamma13 and gamma33 of these crystals were measured by Mach-Zehnder interferometry. The results show that gamma13 (gamma33) increases linearly by ~14% (11%) as the Li2O content decreases from 44.5 mol. % of the as-grown state to 43.4 mol. % of the Li deficient state. This feature is desired for the EO application of the Li deficient MgO:LN crystal. PMID- 27782606 TI - Three axis vector atomic magnetometer utilizing polarimetric technique. AB - The three axis vector magnetic field measurement based on the interaction of a single elliptically polarized light beam with an atomic system is described. The magnetic field direction dependent atomic responses are extracted by the polarimetric detection in combination with laser frequency modulation and magnetic field modulation techniques. The magnetometer geometry offers additional critical requirements like compact size and large dynamic range for space application. Further, the three axis magnetic field is measured using only the reflected signal (one polarization component) from the polarimeter and thus can be easily expanded to make spatial array of detectors and/or high sensitivity field gradient measurement as required for biomedical application. PMID- 27782607 TI - Imaging and image restoration of lens-combined modulated wavefront coding. AB - In this paper, it presents a new wavefront coding (WFC) technology that we call lens-combined modulated wavefront coding (LM-WFC). Based on the LM-WFC design method, we establish a large depth of field and large aperture system. Simulation results indicate that the modulation transfer function of the system has a defocus invariant characteristic, which all typical WFC systems have, with a large depth of field. Experimental results for comparing the LM-WFC imaging system and a traditional imaging system are presented. The comparative results demonstrate that the LM-WFC system has an imaging performance invariant over a wide depth of field range. PMID- 27782608 TI - A compact, low cost Marx bank for generating capillary discharge plasmas. AB - We describe in detail a low power Compact Marx Bank (CMB) circuit that can provide 20 kV, 500 A pulses of approximately 100-200 ns duration. One application is the generation of capillary discharge plasmas of density ~1018 cm-3 used in laser plasma accelerators. The CMB is triggered with a high speed solid state switch and gives a high voltage output pulse with a ns scale rise time into a 50 Omega load (coaxial cable) with <4 ns voltage jitter. Its small size (10 cm * 25 cm * 5 cm) means that it can be placed right next to the capillary discharge in the target chamber to avoid the need to impedance match. The electrical energy required per discharge is <1 J, and the CMB can be run at shot repetition rates of ?1 Hz. This low power requirement means that the circuit can easily be powered by a small lead acid battery and, therefore, can be floated relative to laboratory earth. The CMB is readily scalable and pulses >45 kV are demonstrated in air discharges. PMID- 27782609 TI - Contributed Review: The novel gas puff targets for laser-matter interaction experiments. AB - Various types of targetry are used nowadays in laser matter interaction experiments. Such targets are characterized using different methods capable of acquiring information about the targets such as density, spatial distribution, and temporal behavior. In this mini-review paper, a particular type of target will be presented. The targets under consideration are gas puff targets of various and novel geometries. Those targets were investigated using extreme ultraviolet (EUV) and soft X-ray (SXR) imaging techniques, such as shadowgraphy, tomography, and pinhole camera imaging. Details about characterization of those targets in the EUV and SXR spectral regions will be presented. PMID- 27782610 TI - Development and characterization of a high yield transportable pulsed neutron source with efficient and compact pulsed power system. AB - The results of characterization experiments carried out on a newly developed dense plasma focus device based intense pulsed neutron source with efficient and compact pulsed power system are reported. Its high current sealed pseudospark switch based low inductance capacitor bank with maximum stored energy of ~10 kJ is segregated into four modules of ~2.5 kJ each and it cumulatively delivers peak current in the range of 400 kA-600 kA (corresponding to charging voltage range of 14 kV-18 kV) in a quarter time period of ~2 MUs. The neutron yield performance of this device has been optimized by discretely varying deuterium filling gas pressure in the range of 6 mbar-11 mbar at ~17 kV/550 kA discharge. At ~7 kJ/8.5 mbar operation, the average neutron yield has been measured to be in the order of ~4 * 109 neutrons/pulse which is the highest ever reported neutron yield from a plasma focus device with the same stored energy. The average forward to radial anisotropy in neutron yield is found to be ~2. The entire system is contained on a moveable trolley having dimensions 1.5 m * 1 m * 0.7 m and its operation and control (up to the distance of 25 m) are facilitated through optically isolated handheld remote console. The overall compactness of this system provides minimum proximity to small as well as large samples for irradiation. The major intended application objective of this high neutron yield dense plasma focus device development is to explore the feasibility of active neutron interrogation experiments by utilization of intense pulsed neutron sources. PMID- 27782611 TI - Image quality method as a possible way of in situ monitoring of in-vessel mirrors in a fusion reactor. AB - The plasma-facing (first) mirrors in ITER will be subject to sputtering and/or contamination with rates that will depend on the precise mirror locations. The resulting influence of both these factors can reduce the mirror reflectance (R) and worsen the transmitted image quality (IQ). This implies that monitoring the mirror quality in situ is an actual desire, and the present work is an attempt towards a solution. The method we propose is able to elucidate the reason for degradation of the mirror reflectance: sputtering by charge exchange atoms or deposition of contaminated layers. In case of deposition of contaminants, the mirror can be cleaned in situ, but a rough mirror (due to sputtering) cannot be used anymore and has to be replaced. To demonstrate the feasibility of the IQ method, it was applied to mirror specimens coated with carbon film in laboratory conditions and to mirrors coated with contaminants during exposure in fusion devices (TRIAM-1M and Tore Supra), as well as to mirrors of different materials exposed to sputtering by plasma ions in the DSM-2 plasma stand (in IPP NSC KIPT). PMID- 27782612 TI - Repetition rate multiplication of frequency comb using all-pass fiber resonator. AB - We propose a stable method for repetition rate multiplication of a 250-MHz Er fiber frequency comb by a phase-locked all-pass fiber ring resonator, whose phase locking configuration is simple. The optical path length of the fiber ring resonator is automatically controlled to be accurately an odd multiple of half of the original cavity length using an electronical phase-locking unit with an optical delay line. As for shorter cavity length of the comb, high-order odd multiple is preferable. Because the power loss depends only on the net attenuation of the fiber ring resonator, the energetic efficiency of the proposed method is high. The input and output optical spectrums show that the spectral width of the frequency comb is clearly preserved. Besides, experimental results show less pulse intensity fluctuation and 35 dB suppression ratio of side-modes while providing a good long-term and short-term frequency stability. Higher-order repetition rate multiplication to several GHz can be obtained by using several fiber ring resonators in cascade configuration. PMID- 27782613 TI - Measurement of contact angles in a simulated microgravity environment generated by a large gradient magnetic field. AB - The contact angle is an important parameter that is essential for studying interfacial phenomena. The contact angle can be measured using commercially available instruments. However, these well-developed instruments may not function or may be unsuitable for use in some special environments. A simulated microgravity generated by a large gradient magnetic field is such an environment in which the current measurement instruments cannot be installed. To measure the contact angle in this environment, new tools must be designed and manufactured to be compatible with the size and physical environment. In this study, we report the development and construction of a new setup that was specifically designed for use in a strong magnetic field to measure the contact angle between a levitated droplet and a solid surface. The application of the setup in a large gradient magnetic field was tested, and the contact angles were readily measured. PMID- 27782614 TI - Energy-dispersive small-angle X-ray scattering with cone collimation using X-ray capillary optics. AB - Energy-dispersive small-angle X-ray scattering (ED-SAXS) with an innovative design of cone collimation based on an ellipsoidal single-bounce capillary (ESBC) and a polycapillary parallel X-ray lens (PPXRL) had been explored. Using this new cone collimation system, scattering angle 2theta has a theoretical minimum angle related to the mean half-opening angle of the hollow cone beam of 1.42 mrad, and with the usable X-ray energy ranging from 4 to 30 keV, the resulting observable scattering vector q is down to a minimum value of about 0.003 A-1 (or a Bragg spacing of about 2100 A). However, the absorption of lower energies by X-ray capillary optics, sample transmission, and detector response function limits the application range to lower energy. Cone collimation ED-SAXS experiments carried out on pure water, Lupolen, and in situ temperature-dependent measurement of diacetylenic acid/melamine micelle solid were presented at three different scattering angles 2theta of 0.18 degrees , 0.70 degrees and 1.18 degrees to illustrate the new opportunities offered by this technique as well as its limitations. Also, a comparison has been made by replacing the PPXRL with a pinhole, and the result shows that cone collimation ED-SAXS based on ESBC with PPXRL was helpful in improving the signal-to-noise ratio (i.e., reducing the parasitic background scattering) than ESBC with a pinhole. The cone collimation instrument based on X-ray capillary optics could be considered as a promising tool to perform SAXS experiments, especially cone collimation ED-SAXS has potential application for the in situ temperature-dependent studying on the kinetics of phase transitions. PMID- 27782615 TI - The effect of cavity tuning on oxygen beam currents of an A-ECR type 14 GHz electron cyclotron resonance ion source. AB - The efficiency of the microwave-plasma coupling plays a significant role in the production of highly charged ion beams with electron cyclotron resonance ion sources (ECRISs). The coupling properties are affected by the mechanical design of the ion source plasma chamber and microwave launching system, as well as damping of the microwave electric field by the plasma. Several experiments attempting to optimize the microwave-plasma coupling characteristics by fine tuning the frequency of the injected microwaves have been conducted with varying degrees of success. The inherent difficulty in interpretation of the frequency tuning results is that the effects of microwave coupling system and the cavity behavior of the plasma chamber cannot be separated. A preferable approach to study the effect of the cavity properties of the plasma chamber on extracted beam currents is to adjust the cavity dimensions. The results of such cavity tuning experiments conducted with the JYFL 14 GHz ECRIS are reported here. The cavity properties were adjusted by inserting a conducting tuner rod axially into the plasma chamber. The extracted beam currents of oxygen charge states O3+-O7+ were recorded at various tuner positions and frequencies in the range of 14.00-14.15 GHz. It was observed that the tuner position affects the beam currents of high charge state ions up to several tens of percent. In particular, it was found that at some tuner position / frequency combinations the plasma exhibited "mode hopping" between two operating regimes. The results improve the understanding of the role of plasma chamber cavity properties on ECRIS performances. PMID- 27782616 TI - Calculating vibrational spectra of molecules using tensor train decomposition. AB - We propose a new algorithm for calculation of vibrational spectra of molecules using tensor train decomposition. Under the assumption that eigenfunctions lie on a low-parametric manifold of low-rank tensors we suggest using well-known iterative methods that utilize matrix inversion (locally optimal block preconditioned conjugate gradient method, inverse iteration) and solve corresponding linear systems inexactly along this manifold. As an application, we accurately compute vibrational spectra (84 states) of acetonitrile molecule CH3CN on a laptop in one hour using only 100 MB of memory to represent all computed eigenfunctions. PMID- 27782617 TI - Image method for induced surface charge from many-body system of dielectric spheres. AB - Charged dielectric spheres embedded in a dielectric medium provide the simplest model for many-body systems of polarizable ions and charged colloidal particles. We provide a multiple scattering formulation for the total electrostatic energy for such systems and demonstrate that the polarization energy can be rapidly evaluated by an image method that generalizes the image methods for conducting spheres. Individual contributions to the total electrostatic energy are ordered according to the number of polarized surfaces involved, and each additional surface polarization reduces the energy by a factor of (a/R)3epsilon, where a is the sphere radius, R the average inter-sphere separation, and epsilon the relevant dielectric mismatch at the interface. Explicit expressions are provided for both the energy and the forces acting on individual spheres, which can be readily implemented in Monte Carlo and molecular dynamics simulations of polarizable charged spheres, thereby avoiding costly computational techniques that introduce a surface charge distribution that requires numerical solution. PMID- 27782618 TI - Two-dimensional electronic spectroscopy can fully characterize the population transfer in molecular systems. AB - Excitation energy transfer in complex systems often proceeds through series of intermediate states. One of the goals of time-resolved spectroscopy is to identify the spectral signatures of all of them in the acquired experimental data and to characterize the energy transfer scheme between them. It is well known that in the case of transient absorption spectra such decomposition is ambiguous even if many simplifying considerations are taken. In contrast to transient absorption, absorptive 2D spectra intuitively resemble population transfer matrices. Therefore, it seems possible to decompose the 2D spectra unambiguously. Here we show that all necessary information is encoded in the combination of absorptive 2D and linear absorption spectra. We set up a simple model describing a broad class of absorptive 2D spectra and prove analytically that they can be inverted uniquely towards physical parameters fully determining the species associated spectra of individual constituents together with all connecting intrinsic rate constants. Due to the matrix formulation of the model, it is suitable for fast computer calculation necessary to efficiently perform the inversion numerically by fitting the combination of experimental 2D and absorption spectra. Moreover, the model allows for decomposition of the 2D spectrum into its stimulated emission, ground-state bleach, and excited-state absorption components almost unambiguously. The numerical procedure is illustrated exemplarily. PMID- 27782619 TI - First-principles-based simulation of interlayer water and alkali metal ions in weathered biotite. AB - We performed first-principles-based simulations of weathered biotites (WBs) including alkali metal ions to investigate the adsorption states of interlayer cations and the cation/water distribution in their interlayer. Our simulations suggest that the inclusion of Fe3+ ions in octahedral sheets of WBs alters significantly the vibrational states, the adsorption states of alkali ions, and the cation/water distribution in our WBs. The Al-O bond cleavage suggested to occur in Fe3+-rich regions of WBs upon the H2O adsorption on Al3+ in tetrahedral sheets enhances greatly the dipole moment of adsorbed H2O molecules, thus enhancing the preference for aggregating inner-sphere complexes of heavy alkali ions particularly Cs+. PMID- 27782620 TI - Floquet theory of radical pairs in radiofrequency magnetic fields. AB - We present a new method for calculating the product yield of a radical pair recombination reaction in the presence of a weak time-dependent magnetic field. This method successfully circumvents the computational difficulties presented by a direct solution of the Liouville-von Neumann equation for a long-lived radical pair containing many hyperfine-coupled nuclear spins. Using a modified formulation of Floquet theory, treating the time-dependent magnetic field as a perturbation, and exploiting the slow radical pair recombination, we show that one can obtain a good approximation to the product yield by considering only nearly degenerate sub-spaces of the Floquet space. Within a significant parameter range, the resulting method is found to give product yields in good agreement with exact quantum mechanical results for a variety of simple model radical pairs. Moreover it is considerably more efficient than the exact calculation, and it can be applied to radical pairs containing significantly more nuclear spins. This promises to open the door to realistic theoretical investigations of the effect of radiofrequency electromagnetic radiation on the photochemically induced radical pair recombination reactions in the avian retina which are believed to be responsible for the magnetic compass sense of migratory birds. PMID- 27782621 TI - Statistics of silicate units in binary glasses. AB - In this paper, we derive a new model to determine the distribution of silicate units in binary glasses (or liquids). The model is based on statistical mechanics and assumes grand canonical ensemble of silicate units which exchange energy and network modifiers from the reservoir. This model complements experimental techniques, which measure short range order in glasses such as nuclear magnetic resonance (NMR) spectroscopy. The model has potential in calculating the amounts of liquid-liquid phase segregation and crystal nucleation, and it can be easily extended to more complicated compositions. The structural relaxation of the glass as probed by NMR spectroscopy is also reported, where the model could find its usefulness. PMID- 27782622 TI - Note: Caldeira-Leggett model describes dynamics of hydrogen atoms on graphene. PMID- 27782623 TI - Modeling the spectrum of the 2nu2 and nu4 states of ammonia to experimental accuracy. AB - The vibrational spectrum of ammonia has received an enormous amount of attention due to its potential prevalence in hot exo-planet atmospheres and persistent challenges in assigning and modeling highly excited and often highly perturbed states. Effective Hamiltonian models face challenges due to strong coupling between the large amplitude inversion and the other small amplitude vibrations. To date, only the ground and nu2 positions could be modeled to experimental accuracy using effective Hamiltonians. Several previous attempts to analyze the 2nu2 and nu4 energy levels failed to model both the microwave and infrared transitions to experimental accuracy. In this work, we performed extensive experimental measurements and data analysis for the 2nu2 and nu4 inversion rotation and vibrational transitions. We measured 159 new transition frequencies with microwave precision and assigned 1680 new ones from existing Fourier transform spectra recorded in Synchrotron SOLEIL. The newly assigned data significantly expand the range of assigned quantum numbers; combined with all the previously published high-resolution data, the 2nu2 and nu4 states are reproduced to experimental accuracy using a global model described here. Achieving experimental accuracy required inclusion of a number of terms in the effective Hamiltonian that were neglected in previous work. These terms have also been neglected in the analysis of states higher than 2nu2 and nu4 suggesting that the inversion-rotation-vibration spectrum of ammonia may be far more tractable to effective Hamiltonians than previously believed. PMID- 27782624 TI - Tuning vibrational mode localization with frequency windowing. AB - Local-mode coordinates have previously been shown to be an effective starting point for anharmonic vibrational spectroscopy calculations. This general approach borrows techniques from localized-orbital machinery in electronic structure theory and generates a new set of spatially localized vibrational modes. These modes exhibit a well-behaved spatial decay of anharmonic mode couplings, which, in turn, allows for a systematic, a priori truncation of couplings and increased computational efficiency. Fully localized modes, however, have been found to lead to unintuitive mixtures of characteristic motions, such as stretches and bends, and accordingly large bilinear couplings. In this work, a very simple, tunable localization frequency window is introduced, in order to realize the transition from normal modes to fully localized modes. Partial localization can be achieved by localizing only pairs of modes within this traveling frequency window, which allows for intuitive interpretation of modes. The optimal window size is suggested to be a few hundreds of wave numbers, based on small- to medium-sized test systems, including water clusters and polypeptides. The new sets of partially localized coordinates retain their spatial coupling decay behavior while providing a reduced number of potential energy evaluations for convergence of anharmonic spectra. PMID- 27782627 TI - Modeling of molecular photocells: Application to two-level photovoltaic system with electron-hole interaction. AB - We present a novel simple model to describe molecular photocells where the energy conversion process takes place by a single molecular donor-acceptor complex attached to electrodes. By applying quantum scattering theory, an open quantum system method, the coherent molecular photocell is described by a wave function. We analyze photon absorption, energy conversion, and quantum yield of a molecular photocell by considering the effects of electron-hole interaction and non radiative recombination. We model the exciton creation, dissociation, and subsequent effects on quantum yield in the energy domain. We find that depending on the photocell structure, the electron-hole interaction can normally decrease or abnormally increase the cell efficiency. The proposed model helps to understand the mechanisms of molecular photocells, and it can be used to optimize their yield. PMID- 27782626 TI - Relativistic state-specific multireference coupled cluster theory description for bond-breaking energy surfaces. AB - A four-component (4c) relativistic state specific multireference coupled cluster (4c-SSMRCC) method has been developed and applied to compute the ground state spectroscopic constants of Ag2, Cu2, Au2, and I2. The reference functions used in these calculations are obtained using computationally inexpensive improved virtual orbital-complete active space configuration interaction scheme. Rigorous size-extensivity and insensitivity towards the intruder state problem make our method an interesting choice for the calculation of the dissociation energy surface. To the best of our knowledge, this study is the first implementation of the SSMRCC within the relativistic framework. The overall agreement of our results, employing the smallest model space, with both theoretical and experimental reference values indicates that the 4c-SSMRCC method can be fruitfully used to describe electronic structures and associated properties of systems containing heavy elements. We observe a relativistic bond stabilization for the coinage metal dimers while the I-I bond is weakened by the relativistic effects. PMID- 27782625 TI - Wavelength dependent photoelectron circular dichroism of limonene studied by femtosecond multiphoton laser ionization and electron-ion coincidence imaging. AB - Enantiomers of the monoterpene limonene have been investigated by (2 + 1) resonance enhanced multiphoton ionization and photoelectron circular dichroism employing tuneable, circularly polarized femtosecond laser pulses. Electron imaging detection provides 3D momentum measurement while electron-ion coincidence detection can be used to mass-tag individual electrons. Additional filtering, by accepting only parent ion tagged electrons, can be then used to provide discrimination against higher energy dissociative ionization mechanisms where more than three photons are absorbed to better delineate the two photon resonant, one photon ionization pathway. The promotion of different vibrational levels and, tentatively, different electronic ion core configurations in the intermediate Rydberg states can be achieved with different laser excitation wavelengths (420 nm, 412 nm, and 392 nm), in turn producing different state distributions in the resulting cations. Strong chiral asymmetries in the lab frame photoelectron angular distributions are quantified, and a comparison made with a single photon (synchrotron radiation) measurement at an equivalent photon energy. PMID- 27782628 TI - Geometries of low spin states of multi-centre transition metal complexes through extended broken symmetry variational Monte Carlo. AB - The correct description of the ground state electronic and geometrical properties of multi-centre transition metal complexes necessitates of a high-level description of both dynamical and static correlation effects. In di-metallic complexes, the ground state low spin properties can be computed starting from single-determinants High-Spin (HS) and Broken Symmetry (BS) states by reconstructing an approximated low spin potential energy surface through the extended broken symmetry approach, based on the Heisenberg Hamiltonian. In the present work, we first apply this approach within the variational Monte Carlo method to tackle the geometry optimization of a Fe2S2(SH)42- model complex. To describe the HS and BS wavefunctions, we use a fully optimized unrestricted single determinant with a correlated Jastrow factor able to recover a large amount of dynamical correlation. We compared our results with those obtained by density functional theory and other multiconfigurational approaches, discussing the role of the nodal surface on the structural parameters. PMID- 27782629 TI - Simultaneous manipulation and observation of multiple ro-vibrational eigenstates in solid para-hydrogen. AB - We have experimentally performed the coherent control of delocalized ro vibrational wave packets (RVWs) of solid para-hydrogen (p-H2) by the wave packet interferometry (WPI) combined with coherent anti-Stokes Raman scattering (CARS). RVWs of solid p-H2 are delocalized in the crystal, and the wave function with wave vector k ~ 0 is selectively excited via the stimulated Raman process. We have excited the RVW twice by a pair of femtosecond laser pulses with delay controlled by a stabilized Michelson interferometer. Using a broad-band laser pulse, multiple ro-vibrational states can be excited simultaneously. We have observed the time-dependent Ramsey fringe spectra as a function of the inter pulse delay by a spectrally resolved CARS technique using a narrow-band probe pulse, resolving the different intermediate states. Due to the different fringe oscillation periods among those intermediate states, we can manipulate their amplitude ratio by tuning the inter-pulse delay on the sub-femtosecond time scale. The state-selective manipulation and detection of the CARS signal combined with the WPI is a general and efficient protocol for the control of the interference of multiple quantum states in various quantum systems. PMID- 27782631 TI - Conformation-specific spectroscopy of alkyl benzyl radicals: Effects of a radical center on the CH stretch infrared spectrum of an alkyl chain. AB - An important initial step in the combustion of gasoline and diesel fuels is the abstraction of hydrogen from alkylbenzenes to form resonance-stabilized alkyl benzyl radicals. This work uses, for the first time, double resonance spectroscopy methods to explore the conformation-specific vibronic and infrared spectroscopy of the alpha-ethylbenzyl (alphaEtBz) and alpha-propylbenzyl (alphaPrBz) radicals. Local mode Hamiltonian modeling enables assignment of the alkyl CH stretch IR spectra, accounting for Fermi resonance that complicates aliphatic alkyl CH stretch IR spectroscopy. The ground state conformational preferences of the ethyl and propyl chains are changed from those in the alkylbenzenes themselves, with global minima occurring for an in-plane orientation of the alkyl chain (trans) about its first dihedral angle (phif123, numbers are alkyl C atoms. C1 is CH radical site). This in-plane structure is the only observed conformer for the alpha-EtBz radical, while two conformers, tt and tg' share this orientation at the first dihedral, but differ in the second (phi1234) for the alphaPrBz radical. The in-plane orientation lowers the local site frequencies of the CH2 group stretches immediately adjacent to the benzylic radical site by about 50 cm-1 relative to those in pure alkyl chains or alkylbenzenes. This effect of the radical site is localized on the first CH2 group, with little effect on subsequent members of the alkyl chain. In the D1 excited electronic state, an out-of-plane orientation is preferred for the alkyl chains, leading to torsional mode Franck-Condon activity in the D0-D1 spectra that is both conformer-specific and diagnostic of the conformational change. PMID- 27782630 TI - Time-resolved study of laser initiated shock wave propagation in superfluid 4He. AB - Intense shock waves in superfluid 4He between 1.7 and 2.1 K are generated by rapidly expanding confined plasma from laser ablation of a metal target immersed in the liquid. The resulting shock fronts in the liquid with initial velocities up to ca. Mach 10 are visualized by time-resolved shadowgraph photography. These high intensity shocks decay within 500 ns into less energetic shock waves traveling at Mach 2, which have their lifetime in the microsecond time scale. Based on the analysis using the classical Rankine-Hugoniot theory, the shock fronts created remain in the solid phase up to 1 MUs and the associated thermodynamic state appears outside the previously studied region. The extrapolated initial shock pressure of 0.5 GPa is comparable to typical plasma pressures produced during liquid phase laser ablation. A secondary shock originating from fast heat propagation on the metal surface is also observed and a lower limit estimate for the heat propagation velocity is measured as 7 * 104 m/s. In the long-time limit, the high intensity shocks turn into liquid state waves that propagate near the speed of sound. PMID- 27782632 TI - Electronic spectrum of jet cooled SiCN. AB - We have generated SiCN in a supersonic free expansion, and measured the laser induced fluorescence (LIF) spectrum. Prior to the experiments, ab initio calculations were carried out to obtain the information necessary for searching for the LIF signals. In addition to the X 2Pi state, the optimized structures of three excited states, 2Delta, 2Sigma+, and 2Sigma-, have been obtained. Guided by the predictions, the LIF excitation spectrum of SiCN was observed in the UV region. The rotational structure of the 000 band with the origin, 29 261.639 cm 1, indicated that the electronic transition is A 2Delta-X 2Pi. The spin-orbit (SO) constants of the X 2Pi and A 2Delta states were determined to be 140.824 and 4.944 cm-1, respectively. In the A 2Delta state, the Fermi resonance between the (0, 20, 0) 2Delta and (0, 00, 1) 2Delta vibronic levels was identified. The molecular constants of the X 2Pi state were determined through the simultaneous analysis of the combination differences derived from the present LIF data with the previously reported rotational transitions. The spectroscopic parameters of the A 2Delta state were also obtained from the analysis where the constants of the X 2Pi state, derived above, were fixed at those values. PMID- 27782633 TI - Dimensional reduction of Markov state models from renormalization group theory. AB - Renormalization Group (RG) theory provides the theoretical framework to define rigorous effective theories, i.e., systematic low-resolution approximations of arbitrary microscopic models. Markov state models are shown to be rigorous effective theories for Molecular Dynamics (MD). Based on this fact, we use real space RG to vary the resolution of the stochastic model and define an algorithm for clustering microstates into macrostates. The result is a lower dimensional stochastic model which, by construction, provides the optimal coarse-grained Markovian representation of the system's relaxation kinetics. To illustrate and validate our theory, we analyze a number of test systems of increasing complexity, ranging from synthetic toy models to two realistic applications, built form all-atom MD simulations. The computational cost of computing the low dimensional model remains affordable on a desktop computer even for thousands of microstates. PMID- 27782634 TI - Improved sampling and validation of frozen Gaussian approximation with surface hopping algorithm for nonadiabatic dynamics. AB - In the spirit of the fewest switches surface hopping, the frozen Gaussian approximation with surface hopping (FGA-SH) method samples a path integral representation of the non-adiabatic dynamics in the semiclassical regime. An improved sampling scheme is developed in this work for FGA-SH based on birth and death branching processes. The algorithm is validated for the standard test examples of non-adiabatic dynamics. PMID- 27782635 TI - Structure and dynamics of polyelectrolyte surfactant mixtures under conditions of surfactant excess. AB - Oppositely charged polyelectrolyte (PE) surfactant mixtures can self-assemble into a large variety of mesoscopic structures, so-called polyelectrolyte surfactant complexes (PESCs). These structures directly affect the macroscopic behavior of such solutions. In this study, we investigated mixtures of the cationically charged PE JR 400 and the anionic surfactant SDS with the help of different neutron scattering and fluorescence methods. While an excess of PE charges in semi-dilute solutions causes an increase of viscosity, it has been observed that an excess of surfactant charges reduces the viscosity while precipitation is observed at charge equilibrium. The increase in viscosity had been investigated before and was attributed to the formation of cross links between PE chains. In this publication we focus our attention on the reduction of viscosity which is observed with an excess of surfactant charges. It is found that the PE chains form relatively large and densely packed clusters near the phase boundary on the surfactant rich side, thereby occupying less space and reducing the viscosity. For even higher surfactant concentrations, individual surfactant decorated PE chains are observed and their viscosity is found to be similar to that of the pure PE. PMID- 27782636 TI - Computation of indirect nuclear spin-spin couplings with reduced complexity in pure and hybrid density functional approximations. AB - We present a (sub)linear-scaling algorithm to determine indirect nuclear spin spin coupling constants at the Hartree-Fock and Kohn-Sham density functional levels of theory. Employing efficient integral algorithms and sparse algebra routines, an overall (sub)linear scaling behavior can be obtained for systems with a non-vanishing HOMO-LUMO gap. Calculations on systems with over 1000 atoms and 20 000 basis functions illustrate the performance and accuracy of our reference implementation. Specifically, we demonstrate that linear algebra dominates the runtime of conventional algorithms for 10 000 basis functions and above. Attainable speedups of our method exceed 6 * in total runtime and 10 * in the linear algebra steps for the tested systems. Furthermore, a convergence study of spin-spin couplings of an aminopyrazole peptide upon inclusion of the water environment is presented: using the new method it is shown that large solvent spheres are necessary to converge spin-spin coupling values. PMID- 27782637 TI - Polarity formation in crystals with long range molecular interactions: A Monte Carlo study. AB - Stochastic formation of a bi-polar state in three dimensional arrays of polar molecules with full Coulomb interactions is reproduced by Monte Carlo simulation. The size of the system is comparable to that of a real crystal seed. The spatial decay of the average order parameter is significantly slowed down by the long range interactions and the exact representation of correlation effects in terms of a single characteristic length becomes impossible. Finite size effects and possible scale invariance symmetry of the order parameter are extensively discussed. PMID- 27782638 TI - Perspective: Accurate ro-vibrational calculations on small molecules. AB - In what has been described as the fourth age of quantum chemistry, variational nuclear motion programs are now routinely being used to obtain the vibration rotation levels and corresponding wavefunctions of small molecules to the sort of high accuracy demanded by comparison with spectroscopy. In this perspective, I will discuss the current state-of-the-art which, for example, shows that these calculations are increasingly competitive with measurements or, indeed, replacing them and thus becoming the primary source of data on key processes. To achieve this accuracy ab initio requires consideration of small effects, routinely ignored in standard calculations, such as those due to quantum electrodynamics. Variational calculations are being used to generate huge lists of transitions which provide the input for models of radiative transport through hot atmospheres and to fill in or even replace measured transition intensities. Future prospects such as the study of molecular states near dissociation, which can provide a link with low-energy chemical reactions, are discussed. PMID- 27782639 TI - IR spectra of water droplets in no man's land and the location of the liquid liquid critical point. AB - No man's land is the region in the metastable phase diagram of water where it is very difficult to do experiments on liquid water because of homogeneous nucleation to the crystal. There are a number of estimates of the location in no man's land of the liquid-liquid critical point, if it exists. We suggest that published IR absorption experiments on water droplets in no man's land can provide information about the correct location. To this end, we calculate theoretical IR spectra for liquid water over a wide range of temperatures and pressures, using our E3B3 model, and use the results to argue that the temperature dependence of the experimental spectra is inconsistent with several of the estimated critical point locations, but consistent with others. PMID- 27782640 TI - TINKTEP: A fully self-consistent, mutually polarizable QM/MM approach based on the AMOEBA force field. AB - We present a novel quantum mechanical/molecular mechanics (QM/MM) approach in which a quantum subsystem is coupled to a classical subsystem described by the AMOEBA polarizable force field. Our approach permits mutual polarization between the QM and MM subsystems, effected through multipolar electrostatics. Self consistency is achieved for both the QM and MM subsystems through a total energy minimization scheme. We provide an expression for the Hamiltonian of the coupled QM/MM system, which we minimize using gradient methods. The QM subsystem is described by the onetep linear-scaling DFT approach, which makes use of strictly localized orbitals expressed in a set of periodic sinc basis functions equivalent to plane waves. The MM subsystem is described by the multipolar, polarizable force field AMOEBA, as implemented in tinker. Distributed multipole analysis is used to obtain, on the fly, a classical representation of the QM subsystem in terms of atom-centered multipoles. This auxiliary representation is used for all polarization interactions between QM and MM, allowing us to treat them on the same footing as in AMOEBA. We validate our method in tests of solute-solvent interaction energies, for neutral and charged molecules, demonstrating the simultaneous optimization of the quantum and classical degrees of freedom. Encouragingly, we find that the inclusion of explicit polarization in the MM part of QM/MM improves the agreement with fully QM calculations. PMID- 27782641 TI - Torsion and vibration-torsion levels of the S1 and ground cation electronic states of para-fluorotoluene. AB - We investigate the low-energy transitions (0-570 cm-1) of the S1 state of para fluorotoluene (pFT) using a combination of resonance-enhanced multiphoton ionization and zero-kinetic-energy (ZEKE) spectroscopy and quantum chemical calculations. By using various S1 states as intermediate levels, we obtain ZEKE spectra. The differing activity observed allows detailed assignments to be made of both the cation and S1 low-energy levels. The assignments are in line with the recently published work on toluene from the Lawrance group [J. R. Gascooke et al., J. Chem. Phys. 143, 044313 (2015)], which considered vibration-torsion coupling in depth for the S1 state of toluene. In addition, we investigate whether two bands that occur in the range 390-420 cm-1 are the result of a Fermi resonance; we present evidence for weak coupling between various vibrations and torsions that contribute to this region. This work has led to the identification of a number of misassignments in the literature, and these are corrected. PMID- 27782642 TI - Influence of Marangoni flows on the dynamics of isothermal A + B -> C reaction fronts. AB - The nonlinear dynamics of A + B -> C fronts is analyzed both numerically and theoretically in the presence of Marangoni flows, i.e., convective motions driven by surface tension gradients. We consider horizontal aqueous solutions where the three species A, B, and C can affect the surface tension of the solution, thereby driving Marangoni flows. The resulting dynamics is studied by numerically integrating the incompressible Navier-Stokes equations coupled to reaction diffusion-convection (RDC) equations for the three chemical species. We show that the dynamics of the front cannot be predicted solely on the basis of the one dimensional reaction-diffusion profiles as is the case for buoyancy-driven convection around such fronts. We relate this observation to the structure of Marangoni flows which lead to more complex and exotic dynamics. We find in particular the surprising possibility of a reversal of the front propagation direction in time for some sets of Marangoni numbers, quantifying the influence of each chemical species concentration on the solution surface tension. We explain this reversal analytically and propose a new classification of the convective effects on A + B -> C reaction fronts as a function of the Marangoni numbers. The influence of the layer thickness on the RDC dynamics is also presented. Those results emphasize the importance of flow symmetry properties when studying convective front dynamics in a given geometry. PMID- 27782643 TI - The role of the cationic Pt sites in the adsorption properties of water and ethanol on the Pt4/Pt(111) and Pt4/CeO2(111) substrates: A density functional theory investigation. AB - Finite site platinum particles, Ptn, supported on reduced or unreduced cerium oxide surfaces, i.e., CeO2-x(111) (0 0, the protons are expelled away from the film, leading to an increase in alpha. In particular, in the range 0 < sigmam < eGamma0, self-regulation occurs to realize alpha ? sigmam/eGamma0 for n0 ? nc, where nc is 0.01 mol/L for silica surfaces and is 2 * 10-5 mol/L for carboxyl bearing surfaces. We also examine the charge regulation with decreasing the cell thickness H below the Debye length kappa-1, where a crossover occurs at the Gouy Chapman length. In particular, when sigmam ~ eGamma0 and H ? kappa-1, the surface charges remain only partially screened by ions, leading to a nonvanishing electric field in the interior. PMID- 27782650 TI - Accelerating potential of mean force calculations for lipid membrane permeation: System size, reaction coordinate, solute-solute distance, and cutoffs. AB - Molecular dynamics simulations are capable of predicting the permeability of lipid membranes for drug-like solutes, but the calculations have remained prohibitively expensive for high-throughput studies. Here, we analyze simple measures for accelerating potential of mean force (PMF) calculations of membrane permeation, namely, (i) using smaller simulation systems, (ii) simulating multiple solutes per system, and (iii) using shorter cutoffs for the Lennard Jones interactions. We find that PMFs for membrane permeation are remarkably robust against alterations of such parameters, suggesting that accurate PMF calculations are possible at strongly reduced computational cost. In addition, we evaluated the influence of the definition of the membrane center of mass (COM), used to define the transmembrane reaction coordinate. Membrane-COM definitions based on all lipid atoms lead to artifacts due to undulations and, consequently, to PMFs dependent on membrane size. In contrast, COM definitions based on a cylinder around the solute lead to size-independent PMFs, down to systems of only 16 lipids per monolayer. In summary, compared to popular setups that simulate a single solute in a membrane of 128 lipids with a Lennard-Jones cutoff of 1.2 nm, the measures applied here yield a speedup in sampling by factor of ~40, without reducing the accuracy of the calculated PMF. PMID- 27782654 TI - Two-color vibrational, femtosecond, fully resonant electronically enhanced CARS (FREE-CARS) of gas-phase nitric oxide. AB - A resonantly enhanced, two-color, femtosecond time-resolved coherent anti-Stokes Raman scattering (CARS) approach is demonstrated and used to explore the nature of the frequency- and time-dependent signals produced by gas-phase nitric oxide (NO). Through careful selection of the input pulse wavelengths, this fully resonant electronically enhanced CARS (FREE-CARS) scheme allows rovibronic-state resolved observation of time-dependent rovibrational wavepackets propagating on the vibrationally excited ground-state potential energy surface of this diatomic species. Despite the use of broadband, ultrafast time-resolved input pulses, high spectral resolution of gas-phase rovibronic transitions is observed in the FREE CARS signal, dictated by the electronic dephasing timescales of these states. Analysis and computational simulation of the time-dependent spectra observed as a function of pump-Stokes and Stokes-probe delays provide insight into the rotationally resolved wavepacket motion observed on the excited-state and vibrationally excited ground-state potential energy surfaces of NO, respectively. PMID- 27782655 TI - Nonlocal electrostatics in ionic liquids: The key to an understanding of the screening decay length and screened interactions. AB - Screened electrostatic interactions in ionic liquids are investigated by means of exact statistical mechanical analysis combined with physical arguments that enhance the transparency and conceptual accessibility of the analysis and results. The constituent ions and immersed particles in the liquid can have arbitrary shapes and any internal charge distributions. The decay of the screened electrostatic potential and the free energy of interaction in ionic liquids can be exponentially damped oscillatory (like in molten simple salts) as well as plain exponential and long-ranged (like in dilute electrolyte solutions). Both behaviors are in agreement with the exact statistical mechanical analysis and reasons for their appearances are investigated. Exact but surprisingly simple expressions for the decay parameter kappa of the screened electrostatics are obtained, which replace the classical expression for the Debye-Huckel parameter kappaDH (the reciprocal Debye length). The expressions are applicable both for cases with plain exponential and oscillatory behaviors. The key importance of nonlocal electrostatics is thereby demonstrated explicitly. Dielectric properties of ionic liquids and other electrolytes are investigated, in particular the static dielectric function epsilon(k) and some effective relative permittivities (Ereff and Er*), which take roles that the dielectric constant epsilonr has for polar liquids consisting of electroneutral molecules. The dielectric constant in the latter case, which is the limit of epsilon(k) when the wave number k -> 0, can be expressed solely in terms of dipolar features of the molecules. In contrast to this, the effective dielectric permittivities of ionic liquids have contributions also from quadrupolar, octupolar, and higher multipolar features of the constituent ions. The "dielectric constant" of electrolytes does not exist since epsilon(k)->infinity when k -> 0, a well-known effect of perfect screening. The effective relative permittivities, Ereff, and Er* of ionic liquids are obtained from the non-diverging part of epsilon(k), but not as a k -> 0 limit. Influences of ion associations, especially pairing, are investigated for screened electrostatics and these permittivities. A general, multipolar expansion of epsilon(k) is derived and used to analyze dielectric properties of ionic liquids and other electrolytes. PMID- 27782656 TI - Diffusion quantum Monte Carlo study of martensitic phase transition energetics: The case of phosphorene. AB - Recent technical advances in dealing with finite-size errors make quantum Monte Carlo methods quite appealing for treating extended systems in electronic structure calculations, especially when commonly used density functional theory (DFT) methods might not be satisfactory. We present a theoretical study of martensitic phase transition energetics of a two-dimensional phosphorene by employing diffusion Monte Carlo (DMC) approach. The DMC calculation supports DFT prediction of having a rather diffusive barrier that is characterized by having two transition states, in addition to confirming that the so-called black and blue phases of phosphorene are essentially degenerate. At the same time, the DFT calculations do not provide the quantitative accuracy in describing the energy changes for the martensitic phase transition even when hybrid exchange correlation functional is employed. We also discuss how mechanical strain influences the stabilities of the two phases of phosphorene. PMID- 27782657 TI - Temperature and pressure dependence of the interfacial free energy against a hard surface in contact with water and decane. AB - Theoretical descriptions of molecular-scale solvation frequently invoke contributions proportional to the solvent exposed area, under the tacit expectation that those contributions are tied to a surface tension for macroscopic surfaces. Here we examine the application of revised scaled-particle theory (RSPT) to extrapolate molecular simulation results for the wetting of molecular-to-meso-scale repulsive solutes in liquid water and decane to determine the interfacial free energies of hard, flat surfaces. We show that the RSPT yields interfacial free energies at ambient pressures that are consistently greater than that obtained from the liquid-vapor surface tensions of water and decane by ~4%. Nevertheless, the hard surface and liquid-vapor interfacial free energies are parallel over a broad temperature range at 1 bar indicating similar entropic contributions. With increasing pressure, the hard, flat interfacial free energies exhibit a maximum in the vicinity of ~1000 bars. This non-monotonic behavior in both water and decane reflects solvent dewetting at low pressures, followed by wetting at higher pressures as the solvents are pushed onto the solute. By comparing the results of RSPT against classic scaled-particle theory (CSPT), we show that CSPT systematically predicts greater entropic penalties for interface formation and makes inconsistent predictions between the pressure dependence of the interfacial free energy and solvent contact density with the solute surface. PMID- 27782658 TI - Factorization and recomposition of molecular wave functions. AB - Some situations in the determination of molecular wave functions require to go beyond the Born-Oppenheimer (BO) approximation, with the wave function written as the product of an electronic wave function depending parametrically on the nuclear coordinates and a nuclear wave function. Such situations are usually treated by combining BO products. This form of the wave function leads to coupled equations which determine the nuclear factors of these products. There is another possibility: writing the exact molecular wave function as a single product having formally the same structure as a BO product. This approach has been at the origin of recent developments. We reconsider this problem with the aim of looking at the solutions of the coupled equations which determine the electronic factor of the factorization scheme. It is shown that these coupled equations can be reduced precisely to those encountered with the usual combination of diabatic BO products. PMID- 27782659 TI - Automatic parametrization of non-polar implicit solvent models for the blind prediction of solvation free energies. AB - In this work, a systematic protocol is proposed to automatically parametrize the non-polar part of implicit solvent models with polar and non-polar components. The proposed protocol utilizes either the classical Poisson model or the Kohn Sham density functional theory based polarizable Poisson model for modeling polar solvation free energies. Four sets of radius parameters are combined with four sets of charge force fields to arrive at a total of 16 different parametrizations for the polar component. For the non-polar component, either the standard model of surface area, molecular volume, and van der Waals interactions or a model with atomic surface areas and molecular volume is employed. To automatically parametrize a non-polar model, we develop scoring and ranking algorithms to classify solute molecules. The their non-polar parametrization is obtained based on the assumption that similar molecules have similar parametrizations. A large database with 668 experimental data is collected and employed to validate the proposed protocol. The lowest leave-one-out root mean square (RMS) error for the database is 1.33 kcal/mol. Additionally, five subsets of the database, i.e., SAMPL0-SAMPL4, are employed to further demonstrate that the proposed protocol. The optimal RMS errors are 0.93, 2.82, 1.90, 0.78, and 1.03 kcal/mol, respectively, for SAMPL0, SAMPL1, SAMPL2, SAMPL3, and SAMPL4 test sets. The corresponding RMS errors for the polarizable Poisson model with the Amber Bondi radii are 0.93, 2.89, 1.90, 1.16, and 1.07 kcal/mol, respectively. PMID- 27782660 TI - The shell model for the exchange-correlation hole in the strong-correlation limit. AB - We present a model for the exchange-correlation hole and the exchange-correlation energy in the strong-correlation (SC) limit of density functional theory. The SC limit is useful in the construction of exchange-correlation functionals through interpolation of the adiabatic connection. The new approximation (referred to as shell model) is an improvement of the non-local radius (NLR) model recently proposed by Wagner and Gori-Giorgi [Phys. Rev. A 90, 052512 (2014)]. The NLR model does not correctly reproduce the limit of the strongly correlated homogeneous electron gas and this shortcoming is remedied by the shell model. As in the case of the NLR model, the spherically averaged electron density rho(r,u)=?dOmegau4pirho(r+u) is the starting point for the construction of the shell model and it is also its computational bottleneck. We show how rho(r, u), the NLR, and the shell model can be implemented efficiently. For this purpose, analytical integrals for the normalization and the energy density of the underlying holes are provided. Employing the shell model, we illustrate how improved adiabatic connection interpolations can be constructed. PMID- 27782661 TI - Simulation of entangled polymer solutions. AB - We present a computer simulation of entangled polymer solutions at equilibrium. The chains repel each other via a soft Gaussian potential, appropriate for semi dilute solutions at the scale of a correlation blob. The key innovation to suppress chain crossings is to use a pseudo-continuous model of a backbone which effectively leaves no gaps between consecutive points on the chain, unlike the usual bead-and-spring model. Our algorithm is sufficiently fast to observe the entangled regime using a standard desktop computer. The simulated structural and mechanical correlations are in fair agreement with the expected predictions for a semi-dilute solution of entangled chains. PMID- 27782662 TI - Theory of optical transitions in curved chromophores. AB - Using first order perturbation theory in the Born-Oppenheimer regime of the Frenkel-Holstein model, we develop a theory for the optical transitions in curved chromophores of pi-conjugated polymers. Our key results are that for absorption, A, and emission, I, polarized parallel to the 0-0 transition, I01/I00 ? A01/A00 = S(N), where S(N) = S(1)/IPR is the effective Huang-Rhys parameter for a chromophore of N monomers and IPR is the inverse participation ratio. In contrast, absorption and emission polarized perpendicular to the 0-0 transition acquires vibronic intensity via the Herzberg-Teller effect. This intensity generally increases as the curvature increases and consequently I01/I00 increases (where I01 is the total 0-1 emission intensity). This effect is enhanced for long chromophores and in the anti-adiabatic regime. We show via DMRG calculations that this theory works well in the adiabatic regime relevant to pi-conjugated polymers, i.e., h omega/|J| ? 0.2. PMID- 27782664 TI - Chemically driven fluid transport in long microchannels. AB - Chemical gradients maintained along surfaces can drive fluid flows by diffusio osmosis, which become significant at micro- and nano-scales. Here, by means of mesoscopic simulations, we show that a concentration drop across microchannels with periodically inhomogeneous boundary walls can laterally transport fluids over arbitrarily long distances along the microchannel. The driving field is the secondary local chemical gradient parallel to the channel induced by the periodic inhomogeneity of the channel wall. The flow velocity depends on the concentration drop across the channel and the structure and composition of the channel walls, but it is independent of the overall channel length. Our work thus presents new insight into the fluid transport in long microchannels commonly found in nature and is useful for designing novel micro- or nano-fluidic pumps. PMID- 27782663 TI - Carbon membranes for efficient water-ethanol separation. AB - We demonstrate, on the basis of molecular dynamics simulations, the possibility of an efficient water-ethanol separation using nanoporous carbon membranes, namely, carbon nanotube membranes, nanoporous graphene sheets, and multilayer graphene membranes. While these carbon membranes are in general permeable to both pure liquids, they exhibit a counter-intuitive "self-semi-permeability" to water in the presence of water-ethanol mixtures. This originates in a preferred ethanol adsorption in nanoconfinement that prevents water molecules from entering the carbon nanopores. An osmotic pressure is accordingly expressed across the carbon membranes for the water-ethanol mixture, which agrees with the classic van't Hoff type expression. This suggests a robust and versatile membrane-based separation, built on a pressure-driven reverse-osmosis process across these carbon-based membranes. In particular, the recent development of large-scale "graphene-oxide" like membranes then opens an avenue for a versatile and efficient ethanol dehydration using this separation process, with possible application for bio ethanol fabrication. PMID- 27782665 TI - Structural and spectroscopic characterization of methyl isocyanate, methyl cyanate, methyl fulminate, and acetonitrile N-oxide using highly correlated ab initio methods. AB - Various astrophysical relevant molecules obeying the empirical formula C2H3NO are characterized using explicitly correlated coupled cluster methods (CCSD(T)-F12). Rotational and rovibrational parameters are provided for four isomers: methyl isocyanate (CH3NCO), methyl cyanate (CH3OCN), methyl fulminate (CH3ONC), and acetonitrile N-oxide (CH3CNO). A CH3CON transition state is inspected. A variational procedure is employed to explore the far infrared region because some species present non-rigidity. Second order perturbation theory is used for the determination of anharmonic frequencies, rovibrational constants, and to predict Fermi resonances. Three species, methyl cyanate, methyl fulminate, and CH3CON, show a unique methyl torsion hindered by energy barriers. In methyl isocyanate, the methyl group barrier is so low that the internal top can be considered a free rotor. On the other hand, acetonitrile N-oxide presents a linear skeleton, C3v symmetry, and free internal rotation. Its equilibrium geometry depends strongly on electron correlation. The remaining isomers present a bend skeleton. Divergences between theoretical rotational constants and previous parameters fitted from observed lines for methyl isocyanate are discussed on the basis of the relevant rovibrational interaction and the quasi-linearity of the molecular skeleton. PMID- 27782666 TI - Molecular spin on surface: From strong correlation to dispersion interactions. AB - A reliable prediction of magnetic properties of surface-supported molecules containing 3d/4f spin carriers has challenged the electronic structure theory for decades. Here we tackle this problem with Hubbard-U corrected van der Waals density functional (vdW-DF), incorporating strong correlation effects of the localized electrons and dispersion interactions involved in the molecule-surface binding. By fitting the spin state energetics of a series of Fe(ii) compounds with varying ligand field strength, we find that the optimal U value for vdW-DF is much smaller than that for the local density approximation (LDA) while quite similar to that for the generalized gradient approximation (GGA). We show that although vdW-DF+U overestimates largely the metal-ligand bond distance, the predicted adiabatic high-spin-low-spin energy splitting DeltaEHL is only slightly changed with respect to that obtained using the LDA+U geometries consistent with experiment. Then we use Cu(111)-supported metallocene (M(C5H5)2, M = Fe, and Co) as a prototype example to explore the effects of the molecule-surface interactions. We show that the non-local dispersion interactions, poorly described by LDA and GGA while reasonably captured by vdW-DF, are critical for reproducing DeltaEHL at large molecule-surface distances. Besides, we find that DeltaEHL is decreased by the molecule-metal contact, which is shown to weaken the local ligand field around the magnetic center. PMID- 27782667 TI - New Raman measurements for H2O ice VII in the range of 300 cm-1 to 4000 cm-1 at pressures up to 120 GPa. AB - Raman spectroscopic measurements for H2O ice VII have been conducted to 120 GPa at 300 K in the spectroscopic range of 300-4000 cm-1. Both moissanite and diamond anvils were used for the experiments. This overcomes the problems of overlapping spectra between the diamond anvil and sample, which had prevented the observation of the stretching modes at pressures higher than ~23 GPa in all previous measurements. The new results reveal many bands which have not been reported before. The pressure dependences of the Raman modes show anomalous changes at 13 15, ~27, ~44, ~60, and 90 GPa, implying possible structural changes at these pressures. The new results demonstrate that the predicted symmetric hydrogen bond phase X transition does not occur below 120 GPa. PMID- 27782668 TI - A highly accurate and efficient algorithm for electrostatic interactions of charged particles confined by parallel metallic plates. AB - We present an accurate and efficient algorithm to calculate the electrostatic interaction of charged point particles with partially periodic boundary conditions that are confined along the non-periodic direction by two parallel metallic plates. The method preserves the original boundary conditions, leading to an exact solution of the problem. In addition, the scaling complexity is quasilinear O(Nln(N)), where N is the number of particles in the simulation box. Based on the superposition principle in electrostatics, the problem is split into two electrostatic problems where each can be calculated by the appropriate Poisson solver. The method is applied to NaCl ultra-thin films where its dielectric response with respect to an external bias voltage is investigated. Furthermore, the total charge induced on the metallic boundaries can be calculated to an arbitrary precision. PMID- 27782669 TI - Vapour-liquid coexistence of an active Lennard-Jones fluid. AB - We study a three-dimensional system of self-propelled Lennard-Jones particles using Brownian dynamics simulations. Using recent theoretical results for active matter, we calculate the pressure and report equations of state for the system. Additionally, we chart the vapour-liquid coexistence and show that the coexistence densities can be well described using simple power laws. Lastly, we demonstrate that our out-of-equilibrium system shows deviations from both the law of rectilinear diameters and the law of corresponding states. PMID- 27782671 TI - Ripening kinetics of bubbles: A molecular dynamics study. AB - The ripening kinetics of bubbles is studied by performing molecular dynamics simulations. From the time evolution of a system, the growth rates of individual bubbles are determined. At low temperatures, the system exhibits a t1/2 law and the growth rate is well described by classical Lifshitz-Slyozov-Wagner (LSW) theory for the reaction-limited case. This is direct evidence that the bubble coarsening at low temperatures is reaction-limited. At high temperatures, although the system exhibits a t1/3 law, which suggests that it is diffusion limited, the accuracy of the growth rate is insufficient to determine whether the form is consistent with the prediction of LSW theory for the diffusion-limited case. The gas volume fraction dependence of the coarsening behavior is also studied. Although the behavior of the system at low temperatures has little sensitivity to the gas volume fraction up to 10%, at high temperatures it deviates from the prediction of LSW theory for the diffusion-limited case as the gas volume fraction increases. These results show that the mean-field-like treatment is valid for a reaction-limited system even with a finite volume fraction, while it becomes inappropriate for a diffusion-limited system since classical LSW theory for the diffusion-limited case is valid at the dilute limit. PMID- 27782670 TI - Communication: Role of explicit water models in the helix folding/unfolding processes. AB - In the last years, it has become evident that computer simulations can assume a relevant role in modelling protein dynamical motions for their ability to provide a full atomistic image of the processes under investigation. The ability of the current protein force-fields in reproducing the correct thermodynamics and kinetics systems behaviour is thus an essential ingredient to improve our understanding of many relevant biological functionalities. In this work, employing the last developments of the metadynamics framework, we compare the ability of state-of-the-art all-atom empirical functions and water models to consistently reproduce the folding and unfolding of a helix turn motif in a model peptide. This theoretical study puts in evidence that the choice of the water models can influence the thermodynamic and the kinetics of the system under investigation, and for this reason cannot be considered trivial. PMID- 27782672 TI - State-resolved dynamics study of the H + HS reaction on the 3A' and 3A" states with time-dependent quantum wave packet method. AB - The quantum dynamics calculations of the H + HS (v = 0, j = 0) reaction on the 3A' and 3A" potential energy surfaces (PESs) are performed using the reactant coordinate based time-dependent wave packet method. State-averaged and state resolved results for both channels of the title reaction are presented in the 0.02-1.0 eV collision energy range and compared with those carried out with quasi classical trajectory (QCT) method. Total integral cross sections (ICSs) for both channels are in excellent agreement with previous quantum mechanical (QM) Coriolis coupling results while poorly agree with the QCT ICSs of the exchange channel, particularly near the threshold energy region. The product rotational distributions show that for the abstraction channel, the agreement between our QM and the QCT results improves with increasing collision energy. For the exchange channel, our calculations predict colder rotational distributions as compared to those obtained by QCT calculations. Although the QM total differential cross sections (DCSs) are in qualitatively good agreement with the QCT results, the two sets of the state-to-state DCSs with several peaks exhibit great divergences. The origin of the divergences are traced by analyzing the QM DCS for the H + HS (v = 0, j = 0) -> H2 (v' = 0, j' = 0) + S reaction on the 3A" PES at Ec = 1.0 eV. It is discovered that several groups of J partial waves are involved in the reaction and the shape of the DCS is greatly altered by quantum interferences between them. PMID- 27782673 TI - Simultaneous specific heat, thermal conductivity and imaging evaluations in thin samples of 8CB liquid crystal dispersed with microemulsion of DDAB/water micelles. AB - In this work we use a photopyroelectric calorimetric set up to analyze the transformations occurring in thin samples of liquid crystal-microemulsion system by combining the results of the simultaneously performed high temperature resolution polarization microscopy observations and the temperature dependence of the specific heat, and of the thermal conductivity. This enabled an accurate direct correlation of the observations concerning the different measured quantities for a most comprehensive interpretation of the obtained results. It is found that the I-N conversion progresses in the entire nematic range because of the micelles expelled from the nucleating nematic volumes remaining confined in the residual isotropic material. A hysteretic behavior is observed in the nematic range between cooling and heating run because of the different micelle content in the material during the cooling and heating runs. A moderate hysteresys also over the N-A transition indicated an additional material refinement from micelles during the transition. Finally in samples with different micelle concentration the same maximum micelle content is retained in the nematic and smectic phases. PMID- 27782674 TI - Can we approach the gas-liquid critical point using slab simulations of two coexisting phases? AB - In this paper, we demonstrate that it is possible to approach the gas-liquid critical point of the Lennard-Jones fluid by performing simulations in a slab geometry using a cut-off potential. In the slab simulation geometry, it is essential to apply an accurate tail correction to the potential energy, applied during the course of the simulation, to study the properties of states close to the critical point. Using the Janecek slab-based method developed for two-phase Monte Carlo simulations [J. Janecek, J. Chem. Phys. 131, 6264 (2006)], the coexisting densities and surface tension in the critical region are reported as a function of the cutoff distance in the intermolecular potential. The results obtained using slab simulations are compared with those obtained using grand canonical Monte Carlo simulations of isotropic systems and the finite-size scaling techniques. There is a good agreement between these two approaches. The two-phase simulations can be used in approaching the critical point for temperatures up to 0.97 TC* (T* = 1.26). The critical-point exponents describing the dependence of the density, surface tension, and interfacial thickness on the temperature are calculated near the critical point. PMID- 27782675 TI - Erratum: "Kinetic-energy matrix elements for atomic Hylleraas-CI wave functions" [J. Chem. Phys. 144, 204110 (2016)]. PMID- 27782676 TI - Ab initio molecular dynamics study of H-bonding and proton transfer in the phosphoric acid-N,N-Dimethylformamide system. AB - Car-Parrinello molecular dynamics simulations of phosphoric acid (H3PO4)-N,N dimethylformamide (DMF) mixtures over the whole composition range have been carried out. It has been found that the neutral molecules are the dominant species in this system. The concentration dependences of the average number of H bonds per proton acceptor atom in P=O and C=O groups as well as per proton donor atom in DMFH+ ions towards phosphate species have been discussed. The H-bonding between components in all investigated mixtures of H3PO4 and DMF is possible. A significant fraction of the protonated DMF forms appears at phosphoric acid mole fraction higher than 0.37, indicating a high probability of proton transfer from phosphate species to oxygen atoms in C=O groups. The intermolecular proton transfer between phosphate species themselves is mainly observed when xH3PO4 > 0.19. Satisfactory agreement with available experimental data for structural characteristics of the investigated system was obtained. PMID- 27782677 TI - A new approach to approximate equation-of-motion coupled cluster with triple excitations. AB - Accurate methods for excited, ionized, and electron-attached states are critical to the study of many chemical species such as reactive intermediates, radicals, and ionized systems. The equation-of-motion coupled cluster singles, doubles, and triples (EOM-CCSDT) family of methods is very accurate (roughly similar in accuracy as for CCSDT calculations of the ground state), but the computational cost scales iteratively as the eighth power of the system size. Many approximations already exist, although most either correct only the excited state or require an iterative ??(n7) procedure which can also be prohibitively expensive. In this paper, new methods, termed EOM-CCSD(T)(a) and EOM-CCSD(T)(a)*, are proposed which correct both the ground and excited states based on a shared effective Hamiltonian, and the latter of which includes only non-iterative corrections to both the CCSD and EOM-CCSD energies. These methods are found to significantly improve the description of excited and ionized potential energy surfaces, equilibrium geometries, and harmonic frequencies; the accuracy is very close to that of full EOM-CCSDT. PMID- 27782678 TI - Photoinduced intermolecular dynamics and subsequent fragmentation in VUV-ionized acetamide clusters. AB - Photofragmentation of small gas-phase acetamide clusters (CH3CONH2)n (n <= 10) produced by a supersonic expansion source has been studied using time-of-flight ion mass spectroscopy combined with tunable vacuum-ultraviolet (VUV) synchrotron radiation. Fragmentation channels of acetamide clusters under VUV photoionization resulting in protonated and ammoniated clusters formation were identified with the discussion about the preceding intramolecular rearrangements. Acetamide-2,2,2 d3 clusters were also studied in an experiment with a gas discharge lamp as a VUV light source; comparison with the main experiment gave insights into the mechanism of formation of protonated acetamide clusters, indicating that proton transfer from amino group plays a dominant role in that process. Geometry of the acetamide dimer was discussed and the most stable arrangement was concluded to be achieved when subunits of the dimer are connected via two N-H?O -C hydrogen bonds. Also, the influence of the photon energy on the stability of the clusters and their fragmentation channels has been examined. PMID- 27782679 TI - Infrared Stark and Zeeman spectroscopy of OH-CO: The entrance channel complex along the OH + CO -> trans-HOCO reaction pathway. AB - Sequential capture of OH and CO by superfluid helium droplets leads exclusively to the formation of the linear, entrance-channel complex, OH-CO. This species is characterized by infrared laser Stark and Zeeman spectroscopy via measurements of the fundamental OH stretching vibration. Experimental dipole moments are in disagreement with ab initio calculations at the equilibrium geometry, indicating large-amplitude motion on the ground state potential energy surface. Vibrational averaging along the hydroxyl bending coordinate recovers 80% of the observed deviation from the equilibrium dipole moment. Inhomogeneous line broadening in the zero-field spectrum is modeled with an effective Hamiltonian approach that aims to account for the anisotropic molecule-helium interaction potential that arises as the OH-CO complex is displaced from the center of the droplet. PMID- 27782680 TI - High-pressure behavior of bromine confined in the one-dimensional channels of zeolite AlPO4-5 single crystals. AB - We present a joint experimental and theoretical study on the high-pressure behavior of bromine confined in the one-dimensional (1D) nanochannels of zeolite AlPO4-5 (AFI) single crystals. Raman scattering experiments indicate that loading bromine into AFI single crystals can lead to the formation of bromine molecular chains inside the nanochannels of the crystals. High-pressure Raman and X-ray diffraction studies demonstrate that high pressure can increase the length of the confined bromine molecular chains and modify the inter- and intramolecular interactions of the molecules. The confined bromine shows a considerably different high-pressure behavior to that of bulk bromine. The pressure-elongated bromine molecular chains can be preserved when the pressure is reduced to ambient pressure. Theoretical simulations explain the experimental results obtained from the Raman spectroscopy and X-ray diffraction studies. Furthermore, we find that the intermolecular distance between confined bromine molecules gradually becomes comparable to the intramolecular bond length in bromine molecules upon compression. This may result in the dissociation of the bromine molecules and the formation of 1D bromine atomic chains at pressures above 24 GPa. Our study suggests that the unique nanoconfinement has a considerable effect on the high pressure behavior of bromine, and the confined bromine species concomitantly enhance the structural stability of the host AFI single crystals. PMID- 27782681 TI - A spectroscopic case for SPSi detection: The third-row in a single molecule. AB - In moving beyond the second row of the periodic table for molecules of astronomical and atmospheric significance, the exploration of sulfur and phosphorus chemistry is essential. Additionally, silicon is abundant in most astrophysical environments and is a major component of most rocky bodies. The triatomic molecule composed of each of these atoms is therefore a tantalizing candidate for spectroscopic characterization for astrophysical reasons as well as gaining further understanding into the chemical physics of molecules that are not carbon-based. The current work employs high-level quantum chemical techniques to provide new insights into this simplest of heterogeneous third-row atom systems. The fundamental vibrational frequencies are all within the 350-600 cm-1 range and do not demonstrate strong anharmonicities. These frequencies, rotational constants, vibrationally excited state spectroscopic data, and related isotopic substitution information produced will aid in laboratory experimentation and, even potentially, telescopic observation since modern instruments possess the power to resolve extremely fine details. PMID- 27782682 TI - Photoelectron spectroscopy of the hydroxymethoxide anion, H2C(OH)O. AB - We report the negative ion photoelectron spectroscopy of the hydroxymethoxide anion, H2C(OH)O-. The photoelectron spectra show that 3.49 eV photodetachment produces two distinct electronic states of the neutral hydroxymethoxy radical (H2C(OH)O?). The H2C(OH)O? ground state (X 2A) photoelectron spectrum exhibits a vibrational progression consisting primarily of the OCO symmetric and asymmetric stretches, the OCO bend, as well as combination bands involving these modes with other, lower frequency modes. A high-resolution photoelectron spectrum aids in the assignment of several vibrational frequencies of the neutral H2C(OH)O? radical, including an experimental determination of the H2C(OH)O? 2nu12 overtone of the H-OCO torsional vibration as 220(10) cm-1. The electron affinity of H2C(OH)O? is determined to be 2.220(2) eV. The low-lying A 2A excited state is also observed, with a spectrum that peaks ~0.8 eV above the X 2A state origin. The A 2A state photoelectron spectrum is a broad, partially resolved band. Quantum chemical calculations and photoelectron simulations aid in the interpretation of the photoelectron spectra. In addition, the gas phase acidity of methanediol is calculated to be 366(2) kcal mol-1, which results in an OH bond dissociation energy, D0(H2C(OH)O-H), of 104(2) kcal mol-1, using the experimentally determined electron affinity of the hydroxymethoxy radical. PMID- 27782683 TI - Local complete active space second-order perturbation theory using pair natural orbitals (PNO-CASPT2). AB - We present a CASPT2 method which exploits local approximations to achieve linear scaling of the computational effort with the molecular size, provided the active space is small and local. The inactive orbitals are localized, and the virtual space for each electron pair is spanned by a domain of pair-natural orbitals (PNOs). The configuration space is internally contracted, and the PNOs are defined for uniquely defined orthogonal pairs. Distant pair energies are obtained by multipole approximations, so that the number of configurations that are explicitly treated in the CASPT2 scales linearly with molecular size (assuming a constant active space). The PNOs are generated using approximate amplitudes obtained in a pair-specific semi-canonical basis of projected atomic orbitals (PAOs). The evaluation and transformation of the two-electron integrals use the same parallel local density fitting techniques as recently described for linear scaling PNO-LMP2 (local second-order Moller-Plesset perturbation theory). The implementation of the amplitude equations, which are solved iteratively, employs the local integrated tensor framework. The efficiency and accuracy of the method are tested for excitation energies and correlation energies. It is demonstrated that the errors introduced by the local approximations are very small. They can be well controlled by few parameters for the distant pair approximation, initial PAO domains, and the PNO domains. PMID- 27782684 TI - Technical Note: An oversampling procedure to calculate the MTF of an imaging system from a bar-pattern image. AB - PURPOSE: Line-pair resolution phantoms are used to determine the spatial resolution of medical imaging systems. In some cases, these phantoms are used to determine the maximum number of line-pairs per mm that the system can resolve. In other cases, a numerical determination of the modulation transfer function (MTF) is carried out by means of the analysis of the variance of ROIs on the image. In this note, a new procedure is implemented to calculate the presampled MTF of an imaging system. METHODS: Images of a commercial line-pair phantom are acquired in a flat panel detector. After applying an edge detector and a Radon transform to the image, the direction of the bars in the phantom is calculated. Then, an area of the image that excludes the ends of the bars is determined. Every pixel in this area is used to obtain an oversampled profile on which the MTF is calculated. Every group of line-pairs conforms a periodic wave on this profile. Each of these waves is the output of the system for a square wave input with the same frequency. After extracting a wave, the MTF value for its frequency is calculated as the ratio of its first odd harmonic to the first odd harmonic of the square wave input. The amplitude of this square wave is obtained from two uniform areas on the phantom image. RESULTS: The results obtained are compared to those obtained following the standard edge method, as recommended by the IEC, and show a very good agreement between both methods, in both main directions of the detector and all the dose ranges analyzed. CONCLUSIONS: The presented method is shown accurate and can be used to extend the conventional use of line-pair phantoms in conventional radiology. PMID- 27782685 TI - Coronary artery analysis: Computer-assisted selection of best-quality segments in multiple-phase coronary CT angiography. AB - PURPOSE: The authors are developing an automated method to identify the best quality coronary arterial segment from multiple-phase coronary CT angiography (cCTA) acquisitions, which may be used by either interpreting physicians or computer-aided detection systems to optimally and efficiently utilize the diagnostic information available in multiple-phase cCTA for the detection of coronary artery disease. METHODS: After initialization with a manually identified seed point, each coronary artery tree is automatically extracted from multiple cCTA phases using our multiscale coronary artery response enhancement and 3D rolling balloon region growing vessel segmentation and tracking method. The coronary artery trees from multiple phases are then aligned by a global registration using an affine transformation with quadratic terms and nonlinear simplex optimization, followed by a local registration using a cubic B-spline method with fast localized optimization. The corresponding coronary arteries among the available phases are identified using a recursive coronary segment matching method. Each of the identified vessel segments is transformed by the curved planar reformation (CPR) method. Four features are extracted from each corresponding segment as quality indicators in the original computed tomography volume and the straightened CPR volume, and each quality indicator is used as a voting classifier for the arterial segment. A weighted voting ensemble (WVE) classifier is designed to combine the votes of the four voting classifiers for each corresponding segment. The segment with the highest WVE vote is then selected as the best-quality segment. In this study, the training and test sets consisted of 6 and 20 cCTA cases, respectively, each with 6 phases, containing a total of 156 cCTA volumes and 312 coronary artery trees. An observer preference study was also conducted with one expert cardiothoracic radiologist and four nonradiologist readers to visually rank vessel segment quality. The performance of our automated method was evaluated by comparing the automatically identified best-quality segments identified by the computer to those selected by the observers. RESULTS: For the 20 test cases, 254 groups of corresponding vessel segments were identified after multiple phase registration and recursive matching. The AI-BQ segments agreed with the radiologist's top 2 ranked segments in 78.3% of the 254 groups (Cohen's kappa 0.60), and with the 4 nonradiologist observers in 76.8%, 84.3%, 83.9%, and 85.8% of the 254 groups. In addition, 89.4% of the AI-BQ segments agreed with at least two observers' top 2 rankings, and 96.5% agreed with at least one observer's top 2 rankings. In comparison, agreement between the four observers' top ranked segment and the radiologist's top 2 ranked segments were 79.9%, 80.7%, 82.3%, and 76.8%, respectively, with kappa values ranging from 0.56 to 0.68. CONCLUSIONS: The performance of our automated method for selecting the best-quality coronary segments from a multiple phase cCTA acquisition was comparable to the selection made by human observers. This study demonstrates the potential usefulness of the automated method in clinical practice, enabling interpreting physicians to fully utilize the best available information in cCTA for diagnosis of coronary disease, without requiring manual search through the multiple phases and minimizing the variability in image phase selection for evaluation of coronary artery segments across the diversity of human readers with variations in expertise. PMID- 27782687 TI - Assessing task performance in FFDM, DBT, and synthetic mammography using uniform and anthropomorphic physical phantoms. AB - PURPOSE: The purpose of this study is to quantify the differences in detectability between full field digital mammography (FFDM), digital breast tomosynthesis (DBT), and synthetic mammography (SM) for challenging, low contrast signals, in the context of both a uniform and an anthropomorphic, textured phantom. METHODS: Images of the phantoms were acquired using a Hologic Selenia Dimensions system. Images were taken at 50%, 100%, and 200% of the dose delivered under automatic exposure control (AEC). Low-contrast disks, created using an inkjet printer with iodine-doped ink, were inserted into the phantom. The disks varied in diameter from 210 to 630 MUm, and in local contrast from 1.1% to 2.8% in regular increments. Human observers located the disks in a 4 alternative forced choice experiment. Proportion correct (PC) was computed as the number of correct localizations out of the total number of tries. RESULTS: Overall, scores from FFDM and DBT were consistently greater than scores from SM. At an exposure corresponding to the AEC setting, mean PC scores for the largest disks with the uniform phantom were 0.80 for FFDM, 0.83 for DBT, and 0.66 for SM, with the same rank ordering at other doses. Scores were similar but lower for the nonuniform background. At an exposure twice the AEC setting, however, the difference between uniform and nonuniform scores was most pronounced for DBT alone. Differences between scores for FFDM and SM were statistically significant, while those between FFDM and DBT were not. Scores were used to compute the minimum contrast level needed to reach 62.5% detection rate. The minimum contrast for SM was 36% 81% higher compared to FFDM or DBT, in either background. CONCLUSIONS: This study shows that an anthropomorphic phantom and lesions inserts may be used to conduct a reader study. Detectability was significantly lower for synthetic mammography than for FFDM or DBT, for all conditions. Additionally, observer performance was consistently lower for the anthropomorphic phantom, indicating the greater challenge due to anatomical background. Because of this, it may be important to use realistic phantoms in observer studies in order to draw conclusions that are more clinically relevant. PMID- 27782686 TI - Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz. AB - PURPOSE: Ultrasound neuromodulation is a promising noninvasive technique for controlling neural activity. Previous small animal studies suffered from low targeting specificity because of the low ultrasound frequencies (<690 kHz) used. In this study, the authors demonstrated the capability of focused ultrasound (FUS) neuromodulation in the megahertz-range to achieve superior targeting specificity in the murine brain as well as demonstrate modulation of both motor and sensory responses. METHODS: FUS sonications were carried out at 1.9 MHz with 50% duty cycle, pulse repetition frequency of 1 kHz, and duration of 1 s. The robustness of the FUS neuromodulation was assessed first in sensorimotor cortex, where elicited motor activities were observed and recorded on videos and electromyography. Deeper brain regions were then targeted where pupillary dilation served as an indicative of successful modulation of subcortical brain structures. RESULTS: Contralateral and ipsilateral movements of the hind limbs were repeatedly observed when the FUS was targeted at the sensorimotor cortex. Induced trunk and tail movements were also observed at different coordinates inside the sensorimotor cortex. At deeper targeted-structures, FUS induced eyeball movements (superior colliculus) and pupillary dilation (pretectal nucleus, locus coeruleus, and hippocampus). Histological analysis revealed no tissue damage associated with the FUS sonications. CONCLUSIONS: The motor movements and pupillary dilation observed in this study demonstrate the capability of FUS to modulate cortical and subcortical brain structures without inducing any damage. The variety of responses observed here demonstrates the capability of FUS to perform functional brain mapping. PMID- 27782688 TI - Continuous leaf optimization for IMRT leaf sequencing. AB - PURPOSE: Conventional step-and-shoot intensity modulated radiation therapy leaf sequencing methods, where a nonhomogeneous fluence map is converted to a set of apertures and associated intensities, assume that target fluence is stratified into a fixed number of discrete levels and/or aperture leaf positions are restricted to a discrete set of locations. These assumptions induce a deviation from the planned fluence map and/or reduce the feasible region of potential plans, respectively. A continuous leaf optimization (CLO) framework is developed as a postprocessing methodology to improve upon conventional leaf sequencing so that the resulting plan avoids these two main drawbacks. METHODS: The CLO model directly represents leaf positions and aperture intensities with continuous variables with the goal of reproducing some target fluence profile. Fluence through leaf edges is modeled using the error function, and continuous fluence is approximated using a 0.1 mm discretization across the aperture opening. Conventional leaf sequencing methods provide feasible solutions to the CLO model, and a first-order descent algorithm is used to converge onto a locally optimal solution. RESULTS: As a proof-of-concept, the authors test this framework on 1D (single leaf pair) fluence maps. The CLO model was applied to conventional leaf sequencing and direct aperture optimization solutions. Consistent improvements to existing leaf sequencing methods were found when tested on 232 generated instances of potential target fluence. In addition to improvements in matching the target fluence, the CLO model was able to keep MUs at similar values to the initial conventional sequence. CONCLUSIONS: The CLO model can improve upon existing leaf sequencing methods by avoiding the restrictions of fluence stratification and discretized leaf positions. This study lays the foundation for future models and solution methodologies that can incorporate continuous leaf positions explicitly into the treatment planning model. PMID- 27782689 TI - Online 4D ultrasound guidance for real-time motion compensation by MLC tracking. AB - PURPOSE: With the trend in radiotherapy moving toward dose escalation and hypofractionation, the need for highly accurate targeting increases. While MLC tracking is already being successfully used for motion compensation of moving targets in the prostate, current real-time target localization methods rely on repeated x-ray imaging and implanted fiducial markers or electromagnetic transponders rather than direct target visualization. In contrast, ultrasound imaging can yield volumetric data in real-time (3D + time = 4D) without ionizing radiation. The authors report the first results of combining these promising techniques-online 4D ultrasound guidance and MLC tracking-in a phantom. METHODS: A software framework for real-time target localization was installed directly on a 4D ultrasound station and used to detect a 2 mm spherical lead marker inside a water tank. The lead marker was rigidly attached to a motion stage programmed to reproduce nine characteristic tumor trajectories chosen from large databases (five prostate, four lung). The 3D marker position detected by ultrasound was transferred to a computer program for MLC tracking at a rate of 21.3 Hz and used for real-time MLC aperture adaption on a conventional linear accelerator. The tracking system latency was measured using sinusoidal trajectories and compensated for by applying a kernel density prediction algorithm for the lung traces. To measure geometric accuracy, static anterior and lateral conformal fields as well as a 358 degrees arc with a 10 cm circular aperture were delivered for each trajectory. The two-dimensional (2D) geometric tracking error was measured as the difference between marker position and MLC aperture center in continuously acquired portal images. For dosimetric evaluation, VMAT treatment plans with high and low modulation were delivered to a biplanar diode array dosimeter using the same trajectories. Dose measurements with and without MLC tracking were compared to a static reference dose using 3%/3 mm and 2%/2 mm gamma tests. RESULTS: The overall tracking system latency was 172 ms. The mean 2D root mean-square tracking error was 1.03 mm (0.80 mm prostate, 1.31 mm lung). MLC tracking improved the dose delivery in all cases with an overall reduction in the gamma-failure rate of 91.2% (3%/3 mm) and 89.9% (2%/2 mm) compared to no motion compensation. Low modulation VMAT plans had no (3%/3 mm) or minimal (2%/2 mm) residual gamma-failures while tracking reduced the gamma-failure rate from 17.4% to 2.8% (3%/3 mm) and from 33.9% to 6.5% (2%/2 mm) for plans with high modulation. CONCLUSIONS: Real-time 4D ultrasound tracking was successfully integrated with online MLC tracking for the first time. The developed framework showed an accuracy and latency comparable with other MLC tracking methods while holding the potential to measure and adapt to target motion, including rotation and deformation, noninvasively. PMID- 27782690 TI - Classification of breast lesions using segmented quantitative ultrasound maps of homodyned K distribution parameters. AB - PURPOSE: Statistical modeling of an ultrasound backscattered echo envelope is used for tissue characterization. However, in the presence of complex structures within the analyzed area, estimation of parameters is disturbed and unreliable, e.g., in the case of breast tumor classification. In order to improve the differentiation of breast lesions, the authors proposed a method based on the segmentation of homodyned K distribution parameter maps. Regions within lesions of different scattering properties were extracted and analyzed. In order to improve the classification, the best-performing features were selected from various regions and then combined. METHODS: A radio-frequency data set consisting of 103 breast lesions was used in the authors' analysis. Maps of homodyned K distribution parameters were created using an algorithm based on signal-to-noise ratio, kurtosis, and skewness of fractional-order envelope moments. A Markov random field model was used to segment parametric maps. Features of different segments were extracted and evaluated based on bootstrapping and the receiver operating characteristic curve. To determine the best-performing feature subset, the authors applied the joint mutual information criterion. RESULTS: It was found that there were individual features which performed better than the ones commonly used for lesion characterization, like the parameter obtained through averaging of values over the whole lesion. The authors selected and discussed the best performing features. Properties of different extracted regions were important and improved the distinction between benign and malignant tumors. The best performance was obtained by combining four features with the area under the receiver operating curve of 0.84. CONCLUSIONS: The study showed that the analysis of internal changes in lesion parametric maps leads to a better classification of breast tumors. The authors recommend combining multiple features for characterization, instead of using only one parameter, especially in the case of heterogeneous lesions. PMID- 27782691 TI - Technical Note: scuda: A software platform for cumulative dose assessment. AB - PURPOSE: Accurate tracking of anatomical changes and computation of actually delivered dose to the patient are critical for successful adaptive radiation therapy (ART). Additionally, efficient data management and fast processing are practically important for the adoption in clinic as ART involves a large amount of image and treatment data. The purpose of this study was to develop an accurate and efficient Software platform for CUmulative Dose Assessment (scuda) that can be seamlessly integrated into the clinical workflow. METHODS: scuda consists of deformable image registration (DIR), segmentation, dose computation modules, and a graphical user interface. It is connected to our image PACS and radiotherapy informatics databases from which it automatically queries/retrieves patient images, radiotherapy plan, beam data, and daily treatment information, thus providing an efficient and unified workflow. For accurate registration of the planning CT and daily CBCTs, the authors iteratively correct CBCT intensities by matching local intensity histograms during the DIR process. Contours of the target tumor and critical structures are then propagated from the planning CT to daily CBCTs using the computed deformations. The actual delivered daily dose is computed using the registered CT and patient setup information by a superposition/convolution algorithm, and accumulated using the computed deformation fields. Both DIR and dose computation modules are accelerated by a graphics processing unit. RESULTS: The cumulative dose computation process has been validated on 30 head and neck (HN) cancer cases, showing 3.5 +/- 5.0 Gy (mean+/-STD) absolute mean dose differences between the planned and the actually delivered doses in the parotid glands. On average, DIR, dose computation, and segmentation take 20 s/fraction and 17 min for a 35-fraction treatment including additional computation for dose accumulation. CONCLUSIONS: The authors developed a unified software platform that provides accurate and efficient monitoring of anatomical changes and computation of actually delivered dose to the patient, thus realizing an efficient cumulative dose computation workflow. Evaluation on HN cases demonstrated the utility of our platform for monitoring the treatment quality and detecting significant dosimetric variations that are keys to successful ART. PMID- 27782693 TI - Open access journals benefit authors from more affluent institutions. PMID- 27782692 TI - Interventional dual-energy imaging-Feasibility of rapid kV-switching on a C-arm CT system. AB - PURPOSE: In the last years, dual-energy CT imaging has shown clinical value, thanks to its ability to differentiate materials based on their atomic number and to exploit different properties of images acquired at two different energies. C arm CT systems are used to guide procedures in the interventional suite. Until now, there are no commercially available systems that employ dual-energy material decomposition. This paper explores the feasibility of implementing a fast kV switching technique on a clinically available angiographic system for acquiring dual-energy C-arm CT images. METHODS: As an initial proof of concept, a fast kV switching approach was implemented on an angiographic C-arm system and the peak tube voltage during 3D rotational scans was measured. The tube voltage measurements during fast kV-switching scans were compared to corresponding measurements on kV-constant scans. Additionally, to prove stability of the requested exposure parameters, the accuracy of the delivered tube current and pulse width were also recorded and compared. In a first phantom experiment, the voxel intensity values of the individual tube voltage components of the fast kV switching scans were compared to their corresponding kV-constant scans. The same phantom was used for a simple material decomposition between different iodine concentrations and pure water using a fast kV-switching protocol of 81 and 125 kV. In the last experiment, the same kV-switching protocol as in the phantom scan was used in an in vivo pig study to demonstrate the clinical feasibility. RESULTS: During rapid kV-switching acquisitions, the measured tube voltage of the x-ray tube during fast switching scans has an absolute deviation of 0.23 +/- 0.13 kV compared to the measured tube voltage produced during kV-constant acquisitions. The stability of the peak tube voltage over different scan requests was about 0.10 kV for the low and 0.46 for the high energy kV-switching scans and less than 0.1 kV for kV-constant scans, indicating slightly lower stability for kV-switching scans. The tube current resulted in a relative deviation of -1.6% for the low and 6.6% overestimation for the high tube voltage of the kV-switching scans compared to the kV-constant scans. The pulse width showed no deviation for the longer pulse width and only minor deviations (0.02 +/- 0.02 ms) for the shorter pulse widths compared to the kV-constant scans. The phantom experiment using different iodine concentrations showed an accurate correlation (R2 > 0.99) between the extracted intensity values in the kV-switching and kV-constant reconstructed volumes, and allows for an automatic differentiation between contrast concentration down to 10% (350 mg/ml iodine) and pure water under low noise conditions. Preliminary results of iodine and soft tissue separation showed also promising results in the first in vivo pig study. CONCLUSIONS: The feasibility of dual-energy imaging using a fast kV-switching method on an angiographic C-arm CT system was investigated. Direct measurements of beam quality in the x-ray field demonstrate the stability of the kV-switching method. Phantom and in vivo experiments showed that images did not deviate from those of corresponding kV-constant scans. All performed experiments confirmed the capability of performing fast kV-switching scans on a clinically available C-arm CT system. More complex material decomposition tasks and postprocessing steps will be part of future investigations. PMID- 27782694 TI - Technical assessment of a prototype cone-beam CT system for imaging of acute intracranial hemorrhage. AB - PURPOSE: A cone-beam CT scanner has been developed for detection and monitoring of traumatic brain injury and acute intracranial hemorrhage (ICH) at the point of care. This work presents a technical assessment of imaging performance and dose for the scanner in phantom and cadaver studies as a prerequisite to clinical translation. METHODS: The scanner incorporates a compact, rotating-anode x-ray source and a flat-panel detector (43 * 43 cm2) on a mobile U-arm gantry with source-axis distance = 550 mm and source-detector distance = 1000 mm. Central and peripheral doses were measured in 16 cm diameter CTDI phantoms using a 0.6 cm3 Farmer ionization chamber for various scan techniques and as a function of longitudinal position, including out of field. Spatial resolution, contrast, noise, and image uniformity were assessed in quantitative and anthropomorphic head phantoms. Two reconstruction protocols were evaluated, including filtered backprojection (FBP) for high-resolution bone imaging and penalized weighted least squares (PWLS) reconstruction for low-contrast soft tissue (ICH) visualization. A fresh cadaver was imaged with and without simulated ICH using the scanner as well as a diagnostic multidetector CT (MDCT) scanner using a standard head protocol. Images were interpreted by a fellowship-trained neuroradiologist for imaging tasks of ICH detection, gray-white-CSF differentiation, detection of midline shift, and fracture detection. RESULTS: The nominal scan protocol involved 720 projections acquired over a 360 degrees orbit at 100 kV and 216 mAs, giving a dose (weighted CTDI) of 22.8 mGy (~1.2 mSv effective dose). Out-of-field dose decreased to <10% within 6 cm of the field edge (approximate to the thyroid position). Image uniformity demonstrated <1% variation between the edge of the field (near the cranium) and center of the image. The high-resolution FBP reconstruction protocol showed ~0.9 mm point spread function (PSF) full-width at half-maximum (FWHM). The smooth PWLS reconstruction protocol yielded ~1.2 mm PSF FWHM and contrast-to-noise ratio exceeding 5.7 in ~50 HU spherical ICH, resulting in conspicuous depiction of ICH down to ~2 mm (the smallest diameter investigated). Cadaver images demonstrated good differentiation of brain and CSF (sufficient, but inferior to MDCT, recognizing that the CBCT dose was one-third that of MDCT), excellent visualization of cranial sutures and fracture (potentially superior to MDCT), clear detection of midline shift, and conspicuous detection of ICH. CONCLUSIONS: Technical assessment of the prototype demonstrates dose characteristics and imaging performance consistent with point-of-care detection and monitoring of head injury-most notably, conspicuous detection of ICH-and supports translation of the system to clinical studies. PMID- 27782695 TI - Reconstruction of multiple-pinhole micro-SPECT data using origin ensembles. AB - PURPOSE: The authors are currently developing a dual-resolution multiple-pinhole microSPECT imaging system based on three large NaI(Tl) gamma cameras. Two multiple-pinhole tungsten collimator tubes will be used sequentially for whole body "scout" imaging of a mouse, followed by high-resolution (hi-res) imaging of an organ of interest, such as the heart or brain. Ideally, the whole-body image will be reconstructed in real time such that data need only be acquired until the area of interest can be visualized well-enough to determine positioning for the hi-res scan. The authors investigated the utility of the origin ensemble (OE) algorithm for online and offline reconstructions of the scout data. This algorithm operates directly in image space, and can provide estimates of image uncertainty, along with reconstructed images. Techniques for accelerating the OE reconstruction were also introduced and evaluated. METHODS: System matrices were calculated for our 39-pinhole scout collimator design. SPECT projections were simulated for a range of count levels using the MOBY digital mouse phantom. Simulated data were used for a comparison of OE and maximum-likelihood expectation maximization (MLEM) reconstructions. The OE algorithm convergence was evaluated by calculating the total-image entropy and by measuring the counts in a volume-of-interest (VOI) containing the heart. Total-image entropy was also calculated for simulated MOBY data reconstructed using OE with various levels of parallelization. RESULTS: For VOI measurements in the heart, liver, bladder, and soft-tissue, MLEM and OE reconstructed images agreed within 6%. Image entropy converged after ~2000 iterations of OE, while the counts in the heart converged earlier at ~200 iterations of OE. An accelerated version of OE completed 1000 iterations in <9 min for a 6.8M count data set, with some loss of image entropy performance, whereas the same dataset required ~79 min to complete 1000 iterations of conventional OE. A combination of the two methods showed decreased reconstruction time and no loss of performance when compared to conventional OE alone. CONCLUSIONS: OE-reconstructed images were found to be quantitatively and qualitatively similar to MLEM, yet OE also provided estimates of image uncertainty. Some acceleration of the reconstruction can be gained through the use of parallel computing. The OE algorithm is useful for reconstructing multiple pinhole SPECT data and can be easily modified for real-time reconstruction. PMID- 27782696 TI - Robot-assistant for MRI-guided liver ablation: A pilot study. AB - PURPOSE: Percutaneous ablation under MRI-guidance allows treating otherwise inoperable liver tumors locally using a catheter probe. However, manually placing the probe is an error-prone and time consuming task that requires a considerable amount of training. The aim of this paper was to present a pneumatically actuated robotic instrument that can assist clinicians in MRI-guided percutaneous intervention of the liver and to assess its functionality in a clinical setting. The robot positions a needle-guide inside the MRI scanner bore and assists manual needle insertions outside the bore. METHODS: The robot supports double oblique insertions that are particularly challenging for less experienced clinicians. Additionally, the system employs only standard imaging sequences and can therefore be used on different MRI scanners without requiring prior integration. The repeatability and the accuracy of the robot were evaluated with an optical tracking system. The functionality of the robot was assessed in an initial pilot study on two patients that underwent MRI-guided laser ablation of the liver. RESULTS: The robot positioned the needle-guide in a repeatable manner with a mean error of 0.35 mm and a standard deviation of 0.32 mm. The mean position error corresponding to the needle tip, measured for an equivalent needle length of 195 mm over 25 fixed points, was 2.5 mm with a standard deviation of 1.2 mm. The pilot study confirmed that the robot does not interfere with the equipment used for MRI-guided laser ablation and does not visibly affect the MR images. The robot setup integrated seamlessly within the established clinical workflow. The robot-assisted procedure was successfully completed on two patients, one of which required a complex double oblique insertion. For both patients, the insertion depth and the tumor size were within the range reported for previous MRI-guided percutaneous interventions. A third patient initially enrolled in the pilot study and was considerably heavier than the others, preventing the use of the robot and requiring several freehand insertion attempts. CONCLUSIONS: The robot repeatability and accuracy are appropriate for liver tumors normally treated with MRI-guided ablation. The results of the pilot study endorse the clinical use of the robot in its current form: the robot is fully functional and MRI-compatible in a clinical setting and is suitable for double-oblique needle insertions. PMID- 27782697 TI - Automatic airway-artery analysis on lung CT to quantify airway wall thickening and bronchiectasis. AB - PURPOSE: Bronchiectasis and airway wall thickening are commonly assessed in computed tomography (CT) by comparing the airway size with the size of the accompanying artery. Thus, in order to automate the quantification of bronchiectasis and wall thickening following a similar principle, there is a need for methods that automatically segment the airway and vascular trees, measure their size, and pair each airway branch with its accompanying artery. METHODS: This paper combines and extends existing techniques to present a fully automated pipeline that, given a thoracic chest CT, segments, measures, and pairs airway branches with the accompanying artery, then quantifies airway wall thickening and bronchiectasis by measuring the wall-artery ratio (WAR) and lumen and outer wall airway-artery ratio (AAR). Measurements that do not use the artery size for normalization are also extracted, including wall area percentage (WAP), wall thickness ratio (WTR), and airway diameters. RESULTS: The method was thoroughly evaluated using 8000 manual annotations of airway-artery pairs from 24 full inspiration pediatric CT scans (12 diseased and 12 controls). Limits of agreement between the automatically and manually measured diameters were comparable to interobserver limits of agreement. Differences in automatically obtained WAR, AAR, WAP, and WTR between bronchiectatic subjects and controls were similar as when manual annotations were used: WAR and outer AAR were significantly higher in the bronchiectatic subjects (p < 0.05), but lumen AAR, WAP, and WTR were not. Only measurements that use artery size for normalization led to significant differences between groups, highlighting the importance of airway-artery pairing. CONCLUSIONS: The fully automatic method presented in this paper could replace time-consuming manual annotations and visual scoring methods to quantify abnormal widening and thickening of airways. PMID- 27782698 TI - A pencil beam dose calculation model for CyberKnife system. AB - PURPOSE: CyberKnife system is initially equipped with fixed circular cones for stereotactic radiosurgery. Two dose calculation algorithms, Ray-Tracing and Monte Carlo, are available in the supplied treatment planning system. A multileaf collimator system was recently introduced in the latest generation of system, capable of arbitrarily shaped treatment field. The purpose of this study is to develop a model based dose calculation algorithm to better handle the lateral scatter in an irregularly shaped small field for the CyberKnife system. METHODS: A pencil beam dose calculation algorithm widely used in linac based treatment planning system was modified. The kernel parameters and intensity profile were systematically determined by fitting to the commissioning data. The model was tuned using only a subset of measured data (4 out of 12 cones) and applied to all fixed circular cones for evaluation. The root mean square (RMS) of the difference between the measured and calculated tissue-phantom-ratios (TPRs) and off-center ratio (OCR) was compared. Three cone size correction techniques were developed to better fit the OCRs at the penumbra region, which are further evaluated by the output factors (OFs). The pencil beam model was further validated against measurement data on the variable dodecagon-shaped Iris collimators and a half beam blocked field. Comparison with Ray-Tracing and Monte Carlo methods was also performed on a lung SBRT case. RESULTS: The RMS between the measured and calculated TPRs is 0.7% averaged for all cones, with the descending region at 0.5%. The RMSs of OCR at infield and outfield regions are both at 0.5%. The distance to agreement (DTA) at the OCR penumbra region is 0.2 mm. All three cone size correction models achieve the same improvement in OCR agreement, with the effective source shift model (SSM) preferred, due to their ability to predict more accurately the OF variations with the source to axis distance (SAD). In noncircular field validation, the pencil beam calculated results agreed well with the film measurement of both Iris collimators and the half-beam blocked field, fared much better than the Ray-Tracing calculation. CONCLUSIONS: The authors have developed a pencil beam dose calculation model for the CyberKnife system. The dose calculation accuracy is better than the standard linac based system because the model parameters were specifically tuned to the CyberKnife system and geometry correction factors. The model handles better the lateral scatter and has the potential to be used for the irregularly shaped fields. Comprehensive validations on MLC equipped system are necessary for its clinical implementation. It is reasonably fast enough to be used during plan optimization. PMID- 27782699 TI - Whole-remnant and maximum-voxel SPECT/CT dosimetry in 131I-NaI treatments of differentiated thyroid cancer. AB - PURPOSE: To investigate the possible differences between SPECT/CT based whole remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). METHODS: Eighteen DTC patients were administered 1.11 GBq of 131I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3 7 days after administration. The activity, the remnant mass, and the maximum voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. RESULTS: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 +/- 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in the S values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. CONCLUSIONS: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude. PMID- 27782700 TI - Re-examining TG-142 recommendations in light of modern techniques for linear accelerator based radiosurgery. AB - PURPOSE: The recent development of multifocal stereotactic radiosurgery (SRS) using a single isocenter volumetric modulated arc theory (VMAT) technique warrants a re-examination of the quality assurance (QA) tolerances for routine mechanical QA recommended by the American Association of Physicists in Medicine Task Group Report Number 142. Multifocal SRS can result in targets with small volumes being at a large off-axis distance from the treatment isocenter. Consequently, angular errors in the collimator, patient support assembly (PSA), or gantry could have an increased impact on target coverage. METHODS: The authors performed a retrospective analysis of dose deviations caused by systematic errors in PSA, collimator, and gantry angle at the tolerance level for routine linear accelerator QA as recommended by TG-142. Dosimetric deviations from multifocal SRS plans (N = 10) were compared to traditional single target SRS using dynamic conformal arcs (N = 10). The chief dosimetric quantities used in determining clinical impact were V100% and D99% of the individual planning target volumes and V12Gy of the healthy brain. RESULTS: Induced errors at tolerance levels showed the greatest change in multifocal SRS target coverage for collimator rotations (+/-1.0 degrees ) with the average changes to V100% and D99% being 5% and 6%, respectively, with maximum changes of 33% and 20%. A reduction in the induced error to half the TG-142 tolerance (+/-0.5 degrees ) demonstrated similar changes in coverage loss to traditional single target SRS assessed at the recommended tolerance level. The observed change in coverage for multifocal SRS was reduced for gantry errors (+/-1.0 degrees ) at 2% and 4.5% for V100% and D99%, respectively, with maximum changes of 18% and 12%. Minimal change in coverage was noted for errors in PSA rotation. CONCLUSIONS: This study indicates that institutions utilizing a single isocenter VMAT technique for multifocal disease should pay careful attention to the angular mechanical tolerances in designing a robust and complete QA program. PMID- 27782701 TI - Technical Note: Multicenter study of TrueBeam FFF beams with a new stereotactic diode: Can a common small field signal ratio curve be defined? AB - PURPOSE: Small radiation fields (<30 mm) are typically involved in stereotactic body radiation therapy procedures. Output factor measurements are subjected to large uncertainties. The signal ratio (SR) readings, defined as the ratio of central axis reading, respectively, in the actual field size and in the reference field size, were evaluated in several centers and a common mathematical description of the SR curve was investigated. METHODS: A couple of new unshielded stereotactic diodes (Razor, IBA) was tested under eight different TrueBeams using 10 MV flattering filter free beams with high dose rate (2400 MU/min). Small fields, ranging from 6 to 50 mm, were analyzed in terms of profiles and central axis point measurements. SRs were normalized to 30 mm field and were calculated as a function of nominal field size (NFS) and effective field size (EFS). From SRs acquired using Razor1 (four centers), a theoretical equation was extrapolated. Three centers with Razor2 were used to test the mathematical relationship. Finally, the two diodes were directly compared in the last center. RESULTS: The EFS was systematically smaller than NFS (p < 0.01) for all field size ranges, with mean difference of 0.9 +/- 0.5 mm. The SR fits using the NFS and EFS had, respectively, R2 = 0.989 and R2 ? 0.999. The Razor2 centers' mean deviation from the predicted SRs, using the NFS and EFS fits, was, respectively, 3.4% and 0.5%. The maximum deviations were 5.0% (6 mm field size) for NFS and 1.9% for EFS. Maximum deviation of 0.5% between the two Razors was observed. CONCLUSIONS: EFS measurements were confirmed to be mandatory when comparing SRs over different centers. An equation establishing a functional relation between SRs and the EFS was obtained and tested for the new Razor diode. PMID- 27782702 TI - Improving hyperthermia treatment planning for the pelvis by accurate fluid modeling. AB - PURPOSE: Hyperthermia is an established (neo)adjuvant treatment modality for a number of pelvic malignancies. Optimal treatment of these tumors requires robust treatment planning, but up until now, the urinary bladder was not modeled accurately, making current simulations less reliable. The authors improved the dielectric and thermophysical model of the urinary bladder in their treatment planning system, and showed the improvements using phantom experiments. METHODS: The authors suspended a porcine bladder in muscle tissue equivalent gel and filled it with 120 ml 0.9% saline. The authors heated the phantom during 15 min with their deep hyperthermia device, using clinical settings, and measured the temperature both inside and outside the bladder. The authors simulated the experiment, both using the clinically used treatment planning system, and using the improved model featuring correct dielectric properties for the bladder content and an enhanced thermophysical model, enabling the simulation of convection. RESULTS: Although the dielectric changes have an impact throughout the phantom, the dominant effect is a higher net heat absorption in the bladder. The effects of changing the thermophysical model are limited to the bladder and its surroundings, but result in a very different temperature profile. The temperatures predicted by the simulations using the new bladder model were in much better agreement with the measurements than those predicted by currently used treatment planning system. CONCLUSIONS: Modeling convection in the urinary bladder is very important for accurate hyperthermia treatment planning in the pelvic area. PMID- 27782703 TI - Towards 3D printed multifunctional immobilization for proton therapy: Initial materials characterization. AB - PURPOSE: 3D printing technology is investigated for the purpose of patient immobilization during proton therapy. It potentially enables a merge of patient immobilization, bolus range shifting, and other functions into one single patient specific structure. In this first step, a set of 3D printed materials is characterized in detail, in terms of structural and radiological properties, elemental composition, directional dependence, and structural changes induced by radiation damage. These data will serve as inputs for the design of 3D printed immobilization structure prototypes. METHODS: Using four different 3D printing techniques, in total eight materials were subjected to testing. Samples with a nominal dimension of 20 * 20 * 80 mm3 were 3D printed. The geometrical printing accuracy of each test sample was measured with a dial gage. To assess the mechanical response of the samples, standardized compression tests were performed to determine the Young's modulus. To investigate the effect of radiation on the mechanical response, the mechanical tests were performed both prior and after the administration of clinically relevant dose levels (70 Gy), multiplied with a safety factor of 1.4. Dual energy computed tomography (DECT) methods were used to calculate the relative electron density to water rhoe, the effective atomic number Zeff, and the proton stopping power ratio (SPR) to water SPR. In order to validate the DECT based calculation of radiological properties, beam measurements were performed on the 3D printed samples as well. Photon irradiations were performed to measure the photon linear attenuation coefficients, while proton irradiations were performed to measure the proton range shift of the samples. The directional dependence of these properties was investigated by performing the irradiations for different orientations of the samples. RESULTS: The printed test objects showed reduced geometric printing accuracy for 2 materials (deviation > 0.25 mm). Compression tests yielded Young's moduli ranging from 0.6 to 2940 MPa. No deterioration in the mechanical response was observed after exposure of the samples to 100 Gy in a therapeutic MV photon beam. The DECT-based characterization yielded Zeff ranging from 5.91 to 10.43. The SPR and rhoe both ranged from 0.6 to 1.22. The measured photon attenuation coefficients at clinical energies scaled linearly with rhoe. Good agreement was seen between the DECT estimated SPR and the measured range shift, except for the higher Zeff. As opposed to the photon attenuation, the proton range shifting appeared to be printing orientation dependent for certain materials. CONCLUSIONS: In this study, the first step toward 3D printed, multifunctional immobilization was performed, by going through a candidate clinical workflow for the first time: from the material printing to DECT characterization with a verification through beam measurements. Besides a proof of concept for beam modification, the mechanical response of printed materials was also investigated to assess their capabilities for positioning functionality. For the studied set of printing techniques and materials, a wide variety of mechanical and radiological properties can be selected from for the intended purpose. Moreover the elaborated hybrid DECT methods aid in performing in-house quality assurance of 3D printed components, as these methods enable the estimation of the radiological properties relevant for use in radiation therapy. PMID- 27782704 TI - A gate evaluation of the sources of error in quantitative 90Y PET. AB - PURPOSE: Accurate reconstruction of the dose delivered by 90Y microspheres using a postembolization PET scan would permit the establishment of more accurate dose response relationships for treatment of hepatocellular carcinoma with 90Y. However, the quality of the PET data obtained is compromised by several factors, including poor count statistics and a very high random fraction. This work uses Monte Carlo simulations to investigate what impact factors other than low count statistics have on the quantification of 90Y PET. METHODS: PET acquisitions of two phantoms-a NEMA PET phantom and the NEMA IEC PET body phantom-containing either 90Y or 18F were simulated using gate. Simulated projections were created with subsets of the simulation data allowing the contributions of random, scatter, and LSO background to be independently evaluated. The simulated projections were reconstructed using the commercial software for the simulated scanner, and the quantitative accuracy of the reconstruction and the contrast recovery of the reconstructed images were evaluated. RESULTS: The quantitative accuracy of the 90Y reconstructions were not strongly influenced by the high random fraction present in the projection data, and the activity concentration was recovered to within 5% of the known value. The contrast recovery measured for simulated 90Y data was slightly poorer than that for simulated 18F data with similar count statistics. However, the degradation was not strongly linked to any particular factor. Using a more restricted energy range to reduce the random fraction in the projections had no significant effect. CONCLUSIONS: Simulations of 90Y PET confirm that quantitative 90Y is achievable with the same approach as that used for 18F, and that there is likely very little margin for improvement by attempting to model aspects unique to 90Y, such as the much higher random fraction or the presence of bremsstrahlung in the singles data. PMID- 27782705 TI - Quantification of breast lesion compositions using low-dose spectral mammography: A feasibility study. AB - PURPOSE: The positive predictive power for malignancy can potentially be improved, if the chemical compositions of suspicious breast lesions can be reliably measured in screening mammography. The purpose of this study is to investigate the feasibility of quantifying breast lesion composition, in terms of water and lipid contents, with spectral mammography. METHODS: Phantom and tissue samples were imaged with a spectral mammography system based on silicon-strip photon-counting detectors. Dual-energy calibration was performed for material decomposition, using plastic water and adipose-equivalent phantoms as the basis materials. The step wedge calibration phantom consisted of 20 calibration configurations, which ranged from 2 to 8 cm in thickness and from 0% to 100% in plastic water density. A nonlinear rational fitting function was used in dual energy calibration of the imaging system. Breast lesion phantoms, made from various combinations of plastic water and adipose-equivalent disks, were embedded in a breast mammography phantom with a heterogeneous background pattern. Lesion phantoms with water densities ranging from 0% to 100% were placed at different locations of the heterogeneous background phantom. The water density in the lesion phantoms was measured using dual-energy material decomposition. The thickness and density of the background phantom were varied to test the accuracy of the decomposition technique in different configurations. In addition, an in vitro study was also performed using mixtures of lean and fat bovine tissue of 25%, 50%, and 80% lean weight percentages as the background. Lesions were simulated by using breast lesion phantoms, as well as small bovine tissue samples, composed of carefully weighed lean and fat bovine tissues. The water densities in tissue samples were measured using spectral mammography and compared to measurement using chemical decomposition of the tissue. RESULTS: The thickness of measured and known water contents was compared for various lesion configurations. There was a good linear correlation between the measured and the known values. The root-mean-square errors in water thickness measurements were 0.3 and 0.2 mm for the plastic phantom and bovine tissue backgrounds, respectively. CONCLUSIONS: The results indicate that spectral mammography can be used to accurately characterize breast lesion composition in terms of their equivalent water and lipid contents. PMID- 27782707 TI - High-low reflectivity enhancement based retinal vessel projection for SD-OCT images. AB - PURPOSE: The retinal vessel visualization from spectral-domain optical coherence tomography (SD-OCT) images is important for ocular disease diagnosis and multimodal retinal image processing. The purpose is to display the retinal vessel in a single projection image from 3D SD-OCT images by using the light absorption and shadow characteristics of the retinal vessel. METHODS: The authors present a novel retinal vessel projection method for SD-OCT images, which utilizes the light absorption and shadow characteristics of the retinal vessel, called high low reflectivity enhancement (HLRE) method. The reflectivity of the retinal vessel increases between the internal limiting membrane and inner nuclear layer outer plexiform layer (INL-OPL) layers because of the light absorption, and the reflectivity below the retinal vessel decreases because of the influence of the retinal vessel shadow. A retinal vessel mask image generated based on the reflectivity characteristics of the retinal vessel is used to enhance the subvolume projection image restricted between the INL-OPL and Bruch's membrane layers. RESULTS: Experimental results with 22 SD-OCT cubes from 12 patients and 10 normal persons demonstrate that the authors' method is more effective in displaying the retinal vessel than the summed-voxel projection and other five region restriction based projection methods. The average of the mean difference between the retinal vessel and background regions based on their HLRE method is 0.1921. CONCLUSIONS: The proposed HLRE method was more effective for the visualization of the retinal vessels than the state-of-art methods because it provides higher contrast and distinction. PMID- 27782706 TI - Investigating deformable image registration and scatter correction for CBCT-based dose calculation in adaptive IMPT. AB - PURPOSE: This work aims at investigating intensity corrected cone-beam x-ray computed tomography (CBCT) images for accurate dose calculation in adaptive intensity modulated proton therapy (IMPT) for prostate and head and neck (H&N) cancer. A deformable image registration (DIR)-based method and a scatter correction approach using the image data obtained from DIR as prior are characterized and compared on the basis of the same clinical patient cohort for the first time. METHODS: Planning CT (pCT) and daily CBCT data (reconstructed images and measured projections) of four H&N and four prostate cancer patients have been considered in this study. A previously validated Morphons algorithm was used for DIR of the planning CT to the current CBCT image, yielding a so-called virtual CT (vCT). For the first time, this approach was translated from H&N to prostate cancer cases in the scope of proton therapy. The warped pCT images were also used as prior for scatter correction of the CBCT projections for both tumor sites. Single field uniform dose and IMPT (only for H&N cases) treatment plans have been generated with a research version of a commercial planning system. Dose calculations on vCT and scatter corrected CBCT (CBCTcor) were compared by means of the proton range and a gamma-index analysis. For the H&N cases, an additional diagnostic replanning CT (rpCT) acquired within three days of the CBCT served as additional reference. For the prostate patients, a comprehensive contour comparison of CBCT and vCT, using a trained physician's delineation, was performed. RESULTS: A high agreement of vCT and CBCTcor was found in terms of the proton range and gamma-index analysis. For all patients and indications between 95% and 100% of the proton dose profiles in beam's eye view showed a range agreement of better than 3 mm. The pass rate in a (2%,2 mm) gamma-comparison was between 96% and 100%. For H&N patients, an equivalent agreement of vCT and CBCTcor to the reference rpCT was observed. However, for the prostate cases, an insufficient accuracy of the vCT contours retrieved from DIR was found, while the CBCTcor contours showed very high agreement to the contours delineated on the raw CBCT. CONCLUSIONS: For H&N patients, no considerable differences of vCT and CBCTcor were found. For prostate cases, despite the high dosimetric agreement, the DIR yields incorrect contours, probably due to the more pronounced anatomical changes in the abdomen and the reduced soft-tissue contrast in the CBCT. Using the vCT as prior, these inaccuracies can be overcome and images suitable for accurate delineation and dose calculation in CBCT-based adaptive IMPT can be retrieved from scatter correction of the CBCT projections. PMID- 27782708 TI - Computer-aided detection of intracoronary stent in intravascular ultrasound sequences. AB - PURPOSE: An intraluminal coronary stent is a metal mesh tube deployed in a stenotic artery during percutaneous coronary intervention (PCI), in order to prevent acute vessel occlusion. The identification of struts location and the definition of the stent shape is relevant for PCI planning and for patient follow up. The authors present a fully automatic framework for computer-aided detection (CAD) of intracoronary stents in intravascular ultrasound (IVUS) image sequences. The CAD system is able to detect stent struts and estimate the stent shape. METHODS: The proposed CAD uses machine learning to provide a comprehensive interpretation of the local structure of the vessel by means of semantic classification. The output of the classification stage is then used to detect struts and to estimate the stent shape. The proposed approach is validated using a multicentric data-set of 1,015 images from 107 IVUS sequences containing both metallic and bioabsorbable stents. RESULTS: The method was able to detect struts in both metallic stents with an overall F-measure of 77.7% and a mean distance of 0.15 mm from manually annotated struts, and in bioabsorbable stents with an overall F-measure of 77.4% and a mean distance of 0.09 mm from manually annotated struts. CONCLUSIONS: The results are close to the interobserver variability and suggest that the system has the potential of being used as a method for aiding percutaneous interventions. PMID- 27782709 TI - Proton computed tomography using a 1D silicon diode array. AB - PURPOSE: Proton radiography (PR) and proton computed tomography (PCT) can be used to measure proton stopping power directly. However, practical and cost effective proton imaging detectors are not widely available. In this study, the authors investigated the feasibility of proton imaging using a silicon diode array. METHODS: A one-dimensional silicon diode detector array (1DSDA) was aligned with the central axis (CAX) of the proton beam. Polymethyl methacrylate (PMMA) slabs were used to find the correspondence between the water equivalent thickness (WET) and 1DSDA channel number. Two-dimensional proton radiographs were obtained by translation and rotation of a phantom relative to CAX while the proton nozzle and 1DSDA were kept stationary. A PCT image of one slice of the phantom was reconstructed using filtered backprojection. RESULTS: PR and PCT images of the PMMA cube were successfully acquired using the 1DSDA. The WET of the phantom was measured using PR data. The resolution and maximum error in WET measurement are 2.0 and 1.5 mm, respectively. Structures down to 2.0 mm in size could be resolved completely. Reconstruction of a PCT image showed very good agreement with simulation. Limitations in spatial resolution are attributed to limited spatial sampling, beam collimation, and proton scatter. CONCLUSIONS: The results demonstrate the feasibility of using silicon diode arrays for proton imaging. Such a device can potentially offer fast image acquisition and high spatial and energy resolution for PR and PCT. PMID- 27782710 TI - Individually optimized contrast-enhanced 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinoma. AB - PURPOSE: To develop an individually optimized contrast-enhanced (CE) 4D-computed tomography (CT) for radiotherapy simulation in pancreatic ductal adenocarcinomas (PDA). METHODS: Ten PDA patients were enrolled. Each underwent three CT scans: a 4D-CT immediately following a CE 3D-CT and an individually optimized CE 4D-CT using test injection. Three physicians contoured the tumor and pancreatic tissues. Image quality scores, tumor volume, motion, tumor-to-pancreas contrast, and contrast-to-noise ratio (CNR) were compared in the three CTs. Interobserver variations were also evaluated in contouring the tumor using simultaneous truth and performance level estimation. RESULTS: Average image quality scores for CE 3D CT and CE 4D-CT were comparable (4.0 and 3.8, respectively; P = 0.082), and both were significantly better than that for 4D-CT (2.6, P < 0.001). Tumor-to-pancreas contrast results were comparable in CE 3D-CT and CE 4D-CT (15.5 and 16.7 Hounsfield units (HU), respectively; P = 0.21), and the latter was significantly higher than in 4D-CT (9.2 HU, P = 0.001). Image noise in CE 3D-CT (12.5 HU) was significantly lower than in CE 4D-CT (22.1 HU, P = 0.013) and 4D-CT (19.4 HU, P = 0.009). CNRs were comparable in CE 3D-CT and CE 4D-CT (1.4 and 0.8, respectively; P = 0.42), and both were significantly better in 4D-CT (0.6, P = 0.008 and 0.014). Mean tumor volumes were significantly smaller in CE 3D-CT (29.8 cm3, P = 0.03) and CE 4D-CT (22.8 cm3, P = 0.01) than in 4D-CT (42.0 cm3). Mean tumor motion was comparable in 4D-CT and CE 4D-CT (7.2 and 6.2 mm, P = 0.17). Interobserver variations were comparable in CE 3D-CT and CE 4D-CT (Jaccard index 66.0% and 61.9%, respectively) and were worse for 4D-CT (55.6%) than CE 3D-CT. CONCLUSIONS: CE 4D-CT demonstrated characteristics comparable to CE 3D-CT, with high potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan. PMID- 27782711 TI - The effect of density variation on photon dose calculation and its impact on intensity modulated radiotherapy and stereotactic body radiotherapy. AB - PURPOSE: Inaccurate density information may introduce dose calculation errors when inhomogeneity correction is applied. The aim of the present study was to examine the effect of density variation on photon dose calculation accuracy using the convolution/superposition (CS) algorithm with the focus on newer treatment technologies including intensity modulated radiotherapy, volumetric modulated arc radiotherapy, and stereotactic body radiotherapy (SBRT). METHODS: Calculations were first performed using simple inhomogeneity phantoms in order to determine clinically relevant tolerance levels for different tissue types. The clinical validity of these tolerance levels was then demonstrated by evaluating their dosimetric impact on clinical treatment plans. The dose difference was examined by comparing the dose-volume histogram statistics and the spatial distribution of dose errors calculated on a voxel-by-voxel basis. In order to gain some insight into this issue for the Monte Carlo (MC) algorithm, the authors also performed additional validation using a MC dose calculation system. RESULTS: For soft tissue and bone, the tolerance levels determined from this study appear to be consistent with the values previously calculated using simpler inhomogeneity correction methods. However, the tolerance level for low density lung tissue has been found to be much smaller than what previous studies had reported. The results from this study also suggest that if density variation is restricted within +/-0.02, +/-0.03, and +/-0.10 g/cm3 for lung, soft tissue, and bone, respectively, the resulting dose error in target volumes can be limited to <2% for most clinical cases and <3% for more challenging lung SBRT cases. When the same amount of density variation is introduced, MC algorithm yields ~0.3%-0.9% and ~0.0%-1.2% smaller dose errors for the target and organs-at-risk as compared to CS. CONCLUSIONS: It is important to include lung substitute material into the periodic quality assurance of CT simulators and treatment planning systems. This study suggests that the tolerance value of CT number for lung material is ~ +/- 20 HU in order to keep the associated dose uncertainty at 2%-3% or less. Further studies with larger number of lung cases are warranted to validate this new tolerance value before it can be applied to clinical practice. PMID- 27782712 TI - Use of regularized principal component analysis to model anatomical changes during head and neck radiation therapy for treatment adaptation and response assessment. AB - PURPOSE: To develop standard (SPCA) and regularized (RPCA) principal component analysis models of anatomical changes from daily cone beam CTs (CBCTs) of head and neck (H&N) patients and assess their potential use in adaptive radiation therapy, and for extracting quantitative information for treatment response assessment. METHODS: Planning CT images of ten H&N patients were artificially deformed to create "digital phantom" images, which modeled systematic anatomical changes during radiation therapy. Artificial deformations closely mirrored patients' actual deformations and were interpolated to generate 35 synthetic CBCTs, representing evolving anatomy over 35 fractions. Deformation vector fields (DVFs) were acquired between pCT and synthetic CBCTs (i.e., digital phantoms) and between pCT and clinical CBCTs. Patient-specific SPCA and RPCA models were built from these synthetic and clinical DVF sets. EigenDVFs (EDVFs) having the largest eigenvalues were hypothesized to capture the major anatomical deformations during treatment. RESULTS: Principal component analysis (PCA) models achieve variable results, depending on the size and location of anatomical change. Random changes prevent or degrade PCA's ability to detect underlying systematic change. RPCA is able to detect smaller systematic changes against the background of random fraction-to-fraction changes and is therefore more successful than SPCA at capturing systematic changes early in treatment. SPCA models were less successful at modeling systematic changes in clinical patient images, which contain a wider range of random motion than synthetic CBCTs, while the regularized approach was able to extract major modes of motion. CONCLUSIONS: Leading EDVFs from the both PCA approaches have the potential to capture systematic anatomical change during H&N radiotherapy when systematic changes are large enough with respect to random fraction-to-fraction changes. In all cases the RPCA approach appears to be more reliable at capturing systematic changes, enabling dosimetric consequences to be projected once trends are established early in a treatment course, or based on population models. PMID- 27782713 TI - Fiber Bragg gratings-based sensing for real-time needle tracking during MR-guided brachytherapy. AB - PURPOSE: The development of MR-guided high dose rate (HDR) brachytherapy is under investigation due to the excellent tumor and organs at risk visualization of MRI. However, MR-based localization of needles (including catheters or tubes) has inherently a low update rate and the required image interpretation can be hampered by signal voids arising from blood vessels or calcifications limiting the precision of the needle guidance and reconstruction. In this paper, a new needle tracking prototype is investigated using fiber Bragg gratings (FBG)-based sensing: this prototype involves a MR-compatible stylet composed of three optic fibers with nine sets of embedded FBG sensors each. This stylet can be inserted into brachytherapy needles and allows a fast measurement of the needle deflection. This study aims to assess the potential of FBG-based sensing for real time needle (including catheter or tube) tracking during MR-guided intervention. METHODS: First, the MR compatibility of FBG-based sensing and its accuracy was evaluated. Different known needle deflections were measured using FBG-based sensing during simultaneous MR-imaging. Then, a needle tracking procedure using FBG-based sensing was proposed. This procedure involved a MR-based calibration of the FBG-based system performed prior to the interventional procedure. The needle tracking system was assessed in an experiment with a moving phantom during MR imaging. The FBG-based system was quantified by comparing the gold-standard shapes, the shape manually segmented on MRI and the FBG-based measurements. RESULTS: The evaluation of the MR compatibility of FBG-based sensing and its accuracy shows that the needle deflection could be measured with an accuracy of 0.27 mm on average. Besides, the FBG-based measurements were comparable to the uncertainty of MR-based measurements estimated at half the voxel size in the MR image. Finally, the mean(standard deviation) Euclidean distance between MR- and FBG-based needle position measurements was equal to 0.79 mm(0.37 mm). The update rate and latency of the FBG-based needle position measurement were 100 and 300 ms, respectively. CONCLUSIONS: The FBG-based needle tracking procedure proposed in this paper is able to determine the position of the complete needle, under MR imaging, with better accuracy and precision, higher update rate, and lower latency compared to current MR-based needle localization methods. This system would be eligible for MR-guided brachytherapy, in particular, for an improved needle guidance and reconstruction. PMID- 27782714 TI - Lung surface deformation prediction from spirometry measurement and chest wall surface motion. AB - PURPOSE: The authors have developed and evaluated a method to predict lung surface motion based on spirometry measurements, and chest and abdomen motion at selected locations. METHODS: A patient-specific 3D triangular surface mesh of the lung region was obtained at the end expiratory phase by the threshold-based segmentation method. Lung flow volume changes were recorded with a spirometer for each patient. A total of 192 selected points at a regular spacing of 2 * 2 cm matrix points were used to detect chest wall motion over a total area of 32 * 24 cm covering the chest and abdomen surfaces. QR factorization with column pivoting was employed to remove redundant observations of the chest and abdominal areas. To create a statistical model between the lung surface and the corresponding surrogate signals, the authors developed a predictive model based on canonical ridge regression. Two unique weighting vectors were selected for each vertex on the lung surface; they were optimized during the training process using all other 4D-CT phases except for the test inspiration phase. These parameters were employed to predict the vertex locations of a testing data set. RESULTS: The position of each lung surface mesh vertex was estimated from the motion at selected positions within the chest wall surface and from spirometry measurements in ten lung cancer patients. The average estimation of the 98th error percentile for the end inspiration phase was less than 1 mm (AP = 0.9 mm, RL = 0.6 mm, and SI = 0.8 mm). The vertices located at the lower region of the lung had a larger estimation error as compared with those within the upper region of the lung. The average landmark motion errors, derived from the biomechanical modeling using real surface deformation vector fields (SDVFs), and the predicted SDVFs were 3.0 and 3.1 mm, respectively. CONCLUSIONS: Our newly developed predictive model provides a noninvasive approach to derive lung boundary conditions. The proposed system can be used with personalized biomechanical respiration modeling to derive lung tumor motion during radiation therapy from noninvasive measurements. PMID- 27782715 TI - Isotope independent determination of PET/CT modulation transfer functions from phantom measurements on spheres. AB - PURPOSE: A PET/CT system's imaging capabilities are best described by its point spread function (PSF) in the spatial domain or equivalently by its modulation transfer function (MTF) in the spatial frequency domain. Knowing PSFs or MTFs is a prerequisite for many numerical methods attempting to improve resolution and to reduce the partial volume effect. In PET/CT, the observed PSF is a convolution of the system's intrinsic imaging capabilities including image reconstruction (PSF0) and the positron range function (PRF) of the imaged beta+ emitting isotope. A PRF describes the non-Gaussian distribution of beta+ annihilation events around a hypothetical point source. The main aim was to introduce a new method for determining a PET/CT system's intrinsic MTF (MTF0) from phantom measurements of hot spheres independently of the beta+ emitting isotope used for image acquisition. Secondary aim was to examine non-Gaussian and nonlinear MTFs of a modern iterative reconstruction algorithm. METHODS: PET/CT images of seven phantom spheres with volumes ranging from 0.25 to 16 ml and filled either with 18F or with 68Ga were acquired and reconstructed using filtered back projection (FBP). MTFs were modeled with linear splines. The spline fit iteratively minimized the mean squared error between the acquired PET/CT image and a convolution of the thereof derived PSF with a numerical representation of the imaged hot phantom sphere. For determining MTF0, the numerical sphere representations were convolved with a PRF, simulating a fill with either 18F or 68Ga. The MTFs determined by this so-called MTF fit method were compared with MTFs derived from point source measurements and also compared with MTFs derived with a previously published PSF fit method. The MTF fit method was additionally applied to images reconstructed by a vendor iterative algorithm with PSF recovery (Siemens TrueX). RESULTS: The MTF fit method was able to determine 18F and 68Ga dependent MTFs and MTF0 from FBP reconstructed images. Root-mean-square deviation between fit determined MTFs and point source determined MTFs ranged from 0.023 to 0.039. MTFs from Siemens TrueX reconstructions varied with size of the imaged sphere. CONCLUSIONS: MTF0 can be determined regardless of the imaged isotope, when using existing PRF models for the MTF fit method presented. The method proves that modern iterative PET/CT reconstruction algorithms have nonlinear imaging properties. This behaviour is not accessible by point source measurements. MTFs resulting from these clinically applied algorithms need to be estimated from objects of similar geometry to those intended for clinical imaging. PMID- 27782716 TI - A derivative-free multistart framework for an automated noncoplanar beam angle optimization in IMRT. AB - PURPOSE: The inverse planning of an intensity-modulated radiation therapy (IMRT) treatment requires decisions regarding the angles used for radiation incidence, even when arcs are used. The possibility of improving the quality of treatment plans by an optimized selection of the beam angle incidences-beam angle optimization (BAO)-is seldom done in clinical practice. The inclusion of noncoplanar beam incidences in an automated optimization routine is even more unusual. However, for some tumor sites, the advantage of considering noncoplanar beam incidences is well known. This paper presents the benefits of using a derivative-free multistart framework for the optimization of the noncoplanar BAO problem. METHODS: Multistart methods combine a global strategy for sampling the search space with a local strategy for improving the sampled solutions. The proposed global strategy allows a thorough exploration of the continuous search space of the highly nonconvex BAO problem. To avoid local entrapment, a derivative-free method is used as local procedure. Additional advantages of the derivative-free method include the reduced number of function evaluations required to converge and the ability to use multithreaded computing. Twenty nasopharyngeal clinical cases were selected to test the proposed multistart framework. The planning target volumes included the primary tumor, the high and low risk lymph nodes. Organs-at-risk included the spinal cord, brainstem, optical nerves, chiasm, parotids, oral cavity, brain, thyroid, among others. For each case, a setup with seven equispaced beams was chosen and the resulting treatment plan, using a multicriteria optimization framework, was then compared against the coplanar and noncoplanar plans using the optimal beam setups obtained by the derivative-free multistart framework. RESULTS: The optimal noncoplanar beam setup obtained by the derivative-free multistart framework leads to high quality treatment plans with better target coverage and with improved organ sparing compared to treatment plans using equispaced or optimal coplanar beam angle setups. The noncoplanar treatment plans achieved, e.g., an average reduction in the mean dose of the oral cavity of 6.1 Gy and an average reduction in the maximum-dose of the brainstem of 7 Gy when compared to the equispaced treatment plans. CONCLUSIONS: The noncoplanar BAO problem is an extremely challenging multimodal optimization problem that can be successfully addressed through a thoughtful exploration of the continuous highly nonconvex BAO search space. The proposed framework is capable of calculating high quality treatment plans and thus can be an interesting alternative toward automated noncoplanar beam selection in IMRT treatment planning which is nowadays the natural trend in treatment planning. PMID- 27782717 TI - Quantitative assessment of biliary stent artifacts on MR images: Potential implications for target delineation in radiotherapy. AB - PURPOSE: Biliary stents may cause susceptibility artifacts, gradient-induced artifacts, and radio frequency (RF) induced artifacts on magnetic resonance images, which can hinder accurate target volume delineation in radiotherapy. In this study, the authors investigated and quantified the magnitude of these artifacts for stents of different materials. METHODS: Eight biliary stents made of nitinol, platinum-cored nitinol, stainless steel, or polyethylene from seven vendors, with different lengths (57-98 mm) and diameters (3.0-11.7 mm), were placed in a phantom. To quantify the susceptibility artifacts sequence independently, DeltaB0-maps and T2*-maps were acquired at 1.5 and 3 T. To study the effect of the gradient-induced artifacts at 3 T, signal decay in images obtained with maximum readout gradient-induced artifacts was compared to signal decay in reference scans. To quantify the RF induced artifacts at 3 T, B1-maps were acquired. Finally, DeltaB0-maps and T2*-maps were acquired at 3 T of two pancreatic cancer patients who had received platinum-cored nitinol biliary stents. RESULTS: Outside the stent, susceptibility artifacts dominated the other artifacts. The stainless steel stent produced the largest susceptibility artifacts. The other stents caused decreased T2* up to 5.1 mm (1.5 T) and 8.5 mm (3 T) from the edge of the stent. For sequences with a higher bandwidth per voxel (1.5 T: BWvox > 275 Hz/voxel; 3 T: BWvox > 500 Hz/voxel), the B0-related susceptibility artifacts were negligible (<0.2 voxels). The polyethylene stent showed no artifacts. In vivo, the changes in B0 and T2* induced by the stent were larger than typical variations in B0 and T2* induced by anatomy when the stent was at an angle of 30 degrees with the main magnetic field. CONCLUSIONS: Susceptibility artifacts were dominating over the other artifacts. The magnitudes of the susceptibility artifacts were determined sequence-independently. This method allows to include additional safety margins that ensure target irradiation. PMID- 27782718 TI - Patient-specific quantification of image quality: An automated method for measuring spatial resolution in clinical CT images. AB - PURPOSE: To develop and validate an automated technique for evaluating the spatial resolution characteristics of clinical computed tomography (CT) images. METHODS: Twenty one chest and abdominopelvic clinical CT datasets were examined in this study. An algorithm was developed to extract a CT resolution index (RI) analogous to the modulation transfer function from clinical CT images by measuring the edge-spread function (ESF) across the patient's skin. A polygon mesh of the air-skin boundary was created. The faces of the mesh were then used to measure the ESF across the air-skin interface. The ESF was differentiated to obtain the line-spread function (LSF), and the LSF was Fourier transformed to obtain the RI. The algorithm's ability to detect the radial dependence of the RI was investigated. RIs measured with the proposed method were compared with a conventional phantom-based method across two reconstruction algorithms (FBP and iterative) using the spatial frequency at 50% RI, f50, as the metric for comparison. Three reconstruction kernels were investigated for each reconstruction algorithm. Finally, an observer study was conducted to determine if observers could visually perceive the differences in the measured blurriness of images reconstructed with a given reconstruction method. RESULTS: RI measurements performed with the proposed technique exhibited the expected dependencies on the image reconstruction. The measured f50 values increased with harder kernels for both FBP and iterative reconstruction. Furthermore, the proposed algorithm was able to detect the radial dependence of the RI. Patient specific measurements of the RI were comparable to the phantom-based technique, but the patient data exhibited a large spread in the measured f50, indicating that some datasets were blurrier than others even when the projection data were reconstructed with the same reconstruction algorithm and kernel. Results from the observer study substantiated this finding. CONCLUSIONS: Clinically informed, patient-specific spatial resolution can be measured from clinical datasets. The method is sufficiently sensitive to reflect changes in spatial resolution due to different reconstruction parameters. The method can be applied to automatically assess the spatial resolution of patient images and quantify dependencies that may not be captured in phantom data. PMID- 27782719 TI - Correlation between k-space sampling pattern and MTF in compressed sensing MRSI. AB - PURPOSE: To investigate the relationship between the k-space sampling patterns used for compressed sensing MR spectroscopic imaging (CS-MRSI) and the modulation transfer function (MTF) of the metabolite maps. This relationship may allow the desired frequency content of the metabolite maps to be quantitatively tailored when designing an undersampling pattern. METHODS: Simulations of a phantom were used to calculate the MTF of Nyquist sampled (NS) 32 * 32 MRSI, and four-times undersampled CS-MRSI reconstructions. The dependence of the CS-MTF on the k-space sampling pattern was evaluated for three sets of k-space sampling patterns generated using different probability distribution functions (PDFs). CS-MTFs were also evaluated for three more sets of patterns generated using a modified algorithm where the sampling ratios are constrained to adhere to PDFs. RESULTS: Strong visual correlation as well as high R2 was found between the MTF of CS-MRSI and the product of the frequency-dependant sampling ratio and the NS 32 * 32 MTF. Also, PDF-constrained sampling patterns led to higher reproducibility of the CS MTF, and stronger correlations to the above-mentioned product. CONCLUSIONS: The relationship established in this work provides the user with a theoretical solution for the MTF of CS MRSI that is both predictable and customizable to the user's needs. PMID- 27782720 TI - A general algorithm for calculation of recombination losses in ionization chambers exposed to ion beams. AB - PURPOSE: Dosimetry with ionization chambers in clinical ion beams for radiation therapy requires correction for recombination effects. However, common radiation protocols discriminate between initial and general recombination and provide no universal correction method for the presence of both recombination types in ion beams of charged particles heavier than protons. The advent of multiple field optimization in ion beams, allowing for complex patterns of dose delivery in both temporal and spatial domains, results in new challenges for recombination correction where the resulting recombination depends on the plan delivered. Here, the authors present the open source code IonTracks version 1.0, where the combined initial and general recombination effects in principle can be predicted for any ion beam with arbitrary particle-energy spectrum and temporal structure. METHODS: IonTracks uses track structure theory to distribute the charge carriers in ion tracks. The charge carrier movements are governed by a pair of coupled differential equations, based on fundamental physical properties as charge carrier drift, diffusion, and recombination, which are solved numerically while the initial and general charge carrier recombination is computed. A space charge screening of the electric field is taken into account and the algorithm furthermore allows an inclusion of a free-electron component. RESULTS: The algorithm is numerically stable and in accordance with experimentally validated theories for initial recombination in heavy ion tracks and general recombination in a proton beam. CONCLUSIONS: Given IonTracks' ability to handle arbitrary inputs, IonTracks can in principle be applied to any complex particle field in the spatial and temporal domain. IonTracks is validated against the Jaffe's and Boag's theory of recombination in pulsed beams of multiple ion species. IonTracks is able to calculate the correction factor for initial and general recombination losses in parallel-plate ionization chambers. Even if only few experimental data on recombination effects in ionization chambers are available today, the universal concept of IonTracks is not limited to the ions investigated here. Future experimental investigations of recombination in pulsed and possibly also continuous ion beams may be conducted with IonTracks, which ultimately may lead to a more precise prediction of recombination factors in complex radiation fields. PMID- 27782721 TI - A robust empirical parametrization of proton stopping power using dual energy CT. AB - PURPOSE: In this study the authors present a new method for estimation of proton stopping power ratios (SPRs) using dual energy CT (DECT), which is robust toward CT noise. The authors propose a parametrization for SPR based directly on the CT numbers in a DECT image set, whereby the intermediate steps of estimating the relative electron density, rhoe, and mean excitation energy, I, are avoided. METHODS: The SPR parametrization proposed in this study is a purely empirical fit based on the theoretical SPR values for a list of 34 reference human tissues. To investigate the SPR estimation made with this new method the authors performed a calibration and an evaluation with the method. The authors initially calculated CT numbers using CT energy spectrum characterization parameters obtained from calibration based on a Gammex 467 electron density calibration phantom. These CT numbers were fitted to the theoretical SPR for the reference human tissues using the new SPR parametrization presented in this study. The method was evaluated based on theoretical CT numbers for the reference human tissues. The root-mean square error (RMSE) of the SPR and the proton range error from the continuous slowing down approximation were calculated for the reference human tissues. To test the stability of the parametrization the authors varied the density and elemental composition of the reference human tissues and calculated their new SPR estimates. Further, clinically realistic noise values were added to the theoretical CT numbers to investigate how CT noise affected the estimated water equivalent range through 10 cm of the reference human tissues. All results for the new SPR parametrization were compared to the results obtained using two previously published DECT methods for SPR estimation. Comparisons were also made to a single energy CT (SECT) SPR estimation method, the stoichiometric method, which is commonly used in clinical practise for proton therapy treatment planning. RESULTS: The RMSE for the SPR of the 34 reference human tissues using the new SPR parametrization was 0.12%, compared to 0.19% and 0.28% for the two previously published DECT methods. The SPR parametrization was more stable toward variations of the calcium content in the reference human tissues, but less stable toward density variations and changes to the hydrogen content than the two other DECT methods. When adding noise to the theoretical CT numbers the SPR parametrization gave the lowest water equivalent range errors of all four tested SPR estimation methods (maximum error reduced to 0.4 mm). In all cases tested, the new SPR parametrization outperformed the SECT stoichiometric method. CONCLUSIONS: The new SPR parametrization gave lower RMSEs than the two other published DECT methods, and was in particular more robust against added noise. The method has potential for reducing range uncertainty margins in treatment planning of proton therapy. PMID- 27782722 TI - Simultaneous 4D-CBCT reconstruction with sliding motion constraint. AB - PURPOSE: Current approaches using deformable vector field (DVF) for motion compensated 4D-cone beam CT (CBCT) reconstruction typically utilize an isotropically smoothed DVF between different respiration phases. Such isotropically smoothed DVF does not work well if sliding motion exists between neighboring organs. This study investigated an anisotropic motion modeling scheme by extracting organ boundary local motions (e.g., sliding) and incorporated them into 4D-CBCT reconstruction to optimize the motion modeling and reconstruction methods. METHODS: Initially, a modified simultaneous algebraic reconstruction technique (mSART) was applied to reconstruct high quality reference phase CBCT using all phase projections. The initial DVFs were precalculated and subsequently updated to achieve the optimized solution. During the DVF update, sliding motion estimation was performed by matching the measured projections to the forward projection of the deformed reference phase CBCT. In this process, each moving organ boundary was first segmented. The normal vectors of the boundary DVF were then extracted and incorporated for further DVF optimization. The regularization term in the objective function adaptively regularizes the DVF by (1) isotopically smoothing the DVF within each organ; (2) smoothing the DVF at boundary along the normal direction; and (3) leaving the tangent direction of boundary DVF unsmoothed (i.e., allowing for sliding motion). A nonlinear conjugate gradient optimizer was used. The algorithm was validated on a digital cubic tube phantom with sliding motion, nonuniform rotational B-spline based cardiac-torso (NCAT) phantom, and two anonymized patient data. The relative reconstruction error (RE), the motion trajectory's root mean square error (RMSE) together with its maximum error (MaxE), and the Dice coefficient of the lung boundary were calculated to evaluate the algorithm performance. RESULTS: For the cubic tube and NCAT phantom tests, the REs are 10.2% and 7.4% with sliding motion compensation, compared to 13.4% and 8.9% without sliding modeling. The motion trajectory's RMSE and MaxE for NCAT phantom tests are 0.5 and 0.8 mm with sliding motion constraint compared to 3.5 and 7.3 mm without sliding motion modeling. The Dice coefficients for both NCAT phantom and the patients show a consistent trend that sliding motion constraint achieves better similarity for segmented lung boundary compared with the ground truth or patient reference. CONCLUSIONS: A sliding motion-compensated 4D-CBCT reconstruction and the motion modeling scheme was developed. Both phantom and patient study demonstrated the improved accuracy and motion modeling accuracy in reconstructed 4D-CBCT. PMID- 27782723 TI - Automatic multiorgan segmentation in CT images of the male pelvis using region specific hierarchical appearance cluster models. AB - PURPOSE: Accurate segmentation of pelvic organs in CT images is of great importance in external beam radiotherapy for prostate cancer. The aim of this studying is to develop a novel method for automatic, multiorgan segmentation of the male pelvis. METHODS: The authors' segmentation method consists of several stages. First, a pretreatment includes parameterization, principal component analysis (PCA), and an established process of region-specific hierarchical appearance cluster (RSHAC) model which was executed on the training dataset. After the preprocessing, online automatic segmentation of new CT images is achieved by combining the RSHAC model with the PCA-based point distribution model. Fifty pelvic CT from eight prostate cancer patients were used as the training dataset. From another 20 prostate cancer patients, 210 CT images were used for independent validation of the segmentation method. RESULTS: In the training dataset, 15 PCA modes were needed to represent 95% of shape variations of pelvic organs. When tested on the validation dataset, the authors' segmentation method had an average Dice similarity coefficient and mean absolute distance of 0.751 and 0.371 cm, 0.783 and 0.303 cm, 0.573 and 0.604 cm for prostate, bladder, and rectum, respectively. The automated segmentation process took on average 5 min on a personal computer equipped with Core 2 Duo CPU of 2.8 GHz and 8 GB RAM. CONCLUSIONS: The authors have developed an efficient and reliable method for automatic segmentation of multiple organs in the male pelvis. This method should be useful for treatment planning and adaptive replanning for prostate cancer radiotherapy. With this method, the physicist can improve the work efficiency and stability. PMID- 27782724 TI - Computer aided diagnosis of prostate cancer: A texton based approach. AB - PURPOSE: In this paper the authors propose a texton based prostate computer aided diagnosis approach which bypasses the typical feature extraction process such as filtering and convolution which can be computationally expensive. The study focuses the peripheral zone because 75% of prostate cancers start within this region and the majority of prostate cancers arising within this region are more aggressive than those arising in the transitional zone. METHODS: For the model development, square patches were extracted at random locations from malignant and benign regions. Subsequently, extracted patches were aggregated and clustered using k-means clustering to generate textons that represent both regions. All textons together form a texton dictionary, which was used to construct a texton map for every peripheral zone in the training images. Based on the texton map, histogram models for each malignant and benign tissue samples were constructed and used as a feature vector to train our classifiers. In the testing phase, four machine learning algorithms were employed to classify each unknown sample tissue based on its corresponding feature vector. RESULTS: The proposed method was tested on 418 T2-W MR images taken from 45 patients. Evaluation results show that the best three classifiers were Bayesian network (Az = 92.8% +/- 5.9%), random forest (89.5% +/- 7.1%), and k-NN (86.9% +/- 7.5%). These results are comparable to the state-of-the-art in the literature. CONCLUSIONS: The authors have developed a prostate computer aided diagnosis method based on textons using a single modality of T2-W MRI without the need for the typical feature extraction methods, such as filtering and convolution. The proposed method could form a solid basis for a multimodality magnetic resonance imaging based systems. PMID- 27782725 TI - Polyvinyl chloride as a multimodal tissue-mimicking material with tuned mechanical and medical imaging properties. AB - PURPOSE: The mechanical and imaging properties of polyvinyl chloride (PVC) can be adjusted to meet the needs of researchers as a tissue-mimicking material. For instance, the hardness can be adjusted by changing the ratio of softener to PVC polymer, mineral oil can be added for lubrication in needle insertion, and glass beads can be added to scatter acoustic energy similar to biological tissue. Through this research, the authors sought to develop a regression model to design formulations of PVC with targeted mechanical and multimodal medical imaging properties. METHODS: The design of experiment was conducted by varying three factors-(1) the ratio of softener to PVC polymer, (2) the mass fraction of mineral oil, and (3) the mass fraction of glass beads-and measuring the mechanical properties (elastic modulus, hardness, viscoelastic relaxation time constant, and needle insertion friction force) and the medical imaging properties [speed of sound, acoustic attenuation coefficient, magnetic resonance imaging time constants T1 and T2, and the transmittance of the visible light at wavelengths of 695 nm (Tlambda695) and 532 nm (Tlambda532)] on twelve soft PVC samples. A regression model was built to describe the relationship between the mechanical and medical imaging properties and the values of the three composition factors of PVC. The model was validated by testing the properties of a PVC sample with a formulation distinct from the twelve samples. RESULTS: The tested soft PVC had elastic moduli from 6 to 45 kPa, hardnesses from 5 to 50 Shore OOO-S, viscoelastic stress relaxation time constants from 114.1 to 191.9 s, friction forces of 18 gauge needle insertion from 0.005 to 0.086 N/mm, speeds of sound from 1393 to 1407 m/s, acoustic attenuation coefficients from 0.38 to 0.61 (dB/cm)/MHz, T1 relaxation times from 426.3 to 450.2 ms, T2 relaxation times from 21.5 to 28.4 ms, Tlambda695 from 46.8% to 92.6%, and Tlambda532 from 41.1% to 86.3%. Statistically significant factors of each property were identified. The regression model relating the mechanical and medical imaging properties and their corresponding significant factors had a good fit. The validation tests showed a small discrepancy between the model predicted values and experimental data (all less than 5% except the needle insertion friction force). CONCLUSIONS: The regression model developed in this paper can be used to design soft PVC with targeted mechanical and medical imaging properties. PMID- 27782726 TI - Computerized triplet beam orientation optimization for MRI-guided Co-60 radiotherapy. AB - PURPOSE: Magnetic resonance imaging (MRI)-guided Co-60 provides daily and intrafractional MRI soft tissue imaging for improved target and critical organ tracking. To increase delivery efficiency, the system uses three Co-60 sources at 120 degrees apart, allowing up to 600 cGy combined dose rate at isocenter. Despite the potential tripling in output, creating a delivery plan that uses all three sources is considerably unintuitive. Here, the authors computerize the triplet orientation optimization using column generation, an approach that was demonstrated effective in integrated beam orientation and fluence optimization for noncoplanar therapies. To achieve a better plan quality without increasing the treatment time, the authors then solve a fluence map optimization (FMO) problem while regularizing the fluence maps to reduce the number of deliverable MLC segments. METHODS: Three patients-one prostate, one lung, and one head and neck boost plan (H&NBoost)-were evaluated in this study. For each patient, the beamlet doses were calculated using Monte Carlo, under a 0.35 T magnetic field, for 180 equally spaced coplanar beams grouped into 60 triplets. The beamlet size is 1.05 * 0.5 cm determined by the MLC leaf thickness and step size. The triplets were selected using the column generation algorithm. The FMO problem was formulated using an L2-norm dose fidelity term and an L1-norm anisotropic total variation regularization term, which allows controlling the number of MLC segments, and hence the treatment time, with minimal degradation to the dose. The authors' Fluence Regularization and Optimized Selection of Triplets (FROST) plans were compared against the clinical treatment plans (CLNs) produced by an experienced dosimetrist. PTV homogeneity, max dose, mean dose, D95, D98, and D99 were evaluated. OAR max and mean doses, as well as R50, defined as the ratio of the 50% isodose volume over the planning target volume were investigated. RESULTS: The mean PTV D95, D98, and D99 differ by +0.04%, +0.07%, and +0.25% of the prescription dose between planning methods. The mean PTV homogeneity was virtually same with values at 0.8788 (FROST) and 0.8812 (CLN). R50 decreased by 0.67 comparing FROST to CLN. On average, FROST reduced Dmax and Dmean of OARs by 7.30% and 6.08% of the prescription dose, respectively. The manual CLN planning processes required numerous trial and error runs. The FROST plans on the other hand required minimal human intervention. CONCLUSIONS: Efficient delivery of MRI guided Co-60 therapy needs the output of multiple sources yet suffers from unintuitive and laborious manual beam selection processes. Computerized triplet orientation optimization improves both planning efficiency and plan dosimetry. The novel fluence map regularization provides additional controls over the number of MLC segments and treatment time. PMID- 27782727 TI - Development of a PET/OMRI combined system for simultaneous imaging of positron and free radical probes for small animals. AB - PURPOSE: Positron emission tomography (PET) has high sensitivity for imaging radioactive tracer distributions in subjects. However, it is not possible to image free radical distribution in a subject by PET. Since free radicals are quite reactive, they are related to many diseases, including but not limited to cancer, inflammation, strokes, and heart disease. The Overhauser enhanced magnetic resonance imaging (OMRI) is so far the only method that images free radical distribution in vivo. By combining PET and OMRI, a new hybrid imaging modality might be developed that can simultaneously image the radioactive tracer and free radical distributions. For this purpose, the authors developed a PET/OMRI combined system for small animals. METHODS: The developed PET/OMRI system used an optical fiber-based PET system combined with a permanent magnet based OMRI system. The optical fiber-based PET system uses flexible optical fiber bundles. Eight optical fiber-based block detectors were arranged in a 56 mm diameter ring to form a PET system. The LGSO blocks were located inside the field of-view (FOV) of the OMRI, and the position sensitive photomultiplier tubes were positioned behind the OMRI to minimize the interference between the PET and the OMRI. The OMRI system used a 0.0165 T permanent magnet. The system has an electron spin resonance coil to enhance the MRI signal using the Overhauser effect to image the free radical in the FOV of the PET/OMRI system. RESULTS: The spatial resolution and sensitivity of the optical fiber-based PET system were 1.2 mm FWHM and 1.2% at the central FOV, respectively. The OMRI system imaged the distribution of a nitroxyl radical (NXR) solution. The interference between PET and OMRI was small. Simultaneous imaging of the positron radiotracer and the NXR solution was successfully conducted with the developed PET/OMRI system for phantom and small animal studies. CONCLUSIONS: The authors developed a PET/OMRI combined system with the potential to provide interesting new results in molecular imaging research, such as in vivo molecular and free radical distributions. PMID- 27782728 TI - Automatic segmentation of the glenohumeral cartilages from magnetic resonance images. AB - PURPOSE: Magnetic resonance (MR) imaging plays a key role in investigating early degenerative disorders and traumatic injuries of the glenohumeral cartilages. Subtle morphometric and biochemical changes of potential relevance to clinical diagnosis, treatment planning, and evaluation can be assessed from measurements derived from in vivo MR segmentation of the cartilages. However, segmentation of the glenohumeral cartilages, using approaches spanning manual to automated methods, is technically challenging, due to their thin, curved structure and overlapping intensities of surrounding tissues. Automatic segmentation of the glenohumeral cartilages from MR imaging is not at the same level compared to the weight-bearing knee and hip joint cartilages despite the potential applications with respect to clinical investigation of shoulder disorders. In this work, the authors present a fully automated segmentation method for the glenohumeral cartilages using MR images of healthy shoulders. METHODS: The method involves automated segmentation of the humerus and scapula bones using 3D active shape models, the extraction of the expected bone-cartilage interface, and cartilage segmentation using a graph-based method. The cartilage segmentation uses localization, patient specific tissue estimation, and a model of the cartilage thickness variation. The accuracy of this method was experimentally validated using a leave-one-out scheme on a database of MR images acquired from 44 asymptomatic subjects with a true fast imaging with steady state precession sequence on a 3 T scanner (Siemens Trio) using a dedicated shoulder coil. The automated results were compared to manual segmentations from two experts (an experienced radiographer and an experienced musculoskeletal anatomist) using the Dice similarity coefficient (DSC) and mean absolute surface distance (MASD) metrics. RESULTS: Accurate and precise bone segmentations were achieved with mean DSC of 0.98 and 0.93 for the humeral head and glenoid fossa, respectively. Mean DSC scores of 0.74 and 0.72 were obtained for the humeral and glenoid cartilage volumes, respectively. The manual interobserver reliability evaluated by DSC was 0.80 +/- 0.03 and 0.76 +/- 0.04 for the two cartilages, implying that the automated results were within an acceptable 10% difference. The MASD between the automatic and the corresponding manual cartilage segmentations was less than 0.4 mm (previous studies reported mean cartilage thickness of 1.3 mm). CONCLUSIONS: This work shows the feasibility of volumetric segmentation and separation of the glenohumeral cartilages from MR images. To their knowledge, this is the first fully automated algorithm for volumetric segmentation of the individual glenohumeral cartilages from MR images. The approach was validated against manual segmentations from experienced analysts. In future work, the approach will be validated on imaging datasets acquired with various MR contrasts in patients. PMID- 27782729 TI - An iterative projection-based motion estimation and compensation scheme for head x-ray CT. AB - PURPOSE: Although current computed tomography (CT) systems can scan the head in a very short time, patient motion sometimes still induces artifacts. If motion occurs, one has to repeat the scan; to avoid motion, sedation or anesthesia is sometimes applied. METHODS: The authors propose a method to iteratively estimate and compensate this motion during the reconstruction. In every iteration, the rigid motion was estimated view-by-view and then used to update the system matrix. A multiresolution scheme was used to speed up the convergence of this joint estimation of the image and the motion of the subject. A final iterative reconstruction was performed with the last motion estimate. RESULTS: The method was evaluated on simulations, patient scans, and a phantom study. The quality of the reconstructed images was improved substantially after the compensation. In simulation and phantom studies, root-mean-square error was reduced and mean structural similarity was increased. In the patient studies, most of the motion blurring in the reconstructed images disappeared after the compensation. CONCLUSIONS: The proposed method effectively eliminated motion-induced artifacts in head CT scans. Since only measured raw data are needed for the motion estimation and compensation, the proposed method can be applied retrospectively to clinical helical CT scans affected by motion. PMID- 27782730 TI - Comparison of quantitative Y-90 SPECT and non-time-of-flight PET imaging in post therapy radioembolization of liver cancer. AB - PURPOSE: Radioembolization with yttrium-90 microspheres may be optimized with patient-specific pretherapy treatment planning. Dose verification and validation of treatment planning methods require quantitative imaging of the post-therapy distribution of yttrium-90 (Y-90). Methods for quantitative imaging of Y-90 using both bremsstrahlung SPECT and PET have previously been described. The purpose of this study was to compare the two modalities quantitatively in humans. METHODS: Calibration correction factors for both quantitative Y-90 bremsstrahlung SPECT and a non-time-of-flight PET system without compensation for prompt coincidences were developed by imaging three phantoms. The consistency of these calibration correction factors for the different phantoms was evaluated. Post-therapy images from both modalities were obtained from 15 patients with hepatocellular carcinoma who underwent hepatic radioembolization using Y-90 glass microspheres. Quantitative SPECT and PET images were rigidly registered and the total liver activities and activity distributions estimated for each modality were compared. The activity distributions were compared using profiles, voxel-by-voxel correlation and Bland-Altman analyses, and activity-volume histograms. RESULTS: The mean +/- standard deviation of difference in the total activity in the liver between the two modalities was 0% +/- 9% (range -21%-18%). Voxel-by-voxel comparisons showed a good agreement in regions corresponding roughly to treated tumor and treated normal liver; the agreement was poorer in regions with low or no expected activity, where PET appeared to overestimate the activity. The correlation coefficients between intrahepatic voxel pairs for the two modalities ranged from 0.86 to 0.94. Cumulative activity volume histograms were in good agreement. CONCLUSIONS: These data indicate that, with appropriate reconstruction methods and measured calibration correction factors, either Y-90 SPECT/CT or Y-90 PET/CT can be used for quantitative post-therapy monitoring of Y-90 activity distribution following hepatic radioembolization. PMID- 27782731 TI - A modified TEW approach to scatter correction for In-111 and Tc-99m dual-isotope small-animal SPECT. AB - PURPOSE: In dual-isotope (Tc-99m/In-111) small-animal single-photon emission computed tomography (SPECT), quantitative accuracy of Tc-99m activity measurements is degraded due to the detection of Compton-scattered photons in the Tc-99m photopeak window, which originate from the In-111 emissions (cross talk) and from the Tc-99m emission (self-scatter). The standard triple-energy window (TEW) estimates the total scatter (self-scatter and cross talk) using one scatter window on either side of the Tc-99m photopeak window, but the estimate is biased due to the presence of unscattered photons in the scatter windows. The authors present a modified TEW method to correct for total scatter that compensates for this bias and evaluate the method in phantoms and in vivo. METHODS: The number of unscattered Tc-99m and In-111 photons present in each scatter-window projection is estimated based on the number of photons detected in the photopeak of each isotope, using the isotope-dependent energy resolution of the detector. The camera-head-specific energy resolutions for the 140 keV Tc-99m and 171 keV In-111 emissions were determined experimentally by separately sampling the energy spectra of each isotope. Each sampled spectrum was fit with a Linear + Gaussian function. The fitted Gaussian functions were integrated across each energy window to determine the proportion of unscattered photons from each emission detected in the scatter windows. The method was first tested and compared to the standard TEW in phantoms containing Tc-99m:In-111 activity ratios between 0.15 and 6.90. True activities were determined using a dose calibrator, and SPECT activities were estimated from CT-attenuation-corrected images with and without scatter correction. The method was then tested in vivo in six rats using In-111-liposome and Tc-99m-tetrofosmin to generate cross talk in the area of the myocardium. The myocardium was manually segmented using the SPECT and CT images, and partial volume correction was performed using a template-based approach. The rat heart was counted in a well-counter to determine the true activity. RESULTS: In the phantoms without correction for Compton-scatter, Tc-99m activity quantification errors as high as 85% were observed. The standard TEW method quantified Tc-99m activity with an average accuracy of -9.0% +/- 0.7%, while the modified TEW was accurate within 5% of truth in phantoms with Tc-99m:In-111 activity ratios >=0.52. Without scatter-correction, In-111 activity was quantified with an average accuracy of 4.1%, and there was no dependence of accuracy on the activity ratio. In rat myocardia, uncorrected images were overestimated by an average of 23% +/- 5%, and the standard TEW had an accuracy of -13.8% +/- 1.6%, while the modified TEW yielded an accuracy of -4.0% +/- 1.6%. CONCLUSIONS: Cross talk and self-scatter were shown to produce quantification errors in phantoms as well as in vivo. The standard TEW provided inaccurate results due to the inclusion of unscattered photons in the scatter windows. The modified TEW improved the scatter estimate and reduced the quantification errors in phantoms and in vivo. PMID- 27782732 TI - Flexible radioluminescence imaging for FDG-guided surgery. AB - PURPOSE: Flexible radioluminescence imaging (Flex-RLI) is an optical method for imaging 18F-fluorodeoxyglucose (FDG)-avid tumors. The authors hypothesize that a gadolinium oxysulfide: terbium (GOS:Tb) flexible scintillator, which loosely conforms to the body contour, can enhance tumor signal-to-background ratio (SBR) compared with RLI, which utilizes a flat scintillator. The purpose of this paper is to characterize flex-RLI with respect to alternative modalities including RLI, beta-RLI (RLI with gamma rejection), and Cerenkov luminescence imaging (CLI). METHODS: The photon sensitivity, spatial resolution, and signal linearity of flex RLI were characterized with in vitro phantoms. In vivo experiments utilizing 13 nude mice inoculated with the head and neck (UMSCC1-Luc) cell line were then conducted in accordance with the institutional Administrative Panel on Laboratory Animal Care. After intravenous injection of 18F-FDG, the tumor SBR values for flex-RLI were compared to those for RLI, beta-RLI, and CLI using the Wilcoxon signed rank test. RESULTS: With respect to photon sensitivity, RLI, beta-RLI, and flex-RLI produced 1216.2, 407.0, and 98.6 times more radiance per second than CLI. Respective full-width half maximum values across a 0.5 mm capillary tube were 6.9, 6.4, 2.2, and 1.5 mm, respectively. Flex-RLI demonstrated a near perfect correlation with 18F activity (r = 0.99). Signal uniformity for flex-RLI improved after more aggressive homogenization of the GOS powder with the silicone elastomer during formulation. In vivo, the SBR value for flex-RLI (median 1.29; interquartile range 1.18-1.36) was statistically greater than that for RLI (1.08; 1.02-1.14; p < 0.01) by 26%. However, there was no statistically significant difference in SBR values between flex-RLI and beta-RLI (p = 0.92). Furthermore, there was no statistically significant difference in SBR values between flex-RLI and CLI (p = 0.11) in a more limited dataset. CONCLUSIONS: Flex-RLI provides high quality images with SBRs comparable to those from CLI and beta-RLI in a single 10 s acquisition. PMID- 27782733 TI - Technical Note: Calibrating radiochromic film in beams of uncertain quality. AB - PURPOSE: The dose-response of radiochromic film has been shown to be dependent on the quality of the incident radiation, particularly at low energies. Difficulty therefore arises when a calibration is required for radiation of uncertain energy. This study investigates the ability of a recently published calibration method [see M. Tamponi et al., "A new form of the calibration curve in radiochromic dosimetry. Properties and results," Med. Phys. 43, 4435-4446 (2016)] to reduce the energy-dependence of radiochromic film. This allows for corrections to be applied that may improve the accuracy and precision of measurements taken in beams of uncertain energy or where the beam quality is known but calibration doses cannot be delivered. METHODS: Gafchromic EBT3 film was irradiated with a range of superficial, orthovoltage, and high-energy photon beams. Calibrations were then applied using a typical net optical density approach and compared with the Tamponi et al. method that instead defines the response as a ratio of two net optical densities. To quantify the energy dependence, the response at each beam quality and dose was then normalized to the response at a preselected reference quality. This resulted in a relative measure that could be used to correct the calibration curve at the reference beam quality to any other quality of interest. RESULTS: The Tamponi et al. calibration method resulted in substantially less energy dependence compared to the standard net optical density approach, without compromising the calibration fit. The maximum deviation from the reference beam calibration curve was 7% across the range of energies and doses analyzed, reducing to <3% for doses greater than 200 cGy. However, the ability of the calibration curve to fit the data deteriorated as the curve was refitted with measurements at higher doses than those originally studied. CONCLUSIONS: The Tamponi et al. calibration method, based on the ratio of two net optical densities, considerably reduces the energy dependence of Gafchromic EBT3 film. Manipulating the calibration data in the fashion presented in this study allows for a readily available calibration curve to be corrected to represent calibration curves at different energies. This may be useful when a calibration is desired for a beam where the delivery of a set of calibration doses is problematic, such as with out-of-field measurements, radioactive sources, and imaging applications. PMID- 27782734 TI - Reference-based MRI. AB - PURPOSE: In many clinical MRI scenarios, existing imaging information can be used to significantly shorten acquisition time or to improve Signal to Noise Ratio (SNR). In this paper the authors present a framework, referred to as FASTMER, for fast MRI by exploiting a reference image. METHODS: The proposed approach utilizes the possible similarity of the reference image to the acquired image, which exists in many clinical MRI imaging scenarios. Examples include similarity between adjacent slices in high resolution MRI, similarity between various contrasts in the same scan and similarity between different scans of the same patient. To account for the fact that the reference image may exhibit low similarity with the acquired image the authors develop an iterative weighted reconstruction approach, which tunes the weights according to the degree of similarity. RESULTS: Experimental results demonstrate the performance of the method in three different clinical MRI scenarios: The first example demonstrates SNR improvement in high resolution brain MRI, the second scenario exploits similarity between T2-weighted and fluid-attenuated inversion recovery (FLAIR) for fast FLAIR scanning and the last application utilizes similarity between baseline and follow-up scans for fast follow-up acquisition. The results show that FASTMER outperforms image reconstruction of existing state-of-the-art methods. CONCLUSIONS: The authors present a framework for fast MRI by exploiting a reference image. Recovery is based on an iterative algorithm that supports cases in which similarity to the reference scan is not guaranteed. This extends the applicability of the FASTMER to different MRI scanning scenarios. Thanks to the existence of reference images in various clinical imaging tasks, the proposed framework can play a major role in improving reconstruction in many MR applications. PMID- 27782735 TI - Evaluation of the dose calculation accuracy for small fields defined by jaw or MLC for AAA and Acuros XB algorithms. AB - PURPOSE: Small field measurements are challenging, due to the physical characteristics coming from the lack of charged particle equilibrium, the partial occlusion of the finite radiation source, and to the detector response. These characteristics can be modeled in the dose calculations in the treatment planning systems. Aim of the present work is to evaluate the MU calculation accuracy for small fields, defined by jaw or MLC, for anisotropic analytical algorithm (AAA) and Acuros XB algorithms, relative to output measurements on the beam central axis. METHODS: Single point output factor measurement was acquired with a PTW microDiamond detector for 6 MV, 6 and 10 MV unflattened beams generated by a Varian TrueBeam STx equipped with high definition-MLC. Fields defined by jaw or MLC apertures were set; jaw-defined: 0.6 * 0.6, 0.8 * 0.8, 1 * 1, 2 * 2, 3 * 3, 4 * 4, 5 * 5, and 10 * 10 cm2; MLC-defined: 0.5 * 0.5 cm2 to the maximum field defined by the jaw, with 0.5 cm stepping, and jaws set to: 2 * 2, 3 * 3, 4 * 4, 5 * 5, and 10 * 10 cm2. MU calculation was obtained with 1 mm grid in a virtual water phantom for the same fields, for AAA and Acuros algorithms implemented in the Varian eclipse treatment planning system (version 13.6). Configuration parameters as the effective spot size (ESS) and the dosimetric leaf gap (DLG) were varied to find the best parameter setting. Differences between calculated and measured doses were analyzed. RESULTS: Agreement better than 0.5% was found for field sizes equal to or larger than 2 * 2 cm2 for both algorithms. A dose overestimation was present for smaller jaw-defined fields, with the best agreement, averaged over all the energies, of 1.6% and 4.6% for a 1 * 1 cm2 field calculated by AAA and Acuros, respectively, for a configuration with ESS = 1 mm for both X and Y directions for AAA, and ESS = 1.5 and 0 mm for X and Y directions for Acuros. Conversely, a calculated dose underestimation was found for small MLC-defined fields, with the best agreement averaged over all the energies, of -3.9% and 0.2% for a 1 * 1 cm2 field calculated by AAA and Acuros, respectively, for a configuration with ESS = 0 mm for both directions and both algorithms. CONCLUSIONS: For optimal setting applied in the algorithm configuration phase, the agreement of Acuros calculations with measurements could achieve the 3% for MLC-defined fields as small as 0.5 * 0.5 cm2. Similar agreement was found for AAA for fields as small as 1 * 1 cm2. PMID- 27782736 TI - Effects of high and low sodium diet on blood pressure and heart rate in mice lacking the functional grainyhead-like 1 gene. AB - Hypertension is a major health problem throughout the world because of its high prevalence and its association with increased risk of cardiovascular disease. Two independent studies discovered a locus conferring susceptibility to essential hypertension on chromosome 2, in the 2p25 region, but the causative gene remains unknown. Grainyhead-like 1 (GRHL1) is one of the genes located in this region. Our experiments determined that the Grhl1 -null mice, when fed standard diet, have the same blood pressure as their wild type littermate controls. However, we discovered that blood pressure of these mice increases following high sodium diet and decreases when they are fed low sodium diet, and similar effects were not observed in the control wild type littermates. This suggests that the Grhl1 -null mice are sensitive to the development of salt-sensitive hypertension. Thus it is possible that the GRHL1 gene is involved in the regulation of blood pressure, and it may be the causative gene for the locus of susceptibility to essential hypertension in the 2p25 region. PMID- 27782737 TI - Resveratrol alleviates ethanol-induced hormonal and metabolic disturbances in the rat. AB - Resveratrol is a polyphenol found in different plant species and having numerous health-promoting properties in animals and humans. However, its protective action against deleterious effects of ethanol is poorly elucidated. In the present study, the influence of resveratrol (10 mg/kg/day) on some hormones and metabolic parameters was determined in rats ingesting 10 % ethanol solution for two weeks. Blood levels of insulin, glucagon and adiponectin were affected by ethanol, however, resveratrol partially ameliorated these changes. Moreover, in ethanol drinking rats, liver lipid accumulation was increased, whereas resveratrol was capable of reducing liver lipid content, probably due to decrease in fatty acid synthesis. Resveratrol decreased also blood levels of triglycerides and free fatty acids and reduced gamma-glutamyl transferase activity in animals ingesting ethanol. These results show that resveratrol, already at low dose, alleviates hormonal and metabolic changes induced by ethanol in the rat and may be useful in preventing and treating some consequences of alcohol consumption. PMID- 27782738 TI - Interleukin-10 is differentially expressed in the small intestine and the colon experiencing chronic inflammation and ulcerative colitis induced by dextran sodium sulfate in young pigs. AB - Intestinal inflammation induced with dextran sodium sulfate (DSS) is used to study acute or chronic ulcerative colitis in animal models. Decreased gut tissue anti-inflammatory cytokine IL-10 concentration and mRNA abundance are associated with the development of chronic bowel inflammation. Twelve piglets of 3 days old were fitted with an intragastric catheter and randomly allocated into control and DSS groups by administrating either sterile saline or 1.25 g of DSS/kg body weight (BW) in saline per day, respectively, for 10 days. Growth rate and food conversion efficiency were reduced (p<0.05) in the DSS piglets compared with the control group. Quantitative histopathological grading of inflammation in the jejunum and colon collectively showed that the DSS treatment resulted in 12 fold greater (p<0.05) inflammation severity scoring in the colon than in the jejunum, indicative of chronic ulcerative colitis in the colon. Upper gut permeability endpoint was 27.4 fold higher (p<0.05) in the DSS group compared with the control group. The DSS group had higher concentrations and mRNA abundances (p<0.05) of TNF-alpha and IL-6 in the jejunal and colonic tissues compared with the control group. Colonic concentration and mRNA abundance of IL-10 were reduced (p<0.05), however, jejunal IL-10 mRNA abundance was increased (p<0.05) in the DSS group compared with the control group. In conclusion, administration of DSS at 1.25 g/kg BW for 10 days respectively induced acute inflammation in the jejunum and chronic inflammation and ulcerative colitis in the colon with substantially decreased colonic concentration and mRNA abundance of IL-10 in the young pigs, mimicking the IL-10 expression pattern in humans Associated with chronic bowel inflammation. PMID- 27782739 TI - Body composition is associated with bone and glucose metabolism in postmenopausal women with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is associated with increased fracture risk; the underlying mechanism remains unexplained. This study aimed to investigate the relationships between body composition and bone and glucose metabolism in postmenopausal women with T2DM. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) and body composition. A total of 68 postmenopausal women with T2DM and 71 controls were eligible for the study. In contrast to normal BMD in T2DM, a similar prevalence of low-trauma fractures was observed in both groups. T2DM women had significantly higher Trunk fat% and A/G ratio and significantly lower Legs LM% and Legs FM%. Legs LM% was significantly lower in fractured T2DM group and negatively correlated with glycaemia and HbA1c (p<0.01). Serum osteocalcin was significantly lower in T2DM and inversely correlated with FM%, Trunk FM% and A/G ratio (p<0.01) and positively correlated with Legs FM% and total LM% (p<0.05). In conclusion, abdominal obesity and decrease in muscle mass may contribute to low bone formation in T2DM women. Further research is needed to unravel underlying pathophysiological mechanisms and to determine whether maintenance of muscle mass, especially in the lower extremities and/or reduction of central fat mass can prevent fractures. PMID- 27782740 TI - Vasodilatory responses of renal interlobular arteries to epoxyeicosatrienoic acids analog are not enhanced in Ren-2 transgenic hypertensive rats: evidence against a role of direct vascular effects of epoxyeicosatrienoic acids in progression of experimental heart failure. AB - Pathophysiological mechanisms underlying the development of renal dysfunction and progression of congestive heart failure (CHF) remain poorly understood. Recent studies have revealed striking differences in the role of epoxyeicosatrienoic acids (EETs), active products of cytochrome P-450-dependent epoxygenase pathway of arachidonic acid, in the progression of aorto-caval fistula (ACF)-induced CHF between hypertensive Ren-2 renin transgenic rats (TGR) and transgene-negative normotensive Hannover Sprague-Dawley (HanSD) controls. Both ACF TGR and ACF HanSD strains exhibited marked intrarenal EETs deficiency and impairment of renal function, and in both strains chronic pharmacologic inhibition of soluble epoxide hydrolase (sEH) (which normally degrades EETs) normalized EETs levels. However, the treatment improved the survival rate and attenuated renal function impairment in ACF TGR only. Here we aimed to establish if the reported improved renal function and attenuation of progression of CHF in ACF TGR observed after she blockade depends on increased vasodilatory responsiveness of renal resistance arteries to EETs. Therefore, we examined the responses of interlobar arteries from kidneys of ACF TGR and ACF HanSD rats to EET-A, a new stable 14,15-EET analog. We found that the arteries from ACF HanSD kidneys rats exhibited greater vasodilator responses when compared to the ACF TGR arteries. Hence, reduced renal vasodilatory responsiveness cannot be responsible for the lack of beneficial effects of chronic sEH inhibition on the development of renal dysfunction and progression of CHF in ACF HanSD rats. PMID- 27782741 TI - Apocynin ameliorates pressure overload-induced cardiac remodeling by inhibiting oxidative stress and apoptosis. AB - Oxidative stress plays an important role in pressure overload-induced cardiac remodeling. The purpose of this study was to determine whether apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, attenuates pressure overload-induced cardiac remodeling in rats. After abdominal aorta constriction, the surviving rats were randomly divided into four groups: sham group, abdominal aorta constriction group, apocynin group, captopril group. Left ventricular pathological changes were studied using Masson's trichrome staining. Metalloproteinase-2 (MMP-2) levels in the left ventricle were analyzed by western blot and gelatin zymography. Oxidative stress and apoptotic index were also examined in cardiomyocytes using dihydroethidium and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), respectively. Our results showed that abdominal aorta constriction significantly caused excess collagen deposition and cardiac insult. Treatment with apocynin significantly inhibited deposition of collagen and reduced the level of MMP-2. Furthermore, apocynin also decreased the NADPH oxidase activity, reactive oxygen species production and cardiomyocyte apoptotic index. Interestingly, apocynin only inhibited NADPH oxidase activity without affecting its expression or the level of angiotensin II in the left ventricle. In conclusion, apocynin reduced collagen deposition, oxidative stress, and inhibited apoptosis, ultimately ameliorating cardiac remodeling by mechanisms that are independent of the renin-angiotensin system. PMID- 27782742 TI - Short-term administration of melatonin or ghrelin on diabetic rats: effects on angiotensin II and vasopressin-induced uterine contractility. AB - The aim of the present study was to investigate the effects of Angiotensin II (Ang II) and Arginin-Vasopressin (AVP) on contractility of non-pregnant uterus in diabetic Wistar rats and to explore whether one-week administration of Melatonin (MLT) or Ghrelin (GHR) will change the response of diabetic uterine muscle to AngII and AVP. Uterine horns, prepared by the method of isolated tissues were investigated as well as glycemic profile, blood pressure and body weight. The research of smooth muscle contractions was made by a new method of analysis, characterizing in detail the various phases of the myometrial activity. Differences in the development of the peptide-mediated smooth muscle contractions depending on the phase of the estrous cycle were observed. Experimental diabetes had a pronounced negative effect on force and time-parameters of AngII and AVP stimulated uterine contractions. Administration of GHR or MLT had a beneficial effect on the glycemic status of diabetic rats and partially improved the response of uterine preparations to the peptides. The application of MLT increased both force and time-parameters of Ang II-and AVP-stimulated uterine contractions while treatment with GHR increased power characteristics and shortened contraction and relaxation of the smooth muscle process. PMID- 27782743 TI - The labile iron pool in monocytes reflects the activity of the atherosclerotic process in men with chronic cardiovascular disease. AB - The study investigates the relationship between the labile iron pool (LIP) in circulating monocytes and markers of iron metabolism, inflammation, oxidative stress, endothelial dysfunction and arterial elasticity in patients with chronic cardiovascular disease and in healthy volunteers. The patients with a history of CVEs had significantly higher LIP values than did the control group (1.94+/-0.46 microM vs. 1.62+/-0.49 microM, p=0.02). Except for the leukocyte number (WBCs), the groups did not differ in other inflammatory markers (CRPus, CD 163, MPO, MMP 1). Similarly, there were no differences in the markers of endothelial dysfunction (ICAM, VCAM, E-selectin, vWF). The CVE group had higher pulse pressures, levels of markers of impaired arterial elasticity (AI, Young's modulus, pulsatility, stiffness index), IMT values and ABI values. The LIP concentration was significantly correlated with the transferrin receptor/ferritin ratio, hepcidin levels, VFT content and the ABI and ET values. Patients with a history of CVE have significantly higher concentrations of iron in their intracellular LIP in circulating monocytes than do healthy controls. The independent and significant correlation of LIP with markers of the progression of atherosclerosis and arterial stiffness suggests LIP as a possible novel marker of atherosclerotic activity. PMID- 27782744 TI - Efficacy and safety of human mesenchymal stromal cells in healing of critical size bone defects in immunodeficient rats. AB - To evaluate the preclinical efficacy and safety of human mesenchymal stem cells (hMSC) rapidly expanded in growth medium for clinical use with human serum and recombinant growth factors, we conducted a controlled, randomized trial of plasma clots with hMSC vs. plasma clots only in critical segmental femoral defects in rnu/rnu immunodeficient rats. X-ray, microCT and histomorphometrical evaluation were performed at 8 and 16 weeks. MSC were obtained from healthy volunteers and patients with lymphoid malignancy. Human MSC survived in the defect for the entire duration of the trial. MSC from healthy volunteers, in contrast to hMSC from cancer patients, significantly improved bone healing at 8, but not 16 weeks. However, at 16 weeks, hMSC significantly improved vasculogenesis in residual defect. We conclude that hMSC from healthy donors significantly contributed to the healing of bone defects at 8 weeks and to the vascularisation of residual connective tissue for up to 16 weeks. We found the administration of hMSC to be safe, as no adverse reaction to human cells at the site of implantation and no evidence of migration of hMSC to distant organs was detected. PMID- 27782746 TI - Metabolic status and ghrelin regulate plasma levels and release of ovarian hormones in layer chicks. AB - The aim of the present study was to examine the role of nutritional status, the metabolic hormone ghrelin and their interrelationships in the control of chicken hormones involved in the regulation of reproduction. For this purpose, we identified the effect of food deprivation, administration of ghrelin 1-18 and their combination on plasma levels of testosterone (T), estradiol (E), arginine vasotocin (AVT) and growth hormone (GH) as well as the release of these hormones by isolated and cultured ovarian fragments. It was observed that food deprivation reduces plasma T and E and increases plasma AVT and GH levels. Food restriction also reduced the amount of E produced by isolated ovaries, but it did not affect the ovarian secretion of T and AVT. No ovarian GH secretion was detected. Ghrelin administered to ad libitum fed chickens did not affect plasma T and E levels, but it did increase plasma GH and AVT concentrations. Moreover, it partially prevented the effect of food deprivation on plasma E and AVT levels, but not on T or GH levels. Ghrelin administration to control birds promoted ovarian T, but not E or AVT release and reduced T and no other hormonal outputs in birds subjected to food restriction. Our results (1) confirmed the ovarian origin of the main plasma T and E and the extra-ovarian origin of the main blood AVT and GH; (2) showed that food deprivation-induced suppression of reproduction may be caused by suppression of T and E and the promotion of AVT and GH release; (3) suggest the involvement of ghrelin in control chicken E, AVT and GH output; and (4) indicates that ghrelin can either mimic or modify the effect of the intake of low calories on chicken plasma and ovarian hormones, i.e. it can mediate the effect of metabolic state on hormones involved in the control of reproduction. PMID- 27782745 TI - Obestatin modulates ghrelin's effects on the basal and stimulated testosterone secretion by the testis of rat: an in vitro study. AB - The functional antagonism between obestatin and ghrelin in the testis is under investigation. We investigated the ability of obestatin to counteract the inhibitory effect of ghrelin on basal and stimulated testosterone (T) secretion in vitro. Testicular strips from adult rats were incubated with 10 ng/ml and 100 ng/ml of obestatin alone, ghrelin alone and obestatin + ghrelin. Obestatin modulation of stimulated T secretion was evaluated by incubation of testicular samples with 10 ng/ml and 100 ng/ml obestatin, ghrelin and obestatin + ghrelin in the absence and presence of 10 IU of human chorionic gonadotrophin (hCG). T concentrations in the hCG treated groups were significantly (P<0.0001) higher than those in the control groups. Obestatin caused a significant increase in basal T secretion in a dose-dependent manner; however, obestatin at the both 10 ng/ml and 100 ng/ml significantly (P<0.0001) increased hCG-stimulated T secretion. In contrast, ghrelin in a dose-dependent manner significantly (P<0.001) decreased both basal and hCG-induced T secretion by testicular slices. Obestatin opposed the inhibitory effect of ghrelin on T secretion under both basal and hCG-stimulated conditions at all doses tested. In conclusions, administration of obestatin was able to antagonize the inhibitory effect of ghrelin on testosterone secretion in vitro. PMID- 27782747 TI - Three types of ion channels in the cell membrane of mouse fibroblasts. AB - Patch clamp recordings carried out in the inside-out configuration revealed activity of three kinds of channels: nonselective cation channels, small conductance K(+) channels, and large-conductance anion channels. The nonselective cation channels did not distinguish between Na(+) and K(+). The unitary conductance of these channels reached 28 pS in a symmetrical concentration of 200 mM NaCl. A lower value of this parameter was recorded for the small-conductance K(+) channels and in a 50-fold gradient of K(+) (200 mM/4 mM) it reached 8 pS. The high selectivity of these channels to potassium was confirmed by the reversal potential (-97 mV), whose value was close to the equilibrium potential for potassium (-100 mV). One of the features of the largeconductance anion channels was high conductance amounting to 493 pS in a symmetrical concentration of 200 mM NaCl. The channels exhibited three subconductance levels. Moreover, an increase in the open probability of the channels at voltages close to zero was observed. The anion selectivity of the channels was low, because the channels were permeable to both Cl(-) and gluconate - a large anion. Research on the calcium dependence revealed that internal calcium activates nonselective cation channels and small-conductance K(+) channels, but not largeconductance anion channels. PMID- 27782748 TI - Connexin 50 mutation lowers blood pressure in spontaneously hypertensive rat. AB - We assessed the effect of the previously uncovered gap junction protein alpha 8 (Gja8) mutation present in spontaneously hypertensive rat - dominant cataract (SHR-Dca) strain on blood pressure, metabolic profile, and heart and renal transcriptomes. Adult, standard chow-fed male rats of SHR and SHR-Dca strains were used. We found a significant, consistent 10-15 mmHg decrease in both systolic and diastolic blood pressures in SHR-Dca compared with SHR (P<0.01 and P<0.05, respectively; repeated measures analysis of variance (ANOVA)). With immunohistochemistry, we were able to localize Gja8 in heart, kidney, aorta, liver, and lungs, mostly in endothelium; with no differences in expression between strains. SHR-Dca rats showed decreased body weight, high-density lipoprotein cholesterol concentrations and basal insulin sensitivity in muscle. There were 21 transcripts common to the sets of 303 transcripts in kidney and 487 in heart showing >1.2-fold difference in expression between SHR and SHR-Dca. Tumor necrosis factor was the most significant upstream regulator and glial cell derived neurotrophic factor family ligand-receptor interactions was the common enriched and downregulated canonical pathway both in heart and kidney of SHR-Dca. The connexin 50 mutation L7Q lowers blood pressure in the SHR-Dca strain, decreases high-density lipoprotein cholesterol, and leads to substantial transcriptome changes in heart and kidney. PMID- 27782749 TI - Lower physical fitness in patients with primary aldosteronism is linked to the severity of hypertension and kalemia. AB - Hypokalemia as a typical feature of primary aldosteronism (PA) is associated with muscle weakness and could contribute to lower cardiopulmonary fitness. The aim of this study was to describe cardiopulmonary fitness and exercise blood pressure and their determinants during a symptom-limited exercise stress test in patients with PA. We performed a cross-sectional study of patients with confirmed PA who were included before adrenal vein sampling on whom a symptom-limited exercise stress test with expired gas analysis was performed. Patients were switched to the treatment with doxazosin and verapamil at least two weeks before the study. In 27 patients (17 male) the VO(2peak) was 25.4+/-6.0 ml/kg/min which corresponds to 80.8+/-18.9 % of Czech national norm. Linear regression analysis shows that VO(2peak) depends on doxazosin dose (DX) (p=0.001) and kalemia (p=0.02): VO(2peak) = 4.2 - 1.0 * DX + 7.6 * Kalemia. Patients with higher doxazosin doses had a longer history of hypertension and had used more antihypertensives before examination, thus indicating that VO(2peak) also depends on the severity of hypertension. In patients with PA, lower cardiopulmonary fitness depends inversely on the severity of hypertension and on lower plasma potassium level. PMID- 27782750 TI - Rehabilitation of activities of daily living in virtual environments with intuitive user interface and force feedback. AB - PURPOSE: To investigate the feasibility of using a virtual rehabilitation system with intuitive user interface and force feedback to improve the skills in activities of daily living (ADL). METHOD: A virtual training system equipped with haptic devices was developed for the rehabilitation of three ADL tasks - door unlocking, water pouring and meat cutting. Twenty subjects with upper limb disabilities, supervised by two occupational therapists, received a four-session training using the system. The task completion time and the amount of water poured into a virtual glass were recorded. The performance of the three tasks in reality was assessed before and after the virtual training. Feedback of the participants was collected with questionnaires after the study. RESULTS: The completion time of the virtual tasks decreased during the training (p < 0.01) while the percentage of water successfully poured increased (p = 0.051). The score of the Borg scale of perceived exertion was 1.05 (SD = 1.85; 95% CI = 0.18 1.92) and that of the task specific feedback questionnaire was 31 (SD = 4.85; 95% CI = 28.66-33.34). The feedback of the therapists suggested a positive rehabilitation effect. The participants had positive perception towards the system. CONCLUSIONS: The system can potentially be used as a tool to complement conventional rehabilitation approaches of ADL. Implications for rehabilitation Rehabilitation of activities of daily living can be facilitated using computer assisted approaches. The existing approaches focus on cognitive training rather than the manual skills. A virtual training system with intuitive user interface and force feedback was designed to improve the learning of the manual skills. The study shows that system could be used as a training tool to complement conventional rehabilitation approaches. PMID- 27782751 TI - Osteocutaneous bone flap - a useful variant of the osteoplastic flap in pediatric patients. AB - Traditional teaching describes two types of bone flaps in craniotomies - 'free bone flap' and osteoplastic craniotomies. While in the former, the entire bone flap devoid of soft tissue attachments is removed, in the latter the bone flap that is turned is hinged on a pedicle of temporalis muscle with the aim of retaining its vascular supply. We describe a variant of the latter in 13 pediatric patients in whom the lower margin of the craniotomy was above the attachment of the temporalis muscle and where the bone flap was lifted with all the layers of the scalp including the skin and galea, highlighting the thought process behind its performance and the advantages of the same. PMID- 27782752 TI - Therapy implications of the role of interleukin-2 in cancer. AB - INTRODUCTION: Despite its apparent failure in cancer therapy, IL-2 still remains fundamental in the activation of antitumor immunity. Areas covered: The aim of this review is the reinterpretation of the role of IL-2 in anticancer immunity, according to knowledge gained of the cytokine network, by highlighting its importance in inducing T helper-1 (TH1) cell proliferation, natural killer (NK) actHivation and IL-12 secretion. However, its main negative effect is the stimulation of regulatory T cells (Tregs), which in contrast suppresses anticancer immunity. Expert commentary: Cardiovascular toxicity, which was the main clinical problem at the beginning of IL-2 therapy at high intravenous doses, has almost been completely solved by subcutaneous low-dose IL-2 injection. In order to enhance the anticancer efficacy of IL-2, several strategies have been explored, including chemotherapy and interferon, but up until now no regimen has appeared to be clearly better than IL-2 alone. However, considering the role of immune checkpoints (PD-1 and CTLA-4) in Tregs stimulation, the most effective immunotherapy in the future could be concomitant IL-2 administration, to enhance lymphocyte count, and checkpoint inhibitors, such as anti-PD1 or anti-CTLA-4 monoclonal antibodies, or IL-12, which is also able to counteract IL-2-induced Treg cell generation. Therefore, the time for IL-2 immunotherapy in cancer treatment has finally arrived. PMID- 27782753 TI - Effects of heterogeneous risk factors on psychological distress in adolescents with autism and victimization experiences in Taiwan. AB - PURPOSE: To investigate the prevalence of various types of bullying victimization among adolescents with autism spectrum disorder (ASD) and examine the effects of victimization on the mental health of adolescents with ASD. METHODS: The sample was collected from the Special Needs Education Longitudinal Study (SNELS) database released in 2011. Variables comprising seven psychological distress (PD) items and four types of bullying victimization and family-, school-, and peer related factors were included in a multivariate regression analysis. RESULTS: Exclusion and verbal bullying were most frequently reported, 72.4% of students with ASD experiencing exclusion bullying and 66% of them experiencing verbal bullying. Among the victims, delayed bedtime, use of medication, and conflicts with parents significantly increased PD. By contrast, good relationships with parents and friends and liking school environments relieved PD symptoms. Furthermore, delayed bedtime after 12 a.m. enhanced the effects of exclusion victimization on PD in the participants. CONCLUSIONS: Our results indicated that bullying victimization among adolescents with ASD was a risk factor for their psychological well-being. Nevertheless, good parent-adolescent and interpeer relationships improved their mental health. Our results can serve as a reference in implementing strategies for motivating parents and teachers to pay more attention to the needs of adolescents with ASD. Implications for Rehabilitation More than 80% of adolescents with autism experience at least one type of bullying victimization. Bullying victimization attributes to a major factor influencing mental health of adolescents with autism. Good parent-adolescent and interpeer relationships can play beneficial roles in improving mental health of the adolescents. PMID- 27782755 TI - Erratum. PMID- 27782754 TI - Pulmonary metastases from benign calvarial meningioma: a case report. AB - The most common intracranial tumour is meningioma, which rarely presents with extracranial metastasis, especially in benign cases. We report a case of meningioma recurrence with multiple pulmonary metastases in a patient who had a benign meningioma removed 12 years prior. PMID- 27782756 TI - The Appropriate Use of Breast Massage. PMID- 27782757 TI - Genetic characterization of wild swamp deer populations: ex situ conservation and forensics implications. AB - Swamp deer (Rucervus duvaucelii) is an endemic, Scheduled I species under the Wildlife (Protection) Act 1972, India. According to variations in antler size, it has been classified into three subspecies, namely Western (R. duvaucelii duvaucelii), Central (R. duvaucelii branderi), and Eastern (R. duvaucelii ranjitsinhii). For planning effective ex situ and in situ conservation of a wide ranging species in different bioclimatic regions and in wildlife forensic, the use of genetic characterization in defining morpho/ecotypes has been suggested because of the geographic clines and reproductive isolation. In spite of these morphotypes, very little is known about the genetic characteristics of the three subspecies, hence no strict subspecies-based breeding plan for retaining the evolutionary characteristics in captive populations for subsequent re introduction is available except for a few studies. We describe the genetic characteristics of these three subspecies using cytochrome b of the mtDNA genome (400 bp). The DNA sequence data indicated 11 variable sites within the three subspecies. Two paraphyletic clades, namely the Central India and Western-Eastern populations were found, whereas the Western and Eastern populations are monophyletic with a bootstrap value of 69% within the clade. We suggest the need of sorting these three subspecies using different molecular mtDNA markers in zoos for captive breeding purposes so as to retain the genetic diversity of the separate geographic clines and to use a subspecies-specific fixed-state nucleotide to assess the extent of poaching to avoid any population demography stochastically in India. PMID- 27782759 TI - Zinc supplementation alleviates hyperglycemia and associated metabolic abnormalities in streptozotocin-induced diabetic rats. AB - The cause and effect relationship between diabetes and zinc is complex and unclear. This animal study has examined the potential of zinc supplementation in beneficial modulating hyperglycemia, insulin secretion, and metabolic abnormalities associated with diabetes. The study was conducted in streptozotocin induced diabetic rats. Groups of hyperglycemic rats were subjected to dietary interventions for 6 weeks with zinc supplementation (5 times and 10 times the normal level). Supplemental-zinc-fed diabetic groups showed significant control on hyperglycemia and hypoinsulinemia. There was a significant reduction in protein glycosylation, glucosuria, and urinary excretion of proteins and urea in diabetic animals maintained on a zinc-supplemented diet. Diabetic rats showed significantly higher plasma albumin and lower plasma urea and creatinine levels upon zinc supplementation. Significant alterations in insulin sensitivity indices HOMA-IR, HOMA-B, and QUICKI were also indicated by zinc supplementation. The pathological abnormalities in pancreatic islets of diabetic animals were significantly alleviated by dietary zinc intervention. This study provides the first evidence that zinc supplementation can partially ameliorate the severity of diabetic hyperglycemia and associated metabolic abnormalities, hypoinsulinemia, insulin resistance, and altered pancreatic morphology. Thus, zinc supplementation may offer a significant potential for clinical application in managing diabetic hyperglycemia and related metabolic complications. PMID- 27782758 TI - A Cluster Randomized Trial of Tailored Breastfeeding Support for Women with Gestational Diabetes. AB - BACKGROUND: Women with gestational diabetes mellitus (GDM) and their infants are at increased risk of developing metabolic disease; however, longer breastfeeding is associated with a reduction in these risks. We tested an intervention to increase breastfeeding duration among women with GDM. MATERIALS AND METHODS: We conducted a cluster randomized trial to determine the efficacy of a breastfeeding education and support program for women with GDM. Women were enrolled between 22 and 36 weeks of pregnancy and cluster randomized to an experimental lifestyle intervention or wait-list control group. Breastfeeding duration and intensity were prespecified secondary outcomes of the trial. Duration of exclusive and any breastfeeding was assessed at 6 weeks and at 4, 7, and 10 months postpartum. We quantified differences in breastfeeding rates using Kaplan-Meier estimates, log rank tests, and Cox regression models. RESULTS: We enrolled 100 women, of whom 52% were African American, 31% non-Hispanic white, 11% Hispanic, 9% American Indian or Alaskan Native, 2% Asian, 2% other, and 4% more than one race. In models accounting for within-cluster correlation and adjusted for study site, breastfeeding intention, and African American race, women allocated to the intervention group were less likely to stop breastfeeding (adjusted hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.21-0.74) or to introduce formula (adjusted HR 0.50, 95% CI 0.34-0.72). CONCLUSION: Our results suggest that targeted breastfeeding education for women with GDM is feasible and efficacious. CLINICAL TRIALS REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01809431. PMID- 27782760 TI - Cauda equina syndrome. PMID- 27782761 TI - Comparison of microwave ablation, botulinum toxin injection, and liposuction curettage in the treatment of axillary hyperhidrosis: A systematic review. AB - BACKGROUND: Primary focal axillary hyperhidrosis is a disorder of excessive sweating that can strongly impact quality of life. OBJECTIVE: The objective if this study was to compare microwave ablation (MA), botulinum toxin (BT) injection, and liposuction-curettage (LC) in the treatment of primary axillary hyperhidrosis based on subjective and objective criteria. METHODS: A systematic review of the literature published in French or English between 1 January 1991 and 1 February 2015 was completed using PubMed and Embase databases. RESULTS: 16 of 775 articles were selected based on relevance and criteria of inclusion and exclusion. The three methods proved to be efficient and safe; however, MA and BT had better results when compared to LC in the short term. Both MA and LC showed longer lasting results when compared to BT. However, in the long term, MA was superior to LC. CONCLUSION: MA, LC, and BT injections are safe and efficient minimally invasive alternatives for the treatment of axillary hyperhidrosis. Well designed randomized controlled trials are needed to further compare the efficacy of these techniques. PMID- 27782762 TI - Epidemiology and Clinical Features of Uveitis from Urban Populations in South India. AB - PURPOSE: To report the epidemiology of uveitis in two urban centers in South India. METHODS: Case records seen between January 2014 and December 2014 at two tertiary eye centers in South India were retrospectively reviewed. RESULTS: A total of 1123 patients in the study population had uveitis. Anterior uveitis was seen in 48.9%, posterior in 20.5%, intermediate in 17.3%, and panuveitis in 13.3%. Of these cases, 68.4% were acute uveitis. Pediatric uveitis constituted 6.9% patients. Tuberculosis was the commonest infectious etiology. CONCLUSIONS: Idiopathic uveitis was highest in non-infectious and tuberculosis in infectious etiology. Toxoplasmosis was seen in the pediatric age group. PMID- 27782763 TI - Targeting STOX1 in the therapy of preeclampsia. AB - INTRODUCTION: Preeclampsia is a major pregnancy disease, explained partly by genetic predispositions. STOX1, a transcription factor discovered in 2005, was the first gene directly associated with genetic forms of the disease. Alterations of STOX1 expression as well as STOX1 variants have also been associated to Alzheimer's disease. These observations make of this gene a putative therapeutic target. Area covered: Two major isoforms (STOX1A and STOX1B) are encoded by the gene and are theoretically able to compete for the same binding site, while only the most complete (STOX1A) is supposed to be able to activate gene expression. This makes the ratio between STOX1A and STOX1B as well as their position inside the cell (nucleus or cytoplasm) crucial to understand how STOX1 functions. STOX1 appears to have multiple gene targets, especially in pathways connected to inflammation, oxidative stress, and cell cycle. Expert opinion: STOX1-directed therapies, could be directed either towards its targets (genes or pathways), or directly at STOX1. For this the addressing of STOX1 to various cell compartments could theoretically be modified; also it could be possible of altering the balance between the two isoforms, through selectively inhibiting one of them, possibly improving the outcomes in severe preeclampsia. PMID- 27782764 TI - Oleanane derivatives for pharmaceutical use: a patent review (2000-2016). AB - INTRODUCTION: Oleanolic acid has been considered a good start molecule for synthetic exploitation. Thus hundreds of oleanane triterpenoids have been synthesized and patented. Also many oleanane saponins have been patented for their biological activities and possible pharmaceutical use. Areas covered: Patents reporting the biological activities of oleanane derivatives and saponins with oleanane-type aglycones were examined. Among the synthesized oleanane derivatives, the most promising seem to be 2-cyano-3,12-dioxoolean-1,9(11)-dien 28-oic acid derivatives which interfere with many pathways involved in inflammation, oxidative stress and cell proliferation. Regarding oleanane-type saponins, several patents claiming their antiproliferative activity or their possible use as adjuvants in vaccines, were reported. Expert opinion: Despite the great number of synthesized oleanane triterpenoids, only CDDO-Me entered clinical development as a possible drug for the treatment of chronic kidney disease (CKD) but a phase 3 clinical trial was terminated due to heart-related adverse effects. Further phase 2 clinical trials of CDDO-Me are in progress for the treatment of CKD and PAH (pulmonary arterial hypertension) patients without heart-related risk factors. Additional investigations leading to compounds with an improved activity/toxicity profile along with well-designed preclinical and clinical trials are needed. Regarding oleanane-type saponins, the real perspective seems to be as adjuvants in vaccines. PMID- 27782765 TI - Association of Postpartum Predischarge Depot-Medroxyprogesterone Acetate with In Hospital Breastfeeding Initiation. AB - OBJECTIVE: The primary aim of this study was to examine the association between postpartum predischarge depot-medroxyprogesterone acetate (ppDMPA) and in hospital breastfeeding initiation, and the secondary exploratory aim was to determine if any racial disparities are associated with ppDMPA receipt or its relationship to breastfeeding initiation. MATERIALS AND METHODS: We conducted a cross-sectional retrospective chart review of maternal and newborn records at a large urban academic medical center. Variables extracted included in-hospital feeding choice, obstetrical and sociodemographic variables, infant characteristics, and ppDMPA receipt. The association of ppDMPA and maternal-child characteristics with breastfeeding initiation was examined using logistic regression analysis. RESULTS: Among singleton live births of 919 mother-infant pairs (76.5% African American [AA]), 67% initiated breastfeeding (34% exclusive and 33% mixed) and 31.4% received ppDMPA. Breastfeeding rates differed significantly between AA (60.7%) and non-AA mothers (86.6%), and ppDMPA also differed significantly between AA (37.6%) and non-AA mothers (11.6%). Adjusting for other independent predictors, mothers who received ppDMPA were 1.5 times more likely not to initiate breastfeeding if AA, and 5.2 times more likely not to initiate breastfeeding if non-AA. CONCLUSIONS: ppDMPA receipt was independently associated with decreased rates of breastfeeding initiation. Although more AA mothers received ppDMPA than non-AA, the association of ppDMPA with breastfeeding noninitiation was stronger in non-AA than in AA mothers. Future research should examine this question prospectively to ascertain if there is a cause-effect relationship and should address both physiological effects and social perceptions. PMID- 27782766 TI - Investigating the Physiological and Psychosocial Responses of Single- and Dual Player Exergaming in Young Adults. AB - OBJECTIVE: This study investigated the effect of acute exergaming on the physiological and psychosocial responses of young adults and the modulatory effect of a single- or dual-player game play situation. MATERIALS AND METHODS: Thirty-six participants (19 male; 21.7 +/- 3.8 years; 23.65 +/- 3.17 kg/m2) each completed two 30-minute exergame sessions in a randomized order (single and dual player) while wearing an Actiheart(r) to estimate energy expenditure. Positive and negative affect, subjective vitality, and indices of intrinsic motivation were assessed directly after each gaming bout. RESULTS: There was no significant difference in energy expenditure or psychosocial outcomes between conditions. Although males expended more energy than females in both single- (z = -2.124, P = 0.033) and dual-player situations (z = -2.679, P = 0.007), females reported significantly greater vitality (z = -2.219, P = 0.026) and effort/importance than males (z = -2.001, P = 0.045). Conversely, males reported a greater negative affect (z = -2.872, P = 0.004) and pressure/tension (z = -3.295, P = 0.001). A linear mixed effects model revealed that energy expenditure during exergaming was a significant predictor of interest and enjoyment (P = 0.001) and effort and importance (P = 0.001). This relationship between energy expenditure and psychosocial variables was not modulated by sex or order of gameplay (single or dual player first). CONCLUSION: The present results suggest that females have a more positive psychosocial response to exergaming relative to males, highlighting exergames such as WiiTM boxing as a potential avenue for future interventions seeking to address the low physical activity levels that characterize the young adult population. PMID- 27782767 TI - Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia, part III: Molecular mechanisms. AB - OBJECTIVES: Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response. METHODS: This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed. RESULTS: Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition. CONCLUSIONS: Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice. PMID- 27782768 TI - Extrastriatal dopamine D2/3 receptors and cortical grey matter volumes in antipsychotic-naive schizophrenia patients before and after initial antipsychotic treatment. AB - OBJECTIVES: Long-term dopamine D2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D2/3 receptor binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment. METHODS: Twenty-two initially antipsychotic-naive patients underwent magnetic resonance imaging (MRI), [123I]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N = 13) or zuclopenthixol (N = 9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT. RESULTS: Neither extrastriatal D2/3 receptor BPND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post hoc analyses excluding three patients with cannabis use we found that higher D2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume. CONCLUSIONS: The present data do not support an association between extrastriatal D2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies. PMID- 27782769 TI - Prescription opioid abuse and misuse: gap between primary-care investigator assessment and actual extent of these behaviors among patients with chronic pain. AB - OBJECTIVES: To compare the results of two open-label primary care-based studies that examined investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion relative to patient self-reports and urine drug tests (UDTs). METHODS: Risk assessment data from two open-label, multicenter, primary care-based US studies in patients with chronic pain were compared. RESULTS: In one study (n = 1487), 54.4% of patients were at moderate, 24.8% at high, and 20.8% at low risk based on patients' self-reports at baseline on the Screener and Opioid Assessment for Patients with Pain(r)-Revised questionnaire. Investigators assigned 1.3% of patients as high risk despite 5.0% self-reporting prior illicit drug use and 15.3% with positive UDT(s) for an illicit drug at baseline. In the second study (n = 684), few patients were considered by investigators to be at high risk for misuse (1.6%), abuse (1.8%), or diversion (1.0%). However, 10.4% of patients reported prior illicit drug use; 23.4% had at least one abnormal baseline UDT; 60% of 537 patients reported on the Self Reported Misuse, Abuse, and Diversion questionnaire they took more opioids than prescribed; and 10.9% reported chewing/crushing opioids in the past. Of patients completing the Current Opioid Misuse Measure, 40.6% were classified as having aberrant behaviors. CONCLUSION: A comparison of risk assessment across two studies indicates a tendency for investigators to assess patients as lower risk for opioid-related aberrant behaviors despite a significant proportion self reporting aberrant behavior and/or presenting with illicit UDTs. These consistent findings underline the importance of appropriate implementation of objective measures and self-reporting tools when evaluating risk in patients. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers: NCT00640042 and NCT01179191. PMID- 27782771 TI - Beta-Blockers for Exams Identify Students at High Risk of Psychiatric Morbidity. AB - OBJECTIVES: Beta-blockers relieve the autonomic symptoms of exam-related anxiety and may be beneficial in exam-related and performance anxiety, but knowledge on related psychiatric outcomes is unknown. We hypothesized that beta-blocker therapy for exam-related anxiety identifies young students at risk of later psychiatric events. METHODS: Using Danish nationwide administrative registries, we studied healthy students aged 14-30 years (1996-2012) with a first-time claimed prescription for a beta-blocker during the exam period (May-June); students who were prescribed a beta-blocker for medical reasons were excluded. We matched these students on age, sex, and time of year to healthy and study active controls with no use of beta-blockers. Risk of incident use of antidepressants, incident use of other psychotropic medications, and suicide attempts was examined by cumulative incidence curves for unadjusted associations and multivariable cause-specific Cox proportional hazard analyses for adjusted hazard ratios (HRs). RESULTS: We identified 12,147 healthy students with exam-related beta-blocker use and 12,147 matched healthy students with no current or prior use of beta-blockers (median age, 19 years; 80.3% women). Among all healthy students, 0.14% had a first-time prescription for a beta-blocker during the exam period with the highest proportion among students aged 19 years (0.39%). Eighty-one percent of the students filled only that single prescription for a beta-blocker during follow-up. During follow-up, 2225 (18.3%) beta-blocker users and 1400 (11.5%) nonbeta-blocker users were prescribed an antidepressant (p < 0.0001); 1225 (10.1%) beta-blocker users and 658 (5.4%) nonbeta-blocker users were prescribed a psychotropic drug (p < 0.0001); and 16 (0.13%) beta-blocker users and 6 (0.05%) nonbeta-blocker users attempted suicide (p = 0.03). Exam-related beta-blocker use was associated with an increased risk of antidepressant use (adjusted HRs, 1.68 [95% confidence intervals (CIs), 1.57-1.79], p < 0.0001), other psychotropic medication use (HR, 1.93 [95% CI, 1.76-2.12] p < 0.0001), and suicide attempts (HR, 2.67 [95% CI, 1.04-6.82] p = 0.04). CONCLUSION: In healthy students, use of beta-blockers during the exam period was associated with an increased risk of psychiatric outcomes and might identify psychologically vulnerable students who need special attention. PMID- 27782772 TI - Clinical Patterns and Causes of Intraocular Inflammation in a Uveitis Patient Cohort from Egypt. AB - PURPOSE: To analyze the patterns and causes of intraocular inflammation in patients attending uveitis referral clinics in Egypt. METHODS: The study included 454 patients with uveitis examined both at the Department of Ophthalmology, Alexandria Faculty of Medicine, and tertiary uveitis referral clinics in Cairo and the International Eye Clinic in Upper Egypt, between August 2013 and March 2016. All patients had a comprehensive ocular examination and systemic work-up. Standard diagnostic criteria for uveitis syndromes were employed for all patients and ancillary ocular or systemic investigations were ordered as required by the suspected uveitis entity. RESULTS: The mean age at presentation was 30 years (range: 4-75). The male to female ratio was 1.1:1. Panuveitis was the most common anatomic pattern (43%), followed by anterior (40.7%), posterior (9%), and intermediate uveitis (7.3%). Anterior uveitis was most commonly attributed to pediatric parasitic anterior chamber granulomas (22.2%). Intermediate uveitis was most commonly idiopathic (81.8%). Toxoplasma retinitis was the most common cause of posterior uveitis (31.7%). Behcet disease was the most common cause of panuveitis followed by Vogt-Koyanagi-Harada (VKH) disease (45.6% and 22.1%, respectively). Among non-infectious etiologies, Behcet disease was the most frequent etiology (28.6%), while for infectious causes, herpetic uveitis was found to be the most frequent cause (39.8%). CONCLUSIONS: In this uveitis patient population from Egypt, panuveitis was the most commonly encountered anatomic diagnosis. Behcet disease was the most common identified cause of uveitis followed by VKH disease. Herpes-related uveitides and parasitic granulomas represented the most evident causes of infectious uveitis. PMID- 27782773 TI - Levels of dioxins and dioxin-like PCBs in food of animal origin in the Netherlands during the period 2001-2011. AB - The aim of this study was to assess levels of dioxins (polychlorinated dibenzo-p dioxins and dibenzofurans, PCDD/Fs) and dioxin-like polychlorinated biphenyls (PCBs) (DL-PCBs) in food of animal origin produced in the Netherlands, including potential trends in time. Test results from about 2500 samples of animal derived food products (beef, veal, lamb, chicken, pork, deer, milk and eggs), sampled for the National Residue Monitoring Plan from 2001-2011, were evaluated. Most samples were screened with a bioassay and, if suspected, analysed by GC-HRMS. The fraction of samples which were non-compliant with European maximum levels was rather low, being below 1% for most food products, except for lamb. Exceedance of action levels was particularly observed for lamb and beef. To obtain an insight into background levels, a randomly taken part of the samples was directly analysed by GC-HRMS. In general, only minor decreases in mean PCDD/F and DL-PCB concentrations could be observed for the period 2001-2011. This may be due to a plateauing of current background levels but also to factors like the sensitivity of the analytical method. PMID- 27782770 TI - New experimental models of the blood-brain barrier for CNS drug discovery. AB - INTRODUCTION: The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered: This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion: Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms. PMID- 27782774 TI - Effect of Change in Portal Vein Flow Rates on Hepatic Ablations Created with a Bipolar Radiofrequency Ablation Device. AB - Purpose To investigate the effect of change in portal vein flow rates on the size and shape of ablations created by a bipolar radiofrequency (RF) ablation device. Materials and Methods This study was exempt from institutional animal care and use committee review. An in vitro bovine liver model perfused with autologous blood via the portal vein at three flow rates (60, 80, 100 mL/min per 100 g of liver) was used. Four ablations, two bipolar and two monopolar (control probe), were made in each of five livers perfused at each flow rate. Short- and long-axis diameters were measured from gross specimens, and volume and sphericity index were calculated for each ablation. A general linear mixed model accounting for correlation within the liver was used to evaluate the effects of flow on ablations. Analyses were performed by using software. Results There was no significant difference in the size or shape of ablations created by the bipolar device at the different flow rates (P > .05 for all outcomes). The monopolar device demonstrated the expected inverse association between ablation size and change in flow (P < .01 for all outcomes). The mean +/- standard deviation of short-axis diameter, long-axis diameter, volume, and sphericity index of the bipolar ablations was 4.3 cm +/- 0.1, 4.2 cm +/- 0.1, 41.0 cm3 +/- 1.8, and 1.1 +/- 0.1, respectively. Conclusion Unlike monopolar RF ablation, change in portal vein flow rates does not have a statistically significant effect on the size or shape of ablations created by the bipolar RF ablation device tested. (c) RSNA, 2016. PMID- 27782775 TI - Heavy metals in rice samples on the Torbat-Heidarieh market, Iran. AB - Levels of the heavy metals arsenic (As), cadmium (Cd) and lead (Pb) were determined in rice samples imported from India and Pakistan and marketed in Torbat-Heidarieh, Iran. To assess the safety of dietary intake of these metals by rice, the estimated weekly intake (EWI) was calculated and compared with the provisional tolerable weekly intake (PTWI). The results indicated that mean values for Pb and cadmium in imported rice were considerably higher than the safe limit as set by FAO/WHO. EWI for cadmium and As among the consumed types of imported rice was lower than the PTWI. The results also revealed that the weekly intake of Pb was higher than the maximum weekly intake recommended by WHO/FAO. PMID- 27782776 TI - Nickel in milled rice (Oryza sativa L.) from the three main rice-producing regions in China. AB - Nickel (Ni) concentrations in milled rice obtained from China and their variations among different provinces and varieties, as well as associated health risks, were investigated. Results showed that the mean Ni concentration in milled rice was 0.49 +/- 0.51 mg/kg, which was much higher than reported in United Kingdom, French and Iranian cereals. There were significant variations (P < 0.05) of Ni concentrations in milled rice among different provinces and among varieties in the same province. According to the dietary risk assessment, the mean values of the target hazard quotient for chronic risk ranged from 1.24 to 1.46 for 2-4, 4-7 and 7-11-year-old children, and all values of margin of exposure for hypersensitivity risk were considerably below 10 for all age groups, indicating that the current dietary exposure to Ni in rice is of concern for 2-11-year-old children and Ni-sensitised individuals. It is essential to establish a continuous monitoring programme to control Ni contamination in rice. PMID- 27782778 TI - Surrogate Data Methods Based on a Shuffling of the Trials for Synchrony Detection: The Centering Issue. AB - We investigate several distribution-free dependence detection procedures, all based on a shuffling of the trials, from a statistical point of view. The mathematical justification of such procedures lies in the bootstrap principle and its approximation properties. In particular, we show that such a shuffling has mainly to be done on centered quantities-that is, quantities with zero mean under independence-to construct correct p-values, meaning that the corresponding tests control their false positive (FP) rate. Thanks to this study, we introduce a method, named permutation UE, which consists of a multiple testing procedure based on permutation of experimental trials and delayed coincidence count. Each involved single test of this procedure achieves the prescribed level, so that the corresponding multiple testing procedure controls the false discovery rate (FDR), and this with as few assumptions as possible on the underneath distribution, except independence and identical distribution across trials. The mathematical meaning of this assumption is discussed, and it is in particular argued that it does not mean what is commonly referred in neuroscience to as cross-trials stationarity. Some simulations show, moreover, that permutation UE outperforms the trial-shuffling of Pipa and Grun ( 2003 ) and the MTGAUE method of Tuleau Malot et al. ( 2014 ) in terms of single levels and FDR, for a comparable amount of false negatives. Application to real data is also provided. PMID- 27782777 TI - Identification of novel acetylcholinesterase inhibitors through e-pharmacophore based virtual screening and molecular dynamics simulations. AB - Alzheimer's disease (AD), a progressive neurodegenerative disorder is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine via inhibiting acetylcholinesterase (AChE). The present study involves identification of newer AChE inhibitors by dual approach of e-pharmacophore and structure-based virtual screening of Asinex library. Robustness of docking protocol was validated by enrichment calculation with ROC value .71 and BEDROC value .028. Among 11 selected hits, ZINC72338524 with best MM-GBSA dG binding shows optimal range of CNS properties and ligand-AChE complex stability. Further, molecular dynamics study revealed its molecular interactions with Trp86, Phe338, and Tyr341 amino acid residues of catalytic anionic site and Tyr124, Ser125, and Trp286 amino acid residues of peripheral anionic site. Physicochemical properties and ADMET risk prediction indicates their potential in druggability and safety. PMID- 27782780 TI - Automatization of personal and impersonal discourse with narrative re-telling as a function of age. AB - When older adults retell an impersonal story, the resulting narratives are typically characterized by more prolixity and less coherence than those produced by younger adults. We aimed to determine whether this pattern is also observed when retelling a personal narrative. Younger and older participants told a personal story three consecutive times. With retelling, no evidence of increased coherence or fluency or reduction in hesitancy was observed for either age group. The nature of autobiographical narrative construction explains why such stories are not subject to automatization. A failure to automatize personal narratives is not, therefore, a symptom of aging. PMID- 27782779 TI - Effects of Endurance Training on the Skeletal Muscle Nitric Oxide Metabolism in Insulin-Independent Type 2 Diabetic Men-A Pilot Study. AB - BACKGROUND: Increases in the amount of inducible nitric oxide synthase (iNOS) protein and abnormal production of nitric oxide (NO) in skeletal muscle have been suggested to be associated with peripheral insulin resistance in patients with type 2 diabetes mellitus (T2DM). This pilot study analyzed whether a 3-month endurance training can affect iNOS protein and NO metabolite levels in the vastus lateralis muscle of insulin-independent T2DM men, thereby affecting the patients' glycemic control. Furthermore, serum molecules, which have been shown to activate iNOS protein expression in in vitro experiments, were quantified. METHODS: Eight overweight/obese T2DM men (years = 61 +/- 10) participated in the study. Muscle biopsies and venous blood collections were performed at T1 (6 weeks before training), T2 (1 week before training), and T3 (3 to 4 days after training). Protein contents (iNOS) were determined by Western blotting, nitrite concentrations by chemiluminescence, and serum molecule levels by enzyme-linked immunosorbent assay kits. RESULTS: The training reduced iNOS protein contents significantly (T2-T3: approximately -31%, P = 0.018). Nitrite concentrations as well as fasting glucose and HbA1c decreased, but not significantly. Serum tumor necrosis factor-alpha, thiobarbituric acid-reactive substances (lipid peroxidation as an indirect measure of reactive oxygen species), lipopolysaccharide binding protein, interferon-gamma, and interleukin-1beta showed no significant changes. CONCLUSIONS: The data indicate that the endurance training performed in the present study can reduce iNOS protein contents in insulin-independent T2DM men. Future studies should identify key molecules in iNOS regulation in vivo and fully clarify whether iNOS downregulation can help improve insulin sensitivity in T2DM patients in the long term. PMID- 27782781 TI - Co-creating healthful eating behaviors with very young children: The impact of information overload on primary caregivers. AB - Primary caregivers of very young children are subject to excessive and often disparate information regarding the instilling of healthful eating behaviors. Our study focuses on the integration of the operant resources of primary caregivers (i.e., their knowledge and modeling skills) and that of their very young children (i.e., their self-regulation of energy intake and food preferences) to co-create healthful eating behaviors as a measure to curb overweight and obesity in adulthood. Our two-stage qualitative study makes original contributions demonstrating that primary caregivers' efforts to co-create healthful eating behaviors with their very young children are adversely affected by information overload. PMID- 27782782 TI - Uneven reductions in high school students' alcohol use from 2007 to 2012 by age, sex, and socioeconomic strata. AB - BACKGROUND: Many Western countries have reported declines in adolescent alcohol use. This study examined changes in adolescent alcohol use in New Zealand between 2007 and 2012 and explored variations across sociodemographic strata. METHODS: Data from 2 nationally representative, cross-sectional high school surveys conducted in 2007 (n = 7709) and 2012 (n = 7266) were examined. Changes in the prevalence of drinking in the past 4 weeks were examined among the total sample, as well as the frequency of drinking in the past 4 weeks and typical drinking occasion quantity among drinkers. Only students residing in urban areas were included. Variation in changes was investigated across 4 demographic groups characterized by age (<16 years, >=16 years) and sex. Interactions with household and neighborhood-level socioeconomic position (SEP) identified any differential changes between socioeconomic strata. RESULTS: From 2007 to 2012, significantly fewer students consumed alcohol in the past 4 weeks. Interaction analyses demonstrated that, among young females (<16 years), declines were significantly greater among those of high household SEP when compared with those of low household SEP. Among drinkers, reductions in the frequency of drinking were found among all demographic groups and SEP strata. Interaction analyses revealed that only young males (<16 years) showed significantly reduced typical drinking occasion quantities. Among young females, significant interactions revealed a shift towards increasing typical drinking-occasion quantities among those of low household and neighborhood SEP, whereas their more advantaged counterparts showed no significant change over time. CONCLUSIONS: Fewer drinking occasions characterized the major declines in adolescent drinking between 2007 and 2012. Whereas young males showed reductions in the typical quantity consumed, young females of low household and neighborhood SEP progressed towards higher typical quantities. To address the uneven distribution of alcohol-related harm and improve the targeting of harm reduction initiatives, it remains imperative to examine changes in both the overall shift and shape of the distribution curve. PMID- 27782783 TI - "When This Breaks Down, It's Black Gold": Race and Gender in Agricultural Health and Safety. AB - Farmers are growing older, and fewer new agriculturists are rising to take their place. Concurrently, women and minorities are entering agriculture at an increasing rate. These rates are particularly curious viewed in light of the racialized and gendered nature of agriculture. Slavery and agriculture share strong historical roots, with many male slaves performing agricultural labor. So then, why would African American women choose to engage in agriculture in any form? Participant observation and in-depth interviews with a group of African American women urban farmers in the southeastern United States were asked this question. Interviews with seven such women revealed their perception of self sustainable small-scale agriculture as a departure from, not return to, slavery. The women drew metaphors between the Earth and femininity, believing their work to be uniquely feminine. Production of food for consumption and trade provides a source for community and healthy food amid urban poverty and the plight of food deserts. These data encourage agricultural health and safety professionals and researchers to tackle the health-promoting nature of such work, with the entree of anthropology and other social sciences into the field. In many ways, these women portrayed small-scale food cultivation as an important component of, rather than a threat to, health and safety. Indeed, they viewed such labor as wholly health promoting. Their strong social connections provide a potential means for community-led dissemination of any relevant health and safety information. PMID- 27782784 TI - Prevalence estimates and correlates of elder abuse in the United States: The National Intimate Partner and Sexual Violence Survey. AB - This study examines the prevalence and correlates of psychological abuse and physical abuse against women and men aged 70 or older. Self-report data from 2,185 respondents in the 2010 National Intimate Partner and Sexual Violence Survey (NISVS) were used to create weighted estimates for past-year experiences of abuse. Correlates were then examined using survey logistic regression models. More than 1 in 10 adults who are 70 years of age or older (14.0%) have experienced some form of abuse in the past year, with 12.1% experiencing psychological abuse and 1.7% experiencing physical abuse. One in five victims (20.8%) were abused by both intimate and nonintimate partners. Health care insecurity was the strongest correlate of past-year abuse. The odds of experiencing abuse were 4.53 times greater for those who experienced health care insecurity than for those who did not. This presents a significant challenge for identifying and helping victims of abuse. PMID- 27782785 TI - Patients' preferences for family medicine physicians' video biographies. AB - No studies have assessed prospective patients' opinions regarding physician introductory videos despite their increasing prevalence. Therefore, a within subjects experiment randomly exposed participants to five physician video biographies featuring primarily either personal or professional information. Participants' attitudes were measured. They also selected the physician they would want to visit. Participants chose physicians with whom they perceived the greatest similarity, and indicated greater ease choosing physicians when exposed to biographies containing personal information. Future videos should be between 60 and 90 seconds. Participants appreciated videos' abilities to show physicians' personalities. Participants also stated what else they would like to see included in future videos. PMID- 27782786 TI - Good Gay Buddies for Lifetime: Homosexually Themed Discourse and the Construction of Heteromasculinity Among Chinese Urban Youth. AB - Starting as an Internet meme, the homosexually themed gao-ji discourse recently became popular among Chinese urban youth in describing intimate relationships among heterosexual men. Positioned within a body of scholarship on the interplay between language, homophobia, and the construction of heteromasculinity, this article suggests that the gao-ji discourse manifests a form of male homosociality, through which new boundaries of Chinese heteromasculinity may be renegotiated. Based on qualitative interviews with college students, the article first tracks the genealogy of the gao-ji discourse in the wake of China's booming Internet culture. The main body focuses on unpacking the daily use of the gao-ji discourse, with an attention to the two latent functions it serves (i.e., expanding heteromasculine behaviors and reiterating heteromasculine identities). In conclusion, I argue that the prevalence of the gao-ji discourse mainly resolves straight men's anxieties against the background of growing public awareness of homosexuality; therefore, it cannot necessarily translate into social acceptance of homosexuality. PMID- 27782787 TI - Smart Extraction and Analysis System for Clinical Research. AB - BACKGROUND: With the increasing use of electronic health records (EHRs), there is a growing need to expand the utilization of EHR data to support clinical research. The key challenge in achieving this goal is the unavailability of smart systems and methods to overcome the issue of data preparation, structuring, and sharing for smooth clinical research. MATERIALS AND METHODS: We developed a robust analysis system called the smart extraction and analysis system (SEAS) that consists of two subsystems: (1) the information extraction system (IES), for extracting information from clinical documents, and (2) the survival analysis system (SAS), for a descriptive and predictive analysis to compile the survival statistics and predict the future chance of survivability. The IES subsystem is based on a novel permutation-based pattern recognition method that extracts information from unstructured clinical documents. Similarly, the SAS subsystem is based on a classification and regression tree (CART)-based prediction model for survival analysis. RESULTS: SEAS is evaluated and validated on a real-world case study of head and neck cancer. The overall information extraction accuracy of the system for semistructured text is recorded at 99%, while that for unstructured text is 97%. Furthermore, the automated, unstructured information extraction has reduced the average time spent on manual data entry by 75%, without compromising the accuracy of the system. Moreover, around 88% of patients are found in a terminal or dead state for the highest clinical stage of disease (level IV). Similarly, there is an ~36% probability of a patient being alive if at least one of the lifestyle risk factors was positive. CONCLUSION: We presented our work on the development of SEAS to replace costly and time-consuming manual methods with smart automatic extraction of information and survival prediction methods. SEAS has reduced the time and energy of human resources spent unnecessarily on manual tasks. PMID- 27782790 TI - The Smoking Abstinence Expectancies Questionnaire-Italian Version: Analysis of psychometric properties. AB - The Smoking Abstinence Expectancies Questionnaire is a quick and reliable scale assessing the expected consequences of short-term nicotine abstinence. The present study sought to translate the Smoking Abstinence Expectancies Questionnaire to Italian and assess its psychometric properties. A sample of 366 daily smokers (59.3% female; mean (+/-standard deviation) age = 34.0 +/- 11.2 years; mean (+/-standard deviation) cigarettes smoked per day = 13.2 +/- 7.5; mean (+/-standard deviation) years of smoking = 11.3 +/- 9.2 years) completed the Smoking Abstinence Expectancies Questionnaire and a series of rating scales measuring nicotine dependence, alcohol use, anxiety, and depressive symptoms at baseline and after 3 months (retest). Exploratory and confirmatory factor analyses were conducted. The authors evaluated the factor structure, internal consistency, test-retest reliability, convergent, and discriminant validity. Factor analysis identified a 3-factor solution and confirmatory factor analysis suggested a 3-factor model best fits the data. The Italian version of the Smoking Abstinence Expectancies Questionnaire showed excellent internal consistency and good test-retest reliability. There also was evidence of convergent validity and discriminant validity. The Italian version of the Smoking Abstinence Expectancies Questionnaire showed good psychometric properties although the factor structure differs slightly from the English-language version of the scale (i.e., 3 versus 4 factor model). PMID- 27782789 TI - A Comparison of College Students' Reported Fruit and Vegetable Liking and Intake from Childhood to Adulthood. AB - OBJECTIVES: Fruit and vegetable intake (FVI) is below recommendations and fruit and vegetable liking (FVL) is associated with intake. Greater understanding of college student FVL and FVI is needed; therefore, the study objectives were to compare reported FVL and frequency of FVI in adulthood to recollection of FVL and frequency of fruit and vegetable offering (FVO) in childhood and identify factors related to FVL and FVI in college students. METHODS: A retrospective survey was administered via e-mail to randomly selected college students (18-25 years) from 2 Northwestern universities (n = 676). McNemar's chi-square tests were used to evaluate differences in FVL and FVI scores. Spearman's rank identified an association between current FVL and FVI scores and their recollection of FVO as a child. Pearson's chi-square tests were used to examine differences in FVL and FVI scores within the demographic factors age, gender, year in school, urban/rural, body mass index (BMI), childhood overweight, breastfed, and forced to eat fruits or vegetables. RESULTS: FVL was more frequent in adulthood, but college students reported FVO as a child more frequently than their current FVI. Females reported greater FVL and FVI. Upperclassmen and the 21-25 age group reported greater frequency of vegetable liking and intake compared to underclassmen and the 18-20 age group. Lower vegetable liking and fruit intake were reported for those identifying as overweight, and recollection of FVO in childhood was associated with increased FVL and FVI scores in adulthood. Individuals forced by caregivers to eat vegetables as a child reported a lower vegetable liking than those not forced. CONCLUSIONS: FVL increased from childhood to adulthood, demonstrating a progression; however, recollection of childhood offering was higher than FVI in young adulthood. Results indicate a need for behavioral strategies to increase FVI in college students and encourage offering fruit and vegetables but refrain from forcing children to eat vegetables. PMID- 27782791 TI - Meanings of Care: A Culture-Centered Approach to Left-Behind Family Members in the Countryside of China. AB - Critical studies of health communication foreground the importance of meanings as organizing frameworks for constituting health. The contested and contradictory meanings articulated around health offer insights into the constraining and enabling roles of structures. Through ethnographic fieldwork conducted in a village in China embedded within the activist framework of the culture-centered approach, this project explores understandings of family care amid left-behind families in rural China against the backdrop of the migration of the middle generation of working adults from families located in rural contexts to cities. We work with the culture-centered approach to explore local meanings of care, understanding everyday care as integral to the health of an aging population that has been erased from the discursive space by market reforms and the hegemonic narrative of national development in China. PMID- 27782792 TI - Understanding caregivers' intentions for their child to walk to school: Further application of the theory of planned behavior. AB - Increases in childhood obesity have coincided with declines in active transportation to school. This research builds on largely atheoretical extant literature examining factors that influence walk-to-school behavior through application of the theory of planned behavior (TPB). Understanding caregivers' decision for their child to walk to/from school is key to developing interventions to promote this cost-effective and accessible health behavior. The results from an online survey of 512 caregivers provide support for the TPB, highlighting the important role of subjective norms. This suggests marketers should nurture caregivers' perception that important others approve of walking to school. PMID- 27782793 TI - Girls Get Free Drinks: Undergraduates' Misunderstandings of Heterosexual Privilege. AB - Heterosexual privilege is a challenging concept to teach in undergraduate courses. Using data from self-reflection essays on the first and last days of the semester, we present students' learning and growth in their understanding of heterosexual privilege and their ability to distinguish it from cisgender privilege. The majority of students accurately identified an instance of heterosexual privilege in their lives and discussed the counterpart to privilege: the marginalization and/or disenfranchisement experienced by individuals who hold other sexual identities. This article highlights the two most common misunderstandings of heterosexual privilege that emerged in students' writing. On the first day of class, 18.2% outright denied that heterosexual privilege exists, and 17.6% conflated gender with sexuality. It reduced to 11.9% and 11.3%, respectively, on the last day of class. We saw growth in students' sophistication of perspective even for some students who demonstrated these misunderstandings at the end of the term. PMID- 27782794 TI - Clinical Effect of Rebound Hyperthermia After Cooling Postcardiac Arrest: A Retrospective Cohort Study. AB - Therapeutic hypothermia is used in select patients after out-of-hospital cardiac arrest (OHCA) to improve neurologic outcome. Rebound hyperthermia (RH) is commonly observed post-treatment. Previous studies analyzing the association of RH with clinical outcome have reported conflicting results. The purpose of this study is to examine the impact of RH after completion of therapeutic hypothermia in patients postcardiac arrest. We analyzed a retrospective cohort from our institution. All adults who underwent therapeutic hypothermia post-OHCA were divided into two cohorts depending on the presence/absence of fever (T > 38 degrees C) within 24 hours of completing hypothermia protocol. Clinical outcomes were analyzed at hospital discharge or death. Among 306 patients admitted with OHCA, 117 underwent hypothermia, 97 survived 24 hours postrewarming. Twenty-seven patients (50%) with RH died compared with 20 (47%) without RH (OR, 1.15; 95% CI, 0.52-2.57). Twenty-six patients (67%) with RH had a poor neurologic outcome compared with 27 (63%) without RH (OR 1.19, 95% CI, 0.51-2.74). RH is common after completion of therapeutic hypothermia in comatose patients due to cardiac arrest and is associated with poor neurologic outcomes. We found no significant clinical impact of rebound hypothermia on neurologic outcome or mortality, but our study was underpowered to reveal such impact if it exists. PMID- 27782795 TI - Childhood trauma and psychiatric comorbidities in patients with depressive disorder in primary care in Chile. AB - : Childhood trauma is associated with different psychiatric disorders during adulthood. These disorders are often presented in comorbidity with depression. OBJECTIVE: To establish the relationship between psychiatric comorbidities and childhood traumatic events in patients with depression in Chile. METHODS: Three hundred and ninety-four patients with major depression were assessed using the MINI International Neuropsychiatric Interview and a screening for childhood trauma. RESULTS: Social anxiety disorder was associated with having witnessed domestic violence during childhood (OR = 2.2, CI 1.2 - 3.8), childhood physical abuse (OR = 2.7, CI 1.6 - 4.4), physical injury associated with physical abuse (OR = 2.3, CI 1.3 - 4.7) and sexual abuse by a non-relative (OR = 2.7, CI 1.3 - 4.2). Posttraumatic stress disorder was associated with physical injury associated with physical abuse (OR = 1.9, CI 1.1 - 3.6), sexual abuse by a relative (OR = 3.2, IC 1.8 - 5.9) and sexual abuse by a non-relative (OR = 2.2, CI 1.2 - 4.1). Antisocial personality disorder was associated with traumatic separation from a caregiver (OR = 3.2, CI 1.2 - 8.5), alcohol abuse by a family member (OR = 3.1, CI 1.1 - 8.1), physical abuse (OR = 2.8, CI 1.1 - 6.9) and sexual abuse by a non-relative (OR = 4.8, CI 1.2 - 11.5). Panic disorder was associated with sexual abuse by a relative (OR = 1.9, CI 1.1 - 3.1). Generalized anxiety disorder was associated with sexual abuse by a non-relative (OR = 1.9, CI 1.1- 3.3). CONCLUSIONS: Further clinical recognition is required in patients seeking help for depression in primary care. This recognition must take into account the patient's current psychiatric comorbidities and adverse childhood experiences. PMID- 27782796 TI - Complete mitochondrial genomes of living and extinct pigeons revise the timing of the columbiform radiation. AB - BACKGROUND: Pigeons and doves (Columbiformes) are one of the oldest and most diverse extant lineages of birds. However, the nature and timing of the group's evolutionary radiation remains poorly resolved, despite recent advances in DNA sequencing and assembly and the growing database of pigeon mitochondrial genomes. One challenge has been to generate comparative data from the large number of extinct pigeon lineages, some of which are morphologically unique and therefore difficult to place in a phylogenetic context. RESULTS: We used ancient DNA and next generation sequencing approaches to assemble complete mitochondrial genomes for eleven pigeons, including the extinct Ryukyu wood pigeon (Columba jouyi), the thick-billed ground dove (Alopecoenas salamonis), the spotted green pigeon (Caloenas maculata), the Rodrigues solitaire (Pezophaps solitaria), and the dodo (Raphus cucullatus). We used a Bayesian approach to infer the evolutionary relationships among 24 species of living and extinct pigeons and doves. CONCLUSIONS: Our analyses indicate that the earliest radiation of the Columbidae crown group most likely occurred during the Oligocene, with continued divergence of major clades into the Miocene, suggesting that diversification within the Columbidae occurred more recently than has been reported previously. PMID- 27782797 TI - Fine-scale assessment of genetic diversity of trembling aspen in northwestern North America. AB - BACKGROUND: In North America, the last ice age is the most recent event with severe consequences on boreal species' ranges. Phylogeographic patterns of range expansion in trembling aspen (Populus tremuloides) suggested that Beringia is likely to be a refugium and the "ice-free corridor" in Alberta may represent a region where small populations persisted during the last glacial maximum (LGM). The purpose of this study was to ascertain whether the origins of trembling aspen in western North America are reflected in the patterns of neutral genetic diversity and population structure. A total of 28 sites were sampled covering the northwestern part of aspen's distribution, from Saskatchewan to Alaska. Twelve microsatellite markers were used to describe patterns of genetic diversity. The genetic structure of trembling aspen populations was assessed by using multivariate analyses, Mantel correlograms, neighbor-joining trees and Bayesian analysis. RESULTS: Microsatellite markers revealed little to no neutral genetic structure of P. tremuloides populations in northwestern North America. Low differentiation among populations and small isolation by distance (IBD) were observed. The most probable number of clusters detected by STRUCTURE was K = 3 (?K = 5.9). The individuals in the populations of the 3 clusters share a common gene pool and showed a high level of admixture. No evidence was found that either Beringia or the "ice-free corridor" were refugia. Highest allelic richness (AR) and lowest heterozygosity (Ho) were observed in Alberta foothills of the Rocky Mountains. CONCLUSIONS: Contrary to our hypothesis, our results showed that microsatellite markers revealed little to no genetic structure in P. tremuloides populations. Consequently, no divergent populations were observed near supposed refugia. The lack of detectable refugia in Beringia and in the "ice-free corridor" was due to high levels of gene flow between trembling apsen populations. More favorable environmental conditions for sexual reproduction and successful trembling aspen seedling establishment may have contributed to increase allelic richness through recombination in populations from the Albertan foothills of the Rocky Mountains. PMID- 27782800 TI - Erratum to: Transcriptome analysis of maize resistance to Fusarium graminearum. PMID- 27782798 TI - Spatial pattern of genetic diversity and selection in the MHC class II DRB of three Neotropical bat species. AB - BACKGROUND: Although bats are natural reservoirs of many pathogens, few studies have been conducted on the genetic variation and detection of selection in major histocompatibility complex (MHC) genes. These genes are critical for resistance and susceptibility to diseases, and host-pathogen interactions are major determinants of their extensive polymorphism. Here we examined spatial patterns of diversity of the expressed MHC class II DRB gene of three sympatric Neotropical bats, Carollia perspicillata and Desmodus rotundus (Phyllostomidae), and Molossus molossus (Molossidae), all of which use the same environments (e.g., forests, edge habitats, urban areas). Comparison with neutral marker (mtDNA D loop) diversity was performed at the same time. RESULTS: Twenty-three DRB alleles were identified in 19 C. perspicillata, 30 alleles in 35 D. rotundus and 20 alleles in 28 M. molossus. The occurrence of multiple DRB loci was found for the two Phyllostomidae species. The DRB polymorphism was high in all sampling sites and different signatures of positive selection were detected depending on the environment. The patterns of DRB diversity were similar to those of neutral markers for C. perspicillata and M. molossus. In contrast, these patterns were different for D. rotundus for which a geographical structure was highlighted. A heterozygote advantage was also identified for this species. No recombination or gene conversion event was found and phylogenetic relationships showed a trans species mode of evolution in the Phyllostomids. CONCLUSIONS: This study of MHC diversity demonstrated the strength of the environment and contrasting pathogen pressures in shaping DRB diversity. Differences between positively selected sites identified in bat species highlighted the potential role of gut microbiota in shaping immune responses. Furthermore, multiple geographic origins and/or population admixtures observed in C. perspicillata and M. molossus populations acted as an additional force in shaping DRB diversity. In contrast, DRB diversity of D. rotundus was shaped by environment rather than demographic history. PMID- 27782799 TI - Novel equine tissue miRNAs and breed-related miRNA expressed in serum. AB - BACKGROUND: MiRNAs regulate multiple genes at the post-transcriptional level and therefore play an important role in many biological processes. It has been suggested that miRNA exported outside the cells contribute to inter-cellular communication. Consequently, circulating miRNAs are of particular interest and are promising biomarkers for many diseases. The number of miRNAs annotated in the horse genome is much lower compared to model organisms like human and mouse. We therefore aimed to identify novel equine miRNAs for tissue types and breed in serum. RESULTS: We analysed 71 small RNA-seq libraries derived from nine tissues (gluteus medius, platysma, masseter muscle, heart, liver, cartilage, bone, total blood and serum) using miRDeep2 and miRdentify tools. Known miRNAs represented between 2.3 and 62.9 % of the reads in 71 libraries. A total of 683 novel miRNAs were identified. Breed and tissue type affected the number of miRNAs detected and interestingly, affected its average intensity. A total of 50 miRNAs in serum proved to be potential biomarkers to differentiate specific breed types, of which miR-122, miR-200, miR-483 were over-expressed and miR-328 was under-expressed in ponies compared to Warmbloods. The different miRNAs profiles, as well as the differences in their expression levels provide a foundation for more hypotheses based on the novel miRNAs discovered. CONCLUSIONS: We identified 683 novel equine miRNAs expressed in seven solid tissues, blood and serum. Additionally, our approach evidenced that such data supported identification of specific miRNAs as markers of functions related to breeds or disease tissues. PMID- 27782801 TI - TRIg: a robust alignment pipeline for non-regular T-cell receptor and immunoglobulin sequences. AB - BACKGROUND: T cells and B cells are essential in the adaptive immunity via expressing T cell receptors and immunoglogulins respectively for recognizing antigens. To recognize a wide variety of antigens, a highly diverse repertoire of receptors is generated via complex recombination of the receptor genes. Reasonably, frequencies of the recombination events have been shown to predict immune diseases and provide insights into the development of immunity. The field is further boosted by high-throughput sequencing and several computational tools have been released to analyze the recombined sequences. However, all current tools assume regular recombination of the receptor genes, which is not always valid in data prepared using a RACE approach. Compared to the traditional multiplex PCR approach, RACE is free of primer bias, therefore can provide accurate estimation of recombination frequencies. To handle the non-regular recombination events, a new computational program is needed. RESULTS: We propose TRIg to handle non-regular T cell receptor and immunoglobulin sequences. Unlike all current programs, TRIg does alignments to the whole receptor gene instead of only to the coding regions. This brings new computational challenges, e.g., ambiguous alignments due to multiple hits to repetitive regions. To reduce ambiguity, TRIg applies a heuristic strategy and incorporates gene annotation to identify authentic alignments. On our own and public RACE datasets, TRIg correctly identified non-regularly recombined sequences, which could not be achieved by current programs. TRIg also works well for regularly recombined sequences. CONCLUSIONS: TRIg takes into account non-regular recombination of T cell receptor and immunoglobulin genes, therefore is suitable for analyzing RACE data. Such analysis will provide accurate estimation of recombination events, which will benefit various immune studies directly. In addition, TRIg is suitable for studying aberrant recombination in immune diseases. TRIg is freely available at https://github.com/TLlab/trig . PMID- 27782802 TI - Erratum to: ISOexpresso: a web-based platform for isoform-level expression analysis in human cancer. PMID- 27782803 TI - Co-activator candidate interactions for orphan nuclear receptor NR2E1. AB - BACKGROUND: NR2E1 (Tlx) is an orphan nuclear receptor that regulates the maintenance and self-renewal of neural stem cells, and promotes tumourigenesis. Nr2e1-null mice exhibit reduced cortical and limbic structures and pronounced retinal dystrophy. NR2E1 functions mainly as a repressor of gene transcription in association with the co-repressors atrophin-1, LSD1, HDAC and BCL11A. Recent evidence suggests that NR2E1 also acts as an activator of gene transcription. However, co-activator complexes that interact with NR2E1 have not yet been identified. In order to find potential novel co-regulators for NR2E1, we used a microarray assay for real-time analysis of co-regulator-nuclear receptor interaction (MARCoNI) that contains peptides representing interaction motifs from potential co-regulatory proteins, including known co-activator nuclear receptor box sequences (LxxLL motif). RESULTS: We found that NR2E1 binds strongly to an atrophin-1 peptide (Atro box) used as positive control and to 19 other peptides that constitute candidate NR2E1 partners. Two of these proteins, p300 and androgen receptor (AR), were further validated by reciprocal pull-down assays. The specificity of NR2E1 binding to peptides in the array was evaluated using two single amino acid variants, R274G and R276Q, which disrupted the majority of the binding interactions observed with wild-type NR2E1. The decreased binding affinity of these variants to co-regulators was further validated by pull-down assays using atrophin1 as bait. Despite the high conservation of arginine 274 in vertebrates, its reduced interactions with co-regulators were not significant in vivo as determined by retinal phenotype analysis in single-copy Nr2e1-null mice carrying the variant R274G. CONCLUSIONS: We showed that MARCoNI is a specific assay to test interactions of NR2E1 with candidate co-regulators. In this way, we unveiled 19 potential co-regulator partners for NR2E1, including eight co activators. All the candidates here identified need to be further validated using in vitro and in vivo models. This assay was sensitive to point mutations in NR2E1 ligand binding domain making it useful to identify mutations and/or small molecules that alter binding of NR2E1 to protein partners. PMID- 27782804 TI - Comparative genomic analysis of the compound Brassica napus Rf locus. AB - BACKGROUND: The plant trait of cytoplasmically-inherited male sterility (CMS) and its suppression by nuclear restorer-of-fertility (Rf) genes can be viewed as a genetic arms race between the mitochondrial and nuclear genomes. Most nuclear Rf genes have been shown to encode P-type pentatricopeptide repeat proteins (PPRs). Phylogenetic analysis of P-class PPRs from sequenced plants genomes has shown that Rf-proteins cluster in a distinct clade of P-class PPRs, RFL-PPRs, that display hallmarks of positive evolutionary selection. Genes encoding RFL-PPRs (RFLs) within a given plant genome tend to be closely related both in sequence and position, but a detailed understanding of how such species-specific expansion occurs is lacking. In the canola, (oilseed rape) species Brassica napus, previous work has indicated the nuclear restorer genes for the two native forms of CMS, Rfn (for nap CMS) and Rfp (pol CMS), represent alternate haplotypes, or alleles, of a single nuclear locus. RESULTS: Fine genetic mapping indicates that Rfn does indeed localize to the same genomic region as Rfp. We find this region is enriched in RFL genes, three of which, based on their position and expression, represent potential candidates for Rfn; one of these genes, designated PPR4, is a preferred candidate in that it is not expressed in the nap CMS line. Comparison of the corresponding regions of the genomes of B. rapa, B. oleracea, Arabidopsis thaliana and A. lyrata provides insight into the expansion of this group of RFL genes in different lines of evolutionary descent. CONCLUSIONS: Unlike other nuclear restorer loci containing multiple RFL genes, the RFL genes in the Rf region of B. napus are not present in tandem arrays but rather are dispersed in genomic location. The genes do not share similar flanking non-coding regions and do not contain introns, indicating that they have duplicated primarily through a retrotransposition-mediated process. In contrast, segmental duplication has been responsible for the distribution of the 10 sequences we annotated as RFL genes in the corresponding region of the A. lyrata genome. Our observations define the Brassica Rf locus and indicate that different mechanisms may be responsible for the proliferation of RFL genes even among closely related genomes. PMID- 27782805 TI - Fucosyllactose and L-fucose utilization of infant Bifidobacterium longum and Bifidobacterium kashiwanohense. AB - BACKGROUND: Human milk oligosaccharides (HMOs) are one of the major glycan source of the infant gut microbiota. The two species that predominate the infant bifidobacteria community, Bifidobacterium longum subsp. infantis and Bifidobacterium bifidum, possess an arsenal of enzymes including alpha fucosidases, sialidases, and beta-galactosidases to metabolise HMOs. Recently bifidobacteria were obtained from the stool of six month old Kenyan infants including species such as Bifidobacterium kashiwanohense, and Bifidobacterium pseudolongum that are not frequently isolated from infant stool. The aim of this study was to characterize HMOs utilization by these isolates. Strains were grown in presence of 2'-fucosyllactose (2'-FL), 3'-fucosyllactose (3'-FL), 3'-sialyl lactose (3'-SL), 6'-sialyl-lactose (6'-SL), and Lacto-N-neotetraose (LNnT). We further investigated metabolites formed during L-fucose and fucosyllactose utilization, and aimed to identify genes and pathways involved through genome comparison. RESULTS: Bifidobacterium longum subsp. infantis isolates, Bifidobacterium longum subsp. suis BSM11-5 and B. kashiwanohense strains grew in the presence of 2'-FL and 3'- FL. All B. longum isolates utilized the L-fucose moiety, while B. kashiwanohense accumulated L-fucose in the supernatant. 1,2 propanediol (1,2-PD) was the major metabolite from L-fucose fermentation, and was formed in equimolar amounts by B. longum isolates. Alpha-fucosidases were detected in all strains that degraded fucosyllactose. B. longum subsp. infantis TPY11-2 harboured four alpha-fucosidases with 95-99 % similarity to the type strain. B. kashiwanohense DSM 21854 and PV20-2 possessed three and one alpha fucosidase, respectively. The two alpha-fucosidases of B. longum subsp. suis were 78-80 % similar to B. longum subsp. infantis and were highly similar to B. kashiwanohense alpha-fucosidases (95-99 %). The genomes of B. longum strains that were capable of utilizing L-fucose harboured two gene regions that encoded enzymes predicted to metabolize L-fucose to L-lactaldehyde, the precursor of 1,2 PD, via non-phosphorylated intermediates. CONCLUSION: Here we observed that the ability to utilize fucosyllactose is a trait of various bifidobacteria species. For the first time, strains of B. longum subsp. infantis and an isolate of B. longum subsp. suis were shown to use L-fucose to form 1,2-PD. As 1,2-PD is a precursor for intestinal propionate formation, bifidobacterial L-fucose utilization may impact intestinal short chain fatty acid balance. A L-fucose utilization pathway for bifidobacteria is suggested. PMID- 27782806 TI - Flavonoids and darkness lower PCD in senescing Vitis vinifera suspension cell cultures. AB - BACKGROUND: Senescence is a key developmental process occurring during the life cycle of plants that can be induced also by environmental conditions, such as starvation and/or darkness. During senescence, strict control of genes regulates ordered degradation and dismantling events, the most remarkable of which are genetically programmed cell death (PCD) and, in most cases, an upregulation of flavonoid biosynthesis in the presence of light. Flavonoids are secondary metabolites that play multiple essential roles in development, reproduction and defence of plants, partly due to their well-known antioxidant properties, which could affect also the same cell death machinery. To understand further the effect of endogenously-produced flavonoids and their interplay with different environment (light or dark) conditions, two portions (red and green) of a senescing grapevine callus were used to obtain suspension cell cultures. Red Suspension cell Cultures (RSC) and Green Suspension cell Cultures (GSC) were finally grown under either dark or light conditions for 6 days. RESULTS: Darkness enhanced cell death (mainly necrosis) in suspension cell culture, when compared to those grown under light condition. Furthermore, RSC with high flavonoid content showed a higher viability compared to GSC and were more protected toward PCD, in accordance to their high content in flavonoids, which might quench ROS, thus limiting the relative signalling cascade. Conversely, PCD was mainly occurring in GSC and further increased by light, as it was shown by cytochrome c release and TUNEL assays. CONCLUSIONS: Endogenous flavonoids were shown to be good candidates for exploiting an efficient protection against oxidative stress and PCD induction. Light seemed to be an important environmental factor able to induce PCD, especially in GSC, which lacking of flavonoids were not capable of preventing oxidative damage and signalling leading to senescence. PMID- 27782807 TI - DAMPs, MAMPs, and NAMPs in plant innate immunity. AB - BACKGROUND: Multicellular organisms have evolved systems/mechanisms to detect various forms of danger, including attack by microbial pathogens and a variety of pests, as well as tissue and cellular damage. Detection via cell-surface receptors activates an ancient and evolutionarily conserved innate immune system. RESULT: Potentially harmful microorganisms are recognized by the presence of molecules or parts of molecules that have structures or chemical patterns unique to microbes and thus are perceived as non-self/foreign. They are referred to as Microbe-Associated Molecular Patterns (MAMPs). Recently, a class of small molecules that is made only by nematodes, and that functions as pheromones in these organisms, was shown to be recognized by a wide range of plants. In the presence of these molecules, termed Nematode-Associated Molecular Patterns (NAMPs), plants activate innate immune responses and display enhanced resistance to a broad spectrum of microbial and nematode pathogens. In addition to pathogen attack, the relocation of various endogenous molecules or parts of molecules, generally to the extracellular milieu, as a result of tissue or cellular damage is perceived as a danger signal, and it leads to the induction of innate immune responses. These relocated endogenous inducers are called Damage-Associated Molecular Patterns (DAMPs). CONCLUSIONS: This mini-review is focused on plant DAMPs, including the recently discovered Arabidopsis HMGB3, which is the counterpart of the prototypic animal DAMP HMGB1. The plant DAMPs will be presented in the context of plant MAMPs and NAMPs, as well as animal DAMPs. PMID- 27782808 TI - COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes. AB - BACKGROUND: Compulsivity, the closely linked trait impulsivity and addictive behaviour are associated with several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). All three disorders show impaired fronto striatal functioning, which may be related to altered glutamatergic signalling. Genetic factors are also thought to play an important role in the aetiology of compulsivity-related disorders. METHODS: The COMPULS study is a multi-center study designed to investigate the relationship between the traits compulsivity, impulsivity, and, to a lesser extent, addictive behaviour within and across the neurodevelopmental disorders ADHD, ASD, and OCD. This will be done at the phenotypic, cognitive, neural, and genetic level. In total, 240 participants will take part in COMPULS across four different sites in Europe. Data collection will include diagnostic interviews, behavioural questionnaires, cognitive measures, structural, functional and spectral neuroimaging, and genome-wide genetic information. DISCUSSION: The COMPULS study will offer the unique opportunity to investigate several key aspects of compulsivity across a large cohort of ADHD, ASD and OCD patients. PMID- 27782810 TI - A case report of a cystic fibrosis patient with repeated isolation of Trichosporon mycotoxinivorans identified by a novel short-extraction method. AB - BACKGROUND: Trichosporon mycotoxinivorans is a recently described yeast-like fungal organism and its association as a pathogen for patients with cystic fibrosis (CF) was reported previously. We show the clinical course of a CF patient over 9 years as well as the applications of modern molecular and proteomic identification techniques of this rare fungus. CASE PRESENTATION: We present the case of a 32-year-old male CF patient with sputum cultures continuously positive with the anamorphic yeast T. mycotoxinivorans during 9 years. Furthermore, susceptibility testing of T. mycotoxinivorans to different antifungals were performed. In addition, a rapid identification method of this novel fungal pathogen with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was applied using a simple extraction protocol. CONCLUSIONS: Our case presentation confirms T. mycotoxinivorans as a potential emerging pathogen in patients with CF. However, our CF patient showed mild symptoms over a very long time period of 9 years. A short MALDI-TOF MS procedure allows reliable and rapid identification of T. mycotoxinivorans and therefore should facilitate further study on the clinical relevance and epidemiology of this unusual fungal organism. PMID- 27782809 TI - Clinical and molecular characteristics of Klebsiella pneumoniae ventilator associated pneumonia in mainland China. AB - BACKGROUND: Klebsiella pneumoniae is a prominent nosocomial pathogen that accounts for up to 10 % of all hospital-acquired infections. It is a frequent cause of ventilator-associated pneumonia (VAP). The purpose of this study was to investigate the clinical characteristics of K. pneumoniae-associated VAP and the molecular characteristics of K. pneumoniae strains. METHODS: We retrospectively reviewed 70 mechanically ventilated patients with K. pneumoniae isolated. All K. pneumoniae strains were examined to determine hypermucoviscosity (HV) phenotype, capsular serotypes, virulence genes, multilocus sequence typing and antimicrobial susceptibility. RESULTS: Hypermucoviscosity was found in 14 of 70 (20 %) isolates of K. pneumoniae. Among the 70 patients, 43 cases (61.4 %) developed VAP. Furthermore, VAP was more frequently induced by HV-positive K. pneumoniae (14/14, 100 %) than by HV-negative strains (29/56, 51.7 %). HV-positive K. pneumoniae associated VAP patients were more inclined to develop bacteremia and had a higher mortality rate than HV-negative strains VAP patients. Antibiotic resistance was more frequent in HV- negative strains- than in HV- positive strains-infected patients. The prevalence of rmpA and aerobactin genes were 85.7 % and 85.7 % respectively, and serotypes K1 and K2 accounted for 14.3 % and 28.6 % of the hypermucoviscosity strains, respectively. Strains carrying rmpA and aerobactin genes were significantly associated with HV-phenotype, and rmpA and aerobactin coexisted in HV-positive strains. Multilocus sequence typing analysis identified 24 different sequence types from K. pneumoniae VAP samples. CONCLUSIONS: HV phenotype is the major virulence determinant for mechanically ventilated patients. There was a specific sequence typing (ST) distribution between HV positive and HV-negative strains. PMID- 27782811 TI - The prevalence of drug resistance among treatment-naive HIV-1-infected individuals in China during pre- and post- 2004. AB - BACKGROUND: The widespread use of antiretroviral therapies has led to considerable concerns about the prevalence of drug-resistant, as transmission of drug-resistant (TDR) strains poses a challenge for the control of the HIV-1 epidemic. METHODS: We conducted an epidemiological study enrolling treatment naive HIV-1-positive subjects at the Peking Union Medical College Hospital since 1991. Drug resistance was determined by submitting the sequences to the Stanford University Network HIV-1 database. RESULTS: Of 521 participants, 478 samples were amplified and sequenced successfully. HIV Transmitted drug resistance prevalence in China was determined to be 6.7 %. We did not find significant differences in the TDR rate by demographic characteristics. No significant time trend in the prevalence of overall TDR was observed (p > 0.05). CONCLUSIONS: We identified an intermediate prevalence of transmitted drug resistance (TDR), exhibiting a stable time trend. These findings enhance our understanding of HIV-1 drug resistance prevalence and time trend, and provide some guidelines for the comprehensive public health strategy of TDR prevention. PMID- 27782812 TI - Real time PCR for the rapid identification and drug susceptibility of Mycobacteria present in Bronchial washings. AB - BACKGROUND: Mycobacteria have a spectrum of virulence and different susceptibilities to antibiotics. Distinguishing mycobacterial species is vital as patients with non-tuberculous mycobacterial (NTM) infections present clinical features that are similar to those of patients with tuberculosis. Thus, rapid differentiation of Mycobacterium tuberculosis complex from NTM is critical to administer appropriate treatment. Hence the aim of the study was to rapid identification of mycobacterial species present in bronchial washings using multiplex real time Polymerase Chain Reaction (PCR) and to determine the drug susceptibility in identified mycobacterial species. METHODS: Sputum smear negative bronchoscopy specimens (n = 150) were collected for a period of one year, from patients attending the General Hospital Kandy, Sri Lanka. The specimens were processed with modified Petroff's method and were cultured on Lowenstein- Jensen medium. DNA, extracted from the mycobacterial isolates were subjected to a SYBR green mediated real time multiplex, PCR assay with primers specific for the M. tuberculosis complex, M. avium complex, M. chelonae M.abscessus group and M. fortuitum group. DNA sequencing was performed for the species confirmation, by targeting the 16S rRNA gene and the drug susceptibility testing was performed for the molecularly identified isolates of M. tuberculosis and NTM. RESULTS: The optimized SYBR Green mediated multiplex real-time PCR assay was able to identify the presence of genus Mycobacterium in 25 out of 26 AFB positive isolates, two M. tuberculosis complex, three M. avium complex and two isolates belonging to M. chelonae-M. abscessus group. DNA sequencing confirmed the presence of M. tuberculosis, M. chelonae-M. abscessus, M. intracellulare, M. avium, Rhodococcus sp. and M. celatum. Remaining isolates were identified as Mycobacterium sp. All the NTM isolates were sensitive to amikacin and seven were resistant to ciproflaxacin. Twenty two of the NTM isolates and the isolate Rhodococcus was resistant to clarithromycin. The two isolates of M. tuberculosis were sensitive to all first line anti tuberculosis drugs. CONCLUSION: The optimized SYBR Green mediated multiplex real time PCR assay could be an effective tool for the rapid differentiation of pathogenic M. tuberculosis complex from the opportunistic nontuberculous mycobacteria and also it confirmed the presence of NTM in 15.3 % of the study population. PMID- 27782814 TI - Erratum to: Poor tuberculosis treatment outcomes in Southern Mozambique (2011 2012). PMID- 27782813 TI - Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study. AB - BACKGROUND: Pancreatic adenocarcinoma (PDAC) incidence is increasing worldwide. Several studies have shown that lymphopenia was correlated with a poor prognosis but the potential interest to measure lymphopenia in the pre and post-operative setting as well as its added value among conventional prognostic factors was never investigated. METHODS: Data from two independent cohorts in whom patients underwent resection for pancreatic carcinoma were retrospectively recorded. We examined the association between perioperative findings, pre and post-operative lymphocyte counts and overall survival (OS) in univariate and multivariate analyses. Performance assessment and internal validation of the final model were evaluated with Harrell's C-index, calibration plot and bootstrap sample procedures. RESULTS: Three hundred ninety patients were included in the analysis between 2000 and 2011. Pre and post-operative lymphocyte counts were independent prognostic factors associated with OS in multivariate analysis (p = 0.0128 and p = 0.0764, respectively). The addition of lymphocyte count variable to the conventional parameters identified in multivariate analysis (metastatic lymph node ratio, veinous emboli and adjuvant chemotherapy) significantly improved the model discrimination capacity (bootstrap mean difference = 0.04; 95 % CI, 0.01 0.06). The use of a threshold and combining the categorical (>=1000; <1000) information in pre and post lymphocyte counts permitted the identification of 4 subgroups of patients with different prognosis (p < 0.0001). Finally, the description of patients in long-term remission showed that only 3 of 65 (4.6 %) patients with post-operative lymphocyte count under 1000/mm3 were alive 4 years after surgery contrary to 54 of 236 (22.8 %) patients with a post-operative lymphocyte count above 1000/mm3. CONCLUSION: Pre and post-operative lymphopenia are independent prognostic factors for OS and they have an additive value regarding conventional prognostic factors for death-risk stratification and to predict long-term survival. Lymphopenia should be included as stratification factors in future clinical trial assessing overall survival in pancreatic cancer patients. PMID- 27782815 TI - The complexity of human infected AIV H5N6 isolated from China. AB - BACKGROUND: Novel avian influenza viruses (AIVs) of H7N9, H10N8, and H5N6 are currently circulating in China's poultry flocks, occasionally infecting human and other mammals. Human infected AIV H5N6 in China during 2014-2015 is believed to be a triple reassortant originated from H6N6 and two clades of H5 viruses. The current report suggests that its reassortment history is more complicated. METHODS: Genomes of human infected isolates of AIV H5N6 were searched from the NCBI Influenza Virus Sequence Database and the Global Initiative on Sharing Avian Influenza Data. Sequences shared high identities with each segment of their genomes were obtained through the Basic Local Alignment Search Tool. Alignments were done by mafft-7.037-win32 program; 8 large-scale and then 8 gradually converged phylogenetic trees were constructed by using MEGA5.1/5.2/6.0 Software. RESULTS: The events that each segment of the genomes of human infected AIV H5N6 isolates circulated in China had evolved into its current status might have happened before 2013, and so were they then reassorted into the epidemic AIV H5N6. A/Guangzhou/39715/2014(H5N6) and A/Sichuan/26221/2014(H5N6) had their six internal segments (PB2, PB1, PA, NP, NEP, and M) in common, and were reassorted from AIVs H5N1 in the same period and same region as that of HA, while A/Yunnan/0127/2015(H5N6) derived its six internal segments from AIV H9N2 that has been prevalent in Eastern China since 2008. CONCLUSIONS: AIV H5N6 isolates established from both human and poultry in China during 2014-2015 were heterogeneous; both AIVs H5N1 and H9N2 were involved in the reassortment of AIV H5N6 in China. PMID- 27782816 TI - Erratum to: Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial. PMID- 27782818 TI - Bilateral abducens nerve palsy in an infant case of fulminant acute disseminated encephalomyelitis: a case report. AB - BACKGROUND: Sixth (abducens) nerve palsy (ANP) is far less frequent in children and has not been reported as a sign of acute disseminated encephalomyelitis (ADEM). We present an infant case of ADEM with bilateral abducens nerve palsy (BANP). CASE PRESENTATION: We report one case of BANP in a 15-month-old boy of fulminant ADEM. The patient underwent physical examinations and brain MRI scan three times during about six months follow-up. The patient had BANP and developmental regression when he regained consciousness from a coma, and the signs had persisted for 6-months. CONCLUSIONS: BANP can be a symptom of ADEM. PMID- 27782817 TI - Assessment of predictive performance in incomplete data by combining internal validation and multiple imputation. AB - BACKGROUND: Missing values are a frequent issue in human studies. In many situations, multiple imputation (MI) is an appropriate missing data handling strategy, whereby missing values are imputed multiple times, the analysis is performed in every imputed data set, and the obtained estimates are pooled. If the aim is to estimate (added) predictive performance measures, such as (change in) the area under the receiver-operating characteristic curve (AUC), internal validation strategies become desirable in order to correct for optimism. It is not fully understood how internal validation should be combined with multiple imputation. METHODS: In a comprehensive simulation study and in a real data set based on blood markers as predictors for mortality, we compare three combination strategies: Val-MI, internal validation followed by MI on the training and test parts separately, MI-Val, MI on the full data set followed by internal validation, and MI(-y)-Val, MI on the full data set omitting the outcome followed by internal validation. Different validation strategies, including bootstrap und cross-validation, different (added) performance measures, and various data characteristics are considered, and the strategies are evaluated with regard to bias and mean squared error of the obtained performance estimates. In addition, we elaborate on the number of resamples and imputations to be used, and adopt a strategy for confidence interval construction to incomplete data. RESULTS: Internal validation is essential in order to avoid optimism, with the bootstrap 0.632+ estimate representing a reliable method to correct for optimism. While estimates obtained by MI-Val are optimistically biased, those obtained by MI(-y) Val tend to be pessimistic in the presence of a true underlying effect. Val-MI provides largely unbiased estimates, with a slight pessimistic bias with increasing true effect size, number of covariates and decreasing sample size. In Val-MI, accuracy of the estimate is more strongly improved by increasing the number of bootstrap draws rather than the number of imputations. With a simple integrated approach, valid confidence intervals for performance estimates can be obtained. CONCLUSIONS: When prognostic models are developed on incomplete data, Val-MI represents a valid strategy to obtain estimates of predictive performance measures. PMID- 27782819 TI - Erratum to: The UBC-40 Urothelial Bladder Cancer cell line index: a genomic resource for functional studies. PMID- 27782820 TI - Comparison between two amplicon-based sequencing panels of different scales in the detection of somatic mutations associated with gastric cancer. AB - BACKGROUND: Sequencing data from The Cancer Genome Atlas (TGCA), the International Cancer Genome Consortium and other research institutes have revealed the presence of genetic alterations in several tumor types, including gastric cancer. These data have been combined into a catalog of significantly mutated genes for each cancer type. However, it is unclear to what extent significantly mutated genes need to be examined for detecting genetic alterations in gastric cancer patients. Here, we constructed two custom-made sequencing panels of different scales, the Selective hotspot Panel and the Comprehensive Panel, to analyze genetic alterations in 21 resected specimens endoscopically obtained from 20 gastric cancer patients, and we assessed how many mutations were detectable using these different panels. RESULTS: A total of 21 somatic mutations were identified by the Selective hotspot Panel and 70 mutations were detected by the Comprehensive Panel. All mutations identified by the Selective hotspot Panel were detected by the Comprehensive Panel, with high concordant values of the variant allelic fraction of each mutation (correlation coefficient, R = 0.92). At least one mutation was identified in 13 patients (65 %) by the Selective hotspot Panel, whereas the Comprehensive Panel detected mutations in 19 (95 %) patients. Library preparation and sequencing costs were comparable between the two panels. CONCLUSIONS: Our results indicate the utility of comprehensive panel-based targeted sequencing in gastric cancer. PMID- 27782822 TI - In vitro and in vivo activity of miR-92a-Locked Nucleic Acid (LNA)-Inhibitor against endometrial cancer. AB - BACKGROUND: Endometrial cancer is the most common cancer of the female reproductive tract. Based on our previous studies we speculated that miR-92a exhibited pro-oncogenic properties in endometrial cancer, and therefore its inhibition could be used as a therapeutic measure in this disease. Therefore in the present study we aimed to investigate both in vitro and in vivo if inhibition of miR-92a in endometrial cancer would limit cancer cells proliferation. METHODS: miR-92a expression was evaluated in four endometrial cancer cell lines using qPCR. Inhibition of miR-92a activity was obtained in endometrial cancer cell lines by a transient transfection of a custom designed Locked Nucleic Acid (LNA) Inhibitor, developed to work both in vitro and in vivo. In vitro proliferation studies were performed using xCELLigence RTCA DP system. In vivo experiment was performed in Cby.Cg-Foxn1 < nu>/cmdb mice bearing endometrial cancer xenografts, which were intraperitoneally injected with nine dosages of 25 mg/kg of miR-205 LNA-inhibitor. RESULTS: qPCR revealed increased expression of miR-92a in HEC-1-B, Ishikawa and AN3CA cells. LNA-i-miR-92a inhibited endometrial cancer growth in vitro. It was also demonstrated that systemic administration of LNA-i-miR-92a was feasible and exerted inhibitory effect on endometrial cancer xenograft growth in vivo with only mild toxic effects in treated animals, however the effect was observed until 12th experimental day and the last three dosages did not maintain the attenuating effect with the acceleration of tumor growth observed at the end and after cessation of the intraperitoneal therapy. CONCLUSIONS: Taken together, these results indicate that intraperitoneal delivery of miR-92a-LNA-modified inhibitor is feasible, devoid of significant toxicity and moderately inhibits endometrial cancer growth in vivo, and therefore warrants further studies investigating other routes of inhibitor delivery possibly in other animal models. PMID- 27782821 TI - Implementation of a pragmatic, stepped-wedge cluster randomized trial to evaluate impact of Botswana's Xpert MTB/RIF diagnostic algorithm on TB diagnostic sensitivity and early antiretroviral therapy mortality. AB - BACKGROUND: In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package". METHODS: The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is <=52.5 % and post-Xpert sensitivity >=82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is >=13/100 person-years. DISCUSSION: Only one small previous trial (N = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov: NCT02538952 . PMID- 27782823 TI - Pro-apoptotic and cytotoxic effects of enriched fraction of Elytranthe parasitica (L.) Danser against HepG2 Hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC), the most common type of liver cancer accounts for more than one million deaths worldwide. Current treatment modality for HCC is marginally effective. Plants belonging to Mistletoe family (Loranthaceae) have been used in chemotherapy for many years. The present study was aimed at exploring the anti-proliferative, pro-oxidant and pro-apoptotic potential of stem of Elytranthe parasitica (L.) Danser (EP), a parasitic shrub belonging to Loranthaceae. METHODS: Elytranthe parasitica (L.) Danser, a climbing parasitic shrub was investigated for its cytotoxic activity against HepG2, a hepatocellular carcinoma cell line by Sulforhodamine B (SRB) assay. Further, pro oxidant activity of EP extract/fractions was studied using copper phenanthroline assay. To understand the mechanism of cell death, the pro-apoptotic effects of Hep-G2 cells treated with EP extract/fractions were visualized by dual staining using acridine orange and ethidium bromide, a morphological marker of apoptosis. Phytochemical profiling of EP was explored by estimating the phenol, flavonoid and tannin content in its various fractions and extract. The occurrence of gallic acid, a principal polyphenol in EP extract and fractions was detected and further quantified using HPTLC (High Performance Thin Layer Chromatography) fingerprinting. RESULT: Active fraction of Elytranthe parasitica, EP.DEE exhibited potent cytotoxic activity in a dose dependent manner against HepG2 hepatocellular carcinoma cell line with an IC50 of 56.7 +/- 7.8 MUg/mL. Dual staining with acridine orange and ethidium bromide revealed that HepG2 cells treated with EP active fractions underwent cell death chiefly by apoptosis. Highest phenol, flavonoid and tannin content were observed in active fractions, EP.EA (Ethyl acetate fraction) and EP.DEE (Diethyl ether fraction). Gallic acid was identified and quantified in EP extract and active fractions, EP.DEE and EP.EA. CONCLUSION: Our findings indicate EP active fraction could be a promising contender in the treatment of hepatocellular carcinoma. PMID- 27782824 TI - The C-terminal domain of TPX2 is made of alpha-helical tandem repeats. AB - BACKGROUND: TPX2 (Targeting Protein for Xklp2) is essential for spindle assembly, activation of the mitotic kinase Aurora A and for triggering microtubule nucleation. Homologs of TPX2 in Chordata and plants were previously identified. Currently, proteins of the TPX2 family have little structural information and only small parts are covered by defined protein domains. METHODS: We have used computational sequence analyses and structural predictions of proteins of the TPX2 family, supported with Circular Dichroism (CD) measurements. RESULTS: Here, we report our finding that the C-terminal domain of TPX2, which is responsible of its microtubule nucleation capacity and is conserved in all members of the family, is actually formed by tandem repeats, covering well above 2/3 of the protein. We propose that this region forms a flexible solenoid involved in protein-protein interactions. Structural prediction and molecular modeling, combined with Circular Dichroism (CD) measurements reveal a predominant alpha helical content. Furthermore, we identify full length homologs in fungi and shorter homologs with a different domain organization in diptera (including a paralogous expansion in Drosophila). CONCLUSIONS: Our results, represent the first computational and biophysical analysis of the TPX2 proteins family and help understand the structure and evolution of this conserved protein family to direct future structural studies. PMID- 27782825 TI - Antenatal psychosocial risk status and Australian women's use of primary care and specialist mental health services in the year after birth: a prospective study. AB - BACKGROUND: Poor mental health in the perinatal period can impact negatively on women, their infants and families. Australian State and Territory governments are investing in routine psychosocial assessment and depression screening with referral to services and support, however, little is known about how well these services are used. The aim of this paper is to report on the health services used by women for their physical and mental health needs from pregnancy to 12 months after birth and to compare service use for women who have been identified in pregnancy as having moderate-high psychosocial risk with those with low psychosocial risk. METHODS: One hundred and six women were recruited to a prospective longitudinal study with five points of data collection (2-4 weeks after prenatal booking, 36 weeks gestation, 6 weeks postpartum, 6 months postpartum and 12 months postpartum) was undertaken. Data were collected via face to-face and telephone interviews, relating to psychosocial risk factors, mental health and service use. The prenatal psychosocial risk status of women (data available for 83 of 106 women) was determined using the Antenatal Risk Questionnaire (ANRQ) and was used to compare socio-demographic characteristics and service use of women with 'low' and 'moderate to high' risk of perinatal mental health problems. RESULTS: The findings indicate high use of postnatal universal health services (child and family health nurses, general practitioners) by both groups of women, with limited use of specialist mental health services by women identified with moderate to high risk of mental health problems. While almost all respondents indicated that they would seek help for mental health concerns most had a preference to seek help from partners and family before accessing health professionals. CONCLUSION: These preliminary data support local and international studies that highlight the poor uptake of specialist services for mental health problems in postnatal women, where this may be required. Further research comparing larger samples of women (with low and psychosocial high risk) are needed to explore the extent of any differences and the reasons why women do not access these specialist services. PMID- 27782826 TI - Does the Incredible Years Teacher Classroom Management Training programme have positive effects for young children exhibiting severe externalizing problems in school?: a quasi-experimental pre-post study. AB - BACKGROUND: Young children exhibiting severe externalizing problems in school are at risk of developing several poor outcomes. School-based intervention programs have been found to be effective for students with different problems, including those with behavioral problems, emotional distress, or social problems. The present study investigated whether the IY-TCM programme, as a universal stand alone school intervention programme, reduced severe child externalizing problems as reported by the teacher, and evaluated if these children improved their social competence, internalizing problems, academic performances and student- teacher relationship as a result of the IY TCM training. METHODS: A quasi-experimental pre-post study was conducted, including 21 intervention schools and 22 control schools. Children in 1st - 3rd grade (age 6-8 years) assessed by their teacher as having severe externalizing problems on the Sutter-Eyberg Student Behavior Inventory-Revised (SESBI-R) total Intensity score, were included in the study, N = 83 (65 boys and 18 girls). Treatment effects were evaluated using 3- level linear mixed models analysis. RESULTS: In our study we found no differences in change between the two conditions from baseline to follow-up in externalizing problems, social skills, internalizing problems and closeness with teacher. The intervention condition did however show advantageous development in terms of student-teacher conflicts and increased academic performances. CONCLUSION: The IY Teacher Classroom Management program is not sufficient being a stand-alone universal program in a Norwegian primary school setting, for students with severe externalizing problems. However; some important secondary findings were found. Still, young school children with severe externalizing problems are in need of more comprehensive and tailored interventions. PMID- 27782827 TI - A statistical approach for identifying differential distributions in single-cell RNA-seq experiments. AB - The ability to quantify cellular heterogeneity is a major advantage of single cell technologies. However, statistical methods often treat cellular heterogeneity as a nuisance. We present a novel method to characterize differences in expression in the presence of distinct expression states within and among biological conditions. We demonstrate that this framework can detect differential expression patterns under a wide range of settings. Compared to existing approaches, this method has higher power to detect subtle differences in gene expression distributions that are more complex than a mean shift, and can characterize those differences. The freely available R package scDD implements the approach. PMID- 27782828 TI - Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone. AB - BACKGROUND: The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers. METHODS: mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCoreTM workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis. RESULTS: Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas's molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p = 0.034; HR 1.55) and DLL3 (p = 0.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p = 0.049; HR 0.66) and PIR (p = 0.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p = 0.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p = 0.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p = 0.046; HR 1.65). CONCLUSIONS: We identified four genes with SVZ dependent expression and prognostic significance, among those HES4 and DLL3 as part of Notch signaling, suggesting further evaluation of location-tailored targeted therapies. PMID- 27782829 TI - The effect of skin-to-skin contact at birth, early versus immediate, on the duration of exclusive human lactancy in full-term newborns treated at the Clinica Universidad de La Sabana: study protocol for a randomized clinical trial. AB - BACKGROUND: Human lactancy is a simple and cost-effective strategy that influences infant and maternal mortality rates. Skin-to-skin contact (SSC) is an immediate postpartum period strategy that has proven to benefit the initiation and continuation of human lactation and to decrease hospitalization during the first week of life. This study aims to determine the effect of SSC initiation at birth (immediate versus early) in healthy, full-term newborns treated at the Universidad de La Sabana Clinic on the duration of exclusive human lactation. METHODS/DESIGN: A randomized, blind clinical trial will be performed with full term healthy newborns born at the Universidad de La Sabana Clinic. The blind trial participants will be those persons measuring the results and analyzing the data. The sample size will be calculated for a type I error of 5 %, a two-tailed type II error of 20 %, and an estimated percentage loss of 30 %; 150 infants will be included in each group. Randomization will be performed using permuted, size-6 blocks. Descriptive analysis will be conducted using central tendency and dispersion measurements. A bivariate analysis will be performed to determine which variables are associated with exclusive lactancy at 6 months. For continuous variables, Student's t test will be used for independent samples, and the Wilcoxon rank sum test will be used if the assumptions of normality for the t tests are not fulfilled. The assumption of normality will be evaluated using the Shapiro-Wilk and Kolmogorov-Smirnov tests. Categorical variables in contingency tables will be constructed to assess the independence between variables using the chi-square test, or Fisher's exact test when the assumption of the number of cases is not met by the values in the contingency tables multiplied by two. This will be calculated as a measurement of the effect of relative risk (RR) with confidence intervals; the adjusted measurements will be calculated using a multivariate regression Poisson model. Variables with significant results will be used in the bivariate analysis, and those with biological plausibility will be used for the adjustment. The analysis will be carried out for a two-tailed type I error level of 5 %. The Stata 11 program will be used for data analysis. An interim analysis will be performed upon the submission of half the expected events (106), setting limits for the early termination of the trial according to the method proposed by Pampallona and Tsiatis (1994). INTERVENTION: There will be two SSC randomization groups: early versus immediate. After completing the neonatal adaptation process and based on the group assignment, the mother will be left with her newborn child in hospital accommodation. Prior to discharge, the Infant Breast-Feeding Assessment Tool (IBFAT) will be applied. Monitoring will initially be performed with a face-to-face assessment between 3 and 10 days of life, followed by monthly telephone calls for 6 months to verify lactation status. DISCUSSION: SSC at birth has shown benefits in the short and long term for both the mother and the full-term newborn. Although the meta-analysis that have been done have shown the benefits of this technique, multiple differences in the SSC interventions have been identified because criteria such as the initiation or duration of SSC (dose) have not been unified. Colombia has a malnutrition risk of 11,4 % in the total population for the period 2012-2014, so it is necessary to promote strategies that generate a positive impact on the duration of human lactation, providing support from the clinical setting of humanized delivery which is included in the IAMI strategy (Instituciones Amigas de la Mujer y la Infancia - Friends of Women and Children Institution). Therefore, we propose that the initiation time of SSC in full-term new-borns is related to the duration of exclusive human lactation. TRIAL REGISTRATION: Registered ClinicalTrials.gov Identifier: NCT 02687685 . Registered on 2 February 2016. This study is not yet open for participant recruitment. PMID- 27782831 TI - Civil society participation in the health system: the case of Brazil's Health Councils. AB - BACKGROUND: Brazil created Health Councils to bring together civil society groups, heath professionals, and government officials in the discussion of health policies and health system resource allocation. However, several studies have concluded that Health Councils are not very influential on healthcare policy. This study probes this issue further by providing a descriptive account of some of the challenges civil society face within Brazil's Health Councils. METHODS: Forty semi-structured interviews with Health Council Members at the municipal, state and national levels were conducted in June and July of 2013 and May of 2014. The geographical location of the interviewees covered all five regions of Brazil (North, Northeast, Midwest, Southeast, South) for a total of 5 different municipal Health Councils, 8 different state Health Councils, and the national Health Council in Brasilia. Interview data was analyzed using a thematic approach. RESULTS: Health Councils are limited by a lack of legal authority, which limits their ability to hold the government accountable for its health service performance, and thus hinders their ability to fulfill their mandate. Equally important, their membership guidelines create a limited level of inclusivity that seems to benefit only well-organized civil society groups. There is a reported lack of support and recognition from the relevant government that negatively affects the degree to which Health Council deliberations are implemented. Other deficiencies include an insufficient amount of resources for Health Council operations, and a lack of training for Health Council members. Lastly, strong individual interests among Health Council members tend to influence how members participate in Health Council discussions. CONCLUSIONS: Brazil's Health Councils fall short in providing an effective forum through which civil society can actively participate in health policy and resource allocation decision-making processes. Restrictive membership guidelines, a lack of autonomy from the government, vulnerability to government manipulation, a lack of support and recognition from the government and insufficient training and operational budgets have made Health Council largely a forum for consultation. Our conclusions highlight, that among other issues, Health Councils need to have the legal authority to act independently to promote government accountability, membership guidelines need to be revised in order include members of marginalized groups, and better training of civil society representatives is required to help them make more informed decisions. PMID- 27782830 TI - Patient outcomes after critical illness: a systematic review of qualitative studies following hospital discharge. AB - BACKGROUND: There is growing interest in patient outcomes following critical illness, with an increasing number and different types of studies conducted, and a need for synthesis of existing findings to help inform the field. For this purpose we conducted a systematic review of qualitative studies evaluating patient outcomes after hospital discharge for survivors of critical illness. METHODS: We searched the PubMed, EMBASE, CINAHL, PsycINFO, and CENTRAL databases from inception to June 2015. Studies were eligible for inclusion if the study population was >50 % adults discharged from the ICU, with qualitative evaluation of patient outcomes. Studies were excluded if they focused on specific ICU patient populations or specialty ICUs. Citations were screened in duplicate, and two reviewers extracted data sequentially for each eligible article. Themes related to patient outcome domains were coded and categorized based on the main domains of the Patient Reported Outcomes Measurement Information System (PROMIS) framework. RESULTS: A total of 2735 citations were screened, and 22 full-text articles were eligible, with year of publication ranging from 1995 to 2015. All of the qualitative themes were extracted from eligible studies and then categorized using PROMIS descriptors: satisfaction with life (16 studies), including positive outlook, acceptance, gratitude, independence, boredom, loneliness, and wishing they had not lived; mental health (15 articles), including symptoms of post-traumatic stress disorder, anxiety, depression, and irritability/anger; physical health (14 articles), including mobility, activities of daily living, fatigue, appetite, sensory changes, muscle weakness, and sleep disturbances; social health (seven articles), including changes in friends/family relationships; and ability to participate in social roles and activities (six articles), including hobbies and disability. CONCLUSION: ICU survivors may experience positive emotions and life satisfaction; however, a wide range of mental, physical, social, and functional sequelae occur after hospital discharge. These findings are important for understanding patient-centered outcomes in critical care and providing focus for future interventional studies aimed at improving outcomes of importance to ICU survivors. PMID- 27782832 TI - Factors that influence the implementation of e-health: a systematic review of systematic reviews (an update). AB - BACKGROUND: There is a significant potential for e-health to deliver cost effective, quality health care, and spending on e-health systems by governments and healthcare systems is increasing worldwide. However, there remains a tension between the use of e-health in this way and implementation. Furthermore, the large body of reviews in the e-health implementation field, often based on one particular technology, setting or health condition make it difficult to access a comprehensive and comprehensible summary of available evidence to help plan and undertake implementation. This review provides an update and re-analysis of a systematic review of the e-health implementation literature culminating in a set of accessible and usable recommendations for anyone involved or interested in the implementation of e-health. METHODS: MEDLINE, EMBASE, CINAHL, PsycINFO and The Cochrane Library were searched for studies published between 2009 and 2014. Studies were included if they were systematic reviews of the implementation of e health. Data from included studies were synthesised using the principles of meta ethnography, and categorisation of the data was informed by the Consolidated Framework for Implementation Research (CFIR). RESULTS: Forty-four reviews mainly from North America and Europe were included. A range of e-health technologies including electronic medical records and clinical decision support systems were represented. Healthcare settings included primary care, secondary care and home care. Factors important for implementation were identified at the levels of the following: the individual e-health technology, the outer setting, the inner setting and the individual health professionals as well as the process of implementation. CONCLUSION: This systematic review of reviews provides a synthesis of the literature that both acknowledges the multi-level complexity of e-health implementation and provides an accessible and useful guide for those planning implementation. New interpretations of a large amount of data across e health systems and healthcare settings have been generated and synthesised into a set of useable recommendations for practice. This review provides a further empirical test of the CFIR and identifies areas where additional research is necessary. TRIAL REGISTRATION: PROSPERO, CRD42015017661. PMID- 27782833 TI - Integrins beta1 and beta3 are biomarkers of uterine condition for embryo transfer. AB - BACKGROUND: Clinical ovulation induction induces blood estrogen (E2) in excess of physiological levels, which can hinder uterine receptivity. In contrast, progesterone produces the opposite clinical effect, suggesting that it might be capable of recovering the lost receptivity resulting from exposure to high estrogen levels. Integrins are the most widely used biological markers for monitoring uterine conditions. We studied progesterone-induced changes in integrin beta expression patterns as biomarkers for changes in uterine receptivity in response to increased estrogen levels. METHODS: Endometrial biopsy samples from patients were screened for their estrogen (E2) and progesterone (P4) content and expressing levels of integrin beta1 and beta3. Uterine receptivity was evaluated using human endometrial adenocarcinoma cells in an embryo attachment model. The respective and concatenated effects of embryo attachment and changes in the integrin beta1 and beta3 expression patterns on the adenocarcinoma cell plasma membranes in response to 100 nM concentrations of E2 and P4 were evaluated. RESULTS: Increased blood E2 concentrations were associated with significantly decreased the levels of integrin beta3 expression in uterine biopsy samples. In vitro experiments revealed that a 100 nM E2 concentration inhibited the distribution of integrin beta3 on the plasma membranes of human endometrial adenocarcinoma cells used in the embryo attachment model, and resulted in decreased rates of embryo attachment. In contrast, P4 enhanced the expression of integrin beta1 and promoted its distribution on the plasma membranes. Furthermore, P4 recovered the embryo attachment efficiency that was lost by exposure to 100 nM E2. CONCLUSIONS: Blood E2 and P4 levels and integrin beta3 and beta1 expression levels in uterine biopsy samples should be considered as biomarkers for evaluating uterine receptivity and determining the optimal time for embryo transfer. Trial registration Trial number: ChiCTR-TRC-13003777; Name of registry: Chinese Clinical Trial Registry; Date of registration: 4 September 2013; Date of enrollment of the first study participant: 15 October 2013. PMID- 27782835 TI - Erratum to: Mortality and treatment costs of hospitalized chronic kidney disease patients between the three major health insurance schemes in Thailand. PMID- 27782834 TI - Enhanced stimulation of anti-breast cancer T cells responses by dendritic cells loaded with poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated tumor antigens. AB - BACKGROUND: Developing safe and effective cancer vaccine formulations is a primary focus in the field of cancer immunotherapy. Dendritic cells (DC) are currently employed as cellular vaccine in clinical trials of tumor immunotherapy. Recognizing the critical role of DCs in initiating anti-tumor immunity has resulted in the development of several strategies that target vaccine antigens to DCs to trigger anti-tumor T cell responses. To increase the efficiency of antigen delivery systems for anti-tumor vaccines, encapsulation of tumor-associated antigens in polymer nanoparticles (NPs) has been established. METHODS: In this study, the effect of tumor lysate antigen obtained from three stage III breast cancer tissues encapsulated within PLGA NPs to enhance the DC maturation was investigated. The T-cell immune response activation was then fallowed up. Fresh breast tumors were initially used to generate tumor lysate antigens containing poly lactic-co-glycolic acid (PLGA) NP. The encapsulation efficiency and release kinetics were profiled. The efficiency of encapsulation was measured using Bradford protein assays measuring the dissolved NPs. The stability of released antigen from NPs was verified using SDS-PAGE. To evaluate the hypothesis that NPs enhances antigen presentation, including soluble tumor lysate, tumor lysate containing NPs and control NPs the efficiency of NP-mediated tumor lysate delivery to DCs was evaluated by assessing CD3+ T-cell stimulation after T cell/and DCs co-culture. RESULTS: The rate of encapsulation was increased by enhancing the antigen concentration of tumor lysate. However, increasing the antigen concentration diminished the encapsulation efficiency. In addition, higher initial protein contenting NPs led to a greater cumulative release. All three patients released variable amounts of IFN-gamma, IL-10, IL-12 and IL-4 in response to re-stimulation. T cells stimulated with lysate-pulsed DCs induced a substantial increase in IFN-gamma and IL-12 production. We demonstrated that NPs containing tumor lysate can induce maturation and activation of DCs, as antigen alone does. CONCLUSION: PLGA-NPs are attractive vehicles for protein antigen delivery which effectively induce stimulation and maturation of DCs, allowing not only an enhanced antigen processing and immunogenicity or improved antigen stability, but also the targeted delivery and slow release of antigens. PMID- 27782837 TI - Benefit of prokinetics during enteral nutrition: still searching for a piece of evidence. PMID- 27782836 TI - Macrophage-derived MCPIP1 mediates silica-induced pulmonary fibrosis via autophagy. AB - BACKGROUND: Silicosis is characterized by accumulation of fibroblasts and excessive deposition of extracellular matrix. Monocyte chemotactic protein-1 induced protein 1 (MCPIP1) plays a critical role in fibrosis induced by SiO2. However, the details of the downstream events of MCPIP1 activity in pulmonary fibrosis remain unclear. To elucidate the role of MCPIP1-induced autophagy in SiO2-induced fibrosis, both the upstream molecular mechanisms and the functional effects of SiO2 on cell apoptosis, proliferation and migration were investigated. RESULTS: Experiments using primary cultures of alveolar macrophages from healthy donors and silicosis patients as well as differentiated U937 macrophages demonstrated the following results: 1) SiO2 induced macrophage autophagy in association with enhanced expression of MCPIP1; 2) autophagy promoted apoptosis and activation of macrophages exposed to SiO2, and these events induced the development of silicosis; 3) MCPIP1 facilitated macrophage apoptosis and activation via p53 signaling-mediated autophagy; and 4) SiO2-activated macrophages promoted the proliferation and migration of fibroblasts via the MCPIP1/p53-mediated autophagy pathway. CONCLUSIONS: Our results elucidated a link between SiO2-induced fibrosis and MCPIP1/p53 signaling-mediated autophagy. These findings provide novel insight into the potential targeting of MCPIP1 or autophagy in the development of potential therapeutic strategies for silicosis. PMID- 27782839 TI - Secondary metastasis in the lymph node of the bowel invaded by colon cancer: a report of three cases. AB - BACKGROUND: Secondary metastasis to regional lymph nodes for adjacent bowel invaded by colorectal cancers (CRCs) has not been extensively reviewed. We herein present three such cases. CASE PRESENTATION: The first case is a cancer involving the cecum and sigmoid colon, and its primary site could not be determined even by pathological evaluation. Nodal involvement was revealed both in the mesocolon of the cecum and sigmoid. The second and third cases are a sigmoid colon cancer invading the jejunum and an ascending colon cancer invading the jejunum, respectively. These patients harbored secondary metastases to lymph nodes draining from the invaded small bowel segments. In spite of complete resection, all three patients metachronously developed liver metastases or recurrent disseminated nodules in the pelvis and subsequently died. CONCLUSIONS: In cases of CRC invading another bowel segment, bowel resection with regional lymphadenectomy for both involved segments should be considered to achieve complete resection. However, the radical surgery did not necessarily provide a long-term survival. PMID- 27782838 TI - Parental involvement and association with adolescents' fruit and vegetable intake at follow-up: Process evaluation results from the multi-component school-based Boost intervention. AB - BACKGROUND: Based on the assumption of parental influence on adolescent behavior, multicomponent school-based dietary interventions often include a parental component. The effect of this intervention component is seldom reported and the evidence is inconsistent. We conducted a systematic process evaluation of the parental component and examined whether the leveal of parental involvement in a large multi-component intervention: the Boost study was associated with adolescents' fruit and vegetable (FV) intake at follow-up. METHODS: The Boost study was targeting FV intake among 1,175 Danish 7th graders (~13- year-olds) in the school year 2010/11. The study included a school component: free FV in class and curricular activities; a local community component: fact sheets for sports- and youth clubs; and a parental component: presentation of Boost at a parent school meeting, 6 newsletters to parents, 3 guided student-parent curricular activities, and a student-parent Boost event. STUDY POPULATION: Students whose parent replied to the follow-up survey (n = 347). DATA: Questionnaire data from students, parents and teachers at 20 intervention schools. Process evaluation measures: dose delivered, dose received, appreciation and level of parental involvement. Parental involvement was trichotomized into: low/no (0-2 points), medium (3 points) and high (4-6 points). The association between level of parental involvement and self-reported FV intake (24-h recall), was analyzed using multilevel regression analyses. RESULTS: The Boost study was presented at a parent-school meeting at all intervention schools. The dose delivered was low to moderate for the three other parental elements. Most parents appreciated the intervention and talked with their child about Boost (83.5 %). High, medium and low parental involvement was found among 30.5 %, 29.6 % and 39.4 % of the students respectively. Parental involvement was highest among women. More men agreed that the parental newsletters provided new information. Students with a medium and high level of parental involvement ate 47.5 and 95.2 g more FV per day compared to students with low level/no parental involvement (p = 0.02). CONCLUSIONS: Students with a high level of parental involvement ate significantly more FV at follow-up compared to students with a low level/no parental involvement. Parental involvement in interventions may improve adolescents' FV intake if challenges of implementation can be overcome. TRIAL REGISTRATION: ISRCTN11666034 . Registered 06/01/2012. Retrospectively registered. PMID- 27782840 TI - TIS7 induces transcriptional cascade of methylosome components required for muscle differentiation. AB - BACKGROUND: TPA Induced Sequence 7 acts as a transcriptional co-regulator controlling the expression of genes involved in differentiation of various cell types, including skeletal myoblasts. We and others have shown that TIS7 regulates adult myogenesis through MyoD, one of the essential myogenic regulatory factors. RESULTS: Here, we present data identifying ICln as the specific, novel protein downstream of TIS7 controlling myogenesis. We show that TIS7/ICln epigenetically regulate myoD expression controlling protein methyl transferase activity. In particular, ICln regulates MyoD expression via its interaction with PRMT5 by an epigenetic modification that utilizes symmetrical di-methylation of histone H3 on arginine 8. We provide multiple evidences that TIS7 directly binds DNA, which is a functional feature necessary for its role in transcriptional regulation. CONCLUSION: We present here a molecular insight into TIS7-specific control of MyoD gene expression and thereby skeletal muscle differentiation. PMID- 27782841 TI - The influence of socio-demographic, psychological and knowledge-related variables alongside perceived cooking and food skills abilities in the prediction of diet quality in adults: a nationally representative cross-sectional study. AB - BACKGROUND: Interventions to increase cooking skills (CS) and food skills (FS) as a route to improving overall diet are popular within public health. This study tested a comprehensive model of diet quality by assessing the influence of socio demographic, knowledge- and psychological-related variables alongside perceived CS and FS abilities. The correspondence of two measures of diet quality further validated the Eating Choices Index (ECI) for use in quantitative research. METHODS: A cross-sectional survey was conducted in a quota-controlled nationally representative sample of 1049 adults aged 20-60 years drawn from the Island of Ireland. Surveys were administered in participants' homes via computer-assisted personal interviewing (CAPI) assessing a range of socio-demographic, knowledge- and psychological-related variables alongside perceived CS and FS abilities. Regression models were used to model factors influencing diet quality. Correspondence between 2 measures of diet quality was assessed using chi-square and Pearson correlations. RESULTS: ECI score was significantly negatively correlated with DINE Fat intake (r = -0.24, p < 0.001), and ECI score was significantly positively correlated with DINE Fibre intake (r = 0.38, p < 0.001), demonstrating a high agreement. Findings indicated that males, younger respondents and those with no/few educational qualifications scored significantly lower on both CS and FS abilities. The relative influence of socio-demographic, knowledge, psychological variables and CS and FS abilities on dietary outcomes varied, with regression models explaining 10-20 % of diet quality variance. CS ability exerted the strongest relationship with saturated fat intake (beta = 0.296, p < 0.001) and was a significant predictor of fibre intake (beta = -0.113, p < 0.05), although not for healthy food choices (ECI) (beta = 0.04, p > 0.05). CONCLUSION: Greater CS and FS abilities may not lead directly to healthier dietary choices given the myriad of other factors implicated; however, CS appear to have differential influences on aspects of the diet, most notably in relation to lowering saturated fat intake. Findings suggest that CS and FS should not be singular targets of interventions designed to improve diet; but targeting specific sub-groups of the population e.g. males, younger adults, those with limited education might be more fruitful. A greater understanding of the interaction of factors influencing cooking and food practices within the home is needed. PMID- 27782842 TI - Aqueous extract of Lithospermi radix attenuates oxaliplatin-induced neurotoxicity in both in vitro and in vivo models. AB - BACKGROUND: Oxaliplatin can induce peripheral neuropathy (OXIPN) as an adverse side effect in cancer patients. Until now, no effective preventive or therapeutic drug has been developed; therefore, the dose-limiting factor of OXIPN is still an obstacle in the use of oxaliplatin to treat cancer patients. In the present study, we report for the first time that the aqueous extract of Lithospermi radix (WLR) can attenuate the OXIPN in both in vitro and in vivo neuropathic models. METHODS: The protective effect of WLR on OXIPN was evaluated in vitro by quantifying nerve growth factor (NGF)-stimulated neurite outgrowth in PC12 cells treated with a combination of oxaliplatin and WLR. The neuroprotective potential of WLR was further confirmed by measuring the changes in nociceptive sensitivities to external mechanical stimuli in neuropathic animals induced by oxaliplatin. Histological and immunohistochemical studies were further done to examine the effect of WLR in mouse spinal cords and footpads. RESULTS: Oxaliplatin-induced neurotoxicity in NGF-stimulated PC12 cells. It could reduce the lengths and branching numbers of neuritis in NGF-stimulated PC12 cells. Co treatment of WLR rescued the differentiated PC12 cells from the neurotoxicity of oxaliplatin. In a chronic OXIPN animal model, administration of oxaliplatin i.p. induced enhanced nociceptive sensitivity to mechanical stimuli (25.0 to 72.5 % of response rate) along with spinal activation of microglias and astrocytes and loss of intraepidermal nerve fibers in footpads, which is remarkably suppressed by oral administration of WLR (67.5 to 35 % of response rate at the end of experiment). Cytotoxicity of oxaliplatin determined in human cancer cells was not affected irrespective of the presence of WLR. CONCLUSIONS: In conclusion, we demonstrated that WLR can attenuate OXIPN in both in vitro and in vivo experimental models, which may be in part attributed to its anti-inflammatory activity in the spinal cord and its neuroprotective potential in the peripheral nerve system without affecting the anti-tumor potential of oxaliplatin. Therefore, WLR could be considered as a good starting material to develop a novel therapeutic agent targeting OXIPN. However, further studies should be done to elucidate the underlying mechanism such as molecular targets and active constituent(s) in WLR with neuroprotective potential. PMID- 27782843 TI - Discrimination-related health inequality and role of social capital among marriage migrant women in South Korea. AB - BACKGROUND: This study aimed to evaluate whether social capital could alleviate health inequality against racial discrimination and identify the critical nature of social capital that generates health inequality differences within the social context of South Korea. METHODS: Using the data of the 2009 National Survey of Multicultural Families, a nationally representative sample in which 40,430 foreign wives participated, the concentration index (CI) was used to measure the discrimination-related inequalities in self-rated health and was decomposed into contributing factors. RESULTS: The results showed a significant concentration of poor self-rated health unfavorable to foreign wives who were highly discriminated (CI 0.023, standard error [SE] 0.001, p < .001). However, when the CIs were assessed among the subgroups of different social capital, no discrimination related inequality in health was observed among the group of linking social capital (CI 0.008, SE 0.008, p .332). The total differential decomposition method showed two major factors that generate differences in health inequality between the groups of non-linking and linking social capital: protest against discrimination (35.8 %); experiences of discrimination (28.3 %). CONCLUSIONS: The present results indicated that linking social capital can be a useful resource of health resilience factor that equalizes discrimination-related health inequality among marriage migrant women in South Korea. This study provides additional evidence that social capital needs to be placed in its political context. PMID- 27782845 TI - Chemical composition, anthelmintic, antibacterial and antioxidant effects of Thymus bovei essential oil. AB - BACKGROUND: It has been recently recognized that oxidative stress, helminth and microbial infections are the cause of much illness found in the underdeveloped, developing and developed countries. The present study was undertaken to identify the chemical composition, and to assess anthelmintic, antimicrobial and antioxidant effects of Thymus bovei essential oil. METHODS: The chemical composition of the essential oil was analyzed using gas chromatography mass spectrometry (GC-MS). Antimicrobial activity was tested against the selected strains from American Type Culture Collection (ATCC) and clinical isolates such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Methicillin Resistant Staphylococcus aureus, Candida albicans using MIC assay. The anthelmintic assay was carried out on adult earthworm (Pheretima posthuma), while antioxidant activity was analyzed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. RESULTS: Trans-geraniol (35.38 %), alpha-citral (20.37 %) and beta-citral (14.76 %) were the major compounds comprising 70.51 % of the essential oil. Our results showed that T. bovei essential oil exhibited strong anthelmintic activity, even higher than piperazine citrate, the used reference standard, with potential antioxidant activity almost equal to the Trolox standard. Furthermore, T. bovei essential oil had powerful antibacterial and antifungal activities against the studied pathogens. CONCLUSION: Essential oil of T. bovei exerted excellent antioxidant, antimicrobial, and anthelmintic activities. Moreover, this study found that T. bovei volatile oil contains active substances that could potentially be used as natural preservatives in food and pharmaceutical industries, these substances could also be employed for developing new anthelmintic, antimicrobial and antioxidant agents. PMID- 27782844 TI - Transcriptome-wide effects of inverted SINEs on gene expression and their impact on RNA polymerase II activity. AB - BACKGROUND: Short interspersed elements (SINEs) represent the most abundant group of non-long-terminal repeat transposable elements in mammalian genomes. In primates, Alu elements are the most prominent and homogenous representatives of SINEs. Due to their frequent insertion within or close to coding regions, SINEs have been suggested to play a crucial role during genome evolution. Moreover, Alu elements within mRNAs have also been reported to control gene expression at different levels. RESULTS: Here, we undertake a genome-wide analysis of insertion patterns of human Alus within transcribed portions of the genome. Multiple, nearby insertions of SINEs within one transcript are more abundant in tandem orientation than in inverted orientation. Indeed, analysis of transcriptome-wide expression levels of 15 ENCODE cell lines suggests a cis-repressive effect of inverted Alu elements on gene expression. Using reporter assays, we show that the negative effect of inverted SINEs on gene expression is independent of known sensors of double-stranded RNAs. Instead, transcriptional elongation seems impaired, leading to reduced mRNA levels. CONCLUSIONS: Our study suggests that there is a bias against multiple SINE insertions that can promote intramolecular base pairing within a transcript. Moreover, at a genome-wide level, mRNAs harboring inverted SINEs are less expressed than mRNAs harboring single or tandemly arranged SINEs. Finally, we demonstrate a novel mechanism by which inverted SINEs can impact on gene expression by interfering with RNA polymerase II. PMID- 27782846 TI - Does upregulated host cell receptor expression provide a link between bacterial adhesion and chronic respiratory disease? AB - Expression of the platelet-activating factor receptor is upregulated in the respiratory epithelium of smokers and chronic obstructive pulmonary disease patients. We have recently determined that increased expression of PAFr correlates with higher levels of adhesion to human bronchial epithelial cells by non-typable Haemophilus influenzae and Streptococcus pneumoniae which are major bacterial pathogens in acute exacerbations of COPD. In addition, we found that a PAFr antagonist decreased the adhesion of both respiratory bacterial pathogens to non-cigarette exposure control levels. This highlights the possibility that epithelial receptors, that are upregulated in response to cigarette smoke, could be targeted to specifically block chronic bacterial infections of the lower respiratory tract. In this commentary, we explore the question of whether adhesion to a temporally-upregulated host receptor is a common event in chronic bacterial disease, and as such, could represent a putative therapeutic target for blocking infection by respiratory and other pathogens. PMID- 27782847 TI - Understanding variations in patient screening and recruitment in a multicentre pilot randomised controlled trial: a vignette-based study. AB - BACKGROUND: The INVESTIGATE-I study was designed to inform a future definitive randomised trial of invasive urodynamic testing, compared to basic clinical assessment with noninvasive tests prior to surgical treatment, in women with stress urinary incontinence or stress-predominant mixed urinary incontinence. In a pilot randomised controlled trial, women from seven participating sites were screened, consented and randomised. Overall, 771 patients were identified from clinic notes and correspondence as being potential recruits and were sent the Patient Information Leaflet. Of those screened, 284 were deemed eligible, giving an overall 'screen positive' rate of 37 %. The numbers screened at individual centres varied between 14 and 399; the 'screen positive' rate varied between 22 and 79 % and the percentage of eligible women recruited varied between 55 and 100 %. The aim of this additional substudy was to explore why 'screen positive' rates may have varied so widely between apparently similar sites. RESULTS: All 11 trial staff involved in screening in the seven recruiting sites were asked to evaluate a series of 20 identical vignettes, mainly based on actual general practitioner referral letters. Of the vignettes, 16 mentioned one or more definite inclusion criteria; the remainder had possible inclusions. Four had definite exclusions; 12 had possible exclusions. Free-text comments were sought to clarify the screeners' decisions. For six vignettes everyone agreed that the patient was eligible; for one all agreed she was not eligible; the breakdown for the remainder was mixed. Free-text comments illuminated uncertainties that may have led to variability in judging potential eligibility. CONCLUSIONS: Variability in judgements about potential trial eligibility highlights the importance of explicit and objective inclusion and exclusion criteria, and of agreed strategies for making judgements when information is missing. During the development and planning of trials, vignettes might be a valuable tool for training those involved in screening and recruiting patients, for identifying potential problems and ensuring greater consistency in the application of eligibility criteria. TRIAL REGISTRATION: ISTCTN registry: ISRCTN71327395 , registered on 7 June 2010. PMID- 27782848 TI - Morphological and molecular characterisation of Myxobolus pronini n. sp. (Myxozoa: Myxobolidae) from the abdominal cavity and visceral serous membranes of the gibel carp Carassius auratus gibelio (Bloch) in Russia and China. AB - BACKGROUND: Myxozoa is a well-known economically and ecologically important group of metazoan parasites, phylogenetically related to Cnidaria. High diversity of myxosporeans has been recorded in Russia and China; however, most of the species were solely morphologically characterised. Here, we identified a new gibel carp infecting Myxobolus species and morphologically and molecularly compared the Russian and Chinese isolates of this new myxosporean. RESULTS: Myxobolus pronini n. sp. was found free in the abdominal cavity of Carassius auratus gibelio (Bloch, 1782) in Lake Baikal watershed, Russia, and embedded in the visceral serous membranes of the same fish species in Lake Taibai, Hubei province, China. The morphometric data of the plasmodia and mature spores exhibited some differences between the Russian and Chinese isolates, but SSU rDNA sequences indicated that these two geographical isolates are conspecific. The mature spores from the two locations are obovate in frontal view, with wider anterior than posterior end and lemon-shaped in sutural view. Spores of the Russian isolate were 14.3-16.2 (mean 15.1 +/- 0.2) MUm long, 9.6-10.8 (10.1 +/- 0.1) MUm wide and 6.4-7.4 (6.7 +/- 0.15) MUm thick; those of the Chinese isolate were 13.8-15.6 (14.7 +/- 0.24) MUm long, 9.6-13.3 (9.6 +/- 0.65) MUm wide and 6.2-7.2 (6.6 +/- 0.16) MUm thick. The newly-generated rDNA sequences (including SSU rDNA, ITS and LSU rDNA) from the two isolates represented some variations within the intraspecific range. Homology search by BLAST showed that the newly obtained rDNA sequences do not match any sequences available on GenBank. Phylogenetic analysis based on the aligned partial SSU rDNA sequences indicated that this novel species clustered with several gibel carp-infecting Myxobolus spp. with round anterior end of spores. Additionally, phylogenetic analysis based on all obtained ITS sequences showed that distinct genetic geographical differentiation occurred for this new parasite. CONCLUSIONS: Myxobolus pronini n. sp. is described by integrating morphological, ecological and molecular evidence. Two geographical isolates of this species showed some morphological and genetic differences but within the intraspecific range of variation. PMID- 27782849 TI - Habituation of the startle reflex depends on attention in cannabis users. AB - BACKGROUND: Cannabis use is associated with an attention-dependent deficit in prepulse inhibition of the startle reflex (PPI). The aim of the current study was to investigate startle habituation in cannabis users and healthy controls during two attentional tasks. METHODS: Auditory startle reflex was recorded from orbicularis oculi muscle while participants (12 controls and 16 regular cannabis users) were either attending to or ignoring 100 dB startling pulses. Startle habituation was measured as the absolute reduction in startle magnitude on block 2 (last nine trials) vs. block 1 (first nine trials). RESULTS: Startle habituation with moderate effect sizes was observed in controls and cannabis users only while they were ignoring the startling pulses but not while they were attending to them. Similar results were also observed in controls (lifetime non users of cannabis) and cannabis users with lifetime cannabis use disorders (CUD). CONCLUSION: Startle habituation appears to depend on selective attention but not on cannabis use. Startle habituation was present when attention was directed away from auditory startling pulses in healthy controls and cannabis users. Such a similar pattern of results in both groups suggests that at least a trend exists towards presence of startle habituation regardless of cannabis use or CUD in otherwise healthy members of the general population. PMID- 27782850 TI - Psoriatic arthritis is associated with bone loss of the metacarpals. AB - BACKGROUND: BoneXpert (BX) is a newly developed medical device based on digital X ray radiogrammetry to measure human cortical bone thickness. The aim of this study was to quantify cortical bone loss of the metacarpals in patients with psoriatic arthritis (PsA) and compare these findings with other radiological scoring methods. METHODS: The study includes 104 patients with verified PsA. The BX method was used to measure the Metacarpal Index (MCI) at the metacarpal bones (II-IV). Additionally, the T-score of the MCI (T-scoreMCI) was calculated. Radiographic severity was determined by the Psoriatic Arthritis Ratingen Score (Proliferation Score and Destruction Score) as published by Wassenberg et al. and the Psoriatic Arthritis modified van der Heijde Sharp Score (Joint Space Narrowing Score and Erosion Score). RESULTS: For the total PsA study cohort, the T-scoreMCI was significantly reduced by -1.289 +/- 1.313 SD. The MCI negatively correlated with the Proliferation Score (r = -0.732; p < 0.001) and the Destruction Score (r = -0.771; p < 0.001) of the Psoriatic Arthritis Ratingen Score. Lower coefficients of correlations were observed for the Psoriatic Arthritis modified van der Heijde Sharp Score. In this context, a severity dependent and PsA-related periarticular demineralisation as measured by the MCI was quantified. The strongest reduction of -30.8 % (p < 0.01) was observed for the MCI in the Destruction Score. CONCLUSIONS: The BX MCI score showed periarticular demineralisation and severity-dependent bone loss in patients with PsA. The measurements of the BX technique were able to sensitively differentiate between the different stages of disease manifestation affecting bone integrity and thereby seem to achieve the potential to be a surrogate marker of radiographic progression in PsA. PMID- 27782852 TI - Delivering on the promise of precision cancer medicine. PMID- 27782851 TI - Surefire infusion system versus standard microcatheter use during holmium-166 radioembolization: study protocol for a randomized controlled trial. AB - BACKGROUND: An anti-reflux catheter (ARC) may increase the tumor absorbed dose during radioembolization (RE) by elimination of particle reflux and its effects on hemodynamics. Since the catheter is fixed in a centro-luminal position, it may also increase the predictive accuracy of a scout dose administration before treatment. The purpose of the SIM trial is to compare the effects of ARC use during RE with holmium-166 (166Ho) microspheres in patients with colorectal liver metastases (CRLM), with the use of a standard end-hole microcatheter. METHODS/DESIGN: A within-patient randomized controlled trial (RCT) will be conducted in 25 patients with unresectable chemorefractory liver-dominant CRLM. Study participants will undergo a 166Ho scout dose procedure in the morning and a therapeutic procedure in the afternoon. The ARC will be randomly allocated to the left/right hepatic artery, and a standard microcatheter will be used in the contralateral artery. SPECT/CT imaging will be performed for quantitative analyses of the microsphere distribution directly after the scout and treatment procedure. Baseline and follow-up investigations include 18F-FDG-PET + liver CT, clinical and laboratory examinations. The primary endpoint is the comparison of tumor to non-tumor (T/N) activity ratio in both groups. Secondary endpoints include comparisons of mean absorbed dose in tumors and healthy liver tissue, infusion efficiency, the predictive value of 166Ho scout dose for tumor response. In the entire cohort, a dose-response relationship, clinical toxicity, and overall survival will be assessed. The sample was determined for the expectation that the ARC will increase the T/N ratio by 25 % (mean T/N ratio 2.0 vs. 1.6). DISCUSSION: The SIM trial is a within-patient RCT that will assess whether 166Ho RE treatment can be optimized by using an ARC. TRIAL REGISTRATION: The SIM trial is registered at clinicaltrials.gov ( NCT02208804 ). Registered on 31 July 2014. PMID- 27782853 TI - The preprocessed connectomes project repository of manually corrected skull stripped T1-weighted anatomical MRI data. AB - BACKGROUND: Skull-stripping is the procedure of removing non-brain tissue from anatomical MRI data. This procedure can be useful for calculating brain volume and for improving the quality of other image processing steps. Developing new skull-stripping algorithms and evaluating their performance requires gold standard data from a variety of different scanners and acquisition methods. We complement existing repositories with manually corrected brain masks for 125 T1 weighted anatomical scans from the Nathan Kline Institute Enhanced Rockland Sample Neurofeedback Study. FINDINGS: Skull-stripped images were obtained using a semi-automated procedure that involved skull-stripping the data using the brain extraction based on nonlocal segmentation technique (BEaST) software, and manually correcting the worst results. Corrected brain masks were added into the BEaST library and the procedure was repeated until acceptable brain masks were available for all images. In total, 85 of the skull-stripped images were hand edited and 40 were deemed to not need editing. The results are brain masks for the 125 images along with a BEaST library for automatically skull-stripping other data. CONCLUSION: Skull-stripped anatomical images from the Neurofeedback sample are available for download from the Preprocessed Connectomes Project. The resulting brain masks can be used by researchers to improve preprocessing of the Neurofeedback data, as training and testing data for developing new skull stripping algorithms, and for evaluating the impact on other aspects of MRI preprocessing. We have illustrated the utility of these data as a reference for comparing various automatic methods and evaluated the performance of the newly created library on independent data. PMID- 27782855 TI - Erratum to: Barriers and facilitators to the implementation of orthodontic mini implants in clinical practice: a systematic review. PMID- 27782856 TI - Systems Science for Caribbean Health: the development and piloting of a model for guiding policy on diabetes in the Caribbean. AB - BACKGROUND: Diabetes is highly prevalent in the Caribbean, associated with a high morbidity and mortality and is a recognised threat to economic and social development. Heads of Government in the Caribbean Community came together in 2007 and declared their commitment to reducing the burden of non-communicable diseases (NCDs), including diabetes, by calling for a multi-sectoral, systemic response. To facilitate the development of effective policies, policymakers are being engaged in the development and use of a system dynamics (SD) model of diabetes for Caribbean countries. METHODS: Previous work on a diabetes SD model from the United States of America (USA) is being adapted to a local context for three countries in the region using input from stakeholders, a review of existing qualitative and quantitative data, and collection of new qualitative data. Three country models will be developed using one-on-one stakeholder engagement and iterative revision. An inter-country model will also be developed following a model-building workshop. Models will be compared to each other and to the USA model. The inter-country model will be used to simulate policies identified as priorities by stakeholders and to develop targets for prevention and control. The model and model-building process will be evaluated by stakeholders and a manual developed for use in other high-burden developing regions. DISCUSSION: SD has been applied with success for health policy development in high-income country settings. The utility of SD in developing countries as an aid to policy decision making related to NCDs has not been tested. This study represents the first of its kind. PMID- 27782854 TI - Molecular profiling of advanced solid tumors and patient outcomes with genotype matched clinical trials: the Princess Margaret IMPACT/COMPACT trial. AB - BACKGROUND: The clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical "actionability" of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM). METHODS: Patients with advanced solid tumors aged >=18 years, good performance status, and archival tumor tissue available were prospectively consented. DNA from archival formalin-fixed paraffin-embedded tumor tissue was tested using a MALDI-TOF MS hotspot panel or a targeted next generation sequencing (NGS) panel. Somatic variants were classified according to clinical actionability and an annotated report included in the electronic medical record. Oncologists were provided with summary tables of their patients' molecular profiling results and available mutation-specific clinical trials. Enrolment in genotype-matched versus genotype-unmatched clinical trials following release of profiling results and response by RECIST v1.1 criteria were evaluated. RESULTS: From March 2012 to July 2014, 1893 patients were enrolled and 1640 tested. After a median follow-up of 18 months, 245 patients (15 %) who were tested were subsequently treated on 277 therapeutic clinical trials, including 84 patients (5 %) on 89 genotype-matched trials. The overall response rate was higher in patients treated on genotype-matched trials (19 %) compared with genotype-unmatched trials (9 %; p < 0.026). In a multi-variable model, trial matching by genotype (p = 0.021) and female gender (p = 0.034) were the only factors associated with increased likelihood of treatment response. CONCLUSIONS: Few advanced solid tumor patients enrolled in a prospective institutional molecular profiling trial were treated subsequently on genotype-matched therapeutic trials. In this non-randomized comparison, genotype-enrichment of early phase clinical trials was associated with an increased objective tumor response rate. TRIAL REGISTRATION: NCT01505400 (date of registration 4 January 2012). PMID- 27782857 TI - Increased left ventricular myocardial extracellular volume is associated with longer cardiopulmonary bypass times, biventricular enlargement and reduced exercise tolerance in children after repair of Tetralogy of Fallot. AB - BACKGROUND: Unfavorable left ventricular (LV) remodelling may be associated with adverse outcomes after Tetralogy of Fallot (TOF) repair. We sought to assess T1 cardiovascular magnetic resonance (CMR) markers of diffuse LV myocardial fibrosis in children after TOF repair, and associated factors. METHODS: In this prospective, cross-sectional study, native (=non-contrast) T1 times and extracellular volume fraction (ECV) were quantified in the LV myocardium using CMR. Results were related to ventricular volumes and function, degree of pulmonary regurgitation, as well as surgical characteristics, and exercise capacity. RESULTS: There was no difference in native T1 times or ECV between 31 TOF patients (age at CMR 13.9 +/- 2.4 years, 19 male) and 15 controls (age at CMR 13.4 +/- 2.6 years, 7 male). Female TOF patients had higher ECVs than males (25.2 +/- 2.9 % versus 22.7 +/- 3.3 %, p < 0.05). In the patient group, higher native T1 and ECV correlated with higher Z-Scores of right and left ventricular end diastolic volumes, but not with reduced left and right ventricular ejection fraction or higher pulmonary regurgitation fraction. Longer cardiopulmonary bypass and aortic cross clamp times at surgery correlated with increased native T1 times and ECVs (r = 0.48, p < 0.05 and r = 0.65, p < 0.01, respectively). Maximum workload (percent of predicted for normal) correlated inversely with ECV (r = -0.62, p < 0.05). Higher native T1 times correlated with worse LV longitudinal (r = 0.50, p < 0.05) and mid short axis circumferential strain (r = 0.38, p < 0.05). CONCLUSIONS: As compared to controls, TOF patients did not express higher markers of diffuse fibrosis. Longer cardiopulmonary bypass and aortic cross clamp times at surgery as well as biventricular enlargement and reduced exercise tolerance are associated with markers of diffuse myocardial fibrosis after TOF repair. Female patients have higher markers of diffuse myocardial fibrosis than males. PMID- 27782858 TI - Registration uncertainties between 3D cone beam computed tomography and different reference CT datasets in lung stereotactic body radiation therapy. AB - BACKGROUND: The aim of this study was to analyze differences in couch shifts (setup errors) resulting from image registration of different CT datasets with free breathing cone beam CTs (FB-CBCT). As well automatic as manual image registrations were performed and registration results were correlated to tumor characteristics. METHODS: FB-CBCT image registration was performed for 49 patients with lung lesions using slow planning CT (PCT), average intensity projection (AIP), maximum intensity projection (MIP) and mid-ventilation CTs (MidV) as reference images. Both, automatic and manual image registrations were applied. Shift differences were evaluated between the registered CT datasets for automatic and manual registration, respectively. Furthermore, differences between automatic and manual registration were analyzed for the same CT datasets. The registration results were statistically analyzed and correlated to tumor characteristics (3D tumor motion, tumor volume, superior-inferior (SI) distance, tumor environment). RESULTS: Median 3D shift differences over all patients were between 0.5 mm (AIPvsMIP) and 1.9 mm (MIPvsPCT and MidVvsPCT) for the automatic registration and between 1.8 mm (AIPvsPCT) and 2.8 mm (MIPvsPCT and MidVvsPCT) for the manual registration. For some patients, large shift differences (>5.0 mm) were found (maximum 10.5 mm, automatic registration). Comparing automatic vs manual registrations for the same reference CTs, ?AIP achieved the smallest (1.1 mm) and ?MIP the largest (1.9 mm) median 3D shift differences. The standard deviation (variability) for the 3D shift differences was also the smallest for ?AIP (1.1 mm). Significant correlations (p < 0.01) between 3D shift difference and 3D tumor motion (AIPvsMIP, MIPvsMidV) and SI distance (AIPvsMIP) (automatic) and also for 3D tumor motion (?PCT, ?MidV; automatic vs manual) were found. CONCLUSIONS: Using different CT datasets for image registration with FB-CBCTs can result in different 3D couch shifts. Manual registrations achieved partly different 3D shifts than automatic registrations. AIP CTs yielded the smallest shift differences and might be the most appropriate CT dataset for registration with 3D FB-CBCTs. PMID- 27782860 TI - Evaluation of therapeutic potentials of plant extracts against poultry bacteria threatening public health. AB - BACKGROUND: Plant extracts were evaluated on poultry bacteria known to be threatening public health. This is to develop better bio-therapeutic agents from plant origin. METHODS: Bacteria were isolated from water, feed, crop, gizzard and faeces of layer chicken. Isolates of interest (Escherichia coli, Salmonella enteritidis, Pseudomonas aeruginosa and Klebsiella oxytoca) were subjected to antibiotic susceptibility test. Resistant strains were further evaluated against different plant extracts in comparison to Meropenem (control) using agar diffusion method. RESULTS: E. coli had the highest occurrence (53 %), followed by P. aeruginosa (25 %) and then S. enteritidis (13 %) while the least was K. oxytoca (9 %). Virtually all the isolates exhibited multi-antibiotic resistance (MAR) with gross resistance to Amoxicillin, Erythromycin and Cefuroxine. P. aeruginosa (75 %), S. enteritidis (75 %) and E. coli (63 %), had the highest MAR. Out of the 11 (100 %) plant extracts evaluated, 7 (64 %) were outstanding and showed varied levels of antibacterial activity. Specifically, methanol extract of Mangifera indica Julie cultivar leaf (MJLM) had the highest antibacterial activity, followed by Euadenia trifoliata stem bark (TB03) and Euadenia eminens leaf (TB05). P. aeruginosa was highly susceptible (81.81 %) to the extracts, followed by S. enteritidis (63.64 %) and then E. coli (27.27 %). CONCLUSIONS: MJLM and other extracts have proven to be promising extracts in which to search for bioactive components that can be developed into therapeutic drugs. This may help in the management of antibiotic resistant bacterial isolates from poultry chicken threatening public health. PMID- 27782859 TI - Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions. AB - BACKGROUND: In recent years, immunomodulatory mechanisms of mesenchymal stem/stromal cells (MSCs) from bone marrow and other "classic" sources have been described. However, the phenotypic and functional properties of tumor MSCs are poorly understood. The aim of this study was to analyze the immunosuppressive capacity of cervical cancer-derived MSCs (CeCa-MSCs) on effector T lymphocytes through the purinergic pathway. METHODS: We determined the expression and functional activity of the membrane-associated ectonucleotidases CD39 and CD73 on CeCa-MSCs and normal cervical tissue-derived MSCs (NCx-MSCs). We also analyzed their immunosuppressive capacity to decrease proliferation, activation and effector cytotoxic T (CD8+) lymphocyte function through the generation of adenosine (Ado). RESULTS: We detected that CeCa-MSCs express higher levels of CD39 and CD73 ectonucleotidases in cell membranes compared to NCx-MSCs, and that this feature was associated with the ability to strongly suppress the proliferation, activation and effector functions of cytotoxic T-cells through the generation of large amounts of Ado from the hydrolysis of ATP, ADP and AMP nucleotides. CONCLUSIONS: This study suggests that CeCa-MSCs play an important role in the suppression of the anti-tumor immune response in CeCa through the purinergic pathway. PMID- 27782862 TI - Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade? AB - Anti-programmed cell death 1 (PD1) immunotherapies are among the most effective anti-cancer immunotherapies available; however, a large number of patients present with or develop resistance to them. Unfortunately, very little is known regarding the mechanisms of resistance to such therapies. A recent study sought to identify mutations associated with resistance to anti-PD1 therapy. Results from this study demonstrated that mutations which affected the sensitivity of tumor cells to T-cell-derived interferons, and mutations limiting tumor-cell antigen presentation, could cause acquired resistance. These findings have significant implications for understanding the mechanisms by which anti-PD1 therapies exert their efficacy, comprehending why and how some patients acquire resistance over time, and ultimately guiding the development of combination therapies designed to overcome, or potentially prevent, the development of acquired immunotherapeutic resistance. PMID- 27782861 TI - Acupuncture for the treatment of phantom limb syndrome in lower limb amputees: a randomised controlled feasibility study. AB - BACKGROUND: Post amputation, the complication of phantom limb pain (PLP) is prevalent and difficult to manage. This study aimed to determine whether it was feasible and acceptable to undertake a definitive multicentred randomised controlled trial assessing the effectiveness of acupuncture for treating lower limb amputees with PLP. METHODS: A mixed-methods embedded design, including a randomised controlled trial and semistructured interviews, was undertaken. A total of 15 participants with PLP were randomly assigned to receive either eight pragmatic Traditional Chinese Medicine acupuncture treatments and usual care or usual care alone over 4 weeks. Outcome measures were completed at baseline, weekly throughout the study and at 1 month post completion of the study and included: a numerical pain-rating scale, the Short-Form McGill Pain Questionnaire 2, the EQ-5D-5 L, the Hospital Anxiety and Depression Scale, the Perceived Stress Scale 10-item, the Insomnia Severity Index, and the Patient Global Impression of Change. Post completion of the trial, participants in the acupuncture group were interviewed about their experience. Feasibility-specific data were also collected. RESULTS: Of 24 amputees meeting the study inclusion criteria, 15 agreed to participate (recruitment rate 62.50 %). Qualitatively, acupuncture was perceived to be beneficial and effective. Quantitatively, acupuncture demonstrated clinically meaningful change in average pain intensity (raw change = 2.69) and worst pain intensity (raw change = 4.00). Feasibility-specific data identified that before undertaking a definitive trial, recruitment, practitioner adherence to the acupuncture protocol, completion of outcome measures at 1 month follow-up and blinding should be addressed. Appropriate outcome measures were identified for use in a definitive trial. Data were generated for future sample size calculations (effect size 0.64). Allowing for a 20 % dropout rate, a sample size of 85 participants per group would be needed in a future definitive trial. CONCLUSIONS: A future definitive trial may be possible if the areas identified in this study are addressed. As acupuncture may be effective at treating PLP, and as this feasibility study suggests that a definitive trial may be possible, a multicentred trial with adequate sample size and blinding is now needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02126436 , registered on 4 September 2014. PMID- 27782863 TI - Knowledge of neonatal danger signs among mothers attending well baby clinic in Nakuru Central District, Kenya: cross sectional descriptive study. AB - BACKGROUND: Neonatal mortality has remained high in Kenya despite various efforts being applied to reduce this negative trend. Early detection of neonatal illness is an important step towards improving new born survival. Toward this end there is need for the mothers to be able to identify signs in neonates that signifies severe neonatal illnesses. The objective of the study was to determine the level of knowledge of mothers attending well baby clinics on postnatal neonatal danger signs and determine the associated factors. STUDY DESIGN: Cross sectional descriptive study. STUDY METHODS: Purposive sampling of Health care facilities that provide antenatal, delivery and postnatal services were identified. In each of the selected health facility structured questionnaires were administered to mothers with children aged six weeks to nine months attending well baby clinics. Frequencies, Chi square and multivariate logistic regression were determined using the SPSS software (version 20). RESULTS: During the period of study 414 mothers attending well baby clinics were interviewed. Information on neonatal dangers was not provided to 237 (57.2%) of the postnatal mothers during their antenatal clinic attendance by the health care providers. Majority of mothers 350 (84.5%) identified less than three neonatal danger signs. Hotness of the body (fever) was the commonly recognized danger sign by 310 (74.9%) postnatal mothers. Out of 414 mothers 193 (46.6%), 166 (40.1%), 146 (35.3%) and 24 (5.8%) identified difficulty in breathing, poor sucking, jaundice and lethargy/unconsciousness as new born danger signs respectively. Only 46 (11.1%) and 40 (9.7%) identified convulsion and hypothermia as new born danger signs respectively. Education Level, PNC accompaniment by Spouse, Danger signs information to Mother, Explanation of MCH booklet by Care provider during ANC and Mother read MCH Booklet were factors positively associated with improved knowledge of neonatal danger sign. In multivariate logistic regression none of the factors tested were statistically significant in relation to level of knowledge. CONCLUSION: Knowledge of neonatal danger signs was low among mothers attending well baby clinic despite the information being available in the MCH booklets provided to the mothers during antenatal clinics. PMID- 27782864 TI - Familial Mediterranean fever patients may have unmet needs for treatment of erysipelas-like erythema. PMID- 27782865 TI - Systemic-onset juvenile idiopathic arthritis or incomplete Kawasaki disease: a diagnostic challenge. PMID- 27782866 TI - Increased mortality of incident rheumatoid arthritis versus matched non-RA control subjects: a community-based long-term prospective cohort study. AB - OBJECTIVES: This study aimed to critically investigate all-cause and major-cause mortality of incident rheumatoid arthritis (RA) cases versus matched non-RA comparison (CN) subjects in a long-term prospective cohort. METHODS: Baseline 1974 cohort entry demographic and serum biomarker data on 54 incident RA patients and 216 matched CN subjects were related to their mortality from 1995 through 2015. Mortality of RA patients was also analysed by 3 categories of course responses to therapy assigned by the sole community rheumatologist in 1995 (19 good, 23 fair, and 12 limited). Cox proportional hazards regression models including baseline covariates were used to determine survival from all-causes, cardiovascular disease (CVD), respiratory-related, malignancies, and other causes of death (CODs). RESULTS: Total deaths occurred in 38 (70.4 percent) of 54 RA and 102 (47.7 percent) of 216 CN (p=0.003). Total mortality remained greater (p=0.011) in RA versus CN subjects after adjustment for baseline demographic covariates (HR= 1.66, 95% CI 1.12-2.46). Respiratory-related CODs were also greater (p=0.047) in RA versus CN (HR= 2.69, 95% CI 1.02-7.14) subjects. The RA patients' responses to therapy in 1995 significantly (p=0.004) predicted total mortality. Baseline serum immunological and steroid biomarkers independently predicted total, CVD, and other and unknown CODs. Pre-clinical (1974) ranked biomarker z-score values (1 = lowest, 5 = highest) within matched sets of 1 RA and 4 CN study subjects independently associated with mortality from 1995 through 2015, for both total (CRP, p=0.028 and sIL-2Ralpha, p=0.030) and CVD (CRP, p=0.005 and sTNF-R1, p=0.003) deaths. CONCLUSIONS: Total mortality and respiratory-related CODs were greater in incident RA versus CN subjects. The 35 RA cases who had fair or limited course responses to rheumatologist's therapy had greater mortality than their matched CN, whereas the 19 good RA responders had equivalent survival to CN subjects. The independent CRP and sTNF-R1 biomarker associations with CVD deaths were enhanced by a gradient of their dichotomous z score values in survival models. PMID- 27782867 TI - Predictive significance of CCL21 and CXCL13 levels in the minor salivary glands of patients with Sjogren's syndrome. AB - OBJECTIVES: To investigate whether CCL21 and CXCL13 expression levels in the minor salivary gland are associated with the laboratory and clinical manifestations of Sjogren's syndrome (SS). METHODS: Sociodemographic data on 106 SS patients were obtained and the glandular and extraglandular manifestations of the disease were documented. In addition, minor salivary gland biopsies were performed and the patients' laboratory findings were analysed. European League Against Rheumatism SS disease activity index (ESSDAI) values of SS disease activity at the time of biopsy and the SS disease damage index (SSDDI) values were also recorded. An immunohistochemical approach was used to semiquantitatively measure the CCL21 and CXCL13 expression in the minor salivary glands. RESULTS: The minor salivary glands of SS patients stained positively for CCL21 and CXCL13 in 46.2% (49/106) and 70.7% (75/106) of all cases, respectively. Higher-level expression of CCL21 and CXCL13 was associated with increases in ESR, IgG and rheumatoid factor levels, as well as anti-SS-A and -SS-B titers. A higher focus score and ESSDAI value at the time of biopsy were also associated with these chemokines. In patients with extraglandular manifestations of SS, the prevalence of lymphadenopathy increased with increasing CCL21 levels. CONCLUSIONS: The expression levels of CCL21 and CXCL13 within the lymphocytic infiltrates of SS patients were associated with several laboratory features of the disease as well as lymphadenopathy and the extent of clinical disease activity. CCL21 and CXCL13 levels can therefore serve as useful markers to predict the disease activity and prognosis of patients with SS. PMID- 27782868 TI - Evidence of IL-17 producing innate lymphoid cells in peripheral blood from patients with enteropathic spondyloarthritis. AB - OBJECTIVES: Both the innate and the adaptive immune responses contribute to the onset of chronic inflammation in spondyloarthritis (SpA). The association between SpA and inflammatory bowel disease (IBD, enteropathic SpA-ESpA) has been largely established and suggests a shared pathophysiology. There is evidence that innate lymphoid cells (ILC) are involved in the pathogenesis of both SpA and IBD while no evidence has been reported to date on ESpA. We aimed to analyse for the first time the frequency and cytokine expression of ILC in peripheral blood from ESpA patients compared with both IBD and healthy subjects. Correlations between immunophenotyping and disease activity were also explored. METHODS: ESpA patients (n=20) were prospectively enrolled. Healthy controls (HC, n=10) and IBD patients (n=10) served as control groups. Peripheral blood Interferon (IFN)-gamma and interleukin (IL)-17 expressing T and non-T cells as well as ILC subsets (ILC-1: IFN- gamma +; ILC-3: IL-17+; natural killer-NK) were characterised by flowcytometry. Correlations between IL-17+ cells and SpA disease activity were analysed. RESULTS: ESpA patients showed higher levels of ROR-gamma expressing non T-cells with the respect to the controls. IL-17 producing non-T cells were higher than the HC and positively correlated with IFN-gamma expressing cells levels as well as with SpA disease activity. ESpA showed higher levels of ILC-1 and ILC-3 than both IBD and HC. IFN-gamma expressing NK cells were higher in ESpA than HC. CONCLUSIONS: Our preliminary findings indicate that peripheral blood of ESpA patients is enriched for IL-17 expressing ILC which distinguishes the blood compartment from both IBD and HC. The increased IL-17 production by ILC indicates a novel role for ILC in ESpA. PMID- 27782870 TI - Factors associated with the decision of the rheumatologist to order sacroiliac joints magnetic resonance imaging (SI-MRI) or HLA-B27 testing in the diagnostic work-up of patients with spondyloarthritis in clinical practice. AB - OBJECTIVES: To evaluate the patients' characteristics associated with the clinical decision to request SI-MRI and/or HLA-B27 in patients with SpA in daily practice. METHODS: Patients referred to a rheumatology outpatient-clinic in a national referral-centre were selected. Patients with a clinical diagnosis of SpA according to the rheumatologist were included. SI-MRI and HLA-B27 was available for patients in whom the rheumatologists had ordered these tests. Characteristics associated with ordering SI-MRI or HLA-B27 were identified with univariable analyses. Variables with p-value <0.05 and >80% completeness were selected for further analysis. A multivariable logistic regression analysis was used to evaluate the determinants related with the decision to perform SI-MRI and/or HLA B27 and odds ratios with 95% confidence intervals were calculated. RESULTS: In total, 581 patients with SpA were included in the cohort, 72% were men, mean age 34.6+/-12.1 and disease duration 7.3+/-9.7 years. Of these patients, 24% (n=137) had SI-MRI and 77% (n=441) had HLA-B27 tests ordered. Independently predictive factors for ordering a SI-MRI were the presence of IBP (OR=1.81), enthesitis (OR=1.57) and the number of initial-symptoms at presentation (OR=1.27 per additional symptom present). Independently predictive factors of HLA-B27 testing were the number of initial-symptoms (OR=1.45 per symptom) and uveitis (OR=3.19). CONCLUSIONS: This study strongly suggests that rheumatologists use certain clinical clues to decide if they order expensive and scarce tests in the diagnostic work-up of SpA patients. These manifestations may increase the efficiency of these tests in clinical practice and suggest that clinical reasoning follows principles of Bayesian theory. PMID- 27782869 TI - Assessment of semaphorin 3A and its role in bone remodelling in a group of ankylosing spondylitis patients. AB - OBJECTIVES: Several molecules are involved in the pathogenesis of new bone formation in ankylosing spondylitis (AS). The aim of the present study was to evaluate serum levels of semaphoring 3A in AS and to investigate any correlations with radiographic damage, disease activity, function and treatment. METHODS: AS patients who fulfilled the modified New York criteria were enrolled for this study. Healthy subjects were also enrolled as control group. BASDAI, ASDAS-CRP, BASMI, BASFI, patients and physician VAS, C-reactive protein and erythrocyte sedimentation rate were evaluated at baseline visit. Radiographs of the spine and pelvis performed within six months from the enrolment in the study were collected in all patients. Spinal damage was assessed using the mSASSS. Serum concentrations of semaphorin3A were assessed at baseline and after four months of therapy in patients who started an anti-TNF. RESULTS: Twenty healthy subjects and forty AS patients were enrolled in the study. Of these patients, 15 started anti TNF therapy the day of baseline visit. Semaphorin3A serum concentrations [median (25th-75th)] were similar in AS patients [0.26 (0.20-0.31) ng/ml] and controls [0.28 (0.26-0.3) ng/ml; p=ns). No significant correlation was found between semaphorin 3A serum levels and radiographic damage index. Semaphorin 3A serum levels positively correlated with ESR values (rho=0.37, p=0.049) and with disease activity assessed by the physician VAS (rho=0.47, p<0.01). No differences were found in the semaphorin3A serum levels after 4 months, compared to baseline values. CONCLUSIONS: The results of the present study could contribute to the intriguing topic of bone remodelling in AS. PMID- 27782871 TI - Behcet's disease: an MHC-I-opathy? PMID- 27782873 TI - Completeness of birth and death registration in a rural area of South Africa: the Agincourt health and demographic surveillance, 1992-2014. AB - BACKGROUND: Completeness of vital registration remains very low in sub-Saharan Africa, especially in rural areas. OBJECTIVES: To investigate trends and factors in completeness of birth and death registration in Agincourt, a rural area of South Africa covering a population of about 110,000 persons, under demographic surveillance since 1992. The population belongs to the Shangaan ethnic group and hosts a sizeable community of Mozambican refugees. DESIGN: Statistical analysis of birth and death registration over time in a 22-year perspective (1992-2014). Over this period, major efforts were made by the government of South Africa to improve vital registration. Factors associated with completeness of registration were investigated using univariate and multivariate analysis. RESULTS: Birth registration was very incomplete at onset (7.8% in 1992) and reached high values at end point (90.5% in 2014). Likewise, death registration was low at onset (51.4% in 1992), also reaching high values at end point (97.1% in 2014). For births, the main factors were mother's age (much lower completeness among births to adolescent mothers), refugee status, and household wealth. For deaths, the major factors were age at death (lower completeness among under-five children), refugee status, and household wealth. Completeness increased for all demographic and socioeconomic categories studied and is likely to approach 100% in the future if trends continue at this speed. CONCLUSION: Reaching high values in the completeness of birth and death registration was achieved by excellent organization of the civil registration and vital statistics, a variety of financial incentives, strong involvement of health personnel, and wide-scale information and advocacy campaigns by the South African government. PMID- 27782872 TI - The influence of depression on personality traits in patients with fibromyalgia: a case-control study. AB - OBJECTIVES: We developed this study to investigate the association of fibromyalgia with personality traits, controlling for depression and other potential confounders. METHODS: We assessed personality traits using the Cloninger's Temperament and Character Inventory (TCI) in 78 female patients with fibromyalgia and in a control group of 78 subjects without fibromyalgia. The Mini International Neuropsychiatric Interview was used to assess depression and anxiety diagnoses. To investigate the association between fibromyalgia and the Cloninger's Temperament and Character Inventory we performed unadjusted and adjusted analyses of covariance, using the TCI score as dependent variable and adjusting the model for depression, anxiety and for clinical and socio demographic variables. We used a backward selection method to choose the final model. RESULTS: In the unadjusted analysis, fibromyalgia was associated with all personality traits, except persistency. After adjusting for depression and anxiety, patients with fibromyalgia presented decreased novelty seeking compared to controls; the differences in other personality traits were no longer significant. Novelty seeking was also correlated with the length of history of fibromyalgia and pain intensity. CONCLUSIONS: Decreased novelty seeking may be a personality trait associated with fibromyalgia. Depression and anxiety should be considered potential confounders in the evaluation of personality traits in this population. PMID- 27782874 TI - Corrigendum. AB - [This corrects the article DOI: 10.3402/pba.v6.32981.]. PMID- 27782875 TI - Effects of stachyose on absorption and transportation of tea catechins in mice: possible role of Phase II metabolic enzymes and efflux transporters inhibition by stachyose. AB - BACKGROUND: Nutritional and absorption-promoting properties of stachyose combined with tea catechins (TC) have been revealed. However, the mechanism involved in non-digestible oligosaccharides-mediated enhancement of flavonoid absorption has largely remained elusive. METHODS: This study was designed to investigate the molecular mechanism of stachyose in enhancing absorption and transportation of TC in mice. Mice were orally pre-treated with stachyose (50, 250, and 500 mg/kg.bw) for 0-8 weeks, and 1 h before sacrifice, mice were treated with TC (250 mg/kg.bw). RESULTS: Gas chromatography-mass spectrometry analysis showed that serum concentrations of epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate were dose- and time-dependently elevated with stachyose pre-treatment in mice. Furthermore, pre-treatment with stachyose in mice reduced intestinal sulfotransferase and uridine diphosphate-glucuronosyltransferase levels by 3.3-43.2% and 23.9-30.4%, relative to control mice, respectively. Moreover, intestinal P-glycoprotein and multidrug resistance-associated protein-1 contents were decreased in mice by pre-administration of stachyose in dose- and time-dependent manner. CONCLUSIONS: This is the first time to demonstrate that suppression of Phase II metabolic enzymes and efflux transporters of TC in the intestine can play a major role in increasing absorption of TC by stachyose feeding. PMID- 27782876 TI - Interplay of demographic variables, birth experience, and initial reactions in the prediction of symptoms of posttraumatic stress one year after giving birth. AB - BACKGROUND: There has been increasing research on posttraumatic stress disorder (PTSD) following childbirth in the last two decades. The literature on predictors of who develops posttraumatic stress symptoms (PSS) suggests that both vulnerability and birth factors have an influence, but many studies measure predictors and outcomes simultaneously. OBJECTIVE: In this context, we aimed to examine indirect and direct effects of predictors of PSS, which were measured longitudinally. METHOD: We assessed women within the first days (n=353), 6 weeks, and 12 months (n=183) after having given birth to a healthy infant. The first assessment included questions on demographics, pregnancy, and birth experience. The second and third assessments contained screenings for postpartum depression, PTSD, and general mental health problems, as well as assessing social support and physical well-being. We analysed our data using structural equation modelling techniques (n=277). RESULTS: Our final model showed good fit and was consistent with a diathesis-stress model of PSS. Women who had used antidepressant medication in the 10 years before childbirth had higher PSS at 6 weeks, independent of birth experiences. Subjective birth experience was the early predictor with the highest total effect on later PSS. Interestingly, a probable migration background also had a small but significant effect on PSS via more episiotomies. The null results for social support may have been caused by a ceiling effect. CONCLUSIONS: Given that we measured predictors at different time points, our results lend important support to the etiological model, namely, that there is a vulnerability pathway and a stress pathway leading to PSS. PSS and other psychological measures stayed very stable between 6 weeks and 1 year postpartum, indicating that it is possible to identify women developing problems early. HIGHLIGHTS OF THE ARTICLE: Our results are consistent with a diathesis stress model: vulnerability (antidepressant use in the previous 10 years) influenced posttraumatic stress symptoms at 6 weeks and 1 year, independently of stress (birth-related variables). The strongest predictor of posttraumatic stress symptoms 1 year postpartum was posttraumatic stress symptoms 6 weeks postpartum. This means that women who develop problems could be identified during routinely offered postpartum care. Women with a probable migration background experienced more PSS 1 year after the birth, which was an indirect effect through more episiotomies and more PSS after 6 weeks. PMID- 27782879 TI - Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons. AB - Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. PMID- 27782880 TI - Increasing beta-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis. AB - Mechanical force and Wnt signaling activate beta-catenin-mediated transcription to promote proliferation and tissue expansion. However, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate beta-catenin signaling and cell division. We show that mechanical strain induced Src-dependent phosphorylation of Y654 beta-catenin and increased beta-catenin mediated transcription in mammalian MDCK epithelial cells. Under these conditions, cells accumulated in S/G2 (independent of DNA damage) but did not divide. Activating beta-catenin through Casein Kinase I inhibition or Wnt3A addition increased beta-catenin-mediated transcription and strain-induced accumulation of cells in S/G2. Significantly, only the combination of mechanical strain and Wnt/beta-catenin activation triggered cells in S/G2 to divide. These results indicate that strain-induced Src phosphorylation of beta-catenin and Wnt dependent beta-catenin stabilization synergize to increase beta-catenin-mediated transcription to levels required for mitosis. Thus, local Wnt signaling may fine tune the effects of global mechanical strain to restrict cell divisions during tissue development and homeostasis. PMID- 27782878 TI - NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors. AB - The neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand binding pockets. Through expanded architectural comparisons between these complexes and HIF-1alpha-ARNT, HIF-2alpha-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs. PMID- 27782881 TI - Proteolytic maturation of alpha2delta represents a checkpoint for activation and neuronal trafficking of latent calcium channels. AB - The auxiliary alpha2delta subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides alpha2 and delta. We now show, using alpha2delta constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N type (CaV2.2) calcium channels. Indeed, uncleaved alpha2delta inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of alpha2delta, voltage-dependent activation of channels is promoted, independent from the trafficking role of alpha2delta. Uncleaved alpha2delta does not support trafficking of CaV2.2 channel complexes into neuronal processes, and inhibits Ca2+ entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved alpha2delta subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of alpha2delta then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes. PMID- 27782877 TI - Dpp dependent Hematopoietic stem cells give rise to Hh dependent blood progenitors in larval lymph gland of Drosophila. AB - Drosophila hematopoiesis bears striking resemblance with that of vertebrates, both in the context of distinct phases and the signaling molecules. Even though, there has been no evidence of Hematopoietic stem cells (HSCs) in Drosophila, the larval lymph gland with its Hedgehog dependent progenitors served as an invertebrate model of progenitor biology. Employing lineage-tracing analyses, we have now identified Notch expressing HSCs in the first instar larval lymph gland. Our studies clearly establish the hierarchical relationship between Notch expressing HSCs and the previously described Domeless expressing progenitors. These HSCs require Decapentapelagic (Dpp) signal from the hematopoietic niche for their maintenance in an identical manner to vertebrate aorta-gonadal-mesonephros (AGM) HSCs. Thus, this study not only extends the conservation across these divergent taxa, but also provides a new model that can be exploited to gain better insight into the AGM related Hematopoietic stem cells (HSCs). PMID- 27782889 TI - Clinical outcomes of endoscopic surveillance for gastric ulcers in populations with a high prevalence of gastric cancer. AB - BACKGROUND/AIMS: Although surveillance endoscopy is recommended after the treatment of a benign gastric ulcer in Korea, improved survival, secondary to an endoscopic follow-up strategy, is controversial. Thus, the aim of this study was to understand the results of gastric ulcer surveillance endoscopy and to individualize surveillance endoscopy by analyzing known risk factors for gastric cancer. MATERIALS AND METHODS: In total, 599 (M:F=424:175, median age=55.4 years) patients who were diagnosed with a gastric ulcer and who underwent follow-up endoscopy between January 2003 and August 2014 were retrospectively enrolled in this study. The final results and risk factors of follow-up endoscopy were analyzed. RESULTS: Multivariate analysis of the data between the benign and malignant ulcer groups (benign: malignant=575:24) showed that an elevated border and irregular margins, among other risk factors, were significant indicators of malignancy (p<0.05). Of the 599 patients, 15 (2.5%) were histologically malignant based on the first biopsy results. Nine (1.5%) patients had malignant ulcers on surveillance endoscopy, and all nine were found to have atypia or dysplasia on the first biopsy. Eight of the nine patients had malignant endoscopic features. CONCLUSION: Surveillance endoscopy for gastric ulcers may be unnecessary, except in cases of malignant and pre-malignant endoscopic features on the initial endoscopy. PMID- 27782887 TI - Comparison of the effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on intragastric pH in extensive metabolizer patients with gastroesophageal reflux disease. AB - BACKGROUND/AIMS: Studies on the therapeutic efficacy of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD) have been recently published. In most of these studies, comparison of only two PPIs have been made. There are few studies on the comparison of four or more PPIs. We aimed to compare the acid inhibitory effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on days 1 and 5 of treatment in patients with GERD, who were extensive metabolizers in regard to the CYP2C19 genotype. MATERIALS AND METHODS: Helicobacter pylori-negative with typical symptoms of GERD patients were randomly divided into four treatment groups. Efficacy analysis on days 1 and 5 were performed on the four groups which comprised 10 (esomeprazole), 11 (rabeprazole), 10 (lansoprazole), and 10 (pantoprazole) patients. RESULTS: On day 1 of PPI treatment, the mean percentage of time with intragastric Ph>4 were 54%, 58%, 60%, and 35% for the groups, respectively, and on day 5, these values were 67%, 60%, 68%, and 59%, respectively. Esomeprazole, rabeprazole, and lansoprazole were found to be superior to pantoprazole on the first day of treatment. CONCLUSION: Pantoprazole is a less potent proton pump inhibitor than the other PPIs tested on the first day of treatment. When the time needed to raise the intragatric pH to over 4 was evaluated, esomeprazole was found to have the most rapid action, followed by lansoprazole and rabeprazole. PMID- 27782888 TI - Gastric myoelectrical activity abnormalities of electrogastrography in patients with functional dyspepsia. AB - BACKGROUND/AIMS: Pathogenesis of functional dyspepsia (FD) is unclear and not well documented. Some gastric motility abnormalities have been reported to be important factors. Transcutaneous electrogastrography (EGG) is an experimental method that is used to assess FD. We aimed to compare FD patients with control subjects in terms of motility abnormalities according to the EGG results. MATERIALS AND METHODS: Thirty patients with FD and thirty control subjects were included. EGG was preprandially and postprandially performed. The recordings were analyzed and compared between the two groups. RESULTS: Mean ages of the cases and controls were 31.4+/-9.3 and 32.58+/-7.6 years, respectively. Female subjects constituted 80% of the FD group and 76.67% of the control group. In terms of the preprandial dominant frequency (DF), the FD group demonstrated lower incidence of normal subjects than the control group [13 (43.3%) and 22 (73.3%), respectively] and a higher incidence of bradygastria than the control group [17 (56.7%) and 8 (26.6%), respectively]. In the FD group, the rate of cases with normal postprandial DF was lower than that in the control group [10 (33.3%) and 23 (76.7%), respectively], whereas the rates of bradygastria [18 (60%) and 7 (23.3%), respectively] and tachygastria [2 (6.7%) and 0 (0%), respectively] were higher in the FD group (p<0.05). Preprandial and postprandial DF values were statistically significant in both groups. CONCLUSION: A high incidence of gastric motility and myoelectrical activity abnormalities was observed in patients with FD. EGG is an effective, reliable, and non-invasive method in differentiating the subgroups. After standardization of some parameters, EGG may be an essential and irreplaceable test to diagnose and follow-up FD patients with motor dysfunction. PMID- 27782884 TI - Eukaryotic translation initiation factor 3 plays distinct roles at the mRNA entry and exit channels of the ribosomal preinitiation complex. AB - Eukaryotic translation initiation factor 3 (eIF3) is a central player in recruitment of the pre-initiation complex (PIC) to mRNA. We probed the effects on mRNA recruitment of a library of S. cerevisiae eIF3 functional variants spanning its 5 essential subunits using an in vitro-reconstituted system. Mutations throughout eIF3 disrupt its interaction with the PIC and diminish its ability to accelerate recruitment to a native yeast mRNA. Alterations to the eIF3a CTD and eIF3b/i/g significantly slow mRNA recruitment, and mutations within eIF3b/i/g destabilize eIF2*GTP*Met-tRNAi binding to the PIC. Using model mRNAs lacking contacts with the 40S entry or exit channels, we uncovered a critical role for eIF3 requiring the eIF3a NTD, in stabilizing mRNA interactions at the exit channel, and an ancillary role at the entry channel requiring residues of the eIF3a CTD. These functions are redundant: defects at each channel can be rescued by filling the other channel with mRNA. PMID- 27782882 TI - Release-dependent feedback inhibition by a presynaptically localized ligand-gated anion channel. AB - Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune the neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine. Loss of lgc-46 prolongs evoked release, without altering spontaneous activity. Conversely, a gain-of-function mutation of lgc-46 shortens evoked release to reduce synaptic transmission. This inhibition of presynaptic release requires the anion selectivity of LGC-46, and can ameliorate cholinergic over-excitation in a C. elegans model of excitation-inhibition imbalance. These data demonstrate a novel mechanism of presynaptic negative feedback in which an anion-selective LGIC acts as an auto-receptor to inhibit SV release. PMID- 27782892 TI - Efficacy of synbiotic, probiotic, and prebiotic treatments for irritable bowel syndrome in children: A randomized controlled trial. AB - BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is an important health problem that presents serious social burdens and high costs. Our study investigated the efficacy of synbiotic (Bifidobacterium lactis B94 with inulin), probiotic (B. lactis B94), and prebiotic (inulin) treatment for IBS in a pediatric age group. MATERIAL AND METHODS: This study was randomized, double-blind, controlled, and prospective in design and included 71 children between the ages of 4 and 16 years who were diagnosed with IBS according to the Rome III criteria. The first group received synbiotic treatment [5*109 colony forming units (CFU) of B. lactis B94 and 900 mg inulin]; the second group received probiotic treatment (5*109 CFU B. lactis B94), and the third group received prebiotic treatment (900 mg inulin) twice daily for 4 weeks. RESULTS: Probiotic treatment improved belching-abdominal fullness (p<0.001), bloating after meals (p=0.016), and constipation (p=0.031), and synbiotic treatment improved belching-abdominal fullness (p=<0.001), bloating after meals (p=0.004), constipation (p=0.021), and mucus in the feces (p=0.021). The synbiotic group had a significantly higher percentage of patients with full recovery than the prebiotic group (39.1% vs. 12.5%, p=0.036). CONCLUSION: Administration of synbiotics and probiotics resulted in significant improvements in initial complaints when compared to prebiotics. Additionally, there was a significantly higher number of patients with full recovery from IBS symptoms in the synbiotic group than in the prebiotic group. Therefore, the twice daily administration of synbiotics is suggested for the treatment of children with IBS. PMID- 27782893 TI - Diagnostic evaluation of appendiceal orifice inflammation in ulcerative colitis. AB - BACKGROUND/AIMS: To evaluate the diagnostic significance of appendiceal orifice inflammation (AOI) in ulcerative colitis (UC) patients. MATERIALS AND METHODS: We retrospectively examined data from patients with colitis from May 2010 to January 2014 and assigned them to two groups: UC cases and specific colitis cases. First, we clarified the difference in the AOI+ rate between the two groups. Thereafter, imaging findings of all the patients with colitis were re-examined. Features of AOI alone or in combination with proctitis (referred to as "combination features") were considered as the two separate diagnostic criteria for diagnosing UC. By comparing the current diagnoses with the previous diagnoses, evaluation indexes were obtained. RESULTS: A total of 3582 colitis cases (UC cases: 427; specific colitis cases: 3155) were examined. The mean AOI+ rates in UC and specific colitis cases were 26.2% and 0.7%, respectively; a Chi-squared test indicated that the difference between these rates was statistically significant (x2=6.81; p<0.001, OR=50.99). When the AOI features alone were used to diagnose UC, the sensitivity was 26.2% [95% confidence interval (CI), 22.3%-30.6%], agreement rate was 90.6%, and specificity was 99.3% (95% CI, 98.9%-99.5%). When the combination features were used to diagnose UC, the sensitivity was 26.2% (95% CI, 22.3%-30.6%), agreement rate was 91.1%, and specificity was 99.9% (95% CI, 99.7%-100%). CONCLUSION: Combining AOI features and proctitis may lead to a more effective UC diagnosis and enable physicians to identify this condition more promptly among miscellaneous diseases. PMID- 27782885 TI - gamma-Protocadherin structural diversity and functional implications. AB - Stochastic cell-surface expression of alpha-, beta-, and gamma-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures of ectodomain fragments comprising cell-cell recognition regions of mouse gamma Pcdhs gammaA1, gammaA8, gammaB2, and gammaB7 revealing trans-homodimers, and of C terminal ectodomain fragments from gamma-Pcdhs gammaA4 and gammaB2, which depict cis-interacting regions in monomeric form. Together these structures span the entire gamma-Pcdh ectodomain. The trans-dimer structures reveal determinants of gamma-Pcdh isoform-specific homophilic recognition. We identified and structurally mapped cis-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from gammaB subfamily isoforms formed cis dimers, whereas gammaA isoforms did not, but both gammaA and gammaB isoforms could interact in cis with alpha-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the gamma-Pcdh trans interface, and suggest that subfamily- or isoform-specific cis-interactions may play a role in the Pcdh-mediated neuronal self-recognition code. PMID- 27782890 TI - Pediatric small bowel transplantation: A single-center experience from Turkey. AB - BACKGROUND/AIMS: Small bowel transplantation (SBTx) is a treatment option for patients with serious parenteral nutrition-related problems in intestinal failure. Izmir Tepecik Training Research Hospital Organ Transplantation Center is still the only pediatric intestinal transplant center in Turkey. MATERIAL AND METHODS: This study was approved by the local ethics committee. Patients' data were analyzed from the medical charts and the hospital digital database. Seven isolated SBTxs were performed in six children between 2010 and 2016. RESULTS: One jejunal segment and six partial jejuno-ileal segments were used for seven transplants. All grafts were retrieved from deceased donors (one child and six adult donors). The six recipients had a mean age of 8.8+/-6.9 years (9 months to 17 years; M: 4, F: 2). The mean follow-up period of patients was 727+/-848 (34 to 1950) days. Acute cellular rejection (ACR) rates were 57% (n: 4) in the first 2 months. Graft loss due to severe ACR was seen in one patient. Central line associated fungal (n: 3, 42%) and bacterial infections (n: 3, 42%) were seen in the first 2 months. Two Epstein-Barr virus (EBV) infections were recorded between 3 and 8 months in two patients. Our 1-year patient and graft survival rates were 71% and 71%, respectively. CONCLUSION: SBTx has become a treatment modality for patients with intestinal failures. Management of ACR and infections are still challenging problems in SBTx. Appropriate-sized cadaveric donors are very limited in Turkey for pediatric intestinal transplantation candidates. Although the number of SBTxs performed was small, this study shows promising results. PMID- 27782891 TI - Evaluation of the effectiveness of biofeedback therapy for functional constipation in children. AB - BACKGROUND/AIMS: Defecation disorders are one of the most common problems in pediatric gastroenterology. Treatment includes changes in the diet, pharmacotherapy, and biofeedback therapy. The aim of the present study was to evaluate the effectiveness of biofeedback therapy as assessed by clinical improvement as well as by changes in manometric parameters in children with constipation and pelvic floor dyssynergia (PFD). MATERIALS AND METHODS: A total of 44 children with constipation and PFD hospitalized between 2000 and 2015 were enrolled in this retrospective study. All patients underwent anorectal manometry, and in case of diagnosed PFD, the patient qualified for biofeedback therapy. Amplitudes between extreme and basic pressures during defecation maneuvers in the first and last sessions as well as the difference between them were compared between groups with and without clinical improvement after the last session. RESULTS: A clinical improvement was achieved in 38 (86%) patients. There were no significant differences found in the amplitudes in the first session (mmHg), 94, 65, 115 vs. 112, 55, 170 (median, first quartile, third quartile, respectively; NS: not significant); last session, 36, 27, 52 vs. 41, -38, 66, respectively; or between them, 71, 11, 124 vs. 81, 17, 109, respectively, in the group with versus the group without clinical improvement, respectively. CONCLUSION: Biofeedback therapy has high clinical efficacy, and despite the lack of manometric improvement, it should be used as a treatment method in children in whom dietary and pharmacological procedures do not work, even if we consider the exercises more as a form of psychological training. PMID- 27782883 TI - Lognormal firing rate distribution reveals prominent fluctuation-driven regime in spinal motor networks. AB - When spinal circuits generate rhythmic movements it is important that the neuronal activity remains within stable bounds to avoid saturation and to preserve responsiveness. Here, we simultaneously record from hundreds of neurons in lumbar spinal circuits of turtles and establish the neuronal fraction that operates within either a 'mean-driven' or a 'fluctuation-driven' regime. Fluctuation-driven neurons have a 'supralinear' input-output curve, which enhances sensitivity, whereas the mean-driven regime reduces sensitivity. We find a rich diversity of firing rates across the neuronal population as reflected in a lognormal distribution and demonstrate that half of the neurons spend at least 50 % of the time in the 'fluctuation-driven' regime regardless of behavior. Because of the disparity in input-output properties for these two regimes, this fraction may reflect a fine trade-off between stability and sensitivity in order to maintain flexibility across behaviors. PMID- 27782894 TI - Etiologies, outcomes, and prognostic factors of pediatric acute liver failure: A single center's experience in Turkey. AB - BACKGROUND/AIMS: Our aim was to determine the etiologies, outcomes, and prognostic indicators in children with acute liver failure. MATERIALS AND METHODS: Ninety-one patients who were followed for pediatric acute liver failure (PALF) over a 15-year period were included. Patients who survived with supportive therapy were designated as Group 1, while those who died or underwent liver transplantation were designated as Group 2. RESULTS: There were 37 (40.6%) patients in Group 1 (spontaneous recovery) and 54 (59.4%) patients in Group 2. Thirty-two patients (35.2%) underwent liver transplantation. Infectious and indeterminate causes were the most common etiologies (33% each). Among the infectious causes, hepatitis A (76%) was the most frequent. Hepatic encephalopathy grade 3-4 on admission and during follow-up and high Pediatric Risk of Mortality (PRISM) and Pediatric End-Stage Liver Disease (PELD) scores within the first 24 h were related with a poor prognosis. Group 2 had a more prolonged prothrombin time, higher international normalized ratio, more prolonged activated partial thromboplastin time (aPTT), and higher levels of total and direct bilirubin, ammonia, and lactate (for all, p<0.01). CONCLUSION: Infectious and indeterminate cases constituted the most common etiology of PALF, and the etiology was related to the prognosis in our series. Although high PELD and PRISM scores were related to poor prognoses, no sharp thresholds for individual laboratory tests could be elucidated. Liver transplantation was the only curative treatment for patients with poor prognoses and resulted in high survival rates (1 , 5-, and 10-year survival rates of 81.3%, 81.3%, and 75%, respectively) in our study. PMID- 27782895 TI - Effect of SIRS and sepsis on mortality in alcoholic hepatitis: A systematic review and meta-analysis. AB - BACKGROUND/AIMS: Sepsis is frequently observed in patients with alcoholic hepatitis (AH) and is an important mortality predictor. Several studies have also identified systemic inflammatory response syndrome (SIRS) as a significant prognostic factor. The aim of this study was to systematically review and quantify the effect of SIRS and sepsis on mortality in patients with AH. MATERIALS AND METHODS: MEDLINE and EMBASE were searched from its inception till January 2016. Participants in the included studies were adults with AH and those with developed SIRS or sepsis during hospitalization. We estimated the risk ratio (RR) with a 95% confidence interval (CI) of mortality by comparing participants with SIRS vs. non-SIRS and sepsis vs. non-sepsis. RESULTS: Data were extracted from six studies involving 1,264 patients (of whom 507 had SIRS) and four studies involving 57,529 patients (of whom 1,449 had sepsis). SIRS and sepsis were both significantly associated with mortality with RRs of 2.7 (95% CI 1.74-4.14, I2=50%) and 2.8 (95% CI 1.58-4.93, I2=94%), respectively. CONCLUSION: Not only is sepsis associated with mortality but also SIRS. SIRS may be the initial trigger of cascade events leading to mortality in patients with AH. Identification of the key element of SIRS may thus provide a potential therapeutic target. PMID- 27782896 TI - Variceal bleeding in cirrhotic patients: What is the best prognostic score? AB - BACKGROUND/AIMS: To find the most accurate, suitable, and applicable scoring system for the prediction of outcome in cirrhotic patients with bleeding varices. MATERIALS AND METHODS: A prospective study was conducted comprising 120 cirrhotic patients with acute variceal bleeding who were admitted to Tropical Medicine and Gastroenterology Department in Sohag University Hospital, over a 1-year period (1/2015 to 1/2016). The clinical, laboratory, and endoscopic parameters were studied. Child-Turcotte-Pugh (CTP) classification score, Model for end-stage liver disease (MELD) score, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, and AIMS65 score were calculated for all patients. Univariate and multivariate analyses were performed for all the measured parameters and scores. RESULTS: Of the 120 patients (92 male) admitted during the study period, eight patients (6.67%) died in the hospital. Advanced age, the presence of encephalopathy, rebleeding, and higher serum bilirubin were independent factors associated with higher hospital mortality. The largest area under the receiver operator curve (AUROC) was obtained for the AIMS65 score and SOFA score, followed by the MELD score and APACHEII score, then CTP score, all of which achieved very good performance (AUROC>0.8). AIMS65 score showed the best sensitivity, specificity, and negative and positive predictive values. Although the AIMS65 score was not significantly different from the MELD, SOFA, and APACHEII scores, it was the optimum among them in terms of the prediction of mortality. CONCLUSION: AIMS65 score is the best simple and applicable scoring system for independently predicting mortality in cirrhotic patients with acute variceal bleeding. PMID- 27782897 TI - A nontraumatic intramural duodenal hematoma causing gastric outlet obstruction. PMID- 27782898 TI - Erythromycin triggers intussusception in a pediatric patient with Henoch Schonlein purpura. PMID- 27782899 TI - The development of dry eye disease during tenofovir and entecavir therapy in a patient with chronic hepatitis B. PMID- 27782901 TI - Prescribe medication...Withdraw medication. PMID- 27782900 TI - Ondansetron as the first approach in the management of the patients with acute gastroenteritis visiting the pediatric emergency department: A single-center experience. PMID- 27782902 TI - Giant but silent lesion of the stomach in a geriatric patient. PMID- 27782903 TI - A promising adjuvant chemotherapeutic regimen for resected pancreatic cancer? PMID- 27782904 TI - "Are we ready to change our colorectal cancer screening practice?" Traditional serrated adenomas or serrated adenomas with dysplasia should be regarded as advanced adenomas with high grade dysplasia. PMID- 27782905 TI - Relationship of Self-reported Attentional Fatigue to Perceived Work Ability in Breast Cancer Survivors. AB - BACKGROUND: Breast cancer survivors (BCSs) have identified attentional fatigue, a decrease in the ability to focus, as a persistent daily challenge; however, little is known regarding its impact on work ability. OBJECTIVE: The purpose of this study was to examine the relationship between attentional fatigue and perceived work ability in BCSs controlling for the known covariates of age, education, household income, and time posttreatment. METHODS: A cross-sectional, descriptive design was used. Breast cancer survivors who were currently employed and at least 1 year post-adjuvant treatment participated. Breast cancer survivors completed the Attentional Function Index and Work Ability Index questionnaires. Descriptive statistics, linear regression, and Fisher exact test were used for analysis. RESULTS: Sixty-eight female BCSs, ranging from 29 to 68 years of age (mean, 52.1 [SD, 8.6]) and on average 4.97 (SD, 3.36) years posttreatment, participated. More than one-fourth of BCSs (26.5%) reported poor to moderate perceived work ability, indicating substantial concerns regarding work performance. Attentional fatigue was found to significantly predict perceived work ability (P < .001), explaining 40% of the variance of perceived work ability. CONCLUSIONS: Attentional fatigue is a prevalent symptom posttreatment that is negatively related to perceived work ability in BCSs. IMPLICATIONS FOR PRACTICE: Nurses are in a prime position to assess and intervene to alleviate attentional fatigue to improve work ability. Findings suggest a need for individual, comprehensive survivorship care plans to effectively address symptoms that impact work ability and, ultimately, the quality of life of cancer survivors. PMID- 27782906 TI - Trabectedin in advanced desmoplastic round cell tumors: a retrospective single center series. AB - Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy that occurs with unpredictable chemosensitivity and limited treatment options in the advanced setting. Prognosis is poor, and exploring new treatment options for such diseases is difficult because of its rarity. Clinical activity of trabectedin for advanced DSRCT was scarcely reported in the literature. Here, we report a series of six patients treated with trabectedin for an unresectable DSRCT. After receiving trabectedin, two patients had stable disease with a time to progression of 3 and 3.5 months; four patients experienced disease progression after one cycle, two of them could receive one and two patients another line regiment. Four patients experienced grade 3-4 adverse events, two grade 3 thrombocytopenia, and one neutropenic fever. Prognosis was poor with a median overall survival of 4 (range: 2-14) months. In our experience, trabectedin had limited activity in advanced DSRCT. Further studies are warranted to find effective treatments. PMID- 27782907 TI - Garlic-Induced Surgical Bleeding: How Much Is Too Much? AB - A patient underwent C2-T2 decompression and fusion with excessive intraoperative bleeding and no clear source. The patient denied the use of blood-thinning medications, but had consumed the equivalent of 12 g garlic daily in the days leading up to the surgery. He was treated with desmopressin acetate (DDAVP) and cryoprecipitate with adequate control of bleeding. Garlic is known to have an antiplatelet effect, although the dose range necessary to create a bleeding abnormality has not yet been well described nor has the effect of taking garlic with sertraline or other agents with an established or potential effect on coagulation. PMID- 27782911 TI - Mechanisms and Mediators of the Skeletal Muscle Repeated Bout Effect. AB - Skeletal muscle adapts to exercise-induced damage by orchestrating several but still poorly understood mechanisms that endow protection from subsequent damage. Known widely as the repeated bout effect, we propose that neural adaptations, alterations to muscle mechanical properties, structural remodeling of the extracellular matrix, and biochemical signaling work in concert to coordinate the protective adaptation. PMID- 27782909 TI - Hypertensive nephropathy. Moving from classic to emerging pathogenetic mechanisms. AB - Hypertensive kidney disease classically entails nephroangiosclerosis and hyalinosis with glomerular damage. However, in recent years, several evidences showed that high blood pressure also injures tubular cells, inducing epithelial to-mesenchymal transition and tubulointerstitial fibrosis. Recently investigated mechanisms are also podocyte effacement and loss, which lead to denudation of the glomerular basement membrane and focal adhesion of the tufts to the Bowman's capsule, with reduced filtration and scars. Starting from the classic concept of nephroangiosclerosis, this review examines the recently emerged knowledge of new biochemical and molecular mechanisms underlying the kidney damage in hypertension and discusses how viable podocytes or podocyte-deriving proteins are promising tools for early diagnosis of renal remodelling in hypertension. PMID- 27782912 TI - Exercise is a Novel Promoter of Intestinal Health and Microbial Diversity. AB - Imbalances in the gut microbiota contribute to chronic gut inflammatory diseases. Interestingly, exercise can improve gut health, but generally, little is known about the underlying mechanisms involved. This article represents a conceptual model illustrating exercise's role in diversifying the gut microbiota to improve gut and systemic health. PMID- 27782908 TI - Optimization of Mechanical Ventilation in a 31-Year-Old Morbidly Obese Man With Refractory Hypoxemia. AB - Morbidly obese, critically ill patients are prone to develop hypoxemic respiratory failure and ventilator dependency. The best method for recruiting the lungs of these patients and keeping alveoli open without causing injury remains unclear. We present the case of a 31-year-old patient with severe refractory hypoxemia reversed by lung recruitment maneuvers and subsequent application of positive end-expiratory pressure (PEEP) at a level determined by a decremental PEEP trial. The patient was extubated at a high PEEP level of 22 cm H2O followed by noninvasive ventilatory support after extubation. This case suggests that a recruitment maneuver followed by PEEP titration is necessary in obese patients for optimizing mechanical ventilation. Extubation to noninvasive ventilatory support with the identified optimal PEEP may decrease an inappropriate increased work of breathing and the risk of reintubation. PMID- 27782915 TI - Cutting Close to the Bone: Student Trauma, Free Speech, and Institutional Responsibility in Medical Education. AB - Learning the societal roles and responsibilities of the physician may involve difficult, contentious conversations about topics such as race, gender, sexual orientation, and class, as well as violence, inequities, sexual assault, and child abuse. If not done well, these discussions may be deeply traumatizing to learners for whom these subjects "cut close to the bone." Equally traumatizing is exposure to injustice and mistreatment, as well as to the sights, sounds, and smells of suffering and pain in the clinical years. This potential for iatrogenic educational trauma remains unaddressed, and medical educators must take responsibility for attending to it. Possible solutions include trigger warnings or statements given to students before an educational activity that may cause personal discomfort. The authors of this Perspective assert, however, both that this concept does not distinguish between psychological trauma and discomfort and that well-intentioned trigger warnings target the wrong goal-the avoidance of distress. Exposure to discomfort not only is unavoidable in the practice of medicine but may be crucial to personal and professional moral development. The authors argue that a more appropriate solution is to create safe spaces for dialogues about difficult topics and jarring experiences. This approach places even the notion of free speech under a critical lens-it is not an end in itself but a means to create a professional ethic dedicated to treating all individuals with excellence and justice. Ultimately, this approach aspires to create an inclusive curriculum sensitive to the realities of teaching and learning in increasingly diverse societies. PMID- 27782917 TI - Becoming a Doctor in Different Cultures: Toward a Cross-Cultural Approach to Supporting Professional Identity Formation in Medicine. AB - Becoming a doctor is fundamentally about developing a new, professional identity as a physician, which in and of itself may evoke many emotions. Additionally, medical trainees are increasingly moving from one cultural context to another and are challenged with navigating the resulting shifts in their professional identify. In this Article, the authors aim to address medical professional identity formation from a polyvocal, multidisciplinary, cross-cultural perspective. They delineate the cultural approaches to medical professionalism, reflect on professional identity formation in different cultures and on different theories of identity development, and advocate for a context-specific approach to professional identity formation. In doing so, the authors aim to broaden the developing professional identity formation discourse to include non-Western approaches and notions. PMID- 27782916 TI - The Perils and Rewards of Critical Consciousness Raising in Medical Education. AB - Inequalities in society are reflected in patterns of disease and access to health care, where the disadvantaged suffer most. Traditionally, doctors have kept politics out of their work, even though politics often shape medicine. What political responsibilities, then, should doctors have as they facilitate the learning of medical students? The article in this issue by Kumagai, Jackson, and Razack goes straight to the heart of this question. These authors ask whether educators should be wary of "cutting close to the bone" in discussing issues that may restimulate trauma in some medical students.Kumagai and colleagues suggest that it is actually the ethical responsibility of educators to introduce students to discomfort as a means of raising students' critical consciousness or their ability to sensitively gauge the positions of others and to engage in dialogue to address issues such as inequality and inequity so that previously silent and silenced voices can be heard. The author of this Commentary expands on this argument, further supporting the need to democratize medical culture and politicize doctors. Educators, as expert facilitators of this new critical consciousness raising, must create safe spaces for students to work through issues to avoid educational iatrogenesis. Such an approach to medical education is an extension of the traditional art of medicine, at the core of which are patient care and tolerance. Ethics, aesthetics, and politics can come together in such a reflexive medicine curriculum. PMID- 27782910 TI - Development and Validation of the Beliefs About Personal Weight Survey Among African American Women. AB - The purpose of this study was to develop the Beliefs about Personal Weight Survey among African American women. Sixty-five items were developed from literature and sample participants to characterize beliefs about personal weight in 3 domains: descriptors, causes, and consequences. The items were administered to 150 community-dwelling African American women, 18 to 40 years old, recruited from 5 sites. Factor analysis supported a 4-factor solution with the following dimensions: overweight acceptance, overweight concern, conventional weight regulation, and circumstantial weight regulation. These factors were significantly associated with weight management behaviors and body mass index. Profile analysis indicated distinct factor belief profiles by 3 weight categories. PMID- 27782918 TI - Knowledge Syntheses in Medical Education: Demystifying Scoping Reviews. AB - An unprecedented rise in health professions education (HPE) research has led to increasing attention and interest in knowledge syntheses. There are many different types of knowledge syntheses in common use, including systematic reviews, meta-ethnography, rapid reviews, narrative reviews, and realist reviews. In this Perspective, the authors examine the nature, purpose, value, and appropriate use of one particular method: scoping reviews. Scoping reviews are iterative and flexible and can serve multiple main purposes: to examine the extent, range, and nature of research activity in a given field; to determine the value and appropriateness of undertaking a full systematic review; to summarize and disseminate research findings; and to identify research gaps in the existing literature. Despite the advantages of this methodology, there are concerns that it is a less rigorous and defensible means to synthesize HPE literature. Drawing from published research and from their collective experience with this methodology, the authors present a brief description of scoping reviews, explore the advantages and disadvantages of scoping reviews in the context of HPE, and offer lessons learned and suggestions for colleagues who are considering conducting scoping reviews. Examples of published scoping reviews are provided to illustrate the steps involved in the methodology. PMID- 27782914 TI - Interprofessional Team Training at the Prelicensure Level: A Review of the Literature. AB - PURPOSE: The authors undertook a descriptive analysis review to gain a better understanding of the various approaches to and outcomes of team training initiatives in prelicensure curricula since 2000. METHOD: In July and August 2014, the authors searched the MEDLINE, PsycINFO, Embase, Business Source Premier, and CINAHL databases to identify evaluative studies of team training programs' effects on the team knowledge, communication, and skills of prelicensure students published from 2000 to August 2014. The authors identified 2,568 articles, with 17 studies meeting the selection criteria for full text review. RESULTS: The most common study designs were single-group, pre/posttest studies (n = 7), followed by randomized controlled or comparison trials (n = 6). The Situation, Background, Assessment, Recommendation communication tool (n = 5); crisis resource management principles (n = 6); and high-fidelity simulation (n = 4) were the most common curriculum bases used. Over half of the studies (n = 9) performed training with students from more than one health professions program. All but three used team performance assessments, with most (n = 8) using observed behavior checklists created for that specific study. The majority of studies (n = 16) found improvements in team knowledge, communication, and skills. CONCLUSIONS: Team training appears effective in improving team knowledge, communication, and skills in prelicensure learners. Continued exploration of the best method of team training is necessary to determine the most effective way to move forward in prelicensure interprofessional team education. PMID- 27782920 TI - Successful Integrative Medicine Assessment and Treatment of Chronic Pain Associated With Breast Surgery: A Report of 3 Cases. AB - Presented is the first reported case series of chronic neck and back pain associated with breast scars from breast surgery and successfully treated with an integrative medicine assessment and treatment approach, which included the assessment technique of autonomic response testing and the scar therapy technique of neural therapy. Implications for nursing practice are discussed. PMID- 27782924 TI - Recovery-Oriented Mental Health Practice in a Community Care Unit: An Exploratory Study. AB - A recovery-oriented model of care has become the major focus of mental health service delivery in the state of Victoria, Australia. However, there is a total absence of knowledge of recovery-oriented mental health practice in community care units (CCUs). Therefore, the aims of this exploratory study were to: (a) describe what aspects of the current model of care fit within the domains of recovery; and (b) describe the pragmatic processes that staff use to mold their care within the domains of recovery. Twenty-one key stakeholders provided informed voluntary consent to participate in one-to-one interviews. Six content domains evolved to include: (a) a common vision: "a continuous journey"; (b) promoting hope; (c) promoting autonomy and self-determination; (d) meaningful engagement; (e) holistic and personalized care; and (f) community participation and citizenship. The CCU appeared to be on a journey of transformation toward personal recovery. However, clinicians were grappling with an identified tension among personal recovery and clinical recovery. The tension among personal recovery and clinical recovery may be attributed to the psychosocial rehabilitation model of care, which was previously systemic in Victorian CCUs. PMID- 27782923 TI - Centers for Disease Control and Prevention 2015 Human Papillomavirus Vaccine Recommendations for Sexually Assaulted Patients: A Review and Update. AB - Individuals who have been sexually assaulted are at risk for contracting human papillomavirus (HPV), the most common sexually transmitted infection. One of the best methods in protecting against contracting the HPV is to receive the HPV vaccine. To date, national sexual assault protocols and guidelines do not include information on HPV vaccination. The current 2015 Centers for Disease Control and Prevention has updated their recommendations for sexually assaulted patients to now receive the HPV vaccine. This article reviews information on HPV, HPV vaccines, and specific considerations for patients who have been sexually assaulted. PMID- 27782925 TI - Medicolegal Death Investigation and Hospital Patient Safety and Quality Outcomes: A Naturally Synergistic Collaboration. AB - The role of medicolegal death investigation (MLDI) systems in the assessment of violent deaths (e.g., gunshots, stab wounds, car crashes) is well known. However, the role of MLDI systems in informing healthcare agencies about potential patient safety and quality improvement activities is less understood and thus the main focus of this article. In this article we describes-one agency's initiatives to identify decedents whose circumstances or cause of death had potential relevance for patient safety and quality outcomes and to communicate those findings to acute care hospitals where the decedents were previously treated. We also describes the evaluation of this communication process and provide preliminary outcomes of these efforts. PMID- 27782913 TI - Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. AB - OBJECTIVE: Lu-DKFZ-PSMA-617, a urea-based compound, binds to the extracellular domain of prostate-specific membrane antigen, thus providing an effective target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Before its therapeutic use, it is necessary that the radiation dosimetry of this radiopharmaceutical be studied to determine the safe activity that can be administered in patients to prevent haematological, renal and liver toxicity. The present study thus aimed to assess the pharmacokinetics and dosimetry of Lu-DKFZ PSMA-617 in CRPC patients. MATERIALS AND METHODS: After obtaining ethical clearance from the institute ethics review board, we enrolled mCRPC patients who were positive on a Glu-NH-CO-NH-Lys-(Ahx)-[Ga(HBED-CC)] PET/CT scan. For kidney protection, a cocktail of lysine and arginine diluted in 2 litres of normal saline was infused, starting from 30 to 60 min before Lu-DKFZ-PSMA-617 infusion. The mean administered activity in the overall population was 2.52+/-1.3 GBq. For the purpose of dosimetry, each patient underwent nine planar whole-body scans along with blood and urine sample collection at 0.5, 3.5, 24, 48, 72, 96, 120, 144 and 168 h, respectively. SPECT/CT was performed to derive the volume of salivary glands (parotid and submandibular glands) and tumour. Dosimetric evaluation was carried out using the OLINDA/EXM 1.0 software. RESULTS: A total of 26 mCRPC patients with a mean age of 66.30+/-9.95 years (range: 38-81 years) were recruited. Normal physiological uptake was observed in all the patients in the lacrimal glands, salivary glands (parotid glands and submandibular glands), liver, spleen, kidneys, intestines and urinary bladder. Organs with the highest absorbed doses were the salivary glands, followed by the kidneys, receiving 1.24+/-0.26 and 0.99+/-0.31 mGy/MBq, respectively. The mean absorbed doses to the liver, urinary bladder and red marrow were 0.36+/-0.10, 0.243+/-0.09 and 0.048+/ 0.05 mGy/MBq, respectively. The mean whole-body dose was 0.016+/-0.003 mGy/MBq. CONCLUSION: Lu-DKFZ-PSMA-617 therapy is a safe option in the treatment of mCRPC patients. PMID- 27782922 TI - Chair Yoga: Feasibility and Sustainability Study With Older Community-Dwelling Adults With Osteoarthritis. AB - This study measured the feasibility of completing a randomized control trial on an 8-week seated yoga program for older adults with osteoarthritis. Part of the feasibility of this program was to determine whether participants would continue the yoga practice at home using a guide book after the 8-week program. Findings demonstrated that once participants were not in a group setting for the yoga, they did not continue with yoga practice. This outcome demonstrates the need for group programs for older adults to promote adherence to movement-based programs. (Trial registration: ClinicalTrials.Gov: NCT02113410). PMID- 27782926 TI - Pediatric Oncology Clinic Care Model: Achieving Better Continuity of Care for Patients in a Medium-sized Program. AB - Providing the best care in both the inpatient and outpatient settings to pediatric oncology patients is all programs goal. Using continuous improvement methodologies, we changed from a solely team-based physician care model to a hybrid model. All patients were assigned a dedicated oncologist. There would then be 2 types of weeks of outpatient clinical service. A "Doc of the Day" week where each oncologist would have a specific day in clinic when their assigned patients would be scheduled, and then a "Doc of the Week" week where one physician would cover clinic for the week. Patient satisfaction surveys done before and 14 months after changing the model of care showed that patients were very satisfied with the care they received in both models. A questionnaire to staff 14 months after changing showed that the biggest effect was increased continuity of care, followed by more efficient clinic workflow and increased consistency of care. Staff felt it provided better planning and delivery of care. A hybrid model of care with a primary physician for each patient and assigned clinic days, alternating with weeks of single physician coverage is a feasible model of care for a medium-sized pediatric oncology program. PMID- 27782927 TI - Patterns of Diagnosis and Misdiagnosis in Pediatric Cancer and Relationship to Survival. AB - BACKGROUND: Pediatric cancer is rare and its symptoms are often ambiguous. The aims of this study were to investigate the time needed to make a diagnosis, assess the frequency of misdiagnosis, and to determine whether these factors affected survival. METHODS: A review of records of 364 pediatric patients diagnosed with cancer at the University of Rochester Golisano Children's Hospital between 2004 and 2012 was conducted. Data were extracted on patient and health care system-related factors and clinical outcomes. RESULTS: The median time from symptom onset to diagnosis was shortest for leukemia (18.5 d) and longest for bone tumors (86.5 d). Tumor type was the only factor associated with time to diagnosis. In 52% of cases an incorrect nononcological diagnosis was initially made. Soft tissue sarcomas and brain tumors were misdiagnosed most often. Neither prolonged time to diagnosis nor initial misdiagnosis was associated with reduced survival. Tumor type and presence of metastatic disease at diagnosis were significantly associated with survival. CONCLUSIONS: There is significant variation in the time from symptom onset to diagnosis of pediatric cancers, and incorrect initial diagnostic impressions are common. Despite this there is no impact of prolonged time to diagnosis on survival. PMID- 27782921 TI - Tolerance Limits, Self-understanding, and Stress Resilience in Integrative Recovery of Inflammatory Bowel Disease. AB - People living with chronic inflammatory bowel disease (IBD) experienced that knowledge about their embodied tolerance limits, diet, mental problem solving, and change in lifestyle together with integrative health care could promote recovery from their diagnosed disease in calmer periods of suffering. A hermeneutic approach was used to analyze interviews with patients living with IBD outside hospitals. Thirteen young adults between 18 and 45 years of age in calmer phases of IBD participated in the study. Three main themes emerged from the analysis of the interviews: (1) Understanding limits in embodied tolerance, (2) Restoring balance is creating a new equilibrium, and (3) Creating resilience through integrative care. Anxiety, depression, stress, insomnia, and fatigue are known consequences of IBD and create a lower degree of well-being for the patients. The digestive system is very important in establishing the interface between the body and the external world. Properly functioning digestion, psychosocial stress reduction, and sleep quality are important to rebuild a balanced immune system. Stress resilience during a patient's recovery from IBD requires self-understanding, self-recognition, and psychosocial support from health care professionals at hospital outpatient clinics. PMID- 27782932 TI - Energy drink overconsumption can trigger atrial fibrillation. PMID- 27782933 TI - 'Heart Team' decision-making for cardiac interventional procedures should take into account patients' cognitive function and frailty. PMID- 27782929 TI - Carotid artery stenting renaissance: can tips, tricks and new devices fill the gap? PMID- 27782931 TI - Advances in cachexia and sarcopenia research in the heart failure context: call for action. PMID- 27782930 TI - Biological and chronological age in heart failure: role of immunosenescence. PMID- 27782919 TI - The Causes of Errors in Clinical Reasoning: Cognitive Biases, Knowledge Deficits, and Dual Process Thinking. AB - Contemporary theories of clinical reasoning espouse a dual processing model, which consists of a rapid, intuitive component (Type 1) and a slower, logical and analytical component (Type 2). Although the general consensus is that this dual processing model is a valid representation of clinical reasoning, the causes of diagnostic errors remain unclear. Cognitive theories about human memory propose that such errors may arise from both Type 1 and Type 2 reasoning. Errors in Type 1 reasoning may be a consequence of the associative nature of memory, which can lead to cognitive biases. However, the literature indicates that, with increasing expertise (and knowledge), the likelihood of errors decreases. Errors in Type 2 reasoning may result from the limited capacity of working memory, which constrains computational processes. In this article, the authors review the medical literature to answer two substantial questions that arise from this work: (1) To what extent do diagnostic errors originate in Type 1 (intuitive) processes versus in Type 2 (analytical) processes? (2) To what extent are errors a consequence of cognitive biases versus a consequence of knowledge deficits?The literature suggests that both Type 1 and Type 2 processes contribute to errors. Although it is possible to experimentally induce cognitive biases, particularly availability bias, the extent to which these biases actually contribute to diagnostic errors is not well established. Educational strategies directed at the recognition of biases are ineffective in reducing errors; conversely, strategies focused on the reorganization of knowledge to reduce errors have small but consistent benefits. PMID- 27782928 TI - Survival Pattern of Chronic Myeloid Leukemia in a Pediatric Population in the United States. PMID- 27782934 TI - Proximal femoral focal deficiency associated with fibular duplication and diplopodia and complete agenesis of the tibia: a case report. AB - A 14-year-old boy reported with congenital deformity of the left lower limb, with gross shortening, hip and knee flexion deformities, ankle with equinus deformity, and polydactyly of the left foot. Radiologic examination showed proximal femoral focal deficiency, double fibula, and duplication of the tarsal bones, and a diagnosis of 'proximal femoral focal deficiency associated with fibular duplication and diplopodia with complete agenesis of tibia' was made. Such association of deformities is very rare and poses difficulties in rehabilitation of the case. This patient was managed with elective knee disarticulation, early prosthetic fitment, and gait training. PMID- 27782935 TI - Sporadically occurred bilateral osteochondritis dissecans on the trochlea of the femur: case report. AB - We report the case of a 13-year-old boy with bilateral osteochondritis dissecans in the lateral femoral trochlea of the knees. They were classified as grade 4 in the right knee and grade 1 in the left knee on the basis of the Nelson classification within 1 year after first consultation. In the right knee, the fragment was surgically fixed, but the left knee healed with conservative treatment. This case indicates the possibility that osteochondritis dissecans of the lateral femoral trochlea may develop bilaterally at different times and present at different stages. The case shows the importance of early diagnosis and appropriate treatment on the basis of the stage. PMID- 27782938 TI - Examination of Ricochet Gunshot Wounds From Commonly Encountered Surfaces. AB - Proper interpretation of gunshot wounds is vital for the forensic pathologist and requires experience and expertise, as well as consultation with a firearms and ballistics expert and careful scene investigation in cases of atypical gunshot wounds. This study is the first large-series examining ricochet gunshot wounds involving different firearm calibers. Typical gunshot wounds created from 4 handgun calibers (22 Long Rifle, 9 * 19 mm Parabellum, .40 Smith &Wesson, and .45 Automatic Colt Pistol) and 2 rifle calibers (5.56 and 7.62 mm) were compared with wounds caused by bullets of those same calibers ricocheting off commonly encountered surfaces (concrete, asphalt, aluminum traffic signs, clay brick, and dry wall). Porcine skin, a human skin analog, attached to sheets of cardboard serviced as witness panels for capturing the entrance wounds. Examination of over 150 handgun and rifle entrance wounds established that every caliber and every ricochet surface resulted in atypical features, including irregularity in size or shape, lack of marginal abrasion, or other injuries on the surrounding skin. The most significant factor influencing the variability of the ricochet wounds was the surface the bullet deflected off before striking the body. PMID- 27782942 TI - Intraoperative Hyperoxemia: An Unnecessary Evil? PMID- 27782939 TI - Strangulation by Feeding Tube in a 23-Month-Old With Down Syndrome: Case Report and Review of Literature. AB - Ligature strangulation, although typically homicidal in nature, has been reported as accidental in both the pediatric and adult populations. The unique mode of accidental strangulation with a gastric feeding tube in a 23-month-old with Down syndrome is currently unreported in the literature and has prompted us to report this case and look into safety modifications that can be made to these common medical devices. Given the number of children with gastric feeding tubes and concern over this exact scenario brought up by parents, it is unusual that a similar case has not been reported. PMID- 27782936 TI - The lateral wedge augmentation trochleoplasty in a pediatric population: a 5-year follow-up study. AB - Patellofemoral instability in children requires surgery when recurrent dislocation occurs. The aim of this study is to report the 5-year clinical and radiographic outcomes following lateral wedge augmentation trochleoplasty of the femoral trochlea. This is a review of 23 (mean age: 12.5 years) patients who underwent surgery for recurrent patellar dislocations related to a flat trochlea. In every case, a lateral wedge augmentation trochleoplasty was performed with preservation of the growth plate. This surgery was consistently associated with a soft tissue procedure. All patients were reviewed for a clinical and radiographic evaluation [computed tomography (CT)-scan]. No case of recurrent patellar dislocation was reported and all patients were satisfied with the procedure; three patients reported anterior knee pain after physical activities. CT scan analysis revealed improvement of the trochlear shape measurements in all cases, but osteoarthritis lesions (narrowing of the lateral patellofemoral compartment) were visible on four CT scans. This trochleoplasty technique augmented by a soft tissue procedure on the extensor apparatus led to acceptable clinical mid-term results in terms of stability for patients with a flat trochlea (grade B according to Dejour classification). However, at the 5-year follow-up, four patients showed signs of osteoarthritis on CT scan evaluation. This warrants serious concern in this young population, and alternative methods should be considered whenever possible. PMID- 27782941 TI - Disruption of Memory Consolidation May Explain Patterns of Memory Better Than Emotion-Induced Retrograde Amnesia in Study by Chen et al. PMID- 27782937 TI - Comparison of daytime and after-hours surgical treatment of supracondylar humeral fractures in children. AB - : Reports on different types of surgical procedures show that night-time surgeries are often associated with a high number of complications than daytime surgeries. However, there are no data, and hence evidence that relate the outcome of supracondylar humeral fractures in children to the time of the day when the respective surgical procedure is implemented. In this study, we analyze the clinical and radiological outcomes of pediatric supracondylar humeral fractures surgically treated during daytime and night-time hours. In total, 91 patients with Gartland type-3 fractures were included; 47 patients treated between 0800 and 1700 h were defined as the daytime group and 44 patients treated between 1701 and 0759 h were defined as the after-hours group. Age, sex, affected side, fracture type, and day and time of operation were recorded. Any preoperative neurovascular injuries, open fractures, or ipsilateral fractures were noted. The surgical method, use of a medial pin or pins, operation time, any postoperative neurovascular complications, extent of successful reduction, fixation rate, any resultant deformity, and functional loss rate were evaluated. The two groups did not differ significantly in terms of operation time, open reduction rate, rate of poor reduction, extent of poor functional outcomes, or induction of deformity (P>0.05). The poor fixation rate was significantly greater in the after-hours group than in the daytime group (P<0.05). No significant between-group differences were evident in age, sex, affected side, or length of postoperative follow-up (all P-values>0.05). After-hours treatment of displaced supracondylar humeral fractures in children is associated with a higher poor fixation rate compared with daytime procedures. LEVEL OF EVIDENCE: therapeutic study (retrospective comparative study), Level III. PMID- 27782954 TI - Glaucoma: A Very Old Term Related to Superstition. PMID- 27782946 TI - In Response. PMID- 27782949 TI - Providing Confidence Intervals in Survival Analysis. PMID- 27782945 TI - Remote Effects of Electromagnetic Millimeter Waves on Experimentally Induced Cold Pain: A Double-Blinded Crossover Investigation in Healthy Volunteers. AB - BACKGROUND: The hypoalgesic effect of electromagnetic millimeter waves (MW) is well studied in animal model; however, the results of human research are controversial. The aim of this study was to evaluate the effects of various frequency ranges of MW on hypoalgesia using the cold pressor test (CPT). METHODS: Experimental pain was induced using standardized CPT protocols in 20 healthy male volunteers. The skin of the lower part of sternum was exposed to MW with a frequency of 42.25 GHz (active generator); MW within 50-75 GHz frequency range (noise generator); or an inactive MW device (placebo generator) in a random crossover double-blinded manner. Pain threshold, measured using the CPT, was the primary outcome. Other CPT parameters, heart rate, blood pressure, incidence of subjective sensations (paresthesia) during exposure, as well as quality of volunteers' blinding were also recorded. The end points of the condition with exposure to 42.25 GHz, were compared with baseline; exposure to noise 50-75 GHz; and placebo generators. RESULTS: Pain threshold increased during exposure to the 42.25 GHz generator when compared with baseline: median difference (MD), 1.97 seconds (95% confidence interval [CI], 0.35-3.73) and noise generator: MD, 1.27 seconds (95% CI, 0.05-2.33) but not compared with the placebo generator. Time to onset of cold and increasing pain sensations as well as diastolic blood pressure increased under the exposure to the 42.25 GHz generator when compared with baseline and noise generator. Other outcome measures were comparable among the study conditions. CONCLUSIONS: We were able to partially confirm the previously suggested hypoalgesic effects of low-intensity electromagnetic MW. However, the effect was indistinguishable from the placebo condition in our investigation. PMID- 27782950 TI - Mid-term Clinical Results of CO2 Laser-assisted Sclerectomy Surgery (CLASS) for Open-Angle Glaucoma Treatment. AB - PURPOSE: To evaluate the efficacy and safety of CO2 Laser-assisted Sclerectomy Surgery (CLASS) in primary and pseudoexfoliative open-angle glaucoma. MATERIALS AND METHODS: Single-arm, open-label study included data from 9 medical centers located in 7 countries. Subjects underwent nonpenetrating CLASS procedure with a CO2 laser system (IOPtiMate). Intraocular pressure (IOP) and number of medications were measured at baseline, 1, 2, 4, and 6 weeks, and 3, 6, 12, 24, and 36 months. Complete success was defined as 5<=IOP<=18 mm Hg and at least 20% IOP reduction with no medications, and qualified success as the same with or without medications at 12, 24, and 36 months. RESULTS: A total of 111 consecutive eyes were enrolled in the study, 14 were excluded from the study due to protocol deviation or operator error. The mean age was 69.3+/-12.8 and 73.9% were whites. Percent change in IOP from baseline at 1, 2, and 3 years was, respectively, 45.1%, 46.8%, and 42.5% (P<0.001). Complete success rates after 12, 24, and 36 months were 60.2%, 57.9%, and 47.8%, respectively. Qualified success rates after 12, 24, and 36 months were 79.6%, 91.2%, and 84.8%, respectively. Number of medications dropped from 2.39+/-1.24 to 0.47+/-0.84, 0.53+/-0.75, and 0.71+/-0.89 at 12, 24, and 36 months, respectively (P<0.001). CONCLUSIONS: The CLASS procedure may be a simple and effective treatment for open-angle glaucoma providing extended relief of elevated IOP. PMID- 27782958 TI - Pancreas with Multiple Cysts. PMID- 27782957 TI - Correlation of Transient Elastography With Severity of Cystic Fibrosis-related Liver Disease. AB - OBJECTIVES: The aim of the study was to evaluate whether liver stiffness measurement (LSM), determined by transient elastography, correlates with presence and severity of liver disease in children and young adults with cystic fibrosis (CF). METHODS: Subjects underwent LSM at routine CF visits. Presence and severity of cystic fibrosis liver disease (CFLD) was determined by clinical parameters. Subjects were classified as no CFLD, CFLD without portal hypertension (PHTN), and CFLD with PHTN. LSM was compared with aspartate aminotransferase/platelet ratio index (APRI) as a correlate to severity of CFLD. RESULTS: A total of 249 subjects (53% boys; mean age 14 +/- 7 years; 7 [3%] <2 years and 74 [30%] 18-25 years) underwent LSM. Subjects were classified as 158 (64%) with no CFLD, 73 (29%) CFLD without PHTN, and 18 (7%) CFLD with PHTN. The median (interquartile range) LSM was different among the 3 groups: 4.4 (3.8-5.4), 5.1 (4.4-6.3), and 14.1 (8.8 24.8) kPa, respectively, with all pairwise comparisons different from one another (P < 0.0001). Similarly, median (interquartile range) APRI was different in groups 1 and 2 compared with CFLD with PHTN: 0.22 (0.17-0.27), 0.24 (0.17-0.33), and 0.53 (0.24-0.84), respectively (P < 0.01). Analysis of receiver operating characteristics for discriminating CFLD with PHTN from the other groups resulted in cut-points at 6.2 kPa (LSM) and 0.35 (APRI). LSM was superior to APRI in discriminating CFLD with PHTN from other groups, with areas under the curve 0.91 (LSM) versus 0.78 (APRI) (P = 0.05). CONCLUSIONS: Liver stiffness, as determined by transient elastography, correlates with the presence and severity of CFLD. Although APRI provided some information regarding severity of liver disease, LSM performed better than APRI in this population. PMID- 27782947 TI - Prediction of Outcome After Emergency High-Risk Intra-abdominal Surgery Using the Surgical Apgar Score. AB - BACKGROUND: With current literature quoting mortality rates up to 45%, emergency high-risk abdominal surgery has, compared with elective surgery, a significantly greater risk of death and major complications. The Surgical Apgar Score (SAS) is predictive of outcome in elective surgery, but has never been validated exclusively in an emergency setting. METHODS: A consecutive prospective single center cohort study of 355 adults undergoing emergency high-risk abdominal surgery between June 2013 and May 2014 is presented. The primary outcome measure was 30-day mortality. Secondary outcome measures were postoperative major complications, defined according to the Clavien-Dindo scale as well as the American College of Surgeons' National Surgical Quality Improvement Program guidelines, and intensive care unit admission. The SAS was calculated postoperatively. Cochran-Armitage test for trend was used to evaluate the incidence of both outcomes. Area under the curve was used to demonstrate the scores' discriminatory power. RESULTS: One hundred eighty-one (51.0%) patients developed minor or no complications. The overall incidence of major complications was 32.7% and the overall death rate was 16.3%. Risk of major complications, death, and intensive care unit admission increased significantly with decreasing SAS (P < .001). The score's c-statistics were 0.63. CONCLUSIONS: We have demonstrated the SAS to be significantly predictive but weakly discriminative for major complications and death among adults undergoing emergency high-risk abdominal surgery. Despite its predictive value, the SAS cannot in its current version be recommended as a standalone prognostic tool in an emergency setting. PMID- 27782956 TI - Predictive Value of HRT Stereometric Parameters and Blue-on-Yellow Perimetry Global Indices in Glaucoma-suspected Subjects. AB - OBJECTIVE: To determine subtle changes of Heidelberg retina tomography (HRT) stereometric parameters and blue-on-yellow (B/Y) perimetry global indices for the early diagnosis of glaucoma in suspected subjects. PATIENTS AND METHODS: Cross sectional data on 174 eyes of 87 subjects from a larger cohort, attending the Glaucoma Department of the "G. Gennimatas" General Hospital of Athens from January 2004 to February 2014, were used in the study. Subjects were assigned to 3 groups: (a) "normals" not requiring treatment throughout the study (group 1), (b) suspects who developed glaucoma and required treatment during the study (group 2), and (c) patients with incipient glaucoma (group 3). Specific HRT and B/Y perimetry variables were compared among the 3 groups. RESULTS: Significant differences were established for the following HRT parameters: "reference height" differed significantly between groups 1 and 2 and groups 1 and 3; "cup shape measure" differed significantly between groups 1 and 2 and groups 2 and 3. B/Y perimetry global index "mean deviation" significantly distinguished group 2 from groups 1 and 3. CONCLUSIONS: The results of the present study suggest the predictive value of the HRT stereometric parameters "reference height" and "cup shape measure" and of the B/Y perimetry global index "mean deviation" in glaucoma suspected subjects; further corroboration through longitudinal studies is warranted. PMID- 27782940 TI - Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model. AB - BACKGROUND: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. METHODS: Morphine PK were characterized in C57BL/6J wild-type (WT), diet induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. RESULTS: DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: 8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4). CONCLUSIONS: Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism. PMID- 27782959 TI - Predictive Serum Markers of Gallstone Disease: Gazing Into a Crystal Ball. PMID- 27782943 TI - Preoperative Three-Dimensional Strain Imaging Identifies Reduction in Left Ventricular Function and Predicts Outcomes After Cardiac Surgery. AB - BACKGROUND: Echocardiography-based speckle-tracking strain imaging is an emerging modality to assess left ventricular function. The aim of this study was to investigate the change in left ventricular systolic function after cardiac surgery with 3-dimensional (3D) speckle-tracking strain imaging and to determine whether preoperative 3D strain is an independent predictor of acute and long-term clinical outcomes after aortic valve, mitral valve, and coronary artery bypass grafting operations. METHODS: In total, 163 adult patients undergoing aortic valve, mitral valve, and coronary artery bypass surgeries were enrolled prospectively and had complete data sets. Demographic, operative, and outcome data were collected. 3D transthoracic echocardiograms were preformed preoperatively and on second to fourth postoperative day. Blinded off-line analysis was performed for left ventricular 2-dimensional (2D) ejection fraction (EF2D) and 3D ejection fraction (EF3D) and global peak systolic area, longitudinal, circumferential, and radial strain. RESULTS: 3D global strain correlated well with EF3D. Ventricular function as measured by strain imaging decreased significantly after all types of cardiac surgery. When preoperative EF3D was used, receiver operating characteristic curves identified reference values for 3D global strain corresponding to normal, mildly reduced, and severely reduced ventricular function. Normal ventricular function (EF3D >= 50%) corresponded to 3D global area strain -25%, with area under curve = 0.86 (0.81 0.89). Patients with reduced preoperative 3D global area strain had worse postoperative outcomes, including length of intensive care unit stay (4 vs 3 days, P = .001), major adverse events (27% vs 11%, P = .03), and decreased 1-year event-free survival (69% vs 88%, P = .005). After we controlled for baseline preoperative risk models including European System for Cardiac Operative Risk Evaluation score and surgery type, preoperative strain was an independent predictor of both short- and long-term outcomes, including length of intensive care unit stay, postoperative inotrope score, and 1-year event-free survival. CONCLUSIONS: This study shows that cardiac surgery was associated with an acute reduction in postoperative left ventricular function, when evaluated with 3D strain imaging. In addition, preoperative 3D strain was demonstrated to be an independent predictor of acute and long-term clinical outcomes after cardiac surgery. The use of noninvasive 3D transthoracic echocardiogram strain imaging before cardiac surgery may provide added information to aid in perioperative risk stratification and management for these high-risk patients. PMID- 27782948 TI - Sevoflurane Abolishes Oxygenation Impairment in a Long-Term Rat Model of Acute Lung Injury. AB - BACKGROUND: Patients experiencing acute lung injury (ALI) often need mechanical ventilation for which sedation may be required. In such patients, usually the first choice an intravenously administered drug. However, growing evidence suggests that volatile anesthetics such as sevoflurane are a valuable alternative. In this study, we evaluate pulmonary and systemic effects of long term (24-hour) sedation with sevoflurane compared with propofol in an in vivo animal model of ALI. METHODS: Adult male Wistar rats were subjected to ALI by intratracheal lipopolysaccharide (LPS) application, mechanically ventilated and sedated for varying intervals up to 24 hours with either sevoflurane or propofol. Vital parameters were monitored, and arterial blood gases were analyzed. Inflammation was assessed by the analysis of bronchoalveolar lavage fluid (BALF), cytokines (monocyte chemoattractant protein-1 [MCP-1], cytokine-induced neutrophil chemoattractant protein-1 [CINC-1], interleukin [IL-6], IL-12/12a, transforming growth factor-beta, and IL-10) in blood and lung tissue and inflammatory cells. The alveolocapillary barrier was indirectly assessed by wet to-dry ratio, albumin, and total protein content in BALF. Results are presented as mean +/- standard deviation. RESULTS: After 9 hours of ventilation and sedation, oxygenation index was higher in the LPS/sevoflurane (LPS-S) than in the LPS/propofol group (LPS-P) and reached 400 +/- 67 versus 262 +/- 57 mm Hg after 24 hours (P < .001). Cell count in BALF in sevoflurane-treated animals was lower after 18 hours (P = .001) and 24 hours (P < .001) than in propofol controls. Peak values of CINC-1 and IL-6 in BALF were lower in LPS-S versus LPS-P animals (CINC 1: 2.7 +/- 0.7 vs 4.0 +/- 0.9 ng/mL; IL-6: 9.2 +/- 2.3 vs 18.9 +/- 7.1 pg/mL, both P < .001), whereas IL-10 and MCP-1 did not differ. Also messenger RNAs of CINC-1, IL-6, IL-12a, and IL-10 were significantly higher in LPS-P compared with LPS-S. MCP-1 and transforming growth factor-beta showed no differences. Wet-to dry ratio was lower in LPS-S (5.4 +/- 0.2 vs 5.7 +/- 0.2, P = .016). Total protein in BALF did not differ between P-LPS and S-LPS groups. CONCLUSIONS: Long term sedation with sevoflurane compared with propofol improves oxygenation and attenuates the inflammatory response in LPS-induced ALI. Our findings suggest that sevoflurane may improve lung function when used for sedation in patients with ALI. PMID- 27782960 TI - Enteral Iron Supplementation in Preterm Infants. PMID- 27782963 TI - Th1 and Th17 proinflammatory profile characterizes invariant natural killer T cells in virologically suppressed HIV+ patients with low CD4+/CD8+ ratio. AB - INTRODUCTION: Scanty data exist on the phenotype and functionality of invariant natural killer T (iNKT) cells in HIV-infected (HIV+) patients. METHODS: By flow cytometry, we studied iNKT cells from 54 HIV+ patients who started combined antiretroviral therapy and had undetectable viral load for more than 1 year. Twenty-five maintained a CD4/CD8 ratio less than 0.4, whereas 29 reached a ratio more than 1.1; 32 age-matched and sex-matched patients were healthy controls (CTR). RESULTS: Patients with low ratio had lower percentage of CD4 iNKT cells compared with patients with high ratio and higher CD8 iNKT cell percentage; double-negative iNKT cells were lower in HIV+ patients compared with CTR. Patients with low ratio had higher percentage of CD4 and double-negative iNKT cells expressing CD38 and HLA-DR compared with patients with high ratio. CD4 iNKT cells expressing PD-1 were higher in patients with CD4/CD8 ratio less than 0.4, whereas double-negative iNKT cells expressing PD-1 were lower compared with patients with ratio more than 1.1. Patients with low ratio had higher CD4 iNKT cells producing IL-17, CD8 iNKT cells producing IFN-gamma, TNF-alpha or IFN-gamma and TNF-alpha, and double-negative iNKT cells producing IL-17 or IL-17 and IFN gamma compared with CTR. Activated CD4 (or CD8) T cells correlated with activated CD4 (or CD8) iNKT cells, as well as the percentages of CD4 (or CD8) T cells expressing PD-1 was correlated to that of CD4 (or CD8) iNKT cells expressing PD 1. CONCLUSION: Low CD4/CD8 ratio despite effective combined antiretroviral therapy is associated with altered iNKT cell subsets, enhanced activation, and prominent Th1/Th17 proinflammatory profile. PMID- 27782961 TI - Using the Objective Structured Clinical Examination to Assess ACGME Competencies in Pediatric Gastroenterology Fellows. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education has described 6 core competencies with which trainees should demonstrate proficiency. Using the Objective Structured Clinical Examination (OSCE), we aimed to assess 4 of these competencies among Pediatric Gastrointestinal (GI) fellows (PGs). METHODS: Eight first-year PGs from 6 medical centers in the New York area participated in a 4-station OSCE with trained standardized patient (SP) actors. The cases included an emergency department (ED) consult, or "ED Consult" for lower gastrointestinal bleeding; "Breaking Bad News" focusing on CF nutritional complications; "Second Opinion" for abdominal pain; "Transition of Care" for inflammatory bowel disease. At each station, attending faculty observed the encounters behind a 1-way mirror. SPs and faculties provided immediate feedback to the examined fellows. Previously validated OSCE checklists were used to assess performance. On completion, fellows attended debriefing sessions and completed surveys about the educational value. RESULTS: Median overall milestone competency scores were 6.9 (PC1), 4.8 (PC2), 5.9 (MK1), 5.7 (MK2), 6.4 (ICS1), 6.9 (Prof1), and 6.7 (Prof3). Overall, fellows score highest (7/9) on the inflammatory bowel disease "Transition of Care" case, found the "Breaking Bad News" Cystic Fibrosis OSCE to be the most challenging, and were most comfortable with the "ED Consult" OSCE, as a commonly encountered scenario. Overall, the fellows rated the educational value of the program highly. CONCLUSIONS: To our knowledge, although the OSCE has been validated in other medical fields, this is the first OSCE program developed for PGs fellows. These OSCEs have included Accreditation Council for Graduate Medical Education competencies, serving to assess fellows' skills in these areas while exposing them to challenging medical and psychosocial cases that they may not frequently encounter. PMID- 27782965 TI - Undisclosed HIV infection and antiretroviral therapy use in the Kenya AIDS indicator survey 2012: relevance to national targets for HIV diagnosis and treatment. AB - OBJECTIVES: This analysis assessed the impact of undisclosed HIV infection and antiretroviral therapy (ART) on national estimates of diagnosed HIV and ART coverage in Kenya. METHODS: HIV-positive dried blood spot samples from Kenya's second AIDS Indicator Survey were tested for an antiretroviral biomarker by liquid chromatography-tandem mass spectrometry. Weighted estimates of diagnosed HIV and ART coverage based on self-report were compared with those corrected for undisclosed HIV infection and ART use based on antiretroviral test results. Multivariate analysis determined factors associated with undisclosed HIV infection and ART use among persons on ART. RESULTS: The antiretroviral biomarker was detected in 42.5% [confidence interval (CI) 37.4-47.7] of HIV-infected persons. Antiretroviral drugs were present in 90.7% (CI 86.1-95.2) of HIV infected persons reporting HIV-positive status and receiving ART, 66.7% (CI 59.9 73.4) reporting HIV-positive status irrespective of ART use, 21.0% (CI 13.4-28.6) reporting HIV-negative status, and 19.3% (CI 9.0-29.5) reporting no previous HIV test. After correcting for undisclosed HIV infection and ART use, diagnosed HIV increased from 46.9 to 57.2% and ART coverage increased from 31.8 to 42.8%. Undisclosed HIV infection while on ART was associated with being aged 25-39 years and not visiting a health provider in the past year, while younger age and higher wealth were associated with undisclosed ART use. CONCLUSION: Substantial levels of undisclosed HIV infection and ART use among persons on ART were observed, resulting in diagnosed HIV underestimated by approximately 112000 persons and ART coverage by approximately 131000 persons. Supplementing self-reported ART status with objective measures of ART use in national population-based serosurveys can improve monitoring of HIV diagnosis and treatment targets in countries. PMID- 27782968 TI - Dolutegravir in breast milk and maternal and infant plasma during breastfeeding. PMID- 27782969 TI - omega-3 supplementation in HIV-1-infected individuals with unsuppressed viral load: cause for caution? PMID- 27782962 TI - Causal Evaluation of Acute Recurrent and Chronic Pancreatitis in Children: Consensus From the INSPPIRE Group. AB - OBJECTIVES: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) have been diagnosed in children at increasing rates during the past decade. As pediatric ARP and CP are still relatively rare conditions, little quality evidence is available on which to base the diagnosis and determination of etiology. The aim of the study was to review the current state of the literature regarding the etiology of these disorders and to developed a consensus among a panel of clinically active specialists caring for children with these disorders to help guide the diagnostic evaluation and identify areas most in need of future research. METHODS: A systematic review of the literature was performed and scored for quality, followed by consensus statements developed and scored by each individual in the group for level of agreement and strength of the supporting data using a modified Delphi method. Scores were analyzed for the level of consensus achieved by the group. RESULTS: The panel reached consensus on 27 statements covering the definitions of pediatric ARP and CP, evaluation for potential etiologies of these disorders, and long-term monitoring. Statements for which the group reached consensus to make no recommendation or could not reach consensus are discussed. CONCLUSIONS: This consensus helps define the minimal diagnostic evaluation and monitoring of children with ARP and CP. Even in areas in which we reached consensus, the quality of the evidence is weak, highlighting the need for further research. Improved understanding of the underlying cause will facilitate treatment development and targeting. PMID- 27782967 TI - We need to use the best antiretroviral drugs worldwide to prevent HIV drug resistance. PMID- 27782944 TI - Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia. AB - BACKGROUND: Animal models of peripheral neuropathy produced by a number of manipulations are assessed for the presence of pathologic pain states such as allodynia. Although stimulus-induced behavioral assays are frequently used and important to examine allodynia (ie, sensitivity to light mechanical touch; von Frey fiber test), other measures of behavior that reflect overall function are not only complementary to stimulus-induced responsive measures, but are also critical to gain a complete understanding of the effects of the pain model on quality of life, a clinically relevant aspect of pain on general function. Voluntary wheel-running activity in rodent models of inflammatory and muscle pain is emerging as a reliable index of general function that extends beyond stimulus induced behavioral assays. Clinically, reports of increased pain intensity occur at night, a period typically characterized with reduced activity during the diurnal cycle. We therefore examined in rats whether alterations in wheel-running activity were more robust during the inactive phase compared with the active phase of their diurnal cycle in a widely used rodent model of chronic peripheral neuropathic pain, the sciatic nerve chronic constriction injury (CCI) model. METHODS: In adult male Sprague Dawley rats, baseline (BL) hindpaw threshold responses to light mechanical touch were assessed using the von Frey test before measuring BL activity levels using freely accessible running wheels (1 hour/day for 7 sequential days) to quantify the distance traveled. Running wheel activity BL values are expressed as total distance traveled (m). The overall experimental design was after BL measures, rats underwent either sham or CCI surgery followed by repeated behavioral reassessment of hindpaw thresholds and wheel-running activity levels for up to 18 days after surgery. Specifically, separate groups of rats were assessed for wheel-running activity levels (1 hour total/trial) during the onset (within first 2 hours) of either the (1) inactive (n = 8/group) or (2) active (n = 8/group) phase of the diurnal cycle. An additional group of CCI treated rats (n = 8/group) was exposed to a locked running wheel to control for the potential effects of wheel-running exercise on allodynia. The 1-hour running wheel trial period was further examined at discrete 20-minute intervals to identify possible pattern differences in activity during the first, middle, and last portions of the 1-hour trial. The effect of neuropathy on activity levels was assessed by measuring the change from their respective BLs to distance traveled in the running wheels. RESULTS: Although wheel-running distances between groups were not different at BL from rats examined during either the inactive phase of the diurnal cycle or active phase of the diurnal cycle, sciatic nerve CCI reduced running wheel activity levels compared with sham-operated controls during the inactive phase. In addition, compared with sham controls, bilateral low-threshold mechanical allodynia was observed at all time points after surgical induction of neuropathy in rats with free-wheel and locked-wheel access. Allodynia in CCI compared with shams was replicated in rats whose running wheel activity was examined during the active phase of the diurnal cycle. Conversely, no significant reduction in wheel-running activity was observed in CCI-treated rats compared with sham controls at any time point when activity levels were examined during the active diurnal phase. Finally, running wheel activity patterns within the 1-hour trial period during the inactive phase of the diurnal cycle were relatively consistent throughout each 20-minute phase. CONCLUSIONS: Compared with nonneuropathic sham controls, a profound and stable reduction of running wheel activity was observed in CCI rats during the inactive phase of the diurnal cycle. A concurrent robust allodynia persisted in all rats regardless of when wheel-running activity was examined or whether they ran on wheels, suggesting that acute wheel-running activity does not alter chronic low-intensity mechanical allodynia as measured using the von Frey fiber test. Overall, these data support that acute wheel-running exercise with limited repeated exposures does not itself alter allodynia and offers a behavioral assay complementary to stimulus-induced measures of neuropathic pain. PMID- 27782964 TI - The per-protocol effect of immediate versus deferred antiretroviral therapy initiation. AB - OBJECTIVE: The Strategic Timing of AntiRetroviral Treatment (START) trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation. However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified. To supplement the published intention-to-treat (ITT) effect estimates, here we estimate the per protocol effect of immediate versus deferred ART initiation in START. DESIGN: The START trial randomized 4685 HIV-positive participants with CD4 cell counts more than 500 cells/MUl to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 cell count dropped below 350 cells/MUl or an AIDS diagnosis (deferred initiation group). METHODS: We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate initiation group, and deferred initiation groups had all the trial participants adhered to the protocol. RESULTS: We estimated that the 5-year risk of the composite outcome would have been 3.2% under immediate ART initiation and 7.0% under deferred initiation. The difference of 3.8% (95% confidence interval 1.5, 6.5) was larger than the ITT effect estimate of 3.1%, corresponding to a difference in effect estimates of 0.72% ( 0.35, 2.35). CONCLUSION: The ITT effect estimate may underestimate the benefit of immediate ART initiation by 23%. This estimate can be used by patients and policy makers who need to understand the full extent of the benefit of changes in ART initiation policies. PMID- 27782971 TI - Building trust: The influence of mentoring behaviors on perceptions of health care managers' trustworthiness. AB - BACKGROUND: In health care organizations, trust is critical for effective workplace relationships that ensure patient-centered outcomes. Although research has focused on trust in the relationship between patients and clinicians, less is known about what influences workers to trust their managers. An understanding is needed of the specific behaviors that influence health care workers' evaluations of their managers' trustworthiness. Mentoring research focuses on the developmental assistance that a more experienced worker provides to a less experienced worker. Building upon seminal research on mentoring functions, we argue that health care managers can build trust by providing informational (career-related) and interpersonal (psychosocial) support. PURPOSE: The aim of the study was to investigate the influence of health care managers' informational and interpersonal mentoring behaviors on workers' perceptions of their managers' trustworthiness and the mediating role of trustworthiness on trust in the managers. METHODOLOGY/APPROACH: Surveys were completed during work hours by 315 health care workers at an acute care hospital and associated clinics in the Midwest. FINDINGS: Results showed that managers' mentoring behaviors influenced worker perceptions of their managers' trustworthiness, in terms of ability, integrity, and benevolence. Ability partially mediated the relationship between informational mentoring and trust in managers, whereas integrity and benevolence partially mediated the relationship between interpersonal mentoring and trust in managers. PRACTICE IMPLICATIONS: Health care managers can actively build trust through mentoring behaviors that inspire positive assessments of managers' ability, integrity, and benevolence. PMID- 27782972 TI - Professional networks and the alignment of individual perceptions about medical innovation. AB - BACKGROUND: In recent decades, the role of technology in health care organizations has become increasingly relevant because it enhances health care outcomes and the achievement of clinical goals. Extant research demonstrates that the effectiveness of a medical innovation depends largely on health care professionals' perceptions of its usefulness and impact on their activities and practices. We also know that interaction among social actors contributes to the shaping of their judgments and opinions regarding innovation. PURPOSE: This study investigated the role of professionals' social networks and social capital in the formation of similar individual perceptions about a highly innovative robotic surgical system. METHODOLOGY: We collected data from a sample of 50 professionals, including both physicians and nurses, working in three hospital wards belonging to an Italian hospital organization. Using a survey, we gathered data on professionals' demographic characteristics, the adoption and impact of the new technology, and social networks. We tested our hypotheses using a dyadic perspective and logistic regression quadratic assignment procedures. FINDINGS: Our findings document that professionals' perceptions regarding technological change were more likely to be similar when they were connected and exhibited similarity in some social capital characteristics and adoption behavior. PRACTICE IMPLICATIONS: These results have important implications for health care executives and administrators, as well as for health professionals characterized by high degrees of autonomy and for which organizational change can be affected by professional or organizational resistance. PMID- 27782973 TI - Giving voice to all patients: On patients at the margins and their intention and perceived ability to complain. AB - BACKGROUND: It is now widely established that health care organizations are well advised not only to identify and act upon the concerns of all patient groups but also to encourage and enable them to voice their concerns in the first place. That said, research has begun to reveal that patients differ substantially in their readiness to complain, with many deciding to remain silent even after experiencing severe adverse events. Little research has explored whether patients at the margins (e.g., elderly, disabled, or mentally ill patients) are more likely to remain silent. PURPOSE: We examined the extent to which patients' social (being elderly or poorly educated), physical (having a permanent impairment such as deafness, blindness, or a chronic physical condition), and mental marginality (having a mental illness or learning disability) is associated with their intention and perceived ability to complain. METHODOLOGY: We matched survey and patient record data for hospital inpatients treated in the English National Health Service in 2007. We then computed two-stage probit selection models to estimate the cross-sectional association between patients' social, physical, and mental marginality and their intention (Stage 1, N1 = 58,062) and perceived ability to complain (Stage 2, N2 = 3,765). FINDINGS: Only 6.47% of all patients intended to complain. Of these, only 10.41% indicated that hospital staff provided them with all the information they needed to complain. An additional 14.70% reported to have received at least some of the information needed for this purpose. Patients above 80 not only exhibited significantly lower intentions to complain than their mid-aged counterparts (-1.16%) but also felt considerably less well informed to file a complaint (-5.45%). Similarly, patients suffering from blindness or a severe vision impairment showed a significantly lower perceived ability to complain (-5.20%). PRACTICE IMPLICATIONS: Patients at the margins, especially elderly patients and those with a severe vision impairment, will often remain silent and require special attention, if health care organizations are to listen to-and learn from-the voices of all patients. Our results indicate the need for inclusive complaint procedures designed to fuel organizational learning. Dedicated roles such as case managers and complaint officers might help to make such feedback channels accessible to all patients. PMID- 27782970 TI - Hospital cultural competency as a systematic organizational intervention: Key findings from the national center for healthcare leadership diversity demonstration project. AB - BACKGROUND: Cultural competency or the ongoing capacity of health care systems to provide for high-quality care to diverse patient populations (National Quality Forum, 2008) has been proposed as an organizational strategy to address disparities in quality of care, patient experience, and workforce representation. But far too many health care organizations still do not treat cultural competency as a business imperative and driver of strategy. PURPOSES: The aim of the study was to examine the impact of a systematic, multifaceted, and organizational level cultural competency initiative on hospital performance metrics at the organizational and individual levels. METHODOLOGY/APPROACH: This demonstration project employs a pre-post control group design. Two hospital systems participated in the study. Within each system, two hospitals were selected to serve as the intervention and control hospitals. Executive leadership (C-suite) and all staff at one general medical/surgical nursing unit at the intervention hospitals experienced a systematic, planned cultural competency intervention. Assessments and interventions focused on three organizational level competencies of cultural competency (diversity leadership, strategic human resource management, and patient cultural competency) and three individual level competencies (diversity attitudes, implicit bias, and racial/ethnic identity status). In addition, we evaluated the impact of the intervention on diversity climate and workforce diversity. FINDINGS: Overall performance improvement was greater in each of the two intervention hospitals than in the control hospital within the same health care system. Both intervention hospitals experienced improvements in the organizational level competencies of diversity leadership and strategic human resource management. Similarly, improvements were observed in the individual level competencies for diversity attitudes and implicit bias for Blacks among the intervention hospitals. Furthermore, intervention hospitals outperformed their respective control hospitals with respect to diversity climate. PRACTICE IMPLICATIONS: A focused and systematic approach to organizational change when coupled with interventions that encourage individual growth and development may be an effective approach to building culturally competent health care organizations. PMID- 27782966 TI - Benefits of continuous isoniazid preventive therapy may outweigh resistance risks in a declining tuberculosis/HIV coepidemic. AB - OBJECTIVE: Extending the duration of isoniazid preventive therapy (IPT) among people living with HIV (PLHIV) may improve its effectiveness at both individual and population levels, but could also increase selective pressure in favor of isoniazid-resistant tuberculosis (TB) strains. The objective of this study was to determine the relative importance of these two effects. METHODS: Transmission dynamic model. DESIGN: We created a mathematical model of TB transmission incorporating HIV incidence and treatment, mixed strain latent TB infections, and four different phenotypes of TB drug resistance (pan-susceptible, isoniazid monoresistant, rifampicin monoresistant, and multidrug resistant). We used this model to project the effects of IPT duration on the incidence of isoniazid sensitive and isoniazid-resistant TB as well as mortality among PLHIV. We evaluated the sensitivity of our baseline model, which was calibrated to data from Botswana, to different assumptions about the future trajectory of the TB epidemic. RESULTS: Our model suggests that, in the context of a declining TB epidemic such as that currently observed in Botswana, the incidence and mortality benefits of continuous IPT for PLHIV are likely to outweigh the potential resistance risks associated with long-duration IPT. However, should TB epidemics fail to remain in control, as was observed during the initial emergence of HIV, the selective pressure imposed by widespread use of continuous IPT on isoniazid resistant TB incidence may erode its initial benefits. CONCLUSION: Resistance concerns are likely insufficient to rule out use of continuous IPT when coupled with effective TB treatment, case finding, and HIV control. PMID- 27782977 TI - Iatrogenic Bladder Diverticulum 11 Years After Sacrospinous Ligament Fixation for Apical Prolapse. AB - INTRODUCTION: In this case, we describe a bladder diverticulum due to apical vaginal suspension to the sacrospinous ligament presenting 11 years after surgery. This case report explores her signs and symptoms, diagnostic work-up, surgical intervention, and postoperative course. CASE DESCRIPTION: A 71-year-old G2P2 presented with symptoms of urinary urgency. Work-up including cystoscopy and retrograde fistulogram revealed a bladder diverticulum extending to the level of the sacrospinous ligament. Her surgical history was significant for a sacrospinous ligament fixation 11 years before her symptoms. The iatrogenic bladder diverticulum was removed via robotic-assisted laparoscopic excision. Her postoperative course was benign beyond a urinary tract infection. Her urgency symptoms resolved after treatment. CONCLUSIONS: Iatrogenic injuries can present distant from initial surgery. Permanent foreign material, including suture, may increase the risk of complications. A high level of suspicion is necessary to diagnose complications given the subtle presentation. PMID- 27782981 TI - Clinical Pearls. PMID- 27782975 TI - Obliterative Versus Reconstructive Prolapse Repair for Women Older than 70: Is There an Optimal Approach? AB - OBJECTIVES: This study aimed to evaluate outcomes among women 70 years and older who underwent obliterative compared with reconstructive procedures for pelvic organ prolapse. METHODS: This was a retrospective cohort study of patients 70 years and older who underwent surgical prolapse repair at our institution from January 2004 through June 2010. Only patients with at least 4 weeks of follow-up were included. Patient characteristics and relevant pre, intra, and postoperative information were abstracted from medical records. Severity of postoperative complications was classified using the Dindo surgical classification system. RESULTS: We analyzed 143 (97.3%) patients. Fifty-four (37.8%) women underwent an obliterative procedure, whereas 89 (62.2%) underwent a reconstructive procedure. Twenty-eight (31.5%) women who had a reconstructive surgery met our criteria for recurrent prolapse compared with only 5 (9.3%) women in the obliterative group (P = 0.002).The incidence of intraoperative complication was 4.9%, and the incidence of any postoperative complication was 62.9%. Similar proportions of women who underwent each type of procedure experienced a postoperative complication. However, the severity of the complications differed between the groups (P = 0.02). In particular, 16.9% of women who had a reconstructive procedure experienced a grade III complication according to the Dindo scale compared with 13.0% of women who had an obliterative procedure. CONCLUSIONS: The majority of women 70 years and older do not have high-grade complications after pelvic organ prolapse repair, but women who undergo reconstructive procedures are more likely to experience high-grade complications and recurrent prolapse compared with women who undergo obliterative procedures. PMID- 27782980 TI - The Aging of Academic Optometry. PMID- 27782979 TI - Operationalizing the Measurement of Socioeconomic Position in Our Urogynecology Study Populations: An Illustrative Review. AB - OBJECTIVES: The purpose of this illustrative review is to provide guidance for the measurement of socioeconomic position when conducting health disparities research in urogynecology study populations. METHODS: Deidentified data were extracted from existing investigational review board-approved research databases for illustrative purposes. Attributes collected included the study participant's marital status, level of educational attainment (in number of years of school completed) and occupation as well as the study participant's last/only spouses' level of education and occupation. Average household and female socioeconomic position scores were calculated using two established composite indices: (1) Hollingshead Four Factor Index of Social Position, (2) Green's Socioeconomic Status scores, and 2 single-item indices: (1) Hauser-Warren Socioeconomic Index of Occupation, (2) level of educational attainment. RESULTS: The Hollingshead Four Factor Index of Social Position more than the Hauser-Warren Socioeconomic Index of Occupation provides researchers with a continuous score that is normally distributed with the least skew from the dataset. Their greater standard deviations and low kurtotic values increase the probability that statistically significant differences in health outcomes predicted by socioeconomic position will be detected compared with Green's socioeconomic status scores. CONCLUSIONS: Collection of socioeconomic data is an important first step in gaining a better understanding of health disparities through elimination of confounding bias, and for the development of behavioral, educational, and legislative strategies to eliminate them. We favor average household socioeconomic position scores over female socioeconomic position scores because average household socioeconomic position scores are more reflective of overall resources and opportunities available to each family member. PMID- 27782986 TI - Discussion: Fully Awake Breast Reduction. PMID- 27782982 TI - Surgeon-Controlled Study and Meta-Analysis Comparing FlexHD and AlloDerm in Immediate Breast Reconstruction Outcomes. AB - BACKGROUND: The use of acellular dermal matrix has facilitated immediate prosthesis-based breast reconstruction. However, few studies directly compare surgical outcomes following acellular dermal matrix-based reconstruction with two of the most commonly available materials, AlloDerm and FlexHD. Those studies that are available often do not adequately control for the surgeon as a variable. The authors hypothesize that complication rates will not differ significantly between AlloDerm and FlexHD when practice and surgeon variables are properly controlled. METHODS: Retrospective review was conducted to identify consecutive implant-based reconstruction procedures performed at a tertiary academic medical institution by a single plastic surgeon over 6 years. Univariate and binomial regression analyses were conducted to compare patient characteristics and clinical endpoints across acellular dermal matrix groups (AlloDerm/AlloDerm ready-to-use versus FlexHD Pliable/Perforated). RESULTS: Of the 233 patients that underwent matrix based breast reconstruction, 11 (4.7 percent) developed surgical-site infection. The infection rate was not statistically different between patients who received FlexHD [n = 5 (5.0 percent)] versus AlloDerm [n = 6 (4.6 percent)] on either univariate (p = 0.89) or binomial regression analysis (p = 0.56). Likewise, there were no statistical differences in rates of seroma, hematoma, explantation, or delayed wound healing. CONCLUSIONS: Clinical endpoints of interest were all equivalent between acellular dermal matrix types. This study uniquely reports a single-surgeon case series comparing outcomes between different acellular dermal matrix types. Instead of focusing on acellular dermal matrix as a predictor of outcome, other patient and surgeon factors should be addressed to improve results and innovate better alternatives. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27782978 TI - Relationship of Anatomy and Function: External Anal Sphincter on Transperineal Ultrasound and Anal Incontinence. AB - OBJECTIVE: The aim of this study was to investigate the association of the anatomic integrity of the external anal sphincter (EAS) detected on transperineal ultrasound (TPUS) with symptoms of anal incontinence (AI) as measured by St Mark's Incontinence Score (SMIS) and the visual analog scale (VAS). METHODS: This is an observational, cross-sectional analysis of 486 women who presented to a tertiary urogynecological center between May 2013 and August 2014. They underwent a standardized interview and an examination that involved 3-dimensional/4 dimensional TPUS. The SMIS and VAS were administered if they answered positively to a question on AI. The association between defects of the EAS and symptoms of AI was evaluated using bivariate tests, as well as adjusting for pertinent covariates using multiple linear regression modeling. RESULTS: Of the included patients, 17.1% reported AI, and 15.2% had significant EAS defects (>=4 slices) on TPUS imaging. A significant sonographic defect was diagnosed in 23% of women with AI versus 14% of those without (P = 0.033). Women with symptoms of AI were more likely to have a significant defect on TPUS (odds ratio, 1.878; 95% confidence interval, 1.05-3.37). No significant findings were seen when analyzing SMIS, its components, and VAS against sonographic EAS defects. CONCLUSIONS: The symptom of AI is associated with significant EAS defects detected on TPUS. However, this study failed to show an association between significant EAS defects and the SMIS and VAS. PMID- 27782984 TI - Determining the Cost of Incidental Findings for Patients Undergoing Preoperative Planning for Abdominally Based Perforator Free Flap Breast Reconstruction with Computed Tomographic Angiography. AB - BACKGROUND: Computed tomographic angiography is increasingly used during surgical planning for abdominally based microvascular breast reconstruction. Cost-analysis studies have demonstrated a benefit to the use of computed tomographic angiography, although the secondary costs of incidental findings have not been previously reported. This study investigates the cost of computed tomographic angiography, taking into account the cost of incidental findings found during imaging. METHODS: Patients undergoing preoperative computed tomographic angiography in preparation for autologous abdominally based breast reconstruction from July of 2010 through May of 2014 were included in this study. Patient medical records were reviewed for imaging findings, need for follow-up, and any additional procedures. Costs were determined using the publicly available Healthcare Bluebook. RESULTS: A total of 135 patients underwent computed tomographic angiography in preparation for abdominally based microvascular breast reconstruction. Twenty-eight patients (21 percent) were noted to have clinically significant incidental findings recommended for follow-up imaging or procedures. Inclusion of chest imaging with computed tomographic angiography of the abdomen/pelvis to assess for internal mammary and/or thoracodorsal artery patency increased the incidental findings approximately five-fold. The mean cost of computed tomographic angiography increased by 32 percent, from $1267 to $1677 per patient, when incidental findings were included. CONCLUSIONS: Computed tomography angiography is a tool for the preoperative evaluation of patients desiring autologous breast reconstruction. The true cost of preoperative computed tomographic angiography is likely 30 percent greater than the baseline cost when the subsequent evaluation of incidental findings is included and should be accounted for in future cost-analysis studies. PMID- 27782983 TI - Techniques and Perforator Selection in Single, Dominant DIEP Flap Breast Reconstruction: Algorithmic Approach to Maximize Efficiency and Safety. AB - BACKGROUND: Perforator selection is critical to deep inferior epigastric perforator (DIEP) flap harvest. Commitment to a single perforator has the potential benefit of a simpler dissection, but may increase fat necrosis or perfusion-related complications compared with multiple perforator harvest. METHODS: A 3-year retrospective study was carried out of all patients who underwent DIEP flap breast reconstruction performed by the senior author (M.S. C). Data were collected on patient demographics and surgical outcomes. RESULTS: One hundred eighty-three flaps were performed (105 patients) over 3 years. One hundred fifty-six bilateral (78 patients) and 24 unilateral flaps were included in the final study. Mean age was 47.8 +/- 8.4 years and mean body mass index was 29.1 +/- 5.3 kg/m. Seventy-five percent of flaps were based on single dominant perforators. Single perforators were used in 33.3 percent of flaps weighing over 1000 g, 80 and 74 percent of flaps weighing 500 to 1000 g and less than 500 g, respectively (p = 0.01). There were no differences in overall complications between single- versus multiple-perforator DIEP flaps. Neither body mass index nor flap weight posed additional risk to overall complications. Conversion to a muscle-sparing flap was 9.4 percent. CONCLUSIONS: The authors present an algorithm for perforator selection, stepwise approach to flap harvest, and considerations for intraoperative decision-making in DIEP flap reconstruction. Single-dominant perforator flaps can be safely performed, but inclusion of the largest perforator is critical to flap perfusion. Additional perforators must be weighed against the associated tradeoff with donor-site morbidity. The threshold for conversion to a muscle-sparing flap is reduced with increased clinical experience. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27782976 TI - The Use of Mechanical Bowel Preparation in Pelvic Reconstructive Surgery: A Randomized Controlled Trial. AB - OBJECTIVE: To compare mechanical bowel preparation (MBP) using oral magnesium citrate with sodium phosphate enema to sodium phosphate (NaP) enema alone during minimally invasive pelvic reconstructive surgery. METHODS: We conducted a single blind, randomized controlled trial of MBP versus NaP in women undergoing minimally invasive pelvic reconstructive surgery. The primary outcome was intraoperative quality of the surgical field. Secondary outcomes included surgeon assessment of bowel handling and patient-reported tolerability symptoms. RESULTS: One hundred fifty-three participants were enrolled; 148 completed the study (71 MBP and 77 NaP). Patient demographics, clinical and intraoperative characteristics were similar. Completion of assigned bowel preparation was similar between MBP (97.2%) and NaP (97.4%). The MBP group found the preparation more difficult (P<0.01) and reported more overall discomfort and negative preoperative side effects (all P<=0.01). Quality of surgical field at initial port placement was excellent/good in 80.0% of the MBP group compared with 62.3% in the NaP group (P=0.02). This difference was not maintained by the conclusion of surgery (P=0.18). Similar results were seen in the intent-to-treat population. Surgeons accurately guessed preparation 65.7% of the time for MBP versus 41.6% for NaP (P=0.36). At 2 weeks postoperatively, both reported a median time for return of bowel function of 3.0 (2.0-4.0) days. CONCLUSIONS: Mechanical bowel preparation with oral magnesium citrate before minimally invasive pelvic reconstructive surgery offered initial improvement in the quality of surgical field, but this benefit was not sustained. It was associated with an increase in patient discomfort preoperatively, but did not seem to impact postoperative return of bowel function. LEVEL OF EVIDENCE: I. PMID- 27782985 TI - Fully Awake Breast Reduction. AB - : The authors present 25 cases and an in-depth 4-minute video of fully awake aesthetic breast reduction, which was made possible by thoracic epidural anesthesia. There are obvious and important advantages to this technique. Not only does this allow for intraoperative patient cooperation (i.e., patient self positioning and opinion for comparison of breasts), meaning a shorter and more efficient intraoperative time, there also is a reduction in postoperative pain, complications, recovery, and discharge times. The authors have also enjoyed great success and no complications with this technique in over 150 awake abdominoplasty/total body lift patients. The authors feel that the elimination of the need for general anesthesia by thoracic epidural sensorial-only anesthesia is a highly effective and efficient technique, with very few disadvantages/complications, providing advantages to both patients and surgeons. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27782987 TI - Anaplastic Large Cell Lymphoma: Emerging Consent and Management Patterns among American and International Board Certified Plastic Surgeons. AB - BACKGROUND: Although literature and case reports regarding anaplastic large cell lymphoma (ALCL) continue to increase, changes in plastic surgery practice patterns have not been assessed. METHODS: A 19-question survey was sent electronically to U.S. and international board-certified plastic surgeons. Data were analyzed using chi-square test and logistic regression analysis. RESULTS: A total of 1383 surgeons (U.S., 715; international, 668) responded, at a rate of 13.5 percent, and 36.2 percent of U.S. physicians aspirate late seromas and send for cytologic analysis and 9.5 percent had personal experience with ALCL, equating to at least 193 self-reported cases. Overall, 26.9 percent discuss ALCL risk at the initial consultation every time, and 36.4 percent include ALCL in the informed consent. Compared to U.S. counterparts, Australian, French, and German physicians were five times as likely to include ALCL in consent. Physicians in an academic practice and those frequently (>40 percent) using textured implants were more likely to discuss ALCL in the preoperative consultation. Physicians with personal or colleague experience with ALCL were twice as likely to include ALCL in the consent process. CONCLUSIONS: Only one-third of surgeons are managing late seroma according to U.S. Food and Drug Administration guidelines. ALCL cases are likely being underreported. Collectively, plastic surgeons remain hesitant to change consent pattern. However, specific countries have adapted their consenting processes. Working in academia and frequent textured implant use makes one more likely to discuss ALCL in consultation. Personal or colleague experience makes one twice as likely to include ALCL in the consent. PMID- 27782988 TI - Discussion: Anaplastic Large Cell Lymphoma in the Plastic Surgery Practice: Has It Influenced Practice Patterns? PMID- 27782990 TI - Discussion: Matching the Implant to the Breast: A Systematic Review of Implant Size Selection Systems for Breast Augmentation. PMID- 27782991 TI - The External Nose: The Nasal Arteries and Their Course in Relation to the Nasolabial Fold and Groove. AB - BACKGROUND: The blood supply to the external nose is poorly described. The aim of this study was to identify the different types of blood supply to the external nose and the course of the arteries in relation to the nasolabial fold and groove and to the facial muscles. METHODS: With 96 facial halves of 48 adult specimens, the arteries of the outer nose were dissected, and three-dimensional computed tomographic reconstructions and horizontal sections were made. RESULTS: Three main types of blood supply to the external nose were identified, associated with the different types of facial arteries. Moreover, a deep course of the nasal arteries in relation to the nasolabial fold and a very superficial course in relation to the nasolabial groove were found. CONCLUSION: Knowledge regarding the nasal arteries is clinically relevant for filler injection for aesthetic improvements of the nose and nasolabial fold and for planning local flaps in facial reconstructions and also for rhinoplasty. PMID- 27782989 TI - Matching the Implant to the Breast: A Systematic Review of Implant Size Selection Systems for Breast Augmentation. AB - BACKGROUND: For primary breast augmentation, several implant selection systems have been described to guide the surgeon with choosing from a variety of manufactured implant dimensions and properties. Controversy exists regarding the most efficacious method of selecting an appropriate implant size that best matches the patient's breast. METHODS: The goal of this systematic review was to provide a comprehensive list of documented implant size selection systems, and to critically evaluate them. Implant size selection systems were grouped into categories based on selection principles. Articles were evaluated based on reported outcome measures and methodologic quality. RESULTS: Thirty-three implant size selection systems were included in the final analysis. Only 12 percent of articles (four of 33) reported clinical outcomes that could be compared to accepted literature values or industry standards. Articles that described tissue based planning systems, which use clinical guidelines to determine the optimal patient-specific implant dimensions, were of highest methodologic quality using the Methodological Index for Non-Randomised Studies scale, when compared to systems that used breast "dimensional" analyses that stress tissues to the desire of the patient and/or surgeon, and compared to systems that did not use breast measurement (means +/- SD, 6.0 +/- 1.4, 1.4 +/- 2.3, and 0.0 +/- 0.0, respectively). CONCLUSIONS: There is some evidence to support tissue-based planning as a superior approach to implant size selection planning; studies that used tissue-based planning reported lower reoperation rates compared with industry standards and accepted literature values. The authors offer several suggestions on how to improve the methodologic quality of future studies describing new implant selection systems. PMID- 27782992 TI - Surgical Outcome after Penile Inversion Vaginoplasty: A Retrospective Study of 475 Transgender Women. AB - BACKGROUND: For many transgender women, vaginoplasty is the final stage in the gender-confirming process. Penile inversion vaginoplasty is considered the gold standard for vaginal construction in transgender women. In this study, the authors assessed intraoperative and postoperative complications after penile inversion vaginoplasty. METHODS: All patients who underwent penile inversion vaginoplasty between January of 2000 and January of 2014 were identified retrospectively from the authors' hospital registry. A retrospective chart review was conducted. Outcome measures were intraoperative and postoperative complications, reoperations, secondary surgical procedures, and possible risk factors. RESULTS: Between January of 2000 and January of 2014, 475 patients underwent penile inversion vaginoplasty, 405 of whom did not have and 70 of whom did have additional full-thickness skin grafts. The median patient age at surgery was 38.6 years (range, 18.1 to 70.8 years). Median follow-up was 7.8 years (range, 1.0 to 15.9 years). The most frequently observed intraoperative complication was rectal injury [n = 11 (2.3 percent)]. Short-term postoperative bleeding that required transfusion [n = 23 (4.8 percent)], reoperation [n = 7 (1.5 percent)] or both [n = 2 (0.4 percent)] occurred in some cases. Major complications comprised three (0.6 percent) rectoneovaginal fistulas, which were successfully treated. Revision vaginoplasty was performed in 14 patients (2.9 percent). Comorbid diabetes was associated with a higher risk of local infection (OR, 9.8; p = 0.003; 95 percent CI, 2.8 to 34.4), and use of psychotropic medication predisposed to postoperative urinary retention (OR, 2.1; p = 0.006; 95 percent CI, 1.2 to 3.5). CONCLUSIONS: Successful vaginal construction without the need for secondary functional reoperations was achieved in the majority of patients. Intraoperative complications are scarce. Postoperative complications occur frequently but are generally minor and easily treated. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27782993 TI - Discussion: Surgical Outcome after Penile Inversion Vaginoplasty: A Retrospective Study of 475 Transgender Women. PMID- 27782994 TI - Nostrilplasty by Manipulating the Dilator Naris Muscles: A Pilot Study. AB - : The present study was undertaken to determine whether a more aesthetically acceptable nostril shape could be created by manipulating the dilator naris muscles. Patients who had round or horizontally shaped nostrils were treated by resecting the dilator naris muscle to attenuate the dilating and lateral pulling effect of the muscles. The resected muscle segments were inserted into the nasal tip area to project the nasal tip. Manipulating the dilator muscle shaped the nostril more vertically and enhanced nasal tip augmentation. The ratio of the short axis to the long axis of the nostril was improved significantly. The interaxial angle became more acute. The patient satisfaction score was also increased. A more aesthetically pleasing nostril shape can be produced by resecting and grafting the dilator naris muscle segments. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27782995 TI - The Indian Nose. AB - Despite the growing number of rhinoplasty procedures being performed on Indian patients, there is a very limited body of literature regarding nuances of the Indian rhinoplasty. The authors review the spectrum of nasal phenotypes that fall under the category of the Indian nose; goals of rhinoplasty in these patients; operative techniques that can be used to address them; and, importantly, the specific pitfalls to be avoided in these groups. PMID- 27782996 TI - Comparison of Antibiotic-Coated versus Uncoated Porcine Dermal Matrix. AB - BACKGROUND: The objective of this study was to evaluate the antimicrobial performance of a rifampin/minocycline-coated, non-cross-linked, acellular porcine dermal matrix (XenMatrix AB) compared to an uncoated, non-cross-linked, acellular porcine dermal matrix (Strattice) after implantation/inoculation with methicillin resistant Staphylococcus aureus or Escherichia coli in a dorsal rabbit model. METHODS: Forty male New Zealand White rabbits were bilaterally implanted with XenMatrix AB or Strattice grafts and inoculated with clinically isolated methicillin-resistant S. aureus (5 * 10 colony-forming units/ml) or E. coli (1 * 10 colony-forming units/ml). At 2 and 8 weeks, sites were analyzed for viable methicillin-resistant S. aureus/E. coli colony-forming units, abscess formation, and histologic response (n = 5 rabbits per group per bacterium per time point). RESULTS: XenMatrix AB completely inhibited bacterial colonization of the graft, inhibited abscess formation, reduced inflammation and encapsulation, and improved neovascularization compared with Strattice. XenMatrix AB implants exhibited significantly fewer colony-forming units compared with Strattice implants at 2 weeks (methicillin-resistant S. aureus) (p < 0.01) and at 2 and 8 weeks (E. coli) (p < 0.05). In addition, XenMatrix AB implants demonstrated a significantly lower abscess score at 2 weeks (methicillin-resistant S. aureus) and 8 weeks (E. coli) (p < 0.01 in both cases). For both types of bacteria and both time points evaluated, XenMatrix AB implants exhibited minimal inflammation and encapsulation and a lack of neutrophils. In contrast, Strattice implants displayed marked inflammatory and neutrophilic responses and moderate encapsulation. CONCLUSIONS: This study demonstrated the antimicrobial performance of a rifampin/minocycline coated bioprosthetic (XenMatrix AB) in a rabbit inoculation model. XenMatrix AB completely inhibited bacterial colonization of the graft, with minimal host inflammation and encapsulation, and improved neovascularization compared with Strattice. PMID- 27782998 TI - Dipeptidyl Peptidase-4, Wound Healing, Scarring, and Fibrosis. AB - Scarring and fibrosis are an enormous public health concern, resulting in excessive morbidity and mortality in addition to countless lost health care dollars. Recent advances in cell and developmental biology promise a better understanding of scarring and fibrosis and may translate to new clinical therapies. PMID- 27782997 TI - Topical Minocycline Effectively Decontaminates and Reduces Inflammation in Infected Porcine Wounds. AB - BACKGROUND: Wound infection can impair postoperative healing. Topical antibiotics have potential to treat wound infection and inflammation and minimize the adverse effects associated with systemic antibiotics. METHODS: Full-thickness porcine wounds were infected with Staphylococcus aureus. Using polyurethane wound enclosure devices, wounds were treated with topical 100 MUg/ml minocycline, topical 1000 MUg/ml minocycline, topical saline control, or 4 mg/kg intravenous minocycline. Bacteria were quantified in wound tissue and fluid obtained over 9 hours. Immunosorbent assays were used to analyze inflammatory marker concentrations. Minocycline's effect on in vitro migration and proliferation of human keratinocytes and fibroblasts was tested using scratch assays and metabolic assays, respectively. RESULTS: After 6 hours, 100 and 1000 MUg/ml topical minocycline decreased bacteria in wound tissue to 3.5 +/- 0.87 and 2.9 +/- 2.3 log colony-forming units/g respectively, compared to 8.3 +/- 0.9 log colony forming units/g in control wounds (p < 0.001) and 6.9 +/- 0.2 log colony-forming units/g in wounds treated with 4 mg/kg intravenous minocycline (p < 0.01). After 2 hours, topical minocycline reduced concentrations of the inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha (p < 0.01), and inflammatory cell counts in wound tissue (p < 0.05). In noninfected wounds, topical minocycline significantly reduced interleukin-1beta, interleukin-6, and inflammatory cell counts after 4 hours (p < 0.01). Matrix metalloproteinase-9 concentrations decreased after 1-hour treatment (p < 0.05). Keratinocyte and fibroblast in vitro functions were not adversely affected by 10 MUg/ml minocycline or less. CONCLUSIONS: Topical minocycline significantly reduces bacterial burden and inflammation in infected wounds compared with wounds treated with intravenous minocycline or control wounds. Minocycline also decreases local inflammation independently of its antimicrobial effect. PMID- 27783001 TI - Discussion: Impact of Fronto-Orbital Advancement on Frontal Sinus Volume, Morphology, and Disease in Nonsyndromic Craniosynostosis. PMID- 27782999 TI - A Three-Dimensional Micro-Computed Tomographic Study of the Intraosseous Lunate Vasculature: Implications for Surgical Intervention and the Development of Avascular Necrosis. AB - BACKGROUND: The purpose of this study was to use micro-computed tomography to demonstrate the intraosseous vascularity of the lunate within a three-dimensional orientation to identify areas of greatest perfusion and define vascular "safe zones" for surgical intervention. METHODS: Fourteen upper extremities were injected with a lead-based contrast agent. The lunates were harvested and scanned using a micro-computed tomography scanner. The intraosseous vascularity was incorporated into a three-dimensional image. Vessel number, diameter, distribution, and pattern were evaluated and analyzed. Vascularity of all specimens was projected onto one representative lunate to identity areas of higher and lower vascularity. RESULTS: Twelve specimens had nutrient vessels entering the bone from volar and dorsal; two specimens had no dorsal vessels. The intraosseous vascularity could be classified according to the Y, I, and X patterns described by Gelberman et al. Average number and diameter of vessels were 2.3 and 118.1 MUm, respectively, for volar; and 1.4 and 135.8 MUm, respectively, for dorsal. The long axis of the lunate showed the highest vascularity on both axial and lateral views. Lower vascularity was observed in the dorsoradial and volar-ulnar quadrants on the axial view, and in the proximal part on the lateral view. Lunate shape was not associated with an increase or decrease in nutrient vessels or vascular pattern. CONCLUSIONS: Vascular safe zones were identified, allowing for potentially safer surgical interventions to the lunate. Volar approaches to the lunate may result in localized ischemia in a subset of patients with absent dorsal nutrient vessels. This study may help to better define patients at risk for Kienbock disease. PMID- 27783000 TI - The Influence of Insurance Type on Management of Carpal Tunnel Syndrome: An Analysis of Nationwide Practice Trends. AB - BACKGROUND: The purpose of this study was to evaluate the impact of insurance type on use of diagnostic testing, treatments, and the efficiency of care for patients with carpal tunnel syndrome. METHODS: The 2009 to 2013 Truven MarketScan Databases were used to identify adult patients with carpal tunnel syndrome. Insurance type was categorized as fee-for-service versus capitated managed care. Multivariable regression models were created to evaluate the relationship between insurance type and costs, number of visits, treatment, and electrodiagnostic study use, and controlling for demographic characteristics and comorbidities. RESULTS: The cohort included 233,572 patients, of which 86 percent carried fee for-service insurance. Predicted probabilities were clinically similar between the capitated and fee-for-service insurance types for therapy (0.23 versus 0.24), steroid injection (0.07 versus 0.09), and electrodiagnostic study use (0.44 versus 0.47). The difference in predicted probabilities between the insurance groups was greatest for surgery use (0.22 versus 0.28 for managed care and fee for-service, respectively). The mean number of visits was similar between the two groups (2.1 versus 2.0 visits). In the controlled analysis, managed care was associated with a 10 percent decrease in cost compared to patients with fee-for service (p < 0.001). CONCLUSIONS: Managed care was associated with a lower probability of surgery than fee-for-service, but similar use of less costly services. These data may be used to predict future practice trends with increased implementation of bundled payment reimbursement. Routine collection of validated patient outcomes measures is critical to assess patient outcomes associated with anticipated reduction of surgical services. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 27783005 TI - Discussion: Vascular Perfusion of the Facial Skin: Implications in Allotransplantation of Facial Aesthetic Subunits. PMID- 27783004 TI - Separation of Thoraco-Omphalo-Ischiopagus Conjoined Twins: Surgical Planning, Management, and Outcomes. AB - BACKGROUND: Conjoined twins are a rare medical phenomenon that offers a unique challenge for medical professionals. The complex anatomy of conjoined twins dictates their survival and amenability to separation, making each case different in terms of medical management, surgical planning, and patient outcomes. Thoraco omphalo-ischiopagus twins, joined from the thorax to the pelvis, are one of the rarest orientations recorded in the medical literature, and successful separation of this subset of conjoined twins has not been documented. This report presents a novel case of thoraco-omphalo-ischiopagus tetrapus twins who were successfully separated at 10 months of age. The preoperative planning, operative details, and postoperative course are discussed as they relate to the reconstructive effort. METHODS: Three-dimensional medical modeling was pursued early in the planning process and was used to estimate the soft-tissue requirements for reconstruction and to design custom tissue expanders. RESULTS: The reconstructive effort required postponement until respiratory status was optimized. Even with elaborate preoperative planning, primary closure of the abdomen was limited because of tissue edema and other less predictable patient factors. Delayed closure of the abdominal wall was made possible with negative-pressure wound therapy and secondary flap advancements. CONCLUSION: Preoperative coordination with necessary vendors, a multidisciplinary surgical effort, and optimal timing of the surgical intervention all contribute to the successful separation and long-term survival of thoraco-omphalo-ischiopagus conjoined twins. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27783007 TI - Modification of the Radial Forearm Fasciocutaneous Flap in Partial Pharyngolaryngeal Reconstruction to Minimize Fistula Formation. AB - Reconstruction of pharyngolaryngoesophageal defects following salvage surgery in patients with a history of chemoradiation is a challenging problem with a high incidence of pharyngocutaneous fistula. The authors describe three cases of successful reconstruction of partial pharyngolaryngoesophageal defects using a modified radial forearm free flap with additional dermal reinforcement and review the literature for innovations in the use of radial forearm free flap for reconstruction of these difficult cases. Modification of the radial forearm free flap makes it a versatile, reliable flap that has become the "go-to" flap for partial pharyngolaryngoesophageal reconstruction. PMID- 27783006 TI - The Stanford-ReSurge Burn Scar Contracture Scale for Neck: Development and Initial Validation for Burn Scar Contracture. AB - BACKGROUND: Burn contractures can cause significant disability, particularly in patients in resource-limited settings. However, a gap exists in our ability to measure outcomes in patients with burn contractures of the neck. The objective of this study was to develop and validate the Stanford-ReSurge Burn Scar Contracture Scale-Neck to longitudinally assess functional status and measure functional improvement following contracture release of the neck. METHODS: A literature review was performed to identify scales used in neck assessment and burn assessment. Items were then removed from the pool based on redundancy, feasibility, cultural appropriateness, and applicability to patients in international resource-limited environments. Remaining items were administered to patients with burn contracture of the neck. RESULTS: The initial literature review found 33 scales that were combined to create an initial pool of 714 items, which was first reduced to 40 items. Feedback from field testing then yielded a 20-item outcome tool to assess appearance, activities of daily living, somatosensation, satisfaction, and range of motion, with a floor of 20 and a ceiling score of 100 points. Preliminary testing with 10 patients showed an average preoperative score of 58 points and an average 1-month postoperative score of 42 points. CONCLUSIONS: The authors have created an outcome tool for measuring functional status following burn contracture release of the neck, which can easily be implemented in resource-limited settings where the burden of burn injuries and morbidities is disproportionately high. Ongoing work includes a multicountry study to evaluate validity and reliability. PMID- 27783002 TI - The Changing Nasolabial Dimensions following Repair of Unilateral Cleft Lip: An Anthropometric Study in Late Childhood. AB - BACKGROUND: Repair of unilateral cleft lip and nasal deformity in three dimensions requires anticipation of changes in the fourth dimension that can be determined by periodic and objective assessment. METHODS: Fifty patients with unilateral cleft lip with or without cleft palate underwent primary repair from 1999 to 2004 and were followed through 2014. Anthropometry was performed immediately postoperatively and at a first and second follow-up interval, occurring at an average age of 6.6 and 11.5 years, respectively. Measured differences between cleft and noncleft sides included heminasal width (subnasale alare), cutaneous labial height (subnasale-crista philtri inferior, subalare crista philtri inferior), and transverse labial width at the cutaneous-vermilion border (crista philtri inferior-chelion). Contrasts for the rates of growth were assessed with t tests for correlated measures. Using the same method, the difference between growth on cleft and noncleft sides in the second period was compared to that in the first period. RESULTS: Heminasal width remained narrower on the cleft side, but this difference decreased over time. Subnasale-crista philtri inferior remained longer on the cleft side; there was no difference between the rate of growth on the cleft and noncleft sides in the second period. Subalare-crista philtri inferior remained shorter on the cleft side by a consistent difference at both times of follow-up measurements. Transverse labial width at the cutaneous-vermilion border remained shorter on the cleft side, but this difference decreased in the second period. CONCLUSION: Understanding how nasolabial features change with growth is critical to crafting the initial repair of unilateral cleft lip and nasal deformity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27783008 TI - Functional Neck Dissection: The Operative Technique Series. AB - A clinical case of a patient undergoing right functional neck dissection is presented. A detailed, step-by-step video description highlighting the pearls of the operation accompanies the article. This will be the first of many contributions in a Plastic and Reconstructive Surgery and PRS Global Open Operative Technique Series initiative that endeavors to disseminate plastic and reconstructive knowledge worldwide. PMID- 27783009 TI - Discussion: Functional Neck Dissection: The Operative Technique Series. PMID- 27783010 TI - Venous Thromboembolism: A Comparison of Chronic Spinal Cord Injury and General Surgery Patients in a Metropolitan Veterans Affairs Hospital. AB - BACKGROUND: Venous thromboembolic events result in significant morbidity, mortality, and costly therapeutic interventions. As medical resource allocation strategies are becoming more pervasive, appropriate risk stratification and prophylactic regimens are essential. Previous studies have shown a decreased incidence of perioperative venous thromboembolism in the chronic spinal cord injury population. The question remains of whether chronic spinal cord injury is protective against venous thromboembolism. METHODS: A retrospective review of all cases involving chronic spinal cord injury patients who underwent plastic and reconstructive surgery operations (n = 424) and general surgery patients (n = 777) with a primary outcome of deep venous thrombosis or pulmonary embolism within 90 days of surgery was performed. RESULTS: The incidence of postoperative deep venous thrombosis in the control and spinal cord injury groups was 1.7 percent and 0.2 percent, respectively (p = 0.027). However, such significance was not observed with regard to postoperative pulmonary embolism incidence (p = 0.070). Collectively, the incidence of postoperative venous thromboembolism specifically, deep venous thrombosis or pulmonary embolism-was significantly greater in the general surgery population (p = 0.014). A nearly 10-fold increased risk of venous thromboembolism was seen among the control group (1.9 percent versus 0.2 percent) despite administration of optimal prophylaxis. CONCLUSIONS: This study demonstrates a profoundly low incidence of venous thromboembolism among chronic spinal cord injury patients compared with general surgery patients. Future efforts to elucidate how chronic spinal cord injury confers a protective mechanism may potentially influence the evolution of venous thromboembolism prevention guidelines, and spark the development of alternative prophylactic agents or customized application of prevention efforts. PMID- 27783003 TI - Barriers to Reconstructive Surgery in Low- and Middle-Income Countries: A Cross Sectional Study of 453 Cleft Lip and Cleft Palate Patients in Vietnam. AB - BACKGROUND: Despite health system advances, residents of low- and middle-income countries continue to experience substantial barriers in accessing health care, particularly for specialized care such as plastic and reconstructive surgery. METHODS: A cross-sectional household survey of patients seeking surgical care for cleft lip and/or cleft palate was completed at five Operation Smile International mission sites throughout Vietnam (Hanoi, Nghe An, Hue, Ho Chi Minh City, An Giang, and Bac Lieu) in November of 2014. RESULTS: Four hundred fifty-three households were surveyed. Cost, mistrust of medical providers, and lack of supplies and trained physicians were cited as the most significant barriers to obtaining surgery from local hospitals. There was no significant difference in household income or hospital access between those who had and had not obtained cleft surgery in the past. Fewer households that had obtained cleft surgery in the past were enrolled in health insurance (p < 0.001). Of those households/patients who had surgery previously, 83 percent had their surgery performed by a charity. Forty-three percent of participants did not have access to any other surgical cleft care and 41 percent did not have any other access to nonsurgical cleft care. CONCLUSIONS: The authors highlight barriers specific to surgery in low- and middle-income countries that have not been previously addressed. Patients rely on charitable care outside the centralized health care system; as a result, surgical treatment of cleft lip and palate is delayed beyond the standard optimal window compared with more developed countries. Using these data, the authors developed a more evidence-based framework designed to understand health behaviors and perceptions regarding reconstructive surgical care. PMID- 27783011 TI - Advances and Innovations in Microsurgery. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. summarize the evolution of perforator, chimeric, and free style flaps; 2. define and give examples of supermicrosurgery as well as understand its application in treatment of lymphedema; and 3. appreciate the development and advancements of composite tissue allotransplantation. SUMMARY: Although microsurgery may seem like a highly specialized niche within plastic surgery, it is more than just a discipline that focuses on small anastomoses. It is a tool and a way of thinking that allows us to embody the true tenets of plastic surgery, as quoted by Tagliocozzi. What began as a challenge of returning amputated tissue to the body and achieving wound closure has evolved into a refinement of technique and change in philosophy that empowers the plastic surgeon to work creatively to "restore, rebuild, and make whole." PMID- 27783015 TI - Paging Dr. Google: The Changing Face of Plastic Surgery. PMID- 27783021 TI - Plastic and Reconstructive Surgery Short Articles: How Do They Impact Our Practice? PMID- 27783014 TI - Practical Guidelines for Venous Thromboembolism Prophylaxis in Free Tissue Transfer. AB - BACKGROUND: Venous thromboembolism encompasses a spectrum of disease, ranging from asymptomatic deep vein thrombosis to fatal pulmonary embolism. As microsurgical techniques increase in complexity, the overriding benefit from a microsurgical versus a venous thromboembolism prophylactic regimen remains unclear. This study evaluated the current recommendations and procedure-specific strategies for venous thromboembolism prophylaxis with a focus on the utility of prophylaxis in microsurgical procedures. METHODS: A review was performed to identify all articles discussing the rates of venous thromboembolism in patients undergoing microsurgical procedures. Data were summarized based on body area, including hand, breast, lower extremity, and head and neck. Guidelines for venous thromboembolism prophylaxis in microsurgical cases were established. RESULTS: The available studies demonstrate a reduction in postoperative venous thromboembolism. Unfortunately, chemoprophylaxis continues to be underused throughout plastic surgery, amid concern over the risk of bleeding complications. Based on the best available data, the use of mechanical and chemoprophylaxis should be strongly considered in all microsurgical cases. A preoperative screening algorithm based on a risk-assessment model should be used in all cases to preoperatively characterize and modify risk factors when possible, and plan for perioperative prophylaxis. CONCLUSIONS: Although not completely preventable, venous thromboembolism risks can be reduced with careful preoperative planning and medical history and the judicious use of chemoprophylaxis. Because there does not appear to be an increase in the rate of postoperative bleeding when prophylaxis is administered appropriately, the use of venous thromboembolism prophylaxis should be considered in all microsurgery patients except those at extremely high risk of bleeding. PMID- 27783012 TI - Discussion: Understanding and Overcoming Implicit Gender Bias in Plastic Surgery. PMID- 27783019 TI - Reply: Detection of Perforators Using Smartphone Thermal Imaging. PMID- 27783024 TI - The History of Laparoscopic Appendicostomy With Cecoplication. PMID- 27783013 TI - Medical Student Mentorship in Plastic Surgery: The Mentor's Perspective. AB - BACKGROUND: The reproducible benefits of mentoring to mentees have been studied extensively. However, insights from the mentor perspective are less well described. This study evaluates mentorship of plastic surgery medical students from the attending surgeon's perspective. A comparison is made with a previous publication evaluating mentorship from the medical student's perspective. METHODS: An electronic survey was sent to 1025 active members of the American Council of Academic Plastic Surgeons (ACAPS) and the American Association of Plastic Surgeons (AAPS), with a combined response rate of 23 percent. For individual organizations, the response rate was 40 percent for ACAPS and 24 percent for AAPS. RESULTS: Eighty-three percent of attending surgeons reported participation in medical student mentoring. Mentor demographics and preferences were defined. The majority of mentors are men, older than 50 years, with a clinically focused, academic practice. Although scheduled, one-on-one meetings were the most preferred form of interaction, mentors generally favored group activities. Mentors also preferred to meet less frequently and in less personalized formats than mentees. Mentors perceived enhanced job satisfaction and a sense of "giving back" as most important. The most common barriers included mentor time constraints and lack of exposure to medical students. The presence of plastic surgery involvement in the medical school curriculum correlated directly with the formation of mentoring relationships. CONCLUSIONS: By comparing the perspectives on mentoring between attending surgeons and medical students, discrepancies and similarities were identified. These findings can be used to increase efficacy and strengthen mentoring efforts for medical students in plastic surgery. PMID- 27783023 TI - Single-lung ventilation and oxidative stress: a different perspective on a common practice. AB - PURPOSE OF REVIEW: To summarize what is currently known about the relationship between single-lung ventilation (SLV), oxidative stress, and postoperative disruption of organ function. RECENT FINDINGS: SLV produces progressive alelectasis that is associated with hypoxic pulmonary vasoconstriction and redistribution of blood flow away from the nonventilated lung. This local tissue hypoxia induces the generation of reactive oxygen and reactive nitrogen species, an effect subsequently amplified by lung re-expansion consistent with well described hypoxia/reperfusion responses. Both experimental and clinical data indicate that the magnitude of oxidative and nitrosative stress is related to the duration of SLV and that these stresses affect not only the collapsed/re-expanded lung, but other organs as well. SUMMARY: SLV and subsequent re-expansion of atelectatic lung are associated with the generation of reactive oxygen and nitrogen species that may modulate persistent systemic effects. PMID- 27783022 TI - New trends in interventional pulmonology. AB - PURPOSE OF REVIEW: As the field of interventional pulmonology continues to expand and develop at a rapid pace, anesthesiologists are increasingly called upon to provide well tolerated anesthetic care during these procedures. These patients may not be candidates for surgical treatment and often have multiple comorbidities. It is important for anesthesiologists to familiarize themselves with these procedures and their associated risks and complications. RECENT FINDINGS: The scope of the interventional pulmonologist's practice is varied and includes both diagnostic and therapeutic procedures. Bronchial thermoplasty is now offered as endoscopic treatment of severe asthma. Endobronchial lung volume reduction procedures are currently undergoing clinical trials and may become more commonplace. Interventional pulmonologists are performing medical thoracoscopy for the treatment and diagnosis of pleural disorders. Interventional radiologists are performing complex pulmonary procedures, often requiring anesthesia. SUMMARY: The review summarizes the procedures now commonly performed by interventional pulmonologists and interventional radiologists. It discusses the anesthetic considerations for and common complications of these procedures to prepare anesthesiologists to safely care for these patients. Investigational techniques are also described. PMID- 27783020 TI - Reply: Does the Eyebrow Sag with Aging? An Anthropometric Study of 95 Caucasians from 20 to 79 Years of Age. PMID- 27783025 TI - Early Discharge After Colorectal Resection: The Positive Impact of an Enhanced Recovery Program on a Rural Colorectal Surgery Service. AB - BACKGROUND: Enhanced recovery (ER) programs are policies and protocols meant to improve postoperative recovery after surgery. As a consequence of a smoother recovery, patients can be discharged early. This paper describes the impact of an ER program in colorectal surgery in a rural hospital. MATERIALS AND METHODS: In total, 132 patients had colorectal resection within the ER program. Data were collected prospectively. The ER pathway affects perioperative management in the following ways in order to: (1) improve patient's general condition before surgery, (2) minimize intraoperative surgical trauma by using a laparoscopic approach in all cases, and (3) facilitation of a quicker postoperative return of physiological function. RESULTS: Most (86.4%) of the patients have been operated as elective cases and for a cancer (73.5%). Laparoscopic resection was performed in 63.6% of patients, with a conversion rate of 10.6%. Total morbidity was 18.2%, leak rate was 1.5%, and 90-day mortality rate was 3%. Overall median postoperative stay was 6.5 days. Total length of in-hospital stay was lower in laparoscopic resections (5.5 d), elective cases (6 d), and in younger patients (6 d). Age and laparoscopic access were independent prognostic factors significantly associated with early discharge in elective patients. Overall readmission rate was 9.1% and this was not affected by any preoperative or intraoperative factor within those in this study. CONCLUSIONS: The ER program positively impacted the outcome of colorectal resections also in our rural setting. Discharging patients expeditiously did not affect postoperative morbidity or readmission rate. PMID- 27783027 TI - ERAS Protocol Reduces IL-6 Secretion in Colorectal Laparoscopic Surgery: Results From a Randomized Clinical Trial. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) program applied to colorectal laparoscopic surgery is well known to reduce hospitalization improving short terms outcomes. Its goal is to minimize the surgical stress response in order to maintain the physiological homeostasis altered by surgery. However, there is little knowledge about the involved dynamics in the reduction of the surgical stress that these programs allow. The primary aim of this study was to compare the level of immune and nutritional serum investigators across surgery in patients undergoing elective colorectal laparoscopic surgery within an ERAS protocol or according to a standard care program. MATERIALS AND METHODS: One hundred forty patients undergoing major colorectal laparoscopic surgery were enrolled and randomized in 2 groups (70 per arm).Cortisol, C-reactive protein (CRP), white blood cell count, prolactin, interleukin (IL)-6 levels were collected preoperatively, 1, 3, and 5 days after surgery. Transferrin, prealbumin, albumin, and triglyceride level were collected preoperatively, 1 and 5 days after surgery. Short-term outcomes were also prospectively assessed. RESULTS: IL-6 levels were lower in the ERAS group on 1, 3, and 5 days postoperatively (P<0.05). IL-6 levels in the enhanced group, differently from control group, returned to preoperative level 3 days after surgery. CRP level was lower in the enhanced group on day 1, 3, and 5 (P<0.05). There was no difference in cortisol and prolactin levels between groups. Prealbumin serum level was higher on day 5 (P<0.05) compared to standard group. CONCLUSIONS: ERAS protocol applied to colorectal laparoscopic surgery affects surgical stress response, decreasing IL-6 and CRP levels postoperatively and improving prealbumin postoperative synthesis. PMID- 27783018 TI - Detection of Perforators Using Smartphone Thermal Imaging. PMID- 27783026 TI - Combined Stent Insertion and High-intensity Focused Ultrasound Ablation for Patients With Malignant Obstructive Jaundice. AB - PURPOSE: We aimed to determine the clinical effectiveness of combined stent insertion and high-intensity focused ultrasound (HIFU) ablation for patients with malignant obstructive jaundice (MOJ). MATERIALS AND METHODS: From June 2013 to May 2015, consecutive patients with inoperable MOJ underwent biliary stent with or without HIFU ablation in our center. Treatment-related complications, stent patency time, and survival time were compared between 2 groups. RESULTS: During the enrolled time, a total of 51 patients with MOJ underwent biliary stent with HIFU ablation (n=24) or biliary stent only (n=27) in our center. There was no significant difference in baseline data between 2 groups. Relief of jaundice was achieved in all patients in both groups. Cholangitis was observed in 2 patients in stent with HIFU ablation group and 1 patient in stent only group (P=0.483). Reobstruction of stent was observed in 4 patients in stent with HIFU ablation group and 8 patients in stent only group (P=0.276). The mean stent patency time was 367+/-41 days in stent with HIFU ablation group and 257+/-35 days in stent only group (P=0.037). The mean overall survival was 238+/-31 days in stent with HIFU ablation group and 152+/-20 days in stent only group (P=0.014). CONCLUSIONS: Combined biliary stent insertion and HIFU ablation is a safe and easy method for patients with MOJ, and seems to extend stent patency time and survival when compared with biliary stent only. PMID- 27783030 TI - New anti-hepatitis B virus drugs under development and evaluation. AB - PURPOSE OF REVIEW: Although available therapies can effectively inhibit hepatitis B virus (HBV) replication in patients with active chronic hepatitis B (CHB) infection, therapeutic efficacy is limited because of potential drug resistance, and an inability to mediate viral clearance and to rectify immune impairment in CHB patients. This review will summarize the state-of-the-art for anti-HBV drugs and focus on potential drugs and targets under development and evaluation. RECENT FINDINGS: New developing drugs are evaluated for their antiviral effects in the areas of interference with the viral replication cycle, elimination of covalently closed circular DNA, modulation of host immunity and identification of the La protein and its regulator casein kinase as possible targets for the development of anti-HBV therapies. SUMMARY: These novel compounds and targets have showed great inhibitory effects on HBV replication in vitro and in animal models. Several novel therapies are promising in early clinical trials. Potentially, combination of newly developing and current antiviral drugs may cure CHB in the clinic. PMID- 27783033 TI - SNR Degradation in Undersampled Phase Measurement Systems. AB - A wide range of measuring applications rely on phase estimation on sinusoidal signals. These systems, where the estimation is mainly implemented in the digital domain, can generally benefit from the use of undersampling to reduce the digitizer and subsequent digital processing requirements. This may be crucial when the application characteristics necessarily imply a simple and inexpensive sensor. However, practical limitations related to the phase stability of the band pass filter prior digitization establish restrictions to the reduction of noise bandwidth. Due to this, the undersampling intensity is practically defined by noise aliasing, taking into account the amount of signal-to-noise ratio (SNR) reduction caused by it considering the application accuracy requirements. This work analyzes the relationship between undersampling frequency and SNR reduction, conditioned by the stability requirements of the filter that defines the noise bandwidth before digitization. The effect of undersampling is quantified in a practical situation where phase differences are measured by in-phase and quadrature (I/Q) demodulation for an infrared ranging application. PMID- 27783032 TI - Optical Fiber Temperature and Torsion Sensor Based on Lyot-Sagnac Interferometer. AB - An optical fiber temperature and torsion sensor has been proposed by employing the Lyot-Sagnac interferometer, which was composed by inserting two sections of high-birefringence (HiBi) fiber into the Sagnac loop. The two inserted sections of HiBi fiber have different functions; while one section acts as the temperature sensitive region, the other can be used as reference fiber. The temperature and twist sensor based on the proposed interferometer structure have been experimentally demonstrated. The experimental results show that the envelope of the output spectrum will shift with the temperature evolution. The temperature sensitivity is calculated to be -17.99 nm/ degrees C, which is enlarged over 12 times compared to that of the single Sagnac interferometer. Additionally, the fringe visibility of the spectrum will change due to the fiber twist, and the test results reveal that the fringe visibility and twist angle perfectly conform to a Sine relationship over a 360 degrees twist angle. Consequently, simultaneous torsion and temperature measurement could be realized by detecting the envelope shift and fringe visibility of the spectrum. PMID- 27783031 TI - Association of MTHFR, SLC19A1 Genetic Polymorphism, Serum Folate, Vitamin B12 and Hcy Status with Cognitive Functions in Chinese Adults. AB - BACKGROUND/AIM: Studies have indicated a relationship between either gene polymorphism or in vivo B vitamins' nutritional status with cognition in the elderly. However, the combined effects of MTHFR and SLC19A1gene polymorphism with serum folate and vitamin B12 levels on cognition in Chinese adult population remain unclear. METHODS: Demographic information of 426 Chinese adults aged from 55 to 90 were collected by a well designed self-administered questionnaire. The Montreal Cognitive Assessment test was utilized to evaluate the cognition status of the participants. MTHFR and SLC19A1 genotyping was analyzed using polymerase chain reaction-ligase detection reaction (PCR- LDR) method. Serum folate, vitamin B12 and homocysteine (Hcy) levels were detected by commercial assay kits. Pearson's correlation was used for data analyses and statistical significance was set at p < 0.05. RESULTS: Serum Hcylevels demonstrated a negative correlation with serum folate (r = -0.301) and vitamin B12 (r = -0.292) levels. The negative correlation found between serum Hcy levels and attention ability was observed in all 426 studied subjects (r = -0.122). Subjects with MTHFR 677 T/T and 1298 A/A genotypes demonstrated a higher serum Hcy levels (p < 0.05). Carriers of MTHFR (1298 A/C + C/C and 1793 G/A) and SLC19A1 80 G/G genotypes showed lower abstraction and delayed memory ability, respectively (p < 0.05). Subjects with MTHFR 1793 G/A genotype along with low serum folate concentration demonstrated the lowest name and orientation abilities. The effects of MTHFR 1793 G/A genotype on cognitive performance were dependent on the status of serum vitamin B12. CONCLUSION: Cognition of adults was associated with MTHFR, SLC19A1 gene polymorphism and serum Hcy levels. This study clearly establishes a combined effect of MTHFR gene polymorphism and serum B vitamins levels on cognition in Chinese adults. PMID- 27783040 TI - Sparse Reconstruction for Micro Defect Detection in Acoustic Micro Imaging. AB - Acoustic micro imaging has been proven to be sufficiently sensitive for micro defect detection. In this study, we propose a sparse reconstruction method for acoustic micro imaging. A finite element model with a micro defect is developed to emulate the physical scanning. Then we obtain the point spread function, a blur kernel for sparse reconstruction. We reconstruct deblurred images from the oversampled C-scan images based on l1-norm regularization, which can enhance the signal-to-noise ratio and improve the accuracy of micro defect detection. The method is further verified by experimental data. The results demonstrate that the sparse reconstruction is effective for micro defect detection in acoustic micro imaging. PMID- 27783039 TI - Development of an FBG Sensor Array for Multi-Impact Source Localization on CFRP Structures. AB - We proposed and studied an impact detection system based on a fiber Bragg grating (FBG) sensor array and multiple signal classification (MUSIC) algorithm to determine the location and the number of low velocity impacts on a carbon fiber reinforced polymer (CFRP) plate. A FBG linear array, consisting of seven FBG sensors, was used for detecting the ultrasonic signals from impacts. The edge filter method was employed for signal demodulation. Shannon wavelet transform was used to extract narrow band signals from the impacts. The Gerschgorin disc theorem was used for estimating the number of impacts. We used the MUSIC algorithm to obtain the coordinates of multi-impacts. The impact detection system was tested on a 500 mm * 500 mm * 1.5 mm CFRP plate. The results show that the maximum error and average error of the multi-impacts' localization are 9.2 mm and 7.4 mm, respectively. PMID- 27783036 TI - Effects of MicroRNA-23a on Differentiation and Gene Expression Profiles in 3T3-L1 Adipocytes. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate growth, development, and programmed death of cells. A newly-published study has shown that miRNA-23a could regulate 3T3-L1 adipocyte differentiation. Here, we identified miRNA-23a as a negative regulator of 3T3-L1 adipocyte differentiation again. Over-expression of miRNA-23a inhibited differentiation and decreased lipogenesis as well as down-regulated mRNA and protein expression of both peroxisome proliferator-activated receptor (PPAR) gamma and fatty acid binding protein (FABP) 4, whereas knock down of miRNA-23a showed the opposite effects on differentiation as well as increasing the number of apoptotic cells. Additionally, digital gene expression profiling sequencing (DGE-Seq) was used to assay changes in gene expression profiles following alterations in the level of miR-23a. In total, over-expression or knock down of miRNA-23a significantly changed the expression of 313 and 425 genes, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these genes were mainly involved in the stress response, immune system, metabolism, cell cycle, among other pathways. Additionally, the signal transducer and activator of transcription 1 (Stat1) was shown to be a target of miRNA-23a by computational and dual-luciferase reporter assays that indicated Janus Kinase (Jak)-Stat signal pathway was implicated in regulating adipogenesis mediated by miRNA-23a in adipocytes. PMID- 27783043 TI - Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia. AB - Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic. PMID- 27783042 TI - Translationally Controlled Tumor Protein Stimulates Dopamine Release from PC12 Cells via Ca2+-Independent Phospholipase A2 Pathways. AB - The translationally controlled tumor protein (TCTP), initially identified as a tumor- and growth-related protein, is also known as a histamine-releasing factor (HRF). TCTP is widely distributed in the neuronal systems, but its function is largely uncharacterized. Here, we report a novel function of TCTP in the neurotransmitter release from a neurosecretory, pheochromocytoma (PC12) cells. Treatment with recombinant TCTP (rTCTP) enhanced both basal and depolarization (50 mM KCl)-evoked [3H]dopamine release in concentration- and time-dependent manners. Interestingly, even though rTCTP induced the increase in intracellular calcium levels ([Ca2+]i), the rTCTP-driven effect on dopamine release was mediated by a Ca2+-independent pathway, as evidenced by the fact that Ca2+ modulating agents such as Ca2+ chelators and a voltage-gated L-type Ca2+-channel blocker did not produce any changes in rTCTP-evoked dopamine release. In a study to investigate the involvement of phospholipase A2 (PLA2) in rTCTP-induced dopamine release, the inhibitor for Ca2+-independent PLA2 (iPLA2) produced a significant inhibitory effect on rTCTP-induced dopamine release, whereas this release was not significantly inhibited by Ca2+-dependent cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2) inhibitors. We found that rTCTP-induced dopamine release from neuronal PC12 cells was modulated by a Ca2+-independent mechanism that involved PLA2 in the process, suggesting the regulatory role of TCTP in the neuronal functions. PMID- 27783044 TI - Chemical Constituents from the Aerial Parts of Cyrtopodium paniculatum. AB - We report the first phytochemical study of the neotropical orchid Cyrtopodium paniculatum. Eight new compounds, including one phenanthrene 1, one 9,10-dihydro phenanthrene 2, one hydroxybenzylphenanthrene 3, two biphenanthrenes 4-5, and three 9,10 dihydrophenanthrofurans 6-8, together with 28 known phenolic compounds, mostly stilbenoids, were isolated from the CH2Cl2 extract of its leaves and pseudobulbs. The structures of the new compounds were established on the basis of extensive spectroscopic methods. PMID- 27783045 TI - Exogenous Methyl Jasmonate and Salicylic Acid Induce Subspecies-Specific Patterns of Glucosinolate Accumulation and Gene Expression in Brassica oleracea L. AB - Glucosinolates have anti-carcinogenic properties. In the recent decades, the genetics of glucosinolate biosynthesis has been widely studied, however, the expression of specific genes involved in glucosinolate biosynthesis under exogenous phytohormone treatment has not been explored at the subspecies level in Brassica oleracea. Such data are vital for strategies aimed at selective exploitation of glucosinolate profiles. This study quantified the expression of 38 glucosinolate biosynthesis-related genes in three B. oleracea subspecies, namely cabbage, broccoli and kale, and catalogued associations between gene expression and increased contents of individual glucosinolates under methyl jasmonate (MeJA) and salicylic acid (SA) treatments. Glucosinolate accumulation and gene expression in response to phytohormone elicitation was subspecies specific. For instance, cabbage leaves showed enhanced accumulation of the aliphatic glucoiberin, progoitrin, sinigrin and indolic neoglucobrassicin under both MeJA and SA treatment. MeJA treatment induced strikingly higher accumulation of glucobrassicin (GBS) in cabbage and kale and of neoglucobrassicin (NGBS) in broccoli compared to controls. Notably higher expression of ST5a (Bol026200), CYP81F1 (Bol028913, Bol028914) and CYP81F4 genes was associated with significantly higher GBS accumulation under MeJA treatment compared to controls in all three subspecies. CYP81F4 genes, trans-activated by MYB34 genes, were expressed at remarkably high levels in all three subspecies under MeJA treatment, which also induced in higher indolic NGBS accumulation in all three subspecies. Remarkably higher expression of MYB28 (Bol036286), ST5b, ST5c, AOP2, FMOGS-OX5 (Bol031350) and GSL-OH (Bol033373) was associated with much higher contents of aliphatic glucosinolates in kale leaves compared to the other two subspecies. The genes expressed highly could be utilized in strategies to selectively increase glucosinolate compounds in B. oleracea subspecies. These results promote efforts to develop genotypes of B. oleracea and other species with enhanced levels of desired glucosinolates. PMID- 27783038 TI - Griffithsin: An Antiviral Lectin with Outstanding Therapeutic Potential. AB - Griffithsin (GRFT), an algae-derived lectin, is one of the most potent viral entry inhibitors discovered to date. It is currently being developed as a microbicide with broad-spectrum activity against several enveloped viruses. GRFT can inhibit human immunodeficiency virus (HIV) infection at picomolar concentrations, surpassing the ability of most anti-HIV agents. The potential to inhibit other viruses as well as parasites has also been demonstrated. Griffithsin's antiviral activity stems from its ability to bind terminal mannoses present in high-mannose oligosaccharides and crosslink these glycans on the surface of the viral envelope glycoproteins. Here, we review structural and biochemical studies that established mode of action and facilitated construction of GRFT analogs, mechanisms that may lead to resistance, and in vitro and pre clinical results that support the therapeutic potential of this lectin. PMID- 27783037 TI - miR-155: A Novel Target in Allergic Asthma. AB - MicroRNAs (miRNAs), a class of small non-coding RNAs of 18-24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as modulation of immune responses and oncogenesis. Previous studies have identified miR-155 as a crucial positive regulator of Th1 immune response in autoimmune diseases, but as a suppressor of Th2 immunity in allergic disorders. However, recent studies have found new evidence that miR-155 plays an indispensible role in allergic asthma. This review summarizes the recent findings with respect to miR-155 in immune responses and the underlying mechanisms responsible for miR-155-related allergic diseases, as well as the similarities between miR-155 and glucocorticoids in immunity. PMID- 27783046 TI - Original Synthesis of Fluorenyl Alcohol Derivatives by Reductive Dehalogenation Initiated by TDAE. AB - We report here a novel and easy-to-handle reductive dehalogenation of 9 bromofluorene in the presence of arylaldehydes and dicarbonyl derivatives to give the corresponding fluorenyl alcohol derivatives and Darzens epoxides as by products in tetrakis(dimethylamino)ethylene (TDAE) reaction conditions. The reaction is believed to proceed via two successive single electron transfers to generate the fluorenyl anion which was able to react with different electrophiles. A mechanistic study was conducted to understand the formation of the epoxide derivatives. PMID- 27783052 TI - Trans-Stilbenes in Commercial Grape Juices: Quantification Using HPLC Approaches. AB - Trans-stilbenes belong to the group of polyphenolic phytoalexins, and occur in many plant foods. These compounds have received great attention by researchers due to their well-known beneficial health effects. In the present study a chromatographic method that comprises the use of variable wavelength (VWD) and fluorescence (FLD) detectors in series for the analysis of trans-stilbenes is presented. The relation of peak-area obtained with both detectors is proposed as an alternative and complementary approach for the rapid identification of these phenolic compounds. The proposed method was applied to determine trans-stilbenes in commercial fruit juices. Trans-piceid was the most common trans-stilbene found in the samples analyzed. The method was validated in terms of linearity, sensitivity and repeatability. Appropriate sensitivity and good linearity (r2 > 0.9991) were achieved. PMID- 27783054 TI - Geometric Calibration and Validation of Kompsat-3A AEISS-A Camera. AB - Kompsat-3A, which was launched on 25 March 2015, is a sister spacecraft of the Kompsat-3 developed by the Korea Aerospace Research Institute (KARI). Kompsat 3A's AEISS-A (Advanced Electronic Image Scanning System-A) camera is similar to Kompsat-3's AEISS but it was designed to provide PAN (Panchromatic) resolution of 0.55 m, MS (multispectral) resolution of 2.20 m, and TIR (thermal infrared) at 5.5 m resolution. In this paper we present the geometric calibration and validation work of Kompsat-3A that was completed last year. A set of images over the test sites was taken for two months and was utilized for the work. The workflow includes the boresight calibration, CCDs (charge-coupled devices) alignment and focal length determination, the merge of two CCD lines, and the band-to-band registration. Then, the positional accuracies without any GCPs (ground control points) were validated for hundreds of test sites across the world using various image acquisition modes. In addition, we checked the planimetric accuracy by bundle adjustments with GCPs. PMID- 27783041 TI - Vitamin D and Calcium Intakes, Physical Activity, and Calcaneus BMC among School Going 13-Year Old Malaysian Adolescents. AB - BACKGROUND: Dietary calcium and vitamin D are essential for bone development. Apart from diet, physical activity may potentially improve and sustain bone health. OBJECTIVE: To investigate the relationship between the dietary intake of calcium and vitamin D, physical activity, and bone mineral content (BMC) in 13 year-old Malaysian adolescents. DESIGN: Cross-sectional. SETTING: Selected public secondary schools from the central and northern regions of Peninsular Malaysia. PARTICIPANTS: The subjects were from the Malaysian Health and Adolescents Longitudinal Research Team Cohort study (MyHeARTs). METHODS: The data included seven-day diet histories, anthropometric measurements, and the BMC of calcaneal bone using a portable broadband ultrasound bone densitometer. Nutritionist Pro software was used to calculate the dietary calcium and vitamin D intakes from the diet histories, based on the Nutrient Composition of Malaysian Food Database guidance for the dietary calcium intake and the Singapore Energy and Nutrient Composition of Food Database for vitamin D intake. RESULTS: A total of 289 adolescents (65.7% females) were recruited. The average dietary intakes of calcium and vitamin D were 377 +/- 12 mg/day and 2.51 +/- 0.12 ug/day, respectively, with the majority of subjects failing to meet the Recommended Nutrient Intake (RNI) of Malaysia for dietary calcium and vitamin D. All the subjects had a normal Z-score for the BMC (-2.00 or higher) with a mean of 0.55 +/- 0.01. From the statistical analysis of the factors contributing to BMC, it was found that for those subjects with a higher intake of vitamin D, a higher combination of the intake of vitamin D and calcium resulted in significantly higher BMC quartiles. The regression analysis showed that the BMC might have been influenced by the vitamin D intake. CONCLUSIONS: A combination of the intake of vitamin D and calcium is positively associated with the BMC. PMID- 27783034 TI - Aptamers: A New Technological Platform in Cancer Immunotherapy. AB - The renaissance of cancer immunotherapy is, nowadays, a reality. In the near future, it will be very likely among the first-line treatments for cancer patients. There are several different approaches to modulate the immune system to fight against tumor maladies but, so far, monoclonal antibodies may currently be the most successful immuno-tools used to that end. The number of ongoing clinical trials with monoclonal antibodies has been increasing exponentially over the last few years upon the Food and Drug Administration (FDA) approval of the first immune-checkpoint blockade antibodies. In spite of the proved antitumor effect of these reagents, the unleashing of the immune system to fight cancer cells has a cost, namely auto-inflammatory toxicity. Additionally, only a small fraction of all patients treated with immune-checkpoint antibodies have a clinical benefit. Taking into account all this, it is urgent new therapeutic reagents are developed with a contained toxicity that could facilitate the combination of different immune-modulating pathways to broaden the antitumor effect in most cancer patients. Based on preclinical data, oligonucleotide aptamers could fulfill this need. Aptamers have not only been successfully used as antagonists of immune checkpoint receptors, but also as agonists of immunostimulatory receptors in cancer immunotherapy. The simplicity of aptamers to be engineered for the specific delivery of different types of cargos to tumor cells and immune cells so as to harvest an efficient antitumor immune response gives aptamers a significant advantage over antibodies. In this review all of the recent applications of aptamers in cancer immunotherapy will be described. PMID- 27783049 TI - Correction: Chae, H.S., et al. Anti-Inflammatory Effects of 6,8-Diprenyl-7,4' dihydroxyflavanone from Sophora tonkinensis on Lipopolysaccharide-Stimulated RAW 264.7 Cells. Molecules. 2016, 21, 1049. AB - n/a. PMID- 27783053 TI - Development and Applications of the Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) as a Bioorthogonal Reaction. AB - The emergence of bioorthogonal reactions has greatly broadened the scope of biomolecule labeling and detecting. Of all the bioorthogonal reactions that have been developed, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is the most widely applied one, mainly because of its relatively fast kinetics and high efficiency. However, the introduction of copper species to in vivo systems raises the issue of potential toxicity. In order to reduce the copper-induced toxicity and further improve the reaction kinetics and efficiency, different strategies have been adopted, including the development of diverse copper chelating ligands to assist the catalytic cycle and the development of chelating azides as reagents. Up to now, the optimization of CuAAC has facilitated its applications in labeling and identifying either specific biomolecule species or on the omics level. Herein, we mainly discuss the efforts in the development of CuAAC to better fit the bioorthogonal reaction criteria and its bioorthogonal applications both in vivo and in vitro. PMID- 27783050 TI - Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress. AB - Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca2+ release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of kappa-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca2+ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca2+ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca2+ release and ER stress. PMID- 27783048 TI - Naturally Occurring Cinnamic Acid Sugar Ester Derivatives. AB - Cinnamic acid sugar ester derivatives (CASEDs) are a class of natural product with one or several phenylacrylic moieties linked with the non-anomeric carbon of a glycosyl skeleton part through ester bonds. Their notable anti-depressant and brains protective activities have made them a topic of great interest over the past several decades. In particular the compound 3',6-disinapoylsucrose, the index component of Yuanzhi (a well-known Traditional Chinese Medicine or TCM), presents antidepressant effects at a molecular level, and has become a hotspot of research on new lead drug compounds. Several other similar cinnamic acid sugar ester derivatives are reported in traditional medicine as compounds to calm the nerves and display anti-depression and neuroprotective activity. Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae. This overview discusses the isolation of cinnamic acid sugar ester derivatives from plants, together with a systematic discussion of their distribution, chemical structures and properties and pharmacological activities, with the hope of providing references for natural product researchers and draw attention to these interesting compounds. PMID- 27783047 TI - CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation. AB - Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1alpha transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration. PMID- 27783060 TI - Tobacco Control Progress in Low and Middle Income Countries in Comparison to High Income Countries. AB - The study aimed to describe worldwide levels and trends of tobacco control policy by comparing low and middle income countries with other income categories from 2007 to 2014 and to analyze the corresponding relation to recent changes in smoking prevalence. Policy measure data representing years 2007 to 2014 were collected from all available World Health Organization (WHO) reports on the global tobacco epidemic. Corresponding policy percentage scores (PS) were calculated based on MPOWER measures. Age-standardized smoking prevalence data for years 2010 and 2015 were collected from the WHO Global Health Observatory Data Repository. Trends of PS were analysed with respect to WHO region and OECD country income category. Scatter plots and regression analysis were used to depict the relationship between tobacco control policy of 2010 and change in smoking prevalence between 2015 and 2010 by sex and income category. Combined PS for all countries increased significantly from 47% in 2007 to 61% by 2014 (p < 0.001). When grouped by income category and region, policies were strengthened in all categories, albeit with varying progression. By 2014, tobacco control policy legislation had reached 45% in the Least Developed Countries (LDCs), 59% in Low Middle Income Countries (LMICs), 66% in Upper Middle Income Countries (UMICs) and 70% in High Income Countries (HICs). Overall, there was a negative relationship between higher policy scores and change in smoking prevalence. Although policy strengthening had been conducted between 2007 and 2014, room for considerable global improvement remains, particularly in LDCs. PMID- 27783035 TI - The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus. AB - Human cytomegalovirus is a ubiquitous beta-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an alpha herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane. PMID- 27783056 TI - Metabolic Response to XD14 Treatment in Human Breast Cancer Cell Line MCF-7. AB - XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells. The gained data sets were evaluated by several statistical methods: analysis of variance (ANOVA), clustering analysis, principle component analysis (PCA), and partial least squares discriminant analysis (PLS-DA). Cell proliferation was strongly inhibited by treatment with 50 uM XD14. Samples could be discriminated by time and XD14 concentration using PLS-DA. From the 117 identified metabolites, 67 were significantly altered after XD14 treatment. These metabolites include amino acids, fatty acids, Krebs cycle and glycolysis intermediates, as well as compounds of purine and pyrimidine metabolism. This massive intervention in energy metabolism and the lack of available nucleotides could explain the decreased proliferation rate of the cancer cells. PMID- 27783051 TI - The Efficacy of Non-Pharmacological Interventions on Brain-Derived Neurotrophic Factor in Schizophrenia: A Systematic Review and Meta-Analysis. AB - Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including schizoaffective disorder). Meta-analyses were conducted to examine the effects of NPIs on blood BDNF levels by using the standardized mean differences (SMDs) between the intervention groups and controls. In total, six randomized controlled trials with 289 participants were included. Of them, five studies used exercise, physical training or diet products. One study used cognitive training. Overall, the BDNF levels in the NPI group increased significantly compared with the control groups (SMD = 0.95, 95% confidence interval (CI) = 0.07 to 1.83, p = 0.03). Subgroup analyses indicated beneficial effects of a non-exercise intervention on peripheral BDNF levels (SMD = 0.41, 95% CI = 0.08 to 0.74, p = 0.01). Meta-regression analyses showed that the completion rate influenced the variation in SMD (p = 0.01). Despite insufficient evidence to draw a conclusion, our results suggest that use of NPIs as adjunctive treatments, specifically non-exercise interventions, may affect positively serum or plasma BDNF in patients with schizophrenia. PMID- 27783059 TI - The Other Side: How does Informed Choice Affect Induced Abortions among Reproductive-Age Immigrant Women in China-A Cross-Sectional Study. AB - This study attempted to explore how informed choice on contraceptive methods influenced induced abortions among reproductive-age immigrant women in China. A total of 3230 participants were recruited in Beijing, Shanghai, and Chongqing. Information on informed choice was collected by questionnaires. The annual incidence rate (spells) of induced abortions was 0.46 (1500/3230) among the participants. The sequence from the highest score to the lowest was long-term, short-term and natural contraceptive methods (p < 0.0001). Significant differences of rates in induced abortions were found in region, occupation, length of the first immigration up to now (year), purpose for immigration, number of children, marital status, sex preference, contraceptive methods, deciders of contraceptive methods and side effects. In the zero-inflated negative binomial model, the joint impacts showed when a participant with one child employed condoms or family planning service providers as the deciders of contraceptive methods introduced intrauterine devices, the occurrence of induced abortions was more likely to be reduced. Women who underwent side effects using pills were more likely to have had induced abortions. PMID- 27783061 TI - UV "Indices"-What Do They Indicate? AB - Ultra-Violet (UV) radiation covers the spectrum of wavelengths from 100 to 400 nm. The potency and biological activity for a variety of endpoints differ by wavelength. For monitoring and communication purposes, different UV action spectra have been developed. These spectra use different weighting functions. The action spectrum for erythemal dose is the most widely used one. This erythemal dose per time or dose-rate has been further simplified into a "UV index". Following this example, in our review we use the term "index" or (plural) "indices" in a more general description for all simplified single-value measures for any biologically effective UV dose, e.g., for human non-melanoma skin cancer and for previtamin D production rate. Ongoing discussion about the existence of an increased melanoma risk due to UV-A exposure underscores the uncertainties inherent in current weighting functions. Thus, we performed an online literature search to review the data basis for these indices, to understand their relevance for an individual, and to assess the applicability of the indices for a range of exposure scenarios. Even for natural (solar) UV, the spectral composition varies spatially and temporally. Artificial UV sources and personal protection introduce further variation to the spectral composition. Many biological effects are proposed for UV radiation. Only few endpoints have been studied sufficiently to estimate a reliable index. Weighting functions for chronic effects and most importantly for cancer endpoints have been developed in animal models, and often for proxy endpoints only. Epidemiological studies on biological effects of UV radiation should not only depend on single-value weighted UV dose estimates (indexes) but should strive for a more detailed description of the individual exposure. A better understanding of the adverse and beneficial effects of UV radiation by wavelength would also improve medical counseling and health communication regarding individual health-supportive behavior. PMID- 27783055 TI - Melatonin as a Potential Agent in the Treatment of Sarcopenia. AB - Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered. PMID- 27783070 TI - Enhancement in the electrochemical performance of zirconium/phosphate bi functional coatings on LiNi0.8Co0.15Mn0.05O2 by the removal of Li residuals. AB - The effect of bi-functional coatings consisting of Zr and phosphate (P) on the electrochemical performance of Li1.0Ni0.8Co0.15Mn0.05O2 (NCM) has been investigated. The presence of various types of Zr and P compounds such as oxides (ZrO2 and Li2ZrO3) and phosphates (Zr2P2O9, ZrP2O7 and LiZr2(PO4)3) in the coating was confirmed by experiments as well as density functional theory (DFT) calculations. When the NCM samples were coated with the Zr/P hybrid material, the cycle retention and the amount of removed Li residuals (LiOH, Li2CO3) were enhanced by the synergistic effect from Zr and P. The NCM sample coated with a Zr/P layer with a Zr/P ratio of 1 : 1 exhibited an increase in the initial capacity (209.3 mA h g-1) compared to the pristine sample (207.4 mA h g-1) at 0.1C, owing to the formation of the coating layer. The capacity retention of the Zr/P coated sample (92.4% at the 50th cycle) was also improved compared to that of the pristine NCM sample (90.6% at the 50th cycle). Moreover, the amount of Li residuals in the Zr/P coated NCM sample was greatly reduced from 3693 ppm (pristine NCM) to 2525 ppm (Zr/P = 5 : 5). PMID- 27783069 TI - An atomistic view on carbocyanine photophysics in the realm of RNA. AB - Carbocyanine dyes have a long-standing tradition in fluorescence imaging and spectroscopy, due to their photostability and large spectral separation between individual dye species. Herein, we explore the versatility of cyanine dyes to probe the dynamics of nucleic acids and we report on the interrelation of fluorophores, RNA, and metal ions, namely K+ and Mg2+. Photophysical parameters including the fluorescence lifetime, quantum yield and dynamic anisotropy are monitored as a function of the nucleic acid composition, conformation, and metal ion abundance. Occasional excursions to a non-fluorescent cis-state hint at the remarkable sensitivity of carbocyanines to their local environment. Comparison of time-correlated single photon experiments with all-atom molecular dynamics simulations demonstrate that the propensity of photoisomerization is dictated by sterical constraints imposed on the fluorophore. Structural features in the vicinity of the dye play a crucial role in RNA recognition and have far-reaching implications on the mobility of the fluorescent probe. An atomic level description of the mutual interactions will ultimately benefit the quantitative interpretation of single-molecule FRET measurements on large RNA systems. PMID- 27783066 TI - The search for imaging biomarkers in psychiatric disorders. AB - The field of medicine is moving toward the use of biomarkers for the optimization of individualized care. This is a particular challenge for the field of psychiatry, in which diagnosis is based on a descriptive collection of behaviors without the availability of any objective test to stratify patients. Neuroimaging techniques such as molecular imaging with positron-emission tomography (PET) or structural and functional magnetic resonance imaging (MRI) provide an opportunity to bring psychiatry from an era of subjective descriptive classification into objective and tangible brain-based measures. Here we provide steps toward the development of robust, reliable and valid biomarkers. The success of such development is crucial because it will enable the field of psychiatry to move forward into the era of modern medicine. PMID- 27783064 TI - The implications of the shared genetics of psychiatric disorders. AB - Recent genomic studies have revealed the highly polygenic nature of psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. Many of the individual genetic associations are shared across multiple disorders in a way that points to extensive biological pleiotropy and further challenges the biological validity of existing diagnostic approaches. Here we argue that the existence of risk alleles specific to a single diagnostic category is unlikely. We also highlight some of the important clinical repercussions of pleiotropy. PMID- 27783063 TI - Family Affluence and the Eating Habits of 11- to 15-Year-Old Czech Adolescents: HBSC 2002 and 2014. AB - Socioeconomic inequalities in eating habits have a profound impact on the health of adolescents. The aim of the present study was to evaluate socioeconomic disparities in the eating habits of Czech adolescents and to compare their change between 2002 and 2014. The data from the Czech Health Behavior in School-aged Children (HBSC) study conducted in 2002 and 2014 was utilized. The Family Affluence Scale (FAS) was used to assess socioeconomic disparities. Higher odds of daily consumption of fruit (2002: OR = 1.67; 2014: OR = 1.70, p < 0.001) and vegetables (2002: OR = 1.54; 2014: OR = 1.48, p < 0.001) were associated with high FAS in both genders. Adolescents with higher FAS were less likely to consume sweets (2002: OR = 0.72, p < 0.05) and more likely to eat breakfast on weekdays (2014: OR = 1.19, p < 0.05). In 2002 and 2014, the data showed lower odds of daily consumption of soft drinks (Low: OR = 0.47; Medium: OR = 0.43; High: OR = 0.41, p < 0.001), fruit (Low: OR = 0.73; Medium: OR = 0.74, p < 0.001; High: OR = 0.75, p < 0.05), sweets (Low: OR = 0.71; Medium: OR = 0.79, p < 0.001) and breakfast on weekends (High: OR = 0.70, p < 0.05), and a higher likelihood of eating breakfast on weekdays (Low: OR = 1.26, p < 0.01; Medium: OR = 1.13, p < 0.05). These findings play an important role in future public measures to improve dietary habits and decrease social inequalities in youth. PMID- 27783075 TI - Counterbalancing of morphology and conductivity of poly(3,4 ethylenedioxythiophene) polystyrene sulfonate based flexible devices. AB - The importance of conductive polymer electrodes with a balance between the morphology and electrical conductivity for flexible organic photovoltaic properties has been demonstrated. Highly transparent PEDOT:PSS anodes with controlled conductivity and surface properties were realized by insertion of dimethyl sulfoxide (DMSO) and a fluorosurfactant (Zonyl) as efficient additives and used for flexible organic photovoltaic cells (OPVs) which are based on a bulk heterojunction of polythieno[3,4-b]-thiophene-co-benzodithiophene (PTB7):[6,6]phenyl-C71-butyric acid methyl ester (PC71BM). We investigated the correlation between the electrical properties of PEDOT:PSS electrodes and their influences on the surface morphology of the active materials (PTB7:PC71BM). When the device was prepared from the PEDOT:PSS layer functioning as an anode of OPV through an optimized ratio of 5 vol% of DMSO and 0.1 wt% of fluorosurfactant, the devices exhibited improved fill factor (FF) due to the enhanced coverage of PEDOT:PSS films. These results correlate with reduced photoluminescence and increased charge extraction as seen through Raman spectroscopy and electrical analysis, respectively. The conductive polymer electrode with the balance between the morphology and electrical conductivity can be a useful replacement for brittle electrodes such as those made of indium tin oxide (ITO) as they are more resistant to cracking and bending conditions, which will contribute to the long term operation of flexible devices. PMID- 27783062 TI - Is Pedometer-Determined Physical Activity Decreasing in Czech Adults? Findings from 2008 to 2013. AB - Objective measured trend data are important for public health practice. However, these data are rare for an adult population. Therefore, the aim of this study was to describe time trends in pedometer-determined physical activity of Czech adults (25-65 years) from 2008 to 2013. Participants were Czech national citizens whose physical activity was assessed objectively using a Yamax Digiwalker SW-700 pedometer (Yamax Corporation, Tokyo, Japan) for seven consecutive days in the period 2008 to 2013. The final sample was 4647 Czech adults [M age 41.4 +/- 10 years; M body mass index (BMI) 25.1 +/- 3.7 kg/m2]. The results showed that men took more steps/day (M (Mean) = 10,014; 95% CI (Confidence Interval) = 9864 10,164) than women (M = 9448; 95% CI = 9322-9673) in all age and BMI groups. Mean steps/day declined from 2008 to 2013 by 852 steps/day in men and 1491 steps/day in women. In the whole sample, the proportion of participants who had a sedentary lifestyle (<5000 steps/day) increased by 5.8%; the proportion taking >=10,000 steps/day decreased by 15.8%. In 2013, men and women were 2.67 and 2.05 times, respectively, more likely to have a physically inactive lifestyle (<7500 steps/day) than in 2008. Conversely, in 2008, men and women were 1.68 and 2.46 times, respectively, less likely to have very active lifestyle (>12,500 steps/day). In conclusion, this study suggests that there has been a substantial reduction in physical activity in Czech adults over time. PMID- 27783058 TI - Ubiquitin in Influenza Virus Entry and Innate Immunity. AB - Viruses are obligatory cellular parasites. Their mission is to enter a host cell, to transfer the viral genome, and to replicate progeny whilst diverting cellular immunity. The role of ubiquitin is to regulate fundamental cellular processes such as endocytosis, protein degradation, and immune signaling. Many viruses including influenza A virus (IAV) usurp ubiquitination and ubiquitin-like modifications to establish infection. In this focused review, we discuss how ubiquitin and unanchored ubiquitin regulate IAV host cell entry, and how histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase with ubiquitin-binding activity, mediates IAV capsid uncoating. We also discuss the roles of ubiquitin in innate immunity and its implications in the IAV life cycle. PMID- 27783071 TI - Synthesis, structural characterization and catalysis of ruthenium(ii) complexes based on 2,5-bis(2'-pyridyl)pyrrole ligand. AB - Treatment of the 2,5-bis(2'-pyridyl)pyrrolato (PDP-) anion with {Ru(COD)Cl2}n in THF readily yielded [Ru(PDP)(COD)Cl] (1) in almost quantitative yield. Anion metathesis of 1 in organic solvent by NO3- and OTf- (OTf- = triflato) gave [Ru(PDP)(COD)(NO3)] (2) and [Ru(PDP)(COD)(OTf)] (3), and in aqueous solution by BF4- and PF6- afforded aqueous complexes [Ru(PDP)(COD)(H2O)](BF4) (4+.BF4-) and [Ru(PDP)(COD)(H2O)](PF6) (4+.PF6-), respectively. Treatment of 1 with PhICl2 in CH2Cl2 afforded 5 with halogenated pyrrole. These complexes exhibit similar structure, including one Ru(ii) atom, one 2,5-bis(2'-pyridyl)pyrrole and one monodentate anion or aqua ligand. Each Ru(ii) tightly binds to three adjacent coplanar sites of PDP- ligand to form a meridional configuration. Complex 1 with NaIO4 as the oxidant in EtOAc-CH3CN-H2O (ratio = 3 : 1 : 2) proved to be highly effective in the catalytic oxidation of olefins to carbonyl products. PMID- 27783057 TI - Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack. AB - Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM+/CK+) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a "surrogate" of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well. PMID- 27783065 TI - The promises and challenges of human brain organoids as models of neuropsychiatric disease. AB - Neuropsychiatric disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ) and bipolar disorder (BPD) are of great societal and medical importance, but the complexity of these diseases and the challenges of modeling the development and function of the human brain have made these disorders difficult to study experimentally. The recent development of 3D brain organoids derived from human pluripotent stem cells offers a promising approach for investigating the phenotypic underpinnings of these highly polygenic disorders and for understanding the contribution of individual risk variants and complex genetic background to human pathology. Here we discuss the advantages, limitations and future applications of human brain organoids as in vitro models of neuropsychiatric disease. PMID- 27783077 TI - Apricot and other seed stones: amygdalin content and the potential to obtain antioxidant, angiotensin I converting enzyme inhibitor and hypocholesterolemic peptides. AB - Stones from olives and Prunus genus fruits are cheap and sustainable sources of proteins and could be potential sources of bioactive peptides. The main limitation to the use of these seeds is the presence of amygdalin. This work proposes to determine amygdalin in olive and Prunus seeds and in protein isolates obtained from them. Moreover, antioxidant, angiotensin I converting enzyme (ACE) inhibitor, and hypocholesterolemic properties will be evaluated in hydrolysates obtained from these seeds. Despite some seeds contained amygdalin, all protein isolates were free of this substance. Two different procedures to obtain bioactive peptides from protein isolates were examined: gastrointestinal digestion and processing with Alcalase, Flavourzyme or Thermolysin. Higher antioxidant, ACE inhibitor and hypocholesterolemic activities were observed when proteins were processed with Alcalase, Flavourzyme or Thermolysin. The highest antioxidant and ACE inhibitor capacities were observed for the Prunus genus seed hydrolysates while the highest capacity to reduce micellar cholesterol solubility was observed for the apricot and olive seed hydrolysates. PMID- 27783084 TI - A plasmonic multi-logic gate platform based on sequence-specific binding of estrogen receptors and gold nanorods. AB - A hybrid system made of gold nanorods (AuNRs) and double-stranded DNA (dsDNA) is used to build a versatile multi-logic gate platform, capable of performing six different logic operations. The sequence-specific binding of transcription factors to the DNA drives the optical response of the design. PMID- 27783068 TI - Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis. AB - People diagnosed with neuropsychiatric disorders such as depression, anxiety, addiction or schizophrenia often have dysregulated memory, mood, pattern separation and/or reward processing. These symptoms are indicative of a disrupted function of the dentate gyrus (DG) subregion of the brain, and they improve with treatment and remission. The dysfunction of the DG is accompanied by structural maladaptations, including dysregulation of adult-generated neurons. An increasing number of studies using modern inducible approaches to manipulate new neurons show that the behavioral symptoms in animal models of neuropsychiatric disorders can be produced or exacerbated by the inhibition of DG neurogenesis. Thus, here we posit that the connection between neuropsychiatric disorders and dysregulated DG neurogenesis is beyond correlation or epiphenomenon, and that the regulation of adult-generated DG neurogenesis merits continued and focused attention in the ongoing effort to develop novel treatments for neuropsychiatric disorders. PMID- 27783089 TI - Persistent Corneal Edema Associated With Subconjunctival 5-fluorouracil in an Infant With Primary Congenital Glaucoma. AB - A 3-month-old boy with primary congenital glaucoma developed a transient corneal endothelial opacity after needle bleb revision with adjunctive 5-fluorouracil. This case presents a rare toxicity that, although transient, is concerning due to the potential of amblyopia. The authors review prior cases of corneal opacity associated with 5-fluorouracil. [J Pediatr Ophthalmol Strabismus. 2016;53:e54 e57.]. PMID- 27783080 TI - A new multi-scale method to reveal hierarchical modular structures in biological networks. AB - Biological networks are effective tools for studying molecular interactions. Modular structure, in which genes or proteins may tend to be associated with functional modules or protein complexes, is a remarkable feature of biological networks. Mining modular structure from biological networks enables us to focus on a set of potentially important nodes, which provides a reliable guide to future biological experiments. The first fundamental challenge in mining modular structure from biological networks is that the quality of the observed network data is usually low owing to noise and incompleteness in the obtained networks. The second problem that poses a challenge to existing approaches to the mining of modular structure is that the organization of both functional modules and protein complexes in networks is far more complicated than was ever thought. For instance, the sizes of different modules vary considerably from each other and they often form multi-scale hierarchical structures. To solve these problems, we propose a new multi-scale protocol for mining modular structure (named ISIMB) driven by a node similarity metric, which works in an iteratively converged space to reduce the effects of the low data quality of the observed network data. The multi-scale node similarity metric couples both the local and the global topology of the network with a resolution regulator. By varying this resolution regulator to give different weightings to the local and global terms in the metric, the ISIMB method is able to fit the shape of modules and to detect them on different scales. Experiments on protein-protein interaction and genetic interaction networks show that our method can not only mine functional modules and protein complexes successfully, but can also predict functional modules from specific to general and reveal the hierarchical organization of protein complexes. PMID- 27783083 TI - Extra virgin olive oil: a key functional food for prevention of immune inflammatory diseases. AB - Nowadays, it is clear that an unhealthy diet is one of the prime factors that contributes to the rise of inflammatory diseases and autoimmunity in the populations of both developed and developing countries. The Mediterranean diet has been associated with a reduced incidence of certain pathologies related to chronic inflammation and the immune system. Olive oil, the principal source of dietary lipids of the Mediterranean diet, possesses a high nutritional quality and a particular composition, which is especially relevant in the case of Extra Virgin Olive Oil (EVOO). EVOO is obtained from olives solely by mechanical or other physical preparation methods, under conditions that do not alter the natural composition. EVOO is described as a key bioactive food with multiple beneficial properties and it may be effective in the management of some immune inflammatory diseases. In this review, the key research is summarised which provides evidence of the beneficial effects of EVOO and its minor components focusing on their mechanisms on immune-inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and sclerosis. PMID- 27783090 TI - Dual Intravitreal Injections With Foscarnet and Ganciclovir for Ganciclovir Resistant Recurrent Cytomegalovirus Retinitis in a Congenitally Infected Infant. AB - Resistant strains of cytomegalovirus can be difficult to treat in cases of congenital cytomegalovirus retinitis. The authors describe a case of recurrent bilateral congenital cytomegalovirus retinitis in an immunocompetent newborn with ganciclovir resistance successfully treated uniquely with dual therapy of intravenous ganciclovir and foscarnet and dual intravitreal injections with ganciclovir and foscarnet. [J Pediatr Ophthalmol Strabismus. 2016;53:e58-e60.]. PMID- 27783092 TI - Development of Monofixation Syndrome After Extraction of Dense Cataracts. AB - PURPOSE: If the interruption of macular fusion for an extended period of time is the key event that results in the development of monofixation syndrome, then the decreased macular input caused by dense cataracts may cause monofixation syndrome in adults. This study was designed to test this hypothesis. METHODS: The study design was a retrospective chart review that identified patients with unilateral cataracts at two southern Louisiana medical centers. Patients were assigned to the dense cataract group if a unilateral cataract had been present for at least 3 months and led to a visual acuity of worse than 20/200. Patients in the control group had a unilateral cataract for more than 3 months and visual acuity better than 20/200 in the affected eye. Stereoacuity was assessed using the Titmus or Randot stereo test. A Worth 4-dot test viewed at a distance of 20 feet was used to assess the presence of a macular scotoma. The criteria for monofixation syndrome were met if stereoacuity was less than 60 seconds and the Worth 4-dot test demonstrated central macular scotoma at 20 feet. RESULTS: The dense cataract group's association with monofixation syndrome was statistically significant when compared to the control group (P < .0001). CONCLUSIONS: This study adds dense adult-onset cataracts to the list of causes of monofixation syndrome and reduced stereoacuity. A delay in treating dense lens opacities can result in good visual outcome but an inferior binocular visual outcome (poor stereoacuity). [J Pediatr Ophthalmol Strabismus. 2017;54(1):39-42.]. PMID- 27783102 TI - ? PMID- 27783091 TI - Primary and Secondary Intraocular Lens Implantations in Children With Pediatric Cataract: Visual Acuity and Strabismus at the Age of 2 Years and Older. AB - PURPOSE: To compare the visual outcomes of primary and secondary intraocular lens (IOL) implantations and to identify the risk factors for the development of strabismus in patients with pediatric cataract. METHODS: The records of the pediatric patients who had undergone cataract surgery between January 1999 and November 2014 were reviewed retrospectively. The results of the cases with cataract extraction with primary IOL implantation (primary group) and cases with secondary IOL implantation (secondary group) were compared and the risk factors for the development of strabismus were investigated. RESULTS: This study included 220 eyes of 148 patients who had surgery for pediatric cataract. The mean age of the patients was 6.84 +/- 3.45 years (range: 2 to 17 years) for the primary group at the time of cataract extraction and primary posterior chamber IOL implantation and 8.92 +/- 5.12 years (range: 2 to 18 years) for the secondary group at the time of secondary IOL implantation (P = .118). Strabismus developed in 28 patients (23.73%) in the primary group and 9 patients (30%) in the secondary group (P = .702). At the last postoperative examination, Snellen visual acuity was 0.44 and 0.28 for the primary and secondary groups, respectively (P = .013). There was a negative relationship between visual acuity and the development of strabismus (P = .048), whereas there was a positive relationship between the follow-up period and the development of strabismus (P = .008). CONCLUSIONS: Optic rehabilitation of the pediatric cataract is an important factor in the development of strabismus. These cases should be monitored closely. [J Pediatr Ophthalmol Strabismus. 2017;54(2):97-102.]. PMID- 27783093 TI - The Incidence of Reoperation and Related Risk Factors Among Patients With Infantile Exotropia. AB - PURPOSE: To determine the incidence and related risk factors of reoperation among patients with infantile exotropia who were operated on at Imam Hossein Medical Center, Tehran, Iran, from 2001 to 2015. METHODS: In this study, 82 children (55 girls and 27 boys) with infantile exotropia were divided into two groups 3 months after their first operation: children with horizontal deviation of 10 prism diopters (PD) or less (n = 64; success group) and those with horizontal deviation greater than 10 PD (n = 18; failure group). Patients with deviation of 20 PD or greater were indicated for reoperation. Factors including age at the first operation, preoperative angle of deviation, inferior oblique muscle overaction, dissociated vertical deviation, and A- or V-pattern in relation to reoperation were studied. Sensory status of children older than 5 years was also evaluated using Worth 4-dot and Titmus tests. RESULTS: Reoperation was indicated in 18.3% (n = 15) of patients after 11.5 +/- 19 months of follow-up. Preoperative angle of deviation (P < .001) and surgical approach (P = .017) were statistically different between the failure and success groups. The majority of patients (71%) achieved fusion and gross stereopsis (< 3,000 seconds of arc) after surgery. CONCLUSIONS: According to the results, 18.3% of patients with infantile exotropia, especially those with more preoperative exotropia, needed reoperation to achieve good alignment. Although the recession-resection method had better motor results, the authors could not recommend it as a first operation for all patients with infantile exotropia because it was only performed on patients with amblyopia. Gross stereopsis and binocular fusion were seen in the majority of patients. [J Pediatr Ophthalmol Strabismus. 2017;54(1):22-30.]. PMID- 27783067 TI - Developmental timing and critical windows for the treatment of psychiatric disorders. AB - There is a growing understanding that pathological genetic variation and environmental insults during sensitive periods in brain development have long term consequences on brain function, which range from learning disabilities to complex psychiatric disorders such as schizophrenia. Furthermore, recent experiments in animal models suggest that therapeutic interventions during sensitive periods, typically before the onset of clear neurological and behavioral symptoms, might prevent or ameliorate the development of specific pathologies. These studies suggest that understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is crucial for the development of effective therapies. In this Perspective, I explore the emerging concept of developmental windows in psychiatric disorders, their relevance for understanding disease progression and their potential for the design of new therapies. The limitations and caveats of early interventions in psychiatric disorders are also discussed in this context. PMID- 27783094 TI - Outcomes of Two Surgical Techniques Using Silicone Rod for Frontalis Sling Suspension to Treat Severe Ptosis. AB - PURPOSE: To compare outcomes of two techniques of frontalis silicone sling surgery. METHODS: This retrospective, nonrandomized chart review was performed on patients undergoing frontalis sling surgery between 2008 and 2011. Silicone rods were sutured to the tarsal plate through an eyelid crease incision (open method) or stab incisions (closed method). Data were collected on age, gender, type of surgery, preoperative and postoperative margin reflex distance (MRD), and complications. A successful outcome was defined as a postoperative score of 2 to 4 for MRD or an improvement in MRD. RESULTS: A total of 155 eyelids of 146 patients with ptosis were included. There were 60 patients in the open method group and 85 patients in the closed method group, respectively. Successful outcomes were seen in 30 (50%) patients in the open method and 44 (51.8%) patients in the closed method groups. There were 61 (71.8%) patients in the open method group and 45 (75%) patients in the closed method group who had improved MRD at last follow-up. The main complications were exposure keratitis, eyelash ptosis, and eyelid crease abnormalities that occurred only in the closed method group. CONCLUSIONS: The silicone frontalis sling procedure had the same success rates in both the open and closed methods. Eyelash and eyelid crease abnormalities were unique to the closed method. [J Pediatr Ophthalmol Strabismus. 2017;54(1):52-58.]. PMID- 27783095 TI - Fractional flow reserve derived by coronary computed tomography angiography : A sophisticated analysis method for detecting hemodynamically significant coronary stenosis. PMID- 27783101 TI - Bridging the silos in HIV and Hepatitis C prevention: a cross-provincial qualitative study. AB - OBJECTIVES: The Our Youth Our Response (OYOR) study explored the scope and accessibility of existing youth-oriented human immunodeficiency virus (HIV) and Hepatitis C (HCV) prevention in Atlantic Canada. METHODS: A cross-provincial, qualitative population health and gender-based analytic approach was used in this study. Four hundred and twenty-five documents were part of the initial scoping review, while 47 in-depth interviews across youth-relevant sectors were undertaken to explore the perceptions related to current approaches to youth oriented HIV/HCV prevention policies and programs. The study also conducted focus group discussions with 21 key informants aimed at identifying strategies to address the challenges identified from the interview data. RESULTS: Five overarching themes emerged from our triangulated data in relation to the present state of youth-related HIV/HCV prevention. These included: inter-organizational and intersectoral collaboration; youth engagement; access to testing; harm reduction; and education. CONCLUSIONS: Our findings will assist in informing the next generation for HIV/HCV prevention aimed at youth. Specifically, the results indicate that future prevention initiatives should support the use of intersectoral collaboration, gender-based approaches, and HIV/HCV testing innovation to help de-stigmatize prevention efforts. PMID- 27783109 TI - Combination of zero-valent iron and anaerobic microorganisms immobilized in luffa sponge for degrading 1,1,1-trichloroethane and the relevant microbial community analysis. AB - 1,1,1-Trichloroethane (1,1,1-TCA), a dense non-aqueous phase liquid (DNAPL), is relatively slow to remediate naturally; combination of zero-valent iron and immobilized microorganism is a potential means to accelerate DNAPL biodegradation. We first adopted high density luffa sponge (HDLS) as immobilized microorganism carrier. The experimental results demonstrated that (1) the supernatant liquid microorganisms were the optimal immobilized microorganisms for HDLS and (2) the combination of zero-valent iron and immobilized microorganisms accelerated 1,1,1-TCA transformation. Furthermore, in the long-term remediation process, anaerobic microorganisms produced reductant H2S which was beneficial to zero-valent iron PRBs. Through further study of the microbial community, we found that majority of the sulfate-reducing bacteria (SRB) perfectly adapted to the process of 1,1,1-TCA co-metabolism dechlorination. Desulfobulbus and Desulfococcus potentially were the special SRB that contributed significantly to TCA co-metabolism. Additionally, 1,1,1-TCA induced the generation of new SRB and stimulated the growth of majority of dominating methanogens. The results indicated that they played a constructive role in accelerating the dechlorination of 1,1,1-TCA, reduction of sulfate, and improving the production of CH4. Consequently, combination of zero-valent iron and immobilized microorganisms for remediating groundwater by contaminated 1,1,1-TCA is a sustainable and green remediation technology. Especially for groundwater of SO42- type contaminated by 1,1,1-TCA, in the long-term course of combination degradation, cyclic utilization of H2S to prolong the service life of zero-valent iron PRBs. H2 and CH4 generated to capture as potential energy resource. Based on this, a tentative reaction mechanism for Fe0 biodegradation of 1,1,1-TCA was proposed. PMID- 27783103 TI - Changes in pulmonary function and influencing factors after high-dose intrathoracic radio(chemo)therapy. AB - PURPOSE: Using prospectively collected patient-related, dose-related, and pulmonary function test (PFT) data before radiotherapy (RT) and at several follow up visits after RT, the time course of PFT changes after high-dose radio(chemo)therapy and influencing factors were analyzed. MATERIALS AND METHODS: From April 2012 to October 2015, 81 patients with non-small-cell lung carcinoma (NSCLC), small cell lung carcinoma (SCLC), or esophageal carcinoma where treated with high-dose radio(chemo)therapy. PFT data were collected before treatment and 6 weeks, 12 weeks, and 6 months after RT. The influence of patient- and treatment related factors on PFT was analyzed. RESULTS: Mean forced expiratory volume in 1 s (FEV1) constantly declined during follow-up (p = 0.001). In total, 68% of patients had a reduced FEV1 at 6 months. Mean vital capacity (VC) didn't change during follow-up (p > 0.05). Mean total lung capacity (TLC) showed a constant decline after RT (p = 0.026). At 6 months, 60% of patients showed a decline in VC and 73% in TLC. The mean diffusion capacity for carbon monoxide (DLCO) declined at 6 and 12 weeks, but recovered slightly at 6 months (p < 0.0005). At 6 months, 86% of patients had a reduced DLCO. After treatment, the partial pressure of CO2 in the blood (pCO2) was increased and pO2 was decreased (p > 0.05). Only the pretreatment PFT classification had a significant influence on the post-RT FEV1. CONCLUSION: DLCO seems to be the most reliable indicator for lung tissue damage after thoracic RT. Ventilation parameters appear to be less reliable. Concerning patient- or treatment-related factors, no reliable conclusion can be drawn regarding which factors may be relevant. PMID- 27783098 TI - [Degenerative cerebellar diseases and differential diagnoses]. AB - CLINICAL/METHODICAL ISSUE: Cerebellar syndromes result in distinct clinical symptoms, such as ataxia, dysarthria, dysmetria, intention tremor and eye movement disorders. STANDARD RADIOLOGICAL METHODS: In addition to the medical history and clinical examination, imaging is particularly important to differentiate other diseases, such as hydrocephalus and multi-infarct dementia from degenerative cerebellar diseases. Degenerative diseases with cerebellar involvement include Parkinson's disease, multiple system atrophy as well as other diseases including spinocerebellar ataxia. ACHIEVEMENTS: In addition to magnetic resonance imaging (MRI), nuclear medicine imaging investigations are also helpful for the differentiation. PRACTICAL RECOMMENDATIONS: Axial fluid-attenuated inversion recovery (FLAIR) and T2-weighted sequences can sometimes show a signal increase in the pons as a sign of degeneration of pontine neurons and transverse fibers in the basilar part of the pons. The imaging is particularly necessary to exclude other diseases, such as normal pressure hydrocephalus (NPH), multi infarct dementia and cerebellar lesions. PMID- 27783106 TI - Critical considerations on the predictive value of end-of-treatment FDG-PET in lymphoma. PMID- 27783110 TI - [Arthrodesis of the proximal interphalangeal joint of fingers with tension band wire]. AB - OBJECTIVE: Arthrodesis of the proximal interphalangeal joint of fingers in a functional and pain-free position. INDICATIONS: Primary and secondary osteoarthritis, traumatic joint destruction, posttraumatic malposition, instability, joint destruction due to infection, irreparable extensor and/or flexor tendon lesion, recurrent flexion deformity in Dupuytren's disease, arthritis (e. g., rheumatoid arthritis, psoriatic arthritis), failed resection arthroplasty, failed prosthesis, congenital disorder (e. g., camptodactyly). CONTRAINDICATIONS: Persistent joint infection. SURGICAL TECHNIQUE: Resection of the proximal phalanx head and the middle phalanx base, arthrodesis with figure-of eight tension band wire in a functional position. POSTOPERATIVE MANAGEMENT: Plaster of Paris cast with arthrodesis position of the affected finger and intrinsic plus position of at least one adjacent finger for 2 weeks, custom-made finger splint for 4 weeks. RESULTS: A total of 15 of 16 patients with an arthrodesis of the proximal interphalangeal finger joint of the dominant hand by tension band wire were followed up after an average of 31 months. None was affected by the arthrodesis in everyday live. All patients were very satisfied with the result. Nine of 15 patients were free of pain both at rest and with activity. The average DASH score was 48 points. Grip strength averaged 29 kg, 7 % stronger than the contralateral hand. PMID- 27783114 TI - Mercury in the Blue Marlin (Makaira nigricans) from the Southern Gulf of California: Tissue Distribution and Inter-Annual Variation (2005-2012). AB - With the aim of knowing annual variations of Hg concentrations in muscle and liver of blue marlin (Makaira nigricans) from the southern Gulf of California, fish were collected between 2005 and 2012 in three areas. In general, Hg levels were more elevated in liver than in muscle. Variations of Hg concentrations in muscle and liver among the studied years were not significant. Hg levels in muscle and liver increased significantly with length and weight of fish. In comparison to other studies, Hg levels in muscle and liver were lower. With respect to maximum permissible limits (1.0 ug g-1 wet weight) of Hg in Mexico, the average concentration (1.91 ug g-1 wet weight) in the edible portion (muscle) of blue marlin was over the legal limit; this issue is worth research efforts in relation to the rate of ingestion of this species and the co-occurrence of selenium in the edible portion. PMID- 27783104 TI - Retrieval analysis of ceramic-coated metal-on-polyethylene total hip replacements. AB - PURPOSE: Ceramic coatings have been used in metal-on-polyethylene (MOP) hips to reduce the risk of wear and also infection; the clinical efficacy of this remains unclear. This retrieval study sought to better understand the performance of coated bearing surfaces. METHODS: Forty-three coated MOP components were analysed post-retrieval for evidence of coating loss and gross polyethylene wear. Coating loss was graded using a visual semi-quantitative protocol. Evidence of gross polyethylene wear was determined by radiographic analysis and visual inspection of the retrieved implants. RESULTS: All components with gross polyethylene wear (n = 10) were revised due to a malfunctioning acetabular component; 35 % (n = 15) of implants exhibited visible coating loss and the incidence of polyethylene wear in samples with coating loss was 54 %, significantly (p = 0.02) elevated compared to samples with intact coatings (14 %). CONCLUSIONS: In this study we found evidence of coating loss on metal femoral heads which was associated with increased wear of the corresponding polyethylene acetabular cups. PMID- 27783112 TI - Focus on transfusion, bleeding and thrombosis. PMID- 27783096 TI - NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription. AB - Nuclear paraspeckle assembly transcript 1 (NEAT1) is the crucial structural platform of paraspeckles, which is one type of nuclear bodies. As a stress induced lncRNA, the expression of NEAT1 increases in response to viral infection, but little is known about the role of NEAT1 or paraspeckles in the replication of herpes simplex virus-1 (HSV-1). Here, we demonstrate that HSV-1 infection increases NEAT1 expression and paraspeckle formation in a STAT3-dependent manner. NEAT1 and other paraspeckle protein components, P54nrb and PSPC1, can associate with HSV-1 genomic DNA. By binding with STAT3, PSPC1 is required for the recruitment of STAT3 to paraspeckles and facilitates the interaction between STAT3 and viral gene promoters, finally increasing viral gene expression and viral replication. Furthermore, thermosensitive gel containing NEAT1 siRNA or STAT3 siRNA effectively healed the skin lesions caused by HSV-1 infection in mice. Our results provide insight into the roles of lncRNAs in the epigenetic control of viral genes and into the function of paraspeckles. PMID- 27783097 TI - Breast cancer cells and bone marrow mesenchymal stromal cells: a regulated modulation of the breast tumor in the context of immune response. AB - OBJECTIVE: The role of direct cell-cell interactions mediating selective bone metastasis by breast cancer cells (BCCs) niche is still mostly unknown. MATERIALS AND METHODS: Conditioned medium and direct cell-cell contacts experiments were used to investigate the effect of bone marrow-derived mesenchymal stromal cells (MSCs), osteoprogenitor-like cells (MG-63) and osteosarcoma cells (SaOS-2) on luminal-like (MCF-7) and basal-like (MDA-MB-231) BCCs flow cytometry was used to assess the purity of isolated BCCs and osteoblasts. Expression of osteoblastic markers was investigated by semi-quantitative RT-PCR. RANKL and OPG levels were measured by ELISA. RESULTS: Conditioned medium from MSCs and osteoblasts induced the expression of osteoblastic markers in BCCs. While co-culture assays with SaOS 2 increased the expression of osteoblastic markers in MCF-7 cells, SaOS-2 cell conditioned medium increased the expression of RANKL, PTHrP, VEGF and NOGGIN in MCF-7 cells. Co-cultures with either MG-63 cells or MSCs induced OPG and MMP-2 in both tumor cell lines. Interestingly, conditioned medium from co-cultures of MSCs and MDA-MB-231 cells significantly decreased the proliferation of activated T lymphocytes which was reversed by addition of anti-OPG antibodies to the co cultures. CONCLUSION: Our data suggest that MSCs strongly contribute to the adaptation and invasiveness of breast cancer cells in skeletal tissues. PMID- 27783108 TI - [PEEK cage fusion after anterior cervical corpectomy : Clinical and radiological results in patients with spondylotic myelopathy]. AB - BACKGROUND: Anterior cervical corpectomy and fusion (ACCF) has become a standard procedure for patients with spondylotic myelopathy due to multisegmental stenosis of the cervical canal. In addition to the fusion technique using autogenous bone grafts and titanium implants, synthetic polyetheretherketone (PEEK) cages have been used increasingly during the last years. However, limited evidence on the clinical and radiological results of PEEK cages for ACCF exists in the literature. The study presented here is the largest series to date reporting clinical and radiological outcome as well as complication rates after one to three-level ACCF using PEEK cages augmented by an anterior plate-screw osteosynthesis. MATERIALS AND METHODS: Retrospective study on 101 patients after stand-alone PEEK cage-ACCF with a minimum follow-up of 6 months. The number of hardware failures and implant-related surgical revisions were determined. The rate of subsidence and fusion and the course of lordotic alignment were analysed. The neck disability index (NDI) and the European myelopathy score (EMS) were assessed. RESULTS: Screw complications were detected in 8/101 cases and 3 cases of cage dislocation occurred, resulting in an overall implant related revision rate of 2.9 % (all revision cases showed cage dislocation). The rate of cage subsidence >3 mm was 12 % and solid fusion was achieved in 82 % of the patients. NDI, EMS and lordotic alignment improved significantly. CONCLUSIONS: PEEK cages are a safe and effective alternative to titanium cages or autogenous bone graft for ACCF. Further randomized evaluation of different fusion techniques in ACCF is still necessary. PMID- 27783113 TI - Small bowel neoplasms: enhancement patterns and differentiation using post contrast multiphasic multidetector CT. AB - PURPOSE: The purpose of the present study was to analyze the enhancement patterns of small bowel neoplasms on post-contrast multiphasic multidetector CT and to assess the diagnostic capacity for differentiating five tumor types. METHODS: We performed a retrospective study of data on 92 small bowel neoplasms. The neoplasms were categorized into five groups according to pathology findings, not imaging findings (23 adenocarcinomas; 22 lymphomas; 19 metastases; 18 gastrointestinal stromal tumors [GIST]; 10 neuroendocrine tumors [NET]). RESULTS: GIST and NET demonstrated a hypervascular pattern in the multiphasic dynamic study. Adenocarcinoma and lymphoma showed a delayed enhancement pattern. Metastasis was classified as an intermediate enhancement pattern. The receiver operating characteristic analyses revealed that attenuation thresholds could be set with acceptable accuracies for most of the small bowel neoplasms. CONCLUSIONS: Multiphasic dynamic studies may have the potential to improve the diagnostic capacity of multidetector CT for small bowel neoplasms. PMID- 27783116 TI - [German Society of Urology Congress, Hamburg and the Presidential Medal]. AB - The German Society of Urology (DGU) e. V. meeting has been an integral part of knowledge sharing among national and international experts since 1907. Hamburg was the host city for this meeting nine times (until 2015), including the 47th Annual Meeting of the DGU in 1995 under the presidency of Prof. Dr. U. Jonas (Hannover). As part of the 47th conference, a new insignia in the form of the Presidential Medal was given to the designated successor for the first time. The medal, which is in the form of a chain, was made in a small workshop in Idar Oberstein, Germany. PMID- 27783100 TI - Micro-structural white matter abnormalities in type 2 diabetic patients: a DTI study using TBSS analysis. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have usually been found cognitive impairment associated with brain white matter (WM) abnormalities. However, findings have varied across studies, and any potential relationship with Alzheimer's disease (AD) remains unclear. The aim of this study was to assess the whole-brain WM integrity of T2DM patients and to compare our findings with those of published AD cases. METHODS: In this study, we used diffusion tensor imaging (DTI) combined with tract-based spatial statistics (TBSS) to investigate whole brain WM abnormalities in 48 T2DM patients and 48 healthy controls. The effects of age and gender were also evaluated. RESULTS: In our study, significantly decreasing FA and increasing MD and DA values (P<0.05) were found in some WM regions closely related to the default mode network (DMN), including cingulum, the right frontal lobe involving the right uncinate fasciculus (UF), bilateral parietal lobes involving the superior longitudinal fasciculus (SLF) and the inferior longitudinal fasciculus (ILF), and the right middle temporal gyrus (MTG) involving the UF and the ILF. We also found abnormalities in the thalamus involving the fornix (FX), anterior thalamic radiation (ATR), and posterior thalamic radiation (PTR). The damaged regions above are similar to those found in patients with AD, as reported in previous studies. CONCLUSION: The present study not only provides useful information about the WM regions and tracts affected by T2DM but also offers insight into the underlying neuropathological process in T2DM patients and the relationship between T2DM and AD. PMID- 27783118 TI - Evaluation of training programme uptake in an attempt to reduce obstetric anal sphincter injuries: the SUPPORT programme. AB - INTRODUCTION AND HYPOTHESIS: The objective was to assess the feedback from a quality improvement training programme to reduce obstetric anal sphincter injuries (OASIS). METHODS: Training sessions were organised that included evidence-based information on OASIS risk factors and training on models to measure perineal body length (PBL), perform episiotomies with standard and 60 degrees fixed angle scissors (EPISCISSORS-60(r)), and measure post-delivery episiotomy suture angles with protractor transparencies. Feedback forms using a Likert scale (1-4) were completed and analysed. The setting was an evidence-based quality improvement programme (Strategy for Using Practical aids for Prevention of OASIS, Recording episiotomies and clinician Training [SUPPORT]) at two National Health Service (NHS) Hospitals in the UK. The participants were midwives and doctors attending the SUPPORT training programme RESULTS: All of the participants (100 %) would recommend the training programme to a friend or colleague. 92 % felt that the training session improved their knowledge of the impact of PBL and perineal distension and their knowledge of the relationship between episiotomy angle and OASIS "a lot" or "somewhat". CONCLUSION: Based on this feedback, we recommend the addition of the knowledge content of the SUPPORT programme to other centres providing perineal assessment and repair courses. PMID- 27783121 TI - Raman spectroscopy, electronic microscopy and SPME-GC-MS to elucidate the mode of action of a new antimicrobial food packaging material. AB - One critical challenge when developing a new antimicrobial packaging material is to demonstrate the mode of action of the antimicrobials incorporated into the packaging. For this task, several analytical techniques as well as microbiology are required. In this work, the antimicrobial properties of benzyl isothiocyanate, allyl isothiocyanate and essential oils of cinnamon and oregano against several moulds and bacteria have been evaluated. Benzyl isothiocyanate showed the highest antimicrobial activity and it was selected for developing the new active packaging material. Scanning electron microscopy and Raman spectroscopy were successfully used to demonstrate the mode of action of benzyl isothiocyanate on Escherichia coli. Bacteria exhibited external modifications such as oval shape and the presence of septum surface, but they did not show any disruption or membrane damage. To provide data on the in vitro action of benzyl isothiocyanate and the presence of inhibition halos, the transfer mechanism to the cells was assessed using solid-phase microextraction-gas chromatography-mass spectrometry. Based on the transfer system, action mechanism and its stronger antimicrobial activity, benzyl isothiocyanate was incorporated to two kinds of antimicrobial labels. The labels were stable and active for 140 days against two mould producers of ochratoxin A; Penicillium verrucosum is more sensitive than Aspergillus ochraceus. Details about the analytical techniques and the results obtained are shown and discussed. Graphical Abstract Antimicrobial evaluation of pure compounds, incorporation in the packaging and study for mode of action on S. coli by Raman, SEM and SPME-GC-MS. PMID- 27783117 TI - [Urethral stricture after radiation therapy]. AB - Radiation-induced urethral stricture occurs most often due to radiation for prostate cancer. It is one of the most common side effects of radiotherapy. Stricture rates are lowest in patients undergoing external beam radiation therapy, occur more frequently in those who require brachytherapy and show highest stricture rates in patients receiving a combination of external beam radiation and brachytherapy. Strictures are mostly located at the bulbomembranous part of the urethra. Diagnostic work-up should include basic urologic work-up, ultrasound, uroflowmetric assessment, urethroscopy, retrograde urethrogram and voiding cystourethrography. Endoscopic management such as dilatation and internal urethrotomy has been proposed in short strictures. However these therapies have a high risk for recurrence. The success rate of urethroplasty is higher. Success rates of primary end-to-end anastomosis (EPA) have been reported to be 70-95 %; rates of incontinence are 7-40 %. While success rates of buccal mucosa graft urethroplasty (BMGU) range from 71-78 %, postoperative incontinence occurs in 10.5-44 %. Usually, postoperative incontinence can successfully be treated with an artificial urinary sphincter. It seems like EPA is the treatment of choice for short urethral strictures, whereas BMGU is indicated in longer, more complex strictures. Patients should be counselled with regard to length and location of strictures as well as with regard to postoperative incontinence. PMID- 27783122 TI - Development of an analytical method to determine oxy-PAHs and PAHs in Taxus baccata leaves. AB - An analytical method was developed and optimized for the quantification of 16 polycyclic aromatic hydrocarbons (PAHs) and 12 oxygenated PAHs in Taxus baccata leaves. Emphasis was given to the development of an in-cell cleanup step using pressurized solvent extraction, a cleanup step using solid-phase extraction, and the instrumental analysis by GC-HRMS. Different extraction temperatures (between 50 and 200 degrees C) and Florisil quantities were evaluated for the extraction process. Based on the evaluation of both recoveries and matrix effect factors, a temperature of 200 degrees C and 1 g Florisil was selected as the optimum. However, the in-cell cleanup was not sufficient in the long term due to increasing chromatographic peak broadening, and further cleanup was necessary. Solid-phase extraction (using Florisil) was evaluated, and breakthrough curves were acquired for all target compounds to determine the optimal elution volume and avoiding matrix interference. Recoveries of the target compounds ranged from 58 to 87 % for the PAHs and from 5 to 105 % for the oxy-PAHs. Matrix effects were determined for all individual target compounds. The optimized method was applied to T. baccata samples obtained from ten sampling locations in Ghent, Belgium. This is the first biomonitoring study in Ghent for PAHs and oxy-PAHs. The presence of significant amounts of toxicologically relevant oxygenated PAHs (Oxy PAHs) (can enhance ROS formation in human lung cells) in T. baccata was confirmed (max ?Oxy-PAHs: 230 ng/g; max ?PAHs: 389 ng/g). This means that these oxygenated PAHs are important pollutants and should be included in future monitoring studies. PMID- 27783105 TI - High-efficiency lysis of cervical cancer by allogeneic NK cells derived from umbilical cord progenitors is independent of HLA status. AB - Down-regulation of HLA in tumor cells, low numbers and dysfunctionality of NK cells are commonly observed in patients with end-stage cervical cancer. Adoptive transfer of high numbers of cytotoxic NK cells might be a promising treatment approach in this setting. Here, we explored the cytotoxic efficacy on ten cervical cancer cell lines of activated allogeneic NK cells from two sources, i.e., peripheral blood (PBNK) with and without cetuximab (CET), a tumor-specific monoclonal antibody directed against EGFR, or derived from umbilical cord blood (UCB-NK). Whereas CET monotherapy was ineffective against the panel of cervical cancer cell lines, irrespective of their EGFR expression levels and despite their RAS wt status, it significantly enhanced the in vitro cytotoxic efficacy of activated PBNK (P = 0.002). Equally superior cytotoxicity over activated PBNK alone was achieved by UCB-NK (P < 0.001). Both PBNK- and UCB-NK-mediated cytotoxic activity was dependent on the NK-activating receptors natural killer group 2, member D receptor (NKG2D) and DNAX accessory molecule-1 (DNAM-1) (P < 0.05) and unrelated to expression levels of the inhibitory receptors HLA-E and/or HLA-G. Most strikingly, whereas the PBNK's cytotoxic activity was inversely correlated with HLA-ABC levels (P = 0.036), PBNK + CET and UCB-NK cytotoxicity were entirely independent of HLA-ABC expression. In conclusion, this study provides a rationale to initiate a clinical trial for cervical cancer with adoptively transferred allogeneic NK cells, employing either UCB-NK or PBNK + CET for EGFR-expressing tumors. Adoptive transfer of UCB-NK might serve as a generally applicable treatment for cervical cancer, enabled by HLA-, histology- and HPV-independent killing mechanisms. PMID- 27783124 TI - A new immunoassay of serum antibodies against Peste des petits ruminants virus using quantum dots and a lateral-flow test strip. AB - A fast and ultrasensitive test-strip system combining quantum dots (QDs) with a lateral-flow immunoassay strip (LFIAS) was established for detection of Peste des petits ruminants virus (PPRV) antibody. The highly luminescent water-soluble carboxyl-functionalized QDs were used as the signal output and were conjugated to streptococcal protein G (SPG), which was capable of binding to immunoglobulin G (IgG) from many species through an amide bond to capture the target PPRV IgGs. The PPRV N protein, which was immobilized on the detection zone of the test strip, was expressed by transfecting recombinant Bacmid-PPRV-N with Lipofect into Sf9 insect cells. When exposed to PPRV IgG, QD-SPG bound to PPRV N protein, resulting in the formation of a complex that subsequently produced a bright fluorescent band in response to 365 nm ultraviolet excitation. Sensitivity evaluation showed that the QD-LFIAS limit of detection (LOD) for PPRV antibody was superior to competitive enzyme-linked immunosorbent assay (c-ELISA) and the immunochromatographic strip. No cross reaction was observed when the positive sera of bluetongue virus, canine distemper virus, goat pox virus, and foot-and mouth disease virus were tested. Further evaluation using field samples indicated that the diagnostic specificity and sensitivity of the QD-LFIAS was 99.47 and 97.67 %, respectively, with excellent agreement between QD-LFIAS and c-ELISA. The simple analysis step and objective results that can be obtained within 15 min indicate that this new method shows great promise for rapid, sensitive detection of PPRV IgG for onsite, point-of-care diagnosis and post vaccination evaluation (PVE). Graphical Abstract Ultrasensitive fluorescent QD immunochromotography in combination with recombinant PPRV N protein could be used to detect PPRV antibody in serum. PMID- 27783115 TI - Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells. AB - Currently, it is not well understood how ligands of the aryl hydrocarbon receptor (AhR) modify inflammatory responses triggered by Toll-like receptor (TLR) agonists in human dendritic cells (DCs). Here, we show that AhR ligands 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), the tryptophan derivatives 6-formylindolo[3,2 b] carbazole (FICZ), kynurenine (kyn), and the natural dietary compound indole-3 carbinol (I3C) differentially modify cytokine expression in human monocyte derived DCs (MoDCs). The results show that TLR-activated MoDCs express higher levels of AhR and are more sensitive toward the effects of AhR ligands. Depending on the cytokine, treatment with AhR ligands led to a synergistic or antagonistic effect of the TLR-triggered response in MoDCs. Thus, activation of AhR increased the expression of interleukin (IL)-1beta, but decreased the expression of IL-12A in TLR-activated MoDCs. Furthermore, TCDD and FICZ may have opposite effects on the expression of cytochrome P4501A1 (CYP1A1) in TLR8-activated MoDCs indicating that the effect of the specific AhR ligand may depend on the presence of the specific TLR agonist. Gene silencing showed that synergistic effects of AhR ligands on TLR-induced expression of IL-1beta require a functional AhR and the expression of NF-kappaB RelB. On the other hand, repression of IL-12A by TCDD and FICZ involved the induction of the caudal type homeobox 2 (CDX2) transcription factor. Additionally, the levels of DC surface markers were decreased in MoDCs by TCDD, FICZ and I3C, but not by kyn. Overall, these data demonstrate that AhR modulates TLR-induced expression of cytokines and DC-specific surface markers in MoDCs involving NFkappaB RelB and the immune regulatory factor CDX2. PMID- 27783125 TI - Chemiluminescence lateral flow immunoassay cartridge with integrated amorphous silicon photosensors array for human serum albumin detection in urine samples. AB - A novel and disposable cartridge for chemiluminescent (CL)-lateral flow immunoassay (LFIA) with integrated amorphous silicon (a-Si:H) photosensors array was developed and applied to quantitatively detect human serum albumin (HSA) in urine samples. The presented analytical method is based on an indirect competitive immunoassay using horseradish peroxidase (HRP) as a tracer, which is detected by adding the luminol/enhancer/hydrogen peroxide CL cocktail. The system comprises an array of a-Si:H photosensors deposited on a glass substrate, on which a PDMS cartridge that houses the LFIA strip and the reagents necessary for the CL immunoassay was optically coupled to obtain an integrated analytical device controlled by a portable read-out electronics. The method is simple and fast with a detection limit of 2.5 mg L-1 for HSA in urine and a dynamic range up to 850 mg L-1, which is suitable for measuring physiological levels of HSA in urine samples and their variation in different diseases (micro- and macroalbuminuria). The use of CL detection allowed accurate and objective analyte quantification in a dynamic range that extends from femtomoles to picomoles. The analytical performances of this integrated device were found to be comparable with those obtained using a charge-coupled device (CCD) as a reference off-chip detector. These results demonstrate that integrating the a-Si:H photosensors array with CL-LFIA technique provides compact, sensitive and low-cost systems for CL-based bioassays with a wide range of applications for in-field and point-of care bioanalyses. Graphical Abstract A novel integrated portable device was developed for direct quantitative detection of human serum albumin (HSA) in urine samples, exploiting a chemiluminescence lateral flow immunoassay (LFIA). The device comprises a cartridge that holds the LFIA strip and all the reagents necessary for the analysis, an array of amorphous silicon photosensors, and a custom read-out electronics. PMID- 27783123 TI - Surface coating and matrix effect on the electrophoretic mobility of gold nanoparticles: a capillary electrophoresis-inductively coupled plasma mass spectrometry study. AB - Capillary electrophoresis (CE) is considered as a versatile technique in the size based separation and speciation of nanomaterials. The electrophoretic mobility is determined by charge and size of an analyte which are affected by the surface composition of nanomaterials. Size-dependent differential electrophoretic mobility is used as a mechanism for size-based separation of nanoparticles. Understanding the effect of surface chemistry on the electrophoretic mobility of nanomaterials in CE is critical in obtaining accurate results in retention-based size calculation. A suite of gold nanoparticles (NPs) varied in sizes with different coatings, including citric acid (CA), lipoic acid (LA), tannic acid (TA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), branched polyethyleneimine (BPEI), and bovine serum albumin (BSA), were selected to evaluate their impact to the migration pattern of gold NPs. Additionally, surface coated gold NPs dispersed in Suwannee River humic acid (SRHA) solution and fetal bovine serum (FBS) were used to investigate the matrix effect. It was found that the correlation between NP size and relative electrophoretic mobility is highly dependent on the capping agents. The matrix component in the SRHA solution only exhibited limited influence to the migration of NPs while electrophoretic behaviors were drastically altered in the presence of FBS matrix. PMID- 27783126 TI - Identification of individual red blood cells by Raman microspectroscopy for forensic purposes: in search of a limit of detection. AB - Traces of body fluids can be present at a variety of crime scenes. It is important that forensic investigators have a reliable and nondestructive method of identifying these traces. Of equal importance is establishing the limitations of any method in use, including its detection limit. We have previously reported on the use of Raman microspectroscopy and multivariate data analysis to identify and differentiate body fluids. While many studies use serial dilutions to establish limits of detection, we utilized a different approach and demonstrated that a single red blood cell is sufficient to be correctly identified as blood. The experimental Raman spectra of individual red blood cells were loaded into the previously reported models for body fluid identification, and all were correctly classified as peripheral blood. These results demonstrate that our model can be used to identify peripheral blood, even if there is only a single red blood cell present. Furthermore, a single red blood cell is 5000* smaller than the amount of peripheral blood required to perform DNA analysis in a modern crime laboratory. This means that if a bloodstain is large enough for DNA analysis, Raman microspectroscopy should be able to make a positive identification. Considering that the sample analysis reported here was carried out with a different instrument, not the one used for the previously reported method development, these results also represent a form of method validation. The model's ability to correctly classify spectra acquired on a different instrumental platform is crucial in preparing it for practical application. Graphical Abstract Peripheral blood is of great interest in forensic sciences. While many tests are available for the identification of peripheral blood at a crime scene, most are presumptive and destructive. Here we present results that show our new, nondestructive method can identify peripheral blood using as little as a single red blood cell. PMID- 27783111 TI - Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction. AB - : Recent studies indicate that inflammasomes serve as intracellular machinery to initiate classical cytokine-mediated inflammatory responses and play a crucial role in the pathogenesis of cardiovascular diseases. However, whether or not the activation of endothelial inflammasomes directly causes cell dysfunction or tissue injury without recruitment of inflammatory cells is unknown. We explored the role of endothelial cell inflammasome activation in mediating tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. We used confocal microscopy to study the formation and activation of NOD-like receptor family pyrin domain containing 3 (Nlrp3) inflammasomes and expression of tight junction proteins in coronary arteries of streptozotocin-treated diabetic wild type and Nlrp3 gene-deleted mice. We found that Nlrp3 ablation prevented inflammasome activation and tight junction disassembly in the coronary arterial endothelium of diabetic mice. Similarly, Nlrp3 gene silencing prevented high glucose-induced down-regulation of tight junction proteins in cultured mouse vascular endothelial cells (MVECs). The high glucose-induced tight junction disruption and consequent endothelial permeability were attributed to increased release of the high mobility group box protein-1 (HMGB1), which is dependent on enhanced Nlrp3 inflammasome activity. Mechanistically, reducing reactive oxygen species (ROS) production abolished high glucose-induced inflammasome activation, tight junction disruption, and endothelial hyperpermeability in MVECs. Collectively, the ROS-dependent activation of endothelial Nlrp3 inflammasomes by hyperglycemia may be an important initiating mechanism to cause endothelial dysfunction. These effects could contribute to the early onset of endothelial injury in diabetes. KEY MESSAGE: Endothelial tight junction disruption in diabetes requires Nlrp3 inflammasomes. High glucose activates Nlrp3 inflammasome in endothelial cells via ROS production. Activation of endothelial inflammasome by high glucose triggers release of HMGB1. Blockade of Nlrp3/HMGB1 axis inhibits high glucose-induced endothelial permeability. PMID- 27783134 TI - Network-Guided Key Gene Discovery for a Given Cellular Process. AB - Identification of key genes for a given physiological or pathological process is an essential but still very challenging task for the entire biomedical research community. Statistics-based approaches, such as genome-wide association study (GWAS)- or quantitative trait locus (QTL)-related analysis have already made enormous contributions to identifying key genes associated with a given disease or phenotype, the success of which is however very much dependent on a huge number of samples. Recent advances in network biology, especially network inference directly from genome-scale data and the following-up network analysis, opens up new avenues to predict key genes driving a given biological process or cellular function. Here we review and compare the current approaches in predicting key genes, which have no chances to stand out by classic differential expression analysis, from gene-regulatory, protein-protein interaction, or gene expression correlation networks. We elaborate these network-based approaches mainly in the context of immunology and infection, and urge more usage of correlation network-based predictions. Such network-based key gene discovery approaches driven by information-enriched 'omics' data should be very useful for systematic key gene discoveries for any given biochemical process or cellular function, and also valuable for novel drug target discovery and novel diagnostic, prognostic and therapeutic-efficiency marker prediction for a specific disease or disorder. PMID- 27783132 TI - Orthogonal Protein Translation Using Pyrrolysyl-tRNA Synthetases for Single- and Multiple-Noncanonical Amino Acid Mutagenesis. AB - To date, the two systems most extensively used for noncanonical amino acid (ncAA) incorporation via orthogonal translation are based on the Methanococcus jannaschii TyrRS/tRNA CUATyr and the Methanosarcina barkeri/Methanosarcina mazei PylRS/tRNA CUAPyl pairs. Here, we summarize the development and usage of the pyrrolysine-based system for orthogonal translation, a process that allows for the recombinant production of site-specifically labeled proteins and peptides. Via stop codon suppression in Escherichia coli and mammalian cells, genetically encoded biomolecules can be equipped with a great diversity of chemical functionalities including click chemistry handles, post-translational modifications, and photocaged sidechains. PMID- 27783129 TI - The association between continuity of care and readmission to hospital in patients with severe psychosis. AB - PURPOSE: Providing good continuity of care to patients is considered a vital component of community mental health services, but there is limited evidence that it is associated with good outcomes. We measured service use and a multidimensional concept of continuity of care in 323 patients who were to be discharged from hospital following compulsory treatment for psychosis to investigate the association between continuity and rehospitalisation. METHODS: We conducted a 36-month prospective cohort study of the patients recruited to the Oxford Community Treatment Order Trial (OCTET). We collected data from medical records on eight previously operationalized measures of continuity. We conducted regression analyses to determine the association between these measures and readmission to hospital, time to readmission, and the number of days spent in hospital. RESULTS: Almost two thirds (n = 206, 63.8%) of patients were readmitted. Patients were seen frequently, with a mean of 2.9 (SD = 2.47) contacts a month throughout the follow-up. Less frequent contact was significantly associated with lower odds of rehospitalisation and fewer days in hospital. More changes in the patient's care coordinator were associated with more time in hospital. Patients who had a higher proportion of clinical correspondence copied to them spent fewer days in hospital. CONCLUSION: Patients with severe and relapsing psychotic illness are seen frequently and consistently in community mental health services. Higher levels of patient contact could be a response to the severity of illness rather than a marker of quality of care. Using a simple linear interpretation of contact frequency as a measure of continuity of care in this patient group may be of limited value in modern services. PMID- 27783127 TI - Endovascular Treatment for Near Occlusion of the Internal Carotid Artery : 30-Day Outcome and Long-Term Follow-Up. AB - BACKGROUND: The treatment strategy and the correct incidence of near occlusion (NO) of the internal carotid artery (ICA) is still controversial. In routine radiological imaging NO can easily be misdiagnosed as complete occlusion and there is no consensus on the standard treatment strategy. PURPOSE: To present our perioperative and long-term follow-up results of ICA NO patients treated with carotid artery stenting (CAS). MATERIAL AND METHODS: Between 2004-2014 a total of 182 patients with ICA NO were evaluated for CAS. The study included 132 male (72.5 %) and 50 female (27.5 %) patients with a mean age of 70.2 years. Patients underwent a clinical neurological evaluation and radiological imaging of the carotid arteries before the CAS procedure. Of the patients 80 (44 %) were asymptomatic. The median clinical and carotid Doppler ultrasound (DUS) follow-up period was 64 months (range 18-124 months). RESULTS: In 182 patients CAS were performed, 4 patients (2.2 %) developed minor stroke, 2 patients (1.1 %) developed myocardial infarction but no major stroke or death occurred in the following 30-day period. Asymptomatic restenosis was detected in seven patients (3.8 %) in the follow-up period. CONCLUSION: With sufficient neurological evaluation during pretreatment and posttreatment periods and when the procedure is performed with technologically developed products by an experienced interventional team, CAS is beneficial in patients with ICA NO. PMID- 27783133 TI - Networking Omic Data to Envisage Systems Biological Regulation. AB - To understand how biological processes work, it is necessary to explore the systematic regulation governing the behaviour of the processes. Not only driving the normal behavior of organisms, the systematic regulation evidently underlies the temporal responses to surrounding environments (dynamics) and long-term phenotypic adaptation (evolution). The systematic regulation is, in effect, formulated from the regulatory components which collaboratively work together as a network. In the drive to decipher such a code of lives, a spectrum of technologies has continuously been developed in the post-genomic era. With current advances, high-throughput sequencing technologies are tremendously powerful for facilitating genomics and systems biology studies in the attempt to understand system regulation inside the cells. The ability to explore relevant regulatory components which infer transcriptional and signaling regulation, driving core cellular processes, is thus enhanced. This chapter reviews high throughput sequencing technologies, including second and third generation sequencing technologies, which support the investigation of genomics and transcriptomics data. Utilization of this high-throughput data to form the virtual network of systems regulation is explained, particularly transcriptional regulatory networks. Analysis of the resulting regulatory networks could lead to an understanding of cellular systems regulation at the mechanistic and dynamics levels. The great contribution of the biological networking approach to envisage systems regulation is finally demonstrated by a broad range of examples. PMID- 27783131 TI - Invited Commentary on Stewart and Davis " 'Big data' in mental health research current status and emerging possibilities". PMID- 27783128 TI - Psychosocial factors associated with mother-child violence: a household survey. AB - PURPOSE: The objective of this study was to investigate the psychosocial factors associated with violence by women against their children, using a household survey. METHODS: Households in two neighborhoods in Juiz de Fora, Brazil, with different socioeconomic profiles, were selected through probability sampling and surveyed. A total of 446 women with children up to 18 years of age were interviewed. A sociodemographic questionnaire, the CTSPC (Parent-Child Conflict Tactics Scales), the CES-D (Center for Epidemiologic Studies Depression Scale) and the AUDIT (Alcohol Use Disorders Identification Test) were applied. Using STATA statistical software, logistic regression analysis was performed to investigate the association between psychosocial variables and domestic violence against children. RESULTS: The prevalence of violence by mothers against their children during the 3 months prior to data collection was as follows: psychological aggression, 70.5% (n = 304); corporal punishment, 51.4% (n = 232); and physical maltreatment, 9.8% (n = 46). Women with a higher educational level exhibited lower odds of committing psychological aggression (OR 0.47; CI 0.24 0.91) and corporal punishment (OR 0.32; CI 0.16-0.64). Age was associated with corporal punishment, with older women (OR 0.94; CI 0.91-0.97) reporting a lower frequency of this type of violence against their children. Residing in the neighborhood with higher socioeconomic status reduced the odds of reporting psychological aggression (OR 0.45; CI 0.27-0.75). Maternal depression (OR 3.75; CI 1.51-9.31) and harmful drinking (OR 4.73; CI 1.17-19.10) were risk factors for physical maltreatment. CONCLUSIONS: The results point to the need for preventive strategies for mother-child violence in low and middle income countries, with a focus on the mothers' education and mental health, especially with regard to the younger ones. PMID- 27783135 TI - Cyanobacterial Biofuels: Strategies and Developments on Network and Modeling. AB - Cyanobacteria, the phototrophic microorganisms, have attracted much attention recently as a promising source for environmentally sustainable biofuels production. However, barriers for commercial markets of cyanobacteria-based biofuels concern the economic feasibility. Miscellaneous strategies for improving the production performance of cyanobacteria have thus been developed. Among these, the simple ad hoc strategies resulting in failure to optimize fully cell growth coupled with desired product yield are explored. With the advancement of genomics and systems biology, a new paradigm toward systems metabolic engineering has been recognized. In particular, a genome-scale metabolic network reconstruction and modeling is a crucial systems-based tool for whole-cell-wide investigation and prediction. In this review, the cyanobacterial genome-scale metabolic models, which offer a system-level understanding of cyanobacterial metabolism, are described. The main process of metabolic network reconstruction and modeling of cyanobacteria are summarized. Strategies and developments on genome-scale network and modeling through the systems metabolic engineering approach are advanced and employed for efficient cyanobacterial-based biofuels production. PMID- 27783136 TI - Molecular Phylogenetics: Concepts for a Newcomer. AB - Molecular phylogenetics is the study of evolutionary relationships among organisms using molecular sequence data. The aim of this review is to introduce the important terminology and general concepts of tree reconstruction to biologists who lack a strong background in the field of molecular evolution. Some modern phylogenetic programs are easy to use because of their user-friendly interfaces, but understanding the phylogenetic algorithms and substitution models, which are based on advanced statistics, is still important for the analysis and interpretation without a guide. Briefly, there are five general steps in carrying out a phylogenetic analysis: (1) sequence data preparation, (2) sequence alignment, (3) choosing a phylogenetic reconstruction method, (4) identification of the best tree, and (5) evaluating the tree. Concepts in this review enable biologists to grasp the basic ideas behind phylogenetic analysis and also help provide a sound basis for discussions with expert phylogeneticists. PMID- 27783139 TI - Lack of effect of smoking status on axitinib pharmacokinetics in patients with non-small-cell lung cancer. AB - PURPOSE: Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers. METHODS: Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)-for a nonlinear mixed effects modeling (NONMEM v7.2) analysis. Demographics, smoking status, liver and renal function status, and Eastern Cooperative Oncology Group performance status were tested as covariates. RESULTS: There were 83 (40%) active smokers and 56 (27%) ex-smokers in the pooled dataset. Axitinib pharmacokinetics was adequately described with a linear, two-compartment model with a lagged first-order absorption. Final parameter estimates (inter individual variability) were 16.1 L/h (59.1%) and 45.3 L (54.4%) for systemic clearance (CL) and central volume of distribution (Vc), respectively. Smoking status was found not to alter CL or Vc. Asian ethnicity and body weight were significant covariates for Vc, but were not considered clinically relevant since individual values of Vc for Asians were within the range of non-Asians. CONCLUSIONS: Based on this analysis, smoking status does not affect area under plasma concentration-time curve, and thus no dose adjustment is required for smokers. PMID- 27783130 TI - Pilot study of enhanced social support with automated telephone monitoring after psychiatric hospitalization for depression. AB - BACKGROUND: Following discharge, patients hospitalized for depression are at high risk for poor retention in outpatient care and adverse outcomes. AIMS: Pilot tests a post-hospital monitoring and enhanced support program for depression. METHOD: 48 patients at a Veterans Affairs Medical Center discharged following a depression-related inpatient stay received weekly visits or phone calls for 6 months from their choice of either a family member/friend (n = 19) or a certified peer support specialist (n = 29). Participants also completed weekly automated telephone monitoring calls assessing depressive symptoms and antidepressant medication adherence. RESULTS: Over 90% of participants were more satisfied with their care due to the service. The mean change from baseline to 6 months in depression symptoms was -7.9 (p < 0.05) according to the Patient Health Questionnaire and -11.2 (p < 0.05) according to the Beck Depression Inventory-II for those supported by a family member/friend, whereas those supported by a peer specialist had mean changes of -3.5 (p < 0.05) and -1.7 (p > 0.10), respectively. CONCLUSIONS: Increased contact with a chosen support person coupled with automated telephone monitoring after psychiatric hospitalization is an acceptable service for patients with depression. Those who received the service, and particularly those supported by a family member/friend, experienced reductions in symptoms of depression. PMID- 27783138 TI - Cochlear implantation in patients with definite Meniere's disease. AB - The exact pathomechanism of deafening in Meniere's disease (MD) is still unknown; intoxication of hair cells and neural damage from endolymphatic hydrops is discussed. In the literature, there are only a few reports on hearing outcome of MD patients after treatment with cochlear implantation (CI) whereby especially the comparison of MD vs. non-MD patients with CI differs. In this retrospective study, results in speech understanding [Freiburger Einsilber (FES65) and Hochmair Schulz-Moser test in quiet (HSM) and in noise (HSM + 10 dB)] of 27 implanted MD patients were collected and compared to a matched standard CI cohort. Alternative diagnoses were excluded as far as possible by re-analyzing neuroradiologic imaging. After first fitting, MD patients showed significantly better results in FES and HSM testing compared to controls. At 1-year refitting, this effect could not be seen anymore. To conclude, cochlear implantation is a safe and effective treatment for deafness in MD patients. Results in speech understanding are at least equal compared to general CI recipients. To the best of our knowledge, this retrospective study examined the largest collective of CI users deafened by MD so far. PMID- 27783140 TI - Lower limb reconstruction in tumor patients using modular silver-coated megaprostheses with regard to perimegaprosthetic joint infection: a case series, including 100 patients and review of the literature. AB - PURPOSE AND OBJECTIVE: Bone resection regarding adequate surgical margins is the treatment of choice for malignant bone tumors. In the case of metastasis-related complications, so-called skeletal-related events, it is highly important to achieve pain relief and a stable joint situation to re-mobilize the patients immediately following surgery. To bridge the often large osseous defect zones after tumor resection, both cemented and uncemented modular endoprosthetic systems are widely used. Patients undergoing tumor-related endoprosthetic orthopedic surgery are facing high risk for developing a periprosthetic joint infection (PJI). The immunocompromised condition due to anti-neoplastic treatment and long operation time with large exposure of tissue contributes to a high risk of infection. METHODS: The authors present a case series of 100 patients (31% primary bone tumor and 69% metastasis-related surgery) undergoing tumor-related lower limb salvage surgery with special regard to periprosthetic joint infection and the management of this "difficult to treat" situation. Furthermore, a review of the current literature regarding infection following bone tumor resection and endoprosthetic reconstruction is performed and discussed. RESULTS: The median follow-up was 24 months (range 12-108 months). Ten patients (10%) suffered from a periprosthetic joint infection. We recorded six acute infections (type I) <4 weeks after surgery, one infection >4 weeks after surgery (type II), and three late infections (type III). According to the definition of Laffer et al., three of our patients (30%) are probably free of infection, one patient died of PJI associated sepsis, and five patients were free of infection, but without restoration of the affected joint. CONCLUSION: In conclusion, our own results show that perimegaprosthetic joint infection among silver-coated implants, in patients undergoing tumor-related surgery of the lower limb, is lower compared to non-silver-coated implants. Due to heterogeneity of patients and potential treatment options, the treatment regime should be tailored for the patients' individual situation. PMID- 27783142 TI - Revisiting the Anterior Rectus Sheath Repair for Incisional Hernia: A 10-Year Experience. AB - BACKGROUND: Surgeons continue to seek an incisional hernia repair technique which minimizes cost and morbidity while maximizing durability. We present a single surgeon's experience with a technique described by N.L. Browse and J.P. Chevrel in 1979. METHODS: The Chevrel/Browse repair consists of a bilateral anterior rectus sheath release, hernia sac imbrication, bilateral rectus complex medialization, and repair reinforcement with an anterior prosthetic mesh. Data were collected on all patients who underwent herniorrhaphy between April 2003 and April 2013. RESULTS: A total of 123 patients underwent repair. These had undergone an average of 2.6 prior abdominal operations and 0.7 prior hernia repairs; the average defect size was 64.77 +/- 86.79 cm2. Twelve patients had lateral components release in addition to release of the anterior rectus sheath to achieve midline re-approximation with minimal tension. Synthetic mesh was used in 81 % of repairs and biologic mesh in 19 %. The most common complications were seroma formation (21 %) and incisional skin breakdown (30 %); no deaths occurred. The overall recurrence rate was 5.1 %, and 7 % for the group which had follow-up greater than 36 months. Use of biologic mesh increased the rate of seroma formation compared with synthetic mesh (50 vs. 14 %, p < 0.001), but did not increase the rate of wound breakdown (36.3 vs. 29.6 %, p = 0.72). CONCLUSION: This case series describes the utilization of anterior rectus sheath release and mesh placement which is anterior to the rectus muscle. Hernia recurrence and intra-abdominal complications are observed to be uncommon after repair using this technique. Future prospective randomized studies are warranted. PMID- 27783137 TI - A specific mode of microsatellite instability is a crucial biomarker in adult T cell leukaemia/lymphoma patients. AB - PURPOSE: Microsatellite instability (MSI) has been a long-standing biomarker candidate for drug resistance in tumour cells. Despite numerous clinical studies, the data in the literature are not conclusive. The complexity of the MSI phenomenon in some malignancies may, at least partly, account for the discrepancy. In addition, methodological problems are also pointed out in the assay techniques. We previously established a unique fluorescent technique in which the major methodological problems in conventional assays are overcome. Application of this technique has revealed two distinct modes of microsatellite alterations, i.e. Type A and Type B. More importantly, we demonstrated that Type A MSI is the direct consequence of defective DNA mismatch repair (MMR) that causes cellular resistance against antineoplastic agents. METHOD: We first applied this technique to adult T-cell leukaemia/lymphoma (ATLL). RESULTS: The MSI phenomenon was indeed observed in ATLLs (4/20, 20%). Intriguingly, the observed microsatellite alterations were invariably Type A, which implies that the tumours were MMR-defective. Indeed, clinical outcomes of patients with these MSI+ tumours were significantly worse. Furthermore, multivariate analysis revealed that Type A MSI is an independent prognostic factor. CONCLUSION: These observations strongly suggest the possibility of Type A MSI as a prognostic and potentially predictive biomarker in ATLL. PMID- 27783144 TI - [Diagnostic cardiovascular implants: Implantable loop recorder/pulmonary artery pressure sensor]. PMID- 27783151 TI - A phenomenological model of cell-cell adhesion mediated by cadherins. AB - We present a phenomenological model intended to describe at the protein population level the formation of cell-cell junctions by the local recruitment of homophilic cadherin adhesion receptors. This modeling may have a much wider implication in biological processes since many adhesion receptors, channel proteins and other membrane-born proteins associate in clusters or oligomers at the cell surface. Mathematically, it consists in a degenerate reaction-diffusion system of two partial differential equations modeling the time-space evolution of two cadherin populations over a surface: the first one represents the diffusing cadherins and the second one concerns the fixed ones. After discussing the stability of the solutions of the model, we perform numerical simulations and show relevant analogies with experimental results. In particular, we show patterns or aggregates formation for a certain set of parameters. Moreover, perturbing the stationary solution, both density populations converge in large times to some saturation level. Finally, an exponential rate of convergence is numerically obtained and is shown to be in agreement, for a suitable set of parameters, with the one obtained in some in vitro experiments. PMID- 27783141 TI - Emergency Abdominal Surgery in the Elderly: Can We Predict Mortality? AB - BACKGROUND: The United Kingdom population is ageing. Half of patients requiring an emergency laparotomy are aged over 70, 20 % die within 30 days, and less than half receive good care. Frailty and delay in management are associated with poor surgical outcomes. P-POSSUM risk scoring is widely accepted, but its validity in patients aged over 70 undergoing emergency laparotomy is unclear. AIMS: To assess if P-POSSUM risk stratification reliably predicts inpatient mortality in this group and establish whether those who died within 30 days received delayed care. METHODS: Observational study of consecutive patients aged 70 and over fulfilling the National Emergency Laparotomy Audit criteria from a tertiary hospital. The predictive value of pre-operative P-POSSUM, ASA, lactate and other routine variables was assessed. Surgical review, decision to operate, consultant surgical review, antibiotic prescription, laparotomy and discharge or death time points were assessed by 30-day survival. RESULTS: One hundred and ninety-three patients were included. This represented 46.28 % of those undergoing an emergency laparotomy in our centre. Pre-operative P-POSSUM scoring, ASA grade and lactate were moderate predictors of mortality (AUC 0.784 and 0.771, respectively, lactate AUC 0.705, all p <= 0.001). No correlation existed between pre-operative P-POSSUM and days to death (p = 0.209), nor were there delays in key management timings in those who died in 30 days. CONCLUSIONS: P-POSSUM scoring may predict inpatient mortality with moderate discrimination. Addition of frailty scoring in this high risk group might better identify those with a high risk of mortality after emergency laparotomy and would be a fertile area for further research. PMID- 27783153 TI - Epidermal hydrogen peroxide is not increased in lesional and non-lesional skin of vitiligo. AB - It is widely believed that the loss of the epidermal melanocytes in vitiligo is basically due to excessive oxidative stress. Previous research work described abnormal elevation of the absolute concentration of the epidermal hydrogen peroxide (H2O2) in lesional and non-lesional skin of vitiligo. Based on this finding, our primary research objective was to use this feature as a screening marker in individuals at a great risk of developing vitiligo. Ninety-six patients of non-segmental vitiligo (NSV) of varying durations, skin phototypes, and treatment modalities (psoralen UVA-, narrow band UVB-treated) were recruited for this study. Raman spectroscopic measurements, using an external probehead, of the lesional and non-lesional skin were obtained, and the resulting spectra were analyzed using the Opus software package of the MultiRam spectrometer and the intensity of the peak at 875 cm-1 that represents the absolute concentration of H2O2 was calculated. Contrary to previous reports, in patients of skin phototype IV, the absolute concentrations of H2O2 in non-lesional and lesional NSV of all groups were non-significantly decreased compared to normal control. In patients of NSV of skin phototype V, the decrease in the absolute concentrations of H2O2 was not significant in the untreated group, and a slight non-significant increase in the NBUVB-treated group was noted. However, in the PUVA-treated group, the non lesional skin demonstrated significant increase in the absolute concentration of H2O2, whereas the lesional skin showed only a slight non-significant increase compared to normal control. In NSV patients of skin phototype VI who were previously treated with PUVA, the non-lesional skin showed a slight non significant increase in the absolute concentration of H2O2; however, the lesional skin showed a marked significant decrease compared to normal control and the non lesional skin. Thereof, one can conclude that the epidermal H2O2 is not increased in NSV as previously thought and may not be responsible for the oxidative stress that leads to the melanocytes destruction, the hallmark of vitiligo pathogenesis. PMID- 27783148 TI - Risk factors for thoracic and spinal deformities following lung resection in neonates, infants, and children. AB - PURPOSE: We aimed to identify the risk factors for thoracic and spinal deformities following lung resection during childhood and to elucidate whether thoracoscopic surgery reduces the risk of complications after lung resection. METHODS: We retrospectively examined the medical records of all pediatric patients who underwent lung resection for congenital lung disease at our institution between 1989 and 2014. RESULTS: Seventy-four patients underwent lung resection during the study period and were followed-up. The median age of the patients at the time of surgery was 5 months (range 1 day-13 years), and 22 were neonates. Thoracotomy and thoracoscopy were performed in 25 and 49 patients, respectively. Thoracic or spinal deformities occurred in 28 of the 74 patients (37%). Univariate analyses identified thoracotomy, being a neonate (age: <1 month) at the time of surgery, and being symptomatic at the time of surgery as risk factors for these deformities. However, a multivariate analysis indicated that only thoracotomy and being a neonate were risk factors for deformities. CONCLUSIONS: Thoracoscopic surgery reduced the risk of thoracic and spinal deformities following lung resection in children. We suggest that, where possible, lung resection should be avoided until 2 or 3 months of age. PMID- 27783149 TI - The impact of the preoperative peripheral lymphocyte count and lymphocyte percentage in patients with colorectal cancer. AB - PURPOSE: We evaluated the prognostic significance of the peripheral lymphocyte count and lymphocyte percentage, which reflect the preoperative immune status, in patients with colorectal cancer (CRC) and then compared their accuracy as predictors of the survival. METHODS: We retrospectively reviewed a database of 362 patients. We classified the patients into high lymphocyte count and low lymphocyte count groups. We also classified the patients into high lymphocyte percentage and low lymphocyte percentage groups. RESULTS: The 5-year relapse-free survival (RFS) rate in the high lymphocyte count group tended to be higher than that in the low lymphocyte count group. The 5-year overall survival (OS) rate in the high lymphocyte count group was significantly higher than that in the low lymphocyte count group. In contrast, the 5-year RFS and OS rates in the high lymphocyte percentage group were both significantly higher than those in the low lymphocyte percentage group. A multivariate analysis showed that the lymphocyte percentage was independently associated with the OS. CONCLUSIONS: These findings suggest that the lymphocyte percentage is a good predictor of the OS and may be a stronger predictor of survival than the lymphocyte count in CRC patients. PMID- 27783146 TI - Collagen cell carriers seeded with human urothelial cells for urethral reconstructive surgery: first results in a xenograft minipig model. AB - PURPOSE: Urethral strictures are a common disease of the lower urinary tract in men. At present, the use of buccal mucosa is the method of choice for long or recurrent strictures. However, autologous tissue-engineered grafts are still under investigation for reconstructive urological surgery. The aim of this pilot study was to evaluate the use of human urothelial cells (HUC) seeded on bovine collagen type I-based cell carriers (CCC) in an animal model and to evaluate short-term outcome of the surgical procedure. METHODS: Four male Gottingen minipigs were used with immunosuppression (cyclosporine A) for this pilot xenograft study. HUC obtained from human benign ureteral tissue were stained by PKH26 and seeded on a collagen cell carrier (CCC). Seven weeks after urethral stricture induction and protective vesicostomy, cell-seeded CCC was implanted in the urethra with HUC luminal and antiluminal, respectively. After two weeks animals were euthanized, urethrography and histological assessment were performed. RESULTS: Surgery was technically feasible in all minipigs. Stricture was radiologically established 7 weeks after induction. CCC was visible after two weeks and showed good integration without signs of inflammation or rejection. In the final urethrography, no remaining stricture could be detected. Near porcine urothelium, PKH26-positive areas were found even if partially detached from CCC. Although diminished, immunofluorescence with pankeratin, CK20, E-cadherin and ZO 1 showed intact urothelium in several areas on and nearby CCC. CONCLUSION: Finally, this study demonstrates that the HUC-seeded CCC used as a xenograft in minipigs is technically feasible and shows promising results for further studies. PMID- 27783147 TI - Crowded environments reduce spatial memory in older but not younger adults. AB - Previous studies have reported an age-related decline in spatial abilities. However, little is known about whether the presence of other, task-irrelevant stimuli during learning further affects spatial cognition in older adults. Here we embedded virtual environments with moving crowds of virtual human pedestrians (Experiment 1) or objects (Experiment 2) whilst participants learned a route and landmarks embedded along that route. In subsequent test trials we presented clips from the learned route and measured spatial memory using three different tasks: a route direction task (i.e. whether the video clip shown was a repetition or retracing of the learned route); an intersection direction task; and a task involving identity of the next landmark encountered. In both experiments, spatial memory was tested in two separate sessions: first following learning of an empty maze environment and second using a different maze which was populated. Older adults performed worse than younger adults in all tasks. Moreover, the presence of crowds during learning resulted in a cost in performance to the spatial tasks relative to the 'no crowds' condition in older adults but not in younger adults. In contrast, crowd distractors did not affect performance on the landmark sequence task. There was no age-related cost on performance with object distractors. These results suggest that crowds of human pedestrians selectively capture older adults' attention during learning. These findings offer further insights into how spatial memory is affected by the ageing process, particularly in scenarios which are representative of real-world situations. PMID- 27783150 TI - Greater phenological sensitivity on the higher Tibetan Plateau: new insights from weekly 5 km EVI2 datasets. AB - Plateau vegetation is considered to be highly sensitive to climate change, especially at higher altitudes. Although the Tibetan Plateau has experienced intensive warming over the past few decades, there is much contradictory evidence regarding its phenological variations and the impact of climatic change. In this study, we explored vegetation phenology through the inflexion point-based method with the weekly 0.05 degrees EVI2 datasets from 1982 to 2010. We observed complex spatiotemporal variations in vegetation phenology on the higher Tibetan Plateau from three aspects. From a spatial aspect, the altitudinal gradients of phenological dates, as well as their directions, varied among different altitudes over the past three decades. Compared with delaying with elevation at altitudes below 5000 m, the phenological parameters at altitudes above 5000 m significantly advanced with increasing altitudes. At higher altitudes, much stronger altitudinal gradients (slope) of phenological dates were observed in the 2000s than in the 1980s and 1990s, i.e., 2.19, 3.47, and 3.68 days' advance for start, maximum, and end dates, respectively, compared to less than 1 day's change per 100 m increase in altitude. From a temporal dynamic aspect, when analyzed at different altitudinal bands, the dynamic trends in phenological dates were generally not significant except the advancing trends in the maximum dates at altitudes above 5000 m and the delaying trend in the end dates at altitudes of 4500-5000 m in the twenty-first century. Remarkable elevation dependency was also observed at the pixel level: increasing amplitudes of phenological dynamic trends were observed at higher altitudes when obtaining their minimum around 5000 m. These spatiotemporal variations of vegetation phenology were due to combined effects from both temperature and precipitation: more abundant rainfall and greater magnitudes of dynamic trends were observed in the average daily minimum temperature (slope = 0.08 degrees C/year) and annual precipitation (slope = 2.17 mm/year) at higher altitudes. PMID- 27783156 TI - Arginase activity, urea, and hydroxyproline concentration are reduced in keratoconus keratocytes. AB - PURPOSE: Keratoconus (KC) is a disease characterized by thinning and deformation of the cornea, but its etiology remains unknown. Seventy percent of the corneal stroma consists of collagen, which is composed of three intertwined polypeptide chains with glycine-hydroxyproline-proline repeats along their sequence. Arginase is a cytoplasmatic enzyme and catalyzes the conversion of arginine to urea and ornithine, which serves as a precursor for the endogenous synthesis of proline and hydroxyproline. The purpose of this study was to analyze arginase activity, as well as collagen and urea formation in normal and KC-keratocytes and to determine the impact of urea on keratocyte viability and proliferation in vitro. METHODS: Primary human keratocytes were isolated by digestion in collagenase (1.0 mg/mL) from surgically removed corneas of eight keratoconus patients and eight normal human corneal buttons and cultured in DMEM/Ham's F12 medium supplemented with 5 % fetal calf serum. Arginase activity and urea concentration were measured in cell-lysates, hydroxyproline concentration in supernatant of cultured keratocytes using colorimetric assay. Cell viability and cell proliferation of cultured keratocytes were assessed after treatment with urea at concentrations up to10 mM for 24 h using assays for metabolic activity and DNA replication. RESULTS: Arginase activity and urea concentration in KC-keratocytes decreased by about 50 % compared to normal keratocytes (p = 0.003 and p = 0.008). Hydroxyproline synthesized by cultured KC-keratocytes was also approximately 50 % less compared to normal keratocytes (p = 0.02) and this difference decreased following treatment with 5.0 or 10.0 mM urea (p = 0.02; 0.03), without any change in cell viability (p > 0.09). However, the urea treatment increased modestly (by 20 %) the proliferation rate of KC-keratocytes (p = 0.04; 0.04; 0.04), without any effect on normal cultured keratocytes (p > 0.09). CONCLUSIONS: We identified suppressed arginase activity in the metabolic program of cultured keratoconus keratocytes. The level of urea, as one product of the enzyme arginase was also decreased. This results in impaired collagen synthesis, evidenced in the culture by reduced hydroxyproline concentration. In addition, our data showed that the other product of the arginase reaction, urea supports the proliferation of KC keratocytes, without changes in their viability. The metabolic reprogramming of keratoconus keratocytes and its impact on development of a clinically detectable keratoconus disease has to be further analyzed. PMID- 27783157 TI - 3-Year update on the first case series of hemi-Descemet membrane endothelial keratoplasty. PMID- 27783152 TI - Sex-specific differences in risk factors for in-hospital mortality and complications in patients with acute coronary syndromes : An observational cohort study. AB - BACKGROUND: The goal of this observational cohort study was to examine gender specific differences in the incidence of acute coronary syndrome (ACS), in hospital complications and mortality. METHODS: A cohort of 1550 patients with the primary diagnosis of ACS were enrolled in the study over a period of 4 years. The in-hospital mortality and complications were analyzed as the main outcome measures. RESULTS: Women were significantly older compared to men (71 +/- 11 years vs. 64 +/- 12 years, p < 0.001) and had higher in-hospital mortality and complications due to this age difference. The prevalence of smoking was lower while hypertension and history of angina pectoris was more frequent in women, independent of age. Percutaneous transluminal coronary angioplasty (PTCA) with or without stenting as well as coronary catheterization significantly reduced in hospital mortality and complications while thrombolytic therapy was associated with a 3.3 times increased mortality odds ratio (OR, p = 0.01). Other significant predictors of in-hospital mortality were in-hospital complications (OR 25, p < 0.001) and ST segment elevation myocardial infarction (STEMI, OR 4.5, p < 0.001). CONCLUSIONS: Women differed from men in terms of ACS clinical characteristics, treatment, invasive procedures and survival outcome and some of these effects were age-related. The future emphasis should be based on the prevention of modifiable risk factors and identification of subgroups of female patients that could benefit from more aggressive therapeutic strategies. PMID- 27783145 TI - Infectious agents after liver transplant: etiology, timeline and patients' cell mediated immunity responses. AB - Infections continue to be one of the leading causes of morbidity and mortality in liver transplant recipients. We retrospectively reviewed the symptomatic infectious episodes that occurred during the first year post-transplant to determine time of onset, causative pathogens and cell-mediated immunity response patterns. Ninety-eight of the 202 (48.5%) recipients enrolled developed at least one infectious episode. The total number of infectious episodes was 135: 77 (57.1%) bacterial, 45 (33.3%) viral and 13 (9.6%) fungal. The most frequently isolated bacteria were Escherichia coli (21 isolates) and Klebsiella pneumoniae (19 isolates). Overall, extended-spectrum beta lactamase-producing and methicillin-resistant organisms were responsible for 29 (29/77; 37.7%) infectious episodes. Members of the herpes virus group, in particular cytomegalovirus (34/45 viral infections, 75.5%), were detected. Candida species (9 isolates) followed by Aspergillus species (4 isolates) were isolated. The majority of infections (63%) occurred during the early post-transplant phase (<1 month), whereas only 8/135 episodes (5.9%) were detected after the sixth month (late phase). Significantly lower median ImmuKnow(r) intracellular ATP values in patients who developed bacterial and fungal infections compared to infection-free patients were observed (P < 0.0001 and P = 0.0016, respectively), whereas patients who developed a viral infection had a median intracellular ATP level not statistically different compared to uninfected patients (P = 0.4). Our findings confirm that bacteria are responsible for the majority of symptomatic infections and occur more frequently during the first month post-transplant. The ImmuKnow(r) measurements can be a useful tool for identifying patients at high risk of developing infection, particularly of fungal and bacterial etiology. PMID- 27783154 TI - Hypoparathyroidism after total thyroidectomy in patients with previous gastric bypass. AB - PURPOSE: Case reports suggest that patients with previous gastric bypass have an increased risk of severe hypocalcemia after total thyroidectomy, but there are no population-based studies. The prevalence of gastric bypass before thyroidectomy and the risk of hypocalcemia after thyroidectomy in patients with previous gastric bypass were investigated. METHODS: By cross-linking The Scandinavian Quality Registry for Thyroid, Parathyroid and Adrenal Surgery with the Scandinavian Obesity Surgery Registry patients operated with total thyroidectomy without concurrent or previous surgery for hyperparathyroidism were identified and grouped according to previous gastric bypass. The risk of treatment with intravenous calcium during hospital stay, and with oral calcium and vitamin D at 6 weeks and 6 months postoperatively was calculated by using multiple logistic regression in the overall cohort and in a 1:1 nested case-control analysis. RESULTS: We identified 6115 patients treated with total thyroidectomy. Out of these, 25 (0.4 %) had undergone previous gastric bypass surgery. In logistic regression, previous gastric bypass was not associated with treatment with i.v. calcium (OR 2.05, 95 % CI 0.48-8.74), or calcium and/or vitamin D at 6 weeks (1.14 (0.39-3.35), 1.31 (0.39-4.42)) or 6 months after total thyroidectomy (1.71 (0.40-7.32), 2.28 (0.53-9.75)). In the nested case-control analysis, rates of treatment for hypocalcemia were similar in patients with and without previous gastric bypass. CONCLUSION: Previous gastric bypass surgery was infrequent in patients undergoing total thyroidectomy and was not associated with an increased risk of postoperative hypocalcemia. PMID- 27783155 TI - Regulation of quantal currents determines synaptic strength at neuromuscular synapses in larval Drosophila. AB - Studies of synaptic homeostasis during muscle fiber (MF) growth in Drosophila larvae have focused on the regulation of the quantal content of transmitter release. However, early studies in crayfish and frog suggested that regulation of quantal current size may be an integral mechanism in synaptic homeostasis. To examine this further in Drosophila, we compared the electrical properties, miniature excitatory postsynaptic potentials (minEPSPs) and miniature excitatory postsynaptic currents (minEPSCs) in different-sized MFs in third-instar larvae and for a single MF during larval growth. The third-instar MFs showed differences in input resistance due to differences in size and specific membrane resistance. We found that electrical coupling between MFs did not contribute substantially to the electrical properties; however, the electrode leak conductance and a slower developing increase in membrane conductance can influence the electrical recordings from these MFs. Our results demonstrated that larger MFs had larger minEPSCs to compensate for changes in MF electrical properties. This was most clearly seen for MF4 during larval growth from the second to third instar. During a predicted 80 % decrease in MF input resistance, the minEPSCs showed a 35 % increase in amplitude and 165 % increase in duration. Simulations demonstrated that the increase in minEPSC size resulted in a 129 % increase in minEPSP amplitude for third-instar larvae; this was mainly due to the increase in minEPSC duration. We also found that MFs with common innervation had similar-sized minEPSCs suggesting that MF innervation influences minEPSC size. Overall, the results showed that increased quantal content and quantal current size contribute equally to synaptic homeostasis during MF growth. PMID- 27783159 TI - Potato plants with genetically engineered tropane alkaloid precursors. AB - MAIN CONCLUSION: Solanum tuberosum tropinone reductase I reduced tropinone in vivo. Suppression of tropinone reductase II strongly reduced calystegines in sprouts. Overexpression of putrescine N -methyltransferase did not alter calystegine accumulation. Calystegines are hydroxylated alkaloids formed by the tropane alkaloid pathway. They accumulate in potato (Solanum tuberosum L., Solanaceae) roots and sprouting tubers. Calystegines inhibit various glycosidases in vitro due to their sugar-mimic structure, but functions of calystegines in plants are not understood. Enzymes participating in or competing with calystegine biosynthesis, including putrescine N-methyltransferase (PMT) and tropinone reductases (TRI and TRII), were altered in their activity in potato plants by RNA interference (RNAi) and by overexpression. The genetically altered potato plants were investigated for the accumulation of calystegines and for intermediates of their biosynthesis. An increase in N-methylputrescine provided by DsPMT expression was not sufficient to increase calystegine accumulation. Overexpression and gene knockdown of StTRI proved that S. tuberosum TRI is a functional tropinone reductase in vivo, but no influence on calystegine accumulation was observed. When StTRII expression was suppressed by RNAi, calystegine formation was severely compromised in the transformed plants. Under phytochamber and green house conditions, the StTRII RNAi plants did not show phenotypic alterations. Further investigation of calystegines function in potato plants under natural conditions is enabled by the calystegine deprived StTRII RNAi plants. PMID- 27783165 TI - How Do We Bridge the West and the East in the Treatment for Gastric Cancer? PMID- 27783172 TI - NSF vs. CIN: Aggregated Screening, Safety, and Protocol Tools for Contrast Imaging in the Setting of Renal Insufficiency. PMID- 27783169 TI - Facial trauma in the Trojan War: author's reply. PMID- 27783160 TI - Diagnosis of Raynaud's phenomenon by 99mTc-pertechnetate hand perfusion scintigraphy: a pilot study. AB - We assess the usefulness of 99mTc-pertechnetate hand perfusion scintigraphy in patients with Raynaud's phenomenon (RP). The study population consisted of 18 patients with primary RP, 25 patients with secondary RP within systemic sclerosis (SSc), and ten healthy individuals. Gamma camera dynamic first-pass study during the first 60 s and a static scintigraphy after 5 min were recorded following a bolus injection of 99mTc-pertechnetate via a cubital vein. Regions of interest were drawn on the summed images around the fingers and the palmar region. The fingers-to-palm ratios were then calculated. The mean fingers-to-palm ratio for dynamic study (blood flow) was 0.58 +/- 0.19 for the healthy group, 0.45 +/- 0.18 for the primary RP, and 0.43 +/- 0.21 for the SSc patients. The mean fingers-to palm ratio for static study (blood pool) was 0.44 +/- 0.06 for the healthy group, 0.42 +/- 0.06 for the primary RP, and 0.36 +/- 0.07 for the SSc patients. Analysis of variance showed these differences to be significant (p = 0.039 from blood flow and p = 0.004 from blood pool). The receiver operating characteristic curve showed sensitivity of 80% and a specificity of 60% when using cutoff values of 0.40 for blood flow and sensitivity of 79% and a specificity of 70% when using cutoff values of 0.37 for blood pool. Our method is able to differentiate between patients with normal and those with abnormal microcirculation of the hands. Dynamic study separates the healthy subjects from patients with RP, while static study separates primary from secondary RP. PMID- 27783161 TI - Consequences of CT colonography in stenosing colorectal cancer. AB - BACKGROUND: In patients with stenosing colorectal cancer (CRC), visualization of the entire colon prior to surgery is recommended to exclude synchronous tumors. Therefore, most centers combine computed tomographic colonography (CTC) with staging CT. The aims of this study were to evaluate the yield and clinical implications of CTC. METHODS: In this multicenter retrospective study, patients with stenosing CRC that underwent CTC and subsequent surgery between April 2013 and November 2015 were included. Result of the CTC, its influence on the surgical treatment plan, and final histology report were evaluated. RESULTS: One hundred sixty-two patients with stenosing CRC were included. Nine (5.6 %) synchronous cancers proximal to the stenosing tumor were suspected with CTC. In four of nine patients, the CTC did not change the primary surgical plan because the tumors were located in the same surgical segment. In five of nine patients, CTC changed the surgical treatment plan. Three of these five patients underwent an extended resection and the presence of the tumors was confirmed. Two of these three synchronous CRCs were also visible on abdominal staging CT. In the other two patients, the result of CTC was false positive which led to an unnecessary extended resection in one patient. CONCLUSION: The yield of CTC was relatively low. In only three patients (1.9 %), CTC correctly changed the primary surgical plan, but in two of them, the tumor was also visible on abdominal staging CT. Moreover, in two patients, CTC was false positive. The clinical value of CTC in stenosing CRC appears to be limited. PMID- 27783164 TI - Guidelines for Guidelines: An Assessment of the American Society of Breast Surgeons Contralateral Prophylactic Mastectomy Consensus Statement. PMID- 27783158 TI - Steroid-resistant nephrotic syndrome: a persistent challenge for pediatric nephrology. AB - Steroid-resistant nephrotic syndrome remains a challenge to treat, but various efforts are underway to better understand the pathogenesis and improve patient outcomes. This review provides an update on the newer advances in understanding the molecular etiologies for a variety of podocyte abnormalities, potential circulating factors that may initiate and sustain the steroid-resistant state, genetic mutations, and precision medicine treatment modalities in this continuously perplexing disorder. PMID- 27783171 TI - Reactions to First Postpubertal Female Same-Sex Sexual Experience in the Kinsey Sample: A Comparison of Minors with Peers, Minors with Adults, and Adults with Adults. AB - This study examined reactions to first postpubertal same-sex sexual experience in the Kinsey female same-sex sample (consisting of females with extensive postpubertal same-sex experience) as a function of participant and partner ages. As such, it complemented the Rind and Welter (2016) study, which examined the same in the Kinsey male same-sex sample. Data were collected by Kinsey interviewers between 1939 and 1961 (M year = 1947). Girls under 18 (M age = 14.9), whose sexual experience was with a woman (M age = 26.3), reacted positively just as often as girls under 18 (M age = 14.1) with peers (M age = 15.0) and women (M age = 22.7) with women (M age = 26.3). The positive-reaction rates were, respectively, 85, 82, and 79 %. In a finer-graded analysis, younger adolescent girls (<=14) (M age = 12.8) with women (M age = 27.4) had a high positive-reaction rate (91 %), a rate reached by no other group. For women (M age = 22.2) with same-aged peers (M age = 22.3), this rate was 86 %. Girls with peers or women had no emotionally negative reactions (e.g., fear, disgust, shame, regret); women with women rarely did. Results contradicted prevailing clinical, legal, and lay beliefs that minor-adult sex is inherently traumatic and would be distinguished as such compared to age-concordant sex. The findings are discussed in terms of the time period in which the sexual experiences occurred. PMID- 27783173 TI - The characteristics of social categorization based on the unidimensional variation of gender versus age. AB - The present study explored the characteristics of social categorization based on the unidimensional variation of gender or age using the Garner's Selective Attention Paradigm. The task of the experiment was to judge whether there was a mole on a person's face, and the results showed that young participants' response times were slower when the age or gender of the face stimuli varied, demonstrating that young people, rather than older people, can activate both an age category and a gender category automatically. Meanwhile, all participants' responses to the old faces were slower than that to the young faces. Females reacted faster than males, demonstrating that females tend to have an advantage for face processing. PMID- 27783166 TI - Isolation and characterization of a new enterovirus F in yak feces in the Qinghai Tibetan Plateau. AB - An enterovirus (EV) strain, designated as SWUN-AB001, was isolated in the Qinghai Tibetan Plateau from a yak with severe diarrheal disease. The complete genome of strain SWUN-AB001 was 7,382 bp in length and shared 35.1-68.5% nt identities with bovine EVs belonging to a candidate new type EV-F7. Using the sequence difference values in the VP1 gene as a criterion for demarcating a new serotype/genotype in the Enterovirus genus, strain SWUN-AB001 had only a 71.1% nt and a 79.2% aa identity, in the VP1 region, with the most closely matched EV, further indicating that a new type of EV had been identified. Phylogenetic analysis of the nt sequence of the viral polyprotein and of VP1 genes demonstrated that the virus fell within the EV-F cluster, but was located in a unique lineage. Furthermore, a large-scale surveillance study indicated that the prevalence of this EV in yaks was 31.05% (95% CI = 25.5-37.6%) in 235 animals with diarrhea and 24.13% (95% CI = 17.4-32.4%) in 116 healthy yaks. However, there was no significant difference in virus prevalence between diarrheal and healthy samples. Interestingly, in the Tibet region, diarrheal feces had a higher incidence of EVs than feces of healthy yaks (odd ratios = 6.03, 95% CI = 1.93-18.86), indicating that the incidence of EV was potentially correlated with the clinical symptom of diarrhea in yaks. PMID- 27783168 TI - What range of stimulus intensities should we apply to elicit abnormal muscle response in microvascular decompression for hemifacial spasm? AB - BACKGROUND: Abnormal muscle response (AMR) has been considered as a predictor of the prognosis after microvascular decompression (MVD) for hemifacial spasm (HFS). However, its predictive value has not always been satisfactory. The objective of this work was to confirm an optimal range of stimulus intensities to elicit AMR in surgery. METHODS: Seventy-two consecutive patients with primary HFS treated by MVD were retrospectively included in this study. A wide range of stimulus intensities from 1 to 100 mA was applied in AMR monitoring. The AMR-elicited threshold value was quantitatively traced throughout all surgical procedures. The relationship between clinical outcomes and electrophysiological findings was analyzed. RESULTS: Of the 72 patients, 44 were immediately cured and 24 were delayed cured; the remaining 4 were proved not to be cured in their follow-up periods. The patterns of AMR-elicited threshold changes were categorized into five types, which could only be discriminated with a wide range of stimulus intensities. The constituent ratio of the patterns was significantly different (P < 0.001) among the clinical outcomes. CONCLUSIONS: Some patterns of AMR changes might have been ignored if we had only applied a narrow range of stimulus intensities (1-30 mA) to judge whether AMR disappeared or not. Thus, a wide range of stimulus intensities (1-100 mA) to trace the AMR-elicited threshold values was proposed for a more precise prediction. PMID- 27783174 TI - Micronucleus formation during chromatin condensation and under apoptotic conditions. AB - In early S phase the newly replicated DNA is folded back to increasingly compact structures. The process of chromatin condensation inside the nucleus starts with the formation of a micronucleus observed in five established cell lines (K562, CHO, Indian muntjac, murine preB and SCC). Supercoiling of chromatin generates a polarized end-plate region extruded from the nucleus. The extruded chromatin is turned around itself forming the head portion (micronucleus) visible by fluorescence microscopy until the middle of S phase when chromatin structures are succeeded by distinguishable early forms of chromosomes. The generation of micronuclei upon apoptotic treatment was achieved by the methotrexate (MTX) treatment of cells. A close correlation was found between the frequency of micronucleus and MTX concentration, with low frequency at low (0.1 uM) and increasingly higher frequency between 1 and 100 uM concentrations. Characteristic deformation and shrinkage of nuclei indicated apoptosis. High MTX concentration (100 uM) caused the enlargement and necrotic disruption of nuclei. Inhibition of DNA synthesis during replicative DNA synthesis by biotinylated nucleotide prevented the formation of metaphase chromosomes and elevated the frequency of early intermediates of chromosome condensation including micronucleus formation. Based on these observations the micronucleus is regarded as: (a) a regularly occuring element of early chromatin condensation and (b) a typical sign of nuclear membrane damage under toxic conditions. Explanation is given why the micronucleus is hidden in nuclei under normal chromatin condensation and why chromatin motifs including micronuclei become visible upon cellular damage. PMID- 27783163 TI - Evaluation of Local and Distant Recurrence Patterns in Patients with Triple Negative Breast Cancer According to Age. AB - BACKGROUND: Triple-negative breast cancer (TNBC) subtype and young patient age are both associated with an increased risk of local recurrence (LR) and distant recurrence (DR). In young women with TNBC, it is unclear whether subtype or patient age is driving prognosis. METHODS: Patients treated for primary TNBC from 1998 to 2011 were identified from the breast surgery database. Clinicopathologic characteristics, treatment, and outcomes were compared between patients <40 and >=40 years of age at diagnosis. Multivariate models were used to identify factors independently associated with LR and DR. RESULTS: Among 1930 patients with TNBC, 289 (15 %) were <40 and 1641 (85 %) were >=40 years of age at diagnosis. Younger patients were more likely to present with higher stage disease and more likely to receive mastectomy (p < 0.01), axillary node dissection (p < 0.01), and chemotherapy (p < 0.01). At a median follow-up of 74 (0-201.1) months, there was no difference in LR or disease-free survival (DFS) by age group [5-year LR = 3.9 % (95 % confidence interval (CI) 1.5-6.2) vs. 4.5 % (95 % CI 3.5-5.6) and 5-year DFS = 75.3 % (95 % CI 70.2-80.7) vs. 77.7 % (95 % CI 75.6-79.8), p = 0.94] in patients aged <40 and >=40 years, respectively. On multivariate analysis, larger tumor size, lymphovascular invasion, and nodal positivity were associated with increased risk of DR. Age and type of surgery were not significantly associated with either outcome. CONCLUSIONS: Young age at diagnosis is not an independent risk factor for LR or DR in patients with TNBC. PMID- 27783178 TI - Reply to commentary on: medical ethics: enhanced or undermined by modes of payment? PMID- 27783162 TI - A randomized controlled trial of subcutaneous closed-suction Blake drains for the prevention of incisional surgical site infection after colorectal surgery. AB - BACKGROUND: The effects of subcutaneous closed-suction Blake drain for preventing incisional surgical site infections (SSIs) after colorectal surgery have never been evaluated in a randomized controlled trial (RCT). Thus, we performed a RCT to evaluate the clinical benefits of using a subcutaneous closed-suction Blake drain in patients undergoing colorectal surgery. METHOD: Consecutive patients who underwent colorectal surgery were enrolled in this study. Patients were randomly assigned to the subcutaneous closed-suction drainage arm or the control (no subcutaneous drainage) arm. The primary endpoint was incidence rate of incisional SSIs. And, we performed logistic regression analysis to detect predictive factors for incisional SSIs after colorectal surgery. RESULTS: From November 2012 to September 2014, a total of 240 patients were enrolled in this study. One-hundred seventeen patients who were treated by the control arm and 112 patients by the subcutaneous drainage arm were judged to be eligible for analysis. The incidence of incisional SSIs rate was 8.7 % in the overall patients. The incidence of incisional SSIs rate was 12.8 % in the control arm and 4.5 % in the subcutaneous drainage arm. There was significantly reduction of the incidence in the subcutaneous drainage arm than in the control arm (p = 0.025). Logistic regression analysis demonstrated that thickness of subcutaneous fat >3.0 cm, forced expiratory volume in 1 s as percent of forced vital capacity (FEV1.0 %) >70 %, and subcutaneous drain were independent predictors of postoperative incisional SSIs (p = 0.008, p = 0.004, and p = 0.017, respectively). CONCLUSION: The results of our RCT suggest that a subcutaneous Blake drain is beneficial for preventing incisional SSIs in patients undergoing colorectal surgery. PMID- 27783176 TI - Mutations in MurE, the essential UDP-N-acetylmuramoylalanyl-D-glutamate 2,6 diaminopimelate ligase of Corynebacterium glutamicum: effect on L-lysine formation and analysis of systemic consequences. AB - OBJECTIVES: To explore systemic effects of mutations in the UDP-N acetylmuramoylalanyl-D-glutamate 2,6-diaminopimelate ligase (MurE) of Corynebacterium glutamicum, that leads to extracellular L-lysine accumulation by this bacterium. RESULTS: The analysis of a mutant cohort of C. glutamicum strains carrying all possible 20 amino acids at position 81 of MurE revealed unexpected effects on cellular properties. With increasing L-lysine accumulation the growth rate of the producing strain is reduced. A dynamic flux balance analysis including the flux over MurE fully supports this finding and suggests that further reductions at this flux control point would enhance L-lysine accumulation even further. The strain carrying the best MurE variant MurE-G81K produces 37 mM L-lysine with a yield of 0.17 g/g (L-lysine.HCl/glucose.H2O), bearing no other genetic modification. Interestingly, among the strains with high L-lysine titers, strain variants occur which, despite possessing the desired amino acid substitutions in MurE, have regained close to normal growth and correspondingly lower L-lysine accumulation. Genome analyses of such variants revealed the transposition of mobile genetic elements which apparently annulled the favorable consequences of the MurE mutations on L-lysine formation. CONCLUSION: MurE is an attractive target to achieve high L-lysine accumulation, and product formation is inversely related to the specific growth rate. Moreover, single point mutations leading to elevated L-lysine titers may cause systemic effects on different levels comprising also major genome modifications. The latter caused by the activity of mobile genetic elements, most likely due to the stress conditions being characteristic for microbial metabolite producers. PMID- 27783170 TI - Assessment of ataxia phenotype in a new mouse model of galactose-1 phosphate uridylyltransferase (GALT) deficiency. AB - Despite adequate dietary management, patients with classic galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway. PMID- 27783167 TI - Clinicopathological features of Siewert type II adenocarcinoma: comparison of gastric cardia adenocarcinoma and Barrett's esophageal adenocarcinoma following endoscopic submucosal dissection. AB - OBJECTIVES: Siewert type II esophagogastric junction adenocarcinoma encompasses both gastric cardia adenocarcinoma (GCA) and Barrett's esophageal adenocarcinoma (BEA) due to short-segment Barrett's esophagus. We compared these two types of Siewert type II esophagogastric junction adenocarcinoma in terms of background factors and clinical outcomes of endoscopic submucosal dissection (ESD). METHODS: We enrolled 139 patients (142 lesions) who underwent ESD from 2006 to 2014 at our institution. Background factors evaluated were age, sex, body mass index, hypertension, hyperlipidemia, hyperuricemia, diabetes mellitus, smoking, drinking, double cancer, and endoscopic findings. Clinical outcomes evaluated were procedure time, en bloc resection rate, curative resection rate, and adverse events. RESULTS: There were 87 GCA lesions (61.2%) and 55 BEA lesions. Features of BEA [55 lesions (38.8%)] included a younger age, small diameter, and a protruding type, along with a high frequency of esophageal hiatal hernia and less mucosal atrophy. There were no significant differences in lifestyle-related background factors between the GCA and BEA groups. Curative resection rate was greater for GCA (81%) than for BEA (66%) (P = 0.01). There were no serious adverse events in either group. Among the factors for noncurative resection, lymphovascular invasion and depth of invasion were greater for BEA (33.3 vs. 7 and 20.7 vs. 8.2%, respectively (P < 0.01). Of the noncured patients, 70% underwent additional surgery and none had postoperative lymph node metastasis. CONCLUSIONS: Siewert type II adenocarcinoma encompasses two types of cancers with different etiologies: GCA and BEA. Although there are no significant differences in lifestyle-related background factors between GCA and BEA, BEA is a risk factor for noncurative resection via ESD. PMID- 27783177 TI - Acidithiobacillus ferrivorans SS3 presents little RNA transcript response related to cold stress during growth at 8 degrees C suggesting it is a eurypsychrophile. AB - Acidithiobacillus ferrivorans is an acidophilic bacterium that represents a substantial proportion of the microbial community in a low temperature mining waste stream. Due to its ability to grow at temperatures below 15 degrees C, it has previously been classified as 'psychrotolerant'. Low temperature-adapted microorganisms have strategies to grow at cold temperatures such as the production of cold acclimation proteins, DEAD/DEAH box helicases, and compatible solutes plus increasing their cellular membrane fluidity. However, little is known about At. ferrivorans adaptation strategies employed during culture at its temperature extremes. In this study, we report the transcriptomic response of At. ferrivorans SS3 to culture at 8 degrees C compared to 20 degrees C. Analysis revealed 373 differentially expressed genes of which, the majority were of unknown function. Only few changes in transcript counts of genes previously described to be cold adaptation genes were detected. Instead, cells cultured at cold (8 degrees C) altered the expression of a wide range of genes ascribed to functions in transcription, translation, and energy production. It is, therefore, suggested that a temperature of 8 degrees C imposed little cold stress on At. ferrivorans, underlining its adaptation to growth in the cold as well as suggesting it should be classified as a 'eurypsychrophile'. PMID- 27783175 TI - Short-term outcomes of laparoscopic versus open total colectomy with ileorectal anastomosis: a case-matched analysis from a nationwide database. AB - BACKGROUND: In the current study, we aimed to compare peri- and postoperative 30 day outcomes of patients undergoing laparoscopic versus open total colectomy with ileorectal anastomosis in a case-matched design using data procedure-targeted database. METHODS: Patients who underwent elective total colectomy with ileorectal anastomosis in 2012 and 2013 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Patients were divided into two groups according to the type of surgical approach (laparoscopic and open). Laparoscopic and open groups were matched (1:1) based on age, gender, diagnosis, body mass index, and American Society of Anesthesiologists classification. Comorbidities, perioperative, and short-term (30-day) postoperative outcomes were compared between the matched groups. RESULTS: We identified 1442 patients-549 in the laparoscopic group and 893 patients in the open group. After case matching, there were 326 patients in each group. There were 48 (14.7%) patients who had conversion in the laparoscopic group. The open group had a higher proportion of patients with ascites [0 (0%) vs. 7 (2.1%) p = 0.015], preoperative weight loss [26 (8.0%) vs. 45 (13.8%) p = 0.018], and contaminated wound classifications [Clean/Contaminated 261 (80%) vs. 240 (74%), Contaminated 55 (16.9%) vs. 54 (16.6%), and Dirty/Infected 8 (2.5%) vs. 28 (8.6%), (p = 0.003)]. The laparoscopic group had a significantly longer operative time (242 +/- 98 vs. 202 +/- 116 min, p < 0.001), shorter hospital stay (9.4 +/- 8.5 vs. 13.3 +/- 10.7 days, p < 0.001), and lower ileus rate (23.9 vs. 31.0%, p = 0.045) than the open group. After adjusting for covariates, the differences in terms of operative time and hospital stay remained significant [odds ratio (OR): 0.79, confidence interval (CI) 0.74-0.85 and OR 1.36, CI 1.21-1.52, p < 0.001, respectively]. CONCLUSIONS: Laparoscopic approach for total colectomy with ileorectal anastomosis is associated with a shorter hospital stay but longer operative time compared with an open approach. PMID- 27783180 TI - Klaus Minde (1933-2016). PMID- 27783179 TI - Highly virulent Beauveria bassiana strains against the two-spotted spider mite, Tetranychus urticae, show no pathogenicity against five phytoseiid mite species. AB - Entomopathogenic fungi and predatory mites can independently contribute to suppressing the two-spotted spider mite, Tetranychus urticae Koch. It is important to assess the risk of possible fungal infections in predators when a combination of them are being considered as a tandem control strategy for suppressing T. urticae. The first part of this study tested 12 Beauveria bassiana isolates for virulence in T. urticae. Strains SCWJ-2, SDDZ-9, LNSZ-26, GZGY-1-3 and WLMQ-32 were found to be the most potent, causing 37.6-49.5% adult corrected mortality at a concentration of 1 * 107 m/L conidia 4 days post-treatment. The second part evaluated the pathogenicity of these five strains in five species of predatory phytoseiid mites. The bioassay results indicated that all adult predatory mite mortalities ranged from 7.5 to 9.1% 4 days post-treatment. No viable fungal hyphae were found on predator cadavers. Observations with scanning electron microscopy revealed that conidia were attached to the cuticle of predatory mites within 2-12 h after spraying with strain LNSZ-26, and had germinated within 24-36 h. After 48 h, conidia had gradually been shed from the mites, after none of the conidia had penetrated the cuticular surfaces. In contrast, the germinated conidia successfully penetrated the cuticle of T. urticae, and within 60 h the fungus colonized the mite's body. Our study demonstrated that although several B. bassiana strains displayed a high virulence in T. urticae there was no evident pathogenicity to phytoseiid mites. These findings support the potential use of entomopathogenic fungus in combination with predatory mites in T. urticae control programs. PMID- 27783182 TI - Bottlenecks in bog pine multiplication by somatic embryogenesis and their visualization with the environmental scanning electron microscope. AB - Somatic embryogenesis (SE) is an important biotechnological technique used for the propagation of many pine species in vitro. However, in bog pine, one of the most endangered tree species in the Czech Republic, limitations were observed, which negatively influenced the development and further germination of somatic embryos. Although initiation frequency was very low-0.95 %, all obtained cell lines were subjected to maturation. The best responding cell line (BC1) was used and subjected to six different variants of the maturation media. The media on which the highest number of early-precotyledonary/cotyledonary somatic embryos was formed was supplemented with 121 MUM abscisic acid (ABA) and with 6 % maltose. In the end of maturation experiments, different abnormalities in formation of somatic embryos were observed. For visualization and identification of abnormalities in meristem development during proliferation and maturation processes, the environmental scanning electron microscope was used. In comparison to the classical light microscope, the non-commercial environmental scanning electron microscope AQUASEM II has been found as a very useful tool for the quick recognition of apical meristem disruption and abnormal development. To our knowledge, this is the first report discussing somatic embryogenesis in bog pine. Based on this observation, the cultivation procedure could be enhanced and the method for SE of bog pine optimized. PMID- 27783181 TI - Potassium up-regulates antioxidant metabolism and alleviates growth inhibition under water and osmotic stress in wheat (Triticum aestivum L). AB - Pot experiments were conducted to find out the effectivity of K on Triticum aestivum L cultivars. Polyethylene glycol 6000 (PEG 6000) was used as an osmoticum to induce osmotic stress under sand culture setting up the water potential of external solution at -3 and -5 bars. In pots, plants were raised under restricted and normal irrigation and K was applied in varying doses (0, 20, 40, 60 kg ha-1) and estimation of different physiological and biochemical parameters was done at two developmental stages, i.e., preflowering and flowering. Supplementation of K resulted in obvious increase in growth and activity of antioxidant enzymes in both normal and stressed plants. Added potassium increased total phenols and tannins thereby strengthening the components of both the enzymatic as well as non-enzymatic antioxidant system. Under both normal and stressed conditions, K-fed plants experienced significant increase in the synthesis of osmolytes like free proline, amino acids, and sugars which assumes special significance in growth under water stress conditions. Wheat plants accumulating greater K were able to counteract the water stress-induced changes by maintaining lower Na/K ratio. PMID- 27783184 TI - Corticospinal excitability in the non-dominant hand is affected by BDNF genotype. AB - The objective of this study was to assess the functional state of corticospinal projections in the non-dominant hand according to brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. We investigated this in 34 healthy right handed individuals (12 men, mean age 27.4 +/- 3.4 years) who underwent two experimental sessions consisting of corticospinal excitability measurements with single-pulse transcranial magnetic stimulation (TMS) and hand motor function assessments with a sequential finger motor task of the non-dominant hand. Experimental sessions were separated by periods of at least 2 days to avoid carryover effects. Data were analyzed according to BDNF polymorphism (Val/Val vs. Val/Met vs. Met/Met group). Ten (29.4%), seventeen (50.0%), and seven (20.6%) participants were allocated to the Val/Val, Val/Met, and Met/Met groups, respectively. Motor thresholds to TMS did not differ among groups, but the amplitude of the motor-evoked potentials in the non-dominant hand induced by suprathreshold (120% of MT) TMS was significantly lower in the Met/Met group than in the other two groups (p < 0.05). Movement accuracy and reaction time in the sequential finger motor task showed no significant differences among groups. These results indicate that Met/Met BDNF homozygote status affects corticospinal excitability, and should be controlled for in studies of motor system function using brain stimulation. Our findings may have clinical implications regarding further investigation of the impact of BDNF genotype on the human motor system. PMID- 27783183 TI - Association of sudomotor function with peripheral artery disease in type 2 diabetes. AB - Peripheral artery disease (PAD) is the major risk factor for cardiovascular disease and lower extremity amputation in patients with diabetes. Autonomic neuropathy is a risk factor for cardiovascular-related morbidity and mortality. Sudomotor dysfunction is well established in type 2 diabetes mellitus (T2DM) and reflects small fibre neuropathy, cardiovascular autonomic neuropathy and peripheral sympathetic autonomic neuropathy. However, the relationship between sudomotor dysfunction and PAD remains unexplored. Therefore, the aim of present study was to explore the association of sudomotor function with ankle-brachial index (ABI) and C-reactive protein (CRP) in T2DM. In this cross-sectional study, we recruited 36 consecutive type 2 diabetes patients and 20 age- and sex-matched healthy controls. Sudomotor function was assessed using Sudoscan (Sudoscan-Impeto Medical Device, EZS 01750010193, Paris, France), which detects sweat gland function through measurement of electrochemical skin conductance of both hands and feet. Measurement of ankle-brachial ABI was carried out with sphygmomanometer and Doppler device (Hadeco Bidop ES-100V3). Glycated haemoglobin (HbA1c), fasting plasma glucose, and inflammatory marker CRP were also measured. Type 2 diabetic patients had significantly impaired sudomotor function (48.14 +/- 8.28 vs. 76.48 +/- 6.72 us), lower ABI (0.89 +/- 0.25 vs. 1.15 +/- 0.11) and elevated CRP (5.32 +/- 2.41 vs. 2.45 +/- 1.11 mg/l) as compared to healthy controls, respectively (p < 0.01). Sudoscan scores were found to be inversely correlated with CRP and HbA1c, and directly correlated with ABI (p < 0.05) in the patients. Sudomotor dysfunction is associated with significant peripheral artery disease, vascular inflammation and impaired glycaemic status. PMID- 27783185 TI - Is keratoconus more severe in pediatric population? AB - PURPOSE: To compare the ophthalmic parameters and the severity of keratoconus (KC) in pediatrics and adults at the time of initial diagnosis in an Iranian population. METHODS: KC was diagnosed via slit-lamp examination and Pentacam imaging. In a retrospective observational study, consecutive patients were divided into two groups of pediatrics (<18 years old) and adults (>18 years old). Topographic, keratometric, and tomographic parameters, and severity of KC at the time of diagnosis were compared in both groups. Severity of KC was classified according to Amsler-Krumeich classification. RESULTS: One hundred fifty-eight eyes of 158 pediatric patients and 343 eyes of 343 adults with KC were studied. The mean ages of the pediatric and adult patients were 15 +/- 1.9 and 22 +/- 1.9 years, respectively (p < 0.001). The results revealed that pediatric patients had significantly higher values of anterior and posterior mean, flat and steep keratometry, astigmatism, and maximum elevation and significantly lower central and thinnest corneal thickness (p < 0.05). No significant difference was found regarding sphere, cylinder, manifest refraction spherical equivalent, and uncorrected and best-spectacle corrected visual acuity between the groups (p > 0.05). Pediatric patients had a significantly more severe KC than adult patients according to Amsler-Krumeich classification (p = 0.001). CONCLUSION: Our findings suggest that KC is more severe in pediatrics, hence the fact that they should be closely monitored and intensively treated. PMID- 27783186 TI - Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension. AB - Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2 +/- 9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p = 0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039-1.713; p = 0.03). Moreover, patients with RV-RWT >=0.21 showed better long-term outcomes than did those without (log-rank p = 0.03), while those with RV-RWT >=0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT <0.21 and without mid-term RV reverse remodeling, on the other hand, had worse long-term outcomes than other sub groups. In conclusions, RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our finding may have clinical implications for better management of PH patients. PMID- 27783187 TI - Heart deformation analysis: the distribution of regional myocardial motion patterns at left ventricle. AB - The aim of the present study was to test the hypothesis that heart deformation analysis (HDA) is able to discriminate regional myocardial motion patterns on the left ventricle (LV). Totally 21 healthy volunteers (15 men and 6 women) without documented cardiovascular diseases were recruited. Cine MRI was performed on those subjects at four-chamber, two-chamber, and short-axis views. The variations of segmental myocardial motion indices of the LV, which were measured with the HDA tool, were investigated. Regional displacement, velocity, strain and strain rate were compared between lateral wall and septal wall using t tests. There are significant variations (CoV = 18.0-72.4%) of myocardial motion indices (average over 21 subjects) among 16 myocardial segments. There are significant differences (p < 0.05) between displacement, velocity, strain and strain rate measured at lateral and septal areas of the LV. In conclusion, HDA is able to present different regional LV motion patterns from multiple aspects in healthy volunteers. PMID- 27783189 TI - Understanding the Relationship Between Sports-Relevant Gambling and Being At-Risk for a Gambling Problem Among American Adolescents. AB - Fantasy sports is a growing industry with a reported 56.8 million individuals participating in the United States and Canada alone in 2015. Whereas this activity has attracted considerable public attention, little research has examined its impact on adolescents in spite of their high rates of gambling. The current study examined the relationship between regular participation (more than once a month) in sport-relevant gambling activities among adolescents and those identified as being at-risk for a gambling problem. Questionnaire responses were collected from high school students (N = 6818; 49 % male) in Wood County, Ohio, United States. Statistical analyses revealed that regular involvement in sports betting, fantasy sports betting, and daily fantasy sports betting among adolescents was associated with a higher risk of gambling problems. Further, although males participate more frequently in these activities, females who participate have a stronger likelihood of being at-risk. Students aged 16-19 years old are at a higher risk for developing a gambling problem compared to younger adolescents when regularly engaging in sports-related gambling. Moreover, regularly participating in daily fantasy sports is the strongest predictor of at risk gambling behavior in 13-15 year old students. A hierarchical logistic regression supports that controlling for gender and age, all forms of sport relevant gambling activities are significant predictors of at-risk gambling. This study contributes to a more comprehensive understanding of the impact of sports betting and fantasy sports on adolescents and establishes an initial step for future studies to further investigate these relationships. PMID- 27783188 TI - Interaction, at Ambient Temperature and 80 degrees C, between Minerals and Artificial Seawaters Resembling the Present Ocean Composition and that of 4.0 Billion Years Ago. AB - Probably one of the most important roles played by minerals in the origin of life on Earth was to pre-concentrate biomolecules from the prebiotic seas. There are other ways to pre concentrate biomolecules such as wetting/drying cycles and freezing/sublimation. However, adsorption is most important. If the pre concentration did not occur-because of degradation of the minerals-other roles played by them such as protection against degradation, formation of polymers, or even as primitive cell walls would be seriously compromised. We studied the interaction of two artificial seawaters with kaolinite, bentonite, montmorillonite, goethite, ferrihydrite and quartz. One seawater has a major cation and anion composition similar to that of the oceans of the Earth 4.0 billion years ago (ASW 4.0 Ga). In the other, the major cations and anions are an average of the compositions of the seawaters of today (ASWT). When ASWT, which is rich in Na+ and Cl-, interacted with bentonite and montmorrilonite structural collapse occurred on the 001 plane. However, ASW 4.0 Ga, which is rich in Mg2+ and SO42-, did not induce this behavior. When ASW 4.0 Ga was reacted with the minerals for 24 h at room temperature and 80 degrees C, the release of Si and Al to the fluid was below 1 % of the amount in the minerals-meaning that dissolution of the minerals did not occur. In general, minerals adsorbed Mg2+ and K+ from the ASW 4.0 Ga and these cations could be used for the formation of polymers. Also, when the minerals were mixed with ASW 4.0 Ga at 80 degrees C and ASWT at room temperature or 80 degrees C it caused the precipitation of CaSO4?2H2O and halite, respectively. Finally, further experiments (adsorption, formation of polymers, protection of molecules against degradation, primitive cell wall formation) performed under the conditions described in this paper will probably be more representative of what happened on the prebiotic Earth. PMID- 27783190 TI - A novel Tetra-primer ARMS-PCR based assay for genotyping SNP rs12303764(G/T) of human Unc-51 like kinase 1 gene. AB - Various case-control studies have shown association of single nucleotide polymorphism rs12303764(G/T) in ULK1 with crohn's disease. The techniques used in these studies were time consuming, complicated and require sophisticated/expensive instruments. Therefore, in order to overcome these problems, we have developed a new, rapid and cost effective Tetra-primer ARMS-PCR assay to genotype single nucleotide polymorphism rs12303764(G/T) of ULK1 gene. We manually designed allele specific primers. DNA fragment amplified using outer primers was sequenced to obtain samples with known genotypes (GG, GT and TT) for further use in the development of T-ARMS-PCR assay. Amplification conditions were optimized for parameters; annealing temperature, Taq DNA polymerase and primers. The developed T-ARMS-PCR assay was applied to genotype one hundred samples from healthy individuals. Genotyping results of 10 DNA samples from healthy individuals for rs12303764(G/T) by T-ARMS-PCR assay and sequencing were concordant. The newly developed assay was further applied to genotype samples from 100 healthy individuals of North Indian origin. Genotype frequencies were 9, 34 and 57 % for GG, GT and TT, respectively. Allele frequencies were 0.26 and 0.74 for G and T, respectively. The allele frequencies were in Hardy-Weinberg's equilibrium (p = 0.2443). T-ARMS-PCR assay developed in our laboratory for genotyping rs12303764 (G/T) of ULK1 gene is time saving and cost-effective as compared to the available methods. Furthermore, this is the first study reporting allelic and genotype frequencies of ULK1 rs12303764 (G/T) variants in North Indian population. PMID- 27783192 TI - Why Paid Family and Medical Leave Matters for the Future of America's Families, Businesses and Economy. AB - Paid family and medical leave are vital public policies for promoting large-scale improvements in maternal and child health that can boost our national economy. That is why MomsRising-a national on-the-ground and online grassroots organization with over a million members across the United States-is thrilled by the growing momentum for paid family and medical leave. We are not the least bit surprised that support for this critical policy is growing. The United States is the only industrialized nation in the world without paid family and medical leave, and the fact that these basic workplace protections are missing hurts America's global competitiveness, businesses, economy, and, most importantly, infant and maternal mortality rates. PMID- 27783193 TI - Natural concentrations and reference values for trace elements in soils of a tropical volcanic archipelago. AB - Fernando de Noronha is a small volcanic archipelago in the Southern Atlantic, some 350 km NE of the city of Natal in NE Brazil. These remote volcanic islands represent a largely pristine environment, distant from sources of anthropogenic contamination. This study was carried out to determine the natural concentrations of Ag, Ba, Cd, Co, Cr, Cu, Mo, Ni, Pb, Sb, V and Zn in the A and B horizons of soils of Fernando de Noronha. The aims of the study were twofold: determine whether there is a relationship between the bedrock geology and soils and to establish quality reference values for soils from Fernando de Noronha. Soil samples were subjected to acid digestion by the USEPA method 3051A, and metals were determined by inductively coupled plasma emission spectrophotometry. The results showed that the trace element distribution largely reflects the geochemistry of the underlying volcanic rocks of the Remedios and Quixaba Formations. The results demonstrate that the concentrations of Ba, Cr, Zn, Ni and Cu from the soils of the volcanic Fernando de Noronha archipelago are higher than those found in soils from continental Brazil. However, concentrations of Ni, Cu and Co are lower in soils of the archipelago as compared to other volcanic islands throughout the world. The elevated trace element concentrations of the volcanic parent material of Fernando de Noronha soils seem to be the main factor governing the relatively high natural concentrations of trace elements. PMID- 27783191 TI - Exploring estrogenic activity in lung cancer. AB - It is well known that a connection between xenobiotics inhalation, especially tobacco combustion and Lung Cancer development is strongly significant and indisputable. However, recent studies provide evidence indicating that another factors such as, estrogens are also involved in lung carcinoma biology and metabolism. Although the status of estrogen receptors (ER), in both cancerous and healthy lung tissue has been well documented, there is still inconclusive data with respect of which isoform of the receptor is present in the lungs. However according to several studies, ERbeta appears to be predominant form. Apart from ERs, estrogens can work through a recently discovered G-coupled estrogen receptor. Binding with both types of the receptors causes a signal, which leads to i.e. enhanced cell proliferation. There are many published reports which suggest that estrogen can be synthesized in situ in lung cancer. Some disturbances in the activity and expression levels of enzymes involved in estrogen synthesis were proved. This suggests that increased amounts of sex steroid hormones can affect cells biology and be the reason of the accelerated development and pathogenesis of lung cancer. There also exist phenomena which associate estrogenic metabolism and tobacco combustion and its carcinogenic influence on the lungs. Compounds present in cigarette smoke induce the activity of CYP1B1, the enzyme responsible for estrogenic metabolism and synthesis of their cateholic derivatives. These structures during their redox cycle are able to release reactive oxygen species or form DNA adduct, which generally leads to destruction of genetic material. This process may explain the synergistic effect of smoking and estrogens on estrogen-dependent lung cancer development. PMID- 27783194 TI - Assessment of organochlorine pesticide contamination in waterbirds from an agricultural region, Central China. AB - Twenty-one organochlorine pesticides (OCPs) were measured in the muscle of six predominant waterbird species from Jianghan Plain, Hubei Province, Central China. Among OCPs, DDTs were the most prevalent compounds, with average concentration ranging from 31.1 to 1445 ng/g lipid weight. Little egrets (Egretta garzetta) and Chinese pond herons (Ardeola bacchus) showed significantly higher concentrations of OCPs (p < 0.05) due to their dietary habits and migratory patterns. There were no statistically significant differences (p > 0.05) for most OCPs between sex and age groups. The accumulation profiles of HCHs and DDTs suggested that these OCPs in Jianghan Plain were largely derived from historical usage. Risk assessment indicated that heptachlor could be likely to pose adverse health effects on people consuming ducks in Jianghan Plain. PMID- 27783196 TI - Management of prolactinomas: a survey of physicians from the Middle East and North Africa. AB - BACKGROUND: Prolactinomas are the commonest functional tumors of the pituitary gland. There are still controversies regarding medical therapy in specific clinical situations. Patients may be managed by different specialists in the Middle East and North Africa (MENA) region and no data exist on patterns of clinical management. OBJECTIVES: To ascertain the diagnostic and therapeutic approaches to prolactinomas among relevant professionals from the MENA region. METHODS: An online survey of a large sample of physicians was conducted. The questionnaire covered various aspects of diagnosis and treatment of prolactinomas. 468 respondents were included; 36 % were endocrinologists; 49 % worked in public facilities and 81 % graduated more than 10 years. 40 and 30 % would have seen 1-5 and more than 5 suspected or confirmed prolactinomas over a 6 months period, respectively. RESULTS: Regarding the diagnosis, 30 % of the respondents considered that prolactin levels <100 ng/ml exclude the presence of a prolactinoma. 21 % of respondents considered prolactin levels >250 ng/ml compatible with macroprolactinomas only, whereas others accepted this to be compatible also with microprolactinomas, macroprolactinaemia and drug-induced hyperprolactinemia (50, 42 and 36 % respectively). 71 % of respondents favored the screening for macroprolactin in asymptomatic individuals with hyperprolactinemia. Regarding the treatment, 84 % of respondents would treat microprolactinomas even in the absence of symptoms whereas 72 % of the respondents would treat microprolactinomas only if symptoms exist. 60 and 49 % of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas and microprolactinomas respectively. Similar proportions had no preference of either cabergoline or bromocriptine as the best treatment for macroprolactinoma (27 %) and microprolactinomas (32 %). 46 and 75 % of respondents favored treatment withdrawal 2-3 years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively whereas 10 % of respondents withdraw treatment after menopause in either case. 94 % of respondents considered medical therapy as the primary treatment for microprolactinomas. In case of pregnancy, 49 % considered bromocriptine as the drug of choice for women who wish to become pregnant. 65 and 38 % of respondents advocated discontinuation of treatment with dopamine agonists in patients with microprolactinomas and macroprolactinomas, respectively. Finally, 48 % would allow breast-feeding without restriction, 28 % would restrict it to patients with microprolactinomas and 25 % would not recommend it for women with prolactinomas. CONCLUSIONS: This is the first study of the clinical management of prolactinomas in the MENA region. Some of the practices are not in line with the latest Endocrine and Pituitary Societies guidelines. These warrant further discussions of contemporary guidelines in regional forums. PMID- 27783195 TI - Characterization of the distribution, retention, and efficacy of internal radiation of 188Re-lipid nanocapsules in an immunocompromised human glioblastoma model. AB - Internal radiation strategies hold great promise for glioblastoma (GB) therapy. We previously developed a nanovectorized radiotherapy that consists of lipid nanocapsules loaded with a lipophilic complex of Rhenium-188 (LNC188Re-SSS). This approach resulted in an 83 % cure rate in the 9L rat glioma model, showing great promise. The efficacy of LNC188Re-SSS treatment was optimized through the induction of a T-cell immune response in this model, as it is highly immunogenic. However, this is not representative of the human situation where T-cell suppression is usually encountered in GB patients. Thus, in this study, we investigated the efficacy of LNC188Re-SSS in a human GB model implanted in T-cell deficient nude mice. We also analyzed the distribution and tissue retention of LNC188Re-SSS. We observed that intratumoral infusion of LNCs by CED led to their complete distribution throughout the tumor and peritumoral space without leakage into the contralateral hemisphere except when large volumes were used. Seventy percent of the 188Re-SSS activity was present in the tumor region 24 h after LNC188Re-SSS injection and no toxicity was observed in the healthy brain. Double fractionated internal radiotherapy with LNC188Re-SSS triggered survival responses in the immunocompromised human GB model with a cure rate of 50 %, which was not observed with external radiotherapy. In conclusion, LNC188Re-SSS can induce long term survival in an immunosuppressive environment, highlighting its potential for GB therapy. PMID- 27783197 TI - Identification of intra-hepatic communicating veins through the arch sign on CT scan. AB - PURPOSE: Knowledge of vascular outflow is essential in liver surgery. Communicating veins between the right hepatic vein (RHV) and the middle hepatic vein (MHV) have been described and allowed us to perform new surgical procedures. The aim of this study was to predict the existence of intra-hepatic venous anastomosis by identifying communicating veins on 2D CT-scan imaging. METHODS: We retrospectively analysed data from 32 patients operated on for liver tumours between 2004 and 2013 who underwent a bisegmentectomy VI-VII enlarged to the RHV and/or a bisegmentectomy VII-VIII and/or a left hepatectomy enlarged to the MHV and who had pre and post-operative CT-scans. Patients with cirrhosis were excluded. We first analysed post-operative images and, in patients with a proven collateral vein, looked for evidence of this on pre-operative imaging. We then validated this pre-operative sign against post-operative imaging. RESULTS: Collaterals from both the RHV and the MHV formed an arch visible on pre-operative imaging which predicted the development of intrahepatic venous anastomosis in 20 patients. In 14 patients, a perfect match between the arch sign and development of collaterals was observed (n = 28). Sensitivity, specificity, negative and positive predictive values were 87, 80, 80, and 87%, respectively. Positive and negative likelihood ratio tests were 4.3 and 0.16, respectively. CONCLUSION: Communicating veins between the RHV and the MHV are frequent and can be predicted by the arch sign on 2D CT-scan. Hence the arch sign can be very useful when planning liver surgery. PMID- 27783198 TI - Computer-guided technique evaluation of the bony palate for planning individual implant placement. AB - OBJECTIVE: Different clinical problems may require a surgical approach to the dental arch, such as dentofacial orthopedics, implant-supported dental prothesis, maxillary orthodontics protraction, removable appliances, and posttraumatic dental reconstruction. The aim of this study is to analyze the dental arch size and type for supporting individual dental protheses. MATERIALS AND METHODS: In this study, the reference measurements on the length of the bony palate, maxillary intercanine width, maxillary intermolar width, and the ratio of the maxillary to the palatinal surface were studied in 120 bony palates using a computer software program. RESULTS: The average length of the bony palate, maxilla, and palatine was measured as 104.4 +/- 30.3, 40.05 +/- 4.05, and 15.00 +/- 3.03 mm, respectively. The right and left sides of average width of intermaxillary distances were measured as 13.75 +/- 1.50 and 12.51 +/- 1.50 mm, respectively. The average width of intermolar distance was calculated as 19.82 +/ 1.61 mm (right side) and 18.89 +/- 1.69 mm (left side), respectively. The maxillary dentitions were classified as square (17%), round-square (63.5%), round (14.4%), and round V-shaped arches (5.1%). The round-square ones showed no prominent principal component. Among the maxillary arches, the round arches were characterized by small values and round V-shaped ones with the largest values. Asymmetry between the right and the left bony palate was observed. The areas with equal bony palate on both sides were present in 64.4% of the cases, and in 33.1% of the cases, bony palate was dominant on the right. CONCLUSIONS: The primary principle in reconstructive treatment should be describing geometrical forms and mathematical details of the bony palate. Three-dimensional reference values relative to the dental arch may increase the success of individual treatment of surgical procedures and reduce possible complications. With the help of certain software, this research has made possible to investigate the variability of the dental arch and calculate the variety in measurements and thereby determining the most appropriate implant position, optimizing the implant axis and defining the best surgical and prosthetic solution for the patient. PMID- 27783200 TI - Erratum to: Uric acid in the early risk stratification of ST-elevation myocardial infarction. PMID- 27783199 TI - Compilation and physicochemical classification analysis of a diverse hERG inhibition database. AB - A large and chemically diverse hERG inhibition data set comprised of 6690 compounds was constructed on the basis of ChEMBL bioactivity database and original publications dealing with experimental determination of hERG activities using patch-clamp and competitive displacement assays. The collected data were converted to binary format at 10 uM activity threshold and subjected to gradient boosting machine classification analysis using a minimal set of physicochemical and topological descriptors. The tested parameters involved lipophilicity (log P), ionization (pK a ), polar surface area, aromaticity, molecular size and flexibility. The employed approach allowed classifying the compounds with an overall 75-80 % accuracy, even though it only accounted for non-specific interactions between hERG and ligand molecules. The observed descriptor-response profiles were consistent with common knowledge about hERG ligand binding site, but also revealed several important quantitative trends, as well as slight inter assay variability in hERG inhibition data. The results suggest that even weakly basic groups (pK a < 6) might substantially contribute to hERG inhibition potential, whereas the role of lipophilicity depends on the compound's ionization state, and the influence of log P decreases in the order of bases > zwitterions > neutrals > acids. Given its robust performance and clear physicochemical interpretation, the proposed model may provide valuable information to direct drug discovery efforts towards compounds with reduced risk of hERG-related cardiotoxicity. PMID- 27783201 TI - Comparison of rotational acetabular osteotomy performed with navigation by surgeons with different levels of experience of osteotomies. AB - PURPOSE: Rotational acetabular osteotomy (RAO) is used to treat developmental hip dysplasia (DDH). It requires detailed anatomical knowledge of the pelvic anatomy and three-dimensional cognitive skills. We addressed whether a computer navigation system combined with a preoperative computed tomography-based plan enabled surgeons to perform RAO safely and reliably through a mini-incision regardless of their level of experience with performing osteotomies. METHODS: We enrolled 24 patients (25 hips) with DDH (radiographic grade 0 or 1 osteoarthritic changes: Tonnis classification). Using the navigation system, four surgeons performed RAO via a mini-incision transtrochanteric approach. Two experienced surgeons treated 15 patients (16 hips). Two surgeons with low-level RAO experience treated nine patients (9 hips). Operative data and clinical and radiographic outcomes were compared. Average follow-up was 3.2 years. RESULTS: There were no significant differences in the (1) incision length, operation time, or intraoperative blood loss; (2) numerical pain rating scale score and Western Ontario and McMaster Universities Osteoarthritis Index Scale score at 1, 2 years, and at the latest follow-up; (3) preoperative and postoperative acetabular coverage of the femoral head, postoperative joint congruency, postoperative medial and distal femoral head displacement, or acetabular thickness; and (4) positional accuracy of iliac, pubic, and ischial osteotomy and accuracy of acetabular coverage of the femoral head. CONCLUSIONS: Clinical and radiographic outcomes of RAO with navigation were not influenced by the surgeons' level of osteotomy experience. PMID- 27783202 TI - Protective and pathogenic roles of CD8+ T cells in atherosclerosis. AB - Although infiltration of CD8+ T cells in human atherosclerotic lesions has been described 30 years ago, the role of these cells in lesion development has long remained enigmatic. While experimental models hinted at their pro-atherogenic role based on circumstantial evidence, genetic mouse models of cytotoxic CD8+ T cell-specific immune deficiency suggested no crucial role of these cells in lesion development. However, in recent years, more refined models of adoptive cell transfer, disruption of specific immune regulatory pathways or monoclonal antibody-mediated cell depletion have proposed both atheroprotective and pro atherogenic functions for CD8+ T cells in atherosclerosis. In particular, MHC class I-restricted CD8+ T cell responses may protect from atherosclerosis, and Qa 1 restricted regulatory CD8+ T cells have been defined. In addition, regulatory CD8+CD25+ T cells possess atheroprotective properties. However, CD8+ T cells can also promote monopoiesis in hyperlipidemia, and exert prototypical cytotoxic functions to promote vascular inflammation and macrophage accumulation leading to atherosclerotic lesion development. Here, we review these findings, mostly from experimental studies that reveal a previously unrecognized complexity and important role of CD8+ T cells in atherosclerosis. PMID- 27783203 TI - Cardiotoxicity Associated with Nicotinamide Phosphoribosyltransferase Inhibitors in Rodents and in Rat and Human-Derived Cells Lines. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein that functions as an enzyme, cytokine, growth factor and hormone. As a target for oncology, NAMPT is particularly attractive, because it catalyzes the rate limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. Inhibition of NAMPT generally results in NAD depletion, followed by ATP reduction and loss of cell viability. Herein, we describe NAMPT inhibitor (NAMPTi)-induced cardiac toxicity in rodents following short-term administration (2-7 days) of NAMPTi's. The cardiac toxicity was interpreted as a functional effect leading to congestive heart failure, characterized by sudden death, thoracic and abdominal effusion, and myocardial degeneration. Based on exposures in the initial in vivo safety rodent studies and cardiotoxicity observed, we conducted studies in rat and human in vitro cardiomyocyte cell systems. Based on those results, combined with human cell line potency data, we demonstrated the toxicity is both on-target and likely human relevant. This toxicity was mitigated in vitro by co-administration of nicotinic acid (NA), which can enable NAD production through the NAMPT independent pathway; however, this resulted in only partial mitigation in in vivo studies. This work also highlights the usefulness and predictivity of in vitro cardiomyocyte assays using human cells to rank-order compounds against potency in cell-based pharmacology assays. Lastly, this work strengthens the correlation between cardiomyocyte cell viability and functionality, suggesting that these assays together may enable early assessment of cardiotoxicity in vitro prior to conduct of in vivo studies and potentially reduce subsequent attrition due to cardiotoxicity. PMID- 27783204 TI - Erratum to: Universal Health Coverage in Massachusetts Did Not Change the Trajectory of Arthroplasty Use or Costs. PMID- 27783205 TI - Wild boars as spore dispersal agents of ectomycorrhizal fungi: consequences for community composition at different habitat types. AB - The success of dispersal events depend on the organism's ability to reach and establish in a new habitat. In symbiotic organisms, establishment also depends on the presence of their symbiont partner in the new habitat. For instance, the establishment of obligate ectomycorrhizal (EM) trees outside the forest is largely limited by the presence of EM fungi in soil. Wild boars (Sus scrofa) are important dispersal agents of EM fungal spores, particularly in the moderately dry Mediterranean region. The aim of this study was to explore how EM fungal spores dispersed by wild boars influence the EM fungal community associated with the roots of Pinus halepensis seedlings at different habitat types. Using a greenhouse bioassay, we grew pine seedlings in two soil types: old-field and forest soils mixed with either natural or autoclaved wild boar feces. In both soils, we observed a community dominated by a few EM fungal species. Geopora (85 %) and Suillus (68 %) species dominated the forest and old-field soils, respectively. The addition of natural wild boar feces increased the abundance of Tuber species in both EM fungal communities. However, this effect was more pronounced in pots with old-field soil, leading to a more even community, equally dominated by both Tuber and Suillus species. In forest soil, Geopora maintained dominance, but decreased in abundance (67 %), due to the addition of Tuber species. Our findings indicate that wild boar feces can be an important source for EM inoculum, especially in habitats poor in EM fungi such as old-fields. PMID- 27783206 TI - Procalcitonin is a useful biomarker to predict severe acute cholangitis: a single center prospective study. AB - BACKGROUND: Procalcitonin is being increasingly used to diagnose and grade acute systemic bacterial infection at an early stage of disease onset. The aim of this prospective study was to evaluate the usefulness of procalcitonin for severity grading of acute cholangitis on patient admission. METHODS: Patients with acute cholangitis were prospectively enrolled. The severity of acute cholangitis was graded on the basis of the 2013 Tokyo guidelines (Japanese Society of Hepato Biliary-Pancreatic Surgery, 2013). We compared the ability of procalcitonin level on admission to predict moderate/severe (vs mild) or severe (vs mild/moderate) acute cholangitis with the abilities of white blood cell (WBC) count and C reactive protein (CRP) level. RESULTS: Two hundred thirteen patients were analyzed, and the severity of acute cholangitis was graded as mild, moderate, and severe in 108, 76, and 29 patients respectively. Procalcitonin level, WBC count, and CRP level all increased significantly according to the severity. In the receiver operating characteristic analyses, the area under the curve for procalcitonin for severe acute cholangitis was 0.90 [95% confidence interval (CI) 0.85-0.96] and was significantly greater than that for WBC (0.62; 95% CI 0.48 0.76) and that for CRP (0.70; 95% CI 0.60-0.80). The optimal cutoff value for procalcitonin for prediction of severe acute cholangitis was 2.2 ng/mL (sensitivity 0.97; specificity 0.73; accuracy 0.77). The areas under the curve for procalcitonin, WBC, and CRP for moderate/severe acute cholangitis were not significantly different. CONCLUSIONS: Procalcitonin predicted severe acute cholangitis better than conventional biomarkers. Severe cases for which urgent biliary drainage is indicated might be identified on admission on the basis of the cutoff values for procalcitonin suggested in this study. PMID- 27783207 TI - CNS Impact of Perinatal HIV Infection and Early Treatment: the Need for Behavioral Rehabilitative Interventions Along with Medical Treatment and Care. AB - There is growing concern that although the more severe forms of HIV-associated neurologic deficits are reduced following highly active anti-retroviral therapy (HAART), mild to moderate cognitive disorders may persist for years after HAART initiation and this may occur despite complete plasma viral suppression. According to the UNAIDS 2014 report, there were 3.2 million children living with HIV around the world at the end of 2013 and 91 % of these resided in sub-Saharan Africa. In the same year, only 24 % of children who needed antiretroviral treatment (ART) received it and 190,000 children died of AIDS-related illnesses. We propose that behavioral interventions are needed in combination with medical treatment and care in order to fully address the needs of children and adolescents in Africa living with HIV. In early childhood, caregiver training programs to enhance the developmental milieu of the child with HIV can enhance their cognitive and social development and that such interventions are both feasible and well-accepted by the local population. For school-age children, computerized cognitive rehabilitation training can be an entertaining and engaging way to improve attention, working memory, and problem solving skills for children with HIV. Further dissemination and implementation science work is needed for arriving at cost-effective strategies for scaling up such behavioral interventions in African resource-constrained settings, given that the vast majority of HIV-affected children and youth worldwide presently live in sub Saharan Africa. PMID- 27783209 TI - Isolation of conditional mutations in genes essential for viability of Cryptococcus neoformans. AB - Discovering the genes underlying fundamental processes that enable cells to live and reproduce is a technical challenge, because loss of gene function in mutants results in organisms that cannot survive. This study describes a forward genetics method to identify essential genes in fungi, based on the propensity for Agrobacterium tumefaciens to insert T-DNA molecules into the promoters or 5' untranslated regions of genes and by placing a conditional promoter within the T DNA. Insertions of the promoter of the GAL7 gene were made in the human pathogen Cryptococcus neoformans. Nine strains of 960 T-DNA insertional mutants screened grew on media containing galactose, but had impaired growth on media containing glucose, which suppresses expression from GAL7. T-DNA insertions were found in the homologs of IDI1, MRPL37, NOC3, NOP56, PRE3 and RPL17, all of which are essential in ascomycete yeasts Saccharomyces cerevisiae or Schizosaccharomyces pombe. Altering the carbon source in the medium provided a system to identify phenotypes in response to stress agents. The pre3 proteasome subunit mutant was further characterized. The T-DNA insertion and phenotype co-segregate in progeny from a cross, and the growth defect is complemented by the reintroduction of the wild type gene into the insertional mutant. A deletion allele was generated in a diploid strain, this heterozygous strain was sporulated, and analysis of the progeny provided additional genetic evidence that PRE3 is essential. The experimental design is applicable to other fungi and has other forward genetic applications such as to isolate over-expression suppressors or enhance the production of traits of interest. PMID- 27783208 TI - Non-invasive diagnosis of hepatic steatosis. AB - Non-invasive diagnosis and quantification of hepatic steatosis rely on two different but complementary approaches: biomarkers or imaging techniques, either ultrasound-based such as liver ultrasonography and controlled attenuation parameter (CAP), or computed tomography (CT) and magnetic resonance imaging (MRI). Scores for the detection of steatosis have not gained much popularity in clinical practice so far. CAP, using the M probe, is the most promising technique but needs to be implemented with the XL probe and compared to ultrasound that, despite its limitations, remains the most widely used method. CT, owing to its low sensitivity and the fact that it involves a potential radiation hazard, is inappropriate. Finally, proton density fat fraction measurement by MRI is currently the most accurate and sensitive imaging method, simpler and more practical than magnetic resonance spectroscopy, but restricted, up to now, just to research and clinical trials. PMID- 27783212 TI - Erratum to: Thoracic and cardiovascular surgery in Japan during 2006 : Annual report by the Japanese Association for Thoracic Surgery. PMID- 27783210 TI - Attention in Parkinson's disease with fatigue: evidence from the attention network test. AB - Fatigue is a non-specific symptom that is common in chronic diseases and represents one of the most disabling symptoms in Parkinson's disease. PD patients often experience cognitive deficits related above all to executive functions. The relationship between cognitive changes and fatigue in PD patients has not been explored in depth. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e., alerting, orienting, and executive, by evaluating reaction times (RTs) in response to visual stimuli. To assess the association between fatigue and the efficiency of the attentional networks, according to the Posnerian view, ANT was administered to 15 parkinsonian patients with fatigue (PFS-16 > 2.95), 17 parkinsonian patients without fatigue, and 37 age- and sex-matched healthy controls. Anxiety, depression, quality of sleep, and quality of life were also assessed. Parkinsonian patients displayed significantly longer RTs and lower executive network efficiency than controls. Patients with fatigue displayed significantly lower executive network efficiency than patients without fatigue. Moreover, patients with fatigue exhibited a lower accuracy than either patients without fatigue or controls. Finally, patients without fatigue displayed a more efficient alerting network than either patients with fatigue or controls. Although the pathogenesis of fatigue is multifactorial, our results indicate that fatigue may be closely related to an alteration of the striato-thalamo-cortical loop connecting the neostriatum to the prefrontal cortex, which is also responsible for the executive dysfunction that is typical of Parkinson's disease. PMID- 27783213 TI - A prospective, randomized study of inhaled prostacyclin versus nitric oxide in patients with residual pulmonary hypertension after pulmonary endarterectomy. AB - OBJECTIVES: Pulmonary endarterectomy (PEA) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but postoperative residual hypertension leads to in-hospital mortality. Inhaled epoprostenol sodium (PGI2) and NO are administered for pulmonary hypertension after cardiothoracic surgery. This prospective study provides the first comparative evaluation of the effects of inhaled PGI2 and NO on pulmonary hemodynamics, systemic hemodynamics, and gas exchange in patients developing residual pulmonary hypertension after PEA. METHODS: Thirteen patients were randomized to receive either NO (n = 6) or PGI2 (n = 7) inhalation when pulmonary hypertension persisted after weaning from cardiopulmonary bypass. Hemodynamic and respiratory variables were measured before inhalation of the agent (T0); 30 min (T1), 3 h (T2), and 6 h after inhalation (T3); and the next morning (T4). The NO dose was started at 20 ppm and gradually tapered until extubation, and PGI2 was administered at a dose of 10 ng kg-1 min-1. RESULTS: In both groups, mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) significantly decreased over time until T4 (mean PAP: p < 0.0001; PVR: p = 0.003), while mean systemic arterial blood pressure significantly increased (p = 0.028). There were no significant between group differences in patient characteristics, cardiac index, left atrial pressure, or ratio of arterial oxygen tension to fraction of inspired oxygen. There were no in-hospital deaths. CONCLUSIONS: Both inhaled PGI2 and NO significantly reduced PAP and PVR without adverse effects on systemic hemodynamics in patients who developed residual pulmonary hypertension after PEA. Inhaled PGI2 can be offered as alternative treatment option for residual pulmonary hypertension. PMID- 27783214 TI - Selenium Reduces Early Signs of Tumor Necrosis Factor Alpha-Induced Meniscal Tissue Degradation. AB - Meniscal integrity is a prerequisite for sustained knee joint health and prevention of meniscal degeneration is a main research goal. Cartilage-protective effects of selenium have been described, but little is known about the impact on the meniscus. We therefore investigated the influence of sodium selenite on meniscal explants under tumor necrosis factor-alpha (TNFalpha)-stimulated proinflammatory conditions. Meniscal explant disks (3 mm diameter * 1 mm thickness) were isolated from 2-year-old cattle and incubated with TNFalpha (10 ng/ml) and sodium selenite (low dose, LoD 6.7 ng/ml as being found in Insulin Transferrin-Selenium medium supplements, ITS; medium-dose, MeD 40 ng/ml described as physiological synovial concentration; high dose, HiD 100 ng/ml described as optimal serum concentration). After 3 days of culture glycosaminoglycan (GAG) release (DMMB assay), nitric oxide (NO) production (Griess assay), gene expression of matrix-degrading enzymes (quantitative RT-PCR), and apoptosis rate were determined. TNFalpha led to a significant raise of GAG release and NO production. LoD and MeD selenite significantly reduced the TNFalpha-induced GAG release (by 83, 55 %, respectively), NO production (by 59, 40 %, respectively), and apoptosis (by 68, 39 %, respectively). LoD and MeD selenite showed a tendency to reduce the TNFalpha-mediated increase of inducible NO-synthase (iNOS) levels, LoD selenite furthermore matrix metalloproteinase (MMP)-3 transcription levels and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 levels. LoD and less pronounced MeD selenite show a substantial impact on the early meniscal inflammatory response. To our knowledge this is the first study showing the protective influence of selenium on meniscal tissue maintenance. To understand the superior potency of low-dose selenium on molecular level future studies are needed. PMID- 27783215 TI - Translational medicine: from disease- and patient-specific stem cell research to clinical trials and back again. PMID- 27783216 TI - Clinical and treatment-related predictors of cognition in bipolar disorder: focus on visual paired associative learning. AB - Bipolar disorder (BD) is associated with impairment in cognitive domains such as verbal memory and executive functions. However, visual paired associative learning (PAL) has been far less researched. Neurocognitive dysfunction in BD patients has been related to several clinical factors, but data on the effect of medication are relatively scarce and inconsistent. The aim of our study was to explore the effect of clinical and treatment-related parameters on executive functions and visual memory/learning, including PAL, in BD. Cognitive performance of 60 bipolar I patients and 30 healthy subjects was evaluated by using CANTAB battery tasks targeting spatial recognition memory, PAL and executive functions (set shifting, planning, inhibitory control). Bipolar patients showed poorer performance in PAL, set shifting, planning and inhibitory control than healthy subjects; however, only differences in PAL and planning survived correction for multiple comparisons. Number of previous manic episodes and illness duration predicted worse performance in set shifting and PAL, respectively, whereas current treatment with valproate predicted better performance in PAL. This is one of the first studies to assess clinical and treatment-related predictors of PAL in BD. We report a possibly beneficial effect of valproate on PAL, which warrants further investigation. PMID- 27783217 TI - Lung surfactant metabolism: early in life, early in disease and target in cell therapy. AB - Lung surfactant is a complex mixture of lipids and proteins lining the alveolar epithelium. At the air-liquid interface, surfactant lowers surface tension, avoiding alveolar collapse and reducing the work of breathing. The essential role of lung surfactant in breathing and therefore in life, is highlighted by surfactant deficiency in premature neonates, which causes neonatal respiratory distress syndrome and results in early death after birth. In addition, defects in surfactant metabolism alter lung homeostasis and lead to disease. Special attention should be paid to two important key cells responsible for surfactant metabolism: alveolar epithelial type II cells (AE2C) and alveolar macrophages (AM). On the one hand, surfactant deficiency coming from abnormal AE2C function results in high surface tension, promoting alveolar collapse and mechanical stress in the epithelium. This epithelial injury contributes to tissue remodeling and lung fibrosis. On the other hand, impaired surfactant catabolism by AM leads to accumulation of surfactant in air spaces and the associated altered lung function in pulmonary alveolar proteinosis (PAP). We review here two recent cell therapies that aim to recover the activity of AE2C or AM, respectively, therefore targeting the restoring of surfactant metabolism and lung homeostasis. Applied therapies successfully show either transplantation of healthy AE2C in fibrotic lungs, to replace injured AE2C cells and surfactant, or transplantation of bone marrow-derived macrophages to counteract accumulation of surfactant lipid and proteinaceous material in the alveolar spaces leading to PAP. These therapies introduce an alternative treatment with great potential for patients suffering from lung diseases. PMID- 27783218 TI - Helicobacter pylori-negative gastric cancer: advanced-stage undifferentiated adenocarcinoma located in the pyloric gland area. AB - The incidence of Helicobacter pylori-negative gastric cancer (HpNGC) is extremely low. A 78-year old female without H. pylori infection was diagnosed with type 4 advanced-stage gastric prepylorus cancer. Distal gastrectomy was performed as for HpNGC (cT3N0M0). Histological findings of the resected specimen showed poorly differentiated adenocarcinoma and signet ring cell carcinoma, which were located in the pyloric gland area, diffusely invaded beyond the serosa without lymph node metastasis (pT4aN0M0). Most cases of undifferentiated-type HpNGC are diagnosed in the early stage and are located in the fundic gland area. We report the first case of advanced-stage undifferentiated HpNGC located in the pyloric gland area. PMID- 27783219 TI - Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo. AB - Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 +/- 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons. PMID- 27783221 TI - Expression patterns of Irx genes in the developing chick inner ear. AB - The vertebrate inner ear is a complex three-dimensional sensorial structure with auditory and vestibular functions. The molecular patterning of the developing otic epithelium creates various positional identities, consequently leading to the stereotyped specification of each neurosensory and non-sensory element of the membranous labyrinth. The Iroquois (Iro/Irx) genes, clustered in two groups (A: Irx1, Irx2, and Irx4; and B: Irx3, Irx5, and Irx6), encode for transcriptional factors involved directly in numerous patterning processes of embryonic tissues in many phyla. This work presents a detailed study of the expression patterns of these six Irx genes during chick inner ear development, paying particular attention to the axial specification of the otic anlagen. The Irx genes seem to play different roles at different embryonic periods. At the otic vesicle stage (HH18), all the genes of each cluster are expressed identically. Both clusters A and B seem involved in the specification of the lateral and posterior portions of the otic anlagen. Cluster B seems to regulate a larger area than cluster A, including the presumptive territory of the endolymphatic apparatus. Both clusters seem also to be involved in neurogenic events. At stages HH24/25-HH27, combinations of IrxA and IrxB genes participate in the specification of most sensory patches and some non-sensory components of the otic epithelium. At stage HH34, the six Irx genes show divergent patterns of expression, leading to the final specification of the membranous labyrinth, as well as to cell differentiation. PMID- 27783220 TI - The importance of mammillary body efferents for recency memory: towards a better understanding of diencephalic amnesia. AB - Despite being historically one of the first brain regions linked to memory loss, there remains controversy over the core features of diencephalic amnesia as well as the critical site for amnesia to occur. The mammillary bodies and thalamus appear to be the primary locus of pathology in the cases of diencephalic amnesia, but the picture is complicated by the lack of patients with circumscribed damage. Impaired temporal memory is a consistent neuropsychological finding in Korsakoff syndrome patients, but again, it is unclear whether this deficit is attributable to pathology within the diencephalon or concomitant frontal lobe dysfunction. To address these issues, we used an animal model of diencephalic amnesia and examined the effect of mammillothalamic tract lesions on tests of recency memory. The mammillothalamic tract lesions severely disrupted recency judgements involving multiple items but left intact both recency and familiarity judgements for single items. Subsequently, we used disconnection procedures to assess whether this deficit reflects the indirect involvement of the prefrontal cortex. Crossed-lesion rats, with unilateral lesions of the mammillothalamic tract and medial prefrontal cortex in contralateral hemispheres, were unimpaired on the same recency tests. These results provide the first evidence for the selective importance of mammillary body efferents for recency memory. Moreover, this contribution to recency memory is independent of the prefrontal cortex. More broadly, these findings identify how specific diencephalic structures are vital for key elements of event memory. PMID- 27783222 TI - Development of putative inhibitory neurons in the embryonic and postnatal mouse superficial spinal dorsal horn. AB - The superficial spinal dorsal horn is the first relay station of pain processing. It is also widely accepted that spinal synaptic processing to control the modality and intensity of pain signals transmitted to higher brain centers is primarily defined by inhibitory neurons in the superficial spinal dorsal horn. Earlier studies suggest that the construction of pain processing spinal neural circuits including the GABAergic components should be completed by birth, although major chemical refinements may occur postnatally. Because of their utmost importance in pain processing, we intended to provide a detailed knowledge concerning the development of GABAergic neurons in the superficial spinal dorsal horn, which is now missing from the literature. Thus, we studied the developmental changes in the distribution of neurons expressing GABAergic markers like Pax2, GAD65 and GAD67 in the superficial spinal dorsal horn of wild type as well as GAD65-GFP and GAD67-GFP transgenic mice from embryonic day 11.5 (E11.5) till postnatal day 14 (P14). We found that GABAergic neurons populate the superficial spinal dorsal horn from the beginning of its delineation at E14.5. We also showed that the numbers of GABAergic neurons in the superficial spinal dorsal horn continuously increase till E17.5, but there is a prominent decline in their numbers during the first two postnatal weeks. Our results indicate that the developmental process leading to the delineation of the inhibitory and excitatory cellular assemblies of pain processing neural circuits in the superficial spinal dorsal horn of mice is not completed by birth, but it continues postnatally. PMID- 27783224 TI - Lattice Boltzmann simulation of phase separation under dynamic temperature and shear: Coupling effects of shear convection and thermal diffusion. AB - This paper presents an exploration of the separation behavior and pattern formation in a shear binary fluid with dynamic temperature after slow cooling via coupled lattice Boltzmann method. The phase separation procedure can be divided into three different stages: spinodal decomposition, domain growth, and domain stretch. The effect of thermal diffusion was observed to be more significant than that of shear convection in the spinodal decomposition stage, while the opposite was observed in the domain growth stage. The slow cooling temperature field significantly prolonged the spinodal decomposition stage, and decreased the separated domain size in domain growth stage. The phase behavior and pattern formation from the disordered state into the coexistence state after slow cooling was investigated during the domain stretch stage. Two typical length scales were obtained according to the equilibrium of two phases, where the number of layers in the corresponding domains was controllable by adjusting the Prandtl number for systems of different scales. The manner in which various viscosities and thermal diffusivities influence the morphologies and kinetic characterizations of the materials was also demonstrated: numerical results indicated that decrease in viscosity can cause increase in the growth exponents of separation fronts and velocity of domain growth, as well as increase in thermal diffusion. PMID- 27783223 TI - Value of Treating All Stages of Chronic Hepatitis C: A Comprehensive Review of Clinical and Economic Evidence. AB - INTRODUCTION: The goal of chronic hepatitis C (CHC) treatment is to achieve a sustained virologic response (SVR). The new generation of direct-acting antivirals (DAAs) offers 90-100% SVR rates. However, access to these treatments is generally limited to patients with advanced liver disease. The aim of this review is to provide an overview of the clinical and economic benefits of achieving SVR and to better understand the full value of CHC treatment in all stages of liver disease. METHODS: A comprehensive literature review was performed using the PubMed, Embase, and Cochrane library databases to identify articles examining the clinical, economic, and quality of life benefits associated with SVR. Articles were limited to those published in English language from January 2006 through January 2016. Inclusion criteria were (1) patients with CHC, (2) retrospective and prospective studies, (3) reporting of mortality, liver morbidity, extrahepatic manifestations (EHMs), and economic outcomes and, (4) availability of an abstract or full-text publication. RESULTS: Overall this review identified 354 studies involving more than 500,000 CHC patients worldwide. Evidence from 38 studies (n = 73,861) shows a significant mortality benefit of achieving SVR in patients with all stages of fibrosis. Long-term studies with follow-up of 5-12 years suggest that, particularly among non-cirrhotic patients, there is a significant decrease in mortality in SVR versus non-SVR groups. Ninety nine studies conducted in 235,891 CHC patients in all stages of fibrosis show that SVR reduces liver-related mortality, incidence of hepatocellular carcinoma (HCC), and decompensation. A total of 233 studies show that chronic HCV infection is associated with several serious EHMs, some of which can have high mortality. Evidence from four modeling studies shows that delaying treatment to CHC patient populations could significantly increase mortality, morbidity, and medical costs. CONCLUSIONS: There is a robust body of evidence demonstrating diverse sources of value from achieving SVR in all stages of liver disease. While access to treatment is generally limited to late-stage patients, less restrictive treatment strategies that target HCV eradication have the potential to abate the burdens of mortality, liver morbidity and extrahepatic manifestations, and the associated healthcare costs. PMID- 27783225 TI - Odor-color associations differ with verbal descriptors for odors: A comparison of three linguistically diverse groups. AB - People appear to have systematic associations between odors and colors. Previous research has emphasized the perceptual nature of these associations, but little attention has been paid to what role language might play. It is possible odor color associations arise through a process of labeling; that is, participants select a descriptor for an odor and then choose a color accordingly (e.g., banana odor -> "banana" label -> yellow). If correct, this would predict odor-color associations would differ as odor descriptions differ. We compared speakers of Dutch (who overwhelmingly describe odors by referring to the source; e.g., smells like banana) with speakers of Maniq and Thai (who also describe odors with dedicated, abstract smell vocabulary; e.g., musty), and tested whether the type of descriptor mattered for odor-color associations. Participants were asked to select a color that they associated with an odor on two separate occasions (to test for consistency), and finally to label the odors. We found the hunter gatherer Maniq showed few, if any, consistent or accurate odor-color associations. More importantly, we found the types of descriptors used to name the smells were related to the odor-color associations. When people used abstract smell terms to describe odors, they were less likely to choose a color match, but when they described an odor with a source-based term, their color choices more accurately reflected the odor source, particularly when the odor source was named correctly (e.g., banana odor -> yellow). This suggests language is an important factor in odor-color cross-modal associations. PMID- 27783226 TI - Educating physicians in evidence based medicine: current practices and curricular strategies. AB - INTRODUCTION: Evidence-based medicine (EBM) is an expectation of professional healthcare and a requisite component of medical school curricula. However, upon graduation medical students' EBM skills have been found lacking suggesting a need to examine EBM training. METHODS: This PhD report presents two studies on EBM education. The first study is a literature review that describes and attempts to assess educational interventions for teaching medical students EBM. The second study presents a multi-institutional case study conducted in North America using interviews and curricular materials to identify EBM instructors' perceptions of challenges that may impede medical students' efforts to learn EBM. RESULTS: The literature review analyzed 20 learning interventions from 12 countries that were presented in classrooms (75 %) and clinics (25 %). The steps of EBM were addressed to varying degrees. It was not possible to draw conclusions about the efficacy of the interventions due to lack of detailed reporting. The qualitative study identified four learning challenges: sub-optimal role models, student lack of willingness to admit uncertainty, lack of clinical context, and difficulty mastering EBM skills. To meet these challenges, participants described interventions such as integrating EBM skills with other content/courses, incorporating clinical content into EBM teaching, providing faculty development, using whole-task EBM activities, and longitudinal integration of EBM across the curriculum. CONCLUSION: This PhD report takes steps to describe and assess EBM learning interventions, presents student learning challenges and looks at approaches institutions take to meet them. Educators can use these findings to examine their curriculum and learning environments and, if desired, adopt them for their training. PMID- 27783227 TI - The simulation of UV spectroscopy and electronic analysis of temozolomide and dacarbazine chemical decomposition to their metabolites. AB - The electronic features of anti-tumor agent, temozolomide, and its degradation products (MTIC and metabolite AIC) have been traced by means of UV absorption spectroscopy in vacuo and aqueous media. For comparison, electronic spectra of related structures and drugs (e.g., dacarbazine) were also investigated. These investigations were carried out using time-dependent density functional theory (TD-DFT) method while the conductor like screening model (COSMO) were applied for the inclusion of solvent effects in electronic spectra. From functional benchmarking, two methods; B3LYP and O3LYP were selected among several other methods with 6-311+G(2d,p) basis set aiming to get the best results in accord with the experimental values. An assessment of the obtained spectra has shown that O3LYP functional gives a mean absolute error (MAE) from experimental absorption peaks of 4.3 nm compared to the 7.2 nm MAE value at B3LYP level in aqueous media. Furthermore, since the structural and tautomeric conformers affect the electronic spectra, conformational preferences have been analyzed in temozolomide, dacarbazine, and their related structures. Temozolomide structure possesses two rotamers that differ in the orientation of carboxamide moiety with a small energy difference (energy difference of 1.39 kcal mol-1 in vacuo and 0.35 kcal mol-1 in aqueous media at B3LYP/6-311++G(2df,3pd). The more stable and meta stable TMZ rotamer have shown their absorption maxima at 329-334 nm, respectively, at O3LYP level in aqueous media. Applying statistical calculation according to Boltzmann population formula at 25 degrees C and computed weighed mean estimates the lambdamax of temozolomide at 331 nm, which is in notable agreement with the experimental value (330 nm). Moreover, molecular orbital composition analysis has been conducted in order to interpret these findings. Graphical Abstract Temozolomide and dacarbazine. PMID- 27783228 TI - Possible sequestration of polar gas molecules by superhalogen supported aluminum nitride nanoflakes. AB - The feasibility of having MF3 (where M = Rh, Ir, Pd, Pt, Ag, Au) supported AlN nanoflakes (AlNF) was investigated through density functional theory based calculations. The thermodynamic analysis reveals that the superhalogen MF3 molecules can bind with the host AlNF in a thermodynamically favorable way. The nature of interaction in between the metal centers and the host is of partly covalent type whereas the F centers bind with the host in a non-covalent fashion as vindicated by natural bond orbital and atoms-in a-molecule analyses. An ab initio molecular dynamics study carried out at 298 K temperature confirms the stability of the MF3@AlNF moieties in a dynamical context. The MF3 guests can reduce the HOMO-LUMO gaps of the host nanoflakes. In general, the MF3@AlNF complexes can sequestrate polar adsorbates such as CO, NO, and H2O in a thermodynamically favorable way in most of the cases. An ab initio molecular dynamics calculation illustrates that the MF3@AlNF can adsorb the chosen representative polar molecules in a more favorable way as compared to the corresponding adsorption scenario in the case of pristine AlNF. PMID- 27783229 TI - Molecular insights into the binding of phosphoinositides to the TH domain region of TIPE proteins. AB - Phosphatidylinositols and their phosphorylated derivatives, phosphoinositides, play a central role in regulating diverse cellular functions. These phospholipids have been shown to interact with the hydrophobic TH domain of the tumor necrosis factor (TNF)-alpha-induced protein 8 (TIPE) family of proteins. However, the precise mechanism of interaction of these lipids is unclear. Here we report the binding mode and interactions of these phospholipids in the TH domain, as elucidated using molecular docking and simulations. Results indicate that phosphoinositides bind to the TH domain in a similar way by inserting their lipid tails in the hydrophobic cavity. The exposed head group is stabilized by interactions with critical positively charged residues on the surface of these proteins. Further MD simulations confirmed the dynamic stability of these lipids in the TH domain. This computational analysis thus provides insight into the binding mode of phospholipids in the TH domain of the TIPE family of proteins. Graphical abstract A phosphoinositide (phosphatidylinositol 4-phosphate; PtdIns4P) docked to TIPE2. PMID- 27783231 TI - Effect of salt valency and concentration on structure and thermodynamic behavior of anionic polyelectrolyte Na+-polyethacrylate aqueous solution. AB - The intermolecular structure and solvation enthalpy of anionic polyelectrolyte atactic Na+-polyethacrylate (PEA) in aqueous solution, as a function of added salt concentration C s (dilute to concentrated) and valency (NaCl versus CaCl2), were investigated via molecular dynamics simulations with explicit-ion-solvent and atomistic polymer description. An increase in C s leads to a decrease in alpha, which stabilizes to a constant value beyond critical C s. A significant reduction in R g in the presence of CaCl2 salt was observed, due to ion bridging of PEA by Ca2+ ions, in agreement with results available in literature on other similar polycarboxylates. An increase in salt valency reduces the value of critical C s for the onset of stabilization of the overall size and shape of the polymer chain. The critical C s ratio for the divalent to monovalent salt case is in excellent agreement with results of Langevin dynamics studies on model systems available in the literature. PEA-water H-bond half-life increases with C s for CaCl2, but no appreciable effect is seen for NaCl. The hydration of PEA becomes stronger in the presence of divalent salt. The strength of H-bond interaction energy is greater for cations as compared to anions of the salt. The salt cation effect in displacing water molecules from the vicinity of PEA, with increase in C s, is greater for NaCl solution. The decrease in water coordination to PEA carboxylate groups, due to increased C s, is more pronounced in NaCl solution. The nature of the behavior of the solvation enthalpy of PEA and the type of intermolecular interactions contributing to it, is in agreement with experimental observations from the literature. The hydration enthalpy of PEA in divalent CaCl2 aqueous salt solution is more exothermic compared to monovalent NaCl salt solution, in agreement with experimental data. The solvation of PEA is thermodynamically more favorable in the case of CaCl2 solution. The exothermic solvation enthalpy, H-bond lifetime, number of H-bonds and H-bond interaction energy are greater in magnitude in CaCl2 aqueous solution. PMID- 27783230 TI - Conformational analysis of short polar side-chain amino-acids through umbrella sampling and DFT calculations. AB - Molecular and quantum mechanics calculations were carried out in a series of tripeptides (GXG, where X = D, N and C) as models of the unfolded states of proteins. The selected central amino acids, especially aspartic acid (D) and asparagine (N) are known to present significant average conformations in partially allowed areas of the Ramachandran plot, which have been suggested to be important in unfolded protein regions. In this report, we present the calculation of the propensity values through an umbrella sampling procedure in combination with the calculation of the NMR J-coupling constants obtained by a DFT model. The experimental NMR observations can be reasonably explained in terms of a conformational distribution where PPII and beta basins sum up propensities above 0.9. The conformational analysis of the side chain dihedral angle (chi1), along with the computation of 3J(HalphaHbeta), revealed a preference for the g - and g + rotamers. These may be connected with the presence of intermolecular H-bonding and carbonyl-carbonyl interactions sampled in the PPII and beta basins. Taking into account all those results, it can be established that these residues show a similar behavior to other amino acids in short peptides regarding backbone phi,psi dihedral angle distribution, in agreement with some experimental analysis of capped dipeptides. PMID- 27783232 TI - Determination of the effects of water adsorption on the sensitivity and detonation performance of the explosive JOB-9003 by molecular dynamics simulation. AB - In order to determine the adsorption mechanism of water on the crystal surfaces of the explosive JOB-9003 and the effect of this adsorption on the sensitivity and detonation performance of this explosive, a model of the crystal of JOB-9003 was created in the software package Materials Studio (MS). The adsorption process was simulated, and molecular dynamics simulation was performed with the COMPASS force field in the NPT ensemble to calculate the sensitivity and detonation performance of the explosive. The results show that the maximum trigger bond length decreases whereas the interaction energy of the trigger bond and the cohesive energy density increase after adsorption, indicating that the sensitivity of JOB-9003 decreases. The results for the detonation performance show that the detonation pressure, detonation velocity, and detonation heat decrease upon the adsorption of water, thus illustrating that the detonation performance of JOB-9003 is degraded. In summary, the adsorption of water has a positive effect on the sensitivity and safety of the explosive JOB-9003 but a negative effect on its detonation performance. PMID- 27783233 TI - Computational study of the interaction between NO, NO+, and NO- with H2O. AB - In this computational study the interaction of NO., NO+, and NO- with H2O: [NO- H2O]., 1 ., [NO--H2O]+, 1 + , and [NO--H2O]-, 1 - was analysed. The optimized geometries indicate that the relative position of NO and H2O depends on the total charge: (ON.--H-OH), (NO---H-OH), and (ON+--OH2). Moreover, atomic spin density along with frontier molecular orbitals help to identify the preferred reduction or oxidation sites on the nitric oxide. Thus, quantum theory of atoms in molecules (QTAIM), electron localization function (ELF), and natural bond-bond polarizability (NBBP) methods aid to quantify the electron delocalization level between NO and H2O, 1 + > 1 . > 1 - , and show the predominantly ionic, and covalent character to inter-molecular, and intra-molecular chemical bonds, respectively. Furthermore, the natural bond orbital (NBO) and localized molecular orbital energy decomposition analysis (LMO-EDA) methods enable energy analyses of the interaction between NO and H2O in the complexes 1 ., 1 + , and 1 - . Where, the first method showed that the interaction between the natural bond orbitals in 1 - is more favorable, than in 1 + , and less in 1 ., however, the second method designates that the total interaction energy is lower for 1 + in relation to 1 - and 1 ., due mainly to the electrostatic component. As a final point, analysis of the electrostatic potential surfaces provides a clear and direct explanation for the relative position of the monomers. It also shows that the predominant Coulombic attraction between H2O and the charged NO+, and NO- compounds will be stronger in relation to the neutral NO.. Graphical abstract ?. PMID- 27783234 TI - Fond Memories of our Mentor J. David Hellums, Annals of Biomedical Engineering. PMID- 27783235 TI - Welfare costs in patients with rheumatoid arthritis and their partners compared with matched controls: a register-based study. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease with significant morbidity, mortality, and costs for the individual patient and for society. The purpose of this study was to examine welfare costs in patients with RA including their partners before and after initial diagnosis. Data were collected from population-based registers in the period from 1998 to 2009. A total of 25,547 Danish patients with a diagnosis of RA and 15,660 of their partners were identified and compared with 101,755 randomly selected age- and gender-matched controls and 62,681 control partners. The direct and indirect costs were calculated for patients and their partners and compared to matched controls. These included inpatient and outpatient treatment, medication, income from employment and social transfer payments. Patients with RA had statistically significantly more inpatient and outpatient costs than control subjects, i.e., treatment (?346 vs. ?211), hospitalization (?1261 vs. ?778), and medication use (?654 vs. ?393). The costs associated with the patients were present 11 years before diagnosis of RA (?1592) compared with control subjects (?1172). Furthermore, income from employment was lower for patients (?14,023) than for control subjects (?17,196). Being a partner to a patient with RA was associated with high total welfare costs. This register-based study shows that RA has significant welfare costs for patients, their partners, and society. The differences in total health costs exist up to 11 years before the diagnosis of RA is established. PMID- 27783236 TI - The effectiveness of new triple combination therapy using synthetic disease modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study. AB - The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice. PMID- 27783237 TI - Biologic therapies and infections in the daily practice of three Italian rheumatologic units: a prospective, observational study. AB - Since the introduction of biologics, many concerns about the increased risk of infections have been reported and, to date, the real impact of infections on the daily practice in the rheumatologic centers is still largely unknown. In this work, we evaluated the infection rates associated with the use of biologics in a large cohort of patients. A prospective study, between January 2010 and December 2013, enrolling 731 rheumatic patients, was performed. Demographic and disease characteristics, therapies, comorbidities, and infectious events were recorded and statistically analyzed by multivariate analysis. Two-hundred thirty-five infectious episodes were observed in 28.4 % of patients. About total infections, bacteria were identified in 70.6 % of total cases and viruses in 18.3 %. The most common site of not-serious infection was the urinary tract. Duration of disease, longer follow-up, concomitant steroid therapy, and comorbidities were significantly associated with not-serious infection. In our cohort, 17 episodes fulfilled the criteria of serious infection and occurred in 17 different patients (2.3 %), the majority involving the lower respiratory tract. Serious infections were associated with the beginning of biologics in older age. Our prospective, observational study showed that, in daily practice, a lesser rate of serious as well as not-serious infections may be observed in rheumatic patients treated with biologics than those reported in previous papers. The most common sites of not serious infections are both the urinary and the respiratory tracts, and for serious infections, the respiratory tract. When pathogens were isolated, we did not find any multidrug-resistant organism. PMID- 27783239 TI - Risk scores as useful predictors of perioperative complications in patients with rectal cancer who received radical surgery. AB - BACKGROUND: Rectal cancer is associated with a higher rate of surgical complications. The ability to predict the risk of complications before treatment would facilitate the design of personalized treatment strategies optimally suited for each patient. METHODS: We retrospectively studied 260 patients with rectal cancer who underwent radical surgery to examine the relations between complications and 5 types of risk scores. RESULTS: Complications developed in 56 patients (21.5%). Nineteen patients had infectious complications, 16 had intestinal obstruction, and 12 had other complications. Twelve patients out of 187 patients who received low anterior resection had anastomotic leakage. Estimation of Physiologic Ability and Surgical Stress Comprehensive Risk Score (E PASS CRS) and Neutrophil-to-lymphocyte Ratio (NLR) were significantly related to all complications, infectious complications, and anastomotic leakage. Surgical Apgar Score was significantly related to infectious complications. Prognostic Nutritional Index was significantly related to all complications and intestinal obstruction. Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity was significantly related to all complications, and infectious complications. A multivariate analysis showed that body-mass index, E-PASS CRS, and NLR were independent risk factors for anastomotic leakage. In particular, NLR was the only score that could be evaluated before surgery. CONCLUSIONS: Five types of risk scores were useful methods for evaluating the risks of complications in patients with rectal cancer. NLR is a score that can be evaluated before surgery and predicted the risk of anastomotic leakage, suggesting that it is useful for assessing the need for a diverting colostomy. PMID- 27783240 TI - Integrating Self-Determination and Job Demands-Resources Theory in Predicting Mental Health Provider Burnout. AB - Limited progress has been made in reducing burnout in mental health professionals. Accordingly, we identified factors that might protect against burnout and could be productive focal areas for future interventions. Guided by self-determination theory, we examined whether supervisor autonomy support, self efficacy, and staff cohesion predict provider burnout. 358 staff from 13 agencies completed surveys. Higher levels of supervisor autonomy support, self-efficacy, and staff cohesion were predictive of lower burnout, even after accounting for job demands. Although administrators may be limited in their ability to reduce job demands, our findings suggest that increasing core job resources may be a viable alternative. PMID- 27783241 TI - Fe deficiency induced changes in rice (Oryza sativa L.) thylakoids. AB - Iron deficiency is an important abiotic stress that limits productivity of crops all over the world. We selected a hybrid rice (Oryza sativa L.), LYPJ, which is super high-yield and widely cultured in China, to investigate changes in the components and structure of thylakoid membranes and photosynthetic performance in response to iron deficiency. Our results demonstrated that photosystem I (PSI) is the primary target for iron deficiency, while the changes in photosystem II (PSII) are important for rebuilding a balance in disrupted energy utilization and dissipation caused by differential degradation of photosynthetic components. The result of immunoblot analysis suggested that the core subunit PsaA declined drastically, while PsbA remained relatively stable. Furthermore, several organizational changes of the photosynthetic apparatus were found by BN-PAGE, including a marked decrease in the PSI core complexes, the Cytb 6 /f complex, and the trimeric form of the LHCII antenna, consistent with the observed unstacking grana. The fluorescence induction analysis indicated a descending PSII activity with energy dissipation enhanced markedly. In addition, we proposed that the crippled CO2 assimilation could be compensated by the enhanced of phosphoenolpyruvate carboxylase (PEPC), which is suggested by the decreased ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and photosynthetic efficiency. PMID- 27783238 TI - Putting the Pieces Together in Gilles de la Tourette Syndrome: Exploring the Link Between Clinical Observations and the Biological Basis of Dysfunction. AB - Gilles de la Tourette syndrome is a complex, idiopathic neuropsychiatric disorder whose pathophysiological mechanisms have yet to be elucidated. It is phenotypically heterogeneous and manifests more often than not with both motor and behavioral impairment, although tics are its clinical hallmark. Tics themselves present with a complex profile as they characteristically wax and wane and are often preceded by premonitory somatosensory sensations to which it is said a tic is the response. Highly comorbid with obsessive-compulsive disorder and attention deficit-hyperactivity disorder, it is purported to be an epigenetic, neurodevelopmental spectrum disorder with a complex genetic profile. It has a childhood onset, occurs disproportionately in males, and shows spontaneous symptomatic attenuation by adulthood in the majority of those afflicted. Although not fully understood, its neurobiological basis is linked to dysfunction in the cortico-basal ganglia-thalamo-cortical network. Treatment modalities for Tourette syndrome include behavioral, pharmacological and surgical interventions, but there is presently no cure for the disorder. For those severely affected, deep brain stimulation (DBS) has recently become a viable therapeutic option. A key factor to attaining optimal results from this surgery is target selection, a topic still under debate due to the complex clinical profile presented by GTS patients. Depending on its phenotypic expression and the most problematic aspect of the disorder for the individual, one of three brain regions is most commonly chosen for stimulation: the thalamus, globus pallidus, or nucleus accumbens. Neurophysiological analyses of intra- and post-operative human electrophysiological recordings from clinical DBS studies suggest a link between tic behavior and activity in both the thalamus and globus pallidus. In particular, chronic recordings from the thalamus have shown a correlation between symptomatology and (1) spectral activity in gamma band power and (2) theta/gamma cross frequency coherence. These results suggest gamma oscillations and theta/gamma cross correlation dynamics may serve as biomarkers for dysfunction. While acute and chronic recordings from human subjects undergoing DBS have provided better insight into tic genesis and the neuropathophysiological mechanisms underlying Tourette syndrome, these studies are still sparse and the field would greatly benefit from further investigations. This review reports data and discoveries of scientific and clinical relevance from a wide variety of methods and provides up-to-date information about our current understanding of the pathomechanisms underlying Tourette syndrome. It gives a comprehensive overview of the current state of knowledge and addresses open questions in the field. PMID- 27783243 TI - Management of agricultural waste for removal of heavy metals from aqueous solution: adsorption behaviors, adsorption mechanisms, environmental protection, and techno-economic analysis. AB - In the last decades, Egypt has been suffering from the phenomenon of black cloud resulting from burning rice husk and increasing the demand for water leading to the water crisis. An alternative, low-value and surplus agricultural byproduct (rice husk, RH) has an enormous potential for the removal of Cu(II) ions from water. The present study focuses on the chance of the use of rice husk as a bio adsorbent without any chemical treatment instead of burning it and soiling the environment. The elemental, structural, morphological, surface functional, thermal, and textural characteristics of RH are determined by XRF, XRD, SEM, FT IR, TGA, and BET surface area, respectively, and contributed to the understanding of the adsorption mechanism of Cu(II) ions in aqueous solution. Also, the performance analysis, adsorption mechanism, influencing factors, favorable conditions, etc. are discussed in this article. The results obtained from optimization by batch mode are achieved under the following conditions: initial concentration, 150 ppm; amount of rice husk, 1 g; average particle size, 0.25 mm; temperature, 25 degrees C; pH, 4; agitation rate, 180 rpm; and contact time, 60 min. RH exhibits a high degree of selectivity for Cu(II) adsorption. The adsorption isotherm is fitted well with Langmuir and Freundlich models with R 2 0.998 and 0.997, respectively. The adsorption is well governed by the pseudo second-order kinetics. It is observed that the rate of adsorption improves with decreasing temperature, and the process is exothermic and non-spontaneous. Particular attention has being paid to factors as production processes, fixed/operational cost, production cost, and profit. The techno-economical analysis is presented in this study that provides precise demands on capital for a fixed investment, provisions for operational capital, and finally provisions for revenue. The social, economical, and environmental benefits by industrial point of view using low-cost adsorbent are also discussed. PMID- 27783242 TI - Particle size distribution and gas-particle partitioning of polychlorinated biphenyls in the atmosphere in Beijing, China. AB - Size-fractionated samples of urban particulate matter (PM; <=1.0, 1.0-2.5, 2.5 10, and >10 MUm) and gaseous samples were simultaneously obtained to study the distribution of polychlorinated biphenyls (PCBs) in the atmosphere in Beijing, China. Most recent investigations focused on the analysis of gaseous PCBs, and much less attention has been paid to the occurrence of PCBs among different PM fractions. In the present study, the gas-particle partitioning and size-specific distribution of PCBs in atmosphere were investigated. The total concentrations (gas + particle phase fractions) of Sigma12 dioxin-like PCBs, Sigma7 indicator PCBs, and SigmaPCBs were 1.68, 42.1, and 345 pg/m3, respectively. PCBs were predominantly in the gas phase (86.8-99.0 % of the total concentrations). The gas particle partition coefficients (K p ) of PCBs were found to be a significant linear correlated with the subcooled liquid vapor pressures (P L0) (R 2 = 0.83, P < 0.01). The slope (m r ) implied that the gas-particle partitioning of PCBs was affected both by the mechanisms of adsorption and absorption. In addition, the concentrations of PCBs increased as the particle size decreased (>10, 2.5-10, 1.0 2.5, and <=1.0 MUm), with most of the PCBs contained in the fraction of <=1.0 MUm (53.4 % of the total particulate concentrations). Tetra-CBs were the main homolog in the air samples in the gas phase and PM fractions, followed by tri-CBs. This work will contribute to the knowledge of PCBs among different PM fractions and fill the gap of the size distribution of particle-bound dioxin-like PCBs in the air. PMID- 27783244 TI - Inoculation with endophytic Bacillus megaterium H3 increases Cd phytostabilization and alleviates Cd toxicity to hybrid pennisetum in Cd contaminated aquatic environments. AB - A hydroponic culture experiment was performed to investigate the effects of endophytic Bacillus megaterium H3 on the plant biomass, Cd accumulation and tolerance of hybrid pennisetum, and the mechanisms involved in the different levels of Cd-contaminated aquatic environments. Strain H3 significantly increased the plant growth (ranging from 13 to 71 %) and total Cd uptake (ranging from 41 to 160 %) but decreased Cd translocation factors of hybrid pennisetum treated with 0-20 MUM Cd compared with the controls. Furthermore, most of Cd (71-77 %) was accumulated in the roots of the bacterial-inoculated hybrid pennisetum. Notably, strain H3 could significantly increase the production of oxalic and propanedioic acids (ranging from 18 to 188 %) but decrease the production of phytochelatins of hybrid pennisetum compared to the controls under different levels of Cd stress. The live bacterial-induced increase in organic acid production and decrease in phytochelatins production by hybrid pennisetum might be responsible for the increased plant growth, root Cd accumulation, and Cd toxicity alleviation of the plant under different levels of Cd stress. The results highlight that hybrid pennisetum plus endophytic B. megaterium H3 may be utilized for biomass production and Cd phytostabilization of the plant in the different levels of Cd-contaminated aquatic environments. PMID- 27783245 TI - Leaching of mercury from seal carcasses into Antarctic soils. AB - More than 400 seal mummies and skeletons are now mapped in the northern part of James Ross Island, Antarctica. Decomposing carcasses represent a rare source of both organic matter and associated elements for the soil. Owing to their high trophic position, seals are known to carry a significant mercury body burden. This work focuses on the extent of the mercury input from seal carcasses and shows that such carcasses represent locally significant sources of mercury and methylmercury for the environment. Mercury contents in soil samples from the surrounding areas were determined using a single-purpose AAS mercury analyzer. For the determination of methylmercury, an ultra-sensitive isotopic dilution HPLC ICP-MS technique was used. In the soils lying directly under seal carcasses, mercury contents were higher, with levels reaching almost 40 MUg/kg dry weight of which methylmercury formed up to 2.8 % of the total. The spatial distribution implies rather slow vertical transport to the lower soil layers instead of a horizontal spread. For comparison, the background level of mercury in soils of the investigated area was found to be 8 MUg/kg dry weight, with methylmercury accounting for less than 0.1 %. Apart from the direct mercury input, an enhanced level of nutrients in the vicinity of carcasses enables the growth of lichens and mosses with accumulative ability with respect to metals. The enhanced capacity of soil to retain mercury is also anticipated due to the high content of total organic carbon (from 1.6 to 7.5 %). According to the results, seal remains represent a clear source of mercury in the observed area. PMID- 27783247 TI - Nanostructured ZnO-TiO2 thin film oxide as anode material in electrooxidation of organic pollutants. Application to the removal of dye Amido black 10B from water. AB - Electrochemical oxidative degradation of diazo dye Amido black 10B (AB10B) as model pollutant in water has been studied using nanostructured ZnO-TiO2 thin films deposited on graphite felt (GrF) substrate as anode. The influence of various operating parameters, namely the current intensity, the nature and concentration of catalyst, the nature of electrode materials (anode/cathode), and the adsorption of dye and ambient light were investigated. It was found that the oxidative degradation of AB10B followed pseudo first-order kinetics. The optimal operating conditions for the degradation of 0.12 mM (74 mg L-1) dye concentration and mineralization of its aqueous solution were determined as GrF-ZnO-TiO2 thin film anode, 100 mA current intensity, and 0.1 mM Fe2+ (catalyst) concentration. Under these operating conditions, discoloration of AB10B solution was reached at 60 min while 6 h treatment needed for a mineralization degree of 91 %. Therefore, this study confirmed that the electrochemical process is effective for the degradation of AB10B in water using nanostructured ZnO-TiO2 thin film anodes. PMID- 27783246 TI - Hepatoprotective and nephroprotective effects of sardinelle (Sardinella aurita) protein hydrolysate against ethanol-induced oxidative stress in rats. AB - Ethanol consumption-induced oxidative stress that is a major etiological factor has been proven to play important roles in organs' injury. In the present study, we investigated the protective effect of fish protein hydrolysate prepared from the heads and viscera of sardinelle (Sardinella aurita) (SPH) against the toxicity of ethanol on the liver and kidney of adult male rats. Animals were divided into four groups of six animals each: group C served as control, group Eth received 30 % ethanol solution at the dose of 3 g/kg body weight, group SPH received only 7.27 mg of SPH/kg body weight, and group Eth-SPH received ethanol and SPH simultaneously at the doses of 30 % and 7.27 mg/kg body weight, respectively. All groups were treated by gavage way for 15 days. Ethanol treatment decreased the defense enzymatic system including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), which increased after the co-administration of SPH. Malondialdehyde (MDA) and toxicity biomarker levels such as aspartate transaminase (AST) and alanine transaminase (ALT) and alcaline phosphatase (ALP) and gamma-glutamyl transaminase (GGT) activities were enhanced after chronic ethanol treatment and reduced by co-treatment with SPH. The histological examination of the liver and kidney confirmed biochemical changes in ethanol-treated rats and demonstrated the protective role of SPH. PMID- 27783248 TI - Treatment and reuse of textile wastewaters by mild solar photo-Fenton in the presence of humic-like substances. AB - In this paper, the possibility of reusing textile effluents for new dyeing baths has been investigated. For this purpose, different trichromies using Direct Red 80, Direct Blue 106, and Direct Yellow 98 on cotton have been used. Effluents have been treated by means of a photo-Fenton process at pH 5. Addition of humic like substances isolated form urban wastes is necessary in order to prevent iron deactivation because of the formation of non-active iron hydroxides. Laboratory scale experiments carried out with synthetic effluents show that comparable results were obtained when using as solvent water treated by photo-Fenton with SBO and fresh deionized water. Experiments were scaled up to pilot plant illuminated under sunlight, using in this case a real textile effluent. Decoloration of the effluent could be achieved after moderate irradiation and cotton dyed with this water presented similar characteristics as when deionized water was used. PMID- 27783249 TI - Evaluation of pulsed corona discharge plasma for the treatment of petroleum contaminated soil. AB - Petroleum hydrocarbons released to the environment caused by leakage or illegal dumping pose a threat to human health and the natural environment. In this study, the potential of a pulsed corona discharge plasma system for treating petroleum polluted soils was evaluated. This system removed 76.93 % of the petroleum from the soil in 60 min with an energy efficiency of 0.20 mg/kJ. Furthermore, the energy and degradation efficiencies for the remediation of soil contaminated by single polyaromatic hydrocarbons, such as phenanthrene and pyrene, were also compared, and the results showed that this technology had potential in organic polluted soil remediation. In addition, the role of water molecules was investigated for their direct involvement in the formation and transportation of active species. The increase of soil moisture to a certain extent clearly benefitted degradation efficiency. Then, treated soils were analyzed by FTIR and GC-MS for proposing the degradation mechanism of petroleum. During the plasma discharging processes, the change of functional group and the detection of small aromatic hydrocarbons indicated that the plasma active species attached petroleum hydrocarbons and degradation occurred. This technique reported herein demonstrated significant potential for the remediation of heavily petroleum polluted soil, as well as for the treatment of organic-polluted soils. PMID- 27783250 TI - Lower tier toxicity risk assessment of agriculture pesticides detected on the Rio Madre de Dios watershed, Costa Rica. AB - Costa Rica is a tropical country with one of the highest biodiversity on Earth. It also has an intensive agriculture, and pesticide runoff from banana and pineapple plantations may cause a high toxicity risk to non-target species in rivers downstream the plantations. We performed a first tier risk assessment of the maximum measured concentrations of 32 pesticides detected over 4 years in the River Madre de Dios (RMD) and its coastal lagoon on the Caribbean coast of Costa Rica. Species sensitivity distributions (SSDs) were plotted in order to derive HC5 values for each pesticide, i.e., hazard concentrations for 5 % of the species, often used as environmental criteria values in other countries. We also carried out toxicity tests for selected pesticides with native Costa Rican species in order to calculate risk coefficients according to national guidelines in Costa Rica. The concentrations of herbicides diuron and ametryn and insecticides carbofuran, diazinon, and ethoprophos exceeded either the HC5 value or the lower limit of its 90 % confidence interval suggesting toxic risks above accepted levels. Risk coefficients of diuron and carbofuran derived using local guidelines indicate toxicity risks as well. The assessed fungicides did not present acute toxic risks according to our analysis. Overall, these results show a possible toxicity of detected pesticides to aquatic organisms and provide a comparison of Costa Rican national guidelines with more refined methods for risk assessment based on SSDs. Further higher tier risk assessments of pesticides in this watershed are also necessary in order to consider pesticide water concentrations over time, toxicity from pesticide mixtures, and eventual effects on ecosystem functions. PMID- 27783251 TI - Variations in the isotopic composition of stable mercury isotopes in typical mangrove plants of the Jiulong estuary, SE China. AB - Variations in the composition of stable isotopes of mercury contained in tissues (root, stem, leaf, and hypocotyl or flower) of three typical mangrove plants (Kandelia candel, Aegiceras corniculata, and Bruguiera gymnorhiza), collected from the mangrove wetland of Jiulong estuary, SE China, were used to investigate the sources and transformation of mercury in the mangrove plants. Tissue samples from the plants were digested and mercury in the solution was pre-concentrated with purge-trap method and then analyzed by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). The results showed that the mass dependent fractionation (MDF) of mercury ranged from -2.67 to -0.87 0/00 for delta 202Hg while the mass independent fractionation (MIF) of mercury isotopes ranged from 0.16 to 0.09 and -0.19 to 0.05 0/00 for Delta199Hg and Delta201Hg, respectively, relative to the standard NIST SRM 3133. The ratio of Delta199Hg/Delta201Hg was 0.991, indicating that the mercury had been photo-reduced before being accumulated in mangrove plants. Analyses of the data from MIF studies revealed that the major portion of the mercury measured in leaves (~90 %) originated from the atmosphere while the source of over half of the mercury present in roots was the surficial sediment. This study, the first of its kind investigating the variations in isotopic composition of mercury in the tissues of mangrove plants, could be helpful to identify the source of mercury contamination in mangroves and understand the biogeochemical cycle of mercury in the estuarine mangrove wetlands. PMID- 27783252 TI - Detection of comammox bacteria in full-scale wastewater treatment bioreactors using tag-454-pyrosequencing. AB - The nitrogen cycle has been expanded with the recent discovery of Nitrospira strains that can conduct complete ammonium oxidation (commamox). Their importance in the nitrogen cycle within engineered ecosystems has not yet been analyzed. In this research, the community structure of the Bacteria domain of six full-scale activated sludge systems and three autotrophic nitrogen removal systems in the Netherlands and China has been investigated through tag-454-pyrosequencing. The phylogenetic analyses conducted in the present study showed that just a few of the Nitrospira sequences found in the bioreactors were comammox. Multivariate redundancy analysis of nitrifying genera showed an outcompetition of Nitrosomonas and non-comammox Nitrospira. Operational data from the bioreactors suggested that comammox could be favored at low temperature, low nitrogen substrate, and high dissolved oxygen. The non-ubiquity and low relative abundance of comammox in full scale bioreactors suggested that this phylotype is not very relevant in the nitrogen cycle in wastewater treatment plants. PMID- 27783253 TI - Investigation of the disposal of dead pigs by pig farmers in mainland China by simulation experiment. AB - Dead pigs are a major waste by-product of pig farming. Thus, safe disposal of dead pigs is important to the protection of consumer health and the ecological environment by preventing marketing of slaughtered and processed dead pigs and improper dumping of dead pigs. In this study, a probability model was constructed for the disposal of dead pigs by pig farmers by selecting factors affecting disposal. To that end, we drew on the definition and meaning of behavior probability based on survey data collected from 654 pig farmers in Funing County, Jiangsu Province, China. Moreover, the role of influencing factors in pig farmers' behavioral choices regarding the disposal of dead pigs was simulated by simulation experiment. The results indicated that years of farming had a positive impact on pig farmers' choice of negative disposal of dead pigs. Moreover, there was not a simple linear relationship between scale of farming and pig farmers' behavioral choices related to the disposal of dead pigs. The probability for farmers to choose the safe disposal of dead pigs increased with the improvement of their knowledge of government policies and relevant laws and regulations. Pig farmers' behavioral choice about the disposal of dead pigs was also affected by government subsidy policies, regulation, and punishment. Government regulation and punishment were more effective than subsidy. The findings of our simulation experiment provide important decision-making support for the governance in preventing the marketing of dead pigs at the source. PMID- 27783254 TI - Cases of maternal cannibalism in wild bonobos (Pan paniscus) from two different field sites, Wamba and Kokolopori, Democratic Republic of the Congo. AB - Maternal cannibalism, whereby a mother consumes her own offspring, occurs in various animal taxa and is commonly explained by nutritional stress or environmental pressures. It is rare in nonhuman primates and is considered an aberrant behavior only observed under high-stress conditions. It was therefore surprising when, in the first reported case of cannibalism in wild bonobos, a mother consumed part of the dead infant at LuiKotale. Here we report two more cases of maternal cannibalism by wild bonobos at two different study sites, Wamba and Kokolopori. The dead infants' mothers participated in the cannibalism in both cases. At Kokolopori, although the mother did consume part of the carcass, it was held and shared by another dominant female. At Wamba, the mother was a dominant female within the community and was the primary consumer of the carcass. In both cases, cannibalism resembled other meat-eating events, with the dominant female controlling meat consumption. Infanticide was not observed in either case, but its occurrence could not be ruled out. Although rare, the occurrence of maternal cannibalism at three different study sites suggests that this may represent part of the behavioral repertoire of bonobos, rather than an aberrant behavior. PMID- 27783255 TI - Targeting the protein ubiquitination machinery in melanoma by the NEDD8 activating enzyme inhibitor pevonedistat (MLN4924). AB - Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models. Gene expression microarray and gene set enrichment analyses were performed in cell lines to determine the expression profiles and pathways of sensitivity/resistance. Pharmacodynamic changes in treated-PDTX were also characterized. Results Pevonedistat effectively inhibited cell viability (IC50 < 0.3 MUM) and induced apoptosis in a subset of melanoma cell lines. Sensitive and resistant cell lines exhibited distinct gene expression profiles; sensitive models were enriched for genes involved in DNA repair, replication and cell cycle regulation, while immune response and cell adhesion pathways were upregulated in resistant models. Pevonedistat also reduced tumor growth in melanoma cell line xenografts and PDTX with variable responses. An accumulation of pevonedistat-NEDD8 adduct and CDT1 was observed in sensitive tumors consistent with its mechanism of action. Conclusions This study provided preclinical evidence that NAE inhibition by pevonedistat has anti-tumor activity in melanoma and supports the clinical benefits observed in recent Phase 1 trials of this drug in melanoma patients. Further investigations are warranted to develop rational combinations and determine predictive biomarkers of pevonedistat. PMID- 27783256 TI - Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials. AB - Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities. PMID- 27783258 TI - Interrelationships and Continuities in Symptoms of Oppositional Defiant and Conduct Disorders from Age 4 to 10 in the Community. AB - Childhood oppositional defiant disorder (ODD) has commonly been thought to increase the risk of conduct disorder (CD) in late childhood and adolescence. However, symptoms of CD may also emerge during preschool and middle childhood. The few studies that have examined whether ODD increases the risk of such early onset CD have produced equivocal results, potentially due to methodological issues. In this study, a community sample of Norwegian 4-year-olds (n = 1042, 49.9 % males) was examined bi-annually over four waves of data collection. Symptoms of ODD, CD, attention-deficit/hyperactivity disorder (ADHD), anxiety and depressive disorders were measured through interviews with parents and children using the Preschool Age Psychiatric Assessment and the Child and Adolescent Psychiatric Assessment. The results showed that at all ages, more symptoms of ODD predicted more symptoms of CD at the next age of examination even after adjusting for previous CD and comorbid conditions. The effect of previous ODD on CD two years later did not differ according to gender, SES, or parental cohabitating status at any point in time. There was modest homotypical continuity in symptoms of CD and moderate homotypical continuity in symptoms of ODD. Symptoms of ODD increased from age 4 to 8 and declined to age 10. In conclusion, symptoms of ODD increase the risk of early onset symptoms of CD. The continuity in symptoms of ODD, and to some extent CD, combined with an increased risk of early symptoms of CD forecasted by symptoms of ODD, underscore the importance of detection, prevention and treatment of behavioral disorders already in early childhood. PMID- 27783257 TI - Is Poor Working Memory a Transdiagnostic Risk Factor for Psychopathology? AB - In contrast to historical conceptualizations that framed psychological disorders as distinct, categorical conditions, it is now widely understood that co- and multi-morbidities between disorders are extensive. As a result, there has been a call to better understand the dimensional liabilities that are common to and influence the development of multiple psychopathologies, as supported and exemplified by the National Institutes of Mental Health (NIMH) Research Domain Criteria (RDoC) framework. We use a latent variable SEM approach to examine the degree to which working memory deficits represent a cognitive liability associated with the development of common and discrete dimensions of psychopathology. In a sample of 415 community recruited children aged 8-12 (n = 170 girls), we fit a bi-factor model to parent reports of behavior from the DISC 4 and BASC-2, and included a latent working memory factor as a predictor of the internalizing, externalizing, and general "p-factor." We found that both the general "p-factor" and externalizing (but not internalizing) latent factor were significantly associated with working memory. When a bi-factor model of externalizing symptomology was fit to further explore this relationship, working memory was only correlated with the general externalizing dimension; correlation with specific inattention, hyperactive/impulsive, and oppositional factors did not survive once the general externalizing dimension was taken into consideration. These findings held regardless of the sex of the child. Our results suggest that working memory deficits represent both a common cognitive liability for mental health disorders, and a specific liability for externalizing disorders. PMID- 27783260 TI - The 2016 Albert Lasker Basic Medical Research Award: Oxygen sensing-a mysterious process essential for survival. PMID- 27783259 TI - Technology-based interventions for weight management: current randomized controlled trial evidence and future directions. AB - Obesity is a prevalent health care issue associated with disability, premature morality, and high costs. Behavioral weight management interventions lead to clinically significant weight losses in overweight and obese individuals; however, many individuals are not able to participate in these face-to-face treatments due to limited access, cost, and/or time constraints. Technological advances such as widespread access to the Internet, increased use of smartphones, and newer behavioral self-monitoring tools have resulted in the development of a variety of eHealth weight management programs. In the present paper, a summary of the most current literature is provided along with potential solutions to methodological challenges (e.g., high attrition, minimal participant racial/ethnic diversity, heterogeneity of technology delivery modes). Dissemination and policy implications will be highlighted as future directions for the field of eHealth weight management. PMID- 27783261 TI - Religious Practices and Self-Care in Iranian Patients with Type 2 Diabetes. AB - This study aimed to examine the relationship between religious practices and self care of patients with type 2 diabetes. A descriptive cross-sectional survey was conducted on 154 diabetic patients who were referred to two general teaching hospitals in Qom City (Iran). Data were collected using demographic questionnaire, private and public religious practices, and summary of diabetes self-care activities questionnaires. Data were analyzed using descriptive statistics and statistical tests including independent t test, and Pearson correlation coefficient. Significant positive correlations were observed between religious practices and self-care activities in diabetic patients (p < 0.05). Significant positive correlations were also found between some religious practices and self-care activities subscales (p < 0.05). Healthcare providers should be aware of the role that religion plays in the lives of diabetic patients and be able to take religious factors into account when developing care plans. Doing so will enhance a more patient-centered approach and thereby support patients in their role as self-care decision-makers. PMID- 27783263 TI - HLA-typing analysis following allogeneic bone grafting for sinus lifting. AB - According to the Brazilian Association of Organ Transplants, in 2015, 19,408 bone transplants were performed in Brazil, over 90% by Dental Surgeons. The surgical technique itself has a respectable number of reports regarding its clinical efficacy, as measured by long-term survival of dental implants in grafted areas. Uncertainty remains, however, as to whether fresh frozen grafts from human bone donors remain immunologically innocuous in the body of the host. Six male with no previous medical history of note, including systemic diseases, surgery or blood transfusion were selected. These patients underwent reconstructive procedures (sinus lifting) using fresh frozen human bone from a tissue bank. All patients had venous blood samples collected prior to surgery and 6 months after the procedure. Anti-HLA analysis for the detection of HLA (human leukocyte antigen) antibodies was performed using methods such as the LABScreen PRA Class I and Class II, LABScreen Single Antigen Class I and Class II, Luminex Platform. Reactive individuals to the screening tests (LABScreen PRA) were further investigated to determine the specificity of the antibodies detected (LABScreen Single Antigen) with a cutoff value of median fluorescence intensity >=500. As a result, it was observed that two patients (33%) were positive in screening tests, one presenting with anti-HLA Class I and II sensitization and the other with anti HLA class II. The specificity analysis showed that the patients sensitized to HLA class II presented 4 specificities, 3 of which immunologically relevant. In the second individual, 23 specificities were identified, 6 of which immunologically important for HLA class I and 4 specificities for HLA class II, 3 of these were immunologically important. All specificities detected had average fluorescence. These findings are suggestive that sinus-lifting procedures with allogeneic bone can induce immunological sensitization. PMID- 27783264 TI - ITS Annual Scientific Meeting 2016. PMID- 27783262 TI - Empathy is Associated with Meaning of Life and Mental Health Treatment but not Religiosity Among Brazilian Medical Students. AB - The purpose of this study was to investigate the influence of spirituality, religiosity, personal beliefs, and previous contact with health issues on the level of empathy in medical students. Jefferson Scale of Empathy-Student Version, WHOQOL-Spirituality, Religiousness and Personal Beliefs, and Duke University Religion Index were applied to 285 Brazilian medical students. The findings suggest that meaning of life and previous mental health treatment but not Religiosity were positively related to empathy. We suggest that more attention should be given for prevention and treatment of mental health issues, and further studies are needed to understand and replicate these findings. PMID- 27783265 TI - A parallel and quantitative cell migration assay using a novel multi-well-based device. AB - Cell migration assays for different chemical environments are important for both scientists and clinicians searching for new therapeutics. In this study, we developed a multi-well-based microfluidic chip that has multiple units for different conditions. In each unit, cells can be patterned and then released to observe their migration. Automatic image analysis and model-based data processing were developed to describe the integrated cell migration assay precisely and quickly. As a demonstration, the migration behaviors of two types of cells in eight chemical conditions were studied. The results showed that supplementation with transforming growth factor-beta(TGF-beta) significantly promoted the migration of MCF-7 and MCF-10 A cells compared to several growth factors, such as Epidermal Growth Factor(EGF) and basic fibroblast growth factor(bFGF), as well as a control sample. Cells can migrate particularly fast with two or more mixed supplementary factors, such as TGF-beta + bFGF + EGF, which indicated a synergy effect. Thus, this chip could be used to quantitatively observe cancer cell migration and demonstrated great potential for use in quantitative migration studies and chemical screening. PMID- 27783268 TI - Fixed-Dose Combination Inhalers. AB - In asthma and chronic obstructive pulmonary disease (COPD), an important step in simplifying management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Fixed-dose combination (FDC) therapy might enhance compliance by decreasing the number of medications and/or the number of daily doses. Furthermore, they have the potential for enhancing, sensitizing, and prolonging the effects of monocomponents. Combination therapy with an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA) is considered an important approach for treating patients with asthma and patients with severe COPD who have frequent exacerbations. Several ICS/LABA FDCs are now commercially available or will become available within the next few years for the treatment of COPD and/or asthma. Several studies demonstrate that there are a number of added benefits in using combinations of beta2-agonists and antimuscarinic agents. In particular, LABA/long-acting antimuscarinic agent (LAMA) combination seems to play an important role in optimizing bronchodilation. Several once-daily and twice-daily LABA/LAMA FDCs have been developed or are in clinical development. LAMA/ICS FDCs seem to be useful in COPD and mainly in asthma, in patients with severe asthma and persistent airflow limitation. The rationale behind the ICS/LABA/LAMA FDCs seems logical because all three agents work via different mechanisms on different targets, potentially allowing for lower doses of the individual agents to be used, accompanied by improved side effect profiles. In effect, in clinical practice, concomitant use of all three compounds is common, especially in more severe COPD but also in the treatment of adults with poorly controlled asthma despite maintenance treatment with high-dose ICS and a LABA. PMID- 27783267 TI - Go it alone: four-electron oxidations by mononuclear non-heme iron enzymes. AB - This review discusses the current mechanistic understanding of a group of mononuclear non-heme iron-dependent enzymes that catalyze four-electron oxidation of their organic substrates without the use of any cofactors or cosubstrates. One set of enzymes acts on alpha-ketoacid-containing substrates, coupling decarboxylation to oxygen activation. This group includes 4-hydroxyphenylpyruvate dioxygenase, 4-hydroxymandelate synthase, and CloR involved in clorobiocin biosynthesis. A second set of enzymes acts on substrates containing a thiol group that coordinates to the iron. This group is comprised of isopenicillin N synthase, thiol dioxygenases, and enzymes involved in the biosynthesis of ergothioneine and ovothiol. The final group of enzymes includes HEPD and MPnS that both carry out the oxidative cleavage of the carbon-carbon bond of 2 hydroxyethylphosphonate but generate different products. Commonalities amongst many of these enzymes are discussed and include the initial substrate oxidation by a ferric-superoxo-intermediate and a second oxidation by a ferryl species. PMID- 27783270 TI - Ocular Drug Delivery. AB - Although the eye is an accessible organ for direct drug application, ocular drug delivery remains a major challenge due to multiple barriers within the eye. Key barriers include static barriers imposed by the cornea, conjunctiva, and retinal pigment epithelium and dynamic barriers including tear turnover and blood and lymphatic clearance mechanisms. Systemic administration by oral and parenteral routes is limited by static blood-tissue barriers that include epithelial and endothelial layers, in addition to rapid vascular clearance mechanisms. Together, the static and dynamic barriers limit the rate and extent of drug delivery to the eye. Thus, there is an ongoing need to identify novel delivery systems and approaches to enhance and sustain ocular drug delivery. This chapter summarizes current and recent experimental approaches for drug delivery to the anterior and posterior segments of the eye. PMID- 27783266 TI - Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy. AB - Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application. PMID- 27783269 TI - Anion Channels of Mitochondria. AB - Mitochondria are the "power house" of a cell continuously generating ATP to ensure its proper functioning. The constant production of ATP via oxidative phosphorylation demands a large electrochemical force that drives protons across the highly selective and low-permeable mitochondrial inner membrane. Besides the conventional role of generating ATP, mitochondria also play an active role in calcium signaling, generation of reactive oxygen species (ROS), stress responses, and regulation of cell-death pathways. Deficiencies in these functions result in several pathological disorders like aging, cancer, diabetes, neurodegenerative and cardiovascular diseases. A plethora of ion channels and transporters are present in the mitochondrial inner and outer membranes which work in concert to preserve the ionic equilibrium of a cell for the maintenance of cell integrity, in physiological as well as pathophysiological conditions. For, e.g., mitochondrial cation channels KATP and BKCa play a significant role in cardioprotection from ischemia-reperfusion injury. In addition to the cation channels, mitochondrial anion channels are equally essential, as they aid in maintaining electro-neutrality by regulating the cell volume and pH. This chapter focusses on the information on molecular identity, structure, function, and physiological relevance of mitochondrial chloride channels such as voltage dependent anion channels (VDACs), uncharacterized mitochondrial inner membrane anion channels (IMACs), chloride intracellular channels (CLIC) and the aspects of forthcoming chloride channels. PMID- 27783272 TI - Periportal low attenuation associated with liver metastasis from colorectal cancer: evaluation using multi-detector-row CT with pathological correlation. AB - OBJECTIVES: Periportal low attenuation (PPLA) associated with metastatic liver cancer is occasionally seen on multi-detector-row CT (MDCT). The purpose of this study was to investigate the MDCT patterns of the PPLA and to correlate it with pathological findings. METHODS: We retrospectively reviewed the MDCT images of 63 patients with metastatic liver cancers from colorectal adenocarcinoma. On MDCT scans, PPLA associated with liver metastasis was visualized in six patients with colorectal cancer. In these six patients who had undergone surgical resection, the radiologic-pathologic correlation was analyzed. All patients underwent a single contrast-enhanced MDCT within 1 month before surgical resection. The six liver cancers were pathologically proven to be moderately differentiated adenocarcinoma. We assessed the PPLA on MDCT concerning the distribution patterns and contrast enhancement with pathological correlation. RESULTS: In five of the patients, the PPLA extended to the hilar side from metastatic liver cancer. Pathologically, there was no cancer invasion into the intra-hepatic periportal area; however, massive lymphedema and fibrosis occurred in all six cases. CONCLUSIONS: PPLA on the hilar and peripheral sides of hepatic metastasis from colorectal cancer may be present suggesting lymphedema and fibrosis of portal tracts not always indicating cancer infiltration. PMID- 27783273 TI - HSP70 in human polymorphonuclear and mononuclear leukocytes: comparison of the protein content and transcriptional activity of HSPA genes. AB - Cell-type specific variations are typical for the expression of different members of the HSP70 family. In circulating immune cells, HSP70 proteins interact with units of signaling pathways involved in the immune responses and may promote cell survival in sites of inflammation. In this work, we compared basal HSP70 expression and stress-induced HSP70 response in polymorphonuclear and mononuclear human leukocytes. The intracellular content of inducible and constitutive forms of HSP70 was analyzed in relation to the transcriptional activity of HSPA genes. Hyperthermia was used as the stress model for induction of HSP70 synthesis in the cells. Our results demonstrated that granulocytes (mainly neutrophils) and mononuclear cells differ significantly by both basal HSP70 expression and levels of HSP70 induction under hyperthermia. The differences were observed at the levels of HSPA gene transcription and intracellular HSP70 content. The expression of constitutive Hss70 protein was much higher in mononuclear cells consisting of monocytes and lymphocytes than in granulocytes. At the same time, intact neutrophils showed increased expression of inducible Hsp70 protein compared to mononuclear cells. Heat treatment induced additional expression of HSPA genes in leukocytes. The most pronounced increase in the expression was observed in polymorphonuclear and mononuclear leukocytes for HSPA1A/B. However, in granulocytes, the induction of the transcription of the HSPA8 gene encoding the Hsc70 protein was significantly higher than in mononuclear cells. These variations in transcriptional activity of HSPA genes and intracellular HSP70 content in different populations of leukocytes may reflect specified requirements for the chaperone activity in the cells with a distinct functional role in the immune system. PMID- 27783271 TI - Anti-angiogenic Therapy for Retinal Disease. AB - Recent breakthroughs in our understanding of the molecular pathophysiology of retinal vascular disease have allowed us to specifically target pathological angiogenesis while minimizing damage to the neurosensory retina. This is perhaps best exemplified by the development of therapies targeting the potent angiogenic growth factor and vascular permeability mediator, vascular endothelial growth factor (VEGF). Anti-VEGF therapies, initially introduced for the treatment of choroidal neovascularization in patients with age-related macular degeneration, have also had a dramatic impact on the management of retinal vascular disease and are currently an indispensable component for the treatment of macular edema in patients with diabetic eye disease and retinal vein occlusions. Emerging evidence supports expanding the use of therapies targeting VEGF for the treatment of retinal neovascularization in patients with diabetic retinopathy and retinopathy of prematurity. However, VEGF is among a growing list of angiogenic and vascular hyperpermeability factors that promote retinal vascular disease. Many of these mediators are expressed in response to stabilization of a single family of transcription factors, the hypoxia-inducible factors (HIFs), that regulate the expression of these angiogenic stimulators. Here we review the basic principles driving pathological angiogenesis and discuss the current state of retinal anti angiogenic pharmacotherapy as well as future directions. PMID- 27783274 TI - Encapsulated Hsp70 decreases endotoxin-induced production of ROS and TNFalpha in human phagocytes. AB - Human heat shock protein Hsp70 was experimentally inserted into polyelectrolyte microcapsules. Encapsulated recombinant Hsp70 was studied in terms of its effects on neutrophil apoptosis, the production of reactive oxygen species, and the secretion of tumor necrosis factor alpha by promonocytic THP-1 cells. It was found that encapsulated Hsp70 effectively inhibits neutrophil apoptosis, unlike free exogenous protein used in solution. In THP-1 cells, encapsulated and free Hsp70 reduced LPS-induced tumor necrosis factor alpha production with a similar efficiency. Encapsulated Hsp70 reduces LPS-induced reactive oxygen species production by neutrophils in the course of its release from the microcapsules but not as much as free Hsp70. Thus, the polyelectrolyte microcapsules can be used as containers for the effective delivery of Hsp70 to neutrophils and monocytes to significantly improve the functioning of the innate immune system. PMID- 27783275 TI - A new peritoneal dialysis fluid for Japanese patients: a randomized non inferiority clinical trial of safety and efficacy. AB - BACKGROUND: We report here two new peritoneal dialysis fluids (PDFs) for Japan [BLR 250, BLR 350 (Baxter Limited, Japan)]. The PDFs use two-chamber systems, and have bicarbonate and lactate buffer to a total of 35 mmol/L. In separate trials, the new PDFs were compared to two "standard" systems [PD-4, PD-2 (Baxter Limited, Japan)]. The trials aimed to demonstrate non-inferiority of peritoneal creatinine clearance (pCcr), peritoneal urea clearance (pCurea) and ultrafiltration volume (UF), and compare acid-base and electrolyte balance. METHODS: We performed randomized, multicenter, parallel group, controlled, open-label clinical trials in stable continuous ambulatory peritoneal dialysis (CAPD) patients. The primary endpoints were pCcr and UF. The secondary endpoints were serum bicarbonate and peritoneal urea clearance. The active phase was 8 weeks. These trials were performed as non-inferiority studies, with the lower limit of non-inferiority for pCcr and UF set at 3.2 L/week/1.73 m2 and 0.12 L/day, respectively. RESULTS: 108 patients (28 centers) and 103 patients (29 centers) took part in the two trials. Groups were well balanced at baseline. The investigative PDFs were non-inferior to the "standard" ones in terms of primary endpoints, comparable in terms of pCurea, and superior in terms acid-base balance, especially correcting those with over-alkalinization at baseline. CONCLUSIONS: We demonstrated fundamental functionality of two new PDFs and showed superior acid-base balance. Given the propensity of Japanese CAPD patients for alkalosis, it is important to avoid metabolic alkalosis which is associated with increased cardiovascular mortality risk and accelerated vascular calcification. The new PDFs are important progress of CAPD treatment for Japanese patients. PMID- 27783276 TI - Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome. AB - BACKGROUND: We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS). METHODS: Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2. Serum MZR concentrations from 0 to 4 h after administration were examined within one month of treatment. The concentration curve and peak serum level (C max) of MZR were estimated by the population pharmacokinetic (PPK) parameters of MZR. RESULTS: At 2 years, 10 of 19 patients (52.6 %) in group 1 and 7 of 18 patients (38.9 %) in group 2 achieved complete remission (CR). The time-to-remission curve using the Kaplan-Meier technique revealed an increase in the cumulative CR rate in group 1, but no significant difference between the groups. Meanwhile, there was a significant difference in C max between groups 1 and 2 (mean +/- SD: 1.20 +/- 0.52 vs. 0.76 +/- 0.39 MUg/mL, p = 0.04), and C max levels in CR cases were significantly higher than those in non-CR cases. Receiver operating characteristic analysis showed that C max more than 1.1 ug/mL was necessary for CR in once-a-day administration. CONCLUSION: Administration of MZR once a day is useful when combined with PSL for treatment of IMN with SRNS. In addition, it is important to assay the serum concentration of MZR and to determine C max, and more than 1.1 ug/mL of C max is necessary for CR. PMID- 27783278 TI - Can we prevent BRCA1-associated breast cancer by RANKL inhibition? AB - BRCA1 mutation carriers face a high lifetime risk of breast cancer, estimated at 60 % compared to 10 % in the general population. BRCA1 breast cancers typically have an aggressive course (i.e., high-grade, triple-negative) and are associated with a poor prognosis. At present, primary prevention is limited to prophylactic removal of the unaffected breasts. Effective chemopreventive strategies are not yet available. Emerging evidence suggests that BRCA1 mutation carriers have high circulating levels of progesterone which may play a role in their susceptibility to breast cancer. Recently, the RANK/RANKL system was found to be dysregulated in women with a BRCA1 mutation. Mutation carriers had significantly lower endogenous levels of osteoprotegerin (OPG) than women without a BRCA1 mutation. OPG is an endogenous decoy receptor for RANKL and inhibits RANKL-mediated signaling. RANKL binds to RANK on mammary epithelial cells and stimulates their proliferation and maturation. Low OPG levels may contribute to mammary tumorigenesis through increased proliferation and may explain in part the increased breast cancer risk in BRCA1 mutation carriers. Denosumab is an anti-RANKL monoclonal antibody which is approved to treat osteoporosis and to prevent skeletal damage caused by bone metastases. The emerging role of aberrant RANK-signaling in BRCA1 tumorigenesis suggests that targeting of RANKL may prevent breast cancer among women with germline BRCA1 mutations. Clinical investigations of denosumab are warranted and may lead to a novel chemopreventive approach for breast cancer for high-risk women. PMID- 27783277 TI - EGAR, A Food Protein-Derived Tetrapeptide, Reduces Seizure Activity in Pentylenetetrazole-Induced Epilepsy Models Through alpha-Amino-3-Hydroxy-5-Methyl 4-Isoxazole Propionate Receptors. AB - A primary pathogeny of epilepsy is excessive activation of alpha-amino-3-hydroxy 5-methyl-4-isoxazole propionate receptors (AMPARs). To find potential molecules to inhibit AMPARs, high-throughput screening was performed in a library of tetrapeptides in silico. Computational results suggest that some tetrapeptides bind stably to the AMPAR. We aligned these sequences of tetrapeptide candidates with those from in vitro digestion of the trout skin protein. Among salmon derived products, Glu-Gly-Ala-Arg (EGAR) showed a high biological affinity toward AMPAR when tested in silico. Accordingly, natural EGAR was hypothesized to have anticonvulsant activity, and in vitro experiments showed that EGAR selectively inhibited AMPAR-mediated synaptic transmission without affecting the electrophysiological properties of hippocampal pyramidal neurons. In addition, EGAR reduced neuronal spiking in an in vitro seizure model. Moreover, the ability of EGAR to reduce seizures was evaluated in a rodent epilepsy model. Briefer and less severe seizures versus controls were shown after mice were treated with EGAR. In conclusion, the promising experimental results suggest that EGAR inhibitor against AMPARs may be a target for antiepilepsy pharmaceuticals. Epilepsy is a common brain disorder characterized by the occurrence of recurring, unprovoked seizures. Twenty to 30 % of persons with epilepsy do not achieve adequate seizure control with any drug. Here we provide a possibility in which a natural and edible tetrapeptide, EGAR, can act as an antiepileptic agent. We have combined computation with in vitro experiments to show how EGAR modulates epilepsy. We also used an animal model of epilepsy to prove that EGAR can inhibit seizures in vivo. This study suggests EGAR as a potential pharmaceutical for the treatment of epilepsy. PMID- 27783279 TI - Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer. AB - PURPOSE: This study was performed to evaluate the frequency of mutations in CHEK2, PALB2, MRE11, and RAD50 among Korean patients at high risk for hereditary breast cancer. METHODS: A total of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutation were enrolled to this study. Entire coding regions of CHEK2, PALB2, MRE11, and RAD50 were analyzed using massively parallel sequencing (MPS). Sequence variants detected by MPS were confirmed by Sanger sequencing. RESULTS: Six patients (2.5 %) were found to have pathogenic variants in CHEK2 (n = 1), PALB2 (n = 2), MRE11 (n = 1), and RAD50 (n = 2). Among the pathogenic variants, PALB2 c.2257C>T was previously reported in other studies, while CHEK2 c.1245dupC, PALB2 c.1048C>T, MRE11 c.1773_1774delAA, RAD50 c.1276C>T, and RAD50 c.3811_3813delGAA were newly identified in this study. A total of 15 missense variants were found in the four genes among 26 patients; 7 patients had a variant in CHEK2, 11 in PALB2, 2 in MRE11, and 6 in RAD50. When in silico analyses were performed to the 15 missense variants, six variants (CHEK2 c.686A>G, PALB2 c.1492G>T, PALB2 c.3054G>C, MRE11 c.140C>T, RAD50 c.1456C>T, and RAD50 c.3790C>T) were predicted to be deleterious. CONCLUSIONS: Pathogenic variants in CHEK2, PALB2, MRE11, and RAD50 were detected in a small proportion of Korean patients with features of hereditary breast cancer. PMID- 27783280 TI - Optimal primary febrile neutropenia prophylaxis for patients receiving docetaxel cyclophosphamide chemotherapy for breast cancer: a systematic review. AB - BACKGROUND: Due to the high rate of febrile neutropenia (FN) with docetaxel cyclophosphamide (DC) chemotherapy, primary FN prophylaxis is recommended. However, the optimal choice of prophylaxis [i.e., granulocyte-colony stimulating factors (G-CSF) or antibiotics] is unknown. A systematic review was performed to address this knowledge gap. METHODS: Embase, Ovid Medline, Pubmed, the Cochrane database of systematic reviews, and Cochrane register of controlled trials were searched from 1946 to April 2016 for studies evaluating primary prophylactic FN treatments in breast cancer patients receiving DC chemotherapy. Outcome measures evaluated included: incidence of FN and treatment-related hospitalizations, chemotherapy dose reduction/delays/discontinuations, and adverse events. Screening and data collection were performed by two independent reviewers. RESULTS: Of 2105 identified records, 7 studies (n = 2535) met the pre-specified eligibility criteria. Seven additional studies (n = 621) were identified from prior systematic reviews. There were 3 randomized controlled trials (RCTs) (n = 2256) and 11 retrospective studies (n = 900). Study sample sizes ranged from 30 to 982 patients (median 99.5), evaluating pegfilgrastim (n = 1274), filgrastim (n = 1758), and oral ciprofloxacin (n = 108). Given the heterogeneity of patients and study design, a narrative synthesis of results was performed. Median FN rates with and without primary prophylaxis were 6.6 % (IQR 3.9-10.6 %) and 31.3 % (IQR 25-33 %), respectively. No FN-related deaths were reported. No RCT directly compared G-CSF with antibiotic interventions. CONCLUSIONS: Primary FN prophylaxis reduces the incidence of FN. Despite considerable cost and toxicity differences between G-CSF and antibiotics, there is insufficient data to make a recommendation of one strategy over another. PMID- 27783281 TI - Evaluation of Serum Reaction to Low-Intensity Laser Exposure by Its Solid Phase Structure. AB - The effects of various modes of low-intensity laser exposure on the sera of healthy subjects and patients are studied. It is shown by the cuneiform dehydration method that the serum structure is liable to change in response to certain modes of low-intensity laser exposure. The structure of patients' sera is more sensitive to low-intensity laser exposure. PMID- 27783282 TI - Effects of Melatonin on Differentiation Potential of Ito Cells in Mice with Induced Fibrosis of the Liver. AB - We studied the effects of melatonin on differentiation potential of Ito cells during atypical regeneration of mouse liver under conditions of CCl4-induced fibrosis. The dynamics of fibrosis was traced at the histological level and the effects of melatonin on the differentiation potential of mouse Ito cells were evaluated. Melatonin alleviated fibrotic changes in the liver tissue and reduced differentiation of Ito cells into myofibroblasts under conditions of atypical regeneration of the liver in induced fibrosis. The hepatoprotective role of melatonin was shown. PMID- 27783283 TI - Electron Microscopic Study of the Inner Medulla in Rat Kidneys under Conditions of Vasopressin Treatment Combined with Prostaglandin Synthesis Blockade. AB - Ultrastructural changes in cells of the renal inner medulla involved in the realization of the antidiuretic effect of vasopressin under conditions of prostaglandin synthesis blockade were studied in the kidneys of Wistar rats and endogenous vasopressin-deficient homozygous Brattleboro rats. The results indicated uniform trend to an increase in the number of clathrincoated vesicles under conditions of hormone treatment combined with prostaglandin synthesis blockade in animals with different neurohypophyseal status. These changes reflected translocation of aquaporins and an increase in the permeability of the collecting tubular epithelium for water. Brattleboro rats, but not Wistar rats, exhibited ultrastructural signs of synthesis activation in the epithelium and widening of the intercellular gaps, which could indicate more intense paracellular water transport. PMID- 27783284 TI - Age-Specific Dynamics of Corpus Callosum Development in Children and its Peculiarities in Infantile Cerebral Palsy. AB - The age dynamics of corpus callosum development was studied on magnetic resonance images of the brain in children aged 2-11 years without neurological abnormalities and with infantile cerebral palsy. The areas of the total corpus callosum and its segments are compared in the midsagittal images. Analysis is carried out with the use of an original formula: proportion of areas of the anterior (genu, CC2; and anterior part, CC3) and posterior (isthmus, CC6 and splenium, CC7) segments: kCC=(CC2+CC3)*CC6/CC7. The results characterize age specific dynamics of the corpus callosum development and can be used for differentiation, with high confidence, of the brain of children without neurological abnormalities from the brain patients with infantile cerebral palsy. PMID- 27783285 TI - Changes in the Quantitative Composition of the Population in Delayed Periods After gamma-Radiation Exposure of the Cells in Various Phases of S Period of the First Mitotic Cycle. AB - Using the autoradiographic method, we studied the kinetics of DNA synthesis over the mitotic cycle in mouse corneal epithelium cells in delayed periods after gamma-irradiation in different points of the S phase of the first mitotic cycle. The index labeled cells during 1-3 periods of DNA synthesis most adequately reflects quantitative changes in the cell population composition after cell exposure during the first S period. The relative number of labeled S phase cells in the second mitotic cycle in experiments where the cells were irradiated in the S1 phase of the first S period was 4-fold lower than in experiments where the cells were exposed during S2 phase. This effect is determined by inhibition of the transcription factors activation. It seems that two territorially different sites of the genome controlling the regulatory stimuli and involved in modification of the quantitative composition of the population are responsible for changes in its quantitative balance. PMID- 27783286 TI - Structural and Functional Analysis of the Small Intestine in Rats After Six-Month Long Exposure to Multiwalled Carbon Nanotubes. AB - Structural and functional analysis of the small intestinal villi in outbred rats was performed after treatment with multiwalled carbon nanotube suspension in comparison with the effects of fine charcoal suspension. Chronic (6 months) exposure to nanotubes in a concentration of 0.2 mg/liter and, particularly, 0.5 mg/liter induced significant changes in the small intestine manifested in a decrease in the number of villi without changes in the brush border integrity, increase in the number of destructed villi, and appearance of villi with apical necrosis. These abnormalities were not observed after treatment for a shorter period of time (2 months). PMID- 27783288 TI - Proteomic Profiling of the Blood Serum for Prediction of Premature Delivery. AB - Mass-spectrometric profiling of the serum in women at weeks 16-17 of gestation was carried out in order to detect proteomic predictors of preterm delivery. Changes in the production of 25 proteins (down-regulation for 13 proteins and up regulation for 12 proteins) were detected in the sera of women whose pregnancies eventuated in premature deliveries. Among them, proteins with various regulatory functions were distinguished: antioxidant enzymes, chaperons, cytoskeleton proteins, cell adhesion molecules, and proteins involved in angiogenesis, proteolysis, transcription, inflammation processes, binding and transportation of various ligands. These results indicated the formation of proteomic imbalance as early as during trimester II, this eventually leading to premature delivery. The detected serum proteins were suggested as markers for early prediction of premature delivery. PMID- 27783287 TI - Sensitivity of C6 Glioma Cells Carrying the Human Poliovirus Receptor to Oncolytic Polioviruses. AB - A humanized line of rat C6 glioma cells expressing human poliovirus receptor was obtained and tested for the sensitivity to oncolytic effects of vaccine strains of type 1, 2, and 3 polioviruses. Presentation of the poliovirus receptor on the surface of C6 glioma cells was shown to be a necessary condition for the interaction of cells with polioviruses, but insufficient for complete poliovirus oncolysis. PMID- 27783289 TI - Radiation Stress Changes the Size of Side Population of Human Epithelial Cells. AB - Stem cell cultures are heterogeneous and include true stem cells and progenitor cells. True stem cells are identified by flow cytofluorometry as a cell subset characterized by low accumulation of fluorescent dye rhodamin-123 and forming a side population. Low-dose gamma-irradiation (10-200 mGy) of human skin epithelial stem cells and epithelial H69 tumor cells to was followed by an increase in cell counts by day 7 after the exposure. In parallel, reduction of the side population to 4-30% from the control for epithelial stem cells on the next day after exposure and to 22-36% from the control for H69 cells in 3 days after exposure. The size of the side population remained reduced to 8-37% of that in the control cultures of epithelial stem cells and H69 cells for at least 7 days after exposure. The decrease of the side population fraction of cells was not caused by cell death, but could be due to radiation-induced activation of the signal pathways, regulating the velocity of autoregeneration of the pool of true stem cells and acceleration of their transition to the pool of rapidly proliferating progenitor cells, this leading to an increase in the total cell count in the studied cultures under the effect of low-dose gamma-radiation. PMID- 27783290 TI - Effect of Herbal Homeopathic Monopreparations on the Rate of Tissue Lymphatic Drainage in Healthy Mice. AB - We studied the effects of homeopathic monopreparations of plant origin Atropa Belladonna and Rhus toxicodendron in three dilutions (potencies) on interstitial humoral transport in healthy laboratory mice assessed by the rate of excretion of the lymphotropic label from the mesentery according to the Oyvin's method (vital biomicroscopy of intestinal mesentery in small animals). The homeopathic monopreparations exerted a dose-dependent inhibitory effect on the interstitial transport and lymphatic drainage in tissues of healthy mice. PMID- 27783291 TI - Characteristics of Factors of Protozoa Blastocystis hominis Persistence. AB - Persistence activity manifested in the expression of anti-lysozyme, anti lactoferrin, and antihistone factors promoting inactivation of natural anti infection resistance factors in the body was revealed in Blastocystis hominis protozoa. Activities of these factors were ranged. The frequency of these factors in clinical isolates of blastocyst decreased in the following order: anti lactoferrin activity (84.5+/-3.7%)->anti-lysozyme activity (64.8+/-5.7%)->anti histone activity (48.1+/-2.3%). In healthy humans, the corresponding parameters were 7.3+/-1.3, 5.3+/-0.9, and 3.3+/-0.4%, respectively (p<0.05). It was shown that the studied activities in highly virulent blastocysts were higher than in groups of medium-, low-, and avirulent protozoa. PMID- 27783292 TI - Antiviral Activity of Ergoferon against Group A Rotavirus. AB - Antiviral activity of Ergoferon was studied in vitro on an experimental model of rotavirus infection in MA-104 cell line. In infected cells treated with Ergoferon, rotavirus titer was shown to decrease by 83 and 90% in comparison with cells treated with solvent used for Ergoferon preparation (p<0.05) and distilled water (p<0.05), respectively. These findings demonstrate high anti-rotavirus activity of Ergoferon. PMID- 27783293 TI - Expression of Therapeutic Gene FCU1 Sensitizes Pancreatic Cancer Cells to 5 Fluorocytosine and Enhances the Cytotoxic Effect of 5-Fluorouracil. AB - Hybrid therapeutic gene FCU1 gene was cloned into a lentiviral expression vector and the therapeutic effect of its expression was studied in three pancreatic cancer cell lines. Expression of FCU1 gene sensitized cells of two of three studied pancreatic cancer cell lines to 5-fluorocytosine. In addition, uracil phosphoribosyl transferase activity of the hybrid FCU1 protein increased sensitivity of transfected cells of all three studied pancreatic cancer cell lines to 5-fluorouracil, a standard chemotherapeutic agent. PMID- 27783294 TI - Different Efficiency of Liposomal Forms with Hydrophilic and Hydrophobic Antitumor Agents in Relation to Solid Transplants of Mouse Tumor and Its Metastases in the Liver. AB - Experiments were performed on the model of transplanted mouse tumor with high incidence of liver metastases. Hydrophilic drug cycloplatam (injected intravenously in liposomes) was more potent than "free cycloplatam" (injected intravenously or intraperitoneally in physiological saline) in inhibiting the growth of natural and experimental metastases in the liver. By contrast, liposomal cycloplatam had lower efficiency than free cycloplatam in suppressing the growth of solid tumor. Liposomal and free cortifen (hydrophobic hormonal cytostatic) produced nearly the same effects on solid tumor growth. Our results suggest that liposomal forms of hydrophobic compounds producing nonselective effect on tumor cells (e.g., actinomycin D or Cosmegen), should not have advantages over free forms. PMID- 27783295 TI - Interaction of Serum Antibodies from Breast Cancer Patients with Synthetic Peptides. AB - The blood serum of tumor patients contains antibodies recognizing tumor associated antigens and other molecular products of tumor growth. We studied the interaction of blood antibodies from breast cancer patients with synthetic peptides that were applied on the microchip surface. The serum from healthy volunteers and breast cancer patients was shown to contain antibodies that interact with various peptides. Statistically significant between-group differences were observed in the level of binding with 122 informative peptides (0.01% of the total number of peptides on a microchip). Analysis of antibodies that interact with the peptide panel holds much promise for the diagnostics of breast cancer. PMID- 27783296 TI - Effects of Single Administration of Bupropion on Carboxypeptidase E Activity in Structures of Rat Brain. AB - Depression is associated with changes in the levels of some neurotransmitters in various brain structures. Being the key enzyme of peptide processing, carboxypeptidase E regulates their levels in various structures of the nervous system. Single injection of bupropion induced long-lasting changes in carboxypeptidase E activity in all brain structures. The decrease in enzyme activity observed in 12 and 24 h after bupropion injection confirmed the inhibiting effect of the drug on the hypothalamic-pituitary-adrenal axis. Activation of the enzyme in the medulla oblongata, hypothalamus, and hippocampus observed in 72 h after bupropion administration probably leads to enhanced synthesis and secretion of regulatory peptides (reduced during stress and depression) and stimulation of neurogenesis. Changes in enzyme activity can be a mechanism regulating the level of bioactive peptides involved in the pathogenesis of depression. PMID- 27783298 TI - Interleukin-6 in Sera of Mice Inoculated with Group A Streptococcus and Cultural Supernatants. AB - Dynamics of IL-6 level was studied in blood serum of CBA mice receiving intraperitoneal injections of killed and live culture of group A Streptococcus and its supernatants. It was found that administration of killed culture was followed by a significant rise in IL-6 level (by 4.7 times in 1 h and by 9.3 times in 5 h in comparison with the control). By 24 h, cytokine content was below the control. The highest levels of IL-6 were found after treatment with supernatants of Streptococcus cultures (by 10.5 times in 1 h and by 14.9 times in 5 h, in comparison with the control). Administration of live culture was accompanied by an increase in IL-6 concentration by 3.2 times in 3 h. In this experimental series, the maximum level of IL-6 was found in 48 h (by 5.2 times), and then it gradually decreased below the control. Different dynamics of changes in IL-6 level after administration of killed and live cultures of group A Streptococcus may suggests that they activate different signal pathways. PMID- 27783297 TI - Pulsed Dendritic Cells for the Therapy of Experimental Glioma. AB - We obtained the morphologically, cytofluorometrically, and functionally mature dendritic cells from rats that were pulsed with antigens of the C6 glioma tissue extract. The concentrations of angiogenesis antigens (VEGF, VEGFR-1, and VEGFR-2) and periglioma zone proteins (GFAP, connexin 43, and BSAT1) in the pulsing extract were measured by ELISA. Our results drove us to a conclusion that despite mature phenotype of pulsed dendritic cell, the antigenic composition of glioma tissue extracts should be modified. PMID- 27783299 TI - Antagonistic Activity of Intestinal Lactobacteria from Domestic Fowl against Clinical Isolates of Salmonella enterica. AB - Strain parameters of Salmonellas and Lactobacteria affecting their antagonistic activity were studied using an original method. Real-time PCR was applied for measuring the decrease in the concentration of field isolates of Salmonellas isolated from chickens in the presence of field isolates of Lactobacteria also isolated from the gastrointestinal tract of chickens and broiler chickens. Dispersion analysis showed that the probability of suppression of Salmonella growth by Lactobacteria is determined by strain parameters of both Lactobacteria and Salmonellas (p<0.001). However, strain parameters of Lactobacteria were found to be more important that Salmonella strain parameters during co-culturing. PMID- 27783300 TI - Effect of Ionophores on Activity of Na+,Cl-(HCO 3- )-ATPase. AB - We studied the effects of ionophores on activity of Na+,Cl-(HCO 3- )-ATPase. The most significant effect on the activity of this enzyme was produced by protonophore 2,4-dinitrophenol. The effect of this drug largely depended on the cation and anion composition and pH of the incubation medium and its pH. Activity of Na+,Cl-(HCO 3- )-ATPase increased at neutral and weakly alkaline pH and decreased at pH below 6.5-6.7. In control animals (without histamine injection) with very weak or absent Na+,Cl-(HCO 3- )-ATPase activity, the observed effect of the protonophore on ATPase activity was also virtually absent. The stimulatory effect of other ionophores (monensine, valinomycin, and A23187) was significantly weaker and depended on pH of the incubation medium, its cationic and anionic composition, and concentration of these ionophores. PMID- 27783301 TI - Intensity of Oxidative Stress in Mongoloid and Caucasian Patients with Type 1 Diabetes Mellitus. AB - Specific features of LPO were studied in Mongoloid and Caucasian patients with type 1 diabetes mellitus. The intensity of LPO in Mongoloid patients was lower than in Caucasians: the level of primary and intermediate products was by lower 1.53 and 1.83 times, while total antioxidant activity was elevated by 1.44 times, which was also supported by oxidative stress coefficient (1.35 in Mongoloids and 2.32 in Caucasians). These differences suggest that differentiated approach is required for the treatment of these patients. PMID- 27783303 TI - Amide of Lambertian Acid Suppresses Hyperactivation of Inotropic Glutamate Receptors, but not Synaptic Potentiation in Hippocampal Sections. AB - Amide of lambertian acid suppresses hyperactivation of inotropic glutamate receptors in hippocampal sections induced by a decrease in the level of magnesium ions (a selective blocker of glutamate NMDA receptors). Treatment of the sections with amide of lambertian acid in standard physiological saline does not prevent development of NMDA-dependent synaptic potentiation. Lambertian acid isolated from needles and turpentine of Siberian pine (Pinus sibirica R. Mayr), and its derivatives may become a source of substances with glutamatergic mechanism of action for treatment of cognitive and neurodegenerative disorders. PMID- 27783302 TI - Perinatal Brain Injury is Accompanied by Disturbances in Expression of SLC Protein Superfamily in Endotheliocytes of Hippocampal Microvessels. AB - The peculiarities in expression of transport proteins and the proteins implicated in the control of glycolysis by the cellular components of neurovascular units were examined in animals of different age under normal conditions and after modeled perinatal stress or hypoxic brain injury. In both cases, the specialties in expression of transport proteins in ontogenesis were revealed. The perinatal hypoxic brain injury resulted in up-regulation of MCT1, MCT4, and GLUT4 expression in endotheliocytes of hippocampal microvessels accompanied by transient elevation of HIF-1alpha and GSK3 expression. PMID- 27783304 TI - Regulatory Effects of Urokinase on Mesenchymal Stromal Cell Migration, Proliferation, and Matrix Metalloproteinase Secretion. AB - We studied the effect of urokinase, its recombinant forms, and domain fragments on migration and proliferation of adipose tissue mesenchymal stromal cells (MSCs) and MMP secretion by these cells. Urokinase, but not its recombinant forms, slightly induced directed migration of MSCs. Spontaneous migration of MSCs increased under the action of urokinase or its isolated kringle domain. Migration induced by platelet-derived growth factor was inhibited by proteolytically inactive form of urokinase, the kringle domain, and blocking antibody to urokinase receptor. Urokinase, its proteolytically inactive form, and kringle domain produced no effect on MSC proliferation. In contrast to platelet-derived growth factor, all urokinase forms induced secretion of MMP-9 by MSCs. PMID- 27783305 TI - Role of alpha7-Nicotinic Acetylcholine Receptors of B Cells in the Immunotoxic Effect of Organophosphorus Compounds. AB - Experiments on white non-inbred rats demonstrated that treatment with organophosphorus compound dimethyl dichlorovinyl phosphate (DDVP) decreased T cell-independent antibody production by B cells and blood levels of IL-10 and IL 12; a similar effect was produced by GTS-21, a selective agonist of alpha7 nicotinic acetylcholine receptor. N-nicotinic receptor antagonist chlorisondamine in combination with DDVP partially prevented suppression of antibody production in comparison with the effect observed during intoxication with DDVP. PMID- 27783306 TI - Individual and Day-to-Day Differences in Active Coping Predict Diurnal Cortisol Patterns among Early Adolescent Girls. AB - Prior work has identified alterations in activity of the hypothalamic-pituitary adrenal axis as a potential mechanism underlying stress-induced emotional health problems, which disproportionately impact girls beginning in mid-adolescence. How adolescent girls differ from one another in dispositional coping tendencies and shift specific coping strategies in response to varying stressors have been theorized as important predictors of their adaptation, health, and well-being during this dynamic period of development. The goal of this study was to examine whether individual and day-to-day (within-person) differences in adolescent girls' coping responses are associated with daily patterns of hypothalamic pituitary-adrenal axis activity, indexed by cortisol. Participants were 122 early adolescent girls (M age = 12.39) who provided three saliva samples per day for 3 days and completed daily coping reports, as well as a standard coping survey. Participants and primary caregivers also completed objective life stress interviews. On average, girls who were more likely to respond to interpersonal stress with voluntary engagement (active) coping exhibited generally adaptive daily physiological regulation-steeper diurnal cortisol slopes, lower total diurnal cortisol output, and lower cortisol awakening responses. Chronic interpersonal stress level significantly moderated these associations in different ways for two distinct components of the diurnal pattern-the slope and cortisol awakening responses. Regarding within-person differences, using active coping more than usual was associated with higher waking cortisol the following morning, which may help to prepare adolescent girls for perceived daily demands. These findings highlight the interactive influence of stress and coping in the prediction of daily hypothalamic-pituitary-adrenal axis activity and support the stress-buffering role of active coping for adolescent girls. PMID- 27783307 TI - Therapeutic Effects of AICAR and DOX Conjugated Multifunctional Nanoparticles in Sensitization and Elimination of Cancer Cells via Survivin Targeting. AB - PURPOSE: Resistance to chemotherapy is one of the major problems facing current cancer research. Enhancing tumor cell response to anticancer agents increases chemotherapeutic effectiveness. We have recently addressed this issue and reported on producing multifunctional nanoparticles (Fe3O4@SiO2(FITC) FA/AICAR/DOX) aiming to overcome chemoresistance with synergetic effect of AICAR and DOX. In the present study, we demonstrated that these nanoparticles not only show enhanced cellular uptake and cytotoxic effect but can also show enhanced pro apoptotic and anti-proliferative effects in five different tumor-derived cell lines (A549, HCT-116, HeLa, Jurkat and MIA PaCa-2). METHODS: The nanoparticles were examined by using flow cytometric analyses of apoptosis and cell cycle. In addition, we performed caspase-3 activity assay, which supported our flow cytometric data. Furthermore, we demonstrated the applicability of this approach in a variety of cancer types confirming the potential widespread utility of this approach. RESULTS: With the concept of co-delivery of AICAR and DOX in the nanoparticle formulation, the use of AICAR against survivin (BIRC5) sensitized cancer cells to DOX chemotherapy which resulted in effective cancer cell elimination. These result showed that combination therapy involving both a molecularly targeted therapy and chemotherapeutic agent has the ability to retain and enhance therapeutic efficacy. CONCLUSION: Fe3O4@SiO2(FITC)-FA/AICAR/DOX nanoparticles is superior to monotherapy via the synergetic effect of AICAR and DOX and also the nanoparticle formulation could overcome issues of toxicity with targeted therapy while maintaining the potent anticancer effects of AICAR and DOX. Graphical Abstract Apoptosis analysis of A549 cells by flow cytometry-based PE-annexin-V / 7-ADD double staining treated with low-dose (10 MUg/ml) concentration of (1) Fe3O4@SiO2(FITC)-FA (2) Fe3O4@SiO2(FITC)-FA/AICAR, (3) Fe3O4@SiO2(FITC)-FA/DOX or (4) Fe3O4@SiO2(FITC)-FA/AICAR/DOX nanoparticles. Viable cells labelled with PE-annexin-V(-)/7-ADD(-), early apoptotic cells labelled with PE-annexin-V(+)/7-ADD(-) and apoptotic cells labelled with PE annexin-V(+)/ 7-ADD(+) in flow cytometric graphics. PMID- 27783310 TI - The Frame Constraint on Experimentally Elicited Speech Errors in Japanese. AB - The so-called syllable position effect in speech errors has been interpreted as reflecting constraints posed by the frame structure of a given language, which is separately operating from linguistic content during speech production. The effect refers to the phenomenon that when a speech error occurs, replaced and replacing sounds tend to be in the same position within a syllable or word. Most of the evidence for the effect comes from analyses of naturally occurring speech errors in Indo-European languages, and there are few studies examining the effect in experimentally elicited speech errors and in other languages. This study examined whether experimentally elicited sound errors in Japanese exhibits the syllable position effect. In Japanese, the sub-syllabic unit known as "mora" is considered to be a basic sound unit in production. Results showed that the syllable position effect occurred in mora errors, suggesting that the frame constrains the ordering of sounds during speech production. PMID- 27783308 TI - Congenital Glucose-Galactose Malabsorption in a Turkish Newborn: A Novel Mutation of Na+/Glucose Cotransporter Gene. PMID- 27783309 TI - Lyconadins G and H, Two Rare Lyconadin-Type Lycopodium Alkaloids from Lycopodium complanatum. AB - Two rare lyconadin-type Lycopodium alkaloids, lyconadins G (1) and H (2), together with four known ones (3-6), were isolated from Lycopodium complanatum. The structures were determined on the basis of their spectroscopic analyses, and the absolute configuration of 1 was established by an X-ray crystallographic analysis. It is the first time to establish the absolute configuration of lyconadin-type Lycopodium alkaloid by an X-ray diffraction experiment. In addition, these findings may provide more information for the biosynthesis of lyconadins. PMID- 27783311 TI - Fracture characterization of human cortical bone under mode II loading using the end-notched flexure test. AB - Fracture characterization of human cortical bone under mode II loading was analyzed using a miniaturized version of the end-notched flexure test. A data reduction scheme based on crack equivalent concept was employed to overcome uncertainties on crack length monitoring during the test. The crack tip shear displacement was experimentally measured using digital image correlation technique to determine the cohesive law that mimics bone fracture behavior under mode II loading. The developed procedure was validated by finite element analysis using cohesive zone modeling considering a trapezoidal with bilinear softening relationship. Experimental load-displacement curves, resistance curves and crack tip shear displacement versus applied displacement were used to validate the numerical procedure. The excellent agreement observed between the numerical and experimental results reveals the appropriateness of the proposed test and procedure to characterize human cortical bone fracture under mode II loading. The proposed methodology can be viewed as a novel valuable tool to be used in parametric and methodical clinical studies regarding features (e.g., age, diseases, drugs) influencing bone shear fracture under mode II loading. PMID- 27783313 TI - The status of the performance of medication reviews in German community pharmacies and assessment of the practical performance. AB - Background Pharmacist-led medication reviews have shown to prevent drug-related problems (DRPs). So far, data is rare about the implementation in routine care, the conditions for intensifying this service and the practical skills of community pharmacists to perform medication reviews. Objective To assess the current status of medication review implementation in German community pharmacies and the performance of identifying DRPs in a ficticious patient example. Setting German community pharmacies. Method An online survey was conducted from July to September 2015 including questions about medication reviews currently performed in routine care of community pharmacies and hidden DRPs in a ficticious patient example. Pharmacists were invited via newsletters from three local chambers of pharmacists. Main outcome measure (i) Frequency, conditions for implementation, and criteria of medication reviews currently being performed in routine care, (ii) requested further information to perform medication reviews, and (iii) proportion of pharmacists who identify DRPs in the patient example. Results A total of 143 community pharmacists completed the questionnaire. (i) One hundred and twenty-seven respondents (89 %) reported reviewing the medication regularly in routine care, whereas 56 (39 %) stated that they performed medication reviews between one and five times monthly. For 124 pharmacists (87 %), remuneration would be a necessary condition for performing medication reviews more frequently. When reviewing the medication, 112 (78 %) of the pharmacists considered the criterion 'drug-drug interactions' and 107 (75 %) reviewed the criterion 'correct dosage'. One of the least reviewed criteria was 'effectiveness of medication' [22 (16 %)]. (ii) According to the participants, laboratory values should be available in the community pharmacy, since 87/143 (61 %) would appreciate the GFR and the HbA1c level. Twenty-two of 54 respondents (41 %) would appreciate further administration instructions and 5 of 54 (15 %) think they would benefit from information about the recommended duration of drug use. (iii) Depending on the category, 4 (3 %) to 49 (34 %) of all 143 pharmacists identified the hidden DRP in the patient example. Conclusion German community pharmacists reported reviewing the medication of their patients regularly; however, most of the respondents review the medication very rarely in routine care. Consequently, their practical performance needs to be improved. PMID- 27783312 TI - Educational Scholarship and Technology: Resources for a Changing Undergraduate Medical Education Curriculum. AB - Returning to the original emphasis of higher education, universities have increasingly recognized the value and scholarship of teaching, and medical schools have been part of this educational scholarship movement. At the same time, the preferred learning styles of a new generation of medical students and advancements in technology have driven a need to incorporate technology into psychiatry undergraduate medical education (UGME). Educators need to understand how to find, access, and utilize such educational technology. This article provides a brief historical context for the return to education as scholarship, along with a discussion of some of the advantages to this approach, as well as several recent examples. Next, the educational needs of the current generation of medical students, particularly their preference to have technology incorporated into their education, will be discussed. Following this, we briefly review the educational scholarship of two newer approaches to psychiatry UGME that incorporate technology. We also offer the reader some resources for accessing up to-date educational scholarship for psychiatry UGME, many of which take advantage of technology themselves. We conclude by discussing the need for promotion of educational scholarship. PMID- 27783314 TI - Space Occupying Lesions in the Liver. AB - Space occupying liver lesions usually present with abdominal pain or abnormal physical findings, such as a palpable abdominal mass or distention. Liver lesions identified in children include benign and malignant neoplasms, inflammatory masses, cysts and metastatic lesions. Two-thirds of liver lesions in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Benign lesions of the liver in children include vascular lesions, hamartomas, adenomas, and focal nodular hyperplasia. Although benign and malignant liver masses share some clinical manifestations, however treatment and prognosis differ. Evaluation involves physical examination, imaging evaluation and laboratory investigations such as serological markers [alpha-fetoprotein (AFP)] for malignant liver lesions. Ultrasound is the initial imaging modality of choice because it can detect, characterize, and provide the extent of liver lesions. However, CT or MRI are often subsequently performed for further characterization, assessment of precise extent, and detection of associated metastatic disease in cases of malignant hepatic neoplasm. Serological markers (such as alpha fetoprotein) can be useful in narrowing the differential diagnosis when they are markedly elevated but a substantial number of patients unfortunately do not have high levels of these markers at the time of presentation or cautious interpretation is warranted as AFP level is frequently elevated in infants up to 6 mo of age and may be slightly elevated with benign tumors and with hepatic insult or regeneration. Therefore, a tissue diagnosis is often required to guide subsequent management. The histology and anatomy of a pediatric liver tumor guides the treatment and prognosis. PMID- 27783315 TI - iMAGE cloud: medical image processing as a service for regional healthcare in a hybrid cloud environment. AB - OBJECTIVES: To handle the emergence of the regional healthcare ecosystem, physicians and surgeons in various departments and healthcare institutions must process medical images securely, conveniently, and efficiently, and must integrate them with electronic medical records (EMRs). In this manuscript, we propose a software as a service (SaaS) cloud called the iMAGE cloud. METHODS: A three-layer hybrid cloud was created to provide medical image processing services in the smart city of Wuxi, China, in April 2015. In the first step, medical images and EMR data were received and integrated via the hybrid regional healthcare network. Then, traditional and advanced image processing functions were proposed and computed in a unified manner in the high-performance cloud units. Finally, the image processing results were delivered to regional users using the virtual desktop infrastructure (VDI) technology. Security infrastructure was also taken into consideration. RESULTS: Integrated information query and many advanced medical image processing functions-such as coronary extraction, pulmonary reconstruction, vascular extraction, intelligent detection of pulmonary nodules, image fusion, and 3D printing-were available to local physicians and surgeons in various departments and healthcare institutions. CONCLUSIONS: Implementation results indicate that the iMAGE cloud can provide convenient, efficient, compatible, and secure medical image processing services in regional healthcare networks. The iMAGE cloud has been proven to be valuable in applications in the regional healthcare system, and it could have a promising future in the healthcare system worldwide. PMID- 27783316 TI - The Changing Face of Dermatophytic Infections Worldwide. AB - Dermatophytes evolve along with the geography and socioeconomic conditions. Epidermophyton floccosum, Microsporum audouinii and Trichophyton schoenleinii acted as the major pathogens of superficial fungal diseases 100 years ago, but their frequency decreased dramatically since the middle of the twentieth century and they are limited to some less-developed countries nowadays; meanwhile, frequency of Trichophyton rubrum, Trichophyton interdigitale, Trichophyton tonsurans and Microsporum canis increased gradually, and these fungi have become the major species globally. Some other dermatophytes, i.e., Trichophyton violaceum, Trichophyton verrucosum and Microsporum ferrugineum, are mainly endemic in some parts of Africa, Asia and Europe. At present, T. rubrum is the leading pathogen for skin and nail fungal infections, whereas M. canis, T. tonsurans and T. violaceum present as the predominant dermatophytes involved in tinea capitis. Population mobility, changes in human lifestyle and advents of antifungal drugs will continually drive the dermatophyte evolution in the skin microenvironment. Comprehensive observation is needed to better understand this kind of organisms and prospect the trends of their changes in future. PMID- 27783320 TI - Lignans-rich extract from Herpetospermum caudigerum alleviate physical fatigue in mice. AB - OBJECTIVE: To ascertain anti-fatigue constituents and mechanisms of Herpetospermum caudigerum. METHODS: The 80% ethanol extracts of Herpetospermum caudigerum were partitioned with chloroform, ethyl acetate and n-butanol, respectively. Male Kunming mice were divided into 13 groups with 16 mice in each group: a control group fed with water, 9 groups treated with 3 fractions of Herpetospermum caudigerum (chloroform fraction, ethyl acetate fraction and n butanol fraction) at dose of 80, 160 and 320 mg/kg for the low-dose group, medium dose group and high-dose group, 3 herpetrione (HPE) treated groups fed with HPE at dose of 15, 30, and 60 mg/kg for the low-dose group, medium-dose group and high-dose group. All animals were treated once per day for 30 days. Anti-fatigue activity was assessed through the forced swimming test and serum biochemical parameters including blood lactic acid (BLA), blood urea nitrogen (BUN), malondialdehyde (MDA), hepatic glycogen (HG), lactic dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GPx) determined following the recommended procedures provided by the commercial kits. RESULTS: Compared with the control group, the lignans extract (ethyl acetate fraction) of Herpetospermum caudigerum and HPE could signifificantly prolonged the exhaustive swimming time (P<0.05 or P<0.01), and also increased the HG levels (P<0.05 or P<0.01) and the activities of antioxidant enzymes (SOD, GPx and LDH, P<0.05 or P<0.01); BLA and MDA levels were decreased considerably in lignans extract and HPE treated groups (P<0.05 or P<0.01). HPE also could significantly decrease the BUN contents compared with the control group (P<0.05). The chloroform and n butanol fraction showed no effect on swimming time and biochemical parameters. CONCLUSIONS: The lignans extract had antifatigue activities and HPE may be partly responsible for the anti-fatigue effects of Herpetospermum caudigerum. The possible mechanisms of anti-fatigue activity were related to the decrease of BUN and BLA, the increase of the HG storage and protecting corpuscular membrane by preventing lipid oxidation via modifying several enzyme activities. PMID- 27783317 TI - Toward a Novel Multilocus Phylogenetic Taxonomy for the Dermatophytes. AB - Type and reference strains of members of the onygenalean family Arthrodermataceae have been sequenced for rDNA ITS and partial LSU, the ribosomal 60S protein, and fragments of beta-tubulin and translation elongation factor 3. The resulting phylogenetic trees showed a large degree of correspondence, and topologies matched those of earlier published phylogenies demonstrating that the phylogenetic representation of dermatophytes and dermatophyte-like fungi has reached an acceptable level of stability. All trees showed Trichophyton to be polyphyletic. In the present paper, Trichophyton is restricted to mainly the derived clade, resulting in classification of nearly all anthropophilic dermatophytes in Trichophyton and Epidermophyton, along with some zoophilic species that regularly infect humans. Microsporum is restricted to some species around M. canis, while the geophilic species and zoophilic species that are more remote from the human sphere are divided over Arthroderma, Lophophyton and Nannizzia. A new genus Guarromyces is proposed for Keratinomyces ceretanicus. Thirteen new combinations are proposed; in an overview of all described species it is noted that the largest number of novelties was introduced during the decades 1920-1940, when morphological characters were used in addition to clinical features. Species are neo- or epi-typified where necessary, which was the case in Arthroderma curreyi, Epidermophyton floccosum, Lophophyton gallinae, Trichophyton equinum, T. mentagrophytes, T. quinckeanum, T. schoenleinii, T. soudanense, and T. verrucosum. In the newly proposed taxonomy, Trichophyton contains 16 species, Epidermophyton one species, Nannizzia 9 species, Microsporum 3 species, Lophophyton 1 species, Arthroderma 21 species and Ctenomyces 1 species, but more detailed studies remain needed to establish species borderlines. Each species now has a single valid name. Two new genera are introduced: Guarromyces and Paraphyton. The number of genera has increased, but species that are relevant to routine diagnostics now belong to smaller groups, which enhances their identification. PMID- 27783319 TI - Expecting the holistic regulation from Chinese medicine based on the "solar system" hypothesis of ischemic heart disease. AB - Stenosis of the coronary artery has been considered as an essential component of ischemic heart disease (IHD). Consequently, revascularization [e.g., percutaneous coronary intervention (PCI) and coronary artery bypass] has been the primary therapeutic approach to IHD. Such strategy has indeed revolutionized the management of IHD patients. However, not all patients with myocardial ischemia have visible coronary stenosis. Moreover, cardiovascular events occur in nearly 20% patients with stable coronary artery disease who have undergone PCI. The recently proposed "solar system" hypothesis of IHD postulates that coronary stenosis is only one (albeit important) of its features. Mechanistic contribution and clinical implication of multiple pathophysiological processes beyond coronary stenosis are highlighted in this hypothesis. On the basis of a holistic regulation and individualized medicine, Chinese medicine (CM) has been used in the real-world setting to manage a variety of diseases, including IHD, for more than two thousands years. In this article, we summarize the evidence of CM that supports the "solar system" IHD hypothesis, and argue for a comprehensive approach to IHD. At the theoretical level, the central features of this approach include a holistic view of disease and human subjects, as well as individualized medicine. At the practical level, this approach emphasizes anoxia-tolerance and self-healing. PMID- 27783318 TI - What Role Does Allergy Play in Chronic Ear Disease and Laryngitis? AB - IgE-mediated allergy plays a well-established role in both nasal and pulmonary diseases due to the common epithelium and shared mediator responses of the upper and lower airways. This "unified airway" concept has also been described in other sites within the head and neck that contain similar respiratory mucosa: the middle ear and the larynx. This review will highlight the data suggesting a role for IgE-mediated allergic disease in chronic laryngopharyngeal and middle ear disease and the role for allergy testing to aid in diagnosis and treatment of these disorders. PMID- 27783322 TI - Classifying syndromes in Chinese medicine using multi-label learning algorithm with relevant features for each label. AB - OBJECTIVE: To develop an effective Chinese Medicine (CM) diagnostic model of coronary heart disease (CHD) and to confifirm the scientifific validity of CM theoretical basis from an algorithmic viewpoint. METHODS: Four types of objective diagnostic data were collected from 835 CHD patients by using a self-developed CM inquiry scale for the diagnosis of heart problems, a tongue diagnosis instrument, a ZBOX-I pulse digital collection instrument, and the sound of an attending acquisition system. These diagnostic data was analyzed and a CM diagnostic model was established using a multi-label learning algorithm (REAL). RESULTS: REAL was employed to establish a Xin (Heart) qi defificiency, Xin yang defificiency, Xin yin defificiency, blood stasis, and phlegm fifive-card CM diagnostic model, which had recognition rates of 80.32%, 89.77%, 84.93%, 85.37%, and 69.90%, respectively. CONCLUSIONS: The multi-label learning method established using four diagnostic models based on mutual information feature selection yielded good recognition results. The characteristic model parameters were selected by maximizing the mutual information for each card type. The four diagnostic methods used to obtain information in CM, i.e., observation, auscultation and olfaction, inquiry, and pulse diagnosis, can be characterized by these parameters, which is consistent with CM theory. PMID- 27783323 TI - Diagnostic criterion of blood stasis syndrome for coronary heart disease : Activating Blood Circulation Committee of Chinese Association of Integrative Medicine. PMID- 27783321 TI - Bushen Qiangji Granule () medicated serum inhibits osteogenic differentiation of fibroblasts in ankylosing spondylitis by inhibiting the BMP/Smads signal pathway in vitro. AB - OBJECTIVE: To explore the mechanism of Bushen Qiangji Granule (, BSQJ) in restraining the osteogenic differentiation of ankylosing spondylitis (AS) fifibroblasts. METHODS: Hip joint capsules were obtained from AS patients (n=10) receiving total hip replacement and healthy hip joint capsules from patients with hip fracture (n=10) receiving surgery as a control. Finite fifibroblast lines were established from these tissue samples to observe the effect of BSQJ on suppressing osteogenic differentiation of fifibroblasts. The expression of osteogenic marker gene corebinding factor a1 (Cbfa1) and Smad family proteins were examined by Western blot and real-time quantitative polymerase chain reaction (qPCR). RESULTS: The mRNA expression level of Cbfa1 was significantly higher in AS fibroblasts than that in normal fibroblasts and the expression of pSmad1, pSmad5, Smad4 and Cbfa1 in AS fibroblasts was also higher, demonstrating the activation of the BMP/Smads signal pathway in AS fifibroblasts. BSQJ medicated serum not only restrained the mRNA and protein expression levels of Cbfa1 and inhibited protein expression level of Smad4 but also decreased the expression quantities of pSmad1 and pSmad5. CONCLUSIONS: BSQJ can inhibit osteogenic differentiation of AS fifibroblasts in vitro by suppressing the activation of the BMP/Smads signal pathway. This may be the important molecular mechanism of BSQJ in regulating AS ossifification. PMID- 27783325 TI - The Driving Forces of Cultural Complexity : Neanderthals, Modern Humans, and the Question of Population Size. AB - The forces driving cultural accumulation in human populations, both modern and ancient, are hotly debated. Did genetic, demographic, or cognitive features of behaviorally modern humans (as opposed to, say, early modern humans or Neanderthals) allow culture to accumulate to its current, unprecedented levels of complexity? Theoretical explanations for patterns of accumulation often invoke demographic factors such as population size or density, whereas statistical analyses of variation in cultural complexity often point to the importance of environmental factors such as food stability, in determining cultural complexity. Here we use both an analytical model and an agent-based simulation model to show that a full understanding of the emergence of behavioral modernity, and the cultural evolution that has followed, depends on understanding and untangling the complex relationships among culture, genetically determined cognitive ability, and demographic history. For example, we show that a small but growing population could have a different number of cultural traits from a shrinking population with the same absolute number of individuals in some circumstances. PMID- 27783326 TI - The Association Between Epoxide Hydrolase Genetic Variant and Effectiveness of Nicotine Replacement Therapy in a Han Chinese Population. PMID- 27783329 TI - Erratum to: Effects of nutraceuticals on quality of life and sexual function of perimenopausal women. PMID- 27783327 TI - Extracellular Signal-Regulated Kinase in Nucleus Accumbens Mediates Propofol Self Administration in Rats. AB - Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobiological mechanism underlying propofol reward is not fully understood. The purpose of this study was to investigate the role of extracellular signal-regulated kinase (ERK) signal transduction pathways in the nucleus accumbens (NAc) in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self administration and diminished the expression of p-ERK in the NAc. Moreover, intra NAc injection of U0126 (4 ug/side) attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self administration and its rewarding effects. PMID- 27783332 TI - Achieving and Sustaining Universal Health Coverage: Fiscal Reform of the National Health Insurance in Taiwan. AB - The paper discusses the expansion of the universal health coverage (UHC) in Taiwan through the establishment of National Health Insurance (NHI), and the fiscal crisis it caused. Two key questions are addressed: How did the NHI gradually achieve universal coverage, and yet cause Taiwanese health spending to escalate to fiscal crisis? What measures have been taken to reform the NHI finance and achieve moderate success to date? The main argument of this paper is that the Taiwanese Government did try to implement various reforms to save costs and had moderate success, but the path-dependent process of reform does not allow increasing contribution rates significantly and thereby makes sustainability challenging. PMID- 27783331 TI - Psoriasiform Eruption and Worsening of Pustulosis Palmoplantaris After Treatment with Two Anti-TNF-alpha Inhibitors, Followed by Successful Treatment with Ustekinumab. AB - INTRODUCTION: Tumor necrosis factor (TNF)-alpha inhibitors are widely used for the treatment of inflammatory diseases. One of the side effects of TNF-inhibitors is the development of a psoriatiform eruption, also known as paradoxical psoriasis. In this case report, we describe a patient with this side effect after treatment with adalimumab and etanercept. CASE REPORT: A 45-year-old female was treated with adalimumab 40 mg once every 2 weeks for pustulosis palmoplantaris and psoriatic arthritis. After 2 injections, the patient developed a psoriatiform eruption on her body, which improved after discontinuation of adalimumab but worsened after treatment with etanercept 50 mg twice weekly. Eventually, the patient was treated with topical corticosteroids and ustekinumab 45 mg once every 3 months with a complete remission of the psoriatiform eruption. DISCUSSION: Several case reports and reviews have been published in recent years which describe patients with a psoriatiform eruption after treatment with TNF-alpha inhibitors. The pathogenesis that causes this psoriatic eruption is unclear. In conclusion, we describe a patient with a psoriatiform eruption after treatment with adalimumab and etanercept. This patient had to discontinue the treatment and eventually had a complete response after treatment with topical corticosteroids and treatment with ustekinumab. PMID- 27783328 TI - Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus. AB - Itch (pruritus) is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-L-cysteine (NAC) and N-tert-butyl-alpha-phenylnitrone (PBN) were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetone-diethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin. Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti itch therapy. PMID- 27783330 TI - Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance. AB - Pulmonary alveolar proteinosis (PAP) is a potentially fatal complication of lysinuric protein intolerance (LPI), an inherited disorder of cationic amino acid transport. The patients often present with mild respiratory symptoms, which may rapidly progress to acute respiratory failure responding poorly to conventional treatment with steroids and bronchoalveolar lavations (BALs). The pathogenesis of PAP in LPI is still largely unclear. In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group.Two LPI patients with complicated PAP were treated with experimental inhaled rhuGM-CSF (sargramostim) after poor response to maximal conventional therapy. BAL fluid and cell samples from one patient were studied with light microscopy and transmission electron microscopy.Excellent response to therapy was observed in patient 1 with no compliance problems or side effects. Macrophages with myelin figure-like structures were seen in her BAL sample. Slight improvement of the pulmonary function was evident also in patient 2, but the role of sargramostim could not be properly evaluated due to the complicated clinical situation.In conclusion, inhaled rhuGM-CSF might be of benefit in patients with LPI-associated PAP. PMID- 27783333 TI - Relative efficacy of nicotinamide treatment of a mouse model of infantile Niemann Pick C1 disease. AB - Nicotinamide delivered in drinking water at about 2 g/kg/day significantly prolonged survival and showed a suggestive improvement on memory in the Npc1 nih / Npc1 nih mouse model of infantile NPC1 disease. It is likely that this role is due to its function as a histone deacetylase (HDAC) inhibitor although another HDAC inhibitor, valproic acid, was without effect. Nicotinamide could also work by preventing/reversing oxidative stress. PMID- 27783334 TI - Inactivation of Viruses and Bacteriophages as Models for Swine Hepatitis E Virus in Food Matrices. AB - Hepatitis E virus has been recognised as a food-borne virus hazard in pork products, due to its zoonotic properties. This risk can be reduced by adequate treatment of the food to inactivate food-borne viruses. We used a spectrum of viruses and bacteriophages to evaluate the effect of three food treatments: high pressure processing (HPP), lactic acid (LA) and intense light pulse (ILP) treatments. On swine liver at 400 MPa for 10 min, HPP gave log10 reductions of >=4.2, >=5.0 and 3.4 for feline calicivirus (FCV) 2280, FCV wildtype (wt) and murine norovirus 1 (MNV 1), respectively. Escherichia coli coliphage phiX174 displayed a lower reduction of 1.1, while Escherichia coli coliphage MS2 was unaffected. For ham at 600 MPa, the corresponding reductions were 4.1, 4.4, 2.9, 1.7 and 1.3 log10. LA treatment at 2.2 M gave log10 reductions in the viral spectrum of 0.29-2.1 for swine liver and 0.87-3.1 for ham, with phiX174 and MNV 1, respectively, as the most stable microorganisms. The ILP treatment gave log10 reductions of 1.6-2.8 for swine liver, 0.97-2.2 for ham and 1.3-2.3 for sausage, at 15-60 J cm-2, with MS2 as the most stable microorganism. The HPP treatment gave significantly (p < 0.05) greater virus reduction on swine liver than ham for the viruses at equivalent pressure/time combinations. For ILP treatment, reductions on swine liver were significantly (p < 0.05) greater than on ham for all microorganisms. The results presented here could be used in assessments of different strategies to protect consumers against virus contamination and in advice to food producers. Conservative model indicators for the pathogenic viruses could be suggested. PMID- 27783335 TI - BRCA1 allele-specific expression in genetic predisposed breast/ovarian cancer. AB - Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student's t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R2 > 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring BRCA1 truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far, BRCA1 Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations. PMID- 27783336 TI - Attenuated polyposis of the large bowel: a morphologic and molecular approach. AB - Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 +/- 14 years in men and 48 +/- 13 in women (P = 0.005). Polyps were more numerous in women (37 +/- 26 vs 29 +/- 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (>50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were >50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas >50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (>50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex. PMID- 27783337 TI - The New Frontier of Cardiac Computed Tomography Angiography: Fractional Flow Reserve and Stress Myocardial Perfusion. AB - OPINION STATEMENT: The increased number of patients with coronary artery disease (CAD) in developed countries is of great clinical relevance and involves a large burden of the healthcare system. The management of these patients is focused on relieving symptoms and improving clinical outcomes. Therefore the ideal test would provide the correct diagnosis and actionable information. To this aim, several non-invasive functional imaging modalities are usually used as gatekeeper to invasive coronary angiography (ICA), but their diagnostic yield remains low with limited accuracy when compared to obstructive CAD at the time of ICA or invasive fractional flow reserve (FFR). Invasive FFR is considered the gold standard for the evaluation of functionally relevant CAD. Therefore, an urgent need for non-invasive techniques that evaluate both the functional and morphological severity of CAD is growing. Coronary computed tomography angiography (CCTA) has emerged as a unique non-invasive technique providing coronary artery anatomic imaging. More recently, the evaluation of FFR with CCTA (FFRCT) has demonstrated high diagnostic performance compared to invasive FFR. Additionally, stress myocardial computed tomography perfusion (CTP) represents a novel tool for the diagnosis of ischemia with high diagnostic accuracy. Compared to nuclear imaging and cardiac magnetic resonance imaging, both FFRCT and stress CTP, allow us to integrate the anatomical evaluation of coronary arteries with the functional relevance of coronary artery lesions having the potential to revolutionize the diagnostic paradigm of suspected CAD. FFRCT and stress-CTP could be assimilated in diagnostic pathways of patients with stable CAD and will likely result in a decrease of invasive diagnostic procedures and costs. The current review evaluates the technical aspects and clinical experience of FFRCT and stress-CTP in the evaluation of functionally relevant CAD discussing the strengths and weaknesses of each approach. PMID- 27783338 TI - Coaching for College Students with ADHD. AB - Evidence suggests that ADHD can impair academic achievement in college students and throughout the life span. College students with ADHD are an at-risk population who might benefit from interventions. An offshoot of CBT-oriented therapy that has grown significantly and gained popularity in recent years is ADHD coaching. ADHD coaching is a psychosocial intervention that helps individuals develop skills, strategies, and behaviors to cope with the core impairments associated with ADHD. Most coaching programs are primarily based on a CBT approach and target planning, time management, goal setting, organization, and problem solving. This paper describes ADHD coaching for college students and discusses how coaching is different from standard CBT treatment. This is followed by a review of empirical studies of the effectiveness of ADHD coaching for college students. Finally, some specific considerations and procedures used in coaching are described. PMID- 27783339 TI - Automated Decision-Making and Big Data: Concerns for People With Mental Illness. AB - Automated decision-making by computer algorithms based on data from our behaviors is fundamental to the digital economy. Automated decisions impact everyone, occurring routinely in education, employment, health care, credit, and government services. Technologies that generate tracking data, including smartphones, credit cards, websites, social media, and sensors, offer unprecedented benefits. However, people are vulnerable to errors and biases in the underlying data and algorithms, especially those with mental illness. Algorithms based on big data from seemingly unrelated sources may create obstacles to community integration. Voluntary online self-disclosure and constant tracking blur traditional concepts of public versus private data, medical versus non-medical data, and human versus automated decision-making. In contrast to sharing sensitive information with a physician in a confidential relationship, there may be numerous readers of information revealed online; data may be sold repeatedly; used in proprietary algorithms; and are effectively permanent. Technological changes challenge traditional norms affecting privacy and decision-making, and continued discussions on new approaches to provide privacy protections are needed. PMID- 27783341 TI - Peliosis Hepatis Mimicking Malignant Hypervascular Tumors. AB - BACKGROUND: Peliosis hepatis is an uncommon vascular condition characterized by multiple, randomly distributed, blood-filled, and cyst-like cavities throughout the liver. The unique clinical nature consisting of an asymptomatic, benign, and incidental finding sometimes conceals itself even until autopsy. However, the exact pathomechanism remains as yet unproven. METHOD: We encountered the patient with multiple hypervascular masses in the whole liver and investigated the clinicopathological features underlying this condition. RESULTS: Detailed herein is a case of peliosis hepatis on the basis of our findings. Our patient illustrated a lethal instance which mimicked a malignancy although it is usually an indolent finding. CONCLUSION: Peliosis hepatis should always be borne in mind as a differential diagnosis of atypical hypervascular hepatic lesion, especially in patients with clinical conditions described in the text. PMID- 27783342 TI - An Innovative Emergency Laparoscopic Cholecystectomy Technique; Early Results Towards Complication Free Surgery. AB - BACKGROUND: The performance of laparoscopic cholecystectomy could be a technical challenge. Procedure success depends on multiple factors namely: hepatobiliary anatomical variations, pathologic changes in the gallbladder and surrounding tissues, pre-operative interventional attempts, the individual surgeon's skill and finally patient co-morbidities. Anticipating the attendant challenges, can help to avoid several known complications associated with this procedure. Searching a more reliable anatomical topography to adopt during laparoscopic cholecystectomy is the basis for a safe surgical technique. METHODS: Between January 2012 and August 2015, 525 cases were presented with acute cholecystitis. Patients were classified in to two groups regarding degree of dissection difficulty. The study concept is defined and applied by the author in all study cases. No single case was excluded from the study. RESULTS: Results are processed in comparative way between both groups of the study. The increased risk results in Group B are related to technical difficulties. CONCLUSION: The study has offered a novel anatomical concept and safe surgical technique avoiding exploration of Calot's triangle. The new concept has minimized dissection demands and risk of injury related to the traditional laparoscopic cholecystectomy. The study has proposed a potentially secure and empirical laparoscopic cholecystectomy technique that could be considered in every case. PMID- 27783340 TI - Life Span Studies of ADHD-Conceptual Challenges and Predictors of Persistence and Outcome. AB - There is a renewed interest in better conceptualizing trajectories of attention deficit/hyperactivity disorder (ADHD) from childhood to adulthood, driven by an increased recognition of long-term impairment and potential persistence beyond childhood and adolescence. This review addresses the following major issues relevant to the course of ADHD in light of current evidence from longitudinal studies: (1) conceptual and methodological issues related to measurement of persistence of ADHD, (2) estimates of persistence rate from childhood to adulthood and its predictors, (3) long-term negative outcomes of childhood ADHD and their early predictors, and (4) the recently proposed new adult-onset ADHD. Estimates of persistence vary widely in the literature, and diagnostic criteria, sample characteristics, and information source are the most important factors explaining variability among studies. Evidence indicates that ADHD severity, comorbid conduct disorder and major depressive disorder, and treatment for ADHD are the main predictors of ADHD persistence from childhood to adulthood. Comorbid conduct disorder and ADHD severity in childhood are the most important predictors of adverse outcomes in adulthood among children with ADHD. Three recent population studies suggested the existence of a significant proportion of individuals who report onset of ADHD symptoms and impairments after childhood. Finally, we highlight areas for improvement to increase our understanding of ADHD across the life span. PMID- 27783343 TI - Outcomes After Surgery for Benign and Malignant Small Bowel Obstruction. AB - BACKGROUND: Small bowel obstruction (SBO) is a common diagnosis; however, outcomes of and risk factors for SBO and malignant bowel obstruction (MBO) surgery are not well understood. We sought to characterize outcomes and risk factors for surgery for SBO and MBO. METHODS: A retrospective cohort study was performed utilizing prospectively collected data from the Michigan Surgical Quality Collaborative (7/2012-3/2015). Cases included those with ICD9 diagnosis code of bowel obstruction and CPT codes for lysis of adhesions, intestinal bypass, and small bowel resection. Cases were stratified by disseminated malignancy (MBO). Factors associated with complications and 30-day mortality were evaluated. RESULTS: Two thousand two hundred thirty-three patients underwent surgery for bowel obstruction, including 86 patients (3.9 %) with MBO. MBO patients had an adjusted mortality rate of 14.5 % (benign 5.0 %); the adjusted complication rate was 32.2 % (benign 27.0 %). Factors independently associated with mortality included disseminated cancer, older age, American Society of Anesthesiologists IV/V, cirrhosis, ascites, urinary tract infection, sepsis, albumin <3.5, hematocrit <30, and bowel resection. CONCLUSIONS: Surgery for bowel obstruction carries a relatively high risk for morbidity and mortality, particularly in patients with malignant bowel obstruction. Considering the identified risk factors for mortality may help clinicians make recommendations regarding surgery in the setting of MBO. PMID- 27783345 TI - Speciation and mobility of volatile heavy metals (Cd, Pb, and Tl) in fly ashes. AB - Speciation of volatile metals Cd, Pb, and Tl in fly ashes (FAs) produced from burning of hard coal in stocker-fired boilers (SFBs) was studied. Two grain fractions of fly ash collected in a multicyclone and battery cyclone of the systems of dust separation from three SFB units operating in various urban heating plants were analyzed. The characteristic feature of speciation of the three metals was a large share of labile fractions: Cd (av. 46.1 %), Pb (av. 39.8 %), and Tl (av. 21.6 %). The fraction which most clearly reflected the different chemical properties of the investigated metals was the oxidizable fraction: F(4) Cd-0 %, F(4)-Pb-av. 10.0 %, and F(4)-Tl-av. 30.2 %. The importance of condensation of the volatile metal species on FA particles for shaping speciation of these metals was characterized using the normalized enrichment factor (NEF): Pb (2.3 +/- 0.8) > Tl (1.8 +/- 0.9) ~ Cd (1.7 +/- 0.6). Speciation of heavy metals may also be important economically, because the level of mobility coefficients (K Cd = 0.46, K Pb = 0.40, and K Tl = 0.22) in the case of fly ashes considerably enriched with toxic metals (Cd 4.8 +/- 3.4 mg/kg, Pb 293 +/- 210 mg/kg, and Tl 6.3 +/- 4.5 mg/kg) may limit their utilization range. PMID- 27783344 TI - Aluminum toxicity risk reduction as a result of reduced acid deposition in Adirondack lakes and ponds. AB - In 1990, the US Congress amended the Clean Air Act (CAA) to reduce regional-scale ecosystem degradation from SO x and NO x emissions which have been responsible for acid deposition in regions such as the Adirondack Mountains of New York State. An ecosystem assessment project was conducted from 1994 to 2012 by the Darrin Fresh Water Institute to determine the effect of these emission reduction policies on aquatic systems. The project investigated water chemistry and biota in 30 Adirondack lakes and ponded waters. Although regulatory changes made in response to the 1990 CAA amendments resulted in a reduction of acid deposition within the Adirondacks, the ecosystem response to these reductions is complicated. A statistical analysis of SO4, pH, Al, and DOC data collected during this project demonstrates positive change in response to decreased deposition. The changes in water chemistry also have lowered the risk of Al toxicity to brook trout (Salvelinus fontinalis [Mitchill]), which allowed the re-introduction of this species to Brooktrout Lake from which it had been extirpated. However, pH and labile aluminum (Alim) fluctuate and are not strongly correlated to changes in acid deposition. As such, toxicity to S. fontinalis also is cyclic and provides rationale for the difficulties inherent in re-establishing resident populations in impacted aquatic environments. Overall, aquatic ecosystems of the Adirondacks show a positive response to reduced deposition driven by changes in environmental policy, but the response is more complex and indicates an ecosystem wide interaction between aquatic and watershed components of the ecosystem. PMID- 27783346 TI - Microbiological and hydrogeological assessment of groundwater in southern Italy. AB - This study represents the first investigation of microbiological groundwater pollution as a function of aquifer type and season for the Apulia region of southern Italy. Two hundred and seven wells were randomly selected from those monitored by the Regional Agency for Environmental Protection for emergency use. Both compulsory (Escherichia coli, Total Coliform, and Enterococci) and optional (Pseudomonas aeruginosa, Salmonella spp., Heterotrophic Plate Count at 37 and 22 degrees C) microbiological parameters were assessed regularly at these wells. Groundwater from only 18 of the 207 (8.7 %) wells was potable; these all draw from karst-fissured aquifers. The remaining 189 wells draw from karst-fissured (66.1 %) or porous (33.9 %) aquifers. Of these, 82 (43.4 %) tested negative for Salmonella spp. and P. aeruginosa, while 107 (56.6 %) tested positive for P. aeruginosa (75.7 %), Salmonella spp. (10.3 %), or for both Salmonella spp. and P. aeruginosa (14 %). A logistic regression model shows that the probability of potable groundwater depends on both season and aquifer type. Typically, water samples were more likely to be potable in autumn-winter than in spring-summer periods (odds ratio, OR = 2.1; 95 % confidence interval, 95 % CI = 1.6-2.7) and from karst-fissured rather than porous aquifers (OR = 5.8; 95 % CI = 4.4-7.8). Optional parameters only showed a seasonal pattern (OR = 2.6; 95 % CI = 1.7-3.9). Clearly, further investigation of groundwater microbiological aspects should be carried out to identify the risks of fecal contamination and to establish appropriate protection methods, which take into account the hydrogeological and climatic characteristics of this region. PMID- 27783347 TI - Drought trends based on the VCI and its correlation with climate factors in the agricultural areas of China from 1982 to 2010. AB - Drought is a type of natural disaster that has the most significant impacts on agriculture. Regional drought monitoring based on remote sensing has become popular due to the development of remote sensing technology. In this study, vegetation condition index (VCI) data recorded from 1982 to 2010 in agricultural areas of China were obtained from advanced very high resolution radiometer (AVHRR) data, and the temporal and spatial variations in each drought were analyzed. The relationships between drought and climate factors were also analyzed. The results showed that from 1982 to 2010, the agricultural areas that experienced frequent and severe droughts were mainly concentrated in the northwestern areas and Huang-Huai Plain. Moreover, the VCI increased in the majority of agricultural areas, indicating that the drought frequency decreased over time, and the decreasing trend in the southern region was more notable than that in the northern region. A correlation analysis showed that temperature and wind velocity were the main factors that influenced drought in the agricultural areas of China. From a regional perspective, excluding precipitation, the climate factors had various effects on drought in different regions. However, the correlation between the VCI and precipitation was low, possibly due to the widespread use of artificial irrigation technology, which reduces the reliance of agricultural areas on precipitation. PMID- 27783349 TI - Mapping wetland functions using Earth observation data and multi-criteria analysis. AB - Wetland functional assessment is commonly conducted based on field observations, and thus, is generally limited to small areas. However, there is often a need for wetland managers to obtain information on wetland functional performance over larger areas. For this purpose, we are proposing a new field-based functional assessment procedure in which wetland functions are evaluated and classified into hydrogeomorphic units according to a multi-criteria analysis approach. Wetland related geographic information system layers derived from Earth observation data (LiDAR, multispectral and radar data) are used in this study for a large-scale functional evaluation. These include maps of a hydrogeomorphic units, ditches, vegetation, annual flood duration, biomass, meadows management, and wetland boundaries. To demonstrate the feasibility of this approach, a 132 km2 international long-term ecological research site located in the west of France was assessed. Four wetland functions were evaluated: flood peak attenuation, low water attenuation, denitrification, and habitat. A spatial distribution map of the individual wetland functions was generated, and the intensity levels of the functions were highlighted. Antagonisms between functions within individual hydrogeomorphic units were also identified. Mapping of hydrological, biogeochemical, and ecological wetland functions over large areas can provide an efficient tool for policy makers and other stakeholders including water authorities, nature conservation agencies, and farmers. Specifically, this tool has the potential to provide a mapping of ecosystem services, conservation management priorities, and possible improvements in water resources management. PMID- 27783348 TI - Presence of thallium in the environment: sources of contaminations, distribution and monitoring methods. AB - Thallium is released into the biosphere from both natural and anthropogenic sources. It is generally present in the environment at low levels; however, human activity has greatly increased its content. Atmospheric emission and deposition from industrial sources have resulted in increased concentrations of thallium in the vicinity of mineral smelters and coal-burning facilities. Increased levels of thallium are found in vegetables, fruit and farm animals. Thallium is toxic even at very low concentrations and tends to accumulate in the environment once it enters the food chain. Thallium and thallium-based compounds exhibit higher water solubility compared to other heavy metals. They are therefore also more mobile (e.g. in soil), generally more bioavailable and tend to bioaccumulate in living organisms. The main aim of this review was to summarize the recent data regarding the actual level of thallium content in environmental niches and to elucidate the most significant sources of thallium in the environment. The review also includes an overview of analytical methods, which are commonly applied for determination of thallium in fly ash originating from industrial combustion of coal, in surface and underground waters, in soils and sediments (including soil derived from different parent materials), in plant and animal tissues as well as in human organisms. PMID- 27783350 TI - Knee joint kinematics with dynamic augmentation of primary anterior cruciate ligament repair - a biomechanical study. AB - BACKGROUND: Dynamic augmentation of anterior cruciate ligament tears seems to reduce anteroposterior knee translation close to the pre-injury level. The aim of the present study is to biomechanically investigate the course of translation during a simulated early post-operative phase. It is hypothesized that anteroposterior translation is maintained at the immediate post-operative level over a simulated rehabilitation period of 50'000 gait cycles. METHODS: Eight fresh-frozen human cadaveric knee joints from donors with a mean age of 35.5 (range 25-40) years were subjected to 50'000 cycles of 0 degrees -70 degrees -0 degrees flexion-extension movements in a custom-made test setup. Anteroposterior translation was assessed with simulated Lachman/KT-1000 testing in 0 degrees , 15 degrees , 30 degrees , 60 degrees and 90 degrees of flexion in knee joints treated with the novel technique initially and after 50'000 cycles testing. Statistical analysis was performed using the Wilcoxon Signed-Rank Test. The level of significance was set at p = 0.05. RESULTS: Anteroposterior translation changed non-significantly for all flexion angles between cycle 0 and 50'000 (p = 0.39 to p = 0.89), except for 30 degrees flexion, where a significant increase by 1.4 mm was found (p = 0.03). CONCLUSION: Increase in anteroposterior translation of knees treated with this dynamic augmentation procedure is low. The procedure maintains translation close to the immediate post-operative level over a simulated rehabilitation period of 50'000 gait cycles and therefore supports anterior cruciate ligament repair during biological healing. PMID- 27783352 TI - What can be done when the cored specimen in a Frey procedure for chronic pancreatitis is reported as adenocarcinoma? AB - The aim of this study is to analyze the outcomes of patients with chronic pancreatitis who underwent the Frey procedure and who had a histologic evidence of adenocarcinoma in the cored out specimen.The type of analysis is retrospective. Out of 523 patients who underwent Frey procedure for chronic pancreatitis, seven (five males and two females; age range 42 to 54 years) had histologically proven adenocarcinoma. In the first four cases, intraoperative frozen section was not done. The diagnosis was made on routine histopathology and only one out of four could undergo attempted curative therapy. In the remaining three cases, intraoperative frozen section confirmation was available, and curative resection performed. Only four out of seven had a clear-cut mass lesion: (a) cancer can occur in chronic pancreatitis in the absence of a mass lesion and (b) intraoperative frozen section of the cored specimen is crucial to exercising curative therapeutic options and must be performed routinely. If frozen section is reported as adenocarcinoma, a head resection with repeat frozen of the margins of resection is appropriate. If the adenocarcinoma is reported on regular histopathology after several days, then a total pancreatectomy may be more appropriate. PMID- 27783351 TI - Progression of recurrent acute and chronic pancreatitis: A short-term follow up study from a southern Indian centre. AB - BACKGROUND: Little data exist on the progression of recurrent acute (RAP) and chronic pancreatitis (CP) from regions from where the entity of tropical chronic pancreatitis was originally described. The study aimed to follow up patients with RAP and CP seen at a southern Indian centre for progression of disease over time. METHODS: Prospectively enrolled patients with RAP and CP were followed up, and the alcoholic and idiopathic subgroups were assessed for progression of structural and functional changes in the organ. RESULTS: One hundred and forty patients (RAP = 44; 31.4 %, CP = 96; 68.5 %) were followed up over a median 12.2 (interquartile range 12.0-16.8) months. The cause was alcohol in 31 (22.1 %) and not evident in 109 (77.8 %). The disease progressed from RAP to CP in 7 (15.9 %), 6 (16.2 %) out of 37 in the idiopathic and 1 (14.2 %; p = 1.00) out of 7 in the alcoholic subgroups. Three (42.8 %) and 1 (14.2 %) developed steatorrhea and diabetes mellitus (DM), respectively, and 2 (4.5 %) developed calcification. Established CP progressed in 19 (19.7 %), 1 (1.0 %), 5 (5.2 %), 2 (2.0 %) and 11 (11.4 %) newly developed DM, steatorrhea, calcification and duct dilation during follow up. Among the idiopathic and alcoholic CP, disease progression was seen in 15 (20.8 %) out of 72 and 4 (16.6 %) out of 24 respectively. CONCLUSIONS: Idiopathic RAP and CP progressed during the short-term follow up. This is similar to other etiological forms of pancreatitis, as described from elsewhere in the world. PMID- 27783353 TI - Rectal GIST-Outcomes and viewpoint from a tertiary cancer center. AB - INTRODUCTION: There is scarce data relating to methods to improve sphincter preservation in rectal gastrointestinal stromal tumor (GIST). Increasing the duration of neoadjuvant (NA) imatinib resulting in improved sphincter preservation rate has not been established. This retrospective analysis looks at the rates of sphincter preservation in rectal GIST with NA imatinib and effect of duration of NA imatinib on the same to find out optimum duration of NA with respect to sphincter preservation in rectal GIST patients. METHODS: Twenty-three cases of GIST of lower third of rectum were treated at our centre from 2005 till 2015. NA imatinib was used in a dose of 400 mg. Response evaluation was done every 3 months with a pelvic magnetic resonance imaging. Surgical management was determined by a team of experienced gastrointestinal oncosurgeons. RESULTS: Five patients underwent upfront surgery which included local resection in four patients and abdominoperineal resection in one patient. NA imatinib was used in 69.5 % (16/23) patients. Median duration of NA imatinib was 15 months (3-84 months). Amongst who underwent a sphincter-salvage surgery median duration of NA imatinib was 13 months whereas 18 months in patients who required a sphincter sacrificing surgery (p = 0.683). The radiologic response included partial response in 75 % (12/16) patients, stable disease in 18.7 % (3/16) and one with progressive disease. Definitive surgical resection was possible in 13 patients (81.3 %) after NA imatinib. Median progression-free survival (PFS) was 120 months in the whole cohort whereas median overall survival (OS) was not reached. Four year estimated PFS and OS was 81 % and 100 %, respectively. Median disease-free survival in upfront surgery group vs. neoadjuvant imatinib group was 70 vs. 120 months, respectively (p = 0.039). CONCLUSION: Neoadjuvant imatinib appears to be a useful option in improving chances of sphincter preservation without adversely affecting the outcome. Use of neoadjuvant imatinib leads to improvement in progression-free survival in patients with GIST of lower third of the rectum. PMID- 27783354 TI - Isoflurane use is not associated with prolonged intensive care unit stay following routine cardiac surgery when compared to sevoflurane. PMID- 27783355 TI - In reply: Isoflurane use is not associated with prolonged intensive care unit stay following routine cardiac surgery when compared to sevoflurane. PMID- 27783357 TI - Three-dimensional phase contrast magnetic resonance imaging validated to assess pulmonary artery flow in patients with chronic thromboembolic pulmonary hypertension. AB - In this study, three-dimensional phase contrast magnetic resonance imaging (3D-PC MRI), a novel technique, was validated to assess pulmonary artery (PA) flow in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The MR data of PAs from 3D-PC and two-dimensional PC (2D-PC) from before and after treatment for 3 patients with CTEPH were retrospectively analyzed. Additionally, 3D- and 2D PC MR scans of PA were performed in 5 healthy volunteers. Correlation of stroke volumes (SVs) obtained by 3D-PC and 2D-PC was analyzed using Pearson's correlation coefficients. There was an excellent correlation in the SV of main PA, left PA and right PA between 3D-PC and 2D-PC (main PA: r = 0.91, p < 0.01, left PA: r = 0.72, p < 0.01 and right PA: r = 0.77, p < 0.01). In conclusion, 3D PC MRI was able to accurately quantify the PA flow in patients with CTEPH. PMID- 27783358 TI - Robotic-assisted minimally invasive esophagectomy for treatment of esophageal carcinoma. AB - Minimally invasive esophagectomy (MIE) is technically challenging. Da Vinci Robotic system could improve surgical dissection with additional degree of freedom from robotic arms. This study aimed to assess the feasibility and safety of performing MIE using Da Vinci Robotic system among patients with esophageal cancers. From 2009 to 2013, consecutive patients with esophageal cancers who received robotic-assisted MIE were recruited. We excluded tumors with suspected invasion to adjacent organs. Preoperative staging included EUS, CT thorax and abdomen and bronchoscopy. We perform mobilization of thoracic esophagus with two field lymphadenectomy using robotic system, followed by laparoscopic gastric mobilization and hand-sewn cervical esophagogastric anastomosis. A total of 20 patients were recruited (16 male and 4 female) with mean age of 64.2 +/- 8.8 years. All patients were successfully treated with robotic-assisted MIE with mean operative time of 499.5 +/- 70 min and blood loss of 355.7 +/- 329.6 mls. There was no pulmonary complication, while three patients sustained anastomotic leakage and managed conservatively. The mean hospital stay was 13 +/- 6 days. Five patients had stage I tumors, five had stage II, and nine had stage III disease. One patient had complete response after neoadjuvant chemoradiotherapy. The number of lymph node dissection was 18.2 +/- 13.2, and 2.8 +/- 5.7 nodes involved. The follow-up period was 21 +/- 9 months, and the overall survival was 75 %. Robotic assisted MIE is feasible and safe for treatment of esophageal cancers. The surgical dissection can be enhanced by improved ergonomics from robotic arms and sense of depth from 3D images. PMID- 27783359 TI - Diverging Mobility Trajectories: Grandparent Effects on Educational Attainment in One- and Two-Parent Families in the United States. AB - In recent years, sociological research investigating grandparent effects in three generation social mobility has proliferated, mostly focusing on the question of whether grandparents have a direct effect on their grandchildren's social attainment. This study hypothesizes that prior research has overlooked family structure as an important factor that moderates grandparents' direct effects. Capitalizing on a counterfactual causal framework and multigenerational data from the Panel Study of Income Dynamics, this study examines the direct effect of grandparents' years of education on grandchildren's years of educational attainment and heterogeneity in the effects associated with family structure. The results show that for both African Americans and whites, grandparent effects are the strongest for grandchildren who grew up in two-parent families, followed by those in single-parent families with divorced parents. The weakest effects were marked in single-parent families with unmarried parents. These findings suggest that the increasing diversity of family forms has led to diverging social mobility trajectories for families across generations. PMID- 27783360 TI - The Contributions of Places to Metropolitan Ethnoracial Diversity and Segregation: Decomposing Change Across Space and Time. AB - Although the trend toward greater ethnoracial diversity in the United States has been documented at a variety of geographic scales, most research tracks diversity one scale at a time. Our study bridges scales, asking how the diversity and segregation patterns of metropolitan areas are influenced by shifts in the racial/ethnic composition of their constituent places. Drawing on 1980-2010 decennial census data, we use a new visual tool to compare the distributions of place diversity for 50 U.S. metro areas over three decades. We also undertake a decomposition analysis of segregation within these areas to evaluate hypotheses about the roles of different types of places in ethnoracial change. The decomposition indicates that although principal cities continue to shape the overall diversity of metro areas, their relative impact has declined since 1980. Inner suburbs have experienced substantial increases in diversity during the same period. Places with large white majorities now contribute more to overall metropolitan diversity than in the past. In contrast, majority black and majority Hispanic places contribute less to metropolitan diversity than in the past. The complexity of the patterns we observe is underscored through an inspection of two featured metropolises: Chicago and Dallas. PMID- 27783356 TI - Environmental Metals and Cardiovascular Disease in Adults: A Systematic Review Beyond Lead and Cadmium. AB - Published systematic reviews concluded that there is moderate to strong evidence to infer a potential role of lead and cadmium, widespread environmental metals, as cardiovascular risk factors. For other non-essential metals, the evidence has not been appraised systematically. Our objective was to systematically review epidemiologic studies on the association between cardiovascular disease in adults and the environmental metals antimony, barium, chromium, nickel, tungsten, uranium, and vanadium. We identified a total of 4 articles on antimony, 1 on barium, 5 on chromium, 1 on nickel, 4 on tungsten, 1 on uranium, and 0 on vanadium. We concluded that the current evidence is not sufficient to inform on the cardiovascular role of these metals because of the small number of studies. Few experimental studies have also evaluated the role of these metals in cardiovascular outcomes. Additional epidemiologic and experimental studies, including prospective cohort studies, are needed to understand the role of metals, including exposure to metal mixtures, in cardiovascular disease development. PMID- 27783361 TI - Relationship Transitions and the Risk for Child Maltreatment. AB - Family structure as a risk for child maltreatment has long been viewed as a static state in the child maltreatment literature. Drawing on data from the Fragile Families and Child Wellbeing Study, the author uses a series of individual fixed-effects models to investigate whether particular types of relationship transitions over children's first decade of life are associated with increased risk for maternal and paternal child abuse and maternal neglect. Findings question and confirm a number of long-standing theoretical and empirical findings from the child maltreatment literature. Results indicate that transitions to being single are associated with increased risk for maternal child abuse and neglect. In addition, the frequency and severity of paternal harsh parenting may be closely linked with the nature of fathers' relationship transitions. Last, results largely do not provide support for the theory that the presence of social (nonbiological) fathers increases mothers' risk for engaging in child abuse or neglect. PMID- 27783362 TI - Tissue transglutaminase 2 exerts a tumor-promoting role in hepatitis B virus related hepatocellular carcinoma. AB - Hepatitis B virus (HBV) infection is a major risk factor which can lead to development of hepatocellular carcinoma (HCC). Tissue transglutaminase-2 (TG2) has been shown to be critical for cancer progression. However, how TG2 promotes the progression of HBV-related HCC remains unknown. In this study, we aimed to explore the expression and function of TG2 on HBV-related HCC progression. The expression levels of TG2 were examined in a series of HBV-related HCC tissues and a panel of HCC cell lines. The effects of TG2 knockdown on the proliferation and migration of HBV-related cells were determined. TG2 expression was found to be significantly upregulated in HBV-related HCC tissues. TG2 expression was higher in HBV-related HCC cell lines than HBV-unrelated HCC cell lines. Moreover, inhibition of TG2 in HCC cell lines HepG2.2.15 and Hep3B could inhibit cell proliferation, migration, and invasion in vitro. Our results indicated that TG2 could serve as a promising target for treatment of HBV-related HCC patients. PMID- 27783364 TI - Scanning Electron Microscopy Study of the Antennal Sensilla of Monema flavescens Walker (Lepidoptera: Limacodidae). AB - Monema flavescens Walker (Lepidoptera: Limacodidae) is a serious polyphagous defoliator. Using scanning electron microscopy, the external morphology of the antennal sensilla of this pest was examined for a better understanding of the mechanisms of insect-insect and insect-plant chemical communications. The antennae of M. flavescens were filiform in shape, and 11 morphological types of sensilla were found in both sexes. Six types of likely chemosensory sensilla were identified: uniporous sensilla chaetica, multiporous sensilla trichodea, and four types of multiporous sensilla basiconica. The sensilla identified as likely mechanoreceptors included two subtypes of aporous sensilla chaetica, aporous sensilla coeloconica, aporous sensilla styloconica, and Bohm's bristles, whereas the position of the antennae was monitored by Bohm's bristles. PMID- 27783363 TI - Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group. AB - BACKGROUND AND OBJECTIVES: Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcgammaRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL. METHODS: Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance. RESULTS: Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (p = 0.00046) and in patients with the FCGR3A 158VV genotype (p = 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (p = 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (p = 1.3 * 10 5 and 0.0015, respectively). CONCLUSIONS: A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab 'consumption' (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in FCGR3A-158VV patients. CLINICAL TRIAL REGISTRATION: NCT01370772. PMID- 27783365 TI - Health-Related Fitness Improvements in Morbid Obese Patients After Laparoscopic Sleeve Gastrectomy: a Cohort Study. AB - OBJECTIVE: Laparoscopic sleeve gastrectomy (LSG) has demonstrated high long-term effectiveness and major advantages over other techniques. The objective of this study was to analyze changes in physical fitness parameters in morbidly obese patients during 6 months after LSG. METHODOLOGY: We conducted a descriptive observational study with 6-month follow-up in 72 LSG patients, evaluating changes in body mass index (BMI), functional capacity (6-min walking test), hand grip strength (manual dynamometry), flexibility (fingertip-to-floor test), balance (Flamingo test), physical activity level (International Physical Activity Questionnaire, IPAQ), and perception of general physical fitness (International Fitness Scale [IFIS] questionnaire). RESULTS: The ANOVA revealed significant improvements in BMI, functional capacity, flexibility, balance, and physical activity level (P < 0.001) at 6 months, with an improvement in the perception of physical fitness in most cases. No significant changes were found in dominant hand (P = 0.676) or non-dominant hand (P = 0.222) dynamometry. General physical fitness was positively correlated with BMI and distance in the 6-min test, and was negatively correlated with fingertip-to-floor distance. CONCLUSION: Morbidly obese patients showed major improvements at 6 months after LSG in functional capacity, balance, mobility, and physical activity, with no change in grip strength. These improvements were related to a better self-perception of general physical fitness. PMID- 27783368 TI - Laparoscopic Revision of Roux-en-Y Gastric Bypass to Biliopancreatic Diversion with Duodenal Switch: Technical Points. PMID- 27783367 TI - National Differences in Remission of Type 2 Diabetes Mellitus After Roux-en-Y Gastric Bypass Surgery-Subgroup Analysis of 2-Year Results of the Diabetes Surgery Study Comparing Taiwanese with Americans with Mild Obesity (BMI 30-35 kg/m2). AB - BACKGROUND: The purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Between April 2008 and December 2011, this randomized, controlled clinical trial was conducted at four teaching hospitals in the United States and Taiwan involving 71 participants with mild obesity (BMI 30-35 kg/m2). Thirty-six of 71 participants were randomly assigned to the RYGB group, and the others were in IMM group. Partial or complete remission of T2DM was defined as blood HbA1c < 6.5 % (48 mmol/mol) or <6 % (42 mmol/mol) without any antihyperglycemic medication for at least 1-year duration, respectively. RESULTS: At baseline, Taiwanese participants had a lower BMI, younger age, and shorter duration of T2DM than American participants. At 24 months, weight loss was greater in the RYGB group in both populations than in the IMM group. No IMM participant of either population had partial or complete remission of T2DM. In the RYGB group, a substantial proportion of the subjects achieved complete or partial remission (57 % in Taiwanese and 27 % in American participants, P = 0.08). Logistic regression revealed stimulated C-peptide (Odds ratio 2.22, P = 0.02) but not nationality as a significant predictor of diabetes remission. CONCLUSION: Adding RYGB to lifestyle and medical management was associated with a greater likelihood of remission of T2DM in both Taiwanese and American subjects with mild obesity with type 2 diabetes. Residual beta-cell function at baseline appears to be the major factor predicting remission of T2DM. Trial registry number: clinicaltrials.gov Identifier: NCT00641251. PMID- 27783366 TI - Laparoscopic One-Anastomosis Gastric Bypass: Technique, Results, and Long-Term Follow-Up in 1200 Patients. AB - BACKGROUND: Excellent results have been reported with mini-gastric bypass. We adopted and modified the one-anastomosis gastric bypass (OAGB) concept. Herein is our approach, results, and long-term follow-up (FU). METHODS: Initial 1200 patients submitted to laparoscopic OAGB between 2002 and 2008 were analyzed after a 6-12-year FU. Mean age was 43 years (12-74) and body mass index (BMI) 46 kg/m2 (33-86). There were 697 (58 %) without previous or simultaneous abdominal operations, 273 (23 %) with previous, 203 (17 %) with simultaneous, and 27 (2 %) performed as revisions. RESULTS: Mean operating time (min) was as follows: (a) primary procedure, 86 (45-180); (b) with other operations, 112 (95-230); and (c) revisions, 180 (130-240). Intraoperative complications led to 4 (0.3 %) conversions. Complications prompted operations in 16 (1.3 %) and were solved conservatively in 12 (1 %). Long-term complications occurred in 12 (1 %). There were 2 (0.16 %) deaths. Thirty-day and late readmission rates were 0.8 and 1 %. Cumulative FU was 87 and 70 % at 6 and 12 years. The highest mean percent excess weight loss was 88 % (at 2 years), then 77 and 70 %, 6 and 12 years postoperatively. Mean BMI (kg/m2) decreased from 46 to 26.6 and was 28.5 and 29.9 at those time frames. Remission or improvement of comorbidities was achieved in most patients. The quality of life index was satisfactory in all parameters from 6 months onwards. CONCLUSIONS: Laparoscopic OAGB is safe and effective. It reduces difficulty, operating time, and early and late complications of Roux-en-Y gastric bypass. Long-term weight loss, resolution of comorbidities, and degree of satisfaction are similar to results obtained with more aggressive and complex techniques. It is currently a robust and powerful alternative in bariatric surgery. PMID- 27783369 TI - A Simple Technique of Gastric Pouch Resizing for Inadequate Weight Loss After Roux-en-Y Gastric Bypass. AB - INTRODUCTION: Weight regain after Roux-en-Y gastric bypass (RYGB) is increasingly reported in the literature Debs et al. Surg Obes Relat Dis (2016). Laparoscopic resizing of the gastric pouch and the gastrojejunal anastomosis is an accepted surgical option Nguyen et al. (Obes Surg 25:928-34, 2015); Iannelli et al. (Surg Obes Relat Dis 9:260-7, 2013); Al-Bader et al. (Obes Surg 25:1103-8, 2015). The aim of this video is to present a simple technique of en bloc resection. METHODS: We present the case of a 42-year-old woman with a BMI of 44 kg/m2 who underwent laparoscopic RYGB in 2007. In 2015, she regained weight till reaching a BMI of 38 kg/m2. 3D CT volumetry was performed that showed a pouch volume of 220 cm3 and a gastrojejunal anastomosis diameter of 20 mm. RESULTS: There are often a lot of adherences between the gastric pouch and the residual stomach, which makes the dissection difficult and tedious, with the possibility to devascularize the residual stomach and lead to a gastric fistula from this residual stomach. We present in this video a simple technique of gastric pouch resizing that consists of en bloc resection of the gastric pouch, the residual stomach, and +/- the gastrojejunal anastomosis. We recommend this technique in case of severe adherences and inability to identify a cleavage plane between the excess gastric pouch and the resected stomach. CONCLUSION: Insufficient weight loss or weight regain after RYGBP is becoming more frequently encountered. As a result, revisional surgery will be more frequently performed. This simple technique allows an easier dissection across healthier tissues and is easier to perform in the presence of severe adherences between the gastric pouch and the residual stomach. PMID- 27783370 TI - The Short-Term Effect of Weight Loss Surgery on Volumetric Breast Density and Fibroglandular Volume. AB - PURPOSE: Obesity and breast density are both associated with an increased risk of breast cancer and are potentially modifiable. Weight loss surgery (WLS) causes a significant reduction in the amount of body fat and a decrease in breast cancer risk. The effect of WLS on breast density and its components has not been documented. Here, we analyze the impact of WLS on volumetric breast density (VBD) and on each of its components (fibroglandular volume and breast volume) by using three-dimensional methods. MATERIALS AND METHODS: Fibroglandular volume, breast volume, and their ratio, the VBD, were calculated from mammograms before and after WLS by using VolparaTM automated software. RESULTS: For the 80 women included, average body mass index decreased from 46.0 +/- 7.22 to 33.7 +/- 7.06 kg/m2. Mammograms were performed on average 11.6 +/- 9.4 months before and 10.1 +/- 7 months after WLS. There was a significant reduction in average breast volume (39.4 % decrease) and average fibroglandular volume (15.5 % decrease), and thus, the average VBD increased from 5.15 to 7.87 % (p < 1 * 10-9) after WLS. When stratified by menopausal status and diabetic status, VBD increased significantly in all groups but only perimenopausal and postmenopausal women and non-diabetics experienced a significant reduction in fibroglandular volume. CONCLUSIONS: Breast volume and fibroglandular volume decreased, and VBD increased following WLS, with the most significant change observed in postmenopausal women and non-diabetics. Further studies are warranted to determine how physical and biological alterations in breast density components after WLS may impact breast cancer risk. PMID- 27783372 TI - [Twelve cases of monkeypox virus outbreak in Bangassou District (Central African Republic) in December 2015]. AB - An outbreak of monkeypox occurred in the district of Bangassou in 2015. The monkeypox is a re-emerging zoonosis of viral origin highly contagious. It is an eruptive fever which evolves in an epidemic manner. An investigation was held December 10, 2015, to February 10, 2016 in the focus of the epidemic. Its objective was to describe the epidemic according to the time, places and people and to determine the incidence and lethality of the disease. This was a descriptive study. The data collection was made by interview and using a linear plug composed of several sections. All suspected cases were taken into account. The interview was done with patients or the parents of sick children. The blood and the contents of the lesions were collected and sent to the laboratory of the Institut Pasteur in Bangui for confirmation. Our data were analyzed with Epi info7. In total 12 patients had been registered including 9 secondary cases. Patients aged 31 to 40 years and less than 10 years were most affected. In addition, adults were most affected by the disease (8/12). The average age was 25 years with extremes at 15 months and 41 years. The sex male/female ratio was 1. The overall attack rate of disease and lethality were 0.2 per 1000 inhabitants and 25% respectively. The fatality was 67% among children less than 10 years. Fever and rash were the main symptoms of the disease. Lymphadenopathy was present in 54.5%. Ten of the 12 patients were hospitalized (83%). The average duration of hospitalization was 13 days with the extremes 6 and 28 days. The monkeypox like smallpox remains a serious and fatal disease in children. A survey of animal reservoirs complained to identify strains of the virus is essential. During an outbreak, good communication and isolation of patients may break the chain of transmission. Other measures to limit their contact with the forest or virus reservoirs are to be encouraged. PMID- 27783371 TI - [New insight into Anopheles coluzzii Coetzee & Wilkerson, 2013 larval ecology in the Wouri estuary, Littoral-Cameroon]. AB - Malaria vectors control is essentially based on the use of insecticides against adult mosquitoes. However because of the development of resistance to insecticides, there is now a renewed interest in the management of larval sources. The aim of the present study was to map and characterize the breeding sites of Anopheles coluzzii in the Wouri river estuary in Cameroon. Larval surveys were carried out between December 2013 and August 2014 in rural areas on the island of Manoka and urban area in Youpwe at Douala. Culicidae breeding sites identified were georeferenced and mapped. Their larval productivity was evaluated by the method of "dipping" and their physicochemical parameters measured by spectrophotometry and oximetry. Culicidae collected larvae were reared in the insectarium to the adult stage. Adult mosquitoes were subjected to morphological identification and those belonging to the Anopheles gambiae complex have subsequently been subjected to molecular identification by the PCR-RFLP technique. A total of 240 breeding sites were geo-referenced in the two sites, including 10 types. Abandoned containers and pools were the most frequent breeding sites respectively in Manoka and in Youpwe. After morphological and molecular identification, eleven mosquito species have been identified. Anopheles coluzzii and Culex quinquefasciatus were the most frequent species respectively in Manoka and in Youpwe. Mosquito density was higher in managed gutters and canoes respectively in Manoka and in Youpwe. Culex and Aedes genus were more frequent in the hollow palm and water wells respectively in Manoka and Youpwe. The productivity of breeding sites varied according to the physicochemical parameters. Species richness varied according to the type of breeding site. Anopheles coluzzii was observed for the first time in Cameroon in water storage containers, tires, discarded containers and canoes. This study highlighted diversity in the type of breeding site of An. coluzzii in the Wouri estuary, suggesting the adaptation of this species in its environment. These results could be used to develop an antilarval control strategy in Manoka and in Youpwe. PMID- 27783373 TI - Evaluation of spatial dependence of point spread function-based PET reconstruction using a traceable point-like 22Na source. AB - BACKGROUND: The point spread function (PSF) of positron emission tomography (PET) depends on the position across the field of view (FOV). Reconstruction based on PSF improves spatial resolution and quantitative accuracy. The present study aimed to quantify the effects of PSF correction as a function of the position of a traceable point-like 22Na source over the FOV on two PET scanners with a different detector design. METHODS: We used Discovery 600 and Discovery 710 (GE Healthcare) PET scanners and traceable point-like 22Na sources (<1 MBq) with a spherical absorber design that assures uniform angular distribution of the emitted annihilation photons. The source was moved in three directions at intervals of 1 cm from the center towards the peripheral FOV using a three dimensional (3D)-positioning robot, and data were acquired over a period of 2 min per point. The PET data were reconstructed by filtered back projection (FBP), the ordered subset expectation maximization (OSEM), OSEM + PSF, and OSEM + PSF + time of-flight (TOF). Full width at half maximum (FWHM) was determined according to the NEMA method, and total counts in regions of interest (ROI) for each reconstruction were quantified. RESULTS: The radial FWHM of FBP and OSEM increased towards the peripheral FOV, whereas PSF-based reconstruction recovered the FWHM at all points in the FOV of both scanners. The radial FWHM for PSF was 30-50 % lower than that of OSEM at the center of the FOV. The accuracy of PSF correction was independent of detector design. Quantitative values were stable across the FOV in all reconstruction methods. The effect of TOF on spatial resolution and quantitation accuracy was less noticeable. CONCLUSIONS: The traceable 22Na point-like source allowed the evaluation of spatial resolution and quantitative accuracy across the FOV using different reconstruction methods and scanners. PSF-based reconstruction reduces dependence of the spatial resolution on the position. The quantitative accuracy over the entire FOV of the PET system is good, regardless of the reconstruction methods, although it depends slightly on the position. PMID- 27783374 TI - Quantum Oscillations of Interacting Nanoscale Structural Inhomogeneities in a Domain Wall of Magnetic Stripe Domain. AB - It was established that at low temperatures, quantum oscillations of a pair of interacting nanoscale structural inhomogeneities (vertical Bloch lines) occur in a domain wall of stripe domain in uniaxial ferromagnetic film. The effective mass of vertical Bloch line and conditions for this effect were determined. The effect can be used in the hybrid storage devices bit + q-bit. PMID- 27783375 TI - Green Synthesis and Catalytic Activity of Gold Nanoparticles Synthesized by Artemisia capillaris Water Extract. AB - Gold nanoparticles were synthesized using a water extract of Artemisia capillaris (AC-AuNPs) under different extract concentrations, and their catalytic activity was evaluated in a 4-nitrophenol reduction reaction in the presence of sodium borohydride. The AC-AuNPs showed violet or wine colors with characteristic surface plasmon resonance bands at 534~543 nm that were dependent on the extract concentration. Spherical nanoparticles with an average size of 16.88 +/- 5.47~29.93 +/- 9.80 nm were observed by transmission electron microscopy. A blue shift in the maximum surface plasmon resonance was observed with increasing extract concentration. The face-centered cubic structure of AC-AuNPs was confirmed by high-resolution X-ray diffraction analysis. Based on phytochemical screening and Fourier transform infrared spectra, flavonoids, phenolic compounds, and amino acids present in the extract contributed to the reduction of Au ions to AC-AuNPs. The average size of the AC-AuNPs decreased as the extract concentration during the synthesis was increased. Higher 4-nitrophenol reduction reaction rate constants were observed for smaller sizes. The extract in the AC-AuNPs was removed by centrifugation to investigate the effect of the extract in the reduction reaction. Interestingly, the removal of extracts greatly enhanced their catalytic activity by up to 50.4 %. The proposed experimental method, which uses simple centrifugation, can be applied to other metallic nanoparticles that are green synthesized with plant extracts to enhance their catalytic activity. PMID- 27783376 TI - Sensitive, Selective, and Fast Detection of ppb-Level H2S Gas Boosted by ZnO-CuO Mesocrystal. AB - ZnO-CuO mesocrystal was prepared via topotactic transformation using one-step direct annealing of aqueous precursor solution and assembled into a H2S sensor. The ZnO-CuO mesocrystal-based sensor possesses good linearity and high sensitivity in the low-concentration range (10-200 ppb). Compared to pure CuO, the as-prepared ZnO-CuO mesocrystal sensor exhibited superior H2S sensing performance with a response ranging from 8.6 to 152 % towards H2S concentrations from 10 ppb to 10 ppm when applied at the optimized working temperature of 125 degrees C. The sensor showed excellent repeatability and good selectivity towards H2S gas even at a concentration four orders of magnitude lower than the interfering gases, such as H2, CO2, CO, NO2, acetone, and NH3. The improved sensitivity could be attributed partially to the effective diffusion of analyte gas through the mesocrystal surface and the abundant accessible active sites. Moreover, the nanoscale p-n junctions within the mesocrystal, which could effectively manipulate the local charge carrier concentration, are also beneficial to boost the sensing performance. PMID- 27783377 TI - Tuning of Rashba/Dresselhaus Spin Splittings by Inserting Ultra-Thin InAs Layers at Interfaces in Insulating GaAs/AlGaAs Quantum Wells. AB - The ratio of Rashba and Dresselhaus spin splittings of the (001)-grown GaAs/AlGaAs quantum wells (QWs), investigated by the spin photocurrent spectra induced by circular photogalvanic effect (CPGE) at inter-band excitation, has been effectively tuned by changing the well width of QWs and by inserting a one monolayer-thick InAs layer at interfaces of GaAs/AlGaAs QWs. Reflectance difference spectroscopy (RDS) is also employed to study the interface asymmetry of the QWs, whose results are in good agreement with that obtained by CPGE measurements. It is demonstrated that the inserted ultra-thin InAs layers will not only introduce structure inversion asymmetry (SIA), but also result in additional interface inversion asymmetry (IIA), whose effect is much stronger in QWs with smaller well width. It is also found that the inserted InAs layer brings in larger SIA than IIA. The origins of the additional SIA and IIA introduced by the inserted ultra-thin InAs layer have been discussed. PMID- 27783378 TI - Colloidal Nanomolybdenum Influence upon the Antioxidative Reaction of Chickpea Plants (Cicer arietinum L.). AB - The use of colloidal solutions of metals as micronutrients enhances plant resistance to unfavorable environmental conditions and ensures high yields of food crops. The purpose of the study was a comparative evaluation of presowing treatment with nanomolybdenum and microbiological preparation impact upon the development of adaptive responses in chickpea plants. Oxidative processes did not develop in all variants of the experiment but in variants treated with microbial preparation, and joint action of microbial and nanopreparations even declined, as evidenced by the reduction of thiobarbituric acid reactive substances in photosynthetic tissues by 15 %. The activity of superoxide dismutase increased (by 15 %) in variant "nanomolybdenum" and joint action "microbial + nanomolybdenum," but it decreased by 20 % in variants with microbial preparation treatment. The same dependence was observed in changes of catalase activity. Antioxidant status factor, which takes into account the ratio of antioxidant to pro-oxidant, was the highest in variants with joint action of microbial preparation and nanomolybdenum (0.7), the lowest in variants with microbial treatment only (0.1). Thus, the results show that the action of nanoparticles of molybdenum activated antioxidant enzymes and decreased oxidative processes, thus promoting adaptation of plants. PMID- 27783379 TI - The Sierra Leone Ultrasound Rainbow4Africa Project (SLURP): an observational study of ultrasound effectiveness in developing countries. AB - BACKGROUND: Diagnostic tools available in low-income countries are often really basic even if patients can be as sick as those of the richer countries. Point-of care ultrasound could be a solution for this problem. We studied the impact of ultrasound at the Holy Spirit Hospital, Makeni, Sierra Leone. METHODS: This is a prospective, observational study on outpatients presenting at the HSH. We enrolled continually for 1 month 105 patients asked for ultrasound examination by the caring physician that had to indicate the differential diagnosis hypothesized, the confidence degree about these on a 5-point Likert scale, and the therapy before and after the US. The primary outcome was to measure the difference in the number of differential diagnoses. Secondary outcomes were the rate of new diagnoses, the confidence changes of the visiting physician, and the changes in prescribed therapy or management. Categorical variables were compared using the Chi-square test, and continuous ones using two-tailed Student's test and Likert with the Wilcoxon rank-sum test. RESULTS: 194 differential diagnoses were formulated, with a mean of 1.85 (DS 0.87) diagnoses per patient. 89 (46%) were excluded on the basis of US, reducing the mean of differential diagnosis per patient to 1, 0 (p < 0.001). US also introduced 53 new diagnoses in 42 patients (mean 1.26; SD 0.54), raising the final differential diagnosis from 105 to 158 (+50.5%) that is 1.51 (DS 0.79) per patient. There is a statistically significant reduction (18.6%) in diagnoses per patient after having performed the ultrasound (p < 0.001). The certainty level increased (Wilcoxon rank-sum test: p < 0.001). We did not reach the statistical significance studying the changes in therapy and management because the subgroups for analysis were too small. Nonetheless, we saw interesting changes in drug prescription and referral rate before and after the US. CONCLUSION: Ultrasound is feasible in low-income countries; with it diagnostic hypotheses were reduced and new unexpected diagnoses were introduced. Further studies are needed to explore other strong outcomes like mortality, length of stay in hospital, and money saved with the use of ultrasound in developing countries. PMID- 27783380 TI - Common pitfalls in point-of-care ultrasound: a practical guide for emergency and critical care physicians. AB - BACKGROUND: Point-of-care ultrasonography (POCUS) is a widely used tool in emergency and critical care settings, useful in the decision-making process as well as in interventional guidance. While having an impressive diagnostic accuracy in the hands of highly skilled operators, inexperienced practitioners must be aware of some common misinterpretations that may lead to wrong decisions at the bedside. OBJECTIVES: This article provides a revision list of common POCUS misdiagnoses usually found in practice and offers useful tips to recognize and avoid them. DISCUSSION: The following aspects were selected and reviewed: pericardial effusion vs. pleural vs. ascites vs. epicardial fat; right ventricle dilation in acute pulmonary embolism and inferior vena cava for volume status assessment in cardiac ultrasound; lung point and lung pulse misinterpretations and mirror artifacts vs. lung consolidations in lung ultrasound; peritoneal fluid vs. the stomach and a critical appraisal of gallbladder signs of acute cholecystitis in abdominal ultrasound; the rouleaux phenomenon vs. deep vein thrombosis or acute right strain in vascular ultrasound. CONCLUSIONS: Following some rules in technique and interpretation, and always integrating POCUS findings into the broader clinical context, most POCUS misdiagnosis can be avoided, and thus patients' safety can be enhanced. Being aware of a list of common pitfalls may help to avoid misdiagnoses. PMID- 27783381 TI - Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined etiology: a Groupe de Recherche en Reanimation Respiratoire en Onco-Hematologique (Grrr-OH) study. AB - BACKGROUND: Acute respiratory failure (ARF) is the most frequent complication in patients with hematological malignancies and is associated with high morbidity and mortality. ARF etiologies are numerous, and despite extensive diagnostic workflow, some patients remain with undetermined ARF etiology. METHODS: This is a post-hoc study of a prospective multicenter cohort performed on 1011 critically ill hematological patients. Relationship between ARF etiology and hospital mortality was assessed using a multivariable regression model adjusting for confounders. RESULTS: This study included 604 patients with ARF. All patients underwent noninvasive diagnostic tests, and a bronchoscopy and bronchoalveolar lavage (BAL) was performed in 155 (25.6%). Definite diagnoses were classified into four exclusive etiological categories: pneumonia (44.4%), non-infectious diagnoses (32.6%), opportunistic infection (10.1%) and undetermined (12.9%), with corresponding hospital mortality rates of 40, 35, 55 and 59%, respectively. Overall hospital mortality was 42%. By multivariable analysis, factors associated with hospital mortality were invasive pulmonary aspergillosis (OR 7.57 (95% CI 3.06-21.62); p < 0.005), use of invasive mechanical ventilation (OR 1.65 (95% CI 1.07-2.55); p = 0.02), a SOFA score >7 (OR 3.32 (95% CI 2.15-5.15); p < 0.005) and an undetermined ARF etiology (OR 2.92 (95% CI 1.71-5.07); p < 0.005). CONCLUSIONS: In patients with hematological malignancies and ARF, up to 13% remain with undetermined ARF etiology despite comprehensive diagnostic workup. Undetermined ARF etiology is independently associated with hospital mortality. Studies to guide second-line diagnostic strategies are warranted. ClinicalTrials.Gov NCT01172132. PMID- 27783382 TI - Short-term effects of neuromuscular blockade on global and regional lung mechanics, oxygenation and ventilation in pediatric acute hypoxemic respiratory failure. AB - BACKGROUND: Neuromuscular blockade (NMB) has been shown to improve outcome in acute respiratory distress syndrome (ARDS) in adults, challenging maintaining spontaneous breathing when there is severe lung injury. We tested in a prospective physiological study the hypothesis that continuous administration of NMB agents in mechanically ventilated children with severe acute hypoxemic respiratory failure (AHRF) improves the oxygenation index without a redistribution of tidal volume V T toward non-dependent lung zones. METHODS: Oxygenation index, PaO2/FiO2 ratio, lung mechanics (plateau pressure, mean airway pressure, respiratory system compliance and resistance), hemodynamics (heart rate, central venous and arterial blood pressures), oxygenation [oxygenation index (OI), PaO2/FiO2 and SpO2/FiO2], ventilation (physiological dead space-to-V T ratio) and electrical impedance tomography measured changes in end-expiratory lung volume (EELV), and V T distribution was measured before and 15 min after the start of continuous infusion of rocuronium 1 mg/kg. Patients were ventilated in a time-cycled, pressure-limited mode with pre-set V T. All ventilator settings were not changed during the study. RESULTS: Twenty-two patients were studied (N = 18 met the criteria for pediatric ARDS). Median age (25-75 interquartile range) was 15 (7.8-77.5) weeks. Pulmonary pathology was present in 77.3%. The median lung injury score was 9 (8-10). The overall median CoV and regional lung filling characteristics were not affected by NMB, indicating no ventilation shift toward the non-dependent lung zones. Regional analysis showed a homogeneous time course of lung inflation during inspiration, indicating no tendency to atelectasis after the introduction of NMB. NMB decreased the mean airway pressure (p = 0.039) and OI (p = 0.039) in all patients. There were no significant changes in lung mechanics, hemodynamics and EELV. Subgroup analysis showed that OI decreased (p = 0.01) and PaO2/FiO2 increased (p = 0.02) in patients with moderate or severe PARDS. CONCLUSIONS: NMB resulted in an improved oxygenation index in pediatric patients with AHRF. Distribution of V T and regional lung filling characteristics were not affected. PMID- 27783383 TI - Early Erythrolysis in the Hematoma After Experimental Intracerebral Hemorrhage. AB - Erythrolysis occurs in the clot after intracerebral hemorrhage (ICH), and the release of hemoglobin causes brain injury, but it is unclear when such lysis occurs. The present study examined early erythrolysis in rats. ICH rats had an intracaudate injection of 100 MUl autologous blood, and sham rats had a needle insertion. All rats had T2 and T2* magnetic response imaging (MRI) scanning, and brains were used for histology and CD163 (a hemoglobin scavenger receptor) and DARPP-32 (a neuronal marker) immunohistochemistry. There was marked heterogeneity within the hematoma on T2* MRI, with a hyperintense or isointense core and a hypointense periphery. Hematoxylin and eosin staining in the same animals showed significant erythrolysis in the core with the formation of erythrocyte ghosts. The degree of erythrolysis correlated with the severity of perihematomal neuronal loss. Perihematomal CD163 was increased by day 1 after ICH and may be involved in clearing hemoglobin caused by early hemolysis. Furthermore, ICH resulted in more severe erythrolysis, neuronal loss, and perihematomal CD163 upregulation in spontaneously hypertensive rats compared to Wistar-Kyoto rats. In conclusion, T2*MRI-detectable early erythrolysis occurred in the clot after ICH and activated CD163. Hypertension is associated with enhanced erythrolysis in the hematoma. PMID- 27783384 TI - The Patient Health Questionnaire-9 as a Screening Tool for Depression in Individuals with Type 2 Diabetes Mellitus: The Maastricht Study. AB - OBJECTIVES: To assess the psychometric properties and identify the best cutoff value of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in individuals with type 2 diabetes mellitus (T2DM). DESIGN: Observational population-based cohort study. SETTING: The Maastricht Study. PARTICIPANTS: Individuals with and without T2DM (mean age 58.6 +/- 8.1, 44.6% male) according to an oral glucose tolerance test (N = 2,997). MEASUREMENTS: Depressive disorder and depressive symptoms were measured using the Mini-International Neuropsychiatric Interview (MINI) as the reference and the PHQ-9. Cronbach alpha, Cohen's kappa and receiver operating characteristic (ROC) analyses were used. Differences in factorial structure between participants with and without T2DM were tested using multigroup confirmatory factor analysis. RESULTS: Based on the traditional PHQ-9 cutoff value, 133 (4.4%) participants had depressive symptoms (PHQ-9 score >=10). Internal consistency of the PHQ-9 was good (Cronbach alpha = 0.87 with T2DM, 0.82 without T2DM), the kappa of agreement between the PHQ-9 and the MINI was moderate (0.40 with T2DM, 0.43 without T2DM). Area under the ROC curve for the PHQ-9 was 0.87 in participants with T2DM and 0.88 in those without. A PHQ-9 cutoff score of 5 provided the best sensitivity (92.3%), with acceptable specificity (70.4%), for T2DM, similar to sensitivity and specificity in individuals without T2DM. Factor analysis suggested a similar two-factor structure in both groups (affective and somatic symptoms). CONCLUSION: Patient Health Questionnaire-9 performs well as a screening tool for depressive symptoms in individuals with and without T2DM based on the cutoff value of 5, indicating that the PHQ-9 can be used in two-stage screening in primary care to select individuals with T2DM for further psychological evaluation. PMID- 27783385 TI - From success to persistence: Identifying an evolutionary regime shift in the diverse Paleozoic aquatic arthropod group Eurypterida, driven by the Devonian biotic crisis. AB - Mass extinctions have altered the trajectory of evolution a number of times over the Phanerozoic. During these periods of biotic upheaval a different selective regime appears to operate, although it is still unclear whether consistent survivorship rules apply across different extinction events. We compare variations in diversity and disparity across the evolutionary history of a major Paleozoic arthropod group, the Eurypterida. Using these data, we explore the group's transition from a successful, dynamic clade to a stagnant persistent lineage, pinpointing the Devonian as the period during which this evolutionary regime shift occurred. The late Devonian biotic crisis is potentially unique among the "Big Five" mass extinctions in exhibiting a drop in speciation rates rather than an increase in extinction. Our study reveals eurypterids show depressed speciation rates throughout the Devonian but no abnormal peaks in extinction. Loss of morphospace occupation is random across all Paleozoic extinction events; however, differential origination during the Devonian results in a migration and subsequent stagnation of occupied morphospace. This shift appears linked to an ecological transition from euryhaline taxa to freshwater species with low morphological diversity alongside a decrease in endemism. These results demonstrate the importance of the Devonian biotic crisis in reshaping Paleozoic ecosystems. PMID- 27783387 TI - Testing the reproductive groundplan hypothesis in ants (Hymenoptera: Formicidae). AB - The evolution of complex societies with obligate reproductive division of labor represents one of the major transitions in evolution. In such societies, functionally sterile individuals (workers) perform many of fitness-relevant behaviors including allomaternal ones, without getting any direct fitness benefits. The question of how such worker division of labor has evolved remains controversial. The reproductive groundplan hypothesis (RGPH) offers a powerful proximate explanation for this evolutionary leap. The RGPH argues that the conserved genetic and endocrinological networks regulating fitness-relevant behavior (e g. foraging and brood care) in their solitary ancestors have become decoupled from actual reproduction in the worker caste and now generate worker behavioral phenotypes. However, the empirical support for this hypothesis remains limited to a handful of species making its general validity uncertain. In this study, we combine data from the literature with targeted sampling of key species and apply phylogenetically controlled comparative analysis to investigate if the key prediction of the RGPH, namely an association between allomaternal behavior and an allomaternal physiological state holds in the largest and most species rich clade of social insects, the ants. Our findings clearly support the RPGH as a general framework to understand the evolution of the worker caste and shed light on one of the major transition in evolutionary history. PMID- 27783386 TI - Characterization of resident lymphocytes in human pancreatic islets. AB - The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3+ T cells with a remarkable bias towards CD8+ cells. Central memory and effector memory phenotypes dominated within the CD8+ and CD4+ T cells and most CD8+ T cells were positive for CD69 and up to 50-70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45+ cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8+ T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes. PMID- 27783389 TI - Persistent Retinal Iron in Abusive Head Trauma. AB - Retinal hemosiderin deposition is a histologic indicator of sustained hemorrhage but cannot be used to precisely estimate the elapsed time since an episode of trauma. A 5-month-old male infant was admitted to hospital after acute deterioration. Examination revealed encephalopathy, subdural hematomas, and retinal hemorrhages consistent with abusive head trauma (AHT). At the age of 3, he was readmitted to hospital with spontaneous osteopenic fracture of the right femur. The patient deteriorated and died after unsuccessful resuscitation. Ophthalmopathological investigation showed atrophy of the retina and optic nerve and hemosiderin deposition in both eyes. Retinal hemosiderin deposition is currently generally assumed to disappear within 6-8 weeks after the occurrence of hemorrhage in AHT. This case report describes an infant with bilateral retinal hemosiderin depositions due to hemorrhages sustained from AHT occurring 32 months prior to death. Implications of this finding for the interpretation of retinal hemosiderin depositions in AHT are discussed. PMID- 27783388 TI - Innate and humoral recognition of the products of cell death: differential antigenicity and immunogenicity in lupus. AB - While apoptotic debris is believed to constitute the original antigenic insult in lupus (which is characterized by a time-dependent diversification of autoreactivity), whether such debris and autoantibodies specifically recognizing its constituents mediate differential effects on innate and humoral responses in lupus-prone mice is currently unknown. Apoptotic blebs (as opposed to cellular lysate) enhanced preferentially the maturation of dendritic cells (DCs) from bone marrow precursors drawn from lupus-prone mice. Murine, somatically mutated, apoptotic cell-reactive immunoglobulin (Ig)G monoclonal antibodies demonstrated enhanced recognition of DCs and also displayed a prominent lupus strain-specific bias in mediating DC maturation. Further, immunization of such antibodies specifically in lupus-prone mice resulted in widespread humoral autoreactivity; hypergammaglobulinaemia (a hallmark of systemic autoimmunity) was observed, accompanied by enhanced antibody titres to cellular moieties. Induced antibodies recognized antigens distinct from those recognized by the antibodies employed for immunization; in particular, nephritis-associated anti-double stranded (ds) DNA antibodies and neonatal lupus-associated anti-Ro60 antibodies were elicited by a non-dsDNA, non-Ro60 reactive antibody, and Sm was a favoured target. Further, only in lupus-prone mice did such immunization enhance the kinetics of humoral anti-self responses, resulting in the advanced onset of glomerulosclerosis. These studies reveal that preferential innate and humoral recognition of the products of cell death in a lupus milieu influence the indices associated with autoimmune pathology. PMID- 27783391 TI - Revascularization in Individuals Aged 90 and Older with Critical Lower Limb Ischemia. PMID- 27783390 TI - Age and Sex Distributions of Age-Related Biomarker Values in Healthy Older Adults from the Long Life Family Study. AB - OBJECTIVES: To determine reference values for laboratory tests in individuals aged 85 and older. DESIGN: Cross-sectional cohort study. SETTING: International. PARTICIPANTS: Long Life Family Study (LLFS) participants (N~5,000, age: range 25 110, median 67, 45% male). MEASUREMENTS: Serum biomarkers were selected based on association with aging-related diseases and included complete blood count, lipids (triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol), 25-hydroxyvitamin D2 and D3, vitamin D epi isomer, diabetes mellitus-related biomarkers (adiponectin, insulin, insulin-like growth factor 1, glucose, glycosylated hemoglobin, soluble receptor for advanced glycation endproduct), kidney disease-related biomarkers (albumin, creatinine, cystatin), endocrine biomarkers (dehydroepiandrosterone, sex-hormone binding globulin, testosterone), markers of inflammation (interleukin 6, high-sensitivity C-reactive protein, N-terminal pro b-type natriuretic peptide), ferritin, and transferrin. RESULTS: Of 38 measured biomarkers, 34 were significantly correlated with age. Summary statistics were generated for all biomarkers according to sex and 5-year age increments from 50 and up after excluding participants with diseases and treatments that were associated with biomarkers. A biomarker data set was also generated that will be useful for other investigators seeking to compare biomarker levels between studies. CONCLUSION: Levels of several biomarkers change with older age in healthy individuals. The descriptive statistics identified herein will be useful in future studies and, if replicated in additional studies, might also become useful in clinical practice. The availability of the reference data set will facilitate appropriate calibration of biomarkers measured in different laboratories. PMID- 27783392 TI - Graphic Depictions: Portrayals of Mental Illness in Video Games. AB - Although studies have examined portrayals of mental illness in the mass media, little attention has been paid to such portrayals in video games. In this descriptive study, the fifty highest-selling video games in each year from 2011 to 2013 were surveyed through application of search terms to the Wikia search engine, with subsequent review of relevant footage on YouTube. Depiction categories were then assigned based on the extent of portrayal and qualitative characteristics compared against mental illness stereotypes in cinema. Twenty three of the 96 surveyed games depicted at least one character with mental illness. Forty-two characters were identified as portraying mental illness, with most characters classified under a "homicidal maniac" stereotype, although many characters did not clearly reflect cinema stereotypes and were subcategorized based on the shared traits. Video games contain frequent and varied portrayals of mental illness, with depictions most commonly linking mental illness to dangerous and violent behaviors. PMID- 27783393 TI - Antipsychotics: Mortality Risk Themselves? PMID- 27783394 TI - Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis. AB - NKG2D (KLRK1) is a C-type lectin receptor present on natural killer (NK) cells, gammadelta, CD8+ and CD4+ T cells. Upon ligand binding, NKG2D mediates activatory and co-stimulatory signals to NK cells and activated CD4+ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0.03, odds ratio (OR) = 2.44, 95% confidence interval (CI) = 1.09-5.98 and 10 versus 4%, Pc = 0.04, OR = 2.45, 95% CI = 1.05-6.39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0.03, OR = 0.41, 95% CI = 0.17-0.91 and Pc = 0.04, OR = 0.41, 95% CI = 0.16-0.96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G-C-A-G-A-T-C-C was higher in patients than in controls (12 versus 8%, P = 0.04, OR = 1.61, 95% CI = 1.01-2.55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA. PMID- 27783395 TI - Age Differences in Sequential Speech Production: Articulatory and Physiological Factors. AB - OBJECTIVES: To explore age differences in speech production in relation to orofacial physiology. DESIGN: Cross-sectional quasi-experimental group study. SETTING: General community. PARTICIPANTS: Physically and cognitively healthy volunteers recruited from the community (N = 30), including 15 young (18-39) and 15 older (66-85) adults. MEASUREMENTS: Accuracy and speech rate were calculated during the production of sequences of syllables containing oral vowels, nasal vowels, or both. Lip and tongue muscular strength, muscular endurance, and tactile sensitivity were also measured. RESULTS: Older adults had a slower speech rate than younger adults and greater difficulty articulating nasal vowels. Analyses revealed that age-related decline in lip endurance is associated with decline in accuracy during speech production. CONCLUSION: Older adults are not just slower than younger adults, they also exhibit specific articulatory difficulties. Although many physiological changes in orofacial functions occur in aging, only muscular endurance of the lips is related to age-related differences in speech production. This information is important for the development of speech interventions targeting older adults with speech motor disorders. PMID- 27783397 TI - After 50 years: Future challenges in publishing cancer research. PMID- 27783396 TI - Frailty Levels in Residential Aged Care Facilities Measured Using the Frailty Index and FRAIL-NH Scale. AB - OBJECTIVES: To compare the FRAIL-NH scale with the Frailty Index in assessing frailty in residential aged care facilities. DESIGN: Cross-sectional. SETTING: Six Australian residential aged care facilities. PARTICIPANTS: Individuals aged 65 and older (N = 383, mean aged 87.5 +/- 6.2, 77.5% female). MEASUREMENTS: Frailty was assessed using the 66-item Frailty Index and the FRAIL-NH scale. Other measures examined were dementia diagnosis, level of care, resident satisfaction with care, nurse-reported resident quality of life, neuropsychiatric symptoms, and professional caregiver burden. RESULTS: The FRAIL-NH scale was significantly associated with the Frailty Index (correlation coefficient = 0.81, P < .001). Based on the Frailty Index, 60.8% of participants were categorized as frail and 24.4% as most frail. Based on the FRAIL-NH, 37.5% of participants were classified as frail and 35.9% as most frail. Women were assessed as being frailer than men using both tools (P = .006 for FI; P = .03 for FRAIL-NH). Frailty Index levels were higher in participants aged 95 and older (0.39 +/- 0.13) than in those aged younger than 85 (0.33 +/- 0.13; P = .008) and in participants born outside Australia (0.38 +/- 0.13) than in those born in Australia (0.34 +/- 0.13; P = .01). Both frailty tools were associated with most characteristics that would indicate higher care needs, with the Frailty Index having stronger associations with all of these measures. CONCLUSION: The FRAIL-NH scale is a simple and practical method to screen for frailty in residential aged care facilities. PMID- 27783398 TI - Genome Editing Techniques and Their Therapeutic Applications. AB - Fueled by advances in the field of genetics, the methods available to edit DNA sequences in living cells have continued to develop steadily. These technologies directly impact the fields of gene and cell therapy, where changes in the DNA sequence of target cells offer a route to correct genetic diseases and manipulate disorders like cancer. We review here the expanding menu of genome editing techniques and how they are being applied to therapeutic targets. The methods encompass a myriad of approaches to modify the covalent structure of DNA, including the targeted creation of double-strand breaks that can catalyze genomic changes, as well as the use of retroviruses and transposons to mediate gene addition, recombinases for sequence-specific gene addition and deletion, and base repair for direct sequence changes. The continued growth of the exciting field of genome editing is opening new possibilities for therapeutic intervention. PMID- 27783399 TI - Validation of prostate-specific antigen laboratory values recorded in Surveillance, Epidemiology, and End Results registries. AB - BACKGROUND: Researchers have used prostate-specific antigen (PSA) values collected by central cancer registries to evaluate tumors for potential aggressive clinical disease. An independent study collecting PSA values suggested a high error rate (18%) related to implied decimal points. To evaluate the error rate in the Surveillance, Epidemiology, and End Results (SEER) program, a comprehensive review of PSA values recorded across all SEER registries was performed. METHODS: Consolidated PSA values for eligible prostate cancer cases in SEER registries were reviewed and compared with text documentation from abstracted records. Four types of classification errors were identified: implied decimal point errors, abstraction or coding implementation errors, nonsignificant errors, and changes related to "unknown" values. RESULTS: A total of 50,277 prostate cancer cases diagnosed in 2012 were reviewed. Approximately 94.15% of cases did not have meaningful changes (85.85% correct, 5.58% with a nonsignificant change of <1 ng/mL, and 2.80% with no clinical change). Approximately 5.70% of cases had meaningful changes (1.93% due to implied decimal point errors, 1.54% due to abstract or coding errors, and 2.23% due to errors related to unknown categories). Only 419 of the original 50,277 cases (0.83%) resulted in a change in disease stage due to a corrected PSA value. CONCLUSIONS: The implied decimal error rate was only 1.93% of all cases in the current validation study, with a meaningful error rate of 5.81%. The reasons for the lower error rate in SEER are likely due to ongoing and rigorous quality control and visual editing processes by the central registries. The SEER program currently is reviewing and correcting PSA values back to 2004 and will re-release these data in the public use research file. Cancer 2017;123:697-703. (c) 2016 American Cancer Society. PMID- 27783400 TI - Anticipatory Eye Movements While Watching Continuous Action Across Shots in Video Sequences: A Developmental Study. AB - Eye movements were recorded as 12-month-olds (n = 15), 4-year-olds (n = 17), and adults (n = 19) watched a 15-min video with sequences of shots conveying continuous motion. The central question was whether, and at what age, viewers anticipate the reappearance of objects following cuts to new shots. Adults were more likely than younger viewers to make anticipatory eye movements. Four-year olds responded to transitions more slowly and tended to fixate the center of the screen. Infants' eye movement patterns reflected a tendency to react rather than anticipate. Findings are consistent with the hypothesis that adults integrate content across shots and understand how space is represented in edited video. Results are interpreted with respect to a developing understanding of film editing due to experience and cognitive maturation. PMID- 27783402 TI - Reply to "Antipsychotics: Mortality Risk Themselves?" PMID- 27783401 TI - Shared Risk Factors for Constipation, Fecal Incontinence, and Combined Symptoms in Older U.S. Adults. AB - OBJECTIVES: To estimate the prevalence of constipation, fecal incontinence (FI), and combined symptoms and to identify shared factors associated with bowel symptoms in older U.S. men and women DESIGN: Population-based cross-sectional study. SETTING: National Health and Nutrition Examination Survey (2005-2010). PARTICIPANTS: Women and men aged 50 and older. MEASUREMENTS: Constipation was defined as hard stool consistency on the validated Bristol Stool Form Scale or stool frequency of fewer than three bowel movements per week. FI was defined as at least monthly loss of solid, liquid, or mucus stool. Combined symptoms was defined as constipation and FI. Multinomial multivarible models adjusted for age, race, socioeconomic status, education, self-rated health, depression, impairments in activities of daily living, and number of comorbidities. RESULTS: Women (n = 3,078) reported higher prevalence of bowel symptoms than men (constipation 11.8% vs 4.7%%, FI 11.2% vs 8.6%, combined symptoms 1.4% vs 0.4%). In adjusted models, women had greater odds of having constipation (odds ratio (OR) = 3.0, 95% confidence interval (CI) = 2.3-3.8), FI (OR = 1.4, 95% CI = 1.1-1.8), and combined symptoms (OR = 4.6, 95% CI = 2.0-10.2) than men. Shared risk factors included poor self-rated health and depression symptoms (constipation: OR = 1.8, 95% CI = 1.4-2.4 and OR = 1.8, 95% CI = 1.0-3.2; FI: OR = 1.6, 95% CI = 1.2-2.2 and OR = 2.3 95% CI = 1.4-3.6; combined symptoms: OR = 2.6 95% CI = 1.5-4.8 and OR = 4.6, 95% CI = 1.3-16.4). CONCLUSION: When defining constipation and FI using validated instruments, women had a much higher prevalence of constipation than men, whereas men had a higher prevalence of FI than constipation. Shared risk factors reflect the negative effect that bowel symptoms have on quality of life. PMID- 27783404 TI - Healed Depressed Parasagittal Skull Fractures-A Feature of Archaic Australian Aboriginal Remains. AB - The skeletal remains of eight Australian Aboriginals with healed depressed skull fractures were examined. Male:female ratio 5:3; age range 20-60 yrs. Burial dates by 14 C dating in three cases were 500 years BP (n = 2) and 1300 BP. There were 13 healed depressed skull fractures manifested by shallow indentations of cortical bone and thinning of diploe, with no significant disturbance of the inner skull tables. Nine (69%) were located within 35 mm of the sagittal suture/midline. These lesions represent another acquired feature that might be helpful in suggesting that a skull is from a tribal Aboriginal individual and may be particularly useful if the remains are represented by only fragments of calvarium. While obviously not a finding specific to this population, these healed injuries would be consistent with the possible results of certain types of conflict behavior reported in traditional Aboriginal groups that involved formalized inflicted blunt head trauma. PMID- 27783403 TI - Fear of Falling in Older Mexican Americans: A Longitudinal Study of Incidence and Predictive Factors. AB - OBJECTIVES: To determine predictors of fear of falling in older Mexican Americans over time. DESIGN: Longitudinal study. SETTING: Community-dwelling residents throughout California, Colorado, New Mexico, Arizona, and Texas. PARTICIPANTS: Community-dwelling Mexican Americans aged 72 and older participating in the Hispanic Established Populations for the Epidemiologic Study of the Elderly from 2000-01 to 2010-11 (N = 1,682). MEASUREMENTS: Fear of falling was measured at baseline and at each subsequent wave. Baseline demographic and clinical variables included social support, fall history, depression symptoms, Mini-Mental State Examination (MMSE) score, activity of daily living (ADL) and instrumental ADL (IADL) limitations, and chronic health conditions. RESULTS: Nine hundred fifty three (56.7%) subjects reported fear of falling at baseline, 262 of whom reported severe fear of falling. The predictors of reporting any fear of falling over time included female sex, frequent familial interaction, depression, chronic health conditions, IADL limitations, higher MMSE score, and three or more falls in the last 12 months. Predictors of severe fear of falling included older age, female sex, married, depressive symptoms, chronic health conditions, IADL limitations, higher MMSE score, and fall history. Protective factors included frequent friend interaction and higher levels of education. CONCLUSION: Fear of falling is prevalent in older Mexican-American adults. The presence of friends nearby was shown to be protective against, whereas the presence of family nearby was shown to be predictive of fear of falling. PMID- 27783405 TI - A novel library-independent approach based on high-throughput cultivation in Bioscreen and fingerprinting by FTIR spectroscopy for microbial source tracking in food industry. AB - : Microbiological source tracking (MST) for food industry is a rapid growing area of research and technology development. In this paper, a new library-independent approach for MST is presented. It is based on a high-throughput liquid microcultivation and FTIR spectroscopy. In this approach, FTIR spectra obtained from micro-organisms isolated along the production line and a product are compared to each other. We tested and evaluated the new source tracking approach by simulating a source tracking situation. In this simulation study, a selection of 20 spoilage mould strains from a total of six genera (Alternaria, Aspergillus, Mucor, Paecilomyces, Peyronellaea and Phoma) was used. The simulation of the source tracking situation showed that 80-100% of the sources could be correctly identified with respect to genus/species level. When performing source tracking simulations, the FTIR identification diverged for Phoma glomerata strain in the reference collection. When reidentifying the strain by sequencing, it turned out that the strain was a Peyronellaea arachidicola. The obtained results demonstrated that the proposed approach is a versatile tool for identifying sources of microbial contamination. Thus, it has a high potential for routine control in the food industry due to low costs and analysis time. SIGNIFICANCE AND IMPACT OF THE STUDY: The source tracking of fungal contamination in the food industry is an important aspect of food safety. Currently, all available methods are time consuming and require the use of a reference library that may limit the accuracy of the identification. In this study, we report for the first time, a library-independent FTIR spectroscopic approach for MST of fungal contamination along the food production line. It combines high-throughput microcultivation and FTIR spectroscopy and is specific on the genus and species level. Therefore, such an approach possesses great importance for food safety control in food industry. PMID- 27783406 TI - Episodic weakness and Charcot-marie-tooth disease due to a mitochondrial MT-ATP6 mutation. AB - INTRODUCTION: Episodic muscle weakness is the hallmark of a heterogeneous group of disorders known as periodic paralysis. A majority are due to single nucleotide mutations causing membrane depolarization. METHODS: We report 2 family members with chronic, slowly progressive, distal axonal neuropathy, or Charcot-Marie Tooth disease type 2 (CMT2) and episodic weakness resembling periodic paralysis. RESULTS: Next generation sequencing (NGS) identified a mitochondrial MT-ATP6 mutation m.9185T>C (p.Leu220Pro) in both patients, consistent with a previous report of an association with this phenotype. The episodic weakness has been responsive to acetazolamide therapy for a few decades. By contrast, the underlying axonal neuropathy is quite progressive despite treatment with acetazolamide. CONCLUSIONS: Mitochondrial DNA mutations should be considered in patients with a history of episodic weakness and axonal inherited neuropathy (CMT2). The episodic weakness is responsive to acetazolamide therapy, and electrophysiological testing for periodic paralysis with a long exercise protocol is negative in these cases. Muscle Nerve 55: 922-927, 2017. PMID- 27783407 TI - Efficient PKC inhibitor screening achieved using a quantitative CE-LIF assay. AB - An assay for protein kinase C delta (PKCdelta) activity based on the quantification of a synthetic substrate using capillary electrophoresis with laser-induced fluorescence detection was developed. The peptides labeled with fluorescein isothiocyanate F-ERK (where ERK is extracellular signal-regulated kinase) and the phosphorylated form, P-F-ERK, were utilized for the method development and validation. The migration time of F-ERK and P-F-ERK were 6.3 +/- 0.1 and 8.7 +/- 0.2 min, respectively. LOD and LOQ values of F-ERK were 2 and 6 ng/mL and those of P-F-ERK were 4 and 12 ng/mL. The correlation coefficients obtained from two standard curves were approximately 0.99. The reproducibility and accuracy of the method for F-ERK ranged 1.5-4.7 and 86-109%, respectively, and those for P-F-ERK were 1.6-6.1 and 93-109%, respectively. The activity of PKCdelta was studied in vitro using the human gastric cancer cell line MKN-1. The use of PKCdelta inhibitor candidates, including Go6983, bisindolylmaleimide II, staurosporine, and rottlerin in the assay resulted in IC50 values of 50 nM, 15 nM, 795 nM, and 4 MUM, respectively. Comparison of our assay with a commercial PKC kit revealed that our assay is more adaptable to differing enzyme isoforms. This method has potential for high throughput screening for kinase inhibitors as part of a drug discovery program. PMID- 27783408 TI - Update on: Shigella new serogroups/serotypes and their antimicrobial resistance. AB - Shigellosis represents a major burden of disease in developing countries. A low infectious dose allows the disease to be spread effectively. Although shigellosis is mostly a self-limiting disease, antibiotics are recommended to reduce deaths, disease symptoms and organism-shedding time. However, in India, antimicrobial resistance among the genus Shigella is more common than among any other enteric bacteria. Notably, new serotypes or subserotypes in Shigella are reported from various parts of the world. Identification of new subserotypes of Shigella spp. is becoming a major issue as these strains are nontypeable by conventional serotyping. The commercially available antisera may not cover all possible epitopes of the O lipopolysaccharide antigen of Shigella serotypes. Therefore, molecular methods which most closely approach the resolution of full serotyping are necessary to identify such strains. In addition, the knowledge of a prevalent serotype in various geographic regions may assist in formulating strategies such as the development of a vaccine to prevent infection especially when the immunity to disease is serotype specific, and to understand the disease burden caused by new Shigella serotypes. PMID- 27783411 TI - Recent advances in CE-MS coupling: Instrumentation, methodology, and applications. AB - This review focuses on the latest development of microseparation electromigration methods in capillaries and microfluidic devices coupled with MS for detection and identification of important analytes. It is a continuation of the review article on the same topic by Kleparnik (Electrophoresis 2015, 36, 159-178). A wide selection of 161 relevant articles covers the literature published from June 2014 till May 2016. New improvements in the instrumentation and methodology of MS interfaced with capillary or microfluidic versions of zone electrophoresis, isotachophoresis, and isoelectric focusing are described in detail. The most frequently implemented MS ionization methods include electrospray ionization, matrix-assisted desorption/ionization and inductively coupled plasma ionization. Although the main attention is paid to the development of instrumentation and methodology, representative examples illustrate also applications in the proteomics, glycomics, metabolomics, biomarker research, forensics, pharmacology, food analysis, and single-cell analysis. The combinations of MS with capillary versions of electrochromatography, and micellar electrokinetic chromatography are not included. PMID- 27783412 TI - Emergency uncross-matched blood transfusions in a tertiary neonatal unit. AB - AIM: To determine the neonatal incidence, indications and outcomes following transfusions with emergency uncross-matched O-negative blood. METHODS: A five year retrospective review in a single tertiary neonatal unit was conducted. The blood transfusion laboratory's database was analysed for all infants who had received an emergency released blood transfusion (ERBT) between January 2010 and December 2014. RESULTS: We calculated a total ERBT rate of 0.91 per 1000 live births (39/42 657) and a rate of 0.43 per 1000 in infants >34 weeks' gestation (18/41 637). A rate of 0.14 per 1000 births (6/42 657) received an ERBT as part of newborn stabilisation despite almost half of our infant cohort having intrapartum haemorrhages (n = 18, 46%). One-third (13/39) of all infants who were transfused died. Outcome varied depending on underlying aetiology, gestation and birthweight. The highest mortality was in preterm infants weighing <1000 g, of whom 70% died. CONCLUSION: This study establishes an ERBT rate of <1 per 1000 births, and 0.14 per 1000 infants received an ERBT as part of newborn delivery room stabilisation. ERBTs are associated with a high mortality rate. This study highlights the need for further research and guidelines that clarify the role of ERBTs in newborn stabilisations. PMID- 27783409 TI - Malondialdehyde-Acetaldehyde-Adducted Surfactant Protein Alters Macrophage Functions Through Scavenger Receptor A. AB - BACKGROUND: Reactive aldehydes such as acetaldehyde and malondialdehyde generated as a result of alcohol metabolism and cigarette smoke exposure lead to the formation of malondialdehyde-acetaldehyde-adducted proteins (MAA adducts). These aldehydes can adduct to different proteins such as bovine serum albumin and surfactant protein A or surfactant protein D (SPD). Macrophages play an important role in innate immunity, but the effect of MAA adducts on macrophage function has not yet been examined. Because macrophage scavenger receptor A (SRA; CD204) mediates the uptake of modified proteins, we hypothesized that the effects of MAA modified proteins on macrophage function are primarily mediated through SRA. METHODS: We tested this hypothesis by exposing SPD-MAA to macrophages and measuring functions. SPD-MAA treatment significantly stimulated pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) release in the macrophage cell line, RAW 264.7. RESULTS: A significant reduction in phagocytosis of zymosan particles was also observed. SPD-MAA stimulated a significant dose-dependent increase in TNF-alpha and interleukin (IL)-6 release from peritoneal macrophages (PMs) of wild-type (WT) mice. But significantly less TNF-alpha and IL-6 were released from PMs of SRA-/- mice. We observed a significant reduction in phagocytosis of zymosan particles in PMs from WT mice treated with SPD-MAA. No further SPD-MAA-induced reduction was seen in PMs from SRA-/- mice. SPD-MAA treatment significantly increased SRA mRNA expression, but had no effect on surface receptor protein expression. Protein kinase C alpha inhibitor and NF kappaB inhibitor significantly reduced pro-inflammatory cytokine release in response to SPD-MAA. CONCLUSIONS: In conclusion, our data demonstrate that SRA is important for MAA-adducted protein-mediated effect on macrophage functions. PMID- 27783410 TI - Survey of noninvasive respiratory support practices in Canadian neonatal intensive care units. AB - AIM: To evaluate practice variation with respect to noninvasive respiratory support (NRS) use across Canadian neonatal intensive care units (NICUs). METHODS: A web-based survey was sent to all site investigators of the 30 level 3 NICUs participating in the Canadian Neonatal Network. The survey inquired about the use of five commonly described NRS modes. In addition, the presence and adherence to local guidelines were ascertained. Descriptive analyses were performed to identify variations in practice. RESULTS: In total, 28 (93%) of the 30 tertiary NICUs responded to the survey. Continuous positive airway pressure (CPAP) was employed universally (100%). High-flow nasal cannula (HFNC) was used in 89% of NICUs, biphasic CPAP in 79% and nasal intermittent positive pressure ventilation (NIPPV) in 54%, and nasal high-frequency ventilation was used in 18% of units. Only 61% of all NRS use was guided by local policies, with the lowest being for HFNC (36%). There was a wide range of settings employed and interfaces used for all NRS modes. CONCLUSION: There are significant practice variations in NRS use across Canadian NICUs. Further research is needed to evaluate the significance in relation to pulmonary outcomes to determine optimal NRS strategies. PMID- 27783413 TI - The Issue of Age Estimation in a Modern Skeletal Population: Are Even the More Modern Current Aging Methods Satisfactory for the Elderly? AB - The main idea behind age assessment in adults is related to the analysis of the physiological degeneration of particular skeletal structures with age. The main issues with these procedures are due to the fact that they have not been tested on different modern populations and in different taphonomic contexts and that they tend to underestimate the age of older individuals. The purpose of this study was to test the applicability and the reliability of these methods on a contemporary population of skeletal remains of 145 elderly individuals of known sex and age. The results show that, due to taphonomic influences, some skeletal sites showed a lower survival. Therefore, the methods with the highest percentage of applicability were Lovejoy (89.6%) and Rouge-Maillart (81.3%), followed by Suchey-Brooks (59.3%), and those with the lowest percentage of applicability were Beauthier (26.2%) and Iscan (22.7%). In addition, this research has shown how for older adults the study of both acetabulum and auricular surface may be more reliable for aging. This is also in accordance with the fact that auricular surface and the acetabulum are the areas more frequently surviving taphonomic insult. PMID- 27783414 TI - In reference to Comparative Study on the effects of EGF and bFGF on the healing of human large traumatic perforations of the tympanic membrane. PMID- 27783415 TI - The anti-convulsants lacosamide, lamotrigine, and rufinamide reduce myotonia in isolated human and rat skeletal muscle. AB - INTRODUCTION: In myotonia congenita, loss of ClC-1 Cl- channel function results in skeletal muscle hyperexcitability and myotonia. Anti-myotonic treatment has typically targeted the voltage-gated sodium channel in skeletal muscle (Nav1.4). In this study we explored whether 3 sodium channel-modulating anti-epileptics can reduce myotonia in isolated rat and human muscle. METHODS: Dissected muscles were rendered myotonic by ClC-1 channel inhibition. The ability of the drugs to suppress myotonia was then assessed from subclinical to maximal clinical concentrations. Drug synergy was determined using isobole plots. RESULTS: All drugs were capable of abolishing myotonia in both rat and human muscles. Lamotrigine and rufinamide completely suppressed myotonia at submaximal clinical concentrations, whereas lacosamide had to be raised above the maximal clinical concentration to suppress myotonia completely. A synergistic effect of lamotrigine and rufinamide was observed. CONCLUSION: These findings suggest that lamotrigine and rufinamide could be considered for anti-myotonic treatment in myotonia congenita. Muscle Nerve 56: 136-142, 2017. PMID- 27783416 TI - One- or two-week interval for variceal banding after bleeding: Which one to choose? PMID- 27783417 TI - Reply. PMID- 27783418 TI - The interval of endoscopic variceal ligation: The shorter the better? PMID- 27783419 TI - Effects of compression stockings on ankle muscle H-reflexes during standing. AB - INTRODUCTION: Wearing compression stockings (CS) may improve postural stability through additional cutaneous feedback. The aim of this study was to further determine how wearing CS could influence spinal excitability by investigating ankle muscle H-reflexes. METHODS: Fifteen subjects were asked to stand barefoot on a rigid floor with their eyes open. H-reflex amplitude was measured in the soleus (SOL), fibularis longus (FL), and tibialis anterior (TA) muscles, with and without CS. Concomitant M-waves and baseline electromyographic activity (EMG) were monitored. RESULTS: Baseline EMG activity and concomitant M-wave amplitude remained stable across conditions in all tested muscles. Although CS did not affect the H-reflex in the SOL (+0.8 +/- 19.2%; P = 0.77) and FL (-10.0+/- 33.2%; P = 0.28) muscles, the TA H-reflex was significantly depressed (-21.9% +/- 24.0%; P = 0.03). CONCLUSIONS: These results suggest decreased spinal motoneuron excitability and/or increased presynaptic inhibition of Ia-afferent terminals through increased cutaneous inputs provided by CS while standing. Muscle Nerve 55: 596-598, 2017. PMID- 27783420 TI - Comment on neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment. PMID- 27783421 TI - Gastrointestinal Functionality of Aquatic Animal (Oreochromis niloticus) Carcass in Water Allows Estimating Time of Death. AB - Postmortem changes have been previously studied in some terrestrial animal models, but no prior information is available on aquatic species. Gastrointestinal functionality was investigated in terms of indices, protein concentration, digestive enzyme activity, and scavenging activity, in an aquatic animal model, Nile tilapia, to assess the postmortem changes. Dead fish were floated indoors, and samples were collected within 48 h after death. Stomasomatic index decreased with postmortem time and correlated positively with protein, pepsin-specific activity, and stomach scavenging activity. Also intestosomatic index decreased significantly and correlated positively with protein, specific activity of trypsin, chymotrypsin, amylase, lipase, and intestinal scavenging activity. In their postmortem changes, the digestive enzymes exhibited earlier lipid degradation than carbohydrate or protein. The intestine changed more rapidly than the stomach. The findings suggest that the postmortem changes of gastrointestinal functionality can serve as primary data for the estimation of time of death of an aquatic animal. PMID- 27783422 TI - Thoracic aortic rupture in horses. AB - The aorta can rupture at the aortic root or aortic arch. In most breeds, the aortic root is the likely site and rupture leads to aortocardiac fistula with communication between the aorta and the right atrium, right ventricle and/or the interventricular septum. There is a high prevalence of aortic rupture in young Friesian horses and rupture occurs at the aortic arch with pseudoaneurysm and potentially aortopulmonary fistulation. Echocardiographic and post-mortem techniques must be adapted to identify aortic arch rupture that is not generally identified with standard approaches. Given the narrow genetic base of the Friesian breed and the significant differences found in extracellular matrix composition and metabolism between Friesians and Warmbloods, genetic factors are likely to contribute to the condition in the Friesian breed. PMID- 27783423 TI - Pampered inside, pestered outside? Differences and similarities between plants growing in controlled conditions and in the field. AB - I. 839 II. 839 III. 841 IV. 845 V. 847 VI. 848 VII. 849 VIII. 851 851 852 References 852 Appendix A1 854 SUMMARY: Plant biologists often grow plants in growth chambers or glasshouses with the ultimate aim to understand or improve plant performance in the field. What is often overlooked is how results from controlled conditions translate back to field situations. A meta-analysis showed that lab-grown plants had faster growth rates, higher nitrogen concentrations and different morphology. They remained smaller, however, because the lab plants had grown for a much shorter time. We compared glasshouse and growth chamber conditions with those in the field and found that the ratio between the daily amount of light and daily temperature (photothermal ratio) was consistently lower under controlled conditions. This may strongly affect a plant's source : sink ratio and hence its overall morphology and physiology. Plants in the field also grow at higher plant densities. A second meta-analysis showed that a doubling in density leads on average to 34% smaller plants with strong negative effects on tiller or side-shoot formation but little effect on plant height. We found the r2 between lab and field phenotypic data to be rather modest (0.26). Based on these insights, we discuss various alternatives to facilitate the translation from lab results to the field, including several options to apply growth regimes closer to field conditions. PMID- 27783424 TI - Direct electric current modifies important cellular aspects and ultrastructure features of Candida albicans yeasts: Influence of doses and polarities. AB - Available treatments against human fungal pathogens present high levels of resistance, motivating the development of new antifungal therapies. In this context, the present work aimed to analyze direct electric current (DC) antifungal action, using an in vitro apparatus equipped with platinum electrodes. Candida albicans yeast cells were submitted to three distinct conditions of DC treatment (anodic flow-AF; electroionic flow-EIF; and cathodic flow-CF), as well as different charges, ranging from 0.03 to 2.40 C. Our results indicated C. albicans presented distinct sensibility depending on the DC intensity and polarity applied. Both the colony-forming unit assay and the cytometry flow with propidium iodide indicated a drastic reduction on cellular viability after AF treatment with 0.15 C, while CF- and EIF-treated cells stayed alive when DC doses were increased up to 2.40 C. Additionally, transmission electron microscopy revealed important ultrastructural alterations in AF-treated yeasts, including cell structure disorganization, ruptures in plasmatic membrane, and cytoplasmic rarefaction. This work emphasizes the importance of physical parameters (polarity and doses) in cellular damage, and brings new evidence for using electrotherapy to treat C. albicans pathology process. Bioelectromagnetics. 38:95-108, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27783425 TI - The laparoscopically harvested omentum as a free flap for autologous breast reconstruction. AB - BACKGROUND: In autologous breast reconstruction, abdominal based flaps are by far the most common choice from the wide range of free flaps available. In selected cases, a laparoscopically harvested omental free flap (LHOFF) can be used. Patient satisfaction has not been reported until now. In this article, we report our experience using LHOFF in breast reconstruction including our technique, patient satisfaction, and donor/recipient site complications. PATIENTS AND METHODS: Between 2007 and 2014, six patients underwent autologous breast reconstruction with LHOFF. Four patients had undergone radical mastectomy and two patient developed prosthesis complications after lumpectomy and breast augmentation. The omentum was harvested laparoscopically. The gastroepiploic vessels were anastomosed to the internal mammary vessels. A retrospective chart review was performed to retrieve surgical data. All the patients completed a questionnaire about their outcome. RESULTS: Mean weight of the omentum was 224 g. There were no flap failures. Two patients required a second surgical procedure due to complications. In one patient, a salvage procedure was required due to a venous thrombosis, whereas in the other, there was necrosis of the skin flap. No abdominal complications or volume loss occurred. Mean follow-up was 30.5 months. The aesthetic results were very satisfactory with minimal scars and good breast volume. CONCLUSION: Autologous breast reconstruction using an LHOFF can be used effectively in selected cases. The aesthetic results are pleasing with minimal scarring, good volume, and a soft, natural feeling breast. PMID- 27783426 TI - In reference to endoscopic-assisted transmastoid decompression of petrous apex cholesterol granuloma. PMID- 27783427 TI - A european multicenter study evaluating the flex robotic system in transoral robotic surgery. AB - OBJECTIVES/HYPOTHESIS: To evaluate the application of the Flex Robotic System in transoral robotic surgery (TORS). STUDY DESIGN: Multicenter, prospective, open label, single-armed clinical study. METHODS: A prospective clinical follow-up multicenter study was performed from July 2014 to October 2015 assessing the safety and efficacy of the Medrobotics Flex Robotic System for access and visualization of the oropharynx, hypopharynx, and larynx as well as for resection of benign and malignant lesions. A total of 80 patients were enrolled. Access and visualization of five anatomic subsites (base of tongue, palatine tonsil area, epiglottis, posterior pharyngeal wall, and false vocal cords) were individually graded by the surgeon. Setup times, access and visualization times, surgical results, and adverse events were documented. RESULTS: The relevant anatomic structures could be exposed and visualized properly in 75 patients, who went on to have a surgical procedure performed with the Flex Robotic System. Access and visualization of the palatine tonsil area, posterior pharyngeal wall, epiglottis, and posterior pharyngeal wall were excellent. However, false vocal cords and vocal cords were more difficult to expose. Seventy-two patients were treated successfully with the Flex Robotic System. There were no serious or unanticipated device-related adverse events caused by the Flex Robotic System. CONCLUSIONS: Lesions in the oropharynx, hypopharynx, and larynx could be successfully resected with the Flex Robotic System, specifically developed for TORS. Our study provides evidence that the Flex Robotic System is a safe and effective tool in TORS. Laryngoscope, 2016 127:391-395, 2017. PMID- 27783428 TI - New curricular design in biostatistics to prepare residents for an evidence-based practice and lifelong learning education: a pilot approach. AB - AIM: To develop, implement and evaluate an innovative curriculum in biostatistics in response to the need to foster critical thinking in graduate healthcare education for evidence-based practice and lifelong learning education. METHODOLOGY: The curriculum was designed for first-year residents in a postgraduate endodontic programme using a six-step approach to curriculum development to provide sufficient understanding to critically evaluate biomedical publications, to design the best research strategy to address a specific problem and to analyse data by appropriate statistical test selection. Multiple learner centred instructional methods and formative and summative assessments (written tasks, simulation exercises, portfolios and pre-post knowledge tests) were used to accomplish the learning outcomes. The analysis of the achievement of the group of students and a satisfaction survey for further feedback provided to the residents at the end of the curriculum were used for curriculum evaluation. RESULTS: All residents demonstrated competency at the end of the curriculum. The correct answer rate changed from 36.9% in the pre-test to 79.8% in the post-test. No common errors were detected in the rest of the assessment activities. All participants completed the questionnaire demonstrating high satisfaction for each independent category and with the overall educational programme, instruction and course in general. CONCLUSIONS: The curriculum was validated by the assessment of students' performance and a satisfaction survey, offering an example of a practical approach to the teaching of statistics to prepare students for a successful evidence-based endodontic practice and lifelong learning education as practicing clinicians. PMID- 27783429 TI - Ultrasound lineal measurements predict ventricular volume in posthaemorrhagic ventricular dilatation in preterm infants. AB - AIM: Posthaemorrhagic ventricular dilatation (PHVD) is monitored by conventional two-dimensional ultrasound (2DUS). The aims of this study were to determine the volume of the lateral ventricles using three-dimensional ultrasound (3DUS) in preterm infants with PHVD and to evaluate the relationship between volume and linear measurements. METHODS: Serial 2DUSs and 3DUSs were performed on preterm infants with PHVD admitted to the neonatal intensive care unit at Puerta del Mar Hospital, Cadiz, Spain, from January 2013 to December 2014. The ventricular index, anterior horn width and thalamo-occipital distance were used as ventricular lineal measurements. Ventricular volume was calculated offline. RESULTS: Serial ultrasounds from seven preterm infants were measured. Each linear measurement was significantly associated with volume, and an equation was obtained through a significant multilevel mixed-effects lineal regression model: ventricular volume (cm3 ) = -11.02 + 0.668*VI + 0.817*AHW + 0.256*TOD. Intra observer and interobserver agreement was excellent with an intraclass correlation coefficient of 0.99. CONCLUSION: Lateral ventricular volumes of preterm infants with PHVD could be reliably determined using 3DUS. Ventricular volume could be accurately estimated using three lineal measurements. More studies are needed to address the importance of volume determination in PHVD. PMID- 27783431 TI - An All-Organic Elastomeric Electret Composite. AB - Copolymer nanoparticles with a highly polar repeating unit are blended in an elastic matrix and poled at elevated temperatures. The composite exhibits piezoelectricity due to the overall polarization imparted by the particles, which can be easily modulated thanks to the soft matrix. PMID- 27783432 TI - Award Winners and Abstracts of the 30th Anniversary Symposium of The Protein Society, Baltimore, MD, July 16-19, 2016. PMID- 27783433 TI - President note to 30th Annual Symposium of the Protein Society. PMID- 27783430 TI - Roles of microRNAs in psoriasis: Immunological functions and potential biomarkers. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules, which function in RNA silencing and post-transcriptional regulation of gene expression. Psoriasis is an inflammatory skin disease characterized by the dysfunction of keratinocytes, with the immune dysregulation. We reviewed the recent studies on the roles of miRNAs in psoriasis and showed that miRNAs play key roles in psoriasis, including the regulation of hyperproliferation, cytokine and chemokine production in keratinocyte, as well as mediating immune dysfunction in psoriasis. Furthermore, miRNAs, particularly, circulating miRNAs may serve as novel biomarkers for diagnosis, monitoring therapy response and reflecting the disease severity. Thus, targeting specific miRNAs may be used to develop new therapeutic methods for psoriasis. PMID- 27783434 TI - Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite. AB - Repeated exposure to inhibitory compounds can drive the evolution of resistance, which weakens chemical defence against antagonists. Floral phytochemicals in nectar and pollen have antimicrobial properties that can ameliorate infection in pollinators, but evolved resistance among parasites could diminish the medicinal efficacy of phytochemicals. However, multicompound blends, which occur in nectar and pollen, present simultaneous chemical challenges that may slow resistance evolution. We assessed evolution of resistance by the common bumble bee gut parasite Crithidia bombi to two floral phytochemicals, singly and combined, over 6 weeks (~100 generations) of chronic exposure. Resistance of C. bombi increased under single and combined phytochemical exposure, without any associated costs of reduced growth under phytochemical-free conditions. After 6 weeks' exposure, phytochemical concentrations that initially inhibited growth by > 50%, and exceeded concentrations in floral nectar, had minimal effects on evolved parasite lines. Unexpectedly, the phytochemical combination did not impede resistance evolution compared to single compounds. These results demonstrate that repeated phytochemical exposure, which could occur in homogeneous floral landscapes or with therapeutic phytochemical treatment of managed hives, can cause rapid evolution of resistance in pollinator parasites. We discuss possible explanations for submaximal phytochemical resistance in natural populations. Evolved resistance could diminish the antiparasitic value of phytochemical ingestion, weakening an important natural defence against infection. PMID- 27783435 TI - Fine-tuned regulation of the K+ /H+ antiporter KEA3 is required to optimize photosynthesis during induction. AB - KEA3 is a thylakoid membrane localized K+ /H+ antiporter that regulates photosynthesis by modulating two components of proton motive force (pmf), the proton gradient (?pH) and the electric potential (?psi). We identified a mutant allele of KEA3, disturbed proton gradient regulation (dpgr) based on its reduced non-photochemical quenching (NPQ) in artificial (CO2 -free with low O2 ) air. This phenotype was enhanced in the mutant backgrounds of PSI cyclic electron transport (pgr5 and crr2-1). In ambient air, reduced NPQ was observed during induction of photosynthesis in dpgr, the phenotype that was enhanced after overnight dark adaptation. In contrast, the knockout allele of kea3-1 exhibited a high-NPQ phenotype during steady state in ambient air. Consistent with this kea3 1 phenotype in ambient air, the membrane topology of KEA3 indicated a proton efflux from the thylakoid lumen to the stroma. The dpgr heterozygotes showed a semidominant and dominant phenotype in artificial and ambient air, respectively. In dpgr, the protein level of KEA3 was unaffected but the downregulation of its activity was probably disturbed. Our findings suggest that fine regulation of KEA3 activity is necessary for optimizing photosynthesis. PMID- 27783436 TI - Role of PI-RADSv2 with multiparametric MRI in determining who needs active surveillance or definitive treatment according to PRIAS. AB - PURPOSE: To evaluate the role of Prostate Imaging Reporting and Data System v. 2 (PI-RADSv2) in triaging patients with prostate cancer according to Prostate Cancer Research International: Active Surveillance (PRIAS). MATERIALS AND METHODS: Between January 2012 and December 2014, 456 patients with biopsy-proven cancer underwent multiparametric 3T magnetic resonance imaging (MRI) using T2 weighted, diffusion-weighted, and dynamic contrast-enhanced MRI sequences, and then radical prostatectomy. Two radiologists independently reviewed MR images using PI-RADSv2. For AS, PRIAS required clinical stage